PMID- 24464483 TI - Natural variation of rice strigolactone biosynthesis is associated with the deletion of two MAX1 orthologs. AB - Rice (Oryza sativa) cultivar Azucena--belonging to the Japonica subspecies- exudes high strigolactone (SL) levels and induces high germination of the root parasitic plant Striga hermonthica. Consistent with the fact that SLs also inhibit shoot branching, Azucena is a low-tillering variety. In contrast, Bala, an Indica cultivar, is a low-SL producer, stimulates less Striga germination, and is highly tillered. Using a Bala * Azucena F6 population, a major quantitative trait loci--qSLB1.1--for the exudation of SL, tillering, and induction of Striga germination was detected on chromosome 1. Sequence analysis of the corresponding locus revealed a rearrangement of a 51- to 59-kbp stretch between 28.9 and 29 Mbp in the Bala genome, resulting in the deletion of two cytochrome P450 genes--SLB1 and SLB2--with high homology to the Arabidopsis SL biosynthesis gene, MAX1. Both rice genes rescue the Arabidopsis max1-1 highly branched mutant phenotype and increase the production of the SL, ent-2'-epi-5-deoxystrigol, when overexpressed in Bala. Furthermore, analysis of this region in 367 cultivars of the publicly available Rice Diversity Panel population shows that the rearrangement at this locus is a recurrent natural trait associated with the Indica/Japonica divide in rice. PMID- 24464484 TI - Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice. AB - The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up regulating its target gene AQP2 expression in the collecting ducts. PMID- 24464485 TI - Coarse-grained simulations of the gating current in the voltage-activated Kv1.2 channel. AB - Quantitative structure-based modeling of voltage activation of ion channels is very challenging. For example, it is very hard to reach converging results, by microscopic simulations while macroscopic treatments involve major uncertainties regarding key features. The current work overcomes some of the above challenges by using our recently developed coarse-grained (CG) model in simulating the activation of the Kv1.2 channel. The CG model has allowed us to explore problems that cannot be fully addressed at present by microscopic simulations, while providing insights on some features that are not usually considered in continuum models, including the distribution of the electrolytes between the membrane and the electrodes during the activation process and thus the physical nature of the gating current. Here, we demonstrate that the CG model yields realistic gating charges and free energy landscapes that allow us to simulate the fluctuating gating current in the activation processes. Our ability to simulate the time dependence of the fast gating current allows us to reproduce the observed trend and provides a clear description of its relationship to the landscape involved in the activation process. PMID- 24464487 TI - Methodologies for the establishment of an orthotopic transplantation model of ovarian cancer in mice. AB - This study used different methods to establish an animal model of orthotopic transplantation for ovarian cancer to provide an accurate simulation of the mechanism by which tumor occurs and develops in the human body. We implanted 4T1 breast cancer cells stably-transfected with luciferase into BALB/c mice by using three types of orthotopic transplantation methodologies: (1) cultured cells were directly injected into the mouse ovary; (2) cell suspension was initially implanted under the skin of the mouse neck; after tumor mass formed, the tumor was removed and ground into cell suspension, which was then injected into the mouse ovary; and (3) a subcutaneous tumor mass was first generated, removed, and cut into small pieces, which were directly implanted into the mouse ovary. After these models were established, in vivo luminescence imaging was performed. Results and data were compared among groups. Orthotopic transplantation model established with subcutaneous tumor piece implantation showed a better simulation of tumor development and invasion in mice. This model also displayed negligible response to artificial factors. This study successfully established an orthotopic transplantation model of ovarian cancer with high rates of tumor formation and metastasis by using subcutaneous tumor pieces. This study also provided a methodological basis for future establishment of an animal model of ovarian cancer in humans. PMID- 24464486 TI - Osteopontin is a promoter for hepatocellular carcinoma metastasis: a summary of 10 years of studies. AB - In this review, we summarize the novel findings from our series of studies on the leading metastasis-related gene, osteopontin (OPN). In our previous gene expression profiling study, OPN was identified as one of the leading genes associated with the metastasis of hepatocellular carcinoma (HCC). We focused on OPN to evaluate its prognostic values and important roles in HCC metastasis. A retrospective study of large cohorts of HCC patients demonstrated that plasma OPN level was one of the leading independent prognostic factors for HCC patients, even in the early stage of HCC, and could serve as a surrogate serologic biomarker for monitoring the treatment response and tumor recurrence after HCC resection. Using both in vitro and in vivo investigations, we found that OPN has an important role in metastasis and tumor growth of HCC and is an attractive potential therapeutic target for combating HCC metastasis. We also found that OPN+ HCC cells have much more amplifications at chromosomal regions, and promoter polymorphisms are important in the regulation of OPN expression and tumor growth and lung metastasis of HCC. PMID- 24464488 TI - Clinical significance of para-aortic lymph node dissection and prognosis in ovarian cancer. AB - Lymph node metastasis has an important effect on prognosis of patients with ovarian cancer. Moreover, the impact of para-aortic lymph node (PAN) removal on patient prognosis is still unclear. In this study, 80 patients were divided into groups A and B. Group A consisted of 30 patients who underwent PAN + pelvic lymph node (PLN) dissection, whereas group B consisted of 50 patients who only underwent PLN dissection. Analysis of the correlation between PAN clearance and prognosis in epithelial ovarian cancer was conducted. Nineteen cases of lymph node metastasis were found in group A, among whom seven cases were positive for PAN, three cases for PLN, and nine cases for both PAN and PLN. In group B, 13 cases were positive for lymph node metastasis. Our study suggested that the metastatic rate of lymph node is 40.0%. Lymph node metastasis was significantly correlated with FIGO stage, tumor differentiation, and histological type both in groups A and B (P < 0.05). In groups A and B, the three-year survival rates were 77.9% and 69.0%, and the five-year survival rates were 46.7% and 39.2%, respectively. However, the difference was not statistically significant (P > 0.05). The three-year survival rates of PLN metastasis in groups A and B were 68.5% and 41.4%, and the five-year survival rates were 49.7% and 26.4%, respectively. Furthermore, PLN-positive patients who cleared PAN had significantly higher survival rate (P = 0.044). In group A, the three-year survival rates of positive and negative lymph nodes were 43.5% and 72.7%, and the five-year survival rates were 27.2% and 58.5%, respectively. The difference was statistically significant (P = 0.048). Cox model analysis of single factor suggested that lymph node status affected the survival rate (P < 0.01), which was the death risk factor. Consequently, in ovarian carcinoma cytoreductive surgery, resection of the para-aortic lymph node, which has an important function in clinical treatment and prognosis of patients with ovarian cancer, is necessary. PMID- 24464489 TI - Urologic agents for treatment of bladder dysfunction in neurologic disease. AB - OPINION STATEMENT: Bladder dysfunction, which is commonly associated with neurologic disorders, can present in myriad ways, from complete retention of urine to total urinary incontinence. The multiple options for treating neurogenic bladder dysfunction range from minimally invasive lifestyle changes to major surgical interventions. Interventions may be driven by patient-reported nuisance or by medical necessity, as in the case of impaired compliance with associated upper urinary tract compromise. Pharmacologic treatment has long been the mainstay in the management of bladder dysfunction, particularly for overactive bladder symptoms [1]. While there are many different medications for overactive bladder dysfunction, most are in the category of antimuscarinics. Each medication has a slightly different side effect profile, which may be important in the drug selection process [2]. When these are not tolerated or are ineffective, beta agonists, phosphodiesterase inhibitors, tricyclic antidepressants, and the gamma aminobutyric acid (GABA)-B agonist baclofen can be added or substituted. For difficulty emptying, alpha adrenergic antagonists can be used [3]. Intravesical options are also available for overactive bladder (OAB) symptoms. The most common is botulinum toxin, which works by decreasing the activity of the detrusor smooth muscle, thereby decreasing OAB symptoms [4]. Percutaneous nerve stimulation may also be used [5*]. PMID- 24464491 TI - Association between parents' PTSD severity and children's psychological distress: a meta-analysis. AB - The authors conducted a meta-analysis of studies on the correlation between parents' PTSD symptom severity and children's psychological status. An extensive search of the literature yielded 550 studies that were screened for inclusion criteria (i.e., parent assessed for PTSD, child assessed for distress or behavioral problems, associations between parent PTSD and child status examined). Sixty-two studies were further reviewed, resulting in a final sample of 42 studies. Results yielded a moderate overall effect size r = .35. The authors compared effect sizes for studies where only the parent was exposed to a potentially traumatic event to studies where both parents and children were exposed. A series of moderators related to sample characteristics (sex of parent, type of traumatic event) and study methods (self-report vs. diagnostic interview, type of child assessment administered) were also evaluated. The only significant moderator was type of trauma; the effect size was larger for studies with parent child dyads who were both exposed to interpersonal trauma (r = .46) than for combat veterans and their children (r = .27) and civilian parent-child dyads who were both exposed to war (r = .25). Results support the importance of considering the family context of trauma survivors and highlight areas for future research. PMID- 24464490 TI - Treatment of psychosis and dementia in Parkinson's disease. AB - OPINION STATEMENT: Parkinson's disease (PD) has been increasingly recognized as having a multitude of nonmotor symptoms including psychosis, cognitive impairment and dementia, mood disturbances, fatigue, apathy, and sleep disorders. Psychosis and dementia, in particular, greatly affect quality of life for both patients and caregivers and are associated with poor outcomes. Safe and effective treatment options for psychosis and dementia in PD are much needed. Antipsychotics with dopamine-blocking properties can worsen parkinsonian motor features and have been associated with increased morbidity and mortality in elderly, dementia patients. For treating PD psychosis, a first step would be eliminating confounding variables, such as delirium, infections, or toxic-metabolic imbalances, followed by simplifying parkinsonian medications as tolerated. If additional treatment is warranted after such interventions, clozapine or quetiapine can be implemented at the low dose levels typically needed by PD patients. Although quetiapine is easy to-use in clinical settings, does not require blood count monitoring like clozapine, and is anecdotally beneficial, it remains "investigational" in evidence-based medicine reviews. Though not currently available, the novel 5-HT2a inverse agonist, pimavanserin has shown promise in the treatment of PD psychosis. Current treatments for PD dementia are mostly derived from those utilized in Alzheimer's disease, focusing mainly on cholinesterase inhibitors and memantine, a NMDA receptor antagonist. Rivastigmine, the only Food and Drug Administration approved medication for PD dementia, is a reasonable first choice. Other cholinesterase inhibitors and memantine have not yet achieved recommendation status in evidence-based medicine reviews but are well tolerated in studies of PD dementia patients. At present, there are no approved treatments for mild cognitive impairment in PD, but rasagiline, a selective MAO-B inhibitor, and atomoxetine, a serotonin norepinephrine reuptake inhibitor, have been recently studied. Nonpharmacological interventions, including cognitive therapy, physical activity, music and art therapy, and noninvasive brain stimulation techniques, may be promising options for PD cognitive impairment but await rigorous study. PMID- 24464492 TI - Induction of multipotency in umbilical cord-derived mesenchymal stem cells cultivated under suspension conditions. AB - Due to the limitations in the clinical application of embryonic stem cells (ESC) and induced pluripotent stem cells, mesenchymal stem cells (MSCs) are now much more interesting for cell-based therapy. Although MSCs have several advantages, they are not capable of differentiating to all three embryonic layers (three germ layers) without cultivation under specific induction media. Hence, improvement of MSCs for cell therapy purposes is under intensive study now. In this study, we isolated MSCs from umbilical cord tissue at the single-cell level, by treatment with trypsin, followed by cultivation under suspension conditions to form a colony. These colonies were trypsin resistant, capable of self-renewal differentiation to the three germ layers without any induction, and they were somewhat similar to ESC colonies. The cells were able to grow in both adherent and suspension culture conditions, expressed both the MSCs markers, especially CD105, and the multipotency markers, i.e., SSEA-3, and had a limited lifespan. The cells were expanded under simple culture conditions at the single-cell level and were homogenous. Further and complementary studies are required to understand how trypsin-tolerant mesenchymal stem cells are established. However, our study suggested non-embryonic resources for future cell-based therapy. PMID- 24464494 TI - Neuroendocrine responses to social isolation and paternal deprivation at different postnatal ages in Mandarin voles. AB - Neonatal isolation and paternal deprivation have long lasting effects on the behavior and neuroendocrine system at adulthood. Whether these effects at adulthood are induced by neonatal changes in relevant neuroendocrine parameters lead by these early-life social experiences is not well understood. Whether monogamous rodents exhibit a stress hypo-responsive period (SHRP) also remains unclear. Using the monogamous mandarin vole, we found that 30 min of isolation did not affect levels of corticosterone (CORT) and adrenocorticotropin (ACTH) at postnatal days 8, 10, and 12 displaying a SHRP, but increased these at postnatal days 4, 14, 16, and 18. Isolation increased vasopressin (AVP)-ir neurons in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) from postnatal days 4 to 12, and up-regulated oxytocin (OT)-ir neurons in the PVN at postnatal days 4 and 8 and SON at postnatal day 4. Paternally deprived pups showed increase in ACTH and CORT after 30 min of social isolation from postnatal days 8 to 14, increase in AVP-ir neurons in the PVN from postnatal days 10 to 14, reduction in OT-ir neurons in the PVN from postnatal days 10 to 14 and in the SON at postnatal days 12 and 14. These results indicate that monogamous mandarin voles display a short SHRP which can be disrupted by paternal deprivation. Central AVP and OT levels may also be altered by paternal deprivation and social isolation. We propose that changes in these neuroendocrine parameters induced by early-life social experiences such as those tested here persist and result. PMID- 24464493 TI - Activation of salt shock response leads to solubilisation of mutant huntingtin in Saccharomyces cerevisiae. AB - Formation of cytoplasmic and nuclear aggregates is a hallmark of Huntington's disease (HD). Inhibition of aggregation of mutant huntingtin has been suggested to be a feasible approach to slow down the progress of this neurodegenerative disorder. Exposure to environmental stimuli leads to the activation of the stress response machinery of the cell. In this work, we have investigated the effect of salt shock on the aggregation of mutant huntingtin (103Q-htt) in a yeast model of HD. We found that at an optimum concentration of NaCl, the protein no longer formed aggregates and existed in the soluble form. This led to lower oxidative stress in the cell. Salt shock resulted in the synthesis of the osmolyte glycerol, which was partially responsible for the beneficial effect of stress. Surprisingly, we also found increase in the synthesis of another osmolyte, trehalose. Using deletion strains, we were able to show that the effect on solubilisation of mutant huntingtin is due to the synthesis of optimum amounts of both osmolytes. Stress-induced effect was monitored on gene expression. Genes related to proteins of the osmosensory pathway were upregulated on exposure to salt while those coding for stress response proteins were downregulated when solubilisation of mutant huntingtin occurred. Our study shows that activation of stress response elements can have beneficial effect in the solubilisation of huntingtin in a yeast model of HD. PMID- 24464495 TI - Accounting for linkage disequilibrium in association analysis of diverse populations. AB - The National Human Genome Research Institute's catalog of published genome-wide association studies (GWAS) lists over 10,000 genetic variants collectively associated with over 800 human diseases or traits. Most of these GWAS have been conducted in European-ancestry populations. Findings gleaned from these studies have led to identification of disease-associated loci and biologic pathways involved in disease etiology. In multiple instances, these genomic findings have led to the development of novel medical therapies or evidence for prescribing a given drug as the appropriate treatment for a given individual beyond phenotypic appearances or socially defined constructs of race or ethnicity. Such findings have implications for populations throughout the globe and GWAS are increasingly being conducted in more diverse populations. A major challenge for investigators seeking to follow up genomic findings between diverse populations is discordant patterns of linkage disequilibrium (LD). We provide an overview of common measures of LD and opportunities for their use in novel methods designed to address challenges associated with following up GWAS conducted in European ancestry populations in African-ancestry populations or, more generally, between populations with discordant LD patterns. We detail the strengths and weaknesses associated with different approaches. We also describe application of these strategies in follow-up studies of populations with concordant LD patterns (replication) or discordant LD patterns (transferability) as well as fine-mapping studies. We review application of these methods to a variety of traits and diseases. PMID- 24464496 TI - Elderly bioheat modeling: changes in physiology, thermoregulation, and blood flow circulation. AB - A bioheat model for the elderly was developed focusing on blood flow circulatory changes that influence their thermal response in warm and cold environments to predict skin and core temperatures for different segments of the body especially the fingers. The young adult model of Karaki et al. (Int J Therm Sci 67:41-51, 2013) was modified by incorporation of the physiological thermoregulatory and vasomotor changes based on literature observations of physiological changes in the elderly compared to young adults such as lower metabolism and vasoconstriction diminished ability, skin blood flow and its minimum and maximum values, the sweating values, skin fat thickness, as well as the change in threshold parameter related to core or skin temperatures which triggers thermoregulatory action for sweating, maximum dilatation, and maximum constriction. The developed model was validated with published experimental data for elderly exposure to transient and steady hot and cold environments. Predicted finger skin temperature, mean skin temperature, and core temperature were in agreement with published experimental data at a maximum error less than 0.5 degrees C in the mean skin temperature. The elderly bioheat model showed an increase in finger skin temperature and a decrease in core temperature in cold exposure while it showed a decrease in finger skin temperature and an increase in core temperature in hot exposure. PMID- 24464497 TI - New insights into biometeorology. Foreword. PMID- 24464498 TI - Induction and activation of P-glycoprotein by dihydroxylated xanthones protect against the cytotoxicity of the P-glycoprotein substrate paraquat. AB - Xanthones are a family of compounds with several known biological activities and therapeutic potential for which information on their interaction with membrane transporters is lacking. Knowing that P-glycoprotein (P-gp) acts as a cellular defense mechanism by effluxing its toxic substrates, the aim of this study was to investigate the potential of five dihydroxylated xanthones as inducers of P-gp expression and/or activity and to evaluate whether they could protect Caco-2 cells against the cytotoxicity induced by the toxic P-gp substrate paraquat (PQ). After 24 h of incubation, all tested xanthones caused a significant increase in both P-gp expression and activity, as evaluated by flow cytometry using the UIC2 antibody and rhodamine 123, respectively. Additionally, after a short 45-min incubation, all the tested xanthones induced a rapid increase in P-gp activity, indicating direct pump activation without increased P-gp protein expression. The tested compounds also increased P-gp ATPase activity in MDR1-Sf9 membrane vesicles, demonstrating to be P-gp substrates. Moreover, when simultaneously incubated with PQ, all xanthones significantly reduced the cytotoxicity of the herbicide, and these protective effects were completely reversed upon incubation with a specific P-gp inhibitor. In silico studies evaluating the interactions between xanthones and P-gp in the presence of PQ suggested that a co-transport mechanism may be operating. A quantitative structure-activity relationship model was developed and validated, and the maximal partial charge for an oxygen atom was the descriptor predicted as being implicated in P-gp activation by the dihydroxylated xanthones. These results disclose new perspectives in preventing PQ- and other P-gp substrates-induced poisonings. PMID- 24464499 TI - Integrated proteomic and metabolomic analysis to assess the effects of pure and benzo[a]pyrene-loaded carbon black particles on energy metabolism and motility in the human endothelial cell line EA.hy926. AB - Epidemiological studies suggest that environmental exposure to airborne particulate matter may promote cardiovascular diseases; however, it is not clear whether this observation actually reflects exposure to nanosized particles in the environment. In the present study, the human endothelial cell line EA.hy926 was exposed to pure carbon black and, to mimic exposure to diesel exhaust, carbon black loaded with benzo[a]pyrene to ascertain effects of these particles on the cell proteome and metabolom. Particular emphasis was laid on an extended exposure period (14 days) and a low particle concentration (100 ng/mL). While ROS production essentially remained unaffected, exposure of the cells to the particles resulted in a significantly enhanced cell proliferation. Evaluation of the obtained proteomic and phosphoproteomic data revealed modulations of proteins involved in catalytic processes and cytoskeleton maintenance. The bioinformatic evaluation of the data revealed the possible involvement of the transcription factor peroxisome proliferator-activated receptor gamma. The further analysis of the cytoskeleton indicated changes of the cell motility, which is in agreement with an observed increase in the cellular migration and invasion, and macroscopic changes of the cytoskeleton of the exposed cells. PMID- 24464500 TI - Classifying the adverse mitogenic mode of action of insulin analogues using a novel mechanism-based genetically engineered human breast cancer cell panel. AB - Insulin analogues are widely used in clinical practice. Modifications on the insulin molecular structure can affect the affinity and activation towards two closely related receptor tyrosine kinases: the insulin receptor (INSR) and the insulin-like growth factor 1 receptor (IGF1R). A switch towards higher IGF1R affinity is likely to emphasize mitogenesis rather than glucose metabolism. Relevant well-validated experimental tools to address the insulin analogue activation of either INSR or IGF1R are missing. We have established a panel of human MCF-7 breast cancer cell lines either ectopically expressing the INSR (A or B isoform) in conjunction with a stable knockdown of the IGF1R or ectopically expressing the IGF1R in conjunction with a stable knockdown of the INSR. In these cell lines, we systematically evaluated the INSR and IGF1R receptor activation and downstream mitogenic signalling of all major clinical relevant insulin analogues in comparison with insulin and IGF1R. While most insulin analogues primarily activated the INSR, the mitogenic activation pattern of glargine was highly similar to IGF1 and insulin AspB10, known to bind IGF1R and induce carcinogenesis. Yet, in a long-term proliferation assay, the proliferative effect of glargine was not much different from regular insulin or other insulin analogues. This was caused by the rapid enzymatic conversion into its two metabolic active metabolites M1 and M2, with reduced mitogenic signalling through the IGF1R. In summary, based on our new cell models, we identified a similar mitogenic potency of insulin glargine and AspB10. However, rapid enzymatic conversion of glargine precludes a sustained activation of the IGF1R signalling pathway. PMID- 24464501 TI - Clearance of senescent hepatocytes in a neoplastic-prone microenvironment delays the emergence of hepatocellular carcinoma. AB - Increasing evidence indicates that carcinogenesis is dependent on the tissue context in which it occurs, implying that the latter can be a target for preventive or therapeutic strategies. We tested the possibility that re normalizing a senescent, neoplastic-prone tissue microenvironment would exert a modulatory effect on the emergence of neoplastic disease. Rats were exposed to a protocol for the induction of hepatocellular carcinoma (HCC). Using an orthotopic and syngeneic system for cell transplantation, one group of animal was then delivered 8 million normal hepatocytes, via the portal circulation. Hepatocytes transplantation resulted in a prominent decrease in the incidence of both pre neoplastic and neoplastic lesions. At the end of 1 year 50% of control animals presented with HCC, while no HCC were observed in the transplanted group. Extensive hepatocyte senescence was induced by the carcinogenic protocol in the host liver; however, senescent cells were largely cleared following infusion of normal hepatocytes. Furthermore, levels of Il-6 increased in rats exposed to the carcinogenic protocol, while they returned to near control values in the group receiving hepatocyte transplantation. These results support the concept that strategies aimed at normalizing a neoplastic-prone tissue landscape can modulate progression of neoplastic disease. PMID- 24464502 TI - Sacral arachnoid cyst and perirectal abscess in a case of perineal pain. PMID- 24464503 TI - Lower serum uric acid levels in cerebral amyloid angiopathy: a pilot study. AB - Cerebral amyloid angiopathy (CAA) is a common degenerative disease presenting intracerebral hemorrhage (ICH) in older people. Uric acid (UA) is a natural antioxidant, and may have a beneficial role in neurodegenerative diseases. Nevertheless, the role of UA in CAA remains unknown. In the present study, we compared serum UA levels in CAA-associated ICH patients (n = 82) and age/sex matched controls (n = 82). Serum UA levels in possible CAA were significantly decreased when compared with healthy controls (232.68 +/- 77.70 vs. 309.42 +/- 59.83 MUmol/L; p < 0.001). Furthermore, UA levels in patients clinically diagnosed as probable CAA were significantly lower than those in patients diagnosed as possible CAA (193.06 +/- 56.98 vs. 232.68 +/- 77.70 MUmol/L; p = 0.014). These differences were still significant after adjusting for renal function and dyslipidemia (p < 0.001 and p = 0.002, respectively). However, there were no associations between serum UA levels and the distribution of hemorrhagic lesion, as well as neurological impairment. Our observations indicate that serum UA levels were decreased in CAA patients. UA might play a neuroprotective role in CAA and serve as a potential biomarker for reflecting the severity of Abeta deposition. PMID- 24464505 TI - Myelodysplastic syndromes: 2014 update on diagnosis, risk-stratification, and management. AB - DISEASE OVERVIEW: The myelodysplastic (MDS) are a very heterogeneous group of myeloid disorders characterized by peripheral blood cytopenias and increased risk of transformation to acute myelogenous leukemia (AML). MDS occurs more frequently in older male and in individuals with prior exposure to cytotoxic therapy. DIAGNOSIS: Diagnosis of MDS is based on morphological evidence of dysplasia upon visual examination of a bone marrow aspirate and biopsy. Information obtained from additional studies such as karyotype, flow cytometry or molecular genetics is complementary but not diagnostic. RISK-STRATIFICATION: Prognosis of patients with MDS can be calculated using a number of scoring systems. In general, all these scoring systems include analysis of peripheral cytopenias, percentage of blasts in the bone marrow and cytogenetic characteristics. The most commonly used system is the International Prognostic Scoring System (IPSS). IPSS is likely to be replaced by a new revised score (IPSS-R) and by the incorporation of new molecular markers recently described. RISK-ADAPTED THERAPY: Therapy is selected based on risk, transfusion needs, percent of bone marrow blasts and more recently cytogenetic profile. Goals of therapy are different in lower risk patients than in higher risk. In lower risk, the goal is to decrease transfusion needs and transformation to higher risk disease or AML, as well as to improve survival. In higher risk, the goal is to prolong survival. Current available therapies include growth factor support, lenalidomide, hypomethylating agents, intensive chemotherapy, and allogeneic stem cell transplantation. The use of lenalidomide has significant clinical activity in patients with lower risk disease, anemia, and a chromosome 5 alteration. 5-Azacitidine and decitabine have activity in higher risk MDS. 5-Azacitidine has been shown to improve survival in higher risk MDS. A number of new molecular lesions have been described in MDS that may serve as new therapeutic targets or aid in the selection of currently available agents. Additional supportive care measures may include the use of prophylactic antibiotics and iron chelation. MANAGEMENT OF PROGRESSIVE OR REFRACTORY DISEASE: There are no approved interventions for patients with progressive or refractory disease particularly after hypomethylating based therapy. Options include cytarabine based therapy, transplantation and participation on a clinical trial. PMID- 24464504 TI - MSMB variation and prostate cancer risk: clues towards a possible fungal etiology. AB - BACKGROUND. With recent advances in high-throughput sequencing technologies, many prostate cancer risk loci have been identified, including rs10993994, a single nucleotide polymorphism (SNP) located near the MSMB gene. Variant allele (T) carriers of this SNP produce less prostate secretory protein 94 (PSP94), the protein product of MSMB, and have an increased risk of prostate cancer (approximately 25% per T allele), suggesting that PSP94 plays a protective role in prostate carcinogenesis, although the mechanisms for such protection are unclear. METHODS. We reviewed the literature on possible mechanisms for PSP94 protection for prostate cancer. RESULTS. One possible mechanism is tumor suppression, as PSP94 has been observed to inhibit cell or tumor growth in in vitro and in vivo models. Another novel mechanism, which we propose in this review article, is that PSP94 may protect against prostate cancer by preventing or limiting an intracellular fungal infection in the prostate. This mechanism is based on the recent discovery of PSP94's fungicidal activity in low-calcium environments (such as the cytosol of epithelial cells), and accumulating evidence suggesting a role for inflammation in prostate carcinogenesis. We provide further details of our proposed mechanism in this review article. CONCLUSIONS. To explore this mechanism, future studies should consider screening prostate specimens for fungi using the rapidly expanding number of molecular techniques capable of identifying infectious agents from the entire tree of life. PMID- 24464506 TI - CORR Insights(r): Deltoid-split or deltopectoral approaches for the treatment of displaced proximal humeral fractures? PMID- 24464507 TI - Comparative outcomes of minimally invasive surgery for posterior lumbar fusion: a systematic review. AB - BACKGROUND: Although minimally invasive surgical (MIS) approaches to the lumbar spine for posterior fusion are increasingly being utilized, the comparative outcomes of MIS and open posterior lumbar fusion remain unclear. QUESTIONS/PURPOSES: In this systematic review, we compared MIS and open transforaminal or posterior lumbar interbody fusion (TLIF/PLIF), specifically with respect to (1) surgical end points (including blood loss, surgical time, and fluoroscopy time), (2) clinical outcomes (Oswestry Disability Index [ODI] and VAS pain scores), and (3) adverse events. METHODS: We performed a systematic review of MEDLINE((r)), Embase, Web of Science, and Cochrane Library. Reference lists were manually searched. We included studies with 10 or more patients undergoing MIS compared to open TLIF/PLIF for degenerative lumbar disorders and reporting on surgical end points, clinical outcomes, or adverse events. Twenty-six studies of low- or very low-quality (GRADE protocol) met our inclusion criteria. No significant differences in patient demographics were identified between the cohorts (MIS: n = 856; open: n = 806). RESULTS: Equivalent operative times were observed between the cohorts, although patients undergoing MIS fusion tended to lose less blood, be exposed to more fluoroscopy, and leave the hospital sooner than their open counterparts. Patient-reported outcomes, including VAS pain scores and ODI values, were clinically equivalent between the MIS and open cohorts at 12 to 36 months postoperatively. Trends toward lower rates of surgical and medical adverse events were also identified in patients undergoing MIS procedures. However, in the absence of randomization, selection bias may have influenced these results in favor of MIS fusion. CONCLUSIONS: Current evidence examining MIS versus open TLIF/PLIF is of low to very low quality and therefore highly biased. Results of this systematic review suggest equipoise in surgical and clinical outcomes with equivalent rates of intraoperative surgical complications and perhaps a slight decrease in perioperative medical complications. However, the quality of the current literature precludes firm conclusions regarding the comparative effectiveness of MIS versus open posterior lumbar fusion from being drawn and further higher-quality studies are critically required. PMID- 24464508 TI - Does dual-mobility cup geometry affect posterior horizontal dislocation distance? AB - BACKGROUND: Dual-mobility acetabular cups have been marketed with the purported advantages of reduced dislocation rates and improvements in ROM; however, the relative efficacies of these designs in terms of changing joint stability via ROM and dislocation distance have not been thoroughly evaluated. QUESTIONS/PURPOSES: In custom computer simulation studies, we addressed the following questions: (1) Do variations in component geometry across dual-mobility designs (anatomic, modular, and subhemispheric) affect the posterior horizontal dislocation distances? (2) How do these compare with the measurements obtained with standard hemispheric fixed bearings? (3) What is the effect of head size on posterior horizontal dislocation distances for dual-mobility and standard hemispheric fixed bearings? (4) What are the comparative differences in prosthetic impingement-free ROM between three modern dual-mobility components (anatomic, modular, and subhemispheric), and standard hemispheric fixed bearings? METHODS: CT scans of an adult pelvis were imported into computer-aided design software to generate a dynamic three-dimensional model of the pelvis. Using this software, computer aided design models of three dual-mobility designs (anatomic, modular, and subhemispheric) and standard hemispheric fixed bearings were implanted in the pelvic model and the posterior horizontal dislocation distances measured. Hip ROM simulator software was used to compare the prosthetic impingement-free ROMs of dual-mobility bearings with standard hemispheric fixed-bearing designs. RESULTS: Variations in component design had greater effect on posterior horizontal dislocation distance values than increases in head size in a specific design (p < 0.001). Anatomic and modular dual-mobility designs were found to have greater posterior horizontal dislocation distances than the subhemispheric dual-mobility and standard hemispheric fixed-bearing designs (p < 0.001). Increasing head sizes increased posterior horizontal dislocation distances across all designs (p < 0.001). The subhemispheric dual-mobility implant was found to have the greatest prosthetic impingement-free ROM among all prosthetic designs (p < 0.001; R(2) = 0.86). CONCLUSIONS: The posterior horizontal dislocation distances differ with the individual component geometries of dual-mobility designs, with the anatomic and modular designs showing higher posterior horizontal dislocation distances compared with subhemispheric dual-mobility and standard hemispheric fixed-bearing designs. CLINICAL RELEVANCE: Static, three-dimensional computerized simulation studies suggest differences that may influence the risk of dislocation among components with varying geometries, favoring anatomic and modular dual-mobility designs. Clinical studies are needed to confirm these observations. PMID- 24464509 TI - Comparative study of dietary soy phytoestrogens genistein and equol effects on growth parameters and ovarian development in farmed female beluga sturgeon, Huso huso. AB - Oocyte maturation in fish is a hormonally regulated process. In the light of long term oocyte maturation in beluga, the aim of this research was to study the estrogenic effects of different concentrations of soy dietary genistein (GE) and equol (EQ) on the growth performance and ovary development in farmed female Huso huso. Fish were fed with concentrations 0 (control), 0.2, 0.4, 0.8 and 1.6 g of EQ and GE per kg of isoproteic (CP 45 %) and isoenergetic (19.5 MJ/kg) diets during a year. Blood samples and ovary biopsies were collected from each fish seasonally. The main results of the present experimentation are that growth performance was not affected significantly both in GE and EQ (P > 0.05). EQ at concentration 0.4 g/kg had more estrogenic effects than other concentrations of EQ and GE in beluga so that 64 % of fish were matured sexually. Some reproductive indices such as oocyte diameter, testosterone (T) and 17beta-estradiol (E2) increased significantly at EQ 0.4 g/kg at the end of experiment (P < 0.05), while 17alpha-hydroxy progesterone level (17alpha-OHP) showed no significant changes at all concentrations. Biochemical indices such as calcium, phosphorous and cholesterol increased at GE concentrations, but decreased at EQ concentrations similarly at the end of experiment. There was a negative relationship between plasma phosphorous and alkaline phosphatase enzyme levels. Based on results, EQ at concentration 0.4 g/kg improved oocyte development more than the other concentrations of GE and EQ, and therefore, it can be used as an additive to diets for inducing ovary development in this species. PMID- 24464510 TI - Positron emission tomography imaging of cell death with [(18)F]FPDuramycin. AB - The noninvasive imaging of cell death, including apoptosis and necrosis, is an important tool for the assessment of degenerative diseases and in the monitoring of tumor treatments. Duramycin is a peptide of 19-amino acids. It binds specifically to phosphatidylethanolamine a novel molecular target for cell death. N-(2-(18)F-Fluoropropionyl)duramycin ([(18)F]FPDuramycin) was prepared as a novel positron emission tomography (PET) tracer from the reaction of duramycin with 4 nitrophenyl 2-[(18)F]fluoropropionate ([(18)F]NFP). Compared with control cells (viable tumor cells), the in vitro binding of [(18)F]FPDuramycin with apoptotic cells induced by anti-Fas antibody resulted in a doubling increase, while the binding of [(18)F]FPDuramycin with necrotic cells induced by three freeze and thaw cycles resulted in a threefold increase. Biodistribution study in mice exhibited its rapid blood and renal clearance and predominant accumulation in liver and spleen over 120 min postinjection. Small-animal PET/CT imaging with [(18)F]FPDuramycin proved to be a successful way to visualize in vivo therapeutic induced tumor cell death. In summary, [(18)F]FPDuramycin seems to be a potential PET probe candidate for noninvasive visualization of in vivo cell death sites induced by chemotherapy in tumors. PMID- 24464511 TI - Review of health effects of polybrominated diphenyl ethers (PBDEs)--editorial. PMID- 24464512 TI - Empathy and integrative thinking: Talmudic paradigms for the essentials of a medical interview. AB - Intentional empathy and integrative thinking are essential elements of a medical interview. Yet the repetitive, sometimes monotonous, nature of medical practice can compromise their achievement. Emotional and intellectual fatigue may lead to clouded observation with diagnostic errors resulting. In spite of a long extant pedagogy of teaching interviewing techniques and creative mnemonics, hurdles remain and significant miscues continue. The challenge is one of surmounting these obstacles and of finding 'new' ways to perform 'old' tasks. It is to do what we already know to do but somehow do not. In the essay which follows, two Talmudic legends are identified and discussed as paradigms for empathy and integrative thinking. They are offered as 'literary mnemonics' for potential use in physician-patient encounters. The legends are linked to the insights of contemporary scholars including Jerome Groopman, Danielle Ofri, Roger Martin and others who have considered concepts of cognition, emotion, empathy, 'opposable mind' and integrative thinking in medical and non-medical settings. PMID- 24464513 TI - Stereopsis after successful surgery for rhegmatogenous retinal detachment. AB - BACKGROUND: To evaluate stereopsis after successful surgery for unilateral rhegmatogenous retinal detachment (RD), and to investigate the relationship between stereopsis and clinical factors. METHODS: In 75 patients after RD surgery and 28 age-matched normal subjects, stereopsis was measured using the Titmus Stereo Test (TST) and TNO stereotest. Clinical data were collected, including age, gender, circumferential dimension of retinal tears, area and duration of RD, macular status, surgical procedures, postoperative spherical equivalent, and logarithm of the minimum angle of resolution best-corrected visual acuity (logMAR BCVA), low-contrast visual acuity, postoperative lens status (phakia/pseudophakia), and presence of postoperative epiretinal membrane (ERM), to determine the factors related to stereopsis. RESULTS: Stereopsis in patients after surgery was significantly worse than normal subjects (p < 0.0001). Stereopsis in TST was significantly correlated with the area of RD (p < 0.005), difference of postoperative spherical equivalent between two eyes (p < 0.05), postoperative logMAR BCVA (p < 0.005), difference of postoperative logMAR BCVA between two eyes (p < 0.01), and low-contrast visual acuity (p < 0.05). Stereopsis in TNO stereotest showed significant association with postoperative logMAR BCVA (p < 0.05). Stereopsis in both stereotests were significantly worse in patients with macula-off RD than macula-on RD (p < 0.005, p < 0.01 respectively). No significant relationship was found between stereopsis and other factors. Multiple regression analysis revealed that macular status (on/off) had a significant correlation with both stereopsis in TST and TNO stereotest (p = 0.028, p = 0.019 respectively), whereas other clinical parameters were not relevant. CONCLUSIONS: Stereopsis is significantly deteriorated in patients after RD surgery than in normal subjects. Stereopsis was associated with the difference in refraction between two eyes, postoperative visual acuity and contrast sensitivity, and preoperative macular status. PMID- 24464514 TI - Clinical presentation of severe viral encephalitis with known causative agents in children: a retrospective study on 16 patients hospitalized in a pediatric intensive care unit (2008-2011). AB - A retrospective analysis was conducted in a French pediatric hospital in Lyon. Subjects were 16 patients diagnosed with acute viral encephalitis with identified causative agents who were admitted to the pediatric intensive care unit from 2008 to 2011. The median length of stay was 6 days. The outcome was favorable for 77% of the patients. Analysis of biological and clinical findings based on causative agents did not reveal clinical patterns or neurological findings specific to the causal viruses. Nevertheless, uncommon clinical pictures and severe neurological complications were highlighted, in particular for children with influenza-related encephalitis and herpes simplex encephalitis. This case series exemplifies the difficulties, even pitfalls, in establishing a diagnosis of encephalitis, especially in neonates. It points out significant differences in the clinical presentation of encephalitis in children compared with clinical pictures described in previously published large-scale studies on encephalitis mainly conducted in adults. PMID- 24464515 TI - The ketogenic diet as broad-spectrum treatment for super-refractory pediatric status epilepticus: challenges in implementation in the pediatric and neonatal intensive care units. AB - Refractory status epilepticus carries significant morbidity and mortality. Recent reports have promoted the use of the ketogenic diet as an effective treatment for refractory status epilepticus. We describe our recent experience with instituting the ketogenic diet for 4 critically ill children in refractory status epilepticus, ranging in age from 9 weeks to 13.5 years after failure of traditional treatment. The ketogenic diet allowed these patients to be weaned off continuous infusions of anesthetics without recurrence of status epilepticus, though delayed ketosis and persistently elevated glucose measurements posed special challenges to effective initiation, and none experienced complete seizure cessation. The ease of sustaining myocardial function with fatty acid energy substrates compares favorably over the myocardial toxicity posed by anesthetic doses of barbiturates and contributes to the safety profile of the ketogenic diet. The ketogenic diet can be implemented successfully and safely for the treatment of refractory status epilepticus in pediatric patients. PMID- 24464516 TI - Isolation and characterization of SsmTx-I, a Specific Kv2.1 blocker from the venom of the centipede Scolopendra Subspinipes Mutilans L. Koch. AB - Scolopendra subspinipes mutilans, also known as Chinese red-headed centipede, is a venomous centipede from East Asia and Australasia. Venom from this animal has not been researched as thoroughly as venom from snakes, snails, scorpions, and spiders. In this study, we isolated and characterized SsmTx-I, a novel neurotoxin from the venom of S. subspinipes mutilans. SsmTx-I contains 36 residues with four cysteines forming two disulfide bonds. It had low sequence similarity (<10%) with other identified peptide toxins. By whole-cell recording, SsmTx-I significantly blocked voltage-gated K+ channels in dorsal root ganglion neurons with an IC50 value of 200 nM, but it had no effect on voltage-gated Na+ channels. Among the nine K+ channel subtypes expressed in human embryonic kidney 293 cells, SsmTx-I selectively blocked the Kv2.1 current with an IC50 value of 41.7 nM, but it had little effect on currents mediated by other K+ channel subtypes. Blockage of Kv2.1 by SsmTx-I was not associated with significant alteration of steady-state activation, suggesting that SsmTx-I might act as a simple inhibitor or channel blocker rather than a gating modifier. Our study reported a specific Kv2.1 blocker from centipede venom and provided a basis for future investigations of SsmTx-I, for example on structure-function relationships, mechanism of action, and pharmacological potential. PMID- 24464517 TI - Validity of bioelectrical impedance analysis for measuring changes in body water and percent fat after bariatric surgery. AB - BACKGROUND: Few studies have validated bioelectrical impedance analysis (BIA) following bariatric surgery. METHODS: We examined agreement of BIA (Tanita 310) measures of total body water (TBW) and percent body fat (%fat) before (T0) and 12 months (T12) after bariatric surgery, and change between T0 and T12 with reference measures: deuterium oxide dilution for TBW and three-compartment model (3C) for %fat in a subset of participants (n = 50) of the Longitudinal Assessment of Bariatric Surgery-2. RESULTS: T0 to T12 median (IQR) change in deuterium TBW and 3C %fat was -6.4 L (6.4 L) and -14.8% (13.4%), respectively. There were no statistically significant differences between deuterium and BIA determined TBW [median (IQR) difference: T0 -0.1 L (7.1 L), p = 0.75; T12 0.2 L (5.7 L), p = 0.35; Delta 0.35 L(6.3 L), p = 1.0]. Compared with 3C, BIA underestimated %fat at T0 and T12 [T0 -3.3 (5.6), p < 0.001; T12 -1.7 (5.2), p = 0.04] but not change [0.7 (8.2), p = 0.38]. Except for %fat change, Bland-Altman plots indicated no proportional bias. However, 95% limits of agreement were wide (TBW 15-22 L, %fat 19-20%). CONCLUSIONS: BIA may be appropriate for evaluating group level response among severely obese adults. However, clinically meaningful differences in the accuracy of BIA between individuals exist. PMID- 24464518 TI - To band or not to band--early results of banded sleeve gastrectomy. AB - Laparoscopic sleeve gastrectomy (LSG) is the procedure with the fastest growing numbers worldwide. Although excellent weight loss can be achieved, one major obstacle of LSG is weight regain due to sleeve dilatation. Banded sleeve gastrectomy (BLSG) has been described as an option to counteract sleeve dilatation and ameliorate weight loss over time. In a retrospective study, we analysed 25 patients who underwent BLSG using a MiniMizer(r) ring. Twenty five patients who had previously undergone a conventional LSG were selected for matched-pair analysis. Patient follow-up was 12 months in both groups. Mean preoperative BMI was 56.1 +/- 7.2 kg/m(2) for BLSG and 57.0 +/- 6.3 kg/m(2) for LSG, P = 0.522. Operative time was significantly shorter for BLSG (53 +/- 27 min vs. 68 +/- 20 min, P = 0.0025). Excess weight loss (%EWL) was equal in both groups with %EWL at 12 months of 58.0 +/- 14.6 % for BSLG patients vs. 58.4 +/- 19.2 % for LSG patients. There was no procedure-related mortality in either group. At 12 months postoperative, vomiting was significantly increased in BSLG patients (OR 6.75, P = 0.035). New onset reflux was equal in both groups (OR 0.67, P = 0.469). Ring implantation does not increase the duration of surgery or early surgical complications. Weight loss in the first follow-up year is not influenced, but the incidence of vomiting is raised after 12 months when patients start to increase eating volume. PMID- 24464519 TI - Epagogici eponyms. PMID- 24464520 TI - Enantiomeric separation and simulation studies of pheniramine, oxybutynin, cetirizine, and brinzolamide chiral drugs on amylose-based columns. AB - Solid phase extraction (SPE)-chiral separation of the important drugs pheniramine, oxybutynin, cetirizine, and brinzolamide was achieved on the C18 cartridge and AmyCoat (150 x 46 mm) and Chiralpak AD (25 cm x 0.46 cm id) chiral columns in human plasma. Pheniramine, oxybutynin, cetirizine, and brinzolamide were resolved using n-hexane-2-PrOH-DEA (85:15:0.1, v/v), n-hexane-2-PrOH-DEA (80:20:0.1, v/v), n-hexane-2-PrOH-DEA (70:30:0.2, v/v), and n-hexane-2-propanol (90:10, v/v) as mobile phases. The separation was carried out at 25 +/- 1 oC temperature with detection at 225 nm for cetirizine and oxybutynin and 220 nm for pheniramine and brinzolamide. The flow rates of the mobile phases were 0.5 mL min(-1). The retention factors of pheniramine, oxybutynin, cetirizine and brinzolamide were 3.25 and 4.34, 4.76 and 5.64, 6.10 and 6.60, and 1.64 and 2.01, respectively. The separation factors of these drugs were 1.33, 1.18, 1.09 and 1.20 while their resolutions factors were 1.09, 1.45, 1.63 and 1.25, and 1.15, respectively. The absolute configurations of the eluted enantiomers of the reported drugs were determined by simulation studies. It was observed that the order of enantiomers elution of the reported drugs was S-pheniramine > R pheniramine; R-oxybutynin > S-oxybutynin; S-cetirizine > R-cetirizine; and S brinzolamide > R-brinzolamide. The mechanism of separation was also determined at the supramolecular level by considering interactions and modeling results. The reported SPE-chiral high-performance liquid chromatography (HPLC) methods are suitable for the enantiomeric analyses of these drugs in any biological sample. In addition, simulation studies may be used to determine the absolute configuration of the first and second eluted enantiomers. PMID- 24464521 TI - Sequence kernel association test for survival traits. AB - Rare variant tests have been of great interest in testing genetic associations with diseases and disease-related quantitative traits in recent years. Among these tests, the sequence kernel association test (SKAT) is an omnibus test for effects of rare genetic variants, in a linear or logistic regression framework. It is often described as a variance component test treating the genotypic effects as random. When the linear kernel is used, its test statistic can be expressed as a weighted sum of single-marker score test statistics. In this paper, we extend the test to survival phenotypes in a Cox regression framework. Because of the anticonservative small-sample performance of the score test in a Cox model, we substitute signed square-root likelihood ratio statistics for the score statistics, and confirm that the small-sample control of type I error is greatly improved. This test can also be applied in meta-analysis. We show in our simulation studies that this test has superior statistical power except in a few specific scenarios, as compared to burden tests in a Cox model. We also present results in an application to time-to-obesity using genotypes from Framingham Heart Study SNP Health Association Resource. PMID- 24464522 TI - Gender differences in health-related quality of life associated with abdominal obesity in a Korean population. AB - OBJECTIVES: Overall obesity, as measured by body mass index (BMI), has been associated with a low level of health-related quality of life (HRQOL), but little is known about abdominal obesity. This cross-sectional study aimed to determine whether abdominal obesity, as measured by waist circumference (WC), would be significantly associated with HRQOL independent of overall obesity, and if so, whether the association would differ by gender among the Korean population. DESIGN: Cross-sectional study. SETTING: South Korea. PARTICIPANTS: Using data from the 2007-2009 Korea National Health and Nutrition Examination Survey, a total of 13 754 men and women aged 19-65 years were selected, and information about height (cm), weight (kg), WC (cm) and the EuroQOL-5 Dimensions (EQ-5D) scores for HRQOL were taken. RESULTS: Not only an overall obesity (as categorised into obese, overweight or non-overweight groups based on BMI) but also an abdominal obesity (defined by WC >=90 cm for men and >=85 cm for women) was significantly associated with lower EQ-5D scores, after adjusting for age, gender, socioeconomic variables and a number of comorbidities. Even after adjusting BMI effect, the association between abdominal obesity and lower EQ-5D scores remained significant for women, but not for men. CONCLUSIONS: Among the Korean population aged 19-65 years, abdominal obesity was associated with impaired HRQOL, independently of overall obesity. Furthermore, this association differed by gender, being significant only for women. Therefore, primary healthcare professionals should pay attention to gender differences in the impact of obesity on HRQOL when evaluating population-based health programmes. PMID- 24464523 TI - Antiretroviral therapy is not associated with reduced herpes simplex virus shedding in HIV coinfected adults: an observational cohort study. AB - OBJECTIVES: Herpes simplex virus types 1 and 2 (HSV-1/2) may have adverse consequences on HIV type 1 infection. We quantified the frequency of HSV reactivations in highly active antiretroviral therapy (HAART)-treated adults with HIV, and compared it with that in HAART-naive patients. SETTING: 2 academic hospital sites in Toronto, Canada. PARTICIPANTS: Asymptomatic HAART-naive (n=44) or treated (with HIV RNA <50 copies/mL, n=41) adults with HSV-1 and/or 2, HIV coinfection. OUTCOME MEASURES: HSV-1 and HSV-2 shedding as measured by PCR on oral, genital and anal swabs self-collected daily for 28 days. RESULTS: Of the 85 participants, 88%, 67% and 53% were coinfected with HSV-1, HSV-2 and both HSV types, respectively. Median (IQR) CD4 count was 516 (382, 655) cells/mm(3). HSV (type 1 and/or 2) shedding occurred on a median (IQR) of 7.1% (0, 17.9%) of days in HAART users and 3.6% (0, 10.7%) of days in non-HAART users. No significant relationship was observed between HAART and HSV-1/2 shedding in univariable (OR=1.55, 95% CI 0.83 to 2.87) or multivariable negative binomial models adjusted for sex, baseline CD4 count, recent immigrant status and time since HIV diagnosis (adjusted OR, aOR=1.05, 95% CI 0.43 to 2.58). Similar null results were observed for HSV-2 shedding in HSV-2 seropositive participants (aOR=1.16, 95% CI 0.40 to 3.36) and HSV-1 shedding in HSV-1 seropositive participants (aOR=0.70, 95% CI 0.14 to 3.47). CONCLUSIONS: HSV reactivations persist despite suppressive HAART among adults coinfected with HSV and HIV. Clinical trials of suppressive anti-HSV therapy are warranted in this population. PMID- 24464524 TI - Chronic toxicity of heavy fuel oils to fish embryos using multiple exposure scenarios. AB - The chronic toxicity to rainbow trout (Oncorhynchus mykiss) embryos of heavy fuel oil (HFO) 6303, weathered HFO 6303, HFO 7102, and medium South American (MESA) crude oil was assessed by different exposure regimes. These included water accommodated fractions (WAF; water in contact with floating oil), chemically enhanced WAF (CEWAF; oil dispersed with Corexit 9500), and effluent from columns of gravel coated with stranded oil. Heavy fuel oil WAF was nontoxic and did not contain detectable concentrations of hydrocarbons, likely because the high density and viscosity of HFO prevented droplet formation. In contrast, chemically dispersed HFO and effluent from columns of stranded HFO contained measurable concentrations of alkyl polycyclic aromatic hydrocarbons (PAH), coincident with embryo toxicity. These exposure regimes enhanced the surface area of oil in contact with water, facilitating oil-water partitioning of hydrocarbons. Heavy fuel oil was consistently more toxic to fish than crude oil and the rank order of alkyl PAH concentrations in whole oil were sufficient to explain the rank order of toxicity, regardless of exposure method. Thus, the propensity of HFO to sink and strand in spawning shoals creates a long-term risk to developing fish because of the sustained release of PAHs from HFO to interstitial waters. Further, PAH monitoring is key to accurate risk assessment. PMID- 24464526 TI - Unmet psychosocial needs in haematological cancer: a systematic review. AB - PURPOSE: Psychosocial need implies a desire or requirement for support that underlies a person's psychological, social and emotional wellbeing. This is not a new concept in the wider cancer literature, yet remains a relatively unexplored area in relation to haematological malignancies. The well-recognised differences between haematological and other types of cancer diagnosis warrant further investigation to try and highlight the potential differences in the needs of this patient group. METHOD: A systematic review of key online databases and psycho oncology journals was conducted to identify papers that formally assessed unmet psychosocial needs in adults with a diagnosis of haematological cancer. The breadth of methodologies of included studies made a meta-analytical approach unfeasible, therefore studies were analysed using a narrative synthesis approach. RESULTS: Eighteen studies were found to be relevant and a specific focus was placed on those papers that looked solely at participants with a haematological diagnosis. The key areas of need identified were: psychological need, notably fear of recurrence; information needs; and needs relating to both family and healthcare professionals. Fear of recurrence was the most commonly identified psychosocial need within this literature. CONCLUSIONS: The clinical implications of these findings highlight the need for more widespread access to psychological support for haematology patients and for more to be done to tackle patients' fears and concerns throughout the course of their illness. Assessment and identification of unmet needs is an important step enabling the development of clinical services that support and maintain psychological wellbeing through treatment and into survivorship. PMID- 24464528 TI - Dose-dependent effectiveness of wheel running to attenuate cocaine-seeking: impact of sex and estrous cycle in rats. AB - RATIONALE: Exercise has shown promise as an intervention for drug addiction; however, little is known regarding the exercise conditions that most effectively reduce relapse vulnerability and whether these conditions differ by sex. OBJECTIVE: Here, we examined sex differences in the dose-dependent effects of wheel running, an animal model of exercise, during abstinence on subsequent cocaine-seeking. METHODS: Male and female rats self-administered cocaine (1.5 mg/kg/infusion) under extended access conditions (24 h/day, 4 discrete trials/h) for 10 days. Rats were then given voluntary access to either an unlocked or locked running wheel for 1, 2, 6, or 24 h/day during the 14-day abstinence period. Separate groups of rats were housed in polycarbonate cages during abstinence to control for physical activity that the wheel may provide. Subsequent cocaine-seeking was assessed under a within-session extinction/cue induced reinstatement procedure. Estrous cycle was monitored in females to determine whether the effectiveness of wheel running varied by estrous cycle phase. RESULTS: Although females ran more than males, males were more sensitive to the effects of running and showed a dose-dependent decrease in cocaine-seeking with longer access resulting in greater suppression. The dose-effect relationship was less straightforward in females and access to both a locked and unlocked wheel decreased cocaine-seeking with effects dependent on estrous cycle phase. Notably, extended (6 and 24 h/day), but not limited (1 and 2 h/day) access to a wheel surmounted the heightened vulnerability observed in females during estrus. CONCLUSION: Taken together, our findings suggest that the effectiveness of wheel running is dose-, sex-, and estrous cycle-dependent. PMID- 24464527 TI - Reducing substance use during adolescence: a translational framework for prevention. AB - RATIONALE: Most substance use is initiated during adolescence when substantial development of relevant brain circuitry is still rapidly maturing. Developmental differences in reward processing, behavioral flexibility, and self-regulation lead to changes in resilience or vulnerability to drugs of abuse depending on exposure to risk factors. Intervention and prevention approaches to reducing addiction in teens may be able to capitalize on malleable brain systems in a predictable manner. OBJECTIVE: This review will highlight what is known about how factors that increase vulnerability to addiction, including developmental stage, exposure to early life adversity (ranging from abuse, neglect, and bullying), drug exposure, and genetic predisposition, impact the development of relevant systems. RESULTS AND CONCLUSIONS: Appropriate, early intervention may restore the normal course of an abnormal trajectory and reduce the likelihood of developing a substance use disorder (SUD) later in life. A considerable amount is known about the functional neuroanatomy and/or pharmacology of risky behaviors based on clinical and preclinical studies, but relatively little has been directly translated to reduce their impact on addiction in high-risk children or teenagers. An opportunity exists to effectively intervene before adolescence when substance use is likely to emerge. PMID- 24464529 TI - Cilostazol improves hippocampus-dependent long-term memory in mice. AB - RATIONALE: Phosphodiesterases (PDEs) play an important role in the regulation of intracellular signaling mediated by cyclic adenosine monophosphate (cAMP). Recently, several PDE inhibitors were assessed for their possible cognitive enhancing properties. However, little is known about the effect of PDE3 inhibitors on memory function. OBJECTIVES: We examined how the PDE3 inhibitor cilostazol affects C57BL/6 J mice as they perform various behavioral tasks. After behavioral assessment, brains of the mice were analyzed immunohistochemically to quantify the phosphorylation of cAMP-responsive element binding protein (CREB), a downstream component of the cAMP pathway. RESULTS: Oral administration of cilostazol significantly enhanced recollection of the exact platform location in the Morris water maze probe test. Cilostazol also improved context-dependent long term fear memory, without affecting short-term memory. No apparent effect was observed in cue-dependent fear memory. The results suggest that cilostazol selectively improves hippocampus-dependent long-term memory in these tasks. Cilostazol also significantly increased the number of phosphorylated-CREB positive cells in hippocampal dentate gyrus. CONCLUSIONS: These results suggest that cilostazol may exert its beneficial effects on learning and memory by enhancing the cAMP system in hippocampus, where it increases intracellular cAMP activity. PMID- 24464530 TI - Serotoninergic effects on judgments and social learning of trustworthiness. AB - RATIONALE: Certain disorders, such as depression and anxiety, to which serotonin dysfunction is historically associated, are also associated with lower assessments of other people's trustworthiness. Serotonergic changes are known to alter cognitive responses to threatening stimuli. This effect may manifest socially as reduced apparent trustworthiness of others. Trustworthiness judgments can emerge from either direct observation or references provided by third parties. OBJECTIVE: We assessed whether explicit judgments of trustworthiness and social influences on those judgments are altered by changes within serotonergic systems. METHODS: We implemented a double-blind between-subject design where 20 healthy female volunteers received a single dose of the selective serotonin reuptake inhibitor (SSRI) citalopram (2 * 20 mg), while 20 control subjects (matched on age, intelligence, and years of education) received a placebo. Subjects performed a face-rating task assessing how trustworthy they found 153 unfamiliar others (targets). After each rating, the subjects were told how other subjects, on average, rated the same target. The subjects then performed 30 min of distractor tasks before, unexpectedly, being asked to rate all 153 faces again, in a random order. RESULTS: Compared to subjects receiving a placebo, subjects receiving citalopram rated targets as less trustworthy. They also conformed more to opinions of others, when others rated targets to be even less trustworthy than subjects had initially indicated. The two effects were independent of negative effects of citalopram on subjective state. CONCLUSIONS: This is evidence that serotonin systems can mediate explicit assessment and social learning of the trustworthiness of others. PMID- 24464531 TI - Separate and combined impact of acute naltrexone and alprazolam on subjective and physiological effects of oral d-amphetamine in stimulant users. AB - RATIONALE: Opioid antagonists (e.g., naltrexone) and positive modulators of gamma aminobutyric-acidA (GABAA) receptors (e.g., alprazolam) modestly attenuate the abuse-related effects of stimulants like amphetamine. The use of higher doses to achieve greater efficacy is precluded by side effects. Combining naltrexone and alprazolam might safely maximize efficacy while avoiding the untoward effects of the constituent compounds. OBJECTIVES: The present pilot study tested the hypothesis that acute pretreatment with the combination of naltrexone and alprazolam would not produce clinically problematic physiological effects or negative subjective effects and would reduce the positive subjective effects of d amphetamine to a greater extent than the constituent drugs alone. METHODS: Eight nontreatment-seeking, stimulant-using individuals completed an outpatient experiment in which oral d-amphetamine (0, 15, and 30 mg) was administered following acute pretreatment with naltrexone (0 and 50 mg) and alprazolam (0 and 0.5 mg). Subjective effects, psychomotor task performance, and physiological measures were collected. RESULTS: Oral d-amphetamine produced prototypical physiological and stimulant-like positive subjective effects (e.g., VAS ratings of Active/Alert/Energetic, Good Effect, and High). Pretreatment with naltrexone, alprazolam, and their combination did not produce clinically problematic acute physiological effects or negative subjective effects. Naltrexone and alprazolam each significantly attenuated some of the subjective effects of d-amphetamine. The combination attenuated a greater number of subjective effects than the constituent drugs alone. CONCLUSIONS: The present results support the continued evaluation of an opioid receptor antagonist combined with a GABAA-positive modulator using more clinically relevant experimental conditions like examining the effect of chronic dosing with these drugs on methamphetamine self administration. PMID- 24464532 TI - Preclinical evaluation of a bispecific low-molecular heterodimer targeting both PSMA and GRPR for improved PET imaging and therapy of prostate cancer. AB - BACKGROUND: It has recently been reported that metastases of prostate cancer usually show highly heterogeneous or partly lost prostate-specific membrane antigen (PSMA) expression. In order to image and treat both PSMA positive and negative tissues PSMA targeting probes need to be extended by a further specificity. Since prostate cancer cells usually express both PSMA and gastrin releasing peptide receptor (GRPR) a bispecific low-molecular heterodimeric molecule, addressing both targets at the same time, may significantly improve prostate cancer imaging and therapy. METHODS: The nonapeptide BZH3 representing the GRPR binding part was combined with the urea-based PSMA inhibitor Glu-urea Lys(Ahx)-HBED-CC. The syntheses of the compounds were performed according to standard Fmoc-solid phase peptide synthesis. The binding properties were analyzed by competitive cell binding and internalization experiments. The in vivo targeting properties were investigated by means of biodistribution studies. RESULTS: Cell binding experiments revealed high binding affinities to both GRPR and PSMA expressing cell lines. The heterodimer bound with IC50 -values essentially matching the IC50 values of the respective monomers (25.0 +/- 5.4 nM for PSMA and 9.0 +/- 1.8 nM for GRPR, respectively). In vivo, the heterodimer showed dual targeting of PSMA (5.4%ID/g for PSMA-positive tumors) and GRPR receptors (3.3% ID/g for GRPR-positive tumors) while exhibiting fast pharmacokinetic properties. The clearance from background was comparable to the monomeric PSMA-targeting reference. CONCLUSIONS: The heterodimeric molecule is a promising agent for PET imaging of primary and recurrent prostate cancer covering two receptor entities which might lead to an improved diagnostic sensitivity and therapeutic efficiency. PMID- 24464533 TI - Iron deficiency alters megakaryopoiesis and platelet phenotype independent of thrombopoietin. AB - Iron deficiency is a common cause of reactive thrombocytosis, however, the exact pathways have not been revealed. Here we aimed to study the mechanisms behind iron deficiency-induced thrombocytosis. Within few weeks, iron-depleted diet caused iron deficiency in young Sprague-Dawley rats, as reflected by a drop in hemoglobin, mean corpuscular volume, hepatic iron content and hepcidin mRNA in the liver. Thrombocytosis established in parallel. Moreover, platelets produced in iron deficient animals displayed a higher mean platelet volume and increased aggregation. Bone marrow studies revealed subtle alterations that are suggestive of expansion of megakaryocyte progenitors, an increase in megakaryocyte ploidy and accelerated megakaryocyte differentiation. Iron deficiency did not alter the production of hematopoietic growth factors such as thrombopoietin, interleukin 6 or interleukin 11. Megakaryocytic cell lines grown in iron-depleted conditions exhibited reduced proliferation but increased ploidy and cell size. Our data suggest that iron deficiency increases megakaryopoietic differentiation and alters platelet phenotype without changes in megakaryocyte growth factors, specifically TPO. Iron deficiency-induced thrombocytosis may have evolved to maintain or increase the coagulation capacity in conditions with chronic bleeding. PMID- 24464534 TI - Thermokinetic comparison of trypan blue decolorization by free laccase and fungal biomass. AB - Free laccase and fungal biomass from white-rot fungi were compared in the thermokinetics study of the laccase-catalyzed decolorization of an azo dye, i.e., Trypan Blue. The decolorization in both systems followed a first-order kinetics. The apparent first-order rate constant, k1', value increases with temperature. Apparent activation energy of decolorization was similar for both systems at ~ 22 kJ mol(-1), while energy for laccase inactivation was 18 kJ mol(-1). Although both systems were endothermic, fungal biomass showed higher enthalpy, entropy, and Gibbs free energy changes for the decolorization compared to free laccase. On the other hand, free laccase showed reaction spontaneity over a wider range of temperature (DeltaT = 40 K) as opposed to fungal biomass (DeltaT = 15 K). Comparison of entropy change (DeltaS) values indicated metabolism of the dye by the biomass. PMID- 24464535 TI - Cognitive impairment in heart failure: towards a consensus on screening. PMID- 24464536 TI - Plasma discharge and time-dependence of its effect to bacteria. AB - Several types of plasma discharge have been proven to have a capacity for sterilization. Our goal is to introduce new nonthermal plasma pencil. We used it to sterilize different microbial populations with differing ages. We used a plasma discharge of the following characteristics: radio frequency barrier discharger at atmospheric pressure with a working frequency of 13.56 MHz, and the working gas used was argon. We performed 110 tests with the following microbial populations: Pseudomonas aeruginosa, Staphylococcus aureus, Proteus species, and Klebsiella pneumoniae. All populations were inoculated on the previous day and also on the day of our experiment. We made our evaluations the following day and also after 5 days, with all our microbial populations. Eradication of microbial populations is dependent on the plasma discharge exposure time in all cases. With regard to freshly inoculated microbes, we were able to sterilize agar with intensive exposure lasting for 10 s of colonies Pseudomonas, Proteus, and Klebsiella. The most resistant microbe seems to be S. aureus, which survives 5 s of coherent exposure in half of the cases. Using the lightest plasma discharge exposure, we achieved a maximum of 10(4)-10(5) CFU/mL (colony-forming unit - CFU). Regarding older microbial populations inoculated the day before the experiment, we can only decrease population growth to 10(5) CFU/mL approximately, but never completely sterilize. The plasma discharge with our characteristics could be used for the sterilization of the aforementioned superficially growing microbes, but does not sufficiently affect deeper layers and thus seems to be a limitation for eradication of the already erupted colonies. PMID- 24464537 TI - Editorial. PMID- 24464538 TI - Determinants of premature mortality in a city population: an eight-year observational study concerning subjects aged 18-64. AB - BACKGROUND: Premature deaths constitute 31.1% of all deaths in Lodz. Analysis of the causes of premature deaths may be helpful in the evaluation of health risk factors. Moreover, findings of this study may enhance prophylactic measures. MATERIAL AND METHODS: In 2001, 1857 randomly selected citizens, aged 18-64, were included in the Countrywide Integrated Noncommunicable Diseases Intervention (CINDI) Programme. In 2009, a follow-up study was conducted and information on the subjects of the study was collected concerning their health status and if they continued to live in Lodz. The Cox proportional hazards model was used for evaluation of hazard coefficients. We adjusted our calculations for age and sex. The analysis revealed statistically significant associations between the number of premature deaths of the citizens of Lodz and the following variables: a negative self-evaluation of health - HR = 3.096 (95% CI: 1.729-5.543), poor financial situation - HR = 2.811 (95% CI: 1.183-6.672), occurring in the year preceding the study: coronary pain - HR = 2.754 (95% CI: 1.167-6.494), depression - HR = 2.001 (95% CI: 1.222-3.277) and insomnia - HR = 1.660 (95% CI: 1.029 2.678). Our research study also found a negative influence of smoking on the health status - HR = 2.782 (95% CI: 1.581-4.891). Moreover, we conducted survival analyses according to sex and age with Kaplan-Meier curves. CONCLUSIONS: The risk factors leading to premature deaths were found to be highly significant but possible to reduce by modifying lifestyle-related health behaviours. The confirmed determinants of premature mortality indicate a need to spread and intensify prophylactic activities in Poland, which is a post-communist country, in particular, in the field of cardiovascular diseases. PMID- 24464539 TI - Development of short form questionnaires for the assessment of work capacity in cardiovascular rehabilitation patients. AB - OBJECTIVES: Prevention of job loss is an essential objective of cardiovascular rehabilitation. However, comprehensive and economic diagnostic instruments on work limitations are missing. The present study describes development of short form questionnaires from 2 domains of the WCIB-Cardio item banks for the assessment of work capacity in cardiovascular rehabilitation patients. MATERIALS AND METHODS: 283 cardiovascular rehabilitation patients were recruited from 14 German rehabilitation clinics. Based on the WCIB-Cardio with the domains of cognitive and physical work capacity, we developed a short form for both domains. Item selection criteria were content coverage, content appropriateness, internal consistency reliability (>= 0.8). We used correlation of person location scores of the short forms with person location scores of the full item banks to examine the extent of measurement precision. RESULTS: For each domain of the WCIB-Cardio a short form was developed (cognitive work capacity - 14 items; physical work capacity 7 - items). In both domains psychometric properties were good (person separation index: cognitive work capacity - 0.80; physical work capacity - 0.80). Correlation meaures of the short form with the full item banks showed a high accordance of person locations for both domains (cognitive work capacity: r = 0.97; physical work capacity: r = 0.95). CONCLUSIONS: The calibrated instrument WCIB-Cardio provides the possibility to develop short form questionnaires with high psychometric quality. These short forms make it possible to monitor patient's work capacity in cardiovascular rehabilitation settings in a more economical way. PMID- 24464540 TI - Assessment of construction workers' hydration status using urine specific gravity. AB - OBJECTIVES: The study objective was to assess hydration status by measuring USG among construction workers in Iran. MATERIALS AND METHODS: The study design was comparative and experimental. Sixty participants were randomly selected from the construction workers from a construction campus with a similar type of work, climate and diet and formed 2 groups (individuals exposed to the sun and non exposed individuals). TWL and USG were measured in both groups on 2 consequent days, at the beginning, mid and end of the work shift. RESULTS: USG test showed that mean USG was 1.0213+/-0.0054 in the control group and in the exposed group, where it was significantly higher, it amounted to 1.026+/-0.005. In the exposed group, 38% of workers had a USG level between 1.026-1.030, representing a higher risk of heat illness and impaired performance and 12.72% had a USG level above 1.030 representing a clinically dehydrated status, while this proportion in the control group was 15.2% and 0.58%, respectively. The mean TWL index measure was 215.8+/-5.2 W/m2 for the control group and 144+/-9.8 W/m2 for the exposed group, where, again, it was significantly higher. The Pearson correlation measure showed a significant correlation between USG and TWL. CONCLUSIONS: Strong correlation between TWL, as an indicator of thermal stress and USG shows that USG can be considered as a predictor of thermal stress. The difference between USG among the exposed and non-exposed workers and the increase in USG during midday work show the sensitivity of this measure in different thermal and climatic conditions, whereas, the high level of dehydration among workers despite acceptable TWL level, shows that heat stress management without considering the real hydration status of workers, is insufficient. PMID- 24464541 TI - GIS-based assessment of cancer risk due to benzene in Tehran ambient air. AB - OBJECTIVES: The present study aimed to assess the risk of cancer due to benzene in the ambient air of gas stations and traffic zones in the north of Tehran. The cancer risk was estimated using the population distribution data for benzene levels and the unit risk for benzene proposed by the United States Environmental Protection Agency (US EPA). MATERIAL AND METHODS: Sixteen sampling locations were monitored, once every week, during 5 April 2010 to 25 March 2011. RESULTS: The results showed that the mean annual benzene concentration was 14.51+/-3.17 parts per billion (ppb) for traffic zones and 29.01+/-1.32 ppb for outside gas stations. The risk calculated was 1026*10(-6) for gas station 27 and 955*10(-6) for gas station 139. CONCLUSIONS: According to our results, the annual benzene level in Tehran ambient air is 2 to 20 times higher than the respective value specified in International Standard (1.56 ppb). Moreover, the results showed a notable increase of cancer risks, ranging from 10% to 56%, for the vicinity population close to the gas stations in comparison to the vicinity population in the traffic zones. PMID- 24464542 TI - Photolysis and photocatalysis of ibuprofen in aqueous medium: characterization of by-products via liquid chromatography coupled to high-resolution mass spectrometry and assessment of their toxicities against Artemia salina. AB - The degradation of the pharmaceutical compound ibuprofen (IBP) in aqueous solution induced by direct photolysis (UV-A and UV-C radiation) and photocatalysis (TiO2 /UV-A and TiO2 /UV-C systems) was evaluated. Initially, we observed that whereas photocatalysis (both systems) and direct photolysis with UV C radiation were able to cause an almost complete removal of IBP, the mineralization rates achieved for all the photodegradation processes were much smaller (the highest value being obtained for the TiO2 /UV-C system: 37.7%), even after an exposure time as long as 120 min. Chemical structures for the by products formed under these oxidative conditions (11 of them were detected) were proposed based on the data from liquid chromatography coupled to high-resolution mass spectrometry (LC-HRMS) analyses. Taking into account these results, an unprecedented route for the photodegradation of IBP could thus be proposed. Moreover, a fortunate result was achieved herein: tests against Artemia salina showed that the degradation products had no higher ecotoxicities than IBP, which possibly indicates that the photocatalytic (TiO2 /UV-A and TiO2 /UV-C systems) and photolytic (UV-C radiation) processes can be conveniently employed to deplete IBP in aqueous media. PMID- 24464543 TI - Analysis of aquatic-phase natural organic matter by optimized LDI-MS method. AB - The composition and physiochemical properties of aquatic-phase natural organic matter (NOM) are most important problems for both environmental studies and water industry. Laser desorption/ionization (LDI) mass spectrometry facilitated successful examinations of NOM, as humic and fulvic acids in NOM are readily ionized by the nitrogen laser. In this study, hydrophobic NOMs (HPO NOMs) from river, reservoir and waste water were characterized by this technique. The effect of analytical variables like concentration, solvent composition and laser energy was investigated. The exact masses of small molecular NOM moieties in the range of 200-1200 m/z were determined in reflectron mode. In addition, spectra of post source-decay experiments in this range showed that some compounds from different natural NOMs had the same fragmental ions. In the large mass range of 1200-15,000 Da, macromolecules and their aggregates were found in HPO NOMs from natural waters. Highly humic HPO exhibited mass peaks larger than 8000 Da. On the other hand, the waste water and reservoir water mainly had relatively smaller molecules of about 2000 Da. The LDI-MS measurements indicated that highly humic river waters were able to form large aggregates and membrane foulants, while the HPO NOMs from waste water and reservoir water were unlikely to form large aggregates. PMID- 24464544 TI - Effect of the sarcosine residue on sequence scrambling in peptide b(5) ions. AB - The effect of N-methylation on sequence scrambling in the fragmentation of b5 ions has been investigated by studying a variety of peptides containing sarcosine (N-methylglycine). The product ion mass spectra for the b5 ions derived from Sar A-A-A-Y-A and Sar-A-A-Y-A-A show only minor signals for non-direct sequence ions the major fragmentation reactions occurring from the unrearranged structures. This is in contrast to the b5 ions where the Sar residue is replaced by Ala and sequence scrambling occurs. The b5 ion derived from Y-Sar-A-A-A-A shows a product ion mass spectrum essentially identical to the spectrum of the b5 ion derived from Sar-A-A-A-Y-A, indicating that in the former case macrocyclization has occurred but the macrocyclic form shows a strong preference to reopen to put the Sar residue in the N-terminal position. Similar results were obtained in the comparison of b5 ions derived from A-Sar-A-A-Y-A and Sar-A-A-Y-A-A. The product ion mass spectra of the MH(+) ions of Y-Sar-A-A-A-A and A-Sar-A-A-Y-A show substantial signals for non-direct sequence ions indicating that fragmentation of the MH(+) ions channels extensively through the respective b5 ions and further fragmentation of these species. PMID- 24464545 TI - Does patient compliance with follow-up influence weight loss after gastric bypass surgery? A systematic review and meta-analysis. AB - Gastric bypass surgery is an effective intervention to manage morbid obesity. However, there have been suggestions that patients who do not comply to follow-up lose less weight. This study evaluated the influence of patient's follow-up compliance on weight loss post gastric bypass surgery. From the search of MEDLINE and EMBASE, four studies (n = 365) were identified and majority of these studies concluded that compliance with follow-up leads to increased weight loss. Our meta analysis of these studies found increase in the percentage of excess weight loss (%EWL) at 1-year post gastric bypass surgery (mean difference 6.38 % %EWL, 95 % CI 1.68-11.15) when patients were compliant with follow-up. Therefore, this review found that continued long-term follow up of gastric bypass patients has the potential to increase postoperative weight loss. PMID- 24464546 TI - Validation study of multi-frequency bioelectrical impedance with dual-energy X ray absorptiometry among obese patients. AB - BACKGROUND: Body mass index (BMI) is the most common parameter for classifying nutritional status. However, body composition (BC) may vary considerably among individuals with identical BMIs; consequently, we need to assess BC efficiently. Bariatric surgery is the most effective method for treating obesity. To improve quality assessment of postoperative weight loss, it is essential to assess BC. Multi-frequency bioelectrical impedance analysis (BIA) is a practical assessment instrument, though limited when applied among the obese population. Despite dual energy X-ray absorptiometry (DXA) being the current reference standard, it has physical limitations which restrict its practical application. This study, therefore, sought to correlate the results of BC assessments of same patient population using BIA and DXA. METHODS: This was a cross-sectional validation study with patients invited to undergo a multi-frequency BIA (Inbody 720(r)) and afterwards a DXA examination Statistical analyses were done using the intraclass correlation coefficient (ICC), paired t-test and the Bland-Altman plot analysis. RESULTS: A total of 108 patients were randomly selected, with 73 meeting the criteria for study inclusion. Most were female (89%) and had an average BMI of 40.17 +/- 4.08 kg/m(2). An almost perfect correlation of fat (kg) and fat-free mass (kg) was found in results from the BIA and DXA examination (ICC = 0.832 and ICC = 0.899, respectively). A substantial correlation was also found between the percentage of body fat (%BF) and the percentage of fat-free mass (%FFM). The comparison made between the BIA and DXA using the t-test showed significant differences between all parameters. The Bland-Altman plot showed that the BIA method tends to underestimate the FM and overestimate the LM measurements when compared with DXA. CONCLUSION: BIA proved to be a safe alternative for assessing BC in clinically severely obese patients and thus provides a more accessible evaluation tool for this population. But, consideration should be given to the formula added to the BIA measurement, adjusting the values to differences observed in order to reduce errors when compared with the DXA measurements. PMID- 24464547 TI - Sexually explicit online media and sexual risk among men who have sex with men in the United States. AB - This study aimed to describe sexually explicit online media (SEOM) consumption among men who have sex with men (MSM) in the United States and examine associations between exposure to unprotected anal intercourse (UAI) in SEOM and engagement in both UAI and serodiscordant UAI. MSM in the U.S. who accessed a men seeking-men website in the past year (N = 1,170) were recruited online for a cross-sectional, Internet-based survey of sexual risk and SEOM consumption. In the 3 months prior to interview, more than half (57 %) of the men reported viewing SEOM one or more times per day and almost half (45 %) reported that at least half of the SEOM they viewed portrayed UAI. Compared to participants who reported that 0-24 % of the SEOM they viewed showed UAI, participants who reported that 25-49, 50-74, or 75-100 % of the SEOM they viewed portrayed UAI had progressively increasing odds of engaging in UAI and serodiscordant UAI in the past 3 months. As SEOM has become more ubiquitous and accessible, research should examine causal relations between SEOM consumption and sexual risk-taking among MSM as well as ways to use SEOM for HIV prevention. PMID- 24464548 TI - How to "ascertain" paraphilia? An etymological hint. PMID- 24464549 TI - Effects of religious veiling on Muslim men's attractiveness ratings of Muslim women. AB - Hijab and other Islamic veiling clothing are important social and political symbols for Muslim women's identity. Although recently there has been a large body of literature on the social and political aspects of hijab in Western countries, there has been no investigation of the origin and function of veiling itself. This article hypothesized that religious veiling, which eliminates the estrogen-induced body curves of reproductive age women, decreases men's perceptions of women's physical attractiveness, thereby serving mate guarding functions against rival men. To test this hypothesis. Measures of the motivational appeal and self-reported perceived attractiveness of women exhibiting different degrees of veiling were obtained from 80 Muslim male participants. The results showed that men were more motivated to view women exhibiting the less veiling and rated them more attractive than those women whose bodily curves were less apparent. These results support veiling serving a mate guarding function and reinforcing the marital bond. PMID- 24464551 TI - Analysis of hepatitis C viral kinetics during administration of two nucleotide analogues: sofosbuvir (GS-7977) and GS-0938. AB - BACKGROUND: Sofosbuvir (GS-7977) and GS-0938 are nucleotide analogue HCV polymerase inhibitors, with sofosbuvir being a pyrimidine and GS-0938 being a purine. Mathematical modelling has provided important insights for characterizing HCV RNA decline and for estimating the in vivo effectiveness of single direct acting antiviral agents (DAAs); however it has not been used to characterize viral kinetics with combination DAA therapy. METHODS: We evaluated the antiviral activity of sofosbuvir and GS-0938 given alone and in combination for 14 days in 32 HCV genotype 1 treatment-naive patients (P2938-0212; NUCLEAR study). RESULTS: Viral load declined rapidly in a biphasic manner in all subjects and could be well fitted by assuming that both drugs had a similar and additive level of effectiveness in reducing viral production equal to 99.96%, on average. The model predicted that this level of effectiveness was not reached until 0.6 and 2 days for GS-0938 and sofosbuvir, respectively, and likely represents the time needed to accumulate intracellular triphosphates. Subsequently, both drugs led to a rapid second phase of viral decline with a mean rate of 0.35 d(-1). No effect of IL28B-polymorphism was found on viral kinetic parameters. CONCLUSIONS: Both sofosbuvir and GS-0938 are highly effective at blocking viral production from HCV infected cells. Both drugs led to a rapid and consistent second phase viral decline and exhibited no breakthroughs or other signs of resistance. From a kinetics perspective, because both drugs were of the same class there was little benefit in combining them, suggesting that future DAA combinations should consider utilizing drugs with different modes of action. PMID- 24464550 TI - Sex work among men who have sex with men and transgender women in Bogota. AB - This qualitative study examined sex work among internally displaced male and transgender female sex workers in Bogota, Colombia. Internal displacement has occurred in Colombia as a result of decades of conflict among armed groups and has created large-scale migration from rural to urban areas. Informed by the polymorphous model of sex work, which posits that contextual conditions shape the experience of sex work, we examined three main research questions. The first dealt with how internal displacement was related to the initiation of sex work; the second concerned the effect of agency on sex worker satisfaction; and the third examined how sex work in this context was related to HIV and other risks. Life history interviews were conducted with 26 displaced individuals who had done sex work: 14 were men who have sex with men and 12 were transgender women (natal males). Findings revealed that many participants began doing sex work in the period immediately after displacement, because of a lack of money, housing, and social support. HIV risk was greater during this time due to limited knowledge of HIV and inexperience negotiating safer sex with clients. Other findings indicated that sex workers who exerted more control and choice in the circumstances of their work reported greater satisfaction. In addition, we found that although many sex workers insisted on condom use with clients, several noted that they would sometimes have unprotected sex for additional money. Specific characteristics affecting the experience of sex work among the transgender women were also discussed. PMID- 24464552 TI - Risk of venous thromboembolism among hospitalizations of adults with selected autoimmune diseases. AB - Previous research has suggested autoimmune diseases are risk factors for developing venous thromboembolism (VTE). We assessed whether having diagnoses of selected autoimmune diseases associated with antiphospholipid antibodies- autoimmune hemolytic anemia (AIHA), immune thrombocytopenic purpura (ITP), rheumatoid arthritis (RA), and systemic lupus erythematosus (SLE)--were associated with having a VTE diagnosis among US adult hospitalizations. A cross sectional study was conducted using the 2010 Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality. VTE and autoimmune diseases were identified using International Classification of Diseases, Ninth Revision, Clinical Modification coded diagnoses information. The percentages of hospitalizations with a VTE diagnosis among all non-maternal adult hospitalizations without any of the four autoimmune diseases of interest and among those with AIHA, ITP, RA, and SLE diagnoses were 2.28, 4.46, 3.35, 2.65 and 2.77%, respectively. The adjusted odds ratios (OR) for having a diagnosis of VTE among non-maternal adult hospitalizations with diagnoses of AIHA, ITP, RA, and SLE were 1.25 [95% confidence interval (CI) 1.05 1.49], 1.20 (95% CI 1.07-1.34), 1.17 (95% CI 1.13-1.21), and 1.23 (95% CI 1.15 1.32), respectively, when compared to those without the corresponding conditions. The adjusted OR for a diagnosis of VTE associated with a diagnosis of any of the four autoimmune diseases was 1.20 (95% CI 1.16-1.24). The presence of a diagnosis of AIHA, ITP, RA, and SLE was associated with an increased likelihood of having a VTE diagnosis among the group of all non-maternal adult hospitalizations. PMID- 24464553 TI - Characterizing the effect of cytochrome P450 (CYP) 2C8, CYP2C9, and CYP2D6 genetic polymorphisms on stereoselective N-demethylation of fluoxetine. AB - Fluoxetine (FLX) is one of the most widely prescribed selective serotonin reuptake inhibitors. Although FLX is used as racemate in the clinic, the clinical pharmacokinetics of FLX and its N-demethylation metabolite norfluoxetine (NFLX) show obvious cytochrome P450 (CYP) polymorphism dependency and exhibit marked stereoselectivity. However, the kinetic profiles of CYP variants to FLX remain unclear. In the present study, some variants of human CYP2C8, CYP2C9, and CYP2D6 were first expressed in insect cells, and their catalytic roles with respect to FLX enantiomers were then investigated. CYP2C8.4 and CYP2C9.10 showed significantly lower activity and CYP2C8.3 showed significantly higher activity toward both R- and S-FLX compared with the wildtype, while CYP2C9.3, CYP2C9.13, and CYP2C9.16 showed significantly lower activity only toward R-FLX. Five CYP2C9 variants and CYP2D6.1 exhibited significantly stereoselective kinetic profiles prior to R-FLX, and CYP2C8.3 showed a slight stereoselectivity. Interestingly, obvious substrate inhibition was observed in the CYP2C9 wildtype and its three variants only in the case of R-FLX. Together, these findings suggest that CYP2C9 and CYP2D6 polymorphism may play an important role in the clearance of FLX and also in the stereoselective kinetic profiles of FLX enantiomers. PMID- 24464554 TI - Sensitivity and specificity of real-time reverse transcription polymerase chain reaction, histopathology, and immunohistochemical labeling for the detection of Rift Valley fever virus in naturally infected cattle and sheep. AB - Real-time reverse transcription polymerase chain reaction (real-time RT-PCR), histopathology, and immunohistochemical labeling (IHC) were performed on liver specimens from 380 naturally infected cattle and sheep necropsied during the 2010 Rift Valley fever (RVF) epidemic in South Africa. Sensitivity (Se) and specificity (Sp) of real-time RT-PCR, histopathology, and IHC were estimated in a latent-class model using a Bayesian framework. The Se and Sp of real-time RT-PCR were estimated as 97.4% (95% confidence interval [CI] = 95.2-98.8%) and 71.7% (95% CI = 65-77.9%) respectively. The Se and Sp of histopathology were estimated as 94.6% (95% CI = 91-97.2%) and 92.3% (95% CI = 87.6-95.8%), respectively. The Se and Sp of IHC were estimated as 97.6% (95% CI = 93.9-99.8%) and 99.4% (95% CI = 96.9-100%), respectively. Decreased Sp of real-time RT-PCR was ascribed to cross-contamination of samples. Stratified analysis of the data suggested variations in test accuracy with fetuses and severely autolyzed specimens. The Sp of histopathology in fetuses (83%) was 9.3% lower than the sample population (92.3%). The Se of IHC decreased from 97.6% to 81.5% in the presence of severe autolysis. The diagnostic Se and Sp of histopathology was higher than expected, confirming the value of routine postmortem examinations and histopathology of liver specimens. Aborted fetuses, however, should be screened using a variety of tests in areas endemic for RVF, and results from severely autolyzed specimens should be interpreted with caution. The most feasible testing option for countries lacking suitably equipped laboratories seems to be routine histology in combination with IHC. PMID- 24464555 TI - Issues encountered in development of enzyme-linked immunosorbent assay for use in detecting Influenza A virus subtype H5N1 exposure in swine. AB - A potential mechanism by which highly pathogenic avian Influenza A virus subtype H5N1 could more readily infect human beings is through the infection of and adaptation in pigs. To detect the occurrence of such infection, monitoring of pig populations through serological screening would be highly desirable. In the current study, hemagglutination inhibition assays were able to detect antibodies against H5N1 developed in pigs, but because of antigenic variation between clades, the use of multiple virus strains were required. Whole recombinant virus and recombinant hemagglutinin antigen enzyme-linked immunosorbent assays (ELISAs) were generated that could detect antibody against multiple H5N1 strains, but which also detected antibody against endemic swine influenza viruses. A recombinant hemagglutinin antigen-based ELISA was as effective as the whole virus antigen ELISAs in detecting antibody against the H5N1 virus strains used and eliminated nearly all of the cross-reactivity with non-H5N1 virus antibody. The current study also highlighted the difficulty in establishing a decision (cutoff) value that would effectively counterbalance nonspecific reactivity against sensitivity. The results provide important information and considerations for the development of serological screening assays for highly pathogenic avian H5N1 viruses. PMID- 24464556 TI - Subcutaneous sparganosis, a zoonotic cestodiasis, in two cats. AB - Sparganosis is a zoonotic cestodiasis of human beings and animals caused by plerocercoid or second-stage larvae (sparganum) of pseudophyllidean tapeworms in host tissues. Cats are among definitive hosts in which the larva develops to adult stage in the intestines. Reports on larval infection involving various tissues and organs in cats are scarce. Rare single case reports of visceral sparganosis in cats are previously documented. The present report documents an unusual subcutaneous sparganosis in 2 Domestic Shorthair cats from southern Georgia. Veterinary clinicians should consider sparganosis as differential diagnosis for subcutaneous cyst-like masses in cats. As infected animals and animal tissues are sources of human infection, sparganosis warrants public awareness and due precaution to avoid human infection. PMID- 24464557 TI - A study of classroom acoustics and school teachers' noise exposure, voice load and speaking time during teaching, and the effects on vocal and mental fatigue development. AB - OBJECTIVES: The study investigated the noise exposure in a group of Danish school teachers. The aims were to investigate if noise posed a risk of impairment of hearing and to study the association between classroom acoustical conditions, noise exposure, vocal symptoms, and cognitive fatigue. METHODS: Background noise levels, vocal load and speaking time were measured on 35 teachers during actual classroom teaching. The classrooms were characterized acoustically by measurements of reverberation time. Before and after the workday, the teachers answered a questionnaire on fatigue symptoms and carried out two cognitive test tasks sensitive to mental fatigue. RESULTS: The average noise level during the lessons was 72 dB(A), but during indoor sports activities the average noise level increased 6.6 dB(A). Room reverberation time (range 0.39-0.83 s) had no significant effect on the noise level. The teachers were talking with a raised voice in 61% of the time, and the vocal load increased 0.65 dB(A) per dB(A) increase in the average lesson noise level. An increase in voice symptoms during the workday correlated significantly with individual average noise exposure, and a decrease in performance in the two-back test correlated significantly with individual average vocal load. CONCLUSIONS: Noise exposure in general classrooms posed no risk of noise-induced hearing impairment in school teachers. However, the results provide evidence for an association between noise exposure and vocal load and development of vocal symptoms and cognitive fatigue after work. PMID- 24464558 TI - 19F DOSY NMR analysis for spin systems with nJFF couplings. AB - NMR is a powerful method for identification and quantification of drug components and contaminations. These problems present themselves as mixtures, and here, one of the most powerful tools is DOSY. DOSY works best when there is no spectral overlap between components, so drugs containing fluorine substituents are well suited for DOSY analysis as (19)F spectra are typically very sparse. Here, we demonstrate the use of a modified (19)F DOSY experiment (on the basis of the Oneshot sequences) for various fluorinated benzenes. For compounds with significant (n) JFF coupling constants, as is common, the undesirable J modulation can be efficiently suppressed using the Oneshot45 pulse sequence. This investigation highlights (19)F DOSY as a valuable and robust method for analysis of molecular systems containing fluorine atoms even where there are large fluorine-fluorine couplings. PMID- 24464559 TI - Mutational Spectrum of the CTNS Gene in Egyptian Patients with Nephropathic Cystinosis. AB - BACKGROUND: Nephropathic cystinosis is a rare autosomal recessive disorder caused by mutations in the CTNS gene, encoding for cystinosin, a carrier protein transporting cystine out of lysosomes. Its deficiency leads to cystine accumulation and cell damage in multiple organs, especially in the kidney. In this study, we aimed to provide the first report describing the mutational spectrum of Egyptian patients with nephropathic cystinosis and their genotype phenotype correlation. METHODS: Fifteen Egyptian patients from 13 unrelated families with infantile nephropathic cystinosis were evaluated clinically, biochemically, and genetically. Screening for the common 57-kb deletion was performed by standard multiplex PCR, followed by direct sequencing of the ten coding exons, exon-intron interfaces, and promoter region. RESULTS: None of the 15 Egyptian patients had the 57-kb deletion. Twenty-seven mutant alleles and 12 pathogenic mutations were detected including six novel mutations: two frameshift (c.260_261delTT; p.F87SfsX36, c.1032delCinsTG; p.F345CfsX19), one nonsense (c.734G>A; p.W245fsX), two missense (c.1084G>A; pG362R, c.560A>G; p.K187R), and one intronic splicing mutation (IVS3+5g>t). A novel promoter region mutation (1 593-41C>T) seemed to be detected but was excluded as a pathogenic mutation by quantitative real-time PCR analysis. CONCLUSIONS: This study could be the basis for future genetic counseling and prenatal diagnosis of patients with nephropathic cystinosis in Egyptian and surrounding populations. The screening for the 57-kb deletion is not recommended anymore outside its geographical distribution, especially in the region of the Middle East. A common Middle Eastern mutation (c.681G>A; E227E) was pointed out and discussed. PMID- 24464560 TI - Identification of a microRNA landscape targeting the PI3K/Akt signaling pathway in inflammation-induced colorectal carcinogenesis. AB - Inflammation can contribute to tumor formation; however, markers that predict progression are still lacking. In the present study, the well-established azoxymethane (AOM)/dextran sulfate sodium (DSS)-induced mouse model of colitis associated cancer was used to analyze microRNA (miRNA) modulation accompanying inflammation-induced tumor development and to determine whether inflammation triggered miRNA alterations affect the expression of genes or pathways involved in cancer. A miRNA microarray experiment was performed to establish miRNA expression profiles in mouse colon at early and late time points during inflammation and/or tumor growth. Chronic inflammation and carcinogenesis were associated with distinct changes in miRNA expression. Nevertheless, prediction algorithms of miRNA-mRNA interactions and computational analyses based on ranked miRNA lists consistently identified putative target genes that play essential roles in tumor growth or that belong to key carcinogenesis-related signaling pathways. We identified PI3K/Akt and the insulin growth factor-1 (IGF-1) as major pathways being affected in the AOM/DSS model. DSS-induced chronic inflammation downregulates miR-133a and miR-143/145, which is reportedly associated with human colorectal cancer and PI3K/Akt activation. Accordingly, conditioned medium from inflammatory cells decreases the expression of these miRNA in colorectal adenocarcinoma Caco-2 cells. Overexpression of miR-223, one of the main miRNA showing strong upregulation during AOM/DSS tumor growth, inhibited Akt phosphorylation and IGF-1R expression in these cells. Cell sorting from mouse colons delineated distinct miRNA expression patterns in epithelial and myeloid cells during the periods preceding and spanning tumor growth. Hence, cell-type specific miRNA dysregulation and subsequent PI3K/Akt activation may be involved in the transition from intestinal inflammation to cancer. PMID- 24464561 TI - Editorial. PMID- 24464562 TI - Polymorphisms in the p53 pathway genes and micronucleus occurrence in Chinese vinyl chloride-exposed workers. AB - OBJECTIVES: To investigate the association between polymorphisms in the p53 pathway genes and chromosomal damage in vinyl chloride (VC)-exposed workers. MATERIALS AND METHODS: Cytokinesis block micronucleus test was performed in 310 VC-exposed workers and 149 non-exposed workers to determine chromosomal damage. The polymerase chain reaction and restriction fragment length polymorphism technique were used to detect six SNPs in the p53 pathway genes involved in the cell cycle. RESULTS: There was a highly significant dose-response relationship between VC exposure and chromosomal damage. Individuals carrying the variant genotypes were at higher risk for chromosomal damage compared with their wild type genotype: p53rs1042522, MDM2 Del1518rs3730485, MDM2rs2279744 and GADD45Ars532446. On the other hand, individuals possessing the variant genotype of CDKN2A rs3088440 had significantly decreased risk compared with the corresponding wild-type. CONCLUSIONS: Genetic polymorphisms in P53 pathway genes may have an impact on VC-induced chromosomal damage. PMID- 24464563 TI - Study of lone working magnetic resonance technologists in Western Australia. AB - OBJECTIVES: It is recommended that magnetic resonance (MR) technologists should not work alone due to potential occupational health risks although lone working is legally acceptable. The objective of this study was to investigate the current situation of lone working MR technologists in Western Australia (WA) and any issue against the regulations. MATERIALS AND METHODS: A questionnaire regarding the issues of occupational health of lone working MR technologists was developed based on relevant literature and distributed to WA MR technologists. Descriptive (percentage of frequency, mean and standard deviation) and inferential statistics (Fisher's exact, Chi(2) and t tests, and analysis of variance) were used to analyze the responses of the yes/no, multiple choice and 5 pt scale questions from the returned questionnaires. RESULTS: The questionnaire response rate was 65.6% (59/90). It was found that about half of the MR technologists (45.8%, 27/59) experienced lone working. The private magnetic resonance imaging (MRI) centers were more likely to arrange technologists to work alone (p < 0.05). The respondents expressed positive views on issues of adequacy of training and arrangement, confidence and comfort towards lone working except immediate assistance for emergency (mean: 3). Factors of existence of MRI safety officer (p < 0.05) and nature of lone working (p < 0.001-0.05) affected MR technologists' concerns. CONCLUSIONS: Lone working of MR technologists is common in WA especially in private centers. The training and arrangement provided seem to be adequate for meeting the legal requirements. However, several areas should be improved by the workplaces including enhancement on immediate emergency assistance and concern relief. PMID- 24464564 TI - Epidemiology of physical activity in adult Polish population in the second decade of the 21st century. Results of the NATPOL 2011 study. AB - OBJECTIVES: The aim of the study was to assess physical activity (PA) level in a representative sample of Polish adults. MATERIALS AND METHODS: A cross-sectional analysis was performed among 2413 randomly selected individuals (51.5% women) aged 18-79 years, who participated in the Nationwide Study of Occurrence of Risk Factors of Cardiovascular Diseases NATPOL 2011 (March-July 2011). The study procedures consisted of a questionnaire as well as of anthropometric, blood pressure and biochemical measurements. Leisure-time, occupational and commuting PA were assessed by the use of a questionnaire interview. RESULTS: About 48.2% of adults do exercise for at least 30 minutes on most days of a week. About 11% of the respondents declare a sedentary lifestyle. About 26.5% of working population report hard physical work, while sedentary work is reported by 47.6% of the employed participants. Active commuting is declared by 27.3% of working/studying population. About 47.2%, 36.6%, and 15.3% spend < 15, 15-30, and > 30 min per day, respectively, on this kind of PA. CONCLUSIONS: PA level of more than half of Polish adults is still not satisfactory. Promotion of an active lifestyle should concern mainly leisure-time and commuting PA with paying special attention to substantial differences in various socio-demographic groups. PMID- 24464565 TI - Predictors of mental health in female teachers. AB - OBJECTIVE: Teaching profession is characterised by an above-average rate of psychosomatic and mental health impairment due to work-related stress. The aim of the study was to identify predictors of mental health in female teachers. MATERIAL AND METHODS: A sample of 630 female teachers (average age 47 +/- 7 years) participated in a screening diagnostic inventory. Mental health was surveyed with the General Health Questionnaire GHQ-12. The following parameters were measured: specific work conditions (teacher-specific occupational history), scales of the Effort-Reward-Imbalance (ERI) Questionnaire as well as cardiovascular risk factors, physical complaints (BFB) and personal factors such as inability to recover (FABA), sense of coherence (SOC) and health behaviour. RESULTS: First, mentally fit (MH(+)) and mentally impaired teachers (MH(-)) were differentiated based on the GHQ-12 sum score (MH(+): < 5; MH(-): >= 5); 18% of the teachers showed evidence of mental impairment. There were no differences concerning work-related and cardiovascular risk factors as well as health behaviour between MH(+) and MH(-). Binary logistic regressions identified 4 predictors that showed a significant effect on mental health. The effort-reward ratio proved to be the most relevant predictor, while physical complaints as well as inability to recover and sense of coherence were identified as advanced predictors (explanation of variance: 23%). CONCLUSION: Contrary to the expectations, classic work-related factors can hardly contribute to the explanation of mental health. Additionally, cardiovascular risk factors and health behaviour have no relevant influence. However, effort-reward-ratio, physical complaints and personal factors are of considerable influence on mental health in teachers. These relevant predictors should become a part of preventive arrangements for the conservation of teachers' health in the future. PMID- 24464566 TI - Children's residential exposure to selected allergens and microbial indicators: endotoxins and (1->3)-beta-D-glucans. AB - OBJECTIVES: The study was aimed at assessment of exposure to endotoxins, (1->3) beta-D-glucans and mite, cockroach, cat, dog allergens present in settled dust in premises of children as agents which may be significantly correlated with the occurrence of allergic symptoms and diseases in children. MATERIALS AND METHODS: The study covered 50 homes of one-or two-year-old children in Poland. Samples of settled dust were taken from the floor and the child's bed. The levels of (1->3) beta-D-glucans (floor), endotoxins (floor) and allergens of mite, cat, dog and cockroach (floor and bed) were analyzed. RESULTS: Average geometric concentrations (geometric standard deviation) of endotoxins, (1->3)-beta-D glucans, Der p1, Fel d1, Can f1 and Bla g1 in children homes were on the floor 42 166.0 EU/g (3.2), 20 478.4 ng/g (2.38), 93.9 ng/g (6.58), 119.8 ng/g (13.0), 288.9 ng/g (3.4), 0.72 U/g (4.4) and in their beds (only allergens) 597.8 ng/g (14.2), 54.1 ng/g (4.4), 158.6 ng/g (3.1) 0.6 U/g (2.9), respectively. When the floor was covered with the carpet, higher concentrations of endotoxins, (1->3) beta-D-glucans and allergens (each type) were found in the settled dust (p < 0.05). The trend was opposite in case of allergens (except dog) analyzed from bed dust and significantly higher concentrations were found in the rooms with smooth floor (p < 0.05). CONCLUSIONS: Among the analyzed factors only the type of floor significantly modified both the level of biological indicators and allergens. The results of this study could be the base for verifying a hypothesis that carpeting may have a protective role against high levels of cockroach, dog and cat allergens. PMID- 24464567 TI - Indoor allergens in settled dust from kindergartens in city of Lodz, Poland. AB - OBJECTIVES: The main objective of the study was to determine the levels of house dust mite (Der p1), dog (Can f1), cat (Fel d1) and cockroach (Bla g2) allergens in kindergartens localized in an urban agglomeration. MATERIAL AND METHODS: A quantitative analysis of allergens was carried out in settled dust samples collected by vacuuming the floor surface in three kindergartens (N = 84) and children's clothing (N = 36). The samples were collected in spring-summer and autumn-winter periods as well as at the beginning and end of the week. The allergen dust concentration was determined by enzyme-linked immunoenzymatic assay (ELISA). RESULTS: The mean geometric concentrations (+/-geometric standard deviations) of allergens Der p1, Can f1, Fel d1 and Bla g2 determined in kindergartens were: 0.02 +/- 3.21 MUg/g of dust; 0.97 +/- 4.49 MUg/g of dust; 0.30 +/- 4.43 MUg/g of dust and 0.01 +/- 3.08 MUg/g of dust, respectively. Younger classrooms (children aged from 3 to 4 years) were characterized by almost twice higher mean concentration of allergen Fel d1, as compared to older classrooms (children aged from 5 to 6 years) (p < 0.05). A significant impact of seasonality on the level of dog allergen Can f1 was found (p < 0.05). No significant weekly variation was found in average concentrations of the allergens. Children who had a dog and/or cat at home were characterized by high concentrations of allergens Can f1 and Fel d1 on their clothes (59.2 +/- 5.39 MUg Can f1/g of dust; 3.63 +/- 1.47 MUg Fel d1/g of dust), significantly higher than concentrations of allergens in children who did not have any pets (p < 0.001). CONCLUSIONS: Special attention should be paid to keeping the kindergarten rooms tidy and clean and to an appropriate choice of furnishings and fittings which would prevent the proliferation of the house dust mite and accumulation of allergens. PMID- 24464568 TI - Underdiagnosis of childhood asthma: A comparison of survey estimates to clinical evaluation. AB - OBJECTIVES: Diagnostic patterns play a role in asthma prevalence estimates and could have implications for disease management. We sought to determine the extent to which questionnaire-derived estimates of childhood asthma reflect the disease's true occurrence. MATERIALS AND METHODS: Children aged 6-12 years from Katowice, Poland, were recruited from a cross-sectional survey (N = 1822) via primary schools. Students were categorized into three mutually exclusive groups based on survey responses: "Asthma" (previously diagnosed asthma); "Respiratory symptoms" (no previous diagnosis of asthma and one or more respiratory symptoms during last year), "No respiratory symptoms" (no previous diagnosis of asthma or respiratory symptoms). A sample of children from each group (total N = 456) completed clinical testing to determine asthma presence according to GINA recommendations. RESULTS: Based on the survey, 5.4% of children were classified with asthma, 27.9% with respiratory symptoms, and 66.7% with no respiratory symptoms or asthma. All previously known 41 cases of asthma were confirmed. New diagnoses of asthma were made in 21 (10.9%) and 8 (3.6%) of subjects from the "Respiratory symptoms" (N = 192) and "No respiratory symptoms" (N = 223) groups, respectively. The overall prevalence of childhood asthma, incorporating the results of clinical examination, was 10.8% (95% CI: 9.4-12.2), compared to the questionnaire-derived figure of 5.4% (95% CI: 4.4-6.5%) and affected females more than males. CONCLUSIONS: Asthma prevalence was underestimated in this population possibly resulting from under-presentation or under-diagnosis. This could have potential implications for proper management and well-being of children. Questionnaire estimates of prevalence should be considered carefully in the context of regional diagnostic patterns. PMID- 24464569 TI - The role of occupational activities and work environment in occupational injury and interplay of personal factors in various age groups among Indian and French coalminers. AB - OBJECTIVE: The role of occupational hazards in occupational injury may be mediated by individual factors across various age groups. This study assessed the role of occupational hazards as well as contribution of individual factors to injuries among Indian and French coalminers. MATERIAL AND METHODS: We conducted a case-control study on 245 injured workers and on 330 controls without any injuries from Indian coal mines using face-to-face interviews, and a retrospective study on 516 French coalminers using a self-administered questionnaire including potential occupational and personal factors. Data were analyzed using logistic models. RESULTS: The annual rate of injuries was 5.5% for Indian coalminers and 14.9% for the French ones. Logistic model including all occupational factors showed that major injury causes were: hand-tools, material handling, machines, and environment/work-geological/strata conditions among Indian miners (adjusted odds-ratios 2.01 to 3.30) and biomechanical exposure score among French miners (adjusted odds-ratio 3.01 for score the 1-4, 3.47 for the score 5-7, and 7.26 for score >= 8, vs. score 0). Personal factors among Indian and French coalminers reduced/exacerbated the roles of various occupational hazards to a different extent depending on workers' age. CONCLUSION: We conclude that injury roles of occupational hazards were reduced or exacerbated by personal factors depending on workers' age in both populations. This knowledge is useful when designing prevention which should definitely consider workers' age. PMID- 24464570 TI - Effect of individual finger skin temperature on vibrotactile perception threshold. AB - OBJECTIVES: In healthy people, the vibrotactile perception threshold (VPT) at fingertips depends on a given measurement method and on individual characteristics such as age, gender and finger skin temperature. The aim of the study was to compare the VPT values in 2 groups of healthy subjects with different finger skin temperature. MATERIALS AND METHODS: The study group comprised 56 males and 76 females, who formed pairs matched with respect to age, gender and body mass index (BMI) but differing in terms of finger skin temperature at pre-launch testing. The finger skin temperature of less than 29 degrees C indicated the subjects with "cold hands" and that of more than 29 degrees C, the subjects with "warm hands". The measuring system made use of P8 pallesthesiometer (EMSON-MAT, Poland) and the measurement procedure was in compliance with the ISO 13091-1:2001 standard. VPT measurements were performed for the index, middle and ring fingers of both hands at the frequencies of 4 Hz, 25 Hz, 31.5 Hz, 63 Hz, 125 Hz and 250 Hz. RESULTS: The findings of the study revealed that the mean VPTs among the subjects with "cold hands" were significantly higher than the corresponding values among the subjects with "warm hands". CONCLUSIONS: The type of individual peripheral thermoregulation should be considered when assessing the VPT and determining its reference values. PMID- 24464571 TI - Smoke-free policies and non-smokers' reactions to SHS exposure in small and medium enterprises. AB - INTRODUCTION: Non-smoker employees can significantly improve the existing smoke free policies in the workplace by asserting their right for smoke-free air and confronting smoker colleagues. The aim of the study was to assess the psychological and social drivers of non-smokers' readiness to assert their right for smoke-free air in the workplace. MATERIALS AND METHODS: Twenty-six small-and medium enterprises (SME) with diverse background were randomly selected, and 284 employees agreed to participate in the study. Our study focused on the responses of 85 non-smokers (M age = 34 years, SD = 7.98, 84.2% worked in indoor offices). A cross-sectional design was used and participants completed a structured anonymous questionnaire assessing background and demographic characteristics, and psychosocial predictors of assertiveness intentions. RESULTS: Although more than half of non-smokers reported they were often/almost always bothered by exposure to SHS, roughly one third of them reported having asked their colleagues not to smoke at work. Regression analysis showed that the effects of distal predictors (i.e. annoyance due to SHS exposure) were mediated by past behaviour, attitudes (protection motivation beliefs), social norms, and self-efficacy. CONCLUSIONS: Health beliefs related to SHS exposure, and concerns about workplace health and job performance, social norms and self-efficacy can increase the assertiveness of non-smokers in workplace settings. Related campaigns should focus on communicating normative messages and self-efficacy training to empower non-smoker employees to act assertively towards protecting their smoke-free rights. PMID- 24464572 TI - Further development of a commercial driving simulation for research in occupational medicine. AB - OBJECTIVES: The purpose of this study was to refine a commercial car driving simulation for occupational research. As the effects of ethanol on driving behavior are well established, we choose alcohol as a test compound to investigate the performance of subjects during simulation. MATERIALS AND METHODS: We programmed a night driving scenario consisting of monotonous highway and a rural road on a Foerst F10-P driving simulator. Twenty healthy men, 19-30 years, participated in a pilot study. Subjects were screened for simulator sickness, followed by training on the simulator one hour in total. Experiments were performed in the morning on a separate day. Participants were randomized into either an alcoholized or a control group. All subjects drove two courses consisting of highway and rural road and were sober for the first course. During a 1 h break the ethanol group drank an alcoholic beverage to yield 0.06% blood alcohol concentration (BAC). Generalized linear mixed models were used to analyze the influence of alcohol on driving performance. Among others, independent variables were Simulator Sickness Questionnaire scores and subjective sleepiness. RESULTS: Subjects did not experience simulator sickness during the experiments. Mean BAC before the second test drive was 0.065% in the mildly intoxicated group. There was no clear-cut difference in the number of crashes between 2 groups. BAC of 0.1% would deteriorate mean braking reaction time by 237 ms (SE = 112, p < 0.05). Ethanol slightly impaired the tracking in the right-hand curves (p = 0.058). Braking reaction time improved by 86 ms (SE = 36, p < 0.05) for the second test drive, indicating a learning effect. CONCLUSIONS: In sum, a clear ethanol effect was observed in the driving simulation. This simulation seems suitable for occupational research and produces little simulator sickness. Controlling for possible learning effects is recommended in driving simulation studies. PMID- 24464573 TI - Polish Bibliography of Occupational Medicine, 2012. PMID- 24464574 TI - Weaning from inotropic support and concomitant beta-blocker therapy in severely ill heart failure patients: take the time in order to improve prognosis. AB - AIMS: Beta-blockers improve the prognosis in heart failure (HF), but their introduction may seem impossible in patients dependent on inotropic support. However, many of these patients can be titrated on beta-blockers, but there is little evidence of successful clinical strategies. METHODS AND RESULTS: We analysed the records of inotropy-dependent patients referred for assessment for heart transplantation. Thirty-six patients (45%) could not be weaned (NW) and underwent left ventricular assist device (LVAD) implantation or transplantation, or died. However, 44 (55%) were successfully weaned (SW). Neither the aetiology (ischaemic vs. non-ischaemic) nor cardiac indexes were different in the SW as compared with the NW group (2.27+/-0.5 vs. 2.15+/-0.6 L/min/m2). The NW patients had lower LVEF (15+/-5% vs. 19+/-5%, P=0.001), higher right atrial pressure (12+/ 6 vs. 8+/-6 mmHg, P=0.02), and more severe mitral regurgitation (P<0.001) than the SW patients. At discharge, 35 of 44 SW patients were receiving beta-blockers. In 29 of them, a beta-blocker could only be initiated or continued during concomitant support with i.v. enoximone for a duration of 14.1+/-7.2 days. Patients discharged on a beta-blocker had an LVAD/transplantation-free cumulative survival of 71% during a follow-up of 2074+/-201 days (confidence interval 1679 2470). CONCLUSION: It takes time to put severely ill HF patients on beta-blockers and it may require bridging with inotropes which are independent of beta adrenergic receptors. Whether such a strategy may result in a better clinical outcome warrants further research. PMID- 24464576 TI - Estrogen receptor status of breast stromal cells. PMID- 24464577 TI - Context-dependent role of Grb7 in HER2+ve and triple-negative breast cancer cell lines. AB - Grb7 is an adapter protein, aberrantly co-overexpressed with HER2 and identified as an independent prognostic marker in breast cancer. It has been established that Grb7 exacerbates the cellular growth and migratory behaviour of HER2+ve breast cancer cells. Less is known about Grb7's role in the context of HER2-ve cells. Here we directly compare the effect of stable Grb7 knockdown in oestrogen sensitive (T47D), HER2+ve (SKBR3) and triple-negative (MDA-MB-468 and MDA-MB-231) breast cancer cell lines on anchorage dependent and independent cell growth, wound healing and chemotaxis. All cell lines showed reduced ability to migrate upon Grb7 knockdown, despite their greatly varied endogenous levels of Grb7. Decreased cell proliferation was not observed in any of the cell lines upon Grb7 knockdown; however, decreased ability to form colonies was observed for all but the oestrogen sensitive cell line, depending upon the stringency of the growth conditions. The data reveal that Grb7 plays an important role in breast cancer progression, beyond the context of HER2+ve cell types. PMID- 24464578 TI - A snapshot of ubiquitin chain elongation: lysine 48-tetra-ubiquitin slows down ubiquitination. AB - We have explored the mechanisms of polyubiquitin chain assembly with reconstituted ubiquitination of IkappaBalpha and beta-catenin by the Skp1-cullin 1-betaTrCP F-box protein (SCF(betaTrCP)) E3 ubiquitin (Ub) ligase complex. Competition experiments revealed that SCF(betaTrCP) formed a complex with IkappaBalpha and that the Nedd8 modified E3-substrate platform engaged in dynamic interactions with the Cdc34 E2 Ub conjugating enzyme for chain elongation. Using "elongation intermediates" containing beta-catenin linked with Ub chains of defined length, it was observed that a Lys-48-Ub chain of a length greater than four, but not its Lys-63 linkage counterparts, slowed the rate of additional Ub conjugation. Thus, the Ub chain length and linkage impact kinetic rates of chain elongation. Given that Lys-48-tetra-Ub is packed into compact conformations due to extensive intrachain interactions between Ub subunits, this topology may limit the accessibility of SCF(betaTrCP)/Cdc34 to the distal Ub Lys-48 and result in slowed elongation. PMID- 24464579 TI - Molecular determinants mediating gating of Transient Receptor Potential Canonical (TRPC) channels by stromal interaction molecule 1 (STIM1). AB - Transient receptor potential canonical (TRPC) channels mediate a critical part of the receptor-evoked Ca(2+) influx. TRPCs are gated open by the endoplasmic reticulum Ca(2+) sensor STIM1. Here we asked which stromal interaction molecule 1 (STIM1) and TRPC domains mediate the interaction between them and how this interaction is used to open the channels. We report that the STIM1 Orai1 activating region domain of STIM1 interacts with the TRPC channel coiled coil domains (CCDs) and that this interaction is essential for opening the channels by STIM1. Thus, disruption of the N-terminal (NT) CCDs by triple mutations eliminated TRPC surface localization and reduced binding of STIM1 to TRPC1 and TRPC5 while increasing binding to TRPC3 and TRPC6. Single mutations in TRPC1 NT or C-terminal (CT) CCDs reduced interaction and activation of TRPC1 by STIM1. Remarkably, single mutations in the TRPC3 NT CCD enhanced interaction and regulation by STIM1. Disruption in the TRPC3 CT CCD eliminated regulation by STIM1 and the enhanced interaction caused by NT CCD mutations. The NT CCD mutations converted TRPC3 from a TRPC1-dependent to a TRPC1-independent, STIM1 regulated channel. TRPC1 reduced the FRET between BFP-TRPC3 and TRPC3-YFP and between CFP-TRPC3-YFP upon stimulation. Accordingly, knockdown of TRPC1 made TRPC3 STIM1-independent. STIM1 dependence of TRPC3 was reconstituted by the TRPC1 CT CCD alone. Knockout of Trpc1 and Trpc3 similarly inhibited Ca(2+) influx, and inhibition of Trpc3 had no further effect on Ca(2+) influx in Trpc1(-/-) cells. Cell stimulation enhanced the formation of Trpc1-Stim1-Trpc3 complexes. These findings support a model in which the TRPC3 NT and CT CCDs interact to shield the CT CCD from interaction with STIM1. The TRPC1 CT CCD dissociates this interaction to allow the STIM1 Orai1-activating region within STIM1 access to the TRPC3 CT CCD and regulation of TRPC3 by STIM1. These studies provide evidence that the TRPC channel CCDs participate in channel gating. PMID- 24464580 TI - CCN2 suppresses catabolic effects of interleukin-1beta through alpha5beta1 and alphaVbeta3 integrins in nucleus pulposus cells: implications in intervertebral disc degeneration. AB - The objective of the study was to examine the regulation of CCN2 by inflammatory cytokines, IL-1beta, and TNF-alpha and to determine whether CCN2 modulates IL 1beta-dependent catabolic gene expression in nucleus pulposus (NP) cells. IL 1beta and TNF-alpha suppress CCN2 mRNA and protein expression in an NF-kappaB dependent but MAPK-independent manner. The conserved kappaB sites located at -93/ 86 and -546/-537 bp in the CCN2 promoter mediated this suppression. On the other hand, treatment of NP cells with IL-1beta in combination with CCN2 suppressed the inductive effect of IL-1beta on catabolic genes, including MMP-3, ADAMTS-5, syndecan 4, and prolyl hydroxylase 3. Likewise, silencing of CCN2 in human NP cells resulted in elevated basal expression of several catabolic genes and inflammatory cytokines like IL-6, IL-4, and IL-12 as measured by gene expression and cytokine protein array, respectively. Interestingly, the suppressive effect of CCN2 on IL-1beta was independent of modulation of NF-kappaB signaling. Using disintegrins, echistatin, and VLO4, peptide inhibitors to alphavbeta3 and alpha5beta1 integrins, we showed that CCN2 binding to both integrins was required for the inhibition of IL-1beta-induced catabolic gene expression. It is noteworthy that analysis of human tissues showed a trend of altered expression of these integrins during degeneration. Taken together, these results suggest that CCN2 and inflammatory cytokines form a functional negative feedback loop in NP cells that may be important in the pathogenesis of disc disease. PMID- 24464581 TI - Dynamics of translocation and substrate binding in individual complexes formed with active site mutants of {phi}29 DNA polymerase. AB - The Phi29 DNA polymerase (DNAP) is a processive B-family replicative DNAP. Fluctuations between the pre-translocation and post-translocation states can be quantified from ionic current traces, when individual Phi29 DNAP-DNA complexes are held atop a nanopore in an electric field. Based upon crystal structures of the Phi29 DNAP-DNA binary complex and the Phi29 DNAP-DNA-dNTP ternary complex, residues Tyr-226 and Tyr-390 in the polymerase active site were implicated in the structural basis of translocation. Here, we have examined the dynamics of translocation and substrate binding in complexes formed with the Y226F and Y390F mutants. The Y226F mutation diminished the forward and reverse rates of translocation, increased the affinity for dNTP in the post-translocation state by decreasing the dNTP dissociation rate, and increased the affinity for pyrophosphate in the pre-translocation state. The Y390F mutation significantly decreased the affinity for dNTP in the post-translocation state by decreasing the association rate ~2-fold and increasing the dissociation rate ~10-fold, implicating this as a mechanism by which this mutation impedes DNA synthesis. The Y390F dissociation rate increase is suppressed when complexes are examined in the presence of Mn(2+) rather than Mg(2+). The same effects of the Y226F or Y390F mutations were observed in the background of the D12A/D66A mutations, located in the exonuclease active site, ~30 A from the polymerase active site. Although translocation rates were unaffected in the D12A/D66A mutant, these exonuclease site mutations caused a decrease in the dNTP dissociation rate, suggesting that they perturb Phi29 DNAP interdomain architecture. PMID- 24464582 TI - c-Myc quadruplex-forming sequence Pu-27 induces extensive damage in both telomeric and nontelomeric regions of DNA. AB - Quadruplex-forming DNA sequences are present throughout the eukaryotic genome, including in telomeric DNA. We have shown that the c-Myc promoter quadruplex forming sequence Pu-27 selectively kills transformed cells (Sedoris, K. C., Thomas, S. D., Clarkson, C. R., Muench, D., Islam, A., Singh, R., and Miller, D. M. (2012) Genomic c-Myc quadruplex DNA selectively kills leukemia. Mol. Cancer Ther. 11, 66-76). In this study, we show that Pu-27 induces profound DNA damage, resulting in striking chromosomal abnormalities in the form of chromatid or chromosomal breaks, radial formation, and telomeric DNA loss, which induces gamma H2AX in U937 cells. Pu-27 down-regulates telomeric shelterin proteins, DNA damage response mediators (RAD17 and RAD50), double-stranded break repair molecule 53BP1, G2 checkpoint regulators (CHK1 and CHK2), and anti-apoptosis gene survivin. Interestingly, there are no changes of DNA repair molecules H2AX, BRCA1, and the telomere maintenance gene, hTERT. DeltaB-U937, where U937 cells stably transfected with deleted basic domain of TRF2 is partially sensitive to Pu 27 but exhibits no changes in expression of shelterin proteins. However, there is an up-regulation of CHK1, CHK2, H2AX, BRCA1, and survivin. Telomere dysfunction induced foci assay revealed co-association of TRF1with gamma-H2AX in ATM deficient cells, which are differentially sensitive to Pu-27 than ATM proficient cells. Alt (alternating lengthening of telomere) cells are relatively resistant to Pu-27, but there are no significant changes of telomerase activity in both Alt and non-Alt cells. Lastly, we show that this Pu-27-mediated sensitivity is p53 independent. The data therefore support two conclusions. First, Pu-27 induces DNA damage within both telomeric and nontelomeric regions of the genome. Second, Pu 27-mediated telomeric damage is due, at least in part, to compromise of the telomeric shelterin protein complex. PMID- 24464583 TI - Managing declining yields from ageing tea plantations. AB - Strong growth in the demand for tea requires further increases in the productivity of plantations. Declining or stagnant yields are commonly observed in older plantations. Possible controlling factors for yield decline are reviewed including ageing of plants, chronic disease and sub-optimal soil conditions such as excess soil acidity and low soil organic matter. Management options for addressing these factors are evaluated, including replanting. A systematic approach to decision-making about replanting is presented. Practice for replanting is reviewed and it is concluded that evidence to support a general case for replanting is limited, unless based on the introduction of more productive clones and/or better plant spacing. PMID- 24464585 TI - Regulation of hepatic drug transporter activity and expression by organochlorine pesticides. AB - Organochlorine (OC) pesticides constitute a major class of persistent and toxic organic pollutants, known to modulate drug-detoxifying enzymes. In the present study, OCs were demonstrated to also alter the activity and expression of human hepatic drug transporters. Activity of the sinusoidal influx transporter OCT1 (organic cation transporter 1) was thus inhibited by endosulfan, chlordane, heptachlor, lindane, and dieldrine, but not by dichlorodiphenyltrichloroethane isomers, whereas those of the canalicular efflux pumps MRP2 (multidrug resistance associated protein 2) and BCRP (breast cancer resistance protein) were blocked by endosulfan, chlordane, heptachlor, and chlordecone; this latter OC additionally inhibited the multidrug resistance gene 1 (MDR1)/P-glycoprotein (P-gp) activity. OCs, except endosulfan, were next found to induce MDR1/P-gp and MRP2 mRNA expressions in hepatoma HepaRG cells; some of them also upregulated BCRP. By contrast, expression of sinusoidal transporters was not impaired (organic anion transporting polypeptide (OATP) 1B1 and OATP2B1) or was downregulated (sodium taurocholate co-transporting polypeptide (NTCP) and OCT1). Such regulations of drug transporter activity and expression, depending on the respective nature of OCs and transporters, may contribute to the toxicity of OC pesticides. PMID- 24464584 TI - Aging reduces the expression of lung CINC and MCP-1 mRNA in a P. aeruginosa rat model of infection. AB - We investigated dynamic changes of inflammatory cell infiltration and expression of cytokine-induced neutrophil chemoattractant (CINC) and monocyte chemoattractant protein-1 (MCP-1) mRNA in aged rats with Pseudomonas aeruginosa pulmonary infection. Disease manifestation and lung tissue pathology (lesion dispersion, inflammatory reactions, tissue edema and bleeding) were more severe in aged rats than young rats. At various time points, lung tissue polymorphonuclear neutrophil and mononuclear macrophage numbers were lower in the aged group than the young group (P < 0.05), and at 24 h there was no difference in mononuclear macrophage numbers. After inoculation with P. aeruginosa, CINC and MCP-1 mRNA expression increased in both groups, but the peak lagged in old rats compared with young. Thus, aging can reduce the expression of CINC and MCP-1 mRNA in lung tissues, and reduce the infiltration of neutrophils and monocyte macrophages induced by CINC and MCP-1. This might lead to increased risk of pneumonia in elderly patients. PMID- 24464586 TI - Influenza vaccine and survival in acute heart failure. AB - AIMS: Influenza vaccine is a well-recommended secondary prevention measure for improving survival in patients with coronary artery disease, but it has generally been less studied in heart failure. We ask whether having influenza vaccination is associated with survival among patients with acute heart failure (HF). METHODS AND RESULTS: This was a prospective population-based cohort study accompanied by an analysis of two cross-sectional population samples for external validation of baseline characteristics differences. We analysed all 1964 ambulatory patients with acute HF aged >=50 years who were admitted to the Heart Failure Survey in Israel (HFSIS). We used the Israel Health Survey (IHS) 2009 and the Behavioural Risk Factor Surveillance System (BRFSS) 2003-2004 surveys (274 535 participants) for external validation. In the HFSIS, the multivariate-adjusted hazard ratios for in-hospital, 1 and 4 year mortality outcomes of influenza-vaccinated patients were 0.71 (P = 0.19), 0.81 (P = 0.04), and 0.83 (P = 0.006), respectively. In the IHS validation sample, a recent physician visit [odds ratio (OR) 1.61; 95% confidence interval (CI) 1.43-1.80] or having supplementary health insurance (OR 1.39; 95% CI 1.19-1.61) were associated with higher likelihood of being vaccinated against influenza. In the BRFSS validation sample, having > 1 healthcare providers (OR 2.31; 95% CI 2.22-2.40) or having any healthcare coverage were associated with higher likelihood of being vaccinated (OR 1.59; 95% CI 1.54-1.65). CONCLUSIONS: Influenza vaccine might improve survival among patients with acute HF. This association, however, could be affected by unmeasured confounding and bias due to baseline medical surveillance and socioeconomic differences between vaccinated and non-vaccinated patients. PMID- 24464589 TI - Molecular detection of Rift Valley fever virus in serum samples from selected areas of Tanzania. AB - Rift Valley fever (RVF) is an acute mosquito-borne viral zoonotic disease affecting domestic animals and humans caused by the Rift Valley fever virus (RVFV). The virus belongs to the genus Phlebovirus of the family Bunyaviridae. The main aim of this study was to detect the presence of antibodies to RVFV as well as the virus in the serum samples that were collected from livestock during the 2006/2007 RVF outbreaks in different locations in Tanzania. Analysis of selected samples was done using a RVF-specific inhibition enzyme-linked immunosorbent assay (I-ELISA) and reverse transcription polymerase chain reaction (RT-PCR). Genomic viral RNA was extracted directly from serum samples using a QIAamp Viral RNA Mini Kit (QIAGEN), and a one-step RT-PCR protocol was used to amplify the S segment of RVFV. Positive results were obtained in 39.5% (n = 200) samples using the RVF I-ELISA, and 17.6% (n = 108) of samples were positive by RT PCR. I-ELISA detected 41 (38.7%), 32 (39.0%), and 6 (50.0%) positive results in cattle, goats, and sheep sera, respectively, whereas the RT-PCR detected 11 (0.2%), 7 (0.2%), and 1 (0.1%) positive results in cattle, goats, and sheep sera, respectively. These findings have demonstrated the presence of RVFV in Tanzania during the 2006/2007 RVF outbreaks. To our knowledge, this is the first report to detect RVFV in serum samples from domestic animals in Tanzania using PCR technique. Therefore, a detailed molecular study to characterize the virus from different geographical locations in order to establish the profile of strains circulating in the country and develop more effective and efficient control strategies should be done. PMID- 24464587 TI - A novel mechanism of skin tumor promotion involving interferon-gamma (IFNgamma)/signal transducer and activator of transcription-1 (Stat1) signaling. AB - The current study was designed to explore the role of signal transducer and activator of transcription 1 (Stat1) during tumor promotion using the mouse skin multistage carcinogenesis model. Topical treatment with both 12-O tetradecanoylphorbol-13-acetate (TPA) and 3-methyl-1,8-dihydroxy-9-anthrone (chrysarobin or CHRY) led to rapid phosphorylation of Stat1 on both tyrosine (Y701) and serine (S727) residues in epidermis. CHRY treatment also led to upregulation of unphosphorylated Stat1 (uStat1) at later time points. CHRY treatment also led to upregulation of interferon regulatory factor 1 (IRF-1) mRNA and protein, which was dependent on Stat1. Further analyses demonstrated that topical treatment with CHRY but not TPA upregulated interferon-gamma (IFNgamma) mRNA in the epidermis and that the induction of both IRF-1 and uStat1 was dependent on IFNgamma signaling. Stat1 deficient (Stat1(-/-) ) mice were highly resistant to skin tumor promotion by CHRY. In contrast, the tumor response (in terms of both papillomas and squamous cell carcinomas) was similar in Stat1(-/-) mice and wild-type littermates with TPA as the promoter. Maximal induction of both cyclooxygenase-2 and inducible nitric oxide synthase in epidermis following treatment with CHRY was also dependent on the presence of functional Stat1. These studies define a novel mechanism associated with skin tumor promotion by the anthrone class of tumor promoters involving upregulation of IFNgamma signaling in the epidermis and downstream signaling through activated (phosphorylated) Stat1, IRF-1 and uStat1. PMID- 24464590 TI - HIV-1 genital shedding in HIV-infected patients randomized to second-line lopinavir/ritonavir monotherapy versus tenofovir/lamivudine/lopinavir/ritonavir. AB - BACKGROUND: HIV-1 shedding in genital secretions is associated with HIV transmission risk. Limited data exist on the effect of second-line lopinavir/ritonavir monotherapy (mLPV/r) on genital secretion of HIV RNA. METHODS: We measured HIV-1 in genital secretions of HIV-infected adults at time of failure from non-nucleoside reverse transcriptase inhibitor (NNRTI)-based regimens and at 48 weeks after being randomized to second-line mLPV/r versus tenofovir/lamivudine/LPV/r (TDF/3TC/LPV/r). Plasma and genital secretion (semen, vaginal swab) HIV RNA was quantified by the CobasAmpliprep/TaqMan assay. RESULTS: Forty enrolled (15 on mLPV/r and 25 on TDF/3TC/LPV/r). Median age was 37.8 years and 35% were male. Median baseline CD4(+) T-cell count was 222 cells/mm(3), plasma HIV RNA was 4.1 log10 copies/ml and genital secretion HIV RNA was 2.3 log10 copies/ml. At week 48, the proportion of patients with plasma HIV RNA<50 copies/ml was 13/15 (87%) in mLPV/r and 21/25 (84%) in TDF/3TC/LPV/r arms. Median genital HIV RNA was significantly decreased from baseline in both arms (P=0.009 in mLPV/r and P=0.001 in TDF/3TC/LPV/r). In subjects with suppressed plasma HIV RNA, 12/34 (35%; 6/13 [46%] in the mLPV/r and 6/21 [29%] in the TDF/3TC/LPV/r arms) had detectable HIV RNA (range 74-957 copies/ml) in the genital secretions (P=0.41). By multivariate analysis, the only predictor of having genital HIV RNA>50 copies/ml at week 48 was baseline genital secretion HIV RNA>50 copies/ml (P=0.049). CONCLUSIONS: LPV/r either given alone or in combination with TDF/3TC as second-line treatment achieved high genital secretion HIV RNA suppression rate. Genital secretion HIV RNA remained detectable at low levels in one-third of patients with suppressed plasma viraemia. PMID- 24464591 TI - The application of quantitative NMR for the facile, rapid and reliable determination of clindamycin phosphate in a conventional tablet formulation. AB - Spectroscopic tools such as NMR can be applied to the quantitative analysis of active pharmaceutical ingredients with relative ease and accuracy. Here, we demonstrate the quantification of clindamycin phosphate (CLP) in a conventional tablet formulation, performed using potassium hydrogen phthalate (KHP) as the internal standard and deuterium oxide (D2O) as the NMR solvent. The methyl protons signal of CLP at 0.72 ppm (triplet) relative to the signal of KHP at 7.37 7.40 ppm (multiplet) was used for quantification purposes using (1)H NMR. This method was shown to be specific and linear (r = 0.9997) within the CLP concentration range from 7.2 to 23.1 mg per 0.5 ml of D2O. The maximum relative standard deviation (RSD) of accuracy and precision was calculated at 0.39% and 0.64%, respectively. The limits of detection (LOD) and quantification were 0.04 and 0.11 mg/ml, respectively. The method was highly stable with a calculated RSD of 0.03%. The robustness of the method was demonstrated by changing four different parameters, and the difference among each parameter was <= 0.78%. The findings of this work were in good agreement with previously reported conventional HPLC-based approaches, highlighting its applicability in the determination of other active pharmaceutical ingredients in conventional formulations for quality control purposes. PMID- 24464593 TI - Safety in numbers: target prevalence affects the detection of vehicles during simulated driving. AB - The "low-prevalence effect" refers to the fact that observers often fail to detect rare targets (<5 % prevalence) during visual search tasks. Previous research has demonstrated robust prevalence effects in real-world tasks that employ static images, such as airport luggage screening. No published research has examined prevalence effects in dynamic tasks, such as driving. We conducted a driving simulator experiment to investigate whether target prevalence effects influence the detection of other vehicles while driving. The target vehicles were motorcycles and buses, with prevalence being manipulated both within and between subjects: Half of the subjects experienced a high prevalence of motorcycles with a low prevalence of buses, and half experienced a high prevalence of buses with a low prevalence of motorcycles. Consistent with our hypotheses, drivers detected high-prevalence targets faster than low-prevalence targets for both vehicle types. Overall, our results support the notion that increasing the prevalence of visual search targets makes them more salient, and consequently easier to detect. PMID- 24464592 TI - Lessons learned from negative clinical trials evaluating antithrombotic therapy for ischemic heart disease. AB - The clinical trials that failed to demonstrate significant efficacy may not result in development of new therapy but contribute to better understanding of antithrombotic therapy for ischemic heart disease. Negative trials provide important messages about how to interpret and understand the results of clinical trials and apply these results to clinical practices. Although every aspect of clinical trials may influence the outcomes of trials and interpretation of their results, selection of study subjects, endpoints, and measuring risk/benefit are crucial to success of clinical trial. We will review the recent key negative trials on antithrombotic therapy for ischemic heart disease and discuss about their results and implications. The challenge in the future for the development of antithrombotic therapies is to leverage these "lessons learned" from negative clinical trials to improve the design, conduct, and interpretation of future randomized clinical trials. PMID- 24464594 TI - Incidence of pituitary incidentalomas in patients with adrenal adenomas. AB - With the advent of modern imaging modalities, endocrine incidentalomas are increasingly being discovered. We aimed to investigate the presence of pituitary incidentalomas (PI) in patients with adrenal incidentalomas (AI), and identify potential metabolic correlates in this cohort. 26 patients (18 females) with AI discovered on abdominal computerized tomography were studied. All patients underwent pituitary magnetic resonance imaging (MRI) and endocrine investigations to evaluate functional adrenal pathology, anterior pituitary hormonal status, insulin-resistance indices and presence of metabolic syndrome. Pituitary MRI revealed a microadenoma and a 4*5 mm cyst in 1 patient respectively, and an empty sella in 4 (2 partial) patients. Overall, 6/26 (23%) patients with an AI had evidence of pituitary imaging pathology but only 8% had a PI; none had any evidence of abnormalities in pituitary function. Subclinical hypercortisolism was the only hyperfunctional status detected in 4 patients with AI but was unrelated to the pituitary findings. No abnormality of insulin secretion and action was found between patients with or without pituitary pathology. In the present study 23% of patients with AI had some alteration in pituitary morphology, and 2 a PI without accompanying pituitary hormonal deficit or metabolic derangement. Further studies are required to address this issue and identify a potential pathogenetic mechanism. PMID- 24464595 TI - Delayed recognition of Wolfram syndrome frequently misdiagnosed as type 1 diabetes with early chronic complications. AB - AIMS: Improvements in diagnostic methods and greater genetic awareness have brought remarkable progress in the recognition of monogenic forms of diabetes, including Wolfram syndrome (WFS). WFS is diagnosed based on clinical criteria of coexistence of diabetes mellitus and optic atrophy, and confirmed by molecular analysis; however, the condition is still sometimes misdiagnosed. To begin to understand the reasons for misdiagnosis, we conducted a retrospective analysis of WFS patients who were originally misdiagnosed. MATERIALS AND METHODS: The medical histories of 13 pediatric patients with clinical misdiagnosis of type 1 diabetes and early chronic complications made in the years 1995-2010 and who were subsequently correctly diagnosed with WFS based on genetic testing in 2008-2011 were analyzed. RESULTS: The average age of the patients at diabetes onset was 5 (4.4-6.3) years, and the mean HbA1c level at diagnosis was 9.1+/-2.3%. Initially, all of these patients were treated as having type 1 diabetes with progressive visual impairment despite good metabolic control (mean HbA1c 7.5+/-1.3%). Diagnosis of optic atrophy was made at an average age of 9 (5.9-11.5) years, which corresponds to 4 years after diabetes recognition (p=0.002). At the time of genetic analysis, the average age of the patients was 16 (12-18.7) years, which corresponds to 7 years after recognition of coexistence of diabetes mellitus and optic atrophy (p=0.007). CONCLUSIONS: Delays of at least 7 years occurred before recognition of WFS among a cohort of pediatric patients with diabetes. All patients with WFS were primarily misdiagnosed as having type 1 diabetes. PMID- 24464596 TI - Benefits of the neutrophil-to-lymphocyte ratio for the prediction of gestational diabetes mellitus in pregnant women. AB - AIMS: There is growing consensus in the literature that inflammation plays a central role in the pathophysiology of obesity, Type 2 Diabetes Mellitus (T2DM), Gestational Diabetes Mellitus (GDM) and cardiovascular complications. Measuring the neutrophil-to-lymphocyte ratio (NLR) provides a simple inexpensive method for the assessment of inflammatory status. We investigated the predictive value of pre-procedural (before the oral glucose tolerance test (OGTT)) NLR on the development of GDM in pregnancy. METHODS: 42 women with GDM and 68 women without GDM were included in the study. Complete Blood Count and biochemical tests were followed by a diagnostic 4-point 100-g-OGTT within 2 weeks. GDM was diagnosed by the Carpenter and Coustan criteria. The NLR was calculated from the data. RESULTS: The mean NLR level was significantly higher in GDM women (3.00+/-0.83 vs. 2.26+/-0.43 p<0.001, respectively). In ROC analysis, NLR>2.93 had 76.2% sensitivity and 94.1% specificity in predicting GDM. Logistic regression analysis showed that elevated NLR (OR: 5.512, 95% CI: 1.352-22.475, p=0.017) was an independent variable for predicting GDM in pregnancy. CONCLUSIONS: An elevated NLR level is a powerful and independent predictor of GDM. The results of this study suggested that inflammation plays a central role in the pathogenesis of GDM. PMID- 24464597 TI - The impact of type 2 diabetes and atorvastatin treatment on serum levels of MMP-7 and MMP-8. AB - AIM: Novel members of matrix metalloproteinases (MMPs), MMP-7 and MMP-8, have emerged as predictors of cardiovascular events. Our study aimed to evaluate serum MMP-7 and MMP-8 concentrations in patients with type 2 diabetes mellitus (T2DM) and the effects of atorvastatin on them. METHODS: We enrolled 85 statin-free subjects with concomitant T2DM and hypercholesterolemia, but without overt micro /macro-vascular complications (diabetic group - DG). 42 age- and gender-matched healthy subjects without chronic diseases or therapy served as healthy group (HG). All diabetic patients received fix dose of atorvastatin (20 mg/day). Clinical and anthropometrical parameters, lipids, fasting plasma glucose (FPG), serum MMP-7, MMP-8, their inhibitor (TIMP-1), IL-18, hsCRP and insulin resistance (HOMA-IR) were assayed at baseline in all participants and after 3 months in the DG. RESULTS: At baseline, DG showed higher levels of BMI, systolic blood pressure, insulin resistance and FPG compared to HG (p<0.05). Similarly, DG appeared with elevated concentrations of MMP-7 (4.28+/-1.01 ng/ml vs 2.63+/-1.11 ng/ml, p<0.001), MMP-8 (73.07+/-21.96 ng/ml vs. 21.27+/-10.49 ng/ml, p<0.001) and inflammatory markers (WBC, hsCRP, IL-18, p<0.010). Importantly, atorvastatin treatment improved lipid profile, significantly reduced the concentrations of MMP 7, MMP-8 and inflammatory markers (p<0.01). Moreover, there was considerable suppression of both MMP-7/TIMP-1 and MMP-8/TIMP-1 ratios (p<0.01). In standard multiple regression analysis, the atorvastatin-induced reduction in MMP-7 was independently associated with LDL and IL-18 downregulation (R(2)=0.648, p=0.017). Similarly, IL-18 changes emerged as an independent determinant of MMP-8 alterations (R(2)=0.678, p=0.007). CONCLUSIONS: Hypercholesterolemic patients with T2DM showed elevated MMP-7 and MMP-8 serum concentrations. Atorvastatin reduced the latter concentrations and their ratio with TIMP-1. Those effects seemed mediated by the atorvastatin-induced suppression of inflammatory mediators. ClinicalTrials.gov Identifier: NCT00636766. PMID- 24464598 TI - Outcome of percutaneous transluminal angioplasty in diabetic patients with critical limb ischaemia. AB - OBJECTIVE: We investigated the clinical outcome of percutaneous transluminal angioplasty (PTA) which has not been fully established in diabetic patients with critical limb Ischaemia (CLI) compared with non-diabetics. DESIGN AND PATIENTS: A total of 73 limbs of 52 patients (50 limbs of 34 diabetic patients and 23 limbs of 18 non-diabetics) who underwent PTA for CLI (Rutherford-Becker category 4, 5 or 6) were enrolled. Rates of amputation and restenosis, and ankle brachial index (ABI), were assessed before and after PTA during a 36-month follow-up period. RESULTS: Diabetic patients had a higher rate of major amputations after PTA (10 vs. 0%, P<0.05); however, total amputation (12.0 vs. 8.7%, P=0.62) and restenosis rates (4.0 vs. 8.7%, P=0.38) were not significantly different compared with non diabetic patients. ABI at 3 months after PTA was significantly improved in both diabetic and non-diabetic patients (0.70+/-0.20 vs. 0.93+/-0.19, P<0.01 in diabetic patients; 0.69+/-0.25 vs. 0.92+/-0.17, P<0.01 in non-diabetics). Improved ABI was maintained for 36 months in both groups and did not show a significant difference (0.88+/-0.21 vs. 0.89+/-0.20, P=0.89). CONCLUSION: Our results, showing that the outcome of PTA in diabetic patients is not inferior to that in non-diabetics, suggest the potential benefit of primary PTA, instead of bypass surgery, for CLI in diabetic patients who are at high risk of perioperative complications. PMID- 24464599 TI - Blood ALDH1 and GST activity in diabetes type 2 and its correlation with glycated hemoglobin. AB - There is increasing evidence that oxidative stress (OS) plays a major role in the pathogenesis of diabetes mellitus (DM) and the development of its complications. As one of the consequences of OS is increased lipid peroxidation (LP), the aim of our studies was to check, how the activity of 2 enzymes involved in the detoxification of aldehydes formed during LP, glutathione S-transferase (GST) and aldehyde dehydrogenase 1 (ALDH 1) is changed in patients suffering from DM.GST and ALDH1A1 activities were determined in whole blood samples of DM type 2 patients (n=64) and healthy controls (n=60) using spectrophotometer (for GST activity) and fluorometer (for ALDH1 activity) and they were found to be significantly increased in diabetics when compared with healthy control (p<0.05). Intriguingly, grouping the DM patients on the basis of the glucose level and HbA1c revealed unusually low ALDH activity in the group of patients (n=16) with a relatively high level of these 2 parameters.The increase of ALDH1A1 and GST activity in DM seems to be associated with the severity of the disease and might be a compensatory effect against oxidative stress. Surprisingly low ALDH activity in DM patients with relatively high glucose and HbA1c levels can be a factor predisposing to the development of diabetic complications. PMID- 24464600 TI - CYP2C9*2 allele increases risk for hypoglycemia in POR*1/*1 type 2 diabetic patients treated with sulfonylureas. AB - It is previously shown that carriers of the defective allele CYP2C9*3 that leads to impaired sulfonylurea metabolism are at increased sulfonylurea-induced hypoglycemia risk due to diminished drug metabolism, whereas no effect of CYP2C9*2 allele was found. Recently, a polymorphism in P450 oxidoreductase (POR) gene, assigned as POR*28 allele, was associated with increased CYP2C9 activity. The aim of this study was to assess i) the effect of POR*28 allele on sulfonylurea-induced hypoglycemia risk and ii) the association of CYP2C9*2 allele with hypoglycemia risk in non-carriers of POR*28 allele. The study group consisted of 176 patients with diagnosed type 2 diabetes mellitus (T2DM) treated with sulfonylureas, of whom 92 patients had experienced at least one drug associated hypoglycemic event (cases), while 84 had never experienced a hypoglycemic event (controls). POR*28 allele was detected by use of real-time TaqMan PCR. POR*28 allele was not associated with sulfonyl-urea-induced hypoglycemia. In POR*1/*1 patients, CYP2C9*1/*2 genotype was more common in cases than in controls (32.7 vs. 14.3%, p=0.041). In a model adjusted for age, BMI, duration of T2DM and renal function, and POR*1/*1 entered as a selection variable, CYP2C9*2 allele increased the hypoglycemia risk in response to sulfonylurea (odds ratio: 3.218, p=0.031). In conclusion, our results suggest that POR*28 allele is masking the association of CYP2C9*2 allele with sulfonyl urea-induced hypoglycemia. Therefore, POR*28 allele is an important source of CYP2C9 activity variability and combined with CYP2C9 gene poly-morphisms may explain individual variability in the effect of sulfonylureas. PMID- 24464601 TI - Heavy metals bioconcentration from soil to vegetables and assessment of health risk caused by their ingestion. AB - The present study was undertaken to assess the non-carcinogenic human health risk of heavy metals through the ingestion of locally grown and commonly used vegetables viz. Raphanus sativus (root vegetable), Daucus carota (root vegetable), Benincasa hispida (fruit vegetable) and Brassica campestris leaves (leafy vegetable) in a semi-urbanized area of Haryana state, India. Heavy metal quantification of soil and vegetable samples was done using flame atomic absorption spectrophotometer. Lead, cadmium and nickel concentration in vegetable samples varied in range of 0.12-6.54 mg kg(-1), 0.02-0.67 mg kg(-1) and <0.05 0.41 mg kg(-1), respectively. Cadmium and lead concentration in some vegetable samples exceeded maximum permissible limit given by World Health Organization/Food and Agriculture Organization and Indian standards. Much higher concentrations of Pb (40-190.5 mg kg(-1)), Cd (0.56-9.85 mg kg(-1)) and Ni (3.21 45.87 mg kg(-1)) were reported in corresponding vegetable fields' soils. Correlation analysis revealed the formation of three primary clusters, i.e. Cu Cd, Cd-Pb and Ni-Zn in vegetable fields' soils further supported by cluster analysis and principal component analysis. Bioconcentration factor revealed that heavy metals' uptake was more by leafy vegetable than root and fruit vegetables. Hazard index of all the vegetables was less than unity; thus, the ingestion of these vegetables is unlikely to pose health risks to the target population. PMID- 24464602 TI - Lead, cadmium and zinc in hair samples: relationship with dietary habits and urban environment. AB - This study was performed in order to analyze the relationships between hair zinc, lead, and cadmium with the kind of diet consumed (by recall of the diet consumed the previous 14 days), living area (urban or rural), tobacco smoking, and body mass index (BMI) among 419 individuals of the Canary Archipelago. Median values and interquartile range were 43 MUg/g (18.50-132.50) for zinc, 4.09 MUg/g (2.19 8.38) for lead, and 0.128 MUg/g (0.05-0.30) for cadmium. We observed that hair zinc was markedly elevated among those consuming fish more frequently and, to a lesser amount, among those who consumed meat frequently, among those living in urban areas, and among those with BMI over 25 kg/m(2), keeping a significant relationship with BMI. Hair lead was also higher among fish consumers, showed a trend to higher values among inhabitants of urban areas, and was lower among obese individuals. Hair cadmium was higher among those who consumed less vegetables and fruits. By multivariate analysis, introducing the variables meat, fish, and vegetable consumption, urban/rural; sex; age; and BMI values, we observed that fish consumption (beta = 0.15) was the only variable independently associated to higher zinc levels; fish consumption (beta = 0.15) and meat consumption (beta = 0.17) were related to high cadmium levels, whereas meat consumption was significantly associated to higher hair lead levels (beta = 0.15). Therefore, we conclude that hair zinc, cadmium, and lead seem to depend more heavily on dietary habits than on tobacco consumption or living in rural or urban areas. PMID- 24464603 TI - Oxidative stress increased in pregnant women with iodine deficiency. AB - Iodine is an essential element trace for the synthesis of maternal thyroid hormones needed to support normal fetal development; it also acts as an antioxidant directly or induce antioxidant enzymes indirectly. Iodine deficiency and oxidative stress are associated with pregnancy complications. This study aimed to assess the urinary iodine concentration and its relationship with the antioxidant and oxidative stress status during gestation. Pregnant women were consecutively recruited from an obstetric clinic during all gestation trimesters, and urinary iodine concentration, antioxidant, and oxidative stress were determined. Results showed that 70 % of pregnant women have optimal iodine levels (150-200 MUg/L), while approximately 30 % showed mild iodine deficiency (50-99 MUg/L). Oxidative stress was significantly higher, and the antioxidant status was also compromised as evidenced by decreased total antioxidant status and superoxide dismutase (SOD) activity in pregnant women with mild iodine deficiency than pregnant women with optimal iodine levels. Significant positive correlations were noted between optimal iodine levels and total antioxidant status. Oxidative stress was significantly correlated with mild iodine deficiency. However, no significant correlation was found between iodine levels and SOD and catalase activities. In conclusion, for the first time, these data suggest a correlation between iodine levels and the antioxidant status during pregnancy. PMID- 24464606 TI - Neutrophil to lymphocyte ratio predicts perioperative mortality following open elective repair of abdominal aortic aneurysms. AB - OBJECTIVES: This study assesses the predictive value of neutrophil to lymphocyte ratio (NLR) in relation to 30-day and overall mortality following open abdominal aortic aneurysm (AAA) repairs. In addition, it assess assesses any correlation between NLR and age, size of the AAA and gender. METHODS: Patients undergoing elective or urgent open repair of their AAA by a single surgeon during a 10-year period were included. A pre-operative NLR of >5 was regarded as abnormal. RESULTS: 350 consecutive patients underwent AAA repair. 52 had an NLR>5. 30-day mortality rate was 12/52 (23%) in the NLR>5 group and 20/298 (6.7%) in the NLR<5 group (p = 0.0007). All deaths in the NLR>5 group were due to myocardial infarction. The median NLR was higher in those that died within 30 days at 4.2 [IQR: 2.6-7.5] versus 2.8 [IQR: 2.1-3.8] (p = 0.0001). Overall mortality at 10 years, in the NLR>5 group - 26/52 (50%) was significantly greater than that of the NLR<5 group - 102/298 (34.2%) (p = 0.043). Median NLR of those dying during follow-up was significantly higher in those with a baseline NLR>5 at 3.2 (IQR 2.5 4.6) versus 2.6 (IQR: 2.0-3.6) in those surviving (p = 0.00004). No difference was found between NLR and age, aneurysm size or gender. CONCLUSION: Pre-operative NLR>5 appears to be a significant predictor of both 30-day mortality and long term outcome in elective and urgent open AAA surgery. It is plausible the NLR is identifying a group with sub-clinical cardiovascular disease at risk of peri operative myocardial infarction. PMID- 24464604 TI - Arguments for the sake of endophenotypes: examining common misconceptions about the use of endophenotypes in psychiatric genetics. AB - Endophenotypes are measurable biomarkers that are correlated with an illness, at least in part, because of shared underlying genetic influences. Endophenotypes may improve our power to detect genes influencing risk of illness by being genetically simpler, closer to the level of gene action, and with larger genetic effect sizes or by providing added statistical power through their ability to quantitatively rank people within diagnostic categories. Furthermore, they also provide insight into the mechanisms underlying illness and will be valuable in developing biologically-based nosologies, through efforts such as RDoC, that seek to explain both the heterogeneity within current diagnostic categories and the overlapping clinical features between them. While neuroimaging, electrophysiological, and cognitive measures are currently most used in psychiatric genetic studies, researchers currently are attempting to identify candidate endophenotypes that are less genetically complex and potentially closer to the level of gene action, such as transcriptomic and proteomic phenotypes. Sifting through tens of thousands of such measures requires automated, high throughput ways of assessing, and ranking potential endophenotypes, such as the Endophenotype Ranking Value. However, despite the potential utility of endophenotypes for gene characterization and discovery, there is considerable resistance to endophenotypic approaches in psychiatry. In this review, we address and clarify some of the common issues associated with the usage of endophenotypes in the psychiatric genetics community. PMID- 24464605 TI - Reduced adiponectin signaling due to weight gain results in nonalcoholic steatohepatitis through impaired mitochondrial biogenesis. AB - Obesity and adiponectin depletion have been associated with the occurrence of nonalcoholic fatty liver disease (NAFLD). The goal of this study was to identify the relationship between weight gain, adiponectin signaling, and development of nonalcoholic steatohepatitis (NASH) in an obese, diabetic mouse model. Leptin receptor deficient (Lepr(db/db) ) and C57BL/6 mice were administered a diet high in unsaturated fat (HF) (61%) or normal chow for 5 or 10 weeks. Liver histology was evaluated using steatosis, inflammation, and ballooning scores. Serum, adipose tissue, and liver were analyzed for changes in metabolic parameters, messenger RNA (mRNA), and protein levels. Lepr(db/db) HF mice developed marked obesity, hepatic steatosis, and more than 50% progressed to NASH at each timepoint. Serum adiponectin level demonstrated a strong inverse relationship with body mass (r = -0.82; P < 0.0001) and adiponectin level was an independent predictor of NASH (13.6 MUg/mL; P < 0.05; area under the receiver operating curve (AUROC) = 0.84). White adipose tissue of NASH mice was characterized by increased expression of genes linked to oxidative stress, macrophage infiltration, reduced adiponectin, and impaired lipid metabolism. HF lepr (db/db) NASH mice exhibited diminished hepatic adiponectin signaling evidenced by reduced levels of adiponectin receptor-2, inactivation of adenosine monophosphate activated protein kinase (AMPK), and decreased expression of genes involved in mitochondrial biogenesis and beta-oxidation (Cox4, Nrf1, Pgc1alpha, Pgc1beta and Tfam). In contrast, recombinant adiponectin administration up-regulated the expression of mitochondrial genes in AML-12 hepatocytes, with or without lipid-loading. CONCLUSION: Lepr(db/db) mice fed a diet high in unsaturated fat develop weight gain and NASH through adiponectin depletion, which is associated with adipose tissue inflammation and hepatic mitochondrial dysfunction. We propose that this murine model of NASH may provide novel insights into the mechanism for development of human NASH. PMID- 24464607 TI - Synthesis and biological evaluation of novel N-alkyl tetra- and decahydroisoquinolines: novel antifungals that target ergosterol biosynthesis. AB - A series of N-alkyl trans-decahydroisoquinoline, 1,2,3,4-tetrahydroisoquinoline, and 6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline derivatives were synthesized starting from the respective secondary amines by N-alkylation with alkyl bromides. The compounds with C11-alkyl chains showed antifungal potency comparable to clotrimazole, and inhibit enzymes of the ergosterol biosynthesis (Delta14-reductase and Delta8,7-isomerase), depending on the heterocyclic scaffold and the investigated species. PMID- 24464608 TI - Heart failure association of the European society of cardiology specialist heart failure curriculum. AB - It is well established that organized care of heart failure patients, including specialist management by cardiologists, improves patient outcomes. In response to this, other national training bodies (the UK and the USA) have developed heart failure subspecialty curricula within their Cardiology Training Curricula. In addition, European Society of Cardiology (ESC) subspecialty curricula exist for Interventional Cardiology and Heart Rhythm Management. The purpose of this heart failure curriculum is to provide a framework which can be used as a blueprint for training across Europe. This blueprint mirrors other ESC curricula. Each section has three components: the knowledge required, the skills which are necessary, and the professionalism (attitudes and behaviours) which should be attained. The programme is designed to last 2 years. The first year is devoted to the specialist heart failure module. The second year allows completion of the optional modules of advanced imaging, device therapy for implanters, cardiac transplantation, and mechanical circulatory support. The second year can also be devoted to continuation of specialist heart failure training and/or research for those not wishing to continue with the advanced modules. PMID- 24464609 TI - Efficacy of 3D-positron emission tomography/computed tomography for upper abdomen. AB - Recent advancement in computed tomography (CT) enables us to obtain high spatial resolution image and made it possible to construct extensive high-definition three-dimensional (3D) images. But a lack of contrast resolution in CT alone is still remained problem. Meanwhile, as fluorodeoxyglucose-positron emission tomography (PET) can visualize tumors in high contrast, we can create 3D images fusing the accumulation in tumors on PET/CT images. Such images can play the role of a "map of body" which makes it easy to understand the anatomical information before surgery. We also try to evaluate segmental liver function by using PET/CT fusion images. By using (11) C-methionine PET/contrast-enhanced CT, superior image quality compared to single photon emission computed tomography/CT can be obtained. CT, especially with contrast enhancement for obtaining anatomical imaging information plus PET for obtaining functional imaging information is a highly compatible combination, and adding these two types information will further increase clinical usefulness. PMID- 24464610 TI - Comparison of success rates, learning curves, and inter-subject performance variability of robot-assisted and manual ultrasound-guided nerve block needle guidance in simulation. AB - BACKGROUND: This study focuses on a recently developed robotic nerve block system and its impact on learning regional anaesthesia skills. We compared success rates, learning curves, performance times, and inter-subject performance variability of robot-assisted vs manual ultrasound (US)-guided nerve block needle guidance. The hypothesis of this study is that robot assistance will result in faster skill acquisition than manual needle guidance. METHODS: Five co-authors with different experience with nerve blocks and the robotic system performed both manual and robot-assisted, US-guided nerve blocks on two different nerves of a nerve phantom. Ten trials were performed for each of the four procedures. Time taken to move from a shared starting position till the needle was inserted into the target nerve was defined as the performance time. A successful block was defined as the insertion of the needle into the target nerve. Average performance times were compared using analysis of variance. P<0.05 was considered significant. Data presented as mean (standard deviation). RESULTS: All blocks were successful. There were significant differences in performance times between co-authors to perform the manual blocks, either superficial (P=0.001) or profound (P=0.0001); no statistical difference between co-authors was noted for the robot assisted blocks. Linear regression indicated that the average decrease in time between consecutive trials for robot-assisted blocks of 1.8 (1.6) s was significantly (P=0.007) greater than the decrease for manual blocks of 0.3 (0.3) s. CONCLUSIONS: Robot assistance of nerve blocks allows for faster learning of needle guidance over manual positioning and reduces inter-subject performance variability. PMID- 24464611 TI - Intraoperative use of ketorolac or diclofenac is associated with improved disease free survival and overall survival in conservative breast cancer surgery. AB - BACKGROUND: An association between the use of non-steroidal anti-inflammatory drugs (NSAIDs) and better outcome after mastectomy and lung surgery for cancer has been recently suggested. In a retrospective analysis, we investigated the association between intraoperative NSAIDs use in conservative breast cancer surgery and breast cancer disease-free survival (DFS). Similarly, we also evaluated the association between breast cancer DFS and preoperative neutrophil:lymphocyte ratio (NLR). METHODS: A retrospective analysis of a single centre cohort was performed in breast cancer patients (n=720) with uni- and multivariate analyses, using a Cox regression model. RESULTS: In conservative breast cancer surgery, the intraoperative use of NSAIDs (ketorolac or diclofenac) was associated with an improved DFS {hazard ratio (HR)=0.57 [95% confidence interval (CI): 0.37-0.89], P=0.01} and an improved overall survival (OS) [HR=0.35 (95% CI: 0.17-0.70), P=0.03]. In these patients, an NLR >3.3 (identified by a receiver-operating characteristic curve) was associated with a shorter DFS [HR=1.99 (95% CI: 1.16-3.41), P=0.01] and OS [HR=2.35 (95% CI: 1.02-5.43), P=0.046]. CONCLUSIONS: Intraoperative NSAIDs and higher preoperative NLR are associated with improved outcome in conservative breast cancer surgery. Prospective, randomized trials to evaluate if these associations are causal are warranted. PMID- 24464612 TI - Postoperative visual loss due to complicated mediastinal dissection and haemorrhagic shock treatment during cardiac surgery. AB - We report the case of a patient who underwent third time revision of double heart valve replacement. Mediastinal dissection for right atrium cannulation was complicated by laceration of the superior vena cava; this required temporary rescue clamping of the vessel. The patient suffered complete visual loss related to bilateral retrobulbar haematoma. Acute elevation of superior vena cava pressure due to vascular clamping and administration of large amounts of fluid through the central venous jugular catheter could have caused the postoperative visual loss. PMID- 24464613 TI - Kernel-based learning from both qualitative and quantitative labels: application to prostate cancer diagnosis based on multiparametric MR imaging. AB - Building an accurate training database is challenging in supervised classification. For instance, in medical imaging, radiologists often delineate malignant and benign tissues without access to the histological ground truth, leading to uncertain data sets. This paper addresses the pattern classification problem arising when available target data include some uncertainty information. Target data considered here are both qualitative (a class label) or quantitative (an estimation of the posterior probability). In this context, usual discriminative methods, such as the support vector machine (SVM), fail either to learn a robust classifier or to predict accurate probability estimates. We generalize the regular SVM by introducing a new formulation of the learning problem to take into account class labels as well as class probability estimates. This original reformulation into a probabilistic SVM (P-SVM) can be efficiently solved by adapting existing flexible SVM solvers. Furthermore, this framework allows deriving a unique learned prediction function for both decision and posterior probability estimation providing qualitative and quantitative predictions. The method is first tested on synthetic data sets to evaluate its properties as compared with the classical SVM and fuzzy-SVM. It is then evaluated on a clinical data set of multiparametric prostate magnetic resonance images to assess its performances in discriminating benign from malignant tissues. P-SVM is shown to outperform classical SVM as well as the fuzzy-SVM in terms of probability predictions and classification performances, and demonstrates its potential for the design of an efficient computer-aided decision system for prostate cancer diagnosis based on multiparametric magnetic resonance (MR) imaging. PMID- 24464614 TI - Efficient circular thresholding. AB - Otsu's algorithm for thresholding images is widely used, and the computational complexity of determining the threshold from the histogram is O(N) where N is the number of histogram bins. When the algorithm is adapted to circular rather than linear histograms then two thresholds are required for binary thresholding. We show that, surprisingly, it is still possible to determine the optimal threshold in O(N) time. The efficient optimal algorithm is over 300 times faster than traditional approaches for typical histograms and is thus particularly suitable for real-time applications. We further demonstrate the usefulness of circular thresholding using the adapted Otsu criterion for various applications, including analysis of optical flow data, indoor/outdoor image classification, and non photorealistic rendering. In particular, by combining circular Otsu feature with other colour/texture features, a 96.9% correct rate is obtained for indoor/outdoor classification on the well known IITM-SCID2 data set, outperforming the state-of-the-art result by 4.3%. PMID- 24464615 TI - Crystal structure of a Schistosoma mansoni septin reveals the phenomenon of strand slippage in septins dependent on the nature of the bound nucleotide. AB - Septins are filament-forming GTP-binding proteins involved in important cellular events, such as cytokinesis, barrier formation, and membrane remodeling. Here, we present two crystal structures of the GTPase domain of a Schistosoma mansoni septin (SmSEPT10), one bound to GDP and the other to GTP. The structures have been solved at an unprecedented resolution for septins (1.93 and 2.1 A, respectively), which has allowed for unambiguous structural assignment of regions previously poorly defined. Consequently, we provide a reliable model for functional interpretation and a solid foundation for future structural studies. Upon comparing the two complexes, we observe for the first time the phenomenon of a strand slippage in septins. Such slippage generates a front-back communication mechanism between the G and NC interfaces. These data provide a novel mechanistic framework for the influence of nucleotide binding to the GTPase domain, opening new possibilities for the study of the dynamics of septin filaments. PMID- 24464616 TI - Shedding light on a pervasive problem: a review of research on bullying experiences among children with autism spectrum disorders. AB - Autism spectrum disorders (ASD) are characterized by difficulties with social interaction, verbal and nonverbal communication, and the development and maintenance of interpersonal relationships. As a result, individuals with ASD are at an increased risk of bullying victimization, compared to typically developing peers. This paper reviews the literature that has emerged over the past decade regarding prevalence of bullying involvement in the ASD population, as well as associated psychosocial factors. Directions for future research are suggested, including areas of research that are currently unexplored or underdeveloped. Methodological issues such as defining and measuring bullying, as well as informant validity and reliability, are considered. Implications for intervention are discussed. PMID- 24464617 TI - Erratum to: A Review of Technology-Based Interventions to Teach Academic Skills to Students with Autism Spectrum Disorder. PMID- 24464618 TI - Stability and aggregation of silver and titanium dioxide nanoparticles in seawater: role of salinity and dissolved organic carbon. AB - The behavior and fate of nanoparticles (NPs) in the marine environment are largely unknown and potentially have important environmental and human health implications. The aggregation and fate of NPs in the marine environment are greatly influenced by their interactions with seawater and dissolved organic carbon (DOC). In the present study, the stability and aggregation of 30-nm diameter silver nanoparticles (AgNPs) capped with citrate and polyvinylpyrrolidone (PVP; AgNP-citrate and AgNP-PVP) and 21-nm-diameter titanium dioxide (TiO(2)) NPs as affected by seawater salinity and DOC were investigated by measuring hydrodynamic diameters and zeta potentials. The added DOC (in humic acid form) stabilized the 3 types of NPs when the seawater salinities were <=5 parts per thousand (ppt), but the stabilizing effect of DOC was reduced by a higher salinity (e.g., 30 ppt). In addition, AgNP-PVP was more stable than AgNP citrate in seawater, indicating that surface capping agents and stabilization mechanisms govern the stability and aggregation of NPs. Statistical analysis showed that salinity is the most dominant influence on the stability and aggregation of AgNPs and TiO(2) NPs, followed by DOC. These findings expand our knowledge on the behavior of AgNPs and TiO2 NPs in seawater and indicate that the fate of these NPs will be primarily to aggregate in the water column, precipitate, and accumulate in sediments following release into the marine environment. PMID- 24464619 TI - Sex differences in cardiomyopathies. AB - Cardiomyopathies are a heterogeneous group of heart muscle diseases with a variety of specific phenotypes. According to the contemporary European Society of Cardiology classification, they are classified into hypertrophic (HCM), dilated (DCM), arrhythmogenic right ventricular (ARVC), restrictive (RCM), and unclassified cardiomyopathies. Each class is aetiologically further categorized into inherited (familial) and non-inherited (non-familial) forms. There is substantial evidence that biological sex is a strong modulator of the clinical manifestation of these cardiomyopathies, and sex-specific characteristics are detectable in all classes. For the clinician, it is important to know the sex specific aspects of clinical disease expression and the potential modes of inheritance or the hereditary influences underlying the development of cardiomyopathies, since these may aid in diagnosing such diseases in both sexes. PMID- 24464620 TI - Three-dimensional multidetector computed tomography may aid preoperative planning of the transmanubrial osteomuscular-sparing approach to completely resect superior sulcus tumor. AB - The anterior transcervical-thoracic approach clearly exposes the subclavian vessels and brachial plexus. We believe that this approach is optimal when a superior sulcus tumor (SST) invades the anterior part of the thoracic inlet. However, this approach is not yet widely applied because anatomical relationships in this procedure are difficult to visualize. Three-dimensional tomography can considerably improve preoperative planning, enhance the surgeon's skill and simplify the approach to complex surgical procedures. We applied preoperative 3 dimensional multidetector computed tomography to a case where an SST had invaded the anterior part of the thoracic inlet including the clavicle, sternoclavicular joint, first rib, subclavian vessels and brachial plexus. After the patient underwent induction chemotherapy, we performed the transmanubrial osteomuscular sparing approach and added a third anterolateral thoracotomy with a hemi clamshell incision and completely resected the tumor. PMID- 24464621 TI - Transformation of Brevibacillus, a soil microbe to an uropathogen with hemagglutination trait. AB - An urinary tract infection (UTI) with Brevibacillus agri, an aerobic soil bacteria is discussed. The preliminary urine analysis tested negative for UTI, while the patient was diagnosed with focal pyelonephritis. The urine sample was analyzed for the presence of possible micro-organisms. The isolated micro organism was phenotypically characterized and compared with a standard B. agri strain and an established uropathogen Eschericia coli, CFT073. Each experimental mouse was trans-urethrally infected using 2.5 * 10(8) c.f.u. for the generation of an UTI model. The kidney tissues were stored in buffered 10 % formaldehyde solution for histopathological analysis. The destruction of the glomerular and tubular morphology with prominent hemagglutination in the tubular region in the mouse kidneys were confirmed by light microscopic examination of the H&E stained sections. Hence, the identity of pathogen was confirmed using the 16S rRNA gene sequencing. The phylogenetic tree constructed using the 16S rRNA sequence obtained from the isolated microbial strain showed 99 % similarity with the strain, B. agri AB112716. Finally this study concludes based on the phenotypic characteristics, production of lipopolysaccharide, the ability to aggregate in the presence of ammonium sulphate, agglutinate erythrocytes in the presence of mannose, and the potential to resist the interactions of serum, the possibility that the soil microbe could have undergone genotypic modification to cause UTI. However, further detailed and in-depth genetic analysis are required to point out exactly how the soil bacterium has adapted itself to cause infection in a human subject. PMID- 24464622 TI - The dual effect of ultrasound-targeted microbubble destruction in mediating recombinant adeno-associated virus delivery in renal cell carcinoma: transfection enhancement and tumor inhibition. AB - BACKGROUND: Recombinant adeno-associated virus (rAAV) is recognized as a promising vector for cancer gene therapy, although its low transfer efficiency in less permissive cells limits extensive application. Our previous studies reported that ultrasound-targeted microbubble (MB) destruction (UTMD) enhanced rAAV transfer in its permissive retinal cells. In the present study, we investigated whether UTMD increased rAAV transfer in less permissive human renal cell carcinoma (hRCC) cells and tumors. METHODS: hRCC cells were treated with rAAV2 under different conditions of UTMD, and the viral transfer efficiency and cell viability were analyzed. Fifty-two male nude mice (BALB/c) implanted with hRCC cells were randomly assigned to four groups consisting of rAAV, rAAV + ultrasound and rAAV + UTMD (20 ul and 40 ul of MBs). UTMD was initiated immediately after intratumoral viral injection, and viral transfer efficiency and tumor volumes were analyzed at 12 weeks after infection. RESULTS: The efficiency of non augmented transfer of rAAV2 into hRCC cells was low (17.28 +/- 2.44%). The use of UTMD enhanced viral transfer efficiency by two- to three-fold, and enhanced viral genomic DNA by more than nine-fold, without decreasing cell viability. In vivo studies also showed that UTMD increased rAAV2 transfer in tumor. The enhancements were maintained for a period of 12 weeks. Tumor growth in mice was inhibited by UTMD treatment, and UTMD treatment augmented by MBs (40 ul) produced an even stronger effect. CONCLUSIONS: UTMD enhanced rAAV2 transfer into less permissive RCC cells and tumors, resulting in inhibition of tumor growth, which suggests that UTMD may be a useful delivery tool for cancer gene therapy. PMID- 24464623 TI - Tako-tsubo cardiomyopathy: how to understand possible pathophysiological mechanism and the role of (123)I-MIBG imaging. AB - Tako-tsubo cardiomyopathy (TCM) is an increasingly recognized clinical syndrome characterized by acute reversible apical ventricular dysfunction, commonly preceded by exposure to severe physical or emotional stress. In this review, we give a short overview on clinical presentation and treatment of TCM and discuss the possible pathophysiological mechanisms of TCM and the role of various non invasive imaging modalities in TCM with a focus on the potential role of (123)I meta-iodobenzylguanidine (MIBG) scintigraphy. Currently, the dominating hypothesis on the pathophysiology of TCM postulates that high levels of the neurotransmitter epinephrine may trigger a change in intracellular signaling in ventricular myocytes. More specific, epinephrine stimulates G-protein coupled beta2 adenoreceptors (beta2AR) which are located on ventricular myocytes. Normal levels of this neurotransmitter predominantly stimulate the intracellular G protein, and induce a positive inotropic effect. However, with significant increasing levels of epinephrine, the predominance of stimulation is shifted from G-stimulating to the G-inhibitor protein coupling, which leads to a negative inotropic effect. Interestingly, this negative inotropic effect is the largest in the apical myocardium where the beta2AR:beta1AR ratio is the highest within the heart. Echocardiography and ventriculography are essential to diagnose TCM, but new imaging tools are promising to diagnose TCM and to evaluate therapeutic efficacy. Cardiovascular magnetic resonance can be used to differentiate TCM from other myocardial diseases, such as myocarditis. (123)I-meta-iodobenzylguanidine ((123)I-MIBG) scintigraphy can be used to assess ventricular adrenergic activity and may guide optimization of individual (pharmacological) therapy. These new insights into the possible pathophysiological mechanisms and novel diagnostic imaging modalities can be used as starting point for the development of international guidelines of TCM which may increase the awareness, and optimize the treatment of TCM. PMID- 24464624 TI - Highest intraoperative lactate level could predict postoperative infectious complications after hepatectomy, reflecting the Pringle maneuver especially in chronic liver disease. AB - BACKGROUND: The Pringle maneuver is used to minimize blood loss during liver transection; however, it may cause reperfusion injury, which can cause increased intraoperative lactate levels and an immune compromised state. This may further lead to infectious complications. METHODS: Here, we divided 77 patients who underwent hepatectomy between December 2007 and August 2010 into two groups: the chronic hepatitis and liver cirrhosis (CH + LC) group and normal liver (NL) group. We investigated the effect of the highest intraoperative lactate level on occurrence of infectious complications after hepatectomy by assessing the correlations of the highest intraoperative lactate level with total Pringle time, operative factors, and various parameters in serum after surgery. Parameters showing significant correlations with postoperative complications of Clavien Dindo grade III or higher, with a wound or intra-abdominal infection, were analyzed by using interactive dot diagrams to determine cut-off values with the highest sensitivity and specificity. RESULTS: We noted that, to prevent postoperative infectious complications, the highest lactate level during liver resection should be maintained at <44.0 mg/dL in the NL group and <29.0 mg/dL in the CH + LC group. CONCLUSIONS: Minimizing the highest intraoperative lactate level may be important to prevent increase in postoperative infectious complications after hepatectomy, reflecting the Pringle maneuver especially in chronic liver disease. PMID- 24464625 TI - DNA methyltransferase 1/3a overexpression in sporadic breast cancer is associated with reduced expression of estrogen receptor-alpha/breast cancer susceptibility gene 1 and poor prognosis. AB - DNA methyltransferases (DNMTs), including DNMT1, 3a, and 3b, play an important role in the progression of many malignant tumors. However, it remains unclear whether expression of DNMTs is associated with the development of breast cancer. This study aimed to explore the clinical significance of DNMT proteins in sporadic breast cancer. We investigated the expression of DNMT1, 3a, and 3b in 256 breast cancer and 36 breast fibroadenoma, using immunohistochemistry. The expression of DNMT1 and 3a was significantly higher in breast cancer than in fibroadenoma. In breast cancer, the expression of DNMT1 was significantly correlated with lymph node metastasis (P = 0.020), and the expression of DNMT3a and 3b was significantly correlated with advanced clinical stages (P = 0.046 and 0.012, respectively). Overexpression of DNMT1/3a was correlated with promoter hypermethylation and reduced expression of ERalpha and BRCA1. The expression levels of DNMT1 or DNMT3a were associated with a significantly shorter DFS or OS in a subgroup of breast cancer patients (patients with the age <=50 years old, ERalpha-negative status, or HER2-postive status). The expression of DNMT1 or a combined expression of DNMT1 and 3a was associated with poor prognosis in patients who received chemotherapy and endocrine therapy, but not in patients who received chemotherapy alone. These findings suggest that DNMT1 and 3a may be involved in the progression and prognosis of sporadic breast cancer. PMID- 24464626 TI - The effect of thyroid function on clinical outcome in patients with heart failure. AB - AIMS: Thyroid dysfunction is known to effect cardiac function and is a risk factor for developing heart failure (HF). Data regarding the clinical significance of thyroid-stimulating hormone (TSH) levels alone as a predictor of outcome in patients with HF is sparse. We evaluated the significance of TSH on clinical outcome in a large cohort of patients with chronic HF. METHODS AND RESULTS: Patients with a diagnosis of HF at a Health Maintenance Organization (n = 5599) were followed for cardiac-related hospitalizations and death. Median TSH levels were 2.2 mIU/L (interquartile range 1.4-3.5). We divided patients into quartiles based on TSH levels. Median follow-up time was 434 days and the overall mortality rate was 13.2%. Both a high and a low TSH level was associated with an increased mortality rate. Cox regression analysis after adjustment for other significant predictors demonstrated that the highest TSH quartile was associated with increased mortality compared with those with the lowest mortality [second quartile: TSH 1.4-2.2 mIU/L, hazard ratio (HR) 1.36, 95% confidence interval (CI) 1.08-1.71, P = 0.01]. TSH was also an independent predictor of death and cardiac related hospitalization. Analysis of patients not on levothyroxine treatment (78%) demonstrated that TSH was an even stronger predictor of mortality (HR 1.54, 95% CI 1.17-2.03, P = 0.002). Additional analysis based on accepted clinical cut offs of TSH demonstrated that increasing TSH levels above normal were independently associated with increased mortality and cardiac-related hospitalizations. CONCLUSIONS: Increased TSH levels are associated with worse clinical outcome in patients with HF. Thyroid imbalance confers significant risk in HF and warrants attention. PMID- 24464627 TI - The role of NQO1 polymorphisms in the susceptibility and chemotherapy response of Chinese NSCLC patients. AB - To investigate whether the NAD(P)H: quinone oxidoreductase 1 (NQO1) gene polymorphisms determine the Platinum-based chemotherapy in advanced non-small cell lung cancer (NSCLC) in a Chinese cohort. A total of 391 patients with inoperable advanced stage of NSCLC, namely, stage III (A + B) and IV NSCLC, and 663 age-and sex-matched healthy were enrolled. The effects of chemotherapy were evaluated. NQO1 C609T polymorphism was determined. The NSCLC patients had a significantly higher prevalence of TT than control subjects (33.76 vs. 21.67 %, P < 0.001). For allele comparison, NSCLC subjects had lower T allele frequency than controls as well (55.63 vs. 44.42 %, P < 0.001). multivariate regression analyses showed the TT carriage had a significantly increased risk for development of NSCLC after adjustments with age, sex, smoke, and cancer family history (OR 1.681, 95 % CI 1.242-2.274, P = 0.001). The TT genotype distribution was significantly higher in non-responders than in responders (31.85 vs. 21.96 %, P = 0.003). Logistic regression analysis showed TT genotype carriers had less chance to gain chemotherapy response compared to CC genotype carriers (OR 0.399, P = 0.003) after adjustment with sex, age, tumor histology, disease stage, and chemotherapy regimens. The NQO1 C609T polymorphism is an important molecular marker for advanced NSCLC, since it is associated with the NSCLC risk as well as the response status of platinum-based chemotherapy. PMID- 24464628 TI - Effect of NeuroD gene silencing on the migration and invasion of human pancreatic cancer cells PANC-1. AB - The aim of this study is to investigate the influence of Lenti-EGFP-NeuroD-miR, RNAi lentiviral expression vector, on the expression level of NeuroD and migration, and invasion of PANC-1 cell line. PANC-1 cells were cultured and cotransfected with Lenti-EGFP-NeuroD-miR and Lenti-GFP. The infection rate of lentivirus was determined by fluorescence. The interfering effection by the expression of NeuroD mRNA in PANC-1 cells was analyzed by real-time PCR after transfected. Biological behavior of PANC-1 cells transinfected was observed, and the migration and invasion were studied by transwell assay. Intrapancreatic allografts model in nude mice was established to observe the effects of NeuroD on tumorigenesis, tumor growth, and invasion in vivo. The expression of NeuroD mRNA decreased significantly after RNAi lentivirus transinfecting PANC-1 cell. The cell's migration and invasion ability decreased obviously as soon as down regulate of NeuroD in PANC-1 cells. Comparing with control group, the tumors were smaller in size and the invasiveness was inhibited after 8 weeks intrapancreatic allografts in nude mice. Lenti-EGFP-NeuroD-miR transfected into PANC-1 cells shows a stable, effective, and especial blocking expression of NeuroD in mRNA level. The RNAi of lentiviral vector target NeuroD can reduce the migration and invasion abilities of PANC-1 cells. PMID- 24464629 TI - Heme induces IL-1beta secretion through activating NLRP3 in kidney inflammation. AB - To produce proinflammatory master cytokine IL-1beta in macrophages, two stimulation pathways are needed including TLRs-NF-kappaB axis and NLRPs/ASC caspase-1 axis. Different signals including exogenous and endogenous trigger inflammatory response distinctly. Among them, the role of endogenous stimulators of inflammation is poorly understood. As a component of hemoglobin, free heme is released when hemolysis or extensive cell damage occur which results in inflammatory response. Here, we find that heme induces IL-1beta secretion through activating NLRP3 inflammasome in macrophages. Heme activates NLRP3 through P2X receptors, especially the P2X7R and P2X4R. Most importantly, significantly enhancement of heme level and activation of NLRPs/ASC-caspase-1 axis were observed in mice kidney after unilateral ureteral obstruction which could be inhibited by enforced expression of heme oxygenase-1 (HO-1). Our study proves that heme is a potential danger activator of NLRP3 inflammasome that plays an essential role in IL-1beta secretion during kidney inflammation and provides new insight into the mechanism of innate immune initiation. Further investigation will be beneficial to develop new molecular target and molecular diagnosis indicator in therapy of kidney inflammation. PMID- 24464630 TI - Flow cytometry applications for the analysis of chemokine receptor expression and function. AB - Chemokine receptors play an important role in leukocyte migration, both in physiological and pathological conditions, and the interest in new methodologies for their detection is increasing. In this review, we focused on chemokine receptors detection through flow cytometric approaches, including the use of specific antibodies and fluorescent chemokines, and on approaches aimed at the analysis of their functions, from intracellular trafficking to signaling activities. PMID- 24464631 TI - How does coffee prevent liver fibrosis? Biological plausibility for recent epidemiological observations. PMID- 24464632 TI - Antiretroviral pharmacokinetics in mothers and breastfeeding infants from 6 to 24 weeks post-partum: results of the BAN Study. AB - BACKGROUND: An intensive, prospective, open-label pharmacokinetic (PK) study in a subset of HIV-infected mothers and their uninfected infants enrolled in the Breastfeeding, Antiretroviral and Nutrition (BAN) Study was performed to describe drug exposure and antiviral response. METHODS: Women using Combivir((r)) (zidovudine [ZDV] + lamivudine [3TC]) +Aluvia((r)) (lopinavir/ritonavir [LPV/RTV]) were enrolled. Breast milk (BM), mother plasma (MP) and infant plasma (IP) samples were obtained over 6 h after observed dosing at 6, 12 or 24 weeks post-partum for drug concentrations and HIV RNA. RESULTS: A total of 30 mother/infant pairs (10 each at 6, 12 and 24 weeks post-partum) were enrolled. Relative to MP, BM concentrations of ZDV and 3TC were 35% and 21% higher, respectively, whereas LPV and RTV were 80% lower. Only 3TC was detected in IP with concentrations 96% and 98% lower than MP and BM, respectively. Concentrations in all matrices were similar at 6-24 weeks. The majority (98.3%) of BM concentrations were >HIV(wt) IC50, with one having detectable virus. There was no association between PK parameters and MP or BM HIV RNA. CONCLUSIONS: ZDV and 3TC concentrated in BM whereas LPV and RTV did not, possibly due to protein binding and drug transporter affinity. Undetectable to low antiretroviral concentrations in IP suggest prevention of transmission while breastfeeding may be due to antiretroviral effects on systemic or BM HIV RNA in the mother. Low IP 3TC exposure may predispose an infected infant to HIV resistance, necessitating testing and treating infants early. PMID- 24464633 TI - LIF/STAT3/SOCS3 signaling pathway in murine bone marrow stromal cells suppresses osteoblast differentiation. AB - Leukemia inhibitory factor (LIF) is a pleiotropic cytokine that belongs to the interleukin-6 family and is expressed by multiple tissue types. This study analyzed the effect of LIF on osteoblast differentiation using primary murine bone marrow stromal cells (BMSCs). Colony-forming unit-osteoblast formation by BMSCs was significantly suppressed by LIF treatment. To clarify the mechanism underlying the LIF suppressive effect on osteoblast differentiation, we analyzed the downstream signaling pathway of LIF. LIF/signal transducer and activator of transcription 3 (STAT3) signaling induces the expression of suppressor of cytokine signaling 3 (SOCS3). SOCS3 knockdown experiments have previously demonstrated that short-hairpin SOCS3-BMSCs reversed the LIF suppressive effect. Our results demonstrated that LIF suppresses osteoblast differentiation through the LIF/STAT3/SOCS3 signaling pathway. PMID- 24464634 TI - Cardioprotective role of P38 MAPK during myocardial infarction via parallel activation of alpha-crystallin B and Nrf2. AB - Myocardial infarction (MI) is defined as cardiac cell death due to prolonged ischemia. Although necrotic cell death was considered to be solely responsible for myocyte death during MI, it was recently revealed that apoptosis also plays its part in this death process. Our laboratory has recently shown that endoplasmic reticulum (ER) stress-induced apoptosis is the predominant route for apoptosis during MI and the conventional mitochondrial pathway is bypassed by activation of a small heat shock protein alpha-crystallin B (CRYAB). Since CRYAB is a direct target of P38 mitogen-activated protein kinase (MAPK) cascade, we were prompted to check the role of P38 MAPK in 20-week-old male Wister rats immediately after infarct formation. Interestingly, parallel activation of mitochondrial apoptotic pathway with an increase in ER stress-induced apoptotic load was observed along with decreased activation of CRYAB and Nrf2 (a pro survival protein activated in response to ER stress) in MI rats treated with SB203580, a specific inhibitor of P38alpha and P38beta compared to the MI alone. As a cumulative effect, this inhibitor treatment also resulted in significant increase in the levels of caspase3 activity and TUNEL positivity, the end point apoptotic markers. Furthermore, SB203580-treated hypoxic adult cardiomyocytes showed formation of desmin aggregates which were previously associated with impaired cardiac function. Thus, this study shows for the first time the precise mechanism by which P38 MAPK plays a pro-survival role and confers protection of cardiomyocytes, during infarct formation. PMID- 24464635 TI - Changes in the microvascular structure of mucosal squamous cell carcinoma of the esophagus and their significance in tumor progression. AB - BACKGROUND: To identify the clinical T stage by endoscopy is a major diagnostic goal for superficial esophageal squamous cell carcinoma (ESCC). The completion of a microvascular morphological study of mucosal lesions is necessary to optimize therapy. MATERIALS AND METHODS: Images of 197 intra-papillary capillary loops (IPCLs) captured by magnified endoscopy from 15 esophagectomy specimens were studied for their morphological features and IPCL dimensions. RESULTS: The microvascular morphology was classified into four basic major patterns: 1. spiral loop, 2. wide loop (WL), 3. globular (G) and 4. reticular pattern. The microvascular features and dimensions differed according to the depth of tumor invasion. Especially the mean bundle outline (IPCL diameter) showed significant changes as 20.02, 22.32, and 27.08 MUm, respectively, for M1, M2 and M3, respectively (M1:M2 P < 0.05, M2:M3 P < 0.01). CONCLUSIONS: During tumor stage progression, a high-volume blood demand and cancer cell overgrowth to occupy the laminar propria mucosa (LPM) cause obvious elongation, thickening, branching, irregularity and deformity of the IPCL, which were characteristics of M3 lesions. The results of the present study support and can be applied with the current Japanese classification for improving the diagnostic accuracy, especially to differentiate between M2 and M3 lesions based on the endoscopic findings. PMID- 24464636 TI - Effectiveness of setting numerical targets in the surgical training of residents: a trial to achieve an optimal balance. AB - During the past 10 years, residency training in otorhinolaryngology-head and neck surgery (ORL-HNS) in Japan, especially at university hospitals, has emphasized subspecialization, resulting in insufficiencies in basic surgical techniques with an extreme bias toward acquiring subspecialty surgical case experience. To address this problem, we developed a target-oriented program intended to achieve a more balanced approach to surgical training and performed a 1-year trial of the program at the Jikei University School of Medicine. Fourteen residents with 1 to 4 years of ORL-HNS experience completed the trial. Each resident's competencies in six basic surgical procedures were assessed on the basis of the number of cases handled by the resident, and each resident's case selection bias after implementation of the target-oriented training was examined. The case selection bias in the trial group residents was reduced and their balance in case experience was shown to be improved in comparison with that in control group residents who were trained in the conventional way. In addition, opinion surveys of the participants and supervising otorhinolaryngologists (trainers) indicated that they felt that the new training system had been effective in improving the balance in case experience and improving motivation, and creating greater awareness of training goals and progress. PMID- 24464637 TI - An attentional-adaptation account of spatial negative priming: evidence from event-related potentials. AB - Negative priming (NP) refers to a slower response to a target stimulus if it has been previously ignored. To examine theoretical accounts of spatial NP, we recorded behavioral measures and event-related potentials (ERPs) in a target localization task. A target and distractor briefly appeared, and the participant pressed a key corresponding to the target's location. The probability of the distractor appearing in each of four locations varied, whereas the target appeared with equal probabilities in all locations. We found that response times (RTs) were fastest when the prime distractor appeared in its most probable (frequent) location and when the prime target appeared in the location that never contained a distractor. Moreover, NP effects varied as a function of location: They were smallest when targets followed distractors in the frequent distractor location-a finding not predicted by episodic-retrieval or suppression accounts of NP. The ERP results showed that the P2, an ERP component associated with attentional orientation, was smaller in prime displays when the distractor appeared in its frequent location. Moreover, no differences were apparent between negative-prime and control trials in the N2, which is associated with suppression processes, nor in the P3, which is associated with episodic retrieval processes. These results indicate that the spatial NP effect is caused by both short- and long-term adaptation in preferences based on the history of inspecting unsuccessful locations. This article is dedicated to the memory of Edward E. Smith, and we indicate how this study was inspired by his research career. PMID- 24464638 TI - Regional gray matter volume is associated with rejection sensitivity: a voxel based morphometry study. AB - Rejection sensitivity (RS) can be defined as the disposition that one tends to anxiously expect, readily perceive, and intensely react to rejection. High-RS individuals are more likely to suffer mental disorders. Previous studies have investigated brain activity during social rejection using different kinds of rejection paradigms and have provided neural evidence of individual differences in response to rejection cues, but the association between individual differences in RS and brain structure has never been investigated. In this study, voxel-based morphometry (VBM) was used to investigate the relationship between gray matter volume (GMV) and RS in a large healthy sample of 150 men and 188 women. The participants completed the RS Questionnaire and underwent an anatomical magnetic resonance imaging scan. Multiple regression was used to analyze the correlation between regional GMV and RS scores, adjusting for age, sex, and total brain GMV. These results showed that GMV in the region of the posterior cingulate cortex/precuneus was negatively associated with RS, and GMV in the region of the inferior temporal gyrus was positively correlated with RS. These findings suggest a relationship between individual differences in RS and GMV in brain regions that are primarily related to social cognition. PMID- 24464639 TI - Function and friction at work: a multidimensional analysis of work outcomes in cancer survivors. AB - OBJECTIVES: Cancer survivors can experience difficulties returning to and/or remaining at work. Sociodemographic, health and well-being, symptom burden, functional limitations in relation to work demands, work environment, and various work policies and procedures can be related to work function. METHODS: This study analyzed cross-sectional data of a sample of cancer survivors (n = 1,525) who were diagnosed and treated for various types of cancer. The data were obtained from a survey of cancer survivors collected by the LiveStrong Foundation. Using a cancer survivorship and work model proposed in 2010, this study used structural equation modeling to predict work ability (whether survivors reported lower work ability following cancer) and work sustainability (whether survivors had ever lost or left a job because of cancer, i.e., work retention). Potential predictors included health and well-being, symptom burden (e.g., fatigue, pain, and distress), cancer-related worry, worry about family's cancer risk, functional impairment (i.e., physical, cognitive, and interpersonal), workplace support, and workplace problems. RESULTS: The overall model predicting work ability (CFI = 0.961, TLI = 0.952, and RMSEA = 0.027) indicated that a greater level of functional limitations (B = 5.88, p < 0.01) and workplace problems (B = 0.22, p = 0.05) were significantly related to lower levels of work ability. Structural equation modeling (CFI = 0.961, TLI = 0.952, and RMSEA = 0.027) also indicated that workplace problems was a significant predictor (B = 0.498, p < 0.001) of the likelihood of losing or leaving a job because of cancer. CONCLUSIONS: Functional limitations and problems at work including poor treatment, discrimination, being passed over for promotion, and lack of accommodations were directly related to the ability to work. Problems at work were associated with lower work sustainability (work retention). IMPLICATIONS FOR CANCER SURVIVORS: Employed cancer survivors, health care providers, and employers need to be aware of the potential implications of limitations in function (e.g., physical, cognitive, and interpersonal/social) as it relates to ability to work. In many cases, these functional limitations are responsive to rehabilitation. Workplaces also need to be educated on how to better respond to the needs of cancer survivors at work. PMID- 24464640 TI - Long-term prognostic impact of therapeutic strategies in patients with idiopathic dilated cardiomyopathy: changing mortality over the last 30 years. AB - AIMS: ACE-inhibitors, beta-blockers, implantable cardioverter-defibrillator (ICD) and cardiac resynchronization therapy (CRT) improved prognosis of heart failure. We sought to analyse the long-term prognostic impact of evidence-based integrated therapeutic strategies in patients with idiopathic dilated cardiomyopathy (IDCM). METHODS AND RESULTS: From 1978 to 2007, 853 IDCM patients (45 +/- 15 years, 72% males) were enrolled and classified as follows: Group 1, 110 patients (12.8%) enrolled during 1978-1987; Group 2, 376 patients (44.1%) enrolled during 1988 1997; Group 3, 367 patients (43.1%) enrolled during 1998-2007. ACE inhibitors/angiotensin receptor blockers were administered in 34%, 93%, and 93% (P <0.001), and beta-blockers in 11%, 82%, and 86% (P <0.001) in Groups 1, 2, and 3, respectively; ICDs were implanted in 2%, 14%, and 13% (P = 0.005); mean time to device implantation was lower in Group 3. At 8 years, heart transplant (HTx) free survival rates were 55%, 71%, and 87% in Groups 1, 2, and 3, respectively (P <0.001). Similar progressive improvement was found for pump-failure death (DHF)/HTx, while survival free from sudden death (SD) was significantly improved only in Group 3. Multivariable models considering competing risk indicated early diagnosis (i.e. a baseline less advanced disease stage) and tailored medical therapy (HR 0.44, CI 95% 0.19-0.98) as independent protectors against DHF/HTx. Concerning SD, lower left ventricular ejection fraction emerged as a predictor, while ICD was the only therapy with a protective role (HR 0.08, CI 95% 0.01 0.61). Treatment with digitalis emerged as a predictor of both DHF/HTx and SD. CONCLUSIONS: An effective management and evidence-based integrated therapeutic approach progressively and significantly improved the long-term prognosis of IDCM during the last three decades. PMID- 24464641 TI - Coronary artery-bronchial artery fistulas: report of two Dutch cases with a review of the literature. AB - BACKGROUND: Coronary bronchial artery fistulas (CBFs) are rare anomalies, which may be isolated or associated with other disorders. MATERIALS AND METHODS: Two adult patients with CBFs are described and a PubMed search was performed using the keywords "coronary bronchial artery fistulas" in the period from 2008 to 2013. RESULTS: Twenty-seven reviewed subjects resulting in a total of 31 fistulas were collected. Asymptomatic presentation was reported in 5 subjects (19 %), chest pain (n = 17) was frequently present followed by haemoptysis (n = 7) and dyspnoea (n = 5). Concomitant disorders were bronchiectasis (44 %), diabetes (33 %) and hypertension (28 %). Multimodality and single-modality diagnostic strategies were applied in 56 % and 44 %, respectively. The origin of the CBFs was the left circumflex artery in 61 %, the right coronary artery in 36 % and the left anterior descending artery in 3 %. Management was conservative (22 %), surgical ligation (11 %), percutaneous transcatheter embolisation (30 %), awaiting lung transplantation (7 %) or not reported (30 %). CONCLUSIONS: CBFs may remain clinically silent, or present with chest pain or haemoptysis. CBFs are commonly associated with bronchiectasis and usually require a multimodality approach to be diagnosed. Several treatment strategies are available. This report presents two adult cases with CBFs and a review of the literature. PMID- 24464642 TI - Coronary artery disease and cancer mortality in a cohort of workers exposed to vinyl chloride, carbon disulfide, rotating shift work, and o-toluidine at a chemical manufacturing plant. AB - BACKGROUND: We updated through 2007 the mortality experience of 1,874 workers employed at a New York State chemical manufacturing plant between 1946 and 2006. METHODS: Reassessed exposures to vinyl chloride, carbon disulfide, and shift work and categories of o-toluidine exposure were based on year, department and job title. Standardized mortality ratios (SMR) compared mortality to that of the US population. Internal comparisons used directly standardized rate ratios. RESULTS: Hepatobiliary cancer mortality was elevated among workers ever exposed to vinyl chloride (SMR = 3.80, 95% confidence interval 1.89-6.80); directly standardized rates increased with increasing vinyl chloride exposure duration. No increase in non-Hodgkin lymphoma mortality was observed with vinyl chloride and shift work exposures. Internal comparisons showed increased coronary artery disease mortality among long-term workers exposed to carbon disulfide and shift work for 4 years or more. CONCLUSIONS: Excess coronary artery disease mortality confirms earlier results; further investigation is needed to understand risk factors. PMID- 24464643 TI - NTPDase3 and ecto-5'-nucleotidase/CD73 are differentially expressed during mouse bladder cancer progression. AB - According to the World Health Organization, bladder cancer is the seventh most common cancer among men in the world. The current treatments for this malignancy are not efficient to prevent the recurrence and progression of tumors. Then, researches continue looking for better therapeutic targets which can end up in new and more efficient treatments. One of the recent findings was the identification that the purinergic system was involved in bladder tumorigenesis. The ectonucleotidases, mainly ecto-5'-nucleotidase/CD73 have been revealed as new players in cancer progression and malignity. In this work, we investigated the NTPDase3 and ecto-5'-nucleotidase/CD73 expression in cancer progression in vivo. Bladder tumor was induced in mice by the addition of 0.05 % of N-butyl-N (hydroxybutyl)-nitrosamine (BBN) in the drinking water for 4, 8, 12, 18, and 24 weeks. After this period, mice bladders were removed for histopathology analysis and immunofluorescence assays. The bladder of animals which has received BBN had alterations, mainly inflammation, in initial times of tumor induction. After 18 weeks, mice's bladder has developed histological alterations similar to human transitional cell carcinoma. The cancerous urothelium, from mice that received BBN for 18 and 24 weeks, presented a weak immunostaining to NTPDase3, in contrast to an increased expression of ecto-5'-nucleotidase/CD73. The altered expression of NTPDase3 and ecto-5'-nucleotidase/CD73 presented herein adds further evidence to support the idea that alterations in ectonucleotidases are involved in bladder tumorigenesis and reinforce the ecto-5'-nucleotidase/CD73 as a future biomarker and/or a target for pharmacological therapy of bladder cancer. PMID- 24464645 TI - Heart failure highlights in 2012-2013. AB - Heart failure has become the cardiovascular epidemic of the century. The European Journal of Heart Failure is dedicated to the advancement of knowledge in the field of heart failure management. In 2012 and 2013, several pioneering scientific discoveries and paradigm-shifting clinical trials have been published. In the current paper, we will discuss the most significant novel insights into the pathophysiology, diagnosis, and treatment of heart failure that were published during this period. All relevant research areas are discussed, including pathophysiology, co-morbidities, arrhythmias, biomarkers, clinical trials, and device therapy, including left ventricular assist devices. PMID- 24464644 TI - A yeast screening method to decipher the interaction between the adenosine A2B receptor and the C-terminus of different G protein alpha-subunits. AB - The expression of human G protein-coupled receptors (GPCRs) in Saccharomyces cerevisiae containing chimeric yeast/mammalian Galpha subunits provides a useful tool for the study of GPCR activation. In this study, we used a one-GPCR-one-G protein yeast screening method in combination with molecular modeling and mutagenesis studies to decipher the interaction between GPCRs and the C-terminus of different alpha-subunits of G proteins. We chose the human adenosine A2B receptor (hA2BR) as a paradigm, a typical class A GPCR that shows promiscuous behavior in G protein coupling in this yeast system. The wild-type hA2BR and five mutant receptors were expressed in 8 yeast strains with different humanized G proteins, covering the four major classes: Galphai, Galphas, Galphaq, and Galpha12. Our experiments showed that a tyrosine residue (Y) at the C-terminus of the Galpha subunit plays an important role in controlling the activation of GPCRs. Receptor residues R103(3.50) and I107(3.54) are vital too in G protein coupling and the activation of the hA2BR, whereas L213(IL3) is more important in G protein inactivation. Substitution of S235(6.36) to alanine provided the most divergent G protein-coupling profile. Finally, L236(6.37) substitution decreased receptor activation in all G protein pathways, although to a different extent. In conclusion, our findings shed light on the selectivity of receptor/G protein coupling, which may help in further understanding GPCR signaling. PMID- 24464646 TI - The 55 kDa tissue transglutaminase cross-linking active isoform TG induces cell death. AB - Transamidations are calcium-dependent reactions catalyzed by transglutaminase enzymes. Tissue transglutaminase (TG2 or TGC) is a multifunctional protein with a controversial role in apoptosis. The cross-linking function of transglutaminase enzymes has been shown to play a role in cell death. Human breast cancer cell lines (MCF7 and T47D), which express low endogenous levels of transglutaminase, were transiently transfected with the cross-linking 55 kDa active TG isoform or its precursor the 80 kDa full-length TGC. The increased frequency of apoptosis correlated with the increase in transglutaminase expression and the highest rates of apoptosis were found in cells transfected with the potent TG isoform as compared to the full length TGC. The calcium ionophores A231827 and maitotoxin, which are known to induce transamidation, were found to promote apoptosis, whereas cystamine, an active transglutaminase inhibitor, blocked apoptosis due to the over-expression of the active TG isoform. This is the first time that TG has been used in cellular transfections and the results presented show that TG is a potent inducer of cell death. This finding may help to clarify the conflicting functions of TG in the induction of cell death. The TG-dependent irreversible cross-linking of intracellular proteins, a function previously assigned to TGC, represents an important biochemical event in the induction of the structural changes present in cells during apoptosis. PMID- 24464647 TI - Concomitant evaluation of PMA+ionomycin-induced kinase phosphorylation and cytokine production in T cell subsets by flow cytometry. AB - Methods to detect intracellular kinase signaling intermediates by flow cytometry have been recently developed. Termed "phospho-flow," these methods employ fluorescence-conjugated monoclonal antibodies that recognize phosphorylated epitopes of intracellular kinases, and may be combined with surface phenotypic markers to observe changes in kinase pathways by cellular subset. Effector functions, like cytokine production, are processes intrinsically linked to intracellular signaling and kinase activity within each cell. Methodologies that would simultaneously detect changes to signaling pathways as well as effector responses at the single-cell level would allow for mapping of the functional consequences induced by signaling pathway modifications. However, there are challenges to developing such a combined protocol, relating to the different kinetics of rapid signaling events and the more prolonged time required to induce and observe cytokine responses. In this report, we describe the development of an assay that accommodates differences in protocol conditions and response kinetics, merging phospho-flow cytometry, and intracellular cytokine staining methods into a single experimental protocol. We examined intracellular ERK1/2 phosphorylation and IFN-gamma production by CD4+ and CD8+ T cells upon polyclonal stimulation with PMA and ionomycin, while monitoring expression of the cytolytic molecule perforin and the T cell activation marker CD38. We present a method that allows observation of kinase phosphorylation and cytokine production within the same cell after stimuli, while maintaining a stable cellular phenotype. Monitoring of signaling and effector functions in distinct immune subsets provides a platform to investigate and relate intracellular kinase signaling activity to immune cell effector function and phenotype in disease states. PMID- 24464648 TI - Primary sleep disorder prevalence in patients with newly diagnosed Parkinson's disease. AB - BACKGROUND: Sleep disturbance occurs in up to 96% of patients with established Parkinson's disease (PD). We aimed to assess the prevalence of sleep disturbance in newly diagnosed PD. METHODS: Newly diagnosed PD patients and controls were recruited. Patients had motor, non-motor, and sleep assessments, including sleep questionnaires, respiratory home monitoring, actigraphy, and sleep diaries. Controls completed cognitive assessments, sleep questionnaires, and diaries. RESULTS: A total of 106 patients and 99 controls participated. Sleep questionnaire scores were no different between patients and controls. Daytime naps were increased in PD patients on sleep diaries (P > 0.003). Sleepiness was not associated with any motor or non-motor symptom. Periodic limb movements were increased but not associated with restless legs. CONCLUSIONS: Newly diagnosed PD patients had minimal differences in subjective or objective sleep disturbance compared to controls apart from increased daytime naps and symptoms such as dream enacting behaviors of punching or grabbing. This contrasts with the literature assessing sleep in those with established PD. PMID- 24464649 TI - Statistical analysis of histopathological endpoints. AB - Histopathological assessments of fish from aquatic ecotoxicology studies are being performed with increasing frequency. Aquatic ecotoxicology studies performed for submission to regulatory agencies are usually conducted with multiple subjects (e.g., fish) in each of multiple vessels (replicates) within a water control and within each of several concentrations of a test substance. A number of histopathological endpoints are evaluated in each fish, and a severity score is generally recorded for each endpoint. The severity scores are often recorded using a nonquantitative scale of 0 to 4, with 0 indicating no effect, 1 indicating minimal effect, through 4 for severe effect. Statistical methods often used to analyze these scores suffer from several shortcomings: computing average scores as though scores were quantitative values, considering only the frequency of abnormality while ignoring severity, ignoring any concentration-response trend, and ignoring the possible correlation between responses of individuals within test vessels. A new test, the Rao-Scott Cochran-Armitage by Slices (RSCABS), is proposed that incorporates the replicate vessel experimental design and the biological expectation that the severity of the effect tends to increase with increasing doses or concentrations, while retaining the individual subject scores and taking into account the severity as well as frequency of scores. A power simulation and examples demonstrate the performance of the test. R-based software has been developed to carry out this test and is available free of charge at www.epa.gov/med/Prods_Pubs/rscabs.htm. The SAS-based RSCABS software is available from the first and third authors. PMID- 24464650 TI - Wnt5a suppresses colon cancer by inhibiting cell proliferation and epithelial mesenchymal transition. AB - Colon cancer remains one of the lethal malignancies in the world. Aberrant activation of canonical Wnt/beta-catenin signaling pathway has been observed in colon cancer. In contrast, the non-canonical Wnt signaling functions remain obscure. Wnt5a is a representative non-canonical Wnt ligand which has gained extensive attention nowadays. Wnt5a has been shown to play an important role in EMT in prostate cancer and melanoma, but its role in colon cancer is still ambiguous. Here we have evaluated Wnt5a expression in a large cohort of 217 colon cancers by immunohistochemistry and analyzed its correlation with clinicopathologic characteristics. We found that expression of Wnt5a was diminished significantly in majority of primary colon cancers and negatively related with EMT biomarkers. To further enlighten the mechanism which Wnt5a regulates EMT in vitro, we established ectopic Wnt5a expression models. Protein analysis demonstrated that Wnt5a inhibited EMT and antagonized canonical Wnt signaling in colon cancer cells. Overexpression of Wnt5a impaired cell motility and invasion and inhibited cell proliferation by manipulating Bax. Moreover, Wnt5a suppressed the tumor growth in nude mice and impaired tumorigenicity in vivo. Wnt5a also induced intracellular calcium and activated non-canonical Wnt/Ca(2+) signaling in colon cancer. In summary, although Wnt5a was down regulated in majority of colon cancers, enhanced Wnt5a expression predict preferable outcome in colon cancer patients. Our findings indicate that Wnt5a might act as tumor suppressor by inhibiting cell proliferation and attenuating EMT in colon cancer cells. Wnt5a could be used as a novel prognostic marker and/or therapeutic target for colon cancer in the future. PMID- 24464652 TI - Sleeping Beauty-baculovirus hybrid vectors for long-term gene expression in the eye. AB - BACKGROUND: A baculovirus vector is capable of efficiently transducing many nondiving and diving cell types. However, the potential of baculovirus is restricted for many gene delivery applications as a result of the transient gene expression that it mediates. The plasmid-based Sleeping Beauty (SB) transposon system integrates transgenes into target cell genome efficiently with a genomic integration pattern that is generally considered safer than the integration of many other integrating vectors; yet efficient delivery of therapeutic genes into cells of target tissues in vivo is a major challenge for nonviral gene therapy. In the present study, SB was introduced into baculovirus to obtain novel hybrid vectors that would combine the best features of the two vector systems (i.e. effective gene delivery and efficient integration into the genome), thus circumventing the major limitations of these vectors. METHODS: We constructed and optimized SB-baculovirus hybrid vectors that bear either SB100x transposase or SB transposon in the forward or reverse orientations with respect to the viral backbone The functionality of the novel hybrid vectors was investigated in cell cultures and in a proof-of-concept study in the mouse eye. RESULTS: The hybrid vectors showed high and sustained transgene expression that remained stable and demonstrated no signs of decline during the 2 months follow-up in vitro. These results were verified in the mouse eye where persistent transgene expression was detected two months after intravitreal injection. CONCLUSIONS: Our results confirm that (i) SB-baculovirus hybrid vectors mediate long-term gene expression in vitro and in vivo, and (ii) the hybrid vectors are potential new tools for the treatment of ocular diseases. PMID- 24464651 TI - miR-20a promotes prostate cancer invasion and migration through targeting ABL2. AB - The aberrant expression of microRNAs (miRNAs) has been found in various types of cancer. The present study found miR-20a was significantly up-regulated in prostate cancer compared with normal prostate tissues. Patients with a higher miR 20a expression had a Gleason score of 7-10 and shorter survival time. The transwell and wound healing assays revealed that blocking expression of miR-20a by miR-20a ASO suppresses the invasion and migration of PC-3 and DU145 cells in vitro and also inhibits tumor growth in vivo. Furthermore, we identified miR-20a directly targets the ABL family non-receptor tyrosine kinases ABL2 and negatively regulates the phosphorylation of its downstream gene p190RhoGAP. Knockdown of ABL2 promoted cell invasion and migration and we identified miR-20a-induced cell invasion and migration can be rescued by ABL2. In conclusion, our findings show that miR-20a significantly contributes to the progression of prostate cancer by targeting ABL2. PMID- 24464653 TI - Distinct patterns of sirtuin expression during progression of Alzheimer's disease. AB - Aging is one of the major risk factors for Alzheimer's disease (AD). Sirtuins are associated with prolonged life span. To examine whether the expression levels of sirtuins associate with the progression of AD or not, we performed a comparative immunoblotting and immunohistochemical study of SIRT1, 3, and 5 in the entorhinal cortex and hippocampal subregions and white matter in 45 cases grouped according to Braak and Braak stages of neurofibrillary degeneration. In addition, we compared the expression levels with the local load of tau and amyloid-beta deposits, evaluated using morphometry. Our study revealed that (1) the neuronal subcellular redistribution of SIRT1 parallels the decrease in its expression, suggesting stepwise loss of neuroprotection dependent on the neuronal population; (2) in contrast to SIRT1 and 3, expression of SIRT5 increases during the progression of AD; (3) which might be related to its appearance in activated microglial cells. The complex patterns of the expression of sirtuins in relation to tissue damage should be taken into account when searching for therapies interacting with sirtuins. PMID- 24464654 TI - Contribution of ventricular assist devices to the recovery of failing hearts: a review and the Berlin Heart Center Experience. AB - Ventricular assist-device (VAD) implantation is a life-saving therapy which will later become either a bridge-to-transplantation or definitive therapy if heart transplantation (HTx) is not possible. VAD-supported failing hearts often recover at the molecular and cellular level, but translation of these changes into functionally stable cardiac recovery allowing long-term HTx/VAD-free outcomes after VAD removal is relatively rare, related to the aetiology, severity, and duration of myocardial damage. The reason for the discrepancy between high recovery rates on cellular and molecular levels and the low rate of cardiac recovery allowing VAD explantation is unknown. For selected patients VAD explantation is feasible. HTx/VAD-free outcomes for >15 years are possible even if recovery remains incomplete and the underlying cause for VAD implantation was idiopathic dilated cardiomyopathy. Echocardiography and right heart catheterization are necessary to assess clinically relevant cardiac recovery. Certain echo parameters appeared highly predictive for post-weaning cardiac function and reliable for weaning decisions. The elective therapeutic use of VADs for heart failure (HF) reversal in its earlier stages is a future goal possibly achievable by development of tools to predict HF reversibility already before VAD implantation and increase the number of weaning candidates by improvement of adjunctive therapies to optimize unloading-promoted recovery. The present article summarizes the knowledge about unloading-promoted myocardial recovery and reviews the available data on its clinical relevance, its post-explant stability, and its assessment for decision-making in favour of or against VAD explantation. The review also aims to provide a theoretical and practical basis for clinicians intending to be engaged in this field. PMID- 24464655 TI - Effect of odor preexposure on acquisition of an odor discrimination in dogs. AB - In two experiments, we investigated the impact of odor preexposure treatments on the acquisition of an olfactory discrimination in dogs. In the first experiment, four groups of dogs were each given five days' odor-exposure treatment prior to discrimination training. Dogs in the exposure group were exposed to anise extract (S+) for 30 min daily. Dogs in the Pavlovian-relevant pairing group received six daily delayed-conditioning trials to the same S+. The Pavlovian-irrelevant pairing group received conditioning trials to almond extract (S'). Dogs in the control group received no pretreatment. All of the dogs were then trained to detect S+ from a background pine odor (an AX-vs.-X discrimination). The Pavlovian relevant pairing group acquired the odor discrimination significantly faster than all of the other exposure and control groups, and the remaining groups acquired the discrimination at the same rate as the no-exposure control group. In a second experiment, we extended these results to a within-subjects design using an AX versus-BX discrimination. Six dogs were simultaneously trained on two different odor discriminations, one discrimination in which the S+ was previously Pavlovian conditioned, and one discrimination in which the S+ was novel. All of the dogs learned the odor discrimination with the previously conditioned S+ faster than they learned the novel odor discrimination, replicating the results of Experiment 1, and demonstrating that familiarity in the form of Pavlovian conditioning enhances odor-discrimination training. The potential mechanisms of the facilitated transfer of a Pavlovian conditioned stimulus to discrimination training are discussed. PMID- 24464656 TI - Issues associated with formula milk: the Hong Kong's experience. PMID- 24464657 TI - Infant formula safety concerns and consequences in China. PMID- 24464658 TI - The roles of microRNAs in neuroblastoma. AB - BACKGROUND: Neuroblastoma (NB) is the most common extracranial solid tumor in childhood and displays remarkable heterogeneity in clinical behaviors, ranging from spontaneous regression to rapid progression or resistance to multimodal treatment. Recent evidence has shown that microRNAs (miRNAs), a class of small non-coding RNAs, are involved in tumor development and progression. This article aimed to review recent advances in investigating the roles of miRNAs in NB. METHODS: We searched the PubMed/MEDLINE database for articles about the expression profile, functions and target genes of miRNAs in NB. RESULTS: We reviewed the most recent evidence regarding the functional roles of oncogenic and tumor suppressive miRNAs in NB and application of novel miRNA-based methods for diagnostic, prognostic and therapeutic purposes. CONCLUSIONS: Deregulation of miRNAs is associated with the development and progression of NB, suggesting that miRNAs may serve as novel targets for the treatment of high-risk NB patients. However, their precise functions and underlying mechanisms still warrant further studies. PMID- 24464659 TI - Environmental factors for the development of fetal urinary malformations. AB - BACKGROUND: The development of the kidneys and other organs of the urinary tract also follow the natural rule of gene-environment-lifestyle interaction. Both intrinsic and extrinsic factors may be associated with the etiology of various kinds of urinary malformations. The environmental factors belong to extrinsic factors, which have attracted increasing attention from researchers. METHODS: Publications about urinary malformations were searched from databases such as PubMed, Elsevier, Chemical Abstract, Excerpta Medica, Chinese Hospital Knowledge Database and Wanfang Database. RESULTS: Urinary malformation is associated with low birth weight, maternal diseases, placental insufficiency, maternal drug exposure, and maternal exposure to environmental pesticides. Living environment and socioeconomic factors may also influence the incidence of urinary malformation. CONCLUSION: It is important to understand the association of environmental factors with the development of the renal system and urinary malformation in order to decrease the incidence of urinary malformations. PMID- 24464660 TI - Late and very late onset group B Streptococcus sepsis: one and the same? AB - BACKGROUND: This study aimed to describe the clinical characteristics of group B Streptococcus (GBS) sepsis in infants aged 4-90 days [late onset (LO)] compared to infants >90 days of age [very late onset (VLO)]. METHODS: Microbiology records at Children's Medical Center Dallas were screened. Demographic, clinical, and outcome data were collected for infants with GBS recovered from blood or cerebrospinal fluid culture from January 1, 2006 to July 1, 2012. RESULTS: Totally 48 infants were identified (42 LO, 6 VLO). Infants with VLO sepsis had lower median gestational age (28.5 vs. 39 weeks gestation, P<0.001) and longer median nursery admissions (8.8 vs. 0.5 weeks, P=0.004). When gestational age was controlled for, there were no differences in clinical presentation, intensive care unit admission, length of stay, neurodevelopmental outcome, and mortality. Infants with VLO sepsis were more likely to receive vancomycin (83% vs. 33%, P=0.02) or third-generation cephalosporins (83% vs. 24%, P=0.009), and more likely to continue on those agents even after GBS was identified. CONCLUSIONS: Infants with VLO sepsis had lower gestational ages and longer nursery stays than infants with LO sepsis. Beyond age at presentation, there were no significant differences in clinical presentations, hospital course, frequency of neurodevelopmental sequelae, and mortality in infants presenting with LO vs. VLO GBS sepsis. Infants with VLO sepsis were more likely to receive empiric broad spectrum antimicrobials and more likely to continue receiving broad therapy even following GBS identification. PMID- 24464661 TI - Surveillance of childhood blood lead levels in 11 cities of China. AB - BACKGROUND: Exposure to lead can be deleterious to children's health. Surveillance for blood lead levels (BLLs) is reported every year in the USA and some other countries. However, such reports are lacking in China which has the world's largest population of children. In this study, we provided the latest nationally representative data on BLLs among Chinese children living in cities, described the change in BLLs since 2004, and explored the risk factors for elevated BLLs (EBLLs) among children. METHODS: We studied 12 693 children aged 0 6 years in 2004 and 11 255 children aged 0-6 years in 2010. We evaluated the average BLLs and the prevalence of EBLLs, and a multivariate logistic regression model was used to estimate predictors of EBLLs. RESULTS: The geometric mean BLLs of children aged 0-6 years dropped by 16% (from 46.38 +/- 2.10 MUg/L in 2004 to 38.95 +/- 1.83 MUg/L in 2010), while the prevalence of EBLLs dropped by 87% (from 9.78% in 2004 to 1.32% in 2010). In a multivariate analysis, the following factors were associated with EBLLs: (1) children being cared for at home or at a boarding nursery (compared to children being cared for in a day nursery), (2) children having fathers with a lower education level, and (3) children often eating popcorn and chewing fingernails or sucking fingers were associated with EBLLs. CONCLUSIONS: The results of this study demonstrated a substantial decline in BLLs from 2004 to 2010 among Chinese children 0-6 years living in cities. However, these levels were higher than levels in countries, such as the USA, Canada, Japan and Sweden. These data demonstrate that Chinese children's lead exposure remains a public health problem that requires additional effort and resources. PMID- 24464662 TI - Effects of a long-term physical exercise program with and without diet on obese boys after six-month detraining. AB - BACKGROUND: Most studies on physical fitness and detraining have been conducted on normal-weight children. Their results indicate that any gains regress to the untrained control values during the detraining period. It, therefore, seems necessary to determine how detraining affects the different fitness parameters in obese children. The aim of the present study was to evaluate the effects of detraining (6 months) on kinanthropometry and the components of physical fitness after an intervention (31 months) consisting of a program of exercise and/or diet for obese boys. METHODS: The participants were 18 boys, aged between 8 and 11 years, divided into E and E+D groups according to the program they followed. The E group followed a physical exercise program (three 90-minute sessions/ week), and the E+D group the same physical exercise program plus a low calorie diet. Physical fitness was assessed by the European physical fitness test battery including flamingo balance, plate tapping, sit-andreach, standing broad jump, hand-grip strength, sit-ups, bent-arm hang, 10 * 5-metre shuttle run, and 20 metre endurance shuttle run. The Kruskal-Wallis test was applied to reveal overall intergroup differences (E and E+D groups), and measurements showing significant differences were further analysed for differences between individual groups by the Mann-Whitney U test. RESULTS: In both groups, changes were observed in various physical fitness parameters, especially limb speed (E group, P=0.001; E+D group, P=0.002), agility (E group, P<0.001; E+D group, P<0.001), and aerobic fitness (E group, P=0.009; E+D group, P=0.002). CONCLUSION: Detraining after a long-term intervention based on the combination of exercise program and exercise program plus diet in obese boys does not affect the changes attained during the intervention. PMID- 24464663 TI - Pulmonary hypertension in extremely low birth weight infants: characteristics and outcomes. AB - BACKGROUND: To determine the characteristics and outcomes of pulmonary arterial hypertension (PAH) in extremely low birth weight (ELBW) infants. METHODS: A retrospective case-control study of all ELBW infants admitted to a level III neonatal intensive care unit (NICU) between January 1, 2003 and December 31, 2010. RESULTS: During the study period, 450 ELBW infants were admitted. 6.4% (29/450) were diagnosed with PAH and were matched to 26 controls. The mean gestational age of infants with PAH and their controls were similar [24.5 +/- 1.3 vs. 24.9 +/- 1.8 weeks (P=0.26)]; however the cases were smaller at birth than were controls [640.7 +/- 119.5 vs. 727.0 +/- 184.5 g (P=0.04)]. The diagnosis of PAH was made at a mean postnatal age of 131.8 +/- 53.7 days. Infants with PAH had a higher rate of intrauterine exposure to illicit maternal drug use [12/29 (41%) vs. 1/25 (4%); P=0.001], a longer duration of initial mechanical ventilation [74.9 +/- 28.3 vs. 59.1 +/- 27.8 days; P=0.04)], a higher incidence of severe BPD [23/29 (79%) vs. 13/26 (50%); P=0.02], and a greater NICU mortality rate [12/29 (41%) vs. 4/26 (15%); P=0.04]. CONCLUSION: PAH in ELBW infants is associated with maternal illicit drug use in pregnancy, longer exposure to mechanical ventilation, severe bronchopulmonary dysplasia and a significant increase in early mortality. PMID- 24464664 TI - Neonatal outcomes of very preterm infants from a neonatal intensive care center. AB - BACKGROUND: Information about clinical outcomes of very preterm (VPT) infants in tertiary neonatal intensive care unit (NICU) setting is scant in China. This study aimed to investigate the mortality and morbidity of VPT infants admitted to BaYi Children's Hospital, which serves as a NICU referral center for the city of Beijing, China. METHODS: Retrospectively collected perinatal/neonatal data on all admissions of infants born at <32 weeks of gestational age and subsequently admitted to the VPTNICU from clinical records between October 2010 and September 2011. RESULTS: Totally 729 infants were identified. 90% of VPT infants were outborn. The overall survival of the infants to discharge was 92%, which increased with increasing gestational age (range from 69% at <28 weeks to 99% at 31 weeks). The incidence of bronchopulmonary dysplasia was 4%, retinopathy of prematurity requiring treatment 2%, intraventricular hemorrhage III-IV 6%, and periventricular leukomalacia 2%. 10% of the VPT infants had a major morbidity at discharge. CONCLUSIONS: The outcomes of the VTP infants at this referral NICU were comparable to those in tertiary centers in developed countries. The most common complications were lower than those in other cohorts. Accordingly, high volume NICU may minimize the adverse effects of VPT infants' transport. PMID- 24464665 TI - Efficacy of rituximab therapy in children with refractory nephrotic syndrome: a prospective observational study in Shanghai. AB - BACKGROUND: Idiopathic nephrotic syndrome is the most common glomerular disease in children. This study was undertaken to observe the efficacy and side-effects of rituximab (RTX) in treating children with different types of refractory primary nephrotic syndrome. METHODS: Twelve patients with steroid dependent nephrotic syndrome (SDNS), frequently relapsing nephritic syndrome (FRNS), and steroid resistant nephrotic syndrome (SRNS) were enrolled in our study. There were obvious drug side-effects, and proteinuria remained difficult to control. RTX was administered at a dose of 375 mg/m(2) body surface area, once or twice weekly. RESULTS: The male to female ratio was 3:1, and the onset age was 1.6-8.9 years. There were 9 patients with steroid sensitive nephrotic syndrome (SDNS or FRNS), and 3 patients with SRNS. There were 7 patients with minimal change disease (MCD), 3 patients with focal segmental glomerular sclerosis (FSGS), 1 with focal proliferative glomerulonephritis, and 1 without renal biopsy. The total effective treatment rate of RTX was 91.67%, and for 77.78% of the patients, steroid dosage could be reduced. Six months before and after RTX infusion, the mean steroid dosage was significantly decreased (P=0.014) and the recurrence number was significantly reduced (P<0.001). The results were better in MCD patients than in FSGS patients (P=0.045). There was no significant difference between FRNS/SDNS and SRNS patients (P=0.175). During RTX administration, 3 patients developed skin rashes, 1 developed hypotension, and 1 developed a fever. One patient experienced a persistent decrease in serum immunoglobulin level but without serious infection. CONCLUSION: RTX was effective in the treatment of refractory nephrotic syndrome, and it could significantly reduce the use of steroid and immunosuppressants. PMID- 24464666 TI - Clinical characteristics and mutation analysis of propionic acidemia in Thailand. AB - BACKGROUND: Propionic acidemia (PA) is caused by a deficiency of propionyl CoA carboxylase. A characteristic urine organic acid profile includes 3 hydroxypropionate, methylcitrate, tiglylglycine, and propionylglycine. The diagnosis of PA is confirmed by detection of mutations in the PCCA or PCCB genes. We herein report the clinical and molecular findings of four Thai patients with PA. METHODS: Clinical findings of four Thai patients with PA were retrospectively reviewed. Urine organic acids were analyzed by gas chromatography-mass spectrometry. PCR-sequencing analyses of encoding exons and intron/exon boundaries of the PCCA and PCCB genes were performed. RESULTS: All patients had neonatal onset of PA. One patient died of cardiomyopathy, and another one of pneumonia and metabolic decompensation. The remainder experienced significant neurocognitive impairment. Mutation analysis of the PCCA gene identified homozygous c.1284+1G>A in patient 1, c.230G>A (p.R77Q) and c.1855C>T (p.R619X) in patient 2, homozygous c.2125T>C (p.S709P) in patient 3, and only one mutant allele, c.231+1G>T in patient 4. No PCCB mutation was identified. Four mutations including c.230G>A, c.231+1G>T, c.1855C>T, and c.2125T>C have not been reported previously. CONCLUSIONS: The clinical and molecular study of these Thai patients provided additional knowledge of the genotype and phenotype characteristics of PA. The results of the study suggested that PCCA mutations in Asian populations were distinct from those of other populations. PMID- 24464667 TI - Delivery room surgery: an applicable therapeutic strategy for gastroschisis in developing countries. AB - BACKGROUND: The survival rate of infants with gastroschisis has improved significantly. It is over 90% in developed countries, but 50% in developing countries. This study aimed to investigate the factors improving the survival rate of infants with gastroschisis in developing countries. METHODS: Neonates meeting the inclusion criteria, who presented to our center since the establishment of delivery room surgery, were enrolled into this retrospective study. Data were evaluated specifically to determine the role of delivery room surgery in reducing the mortality and morbidity of infants with gastroschisis and to identify factors optimizing the conditions of outborn infants. RESULTS: A total of 64 infants were identified. The overall survival rate of the infants was 60.9%. The survival rate of infants in inborns was 76.5%, and the survival rate of infants in outborns was 43.3%. Infants of the outborn group took more time to reach full enteral feeding, and were more likely to require a prolonged stay in hospital when compared with those of the inborn group. Logistic analysis identified that the surgical technique, the presence of sepsis and intestinal necrosis could be expected to influence the outcome of gastroschisis. CONCLUSIONS: The strategy of delivery of patients in a center prepared to perform delivery room closure of gastroschisis appears to improve the survival of patients with gastroschisis. Further reduction in mortality rates will depend on improved conditions of outborn infants. PMID- 24464668 TI - Timing and secular trend of pubertal development in Beijing girls. AB - BACKGROUND: Historical research is limited in changes in pubertal development in Chinese girls. We aimed to identify the timing of pubertal characteristics and the secular trend of menarche age among Beijing girls from the 1980s through the 2000s. METHODS: Six data sets were analyzed, including the Beijing Child and Adolescent Metabolic Syndrome study in 2004, where 9778 Bejing girls aged 6-18 years were studied. The Fetal Origins of Adult Disease study provided retrospective menarche age from 1940 through 1960. Other four studies were conducted in Beijing to obtain supplementary information to assess secular trend in menarche age. Linear regression method was used to analyze the data. RESULTS: Among Beijing girls in 2004, the median age at menarche was 12.1 years, which was 0.6 years earlier in urban than in rural areas. The median age at Breast Tanner Stage 2 was 9.5 +/- 1.2 years, representing 9.4 +/- 1.1 years and 9.6 +/- 1.2 years for urban and rural girls, respectively. In contrast, the median age at Pubic Hair Tanner Stage 2 was 11.1 +/- 1.1 years, representing 10.8 +/- 1.1 and 11.4 +/- 1.1 years for urban and rural girls, respectively. The menarche age of urban girls decreased by 4.2 months per decade, and that of rural girls by 9.6 months per decade from 1980 to 2004. CONCLUSIONS: Urban girls mature earlier than rural girls in Beijing. A secular trend towards earlier menarche was observed between the 1980s and the 2000s. PMID- 24464669 TI - A pediatric case series of abdominal epilepsy. AB - BACKGROUND: Abdominal epilepsy (AE) is an infrequent cause of recurrent abdominal pain in children. It is characterized by paroxysmal episodes of abdominal pain, a variety of other abdominal complaints, electroencephalogram abnormalities, and response to anti-epileptic agents. We described the clinical profile of six patients with AE. METHODS: We conducted a retrospective survey of AE in children from the records of the hospital. The diagnosis of AE was dependent on recurrent abdominal symptoms, subtle central nervous system abnormalities, electroencephalogram abnormalities and response to anticonvulsant agents. RESULTS: The six patients were diagnosed with AE. The incidence of the disease was 0.07% in all admissions to the pediatric ward. Recurrent pain was common in all patients except two who had additional recurrent vomiting. In this series, the boy to girl ratio (1:2) was unequal. CONCLUSION: High suspicion is required for the diagnosis of AE after exclusion of other possible causes. PMID- 24464670 TI - Prevention of metabolic decompensation in an infant with mutase deficient methylmalonic aciduria undergoing cardiopulmonary bypass. AB - BACKGROUND: Effects of circulatory arrest upon an inborn error of metabolism patient are unknown. METHODS: A retrospective chart review was performed of outcome and biochemical parameters obtained during palliative cardiac surgery for a mutase-deficient methylmalonic aciduria patient with Ebstein's cardiac anomaly was performed. RESULTS: The levels of ammonia, methylmalonic acid, free carnitine, and propionylcarnitine of the patient were improved. The patient survived surgery following institution of four metabolic treatment principles: 1) restriction of toxic substrate; 2) promotion of anabolism via administration of carbohydrate and lipid calories; 3) administration of detoxifying levocarnitine and sodium benzoate; and 4) cobalamin enzymatic co-factor administration. The patient died from post-operative dysrhythmia and was posthumously determined to have compound heterozygosity for mutations predicting severe, cobalamin non responsive disease: c.322C>T/c.1233del3 (p.R108C/p.DeltaI412). CONCLUSION: Metabolic decompensation is preventable during cardiopulmonary bypass and cardioplegia using four principles of metabolic treatment. PMID- 24464671 TI - Colon carcinoma treated with oxaliplatin and capecitabine in a 12-year-old child. AB - BACKGROUND: XELOX (oxaliplatin 130 mg/m(2) iv, capecitabine 1000 mg/m(2) bid oral d1-14, q3w) chemotherapy has never been used in children. In this report, we present a case of a 12-year-old girl with colon adenocarcinoma, treated with surgery and XELOX chemotherapy. METHODS: On admission, the girl complained of abdominal pain and intestinal obstruction. Physical examination revealed a distended abdomen with tenderness on the left upper quadrant. Barium enema revealed a stenotic lesion at the distal end of the transverse colon, and abdominal computed tomography showed acute obstruction and a colonic mass. Laparotomy was performed after the failure of conservative treatment. RESULTS: The mass was originated from the transverse colon. Frozen sections of the specimens revealed an adenocarcinoma. Transverse colectomy was performed and regional lymph nodes were removed. Pathological examination confirmed that the mass was a poorly differentiated adenocarcinoma, and XELOX chemotherapy was used. No evidence of recurrent or metastatic tumor was found after 18 months. CONCLUSION: Although complete resection is the most effective treatment, XELOX chemotherapy is beneficial to the improvement of clinical outcome of patients with colon adenocarcinoma. PMID- 24464672 TI - The concepts of assent and parental permission in pediatrics. PMID- 24464673 TI - Author reply: To PMID 23775677. PMID- 24464674 TI - Eosinophil cationic protein in Henoch-Schonlein purpura. PMID- 24464675 TI - Neonatal heart murmur: is it useful for the diagnosis of congenital heart diseases? PMID- 24464676 TI - Risks of musculoskeletal disorders among betel quid preparers in Taiwan. AB - BACKGROUND: Betel quid chewing is common in Taiwan. The work of betel quid preparers is characterized by long hours of static work, awkward working posture and highly repetitive hand/wrist motion. However, the musculoskeletal health of betel quid preparers receives very little attention. METHODS: The Chinese version of the Standardized Nordic Musculoskeletal Questionnaire (NMQ) was administered, and electrogoniometers and electromyography were used in this cross-sectional study to characterize the hand/wrist motion of the subjects. Physical examinations on the thumbs and wrists of the subjects were conducted by means of Phalen's test and Finkelstein's test, respectively. RESULTS: Among the 225 participants, more than 95% attributed their musculoskeletal complaints to their work, and shoulder, neck, hand/wrist, and lower back discomfort were most frequently reported. More than 70% of the preparers did not seek medical treatment for their musculoskeletal problems. Based on the physical examination, 24% of the participants had suspected symptom of either carpal tunnel syndrome (CTS) or DeQuervain's tenosynovitis. The instrumental measurements indicated that betel quid preparation is characterized by extreme angle ranges and moderate repetition of wrist motion as well as low forceful exertion. CONCLUSIONS: This study concludes that betel quid preparers are a high risk group of developing musculoskeletal disorders (MSDs). Future studies by electrogoniometers and detailed physical examination on betel quid preparers are needed to determine the predisposing factors for CTS. Some intervention measures to prevent MSDs and to lessen psychological stress for this group of workers are strongly suggested. PMID- 24464677 TI - Disease spread through contiguity and axonal tracts in primary lateral sclerosis. AB - Our goal in this report was to determine whether symptom progression in primary lateral sclerosis (PLS) was consistent with disease spread through axonal pathways or contiguous cortical regions. The date of symptom onset in each limb and cranial region was obtained from 45 PLS patient charts. Each appearance of symptoms in a new body region was classified as axonal, contiguous, possibly contiguous, or unrelated, according to whether the somatotopic representations were adjacent in the cortex. Of 152 spread events, the first spread event was equally divided between axonal (22) and contiguous (23), but the majority of subsequent spread events were classified as contiguous. Symptom progression in PLS patients is consistent with disease spread along axonal tracts and by local cortical spread. Both were equally likely for the first spread event, but local cortical spread was predominant thereafter, suggesting that late degeneration does not advance through long axonal tracts. PMID- 24464678 TI - Split-gate organic field-effect transistors for high-speed operation. AB - Split-gate organic field-effect transistors have been developed for high-speed operation. Owing to the combination of reduced contact resistance and minimized parasitic capacitance, the devices have fast switching characteristics. The cutoff frequencies for the vacuum-evaporated devices and the solution-processed devices are 20 and 10 MHz, respectively. A speed of 10 MHz is the fastest device reported so far among solution-processed organic transistors. PMID- 24464679 TI - Calcium- and integrin-binding protein-1 is down-regulated in the sperm of patients with oligoasthenozoospermia : CIB1 expression in patients with oligoasthenozoospermia. AB - PURPOSE: The aim of this study was to determine whether altered expression and distribution of calcium- and integrin-binding protein-1 (CIB1) is involved in the pathogenesis of patients with oligoasthenozoospermia. METHODS: Sperm samples were obtained from 25 infertile Chinese men who had failed to achieve conception after a period of 1-2 y and had been referred to the Reproductive Laboratory of the second hospital affiliated to the Shandong University of Traditional Chinese Medicine. Participants were divided into two groups: oligoasthenozoospermia (n = 13) and asthenozoospermia (n = 12); as a third group, fertile men (n = 19) were included as controls. The expression levels of mRNA and protein levels of CIB1 and cyclin-dependent kinase 1 (CDK1) were measured using qRT-PCR and western blotting. RESULTS: mRNA and protein expression levels of CIB1 were decreased in the oligoasthenozoospermia patients. Interestingly mRNA and protein expression levels of CDK1 were increased in the oligoasthenozoospermia patients. CONCLUSION: The results of the present study indicate that that CIB1 may be involved in the pathogenesis of oligoasthenozoospermia by the CDK1 signaling pathway. PMID- 24464680 TI - Ipomovirus--an atypical genus in the family Potyviridae transmitted by whiteflies. AB - Ipomoviruses (genus Ipomovirus) are whitefly-transmitted viruses assigned to the family Potyviridae. They are characterised by filamentous flexible particles and a positive-sense single-stranded RNA (+ssRNA) genome. The viral genome is translated into a polyprotein precursor, which is processed into mature proteins and a short overlapping open reading frame. The genus Ipomovirus contains four accepted species and one unapproved species, and two other tentative members have recently been characterised. Ipomoviruses cause serious economic losses in many important crops, including cassava, sweet potato, cucurbits, tomato and aubergine. These viruses are transmitted by whiteflies in a non-circulative, semi persistent manner, the virions being retained on the external surface of the vectors' mouthparts for a few days or weeks. Comparison of the available complete genome sequences of different ipomoviruses revealed differences in their genome organisation and a considerable variation in their proteins and conserved motifs that may reflect functional differences. This review summarises the current knowledge of the members within the genus Ipomovirus, focusing on genome organisation, taxonomic classification and the mechanism by which they are transmitted. PMID- 24464681 TI - Influence of carbon and metal oxide nanomaterials on aqueous concentrations of the munition constituents cyclotrimethylenetrinitramine (RDX) and tungsten. AB - There is an increasing likelihood of interactions between nanomaterials and munitions constituents in the environment resulting from the use of nanomaterials as additives to energetic formulations and potential contact in waste streams from production facilities and runoff from training ranges. The purpose of the present research was to determine the ability of nano-aluminum oxide (Al(2)O(3)) and multiwalled carbon nanotubes (MWCNTs) to adsorb the munitions constituents cyclotrimethylenetrinitramine (RDX) and tungsten (W) from aqueous solution as a first step in determining the long-term exposure, transport, and bioavailability implications of such interactions. The results indicate significant adsorption of RDX by MWCNTs and of W by nano-Al(2)O(3) (but not between W and MWCNT or RDX and nano-Al(2)O(3)). Kinetic sorption and desorption investigations indicated that the most sorption occurs nearly instantaneously (<5 min), with a relatively slower, secondary binding leading to statistically significant but relatively smaller increases in adsorption over 30 d. The RDX sorption that occurred during the initial interaction was irreversible, with long-term, reversible sorption likely the result of a secondary interaction; as interaction time increased, however, the portion of W irreversibly sorbed onto nano-Al(2)O(3) also increased. The present study shows that strong interactions between some munitions constituents and nanomaterials following environmental release are likely. Time dependent binding has implications for the bioavailability, migration, transport, and fate of munitions constituents in the environment. PMID- 24464683 TI - Is the prognosis in patients with diabetes and heart failure a matter of unsatisfactory management? An observational study from the Swedish Heart Failure Registry. AB - AIMS: To analyse the long-term outcome, risk factor panorama, and treatment pattern in patients with heart failure (HF) with and without type 2 diabetes (T2DM) from a daily healthcare perspective. METHODS AND RESULTS: Patients with (n=8809) and without (n=27,465) T2DM included in the Swedish Heart Failure Registry (S-HFR) 2003-2011 due to a physician-based HF diagnosis were prospectively followed for long-term mortality (median follow-up time: 1.9 years, range 0-8.7 years). Left ventricular function expressed as EF did not differ between patients with and without T2DM. Survival was significantly shorter in patients with T2DM, who had a median survival time of 3.5 years compared with 4.6 years (P<0.0001). In subjects with T2DM. unadjusted and adjusted odds ratios (ORs) for mortality were 1.37 [95% confidence interval (CI) 1.30-1.44) and 1.60 (95% CI 1.50-1.71), and T2DM predicted mortality in all age groups. Ischaemic heart disease was an important predictor for mortality (OR 1.68, 95% CI 1.47 1.94), more abundant in patients with T2DM (59% vs. 45%) among whom only 35% had been subjected to coronary angiography and 32% to revascularization. Evidence based pharmacological HF treatment was somewhat more extensive in patients with T2DM. CONCLUSION: The combination of T2DM and HF seriously compromises long-term prognosis. Ischaemic heart disease was identified as one major contributor; however, underutilization of available diagnostic and therapeutic facilities for ischaemic heart disease was obvious and may be an important area for future improvement in patients with T2DM and HF. PMID- 24464684 TI - Passages 2014. PMID- 24464682 TI - Genome complexity in the coelacanth is reflected in its adaptive immune system. AB - We have analyzed the available genome and transcriptome resources from the coelacanth in order to characterize genes involved in adaptive immunity. Two highly distinctive IgW-encoding loci have been identified that exhibit a unique genomic organization, including a multiplicity of tandemly repeated constant region exons. The overall organization of the IgW loci precludes typical heavy chain class switching. A locus encoding IgM could not be identified either computationally or by using several different experimental strategies. Four distinct sets of genes encoding Ig light chains were identified. This includes a variant sigma-type Ig light chain previously identified only in cartilaginous fishes and which is now provisionally denoted sigma-2. Genes encoding alpha/beta and gamma/delta T-cell receptors, and CD3, CD4, and CD8 co-receptors also were characterized. Ig heavy chain variable region genes and TCR components are interspersed within the TCR alpha/delta locus; this organization previously was reported only in tetrapods and raises questions regarding evolution and functional cooption of genes encoding variable regions. The composition, organization and syntenic conservation of the major histocompatibility complex locus have been characterized. We also identified large numbers of genes encoding cytokines and their receptors, and other genes associated with adaptive immunity. In terms of sequence identity and organization, the adaptive immune genes of the coelacanth more closely resemble orthologous genes in tetrapods than those in teleost fishes, consistent with current phylogenomic interpretations. Overall, the work reported described herein highlights the complexity inherent in the coelacanth genome and provides a rich catalog of immune genes for future investigations. PMID- 24464686 TI - Antioxidant, oxidative DNA damage protective and antimicrobial activities of the plant Trigonella foenum-graecum. AB - BACKGROUND: The plant Trigonella foenum-gracecum (TFG) is used as antidiabetic and diuretic. In order to ascertain antioxidant potential of leaf (early and mature) and seed of TFG, total phenolics, free radical scavenging assay, superoxide anion radical scavenging activity, reducing power, lipid peroxidation, ferric thiocyanate assay, hydroxyl radical scavenging activity and DNA damage protective activities were determined. The study was further carried out to assay the antimicrobial activity and HPLC analysis of plant parts. RESULTS: Ethanol extracts of leaf (early and mature) exhibited a high content of phenolics (54.79 and 41.28 g kg(-1) GAE) when it was compared with seed extract (23.85 g kg(-1) GAE). Results showed that mature TFG leaf extract had the lowest IC50 for the free radical scavenging assay (IC50 = 2.23 mg mL(-1)), superoxide anion radical scavenging activity (IC50 = 2.71 mg mL(-1)), hydroxyl radical scavenging activity (IC50 = 17.30 mg mL(-1)) and highest reducing power (10.14 ascorbic acid equivalents mL(-1)). However, the ethanol seed extract showed the maximum inhibition of lipid peroxidation and the ferric thiocyanate assay. Mature leaf also showed the maximum DNA damage protection activity and higher concentration of phytochemicals. CONCLUSION: The results showed that the mature TFG leaf had a higher antioxidant activity, which may be due to the presence of total phenolics. It may be used in herbal drugs or as a nutritional supplement. PMID- 24464687 TI - The relationship between left ventricular ejection fraction and mortality in patients with acute heart failure: insights from the ASCEND-HF Trial. AB - AIM: Acute decompensated heart failure (ADHF) is associated with significant morbidity and mortality but the relationship between LVEF and outcomes is unclear. We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. METHODS AND RESULTS: We explored the association between LVEF and 30 and 180 day mortality in 7007 ADHF patients enrolled in the Acute Studies of Nesiritide in Decompensated Heart Failure (ASCEND-HF) trial. LVEF was analysed both as a continuous variable and according to three categories: < 40% (LowEF), 40-50% [intermediate EF (IntEF)], and > 50% [preserved ejection fraction (PresEF)]. Of the patients in the trial, 4474 (78.7%) had LowEF, 674 (11.9%) had IntEF, and 539 (9.5%) had PresEF. The unadjusted 30 and 180 day mortality was similar for LowEF (3.7%, 12.3%), IntEF (3.4%, 13.1%), and PresEF (4.3%, 14.1%), respectively (P > 0.05). After multivariable adjustment, the hazard ratio (HR) for 180 day mortality remained similar for the LowEF [HR 0.96, 95% confidence interval (CI) 0.75-1.24; P = 0.77] and IntEF (0.91, 95% CI 0.66-1.3; P = 0.58) compared to PresEF patients. By contrast, when LVEF was evaluated as a continuous measure, it exhibited a U-shaped pattern with mortality. After matching for age and sex, the mortality risk attributed to LVEF was attenuated, as the LVEF increased as a continuous variable over 35%. However, in patients with EF < 35%, the mortality risk continue to increase as the LVEF declined. CONCLUSIONS: Among patients with ADHF, the unadjusted mortality rates are similar across LVEF strata. However, after accounting for key patient variables, the mortality risk increases as EF falls below 35%. These data will be useful in planning future studies of ADHF. CLINICAL TRIAL REGISTRATION: www.clinicaltrials.gov identifier: NCT00475852. PMID- 24464688 TI - Behavioural studies of faecal continence in the rat. AB - BACKGROUND: A behavioural animal model of faecal continence and/or incontinence would be of value in experimental studies of the mechanisms by which sacral neuromodulation can effect continence mechanisms in humans. AIM: The aim of this behavioural study was to establish whether the rat, an obligate coprophagic species, exhibits patterns of faecal continence. METHODS: Standard rat cages were modified to consist of a food and drink area, a nesting area and an empty latrine area. Three floor pressure pads were connected to hour meters to record the time spent in each area over the course of 4 days. The door to the latrine was open for 2 days and closed for another 2 days to create a physical barrier that could only be surmounted by climbing over a partition. RESULTS: In the first 2 days, most faecal pellets (74 +/- 20 %; p < 0.0001) were deposited in the latrine and this was not changed by door closure (81 +/- 13 %). Door closure had no effect per se on pellet output (p = 0.99), nor did it alter the place preference for defaecation (p = 0.17, two factor ANOVA). Rats spent less time in the latrine area accounting for 23 and 13 % of total time before and after the door was closed, respectively. Normal and infrared videography showed that the place preference for pellets was not due to pellet collection for coprophagic purposes. CONCLUSIONS: The rat demonstrates place preference for defaecation and may drop pellets to mark remote boundaries. This simple method may prove useful in future animal studies of neuropathic faecal incontinence and refinement of neuromodulation interventions that lack placebo effects. PMID- 24464689 TI - Association between calcaneus quantitative ultrasound (QUS) parameters and thyroid status in middle-aged and elderly Chinese men with euthyroidism: a population-based cross-sectional study. AB - Although it is generally accepted that thyroid hormones affect bone metabolism, there is little data on the association of thyroid antibodies with bone status. We aimed to investigate the association between thyroid hormones or antibodies and quantitative ultrasound (QUS) parameters. This was a cross-sectional, population-based study conducted in Nanjing, China. A total of 1,001 Chinese men over 40 years were enrolled. We measured free triiodothyronine, free thyroxin (fT4), thyroid-stimulating hormone, anti-thyroid peroxidase (anti-TPO), anti thyroglobulin, 25-hydroxyvitamin D, and QUS parameters. After adjusting for potential confounders, QUS values decreased from the lowest to highest tertiles of fT4 in euthyroid men [quantitative ultrasound index (QUI) p = 0.002, broadband ultrasound attenuation (BUA) p = 0.000, speed of sound (SOS) p = 0.009, respectively]. Men with high anti-TPO levels (>=200 IU/ml) were found to have lower QUI (p = 0.030), BUA (p = 0.034), and SOS (p = 0.041) values than controls (<200 IU/ml). The prevalence of vitamin D deficiency was significantly higher in individuals with high anti-TPO than those in lower levels (87.5 vs. 59.5 %, p = 0.001). Our results suggest that high fT4 or anti-TPO values are associated with lower QUS parameters. Prospective studies are needed to confirm the precise relationship between thyroid status and osteoporosis. PMID- 24464690 TI - Fabrication of omentum-based matrix for engineering vascularized cardiac tissues. AB - Fabricating three-dimensional, biocompatible microenvironments to support functional tissue assembly remains a key challenge in cardiac tissue engineering. We hypothesized that since the omentum can be removed from patients by minimally invasive procedures, the obtained underlying matrices can be manipulated to serve as autologous scaffolds for cardiac patches. Here we initially characterized the structural, biochemical and mechanical properties of the obtained matrix, and demonstrated that cardiac cells cultivated within assembled into elongated and aligned tissues, generating a strong contraction force. Co-culture with endothelial cells resulted in the formation of blood vessel networks in the patch without affecting its function. Finally, we have validated that omental scaffolds can support mesenchymal and induced pluripotent stem cells culture, thus may serve as a platform for engineering completely autologous tissues. We envision that this approach may be suitable for treating the infarcted heart and may open up new opportunities in the broader field of tissue engineering and personalized regenerative medicine. PMID- 24464691 TI - Molecular epidemiology of colonizing and disease-causing Klebsiella pneumoniae in paediatric patients. AB - Klebsiella pneumoniae causes a range of clinical disease in paediatric patients and is of increasing concern due to growing antibiotic resistance, yet little is known about the relative distribution of commensal and pathogens throughout the population structure of K. pneumoniae. We conducted a prospective, observational study of 92 isolates from Seattle Children's Hospital, including 49 disease isolates from blood and urine (13 and 36 isolates, respectively) and 43 colonization isolates from stool. Susceptibility to 20 antimicrobials was evaluated using disc diffusion, VITEK 2 and Etest. Strain relatedness was investigated using multilocus sequence typing (MLST). Demographic and clinical characteristics were largely similar between disease and colonization cohorts, with 85.7 and 74.4 % of disease and colonization cohort patients, respectively, having an underlying medical condition; the sole exception was a relative abundance of patients with urologic or renal abnormalities in the disease cohort, consistent with the predominance of urine specimens among the disease isolates. With regard to antibiotic susceptibility properties, no significant differences were noted between the disease and colonization cohorts. Using molecular analysis, 71 unique sequence types (STs) were distinguished, with novel MLST findings evident in both cohorts; 43 (46.7 %) isolates represented novel STs, including 22 with a novel allele sequence. Thirteen STs contained multiple isolates and all seven isolates with resistance to three or more antibiotic classes were within one of four multirepresentative STs. This study demonstrates that nearly half of paediatric Klebsiella isolates represent novel STs, with clustering of multidrug resistance within specific STs. These findings expand our understanding of the intersection of bacterial population structure, human colonization ecology and multidrug resistance in K. pneumoniae. PMID- 24464692 TI - Molecular evolution of the haemagglutinin-neuraminidase gene in human parainfluenza virus type 3 isolates from children with acute respiratory illness in Yamagata prefecture, Japan. AB - We conducted detailed genetic analyses of the haemagglutinin-neuraminidase (HN) gene in 272 human parainfluenza virus type 3 (HPIV3) isolates from children with acute respiratory illness during the period 2002-2009 in Yamagata prefecture, Japan. A phylogenetic tree reconstructed by the Bayesian Markov chain Monte Carlo method showed that the strains diversified at around 1946 and that the rate of molecular evolution was 1.10*10(-3) substitutions per site per year. Identity was high among the present strains (<90 %) and the pairwise-distances were short. Furthermore, we found four positive selection sites and some key amino acid substitutions in active/catalytic sites of the HN protein. The results suggest that the HN gene of HPIV3 in the present strains evolved rapidly, similarly to other virus genes such as the G gene of respiratory syncytial virus. However, the biological functions and detailed structures of the HN glycoprotein in some of these strains may have been altered. PMID- 24464694 TI - Faecal Escherichia coli from patients with E. coli urinary tract infection and healthy controls who have never had a urinary tract infection. AB - Urinary tract infections (UTIs) are primarily caused by Escherichia coli with the patient's own faecal flora acting as a reservoir for the infecting E. coli. Here we sought to characterize the E. coli faecal flora of UTI patients and healthy controls who had never had a UTI. Up to 20 E. coli colonies from each rectal swab were random amplified polymorphic DNA (RAPD) typed for clonality, dominance in the sample and correlation to the infecting UTI isolate in patients. Each distinct clone was phylotyped and tested for antimicrobial susceptibility. Eighty seven per cent of the UTI patients carried the infecting strain in their faecal flora, and faecal clones causing UTI were more often dominant in the faecal flora. Patients had a larger diversity of E. coli in their gut flora by carrying more unique E. coli clones compared to controls, and patient faecal clones were more often associated with multidrug resistance compared to controls. We found a similar phylotype distribution of faecal clones from UTI patients and healthy controls, including a large proportion of B2 isolates in the control group. Faecal-UTI isolates from patients were more often associated with multidrug resistance compared to faecal-only clones, indicating a link between UTI virulence and antimicrobial resistance. Intake of any antibiotic less than 6 months prior to inclusion in the experiment occurred significantly more in patients with UTI than in controls. In contrast, presence of an intrauterine device was significantly more common in controls indicating a protective effect against UTI. In conclusion, healthy controls have a large proportion of potentially pathogenic E. coli phylotypes in their faecal flora without this causing infection. PMID- 24464693 TI - Role of Pseudomonas aeruginosa AmpR on beta-lactam and non-beta-lactam transient cross-resistance upon pre-exposure to subinhibitory concentrations of antibiotics. AB - Pseudomonas aeruginosa is one of the most dreaded opportunistic pathogens accounting for 10 % of hospital-acquired infections, with a 50 % mortality rate in chronically ill patients. The increased prevalence of drug-resistant isolates is a major cause of concern. Resistance in P. aeruginosa is mediated by various mechanisms, some of which are shared among different classes of antibiotics and which raise the possibility of cross-resistance. The goal of this study was to explore the effect of subinhibitory concentrations (SICs) of clinically relevant antibiotics and the role of a global antibiotic resistance and virulence regulator, AmpR, in developing cross-resistance. We investigated the induction of transient cross-resistance in P. aeruginosa PAO1 upon exposure to SICs of antibiotics. Pre-exposure to carbapenems, specifically imipenem, even at 3 ng ml( 1), adversely affected the efficacy of clinically used penicillins and cephalosporins. The high beta-lactam resistance was due to elevated expression of both ampC and ampR, encoding a chromosomal beta-lactamase and its regulator, respectively. Differences in the susceptibility of ampR and ampC mutants suggested non-AmpC-mediated regulation of beta-lactam resistance by AmpR. The increased susceptibility of P. aeruginosa in the absence of ampR to various antibiotics upon SIC exposure suggests that AmpR plays a major role in the cross resistance. AmpR was shown previously to be involved in resistance to quinolones by regulating MexEF-OprN efflux pump. The data here further indicate the role of AmpR in cross-resistance between quinolones and aminoglycosides. This was confirmed using quantitative PCR, where expression of the mexEF efflux pump was further induced by ciprofloxacin and tobramycin, its substrate and a non substrate, respectively, in the absence of ampR. The data presented here highlight the intricate cross-regulation of antibiotic resistance pathways at SICs of antibiotics and the need for careful assessment of the order of antibiotic regimens as this may have dire consequences. Targeting a global regulator such as AmpR that connects diverse pathways is a feasible therapeutic approach to combat P. aeruginosa pathogenesis. PMID- 24464695 TI - A novel high-throughput method for molecular serotyping and serotype-specific quantification of Streptococcus pneumoniae using a nanofluidic real-time PCR system. AB - Serotype-specific quantification data are essential for elucidating the complex epidemiology of Streptococcus pneumoniae and evaluating pneumococcal vaccine efficacy. Various PCR-based assays have been developed to circumvent the drawback of labour-intensive and time-consuming culture-based procedures for serotype determination and quantification of pneumococcus. Here, we applied a nanofluidic real-time PCR system to establish a novel assay. Twenty-nine primer pairs, 13 of which were newly designed, were selected for the assay to cover 50 serotypes including all currently available conjugate and polysaccharide vaccine serotypes. All primer pairs were evaluated for their sensitivity, specificity, efficiency, repeatability, accuracy and reproducibility on the Fluidigm Biomark HD System, a nanofluidic real-time PCR system, by drawing standard curves with a serial dilution of purified DNA. We applied the assay to 52 nasopharyngeal swab samples from patients with pneumonia confirmed by chest X-ray to validate its accuracy. Minimum detection levels of this novel assay using the nanofluidic real-time PCR system were comparable to the conventional PCR-based assays (between 30 and 300 copies per reaction). They were specific to their targets with good repeatability (sd of copy number of 0.1), accuracy (within +/-0.1 fold difference in log10 copy number) and reproducibility (sd of copy number of 0.1). When artificially mixed DNA samples consisting of multiple serotypes in various ratios were tested, all the serotypes were detected proportionally, including a minor serotype of one in 1000 copies. In the nasopharyngeal samples, the PCR system detected all the culture-positive samples and 22 out of 23 serotypes identified by the conventional method were matched with PCR results. We conclude that this novel assay, which is able to differentially quantify 29 pneumococcus groups for 45 test samples in a single run, is applicable to the large-scale epidemiological study of pneumococcus. We believe that this assay will facilitate our understanding of the roles of serotype-specific bacterial loads and implications of multiple serotype detections in pneumococcal diseases. PMID- 24464696 TI - Simultaneous isolation of emm89-type Streptococcus pyogenes strains with a wild type or mutated covS gene from a single streptococcal toxic shock syndrome patient. AB - Streptococcal toxic shock syndrome (STSS) is a re-emerging infectious disease in many developed countries. Recent studies have suggested that mutations in CovRS, a two-component regulatory system in Streptococcus pyogenes, play important roles in the pathogenesis of STSS. However, in vivo evidence of the significance of CovRS in human infections has not been fully demonstrated. We investigated five S. pyogenes strains isolated simultaneously from the pharynx, sputum, knee joint, cerebrospinal fluid and blood of a single STSS patient. All were emm89-type strains, and multilocus sequence typing (MLST) analysis revealed that the strains of pharynx and blood were isogenic. The growth rates of the strains from pharynx and sputum were faster than those of the other strains. Protein profiles of the culture supernatants of strains from the pharynx and sputum were also different from those of the other strains. Sequence analyses revealed that strains from the knee joint, cerebrospinal fluid and blood contained a single nucleotide difference in the covS coding region, resulting in one amino acid change, compared with the other strains. Introduction of a plasmid containing the covS gene from the pharynx strain to the blood strain increased the production of SpeB protein. This suggests that the one amino acid alteration in CovS was relevant to pathogenesis. This report supports the idea that mutated CovS plays important roles in vivo in the dissemination of S. pyogenes from the upper respiratory tract of human to aseptic tissues such as blood and cerebrospinal fluid. PMID- 24464697 TI - Is there any value in measuring faecal calprotectin in Clostridium difficile positive faecal samples? AB - Markers of intestinal inflammation have been proposed for inclusion in Clostridium difficile diagnostic algorithms. Faecal calprotectin (f-Cp), a sensitive marker of intestinal inflammation, was evaluated for utility in C. difficile diagnosis in the hospital setting. One hundred and twenty C. difficile positive and 99 C. difficile negative faecal samples of hospital-acquired diarrhoea were analysed for f-Cp using a quantitative ELISA. C. difficile positivity was confirmed using ELISAs for either toxins (n = 45) or glutamate dehydrogenase (GDH) with toxin gene confirmation (n = 75). Non-parametric ANOVA (Kruskal-Wallis) was used for data analysis. C. difficile positive samples had higher (P<0.05) median (interquartile range) f-Cp levels; 336 ug g(-1) (208-536) for toxin and 249 ug g(-1) (155-498) for GDH and toxin gene positive compared with 106 ug g(-1) (46-176) for C. difficile and culture-negative faecal samples. Five C. difficile positive samples were f-Cp negative (<50 ug g(-1)). A f-Cp concentration >50 ug g(-1) was 96 % sensitive and 26 % specific for C. difficile, with area under the ROC curve of 0.82. There is no role for f-CP alone in predicting C. difficile infection in hospital-acquired diarrhoea due to its low specificity. PMID- 24464698 TI - The epidemiology of life-threatening work-related injury--a demonstration paper. AB - BACKGROUND: Workers' compensation (WC) data traditionally provides information to stakeholders on work-related disabling injuries. It is important to complement this with information on serious threat to life (TTL) injury, which is the focus of this paper. METHODS: In this cross-sectional descriptive epidemiological study, based on New Zealand's WC data linked to hospital discharge data, TTL was measured using the ICD10-based Injury Severity Score (ICISS); ICISS <= 0.941 was used to define serious TTL injury. RESULTS: During 2002-2004, there was an average of 368 serious TTL work-related injury cases annually. The distribution of these injuries was very different from those traditionally found using WC data to describe disabling injury. For example, for serious TTL injury the main injury types included traumatic brain injury, whereas for disabling injury it was sprains and dislocations. CONCLUSIONS: The method presented provides the opportunity for government agencies to produce a national description of the epidemiology of serious TTL work-related injuries. PMID- 24464699 TI - Efflux pump-mediated antibiotics resistance: insights from computational structural biology. AB - The continuous rise of bacterial resistance against formerly effective pharmaceuticals is a major challenge for biomedical research. Since the first computational studies published seven years ago the simulation-based investigation of antibiotics resistance mediated by multidrug efflux pumps of the resistance nodulation division (RND) protein super family has grown into a vivid field of research. Here we review the employment of molecular dynamics computer simulations to investigate RND efflux pumps focusing on our group's recent contributions to this field studying questions of energy conversion and substrate transport in the inner membrane antiporter AcrB in Escherichia coli as well as access regulation and gating mechanism in the outer membrane efflux ducts TolC and OprM in E. coli and Pseudomonas aeruginosa. PMID- 24464700 TI - Exploring inhibitory potential of Curcumin against various cancer targets by in silico virtual screening. AB - Various types of cancer accounts for 10% of total death worldwide which necessitates better therapeutic strategies. Curcumin, a curcuminoid present in Curcuma longa, shown to exhibit antioxidant, anti-inflammatory and anticarcinogenic properties. Present study, we aimed to analyze inhibitory properties of curcumin towards virulent proteins for various cancers by computer aided virtual screening. Based on literature studies, twenty two receptors were selected which have critical virulent functions in various cancer. The binding efficiencies of curcumin towards selected targets were studied by molecular docking. Out of all, curcumin showed best results towards epidermal growth factor (EGF), virulent protein of gastric cancer; glutathione-S-transferase Pi gene (GST PI), virulent protein for prostate cancer; platelet-derived growth factor alpha (PDGFA), virulent protein for mesothelioma and glioma compared with their natural ligands. The calculated binding energies of their docked conformations with curcumin found to be -7.59 kcal/mol, -7.98 kcal/mol and -7.93 kcal/mol respectively. Further, a comparative study was performed to screen binding efficiency of curcumin with two conventional antitumor agents, litreol and triterpene. Docking studies revealed that calculated binding energies of docked complex of litreol and EGF, GST-PI and PDGFA were found to be -5.08 kcal/mol, 3.69 kcal/mol and -1.86 kcal/mol respectively. The calculated binding energies of triterpene with EGF and PDGFA were found to be -4.02 kcal/mol and -3.11 kcal/mol respectively, whereas GST-PI showed +6.07 kcal/mol, indicate poor binding. The predicted pharmacological features of curcumin found to be better than litreol and triterpene. Our study concluded that curcumin has better interacting properties towards these cancer targets than their normal ligands and conventional antitumor agents. Our data pave insight for designing of curcumin as novel inhibitors against various types of cancer. PMID- 24464701 TI - A theoretical study on the mechanism of a superficial mutation inhibiting the enzymatic activity of CYP1A2. AB - CYP1A2, one of the major members of cytochrome P450 in human liver, participates in the metabolism of various drugs. While most harmful mutations are located near the catalytic core of CYP1A2, a recently found loss-of-function mutation, F186L, is on the surface. By far, function of this superficial residue remains unclear. In this paper, 7-ethoxyresorufin, a widely used agent in benchmarking the O deethylation activities of CYP1A subfamily enzymes, was employed as a substrate to investigate the impact of the F186L mutation through ensemble docking and molecular dynamics simulations. It was found that the F186L mutation altered the binding inclination of the substrate through a series of changes on the catalytic pocket, which are, actually, long-range effects. The activities of access channels in the enzyme are also affected by the F186L mutation and the substrate binding. Based on these findings, a detailed mechanism of how F186 regulates the functions of CYP1A2 was proposed, and it may shed light on the diverse effects of SNPs and the personalized drug design. PMID- 24464702 TI - Structural characterization and mutational assessment of podocin - a novel drug target to nephrotic syndrome - an in silico approach. AB - Non-synonymous single nucleotide changes (nSNC) are coding variants that introduce amino acid changes in their corresponding proteins. They can affect protein function; they are believed to have the largest impact on human health compared with SNCs in other regions of the genome. Such a sequence alteration directly affects their structural stability through conformational changes. Presence of these conformational changes near catalytic site or active site may alter protein function and as a consequence receptor-ligand complex interactions. The present investigation includes assessment of human podocin mutations (G92C, P118L, R138Q, and D160G) on its structure. Podocin is an important glomerular integral membrane protein thought to play a key role in steroid resistant nephrotic syndrome. Podocin has a hairpin like structure with 383 amino acids, it is an integral protein homologous to stomatin, and acts as a molecular link in a stretch-sensitive system. We modeled 3D structure of podocin by means of Modeller and validated via PROCHECK to get a Ramachandran plot (88.5% in most favored region), main chain, side chain, bad contacts, gauche and pooled standard deviation. Further, a protein engineering tool Triton was used to induce mutagenesis corresponding to four variants G92C, P118L, R138Q and D160G in the wild type. Perusal of energies of wild and mutated type of podocin structures confirmed that mutated structures were thermodynamically more stable than wild type and therefore biological events favored synthesis of mutated forms of podocin than wild type. As a conclusive part, two mutations G92C (-8179.272 kJ/mol) and P118L (-8136.685 kJ/mol) are more stable and probable to take place in podocin structure over wild podocin structure (-8105.622 kJ/mol). Though there is lesser difference in mutated and wild type (approximately, 74 and 35 kJ/mol), it may play a crucial role in deciding why mutations are favored and occur at the genetic level. PMID- 24464703 TI - Combination of site directed mutagenesis and secondary structure analysis predicts the amino acids essential for stability of M. leprae MurE. AB - The life-threatening infections caused by Mycobacterium leprae (Mle) remain a major challenge in developing countries as well as globe and there is a need to design potent anti-leprosy drugs. In our previous studies, ATP-dependent Mle-MurE ligase involved in biosynthesis of peptidoglycan was identified as one of the common drug targets, homology modeled and reported. In this work in silico site directed mutagenesis study was carried out on the homology modeled Mle-MurE ligase. This predicted the amino acids essential for stability. In addition, the distribution of these residues in different secondary structures and in active sites was analyzed. Finally, the role of the conserved residues in stability and function was analyzed. The availability of Mle-MurE ligase built model together with insights gained from stability studies and docking studies will promote the rational design of potent and selective Mle-MurE ligase inhibitors as anti leprosy therapeutics. PMID- 24464704 TI - Application of a subtractive genomics approach for in silico identification and characterization of novel drug targets in Mycobacterium tuberculosis F11. AB - Extensive dead ends or host toxicity of the conventional approaches of drug development can be avoided by applying the in silico subtractive genomics approach in the designing of potential drug target against bacterial diseases. This study utilizes the advanced in silico genome subtraction methodology to design potential and pathogen specific drug targets against Mycobacterium tuberculosis, causal agent of deadly tuberculosis. The whole proteome of Mycobacterium tuberculosis F11 containing 3941 proteins have been analyzed through a series of subtraction methodologies to remove paralogous proteins and proteins that show extensive homology with human. The subsequent exclusion of these proteins ensured the absence of host cytotoxicity and cross reaction in the identified drug targets. The high stringency (expectation value 10(-100)) analysis of the remaining 2935 proteins against database of essential genes resulted in 274 proteins to be essential for Mycobacterium tuberculosis F11. Comparative analysis of the metabolic pathways of human and Mycobacterium tuberculosis F11 by KAAS at the KEGG server sorted out 20 unique metabolic pathways in Mycobacterium tuberculosis F11 that involve the participation of 30 essential proteins. Subcellular localization analysis of these 30 essential proteins revealed 7 proteins with outer membrane potentialities. All these proteins can be used as a potential therapeutic target against Mycobacterium tuberculosis F11 infection. 66 of the 274 essential proteins were uncharacterized (described as hypothetical) and functional classification of these proteins showed that they belonged to a wide variety of protein classes including zinc binding proteins, transferases, transmembrane proteins, other metal ion binding proteins, oxidoreductase, and primary active transporters etc. 2D and 3D structures of these 15 membrane associated proteins were predicted using PRED TMBB and homology modeling by Swiss model workspace respectively. The identified drug targets are expected to be of great potential for designing novel anti tuberculosis drugs and further screening of the compounds against these newly targets may result in discovery of novel therapeutic compounds that can be effective against Mycobacterium tuberculosis. PMID- 24464705 TI - Phylogenetic analysis of gammaproteobacterial arsenate reductase proteins specific to Enterobacteriaceae family, signifying arsenic toxicity. AB - This study focuses on the phylogenetic analysis of all the ArsC protein sequences, obtained from similarity search against Gammaproteobacteria, and also studies the role of Gammaproteobacterial family in arsenic toxicity. The ars gene provides arsenic tolerance for microbial cell system and encodes for an arsenate reductase (ArsC), which is essential for arsenate resistance that converts arsenate into arsenite. Phylogenetic analysis offers an opportunity to understand the evolutionary relationship between organisms of interest. The phylogenetic experiment was set up for all possible ArsC sequences in class Gammaproteobacteria. The results suggested a wide similarity between ArsC sequences in the species of Enterobacteriaceae family rather than other families in Gammaproteobacteria. The three evolutionary clades revealed a role of Enterobacteriaceae species, which has the capability to code ArsC protein. Further phylogenetic analysis of ArsC crystal structure sequences has also shown the separate cluster of Enterobacter species. The overall phylogeny of the ArsC protein sequences suggests the species of Enterobacteriaceae family express more among all family of Gammaproteobacteria. This study could be advantageous to emphasize the importance of Enterobacteriaceae in arsenic toxicity. PMID- 24464706 TI - Molecular modeling of ABC transporter system - permease proteins from Microcoleus chthonoplastes PCC 7420 for effective binding against secreted aspartyl proteinases in Candida albicans - a therapeutic intervention. AB - Secreted aspartyl proteinases (SAP) are the key virulence factors that play a central role in the pathogenesis of Candida albicans and always are the best target for designing potent antifungal agents. Cyanobacteria have already been recognized to provide chemical and pharmacological novelty and diversity over conventional sources of drugs for combating major diseases ranging from AIDS to cancer. In this study, the two ABC transporter systems - permease proteins from Microcoleus chthonoplastes PCC 7420 were modeled and the protein-protein interaction assessment of the modeled proteins with selective secreted aspartyl proteinases of Candida albicans was attempted. The modeled proteins were assigned PMDB IDs PM0077423 and PM0077424. The secreted aspartyl protease 5 of Candida albicans showed effective interaction with ABC transporter permease protein 2 of Microcoleus chthonoplastes PCC 7420. Hydrophobic interactions were found between Tyr, Phe and Pro in chain A and Pro and Tyr in chain B. Our results of the docked complexes clearly demonstrated the potentiality of permease proteins in arresting the virulence nature of SAP of Candida albicans effectively. This study is first of its kind in addressing the therapeutic intervention of virulence nature of Candida albicans by the cyanobacterial system. PMID- 24464707 TI - Prediction of human volume of distribution values for drugs using linear and nonlinear quantitative structure pharmacokinetic relationship models. AB - In the present study the volume of distribution values in humans of 121 drugs was estimated using quantitative structure pharmacokinetic relationship analysis. The multiple linear regression (MLR) method and nonlinear artificial neural network (ANN) and support vector machines (SVM) were employed for modeling. The theoretically calculated molecular descriptors were used for modeling and best set of descriptors selected by correlation based feature selection (CFS) method. The performance and predictive capability of linear method was investigated and compared with nonlinear method. The ANN gave better model with an average fold error of 1.66. The test set prediction accuracy shows human volume of distribution values could be predicted, on average, within 2-fold of the actual value. PMID- 24464708 TI - ESSPRI and other patient-reported indices in patients with primary Sjogren's syndrome during 100 consecutive outpatient visits at one rheumatological clinic. AB - OBJECTIVE: A European League Against Rheumatism (EULAR) SS disease activity index (ESSDAI) and a patient-reported index (ESSPRI) have recently been developed and validated. In our previous study the ESSDAI correlated significantly with serum beta2 microglobulin concentration. We now aim to establish whether the ESSPRI is also associated with serum beta2 microglobulin or with other patient-reported indices. METHODS: The data on 100 consecutive visits of patients with primary SS (pSS) were reviewed from the patient charts. Patients who had filled out the ESSPRI questionnaire and fulfilled at least four of the revised American-European consensus group criteria for pSS were included. Data were gathered on the ESSPRI (0-10 cm) and on the patient's global health assessment [visual analogue scale (VAS) 0-10 cm] (PGH-VAS), pain-VAS (0-10 cm) and HAQ (range 0-3). RESULTS: The ESSPRI correlated significantly with the PGH-VAS (r = 0.753, P < 0.0001), pain VAS (r = 0.656, P < 0.0001) and HAQ (r = 0.542, P < 0.0001) (Spearman's correlation). It also correlated weakly with serum beta2 microglobulin (r = 0.214, P = 0.043) and ESR levels (r = 0.235, P = 0.019). CONCLUSION: The ESSPRI correlated significantly with other patient-reported indices, serum beta2 microglobulin and ESR in patients with pSS. Our results support the view that the ESSPRI is a useful tool in the follow-up of patients with pSS. PMID- 24464709 TI - The Canadian systemic sclerosis oral health study: orofacial manifestations and oral health-related quality of life in systemic sclerosis compared with the general population. AB - OBJECTIVE: The aim of this study was to compare oral abnormalities and oral health-related quality of life (HRQoL) of patients with SSc with the general population. METHODS: SSc patients and healthy controls were enrolled in a multisite cross-sectional study. A standardized oral examination was performed. Oral HRQoL was measured with the Oral Health Impact Profile (OHIP). Multivariate regression analyses were performed to identify associations between SSc, oral abnormalities and oral HRQoL. RESULTS: We assessed 163 SSc patients and 231 controls. SSc patients had more decayed teeth (SSc 0.88, controls 0.59, P = 0.0465) and periodontal disease [number of teeth with pocket depth (PD) >3 mm or clinical attachment level (CAL) >=5.5 mm; SSc 5.23, controls 2.94, P < 0.0001]. SSc patients produced less saliva (SSc 147.52 mg/min, controls 163.19 mg/min, P = 0.0259) and their interincisal distance was smaller (SSc 37.68 mm, controls 44.30 mm, P < 0.0001). SSc patients had significantly reduced oral HRQoL compared with controls (mean OHIP score: SSc 41.58, controls 26.67, P < 0.0001). Multivariate regression analyses confirmed that SSc was a significant independent predictor of missing teeth, periodontal disease, interincisal distance, saliva production and OHIP scores. CONCLUSION: Subjects with SSc have impaired oral health and oral HRQoL compared with the general population. These data can be used to develop targeted interventions to improve oral health and HRQoL in SSc. PMID- 24464710 TI - Proteasome inhibitors for malignancy-related Lambert-Eaton myasthenic syndrome. AB - Lambert-Eaton myasthenic syndrome (LEMS) is an autoimmune disorder characterized by autoantibodies against presynaptic voltage-gated calcium channels that impair neuromuscular transmission. Malignancies, especially small cell lung cancer (SCLC), have been associated with LEMS and account for approximately 60% of cases, making malignancy management a central step in LEMS therapy. In addition, immunosuppressive therapy is also recommended for symptomatic control. Interestingly, both pathological and epidemiological data suggest that the autoimmune response can inhibit progression of tumors in malignancy-associated LEMS. Thus, conventional broad-spectrum immunosuppressants may not be effective agents for treatment of LEMS, especially in those with malignancy-associated LEMS. Recent preclinical and clinical studies have indicated that proteasome inhibitors can eliminate antibody-producing cells efficiently, block dendritic cell maturation, and have anti-tumor activity. We hypothesize that proteasome inhibitors may be promising agents for treatment of malignancy-related LEMS. PMID- 24464712 TI - Irisin ERKs the fat. PMID- 24464713 TI - Enteroviral infections and development of type 1 diabetes: The Brothers Karamazov within the CVBs. PMID- 24464714 TI - GLP-1--a candidate humoral mediator for glucose control after Roux-en-Y gastric bypass. PMID- 24464715 TI - LY2605541--a preferential hepato-specific insulin analogue. PMID- 24464716 TI - Turning off a viral/lipid sensor improves type 2 diabetes. PMID- 24464717 TI - Functional MRI signal fluctuations: a preclinical biomarker for cognitive impairment in type 2 diabetes? PMID- 24464718 TI - GLP-1: the oracle for gastric bypass? PMID- 24464719 TI - Aldose reductase meets histone acetylation: a new role for an old player. PMID- 24464720 TI - Toward personalized prevention of obesity: can vitamin D negate the FTO effect? PMID- 24464721 TI - Give the receptor a brake: slowing gastric emptying by GLP-1. PMID- 24464723 TI - Property-based design: optimization and characterization of polyvinyl alcohol (PVA) hydrogel and PVA-matrix composite for artificial cornea. AB - Each approach for artificial cornea design is toward the same goal: to develop a material that best mimics the important properties of natural cornea. Accordingly, the selection and optimization of corneal substitute should be based on their physicochemical properties. In this study, three types of polyvinyl alcohol (PVA) hydrogels with different polymerization degree (PVA1799, PVA2499 and PVA2699) were prepared by freeze-thawing techniques. After characterization in terms of transparency, water content, water contact angle, mechanical property, root-mean-square roughness and protein adsorption behavior, the optimized PVA2499 hydrogel with similar properties of natural cornea was selected as a matrix material for artificial cornea. Based on this, a biomimetic artificial cornea was fabricated with core-and-skirt structure: a transparent PVA hydrogel core, surrounding by a ringed PVA-matrix composite skirt that composed of graphite, Fe-doped nano hydroxyapatite (n-Fe-HA) and PVA hydrogel. Different ratio of graphite/n-Fe-HA can tune the skirt color from dark brown to light brown, which well simulates the iris color of Oriental eyes. Moreover, morphologic and mechanical examination showed that an integrated core-and-skirt artificial cornea was formed from an interpenetrating polymer network, no phase separation appeared on the interface between the core and the skirt. PMID- 24464724 TI - Endothelial tubes form from intracellular vacuoles in implanted biomaterial in vivo of rat. AB - When the porous biomaterials are used to implant in vivo of animal for repairing wound, the angiogenesis in microenvironment of porous biomaterial is a key process in order to achieve the goal of treatment. While clarifying the process of vascularization and its mechanism is of great significance for design and development of medical biomaterials. In this area, it is noted that the endothelial tubes of new capillaries are formed by intracellular vacuoles, which has been proved in vitro model of angiogenesis. However, there is still no conclusive evidence in vivo model for mammals. By experimental tracking and observation of angiogenesis in the biomaterials implanted in rats, the angiogenesis process and the characteristics were explored. This study focused on the behavior of endothelial cell (EC)s and the capillary lumen formatting from EC cord in sprouting. Through marking and observing the ECs, the experimental evidences of angiogenesis after implanted materials into rats were obtained, which including various stages, such as rapidly proliferating of ECs, assembling of ECs to build up cell cord and vacuoles formation in ECs. An important mechanism of lumen formation for mammal in vivo was proved, which complemented the experimental results of the assembly of endothelial tubes in vivo through the formation and fusion of vacuoles for transgenic zebrafish. Our results provide support for the model of lumen formation of new capillary in mammal. PMID- 24464725 TI - Chemical class rotations for control of Bemisia tabaci (Hemiptera: Aleyrodidae) on poinsettia and their effect on cryptic species population composition. AB - BACKGROUND: Bemisia tabaci, a polyphagous insect with over 900 host plants, is an effective vector of more than 100 plant viruses. Being highly fecund, B. tabaci has the potential to develop insecticide resistance rapidly, as demonstrated by reports of use failures with MEAM1 and MED cryptic species (commonly known as biotypes B and Q respectively). Insecticide resistance management is a key component of pest management practices. The research herein studied season-long rotational management programs on poinsettia and their impact on the ratio of MEAM1:MED cryptic species in the surviving treated populations. RESULTS: In all four experiments, only three of the treatments completely eliminated the adult or immature whiteflies, but all significantly reduced the populations. Out of 18 active ingredients tested, dinotefuran (applied as a soil drench) was the most efficacious against both MEAM1 and MED cryptic species compared with the other chemical or biorational insecticides evaluated. Reduced susceptibility of MED was reported against a variety of treatment regimes. CONCLUSION: Rotations can be used to manage MEAM1 and MED cryptic species and maintain a very low population level or completely eliminate Bemisia on poinsettia. It is imperative to continue to emphasize the importance of rotating among different modes of action in pest management programs in order to retain effective chemistries for as long as possible in the market place. PMID- 24464726 TI - Real-time quantification of matrix metalloproteinase and integrin alphavbeta3 expression during biomaterial-associated infection in a murine model. AB - Biomaterial implants and devices increase the risk of microbial infections due to the biofilm mode of growth of infecting bacteria on implant materials, in which bacteria are protected against antibiotic treatment and the local immune system. Matrix-metalloproteinases (MMPs) and cell surface integrin receptors facilitate transmigration of inflammatory cells toward infected or inflamed tissue. This study investigates the relationship between MMP- and integrin-expression and the clearance of infecting Staphylococcus aureus around implanted biomaterials in a murine model.MMP- and integrin alphavbeta3-expression were monitored in mice, with and without subcutaneously implanted biomaterial samples, in the absence and presence of bioluminescent S. aureus Xen36. Staphylococcal persistence was imaged longitudinally over time using bioluminescence imaging. The activatable MMPSense(r)680 and integrin-targeted IntegriSense(r)750 probes were injected on different days after implantation and their signal intensity and localisation monitored using fluorescence imaging. After sacrifice 7 or 16 days post implantation, staphylococci from biomaterial samples and surrounding tissues were cultured on agar-plates and presence of host inflammatory cells was histologically evaluated.MMP- and integrin-expression were equally enhanced in presence of staphylococci or biomaterials up to 7 days post-implantation, but their localisation along the biomaterial samples differed. Bacterial clearance from tissue was higher in the absence of biomaterials. It is of clinical relevance that MMP- and integrin-expression were enhanced in presence of both staphylococci and biomaterials, although the immune system in the presence of biomaterials remained hampered in eradicating bacteria during the first 7 days post-implantation. PMID- 24464727 TI - Fatigue failure of osteocyte cellular processes: implications for the repair of bone. AB - The physical effects of fatigue failure caused by cyclic strain are important and for most materials well understood. However, nothing is known about this mode of failure in living cells. We developed a novel method that allowed us to apply controlled levels of cyclic displacement to networks of osteocytes in bone. We showed that under cyclic loading, fatigue failure takes place in the dendritic processes of osteocytes at cyclic strain levels as low as one tenth of the strain needed for instantaneous rupture. The number of cycles to failure was inversely correlated with the strain level. Further experiments demonstrated that these failures were not artefacts of our methods of sample preparation and testing, and that fatigue failure of cell processes also occurs in vivo. This work is significant as it is the first time it has been possible to conduct fatigue testing on cellular material of any kind. Many types of cells experience repetitive loading which may cause failure or damage requiring repair. It is clinically important to determine how cyclic strain affects cells and how they respond in order to gain a deeper understanding of the physiological processes stimulated in this manner. The more we understand about the natural repair process in bone the more targeted the intervention methods may become if disruption of the repair process occurred. Our results will help to understand how the osteocyte cell network is disrupted in the vicinity of matrix damage, a crucial step in bone remodelling. PMID- 24464728 TI - Osteonecrosis with the use of polymethylmethacrylate cement for hip replacement: thermal-induced damage evidenced in vivo by decreased osteocyte viability. AB - Thermal damage to host bone is a possible source of compromise of fixation in patients undergoing cemented total hip replacement (THR). Data on the subject to date are derived from mathematical modelling powered by animal studies. The aim of this study was to assess the effect of cement thickness on osteocyte viability in a population of patients undergoing cemented THR. An in vivo model was designed and validated by means of a finite element analysis. During standard hip joint replacement in 14 patients, the femoral necks were exposed before final resection to the heat of a curing cement mantle equivalent to 2.5 (Group 1) or 5 mm (Group 2) in vivo in the cemented acetabulum. Matched controls were collected for each patient. Osteocyte counts and viability were assessed by means of haematoxylin and eosin (H&E) stain and lactate dehydrogenase (LDH) assay. Ex vivo experiments were performed to determine the extent of thermal insult. H&E staining proved unreliable for assessing thermal insult in the short term. The LDH assay was reliable and demonstrated a significant reduction in osteocyte viability to a depth of 2.19 mm in group 1 and 9.19 mm in group 2. There was a significant difference between the groups at all depths. The ex vivo experiments revealed thermoclines indicating that host bone in the population undergoing cemented THR is more sensitive to the thermal insult delivered by curing polymethylmethacrylate cement than previously believed. This thermal insult may weaken the fixation between bone and cement and contribute towards aseptic loosening, the commonest cause of failure of THRs. PMID- 24464729 TI - Early endothelial progenitor cells as a source of myeloid cells to improve the pre-vascularisation of bone constructs. AB - According to present knowledge, blood derived endothelial progenitor cells (EPC) might act as proangiogenic myeloid cells, which play a fundamental role in the regulation of angiogenesis and blood vessel reorganisation. In this context, we have evaluated the contribution of endogenous myeloid cells in co-cultures of blood derived outgrowth endothelial cells (OEC) and osteogenic cells. In addition, we investigated the role of EPC as a potential source of myeloid cells in the formation of vascular structures in an in vitro model consisting of mesenchymal stem cells (MSC) and OEC. For this purpose, we added EPCs to co cultures of MSC and OECs. Vascular structures and the co-localisation of myeloid cells were analysed by confocal laser microscopy (CLSM) for endothelial and myeloid markers and quantitative image analysis. The molecular effects of myeloid cells were evaluated by quantitative real time PCR, ELISA and protein arrays from cell culture supernatants and lysates. Endogenous myeloid cells were significantly co-localised with angiogenic structures in co-cultures of OEC and osteogenic cells. The active addition of EPC to co-cultures of OEC and MSC resulted in a statistically approved increase in the formation of prevascular structures at early stages of the co-culture process. In addition, we observed an increase of endothelial markers, indicating beneficial effects of EPC or myeloid cells on endothelial cell growth. Furthermore, real time PCR indicated high expression levels of CD68, CD11b and CD163 in co-cultures of EPC and MSC indicating that EPC act at least partly as macrophage like-cells. PMID- 24464731 TI - Letter from the Editor. PMID- 24464730 TI - Targeting estrogen receptor-beta for the prevention of nonmelanoma skin cancer. AB - The potential for targeting estrogen receptor (ER)-beta in various cancer models has been gaining considerable attention in recent years. In this issue of the journal, Chaudhary and colleagues demonstrate markedly decreased ultraviolet B (UVB)-induced skin cancer in a mouse model using a highly specific ER-beta agonist, ERB-041. The mechanisms that underlie this strong inhibitory effect are mediated by inhibition of proinflammatory signaling and epithelial-mesenchymal transition (EMT). The changes in EMT were due in part to modulation of WNT/beta catenin signaling. Collectively, the results from these studies provide important new insights into the mechanisms by which the ER-beta agonist ERB-041 inhibits UVB-induced skin cancer and opens the door for future studies that could examine combinatorial approaches for UVB-dependent skin cancer chemoprevention. PMID- 24464732 TI - An eco-friendly, quick and cost-effective method for the quantification of acrylamide in cereal-based baby foods. AB - BACKGROUND: The presence of acrylamide in cereal-based baby foods is a matter of great concern owing to its possible health effects. Derivatization followed by gas chromatography/mass spectrometry (GC/MS) is one of the most common methods to quantify acrylamide. However, it requires the use of toxic chemicals and is time consuming. The aim of this study was to develop an eco-friendly, rapid and inexpensive method for the determination of acrylamide in cereal-based baby foods. RESULTS: The method involves defatting with n-hexane, extraction into water, precipitation of proteins, bromination, extraction into ethyl acetate and injection into a GC/MS system. The effects of defatting, precipitation, treatment with triethylamine, addition of internal standard and column selection were reviewed. A flow chart for acrylamide analysis was prepared. To evaluate the applicability of the method, 62 different cereal-based baby foods were analyzed. The levels of acrylamide ranged from not detected (below the limit of detection) to 660 ug kg(-1). CONCLUSION: The method is more eco-friendly and less expensive because it consumes very little solvent relative to other methods using bromine solutions and ethyl acetate. In addition, sample pre-treatment requires no solid phase extraction or concentration steps. The method is recommended for the determination of trace acrylamide in complex cereal-based baby food products. PMID- 24464733 TI - Transient photocurrent response of small-molecule bulk heterojunction solar cells. AB - Transient photocurrent measurements are used to investigate the effects of processing additives on charge transport in small molecule bulk heterojunction solar cells. The additive decreased carrier recombination rates and improved carrier mobility, both of which are beneficial to carrier extraction. Geminate recombination of charge transfer excitons is ruled out by the data. PMID- 24464734 TI - Additional use of a phosphodiesterase 5 inhibitor in patients with pulmonary hypertension secondary to chronic systolic heart failure: a meta-analysis. AB - AIMS: Increased indiscriminate use of pulmonary artery hypertension-targeted drugs has been observed in patients with pulmonary hypertension (PH) secondary to heart failure. We performed a meta-analysis to evaluate the chronic effects of using phosphodiesterase 5 (PDE5) inhibitors to treat patients with PH secondary to chronic systolic heart failure. METHODS AND RESULTS: PubMed, EMBASE, and the Cochrane Library were searched up to October 2013 for randomized controlled trials (RCTs) assessing PDE5 inhibitor treatments in PH patients secondary to chronic heart failure. Six RCTs involving 206 chronic systolic heart failure patients with PH complications were included. Sildenafil was used in all trials. Sildenafil treatment resulted in fewer hospital admissions compared with the placebo treatment (3.15% vs. 12.20%; risk ratio 0.29; 95% confidence interval 0.11-0.77). Various haemodynamic parameters were improved with additional sildenafil treatment, including reduced mean pulmonary artery pressure [weighted mean difference (WMD) -5.71 mmHg, P<0.05] and pulmonary vascular resistance (WMD 81.5 dynes/cm(-5), P<0.00001), increased LVEF (WMD 3.95%, P<0.01), and unchanged heart rate and blood pressure. The exercise capacity improved (oxygen consumption at peak exercise, WMD 3.20 mL/min(-1)/kg(-1), P<0.00001; ventilation to CO2 production slope, WMD -5.89, P<0.00001), and the clinical symptoms were relieved based on the breathlessness (WMD 7.72, P<0.00001), fatigue (WMD 2.28, P<0.05), and emotional functioning (WMD 5.92, P<0.00001) scores. CONCLUSIONS: Additional sildenafil treatment is a potential therapeutic method to improve pulmonary exercise capacity and quality of life by ameliorating PH in patients with chronic systolic heart failure. PMID- 24464735 TI - US population aging and demand for inpatient services. AB - US inpatient capacity increased until the 1970s, then declined. The US Census Bureau expects the population aged >=65 years to more than double by 2050. The implications for national inpatient capacity requirements have not been quantified. Our objective was to calculate the number of hospital admissions that will be necessitated by population aging, ceteris paribus. We estimated 2011 nationwide age-specific hospitalization rates using data from the Nationwide Inpatient Sample and Census data. We applied these rates to the population expected by the Census Bureau to exist through 2050. By 2050, the US population is expected to increase by 41%. Our analysis suggests that based on expected changes in the population age structure by then, the annual number of hospitalizations will increase by 67%. Thus, inpatient capacity would have to expand 18% more than population growth to meet demand. Total aggregate inpatient days is projected to increase 22% more than population growth. The total projected growth in required inpatient capacity is 72%, accounting for both number of admissions and length of stay. This analysis accounts only for changes in the population's age structure. Other factors could increase or decrease demand, as discussed in the article. PMID- 24464736 TI - Improvement of cardiac function with device-based diaphragmatic stimulation in chronic heart failure patients: the randomized, open-label, crossover Epiphrenic II Pilot Trial. AB - AIMS: Device-based pacing-induced diaphragmatic stimulation (PIDS) may have therapeutic potential for chronic heart failure (HF) patients. We studied the effects of PIDS on cardiac function and functional outcomes. METHODS AND RESULTS: In 24 chronic HF patients with CRT, an additional electrode was attached to the left diaphragm. Randomized into two groups, patients received the following PIDS modes for 3 weeks in a different sequence: (i) PIDS off (control group); (ii) PIDS 0 ms mode (PIDS simultaneously with ventricular CRT pulse); or (iii) PIDS optimized mode (PIDS with optimized delay to ventricular CRT pulse). For PIDS optimization, acoustic cardiography was used. Effects of each PIDS mode on dyspnoea, power during exercise testing, and LVEF were assessed. Dyspnoea improved with the PIDS 0 ms mode (P = 0.057) and the PIDS optimized mode (P = 0.034) as compared with the control group. Maximal power increased from median 100.5 W in the control group to 104.0 W in the PIDS 0 ms mode (P = 0.092) and 109.5 W in the PIDS optimized mode (P = 0.022). Median LVEF was 33.5% in the control group, 33.0% in the PIDS 0 ms mode, and 37.0% in the PIDS optimized mode (P = 0.763 and P = 0.009 as compared with the control group, respectively). PIDS was asymptomatic in all patients. CONCLUSION: PIDS improves dyspnoea, working capacity, and LVEF in chronic HF patients over a 3 week period in addition to CRT. This pilot study demonstrates proof of principle of an innovative technology which should be confirmed in a larger sample. TRIAL REGISTRATION: NCT00769678. PMID- 24464737 TI - Quercetin-containing self-nanoemulsifying drug delivery system for improving oral bioavailability. AB - Quercetin is a dietary flavonoid with potential chemoprotective effects, but has low bioavailability because of poor aqueous solubility and low intestinal absorption. A quercetin-containing self-nanoemulsifying drug delivery system (Q SNEDDS) was developed to form oil-in-water nanoemulsions in situ for improving quercetin oral bioavailability. On the basis of the quercetin solubility, emulsifying ability, and stability after dispersion in an aqueous phase, an optimal SNEDDS consisting of castor oil, Tween(r) 80, Cremophor(r) RH 40, and PEG 400 (20:16:34:30, w/w) was identified. Upon mixing with water, Q-SNEDDS formed a nanoemulsion having a droplet size of 208.8 +/- 4.5 nm and zeta potential of 26.3 +/- 1.2 mV. The presence of Tween(r) 80 and PEG 400 increased quercetin solubility and maintained supersaturated quercetin concentrations (5 mg/mL) for >1 month. The optimized Q-SNEDDS significantly improved quercetin transport across a human colon carcinoma (Caco-2) cell monolayer. Fluorescence imaging demonstrated rapid absorption of the Q-SNEDDS within 40 min of oral ingestion. Following oral administration of Q-SNEDDS in rats (15 mg/kg), the area under the concentration curve and maximum concentration of plasma quercetin after 24 h increased by approximately twofold and threefold compared with the quercetin control suspension. These data suggest that this Q-SNEDDS formulation can enhance the solubility and oral bioavailability of quercetin for appropriate clinical application. PMID- 24464739 TI - N-terminal beta-strand swapping in a consensus-derived alternative scaffold driven by stabilizing hydrophobic interactions. AB - The crystal structure of an N-terminal beta-strand-swapped consensus-derived tenascin FN3 alternative scaffold has been determined. A comparison with the unswapped structure reveals that the side chain of residue F88 orients differently and packs more tightly with the hydrophobic core of the domain. Dimer formation also results in the burial of a hydrophobic patch on the surface of the domain. Thus, it appears that tighter packing of F88 in the hydrophobic core and burial of surface hydrophobicity provide the driving forces for the N-terminal beta-strand swapping, leading to the formation of a stable compact dimer. PMID- 24464740 TI - Ecotoxicological effects of perfluorooctanoic acid on freshwater microalgae Chlamydomonas reinhardtii and Scenedesmus obliquus. AB - As a persistent bioaccumulative compound, perfluorooctanoic acid (PFOA) is found in various ecosystems and receives growing attention. The acute toxicity of PFOA was tested on 2 freshwater microalgae, Chlamydomonas reinhardtii and Scenedesmus obliquus. The 96-h concentration for 50% of maximal effect (EC50) values were measured, physiological responses of the algae were investigated, and uptake of PFOA by the algae was quantified. The EC50 values for C. reinhardtii and S. obliquus were 51.9 +/- 1.0 mg/L and 44.0 +/- 1.5 mg/L PFOA, respectively. After 8 d exposure to PFOA ranging from 10 mg/L to 40 mg/L, the growth of C. reinhardtii was significantly inhibited, whereas that of S. obliquus was only slightly suppressed. Increases in malonaldehyde and proline levels were observed in the 2 algae when exposed to PFOA at certain concentrations, for instance, 20 mg/L and 40 mg/L, which is indicative of the trigger of a defensive mechanism. The percentage of PFOA that was adsorbed by the algae after 8-d exposure at a dosage between 5 mg/L and 20 mg/L ranged from 5.5% to 7.5%, and the uptake of PFOA by the algae exceeded 10%. PMID- 24464741 TI - Microfabrication of channel arrays promotes vessel-like network formation in cardiac cell construct and vascularization in vivo. AB - Pre-vascularization is important for the reconstruction of dense and metabolically active myocardial tissue and its integration with the host myocardium after implantation. Herein, we demonstrate that the fabrication of micro-channels in alginate scaffold combined with the presentation of adhesion peptides and an angiogenic growth factor promote vessel-like networks in the construct, both in vitro and in vivo. Using a CO2 laser engraving system, 200 um diameter channels were formed from top to bottom of the 2 mm thick alginate scaffold, with a channel-to-channel distance of 400 um. Cells were seeded in a sequential manner onto the scaffolds: first, human umbilical vascular endothelial cells (HUVECs) were seeded and cultured for three days, then neonatal rat cardiomyocytes (CMs) and cardiofibroblasts were added at a final cell ratio of 50:35:15, respectively, and the constructs were cultivated for an additional seven days. A vessel-like network was formed within the cell constructs, wherein HUVECs were organized around the channels in a multilayer manner, while the CMs were located in-between the channels and exhibited the characteristic morphological features of a mature cardiac fiber. Acellular scaffolds with the affinity-bound basic fibroblast growth factor were implanted subcutaneously in mice. Increased cell penetration into the channeled scaffold and greater vessel density were found in comparison with the nonchanneled scaffolds. Our results thus point to the importance of micro-channels as a major structural promoter of vascularization in scaffolds, in conjunction with the sequential preculture of ECs and angiogenic factor presentation. PMID- 24464742 TI - Contingent workers: Workers' compensation data analysis strategies and limitations. AB - The growth of the contingent workforce presents many challenges in the occupational safety and health arena. State and federal laws impose obligations and rights on employees and employers, but contingent work raises issues regarding responsibilities to maintain a safe workplace and difficulties in collecting and reporting data on injuries and illnesses. Contingent work may involve uncertainty about the length of employment, control over the labor process, degree of regulatory, or statutory protections, and access to benefits under workers' compensation. The paper highlights differences in regulatory protections and benefits among various types of contingent workers and how these different arrangements affect safety incentives. It discusses challenges caused by contingent work for accurate data reporting in existing injury and illness surveillance and benefit programs, differences between categories of contingent work in their coverage in various data sources, and opportunities for overcoming obstacles to effectively using workers' compensation data. PMID- 24464743 TI - A limited CpG-containing oligodeoxynucleotide therapy regimen induces sustained suppression of allergic airway inflammation in mice. AB - BACKGROUND: CpG-containing oligodeoxynucleotides (CpG-ODNs) are potent inhibitors of T helper 2 mediated allergic airway disease in sensitised mice challenged with allergen. A single treatment has transient effects but a limited series of treatments has potential to achieve clinically meaningful sustained inhibition of allergic airway disease. OBJECTIVE: To optimise the treatment regimen for sustained efficacy and to determine the mechanisms of action in mice of an inhaled form of CpG-ODN being developed for human asthma treatment. METHODS: We set up a chronic allergic-asthma model using ragweed-sensitised mice exposed weekly to intranasal ragweed. Using this model, the effects of a limited series of weekly intranasal 1018 ISS (CpG-ODN; B-class) treatments were evaluated during treatment and for several weeks after treatments had stopped but weekly allergen exposures continued. Treatment efficacy was evaluated by measuring effects on lung T helper 2 cytokines and eosinophilia, and lung dendritic cell function and T-cell responses. RESULTS: Twelve intranasal 1018 ISS treatments induced significant suppression of bronchoalveolar lavage eosinophilia and interleukin 4, 5 and 13 levels. This suppression of allergic T helper 2 parameters was maintained through 13 weekly ragweed exposures administered after treatment cessation. Subsequent experiments demonstrated that at least five treatments were required for lasting suppression. Although CpG-ODN induced moderate T helper 1 responses, suppression of allergic airway disease did not require interferon gamma but was associated with induction of a regulatory T-cell response. CONCLUSIONS: A short series of CpG-ODN treatments results in sustained suppression of allergic lung inflammation induced by a clinically relevant allergen. PMID- 24464744 TI - Follicular-patterned afflictions of the thyroid gland: reappraisal of the most discussed entity in endocrine pathology. AB - The past 25 years has seen a marked increase in our understanding of thyroid neoplasia, from the interrelationship with radiation exposure, the definition of variants of papillary carcinoma, to the application of molecular biology techniques to capture a more basic definition of tumor development, diagnosis, and prognostic implications. No other group of thyroid tumors has been studied as much as those with follicular pattern. In this review, we present a reappraisal of these controversial lesions in light of the issues with the diagnostic problems and classification schemes of follicular thyroid lesions, with emphasis on the progress made in the past quarter century and a focus on the current persistent controversies. PMID- 24464745 TI - Implantable device diagnostics on day of discharge identify heart failure patients at increased risk for early readmission for heart failure. AB - AIMS: We hypothesized that diagnostic data in implantable devices evaluated on the day of discharge from a heart failure hospitalization (HFH) can identify patients at risk for HF readmission (HFR) within 30 days. METHODS AND RESULTS: In this retrospective analysis of four studies enrolling patients with CRT devices, we identified patients with a HFH, device data on the day of discharge, and 30 day post-discharge clinical follow-up. Four diagnostic criteria were evaluated on the discharge day: (i) intrathoracic impedance>8 Omega below reference impedance; (ii) AF burden>6 h; (iii) CRT pacing<90%; and (iv) night heart rate>80 b.p.m. Patients were considered to have higher risk for HFR if >=2 criteria were met, average risk if 1 criterion was met, and lower risk if no criteria were met. A Cox proportional hazards model was used to compare the groups. The data cohort consisted of a total of 265 HFHs in 175 patients, of which 36 (14%) were followed by HFR. On the discharge day, >=2 criteria were met in 43 (16% of 265 HFHs), only 1 criterion was met in 92 (35%), and none of the four criteria were met in 130 HFHs (49%); HFR rates were 28, 16, and 7%, respectively. HFH with >=2 criteria met was five times more likely to have HFR compared with HFH with no criteria met (adjusted hazard ratio 5.0; 95% confidence interval 1.9-13.5, P=0.001). CONCLUSION: Device-derived diagnostic criteria evaluated on the day of discharge identified patients at significantly higher risk of HFR. PMID- 24464746 TI - Plasma galectin 3 and heart failure risk in the Physicians' Health Study. AB - AIMS: We sought to test the hypothesis that plasma galectin 3 (Gal-3) is positively associated with the risk of heart failure (HF) in male subjects. METHODS AND RESULTS: While Gal-3 has been reported as prognostic factor in HF patients, limited data are available on the role of Gal-3 in the development of HF. We used a prospective nested-case control study (n = 462 cases and 462 controls) within the Physicians' Health Study for current analyses. For each case of HF, we randomly selected one control among subjects that were alive and free of HF at the time of index case occurrence and matched on age, race, and time of blood collection. Gal-3 was measured using ELISA and we used conditional logistic regression to compute adjusted odds ratios. Mean age at baseline was 58.3 y and median log-Gal-3 was 1.50 (IQR: 1.20-1.73) ng/ml. Cubic splines suggested a non linear relation between Gal-3 and HF. Odds ratios (95% CI) for HF were 1.0 (ref), 0.89 (0.58-1.38), 1.08 (0.71-1.67), and 1.57 (1.03-2.39) across consecutive quartiles of Gal-3 after adjustment for body mass index, diabetes, atrial fibrillation, hypertension, C-reactive protein, alcohol, smoking, and exercise. The Gal-3-HF relation was seen for HF with and without antecedent coronary heart disease. CONCLUSIONS: Our data are consistent with a positive non-linear association between Gal-3 and HF risk in male subjects. PMID- 24464747 TI - Mechanistic comparison of Bacillus subtilis 6S-1 and 6S-2 RNAs--commonalities and differences. AB - Bacterial 6S RNAs bind to the housekeeping RNA polymerase (sigma(A)-RNAP in Bacillus subtilis) to regulate transcription in a growth phase-dependent manner. B. subtilis expresses two 6S RNAs, 6S-1 and 6S-2 RNA, with different expression profiles. We show in vitro that 6S-2 RNA shares hallmark features with 6S-1 RNA: Both (1) are able to serve as templates for pRNA transcription; (2) bind with comparable affinity to sigma(A)-RNAP; (3) are able to specifically inhibit transcription from DNA promoters, and (4) can form stable 6S RNA:pRNA hybrid structures that (5) abolish binding to sigma(A)-RNAP. However, pRNAs of equal length dissociate faster from 6S-2 than 6S-1 RNA, owing to the higher A,U-content of 6S-2 pRNAs. This could have two mechanistic implications: (1) Short 6S-2 pRNAs (<10 nt) dissociate faster instead of being elongated to longer pRNAs, which could make it more difficult for 6S-2 RNA-stalled RNAP molecules to escape from the sequestration; and (2) relative to 6S-1 RNA, 6S-2 pRNAs of equal length will dissociate more rapidly from 6S-2 RNA after RNAP release, which could affect pRNA turnover or the kinetics of 6S-2 RNA binding to a new RNAP molecule. As 6S-2 pRNAs have not yet been detected in vivo, we considered that cellular RNAP release from 6S-2 RNA might occur via 6S-1 RNA displacing 6S-2 RNA from the enzyme, either in the absence of pRNA transcription or upon synthesis of very short 6S-2 pRNAs (~ 5-mers, which would escape detection by deep sequencing). However, binding competition experiments argued against these possibilities. PMID- 24464748 TI - Estrogen-provided cardiac protection following burn trauma is mediated through a reduction in mitochondria-derived DAMPs. AB - Mitochondria-derived danger-associated molecular patterns (DAMPs) play important roles in sterile inflammation after acute injuries. This study was designed to test the hypothesis that 17beta-estradiol protects the heart via suppressing myocardial mitochondrial DAMPs after burn injury using an animal model. Sprague Dawley rats were given a third-degree scald burn comprising 40% total body surface area (TBSA). 17beta-Estradiol, 0.5 mg/kg, or control vehicle was administered subcutaneously 15 min following burn. The heart was harvested 24 h postburn. Estradiol showed significant inhibition on the productivity of H2O2 and oxidation of lipid molecules in the mitochondria. Estradiol increased mitochondrial antioxidant defense via enhancing the activities and expression of superoxide dismutase (SOD) and glutathione peroxidase (GPx). Estradiol also protected mitochondrial respiratory function and structural integrity. In parallel, estradiol remarkably decreased burn-induced release of mitochondrial cytochrome c and mitochondrial DNA (mtDNA) into cytoplasm. Further, estradiol inhibited myocardial apoptosis, shown by its suppression on DNA laddering and downregulation of caspase 1 and caspase 3. Estradiol's anti-inflammatory effect was demonstrated by reduction in systemic and cardiac cytokines (TNF-alpha, IL 1beta, and IL-6), decrease in NF-kappaB activation, and attenuation of the expression of inflammasome component ASC in the heart of burned rats. Estradiol provided cardiac protection was shown by reduction in myocardial injury marker troponin-I, amendment of heart morphology, and improvement of cardiac contractility after burn injury. Together, these data suggest that postburn administration of 17beta-estradiol protects the heart via an effective control over the generation of mitochondrial DAMPs (mtROS, cytochrome c, and mtDNA) that incite cardiac apoptosis and inflammation. PMID- 24464749 TI - Novel role of aminopeptidase-A in angiotensin-(1-7) metabolism post myocardial infarction. AB - Aminopeptidase-A (APA) is a less well-studied enzyme of the renin-angiotensin system. We propose that it is involved in cardiac angiotensin (ANG) metabolism and its pathologies. ANG-(1-7) can ameliorate remodeling after myocardial injury. The aims of this study are to (1) develop mass spectrometric (MS) approaches for the assessment of ANG processing by APA within the myocardium; and (2) investigate the role of APA in cardiac ANG-(1-7) metabolism after myocardial infarction (MI) using sensitive MS techniques. MI was induced in C57Bl/6 male mice by ligating the left anterior descending (LAD) artery. Frozen mouse heart sections (in situ assay) or myocardial homogenates (in vitro assay) were incubated with the endogenous APA substrate, ANG II. Results showed concentration and time-dependent cardiac formation of ANG III from ANG II, which was inhibited by the specific APA inhibitor, 4-amino-4-phosphonobutyric acid. Myocardial APA activity was significantly increased 24 h after LAD ligation (0.82 +/- 0.02 vs. 0.32 +/- 0.02 rhomol.min(-1).MUg(-1), MI vs. sham, P < 0.01). Both MS enzyme assays identified the presence of a new peptide, ANG-(2-7), m/z 784, which accumulated in the MI (146.45 +/- 6.4 vs. 72.96 +/- 7.0%, MI vs. sham, P < 0.05). Use of recombinant APA enzyme revealed that APA is responsible for ANG-(2-7) formation from ANG-(1-7). APA exhibited similar substrate affinity for ANG-(1-7) compared with ANG II {Km (ANG II) = 14.67 +/- 1.6 vs. Km [ANG-(1-7)] = 6.07 +/- 1.12 MUmol/l, P < 0.05}. Results demonstrate a novel role of APA in ANG-(1-7) metabolism and suggest that the upregulation of APA, which occurs after MI, may deprive the heart of cardioprotective ANG-(1-7). Thus APA may serve as a potentially novel therapeutic target for management of tissue remodeling after MI. PMID- 24464750 TI - Vascular endothelial growth factor-C: its unrevealed role in fibrogenesis. AB - Vascular endothelial growth factor (VEGF)-C is a key mediator of lymphangiogenesis. Our recent study shows that VEGF-C/VEGF receptors (VEGFR)-3 are significantly increased in the infarcted rat myocardium, where VEGFR-3 is expressed not only in lymph ducts but also in myofibroblasts, indicating that VEGF-C has an unrevealed role in fibrogenesis during cardiac repair. The current study is to explore the regulation and molecular mechanisms of VEGF-C in fibrogenesis. The potential regulation of VEGF-C on myofibroblast differentiation/growth/migration, collagen degradation/synthesis, and transforming growth factor (TGF)-beta and ERK pathways was detected in cultured cardiac myofibroblasts. Our results showed that VEGF-C significantly increased myofibroblast proliferation, migration, and type I/III collagen production. Matrix metalloproteinase (MMP)-2 and -9 were significantly elevated in the medium of VEGF-C-treated cells, coincident with increased tissue inhibitor of metalloproteinase (TIMP)-1 and TIMP-2. Furthermore, VEGF-C activated the TGF beta1 pathway and ERK phosphorylation, which was significantly suppressed by TGF beta or ERK blockade. This is the first study indicating that in addition to lymphangiogenesis, VEGF-C is also involved in fibrogenesis through stimulation of myofibroblast proliferation, migration, and collagen synthesis, via activation of the TGF-beta1 and ERK pathways. PMID- 24464752 TI - Ranolazine improves diastolic function in spontaneously hypertensive rats. AB - Diastolic dysfunction can lead to heart failure with preserved ejection fraction, for which there is no effective therapeutic. Ranolazine has been reported to reduce diastolic dysfunction, but the specific mechanisms of action are unclear. The effect of ranolazine on diastolic function was examined in spontaneously hypertensive rats (SHRs), where left ventricular relaxation is impaired and stiffness increased. The objective of this study was to determine whether ranolazine improves diastolic function in SHRs and identify the mechanism(s) by which improvement is achieved. Specifically, to test the hypothesis that ranolazine, by inhibiting late sodium current, reduces Ca(2+) overload and promotes ventricular relaxation and reduction in diastolic stiffness, the effects of ranolazine or vehicle on heart function and the response to dobutamine challenge were evaluated in aged male SHRs and Wistar-Kyoto rats by echocardiography and pressure-volume loop analysis. The effects of ranolazine and the more specific sodium channel inhibitor tetrodotoxin were determined on the late sodium current, sarcomere length, and intracellular calcium in isolated cardiomyocytes. Ranolazine reduced the end-diastolic pressure-volume relationship slope and improved diastolic function during dobutamine challenge in the SHR. Ranolazine and tetrodotoxin also enhanced cardiomyocyte relaxation and reduced myoplasmic free Ca(2+) during diastole at high-stimulus rates in the SHR. The density of the late sodium current was elevated in SHRs. In conclusion, ranolazine was effective in reducing diastolic dysfunction in the SHR. Its mechanism of action, at least in part, is consistent with inhibition of the increased late sodium current in the SHR leading to reduced Ca(2+) overload. PMID- 24464751 TI - Phosphodiesterase-5 activity exerts a coronary vasoconstrictor influence in awake swine that is mediated in part via an increase in endothelin production. AB - Nitric oxide (NO)-induced coronary vasodilation is mediated through production of cyclic guanosine monophosphate (cGMP) and through inhibition of the endothelin-1 (ET) system. We previously demonstrated that phosphodiesterase-5 (PDE5)-mediated cGMP breakdown and ET each exert a vasoconstrictor influence on coronary resistance vessels. However, little is known about the integrated control of coronary resistance vessel tone by these two vasoconstrictor mechanisms. In the present study, we investigated the contribution of PDE5 and ET to the regulation of coronary resistance vessel tone in swine both in vivo, at rest and during graded treadmill exercise, and in vitro. ETA/ETB receptor blockade with tezosentan (3 mg/kg iv) and PDE5 inhibition with EMD360527 (300 MUg.min(-1).kg( 1) iv) each produced coronary vasodilation at rest and during exercise as well as in preconstricted isolated coronary small arteries. In contrast, tezosentan failed to produce further coronary vasodilation in the presence of EMD360527, both in vivo and in vitro. Importantly, EMD360527 (3 MUM) and cGMP analog 8-Br cGMP (100 MUM) had no significant effects on ET-induced contractions of isolated porcine coronary small arteries, suggesting unperturbed ET receptor responsiveness. In contrast, PDE5 inhibition and cGMP blunted the contractions produced by the ET precursor Big ET, but only in vessels with intact endothelium, suggesting that PDE5 inhibition limited ET production in the endothelium of small coronary arteries. In conclusion, PDE5 activity exerts a vasoconstrictor influence on coronary resistance vessels that is mediated, in part, via an increase in endothelial ET production. PMID- 24464754 TI - Interaction between respiration and right versus left ventricular volumes at rest and during exercise: a real-time cardiac magnetic resonance study. AB - Breathing-induced changes in intrathoracic pressures influence left ventricular (LV) and right ventricular (RV) volumes, the exact nature and extent of which have not previously been evaluated in humans. We sought to examine this "respiratory pump" using novel real-time cardiac magnetic resonance (CMR) imaging. Eight healthy subjects underwent serial multislice real-time CMR during normal breathing, breath holding, and the Valsalva maneuver. Subsequently, a separate cohort of nine subjects underwent real-time CMR at rest and during incremental exercise. LV and RV end-diastolic volume (EDV) and end-systolic volume (ESV) and diastolic and systolic eccentricity indexes were determined at peak inspiration and expiration. During normal breathing, inspiration resulted in an increase in RV volumes [RVEDV: +18 +/- 8%, RVESV: +14 +/- 12%, and RV stroke volume (SV): +21 +/- 10%, P < 0.01] and an opposing decrease in LV volumes (P < 0.0001 for interaction). During end-inspiratory breath holding, RV SV decreased by 9 +/- 10% (P = 0.046), whereas LV SV did not change. During the Valsalva maneuver, volumes decreased in both ventricles (RVEDV: -29 +/- 11%, RVESV: -16 +/ 14%, RV SV: -36 +/- 14%, LVEDV: -22 +/- 17%, and LV SV: -25 +/- 17%, P < 0.01). The reciprocal effect of respiration on LV and RV volumes was maintained throughout exercise. The diastolic and systolic eccentricity indexes were greater during inspiration than during expiration, both at rest and during exercise (P < 0.0001 for both). In conclusion, ventricular volumes oscillate with respiratory phase such that RV and LV volumes are maximal at peak inspiration and expiration, respectively. Thus, interpretation of RV versus LV volumes requires careful definition of the exact respiratory time point for proper interpretation, both at rest and during exercise. PMID- 24464753 TI - Resveratrol promotes endothelial cell wound healing under laminar shear stress through an estrogen receptor-alpha-dependent pathway. AB - Restenosis is an adverse outcome of angioplasty, characterized by vascular smooth muscle cell (VSMC) hyperplasia. However, therapies targeting VSMC proliferation delay re-endothelialization, increasing the risk of thrombosis. Resveratrol (RESV) inhibits restenosis and promotes re-endothelialization after arterial injury, but in vitro studies assessing RESV-mediated effects on endothelial cell growth contradict these findings. We thus hypothesized that fluid shear stress, mimicking physiological blood flow, would recapitulate RESV-dependent endothelial cell wound healing. Since RESV is an estrogen receptor (ER) agonist, we tested whether RESV promotes re-endothelialization through an ER-alpha-dependent mechanism. Mice fed a high-fat diet or a diet supplemented with RESV were subjected to carotid artery injury. At 7 days after injury, RESV significantly accelerated re-endothelialization compared with vehicle. In vitro wound healing assays demonstrated that RESV exhibits cell-type selectivity, inhibiting VSMC, but not endothelial cell growth. Under laminar shear stress (LSS), RESV dramatically enhanced endothelial cell wound healing and increased both the activation of extracellular signal-regulated kinase (ERK) and endothelial cell proliferation. Under LSS, small interfering RNA against ER-alpha, but not endothelial nitric oxide synthase, abolished RESV-induced ERK activation, endothelial cell proliferation, and wound healing. Thus these studies suggest that the EC phenotype induced by LSS better models the prohealing effects of RESV and that RESV and LSS interact to promote an ER-alpha-dependent mitogenic effect in endothelial cells. PMID- 24464755 TI - Contractile dysfunction in a mouse model expressing a heterozygous MYBPC3 mutation associated with hypertrophic cardiomyopathy. AB - The etiology of hypertrophic cardiomyopathy (HCM) has been ascribed to mutations in genes encoding sarcomere proteins. In particular, mutations in MYBPC3, a gene which encodes cardiac myosin binding protein-C (cMyBP-C), have been implicated in over one third of HCM cases. Of these mutations, 70% are predicted to result in C'-truncated protein products, which are undetectable in tissue samples. Heterozygous carriers of these truncation mutations exhibit varying penetrance of HCM, with symptoms often occurring later in life. We hypothesize that heterozygous carriers of MYBPC3 mutations, while seemingly asymptomatic, have subtle functional impairments that precede the development of overt HCM. This study compared heterozygous (+/t) knock-in MYBPC3 truncation mutation mice with wild-type (+/+) littermates to determine whether functional alterations occur at the whole-heart or single-cell level before the onset of hypertrophy. The +/t mice show ~40% reduction in MYBPC3 transcription, but no changes in cMyBP-C level, phosphorylation status, or cardiac morphology. Nonetheless, +/t mice show significantly decreased maximal force development at sarcomere lengths of 1.9 MUm (+/t 68.5 +/- 4.1 mN/mm(2) vs. +/+ 82.2 +/- 3.2) and 2.3 MUm (+/t 79.2 +/- 3.1 mN/mm(2) vs. +/+ 95.5 +/- 2.4). In addition, heterozygous mice show significant reductions in vivo in the early/after (E/A) (+/t 1.74 +/- 0.12 vs. +/+ 2.58 +/- 0.43) and E'/A' (+/t 1.18 +/- 0.05 vs. +/+ 1.52 +/- 0.15) ratios, indicating diastolic dysfunction. These results suggest that seemingly asymptomatic heterozygous MYBPC3 carriers do suffer impairments that may presage the onset of HCM. PMID- 24464757 TI - Cardiac contraction, calcium transients, and myofilament calcium sensitivity fluctuate with the estrous cycle in young adult female mice. AB - This study established conditions to induce regular estrous cycles in female C57BL/6J mice and investigated the impact of the estrous cycle on contractions, Ca2+ transients, and underlying cardiac excitation-contraction (EC)-coupling mechanisms. Daily vaginal smears from group-housed virgin female mice were stained to distinguish estrous stage (proestrus, estrus, metestrus, diestrus). Ventricular myocytes were isolated from anesthetized mice. Contractions and Ca2+ transients were measured simultaneously (4 Hz, 37 degrees C). Interestingly, mice did not exhibit regular cycles unless they were exposed to male pheromones in bedding added to their cages. Field-stimulated myocytes from mice in estrus had larger contractions (~2-fold increase), larger Ca2+ transients (~1.11-fold increase), and longer action potentials (>2-fold increase) compared with other stages. Larger contractions and Ca2+ transients were not observed in estrus myocytes voltage-clamped with shorter action potentials. Voltage-clamp experiments also demonstrated that estrous stage had no effect on Ca2+ current, EC-coupling gain, diastolic Ca2+, sarcoplasmic reticulum (SR) Ca2+ content, or fractional release. Although contractions were largest in estrus, myofilament Ca2+ sensitivity was lowest (EC50 values ~1.15-fold higher) in conjunction with increased phosphorylation of myosin binding protein C in estrus. Contractions were enhanced in ventricular myocytes from mice in estrus because action potential prolongation increased SR Ca2+ release. These findings demonstrate that cyclical changes in reproductive hormones associated with the estrous cycle can influence myocardial electrical and contractile function and modify Ca2+ homeostasis. However, such changes are unlikely to occur in female mice housed in groups under conventional conditions, since these mice do not exhibit regular estrous cycles. PMID- 24464756 TI - Enhanced large conductance K+ channel activity contributes to the impaired myogenic response in the cerebral vasculature of Fawn Hooded Hypertensive rats. AB - Recent studies have indicated that the myogenic response (MR) in cerebral arteries is impaired in Fawn Hooded Hypertensive (FHH) rats and that transfer of a 2.4 megabase pair region of chromosome 1 (RNO1) containing 15 genes from the Brown Norway rat into the FHH genetic background restores MR in a FHH.1(BN) congenic strain. However, the mechanisms involved remain to be determined. The present study examined the role of the large conductance calcium-activated potassium (BK) channel in impairing the MR in FHH rats. Whole-cell patch-clamp studies of cerebral vascular smooth muscle cells (VSMCs) revealed that iberiotoxin (IBTX; BK inhibitor)-sensitive outward potassium (K+) channel current densities are four- to fivefold greater in FHH than in FHH.1(BN) congenic strain. Inside-out patches indicated that the BK channel open probability (NPo) is 10 fold higher and IBTX reduced NPo to a greater extent in VSMCs isolated from FHH than in FHH.1(BN) rats. Voltage sensitivity of the BK channel is enhanced in FHH as compared with FHH.1(BN) rats. The frequency and amplitude of spontaneous transient outward currents are significantly greater in VSMCs isolated from FHH than in FHH.1(BN) rats. However, the expression of the BK-alpha and -beta-subunit proteins in cerebral vessels as determined by Western blot is similar between the two groups. Middle cerebral arteries (MCAs) isolated from FHH rats exhibited an impaired MR, and administration of IBTX restored this response. These results indicate that there is a gene on RNO1 that impairs MR in the MCAs of FHH rats by enhancing BK channel activity. PMID- 24464758 TI - Mechanism of reentry induction by a 9-V battery in rabbit ventricles. AB - Although the application of a 9-V battery to the epicardial surface is a simple method of ventricular fibrillation induction, the fundamental mechanisms underlying this process remain unstudied. We used a combined experimental and modelling approach to understand how the interaction of direct current (DC) from a battery may induce reentrant activity within rabbit ventricles and its dependence on battery application timing and duration. A rabbit ventricular computational model was used to simulate 9-V battery stimulation for different durations at varying onset times during sinus rhythm. Corresponding high resolution optical mapping measurements were conducted on rabbit hearts with DC stimuli applied via a relay system. DC application to diastolic tissue induced anodal and cathodal make excitations in both simulations and experiments. Subsequently, similar static epicardial virtual electrode patterns were formed that interacted with sinus beats but did not induce reentry. Upon battery release during diastole, break excitations caused single ectopics, similar to application, before sinus rhythm resumed. Reentry induction was possible for short battery applications when break excitations were slowed and forced to take convoluted pathways upon interaction with refractory tissue from prior make excitations or sinus beats. Short-lived reentrant activity could be induced for battery release shortly after a sinus beat for longer battery applications. In conclusion, the application of a 9-V battery to the epicardial surface induces reentry through a complex interaction of break excitations after battery release with prior induced make excitations or sinus beats. PMID- 24464759 TI - Anxiolytic-like effects of mitragynine in the open-field and elevated plus-maze tests in rats. AB - The effects of mitragynine on anxiety-related behaviours in the open-field and elevated plus-maze tests were evaluated. Male Sprague-Dawley rats were orally treated with mitragynine (10, 20 and 40 mg/kg) or diazepam (10 mg/kg) 60 min before behavioural testing. Mitragynine doses used in this study were selected on the basis of approximately human equivalent doses with reference to our previous literature reports. Acute administration of mitragynine (10, 20 and 40 mg/kg) or diazepam (10 mg/kg) increased central zone and open arms exploration in the open field and elevated plus-maze tests respectively. These anxiolytic-like effects of mitragynine were effectively antagonized by intraperitoneal administration of naloxone (2 mg/kg), flumazenil (10 mg/kg), sulpiride (0.5 mg/kg) or SCH 23390 (0.02 mg/kg) 15 min before mitragynine treatments. These findings reveal that the acute administration of mitragynine produces anxiolytic-like effects and this could be possibly attributed to the interactions among opioidergic, GABAergic and dopaminergic systems in brain regions involved in anxiety. PMID- 24464760 TI - Protective effects of Althaea officinalis L. extract in 6-hydroxydopamine-induced hemi-Parkinsonism model: behavioral, biochemical and histochemical evidence. AB - It is well known that Parkinson's disease (PD) is the second most common neurodegenerative disorder in humans. In this regard, the neuroprotective effect of Althaea officinalis (AO) has already been reported. Therefore, this study examined whether administration of AO extract would improve behavioral, biochemical and structural abnormalities in an experimental animal model of PD in rats. For this purpose, we induced hemi-Parkinsonism by unilateral intranigral injection of 6-hydroxydopamine (6-OHDA, 8 MUg/5 MUl saline-ascorbate). The rats were pretreated i.p. with AO extract (10 mg/kg) started 6 days before surgery and continued until the 3rd day post-surgery. Regarding oxidative stress, brain MDA concentration (as a lipid peroxidation marker) increased significantly in the 6 OHDA-administered group in comparison with rats pretreated with AO extract. It was found that AO treatment attenuated rotational behavior in the 6-OHDA administered group and protected the neurons of substantia nigra pars compacta against 6-OHDA toxicity. Overall, AO extract administration indicated neuroprotective effects against 6-OHDA-induced hemi-Parkinsonism in rats. PMID- 24464761 TI - Angiotensin axis blockade, hypotension, and acute kidney injury in elective major orthopedic surgery. AB - BACKGROUND: Patients presenting for surgery with angiotensin axis blockade (AAB) from therapy with either angiotensin-converting enzyme inhibitors or angiotensin receptor blockers experience an increased incidence of perioperative hypotension. Acute kidney injury (AKI) in patients receiving preoperative AAB has been demonstrated after lung, vascular, and cardiac surgery. However, there is little literature evaluating the hypotensive and renal effects of preoperative AAB and major orthopedic surgery. METHODS: We performed a retrospective chart review of 1154 patients who underwent spinal fusion, total knee arthroplasty, or total hip arthroplasty during the 2010 calendar year in our academic medical center. RESULTS: A total of 922 patients met inclusion criteria, 343 (37%) received preoperative AAB. Postinduction hypotension (systolic blood pressure <=80 mm Hg for 5 minutes) was significantly higher in patients receiving AAB when compared to those not so treated (12.2% vs 6.7%; odds ratio [OR]: 1.93, P = 0.005). Of the 922 patients, 798 had documented measurements of both preoperative and postoperative creatinine. Postoperative AKI was significantly higher in patients receiving AAB therapy (8.3% vs 1.7%; OR: 5.40, P < 0.001), remaining significant after adjusting for covariates including hypotension (OR: 2.60, P = 0.042). Developing AKI resulted in a significantly higher mean length of stay (5.76 vs 3.28 days, P < 0.001) but no difference in 2-year mortality. CONCLUSIONS: Patients undergoing major elective orthopedic surgery who receive preoperative AAB therapy,have an associated increased risk of postinduction hypotension and postoperative acute kidney injury resulting in a greater hospital length of stay. PMID- 24464762 TI - Novel graphene/carbon nanotube composite fibers for efficient wire-shaped miniature energy devices. AB - Novel nanostructured composite fibers based on graphene and carbon nanotubes are developed with high tensile strength, electrical conductivity, and electrocatalytic activity. As two application demonstrations, these composite fibers are used to fabricate flexible, wire-shaped dye-sensitized solar cells and electrochemical supercapacitors, both with high performances, for example, a maximal energy conversion efficiency of 8.50% and a specific capacitance of ca. 31.50 F g(-1). These miniature wire-shaped devices are further shown to be promising for flexible and portable electronic facilities. PMID- 24464763 TI - The relationship between body fat mass percentiles and inflammation in children. AB - OBJECTIVE: Obesity has been associated with markers of increased systemic inflammation in both human and animal studies. Increased inflammation is linked to metabolic and cardiovascular disease. The objective of this study was to evaluate the association between percentile body fat and inflammation in a nationally representative sample of US children. METHODS: 6,950 children 8-18 years of age between 1999 and 2004 were studied. Measurement of body fat percentage was measured by dual-energy X-ray absorptiometry scan and converted to an age- and sex-adjusted percentile. The main outcome measures were abnormal c reactive protein (CRP > 1.0 mg/dl) and absolute neutrophil count (ANC > 6,600). RESULTS: Children with higher levels of body fat (>=70th percentile) had a higher odds of having elevated CRP (OR 2.88-10.69) and elevated ANC (OR 2.14-3.24) compared with children with body fat <70th percentile. CONCLUSIONS: The link between inflammation and body fat in children warrants further longitudinal research to understand the temporal relationship between overweight/obesity and inflammation in the pediatric obese population and its implications for chronic disease risk. PMID- 24464764 TI - Fate and survival of Salmonella Typhimurium and Escherichia coli O157:H7 in repacked soil lysimeters after application of cattle slurry and human urine. AB - BACKGROUND: Use of cattle slurry as a fertiliser is common practice around the world. Human urine use is not as common, but owing to its fertiliser value this might change in the future. It is essential to minimise the transfer of enteric pathogens through fertilisation, with respect to both animal and public health. Therefore the objective of this research was to study the survival and transport of Salmonella Typhimurium and Escherichia coli O157:H7 in two agricultural soils when applied to soil along with either cattle slurry or human urine over a period of 180 days. RESULTS: Both Salmonella and E. coli O157:H7 were more rapidly reduced when applied together with human urine than when applied with cattle slurry. However, both pathogens persisted in low amounts at 20 and 50 cm depth in both soils throughout the whole study period. No Salmonella or E. coli O157:H7 was detected in the leachate over the 180 day study. CONCLUSION: The risk of disease transmission is higher when cattle slurry is used as fertiliser compared with human urine. However, the risk of groundwater infiltration would be low as long as water velocity through the soil is moderate. Increased knowledge of pathogen persistence in soil after fertiliser application is a valuable tool for improving risk evaluations and formulating guidelines for the use of cattle and/or human wastes in cropping soils. PMID- 24464765 TI - 3D printing of composite tissue with complex shape applied to ear regeneration. AB - In the ear reconstruction field, tissue engineering enabling the regeneration of the ear's own tissue has been considered to be a promising technology. However, the ear is known to be difficult to regenerate using traditional methods due to its complex shape and composition. In this study, we used three-dimensional (3D) printing technology including a sacrificial layer process to regenerate both the auricular cartilage and fat tissue. The main part was printed with poly caprolactone (PCL) and cell-laden hydrogel. At the same time, poly-ethylene glycol (PEG) was also deposited as a sacrificial layer to support the main structure. After complete fabrication, PEG can be easily removed in aqueous solutions, and the procedure for removing PEG has no effect on the cell viability. For fabricating composite tissue, chondrocytes and adipocytes differentiated from adipose-derived stromal cells were encapsulated in hydrogel to dispense into the cartilage and fat regions, respectively, of ear-shaped structures. Finally, we fabricated the composite structure for feasibility testing, satisfying expectations for both the geometry and anatomy of the native ear. We also carried out in vitro assays for evaluating the chondrogenesis and adipogenesis of the cell-printed structure. As a result, the possibility of ear regeneration using 3D printing technology which allowed tissue formation from the separately printed chondrocytes and adipocytes was demonstrated. PMID- 24464766 TI - Neurological presentations of the antiphospholipid syndrome: three illustrative cases. AB - The antiphospholipid syndrome (APS) is defined by the association of high titers of antiphospholipid antibodies (aPLs) with thrombotic events and/or obstetrical problems. APS can be isolated or associated with immune system diseases. Several central nervous system (CNS) manifestations have been reported in APS, but are still not included in the international diagnostic criteria. We present here three cases of APS revealed by CNS manifestations. The first patient had a primary APS with stroke, dementia, epilepsy and the "so-called" Liebman-Sacks disease, a subacute thrombotic non-bacterial valvulopathy. The second one developed a primary APS with a Sneddon syndrome, while the third case is a neurolupus-associated APS with subacute encephalopathy, chorea, stroke, and epilepsy. The pathogenesis of the APS is related to both prothrombotic and immunologic effects of the aPLs. Long-term anticoagulation by low-weight heparin or warfarin is currently recommended in APS. We propose to search the presence of aPLs in any case of young adults' stroke, unexplained dementia, and acquired chorea. PMID- 24464767 TI - Left ventricular function in alpha-sarcoglycanopathy and gamma-sarcoglycanopathy. AB - Sarcoglycanopathies are autosomic recessive muscular dystrophies, secondary to mutations of the sarcoglycan complex. Heart can be involved in sarcoglycanopathies. We sought to analyse left ventricular function in patients with alpha-sarcoglycanopathy and gamma-sarcoglycanopathy. We conducted a retrospective study that aimed to analyse clinical and echocardiographic data of patients with sarcoglycanopathies. Our study included 19 patients: eight patients with alpha-sarcoglycanopathy and 11 patients with gamma-sarcoglycanopathy. Mean age was 37.8 +/- 8.7 years in alpha-sarcoglycanopathy and 36 +/- 7.3 years in gamma-sarcoglycanopathy. Mean VC was, respectively, 36.3 +/- 18 % in alpha sarcoglycanopathy and 23.5 +/- 6.8 % in gamma-sarcoglycanopathy (p 0.05). 1/8 patients disclosed a left ventricular dysfunction with a left ventricular ejection fraction (LVEF) <50 % in alpha-sarcoglycanopathy, whereas 5/11 patients disclosed a left ventricular dysfunction (LVEF < 50 %) in gamma sarcoglycanopathy. LV was altered in gamma-sarcoglycanopathy than in alpha sarcoglycanopathy (LVEF at 45.6 +/- 18 vs. 59.6 +/- 5.9 % p 0.018). We found a significant alteration of the left ventricular function in gamma sarcoglycanopathy compared to alpha-sarcoglycanopathy. PMID- 24464768 TI - Hemorrhagic synovial cyst as an 'evanescing' spinal cervical mass: an issue for differential diagnosis. PMID- 24464769 TI - Are age-related differences in the consequence of work injury greater when occupational physical demands are high? AB - BACKGROUND: To examine if age differences in the consequences of work injury are exacerbated when occupational physical demands are higher. METHODS: A secondary analysis of workers' compensation claims in British Columbia (N = 373,672). Regression models examined the relationship between age and health care expenditures, days of wage replacement and the occurrence of long-term-disability following a work-related injury in occupations with lower and higher physical demands. Models were adjusted for individual and injury related covariates. RESULTS: Older age and higher occupational physical demands were associated with worse work-injury outcomes. The relationship between age and each outcome was not exacerbated when occupational physical demands were higher compared to when they were lower. Counter to our hypotheses age differences in health care expenditures were smaller among women in more demanding occupations. CONCLUSIONS: In this study, we found no evidence that the relationship between age and the consequences of work injury is exacerbated when physical occupational demands are high. PMID- 24464770 TI - Local sequence of protein beta-strands influences twist and bend angles. AB - beta-Sheet twisting is thought to be mainly determined by interstrand hydrogen bonds with little contribution from side chains, but some proteins have large, flat beta-sheets, suggesting that side chains influence beta-structures. We therefore investigated the relationship between amino acid composition and twists or bends of beta-strands. We calculated and statistically analyzed the twist and bend angles of short frames of beta-strands in known protein structures. The most frequent twist angles were strongly negatively correlated with the proportion of hydrophilic amino acid residues. The majority of hydrophilic residues (except serine and threonine) were found in the edge regions of beta-strands, suggesting that the side chains of these residues likely do not affect beta-strand structure. In contrast, the majority of serine, threonine, and asparagine side chains in beta-strands made contacts with a nitrogen atom of the main chain, suggesting that these residues suppress beta-strand twisting. PMID- 24464771 TI - Anaesthetic regimens for day-procedure laparoscopic cholecystectomy. AB - BACKGROUND: Day surgery involves admission of selected patients to hospital for a planned surgical procedure with the patients returning home on the same day. An anaesthetic regimen usually involves a combination of an anxiolytic, an induction agent, a maintenance agent, a method of maintaining the airway (laryngeal mask versus endotracheal intubation), and a muscle relaxant. The effect of anaesthesia may continue after the completion of surgery and can delay discharge. Various regimens of anaesthesia have been suggested for day-procedure laparoscopic cholecystectomy. OBJECTIVES: To compare the benefits and harms of different anaesthetic regimens (risks of mortality and morbidity, measures of recovery after surgery) in patients undergoing day-procedure laparoscopic cholecystectomy. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 10, 2013), MEDLINE (PubMed) (1987 to November 2013), EMBASE (OvidSP) (1987 to November 2013), Science Citation Index Expanded (ISI Web of Knowledge) (1987 to November 2013), LILACS (Virtual Health Library) (1987 to November 2013), metaRegister of Controlled Trials (http://www.controlled-trials.com/mrct/) (November 2013), World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) portal (November 2013), and ClinicalTrials.gov (November 2013). SELECTION CRITERIA: We included randomized clinical trials comparing different anaesthetic regimens during elective day-procedure laparoscopic cholecystectomy (irrespective of language or publication status). DATA COLLECTION AND ANALYSIS: Two authors independently assessed trials for inclusion and independently extracted the data. We calculated the risk ratio, rate ratio or mean difference with 95% confidence intervals based on intention-to-treat or available data analysis. MAIN RESULTS: We included 11 trials involving 1069 participants at low anaesthetic risk. The sample size varied from 40 to 300 participants. We included 23 comparisons. All trials were at a high risk of bias. We were unable to perform a meta-analysis because there were no two trials involving the same comparison. Primary outcomes included perioperative mortality, serious morbidity and proportion of patients who were discharged on the same day. There were no perioperative deaths or serious adverse events in either group in the only trial that reported this information (0/60). There was no clear evidence of a difference in the proportion of patients who were discharged on the same day between any of the comparisons. Overall, 472/554 patients (85%) included in this review were discharged as day procedure laparoscopic cholecystectomy patients. Secondary outcomes included hospital readmissions, health-related quality of life, pain, return to activity and return to work. There was no clear evidence of a difference in hospital readmissions within 30 days in the only comparison in which this outcome was reported. One readmission was reported in the 60 patients (2%) in whom this outcome was assessed. Quality of life was not reported in any of the trials. There was no clear evidence of a difference in the pain intensity, measured by a visual analogue scale, between comparators in the only trial which reported the pain intensity at between four and eight hours after surgery. Times to return to activity and return to work were not reported in any of the trials. AUTHORS' CONCLUSIONS: There is currently insufficient evidence to conclude that one anaesthetic regimen for day-procedure laparoscopic cholecystectomy is to be preferred over another. However, the data are sparse (that is, there were few trials under each comparison and the trials had few participants) and further well designed randomized trials at low risk of bias and which are powered to measure differences in clinically important outcomes are necessary to determine the optimal anaesthetic regimen for day-procedure laparoscopic cholecystectomy, one of the commonest procedures performed in the western world. PMID- 24464772 TI - Evaluation of lipopeptide (daptomycin) aggregation using fluorescence, light scattering, and nuclear magnetic resonance spectroscopy. AB - The aggregation behavior and critical aggregation concentration (CAC) values of daptomycin in aqueous solutions were evaluated under the external factors of pH, temperature, daptomycin concentration, and calcium ions concentration by using the complementary characterization techniques, fluorescence, dynamic and static light scattering, and nuclear magnetic resonance (NMR) spectroscopy. On the basis of the intrinsic fluorescence resonance energy transfer of daptomycin, the CAC values were identified by an upward inflection of the fluorescence emission from Kyn-13 at 460 nm. The pH-dependent CAC values were determined to be 0.14 mM at pH 3.0, 0.12 mM at pH 4.0, and 0.20 mM at pH 2.5 and 5.0. The CAC values obtained by fluorescence spectroscopy were confirmed by dynamic light scattering and NMR spectroscopy. PMID- 24464773 TI - The naturally occurring carcinogen ptaquiloside is present in groundwater below bracken vegetation. AB - The present study demonstrates unequivocally the presence of the natural carcinogen ptaquiloside and its transformation product pterosin B in groundwater and surface water. Groundwater concentrations up to 0.23 nmol/L (92 ng/L) ptaquiloside and up to 2.2 nmol/L (0.47 ug/L) pterosin B were found. Of 21 groundwater samples, 5 contained ptaquiloside, exceeding the estimated threshold for drinking water (1.3-40 pmol/L). The results are critical for water abstraction in bracken-infested areas. PMID- 24464774 TI - Impact of elevated heart rate on clinical outcomes in patients with heart failure with reduced and preserved ejection fraction: a report from the CHART-2 Study. AB - AIMS: It is still controversial whether elevated baseline heart rate (HR) is associated with higher mortality in patients with heart failure (HF) with preserved ejection fraction (HFpEF). We compared the impacts of baseline HR on mortality in patients with HFpEF and those with HF with reduced ejection fraction (HFrEF). METHODS AND RESULTS: We enrolled consecutive 2688 patients in Stage C or D HF with sinus rhythm from our Chronic Heart Failure Analysis and Registry in the Tohoku District 2 (CHART-2) Study (n = 10 219). The prognostic impact of HR increase was compared between the two groups, defined as left ventricular ejection fraction of < 50% (HFrEF) and > 50% (HFpEF). Cox regression analysis revealed that elevated baseline HR was associated with increased all-cause mortality in both groups [hazard ratio for the highest tertile (HH) 1.77 in HFrEF, P = 0.008; HH1.82 in HFpEF, P = 0.001]. However, as for mode of death, elevated HR was associated with cardiovascular (CV) death in HFpEF (HH 2.17, P = 0.012), but the association was modest in HFrEF (HH1.49, P = 0.14): in particular, impact on HF death was different between HFpEF (HH 3.79, P = 0.020) and HFrEF (HH 1.07, P = 0.864). In contrast, the prognostic impact of baseline HR on non-CV death was noted only in patients with HFrEF. beta-Blocker therapy was associated with reduced HF mortality in HFrEF (hazard ratio 0.49, P = 0.038) but not in HFpEF (hazard ratio 0.64, P = 0.321). CONCLUSIONS: Elevated HR was associated with increased CV death in HFpEF compared with HFrEF, although its impact on all-cause mortality was comparable between the two groups. PMID- 24464775 TI - Nonadministration of thromboprophylaxis in hospitalized patients with HIV: a missed opportunity for prevention? AB - BACKGROUND: Hospitalized patients with human immunodeficiency virus (HIV) appear to be at increased risk of venous thromboembolism. Previous work at our institution has demonstrated that the proportion of doses administered varies between patients and locations. OBJECTIVE: To compare the proportion of doses of thromboprophylaxis not administered between patients with and without HIV. DESIGN: Using retrospective data, the proportion of nonadministered doses was determined in all hospitalized adults and stratified by HIV status. SETTING: Large, urban, academic medical center in Baltimore, Maryland. PATIENTS: Data were available for 4947 patient visits, 583 of which were by patients with HIV. Most visits by patients with HIV were to a designated HIV care unit. MEASUREMENTS: Proportion of doses of thromboprophylaxis not administered, and documented reasons for dose nonadministration. RESULTS: A total of 42,870 doses were prescribed. The proportion of doses not administered was greater for patients with HIV (23.5%) compared with patients without HIV (16.1%, odds ratio [OR]: 1.59, 95% confidence interval [CI]: 1.49-1.70, P < 0.001). Documented dose refusal accounted for a greater proportion of nonadministered doses in patients with HIV (15.9% vs 10.8%, OR: 1.56, 95% CI: 1.43-1.70, P < 0.0001). On the HIV care unit, the proportion of doses not administered was greater for patients with HIV (26.4% vs 13.1%, OR: 2.39, 95% CI: 1.93-2.96, P < 0.001). Within this unit, documented dose refusal was greater for patients with HIV (13.7% vs 10.7%, OR: 1.32, 95% CI: 1.16-1.51, P < 0.0001). CONCLUSIONS: Nonadministration and documented refusal of thromboprophylaxis appear to be more common in patients with HIV at our institution. PMID- 24464776 TI - Degradation mechanisms of the Tomato yellow leaf curl virus coat protein following inoculation of tomato plants by the whitefly Bemisia tabaci. AB - BACKGROUND: Tomato yellow leaf curl virus (TYLCV) is a begomovirus infecting tomato cultures worldwide. TYLCV is transmitted to plants by the whitefly Bemisia tabaci. Once in the plant, the virus is subjected to attack by the host-plant defences, which may include sequestration in aggregates, proteolysis, ubiquitination, 26S proteasome degradation and autophagy. Elucidating how the virus avoids destruction will make it possible to understand infection and possibly devise countermeasures. RESULTS: The accumulation of viral coat protein (CP) and of viral DNA in plants is a marker of a successful virus transmission by B. tabaci. In response to infection, tomato tissues display multiple ways of degrading TYLCV proteins and DNA. In this study it is shown that CP (in soluble and insoluble states) is the target of protease digestion, 26S proteasome degradation and autophagy. The highest degradation capacity was detected among soluble proteins and proteins in large aggregates/inclusion bodies; cytoplasmic extracts displayed higher activity than nuclear fractions. The very same fractions possessed the highest capacity to degrade viral genomic DNA. Separately, 26S proteasome degradation was associated with large aggregates (more pronounced in the nuclear than in the cytoplasmic fractions), which are indicators of a successful abduction of plants by viruses. Autophagy/lysosome/vacuole degradation was a characteristic of intermediate aggregates, sequestering the CP in the cytoplasm and retarding the development of large aggregates. Chloroplast proteases were active in soluble as well as in insoluble protein extracts. CONCLUSIONS: To the best of the authors' knowledge, this study is the first attempt to identify elements of the virus-targeted degradation machinery, which is a part of the plant response to virus invasion. PMID- 24464777 TI - Increased plasma level of soluble urokinase plasminogen activator receptor is associated with incidence of heart failure but not atrial fibrillation. AB - AIMS: Soluble urokinase plasminogen activator receptor (suPAR) in plasma is a novel inflammatory marker thought to be released from the cell surface of neutrophils, T cells, and macrophages. Other inflammatory markers, mainly acute phase proteins produced in the liver, have been associated with the incidence of heart failure (HF) and atrial fibrillation (AF). We investigated the association between suPAR and incident HF and AF in a population-based cohort. METHODS AND RESULTS: Soluble urokinase plasminogen activator receptor was measured in 4530 subjects (aged 46-68 years, 61% women), who participated in the Malmo Diet and Cancer study during 1991-1996. Incident cases of HF and AF were identified from the Swedish hospital discharge register during a median follow-up of 16.3 years. During follow-up, 109 subjects (55% men) were diagnosed with new-onset HF and 321 individuals (50% men) with AF. suPAR was significantly associated with increased plasma levels of NT-proBNP (P<0.001). suPAR was significantly associated with incidence of HF [hazard ratio (HR) for the third vs. first tertile 3.33, 95% confidence interval (CI) 1.91-5.81 after adjustment for age and sex; and HR 1.82, 95% CI 1.02-3.27, P for trend 0.018 after adjustment for conventional risk factors and biomarkers]. suPAR was significantly associated with incidence of AF, when adjusted for age and sex (HR 1.40, 95% CI 1.06-1.85). However, this relationship was non-significant after adjustment for conventional risk factors and biomarkers. CONCLUSION: Soluble urokinase plasminogen activator receptor was associated with increased plasma levels of NT-proBNP and incidence of HF, but not with AF among middle-aged subjects. PMID- 24464778 TI - Efficient and stable white organic light-emitting diodes employing a single emitter. AB - Using a single tetradentate platinum emitter dubbed Pt7O7, efficient and stable white organic light-emitting diodes are developed. The excimer-based white devices achieve an external quantum efficiency (EQE) of 24.5%, coordinates of (0.37, 0.42) based on the Commission internationale de l'eclairage (CIE) system, and a color rendering index (CRI) of 70. Moreover, devices of Pt7O7 in a stable structure demonstrate operational lifetimes (50% initial luminance) of 36 h at an elevated driving current of 20 mA cm2, which corresponds to over 10,000 h at 100 cd m2. PMID- 24464779 TI - Effects of ZnO nanoparticles and microwave heating on the sterilization and product quality of vacuum-packaged Caixin. AB - BACKGROUND: The sterilization of vacuum-packaged Caixin (Brassica chinensis L.), which is a green-leafy vegetable and also a low-acid food, remains a difficult problem. In this study, effects of ZnO nanoparticles and microwave heating on the sterilization and product quality of vacuum-packaged Caixin were investigated. RESULTS: Addition of ZnO nanoparticle suspension at 0.01-0.02 g kg(-1) reduced the number of bacterial colonies. The antibacterial activity was enhanced with the increased amount of ZnO nanoparticles. Microwave heating (915 and 2450 MHz) was used to sterilize Caixin samples. Samples had good product quality (better greenness, chroma and hue angle values, lower browning index and acceptable texture) and the lowest total colony number under the microwave heating condition of 400 W 150 s (2450 MHz). CONCLUSION: The best sterilization condition was observed under 2450 MHz microwave (400 W 150 s) heating combined with 0.02 g kg( 1) ZnO nanoparticle addition, which led to a total colony number of <1 log CFU g( 1) in Caixin samples within 7 days. PMID- 24464780 TI - A phase II study of preoperative capecitabine in women with operable hormone receptor positive breast cancer. AB - Conventional preoperative chemotherapy regimens have only limited efficacy in hormone receptor positive (HR+) breast cancer and new approaches are needed. We hypothesized that capecitabine, which is effective in metastatic breast cancer, may be an active preoperative treatment for HR+ breast cancer. Women with HR+, HER2-negative operable breast cancer received capecitabine, 2000 mg/m(2) daily in divided doses for 14 days, followed by a 7-day rest period. Treatment was repeated every 21 days for a total of four cycles. The primary endpoint of the study was to determine the rate of pathological complete response (pCR). Because of slow accrual, the study was closed after 24 patients were enrolled. Three patients had a complete clinical response, and eight patients had a partial clinical response, for an overall clinical response rate of 45.8%. There were no cases of pCR. Of the 22 patients who had pathological response assessment by the Miller-Payne grading system, there were six grade 3 responses, and no grade 4 or 5 responses. Toxicity was manageable: the only grade 3 toxicities observed were one case each of diarrhea, palmar plantar erythrodysesthesia, hypokalemia, and mucositis. There was no association between baseline levels, or change in level from baseline to cycle 1, or from baseline to time of surgery, of thymidine phosphorylase (TYMP), thymidylate synthase (TYMS), dihydropyrimidine dehydrogenase (DPYD), or Ki67 and pathological, clinical, or radiographic response. Preoperative capecitabine is a well-tolerated regimen, but appears not lead to pCR when used as monotherapy in HR+ breast cancer. PMID- 24464781 TI - Chicago classification of high-resolution esophageal manometry: is old the gold or is new better? PMID- 24464782 TI - Cation-pi interactions of methylated ammonium ions: a quantum mechanical study. AB - Cation-pi interactions of methylated ammonium ions play a key role in a broad range of biochemical systems. These include methyl-lysine binding proteins which bind to methylated sites on histone proteins, lysine demethylase enzymes which demethylate these sites, and neurotransmitter receptor complexes which bind choline-derived ligands. Recognition in these systems is achieved through an 'aromatic cage' motif in the binding site. Here we use high-level quantum mechanical calculations to address how cation-pi interactions of methylated ammonium ions are modulated by a change in methylation state and interaction geometry. We survey methyl-lysine and choline-derived complexes in the Protein Databank to validate our results against available structural data. A quantitative description of cation-pi interactions of methylated ammonium systems is critical to structure-based efforts to target methyl-lysine binding proteins and demethylase enzymes in the treatment of unregulated transcriptional control, and neurotransmitter receptors in the treatment of neurological disease. It is our hope that our work will serve as a benchmark for the development of physical chemistry based force fields that can accurately model the contribution of cation pi interactions to binding and specificity in these systems. PMID- 24464783 TI - Impact of extended-spectrum beta-lactamase-producing organisms on clinical and economic outcomes in patients with urinary tract infection. AB - OBJECTIVE: To compare clinical and economic outcomes between patients with urinary tract infection (UTI) due to extended-spectrum beta-lactamase-producing Escherichia coli and Klebsiella species (ESBL-EK) versus patients with non-ESBL EK UTI. PATIENTS AND METHODS: Eighty-four (3.6%) of 2345 patients admitted between September 1, 2011 and August 31, 2012 with UTI were positive for ESBL-EK. Fifty-five ESBL-EK UTI (cases) and matched controls (non-ESBL-EK UTI) were included in the analysis. Clinical and economic outcomes were compared between cases and controls for statistical significance. RESULTS: Cases were more likely to have diabetes mellitus, a history of recurrent UTIs, recently received antibiotics, recently been hospitalized, and had previous isolation of an ESBL producing organism compared with controls. Failure of initial antibiotic regimen (62% vs 6%; P < 0.001) and time to appropriate antibiotic therapy (51 vs 2.5 hours; P < 0.001) were greater in cases. The median cost of care was greater (additional $3658; P = 0.02) and the median length of stay (LOS) prolonged for cases (6 vs 4 days; P = 0.02) despite similar hospital reimbursement (additional $469; P = 0.56). Although not significant, infection-related mortality (7.2% vs 1.8%) and 30-day UTI readmission (7.2% vs 3.6%) were higher in ESBL-EK cases. CONCLUSIONS: UTI caused by ESBL-EK is associated with significant clinical and economic burden. The cost of care and LOS of patients with ESBL-EK UTI were 1.5 times those caused by non-ESBL-EK. Importantly, the additional cost of care is a liability to the hospital, as this is not offset by reimbursement. Appropriate and timely initial antibiotics may minimize the ESBL-EK impact on outcomes of patients with UTI. PMID- 24464784 TI - Polymeric implants for the delivery of green tea polyphenols. AB - Polymeric implants (millirods) have been tested for local delivery of chemotherapeutic agents in cancer treatment. Modeling of drug release profiles is critical as it may provide theoretical insights on rational implant design. In this study, a biodegradable poly (epsilon-caprolactone) (PCL) polymeric implant delivery system was tested to deliver green tea polyphenols (GTPs), both in vitro and in vivo. Factors including polymer compositions, supplements, drug loads, and surface area of implants were investigated. Our data showed that GTPs were released from PCL implants continuously for long durations, and drug load was the main determining factor of GTPs release. Furthermore, rates of in vitro release and in vivo release in the rat model followed similar kinetics for up to 16 months. A mathematical model was deduced and discussed. GTP implants have the potential to be used systemically and locally at the tumor site as an alternative strategy. PMID- 24464785 TI - Targeted deletion of RasGRP1 impairs skin tumorigenesis. AB - Ras is frequently activated in cutaneous squamous cell carcinoma, a prevalent form of skin cancer. However, the pathways that contribute to Ras-induced transformation have not been entirely elucidated. We have previously demonstrated that in transgenic mice, overexpression of the Ras activator RasGRP1 promotes the formation of spontaneous skin tumors and enhances malignant progression in the multistage carcinogenesis skin model that relies on the oncogenic activation of H Ras. Utilizing a RasGRP1 knockout mouse model (RasGRP1 KO), we now show that lack of RasGRP1 reduced the susceptibility to skin tumorigenesis. The dependency on RasGRP1 was associated with a diminished response to the phorbol ester tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Specifically, we found impairment of epidermal hyperplasia induced by TPA through keratinocyte proliferation. Using a keratinocyte cell line that carries a ras oncogenic mutation, we also demonstrated that RasGRP1 could further activate Ras in response to TPA. Thus, we propose that RasGRP1 upregulates signaling from Ras and contributes to epidermal tumorigenesis by increasing the total dosage of active Ras. PMID- 24464786 TI - IL-23 selectively promotes the metastasis of colorectal carcinoma cells with impaired Socs3 expression via the STAT5 pathway. AB - Interleukin-23 (IL-23) is a conventional proinflammatory IL related to colorectal carcinoma (CRC). The signal transducer and activator of transcription (STAT) and suppressors of cytokine signaling (Socs) molecules, respectively, serve as agonists and antagonists of IL-23-associated inflammation. However, it remains unknown whether IL-23 directly affects CRC metastasis. In this study, we measured the metastasis of several human CRC cell lines stimulated by IL-23 in vitro and in vivo. Interestingly, the prometastasis effect of IL-23 was observed only in SW 620 cells. IL-23-associated migration and invasion was mediated by the phosphorylation of STAT5. The expression of Socs3 in SW-620 was impaired by IL-23 via DNA methylation and DNA methyltransferase-1 (DNMT-1)-dependent way. The DNMT 1-associated regulation was not observed in the other three cells. Socs3 was further confirmed to inhibit the prometastatic function of IL-23 both in vitro and in vivo. We analyzed the clinical correlation between the level of IL-23 in tumors and the metastasis of CRC and found that higher IL-23 levels along with lower Socs3 in CRC tissues accounted for more metastatic cases. In conclusion, it was demonstrated that IL-23, assisted by STAT5, might only promote the metastasis of CRC with deficient Socs3 expression in which IL-23-induced DNMT-1 was involved. It was elucidated that Socs3 seemed to be one of the important factors that mediate the selectivity of IL-23. Taken together, these discoveries give rise to new insights into the role of IL-23 in cancer biology and provide additional preclinical data regarding IL-23-associated therapy for CRC. PMID- 24464787 TI - The oncoprotein HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. AB - Tumor angiogenesis plays an important role in the development of cancer. Previously, we reported that hepatitis B X-interacting protein (HBXIP) functioned as an oncoprotein in breast cancer. However, the role of HBXIP in angiogenesis in breast cancer remains poorly understood. In the present study, we show that the oncoprotein HBXIP plays crucial roles in the event. We observed that the expression levels of HBXIP were positively correlated with those of fibroblast growth factor 8 (FGF8) or vascular endothelial growth factor (VEGF) in clinical breast cancer tissues. Then, we demonstrated that HBXIP was able to upregulate FGF8 through activation of its promoter involving direct binding to cAMP response element-binding protein (CREB) in breast cancer cells and thereby increased its secretion. Strikingly, we identified another pathway that HBXIP upregulated FGF8 and VEGF through inhibiting miRNA-503, which directly targeted 3' untranslated region of FGF8 or VEGF mRNA in the cells. Moreover, we revealed that HBXIP induced FGF8 could upregulate VEGF expression through activating phosphoinositide 3-kinase (PI3K)/Akt/hypoxia-inducible factor 1-alpha (HIF1alpha) signaling and increase its secretion. In function, matrigel angiogenesis assay and hemoglobin content analysis uncovered that HBXIP-enhanced FGF8/VEGF boosted tumor angiogenesis and growth in breast cancer in vitro and in vivo in a paracrine/autocrine manner. Thus, we conclude that HBXIP enhances angiogenesis and growth of breast cancer through modulating FGF8 and VEGF. Our finding provides new insights into the mechanism of tumor angiogenesis in breast cancer. Therapeutically, HBXIP may serve as a novel target of tumor angiogenesis. PMID- 24464788 TI - Effect of comorbidities on outcomes and angiotensin converting enzyme inhibitor effects in patients with predominantly left ventricular dysfunction and heart failure. AB - AIMS: Comorbidities are frequent in heart failure and impact outcomes. It is not known whether comorbidities are associated with outcomes in asymptomatic left ventricular dysfunction compared to clinical heart failure and whether comorbidities interfere with treatment effects. Our objective was to assess comorbidities and their effects on outcomes in predominantly asymptomatic populations without previous heart failure treatment of the SOLVD prevention trial, compared to symptomatic heart failure patients of SOLVD treatment and to evaluate associations to the effect of enalapril. METHODS AND RESULTS: This post hoc analysis from the SOLVD prevention and SOLVD treatment trials includes 4228 patients with left ventricular dysfunction and 2569 patients with heart failure. The preexisting comorbidities hypertension, diabetes mellitus, pulmonary disease, angina pectoris, renal impairment, and anaemia were similar in SOLVD treatment and SOLVD prevention, with a higher prevalence in SOLVD treatment. Comorbidities are significantly associated with the primary composite of SOLVD time to death or heart failure hospitalization (SOLVD prevention: HR 4.8, CI: 3.2-7.18, P < 0.0001; SOLVD treatment: HR 2.9, CI: 2.12-3.95, P < 0.0001 for more than four comorbidities vs. no comorbidities), and to death, heart failure hospitalization, and cardiovascular death where the effect of the number of coexisting comorbidities was additive. There was no significant interaction of comorbidities with treatment effects of enalapril. CONCLUSION: Comorbidities increased events in asymptomatic left ventricular dysfunction and in symptomatic heart failure, but did not interfere with the effects of enalapril. Comorbidities need to be adequately addressed in clinical trials, which should also involve non-cardiac treatments in order to improve outcome for heart failure patients. PMID- 24464789 TI - Ranolazine protects from doxorubicin-induced oxidative stress and cardiac dysfunction. AB - AIMS: Doxorubicin is widely used against cancer; however, it can produce heart failure (HF). Among other hallmarks, oxidative stress is a major contributor to HF pathophysiology. The late INa inhibitor ranolazine has proven effective in treating experimental HF. Since elevated [Na+]i is present in failing myocytes, and has been recently linked with reactive oxygen species (ROS) production, our aim was to assess whether ranolazine prevents doxorubicin-induced cardiotoxicity, and whether blunted oxidative stress is a mechanism accounting for such protection. METHODS AND RESULT: In C57BL6 mice, doxorubicin treatment for 7 days produced LV dilation and decreased echo-measured fractional shortening (FS). Ranolazine (305 mg/kg/day) prevented LV dilation and dysfunction when co administered with doxorubicin. Doxorubicin-induced cardiotoxicity was accompanied instead by elevations in atrial natriuretic peptide (ANP), BNP, connective tissue growth factor (CTGF), and matrix metalloproteinase 2 (MMP2) mRNAs, which were not elevated on co-treatment with ranolazine. Alterations in extracellular matrix remodelling were confirmed by an increase in interstitial collagen, which did not rise in ranolazine-co-treated hearts. Levels of poly(ADP-ribose) polymerase (PARP) and pro-caspase-3 measured by western blotting were lowered with doxorubicin, with increased cleavage of caspase-3, indicating activation of the proapoptotic machinery. Again, ranolazine prevented this activation. Furthermore, in HL-1 cardiomyocytes transfected with HyPer to monitor H2O2 emission, besides reducing the extent of cell death, ranolazine prevented the occurrence of oxidative stress caused by doxorubicin. Interestingly, similar protective results were obtained with the Na+/Ca2+ exchanger (NCX) inhibitor KB-R7943. CONCLUSIONS: Ranolazine protects against experimental doxorubicin cardiotoxicity. Such protection is accompanied by a reduction in oxidative stress, suggesting that INa modulates cardiac redox balance, resulting in functional and morphological derangements. PMID- 24464790 TI - Transmission specificities of plant viruses with the newly identified species of the Bemisia tabaci species complex. AB - Bemisia tabaci has had a colorful nomenclatural past and is now recognized as a species complex. This new species framework has added many new areas of research including adding new insight into the virus transmission specificity of the species in the B. tabaci species complex. There is a wide disparity in what is known about the transmission of plant viruses by different members of the B. tabaci species complex. In this paper, we have synthesized the transmission specificities of the plant viruses transmitted by species belonging to the complex. There are five genera of plant viruses with members that are transmitted by species of the B. tabaci species complex. The transmission of viruses belonging to two of these, Begomovirus and Crinivirus, are well studied and much is known in regards to the relationship between species and transmission and etiology. This is in contrast to viruses of the genera, Torradovirus and Carlavirus, for which very little is known inregards to their transmission. This is the first attempt to integrate viral data within the new B. tabaci species complex framework. It is clear that matching historical transmission data with the current species framework is difficult due to the lack of awareness of the underlying genetic diversity within B. tabaci. We encourage all researchers to determine which species of B. tabaci they are using to facilitate association of phenotypic traits with particular members of the complex. PMID- 24464791 TI - Mupirocin/chlorexidine to prevent methicillin-resistant Staphylococcus aureus infections: post hoc analysis of a placebo-controlled, randomized trial using mupirocin/chlorhexidine and polymyxin/tobramycin for the prevention of acquired infections in intubated patients. AB - PURPOSE: The reduction in acquired infections (AI) due to methicillin-resistant Staphylococcus aureus (MRSA) with the mupirocin/chlorhexidine (M/C) decontamination regimen has not been well studied in intubated patients. We performed post hoc analysis of a prior trial to assess the impact of M/C on MRSA AI and colonization. METHODS: We conducted a multicenter, placebo-controlled, randomized, double-blind study with the primary aim to reduce all-cause AI. The two regimens used [topical polymyxin and tobramycin (P/T), nasal mupirocin with chlorhexidine body wash (M/C), or corresponding placebos for each regimen] were administered according to a 2 * 2 factorial design. Participants were intubated patients in the intensive care units of three French university hospitals. The patients enrolled in the study (n = 515) received either active P/T (n = 130), active M/C (n = 130), both active regimens (n = 129), or placebos only (n = 126) for the period of intubation and an additional 24 h. The incidence and incidence rates (per 1,000 study days) of MRSA AI were assessed. Due to the absence of a statistically significant interaction between the two regimens, analysis was performed at the margins by comparing all patient receiving M/C (n = 259) to all patients not receiving M/C (n = 256), and all patients receiving P/T (n = 259) to all patients not receiving P/T (n = 256). RESULTS: Incidence [odds ratio (OR) 0.39, 95 % confidence interval (CI) (0.16-0.96), P = 0.04] and incidence rates [incidence rate ratio (IRR) 0.41, 95 % CI 0.17-0.97, P = 0.05] of MRSA AI were significantly lower with the use of M/C. We also observed an increase in the incidence (OR 2.50, 95 % CI 1.01-6.15, P = 0.05) and the incidence rate (IRR 2.90, 95 % CI 1.20-8.03, P = 0.03) of MRSA AI with the use of P/T. CONCLUSION: Among our study cohort of intubated patients, the use of M/C significantly reduced MRSA AI. PMID- 24464792 TI - Methicillin-resistant Staphylococcus aureus as a cause of invasive infections in Central Africa: a case report and review of the literature. AB - INTRODUCTION: Community-acquired methicillin-resistant Staphylococcus aureus (CA MRSA) colonization and infection are increasingly being reported worldwide and are associated with severe illness. The vast majority of MRSA infections are skin and soft tissue infections, while invasive disease remains rare. In Western countries, the epidemiology of MRSA is well documented, but from Central Africa, reports on MRSA are very limited. METHODS: Case presentation and review of the literature. The clinical features, epidemiology, and characteristics of MRSA in Central Africa, as well as the treatment options, are discussed. We present a case of severe invasive CA-MRSA infection with pneumonia, pericarditis, and bacteremia in a previously healthy young woman in Gabon. Several virulence factors, like Panton-Valentine leukocidin and type I arginine catabolic mobile element, may play a role in the ability of CA-MRSA to cause severe invasive infections. Based on studies from Gabon and Cameroon (no reports were available from other countries), we find that the prevalence of MRSA is relatively low in this region. Treatment depends primarily on local prevalence and resistance profile of MRSA combined with clinical characteristics. CONCLUSION: Severe invasive infection with CA-MRSA is a rare disease presentation in Central Africa, where this pathogen is still relatively uncommon. However, cases of MRSA may be complicated by the human immunodeficiency virus (HIV) and tuberculosis epidemics, and also the limited availability of effective antibiotics. PMID- 24464793 TI - Antiepileptic drugs for the primary and secondary prevention of seizures after stroke. AB - BACKGROUND: This is an updated version of the original Cochrane review published in 2010, Issue 1. Seizures after stroke are an important clinical problem, and they may be associated with poor outcome. The effects of antiepileptic drugs for the primary and secondary prevention of seizures after stroke remain unclear. OBJECTIVES: We aimed to assess the effects of antiepileptic drugs for the primary and secondary prevention of seizures after stroke. SEARCH METHODS: We searched the Specialised Registers of the Cochrane Epilepsy Group (12 August 2013) and the Cochrane Stroke Group (12 August 2013), the Cochrane Central Register of Controlled Trials (CENTRAL, The Cochrane Library 2013, Issue 7), and MEDLINE (OVID, 1946 to 12 August 2013). We also checked the reference lists of articles retrieved from these searches. SELECTION CRITERIA: Randomised and quasi randomised controlled trials in which participants were assigned to treatment or control group (placebo or no drug). DATA COLLECTION AND ANALYSIS: Two review authors independently screened all the titles, abstracts, and keywords of publications identified by the searches to assess their eligibility, and both review authors assessed their suitability for inclusion according to prespecified selection criteria. We included only one study for data collection and analysis. MAIN RESULTS: We found only one trial that fulfilled the study inclusion criteria of comparison of the effects of an antiepileptic drug with placebo (or no drug) for the primary or secondary prevention of seizures after stroke. This was a prospective randomised, double-blind, placebo-controlled trial comparing valproic acid with placebo for primary prevention of seizures in 72 adults (over 18 years of age) with spontaneous non-aneurysmal, non-traumatic intracerebral haemorrhage; no statistically significant difference in outcome (seizure occurrence at one year) was demonstrated between groups. AUTHORS' CONCLUSIONS: Currently, there is insufficient evidence to support the routine use of antiepileptic drugs for the primary or secondary prevention of seizures after stroke. Further well-conducted research is needed for this important clinical problem. PMID- 24464794 TI - Indium-bridged [1]ferrocenophanes. AB - Indium-bridged [1]ferrocenophanes ([1]FCPs) and [1.1]ferrocenophanes ([1.1]FCPs) were synthesized from dilithioferrocene species and indium dichlorides. The reaction of Li2fc?tmeda (fc = (H4C5)2Fe) and (Mamx)InCl2 (Mamx = 6-(Me2NCH2)-2,4 tBu2C6H2) gave a mixture of the [1]FCP (Mamx)Infc (4(1)), the [1.1]FCP [(Mamx)Infc]2 (4(2)), and oligomers [(Mamx)Infc]n (4(n)). In a similar reaction, employing the enantiomerically pure, planar-chiral (Sp,Sp)-1,1'-dibromo-2,2' diisopropylferrocene (1) as a precursor for the dilithioferrocene derivative Li2fc(iPr2), equipped with two iPr groups in the alpha position, gave the inda[1]ferrocenophane 5(1) [(Mamx)Infc(iPr2)] selectively. Species 5(1) underwent ring-opening polymerization to give the polymer 5(n). The reaction between Li2fc(iPr2) and Ar'InCl2 (Ar' = 2-(Me2NCH2)C6H4) gave an inseparable mixture of the [1]FCP Ar'Infc(iPr2) (6(1)) and the [1.1]FCP [Ar'Infc(iPr2)]2 (6(2)). Hydrogenolysis reactions (BP86/TZ2P) of the four inda[1]ferrocenophanes revealed that the structurally most distorted species (5(1)) is also the most strained [1]FCP. PMID- 24464795 TI - "Shaken baby syndrome" and forensic pathology. PMID- 24464796 TI - A brief history of fatal child maltreatment and neglect. AB - Child abuse encompasses four major forms of abuse: physical abuse, sexual abuse, psychological abuse, and neglect. The United States retains one of the worst records of child abuse in the industrialized world. It has also been determined that a large portion of these cases are missed and go undocumented in state and federal reporting agencies. In addition, disparate risk factors have been identified for physical abuse and neglect cases, but substance abuse has been found to be a significant factor in all forms of abuse. Fatal child maltreatment and neglect investigations require a multi-pronged and multidisciplinary approach requiring the coordination and information gathering from various agencies. A major difficulty in determining the accidental or non-accidental nature of these cases is that the account surrounding the events of the death of child is acquired from the caretaker. In this review, we outline common diagnostic characteristics and patterns of non-accidental injuries and neglect as a result of nutritional deprivation. PMID- 24464797 TI - Modelling the effect of myosin X motors on filopodia growth. AB - We present a numerical simulation study of the dynamics of filopodial growth in the presence of active transport by myosin X motors. We employ both a microscopic agent-based model, which captures the stochasticity of the growth process, and a continuum mean-field theory which neglects fluctuations. We show that in the absence of motors, filopodia growth is overestimated by the continuum mean-field theory. Thus fluctuations slow down the growth, especially when the protrusions are driven by a small number (10 or less) of F-actin fibres, and when the force opposing growth (coming from membrane elasticity) is large enough. We also show that, with typical parameter values for eukaryotic cells, motors are unlikely to provide an actin transport mechanism which enhances filopodial size significantly, unless the G-actin concentration within the filopodium greatly exceeds that of the cytosol bulk. We explain these observations in terms of order of-magnitude estimates of diffusion-induced and advection-induced growth of a bundle of Brownian ratchets. PMID- 24464798 TI - Genetic and virulence variation in an environmental population of the opportunistic pathogen Aspergillus fumigatus. AB - Environmental populations of the opportunistic pathogen Aspergillus fumigatus have been shown to be genotypically diverse and to contain a range of isolates with varying pathogenic potential. In this study, we combined two RAPD primers to investigate the genetic diversity of environmental isolates from Manchester collected monthly over 1 year alongside Dublin environmental isolates and clinical isolates from patients. RAPD analysis revealed a diverse genotype, but with three major clinical isolate clusters. When the pathogenicity of clinical and Dublin isolates was compared with a random selection of Manchester isolates in a Galleria mellonella larvae model, as a group, clinical isolates were significantly more pathogenic than environmental isolates. Moreover, when relative pathogenicity of individual isolates was compared, clinical isolates were the most pathogenic, Dublin isolates were the least pathogenic and Manchester isolates showed a range in pathogenicity. Overall, this suggests that the environmental population is genetically diverse, displaying a range in pathogenicity, and that the most pathogenic strains from the environment are selected during patient infection. PMID- 24464799 TI - A short sequence within subdomain N1 of region A of the Staphylococcus aureus MSCRAMM clumping factor A is required for export and surface display. AB - Clumping factor A (ClfA) is the archetypal fibrinogen-binding surface protein of Staphylococcus aureus and a member of the microbial surface component recognizing adhesive matrix molecules (MSCRAMM) family. An N-terminal signal sequence directs export of the MSCRAMM by the Sec pathway and the C-terminal cell wall-anchoring domain allows covalent attachment of ClfA to peptidoglycan by sortase. Region A of ClfA comprises three independently folded subdomains N1, N2 and N3. Subdomains N2N3 comprise IgG-like folds and promote fibrinogen binding. Nothing is known about the structure or function of subdomain N1. Here we demonstrate an unexpected role for N1 in the export and surface localization of ClfA. Attempted expression of a ClfA variant lacking subdomain N1 resulted in impaired growth of S. aureus and accumulation of ClfA protein in the cytoplasm and cytoplasmic membrane. The presence of residues 211-228 of N1 was required to allow display of ClfA on the bacterial surface. The importance of this region was confirmed when a ClfA variant lacking residues 211-220 was also mislocalized to the cytoplasm and cytoplasmic membrane. However, these residues were not required for export of ClfA lacking the Ser-Asp repeats that link region A to the wall-anchoring domain. Similarly, subdomain N1 of a related MSCRAMM fibronectin-binding protein B was required for export and surface display of the full-length protein, but not a derivative lacking fibronectin-binding repeats. In summary, we demonstrate that residues in the N1 subdomain are required for export and cell wall localization of S. aureus MSCRAMM proteins. PMID- 24464800 TI - NtcA is responsible for accumulation of the small isoform of ferredoxin:NADP oxidoreductase. AB - In several cyanobacteria, petH, the gene encoding ferredoxin:NADP oxidoreductase (FNR), is transcribed from at least two promoters depending on growth conditions. Two transcripts (short and long) are translated from two different translation initiation sites, resulting in two isoforms (large and small, respectively). Here, we show that in Synechocystis PCC6803 the global transcriptional regulator NtcA activates transcription from the distal petH promoter. Modification of the NtcA-binding site prevents NtcA binding to the promoter in vitro and abolishes accumulation of the small isoform of FNR in vivo. We also demonstrate that a similar petH transcription and translation regime occurs in other cyanobacteria. The conditions under which this system operates provide hints for the function of each FNR isoform. PMID- 24464801 TI - Partial least square and k-nearest neighbor algorithms for improved 3D quantitative spectral data-activity relationship consensus modeling of acute toxicity. AB - A diverse set of 154 chemicals that included US Food and Drug Administration regulated compounds tested for their aquatic toxicity in Daphnia magna were modeled by a 3-dimensional quantitative spectral data-activity relationship (3D QSDAR). Two distinct algorithms, partial least squares (PLS) and Tanimoto similarity-based k-nearest neighbors (KNN), were used to process bin occupancy descriptor matrices obtained after tessellation of the 3D-QSDAR space into regularly sized bins. The performance of models utilizing bins ranging in size from 2 ppm * 2 ppm * 0.5 A to 20 ppm * 20 ppm * 2.5 A was explored. Rigorous quality-control criteria were imposed: 1) 100 randomized 20% hold-out test sets were generated and the average R(2) test of the respective models was used as a measure of their performance, and 2) a Y-scrambling procedure was used to identify chance correlations. A consensus between the best-performing composite PLS model using 0.5 A * 14 ppm * 14 ppm bins and 10 latent variables (average R(2) test = 0.770) and the best composite KNN model using 0.5 A * 8 ppm * 8 ppm and 2 neighbors (average R(2) test = 0.801) offered an improvement of about 7.5% (R(2) test consensus = 0.845). Projection of the most frequently occurring bins on the standard coordinate space indicated that the presence of a primary or secondary amino group-substituted aromatic systems-would result in an increased toxic effect in Daphnia. The presence of a second aromatic ring with highly electronegative substituents 5 A to 7 A apart from the first ring would lead to a further increase in toxicity. PMID- 24464802 TI - Indiplon is hydrolyzed by arylacetamide deacetylase in human liver. AB - Human arylacetamide deacetylase (AADAC) catalyzes the hydrolysis of some clinically used drugs, but the information available on its substrates is limited. To increase our knowledge of the AADAC substrates, we examined whether AADAC catalyzes the hydrolysis of indiplon, which was initially developed as a hypnotic sedative drug. It has been reported that approximately 30-40% of the administered indiplon was hydrolyzed to deacetylindiplon in humans, but the enzyme responsible for this hydrolysis had not been identified. We detected high levels of indiplon hydrolase activity in human liver microsomes (HLMs), but the levels found in human liver cytosol and plasma were scarcely detectable. Recombinant AADAC showed a high level of indiplon hydrolase activity, whereas recombinant carboxylesterase 1 (CES1) and 2 (CES2) showed marginal activity. The indiplon hydrolase activity of HLM was potently inhibited by vinblastine, a potent inhibitor of AADAC and CES2, but it was not inhibited by digitonin and telmisartan, inhibitors of CES1 and CES2, respectively. In a panel of 24 individual HLM samples, the indiplon hydrolase activities were significantly correlated with the hydrolase activities of flutamide, phenacetin, and rifampicin, which are known AADAC substrates. An HLM sample with a homozygous AADAC*3 allele, which was previously found to exhibit decreased enzyme activity, showed the lowest indiplon hydrolase activity among the 24 tested samples. Collectively, we found that human AADAC is responsible for the hydrolysis of indiplon. Thus, we can add indiplon to the list of human AADAC substrates. PMID- 24464803 TI - The pharmacokinetics, metabolism, and clearance mechanisms of tofacitinib, a janus kinase inhibitor, in humans. AB - Tofacitinib is a novel, oral Janus kinase inhibitor. The objectives of this study were to summarize the pharmacokinetics and metabolism of tofacitinib in humans, including clearance mechanisms. Following administration of a single 50-mg (14)C labeled tofacitinib dose to healthy male subjects, the mean (standard deviation) total percentage of administered radioactive dose recovered was 93.9% (+/-3.6), with 80.1% (+/-3.6) in the urine (28.8% parent), and 13.8% (+/-1.9) in feces (0.9% parent). Tofacitinib was rapidly absorbed, with plasma concentrations and total radioactivity peaking at around 1 hour after oral administration. The mean terminal phase half-life was approximately 3.2 hours for both parent drug and total radioactivity. Most (69.4%) circulating radioactivity in plasma was parent drug, with all metabolites representing less than 10% each of total circulating radioactivity. Hepatic clearance made up around 70% of total clearance, while renal clearance made up the remaining 30%. The predominant metabolic pathways of tofacitinib included oxidation of the pyrrolopyrimidine and piperidine rings, oxidation of the piperidine ring side-chain, N-demethylation and glucuronidation. Cytochrome P450 (P450) profiling indicated that tofacitinib was mainly metabolized by CYP3A4, with a smaller contribution from CYP2C19. This pharmacokinetic characterization of tofacitinib has been consistent with its clinical experience in drug-drug interaction studies. PMID- 24464804 TI - High daily dose and being a substrate of cytochrome P450 enzymes are two important predictors of drug-induced liver injury. AB - Drug-induced liver injury (DILI) is complicated and difficult to predict. It has been observed that drugs with extensive hepatic metabolism have a higher likelihood of causing DILI. Cytochrome P450 (P450) enzymes are primarily involved in hepatic metabolism. Identifying the associations of DILI with drugs that are P450 substrates, inhibitors, or inducers will be extremely helpful to clinicians during the decision-making process of caring for a patient suspected of having DILI. We collected metabolism data on P450 enzymes for 254 orally administered drugs in the Liver Toxicity Knowledge Base Benchmark Dataset with a known daily dose, and applied logistic regression to identify these associations. We revealed that drugs that are substrates of P450 enzymes have a higher likelihood of causing DILI [odds ratio (OR), 3.99; 95% confidence interval (95% CI), 2.07-7.67; P < 0.0001], which is dose-independent, and drugs that are P450 inhibitors have a higher likelihood of generating DILI only when they are administered at high daily doses (OR, 6.03; 95% CI, 1.32-27.5; P = 0.0098). However, drugs that are P450 inducers are not observed to be associated with DILI (OR, 1.55; 95% CI, 0.65 3.68; P = 0.3246). Our findings will be useful in identifying the suspected medication as a cause of liver injury in clinical settings. PMID- 24464806 TI - Stem cell therapy in ALS: Possible benefit? PMID- 24464805 TI - The effect of ABCG2 and ABCC4 on the pharmacokinetics of methotrexate in the brain. AB - Methotrexate (MTX) is the cornerstone of chemotherapy for primary central nervous system lymphoma, yet how the blood-brain barrier (BBB) efflux transporters ABCG2 and ABCC4 influence the required high-dose therapy is unknown. To evaluate their role, we used four mouse strains, C57BL/6 (wild-type; WT), Abcg2(-/-), Abcc4(-/ ), and Abcg2(-/-);Abcc4(-/-) (double knockout; DKO) to conduct brain microdialysis studies after single intravenous MTX doses of 50 mg/kg. When the area under the concentration-time curve for plasma (AUC(plasma)) was used to assess systemic exposure to MTX, the rank order was Abcc4(-/-) < WT < Abcg2(-/-) < Abcg2(-/-)Abcc4(-/-). Only the DKO exposure was significantly higher than that of the WT group (P < 0.01), a reflection of the role of Abcg2 in biliary excretion and Abcc4 in renal excretion. MTX brain interstitial fluid concentrations obtained by microdialysis were used to calculate the area under the concentration-time curve for the brain (AUC(brain)), which found the rank order of exposure to be WT < Abcc4(-/-) < Abcg2(-/-) < Abcg2(-/-)Abcc4(-/-) with the largest difference being 4-fold: 286.13 +/- 130 MUg*min/ml (DKO) versus 66.85 +/- 26 (WT). Because the transporters affected the systemic disposition of MTX, particularly in the DKO group, the ratio of the AUC(brain)/AUC(plasma) or the brain/plasma partition coefficient Kp was calculated, revealing that the DKO strain had a significantly higher value (0.23 +/- 0.09) than the WT strain (0.11 +/- 0.05). Both Abcg2 and Abcc4 limited BBB penetration of MTX; however, only when both drug efflux pumps were negated did the brain accumulation of MTX significantly increase. These findings indicate a contributory role of both ABCG2 and ABCC4 to limiting MTX distribution in patients. PMID- 24464807 TI - Nanoparticles and the lung: friend or foe? AB - Nanomedicine is a rapidly evolving field with high potential for developing novel research, diagnosis, and/or therapeutic approaches for lung diseases. However, for engineered nanomaterials to reach their true potential, there are still a number of unanswered questions regarding nanomaterial vs. tissue properties that dictate lung cellular uptake, distribution, and intracellular effects, and particle vs. tissue factors that determine toxicity vs. beneficial effects in the lung. Some of these key questions are highlighted in this Perspectives. Addressing these important issues will help improve nanoparticle design and enhance enthusiasm for more widespread use of nanotechnology in pulmonary medicine. PMID- 24464808 TI - Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension. AB - We previously observed that transgelin was preferentially expressed in human pulmonary arterial smooth muscle cells (PAMSCs) under hypoxia and that the upregulation of transgelin was independent of hypoxia-inducible factor 1alpha (HIF-1alpha). Reduced transgelin expression was accompanied by significantly impaired migration ability in vitro. However, the regulation mechanism of transgelin and its function in preventing hypoxic pulmonary hypertension (HPH) was unclear. In the present study, RNA interference with hypoxia-inducible factor 2alpha (HIF-2alpha) was employed in human PASMCs. Transgelin expression was diminished in HIF-2alpha-siRNA-treated cells at both the mRNA and protein levels under hypoxia. However, HIF-2alpha did not transactivate the transgelin promoter directly. TGF-beta1 concentration in human PASMCs culture medium was higher under hypoxia, and the accumulated TGF-beta1 under hypoxia was regulated by HIF-2alpha. Furthermore, luciferase and chromatin immunoprecipitation assays indicated that TGF-beta1/Smad3 could bind to the transgelin promoter, resulting in increased transgelin expression. In addition to nonintact cellular migration, inhibition of transgelin expression resulted in impaired proliferation in vitro under hypoxia. A lentiviral vector used to inhibit transgelin expression was constructed and intratracheally instilled in rats 3 wk prior to hypoxia treatment. Our final results indicated that inhibition of transgelin expression locally could attenuate increased right ventricular systolic pressure and its associated cardiac and pulmonary vessel remodeling under hypoxia. Our findings indicate that HIF-2alpha upregulates transgelin indirectly and that accumulated TGF-beta1 is a mediator in the upregulation of transgelin by HIF-2alpha under hypoxia. Inhibition of transgelin expression locally could prevent HPH and pulmonary vascular remodeling in vivo. PMID- 24464810 TI - Neurofilament Heavy polypeptide CpG island methylation associates with prognosis of renal cell carcinoma and prediction of antivascular endothelial growth factor therapy response. AB - Neurofilament Heavy polypeptid (NEFH) belongs to the group of type IV intermediate filament proteins. DNA methylation of the NEFH promoter and loss of expression have previously been shown to activate the AKT/beta-catenin pathway in tumor cells. When identifying hypermethylation of the NEFH CpG island (CGI) in renal cell cancer (RCC) we asked whether methylation could provide clinical or prognostic information for RCC and/or predict therapy response in patients with metastatic RCC (mRCC) undergoing antiangiogenic therapy. Relative methylation of the NEFH CGI was analyzed in 132 RCC samples and 83 paired normal tissues using quantitative methylation-specific PCR. Results were statistically compared with tumor histology, clinicopathological parameters, progression-free survival (PFS) as well as with overall survival (OS) in a subset of 18 mRCC patients following antiangiogenic therapy regimens. The NEFH CGI methylation demonstrated a tumor specific increase (P < 0.001), association with advanced disease (P < 0.001), and distant metastasis (P = 0.005). Higher relative methylation was also significantly associated with a poor PFS (HR = 8.6, P < 0.001) independent from the covariates age, gender, diameter of tumors, state of advanced disease, and local and distant metastasis. Median OS following targeted therapy was 29.8 months for patients with low methylation versus 9.8 months for the group with high methylation (P = 0.028). We identified NEFH methylation as a candidate epigenetic marker for prognosis of RCC patients as well as prediction of anti vascular endothelial growth factor-based therapy response. PMID- 24464811 TI - Programmable System-on-Chip (PSoC) Embedded Readout Designs for Liquid Helium Level Sensors. AB - This article reports the development of programmable system-on-chip (PSoC)-based embedded readout designs for liquid helium level sensors using resistive liquid vapor discriminators. The system has been built for the measurement of liquid helium level in a concave-bottomed, helmet-shaped, fiber-reinforced plastic cryostat for magnetoencephalography. This design incorporates three carbon resistors as cost-effective sensors, which are mounted at desired heights inside the cryostat and were used to infer the liquid helium level by measuring their temperature-dependent resistance. Localized electrical heating of the carbon resistors was used to discriminate whether the resistor is immersed in liquid helium or its vapor by exploiting the difference in the heat transfer rates in the two environments. This report describes a single PSoC chip for the design and development of a constant current source to drive the three carbon resistors, a multiplexer to route the sensor outputs to the analog-to-digital converter (ADC), a buffer to avoid loading of the sensors, an ADC for digitizing the data, and a display using liquid crystal display cum light-emitting diode modules. The level sensor readout designed with a single PSoC chip enables cost-effective and reliable measurement system design. PMID- 24464812 TI - Automated Dissolution for Enteric-Coated Aspirin Tablets: A Case Study for Method Transfer to a RoboDis II. AB - Dissolution method transfer is a complicated yet common process in the pharmaceutical industry. With increased pharmaceutical product manufacturing and dissolution acceptance requirements, dissolution testing has become one of the most labor-intensive quality control testing methods. There is an increased trend for automation in dissolution testing, particularly for large pharmaceutical companies to reduce variability and increase personnel efficiency. There is no official guideline for dissolution testing method transfer from a manual, semi automated, to automated dissolution tester. In this study, a manual multipoint dissolution testing procedure for an enteric-coated aspirin tablet was transferred effectively and reproducibly to a fully automated dissolution testing device, RoboDis II. Enteric-coated aspirin samples were used as a model formulation to assess the feasibility and accuracy of media pH change during continuous automated dissolution testing. Several RoboDis II parameters were evaluated to ensure the integrity and equivalency of dissolution method transfer from a manual dissolution tester. This current study provides a systematic outline for the transfer of the manual dissolution testing protocol to an automated dissolution tester. This study further supports that automated dissolution testers compliant with regulatory requirements and similar to manual dissolution testers facilitate method transfer. PMID- 24464809 TI - Mechanisms of phagocytosis and host clearance of Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is an opportunistic bacterial pathogen responsible for a high incidence of acute and chronic pulmonary infection. These infections are particularly prevalent in patients with chronic obstructive pulmonary disease and cystic fibrosis: much of the morbidity and pathophysiology associated with these diseases is due to a hypersusceptibility to bacterial infection. Innate immunity, primarily through inflammatory cytokine production, cellular recruitment, and phagocytic clearance by neutrophils and macrophages, is the key to endogenous control of P. aeruginosa infection. In this review, we highlight recent advances toward understanding the innate immune response to P. aeruginosa, with a focus on the role of phagocytes in control of P. aeruginosa infection. Specifically, we summarize the cellular and molecular mechanisms of phagocytic recognition and uptake of P. aeruginosa, and how current animal models of P. aeruginosa infection reflect clinical observations in the context of phagocytic clearance of the bacteria. Several notable phenotypic changes to the bacteria are consistently observed during chronic pulmonary infections, including changes to mucoidy and flagellar motility, that likely enable or reflect their ability to persist. These traits are likewise examined in the context of how the bacteria avoid phagocytic clearance, inflammation, and sterilizing immunity. PMID- 24464813 TI - Analysis of Airborne Biomarkers for Point-of-Care Diagnostics. AB - Treatable diseases continue to exact a heavy burden worldwide despite powerful advances in treatment. Diagnostics play crucial roles in the detection, management, and ultimate prevention of these diseases by guiding the allocation of precious medical resources. Motivated by globalization and evolving disease, and enabled by advances in molecular pathology, the scientific community has produced an explosion of research on miniaturized integrated biosensor platforms for disease detection. Low-cost, automated tests promise accessibility in low resource settings by loosening constraints around infrastructure and usability. To address the challenges raised by invasive and intrusive sample collection, researchers are exploring alternative biomarkers in various specimens. Specifically, patient-generated airborne biomarkers suit minimally invasive collection and automated analysis. Disease biomarkers are known to exist in aerosols and volatile compounds in breath, odor, and headspace, media that can be exploited for field-ready diagnostics. This article reviews global disease priorities and the characteristics of low-resource settings. It surveys existing technologies for the analysis of bioaerosols and volatile organic compounds, and emerging technologies that could enable their translation to the point of care. Engineering advances promise to enable appropriate diagnostics by detecting chemical and microbial markers. Nonetheless, further innovation and cost reduction are needed for these technologies to broadly affect global health. PMID- 24464814 TI - Flexible End2End Workflow Automation of Hit-Discovery Research. AB - The article considers a new approach of more complex laboratory automation at the workflow layer. The authors purpose the automation of end2end workflows. The combination of all relevant subprocesses-whether automated or manually performed, independently, and in which organizational unit-results in end2end processes that include all result dependencies. The end2end approach focuses on not only the classical experiments in synthesis or screening, but also on auxiliary processes such as the production and storage of chemicals, cell culturing, and maintenance as well as preparatory activities and analyses of experiments. Furthermore, the connection of control flow and data flow in the same process model leads to reducing of effort of the data transfer between the involved systems, including the necessary data transformations. This end2end laboratory automation can be realized effectively with the modern methods of business process management (BPM). This approach is based on a new standardization of the process-modeling notation Business Process Model and Notation 2.0. In drug discovery, several scientific disciplines act together with manifold modern methods, technologies, and a wide range of automated instruments for the discovery and design of target based drugs. The article discusses the novel BPM-based automation concept with an implemented example of a high-throughput screening of previously synthesized compound libraries. PMID- 24464815 TI - Effects of Electromagnetic Fields on Automated Blood Cell Measurements. AB - The aim of this study is to investigate whether the electromagnetic fields associated with mobile phones and/or laptops interfere with blood cell counts of hematology analyzers. Random blood samples were analyzed on an Aperture Impedance hematology analyzer. The analysis was performed in four ways: (A) without the presence of any mobile phone or portable computer in use, (B) with mobile phones in use (B1: one mobile, B4: four mobiles), (C) with portable computers (laptops) in use (C1: one laptop, C3: three laptops), and (D) with four mobile phones and three laptops in use simultaneously. The results obtained demonstrated a statistically significant decrease in neutrophil, erythrocyte, and platelet count and an increase in lymphocyte count, mean corpuscular volume, and red blood cell distribution width, notably in the B4 group. Despite this statistical significance, in clinical practice, only the red blood cell reduction could be taken into account, as the mean difference between the A and B4 group was 60,000 cells/uL. In group D, the analyzer gave odd results after 11 measurements and finally stopped working. The combined and multiple use of mobile phones and computers affects the function of hematology analyzers, leading to false results. Consequently, the use of such electronic devices must be avoided. PMID- 24464816 TI - PRIMSIPLR: prediction of inner-membrane situated pore-lining residues for alpha helical transmembrane proteins. AB - Transmembrane proteins such as transporters and channels mediate the passage of inorganic and organic substances across biological membranes through their central pore. Pore-lining residues (PLRs) that make direct contacts to the substrates have a crucial impact on the function of the protein and, hence, their identification is a key step in mechanistic studies. Here, we established a nonredundant data set containing the three-dimensional (3D) structures of 90 alpha-helical transmembrane proteins and annotated the PLRs of these proteins by a pore identification software. A support vector machine was then trained to distinguish PLRs from other residues based on the protein sequence alone. Using sixfold cross-validation, our best performing predictor gave a Matthews's correlation coefficient of 0.41 with an accuracy of 0.86, sensitivity of 0.61, and specificity of 0.89, respectively. We provide a novel software tool that will aid biomedical scientists working on transmembrane proteins with unknown 3D structures. Both standalone version and web service are freely available from the URL http://service.bioinformatik.uni-saarland.de/PRIMSIPLR/. PMID- 24464817 TI - Radiation exposure to nuclear medicine staff involved in PET/CT practice in Serbia. AB - The purpose of this work is to evaluate the radiation exposure to nuclear medicine (NM) staff in the two positron emission tomography-computed tomography centres in Serbia and to investigate the possibilities for dose reduction. Dose levels in terms of Hp(10) for whole body and Hp(0.07) for hands of NM staff were assessed using thermoluminescence and electronic personal dosemeters. The assessed doses per procedure in terms of Hp(10) were 4.2-7 and 5-6 MUSv, in two centres, respectively, whereas the extremity doses in terms of Hp(0.07) in one of the centres was 34-126 MUSv procedure(-1). The whole-body doses per unit activity were 17-19 and 21-26 MUSv GBq(-1) in two centres, respectively, and the normalised finger dose in one centre was 170-680 MUSv GBq(-1). The maximal estimated annual whole-body doses in two centres were 3.4 and 2.0 mSv, while the corresponding extremity dose in the later one was 45 mSv. Improvements as introduction of automatic dispensing system and injection and optimisation of working practice resulted in dose reduction ranging from 12 up to 67 %. PMID- 24464818 TI - Measurement models for passive dosemeters in view of uncertainty evaluation using the Monte Carlo method. AB - Two measurement models for passive dosemeters such as thermoluminescent dosemeter, optically stimulated luminescence, radio-photoluminescence, photographic film or track etch are discussed. The first model considers the dose evaluation with the reading equipment as a single measurement, the one-stage model. The second model considers the build-up of a latent signal or latent image in the detector during exposure and the evaluation using a reader system as two separate measurements, the two-stage model. It is discussed that the two-stage model better reflects the cause and effect relations and the course of events in the daily practice of a routine dosimetry service. The one-stage model will be non-linear in crucial input quantities which can give rise to erroneous behavior of the uncertainty evaluation based on the law of propagation of uncertainty. Input quantities that show an asymmetric probability distributions propagate through the one-stage model in a physically not relevant way. PMID- 24464819 TI - Measurements of eye lens doses in interventional cardiology using OSL and electronic dosemeters?. AB - The purpose of this paper is to test the appropriateness of OSL and electronic dosemeters to estimate eye lens doses at interventional cardiology environment. Using TLD as reference detectors, personal dose equivalent was measured in phantoms and during clinical procedures. For phantom measurements, OSL dose values resulted in an average difference of -15 % vs. TLD. Tests carried out with other electronic dosemeters revealed differences up to +/-20 % versus TLD. With dosemeters positioned outside the goggles and when TLD doses were >20 MUSv, the average difference OSL vs. TLD was -9 %. Eye lens doses of almost 700 MUSv per procedure were measured in two cases out of a sample of 33 measurements in individual clinical procedures, thus showing the risk of high exposure to the lenses of the eye when protection rules are not followed. The differences found between OSL and TLD are acceptable for the purpose and range of doses measured in the survey. PMID- 24464820 TI - FRET-based and other fluorescent proteinase probes. AB - The continuous detection of enzyme activities and their application in medical diagnostics is one of the challenges in the translational sciences. Proteinases represent one of the largest groups of enzymes in the human genome and many diseases are based on malfunctions of proteolytic activity. Fluorescent sensors may shed light on regular and irregular proteinase activity in vitro and in vivo and provide a deeper insight into the function of these enzymes and their role in pathophysiological processes. The focus of this review is on Forster resonance energy transfer (FRET)-based proteinase sensors and reporters because these probes are most likely to provide quantitative data. The medical relevance of proteinases are discussed using lung diseases as a prominent example. Probe design and probe targeting are described and fluorescent probe development for disease-relevant proteinases, including matrix-metalloproteinases, cathepsins, caspases, and other selected proteinases, is reviewed. PMID- 24464821 TI - Competing designs for drug combination in phase I dose-finding clinical trials. AB - The aim of phase I combination dose-finding studies in oncology is to estimate one or several maximum tolerated doses (MTDs) from a set of available dose levels of two or more agents. Combining several agents can indeed increase the overall anti-tumor action but at the same time also increase the toxicity. It is, however, unreasonable to assume the same dose-toxicity relationship for the combination as for the simple addition of each single agent because of a potential antagonist or synergistic effect. Therefore, using single-agent dose finding methods for combination therapies is not appropriate. In recent years, several authors have proposed novel dose-finding designs for combination studies, which use either algorithm-based or model-based methods. The aim of our work was to compare, via a simulation study, six dose-finding methods for combinations proposed in recent years. We chose eight scenarios that differ in terms of the number and location of the true MTD(s) in the combination space. We then compared the performance of each design in terms of correct combination selection, patient allocation, and mean number of observed toxicities during the trials. Our results showed that the model-based methods performed better than the algorithm-based ones. However, none of the compared model-based designs gave consistently better results than the others. PMID- 24464822 TI - Adaptation to nicotine in the facultative tobacco-feeding hemipteran Bemisia tabaci. AB - BACKGROUND: Plant defensive metabolites such as nicotine can provide barriers to host-range expansion by generalist herbivores. Nicotine is one of the most abundant and toxic plant secondary metabolites in nature and is defined by high toxicity to plant-feeding insects. There is significant variation in nicotine tolerance among Bemisia tabaci (tobacco whitefly) isolates. Some nicotine tolerant B. tabaci strains can consume 40-fold higher nicotine levels than susceptible strains, and also show cross-resistance to neonicotinoid insecticides. In this study, biological and molecular assays were used to investigate the responses of B. tabaci strains that differ in their ability to tolerate dietary nicotine. RESULTS: Egg laying and honeydew secretion bioassays as well as gene expression microarrays were used to measure B. tabaci biological parameters and gene transcripts misregulated in response to nicotine in resistant and susceptible strains. The resistant B. tabaci strain laid significantly fewer eggs and excreted more honeydew on a tobacco strain with high levels of nicotine, suggesting a fitness cost effect. The molecular response was drastic in the susceptible strain, while the resistant strain exhibited moderate response. Higher expression of the previously identified CYP6CM1 P450 monooxygenase gene related to the resistance to neonicotinoids, as well as other P450s and metabolic genes, was identified in the resistant and susceptible strains after exposure to nicotine. CONCLUSIONS: Nicotine is a very toxic plant natural compound, and its mode of action resembles that of synthetic neonicotinoids. The biological and molecular responses observed in this study suggest that nicotine may play an important role in providing barriers for host-plant expansion by generalists, and may act as a natural factor that contributes to the development of insect populations resistant to synthetic pesticides. PMID- 24464823 TI - Maximized mucoadhesion and skin permeation of anti-AIDS-loaded niosomal gels. AB - The low permeability of the anti-AIDS, tenofovir, limits its antiretroviral clinical potency. The proposed study aimed at assessing the critical biological responses of tenofovir through the development and optimization of its surfactant based niosomal gels intended for vaginal delivery. Fatty acid chain length of the amphiphile and cholesterol loading were optimized using a 32 full factorial design. Vesicular size, shape and surface charge, drug entrapment efficiency, in vitro release, and skin permeation were used to assess the gels. In addition, their biological performance on Lactobacillus crispatus viability and mucoadhesion to porcine vaginal tissue was also assessed. Within the design space, mucoadhesion percentage ranged from 6.2% to 28.6% and increased nonlinearly by decreasing niosomal vesicular size and linearly by increasing surface charge. Moreover, these gels were not cytotoxic to Lactobacillus crispatus for 48 h. For maximizing tenofovir entrapment, percutaneous permeation, and mucoadhesion while achieving sustained-release features, an optimum formulation was proposed with the shortest length of fatty chain and 0.48 mM cholesterol content. Overall, applying quality by design paradigm to the development of tenofovir niosomal gels not only offered a promising nanomedicine for the vaginal microbicide delivery but also unveiled the critical formulation interactions influencing its biological performance. PMID- 24464824 TI - A deadly organometallic luminescent probe: anticancer activity of a ReI bisquinoline complex. AB - The photophysical properties of [Re(CO)3 (L-N3)]Br (L-N3 =2-azido-N,N bis[(quinolin-2-yl)methyl]ethanamine), which could not be localized in cancer cells by fluorescence microscopy, have been revisited in order to evaluate its use as a luminescent probe in a biological environment. The Re(I) complex displays concentration-dependent residual fluorescence besides the expected phosphorescence, and the nature of the emitting excited states have been evaluated by DFT and time-dependent (TD) DFT methods. The results show that fluorescence occurs from a (1) LC/MLCT state, whereas phosphorescence mainly stems from a (3) LC state, in contrast to previous assignments. We found that our luminescent probe, [Re(CO)3 (L-N3)]Br, exhibits an interesting cytotoxic activity in the low micromolar range in various cancer cell lines. Several biochemical assays were performed to unveil the cytotoxic mechanism of the organometallic Re(I) bisquinoline complex. [Re(CO)3 (L-N3)]Br was found to be stable in human plasma indicating that [Re(CO)3 (L-N3)]Br itself and not a decomposition product is responsible for the observed cytotoxicity. Addition of [Re(CO)3 (L-N3)]Br to MCF-7 breast cancer cells grown on a biosensor chip micro-bioreactor immediately led to reduced cellular respiration and increased glycolysis, indicating a large shift in cellular metabolism and inhibition of mitochondrial activity. Further analysis of respiration of isolated mitochondria clearly showed that mitochondrial respiratory activity was a direct target of [Re(CO)3 (L-N3)]Br and involved two modes of action, namely increased respiration at lower concentrations, potentially through increased proton transport through the inner mitochondrial membrane, and efficient blocking of respiration at higher concentrations. Thus, we believe that the direct targeting of mitochondria in cells by [Re(CO)3 (L-N3)]Br is responsible for the anticancer activity. PMID- 24464825 TI - Dysregulation of diverse ion transport pathways controlling cell volume homoestasis contribute to neuroglial cell injury following ischemic stroke. PMID- 24464826 TI - An uncommon cause of radial access failure. PMID- 24464827 TI - Hospitalized heart failure patients with preserved vs. reduced ejection fraction in Dubai, United Arab Emirates: a prospective study. AB - AIMS: To compare the baseline characteristics, pharmacological treatment, and in hospital outcomes across hospitalized heart failure (HF) patients with preserved LVEF (HF-PEF) and those with reduced LVEF (HF-REF). METHOD AND RESULTS: This was a prospective analysis of consecutive patients admitted with decompensated HF at two government hospitals in the United Arab Emirates, from 1 December 2011 to 30 November 2012. Multivariate factors of HF-PEF vs. HF-REF included elevated systolic blood pressure [odds ratio (OR) 1.02; 95% confidence interval (CI) 1.01 1.03], heart rate (OR 0.98; 95% CI 0.97-0.99), age (OR 1.02; 95% CI 1.01-1.04), female sex (OR 2.38; 95% CI 1.41-4.03), angina or myocardial infarction (OR 0.42; 95% CI 0.25-0.71), AF (OR 1.82; 95% CI 1.05-3.15), COPD or asthma (OR 2.80; 95% CI 1.47-5.35), Charlson Comorbidity Index score (OR 0.75; 95% CI 0.64-0.88), and anaemia (OR 2.97; 95% CI 1.64-5.38). In-hospital outcomes were similar between the two groups. However, patients with HF-PEF were less likely to be prescribed HF medication, and used more anticoagulants and fewer antiplatelet medications. CONCLUSION: These results suggest that patients with HF-PEF are older, more often female, and have higher prevalence of respiratory diseases and AF. Compared with developed countries, hospitalized HF patients in the Middle East are 10 years younger and have a higher prevalence of diabetes mellitus, and the majority have HF-REF. PMID- 24464828 TI - Restrictive mitral annuloplasty with or without surgical ventricular reconstruction in ischaemic cardiomyopathy: impacts on neurohormonal activation, reverse left ventricular remodelling and survival. AB - AIMS: In the STICH trial, adding surgical ventricular reconstruction (SVR) to coronary artery bypass grafting (CABG) reduced LV end-systolic volume index (LVESVI) by 19%, as compared with 6% with CABG alone, providing no survival or functional benefits. Herein, we compared the efficacy of restrictive mitral annuloplasty (RMA) alone with that of RMA combined with SVR in patients with functional mitral regurgitation (MR). METHODS AND RESULTS: One hundred and six patients with ischaemic cardiomyopathy underwent RMA with (n = 52) or without SVR (n = 54) for functional MR. Pre- and post-operative (1 month) left ventriculography and longitudinal measurements of plasma BNP were performed. Pre operatively, patients who underwent RMA plus SVR had a larger LVESVI (126 +/- 26 vs. 100 +/- 24 mL/m(2) , P < 0.0001). After surgery, RMA plus SVR reduced LVESVI more than RMA alone (43% vs. 22%, P <0.0001), yielding a nearly identical post operative LVESVI (71 +/- 17 vs. 78 +/- 26 mL/m(2) ). Survival rate was not different between the groups (4-year survival, 62% vs. 62%, P = 0.99), though among patients with pre-operative LVESVI ranging from 105 to 150 mL/m(2) , that was higher in the RMA plus SVR group (73% vs. 40%, P = 0.046), accompanied by a larger percentage reduction in plasma BNP from baseline to the latest follow-up examination (63 +/- 34% vs. 34 +/- 46%, P = 0.012). After propensity score adjustment, patients with LVESVI ranging from 105 to 150 mL/m(2) who underwent RMA alone showed a greater association with mortality (hazard ratio 7.5, 95% confidence interval 2.1-27, P = 0.010), as compared with those with LVESVI <105 mL/m(2) who underwent RMA alone. CONCLUSIONS: RMA plus SVR reduced LVESVI to a greater degree than RMA alone, neutralizing anticipated worse prognosis. Selected patients with functional MR and advanced LV remodelling may benefit by adding SVR to RMA. PMID- 24464829 TI - Chromosomal aneuploidy affects the global proteome equilibrium of colorectal cancer cells. AB - BACKGROUND: Chromosomal aneuploidy has been identified as a prognostic factor in the majority of sporadic carcinomas. However, it is not known how chromosomal aneuploidy affects chromosome-specific protein expression in particular, and the cellular proteome equilibrium in general. OBJECTIVE: The aim was to detect chromosomal aneuploidy-associated expression changes in cell clones carrying trisomies found in colorectal cancer. METHODS: We used microcell-mediated chromosomal transfer to generate three artificial trisomic cell clones of the karyotypically stable, diploid, yet mismatch-deficient, colorectal cancer cell line DLD1--each of them harboring one extra copy of either chromosome 3, 7 or 13. Protein expression differences were assessed by two-dimensional gel electrophoresis and mass spectrometry, compared to whole-genome gene expression data, and evaluated by PANTHER classification system and Ingenuity Pathway Analysis (IPA). RESULTS: In total, 79 differentially expressed proteins were identified between the trisomic clones and the parental cell line. Up-regulation of PCNA and HMGB1 as well as down-regulation of IDH3A and PSMB3 were revealed as trisomy-associated alterations involved in regulating genome stability. CONCLUSIONS: These results show that trisomies affect the expression of genes and proteins that are not necessarily located on the trisomic chromosome, but reflect a pathway-related alteration of the cellular equilibrium. PMID- 24464830 TI - MRI default mode network connectivity is associated with functional outcome after cardiopulmonary arrest. AB - BACKGROUND: We hypothesized that the degree of preserved functional connectivity within the DMN during the first week after cardiopulmonary arrest (CPA) would be associated with functional outcome at hospital discharge. METHODS: Initially comatose CPA survivors with indeterminate prognosis at 72 h were enrolled. Seventeen CPA subjects between 4 and 7 days after CPA and 17 matched controls were studied with task-free fMRI. Independent component analysis was performed to delineate the DMN. Connectivity strength in the DMN was compared between CPA subjects and controls, as well as between CPA subjects with good outcome (discharge Cerebral Performance Category or CPC 1-2) and those with bad outcome (CPC 3-5). The relationship between connectivity strength in the posterior cingulate cortex (PCC) and precuneus (PC) within the DMN with discharge CPC was evaluated using linear regression. RESULTS: Compared to controls, CPA subjects had significantly lower connectivity strength in subregions of the DMN, the PCC and PC (p < 0.0001). Furthermore, connectivity strength in the PCC and PC was greater in CPA subjects with good outcome (n = 8) than those with bad outcome (n = 9) (p < 0.003). Among CPA subjects, the connectivity strength in the PCC and PC showed strong linear correlations with the discharge CPC (p < 0.005). CONCLUSIONS: Among initially comatose CPA survivors with indeterminate prognosis, task-free fMRI demonstrated graded disruption of DMN connectivity, especially in those with bad outcomes. If confirmed, connectivity strength in the PC/PCC may provide a clinically useful prognostic marker for functional recovery after CPA. PMID- 24464831 TI - Neuraxial blockade for the prevention of postoperative mortality and major morbidity: an overview of Cochrane systematic reviews. AB - BACKGROUND: Various beneficial effects derived from neuraxial blocks have been reported. However, it is unclear whether these effects have an influence on perioperative mortality and major pulmonary/cardiovascular complications. OBJECTIVES: Our primary objective was to summarize Cochrane systematic reviews that assess the effects of neuraxial blockade on perioperative rates of death, chest infection and myocardial infarction by integrating the evidence from all such reviews that have compared neuraxial blockade with or without general anaesthesia versus general anaesthesia alone for different types of surgery in various populations. Our secondary objective was to summarize the evidence on adverse effects (an adverse event for which a causal relation between the intervention and the event is at least a reasonable possibility) of neuraxial blockade. Within the reviews, studies were selected using the same criteria. METHODS: A search was performed in the Cochrane Database of Systematic Reviews on July 13, 2012. We have (1) included all Cochrane systematic reviews that examined participants of any age undergoing any type of surgical (open or endoscopic) procedure, (2) compared neuraxial blockade versus general anaesthesia alone for surgical anaesthesia or neuraxial blockade plus general anaesthesia versus general anaesthesia alone for surgical anaesthesia and (3) included death, chest infection, myocardial infarction and/or serious adverse events as outcomes. Neuraxial blockade could consist of epidural, caudal, spinal or combined spinal epidural techniques administered as a bolus or by continuous infusion. Studies included in these reviews were selected on the basis of the same criteria. Reviews and studies were selected independently by two review authors, who independently performed data extraction when data differed from one of the selected reviews. Data were analysed by using Review Manager Version 5.1 and Comprehensive Meta Analysis Version 2.2.044. MAIN RESULTS: Nine Cochrane reviews were selected for this overview. Their scores on the Overview Quality Assessment Questionnaire varied from four to six of a maximal possible score of seven. Compared with general anaesthesia, neuraxial blockade reduced the zero to 30-day mortality (risk ratio [RR] 0.71, 95% confidence interval [CI] 0.53 to 0.94; I(2) = 0%) based on 20 studies that included 3006 participants. Neuraxial blockade also decreased the risk of pneumonia (RR 0.45, 95% CI 0.26 to 0.79; I(2) = 0%) based on five studies that included 400 participants. No difference was detected in the risk of myocardial infarction between the two techniques (RR 1.17, 95% CI 0.57 to 2.37; I(2) = 0%) based on six studies with 849 participants. Compared with general anaesthesia alone, the addition of a neuraxial block to general anaesthesia did not affect the zero to 30-day mortality (RR 1.07, 95% CI 0.76 to 1.51; I(2) = 0%) based on 18 studies with 3228 participants. No difference was detected in the risk of myocardial infarction between combined neuraxial blockade general anaesthesia and general anaesthesia alone (RR 0.69, 95% CI 0.44 to 1.09; I(2) = 0%) based on eight studies that included 1580 participants. The addition of a neuraxial block to general anaesthesia reduced the risk of pneumonia (RR 0.69, 95% CI 0.49 to 0.98; I(2) = 9%) after adjustment for publication bias and based on nine studies that included 2433 participants. The quality of the evidence was judged as moderate for all six comparisons.No serious adverse events (seizure or cardiac arrest related to local anaesthetic toxicity, prolonged central or peripheral neurological injury lasting longer than one month or infection secondary to neuraxial blockade) were reported. The quality of the reporting score of complications related to neuraxial blocks was nine (four to 12 (median range)) of a possible maximum score of 14. AUTHORS' CONCLUSIONS: Compared with general anaesthesia, a central neuraxial block may reduce the zero to 30-day mortality for patients undergoing surgery with intermediate to high cardiac risk (level of evidence, moderate). Further research is required. PMID- 24464832 TI - Augmented reality in medical education? AB - Learning in the medical domain is to a large extent workplace learning and involves mastery of complex skills that require performance up to professional standards in the work environment. Since training in this real-life context is not always possible for reasons of safety, costs, or didactics, alternative ways are needed to achieve clinical excellence. Educational technology and more specifically augmented reality (AR) has the potential to offer a highly realistic situated learning experience supportive of complex medical learning and transfer. AR is a technology that adds virtual content to the physical real world, thereby augmenting the perception of reality. Three examples of dedicated AR learning environments for the medical domain are described. Five types of research questions are identified that may guide empirical research into the effects of these learning environments. Up to now, empirical research mainly appears to focus on the development, usability and initial implementation of AR for learning. Limited review results reflect the motivational value of AR, its potential for training psychomotor skills and the capacity to visualize the invisible, possibly leading to enhanced conceptual understanding of complex causality. PMID- 24464833 TI - Microstimulation of afferents in the sacral dorsal root ganglia can evoke reflex bladder activity. AB - AIMS: Pudendal afferent fibers can be excited using electrical stimulation to evoke reflex bladder activity. While this approach shows promise for restoring bladder function, stimulation of desired pathways, and integration of afferent signals for sensory feedback remains challenging. At sacral dorsal root ganglia (DRG), the convergence of pelvic and pudendal afferent fibers provides a unique location for access to lower urinary tract neurons. Our goal in this study was to demonstrate the potential of microstimulation in sacral DRG for evoking reflex bladder responses. METHODS: Penetrating microelectrode arrays were inserted in the left S1 and S2 DRG of six anesthetized adult male cats. While the bladder volume was held at a level below the leak volume, single and multiple channel stimulation was performed using various stimulation patterns. RESULTS: Reflex bladder excitation was observed in five cats, for stimulation in either S1 or S2 DRG at 1 Hz and 30-33 Hz with a pulse amplitude of 10-50 uA. Bladder relaxation was observed during a few trials. Adjacent electrodes frequently elicited very different responses. CONCLUSIONS: These results demonstrate the potential of low current microstimulation to recruit reflexive bladder responses. An approach such as this could be integrated with DRG recordings of bladder afferents to provide a closed-loop bladder neuroprosthesis. PMID- 24464834 TI - Long-term survival after alcohol septal ablation for hypertrophic obstructive cardiomyopathy: a comparison with general population. AB - AIMS: We decided to determine the long-term survival of patients after alcohol septal ablation (ASA) for hypertrophic obstructive cardiomyopathy (HOCM) and compare this with the general population. METHODS AND RESULTS: A total of 178 highly symptomatic, consecutive patients (58 +/- 12 years, 53% women) were treated by ASA between April 1998 and April 2013 and followed-up for 4.8 years (IQR 2.1-7.5). At baseline, 155 patients (87%) suffered from dyspnoea >=3 class of NYHA; at the most recent examination, 87 patients (49%) and 23 patients (13%) reported dyspnoea of NYHA class 1 and >=3, respectively. The left ventricular outflow gradient was significantly reduced (68 +/- 42 vs. 20 +/- 25 mmHg; P < 0.01). A total of 19 deaths (11%) occurred during 925 patient-years, which means an overall mortality rate of 2.1% per year. Survival free of all-cause mortality at 1, 5, and 10 years was 97% (95% CI, 93-99%), 92% (95% CI, 87-96%), and 82% (95% CI, 70-90%), respectively. This observed mortality was comparable to the expected survival for age- and sex-comparable general population (P = 0.34). According to multivariate analysis, the only independent predictor of all-cause mortality was age at ASA (hazard ratio 1.09, 95% CI 1.04-1.14; P < 0.01). CONCLUSIONS: This study suggests that in patients with HOCM and important symptoms who underwent ASA, long-term survival after the procedure did not differ significantly from that of the general population. PMID- 24464835 TI - Rebuilding a macromolecular membrane complex at the atomic scale: case of the Kir6.2 potassium channel coupled to the muscarinic acetylcholine receptor M2. AB - Ion channel-coupled receptors (ICCR) are artificial proteins built from a G protein-coupled receptor and an ion channel. Their use as molecular biosensors is promising in diagnosis and high-throughput drug screening. The concept of ICCR was initially validated with the combination of the muscarinic receptor M2 with the inwardly rectifying potassium channel Kir6.2. A long protein engineering phase has led to the biochemical characterization of the M2-Kir6.2 construct. However, its molecular mechanism remains to be elucidated. In particular, it is important to determine how the activation of M2 by its agonist acetylcholine triggers the modulation of the Kir6.2 channel via the M2-Kir6.2 linkage. In the present study, we have developed and validated a computational approach to rebuild models of the M2-Kir6.2 chimera from the molecular structure of M2 and Kir6.2. The protocol was first validated on the known protein complexes of the MU opioid Receptor, the CXCR4 receptor and the Kv1.2 potassium channel. When applied to M2-Kir6.2, our protocol produced two possible models corresponding to two different orientations of M2. Both models highlights the role of the M2 helices I and VIII in the interaction with Kir6.2, as well as the role of the Kir6.2 N terminus in the channel opening. Those two hypotheses will be explored in a future experimental study of the M2-Kir6.2 construct. PMID- 24464836 TI - Variable concentration of soil-applied insecticides in potato over time: implications for management of Leptinotarsa decemlineata. AB - BACKGROUND: Select populations of Colorado potato beetle, Leptinotarsa decemlineata, in Wisconsin have recently become resistant to soil-applied neonicotinoids in potato. Sublethal insecticide concentrations persisting in foliage through the growing season may select for resistance over successive years of use. Over the 2 years of this study, the aim was to document the in plant insecticide concentrations over time that result from four different types of soil-applied insecticide delivery for thiamethoxam and imidacloprid in potato, and to measure the impact upon L. decemlineata populations following treatments. After plant emergence, insect life stages were counted and plant tissue was assayed weekly for nine consecutive weeks using ELISA. RESULTS: Peak concentration of both imidacloprid and thiamethoxam occurred in the first sample week following plant emergence. The average concentration of both insecticides dissipated sharply over time as the plant canopy expanded 50 days after planting in all delivery treatments. Both insecticides were detected at low levels during the later weeks of the study. Among-plant concentrations of both neonicotinoids were highly variable throughout the season. Populations of L. decemlineata continued to develop and reproduce throughout the period of declining insecticide concentrations. CONCLUSION: Sublethal, chronic exposure to soil-applied systemic insecticides resulting from these delivery methods may accelerate selection for resistant insects in potato. PMID- 24464837 TI - Tissue kallikrein protects rat hippocampal CA1 neurons against cerebral ischemia/reperfusion-induced injury through the B2R-Raf-MEK1/2-ERK1/2 pathway. AB - We have documented that tissue kallikrein (TK) prevents neurons from hypoxia/reoxygenation injury through the B2R-ERK1/2 pathway and the antihypoxic function of TK through Homer1b/c-ERK1/2 signaling pathways. The present study investigates the molecular mechanisms of exogenous TK activation of the B2R ERK1/2 pathway through the beta-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module in vivo. The cresyl violet staining results indicated that exogenous TK protected the rat hippocampal CA1 neurons against cerebral ischemia/reperfusion (I/R) injury. The immunoprecipitation (IP) and immunoblotting (IB) results revealed that exogenous TK upregulated the beta-arrestin-2 assembled B2R-Raf MEK1/2 signaling module and upregulated the phosphorylation of Raf (p-Raf), MEK1/2 (p-MEK1/2), and ERK1/2 (p-ERK1/2). Meanwhile, exogenous TK upregulated the expression of nuclear factor-kappaB (NF-kappaB), depressed the release of cytochrome c (Cyt c) and bax from mitochondria to the cytosol, and depressed the activation of caspase-3. Take together, our results suggest that exogenous TK attenuated the cerebral I/R induced rat hippocampal CA1 neurons injury through activating the beta-arrestin-2 assembled B2R-Raf-MEK1/2 signaling module and that the activated B2R-Raf-MEK1/2 signaling module could upregulate the expression of NF-kappaB, decrease the release of cytochrome c and bax from mitochondria to the cytosol, and depress the activation of caspase-3. PMID- 24464838 TI - Cocaine- or stress-induced metaplasticity of LTP in the dorsal and ventral hippocampus. AB - Despite the well documented role of the hippocampus in various modes of drug reinstatement behavior, the persisting effects of in vivo cocaine exposure on hippocampal synaptic plasticity are not sufficiently understood. In this report we investigated the effects of cocaine conditioning on long-term potentiation (LTP) in the CA1 region of hippocampus along its septotemporal axis. Male Sprague Dawley rats experienced a behavioral protocol, in which locomotor activity was monitored in response to various conditioning treatments. LTP was measured in ex vivo slice preparations taken 1-2 weeks after the last behavioral session from the ventral (vH) and dorsal (dH) sectors of hippocampus. Unexpectedly, experiencing the minor intermittent stimuli of the behavioral protocol caused stress-induced metaplastic changes in both vH (increased LTP) and dH (decreased LTP) in the saline conditioned rats relative to behaviorally naive controls. These stress effects in the vH and dH were blocked by conditioning with either mineralocorticoid (spironolactone) or glucocorticoid (mifepristone) antagonists, respectively. Stress-induced metaplasticity in the vH was also prevented by prior administration of the kappa opioid antagonist nor-binaltorphimine. Cocaine conditioning induced locomotor sensitization and significantly increased LTP in the vH without causing significant change in LTP in the dH. Cocaine-induced metaplasticity in the vH was prevented by co-administration of the dopamine D2 like antagonist eticlopride during cocaine conditioning, but not by co administration of the D1/5 antagonist SCH 23390. Our results suggest that the functional connectivity of hippocampus is altered by metaplastic triggers such as exposure to drugs of abuse and/or stressors, thereby shifting the efferent output of hippocampus from dH (cortical) toward vH (limbic) influenced circuits. PMID- 24464839 TI - Targeting of tumor endothelial cells combining 2 Gy/day of X-ray with Everolimus is the effective modality for overcoming clinically relevant radioresistant tumors. AB - Radiotherapy is widely used to treat cancer because it has the advantage of physically and functionally conserving the affected organ. To improve radiotherapy and investigate the molecular mechanisms of cellular radioresistance, we established a clinically relevant radioresistant (CRR) cell line, SAS-R, from SAS cells. SAS-R cells continue to proliferate when exposed to fractionated radiation (FR) of 2 Gy/day for more than 30 days in vitro. A xenograft tumor model of SAS-R was also resistant to 2 Gy/day of X-rays for 30 days. The density of blood vessels in SAS-R tumors was higher than in SAS tumors. Everolimus, a mammalian target of rapamycin (mTOR) inhibitor, sensitized microvascular endothelial cells to radiation, but failed to radiosensitize SAS and SAS-R cells in vitro. Everolimus with FR markedly reduced SAS and SAS-R tumor volumes. Additionally, the apoptosis of endothelial cells (ECs) increased in SAS R tumor tissues when both Everolimus and radiation were administered. Both CD34 positive and tomato lectin-positive blood vessel densities in SAS-R tumor tissues decreased remarkably after the Everolimus and radiation treatment. Everolimus induced apoptosis of vascular ECs in response to radiation was also followed by thrombus formation that leads to tumor necrosis. We conclude that FR combined with Everolimus may be an effective modality to overcome radioresistant tumors via targeting tumor ECs. PMID- 24464840 TI - Accurate LC-ESI-MS/MS quantification of 2'-deoxymugineic acid in soil and root related samples employing porous graphitic carbon as stationary phase and a 13C4 labeled internal standard. AB - For the first time the phytosiderophore 2'-deoxymugineic acid (DMA) could be accurately quantified by LC-MS/MS in plant and soil related samples. For this purpose a novel chromatographic method employing porous graphitic carbon as stationary phase combined with ESI-MS/MS detection in selected reaction monitoring was developed. Isotope dilution was implemented by using in-house synthesized DMA as external calibrant and 13C4-labeled DMA as internal standard (concentration levels of standards 0.1-80 MUM, determination coefficient of linear regression R2 > 0.9995). Sample preparation involved acidification of the samples in order to obtain complete dissociation of metal-DMA complexes. Excellent matrix related LOD and LOQ depending on different experimental setups were obtained in the range of 3-34 nM and 11-113 nM, respectively. Standard addition experiments and the implementation of the internal 13C4-DMA standard proved the accuracy of the quantification strategy even in complex matrices such as soil solution. The repeatability of the method, including sample preparation, expressed as short- and long term precision was below 4 and 5% RSD, respectively. Finally, application in the context of plant and soil research to samples from rhizosphere sampling via micro suction cups, from soil solutions and soil adsorption/extraction studies revealed a DMA concentration range from 0.1 to 235 MUM. PMID- 24464842 TI - Trilogy of foregut atresia without genetic abnormality: exception to the Martinez Frias syndrome. AB - We present a case of oesophageal atresia with distal tracheo-oesophageal fistula and duodenal atresia, which later on was detected to have cystic variant of biliary atresia. He underwent primacy repair of oesophageal atresia with ligation of distal tracheo-oesophageal fistula and duodenoduodenostomy. He later developed features of obstructive jaundice, and on investigation was diagnosed to have cystic variant of biliary atresia which was initially confused with iatrogenic biliary obstruction. Exploration and operative cholangiogram with biopsy confirmed cystic variant of biliary atresia and underwent successful Kasai procedure. Our case effectively demonstrates a rare triology of foregut atresia without an apparent genetic association. It highlights stepwise systematic management of foregut atresias in this patient and demonstration of cystic variant of biliary atresia. Even though these are rarely seen, still the clinician should be aware of such a possibility and should adopt a multimodality approach to diagnose and an aggressive approach to manage the condition. PMID- 24464841 TI - Inhibitory activities of trichostatin a in U87 glioblastoma cells and tumorsphere derived cells. AB - Epigenetic alterations have been increasingly implicated in glioblastoma (GBM) pathogenesis, and epigenetic modulators including histone deacetylase inhibitors (HDACis) have been investigated as candidate therapies. GBMs are proposed to contain a subpopulation of glioblastoma stem cells (GSCs) that sustain tumor progression and therapeutic resistance and can form tumorspheres in culture. Here, we investigate the effects of the HDACi trichostatin A (TSA) in U87 GBM cultures and tumorsphere-derived cells. Using approaches that include a novel method to measure tumorsphere sizes and the area covered by spheres in GBM cultures, as well as a nuclear morphometric analysis, we show that TSA reduced proliferation and colony sizes, led to G2/M arrest, induced alterations in nuclear morphology consistent with cell senescence, and increased the protein content of GFAP, but did not affect migration, in cultured human U87 GBM cells. In cells expanded in tumorsphere assays, TSA reduced sphere formation and induced neuron-like morphological changes. The expression of stemness markers in these cells was detected by reverse transcriptase polymerase chain reaction. These findings indicate that HDACis can inhibit proliferation, survival, and tumorsphere formation, and promote differentiation of U87 GBM cells, providing further evidence for the development of HDACis as potential therapeutics against GBM. PMID- 24464843 TI - Treatment of Kaposi sarcoma in children with HIV-1 infection. AB - BACKGROUND: Kaposi sarcoma (KS) remains the second most frequently diagnosed HIV related malignancy (HRM) worldwide and most common HRM in sub-Saharan Africa where HIV is most prevalent and human herpesvirus 8 (HHV-8), the precipitating agent for the development of KS, is endemic. The majority of KS patients would likely benefit from systemic chemotherapy in addition to the initiation of antiretroviral therapy (ART). However, as paediatric staging and treatment criteria are not readily available, there are no uniform treatment criteria. OBJECTIVES: To describe the efficacy and effectiveness of current treatment options for HIV-associated KS in ART-treated paediatric populations. SEARCH METHODS: We used standard Cochrane methods to search electronic databases and conference proceedings with relevant search terms without limits to language. SELECTION CRITERIA: Randomised controlled trials, cohort studies, and case control studies of HIV-infected infants and children <18 years old treated with ART and diagnosed with KS. DATA COLLECTION AND ANALYSIS: Abstracts of all studies identified by electronic or bibliographic scanning were examined independently by two authors. We initially identified 920 references and examined 15 in detail for study eligibility. Data were abstracted independently using a standardised abstraction form. MAIN RESULTS: After initially screening 920 titles, 15 full text articles were closely examined by two authors. We identified four cohort studies that met our inclusion criteria for data extraction, coding, and potential meta-analysis.Using the Newcastle-Ottawa Scale and Cochrane risk of bias assessments, all observational studies had cohorts that were representative of average (treated and untreated) HIV-infected children with Kaposi sarcoma. For all outcomes of interest, no study adjusted for any other potential confounders. Two of four observational studies either explicitly described complete follow up of the study participants and/or described the characteristics of the participants lost to follow up.The use of ART together with a chemotherapeutic regimen versus ART alone appears to increase the likelihood of KS remission in HIV-infected children diagnosed with KS, although data are sparse and not adequately adjusted for staging of disease and comorbidities. Additionally, though data are sparse, the use of ART together with a chemotherapeutic regimen versus chemotherapy alone in some analyses appears to increase the likelihood of KS remission and reduce the risk of death in HIV-infected children diagnosed with KS.In this analysis, we found that the quality of evidence was very low due to small sample sizes and a paucity of paediatric literature. AUTHORS' CONCLUSIONS: Data describing the efficacy of different treatment options for pediatric KS, to include chemotherapy and ART, are sparse. However, the use of ART together with a chemotherapy regimen may be superior to the use of ART alone or of chemotherapy alone. PMID- 24464844 TI - Modulating potency: Physicochemical characteristics are a determining factor of TLR4-agonist nanosuspension activity. AB - Activity of adjuvanted vaccines is difficult to predict in vitro and in vivo. The wide compositional and conformational range of formulated adjuvants, from aluminum salts to oil-in-water emulsions, makes comparisons between physicochemical and immunological properties difficult. Even within a formulated adjuvant class, excipient selection and concentration can alter potency and physicochemical properties of the mixture. Complete characterization of physicochemical properties of adjuvanted vaccine formulations and relationship to biological response is necessary to move beyond a guess-and-check paradigm toward directed development. Here we present a careful physicochemical characterization of a two-component nanosuspension containing synthetic TLR-4 agonist glucopyranosyl lipid adjuvant (GLA) and 1,2-dipalmitoyl-sn-glycero-3 phosphocholine (DPPC) at various molar ratios. Physicochemical properties were compared with potency, as measured by stimulation of cytokine production in human whole blood. We found a surprising, nonlinear relationship between physicochemical properties and GLA-DPPC ratios that corresponded well with changes in biological activity. We discuss these data in light of the current understanding of TLR4 activation and the conformation-potency relationship in development of adjuvanted vaccines. PMID- 24464845 TI - Effect of increasing pump speed during exercise on peak oxygen uptake in heart failure patients supported with a continuous-flow left ventricular assist device. A double-blind randomized study. AB - AIMS: Continuous-flow left ventricular assist device (CF-LVAD) implantation is associated with improved quality of life, but the effect on exercise capacity is less well documented. It is uncertain whether a fixed CF-LVAD pump speed, which allows for sufficient circulatory support at rest, remains adequate during exercise. The aim of this study was to evaluate the effects of fixed versus incremental pump speed on peak oxygen uptake (peak VO2) during a maximal exercise test. METHODS AND RESULTS: In CF-LVAD (HeartMate II) patients exercise testing measuring peak oxygen uptake (VO2) was performed on an ergometer bike twice in one day: once with fixed pump speed (testfix) and once with incremental pump speed (testinc). The order of testfix and testinc in each patient was determined by randomization. During testinc pump speed was increased from the baseline value by 400 rpm/2 min. Fourteen patients (aged 23-69 years) were included with a mean support duration of 465+/-483 days. Baseline CF-LVAD speed was 9357+/-238 rpm and during testinc speed was increased by a mean of 1486+/-775 rpm. Mean peak VO2 was significantly higher in testinc compared with testfix (15.4+/-5.9 mL/kg/min vs. 14.1+/-6.3 mL/kg/min; P=0.012), corresponding to a 9.2% increase. All exercise tests (n=28) were adequately performed with RER>1. CONCLUSION: Increasing pump speed during exercise augments peak VO2 in patients supported with CF-LVADs. An automatic speed-change function in future generations of CF-LVADs might improve functional capacity. PMID- 24464846 TI - A temporal window of vulnerability for development of atrial fibrillation with advancing heart failure. AB - AIMS: Heart failure (HF) is associated with development of AF and life threatening ventricular tachycardia and fibrillation (VT/VF). Vulnerability to development of AF and VT/VF at different stages of HF and the underlying pathophysiological mechanisms are poorly defined. The present study was designed to determine the time-course of development of electrical and structural remodelling of the atria and ventricles, and their contribution to induction of AF and VT/VF in a canine model of HF. METHODS AND RESULTS: Dogs were ventricular tachypaced (VTP) for 2-3 weeks or 5-6 weeks ('early' and 'late' HF, respectively). Electrophysiological studies were performed in isolated atrial and ventricular preparations and correlated with cardiac dimensions and haemodynamic parameters recorded in vivo. Vulnerability to programmed electrical stimulation induced AF was greater in early vs. late stages of HF (78% vs. 38%). In contrast, VT/VF was inducible in late but not in early stages of HF (38% vs. 0%). The temporal distinction in atrial and ventricular arrhythmia susceptibility was associated with a much more rapid development of electrical and structural remodelling in atria. Vulnerability to AF developed following moderate electro structural remodelling and waned with further progression to severe remodelling, which averted rapid atrial activation. CONCLUSIONS: A temporal window of vulnerability for AF appears relatively early during development of VTP-induced HF in dogs, whereas VT/VF vulnerability is observed at more advanced stages of HF. These findings, if confirmed in humans, may have clinical implications with regard to prognosis and approach to therapy of patients with HF. PMID- 24464847 TI - Identifying with fictive characters: structural brain correlates of the personality trait 'fantasy'. AB - The perception of oneself as absorbed in the thoughts, feelings and happenings of a fictive character (e.g. in a novel or film) as if the character's experiences were one's own is referred to as identification. We investigated whether individual variation in the personality trait of identification is associated with individual variation in the structure of specific brain regions, using surface and volume-based morphometry. The hypothesized regions of interest were selected on the basis of their functional role in subserving the cognitive processing domains considered important for identification (i.e. mental imagery, empathy, theory of mind and merging) and for the immersive experience called 'presence'. Controlling for age, sex, whole-brain volume and other traits, identification covaried significantly with the left hippocampal volume, cortical thickness in the right anterior insula and the left dorsal medial prefrontal cortex, and with gray matter volume in the dorsolateral prefrontal cortex. These findings show that trait identification is associated with structural variation in specific brain regions. The findings are discussed in relation to the potential functional contribution of these regions to identification. PMID- 24464848 TI - Encoding-related EEG oscillations during memory formation are modulated by mood state. AB - Mood states have a strong impact on how we process incoming information. It has been proposed that positive mood facilitates elaborative, relational encoding, whereas negative mood promotes a more careful, stimulus-driven encoding style. Previous electrophysiological studies have linked successful information encoding to power increases in slow (<8 Hz) delta/theta and fast (>30 Hz) gamma oscillations, as well as to power decreases in midrange (8-30 Hz) alpha/beta oscillations. Whether different mood states modulate encoding-related oscillations has not been investigated yet. In order to address this question, we used an experimental mood induction procedure and recorded electroencephalograms from 20 healthy participants while they performed a free recall memory task after positive and negative mood induction. We found distinct oscillatory patterns in positive and negative mood. Successful encoding in positive mood was accompanied by widespread power increases in the delta band, whereas encoding success in negative mood was specifically accompanied by frontal power decreases in the beta band. On the behavioral level, memory performance was enhanced in positive mood. Our findings show that mood differentially modulates the neural correlates of successful information encoding and thus contribute to an understanding of how mood shapes different processing styles. PMID- 24464849 TI - A screening tool for clinically relevant urinary incontinence. AB - AIMS: The Michigan Incontinence Symptom Index (M-ISI) is a validated measure for urinary incontinence. This study evaluates the M-ISI as a screening tool for clinically relevant urinary incontinence in a population-based sample of women. METHODS: The Establishing the Prevalence of Incontinence (EPI) Study is a case control, population-based study that enrolled women ages 35-64, with and without urinary incontinence. The M-ISI is a validated questionnaire with subdomains for stress and urgency urinary incontinence. Two hundred fourteen EPI subjects underwent a clinical evaluation and urodynamic testing to establish the presence and type of urinary incontinence, and also completed the M-ISI. The M-ISI scores were evaluated using receiver operating characteristic (ROC) curves to determine the optimal diagnostic threshold scores above which women were likely to have clinically relevant urinary incontinence. RESULTS: The optimal M-ISI diagnostic threshold scores were determined to be >= 3 for the stress urinary incontinence subdomain (area under the curve of 0.79), >= 5 for the urgency urinary incontinence subdomain (area under the curve of 0.88), and >= 7 for the Total M ISI score (area under the curve of 0.89). The sensitivity and specificity of the M-ISI questionnaire for stress, urgency, and total urinary incontinence were 77% and 73%, 86% and 76%, and 84% and 75%, respectively. CONCLUSIONS: The M-ISI may be used to screen for clinically relevant urinary incontinence with high sensitivity and specificity among women ages 35-64. A brief, self-administered tool such as the M-ISI can help health care providers identify and manage women with urinary incontinence. PMID- 24464850 TI - Astrocyte glycogenolysis is triggered by store-operated calcium entry and provides metabolic energy for cellular calcium homeostasis. AB - Astrocytic glycogen, the only storage form of glucose in the brain, has been shown to play a fundamental role in supporting learning and memory, an effect achieved by providing metabolic support for neurons. We have examined the interplay between glycogenolysis and the bioenergetics of astrocytic Ca(2+) homeostasis, by analyzing interdependency of glycogen and store-operated Ca(2+) entry (SOCE), a mechanism in cellular signaling that maintains high endoplasmatic reticulum (ER) Ca(2+) concentration and thus provides the basis for store dependent Ca(2+) signaling. We stimulated SOCE in primary cultures of murine cerebellar and cortical astrocytes, and determined glycogen content to investigate the effects of SOCE on glycogen metabolism. By blocking glycogenolysis, we tested energetic dependency of SOCE-related Ca(2+) dynamics on glycogenolytic ATP. Our results show that SOCE triggers astrocytic glycogenolysis. Upon inhibition of adenylate cyclase with 2',5'-dideoxyadenosine, glycogen content was no longer significantly different from that in unstimulated control cells, indicating that SOCE triggers astrocytic glycogenolysis in a cAMP dependent manner. When glycogenolysis was inhibited in cortical astrocytes by 1,4 dideoxy-1,4-imino-D-arabinitol, the amount of Ca(2+) loaded into ER via sarco/endoplasmic reticulum Ca(2)-ATPase (SERCA) was reduced, which suggests that SERCA pumps preferentially metabolize glycogenolytic ATP. Our study demonstrates SOCE as a novel pathway in stimulating astrocytic glycogenolysis. We also provide first evidence for a new functional role of brain glycogen, in providing local ATP to SERCA, thus establishing the bioenergetic basis for astrocytic Ca(2+) signaling. This mechanism could offer a novel explanation for the impact of glycogen on learning and memory. PMID- 24464851 TI - Prediction risk chart for scleroderma digital ulcers: a composite predictive model based on capillaroscopic, demographic and clinico-serological parameters. AB - BACKGROUND: Digital ulcers (DU) affect 50% of systemic sclerosis (SSc) patients, representing a challenging clinical problem. Despite a high negative predictive value, capillaroscopic scores proposed to select patients at risk for DU show an inadequate positive predictive value, especially in patients without previous DU. AIM OF THIS STUDY: To increase the predictive value for DU development of capillaroscopy, through a predictive risk chart taking into account capillaroscopic, demographic, and clinico-serological parameters. PATIENTS AND METHODS: Two hundred and nineteen unselected SSc patients from 8 Italian Rheumatology Centers were consecutively enrolled during a 6-month period. Demographic, clinical, serological and instrumental data and capillaroscopy skin ulcers risk index (CSURI) were collected. RESULTS: A multivariate logistic regression analysis showed a significant positive association between DU appearance and male gender, DU history, altered CSURI, and ESR. A prediction risk chart of the development of DU within 6 months were built on the basis of the above parameters. According to the risk level, four risk classes were identified: low (<=19.3%); medium (>19.3%, <=58.6%); high (>58.6%, <=89.2%), and very high risk (>89.2%). CONCLUSIONS: The systematic evaluation of the above parameters can be helpful to identify patients at risk to develop DU optimizing preventive vasoactive therapy. PMID- 24464852 TI - Bionimbus: a cloud for managing, analyzing and sharing large genomics datasets. AB - BACKGROUND: As large genomics and phenotypic datasets are becoming more common, it is increasingly difficult for most researchers to access, manage, and analyze them. One possible approach is to provide the research community with several petabyte-scale cloud-based computing platforms containing these data, along with tools and resources to analyze it. METHODS: Bionimbus is an open source cloud computing platform that is based primarily upon OpenStack, which manages on demand virtual machines that provide the required computational resources, and GlusterFS, which is a high-performance clustered file system. Bionimbus also includes Tukey, which is a portal, and associated middleware that provides a single entry point and a single sign on for the various Bionimbus resources; and Yates, which automates the installation, configuration, and maintenance of the software infrastructure required. RESULTS: Bionimbus is used by a variety of projects to process genomics and phenotypic data. For example, it is used by an acute myeloid leukemia resequencing project at the University of Chicago. The project requires several computational pipelines, including pipelines for quality control, alignment, variant calling, and annotation. For each sample, the alignment step requires eight CPUs for about 12 h. BAM file sizes ranged from 5 GB to 10 GB for each sample. CONCLUSIONS: Most members of the research community have difficulty downloading large genomics datasets and obtaining sufficient storage and computer resources to manage and analyze the data. Cloud computing platforms, such as Bionimbus, with data commons that contain large genomics datasets, are one choice for broadening access to research data in genomics. PMID- 24464853 TI - Auditing the multiply-related concepts within the UMLS. AB - OBJECTIVE: This work focuses on multiply-related Unified Medical Language System (UMLS) concepts, that is, concepts associated through multiple relations. The relations involved in such situations are audited to determine whether they are provided by source vocabularies or result from the integration of these vocabularies within the UMLS. METHODS: We study the compatibility of the multiple relations which associate the concepts under investigation and try to explain the reason why they co-occur. Towards this end, we analyze the relations both at the concept and term levels. In addition, we randomly select 288 concepts associated through contradictory relations and manually analyze them. RESULTS: At the UMLS scale, only 0.7% of combinations of relations are contradictory, while homogeneous combinations are observed in one-third of situations. At the scale of source vocabularies, one-third do not contain more than one relation between the concepts under investigation. Among the remaining source vocabularies, seven of them mainly present multiple non-homogeneous relations between terms. Analysis at the term level also shows that only in a quarter of cases are the source vocabularies responsible for the presence of multiply-related concepts in the UMLS. These results are available at: http://www.isped.u bordeaux2.fr/ArticleJAMIA/results_multiply_related_concepts.aspx. DISCUSSION: Manual analysis was useful to explain the conceptualization difference in relations between terms across source vocabularies. The exploitation of source relations was helpful for understanding why some source vocabularies describe multiple relations between a given pair of terms. PMID- 24464854 TI - Dominant fitness costs of abamectin resistance in Plutella xylostella. AB - BACKGROUND: The TH-Abm strain of Plutella xylostella, exhibiting 23 670-fold resistance to abamectin, was selected from a field-evolved multiresistant population. By repeated backcrossing to a susceptible strain (Roth) and selection with abamectin, the resistance trait of TH-Abm was introgressed into Roth to generate a near-isogenic strain (Roth-Abm). Fitness costs associated with abamectin resistance were examined in Roth-Abm. RESULTS: Compared with Roth, Roth Abm obtained 11 500-fold resistance to abamectin and 364 000-, 12- and 12-fold cross-resistance to emamectin benzoate, spinosad and fipronil respectively. Roth Abm has a significantly longer pupal development time, lesser female pupal weight and lower larval survival than Roth. Female fecundity and egg viability are significantly lower in Roth-Abm than in Roth. All of the above fitness components of the F1 progeny from Roth * Roth-Abm are similar to those of Roth-Abm and are significantly lower than those of Roth. By comparing with the net replacement rate (R0 ) of Roth, the fitness of Roth-Abm, F1a (Roth male * Roth-Abm) and F1b (Roth female * Roth-Abm) are 0.50, 0.50 and 0.53 respectively. CONCLUSION: Abamectin resistance in Roth-Abm results in significant fitness costs, and the fitness costs are autosomal and dominant. Rotation of abamectin with other insecticides without cross-resistance could be especially useful for delaying abamectin resistance in P. xylostella. PMID- 24464855 TI - Projecting the impacts of climate change on skipjack tuna abundance and spatial distribution. AB - Climate-induced changes in the physical, chemical, and biological environment are expected to increasingly stress marine ecosystems, with important consequences for fisheries exploitation. Here, we use the APECOSM-E numerical model (Apex Predator ECOSystem Model - Estimation) to evaluate the future impacts of climate change on the physiology, spatial distribution, and abundance of skipjack tuna, the worldwide most fished species of tropical tuna. The main novelties of our approach lie in the mechanistic link between environmental factors, metabolic rates, and behavioral responses and in the fully three dimensional representation of habitat and population abundance. Physical and biogeochemical fields used to force the model are provided by the last generation of the IPSL-CM5 Earth System Model run from 1990 to 2100 under a 'business-as-usual' scenario (RCP8.5). Our simulations show significant changes in the spatial distribution of skipjack tuna suitable habitat, as well as in their population abundance. The model projects deterioration of skipjack habitat in most tropical waters and an improvement of habitat at higher latitudes. The primary driver of habitat changes is ocean warming, followed by food density changes. Our projections show an increase of global skipjack biomass between 2010 and 2050 followed by a marked decrease between 2050 and 2095. Spawning rates are consistent with population trends, showing that spawning depends primarily on the adult biomass. On the other hand, growth rates display very smooth temporal changes, suggesting that the ability of skipjack to keep high metabolic rates in the changing environment is generally effective. Uncertainties related to our model spatial resolution, to the lack or simplification of key processes and to the climate forcings are discussed. PMID- 24464856 TI - Glucagon-like peptide-1 protects synaptic and learning functions from neuroinflammation in rodents. AB - Glucagon-like peptide-1 (GLP-1) is derived from the processing of proglucagon in intestinal L-cells and releases insulin from pancreatic beta-cells as an incretin. The GLP-1 receptor has been proposed as a possible therapeutic target for the treatment of Alzheimer's disease, in which neuroinflammation is critical in the pathogenesis. The present study investigates whether GLP-1 (7-36) amide, an active fragment of GLP-1, protected against synaptic impairments induced by inflammation-related injurious agents (lipopolysaccharide [LPS], interleukin 1beta [IL-1beta], and H2 O2). In the Y-maze test, LPS (10 MUg/mouse, i.c.v) significantly decreased the percentage alternation. Pretreatment with GLP-1 (7 36) amide (0.09-0.9 nmol/mouse, i.c.v.) prevented an impairment in spontaneous alternation performance. Pretreatment with LPS (10 MUg/ml, 2 hr) impaired LTP induction but not paired-pulse facilitation in the CA1 region of rat hippocampal slices. This impairment was prevented by cotreatment with GLP-1 (7-36) amide (50 nM). IL-1beta (0.57 nM) or H2 O2 (50 MUM) also impaired LTP induction. This impairment was prevented by GLP-1 (7-36) amide (50 nM). These results suggest that GLP-1 (7-36) amide improves the synaptic impairments induced by inflammation related injurious agents in the CA1 region of the hippocampus. PMID- 24464857 TI - Stable MCC binding to the APC/C is required for a functional spindle assembly checkpoint. AB - The spindle assembly checkpoint (SAC) delays progression into anaphase until all chromosomes have aligned on the metaphase plate by inhibiting Cdc20, the mitotic co-activator of the APC/C. Mad2 and BubR1 bind and inhibit Cdc20, thereby forming the mitotic checkpoint complex (MCC), which can bind stably to the APC/C. Whether MCC formation per se is sufficient for a functional SAC or MCC association with the APC/C is required remains unclear. Here, we analyze the role of two conserved motifs in Cdc20, IR and C-Box, in binding of the MCC to the APC/C. Mutants in both motifs assemble the MCC normally, but IR motif integrity is particularly important for stable binding to the APC/C. Cells expressing Cdc20 with a mutated IR motif have a compromised SAC, as uninhibited Cdc20 can compete with the MCC for APC/C binding and activate it. We thus show that stable MCC association with the APC/C is critical for a functional SAC. PMID- 24464858 TI - Beneficial effect of candesartan and lisinopril against haloperidol-induced tardive dyskinesia in rat. AB - INTRODUCTION: Tardive dyskinesia is a serious motor disorder of the orofacial region, resulting from chronic neuroleptic treatment of schizophrenia. Candesartan (AT1 antagonist) and lisinopril (ACE inhibitor) has been reported to possess antioxidant and neuroprotective effects. The present study is designed to investigate the effect of candesartan and lisinopril on haloperidol-induced orofacial dyskinesia and oxidative damage in rats. MATERIALS AND METHODS: Tardive dyskinesia was induced by administering haloperidol (1 mg/kg i.p.) and concomitantly treated with candesartan (3 and 5 mg/kg p.o.) and lisinopril (10 and 15 mg/kg p.o.) for 3 weeks in male Wistar rats. Various behavioral parameters were assessed on days 0, 7, 14 and 21 and biochemical parameters were estimated at day 22. RESULTS: Chronic administration of haloperidol significantly increased stereotypic behaviors in rats, which were significantly improved by administration of candesartan and lisinopril. Chronic administration of haloperidol significantly increased oxidative stress and neuro-inflammation in the striatum region of the rat's brain. Co-administration of candesartan and lisinopril significantly attenuated the oxidative damage and neuro-inflammation in the haloperidol-treated rat. CONCLUSIONS: The present study supports the therapeutic use of candesartan and lisinopril in the treatment of typical antipsychotic-induced orofacial dyskinesia and possible antioxidant and neuro inflammatory mechanisms. PMID- 24464859 TI - IgA nephropathy with early kidney disease is associated with increased arterial stiffness and renin-angiotensin system activity. AB - BACKGROUND: IgA nephropathy is associated with increased cardiovascular risk, though whether this is due to loss of kidney function or proteinuria is unclear. METHODS: For this study 10 normotensive IgA nephropathy subjects with early kidney disease (41+/-5 yrs, glomerular filtration rate (GFR) 87+/-9 ml/min, proteinuria 720+/-300 mg/d) and 10 gender- and blood pressure-matched healthy controls (36+/-1 yrs, estimated GFR 102+/-5 ml/min, proteinuria 70+/-6 mg/d) were studied in high-salt balance. Blood pressure and arterial stiffness, expressed as pulse wave velocity and aortic augmentation index, were measured at baseline and in response to 60 min of angiotensin II (AngII) infusion. RESULTS: At baseline, IgA nephropathy subjects demonstrated similar pulse wave velocity (8.6+/-0.7 vs. 8.0+/-0.4 m/s, p=0.5) but increased aortic augmentation index (12.6+/-3.1 vs. 1.8+/-4%, p=0.04) and a trend towards increased circulating renin-angiotensin system (RAS) components (plasma renin activity, 0.55+/-0.18 vs. 0.21+/-0.05 ng/l/s, p=0.08; angiotensin II, 25+/-5 vs. 16+/-1 ng/l, p=0.08) compared with controls. However, despite similar baseline blood pressure values (p=0.8), IgA nephropathy was associated with reduced arterial sensitivity to AngII challenge (Deltamean arterial pressure: 19+/-4 vs. 29+/-1 mm Hg, p=0.05; Deltapulse wave velocity: -0.06+/-0.6 vs. 1.5+/-0.3 m/s, p=0.07) compared with controls, even after multivariate analysis. CONCLUSION: Even in the setting of early kidney disease, IgA nephropathy is associated with increased arterial stiffness and decreased angiotensin II responsiveness, a marker of increased RAS activity. PMID- 24464860 TI - Aldosterone-induced inflammatory response of mesangial cells via angiotension II receptors. AB - INTRODUCTION: In this study, we investigated whether AngII receptors (AT1a and AT2) contributed to the development of the aldosterone-induced inflammatory response of rat mesangial cells (RMCs). MATERIALS AND METHODS: RMCs were isolated from the glomeruli of normal or diabetic rats which were produced by injection of streptozotocin, and cultured in high-glucose media. In order to evaluate the effects of aldosterone, the expression of AT1a, AT2, NF-kappaB and MCP-1 was detected. In addition, in order to evaluate the role of Ang II receptors, AT1a and AT2 genes were blocked and the expression of NF-kappaB and MCP-1 was detected. Moreover, for assessing the relationship between NF-kappaB and MCP-1, the NF-kappaB gene was blocked and MCP-1 expression was detected. RESULTS: Aldosterone significantly increased AT1a, AT2, NF-kappaB and MCP-1 levels in RMCs in a dose-dependent manner, whereas eplerenone (EPI), a selective aldosterone antagonist, partly inhibited the effects of aldosterone. When AT1a and AT2 genes were blocked, the expression of NF-kappaB and MCP-1 was greatly inhibited. Moreover, when the NF-kappaB gene was silenced, the expression of MCP-1 was reduced. CONCLUSION: We demonstrated that aldosterone induced an inflammatory response in RMCs cultured in high-glucose media via the AT1a and AT2 pathways. PMID- 24464861 TI - The effects of nonspecific HIF1alpha inhibitors on development of castrate resistance and metastases in prostate cancer. AB - Expression of hypoxia-inducible factor (HIF)1alpha increases the risk of castrate resistant prostate cancer (CRPC) and metastases in patients on androgen deprivation therapy (ADT) for prostate cancer (PC). We aimed to investigate the effects of nonspecific HIF1alpha inhibitors (Digoxin, metformin, and angiotensin 2 receptor blockers) on development of CRPC and metastases while on ADT. A retrospective review of prospectively collected medical records was conducted of all men who had continuous ADT as first-line therapy for CRPC at the Austin Hospital from 1983 to 2011. Association between HIF1alpha inhibitor medications and time to develop CRPC was investigated using actuarial statistics. Ninety eight patients meeting the criteria were identified. Eighteen patients (21.4%) were treated with the nonspecific HIF1alpha inhibitors. Both groups had similar characteristics, apart from patients on HIF1alpha inhibitors being older (70 years vs. 63.9 years). The median CRPC-free survival was longer in men using HIF1alpha inhibitors compared to those not on inhibitors (6.7 years vs. 2.7 years, P = 0.01) and there was a 71% reduction in the risk of developing CRPC (HR 0.29 [95% CI 0.10-0.78] P = 0.02) after adjustment for Gleason score, age, and prostate-specific antigen (PSA). The median metastasis-free survival in men on HIF1alpha inhibitors was also significantly longer compared to those on no inhibitors (5.1 years vs. 2.6 years, P = 0.01) with an 81% reduction in the risk of developing metastases (HR 0.19 [CI 0.05-0.76] P = 0.02) after adjustment for Gleason score, age, and PSA. Nonspecific HIF1alpha inhibitors appear to increase the progression-free survival and reduce the risk of developing CRPC and metastases in patients on continuous ADT. PMID- 24464862 TI - Salinity influences on the uptake of silver nanoparticles and silver nitrate by marine medaka (Oryzias melastigma). AB - With increasing use of silver nanoparticles (AgNPs), concerns about their potential deleterious effects on aquatic ecosystems have increased. Most previous studies have focused on the toxicity of AgNPs while their bioavailability has been seldom investigated. The present study examined the effects of salinity on the aggregation kinetics as well as the bioavailability of commercial 80-nm citrate-coated AgNPs (c-AgNPs) in the presence or absence of a nonionic surfactant (Tween 20) to marine medaka (Oryzias melastigma). In addition, the uptake of soluble Ag was quantified for comparison and for deducting the uptake of soluble Ag during AgNP exposure by applying a biokinetic model. The authors found that the addition of Tween 20 immediately slowed down the process of aggregation of AgNPs, and an elevated amount of Tween 20 (20 uM) kept AgNPs well dispersed, even in the 30-psu salinity medium. Uptake rate constants (ku ) of AgNPs were less than half the soluble Ag at low salinities (1 psu and 5 psu), while limited bioavailability of c-AgNPs was observed at high salinities (15 psu and 30 psu). However, the Tween 20-stabilized AgNPs (t-AgNPs) were accumulated by medaka at comparable rates as the soluble Ag, indicating the importance of dispersion for bioavailability of AgNPs in a highly ionic environment. The present study provided the first insight of the bioavailability of AgNPs to fish in a high-ionic environment. More studies are needed to gain a full understanding of bioavailability of AgNPs in marine environments. PMID- 24464864 TI - Response to (resynchronization) therapy in chronic heart failure: time for a different approach. PMID- 24464863 TI - Effect of carnosine alone or combined with alpha-tocopherol on hepatic steatosis and oxidative stress in fructose-induced insulin-resistant rats. AB - A diet high in fructose (HFr) induces insulin resistance in animals. Free radicals are involved in the pathogenesis of HFr-induced insulin resistance. Carnosine (CAR) is a dipeptide with antioxidant properties. We investigated the effect of CAR alone or in combination with alpha-tocopherol (CAR + TOC) on HFr induced insulin-resistant rats. Rats fed with HFr containing 60% fructose received CAR (2 g/L in drinking water) with/without TOC (200 mg/kg, i.m. twice a week) for 8 weeks. Insulin resistance, serum lipids, inflammation markers, hepatic lipids, lipid peroxides, and glutathione (GSH) levels together with glutathione peroxidase (GSH-Px) and superoxide dismutase 1 (CuZnSOD; SOD1) activities and their protein expressions were measured. Hepatic histopathological examinations were performed. HFr was observed to cause insulin resistance, inflammation and hypertriglyceridemia, and increased triglyceride and lipid peroxide levels in the liver. GSH-Px activity and expression decreased, but GSH levels and SOD1 activity and expression did not alter in HFr rats. Hepatic marker enzyme activities in serum increased and marked macro- and microvesicular steatosis were seen in the liver. CAR treatment did not alter insulin resistance and hypertriglyceridemia, but it decreased steatosis and lipid peroxidation without any change in the antioxidant system of the liver. However, CAR + TOC treatment decreased insulin resistance, inflammation, hepatic steatosis, and lipid peroxidation and increased GSH-Px activity and expression in the liver. Our results may indicate that CAR + TOC treatment is more effective to decrease HFr induced insulin resistance, inflammation, hepatic steatosis, and dysfunction and pro-oxidant status in rats than CAR alone. PMID- 24464865 TI - [A case of parental alienation]. AB - The clinical term "Parental Alienation Syndrome" (PAS) was introduced in 1984 by Richard Gardner, an American psychiatrist. Gardner described PAS and its symptoms, as a personality disorder, which appears chiefly in connection to child custody disputes wherein a child turns suddenly and massively against the non custodial parent without reasonable grounds for doing so. This action by the child is a result of the custodial parent's emotionally abusive attempts to incite the child against the non-custodial parent.Where the child's rejection is based on some real past experience, there is not PAS. PAS only occurs as a result of the custodial parent's actions. Despite intensive effort, PAS was not included in the new DSM-V. In this case, a particularly impressive case history of parental alienation is described and discussed. PMID- 24464866 TI - [Compulsory sterilization: the psychiatric hospital of Klagenfurt under national socialism]. PMID- 24464867 TI - Efficacy of endoscopic gastroduodenal stenting for gastric outlet obstruction due to unresectable advanced gastric cancer: a prospective multicenter study. AB - BACKGROUND AND OBJECTIVES: Gastroduodenal stents for gastric outlet obstruction due to unresectable advanced gastric cancer are increasingly used; however, their effects have not been fully evaluated. METHODS: A multicenter prospective observational study was performed. Patients were eligible if they had stage IV gastric cancer with a gastric outlet obstruction scoring system (GOOSS) score of 0 (no oral intake) or 1 (liquids only). Self-expandable metallic stents were delivered endoscopically. The effects of stents were evaluated. RESULTS: Twenty patients were enrolled and 18 were eligible (15 men, three women; median age, 70 years). Stent placement was successfully performed in all patients, with no complications. After stenting, a GOOSS score of 2 (soft solids only) or 3 (low residue or full diet) was achieved in 13 (72%) patients. An improvement in the GOOSS score by one or more points was obtained in 16 (94%) patients. The median duration of fasting and hospital stay was 3 (range, 0-9) days and 18 (6-168) days, respectively. Chemotherapy was performed after stenting in 13 (72%) patients. CONCLUSIONS: Gastroduodenal stents are thought to be feasible, safe, and effective for gastric outlet obstruction due to unresectable advanced gastric cancer, with rapid clinical relief and a short hospital stay. PMID- 24464868 TI - Does endolymphatic sac decompression surgery prevent bilateral development of unilateral Meniere disease? AB - OBJECTIVES/HYPOTHESIS: The aim of the study was to elucidate whether endolymphatic sac decompression surgery (ESDS) has the potential to prevent unilateral Meniere disease (MD) from becoming bilateral. STUDY DESIGN: Prospective case-control study at tertiary referral center. METHODS: Between 1996 and 2008, we performed a glycerol test (G-test) and electrocochleography (ECoG) on 237 patients with intractable unilateral MD. We performed ESDS on 179 patients (144 with no endolymphatic hydrops and 35 with silent endolymphatic hydrops in the contralateral ear). The other 58 patients (40 without endolymphatic hydrops and 18 with silent endolymphatic hydrops in the contralateral ear) were given available medical treatments. All underwent regular follow-up for at least 5 years. RESULTS: Altogether, 22.4% (53 of 237) of patients with clinically diagnosed unilateral intractable MD had silent endolymphatic hydrops in the contralateral ear using G-test and ECoG. In the nonsurgical group, six of 40 patients with unilateral MD with no endolymphatic hydrops in the contralateral ear developed bilateral disease, whereas in the surgical group 12 of 144 patients did so (P = .231, Fisher test). In the nonsurgical group, nine of 18 patients with unilateral MD and silent endolymphatic hydrops developed the disease in the contralateral ear, whereas in the surgical group six of 35 patients developed bilateral disease (P = .022, Fisher test). CONCLUSIONS: The present findings suggest that ESDS may decrease the incidence of developing MD in silent endolymphatic hydronic contralateral ears diagnosed with G-test and ECoG within the first 5 postoperative years. PMID- 24464869 TI - Solution-processed 2D niobium diselenide nanosheets as efficient hole-transport layers in organic solar cells. AB - Thin-layer, two-dimensional NbSe2 nanosheets with lower trap density have been obtained and act as an alternative hole-transporting layer to replace MoO3 in organic solar cells. If poly({4,8-bis[(2-ethylhexyl)oxy]benzo[1,2-b:4,5 b']dithiophene-2,6-diyl}{3-fluoro-2-[(2-ethylhexyl)carbonyl]thieno[3,4 b]thiophenediyl}):[6,6]-phenyl-C71-butyric acid methyl ester acts as an active layer, a power conversion efficiency of 8.10 % has been achieved without any further thermal treatment. The properties of this hole-transporting layer were investigated and the improvements in the devices are discussed. PMID- 24464870 TI - mir-300 promotes self-renewal and inhibits the differentiation of glioma stem like cells. AB - MicroRNAs (miRNAs) are small noncoding RNAs that have been critically implicated in several human cancers. miRNAs are thought to participate in various biological processes, including proliferation, cell cycle, apoptosis, and even the regulation of the stemness properties of cancer stem cells. In this study, we explore the potential role of miR-300 in glioma stem-like cells (GSLCs). We isolated GSLCs from glioma biopsy specimens and identified the stemness properties of the cells through neurosphere formation assays, multilineage differentiation ability analysis, and immunofluorescence analysis of glioma stem cell markers. We found that miR-300 is commonly upregulated in glioma tissues, and the expression of miR-300 was higher in GSLCs. The results of functional experiments demonstrated that miR-300 can enhance the self-renewal of GSLCs and reduce differentiation toward both astrocyte and neural fates. In addition, LZTS2 is a direct target of miR-300. In conclusion, our results demonstrate the critical role of miR-300 in GSLCs and its functions in LZTS2 inhibition and describe a new approach for the molecular regulation of tumor stem cells. PMID- 24464871 TI - Variability of pudendal and median nerve sensory perception thresholds in healthy persons. AB - BACKGROUND: Normative current perception thresholds (CPTs) are used for the evaluation of sensory function in a variety of diseases. AIMS: To evaluate the reproducibility of CPT measurements with sinusoidal current in healthy volunteers. METHODS: Neuroselective CPT evaluations of the median and pudendal nerve in healthy volunteers were repeated with 1 week interval (T1 and T2). RESULTS: In the study group (N = 41) no difference between genders for age (MW-U: P = 0.91) and BMI (t-test: P = 0.18) were found. No significant difference between T1 and T2 was found (Paired t-test: all P-values > 0.05), although the intraclass correlation for each person was low. The variability of measures for the pudendal nerve was: ICC 2 kHz: 0.41; 250 Hz: 0.30; 5 Hz: 0.38, and for the median nerve respectively: 0.58; 0.46; 0.40. Normal CPTs were shown for the pudendal nerve: 2 kHz: 51%; 250 Hz: 76%; 5 Hz: 71%, and median nerve respectively: 78%; 98%; 80%. The pudendal nerve showed more deviating values compared to the median nerve. CONCLUSION: Both nerves showed deviating values. CPT values with sinusoidal current assessed with 1 week interval, showed a weak intraclass correlation. This finding limits the use of CPT values with this current for longitudinal studies. PMID- 24464872 TI - HDAC6 inhibition results in tau acetylation and modulates tau phosphorylation and degradation in oligodendrocytes. AB - Histone deacetylase 6 (HDAC6) is a unique member of the HDAC family. It is localized within the cytoplasm and has unique substrate specificities for nonhistone proteins, such as alpha-tubulin. Furthermore, it plays a major role in protein aggregate formation and recently was demonstrated to interact with the microtubule associated protein tau and tau was identified as a possible substrate for HDAC6 in neurons. This study was undertaken to investigate whether HDAC6 is present in oligodendrocytes and whether it is involved in tubulin and tau acetylation in these cells. We show for the first time that HDAC6 is expressed in cultured rat brain oligodendrocytes. Its inhibition by the specific HDAC6 inhibitor tubastatin A (TST) leads to morphological alterations, microtubule bundling, and tubulin acetylation, and changes in tau-isoform expression and phosphorylation. Furthermore, the microtubule binding activity of tau was reduced. Using the oligodendroglial cell lines OLN-t40 and OLN-t44, which were genetically engineered to express either the longest human tau isoform with four microtubule binding repeats (4R-tau), or the shortest tau isoform with three repeats (3R-tau), respectively, we demonstrate that tau is acetylated by HDAC6 within the 4R-binding domain. Tau acetylation reduced its turnover rate and acetylated tau was degraded slower in these cells. TST and shRNA-mediated knockdown of HDAC6 in oligodendroglia cells caused an increase in pathological hyperphosphorylated tau detectable with the 12E8 antibody. Hence HDAC6 and dysregulation of the deacetylation and acetylation process in oligodendrocytes may contribute to diseases with oligodendroglial pathology. PMID- 24464873 TI - Photodynamic therapy with the novel photosensitizer chlorophyllin f induces apoptosis and autophagy in human bladder cancer cells. AB - BACKGROUND AND OBJECTIVES: Our group recently synthesized a new, low-cost photosensitizer, chlorophyllin f. In this study, the effects of chlorophyllin f mediated photodynamic therapy (PDT) and its potential mechanisms were examined in human bladder cancer cells. MATERIALS AND METHODS: MitoTracker(r) Green probe and LysoTracker(r) Green probe were used to label mitochondria and lysosomes, revealing the intracellular localization of chlorophyllin f in 5637 and T24 cells by confocal laser scanning microscopy (CLSM). The cells were treated with chlorophyllin f-mediated PDT; the photo-cytotoxicity of chlorophyllin f was monitored using the Cell Counting Kit-8 assay, and apoptosis was measured by Annexin V-FITC/PI dual staining. Western blotting, transmission electron microscopy (TEM), and staining with Cyto-ID(r) Autophagy Detection dye, monodansylcadaverine (MDC) and acridine orange were performed to assess autophagy. The role of autophagy was examined by measuring cell viability and apoptosis in both cell lines pretreated with the autophagy inhibitor 3 methyladenine (3-MA). RESULTS: Chlorophyllin f showed affinity for mitochondria and lysosomes. It exhibited significant photocytotoxicity, resulting in a maximum of 86.51% and 84.88% cell death in 5637 and T24 cells, respectively. Additionally, chlorophyllin f-mediated PDT (f-PDT) also induced a significantly higher percentage of apoptosis in treated cells compared to the control groups (P < 0.05). Moreover, the expression of Beclin1 protein and the proportion of LC3 II:LC3-I in both cell lines significantly increased after f-PDT. Autophagy, characterized by an increase in the formation of Cyto-ID(r) Autophagy Detection dye-labeled autophagosomes, MDC fluorescent dye-labeled autophagic vacuoles and acridine orange-labeled acidic vesicular organelles (AVOs), was observed in f-PDT treated cells. TEM also revealed double-membrane autophagosome structures 1 hour after f-PDT. Most importantly, when pretreated with 3-MA, the two cell lines showed more significant photo-cytotoxicity and apoptotic cell death compared to those exposed to f-PDT alone (P < 0.05). CONCLUSION: Chlorophyllin f-mediated PDT exerts anti-tumor activity by inducing apoptosis and autophagy, and most importantly, autophagy inhibition enhances f-PDT-mediated apoptotic cell death. These results suggest that chlorophyllin f is a new, effective photosensitizer and that the combination of f-PDT with autophagy inhibitors may be an attractive therapeutic strategy against human non-muscle invasive bladder cancer. PMID- 24464875 TI - Forest defoliator outbreaks under climate change: effects on the frequency and severity of outbreaks of five pine insect pests. AB - To identify general patterns in the effects of climate change on the outbreak dynamics of forest-defoliating insect species, we examined a 212-year record (1800-2011) of outbreaks of five pine-defoliating species (Bupalus piniarius, Panolis flammea, Lymantria monacha, Dendrolimus pini, and Diprion pini) in Bavaria, Germany for the evidence of climate-driven changes in the severity, cyclicity, and frequency of outbreaks. We also accounted for historical changes in forestry practices and examined effects of past insecticide use to suppress outbreaks. Analysis of relationships between severity or occurrence of outbreaks and detrended measures of temperature and precipitation revealed a mixture of positive and negative relationships between temperature and outbreak activity. Two moth species (P. flammea and Dendrolimus pini) exhibited lower outbreak activity following years or decades of unusually warm temperatures, whereas a sawfly (Diprion pini), for which voltinism is influenced by temperature, displayed increased outbreak occurrence in years of high summer temperatures. We detected only one apparent effect of precipitation, which showed Dendrolimus pini outbreaks tending to follow drought. Wavelet analysis of outbreak time series suggested climate change may be associated with collapse of L. monacha and Dendrolimus pini outbreak cycles (loss of cyclicity and discontinuation of outbreaks, respectively), but high-frequency cycles for B. piniarius and P. flammea in the late 1900s. Regional outbreak severity was generally not related to past suppression efforts (area treated with insecticides). Recent shifts in forestry practices affecting tree species composition roughly coincided with high frequency outbreak cycles in B. piniarius and P. flammea but are unlikely to explain the detected relationships between climate and outbreak severity or collapses of outbreak cycles. Our results highlight both individualistic responses of different pine-defoliating species to climate changes and some patterns that are consistent across defoliator species in this and other forest systems, including collapsing of population cycles. PMID- 24464876 TI - Selection of a mineralocorticoid receptor antagonist for patients with hypertension or heart failure. AB - Clinical trials have demonstrated morbidity and mortality benefits of mineralocorticoid receptor antagonists (MRAs) in patients with heart failure. These studies have used either spironolactone or eplerenone as the MRA. It is generally believed that these two agents have the same effects, and the data from studies using one drug could be extrapolated for the other. National and international guidelines do not generally discriminate between spironolactone and eplerenone, but strongly recommend using an MRA for patients with heart failure due to LV systolic dysfunction and post-infarct LV systolic dysfunction. There are no major clinical trials directly comparing the efficacy of these two drugs. This article aims to compare the pharmacokinetics and pharmacodynamics of spironolactone and eplerenone, and to analyse the available data for their cardiovascular indications and adverse effects. We have also addressed the role of special circumstances including co-morbidities, concomitant drug therapy, cost, and licensing restrictions in choosing an appropriate MRA for a particular patient, thus combining an evidence-based approach with personalized medicine. PMID- 24464874 TI - Prior antipsychotic drug treatment prevents response to novel antipsychotic agent in the methylazoxymethanol acetate model of schizophrenia. AB - Trials of novel compounds for the treatment of schizophrenia are typically tested in patients following brief withdrawal of ongoing medication despite known long term changes in the dopamine (DA) system following chronic antipsychotic drug therapy. The present study explored the impact of withdrawal from repeated haloperidol (HAL) treatment, as well as the response to a novel alpha5 gamma aminobutyric acid (GABA(A)) receptor positive allosteric modulator (alpha5PAM), on the activity of the DA system in the methylazoxymethanol acetate (MAM) neurodevelopmental model of schizophrenia. Electrophysiological recordings were conducted from DA neurons in the ventral tegmental area of MAM and saline (SAL) rats following 7-day withdrawal from repeated HAL (21 d, 0.6 mg/kg, orally). In separate animals, amphetamine-induced locomotion was measured to assess changes in DA behavioral sensitivity. SAL rats withdrawn from HAL demonstrated reduced spontaneous DA neuron activity along with an enhanced locomotor response to amphetamine, indicative of the development of DA supersensitivity. Both alpha5PAM treatment and ventral hippocampal (vHPC) inactivation reversed the DA neuron depolarization block following HAL withdrawal in SAL rats. In contrast, MAM rats withdrawn from HAL exhibited reduced spontaneous DA activity and enhanced locomotor response to amphetamine compared with untreated SAL rats; however, this condition was unresponsive to alpha5PAM treatment or vHPC inactivation. Withdrawal from prior HAL treatment interferes with the therapeutic actions of this novel treatment in the MAM model of schizophrenia. Consequently, testing novel compounds on chronically treated schizophrenia patients may be ineffective. PMID- 24464877 TI - Primary cilia mediate sonic hedgehog signaling to regulate neuronal-like differentiation of bone mesenchymal stem cells for resveratrol induction in vitro. AB - Mesenchymal stem cells (MSCs) can differentiate into neuronal-like cell types under specific conditions. The classical antioxidant inducers such as beta mercaptoethanol (BME), butylated hydroxyanisol (BHA), and dimethylsulfoxide (DMSO) are limited in clinical because of toxicity. Resveratrol, a safer, natural antioxidant, can stimulate osteoblastic differentiation of MSCs. However, its effect of inducing MSCs to differentiate into neuronal-like cells is less well studied, and its differentiated mechanisms are not well understood. Sonic hedgehog (Shh) signaling, mediated by the primary cilia, is crucial for embryonic development and tissue differentiation, but relatively little is known about the role of Shh signaling and primary cilia in neuronal-like differentiation of MSCs. Here we show that primary cilia, harboring patched 1 (Ptc1), are present in growth-arrested MSCs and that smoothened (Smo) and Gli1 are present in cytoplasm of MSCs, which are important components of the Shh signaling pathway. After resveratrol induction, MSCs acquire neuronal-like cell morphologies and phenotypes, Smo translocates to the primary cilia, Gli1 enters the nucleus, and expressions of Smo and Gli1 proteins increase, which can be inhibited by cyclopamine, a Smo antagonist. Meanwhile, Smo agonist (SAG) attains similar effects compared with the resveratrol group. These data indicate that resveratrol can induce MSCs to differentiate into neuronal-like cells and activate Shh signaling pathway in the primary cilia. Moreover, the primary cilia and Shh signaling are essential for resveratrol inducing neuronal-like differentiation of MSCs. Our finding is important for understanding the neuronal-like differentiation mechanism of MSCs for resveratrol and promoting its clinical therapeutic utility. PMID- 24464878 TI - Vestibular loss promotes procedural response during a spatial task in rats. AB - Declarative memory refers to a spatial strategy using numerous sources of sensory input information in which visual and vestibular inputs are assimilated in the hippocampus. In contrast, procedural memory refers to a response strategy based on motor skills and familiar gestures and involves the striatum. Even if vestibular loss impairs hippocampal activity and spatial memory, vestibular lesioned rats remain able to find food rewards during complex spatial memory task. Since hippocampal lesions induce a switch from declarative memory to procedural memory, we hypothesize that vestibular-lesioned rats use a strategy other than that of hippocampal spatial response to complete the task and to counterbalance the loss of vestibular information. We test, in a reverse T-maze paradigm, the types of strategy vestibular-lesioned rats preferentially uses in a spatial task. We clearly demonstrate that all vestibular-lesioned rats shift to a response strategy to solve the spatial task, while control rats use spatial and response strategies equally. We conclude that the loss of vestibular informations leading to spatial learning impairments is not offset at the hippocampus level by integration process of other sense mainly visual informations; but favors a response strategy through procedural memory most likely involving the striatum, cerebellum, and motor learning. PMID- 24464879 TI - Basaloid squamous cell carcinoma of the head and neck: location means everything. AB - BACKGROUND AND OBJECTIVES: Head and neck basaloid squamous cell carcinoma (BSCC) is increasingly recognized as a malignancy with an evolving duel behavior. Our objective was to describe the site-specific presentation and prognosis of head and neck BSCC in comparison to conventional-type squamous cell carcinoma (SCC) using population-based data. METHODS: A total of 1,083 BSCC patients and 66,929 conventional-type SCC patients, diagnosed between 2000 and 2008, were identified using the Surveillance, Epidemiology, and End Results database. Clinicopathologic data were compared using chi(2) analysis. Kaplan-Meier analysis was used to estimate site-stratified disease-specific survival (DSS). BSCC's independent effect on DSS was assessed by multivariable regression analysis. RESULTS: The oropharynx (61.9%) was the most frequent BSCC site; compared to the larynx (33.3%) in conventional-type SCC. More BSCC patients presented with advanced stage disease (78.4% vs. 60.1%, P < 0.001). On multivariable analysis, DSS was significantly better in the BSCC group when tumors were located in the oropharynx. Conversely, DSS was worse for BSCC patients with laryngeal tumors. DSS was similar among patients with sinonasal, nasopharyngeal, hypopharyngeal, and oral tumors. CONCLUSIONS: BSCC's propensity for advanced-stage presentation was confirmed in this study. However, BSCC appears to carry a paradoxically similar, or better, prognosis compared to conventional-type SCC in most cases. PMID- 24464880 TI - Engineering biomolecular microenvironments for cell instructive biomaterials. AB - Engineered cell instructive microenvironments with the ability to stimulate specific cellular responses are a topic of high interest in the fabrication and development of biomaterials for application in tissue engineering. Cells are inherently sensitive to the in vivo microenvironment that is often designed as the cell "niche." The cell "niche" comprising the extracellular matrix and adjacent cells, influences not only cell architecture and mechanics, but also cell polarity and function. Extensive research has been performed to establish new tools to fabricate biomimetic advanced materials for tissue engineering that incorporate structural, mechanical, and biochemical signals that interact with cells in a controlled manner and to recapitulate the in vivo dynamic microenvironment. Bioactive tunable microenvironments using micro and nanofabrication have been successfully developed and proven to be extremely powerful to control intracellular signaling and cell function. This Review is focused in the assortment of biochemical signals that have been explored to fabricate bioactive cell microenvironments and the main technologies and chemical strategies to encode them in engineered biomaterials with biological information. PMID- 24464881 TI - The 1st International Consensus Meeting on Periprosthetic Joint Infection. PMID- 24464883 TI - Wound management. PMID- 24464885 TI - Spacers. PMID- 24464886 TI - Irrigation and debridement. PMID- 24464887 TI - Antibiotic treatment and timing of reimplantation. PMID- 24464888 TI - One-stage versus two-stage exchange. PMID- 24464889 TI - Management of fungal or atypical periprosthetic joint infections. PMID- 24464890 TI - Oral antibiotic therapy. PMID- 24464891 TI - Prevention of late PJI. PMID- 24464892 TI - Mitigation and education. PMID- 24464894 TI - Proceedings of the International Consensus Meeting on Periprosthetic Joint Infection. Foreword. PMID- 24464895 TI - Perioperative skin preparation. PMID- 24464896 TI - Perioperative antibiotics. PMID- 24464899 TI - Operative environment. PMID- 24464900 TI - Blood conservation. PMID- 24464902 TI - Prosthesis selection. PMID- 24464903 TI - Diagnosis of periprosthetic joint infection. PMID- 24464904 TI - Approaching a decade. PMID- 24464905 TI - Dynamics of beta-adrenergic/cAMP signaling and morphological changes in cultured astrocytes. AB - The morphology of astrocytes, likely regulated by cAMP, determines the structural association between astrocytes and the synapse, consequently modulating synaptic function. beta-Adrenergic receptors (beta-AR), which increase cytosolic cAMP concentration ([cAMP]i ), may affect cell morphology. However, the real-time dynamics of beta-AR-mediated cAMP signaling in single live astrocytes and its effect on cell morphology have not been studied. We used the fluorescence resonance energy transfer (FRET)-based cAMP biosensor Epac1-camps to study time dependent changes in [cAMP]i ; morphological changes in primary rat astrocytes were monitored by real-time confocal microscopy. Stimulation of beta-AR by adrenaline, noradrenaline, and isoprenaline, a specific agonist of beta-AR, rapidly increased [cAMP]i (~15 s). The FRET signal response, mediated via beta AR, was faster than in the presence of forskolin (twofold) and dibutyryl-cAMP (>35-fold), which directly activate adenylyl cyclase and Epac1-camps, respectively, likely due to slow entry of these agents into the cytosol. Oscillations in [cAMP]i have not been recorded, indicating that cAMP-dependent processes operate in a slow time domain. Most Epac1-camps expressing astrocytes revealed a morphological change upon beta-AR activation and attained a stellate morphology within 1 h. The morphological changes exhibited a bell-shaped dependency on [cAMP]i . The 5-10% decrease in cell cross-sectional area and the 30-50% increase in cell perimeter are likely due to withdrawal of the cytoplasm to the perinuclear region and the appearance of protrusions on the surface of astrocytes. Because astrocyte processes ensheath neurons, beta-AR/cAMP-mediated morphological changes can modify the geometry of the extracellular space, affecting synaptic, neuronal, and astrocyte functions in health and disease. PMID- 24464906 TI - Forest biomass carbon sinks in East Asia, with special reference to the relative contributions of forest expansion and forest growth. AB - Forests play an important role in regional and global carbon (C) cycles. With extensive afforestation and reforestation efforts over the last several decades, forests in East Asia have largely expanded, but the dynamics of their C stocks have not been fully assessed. We estimated biomass C stocks of the forests in all five East Asian countries (China, Japan, North Korea, South Korea, and Mongolia) between the 1970s and the 2000s, using the biomass expansion factor method and forest inventory data. Forest area and biomass C density in the whole region increased from 179.78 * 10(6) ha and 38.6 Mg C ha(-1) in the 1970s to 196.65 * 10(6) ha and 45.5 Mg C ha(-1) in the 2000s, respectively. The C stock increased from 6.9 Pg C to 8.9 Pg C, with an averaged sequestration rate of 66.9 Tg C yr( 1). Among the five countries, China and Japan were two major contributors to the total region's forest C sink, with respective contributions of 71.1% and 32.9%. In China, the areal expansion of forest land was a larger contributor to C sinks than increased biomass density for all forests (60.0% vs. 40.0%) and for planted forests (58.1% vs. 41.9%), while the latter contributed more than the former for natural forests (87.0% vs. 13.0%). In Japan, increased biomass density dominated the C sink for all (101.5%), planted (91.1%), and natural (123.8%) forests. Forests in South Korea also acted as a C sink, contributing 9.4% of the total region's sink because of increased forest growth (98.6%). Compared to these countries, the reduction in forest land in both North Korea and Mongolia caused a C loss at an average rate of 9.0 Tg C yr(-1), equal to 13.4% of the total region's C sink. Over the last four decades, the biomass C sequestration by East Asia's forests offset 5.8% of its contemporary fossil-fuel CO2 emissions. PMID- 24464908 TI - Re: "Examination of how neighborhood definition influences measurements of youths' access to tobacco retailers: a methodological note on spatial misclassification". PMID- 24464907 TI - Calcium ion influx in microglial cells: physiological and therapeutic significance. AB - Microglial cells, the immunocompetent cells of the central nervous system (CNS), exhibit a resting phenotype under healthy conditions. In response to injury, however, they transform into an activated state, which is a hallmark feature of many CNS diseases. Factors or agents released from the neurons, blood vessels, and/or astrocytes could activate these cells, leading to their functional and structural modifications. Microglial cells are well equipped to sense environmental changes within the brain under both physiological and pathological conditions. Entry of calcium ions (Ca(2+)) plays a critical role in the process of microglial transformation; several channels and receptors have been identified on the surface of microglial cells. These include store-operated channel, Orai1, and its sensor protein, stromal interaction molecule 1 (STIM1), in microglial cells, and their functions are modulated under pathological stimulations. Transient receptor potential (TRP) channels and voltage- and ligand-gated channels (ionotropic and metabotropic receptors) are also responsible for Ca(2+) influx into the microglial cells. An elevation of intracellular Ca(2+) concentration subsequently regulates microglial cell functions by activating a diverse array of Ca(2+)-sensitive signaling cascades. Perturbed Ca(2+) homeostasis contributes to the progression of a number of CNS disorders. Thus, regulation of Ca(2+) entry into microglial cells could be a pharmacological target for several CNS-related pathological conditions. This Review addresses the recent insights into microglial cell Ca(2+) influx mechanisms, their roles in the regulation of functions, and alterations of Ca(2+) entry in specific CNS disorders. PMID- 24464909 TI - A comparison of confounding adjustment methods for assessment of asthma controller medication effectiveness. AB - We compared the impact of 3 confounding adjustment procedures-covariate-adjusted regression, propensity score regression, and high-dimensional propensity score regression-to assess the effects of selected asthma controller medication use (leukotriene antagonists and inhaled corticosteroids) on the following 4 asthma related adverse outcomes: emergency department visits, hospitalizations, oral corticosteroid use, and the composite outcome of these. We examined a cohort of 24,680 new users who were 4-17 years of age at the incident dispensing from the Population-Based Effectiveness in Asthma and Lung Diseases (PEAL) Network of 5 commercial health plans and TennCare, the Tennessee Medicaid program, during the period January 1, 2004, to December 31, 2010. The 3 methods yielded similar results, indicating that pediatric patients treated with leukotriene antagonists were no more likely than those treated with inhaled corticosteroids to experience adverse outcomes. Children in the TennCare population who had a diagnosis of allergic rhinitis and who then initiated the use of leukotriene antagonists were less likely to experience an asthma-related emergency department visit. A plausible explanation is that our data set is large enough that the 2 advanced propensity score-based analyses do not have advantages over the traditional covariate-adjusted regression approach. We provide important observations on how to correctly apply the methods in observational data analysis and suggest statistical research areas that need more work to guide implementation. PMID- 24464910 TI - Functionalized graphene-based cathode for highly reversible lithium-sulfur batteries. AB - In this article, we highlight the salient issues in the development of lithium sulfur battery (LSB) cathodes, present different points of view in solving them, and argue, why in the future, functionalized graphene or graphene oxide might be the ultimate solution towards LSB commercialization. As shown by previous studies and also in our recent work, functionalized graphene and graphene oxide enhance the reversibility of the charge-discharge process by trapping polysulfides in the oxygen functional groups on the graphene surface, thus minimizing polysulfide dissolution. This will be helpful for the rational design of new cathode structures based on graphene for LSBs with minimal capacity fading, low extra cost, and without the unnecessary weight increase caused by metal/metal oxide additives. PMID- 24464911 TI - Predicting survival in heart failure: validation of the MAGGIC heart failure risk score in 51,043 patients from the Swedish heart failure registry. AB - AIMS: The aim of this study was to evaluate the performance of a recently developed risk score for mortality in heart failure by external validation in a national heart failure registry. METHODS AND RESULTS: From 13 routinely available patient characteristics, the Meta-analysis Global Group in Chronic Heart Failure (MAGGIC) constructed a risk score for prediction of mortality in heart failure. We included 51 043 patients from the national Swedish Heart Failure Registry and calculated the MAGGIC risk score for each patient. The outcome measure was 3-year mortality. The predicted probability of death obtained from the calculated risk score was compared with the observed 3-year mortality, and model discrimination and calibration were assessed by formal tests and graphical means. The overall 3 year mortality in the study population was 39.4% and the MAGGIC project heart failure risk score predicted mortality was 36.4% (observed to expected ratio: 1.08). Discrimination was excellent overall (C index = 0.741). The difference between the model-predicted and the observed 3-year mortality in the six risk groups varied between 5% and -12%. Calibration plots demonstrated slight overprediction for the lowest risk patients, and underprediction in high risk patients. CONCLUSION: The MAGGIC project heart failure risk score demonstrated an excellent ability to categorize patients in separate risk strata. Although the predicted 3-year mortality risk was higher in low risk groups and lower in high risk groups compared with the observed 3-year mortality in the Swedish Heart Failure Registry, the MAGGIC project heart failure risk score performed well in a large nationwide contemporary external validation cohort. PMID- 24464913 TI - Subclinical thyroid disease and heart failure. PMID- 24464912 TI - In vivo absolute quantification for mouse muscle metabolites using an inductively coupled synthetic signal injection method and newly developed (1) H/(31) P dual tuned probe. AB - PURPOSE: To obtain robust estimates of (31) P metabolite content in mouse skeletal muscles using our recently developed MR absolute quantification method and a custom-built (1) H/(31) P dual tuned radiofrequency (RF) coil optimized for mouse leg. MATERIALS AND METHODS: We designed and fabricated a probe consisting of two dual tuned (1) H/(31) P solenoid coils: one leg was inserted to each solenoid. The mouse leg volume coil was incorporated with injector coils for MR absolute quantification. The absolute quantification method uses a synthetic reference signal injection approach and solves several challenges in MR absolute quantification including changes of coil loading and receiver gains. RESULTS: The (1) H/(31) P dual tuned probe was composed of two separate solenoid coils, one for each leg, to increase coil filling factors and signal-to-noise ratio. Each solenoid was equipped with a second coil to allow injection of reference signals. (31) P metabolite concentrations determined for normal mice were well within the expected range reported in the literature. CONCLUSION: We developed an RF probe and an absolute quantification approach adapted for mouse skeletal muscle. PMID- 24464914 TI - CAF-secreted annexin A1 induces prostate cancer cells to gain stem cell-like features. AB - Annexin A1 (AnxA1), a phospholipid-binding protein and regulator of glucocorticoid-induced inflammatory signaling, has implications in cancer. Here, a role for AnxA1 in prostate adenocarcinoma was determined using primary cultures and a tumor cell line (cE1), all derived from the conditional Pten deletion mouse model of prostate cancer. AnxA1 secretion by prostate-derived cancer-associated fibroblasts (CAF) was significantly higher than by normal prostate fibroblasts (NPF). Prostate tumor cells were sorted to enrich for epithelial subpopulations based on nonhematopoietic lineage, high SCA-1, and high or medium levels of CD49f. Compared with controls, AnxA1 enhanced stem cell-like properties in high- and medium-expression subpopulations of sorted cE1 and primary cells, in vitro, through formation of greater number of spheroids with increased complexity, and in vivo, through generation of more, larger, and histologically complex glandular structures, along with increased expression of p63, a basal/progenitor marker. The differentiated medium-expression subpopulations from cE1 and primary cells were most susceptible to gain stem cell-like properties as shown by increased spheroid and glandular formation. Further supporting this increased plasticity, AnxA1 was shown to regulate epithelial-to-mesenchymal transition in cE1 cells. These results suggest that CAF-secreted AnxA1 contributes to tumor stem cell dynamics via two separate but complementary pathways: induction of a dedifferentiation process leading to generation of stem-like cells from a subpopulation of cancer epithelial cells and stimulation of proliferation and differentiation of the cancer stem-like cells. IMPLICATIONS: AnxA1 participates in a paradigm in which malignant prostate epithelial cells that are not cancer stem cells are induced to gain cancer stem cell-like properties. PMID- 24464915 TI - PAI-1 leads to G1-phase cell-cycle progression through cyclin D3/cdk4/6 upregulation. AB - The canonical function of plasminogen activator inhibitor-1 (PAI-1/SERPINE1) is as an inhibitor of urokinase-type plasminogen activator for blood clot maintenance, but it is now also considered a pleiotropic factor that can exert diverse cellular and tumorigenic effects. However, the mechanism controlling its pleiotropic effects is far from being understood. To elucidate the tumorigenic role of PAI-1, we tested the effects of PAI-1 after manipulation of its expression or through the use of a small-molecule inhibitor, tiplaxtinin. Downregulation of PAI-1 significantly reduced cellular proliferation through an inability to progress from the G(0-G1) phase of the cell cycle. Accordingly, overexpression of PAI-1 augmented proliferation by encouraging S-phase entry. Biochemically, cell-cycle arrest was associated with the depletion of the G(1) phase transition complexes, cyclin D3/cdk4/6 and cyclin E/cdk2, in parallel with the upregulation of the cell-cycle inhibitors p53, p21Cip1/Waf1, and p27Kip1. PAI 1 depletion significantly decreased the tumor size of urothelial T24 and UM-UC-14 xenografts, and overexpression of PAI-1 substantially increased the tumor size of HeLa xenografts. Finally, immunohistochemical analysis of human bladder and cervical tumor tissue microarrays revealed increased expression of PAI-1 in cancerous tissue, specifically in aggressive tumors, supporting the relevance of this molecule in human tumor biology. IMPLICATIONS: Targeting PAI-1 has beneficial antitumoral effects and should be further investigated clinically. PMID- 24464916 TI - FAK inhibition abrogates the malignant phenotype in aggressive pediatric renal tumors. AB - Despite the tremendous advances in the treatment of childhood kidney tumors, there remain subsets of pediatric renal tumors that continue to pose a therapeutic challenge, mainly malignant rhabdoid kidney tumors and nonosseous renal Ewing sarcoma. Children with advanced, metastatic, or relapsed disease have a poor disease-free survival rate. Focal adhesion kinase (FAK) is a nonreceptor tyrosine kinase that is important in many facets of tumor development and progression. FAK has been found in other pediatric solid tumors and in adult renal cellular carcinoma, leading to the hypothesis that FAK contributes to pediatric kidney tumors and would affect cellular survival. In the current study, FAK was present and phosphorylated in pediatric kidney tumor specimens. Moreover, the effects of FAK inhibition upon G401 and SK-NEP-1 cell lines were examined using a number of parallel approaches to block FAK, including RNA interference and small-molecule FAK inhibitors. FAK inhibition resulted in decreased cellular survival, invasion and migration, and increased apoptosis. Furthermore, small molecule inhibition of FAK led to decreased SK-NEP-1 xenograft growth in vivo. These data deepen the knowledge of the tumorigenic process in pediatric renal tumors, and provide desperately needed therapeutic strategies and targets for these rare, but difficult to treat, malignancies. IMPLICATIONS: This study provides a fundamental understanding of tumorigenesis in difficult to treat renal tumors and provides an impetus for new avenues of research and potential for novel, targeted therapies. PMID- 24464917 TI - Fhit regulates EMT targets through an EGFR/Src/ERK/Slug signaling axis in human bronchial cells. AB - In many cancers, including lung carcinomas, Fragile histidine triad (Fhit) is frequently decreased or lost. Fhit status has recently been shown to be associated with elevated in vitro and in vivo invasiveness in lung cancer. Tumor cell invasion is facilitated by epithelial-mesenchymal transition (EMT), a process by which tumor cells lose their epithelial features to acquire a mesenchymal cell-like phenotype. In this study, the mechanism underlying Fhit regulated EMT was deciphered. Using Slug knockdown, pharmacologic inhibitors PD98059, PP1, and gefitinib as well as an anti-EGFR antibody, it was demonstrated that Fhit silencing in bronchial cells induced overexpression of two primary EMT associated targets, MMP-9 and vimentin, to regulate cell invasion dependent on an EGFR/Src/ERK/Slug signaling pathway. Moreover, ectopic expression of Fhit in Fhit deficient lung cancer cells downregulated this pathway. Finally, an inverse correlation was observed between Fhit and phospho-EGFR levels in a cohort of human squamous cell lung carcinoma specimens. These results demonstrate a Fhit dependent mechanism in the control of EMT-regulated EGFR signaling. IMPLICATIONS: This study adds new insight into the regulatory mechanism of EMT, a process known to increase resistance to conventional and targeted therapies in lung cancer. PMID- 24464918 TI - Chromosomal microarray analysis allows prenatal detection of low level mosaic autosomal aneuploidy. PMID- 24464919 TI - Algal growth stimulation and toxicity in response to exposure to the new insensitive military high-nitrogen energetic triaminoguanidinium-1-methyl-5 nitriminotetrazolate. AB - Triaminoguanidinium-1-methyl-5-nitriminotetrazolate (TAG-MNT) is a nitrogen-rich energetic compound being developed as a potential component of insensitive munition formulations. The purpose of the present study was to assess the toxicity of TAG-MNT to the green alga Pseudokirchneriella subcapitata as well as to determine whether the high N content of TAG-MNT could result in increased algal growth in aquatic systems and potentially contribute to eutrophication using a 96-h algal growth bioassay in N-limited test media. Results were compared with algal exposures to current-use energetics 2,4,6-trinitrotoluene (TNT) and royal demolition explosive (RDX). The TNT exposure resulted in a lowest-observed adverse-effect concentration (LOAEC) for algal growth of 1.72 mg/L and a 50% inhibition concentration (IC50) and 95% confidence limits of 0.972 mg/L (0.955, 0.973). The RDX algal growth LOAEC was 0.10 mg/L, and the RDX IC50 was 0.635 (0.416, 0.875). Neither TNT nor RDX exposure resulted in stimulation of algal growth. In repeated testing, TAG-MNT exposure resulted in LOAECs of 0.55 and 5.20 mg/L. Stimulation of algal growth was observed at 0.06 mg/L at a mean increase of 163.2% (+/- 71.7) relative to the control in TAG-MNT test A and at the 0.005 mg/L treatment at a mean increase of 174.3% (+/- 59.9) in TAG-MNT test B. The authors' results indicate the potential for high-N energetics to significantly stimulate algal growth at low concentrations in N-limited systems. PMID- 24464920 TI - Ependymoblastoma of the brainstem: MRI findings and differential diagnosis. AB - Ependymoblastoma (EBL) is a rare malignant CNS tumor of early childhood, listed as a subgroup of primitive neuroectodermal tumors (PNET) in the 2007 WHO Classification of Tumours of the Central Nervous System. Histologically, EBL can be defined by multilayered, mitotically active "ependymoblastic" rosettes with central lumen as a histological hallmark. The prognosis seems to be far inferior to other embryonal CNS tumors, and known clinical and MRI characteristics of EBL are based on scattered case reports. We present and discuss two uncommon cases of histopathologically confirmed ependymoblastoma that both seem to originate from the brainstem. PMID- 24464921 TI - Ultrasound-guided block of sciatic and femoral nerves: an anatomical study. AB - The sheep is a popular animal model for human biomechanical research involving invasive surgery on the hind limb. These painful procedures can only be ethically justified with the application of adequate analgesia protocols. Regional anaesthesia as an adjunct to general anaesthesia may markedly improve well-being of these experimental animals during the postoperative period due to a higher analgesic efficacy when compared with systemic drugs, and may therefore reduce stress and consequently the severity of such studies. As a first step 14 sheep cadavers were used to establish a new technique for the peripheral blockade of the sciatic and the femoral nerves under sonographic guidance and to evaluate the success rate by determination of the colorization of both nerves after an injection of 0.5 mL of a 0.1% methylene blue solution. First, both nerves were visualized sonographically. Then, methylene blue solution was injected and subsequently the length of colorization was measured by gross anatomical dissection of the target nerves. Twenty-four sciatic nerves were identified sonographically in 12 out of 13 cadavers. In one animal, the nerve could not be ascertained unequivocally and, consequently, nerve colorization failed. Twenty femoral nerves were located by ultrasound in 10 out of 13 cadavers. In three cadavers, signs of autolysis impeded the scan. This study provides a detailed anatomical description of the localization of the sciatic and the femoral nerves and presents an effective and safe yet simple and rapid technique for performing peripheral nerve blocks with a high success rate. PMID- 24464922 TI - Anaesthesia in medetomidine premedicated New Zealand White rabbits: a comparison between intravenous sufentanil-midazolam and isoflurane anaesthesia for orthopaedic surgery. AB - Eighteen female New Zealand White rabbits (3.9 +/- 0.4 kg) were anaesthetized with sufentanil-midazolam by intravenous infusion (SUF-MID, n = 9) or isoflurane (ISO, n = 9) for bilateral creation of an osteochondral defect in the medial femur condyle. Subcutaneous premedication with 0.1 mg/kg medetomidine and anaesthesia induction by intravenous infusion of 1.1 ug/kg sufentanil and 0.2 mg/kg midazolam were identical in both groups. During surgery (60 min), the effects on respiratory and circulatory variables serum lactate, total protein and blood glucose were examined. Intermittent positive pressure ventilation (IPPV) was initiated if apnoea lasted>30 s or if end-tidal CO2 >=8 kPa. The righting reflex was lost in 3 min. IPPV was necessary during most of the anaesthesia for most of the rabbits. Maintenance doses during surgery were 2.0 ug/kg/h sufentanil and 0.4 mg/kg/h midazolam, and 1.4% isoflurane, respectively. Mean arterial blood pressure (MAP) was higher in group SUF-MID than group ISO during surgery (63 +/- 12 vs 50 +/- 8 mmHg). In group ISO the heart rate was higher during surgery than before anaesthesia (197 +/- 26 vs 158 +/- 40 bpm) as was blood glucose (9 +/- 2 vs 12 +/- 3 mmol/L). Serum lactate levels remained unchanged whereas total protein decreased in both groups. Time to recover from anaesthesia did not differ between groups (20 min). Intravenous sufentanil-midazolam infusion provided surgical anaesthesia with a higher MAP than isoflurane anaesthesia. The protocol can be useful in situations in which gas anaesthesia cannot be used or in animals with limited cardiovascular reserves. However, IPPV is necessary. PMID- 24464923 TI - The -786T > C polymorphism in the NOS3 gene is associated with increased cancer risk. AB - The -786T > C polymorphism in NOS3 gene may affect the DNA repair pathways and be associated with risk of cancer. However, the results of previous studies are inconsistent. The objective of this study is to investigate the association between the -786T > C polymorphism in NOS3 and risk of cancer by meta-analysis. We searched PubMed, Embase, CNKI, and Wanfang databases and the last search was updated on Sept. 20, 2013. Statistical analysis was performed using Revman4.2 and Stata10.0 software. A total of 9 case-control studies concerning 4,089 cases and 3,847 controls were included. The results suggested a significant association between the -786T > C polymorphism in NOS3 and cancer risk (CC vs. TT + CT; OR = 1.30, 95% CI = 1.07-1.57, P = 0.007) in total analysis. In the subgroup analysis by ethnicity and cancer types, significant associations were found in the breast cancer subgroup (OR 1.51, 95% CI 1.07-2.12; P = 0.02) and European subgroup (OR 1.26, 95% CI 1.01-1.58; P = 0.04). The current meta-analysis suggested that the 786T > C polymorphisms in NOS3 may be a risk factor for cancer. In the future, more case-control studies are needed to validate our results. PMID- 24464924 TI - Upregulation of SCC-S2 in immune cells and tumor tissues of papillary thyroid carcinoma. AB - Studies have shown that SCC-S2 can be detected in cancer cells, but its relation with thyroid cancer remains uncertain. In the current study, we investigated SCC S2 expression in thyroid cancer from the immune cell perspective and tumor tissue perspective. Levels of SCC-S2 in CD4+ T cells, CD8+ T cells, monocytes, natural killer (NK) T cells, tumor tissues, and adjacent noncancerous thyroid tissues were tested by real-time reverse transcription PCR and Western blot. Results revealed that mRNA and protein levels of SCC-S2 were significantly increased in peripheral CD4+ (mRNA, 1.90-fold; protein, 1.55-fold) and CD8+ T cells (mRNA, 2.37-fold; protein, 1.72-fold) but not monocytes and NKT cells in patients than in healthy donors. Further elevated mRNA level but not protein expression was observed in tumor-infiltrating CD4+ T cells, whereas both mRNA level and protein expression were further increased in tumor-infiltrating CD8+ T cells. Also, mRNA and protein levels of SCC-S2 in thyroid tissues were significantly elevated than those in adjacent noncancerous thyroid tissues. Moreover, patients with cervical lymph node metastasis presented clearly higher mRNA and protein expression of SCC S2 compared to those without cervical lymph node metastasis (p < 0.05). These results suggest that SCC-S2 may play roles in affecting both immune cells and tumor cells in the thyroid and may indicate a novel pathway for understanding the pathogenesis of the disease. PMID- 24464925 TI - GH1 T1663A polymorphism and cancer risk: a meta-analysis of case-control studies. AB - Many studies have demonstrated that the most common polymorphism (T1663A, rs2665802) in the promoter region of growth hormone 1 (GH1) gene might play an important role in cancer development and progression. This meta-analysis aims to investigate a more precise estimation of the relationship between GH1 T1663A polymorphism and cancer risk. We searched CISCOM, CINAHL, Web of Science, PubMed, Google Scholar, EBSCO, Cochrane Library, and CBM databases from inception through October 1st, 2013. Meta-analysis was performed using the STATA 12.0 software. Seven studies were included with a total of 4,018 cancer patients and 5,308 healthy controls. Our meta-analysis results revealed that GH1 T1663A polymorphism was associated with increased cancer risks. Subgroup analysis by cancer type showed significant associations between GH1 T1663A polymorphism and increased colorectal cancer risk, but there was no evidence of any association with breast cancer. Further subgroup analysis based on ethnicity indicated that GH1 T1663A polymorphism might increase cancer risks among Asian populations. However, no statistically significant association was found among Caucasian populations. Meta regression analyses also suggested that cancer type and ethnicity may be the main sources of heterogeneity. No publication bias was detected in this meta-analysis. The present meta-analysis indicates that GH1 T1663A polymorphism may contribute to the risk of colorectal cancer, especially among Asian populations. PMID- 24464926 TI - The prognosis and clinicopathology of CXCR4 in gastric cancer patients: a meta analysis. AB - The chemokine receptor 4 (CXCR4) has been widely investigated in diagnosis and prognosis of gastric cancer (GC). However, the impact of CXCR4 on GC patients remains controversial; Here, we conducted a meta-analysis to obtain the precise role of CXCR4 in GC prognosis and clinicopathology. Thirteen published studies with a total of 1,936 patients were included. Original data included the hazard ratio (HR) of overall survival (OS) and odds ratio (OR) in GC patients. We combined HR/OR with 95% confidence interval (CI) to estimate the hazard. In this study, OS was significantly related to CXCR4 expression, with the HR 2.63 (95% CI 1.69-4.09; p < 0.0001), and a significant correlation was also revealed between CXCR4 expression and stage (I + II, +) (OR 0.52, 95% CI 0.32-0.83; p = 0.007), depth of invasion (T1/T2, +) (OR 0.44, 95% CI 0.27-0.73; p = 0.001), lymph node metastasis (LN, +) (OR 2.30, 95% CI 1.57-3.36; p < 0.0001), as well as vascular invasion (vas.inv, +) (OR 0.72, 95% CI 0.53-0.98; p = 0.04). Heterogeneity was observed among the included studies with OS (I(2) = 51%), stage (I(2) = 78%), depth of invasion (I(2) = 74%), lymph node metastasis (I(2) = 64%), and histology differentiation (I(2) = 79%). No publication bias was observed. In conclusion, this meta-analysis showed CXCR4 expression indicates poor prognosis in GC patients with advanced stage or deep invasion in GC tissues, which also implied lymph node metastasis and vascular invasion. Thus, CXCR4 could help predict patient prognosis and guide clinical diagnosis and treatment. PMID- 24464927 TI - The impact of cell proliferation markers and p53 mutation status on prognosis of non-metastatic colon cancer. AB - BACKGROUND AND OBJECTIVES: We aimed to evaluate the prognostic value of cell cycle proteins and p53 together with clinicopathologic features in non-metastatic resected colon cancer. METHODS: One hundred nine patients who were diagnosed with resected colon cancer between 2006 and 2011 were analyzed retrospectively. Immunohistochemical staining analyses were used to evaluate the expression of cyclins D1 and A, p53 and Ki-67 in tumor tissue. RESULTS: High cyclin D1 and cyclin A expression was more common in stage II than stage III tumors. Disease recurrence was more frequent in tumors with low cyclin D1 expression (P = 0.05). No significant association was observed between p53, Ki-67 or cyclin A expression and the risk of relapse and/or death. Multivariate analysis showed that the strongest predictor for a shorter disease-free survival period was extracapsular nodal invasion (ECNI). CONCLUSIONS: We were not able to establish a strong association between patient prognosis and cyclins D1 and A, p53 or Ki-67 expression. However, a negative correlation between cyclin D1 and cyclin A expression and disease stage as well as more frequent relapses in patients with low expression of cyclin D1 suggested that cyclins may be predictive for early relapse in non-metastatic colon cancer. PMID- 24464928 TI - Selective conversion of biorefinery lignin into dicarboxylic acids. AB - The emerging biomass-to-biofuel conversion industry has created an urgent need for identifying new applications for biorefinery lignin. This paper demonstrates a new route to producing dicarboxylic acids from biorefinery lignin through chalcopyrite-catalyzed oxidation in a highly selective process. Up to 95 % selectivity towards stable dicarboxylic acids was obtained for several types of biorefinery lignin and model compounds under mild, environmentally friendly reaction conditions. The findings from this study paved a new avenue to biorefinery lignin conversions and applications. PMID- 24464929 TI - Improvements in hip muscle performance result in increased use of the hip extensors and abductors during a landing task. AB - BACKGROUND: Impaired hip muscle performance has been implicated as a contributing factor to the increased risk of anterior cruciate ligament (ACL) injury in women. PURPOSE: To determine the influence of a hip-focused training program on lower extremity biomechanics during a drop-jump task. STUDY DESIGN: Descriptive laboratory study. METHODS: Twenty-one recreationally active women (18-25 years of age) participated in a 4-week training program consisting of hip-focused plyometric and balance perturbation exercises (3 times/wk, 30 min/session). Maximum isometric strength of the hip extensors, hip abductors, and knee extensors was assessed, along with lower extremity biomechanics during a drop jump task. All assessments were performed within 5 days of initiation and completion of the training program. RESULTS: After training, subjects demonstrated significantly greater maximum isometric strength of the hip extensors (2.87 +/- 0.7 vs 3.11 +/- 0.7 N.m/kg; P < .01) and hip abductors (2.08 +/- 0.7 vs 2.23 +/- 0.07 N.m/kg; P = .004). No significant difference in knee extensor strength was observed. After training, subjects landed with significantly greater peak knee flexion (94.0 degrees +/- 8.5 degrees vs 98.0 degrees +/- 10.1 degrees ; P < .001) and hip flexion (83.4 degrees +/- 7.6 degrees vs 89.9 degrees +/- 8.8 degrees ; P = .008) and a lower knee/hip extensor moment ratio (1.33 +/- 0.6 vs 0.99 +/- 0.3; P = .001). In addition, subjects demonstrated significantly lower peak knee abduction angles (6.8 degrees +/- 3.3 degrees vs 5.6 degrees +/- 3.1 degrees ; P = .04) and average knee adductor moments (0.06 +/- 0.1 vs -0.02 +/- 0.1 N.m/kg; P < .001). CONCLUSION: Changes in lower extremity biomechanics consistent with decreased risk for ACL injury were observed after participation in a hip-focused training program. CLINICAL RELEVANCE: The study results suggest that ACL injury prevention programs targeting hip muscle performance may be important in mitigating biomechanical risk factors associated with ACL injury in women. PMID- 24464930 TI - Targeting-triggered porphysome nanostructure disruption for activatable photodynamic therapy. AB - Photodynamic therapy (PDT) and photothermal therapy (PTT) possess advantages over the conventional therapies with additional treatment selectivity achieved with local laser irradiation. Comparing to PTT that ablates target tissue via thermal necrosis, PDT induces target cell death via singlet oxygen without damaging the underling connective tissue, thus preserving its biological function. Activatable photosensitizers provide an additional level of treatment selectivity via the disease-associated activation mechanism. In this study, folate-conjugated porphysomes are introduced as targeting-triggered activatable nano-sized beacons for PDT. Porphysomes are reported previously as the most stable and efficient delivery system of porphyrin, but their nanostructure converts the singlet oxygen generation mechanism to thermal ablation mechanism. By folate-receptor-mediated endocytosis, folate-porphysomes are internalized into cells rapidly and resulted in efficient disruption of nanostructures, thus switching back on the photodynamic activity of the densely packed porphyrins for effective PDT. In both in vitro and in vivo studies, folate-porphysomes can achieve folate receptor selective PDT efficacy, which proves the robustness of targeting-triggered PDT activation of porphysome nanostructure for highly selective tumor ablation. The formulation of porphysomes can be modified with other targeting ligands as activatable photosensitizers for personalized treatment in future. PMID- 24464931 TI - Estimated urinary sodium excretion and risk of heart failure in men and women in the EPIC-Norfolk study. AB - AIMS: Interventional trials provide evidence for a beneficial effect of reduced dietary sodium intake on blood pressure. The association of sodium intake with heart failure which is a long-term complication of hypertension has not been examined. METHODS AND RESULTS: Hazard ratios [HRs, 95% confidence interval (CI)] of heart failure comparing quintiles of estimated 24 h urinary sodium excretion (USE) were calculated in apparently healthy men (9017) and women (10,840) aged 39 79 participating in the EPIC study in Norfolk. During a mean follow-up of 12.9 years, 1210 incident cases of heart failure occurred. Compared with the reference category (128 mmol/day<=USE<=148 mmol/day), the top quintile (USE>=191 mmol/day) was associated with a significantly increased hazard of heart failure (1.32, 1.07 1.62) in multivariable analysis adjusting for age, sex, body mass index, diabetes, cholesterol, social class, educational level, smoking, physical activity, and alcohol consumption, with a marked attenuation (1.21, 0.98-1.49) when further adjusting for blood pressure. The bottom quintile (USE<=127 mmol/day) was also associated with an increased hazard of heart failure (1.29, 1.04-1.60) in multivariable analysis without relevant attenuation by blood pressure adjustment (1.26, 1.02-1.56), but with substantial attenuation when adjusting for interim ischaemic heart disease and baseline C-reactive protein levels and exclusion of events during the first 2 years (1.18, 0.96-1.47). CONCLUSION: We demonstrate a U-shaped association between USE and heart failure risk in an apparently healthy middle-aged population. The risk associated with the high range of USE was attenuated after adjustment for blood pressure, whereas the risk associated with the low range of USE was attenuated after adjustment for pre-existing disease processes. PMID- 24464932 TI - Connective tissue growth factor and cardiac diastolic dysfunction: human data from the Taiwan diastolic heart failure registry and molecular basis by cellular and animal models. AB - AIMS: Connective tissue growth factor (CTGF) is an emerging marker for tissue fibrosis. We investigated the association between CTGF and cardiac diastolic function using cellular and animal models and clinical human data. METHODS AND RESULTS: A total of 125 patients with a diagnosis of diastolic heart failure (DHF) were recruited from 1283 patients of the Taiwan Diastolic Heart Failure Registry. The severity of DHF was determined by tissue Doppler imaging (E/e'). Cardiac magnetic resonance imaging (CMRI) was used to evaluate myocardial fibrosis in some of the patients (n = 25). Stretch of cardiomyocytes on a flexible membrane base serves as a cellular phenotype of cardiac diastolic dysfunction (DD). A canine model of DD was induced by aortic banding. A significant correlation was found between plasma CTGF and E/e' in DHF patients. The severity of cardiac fibrosis evaluated by CMRI also correlated with CTGF. In the cell model, stretch increased secretion of CTGF from cardiomyocytes. In the canine model, myocardial tissue CTGF expression and fibrosis significantly increased after 2 weeks of aortic banding. Notably, the expression of CTGF paralleled the severity of LV DD (r = 0.40, P < 0.001 for E/e') and haemodynamic changes (r = 0.80, P < 0.001). After adjusting for confounding factors, CTGF levels still correlated with diastolic parameters in both human and canine models (human plasma CTGF, P < 0.001; canine tissue CTGF, P = 0.04). CONCLUSION: Plasma CTGF level correlated with the severity of DD and tissue fibrosis in DHF patients. The mechanism may be through myocardial stretch. Our study indicated that CTGF may serve as an early marker for DHF. PMID- 24464933 TI - Levels of physical activity in patients with severe psoriasis: a cross-sectional questionnaire study. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease associated with increased cardiovascular mortality, secondary to the increased prevalence of cardiovascular risk factors and premature atherosclerosis. Physical activity is a vital component in prevention and management of cardiovascular disease. Few studies have examined the level of physical activity in psoriasis patients, using validated questionnaires or other objective assessment tools. OBJECTIVE: The aim of this study was to analyze and compare physical activity undertaken by patients with severe psoriasis and healthy controls, using the International Physical Activity Questionnaire-Short Form (IPAQ-S), a validated instrument for assessing physical activity. METHODS: Ninety patients with severe plaque-type psoriasis and 160 healthy subjects were enrolled in the present study. Physical activity was evaluated using IPAQ-S. RESULTS: Psoriasis patients had reduced levels of physical activity compared with non-psoriasis patients, regardless of sex or whether the variable was continuous or categorical. The odds ratio for low-level physical activity for psoriasis patients, compared with controls, was 3.42 (95% CI 1.47-7.91), indicating that this severe psoriasis population did not undertake recommended levels of physical activity. CONCLUSIONS: Psoriasis patients exhibit decreased levels of physical activity, possibly for both psychological and physiological reasons. The lack of physical activity may contribute to the increased risk of cardiovascular disease in psoriasis patients, in addition to the intrinsic risks related to systemic inflammation and psoriasis-linked comorbidities. Regular physical activity should be encouraged in all psoriasis patients because of its beneficial effects on systemic inflammation and cardiometabolic comorbidities associated with psoriasis. PMID- 24464934 TI - Atopic dermatitis: an evidence-based treatment update. AB - BACKGROUND: Atopic dermatitis (AD) is a common inflammatory disorder of skin with significant comorbidities. AD care often requires a combination of treatment approaches, including emollients, topical steroids, systemic immunosuppressants and/or phototherapy. PURPOSE: Our purpose was to review recent randomized controlled trials (RCT) and systematic reviews of AD treatments. METHODS: A MEDLINE search was performed focusing on RCTs of AD treatments, with a sample size >= 15, and systematic reviews published from 2011 to 2013, limited to the English language. A total of 53 manuscripts met the inclusion/exclusion criteria, including 44 RCTs and nine systematic reviews. RESULTS: Investigator-initiated RCTs support the use of the systemic agents cyclosporine, methotrexate, azathioprine and mycophenolate mofetil. In one RCT, petrolatum was found to be as effective as creams containing ceramides or glycyrrhetinic acid. Additional therapeutic approaches supported by RCTs include balneotherapy, oral and/or topical probiotics, nutritional interventions, vitamin D with or without vitamin E supplementation, as well as several new topical and complementary medicines. CONCLUSIONS: Advances have been made with respect to AD treatment in the past few years through the use of well designed RCTs and comparative efficacy studies. However, more well designed RCTs and investigator-initiated studies are needed in order to improve the care of AD patients. PMID- 24464935 TI - The role of reciprocal activation of cAbl and Mst1 in the oxidative death of cultured astrocytes. AB - The protein kinase Mst1 (mammalian Sterile 20-like kinase 1) likely plays a role in oxidative neuronal cell death as a target of its activator, cAbl. We previously found that H2O2-induced death of astrocytes is mediated by cAbl in a metallothionein-3 (Mt3)-dependent manner. In the present study, we examined a possible role for Mst1 in the oxidative death of astrocytes. Treatment of cortical astrocytes with 170 uM H2O2 activated Mst1. Knockdown of Mst1 reduced H2O2-induced cell death, indicating that Mst1 activation contributes to astrocytic cell death. STI571, an inhibitor of cAbl, blocked induction/activation of Mst1 and H2O2-induced cell death. However, Mst1 silencing also inhibited induction/activation of cAbl, suggesting that the two kinases are regulated by a reciprocal activating mechanism. The zinc chelator TPEN blocked induction/activation of cAbl and Mst1, indicating that these phenomena are dependent on the rise of intracellular zinc. Moreover, H2O2 exposure did not increase free zinc levels in Mt3-null astrocytes, suggesting that the increased levels of free zinc were largely from Mt3. Consistent with the involvement of FoxO1/3, which may play a role in the Mst1-cell death cascade, we found an increase in the level of phosphorylated FoxO1/3 in H2O2-treated astrocytes. Moreover, inhibition of cAbl or Mst1 reversed this effect. The present results suggest the interesting possibility that cAbl and Mst1 are reciprocally activated under oxidative stress conditions in astrocytes. Both kinases appear to be regulated by changes in the levels of free zinc originating from Mt3 and contribute to oxidative cell death through a FoxO-dependent mechanism. PMID- 24464936 TI - An improved approach for remotely sensing water stress impacts on forest C uptake. AB - Given that forests represent the primary terrestrial sink for atmospheric CO2 , projections of future carbon (C) storage hinge on forest responses to climate variation. Models of gross primary production (GPP) responses to water stress are commonly based on remotely sensed changes in canopy 'greenness' (e.g., normalized difference vegetation index; NDVI). However, many forests have low spectral sensitivity to water stress (SSWS) - defined here as drought-induced decline in GPP without a change in greenness. Current satellite-derived estimates of GPP use a vapor pressure deficit (VPD) scalar to account for the low SWSS of forests, but fail to capture their responses to water stress. Our objectives were to characterize differences in SSWS among forested and nonforested ecosystems, and to develop an improved framework for predicting the impacts of water stress on GPP in forests with low SSWS. First, we paired two independent drought indices with NDVI data for the conterminous US from 2000 to 2011, and examined the relationship between water stress and NDVI. We found that forests had lower SSWS than nonforests regardless of drought index or duration. We then compared satellite-derived estimates of GPP with eddy-covariance observations of GPP in two deciduous broadleaf forests with low SSWS: the Missouri Ozark (MO) and Morgan Monroe State Forest (MMSF) AmeriFlux sites. Model estimates of GPP that used VPD scalars were poorly correlated with observations of GPP at MO (r(2) = 0.09) and MMSF (r(2) = 0.38). When we included the NDVI responses to water stress of adjacent ecosystems with high SSWS into a model based solely on temperature and greenness, we substantially improved predictions of GPP at MO (r(2) = 0.83) and for a severe drought year at the MMSF (r(2) = 0.82). Collectively, our results suggest that large-scale estimates of GPP that capture variation in SSWS among ecosystems could improve predictions of C uptake by forests under drought. PMID- 24464937 TI - The early inflammatory response after flexor tendon healing: a gene expression and histological analysis. AB - Despite advances in surgical techniques over the past three decades, tendon repairs remain prone to poor clinical outcomes. Previous attempts to improve tendon healing have focused on the later stages of healing (i.e., proliferation and matrix synthesis). The early inflammatory phase of tendon healing, however, is not fully understood and its modulation during healing has not yet been studied. Therefore, the purpose of this work was to characterize the early inflammatory phase of flexor tendon healing with the goal of identifying inflammation-related targets for future treatments. Canine flexor tendons were transected and repaired using techniques identical to those used clinically. The inflammatory response was monitored for 9 days. Temporal changes in immune cell populations and gene expression of inflammation-, matrix degradation-, and extracellular matrix-related factors were examined. Gene expression patterns paralleled changes in repair-site cell populations. Of the observed changes, the most dramatic effect was a greater than 4,000-fold up-regulation in the expression of the pro-inflammatory factor IL-1beta. While an inflammatory response is likely necessary for healing to occur, high levels of pro inflammatory cytokines may result in collateral tissue damage and impaired tendon healing. These findings suggest that future tendon treatment approaches consider modulation of the inflammatory phase of healing. PMID- 24464938 TI - Ophthalmic adverse drug reactions to systemic drugs: a systematic review. AB - PURPOSE: To perform a comprehensive and systematic review regarding ophthalmic adverse drug reactions (ADRs) to systemic drugs to: (i) systematically summarize existing evidence, (ii) identify areas, ophthalmic ADRs or drugs that lacked systematization or assessment (namely drugs with original studies characterizing specific ophthalmic ADRs but without causality assessment nor without meta analysis). METHODS: Systematic review of several electronic databases (last search 1/7/2012): Medline, SCOPUS, ISI web of knowledge, ISI Conference Proceedings, International Pharmaceutical Abstracts and Google scholar. Search query included: eye, ocular, ophthalmic, ophthalmology, adverse and reaction. Inclusion criteria were: (i) Primary purpose was to assess an ophthalmic ADR to a systemic medication; (ii) Patient evaluation performed by an ophthalmologist; (iii) Studies that specified diagnostic criteria for an ocular ADR. Different types of studies were included and analyzed separately. Two independent reviewers assessed eligibility criteria, extracted data and evaluated risk of bias. RESULTS: From 562 studies found, 32 were included (1 systematic review to sildenafil, 11 narrative reviews, 1 trial, 1 prospective study, 6 transversal studies, 6 spontaneous reports and 6 case series). Drugs frequently involved included amiodarone, sildenafil, hydroxychloroquine and biphosphonates. Frequent ophthalmic ADRs included: keratopathy, dry eye and retinopathy. CONCLUSIONS: To increase evidence about ophthalmic ADRs, there is a need for performing specific systematic reviews, applying strictly the World Health Organization's (WHO) definition of ADR and WHO causality assessment of ADRs. Some ophthalmic ADRs may be frequent, but require ophthalmological examination; therefore, ophthalmologists' education and protocols of collaboration between other specialties whenever they prescribe high-risk drugs are suggestions for the future. PMID- 24464939 TI - Activation of peroxisome proliferator-activated receptor-beta/delta (PPAR beta/delta) inhibits human breast cancer cell line tumorigenicity. AB - The effect of activation and overexpression of the nuclear receptor PPAR beta/delta in human MDA-MB-231 (estrogen receptor-negative; ER(-)) and MCF7 (estrogen-receptor-positive; ER(+)) breast cancer cell lines was examined. Target gene induction by ligand activation of PPAR-beta/delta was increased by overexpression of PPAR-beta/delta compared with controls. Overexpression of PPAR beta/delta caused a decrease in cell proliferation in MCF7 and MDA-MB-231 cells compared with controls, whereas ligand activation of PPAR-beta/delta further inhibited proliferation of MCF7 but not MDA-MB-231 cells. Overexpression and/or ligand activation of PPAR-beta/delta in MDA-MB-231 or MCF7 cells had no effect on experimental apoptosis. Decreased clonogenicity was observed in both MDA-MB-231 and MCF7 overexpressing PPAR-beta/delta in response to ligand activation of PPAR beta/delta as compared with controls. Ectopic xenografts developed from MDA-MB 231 and MCF7 cells overexpressing PPAR-beta/delta were significantly smaller, and ligand activation of PPAR-beta/delta caused an even greater reduction in tumor volume as compared with controls. Interestingly, the decrease in MDA-MB-231 tumor size after overexpressing PPAR-beta/delta and ligand activation of PPAR beta/delta correlated with increased necrosis. These data show that ligand activation and/or overexpression of PPAR-beta/delta in two human breast cancer cell lines inhibits relative breast cancer tumorigenicity and provide further support for the development of ligands for PPAR-beta/delta to specifically inhibit breast carcinogenesis. These new cell-based models will be invaluable tools for delineating the role of PPAR-beta/delta in breast cancer and evaluating the effects of PPAR-beta/delta agonists. PMID- 24464940 TI - Cell fusion phenomena detected after in utero transplantation of Ds-red-harboring porcine amniotic fluid stem cells into EGFP transgenic mice. AB - OBJECTIVES: Amniotic fluid stem cells (AFSCs) are derived from the amniotic fluid of the developing fetus and can give rise to diverse differentiated cells of ectoderm, mesoderm, and endoderm lineages. Intrauterine transplantation is an approach used to cure inherited genetic fetal defects during the gestation period of pregnant dams. Certain disease such as osteogenesis imperfecta was successfully treated in affected fetal mice using this method. However, the donor cell destiny remains uncertain. METHODS: The purpose of this study was to investigate the biodistribution and cell fate of Ds-red-harboring porcine AFSCs (Ds-red pAFSCs) after intrauterine transplantation into enhanced green fluorescent protein-harboring fetuses of pregnant mice. Pregnant mice (12.5 days) underwent open laparotomy with intrauterine pAFSC transplantation (5 * 10(4) cells per pup) into fetal peritoneal cavity. RESULTS: Three weeks after birth, the mice were sacrificed. Several samples from different organs were obtained for histological examination and flow cytometric analysis. Ds-red pAFSCs migrated most frequently into the intestines. Furthermore, enhanced green fluorescent protein and red fluorescent protein signals were co-expressed in the intestine and liver cells via immunohistochemistry studies. CONCLUSION: In utero xenotransplantation of pAFSCs fused with recipient intestinal cells instead of differentiating or maintaining the undifferentiated status in the tissue. PMID- 24464941 TI - Neuroimaging Evidence of Motor Control and Pain Processing in the Human Midcingulate Cortex. AB - Human neuroimaging and virus-tracing studies in monkey predict that motor control and pain processes should overlap in anterior midcingulate cortex (aMCC), but there is currently no direct evidence that this is the case. We used a novel functional magnetic resonance imaging paradigm to examine brain activity while subjects performed a motor control task, experienced a pain-eliciting stimulus on their hand, and performed the motor control task while also experiencing the pain eliciting stimulus. Our experiment produced 3 novel results. First, group-level analyses showed that when separate trials of motor control and pain processing were performed, overlapping functional activity was found in the same regions of aMCC, supplementary motor area (SMA), anterior insula, and putamen. Secondly, increased activity was found in the aMCC and SMA when motor control and pain processing occurred simultaneously. Thirdly, individual-level analyses showed that 93% of subjects engaged the same region of aMCC during separate trials of motor control and pain processing irrespective of differences in the sulcal/gyral morphology of the cingulate cortex across individuals. These observations provide direct evidence in humans that the same region of aMCC is engaged for motor control and pain processing. PMID- 24464942 TI - Locus Coeruleus Stimulation Facilitates Long-Term Depression in the Dentate Gyrus That Requires Activation of beta-Adrenergic Receptors. AB - Synaptic plasticity comprises a cellular mechanism through which the hippocampus most likely enables memory formation. Neuromodulation, related to arousal, is a key aspect in information storage. The activation of locus coeruleus (LC) neurons by novel experience leads to noradrenaline release in the hippocampus at the level of the dentate gyrus (DG). We explored whether synaptic plasticity in the DG is influenced by activation of the LC via electrical stimulation. Coupling of test-pulses that evoked stable basal synaptic transmission in the DG with stimulation of the LC induced beta-adrenoreceptor-dependent long-term depression (LTD) at perforant path-DG synapses in adult rats. Furthermore, persistent LTD (>24 h) induced by perforant path stimulation also required activation of beta adrenergic receptors: Whereas a beta-adrenergic receptor antagonist (propranolol) prevented, an agonist (isoproterenol) strengthened the persistence of LTD for over 24 h. These findings support the hypothesis that persistent LTD in the DG is modulated by beta-adrenergic receptors. Furthermore, LC activation potently facilitates DG LTD. This suggests in turn that synaptic plasticity in the DG is tightly regulated by activity in the noradrenergic system. This may reflect the role of the LC in selecting salient information for subsequent synaptic processing in the hippocampus. PMID- 24464943 TI - Mixing of Chromatic and Luminance Retinal Signals in Primate Area V1. AB - Vision emerges from activation of chromatic and achromatic retinal channels whose interaction in visual cortex is still poorly understood. To investigate this interaction, we recorded neuronal activity from retinal ganglion cells and V1 cortical cells in macaques and measured their visual responses to grating stimuli that had either luminance contrast (luminance grating), chromatic contrast (chromatic grating), or a combination of the two (compound grating). As with parvocellular or koniocellular retinal ganglion cells, some V1 cells responded mostly to the chromatic contrast of the compound grating. As with magnocellular retinal ganglion cells, other V1 cells responded mostly to the luminance contrast and generated a frequency-doubled response to equiluminant chromatic gratings. Unlike magnocellular and parvocellular retinal ganglion cells, V1 cells formed a unimodal distribution for luminance/color preference with a 2- to 4-fold bias toward luminance. V1 cells associated with positive local field potentials in deep layers showed the strongest combined responses to color and luminance and, as a population, V1 cells encoded a diverse combination of luminance/color edges that matched edge distributions of natural scenes. Taken together, these results suggest that the primary visual cortex combines magnocellular and parvocellular retinal inputs to increase cortical receptive field diversity and to optimize visual processing of our natural environment. PMID- 24464945 TI - Identifying active functionalities on few-layered graphene catalysts for oxidative dehydrogenation of isobutane. AB - The general consensus in the studies of nanostructured carbon catalysts for oxidative dehydrogenation (ODH) of alkanes to olefins is that the oxygen functionalities generated during synthesis and reaction are responsible for the catalytic activity of these nanostructured carbons. Identification of the highly active oxygen functionalities would enable engineering of nanocarbons for ODH of alkanes. Few-layered graphenes were used as model catalysts in experiments to synthesize reduced graphene oxide samples with varying oxygen concentrations, to characterize oxygen functionalities, and to measure the activation energies for ODH of isobutane. Periodic density functional theory calculations were performed on graphene nanoribbon models with a variety of oxygen functionalities at the edges to calculate their thermal stability and to model reaction mechanisms for ODH of isobutane. Comparing measured and calculated thermal stability and activation energies leads to the conclusion that dicarbonyls at the zigzag edges and quinones at armchair edges are appropriately balanced for high activity, relative to other model functionalities considered herein. In the ODH of isobutane, both dehydrogenation and regeneration of catalytic sites are relevant at the dicarbonyls, whereas regeneration is facile compared with dehydrogenation at quinones. The catalytic mechanism involves weakly adsorbed isobutane reducing functional oxygen and leaving as isobutene, and O2 in the feed, weakly adsorbed on the hydrogenated functionality, reacting with that hydrogen and regenerating the catalytic sites. PMID- 24464944 TI - Convergent BOLD and Beta-Band Activity in Superior Temporal Sulcus and Frontolimbic Circuitry Underpins Human Emotion Cognition. AB - The processing of social information in the human brain is widely distributed neuroanatomically and finely orchestrated over time. However, a detailed account of the spatiotemporal organization of these key neural underpinnings of human social cognition remains to be elucidated. Here, we applied functional magnetic resonance imaging (fMRI) and magnetoencephalography (MEG) in the same participants to investigate spatial and temporal neural patterns evoked by viewing videos of facial muscle configurations. We show that observing the emergence of expressions elicits sustained blood oxygenation level-dependent responses in the superior temporal sulcus (STS), a region implicated in processing meaningful biological motion. We also found corresponding event related changes in sustained MEG beta-band (14-30 Hz) oscillatory activity in the STS, consistent with the possible role of beta-band activity in visual perception. Dynamically evolving fearful and happy expressions elicited early (0 400 ms) transient beta-band activity in sensorimotor cortex that persisted beyond 400 ms, at which time it became accompanied by a frontolimbic spread (400-1000 ms). In addition, individual differences in sustained STS beta-band activity correlated with speed of emotion recognition, substantiating the behavioral relevance of these signals. This STS beta-band activity showed valence-specific coupling with the time courses of facial movements as they emerged into full blown fearful and happy expressions (negative and positive coupling, respectively). These data offer new insights into the perceptual relevance and orchestrated function of the STS and interconnected pathways in social-emotion cognition. PMID- 24464946 TI - Two-dimensional speckle tracking echocardiography combined with high-sensitive cardiac troponin T in early detection and prediction of cardiotoxicity during epirubicine-based chemotherapy. AB - AIMS: To investigate whether alterations of myocardial strain and high-sensitive cardiac troponin T (cTnT) could predict future cardiac dysfunction in patients after epirubicin exposure. METHODS: Seventy-five patients with non-Hodgkin lymphoma treated with epirubicin were studied. Blood collection and echocardiography were performed at baseline, 1 day after the third cycle, and 1 day after completion of chemotherapy. Patients were studied using echocardiography during follow-up. Global longitudinal (GLS), circumferential (GCS), and radial strain (GRS) were calculated using speckle tracking echocardiography. Left ventricular ejection fraction was analysed by real-time 3D echocardiography. Cardiotoxicity was defined as a reduction of the LVEF of >=5% to <55% with symptoms of heart failure or an asymptomatic reduction of the LVEF of >=10% to <55%. RESULTS: Fourteen patients (18.67%) developed cardiotoxicity after treatment. GLS (-18.48 +/- 1.72% vs. -15.96 +/- 1.6%), GCS (-20.93 +/- 2.86% vs. -19.20 +/- 3.21%), and GRS (39.23 +/- 6.44% vs. 34.98 +/- 6.2%) were markedly reduced and cTnT was elevated from 0.0010 +/- 0.0020 to 0.0073 +/- 0.0038 ng/mL (P all < 0.01) at the completion of chemotherapy compared with baseline values. A >15.9% decrease in GLS [sensitivity, 86%; specificity, 75%; area under the curve (AUC) = 0.815; P = 0.001] and a >0.004 ng/mL elevation in cTnT (sensitivity, 79%; specificity, 64%; AUC = 0.757; P = 0.005) from baseline to the third cycle of chemotherapy predicted later cardiotoxicity. The decrease in GLS remained the only independent predictor of cardiotoxicity (P = 0.000). CONCLUSIONS: GLS combined with cTnT may provide a reliable and non-invasive method to predict cardiac dysfunction in patients receiving anthracycline-based chemotherapy. PMID- 24464948 TI - Some thoughts on how to do good quality peer review. PMID- 24464949 TI - Psychometric properties of the Child PTSD Symptom Scale in Latino children. AB - The Child PTSD Symptom Scale (Foa, Johnson, Feeny, & Treadwell, ) is a self report measure of posttraumatic stress disorder symptoms (PTSD) in children and adolescents. Despite widespread use of this measure, no study to our knowledge has examined its psychometric properties in Latino children. This study examined the factor structure, internal consistency, and convergent validity of the measure utilizing a sample of 161 Latino students (M = 11.42 years, SD = 0.70) at high risk of exposure to community violence. Confirmatory factor analyses suggested that a 3-factor model consistent with the Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, ) provided the best fit to the data. Internal consistency of the total scale and subscales was high when completed in English or Spanish. All Child PTSD Symptom Scale scores were positively correlated with violence exposure. As additional evidence of convergent validity, scores evidenced stronger correlations with internalizing symptoms than with externalizing symptoms. Results supported the use of the Child PTSD Symptom Scale as a measure of PTSD severity in Latino children, but additional research is needed to determine appropriate clinical cutoffs for Latino youths exposed to chronic levels of violence. Implications for clinical practice and future research are discussed. PMID- 24464947 TI - Prognostic factors that increase the risk for reduced white matter volumes and deficits in attention and learning for survivors of childhood cancers. AB - OBJECTIVE: In children, CNS-directed cancer therapy is thought to result in decreased cerebral white matter volumes (WMV) and subsequent neurocognitive deficits. This study was designed as a prospective validation of the purported reduction in WMV, associated influential factors, and its relationship to neurocognitive deficits in a very large cohort of both acute lymphoblastic leukemia (ALL) and malignant brain tumors (BT) survivors in comparison to an age similar cohort of healthy sibling controls. PROCEDURES: The effects of host characteristics and CNS treatment intensity on WMV were investigated in 383 childhood cancer survivors (199 ALL, 184 BT) at least 12 months post-completion of therapy and 67 healthy siblings that served as a control group. t-Tests and multiple variable linear models were used to assess cross-sectional WMV and its relation with neurocognitive function. RESULTS: BT survivors had lower WMV than ALL survivors, who had less than the control group. Increased CNS treatment intensity, younger age at treatment, and greater time since treatment were significantly associated with lower WMV. Additionally, cancer survivors did not perform as well as the control group on neurocognitive measures of intelligence, attention, and academic achievement. Reduced WMV had a larger impact on estimated IQ among females and children treated at a younger age. CONCLUSIONS: Survivors of childhood cancer that have undergone higher intensity therapy at a younger age have significantly less WMV than their peers and this difference increases with time since therapy. Decreased WMV is associated with significantly lower scores in intelligence, attention, and academic performance in survivors. PMID- 24464950 TI - NUCB2/nesfatin-1: a new adipokine expressed in human and murine chondrocytes with pro-inflammatory properties, an in vitro study. AB - Nesfatin-1 is a recently discovered satiety-inducing adipokine identified in hypothalamic regions that regulates energy balance. So far, no data exist on NUCB2/nesfatin-1 localization in human and murine chondrocytes. Here, we therefore investigated NUCB2/nesfatin-1 gene and protein expression in human and murine chondrocytes and the effect of nesfatin-1 on pro-inflammatory cytokines expression. Peptide localization was performed by laser confocal microscopy, NUCB2 mRNA expression was studied by RT-PCR and protein secretion was measured by XMap technology and Western blot analysis. First, we demonstrated cytoplasmic localization of NUCB2/nesfatin-1 peptide in both human and murine chondrocytes. We present evidence that both mRNA and protein expression of NUCB2 were increased during the differentiation of ATDC5 murine chondrocyte cell line. Furthermore, we demonstrated that nesfatin-1 induces IL-6 and MIP-1alpha mRNA expression and protein secretion in ATDC-5 cells challenged with IL-1, and also increases COX-2 mRNA expression in these cells. Finally, nesfatin-1 provoked a clear induction of pro-inflammatory agents, such as COX-2, IL-8, IL-6, and MIP-1alpha in human primary chondrocytes from OA patients. PMID- 24464951 TI - Ethical issues related to caring for low birth weight infants. AB - BACKGROUND: Currently preterm births are the leading causes of newborn deaths and newborn mortality in developed countries. Infants born prematurely remain vulnerable to many acute complications and long-term disabilities. There is a growing concern surrounding the moral and ethical implications of the complex and technological care being provided to extremely low birth weight infants in neonatal intensive care units in the developed nations. RESEARCH PURPOSE: The purpose of this study was to describe the ethical and moral issues that neonatal intensive care nurses experience when caring for low birth weight preterm infants and their families. RESEARCH DESIGN: A phenomenological method design was used to describe the lived experiences of nurses with ethical and moral issues encountered in the neonatal intensive care unit. One-on-one, semi-structured interviews using open-ended questions were used to gather data from the participants. RESEARCH PARTICIPANTS: The setting for this study was a 97-bed neonatal intensive care. A total of 16 female nurses were interviewed. ETHICAL CONSIDERATIONS: Approval to conduct the research study was obtained from the institutional review board of the hospital where the study was conducted. Formal signed consent was obtained from each participant. To ensure confidentiality, each participant was asked to choose a confederate name to be used in the interview and the transcriptions. FINDINGS: The thematic analysis identified five recurring themes: (a) at the edge of viability, (b) infant pain and discomfort, (c) crucial decisions, (d) communicating with parents, and (e) letting go. CONCLUSION: Neonatal intensive care unit nurses indicated that they often had challenges to their own sense of morality as they struggled to protect the infant from pain and unnecessary discomfort, provide care to an infant and their family whom they thought was faced with a lifetime of challenges and poor health, accepting decisions made by parents, and feeling as if parents were not adequately informed about outcomes. PMID- 24464952 TI - Conditioned Subjective Responses to Socially Relevant Stimuli in Social Anxiety Disorder and Subclinical Social Anxiety. AB - Although enhanced fear conditioning has been implicated in the origins of social anxiety disorder (SAD), laboratory evidence in support of this association is limited. Using a paradigm employing socially relevant unconditioned stimuli, we conducted two separate studies to asses fear conditioning in individuals with SAD and non-clinical individuals with high social anxiety (subclinical social anxiety [SSA]). They were compared with age-matched and gender-matched individuals with another anxiety disorder (panic disorder with agoraphobia) and healthy controls (Study 1) and with individuals with low social anxiety (Study 2). Contrary to our expectations, in both studies, self-report measures (ratings of anxiety, unpleasantness and arousal to the conditioned stimuli) of fear conditioning failed to discriminate between SAD or SSA and the other participant groups. Our results suggest that enhanced fear conditioning does not play a major role in pathological social anxiety. KEY PRACTITIONER MESSAGE: We used a social conditioning paradigm to study fear conditioning in clinical and subclinical social anxiety. We found no evidence of enhanced fear conditioning in social anxiety individuals. Enhanced fear conditioning may not be a hallmark of pathological social anxiety. PMID- 24464953 TI - The renal arterial resistance index: a marker of renal function with an independent and incremental role in predicting heart failure progression. AB - AIMS: The renal arterial resistance index (RRI) is a measure of renal blood flow obtained by Doppler ultrasonography, which has been demonstrated to reflect both vascular and parenchymal renal abnormalities. The aim of the study was to evaluate clinical correlates and the prognostic relevance of RRI in a group of patients affected by chronic heart failure (CHF). METHODS AND RESULTS: We enrolled 250 CHF outpatients in a stable clinical condition and receiving conventional therapy. Peak systolic velocity and end-diastolic velocity of a segmental renal artery were obtained by pulsed Doppler flow. Then the RRI was calculated. Standard renal function assessment was obtained by the measurement of creatinine serum levels and the estimation of the glomerular filtration rate (GFR). During follow-up (21.4 +/- 11.3 months), 41 patients experienced heart failure progression (hospitalization and/or heart transplantation and/or death due to worsening heart failure). Considered as a continuous variable, RRI was associated with events at univariate [hazard ratio (HR) 1.14; 95% confidence interval (CI) 1.09-1.19; P < 0.001] as well as at multivariate Cox regression analysis (HR 1.08; 95% CI 1.02-1.13; P = 0.004) after correction for independent predictors of the reference model. When the RRI was added to the reference model including GFR, a significant improvement of reclassification according to both category-free net reclassification improvement (NRI, 47%; 95% CI 13-80%; P = 0.006) and integrated discrimination improvement (IDI, 0.034; 95% CI 0.006-0.061; P = 0.016) was observed. CONCLUSIONS: Quantification of arterial renal perfusion provides a new parameter that independently predicts CHF patient outcome, thus strengthening its possible role in current clinical practice in order to better characterize renal function and stratify patients' prognosis. PMID- 24464954 TI - Synchronous fire activity in the tropical high Andes: an indication of regional climate forcing. AB - Global climate models suggest enhanced warming of the tropical mid and upper troposphere, with larger temperature rise rates at higher elevations. Changes in fire activity are amongst the most significant ecological consequences of rising temperatures and changing hydrological properties in mountainous ecosystems, and there is a global evidence of increased fire activity with elevation. Whilst fire research has become popular in the tropical lowlands, much less is known of the tropical high Andean region (>2000 masl, from Colombia to Bolivia). This study examines fire trends in the high Andes for three ecosystems, the Puna, the Paramo and the Yungas, for the period 1982-2006. We pose three questions: (i) is there an increased fire response with elevation? (ii) does the El Nino- Southern Oscillation control fire activity in this region? (iii) are the observed fire trends human driven (e.g., human practices and their effects on fuel build-up) or climate driven? We did not find evidence of increased fire activity with elevation but, instead, a quasicyclic and synchronous fire response in Ecuador, Peru and Bolivia, suggesting the influence of high-frequency climate forcing on fire responses on a subcontinental scale, in the high Andes. ENSO variability did not show a significant relation to fire activity for these three countries, partly because ENSO variability did not significantly relate to precipitation extremes, although it strongly did to temperature extremes. Whilst ENSO did not individually lead the observed regional fire trends, our results suggest a climate influence on fire activity, mainly through a sawtooth pattern of precipitation (increased rainfall before fire-peak seasons (t-1) followed by drought spells and unusual low temperatures (t0), which is particularly common where fire is carried by low fuel loads (e.g., grasslands and fine fuel). This climatic sawtooth appeared as the main driver of fire trends, above local human influences and fuel build-up cyclicity. PMID- 24464955 TI - Serum hyperglycosylated human chorionic gonadotrophin at 14-17 weeks of gestation does not predict preeclampsia. AB - INTRODUCTION: Low first-trimester serum concentrations of hyperglycosylated human chorionic gonadotrophin (hCG-h) predict later preeclampsia. We studied whether serum hCG-h at 14-17 weeks of pregnancy also predicts preeclampsia alone or combined with placental growth factor (PlGF) and soluble vascular endothelial growth factor 1 (sVEGFR-1). METHODS: We conducted a nested case-control study comprising 55 women with subsequent preeclampsia, 21 with gestational hypertension, 30 with a small-for-gestational-age infant, and 83 controls. Serum concentrations of hCG-h, proportion of hCG-h to hCG (%hCG-h), PlGF, and sVEGFR-1 were converted to multiples of the medians (MoMs) adjusted for gestational age. RESULTS: Concentrations of hCG-h or %hCG-h did not differ between women with subsequent preeclampsia and controls. In women with subsequent preeclampsia, PlGF was lower (0.62 MoM) than in controls (P < 0.001). In receiver-operating characteristics curve analysis for the prediction of preeclampsia, the area under the curve for hCG-h or %hCG-h was not significantly different from 0.5, whereas that for PlGF was 0.746 (95% confidence interval, 0.656-0.836; P < 0.001). Combining hCG-h or %hCG-h with PlGF did not improve the prognostic value. CONCLUSIONS: Serum hCG-h did not improve prediction of preeclampsia in the second trimester. PMID- 24464956 TI - Role of cathepsin E in decidual macrophage of patients with recurrent miscarriage. AB - In a previous study, we reported that the cathepsin-cystatin system caused endometrial dysfunction in early pregnancy. Here, we investigated the existence and contribution of cathepsin E in early pregnancy in patients with recurrent miscarriage (RM). The effect of cathepsin deficiency on fertility and female reproductive organs were also analyzed in CatE(-/-) mice. Human studies were conducted in a hospital setting, with informed consent. Cervical mucus was collected from RM patients in early pregnancy (4-6 gestational weeks, n = 21), and the pregnancy outcome was compared prospectively. The cathepsin E expression in decidua of RM patients (n = 49) and normal pregnant women undergoing elective surgical abortion (n = 24) was measured using SDS-PAGE, and western blot analysis. Decidual macrophages were isolated from RM patients (n = 6) and stimulated by lipopolysaccharide (LPS) and interferon gamma (IFN-gamma). Results from the mouse model showed that CatE(-/-) mice were fertile, but the litter number was significantly smaller. The uterus of CatE(-/-) mice showed granulation tissue. In human samples, protease activity of cathepsin E measured with Fluorescence-Quenching Substrate (KYS-1) in cervical mucus of patients who developed miscarriage was markedly decreased compared with patients without RM. The expression of cathepsin E in decidua, semi-quantified by SDS-PAGE, western blot analysis was significantly lower in RM patients compared with patients without RM. By double staining immunofluorescence, the staining of cathepsin E was observed in CD14 or CD68 positive cells in all deciduas. Upon stimulation with LPS and IFN-gamma, the expression of cathepsin E in cell lysate of decidual macrophages was markedly reduced in RM patients compared with controls. The results suggested that decreased activity of cathepsin E produced by decidual macrophages might be responsible for the induction of miscarriages in some RM patients. PMID- 24464957 TI - Energetic aqueous rechargeable sodium-ion battery based on Na2 CuFe(CN)6 -NaTi2 (PO4 )3 intercalation chemistry. AB - Aqueous rechargeable sodium-ion batteries have the potential to meet growing demand for grid-scale electric energy storage because of the widespread availability and low cost of sodium resources. In this study, we synthesized a Na rich copper hexacyanoferrate(II) Na2 CuFe(CN)6 as a high potential cathode and used NaTi2 (PO4 )3 as a Na-deficient anode to assemble an aqueous sodium ion battery. This battery works very well with a high average discharge voltage of 1.4 V, a specific energy of 48 Wh kg(-1) , and an excellent high-rate cycle stability with approximately 90 % capacity retention over 1000 cycles, achieving a new record in the electrochemical performance of aqueous Na-ion batteries. Moreover, all the anode, cathode, and electrolyte materials are low cost and naturally abundant and are affordable for widespread applications. PMID- 24464958 TI - How long should we maintain long-term azithromycin treatment in cystic fibrosis patients? PMID- 24464959 TI - Heterocycles 33: lipophilicity of a new class of thioethers estimated by reversed phase thin-layer chromatography and different computational methods. AB - The retention behavior for a series of new polyheterocyclic compounds containing azolic rings (1,3-thiazole, 1,2,4-triazole, 1,3,4-oxadiazole, 1,3,4-thiadiazole) has been investigated using reversed-phase thin-layer chromatography. Different approaches and computational methods were employed to evaluate their lipophilicity indices derived from chromatographic parameters. The obtained experimental results were correlated with various lipophilicity indices estimated via different computer software and internet websites. A strong correlation between experimental and computed results was observed. Furthermore, the lipophilicity parameters obtained by applying principal component analysis divided the investigated compounds into four groups according to their structural similarities. PMID- 24464960 TI - Levosimendan improves renal function in acute decompensated heart failure: possible underlying mechanisms. AB - AIMS: The cardio-renal syndrome plays a critical role in acute heart failure (HF). Levosimendan, an inodilator drug, has a positive but controversial effect on kidney. Our aim was to evaluate its effects on both renal and systemic haemodynamic parameters as well as on renal function, explaining the possible mechanisms involved. METHODS AND RESULTS: Patients with acute decompensated HF, moderate renal impairment, wedge pressure >20 mmHg and EF <40% were eligible. Twenty-one patients were randomized to infusion of levosimendan or placebo, on top of standard therapy. Systemic haemodynamic parameters (wedge and cardiac output) were evaluated at baseline and at 8, 16, 24, 48, and 72 h. An intravascular renal artery Doppler exam was performed at baseline, after levosimendan bolus, and 1 h thereafter. Renal blood flow, glomerular filtration rate (GFR), cystatin C, blood urea nitrogen (BUN), urinary output, sodium excretion, and plasma sodium were measured. The effect of levosimendan was beneficial and significantly different from placebo on several renal and cardiac parameters. Specifically, the levosimendan and placebo group exhibited significantly different changes over time in GFR (P = 0.037), renal blood flow (P = 0.037), and renal artery diameter (P = 0.033), with ensuing improvements in serum levels of BUN (P = 0.014), creatinine (P = 0.042), and cystatin C (P = 0.05). Concomitantly, levosimendan provided a significant increase in urine output up to 72 h (P = 0.02). These beneficial results on renal parameters were accompanied by similarly significant and favourable changes in cardiac index (P = 0.029) and PCWP (P < 0.001). CONCLUSION: Levosimendan, in acute decompensated HF, has an immediate renoprotective effect, mediated by an increase in renal blood flow, due to a selective renal arterial and venous vasodilating action. TRIAL REGISTRATION: NCT00527059. PMID- 24464961 TI - Disruption of the anterior-posterior rotator cuff force balance alters joint function and leads to joint damage in a rat model. AB - The rotator cuff assists in shoulder movement and provides dynamic stability to the glenohumeral joint. Specifically, the anterior-posterior (AP) force balance, provided by the subscapularis anteriorly and the infraspinatus and teres minor posteriorly, is critical for joint stability and concentric rotation of the humeral head on the glenoid. However, limited understanding exists of the consequences associated with disruption of the AP force balance (due to tears of both the supraspinatus and infraspinatus tendons) on joint function and joint damage. We investigated the effect of disrupting the APforce balance on joint function and joint damage in an overuse rat model. Twenty-eight rats underwent 4 weeks of overuse to produce a tendinopathic condition and were then randomized into two surgical groups: Detachment of the supraspinatus only or detachment of the supraspinatus and infraspinatus tendons. Rats were then gradually returned to their overuse protocol. Quantitative ambulatory measures including medial/lateral, propulsion, braking, and vertical forces were significantly different between groups. Additionally, cartilage and adjacent tendon properties were significantly altered. These results identify joint imbalance as a mechanical mechanism for joint damage and demonstrate the importance of preserving rotator cuff balance when treating active cuff tear patients. PMID- 24464963 TI - Are autoantibodies to RNA-polymerase III to be incorporated in routine diagnostic laboratory algorithms for systemic autoimmune rheumatic diseases? PMID- 24464964 TI - Impact of decreased heparin dose for flush-lock of implanted venous access ports in pediatric oncology patients. AB - BACKGROUND: Faced with a lack of evidence, institutions often develop local protocols for use of heparin to flush-lock venous access ports. Our objective was to evaluate catheter-related complications in patients after introduction of a lower-concentration heparin flush protocol. PROCEDURE: Patients with implanted vascular access devices followed by a Pediatric Oncology service were exposed to a practice change in which heparin dose for flush-lock was decreased from 5 ml of 100 units/ml to 5 ml of 10 units/ml. Outcome measures included port malfunctions leading to use of intra-port tissue plasminogen activator (tPA), and positive blood cultures. RESULTS: Rates of tPA usage were statistically similar before and after the practice change (0.82 compared to 0.59 per 100 line days absolute change -0.23, 95% CI -0.66, 0.20). Positive blood culture rates were also statistically similar before and after the practice change. CONCLUSIONS: Children with implanted ports had similar complication rates and care safety measures whether their ports were flushed with 10 units/ml of heparin or 100 units/ml. Standardizing flush-locks to lower doses of heparin may be a promising approach to maintaining port patency without compromising patient safety. PMID- 24464965 TI - Assessment and treatment of challenging behaviour for individuals with intellectual disability: a research review. AB - BACKGROUND: Challenging behaviour is frequently associated with the presence of intellectual disability. If not effectively treated, chronic challenging behaviour can negatively impact a variety of quality of life outcomes for individuals with intellectual disability. METHODS AND RESULTS: We review the current status of research relating to the assessment and treatment of challenging behaviour for people with intellectual disability. We briefly review the history of interventions for challenging behaviour that led to the development of function-based approaches widely in use today. We then discuss the various operant functions of challenging behaviour, functional behaviour assessment technologies and reinforcement-based interventions. CONCLUSIONS: We conclude with a discussion of future directions that include models of prevention, ecological validity of assessment procedures and the widespread use of comprehensive behavioural support programmes. PMID- 24464962 TI - Morbidity and mortality in the antiphospholipid syndrome during a 10-year period: a multicentre prospective study of 1000 patients. AB - OBJECTIVES: To assess the prevalence of the main causes of morbi-mortality in the antiphospholipid syndrome (APS) during a 10-year-follow-up period and to compare the frequency of early manifestations with those that appeared later. METHODS: In 1999, we started an observational study of 1000 APS patients from 13 European countries. All had medical histories documented when entered into the study and were followed prospectively during the ensuing 10 years. RESULTS: 53.1% of the patients had primary APS, 36.2% had APS associated with systemic lupus erythematosus and 10.7% APS associated with other diseases. Thrombotic events appeared in 166 (16.6%) patients during the first 5-year period and in 115 (14.4%) during the second 5-year period. The most common events were strokes, transient ischaemic attacks, deep vein thromboses and pulmonary embolism. 127 (15.5%) women became pregnant (188 pregnancies) and 72.9% of pregnancies succeeded in having one or more live births. The most common obstetric complication was early pregnancy loss (16.5% of the pregnancies). Intrauterine growth restriction (26.3% of the total live births) and prematurity (48.2%) were the most frequent fetal morbidities. 93 (9.3%) patients died and the most frequent causes of death were severe thrombosis (36.5%) and infections (26.9%). Nine (0.9%) cases of catastrophic APS occurred and 5 (55.6%) of them died. The survival probability at 10 years was 90.7%. CONCLUSIONS: Patients with APS still develop significant morbidity and mortality despite current treatment. It is imperative to increase the efforts in determining optimal prognostic markers and therapeutic measures to prevent these complications. PMID- 24464966 TI - A measurable impact of a self-practice/self-reflection programme on the therapeutic skills of experienced cognitive-behavioural therapists. AB - The need for effective training methods for enhancing cognitive-behavioural therapist competency is not only relevant to new therapists but also to experienced therapists looking to retain and further enhance their skills. Self practice/self-reflection (SP/SR) is a self-experiential cognitive-behavioural therapy (CBT) training programme, which combines the experience of practicing CBT methods on oneself with structured reflection on the implications of the experience for clinical practice. In order to build on previous qualitative studies of SP/SR, which have mainly focused on trainee CBT therapists, the aim of the current study was to quantify the impact of SP/SR on the therapeutic skills of an experienced cohort of CBT therapists. Fourteen CBT therapists were recruited to participate in an SP/SR programme specifically adapted for experienced therapists. In the context of a quasi-experimental design including multiple baselines within a single-case methodology, therapists provided self ratings of technical cognitive therapy skill and interpersonal empathic skill at four critical time points: baseline, pre-SP/SR and post-SP/SR and follow-up. Analysis of programme completers (n = 7) indicated that SP/SR enhances both technical skill and interpersonal therapeutic skill. Further intention-to-treat group (n = 14) analyses including both those who left the programme early (n = 3) and those who partially completed the programme (n = 4) added to the robustness of findings with respect to technical cognitive therapy skills but not interpersonal empathic skills. It was concluded that SP/SR, as a training and development programme, could offer an avenue to further therapeutic skill enhancement in already experienced CBT therapists. PMID- 24464967 TI - The kidney in congestive heart failure: 'are natriuresis, sodium, and diuretics really the good, the bad and the ugly?'. AB - This review discusses renal sodium handling in heart failure. Increased sodium avidity and tendency to extracellular volume overload, i.e. congestion, are hallmark features of the heart failure syndrome. Particularly in the case of concomitant renal dysfunction, the kidneys often fail to elicit potent natriuresis. Yet, assessment of renal function is generally performed by measuring serum creatinine, which has inherent limitations as a biomarker for the glomerular filtration rate (GFR). Moreover, glomerular filtration only represents part of the nephron's function. Alterations in the fractional reabsorptive rate of sodium are at least equally important in emerging therapy-refractory congestion. Indeed, renal blood flow decreases before the GFR is affected in congestive heart failure. The resulting increased filtration fraction changes Starling forces in peritubular capillaries, which drive sodium reabsorption in the proximal tubules. Congestion further stimulates this process by augmenting renal lymph flow. Consequently, fractional sodium reabsorption in the proximal tubules is significantly increased, limiting sodium delivery to the distal nephron. Orthosympathetic activation probably plays a pivotal role in those deranged intrarenal haemodynamics, which ultimately enhance diuretic resistance, stimulate neurohumoral activation with aldosterone breakthrough, and compromise the counter-regulatory function of natriuretic peptides. Recent evidence even suggests that intrinsic renal derangements might impair natriuresis early on, before clinical congestion or neurohumoral activation are evident. This represents a paradigm shift in heart failure pathophysiology, as it suggests that renal dysfunction-although not by conventional GFR measurements-is driving disease progression. In this respect, a better understanding of renal sodium handling in congestive heart failure is crucial to achieve more tailored decongestive therapy, while preserving renal function. PMID- 24464968 TI - Non-invasive assessment of upper and lower airway infection and inflammation in CF patients. AB - BACKGROUND: The upper (UAW) and lower (LAW) airways of patients with cystic fibrosis (CF) have the same ion-channel defects, but little is known about similarities and differences in host immunological responses at the two levels. AIM: Identification and comparison of both levels' pathogen colonization and resulting immunological host responses. METHODS: The UAW and LAW of 40 CF patients were non-invasively assessed by nasal lavage and induced sputum. Pathogen colonization, cytology, and the concentrations of inflammatory mediators (TNF-alpha, MPO, matrix metalloprotease (MMP)-9, tissue inhibitor of metalloprotease (TIMP)-1, regulated upon activation, normal T-cell expressed and presumably secreted (RANTES), and interleukin (IL)-1beta, -5, -6, -8, and -10) were measured. RESULTS: Inflammatory responses were more pronounced in the LAW than the UAW. Pseudomonas aeruginosa LAW colonization is accompanied by a significantly enhanced neutrophil (PMN)-dominated response (P = 0.041) and IL-8 concentration (P = 0.01) not observed in P. aeruginosa UAW colonization. In contrast, sinonasal P. aeruginosa colonization resulted in elevated RANTES (P = 0.039) and reduced MMP-9 (P = 0.023) and TIMP-1 (P = 0.035) concentrations. Interestingly, LAW P. aeruginosa colonization was associated with reduced sinonasal concentrations of MMP-9 (P = 0.01) and TIMP-1 (P = 0.02), a finding independent of UAW colonization for MMP-9. CONCLUSION: CF UAW and LAW show distinct inflammatory profiles and differentiated responses upon P. aeruginosa colonization. Assessment of UAW colonization and MMP-9 are predictive of chronic pulmonary colonization with P. aeruginosa. Thus, this linkage between CF UAW and LAW can provide new clinical and scientific implications. PMID- 24464969 TI - An exploration of the therapeutic alliance within a telephone-based cognitive behaviour therapy for individuals with experience of psychosis. AB - OBJECTIVES: This study investigated the therapeutic alliance (TA) between clients and therapists involved in a telephone-based cognitive behaviour therapy (CBT) oriented psychological intervention for individuals experiencing psychosis. DESIGN: The telephone intervention involved recovery-focused CBT with use of a self-help guide and group intervention co-facilitated by colleagues with personal experience of psychosis. It was delivered as part of a Participant Preference Trial. METHODS: Twenty-one client/therapist dyads were examined within this study. In addition to a measure of TA, clients completed measures of depression, social functioning, symptom severity, and strength of treatment preference, while therapists completed measures related to the level of shared formulation, therapist confidence, and therapeutic change estimates. RESULTS: Therapeutic alliance levels were comparable to previously reported face-to-face psychosis intervention studies. Clients consistently reported significantly higher TA ratings compared to therapists. Depression scores and the strength of preference for treatment were significantly associated with client TA. Greater therapist perceived change was associated with higher therapist rated TA, while higher numbers of missed therapy sessions associated with lower therapist ratings. CONCLUSIONS: Telephone-based psychosis interventions may support the formation of positive relationships that are comparable to the quality of relationships developed between therapists and clients during face-to-face CBT therapy. Methodological limitations including low participant numbers and heightened risk of a Type I error necessitate caution when interpreting findings. Further research into therapist and client variables associated with TA is required. PRACTITIONER POINTS: Telephone delivered interventions to support people with psychosis-related difficulties can result in the development of a good quality TA between therapists and clients. There is a significant difference between therapist and client ratings of TA. Clients tend to score the quality of the TA significantly more highly than therapists. Providing clients with choice when participating in therapeutic interventions could potentially contribute towards improved TA reporting by clients. PMID- 24464970 TI - Alkylamine-tethered stable metal-organic framework for CO(2) capture from flue gas. AB - Different alkylamine molecules were post-synthetically tethered to the unsaturated Cr(III) centers in the metal-organic framework MIL-101. The resultant metal-organic frameworks show almost no N2 adsorption with significantly enhanced CO2 capture under ambient conditions as a result of the interaction between amine groups and CO2 molecules. Given the extraordinary stability, high CO2 uptake, ultrahigh CO2 /N2 selectivity, and mild regeneration energy, MIL-101 diethylenetriamine holds exceptional promise for post-combustion CO2 capture and CO2 /N2 separation. PMID- 24464971 TI - Loss of mismatched HLA in myeloid/NK cell precursor acute leukemia relapse after T cell-replete haploidentical hematopoietic stem cell transplantation. AB - Myeloid/natural killer cell precursor acute leukemia (MNKL) is an aggressive disease with a high relapse rate even after allogeneic hematopoietic stem cell transplantation (SCT). We report a patient with MNKL who had a donor lymphocyte infusion (DLI) for relapse after T cell-replete human leukocyte antigen (HLA) haploidentical SCT, but relapsed again 20 months later with loss of mismatched HLA. This case suggests that a strong graft-versus-leukemia effect of haploidentical SCT can be expected in MNKL patients. In the haploidentical setting, DLI should be considered for patients with relapsed leukemia whose leukemic cells have not lost HLA cell surface expression. PMID- 24464972 TI - Perspectives of employees with intellectual disabilities on themes relevant to their job satisfaction. an explorative study using photovoice. AB - BACKGROUND: This study explored the perspectives of people with intellectual disabilities on themes relevant to their job satisfaction in integrated and sheltered employment. METHOD: The photovoice method was used. Nine participants with moderate to mild intellectual disabilities, working in integrated and sheltered employment, took pictures of aspects related to their job satisfaction. Each participant was subsequently interviewed about his/her pictures. Interview transcripts were content analysed to distinguish themes. RESULTS: Nine themes were found: the nature of the work itself, working conditions, experienced job demands, social relations at work, received support, perceived autonomy, opportunities for using competencies, opportunities for growth and development and meaningfulness. All themes were applicable in integrated and sheltered employment. CONCLUSIONS: From the perspective of people with intellectual disabilities, various themes relate to their job satisfaction, either in positive or negative ways. Photovoice appeared to be a valuable approach, facilitating participants in expressing their views and providing in-depth information. PMID- 24464973 TI - Cardiovascular mortality and chronotropic incompetence in systolic heart failure: the importance of a reappraisal of current cut-off criteria. AB - AIMS: An independent role for the exercise-induced heart rate (HR) response-and specifically the chronotropic incompetence (CI)-in the prognosis of heart failure (HF) is still debated. The multicentre study reported here sought to investigate the prognostic values of HR and CI variables on cardiovascular mortality in a large cohort of systolic HF patients. METHODS AND RESULTS: A total of 1045 HF patients were recruited and prospectively followed in three Italian HF centres. The study endpoint was cardiovascular mortality. Besides a full clinical examination, each patient underwent a maximal cardiopulmonary exercise test at study enrolment. The age-predicted peak HR (%pHR) and the peak HR reserve (%pHRR) according to different cut-off values (60-80% of the maximum predicted) were adopted to identify the presence of CI. The median follow-up was 876 days (interquartile range 386-1590 days). Cardiovascular death occurred in 145 cases (13.8%). Besides LVEF, peak oxygen uptake, ventilation vs. carbon dioxide production slope, and beta-blocker therapy, the multivariate analysis showed that both %pHR and %pHRR were able to predict prognosis when considered as continuous variables. Conversely, the presence of CI was associated with the study endpoint only when the 70% (%pHR <70%, hazard ratio 1.80, confidence interval 1.24-2.61, P = 0.002; %pHRR <70%, hazard ratio 1.77, confidence interval 1.09-2.86, P = 0.020) or the 65% cut-off values (%pHR <65%, hazard ratio 2.04, confidence interval 1.34 3.10, P = 0.001; %pHRR <65%, hazard ratio 1.54, confidence interval 1.03-2.32, P = 0.038) were adopted. CONCLUSIONS: Our findings demonstrated an additive role of CI in stratifying cardiovascular mortality. Both the 65% and the 70% cut-off values, regardless of the method (%pHR and %pHRR), allow identification of HF patients with the worst prognosis, thus supporting such definitions of CI in HF. PMID- 24464974 TI - Long-term efficacy and safety of aerosolized tobramycin 300 mg/4 ml in cystic fibrosis. AB - INTRODUCTION: Aerosolized tobramycin is a standard of care for chronic Pseudomonas aeruginosa (Pa) infection in patients with cystic fibrosis (CF). OBJECTIVES: The long-term safety and efficacy of intermittent (28-day "on"/"off" cycles) inhaled tobramycin nebulization solution 300 mg/4 ml (TNS4, Bramitob((r))/Bethkis((r))) was assessed over 56 weeks in CF patients aged >=6 years having baseline 1 sec forced expiratory volume (FEV(1)) 40-80% predicted. METHODS: Patients were initially randomized in an 8-week open-label trial (core phase) to compare TNS4 (N = 159) and tobramycin 300 mg/5 ml (TNS5, TOBI((r))) (N = 165). A subset of patients continued in a 48-week, single-arm extension receiving TNS4 only. The primary endpoint of the core phase was to demonstrate the non-inferiority of TNS4 compared to TNS5 in terms of absolute change from baseline to week 4 in FEV(1) % predicted. The assessment of long-term safety was the primary purpose of the extension phase. Throughout all phases of the study, microbiological assessments, adverse events, and audiometry findings were also evaluated. RESULTS: In the core phase (N = 321), FEV(1) (% predicted) increased from baseline (absolute change) following a single on-treatment cycle for both TNS4 (7.0%) and TNS5 (7.5%) and the non-inferiority between treatments was met [difference between treatments of -0.5 (95% CI: -2.6; 1.6)]. These improvements were maintained throughout the extension phase (N = 209), ranging throughout the study between 5.1% (95% CI: 3.2; 6.9) and 8.1% (95% CI: 6.8; 9.4) compared to baseline. Pa sputum count reductions ranged between 0.6 (95% CI: 0.2; 0.9) to 2.3 (95% CI: 2.0; 2.6) log10 CFU/g throughout the 56 weeks. No remarkable safety issues were identified throughout both study phases, with similar percentages of patients reporting adverse events in the two treatment groups during the 8-week core phase [TNS4 (31.4%); TNS5 (28.0%)]. CONCLUSIONS: Overall, TNS4 demonstrated short-term clinical benefits similar to TNS5 which were maintained during the long-term use of TNS4 and was also associated with a favorable tolerability profile. PMID- 24464975 TI - The role of Pten/Akt signaling pathway involved in BPA-induced apoptosis of rat Sertoli cells. AB - Bisphenol-A (BPA), one of endocrine-disrupting chemicals, is a male reproductive toxicant. Previous studies have revealed the direct cytotoxicity of BPA in many cultured cells, such as mitotic aneuploidy in embryonic cells and somatic cells, and apoptosis in neurons and testicular Sertoli cells. To understand the action of BPA and assess its risk, the Pten/Akt pathway was investigated in cultured Sertoli cells to elucidate the mechanism of the reproductive effects of BPA. The results showed that over 50 MUM BPA treatment could decrease the viability of Sertoli cells and cause more apoptosis. In addition, BPA could induce the increase in mRNA levels of Pten and Akt. The protein level of Pten was increased; however, the protein levels of phospho-Akt and procaspase-3 were decreased after BPA exposure. Taken together, observed results suggested that the Pten/Akt pathway might be involved in the apoptotic effects of BPA on Sertoli cells. PMID- 24464976 TI - Surgical management of perihilar cholangiocarcinoma: a Khon Kaen experience. AB - Cholangiocarcinoma is the most common cancer in the northeast of Thailand. Most of the patients present when the disease is in an advanced stage. Improvement of preoperative diagnoses and surgical techniques provide more satisfactory results. Herein we reviewed our 30-year experience in management of perihilar cholangiocarcinoma in Khon Kaen northeast Thailand. Between 1982 and 2012 we reviewed four specific studies of perihilar cholangiocarcinoma in Srinagarind Hospital, Khon Kaen, Thailand. The first study focused on advanced surgical pathology and palliative surgery, which were used to treat obstructive jaundice cholangiocarcinoma patients. Long-term survival in this study was rare with a one year survival of just 15%. The second study was conducted on 30 consecutive cases of perihilar cholangiocarcinoma who presented with obstructive jaundice without preoperative biliary drainage. All the patients underwent major liver resection with bilio-enteric reconstruction. Perioperative mortality was 6.7% without a 5 year survival. The third study aimed to analyze the survival rates and factors affecting survival in extrahepatic CCA patients following surgical treatment at Srinagarind Hospital and concluded that resection margins are an important prognostic factor. The last study objective was the analysis of curative surgical attempt in 99 consecutive perihilar cholangiocarcinoma and results showed that R0 resection could improve long-term survival. We evaluated four studies of perihilar cholangiocarcinoma in Srinagarind Hospital, Khon Kaen, Thailand from 1982-2012. Viewed chronologically there has been a progressive improvement of diagnosis and surgical treatment during the past 30 years. Despite these advances the 5-year survival rate remains unsatisfactorily low. Future improvement of patient selection and surgical techniques can lead to a greater survival rate for patients. PMID- 24464977 TI - Preventing severe respiratory syncytial virus disease: passive, active immunisation and new antivirals. AB - In most high-income countries palivizumab prophylaxis is considered safe, efficacious and cost-effective for preventing respiratory syncytial virus (RSV) hospital admissions among specific subgroups of infants born preterm, with chronic lung disease or with congenital heart disease. Virtually all babies acquire RSV during infancy and previously healthy babies are not eligible to receive palivizumab. Emerging evidence suggests some benefit of palivizumab use in reducing recurrent wheeze among infants born preterm. Better longitudinal studies are needed to examine its clinical and cost-effectiveness on recurrent and chronic respiratory illness and associated healthcare burden on resources in the community and hospitals. Since 99% of child deaths attributed to RSV occur in resource poor countries where expensive prophylaxis is not available or affordable, palivizumab has limited potential to impact on the current global burden of RSV lower respiratory tract infection (LRTI). A range of candidate vaccines for active immunisation against RSV are now in clinical trials. Two promising new antivirals are also currently in phase I/II trials to test their effectiveness in preventing severe RSV LRTI. These agents may be effective in preventing severe disease and phase III studies are in development. In the absence of effective active immunisation against RSV infection, population level approaches to prevent severe RSV LRTI should continue to focus on reducing prenatal and environmental risk factors including prematurity, smoking and improving hygiene practices. PMID- 24464978 TI - Gene therapy in cystic fibrosis. AB - The principal cause of morbidity and mortality in cystic fibrosis (CF) is pulmonary disease, so the focus of new treatments in this condition is primarily targeted at the lungs. Since the cloning of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene in 1989, there has been significant interest in the possibility of gene therapy as a treatment for CF. Early studies using viral vectors carrying a healthy CFTR plasmid highlighted the difficulties with overcoming the body's host defences. This article reviews the work on gene therapy in CF to date and describes the ongoing work of the UK CF Gene Therapy Consortium in investigating the potential of gene therapy as a treatment for patients with CF. PMID- 24464979 TI - The impact of kidney function on outcomes following high risk myocardial infarction: findings from 27 610 patients. AB - AIMS: Renal dysfunction is associated with poor cardiovascular outcome. We investigated the relationship of kidney function and long-term cardiovascular outcomes in patients with high risk myocardial infarction. METHODS AND RESULTS: We studied 27 610 patients from four randomized trials of acute myocardial infarction complicated by heart failure and/or LV dysfunction (LVEF <=40%). Two trials excluded patients with serum creatinine >=2.5 mg/dL. Patients were grouped by estimated glomerular filtration rate (eGFR) using the four-component Modification of Diet in Renal Disease equation. We used adjusted Cox proportional hazard models to compare mortality and composite cardiovascular events among eGFR groups. Median follow-up was 23 months. The eGFR was approximately normally distributed, with a mean +/- SD of 69.1 +/- 20.2 mL/min/1.73 m(2) . Co morbidities were more prevalent with lower eGFR. The risk of death or composite outcome of cardiovascular death, myocardial infarction, stroke, or heart failure hospitalization increased with declining eGFR. Below 75 mL/min/1.73 m(2) , each 10 unit reduction of eGFR was associated with an adjusted hazard ratio for death of 1.13 (95% confidence interval, 1.11-1.15) and composite cardiovascular outcome of 1.09 (95% confidence interval, 1.08-1.10). Older patients (>=75 years) with low LVEF (<30%) had a higher incidence of mortality and adverse cardiovascular events across eGFR categories. CONCLUSIONS: Reduced eGFR is strongly and independently associated with poor cardiovascular outcome following high risk myocardial infarction. In these patients, the combination of older age and poor LV systolic function is associated with increased risk of adverse events. PMID- 24464980 TI - Multilayer films by blending heparin with semisynthetic cellulose sulfates: Physico-chemical characterization and cell responses. AB - Here, we report fabrication of polyelectrolyte multilayers by blending a natural glycosaminoglycan (heparin) with semisynthetic cellulose sulfates as polyanions paired with polycation chitosan. Two types of polyanionic blends were prepared by mixing heparin with either cellulose sulfates (CS) of high (CS2.6) or intermediate (CS1.6) sulfation degree in equal mass ratios. Multilayer growth was monitored by surface plasmon resonance (SPR) and quartz crystal micro balance with dissipation monitoring (QCM-D) where as surface wettability was measured by water contact angle measurements (WCA). Both SPR and QCM-D showed differences in biomolecular mass adsorption and dissipation values for different multilayers and also helped in estimating the hydration levels of layers. WCA indicated arrangement of polyanion and polycation layers within the multilayer systems, weather distinct layers, or more intermingled multilayers were established. Overall physico-chemical characterization data suggested a dominating incorporation of heparin over CS in blend multilayer systems. Biological interactions of these blend multilayers investigated with C2C12 cells also indicated a leading contribution of heparin in the blend systems. This current study suggested that heparin was preferentially incorporated over CS that are highly sulfated and points towards the dominance of carboxylic groups over sulfate groups in interacting with amino groups of chitosan. PMID- 24464981 TI - Cardiorespiratory fitness and risk of heart failure: a population-based follow-up study. AB - AIM: To examine the relationship between cardiorespiratory fitness (CRF) and risk of incident heart failure (HF). METHODS AND RESULTS: Cardiorespiratory fitness, as measured by maximal oxygen uptake (VO2 max), was assessed at baseline in a prospective cohort of 1873 men aged 42-61 years without HF or chronic respiratory disease. During a mean follow-up of 20.4 years, 152 incident HF events were recorded. Within-person variability was calculated using data from repeat measurements taken 11 years apart. The age-adjusted hazard ratio (HR) per unit increase (1 mL/kg/min of VO2 max) in CRF was 0.89 [95% confidence interval (CI) 0.86-0.93], which was minimally attenuated to 0.94 (95% CI 0.90-0.98) after further adjustment for established HF risk factors (body mass index, systolic blood pressure, history of cardiovascular disease, diabetes, heart rate, and LV hypertrophy) and incident coronary events as a time-varying covariate. In a comparison of extreme quartiles of CRF levels (VO2 max >=35.4 vs. <=25.7 mL/kg/min), the corresponding HRs were 0.27 (0.15-0.50) and 0.48 (0.25-0.92), respectively. Each 1 MET (metabolic equivalent of oxygen consumption) increment in CRF was associated with a 21% (7-33%) reduction in multivariable adjusted risk of HF. Addition of CRF to a HF risk prediction model containing established risk factors did not significantly improve risk discrimination (C-index change = 0.0164, P = 0.07). CONCLUSIONS: In this Finnish population, there is a strong, inverse, and independent association between long-term CRF and HF risk, consistent with a dose-response relationship. The protective effect of CRF on HF risk warrants further evaluation. PMID- 24464982 TI - Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer's disease: studies in animal models. AB - A growing body of animal and epidemiological studies suggest that metabolic diseases such as obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus are associated with the development of cognitive impairment, dementia and Alzheimer's disease, particularly in aging. Several lines of evidence suggest that insulin signalling dysfunction produces these metabolic alterations and underlie the development of these neurodegenerative diseases. In this article, we address normal insulin function in the synapse; we review and discuss the physiopathological hallmarks of synaptic insulin signalling dysfunction associated with metabolic alterations. Additionally, we describe and review the major animal models of obesity, insulin resistance, metabolic syndrome and type 2 diabetes mellitus. The comprehensive knowledge of the molecular mechanisms behind the association of metabolic alterations and cognitive impairment could facilitate the early detection of neurodegenerative diseases in patients with metabolic alterations, with treatment that focus on neuroprotection. It could also help in the development of metabolic-based therapies and drugs for using in dementia and Alzheimer's disease patients to alleviate their symptoms in a more efficient and comprehensive way. PMID- 24464983 TI - Discrepancy between echocardiographic and patient-reported health status response to cardiac resynchronization therapy: results of the PSYHEART-CRT study. AB - AIMS: The current study examined the degree of agreement between echocardiographic and patient-reported health status response to CRT 6 months after implantation, and evaluated the differences in pre-implantation characteristics of patients with concordant and discordant echocardiographic and health status responses. METHODS AND RESULTS: Consecutively implanted CRT defibrillator patients (n = 109, mean age = 65.4 +/- 10.1 years, 74 men) were recruited from the University Medical Center Utrecht, The Netherlands. Prior to implantation and 6 months post-implantation, all patients underwent echocardiography and completed the Kansas City Cardiomyopathy Questionnaire (KCCQ). Echocardiographic response was defined as a relative reduction of >=15% in LV end-systolic volume; an improvement of >=10 points in KCCQ score indicated a health status response. In the 54 patients with discordant responses, 25 (22.9%) had an echocardiographic response but no health status response and 29 (26.6%) had a health status response but no echocardiographic response. Patients with concordant and discordant responses differed on various pre-implantation characteristics, including sex, employment status, LV volumes, and pre implantation KCCQ score. In multivariable analysis, pre-implantation KCCQ score [odds ratio (OR) = 0.91, 95% confidence interval (CI) = 0.88-0.95, P < 0.001] and QRS duration (OR = 1.03, 95% CI = 1.01-1.06, P = 0.009) were the only characteristics associated with health status response to CRT. CONCLUSIONS: Our results show a large discrepancy between echocardiographic and patient-reported health status response to CRT. The most important predictor of health status response was the pre-implantation health status score. These results emphasize that disease-specific health status measures may have additional value over 'objective' measures of CRT response and should be incorporated in clinical practice. PMID- 24464984 TI - Oncological benefit of preoperative endoscopic biliary drainage in patients with hilar cholangiocarcinoma. AB - Due to advances in endoscopic equipment and techniques, preoperative endoscopic biliary drainage (EBD) has been developed to serve as an alternative to percutaneous transhepatic biliary drainage (PTBD). This study sought to clarify the benefit of EBD in comparison to PTBD in patients who underwent radical resections of hilar cholangiocarcinoma. One hundred and forty-one patients underwent radical surgery for hilar cholangiocarcinoma between 2000 and 2008 were retrospectively divided into two groups based on the type of preoperative biliary drainage, PTBD (n = 67) or EBD (n = 74). We investigated if the different biliary drainage methods affected postoperative survival and mode of recurrence after median observation period of 82 months. The survival rate for patients who underwent EBD was significantly higher than those who had PTBD (P = 0.004). Multivariate analysis revealed that PTBD was one of the independent factors predictive of poor survival (hazard ratio: 2.075, P = 0.003). Patients with PTBD more frequently developed peritoneal seeding in comparison to those who underwent EBD (P = 0.0003). PTBD was the only independent factor predictive of peritoneal seeding. In conclusion, EBD might confer an improved prognosis over PTBD due to prevention of peritoneal seeding, and is recommended as the initial procedure for preoperative biliary drainage in patients with hilar cholangiocarcinoma. PMID- 24464985 TI - Determination of the in vivo degradation mechanism of PEGDA hydrogels. AB - Poly(ethylene glycol) (PEG) hydrogels are one of the most extensively utilized biomaterials systems due to their established biocompatibility and highly tunable properties. It is widely acknowledged that traditional acrylate-derivatized PEG (PEGDA) hydrogels are susceptible to slow degradation in vivo and are therefore unsuitable for long-term implantable applications. However, there is speculation whether the observed degradation is due to hydrolysis of endgroup acrylate esters or oxidation of the ether backbone, both of which are possible in the foreign body response to implanted devices. PEG diacrylamide (PEGDAA) is a polyether based hydrogel system with similar properties to PEGDA but with amide linkages in place of the acrylate esters. This provides a hydrolytically-stable control that can be used to isolate the relative contributions of hydrolysis and oxidation to the in vivo degradation of PEGDA. Here we show that PEGDAA hydrogels remained stable over 12 weeks of subcutaneous implantation in a rat model while PEGDA hydrogels underwent significant degradation as indicated by both increased swelling ratio and decreased modulus. As PEGDA and PEGDAA have similar susceptibility to oxidation, these results demonstrate for the first time that the primary in vivo degradation mechanism of PEGDA is hydrolysis of the endgroup acrylate esters. Additionally, the maintenance of PEGDAA hydrogel properties in vivo indicates their suitability for long-term implants. These studies serve to elucidate key information about a widely used biomaterial system to allow for better implantable device design and to provide a biostable replacement option for PEGDA in applications that require long-term stability. PMID- 24464986 TI - Response of filopodia and lamellipodia to surface topography on micropatterned silk fibroin films. AB - Cell-microstructure surface interactions play a significant role in tissue engineering to guide cell spreading and migration. However, the mechanisms underlying cell-topography interactions are complex and remain elusive. To address this topic, microsphere array patterns were prepared on silk fibroin films through polystyrene microsphere self-assembly, followed by culturing rat bone marrow derived mesenchymal stem cells on the films to study cell-substrate interactions. Filopodia sensed and anchored to the microspheres to form initial attachments before spreading. Importantly, the anchored filopodia converted into lamellipodia, and this conversion initiated the directional formation of lamellipodia. Therefore, the conversion of exploratory filopodia into lamellipodia was the main driving force for directional extension of the lamellipodia. Correspondingly, cell spreading, morphology, and migration were modulated by pseudopodial recognition and conversion. This finding demonstrated that filopodia not only act as an antenna to detect microenvironment but also serve as skeleton to guide lamellipodial extension for directing cell motions. The micropatterned films promoted cell adhesion and proliferation due to accelerated lamellipodia formation and cell spreading, with recognition and conversion of filopodia into lamellipodia as a critical role in cell response to surface topography. PMID- 24464987 TI - Review of hepatopancreatoduodenectomy for biliary cancer: an extended radical approach of Japanese origin. AB - Cholangiocarcinomas exhibit various modes of local extension, and some tumors can only be completely resected by hepatopancreatoduodenectomy (HPD), which is defined as the resection of the whole extrahepatic biliary system with the adjacent liver and pancreatoduodenum. Since Takasaki et al. introduced HPD for locally advanced gallbladder cancer in 1980, Japanese hepatobiliary surgeons have aggressively challenged this extended procedure for advanced biliary tumors. Early experiences with HPD were frequently associated with liver failure and sequential mortality, leading to an underestimation of the survival benefit of HPD. However, with improvements in surgical techniques and perioperative patient care, including portal vein embolization, over the last two decades, the mortality rate after HPD has gradually decreased. Recent studies have demonstrated a favorable survival in cholangiocarcinoma, provided that R0 resection is achieved. In contrast, HPD for gallbladder cancer remains controversial because of the extremely poor survival, although the study populations have been limited. HPD can be performed with low mortality and offers a better probability of long-term survival in patients with cholangiocarcinoma. We should consider HPD to be a standard approach for laterally advanced cholangiocarcinomas that are otherwise unresectable. PMID- 24464988 TI - Lack of consensus on tests and criteria for generalized joint hypermobility, Ehlers-Danlos syndrome: hypermobile type and joint hypermobility syndrome. AB - The objectives of this study were to register clinicians performance and opinion of importance of clinical tests for generalized joint hypermobility (GJH), Ehlers Danlos syndrome, hypermobility type (EDS-HT) and joint hypermobility syndrome (JHS), and to reach a consensus among clinicians on criteria for diagnosing GJH, EDS-HT and JHS. A panel of clinicians answered questions about how to perform and interpret clinical tests and rated test importance on an 11-box scale. The questionnaire was developed on the basis of information from focus groups and the literature. Cronbach's alpha was used as a measure of internal consistency/consensus among the panelists. The results showed Cronbach's alpha on importance score of items for diagnosing GJH, EDS-HT and JHS was 0.61, 0.79, and 0.44, respectively. Panelist-group correlation for the three conditions varied substantially (-0.46 to 0.89, 0.03 to 0.68, and -0.07 to 0.68) indicating heterogeneity among the panelists. There was agreement on which tests to use, but performance of the tests (i.e., the specific maneuvers) varied considerably inclusive use of tests with unknown reliability. Furthermore, agreement on the diagnostic criteria varied. We conclude that the level of consensus for the importance of various items for diagnosing GJH, EDS-HT and JHS, was below the required limit (Cronbach's alpha >0.90) for clinical decision-making and diagnosing. Consensus on tests and criteria through a Delphi process could not be reached. Better descriptions of, and reliability studies on, test maneuvers and criteria sets for these conditions are needed. Subsequent intensive training and implementation of these tests and criteria, nationally as well as internationally should be established. PMID- 24464989 TI - Recent advances in 3D computed tomography techniques for simulation and navigation in hepatobiliary pancreatic surgery. AB - A few years ago it could take several hours to complete a 3D image using a 3D workstation. Thanks to advances in computer science, obtaining results of interest now requires only a few minutes. Many recent 3D workstations or multimedia computers are equipped with onboard 3D virtual patient modeling software, which enables patient-specific preoperative assessment and virtual planning, navigation, and tool positioning. Although medical 3D imaging can now be conducted using various modalities, including computed tomography (CT), magnetic resonance imaging (MRI), positron emission tomography (PET), and ultrasonography (US) among others, the highest quality images are obtained using CT data, and CT images are now the most commonly used source of data for 3D simulation and navigation image. If the 2D source image is bad, no amount of 3D image manipulation in software will provide a quality 3D image. In this exhibition, the recent advances in CT imaging technique and 3D visualization of the hepatobiliary and pancreatic abnormalities are featured, including scan and image reconstruction technique, contrast-enhanced techniques, new application of advanced CT scan techniques, and new virtual reality simulation and navigation imaging. PMID- 24464990 TI - A variant within FGF1 is associated with Alzheimer's disease in the Han Chinese population. AB - Alzheimer's disease (AD) is the most common neurodegenerative disorder characterized by the accumulation of amyloid beta (Abeta) plaques and Tau containing neurofibrillary tangles in vulnerable brain areas. The progression of AD is well correlated with hippocampal neuron loss which highly suggests genes associated with neuron survival would be important for AD pathogenesis. According to the recent results of genome-wide association studies (GWAS) and other reported studies, we selected two single nucleotide polymorphisms (SNPs), rs3765728 within tumor protein p73 (P73), and rs34011 within fibroblast growth factor 1 (FGF1), both genes were related to neuron survival. We analyzed the distribution of rs3765728 and rs34011 in 1,083 Chinese subjects including 429 unrelated sporadic AD patients and 654 unrelated age and gender-matched control subjects. We found that the genotype distribution of rs34011 was significantly different between AD and control group (chi(2) = 9.048, df = 2, P = 0.011). Logistic regression manifested the risk of AD increased in TT genotype carriers in total subjects (Wald = 8.892, df = 1, P = 0.003, odds ratio [OR]:2.009, 95% confidence interval [95%CI]: 1.270-3.178). This effect was also found in APOE epsilon4 carrier group (Wald = 7.844, df = 1, P = 0.005, OR: 4.201, 95%CI: 1.539 11.472), suggesting the rs34011 has a synergetic effect of APOE on AD risk. However, no association was observed between rs3765728 and AD in the Han Chinese population (chi(2) = 0.431, df = 2, P = 0.806). PMID- 24464992 TI - Interplay between pre-mRNA splicing and microRNA biogenesis within the supraspliceosome. AB - MicroRNAs (miRNAs) are central regulators of gene expression, and a large fraction of them are encoded in introns of RNA polymerase II transcripts. Thus, the biogenesis of intronic miRNAs by the microprocessor and the splicing of their host introns by the spliceosome require coordination between these processing events. This cross-talk is addressed here. We show that key microprocessor proteins Drosha and DGCR8 as well as pre-miRNAs cosediment with supraspliceosomes, where nuclear posttranscriptional processing is executed. We further show that inhibition of splicing increases miRNAs expression, whereas knock-down of Drosha increases splicing. We identified a novel splicing event in intron 13 of MCM7, where the miR-106b-25 cluster is located. The unique splice isoform includes a hosted pre-miRNA in the extended exon and excludes its processing. This indicates a possible mechanism of altering the levels of different miRNAs originating from the same transcript. Altogether, our study indicates interplay between the splicing and microprocessor machineries within a supraspliceosome context. PMID- 24464993 TI - Persistently stalled replication forks inhibit nucleotide excision repair in trans by sequestering Replication protein A. AB - Rev3, the catalytic subunit of DNA polymerase zeta, is essential for translesion synthesis of cytotoxic DNA photolesions, whereas the Rev1 protein plays a noncatalytic role in translesion synthesis. Here, we reveal that mammalian Rev3( /-) and Rev1(-/-) cell lines additionally display a nucleotide excision repair (NER) defect, specifically during S phase. This defect is correlated with the normal recruitment but protracted persistence at DNA damage sites of factors involved in an early stage of NER, while repair synthesis is affected. Remarkably, the NER defect becomes apparent only at 2 h post-irradiation indicating that Rev3 affects repair synthesis only indirectly, rather than performing an enzymatic role in NER. We provide evidence that the NER defect is caused by scarceness of Replication protein A (Rpa) available to NER, resulting from its sequestration at stalled replication forks. Also the induction of replicative stress using hydroxyurea precludes the accumulation of Rpa at photolesion sites, both in Rev3(-/-) and in wild-type cells. These data support a model in which the limited Rpa pool coordinates replicative stress and NER, resulting in increased cytotoxicity of ultraviolet light when replicative stress exceeds a threshold. PMID- 24464994 TI - Computational modeling identifies key gene regulatory interactions underlying phenobarbital-mediated tumor promotion. AB - Gene regulatory interactions underlying the early stages of non-genotoxic carcinogenesis are poorly understood. Here, we have identified key candidate regulators of phenobarbital (PB)-mediated mouse liver tumorigenesis, a well characterized model of non-genotoxic carcinogenesis, by applying a new computational modeling approach to a comprehensive collection of in vivo gene expression studies. We have combined our previously developed motif activity response analysis (MARA), which models gene expression patterns in terms of computationally predicted transcription factor binding sites with singular value decomposition (SVD) of the inferred motif activities, to disentangle the roles that different transcriptional regulators play in specific biological pathways of tumor promotion. Furthermore, transgenic mouse models enabled us to identify which of these regulatory activities was downstream of constitutive androstane receptor and beta-catenin signaling, both crucial components of PB-mediated liver tumorigenesis. We propose novel roles for E2F and ZFP161 in PB-mediated hepatocyte proliferation and suggest that PB-mediated suppression of ESR1 activity contributes to the development of a tumor-prone environment. Our study shows that combining MARA with SVD allows for automated identification of independent transcription regulatory programs within a complex in vivo tissue environment and provides novel mechanistic insights into PB-mediated hepatocarcinogenesis. PMID- 24464995 TI - The crystal structure of TDP-43 RRM1-DNA complex reveals the specific recognition for UG- and TG-rich nucleic acids. AB - TDP-43 is an important pathological protein that aggregates in the diseased neuronal cells and is linked to various neurodegenerative disorders. In normal cells, TDP-43 is primarily an RNA-binding protein; however, how the dimeric TDP 43 binds RNA via its two RNA recognition motifs, RRM1 and RRM2, is not clear. Here we report the crystal structure of human TDP-43 RRM1 in complex with a single-stranded DNA showing that RRM1 binds the nucleic acid extensively not only by the conserved beta-sheet residues but also by the loop residues. Mutational and biochemical assays further reveal that both RRMs in TDP-43 dimers participate in binding of UG-rich RNA or TG-rich DNA with RRM1 playing a dominant role and RRM2 playing a supporting role. Moreover, RRM1 of the amyotrophic lateral sclerosis-linked mutant D169G binds DNA as efficiently as the wild type; nevertheless, it is more resistant to thermal denaturation, suggesting that the resistance to degradation is likely linked to TDP-43 proteinopathies. Taken together all the data, we suggest a model showing that the two RRMs in each protomer of TDP-43 homodimer work together in RNA binding and thus the dimeric TDP-43 recognizes long clusters of UG-rich RNA to achieve high affinity and specificity. PMID- 24464996 TI - Differential RISC association of endogenous human microRNAs predicts their inhibitory potential. AB - It has previously been assumed that the generally high stability of microRNAs (miRNAs) reflects their tight association with Argonaute (Ago) proteins, essential components of the RNA-induced silencing complex (RISC). However, recent data have suggested that the majority of mature miRNAs are not, in fact, Ago associated. Here, we demonstrate that endogenous human miRNAs vary widely, by >100-fold, in their level of RISC association and show that the level of Ago binding is a better indicator of inhibitory potential than is the total level of miRNA expression. While miRNAs of closely similar sequence showed comparable levels of RISC association in the same cell line, these varied between different cell types. Moreover, the level of RISC association could be modulated by overexpression of complementary target mRNAs. Together, these data indicate that the level of RISC association of a given endogenous miRNA is regulated by the available RNA targetome and predicts miRNA function. PMID- 24464997 TI - MLV integration site selection is driven by strong enhancers and active promoters. AB - Retroviruses integrate into the host genome in patterns specific to each virus. Understanding the causes of these patterns can provide insight into viral integration mechanisms, pathology and genome evolution, and is critical to the development of safe gene therapy vectors. We generated murine leukemia virus integrations in human HepG2 and K562 cells and subjected them to second generation sequencing, using a DNA barcoding technique that allowed us to quantify independent integration events. We characterized >3,700,000 unique integration events in two ENCODE-characterized cell lines. We find that integrations were most highly enriched in a subset of strong enhancers and active promoters. In both cell types, approximately half the integrations were found in <2% of the genome, demonstrating genomic influences even narrower than previously believed. The integration pattern of murine leukemia virus appears to be largely driven by regions that have high enrichment for multiple marks of active chromatin; the combination of histone marks present was sufficient to explain why some strong enhancers were more prone to integration than others. The approach we used is applicable to analyzing the integration pattern of any exogenous element and could be a valuable preclinical screen to evaluate the safety of gene therapy vectors. PMID- 24464998 TI - The RNase H-like superfamily: new members, comparative structural analysis and evolutionary classification. AB - Ribonuclease H-like (RNHL) superfamily, also called the retroviral integrase superfamily, groups together numerous enzymes involved in nucleic acid metabolism and implicated in many biological processes, including replication, homologous recombination, DNA repair, transposition and RNA interference. The RNHL superfamily proteins show extensive divergence of sequences and structures. We conducted database searches to identify members of the RNHL superfamily (including those previously unknown), yielding >60 000 unique domain sequences. Our analysis led to the identification of new RNHL superfamily members, such as RRXRR (PF14239), DUF460 (PF04312, COG2433), DUF3010 (PF11215), DUF429 (PF04250 and COG2410, COG4328, COG4923), DUF1092 (PF06485), COG5558, OrfB_IS605 (PF01385, COG0675) and Peptidase_A17 (PF05380). Based on the clustering analysis we grouped all identified RNHL domain sequences into 152 families. Phylogenetic studies revealed relationships between these families, and suggested a possible history of the evolution of RNHL fold and its active site. Our results revealed clear division of the RNHL superfamily into exonucleases and endonucleases. Structural analyses of features characteristic for particular groups revealed a correlation between the orientation of the C-terminal helix with the exonuclease/endonuclease function and the architecture of the active site. Our analysis provides a comprehensive picture of sequence-structure-function relationships in the RNHL superfamily that may guide functional studies of the previously uncharacterized protein families. PMID- 24464999 TI - Correction of sequence-dependent ambiguous bases (Ns) from the 454 pyrosequencing system. AB - Pyrosequencing of the 16S ribosomal RNA gene (16S) has become one of the most popular methods to assess microbial diversity. Pyrosequencing reads containing ambiguous bases (Ns) are generally discarded based on the assumptions of their non-sequence-dependent formation and high error rates. However, taxonomic composition differed by removal of reads with Ns. We determined whether Ns from pyrosequencing occur in a sequence-dependent manner. Our reads and the corresponding flow value data revealed occurrence of sequence-specific N errors with a common sequential pattern (a homopolymer + a few nucleotides with bases other than the homopolymer + N) and revealed that the nucleotide base of the homopolymer is the true base for the following N. Using an algorithm reflecting this sequence-dependent pattern, we corrected the Ns in the 16S (86.54%), bphD (81.37%) and nifH (81.55%) amplicon reads from a mock community with high precisions of 95.4, 96.9 and 100%, respectively. The new N correction method was applicable for determining most of Ns in amplicon reads from a soil sample, resulting in reducing taxonomic biases associated with N errors and in shotgun sequencing reads from public metagenome data. The method improves the accuracy and precision of microbial community analysis and genome sequencing using 454 pyrosequencing. PMID- 24465001 TI - Sorafenib: is a partial response and stabilization of disease greater than 70% a modest response? AB - Extract: Dear Editors, I read with great interest the recently published meta analysis on sorafenib use in patients with radioiodine refractory thyroid cancer (Shen et al. 2013). In this study, 7 investigations were analyzed and pooled results showed than more than 70% of patients achieved a partial response (PR) or stabilization of disease (SD) with a median progression free survival of one year. Also, the authors showed than around 80% of patients presented side effects when all grades adverse events (AE) were considered. The authors concluded that sorafenib showed only a modest effect in patients with advanced thyroid cancer. I wonder if 70% of PR plus SD would be considered as a modest response to treatment in patients with advanced progressive disease with few other therapeutic options available at this moment. PMID- 24465000 TI - MLL fusion proteins link transcriptional coactivators to previously active CpG rich promoters. AB - Mixed-lineage leukemia (MLL) maintains the expression of cellular memory genes during development, while leukemic MLL fusion proteins aberrantly maintain expression of hematopoietic stem cell program genes such as HOXA9 to cause leukemia. However, the molecular mechanism of gene activation is unclear. Here we show that only two functional modules are necessary and sufficient for target recognition: those that bind to non-methylated CpGs and di-/tri-methylated histone H3 lysine 36 (H3K36me2/3). An artificial protein composed of the two targeting modules and an interaction domain for AF4-family coactivators can functionally substitute for MLL fusion proteins. Because H3K36me2/3 markers are indicative of active transcription, MLL fusion proteins target previously active CpG-rich genes and activate transcription by recruiting coactivators thereto. Our results indicate that such chromatin context-dependent gene activation is the fundamental mechanism by which MLL fusion proteins maintain the expression of the cellular memory/hematopoietic stem cell program genes. PMID- 24465002 TI - Transcription factor RFX1 is crucial for maintenance of genome integrity in Fusarium graminearum. AB - The survival of cellular organisms depends on the faithful replication and transmission of DNA. Regulatory factor X (RFX) transcription factors are well conserved in animals and fungi, but their functions are diverse, ranging from the DNA damage response to ciliary gene regulation. We investigated the role of the sole RFX transcription factor, RFX1, in the plant-pathogenic fungus Fusarium graminearum. Deletion of rfx1 resulted in multiple defects in hyphal growth, conidiation, virulence, and sexual development. Deletion mutants of rfx1 were more sensitive to various types of DNA damage than the wild-type strain. Septum formation was inhibited and micronuclei were produced in the rfx1 deletion mutants. The results of the neutral comet assay demonstrated that disruption of rfx1 function caused spontaneous DNA double-strand breaks (DSBs). The transcript levels of genes involved in DNA DSB repair were upregulated in the rfx1 deletion mutants. DNA DSBs produced micronuclei and delayed septum formation in F. graminearum. Green fluorescent protein (GFP)-tagged RFX1 localized in nuclei and exhibited high expression levels in growing hyphae and conidiophores, where nuclear division was actively occurring. RNA-sequencing-based transcriptomic analysis revealed that RFX1 suppressed the expression of many genes, including those required for the repair of DNA damage. Taken together, these findings indicate that the transcriptional repressor rfx1 performs crucial roles during normal cell growth by maintaining genome integrity. PMID- 24465004 TI - Large-scale reconstruction of 3D structures of human chromosomes from chromosomal contact data. AB - Chromosomes are not positioned randomly within a nucleus, but instead, they adopt preferred spatial conformations to facilitate necessary long-range gene-gene interactions and regulations. Thus, obtaining the 3D shape of chromosomes of a genome is critical for understanding how the genome folds, functions and how its genes interact and are regulated. Here, we describe a method to reconstruct preferred 3D structures of individual chromosomes of the human genome from chromosomal contact data generated by the Hi-C chromosome conformation capturing technique. A novel parameterized objective function was designed for modeling chromosome structures, which was optimized by a gradient descent method to generate chromosomal structural models that could satisfy as many intra chromosomal contacts as possible. We applied the objective function and the corresponding optimization method to two Hi-C chromosomal data sets of both a healthy and a cancerous human B-cell to construct 3D models of individual chromosomes at resolutions of 1 MB and 200 KB, respectively. The parameters used with the method were calibrated according to an independent fluorescence in situ hybridization experimental data. The structural models generated by our method could satisfy a high percentage of contacts (pairs of loci in interaction) and non-contacts (pairs of loci not in interaction) and were compatible with the known two-compartment organization of human chromatin structures. Furthermore, structural models generated at different resolutions and from randomly permuted data sets were consistent. PMID- 24465003 TI - The RSC chromatin remodeling complex has a crucial role in the complete remodeler set for yeast PHO5 promoter opening. AB - Although yeast PHO5 promoter chromatin opening is a founding model for chromatin remodeling, the complete set of involved remodelers remained unknown for a long time. The SWI/SNF and INO80 remodelers cooperate here, but nonessentially, and none of the many tested single or combined remodeler gene mutations could prevent PHO5 promoter opening. RSC, the most abundant and only remodeler essential for viability, was a controversial candidate for the unrecognized remodeling activity but unassessed in vivo. Now we show that remodels the structure of chromatin (RSC) is crucially involved in PHO5 promoter opening. Further, the isw1 chd1 double deletion also delayed chromatin remodeling. Strikingly, combined absence of RSC and Isw1/Chd1 or Snf2 abolished for the first time promoter opening on otherwise sufficient induction in vivo. Together with previous findings, we recognize now a surprisingly complex network of five remodelers (RSC, SWI/SNF, INO80, Isw1 and Chd1) from four subfamilies (SWI/SNF, INO80, ISWI and CHD) as involved in PHO5 promoter chromatin remodeling. This is likely the first described complete remodeler set for a physiological chromatin transition. RSC was hardly involved at the coregulated PHO8 or PHO84 promoters despite cofactor recruitment by the same transactivator and RSC's presence at all three promoters. Therefore, promoter-specific chromatin rather than transactivators determine remodeler requirements. PMID- 24465006 TI - The effect of hyperkalaemia on cardiac rhythm devices. AB - In patients with pacemakers, hyperkalaemia causes three important abnormalities that usually become manifest when the K level exceeds 7 mEq/L: (i) widening of the paced QRS complex from delayed intraventricular conduction velocity, (ii) Increased atrial and ventricular pacing thresholds that may cause failure to capture. In this respect, the atria are more susceptible to loss of capture than the ventricles, and (iii) Increased latency (usually with ventricular pacing) manifested by a greater delay of the interval from the pacemaker stimulus to the onset of depolarization. First-degree ventricular pacemaker exit block may progress to second-degree Wenckebach (type I) exit block characterized by gradual prolongation of the interval from the pacemaker stimulus to the onset of the paced QRS complex ultimately resulting in an ineffectual stimulus. The disturbance may then progress to 2 : 1, 3 : 1 pacemaker exit block, etc., and eventually to complete exit block with total lack of capture. Ventricular undersensing is uncommonly observed because of frequent antibradycardia pacing. During managed ventricular pacing, hyperkalaemia-induced marked first-degree atrioventricular block may induce a pacemaker syndrome. With implantable cardioverter-defibrillators (ICDs) oversensing of the paced or spontaneous T-wave may occur. The latter may cause inappropriate shocks. A raised impedance from the right ventricular coil to the superior vena cava coil may become an important sign of hyperkalaemia in the asymptomatic or the minimally symptomatic ICD patient. PMID- 24465005 TI - A widespread bacteriophage abortive infection system functions through a Type IV toxin-antitoxin mechanism. AB - Bacterial abortive infection (Abi) systems are 'altruistic' cell death systems that are activated by phage infection and limit viral replication, thereby providing protection to the bacterial population. Here, we have used a novel approach of screening Abi systems as a tool to identify and characterize toxin antitoxin (TA)-acting Abi systems. We show that AbiE systems are encoded by bicistronic operons and function via a non-interacting (Type IV) bacteriostatic TA mechanism. The abiE operon was negatively autoregulated by the antitoxin, AbiEi, a member of a widespread family of putative transcriptional regulators. AbiEi has an N-terminal winged-helix-turn-helix domain that is required for repression of abiE transcription, and an uncharacterized bi-functional C-terminal domain, which is necessary for transcriptional repression and sufficient for toxin neutralization. The cognate toxin, AbiEii, is a predicted nucleotidyltransferase (NTase) and member of the DNA polymerase beta family. AbiEii specifically bound GTP, and mutations in conserved NTase motifs (I-III) and a newly identified motif (IV), abolished GTP binding and subsequent toxicity. The AbiE systems can provide phage resistance and enable stabilization of mobile genetic elements, such as plasmids. Our study reveals molecular insights into the regulation and function of the widespread bi-functional AbiE Abi-TA systems and the biochemical properties of both toxin and antitoxin proteins. PMID- 24465007 TI - Removal of a chronically implanted active-fixation coronary sinus pacing lead using the Cook Evolution(C) lead extraction sheath. PMID- 24465008 TI - Expression of EpCAM(MF) and EpCAM(MT) variants in human carcinomas. AB - AIMS: Regulated intramembrane proteolysis has been shown to be an important mechanism for oncogenic activation of epithelial cell adhesion molecule (EpCAM) through nuclear translocation of the intracellular domain EpICD. Recent studies have identified new membrane-bound EpCAM variants. To evaluate the prevalence of two membranous EpCAM variants in human tumours, we performed a large-scale expression analysis using specific antibodies against the extracellular domain EpEX (MOC-31 clone) and the intracellular domain EpICD (9-2 clone) of the EpCAM antigen by immunohistochemistry. MATERIAL AND METHODS: Two multi-tissue microarrays (TMA) series containing 1564 tissue samples each of 53 different histological tumour types were stained and compared. One TMA was stained for EpEX and one for EpICD. Membranous full-length EpCAM (EpCAM(MF)) expression in tissues was defined by the expression of EpEX and EpICD, while the truncated variant of EpCAM (EpCAM(MT)) was characterised by a significant loss of membranous EpICD expression compared with EpEX expression. RESULTS: We defined tumours with high EpCAM(MT) expression (ie, cancers of the endometrium and bladder), tumours with intermediate (ie, gastric, pancreatic, colorectal and oesophageal cancer) and tumours with low rates of expression of the EpCAM(MT) variant (ie, lung, ovarian, gallbladder, breast and prostate cancer). CONCLUSIONS: Our results indicate that loss of membranous EpICD expression is a common event in human epithelial carcinomas, arguing for the expression of different degrees of EpCAM(MF) and EpCAM(MT) variants across the most important tumour entities. Future studies evaluating the prognostic and predictive role of these variants in human malignancies, especially in patients treated with EpCAM-specific antibodies, are clearly warranted. PMID- 24465010 TI - Cross-talk between reactive oxygen species and polyamines in regulation of ion transport across the plasma membrane: implications for plant adaptive responses. AB - Many stresses are associated with increased accumulation of reactive oxygen species (ROS) and polyamines (PAs). PAs act as ROS scavengers, but export of putrescine and/or PAs to the apoplast and their catabolization by amine oxidases gives rise to H2O2 and other ROS, including hydroxyl radicals ((*)OH). PA catabolization-based signalling in apoplast is implemented in plant development and programmed cell death and in plant responses to a variety of biotic and abiotic stresses. Central to ROS signalling is the induction of Ca(2+) influx across the plasma membrane. Different ion conductances may be activated, depending on ROS, plant species, and tissue. Both H2O2 and (*)OH can activate hyperpolarization-activated Ca(2+)-permeable channels. (*)OH is also able to activate both outward K(+) current and weakly voltage-dependent conductance (ROSIC), with a variable cation-to-anion selectivity and sensitive to a variety of cation and anion channel blockers. Unexpectedly, PAs potentiated (*)OH-induced K(+) efflux in vivo, as well as ROSIC in isolated protoplasts. This synergistic effect is restricted to the mature root zone and is more pronounced in salt sensitive cultivars compared with salt-tolerant ones. ROS and PAs suppress the activity of some constitutively expressed K(+) and non-selective cation channels. In addition, both (*)OH and PAs activate plasma membrane Ca(2+)-ATPase and affect H(+) pumping. Overall, (*)OH and PAs may provoke a substantial remodelling of cation and anion conductance at the plasma membrane and affect Ca(2+) signalling. PMID- 24465009 TI - Sequential action of FRUITFULL as a modulator of the activity of the floral regulators SVP and SOC1. AB - The role in flowering time of the MADS-box transcription factor fruitfulL (FUL) has been proposed in many works. FUL has been connected to several flowering pathways as a target of the photoperiod, ambient temperature, and age pathways and it is has been shown to promote flowering in a partially redundant manner with suppressor of overexpression of constans 1 (SOC1). However, the position of FUL in these genetic networks, as well as the functional output of FUL activity during floral transition, remains unclear. In this work, a genetic approach has been undertaken to understand better the functional hierarchies involving FUL and other MADS-box factors with well established roles as floral integrators such as SOC1, short vegetative phase (svp) or flowering locus C (FLC). Our results suggest a prominent role of FUL in promoting reproductive transition when photoinductive signalling is suppressed by short-day conditions or by high levels of FLC expression, as in non-vernalized winter ecotypes. A model is proposed where the sequential formation of FUL-SVP and FUL-SOC1 heterodimers may mediate the vegetative and meristem identity transitions, counteracting the repressive effect of FLC and SVP on flowering. PMID- 24465012 TI - Probiotic Lactobacillus rhamnosus inhibits the formation of neutrophil extracellular traps. AB - Neutrophil extracellular traps (NETs) are an essential component of the antimicrobial repertoire and represent an effective means by which neutrophils capture, contain, and kill microorganisms. However, the uncontrolled or excessive liberation of NETs also damages surrounding cells and can contribute to disease pathophysiology. Alterations in the gut microbiota, as well as the presence of local and systemic markers of inflammation, are strongly associated with the manifestation of a spectrum of intestinal disorders, including chronic inflammatory bowel disease. Although probiotics exert beneficial effects on gut homeostasis, their direct effect on neutrophils, which are abundant in the setting of intestinal inflammation, remains unclear. In this study, we investigated the effects of nonpathogenic, enteropathogenic, and probiotic bacteria on the dynamics of NET formation. Using murine bone marrow-derived neutrophils and the neutrophil-differentiated human myeloid cell line d.HL-60, we demonstrate for the first time, to our knowledge, that probiotic Lactobacillus rhamnosus strain GG inhibits both PMA- and Staphylococcus aureus-induced formation of NETs. Moreover, probiotic L. rhamnosus strain GG had potent antioxidative activity: dampening reactive oxygen species production and phagocytic capacity of the neutrophils while protecting against cell cytotoxicity. Within the milieu of the gut, this represents a novel mechanism by which probiotics can locally dampen innate immune responses and confer desensitization toward luminal Ags. PMID- 24465011 TI - Modulation of nonneutralizing HIV-1 gp41 responses by an MHC-restricted TH epitope overlapping those of membrane proximal external region broadly neutralizing antibodies. AB - A goal of HIV-1 vaccine development is to elicit broadly neutralizing Abs (BnAbs), but current immunization strategies fail to induce BnAbs, and for unknown reasons, often induce nonneutralizing Abs instead. To explore potential host genetic contributions controlling Ab responses to the HIV-1 Envelope, we have used congenic strains to identify a critical role for MHC class II restriction in modulating Ab responses to the membrane proximal external region (MPER) of gp41, a key vaccine target. Immunized H-2(d)-congenic strains had more rapid, sustained, and elevated MPER(+) Ab titers than those bearing other haplotypes, regardless of immunogen, adjuvant, or prime or boost regimen used, including formulations designed to provide T cell help. H-2(d)-restricted MPER(+) serum Ab responses depended on CD4 TH interactions with class II (as revealed in immunized intra-H-2(d/b) congenic or CD154(-/-) H-2(d) strains, and by selective abrogation of MPER restimulated, H-2(d)-restricted primed splenocytes by class II blocking Abs), and failed to neutralize HIV-1 in the TZM-b/l neutralization assay, coinciding with lack of specificity for an aspartate residue in the neutralization core of BnAb 2F5. Unexpectedly, H-2(d)-restricted MPER(+) responses functionally mapped to a core TH epitope partially overlapping the 2F5/z13/4E10 BnAb epitopes as well as nonneutralizing B cell-Ab binding residues. We propose that class II restriction contributes to the general heterogeneity of nonneutralizing gp41 responses induced by Envelope. Moreover, the proximity of TH and B cell epitopes in this restriction may have to be considered in redesigning minimal MPER immunogens aimed at exclusively binding BnAb epitopes and triggering MPER(+) BnAbs. PMID- 24465013 TI - alpha-Galactosylceramide but not phenyl-glycolipids induced NKT cell anergy and IL-33-mediated myeloid-derived suppressor cell accumulation via upregulation of egr2/3. AB - Strategies for cancer immunotherapy include activating immune system for therapeutic benefit or blockade of immune checkpoints. To harness innate immunity to fight cancer, alpha-galactosylceramide (alpha-GalCer) has been used to activate NKT cells. Unfortunately, administration of alpha-GalCer causes long term NKT cell anergy, but the molecular mechanism is unclear. In this study, we showed that alpha-GalCer-triggered egr2/3, which induced programmed death 1 and cbl-b in NKT cells, leading to NKT cell anergy. We also uncovered the induction of the immunosuppressive myeloid-derived suppressor cells (MDSCs) in the spleen by alpha-GalCer that might attenuate its antitumor efficacy. The accumulation of MDSC was accompanied by 20-fold rise in their arg-1 mRNAs and enhanced expression of programmed death 1/programmed death ligand 1. Furthermore, alpha-GalCer induced egr-2/3 in hepatic NKT cells upregulated their TRAIL in addition to Fas ligand (FasL) and induced alarm signaling molecule IL-33 in Kupffer cells, presumably because of liver damage triggered by TRAIL/FasL. We further demonstrated that IL-33-stimulated macrophages produce G-CSF, which in turn, boosted MDSCs. Thus, alpha-GalCer-induced FasL/TRAIL and IL-33 provided a novel mechanism underlying alpha-GalCer-induced hepatotoxicity and MDSC accumulation. In contrast, analogs of alpha-GalCer containing phenyl group in the lipid tail could neither induce NKT anergy nor enhance MDSCs accumulation. Furthermore, tumor-infiltrating MDSCs in mice injected repeatedly with alpha-GalCer were 2 fold higher than those treated with phenyl-glycolipids. These results not only revealed the induction of MDSC via IL-33 as a new mechanism for alpha-GalCer elicited immunosuppression but also provided one of the mechanisms underlying the superior antitumor potency of phenyl-glycolipids. Our findings have important implications for the development of NKT-stimulatory glycolipids as vaccine adjuvants and anticancer therapeutics. PMID- 24465014 TI - HIV Nef expression favors the relative preservation of CD4+ T regulatory cells that retain some important suppressive functions. AB - HIV-1 infection causes depletion and/or dysfunction of distinct CD4(+) T cell subsets and may affect these differently. Using the CD4C/HIV-1(Nef) transgenic (Tg) mice as a model, we report that HIV-1 Nef causes depletion of total CD4(+) T cells, but preserves and relatively enriches CD4(+) regulatory T cells (Treg). We found that Nef-mediated CD4(+) Treg enrichment is the direct result of Nef expression in CD4(+) T cells, occurs independently of Nef-induced lymphopenia, and most likely results from multiple mechanisms: lower apoptosis, enhanced cell division, and increased generation from precursors. Interestingly, Tg Treg relative enrichment could be reversed by enhancing Lck activity. Most importantly, we show that, in contrast to Tg helper CD4(+) T cells that have lost their function, Nef-expressing CD4(+) Treg retain their regulatory function in vitro and also in vivo, under some settings. In particular, we found that Treg prevent expansion of Tg B and non-Treg T cells in vivo. Our study reveals that Nef affects distinct CD4(+) T cell subsets differently and uncovers the high proliferative potential of B and non-Treg T cells in this mouse model. PMID- 24465015 TI - Streptococcus pyogenes biofilm growth in vitro and in vivo and its role in colonization, virulence, and genetic exchange. AB - BACKGROUND: Group A streptococcus (GAS) commonly colonizes the oropharynx and nonintact skin. However, colonization has been little studied and the role of biofilm formation is unclear, as biofilm experiments to date have not been conducted under conditions that mimic the host environment. METHODS: In this study we grew GAS biofilms on human keratinocytes under various environmental conditions and used this model to evaluate colonization, invasive disease and natural transformation. RESULTS: GAS grown on epithelial cells, but not biofilms grown on abiotic surfaces, produced biofilms with characteristics similar to in vivo colonization. These biofilm bacteria showed a 100-fold higher bacterial burden of nasal-associated lymphoid tissue in mice than broth-grown bacteria, and were not virulent during septic infection, which was attributed in part to down regulation of genes typically involved in localized and invasive disease. We also showed for the first time that GAS were naturally transformable when grown in biofilms and during colonization of NALT in vivo. CONCLUSIONS: These findings provide novel model systems to study biofilm formation of GAS in vitro and in vivo, suggest an important role for biofilm formation during GAS colonization, and provide an explanation for the known genome diversity within the GAS population. PMID- 24465017 TI - Health in all policies--from what to how. PMID- 24465018 TI - Political determinants of health. PMID- 24465016 TI - Quercetin reduces obesity-associated ATM infiltration and inflammation in mice: a mechanism including AMPKalpha1/SIRT1. AB - Adipose tissue macrophage (ATM) plays a central role in obesity-associated inflammation and insulin resistance. Quercetin, a dietary flavonoid, possesses anti-inflammation and anti-insulin resistance properties. However, it is unclear whether quercetin can alleviate high-fat diet (HFD)-induced ATM infiltration and inflammation in mice. In this study, 5-week-old C57BL/6 mice were fed low-fat diet, HFD, or HFD with 0.l% quercetin for 12 weeks, respectively. Dietary quercetin reduced HFD-induced body weight gain and improved insulin sensitivity and glucose intolerance in mice. Meanwhile, dietary quercetin enhanced glucose transporter 4 translocation and protein kinase B signal in epididymis adipose tissues (EATs), suggesting that it heightened glucose uptake in adipose tissues. Histological and real-time PCR analysis revealed that quercetin attenuated mast cell and macrophage infiltration into EATs in HFD-fed mice. Dietary quercetin also modified the phenotype ratio of M1/M2 macrophages, lowered the levels of proinflammatory cytokines, and enhanced adenosine monophosphate-activated protein kinase (AMPK) alpha1 phosphorylation and silent information regulator 1 (SIRT1) expression in EATs. Further, using AMPK activator 5-aminoimidazole-4-carboxamide 1-beta4-ribofuranoside and inhibitor Compound C, we found that quercetin inhibited polarization and inflammation of mouse bone marrow-derived macrophages through an AMPKalpha1/SIRT1-mediated mechanism. In conclusion, dietary quercetin might suppress ATM infiltration and inflammation through the AMPKalpha1/SIRT1 pathway in HFD-fed mice. PMID- 24465021 TI - The combined influence of fat consumption and repeated mental stress on brachial artery flow-mediated dilatation: a preliminary study. AB - Experienced separately, both acute mental stress and high-fat meal consumption can transiently impair endothelial function, and the purpose of the present study was to investigate their combined impact. On four separate days, 10 healthy men (23 years old) underwent brachial artery flow-mediated dilatation (FMD) tests, before and hourly for 4 h post-consumption of a high-fat (HFM; 54 g fat) or low fat meal (LFM; 0 g fat; each meal ~ 1000 calories), with hourly mental stress (mental arithmetic, speech) or control (counting) tasks (conditions HFM+S, LFM+S, HFM and LFM). Data are presented as means +/- SD. Plasma triglycerides increased and remained elevated after the high-fat but not the low-fat meal (P = 0.004) and were not affected by mental stress (P = 0.329). Indices of stress reactivity increased during mental stress tasks (mean arterial pressure, ~ 20 mmHg; heart rate, ~ 22 beats min(-1); salivary cortisol, ~ 2.37 nmol l(-1); and plasma noradrenaline, ~ 0.17 ng ml(-1)) and were not influenced by meal (P > 0.05). There was no effect of the type of meal on FMD (P = 0.562); however, FMD was 4.5 +/- 0.5% in the control conditions and 5.8 +/- 0.6% in the mental stress conditions (P = 0.087), and this difference was significant when normalized for the shear stress stimulus (FMD/area under the curve of shear stress, P = 0.045). Overall, these preliminary data suggest that postprandial FMD was augmented with mental stress irrespective of meal type. These results are contrary to previous reports of impaired endothelial function after mental stress or fat consumption independently and highlight the need to further investigate the mechanisms underlying the interactions between these factors. PMID- 24465022 TI - Effect of acute moderate exercise on induced inflammation and arterial function in older adults. AB - Acute inflammation reduces flow-mediated vasodilatation and increases arterial stiffness in young healthy individuals. However, this response has not been studied in older adults. The aim of this study, therefore, was to evaluate the effect of acute induced systemic inflammation on endothelial function and wave reflection in older adults. Furthermore, an acute bout of moderate-intensity aerobic exercise can be anti-inflammatory. Taken together, we tested the hypothesis that acute moderate-intensity endurance exercise, immediately preceding induced inflammation, would be protective against the negative effects of acute systemic inflammation on vascular function. Fifty-nine healthy volunteers between 55 and 75 years of age were randomized to an exercise or a control group. Both groups received a vaccine (induced inflammation) and sham (saline) injection in a counterbalanced crossover design. Inflammatory markers, endothelial function (flow-mediated vasodilatation) and measures of wave reflection and arterial stiffness were evaluated at baseline and at 24 and 48 h after injections. There were no significant differences in endothelial function and arterial stiffness between the exercise and control group after induced inflammation. The groups were then analysed together, and we found significant differences in the inflammatory markers 24 and 48 h after induction of acute inflammation compared with sham injection. However, flow-mediated vasodilatation, augmentation index normalized for heart rate (AIx75) and beta-stiffness did not change significantly. Our results suggest that acute inflammation induced by influenza vaccination did not affect endothelial function in older adults. PMID- 24465023 TI - Contraceptive use among women presenting to pharmacies for emergency contraception: an opportunity for intervention. AB - OBJECTIVES: Most women who use emergency contraception (EC) do so because of unprotected sexual intercourse or condom failure and so remain at risk of pregnancy unless they commence an effective method of contraception. In Great Britain, increasingly women now choose to obtain EC from a pharmacy; however, pharmacists do not currently provide effective ongoing contraception. We sought to determine the views of women obtaining EC from pharmacies and clinicians working in sexual and reproductive health care (SRH) about the possibility of pharmacists providing a temporary supply of a progestogen-only pill (POP) together with EC. METHODS: Self-administered, anonymous questionnaires of (1) women requesting EC from pharmacies in Edinburgh, Scotland and (2) SRH clinicians attending a major UK scientific meeting. RESULTS: A total of 211/232 women completed questionnaires in pharmacies (a 91% response rate). Of those women not using a hormonal method of contraception at the time of EC (n=166; 79%), almost half (44%) wished to use an effective method. Most women (64%) agreed that the option of a pharmacist being able to supply a POP would have been helpful. Among the SRH clinicians, 110 completed questionnaires out of 150 distributed (a 73% response rate). The majority of respondents (92%) were positive about a pharmacist supplying a POP at the time of EC. CONCLUSIONS: A reasonable proportion of women requesting EC would like to start using an effective contraceptive method. Both the women and the SRH clinicians we surveyed are positive about the option of a short supply of a POP being provided by the pharmacy in the UK together with EC. PMID- 24465024 TI - Young men and the morning after: a missed opportunity for emergency contraception provision? AB - OBJECTIVES: Although adolescents and young adults of lower socioeconomic status (SES) are disproportionately affected by unintended pregnancies, research on experiences with emergency contraception (EC) in this population has lagged. Furthermore, it is unclear whether EC-related knowledge and behaviour varies between young men and women. This study investigated knowledge, attitudes and experiences with EC among low SES young men and women aged 18-25 years. METHODS: One hundred and ninety-eight new enrollees at two Los Angeles primary medical care clinics completed surveys about their knowledge, past use and likelihood of using EC. Chi square (chi(2)) and regression analyses assessed gender differences in knowledge and attitudes. RESULTS: Women were more likely than men to accurately answer questions about EC and its use. Across both sexes, accurate knowledge predicted future willingness to use EC. Only half the women and a third of men knew that EC could be directly dispensed by pharmacists; even fewer knew that the legal access age for EC was 17 years (13%) or that men could access EC from pharmacies for their female partners (24%). Although respondents most commonly reported that friends were their source of current information about EC, both men and women chose health care professionals as their desired source of future information about EC. CONCLUSIONS: Young men in this sample were significantly less knowledgeable than young women about EC. Educating young men about EC by health care providers during routine visits may be a unique opportunity to increase EC knowledge, access and use among low-income young couples to decrease undesired pregnancies. PMID- 24465025 TI - German general practitioners' views on their involvement and role in cancer care: a qualitative study. AB - BACKGROUND: The multidisciplinary and sequential nature of cancer care makes continuity of care for patients difficult. Cancer patients have often known their general practitioners (GPs) for years and are often in constant contact with them. Objective(s). We examined German GPs' views on their involvement in the care of cancer patients. METHODS: We conducted semi-structured interviews with 30 German GPs. Purposeful sampling was applied to secure maximum heterogeneity. Interviews were recorded, transcribed and then analyzed using qualitative content analysis according to Mayring. RESULTS: GPs perceive a clear involvement in the latter phase of cancer care but a mainly sporadic role (as and when required) in earlier phases. They think that greater care contributions from GPs are generally beneficial to cancer patients, as their ability to take the patient's history, surroundings and co-morbidities into account enables them to provide more patient centred care. GPs want to stay involved and to know how their cancer patients are progressing, and they complain about slow or non-existent information sharing between providers, as well as insufficient care coordination. They pro-actively try to overcome these obstacles through direct contact with patients and physicians, and by building networks of trusted care providers. CONCLUSIONS: Given their long-lasting and close relationships with cancer patients, GPs are in a position to accompany them throughout the whole process of cancer care. However, such general involvement is as yet uncommon. Shared care models may have the potential to take into account the complementary character of primary and specialist care. PMID- 24465027 TI - Authors' response: Surgery rates in IBD. PMID- 24465026 TI - Longitudinal assessment of the menopausal transition, endogenous sex hormones, and perception of physical functioning: the Study of Women's Health Across the Nation. AB - BACKGROUND: To evaluate the longitudinal associations between menopausal status, related hormonal changes, and level of self-reported physical functioning. METHODS: Study included 2,495 women (age: 45-57 between 2000 and 2001) from the Study of Women's Health Across the Nation. Physical functioning scale of the Medical Outcomes Study Short-Form (SF-36; score 0-100) was categorized as: no limitation (86-100), moderate limitation (51-85), and substantial limitation (0 50). Study variables were collected between 2000 (visit-04) and 2011 (visit-12) at five timepoints. Statistical models were adjusted for age at visit-04, time since visit-04, ethnicity, site, economic status, level and change in body mass index, level and change in physical activity, and presence of comorbid conditions. RESULTS: In final models, natural and surgical postmenopausal women had significantly higher odds of functional limitation, compared with premenopausal women. Less reduction in estradiol and testosterone since visit-04 were significantly associated with lower odds of functional limitation, while greater increase in sex hormone-binding globulin was associated with higher odds of functional limitation. CONCLUSIONS: Our findings suggest the menopause-related changes in endogenous sex hormones as a possible mechanism of action to explain the greater limitation in physical functioning reported in women at midlife. PMID- 24465028 TI - Revival of 5-HT3 antagonism as treatment of IBS-D? PMID- 24465029 TI - A novel twist in polycystic liver disease. PMID- 24465031 TI - Estimating time-varying effects for overdispersed recurrent events data with treatment switching. AB - In the analysis of multivariate event times, frailty models assuming time independent regression coefficients are often considered, mainly due to their mathematical convenience. In practice, regression coefficients are often time dependent and the temporal effects are of clinical interest. Motivated by a phase III clinical trial in multiple sclerosis, we develop a semiparametric frailty modelling approach to estimate time-varying effects for overdispersed recurrent events data with treatment switching. The proposed model incorporates the treatment switching time in the time-varying coefficients. Theoretical properties of the proposed model are established and an efficient expectation-maximization algorithm is derived to obtain the maximum likelihood estimates. Simulation studies evaluate the numerical performance of the proposed model under various temporal treatment effect curves. The ideas in this paper can also be used for time-varying coefficient frailty models without treatment switching as well as for alternative models when the proportional hazard assumption is violated. A multiple sclerosis dataset is analysed to illustrate our methodology. PMID- 24465030 TI - GSTP1 and TNF Gene variants and associations between air pollution and incident childhood asthma: the traffic, asthma and genetics (TAG) study. AB - BACKGROUND: Genetics may partially explain observed heterogeneity in associations between traffic-related air pollution and incident asthma. OBJECTIVE: Our aim was to investigate the impact of gene variants associated with oxidative stress and inflammation on associations between air pollution and incident childhood asthma. METHODS: Traffic-related air pollution, asthma, wheeze, gene variant, and potential confounder data were pooled across six birth cohorts. Parents reported physician-diagnosed asthma and wheeze from birth to 7-8 years of age (confirmed by pediatric allergist in two cohorts). Individual estimates of annual average air pollution [nitrogen dioxide (NO2), particulate matter <= 2.5 MUm (PM2.5), PM2.5 absorbance, ozone] were assigned to each child's birth address using land use regression, atmospheric modeling, and ambient monitoring data. Effect modification by variants in GSTP1 (rs1138272/Ala114Val and rs1695/IIe105Val) and TNF (rs1800629/G-308A) was investigated. RESULTS: Data on asthma, wheeze, potential confounders, at least one SNP of interest, and NO2 were available for 5,115 children. GSTP1 rs1138272 and TNF rs1800629 SNPs were associated with asthma and wheeze, respectively. In relation to air pollution exposure, children with one or more GSTP1 rs1138272 minor allele were at increased risk of current asthma [odds ratio (OR) = 2.59; 95% CI: 1.43, 4.68 per 10 MUg/m3 NO2] and ever asthma (OR = 1.64; 95% CI: 1.06, 2.53) compared with homozygous major allele carriers (OR = 0.95; 95% CI: 0.68, 1.32 for current and OR = 1.20; 95% CI: 0.98, 1.48 for ever asthma; Bonferroni-corrected interaction p = 0.04 and 0.01, respectively). Similarly, for GSTP1 rs1695, associations between NO2 and current and ever asthma had ORs of 1.43 (95% CI: 1.03, 1.98) and 1.36 (95% CI: 1.08, 1.70), respectively, for minor allele carriers compared with ORs of 0.82 (95% CI: 0.52, 1.32) and 1.12 (95% CI: 0.84, 1.49) for homozygous major allele carriers (Bonferroni-corrected interaction p-values 0.48 and 0.09). There were no clear differences by TNF genotype. CONCLUSIONS: Children carrying GSTP1 rs1138272 or rs1695 minor alleles may constitute a susceptible population at increased risk of asthma associated with air pollution. PMID- 24465032 TI - Eddy covariance measurements of carbon dioxide, latent and sensible energy fluxes above a meadow on a mountain slope. AB - Carbon dioxide, latent and sensible energy fluxes were measured by means of the eddy covariance method above a mountain meadow situated on a steep slope in the Stubai Valley/Austria, based on the hypothesis that, due to the low canopy height, measurements can be made in the shallow equilibrium layer where the wind field exhibits characteristics akin to level terrain. In order to test the validity of this hypothesis and to identify effects of complex terrain in the turbulence measurements, data were subjected to a rigorous testing procedure using a series of quality control measures established for surface layer flows. The resulting high-quality data set comprised 36 % of the original observations, the substantial reduction being mainly due to a change in surface roughness and associated fetch limitations in the wind sector dominating during nighttime and transition periods. The validity of the high-quality data set was further assessed by two independent tests: i) a comparison with the net ecosystem carbon dioxide exchange measured by means of ecosystem chambers and ii) the ability of the eddy covariance measurements to close the energy balance. The net ecosystem CO2 exchange measured by the eddy covariance method agreed reasonably with ecosystem chamber measurements. The assessment of the energy balance closure showed that there was no significant difference in the correspondence between the meadow on the slope and another one situated on flat ground at the bottom of the Stubai Valley, available energy being underestimated by 28 and 29 %, respectively. We thus conclude that, appropriate quality control provided, the eddy covariance measurements made above a mountain meadow on a steep slope are of similar quality as compared to flat terrain. PMID- 24465033 TI - Mexican-origin Early Adolescents' Ethnic Socialization, Ethnic Identity, and Psychosocial Functioning. AB - The current study examined how parental ethnic socialization informed adolescents' ethnic identity development and, in turn, youths' psychosocial functioning (i.e., mental health, social competence, academic efficacy, externalizing behaviors) among 749 Mexican-origin families. In addition, school ethnic composition was examined as a moderator of these associations. Findings indicated that mothers' and fathers' ethnic socialization were significant longitudinal predictors of adolescents' ethnic identity, although fathers' ethnic socialization interacted significantly with youths' school ethnic composition in 5th grade to influence ethnic identity in 7th grade. Furthermore, adolescents' ethnic identity was significantly associated with increased academic self efficacy and social competence, and decreased depressive symptoms and externalizing behaviors. Findings support theoretical predictions regarding the central role parents play in Mexican-origin adolescents' normative developmental processes and adjustment and, importantly, underscore the need to consider variability that is introduced into these processes by features of the social context such as school ethnic composition. PMID- 24465034 TI - A revised estimate of the burden of illness of gout. AB - BACKGROUND: Gout is a chronic, inflammatory arthritis characterized by painful and debilitating acute/episodic flares. Until recently, gout has been regarded as a minor medical problem, in part because the associated economic burden has not been appreciated. Previous literature on this subject focused on the costs associated with acute episodes of gout rather than on the long-term medical and economic implications of this chronic disorder. OBJECTIVE: Our aim was to estimate the current impact of gout in the United States with respect to disability and economic costs. METHODS: THE FOLLOWING DATA SOURCES WERE USED: published data on the incremental economic burden of gout; statistics from the US Census Bureau and the US Bureau of Labor Statistics; and recent epidemiological and clinical literature concerning the course, treatment, and outcomes of the disease. Disability is expressed as days of lost productivity. Charges for gout related treatments were used as direct cost inputs. RESULTS: Gout affects an estimated 8 million Americans, among whom those working have an average of almost 5 more absence days annually than workers without gout. On average, the incremental annual cost of care for a gout patient is estimated at >$3000 compared with a nongouty individual. Even though comorbidities common in gout patients account for a portion of this increased economic burden, the total annual cost attributable to gout patients in the United States is likely in the tens of billions of dollars and comparable to those of other major chronic disorders, such as migraine and Parkinson's disease. CONCLUSIONS: The economic burden of gout is most readily assessable in patients whose acute arthritic flares result in emergency department visits, bedridden days, and episodic loss of productivity. Chronic progression of the disease can also result in long-term impairment of function and health-related quality of life, but the contribution of chronic gout to the economic burden is more difficult to quantitate because gout is frequently associated with serious cardiovascular, metabolic, and renal comorbidities. Recent demonstration that successful gout management can reverse functional deficits in many chronic gout patients, however, supports the views that chronic gout contributes substantially to the medical and thus economic costs of these patients and that early and aggressive efforts to improve gout outcomes are likely to reduce the associated economic burden. PMID- 24465035 TI - The effect of trapidil and bevacizumab on tracheal anastomotic wound healing. AB - BACKGROUND: Although bevacizumab has deleterious effects on the healing of colonic anastomoses, trapidil improves wound healing of colonic and tracheal anastomoses. OBJECTIVE: We aimed to assess the effects of bevacizumab and trapidil on wound healing after tracheal transection. MATERIALS AND METHODS: We evaluated 35 rats divided in 5 groups: bevacizumab (Group I, n = 7), trapidil (Group II, n = 7), trapidil + bevacizumab (Group III, n = 7), controls (Group IV, n = 7), and sham (Group V, n = 7). Anastomotic healing was assessed by measurement of bursting pressure and inflammation score at the anastomotic region on the seventh day. RESULTS: The bursting pressures of Group II, Group III, and Group V were significantly higher than controls (P = 0.001, P = 0.033, and P = 0.035, respectively). Fibrosis was significantly high in the sham group when compared with the other four groups (P = 0.047). CONCLUSIONS: Although bevacizumab seems to impair anastomotic healing, trapidil can be suggested to improve tracheal anastomoses. PMID- 24465036 TI - Antitumor Activities of Rauwolfia vomitoria Extract and Potentiation of Carboplatin Effects Against Ovarian Cancer. AB - BACKGROUND: Tumor resistance to platinum-based drugs has been an obstacle to the treatment of ovarian cancer. Extract of the plant Rauwolfia vomitoria has long been used by cancer patients. However, there have not been systematic studies of its anticancer activity. OBJECTIVE: In an effort to enhance the effectiveness of platinum-based drugs, we investigated the anticancer effect of a Rauwolfia vomitoria extract (Rau), both alone and in combination with carboplatin (Cp). METHODS: In vitro cytotoxicity and colony formation were evaluated in several ovarian cancer cell lines. In vivo effects were evaluated in an intraperitoneal ovarian cancer mouse model. The combination of Rau and Cp was assessed using Chou Talalay's constant ratio design and median effect analysis based on the isobologram principle to determine the combination index values. RESULTS: Rau decreased cell growth in all 3 tested ovarian cancer cell lines dose dependently and completely inhibited formation of colonies in soft agar. Apoptosis was induced in a time- and dose-dependent manner and was the predominant form of Rau induced cell death. Synergy of Rau with Cp was detected, with combination index values <1 and dose reduction index values for Cp ranging from 1.7- to 7-fold. Tumor growth in mice was significantly suppressed by 36% or 66% with Rau treatment alone at a low (20 mg/kg) or a high dose (50 mg/kg), respectively, an effect comparable to that of Cp alone. The volume of ascitic fluid and the number of nonblood cells in ascites were also significantly decreased. Combining Rau with Cp remarkably enhanced the effect of Cp and reduced tumor burden by 87% to 90% and ascites volume by 89% to 97%. CONCLUSIONS: Rau has potent antitumor activity and in combination significantly enhances the effect of Cp against ovarian cancer. PMID- 24465037 TI - The use of platelet-rich fibrin in combination with biphasic calcium phosphate in the treatment of bone defects: a histologic and histomorphometric study. AB - BACKGROUND: Platelet-rich fibrin (PRF) is a leukocyte and platelet concentrate containing many growth factors. Its potential for hard tissue augmentation as a sole grafting material or in combination with other grafting materials has been investigated in many studies. OBJECTIVE: The aim of this histologic study was to evaluate the efficacy of PRF mixed with biphasic calcium phosphate (BCP) on bone regeneration in surgically created bone defects. METHODS: Defects 5 mm in diameter were created in both tibias of 6 sheep. The defects were left empty or grafted with BCP, PRF, or BCP+PRF. Animals were killed at 10, 20, and 40 days. The specimens underwent histologic and histomorphometric analysis. RESULTS: None of the groups displayed any signs of necrosis. Inflammation was observed in all groups at 10 days; 2 specimens of PRF+BCP and all empty defects showed inflammatory cell infiltration at 20 days. During the 40-day evaluation period, the PRF+BCP group showed the highest ratios of new bone. The other 3 groups showed statistically similar results. In the BCP and PRF+BCP groups, the residual graft ratios were decreased at consecutive time intervals. The difference between the 2 groups was not statistically significant during follow-up. CONCLUSIONS: The current study revealed a histomorphometric increase in bone formation with the addition of PRF to BCP in surgically created defects in sheep tibia. PMID- 24465038 TI - Effects of dexmedetomidine and midazolam on motor coordination and analgesia: a comparative analysis. AB - OBJECTIVE: We compared the effects of 2 sedative drugs, dexmedetomidine and midazolam, on motor performance and analgesic efficacy in a rat model. MATERIALS AND METHODS: Rats were randomly divided into the following 4 groups on the basis of the treatment received. The first group received 83 ug/kg/min midazolam; the second, 1 ug/kg/min dexmedetomidine; the third, 83 ug/kg/min morphine; and the fourth was a control group. The rats were measured motor coordination and pain reflexes by using rotarod, accelerod, hot plate, and tail flick tests. RESULTS: At all the tested speeds, the midazolam-injected rats remained on the rotarod longer than did the dexmedetomidine-injected rats. Furthermore, in the 10-minute accelerod test, the midazolam-injected rats remained for a longer duration than did the dexmedetomidine-injected rats. The latency time for the hot plate test was significantly higher at 10 minutes and 20 minutes in the dexmedetomidine group than in the midazolam group. Further, the latency time at 10 minutes for the tail flick test was greater in the dexmedetomidine group than in the midazolam group. CONCLUSIONS: In this rat model, midazolam results in faster recovery of motor coordination performance when compared with dexmedetomidine. PMID- 24465039 TI - The effects of zileuton and montelukast in reperfusion-induced arrhythmias in anesthetized rats. AB - BACKGROUND: 5-Lipoxygenase is an enzyme involved in the synthesis of leukotriene eicosanoids from arachidonic acid. The therapeutic potential of zileuton, an inhibitor of 5-lipoxygenase, and montelukast, a cysteinyl leukotriene receptor antagonist, for the treatment of ischemia/reperfusion (I/R) injury of the heart has been proposed in a few studies. However, the effects of zileuton and montelukast on I/R-induced arrhythmias have not been determined. OBJECTIVE: We assessed the possible protective effects of zileuton and montelukast against I/R induced arrhythmias. METHODS: Forty-five male Wistar albino rats were divided into 5 groups, each containing 9 rats. Group 1: control, Groups 2 and 3: rats treated with montelukast (10 and 30 mg/kg IP); and Groups 4 and 5: rats treated with zileuton (1 and 3 mg/kg IV) 15 minutes before the induction of ischemia. Ischemia and reperfusion were induced by occluding the left main coronary artery of anesthetized rats for 6 minutes followed by reopening the artery for 6 minutes. RESULTS: Both doses of zileuton decreased the mean [SE] arrhythmia score (zileuton 1 mg/kg: 1.4 [0.8]; zileuton 3 mg/kg: 1.3 [0.5] vs control: 2.9 [0.3]; P < 0.05), the duration of ventricular tachycardia, and the total length of arrhythmias, but montelukast was not effective to decrease the ventricular arrhythmias during the 6 minutes of reperfusion. CONCLUSIONS: The results indicate for the first time that zileuton exerts an antiarrhythmic effect at different doses and that montelukast is not effective against I/R-induced arrhythmias. These results indicate that zileuton may be a candidate for drug treatment of I/R-induced arrhythmias. PMID- 24465040 TI - The effect of iloprost on renal function in patients with critical limb ischemia. AB - BACKGROUND: Iloprost, which has efficacy in the microvascular space, is shown to have beneficial effects on the kidney, which has an extensive microvascular network. OBJECTIVE: We aimed to evaluate the effect of iloprost treatment on kidney functions in patients with critical limb ischemia. METHODS: Forty-eight patients with critical limb ischemia who were not suitable for revascularization and who were treated with iloprost were evaluated prospectively in our clinic between September 2010 and December 2012. The patients were divided into 2 groups as patients with chronic renal dysfunction (Group I) and patients with normal renal function (Group II). Urine albumin:creatinine ratio and glomerular filtration rate (GFR) calculated using serum creatinine and serum cystatin C (GFRcyc) were used to establish the presence of renal dysfunction. The decrease analgesic requirement, walking distance, reduction in ulcer diameter, the increase in ankle-brachial index, and changes in The Society of Vascular Surgery/International Society of Cardiovascular Surgery criteria were used in the evaluation of treatment response. RESULTS: Opioid analgesic requirement and decubitus pain disappeared after treatment in 58.3% (n = 28) of subjects. Walking distance increased in 66.6% (n = 32). Iloprost treatment significantly increased ankle-brachial index (P < 0.01). In Group I the levels of serum urea, creatinine, and cystatin C significantly decreased (P < 0.05), whereas GFRcyc and GFR calculated using the equation of the Chronic Kidney Disease Epidemiology Collaboration (ie, GFR expressed for specified race, sex, and serum creatinine in milligrams per deciliter) was increased significantly compared with pretreatment levels (P < 0.05). No significant change was observed in urine albumin:creatinine ratio (P > 0.05). CONCLUSIONS: The use of iloprost in critical limb ischemia can slow down the progress of early stage renal damage. GFRcyc and cystatin C, which are indicators of early stage chronic renal dysfunction, can be used for the evaluation of treatment response. PMID- 24465041 TI - Comparison of Propofol and Ketamine-Propofol Mixture (Ketofol) on Laryngeal Tube Suction II Conditions and Hemodynamics: A Randomized, Prospective, Double-Blind Trial. AB - OBJECTIVE: The aim of our study is to compare the effect of ketamine-propofol mixture (ketofol) and propofol on the laryngeal tube-Suction II (LTS II) insertion conditions and hemodynamics. METHODS: Eighty American Society of Anesthesiologists class 1 and 2 patients were divided into 2 random groups to receive either 1 ug/kg remifentanil and propofol 2 mg/kg in Group P (n = 40), or 1 ug/kg remifentanil and ketofol (using a 1:1 single syringe mixture of 5 mg/mL ketamine and 5 mg/mL propofol) in Group K (n = 40) before induction of anesthesia. After induction, LTS II was inserted. Heart rate and noninvasive blood pressure were recorded before induction of anesthesia (t0); immediately following induction (t1); immediately after LTS II insertion (t2); and 3 minutes (t3), 5 minutes (t4), and 10 (t5) minutes after LTS II insertion. Conditions of insertion of LTS II were assessed and scored 1 to 3 using 6 variables as follows: mouth opening, swallowing, coughing, head and body movements, laryngospasm, and ease of LTS II insertion by the same experienced anesthesiologist who did not know the agents. LTS II insertion summed score was prepared depending upon these variables. RESULTS: In regard to LTS II insertion summed score, Group K was more favorable than Group P (P < 0.05). Apnea duration was longer in Group P (385.0 seconds [range = 195.0-840.0 seconds]) compared with Group K (325.50 seconds [range = 60.0-840.0 seconds]) but this was not statically significant. The heart rate values were significantly lower at all measurement intervals in both groups compared with the baseline values (P < 0.05). There was no difference in heart rate between Group P and Group K. The mean arterial pressure values were significantly lower at all measurement intervals in Group P compared with baseline values (P < 0.05). In Group K, the mean arterial pressure values were significantly lower at all measurement intervals compared with the baseline values, except t2 (P < 0.05). There was a significant difference between Group P and Group K in terms of mean arterial pressure at t3 (P < 0.05). CONCLUSIONS: We found that ketofol provided better insertion summed score for LTS II than propofol, with minimal hemodynamic changes. PMID- 24465042 TI - Is There an Association Between Synovial CD30+ T Lymphocyte Count and Chondral Lesion Depth? AB - BACKGROUND: Exact role of the inflammation in osteoarthritis is still unclear, but it is thought to originate from synovitis due to micro-crystals or breakdown products of the cartilage. OBJECTIVE: To determine the effect of CD30+ T lymphocytes on the development of osteoarthritis by comparing the lesion depth and synovial CD30+ count in patients with chondral lesions undergoing knee joint arthroscopy. DESIGN: A total of 79 patients with chondral lesions detected during arthroscopy were categorized in 4 different groups based on chondral lesion classification. CD30+ lymphocyte counts were calculated using flow cytometry on synovial fluid samples obtained at the time of initial entrance into the joint and compared between the groups. In addition, biopsy samples obtained from the suprapatellar bursa were stained for histologic examination to identify existence of CD30+ lymphocytes in the synovium. RESULTS: Although there were no significant differences between the first 3 groups in terms of synovial fluid CD30+ lymphocyte counts, patients in Group IV had significantly higher counts (6.2 8 [2.48] vs 2.51 [1.84], 2.97 [2.40], and 3.80 [2.07], respectively; P < 0.05). Except for a single patient with a Grade III chondral lesion, there were no cases of CD30 positivity in synovial tissue. Also there was a correlation between CD30 levels and chondral lesion depth when controlled for age. CONCLUSIONS: Our results indicate higher CD30+ lymphocyte counts in patients with modified Outerbridge Grade IV chondral lesions than in other groups. The origin of the CD30+ lymphocytes may not be the synovial tissue per se. Thus, it was hypothesized that the injured chondral tissues and the associated subchondral structures might have been the source of CD30+ lymphocytes with a possible influence on the development of osteoarthritis. PMID- 24465043 TI - Comparative Bioavailability and Tolerability of a Single 2-mg Dose of 2 Repaglinide Tablet Formulations in Fasting, Healthy Chinese Male Volunteers: An Open-Label, Randomized-Sequence, 2-Period Crossover Study. AB - BACKGROUND: Repaglinide, an oral insulin secretagogue, was the first meglitinide analogue to be approved for use in patients with type 2 diabetes mellitus. OBJECTIVE: In our study, the bioavailability and tolerability of the proposed generic formulation with the established reference formulation of repaglinide 2 mg were compared in a fasting, healthy Chinese male population. METHODS: This 2 week, open-label, randomized-sequence, single-dose, 2-period crossover study was conducted in 22 healthy native Han Chinese male volunteers. Eligible subjects were randomly assigned in a 1:1 ratio to receive a single 2-mg dose of the test or reference formulation, followed by a 7-day washout period and administration of the alternate formulation. After an overnight fast, subjects received a single oral dose of repaglinide (2 mg). Blood samples were drawn at predetermined time points (0, 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2.0, 2.5, 3.0, 4.0, 5.0, and 6.0 hours). All plasma concentrations of repaglinide were measured by LC-MS/MS. The observed Cmax, Tmax, t1/2, and AUC were assessed. The formulations were to be considered bioequivalent if the ln-transformed ratios of Cmax and AUC were within the predetermined bioequivalence range of 80% to 125% established by the State Food and Drug Administration of the People's Republic of China. Tolerability was assessed throughout the study via subject interview, vital signs, and blood sampling. RESULTS: The mean (SD) age of the subjects was 24.2 (2.3) years; their mean (SD) weight was 62.6 (5.8) kg, their mean (SD) height was 172 (5.7) cm, and their mean (SD) body mass index was 21.0 (1.1). The mean (SD) Cmax for repaglinide with the test and reference formulations were 20.0 (5.1) and 18.7 (8.7) ng/mL. The AUC0-t for the test formulation was 46.3 (15.1) and AUC0 infinity was 47.9 (16.5) ng(*)h/mL. With the reference formulation, the corresponding values were 46.4 (26.1) and 49.0 (31.3) ng(*)h/mL. The mean (SD) Tmax values with the test and reference formulations were 1.2 (0.7) hours and 1.5 (0.8) hours and the mean (SD) values t1/2 values were 1.0 (0.3), and 0.9 (0.3) hours, respectively. The ln-transformed ratios of Cmax, AUC0-t, and AUC0-infinity were 113.6:1, 105.6:1, and 104.7:1. The corresponding 90% CIs were 99.8 to 129.2, 93.4 to 119.5, and 91.8 to 119.5, respectively. CONCLUSIONS: This single-dose study found that the test and reference formulations of repaglinide met the regulatory criteria for bioequivalence in these fasting, healthy Chinese male volunteers. Both formulations appeared to be well tolerated. ClinicalTrials.gov identifier: 2012L01684. PMID- 24465044 TI - Comparative bioavailability and tolerability of single and multiple doses of 2 diclofenac sodium sustained-release tablet formulations in fasting, healthy chinese male volunteers. AB - BACKGROUND: Diclofenac is a nonsteroidal anti-inflammatory drug used for the treatment of patients with osteoarthritis. OBJECTIVES: Our primary objective was to compare bioavailability and tolerability of a generic sustained-release tablet with the established reference sustained-release tablet of diclofenac sodium in a fasting, healthy Chinese male population. METHODS: A randomized, open-label, single- and multiple-dose study design was used. After the single dose, volunteers received diclofenac sodium sustained-release tablet once daily for 5 days. In the single-dose phase, blood samples were collected from 0 to 36 hours after drug administration. In the multiple-dose phase, samples were obtained before drug administration at 8:00 am on Days 3 and 4 to determine Cmin,ss of diclofenac sodium; on Day 5, samples were collected from 0 to 36 hours. Adverse events were monitored via subject interview, vital signs, and blood sampling. RESULTS: Twenty-four Chinese male volunteers were enrolled. The pharmacokinetic parameters (mean [SD]) for diclofenac after single dose of 75 and 100 mg were: Cmax 473.5 [179.5] and 546.6 [154.9] ng/mL; AUC0-infinity 3841.2 [1402.3], and 5019.1 [2,314.0] ng.h/mL; Tmax 4.9 [2.4], and 4.3 [2.2] hours; t1/2 5.9 [2.5], and 6.0 [2.2] hours. Mean [SD] values after multiple doses of 75 and 100 mg were: Cmax,ss 525.6 [127.4] and 650.5 [167.0] ng/mL, Cmin,ss 33.9 [20.9] and 62.9 [34.9] ng/mL, AUCss 4316.3 [633.0] and 5335.1 [1291.9] ng.h/mL, Cav,ss 179.8 [26.4] and 222.3 [53.8] ng/mL, Tmax 5.1 [1.8] and 4.5 [0.9] hours and t1/2 5.2 [2.9] and 5.5 [2.8] hours, respectively. CONCLUSIONS: This diclofenac sodium 75 mg tablet has features compatible with the 100 mg sustained-release tablet and appeared to be well tolerated. ClinicalTrials.gov identifier: 2010L01969. PMID- 24465045 TI - Ursolic Acid provides kidney protection in diabetic rats. AB - BACKGROUND: Diabetic nephropathy (DN) is one of the most serious microvascular complications of diabetes and the leading cause of end-stage renal failure. However, the treatment of DN is still a problem in the world. Inflammatory process plays a critical role in the development of DN. Therefore, anti inflammatory treatment of DN is worth exploring now and in the future. OBJECTIVE: The study aimed to evaluate the impact of ursolic acid (UA) on renal function in streptozotocin-induced diabetes. METHODS: Rats with streptozotocin-induced diabetes were treated with UA for 16 weeks. After 16 weeks, urine albumin excretion, serum creatinine, and blood urea nitrogen were measured. In addition, renal oxidative stress level, nuclear factor kappa-B (NF-kappaB) activity, P selectin expression, and kidney histopathologic changes were evaluated. RESULTS: Sixteen weeks following streptozotocin injection, the rats produced significant alteration in renal function and increased oxidative stress, NF-kappaB activity, and P-selectin expression in the kidneys. Interestingly, UA significantly prevented biochemical and histopathologic changes in the kidneys associated with diabetes. Compared with untreated diabetic rats, UA treatment lowered urine albumin excretion, renal oxidative stress level, NF-kappaB activity, and P selectin expression. Moreover, UA treatment also improved renal histopathologic changes in rats with diabetes. CONCLUSIONS: UA treatment exhibited a protective effect on kidneys in diabetic rats, implying that UA could be a potential treatment for diabetic nephropathy. PMID- 24465046 TI - Comparison of intrathecal levobupivacaine combined with sufentanil, fentanyl, or placebo for elective caesarean section: a prospective, randomized, double-blind, controlled study. AB - BACKGROUND: The addition of opioids to local anesthetics contributes to the quality of spinal anesthesia and postoperative analgesia. OBJECTIVE: In our prospective, randomized, double-blind, controlled study, our aim was to compare the effect of low-dose sufentanil plus levobupivacaine or a fentanyl plus levobupivacaine mixture on anesthesia quality, block characteristics, newborn and mother well-being, surgeon satisfaction, and duration of postoperative analgesia. METHODS: Ninety-three patients were randomized into 3 groups (n = 31). Patients in Group C received 0.5% levobupivacaine (2.2 +/- 0.2 mL), Group S received 2.5 ug sufentanil plus 0.5% levobupivacaine (2.2 +/- 0.2 mL), and Group F received 10 ug fentanyl plus 0.5% levobupivacaine (2.2 +/- 0.2 mL) intrathecally completed to a volume of 3 mL with the addition of saline in all groups. Patients' demographics, sensory and motor block characteristics, hemodynamics, Apgar scores, umbilical blood gas values, maternal side effects, surgeon satisfaction score, time to first analgesia requirement, and additional analgesic use within 24 hours were recorded. RESULTS: In Group S and Group F, target levels of sensory and motor block were achieved more rapidly (P < 0.001). The hemodynamic values were lower (P < 0.05), and the duration of sensory blockade and the time of first analgesic requirement were longer (P < 0.001) in Group S. Additional analgesic requirement during first 24-hour period was lowest in Group S, and highest in Group C (P < 0.001). Apgar scores and umbilical blood gas samples were similar between groups. Postoperative pruritus was more frequent in Group S (P < 0.001) and surgeon satisfaction score was significantly lower in Group C (P = 0.003). CONCLUSIONS: We suggest that the addition of sufentanil and fentanyl to intrathecal levobupivacaine during caesarean section surgery is more effective than the administration of levobupivacaine alone. The addition of sufentanil to levobupivacaine allowed rapid onset time for sensory and motor block levels. It also extended the duration of postoperative analgesia and led to a decrease in total analgesic requirement. ClinicalTrials.gov identifier: NCT01858090. PMID- 24465047 TI - Possible therapeutic effect of trilostane in rodent models of inflammation and nociception. AB - BACKGROUND: Trilostane was identified in an in vivo screen of compounds in a lipopolysaccharide model of inflammation to support a repurposing effort. There is no previous documentation of any anti-inflammatory effects of trilostane. OBJECTIVE: The aim of this study was to elucidate the novel pharmacologic activity of trilostane in a series of inflammation and nociception signal-finding models. METHODS: Anti-inflammatory effects of trilostane were evaluated in lipopolysaccharide-induced systemic and lung inflammation models and in a 2,4 dinitrofluorobenzene-induced delayed-type hypersensitivity (DTH) model in the mouse ear. The analgesic activities of trilostane were evaluated in a hot plate nociception model as a function of paw-withdrawal latency and in the formalin induced nociception model with a behavioral end point. In all studies, trilostane was administered 15 minutes before challenge. In the DTH model, the animals were given a second dose 24 hours after the first dose. RESULTS: Trilostane inhibited tumor necrosis factor-alpha and monocyte chemoattractant protein-1 production in the lipopolysaccharide-induced systemic and pulmonary inflammation models. It also significantly reduced ear swelling in the 2,4-dinitrofluorobenzene-induced DTH model. In the hot plate nociception model, trilostane increased the latency of paw-licking behavior. Trilostane also significantly reduced the duration of pain behaviors in the late phase of the formalin-induced inflammatory pain model. CONCLUSIONS: These signal-finding studies suggest that trilostane has novel anti inflammatory and analgesic properties. PMID- 24465048 TI - Association of Weight Loss and Medication Adherence Among Adults With Type 2 Diabetes Mellitus: SHIELD (Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes). AB - BACKGROUND: Adherence to prescribed diabetes medications is suboptimal, which can lead to poor glycemic control and diabetic complications. Treatment-related weight gain is a side effect of some oral antidiabetic agents and insulin, which may negatively affect adherence to therapy. OBJECTIVE: This study investigated whether adults with type 2 diabetes mellitus (T2DM) who lost weight had better medication adherence than those who gained weight. METHODS: Weight change over 1 year (2007 to 2008) was assessed among respondents in the US Study to Help Improve Early evaluation and management of risk factors Leading to Diabetes (SHIELD). Weight loss of >1.0%, >=3%, and >=5% of weight was compared with weight gain of >=1.0%. Medication adherence was assessed using the Morisky 4-item questionnaire for medication-taking behavior, with lower scores representing better adherence. RESULTS: There were 746 T2DM respondents who lost >1.0%, 483 who lost >=3%, 310 who lost >=5%, and 670 who gained >=1.0% of weight. Each weight-loss group had significantly lower Morisky scores than the weight-gain group; mean scores of 0.389 versus 0.473 (P = 0.050) for the >1.0% weight-loss group, 0.365 versus 0.473 (P = 0.026) for the >=3% weight-loss group, and 0.334 versus 0.473 (P = 0.014) for the >=5% weight-loss group. Significantly fewer respondents who lost weight had received insulin, sulfonylurea, or thiazolidinedione therapy (57%) compared with respondents who gained weight (64%) (P = 0.002). Demographics, exercise habits, and dieting were similar between weight-loss and weight-gain groups. CONCLUSIONS: T2DM respondents with weight loss had significantly better medication adherence and were less likely to be on treatment regimens that increase weight than T2DM respondents with weight gain. These findings suggest that strategies that lead to weight loss, including use of diabetes medications associated with weight loss, may improve medication adherence. PMID- 24465049 TI - Efficacy of lung recruitment maneuver with high-level positive end-expiratory pressure in patients with influenza-associated acute respiratory distress: a single-center prospective study. AB - BACKGROUND: The latest data released to the public from the Chinese Ministry of Health reported 120,940 confirmed H1N1 cases and 659 deaths on the Chinese mainland. OBJECTIVE: We performed a prospective, single-center study to investigate the efficacy of lung recruitment maneuver (RM) with high-level positive end-expiratory pressure (PEEP) in patients with the 2009 influenza A (H1N1)-associated acute respiratory distress syndrome (ARDS). METHODS: Eighty four patients with H1N1-associated ARDS were admitted to emergency intensive care units between October 2009 and February 2012. During pressure control ventilation, if arterial oxygen saturation (SpO2) is consistently <88% for >30 minutes, an RM with high-level PEEP is performed to normalize lung volume at 30 cmH2O for 60 seconds. The RM was considered initially a responder if SpO2 increased >3% within 15 minutes; otherwise, an SpO2 increase <3% would be considered initially a nonresponder. Variations on oxygen metabolism and hemodynamic parameters were also measured before and after initial RM with high level PEEP. RESULTS: After the initial RM, 40 patients (47.6%) with influenza associated ARDS displayed an increase (>=3%) in SpO2 (the responder group), and 44 patients (52.4%) had no significant improvement (<3%) in SpO2 (the nonresponder group). Among 84 patients with influenza-associated ARDS, 56 patients survived and 28 patients died. There was significant difference in mortality rate between the responder group and the nonresponder group (7 out of 40 vs 18 out of 44; P = 0.019). The initial PEEP level in the responder group was lower than that of the nonresponder group (P = 0.028). The initial mean duration of mechanical ventilation in the responder group was also shorter than that of the nonresponder group (P = 0.011). Furthermore, the initial dynamic lung-thorax compliance was obviously higher in the initially responder group than in the nonresponder group (P = 0.038). CONCLUSIONS: Initial response of lung RM with high-level PEEP may be associated with good clinical outcome of patients with influenza-associated ARDS. The initial PEEP level, duration of mechanical ventilation, and dynamic lung-thorax compliance dynamic lung-thorax compliance may be potential factors in influencing the initial response to RM. PMID- 24465050 TI - The effects of gliclazide, metformin, and acarbose on body composition in patients with newly diagnosed type 2 diabetes mellitus. AB - BACKGROUND: Although numerous clinical trials have evaluated the body weight change achieved using diabetes medications alone or in combinations, the composition of body weight change in these clinical trials has rarely been assessed. OBJECTIVE: We aimed to evaluate the effects of gliclazide, metformin, and acarbose monotherapy on body composition, fat distribution, and other cardiometabolic risk factors in patients with newly diagnosed type 2 diabetes. METHODS: A total of 86 patients with newly diagnosed type 2 diabetes mellitus were randomly assigned to receive gliclazide, metformin, or acarbose for 6 months. Dual-energy x-ray absorptiometry; abdominal computed tomography scans; and measurements of adiponectin, leptin, and lipid levels were performed before and after 6-month monodrug therapy. RESULTS: Blood glucose and glycosylated hemoglobin levels significantly improved after 6 months of monodrug therapy. During the 6 months of use of the 3 antidiabetes medications, the majority of participants experienced fat mass loss and lean mass gain. Metformin monotherapy in patients with newly diagnosed type 2 diabetes led to a significant decrease in percent body fat (P = 0.029) and body fat mass (P = 0.038). Levels of serum total cholesterol (P = 0.004), triglycerides (P = 0.014), and adiponectin (P = 0.001) took a favorable turn after metformin treatment. The 3 antidiabetes medications caused no significant change in abdominal fat distribution, waist circumstance, and blood pressure during the 6 months. CONCLUSIONS: Our results suggest metformin therapy in patients with newly diagnosed type 2 diabetes can improve cardiometabolic risk markers. Moreover, body composition change induced by gliclazide and acarbose was not likely to be simple fat deposition. PMID- 24465051 TI - Temperature dependent operation of PSAPD-based compact gamma camera for SPECT imaging. AB - We investigated the dependence of image quality on the temperature of a position sensitive avalanche photodiode (PSAPD)-based small animal single photon emission computed tomography (SPECT) gamma camera with a CsI:Tl scintillator. Currently, nitrogen gas cooling is preferred to operate PSAPDs in order to minimize the dark current shot noise. Being able to operate a PSAPD at a relatively high temperature (e.g., 5 degrees C) would allow a more compact and simple cooling system for the PSAPD. In our investigation, the temperature of the PSAPD was controlled by varying the flow of cold nitrogen gas through the PSAPD module and varied from -40 degrees C to 20 degrees C. Three experiments were performed to demonstrate the performance variation over this temperature range. The point spread function (PSF) of the gamma camera was measured at various temperatures, showing variation of full-width-half-maximum (FWHM) of the PSF. In addition, a 99mTc-pertechnetate (140 keV) flood source was imaged and the visibility of the scintillator segmentation (16*16 array, 8 mm * 8 mm area, 400 MUm pixel size) at different temperatures was evaluated. Comparison of image quality was made at -25 degrees C and 5 degrees C using a mouse heart phantom filled with an aqueous solution of 99mTc-pertechnetate and imaged using a 0.5 mm pinhole collimator made of tungsten. The reconstructed image quality of the mouse heart phantom at 5 degrees C degraded in comparision to the reconstructed image quality at -25 degrees C. However, the defect and structure of the mouse heart phantom were clearly observed, showing the feasibility of operating PSAPDs for SPECT imaging at 5 degrees C, a temperature that would not need the nitrogen cooling. All PSAPD evaluations were conducted with an applied bias voltage that allowed the highest gain at a given temperature. PMID- 24465052 TI - On constrained and regularized high-dimensional regression. AB - High-dimensional feature selection has become increasingly crucial for seeking parsimonious models in estimation. For selection consistency, we derive one necessary and sufficient condition formulated on the notion of degree-of separation. The minimal degree of separation is necessary for any method to be selection consistent. At a level slightly higher than the minimal degree of separation, selection consistency is achieved by a constrained L0-method and its computational surrogate-the constrained truncated L1-method. This permits up to exponentially many features in the sample size. In other words, these methods are optimal in feature selection against any selection method. In contrast, their regularization counterparts-the L0-regularization and truncated L1-regularization methods enable so under slightly stronger assumptions. More importantly, sharper parameter estimation/prediction is realized through such selection, leading to minimax parameter estimation. This, otherwise, is impossible in absence of a good selection method for high-dimensional analysis. PMID- 24465053 TI - Bayesian nonparametric regression with varying residual density. AB - We consider the problem of robust Bayesian inference on the mean regression function allowing the residual density to change flexibly with predictors. The proposed class of models is based on a Gaussian process prior for the mean regression function and mixtures of Gaussians for the collection of residual densities indexed by predictors. Initially considering the homoscedastic case, we propose priors for the residual density based on probit stick-breaking (PSB) scale mixtures and symmetrized PSB (sPSB) location-scale mixtures. Both priors restrict the residual density to be symmetric about zero, with the sPSB prior more flexible in allowing multimodal densities. We provide sufficient conditions to ensure strong posterior consistency in estimating the regression function under the sPSB prior, generalizing existing theory focused on parametric residual distributions. The PSB and sPSB priors are generalized to allow residual densities to change nonparametrically with predictors through incorporating Gaussian processes in the stick-breaking components. This leads to a robust Bayesian regression procedure that automatically down-weights outliers and influential observations in a locally-adaptive manner. Posterior computation relies on an efficient data augmentation exact block Gibbs sampler. The methods are illustrated using simulated and real data applications. PMID- 24465054 TI - Web-based tools for modelling and analysis of multivariate data: California ozone pollution activity. AB - This article presents a hands-on web-based activity motivated by the relation between human health and ozone pollution in California. This case study is based on multivariate data collected monthly at 20 locations in California between 1980 and 2006. Several strategies and tools for data interrogation and exploratory data analysis, model fitting and statistical inference on these data are presented. All components of this case study (data, tools, activity) are freely available online at: http://wiki.stat.ucla.edu/socr/index.php/SOCR_MotionCharts_CAOzoneData. Several types of exploratory (motion charts, box-and-whisker plots, spider charts) and quantitative (inference, regression, analysis of variance (ANOVA)) data analyses tools are demonstrated. Two specific human health related questions (temporal and geographic effects of ozone pollution) are discussed as motivational challenges. PMID- 24465055 TI - Headed towards Equality? Housework Change in Comparative Perspective. AB - This paper examined gendered housework in the larger context of comparative social change, asking specifically whether cross-national differences in domestic labor patterns converge over time. Our analysis of data from 13 countries (N =11,065) from the 1994 and 2002 International Social Survey Program (ISSP), confirmed that social context matters in shaping couples' division of labor at home, but also showed that context affects patterns of change. Our results suggested that, compared to the most egalitarian countries, the shift in housework patterns was greatest among the most traditional countries. This provides support for the thesis of cultural convergence, but the evidence did not suggest that such convergence will lead to complete equality in the foreseeable future. PMID- 24465056 TI - Indicators of Adolescent Depression and Relationship Progression in Emerging Adulthood. AB - Adolescent depression may be associated with future relationship problems that have long-term consequences given the developmental importance and health benefits of forming committed unions in emerging adulthood. The authors examined associations between emotional and behavioral indicators of adolescent depression (depressive symptoms, alcohol problems, and suicidal ideation) and romantic relationship and union formation and dissolution in emerging adulthood (n = 14,146) using the National Longitudinal Study of Adolescent Health. Adolescent alcohol problems were associated with more romantic relationships in emerging adulthood. Emerging adults with depressive symptoms or alcohol problems in adolescence were significantly more likely to enter into a cohabiting union, and those with adolescent alcohol problems were less likely to marry. Cohabiting emerging adults with a history of adolescent depressive symptoms were less likely to marry, whereas suicidal ideation was associated with a decreased likelihood of cohabitation dissolution. Implications for future research are discussed. PMID- 24465057 TI - Species-specific effect of macrobenthic assemblages on meiobenthos and nematode community structure in shallow sandy sediments. AB - Three functionally different macrofaunal species (the filter- and/or surface deposit-feeding polychaete Hediste diversicolor, and the suspension-feeding bivalves Mya arenaria and Cerastoderma glaucum) were introduced as single- and two-species treatments into microcosms containing sandy sediment with a natural meiofaunal community. H. diversicolor is a burrowing species building a system of galleries, C. glaucum lives actively near the sediment surface acting as a biodiffuser and M. arenaria buries deeply and leads a sessile lifestyle. It is shown that H. diversicolor extended the vertical distribution of meiofauna into deeper sediment layers compared to the control and non-Hediste treatments. The response of the nematode community varied significantly among treatments and was dependant on the macrobenthic species composition but not on the species number. Nematode assemblages in all treatments with the polychaete, both in monoculture and with either bivalve, differed significantly from those recorded in other treatments and were more similar than replicates within any other single treatment. H. diversicolor also appeared to have stimulated nematode species diversity. The present study demonstrated that the impact of macrobenthic assemblages on meiofauna is not a simple summation of individual species effects but is species specific. PMID- 24465058 TI - Physicochemical and Mechanical Evaluation of Cation-Modified ACP Acrylic Resin Composites. PMID- 24465059 TI - Synthetic Routes to a Series of Proximal and Distal 2'-Deoxy Fleximers. AB - Two series of innovative 2'-deoxy nucleoside analogues have been designed where the nucleobase has been split into its imidazole and pyrimidine subunits. This structural modification serves to introduce flexibility into the nucleobase scaffold while still retaining the elements required for recognition. The synthetic efforts to realize these analogues are described within. PMID- 24465061 TI - The genetic and environmental overlap between aggressive and non-aggressive antisocial behavior in children and adolescents using the self-report delinquency interview (SR-DI). AB - PURPOSE: This study investigated genetic and environmental commonalities and differences between aggressive and non-aggressive antisocial behavior (ASB) in male and female child and adolescent twins, based on a newly developed self report questionnaire with good reliability and external validity - the Self Report Delinquency Interview (SR-DI). METHODS: Subjects were 780 pairs of twins assessed through laboratory interviews at three time points in a longitudinal study, during which the twins were: (1) ages 9-10 years; (2) age 11-13 years, and (3) age 16-18 years. RESULTS: Sex differences were repeatedly observed for mean levels of ASB. In addition, diverse change patterns of genetic and environmental emerged, as a function of sex and form of ASB, during the development from childhood to adolescence. Although there was some overlap in etiologies of aggressive and non-aggressive ASB, predominantly in shared environmental factors, their genetic overlap was moderate and the non-shared environmental overlap was low. CONCLUSIONS: Taken together, these results reinforced the importance of differentiating forms of ASB and further investigating sex differences in future research. These results should be considered in future comparisons between youth self-report and parental or teacher report of child and adolescent behavior, and may help elucidate commonalities and differences among informants. PMID- 24465060 TI - The Roles of Perceived Neighborhood Disorganization, Social Cohesion, and Social Control in Urban Thai Adolescents' Substance Use and Delinquency. AB - Substance use and delinquency in Thai adolescents are growing public health concerns. Research has linked neighborhood characteristics to these outcomes, with explanations focused on neighborhood disorganization, social cohesion, and social control. This study examines the independent associations of these neighborhood constructs with Thai adolescents' substance use and delinquency, through peer deviance, to determine which neighborhood aspects are particularly important. Families (N=420) with adolescents aged 13-14 were randomly selected from 7 districts in Bangkok, Thailand. Structural equation modeling showed that adolescents', but not parents', perceptions of greater disorganization were related to increased rates of both minor and serious delinquency. Surprisingly, greater neighborhood cohesion was related to greater minor delinquency. Peer deviance was unrelated to neighborhood variables. Findings can inform prevention strategies for Thai adolescents, as results suggest that neighborhoods are important for adolescent behaviors regardless of culture. Further work should help communities make use of social cohesion to benefit residents. PMID- 24465062 TI - Relative Impact of Violence Exposure and Immigrant Stressors on Latino Youth Psychopathology. AB - Latino youth in a low-income urban community are at high risk of exposure to violence. Given an accumulation of factors before, during, and following migration, immigrant youth may be at increased risk of exposure to violence and other relevant stressors (e.g., acculturation stress, language proficiency, acculturation/enculturation, and parental separations). Utilizing a short-term longitudinal design, we assessed exposure to violence and immigrant stressors and examined their relative impact on psychopathology in a sample of 164 Latino youth. Immigrant youth reported greater exposure to immigrant stressors relative to native-born peers, but few differences in rates of exposure to violence emerged. When considered alongside relevant immigration stressors, exposure to violence emerged as the strongest predictor of youth psychopathology. Results suggest that some types of stressors have more consistently deleterious effects on mental health and understanding resilient outcomes may entail considering the meaning attributed to stressors and the resources available to cope with stressors. PMID- 24465063 TI - Spatiotemporal coupling between speech and manual motor actions. AB - Much evidence has been found for pervasive links between the manual and speech motor systems, including evidence from infant development, deictic pointing, and repetitive tapping and speaking tasks. We expand on the last of these paradigms to look at intra- and cross-modal effects of emphatic stress, as well as the effects of coordination in the absence of explicit rhythm. In this study, subjects repeatedly tapped their finger and synchronously repeated a single spoken syllable. On each trial, subjects placed an emphatic stress on one finger tap or one spoken syllable. Results show that both movement duration and magnitude are affected by emphatic stress regardless of whether that stress is in the same domain (e.g., effects on the oral articulators when a spoken repetition is stressed) or across domains (e.g., effects on the oral articulators when a tap is stressed). Though the size of the effects differs between intra-and cross domain emphases, the implementation of stress affects both motor domains, indicating a tight connection. This close coupling is seen even in the absence of stress, though it is highlighted under stress. The results of this study support the idea that implementation of prosody is not domain-specific but relies on general aspects of the motor system. PMID- 24465064 TI - A linear S-bridged trinuclear cobalt(III) complex with 2-aminobenzenethiol: Synthesis, crystal structure, and spectroscopic characterization. AB - Treatment of cobalt(II) perchlorate hexahydrate with 2 molar equiv. of 2 aminobenzenethiol (Habt) in acetonitrile afforded a tricationic tricobalt complex, [Co{Co(abt)3}2](ClO4)3.2CH3CN, by aerial oxidation. The molecular structure of the meso (DeltaLambda) form of the complex was determined by X-ray crystallography. In the complex cation, the central Co is coordinated by six thiolate groups from two terminal fac(S)-[Co(abt)3] units in an octahedral geometry, forming a linear S-bridged tricobalt structure. PMID- 24465065 TI - Trend and impact of international collaboration in clinical medicine papers published in Malaysia. AB - Research collaboration is the way forward in order to improve quality and impact of its research findings. International research collaboration has resulted in international co-authorship in scientific communications and publications. This study highlights the collaborating research and authorship trend in clinical medicine in Malaysia from 2001 to 2010. Malaysian-based author affiliation in the Web of Science (Science Citation Index Expanded) and clinical medicine journals (n = 999) and articles (n = 3951) as of 30th Oct 2011 were downloaded. Types of document analyzed were articles and reviews, and impact factors (IF) in the 2010 Journal Citation Report Science Edition were taken to access the quality of the articles. The number of publications in clinical medicine increased from 4.5 % (n = 178) in 2001 to 23.9 % (n = 944) in 2010. The top three contributors in the subject categories are Pharmacology and Pharmacy (13.9 %), General and Internal Medicine (13.6 %) and Tropical Medicine (7.3 %). By journal tier system: Tier 1 (18.7 %, n = 738), Tier 2 (22.5 %, n = 888), Tier 3 (29.6 %, n = 1170), Tier 4 (27.2 %, n = 1074), and journals without IF (2.1 %, n = 81). University of Malaya was the most productive. Local collaborators accounted for 60.3 % and international collaborations 39.7 %. Articles with international collaborations appeared in journals with higher journal IFs than those without international collaboration. They were also cited more significantly than articles without international collaborations. Citations, impact factor and journal tiers were significantly associated with international collaboration in Malaysia's clinical medicine publications. Malaysia has achieved a significant number of ISI publications in clinical medicine participation in international collaboration. PMID- 24465066 TI - Interactive processing of contrastive expressions by Russian children. AB - Children's ability to interpret color adjective noun phrases (e.g., red butterfly) as contrastive was examined in an eyetracking study with 6-year-old Russian children. Pitch accent placement (on the adjective red, or on the noun butterfly) was compared within a visual context containing two red referents (a butterfly and a fox) when only one of them had a contrast member (a purple butterfly) or when both had a contrast member (a purple butterfly and a grey fox). Contrastiveness was enhanced by the Russian-specific 'split constituent' construction (e.g., Red put butterfly . . .) in which a contrastive interpretation of the color term requires pitch accent on the adjective, with the nonsplit sentences serving as control. Regardless of the experimental manipulations, children had to wait until hearing the noun (butterfly) to identify the referent, even in splits. This occurred even under conditions for which the prosody and the visual context allow adult listeners to infer the relevant contrast set and anticipate the referent prior to hearing the noun (accent on the adjective in 1-Contrast scenes). Pitch accent on the adjective did facilitate children's referential processing, but only for the nonsplit constituents. Moreover, visual contexts that encouraged the correct contrast set (1-Contrast) only facilitated referential processing after hearing the noun, even in splits. Further analyses showed that children can anticipate the reference like adults but only when the contrast set is made salient by the preceding supportive discourse, that is, when the inference about the intended contrast set is provided by the preceding utterance. PMID- 24465067 TI - Geometric Sensitivity of a Pinhole Collimator. AB - Geometric sensitivity for single photon emission computerized tomography (SPECT) is given by a double integral over the detection plane. It would be useful to be able to explicitly evaluate this quantity. This paper shows that the inner integral can be evaluated in the situation where there is no gamma ray penetration of the material surrounding the pinhole aperature. This is done by converting the integral to an integral in the complex plane and using Cauchy's theorem to replace it by one which can be evaluated in terms of elliptic functions. PMID- 24465069 TI - Open- vs. closed-path eddy covariance measurements of the net ecosystem carbon dioxide and water vapour exchange: a long-term perspective. AB - The differential design, deployment and data post-processing of open- (OP) and closed-path (CP) eddy covariance systems is a potential source of bias for ongoing global flux synthesis activities. Here we use a unique six year data set of concurrent CP and OP carbon dioxide (CO2) and water vapour (H2O) eddy covariance flux measurements above a temperate mountain grassland in Austria to explore the consequences of these differences on a long-term basis. The theoretically based transfer function approach was able to account and correct for the differences in low-pass filtering between the two systems. Corrected CO2 and H2O fluxes exhibited excellent 1:1 correspondence, but the CP system tended to underestimate OP H2O fluxes during conditions of high air temperature, wind speed and global radiation, large sun angles and low relative humidity. Corrections for self-heating of the OP infra-red gas analyser had a very small effect on these relationships. Energy balance closure was slightly more favourable for the OP system. No significant differences were found for the random flux uncertainty of both systems. A larger fraction of OP data had to be excluded because of obstructions of the infra-red path by water and snow. This, however, did not translate into a correspondingly larger fraction of accepted CP flux values, because of a larger percentage of CP flux data failing on the stationarity test. Integrated over the annual cycle, the CP system yielded on average a more positive net ecosystem CO2 exchange (25 vs. 0 gC m-2 y-1) and a lower evapotranspiration (465 vs. 549 mm y-1) as compared to the OP system. PMID- 24465068 TI - Cumulative exposure to neighborhood context: consequences for health transitions over the adult life course. AB - Over the last two decades, research has assessed the relationship between neighborhood socioeconomic factors and individual health. However, existing research is based almost exclusively on cross-sectional data, ignoring the complexity in health transitions that may be shaped by long-term residential exposures. We address these limitations by specifying distinct health transitions over multiple waves of a 15-year study of American adults. We focus on transitions between a hierarchy of health states, (free from health problems, onset of health problems, and death), not just gradients in a single health indicator over time, and use a cumulative measure of exposure to neighborhoods over adulthood. We find that cumulative exposure to neighborhood disadvantage has significant effects on functional decline and mortality. Research ignoring a persons' history of exposure to residential contexts over the life course runs the risk of underestimating the role of neighborhood disadvantage on health. PMID- 24465070 TI - On the consequences of the energy imbalance for calculating surface conductance to water vapour. AB - The Penman-Monteith combination equation, which is most frequently used to derive the surface conductance to water vapour (Gs), implicitly assumes the energy balance to be closed. Any energy imbalance (positive or negative) will thus affect the calculated Gs. Using eddy covariance energy flux data from a temperate grassland and a desert shrub ecosystem we explored five possible approaches of closing the energy imbalance and show that calculated Gs may differ considerably between these five approaches depending on the relative magnitudes of sensible and latent heat fluxes, and the magnitude and sign of the energy imbalance. Based on our limited understanding of the nature of the energy imbalance, we tend to favour an approach which preserves the Bowen-ratio and closes the energy balance on a larger time scale. PMID- 24465071 TI - Leaf and ecosystem response to soil water availability in mountain grasslands. AB - Climate change is expected to affect the Alps by increasing the frequency and intensity of summer drought events with negative impacts on ecosystem water resources. The response of CO2 and H2O exchange of a mountain grassland to natural fluctuations of soil water content was evaluated during 2001-2009. In addition, the physiological performance of individual mountain forb and graminoid plant species under progressive soil water shortage was explored in a laboratory drought experiment. During the 9-year study period the natural occurrence of moderately to extremely dry periods did not lead to substantial reductions in net ecosystem CO2 exchange and evapotranspiration. Laboratory drought experiments confirmed that all the surveyed grassland plant species were insensitive to progressive soil drying until very low soil water contents (<0.01 m3 m-3) were reached after several days of drought. In field conditions, such a low threshold was never reached. Re-watering after a short-term drought event (5+/-1 days) resulted in a fast and complete recovery of the leaf CO2 and H2O gas exchange of the investigated plant species. We conclude that the present-day frequency and intensity of dry periods does not substantially affect the functioning of the investigated grassland ecosystem. During dry periods the observed "water spending" strategy employed by the investigated mountain grassland species is expected to provide a cooling feedback on climate warming, but may have negative consequences for down-stream water users. PMID- 24465072 TI - Can an energy balance model provide additional constraints on how to close the energy imbalance? AB - Elucidating the causes for the energy imbalance, i.e. the phenomenon that eddy covariance latent and sensible heat fluxes fall short of available energy, is an outstanding problem in micrometeorology. This paper tests the hypothesis that the full energy balance, through incorporation of additional independent measurements which determine the driving forces of and resistances to energy transfer, provides further insights into the causes of the energy imbalance and additional constraints on energy balance closure options. Eddy covariance and auxiliary data from three different biomes were used to test five contrasting closure scenarios. The main result of our study is that except for nighttime, when fluxes were low and noisy, the full energy balance generally did not contain enough information to allow further insights into the causes of the imbalance and to constrain energy balance closure options. Up to four out of the five tested closure scenarios performed similarly and in up to 53% of all cases all of the tested closure scenarios resulted in plausible energy balance values. Our approach may though provide a sensible consistency check for eddy covariance energy flux measurements. PMID- 24465073 TI - Not just for poor kids: The impact of universal free school breakfast on meal participation and student outcomes. AB - This paper examines the impact of the implementation of a universal free school breakfast policy on meals program participation, attendance, and academic achievement. In 2003, New York City made school breakfast free for all students regardless of income, while increasing the price of lunch for those ineligible for meal subsidies. Using a difference-indifference estimation strategy, we derive plausibly causal estimates of the policy's impact by exploiting within and between group variation in school meal pricing before and after the policy change. Our estimates suggest that the policy resulted in small increases in breakfast participation both for students who experienced a decrease in the price of breakfast and for free-lunch eligible students who experienced no price change. The latter suggests that universal provision may alter behavior through mechanisms other than price, highlighting the potential merits of universal provision over targeted services. We find limited evidence of policy impacts on academic outcomes. PMID- 24465074 TI - Mechanistic Studies of Azaphilic versus Carbophilic Activation by Gold(I) in the Gold/Palladium Dual-Catalyzed Rearrangement of Alkenyl Vinyl Aziridines. AB - A vinyl aziridine activation strategy cocatalyzed by palladium(0) and a gold(I) Lewis acid has been developed. This rearrangement installs a C-C and a C-N bond in one synthetic step to form pyrrolizidine and indolizidine products. Two proposed mechanistic roles for the gold cocatalyst were considered: (1) carbophilic gold catalysis or (2) azaphilic gold catalysis. Mechanistic studies support an azaphilic Lewis acid activation of the aziridine over a carbophilic Lewis acid activation of the alkene. PMID- 24465075 TI - Photoinduced Brook-Type Rearrangement of Acylcyclopolysilanes. AB - Previously unknown 1,1,4-tris(trimethylsilyl)-4-acyldodecamethylcyclohexasilanes (Me3Si)2Si6Me12(Me3Si)COR (16a, R = tert-butyl; 16b, R = 1-adamantyl) have been synthesized by the reaction of the potassium silanides (Me3Si)2Si6Me12(Me3Si)K with acid chlorides ClCOR, and their photochemical rearrangement reactions have been studied. The molecular structures of 16a,b as determined by single-crystal X ray diffraction analysis exhibit an unusual twist-boat conformation of the cyclohexasilane ring. When 16a,b were photolyzed with lambda >300 nm radiation, they underwent Brook type 1,3-Si -> O migration reactions to generate the cyclohexasilanes 17a,b with exocyclic Si=C bonds along with smaller amounts of the ring-enlarged species 19a,b with endocyclic Si=C double bonds. While 17a,b were stable enough to allow characterization by NMR and UV absorption spectroscopy, the less stable products 19a,b could only be observed in the form of their methanol adducts. PMID- 24465076 TI - Equilibrium Study of Pd(dba)2 and P(OPh)3 in the Pd-Catalyzed Allylation of Aniline by Allyl Alcohol. AB - Reaction of Pd(dba)2 and P(OPh)3 shows a unique equilibrium where the Pd[P(OPh)3]3 complex is favored over both Pd(dba)[P(OPh)3]2 and Pd[P(OPh)3]4 complexes at room temperature. At a lower temperature, Pd[P(OPh)3]4 becomes the most abundant complex in solution. X-ray studies of Pd[P(OPh)3]3 and Pd(dba)[P(OPh)3]2 complexes show that both complexes have a trigonal geometry with a Pd-P distance of 2.25 A due to the pi-acidity of the phosphite ligand. In solution, pure Pd(dba)[P(OPh)3]2 complex equilibrates to the favored Pd[P(OPh)3]3 complex, which is the most stable complex of those studied, and also forms the most active catalytic species. This catalyst precursor dissociates one ligand to give the reactive Pd[P(OPh)3]2, which performs an oxidative addition of nonmanipulated allyl alcohol to generate the pi-allyl-Pd[P(OPh)3]2 intermediate according to ESI-MS studies. PMID- 24465078 TI - APPROXIMATING POWER OF THE UNCONDITIONAL TEST FOR CORRELATED BINARY PAIRS. AB - We provide a simple and good approximation of power of the unconditional test for two correlated binary variables. Suissa and Shuster (1991) described the exact unconditional test. The most commonly used statistical test in this setting, McNemar's test, is exact conditional on the sum of the discordant pairs. Although asymptotically the conditional and unconditional versions coincide, a long standing debate surrounds the choice between them. Several power approximations have been studied for both methods (Miettinen, 1968; Bennett and Underwood, 1970; Connett, Smith, and McHugh, 1987; Connor, 1987; Suissa and Shuster, 1991; Lachenbruch, 1992; Lachin, 1992). For the unconditional approach most existing power approximations use the Gaussian distribution, while the accurate ("exact") method is computationally burdensome. A new approximation uses the F statistic corresponding to a paired-data T test computed from the difference scores of the binary outcomes. Enumeration of all possible 2 * 2 tables for small sample sizes allowed evaluation of both test size and power. The new approximation compares favorably to others due to the combination of ease of use and accuracy. PMID- 24465077 TI - Structural Consequences of Chromophore Formation and Exploration of Conserved Lid Residues amongst Naturally Occurring Fluorescent Proteins. AB - Computational methods were used to generate the lowest energy conformations of the immature precyclized forms of the 28 naturally occurring GFP-like proteins deposited in the pdb. In all 28 GFP-like proteins, the beta-barrel contracts upon chromophore formation and becomes more rigid. Our prior analysis of over 260 distinct naturally occurring GFP-like proteins revealed that most of the conserved residues are located in the top and bottom of the barrel in the turns between the beta-sheets.(1) Structural analyses, molecular dynamics simulations and the Anisotropic Network Model were used to explore the role of these conserved lid residues as possible folding nuclei. Our results are internally consistent and show that the conserved residues in the top and bottom lids undergo relatively less translational movement than other lid residues, and a number of these residues may play an important role as hinges or folding nuclei in the fluorescent proteins. PMID- 24465079 TI - Properties of Doubly-Truncated Gamma Variables. AB - The truncated gamma distribution has been widely studied, primarily in life testing and reliability settings. Most work has assumed an upper bound on the support of the random variable, i.e. the space of the distribution is (0, u). We consider a doubly-truncated gamma random variable restricted by both a lower (l) and upper (u) truncation point, both of which are considered known. We provide simple forms for the density, cumulative distribution function (CDF), moment generating function, cumulant generating function, characteristic function, and moments. We extend the results to describe the density, CDF, and moments of a doubly-truncated noncentral chi-square variable. PMID- 24465080 TI - NON-HOMOGENEOUS POISSON PROCESS MODEL FOR GENETIC CROSSOVER INTERFERENCE. AB - The genetic crossover interference is usually modeled with a stationary renewal process to construct the genetic map. We propose two non-homogeneous, also dependent, Poisson process models applied to the known physical map. The crossover process is assumed to start from an origin and to occur sequentially along the chromosome. The increment rate depends on the position of the markers and the number of crossover events occurring between the origin and the markers. We show how to obtain parameter estimates for the process and use simulation studies and real Drosophila data to examine the performance of the proposed models. PMID- 24465081 TI - Nonparametric Comparison for Multivariate Panel Count Data. AB - Multivariate panel count data often occur when there exist several related recurrent events or response variables defined by occurrences of related events. For univariate panel count data, several nonparametric treatment comparison procedures have been developed. However, it does not seem to exist a nonparametric procedure for multivariate cases. Based on differences between estimated mean functions, this paper proposes a class of nonparametric test procedures for multivariate panel count data. The asymptotic distribution of the new test statistics is established and a simulation study is conducted. Also the new procedures are applied to a skin cancer problem that motivated this study. PMID- 24465083 TI - Cloning and Expression Analysis of a Gene Encoding for Ascorbate Peroxidase and Responsive to Salt Stress in Beet (Beta vulgaris). AB - BvpAPX is a full-length cDNA-encoding peroxisomal ascorbate peroxidase isolated from leaves of salt-stressed beet (Beta vulgaris) plants. A high level of identity has been reported between the deduced amino acid sequence of BvpAPX and other known ascorbate peroxidases. The genomic sequence of BvpAPX revealed a gene composed of 5 exons and 4 introns. Several sequence motifs revealed in the 5'UTR region of the gene confer to BvpAPX a putative responsiveness to various abiotic stresses. We determined the effect of salt stress on BvpAPX expression in leaves of the cultivated beet varieties, Huzar and Janosik, and their wild salt-tolerant relative B. vulgaris ssp. maritima. Plants were subjected to salt stress during a 32-day culture period (long-term salt treatment). An alternative salinization protocol consisted of an 18-h incubation of detached beet leaves in media supplemented with toxic salt concentrations (short-term salt treatment). RT-Q-PCR analysis revealed that BvpAPX expression markedly increased in leaves of plants subjected to conditions of long-term treatment with salinity, whereas BvpAPX transcript levels remained unaffected in detached leaves during short-term salt treatment. In addition, several leaf redox system parameters, such as ascorbate peroxidase activity or ascorbic acid, hydrogen peroxide, and lipid hydroperoxide concentration, were determined in the leaves of beet plants subjected to salt stress conditions. PMID- 24465082 TI - Farnesoid X receptor-Acting through bile acids to treat metabolic disorders. AB - Farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily and plays an important role in maintaining bile acid, lipid and glucose homeostasis. Bile acids are endogenous ligands for FXR. However, bile acids may also activate pathways independent of FXR. The development of specific FXR agonists has provided important insights into the role of FXR in metabolism. Recent data have demonstrated that FXR is a therapeutic target for treatment of certain metabolic disorders. This review will focus on recent advances in the role of FXR in metabolic disease. PMID- 24465086 TI - Priming Lexical Neighbors of Spoken Words: Effects of Competition and Inhibition. AB - Two experiments employing an auditory priming paradigm were conducted to test predictions of the Neighborhood Activation Model of spoken word recognition (Luce & Pisoni, 1989, Neighborhoods of words in the mental lexicon. Manuscript under review). Acoustic-phonetic similarity, neighborhood densities, and frequencies of prime and target words were manipulated. In Experiment 1, priming with low frequency, phonetically related spoken words inhibited target recognition, as predicted by the Neighborhood Activation Model. In Experiment 2, the same prime target pairs were presented with a longer inter-stimulus interval and the effects of priming were eliminated. In both experiments, predictions derived from the Neighborhood Activation Model regarding the effects of neighborhood density and word frequency were supported. The results are discussed in terms of competing activation of lexical neighbors and the dissociation of activation and frequency in spoken word recognition. PMID- 24465084 TI - Overexpression of PtSOS2 Enhances Salt Tolerance in Transgenic Poplars. AB - Protein kinases are major signal transduction factors that have a central role in mediating acclimation to environmental changes in eukaryotic organisms. In this study, we cloned and identified three salt overly sensitive 2 (SOS2) genes in the woody plant Populus trichocarpa, designated as PtSOS2.1, PtSOS2.2, and PtSOS2.3, which were transformed into hybrid poplar clone T89 (Populus tremula* Populus tremuloides Michx clone T89) mediated by Agrobacterium tumefaciens. Southern and northern blot analyses verified that the three genes integrated into the plant genome, and were expressed at a stable transcription level. Meanwhile, overexpression of all three PtSOS2 genes did not retard the growth of plants under normal conditions. Instead, it promoted growth in both agar-medium and soil conditions in response to salinity stress. Under salt stress, overexpression of PtSOS2.1, PtSOS2.2, and PtSOS2.3 increased the concentrations of proline and photosynthetic pigments, and the relative water content (RWC), and the activity of antioxidant enzymes, and decreased the malondialdehyde (MDA) concentrations in transgenic lines compared to the control. These results suggest that overexpression of PtSOS2 plays a significant role in improving the salt tolerance of poplars, reducing the damage to membrane structures, and enhancing osmotic adjustment and antioxidative enzyme regulation under salt stress. PMID- 24465085 TI - An Optimized Protocol to Increase Virus-Induced Gene Silencing Efficiency and Minimize Viral Symptoms in Petunia. AB - Virus-induced gene silencing (VIGS) is used to down-regulate endogenous plant genes. VIGS efficiency depends on viral proliferation and systemic movement throughout the plant. Although tobacco rattle virus (TRV)-based VIGS has been successfully used in petunia (Petunia * hybrida), the protocol has not been thoroughly optimized for efficient and uniform gene down-regulation in this species. Therefore, we evaluated six parameters that improved VIGS in petunia. Inoculation of mechanically wounded shoot apical meristems induced the most effective and consistent silencing compared to other methods of inoculation. From an evaluation of ten cultivars, a compact petunia variety, 'Picobella Blue', exhibited a 1.8-fold higher CHS silencing efficiency in corollas. We determined that 20 degrees C day/18 degrees C night temperatures induced stronger gene silencing than 23 degrees C/18 degrees C or 26 degrees C/18 degrees C. The development of silencing was more pronounced in plants that were inoculated at 3 4 versus 5 weeks after sowing. While petunias inoculated with pTRV2-NbPDS or pTRV2-PhCHS showed very minimal viral symptoms, plants inoculated with the pTRV2 empty vector (often used as a control) were stunted and developed severe necrosis, which often led to plant death. Viral symptoms were eliminated by developing a control construct containing a fragment of the green fluorescent protein (pTRV2-sGFP). These optimization steps increased the area of chalcone synthase (CHS) silencing by 69 % and phytoene desaturase (PDS) silencing by 28 %. This improved VIGS protocol, including the use of the pTRV2-sGFP control plants, provides stronger down-regulation for high-throughput analyses of gene function in petunia. PMID- 24465087 TI - A CROSS-CULTURAL STUDY OF THE EXPERIENTIAL STRUCTURE OF EMOTIONS OF DISTRESS: PRELIMINARY FINDINGS IN A SAMPLE OF FEMALE JAPANESE AND AMERICAN COLLEGE STUDENTS. AB - Negative emotions such as anger, sadness and fear are universal; however, there is cultural variability in the ways that specific emotions cluster together. This Experience Sampling Method study collected daily life emotions of distress for 44 American and 50 Japanese college students. These women reported their experiences of 37 distresses once a day for seven days. Cluster Analysis revealed that Americans had upset, depression, hostility and dependency clusters. The Japanese had depression, sad/angry, gloomy, hate and interpersonal clusters. Cultural analysis of idioms of distress and clinical implications are discussed. PMID- 24465088 TI - All together now: Integrating biofilm research across disciplines. AB - Bacterial biofilms are integrated, multi-species communities of cells that adhere to almost any surface and are fundamental to the ecology and biology of bacteria. Not only do biofilms contribute to human health and disease, they also play important roles in the context of energy and the environment. The formation of biofilms requires interactions between bacteria and the surfaces they colonize, and both microbe and surface can impact the structure, function, and composition of these communities. Bacteria in biofilms exhibit surprisingly sophisticated social behavior, both cooperative and competitive, made possible by their cell biology. However, they are also hierarchically organized systems governed by complex physical and chemical interactions. Because of this, the study of bacterial biofilms has recently attracted the attention of materials scientists, physicists, chemists, and nanotechnology experts who import not only new tools, but also new concepts and perspectives. This issue reviews recent progress in multidisciplinary studies of biofilms. PMID- 24465089 TI - Transforming prevention systems in the United States and the Netherlands using Communities That Care Promising prevention in the eyes of Josine Junger-Tas. AB - Josine Junger-Tas introduced the Communities That Care (CTC) prevention system to the Netherlands as a promising approach to address the growing youth violence and delinquency. Using data from a randomized trial of CTC in the United States and a quasi-experimental study of CTC in the Netherlands, this article describes the results of a comparison of the implementation of CTC in 12 U.S. communities and 5 Dutch neighborhoods. CTC communities in both countries achieved higher stages of a science-based approach to prevention than control communities, but full implementation of CTC in the Netherlands was hampered by the very small list of prevention programs tested and found effective in the Dutch context. PMID- 24465090 TI - Face expressive lifting (FEL): an original surgical concept combined with bipolar radiofrequency. AB - BACKGROUND: Aging can lead to changes in facial expressions, transforming the positive youth expression of happiness to negative expressions as sadness, tiredness, and disgust. Local skin distension is another consequence of aging, which can be difficult to treat with rejuvenation procedures. The "face expressive lifting" (FEL) is an original concept in facial rejuvenation surgery. On the one hand, FEL integrates established convergent surgical techniques aiming to correct the age-related negative facial expressions. On the other hand, FEL incorporates novel bipolar RF technology aiming to correct local skin distension. METHODS: One hundred twenty-six patients underwent FEL procedure. Facial expression and local skin distension were assessed with 2 years follow-up. RESULTS: There was a correction of negative facial expression for 96 patients (76 %) and a tightening of local skin distension in 100 % of cases. CONCLUSIONS: FEL is an effective procedure taking into account and able to correct both age related negative changes in facial expression and local skin distension using radiofrequency. Level of Evidence: Level IV, therapeutic study. PMID- 24465091 TI - Brachial lifting using the balanced triple-vector (BTV) technique with dual opposing flaps. AB - BACKGROUND: Brachioplasty often involves removing excess skin. Many traditional approaches to this form of surgery are prone to complications and imperfect healing of the incisions. Traditional techniques usually take little or no account of the force vectors that are subsequently applied to the incision after the operation. This contributes towards scarring and other complications. METHOD: The proposed technique involves the explicit application of three balanced force vectors that greatly reduce scar-related complications. Although the scar is longer, it is on the medial side of the arm and usually fades away completely over time, with greatly improved aesthetic results. A closely related aspect of this technique is the application of anthropometric techniques in order to plan the operation for best results. RESULTS: The proposed technique has been applied in practice to 23 patients. There were no long-term complications. Temporary paresthesia was observed in 5 patients and temporary swelling of hands in 2 patients. One case of seroma was also detected. Two patient required surgical scar revision. One patient was unsastified with the final scar quality. CONCLUSIONS: Due to the superficial resection in this technique, no damage to the subcutaneous tissue and lymphatic network occurs, resulting in a more predictable outcome with greatly reduced risk of complications. This technique is particularly good at reducing the scar retraction issues most common when using other single-vector approaches. Level of Evidence: Level IV, therapeutic study. PMID- 24465092 TI - Use of a Pteridine Moiety to Track DNA Uptake in Cells. AB - Fluorescence labeled oligonucleotides have a long history of being used to monitor nucleic acid transport and uptake. However, it is not known if the fluorescent moiety itself physically limits the number of pathways that can be used by the cell due to steric, hydrophobic, or other chemical characteristics. Here, we report a method for comparing the uptake kinetics of oligonucleotides labeled either with the fluorescent pteridine, 3-methyl-8-(2-deoxy-beta-D ribofuranosyl) isoxanthopterin (3MI), or the common fluorophore 5 carboxyfluorescein (5-FAM). We use a multiphoton microscopic technique to monitor nucleic acid uptake LLC-PK1, a pig renal tubular cell line that is known to have multiple uptake pathways. We find that the two fluorophores enter the cells at different rates, suggesting that choice of fluorescent moiety influences the uptake pathway used by a cell. Finally, we reconstituted an LLC-PK1 membrane channel that is selective for nucleic acids in planar lipid bilayers, and tested the ability of the labeled nucleic acids to permeate the channel. We find that 3MI, and not 5-FAM labeled oligonucleotides can traverse the plasma membrane through the channel. These results have implications for future studies aimed at delivering pteridine moieties to cells and for tracking nucleic acid transport into tissues. PMID- 24465093 TI - High average power Yb:CaF2 femtosecond amplifier with integrated simultaneous spatial and temporal focusing for laser material processing. AB - A watt level, 10-kilohertz repetition rate chirped pulse amplification system that has an integrated simultaneous spatial and temporal focusing (SSTF) processing system is demonstrated for the first time. SSTF significantly reduces nonlinear effects normally detrimental to beam control enabling the use of a low numerical aperture focus to quickly treat optically transparent materials over a large area. The integrated SSTF system has improved efficiency compared to previously reported SSTF designs, which combined with the high repetition rate of the laser, further optimizes its capability to provide rapid, large volume processing. PMID- 24465094 TI - Ionic Size Effects: Generalized Boltzmann Distributions, Counterion Stratification, and Modified Debye Length. AB - Near a charged surface, counterions of different valences and sizes cluster; and their concentration profiles stratify. At a distance from such a surface larger than the Debye length, the electric field is screened by counterions. Recent studies by a variational mean-field approach that includes ionic size effects and by Monte Carlo simulations both suggest that the counterion stratification is determined by the ionic valence-to-volume ratios. Central in the mean-field approach is a free-energy functional of ionic concentrations in which the ionic size effects are included through the entropic effect of solvent molecules. The corresponding equilibrium conditions define the generalized Boltzmann distributions relating the ionic concentrations to the electrostatic potential. This paper presents a detailed analysis and numerical calculations of such a free energy functional to understand the dependence of the ionic charge density on the electrostatic potential through the generalized Boltzmann distributions, the role of ionic valence-to-volume ratios in the counterion stratification, and the modification of Debye length due to the effect of ionic sizes. PMID- 24465095 TI - The paradigm shifts in the management of breast cancer-have we finally arrived? PMID- 24465096 TI - Situs Inversus Totalis (SIT) with Hepatocellular Carcinoma (HCC): A Rare Case Report and Review of 12 Other Cases. AB - Hepatocellular carcinoma (HCC) is the seventh-most common malignancy in males and ninth in females with incidence of one million new cases every year. Situs inversus totalis (SIT) is a rare congenital condition, in which there is a mirror image transposition of both the abdominal and thoracic viscera. There are very few reported cases of HCC developing in people with SIT. In this review, we present a new case of HCC with SIT, and a review of literatures published between 1983 and 2011 on it. The literatures in English were searched through PubMed and Google Scholar, while those in Japanese language were accessed through J-EAST and translated in English with the help of Google translator on 22 April 2012. There are 6 English and 6 Japanese literatures showing 12 published cases, of which 10 cases were from Japan, 1 from Taiwan and 1 from China. Our case is probably the first case in the world beyond these regions. The articles containing adequate information, such as patient age and sex, investigations, diagnosis, type of congenital anomalies and methods of surgery, were reviewed. On reviewing the literature, we observed that clinical manifestations, laboratory findings and etiology correlate well with HCC, while anomalous hepatic vascularity correlates well with SIT. The reason for high incidence of HCC with SIT in Japan is not well correlated, but may be explained by higher incidence of SIT. All varieties of hepatic resection were feasible in cases of SIT. PMID- 24465097 TI - Management of lactational mastitis and breast abscesses: review of current knowledge and practice. AB - Most breast abscesses develops as a complication of lactational mastitis. The incidence of breast abscess ranges from 0.4 to 11 % of all lactating mothers. The traditional management of breast abscesses involves incision and drainage of pus along with antistaphylococcal antibiotics, but this is associated with prolonged healing time, regular dressings, difficulty in breast feeding, and the possibility of milk fistula with unsatisfactory cosmetic outcome. It has recently been reported that breast abscesses can be treated by repeated needle aspirations and suction drainage. The predominance of Staphylococcus aureus allows a rational choice of antibiotic without having to wait for the results of bacteriological culture. Many antibiotics are secreted in milk, but penicillin, cephalosporins, and erythromycin, however, are considered safe. Where an abscess has formed, aspiration of the pus, preferably under ultrasound control, has now supplanted open surgery as the first line of treatment. PMID- 24465098 TI - Surgical treatment of fresh complete acromioclavicular dislocation by coracoid process transfer and k-wire transfixation. AB - Acromioclavicular dislocations are very common shoulder injuries. The optimal treatment for acute high-grade acromioclavicular joint injury remains a matter of debate. The purpose of this study was to evaluate the results of surgical treatment of complete acromioclavicular dislocation using coracoid process transfer and temporary K-wire transfixation. Twenty-one patients with complete acromioclavicular dislocation underwent coracoid process transfer and temporary K wire transfixation. Patients were assessed at the follow-up based on visual analog scores (VAS), the Constant-Murley scoring system and the UCLA shoulder rating system. Radiographs were taken to check up vertical instability. The mean follow-up was 32.1 months (25-47 months). The mean Constant and Murley score and UCLA shoulder rating score was 89.9 +/- 8.4 and 30.1 +/- 4.4. There were fourteen excellent functional results and six results and one poor result. The overall rate of satisfaction, which means an excellent or good result, was 95.2 %. Nineteen patients (90.4 %) maintained their previous jobs or resume their daily activities. The mean final pain score, as measured from 1 to 10 on the visual analog scale, was 1.91 +/- 1.09. The radiographic analysis revealed twenty patients had maintained reduction at the final follow-up. The coracoid process transfer and temporary K-wire transfixation is a reliable treatment for a complete acromioclavicular dislocation. PMID- 24465099 TI - Surgical incision by high frequency cautery. AB - Traditionally, the knife has been used to make surgical incisions on the skin, but recent data suggest that diathermy blade allows the incision to be made more quickly, with less blood loss, less postoperative pain and no adverse effects on wound healing or cosmetic effect. PMID- 24465100 TI - Platelet count as a prognostic indicator in burn septicemia. AB - Evaluation of platelet count and its significance in early detection of post burn septicemia for commencement of timely vigorous treatment against it. Studies investigating the role of platelets and platelet count in burn patients are rare, rather old and mostly presenting case reports. Septicemia is the most important cause of mortality in burns. Burn patients can only be saved if septicemia is detected early which requires very sensitive prognostic indicator. Total 594 adult burn patients were studied, by observing them for septicemia and studying their subsequent platelet counts using visual method. In non-survivors (256) gradual decline in platelet count was observed and minimal platelet count was observed before death of the patient, while in survivors (338) gradual rise in platelet count was observed. No significant variation observed in other laboratory parameters such as total neutrophil count and serum creatinine. In significant number of non survivor (62.11%) platelet count was low before their death and in significant number of survivor (86.09%) platelet count was normal before their discharge. Thus it is conclude that serial declining platelet count is a very sensitive prognostic factor in early detection of post burn septicemia. PMID- 24465101 TI - Acute biliary pancreatitis: an experience in a tertiary level hospital of Nepal. AB - Acute Biliary Pancreatitis is one of the commonest forms of pancreatitis in Nepal. Controversies exist as to the most appropriate way of management of these cases. The present study was carried out to evaluate the management and outcome of Acute Biliary Pancreatitis cases in a tertiary level hospital of Nepal. A retrospective analysis of the patients managed with Acute Biliary Pancreatits was done. All patients admitted with the diagnosis of Acute Biliary Pancreatitis over a period of 2 years were included in the study. The variables measured were age, sex, clinical presentation, laboratory investigations, mode of treatment and outcome. A total of 45 cases had Acute Biliary Pancreatitis suggesting a prevalence of 28 %. The mean age was 45 +/- 10 year. 39 patients (86.6 %) were treated with conservative management. 23 patients (54 %) had an uneventful recovery without any complications. 21 patients (46 %) developed some form of complications but recovered successfully. Mortality was seen in only one patient in the conservatively treated group. In a resource poor setting such as Nepal, definitive management is not always possible. Conservative management of Acute Biliary Pancreatitis has a favorable outcome in the majority of our patients with acceptable morbidity and mortality. Definitive management can be safely performed during index admission where possible. PMID- 24465102 TI - Demographic profile of hand injuries in an industrial town of north India: a review of 436 patients. AB - There are not many injuries that rival the injured hand in complexity. A better understanding of biologic, behavioral, and socioeconomic risk factors potentially associated with hand injuries can help identify those individuals most at risk and define potential preventative measures to help reduce the incidence. We present a prospective study of 436 consecutive patients of hand and forearm injury treated over a period of 2 years. A serial recording of the demographic profile of the patient along with the type & cause of injury sustained, hand dominance, duration of hospital stay, time lag between injury and admission, type surgery preformed with intra-operative findings and the cost analysis was done. An expected male dominance in economically viable individuals of 21 to 30 years formed 50 % of the patients of which 22.9 % were labourers and students each. The malady was altercation (27.5 %) followed by industrial & road accidents. Post prandial period was most notorious with multiple neuro (27.05 %) vasculo (39.34 %) tendinous (60.66 %) injury common with even simple lacerations. Dominant hand injury was commonest. It is challenging to assess and treat an injured hand. This study defines the demography and the etiology behind the various cases of hand and forearm injury with the detailed trauma profile. The limitation of the study was absence of functional outcome. The necessity of hand trauma registry is a pre requisite to quantify the burden of hand injuries and formulate a prevention strategy. PMID- 24465103 TI - Improvement in Blood Supply After "Heparin-Dextran" Therapy in Patients of Buerger's Disease with Critical Limb Ischemia. AB - Alleviating the agonizing pain of critical limb ischemia (CLI) in patients of Buerger's disease (BD) has been challenging, due to lack of definitive treatment; "Heparin-Dextran" infusion has been tried in this study. Assessment of clinical improvement and vascular changes following therapy. Patients with CLI admitted to emergency surgical ward were studied prospectively. BD was diagnosed by Shionoya's criteria, and confirmed by digital subtraction angiography (DSA). Heparin and Dextran intravenous infusion was administered for 10 days. Severity of rest pain, ischemic changes in the feet, claudication distance and ankle brachial index (ABI) were estimated prior to therapy, at completion and 3 weeks after therapy. Vascular changes were assessed by CT angiography (CTA) performed prior to and 3 weeks after therapy. Twenty consecutive patients were studied. Successful hemodilution reflected by decreased hematocrit (37.4 % to 32.6 %, p < 0.05) and increased mean ABI (0.46 to 0.83, p < 0.01), improved rest pain in 75 % patients (p < 0.001), increased claudication distance in 94 % (p < 0.05) and ulcers healing in 70 % patients. CTA revealed recanalised vessels (decreased length of occluded segments) in 10 (50 %, p = 0.005), increased collaterals in 12 (60 %, p < 0.01) and improved distal run-off in 13 (65 %, p < 0.01) patients. "Heparin-Dextran" therapy in patients of CLI from BD improves tissue perfusion by increasing collaterals and recanalisation of vessels, resulting in significant relief from rest pain and clinical improvements. CTA is as efficacious as DSA for evaluation of BD. PMID- 24465104 TI - Treatment of early and delayed esophageal perforation. AB - Esophageal perforations are life threatening emergencies associated with high morbidity and mortality. We report on 22 consecutive patients (age 20-86; 13 female and 9 male) with an oesophageal perforation treated at the university hospital Duesseldorf. The patients' charts were reviewed and follow-up was completed for all patients until demission, healed reconstruction or death. Patients' history, clinical presentation, time interval to surgical presentation, and treatment modality were recorded and correlated with patients' outcome. Six esophageal perforations were due to a Boerhaave-syndrome, eleven caused by endoscopic perforation, two after osteosynthesis of the cervical spine and three foreign body induced. In 7 patients a primary local suture was performed, in 4 cases a supplemental muscle flap was interposed, and 7 patients underwent an oesophageal resection. Four patients were treated without surgery (three esophageal stent implantations, one conservative treatment). Eleven patients (50 %) were presented within 24 h of perforation, and 11 patients (50 %) afterwards. Time delay correlates with survival. In 17 (80.9 %) cases a surgical sufficient reconstruction could be achieved. One (4.7 %) patient is waiting for reconstruction after esophagectomy. Four (18.2 %) patients died. A small subset of patients can be treated conservatively by stenting of the Esophagus, if the patient presents early. In the majority of patients a primary repair (muscle flap etc.) can be performed with good prognosis. If the patient presents delayed with extensive necrosis or mediastinitis, oesophagectomy and secondary repair is the only treatment option with high mortality. PMID- 24465105 TI - Taking up subfascial endoscopic perforator surgery for patients of lower limb varicose veins with below knee perforators, in a government medical college-a review of eleven cases. AB - Varicose veins are the most common manifestation of chronic venous insufficiency (CVI) worldwide. They interfere with the patients' daily activities and hamper their professional endeavors, and therefore need to be addressed at the earliest with the best tools. Eleven patients of varicose veins of the lower limb with below knee perforators underwent subfascial endoscopic perforator surgery (SEPS) from October 2010 to December 2011 in our institute. The procedure was successfully completed in all 11 patients. The mean operating time was 78 min (60 96 min). The results showed a favorable outcome for the patients in terms of faster recovery and less morbidity. PMID- 24465106 TI - Impact of supplementing preoperative intravenous omega 3 Fatty acids in fish oil on immunomodulation in elderly patients undergoing hip surgery. AB - The aim of this study was to evaluate the immunomodulatory effects of supplementing intravenous omega-3 fatty acids in fish oil (IVFO) in elderly patients undergoing hip surgery. This was a single centre, randomized, controlled, comparative, phase IV study in elderly patients undergoing hip surgery. The subjects, within the age range of 50-90 years, were assigned randomly to the group receiving intravenous omega-3 fatty acids in fish oil (IVFO, Omegaven(r)) or the control group not receiving intravenous fish oil (n = 20 in each group). IL-6, IL-8, IL-10, and HS-CRP levels were the inflammatory markers assessed in this study. The within-group comparison was done by paired t test and between-group comparison by unpaired t-test. At day 4, IL-6 values in the IVFO group decreased as compared to day 0. At day 4, IL-8 mean values increased for both IVFO and control groups. This increase was highly significant in the control group (P = 0.0182). IL 10 values decreased at day 4 and increased at day 8 in the IVFO group. Increase in HS-CRP levels was nonsignificant at day 4 in the IVFO group (P = 0.60) and significant at day 8 for the control group (P = 0.0084) as compared to day 0. Various biochemical parameters including albumin, protein, SGOT, SGPT, blood glucose, and urea values generated evidence regarding the safety profile of IVFO. This study suggests a role for IVFO in the short-term suppression of inflammatory mediators for patients undergoing hip surgery. However, further, larger trials may be needed to establish its definitive role in this patient population. PMID- 24465107 TI - Nanotechnology for surgeons. AB - Surgeons are constantly looking for minimally invasive ways to treat their patients, as recovery is faster when a lesser trauma is inflicted upon a patient, scarring is lessened and there are usually fewer complications in the aftermath of the operation. Through nanotechnology, tiny biosensors could be constructed which could take these factors into account, thus shortening a patients recovery period and saving hospitals money, reducing infection rates within the hospital, reducing the waiting lists for operation and allowing doctors to treat more patients in the same period of time. One of the greatest achievements of nanotechnology in surgery will be what we call the "ideal graft"; that is, biocompatible and durable "repairs" of parts of the body like arteries, joints or even organs. At first, these repairs will be used for healing, but soon afterwards, they will be used for transcendence: to enhance current human abilities. PMID- 24465108 TI - Aneurysm of external jugular vein mimicking hemangioma of neck. AB - Venous aneurysms are one of the rare causes of neck swellings. Among neck veins, external jugular vein aneurysms are uncommon. We present a case of a woman who presented with a nontender compressible swelling in the left lower neck region, which initially thought to be hemangioma, was later found to be external jugular vein aneurysm on Doppler ultrasound and CT angiography. PMID- 24465109 TI - Pulsatile scalp swelling. AB - Metastasis from follicular carcinoma is usually blood-borne. Here, we present a case of skull metastasis with intracranial extension presenting as a pulsatile scalp swelling from the follicular thyroid carcinoma. PMID- 24465110 TI - Training in trauma care. PMID- 24465111 TI - Long-range Mobile Technology is the Future of Providing Bespoke Surgical Interventions. PMID- 24465112 TI - Would a Massive Intra-abdominal Malignant Peripheral Nerve Sheath Tumor with Growth into the Inguinal Canal and Scrotum Preclude Surgical Option? A Case Report and Review of Literature. AB - Malignant peripheral nerve sheath tumors (MPNST) are rare spindle-cell sarcomas derived from Schwann cells or pluripotent cells of the neural crest accounting for less than 10 % of all soft tissue sarcomas. They arise from major or minor peripheral nerve fibers or their sheaths. The World Health Organization coined the term MPNST for tumors of neurogenic origin with similar biological behavior replacing all the previous heterogeneous and, often, confusing nomenclature including malignant schwannoma, malignant neurilemmoma, and neurofibrosarcoma. The retroperitoneum and the lower extremities are the most common sites, but MPNST may arise anywhere in the body. Its location in the retroperitoneum in a patient without neurofibromatosis is an exceedingly rare occurrence. Imaging is routinely performed to assess the extent of the disease and to plan surgical resection. Surgical resection is the first line of therapy, ideally with total removal of the tumor. Owing to a high risk of recurrence with incomplete resection, postoperative irradiation and chemotherapy are necessary; however, they are often used as adjuvant therapy even if the tumor is completely resected. PMID- 24465113 TI - Peroral Endoscopic Myotomy (POEM) in a Patient with Complete Heart Block-a Case Report. AB - Achalasia cardia is the commonest esophageal motility disorder. Recently, a new endoscopic procedure-peroral endoscopic myotomy (POEM)-has emerged for treating this chronic and debilitating condition. It has shown comparable success rates in prospective studies with conventional Heller's myotomy with lesser rates of postoperative reflux. Literature regarding this procedure from India is scarce due to its limited availability. This case report illustrates the use of POEM in a patient with a permanent cardiac pacemaker and demonstrates its safety and efficacy in such a situation. PMID- 24465114 TI - Optical Trapping Enabled Parallel Delivery of Biological Stimuli with High Spatial and Temporal Resolution. AB - We have developed a method that employs nanocapsules, optical trapping, and single-pulse laser photolysis for delivering bioactive molecules to cells with both high spatial and temporal resolutions. This method is particularly suitable for a cell-culture setting, in which a single nanocapsule can be optically trapped and positioned at a pre-defined location next to the cell, followed by single-pulse laser photolysis to release the contents of the nanocapsule onto the cell. To parallelize this method such that a large array of nanocapsules can be manipulated, positioned, and photolyzed simultaneously, we have turned to the use of spatial light modulators and holographic beam shaping techniques. This paper outlines the progress we have made so far and details the issues we had to address in order to achieve efficient parallel optical manipulations of nanocapsules and particles. PMID- 24465115 TI - A Patient-Specific Segmentation Framework for Longitudinal MR Images of Traumatic Brain Injury. AB - Traumatic brain injury (TBI) is a major cause of death and disability worldwide. Robust, reproducible segmentations of MR images with TBI are crucial for quantitative analysis of recovery and treatment efficacy. However, this is a significant challenge due to severe anatomy changes caused by edema (swelling), bleeding, tissue deformation, skull fracture, and other effects related to head injury. In this paper, we introduce a multi-modal image segmentation framework for longitudinal TBI images. The framework is initialized through manual input of primary lesion sites at each time point, which are then refined by a joint approach composed of Bayesian segmentation and construction of a personalized atlas. The personalized atlas construction estimates the average of the posteriors of the Bayesian segmentation at each time point and warps the average back to each time point to provide the updated priors for Bayesian segmentation. The difference between our approach and segmenting longitudinal images independently is that we use the information from all time points to improve the segmentations. Given a manual initialization, our framework automatically segments healthy structures (white matter, grey matter, cerebrospinal fluid) as well as different lesions such as hemorrhagic lesions and edema. Our framework can handle different sets of modalities at each time point, which provides flexibility in analyzing clinical scans. We show results on three subjects with acute baseline scans and chronic follow-up scans. The results demonstrate that joint analysis of all the points yields improved segmentation compared to independent analysis of the two time points. PMID- 24465116 TI - Neurosurgery Simulation Using Non-linear Finite Element Modeling and Haptic Interaction. AB - Real-time surgical simulation is becoming an important component of surgical training. To meet the real-time requirement, however, the accuracy of the biomechancial modeling of soft tissue is often compromised due to computing resource constraints. Furthermore, haptic integration presents an additional challenge with its requirement for a high update rate. As a result, most real time surgical simulation systems employ a linear elasticity model, simplified numerical methods such as the boundary element method or spring-particle systems, and coarse volumetric meshes. However, these systems are not clinically realistic. We present here an ongoing work aimed at developing an efficient and physically realistic neurosurgery simulator using a non-linear finite element method (FEM) with haptic interaction. Real-time finite element analysis is achieved by utilizing the total Lagrangian explicit dynamic (TLED) formulation and GPU acceleration of per-node and per-element operations. We employ a virtual coupling method for separating deformable body simulation and collision detection from haptic rendering, which needs to be updated at a much higher rate than the visual simulation. The system provides accurate biomechancial modeling of soft tissue while retaining a real-time performance with haptic interaction. However, our experiments showed that the stability of the simulator depends heavily on the material property of the tissue and the speed of colliding objects. Hence, additional efforts including dynamic relaxation are required to improve the stability of the system. PMID- 24465117 TI - Methods for Monitoring Erosion Using Optical Coherence Tomography. AB - Since optical coherence tomography is well suited for measuring small dimensional changes on tooth surfaces it has great potential for monitoring tooth erosion. The purpose of this study was to explore different approaches for monitoring the erosion of enamel. Application of an acid resistant varnish to protect the tooth surface from erosion has proven effective for providing a reference surface for in vitro studies but has limited potential for in vivo studies. Two approaches which can potentially be used in vivo were investigated. The first approach is to measure the remaining enamel thickness, namely the distance from the tooth surface to the dentinal-enamel junction (DEJ). The second more novel approach is to irradiate the surface with a carbon dioxide laser to create a reference layer which resists erosion. Measuring the remaining enamel thickness proved challenging since the surface roughening and subsurface demineralization that commonly occurs during the erosion process can prevent resolution of the underlying DEJ. The areas irradiated by the laser manifested lower rates of erosion compared to the non-irradiated areas and this method appears promising but it is highly dependent on the severity of the acid challenge. PMID- 24465118 TI - 3D of Brain Shape and Volume After Cranial Vault Remodeling Surgery for Craniosynostosis Correction in Infants. AB - The skull of young children is made up of bony plates that enable growth. Craniosynostosis is a birth defect that causes one or more sutures on an infant's skull to close prematurely. Corrective surgery focuses on cranial and orbital rim shaping to return the skull to a more normal shape. Functional problems caused by craniosynostosis such as speech and motor delay can improve after surgical correction, but a post-surgical analysis of brain development in comparison with age-matched healthy controls is necessary to assess surgical outcome. Full brain segmentations obtained from pre- and post-operative computed tomography (CT) scans of 8 patients with single suture sagittal (n=5) and metopic (n=3), non syndromic craniosynostosis from 41 to 452 days-of-age were included in this study. Age-matched controls obtained via 4D acceleration-based regression of a cohort of 402 full brain segmentations from healthy controls magnetic resonance images (MRI) were also used for comparison (ages 38 to 825 days). 3D point-based models of patient and control cohorts were obtained using SPHARM-PDM shape analysis tool. From a full dataset of regressed shapes, 240 healthy regressed shapes between 30 and 588 days-of-age (time step = 2.34 days) were selected. Volumes and shape metrics were obtained for craniosynostosis and healthy age matched subjects. Volumes and shape metrics in single suture craniosynostosis patients were larger than age-matched controls for pre- and post-surgery. The use of 3D shape and volumetric measurements show that brain growth is not normal in patients with single suture craniosynostosis. PMID- 24465119 TI - Effects of Severe Mental Illness Education on MSW Student Attitudes About Schizophrenia. AB - Social work students (n = 60) in a master's-level course on severe mental illness participated in a quasi-experimental study examining the degree to which increased knowledge about and contact with individuals with schizophrenia during the course would impact their attitudes toward people with the disorder. Results revealed significant improvement in student knowledge and general attitudes after the course, and indicated that increased knowledge about schizophrenia was only related to general attitudinal improvement when accompanied by increased personal social contact. Implications for education on severe mental illnesses, and value and attitude development in social work education are discussed. PMID- 24465120 TI - A Distributed Platform for Global-Scale Agent-Based Models of Disease Transmission. AB - The Global-Scale Agent Model (GSAM) is presented. The GSAM is a high-performance distributed platform for agent-based epidemic modeling capable of simulating a disease outbreak in a population of several billion agents. It is unprecedented in its scale, its speed, and its use of Java. Solutions to multiple challenges inherent in distributing massive agent-based models are presented. Communication, synchronization, and memory usage are among the topics covered in detail. The memory usage discussion is Java specific. However, the communication and synchronization discussions apply broadly. We provide benchmarks illustrating the GSAM's speed and scalability. PMID- 24465121 TI - Limitations of the Patient Health Questionnaire in Identifying Anxiety and Depression: Many Cases Are Undetected. AB - OBJECTIVE: To determine the concordance between the Structured Clinical Interview for DSM-IV (SCID) and the Patient Health Questionnaire (PHQ) in diagnosing anxiety and depressive disorders. METHOD: Fifty women seeking psychiatric services for their children at two mental health centers in Western Pennsylvania were assessed for anxiety and depressive disorders using the SCID and the PHQ. RESULTS: Twenty-five women met SCID criteria for at least one anxiety disorder, 11 (44%) of whom the PHQ failed to identify. The PHQ was particularly limited in identifying individuals with anxiety disorders other than panic disorder. Seventeen women met SCID criteria for at least one major depressive disorder, 6 (35%) of whom the PHQ failed to identify. The PHQ was particularly limited in identifying depressed individuals with dysthymia. CONCLUSIONS: Caution should be used when screening for anxiety and depression with the PHQ. Implications for improving diagnostic accuracy in social work practice are discussed. PMID- 24465122 TI - Nonlinear light scattering in molecules triggered by an impulsive X-ray Raman process. AB - The time-and-frequency resolved nonlinear light scattering (NLS) signals from a time evolving charge distribution of valence electrons prepared by impulsive X ray pulses are calculated using a superoperator Green's function formalism. The signal consists of a coherent ~ N2-scaling difference frequency generation and an incoherent fluorescence ~ N-scaling component where N is the number of active molecules. The former is given by the classical Larmor formula based on the time dependent charge density. The latter requires additional information about the electronic structure and may be recast in terms of transition amplitudes representing quantum matter pathways. PMID- 24465124 TI - Visualizing Multiple Quantile Plots. AB - Multiple-quantile plots provide a powerful graphical method for comparing the distributions of two or more populations. This article develops a method of visualizing triple-quantile plots and their associated confidence tubes, thus extending the notion of a quantile-quantile (QQ) plot to three dimensions. More specifically, we consider three independent one-dimensional random samples with corresponding quantile functions Q1, Q2, and Q3. The triple-quantile (QQQ) plot is then defined as the three-dimensional curve Q(p) = (Q1(p), Q2(p), Q3(p)), where 0 < p < 1. The empirical likelihood method is used to derive simultaneous distribution-free confidence tubes for Q. We apply our method to an economic case study of strike durations and to an epidemiological study involving the comparison of cholesterol levels among three populations. These data as well as the Mathematica code for computation of the tubes are available in the online supplementary materials. PMID- 24465123 TI - Inhibitory effect of N-ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1 carbothioamide on Haemophilus spp. planktonic or biofilm-forming cells. AB - During this study, we have investigated in vitro activity of N-substituted-3 amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1-carbothioamide derivatives with N ethyl, N-(4-metoxyphenyl) and N-cyclohexyl substituents against Gram-negative Haemophilus influenzae and H. parainfluenzae bacteria. A spectrophotometric assay was used in order to determine the bacterial growth and biofilm formation using a microtiter plate to estimate minimal inhibitory concentration (MIC) and minimal biofilm inhibitory concentration (MBIC). Among the tested N-substituted pyrazole derivatives, only N-ethyl-3-amino-5-oxo-4-phenyl-2,5-dihydro-1H-pyrazole-1 carbothioamide showed a significant in vitro activity against both planktonic cells of H. parainfluenzae (MIC = 0.49-31.25 MUg ml-1) and H. influenzae (MIC = 0.24-31.25 MUg ml-1) as well as biofilm-forming cells of H. parainfluenzae (MBIC = 0.24-31.25 MUg ml-1) and H. influenzae (MBIC = 0.49 to >=31.25 MUg ml-1). The pyrazole compound exerted higher inhibitory effect both on the growth of planktonic cells and biofilm formation by penicillinase-positive and penicillinase-negative isolates of H. parainfluenzae than the activity of commonly used antibiotics such as ampicillin. No cytotoxicity of the tested compound in vitro at concentrations used was found. The tested pyrazole N-ethyl derivative could be considered as a compound for the design of agents active against both pathogenic H. influenzae and opportunistic H. parainfluenzae, showing also anti-biofilm activity. This appears important because biofilms are determinants of bacterial persistence in long-term and recurrent infections recalcitrant to standard therapy. PMID- 24465125 TI - Endothelial distance after phakic iris-fixated intraocular lens implantation: a new safety reference. AB - PURPOSE: To evaluate the distance between the endothelial surface of the cornea to the anterior edge of an Artiflex(r) phakic intraocular lens (IOL) implant to improve the safety profile of this implant. METHODS: This is a retrospective clinical case series of 45 patients who had Artiflex phakic IOL implantation (Artiflex p-IOL) with a follow-up period of 3 years. A Pentacam HR imaging system was used to measure the distance from various points of the anterior edge of the Artiflex IOL to the endothelial surface of the cornea, which we called endothelial-IOL (E-IOL) distance, in 45 eyes. The E-IOL distances were assessed at 1, 3, 6, 12, 24, and 36 months. Corresponding correlations of central endothelial distance to temporal and nasal edges and center of the IOL anterior surface were tabulated. RESULTS: Mean follow-up was 21.39+/-11.28 months. A statistically significant reduction of the E-IOL distance was observed over the follow-up period (P<0.05), with the mean annual reduction being 24.70 MUm. A strong positive correlation between the E-IOL distance of the edges of the IOL and the central distance was observed (correlation coefficients nasal/central: month 1, 0.905; month 36, 0.806; temporal/central: month 1, 0.906; month 36, 0.806; P<0.001). Moderate negative correlations were found between the spherical equivalent power of the implanted IOL and the E-IOL distance (correlation coefficients -0.271 to -0.412, P>0.05). For an E-IOL distance of the IOL edge >1500 MUm, the distance from the endothelium to the central point of the p-IOL optic should be a minimum of 1,700 MUm to improve the safety profile for Artiflex p-IOL implantation and reduce the potential complication of accelerated endothelial cell loss. CONCLUSION: After Artiflex IOL implantation, the mean annual reduction of the E-IOL distance was 25 MUm. A negative correlation existed between the spherical equivalent power of the implanted IOL and the postoperative E-IOL distance. The minimum E-IOL distance from the center of the IOL to minimize the risk of endothelial cell loss was 1.7 mm. This distance, as is the 1.5 mm initially proposed by Baikoff, is a postoperative value. We cannot make that assumption for the preoperative evaluation, as the morphometry of the anterior chamber changes with the implant. PMID- 24465126 TI - Changes in surface expression of N-methyl-D-aspartate receptors in the striatum in a rat model of Parkinson's disease. AB - BACKGROUND: N-methyl-D-aspartate (NMDA) receptors play a central role in glutamatergic synaptic transmission in the mammalian brain and are linked to the pathophysiology and symptomatology of Parkinson's disease (PD). However, changes in NMDA receptor expression in distinct subcellular compartments in PD have not been elucidated. In this study, we investigated changes in subcellular expression of NMDA receptors in striatal neurons in a rodent PD model. METHODS: Intracranial injection of the neurotoxin 6-hydroxydopamine (6-OHDA) was selectively lesioned into the nigrostriatal dopaminergic pathway in adult Sprague Dawley rats, which is a common rat model of PD. A surface receptor crosslinking assay was conducted to examine the response of individual NMDA receptor subunits to dopamine depletion in isolated and confined surface and intracellular compartments of striatal neurons. RESULTS: In PD rats where 6-OHDA was selectively lesioned, surface expression of NMDA receptor GluN1 subunits as detected by surface protein crosslinking assays was increased in the striatum. In contrast, intracellular levels of GluN1 were decreased in the lesioned region. The NMDA receptor GluN2B subunit was elevated in its abundance in the surface pool of the lesioned striatum, while intracellular GluN2B levels were not altered. GluN2A subunits in both surface and intracellular fractions remained stable. In addition, total cellular levels of striatal GluN1 and GluN2A were not changed in lesioned tissue, while total GluN2B proteins showed an increase. CONCLUSION: These results demonstrate the differential sensitivity of principal NMDA receptor subunits to dopamine depletion. GluN1 and GluN2B expression in the distinct surface compartment underwent upregulation in striatal neurons after selective lesions of the dopaminergic pathway by 6-OHDA. PMID- 24465127 TI - Resistance exercise performance variability at submaximal intensities in older and younger adults. AB - We assessed the variability in the number of repetitions completed at submaximal loads in three resistance tasks in older (N=32, 16 female, 74.3+/-5.4 years) and younger (N=16, 8 female, 22.8+/-1.8 years) men and women. One repetition maximum (1RM) was determined on two separate visits on three tasks: leg press (LP), leg extension (LE), and bicep curl (BC). Subjects then completed repetitions to failure on each of the three tasks during two visits, a minimum of 48 hours apart, at either 60% 1RM or 80% 1RM. High reliability for all 1RM assessments was observed. Greater muscular strength was observed in younger compared to older men and women on all tasks (P<0.05). At both 60% and 80% 1RM, considerable interindividual variability was observed in the number of repetitions completed. However, the average number of repetitions completed by younger and older men and women at 60% and 80% 1RM in each of the three tasks was similar, with the only significant difference occurring between younger and older men at 80% 1RM on the leg press (P=0.0258). We did not observe any abnormal blood pressure responses to either the 1RM testing or maximal repetition testing sessions. Considerable interindividual variability was observed in the number of repetitions completed by younger and older men and women at relative intensities typical of resistance training programs. Practitioners should give consideration to individual variability when attempting to maximize the benefits of resistance training. PMID- 24465128 TI - Measuring quality of sleep and autonomic nervous function in healthy Japanese women. AB - The purpose of this study was to determine the relationship between quality of sleep and autonomic nervous functioning in healthy adult Japanese women using three measures, namely, the Pittsburgh Sleep Quality Index (PSQI) for subjective assessment of sleep quality, actigraphy for objective assessment of sleep, and heart rate variability using high frequency and low frequency domains. Participants were 31 healthy women in their 20s to 40s who met the selection criteria, including having normal monthly menstrual periods. Participants were categorized as good or poor sleepers according to their PSQI score. Median correlation coefficients of activity count and high frequency were -0.62 (range 0.43 to -0.84) for good sleepers and -0.45 (range 0.003 to -0.64) for poor sleepers. Good sleepers showed a significantly higher correlation of activity count and high frequency (Z=-2.11, P<0.05). Median correlation coefficients of activity count and low frequency/high frequency were 0.54 (range 0.29-0.73) for good sleepers and 0.41 (range 0.11-0.63) for poor sleepers. The PSQI, actigraphy data, and heart rate variability results showed positive correlations between sleep time as measured by PSQI and duration of inactivity as measured by actigraphy (r=0.446, P<0.05) and sleep time as measured by actigraphy (r=0.377, P<0.05), and a negative correlation between sleep time as measured by PSQI and the correlation coefficients of activity count and high frequency (r=-0.460, P<0.01). These results support the finding that sleep-wake rhythms can be monitored efficiently with actigraphy, providing accurate data that can support the diagnosis of sleeping disorders. Furthermore, actigraphy data were associated with heart rate variability and PSQI findings, but only in subjects who were poor sleepers. Actigraphy is an accurate, efficient, rapid, and inexpensive test for determining objective and subjective sleeping problems, and can also be used in clinical tests for sleep assessment. PMID- 24465129 TI - Mental health and burnout in primary and secondary school teachers in the remote mountain areas of Guangdong Province in the People's Republic of China. AB - BACKGROUND: A growing number of studies have shown that education is a work context in which professionals (teachers) seem likely to suffer from burnout that may be associated with low levels of mental health. Although there is a demonstrated need to improve the mental health and burnout levels among teachers, little is known about their mental health status, particularly with respect to graduating class teachers in remote mountain areas with undeveloped economies. The purpose of this study was to survey mental health and burnout among graduating class teachers in remote mountain areas and to examine the influence of moderating variables. METHODS: We conducted a multilevel analysis of 590 graduating class teachers from 42 primary and secondary schools in remote mountain areas of Guangdong province in the People's Republic of China. The outcome variable of self-reported mental health was measured by the Symptom Checklist-90 (SCL-90), and burnout was measured by the Chinese Maslach Burnout Inventory for primary and secondary school teachers. RESULTS: The status of both mental health and burnout among the respondents was significantly more troubling than the national norm used as a reference (P<0.05 or P<0.01). Each factor in the SCL-90 had a significant correlation with burnout (P<0.01). All factors of the SCL-90 were entered into the regression equation for each dimension of burnout (P<0.01). The factor having the greatest impact on emotional exhaustion and depersonalization was anxiety (beta 0.187 and 0.178, respectively). The factor having the greatest impact on reduced personal accomplishment and intellectual burnout was somatization (beta -0.214 and 0.185, respectively). CONCLUSION: The current outlook for the status of mental health and burnout among teachers in remote mountain areas of Guangdong is not good. The level of mental health among these teachers is lower than the national average, and the level of burnout is higher. Mental health status has obvious effects on burnout among these teachers. PMID- 24465130 TI - Poor versus good sleepers in patients under treatment for sleep-related breathing disorders: better is not good enough. PMID- 24465131 TI - Risk factors for mortality in Asian Taiwanese patients with methanol poisoning. AB - INTRODUCTION: Methanol poisoning continues to be a serious public health issue in Taiwan, but very little work has been done to study the outcomes of methanol toxicity in the Asian population. In this study, we examined the value of multiple clinical variables in predicting mortality after methanol exposure. METHODS: We performed a retrospective observational study on patients with acute poisoning who were admitted to the Chang Gung Memorial Hospital over a period of 9 years (2000-2008). Out of the 6,347 patients, only 32 suffered methanol intoxication. The demographic, clinical, laboratory, and mortality data were obtained for analysis. RESULTS: Most patients were middle aged (46.1+/-13.8 years), male (87.5%), and habitual alcohol consumers (75.0%). All the poisonings were from an oral exposure (96.9%), except for one case of intentionally injected methanol (3.1%). After a latent period of 9.3+/-10.1 hours, many patients began to experience hypothermia (50.0%), hypotension (15.6%), renal failure (59.4%), respiratory failure (50.0%), and consciousness disturbance (Glasgow coma scale [GCS] score 10.5+/-5.4). Notably, the majority of patients were treated with ethanol antidote (59.4%) and hemodialysis (58.1%). The remaining 41.6% of patients did not meet the indications for ethanol therapy. At the end of analysis, there were six (18.8%), 15 (46.9%), and eleven (34.4%) patients alive, alive with chronic complications, and dead, respectively. In a multivariate Cox regression model, it was revealed that the GCS score (odds ratio [OR] 0.816, 95% confidence interval [CI] 0.682-0.976) (P=0.026), hypothermia (OR 168.686, 95% CI 2.685-10,595.977) (P=0.015), and serum creatinine level (OR 4.799, 95% CI 1.321 17.440) (P=0.017) were significant risk factors associated with mortality. CONCLUSION: The outcomes (mortality rate 34.4%) of the Taiwanese patients subjected to intensive detoxification protocols were comparable with published data from other international poison centers. Furthermore, the analytical results indicate that GCS score, hypothermia, and serum creatinine level help predict mortality after methanol poisoning. PMID- 24465132 TI - Drug treatment of type 2 diabetes mellitus in patients for whom metformin is contraindicated. AB - Metformin is considered an initial drug of choice for type 2 diabetes mellitus by leading recommendations. When contraindications to its use exist or patients cannot tolerate it due to adverse effects, clinicians have a variety of other classes of agents to treat hyperglycemia associated with type 2 diabetes mellitus. Each class of agent has its own benefit and safety profile. There are numerous factors to consider when selecting another agent in lieu of metformin including, but not limited to, overall efficacy in A1c reduction, adverse effect profile, cost, and patient preference. The number of factors influencing the decision process presents challenges and often no one specific agent is ideal. Each pharmacotherapeutic class of agents alternative to metformin for the treatment of hyperglycemia in type 2 diabetes mellitus as initial monotherapy is reviewed. PMID- 24465133 TI - Bilateral renal artery thrombosis in inherited thrombophilia: a rare cause of acute kidney injury. AB - We describe the case of a 47-year-old man who developed significant acute, and subsequently chronic, kidney injury due to bilateral renal infarction. This occurred in the context of a combined inherited thrombophilia including antithrombin III deficiency and a prothrombin gene mutation. Bilateral renal artery thrombosis developed despite prophylactic treatment for thromboembolism. Arterial thrombosis is rare in the context of inherited thrombophilia and bilateral renal infarction is an unusual cause of acute kidney injury. Bilateral renal infarction due to primary renal artery thrombosis has not been previously described in antithrombin III deficiency, either as an isolated defect or in combination with other hereditary thrombophilia. PMID- 24465134 TI - Microvascular pericytes in healthy and diseased kidneys. AB - Pericytes are interstitial mesenchymal cells found in many major organs. In the kidney, microvascular pericytes are defined anatomically as extensively branched, collagen-producing cells in close contact with endothelial cells. Although many molecular markers have been proposed, none of them can identify the pericytes with satisfactory specificity or sensitivity. The roles of microvascular pericytes in kidneys were poorly understood in the past. Recently, by using genetic lineage tracing to label collagen-producing cells or mesenchymal cells, the elusive characteristics of the pericytes have been illuminated. The purpose of this article is to review recent advances in the understanding of microvascular pericytes in the kidneys. In healthy kidney, the pericytes are found to take part in the maintenance of microvascular stability. Detachment of the pericytes from the microvasculature and loss of the close contact with endothelial cells have been observed during renal insult. Renal microvascular pericytes have been shown to be the major source of scar-forming myofibroblasts in fibrogenic kidney disease. Targeting the crosstalk between pericytes and neighboring endothelial cells or tubular epithelial cells may inhibit the pericyte-myofibroblast transition, prevent peritubular capillary rarefaction, and attenuate renal fibrosis. In addition, renal pericytes deserve attention for their potential to produce erythropoietin in healthy kidneys as pericytes stand in the front line, sensing the change of oxygenation and hemoglobin concentration. Further delineation of the mechanisms underlying the reduced erythropoietin production occurring during pericyte-myofibroblast transition may be promising for the development of new treatment strategies for anemia in chronic kidney disease. PMID- 24465135 TI - Intravenous acetaminophen is superior to ketamine for postoperative pain after abdominal hysterectomy: results of a prospective, randomized, double-blind, multicenter clinical trial. AB - BACKGROUND: In recent years, intravenously (IV) administered acetaminophen has become one of the most common perioperative analgesics. Despite its now-routine use, IV acetaminophen's analgesic comparative efficacy has never been compared with that of ketamine, a decades-old analgesic familiar to obstetricians, gynecologists, and anesthesiologists alike. This doubleblind clinical trial aimed to evaluate the analgesic effects of ketamine and IV acetaminophen on postoperative pain after abdominal hysterectomy. METHODS: Eighty women aged 25-70 years old and meeting inclusion and exclusion criteria were randomly allocated into two groups of 40 to receive either IV acetaminophen or ketamine intraoperatively. Postoperatively, each patient had patient-controlled analgesia. Pain and sedation (Ramsay Sedation Scale) were documented based on the visual analog scale in the recovery room and at 4 hours, 6 hours, 12 hours, and 24 hours after the surgery. Hemodynamic changes, adverse medication effects, and the need for breakthrough meperidine were also recorded for both groups. Data were analyzed by repeated-measures analysis of variance. RESULTS: Visual analog scale scores were significantly lower in the IV acetaminophen group at each time point (P<0.05), and this group required significantly fewer doses of breakthrough analgesics compared with the ketamine group (P=0.039). The two groups had no significant differences in terms of adverse effects. CONCLUSION: Compared with ketamine, IV acetaminophen significantly improved postoperative pain after abdominal hysterectomy. PMID- 24465136 TI - Improving medication management after a hospitalization with pharmacist home visits and electronic personal health records: an observational study. AB - BACKGROUND: Substantial opportunity exists to improve medication management in the period following a hospital discharge. The objective of this study was to assess and improve medication management during care transitions through pharmacist home visits and the use of an electronic personal health record (ePHR) system. METHODS: Recently discharged patients aged 50 years or older and having a chronic medical condition were offered the opportunity to meet with a pharmacist in the home setting to review medication instructions and receive a demonstration of an ePHR system. Patients agreeable to using the ePHR system were offered pharmacist support with setting up the ePHR system, having emphasis on documenting and reviewing medication regimens. Medication-related problems identified by the pharmacist during the visit were categorized according to ePHR use and by other characteristics. RESULTS: Thirty recently discharged patients with chronic disease were visited by a pharmacist over a 6-month period. The percentage of medication-related problems identified by the pharmacist was greater among those patients who agreed to use the ePHR system, as compared with patients whose visit did not include use of the ePHR (75% versus 40%, respectively; P=0.06). Differing types of medication-related problems were identified, including therapy duplications, lack of use of clinically important therapies, and patient nonadherence. CONCLUSION: For some patients, the home setting can be a suitable venue for medication review and education after discharge from hospital. Assisting patients with setting up the ePHR system may enhance pharmacists' ability to identify and resolve medication-related problems that may lead to rehospitalization. PMID- 24465137 TI - Comparative digital cartilage histology for human and common osteoarthritis models. AB - PURPOSE: This study addresses the species-specific and site-specific details of weight-bearing articular cartilage zone depths and chondrocyte distributions among humans and common osteoarthritis (OA) animal models using contemporary digital imaging tools. Histological analysis is the gold-standard research tool for evaluating cartilage health, OA severity, and treatment efficacy. Historically, evaluations were made by expert analysts. However, state-of-the-art tools have been developed that allow for digitization of entire histological sections for computer-aided analysis. Large volumes of common digital cartilage metrics directly complement elucidation of trends in OA inducement and concomitant potential treatments. MATERIALS AND METHODS: Sixteen fresh human knees, 26 adult New Zealand rabbit stifles, and 104 bovine lateral plateaus were measured for four cartilage zones and the cell densities within each zone. Each knee was divided into four weight-bearing sites: the medial and lateral plateaus and femoral condyles. RESULTS: One-way analysis of variance followed by pairwise multiple comparisons (Holm-Sidak method at a significance of 0.05) clearly confirmed the variability between cartilage depths at each site, between sites in the same species, and between weight-bearing articular cartilage definitions in different species. CONCLUSION: The present study clearly demonstrates multisite, multispecies differences in normal weight-bearing articular cartilage, which can be objectively quantified by a common digital histology imaging technique. The clear site-specific differences in normal cartilage must be taken into consideration when characterizing the pathoetiology of OA models. Together, these provide a path to consistently analyze the volume and variety of histologic slides necessarily generated by studies of OA progression and potential treatments in different species. PMID- 24465138 TI - Involvement of genetic and environmental factors in the onset of depression. AB - First, this article provides a brief overview of the previous hypotheses regarding depression and then focuses on involvement of genetic and environmental factors in development of depression. According to epidemiological research, 30~40% of occurrences of bipolar disorder involve a genetic factor. Therefore, environmental factors play a more important role in development of depression. Resilience and resistance to stress are common; therefore, although a certain extent of stress might be received during the embryonic or perinatal period, having a genetic predisposition to mental disorders does not imply that a mental disorder will develop. However, having a genetic predisposition to disorders does weaken resistance to stresses received during puberty, and without the ability to recover, a mental disorder is triggered. The importance of epigenetics in maintaining normal development and biology is reflected by the observation that development of many diseases occurs when the wrong type of epigenetic marks are introduced or are added at the wrong time or in the wrong place. Involvement of genetic and environmental factors in the onset of depression was investigated in relation to epigenetics. When mice with the disrupted in schizophrenia 1 (DISC1) abnormal gene received isolated rearing stress, depression-like abnormal behaviors and decreased gene expression of tyrosine hydroxylase in the frontal cortex by epigenetical suppression via DNA methylation were observed. Decrease of dopamine in the frontal cortex triggers behavioral disorders. Administration of a glucocorticoid receptor antagonist resulted in full recovery from neurological and behavioral disorders. These results suggest a new therapeutic approach to depression. PMID- 24465139 TI - New Perspectives of Dyrk1A Role in Neurogenesis and Neuropathologic Features of Down Syndrome. AB - Down syndrome (DS) is one of the most common genetic disorders accompanying with mental retardation, cognitive impairment, and deficits in learning and memory. The brains with DS also display many neuropathological features including alteration in neurogenesis and synaptogenesis and early onset of Alzheimer's disease (AD)-like symptoms. Triplication of all or a part of human chromosome 21, especially the 21q22.1~21q22.3 region called 'Down syndrome critical region (DSCR)', has been considered as the main cause of DS. One gene product of DSCR, dual-specificity tyrosine-phosphorylation-regulated kinase 1A (Dyrk1A), has been highlighted as a key contributor to the neural consequences of DS. This minireview summarizes accumulating recent reports about Dyrk1A involvement in the neuritogenesis, synaptogenesis, and AD-like neurofibrillary tangle formation, which is mainly focusing on Dyrk1A-mediated regulation of cytoskeletal proteins, such as tubulin, actin, and microtubule-associated protein tau. Understanding the molecular mechanisms of these phenomena may provide us a rational for new preventive and therapeutic treatment of DS. PMID- 24465140 TI - LRRK2 as a Potential Genetic Modifier of Synucleinopathies: Interlacing the Two Major Genetic Factors of Parkinson's Disease. AB - Parkinson's disease (PD) and related Lewy body diseases are characterized by deposition of alpha-synuclein aggregates in both the central nervous system and peripheral nervous system. Synucleinopathy lesions spread to larger brain areas as the disease progresses, and prion-like cell-to-cell transmission of aggregated alpha-synuclein is thought to be the underlying mechanism for this pathological spreading. LRRK2 is another protein linked to the pathogenesis of PD, and its presence in Lewy bodies has attracted much attention as to whether LRRK2 and alpha-synuclein interplay during the pathogenesis of PD. However, the relationship between these two crucial proteins still remains unclear. In this review article, we will discuss the current state of knowledge in terms of how these proteins cause the disease and provide the hypothetical mechanisms by which LRRK2 might modify the generation and progression of synucleinopathy. PMID- 24465141 TI - Curcumin can prevent the changes in cerebellar structure and function induced by sodium metabisulfite in rat. AB - Sulfites are used as anti-microbial and anti-oxidant agents in the food and pharmaceutical industries. Curcumin, a flavonoid, is an Asian spice that shows neuroprotective activities. The current study aimed to stereologically assess the rats' cerebellar cortex and rotarod performance following sulfite exposure and determine the possible neuroprotective potential of curcumin. The rats were divided into five groups: distilled water, olive oil, curcumin (100 mg/kg/day), sodium metabisulfite (25 mg/kg/day), and sodium metabisulfite+curcumin. At 56 days after treatment, rotarod performance was tested, and then the cerebellum was removed for stereological analysis. The study results revealed 31%, 36%, 19% and 24% decrease in the total volume of the cerebellum, cortex, the total number of the Purkinje cells and length of the nerve fibers in the cortex per Purkinje, respectively in the sodium metabisulfite-treated rats compared to the distilled water group (p<0.01). The pre-trained animals on the rotarod apparatus were tested first on the fixed speed rotarod protocol followed by the accelerating rotarod protocol two days later. The results showed a significant decrease in the latency to fall in both test in sulfite-treated rats. The sulfite effects on the structural parameters and rotarod performance were significantly protected by the concomitant curcumin treatment (p<0.001). Sulfite can induce structural and functional changes in the rats' cerebellum and concomitant curcumin prescription plays a neuroprotective role. PMID- 24465142 TI - The Effect of Agmatine on Expression of IL-1beta and TLX Which Promotes Neuronal Differentiation in Lipopolysaccharide-Treated Neural Progenitors. AB - Differentiation of neural progenitor cells (NPCs) is important for protecting neural cells and brain tissue during inflammation. Interleukin-1 beta (IL-1beta) is the most common pro- inflammatory cytokine in brain inflammation, and increased IL-1beta levels can decrease the proliferation of NPCs. We aimed to investigate whether agmatine (Agm), a primary polyamine that protects neural cells, could trigger differentiation of NPCs by activating IL-1beta in vitro. The cortex of ICR mouse embryos (E14) was dissociated to culture NPCs. NPCs were stimulated by lipopolysaccharide (LPS). After 6 days, protein expression of stem cell markers and differentiation signal factors was confirmed by using western blot analysis. Also, immunocytochemistry was used to confirm the cell fate. Agm treatment activated NPC differentiation significantly more than in the control group, which was evident by the increased expression of a neuronal marker, MAP2, in the LPS-induced, Agm-treated group. Differentiation of LPS-induced, Agm treated NPCs was regulated by the MAPK pathway and is thought to be related to IL 1beta activation and decreased expression of TLX, a transcription factor that regulates NPC differentiation. Our results reveal that Agm can promote NPC differentiation to neural stem cells by modulating IL-1beta expression under inflammatory condition, and they suggest that Agm may be a novel therapeutic strategy for neuroinflammatory diseases. PMID- 24465143 TI - Distribution of the Immunoreactivity for Glycoprotein M6B in the Neurogenic Niche and Reactive Glia in the Injury Penumbra Following Traumatic Brain Injury in Mice. AB - The location and morphology of astrocytes are known to contribute to their diversity, and this diversity is often associated with their selective functions. However, molecular markers for astrocyte subtypes are largely unknown. In this study, we found that the immunoreactivity for glycoprotein GPM6B (M6B-IR) is preferentially expressed in the astrocytes associated with ventricles or neurogenic regions of the adult mouse brain. In particular, M6B-IR in the neurogenic niche was confined to glial fibrillary acidic protein- or nestin expressing neural stem cells. Furthermore, in the injury penumbra, reactive astrocytes expressing nestin also exhibited strong M6B-IR. These results reveal that GPM6B is a potential molecular marker for a subset of astrocytes, as well as for the injury-dependent activation of astrocytes. PMID- 24465144 TI - Mitochondrial dysfunction of immortalized human adipose tissue-derived mesenchymal stromal cells from patients with Parkinson's disease. AB - Mitochondrial dysfunction in dopaminergic neurons of patients with idiopathic and familial Parkinson's disease (PD) is well known although the underlying mechanism is not clear. We established a homogeneous population of human adipose tissue derived mesenchymal stromal cells (hAD-MSCs) from human adult patients with early onset hereditary familial Parkin-defect PD as well as late-onset idiopathic PD by immortalizing cells with the hTERT gene to better understand the underlying mechanism of PD. The hAD-MSCs from patients with idiopathic PD were designated as "PD", from patients with Parkin-defect PD as "Parkin" and from patients with pituitary adenomas as "non-PD" in short. The pGRN145 plasmid containing hTERT was introduced to establish telomerase immortalized cells. The established hTERT immortalized cell lines showed chromosomal aneuploidy sustained stably over two years. The morphological study of mitochondria in the primary and immortalized hAD-MSCs showed that the mitochondria of the non-PD were normal; however, those of the PD and Parkin were gradually damaged. A striking decrease in mitochondrial complex I, II, and IV activities was observed in the hTERT-immortalized cells from the patients with idiopathic and Parkin-defect PD. Comparative Western blot analyses were performed to investigate the expressions of PD specific marker proteins in the hTERT-immortalized cell lines. This study suggests that the hTERT immortalized hAD-MSC cell lines established from patients with idiopathic and familial Parkin-defect PD could be good cellular models to evaluate mitochondrial dysfunction to better understand the pathogenesis of PD and to develop early diagnostic markers and effective therapy targets for the treatment of PD. PMID- 24465145 TI - HMGB1-Binding Heptamer Confers Anti-Inflammatory Effects in Primary Microglia Culture. AB - High mobility group box 1 (HMGB1) is an endogenous danger signal molecule. In the postischemic brain, HMGB1 is massively released during NMDA-induced acute damage and triggers inflammatory processes. In a previous study, we demonstrated that intranasally delivered HMGB1 binding heptamer peptide (HBHP; HMSKPVQ) affords robust neuroprotective effects in the ischemic brain after middle cerebral artery occlusion (MCAO, 60 minutes). In the present study, we investigated HBHP-induced anti-inflammatory effects on microglia activation. In LPS-treated primary microglia culture, HMGB1 was rapidly released and accumulated in culture media. Furthermore, LPS-conditioned media collected from primary microglia cultures (LCM) activated naive microglia and markedly induced NO and proinflammatory cytokines. However, the suppression of HMGB1 by siRNA-HMGB1, HMGB1 A box, or anti HMGB1 antibody significantly attenuated LCM-induced microglial activation, suggesting that HMGB1 plays a critical role in this process. A pull-down assay using biotin-labeled HBHP showed that HBHP binds directly to HMGB1 (more specifically to HMGB1 A box) in LCM. In addition, HBHP consistently inhibited LCM induced microglial activation and suppressed the inductions of iNOS and proinflammatory cytokines. Together these results suggest that HBHP confers anti inflammatory effects in activated microglia cultures by forming a complex with HMGB1. PMID- 24465146 TI - Absence of Delayed Neuronal Death in ATP-Injected Brain: Possible Roles of Astrogliosis. AB - Although secondary delayed neuronal death has been considered as a therapeutic target to minimize brain damage induced by several injuries, delayed neuronal death does not occur always. In this study, we investigated possible mechanisms that prevent delayed neuronal death in the ATP-injected substantia nigra (SN) and cortex, where delayed neuronal death does not occur. In both the SN and cortex, ATP rapidly induced death of the neurons and astrocytes in the injection core area within 3 h, and the astrocytes in the penumbra region became hypertropic and rapidly surrounded the damaged areas. It was observed that the neurons survived for up to 1-3 months in the area where the astrocytes became hypertropic. The damaged areas of astrocytes gradually reduced at 3 days, 7 days, and 1-3 months. Astrocyte proliferation was detectable at 3-7 days, and vimentin was expressed in astrocytes that surrounded and/or protruded into the damaged sites. The NeuN positive cells also reappeared in the injury sites where astrocytes reappeared. Taken together, these results suggest that astroycte survival and/or gliosis in the injured brain may be critical for neuronal survival and may prevent delayed neuronal death in the injured brain. PMID- 24465147 TI - Zinc-triggered induction of tissue plasminogen activator and plasminogen in endothelial cells and pericytes. AB - Cerebral amyloid angiopathy (CAA) is common in patients with Alzheimer's disease (AD) and may contribute to cerebral hemorrhage. We previously demonstrated that tissue plasminogen activator (tPA) and plasminogen (PLG) accumulated at the periphery of compact amyloid-cored plaques and in the walls of CAA-containing blood vessels in the brains of Tg2576 mice, a widely used AD mouse model. We had also observed that zinc-triggered tPA and PLG induction were observed in mouse cortical cultures. Because zinc also accumulates in amyloid plaques and blood vessel walls in AD brains, we examined whether zinc increases mRNA and protein levels of tPA and PLG in brain endothelial cells and pericytes. Four hours after the exposure of brain endothelial cells (bEnd.3) to 40 uM zinc, the mRNA and protein expressions of tPA and its substrate PLG were significantly increased. In the case of brain pericyte cultures, increases in tPA and PLG expression were also detected 2 hr after treatment. However, amyloid-beta (Abeta)1-42 oligomers did not augment tPA and PLG expression in bEnd.3 cells and pericytes, suggesting that zinc but not Abeta induces tPA and PLG accumulation in CAA found in the AD brain. PMID- 24465148 TI - Developmental Role of Anoctamin-1/TMEM16A in Ca(2+)-Dependent Volume Change in Supporting Cells of the Mouse Cochlea. AB - Mammalian cochlea undergoes morphological and functional changes during the postnatal period, around the hearing onset. Major changes during the initial 2 postnatal weeks of mouse include maturation of sensory hair cells and supporting cells, and acquisition of afferent and efferent innervations. During this period, supporting cells in the greater epithelial ridge (GER) of the cochlea exhibit spontaneous and periodic activities which involves ATP, increase in intracellular Ca(2+), and cell volume change. This Ca(2+)-dependent volume change has been proposed to involve chloride channels or transporters. We found that the spontaneous volume changes were eliminated by anion channel blocker, 100 uM NPPB. Among candidates, expression of Anoctamin-1 (Ano1 or TMEM16A), bestriphin-1 and NKCC1 were investigated in whole-mount cochlea of P9-10 mice. Immunolabeling indicated high level of Ano1 expression in the GER, but not of betrophin-1 or NKCC1. Double-labeling with calretinin and confocal image analysis further elucidated the cellular localization of Ano1 immunoreactivity in supporting cells. It was tested if the Ano1 expression exhibits similar time course to the spontaneous activities in postnatal cochlear supporting cells. Cochlear preparations from P2-3, P5-6, P9-10, P15-16 mice were subjected to immunolabeling. High level of Ano1 immunoreactivity was observed in the GER of P2 3, P5-6, P9-10 cochleae, but not of P15-17 cochleae. Taken together, the localization and time course in Ano1 expression pattern correlates with the spontaneous, periodic volume changes recorded in postnatal cochlear supporting cells. From these results we propose that Ano1 is the pacemaker of spontaneous activities in postnatal cochlea. PMID- 24465149 TI - Reliability and validity of the korean version of the lifespan sibling relationship scale. AB - The sibling relationship and its potential impact on neurodevelopment and mental health are important areas of neuroscientific research. Validation of the tools assessing the quality of the sibling relationship would be the first essential step for conducting neurobiological and psychosocial studies related to the sibling relationship. However, to the best of our knowledge, no sibling relationship assessment tools have been empirically validated in Korean. We aimed to evaluate the psychometric properties of the Korean version of the Lifespan Sibling Relationship Scale (LSRS), which is one of the most commonly used self report questionnaires to assess the quality of the sibling relationship. A total of 109 adults completed a series of self-report questionnaires including the LSRS, the mental health subscale of the Medical Outcomes Study-Short Form 36 version 2 (SF36v2), the Satisfaction with Life Scale (SLS), and the Marlowe Crowne Social Desirability Scale (MC-SDS). The internal consistency, subscale intercorrelations, one-week test-retest reliability, convergent validity, divergent validity, and the construct validity were assessed. All six subscale scores and the total score of the LSRS demonstrated good internal consistency (Cronbach's alpha=0.85-0.94) and good test-retest reliability (intraclass correlation coefficient=0.77-0.92). Correlations of the LSRS with the SF36v2 mental health score (r=0.32, p=0.01) and with the SLS (r=0.27, p=0.04) supported the good convergent validity. The divergent validity was shown by the non significant correlation of the LSRS with the MC-SDS (r=0.15, p=0.26). Two factors were extracted through factor analysis, which explained 78.63% of the total variance. The three Adult subscales loaded on the first factor and the three Child subscales loaded on the second factor. Results suggest that the Korean version of the LSRS is a reliable and valid tool for examining the sibling relationship. PMID- 24465150 TI - Anti-LGI1 Limbic Encephalitis Presented with Atypical Manifestations. AB - Anti-leucine-rich glioma inactivated-1 (LGI1) limbic encephalitis (LE) is a rare neurological disorder that has a subacute course of progressive encephalopathy and fasciobrachial dystonic seizures. We report a patient with anti-LGI1 LE that presented with atypical manifestations that complicated the diagnosis. A 62-year old woman presented with a chronic course of memory disturbance and a subsequent relapse with an altered mental status after 10 months. The patient reported frequent chest pain of squeezing and dull nature, typically lasting 10-30 seconds. The chest pain was related to partial seizures, which were confirmed by video-EEG monitoring. Anti-LGI1 antibody was identified in serum and CSF. The patient's symptoms improved by immune modulation treatment. Patients with anti LGI1 LE can experience atypical partial seizures, and a chronic relapsing course. Clinical suspicions and video-EEG monitoring are helpful for the early diagnosis and effective immune modulation. PMID- 24465151 TI - Major Challenges for the Modern Chemistry in Particular and Science in General. AB - In the past few hundred years, science has exerted an enormous influence on the way the world appears to human observers. Despite phenomenal accomplishments of science, science nowadays faces numerous challenges that threaten its continued success. As scientific inventions become embedded within human societies, the challenges are further multiplied. In this critical review, some of the critical challenges for the field of modern chemistry are discussed, including: (a) interlinking theoretical knowledge and experimental approaches; (b) implementing the principles of sustainability at the roots of the chemical design; (c) defining science from a philosophical perspective that acknowledges both pragmatic and realistic aspects thereof; (d) instigating interdisciplinary research; (e) learning to recognize and appreciate the aesthetic aspects of scientific knowledge and methodology, and promote truly inspiring education in chemistry. In the conclusion, I recapitulate that the evolution of human knowledge inherently depends upon our ability to adopt creative problem-solving attitudes, and that challenges will always be present within the scope of scientific interests. PMID- 24465152 TI - An expedient synthesis of 6-vinylfulvene. AB - 6-Vinylfulvenes constitute a class of fulvenes that are difficult to access due to the lack of a general method for their synthesis. In particular, the unsubstituted parent system has been very difficult to obtain by existing methods. In this communication we describe a convenient 3-step protocol for the synthesis of the title compound by way of sulfide oxidation and subsequent sulfoxide elimination. PMID- 24465153 TI - Just passing through: the effect of the Master Settlement Agreement on estimated cigarette tax price pass-through. AB - In 1998, cigarette manufacturers and state attorneys general in the United States settled a group of lawsuits in an agreement known as the Master Settlement Agreement (MSA). Among the provisions of this agreement were a set of mandated escrow payments to the states that would be based on cigarette sales. The result of these provisions is that the apparent relationship between taxes and prices changed substantially following implementation of the MSA. This article estimates whether the MSA escrow amounts are reflected in prices and compares the pass through rate of state and federal cigarette taxes only and the rate when one adds escrow payments. We find much different pass-through rates for the two measures. State and federal taxes are not fully passed to smokers. In years that escrow payments were made, cigarette prices increased by more than the sum of the state and federal taxes and the escrow payments. PMID- 24465154 TI - Gas Phase Dissociation Behavior of Acyl-Arginine Peptides. AB - The gas phase dissociation behavior of peptides containing acyl-arginine residues is investigated. These acylations are generated via a combination of ion/ion reactions between arginine-containing peptides and N-hydroxysuccinimide (NHS) esters and subsequent tandem mass spectrometry (MS/MS). Three main dissociation pathways of acylated arginine, labeled Paths 1-3, have been identified and are dependent on the acyl groups. Path 1 involves the acyl-arginine undergoing deguanidination, resulting in the loss of the acyl group and dissociation of the guanidine to generate an ornithine residue. This pathway generates selective cleavage sites based on the recently discussed "ornithine effect". Path 2 involves the coordinated losses of H2O and NH3 from the acyl-arginine side chain while maintaining the acylation. We propose that Path 2 is initiated via cyclization of the delta-nitrogen of arginine and the C-terminal carbonyl carbon, resulting in rapid rearrangement from the acyl-arginine side chain and the neutral losses. Path 3 occurs when the acyl group contains alpha-hydrogens and is observed as a rearrangement to regenerate unmodified arginine while the acylation is lost as a ketene. PMID- 24465155 TI - Comparison of nanowire pellicles for plasma membrane enrichment: coating nanowires on cell. AB - A study is reported on the effect of nanowire density on the ease of pellicle formation and the enrichment of plasma membrane proteins for analysis by mass spectrometry. An optimized synthesis is reported for iron silicate nanowires with a narrow size range of 900 +/-400 nm in length and 200 nm diameter. The nanowires were coated with Al2O3 and used to form pellicles around suspended multiple myeloma cells, which acted as a model for cells recovered from tissue samples. Lighter alumina-coated silica nanowires were also synthesized (Kim et al. 2013), which allowed a comparison of the construction of the two pellicles and of the effect of nanowire density on plasma membrane enrichment. Evidence is offered that the dense nanowire pellicle does not crush or distort these mammalian cells. Finally, the pellicles were incorporated into a mass-spectrometry-based proteomic workflow to analyze transmembrane proteins in the plasma membrane. In contrast to a prior comparison of the effect of density with nanoparticles pellicles (Choksawangkarn et al. 2013), nanowire density was not found to significantly affect the enrichment of the plasma membrane. However, nanowires with a favorable aspect for pellicle formation are more easily and reliably produced with iron silicate than with silica. Additionally, the method for pellicle formation was optimized through the use of iron silicate nanowires (ISNW), which is crucial to the improvement of PM protein enrichment and analysis. PMID- 24465156 TI - Effects of a pre-workout supplement on lean mass, muscular performance, subjective workout experience and biomarkers of safety. AB - In this prospective, randomized, double-blind, trial conducted in two parts, we examined the effects of a multi-ingredient pre-exercise workout supplement blend of creatine, betaine and a dendrobium extract (MMP) on safety, performance, and body composition in healthy men and women undergoing a supervised program of resistance exercise. Part 1 was an acute hemodynamic safety study wherein forty young, healthy men and women (26.2 +/- 5.3 years, 70.4 +/- 3.3 inches, 83.7 +/- 14.9 kg, 26.0 +/- 3.2 kg?m(-2)) ingest one dose of either the MMP or comparator in a randomized, double-blind, comparator controlled, crossover fashion before having their resting heart rate, blood, ECG and comprehensive blood chemistry and blood counts completed. Systolic (SBP) and diastolic (DBP) blood pressures were generally raised (3.0-5.4 mm Hg, p<0.01) following supplementation with MPP whereas in the comparator group SBP was marginally reduced by 0.3 to 1.2 mm Hg, p>0.05 at all time points) and DBP was increased (3.0 - 3.9 mm Hg, p<0.05 at all time points). No changes in EKG-corrected QT interval were observed, and no serious adverse events were reported. Part 2 was a six-week training study wherein forty-three young, healthy men and women (24.3 +/- 2.9 years, 70.5 +/- 3.1 inches, 83.8 +/- 9.6 kg, 26.1 +/- 2.7 kg?m(-2)) supplemented with daily pre workout doses of either the MPP or a comparator in a randomized, double-blind, comparator-controlled fashion while following a standardized resistance training program for six weeks. MPP and the comparator were isocaloric and delivered the same amount of caffeine. Significant improvements in visual analog scale (VAS) scores for energy (p<0.024) and concentration (p<0.041) were found along with consistently higher levels of focus accompanied by less fatigue when MPP was consumed in comparison to comparator during upper body muscular strength endurance tests at weeks 3 and 6. MPP supplementation for 6 weeks did not improve dual-energy x-ray absorptiometry (DEXA) measures of body composition or objective assessments of exercise performance. Overall, MPP use and administration was well tolerated. Self-reported scores for energy and concentration were significantly greater. Over a six-week training and supplementation period, MPP use was not associated with improvements in performance or body composition. Future studies should confirm these effects over a more prolonged training period. PMID- 24465157 TI - Comparison of laparoscopic versus open left hemihepatectomy for left-sided hepatolithiasis. AB - PURPOSE: The purpose of this study was to evaluate and compare the perioperative and long-term outcomes of open versus laparoscopic left hemihepatectomy (OLH vs. LLH) for left-sided hepatolithiasis. METHODS: Between October 2007 and June 2012, 149 patients with left-sided hepatolithiasis who underwent LLH (n = 37) or OLH (n = 112) were evaluated. The perioperative and long-term outcomes that were reviewed included the stone clearance rate, operative morbidity and mortality, and the stone recurrence rate. RESULTS: The mean operative time of the LLH group was significantly longer than that of the OLH group (257+/-50.4 minutes vs. 237+/ 75.5 minutes, p = 0.022), but the mean hospital stay was significantly shorter (8.8+/-4.10 vs. 14.1+/-4.98 days, p < 0.001). Postoperative complications were noted in four and twenty cases among LLH and OLH patients, respectively (p = 0.982). The initial clearance rate of intrahepatic duct (IHD) stones was 100% and 96.4% in the LLH and OLH groups, respectively, but all remnant stones (n = 4, OLH group) were resolved postoperatively. There were two cases of recurrence of IHD stones in OLH patients, but none in LLH patients (p = 0.281). CONCLUSIONS: In left-sided hepatolithiasis, LLH was safe and effective: it resulted in low postoperative morbidity, no mortality and a high stone clearance rate, and there were no incidences of recurrence in our study. The potential benefits of LLH include a shorter hospital stay and a faster return to oral intake. If consideration is given to the appropriate indication criteria, including the extent of hepatectomy and the location and distribution of lesions, LLH may be an excellent choice for treatment of left-sided hepatolithiasis. PMID- 24465158 TI - Anatomical analysis on the lateral bone window of the sella turcica: a study on 530 adult dry skull base specimens. AB - OBJECTIVE: To investigate the morphometric characteristics of the lateral bone window (LBW) of the sella turica. METHODS: A descriptive anatomical study of LBW was performed in 530 cases of dry skull base specimens with relatively complete sella turcica. Detailed morphometric characteristics such as dimensions and classification of the LBW was studied. All data analysis was performed using SPSS 17.0 statistical software. RESULTS: LBW is located in the lateral bony structures of sella turcica. The mean area sizes of the LBW were 75.99 +/- 25.81 mm(2) (left) and 76.00 +/- 25.53 mm(2) (right). There was no significant difference and there was a good positive correlation between bilateral areas of the LBWs. The area size of the LBWs is graded as follows: Grade A (< 60 mm(2)), B (60~90 mm(2)) and C (> 90 mm(2)). LBW morphology was typed as follows: Type I, II, III, IV. And Tpye III includes Type IIIa and IIIb; Type IV includes Type IVa, IVb, IVc, IVd. CONCLUSIONS: The lateral bone window of sella turcica is an important structure located between pituiary fossa and parasellar region. The morphological measurements and variations of LBW in this study will provide preliminary data for further anatomical study of sella turcica. Moreover, knowing detailed anatomy of this region is essential for neurosurgeons who make surgery on cranial base or for teaching about the sella turcica in the neuroanatomy lab. PMID- 24465159 TI - Single nucleotide polymorphisms in the metastasis-associated in colon cancer-1 gene predict the recurrence of hepatocellular carcinoma after transplantation. AB - BACKGROUND: The newly identified metastasis-associated in colon cancer-1 (MACC1) gene is involved in angiogenesis, epithelial-to-mesenchymal transition (EMT), invasiveness, and metastasis in a variety of malignancies. Overexpression of MACC1 gene is a prognostic marker for poor outcome of hepatocellular carcinoma (HCC) patients. However, the association between genetic polymorphisms of MACC1 gene and poor outcome in HCC has been not been performed. We therefore investigated the correlation of MACC1 single nucleotide polymorphisms (SNPs) with tumor recurrence and overall survival in HCC patients undergoing liver transplantation (LT). METHODS: The study included 187 HCC patients treated with LT. Five polymorphisms in the MACC1 gene (rs1990172, rs3735615, rs4721888, rs2241056, rs975263) were genotyped in 183 cases of tumorous tissue sample and 117 cases of adjacent normal tissue sample using SNaP-Shot assays. The association of SNPs with tumor recurrence and overall survival was then analyzed by additive, dominant, recessive, and overdominant models in a cohort of 156 HCC patients. RESULTS: In terms of tumor recurrence, heterozygous of SNP rs1990172 and SNP rs975263 showed a significant high risk of relapse using univariate and multivariate analysis (overdominant, HR(95%CI)=2.27 [1.41-3.66], P=0.001; HR(95%CI)=2.16 [1.37-3.39], P=0.001). But the difference between heterozygous of these two SNPs and overall survival did not reach a significance in all models. The other three investigated SNPs were not significantly associated with tumor recurrence and overall survival (P>0.05). In addition, we found no significant difference in genotype frequencies between HCC and controls. CONCLUSIONS: Our data suggest that SNP rs1990172 and SNP rs975263 in the MACC1 gene may be potential genetic markers for HCC recurrence in LT patients. PMID- 24465160 TI - Serum osteocalcin is significantly related to indices of obesity and lipid profile in Malaysian men. AB - BACKGROUND AND AIM: Recent studies revealed a possible reciprocal relationship between the skeletal system and obesity and lipid metabolism, mediated by osteocalcin, an osteoblast-specific protein. This study aimed to validate the relationship between serum osteocalcin and indices of obesity and lipid parameters in a group of Malaysian men. METHODS: A total of 373 men from the Malaysian Aging Male Study were included in the analysis. Data on subjects' demography, body mass index (BMI), body fat (BF) mass, waist circumference (WC), serum osteocalcin and fasting lipid levels were collected. Bioelectrical impendence (BIA) method was used to estimate BF. Multiple linear and binary logistic regression analyses were performed to analyze the association between serum osteocalcin and the aforementioned variables, with adjustment for age, ethnicity and BMI. RESULTS: Multiple regression results indicated that weight, BMI, BF mass, BF %, WC were significantly and negatively associated with serum osteocalcin (p < 0.001). There was a significant positive association between serum osteocalcin and high density lipoprotein (HDL) cholesterol (p = 0.032). Binary logistic results indicated that subjects with low serum osteocalcin level were more likely to be associated with high BMI (obese and overweight), high BF%, high WC and low HDL cholesterol (p < 0.05). Subjects with high osteocalcin level also demonstrated high total cholesterol level (p < 0.05) but this association was probably driven by high HDL level. These variables were not associated with serum C-terminal of telopeptide crosslinks in the subjects (p > 0.05). CONCLUSION: Serum osteocalcin is associated with indices of obesity and HDL level in men. These relationships should be validated by a longitudinal study, with comprehensive hormone profile testing. PMID- 24465161 TI - A nonsense mutation of gammaD-crystallin associated with congenital nuclear and posterior polar cataract in a Chinese family. AB - OBJECTIVE: The goal of this study was to characterize the disease-causing mutations in a Chinese family with congenital nuclear and posterior polar cataracts. METHODS: Clinical data of patients in the family were recorded using slit-lamp photography and high definition video. Genomic DNA samples were extracted from the peripheral blood of the pedigree members and 100 healthy controls. Mutation screening was performed in the candidate genes by bi directional sequencing of the amplified products. RESULTS: The congenital cataract phenotype of the pedigree was identified by slit-lamp examinations and observation during surgery as nuclear and posterior polar cataracts. Through the sequencing of the candidate genes, a heterozygous c. 418C>T change was detected in the coding region of the gammaD-crystallin gene (CRYGD). As a result of this change, a highly conserved arginine residue was replaced by a stop codon (p. R140X). This change was discovered among all of the affected individuals with cataracts, but not among the unaffected family members or the 100 ethnically matched controls. CONCLUSIONS: This study identified a novel congenital nuclear and posterior polar cataract phenotype caused by the recurrent mutation p. R140X in CRYGD. PMID- 24465162 TI - Aberrant DNA methylation of G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a potential biomarker for hepatitis B Virus associated hepatocellular carcinoma. AB - BACKGROUND: G-protein-coupled bile acid receptor Gpbar1 (TGR5) is a newly identified liver tumor suppressor in carcinogenesis. This present study was therefore to determine the potential value of serum TGR5 promoter methylation in identifying hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) patients. METHODS: The circulating cell-free DNA (cfDNA) was extracted from a retrospective dataset including 160 HCC, 88 CHB and 45 healthy controls (HCs). Methylation status of TGR5 promoter was examined by methylation-specific polymerase chain reaction (MSP). RESULTS: Hypermethylation of the TGR5 promoter occurred significantly more frequent in HCC (77/160, 48.13%) than CHB (12/88, 13.64%; p<0.01) and HCs (2/45, 4.44%; p<0.01). The methylation rate of TGR5 in HCC patients >=60 years old was significantly higher than those <60 years old (p<0.05). Alpha fetoprotein (AFP) had sensitivity of 58.13%, 30.63% and 24.38% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had sensitivity of 81.25%, 68.13% and 65%. AFP had specificity of 47.73%, 92.05% and 98.86% at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had specificity of 38.64%, 78.41% and 85.23%. AFP had Youden index of 0.06, 0.23 and 0.23 at cut-off points of 20, 200 and 400ng/ml respectively; while TGR5 methylation combined AFP had Youden index of 0.20, 0.47 and 0.50. CONCLUSIONS: Our findings strongly suggested the combination of serum TGR5 promoter methylation and AFP enhanced the diagnostic value of AFP alone in discriminating HCC from CHB patients. PMID- 24465163 TI - Intracellular distributing and interferon-gamma secretion of human interleukin-18 in BxPC-3 cells. AB - OBJECTIVE: To investigate the characteristics of interleukin-18 (IL-18) in vitro, explore IL-18, interferon-gamma (IFN-gamma) and interleukin-2 (IL-2) secretive activity in BxPC-3 line cells with interleukin-18 mutants. METHODS: Human IL-18 full-length gene (hIL-18-F) and the hIL-18 presumed mature protein gene (hIL-18 M) were inserted into the expression vector pEGFP-N1, to construct recombinant plasmids as Mu0, Mu1, Mu2, Mu3, and Mu4, and the recombinant plasmids were then transferred into BxPC-3 line cells. There are significant differences between Mu1, Mu2 and the pEGFP-C1 control group (P<0.05) by 3-(4,5-dimethiazol- 2-yl)- 2,5-diphenyltetrazolium bromide (MTT) for a proliferation assay, and the fluorescence of the Mu1 and Mu 2 appeared targeted to the membranous region in the BxPC-3 cells after transfected 24h by confocal laser scanning microscope (OLSM).To characterize the intracellular distribution of hIL-18, recombinant IL 18 were each fused to the enhanced green fluorescent protein gene, and expressed in BxPC-3 cells. RESULTS: Results showed that the Mu1 tended to the membranous region in BxPC-3 cells, this indicates that the N-terminal former amino acid peptide helped ChIL-18 target to BxPC-3 cellS membranes. ELISA results demonstrated that IFN-gamma and IL-18 secreted levels of BxPC-3 cells transfecting with recombinant plasmid showed an significant difference (P<0.01); refers to IL-2 expression, the two BxPC-3 cells groups transfecting with recombinant plasmid have no significant function (P>0.05). CONCLUSIONS: The results showed that hIL-18 and hIL-18 presumed mature protein can induce the secretion of IFN-gamma in BxPC-3 cells, and increase the expression of IL-18, but they have no effects on IL-2. PMID- 24465164 TI - Sex-steroid regulation of relaxin receptor isoforms (RXFP1 & RXFP2) expression in the patellar tendon and lateral collateral ligament of female WKY rats. AB - The incidence of non-contact knee injury was found higher in female than in male and is related to the phases of the menstrual cycle. This raised the possibility that female sex-steroids are involved in the mechanism underlying this injury via affecting the expression of the receptors for relaxin, a peptide hormone known to modulate ligament laxity. Therefore, this study aims to investigate the effect of sex-steroids on relaxin receptor isoforms (RXFP1 & RXFP2) expression in the ligaments and tendons of the knee. METHODS: Ovariectomized adult female WKY rats were treated with different doses of estrogen (0.2, 2, 20 MUg/kg), progesterone (4mg) and testosterone (125 & 250MUg/kg) for three consecutive days. At the end of the treatment, the animals were sacrificed and the patellar tendon and lateral collateral ligament were harvested for mRNA and protein expression analyses by Real Time PCR and Western blotting respectively. RESULTS: RXFP1, the main isoform expressed in these knee structures and RXFP2 showed a dose-dependent increase in expression with estrogen. Progesterone treatment resulted in an increase while testosterone caused a dose-dependent decrease in the mRNA and protein expression of both relaxin receptor isoforms. DISCUSSION: Progesterone and high dose estrogen up-regulate while testosterone down-regulates RXFP1 and RXFP2 expression in the patellar tendon and lateral collateral ligament of rat's knee. CONCLUSION: Relaxin receptor isoforms up-regulation by progesterone and high dose estrogen could provide the basis for the reported increase in knee laxity while down regulation of these receptor isoforms by testosterone could explain low incidence of non-contact knee injury in male. PMID- 24465165 TI - Retrospective evaluation of standard diagnostic procedures in identification of the causes of new-onset syndrome of inappropriate antidiuresis. AB - BACKGROUND: Many diagnostic procedures are conducted in patients with syndrome of inappropriate antidiuresis (SIAD). However, the contribution in identification of the cause of SIAD remains unknown. METHODS: The study was conducted at Kaohsiung Veterans General Hospital in southern Taiwan. From January 2000 to December 2009, medical records of 439 adult patients hospitalized for new-onset SIAD at a single center were retrospectively collected. All diagnostic procedures during hospitalization were divided into four groups: chest/lung, central nervous system, abdomen, and bone marrow to evaluate their positive rate leading to the cause of SIAD. Factors associated with "procedures leading to the cause" were also analyzed to improve efficacy of survey. RESULTS: Cause of SIAD was identified in 267 (60.8%). Of them, 150 were pulmonary disorders, 44 were drugs, 37 were central nervous system disorders, 32 were malignancy and 4 were post surgery. Survey for chest/lung, central nervous system, abdomen, and bone marrow were performed in 96.6%, 29.2%, 38.0% and 3.6% of patients, respectively; positive findings leading to the cause of SIAD were 39.6%, 12.5%, 5.3% and 6.3%, respectively. Among the diagnostic procedures, chest x-ray (424/439, 96.6%) was most frequently performed with the highest identification rate of 34.7% (147 cases). Major significant independent factors that associated with "procedure leading to a cause" were: absence of SIAD-associated drug history, presence of fever/chills, and presence of respiratory symptoms. Cause of SIAD became evident later during the follow-up period in 10 of 172 (5.8%) patients who were initially thought to be cause-unknown. Malignancy was the cause for 5 cases and pulmonary tuberculosis was for the other five. Eight of these causes became evident within one year after the diagnosis of SIAD. CONCLUSIONS: SIAD with unidentified causes were prevalent. Current diagnostic procedures remain not satisfying in determining the cause of SIAD, but chest radiograph did demonstrate higher diagnostic rate, especially in patients presented with fever, chills, respiratory symptoms, and without SIAD-associated drug history. Patients with unidentified cause should be followed for at least one year when most hidden causes (e.g. malignancy and tuberculosis) become obvious. PMID- 24465166 TI - Prolyl endopeptidase activity is correlated with colorectal cancer prognosis. AB - BACKGROUND AND OBJECTIVE: Prolyl endopeptidase (PEP) (EC 3.4.21.26) is a serine peptidase involved in differentiation, development and proliferation processes of several tissues. Recent studies have demonstrated the increased expression and activity of this cytosolic enzyme in colorectal cancer (CRC). However, there are no available data about the impact of this peptidase in the biological aggressiveness of this tumor in patient survival. METHODS: The activity of PEP in tissue (n=80) and plasma (n=40) of patients with CRC was prospectively analyzed by fluorimetric methods. Results were correlated with the most important classic pathological data related to aggressiveness, with 5-year survival rates and other clinical variables. RESULTS: 1) PEP is more active in early phases of CRC; 2) Lower levels of the enzyme in tumors were located in the rectum and this decrease could be related with preoperative chemo-radiotherapy; 3) PEP activity in tissue was higher in patients with better overall and disease-free survival (log-rank p<0.01, Cox analysis p<0.01); 4) Plasmatic PEP activity was significantly higher in CRC patients than in healthy individuals and this was associated with distant metastases and with worse overall and disease-free survivals (log-rank p<0.05, Cox analysis p<0.05). CONCLUSIONS: PEP activity in tissue and plasma from CRC patients is an independent prognostic factor in survival. The determination of PEP activity in the plasma may be a safe, minimally invasive and inexpensive way to define the aggressiveness of CRC in daily practice. PMID- 24465167 TI - Masticatory deficiency as a risk factor for cognitive dysfunction. AB - Several studies have demonstrated that chewing helps to maintain cognitive functions in brain regions including the hippocampus, a central nervous system (CNS) region vital for memory and learning. Epidemiological studies suggest that masticatory deficiency is associated with development of dementia, which is related to spatial memory deficits especially in older animals. The purpose of this paper is to review recent work on the effects of masticatory impairment on cognitive functions both in experimental animals and humans. We show that several mechanisms may be involved in the cognitive deficits associated with masticatory deficiency. The epidemiological data suggest a positive correlation between masticatory deficit and Alzheimer's disease. It may be concluded that chewing has important implications for the mechanisms underlying certain cognitive abilities. PMID- 24465168 TI - Gene expression analysis of TREM1 and GRK2 in polymorphonuclear leukocytes as the surrogate biomarkers of acute bacterial infections. AB - OBJECTIVE: In the acute stage of infectious diseases such as pneumonia and sepsis, sequelae hypercytokinemia and cytokine storm are often observed simultaneously. During bacterial infections, activated polymorphonuclear leukocytes (PMNs) cause inflammation and organ dysfunction in severely ill patients. Gene expression of the triggering receptor on myeloid cells (TREM)-1 and G-coupled-protein receptor kinase (GRK)-2 in PMNs isolated from patients was analysed to identify genes correlated with the severity of pathophysiological conditions. METHODS: mRNA levels of TREM1 and GRK2 in the PMNs from 26 patients (13 with pneumonia, 5 with severe sepsis, and 8 with septic shock) were analysed by using quantitative real-time PCR. The synthesised soluble form (s)TREM-1 was incubated with normal PMNs to investigate its biological functions in vitro. RESULTS: Copies of TREM1 transcript were 0.7- to 2.1-fold higher in patients with pneumonia compared to those of normal subjects; the average fold-change was 1.1 fold. The mRNA levels of patients suffering from severe sepsis and septic shock were 0.34- and 0.33-fold lower compared to those of healthy subjects, respectively. TREM1 mRNA levels in 5 of 26 patients in convalescent stages recovered to normal levels. The mRNA levels of GRK2 in the PMNs of patients were also downregulated. The synthesised sTREM-1 upregulated the mRNA levels of TREM1 in normal PMNs. CONCLUSIONS: TREM1 mRNA levels were inversely correlated with the severity of pathophysiological conditions in acute bacterial infections. The gene expression levels of TREM1 in PMNs isolated from patients with bacterial infections may be used as a surrogate biomarker for determining the severity. PMID- 24465169 TI - A collection of micrographs: where science and art meet. AB - Micrographs obtained using different instrumental techniques are presented with the purpose of demonstrating their artistic qualities. The quality of uniformity currently dominates the aesthetic assessment in scientific practice and is discussed in relation to the classical appreciation of the interplay between symmetry and asymmetry in arts. It is argued that scientific and artistic qualities have converged and inspired each other throughout millennia. With scientific discoveries and inventions enriching the world of communication, broadening the space for artistic creativity and making artistic products more accessible than ever, science inevitably influences artistic creativity. On the other hand, the importance of aesthetic principles in guiding scientific conduct has been appreciated by some of the most creative scientific minds. Science and arts can be thus considered as parallel rails of a single railroad track. Only when precisely coordinated is the passing of the train of human knowledge enabled. The presented micrographs, occupying the central part of this discourse, are displayed with the purpose of showing the rich aesthetic character of even the most ordinary scientific images. The inherent aesthetic nature of scientific imagery and the artistic nature of scientific conduct have thus been offered as the conclusion. PMID- 24465170 TI - TIME INVARIANT MULTI ELECTRODE AVERAGING FOR BIOMEDICAL SIGNALS. AB - One of the biggest challenges in averaging ECG or EEG signals is to overcome temporal misalignments and distortions, due to uncertain timing or complex non stationary dynamics. Standard methods average individual leads over a collection of epochs on a time-sample by time-sample basis, even when multi-electrode signals are available. Here we propose a method that averages multi electrode recordings simultaneously by using spatial patterns and without relying on time or frequency. PMID- 24465171 TI - Online Technologies for Health Information and Education: A literature review. AB - There is a growing body of research focused on the use of social media and Internet technologies for health education and information sharing. The authors reviewed literature on this topic, with a specific focus on the benefits and concerns associated with using online social technologies as health education and communication tools. Studies suggest that social media technologies have the potential to safely and effectively deliver health education, if privacy concerns are addressed. Utility of social media-based health education and communication will improve as technology developers and public health officials determine ways to improve information accuracy and address privacy concerns. PMID- 24465172 TI - Apoplastic diffusion barriers in Arabidopsis. AB - During the development of Arabidopsis and other land plants, diffusion barriers are formed in the apoplast of specialized tissues within a variety of plant organs. While the cuticle of the epidermis is the primary diffusion barrier in the shoot, the Casparian strips and suberin lamellae of the endodermis and the periderm represent the diffusion barriers in the root. Different classes of molecules contribute to the formation of extracellular diffusion barriers in an organ- and tissue-specific manner. Cutin and wax are the major components of the cuticle, lignin forms the early Casparian strip, and suberin is deposited in the stage II endodermis and the periderm. The current status of our understanding of the relationships between the chemical structure, ultrastructure and physiological functions of plant diffusion barriers is discussed. Specific aspects of the synthesis of diffusion barrier components and protocols that can be used for the assessment of barrier function and important barrier properties are also presented. PMID- 24465176 TI - Some salt with your statin, professor? AB - We know that clinical trials sponsored by the pharmaceutical industry are likely to exaggerate benefit and minimise harms. But do these biases extend to their sponsorship of non-human animal research? Using systematic review and meta analysis Bero and colleagues show that, in the case of statins, things are a little more complicated. While the conclusions of industry-sponsored studies were indeed more enthusiastic than warranted by their data, the data themselves painted a picture more conservative than was seen in non-industry-sponsored studies. This behaviour is consistent with maximising the return on investment, seeking robust data before embarking on a clinical trial, and, once that investment has been made, making every effort to "prove" that the drug is safe and effective if this is at all credible. The findings suggest that there is something different about industry-sponsored non-human animal research, perhaps reflecting higher standards than is the case elsewhere. Perhaps the academic community can learn something from our colleagues in the commercial sector. PMID- 24465175 TI - Left brain, right brain: facts and fantasies. AB - Handedness and brain asymmetry are widely regarded as unique to humans, and associated with complementary functions such as a left-brain specialization for language and logic and a right-brain specialization for creativity and intuition. In fact, asymmetries are widespread among animals, and support the gradual evolution of asymmetrical functions such as language and tool use. Handedness and brain asymmetry are inborn and under partial genetic control, although the gene or genes responsible are not well established. Cognitive and emotional difficulties are sometimes associated with departures from the "norm" of right handedness and left-brain language dominance, more often with the absence of these asymmetries than their reversal. PMID- 24465174 TI - Cellulose synthesis and its regulation. AB - Cellulose, the most abundant biopolymer synthesized on land, is made of linear chains of beta (1-4) linked D-glucose. As a major structural component of the cell wall, cellulose is important not only for industrial use but also for plant growth and development. Cellulose microfibrils are tethered by other cell wall polysaccharides such as hemicellulose, pectin, and lignin. In higher plants, cellulose is synthesized by plasma membrane-localized rosette cellulose synthase complexes. Despite the recent advances using a combination of molecular genetics, live cell imaging, and spectroscopic tools, many aspects of the cellulose synthesis remain a mystery. In this chapter, we highlight recent research progress towards understanding the mechanism of cellulose synthesis in Arabidopsis. PMID- 24465173 TI - Cytokinins. AB - Cytokinins are N (6) substituted adenine derivatives that affect many aspects of plant growth and development, including cell division, shoot initiation and growth, leaf senescence, apical dominance, sink/source relationships, nutrient uptake, phyllotaxis, and vascular, gametophyte, and embryonic development, as well as the response to biotic and abiotic factors. Molecular genetic studies in Arabidopsis have helped elucidate the mechanisms underlying the function of this phytohormone in plants. Here, we review our current understanding of cytokinin biosynthesis and signaling in Arabidopsis, the latter of which is similar to bacterial two-component phosphorelays. We discuss the perception of cytokinin by the ER-localized histidine kinase receptors, the role of the AHPs in mediating the transfer of the phosphoryl group from the receptors to the response regulators (ARRs), and finally the role of the large ARR family in cytokinin function. The identification and genetic manipulation of the genes involved in cytokinin metabolism and signaling have helped illuminate the roles of cytokinins in Arabidopsis. We discuss these diverse roles, and how other signaling pathways influence cytokinin levels and sensitivity though modulation of the expression of cytokinin signaling and metabolic genes. PMID- 24465177 TI - Limiting damage during infection: lessons from infection tolerance for novel therapeutics. AB - The distinction between pathogen elimination and damage limitation during infection is beginning to change perspectives on infectious disease control, and has recently led to the development of novel therapies that focus on reducing the illness caused by pathogens (''damage limitation'')rather than reducing pathogen burdens directly (''pathogen elimination''). While beneficial at the individual host level, the population consequences of these interventions remain unclear. To address this issue,we present a simple conceptual framework for damage limitation during infection that distinguishes between therapies that are either host centric (pro-tolerance) or pathogen-centric (anti-virulence). We then draw on recent developments from the evolutionary ecology of disease tolerance to highlight some potential epidemiological and evolutionary responses of pathogens to medical interventions that target the symptoms of infection. Just as pathogens are known to evolve in response to antimicrobial and vaccination therapies, we caution that claims of ''evolution-proof'' anti-virulence interventions may be premature, and further, that in infections where virulence and transmission are linked, reducing illness without reducing pathogen burden could have non-trivial epidemiological and evolutionary consequences that require careful examination. PMID- 24465178 TI - Nonindustry-sponsored preclinical studies on statins yield greater efficacy estimates than industry-sponsored studies: a meta-analysis. AB - Industry-sponsored clinical drug studies are associated with publication of outcomes that favor the sponsor, even when controlling for potential bias in the methods used. However, the influence of sponsorship bias has not been examined in preclinical animal studies. We performed a meta-analysis of preclinical statin studies to determine whether industry sponsorship is associated with either increased effect sizes of efficacy outcomes and/or risks of bias in a cohort of published preclinical statin studies. We searched Medline (January 1966-April 2012) and identified 63 studies evaluating the effects of statins on atherosclerosis outcomes in animals. Two coders independently extracted study design criteria aimed at reducing bias, results for all relevant outcomes, sponsorship source, and investigator financial ties. The I(2) statistic was used to examine heterogeneity. We calculated the standardized mean difference (SMD) for each outcome and pooled data across studies to estimate the pooled average SMD using random effects models. In a priori subgroup analyses, we assessed statin efficacy by outcome measured, sponsorship source, presence or absence of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. The effect of statins was significantly larger for studies sponsored by nonindustry sources (-1.99; 95% CI -2.68, -1.31) versus studies sponsored by industry (-0.73; 95% CI -1.00, -0.47) (p value<0.001). Statin efficacy did not differ by disclosure of financial conflict information, use of an optimal time window for outcome assessment, accounting for all animals, inclusion criteria, blinding, and randomization. Possible reasons for the differences between nonindustry- and industry-sponsored studies, such as selective reporting of outcomes, require further study. PMID- 24465179 TI - Def1 promotes the degradation of Pol3 for polymerase exchange to occur during DNA damage--induced mutagenesis in Saccharomyces cerevisiae. AB - DNA damages hinder the advance of replication forks because of the inability of the replicative polymerases to synthesize across most DNA lesions. Because stalled replication forks are prone to undergo DNA breakage and recombination that can lead to chromosomal rearrangements and cell death, cells possess different mechanisms to ensure the continuity of replication on damaged templates. Specialized, translesion synthesis (TLS) polymerases can take over synthesis at DNA damage sites. TLS polymerases synthesize DNA with a high error rate and are responsible for damage-induced mutagenesis, so their activity must be strictly regulated. However, the mechanism that allows their replacement of the replicative polymerase is unknown. Here, using protein complex purification and yeast genetic tools, we identify Def1 as a key factor for damage-induced mutagenesis in yeast. In in vivo experiments we demonstrate that upon DNA damage, Def1 promotes the ubiquitylation and subsequent proteasomal degradation of Pol3, the catalytic subunit of the replicative polymerase delta, whereas Pol31 and Pol32, the other two subunits of polymerase delta, are not affected. We also show that purified Pol31 and Pol32 can form a complex with the TLS polymerase Rev1. Our results imply that TLS polymerases carry out DNA lesion bypass only after the Def1-assisted removal of Pol3 from the stalled replication fork. PMID- 24465180 TI - Imre Festetics and the Sheep Breeders' Society of Moravia: Mendel's Forgotten "Research Network". AB - Contemporary science thrives on collaborative networks, but these can also be found elsewhere in the history of science in unexpected places. When Mendel turned his attention to inheritance in peas he was not an isolated monk, but rather the latest in a line of Moravian researchers and agriculturalists who had been thinking about inheritance for half a century. Many of the principles of inheritance had already been sketched out by Imre Festetics, a Hungarian sheep breeder active in Brno. Festetics, however, was ultimately hindered by the complex nature of his study traits, aspects of wool quality that we now know to be polygenic. Whether or not Mendel was aware of Festetics's ideas,both men were products of the same vibrant milieu in 19th-century Moravia that combined theory and agricultural practice to eventually uncover the rules of inheritance. PMID- 24465182 TI - A footnote to the evolution of digits. PMID- 24465181 TI - Conservation and divergence of regulatory strategies at Hox Loci and the origin of tetrapod digits. AB - The evolution of tetrapod limbs from fish fins enabled the conquest of land by vertebrates and thus represents a key step in evolution. Despite the use of comparative gene expression analyses, critical aspects of this transformation remain controversial, in particular the origin of digits. Hoxa and Hoxd genes are essential for the specification of the different limb segments and their functional abrogation leads to large truncations of the appendages. Here we show that the selective transcription of mouse Hoxa genes in proximal and distal limbs is related to a bimodal higher order chromatin structure, similar to that reported for Hoxd genes, thus revealing a generic regulatory strategy implemented by both gene clusters during limb development. We found the same bimodal chromatin architecture in fish embryos, indicating that the regulatory mechanism used to pattern tetrapod limbs may predate the divergence between fish and tetrapods. However, when assessed in mice, both fish regulatory landscapes triggered transcription in proximal rather than distal limb territories, supporting an evolutionary scenario whereby digits arose as tetrapod novelties through genetic retrofitting of preexisting regulatory landscapes. We discuss the possibility to consider regulatory circuitries, rather than expression patterns, as essential parameters to define evolutionary synapomorphies. PMID- 24465183 TI - Use of Speaker's Gaze and Syntax in Verb Learning. AB - Speaker eye gaze and gesture are known to help child and adult listeners establish communicative alignment and learn object labels. Here we consider how learners use these cues, along with linguistic information, to acquire abstract relational verbs. Test items were perspective verb pairs (e.g., chase/flee, win/lose), which pose a special problem for observational accounts of word learning because their situational contexts overlap very closely; the learner must infer the speaker's chosen perspective on the event. Two cues to the speaker's perspective on a depicted event were compared and combined: (a) the speaker's eye gaze to an event participant (e.g., looking at the Chaser vs. looking at the Flee-er) and (b) the speaker's linguistic choice of which event participant occupies Subject position in his utterance. Participants (3-, 4-, and 5-year-olds) were eye-tracked as they watched a series of videos of a man describing drawings of perspective events (e.g., a rabbit chasing an elephant). The speaker looked at one of the two characters and then uttered either an utterance that was referentially uninformative (He's mooping him) or informative (The rabbit's mooping the elephant/The elephant's mooping the rabbit) because of the syntactic positioning of the nouns. Eye-tracking results showed that all participants regardless of age followed the speaker's gaze in both uninformative and informative contexts. However, verb-meaning choices were responsive to speaker's gaze direction only in the linguistically uninformative condition. In the presence of a linguistically informative context, effects of speaker gaze on meaning were minimal for the youngest children to nonexistent for the older populations. Thus children, like adults, can use multiple cues to inform verb meaning choice but rapidly learn that the syntactic positioning of referring expressions is an especially informative source of evidence for these decisions. PMID- 24465184 TI - Children Use Different Cues to Guide Noun and Verb Extensions. AB - Learning new words involves decoding both how a word fits the current situation and how it could be used in new situations. Three studies explore how two types of cues- sentence structure and the availability of multiple instances-- affect children's extensions of nouns and verbs. In each study, 21/2-year-olds heard nouns, verbs or no new word while seeing the experimenter use a novel object to perform an action; at test, they were asked to extend the word. In Study 1, children hearing nouns in simple sentences used object shape as the basis for extension even though, during the learning phase, they saw multiple objects in motion; children in the other conditions responded randomly. Study 2 shows that by changing in the type of sentences used in the noun and verb conditions, not only is the shape bias disrupted but children are successful in extending new verbs. In a final study, access to multiple examples was replaced by a direct teaching context, and produced findings similar to those in Study 2. An implication of this result is that seeing multiple examples can be as effective as receiving direct instruction from an adult. Overall, the set of results suggests the mix of cues available during learning influences noun and verb extensions differently. The findings are important for understanding how the ability to extend words emerges in complex contexts. PMID- 24465185 TI - A risk prediction model for the assessment and triage of women with hypertensive disorders of pregnancy in low-resourced settings: the miniPIERS (Pre-eclampsia Integrated Estimate of RiSk) multi-country prospective cohort study. AB - BACKGROUND: Pre-eclampsia/eclampsia are leading causes of maternal mortality and morbidity, particularly in low- and middle- income countries (LMICs). We developed the miniPIERS risk prediction model to provide a simple, evidence-based tool to identify pregnant women in LMICs at increased risk of death or major hypertensive-related complications. METHODS AND FINDINGS: From 1 July 2008 to 31 March 2012, in five LMICs, data were collected prospectively on 2,081 women with any hypertensive disorder of pregnancy admitted to a participating centre. Candidate predictors collected within 24 hours of admission were entered into a step-wise backward elimination logistic regression model to predict a composite adverse maternal outcome within 48 hours of admission. Model internal validation was accomplished by bootstrapping and external validation was completed using data from 1,300 women in the Pre-eclampsia Integrated Estimate of RiSk (fullPIERS) dataset. Predictive performance was assessed for calibration, discrimination, and stratification capacity. The final miniPIERS model included: parity (nulliparous versus multiparous); gestational age on admission; headache/visual disturbances; chest pain/dyspnoea; vaginal bleeding with abdominal pain; systolic blood pressure; and dipstick proteinuria. The miniPIERS model was well-calibrated and had an area under the receiver operating characteristic curve (AUC ROC) of 0.768 (95% CI 0.735-0.801) with an average optimism of 0.037. External validation AUC ROC was 0.713 (95% CI 0.658-0.768). A predicted probability >=25% to define a positive test classified women with 85.5% accuracy. Limitations of this study include the composite outcome and the broad inclusion criteria of any hypertensive disorder of pregnancy. This broad approach was used to optimize model generalizability. CONCLUSIONS: The miniPIERS model shows reasonable ability to identify women at increased risk of adverse maternal outcomes associated with the hypertensive disorders of pregnancy. It could be used in LMICs to identify women who would benefit most from interventions such as magnesium sulphate, antihypertensives, or transportation to a higher level of care. PMID- 24465186 TI - Scale-up of malaria rapid diagnostic tests and artemisinin-based combination therapy: challenges and perspectives in sub-Saharan Africa. PMID- 24465188 TI - Home blood pressure monitoring: new evidence for an expanded role. PMID- 24465189 TI - PragmatiX: An Interactive Tool for Visualizing the Creation Process Behind Collaboratively Engineered Ontologies. AB - With the emergence of tools for collaborative ontology engineering, more and more data about the creation process behind collaborative construction of ontologies is becoming available. Today, collaborative ontology engineering tools such as Collaborative Protege offer rich and structured logs of changes, thereby opening up new challenges and opportunities to study and analyze the creation of collaboratively constructed ontologies. While there exists a plethora of visualization tools for ontologies, they have primarily been built to visualize aspects of the final product (the ontology) and not the collaborative processes behind construction (e.g. the changes made by contributors over time). To the best of our knowledge, there exists no ontology visualization tool today that focuses primarily on visualizing the history behind collaboratively constructed ontologies. Since the ontology engineering processes can influence the quality of the final ontology, we believe that visualizing process data represents an important stepping-stone towards better understanding of managing the collaborative construction of ontologies in the future. In this application paper, we present a tool - PragmatiX - which taps into structured change logs provided by tools such as Collaborative Protege to visualize various pragmatic aspects of collaborative ontology engineering. The tool is aimed at managers and leaders of collaborative ontology engineering projects to help them in monitoring progress, in exploring issues and problems, and in tracking quality-related issues such as overrides and coordination among contributors. The paper makes the following contributions: (i) we present PragmatiX, a tool for visualizing the creation process behind collaboratively constructed ontologies (ii) we illustrate the functionality and generality of the tool by applying it to structured logs of changes of two large collaborative ontology-engineering projects and (iii) we conduct a heuristic evaluation of the tool with domain experts to uncover early design challenges and opportunities for improvement. Finally, we hope that this work sparks a new line of research on visualization tools for collaborative ontology engineering projects. PMID- 24465187 TI - Risk stratification by self-measured home blood pressure across categories of conventional blood pressure: a participant-level meta-analysis. AB - BACKGROUND: The Global Burden of Diseases Study 2010 reported that hypertension is worldwide the leading risk factor for cardiovascular disease, causing 9.4 million deaths annually. We examined to what extent self-measurement of home blood pressure (HBP) refines risk stratification across increasing categories of conventional blood pressure (CBP). METHODS AND FINDINGS: This meta-analysis included 5,008 individuals randomly recruited from five populations (56.6% women; mean age, 57.1 y). All were not treated with antihypertensive drugs. In multivariable analyses, hazard ratios (HRs) associated with 10-mm Hg increases in systolic HBP were computed across CBP categories, using the following systolic/diastolic CBP thresholds (in mm Hg): optimal, <120/<80; normal, 120 129/80-84; high-normal, 130-139/85-89; mild hypertension, 140-159/90-99; and severe hypertension, >=160/>=100. Over 8.3 y, 522 participants died, and 414, 225, and 194 had cardiovascular, cardiac, and cerebrovascular events, respectively. In participants with optimal or normal CBP, HRs for a composite cardiovascular end point associated with a 10-mm Hg higher systolic HBP were 1.28 (1.01-1.62) and 1.22 (1.00-1.49), respectively. At high-normal CBP and in mild hypertension, the HRs were 1.24 (1.03-1.49) and 1.20 (1.06-1.37), respectively, for all cardiovascular events and 1.33 (1.07-1.65) and 1.30 (1.09-1.56), respectively, for stroke. In severe hypertension, the HRs were not significant (p>=0.20). Among people with optimal, normal, and high-normal CBP, 67 (5.0%), 187 (18.4%), and 315 (30.3%), respectively, had masked hypertension (HBP>=130 mm Hg systolic or >=85 mm Hg diastolic). Compared to true optimal CBP, masked hypertension was associated with a 2.3-fold (1.5-3.5) higher cardiovascular risk. A limitation was few data from low- and middle-income countries. CONCLUSIONS: HBP substantially refines risk stratification at CBP levels assumed to carry no or only mildly increased risk, in particular in the presence of masked hypertension. Randomized trials could help determine the best use of CBP vs. HBP in guiding BP management. Our study identified a novel indication for HBP, which, in view of its low cost and the increased availability of electronic communication, might be globally applicable, even in remote areas or in low-resource settings. PMID- 24465191 TI - Current practice in software development for computational neuroscience and how to improve it. AB - Almost all research work in computational neuroscience involves software. As researchers try to understand ever more complex systems, there is a continual need for software with new capabilities. Because of the wide range of questions being investigated, new software is often developed rapidly by individuals or small groups. In these cases, it can be hard to demonstrate that the software gives the right results. Software developers are often open about the code they produce and willing to share it, but there is little appreciation among potential users of the great diversity of software development practices and end results, and how this affects the suitability of software tools for use in research projects. To help clarify these issues, we have reviewed a range of software tools and asked how the culture and practice of software development affects their validity and trustworthiness. We identified four key questions that can be used to categorize software projects and correlate them with the type of product that results. The first question addresses what is being produced. The other three concern why, how, and by whom the work is done. The answers to these questions show strong correlations with the nature of the software being produced, and its suitability for particular purposes. Based on our findings, we suggest ways in which current software development practice in computational neuroscience can be improved and propose checklists to help developers, reviewers, and scientists to assess the quality of software and whether particular pieces of software are ready for use in research. PMID- 24465192 TI - Bioinformatics projects supporting life-sciences learning in high schools. AB - The interdisciplinary nature of bioinformatics makes it an ideal framework to develop activities enabling enquiry-based learning. We describe here the development and implementation of a pilot project to use bioinformatics-based research activities in high schools, called "Bioinformatics@school." It includes web-based research projects that students can pursue alone or under teacher supervision and a teacher training program. The project is organized so as to enable discussion of key results between students and teachers. After successful trials in two high schools, as measured by questionnaires, interviews, and assessment of knowledge acquisition, the project is expanding by the action of the teachers involved, who are helping us develop more content and are recruiting more teachers and schools. PMID- 24465193 TI - Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites. AB - Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter MU, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, MU was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery. PMID- 24465194 TI - Combinatorial modeling of chromatin features quantitatively predicts DNA replication timing in Drosophila. AB - In metazoans, each cell type follows a characteristic, spatio-temporally regulated DNA replication program. Histone modifications (HMs) and chromatin binding proteins (CBPs) are fundamental for a faithful progression and completion of this process. However, no individual HM is strictly indispensable for origin function, suggesting that HMs may act combinatorially in analogy to the histone code hypothesis for transcriptional regulation. In contrast to gene expression however, the relationship between combinations of chromatin features and DNA replication timing has not yet been demonstrated. Here, by exploiting a comprehensive data collection consisting of 95 CBPs and HMs we investigated their combinatorial potential for the prediction of DNA replication timing in Drosophila using quantitative statistical models. We found that while combinations of CBPs exhibit moderate predictive power for replication timing, pairwise interactions between HMs lead to accurate predictions genome-wide that can be locally further improved by CBPs. Independent feature importance and model analyses led us to derive a simplified, biologically interpretable model of the relationship between chromatin landscape and replication timing reaching 80% of the full model accuracy using six model terms. Finally, we show that pairwise combinations of HMs are able to predict differential DNA replication timing across different cell types. All in all, our work provides support to the existence of combinatorial HM patterns for DNA replication and reveal cell-type independent key elements thereof, whose experimental investigation might contribute to elucidate the regulatory mode of this fundamental cellular process. PMID- 24465195 TI - The brain ages optimally to model its environment: evidence from sensory learning over the adult lifespan. AB - The aging brain shows a progressive loss of neuropil, which is accompanied by subtle changes in neuronal plasticity, sensory learning and memory. Neurophysiologically, aging attenuates evoked responses--including the mismatch negativity (MMN). This is accompanied by a shift in cortical responsivity from sensory (posterior) regions to executive (anterior) regions, which has been interpreted as a compensatory response for cognitive decline. Theoretical neurobiology offers a simpler explanation for all of these effects--from a Bayesian perspective, as the brain is progressively optimized to model its world, its complexity will decrease. A corollary of this complexity reduction is an attenuation of Bayesian updating or sensory learning. Here we confirmed this hypothesis using magnetoencephalographic recordings of the mismatch negativity elicited in a large cohort of human subjects, in their third to ninth decade. Employing dynamic causal modeling to assay the synaptic mechanisms underlying these non-invasive recordings, we found a selective age-related attenuation of synaptic connectivity changes that underpin rapid sensory learning. In contrast, baseline synaptic connectivity strengths were consistently strong over the decades. Our findings suggest that the lifetime accrual of sensory experience optimizes functional brain architectures to enable efficient and generalizable predictions of the world. PMID- 24465196 TI - Modeling within-host effects of drugs on Plasmodium falciparum transmission and prospects for malaria elimination. AB - Achieving a theoretical foundation for malaria elimination will require a detailed understanding of the quantitative relationships between patient treatment-seeking behavior, treatment coverage, and the effects of curative therapies that also block Plasmodium parasite transmission to mosquito vectors. Here, we report a mechanistic, within-host mathematical model that uses pharmacokinetic (PK) and pharmacodynamic (PD) data to simulate the effects of artemisinin-based combination therapies (ACTs) on Plasmodium falciparum transmission. To contextualize this model, we created a set of global maps of the fold reductions that would be necessary to reduce the malaria R C (i.e. its basic reproductive number under control) to below 1 and thus interrupt transmission. This modeling was applied to low-transmission settings, defined as having a R 0<10 based on 2010 data. Our modeling predicts that treating 93-98% of symptomatic infections with an ACT within five days of fever onset would interrupt malaria transmission for ~91% of the at-risk population of Southeast Asia and ~74% of the global at-risk population, and lead these populations towards malaria elimination. This level of treatment coverage corresponds to an estimated 81-85% of all infected individuals in these settings. At this coverage level with ACTs, the addition of the gametocytocidal agent primaquine affords no major gains in transmission reduction. Indeed, we estimate that it would require switching ~180 people from ACTs to ACTs plus primaquine to achieve the same transmission reduction as switching a single individual from untreated to treated with ACTs. Our model thus predicts that the addition of gametocytocidal drugs to treatment regimens provides very small population-wide benefits and that the focus of control efforts in Southeast Asia should be on increasing prompt ACT coverage. Prospects for elimination in much of Sub-Saharan Africa appear far less favorable currently, due to high rates of infection and less frequent and less rapid treatment. PMID- 24465197 TI - Consequences of converting graded to action potentials upon neural information coding and energy efficiency. AB - Information is encoded in neural circuits using both graded and action potentials, converting between them within single neurons and successive processing layers. This conversion is accompanied by information loss and a drop in energy efficiency. We investigate the biophysical causes of this loss of information and efficiency by comparing spiking neuron models, containing stochastic voltage-gated Na(+) and K(+) channels, with generator potential and graded potential models lacking voltage-gated Na(+) channels. We identify three causes of information loss in the generator potential that are the by-product of action potential generation: (1) the voltage-gated Na(+) channels necessary for action potential generation increase intrinsic noise and (2) introduce non linearities, and (3) the finite duration of the action potential creates a 'footprint' in the generator potential that obscures incoming signals. These three processes reduce information rates by ~50% in generator potentials, to ~3 times that of spike trains. Both generator potentials and graded potentials consume almost an order of magnitude less energy per second than spike trains. Because of the lower information rates of generator potentials they are substantially less energy efficient than graded potentials. However, both are an order of magnitude more efficient than spike trains due to the higher energy costs and low information content of spikes, emphasizing that there is a two-fold cost of converting analogue to digital; information loss and cost inflation. PMID- 24465198 TI - VBA: a probabilistic treatment of nonlinear models for neurobiological and behavioural data. AB - This work is in line with an on-going effort tending toward a computational (quantitative and refutable) understanding of human neuro-cognitive processes. Many sophisticated models for behavioural and neurobiological data have flourished during the past decade. Most of these models are partly unspecified (i.e. they have unknown parameters) and nonlinear. This makes them difficult to peer with a formal statistical data analysis framework. In turn, this compromises the reproducibility of model-based empirical studies. This work exposes a software toolbox that provides generic, efficient and robust probabilistic solutions to the three problems of model-based analysis of empirical data: (i) data simulation, (ii) parameter estimation/model selection, and (iii) experimental design optimization. PMID- 24465199 TI - An allosteric signaling pathway of human 3-phosphoglycerate kinase from force distribution analysis. AB - 3-Phosphogycerate kinase (PGK) is a two domain enzyme, which transfers a phosphate group between its two substrates, 1,3-bisphosphoglycerate bound to the N-domain and ADP bound to the C-domain. Indispensable for the phosphoryl transfer reaction is a large conformational change from an inactive open to an active closed conformation via a hinge motion that should bring substrates into close proximity. The allosteric pathway resulting in the active closed conformation has only been partially uncovered. Using Molecular Dynamics simulations combined with Force Distribution Analysis (FDA), we describe an allosteric pathway, which connects the substrate binding sites to the interdomain hinge region. Glu192 of alpha-helix 7 and Gly394 of loop L14 act as hinge points, at which these two secondary structure elements straighten, thereby moving the substrate-binding domains towards each other. The long-range allosteric pathway regulating hPGK catalytic activity, which is partially validated and can be further tested by mutagenesis, highlights the virtue of monitoring internal forces to reveal signal propagation, even if only minor conformational distortions, such as helix bending, initiate the large functional rearrangement of the macromolecule. PMID- 24465200 TI - Leadership and path characteristics during walks are linked to dominance order and individual traits in dogs. AB - Movement interactions and the underlying social structure in groups have relevance across many social-living species. Collective motion of groups could be based on an "egalitarian" decision system, but in practice it is often influenced by underlying social network structures and by individual characteristics. We investigated whether dominance rank and personality traits are linked to leader and follower roles during joint motion of family dogs. We obtained high resolution spatio-temporal GPS trajectory data (823,148 data points) from six dogs belonging to the same household and their owner during 14 30-40 min unleashed walks. We identified several features of the dogs' paths (e.g., running speed or distance from the owner) which are characteristic of a given dog. A directional correlation analysis quantifies interactions between pairs of dogs that run loops jointly. We found that dogs play the role of the leader about 50 85% of the time, i.e. the leader and follower roles in a given pair are dynamically interchangable. However, on a longer timescale tendencies to lead differ consistently. The network constructed from these loose leader-follower relations is hierarchical, and the dogs' positions in the network correlates with the age, dominance rank, trainability, controllability, and aggression measures derived from personality questionnaires. We demonstrated the possibility of determining dominance rank and personality traits of an individual based only on its logged movement data. The collective motion of dogs is influenced by underlying social network structures and by characteristics such as personality differences. Our findings could pave the way for automated animal personality and human social interaction measurements. PMID- 24465201 TI - Correlation between oncogenic mutations and parameter sensitivity of the apoptosis pathway model. AB - One of the major breakthroughs in oncogenesis research in recent years is the discovery that, in most patients, oncogenic mutations are concentrated in a few core biological functional pathways. This discovery indicates that oncogenic mechanisms are highly related to the dynamics of biologic regulatory networks, which govern the behaviour of functional pathways. Here, we propose that oncogenic mutations found in different biological functional pathways are closely related to parameter sensitivity of the corresponding networks. To test this hypothesis, we focus on the DNA damage-induced apoptotic pathway--the most important safeguard against oncogenesis. We first built the regulatory network that governs the apoptosis pathway, and then translated the network into dynamics equations. Using sensitivity analysis of the network parameters and comparing the results with cancer gene mutation spectra, we found that parameters that significantly affect the bifurcation point correspond to high-frequency oncogenic mutations. This result shows that the position of the bifurcation point is a better measure of the functionality of a biological network than gene expression levels of certain key proteins. It further demonstrates the suitability of applying systems-level analysis to biological networks as opposed to studying genes or proteins in isolation. PMID- 24465202 TI - Bayesian reconstruction of disease outbreaks by combining epidemiologic and genomic data. AB - Recent years have seen progress in the development of statistically rigorous frameworks to infer outbreak transmission trees ("who infected whom") from epidemiological and genetic data. Making use of pathogen genome sequences in such analyses remains a challenge, however, with a variety of heuristic approaches having been explored to date. We introduce a statistical method exploiting both pathogen sequences and collection dates to unravel the dynamics of densely sampled outbreaks. Our approach identifies likely transmission events and infers dates of infections, unobserved cases and separate introductions of the disease. It also proves useful for inferring numbers of secondary infections and identifying heterogeneous infectivity and super-spreaders. After testing our approach using simulations, we illustrate the method with the analysis of the beginning of the 2003 Singaporean outbreak of Severe Acute Respiratory Syndrome (SARS), providing new insights into the early stage of this epidemic. Our approach is the first tool for disease outbreak reconstruction from genetic data widely available as free software, the R package outbreaker. It is applicable to various densely sampled epidemics, and improves previous approaches by detecting unobserved and imported cases, as well as allowing multiple introductions of the pathogen. Because of its generality, we believe this method will become a tool of choice for the analysis of densely sampled disease outbreaks, and will form a rigorous framework for subsequent methodological developments. PMID- 24465204 TI - HIV-1 accessory proteins adapt cellular adaptors to facilitate immune evasion. PMID- 24465205 TI - Variation in RNA virus mutation rates across host cells. AB - It is well established that RNA viruses exhibit higher rates of spontaneous mutation than DNA viruses and microorganisms. However, their mutation rates vary amply, from 10(-6) to 10(-4) substitutions per nucleotide per round of copying (s/n/r) and the causes of this variability remain poorly understood. In addition to differences in intrinsic fidelity or error correction capability, viral mutation rates may be dependent on host factors. Here, we assessed the effect of the cellular environment on the rate of spontaneous mutation of the vesicular stomatitis virus (VSV), which has a broad host range and cell tropism. Luria Delbruck fluctuation tests and sequencing showed that VSV mutated similarly in baby hamster kidney, murine embryonic fibroblasts, colon cancer, and neuroblastoma cells (approx. 10(-5) s/n/r). Cell immortalization through p53 inactivation and oxygen levels (1-21%) did not have a significant impact on viral replication fidelity. This shows that previously published mutation rates can be considered reliable despite being based on a narrow and artificial set of laboratory conditions. Interestingly, we also found that VSV mutated approximately four times more slowly in various insect cells compared with mammalian cells. This may contribute to explaining the relatively slow evolution of VSV and other arthropod-borne viruses in nature. PMID- 24465206 TI - Intranasal vaccination promotes detrimental Th17-mediated immunity against influenza infection. AB - Influenza disease is a global health issue that causes significant morbidity and mortality through seasonal epidemics. Currently, inactivated influenza virus vaccines given intramuscularly or live attenuated influenza virus vaccines administered intranasally are the only approved options for vaccination against influenza virus in humans. We evaluated the efficacy of a synthetic toll-like receptor 4 agonist CRX-601 as an adjuvant for enhancing vaccine-induced protection against influenza infection. Intranasal administration of CRX-601 adjuvant combined with detergent split-influenza antigen (A/Uruguay/716/2007 (H3N2)) generated strong local and systemic immunity against co-administered influenza antigens while exhibiting high efficacy against two heterotypic influenza challenges. Intranasal vaccination with CRX-601 adjuvanted vaccines promoted antigen-specific IgG and IgA antibody responses and the generation of polyfunctional antigen-specific Th17 cells (CD4(+)IL-17A(+)TNFalpha(+)). Following challenge with influenza virus, vaccinated mice transiently exhibited increased weight loss and morbidity during early stages of disease but eventually controlled infection. This disease exacerbation following influenza infection in vaccinated mice was dependent on both the route of vaccination and the addition of the adjuvant. Neutralization of IL-17A confirmed a detrimental role for this cytokine during influenza infection. The expansion of vaccine-primed Th17 cells during influenza infection was also accompanied by an augmented lung neutrophilic response, which was partially responsible for mediating the increased morbidity. This discovery is of significance in the field of vaccinology, as it highlights the importance of both route of vaccination and adjuvant selection in vaccine development. PMID- 24465207 TI - Absence of intestinal PPARgamma aggravates acute infectious colitis in mice through a lipocalin-2-dependent pathway. AB - To be able to colonize its host, invading Salmonella enterica serovar Typhimurium must disrupt and severely affect host-microbiome homeostasis. Here we report that S. Typhimurium induces acute infectious colitis by inhibiting peroxisome proliferator-activated receptor gamma (PPARgamma) expression in intestinal epithelial cells. Interestingly, this PPARgamma down-regulation by S. Typhimurium is independent of TLR-4 signaling but triggers a marked elevation of host innate immune response genes, including that encoding the antimicrobial peptide lipocalin-2 (Lcn2). Accumulation of Lcn2 stabilizes the metalloproteinase MMP-9 via extracellular binding, which further aggravates the colitis. Remarkably, when exposed to S. Typhimurium, Lcn2-null mice exhibited a drastic reduction of the colitis and remained protected even at later stages of infection. Our data suggest a mechanism in which S. Typhimurium hijacks the control of host immune response genes such as those encoding PPARgamma and Lcn2 to acquire residence in a host, which by evolution has established a symbiotic relation with its microbiome community to prevent pathogen invasion. PMID- 24465208 TI - Induction of a stringent metabolic response in intracellular stages of Leishmania mexicana leads to increased dependence on mitochondrial metabolism. AB - Leishmania parasites alternate between extracellular promastigote stages in the insect vector and an obligate intracellular amastigote stage that proliferates within the phagolysosomal compartment of macrophages in the mammalian host. Most enzymes involved in Leishmania central carbon metabolism are constitutively expressed and stage-specific changes in energy metabolism remain poorly defined. Using (13)C-stable isotope resolved metabolomics and (2)H2O labelling, we show that amastigote differentiation is associated with reduction in growth rate and induction of a distinct stringent metabolic state. This state is characterized by a global decrease in the uptake and utilization of glucose and amino acids, a reduced secretion of organic acids and increased fatty acid beta-oxidation. Isotopomer analysis showed that catabolism of hexose and fatty acids provide C4 dicarboxylic acids (succinate/malate) and acetyl-CoA for the synthesis of glutamate via a compartmentalized mitochondrial tricarboxylic acid (TCA) cycle. In vitro cultivated and intracellular amastigotes are acutely sensitive to inhibitors of mitochondrial aconitase and glutamine synthetase, indicating that these anabolic pathways are essential for intracellular growth and virulence. Lesion-derived amastigotes exhibit a similar metabolism to in vitro differentiated amastigotes, indicating that this stringent response is coupled to differentiation signals rather than exogenous nutrient levels. Induction of a stringent metabolic response may facilitate amastigote survival in a nutrient poor intracellular niche and underlie the increased dependence of this stage on hexose and mitochondrial metabolism. PMID- 24465209 TI - Detection of host-derived sphingosine by Pseudomonas aeruginosa is important for survival in the murine lung. AB - Pseudomonas aeruginosa is a common environmental bacterium that is also a significant opportunistic pathogen, particularly of the human lung. We must understand how P. aeruginosa responds to the lung environment in order to identify the regulatory changes that bacteria use to establish and maintain infections. The P. aeruginosa response to pulmonary surfactant was used as a model to identify transcripts likely induced during lung infection. The most highly induced transcript in pulmonary surfactant, PA5325 (sphA), is regulated by an AraC-family transcription factor, PA5324 (SphR). We found that sphA was specifically induced by sphingosine in an SphR-dependent manner, and also via metabolism of sphingomyelin, ceramide, or sphingoshine-1-phosphate to sphingosine. These sphingolipids not only play a structural role in lipid membranes, but some are also intracellular and intercellular signaling molecules important in normal eukaryotic cell functions as well as orchestrating immune responses. The members of the SphR transcriptome were identified by microarray analyses, and DNA binding assays showed specific interaction of these promoters with SphR, which enabled us to determine the consensus SphR binding site. SphR binding to DNA was modified by sphingosine and we used labeled sphingosine to demonstrate direct binding of sphingosine by SphR. Deletion of sphR resulted in reduced bacterial survival during mouse lung infection. In vitro experiments show that deletion of sphR increases sensitivity to the antimicrobial effects of sphingosine which could, in part, explain the in vivo phenotype. This is the first identification of a sphingosine-responsive transcription factor in bacteria. We predict that SphR transcriptional regulation may be important in response to many sites of infection in eukaryotes and the presence of homologous transcription factors in other pathogens suggests that sphingosine detection is not limited to P. aeruginosa. PMID- 24465210 TI - Preservation of tetherin and CD4 counter-activities in circulating Vpu alleles despite extensive sequence variation within HIV-1 infected individuals. AB - The HIV-1 Vpu protein is expressed from a bi-cistronic message late in the viral life cycle. It functions during viral assembly to maximise infectious virus release by targeting CD4 for proteosomal degradation and counteracting the antiviral protein tetherin (BST2/CD317). Single genome analysis of vpu repertoires throughout infection in 14 individuals infected with HIV-1 clade B revealed extensive amino acid diversity of the Vpu protein. For the most part, this variation in Vpu increases over the course of infection and is associated with predicted epitopes of the individual's MHC class I haplotype, suggesting CD8+ T cell pressure is the major driver of Vpu sequence diversity within the host. Despite this variability, the Vpu functions of targeting CD4 and counteracting both physical virus restriction and NF-kappaB activation by tetherin are rigorously maintained throughout HIV-1 infection. Only a minority of circulating alleles bear lesions in either of these activities at any given time, suggesting functional Vpu mutants are heavily selected against even at later stages of infection. Comparison of Vpu proteins defective for one or several functions reveals novel determinants of CD4 downregulation, counteraction of tetherin restriction, and inhibition of NF-kappaB signalling. These data affirm the importance of Vpu functions for in vivo persistence of HIV-1 within infected individuals, not simply for transmission, and highlight its potential as a target for antiviral therapy. PMID- 24465211 TI - Origin, migration routes and worldwide population genetic structure of the wheat yellow rust pathogen Puccinia striiformis f.sp. tritici. AB - Analyses of large-scale population structure of pathogens enable the identification of migration patterns, diversity reservoirs or longevity of populations, the understanding of current evolutionary trajectories and the anticipation of future ones. This is particularly important for long-distance migrating fungal pathogens such as Puccinia striiformis f.sp. tritici (PST), capable of rapid spread to new regions and crop varieties. Although a range of recent PST invasions at continental scales are well documented, the worldwide population structure and the center of origin of the pathogen were still unknown. In this study, we used multilocus microsatellite genotyping to infer worldwide population structure of PST and the origin of new invasions based on 409 isolates representative of distribution of the fungus on six continents. Bayesian and multivariate clustering methods partitioned the set of multilocus genotypes into six distinct genetic groups associated with their geographical origin. Analyses of linkage disequilibrium and genotypic diversity indicated a strong regional heterogeneity in levels of recombination, with clear signatures of recombination in the Himalayan (Nepal and Pakistan) and near-Himalayan regions (China) and a predominant clonal population structure in other regions. The higher genotypic diversity, recombinant population structure and high sexual reproduction ability in the Himalayan and neighboring regions suggests this area as the putative center of origin of PST. We used clustering methods and approximate Bayesian computation (ABC) to compare different competing scenarios describing ancestral relationship among ancestral populations and more recently founded populations. Our analyses confirmed the Middle East-East Africa as the most likely source of newly spreading, high-temperature-adapted strains; Europe as the source of South American, North American and Australian populations; and Mediterranean-Central Asian populations as the origin of South African populations. Although most geographic populations are not markedly affected by recent dispersal events, this study emphasizes the influence of human activities on recent long-distance spread of the pathogen. PMID- 24465213 TI - The SET domain proteins SUVH2 and SUVH9 are required for Pol V occupancy at RNA directed DNA methylation loci. AB - RNA-directed DNA methylation (RdDM) is required for transcriptional silencing of transposons and other DNA repeats in Arabidopsis thaliana. Although previous research has demonstrated that the SET domain-containing SU(VAR)3-9 homologs SUVH2 and SUVH9 are involved in the RdDM pathway, the underlying mechanism remains unknown. Our results indicated that SUVH2 and/or SUVH9 not only interact with the chromatin-remodeling complex termed DDR (DMS3, DRD1, and RDM1) but also with the newly characterized complex composed of two conserved Microrchidia (MORC) family proteins, MORC1 and MORC6. The effect of suvh2suvh9 on Pol IV dependent siRNA accumulation and DNA methylation is comparable to that of the Pol V mutant nrpe1 and the DDR complex mutant dms3, suggesting that SUVH2 and SUVH9 are functionally associated with RdDM. Our CHIP assay demonstrated that SUVH2 and SUVH9 are required for the occupancy of Pol V at RdDM loci and facilitate the production of Pol V-dependent noncoding RNAs. Moreover, SUVH2 and SUVH9 are also involved in the occupancy of DMS3 at RdDM loci. The putative catalytic active site in the SET domain of SUVH2 is dispensable for the function of SUVH2 in RdDM and H3K9 dimethylation. We propose that SUVH2 and SUVH9 bind to methylated DNA and facilitate the recruitment of Pol V to RdDM loci by associating with the DDR complex and the MORC complex. PMID- 24465214 TI - Loss and recovery of genetic diversity in adapting populations of HIV. AB - The evolution of drug resistance in HIV occurs by the fixation of specific, well known, drug-resistance mutations, but the underlying population genetic processes are not well understood. By analyzing within-patient longitudinal sequence data, we make four observations that shed a light on the underlying processes and allow us to infer the short-term effective population size of the viral population in a patient. Our first observation is that the evolution of drug resistance usually occurs by the fixation of one drug-resistance mutation at a time, as opposed to several changes simultaneously. Second, we find that these fixation events are accompanied by a reduction in genetic diversity in the region surrounding the fixed drug-resistance mutation, due to the hitchhiking effect. Third, we observe that the fixation of drug-resistance mutations involves both hard and soft selective sweeps. In a hard sweep, a resistance mutation arises in a single viral particle and drives all linked mutations with it when it spreads in the viral population, which dramatically reduces genetic diversity. On the other hand, in a soft sweep, a resistance mutation occurs multiple times on different genetic backgrounds, and the reduction of diversity is weak. Using the frequency of occurrence of hard and soft sweeps we estimate the effective population size of HIV to be 1.5 x 10(5) (95% confidence interval [0.8 x 10(5),4.8 x 10(5)]). This number is much lower than the actual number of infected cells, but much larger than previous population size estimates based on synonymous diversity. We propose several explanations for the observed discrepancies. Finally, our fourth observation is that genetic diversity at non-synonymous sites recovers to its pre fixation value within 18 months, whereas diversity at synonymous sites remains depressed after this time period. These results improve our understanding of HIV evolution and have potential implications for treatment strategies. PMID- 24465215 TI - Down-regulation of Rad51 activity during meiosis in yeast prevents competition with Dmc1 for repair of double-strand breaks. AB - Interhomolog recombination plays a critical role in promoting proper meiotic chromosome segregation but a mechanistic understanding of this process is far from complete. In vegetative cells, Rad51 is a highly conserved recombinase that exhibits a preference for repairing double strand breaks (DSBs) using sister chromatids, in contrast to the conserved, meiosis-specific recombinase, Dmc1, which preferentially repairs programmed DSBs using homologs. Despite the different preferences for repair templates, both Rad51 and Dmc1 are required for interhomolog recombination during meiosis. This paradox has recently been explained by the finding that Rad51 protein, but not its strand exchange activity, promotes Dmc1 function in budding yeast. Rad51 activity is inhibited in dmc1Delta mutants, where the failure to repair meiotic DSBs triggers the meiotic recombination checkpoint, resulting in prophase arrest. The question remains whether inhibition of Rad51 activity is important during wild-type meiosis, or whether inactivation of Rad51 occurs only as a result of the absence of DMC1 or checkpoint activation. This work shows that strains in which mechanisms that down regulate Rad51 activity are removed exhibit reduced numbers of interhomolog crossovers and noncrossovers. A hypomorphic mutant, dmc1-T159A, makes less stable presynaptic filaments but is still able to mediate strand exchange and interact with accessory factors. Combining dmc1-T159A with up-regulated Rad51 activity reduces interhomolog recombination and spore viability, while increasing intersister joint molecule formation. These results support the idea that down regulation of Rad51 activity is important during meiosis to prevent Rad51 from competing with Dmc1 for repair of meiotic DSBs. PMID- 24465216 TI - A neurotoxic glycerophosphocholine impacts PtdIns-4, 5-bisphosphate and TORC2 signaling by altering ceramide biosynthesis in yeast. AB - Unbiased lipidomic approaches have identified impairments in glycerophosphocholine second messenger metabolism in patients with Alzheimer's disease. Specifically, we have shown that amyloid-beta42 signals the intraneuronal accumulation of PC(O-16:0/2:0) which is associated with neurotoxicity. Similar to neuronal cells, intracellular accumulation of PC(O 16:0/2:0) is also toxic to Saccharomyces cerevisiae, making yeast an excellent model to decipher the pathological effects of this lipid. We previously reported that phospholipase D, a phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2) binding protein, was relocalized in response to PC(O-16:0/2:0), suggesting that this neurotoxic lipid may remodel lipid signaling networks. Here we show that PC(O-16:0/2:0) regulates the distribution of the PtdIns(4)P 5-kinase Mss4 and its product PtdIns(4,5)P2 leading to the formation of invaginations at the plasma membrane (PM). We further demonstrate that the effects of PC(O-16:0/2:0) on the distribution of PM PtdIns(4,5)P2 pools are in part mediated by changes in the biosynthesis of long chain bases (LCBs) and ceramides. A combination of genetic, biochemical and cell imaging approaches revealed that PC(O-16:0/2:0) is also a potent inhibitor of signaling through the Target of rampamycin complex 2 (TORC2). Together, these data provide mechanistic insight into how specific disruptions in phosphocholine second messenger metabolism associated with Alzheimer's disease may trigger larger network-wide disruptions in ceramide and phosphoinositide second messenger biosynthesis and signaling which have been previously implicated in disease progression. PMID- 24465217 TI - 3' Untranslated regions mediate transcriptional interference between convergent genes both locally and ectopically in Saccharomyces cerevisiae. AB - Paired sense and antisense (S/AS) genes located in cis represent a structural feature common to the genomes of both prokaryotes and eukaryotes, and produce partially complementary transcripts. We used published genome and transcriptome sequence data and found that over 20% of genes (645 pairs) in the budding yeast Saccharomyces cerevisiae genome are arranged in convergent pairs with overlapping 3'-UTRs. Using published microarray transcriptome data from the standard laboratory strain of S. cerevisiae, our analysis revealed that expression levels of convergent pairs are significantly negatively correlated across a broad range of environments. This implies an important role for convergent genes in the regulation of gene expression, which may compensate for the absence of RNA dependent mechanisms such as micro RNAs in budding yeast. We selected four representative convergent gene pairs and used expression assays in wild type yeast and its genetically modified strains to explore the underlying patterns of gene expression. Results showed that convergent genes are reciprocally regulated in yeast populations and in single cells, whereby an increase in expression of one gene produces a decrease in the expression of the other, and vice-versa. Time course analysis of the cell cycle illustrated the functional significance of this relationship for the three pairs with relevant functional roles. Furthermore, a series of genetic modifications revealed that the 3'-UTR sequence plays an essential causal role in mediating transcriptional interference, which requires neither the sequence of the open reading frame nor the translation of fully functional proteins. More importantly, transcriptional interference persisted even when one of the convergent genes was expressed ectopically (in trans) and therefore does not depend on the cis arrangement of convergent genes; we conclude that the mechanism of transcriptional interference cannot be explained by the transcriptional collision model, which postulates a clash between simultaneous transcriptional processes occurring on opposite DNA strands. PMID- 24465218 TI - Functional divergence and evolutionary turnover in mammalian phosphoproteomes. AB - Protein phosphorylation is a key mechanism to regulate protein functions. However, the contribution of this protein modification to species divergence is still largely unknown. Here, we studied the evolution of mammalian phosphoregulation by comparing the human and mouse phosphoproteomes. We found that 84% of the positions that are phosphorylated in one species or the other are conserved at the residue level. Twenty percent of these conserved sites are phosphorylated in both species. This proportion is 2.5 times more than expected by chance alone, suggesting that purifying selection is preserving phosphoregulation. However, we show that the majority of the sites that are conserved at the residue level are differentially phosphorylated between species. These sites likely result from false-negative identifications due to incomplete experimental coverage, false-positive identifications and non-functional sites. In addition, our results suggest that at least 5% of them are likely to be true differentially phosphorylated sites and may thus contribute to the divergence in phosphorylation networks between mouse and humans and this, despite residue conservation between orthologous proteins. We also showed that evolutionary turnover of phosphosites at adjacent positions (in a distance range of up to 40 amino acids) in human or mouse leads to an over estimation of the divergence in phosphoregulation between these two species. These sites tend to be phosphorylated by the same kinases, supporting the hypothesis that they are functionally redundant. Our results support the hypothesis that the evolutionary turnover of phosphorylation sites contributes to the divergence in phosphorylation profiles while preserving phosphoregulation. Overall, our study provides advanced analyses of mammalian phosphoproteomes and a framework for the study of their contribution to phenotypic evolution. PMID- 24465219 TI - Arabidopsis AL PHD-PRC1 complexes promote seed germination through H3K4me3-to H3K27me3 chromatin state switch in repression of seed developmental genes. AB - Seed germination and subsequent seedling growth define crucial steps for entry into the plant life cycle. For those events to take place properly, seed developmental genes need to be silenced whereas vegetative growth genes are activated. Chromatin structure is generally known to play crucial roles in gene transcription control. However, the transition between active and repressive chromatin states during seed germination is still poorly characterized and the underlying molecular mechanisms remain largely unknown. Here we identified the Arabidopsis PHD-domain H3K4me3-binding ALFIN1-like proteins (ALs) as novel interactors of the Polycomb Repressive Complex 1 (PRC1) core components AtBMI1b and AtRING1a. The interactions were confirmed by diverse in vitro and in vivo assays and were shown to require the AL6 N-terminus containing PAL domain conserved in the AL family proteins and the AtRING1a C-terminus containing RAWUL domain conserved in animal and plant PRC1 ring-finger proteins (including AtRNIG1a/b and AtBMI1a/b). By T-DNA insertion mutant analysis, we found that simultaneous loss of AL6 and AL7 as well as loss of AtBMI1a and AtBMI1b retards seed germination and causes transcriptional derepression and a delayed chromatin state switch from H3K4me3 to H3K27me3 enrichment of several seed developmental genes (e.g. ABI3, DOG1, CRU3, CHO1). We found that AL6 and the PRC1 H3K27me3 reader component LHP1 directly bind at ABI3 and DOG1 loci. In light of these data, we propose that AL PHD-PRC1 complexes, built around H3K4me3, lead to a switch from the H3K4me3-associated active to the H3K27me3-associated repressive transcription state of seed developmental genes during seed germination. Our finding of physical interactions between PHD-domain proteins and PRC1 is striking and has important implications for understanding the connection between the two functionally opposite chromatin marks: H3K4me3 in activation and H3K27me3 in repression of gene transcription. PMID- 24465220 TI - New microRNAs in Drosophila--birth, death and cycles of adaptive evolution. AB - The origin and evolution of new microRNAs (miRNAs) is important because they can impact the transcriptome broadly. As miRNAs can potentially emerge constantly and rapidly, their rates of birth and evolution have been extensively debated. However, most new miRNAs identified appear not to be biologically significant. After an extensive search, we identified 12 new miRNAs that emerged de novo in Drosophila melanogaster in the last 4 million years (Myrs) and have been evolving adaptively. Unexpectedly, even though they are adaptively evolving at birth, more than 94% of such new miRNAs disappear over time. They provide selective advantages, but only for a transient evolutionary period. After 30 Myrs, all surviving miRNAs make the transition from the adaptive phase of rapid evolution to the conservative phase of slow evolution, apparently becoming integrated into the transcriptional network. During this transition, the expression shifts from being tissue-specific, predominantly in testes and larval brain/gonads/imaginal discs, to a broader distribution in many other tissues. Interestingly, a measurable fraction (20-30%) of these conservatively evolving miRNAs experience "evolutionary rejuvenation" and begin to evolve rapidly again. These rejuvenated miRNAs then start another cycle of adaptive - conservative evolution. In conclusion, the selective advantages driving evolution of miRNAs are themselves evolving, and sometimes changing direction, which highlights the regulatory roles of miRNAs. PMID- 24465221 TI - A cell cycle and nutritional checkpoint controlling bacterial surface adhesion. AB - In natural environments, bacteria often adhere to surfaces where they form complex multicellular communities. Surface adherence is determined by the biochemical composition of the cell envelope. We describe a novel regulatory mechanism by which the bacterium, Caulobacter crescentus, integrates cell cycle and nutritional signals to control development of an adhesive envelope structure known as the holdfast. Specifically, we have discovered a 68-residue protein inhibitor of holdfast development (HfiA) that directly targets a conserved glycolipid glycosyltransferase required for holdfast production (HfsJ). Multiple cell cycle regulators associate with the hfiA and hfsJ promoters and control their expression, temporally constraining holdfast development to the late stages of G1. HfiA further functions as part of a 'nutritional override' system that decouples holdfast development from the cell cycle in response to nutritional cues. This control mechanism can limit surface adhesion in nutritionally sub optimal environments without affecting cell cycle progression. We conclude that post-translational regulation of cell envelope enzymes by small proteins like HfiA may provide a general means to modulate the surface properties of bacterial cells. PMID- 24465222 TI - The sense and sensibility of strand exchange in recombination homeostasis. PMID- 24465223 TI - FGFR1-Frs2/3 signalling maintains sensory progenitors during inner ear hair cell formation. AB - Inner ear mechanosensory hair cells transduce sound and balance information. Auditory hair cells emerge from a Sox2-positive sensory patch in the inner ear epithelium, which is progressively restricted during development. This restriction depends on the action of signaling molecules. Fibroblast growth factor (FGF) signalling is important during sensory specification: attenuation of Fgfr1 disrupts cochlear hair cell formation; however, the underlying mechanisms remain unknown. Here we report that in the absence of FGFR1 signaling, the expression of Sox2 within the sensory patch is not maintained. Despite the down regulation of the prosensory domain markers, p27(Kip1), Hey2, and Hes5, progenitors can still exit the cell cycle to form the zone of non-proliferating cells (ZNPC), however the number of cells that form sensory cells is reduced. Analysis of a mutant Fgfr1 allele, unable to bind to the adaptor protein, Frs2/3, indicates that Sox2 maintenance can be regulated by MAP kinase. We suggest that FGF signaling, through the activation of MAP kinase, is necessary for the maintenance of sensory progenitors and commits precursors to sensory cell differentiation in the mammalian cochlea. PMID- 24465225 TI - Editor's Introduction to This Issue. PMID- 24465224 TI - Differential effects of collagen prolyl 3-hydroxylation on skeletal tissues. AB - Mutations in the genes encoding cartilage associated protein (CRTAP) and prolyl 3 hydroxylase 1 (P3H1 encoded by LEPRE1) were the first identified causes of recessive Osteogenesis Imperfecta (OI). These proteins, together with cyclophilin B (encoded by PPIB), form a complex that 3-hydroxylates a single proline residue on the alpha1(I) chain (Pro986) and has cis/trans isomerase (PPIase) activity essential for proper collagen folding. Recent data suggest that prolyl 3 hydroxylation of Pro986 is not required for the structural stability of collagen; however, the absence of this post-translational modification may disrupt protein protein interactions integral for proper collagen folding and lead to collagen over-modification. P3H1 and CRTAP stabilize each other and absence of one results in degradation of the other. Hence, hypomorphic or loss of function mutations of either gene cause loss of the whole complex and its associated functions. The relative contribution of losing this complex's 3-hydroxylation versus PPIase and collagen chaperone activities to the phenotype of recessive OI is unknown. To distinguish between these functions, we generated knock-in mice carrying a single amino acid substitution in the catalytic site of P3h1 (Lepre1(H662A) ). This substitution abolished P3h1 activity but retained ability to form a complex with Crtap and thus the collagen chaperone function. Knock-in mice showed absence of prolyl 3-hydroxylation at Pro986 of the alpha1(I) and alpha1(II) collagen chains but no significant over-modification at other collagen residues. They were normal in appearance, had no growth defects and normal cartilage growth plate histology but showed decreased trabecular bone mass. This new mouse model recapitulates elements of the bone phenotype of OI but not the cartilage and growth phenotypes caused by loss of the prolyl 3-hydroxylation complex. Our observations suggest differential tissue consequences due to selective inactivation of P3H1 hydroxylase activity versus complete ablation of the prolyl 3-hydroxylation complex. PMID- 24465226 TI - Interplay between Epigenetics and Genetics in Cancer. AB - Genomic instability, which occurs through both genetic mechanisms (underlying inheritable phenotypic variations caused by DNA sequence-dependent alterations, such as mutation, deletion, insertion, inversion, translocation, and chromosomal aneuploidy) and epigenomic aberrations (underlying inheritable phenotypic variations caused by DNA sequence-independent alterations caused by a change of chromatin structure, such as DNA methylation and histone modifications), is known to promote tumorigenesis and tumor progression. Mechanisms involve both genomic instability and epigenomic aberrations that lose or gain the function of genes that impinge on tumor suppression/prevention or oncogenesis. Growing evidence points to an epigenome-wide disruption that involves large-scale DNA hypomethylation but specific hypermethylation of tumor suppressor genes, large blocks of aberrant histone modifications, and abnormal miRNA expression profile. Emerging molecular details regarding the modulation of these epigenetic events in cancer are used to illustrate the alterations of epigenetic molecules, and their consequent malfunctions could contribute to cancer biology. More recently, intriguing evidence supporting that genetic and epigenetic mechanisms are not separate events in cancer has been emerging; they intertwine and take advantage of each other during tumorigenesis. In addition, we discuss the collusion between epigenetics and genetics mediated by heterochromatin protein 1, a major component of heterochromatin, in order to maintain genome integrity. PMID- 24465227 TI - Application of cancer genomics to solve unmet clinical needs. AB - The large amount of data on cancer genome research has contributed to our understanding of cancer biology. Indeed, the genomics approach has a strong advantage for analyzing multi-factorial and complicated problems, such as cancer. It is time to think about the actual usage of cancer genomics in the clinical field. The clinical cancer field has lots of unmet needs in the management of cancer patients, which has been defined in the pre-genomic era. Unmet clinical needs are not well known to bioinformaticians and even non-clinician cancer scientists. A personalized approach in the clinical field will bring potential additional challenges to cancer genomics, because most data to now have been population-based rather than individual-based. We can maximize the use of cancer genomics in the clinical field if cancer scientists, bioinformaticians, and clinicians think and work together in solving unmet clinical needs. In this review, we present one imaginary case of a cancer patient, with which we can think about unmet clinical needs to solve with cancer genomics in the diagnosis, prediction of prognosis, monitoring the status of cancer, and personalized treatment decision. PMID- 24465228 TI - Genomic profiling of liver cancer. AB - Development of liver cancers is driven largely by genomic alterations that deregulate signaling pathways, influencing growth and survival of cancer cells. Because of the hundreds or thousands of genomic/epigenomic alterations that have accumulated in the cancer genome, it is very challenging to find and test candidate genes driving tumor development and progression. Systematic studies of the liver cancer genome have become available in recent years. These studies have uncovered new potential driver genes, including those not previously known to be involved in the development of liver cancer. Novel approaches combining multiple datasets from patient tissues have created an unparalleled opportunity to uncover potential new therapeutic targets and prognostic/predictive biomarkers for personalized therapy that can improve clinical outcomes of the patients with liver cancer. PMID- 24465229 TI - Perspectives on clinical informatics: integrating large-scale clinical, genomic, and health information for clinical care. AB - The advances in electronic medical records (EMRs) and bioinformatics (BI) represent two significant trends in healthcare. The widespread adoption of EMR systems and the completion of the Human Genome Project developed the technologies for data acquisition, analysis, and visualization in two different domains. The massive amount of data from both clinical and biology domains is expected to provide personalized, preventive, and predictive healthcare services in the near future. The integrated use of EMR and BI data needs to consider four key informatics areas: data modeling, analytics, standardization, and privacy. Bioclinical data warehouses integrating heterogeneous patient-related clinical or omics data should be considered. The representative standardization effort by the Clinical Bioinformatics Ontology (CBO) aims to provide uniquely identified concepts to include molecular pathology terminologies. Since individual genome data are easily used to predict current and future health status, different safeguards to ensure confidentiality should be considered. In this paper, we focused on the informatics aspects of integrating the EMR community and BI community by identifying opportunities, challenges, and approaches to provide the best possible care service for our patients and the population. PMID- 24465230 TI - A primer for disease gene prioritization using next-generation sequencing data. AB - High-throughput next-generation sequencing (NGS) technology produces a tremendous amount of raw sequence data. The challenges for researchers are to process the raw data, to map the sequences to genome, to discover variants that are different from the reference genome, and to prioritize/rank the variants for the question of interest. The recent development of many computational algorithms and programs has vastly improved the ability to translate sequence data into valuable information for disease gene identification. However, the NGS data analysis is complex and could be overwhelming for researchers who are not familiar with the process. Here, we outline the analysis pipeline and describe some of the most commonly used principles and tools for analyzing NGS data for disease gene identification. PMID- 24465232 TI - Current status, challenges, policies, and bioethics of biobanks. AB - Many biobanks were established as biorepositories for biomedical research, and a number of biobanks were founded in the 1990s. The main aim of the biobank is to store and to maintain biomaterials for studying chronic disease, identifying risk factors of specific diseases, and applying personalized drug therapies. This report provides a review of biobanks, including Korean biobanks and an analysis of sample volumes, regulations, policies, and ethical issues of the biobank. Until now, the top 6 countries according to the number of large-scale biobanks are the United Kingdom, United States, Sweden, France, the Netherlands, and Italy, and there is one major National Biobank of Korea (NBK) and 17 regional biobanks in Korea. Many countries have regulations and guidelines for the biobanks, and the importance of good management of biobanks is increasing. Meanwhile, according to a first survey of 456 biobank managers in the United States, biobankers are concerned with the underuse of the samples in their repositories, which need to be advertised for researchers. Korea Biobank Network (KBN) project phase II (2013-2015) was also planned for the promotion to use biospecimens in the KBN. The KBN is continuously introducing for researchers to use biospecimens in the biobank. An accreditation process can also be introduced for biobanks to harmonize collections and encourage use of biospecimens in the biobanks. KBN is preparing an on-line application system for the distribution of biospecimens and a biobank accreditation program and is trying to harmonize the biobanks. PMID- 24465233 TI - Introduction to international ethical standards related to genetics and genomics. AB - The rapid advances in genetic knowledge and technology raise various, sometimes unprecedented, ethical dilemmas in the scientific community as well as the public realm. To deal with these dilemmas, the international community has prepared and issued ethical standards in various formats. In this review, seven international standards regarding genetics and genomics will be briefly introduced in chronological order. Critical reflections on them will not be provided in this review, and naturally, they have their own problems and shortcomings. However, a common set of the principles expressed in them will be highlighted here, because they are still relevant, and many of them will be more relevant in the future. Some of the interesting contents will be selected and described. After that, the morality of one recent event related to whole-genome sequencing and person identifiable genetic data will be explored based on those international standards. PMID- 24465231 TI - Review of biological network data and its applications. AB - Studying biological networks, such as protein-protein interactions, is key to understanding complex biological activities. Various types of large-scale biological datasets have been collected and analyzed with high-throughput technologies, including DNA microarray, next-generation sequencing, and the two hybrid screening system, for this purpose. In this review, we focus on network based approaches that help in understanding biological systems and identifying biological functions. Accordingly, this paper covers two major topics in network biology: reconstruction of gene regulatory networks and network-based applications, including protein function prediction, disease gene prioritization, and network-based genome-wide association study. PMID- 24465234 TI - Receptor for Advanced Glycation Endproducts (RAGE), Its Ligands, and Soluble RAGE: Potential Biomarkers for Diagnosis and Therapeutic Targets for Human Renal Diseases. AB - Receptor for advanced glycation endproducts (RAGE) is a multi-ligand receptor that is able to bind several different ligands, including advanced glycation endproducts, high-mobility group protein (B)1 (HMGB1), S-100 calcium-binding protein, amyloid-beta-protein, Mac-1, and phosphatidylserine. Its interaction is engaged in critical cellular processes, such as inflammation, proliferation, apoptosis, autophagy, and migration, and dysregulation of RAGE and its ligands leads to the development of numerous human diseases. In this review, we summarize the signaling pathways regulated by RAGE and its ligands identified up to date and demonstrate the effects of hyper-activation of RAGE signals on human diseases, focused mainly on renal disorders. Finally, we propose that RAGE and its ligands are the potential targets for the diagnosis, monitoring, and treatment of numerous renal diseases. PMID- 24465235 TI - Study of Modern Human Evolution via Comparative Analysis with the Neanderthal Genome. AB - Many other human species appeared in evolution in the last 6 million years that have not been able to survive to modern times and are broadly known as archaic humans, as opposed to the extant modern humans. It has always been considered fascinating to compare the modern human genome with that of archaic humans to identify modern human-specific sequence variants and figure out those that made modern humans different from their predecessors or cousin species. Neanderthals are the latest humans to become extinct, and many factors made them the best representatives of archaic humans. Even though a number of comparisons have been made sporadically between Neanderthals and modern humans, mostly following a candidate gene approach, the major breakthrough took place with the sequencing of the Neanderthal genome. The initial genome-wide comparison, based on the first draft of the Neanderthal genome, has generated some interesting inferences regarding variations in functional elements that are not shared by the two species and the debated admixture question. However, there are certain other genetic elements that were not included or included at a smaller scale in those studies, and they should be compared comprehensively to better understand the molecular make-up of modern humans and their phenotypic characteristics. Besides briefly discussing the important outcomes of the comparative analyses made so far between modern humans and Neanderthals, we propose that future comparative studies may include retrotransposons, pseudogenes, and conserved non-coding regions, all of which might have played significant roles during the evolution of modern humans. PMID- 24465236 TI - Somatic mutaome profile in human cancer tissues. AB - Somatic mutation is a major cause of cancer progression and varied responses of tumors against anticancer agents. Thus, we must obtain and characterize genome wide mutational profiles in individual cancer subtypes. The Cancer Genome Atlas database includes large amounts of sequencing and omics data generated from diverse human cancer tissues. In the present study, we integrated and analyzed the exome sequencing data from ~3,000 tissue samples and summarized the major mutant genes in each of the diverse cancer subtypes and stages. Mutations were observed in most human genes (~23,000 genes) with low frequency from an analysis of 11 major cancer subtypes. The majority of tissue samples harbored 20-80 different mutant genes, on average. Lung cancer samples showed a greater number of mutations in diverse genes than other cancer subtypes. Only a few genes were mutated with over 5% frequency in tissue samples. Interestingly, mutation frequency was generally similar between non-metastatic and metastastic samples in most cancer subtypes. Among the 12 major mutations, the TP53, USH2A, TTN, and MUC16 genes were found to be frequent in most cancer types, while BRAF, FRG1B, PBRM1, and VHL showed lineage-specific mutation patterns. The present study provides a useful resource to understand the broad spectrum of mutation frequencies in various cancer types. PMID- 24465237 TI - Characterization of H460R, a Radioresistant Human Lung Cancer Cell Line, and Involvement of Syntrophin Beta 2 (SNTB2) in Radioresistance. AB - A radioresistant cell line was established by fractionated ionizing radiation (IR) and assessed by a clonogenic assay, flow cytometry, and Western blot analysis, as well as zymography and a wound healing assay. Microarray was performed to profile global expression and to search for differentially expressed genes (DEGs) in response to IR. H460R cells demonstrated increased cell scattering and acidic vesicular organelles compared with parental cells. Concomitantly, H460R cells showed characteristics of increased migration and matrix metalloproteinase activity. In addition, H460R cells were resistant to IR, exhibiting reduced expression levels of ionizing responsive proteins (p-p53 and gamma-H2AX); apoptosis-related molecules, such as cleaved poly(ADP ribose) polymerase; and endoplasmic reticulum stress-related molecules, such as glucose regulated protein (GRP78) and C/EBP-homologous protein compared with parental cells, whereas the expression of anti-apoptotic X-linked inhibitor of apoptosis protein was increased. Among DEGs, syntrophin beta 2 (SNTB2) significantly increased in H460R cells in response to IR. Knockdown of SNTB2 by siRNA was more sensitive than the control after IR exposure in H460, H460R, and H1299 cells. Our study suggests that H460R cells have differential properties, including cell morphology, potential for metastasis, and resistance to IR, compared with parental cells. In addition, SNTB2 may play an important role in radioresistance. H460R cells could be helpful in in vitro systems for elucidating the molecular mechanisms of and discovering drugs to overcome radioresistance in lung cancer therapy. PMID- 24465238 TI - Genetic Variations of ABCC2 Gene Associated with Adverse Drug Reactions to Valproic Acid in Korean Epileptic Patients. AB - The multidrug resistance protein 2 (MRP2, ABCC2) gene may determine individual susceptibility to adverse drug reactions (ADRs) in the central nervous system (CNS) by limiting brain access of antiepileptic drugs, especially valproic acid (VPA). Our objective was to investigate the effect of ABCC2 polymorphisms on ADRs caused by VPA in Korean epileptic patients. We examined the association of ABCC2 single-nucleotide polymorphisms and haplotype frequencies with VPA related to adverse reactions. In addition, the association of the polymorphisms with the risk of VPA related to adverse reactions was estimated by logistic regression analysis. A total of 41 (24.4%) patients had shown VPA-related adverse reactions in CNS, and the most frequent symptom was tremor (78.0%). The patients with CNS ADRs were more likely to have the G allele (79.3% vs. 62.7%, p = 0.0057) and the GG genotype (61.0% vs. 39.7%, p = 0.019) at the g.-1774delG locus. The frequency of the haplotype containing g.-1774Gdel was significantly lower in the patients with CNS ADRs than without CNS ADRs (15.8% vs. 32.3%, p = 0.0039). Lastly, in the multivariate logistic regression analysis, the presence of the GG genotype at the g.-1774delG locus was identified as a stronger risk factor for VPA related to ADRs (odds ratio, 8.53; 95% confidence interval, 1.04 to 70.17). We demonstrated that ABCC2 polymorphisms may influence VPA-related ADRs. The results above suggest the possible usefulness of ABCC2 gene polymorphisms as a marker for predicting response to VPA-related ADRs. PMID- 24465239 TI - TT Mutant Homozygote of Kruppel-like Factor 5 Is a Key Factor for Increasing Basal Metabolic Rate and Resting Metabolic Rate in Korean Elementary School Children. AB - We investigated the contribution of genetic variations of KLF5 to basal metabolic rate (BMR) and resting metabolic rate (RMR) and the inhibition of obesity in Korean children. A variation of KLF5 (rs3782933) was genotyped in 62 Korean children. Using multiple linear regression analysis, we developed a model to predict BMR in children. We divided them into several groups; normal versus overweight by body mass index (BMI) and low BMR versus high BMR by BMR. There were no differences in the distributions of alleles and genotypes between each group. The genetic variation of KLF5 gene showed a significant correlation with several clinical factors, such as BMR, muscle, low-density lipoprotein cholesterol, and insulin. Children with the TT had significantly higher BMR than those with CC (p = 0.030). The highest muscle was observed in the children with TT compared with CC (p = 0.032). The insulin and C-peptide values were higher in children with TT than those with CC (p= 0.029 vs. p = 0.004, respectively). In linear regression analysis, BMI and muscle mass were correlated with BMR, whereas insulin and C-peptide were not associated with BMR. In the high-BMR group, we observed that higher muscle, fat mass, and C-peptide affect the increase of BMR in children with TT (p < 0.001, p < 0.001, and p = 0.018, respectively), while Rohrer's index could explain the usual decrease in BMR (adjust r(2) = 1.000, p < 0.001, respectively). We identified a novel association between TT of KLF5 rs3782933 and BMR in Korean children. We could make better use of the variation within KLF5 in a future clinical intervention study of obesity. PMID- 24465240 TI - Phylogeny of flavobacteria group isolated from freshwater using multilocus sequencing analysis. AB - Sequence analysis of the 16S rRNA gene has been widely used for the classification of microorganisms. However, we have been unable to clearly identify five Flavobacterium species isolated from a freshwater by using the gene as a single marker, because the evolutionary history is incomplete and the pace of DNA substitutions is relatively rapid in the bacteria. In this study, we tried to classify Flavobacterium species through multilocus sequence analysis (MLSA), which is a practical and reliable technique for the identification or classification of bacteria. The five Flavobacterium species isolated from freshwater and 37 other strains were classified based on six housekeeping genes: gyrB, dnaK, tuf, murG, atpA, and glyA. The genes were amplified by PCR and subjected to DNA sequencing. Based on the combined DNA sequence (4,412 bp) of the six housekeeping genes, we analyzed the phylogenetic relationship among the Flavobacterium species. The results indicated that MLSA, based on the six housekeeping genes, is a trustworthy method for the identification of closely related Flavobacterium species. PMID- 24465241 TI - Forensic Body Fluid Identification by Analysis of Multiple RNA Markers Using NanoString Technology. AB - RNA analysis has become a reliable method of body fluid identification for forensic use. Previously, we developed a combination of four multiplex quantitative PCR (qRT-PCR) probes to discriminate four different body fluids (blood, semen, saliva, and vaginal secretion). While those makers successfully identified most body fluid samples, there were some cases of false positive and negative identification. To improve the accuracy of the identification further, we tried to use multiple markers per body fluid and adopted the NanoString nCounter system instead of a multiplex qRT-PCR system. After measuring tens of RNA markers, we evaluated the accuracy of each marker for body fluid identification. For body fluids, such as blood and semen, each body fluid specific marker was accurate enough for perfect identification. However, for saliva and vaginal secretion, no single marker was perfect. Thus, we designed a logistic regression model with multiple markers for saliva and vaginal secretion and achieved almost perfect identification. In conclusion, the NanoString nCounter is an efficient platform for measuring multiple RNA markers per body fluid and will be useful for forensic RNA analysis. PMID- 24465242 TI - Molecular vibration-activity relationship in the agonism of adenosine receptors. AB - The molecular vibration-activity relationship in the receptor-ligand interaction of adenosine receptors was investigated by structure similarity, molecular vibration, and hierarchical clustering in a dataset of 46 ligands of adenosine receptors. The resulting dendrogram was compared with those of another kind of fingerprint or descriptor. The dendrogram result produced by corralled intensity of molecular vibrational frequency outperformed four other analyses in the current study of adenosine receptor agonism and antagonism. The tree that was produced by clustering analysis of molecular vibration patterns showed its potential for the functional classification of adenosine receptor ligands. PMID- 24465243 TI - hpvPDB: An Online Proteome Reserve for Human Papillomavirus. AB - Human papillomavirus (HPV) infection is the leading cause of cancer mortality among women worldwide. The molecular understanding of HPV proteins has significant connotation for understanding their intrusion in the host and designing novel protein vaccines and anti-viral agents, etc. Genomic, proteomic, structural, and disease-related information on HPV is available on the web; yet, with trivial annotations and more so, it is not well customized for data analysis, host-pathogen interaction, strain-disease association, drug designing, and sequence analysis, etc. We attempted to design an online reserve with comprehensive information on HPV for the end users desiring the same. The Human Papillomavirus Proteome Database (hpvPDB) domiciles proteomic and genomic information on 150 HPV strains sequenced to date. Simultaneous easy expandability and retrieval of the strain-specific data, with a provision for sequence analysis and exploration potential of predicted structures, and easy access for curation and annotation through a range of search options at one platform are a few of its important features. Affluent information in this reserve could be of help for researchers involved in structural virology, cancer research, drug discovery, and vaccine design. PMID- 24465244 TI - Focused fluorescence excitation with time-reversed ultrasonically encoded light and imaging in thick scattering media. AB - Scattering dominates light propagation in biological tissue, and therefore restricts both resolution and penetration depth in optical imaging within thick tissue. As photons travel into the diffusive regime-typically 1 mm beneath human skin, their trajectories transition from ballistic to diffusive due to increased number of scattering events, which makes it impossible to focus, much less track, photon paths. Consequently, imaging methods that rely on controlled light illumination are ineffective in deep tissue. This problem has recently been addressed by a novel method capable of dynamically focusing light in thick scattering media via time reversal of ultrasonically encoded (TRUE) diffused light. Here, using photorefractive materials as phase conjugate mirrors, we show a direct visualization and dynamic control of optical focusing with this light delivery method, and demonstrate its application for focused fluorescence excitation and imaging in thick turbid media. These abilities are increasingly critical to understanding the dynamic interactions of light with biological matter and processes at different system levels, as well as their applications for biomedical diagnosis and therapy. PMID- 24465245 TI - In Vitro Degradation Behavior of Ternary Mg-Zn-Se and Mg-Zn-Cu Alloys as Biomaterials. AB - In this study, the corrosion behavior of Mg-Zn-Se and Mg-Zn-Cu alloys was investigated to evaluate their corrosion behavior related to use as implantable biomaterials. The corrosion behavior of these alloys and a commercially available Mg-Zn alloy were examined using static solution electrochemical testing, dynamic solution gravimetric testing, ion leaching testing, and microscopic evaluation. Fluctuations in the pH of the Dulbecco's Modified Eagles Medium (DMEM) used for the gravimetric and ion leaching immersion testing were also recorded over the 30 day duration to assess whether the media conditions induced by the alloy degradation would permit for cellular survival. Weight loss experimentation and electrochemical tests revealed the Mg-Zn-Cu alloy to have the greatest corrosion rate. PMID- 24465247 TI - Transcranial direct current stimulation in schizophrenia. AB - Transcranial direct current stimulation (tDCS) is an upcoming treatment modality for patients with schizophrenia. A series of recent observations have demonstrated improvement in clinical status of schizophrenia patients with tDCS. This review summarizes the research work that has examined the effects of tDCS in schizophrenia patients with respect to symptom amelioration, cognitive enhancement and neuroplasticity evaluation. tDCS is emerging as a safe, rapid and effective treatment for various aspects of schizophrenia symptoms ranging from auditory hallucinations-for which the effect is most marked, to negative symptoms and cognitive symptoms as well. An interesting line of investigation involves using tDCS for altering and examining neuroplasticity in patients and healthy subjects and is likely to lead to new insights into the neurological aberrations and pathophysiology of schizophrenia. The mechanistic aspects of the technique are discussed in brief. Future work should focus on establishing the clinical efficacy of this novel technique and on evaluating this modality as an adjunct to cognitive enhancement protocols. Understanding the mechanism of action of tDCS as well as the determinants and neurobiological correlates of clinical response to tDCS remains an important goal, which will help us expand the clinical applications of tDCS for the treatment of patients with schizophrenia. PMID- 24465248 TI - Effects of Color Temperature and Brightness on Electroencephalogram Alpha Activity in a Polychromatic Light-emitting Diode. AB - OBJECTIVE: It has been reported that working and learning efficiency might be increased through artificially controlling the color temperature and brightness of light. However, the neurological bases of these outcomes are not well established. Our study was designed to observe whether electroencephalogram (EEG) alpha frequency, as a candidate biological marker, demonstrates significant changes in response to alterations of specific light parameters. METHODS: Thirty two healthy subjects performed cognitive tasks under four different polychromatic light conditions: a combination of two different levels of color temperature (2766K vs. 5918K) and brightness (300 lux vs. 600 lux). Spectrum analyses were performed on alpha frequency. RESULTS: Subjects reported that they felt more pleasant in bright conditions and more relaxed in warm color temperature conditions. Our findings indicate that alpha power increases in warm, low-light and cool, high-light conditions, and there is a significant interaction between color temperature and brightness. CONCLUSION: EEGs might serve as a useful biological marker for further research related to the effects of polychromatic light on cognitive function. PMID- 24465246 TI - The neuroimmunology of schizophrenia. AB - Schizophrenia (SCZ) is a polygenic, multi-factorial disorder and a definitive understanding of its pathophysiology has been lacking since it was first described more than a century ago. The predominant pharmacological approach used to treat SCZ is the use of dopamine receptor antagonists. The fact that many patients remain symptomatic, despite complying with medication regimens, emphasises the need for a more encompassing explanation for both the causes and treatment of SCZ. Recent neuroanatomical, neurobiological, environmental and genetic studies have revived the idea that inflammatory pathways are involved in the pathogenesis of SCZ. These new insights have emerged from multiple lines of evidence, including the levels of inflammatory proteins in the central nervous system of patients with SCZ and animal models. This review focuses on aberrant inflammatory mechanisms present both before and during the onset of the psychotic symptoms that characterise SCZ and discusses recent research into adjunctive immune system modulating therapies for its more effective treatment. PMID- 24465249 TI - Long-term Efficacy and Tolerability of Perospirone for Young Help-seeking People at Clinical High Risk: a Preliminary Open Trial. AB - OBJECTIVE: Interest in the "at-risk mental state" (ARMS) for psychosis has increased because early intervention is expected to delay or prevent the onset of schizophrenia. However, the optimum intervention strategy remains controversial, especially with regard to antipsychotics. Although administration of antipsychotic medications is often associated with adverse effects and raises ethical considerations, recent studies have shown that some novel antipsychotics are safer and more tolerable for young people than conventional antipsychotics. We investigated whether administration of perospirone, a combined serotonin (5 HT)/dopamine antagonist and 5-HT1A receptor agonist, could alleviate prodromal symptoms and be well tolerated by clinical high risk patients. METHODS: The participants were outpatients seeking help. The Structured Interview for Prodromal Symptoms was performed in patients identified as being at clinical high risk. The Scale of Prodromal Symptoms (SOPS) was also completed and changes of subjective experience were assessed with the Subjective Well-being under Neuroleptics, short version. The incidence of akathisia was recorded by using the Barnes Akathisia Scale. Subjects were monitored for 26 weeks after starting medication. RESULTS: SOPS scores improved significantly after 26 weeks of perospirone therapy, while BAS scores did not show deterioration. No serious adverse events occurred during the study. CONCLUSION: This trial suggests that perospirone therapy provides a clinical benefit for clinical high risk subjects without causing serious adverse events. Although further placebo-controlled studies are needed for confirmation, perospirone might be one of optimum treatments for individuals at imminent risk of psychosis. PMID- 24465250 TI - Comparative Study of Heart Rate Variability in Patients with Schizophrenia, Bipolar Disorder, Post-traumatic Stress Disorder, or Major Depressive Disorder. AB - OBJECTIVE: Heart rate variability (HRV) changes as a function of psychiatric illness. This study aimed to evaluate HRV among patients with various psychiatric disorders. METHODS: The present study recruited patients with schizophrenia (n=35), bipolar disorder (n=41), post-traumatic stress disorder (PTSD; n=34), or major depressive disorder (n=34) as well as healthy controls (n=27). The time domain analysis (the standard deviation of all RR intervals [SDNN] and the square root of the mean squared differences of successive normal sinus intervals [RMSSD]), the frequency-domain analysis (very low frequency, low frequency [LF], high frequency [HF], and total power [TP]), and a non-linear complexity measure the approximate entropy were computed. RESULTS: SDNN and HF were significantly reduced in patients with schizophrenia compared with healthy controls. SDNN, RMSSD, TP, LF, and HF were significantly reduced in bipolar patients compared with healthy controls. HF was significantly reduced in PTSD patients compared with healthy controls. CONCLUSION: Our findings indicate that HRV is not sufficiently powerful to discriminate among various psychiatric illnesses. However, our results suggest that HRV, particularly HF, could be used as a tool for discriminating between psychiatric patients and healthy controls. PMID- 24465251 TI - Effects of antipsychotics on the inflammatory response system of patients with schizophrenia in peripheral blood mononuclear cell cultures. AB - OBJECTIVE: We investigated the effects of antipsychotics on immune-challenged peripheral blood mononuclear cell (PBMC) cultures. METHODS: Blood samples were collected from twelve patients with first-episode schizophrenia. The PBMCs were separated and cultures were prepared and stimulated with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly[I:C]), and then separately treated with a typical antipsychotic (haloperidol) or atypical antipsychotic (clozapine, quetiapine, or risperidone). Pro-inflammatory (interferon gamma [IFN-gamma]) and anti-inflammatory (interleukin [IL]-4 and IL-10) cytokine levels were measured in the LPS- or poly(I:C)-stimulated PBMC cultures treated with antipsychotics. RESULTS: Haloperidol and quetiapine significantly increased the IL-4 levels (p<0.05) in LPS-stimulated PBMC cultures, while clozapine and quetiapine significantly enhanced the IL-4 levels (p<0.05) in poly(I:C)-stimulated PBMC cultures. Only treatment with haloperidol resulted in a significant increase in IL-10 production (p<0.05) in LPS-stimulated PBMC cultures, whereas clozapine, quetiapine, and risperidone treatment significantly increased IL-10 production (p<0.05) in poly(I:C)-stimulated PBMC cultures. All of the antipsychotics reduced the IFN-gamma level significantly (p<0.05) in LPS- and poly(I:C)-stimulated PBMC cultures. CONCLUSION: Antipsychotic treatment altered immune function by raising the levels of anti-inflammatory cytokines (IL-4 and IL-10) and suppressing the levels of pro-inflammatory cytokines (IFN-gamma). PMID- 24465252 TI - The Influence of Previous Antipsychotic Polypharmacy Versus Monotherapy on the Effectiveness of Antipsychotic after Switching to Paliperidone Extended-release. AB - OBJECTIVE: Although antipsychotic polypharmacy is widely used in the pharmacotherapy of schizophrenia, its effectiveness is controversial. In particular, clinicians tend to avoid switching to monotherapy in patients who have been prescribed polypharmacy. In the present study, the authors investigate whether there is difference in time to discontinuation of antipsychotics between patients on previous monotherapy or polypharmacy. METHODS: Pooled analysis was conducted on two 24-week, multicenter, open-label, non-comparative studies that were originally designed to investigate the effectiveness of switching to paliperidone extended-release (ER) in patients with schizophrenia. Patients were divided into two groups according to previously prescribed antipsychotics, that is, to a polypharmacy group or a monotherapy group. The primary outcome measure was time to discontinuation of paliperidone ER. In addition, the authors sought to identify clinical variables that influence time to discontinuation. RESULTS: Before switching to paliperidone ER, 535 of 673 (79.5%) patients were prescribed antipsychotic monotherapy, and the remaining 138 (20.5%) patients were prescribed antipsychotic polypharmacy. No significant differences in time to discontinuation of paliperidone ER were observed between the polypharmacy and monotherapy groups. Personal and social performance scale score was the only factor found to influence time to discontinuation of paliperidone ER. No differences in psychopathology or adverse effects were found between the monotherapy and polypharmacy groups. CONCLUSION: Our results suggest that number of antipsychotics prescribed before switching to monotherapy does not influence clinical prognosis in patients with schizophrenia. PMID- 24465253 TI - Simultaneous Screening of 177 Drugs of Abuse in Urine Using Ultra-performance Liquid Chromatography with Tandem Mass Spectrometry in Drug-intoxicated Patients. AB - OBJECTIVE: The demand for rapid and broad clinical toxicology screening methods to identify drugs of abuse and medicinal drugs is increasing steadily. Liquid chromatography-tandem mass spectrometry (LC-TMS) is increasingly used to screen for drugs of abuse and to identify a wide range of drugs and metabolites in clinical samples. We revised a high-throughput and rapid ultra-performance (UP) LC-TMS method for simultaneous screening of 177 of the most prevalent medicinal drugs and drugs of abuse in urine and validated the quality of performance using system suitability mixture (SSM) and quality control (QC) materials. METHODS: We assessed the limits of detection (LOD) using high concentrations of the test substances. The method was applied to 473 urine samples obtained from patients intoxicated with drugs who visited the emergency center. RESULTS: The retention time, peak area, and total ion chromatogram of the SSM and QC materials were within the acceptance criteria of the pre-defined acceptance interval. The LODs were <62 ng/ml for 12 commonly encountered drugs. In total, 418 patients (88.4%) tested positive for one or more medicinal drugs or drugs of abuse. Twenty-eight drugs were detected over ten times; the most commonly detected were zolpidem, ephedrine, paracetamol, and chlorpheniramine. CONCLUSION: The UPLC-TMS method provided excellent performance for simultaneous screening of a large number of the drugs of abuse in urine samples. We conclude that this robust technique is useful for screening for a large number of drugs and for rapid screening of the most commonly encountered substances in emergency cases. PMID- 24465254 TI - Blonanserin-induced Mood Alteration in Schizophrenia and Schizoaffective Disorder: Two Cases. AB - We report two outpatients, one with schizophrenia and one with schizoaffective disorder, who developed manic or hypomanic episodes following the initiation of blonanserin during the course of treatment. Blonanserin is a novel antipsychotic that acts as a 5-HT and D2 receptor antagonist. Both patients developed hypomanic episodes within 2 weeks of receiving a small dose (6-8 mg) of blonanserin, and one patient later developed full-blown mania; both episodes ended within 1 month of discontinuing blonanserin. The mood alteration observed in these cases suggests a possible antidepressant effect of blonanserin; thus, clinicians should monitor mood changes when administering this antipsychotic. PMID- 24465255 TI - Successful Early Clozapine Trial in the Treatment of First-episode Schizophrenia: A Case Report. AB - Clozapine remains the treatment of choice in refractory schizophrenia despite its various requirement to prescribe, such as mandatory blood monitoring program and various metabolic complication. Currently, clozapine is recommended only after two failed adequate antipsychotics trials. We report a case of a successful early clozapine trial in the treatment of first-episode schizophrenia patient, considering poor treatment response and repeated self-injurious behavior. This case highlights the efficacy of an early clozapine trial as a second-line treatment for first-episode schizophrenia in contrast to switching or combination treatment strategy. PMID- 24465256 TI - MyRisk_Stroke Calculator: A Personalized Stroke Risk Assessment Tool for the General Population. AB - BACKGROUND AND PURPOSE: There is a variety of stroke risk factors, and engaging individuals in reducing their own personal risk is hugely relevant and could be an optimal dissemination strategy. The aim of the present study was to estimate the stroke risk for specific combinations of health- and lifestyle-related factors, and to develop a personalized stroke-risk assessment tool for health professionals and the general population (called the MyRisk_Stroke Calculator). METHODS: This population-based, longitudinal study followed a historical cohort formed from the 1992 or 1998 Sante Quebec Health Surveys with information for linkage to health administrative databases. Stroke risk factors were ascertained at the time of survey, and stroke was determined from hospitalizations and death records. Cox proportional hazards models were used, modeling time to stroke in relationship to all variables. RESULTS: A total of 358 strokes occurred among a cohort of 17805 persons (men=8181) who were followed for approximately 11 years (i.e., -200000 person-years). The following regression parameters were used to produce 10-year stroke-risk estimates and assign risk points: for age (1 point/year after age 20 years), male sex (3 points), low education (4 points), renal disease (8 points), diabetes (7 points), congestive heart failure (5 points), peripheral arterial disease (2 points), high blood pressure (2 points), ischemic heart disease (1 point), smoking (8 points), >7 alcoholic drinks per week (3 points), low physical activity (2 points), and indicators of anger (4 points), depression (4 points), and anxiety (3 points). According to MyRisk_Stroke Calculator, a person with <50, 75, and 90 risk points has a 10-year stroke risk of <3%, 28%, and >75%, respectively. CONCLUSIONS: The MyRisk_Stroke Calculator is a simple method of disseminating information to the general population about their stroke risk. PMID- 24465257 TI - Axon count and sympathetic skin responses in lumbosacral radiculopathy. AB - BACKGROUND AND PURPOSE: Electrodiagnostic studies can be used to confirm the diagnosis of lumbosacral radiculopathies, but more sensitive diagnostic methods are often needed to measure the ensuing motor neuronal loss and sympathetic failure. METHODS: Twenty-six patients with lumbar radiculopathy and 30 controls were investigated using nerve conduction studies, motor unit number estimation (MUNE), testing of the sympathetic skin response (SSR), quantitative electromyography (QEMG), and magnetic resonance myelography (MRM). RESULTS: Using QEMG as the gold standard, the sensitivity and specificity of MUNE for the abductor hallucis longus muscle were 71.4% and 70%, respectively. While they were 75% and 68.8%, respectively, when used MRM as gold standard. The sensitivity and specificity of MUNE for the extensor digitorum brevis muscle were 100% and 84.1%, respectively, when the peroneal motor amplitude as the gold standard. The SSR latency was slightly longer in the patients than in the controls. CONCLUSIONS: MUNE is a simple and sensitive test for evaluating autonomic function and for diagnosing lumbosacral radiculopathy in patients. MUNE could be used routinely as a guide for the rehabilitation of patients with radiculopathies. SSR measurements may reveal subtle sympathetic abnormalities in patients with lumbosacral radiculopathy. PMID- 24465258 TI - Outcomes of endovascular mechanical thrombectomy and intravenous tissue plasminogen activator for the treatment of vertebrobasilar stroke. AB - BACKGROUND AND PURPOSE: Aggressive treatment of posterior-circulation occlusions is important due to the high rates of morbidity and mortality associated with these infarctions. A large administrative database was evaluated to determine the outcomes of mechanical thrombectomy and intravenous tissue plasminogen activator (IV-tPA) for the treatment of posterior-circulation (vertebrobasilar) strokes. Outcomes were compared across age groups. METHODS: The United States Nationwide Inpatient Sample was used to evaluate the outcomes of patients treated for posterior-circulation acute ischemic stroke between 2006 and 2010. Patients who underwent endovascular mechanical thrombectomy and IV-tPA were selected. Primary outcomes were discharge status and mortality; secondary outcomes were length of stay, rate of intracranial hemorrhage, tracheostomy, and percutaneous endoscopic gastrostomy/jejunostomy tube placement. Outcomes were grouped according to age (i.e., <50, 50-64, and >=65 years). Chi-squared test and Student's t-test were used for comparisons of categorical and continuous variables, respectively. RESULTS: During 2006-2010 there were 36,675 patients who had discharge International Classification of Diseases (9th edition) codes indicating posterior circulation strokes. Of these, 631 (1.7%) underwent mechanical thrombectomy and 1554 (4.2%) underwent IV-tPA. The in-hospital mortality rate for mechanical thrombectomy patients was significantly lower for those aged <50 years than for those aged 50-64 years (30.4% versus 47.4%, p<0.01) and those aged >=65 years (30.4% versus 43.0%, p<=0.01). Age had no effect on the in-hospital mortality for IV-tPA patients, with an incidence of 22.7% for patients aged <50 years, compared to 25.4% for patients aged 50-64 years (p=0.46) and 23.0% for patients aged >=65 years (p=0.92). CONCLUSIONS: Patients requiring IV-tPA and/or mechanical thrombectomy for the treatment of posterior-circulation strokes suffer from high mortality rates. Increased age is associated with significantly higher mortality rates among posterior-circulation stroke patients who require mechanical thrombectomy. PMID- 24465259 TI - Clinical and Pathological Features of Korean Patients with DNM2-Related Centronuclear Myopathy. AB - BACKGROUND AND PURPOSE: Centronuclear myopathy (CNM) is characterized by the presence of central nuclei within a large number of muscle fibers. Mutations of the dynamin 2 gene (DNM2) are common causes of autosomal dominant or sporadic CNM. The aim of this study was to characterize the clinical and pathological features of CNM relative to the presence of DNM2 mutations. METHODS: Six patients with clinical and pathological features of CNM were recruited. Detailed clinical and pathological findings were analyzed according to the presence of DNM2 mutations. RESULTS: We detected DNM2 mutations in four of the six sporadic CNM patients, and identified the following distinct clinical and pathological features in those patients with DNM2 mutations: preferential involvement of the distal lower limbs, typical nuclear centralization, and radially distributed sarcoplasmic strands in muscle pathology. In contrast, those without DNM2 mutations exhibited rather diffuse muscular involvement, and nuclear internalization and myofibrillar disorganization were more pronounced features of their muscle pathology. CONCLUSIONS: These findings suggest the presence of specific features in Korean CNM patients. A detailed clinical and pathological examination of CNM patients would be helpful for molecular genetic analyses of this condition. PMID- 24465260 TI - CAG-Expansion Haplotype Analysis in a Population with a Low Prevalence of Huntington's Disease. AB - BACKGROUND AND PURPOSE: The prevalence of Huntington's disease (HD) among East Asians is less than one-tenth of that among Caucasians. Such a low prevalence may be attributable to a lack of carriers of specific predisposing haplogroups associated with the high instability of the Huntingtin gene (HTT). The aim of this study was to evaluate the association between specific HTT haplogroups and the occurrence of HD in a Thai population. METHODS: CAG-repeat sizes and HTT haplotypes were analyzed in 18 Thai HD patients and 215 control subjects. Twenty two tagging single-nucleotide polymorphisms (tSNPs) were genotyped. RESULTS: Only 18 patients from 15 unrelated families were identified over the last 17 years. Pathological CAG-repeat alleles ranged from 39 to 48 repeats (43.5+/-3.0, mean+/ SD), and normal alleles ranged from 9 to 24 repeats (16.49+/-1.74). Only two of the chromosomes studied comprised intermediate alleles. Unlike the Caucasian data, all but 1 of the 22 tSNPs were not associated with the occurrence of HD. The predisposing haplogroups for Caucasian HD (haplogroups A1 and A2) are very rare in Thai patients (<4%). Both HD and normal chromosomes are commonly haplogroups A5 and C, in contrast to the case for Chinese and Japanese patients, in whom only haplogroup C was common in HD chromosomes. The frequency of CAG repeat sizes of haplogroup A5 and C were also similarly distributed. CONCLUSIONS: HD chromosomes of Thai patients may arise randomly from each haplogroup, with a similar mutation rate. This rate is much lower than the CAG expansions from Caucasian HD haplogroups. These data suggest that the different mechanisms underlie CAG expansion in Thai and Caucasian patients. PMID- 24465261 TI - Primary Position Upbeat Nystagmus during an Acute Attack of Multiple Sclerosis. AB - BACKGROUND AND PURPOSE: Ocular manifestation is one of the frequent signs of an acute attack in multiple sclerosis (MS), although primary position upbeat nystagmus (PPUN) is rare. The purpose of this study is to determine the incidence of PPUN in MS and to determine the lesions that are responsible for this sign. METHODS: The medical records of 120 MS patients with acute brain lesions were reviewed over a consecutive period of 9 years; of these, 6 patients were found to have PPUN. Other ocular motor abnormalities were analyzed in combination with upbeat nystagmus, video-oculographic findings, and lesions detected on brain MRI. RESULTS: Lesions in the pontine tegmentum involving the medial longitudinal fasciculus (MLF) and ventral tegmental tract (VTT) were the most common, being observed in three of the six patients with PPUN. One patient exhibited caudal medullary lesions bilaterally affecting the paramedian portion of the posterior tegmentum, and two patients exhibited multiple lesions involving the pons with the cerebral peduncle or medulla. In five patients, other ocular motor dysfunctions, such as gaze-evoked nystagmus (n=3) and internuclear ophthalmoplegia (n=1), were found in combination with upbeat nystagmus. CONCLUSIONS: PPUN is an infrequent, ocular manifestation noted during an acute attack of MS, and was observed in 5% of the present cases. Brainstem lesions in these cases primarily involved the pontine tegmentum and the caudal medulla. These findings support the theory that upbeat nystagmus is attributable to damage to the upward vestibulo-ocular reflex pathway related to the vestibular nucleus, VTT, and interconnecting pathways. PMID- 24465262 TI - Prevalence and related factors for high-risk of obstructive sleep apnea in a large korean population: results of a questionnaire-based study. AB - BACKGROUND AND PURPOSE: A population-based door-to-door study of cross-sectional methods for assessing the prevalence and factors related to a high risk of obstructive sleep apnea (OSA) was conducted using the Korean version of the Berlin Questionnaire (K-BQ). METHODS: Pooled data collected from Community Health Surveys by the Korea Center for Disease Control and Prevention were analyzed. Of 8,140 respondents from the population, 7,955 were finally included in this study. RESULTS: Of the 7,955 included subjects, 15.7% of the men and 9.8% of the women were at high risk of OSA. Significant differences were found in the following factors between the subjects with a high risk of OSA: gender, age, marital status, educational level, occupation, and presence of smoking, harmful alcohol use, and chronic diseases. Male sex, harmful alcohol use, and the presence of chronic diseases were identified as factors independently associated with a high risk of OSA. CONCLUSIONS: This is the first study to confirm the usefulness of the K-BQ to study the prevalence of OSA in the Korean general population. The findings demonstrate that harmful alcohol use and chronic diseases are very common characteristics among those with a high risk of OSA. PMID- 24465263 TI - Clinical manifestations in paroxysmal kinesigenic dyskinesia patients with proline-rich transmembrane protein 2 gene mutation. AB - BACKGROUND AND PURPOSE: Given the diverse phenotypes including combined non dyskinetic symptoms in patients harboring mutations of the gene encoding proline rich transmembrane protein 2 (PRRT2), the clinical significance of these mutations in paroxysmal kinesigenic dyskinesia (PKD) is questionable. In this study, we investigated the clinical characteristics of PKD patients with PRRT2 mutations. METHODS: Familial and sporadic PKD patients were enrolled and PRRT2 gene sequencing was performed. Demographic and clinical data were compared between PKD patients with and without a PRRT2 mutation. RESULTS: Among the enrolled PKD patients (8 patients from 5 PKD families and 19 sporadic patients), PRRT2 mutations were detected in 3 PKD families (60%) and 2 sporadic cases (10.5%). All familial patients with a PRRT2 gene mutation had the c.649dupC mutation, which is the most commonly reported mutation. Two uncommon mutations (c.649delC and c.629dupC) were detected only in the sporadic cases. PKD patients with PRRT2 mutation were younger at symptom onset and had more non-dyskinetic symptoms than those without PRRT2 mutation. However, the characteristics of dyskinetic movement did not differ between the two groups. CONCLUSIONS: This is the first study of PRRT2 mutations in Korea. The presence of a PRRT2 mutation was more strongly related to familial PKD, and was clinically related with earlier age of onset and common non-dyskinetic symptoms in PKD patients. PMID- 24465264 TI - Novel partial anomalous pulmonary venous connection associated with brain abscess. AB - BACKGROUND: Right-to-left vascular shunts are associated with brain abscess. CASE REPORT: We present a 47-year-old female with a cryptogenic left thalamic abscess on which Streptococcus mitis grew upon aspiration. Computed tomography of the chest with contrast agent revealed an anomalous connection between the left superior pulmonary and brachiocephalic veins. A right-to-left shunt was confirmed in a transthoracic echocardiogram study in which bubbles were injected into the left arm; this shunt had not previously been noted upon right-arm injection. CONCLUSIONS: We recommend aggressive evaluation for right-to-left shunts in patients who present with cryptogenic brain abscesses. In addition to imaging, this should include a bubble-based study with left-arm saline injection. PMID- 24465265 TI - Unilateral reversible posterior leukoencephalopathy syndrome after coiling of an aneurysm. AB - BACKGROUND: Reversible posterior leukoencephalopathy syndrome (RPLS) is radiologically characterized by symmetrical subcortical areas of vasogenic edema that are preferentially parieto-occipital, and it typically resolves after appropriate treatment. CASE REPORT: We present a patient with strikingly unilateral RPLS that developed 21 days after coiling of an anterior communicating artery aneurysm and several days of triple-H therapy. Cortical and subcortical vasogenic edema and enhancement developed only in the left hemisphere, with a pattern suggesting RPLS. After 7 months the lesions had nearly completely resolved. CONCLUSIONS: The pathophysiological mechanism underlying RPLS is still not well understood, which makes it difficult to explain the unilateral appearance in this case. Since the imaging findings may be confused with other conditions such as ischemia, recognition of RPLS after coiling is necessary in order to avoid inadequate treatment. PMID- 24465266 TI - Clinical and molecular study of the extracellular matrix protein 1 gene in a spanish family with lipoid proteinosis. AB - BACKGROUND: Lipoid proteinosis (LP) is a rare autosomal recessive disorder characterized by a hoarse voice, variable scarring, and infiltration of the skin and mucosa. This disease is associated with mutations of the gene encoding extracellular matrix protein 1 (ECM1). CASE REPORT: This was a clinical and molecular study of a new case of LP with a severe phenotype. A 35-year-old female born to nonconsanguineous parents developed dermatological and extracutaneous symptoms in her 9th month of life. The neurological abnormalities of the disease began to appear at the age of 19 years. Computed tomography revealed cranial calcifications. CONCLUSIONS: The diagnosis of LP was confirmed by histopathological findings and direct sequencing of ECM1. A new homozygous nonsense mutation was identified in exon 7 of ECM1, c.1076G>A (p.Trp359(*)). This mutation was not detected in 106 chromosomes of healthy individuals with a similar demographic origin. Microsatellite markers around ECM1 were used to construct the haplotype in both the parents and the patient. Reports on genotype phenotype correlations in LP point to a milder phenotype in carriers of missense mutations in the Ecm1a isoform, whereas mutations in the Ecm1b isoform are thought to be associated with more severe phenotypes. The present findings in a Spanish patient carrying a truncating mutation in exon 7 revealed complete dermatological and neurological manifestations. PMID- 24465267 TI - Myasthenia in acquired neuromyotonia. AB - BACKGROUND: Acquired neuromyotonia (NMT) forms part of the spectrum of acquired peripheral nerve hyperexcitability syndrome, and is thought to be caused by antibodies to voltage-gated potassium channels (VGKC). Exertional weakness is unusual unless autoimmune myasthenia gravis (MG) is superimposed. CASE REPORT: A case of acquired NMT accompanied by exertional weakness without coexistence of seropositive MG is reported herein. CONCLUSIONS: Clinical and electrophysiological observations suggest that the cholinergic overactivity in NMT can compromise the safety factor sufficiently to cause a defect in neuromuscular junction transmission. PMID- 24465268 TI - Cervical myelitis mimicking intractable occipital neuralgia. PMID- 24465269 TI - An Attenuated CMV Vaccine with a Deletion in Tegument Protein GP83 (pp65 Homolog) Protects against Placental Infection and Improves Pregnancy Outcome in a Guinea Pig Challenge Model. AB - AIMS: Congenital human cytomegalovirus (HCMV) infection can lead to long-term neurodevelopmental sequelae, including mental retardation and sensorineural hearing loss. Preconception vaccine strategies relevant to prevention of HCMV mediated injury to the newborn can be studied in the guinea pig cytomegalovirus (GPCMV) model. The objectives of this study were: 1) to assess in guinea pigs the protective efficacy against congenital infection and disease of a recombinant live, attenuated vaccine with a targeted deletion of the GPCMV homolog of the HCMV pUL83 tegument protein, GP83; and, 2) to compare the extent of placental infection in vaccine and control groups, using an in situ hybridization (ISH) assay. MATERIALS AND METHODS: Outbred Hartley guinea pigs were vaccinated prior to pregnancy with a two-dose series of 5*104 pfu of vAM409, a GP83 deletion virus. Deletion of the GP83 gene resulted in an attenuated virus, and vAM409 vaccinated animals did not demonstrate evidence of DNAemia following vaccination, although ELISA antibody responses were comparable to those observed in natural infection. After mating, pregnant animals were challenged with salivary gland adapted (SG) GPCMV (1*106 pfu) in the second trimester, and pregnancy outcomes were compared to controls. RESULTS: Compared to placebo-immunized controls, vaccination resulted in significantly reduced maternal DNAemia following SG challenge, and there was significantly decreased pup mortality in litters born to vaccinated dams (3/29; 10%), compared to control (35/50; 70%; p<0.001). By in situ hybridization study, recovered placentas in the vAM409 vaccine group demonstrated reduced infection and fewer infectious foci compared to the control group. CONCLUSIONS: In summary, preconception immunization with a GP83 deletion vaccine reduced maternal DNAemia and results in protection against congenital GPCMV-associated pup mortality compared to unvaccinated controls. Vaccination resulted in reduced placental infection, probably related to the reduction in maternal DNAemia. Although the pp65 homolog in GPCMV, GP83, is a known target of protective T cell immune responses, it is nevertheless dispensable for effective vaccination against maternal and fetal CMV disease in this model. PMID- 24465271 TI - Visualization of protease activity in vivo using an activatable photo-acoustic imaging probe based on CuS nanoparticles. AB - Herein, we for the first time report a novel activatable photoacoustic (PA) imaging nano-probe for in vivo detection of cancer-related matrix metalloproteinases (MMPs). A black hole quencher 3 (BHQ3) which absorbs red light is conjugated to near-infrared (NIR)-absorbing copper sulfide (CuS) nanoparticles via a MMP-cleavable peptide linker. The obtained CuS-peptide-BHQ3 (CPQ) nano probe exhibits two distinctive absorption peaks at 630 nm and 930 nm. Inside the tumor microenvironment where MMPs present, the MMP-sensitive peptide would be cleaved, releasing BHQ3 from the CuS nanoparticles, the former of which as a small molecule is then rapidly cleared out from the tumor, whereas the latter of which as large nanoparticles would retain inside the tumor for a much longer period of time. As the result, the PA signal at 680 nm which is contributed by BHQ3 would be quickly diminished while that at 930 nm would be largely retained. The PA signal ratio of 680 nm / 930 nm could thus serve as an in vivo indicator of MMPs activity inside the tumor. Our work presents a novel strategy of in vivo sensing of MMPs based on PA imaging, which should offer remarkably improved detection depth compared with traditional optical imaging techniques. PMID- 24465270 TI - MicroRNA-206: a promising theranostic marker. AB - MicroRNAs (miRs) are small non-coding RNAs that negatively regulate gene expression by binding to the 3' untranslated regions (3'UTR) of their target mRNAs. MiRs were shown to play pivotal roles in tissue development and function and are also involved in the pathogenesis of various diseases including cancer. MicroRNA-206, which belongs to the group of so-called "myomiRs", is one of the most studied miRs thus far. In addition to being involved in skeletal muscle development and pathology, it has also been established that it is involved in the pathogenesis of numerous diseases including heart failure, chronic obstructive pulmonary disease, Alzheimer's disease and various types of cancers. The aim of this review is to provide a complex overview of microRNA-206, including regulating its expression, a brief description of its known functions in skeletal muscle and a complex overview of its roles in the biology and pathology of other tissues, emphasizing its significant diagnostic and therapeutic potential. PMID- 24465272 TI - Folate receptor-targeting gold nanoclusters as fluorescence enzyme mimetic nanoprobes for tumor molecular colocalization diagnosis. AB - Nanoprobes with enzyme-like properties attracted a growing interest in early screening and diagnosis of cancer. To achieve high accuracy and specificity of tumor detection, the design and preparation of enzyme mimetic nanoprobes with high enzyme activity, tumor targeting and excellent luminescence property is highly desirable. Herein, we described a novel kind of fluorescence enzyme mimetic nanoprobe based on folate receptor-targeting Au nanoclusters. The nanoprobes exhibited excellent stability, low cytotoxicity, high fluorescence and enzyme activity. We demonstrated that the nanoprobes could be used for tumor tissues fluorescence/visualizing detection. For the same tumor tissue slice, the nanoprobes peroxidase staining and fluorescent staining were obtained simultaneously, and the results were mutually complementary. Therefore, the fluorescence enzyme mimetic nanoprobes could provide a molecular colocalization diagnosis strategy, efficiently avoid false-positive and false-negative results, and further improve the accuracy and specificity of cancer diagnoses. By examining different clinical samples, we demonstrated that the nanoprobes could distinguish efficiently cancerous cells from normal cells, and exhibit a clinical potential for cancer diagnosis. PMID- 24465273 TI - Identification of volatile biomarkers of gastric cancer cells and ultrasensitive electrochemical detection based on sensing interface of Au-Ag alloy coated MWCNTs. AB - Successful development of novel electrochemical biosensing interface for ultrasensitive detection of volatile biomarkers of gastric cancer cells is a challenging task. Herein we reported to screen out novel volatile biomarkers associated with gastric cancer cells and develop a novel Au-Ag alloy composites coated MWCNTs as sensing interface for ultrasensitive detection of volatile biomarkers. MGC-803 gastric cancer cells and GES-1 gastric mucous cells were cultured in serum-free media. The sample preparation approaches and HS-SPME conditions were optimized for screening volatile biomarkers. Volatiles emitted from the headspace of the cells/medium culture were identified using GC-MS. The Au-Ag nanoparticles-coated multiwalled carbon nanotubes were prepared as a sensing interface for detection of volatile biomarkers. Results showed that eight different volatile metabolites were screened out between MGC-803 cells and GES-1 cells. Two compounds such as 3-octanone and butanone were specifically present in the headspace of the MGC-803 cells. Three volatiles such as 4-isopropoxybutanol, nonanol and 4-butoxy 1-butanol coexisted in the headspace of both the MGC-803 cells and the GES-1 cells, their concentrations in the headspace of the GES 1cells were markedly higher than those in the MGC-803 cells, three volatiles such as formic acid propyl ester, 1.4-butanediol and 2, 6, 11-trimethyl dodecane solely existed in the headspace of the GES-1 cells. The nanocomposites of MWNTs loaded with Au-Ag nanoparticles were prepared as a electrochemical sensing interface for detection of two volatile biomarkers, cyclic voltammetry studies showed that the fabricated sensor could detect 3-octanone in the range of 0~0.0025% (v/v) and with a detection limitation of 0.3 ppb, could detect butanone in the range of 0 ~ 0.055% (v/v), and with a detection limitation of 0.5 ppb, and exhibited good selectivity. The novel electrochemical biosensor combined with volatile biomarkers of gastric cancer owns great potential in applications such as early diagnosis and the prognosis of gastric cancer in near future. PMID- 24465274 TI - Gold nanocage-photosensitizer conjugates for dual-modal image-guided enhanced photodynamic therapy. AB - We have demonstrated that gold nanocage-photosensitizer conjugates can enable dual image-guided delivery of photosensitizer and significantly improve the efficacy of photodynamic therapy in a murine model. The photosensitizer, 3 devinyl-3-(1'-hexyloxyethyl)pyropheophorbide (HPPH), was noncovalently entrapped in the poly(ethylene glycol) monolayer coated on the surface of gold nanocages. The conjugate is stable in saline solutions, while incubation in protein rich solutions leads to gradual unloading of the HPPH, which can be monitored optically by fluorescence and photoacoustic imaging. The slow nature of the release in turn results in an increase in accumulation of the drug within implanted tumors due to the passive delivery of gold nanocages. Furthermore, the conjugate is found to generate more therapeutic singlet oxygen and have a lower IC50 value than the free drug alone. Thus the conjugate shows significant suppression of tumor growth as compared to the free drug in vivo. Short-term study showed neither toxicity nor phenotypical changes in mice at therapeutic dose of the conjugates or even at 100-fold higher than therapeutic dose of gold nanocages. PMID- 24465276 TI - Multi-scale optical imaging of the delayed type hypersensitivity reaction attenuated by rapamycin. AB - Neutrophils and monocytes/macrophages (MMs) play important roles in the development of cell-mediated delayed type hypersensitivity (DTH). However, the dynamics of neutrophils and MMs during the DTH reaction and how the immunosuppressant rapamycin modulates their behavior in vivo are rarely reported. Here, we take advantage of multi-scale optical imaging techniques and a footpad DTH reaction model to non-invasively investigate the dynamic behavior and properties of immune cells from the whole field of the footpad to the cellular level. During the classic elicitation phase of the DTH reaction, both neutrophils and MMs obviously accumulated at inflammatory foci at 24 h post-challenge. Rapamycin treatment resulted in advanced neutrophil recruitment and vascular hyperpermeability at an early stage (4 h), the reduced accumulation of neutrophils (> 50% inhibition ratio) at 48 h, and the delayed involvement of MMs in inflammatory foci. The motility parameters of immune cells in the rapamycin treated reaction at 4 h post-challenge displayed similar mean velocities, arrest durations, mean displacements, and confinements as the classic DTH reaction at 24 h. These results indicate that rapamycin treatment shortened the initial preparation stage of the DTH reaction and attenuated its intensity, which may be due to the involvement of T helper type 2 cells or regulatory T cells. PMID- 24465275 TI - Nanoparticle drug- and gene-eluting stents for the prevention and treatment of coronary restenosis. AB - Percutaneous coronary intervention (PCI) has become the most common revascularization procedure for coronary artery disease. The use of stents has reduced the rate of restenosis by preventing elastic recoil and negative remodeling. However, in-stent restenosis remains one of the major drawbacks of this procedure. Drug-eluting stents (DESs) have proven to be effective in reducing the risk of late restenosis, but the use of currently marketed DESs presents safety concerns, including the non-specificity of therapeutics, incomplete endothelialization leading to late thrombosis, the need for long-term anti-platelet agents, and local hypersensitivity to polymer delivery matrices. In addition, the current DESs lack the capacity for adjustment of the drug dose and release kinetics appropriate to the disease status of the treated vessel. The development of efficacious therapeutic strategies to prevent and inhibit restenosis after PCI is critical for the treatment of coronary artery disease. The administration of drugs using biodegradable polymer nanoparticles as carriers has generated immense interest due to their excellent biocompatibility and ability to facilitate prolonged drug release. Despite the potential benefits of nanoparticles as smart drug delivery and diagnostic systems, much research is still required to evaluate potential toxicity issues related to the chemical properties of nanoparticle materials, as well as to their size and shape. This review describes the molecular mechanism of coronary restenosis, the use of DESs, and progress in nanoparticle drug- or gene-eluting stents for the prevention and treatment of coronary restenosis. PMID- 24465278 TI - Lineage tracing quantification reveals symmetric stem cell division in Drosophila male germline stem cells. AB - In the homeostatic state, adult stem cells divide either symmetrically to increase the stem cell number to compensate stem cell loss, or asymmetrically to maintain the population while producing differentiated cells. We have investigated the mode of stem cell division in the testes of Drosophila melanogaster by lineage tracing and confirm the presence of symmetric stem cell division in this system. We found that the rate of symmetric division is limited to 1-2% of total germline stem cell (GSC) divisions, but it increases with expression of a cell adhesion molecule, E-cadherin, or a regulator of the actin cytoskeleton, Moesin, which may modulate adhesiveness of germ cells to the stem cell niche. Our results indicate that the decision regarding asymmetric vs. symmetric division is a dynamically regulated process that contributes to tissue homeostasis, responding to the needs of the tissue. PMID- 24465277 TI - Quantitative liver-specific protein fingerprint in blood: a signature for hepatotoxicity. AB - We discuss here a new approach to detecting hepatotoxicity by employing concentration changes of liver-specific blood proteins during disease progression. These proteins are capable of assessing the behaviors of their cognate liver biological networks for toxicity or disease perturbations. Blood biomarkers are highly desirable diagnostics as blood is easily accessible and baths virtually all organs. Fifteen liver-specific blood proteins were identified as markers of acetaminophen (APAP)-induced hepatotoxicity using three proteomic technologies: label-free antibody microarrays, quantitative immunoblotting, and targeted iTRAQ mass spectrometry. Liver-specific blood proteins produced a toxicity signature of eleven elevated and four attenuated blood protein levels. These blood protein perturbations begin to provide a systems view of key mechanistic features of APAP-induced liver injury relating to glutathione and S adenosyl-L-methionine (SAMe) depletion, mitochondrial dysfunction, and liver responses to the stress. Two markers, elevated membrane-bound catechol-O methyltransferase (MB-COMT) and attenuated retinol binding protein 4 (RBP4), report hepatic injury significantly earlier than the current gold standard liver biomarker, alanine transaminase (ALT). These biomarkers were perturbed prior to onset of irreversible liver injury. Ideal markers should be applicable for both rodent model studies and human clinical trials. Five of these mouse liver specific blood markers had human orthologs that were also found to be responsive to human hepatotoxicity. This panel of liver-specific proteins has the potential to effectively identify the early toxicity onset, the nature and extent of liver injury and report on some of the APAP-perturbed liver networks. PMID- 24465279 TI - Master equation-based analysis of a motor-clutch model for cell traction force. AB - Microenvironmental mechanics play an important role in determining the morphology, traction, migration, proliferation, and differentiation of cells. A stochastic motor-clutch model has been proposed to describe this stiffness sensitivity. In this work, we present a master equation-based ordinary differential equation (ODE) description of the motor-clutch model, from which we derive an analytical expression to for a cell's optimum stiffness (i.e. the stiffness at which the traction force is maximal). This analytical expression provides insight into the requirements for stiffness sensing by establishing fundamental relationships between the key controlling cell-specific parameters. We find that the fundamental controlling parameters are the numbers of motors and clutches (constrained to be nearly equal), and the time scale of the on-off kinetics of the clutches (constrained to favor clutch binding over clutch unbinding). Both the ODE solution and the analytical expression show good agreement with Monte Carlo motor-clutch output, and reduce computation time by several orders of magnitude, which potentially enables long time scale behaviors (hours-days) to be studied computationally in an efficient manner. The ODE solution and the analytical expression may be incorporated into larger scale models of cellular behavior to bridge the gap from molecular time scales to cellular and tissue time scales. PMID- 24465280 TI - First eddy covariance flux measurements by PTR-TOF. AB - The recently developed PTR-TOF instrument was evaluated to measure methanol fluxes emitted from grass land using the eddy covariance method. The high time resolution of the PTR-TOF allowed storing full mass spectra up to m/z 315 with a frequency of 10 Hz. Three isobaric ions were found at a nominal mass of m/z 33 due to the high mass resolving power of the PTR-TOF. Only one of the three peaks contributed to eddy covariance fluxes. The exact mass of this peak agrees well with the exact mass of protonated methanol (m/z 33.0335). The eddy covariance methanol fluxes measured with PTR-TOF were compared to virtual disjunct eddy covariance methanol fluxes simultaneously measured with a conventional PTR-MS. The methanol fluxes from both instruments show excellent agreement. PMID- 24465282 TI - Information flow in heterogeneously interacting systems. AB - Motivated by studies on the dynamics of heterogeneously interacting systems in neocortical neural networks, we studied heterogeneously-coupled chaotic systems. We used information-theoretic measures to investigate directions of information flow in heterogeneously coupled Rossler systems, which we selected as a typical chaotic system. In bi-directionally coupled systems, spontaneous and irregular switchings of the phase difference between two chaotic oscillators were observed. The direction of information transmission spontaneously switched in an intermittent manner, depending on the phase difference between the two systems. When two further oscillatory inputs are added to the coupled systems, this system dynamically selects one of the two inputs by synchronizing, selection depending on the internal phase differences between the two systems. These results indicate that the effective direction of information transmission dynamically changes, induced by a switching of phase differences between the two systems. PMID- 24465281 TI - Time domain measures of inter-channel EEG correlations: a comparison of linear, nonparametric and nonlinear measures. AB - Correlations between ten-channel EEGs obtained from thirteen healthy adult participants were investigated. Signals were obtained in two behavioral states: eyes open no task and eyes closed no task. Four time domain measures were compared: Pearson product moment correlation, Spearman rank order correlation, Kendall rank order correlation and mutual information. The psychophysiological utility of each measure was assessed by determining its ability to discriminate between conditions. The sensitivity to epoch length was assessed by repeating calculations with 1, 2, 3, ..., 8 s epochs. The robustness to noise was assessed by performing calculations with noise corrupted versions of the original signals (SNRs of 0, 5 and 10 dB). Three results were obtained in these calculations. First, mutual information effectively discriminated between states with less data. Pearson, Spearman and Kendall failed to discriminate between states with a 1 s epoch, while a statistically significant separation was obtained with mutual information. Second, at all epoch durations tested, the measure of between-state discrimination was greater for mutual information. Third, discrimination based on mutual information was more robust to noise. The limitations of this study are discussed. Further comparisons should be made with frequency domain measures, with measures constructed with embedded data and with the maximal information coefficient. PMID- 24465283 TI - Visual pattern discrimination by population retinal ganglion cells' activities during natural movie stimulation. AB - In the visual system, neurons often fire in synchrony, and it is believed that synchronous activities of group neurons are more efficient than single cell response in transmitting neural signals to down-stream neurons. However, whether dynamic natural stimuli are encoded by dynamic spatiotemporal firing patterns of synchronous group neurons still needs to be investigated. In this paper we recorded the activities of population ganglion cells in bullfrog retina in response to time-varying natural images (natural scene movie) using multi electrode arrays. In response to some different brief section pairs of the movie, synchronous groups of retinal ganglion cells (RGCs) fired with similar but different spike events. We attempted to discriminate the movie sections based on temporal firing patterns of single cells and spatiotemporal firing patterns of the synchronous groups of RGCs characterized by a measurement of subsequence distribution discrepancy. The discrimination performance was assessed by a classification method based on Support Vector Machines. Our results show that different movie sections of the natural movie elicited reliable dynamic spatiotemporal activity patterns of the synchronous RGCs, which are more efficient in discriminating different movie sections than the temporal patterns of the single cells' spike events. These results suggest that, during natural vision, the down-stream neurons may decode the visual information from the dynamic spatiotemporal patterns of the synchronous group of RGCs' activities. PMID- 24465284 TI - A modular latching chain. AB - Many cognitive tasks involve transitions between distinct mental processes, which may range from discrete states to complex strategies. The ability of cortical networks to combine discrete jumps with continuous glides along ever changing trajectories, dubbed latching dynamics, may be essential for the emergence of the unique cognitive capacities of modern humans. Novel trajectories have to be followed in the multidimensional space of cortical activity for novel behaviours to be produced; yet, not everything changes: several lines of evidence point at recurring patterns in the sequence of activation of cortical areas in a variety of behaviours. To extend a mathematical model of latching dynamics beyond the simple unstructured auto-associative Potts network previously analysed, we introduce delayed structured connectivity and hetero-associative connection weights, and we explore their effects on the dynamics. A modular model in the small-world regime is considered, with modules arranged on a ring. The synaptic weights include a standard auto-associative component, stabilizing distinct patterns of activity, and a hetero-associative component, favoring transitions from one pattern, expressed in one module, to the next, in the next module. We then study, through simulations, how structural parameters, like those regulating rewiring probability, noise and feedback connections, determine sequential association dynamics. PMID- 24465285 TI - Exponential input-to-state stability of recurrent neural networks with multiple time-varying delays. AB - In this paper, input-to-state stability problems for a class of recurrent neural networks model with multiple time-varying delays are concerned with. By utilizing the Lyapunov-Krasovskii functional method and linear matrix inequalities techniques, some sufficient conditions ensuring the exponential input-to-state stability of delayed network systems are firstly obtained. Two numerical examples and its simulations are given to illustrate the efficiency of the derived results. PMID- 24465286 TI - A linear model for characterization of synchronization frequencies of neural networks. AB - The synchronization frequency of neural networks and its dynamics have important roles in deciphering the working mechanisms of the brain. It has been widely recognized that the properties of functional network synchronization and its dynamics are jointly determined by network topology, network connection strength, i.e., the connection strength of different edges in the network, and external input signals, among other factors. However, mathematical and computational characterization of the relationships between network synchronization frequency and these three important factors are still lacking. This paper presents a novel computational simulation framework to quantitatively characterize the relationships between neural network synchronization frequency and network attributes and input signals. Specifically, we constructed a series of neural networks including simulated small-world networks, real functional working memory network derived from functional magnetic resonance imaging, and real large-scale structural brain networks derived from diffusion tensor imaging, and performed synchronization simulations on these networks via the Izhikevich neuron spiking model. Our experiments demonstrate that both of the network synchronization strength and synchronization frequency change according to the combination of input signal frequency and network self-synchronization frequency. In particular, our extensive experiments show that the network synchronization frequency can be represented via a linear combination of the network self-synchronization frequency and the input signal frequency. This finding could be attributed to an intrinsically-preserved principle in different types of neural systems, offering novel insights into the working mechanism of neural systems. PMID- 24465287 TI - Vague-to-crisp dynamics of percept formation modeled as operant (selectionist) process. AB - We model the vague-to-crisp dynamics of forming percepts in the brain by combining two methodologies: dynamic logic (DL) and operant learning process. Forming percepts upon the presentation of visual inputs is likened to model selection based on sampled evidence. Our framework utilizes the DL in selecting the correct "percept" among competing ones, but uses an intrinsic reward mechanism to allow stochastic online update in lieu of performing the optimization step of the DL framework. We discuss the connection of our framework with cognitive processing and the intentional neurodynamic cycle. PMID- 24465288 TI - Signal integration on the dendrites of a pyramidal neuron model. AB - This paper studied the synaptic and dendritic integration with different spatial distributions of synapses on the dendrites of a biophysically-detailed layer 5 pyramidal neuron model. It has been observed that temporally synchronous and spatially clustered synaptic inputs make dendrites perform a highly nonlinear integration. The effect of clustering degree of synaptic distribution on neuronal responsiveness is investigated by changing the number of top apical dendrites where active synapses are allocated. The neuron shows maximum responsiveness to synaptic inputs which have an intermediate clustering degree of spatial distribution, indicating complex interactions among dendrites with the existence of nonlinear synaptic and dendritic integrations. PMID- 24465289 TI - Breastfeeding During Early Infancy is Associated with a Lower Incidence of Febrile Illnesses. AB - Human breast milk is known to contain immunoprotective, antimicrobial, and anti inflammatory agents. In a prospective clinical study of dengue virus infections during infancy, we examined the correlation between breastfeeding and the development of febrile illnesses in an infant population. We found that breastfeeding status and the frequency of breastfeeding during early infancy was associated with a lower incidence of febrile illnesses. PMID- 24465290 TI - Alcohol consumption among Chilean adolescents: Examining individual, peer, parenting and environmental factors. AB - AIMS: This study examined whether adolescents from Santiago, Chile who had never drunk alcohol differed from those who had drunk alcohol but who had never experienced an alcohol-related problem, as well as from those who had drunk and who had experienced at least one alcohol-related problem on a number of variables from four domains - individual, peers, parenting, and environmental. DESIGN: Cross-sectional. SETTING: Community based sample. PARTICIPANTS: 909 adolescents from Santiago, Chile. MEASUREMENTS: Data were analyzed with multinomial logistic regression to compare adolescents who had never drunk alcohol (non-drinkers) with i) those that had drunk but who had experienced no alcohol-related problems (non problematic drinkers) and ii) those who had drunk alcohol and had experienced at least one alcohol-related problem (problematic drinkers). The analyses included individual, peer, parenting, and environmental factors while controlling for age, sex, and socioeconomic status. FINDINGS: Compared to non-drinkers, both non problematic and problematic drinkers were older, reported having more friends who drank alcohol, greater exposure to alcohol ads, lower levels of parental monitoring, and more risk-taking behaviors. In addition, problematic drinkers placed less importance on religious faith to make daily life decisions and had higher perceptions of neighborhood crime than non-drinkers. CONCLUSIONS: Prevention programs aimed at decreasing problematic drinking could benefit from drawing upon adolescents' spiritual sources of strength, reinforcing parental tools to monitor their adolescents, and improving environmental and neighborhood conditions. PMID- 24465291 TI - LEARNING LOCAL DIRECTED ACYCLIC GRAPHS BASED ON MULTIVARIATE TIME SERIES DATA. AB - Multivariate time series (MTS) data such as time course gene expression data in genomics are often collected to study the dynamic nature of the systems. These data provide important information about the causal dependency among a set of random variables. In this paper, we introduce a computationally efficient algorithm to learn directed acyclic graphs (DAGs) based on MTS data, focusing on learning the local structure of a given target variable. Our algorithm is based on learning all parents (P), all children (C) and some descendants (D) (PCD) iteratively, utilizing the time order of the variables to orient the edges. This time series PCD-PCD algorithm (tsPCD-PCD) extends the previous PCD-PCD algorithm to dependent observations and utilizes composite likelihood ratio tests (CLRTs) for testing the conditional independence. We present the asymptotic distribution of the CLRT statistic and show that the tsPCD-PCD is guaranteed to recover the true DAG structure when the faithfulness condition holds and the tests correctly reject the null hypotheses. Simulation studies show that the CLRTs are valid and perform well even when the sample sizes are small. In addition, the tsPCD-PCD algorithm outperforms the PCD-PCD algorithm in recovering the local graph structures. We illustrate the algorithm by analyzing a time course gene expression data related to mouse T-cell activation. PMID- 24465363 TI - Participation during first social encounters in schizophrenia. AB - BACKGROUND: Patients with a diagnosis of schizophrenia are socially excluded. The aim of this study was to investigate how patients participate in first encounters with unfamiliar healthy participants, who are unaware of their diagnosis. METHODS: Patterns of participation were investigated during interactions involving three-people. Three conversation roles were analysed: (i) speaker, (ii) primary recipient- focus of the speaker's attention and (iii) secondary recipient unaddressed individual. Twenty patient interactions (1 patient, 2 healthy controls) and 20 control interactions (3 healthy participants) were recorded and motion captured in 3D. The participation of patients and their partners, in each conversation role, was compared with controls at the start, middle and end of the interaction. The relationship between patients' participation, their symptoms and the rapport others experienced with them was also explored. RESULTS: At the start of the interaction patients spoke less (beta = -.639, p = .02) and spent more time as secondary recipient (beta = .349, p = .02). Patients' participation at the middle and end of the interaction did not differ from controls. Patients' partners experienced poorer rapport with patients who spent more time as a primary recipient at the start of the interaction (Rho(11) = -.755, p<.01). Patients' participation was not associated with symptoms. CONCLUSION: Despite their increased participation over time, patients' initial participation appears to be associated with others' experience of rapport with them. Thus, the opening moments of patients' first encounters appear to be interpersonally significant. Further investigation of patient and others' behaviour during these critical moments is warranted in order to understand, and possibly develop interventions to address, the difficulties schizophrenia patients experience here. PMID- 24465364 TI - Canine parvovirus VP2 protein expressed in silkworm pupae self-assembles into virus-like particles with high immunogenicity. AB - The VP2 structural protein of parvovirus can produce virus-like particles (VLPs) by a self-assembly process in vitro, making VLPs attractive vaccine candidates. In this study, the VP2 protein of canine parvovirus (CPV) was expressed using a baculovirus expression system and assembled into parvovirus-like particles in insect cells and pupae. Electron micrographs of VLPs showed that they were very similar in size and morphology when compared to the wild-type parvovirus. The immunogenicity of the VLPs was investigated in mice and dogs. Mice immunized intramuscularly with purified VLPs, in the absence of an adjuvant, elicited CD4(+) and CD8(+) T cell responses and were able to elicit a neutralizing antibody response against CPV, while the oral administration of raw homogenates containing VLPs to the dogs resulted in a systemic immune response and long lasting immunity. These results demonstrate that the CPV-VLPs stimulate both cellular and humoral immune responses, and so CPV-VLPs may be a promising candidate vaccine for the prevention of CPV-associated disease. PMID- 24465365 TI - Nasopharyngeal carriage and transmission of Streptococcus pneumoniae in American Indian households after a decade of pneumococcal conjugate vaccine use. AB - BACKGROUND: Young children played a major role in pneumococcal nasopharyngeal carriage, acquisition, and transmission in the era before pneumococcal conjugate vaccine (PCV) use. Few studies document pneumococcal household dynamics in the routine-PCV7 era. METHODS: We investigated age-specific acquisition, household introduction, carriage clearance, and intra-household transmission in a prospective, longitudinal, observational cohort study of pneumococcal nasopharyngeal carriage in 300 American Indian households comprising 1,072 participants between March 2006 and March 2008. RESULTS: Pneumococcal acquisition rates were 2-6 times higher in children than adults. More household introductions of new pneumococcal strains were attributable to children <9 years than adults >=17 years (p<0.001), and older children (2-8 years) than younger children (<2 years) (p<0.008). Compared to children <2 years, carriage clearance was more rapid in older children (2-4 years, HRclearance 1.53 [95% CI: 1.22, 1.91]; 5-8 years, HRclearance 1.71 [1.36, 2.15]) and adults (HRclearance 1.75 [1.16, 2.64]). Exposure to serotype-specific carriage in older children (2-8 years) most consistently increased the odds of subsequently acquiring that serotype for other household members. CONCLUSIONS: In this community with a high burden of pneumococcal colonization and disease and routine PCV7 use, children (particularly older children 2-8 years) drive intra-household pneumococcal transmission: first, by acquiring, introducing, and harboring pneumococcus within the household, and then by transmitting acquired serotypes more efficiently than household members of other ages. PMID- 24465366 TI - Association between HLA variations and chronic hepatitis B virus infection in Saudi Arabian patients. AB - Hepatitis B virus (HBV) infection is a leading cause of liver diseases including cirrhosis and hepatocellular carcinoma. Human leukocyte antigens (HLAs) play an important role in the regulation of immune response against infectious organisms, including HBV. Recently, several genome-wide association (GWAS) studies have shown that genetic variations in HLA genes influence disease progression in HBV infection. The aim of this study was to investigate the role of HLA genetic polymorphisms and their possible role in HBV infection in Saudi Arabian patients. Variations in HLA genes were screened in 1672 subjects who were divided according to their clinical status into six categories as follows; clearance group, inactive carriers, active carriers, cirrhosis, hepatocellular carcinoma (HCC) patients and uninfected healthy controls. Three single nucleotide polymorphisms (SNPs) belonged to HLA-DQ region (rs2856718, rs7453920 and rs9275572) and two SNPs belonged to HLA-DP (rs3077 and rs9277535) were studied. The SNPs were genotyped by PCR-based DNA sequencing (rs2856718) and allele specific TaqMan genotyping assays (rs3077, rs7453920, rs9277535 and rs9275572). The results showed that rs2856718, rs3077, rs9277535 and rs9275572 were associated with HBV infection (p = 0.0003, OR = 1.351, CI = 1.147-1.591; p = 0.041, OR = 1.20, CI = 1.007-1.43; p = 0.045, OR = 1.198, CI = 1.004-1.43 and p = 0.0018, OR = 0.776, CI = 0.662-0.910, respectively). However, allele frequency of rs2856718, rs7453920 and rs9275572 were found more in chronically infected patients when compared to clearance group infection (p = 0.0001, OR = 1.462, CI = 1.204-1.776; p = 0.0178, OR = 1.267, CI = 1.042-1.540 and p = 0.010, OR = 0.776, CI = 0.639-0.942, respectively). No association was found when polymorphisms in HLA genes were compared in active carriers versus cirrhosis/HCC patients. In conclusion, these results suggest that variations in HLA genes could affect susceptibility to and clearance of HBV infection in Saudi Arabian patients. PMID- 24465367 TI - Computer simulation of leadership, consensus decision making and collective behaviour in humans. AB - The aim of this study is to evaluate the reliability of a crowd simulation model developed by the authors by reproducing Dyer et al.'s experiments (published in Philosophical Transactions in 2009) on human leadership and consensus decision making in a computer-based environment. The theoretical crowd model of the simulation environment is presented, and its results are compared and analysed against Dyer et al.'s original experiments. It is concluded that the simulation results are largely consistent with the experiments, which demonstrates the reliability of the crowd model. Furthermore, the simulation data also reveals several additional new findings, namely: 1) the phenomena of sacrificing accuracy to reach a quicker consensus decision found in ants colonies was also discovered in the simulation; 2) the ability of reaching consensus in groups has a direct impact on the time and accuracy of arriving at the target position; 3) the positions of the informed individuals or leaders in the crowd could have significant impact on the overall crowd movement; and 4) the simulation also confirmed Dyer et al.'s anecdotal evidence of the proportion of the leadership in large crowds and its effect on crowd movement. The potential applications of these findings are highlighted in the final discussion of this paper. PMID- 24465368 TI - Minimum pricing of alcohol versus volumetric taxation: which policy will reduce heavy consumption without adversely affecting light and moderate consumers? AB - BACKGROUND: We estimate the effect on light, moderate and heavy consumers of alcohol from implementing a minimum unit price for alcohol (MUP) compared with a uniform volumetric tax. METHODS: We analyse scanner data from a panel survey of demographically representative households (n = 885) collected over a one-year period (24 Jan 2010-22 Jan 2011) in the state of Victoria, Australia, which includes detailed records of each household's off-trade alcohol purchasing. FINDINGS: The heaviest consumers (3% of the sample) currently purchase 20% of the total litres of alcohol (LALs), are more likely to purchase cask wine and full strength beer, and pay significantly less on average per standard drink compared to the lightest consumers (A$1.31 [95% CI 1.20-1.41] compared to $2.21 [95% CI 2.10-2.31]). Applying a MUP of A$1 per standard drink has a greater effect on reducing the mean annual volume of alcohol purchased by the heaviest consumers of wine (15.78 LALs [95% CI 14.86-16.69]) and beer (1.85 LALs [95% CI 1.64-2.05]) compared to a uniform volumetric tax (9.56 LALs [95% CI 9.10-10.01] and 0.49 LALs [95% CI 0.46-0.41], respectively). A MUP results in smaller increases in the annual cost for the heaviest consumers of wine ($393.60 [95% CI 374.19-413.00]) and beer ($108.26 [95% CI 94.76-121.75]), compared to a uniform volumetric tax ($552.46 [95% CI 530.55-574.36] and $163.92 [95% CI 152.79-175.03], respectively). Both a MUP and uniform volumetric tax have little effect on changing the annual cost of wine and beer for light and moderate consumers, and likewise little effect upon their purchasing. CONCLUSIONS: While both a MUP and a uniform volumetric tax have potential to reduce heavy consumption of wine and beer without adversely affecting light and moderate consumers, a MUP offers the potential to achieve greater reductions in heavy consumption at a lower overall annual cost to consumers. PMID- 24465369 TI - Mice lacking natural killer T cells are more susceptible to metabolic alterations following high fat diet feeding. AB - Current estimates suggest that over one-third of the adult population has metabolic syndrome and three-fourths of the obese population has non-alcoholic fatty liver disease (NAFLD). Inflammation in metabolic tissues has emerged as a universal feature of obesity and its co-morbidities, including NAFLD. Natural Killer T (NKT) cells are a subset of innate immune cells that abundantly reside within the liver and are readily activated by lipid antigens. There is general consensus that NKT cells are pivotal regulators of inflammation; however, disagreement exists as to whether NKT cells exert pathogenic or suppressive functions in obesity. Here we demonstrate that CD1d(-/-) mice, which lack NKT cells, were more susceptible to weight gain and fatty liver following high fat diet (HFD) feeding. Compared with their WT counterparts, CD1d(-/-) mice displayed increased adiposity and greater induction of inflammatory genes in the liver suggestive of the precursors of NAFLD. Calorimetry studies revealed a significant increase in food intake and trends toward decreased metabolic rate and activity in CD1d(-/-) mice compared with WT mice. Based on these findings, our results suggest that NKT cells play a regulatory role that helps to prevent diet-induced obesity and metabolic dysfunction and may play an important role in mechanisms governing cross-talk between metabolism and the immune system to regulate energy balance and liver health. PMID- 24465370 TI - Network analysis reveals distinct clinical syndromes underlying acute mountain sickness. AB - Acute mountain sickness (AMS) is a common problem among visitors at high altitude, and may progress to life-threatening pulmonary and cerebral oedema in a minority of cases. International consensus defines AMS as a constellation of subjective, non-specific symptoms. Specifically, headache, sleep disturbance, fatigue and dizziness are given equal diagnostic weighting. Different pathophysiological mechanisms are now thought to underlie headache and sleep disturbance during acute exposure to high altitude. Hence, these symptoms may not belong together as a single syndrome. Using a novel visual analogue scale (VAS), we sought to undertake a systematic exploration of the symptomatology of AMS using an unbiased, data-driven approach originally designed for analysis of gene expression. Symptom scores were collected from 292 subjects during 1110 subject days at altitudes between 3650 m and 5200 m on Apex expeditions to Bolivia and Kilimanjaro. Three distinct patterns of symptoms were consistently identified. Although fatigue is a ubiquitous finding, sleep disturbance and headache are each commonly reported without the other. The commonest pattern of symptoms was sleep disturbance and fatigue, with little or no headache. In subjects reporting severe headache, 40% did not report sleep disturbance. Sleep disturbance correlates poorly with other symptoms of AMS (Mean Spearman correlation 0.25). These results challenge the accepted paradigm that AMS is a single disease process and describe at least two distinct syndromes following acute ascent to high altitude. This approach to analysing symptom patterns has potential utility in other clinical syndromes. PMID- 24465371 TI - Antibiotic resistance determinants in a Pseudomonas putida strain isolated from a hospital. AB - Environmental microbes harbor an enormous pool of antibiotic and biocide resistance genes that can impact the resistance profiles of animal and human pathogens via horizontal gene transfer. Pseudomonas putida strains are ubiquitous in soil and water but have been seldom isolated from humans. We have established a collection of P. putida strains isolated from in-patients in different hospitals in France. One of the isolated strains (HB3267) kills insects and is resistant to the majority of the antibiotics used in laboratories and hospitals, including aminoglycosides, beta-lactams, cationic peptides, chromoprotein enediyne antibiotics, dihydrofolate reductase inhibitors, fluoroquinolones and quinolones, glycopeptide antibiotics, macrolides, polyketides and sulfonamides. Similar to other P. putida clinical isolates the strain was sensitive to amikacin. To shed light on the broad pattern of antibiotic resistance, which is rarely found in clinical isolates of this species, the genome of this strain was sequenced and analysed. The study revealed that the determinants of multiple resistance are both chromosomally-borne as well as located on the pPC9 plasmid. Further analysis indicated that pPC9 has recruited antibiotic and biocide resistance genes from environmental microorganisms as well as from opportunistic and true human pathogens. The pPC9 plasmid is not self-transmissible, but can be mobilized by other bacterial plasmids making it capable of spreading antibiotic resistant determinants to new hosts. PMID- 24465372 TI - Role of the plasticity-associated transcription factor zif268 in the early phase of instrumental learning. AB - Gene transcription is essential for learning, but the precise role of transcription factors that control expression of many other genes in specific learning paradigms is yet poorly understood. Zif268 (Krox24/Egr-1) is a transcription factor and an immediate-early gene associated with memory consolidation and reconsolidation, and induced in the striatum after addictive drugs exposure. In contrast, very little is known about its physiological role at early stages of operant learning. We investigated the role of Zif268 in operant conditioning for food. Zif268 expression was increased in all regions of the dorsal striatum and nucleus accumbens in mice subjected to the first session of operant conditioning. In contrast, Zif268 increase in the dorsomedial caudate putamen and nucleus accumbens core was not detected in yoked mice passively receiving the food reward. This indicates that Zif268 induction in these structures is linked to experiencing or learning contingency, but not to reward delivery. When the task was learned (5 sessions), Zif268 induction disappeared in the nucleus accumbens and decreased in the medial caudate-putamen, whereas it remained high in the lateral caudate-putamen, previously implicated in habit formation. In transgenic mice expressing green fluorescent protein (GFP) in the striatonigral neurons, Zif268 induction occured after the first training session in both GFP-positive and negative neurons indicating an enhanced Zif268 expression in both striatonigral and striatopallidal neurons. Mutant mice lacking Zif268 expression obtained less rewards, but displayed a normal discrimination between reinforced and non-reinforced targets, and an unaltered approach to food delivery box. In addition, their motivation to obtain food rewards, evaluated in a progressive ratio schedule, was blunted. In conclusion, Zif268 participates in the processes underlying performance and motivation to execute food-conditioned instrumental task. PMID- 24465373 TI - Arctic lineage-canine distemper virus as a cause of death in Apennine wolves (Canis lupus) in Italy. AB - Canine distemper virus (CDV) infection is a primary threat affecting a wide number of carnivore species, including wild animals. In January 2013, two carcasses of Apennine wolves (Canis lupus) were collected in Ortona dei Marsi (L'Aquila province, Italy) by the local Veterinary Services. CDV was immediately identified either by RT-PCR or immunohistochemistry in lung and central nervous tissue samples. At the same time, severe clinical signs consistent with CDV infection were identified and taped (Videos S1-S3) from three wolves rescued in the areas surrounding the National Parks of the Abruzzi region by the Veterinary Services. The samples collected from these symptomatic animals also turned out CDV positive by RT-PCR. So far, 30 carcasses of wolves were screened and CDV was detected in 20 of them. The sequencing of the haemagglutinin gene and subsequent phylogenetic analysis demonstrated that the identified virus belonged to the CDV Arctic lineage. Strains belonging to this lineage are known to circulate in Italy and in Eastern Europe amongst domestic dogs. To the best of our knowledge this is the first report of CDV Arctic lineage epidemics in the wild population in Europe. PMID- 24465374 TI - Protein disulfide-isomerase interacts with a substrate protein at all stages along its folding pathway. AB - In contrast to molecular chaperones that couple protein folding to ATP hydrolysis, protein disulfide-isomerase (PDI) catalyzes protein folding coupled to formation of disulfide bonds (oxidative folding). However, we do not know how PDI distinguishes folded, partly-folded and unfolded protein substrates. As a model intermediate in an oxidative folding pathway, we prepared a two-disulfide mutant of basic pancreatic trypsin inhibitor (BPTI) and showed by NMR that it is partly-folded and highly dynamic. NMR studies show that it binds to PDI at the same site that binds peptide ligands, with rapid binding and dissociation kinetics; surface plasmon resonance shows its interaction with PDI has a Kd of ca. 10(-5) M. For comparison, we characterized the interactions of PDI with native BPTI and fully-unfolded BPTI. Interestingly, PDI does bind native BPTI, but binding is quantitatively weaker than with partly-folded and unfolded BPTI. Hence PDI recognizes and binds substrates via permanently or transiently unfolded regions. This is the first study of PDI's interaction with a partly-folded protein, and the first to analyze this folding catalyst's changing interactions with substrates along an oxidative folding pathway. We have identified key features that make PDI an effective catalyst of oxidative protein folding - differential affinity, rapid ligand exchange and conformational flexibility. PMID- 24465375 TI - BDNF polymorphisms are linked to poorer working memory performance, reduced cerebellar and hippocampal volumes and differences in prefrontal cortex in a Swedish elderly population. AB - BACKGROUND: Brain-derived neurotrophic factor (BDNF) links learning, memory and cognitive decline in elderly, but evidence linking BDNF allele variation, cognition and brain structural differences is lacking. METHODS: 367 elderly Swedish men (n = 181) and women (n = 186) from Prospective Investigation of the Vasculature in Uppsala seniors (PIVUS) were genotyped and the BDNF functional rs6265 SNP was further examined in subjects who completed the Trail Making Task (TMT), verbal fluency task, and had a magnetic resonance imaging (MRI) scan. Voxel-based morphometry (VBM) examined brain structure, cognition and links with BDNF. RESULTS: The functional BDNF SNP (rs6265,) predicted better working memory performance on the TMT with positive association of the Met rs6265, and was linked with greater cerebellar, precuneus, left superior frontal gyrus and bilateral hippocampal volume, and reduced brainstem and bilateral posterior cingulate volumes. CONCLUSIONS: The functional BDNF polymorphism influences brain volume in regions associated with memory and regulation of sensorimotor control, with the Met rs6265 allele potentially being more beneficial to these functions in the elderly. PMID- 24465376 TI - Climate and the individual: inter-annual variation in the autumnal activity of the European badger (Meles meles). AB - We establish intra-individual and inter-annual variability in European badger (Meles meles) autumnal nightly activity in relation to fine-scale climatic variables, using tri-axial accelerometry. This contributes further to understanding of causality in the established interaction between weather conditions and population dynamics in this species. Modelling found that measures of daylight, rain/humidity, and soil temperature were the most supported predictors of ACTIVITY, in both years studied. In 2010, the drier year, the most supported model included the SOLAR*RH interaction, RAIN, and 30cmTEMP (w = 0.557), while in 2012, a wetter year, the most supported model included the SOLAR*RH interaction, and the RAIN*10cmTEMP (w = 0.999). ACTIVITY also differed significantly between individuals. In the 2012 autumn study period, badgers with the longest per noctem activity subsequently exhibited higher Body Condition Indices (BCI) when recaptured. In contrast, under drier 2010 conditions, badgers in good BCI engaged in less per noctem activity, while badgers with poor BCI were the most active. When compared on the same calendar dates, to control for night length, duration of mean badger nightly activity was longer (9.5 hrs +/-3.3 SE) in 2010 than in 2012 (8.3 hrs +/-1.9 SE). In the wetter year, increasing nightly activity was associated with net-positive energetic gains (from BCI), likely due to better foraging conditions. In a drier year, with greater potential for net negative energy returns, individual nutritional state proved crucial in modifying activity regimes; thus we emphasise how a 'one size fits all' approach should not be applied to ecological responses. PMID- 24465377 TI - Spatial variation in soil properties among North American ecosystems and guidelines for sampling designs. AB - Soils are highly variable at many spatial scales, which makes designing studies to accurately estimate the mean value of soil properties across space challenging. The spatial correlation structure is critical to develop robust sampling strategies (e.g., sample size and sample spacing). Current guidelines for designing studies recommend conducting preliminary investigation(s) to characterize this structure, but are rarely followed and sampling designs are often defined by logistics rather than quantitative considerations. The spatial variability of soils was assessed across ~1 ha at 60 sites. Sites were chosen to represent key US ecosystems as part of a scaling strategy deployed by the National Ecological Observatory Network. We measured soil temperature (Ts) and water content (SWC) because these properties mediate biological/biogeochemical processes below- and above-ground, and quantified spatial variability using semivariograms to estimate spatial correlation. We developed quantitative guidelines to inform sample size and sample spacing for future soil studies, e.g., 20 samples were sufficient to measure Ts to within 10% of the mean with 90% confidence at every temperate and sub-tropical site during the growing season, whereas an order of magnitude more samples were needed to meet this accuracy at some high-latitude sites. SWC was significantly more variable than Ts at most sites, resulting in at least 10* more SWC samples needed to meet the same accuracy requirement. Previous studies investigated the relationship between the mean and variability (i.e., sill) of SWC across space at individual sites across time and have often (but not always) observed the variance or standard deviation peaking at intermediate values of SWC and decreasing at low and high SWC. Finally, we quantified how far apart samples must be spaced to be statistically independent. Semivariance structures from 10 of the 12-dominant soil orders across the US were estimated, advancing our continental-scale understanding of soil behavior. PMID- 24465378 TI - Imaging liver lesions using grating-based phase-contrast computed tomography with bi-lateral filter post-processing. AB - X-ray phase-contrast imaging shows improved soft-tissue contrast compared to standard absorption-based X-ray imaging. Especially the grating-based method seems to be one promising candidate for clinical implementation due to its extendibility to standard laboratory X-ray sources. Therefore the purpose of our study was to evaluate the potential of grating-based phase-contrast computed tomography in combination with a novel bi-lateral denoising method for imaging of focal liver lesions in an ex vivo feasibility study. Our study shows that grating based phase-contrast CT (PCCT) significantly increases the soft-tissue contrast in the ex vivo liver specimens. Combining the information of both signals- absorption and phase-contrast--the bi-lateral filtering leads to an improvement of lesion detectability and higher contrast-to-noise ratios. The normal and the pathological tissue can be clearly delineated and even internal structures of the pathological tissue can be visualized, being invisible in the absorption-based CT alone. Histopathology confirmed the presence of the corresponding findings in the analyzed tissue. The results give strong evidence for a sufficiently high contrast for different liver lesions using non-contrast-enhanced PCCT. Thus, ex vivo imaging of liver lesions is possible with a polychromatic X-ray source and at a spatial resolution of ~100 um. The post-processing with the novel bi-lateral denoising method improves the image quality by combining the information from the absorption and the phase-contrast images. PMID- 24465379 TI - Niches, population structure and genome reduction in Ochrobactrum intermedium: clues to technology-driven emergence of pathogens. AB - Ochrobactrum intermedium is considered as an emerging human environmental opportunistic pathogen with mild virulence. The distribution of isolates and sequences described in literature and databases showed frequent association with human beings and polluted environments. As population structures are related to bacterial lifestyles, we investigated by multi-locus approach the genetic structure of a population of 65 isolates representative of the known natural distribution of O. intermedium. The population was further surveyed for genome dynamics using pulsed-field gel electrophoresis and genomics. The population displayed a clonal epidemic structure with events of recombination that occurred mainly in clonal complexes. Concerning biogeography, clones were shared by human and environments and were both cosmopolitan and local. The main cosmopolitan clone was genetically and genomically stable, and grouped isolates that all harbored an atypical insertion in the rrs. Ubiquitism and stability of this major clone suggested a clonal succes in a particular niche. Events of genomic reduction were detected in the population and the deleted genomic content was described for one isolate. O. intermedium displayed allopatric characters associated to a tendancy of genome reduction suggesting a specialization process. Considering its relatedness with Brucella, this specialization might be a commitment toward pathogenic life-style that could be driven by technological selective pressure related medical and industrial technologies. PMID- 24465380 TI - Whey protein hydrolysate enhances HSP90 but does not alter HSP60 and HSP25 in skeletal muscle of rats. AB - Whey protein hydrolysate (WPH) intake has shown to increase HSP70 expression. The aim of the present study was to investigate whether WPH intake would also influences HSP90, HSP60 and HSP25 expression, as well as associated parameters. Forty-eight male Wistar rats were divided into sedentary (unstressed) and exercised (stressed) groups, and were fed with three different sources of protein: whey protein (WP), whey protein hydrolysate (WPH) and casein (CAS) as a control, based on the AIN93G diet for 3 weeks. WPH intake increased HSP90 expression in both sedentary and exercised animals compared to WP or CAS, however no alteration was found from exercise or diet to HSP60 or HSP25. Co-chaperone Aha1 and p-HSF1 were also increased in the exercised animals fed with WPH in comparison with WP or CAS, consistent with enhanced HSP90 expression. VEGF and p AKT were increased in the WPH exercised group. No alteration was found in BCKDH, PI3-Kinase (p85), GFAT, OGT or PGC for diet or exercise. The antioxidant system GPx, catalase and SOD showed different responses to diet and exercise. The data indicate that WPH intake enhanced factors related to cell survival, such as HSP90 and VEGF, but does not alter HSP60 or HSP25 in rat skeletal muscle. PMID- 24465381 TI - Trade integration and trade imbalances in the European Union: a network perspective. AB - We study the ever more integrated and ever more unbalanced trade relationships between European countries. To better capture the complexity of economic networks, we propose two global measures that assess the trade integration and the trade imbalances of the European countries. These measures are the network (or indirect) counterparts to traditional (or direct) measures such as the trade to-GDP (Gross Domestic Product) and trade deficit-to-GDP ratios. Our indirect tools account for the European inter-country trade structure and follow (i) a decomposition of the global trade flow into elementary flows that highlight the long-range dependencies between exporting and importing economies and (ii) the commute-time distance for trade integration, which measures the impact of a perturbation in the economy of a country on another country, possibly through intermediate partners by domino effect. Our application addresses the impact of the launch of the Euro. We find that the indirect imbalance measures better identify the countries ultimately bearing deficits and surpluses, by neutralizing the impact of trade transit countries, such as the Netherlands. Among others, we find that ultimate surpluses of Germany are quite concentrated in only three partners. We also show that for some countries, the direct and indirect measures of trade integration diverge, thereby revealing that these countries (e.g. Greece and Portugal) trade to a smaller extent with countries considered as central in the European Union network. PMID- 24465382 TI - Synthesis, tribological and hydrolysis stability study of novel benzotriazole borate derivative. AB - Benzotriazole and borate derivatives have long been used as multifunctional additives to lubricants. A novel, environmentally friendly additive borate ester (NHB), which contains boron, ethanolamine, and benzotriazole groups in one molecule, was synthesized by a multi-step reaction, and its tribological properties in rapeseed oil (RSO) were investigated by a four-ball tribometer. The hydrolysis stability of the additive was investigated by half-time and open observation methods, and the mechanism of hydrolysis stability was discussed through Gaussian calculation. The novel compound NHB showed excellent performance under extreme pressure, against wearing, and in reducing friction, and its hydrolysis time is more than 1,220 times, which is better than that of triethyl borate. The mass ratio of NHB is bigger than that of the mixed liquid of triethyl borate and ethanolamine. The lone electron of amino N atoms forms a coordination effect with the B atom to compensate for the shortage of electrons in the B atom and to improve the hydrolysis stability of NHB. The surface morphology and the traces of different elements in the tribofilms formed with 1.0 wt.% NHB in were detected with scanning electron microscopy(SEM), energy dispersive X-ray spectroscopy (EDX)and X-ray photoelectron spectroscopy(XPS). The results shown that the additive caused a tribochemical reaction with the steel ball surface during the lubricating process. A mixed boundary lubrication film that contains organic nitrogen and inorganic salts, such as BN, B2O3, FeOx, Fe-O-B, and FeB, was also formed, and the formation of the lubricating film improved the tribological properties of the base oil. PMID- 24465384 TI - Equations for lipid normalization of carbon stable isotope ratios in aquatic bird eggs. AB - Stable isotope ratios are biogeochemical tracers that can be used to determine the source of nutrients and contaminants in avian eggs. However, the interpretation of stable carbon ratios in lipid-rich eggs is complicated because (13)C is depleted in lipids. Variation in (13)C abundance can therefore be obscured by variation in percent lipids. Past attempts to establish an algebraic equation to correct carbon isotope ratios for lipid content in eggs have been unsuccessful, possibly because they relied partly on data from coastal or migratory species that may obtain egg lipids from different habitats than egg protein. We measured carbon, nitrogen and sulphur stable isotope ratios in 175 eggs from eight species of aquatic birds. Carbon, nitrogen and sulphur isotopes were enriched in lipid-extracted egg samples compared with non extracted egg samples. A logarithmic equation using the C?N ratio and carbon isotope ratio from the non extracted egg tissue calculated 90% of the lipid-extracted carbon isotope ratios within +/-0.50/00. Calculating separate equations for eggs laid by species in different habitats (pelagic, offshore and terrestrial-influenced) improved the fit. A logarithmic equation, rather than a linear equation as often used for muscle, was necessary to accurately correct for lipid content because the relatively high lipid content of eggs compared with muscle meant that a linear relationship did not accurately approximate the relationship between percent lipids and the C?N ratio. Because lipid extraction alters sulphur and nitrogen isotope ratios (and cannot be corrected algebraically), we suggest that isotopic measurement on bulk tissue followed by algebraic lipid normalization of carbon stable isotope ratio is often a good solution for homogenated eggs, at least when it is not possible to complete separate chemical analyses for each isotope. PMID- 24465383 TI - Involvement of suppressive B-lymphocytes in the mechanism of tolerogenic dendritic cell reversal of type 1 diabetes in NOD mice. AB - The objective of the study was to identify immune cell populations, in addition to Foxp3+ T-regulatory cells, that participate in the mechanisms of action of tolerogenic dendritic cells shown to prevent and reverse type 1 diabetes in the Non-Obese Diabetic (NOD) mouse strain. Co-culture experiments using tolerogenic dendritic cells and B-cells from NOD as well as transgenic interleukin-10 promoter-reporter mice along with transfer of tolerogenic dendritic cells and CD19+ B-cells into NOD and transgenic mice, showed that these dendritic cells increased the frequency and numbers of interleukin-10-expressing B-cells in vitro and in vivo. The expansion of these cells was a consequence of both the proliferation of pre-existing interleukin-10-expressing B-lymphocytes and the conversion of CD19+ B-lymphcytes into interleukin-10-expressing cells. The tolerogenic dendritic cells did not affect the suppressive activity of these B cells. Furthermore, we discovered that the suppressive murine B-lymphocytes expressed receptors for retinoic acid which is produced by the tolerogenic dendritic cells. These data assist in identifying the nature of the B-cell population increased in response to the tolerogenic dendritic cells in a clinical trial and also validate very recent findings demonstrating a mechanistic link between human tolerogenic dendritic cells and immunosuppressive regulatory B cells. PMID- 24465385 TI - Genome-wide DNA methylation profiling in cultured eutopic and ectopic endometrial stromal cells. AB - The objective of this study was to characterize the genome-wide DNA methylation profiles of isolated endometrial stromal cells obtained from eutopic endometria with (euESCa) and without endometriosis (euESCb) and ovarian endometrial cysts (choESC). Three samples were analyzed in each group. The infinium methylation array identified more hypermethylated and hypomethylated CpGs in choESC than in euESCa, and only a few genes were methylated differently in euESCa and euESCb. A functional analysis revealed that signal transduction, developmental processes, immunity, etc. were different in choESC and euESCa. A clustering analysis and a principal component analysis performed based on the methylation levels segregated choESC from euESC, while euESCa and euESCb were identical. A transcriptome analysis was then conducted and the results were compared with those of the DNA methylation analysis. Interestingly, the hierarchical clustering and principal component analyses showed that choESC were segregated from euESCa and euESCb in the DNA methylation analysis, while no segregation was recognized in the transcriptome analysis. The mRNA expression levels of the epigenetic modification enzymes, including DNA methyltransferases, obtained from the specimens were not significantly different between the groups. Some of the differentially methylated and/or expressed genes (NR5A1, STAR, STRA6 and HSD17B2), which are related with steroidogenesis, were validated by independent methods in a larger number of samples. Our findings indicate that different DNA methylation profiles exist in ectopic ESC, highlighting the benefits of genome wide DNA methylation analyses over transcriptome analyses in clarifying the development and characterization of endometriosis. PMID- 24465386 TI - A new species of river dolphin from Brazil or: how little do we know our biodiversity. AB - True river dolphins are some of the rarest and most endangered of all vertebrates. They comprise relict evolutionary lineages of high taxonomic distinctness and conservation value, but are afforded little protection. We report the discovery of a new species of a river dolphin from the Araguaia River basin of Brazil, the first such discovery in nearly 100 years. The species is diagnosable by a series of molecular and morphological characters and diverged from its Amazonian sister taxon 2.08 million years ago. The estimated time of divergence corresponds to the separation of the Araguaia-Tocantins basin from the Amazon basin. This discovery highlights the immensity of the deficit in our knowledge of Neotropical biodiversity, as well as vulnerability of biodiversity to anthropogenic actions in an increasingly threatened landscape. We anticipate that this study will provide an impetus for the taxonomic and conservation reanalysis of other taxa shared between the Araguaia and Amazon aquatic ecosystems, as well as stimulate historical biogeographical analyses of the two basins. PMID- 24465387 TI - Economic evaluation of brief psychodynamic interpersonal therapy in patients with multisomatoform disorder. AB - BACKGROUND: A brief psychodynamic interpersonal therapy (PIT) in patients with multisomatoform disorder has been recently shown to improve health-related quality of life. AIMS: To assess cost-effectiveness of PIT compared to enhanced medical care in patients with multisomatoform disorder. METHOD: An economic evaluation alongside a randomised controlled trial (International Standard Randomised Controlled Trial Number ISRCTN23215121) conducted in 6 German academic outpatient centres was performed. Incremental cost-effectiveness ratio (ICER) was calculated from the statutory health insurance perspective on the basis of quality adjusted life years (QALYs) gained at 12 months. Uncertainty surrounding the cost-effectiveness of PIT was presented by means of a cost-effectiveness acceptability curve. RESULTS: Based on the complete-case analysis ICER was 41840 Euro per QALY. The results did not change greatly with the use of multiple imputation (ICER = 44222) and last observation carried forward (LOCF) approach to missing data (ICER = 46663). The probability of PIT being cost-effective exceeded 50% for thresholds of willingness to pay over 35 thousand Euros per QALY. CONCLUSIONS: Cost-effectiveness of PIT is highly uncertain for thresholds of willingness to pay under 35 thousand Euros per QALY. PMID- 24465388 TI - MHD boundary layer slip flow and heat transfer of ferrofluid along a stretching cylinder with prescribed heat flux. AB - This study investigates the magnetohydrodynamic (MHD) flow of ferrofluid along a stretching cylinder. The velocity slip and prescribed surface heat flux boundary conditions are employed on the cylinder surface. Water as conventional base fluid containing nanoparticles of magnetite (Fe3O4) is used. Comparison between magnetic (Fe3O4) and non-magnetic (Al2O3) nanoparticles is also made. The governing non-linear partial differential equations are reduced to non-linear ordinary differential equations and then solved numerically using shooting method. Present results are compared with the available data in the limiting cases. The present results are found to be in an excellent agreement. It is observed that with an increase in the magnetic field strength, the percent difference in the heat transfer rate of magnetic nanoparticles with Al2O3 decreases. Surface shear stress and the heat transfer rate at the surface increase as the curvature parameter increases, i.e curvature helps to enhance the heat transfer. PMID- 24465389 TI - Does assessment type matter? A measurement invariance analysis of online and paper and pencil assessment of the Community Assessment of Psychic Experiences (CAPE). AB - BACKGROUND: The psychometric properties of an online test are not necessarily identical to its paper and pencil original. The aim of this study is to test whether the factor structure of the Community Assessment of Psychic Experiences (CAPE) is measurement invariant with respect to online vs. paper and pencil assessment. METHOD: The factor structure of CAPE items assessed by paper and pencil (N = 796) was compared with the factor structure of CAPE items assessed by the Internet (N = 21,590) using formal tests for Measurement Invariance (MI). The effect size was calculated by estimating the Signed Item Difference in the Sample (SIDS) index and the Signed Test Difference in the Sample (STDS) for a hypothetical subject who scores 2 standard deviations above average on the latent dimensions. RESULTS: The more restricted Metric Invariance model showed a significantly worse fit compared to the less restricted Configural Invariance model (chi(2)(23) = 152.75, p<0.001). However, the SIDS indices appear to be small, with an average of -0.11. A STDS of -4.80 indicates that Internet sample members who score 2 standard deviations above average would be expected to score 4.80 points lower on the CAPE total scale (ranging from 42 to 114 points) than would members of the Paper sample with the same latent trait score. CONCLUSIONS: Our findings did not support measurement invariance with respect to assessment method. Because of the small effect sizes, the measurement differences between the online assessed CAPE and its paper and pencil original can be neglected without major consequences for research purposes. However, a person with a high vulnerability for psychotic symptoms would score 4.80 points lower on the total scale if the CAPE is assessed online compared to paper and pencil assessment. Therefore, for clinical purposes, one should be cautious with online assessment of the CAPE. PMID- 24465390 TI - Expression and functional characterization of membrane-integrated mammalian corticotropin releasing factor receptors 1 and 2 in Escherichia coli. AB - Corticotropin-Releasing Factor Receptors (CRFRs) are class B1 G-protein-coupled receptors, which bind peptides of the corticotropin releasing factor family and are key mediators in the stress response. In order to dissect the receptors' binding specificity and enable structural studies, full-length human CRFR1alpha and mouse CRFR2beta as well as fragments lacking the N-terminal extracellular domain, were overproduced in E. coli. The characteristics of different CRFR2beta PhoA gene fusion products expressed in bacteria were found to be in agreement with the predicted ones in the hepta-helical membrane topology model. Recombinant histidine-tagged CRFR1alpha and CRFR2beta expression levels and bacterial subcellular localization were evaluated by cell fractionation and Western blot analysis. Protein expression parameters were assessed, including the influence of E. coli bacterial hosts, culture media and the impact of either PelB or DsbA signal peptide. In general, the large majority of receptor proteins became inserted in the bacterial membrane. Across all experimental conditions significantly more CRFR2beta product was obtained in comparison to CRFR1alpha. Following a detergent screen analysis, bacterial membranes containing CRFR1alpha and CRFR2beta were best solubilized with the zwitterionic detergent FC-14. Binding of different peptide ligands to CRFR1alpha and CRFR2beta membrane fractions were similar, in part, to the complex pharmacology observed in eukaryotic cells. We suggest that our E. coli expression system producing functional CRFRs will be useful for large-scale expression of these receptors for structural studies. PMID- 24465391 TI - Temporal features of spike trains in the moth antennal lobe revealed by a comparative time-frequency analysis. AB - The discrimination of complex sensory stimuli in a noisy environment is an immense computational task. Sensory systems often encode stimulus features in a spatiotemporal fashion through the complex firing patterns of individual neurons. To identify these temporal features, we have developed an analysis that allows the comparison of statistically significant features of spike trains localized over multiple scales of time-frequency resolution. Our approach provides an original way to utilize the discrete wavelet transform to process instantaneous rate functions derived from spike trains, and select relevant wavelet coefficients through statistical analysis. Our method uncovered localized features within olfactory projection neuron (PN) responses in the moth antennal lobe coding for the presence of an odor mixture and the concentration of single component odorants, but not for compound identities. We found that odor mixtures evoked earlier responses in biphasic response type PNs compared to single components, which led to differences in the instantaneous firing rate functions with their signal power spread across multiple frequency bands (ranging from 0 to 45.71 Hz) during a time window immediately preceding behavioral response latencies observed in insects. Odor concentrations were coded in excited response type PNs both in low frequency band differences (2.86 to 5.71 Hz) during the stimulus and in the odor trace after stimulus offset in low (0 to 2.86 Hz) and high (22.86 to 45.71 Hz) frequency bands. These high frequency differences in both types of PNs could have particular relevance for recruiting cellular activity in higher brain centers such as mushroom body Kenyon cells. In contrast, neurons in the specialized pheromone-responsive area of the moth antennal lobe exhibited few stimulus-dependent differences in temporal response features. These results provide interesting insights on early insect olfactory processing and introduce a novel comparative approach for spike train analysis applicable to a variety of neuronal data sets. PMID- 24465392 TI - Induction of endoplasmic reticulum-derived replication-competent membrane structures by West Nile virus non-structural protein 4B. AB - Replication of flaviviruses (family Flaviviridae) occurs in specialized virus induced membrane structures (IMS). The cellular composition of these IMS varies for different flaviviruses implying different organelle origins for IMS biogenesis. The role of flavivirus non-structural (NS) proteins for the alteration of IMS remains controversial. In this report, we demonstrate that West Nile virus strain New York 99 (WNVNY99) remodels the endoplasmic reticulum (ER) membrane to generate specialized IMS. Within these structures, we observed an element of the cis-Golgi, viral double-stranded RNA, and viral-envelope, NS1, NS4A and NS4B proteins using confocal immunofluorescence microscopy. Biochemical analysis and microscopy revealed that NS4B lacking the 2K-signal peptide associates with the ER membrane where it initiates IMS formation in WNV-infected cells. Co-transfection studies indicated that NS4A and NS4B always remain co localized in the IMS and are associated with the same membrane fractions, suggesting that these proteins function cooperatively in virus replication and may be an ideal target for antiviral drug discovery. PMID- 24465393 TI - Molecular and cellular features of murine craniofacial and trunk neural crest cells as stem cell-like cells. AB - The outstanding differentiation capacities and easier access from adult tissues, cells derived from neural crest cells (NCCs) have fascinated scientists in developmental biology and regenerative medicine. Differentiation potentials of NCCs are known to depend on their originating regions. Here, we report differential molecular features between craniofacial (cNCCs) and trunk (tNCCs) NCCs by analyzing transcription profiles and sphere forming assays of NCCs from P0-Cre/floxed-EGFP mouse embryos. We identified up-regulation of genes linked to carcinogenesis in cNCCs that were not previously reported to be related to NCCs, which was considered to be, an interesting feature in regard with carcinogenic potentials of NCCs such as melanoma and neuroblastoma. Wnt signal related genes were statistically up-regulated in cNCCs, also suggesting potential involvement of cNCCs in carcinogenesis. We also noticed intense expression of mesenchymal and neuronal markers in cNCCs and tNCCs, respectively. Consistent results were obtained from in vitro sphere-forming and differentiation assays. These results were in accordance with previous notion about differential potentials of cNCCs and tNCCs. We thus propose that sorting NCCs from P0-Cre/floxed-EGFP mice might be useful for the basic and translational research of NCCs. Furthermore, these newly-identified genes up-regulated in cNCC would provide helpful information on NC-originating tumors, developmental disorders in NCC derivatives, and potential applications of NCCs in regenerative medicine. PMID- 24465394 TI - Discovery of a novel target for the dysglycemic chromogranin A fragment pancreastatin: interaction with the chaperone GRP78 to influence metabolism. AB - RATIONALE: The chromogranin A-derived peptide pancreastatin (PST) is a dysglycemic, counter-regulatory peptide for insulin action, especially in liver. Although previous evidence for a PST binding protein has been reported, such a receptor has not been identified or sequenced. METHODS AND RESULTS: We used ligand affinity to purify the PST target, with biotinylated human PST (hCHGA273 301-amide) as "bait" and mouse liver homogenate as "prey", and identified GRP78 (a.k.a. "78 kDa Glucose Regulated Protein", HSPA5, BIP) as a major interacting partner of PST. GRP78 belongs to the family of heat shock proteins (chaperones), involved in several cellular processes including protein folding and glucose metabolism. We analyzed expression of GRP78 in the absence of PST in a mouse knockout model lacking its precursor CHGA: hepatic transcriptome data revealed global over-expression of not only GRP78 but also other heat shock transcripts (of the "adaptive UPR") in CHGA(-/-) mice compared to wild-type (+/+). By contrast, we found a global decline in expression of hepatic pro-apoptotic transcripts in CHGA(-/-) mice. GRP78's ATPase enzymatic activity was dose dependently inhibited by PST (IC50~5.2 uM). PST also inhibited the up-regulation of GRP78 expression during UPR activation (by tunicamycin) in hepatocytes. PST inhibited insulin-stimulated glucose uptake in adipocytes, and increased hepatic expression of G6Pase (the final step in gluconeogenesis/glycogenolysis). In hepatocytes not only PST but also other GRP78-ATPase inhibitors (VER-155008 or ADP) increased G6Pase expression. GRP78 over-expression inhibited G6Pase expression in hepatocytes, with partial restoration by GRP78-ATPase inhibitors PST, VER-155008, or ADP. CONCLUSIONS: Our results indicate that an unexpected major hepatic target of PST is the adaptive UPR chaperone GRP78. PST not only binds to GRP78 (in pH-dependent fashion), but also inhibits GRP78's ATPase enzymatic activity, and impairs its biosynthetic response to UPR activation. PST decreases insulin-stimulated cellular glucose uptake, and PST as well as other chaperone ATPase activity inhibitors augment expression of G6Pase; GRP78 over expression antagonizes this PST action. Analysis of the novel PST/GRP78 interaction may provide a new avenue of investigation into cellular glycemic control as well as dysglycemia. PMID- 24465395 TI - Epigenetic reprogramming in Mist1(-/-) mice predicts the molecular response to cerulein-induced pancreatitis. AB - Gene expression is affected by modifications to histone core proteins within chromatin. Changes in these modifications, or epigenetic reprogramming, can dictate cell fate and promote susceptibility to disease. The goal of this study was to determine the extent of epigenetic reprogramming in response to chronic stress that occurs following ablation of MIST1 (Mist1(-/-) ), which is repressed in pancreatic disease. Chromatin immunoprecipitation for trimethylation of lysine residue 4 on histone 3 (H3K4Me3) in purified acinar cells from wild type and Mist1(-/-) mice was followed by Next Generation sequencing (ChIP-seq) or ChIP qPCR. H3K4Me3-enriched genes were assessed for expression by qRT-PCR in pancreatic tissue before and after induction of cerulein-induced pancreatitis. While most of H3K4Me3-enrichment is restricted to transcriptional start sites, >25% of enrichment sites are found within, downstream or between annotated genes. Less than 10% of these sites were altered in Mist1(-/-) acini, with most changes in H3K4Me3 enrichment not reflecting altered gene expression. Ingenuity Pathway Analysis of genes differentially-enriched for H3K4Me3 revealed an association with pancreatitis and pancreatic ductal adenocarcinoma in Mist1(-/-) tissue. Most of these genes were not differentially expressed but several were readily induced by acute experimental pancreatitis, with significantly increased expression in Mist1(-/-) tissue relative to wild type mice. We suggest that the chronic cell stress observed in the absence of MIST1 results in epigenetic reprogramming of genes involved in promoting pancreatitis to a poised state, thereby increasing the sensitivity to events that promote disease. PMID- 24465396 TI - Genome wide expression profiling during spinal cord regeneration identifies comprehensive cellular responses in zebrafish. AB - BACKGROUND: Among the vertebrates, teleost and urodele amphibians are capable of regenerating their central nervous system. We have used zebrafish as a model to study spinal cord injury and regeneration. Relatively little is known about the molecular mechanisms underlying spinal cord regeneration and information based on high density oligonucleotide microarray was not available. We have used a high density microarray to profile the temporal transcriptome dynamics during the entire phenomenon. RESULTS: A total of 3842 genes expressed differentially with significant fold changes during spinal cord regeneration. Cluster analysis revealed event specific dynamic expression of genes related to inflammation, cell death, cell migration, cell proliferation, neurogenesis, neural patterning and axonal regrowth. Spatio-temporal analysis of stat3 expression suggested its possible function in controlling inflammation and cell proliferation. Genes involved in neurogenesis and their dorso-ventral patterning (sox2 and dbx2) are differentially expressed. Injury induced cell proliferation is controlled by many cell cycle regulators and some are commonly expressed in regenerating fin, heart and retina. Expression pattern of certain pathway genes are identified for the first time during regeneration of spinal cord. Several genes involved in PNS regeneration in mammals like stat3, socs3, atf3, mmp9 and sox11 are upregulated in zebrafish SCI thus creating PNS like environment after injury. CONCLUSION: Our study provides a comprehensive genetic blue print of diverse cellular response(s) during regeneration of zebrafish spinal cord. The data highlights the importance of different event specific gene expression that could be better understood and manipulated further to induce successful regeneration in mammals. PMID- 24465397 TI - Overactivation of intestinal SREBP2 in mice increases serum cholesterol. AB - Sterol Response Element Binding Protein 2 (SREBP2) transcription factor is a master regulator of cholesterol homeostasis. Treatment with statins, inhibitors of cholesterol synthesis, activates intestinal SREBP2, which may hinder their cholesterol-lowering effects. Overactivation of SREBP2 in mouse liver was shown to have no effect on plasma cholesterol. However, the influence of activating intestinal SREBP2 on plasma cholesterol is not known. We have generated a novel transgenic mouse model with intestine specific overexpression of active SREBP2 (ISR2) driven by villin promoter. ISR2 mice showed overexpression of active SREBP2 specifically in the intestine. Microarray analysis of jejunal RNA from ISR2 mice showed a significant increase in genes involved in fatty acid and cholesterol synthesis. Cholesterol and triglyceride (TG) in jejunum and liver (mg/g protein) were significantly increased in ISR2 vs wild type mice. Serum Cholesterol was significantly increased in VLDL and LDL fractions whereas the level of serum triglycerides was decreased in ISR2 vs wild type mice. In conclusion, activation of intestinal SREBP2 alone seems to be sufficient to increase plasma cholesterol, highlighting the essential role of intestine in maintaining cholesterol homeostasis in the body. PMID- 24465398 TI - Electroretinogram monitoring of dose-dependent toxicity after ophthalmic artery chemosurgery in retinoblastoma eyes: six year review. AB - PURPOSE: To report electroretinogram responses of retinoblastoma children under anesthesia before and after treatment with chemotherapeutic drugs (melphalan, topotecan, carboplatin) delivery by ophthalmic artery chemosurgery (OAC). METHODS: A cohort study of 81 patients with retinoblastoma treated with OAC. All patients treated with OAC at our center through May 2012 for whom the requisite ERG data were available are included in the analysis. This study recorded the ERG 30 Hz flicker amplitude response changes from baseline, at 3 and 12 months following OAC treatment completion. Both univariate and multivariate linear regression models were evaluated, with generalized estimating equations to correct for correlations within patients. Independent numerical variables included maximum doses and cumulative doses of melphalan, topotecan and carboplatin. RESULTS: By univariate analysis, both melphalan and topotecan appear to be associated with changes in ERG amplitude at both 3 and 12 months; but for the most part, these changes are minimal and likely clinically insignificant. By multivariate analysis, maximum and cumulative melphalan have a modest, temporary effect on the ERG amplitude change, which is apparent at 3 months but no longer evident at 12 months after completing treatment. By multivariate analysis, topotecan and carboplatin do not appear to adversely effect the change in ERG response. CONCLUSION: Melphalan has the strongest, and carboplatin the weakest association with reduction in ERG response amplitudes; but for the most part, these changes are minimal and likely clinically insignificant. These conclusions apply only over the dose ranges used here, and should be applied with caution. PMID- 24465399 TI - Global dormancy of metastases due to systemic inhibition of angiogenesis. AB - Autopsy studies of adults dying of non-cancer causes have shown that virtually all of us possess occult, cancerous lesions. This suggests that, for most individuals, cancer will become dormant and not progress, while only in some will it become symptomatic disease. Meanwhile, it was recently shown in animal models that a tumor can produce both stimulators and inhibitors of its own blood supply. To explain the autopsy findings in light of the preclinical research data, we propose a mathematical model of cancer development at the organism scale describing a growing population of metastases, which, together with the primary tumor, can exert a progressively greater level of systemic angiogenesis inhibitory influence that eventually overcomes local angiogenesis stimulation to suppress the growth of all lesions. As a departure from modeling efforts to date, we look not just at signaling from and effects on the primary tumor, but integrate over this increasingly negative global signaling from all sources to track the development of total tumor burden. This in silico study of the dynamics of the tumor/metastasis system identifies ranges of parameter values where mutual angio-inhibitory interactions within a population of tumor lesions could yield global dormancy, i.e., an organism-level homeostatic steady state in total tumor burden. Given that mortality arises most often from metastatic disease rather than growth of the primary per se, this finding may have important therapeutic implications. PMID- 24465400 TI - Risk factors for repetition of self-harm: a systematic review of prospective hospital-based studies. AB - BACKGROUND: Self-harm entails high costs to individuals and society in terms of suicide risk, morbidity and healthcare expenditure. Repetition of self-harm confers yet higher risk of suicide and risk assessment of self-harm patients forms a key component of the health care management of self-harm patients. To date, there has been no systematic review published which synthesises the extensive evidence on risk factors for repetition. OBJECTIVE: This review is intended to identify risk factors for prospective repetition of self-harm after an index self-harm presentation, irrespective of suicidal intent. DATA SOURCES: PubMed, PsychInfo and Scirus were used to search for relevant publications. We included cohort studies which examining factors associated with prospective repetition among those presenting with self-harm to emergency departments. Journal articles, abstracts, letters and theses in any language published up to June 2012 were considered. Studies were quality-assessed and synthesised in narrative form. RESULTS: A total of 129 studies, including 329,001 participants, met our inclusion criteria. Some factors were studied extensively and were found to have a consistent association with repetition. These included previous self harm, personality disorder, hopelessness, history of psychiatric treatment, schizophrenia, alcohol abuse/dependence, drug abuse/dependence, and living alone. However, the sensitivity values of these measures varied greatly across studies. Psychological risk factors and protective factors have been relatively under researched but show emerging associations with repetition. Composite risk scales tended to have high sensitivity but poor specificity. CONCLUSIONS: Many risk factors for repetition of self-harm match risk factors for initiation of self harm, but the most consistent evidence for increased risk of repetition comes from long-standing psychosocial vulnerabilities, rather than characteristics of an index episode. The current review will enhance prediction of self-harm and assist in the efficient allocation of intervention resources. PMID- 24465401 TI - A glycosaminoglycan based, modular tissue scaffold system for rapid assembly of perfusable, high cell density, engineered tissues. AB - The limited ability to vascularize and perfuse thick, cell-laden tissue constructs has hindered efforts to engineer complex tissues and organs, including liver, heart and kidney. The emerging field of modular tissue engineering aims to address this limitation by fabricating constructs from the bottom up, with the objective of recreating native tissue architecture and promoting extensive vascularization. In this paper, we report the elements of a simple yet efficient method for fabricating vascularized tissue constructs by fusing biodegradable microcapsules with tunable interior environments. Parenchymal cells of various types, (i.e. trophoblasts, vascular smooth muscle cells, hepatocytes) were suspended in glycosaminoglycan (GAG) solutions (4%/1.5% chondroitin sulfate/carboxymethyl cellulose, or 1.5 wt% hyaluronan) and encapsulated by forming chitosan-GAG polyelectrolyte complex membranes around droplets of the cell suspension. The interior capsule environment could be further tuned by blending collagen with or suspending microcarriers in the GAG solution These capsule modules were seeded externally with vascular endothelial cells (VEC), and subsequently fused into tissue constructs possessing VEC-lined, inter-capsule channels. The microcapsules supported high density growth achieving clinically significant cell densities. Fusion of the endothelialized, capsules generated three dimensional constructs with an embedded network of interconnected channels that enabled long-term perfusion culture of the construct. A prototype, engineered liver tissue, formed by fusion of hepatocyte-containing capsules exhibited urea synthesis rates and albumin synthesis rates comparable to standard collagen sandwich hepatocyte cultures. The capsule based, modular approach described here has the potential to allow rapid assembly of tissue constructs with clinically significant cell densities, uniform cell distribution, and endothelialized, perfusable channels. PMID- 24465402 TI - Texting and walking: strategies for postural control and implications for safety. AB - There are concerns about the safety of texting while walking. Although evidence of negative effects of mobile phone use on gait is scarce, cognitive distraction, altered mechanical demands, and the reduced visual field associated with texting are likely to have an impact. In 26 healthy individuals we examined the effect of mobile phone use on gait. Individuals walked at a comfortable pace in a straight line over a distance of ~8.5 m while; 1) walking without the use of a phone, 2) reading text on a mobile phone, or 3) typing text on a mobile phone. Gait performance was evaluated using a three-dimensional movement analysis system. In comparison with normal waking, when participants read or wrote text messages they walked with: greater absolute lateral foot position from one stride to the next; slower speed; greater rotation range of motion (ROM) of the head with respect to global space; the head held in a flexed position; more in-phase motion of the thorax and head in all planes, less motion between thorax and head (neck ROM); and more tightly organized coordination in lateral flexion and rotation directions. While writing text, participants walked slower, deviated more from a straight line and used less neck ROM than reading text. Although the arms and head moved with the thorax to reduce relative motion of the phone and facilitate reading and texting, movement of the head in global space increased and this could negatively impact the balance system. Texting, and to a lesser extent reading, modify gait performance. Texting or reading on a mobile phone may pose an additional risk to safety for pedestrians navigating obstacles or crossing the road. PMID- 24465403 TI - MET genetic abnormalities unreliable for patient selection for therapeutic intervention in oropharyngeal squamous cell carcinoma. AB - BACKGROUND: Identification of MET genetic alteration, mutation, or amplification in oropharyngeal squamous cell carcinoma (OPSCC) could lead to development of MET selective kinase inhibitors. The aim of this study was to assess the frequency and prognostic value of MET gene mutation, amplification, and protein expression in primary OPSCC. METHODS: A retrospective chart review was conducted of patients treated for single primary OPSCC between January 2007 and December 2009. Pre treatment OPSCC tissue samples were analyzed for MET mutations, gene amplification, and overexpression using Sanger sequencing, FISH analysis, and immunohistochemistry respectively. Univariate and multivariate analyses were used to analyze correlations between molecular abnormalities and patient survival. RESULTS: 143 patients were included in this study. Six cases (4%) were identified that had a genetic variation, but previously described mutations such as p.Tyr1235Asp (Y1235D) or p.Tyr1230Cys (Y1230C) were not detected. There were 15 high polysomy cases, and only 3 cases met the criteria for true MET amplification, with >=10% amplified cells per case. Immunohistochemistry evaluation showed 43% of cases were c-MET negative and in 57% c-MET was observed at the tumor cell level. Multivariate analysis showed no significant association between MET mutation, amplification, or expression and survival. CONCLUSIONS: Our study shows a low frequency of MET mutations and amplification in this cohort of OPSCC. There was no significant correlation between MET mutations, amplification, or expression and patient survival. These results suggest that patient selection based on these MET genetic abnormalities may not be a reliable strategy for therapeutic intervention in OPSCC. PMID- 24465404 TI - Qualitative meta-synthesis of user experience of computerised therapy for depression and anxiety. AB - OBJECTIVE: Computerised therapies play an integral role in efforts to improve access to psychological treatment for patients with depression and anxiety. However, despite recognised problems with uptake, there has been a lack of investigation into the barriers and facilitators of engagement. We aimed to systematically review and synthesise findings from qualitative studies of computerised therapies, in order to identify factors impacting on engagement. METHOD: Systematic review and meta-synthesis of qualitative studies of user experiences of computer delivered therapy for depression and/or anxiety. RESULTS: 8 studies were included in the review. All except one were of desktop based cognitive behavioural treatments. Black and minority ethnic and older participants were underrepresented, and only one study addressed users with a co morbid physical health problem. Through synthesis, we identified two key overarching concepts, regarding the need for treatments to be sensitive to the individual, and the dialectal nature of user experience, with different degrees of support and anonymity experienced as both positive and negative. We propose that these factors can be conceptually understood as the 'non-specific' or 'common' factors of computerised therapy, analogous to but distinct from the common factors of traditional face-to-face therapies. CONCLUSION: Experience of computerised therapy could be improved through personalisation and sensitisation of content to individual users, recognising the need for users to experience a sense of 'self' in the treatment which is currently absent. Exploiting the common factors of computerised therapy, through enhancing perceived connection and collaboration, could offer a way of reconciling tensions due to the dialectal nature of user experience. Future research should explore whether the findings are generalisable to other patient groups, to other delivery formats (such as mobile technology) and other treatment modalities beyond cognitive behaviour therapy. The proposed model could aid the development of enhancements to current packages to improve uptake and support engagement. PMID- 24465405 TI - Phylogenetic and biological significance of evolutionary elements from metazoan mitochondrial genomes. AB - The evolutionary history of living species is usually inferred through the phylogenetic analysis of molecular and morphological information using various mathematical models. New challenges in phylogenetic analysis are centered mostly on the search for accurate and efficient methods to handle the huge amounts of sequence data generated from newer genome sequencing. The next major challenge is the determination of relationships between the evolution of structural elements and their functional implementation, which is largely ignored in previous analyses. Here, we described the discovery of structural elements in metazoan mitochondrial genomes, termed key K-strings, that can serve as a basis for phylogenetic tree construction. Although comprising only a small fraction (0.73%) of all K-strings, these key K-strings are pivotal to the tree construction because they allow for a significant reduction in the computational time required to construct phylogenetic trees, and more importantly, they make significant improvement to the results of phylogenetic inference. The trees constructed from the key K-strings were consistent overall to our current view of metazoan phylogeny and exhibited a more rational topology than the trees constructed by using other conventional methods. Surprisingly, the key K-strings tended to accumulate in the conserved regions of the original sequences, which were most likely due to strong selection pressure. Furthermore, the special structural features of the key K-strings should have some potential applications in the study of the structures and functions relationship of proteins and in the determination of evolutionary trajectory of species. The novelty and potential importance of key K-strings lead us to believe that they are essential evolutionary elements. As such, they may play important roles in the process of species evolution and their physical existence. Further studies could lead to discoveries regarding the relationship between evolution and processes of speciation. PMID- 24465407 TI - Relationship between aldosterone and the metabolic syndrome in patients with obstructive sleep apnea hypopnea syndrome: effect of continuous positive airway pressure treatment. AB - BACKGROUND: Metabolic syndrome (MS) occurs frequently in patients with obstructive sleep apnea-hypopnea syndrome (OSAHS). We hypothesized that aldosterone levels are elevated in OSAHS and associated with the presence of MS. METHODS: We studied 66 patients with OSAHS (33 with MS and 33 without MS) and 35 controls. The occurrence of the MS was analyzed according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) clinical criteria. Measurements of plasma renin activity (PRA), aldosterone, aldosterone:PRA ratio, creatinine, glucose, triglycerides, cholesterol and HDL cholesterol were obtained at baseline and after CPAP treatment. RESULTS: Aldosterone levels were associated with the severity of OSAHS and higher than controls (p = 0.046). Significant differences in aldosterone levels were detected between OSAHS patients with and without MS (p = 0.041). A significant reduction was observed in the aldosterone levels in patients under CPAP treatment (p = 0.012). CONCLUSION: This study shows that aldosterone levels are elevated in OSAHS in comparison to controls, and that CPAP therapy reduces aldosterone levels. It also shows that aldosterone levels are associated with the presence of metabolic syndrome, suggesting that aldosterone excess might predispose or aggravate the metabolic and cardiovascular complications of OSAHS. TRIAL REGISTRATION: The study is not a randomized controlled trial and was not registered. PMID- 24465406 TI - Nitrous oxide production in sputum from cystic fibrosis patients with chronic Pseudomonas aeruginosa lung infection. AB - Chronic lung infection by Pseudomonas aeruginosa is the major severe complication in cystic fibrosis (CF) patients, where P. aeruginosa persists and grows in biofilms in the endobronchial mucus under hypoxic conditions. Numerous polymorphonuclear leukocytes (PMNs) surround the biofilms and create local anoxia by consuming the majority of O2 for production of reactive oxygen species (ROS). We hypothesized that P. aeruginosa acquires energy for growth in anaerobic endobronchial mucus by denitrification, which can be demonstrated by production of nitrous oxide (N2O), an intermediate in the denitrification pathway. We measured N2O and O2 with electrochemical microsensors in 8 freshly expectorated sputum samples from 7 CF patients with chronic P. aeruginosa infection. The concentrations of NO3(-) and NO2(-) in sputum were estimated by the Griess reagent. We found a maximum median concentration of 41.8 uM N2O (range 1.4-157.9 uM N2O). The concentration of N2O in the sputum was higher below the oxygenated layers. In 4 samples the N2O concentration increased during the initial 6 h of measurements before decreasing for approximately 6 h. Concomitantly, the concentration of NO3(-) decreased in sputum during 24 hours of incubation. We demonstrate for the first time production of N2O in clinical material from infected human airways indicating pathogenic metabolism based on denitrification. Therefore, P. aeruginosa may acquire energy for growth by denitrification in anoxic endobronchial mucus in CF patients. Such ability for anaerobic growth may be a hitherto ignored key aspect of chronic P. aeruginosa infections that can inform new strategies for treatment and prevention. PMID- 24465409 TI - Association between statin use and short-term outcome based on severity of ischemic stroke: a cohort study. AB - BACKGROUND: Statins reportedly improve clinical outcomes for ischemic stroke patients. However, it is unclear whether the contribution of statin treatment varies depending on the severity of stroke. We sought to investigate the relationship between statin use and the outcome of acute first-ever ischemic stroke patients stratified by stroke severity. METHODS: A total of 7,455 acute first-ever ischemic stroke patients without statin treatment before onset were eligible from the China National Stroke Registry. A National Institutes of Health Stroke Scale (NIHSS) score of 0 to 4 was defined as minor stroke, and a NIHSS score of >4 was defined as non-minor stroke. We analyzed the association between statin use during hospitalization and mortality as well as functional outcome (measured by a modified Rankin Scale score of 0-5) at 3 months after onset using multivariable logistic regression models. RESULTS: A total of 3,231 (43.3%) patients received statin treatment during hospitalization. Multivariable analysis showed that statin use during hospitalization decreased mortality of ischemic stroke patients (OR, 0.51; 95%CI, 0.38-0.67), but did not improve poor functional outcomes (OR, 0.95; 95CI%, 0.81-1.11) at 3 months. The interaction between statin use and stroke severity was significant both in dependence and death outcome (P = 0.04 for dependence outcome, P = 0.03 for death outcome). After stratification by stroke severity, statin use during hospitalization decreased the mortality of stroke (OR, 0.44; 95%CI, 0.31-0.62) and poor functional outcome (OR, 0.73; 95%CI, 0.57-0.92) at 3 months in the non-minor stroke group. CONCLUSIONS: Statin use during hospitalization may improve the clinical outcome of acute first-ever ischemic stroke depending on the severity of stroke. Non-minor stroke patients may obtain benefit from statin treatment with improvements in poor functional outcomes and mortality. PMID- 24465408 TI - Metformin: a potential therapeutic agent for recurrent colon cancer. AB - Accumulating evidence suggests that metformin, a biguanide class of anti-diabetic drugs, possesses anti-cancer properties. However, most of the studies to evaluate therapeutic efficacy of metformin have been on primary cancer. No information is available whether metformin could be effectively used for recurrent cancer, specifically colorectal cancer (CRC) that affects up to 50% of patients treated by conventional chemotherapies. Although the reasons for recurrence are not fully understood, it is thought to be due to re-emergence of chemotherapy-resistant cancer stem/stem-like cells (CSCs/CSLCs). Therefore, development of non-toxic treatment strategies targeting CSCs would be of significant therapeutic benefit. In the current investigation, we have examined the effectiveness of metformin, in combination with 5-fluorouracil and oxaliplatin (FuOx), the mainstay of colon cancer therapeutics, on survival of chemo-resistant colon cancer cells that are highly enriched in CSCs/CSLCs. Our data show that metformin acts synergistically with FuOx to (a) induce cell death in chemo resistant (CR) HT-29 and HCT-116 colon cancer cells, (b) inhibit colonospheres formation and (c) enhance colonospheres disintegration. In vitro cell culture studies have further demonstrated that the combinatorial treatment inhibits migration of CR colon cancer cells. These changes were associated with increased miRNA 145 and reduction in miRNA 21. Wnt/beta-catenin signaling pathway was also down-regulated indicating its pivotal role in regulating the growth of CR colon cancer cells. Data from SCID mice xenograft model of CR HCT-116 and CR HT-29 cells show that the combination of metformin and FuOX is highly effective in inhibiting the growth of colon tumors as evidenced by ~ 50% inhibition in growth following 5 weeks of combination treatment, when compared with the vehicle treated controls. Our current data suggest that metformin together with conventional chemotherapy could be an effective treatment regimen for recurring colorectal cancer (CRC). PMID- 24465410 TI - Lesions of cholinergic pedunculopontine tegmental nucleus neurons fail to affect cocaine or heroin self-administration or conditioned place preference in rats. AB - Cholinergic input to the ventral tegmental area (VTA) is known to contribute to reward. Although it is known that the pedunculopontine tegmental nucleus (PPTg) provides an important source of excitatory input to the dopamine system, the specific role of PPTg cholinergic input to the VTA in cocaine reward has not been previously determined. We used a diphtheria toxin conjugated to urotensin-II (Dtx::UII), the endogenous ligand for urotensin-II receptors expressed by PPTg cholinergic but not glutamatergic or GABAergic cells, to lesion cholinergic PPTg neurons. Dtx::UII toxin infusion resulted in the loss of 95.78 (+/-0.65)% of PPTg cholinergic cells but did not significantly alter either cocaine or heroin self administration or the development of cocaine or heroin conditioned place preferences. Thus, cholinergic cells originating in PPTg do not appear to be critical for the rewarding effects of cocaine or of heroin. PMID- 24465411 TI - SIV vpx is essential for macrophage infection but not for development of AIDS. AB - Analysis of rhesus macaques infected with a vpx deletion mutant virus of simian immunodeficiency virus mac239 (SIVDeltavpx) demonstrates that Vpx is essential for efficient monocyte/macrophage infection in vivo but is not necessary for development of AIDS. To compare myeloid-lineage cell infection in monkeys infected with SIVDeltavpx compared to SIVmac239, we analyzed lymphoid and gastrointestinal tissues from SIVDeltavpx-infected rhesus (n = 5), SIVmac239 infected rhesus with SIV encephalitis (7 SIV239E), those without encephalitis (4 SIV239noE), and other SIV mutant viruses with low viral loads (4 SIVDeltanef, 2 SIVDelta3). SIV+ macrophages and the percentage of total SIV+ cells that were macrophages in spleen and lymph nodes were significantly lower in rhesus infected with SIVDeltavpx (2.2%) compared to those infected with SIV239E (22.7%), SIV239noE (8.2%), and SIV mutant viruses (10.1%). In colon, SIVDeltavpx monkeys had fewer SIV+ cells, no SIV+ macrophages, and lower percentage of SIV+ cells that were macrophages than the other 3 groups. Only 2 SIVDeltavpx monkeys exhibited detectable virus in the colon. We demonstrate that Vpx is essential for efficient macrophage infection in vivo and that simian AIDS and death can occur in the absence of detectable macrophage infection. PMID- 24465412 TI - Immune response elicited by DNA vaccination using Lactococcus lactis is modified by the production of surface exposed pathogenic protein. AB - In this study, we compared immune responses elicited by DNA immunization using Lactococcus lactis or L. lactis expressing the Staphylococcus aureus invasin Fibronectin Binding Protein A (FnBPA) at its surface. Both strains carried pValac:BLG, a plasmid containing the cDNA of Beta-Lactoglobulin (BLG), and were designated LL-BLG and LL-FnBPA+ BLG respectively. A TH2 immune response characterized by the secretion of IL-4 and IL-5 in medium of BLG reactivated splenocytes was detected after either oral or intranasal administration of LL FnBPA+ BLG. In contrast, intranasal administration of LL-BLG elicited a TH1 immune response. After BLG sensitization, mice previously intranasally administered with LL-BLG showed a significantly lower concentration of BLG specific IgE than the mice non-administered. Altenatively administration of LL FnBPA+ BLG didn't modify the BLG-specific IgE concentration obtained after sensitization, thus confirming the TH2 orientation of the immune response. To determine if the TH2-skewed immune response obtained with LL-FnBpA+ BLG was FnBPA specific or not, mice received another L. lactis strain producing a mutated form of the Listeria monocytogenes invasin Internalin A intranasally, allowing thus the binding to murine E-cadherin, and containing pValac:BLG (LL-mInlA+ BLG). As with LL-FnBPA+ BLG, LL-mInlA+ BLG was not able to elicit a TH1 immune response. Furthermore, we observed that these difference were not due to the peptidoglycan composition of the cell wall as LL-FnBPA+ BLG, LL-mInlA+ BLG and LL-BLG strains shared a similar composition. DNA vaccination using LL-BLG elicited a pro inflammatory TH1 immune response while using LL-FnBPA+ BLG or LL-mInlA+ BLG elicited an anti-inflammatory TH2 immune response. PMID- 24465413 TI - Angiotensin-induced abdominal aortic aneurysms in hypercholesterolemic mice: role of serum cholesterol and temporal effects of exposure. AB - OBJECTIVE: Understanding variations in size and pattern of development of angiotensin II (Ang II)-induced abdominal aortic aneurysms (AAA) may inform translational research strategies. Thus, we sought insight into the temporal evolution of AAA in apolipoprotein (apo)E(-/-) mice. APPROACH: A cohort of mice underwent a 4-week pump-mediated infusion of saline (n = 23) or 1500 ng/kg/min of Ang II (n = 85) and AAA development was tracked via in vivo ultrasound imaging. We adjusted for hemodynamic covariates in the regression models for AAA occurrence in relation to time. RESULTS: The overall effect of time was statistically significant (p<0.001). Compared to day 7 of AngII infusion, there was no decrease in the log odds of AAA occurrence by day 14 (-0.234, p = 0.65), but compared to day 21 and 28, the log odds decreased by 9.07 (p<0.001) and 2.35 (p = 0.04), respectively. Hemodynamic parameters were not predictive of change in aortic diameter (Delta) (SBP, p = 0.66; DBP, p = 0.66). Mean total cholesterol (TC) was higher among mice with large versus small AAA (601 vs. 422 mg/ml, p<0.0001), and the difference was due to LDL. AngII exposure was associated with 0.43 mm (95% CI, 0.27 to 0.61, p<0.0001) increase in aortic diameter; and a 100 mg/dl increase in mean final cholesterol level was associated with a 12% (95% CI, 5.68 to 18.23, p<0.0001) increase in aortic diameter. Baseline cholesterol was not associated with change in aortic diameter (p = 0.86). CONCLUSIONS: These are the first formal estimates of a consistent pattern of Ang II-induced AAA development. The odds of AAA occurrence diminish after the second week of Ang II infusion, and TC is independently associated with AAA size. PMID- 24465414 TI - Computational estimates of membrane flow and tension gradient in motile cells. AB - All parts of motile cells, including the plasma membrane, have to translocate in the direction of locomotion. Both directed intracellular membrane transport coupled with polarized endo- and exocytosis and fluid flow in the plane of the plasma membrane can contribute to this overall plasma membrane translocation. It remains unclear how strong a force is required to generate this flow. We numerically solve Stokes equations for the viscous membrane flow across a flat plasma membrane surface in the presence of transmembrane proteins attached to the cytoskeleton and find the membrane tension gradient associated with this flow. This gradient is sensitive to the size and density of the transmembrane proteins attached to the cytoskeleton and can become significant enough to slow down cell movement. We estimate the influence of intracellular membrane transport and actin growth and contraction on the tension gradient, and discuss possible 'tank tread' flow at ventral and dorsal surfaces. PMID- 24465415 TI - Both dietary supplementation with monosodium L-glutamate and fat modify circulating and tissue amino acid pools in growing pigs, but with little interactive effect. AB - BACKGROUND: The Chinese population has undergone rapid transition to a high-fat diet. Furthermore, monosodium L-glutamate (MSG) is widely used as a daily food additive in China. Little information is available on the effects of oral MSG and dietary fat supplementation on the amino acid balance in tissues. The present study aimed to determine the effects of both dietary fat and MSG on amino acid metabolism in growing pigs, and to assess any possible interactions between these two nutrients. METHODS AND RESULTS: Four iso-nitrogenous and iso-caloric diets (basal diet, high fat diet, basal diet with 3% MSG and high fat diet with 3% MSG) were provided to growing pigs. The dietary supplementation with fat and MSG used alone and in combination were found to modify circulating and tissue amino acid pools in growing pigs. Both dietary fat and MSG modified the expression of gene related to amino acid transport in jejunum. CONCLUSIONS: Both dietary fat and MSG clearly influenced amino acid content in tissues but in different ways. Both dietary fat and MSG enhance the absorption of amino acids in jejunum. However, there was little interaction between the effects of dietary fat and MSG. PMID- 24465416 TI - Female-biased symbionts and tomato yellow leaf curl virus infections in Bemisia tabaci. AB - The female-biased infection of facultative symbionts has been found in Bemisia tabaci; however, whether there are any differences in tomato yellow leaf curl virus (TYLCV) and obligate symbiont infection rates between females and males is unknown. Determining whether such differences exist would be very important for understanding the spread of the plant virus and of the symbionts. We compared both symbiont infection types, including obligate and facultative symbionts, and the rates of TYLCV infection in both sexes in five field populations from Jiangsu Province, China. The obligate symbiont Portiera aleyrodidarum was not found in every whitefly tested. In all tested populations, more females than males were found to harbor P. aleyrodidarum; and more females than males also harbored Hamiltonella defense, the most common facultative symbiont as well as Cardinium. In addition to female-biased symbiont infections, there were also female-biased TYLCV infections, and the infection frequencies of this plant virus in females were higher than those in males. Taken together, these results suggested that both the female-biased symbiont infections and female-biased TYLCV infections promoted the rapid spread of TYLCV in China. PMID- 24465417 TI - Alterations in postural control during the world's most challenging mountain ultra-marathon. AB - We investigated postural control (PC) effects of a mountain ultra-marathon (MUM): a 330-km trail run with 24000 m of positive and negative change in elevation. PC was assessed prior to (PRE), during (MID) and after (POST) the MUM in experienced ultra-marathon runners (n = 18; finish time = 126 +/- 16 h) and in a control group (n = 8) with a similar level of sleep deprivation. Subjects were instructed to stand upright on a posturographic platform over a period of 51.2 seconds using a double-leg stance under two test conditions: eyes open (EO) and eyes closed (EC). Traditional measures of postural stability (center of pressure trajectory analysis) and stabilogram-diffusion analysis (SDA) parameters were analysed. For the SDA, a significantly greater short-term effective diffusion was found at POST compared with PRE in the medio-lateral (ML; Dxs) and antero-posterior (AP) directions (Dys) in runners (p<0.05) The critical time interval (Ctx) in the ML direction was significantly higher at MID (p<0.001) and POST (p<0.05) than at PRE in runners. At MID (p<0.001) and POST (p<0.05), there was a significant difference between the two groups. The critical displacement (Cdx) in the ML was significantly higher at MID and at POST (p<0.001) compared with PRE for runners. A significant difference in Cdx was observed between groups in EO at MID (p<0.05) and POST (p<0.005) in the ML direction and in EC at POST in the ML and AP directions (p<0.05). Our findings revealed significant effects of fatigue on PC in runners, including, a significant increase in Ctx (critical time in ML plan) in EO and EC conditions. Thus, runners take longer to stabilise their body at POST than at MID. It is likely that the mountainous characteristics of MUM (unstable ground, primarily uphill/downhill running, and altitude) increase this fatigue, leading to difficulty in maintaining balance. PMID- 24465418 TI - How patients take malaria treatment: a systematic review of the literature on adherence to antimalarial drugs. AB - BACKGROUND: High levels of patient adherence to antimalarial treatment are important in ensuring drug effectiveness. To achieve this goal, it is important to understand levels of patient adherence, and the range of study designs and methodological challenges involved in measuring adherence and interpreting results. Since antimalarial adherence was reviewed in 2004, there has been a major expansion in the use of artemisinin-based combination therapies (ACTs) in the public sector, as well as initiatives to make them more widely accessible through community health workers and private retailers. These changes and the large number of recent adherence studies raise the need for an updated review on this topic. OBJECTIVE: We conducted a systematic review of studies reporting quantitative results on patient adherence to antimalarials obtained for treatment. RESULTS: The 55 studies identified reported extensive variation in patient adherence to antimalarials, with many studies reporting very high adherence (90-100%) and others finding adherence of less than 50%. We identified five overarching approaches to assessing adherence based on the definition of adherence and the methods used to measure it. Overall, there was no clear pattern in adherence results by approach. However, adherence tended to be higher among studies where informed consent was collected at the time of obtaining the drug, where patient consultations were directly observed by research staff, and where a diagnostic test was obtained. CONCLUSION: Variations in reported adherence may reflect factors related to patient characteristics and the nature of their consultation with the provider, as well as methodological variations such as interaction between the research team and patients before and during the treatment. Future studies can benefit from an awareness of the impact of study procedures on adherence outcomes, and the identification of improved measurement methods less dependent on self-report. PMID- 24465419 TI - Neurological involvement in primary Sjogren syndrome: a focus on central nervous system. AB - OBJECTIVES: Sjogren syndrome is an autoimmune disease involving mainly salivary and lacrimal glands. Beyond widely described PNS involvement, high variable prevalence of CNS manifestations ranging from 2.5 and 60% of all pSS patients has been reported, without specific syndrome definition. The aim of this cohort study was to evaluate the prevalence of CNS signs and symptoms in pSS patients and to identify possible biomarkers of CNS damage. METHODS: 120 patients with pSS diagnosis according to the 2002 American-European Consensus Group criteria were enrolled after exclusion of secondary causes. All patients underwent to a wide neurological, neuropsychological, psychiatric, neuroradiological and ultrasonographic evaluation. RESULTS: Central and peripheral nervous system involvement was observed in 81 patients with a prevalence of 67.5%. The prevalence of CNS involvement was significantly higher than PNS disease (p 0.001). 68 patients (84%) shown non-focal CNS symptoms and 64 (79%) focal CNS deficits with headache as the most common feature (46.9%), followed by cognitive (44.4%) and mood disorders (38.3%). Particularly, we observed a high prevalence of migraine without aura, subcortical frontal executive functions and verbal memory impairment and apathy/alexythimia. MR spectroscopy revealed a reduction of NAA levels or NAA/Cr ratio decrease in subcortical frontal and basal ganglia white matter, while ultrasonography showed an impairment of microvasculature response. At multivariate analysis, headache, cognitive disorders and psychiatric symptoms was significantly associated to serological markers (anti-SSA), MRS and ultrasonographic features. CONCLUSIONS: The higher prevalence of MWO-mimic headache, cognitive dys-executive syndrome and mood disorders observed in this series confirmed previous evidences of a higher diffused CNS compromission rather than focal involvement such as SM-like clinical course or NMO-like syndrome. The association with immunological biomarkers, metabolic cerebral dysfunction and microvascular damage suggests a possible endothelial dysfunction of the cerebral microcirculation or a potential inflammation-mediated shift of the neurovascular coupling. PMID- 24465420 TI - A part-based probabilistic model for object detection with occlusion. AB - The part-based method has been a fast rising framework for object detection. It is attracting more and more attention for its detection precision and partial robustness to the occlusion. However, little research has been focused on the problem of occlusion overlapping of the part regions, which can reduce the performance of the system. This paper proposes a part-based probabilistic model and the corresponding inference algorithm for the problem of the part occlusion. The model is based on the Bayesian theory integrally and aims to be robust to the large occlusion. In the stage of the model construction, all of the parts constitute the vertex set of a fully connected graph, and a binary variable is assigned to each part to indicate its occlusion status. In addition, we introduce a penalty term to regularize the argument space of the objective function. Thus, the part detection is formulated as an optimization problem, which is divided into two alternative procedures: the outer inference and the inner inference. A stochastic tentative method is employed in the outer inference to determine the occlusion status for each part. In the inner inference, the gradient descent algorithm is employed to find the optimal positions of the parts, in term of the current occlusion status. Experiments were carried out on the Caltech database. The results demonstrated that the proposed method achieves a strong robustness to the occlusion. PMID- 24465422 TI - Development of a new method to track multiple honey bees with complex behaviors on a flat laboratory arena. AB - A computer program that tracks animal behavior, thereby revealing various features and mechanisms of social animals, is a powerful tool in ethological research. Because honeybee colonies are populated by thousands of bees, individuals co-exist in high physical densities and are difficult to track unless specifically tagged, which can affect behavior. In addition, honeybees react to light and recordings must be made under special red-light conditions, which the eyes of bees perceive as darkness. The resulting video images are scarcely distinguishable. We have developed a new algorithm, K-Track, for tracking numerous bees in a flat laboratory arena. Our program implements three main processes: (A) The object (bee's) region is detected by simple threshold processing on gray scale images, (B) Individuals are identified by size, shape and spatiotemporal positional changes, and (C) Centers of mass of identified individuals are connected through all movie frames to yield individual behavioral trajectories. The tracking performance of our software was evaluated on movies of mobile multi-artificial agents and of 16 bees walking around a circular arena. K Track accurately traced the trajectories of both artificial agents and bees. In the latter case, K-track outperformed Ctrax, well-known software for tracking multiple animals. To investigate interaction events in detail, we manually identified five interaction categories; 'crossing', 'touching', 'passing', 'overlapping' and 'waiting', and examined the extent to which the models accurately identified these categories from bee's interactions. All 7 identified failures occurred near a wall at the outer edge of the arena. Finally, K-Track and Ctrax successfully tracked 77 and 60 of 84 recorded interactive events, respectively. K-Track identified multiple bees on a flat surface and tracked their speed changes and encounters with other bees, with good performance. PMID- 24465421 TI - Folic acid supplementation promotes mammary tumor progression in a rat model. AB - Folic acid supplementation may prevent the development of cancer in normal tissues but may promote the progression of established (pre)neoplastic lesions. However, whether or not folic acid supplementation can promote the progression of established (pre)neoplastic mammary lesions is unknown. This is a critically important issue because breast cancer patients and survivors in North America are likely exposed to high levels of folic acid owing to folic acid fortification and widespread supplemental use after cancer diagnosis. We investigated whether folic acid supplementation can promote the progression of established mammary tumors. Female Sprague-Dawley rats were placed on a control diet and mammary tumors were initiated with 7,12-dimethylbenza[a]anthracene at puberty. When the sentinel tumor reached a predefined size, rats were randomized to receive a diet containing the control, 2.5x, 4x, or 5x supplemental levels of folic acid for up to 12 weeks. The sentinel mammary tumor growth was monitored weekly. At necropsy, the sentinel and all other mammary tumors were analyzed histologically. The effect of folic acid supplementation on the expression of proteins involved in proliferation, apoptosis, and mammary tumorigenesis was determined in representative sentinel adenocarcinomas. Although no clear dose-response relationship was observed, folic acid supplementation significantly promoted the progression of the sentinel mammary tumors and was associated with significantly higher sentinel mammary tumor weight and volume compared with the control diet. Furthermore, folic acid supplementation was associated with significantly higher weight and volume of all mammary tumors. The most significant and consistent mammary tumor-promoting effect was observed with the 2.5x supplemental level of folic acid. Folic acid supplementation was also associated with an increased expression of BAX, PARP, and HER2. Our data suggest that folic acid supplementation may promote the progression of established mammary tumors. The potential tumor-promoting effect of folic acid supplementation in breast cancer patients and survivors needs further clarification. PMID- 24465423 TI - Investigating the early stages of person perception: the asymmetry of social categorization by sex vs. age. AB - Early perceptual operations are central components of the dynamics of social categorization. The wealth of information provided by facial cues presents challenges to our understanding of these early stages of person perception. The current study aimed to uncover the dynamics of processing multiply categorizable faces, notably as a function of their gender and age. Using a modified four choice version of a mouse-tracking paradigm (which assesses the relative dominance of two categorical dimensions), the relative influence that sex and age have on each other during categorization of infant, younger adult, and older adult faces was investigated. Results of these experiments demonstrate that when sex and age dimensions are simultaneously categorized, only for infant faces does age influence sex categorization. In contrast, the sex of both young and older adults was shown to influence age categorization. The functional implications of these findings are discussed in light of previous person perception research. PMID- 24465424 TI - Anthelmintic efficacy of gold nanoparticles derived from a phytopathogenic fungus, Nigrospora oryzae. AB - Exploring a green chemistry approach, this study brings to the fore, the anthelmintic efficacy of gold nanoparticles, highlighting the plausible usage of myconanotechnology. Gold nanoparticles of ~6 to ~18 nm diameter were synthesized by treating the mycelia-free culture filtrate of the phytopathogenic fungus with gold chloride. Their size and morphology were confirmed by UV-Vis spectroscopy, DLS data, AFM and TEM images. The XRD studies reveal a crystalline nature of the nanoparticles, which are in cubic phase. The FTIR spectroscopic studies before and after the formation of nanoparticles show the presence of possible functional groups responsible for the bio-reduction and capping of the synthesized gold nanoparticles. The latter were tested as vermifugal agents against a model cestode Raillietina sp., an intestinal parasite of domestic fowl. Further, ultrastructural and biochemical parameters were used to corroborate the efficacy study. PMID- 24465425 TI - Progesterone therapy, endothelial function and cardiovascular risk factors: a 3 month randomized, placebo-controlled trial in healthy early postmenopausal women. AB - BACKGROUND: Progesterone is effective treatment for hot flushes/night sweats. The cardiovascular effects of progesterone therapy are unknown but evidence suggests that premenopausal normal estradiol with also normal progesterone levels may provide later cardiovascular protection. We compared the effects of progesterone to placebo on endothelial function, weight, blood pressure, metabolism, lipids, inflammation and coagulation. METHODS AND RESULTS: We conducted a randomized, double-blind, 3-month placebo-controlled trial of progesterone (300 mg daily) among 133 healthy postmenopausal women in Vancouver, Canada from 2003-2009. Endothelial function by venous occlusion plethysmography was a planned primary outcome. Enrolled women were 1-11 y since last menstruation, not using hormones (for >6 months), non-smoking, without diabetes, hypertension, heart disease or their medications. Randomized (1?1) women (55 +/- 4 years, body mass index 25 +/- 3) initially had normal blood pressure, fasting lipid, glucose and electrocardiogram results. Endothelial function (% forearm blood flow above saline) was not changed with progesterone (487 +/- 189%, n = 18) compared with placebo (408 +/- 278%, n = 16) (95% CI diff [-74 to 232], P = 0.30). Progesterone (n = 65) and placebo (n = 47) groups had similar changes in systolic and diastolic blood pressure, resting heart rate, weight, body mass index, waist circumference, total cholesterol, low-density lipoprotein cholesterol and triglyceride levels. High-density lipoprotein was lower (-0.14 mmol/L, P = 0.001) on progesterone compared with placebo. Fasting glucose, hs-C-reactive protein, albumin and D-dimer changes were all comparable to placebo. Framingham General Cardiovascular Risk Profile scores were initially low and remained low with progesterone therapy and not statistically different from placebo. CONCLUSIONS: Results indicate that progesterone has short-term cardiovascular safety. Endothelial function, weight, blood pressure, waist circumference, inflammation and coagulation were unchanged as were lipids except for HDL-C. The statistically significant decrease in HDL-C levels was not clinically important (based on lack of Cardiovascular Risk Profile change). TRIAL REGISTRATION: ClinicalTrials.gov NCT00152438. PMID- 24465427 TI - High diversity in cretaceous ichthyosaurs from Europe prior to their extinction. AB - BACKGROUND: Ichthyosaurs are reptiles that inhabited the marine realm during most of the Mesozoic. Their Cretaceous representatives have traditionally been considered as the last survivors of a group declining since the Jurassic. Recently, however, an unexpected diversity has been described in Upper Jurassic Lower Cretaceous deposits, but is widely spread across time and space, giving small clues on the adaptive potential and ecosystem control of the last ichthyosaurs. The famous but little studied English Gault Formation and 'greensands' deposits (the Upper Greensand Formation and the Cambridge Greensand Member of the Lower Chalk Formation) offer an unprecedented opportunity to investigate this topic, containing thousands of ichthyosaur remains spanning the Early-Late Cretaceous boundary. METHODOLOGY/PRINCIPAL FINDINGS: To assess the diversity of the ichthyosaur assemblage from these sedimentary bodies, we recognized morphotypes within each type of bones. We grouped these morphotypes together, when possible, by using articulated specimens from the same formations and from new localities in the Vocontian Basin (France); a revised taxonomic scheme is proposed. We recognize the following taxa in the 'greensands': the platypterygiines 'Platypterygius' sp. and Sisteronia seeleyi gen. et sp. nov., indeterminate ophthalmosaurines and the rare incertae sedis Cetarthrosaurus walkeri. The taxonomic diversity of late Albian ichthyosaurs now matches that of older, well-known intervals such as the Toarcian or the Tithonian. Contrasting tooth shapes and wear patterns suggest that these ichthyosaurs colonized three distinct feeding guilds, despite the presence of numerous plesiosaur taxa. CONCLUSION/SIGNIFICANCE: Western Europe was a diversity hot-spot for ichthyosaurs a few million years prior to their final extinction. By contrast, the low diversity in Australia and U.S.A. suggests strong geographical disparities in the diversity pattern of Albian-early Cenomanian ichthyosaurs. This provides a whole new context to investigate the extinction of these successful marine reptiles, at the end of the Cenomanian. PMID- 24465426 TI - Glucopyranosyl lipid A adjuvant significantly enhances HIV specific T and B cell responses elicited by a DNA-MVA-protein vaccine regimen. AB - Using a unique vaccine antigen matched and single HIV Clade C approach we have assessed the immunogenicity of a DNA-poxvirus-protein strategy in mice and rabbits, administering MVA and protein immunizations either sequentially or simultaneously and in the presence of a novel TLR4 adjuvant, GLA-AF. Mice were vaccinated with combinations of HIV env/gag-pol-nef plasmid DNA followed by MVA-C (HIV env/gag-pol-nef) with HIV CN54gp140 protein (+/-GLA-AF adjuvant) and either co-administered in different muscles of the same animal with MVA-C or given sequentially at 3-week intervals. The DNA prime established a population of B cells that were able to mount a statistically significant anamnestic response to the boost vaccines. The greatest antigen-specific antibody response was observed in animals that received all vaccine components. Moreover, a high proportion of the total mucosal IgG (20 - 50%) present in the vaginal vault of these vaccinated animals was vaccine antigen-specific. The potent elicitation of antigen-specific immune responses to this vaccine modality was also confirmed in rabbits. Importantly, co-administration of MVA-C with the GLA-AF adjuvanted HIV CN54gp140 protein significantly augmented the antigen-specific T cell responses to the Gag antigen, a transgene product expressed by the MVA-C vector in a separate quadriceps muscle. We have demonstrated that co-administration of MVA and GLA-AF adjuvanted HIV CN54gp140 protein was equally effective in the generation of humoral responses as a sequential vaccination modality thus shortening and simplifying the immunization schedule. In addition, a significant further benefit of the condensed vaccination regime was that T cell responses to proteins expressed by the MVA-C were potently enhanced, an effect that was likely due to enhanced immunostimulation in the presence of systemic GLA-AF. PMID- 24465428 TI - Evidence for site-specific occupancy of the mitochondrial genome by nuclear transcription factors. AB - Mitochondria contain their own circular genome, with mitochondria-specific transcription and replication systems and corresponding regulatory proteins. All of these proteins are encoded in the nuclear genome and are post-translationally imported into mitochondria. In addition, several nuclear transcription factors have been reported to act in mitochondria, but there has been no comprehensive mapping of their occupancy patterns and it is not clear how many other factors may also be found in mitochondria. Here we address these questions by using ChIP seq data from the ENCODE, mouseENCODE and modENCODE consortia for 151 human, 31 mouse and 35 C. elegans factors. We identified 8 human and 3 mouse transcription factors with strong localized enrichment over the mitochondrial genome that was usually associated with the corresponding recognition sequence motif. Notably, these sites of occupancy are often the sites with highest ChIP-seq signal intensity within both the nuclear and mitochondrial genomes and are thus best explained as true binding events to mitochondrial DNA, which exist in high copy number in each cell. We corroborated these findings by immunocytochemical staining evidence for mitochondrial localization. However, we were unable to find clear evidence for mitochondrial binding in ENCODE and other publicly available ChIP-seq data for most factors previously reported to localize there. As the first global analysis of nuclear transcription factors binding in mitochondria, this work opens the door to future studies that probe the functional significance of the phenomenon. PMID- 24465429 TI - Age-based hiring discrimination as a function of equity norms and self-perceived objectivity. AB - Participants completed a questionnaire priming them to perceive themselves as either objective or biased, either before or after evaluating a young or old job applicant for a position linked to youthful stereotypes. Participants agreed that they were objective and tended to disagree that they were biased. Extending past research, both the objective and bias priming conditions led to an increase in age discrimination compared to the control condition. We also investigated whether equity norms reduced age discrimination, by manipulating the presence or absence of an equity statement reminding decision-makers of the legal prohibitions against discrimination "on the basis of age, disability, national or ethnic origin, race, religion, or sex." The presence of equity norms increased enthusiasm for both young and old applicants when participants were not already primed to think of themselves as objective, but did not reduce age-based hiring discrimination. Equity norms had no effect when individuals thought of themselves as objective - they preferred the younger more than the older job applicant. However, the presence of equity norms did affect individuals' perceptions of which factors were important to their hiring decisions, increasing the perceived importance of applicants' expertise and decreasing the perceived importance of the applicants' age. The results suggest that interventions that rely exclusively on decision-makers' intentions to behave equitably may be ineffective. PMID- 24465430 TI - Role of macrophages in the altered epithelial function during a type 2 immune response induced by enteric nematode infection. AB - Parasitic enteric nematodes induce a type 2 immune response characterized by increased production of Th2 cytokines, IL-4 and IL-13, and recruitment of alternatively activated macrophages (M2) to the site of infection. Nematode infection is associated with changes in epithelial permeability and inhibition of sodium-linked glucose absorption, but the role of M2 in these effects is unknown. Clodronate-containing liposomes were administered prior to and during nematode infection to deplete macrophages and prevent the development of M2 in response to infection with Nippostrongylus brasiliensis. The inhibition of epithelial glucose absorption that is associated with nematode infection involved a macrophage dependent reduction in SGLT1 activity, with no change in receptor expression, and a macrophage-independent down-regulation of GLUT2 expression. The reduced transport of glucose into the enterocyte is compensated partially by an up regulation of the constitutive GLUT1 transporter consistent with stress-induced activation of HIF-1alpha. Thus, nematode infection results in a "lean" epithelial phenotype that features decreased SGLT1 activity, decreased expression of GLUT2 and an emergent dependence on GLUT1 for glucose uptake into the enterocyte. Macrophages do not play a role in enteric nematode infection-induced changes in epithelial barrier function. There is a greater contribution, however, of paracellular absorption of glucose to supply the energy demands of host resistance. These data provide further evidence of the ability of macrophages to alter glucose metabolism of neighboring cells. PMID- 24465432 TI - Linear mixed effects models under inequality constraints with applications. AB - Constraints arise naturally in many scientific experiments/studies such as in, epidemiology, biology, toxicology, etc. and often researchers ignore such information when analyzing their data and use standard methods such as the analysis of variance (ANOVA). Such methods may not only result in a loss of power and efficiency in costs of experimentation but also may result poor interpretation of the data. In this paper we discuss constrained statistical inference in the context of linear mixed effects models that arise naturally in many applications, such as in repeated measurements designs, familial studies and others. We introduce a novel methodology that is broadly applicable for a variety of constraints on the parameters. Since in many applications sample sizes are small and/or the data are not necessarily normally distributed and furthermore error variances need not be homoscedastic (i.e. heterogeneity in the data) we use an empirical best linear unbiased predictor (EBLUP) type residual based bootstrap methodology for deriving critical values of the proposed test. Our simulation studies suggest that the proposed procedure maintains the desired nominal Type I error while competing well with other tests in terms of power. We illustrate the proposed methodology by re-analyzing a clinical trial data on blood mercury level. The methodology introduced in this paper can be easily extended to other settings such as nonlinear and generalized regression models. PMID- 24465431 TI - Familial young-onset diabetes, pre-diabetes and cardiovascular disease are associated with genetic variants of DACH1 in Chinese. AB - In Asia, young-onset type 2 diabetes (YOD) is characterized by obesity and increased risk for cardiovascular disease (CVD). In a genome-wide association study (GWAS) of 99 Chinese obese subjects with familial YOD diagnosed before 40 year-old and 101 controls, the T allele of rs1408888 in intron 1 of DACH1(Dachshund homolog 1) was associated with an odds ratio (OR) of 2.49(95% confidence intervals:1.57-3.96, P = 8.4 * 10(-5)). Amongst these subjects, we found reduced expression of DACH1 in peripheral blood mononuclear cells (PBMC) from 63 cases compared to 65 controls (P = 0.02). In a random cohort of 1468 cases and 1485 controls, amongst top 19 SNPs from GWAS, rs1408888 was associated with type 2 diabetes with a global P value of 0.0176 and confirmation in a multiethnic Asian case-control cohort (7370/7802) with an OR of 1.07(1.02-1.12, P(meta) = 0.012). In 599 Chinese non-diabetic subjects, rs1408888 was linearly associated with systolic blood pressure and insulin resistance. In a case-control cohort (n = 953/953), rs1408888 was associated with an OR of 1.54(1.07-2.22, P = 0.019) for CVD in type 2 diabetes. In an autopsy series of 173 non-diabetic cases, TT genotype of rs1408888 was associated with an OR of 3.31(1.19-9.19, P = 0.0214) and 3.27(1.25-11.07, P = 0.0184) for coronary heart disease (CHD) and coronary arteriosclerosis. Bioinformatics analysis revealed that rs1408888 lies within regulatory elements of DACH1 implicated in islet development and insulin secretion. The T allele of rs1408888 of DACH1 was associated with YOD, prediabetes and CVD in Chinese. PMID- 24465433 TI - Multimorbidity patterns in a national representative sample of the Spanish adult population. AB - BACKGROUND: In the context of population aging, multimorbidity has emerged as a growing concern in public health. However, little is known about multimorbidity patterns and other issues surrounding chronic diseases. The aim of our study was to examine multimorbidity patterns, the relationship between physical and mental conditions and the distribution of multimorbidity in the Spanish adult population. METHODS: Data from this cross-sectional study was collected from the COURAGE study. A total of 4,583 participants from Spain were included, 3,625 aged over 50. An exploratory factor analysis was conducted to detect multimorbidity patterns in the population over 50 years of age. Crude and adjusted binary logistic regressions were performed to identify individual associations between physical and mental conditions. RESULTS: THREE MULTIMORBIDITY PATTERNS ROSE: 'cardio-respiratory' (angina, asthma, chronic lung disease), 'mental-arthritis' (arthritis, depression, anxiety) and the 'aggregated pattern' (angina, hypertension, stroke, diabetes, cataracts, edentulism, arthritis). After adjusting for covariates, asthma, chronic lung disease, arthritis and the number of physical conditions were associated with depression. Angina and the number of physical conditions were associated with a higher risk of anxiety. With regard to multimorbidity distribution, women over 65 years suffered from the highest rate of multimorbidity (67.3%). CONCLUSION: Multimorbidity prevalence occurs in a high percentage of the Spanish population, especially in the elderly. There are specific multimorbidity patterns and individual associations between physical and mental conditions, which bring new insights into the complexity of chronic patients. There is need to implement patient-centered care which involves these interactions rather than merely paying attention to individual diseases. PMID- 24465434 TI - A 19-nucleotide insertion in the leader sequence of avian leukosis virus subgroup J contributes to its replication in vitro but is not related to its pathogenicity in vivo. AB - Subgroup J avian leukosis virus (ALV-J) was first isolated from meat-type chickens that had developed myeloid leukosis and since 2008, ALV-J infections in chickens have become widespread in China. A comparison of the sequence of ALV-J epidemic isolates with HPRS-103, the ALV-J prototype virus, revealed several distinct features, one of which is a 19-nucleotide (nt) insertion in the leader sequence. To determine the role of the 19-nt insertion in ALV-J pathogenicity, a pair of viruses were constructed and rescued. The first virus was an ALV-J Chinese isolate (designated rSD1009) containing the 19-nt insertion in its leader sequence. The second virus was a clone, in which the leader sequence had a deleted 19-nt sequence (designated rSD1009?19). Compared with rSD1009?19, rSD1009 displayed a moderate growth advantage in vitro. However, no differences were demonstrated in either viral replication or oncogenicity between the two rescued viruses in chickens. These results indicated that the 19-nt insertion contributed to ALV-J replication in vitro but was not related to its pathogenicity in vivo. PMID- 24465435 TI - Possible race and gender divergence in association of genetic variations with plasma von Willebrand factor: a study of ARIC and 1000 genome cohorts. AB - The synthesis, secretion and clearance of von Willebrand factor (VWF) are regulated by genetic variations in coding and promoter regions of the VWF gene. We have previously identified 19 single nucleotide polymorphisms (SNPs), primarily in introns that are associated with VWF antigen levels in subjects of European descent. In this study, we conducted race by gender analyses to compare the association of VWF SNPs with VWF antigen among 10,434 healthy Americans of European (EA) or African (AA) descent from the Atherosclerosis Risk in Communities (ARIC) study. Among 75 SNPs analyzed, 13 and 10 SNPs were associated with VWF antigen levels in EA male and EA female subjects, respectively. However, only one SNP (RS1063857) was significantly associated with VWF antigen in AA females and none was in AA males. Haplotype analysis of the ARIC samples and studying racial diversities in the VWF gene from the 1000 genomes database suggest a greater degree of variations in the VWF gene in AA subjects as compared to EA subjects. Together, these data suggest potential race and gender divergence in regulating VWF expression by genetic variations. PMID- 24465436 TI - Tractography of the brainstem in major depressive disorder using diffusion tensor imaging. AB - BACKGROUND: The brainstem is the main region that innervates neurotransmitter release to the Hypothalamic-Pituitary Adrenal (HPA) axis and fronto-limbic circuits, two key brain circuits found to be dysfunctional in Major Depressive Disorder (MDD). However, the brainstem's role in MDD has only been evaluated in limited reports. Using Diffusion Tensor Imaging (DTI), we investigated whether major brainstem white matter tracts that relate to these two circuits differ in MDD patients compared to healthy controls. METHODS: MDD patients (n = 95) and age and gender-matched controls (n = 34) were assessed using probabilistic tractography of DTI to delineate three distinct brainstem tracts: the nigrostriatal tract (connecting brainstem to striatum), solitary tract (connecting brainstem to amygdala) and corticospinal tract (connecting brainstem to precentral cortex). Fractional anisotropy (FA) was used to measure the white matter integrity of these tracts, and measures were compared between MDD and control participants. RESULTS: MDD participants were characterized by a significant and specific decrease in white matter integrity of the right solitary tract (p<0.009 using independent t-test), which is a "bottom up" afferent pathway that connects the brainstem to the amygdala. This decrease was not related to symptom severity. CONCLUSIONS: The results provide new evidence to suggest that structural connectivity between the brainstem and the amygdala is altered in MDD. These results are interesting in light of predominant theories regarding amygdala mediated emotional reactivity observed in functional imaging studies of MDD. The characterization of altered white matter integrity in the solitary tract in MDD supports the possibility of dysfunctional brainstem-amygdala connectivity impacting vulnerable circuits in MDD. PMID- 24465437 TI - A psychometric measure of working memory capacity for configured body movement. AB - Working memory (WM) models have traditionally assumed at least two domain specific storage systems for verbal and visuo-spatial information. We review data that suggest the existence of an additional slave system devoted to the temporary storage of body movements, and present a novel instrument for its assessment: the movement span task. The movement span task assesses individuals' ability to remember and reproduce meaningless configurations of the body. During the encoding phase of a trial, participants watch short videos of meaningless movements presented in sets varying in size from one to five items. Immediately after encoding, they are prompted to reenact as many items as possible. The movement span task was administered to 90 participants along with standard tests of verbal WM, visuo-spatial WM, and a gesture classification test in which participants judged whether a speaker's gestures were congruent or incongruent with his accompanying speech. Performance on the gesture classification task was not related to standard measures of verbal or visuo-spatial working memory capacity, but was predicted by scores on the movement span task. Results suggest the movement span task can serve as an assessment of individual differences in WM capacity for body-centric information. PMID- 24465438 TI - B vitamin and/or n-3 fatty acid supplementation and health-related quality of life: ancillary findings from the SU.FOL.OM3 randomized trial. AB - BACKGROUND: Despite growing attention to nutrition and quality of life in cardiovascular disease survivors, the impact of dietary factors according to disease type or to quality of life domain is poorly understood. We investigated the effects of B vitamin and/or n-3 fatty acid supplementation on health-related quality of life among survivors of stroke, myocardial infarction, or unstable angina. METHODS: We performed ancillary analyses of the SU.FOL.OM3 trial (2003 2009; France). In total, 2,501 men (mean age = 61 y) and women (mean age = 63 y) were randomized in a 2*2 factorial design to: 1) 0.56 mg 5-methyl tetrahydrofolate, 3 mg vitamin B6, 0.02 mg vitamin B12; 2) 600 mg eicosapentaenoic and docosahexaenoic acids in a 2?1 ratio; 3) B vitamins and n-3 fatty acids combined; or 4) placebo. Health-related quality of life was evaluated at follow-up with the Medical Outcomes Study 36-Item Short Form Health Survey. Data from 2,029 individuals were used in this analysis. RESULTS: After 3.1+/-0.4 y, no effects of supplementation with either B vitamins or n-3 fatty acids on quality of life (physical or mental health domains) were found. However, participants receiving B vitamins had slightly more activity limitations due to emotional problems compared with those not receiving B vitamins (mean difference = 3.8; 95% CI: 0.4, 7.1). A significant interaction of treatment by prior disease revealed an inverse association between n-3 fatty acids and vitality among myocardial infarction survivors (mean difference = 2.9; 95% CI: 0.5, 5.2). CONCLUSIONS: There were no beneficial effects of supplementation with relatively low doses of B vitamins or n-3 fatty acids on health-related quality of life in cardiovascular disease survivors. The adverse effects of B vitamins on activity limitations and of n-3 fatty acids on vitality among individuals with prior myocardial infarction merit confirmation. PMID- 24465439 TI - Aberrant activation of the WNT/beta-catenin signaling pathway in lupus nephritis. AB - OBJECTIVE: The canonical WNT pathway has been implicated as playing important roles in the pathogenesis of a variety of kidney diseases. Recently, WNT pathway activity was reported to be elevated in the renal tissue of a lupus mouse model. This study aimed to evaluate the potential role of the WNT pathway in the pathogenesis of human lupus nephritis. METHODS: The expression of beta-catenin was evaluated in renal biopsy specimens from lupus nephritis patients and control kidney tissues by immunohistochemistry and western blotting. Real-time polymerase chain reaction (RT-PCR) was used to detect RNA expression of beta-catenin, Dkk-1 and Axin2. Plasma concentrations of Dkk-1 were measured by ELISA. RESULTS: Immunohistochemistry and western blotting revealed increased expression of beta catenin in the kidneys of patients with lupus nephritis compared with control kidney tissues (p<0.05), accompanied by an increase in mRNA expression of beta catenin (p<0.01) and axin2 (p<0.05). beta-catenin was significantly greater in LN patients without renal interstitial fibrosis compared with those with renal interstitial fibrosis (p<0.01) at the mRNA expression level; the increase in beta catenin mRNA positively correlated with the creatinine clearance rate (Ccr) and negatively correlated with chronicity indices of renal tissue injury. Greater plasma Dkk-1 concentrations were found in LN patients compared with controls (p<0.05). Plasma Dkk-1 concentrations also correlated negatively with anti-dsDNA antibody levels and positively with serum C3 levels. CONCLUSIONS: The canonical WNT/beta-catenin signaling pathway was activated in lupus nephritis patients, accompanied by an increase in plasma levels of Dkk-1. Altered WNT/beta-catenin signaling was related to the pathogenesis of lupus nephritis and might play a role in renal fibrosis. PMID- 24465440 TI - Engineering the Saccharomyces cerevisiae beta-oxidation pathway to increase medium chain fatty acid production as potential biofuel. AB - Fatty acid-derived biofuels and biochemicals can be produced in microbes using beta-oxidation pathway engineering. In this study, the beta-oxidation pathway of Saccharomyces cerevisiae was engineered to accumulate a higher ratio of medium chain fatty acids (MCFAs) when cells were grown on fatty acid-rich feedstock. For this purpose, the haploid deletion strain Deltapox1 was obtained, in which the sole acyl-CoA oxidase encoded by POX1 was deleted. Next, the POX2 gene from Yarrowia lipolytica, which encodes an acyl-CoA oxidase with a preference for long chain acyl-CoAs, was expressed in the Deltapox1 strain. The resulting Deltapox1 [pox2+] strain exhibited a growth defect because the beta-oxidation pathway was blocked in peroxisomes. To unblock the beta-oxidation pathway, the gene CROT, which encodes carnitine O-octanoyltransferase, was expressed in the Deltapox1 [pox2+] strain to transport the accumulated medium chain acyl-coAs out of the peroxisomes. The obtained Deltapox1 [pox2+, crot+] strain grew at a normal rate. The effect of these genetic modifications on fatty acid accumulation and profile was investigated when the strains were grown on oleic acids-containing medium. It was determined that the engineered strains Deltapox1 [pox2+] and Deltapox1 [pox2+, crot+] had increased fatty acid accumulation and an increased ratio of MCFAs. Compared to the wild-type (WT) strain, the total fatty acid production of the strains Deltapox1 [pox2+] and Deltapox1 [pox2+, crot+] were increased 29.5% and 15.6%, respectively. The intracellular level of MCFAs in Deltapox1 [pox2+] and Deltapox1 [pox2+, crot+] increased 2.26- and 1.87-fold compared to the WT strain, respectively. In addition, MCFAs in the culture medium increased 3.29 fold and 3.34-fold compared to the WT strain. These results suggested that fatty acids with an increased MCFAs ratio accumulate in the engineered strains with a modified beta-oxidation pathway. Our approach exhibits great potential for transforming low value fatty acid-rich feedstock into high value fatty acid derived products. PMID- 24465441 TI - Cenozoic planktonic marine diatom diversity and correlation to climate change. AB - Marine planktonic diatoms export carbon to the deep ocean, playing a key role in the global carbon cycle. Although commonly thought to have diversified over the Cenozoic as global oceans cooled, only two conflicting quantitative reconstructions exist, both from the Neptune deep-sea microfossil occurrences database. Total diversity shows Cenozoic increase but is sample size biased; conventional subsampling shows little net change. We calculate diversity from a separately compiled new diatom species range catalog, and recalculate Neptune subsampled-in-bin diversity using new methods to correct for increasing Cenozoic geographic endemism and decreasing Cenozoic evenness. We find coherent, substantial Cenozoic diversification in both datasets. Many living cold water species, including species important for export productivity, originate only in the latest Miocene or younger. We make a first quantitative comparison of diatom diversity to the global Cenozoic benthic ?(18)O (climate) and carbon cycle records (?(13)C, and 20-0 Ma pCO2). Warmer climates are strongly correlated with lower diatom diversity (raw: rho = .92, p<.001; detrended, r = .6, p = .01). Diatoms were 20% less diverse in the early late Miocene, when temperatures and pCO2 were only moderately higher than today. Diversity is strongly correlated to both ?(13)C and pCO2 over the last 15 my (for both: r>.9, detrended r>.6, all p<.001), but only weakly over the earlier Cenozoic, suggesting increasingly strong linkage of diatom and climate evolution in the Neogene. Our results suggest that many living marine planktonic diatom species may be at risk of extinction in future warm oceans, with an unknown but potentially substantial negative impact on the ocean biologic pump and oceanic carbon sequestration. We cannot however extrapolate our my-scale correlations with generic climate proxies to anthropogenic time-scales of warming without additional species-specific information on proximate ecologic controls. PMID- 24465442 TI - Genetic polymorphism characteristics of Brucella canis isolated in China. AB - In China, brucellosis is an endemic disease typically caused by Brucella melitensis infection (biovars 1 and 3). Brucella canis infection in dogs has not traditionally recognized as a major problem. In recent years however, brucellosis resulting from Brucella canis infection has also been reported, suggesting that infections from this species may be increasing. Data concerning the epidemiology of brucellosis resulting from Brucella canis infection is limited. Therefore, the purpose of this study was to assess the diversity among Chinese Brucella canis strains for epidemiological purposes. First, we employed a 16-marker VNTR assay (Brucella MLVA-16) to assess the diversity and epidemiological relationship of 29 Brucella canis isolates from diverse locations throughout China with 38 isolates from other countries. MLVA-16 analysis separated the 67 Brucella canis isolates into 57 genotypes that grouped into five clusters with genetic similarity coefficients ranging from 67.73 to 100%. Moreover, this analysis revealed a new genotype (2-3-9-11-3-1-5-1:118), which was present in two isolates recovered from Guangxi in 1986 and 1987. Second, multiplex PCR and sequencing analysis were used to determine whether the 29 Chinese Brucella canis isolates had the characteristic BMEI1435 gene deletion. Only two isolates had this deletion. Third, amplification of the omp25 gene revealed that 26 isolates from China had a T545C mutation. Collectively, this study reveals that considerable diversity exists among Brucella canis isolates in China and provides resources for studying the genetic variation and microevolution of Brucella. PMID- 24465443 TI - Randomised pharmacokinetic trial of rifabutin with lopinavir/ritonavir antiretroviral therapy in patients with HIV-associated tuberculosis in Vietnam. AB - BACKGROUND: Rifampicin and protease inhibitors are difficult to use concomitantly in patients with HIV-associated tuberculosis because of drug-drug interactions. Rifabutin has been proposed as an alternative rifamycin, but there is concern that the current recommended dose is suboptimal. The principal aim of this study was to compare bioavailability of two doses of rifabutin (150 mg three times per week and 150 mg daily) in patients with HIV-associated tuberculosis who initiated lopinavir/ritonavir-based antiretroviral therapy in Vietnam. Concentrations of lopinavir/ritonavir were also measured. METHODS: This was a randomized, open label, multi-dose, two-arm, cross-over trial, conducted in Vietnamese adults with HIV-associated tuberculosis in Ho Chi Minh City (Clinical trial registry number NCT00651066). Rifabutin pharmacokinetics were evaluated before and after the introduction of lopinavir/ritonavir -based antiretroviral therapy using patient randomization lists. Serial rifabutin and 25-O-desacetyl rifabutin concentrations were measured during a dose interval after 2 weeks of rifabutin 300 mg daily, after 3 weeks of rifabutin 150 mg daily with lopinavir/ritonavir and after 3 weeks of rifabutin 150 mg three times per week with lopinavir/ritonavir. RESULTS: Sixteen and seventeen patients were respectively randomized to the two arms, and pharmacokinetic analysis carried out in 12 and 13 respectively. Rifabutin 150 mg daily with lopinavir/ritonavir was associated with a 32% mean increase in rifabutin average steady state concentration compared with rifabutin 300 mg alone. In contrast, the rifabutin average steady state concentration decreased by 44% when rifabutin was given at 150 mg three times per week with lopinavir/ritonavir. With both dosing regimens, 2 - 5 fold increases of the 25-O desacetyl- rifabutin metabolite were observed when rifabutin was given with lopinavir/ritonavir compared with rifabutin alone. The different doses of rifabutin had no significant effect on lopinavir/ritonavir plasma concentrations. CONCLUSIONS: Based on these findings, rifabutin 150 mg daily may be preferred when co-administered with lopinavir/ritonavir in patients with HIV-associated tuberculosis. TRIAL REGISTRATION: ClinicalTrials.gov NCT00651066. PMID- 24465444 TI - A cluster randomized controlled trial evaluating the efficacy of peer mentors to support South African women living with HIV and their infants. AB - OBJECTIVE: We evaluate the effect of clinic-based support by HIV-positive Peer Mentors, in addition to standard clinic care, on maternal and infant well-being among Women Living with HIV (WLH) from pregnancy through the infant's first year of life. METHODS: In a cluster randomized controlled trial in KwaZulu-Natal, South Africa, eight clinics were randomized for pregnant WLH to receive either: a Standard Care condition (SC; 4 clinics; n = 656 WLH); or an Enhanced Intervention (EI; 4 clinics; n = 544 WLH). WLH in the EI were invited to attend four antenatal and four postnatal meetings led by HIV-positive Peer Mentors, in addition to SC. WLH were recruited during pregnancy, and at least two post-birth assessment interviews were completed by 57% of WLH at 1.5, 6 or 12 months. EI's effect was ascertained on 19 measures of maternal and infant well-being using random effects regressions to control for clinic clustering. A binomial test for correlated outcomes evaluated EI's overall efficacy. FINDINGS: WLH attended an average of 4.1 sessions (SD = 2.0); 13% did not attend any sessions. Significant overall benefits were found in EI compared to SC using the binomial test. Secondarily, over time, WLH in the EI reported significantly fewer depressive symptoms and fewer underweight infants than WLH in the SC condition. EI WLH were significantly more likely to use one feeding method for six months and exclusively breastfeed their infants for at least 6 months. CONCLUSIONS: WLH benefit by support from HIV positive Peer Mentors, even though EI participation was partial, with incomplete follow-up rates from 6-12 months. TRIAL REGISTRATION: ClinicalTrials.gov NCT00972699. PMID- 24465445 TI - Brain processing of visual stimuli representing sexual penetration versus core and animal-reminder disgust in women with lifelong vaginismus. AB - It has been proposed that disgust evolved to protect humans from contamination. Through eliciting the overwhelming urge to withdraw from the disgusting stimuli, it would facilitate avoidance of contact with pathogens. The physical proximity implied in sexual intercourse provides ample opportunity for contamination and may thus set the stage for eliciting pathogen disgust. Building on this, it has been argued that the involuntary muscle contraction characteristic of vaginismus (i.e., inability to have vaginal penetration) may be elicited by the prospect of penetration by potential contaminants. To further investigate this disgust-based interpretation of vaginismus (in DSM-5 classified as a Genito-Pelvic Pain/Penetration Disorder, GPPPD) we used functional magnetic resonance imaging (fMRI) to examine if women with vaginismus (n = 21) show relatively strong convergence in their brain responses towards sexual penetration- and disgust related pictures compared to sexually asymptomatic women (n = 21) and women suffering from vulvar pain (dyspareunia/also classified as GPPPD in the DSM-5, n = 21). At the subjective level, both clinical groups rated penetration stimuli as more disgusting than asymptomatic women. However, the brain responses to penetration stimuli did not differ between groups. In addition, there was considerable conjoint brain activity in response to penetration and disgust pictures, which yield for both animal-reminder (e.g., mutilation) and core (e.g., rotten food) disgust domains. However, this overlap in brain activation was similar for all groups. A possible explanation for the lack of vaginismus specific brain responses lies in the alleged female ambiguity (procreation/pleasure vs. contamination/disgust) toward penetration: generally in women a (default) disgust response tendency may prevail in the absence of sexual readiness. Accordingly, a critical next step would be to examine the processing of penetration stimuli following the induction of sexual arousal. PMID- 24465446 TI - Functional analysis of water stress-responsive soybean GmNAC003 and GmNAC004 transcription factors in lateral root development in arabidopsis. AB - In Arabidopsis, NAC (NAM, ATAF and CUC) transcription factors have been found to promote lateral root number through the auxin signaling pathway. In the present study, the role of water stress-inducible soybean GmNAC003 and GmNAC004 genes in the enhancement of lateral root development under water deficit conditions was investigated. Both genes were highly expressed in roots, leaves and flowers of soybean and were strongly induced by water stress and moderately induced by a treatment with abscisic acid (ABA). They showed a slight response to treatment with 2,4-dichlorophenoxyacetic acid (2,4-D). The transgenic Arabidopsis plants overexpressing GmNAC004 showed an increase in lateral root number and length under non-stress conditions and maintained higher lateral root number and length under mild water stress conditions compared to the wild-type (WT), while the transgenic plants overexpressing GmNAC003 did not show any response. However, LR development of GmNAC004 transgenic Arabidopsis plants was not enhanced in the water-stressed compared to the well-watered treatment. In the treatment with ABA, LR density of the GmNAC004 transgenic Arabidopsis was less suppressed than that of the WT, suggesting that GmNAC004 counteracts ABA-induced inhibition of lateral root development. In the treatment with 2,4-D, lateral root density was enhanced in both GmNAC004 transgenic Arabidopsis and WT plants but the promotion was higher in the transgenic plants. Conversely, in the treatment with naphthylphthalamic acid (NPA), lateral root density was inhibited and there was no difference in the phenotype of the GmNAC004 transgenic Arabidopsis and WT plants, indicating that auxin is required for the action of GmNAC004. Transcript analysis for a number of known auxin and ABA related genes showed that GmNAC004's role may suppress ABA signaling but promote auxin signaling to increase lateral root development in the Arabidopsis heterologous system. PMID- 24465447 TI - Do CS-US pairings actually matter? A within-subject comparison of instructed fear conditioning with and without actual CS-US pairings. AB - Previous research showed that instructions about CS-US pairings can lead to fear of the CS even when the pairings are never presented. In the present study, we examined whether the experience of CS-US pairings adds to the effect of instructions by comparing instructed conditioning with and without actual CS-US pairings in a within-subject design. Thirty-two participants saw three fractals as CSs (CS(+)1, CS(+)2, CS(-)) and received electric shocks as USs. Before the start of a so-called training phase, participants were instructed that both CS(+)1 and CS(+)2 would be followed by the US, but only CS(+)1 was actually paired with the US. The absence of the US after CS(+)2 was explained in such a way that participants would not doubt the instructions about the CS(+)2-US relation. After the training phase, a test phase was carried out. In this phase, participants expected the US after both CS(+)s but none of the CS(+)s was actually paired with the US. During test, self-reported fear was initially higher for CS(+)1 than for CS(+)2, which indicates that the experience of actual CS-US pairings adds to instructions about these pairings. On the other hand, the CS(+)s elicited similar skin conductance responses and US expectancies. Theoretical and clinical implications are discussed. PMID- 24465448 TI - Why publishing everything is more effective than selective publishing of statistically significant results. AB - BACKGROUND: De Winter and Happee examined whether science based on selective publishing of significant results may be effective in accurate estimation of population effects, and whether this is even more effective than a science in which all results are published (i.e., a science without publication bias). Based on their simulation study they concluded that "selective publishing yields a more accurate meta-analytic estimation of the true effect than publishing everything, (and that) publishing nonreplicable results while placing null results in the file drawer can be beneficial for the scientific collective" (p.4). METHODS AND FINDINGS: Using their scenario with a small to medium population effect size, we show that publishing everything is more effective for the scientific collective than selective publishing of significant results. Additionally, we examined a scenario with a null effect, which provides a more dramatic illustration of the superiority of publishing everything over selective publishing. CONCLUSION: Publishing everything is more effective than only reporting significant outcomes. PMID- 24465449 TI - A comparison of the predictive power of anthropometric indices for hypertension and hypotension risk. AB - BACKGROUND AND AIMS: It is commonly accepted that body fat distribution is associated with hypertension, but the strongest anthropometric indicator of the risk of hypertension is still controversial. Furthermore, no studies on the association of hypotension with anthropometric indices have been reported. The objectives of the present study were to determine the best predictors of hypertension and hypotension among various anthropometric indices and to assess the use of combined indices as a method of improving the predictive power in adult Korean women and men. METHODS: For 12789 subjects 21-85 years of age, we assessed 41 anthropometric indices using statistical analyses and data mining techniques to determine their ability to discriminate between hypertension and normotension as well as between hypotension and normotension. We evaluated the predictive power of combined indices using two machine learning algorithms and two variable subset selection techniques. RESULTS: The best indicator for predicting hypertension was rib circumference in both women (p = <0.0001; OR = 1.813; AUC = 0.669) and men (p = <0.0001; OR = 1.601; AUC = 0.627); for hypotension, the strongest predictor was chest circumference in women (p = <0.0001; OR = 0.541; AUC = 0.657) and neck circumference in men (p = <0.0001; OR = 0.522; AUC = 0.672). In experiments using combined indices, the areas under the receiver operating characteristic curves (AUC) for the prediction of hypertension risk in women and men were 0.721 and 0.652, respectively, according to the logistic regression with wrapper-based variable selection; for hypotension, the corresponding values were 0.675 in women and 0.737 in men, according to the naive Bayes with wrapper-based variable selection. CONCLUSIONS: The best indicators of the risk of hypertension and the risk of hypotension may differ. The use of combined indices seems to slightly improve the predictive power for both hypertension and hypotension. PMID- 24465450 TI - Barriers to advance care planning in cancer, heart failure and dementia patients: a focus group study on general practitioners' views and experiences. AB - BACKGROUND: The long-term and often lifelong relationship of general practitioners (GPs) with their patients is considered to make them the ideal initiators of advance care planning (ACP). However, in general the incidence of ACP discussions is low and ACP seems to occur more often for cancer patients than for those with dementia or heart failure. OBJECTIVE: To identify the barriers, from GPs' perspective, to initiating ACP and to gain insight into any differences in barriers between the trajectories of patients with cancer, heart failure and dementia. METHOD: Five focus groups were held with GPs (n = 36) in Flanders, Belgium. The focus group discussions were transcribed verbatim and analyzed using the method of constant comparative analysis. RESULTS: THREE TYPES OF BARRIERS WERE DISTINGUISHED: barriers relating to the GP, to the patient and family and to the health care system. In cancer patients, a GP's lack of knowledge about treatment options and the lack of structural collaboration between the GP and specialist were expressed as barriers. Barriers that occured more often with heart failure and dementia were the lack of GP familiarity with the terminal phase, the lack of key moments to initiate ACP, the patient's lack of awareness of their diagnosis and prognosis and the fact that patients did not often initiate such discussions themselves. The future lack of decision-making capacity of dementia patients was reported by the GPs as a specific barrier for the initiation of ACP. CONCLUSION: The results of our study contribute to a better understanding of the factors hindering GPs in initiating ACP. Multiple barriers need to be overcome, of which many can be addressed through the development of practical guidelines and educational interventions. PMID- 24465452 TI - The increasing predictive validity of self-rated health. AB - Using the 1980 to 2002 General Social Survey, a repeated cross-sectional study that has been linked to the National Death Index through 2008, this study examines the changing relationship between self-rated health and mortality. Research has established that self-rated health has exceptional predictive validity with respect to mortality, but this validity may be deteriorating in light of the rapid medicalization of seemingly superficial conditions and increasingly high expectations for good health. Yet the current study shows the validity of self-rated health is increasing over time. Individuals are apparently better at assessing their health in 2002 than they were in 1980 and, for this reason, the relationship between self-rated health and mortality is considerably stronger across all levels of self-rated health. Several potential mechanisms for this increase are explored. More schooling and more cognitive ability increase the predictive validity of self-rated health, but neither of these influences explains the growing association between self-rated health and mortality. The association is also invariant to changing causes of death, including a decline in accidental deaths, which are, by definition, unanticipated by the individual. Using data from the final two waves of data, we find suggestive evidence that exposure to more health information is the driving force, but we also show that the source of information is very important. For example, the relationship between self-rated health and mortality is smaller among those who use the internet to find health information than among those who do not. PMID- 24465451 TI - Surfactant secretion in LRRK2 knock-out rats: changes in lamellar body morphology and rate of exocytosis. AB - Leucine-rich repeat kinase 2 (LRRK2) is known to play a role in the pathogenesis of various diseases including Parkinson disease, morbus Crohn, leprosy and cancer. LRRK2 is suggested to be involved in a number of cell biological processes such as vesicular trafficking, transcription, autophagy and lysosomal pathways. Recent histological studies of lungs of LRRK2 knock-out (LRRK2 -/-) mice revealed significantly enlarged lamellar bodies (LBs) in alveolar type II (ATII) epithelial cells. LBs are large, lysosome-related storage organelles for pulmonary surfactant, which is released into the alveolar lumen upon LB exocytosis. In this study we used high-resolution, subcellular live-cell imaging assays to investigate whether similar morphological changes can be observed in primary ATII cells from LRRK2 -/- rats and whether such changes result in altered LB exocytosis. Similarly to the report in mice, ATII cells from LRRK2 -/- rats contained significantly enlarged LBs resulting in a >50% increase in LB volume. Stimulation of ATII cells with ATP elicited LB exocytosis in a significantly increased proportion of cells from LRRK2 -/- animals. LRRK2 -/- cells also displayed increased intracellular Ca(2+) release upon ATP treatment and significant triggering of LB exocytosis. These findings are in line with the strong Ca(2+)-dependence of LB fusion activity and suggest that LRRK2 -/- affects exocytic response in ATII cells via modulating intracellular Ca(2+) signaling. Post-fusion regulation of surfactant secretion was unaltered. Actin coating of fused vesicles and subsequent vesicle compression to promote surfactant expulsion were comparable in cells from LRRK2 -/- and wt animals. Surprisingly, surfactant (phospholipid) release from LRRK2 -/- cells was reduced following stimulation of LB exocytosis possibly due to impaired LB maturation and surfactant loading of LBs. In summary our results suggest that LRRK2 -/- affects LB size, modulates intracellular Ca(2+) signaling and promotes LB exocytosis upon stimulation of ATII cells with ATP. PMID- 24465454 TI - Factors affecting de novo urinary retention after Holmium laser enucleation of the prostate. AB - OBJECTIVE: Patients can experience urinary retention (UR) after Holmium laser enucleation of the prostate (HoLEP) that requires bladder distension during the procedure. The aim of this retrospective study is to identify factors affecting the UR after HoLEP. MATERIALS AND METHODS: 336 patients, which underwent HoLEP for a symptomatic benign prostatic hyperplasia between July 2008 and March 2012, were included in this study. Urethral catheters were routinely removed one or two days after surgery. UR was defined as the need for an indwelling catheter placement following a failure to void after catheter removal. Demographic and clinical parameters were compared between the UR (n = 37) and the non-urinary retention (non-UR; n = 299) groups. RESULTS: The mean age of patients was 68.3 (+/-6.5) years and the mean operative time was 75.3 (+/-37.4) min. Thirty seven patients (11.0%) experienced a postoperative UR. UR patients voided catheter free an average of 1.9 (+/-1.7) days after UR. With regard to the causes of UR, 24 (7.1%) and 13 (3.9%) patients experienced a blood clot-related UR and a non-clot related UR respectively. Using multivariate analysis (p<0.05), we found significant differences between the UR and the non-UR groups with regard to a morcellation efficiency (OR 0.701, 95% CI 0.498-0.988) and a bleeding-related complication, such as, a reoperation for bleeding (OR 0.039, 95% CI 0.004-0.383) or a transfusion (OR 0.144, 95% CI 0.027-0.877). Age, history of diabetes, prostate volume, pre-operative post-void residual, bladder contractility index, learning curve, and operative time were not significantly associated with the UR (p>0.05). CONCLUSIONS: De novo UR after HoLEP was found to be self-limited and it was not related to learning curve, patient age, diabetes, or operative time. Efficient morcellation and careful control of bleeding, which reduces clot formation, decrease the risk of UR after HoLEP. PMID- 24465455 TI - Potential impacts of climate warming on water supply reliability in the Tuolumne and Merced River Basins, California. AB - We present an integrated hydrology/water operations simulation model of the Tuolumne and Merced River Basins, California, using the Water Evaluation and Planning (WEAP) platform. The model represents hydrology as well as water operations, which together influence water supplied for agricultural, urban, and environmental uses. The model is developed for impacts assessment using scenarios for climate change and other drivers of water system behavior. In this paper, we describe the model structure, its representation of historical streamflow, agricultural and urban water demands, and water operations. We describe projected impacts of climate change on hydrology and water supply to the major irrigation districts in the area, using uniform 2 degrees C, 4 degrees C, and 6 degrees C increases applied to climate inputs from the calibration period. Consistent with other studies, we find that the timing of hydrology shifts earlier in the water year in response to temperature warming (5-21 days). The integrated agricultural model responds with increased water demands 2 degrees C (1.4-2.0%), 4 degrees C (2.8-3.9%), and 6 degrees C (4.2-5.8%). In this sensitivity analysis, the combination of altered hydrology and increased demands results in decreased reliability of surface water supplied for agricultural purposes, with modeled quantity-based reliability metrics decreasing from a range of 0.84-0.90 under historical conditions to 0.75-0.79 under 6 degrees C warming scenario. PMID- 24465453 TI - The diagnostic performance of coronary artery angiography with 64-MSCT and post 64-MSCT: systematic review and meta-analysis. AB - PURPOSE: To comprehensively investigate the diagnostic performance of coronary artery angiography with 64-MDCT and post 64-MDCT. MATERIALS AND METHODS: PubMed was searched for all published studies that evaluated coronary arteries with 64 MDCT and post 64-MDCT. The clinical diagnostic role was evaluated by applying the likelihood ratios (LRs) to calculate the post-test probability based on Bayes' theorem. RESULTS: 91 studies that met our inclusion criteria were ultimately included in the analysis. The pooled positive and negative LRs at patient level were 8.91 (95% CI, 7.53, 10.54) and 0.02 (CI, 0.01, 0.03), respectively. For studies that did not claim that non-evaluable segments were included, the pooled positive and negative LRs were 11.16 (CI, 8.90, 14.00) and 0.01 (CI, 0.01, 0.03), respectively. For studies including uninterruptable results, the diagnostic performance decreased, with the pooled positive LR 7.40 (CI, 6.00, 9.13) and negative LR 0.02 (CI, 0.01, 0.03). The areas under the summary ROC curve were 0.98 (CI, 0.97 to 0.99) for 64-MDCT and 0.96 (CI, 0.94 to 0.98) for post 64-MDCT, respectively. For references explicitly stating that the non-assessable segments were included during analysis, a post-test probability of negative results >95% and a positive post-test probability <95% could be obtained for patients with a pre-test probability of <73% for coronary artery disease (CAD). On the other hand, when the pre-test probability of CAD was >73%, the diagnostic role was reversed, with a positive post-test probability of CAD >95% and a negative post test probability of CAD <95%. CONCLUSION: The diagnostic performance of post 64 MDCT does not increase as compared with 64-MDCT. CTA, overall, is a test of exclusion for patients with a pre-test probability of CAD<73%, while for patients with a pre-test probability of CAD>73%, CTA is a test used to confirm the presence of CAD. PMID- 24465456 TI - Flexible integration of laser myringotomy and ventilation tube for bilateral Otitis media with effusion: analysis of laser tympanostomy versus ventilation tube. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of laser myringotomy (LM) compared to ventilation tube (VT), and to assess the clinical success criteria of LM-assisted VT insertion as the flexible alternatives avoiding GA for the treatment of bilateral consistent otitis media with effusion (OME). METHODS AND FINDINGS: LM under topical anesthesia was followed by VT insertion in cooperative children using Acuspot(r) 712 CO2 laser micromanipulator attached microscope. Sixty children failed VT and bilateral laser tympanostomy was done (group LL), and 130 children tolerated VT on one side but LM on the other side (group LV). The efficacy of LM was compared to VT regarding recurrent effusion and reoperation as the outcome measure; firstly, by ear-to-ear matched pair analysis in LV, and secondly between LL vs. LV. Long-term outcome was compared to control group who received both VT under GA (group GAVT) regarding the outcome of additional VT and GA. RESULTS: The effectiveness of LM per ear was equivocal as 46.9% and 40.8% in LV and LL respectively; but the effectiveness per children was further lower in LL as 28.3%, which was a limitation of LM for bilateral OME. LL required reoperation in 71.7% mostly requiring impending GA in 51.7% within 4.7 months, thus was a controversial treatment. But LV required GA in 20.8% during the 27.2 months long-term follow-up, which was second set of VT and adenoidectomy that were also comparably required in GAVT control with multiple GA. CONCLUSION: Standard GAVT was more recommended for bilateral OME than bilateral LM (LL) in our practice. But LM was selectively effective for some children, that combined approach with LM plus VT provided comparable period to outgrow OME as effectively as GAVT, when LM was supplemented with one VT side with recovered hearing. PMID- 24465457 TI - Plasma selenium biomarkers in low income black and white americans from the southeastern United States. AB - Biomarkers of selenium are necessary for assessing selenium status in humans, since soil variation hinders estimation of selenium intake from foods. In this study, we measured the concentration of plasma selenium, selenoprotein P (SEPP1), and glutathione peroxidase (GPX3) activity and their interindividual differences in 383 low-income blacks and whites selected from a stratified random sample of adults aged 40-79 years, who were participating in a long-term cohort study in the southeastern United States (US). We assessed the utility of these biomarkers to determine differences in selenium status and their association with demographic, socio-economic, dietary, and other indicators. Dietary selenium intake was assessed using a validated food frequency questionnaire designed for the cohort, matched with region-specific food selenium content, and compared with the US Recommended Dietary Allowances (RDA) set at 55 ug/day. We found that SEPP1, a sensitive biomarker of selenium nutritional status, was significantly lower among blacks than whites (mean 4.4 +/- 1.1 vs. 4.7 +/- 1.0 mg/L, p = 0.006), with blacks less than half as likely to have highest vs. lowest quartile SEPP1 concentration (Odds Ratio (OR) 0.4, 95% Confidence Interval (CI) 0.2-0.8). The trend in a similar direction was observed for plasma selenium among blacks and whites, (mean 115 +/- 15.1 vs. 118 +/- 17.7 ug/L, p = 0.08), while GPX3 activity did not differ between blacks and whites (136 +/- 33.3 vs. 132 +/- 33.5 U/L, p = 0.320). Levels of the three biomarkers were not correlated with estimated dietary selenium intake, except for SEPP1 among 10% of participants with the lowest selenium intake (<= 57 ug/day). The findings suggest that SEPP1 may be an effective biomarker of selenium status and disease risk in adults and that low selenium status may disproportionately affect black and white cohort participants. PMID- 24465458 TI - Dihydroartemisinin-piperaquine treatment of multidrug resistant falciparum and vivax malaria in pregnancy. AB - BACKGROUND: Artemisinin combination therapy (ACT) is recommended for the treatment of multidrug resistant malaria in the second and third trimesters of pregnancy, but the experience with ACTs is limited. We review the exposure of pregnant women to the combination dihydroartemisinin-piperaquine over a 6 year period. METHODS: From April 2004-June 2009, a prospective hospital-based surveillance screened all pregnant women for malaria and documented maternal and neonatal outcomes. RESULTS: Data were available on 6519 pregnant women admitted to hospital; 332 (5.1%) women presented in the first trimester, 324 (5.0%) in the second, 5843 (89.6%) in the third, and in 20 women the trimester was undocumented. Peripheral parasitaemia was confirmed in 1682 women, of whom 106 (6.3%) had severe malaria. Of the 1217 women admitted with malaria in the second and third trimesters without an impending adverse outcome, those treated with DHP were more likely to be discharged with an ongoing pregnancy compared to those treated with a non-ACT regimen (Odds Ratio OR = 2.48 [1.26-4.86]); p = 0.006. However in the first trimester 63% (5/8) of women treated with oral DHP miscarried compared to 2.6% (1/38) of those receiving oral quinine; p<0.001. Of the 847 women admitted for delivery those reporting a history of malaria during their pregnancy who had been treated with quinine-based regimens rather than DHP had a higher risk of malaria at delivery (adjusted OR = 1.56 (95%CI 0.97-2.5), p = 0.068) and perinatal mortality (adjusted OR = 3.17 [95%CI: 1.17-8.60]; p = 0.023). CONCLUSIONS: In the second and third trimesters of pregnancy, a three day course of DHP simplified antimalarial treatment and had significant benefits over quinine-based regimens in reducing recurrent malaria and poor fetal outcome. These data provide reassuring evidence for the rational design of prospective randomized clinical trials and pharmacokinetic studies. PMID- 24465459 TI - Utilizing nanobody technology to target non-immunodominant domains of VAR2CSA. AB - Placental malaria is a major health problem for both pregnant women and their fetuses in malaria endemic regions. It is triggered by the accumulation of Plasmodium falciparum-infected erythrocytes (IE) in the intervillous spaces of the placenta and is associated with foetal growth restriction and maternal anemia. IE accumulation is supported by the binding of the parasite-expressed protein VAR2CSA to placental chondroitin sulfate A (CSA). Defining specific CSA binding epitopes of VAR2CSA, against which to target the immune response, is essential for the development of a vaccine aimed at blocking IE adhesion. However, the development of a VAR2CSA adhesion-blocking vaccine remains challenging due to (i) the large size of VAR2CSA and (ii) the extensive immune selection for polymorphisms and thereby non-neutralizing B-cell epitopes. Camelid heavy-chain-only antibodies (HcAbs) are known to target epitopes that are less immunogenic to classical IgG and, due to their small size and protruding antigen binding loop, able to reach and recognize cryptic, conformational epitopes which are inaccessible to conventional antibodies. The variable heavy chain (VHH) domain is the antigen-binding site of camelid HcAbs, the so called Nanobody, which represents the smallest known (15 kDa) intact, native antigen-binding fragment. In this study, we have used the Nanobody technology, an approach new to malaria research, to generate small and functional antibody fragments recognizing unique epitopes broadly distributed on VAR2CSA. PMID- 24465460 TI - Soil aggregates and associated organic matter under conventional tillage, no tillage, and forest succession after three decades. AB - Impacts of land use on soil organic C (SOC) are of interest relative to SOC sequestration and soil sustainability. The role of aggregate stability in SOC storage under contrasting land uses has been of particular interest relative to conventional tillage (CT) and no-till (NT) agriculture. This study compares soil structure and SOC fractions at the 30-yr-old Horseshoe Bend Agroecosystem Experiment (HSB). This research is unique in comparing NT and CT with adjacent land concurrently undergoing forest succession (FS) and in sampling to depths (15 28 cm) previously not studied at HSB. A soil moving experiment (SME) was also undertaken to monitor 1-yr changes in SOC and aggregation. After 30 years, enhanced aggregate stability under NT compared to CT was limited to a depth of 5 cm, while enhanced aggregate stability under FS compared to CT occurred to a depth of 28 cm and FS exceeded NT from 5-28 cm. Increases in SOC concentrations generally followed the increases in stability, except that no differences in SOC concentration were observed from 15-28 cm despite greater aggregate stability. Land use differences in SOC were explained equally by differences in particulate organic carbon (POC) and in silt-clay associated fine C. Enhanced structural stability of the SME soil was observed under FS and was linked to an increase of 1 Mg SOC ha(-1) in 0-5 cm, of which 90% could be attributed to a POC increase. The crushing of macroaggregates in the SME soil also induced a 10% reduction in SOC over 1 yr that occurred under all three land uses from 5-15 cm. The majority of this loss was in the fine C fraction. NT and FS ecosystems had greater aggregation and carbon storage at the soil surface but only FS increased aggregation below the surface, although in the absence of increased carbon storage. PMID- 24465462 TI - Predicting active users' personality based on micro-blogging behaviors. AB - Because of its richness and availability, micro-blogging has become an ideal platform for conducting psychological research. In this paper, we proposed to predict active users' personality traits through micro-blogging behaviors. 547 Chinese active users of micro-blogging participated in this study. Their personality traits were measured by the Big Five Inventory, and digital records of micro-blogging behaviors were collected via web crawlers. After extracting 839 micro-blogging behavioral features, we first trained classification models utilizing Support Vector Machine (SVM), differentiating participants with high and low scores on each dimension of the Big Five Inventory [corrected]. The classification accuracy ranged from 84% to 92%. We also built regression models utilizing PaceRegression methods, predicting participants' scores on each dimension of the Big Five Inventory. The Pearson correlation coefficients between predicted scores and actual scores ranged from 0.48 to 0.54. Results indicated that active users' personality traits could be predicted by micro-blogging behaviors. PMID- 24465461 TI - The biological effect of large single doses: a possible role for non-targeted effects in cell inactivation. AB - BACKGROUND AND PURPOSE: Novel radiotherapy techniques increasingly use very large dose fractions. It has been argued that the biological effect of large dose fractions may differ from that of conventional fraction sizes. The purpose was to study the biological effect of large single doses. MATERIAL AND METHODS: Clonogenic cell survival of MCF7 and MDA-MB-231 cells was determined after direct X-ray irradiation, irradiation of feeder cells, or transfer of conditioned medium (CM). Cell-cycle distributions and the apoptotic sub-G1 fraction were measured by flow cytometry. Cytokines in CM were quantified by a cytokine antibody array. gammaH2AX foci were detected by immunofluorescence microscopy. RESULTS: The surviving fraction of MCF7 cells irradiated in vitro with 12 Gy showed an 8.5 fold decrease (95% c.i.: 4.4-16.3; P<0.0001) when the density of irradiated cells was increased from 10 to 50*10(3) cells per flask. Part of this effect was due to a dose-dependent transferrable factor as shown in CM experiments in the dose range 5-15 Gy. While no effect on apoptosis and cell cycle distribution was observed, and no differentially expressed cytokine could be identified, the transferable factor induced prolonged expression of gammaH2AX DNA repair foci at 1-12 h. CONCLUSIONS: A dose-dependent non-targeted effect on clonogenic cell survival was found in the dose range 5-15 Gy. The dependence of SF on cell numbers at high doses would represent a "cohort effect" in vivo. These results support the hypothesis that non-targeted effects may contribute to the efficacy of very large dose fractions in radiotherapy. PMID- 24465463 TI - PR65A phosphorylation regulates PP2A complex signaling. AB - Serine-threonine Protein phosphatase 2 A (PP2A), a member of the PPP family of phosphatases, regulates a variety of essential cellular processes, including cell cycling, DNA replication, transcription, translation, and secondary signaling pathways. In the heart, increased PP2A activity/signaling has been linked to cardiac remodeling, contractile dysfunction and, in failure, arrythmogenicity. The core PP2A complex is a hetero-trimeric holoenzyme consisting of a 36 kDa catalytic subunit (PP2Ac); a regulatory scaffold subunit of 65 kDa (PR65A or PP2Aa); and one of at least 18 associated variable regulatory proteins (B subunits) classified into 3 families. In the present study, three in vivo sites of phosphorylation in cardiac PR65A are identified (S303, T268, S314). Using HEK cells transfected with recombinant forms of PR65A with phosphomimetic (P-PR65A) and non-phosphorylated (N-PR65A) amino acid substitutions at these sites, these phosphorylations were shown to inhibit the interaction of PR65A with PP2Ac and PP2A holoenzyme signaling. Forty-seven phospho-proteins were increased in abundance in HEK cells transfected with P-PR65A versus N-PR65A by phospho-protein profiling using 2D-DIGE analysis on phospho-enriched whole cell protein extracts. Among these proteins were elongation factor 1alpha (EF1A), elongation factor 2, heat shock protein 60 (HSP60), NADPH-dehydrogenase 1 alpha sub complex, annexin A, and PR65A. Compared to controls, failing hearts from the Dahl rat had less phosphorylated PR65A protein abundance and increased PP2A activity. Thus, PR65A phosphorylation is an in vivo mechanism for regulation of the PP2A signaling complex and increased PP2A activity in heart failure. PMID- 24465464 TI - Pneumococcal carriage in sub-Saharan Africa--a systematic review. AB - BACKGROUND: Pneumococcal epidemiology varies geographically and few data are available from the African continent. We assess pneumococcal carriage from studies conducted in sub-Saharan Africa (sSA) before and after the pneumococcal conjugate vaccine (PCV) era. METHODS: A search for pneumococcal carriage studies published before 2012 was conducted to describe carriage in sSA. The review also describes pneumococcal serotypes and assesses the impact of vaccination on carriage in this region. RESULTS: Fifty-seven studies were included in this review with the majority (40.3%) from South Africa. There was considerable variability in the prevalence of carriage between studies (I-squared statistic = 99%). Carriage was higher in children and decreased with increasing age, 63.2% (95% CI: 55.6-70.8) in children less than 5 years, 42.6% (95% CI: 29.9-55.4) in children 5-15 years and 28.0% (95% CI: 19.0-37.0) in adults older than 15 years. There was no difference in the prevalence of carriage between males and females in 9/11 studies. Serotypes 19F, 6B, 6A, 14 and 23F were the five most common isolates. A meta-analysis of four randomized trials of PCV vaccination in children aged 9-24 months showed that carriage of vaccine type (VT) serotypes decreased with PCV vaccination; however, overall carriage remained the same because of a concomitant increase in non-vaccine type (NVT) serotypes. CONCLUSION: Pneumococcal carriage is generally high in the African continent, particularly in young children. The five most common serotypes in sSA are among the top seven serotypes that cause invasive pneumococcal disease in children globally. These serotypes are covered by the two PCVs recommended for routine childhood immunization by the WHO. The distribution of serotypes found in the nasopharynx is altered by PCV vaccination. PMID- 24465465 TI - Transplantation of autologous adipose stem cells lacks therapeutic efficacy in the experimental autoimmune encephalomyelitis model. AB - Multiple sclerosis (MS), characterized by chronic inflammation, demyelination, and axonal damage, is a complicated neurological disease of the human central nervous system. Recent interest in adipose stromal/stem cell (ASCs) for the treatment of CNS diseases has promoted further investigation in order to identify the most suitable ASCs. To investigate whether MS affects the biologic properties of ASCs and whether autologous ASCs from MS-affected sources could serve as an effective source for stem cell therapy, cells were isolated from subcutaneous inguinal fat pads of mice with established experimental autoimmune encephalomyelitis (EAE), a murine model of MS. ASCs from EAE mice and their syngeneic wild-type mice were cultured, expanded, and characterized for their cell morphology, surface antigen expression, osteogenic and adipogenic differentiation, colony forming units, and inflammatory cytokine and chemokine levels in vitro. Furthermore, the therapeutic efficacy of the cells was assessed in vivo by transplantation into EAE mice. The results indicated that the ASCs from EAE mice displayed a normal phenotype, typical MSC surface antigen expression, and in vitro osteogenic and adipogenic differentiation capacity, while their osteogenic differentiation capacity was reduced in comparison with their unafflicted control mice. The ASCs from EAE mice also demonstrated increased expression of pro-inflammatory cytokines and chemokines, specifically an elevation in the expression of monocyte chemoattractant protein-1 and keratin chemoattractant. In vivo, infusion of wild type ASCs significantly ameliorate the disease course, autoimmune mediated demyelination and cell infiltration through the regulation of the inflammatory responses, however, mice treated with autologous ASCs showed no therapeutic improvement on the disease progression. PMID- 24465466 TI - Systematic review and meta-analysis of the clinical efficacy and adverse effects of Chinese herbal decoction for the treatment of gout. AB - BACKGROUND: In East Asia, numerous reports describe the utilization of traditional Chinese herbal decoctions to treat gout. However, the reported clinical effects vary. OBJECTIVES: In this study, we reviewed and analyzed a large number of randomized controlled clinical trials to systematically assess the clinical efficacy and adverse reactions of Chinese herbal decoctions for treating gout. METHODS: We performed a comprehensive search of databases, such as PubMed, EMBASE, the Cochrane Central Register of Controlled Trials, Chinese biomedical literature database, et al. In addition, we manually searched the relevant meeting information in the library of the Third Military Medical University. RESULTS: Finally, 17 randomized controlled trials with a sample size of 1,402 cases met the criteria and were included in the study. The results of the meta-analysis showed that when gout had progressed to the stage of acute arthritis, there was no significant difference in clinical efficacy between Chinese herbal decoctions and traditional Western medicine, as indicated based on the following parameters: serum uric acid (standardized mean difference (SMD):0.35, 95% confidence interval (CI): 0.03 to 0.67), C reactive protein (SMD: 0.25, 95% CI: -0.18 to 0.69), erythrocyte sedimentation rate (SMD: 0.21, 95% CI: 0.02 to 0.45) and overall clinical response (relative risk (RR): 1.05, 95% CI: 1.01 to 1.10). However, the Chinese herbal decoction was significantly better than traditional Western medicine in controlling adverse drug reactions (RR: 0.06, 95% CI: 0.03 to 0.13). CONCLUSIONS: Through a systematic review of the clinical efficacy and safety of Chinese herbal decoctions and traditional Western medicine for the treatment of gout, we found that Chinese herbal decoction and traditional Western medicine led to similar clinical efficacy, but the Chinese herbal decoctions were superior to Western medicine in terms of controlling adverse drug reactions. PMID- 24465467 TI - Generation of "virtual" control groups for single arm prostate cancer adjuvant trials. AB - It is difficult to construct a control group for trials of adjuvant therapy (Rx) of prostate cancer after radical prostatectomy (RP) due to ethical issues and patient acceptance. We utilized 8 curve-fitting models to estimate the time to 60%, 65%, ... 95% chance of progression free survival (PFS) based on the data derived from Kattan post-RP nomogram. The 8 models were systematically applied to a training set of 153 post-RP cases without adjuvant Rx to develop 8 subsets of cases (reference case sets) whose observed PFS times were most accurately predicted by each model. To prepare a virtual control group for a single-arm adjuvant Rx trial, we first select the optimal model for the trial cases based on the minimum weighted Euclidean distance between the trial case set and the reference case set in terms of clinical features, and then compare the virtual PFS times calculated by the optimum model with the observed PFSs of the trial cases by the logrank test. The method was validated using an independent dataset of 155 post-RP patients without adjuvant Rx. We then applied the method to patients on a Phase II trial of adjuvant chemo-hormonal Rx post RP, which indicated that the adjuvant Rx is highly effective in prolonging PFS after RP in patients at high risk for prostate cancer recurrence. The method can accurately generate control groups for single-arm, post-RP adjuvant Rx trials for prostate cancer, facilitating development of new therapeutic strategies. PMID- 24465468 TI - How much is enough? Minimal responses of water quality and stream biota to partial retrofit stormwater management in a suburban neighborhood. AB - Decentralized stormwater management approaches (e.g., biofiltration swales, pervious pavement, green roofs, rain gardens) that capture, detain, infiltrate, and filter runoff are now commonly used to minimize the impacts of stormwater runoff from impervious surfaces on aquatic ecosystems. However, there is little research on the effectiveness of retrofit, parcel-scale stormwater management practices for improving downstream aquatic ecosystem health. A reverse auction was used to encourage homeowners to mitigate stormwater on their property within the suburban, 1.8 km(2) Shepherd Creek catchment in Cincinnati, Ohio (USA). In 2007-2008, 165 rain barrels and 81 rain gardens were installed on 30% of the properties in four experimental (treatment) subcatchments, and two additional subcatchments were maintained as controls. At the base of the subcatchments, we sampled monthly baseflow water quality, and seasonal (5*/year) physical habitat, periphyton assemblages, and macroinvertebrate assemblages in the streams for the three years before and after treatment implementation. Given the minor reductions in directly connected impervious area from the rain barrel installations (11.6% to 10.4% in the most impaired subcatchment) and high total impervious levels (13.1% to 19.9% in experimental subcatchments), we expected minor or no responses of water quality and biota to stormwater management. There were trends of increased conductivity, iron, and sulfate for control sites, but no such contemporaneous trends for experimental sites. The minor effects of treatment on streamflow volume and water quality did not translate into changes in biotic health, and the few periphyton and macroinvertebrate responses could be explained by factors not associated with the treatment (e.g., vegetation clearing, drought conditions). Improvement of overall stream health is unlikely without additional treatment of major impervious surfaces (including roads, apartment buildings, and parking lots). Further research is needed to define the minimum effect threshold and restoration trajectories for retrofitting catchments to improve the health of stream ecosystems. PMID- 24465469 TI - Social alienation in schizophrenia patients: association with insula responsiveness to facial expressions of disgust. AB - INTRODUCTION: Among the functional neuroimaging studies on emotional face processing in schizophrenia, few have used paradigms with facial expressions of disgust. In this study, we investigated whether schizophrenia patients show less insula activation to macro-expressions (overt, clearly visible expressions) and micro-expressions (covert, very brief expressions) of disgust than healthy controls. Furthermore, departing from the assumption that disgust faces signal social rejection, we examined whether perceptual sensitivity to disgust is related to social alienation in patients and controls. We hypothesized that high insula responsiveness to facial disgust predicts social alienation. METHODS: We used functional magnetic resonance imaging to measure insula activation in 36 schizophrenia patients and 40 healthy controls. During scanning, subjects passively viewed covert and overt presentations of disgust and neutral faces. To measure social alienation, a social loneliness scale and an agreeableness scale were administered. RESULTS: Schizophrenia patients exhibited reduced insula activation in response to covert facial expressions of disgust. With respect to macro-expressions of disgust, no between-group differences emerged. In patients, insula responsiveness to covert faces of disgust was positively correlated with social loneliness. Furthermore, patients' insula responsiveness to covert and overt faces of disgust was negatively correlated with agreeableness. In controls, insula responsiveness to covert expressions of disgust correlated negatively with agreeableness. DISCUSSION: Schizophrenia patients show reduced insula responsiveness to micro-expressions but not macro-expressions of disgust compared to healthy controls. In patients, low agreeableness was associated with stronger insula response to micro- and macro-expressions of disgust. Patients with a strong tendency to feel uncomfortable with social interactions appear to be characterized by a high sensitivity for facial expression signaling social rejection. Given the associations of insula responsiveness to covert disgust expression with low agreeableness in healthy individuals, insula responsiveness to expressions of disgust might be in general a neural marker of the personality trait of agreeableness. PMID- 24465470 TI - An example of how barcodes can clarify cryptic species: the case of the calanoid copepod Mastigodiaptomus albuquerquensis (Herrick). AB - BACKGROUND: The freshwater calanoid Mastigodiaptomus is a genus with high richness in the Americas and is composed of nine species, seven recorded in Mexico and four that are apparently endemic to small areas. Mastigodiaptomus albuquerquensis is a common, widely distributed species ranging from the southern USA to Central America. This species can be easily identified by a notable butterfly-like sclerotization on the basis of the right fifth leg of males. Nevertheless, morphological differences observed among populations throughout this species distributional range have led to the description of several related species or subspecies, such as M. albuquerquensis patzcuarensis from Lake Patzcuaro in the Central Plateau of Mexico. METHODS: Genetic results based on barcodes, morphology based on scanning electron and light microscopy images, and morphometric analyses were used to describe cryptic species within the M. albuquerquensis complex. RESULTS: The morphological analyses coincided partially with the genetic markers, suggesting the existence of at least two sibling species: M. albuquerquensis s. str. and M. patzcuarensis. A third species was genetically separated but was morphologically indistinguishable from the M. patzcuarensis group. CONCLUSIONS: Hidden diversity has been a major problem in establishing real patterns of species distribution and genetic acquisition from megadiverse hotspots such as Mexico, where the Nearctic and the Neotropical regions of the Americas meet. Barcodes can help taxonomists to reveal and formally name these new species. Here, we describe two of three potential species highlighted by the use of barcodes: M. albuquerquensis s. str. in the northern semi-desert and M. patzcuarensis on the Central Plateau at more than 2000 m above sea level. PMID- 24465471 TI - Cognitive function in peripheral autonomic disorders. AB - OBJECTIVE: aims of the current study were 1) to evaluate global cognitive function in patients with autonomic failure (AF) of peripheral origin and 2) to investigate the effect of a documented fall in blood pressure (BP) fulfilling the criteria for orthostatic hypotension (OH) on cognitive performances. METHODS: we assessed 12 consecutive patients (10 males, 68+/-7 years old) with pure AF (PAF) or autoimmune autonomic neuropathy (AAN) and 12 age- and gender-matched controls. All patients had no clinical signs of central nervous system involvement and normal brain CT/MRI scan. Cognitive function was assessed on two consecutive days in 3 conditions: on day 1, while sitting, by means of a comprehensive battery of neuropsychological tests; on day 2, while tilted (HUT) and during supine rest (supine) in a randomized manner. BP and heart rate (HR) were continuously recorded non-invasively for the whole duration of the examination. RESULTS: patients with PAF or AAN displayed a preserved global cognitive function while sitting. However, compared to supine assessment, during HUT patients scored significantly worse during the Trail Making Test A and B, Barrage test, Analogies test, Immediate Visual Memory, Span Forward and Span Backward test. Pathological scores, with regard to Italian normative range values, were observed only during HUT in the Barrage test and in the Analogies test in 3 and 6 patients respectively. On the contrary, in healthy controls, results to neuropsychological tests were not significantly different, during HUT compared to supine rest. CONCLUSIONS: these data demonstrate that patients with PAF and AAN present a normal sitting global cognitive evaluation. However, their executive functions worsen significantly during the orthostatic challenge, possibly because of transient frontal lobes hypoperfusion. PMID- 24465472 TI - Docosahexaenoic acid decreases pro-inflammatory mediators in an in vitro murine adipocyte macrophage co-culture model. AB - Paracrine interactions between adipocytes and macrophages contribute to chronic inflammation in obese adipose tissue. Dietary strategies to mitigate such inflammation include long-chain polyunsaturated fatty acids, docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, which act through PPARgamma-dependent and independent pathways. We utilized an in vitro co-culture model designed to mimic the ratio of macrophages:adipocytes in obese adipose tissue, whereby murine 3T3 L1 adipocytes were cultured with RAW 264.7 macrophages in direct contact, or separated by a trans-well membrane (contact-independent mechanism), with 125 uM of albumin-complexed DHA, EPA, palmitic acid (PA), or albumin alone (control). Thus, we studied the effect of physical cell contact versus the presence of soluble factors, with or without a PPARgamma antagonist (T0070907) in order to elucidate putative mechanisms. After 12 hr, DHA was the most anti-inflammatory, decreasing MCP1 and IL-6 secretion in the contact system (-57%, -63%, respectively, p <= 0.05) with similar effects in the trans-well system. The trans well system allowed for isolation of cell types for inflammatory mediator analysis. DHA decreased mRNA expression (p<0.05) of Mcp1 (-7.1 fold) and increased expression of the negative regulator, Mcp1-IP (+1.5 fold). In macrophages, DHA decreased mRNA expression of pro-inflammatory M1 polarization markers (p <= 0.05), Nos2 (iNOS; -7 fold), Tnfalpha (-4.2 fold) and Nfkappab ( 2.3 fold), while increasing anti-inflammatory Tgfbeta1 (+1.7 fold). Interestingly, the PPARgamma antagonist co-administered with DHA or EPA in co culture reduced (p <= 0.05) adiponectin cellular protein, without modulating other cytokines (protein or mRNA). Overall, our findings suggest that DHA may lessen the degree of MCP1 and IL-6 secreted from adipocytes, and may reduce the degree of M1 polarization of macrophages recruited to adipose tissue, thereby decreasing the intensity of pro-inflammatory cross-talk between adipocytes and macrophages in obese adipose tissue. PMID- 24465473 TI - A genome-wide association study identifies a locus on TERT for mean telomere length in Han Chinese. AB - Leukocyte telomere length (LTL) is a predictor of aging and a number of age related diseases. We performed genome-wide association studies of mean LTL in 2632 individuals,with a two-stage replication in 3917 individuals from Chinese populations. To further validate our findings, we get the results of 696 samples from a cohort of European ancestry. We identified two loci associated with LTL that map in telomerase reverse transcriptase (TERT; rs2736100, P = 1.93*10(-5)) on chromosome 5p15.33 and near keratin 80 (KRT80; rs17653722, P = 6.96*10(-6)) on 12q13.13. In Chinese population each C allele of rs2736100 and T allele of rs17653722 was associated with a longer mean telomere length of 0.026 and 0.059 T/S, respectively, equivalent to about 3 and 7 years of average age-related telomere attrition. Our findings provide new insights into telomere regulatory mechanism and even pathogenesis of age-related diseases. PMID- 24465474 TI - Reciprocal modulation of surface expression of annexin A2 in a human umbilical vein endothelial cell-derived cell line by eicosapentaenoic acid and docosahexaenoic acid. AB - BACKGROUND: Annexin A2 (ANXA2), a member of the annexin family of cytosolic Ca(2+)-binding proteins, plays a pivotal role in vascular biology. Small amounts of this protein and S100A10 protein are exposed on the surface of endothelial cells (ECs). They control fibrinolysis by recruiting tissue-type and urokinase type plasminogen activators from the plasma. Nutritional studies indicate that two major long-chain polyunsaturated fatty acids (PUFAs), i.e., eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), provide benefits for EC functions. The effects of EPA and DHA on the plasminogen/plasmin system have not been characterized. METHODOLOGY/PRINCIPAL FINDINGS: Proteomic analysis of a cultured human umbilical vein EC-derived cell line, HUV-EC-C, showed that cell-associated ANXA2 decreased with EPA treatment and increased with DHA. A small fraction of ANXA2 was bound to the cell surface, which was also affected by these PUFAs following the same trends. Cell surface expression was negatively regulated by protein kinase C (PKC) alpha-mediated Ser-phosphorylation, which was up- and down regulated by EPA and DHA, respectively. These PUFAs differentially affected a small fraction of caveolae/rafts-associated ANXA2. In addition to chymotrypsin like activity in the serum, newly activated plasmin cleaved the ANXA2 on the cell surface at distinct sites in the N-terminal sequence. ANXA2 also bound to membranes released in the medium, which was similarly processed by these proteases. Both the PUFAs did not directly affect the release. CONCLUSION/SIGNIFICANCE: These results suggest that EPA and DHA reciprocally control cell surface location of ANXA2. Moreover, cleavage of this protein by plasmin likely resulted in autodigestion of the platform for formation of this protease. In conjunction with termination of the proteolysis by rapid inactivation of plasmin by alpha-2-antiplasmin and other polypeptide inhibitors, this feedback mechanism may emphasize the benefits of these PUFA in regulation of the initiation of fibrinolysis on the surface of ECs. PMID- 24465475 TI - The seroepidemiology of Haemophilus influenzae type b prior to introduction of an immunization programme in Kathmandu, Nepal. AB - Haemophilus influenzae type b (Hib) is now recognized as an important pathogen in Asia. To evaluate disease susceptibility, and as a marker of Hib transmission before routine immunization was introduced in Kathmandu, 71 participants aged 7 months-77 years were recruited and 15 cord blood samples were collected for analysis of anti-polyribosylribitol phosphate antibody levels by enzyme-linked immunosorbent assay. Only 20% of children under 5 years old had levels considered protective (>0.15 ug/ml), rising to 83% of 15-54 year-olds. Prior to introduction of Hib vaccine in Kathmandu, the majority of young children were susceptible to disease. PMID- 24465476 TI - Metabolic engineering Camelina sativa with fish oil-like levels of DHA. AB - BACKGROUND: Omega-3 long-chain (>=C20) polyunsaturated fatty acids (omega3 LC PUFA) such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are critical for human health and development [corrected].. Numerous studies have indicated that deficiencies in these fatty acids can increase the risk or severity of cardiovascular, inflammatory and other diseases or disorders. EPA and DHA are predominantly sourced from marine fish although the primary producers are microalgae. Much work has been done to engineer a sustainable land-based source of EPA and DHA to reduce pressure on fish stocks in meeting future demand, with previous studies describing the production of fish oil-like levels of DHA in the model plant species, Arabidopsis thaliana. PRINCIPAL FINDINGS: In this study we describe the production of fish oil-like levels (>12%) of DHA in the oilseed crop species Camelina sativa achieving a high omega3/omega6 ratio. The construct previously transformed in Arabidopsis as well as two modified construct versions designed to increase DHA production were used. DHA was found to be stable to at least the T5 generation and the EPA and DHA were found to be predominantly at the sn-1,3 positions of triacylglycerols. Transgenic and parental lines did not have different germination or seedling establishment rates. CONCLUSIONS: DHA can be produced at fish oil-like levels in industrially-relevant oilseed crop species using multi-gene construct designs which are stable over multiple generations. This study has implications for the future of sustainable EPA and DHA production from land-based sources. PMID- 24465477 TI - A risk function for behavioral disruption of Blainville's beaked whales (Mesoplodon densirostris) from mid-frequency active sonar. AB - There is increasing concern about the potential effects of noise pollution on marine life in the world's oceans. For marine mammals, anthropogenic sounds may cause behavioral disruption, and this can be quantified using a risk function that relates sound exposure to a measured behavioral response. Beaked whales are a taxon of deep diving whales that may be particularly susceptible to naval sonar as the species has been associated with sonar-related mass stranding events. Here we derive the first empirical risk function for Blainville's beaked whales (Mesoplodon densirostris) by combining in situ data from passive acoustic monitoring of animal vocalizations and navy sonar operations with precise ship tracks and sound field modeling. The hydrophone array at the Atlantic Undersea Test and Evaluation Center, Bahamas, was used to locate vocalizing groups of Blainville's beaked whales and identify sonar transmissions before, during, and after Mid-Frequency Active (MFA) sonar operations. Sonar transmission times and source levels were combined with ship tracks using a sound propagation model to estimate the received level (RL) at each hydrophone. A generalized additive model was fitted to data to model the presence or absence of the start of foraging dives in 30-minute periods as a function of the corresponding sonar RL at the hydrophone closest to the center of each group. This model was then used to construct a risk function that can be used to estimate the probability of a behavioral change (cessation of foraging) the individual members of a Blainville's beaked whale population might experience as a function of sonar RL. The function predicts a 0.5 probability of disturbance at a RL of 150 dBrms re uPa (CI: 144 to 155) This is 15dB lower than the level used historically by the US Navy in their risk assessments but 10 dB higher than the current 140 dB step function. PMID- 24465478 TI - A new metabolomic signature in type-2 diabetes mellitus and its pathophysiology. AB - OBJECTIVE: The objective of the current study was to find a metabolic signature associated with the early manifestations of type-2 diabetes mellitus. RESEARCH DESIGN AND METHOD: Modern metabolic profiling technology (MxPTM Broad Profiling) was applied to find early alterations in the plasma metabolome of type-2 diabetic patients. The results were validated in an independent study. Eicosanoid and single inon monitoring analysis (MxPTM Eicosanoid and MxPTM SIM analysis) were performed in subsets of samples. RESULTS: A metabolic signature including significantly increased levels of glyoxylate as a potential novel marker for early detection of type-2 diabetes mellitus was identified in an initial study (Study1). The signature was significantly altered in fasted diabetic and pre diabetic subjects and in non-fasted subjects up to three years prior to the diagnosis of type-2 diabetes; most alterations were also consistently found in an independent patient group (Study 2). In Study 2 diabetic and most control subjects suffered from heart failure. In Study 1 a subgroup of diabetic subjects, with a history of use of anti-hypertensive medication further showed a more pronounced increase of glyoxylate levels, compared to a non-diabetic control group when tested in a hyperglycemic state. In the context of a prior history of anti-hypertensive medication, alterations in hexosamine and eicosanoid levels were also found. CONCLUSION: A metabolic signature including glyoxylate was associated with type-2 diabetes mellitus, independent of the fasting status and of occurrence of another major disease. The same signature was also found to be associated with pre-diabetic subjects. Glyoxylate levels further showed a specifically strong increase in a subgroup of diabetic subjects. It could represent a new marker for the detection of medical subgroups of diabetic subjects. PMID- 24465479 TI - The leukotriene B4/BLT1 axis is a key determinant in susceptibility and resistance to histoplasmosis. AB - The bioactive lipid mediator leukotriene B4 (LTB4) greatly enhances phagocyte antimicrobial functions against a myriad of pathogens. In murine histoplasmosis, inhibition of the LT-generating enzyme 5-lypoxigenase (5-LO) increases the susceptibility of the host to infection. In this study, we investigated whether murine resistance or susceptibility to Histoplasma capsulatum infection is associated with leukotriene production and an enhancement of in vivo and/or in vitro antimicrobial effector function. We show that susceptible C57BL/6 mice exhibit a higher fungal burden in the lung and spleen, increased mortality, lower expression levels of 5-LO and leukotriene B4 receptor 1 (BLT1) and decreased LTB4 production compared to the resistant 129/Sv mice. Moreover, we demonstrate that endogenous and exogenous LTs are required for the optimal phagocytosis of H. capsulatum by macrophages from both murine strains, although C57BL/6 macrophages are more sensitive to the effects of LTB4 than 129/Sv macrophages. Therefore, our results provide novel evidence that LTB4 production and BLT1 signaling are required for a histoplasmosis-resistant phenotype. PMID- 24465480 TI - Interleukin-4-mediated 15-lipoxygenase-1 trans-activation requires UTX recruitment and H3K27me3 demethylation at the promoter in A549 cells. AB - Arachidonate 15-lipoxygenase-1 (ALOX15) oxygenates polyunsaturated fatty acids and bio-membranes, generating multiple lipid signalling mediators involved in inflammation. Several lines of evidence indicate that ALOX15 activation in the respiratory tract contributes to asthma progression. Recent experimental data reveals that histone modification at the promoter plays a critical role in ALOX15 gene transcription. In the present study, we examined the status of histone H3 trimethyl-lysine 27 (H3K27me3) at the ALOX15 promoter by chromatin immunoprecipitation assay in human lung epithelial carcinoma A549 cells incubated with or without interleukin (IL)-4. We identified demethylation of H3K27me3 at the ALOX15 promoter after IL-4 treatment. Furthermore, we found that the H3K27me2/3-specific demethylase, ubiquitously transcribed tetratricopeptide repeat, X chromosome (UTX), mediates the H3K27me3 demethylation during ALOX15 transcriptional activation. When UTX expression was knocked down using siRNA, IL 4-mediated H3K27me3 demethylation and ALOX15 induction were significantly attenuated. The critical role of UTX in ALOX15 expression was confirmed in human monocytes and the Hodgkin lymphoma (HL) cell line L1236, but was in these cells not related to H3K27me3-demethylase activity. These results demonstrate that UTX is implicated in IL-4 mediated transcriptional activation of the ALOX15 gene. PMID- 24465481 TI - Adrenergic beta2 receptor activation stimulates anti-inflammatory properties of dendritic cells in vitro. AB - Vagal nerve efferent activation has been shown to ameliorate the course of many inflammatory disease states. This neuro-modulatory effect has been suggested to rest on acetylcholine receptor (AChR) activation on tissue macrophages or dendritic cells (DCs). In more recent studies, vagal anti-inflammatory activity was shown involve adrenergic, splenic, pathways. Here we provide evidence that the adrenergic, rather than cholinergic, receptor activation on bone marrow derived DCs results in enhanced endocytosis uptake, enhanced IL-10 production but a decreased IL-6, IL-12p70 and IL-23 production. In antigen specific T cell stimulation assays, adrenergic beta2 receptor activation on bone marrow DCs led to an enhanced potential to induce Foxp3 positive suppressive Treg cells. These effects were independent of IL10-R activation, TGFbeta release, or retinoic acid (RA) secretion. Hence, adrenergic receptor beta2 activation modulates DC function resulting in skewing towards anti-inflammatory T cell phenotypes. PMID- 24465482 TI - Efficient reprogramming of naive-like induced pluripotent stem cells from porcine adipose-derived stem cells with a feeder-independent and serum-free system. AB - Induced pluripotent stem cells (iPSCs) are somatic cells reprogrammed by ectopic expression of transcription factors or small molecule treatment, which resemble embryonic stem cells (ESCs). They hold great promise for improving the generation of genetically modified large animals. However, few porcine iPSCs (piPSCs) lines obtained currently can support development of cloned embryos. Here, we generated iPSCs from porcine adipose-derived stem cells (pADSCs), using drug-inducible expression of defined human factors (Oct4, Sox2, c-Myc and Klf4). Reprogramming of iPSCs from pADSCs was more efficient than from fibroblasts, regardless of using feeder-independent or feeder-dependent manners. By addition of Lif-2i medium containing mouse Lif, CHIR99021 and PD0325901 (Lif-2i), naive-like piPSCs were obtained under feeder-independent and serum-free conditions. These successfully reprogrammed piPSCs were characterized by short cell cycle intervals, alkaline phosphatase (AP) staining, expression of Oct4, Sox2, Nanog, SSEA3 and SSEA4, and normal karyotypes. The resemblance of piPSCs to naive ESCs was confirmed by their packed dome morphology, growth after single-cell dissociation, Lif-dependency, up-regulation of Stella and Eras, low expression levels of TRA-1-60, TRA-1-81 and MHC I and activation of both X chromosomes. Full reprogramming of naive-like piPSCs was evaluated by the significant up-regulation of Lin28, Esrrb, Utf1 and Dppa5, differentiating into cell types of all three germ layers in vitro and in vivo. Furthermore, nuclear transfer embryos from naive-like piPSCs could develop to blastocysts with improved quality. Thus, we provided an efficient protocol for generating naive-like piPSCs from pADSCs in a feeder-independent and serum-free system with controlled regulation of exogenous genes, which may facilitate optimization of culture media and the production of transgenic pigs. PMID- 24465483 TI - PSCC: sensitive and reliable population-scale copy number variation detection method based on low coverage sequencing. AB - BACKGROUND: Copy number variations (CNVs) represent an important type of genetic variation that deeply impact phenotypic polymorphisms and human diseases. The advent of high-throughput sequencing technologies provides an opportunity to revolutionize the discovery of CNVs and to explore their relationship with diseases. However, most of the existing methods depend on sequencing depth and show instability with low sequence coverage. In this study, using low coverage whole-genome sequencing (LCS) we have developed an effective population-scale CNV calling (PSCC) method. METHODOLOGY/PRINCIPAL FINDINGS: In our novel method, two step correction was used to remove biases caused by local GC content and complex genomic characteristics. We chose a binary segmentation method to locate CNV segments and designed combined statistics tests to ensure the stable performance of the false positive control. The simulation data showed that our PSCC method could achieve 99.7%/100% and 98.6%/100% sensitivity and specificity for over 300 kb CNV calling in the condition of LCS (~2*) and ultra LCS (~0.2*), respectively. Finally, we applied this novel method to analyze 34 clinical samples with an average of 2* LCS. In the final results, all the 31 pathogenic CNVs identified by aCGH were successfully detected. In addition, the performance comparison revealed that our method had significant advantages over existing methods using ultra LCS. CONCLUSIONS/SIGNIFICANCE: Our study showed that PSCC can sensitively and reliably detect CNVs using low coverage or even ultra-low coverage data through population scale sequencing. PMID- 24465484 TI - Bacterial communities in Malagasy soils with differing levels of disturbance affecting botanical diversity. AB - Madagascar is well-known for the exceptional biodiversity of its macro-flora and fauna, but the biodiversity of Malagasy microbial communities remains relatively unexplored. Understanding patterns of bacterial diversity in soil and their correlations with above-ground botanical diversity could influence conservation planning as well as sampling strategies to maximize access to bacterially derived natural products. We present the first detailed description of Malagasy soil bacterial communities from a targeted 16S rRNA gene survey of greater than 290,000 sequences generated using 454 pyrosequencing. Two sampling plots in each of three forest conservation areas were established to represent different levels of disturbance resulting from human impact through agriculture and selective exploitation of trees, as well as from natural impacts of cyclones. In parallel, we performed an in-depth characterization of the total vascular plant morphospecies richness within each plot. The plots representing different levels of disturbance within each forest did not differ significantly in bacterial diversity or richness. Changes in bacterial community composition were largest between forests rather than between different levels of impact within a forest. The largest difference in bacterial community composition with disturbance was observed at the Vohibe forest conservation area, and this difference was correlated with changes in both vascular plant richness and soil pH. These results provide the first survey of Malagasy soil bacterial diversity and establish a baseline of botanical diversity within important conservation areas. PMID- 24465485 TI - Bayesian analysis of congruence of core genes in Prochlorococcus and Synechococcus and implications on horizontal gene transfer. AB - It is often suggested that horizontal gene transfer is so ubiquitous in microbes that the concept of a phylogenetic tree representing the pattern of vertical inheritance is oversimplified or even positively misleading. "Universal proteins" have been used to infer the organismal phylogeny, but have been criticized as being only the "tree of one percent." Currently, few options exist for those wishing to rigorously assess how well a universal protein phylogeny, based on a relative handful of well-conserved genes, represents the phylogenetic histories of hundreds of genes. Here, we address this problem by proposing a visualization method and a statistical test within a Bayesian framework. We use the genomes of marine cyanobacteria, a group thought to exhibit substantial amounts of HGT, as a test case. We take 379 orthologous gene families from 28 cyanobacteria genomes and estimate the Bayesian posterior distributions of trees - a "treecloud" - for each, as well as for a concatenated dataset based on putative "universal proteins." We then calculate the average distance between trees within and between all treeclouds on various metrics and visualize this high-dimensional space with non-metric multidimensional scaling (NMMDS). We show that the tree space is strongly clustered and that the universal protein treecloud is statistically significantly closer to the center of this tree space than any individual gene treecloud. We apply several commonly-used tests for incongruence/HGT and show that they agree HGT is rare in this dataset, but make different choices about which genes were subject to HGT. Our results show that the question of the representativeness of the "tree of one percent" is a quantitative empirical question, and that the phylogenetic central tendency is a meaningful observation even if many individual genes disagree due to the various sources of incongruence. PMID- 24465486 TI - On the origin and evolutionary history of NANOG. AB - Though pluripotency is well characterized in mammals, many questions remain to be resolved regarding its evolutionary history. A necessary prerequisite for addressing this issue is to determine the phylogenetic distributions and orthology relationships of the transcription factor families sustaining or modulating this property. In mammals, the NANOG homeodomain transcription factor is one of the core players in the pluripotency network. However, its evolutionary history has not been thoroughly studied, hindering the interpretation of comparative studies. To date, the NANOG family was thought to be monogenic, with numerous pseudogenes described in mammals, including a tandem duplicate in Hominidae. By examining a wide-array of craniate genomes, we provide evidence that the NANOG family arose at the latest in the most recent common ancestor of osteichthyans and that NANOG genes are frequently found as tandem duplicates in sarcopterygians and as a single gene in actinopterygians. Their phylogenetic distribution is thus reminiscent of that recently shown for Class V POU paralogues, another key family of pluripotency-controlling factors. However, while a single ancestral duplication has been reported for the Class V POU family, we suggest that multiple independent duplication events took place during evolution of the NANOG family. These multiple duplications could have contributed to create a layer of complexity in the control of cell competence and pluripotency, which could explain the discrepancies relative to the functional evolution of this important gene family. Further, our analysis does not support the hypothesis that loss of NANOG and emergence of the preformation mode of primordial germ cell specification are causally linked. Our study therefore argues for the need of further functional comparisons between NANOG paralogues, notably regarding the novel duplicates identified in sauropsids and non-eutherian mammals. PMID- 24465487 TI - Metabolic flexibility as a major predictor of spatial distribution in microbial communities. AB - A better understand the ecology of microbes and their role in the global ecosystem could be achieved if traditional ecological theories can be applied to microbes. In ecology organisms are defined as specialists or generalists according to the breadth of their niche. Spatial distribution is often used as a proxy measure of niche breadth; generalists have broad niches and a wide spatial distribution and specialists a narrow niche and spatial distribution. Previous studies suggest that microbial distribution patterns are contrary to this idea; a microbial generalist genus (Desulfobulbus) has a limited spatial distribution while a specialist genus (Methanosaeta) has a cosmopolitan distribution. Therefore, we hypothesise that this counter-intuitive distribution within generalist and specialist microbial genera is a common microbial characteristic. Using molecular fingerprinting the distribution of four microbial genera, two generalists, Desulfobulbus and the methanogenic archaea Methanosarcina, and two specialists, Methanosaeta and the sulfate-reducing bacteria Desulfobacter were analysed in sediment samples from along a UK estuary. Detected genotypes of both generalist genera showed a distinct spatial distribution, significantly correlated with geographic distance between sites. Genotypes of both specialist genera showed no significant differential spatial distribution. These data support the hypothesis that the spatial distribution of specialist and generalist microbes does not match that seen with specialist and generalist large organisms. It may be that generalist microbes, while having a wider potential niche, are constrained, possibly by intrageneric competition, to exploit only a small part of that potential niche while specialists, with far fewer constraints to their niche, are more capable of filling their potential niche more effectively, perhaps by avoiding intrageneric competition. We suggest that these counter intuitive distribution patterns may be a common feature of microbes in general and represent a distinct microbial principle in ecology, which is a real challenge if we are to develop a truly inclusive ecology. PMID- 24465488 TI - Spike firing and IPSPs in layer V pyramidal neurons during beta oscillations in rat primary motor cortex (M1) in vitro. AB - Beta frequency oscillations (10-35 Hz) in motor regions of cerebral cortex play an important role in stabilising and suppressing unwanted movements, and become intensified during the pathological akinesia of Parkinson's Disease. We have used a cortical slice preparation of rat brain, combined with concurrent intracellular and field recordings from the primary motor cortex (M1), to explore the cellular basis of the persistent beta frequency (27-30 Hz) oscillations manifest in local field potentials (LFP) in layers II and V of M1 produced by continuous perfusion of kainic acid (100 nM) and carbachol (5 uM). Spontaneous depolarizing GABA-ergic IPSPs in layer V cells, intracellularly dialyzed with KCl and IEM1460 (to block glutamatergic EPSCs), were recorded at -80 mV. IPSPs showed a highly significant (P< 0.01) beta frequency component, which was highly significantly coherent with both the Layer II and V LFP oscillation (which were in antiphase to each other). Both IPSPs and the LFP beta oscillations were abolished by the GABAA antagonist bicuculline. Layer V cells at rest fired spontaneous action potentials at sub beta frequencies (mean of 7.1+1.2 Hz; n = 27) which were phase-locked to the layer V LFP beta oscillation, preceding the peak of the LFP beta oscillation by some 20 ms. We propose that M1 beta oscillations, in common with other oscillations in other brain regions, can arise from synchronous hyperpolarization of pyramidal cells driven by synaptic inputs from a GABA-ergic interneuronal network (or networks) entrained by recurrent excitation derived from pyramidal cells. This mechanism plays an important role in both the physiology and pathophysiology of control of voluntary movement generation. PMID- 24465489 TI - Identification of a distinct small cell population from human bone marrow reveals its multipotency in vivo and in vitro. AB - Small stem cells, such as spore-like cells, blastomere-like stem cells (BLSCs), and very-small embryonic-like stem cells (VSELs) have been described in recent studies, although their multipotency in human tissues has not yet been confirmed. Here, we report the discovery of adult multipotent stem cells derived from human bone marrow, which we call StemBios (SB) cells. These isolated SB cells are smaller than 6 im and are DAPI+ and Lgr5+ (Leucine-Rich Repeat Containing G Protein-Coupled Receptor 5). Because Lgr5 has been characterized as a stem cell marker in the intestine, we hypothesized that SB cells may have a similar function. In vivo cell tracking assays confirmed that SB cells give rise to three types of cells, and in vitro studies demonstrated that SB cells cultured in proprietary media are able to grow to 6-25 im in size. Once the SB cells have attached to the wells, they differentiate into different cell lineages upon exposure to specific differentiation media. We are the first to demonstrate that stem cells smaller than 6 im can differentiate both in vivo and in vitro. In the future, we hope that SB cells will be used therapeutically to cure degenerative diseases. PMID- 24465490 TI - The value and distribution of high-density lipoprotein subclass in patients with acute coronary syndrome. AB - BACKGROUND: High-density lipoprotein (HDL) enhances cholesterol efflux from the arterial wall and exhibits potent anti-inflammatory and anti-atherosclerosis (AS) properties. Whether raised HDL levels will clinically benefit patients with acute coronary syndrome (ACS) and the value at which these effects will be apparent, however, is debatable. This study examined the HDL subclass distribution profile in patients with ACS. METHODS: Plasma HDL subclasses were measured in 158 patients with established ACS and quantified by two-dimensional gel electrophoresis and immunoblotting. ACS diagnosis was based on symptoms of cardiac ischemia, electrocardiogram (ECG) abnormalities, speciality cardiac enzyme change along with presence of coronary heart disease (CHD) on coronary angiography. RESULTS: The small-sized prebeta1-HDL, HDL3b, and HDL3a levels were significantly higher, and the large-sized HDL2a and HDL2b levels were significantly lower in patients with ACS than in those with stable angina pectoris (SAP) and in normal control subjects. Meanwhile, with an elevation in the low-density lipoprotein cholesterol (LDL-C), fasting plasma glucose (FPG), body mass index (BMI), and blood pressure (BP), and the reduction in the high density lipoprotein cholesterol (HDL-C) levels, the HDL2b contents significantly decreased and the prebeta1-HDL contents significantly increased in patients with ACS. The correlation analysis revealed that the apolipoprotein (apo)A-I levels were positively and significantly with all HDL subclasses contents; plasma total cholesterol (TC) and fasting plasma glucose (FPG) levels were inversely associated with HDL2a, and HDL2b. Moreover, the FPG levels were positively related to HDL3c, HDL3b, and HDL3a in ACS patients. CONCLUSION: The HDL subclass distribution profile remodeling was noted in the patients with ACS. Plasma lipoprotein and FPG levels, BP, and BMI play an important role in the HDL subclass metabolism disorder for patients with ACS. The HDL subclass distribution phenotype might be useful as a novel biomarker to assist in the risk stratification of patients with ACS. PMID- 24465491 TI - Molecular cytogenetic characterization of the dioecious Cannabis sativa with an XY chromosome sex determination system. AB - Hemp (Cannabis sativa L.) was karyotyped using by DAPI/C-banding staining to provide chromosome measurements, and by fluorescence in situ hybridization with probes for 45 rDNA (pTa71), 5S rDNA (pCT4.2), a subtelomeric repeat (CS-1) and the Arabidopsis telomere probes. The karyotype has 18 autosomes plus a sex chromosome pair (XX in female and XY in male plants). The autosomes are difficult to distinguish morphologically, but three pairs could be distinguished using the probes. The Y chromosome is larger than the autosomes, and carries a fully heterochromatic DAPI positive arm and CS-1 repeats only on the less intensely DAPI-stained, euchromatic arm. The X is the largest chromosome of all, and carries CS-1 subtelomeric repeats on both arms. The meiotic configuration of the sex bivalent locates a pseudoautosomal region of the Y chromosome at the end of the euchromatic CS-1-carrying arm. Our molecular cytogenetic study of the C. sativa sex chromosomes is a starting point for helping to make C. sativa a promising model to study sex chromosome evolution. PMID- 24465492 TI - Extreme fire severity patterns in topographic, convective and wind-driven historical wildfires of Mediterranean pine forests. AB - Crown fires associated with extreme fire severity are extremely difficult to control. We have assessed fire severity using differenced Normalized Burn Ratio (dNBR) from Landsat imagery in 15 historical wildfires of Pinus halepensis Mill. We have considered a wide range of innovative topographic, fuel and fire behavior variables with the purposes of (1) determining the variables that influence fire severity patterns among fires (considering the 15 wildfires together) and (2) ascertaining whether different variables affect extreme fire severity within the three fire types (topographic, convective and wind-driven fires). The among-fires analysis showed that fires in less arid climates and with steeper slopes had more extreme severity. In less arid conditions there was more crown fuel accumulation and closer forest structures, promoting high vertical and horizontal fuel continuity and extreme fire severity. The analyses carried out for each fire separately (within fires) showed more extreme fire severity in areas in northern aspects, with steeper slopes, with high crown biomass and in climates with more water availability. In northern aspects solar radiation was lower and fuels had less water limitation to growth which, combined with steeper slopes, produced more extreme severity. In topographic fires there was more extreme severity in northern aspects with steeper slopes and in areas with more water availability and high crown biomass; in convection-dominated fires there was also more extreme fire severity in northern aspects with high biomass; while in wind-driven fires there was only a slight interaction between biomass and water availability. This latter pattern could be related to the fact that wind-driven fires spread with high wind speed, which could have minimized the effect of other variables. In the future, and as a consequence of climate change, new zones with high crown biomass accumulated in non-common drought areas will be available to burn as extreme severity wildfires. PMID- 24465493 TI - High blood pressure and its association with body weight among children and adolescents in the United Arab Emirates. AB - OBJECTIVES: To estimate the prevalence of high blood pressure (BP) and its relationship with obesity among children and adolescents. METHODOLOGY/PRINCIPAL FINDINGS: In this cross-sectional population (Emirati) representative study, we invited a random sample of 1600 students (grades 1-12) attending 23 out of all 246 schools in the Emirate of Abu Dhabi, United Arab Emirates. But analysis was restricted to Emirati nationals aged 6-17 years. We measured BP, height, weight, waist circumferences (WC), and calculated body mass index (BMI) by standard methods. BP levels >= 90(th) percentile but <95(th) percentile and >= 95(th) for age, sex, and height (CDC percentiles) were classified as pre-hypertension (pre HTN) and hypertension (HTN), respectively. Associations between BP, age, BMI, WC, and sex, were investigated by (multiple) linear regression methods. A total of 999 (47% girls) students provided complete results. The prevalence of pre-HTN was 10.5% and 11.4% and the prevalence of HTN was 15.4% and 17.8% among boys and girls, respectively. The prevalence of systolic/diastolic HTN was 14.4%/2.5% and 14.8/7.4% among boys and girls, respectively. BMI CDC percentile was positively correlated with WC percentile (r = 0.734, p<0.01), and both systolic (r = 0.34, p<0.001) and diastolic (r = 0.21, p<0.001) standardized BP. WC percentile was less strongly correlated with standardized SBP (r = 0.255, p<0.01) and DBP (r = 0.175, p<0.01) than BMI. CONCLUSIONS/SIGNIFICANCE: The prevalence of elevated BP, notably systolic was significantly high among the Emirati children and adolescents in Abu Dhabi. High BP was strongly related to body weight, and appears more strongly associated with BMI than WC. Further studies are required to investigate the impact of childhood obesity on HTN. PMID- 24465494 TI - Global state measures of the dentate gyrus gene expression system predict antidepressant-sensitive behaviors. AB - BACKGROUND: Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine are the most common form of medication treatment for major depression. However, approximately 50% of depressed patients fail to achieve an effective treatment response. Understanding how gene expression systems respond to treatments may be critical for understanding antidepressant resistance. METHODS: We take a novel approach to this problem by demonstrating that the gene expression system of the dentate gyrus responds to fluoxetine (FLX), a commonly used antidepressant medication, in a stereotyped-manner involving changes in the expression levels of thousands of genes. The aggregate behavior of this large-scale systemic response was quantified with principal components analysis (PCA) yielding a single quantitative measure of the global gene expression system state. RESULTS: Quantitative measures of system state were highly correlated with variability in levels of antidepressant-sensitive behaviors in a mouse model of depression treated with fluoxetine. Analysis of dorsal and ventral dentate samples in the same mice indicated that system state co-varied across these regions despite their reported functional differences. Aggregate measures of gene expression system state were very robust and remained unchanged when different microarray data processing algorithms were used and even when completely different sets of gene expression levels were used for their calculation. CONCLUSIONS: System state measures provide a robust method to quantify and relate global gene expression system state variability to behavior and treatment. State variability also suggests that the diversity of reported changes in gene expression levels in response to treatments such as fluoxetine may represent different perspectives on unified but noisy global gene expression system state level responses. Studying regulation of gene expression systems at the state level may be useful in guiding new approaches to augmentation of traditional antidepressant treatments. PMID- 24465495 TI - Large scale identification and categorization of protein sequences using structured logistic regression. AB - BACKGROUND: Structured Logistic Regression (SLR) is a newly developed machine learning tool first proposed in the context of text categorization. Current availability of extensive protein sequence databases calls for an automated method to reliably classify sequences and SLR seems well-suited for this task. The classification of P-type ATPases, a large family of ATP-driven membrane pumps transporting essential cations, was selected as a test-case that would generate important biological information as well as provide a proof-of-concept for the application of SLR to a large scale bioinformatics problem. RESULTS: Using SLR, we have built classifiers to identify and automatically categorize P-type ATPases into one of 11 pre-defined classes. The SLR-classifiers are compared to a Hidden Markov Model approach and shown to be highly accurate and scalable. Representing the bulk of currently known sequences, we analysed 9.3 million sequences in the UniProtKB and attempted to classify a large number of P-type ATPases. To examine the distribution of pumps on organisms, we also applied SLR to 1,123 complete genomes from the Entrez genome database. Finally, we analysed the predicted membrane topology of the identified P-type ATPases. CONCLUSIONS: Using the SLR based classification tool we are able to run a large scale study of P-type ATPases. This study provides proof-of-concept for the application of SLR to a bioinformatics problem and the analysis of P-type ATPases pinpoints new and interesting targets for further biochemical characterization and structural analysis. PMID- 24465496 TI - The 'Densitometric Image Analysis Software' and its application to determine stepwise equilibrium constants from electrophoretic mobility shift assays. AB - Current software applications for densitometric analysis, such as ImageJ, QuantityOne (BioRad) and the Intelligent or Advanced Quantifier (Bio Image) do not allow to take the non-linearity of autoradiographic films into account during calibration. As a consequence, quantification of autoradiographs is often regarded as problematic, and phosphorimaging is the preferred alternative. However, the non-linear behaviour of autoradiographs can be described mathematically, so it can be accounted for. Therefore, the 'Densitometric Image Analysis Software' has been developed, which allows to quantify electrophoretic bands in autoradiographs, as well as in gels and phosphorimages, while providing optimized band selection support to the user. Moreover, the program can determine protein-DNA binding constants from Electrophoretic Mobility Shift Assays (EMSAs). For this purpose, the software calculates a chosen stepwise equilibrium constant for each migration lane within the EMSA, and estimates the errors due to non uniformity of the background noise, smear caused by complex dissociation or denaturation of double-stranded DNA, and technical errors such as pipetting inaccuracies. Thereby, the program helps the user to optimize experimental parameters and to choose the best lanes for estimating an average equilibrium constant. This process can reduce the inaccuracy of equilibrium constants from the usual factor of 2 to about 20%, which is particularly useful when determining position weight matrices and cooperative binding constants to predict genomic binding sites. The MATLAB source code, platform-dependent software and installation instructions are available via the website http://micr.vub.ac.be. PMID- 24465497 TI - Overexpression of dimethylarginine dimethylaminohydrolase 1 attenuates airway inflammation in a mouse model of asthma. AB - Levels of asymmetric dimethylarginine (ADMA), an endogenous inhibitor of nitric oxide synthase, are increased in lung, sputum, exhaled breath condensate and plasma samples from asthma patients. ADMA is metabolized primarily by dimethylarginine dimethylaminohydrolase 1 (DDAH1) and DDAH2. We determined the effect of DDAH1 overexpression on development of allergic inflammation in a mouse model of asthma. The expression of DDAH1 and DDAH2 in mouse lungs was determined by RT-quantitative PCR (qPCR). ADMA levels in bronchoalveolar lavage fluid (BALF) and serum samples were determined by mass spectrometry. Wild type and DDAH1 transgenic mice were intratracheally challenged with PBS or house dust mite (HDM). Airway inflammation was assessed by bronchoalveolar lavage (BAL) total and differential cell counts. The levels of IgE and IgG1 in BALF and serum samples were determined by ELISA. Gene expression in lungs was determined by RNA-Seq and RT-qPCR. Our data showed that the expression of DDAH1 and DDAH2 was decreased in the lungs of mice following HDM exposure, which correlated with increased ADMA levels in BALF and serum. Transgenic overexpression of DDAH1 resulted in decreased BAL total cell and eosinophil numbers following HDM exposure. Total IgE levels in BALF and serum were decreased in HDM-exposed DDAH1-transgenic mice compared to HDM-exposed wild type mice. RNA-Seq results showed downregulation of genes in the inducible nitric oxide synthase (iNOS) signaling pathway in PBS treated DDAH1-transgenic mice versus PBS-treated wild type mice and downregulation of genes in IL-13/FOXA2 signaling pathway in HDM-treated DDAH1 transgenic mice versus HDM-treated wild type mice. Our findings suggest that decreased expression of DDAH1 and DDAH2 in the lungs may contribute to allergic asthma and overexpression of DDAH1 attenuates allergen-induced airway inflammation through modulation of Th2 responses. PMID- 24465498 TI - Correlated diffusion of colloidal particles near a liquid-liquid interface. AB - Optical microscopy and multi-particle tracking are used to investigate the cross correlated diffusion of quasi two-dimensional colloidal particles near an oil water interface. The behaviors of the correlated diffusion along longitudinal and transverse direction are asymmetric. It is shown that the characteristic length for longitudinal and transverse correlated diffusion are particle diameter d and the distance z from particle center to the interface, respectively, for large particle separation z. The longitudinal and transverse correlated diffusion coefficient D||(r) and D[perpendicular](r) are independent of the colloidal area fraction n when n < 0.3, which indicates that the hydrodynamic interactions(HIs) among the particles are dominated by HIs through the surrounding fluid for small n. For high area fraction n > 0.4 the power law exponent for the spatial decay of [Formula: see text] begins to decrease, which suggests the HIs are more contributed from the 2D particle monolayer self for large n. PMID- 24465499 TI - Development of ultra-high-density screening tools for microbial "omics". AB - High-throughput genetic screens in model microbial organisms are a primary means of interrogating biological systems. In numerous cases, such screens have identified the genes that underlie a particular phenotype or a set of gene-gene, gene-environment or protein-protein interactions, which are then used to construct highly informative network maps for biological research. However, the potential test space of genes, proteins, or interactions is typically much larger than current screening systems can address. To push the limits of screening technology, we developed an ultra-high-density, 6144-colony arraying system and analysis toolbox. Using budding yeast as a benchmark, we find that these tools boost genetic screening throughput 4-fold and yield significant cost and time reductions at quality levels equal to or better than current methods. Thus, the new ultra-high-density screening tools enable researchers to significantly increase the size and scope of their genetic screens. PMID- 24465500 TI - Extracellular matrix density regulates the rate of neovessel growth and branching in sprouting angiogenesis. AB - Angiogenesis is regulated by the local microenvironment, including the mechanical interactions between neovessel sprouts and the extracellular matrix (ECM). However, the mechanisms controlling the relationship of mechanical and biophysical properties of the ECM to neovessel growth during sprouting angiogenesis are just beginning to be understood. In this research, we characterized the relationship between matrix density and microvascular topology in an in vitro 3D organ culture model of sprouting angiogenesis. We used these results to design and calibrate a computational growth model to demonstrate how changes in individual neovessel behavior produce the changes in vascular topology that were observed experimentally. Vascularized gels with higher collagen densities produced neovasculatures with shorter vessel lengths, less branch points, and reduced network interconnectivity. The computational model was able to predict these experimental results by scaling the rates of neovessel growth and branching according to local matrix density. As a final demonstration of utility of the modeling framework, we used our growth model to predict several scenarios of practical interest that could not be investigated experimentally using the organ culture model. Increasing the density of the ECM significantly reduced angiogenesis and network formation within a 3D organ culture model of angiogenesis. Increasing the density of the matrix increases the stiffness of the ECM, changing how neovessels are able to deform and remodel their surroundings. The computational framework outlined in this study was capable of predicting this observed experimental behavior by adjusting neovessel growth rate and branching probability according to local ECM density, demonstrating that altering the stiffness of the ECM via increasing matrix density affects neovessel behavior, thereby regulated vascular topology during angiogenesis. PMID- 24465501 TI - Grape seed extract dose-responsively decreases disease severity in a rat model of mucositis; concomitantly enhancing chemotherapeutic effectiveness in colon cancer cells. AB - OBJECTIVE: Mucositis is a serious disorder of the gastrointestinal tract that results from cancer chemotherapy. We investigated the effects of increasing grape seed extract doses on the severity of chemotherapy in a rat model and its coincident impact on chemotherapeutic effectiveness in colon cancer cells. DESIGN: Female Dark Agouti rats were gavaged with grape seed extract (400-1000 mg/kg) or water (day 3-11) and were injected intraperitoneally with 5 Fluorouracil (150 mg/kg) or saline (control) on day 9 to induce mucositis. Daily metabolic data were collected and rats were sacrificed on day 12. Intestinal tissues were collected for histological and myeloperoxidase analyses. Caco-2 cell viability was examined in response to grape seed extract in combination with 5 Fluorouracil by 3-(4,5-Dimethylthiazol-2yl)-2,5-diphenyl-tetrazolium bromide) assay. RESULTS: Compared with 5-Fluorouracil controls, grape seed extract (400 1000 mg/kg) significantly decreased the histological damage score (P<0.05) in the jejunum. Grape seed extract (1000 mg/kg) increased jejunal crypt depth by 25% (P<0.05) in 5-Fluorouracil treated rats compared to 5-Fluorouracil controls, and attenuated the 5-Fluorouracil -induced reduction of mucosal thickness (25%, P<0.05). Grape seed extract (600 mg/kg) decreased myeloperoxidase activity by 55% (P<0.01) compared to 5-Fluorouracil controls. Grape seed extract was more effective at ameliorating 5-Fluorouracil induced intestinal injury, with effects most pronounced in the proximal jejunum. Grape seed extract (10-25 ug/mL) significantly enhanced the growth-inhibitory effects of 5-Fluorouracil by 26% (P<0.05) in Caco-2 cells and was more potent than 5-Fluorouracil at 50-100 ug/mL. CONCLUSION: Grape seed extract may represent a new therapeutic option to decrease the symptoms of intestinal mucositis while concurrently impacting on the viability of colon cancer cells. PMID- 24465502 TI - CD4+ primary T cells expressing HCV-core protein upregulate Foxp3 and IL-10, suppressing CD4 and CD8 T cells. AB - Adaptive T cell responses are critical for controlling HCV infection. While there is clinical evidence of a relevant role for regulatory T cells in chronic HCV infected patients, based on their increased number and function; mechanisms underlying such a phenomena are still poorly understood. Accumulating evidence suggests that proteins from Hepatitis C virus can suppress host immune responses. We and others have shown that HCV is present in CD4+ lymphocytes from chronically infected patients and that HCV-core protein induces a state of unresponsiveness in the CD4+ tumor cell line Jurkat. Here we show that CD4+ primary T cells lentivirally transduced with HCV-core, not only acquire an anergic phenotype but also inhibit IL-2 production and proliferation of bystander CD4+ or CD8+ T cells in response to anti-CD3 plus anti-CD28 stimulation. Core-transduced CD4+ T cells show a phenotype characterized by an increased basal secretion of the regulatory cytokine IL-10, a decreased IFN-gamma production upon stimulation, as well as expression of regulatory T cell markers, CTLA-4, and Foxp3. A significant induction of CD4+CD25+CD127(low)PD-1(high)TIM-3(high) regulatory T cells with an exhausted phenotype was also observed. Moreover, CCR7 expression decreased in HCV core expressing CD4+ T cells explaining their sequestration in inflamed tissues such as the infected liver. This work provides a new perspective on de novo generation of regulatory CD4+ T cells in the periphery, induced by the expression of a single viral protein. PMID- 24465503 TI - Mobile HIV screening in Cape Town, South Africa: clinical impact, cost and cost effectiveness. AB - BACKGROUND: Mobile HIV screening may facilitate early HIV diagnosis. Our objective was to examine the cost-effectiveness of adding a mobile screening unit to current medical facility-based HIV testing in Cape Town, South Africa. METHODS AND FINDINGS: We used the Cost Effectiveness of Preventing AIDS Complications International (CEPAC-I) computer simulation model to evaluate two HIV screening strategies in Cape Town: 1) medical facility-based testing (the current standard of care) and 2) addition of a mobile HIV-testing unit intervention in the same community. Baseline input parameters were derived from a Cape Town-based mobile unit that tested 18,870 individuals over 2 years: prevalence of previously undiagnosed HIV (6.6%), mean CD4 count at diagnosis (males 423/uL, females 516/uL), CD4 count-dependent linkage to care rates (males 31%-58%, females 49% 58%), mobile unit intervention cost (includes acquisition, operation and HIV test costs, $29.30 per negative result and $31.30 per positive result). We conducted extensive sensitivity analyses to evaluate input uncertainty. Model outcomes included site of HIV diagnosis, life expectancy, medical costs, and the incremental cost-effectiveness ratio (ICER) of the intervention compared to medical facility-based testing. We considered the intervention to be "very cost effective" when the ICER was less than South Africa's annual per capita Gross Domestic Product (GDP) ($8,200 in 2012). We projected that, with medical facility based testing, the discounted (undiscounted) HIV-infected population life expectancy was 132.2 (197.7) months; this increased to 140.7 (211.7) months with the addition of the mobile unit. The ICER for the mobile unit was $2,400/year of life saved (YLS). Results were most sensitive to the previously undiagnosed HIV prevalence, linkage to care rates, and frequency of HIV testing at medical facilities. CONCLUSION: The addition of mobile HIV screening to current testing programs can improve survival and be very cost-effective in South Africa and other resource-limited settings, and should be a priority. PMID- 24465504 TI - MicroRNA 135a suppresses lymph node metastasis through down-regulation of ROCK1 in early gastric cancer. AB - MicroRNAs (miRNAs) play a critical role in gastric cancer progression and metastasis. This study investigated the role of miRNA-135a in early gastric cancer (EGC) including lymph node (LN) metastasis. We examined the correlation between miRNA-135a expression and clinical outcomes in 59 patients who underwent surgery for EGC. Using gastric cancer cell lines, we performed functional and target gene analyses. miRNA-135a expression was down-regulated in 33.9% of patients. These patients showed a significantly more advanced stage (TNM stage >= IB, 35.0% vs. 12.8%, p = 0.045) and higher rate of LN metastasis (30.0% vs. 5.1%, p = 0.014) than those with up-regulation of miRNA-135a expression. In a multivariate analysis, down-regulation of miRNA-135a was an independent risk factor for LN metastasis (adjusted odds ratio, 8.04; 95% confidence interval, 1.08-59.81; p = 0.042). Functional analyses using gastric cancer cell lines showed that miRNA-135a suppressed cell viability, epithelial-mesenchymal transition, cell invasion, and migration. ROCK1 was a target of miRNA-135a and its expression was inversely correlated to that of miRNA-135a. ROCK1 expression was significantly increased in EGC patients with LN metastasis than in those without LN metastasis. Our results confirm the tumor-suppressive role of miRNA 135a, and demonstrate its role in LN metastasis in EGC. miRNA-135a and its target gene ROCK1 may be novel therapeutic and prognostic targets for EGC. PMID- 24465505 TI - Long-term effect of different physical activity levels on subclinical atherosclerosis in middle-aged men: a 25-year prospective study. AB - BACKGROUND: The purpose of the study was to investigate the influence of lifetime physical activity (PA) on selected indices of atherosclerosis in longitudinal observation of middle-aged men. METHODS: The subject of the study was a cohort of 101 men (mean age 59,7 +/- 9,0 years), free of cardiovascular symptoms and treatment, participating in follow-up examinations in the years 1985/90-2011/12. Self-report PA was assessed by interviewer-administered Seven-Day PA Recall and Historical PA questionnaire. Subclinical atherosclerosis was measured by assessing the coronary artery calcification (CAC) according to Agatston's method using multi-slice computed tomography; the carotid intima-media thickness (IMT) using high-resolution B-mode ultrasound; and the reactive hyperemia index (RHI) using peripheral arterial tonometry (EndoPAT2000). The participants were initially divided into three groups according to tertiles of exercise-related energy expenditure (EE) in kcal/week at baseline, i.e. <2050 (low-to-moderate; n = 33), 2050-3840 (high; n = 34), >3840 (very high; n = 34). RESULTS: The low-to moderate, high and very high PA groups were comparable in terms of age and atherosclerosis risk factors at baseline. No linear relationship was found between PA and CAC, IMT and RHI. Men who maintained low-to-moderate (n = 26), high (n = 21) and very high (n = 15) PA level had the mean CAC of 286.1 +/- 361.9, 10.7 +/- 28.9, and 106.1 +/- 278.3 (p<0.001 for low-to moderate vs high; p<0.05 for low-to-moderate vs very high); the mean IMT of 0.751 +/- 0.19 mm, 0,641 +/- 0.26 mm, and 0.750 +/- 0.60 mm (p>0.05); and the mean RHI of 1.69 +/- 0.4, 2.00 +/- 0.4, and 2.13 +/- 0.5 (p for trend = 0.050), respectively. No cases of CAC>400, IMT >= 0.9 and RHI<1.67 were noted only among men with maintained high PA level. At final examination men with high and very high PA had more favorable cardiometabolic profile than men with lower PA. CONCLUSIONS: Maintaining regular high PA level through young and middle adulthood may protect against atherosclerosis as measured by CAC, IMT and RHI. PMID- 24465506 TI - Clinical impact of fluoroquinolone-resistant Escherichia coli in the fecal flora of hematological patients with neutropenia and levofloxacin prophylaxis. AB - BACKGROUND: Fluoroquinolone prophylaxis in patients with neutropenia and hematological malignancies is said to be effective on febrile netropenia (FN) related infection and mortality; however, the emergence of antibiotic resistance has become a concern. Ciprofloxacin and levofloxacin prophylaxis are most commonly recommended. A significant increase in the rate of quinolone-resistant Escherichia coli in fecal flora has been reported following ciprofloxacin prophylaxis. The acquisition of quinolone-resistant E. coli after levofloxacin use has not been evaluated. METHODS: We prospectively examined the incidence of quinolone-resistant E. coli isolates recovered from stool cultures before and after levofloxacin prophylaxis in patients with neutropenia from August 2011 to May 2013. Some patients received chemotherapy multiple times. RESULTS: In this trial, 68 patients were registered. Levofloxacin-resistant E. coli isolates were detected from 11 and 13 of all patients before and after the prophylaxis, respectively. However, this was not statistically significant (P = 0.65). Multiple prophylaxis for sequential chemotherapy did not induce additional quinolone resistance among E. coli isolates. Interestingly, quinolone-resistant E. coli, most of which were extended-spectrum beta-lactamase (ESBL) producers, were already detected in approximately 20% of all patients before the initiation of prophylaxis. FN-related bacteremia developed in 2 patients, accompanied by a good prognosis. CONCLUSIONS: Levofloxacin prophylaxis for neutropenia did not result in a significant acquisition of quinolone-resistant E. coli. However, we detected previous colonization of quinolone-resistant E. coli before prophylaxis, which possibly reflects the spread of ESBL. The epidemic spread of resistant E. coli as a local factor may influence strategies toward the use of quinolone prophylaxis. PMID- 24465507 TI - Cell morphogenesis proteins are translationally controlled through UTRs by the Ndr/LATS target Ssd1. AB - Eukaryotic cells control their growth and morphogenesis to maintain integrity and viability. Free-living cells are further challenged by their direct interaction with the environment and in many cases maintain a resilient cell wall to stay alive under widely varying conditions. For these organisms, stringent and highly localized control of the cell wall's remodeling and expansion is crucial for cell growth and reproduction. In the budding yeast Saccharomyces cerevisiae the RNA binding protein Ssd1 helps control cell wall remodeling by repressing translation of proteins involved in wall expansion. Ssd1 is itself negatively regulated by the highly conserved Ndr/LATS protein kinase Cbk1. We sought to identify mRNA regions that confer Ssd1-mediated translational control. After validating a GFP reporter system as a readout of Ssd1 activity we found that 3' untranslated regions of the known Ssd1 targets CTS1, SIM1 and UTH1 are sufficient for Cbk1 regulated translational control. The 5' untranslated region of UTH1 also facilitated Ssd1-mediated translational control in a heterologous context. The CTS1 and SIM1 3' untranslated regions confer Ssd1 binding, and the SIM1 3' untranslated region improves Ssd1 immunoprecipitation of the endogenous SIM1 transcript. However, SIM1's 3' untranslated region is not essential for Ssd1 regulated control of the message's translation. We propose that Ssd1 regulates translation of its target message primarily through UTRs and the SIM1 message through multiple potential points of interaction, permitting fine translational control in various contexts. PMID- 24465508 TI - The role of flotillins in regulating abeta production, investigated using flotillin 1-/-, flotillin 2-/- double knockout mice. AB - Flotillin 1 and flotillin 2 associate in the plasma membrane to form microdomains that have roles in cell signaling, regulation of cell-cell contacts, membrane cytoskeletal interactions, and endocytosis. They are thought to be involved in the trafficking and hence processing of the Amyloid Precursor Protein, APP. In this study we set out to obtain in vivo confirmation of a link between flotillins and cleavage of APP to release amyloidogenic Abeta peptide, and to generate tools that would allow us to ask whether flotillins are functionally redundant. We used a mouse model for Abeta-dependent cerebral amyloidosis, APPPS1 mice, combined with deletion of either flotillin 1 singly, or flotillin 1 and flotillin 2 together. There was a small but significant reduction in Abeta levels, and the abundance of congo-red stained plaques, in brains of 12 week old mice lacking flotillin 1. A similar reduction in Abeta levels was observed in the flotillin 1 /-, flotillin 2-/- double knockouts. We did not observe large effects on the clustering or endocytosis of APP in flotillin 1-/- mouse embryonic fibroblasts. We conclude that flotillins are likely to play some role in APP trafficking or processing, but the relevant cellular mechanisms require more investigation. The availability of flotillin 1-/-, flotillin 2-/- mice, which have no overt phenotypes, will facilitate research into flotillin function in vivo. PMID- 24465509 TI - Blockade of mast cell activation reduces cutaneous scar formation. AB - Damage to the skin initiates a cascade of well-orchestrated events that ultimately leads to repair of the wound. The inflammatory response is key to wound healing both through preventing infection and stimulating proliferation and remodeling of the skin. Mast cells within the tissue are one of the first immune cells to respond to trauma, and upon activation they release pro-inflammatory molecules to initiate recruitment of leukocytes and promote a vascular response in the tissue. Additionally, mast cells stimulate collagen synthesis by dermal fibroblasts, suggesting they may also influence scar formation. To examine the contribution of mast cells in tissue repair, we determined the effects the mast cell inhibitor, disodium cromoglycate (DSCG), on several parameters of dermal repair including, inflammation, re-epithelialization, collagen fiber organization, collagen ultrastructure, scar width and wound breaking strength. Mice treated with DSCG had significantly reduced levels of the inflammatory cytokines IL-1alpha, IL-1beta, and CXCL1. Although DSCG treatment reduced the production of inflammatory mediators, the rate of re-epithelialization was not affected. Compared to control, inhibition of mast cell activity caused a significant decrease in scar width along with accelerated collagen re organization. Despite the reduced scar width, DSCG treatment did not affect the breaking strength of the healed tissue. Tryptase beta1 exclusively produced by mast cells was found to increase significantly in the course of wound healing. However, DSCG treatment did not change its level in the wounds. These results indicate that blockade of mast cell activation reduces scar formation and inflammation without further weakening the healed wound. PMID- 24465510 TI - The exact distributions of F(IS) under partial asexuality in small finite populations with mutation. AB - Reproductive systems like partial asexuality participate to shape the evolution of genetic diversity within populations, which is often quantified by the inbreeding coefficient F IS. Understanding how those mating systems impact the possible distributions of F IS values in theoretical populations helps to unravel forces shaping the evolution of real populations. We proposed a population genetics model based on genotypic states in a finite population with mutation. For populations with less than 400 individuals, we assessed the impact of the rates of asexuality on the full exact distributions of F IS, the probabilities of positive and negative F IS, the probabilities of fixation and the probabilities to observe changes in the sign of F IS over one generation. After an infinite number of generations, we distinguished three main patterns of effects of the rates of asexuality on genetic diversity that also varied according to the interactions of mutation and genetic drift. Even rare asexual events in mainly sexual populations impacted the balance between negative and positive F IS and the occurrence of extreme values. It also drastically modified the probability to change the sign of F IS value at one locus over one generation. When mutation prevailed over genetic drift, increasing rates of asexuality continuously increased the variance of F IS that reached its highest value in fully asexual populations. In consequence, even ancient asexual populations showed the entire F IS spectrum, including strong positive F IS. The prevalence of heterozygous loci only occurred in full asexual populations when genetic drift dominated. PMID- 24465511 TI - Simulation of dilated heart failure with continuous flow circulatory support. AB - Lumped parameter models have been employed for decades to simulate important hemodynamic couplings between a left ventricular assist device (LVAD) and the native circulation. However, these studies seldom consider the pathological descending limb of the Frank-Starling response of the overloaded ventricle. This study introduces a dilated heart failure model featuring a unimodal end systolic pressure-volume relationship (ESPVR) to address this critical shortcoming. The resulting hemodynamic response to mechanical circulatory support are illustrated through numerical simulations of a rotodynamic, continuous flow ventricular assist device (cfVAD) coupled to systemic and pulmonary circulations with baroreflex control. The model further incorporated septal interaction to capture the influence of left ventricular (LV) unloading on right ventricular function. Four heart failure conditions were simulated (LV and bi-ventricular failure with/without pulmonary hypertension) in addition to normal baseline. Several metrics of LV function, including cardiac output and stroke work, exhibited a unimodal response whereby initial unloading improved function, and further unloading depleted preload reserve thereby reducing ventricular output. The concept of extremal loading was introduced to reflect the loading condition in which the intrinsic LV stroke work is maximized. Simulation of bi-ventricular failure with pulmonary hypertension revealed inadequacy of LV support alone. These simulations motivate the implementation of an extremum tracking feedback controller to potentially optimize ventricular recovery. PMID- 24465512 TI - Robust prognostic gene expression signatures in bladder cancer and lung adenocarcinoma depend on cell cycle related genes. AB - Few prognostic biomarkers are approved for clinical use primarily because their initial performance cannot be repeated in independent datasets. We posited that robust biomarkers could be obtained by identifying deregulated biological processes shared among tumor types having a common etiology. We performed a gene set enrichment analysis in 20 publicly available gene expression datasets comprising 1968 patients having one of the three most common tobacco-related cancers (lung, bladder, head and neck) and identified cell cycle related genes as the most consistently prognostic class of biomarkers in bladder (BL) and lung adenocarcinoma (LUAD). We also found the prognostic value of 13 of 14 published BL and LUAD signatures were dependent on cell cycle related genes, supporting the importance of cell cycle related biomarkers for prognosis. Interestingly, no prognostic gene classes were identified in squamous cell lung carcinoma or head and neck squamous cell carcinoma. Next, a specific 31 gene cell cycle proliferation (CCP) signature, previously derived in prostate tumors was evaluated and found predictive of outcome in BL and LUAD cohorts in univariate and multivariate analyses. Specifically, CCP score significantly enhanced the predictive ability of multivariate models based on standard clinical variables for progression in BL patients and survival in LUAD patients in multiple cohorts. We then generated random CCP signatures of various sizes and found sets of 10-15 genes had robust performance in these BL and LUAD cohorts, a finding that was confirmed in an independent cohort. Our work characterizes the importance of cell cycle related genes in prognostic signatures for BL and LUAD patients and identifies a specific signature likely to survive additional validation. PMID- 24465513 TI - A newly emerging HIV-1 recombinant lineage (CRF58_01B) disseminating among people who inject drugs in Malaysia. AB - The HIV epidemic is primarily characterised by the circulation of HIV-1 group M (main) comprising of 11 subtypes and sub-subtypes (A1, A2, B-D, F1, F2, G, H, J, and K) and to date 55 circulating recombinant forms (CRFs). In Southeast Asia, active inter-subtype recombination involving three main circulating genotypes- subtype B (including subtype B', the Thai variant of subtype B), CRF01_AE, and CRF33_01B--have contributed to the emergence of novel unique recombinant forms. In the present study, we conducted the molecular epidemiological surveillance of HIV-1 gag-RT genes among 258 people who inject drugs (PWIDs) in Kuala Lumpur, Malaysia, between 2009 and 2011 whereby a novel CRF candidate was recently identified. The near full-length genome sequences obtained from six epidemiologically unlinked individuals showed identical mosaic structures consisting of subtype B' and CRF01_AE, with six unique recombination breakpoints in the gag-RT, pol, and env regions. Among the high-risk population of PWIDs in Malaysia, which was predominantly infected by CRF33_01B (>70%), CRF58_01B circulated at a low but significant prevalence (2.3%, 6/258). Interestingly, the CRF58_01B shared two unique recombination breakpoints with other established CRFs in the region: CRF33_01B, CRF48_01B, and CRF53_01B in the gag gene, and CRF15_01B (from Thailand) in the env gene. Extended Bayesian Markov chain Monte Carlo sampling analysis showed that CRF58_01B and other recently discovered CRFs were most likely to have originated in Malaysia, and that the recent spread of recombinant lineages in the country had little influence from neighbouring countries. The isolation, genetic characterization, and evolutionary features of CRF58_01B among PWIDs in Malaysia signify the increasingly complex HIV-1 diversity in Southeast Asia that may hold an implication on disease treatment, control, and prevention. PMID- 24465514 TI - The emotional toll of hell: cross-national and experimental evidence for the negative well-being effects of hell beliefs. AB - Though beliefs in Heaven and Hell are related, they are associated with different personality characteristics and social phenomena. Here we present three studies measuring Heaven and Hell beliefs' associations with and impact on subjective well-being. We find that a belief in Heaven is consistently associated with greater happiness and life satisfaction while a belief in Hell is associated with lower happiness and life satisfaction at the national (Study 1) and individual (Study 2) level. An experimental priming study (Study 3) suggests that these differences are mainly driven by the negative emotional impact of Hell beliefs. Possible cultural evolutionary explanations for the persistence of such a distressing religious concept are discussed. PMID- 24465515 TI - Low-molecular weight heparin increases circulating sFlt-1 levels and enhances urinary elimination. AB - RATIONALE: Preeclampsia is a devastating medical complication of pregnancy which leads to maternal and fetal morbidity and mortality. While the etiology of preeclampsia is unclear, human and animal studies suggest that excessive circulating levels of soluble fms-like tyrosine-kinase-1 (sFlt-1), an alternatively spliced variant of VEGF-receptor1, contribute to the signs and symptoms of preeclampsia. Since sFlt-1 binds to heparin and heparan sulfate proteoglycans, we hypothesized that the anticoagulant heparin, which is often used in pregnancy, may interfere with the levels, distribution and elimination of sFlt-1 in vivo. OBJECTIVE: We systematically determined serum and urine levels of angiogenic factors in preeclamptic women before and after administration of low molecular weight heparin and further characterized the interaction with heparin in biochemical studies. METHODS AND RESULTS: Serum and urine samples were used to measure sFlt-1 levels before and after heparin administration. Serum levels of sFlt-1 increased by 25% after heparin administration in pregnant women. The magnitude of the increase in circulating sFlt-1 correlated with initial sFlt-1 serum levels. Urinary sFlt-1 levels were also elevated following heparin administration and levels of elimination were dependent on the underlying integrity of the glomerular filtration barrier. Biochemical binding studies employing cation exchange chromatography revealed that heparin bound sFlt-1 had decreased affinity to negatively charged surfaces when compared to sFlt-1 alone. CONCLUSION: Low molecular weight heparin administration increased circulating sFlt1 levels and enhanced renal elimination. We provide evidence that both effects may be due to heparin binding to sFlt1 and masking the positive charges on sFlt1 protein. PMID- 24465516 TI - Metabolism of N-acylated-dopamine. AB - N-oleoyl-dopamine (OLDA) is a novel lipid derivative of dopamine. Its biological action includes the interaction with dopamine and the transient receptor potential vanilloid (TRPV1) receptors. It seems to be synthesized in a dopamine like manner, but there has been no information on its degradation. The aim of the study was, therefore, to determine whether OLDA metabolism proceeds the way dopamine proper does. We addressed the issue by examining the occurrence of O methylation of exogenously supplemented OLDA via catechol-O-methyltransferase (COMT) under in vitro, ex vivo, and in vivo conditions using rat brain tissue. The results show that OLDA was methylated by COMT in all conditions studied, yielding the O-methylated derivative. The methylation was reversed by tolcapone, a potent COMT inhibitor, in a dose-dependent manner. We conclude that OLDA enters the metabolic pathway of dopamine. Methylation of OLDA may enhance its bioactive properties, such as the ability to interact with TRPV1 receptors. PMID- 24465517 TI - Genome-wide analysis of promoters: clustering by alignment and analysis of regular patterns. AB - In this paper we perform a genome-wide analysis of H. sapiens promoters. To this aim, we developed and combined two mathematical methods that allow us to (i) classify promoters into groups characterized by specific global structural features, and (ii) recover, in full generality, any regular sequence in the different classes of promoters. One of the main findings of this analysis is that H. sapiens promoters can be classified into three main groups. Two of them are distinguished by the prevalence of weak or strong nucleotides and are characterized by short compositionally biased sequences, while the most frequent regular sequences in the third group are strongly correlated with transposons. Taking advantage of the generality of these mathematical procedures, we have compared the promoter database of H. sapiens with those of other species. We have found that the above-mentioned features characterize also the evolutionary content appearing in mammalian promoters, at variance with ancestral species in the phylogenetic tree, that exhibit a definitely lower level of differentiation among promoters. PMID- 24465518 TI - Sex-specific differences in pathogen susceptibility in honey bees (Apis mellifera). AB - Sex-related differences in susceptibility to pathogens are a common phenomenon in animals. In the eusocial Hymenoptera the two female castes, workers and queens, are diploid and males are haploid. The haploid susceptibility hypothesis predicts that haploid males are more susceptible to pathogen infections compared to females. Here we test this hypothesis using adult male (drone) and female (worker) honey bees (Apis mellifera), inoculated with the gut endoparasite Nosema ceranae and/or black queen cell virus (BQCV). These pathogens were chosen due to previously reported synergistic interactions between Nosema apis and BQCV. Our data do not support synergistic interactions between N. ceranae and BQCV and also suggest that BQCV has limited effect on both drone and worker health, regardless of the infection level. However, the data clearly show that, despite lower levels of N. ceranae spores in drones than in workers, Nosema-infected drones had both a higher mortality and a lower body mass than non-infected drones, across all treatment groups, while the mortality and body mass of worker bees were largely unaffected by N. ceranae infection, suggesting that drones are more susceptible to this pathogen than workers. In conclusion, the data reveal considerable sex specific differences in pathogen susceptibility in honey bees and highlight the importance of ultimate measures for determining susceptibility, such as mortality and body quality, rather than mere infection levels. PMID- 24465520 TI - A unified approach to linking experimental, statistical and computational analysis of spike train data. AB - A fundamental issue in neuroscience is how to identify the multiple biophysical mechanisms through which neurons generate observed patterns of spiking activity. In previous work, we proposed a method for linking observed patterns of spiking activity to specific biophysical mechanisms based on a state space modeling framework and a sequential Monte Carlo, or particle filter, estimation algorithm. We have shown, in simulation, that this approach is able to identify a space of simple biophysical models that were consistent with observed spiking data (and included the model that generated the data), but have yet to demonstrate the application of the method to identify realistic currents from real spike train data. Here, we apply the particle filter to spiking data recorded from rat layer V cortical neurons, and correctly identify the dynamics of an slow, intrinsic current. The underlying intrinsic current is successfully identified in four distinct neurons, even though the cells exhibit two distinct classes of spiking activity: regular spiking and bursting. This approach--linking statistical, computational, and experimental neuroscience--provides an effective technique to constrain detailed biophysical models to specific mechanisms consistent with observed spike train data. PMID- 24465519 TI - Systematic review of the properties of tools used to measure outcomes in anxiety intervention studies for children with autism spectrum disorders. AB - BACKGROUND: Evidence about relevant outcomes is required in the evaluation of clinical interventions for children with autism spectrum disorders (ASD). However, to date, the variety of outcome measurement tools being used, and lack of knowledge about the measurement properties of some, compromise conclusions regarding the most effective interventions. OBJECTIVES: This two-stage systematic review aimed to identify the tools used in studies evaluating interventions for anxiety for high-functioning children with ASD in middle childhood, and then to evaluate the tools for their appropriateness and measurement properties. METHODS: Electronic databases including Medline, PsychInfo, Embase, and the Cochrane database and registers were searched for anxiety intervention studies for children with ASD in middle childhood. Articles examining the measurement properties of the tools used were then searched for using a methodological filter in PubMed, and the quality of the papers evaluated using the COSMIN checklist. RESULTS: Ten intervention studies were identified in which six tools measuring anxiety and one of overall symptom change were used as primary outcomes. One further tool was included as it is recommended for standard use in UK children's mental health services. Sixty three articles on the properties of the tools were evaluated for the quality of evidence, and the quality of the measurement properties of each tool was summarised. CONCLUSIONS: Overall three questionnaires were found robust in their measurement properties, the Spence Children's Anxiety Scale, its revised version - the Revised Children's Anxiety and Depression Scale, and also the Screen for Child Anxiety Related Emotional Disorders. Crucially the articles on measurement properties provided almost no evidence on responsiveness to change, nor on the validity of use of the tools for evaluation of interventions for children with ASD. PROSPERO REGISTRATION NUMBER: CRD42012002684. PMID- 24465521 TI - Mitochondrial p38beta and manganese superoxide dismutase interaction mediated by estrogen in cardiomyocytes. AB - AIMS: While etiology behind the observed acceleration of ischemic heart disease in postmenopausal women is poorly understood, collective scientific data suggest cardioprotective effects of the endogenous female sex hormone, estrogen. We have previously shown that 17beta-estradiol (E2) protects cardiomyocytes exposed to hypoxia-reoxygenation (H/R) by inhibiting p38alpha - p53 signaling in apoptosis and activating pro-survival p38beta mitogen activated protein kinase (p38beta MAPK), leading to suppression of reactive oxygen species (ROS) post H/R. However, little is known about the mechanism behind the antioxidant actions of E2 dependent p38beta. The aim of this study is to determine whether the cytoprotection by estrogen involves regulation of manganese superoxide dismutase (MnSOD), a major mitochondrial ROS scavenging enzyme, via cardiac p38beta. METHODS AND RESULTS: We identified mitochondrial p38beta by immunocytochemistry and by immunoblotting in mitochondria isolated from neonatal cardiomyocytes of Sprague-Dawley rats. E2 facilitated the mitochondrial localization of the active form of the kinase, phosphorylated p38beta (p-p38beta). E2 also reduced the H/R induced mitochondrial membrane potential decline, augmented the MnSOD activity and suppressed anion superoxide generation, while the dismutase protein expression remained unaltered. Co-immunoprecipitation studies showed physical association between MnSOD and p38beta. p38beta phosphorylated MnSOD in an E2 dependent manner in in-vitro kinase assays. CONCLUSION: This work demonstrates for the first time a mitochondrial pool of active p38beta and E2-mediated phosphorylation of MnSOD by the kinase. The results shed light on the mechanism behind the cytoprotective actions of E2 in cardiomyocytes under oxidative stress. PMID- 24465522 TI - Systemic and local inflammatory response in women with preterm prelabor rupture of membranes. AB - OBJECTIVE: To evaluate the inflammatory pattern in maternal circulation, amniotic cavity, cervix and vagina from women with preterm prelabor rupture of membranes (PPROM) considering the occurrence of microbial invasion of the amniotic cavity (MIAC). METHODOLOGY: A prospective study was performed in 58 women with PPROM before 34+0 weeks of gestational age. Twenty-six proteins were analyzed by a multiple immunoassay in samples of amniotic fluid, serum, cervix and vagina. Association of an inflammatory response in the invasive and non-invasive samples with MIAC was investigated. RESULTS: The rate of MIAC was 36.2% (21/58). Both amniotic fluid IL-6 and cervical C-reactive protein (CRP) showed to be independent predictors of MIAC. A cut-off level of cervical CRP>=1836 pg/mL showed a detection rate of 75%, false positive rate of 19% and positive and negative predictive values to predict MIAC of 67% and 87%, respectively. There were no independent biomarkers of MIAC either in the serum or vaginal compartment. CONCLUSION: A cervical inflammatory response mediated by CRP was observed in PPROM women with MIAC. Evaluation of serum or vaginal samples did not add valuable information regarding the outcome evaluated. PMID- 24465523 TI - Influence of aggregation and route of injection on the biodistribution of mouse serum albumin. AB - Protein aggregates are a major risk factor for immunogenicity. Until now most studies on aggregate-driven immunogenicity have focused on linking physicochemical features of the aggregates to the formation of anti-drug antibodies. Lacking is however, basic knowledge on the effect of aggregation on the biodistribution and clearance of therapeutic proteins in vivo. The aim of current study was to get insight into the effect of aggregation on biodistribution in mice using different routes of administration. Fluorescently labeled stressed and unstressed mouse serum albumin was injected via different routes in mice and detected via in vivo fluorescence imaging up to 48 hrs post injection. We found that biodistribution of stressed MSA significantly differed from its unstressed counterpart. Subcutaneous and intramuscular administration resulted in accumulation of protein at the site of injection, from which clearance of stressed MSA was considerably slower than clearance of unstressed MSA. Upon intravenous and intraperitoneal injection of stressed MSA, fluorescent "hotspots" were observed in the spleens, livers and lungs. Further and more detailed examination of biodistribution after intraperitoneal injection showed higher fluorescence in most of tested organs suggesting more efficient diffusion and/or lymphatic uptake from peritoneum of unstressed MSA than the stressed formulation. PMID- 24465524 TI - Effects of marine and freshwater macroalgae on in vitro total gas and methane production. AB - This study aimed to evaluate the effects of twenty species of tropical macroalgae on in vitro fermentation parameters, total gas production (TGP) and methane (CH4) production when incubated in rumen fluid from cattle fed a low quality roughage diet. Primary biochemical parameters of macroalgae were characterized and included proximate, elemental, and fatty acid (FAME) analysis. Macroalgae and the control, decorticated cottonseed meal (DCS), were incubated in vitro for 72 h, where gas production was continuously monitored. Post-fermentation parameters, including CH4 production, pH, ammonia, apparent organic matter degradability (OMd), and volatile fatty acid (VFA) concentrations were measured. All species of macroalgae had lower TGP and CH4 production than DCS. Dictyota and Asparagopsis had the strongest effects, inhibiting TGP by 53.2% and 61.8%, and CH4 production by 92.2% and 98.9% after 72 h, respectively. Both species also resulted in the lowest total VFA concentration, and the highest molar concentration of propionate among all species analysed, indicating that anaerobic fermentation was affected. Overall, there were no strong relationships between TGP or CH4 production and the >70 biochemical parameters analysed. However, zinc concentrations >0.10 g x kg( 1) may potentially interact with other biochemical components to influence TGP and CH4 production. The lack of relationship between the primary biochemistry of species and gas parameters suggests that significant decreases in TGP and CH4 production are associated with secondary metabolites produced by effective macroalgae. The most effective species, Asparagopsis, offers the most promising alternative for mitigation of enteric CH4 emissions. PMID- 24465525 TI - Nitrophenol chemi-sensor and active solar photocatalyst based on spinel hetaerolite nanoparticles. AB - In this contribution, a significant catalyst based on spinel ZnMn2O4 composite nanoparticles has been developed for electro-catalysis of nitrophenol and photo catalysis of brilliant cresyl blue. ZnMn2O4 composite (hetaerolite) nanoparticles were prepared by easy low temperature hydrothermal procedure and structurally characterized by X-ray powder diffraction (XRD), field emission scanning electron microscopy (FESEM), X-ray photoelectron spectroscopy (XPS), Fourier transform infrared (FTIR) and UV-visible spectroscopy which illustrate that the prepared material is optical active and composed of well crystalline body-centered tetragonal nanoparticles with average size of ~ 38 +/- 10 nm. Hetaerolite nanoparticles were applied for the advancement of a nitrophenol sensor which exhibited high sensitivity (1.500 uAcm(-2) mM(-1)), stability, repeatability and lower limit of detection (20.0 uM) in short response time (10 sec). Moreover, hetaerolite nanoparticles executed high solar photo-catalytic degradation when applied to brilliant cresyl blue under visible light. PMID- 24465526 TI - Noblesse oblige? Social status and economic inequality maintenance among politicians. AB - Economic inequality is at historically high levels in the United States and is among the most pressing issues facing society. And yet, predicting the behavior of politicians with respect to their support of economic inequality remains a significant challenge. Given that high status individuals tend to conceive of the current structure of society as fair and just, we expected that high status members of the U.S. House of Representatives would be more likely to support economic inequality in their legislative behavior than would their low status counterparts. Results supported this prediction particularly among Democratic members of Congress: Whereas Republicans tended to support legislation increasing economic inequality regardless of their social status, the social status of Democrats - measured in terms of average wealth, race, or gender - was a significant predictor of support for economic inequality. Policy implications of the observed relationship between social status and support for economic inequality are considered. PMID- 24465527 TI - Targeting cadherin-17 inactivates Ras/Raf/MEK/ERK signaling and inhibits cell proliferation in gastric cancer. AB - Cadherin-17 (CDH17), one member of 7D-cadherin superfamily, was overexpressed in gastric cancer (GC) and was associated with poor survival, tumor recurrence, metastasis, and advanced tumor stage. So far the cellular function and signaling mechanism of CDH17 in GC remains unclear. In this study, we showed that over 66% of GC cell lines (20/30) were CDH17 positive. Tissue microarray (TMA) assay showed that 73.6% Chinese GC tissues (159/216) were CDH17 positive, while 37% respective adjacent normal tissues were CDH17 positive. Knockdown of CDH17 inhibited cell proliferation, migration, adhesion and colony formation, and also induced a cell cycle arrest and apoptosis in AGS human GC cells. On the other side, overexpression of CDH17 facilitated MGC-803 GC tumor growth in nude mice. Antibody array and Western blotting assay demonstrated that knockdown of CDH17 in AGS cells down-regulated integrin beta series proteins, further inactivated the Ras/Raf/MEK/ERK pathway and led to p53 and p21 accumulation, which resulted in proliferation inhibition, cell-cycle arrest and apoptosis induction. Collectively, our data firstly demonstrate the capacity of CDH17 to regulate the activity of Ras/Raf/MEK/ERK pathway for cell proliferation in GC, and suggest that CDH17 can serve as an attractive therapeutic target for future research. PMID- 24465528 TI - Fitting characteristics of N95 filtering-facepiece respirators used widely in China. AB - BACKGROUND: Millions of people rely on N95 filtering facepiece respirators to reduce the risk of airborne particles and prevent them from respiratory infections. However, there are no respirator fit testing and training regulations in China. Meanwhile, no study has been conducted to investigate the fit of various respirators. The objective of this study was to investigate whether people obtained adequate fit when wearing N95 filtering facepiece respirators (FFRs) used widely in China. METHODS: Fifty adult participants selected using the Chinese respirator fit test panel donned 10 common models of N95 FFRs. Fit factors (FF) and inward leakage were measured using the TSI PortaCount Plus. Each subject was tested with three replications for each model. A subject was considered to pass the fit test when at least two of the three FFs were greater than 100. Two models were conducted fit tests before and after training to assess the role of training. RESULTS: The geometric mean FFs for each model and trained subjects ranged from <10 to 74.0. The fifth percentile FFs for only two individual respirator models were greater than 10 which is the expected level of performance for FFRs. The passing rates for these two models of FFRs were 44.7% and 20.0%. The passing rates were less than 10.0% for the other eight models. There were 27 (54%) participants who passed none of the 10 FFRs. The geometric mean FFs for both models when the subjects received training (49.7 and 74.0) were significantly larger than those when the same group of subjects did not receive any training (29.0 and 30.9) (P<0.05). CONCLUSIONS: FFRs used widely in China should be improved according to Chinese facial dimensions. Respirator users could benefit from respirator training and fit testing before using respirators. PMID- 24465529 TI - Trace element distribution in selected edible tissues of zebu (Bos indicus) cattle slaughtered at Jimma, SW Ethiopia. AB - The amount of trace elements present in edible bovine tissues is of importance for both animal health and human nutrition. This study presents data on trace element concentrations in semitendinosus and cardiac muscles, livers and kidneys of 60 zebu (Bos indicus) bulls, sampled at Jimma, Ethiopia. From 28 of these bulls, blood samples were also obtained. Deficient levels of copper were found in plasma, livers, kidneys and semitendinosus muscles. Suboptimal selenium concentrations were found in plasma and semitendinosus muscles. Semitendinosus muscles contained high iron concentrations. Trace elements were mainly stored in the liver, except for iron and selenium. Cardiac muscles generally contained higher concentrations of trace elements than semitendinous muscles except for zinc. A strong association was found between liver and kidney concentrations of copper, iron, cobalt and molybdenum. Liver storage was well correlated with storage in semitendinosus muscle for selenium and with cardiac muscle for cobalt and selenium. Plasma concentrations of copper, selenium, cobalt were well related with their respective liver concentrations and for cobalt and selenium, also with cardiac muscle concentrations. The data suggest multiple trace element deficiencies in zebu cattle in South-West Ethiopia, with lowered tissue concentrations as a consequence. Based on the comparison of our data with other literature, trace element concentrations in selected edible tissues of Bos indicus seem quite similar to those in Bos taurus. However, tissue threshold values for deficiency in Bos taurus cattle need to be refined and their applicability for Bos indicus cattle needs to be evaluated. PMID- 24465530 TI - Responses of bacterial communities in arable soils in a rice-wheat cropping system to different fertilizer regimes and sampling times. AB - Soil physicochemical properties, soil microbial biomass and bacterial community structures in a rice-wheat cropping system subjected to different fertilizer regimes were investigated in two seasons (June and October). All fertilizer regimes increased the soil microbial biomass carbon and nitrogen. Both fertilizer regime and time had a significant effect on soil physicochemical properties and bacterial community structure. The combined application of inorganic fertilizer and manure organic-inorganic fertilizer significantly enhanced the bacterial diversity in both seasons. The bacterial communities across all samples were dominated by Proteobacteria, Acidobacteria and Chloroflexi at the phylum level. Permutational multivariate analysis confirmed that both fertilizer treatment and season were significant factors in the variation of the composition of the bacterial community. Hierarchical cluster analysis based on Bray-Curtis distances further revealed that bacterial communities were separated primarily by season. The effect of fertilizer treatment is significant (P = 0.005) and accounts for 7.43% of the total variation in bacterial community. Soil nutrients (e.g., available K, total N, total P and organic matter) rather than pH showed significant correlation with the majority of abundant taxa. In conclusion, both fertilizer treatment and seasonal changes affect soil properties, microbial biomass and bacterial community structure. The application of NPK plus manure organic-inorganic fertilizer may be a sound fertilizer practice for sustainable food production. PMID- 24465531 TI - Divergent Wnt8a gene expression in teleosts. AB - The analysis of genes in evolutionarily distant but morphologically similar species is of major importance to unravel the changes in genomes over millions of years, which led to gene silencing and functional diversification. We report the analysis of Wnt8a gene expression in the medakafish and provide a detailed comparison to other vertebrates. In all teleosts analyzed there are two paralogous Wnt8a copies. These show largely overlapping expression in the early developing zebrafish embryo, an evolutionarily distant relative of medaka. In contrast to zebrafish, we find that both maternal and zygotic expression of particularly one Wnt8a paralog has diverged in medaka. While Wnt8a1 expression is mostly conserved at early embryonic stages, the expression of Wnt8a2 differs markedly. In addition, both genes are distinctly expressed during organogenesis unlike the zebrafish homologs, which may hint at the emergence of functional diversification of Wnt8a ligands during evolution. PMID- 24465532 TI - Women's preferences regarding infant or maternal antiretroviral prophylaxis for prevention of mother-to-child transmission of HIV during breastfeeding and their views on Option B+ in Dar es Salaam, Tanzania. AB - BACKGROUND: The WHO 2010 guidelines for prevention of mother-to-child transmission (PMTCT) of HIV recommended prophylactic antiretroviral treatment (ART) either for infants (Option A) or mothers (Option B) during breastfeeding for pregnant women with a CD4 count of >350 cell/uL in low-income countries. In 2012, WHO proposed that all HIV-infected pregnant women should receive triple ART for life (B+) irrespective of CD4 count. Tanzania has recently switched from Option A to B+, with a few centers practicing B. However, more information on the real-life feasibility of these options is needed. This qualitative study explored women's preferences for Option A vs B and their views on Option B+ in Dar es Salaam, Tanzania. METHODS: We conducted four focus group discussions with a total of 27 pregnant women with unknown HIV status, attending reproductive and child health clinics, and 31 in-depth interviews among HIV-infected pregnant and post delivery women, 17 of whom were also asked about B+. RESULTS: Most participants were in favor of Option B compared to A. The main reasons for choosing Option B were: HIV-associated stigma, fear of drug side-effects on infants and difficult logistics for postnatal drug adherence. Some of the women asked about B+ favored it as they agreed that they would eventually need ART for their own survival. Some were against B+ anticipating loss of motivation after protecting the child, fearing drug side-effects and not feeling ready to embark on lifelong medication. Some were undecided. CONCLUSION: Option B was preferred. Since Tanzania has recently adopted Option B+, women with CD4 counts of >350 cell/uL should be counseled about the possibility to "opt-out" from ART after cessation of breastfeeding. Drug safety and benefits, economic concerns and available resources for laboratory monitoring and evaluation should be addressed during B+ implementation to enhance long-term feasibility and effectiveness. PMID- 24465533 TI - Mutual use of trail-following chemical cues by a termite host and its inquiline. AB - Termite nests are often secondarily inhabited by other termite species ( = inquilines) that cohabit with the host. To understand this association, we studied the trail-following behaviour in two Neotropical species, Constrictotermes cyphergaster (Termitidae: Nasutitermitinae) and its obligatory inquiline, Inquilinitermes microcerus (Termitidae: Termitinae). Using behavioural experiments and chemical analyses, we determined that the trail-following pheromone of C. cyphergaster is made of neocembrene and (3Z,6Z,8E)-dodeca-3,6,8 trien-1-ol. Although no specific compound was identified in I. microcerus, workers were able to follow the above compounds in behavioural bioassays. Interestingly, in choice tests, C. cyphergaster prefers conspecific over heterospecific trails while I. microcerus shows the converse behaviour. In no choice tests with whole body extracts, C. cyphergaster showed no preference for, while I. microcerus clearly avoided heterospecific trails. This seems to agree with the hypothesis that trail-following pheromones may shape the cohabitation of C. cyphergaster and I. microcerus and reinforce the idea that their cohabitation is based on conflict-avoiding strategies. PMID- 24465534 TI - Study on the trend and disease burden of injury deaths in Chinese population, 2004-2010. AB - Injuries are a growing public health concern in China, accounting for more than 30% of all Person Years of Life Lost (PYLL) due to premature mortality. This study analyzes the trend and disease burden of injury deaths in Chinese population from 2004 to 2010, using data from the National Disease Surveillance Points (DSPs) system, as injury deaths are classified based on the International Classification of Disease-10(th) Revision (ICD-10). We observed that injury death accounted for nearly 10% of all deaths in China throughout the period 2004-2010, and the injury mortality rates were higher in males than those in females, and higher in rural areas than in urban areas. Traffic crashes (33.79-38.47% of all injury deaths) and suicides (16.20-22.01%) were the two leading causes of injury deaths. Alarmingly, suicide surpassed traffic crashes as the leading cause of injury mortality in rural females, yet adults aged 65 and older suffered the greatest number of fatal falls (20,701 deaths, 2004-2010). The burden of injury among men (72.11%) was about three times more than that of women's (28.89%). This study provides indispensible evidence that China Authority needs to improve the surveillance and deterrence of three major types of injuries: Traffic-related injury deaths should be targeted for injury prevention activities in all population, people aged 65+ should be encouraged to take individual fall precautions, and prevention of suicidal behavior in rural females should be another key priority for the government of China. PMID- 24465535 TI - Disturbances in pro-oxidant-antioxidant balance after passive body overheating and after exercise in elevated ambient temperatures in athletes and untrained men. AB - The aim of the study was to investigate pro-oxidant-antioxidant balance in two series of examinations with two types of stressors (exogenous heat and the combined exogenous and endogenous heat) in trained and untrained men. The exogenous stressor was provided by Finnish sauna session, whereas the combined stressor was represented by the exercise in elevated ambient temperature. The men from the two groups performed the physical exercise on a cycle ergometer with the load of 53 +/- 2% maximal oxygen uptake at the temperature of 33 +/- 1 degrees C and relative humidity of 70% until their rectal temperature rose by 1.2 degrees C. After a month from completion of the exercise test the subjects participated in a sauna bathing session with the temperature of 96 +/- 2 degrees C, and relative humidity of 16 +/- 5%. 15-minutes heating and 2-minute cool-down in a shower with the temperature of 20 degrees C was repeated until rectal temperature rose by 1.2 degrees C compared to the initial value. During both series of tests rectal temperature was measured at 5-minute intervals. Before both series of tests and after them body mass was measured and blood samples were taken for biochemical tests. Serum total protein, serum concentration of lipid peroxidation products and serum antioxidants were determined. The athletes were characterized by higher level of antioxidant status and lower concentration of lipid peroxidation products. Physical exercise at elevated ambient temperature caused lower changes in oxidative stress indices compared to sauna bathing. Sauna induced a shift in pro-oxidant-antioxidant balance towards oxidation, which was observed less intensively in the athletes compared to the untrained men. This leads to the conclusion that physical exercise increases tolerance to elevated ambient temperature and oxidative stress. PMID- 24465536 TI - Patterning the cone mosaic array in zebrafish retina requires specification of ultraviolet-sensitive cones. AB - Cone photoreceptors in teleost fish are organized in precise, crystalline arrays in the epithelial plane of the retina. In zebrafish, four distinct morphological/spectral cone types occupy specific, invariant positions within a regular lattice. The cone lattice is aligned orthogonal and parallel to circumference of the retinal hemisphere: it emerges as cones generated in a germinal zone at the retinal periphery are incorporated as single-cell columns into the cone lattice. Genetic disruption of the transcription factor Tbx2b eliminates most of the cone subtype maximally sensitive to ultraviolet (UV) wavelengths and also perturbs the long-range organization of the cone lattice. In the tbx2b mutant, the other three cone types (red, green, and blue cones) are specified in the correct proportion, differentiate normally, and acquire normal, planar polarized adhesive interactions mediated by Crumbs 2a and Crumbs 2b. Quantitative image analysis of cell adjacency revealed that the cones in the tbx2b mutant primarily have two nearest neighbors and align in single-cell-wide column fragments that are separated by rod photoreceptors. Some UV cones differentiate at the dorsal retinal margin in the tbx2b mutant, although they are severely dysmorphic and are eventually eliminated. Incorporating loss of UV cones during formation of cone columns at the margin into our previously published mathematical model of zebrafish cone mosaic formation (which uses bidirectional interactions between planar cell polarity proteins and anisotropic mechanical stresses in the plane of the retinal epithelium to generate regular columns of cones parallel to the margin) reproduces many features of the pattern disruptions seen in the tbx2b mutant. PMID- 24465537 TI - Increased HEV seroprevalence in patients with autoimmune hepatitis. AB - BACKGROUND: Hepatitis E virus (HEV) infection takes a clinically silent, self limited course in the far majority of cases. Chronic hepatitis E has been reported in some cohorts of immunocompromised individuals. The role of HEV infections in patients with autoimmune hepatitis (AIH) is unknown. METHODS: 969 individuals were tested for anti-HEV antibodies (MP-diagnostics) including 208 patients with AIH, 537 healthy controls, 114 patients with another autoimmune disease, rheumatoid arthritis (RA), and 109 patients with chronic HCV- or HBV infection (HBV/HCV). Patients with AIH, RA and HBV/HCV were tested for HEV RNA. HEV-specific proliferative T cell responses were investigated using CFSE staining and in vitro stimulation of PBMC with overlapping HEV peptides. RESULTS: HEV antibodies tested more frequently positive in patients with AIH (n = 16; 7.7%) than in healthy controls (n = 11; 2.0%; p = 0.0002), patients with RA (n = 4; 3.5%; p = 0.13) or patients with HBV/HCV infection (n = 2; 2.8%; p = 0.03). HEV specific T cell responses could be detected in all anti-HEV-positive AIH patients. One AIH patient receiving immunosuppression with cyclosporin and prednisolone and elevated ALT levels had acute hepatitis E but HEV viremia resolved after reducing immunosuppressive medication. None of the RA or HBV/HCV patients tested HEV RNA positive. CONCLUSIONS: Patients with autoimmune hepatitis but not RA or HBV/HCV patients are more likely to test anti-HEV positive. HEV infection should been ruled out before the diagnosis of AIH is made. Testing for HEV RNA is also recommended in AIH patients not responding to immunosuppressive therapy. PMID- 24465538 TI - The impact of acute brain dysfunction in the outcomes of mechanically ventilated cancer patients. AB - INTRODUCTION: Delirium and coma are a frequent source of morbidity for ICU patients. Several factors are associated with the prognosis of mechanically ventilated (MV) cancer patients, but no studies evaluated delirium and coma (acute brain dysfunction). The present study evaluated the frequency and impact of acute brain dysfunction on mortality. METHODS: The study was performed at National Cancer Institute, Rio de Janeiro, Brazil. We prospectively enrolled patients ventilated >48 h with a diagnosis of cancer. Acute brain dysfunction was assessed during the first 14 days of ICU using RASS/CAM-ICU. Patients were followed until hospital discharge. Univariate and multivariable analysis were performed to evaluate factors associated with hospital mortality. RESULTS: 170 patients were included. 73% had solid tumors, age 65 [53-72 (median, IQR 25% 75%)] years. SAPS II score was 54[46-63] points and SOFA score was (7 [6-9]) points. Median duration of MV was 13 (6-21) days and ICU stay was 14 (7.5-22) days. ICU mortality was 54% and hospital mortality was 66%. Acute brain dysfunction was diagnosed in 161 patients (95%). Survivors had more delirium/coma free days [4(1,5-6) vs 1(0-2), p<0.001]. In multivariable analysis the number of days of delirium/coma-free days were associated with better outcomes as they were independent predictors of lower hospital mortality [0.771 (0.681 to 0.873), p<0.001]. CONCLUSIONS: Acute brain dysfunction in MV cancer patients is frequent and independently associated with increased hospital mortality. Future studies should investigate means of preventing or mitigating acute brain dysfunction as they may have a significant impact on clinical outcomes. PMID- 24465539 TI - Mutation analysis of the ERCC4/FANCQ gene in hereditary breast cancer. AB - The ERCC4 protein forms a structure-specific endonuclease involved in the DNA damage response. Different cancer syndromes such as a subtype of Xeroderma pigmentosum, XPF, and recently a subtype of Fanconi Anemia, FA-Q, have been attributed to biallelic ERCC4 gene mutations. To investigate whether monoallelic ERCC4 gene defects play some role in the inherited component of breast cancer susceptibility, we sequenced the whole ERCC4 coding region and flanking untranslated portions in a series of 101 Byelorussian and German breast cancer patients selected for familial disease (set 1, n = 63) or for the presence of the rs1800067 risk haplotype (set 2, n = 38). This study confirmed six known and one novel exonic variants, including four missense substitutions but no truncating mutation. Missense substitution p.R415Q (rs1800067), a previously postulated breast cancer susceptibility allele, was subsequently screened for in a total of 3,698 breast cancer cases and 2,868 controls from Germany, Belarus or Russia. The Gln415 allele appeared protective against breast cancer in the German series, with the strongest effect for ductal histology (OR 0.67; 95%CI 0.49; 0.92; p = 0.003), but this association was not confirmed in the other two series, with the combined analysis yielding an overall Mantel-Haenszel OR of 0.94 (95% CI 0.81; 1.08). There was no significant effect of p.R415Q on breast cancer survival in the German patient series. The other three detected ERCC4 missense mutations included two known rare variants as well as a novel substitution, p.E17V, that we identified on a p.R415Q haplotype background. The p.E17V mutation is predicted to be probably damaging but was present in just one heterozygous patient. We conclude that the contribution of ERCC4/FANCQ coding mutations to hereditary breast cancer in Central and Eastern Europe is likely to be small. PMID- 24465540 TI - Atheroprotective effect of oleoylethanolamide (OEA) targeting oxidized LDL. AB - Dietary fat-derived lipid oleoylethanolamide (OEA) has shown to modulate lipid metabolism through a peroxisome proliferator-activated receptor-alpha (PPAR alpha)-mediated mechanism. In our study, we further demonstrated that OEA, as an atheroprotective agent, modulated the atherosclerotic plaques development. In vitro studies showed that OEA antagonized oxidized LDL (ox-LDL)-induced vascular endothelial cell proliferation and vascular smooth muscle cell migration, and suppressed lipopolysaccharide (LPS)-induced LDL modification and inflammation. In vivo studies, atherosclerosis animals were established using balloon-aortic denudation (BAD) rats and ApoE(-/-) mice fed with high-caloric diet (HCD) for 17 or 14 weeks respectively, and atherosclerotic plaques were evaluated by oil red staining. The administration of OEA (5 mg/kg/day, intraperitoneal injection, i.p.) prevented or attenuated the formation of atherosclerotic plaques in HCD-BAD rats or HCD-ApoE(-/-) mice. Gene expression analysis of vessel tissues from these animals showed that OEA induced the mRNA expressions of PPAR-alpha and downregulated the expression of M-CFS, an atherosclerotic marker, and genes involved in oxidation and inflammation, including iNOS, COX-2, TNF-alpha and IL 6. Collectively, our results suggested that OEA exerted a pharmacological effect on modulating atherosclerotic plaque formation through the inhibition of LDL modification in vascular system and therefore be a potential candidate for anti atherosclerosis drug. PMID- 24465541 TI - Identification of a new epitope in uPAR as a target for the cancer therapeutic monoclonal antibody ATN-658, a structural homolog of the uPAR binding integrin CD11b (alphaM). AB - The urokinase plasminogen activator receptor (uPAR) plays a role in tumor progression and has been proposed as a target for the treatment of cancer. We recently described the development of a novel humanized monoclonal antibody that targets uPAR and has anti-tumor activity in multiple xenograft animal tumor models. This antibody, ATN-658, does not inhibit ligand binding (i.e. uPA and vitronectin) to uPAR and its mechanism of action remains unclear. As a first step in understanding the anti-tumor activity of ATN-658, we set out to identify the epitope on uPAR to which ATN-658 binds. Guided by comparisons between primate and human uPAR, epitope mapping studies were performed using several orthogonal techniques. Systematic site directed and alanine scanning mutagenesis identified the region of aa 268-275 of uPAR as the epitope for ATN-658. No known function has previously been attributed to this epitope Structural insights into epitope recognition were obtained from structural studies of the Fab fragment of ATN-658 bound to uPAR. The structure shows that the ATN-658 binds to the DIII domain of uPAR, close to the C-terminus of the receptor, corroborating the epitope mapping results. Intriguingly, when bound to uPAR, the complementarity determining region (CDR) regions of ATN-658 closely mimic the binding regions of the integrin CD11b (alphaM), a previously identified uPAR ligand thought to be involved in leukocyte rolling, migration and complement fixation with no known role in tumor progression of solid tumors. These studies reveal a new functional epitope on uPAR involved in tumor progression and demonstrate a previously unrecognized strategy for the therapeutic targeting of uPAR. PMID- 24465542 TI - Development of a highly sensitive and specific method for detection of circulating tumor cells harboring somatic mutations in non-small-cell lung cancer patients. AB - BACKGROUND: Oncogenic mutations are powerful predictive biomarkers for molecularly targeted cancer therapies. For mutation detection patients have to undergo invasive tumor biopsies. Alternatively, archival samples are used which may no longer reflect the actual tumor status. Circulating tumor cells (CTC) could serve as an alternative platform to detect somatic mutations in cancer patients. We sought to develop a sensitive and specific assay to detect mutations in the EGFR gene in CTC from lung cancer patients. METHODS: We developed a novel assay based on real-time polymerase chain reaction (PCR) and melting curve analysis to detect activating EGFR mutations in blood cell fractions enriched in CTC. Non-small-cell lung cancer (NSCLC) was chosen as disease model with reportedly very low CTC counts. The assay was prospectively validated in samples from patients with EGFR-mutant and EGFR-wild type NSCLC treated within a randomized clinical trial. Sequential analyses were conducted to monitor CTC signals during therapy and correlate mutation detection in CTC with treatment outcome. RESULTS: Assay sensitivity was optimized to enable detection of a single EGFR-mutant CTC/mL peripheral blood. CTC were detected in pretreatment blood samples from all 8 EGFR-mutant lung cancer patients studied. Loss of EGFR-mutant CTC signals correlated with treatment response, and its reoccurrence preceded relapse. CONCLUSIONS: Despite low abundance of CTC in NSCLC oncogenic mutations can be reproducibly detected by applying an unbiased CTC enrichment strategy and highly sensitive PCR and melting curve analysis. This strategy may enable non invasive, specific biomarker diagnostics and monitoring in patients undergoing targeted cancer therapies. PMID- 24465543 TI - Media coverage of medical journals: do the best articles make the news? AB - BACKGROUND: News coverage of medical research is followed closely by many Americans and affects the practice of medicine and influence of scientific research. Prior work has examined the quality of media coverage, but no investigation has characterized the choice of stories covered in a controlled manner. We examined whether the media systematically covers stories of weaker study design. METHODS: We compared study characteristics of 75 clinically oriented journal articles that received coverage in the top five newspapers by circulation against 75 clinically-oriented journal articles that appeared in the top five medical journals by impact factor over a similar timespan. Subgroup analysis was performed to determine whether differences between investigations from both sources varied by study type (randomized controlled trial [RCT] or observational study). RESULTS: Investigations receiving coverage from newspapers were less likely to be RCTs (17% vs. 35%, p = 0.016) and more likely to be observational studies (75% vs. 47%, p<0.001). No difference was observed in number of people studied (median: 1034 vs. 1901, p = 0.14) or length of follow-up (median: 1.80 vs. 1.00 years, p = 0.22). In subgroup analysis, observational studies from the media used smaller sample sizes (median: 1984 vs. 21136, p = 0.029) and were more likely to be cross-sectional (71% vs. 31%, p<0.001), while no differences were observed for RCTs. CONCLUSIONS: Newspapers were more likely to cover observational studies and less likely to cover RCTs than high impact journals. Additionally, when the media does cover observational studies, they select articles of inferior quality. Newspapers preferentially cover medical research with weaker methodology. PMID- 24465544 TI - Association between polymorphisms in XRCC1 gene and treatment outcomes of patients with advanced gastric cancer: a systematic review and meta-analysis. AB - BACKGROUND: Many reports have shown inconsistent results on the relationship between single nucleotide polymorphisms (SNPs) of X-ray repair cross complementing protein (XRCC1) gene and platinum-based chemotherapeutic efficacy. This meta-analysis aimed to summarize published data about the association between two SNPs of XRCC1 (Arg194Trp and Arg399Gln) and treatment outcomes of patients with advanced gastric cancer. METHODOLOGY/PRINCIPAL FINDINGS: We retrieved the relevant articles from MEDLINE, Web of Knowledge, and the China National Knowledge Infrastructure (CNKI) databases. Studies were selected according to specific inclusion and exclusion criteria. Study quality was assessed according to the guidelines outlined by Hayden, et al. and PRISMA guidelines. We estimated the odds ratio (OR) for response rate versus no response after platinum-based chemotherapy. Progression-free survival (PFS) and overall survival (OS) were evaluated by pooled Cox proportional hazard ratios (HRs) and 95% confidence intervals (CIs). We found that none of the XRCC1 Arg194Trp and Arg399Gln polymorphisms was significantly associated with tumor response. Stratified analysis by ethnicity or sensitivity analysis also showed that XRCC1 SNPs were not related with chemotherapy response. Patients with minor variant A allele were likely to have poorer 2-year survival rate than those with G/G genotype. However, in the group of 5-year follow up, there was no significant association between the A allele and OS yet. CONCLUSIONS/SIGNIFICANCE: There is no evidence to support the use of XRCC1 Arg194Trp and Arg399Gln polymorphisms as prognostic predictors of TR and PFS in gastric patients treated with platinum based chemotherapy. The relationship between minor variant A allele and OS requires further verification. PMID- 24465545 TI - Binding of HSV-1 glycoprotein K (gK) to signal peptide peptidase (SPP) is required for virus infectivity. AB - Glycoprotein K (gK) is a virion envelope protein of herpes simplex virus types 1 (HSV-1) and 2 (HSV-2), which plays important roles in virion entry, morphogenesis and egress. Two-hybrid and pull-down assays were utilized to demonstrate that gK and no other HSV-1 genes specifically binds to signal peptide peptidase (SPP), also known as minor histocompatibility antigen H13. SPP dominant negative mutants, shRNA against SPP significantly reduced HSV-1 replication in vitro. SPP also affected lysosomes and ER responses to HSV-1 infection. Thus, in this study we have shown for the first time that gK, despite its role in fusion and egress, is also involved in binding the cytoplasmic protein SPP. These results also suggest that SPP plays an important role in viral replication and possibly virus pathogenesis. This makes SPP unique in that its function appears to be required by the virus as no other protein can compensate its loss in terms of viral replication. PMID- 24465546 TI - ASXL1 but not TET2 mutations adversely impact overall survival of patients suffering systemic mastocytosis with associated clonal hematologic non-mast-cell diseases. AB - Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) is a rare and heterogeneous subtype of SM and few studies on this specific entity have been reported. Sixty two patients with Systemic mastocytosis with associated hematologic clonal non-mast cell disease (SM-AHNMD) were presented. Myeloid AHNMD was the most frequent (82%) cases. This subset of patients were older, had more cutaneous lesions, splenomegaly, liver enlargement, ascites; lower bone mineral density and hemoglobin levels and higher tryptase level than lymphoid AHNMD. Defects in KIT, TET2, ASXL1 and CBL were positive in 87%, 27%, 14%, and 11% of cases respectively. The overall survival of patients with SM-AHNMD was 85.2 months. Within the myeloid group, SM-MPN fared better than SM-MDS or SM-AML (p = 0.044,). In univariate analysis, the presence of C findings, the AHNMD subtypes (SM-MDS/CMML/AML versus SM-MPN/hypereosinophilia) (p = 0.044), Neutropenia (p = 0.015), high monocyte level (p = 0.015) and the presence of ASXL1 mutation had detrimental effects on OS (p = 0.007). In multivariate analysis and penalized Cox model, only the presence of ASXL1 mutation remained an independent prognostic factor that negatively affected OS (p = 0.035). SM-AHNMD is heterogeneous with variable prognosis according to the type of the AHNMD. ASXL1 is mutated in a subset of myeloid AHNMD and adversely impact on OS. PMID- 24465547 TI - Myosin II ATPase activity mediates the long-term potentiation-induced exodus of stable F-actin bound by drebrin A from dendritic spines. AB - The neuronal actin-binding protein drebrin A forms a stable structure with F actin in dendritic spines. NMDA receptor activation causes an exodus of F-actin bound by drebrin A (DA-actin) from dendritic spines, suggesting a pivotal role for DA-actin exodus in synaptic plasticity. We quantitatively assessed the extent of DA-actin localization to spines using the spine-dendrite ratio of drebrin A in cultured hippocampal neurons, and found that (1) chemical long-term potentiation (LTP) stimulation induces rapid DA-actin exodus and subsequent DA-actin re-entry in dendritic spines, (2) Ca(2+) influx through NMDA receptors regulates the exodus and the basal accumulation of DA-actin, and (3) the DA-actin exodus is blocked by myosin II ATPase inhibitor, but is not blocked by myosin light chain kinase (MLCK) or Rho-associated kinase (ROCK) inhibitors. These results indicate that myosin II mediates the interaction between NMDA receptor activation and DA actin exodus in LTP induction. Furthermore, myosin II seems to be activated by a rapid actin-linked mechanism rather than slow MLC phosphorylation. Thus the myosin-II mediated DA-actin exodus might be an initial event in LTP induction, triggering actin polymerization and spine enlargement. PMID- 24465548 TI - How early can myocardial iron overload occur in beta thalassemia major? AB - BACKGROUND: Myocardial siderosis is the most common cause of death in patients with beta thalassemia major(TM). This study aimed at investigating the occurrence, prevalence and severity of cardiac iron overload in a young Chinese population with beta TM. METHODS AND RESULTS: We analyzed T2* cardiac magnetic resonance (CMR), left ventricular ejection fraction (LVEF) and serum ferritin (SF) in 201 beta TM patients. The median age was 9 years old. Patients received an average of 13 units of blood per year. The median SF level was 4536 ng/ml and 165 patients (82.1%) had SF>2500 ng/ml. Myocardial iron overload was detected in 68 patients (33.8%) and severe myocardial iron overload was detected in 26 patients (12.6%). Twenty-two patients <=10 years old had myocardial iron overload, three of whom were only 6 years old. No myocardial iron overload was detected under the age of 6 years. Median LVEF was 64% (measured by CMR in 175 patients). Five of 6 patients with a LVEF<56% and 8 of 10 patients with cardiac disease had myocardial iron overload. CONCLUSIONS: The TM patients under follow up at this regional centre in China patients are younger than other reported cohorts, more poorly-chelated, and have a high burden of iron overload. Myocardial siderosis occurred in patients younger than previously reported, and was strongly associated with impaired LVEF and cardiac disease. For such poorly chelated TM patients, our data shows that the first assessment of cardiac T2* should be performed as early as 6 years old. PMID- 24465549 TI - A conserved non-canonical docking mechanism regulates the binding of dual specificity phosphatases to cell integrity mitogen-activated protein kinases (MAPKs) in budding and fission yeasts. AB - Dual-specificity MAPK phosphatases (MKPs) are essential for the negative regulation of MAPK pathways. Similar to other MAPK-interacting proteins, most MKPs bind MAPKs through specific docking domains known as D-motifs. However, we found that the Saccharomyces cerevisiae MKP Msg5 binds the MAPK Slt2 within the cell wall integrity (CWI) pathway through a distinct motif (IYT). Here, we demonstrate that the IYT motif mediates binding of the Msg5 paralogue Sdp1 to Slt2 as well as of the MKP Pmp1 to its CWI MAPK counterpart Pmk1 in the evolutionarily distant yeast Schizosaccharomyces pombe. As a consequence, removal of the IYT site in Msg5, Sdp1 and Pmp1 reduces MAPK trapping caused by the overexpression of catalytically inactive versions of these phosphatases. Accordingly, an intact IYT site is necessary for inactive Sdp1 to prevent nuclear accumulation of Slt2. We also show that both Ile and Tyr but not Thr are essential for the functionality of the IYT motif. These results provide mechanistic insight into MKP-MAPK interplay and stress the relevance of this conserved non-canonical docking site in the regulation of the CWI pathway in fungi. PMID- 24465550 TI - Maternal neurofascin-specific autoantibodies bind to structures of the fetal nervous system during pregnancy, but have no long term effect on development in the rat. AB - Neurofascin was recently reported as a target for axopathic autoantibodies in patients with multiple sclerosis (MS), a response that will exacerbate axonal pathology and disease severity in an animal model of multiple sclerosis. As transplacental transfer of maternal autoantibodies can permanently damage the developing nervous system we investigated whether intrauterine exposure to this neurofascin-specific response had any detrimental effect on white matter tract development. To address this question we intravenously injected pregnant rats with either a pathogenic anti-neurofascin monoclonal antibody or an appropriate isotype control on days 15 and 18 of pregnancy, respectively, to mimic the physiological concentration of maternal antibodies in the circulation of the fetus towards the end of pregnancy. Pups were monitored daily with respect to litter size, birth weight, growth and motor development. Histological studies were performed on E20 embryos and pups sacrificed on days 2, 10, 21, 32 and 45 days post partum. RESULTS: Immunohistochemistry for light and confocal microscopy confirmed passively transferred anti-neurofascin antibody had crossed the placenta to bind to distinct structures in the developing cortex and cerebellum. However, this did not result in any significant differences in litter size, birth weight, or general physical development between litters from control mothers or those treated with the neurofascin-specific antibody. Histological analysis also failed to identify any neuronal or white matter tract abnormalities induced by the neurofascin-specific antibody. CONCLUSIONS: We show that transplacental transfer of circulating anti-neurofascin antibodies can occur and targets specific structures in the CNS of the developing fetus. However, this did not result in any pre- or post-natal abnormalities in the offspring of the treated mothers. These results assure that even if anti-neurofascin responses are detected in pregnant women with multiple sclerosis these are unlikely to have a negative effect on their children. PMID- 24465551 TI - Cysteine peptidases as schistosomiasis vaccines with inbuilt adjuvanticity. AB - Schistosomiasis is caused by several worm species of the genus Schistosoma and afflicts up to 600 million people in 74 tropical and sub-tropical countries in the developing world. Present disease control depends on treatment with the only available drug praziquantel. No vaccine exists despite the intense search for molecular candidates and adjuvant formulations over the last three decades. Cysteine peptidases such as papain and Der p 1 are well known environmental allergens that sensitize the immune system driving potent Th2-responses. Recently, we showed that the administration of active papain to mice induced significant protection (P<0.02, 50%) against an experimental challenge infection with Schistosoma mansoni. Since schistosomes express and secrete papain-like cysteine peptidases we reasoned that these could be employed as vaccines with inbuilt adjuvanticity to protect against these parasites. Here we demonstrate that sub-cutaneous injection of functionally active S. mansoni cathepsin B1 (SmCB1), or a cathepsin L from a related parasite Fasciola hepatica (FhCL1), elicits highly significant (P<0.0001) protection (up to 73%) against an experimental challenge worm infection. Protection and reduction in worm egg burden were further increased (up to 83%) when the cysteine peptidases were combined with other S. mansoni vaccine candidates, glyceraldehyde 3-phosphate dehydrogenase (SG3PDH) and peroxiredoxin (PRX-MAP), without the need to add chemical adjuvants. These studies demonstrate the capacity of helminth cysteine peptidases to behave simultaneously as immunogens and adjuvants, and offer an innovative approach towards developing schistosomiasis vaccines. PMID- 24465552 TI - A novel role for p115RhoGEF in regulation of epithelial plasticity. AB - Epithelial plasticity plays a critical role during physiological processes, such as wound healing and tissue regeneration, and dysregulation of epithelial plasticity can lead to pathological conditions, such as cancer. Cell-cell junctions are a critical feature of epithelial cells and loss of junctions is associated with acquisition of mesenchymal features, such as enhanced protrusion and migration. Although Rho has been implicated in regulation of junctions in epithelial cells, the role of Rho signaling in the regulation of epithelial plasticity has not been understood. We show that members of the RGS RhoGEFs family play a critical role in regulation of epithelial cell-cell junctions in breast epithelial cells. We identify a novel role for p115RhoGEF in regulation of epithelial plasticity. Loss of p115RhoGEF leads to decreased junctional E cadherin and enhanced protrusiveness and migration. Conversely, overexpression of p115RhoGEF enhanced junctional E-cadherin and inhibited cell protrusion and migration. siRNA screen of 23 Rho effectors showed that members of the Diaphanous Related Formin (DRF) family are required for p115RhoGEF-mediated changes in epithelial plasticity. Thus, our data indicates a novel role for p115RhoGEF in regulation of epithelial plasticity, which is dependent on Rho-DRF signaling module. PMID- 24465553 TI - The development of a high density linkage map for black tiger shrimp (Penaeus monodon) based on cSNPs. AB - Transcriptome sequencing using Illumina RNA-seq was performed on populations of black tiger shrimp from India. Samples were collected from (i) four landing centres around the east coastline (EC) of India, (ii) survivors of a severe WSSV infection during pond culture (SUR) and (iii) the Andaman Islands (AI) in the Bay of Bengal. Equal quantities of purified total RNA from homogenates of hepatopancreas, muscle, nervous tissue, intestinal tract, heart, gonad, gills, pleopod and lymphoid organs were combined to create AI, EC and SUR pools for RNA sequencing. De novo transcriptome assembly resulted in 136,223 contigs (minimum size 100 base pairs, bp) with a total length 61 Mb, an average length of 446 bp and an average coverage of 163* across all pools. Approximately 16% of contigs were annotated with BLAST hit information and gene ontology annotations. A total of 473,620 putative SNPs/indels were identified. An Illumina iSelect genotyping array containing 6,000 SNPs was developed and used to genotype 1024 offspring belonging to seven full-sibling families. A total of 3959 SNPs were mapped to 44 linkage groups. The linkage groups consisted of between 16-129 and 13-130 markers, of length between 139-10.8 and 109.1-10.5 cM and with intervals averaging between 1.2 and 0.9 cM for the female and male maps respectively. The female map was 28% longer than the male map (4060 and 2917 cM respectively) with a 1.6 higher recombination rate observed for female compared to male meioses. This approach has substantially increased expressed sequence and DNA marker resources for tiger shrimp and is a useful resource for QTL mapping and association studies for evolutionarily and commercially important traits. PMID- 24465554 TI - Eight new genomes and synthetic controls increase the accessibility of rapid melt MAMA SNP typing of Coxiella burnetii. AB - The case rate of Q fever in Europe has increased dramatically in recent years, mainly because of an epidemic in the Netherlands in 2009. Consequently, there is a need for more extensive genetic characterization of the disease agent Coxiella burnetii in order to better understand the epidemiology and spread of this disease. Genome reference data are essential for this purpose, but only thirteen genome sequences are currently available. Current methods for typing C. burnetii are criticized for having problems in comparing results across laboratories, require the use of genomic control DNA, and/or rely on markers in highly variable regions. We developed in this work a method for single nucleotide polymorphism (SNP) typing of C. burnetii isolates and tissue samples based on new assays targeting ten phylogenetically stable synonymous canonical SNPs (canSNPs). These canSNPs represent previously known phylogenetic branches and were here identified from sequence comparisons of twenty-one C. burnetii genomes, eight of which were sequenced in this work. Importantly, synthetic control templates were developed, to make the method useful to laboratories lacking genomic control DNA. An analysis of twenty-one C. burnetii genomes confirmed that the species exhibits high sequence identity. Most of its SNPs (7,493/7,559 shared by >1 genome) follow a clonal inheritance pattern and are therefore stable phylogenetic typing markers. The assays were validated using twenty-six genetically diverse C. burnetii isolates and three tissue samples from small ruminants infected during the epidemic in the Netherlands. Each sample was assigned to a clade. Synthetic controls (vector and PCR amplified) gave identical results compared to the corresponding genomic controls and are viable alternatives to genomic DNA. The results from the described method indicate that it could be useful for cheap and rapid disease source tracking at non-specialized laboratories, which requires accurate genotyping, assay accessibility and inter-laboratory comparisons. PMID- 24465555 TI - Primary EBV infection induces an expression profile distinct from other viruses but similar to hemophagocytic syndromes. AB - Epstein-Barr Virus (EBV) causes infectious mononucleosis and establishes lifelong infection associated with cancer and autoimmune disease. To better understand immunity to EBV, we performed a prospective study of natural infection in healthy humans. Transcriptome analysis defined a striking and reproducible expression profile during acute infection but no lasting gene changes were apparent during latent infection. Comparing the EBV response profile to multiple other acute viral infections, including influenza A (influenza), respiratory syncytial virus (RSV), human rhinovirus (HRV), attenuated yellow fever virus (YFV), and Dengue fever virus (DENV), revealed similarity only to DENV. The signature shared by EBV and DENV was also present in patients with hemophagocytic syndromes, suggesting these two viruses cause uncontrolled inflammatory responses. Interestingly, while EBV induced a strong type I interferon response, a subset of interferon induced genes, including MX1, HERC5, and OAS1, were not upregulated, suggesting a mechanism by which viral antagonism of immunity results in a profound inflammatory response. These data provide an important first description of the response to a natural herpesvirus infection in humans. PMID- 24465556 TI - Potential role of the bovine rumen microbiome in modulating milk composition and feed efficiency. AB - Ruminants are completely dependent on their microbiota for feed digestion and consequently, their viability. It is therefore tempting to hypothesize a connection between the composition and abundance of resident rumen bacterial taxa and the physiological parameters of the host. Using a pyrosequencing approach, we characterized the rumen bacterial community composition in 15 dairy cows and their physiological parameters. We analyzed the degree of divergence between the different animals and found that some physiological parameters, such as milk yield and composition, are highly correlated with the abundance of various bacterial members of the rumen microbiome. One apparent finding was a strong correlation between the ratio of the phyla Firmicutes to Bacteroidetes and milk fat yield. These findings paralleled human studies showing similar trends of increased adiposity with an increase in Bacteroidetes. This correlation remained evident at the genus level, where several genera showed correlations with the animals' physiological parameters. This suggests that the bacterial community has a role in shaping host physiological parameters. A deeper understanding of this process may allow us to modulate the rumen microbiome for better agricultural yield through bacterial community design. PMID- 24465557 TI - Association between glucocorticoid receptor methylation and hippocampal subfields in major depressive disorder. AB - BACKGROUND: DNA methylation in the promoter region of the glucocorticoid receptor gene (NR3C1) is closely associated with childhood adversity and suicide. However, few studies have examined NR3C1 methylation in relation to major depressive disorder (MDD) and hippocampal subfield volumes. We investigated the possible association between NR3C1 methylation and structural brain alterations in MDD in comparison with healthy controls. METHODS: We compared the degree of NR3C1 promoter methylation in the peripheral blood of non-psychotic outpatients with MDD and that of healthy controls. Correlations among NR3C1 promoter methylation, structural abnormalities in hippocampal subfield volumes and whole-brain cortical thickness, and clinical variables were also analyzed. RESULTS: In total, 117 participants (45 with MDD and 72 healthy controls) were recruited. Patients with MDD had significantly lower methylation than healthy controls at 2 CpG sites. In MDD, methylations had positive correlations with the bilateral cornu ammonis (CA) 2-3 and CA4-dentate gyrus (DG) subfields. However, in healthy controls, methylations had positive correlation with the subiculum and presubiculum. There were no differences in total and subfield volumes of the hippocampus between patients with MDD and healthy controls. Compared with healthy controls, patients with MDD had a significantly thinner cortex in the left rostromiddle frontal, right lateral orbitofrontal, and right pars triangularis areas. CONCLUSIONS: Lower methylation in the NR3C1 promoter, which might have compensatory effects relating to CA2-3 and CA4-DG, is a distinct epigenetic characteristic in non psychotic outpatients with MDD. Future studies with a longitudinal design and a comprehensive neurobiological approach are warranted in order to elucidate the effects of NR3C1 methylation. PMID- 24465558 TI - High-risk cervical human papillomavirus infections among human immunodeficiency virus-positive women in the Bahamas. AB - BACKGROUND: High-risk (HR) HPV genotypes other than 16 and 18 have been detected in a significant proportion of immunocompromised females. We aim to evaluate the frequency of HR HPV genotypes in a population of HIV-positive Caribbean women. METHODS: One hundred sixty-seven consecutive, non-pregnant, HIV-positive females >=18 years were recruited in this study. Each participant received a vaginal examination, PAP smear, and completed a questionnaire. DNA was extracted for HPV testing in 86 patients. RESULTS: Mean age was 39.1 years for women positive for HR HPV and 43.1 years for women negative for HR HPV (P value = 0.040). 78% (130/167) of the women had HR HPV infections; the prevalence of abnormal cervical cytology was 38% among women who were HR HPV-positive compared to women who were HR HPV-negative (22%). Fifty-one percent of the 86 women with available genotype carried infections with HPV 16 and/or HPV 18; genotypes of unknown risk were also frequently observed. Women who had a CD4+ count of <=200 had 7 times increased odds of carrying HR HPV infection in comparison to women with CD4+>200. CONCLUSIONS: HR HPV infections in HIV infected females may consist of more than just HPV 16 and 18, but also HPV 52 and 58. Further studies are needed to determine whether HPV 52 and 58 play a significant role in the development of cervical cytological abnormalities in HIV+ women. PMID- 24465559 TI - Photodynamic therapy in Pythium insidiosum - an in vitro study of the correlation of sensitizer localization and cell death. AB - Pythiosis is an infectious disease caused by Pythium insidiosum, a fungus-like organism. Due to the lack of ergosterol on its cell membrane, antibiotic therapy is ineffective. The conventional treatment is surgery, but lesion recurrence is frequent, requiring several resections or limb amputation. Photodynamic therapy uses photo-activation of drugs and has the potential to be an attractive alternative option. The in vitro PDT response on the growing of Pythium insidiosum culture was investigated using three distinct photosensitizers: methylene blue, Photogem, and Photodithazine. The photosensitizer distribution in cell structures and the PDT response for incubation times of 30, 60, and 120 minutes were evaluated. Methylene blue did not penetrate in the pathogen's cell and consequently there was no PDT inactivation. Photogem showed heterogenous distribution in the hyphal structure with small concentration inside the cells. Porphyrin-PDT response was heterogenous, death and live cells were observed in the treated culture. After 48 hours, hyphae regrowth was observed. Photodithazine showed more homogenous distribution inside the cell and with the specific intracellular localization dependent on incubation time. Photodithazine first accumulates in intracellular vacuoles, and at incubation times of one hour, it is located at all cell membranes. Higher inhibition of the growing rates was achieved with Photodithazine -PDT, over 98%. Our results showed that the photosensitizers that cross more efficiently the Pythium insidiosum membranes are able to cause extensive damage to the organism under illumination and therefore, are the best options for clinical treatment. PMID- 24465561 TI - Does competition work as a motivating factor in e-learning? A randomized controlled trial. AB - BACKGROUND AND AIMS: Examinations today are often computerized and the primary motivation and curriculum is often based on the examinations. This study aims to test if competition widgets in e-learning quiz modules improve post-test and follow-up test results and self-evaluation. The secondary aim is to evaluate improvements during the training period comparing test-results and number of tests taken. METHODS: Two groups were randomly assigned to either a quiz-module with competition widgets or a module without. Pre-, post- and follow up test results were recorded. Time used within the modules was measured and students reported time studying. Students were able to choose questions from former examinations in the quiz-module. RESULTS: Students from the competing group were significantly better at both post-and follow-up-test and had a significantly better overall learning efficiency than those from the non-competing group. They were also significantly better at guessing their post-test results. CONCLUSION: Quiz modules with competition widgets motivate students to become more active during the module and stimulate better total efficiency. They also generate improved self-awareness regarding post-test-results. PMID- 24465560 TI - Innate functions of immunoglobulin M lessen liver gene transfer with helper dependent adenovirus. AB - The immune system poses obstacles to viral vectors, even in the first administration to preimmunized hosts. We have observed that the livers of B cell deficient mice were more effectively transduced by a helper-dependent adenovirus serotype-5 (HDA) vector than those of WT mice. This effect was T-cell independent as shown in athymic mice. Passive transfer of the serum from adenovirus-naive WT to Rag1KO mice resulted in a reduction in gene transfer that was traced to IgM purified from serum of adenovirus-naive mice. To ascribe the gene transfer inhibition activity to either adenoviral antigen-specific or antigen-unspecific functions of IgM, we used a monoclonal IgM antibody of unrelated specificity. Both the polyclonal and the irrelevant monoclonal IgM inhibited gene transfer by the HDA vector to either cultured hepatocellular carcinoma cells or to the liver of mice in vivo. Adsorption of polyclonal or monoclonal IgMs to viral capsids was revealed by ELISAs on adenovirus-coated plates. These observations indicate the existence of an inborn IgM mechanism deployed against a prevalent virus to reduce early post-infection viremia. In conclusion, innate IgM binding to adenovirus serotype-5 capsids restrains gene-transfer and offers a mechanism to be targeted for optimization of vector dosage in gene therapy with HDA vectors. PMID- 24465562 TI - Did vaccination slow the spread of bluetongue in France? AB - Vaccination is one of the most efficient ways to control the spread of infectious diseases. Simulations are now widely used to assess how vaccination can limit disease spread as well as mitigate morbidity or mortality in susceptible populations. However, field studies investigating how much vaccines decrease the velocity of epizootic wave-fronts during outbreaks are rare. This study aimed at investigating the effect of vaccination on the propagation of bluetongue, a vector-borne disease of ruminants. We used data from the 2008 bluetongue virus serotype 1 (BTV-1) epizootic of southwest France. As the virus was newly introduced in this area, natural immunity of livestock was absent. This allowed determination of the role of vaccination in changing the velocity of bluetongue spread while accounting for environmental factors that possibly influenced it. The average estimated velocity across the country despite restriction on animal movements was 5.4 km/day, which is very similar to the velocity of spread of the bluetongue virus serotype 8 epizootic in France also estimated in a context of restrictions on animal movements. Vaccination significantly reduced the propagation velocity of BTV-1. In comparison to municipalities with no vaccine coverage, the velocity of BTV-1 spread decreased by 1.7 km/day in municipalities with immunized animals. For the first time, the effect of vaccination has been quantified using data from a real epizootic whilst accounting for environmental factors known to modify the velocity of bluetongue spread. Our findings emphasize the importance of vaccination in limiting disease spread across natural landscape. Finally, environmental factors, specifically those related to vector abundance and activity, were found to be good predictors of the velocity of BTV-1 spread, indicating that these variables need to be adequately accounted for when evaluating the role of vaccination on bluetongue spread. PMID- 24465563 TI - 1H NMR-based metabolite profiling of plasma in a rat model of chronic kidney disease. AB - Chronic kidney disease (CKD) is characterized by the gradual loss of the kidney function to excrete wastes and fluids from the blood. (1)H NMR-based metabolomics was exploited to investigate the altered metabolic pattern in rats with CKD induced by surgical reduction of the renal mass (i.e., 5/6 nephrectomy (5/6 Nx)), particularly for identifying specific metabolic biomarkers associated with early of CKD. Plasma metabolite profiling was performed in CKD rats (at 4- or 8-weeks after 5/6 Nx) compared to sham-operated rats. Principle components analysis (PCA), partial least squares-discriminant analysis (PLS-DA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) score plots showed a significant separation between the groups. The resulting metabolic profiles demonstrated significantly increased plasma levels of organic anions, including citrate, beta-hydroxybutyrate, lactate, acetate, acetoacetate, and formate in CKD. Moreover, levels of alanine, glutamine, and glutamate were significantly higher. These changes were likely to be associated with complicated metabolic acidosis in CKD for counteracting systemic metabolic acidosis or increased protein catabolism from muscle. In contrast, levels of VLDL/LDL (CH2)n and N acetylglycoproteins were decreased. Taken together, the observed changes of plasma metabolite profiles in CKD rats provide insights into the disturbed metabolism in early phase of CKD, in particular for the altered metabolism of acid-base and/or amino acids. PMID- 24465564 TI - Capturing intracellular pH dynamics by coupling its molecular mechanisms within a fully tractable mathematical model. AB - We describe the construction of a fully tractable mathematical model for intracellular pH. This work is based on coupling the kinetic equations depicting the molecular mechanisms for pumps, transporters and chemical reactions, which determine this parameter in eukaryotic cells. Thus, our system also calculates the membrane potential and the cytosolic ionic composition. Such a model required the development of a novel algebraic method that couples differential equations for slow relaxation processes to steady-state equations for fast chemical reactions. Compared to classical heuristic approaches based on fitted curves and ad hoc constants, this yields significant improvements. This model is mathematically self-consistent and allows for the first time to establish analytical solutions for steady-state pH and a reduced differential equation for pH regulation. Because of its modular structure, it can integrate any additional mechanism that will directly or indirectly affect pH. In addition, it provides mathematical clarifications for widely observed biological phenomena such as overshooting in regulatory loops. Finally, instead of including a limited set of experimental results to fit our model, we show examples of numerical calculations that are extremely consistent with the wide body of intracellular pH experimental measurements gathered by different groups in many different cellular systems. PMID- 24465565 TI - The effect of exercise intensity on endothelial function in physically inactive lean and obese adults. AB - PURPOSE: To examine the effects of exercise intensity on acute changes in endothelial function in lean and obese adults. METHODS: Sixteen lean (BMI <25, age 23 +/- 3 yr) and 10 obese (BMI >30, age 26 +/- 6 yr) physically inactive adults were studied during 3 randomized admissions [control (C, no exercise), moderate-intensity exercise (M, @ lactate threshold (LT)) and high-intensity exercise (H, midway between LT and VO2peak) (30 min)]. Endothelial function was assessed by flow-mediated dilation (FMD) at baseline and 1, 2, and 4 h post exercise. RESULTS: RM ANCOVA revealed significant main effects for group, time, and group x condition interaction (p<0.05). A diurnal increase in FMD was observed in lean but not obese subjects. Lean subjects exhibited greater increases in FMD than obese subjects (p = 0.0005). In the obese group a trend was observed for increases in FMD at 2- and 4-hr after M (p = 0.08). For lean subjects, FMD was significantly elevated at all time points after H. The increase in FMD after H in lean subjects (3.2 +/- 0.5%) was greater than after both C (1.7 +/- 0.4%, p = 0.015) and M (1.4 +/- 0.4%, p = 0.002). FMD responses of lean and obese subjects significantly differed after C and H, but not after M. CONCLUSION: In lean young adults, high-intensity exercise acutely enhances endothelial function, while moderate-intensity exercise has no significant effect above that seen in the absence of exercise. The FMD response of obese adults is blunted compared to lean adults. Diurnal variation should be considered when examining the effects of acute exercise on FMD. PMID- 24465566 TI - Molecular and genetic characterization of natural HIV-1 Tat Exon-1 variants from North India and their functional implications. AB - BACKGROUND: Designing an ideal vaccine against HIV-1 has been difficult due to enormous genetic variability as a result of high replication rate and lack of proofreading activity of reverse transcriptase leading to emergence of genetic variants and recombinants. Tat transactivates HIV-1 LTR, resulting in a remarkable increase in viral gene expression, and plays a vital role in pathogenesis. The aim of this study was to characterize the genetic variations of Tat exon-1 from HIV-1 infected patients from North India. METHODS: Genomic DNA was isolated from PBMCs and Tat exon-1 was PCR amplified with specific primers followed by cloning, sequencing and sequence analyses using bioinformatic tools for predicting HIV-1 subtypes, recombination events, conservation of domains and phosphorylation sites, and LTR transactivation by luciferase assay. RESULTS: Phylogenetic analysis of Tat exon-1 variants (n = 120) revealed sequence similarity with South African Tat C sequences and distinct geographical relationships were observed for B/C recombinants. Bootscan analysis of our variants showed 90% homology to Tat C and 10% to B/C recombinants with a precise breakpoint. Natural substitutions were observed with high allelic frequencies which may be beneficial for virus. High amino acid conservation was observed in Tat among Anti Retroviral Therapy (ART) recipients. Barring few changes, most of the functional domains, predicted motifs and phosphorylation sites were well conserved in most of Tat variants. dN/dS analysis revealed purifying selection, implying the importance of functional conservation of Tat exon-1. Our Indian Tat C variants and B/C recombinants showed differential LTR transactivation. CONCLUSIONS: The possible role of Tat exon-1 variants in shaping the current HIV 1 epidemic in North India was highlighted. Natural substitutions across conserved functional domains were observed and provided evidence for the emergence of B/C recombinants within the ORF of Tat exon-1. These events are likely to have implications for viral pathogenesis and vaccine formulations. PMID- 24465567 TI - Intraflagellar transport gene expression associated with short cilia in smoking and COPD. AB - Smoking and COPD are associated with decreased mucociliary clearance, and healthy smokers have shorter cilia in the large airway than nonsmokers. We hypothesized that changes in cilia length are consistent throughout the airway, and we further hypothesized that smokers with COPD have shorter cilia than healthy smokers. Because intraflagellar transport (IFT) is the process by which cilia of normal length are produced and maintained, and alterations in IFT lead to short cilia in model organisms, we also hypothesized that smoking induces changes in the expression of IFT-related genes in the airway epithelium of smokers and smokers with COPD. To assess these hypotheses, airway epithelium was obtained via bronchoscopic brushing. Cilia length was assessed by measuring 100 cilia (10 cilia on each of 10 cells) per subject and Affymetrix microarrays were used to evaluate IFT gene expression in nonsmokers and healthy smokers in 2 independent data sets from large and small airway as well as in COPD smokers in a data set from the small airway. In the large and small airway epithelium, cilia were significantly shorter in healthy smokers than nonsmokers, and significantly shorter in COPD smokers than in both healthy smokers and nonsmokers. The gene expression data confirmed that a set of 8 IFT genes were down-regulated in smokers in both data sets; however, no differences were seen in COPD smokers compared to healthy smokers. These results support the concept that loss of cilia length contributes to defective mucociliary clearance in COPD, and that smoking induced changes in expression of IFT genes may be one mechanism of abnormally short cilia in smokers. Strategies to normalize cilia length may be an important avenue for novel COPD therapies. PMID- 24465568 TI - Prediction of long-term mortality by preoperative health-related quality-of-life in elderly onco-surgical patients. AB - OBJECTIVE: Aim of this study was to evaluate the association between preoperative health-related quality of life (HRQoL) and mortality in a cohort of elderly patients (>65 years) with gastrointestinal, gynecological and genitourinary carcinomas. DESIGN: Prospective cohort pilot study. SETTING: Tertiary university hospital in Germany. PATIENTS: Between June 2008 and July 2010 and after ethical committee approval and written informed consent, 126 patients scheduled for onco surgery were included. Prior to surgery as well as 3 and 12 months postoperatively all participants completed the EORTC-QLQ-C30 questionnaire (measuring self-reported health-related quality of life). Additionally, demographic and clinical data including the Mini Mental State Examination (MMSE) were collected. Surgery and anesthesia were conducted according to the standard operating procedures. Primary endpoint was the cumulative mortality rate over 12 months after one year. Changes in Quality of life were considered as secondary outcome. RESULTS: Mortality after one year was 28%. In univariable and multivariable logistic regression analysis baseline HRQoL self-reported cognitive function (OR per point: 0.98; CI 95% 0.96-0.99; p = 0.024) and higher symptom burden for appetite loss (per point: OR 1.02; CI 95% 1.00-1.03; p = 0.014) were predictive for long-term mortality. Additionally the MMSE as an objective measure of cognitive impairment (per point: OR 0.69; CI 95% 0.51-0.96; p = 0.026) as well as severity of surgery (OR 0.31; CI 95% 0.11-0.93; p = 0.036) were predictive for long-term mortality. Global health status 12 months after surgery was comparable to the baseline levels in survivors despite moderate impairments in other domains. CONCLUSION: This study showed that objective and self-reported cognitive functioning together with appetite loss were prognostic for mortality in elderly cancer patients. In addition, impaired cognitive dysfunction and severity of surgery were predictive for one-year mortality whereas in this selected population scheduled for surgery age, gender, cancer site and metastases were not. PMID- 24465569 TI - The duration of gastrointestinal and joint symptoms after a large waterborne outbreak of gastroenteritis in Finland in 2007--a questionnaire-based 15-month follow-up study. AB - An extensive drinking water-associated gastroenteritis outbreak took place in the town of Nokia in Southern Finland in 2007. 53% of the exposed came down with gastroenteritis and 7% had arthritis-like symptoms (joint swelling, redness, warmth or pain in movement) according to a population-based questionnaire study at 8 weeks after the incident. Campylobacter and norovirus were the main pathogens. A follow-up questionnaire study was carried out 15 months after the outbreak to evaluate the duration of gastrointestinal and joint symptoms. 323 residents of the original contaminated area were included. The response rate was 53%. Participants were inquired about having gastroenteritis during the outbreak and the duration of symptoms. Of those with gastroenteritis, 43% reported loose stools and abdominal pain or distension after the acute disease. The prevalence of symptoms declined promptly during the first 3 months but at 15 months, 11% reported continuing symptoms. 32% of the respondents with gastroenteritis reported subsequent arthritis-like symptoms. The disappearance of arthritis-like symptoms was more gradual and they levelled off only after 5 months. 19% showed symptoms at 15 months. Prolonged gastrointestinal symptoms correlated to prolonged arthritis-like symptoms. High proportion of respondents continued to have arthritis-like symptoms at 15 months after the epidemic. The gastrointestinal symptoms, instead, had declined to a low level. PMID- 24465570 TI - Immunogenicity, impact on carriage and reactogenicity of 10-valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine in Kenyan children aged 1-4 years: a randomized controlled trial. AB - BACKGROUND: The impact on carriage and optimal schedule for primary vaccination of older children with 10-valent pneumococcal non-typeable Haemophilus influenzae protein-D conjugate vaccine (PHiD-CV) are unknown. METHODS: 600 Kenyan children aged 12-59 months were vaccinated at days 0, 60 and 180 in a double-blind randomized controlled trial according to the following vaccine sequence: Group A: PHiD-CV, PHiD-CV, diphtheria/tetanus/acellular pertussis vaccine (DTaP); Group B: PHiD-CV, DTaP, PHiD-CV; Group C: hepatitis A vaccine (HAV), DTaP, HAV. Nasopharyngeal carriage of Streptococcus pneumoniae was measured at five timepoints. In 375 subjects, serotype-specific responses were measured by 22F inhibition ELISA and opsonophagocytic killing assays (OPA) one month after vaccination. RESULTS: Following one dose of PHiD-CV, >90% of recipients developed IgG>=0.35 ug/mL to serotypes 1, 4, 5, 7F, 9V and 18C and OPA>=8 to serotypes 4, 7F, 9V, 18C, 23F. After a second dose >90% of recipients had IgG>=0.35 ug/mL to all vaccine serotypes and OPA>=8 to all vaccine serotypes except 1 and 6B. At day 180, carriage of vaccine-type pneumococci was 21% in recipients of two doses of PHiD-CV (Group A) compared to 31% in controls (p = 0.04). Fever after dose 1 was reported by 41% of PHiD-CV recipients compared to 26% of HAV recipients (p<0.001). Other local and systemic adverse experiences were similar between groups. CONCLUSIONS: Vaccination of children aged 12-59 months with two doses of PHiD-CV two to six months apart was immunogenic, reduced vaccine-type pneumococcal carriage and was well-tolerated. Administration of PHiD-CV would be expected to provide effective protection against vaccine-type disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01028326. PMID- 24465571 TI - Estimation of parameters in the two-compartment model for exhaled nitric oxide. AB - The fractional concentration of exhaled nitric oxide (FeNO) is a biomarker of airway inflammation that is being increasingly considered in clinical, occupational, and epidemiological applications ranging from asthma management to the detection of air pollution health effects. FeNO depends strongly on exhalation flow rate. This dependency has allowed for the development of mathematical models whose parameters quantify airway and alveolar compartment contributions to FeNO. Numerous methods have been proposed to estimate these parameters using FeNO measured at multiple flow rates. These methods--which allow for non-invasive assessment of localized airway inflammation--have the potential to provide important insights on inflammatory mechanisms. However, different estimation methods produce different results and a serious barrier to progress in this field is the lack of a single recommended method. With the goal of resolving this methodological problem, we have developed a unifying framework in which to present a comprehensive set of existing and novel statistical methods for estimating parameters in the simple two-compartment model. We compared statistical properties of the estimators in simulation studies and investigated model fit and parameter estimate sensitivity across methods using data from 1507 schoolchildren from the Southern California Children's Health Study, one of the largest multiple flow FeNO studies to date. We recommend a novel nonlinear least squares model with natural log transformation on both sides that produced estimators with good properties, satisfied model assumptions, and fit the Children's Health Study data well. PMID- 24465572 TI - Intensified tuberculosis case-finding in HIV-positive adults managed at Ethiopian health centers: diagnostic yield of Xpert MTB/RIF compared with smear microscopy and liquid culture. AB - BACKGROUND: Detection of active tuberculosis (TB) before antiretroviral therapy (ART) initiation is important, but optimal diagnostic methods for use in resource limited settings are lacking. We assessed the prevalence of TB, evaluated the diagnostic yield of Xpert MTB/RIF in comparison with smear microscopy and culture, and the impact of Xpert results on clinical management in HIV-positive adults eligible for ART at health centers in a region of Ethiopia. METHODS: Participants were prospectively recruited and followed up at 5 health centers. Trained nurses collected data on socio-demographic characteristics, medical history and symptoms, and performed physical examination. Two paired morning sputum samples were obtained, and lymph node aspirates in case of lymphadenopathy. Diagnostic yield of Xpert MTB/RIF in sputum was compared with smear microscopy and liquid culture. RESULTS: TB was diagnosed in 145/812 participants (17.9%), with bacteriological confirmation in 137 (16.9%). Among bacteriologically confirmed cases, 31 were smear-positive (22.6%), 96 were Xpert positive (70.1%), and 123 were culture-positive (89.8%). Xpert MTB/RIF increased the TB detection rate by 64 cases (47.4%) compared with smear microscopy. The overall sensitivity of Xpert MTB/RIF was 66.4%, and was not significantly lower when testing one compared with two samples. While Xpert MTB/RIF was 46.7% sensitive among patients with CD4 cell counts >200 cells/mm(3), this increased to 82.9% in those with CD4 cell counts <=100 cells/mm(3). Compared with Xpert positive TB patients, Xpert-negative cases had less advanced HIV and TB disease characteristics. CONCLUSIONS: Previously undiagnosed TB is common among HIV positive individuals managed in Ethiopian health centers. Xpert MTB/RIF increased TB case detection, especially in patients with advanced immunosuppression. An algorithm based on the use of a single morning sputum sample for individuals with negative sputum smear microscopy could be considered for intensified case finding in patients eligible for ART. However, technical and cost-effectiveness issues relevant for low-income countries warrant further study. PMID- 24465573 TI - Adverse effects from clenbuterol and ractopamine on nematode Caenorhabditis elegans and the underlying mechanism. AB - In the present study, we used Caenorhabditis elegans assay system to investigate in vivo toxicity from clentuberol and ractopamine and the possible underlying mechanism. Both acute and prolonged exposures to clentuberol or ractopamine decreased brood size and locomotion behavior, and induced intestinal autofluorescence and reactive oxygen species (ROS) production. Although acute exposure to the examined concentrations of clentuberol or ractopamine did not induce lethality, prolonged exposure to 10 ug/L of clentuberol and ractopamine reduced lifespan. At relatively high concentrations, ractopamine exhibited more severe toxicity than clentuberol on nematodes. Overexpression of sod-2 gene encoding a Mn-SOD to prevent induction of oxidative stress effectively inhibited toxicity from clentuberol or ractopamine. Besides oxidative stress, we found that clentuberol might reduce lifespan through influencing insulin/IGF signaling pathway; however, ractopamine might reduce lifespan through affecting both insulin/IGF signaling pathway and TOR signaling pathway. Ractopamine more severely decreased expression levels of daf-16, sgk-1, skn-1, and aak-2 genes than clentuberol, and increased expression levels of daf-2 and age-1 genes at the examined concentration. Therefore, the C. elegans assay system may be useful for assessing the possible toxicity from weight loss agents, and clentuberol and ractopamine may induce toxicity through different molecular mechanisms. PMID- 24465574 TI - Magnesium enhances exercise performance via increasing glucose availability in the blood, muscle, and brain during exercise. AB - Glucose mobilization and utilization in the periphery and central nervous system are important during exercise and are responsible for exercise efficacy. Magnesium (Mg) is involved in energy production and plays a role in exercise performance. This study aimed to explore the effects of Mg on the dynamic changes in glucose and lactate levels in the muscle, blood and brain of exercising rats using a combination of auto-blood sampling and microdialysis. Sprague-Dawley rats were pretreated with saline or magnesium sulfate (MgSO4, 90 mg/kg, i.p.) 30 min before treadmill exercise (20 m/min for 60 min). Our results indicated that the muscle, blood, and brain glucose levels immediately increased during exercise, and then gradually decreased to near basal levels in the recovery periods of both groups. These glucose levels were significantly enhanced to approximately two fold (P<0.05) in the Mg group. Lactate levels in the muscle, blood, and brain rapidly and significantly increased in both groups during exercise, and brain lactate levels in the Mg group further elevated (P<0.05) than those in the control group during exercise. Lactate levels significantly decreased after exercise in both groups. In conclusion, Mg enhanced glucose availability in the peripheral and central systems, and increased lactate clearance in the muscle during exercise. PMID- 24465575 TI - Presence and analysis of plasmids in human and animal associated arcobacter species. AB - In this study, we report the screening of four Arcobacter species for the presence of small and large plasmids. Plasmids were present in 9.9% of the 273 examined strains. One Arcobacter cryaerophilus and four Arcobacter butzleri plasmids were selected for further sequencing. The size of three small plasmids isolated from A. butzleri and the one from A. cryaerophilus strains ranged between 4.8 and 5.1 kb, and the size of the large plasmid, isolated from A. butzleri, was 27.4 kbp. The G+C content of all plasmids ranged between 25.4% and 26.2%. A total of 95% of the large plasmid sequence represents coding information, which contrasts to the 20 to 30% for the small plasmids. Some of the open reading frames showed a high homology to putative conserved domains found in other related organisms, such as replication, mobilization and genes involved in type IV secretion system. The large plasmid carried 35 coding sequences, including seven genes in a contiguous region of 11.6 kbp that encodes an orthologous type IV secretion system found in the Wolinella succinogenes genome, Helicobacter pylori and Campylobacter jejuni plasmids, which makes this plasmid interesting for further exploration. PMID- 24465576 TI - Do pioneer cells exist? AB - Most mathematical models of collective cell spreading make the standard assumption that the cell diffusivity and cell proliferation rate are constants that do not vary across the cell population. Here we present a combined experimental and mathematical modeling study which aims to investigate how differences in the cell diffusivity and cell proliferation rate amongst a population of cells can impact the collective behavior of the population. We present data from a three-dimensional transwell migration assay that suggests that the cell diffusivity of some groups of cells within the population can be as much as three times higher than the cell diffusivity of other groups of cells within the population. Using this information, we explore the consequences of explicitly representing this variability in a mathematical model of a scratch assay where we treat the total population of cells as two, possibly distinct, subpopulations. Our results show that when we make the standard assumption that all cells within the population behave identically we observe the formation of moving fronts of cells where both subpopulations are well-mixed and indistinguishable. In contrast, when we consider the same system where the two subpopulations are distinct, we observe a very different outcome where the spreading population becomes spatially organized with the more motile subpopulation dominating at the leading edge while the less motile subpopulation is practically absent from the leading edge. These modeling predictions are consistent with previous experimental observations and suggest that standard mathematical approaches, where we treat the cell diffusivity and cell proliferation rate as constants, might not be appropriate. PMID- 24465577 TI - Motor imagery learning modulates functional connectivity of multiple brain systems in resting state. AB - BACKGROUND: Learning motor skills involves subsequent modulation of resting-state functional connectivity in the sensory-motor system. This idea was mostly derived from the investigations on motor execution learning which mainly recruits the processing of sensory-motor information. Behavioral evidences demonstrated that motor skills in our daily lives could be learned through imagery procedures. However, it remains unclear whether the modulation of resting-state functional connectivity also exists in the sensory-motor system after motor imagery learning. METHODOLOGY/PRINCIPAL FINDINGS: We performed a fMRI investigation on motor imagery learning from resting state. Based on previous studies, we identified eight sensory and cognitive resting-state networks (RSNs) corresponding to the brain systems and further explored the functional connectivity of these RSNs through the assessments, connectivity and network strengths before and after the two-week consecutive learning. Two intriguing results were revealed: (1) The sensory RSNs, specifically sensory-motor and lateral visual networks exhibited greater connectivity strengths in precuneus and fusiform gyrus after learning; (2) Decreased network strength induced by learning was proved in the default mode network, a cognitive RSN. CONCLUSIONS/SIGNIFICANCE: These results indicated that resting-state functional connectivity could be modulated by motor imagery learning in multiple brain systems, and such modulation displayed in the sensory-motor, visual and default brain systems may be associated with the establishment of motor schema and the regulation of introspective thought. These findings further revealed the neural substrates underlying motor skill learning and potentially provided new insights into the therapeutic benefits of motor imagery learning. PMID- 24465578 TI - The phloem-sap feeding mealybug (Ferrisia virgata) carries 'Candidatus Liberibacter asiaticus' populations that do not cause disease in host plants. AB - 'Candidatus Liberibacter asiaticus' (Las) is the primary causal agent of huanglongbing (HLB), the most devastating disease of citrus worldwide. There are three known insect vectors of the HLB-associated bacteria, and all are members of the Hemiptera: Diaphorina citri (Psyllidae), Trioza erytreae (Triozidae), and Cacopsylla (Psylla) citrisuga (Psyllidae). In this study, we found that another hemipteran, the striped mealybug Ferrisia virgata (Cockerell) (Hemiptera: Pseudococcidae), was able to acquire and retain Las bacteria. The bacterial titers were positively correlated with the feeding acquisition time on Las infected leaf discs, with a two-weeks feeding period resulting in Ct values ranging from 23.1 to 36.1 (8.24 * 10(7) to 1.07 * 10(4) Las cells per mealybug). We further discovered that the prophage/phage populations of Las in the mealybugs were different from those of Las in psyllids based on Las prophage-specific molecular markers: infected psyllids harbored the Las populations with prophage/phage FP1 and FP2, while infected mealybugs carried the Las populations with the iFP3 being the dominant prophage/phage. As in the psyllids, Las bacteria were shown to move through the insect gut wall to the salivary glands after being ingested by the mealybug based on a time-course quantitative polymerase chain reaction (qPCR) assay of the dissected digestive systems. However, Las populations transmitted by the mealybugs did not cause disease in host plants. This is the first evidence of genetic difference among Las populations harbored by different insect vectors and difference among Las populations with respect to whether or not they cause disease in host plants. PMID- 24465579 TI - Influences of COMT and 5-HTTLPR polymorphisms on cognitive flexibility in healthy women: inhibition of prepotent responses and memory updating. AB - Understanding genetic factors that affect monoamine neurotransmitters flux in prefrontal cortex may help to further specify the complex neurobiological processes that underlie cognitive function and dysfunction in health and illness. The current study examined the associations between the polymorphisms of dopaminergic (COMT Met158Val) and serotoninergic (5-HTTLPR) genes and the sequential pattern of responses in a motor random generation task providing well established indexes for executive functioning in a large sample of 255 healthy women. Participants homozygous for the Met allele of the COMT polymorphism showed impaired inhibition of prepotent responses, whereas individuals homozygous for the s-allele of the 5-HTTLPR showed a restricted ability to update information in working memory. Taken together the results indicate differentiated influences of dopaminergic and serotonergic genes on important and definite executive sub processes related to cognitive flexibility. PMID- 24465580 TI - Crowdsourcing awareness: exploration of the ovarian cancer knowledge gap through Amazon Mechanical Turk. AB - BACKGROUND: Ovarian cancer is the most lethal gynecologic disease in the United States, with more women dying from this cancer than all gynecological cancers combined. Ovarian cancer has been termed the "silent killer" because some patients do not show clear symptoms at an early stage. Currently, there is a lack of approved and effective early diagnostic tools for ovarian cancer. There is also an apparent severe knowledge gap of ovarian cancer in general and of its indicative symptoms among both public and many health professionals. These factors have significantly contributed to the late stage diagnosis of most ovarian cancer patients (63% are diagnosed at Stage III or above), where the 5 year survival rate is less than 30%. The paucity of knowledge concerning ovarian cancer in the United States is unknown. METHODS: The present investigation examined current public awareness and knowledge about ovarian cancer. The study implemented design strategies to develop an unbiased survey with quality control measures, including the modern application of multiple statistical analyses. The survey assessed a reasonable proxy of the US population by crowdsourcing participants through the online task marketplace Amazon Mechanical Turk, at a highly condensed rate of cost and time compared to traditional recruitment methods. CONCLUSION: Knowledge of ovarian cancer was compared to that of breast cancer using repeated measures, bias control and other quality control measures in the survey design. Analyses included multinomial logistic regression and categorical data analysis procedures such as correspondence analysis, among other statistics. We confirmed the relatively poor public knowledge of ovarian cancer among the US population. The simple, yet novel design should set an example for designing surveys to obtain quality data via Amazon Mechanical Turk with the associated analyses. PMID- 24465581 TI - MMP9 processing of HSPB1 regulates tumor progression. AB - Matrix metalloproteinases regulate pathophysiological events by processing matrix proteins and secreted proteins. Previously, we demonstrated that soluble heat shock protein B1 (HSPB1) is released primarily from endothelial cells (ECs) and regulates angiogenesis via direct interaction with vascular endothelial growth factor (VEGF). Here we report that MMP9 can cleave HSPB1 and release anti angiogenic fragments, which play a key role in tumorprogression. We mapped the cleavage sites and explored their physiological relevance during these processing events. HSPB1 cleavage by MMP9 inhibited VEGF-induced ECs activation and the C terminal HSPB1 fragment exhibited more interaction with VEGF than did full-length HSPB1. HSPB1 cleavage occurs during B16F10 lung progression in wild-type mice. Also, intact HSPB1 was more detected on tumor endothelium of MMP9 null mice than wild type mice. Finally, we confirmed that secretion of C-terminal HSPB1 fragment was significantly inhibited lung and liver tumor progression of B16F10 melanoma cells and lung tumor progression of CT26 colon carcinoma cells, compared to full length HSPB1. These data suggest that in vivo MMP9-mediated processing of HSPB1 acts to regulate VEGF-induced ECs activation for tumor progression, releasing anti-angiogenic HSPB1 fragments. Moreover, these findings potentially explain an anti-target effect for the failure of MMP inhibitors in clinical trials, suggesting that MMP inhibitors may have pro-tumorigenic effects by reducing HSPB1 fragmentation. PMID- 24465582 TI - Vocal fold augmentation with injectable polycaprolactone microspheres/pluronic F127 hydrogel: long-term in vivo study for the treatment of glottal insufficiency. AB - There is increasing demand for reconstruction of glottal insufficiency. Several injection materials have been examined for this purpose, but all had limitations, such as poor long-term durability, migration from the injection site, inflammation, granuloma formation, and interference with vocal fold vibration due to viscoelastic mismatch. Here, we developed a novel injection material, consisting of polycaprolactone (PCL) microspheres, which exhibits better viscoelasticity than conventional materials, and Pluronic F127 carrier, which decreases the migration of the injection materials. The material was injected into rabbits with glottal insufficiency and compared with the FDA-approved injection material, calcium hydroxylapatite (CaHA). Endoscopic and histological examinations indicated that PCL/Pluronic F127 remained at the injection site with no inflammatory response or granuloma formation, whereas CaHA leaked out and migrated from the injection site. Therefore, vocal fold augmentation was almost completely retained during the 12-month follow-up period in this study. Moreover, induced phonation and high-speed recording of vocal fold vibration showed decreased vocal fold gap area in the PCL/Pluronic F127 group. Our newly developed injection material, PCL/Pluronic F127, permits efficient augmentation of paralyzed vocal fold without complications, a concept that can be applied clinically, as demonstrated by the successful long-term follow-up. PMID- 24465583 TI - The Plasmodium falciparum translationally controlled tumor protein (TCTP) is incorporated more efficiently into B cells than its human homologue. AB - Plasmodium falciparum secretes a homologue of the translationally controlled tumor protein (TCTP) into serum of infected individuals, although its role in pathogenesis or virulence is unknown. To determine the effect of P. falciparum TCTP on B cells as compared to human TCTP, fluorescently labeled proteins were incubated on primary cultures of mouse splenic B cells and analyzed by flow cytometry and confocal microscopy. Our results indicate that both recombinant proteins are incorporated into B cells, but differ significantly in their rate and percentage of incorporation, being significantly higher for P. falciparum TCTP. Furthermore, P. falciparum TCTP showed a lower B cell proliferative effect than human TCTP, suggesting a mechanism through which the former could interfere in the host's immune response. PMID- 24465584 TI - Blunted response to combination antiretroviral therapy in HIV elite controllers: an international HIV controller collaboration. AB - OBJECTIVE: HIV "elite controllers" (ECs) spontaneously control viral load, but some eventually require combination antiretroviral treatment (cART), due to a loss of viral control or a decline in CD4 T-cell counts. Here we studied the CD4 T-cell count dynamics after cART initiation among 34 ECs followed in U.S. and European cohorts, by comparison with chronically viremic patients (VIRs). METHODS: ECs were defined as patients with at least >=5 viral load (VL) measurements below 400 copies/mL during at least a 5-year period despite never receiving ART and were selected from the French ANRS CO18 cohort, the U.S. SCOPE cohort, the International HIV Controllers study and the European CASCADE collaboration. VIRs were selected from the ANRS COPANA cohort of recently diagnosed (<1 year) ART-naive HIV-1-infected adults. CD4 T-cell count dynamics after cART initiation in both groups were modelled with piecewise mixed linear models. RESULTS: After cART initiation, CD4 T-cell counts showed a biphasic rise in VIRs with: an initial rapid increase during the first 3 months (+0.63?CD4/month), followed by +0.19?CD4/month. This first rapid phase was not observed in ECs, in whom the CD4Tc count increased steadily, at a rate similar to that of the second phase observed in VIRs. After cART initiation at a CD4 T-cell count of 300/mm(3), the estimated mean CD4 T-cell gain during the first 12 months was 139/mm(3) in VIRs and 80/mm(3) in ECs (p = 0.048). CONCLUSIONS: cART increases CD4 T-cell counts in elite controllers, albeit less markedly than in other patients. PMID- 24465585 TI - Atoxic derivative of botulinum neurotoxin A as a prototype molecular vehicle for targeted delivery to the neuronal cytoplasm. AB - We have previously described genetic constructs and expression systems that enable facile production of recombinant derivatives of botulinum neurotoxins (BoNTs) that retain the structural and trafficking properties of wt BoNTs. In this report we describe the properties of one such derivative, BoNT/A ad, which was rendered atoxic by introducing two amino acid mutations to the light chain (LC) of wt BoNT/A, and which is being developed as a molecular vehicle for delivering drugs to the neuronal cytoplasm. The neuronal binding, internalization, and intracellular trafficking of BoNT/A ad in primary hippocampal cultures was evaluated using three complimentary techniques: flow cytometry, immunohistochemistry, and Western blotting. Neuronal binding of BoNT ad was significantly increased when neurons were incubated in depolarizing medium. Flow cytometry demonstrated that BoNT/A ad internalized into neurons but not glia. After 24 hours, the majority of the neuron-bound BoNT/A ad became internalized, as determined by its resistance to pronase E-induced proteolytic degradation of proteins associated with the plasma membrane of intact cells. Significant amounts of the atoxic LC accumulated in a Triton X-100-extractable fraction of the neurons, and persisted as such for at least 11 days with no evidence of degradation. Immunocytochemical analysis demonstrated that the LC of BoNT/A ad was translocated to the neuronal cytoplasm after uptake and was specifically targeted to SNARE proteins. The atoxic LC consistently co-localized with synaptic markers SNAP-25 and VAMP-2, but was rarely co-localized with markers for early or late endosomes. These data demonstrate that BoNT/A ad mimics the trafficking properties of wt BoNT/A, confirming that our platform for designing and expressing BoNT derivatives provides an accessible system for elucidating the molecular details of BoNT trafficking, and can potentially be used to address multiple medical and biodefense needs. PMID- 24465586 TI - A comparison of midline and tracheal gene regulation during Drosophila development. AB - Within the Drosophila embryo, two related bHLH-PAS proteins, Single-minded and Trachealess, control development of the central nervous system midline and the trachea, respectively. These two proteins are bHLH-PAS transcription factors and independently form heterodimers with another bHLH-PAS protein, Tango. During early embryogenesis, expression of Single-minded is restricted to the midline and Trachealess to the trachea and salivary glands, whereas Tango is ubiquitously expressed. Both Single-minded/Tango and Trachealess/Tango heterodimers bind to the same DNA sequence, called the CNS midline element (CME) within cis-regulatory sequences of downstream target genes. While Single-minded/Tango and Trachealess/Tango activate some of the same genes in their respective tissues during embryogenesis, they also activate a number of different genes restricted to only certain tissues. The goal of this research is to understand how these two related heterodimers bind different enhancers to activate different genes, thereby regulating the development of functionally diverse tissues. Existing data indicates that Single-minded and Trachealess may bind to different co-factors restricted to various tissues, causing them to interact with the CME only within certain sequence contexts. This would lead to the activation of different target genes in different cell types. To understand how the context surrounding the CME is recognized by different bHLH-PAS heterodimers and their co-factors, we identified and analyzed novel enhancers that drive midline and/or tracheal expression and compared them to previously characterized enhancers. In addition, we tested expression of synthetic reporter genes containing the CME flanked by different sequences. Taken together, these experiments identify elements overrepresented within midline and tracheal enhancers and suggest that sequences immediately surrounding a CME help dictate whether a gene is expressed in the midline or trachea. PMID- 24465587 TI - Skewed distribution of IL-7 receptor-alpha-expressing effector memory CD8+ T cells with distinct functional characteristics in oral squamous cell carcinoma. AB - CD8(+) T cells play important roles in anti-tumor immunity but distribution profile or functional characteristics of effector memory subsets during tumor progression are unclear. We found that, in oral squamous carcinoma patients, circulating CD8(+) T cell pools skewed toward effector memory subsets with the distribution frequency of CCR7(-)CD45RA(-)CD8(+) T cells and CCR7(-) CD45RA(+)CD8(+) T cells negatively correlated with each other. A significantly higher frequency of CD127(lo) CCR7(-)CD45RA(-)CD8(+) T cells or CCR7( )CD45RA(+)CD8(+) T cells among total CD8(+) T cells was found in peripheral blood or tumor infiltrating lymphocytes, but not in regional lymph nodes. The CD127(hi) CCR7(-)CD45RA(-)CD8(+) T cells or CCR7(-)CD45RA(+)CD8(+) T cells maintained significantly higher IFN-gamma, IL-2 productivity and ex vivo proliferative capacity, while the CD127(lo) CCR7(-)CD45RA(-)CD8(+) T cells or CCR7( )CD45RA(+)CD8(+) T cells exhibited higher granzyme B productivity and susceptibility to activation induced cell death. A higher ratio of CCR7( )CD45RA(+)CD8(+) T cells to CCR7(-)CD45RA(-)CD8(+) T cells was associated with advanced cancer staging and poor differentiation of tumor cells. Therefore, the CD127(lo) CCR7(-)CD45RA(-)CD8(+) T cells and CCR7(-)CD45RA(+)CD8(+) T cells are functionally similar CD8(+) T cell subsets which exhibit late differentiated effector phenotypes and the shift of peripheral CD8(+) effector memory balance toward CCR7(-)CD45RA(+)CD8(+) T cells is associated with OSCC progression. PMID- 24465588 TI - Study of 320-slice dynamic volume CT perfusion in different pathologic types of kidney tumor: preliminary results. AB - OBJECTIVE: To investigate microcirculatory differences between pathologic types of kidney tumor using 320-slice dynamic volume CT perfusion. METHODS: Perfusion imaging with 320-slice dynamic volume CT was prospectively performed in 85 patients with pathologically proven clear cell renal cell carcinoma (RCC) (n = 66), papillary RCC (n = 7), chromophobe RCC (n = 5), angiomyolipoma (AML) with minimal fat (n = 7), or RCC (n = 78). Equivalent blood volume (Equiv BV), permeability surface-area product (PS; clearance/unit volume = permeability), and blood flow (BF) of tumor and normal renal cortex were measured and analyzed. Effective radiation dose was calculated. RESULTS: There was a significant difference in all three parameters between tumor and normal renal cortex (P<0.001). Equiv BV was significantly different between RCC and AML with minimal fat (P = 0.038) and between clear cell RCC and AML with minimal fat (P<0.001). Mean Equiv BV and BF were significantly higher in clear cell RCC than in papillary RCC (P<0.001 for both) and mean Equiv BV was higher in clear cell RCC than in chromophobe RCC (P<0.001). The effective radiation dose of the CT perfusion protocol was 18.5 mSv. CONCLUSION: Perfusion imaging using 320-slice dynamic volume CT can be used to evaluate hemodynamic features of the whole kidney and kidney tumors, which may be useful in the differential diagnosis of these four pathologic types of kidney tumor. PMID- 24465589 TI - The truncated isoform of somatostatin receptor5 (sst5TMD4) is associated with poorly differentiated thyroid cancer. AB - Somatostatin receptors (ssts) are expressed in thyroid cancer cells, but their biological significance is not well understood. The aim of this study was to assess ssts in well differentiated (WDTC) and poorly differentiated thyroid cancer (PDTC) by means of imaging and molecular tools and its relationship with the efficacy of somatostatin analog treatment. Thirty-nine cases of thyroid carcinoma were evaluated (20 PDTC and 19 WDTC). Depreotide scintigraphy and mRNA levels of sst-subtypes, including the truncated variant sst5TMD4, were carried out. Depreotide scans were positive in the recurrent tumor in the neck in 6 of 11 (54%) PDTC, and in those with lung metastases in 5/11 cases (45.4%); sst5TMD4 was present in 18/20 (90%) of PDTC, being the most densely expressed sst-subtype, with a 20-fold increase in relation to sst2. In WDTC, sst2 was the most represented, while sst5TMD4 was not found; sst2 was significantly increased in PDTC in comparison to WDTC. Five depreotide positive PDTC received octreotide for 3-6 months in a pilot study with no changes in the size of the lesions in 3 of them, and a significant increase in the pulmonary and cervical lesions in the other 2. All PDTC patients treated with octreotide showed high expression of sst5TMD4. ROC curve analysis demonstrated that only sst5TMD4 discriminates between PDTC and WDTC. We conclude that sst5TMD4 is overexpressed in PDTC and may be involved in the lack of response to somatostatin analogue treatment. PMID- 24465590 TI - A conditional mouse mutant in the tumor suppressor SdhD gene unveils a link between p21(WAF1/Cip1) induction and mitochondrial dysfunction. AB - Mutations in mitochondrial complex II (MCII; succinate dehydrogenase, Sdh) genes cause familiar pheochromocytoma/paraganglioma tumors. Several mechanisms have been proposed to account for Sdh-mutation-induced tumorigenesis, the most accepted of which is based on the constitutive expression of the hypoxia inducible factor 1alpha (Hif1alpha) at normal oxygen tension, a theory referred to as "pseudo-hypoxic drive". Other molecular processes, such as oxidative stress, apoptosis, or chromatin remodeling have been also proposed to play a causative role. Nevertheless, the actual contribution of each of these mechanisms has not been definitively established. Moreover, the biological factors that determine the tissue-specificity of these tumors have not been identified. In this work, we made use of the inducible SDHD-ESR mouse, a conditional mutant in the SdhD gene, which encodes the small subunit of MCII, and that acts as a tumor suppressor gene in humans. The analysis of the Hif1alpha pathway in SDHD-ESR tissues and in two newly derived cell lines after complete SdhD loss -a requirement for hereditary paraganglioma type-1 tumor formation in humans- partially recapitulated the "pseudo-hypoxic" response and rendered inconsistent results. Therefore, we performed microarray analysis of adrenal medulla and kidney in order to identify other early gene expression changes elicited by SdhD deletion. Our results revealed that each mutant tissue displayed different variations in their gene expression profiles affecting to different biological processes. However, we found that the Cdkn1a gene was up-regulated in both tissues. This gene encodes the cyclin-dependent kinase inhibitor p21(WAF1/Cip1), a factor implicated in cell cycle, senescence, and cancer. The two SDHD-ESR cell lines also showed accumulation of this protein. This new and unprecedented evidence for a link between SdhD dysfunction and p21(WAF1/Cip1) will open new avenues for the study of the mechanisms that cause tumors in Sdh mutants. Finally, we discuss the actual role of Hif1alpha in tumorigenesis. PMID- 24465591 TI - The BDNF/TrkB signaling pathway is involved in heat hyperalgesia mediated by Cdk5 in rats. AB - BACKGROUND: Cyclin-dependent kinase 5 (Cdk5) has been shown to play an important role in mediating inflammation-induced heat hyperalgesia. However, the underlying mechanism remains unclear. The aim of this study was to determine whether roscovitine, an inhibitor of Cdk5, could reverse the heat hyperalgesia induced by peripheral injection of complete Freund's adjuvant (CFA) via the brain-derived neurotrophic factor (BDNF)-tyrosine kinase B (TrkB) signaling pathway in the dorsal horn of the spinal cord in rats. RESULTS: Heat hyperalgesia induced by peripheral injection of CFA was significantly reversed by roscovitine, TrkB-IgG, and the TrkB inhibitor K252a, respectively. Furthermore, BDNF was significantly increased from 0.5 h to 24 h after CFA injection in the spinal cord dorsal horn. Intrathecal adminstration of the Cdk5 inhibitor roscovitine had no obvious effects on BDNF levels. Increased TrkB protein level was significantly reversed by roscovitine between 0.5 h and 6 h after CFA injection. Cdk5 and TrkB co immunoprecipitation results suggested Cdk5 mediates the heat hyperalgesia induced by CFA injection by binding with TrkB, and the binding between Cdk5 and TrkB was markedly blocked by intrathecal adminstration of roscovitine. CONCLUSION: Our data suggested that the BDNF-TrkB signaling pathway was involved in CFA-induced heat hyperalgesia mediated by Cdk5. Roscovitine reversed the heat hyperalgesia induced by peripheral injection of CFA by blocking BDNF/TrkB signaling pathway, suggesting that severing the close crosstalk between Cdk5 and the BDNF/TrkB signaling cascade may present a potential target for anti-inflammatory pain. PMID- 24465593 TI - The vertebrate RCAN gene family: novel insights into evolution, structure and regulation. AB - Recently there has been much interest in the Regulators of Calcineurin (RCAN) proteins which are important endogenous modulators of the calcineurin-NFATc signalling pathway. They have been shown to have a crucial role in cellular programmes such as the immune response, muscle fibre remodelling and memory, but also in pathological processes such as cardiac hypertrophy and neurodegenerative diseases. In vertebrates, the RCAN family form a functional subfamily of three members RCAN1, RCAN2 and RCAN3 whereas only one RCAN is present in the rest of Eukarya. In addition, RCAN genes have been shown to collocate with RUNX and CLIC genes in ACD clusters (ACD21, ACD6 and ACD1). How the RCAN genes and their clustering in ACDs evolved is still unknown. After analysing RCAN gene family evolution using bioinformatic tools, we propose that the three RCAN vertebrate genes within the ACD clusters, which evolved from single copy genes present in invertebrates and lower eukaryotes, are the result of two rounds of whole genome duplication, followed by a segmental duplication. This evolutionary scenario involves the loss or gain of some RCAN genes during evolution. In addition, we have analysed RCAN gene structure and identified the existence of several characteristic features that can be involved in RCAN evolution and gene expression regulation. These included: several transposable elements, CpG islands in the 5' region of the genes, the existence of antisense transcripts (NAT) associated with the three human genes, and considerable evidence for bidirectional promoters that regulate RCAN gene expression. Furthermore, we show that the CpG island associated with the RCAN3 gene promoter is unmethylated and transcriptionally active. All these results provide timely new insights into the molecular mechanisms underlying RCAN function and a more in depth knowledge of this gene family whose members are obvious candidates for the development of future therapies. PMID- 24465594 TI - Angiopoietin-like protein 2 induced by mechanical stress accelerates degeneration and hypertrophy of the ligamentum flavum in lumbar spinal canal stenosis. AB - Chronic inflammation and subsequent fibrosis induced by mechanical stress play an important role in ligamentum flavum (LF) hypertrophy and degeneration in patients with lumbar spinal canal stenosis (LSCS). Angiopoietin-like protein 2 (Angptl2) is a chronic inflammatory mediator induced under various pathological conditions and increases the expression of TGF-beta1, which is a well-characterized mediator in LF hypertrophy. We investigated whether Angptl2 is induced by mechanical stress, and whether it contributes to LF hypertrophy and degeneration by activating the TGF-beta1 signaling cascade. In this study, we investigated human LF tissue and LF fibroblasts isolated from patients who underwent lumbar surgery. We found that Angptl2 was abundantly expressed in fibroblasts of hypertrophied LF tissues at both the mRNA and protein levels. This expression was not only positively correlated with LF thickness and degeneration but also positively correlated with lumbar segmental motion. Our in vitro experiments with fibroblasts from hypertrophied LF tissue revealed that mechanical stretching stress increases the expression and secretion of Angptl2 via activation of calcineurin/NFAT pathways. In hypertrophied LF tissue, expression of TGF-beta1 mRNA was also increased and TGF-beta1/Smad signaling was activated. Angptl2 expression in LF tissue was positively correlated with the expression of TGF beta1 mRNA, suggesting cooperation between Angptl2 and TGF-beta1 in the pathogenesis of LF hypertrophy. In vitro experiments revealed that Angptl2 increased levels of TGF-beta1 and its receptors, and also activated TGF beta1/Smad signaling. Mechanical stretching stress increased TGF-beta1 mRNA expression, which was partially attenuated by treatment with a calcineurin/NFAT inhibitor or Angptl2 siRNA, indicating that induction of TGF-beta1 expression by mechanical stretching stress is partially mediated by Angptl2. We conclude that expression of Angptl2 induced by mechanical stress in LF fibroblasts promotes LF tissue degeneration by activation of TGF-beta1/Smad signaling, which results in LF hypertrophy in patients with LSCS. PMID- 24465592 TI - Association between CASP8 -652 6N del polymorphism (rs3834129) and colorectal cancer risk: results from a multi-centric study. AB - The common -652 6N del variant in the CASP8 promoter (rs3834129) has been described as a putative low-penetrance risk factor for different cancer types. In particular, some studies suggested that the deleted allele (del) was inversely associated with CRC risk while other analyses failed to confirm this. Hence, to better understand the role of this variant in the risk of developing CRC, we performed a multi-centric case-control study. In the study, the variant -652 6N del was genotyped in a total of 6,733 CRC cases and 7,576 controls recruited by six different centers located in Spain, Italy, USA, England, Czech Republic and the Netherlands collaborating to the international consortium COGENT (COlorectal cancer GENeTics). Our analysis indicated that rs3834129 was not associated with CRC risk in the full data set. However, the del allele was under-represented in one set of cases with a family history of CRC (per allele model OR = 0.79, 95% CI = 0.69-0.90) suggesting this allele might be a protective factor versus familial CRC. Since this multi-centric case-control study was performed on a very large sample size, it provided robust clarification of the effect of rs3834129 on the risk of developing CRC in Caucasians. PMID- 24465595 TI - Coping with unpredictability: dopaminergic and neurotrophic responses to omission of expected reward in Atlantic salmon (Salmo salar L.). AB - Comparative studies are imperative for understanding the evolution of adaptive neurobiological processes such as neural plasticity, cognition, and emotion. Previously we have reported that prolonged omission of expected rewards (OER, or 'frustrative nonreward') causes increased aggression in Atlantic salmon (Salmo salar). Here we report changes in brain monoaminergic activity and relative abundance of brain derived neurotrophic factor (BDNF) and dopamine receptor mRNA transcripts in the same paradigm. Groups of fish were initially conditioned to associate a flashing light with feeding. Subsequently, the expected food reward was delayed for 30 minutes during two out of three meals per day in the OER treatment, while the previously established routine was maintained in control groups. After 8 days there was no effect of OER on baseline brain stem serotonin (5-HT) or dopamine (DA) activity. Subsequent exposure to acute confinement stress led to increased plasma cortisol and elevated turnover of brain stem DA and 5-HT in all animals. The DA response was potentiated and DA receptor 1 (D1) mRNA abundance was reduced in the OER-exposed fish, indicating a sensitization of the DA system. In addition OER suppressed abundance of BDNF in the telencephalon of non-stressed fish. Regardless of OER treatment, a strong positive correlation between BDNF and D1 mRNA abundance was seen in non-stressed fish. This correlation was disrupted by acute stress, and replaced by a negative correlation between BDNF abundance and plasma cortisol concentration. These observations indicate a conserved link between DA, neurotrophin regulation, and corticosteroid signaling pathways. The results also emphasize how fish models can be important tools in the study of neural plasticity and responsiveness to environmental unpredictability. PMID- 24465596 TI - Hovenia dulcis Thunb extract and its ingredient methyl vanillate activate Wnt/beta-catenin pathway and increase bone mass in growing or ovariectomized mice. AB - The Wnt/beta-catenin pathway is a potential target for development of anabolic agents to treat osteoporosis because of its role in osteoblast differentiation and bone formation. However, there is no clinically available anti-osteoporosis drug that targets this Wnt/beta-catenin pathway. In this study, we screened a library of aqueous extracts of 350 plants and identified Hovenia dulcis Thunb (HDT) extract as a Wnt/beta-catenin pathway activator. HDT extract induced osteogenic differentiation of calvarial osteoblasts without cytotoxicity. In addition, HDT extract increased femoral bone mass without inducing significant weight changes in normal mice. In addition, thickness and area of femoral cortical bone were also significantly increased by the HDT extract. Methyl vanillate (MV), one of the ingredients in HDT, also activated the Wnt/beta catenin pathway and induced osteoblast differentiation in vitro. MV rescued trabecular or cortical femoral bone loss in the ovariectomized mice without inducing any significant weight changes or abnormality in liver tissue when administrated orally. Thus, natural HDT extract and its ingredient MV are potential anabolic agents for treating osteoporosis. PMID- 24465597 TI - A new multicolor bioluminescence imaging platform to investigate NF-kappaB activity and apoptosis in human breast cancer cells. AB - BACKGROUND: Evaluation of novel drugs for clinical development depends on screening technologies and informative preclinical models. Here we developed a multicolor bioluminescent imaging platform to simultaneously investigate transcription factor NF-kappaB signaling and apoptosis. METHODS: The human breast cancer cell line (MDA-MB-231) was genetically modified to express green, red and blue light emitting luciferases to monitor cell number and viability, NF-kappaB promoter activity and to perform specific cell sorting and detection, respectively. The pro-luciferin substrate Z-DEVD-animoluciferin was employed to determine apoptotic caspase 3/7 activity. We used the cell line for the in vitro evaluation of natural compounds and in vivo optical imaging of tumor necrosis factor TNFalpha-induced NF-kappaB activation. RESULTS: Celastrol, resveratrol, sulphoraphane and curcumin inhibited the NF-kappaB promoter activity significantly and in a dose dependent manner. All compounds except resveratrol induced caspase 3/7 dependent apoptosis. Multicolor bioluminescence in vivo imaging allowed the investigation of tumor growth and NF-kappaB induction in a mouse model of breast cancer. CONCLUSION: Our new method provides an imaging platform for the identification, validation, screening and optimization of compounds acting on NF-kappaB signaling and apoptosis both in vitro and in vivo. PMID- 24465598 TI - Transcription regulation of HYPK by Heat Shock Factor 1. AB - HYPK (Huntingtin Yeast Partner K) was originally identified by yeast two-hybrid assay as an interactor of Huntingtin, the protein mutated in Huntington's disease. HYPK was characterized earlier as an intrinsically unstructured protein having chaperone-like activity in vitro and in vivo. HYPK has the ability of reducing rate of aggregate formation and subsequent toxicity caused by mutant Huntingtin. Further investigation revealed that HYPK is involved in diverse cellular processes and required for normal functioning of cells. In this study we observed that hyperthermia increases HYPK expression in human and mouse cells in culture. Expression of exogenous Heat Shock Factor 1 (HSF1), upon heat treatment could induce HYPK expression, whereas HSF1 knockdown reduced endogenous as well as heat-induced HYPK expression. Putative HSF1-binding site present in the promoter of human HYPK gene was identified and validated by reporter assay. Chromatin immunoprecipitation revealed in vivo interaction of HSF1 and RNA polymerase II with HYPK promoter sequence. Additionally, acetylation of histone H4, a known epigenetic marker of inducible HSF1 binding, was observed in response to heat shock in HYPK gene promoter. Overexpression of HYPK inhibited cells from lethal heat-induced death whereas knockdown of HYPK made the cells susceptible to lethal heat shock-induced death. Apart from elevated temperature, HYPK was also upregulated by hypoxia and proteasome inhibition, two other forms of cellular stress. We concluded that chaperone-like protein HYPK is induced by cellular stress and under transcriptional regulation of HSF1. PMID- 24465599 TI - A semi-automatic method to extract canal pathways in 3D micro-CT images of Octocorals. AB - The long-term goal of our study is to understand the internal organization of the octocoral stem canals, as well as their physiological and functional role in the growth of the colonies, and finally to assess the influence of climatic changes on this species. Here we focus on imaging tools, namely acquisition and processing of three-dimensional high-resolution images, with emphasis on automated extraction of canal pathways. Our aim was to evaluate the feasibility of the whole process, to point out and solve - if possible - technical problems related to the specimen conditioning, to determine the best acquisition parameters and to develop necessary image-processing algorithms. The pathways extracted are expected to facilitate the structural analysis of the colonies, namely to help observing the distribution, formation and number of canals along the colony. Five volumetric images of Muricea muricata specimens were successfully acquired by X-ray computed tomography with spatial resolution ranging from 4.5 to 25 micrometers. The success mainly depended on specimen immobilization. More than [Formula: see text] of the canals were successfully detected and tracked by the image-processing method developed. Thus obtained three-dimensional representation of the canal network was generated for the first time without the need of histological or other destructive methods. Several canal patterns were observed. Although most of them were simple, i.e. only followed the main branch or "turned" into a secondary branch, many others bifurcated or fused. A majority of bifurcations were observed at branching points. However, some canals appeared and/or ended anywhere along a branch. At the tip of a branch, all canals fused into a unique chamber. Three-dimensional high-resolution tomographic imaging gives a non-destructive insight to the coral ultrastructure and helps understanding the organization of the canal network. Advanced image-processing techniques greatly reduce human observer's effort and provide methods to both visualize and quantify the structures of interest. PMID- 24465600 TI - Modulation of fibroblast growth factor 19 expression by bile acids, meal replacement and energy drinks, milk, and coffee. AB - BACKGROUND: The enterohepatic pathway involving the fibroblast growth factor 19 (FGF19) and bile acids (BA) has been linked with the etiology and remission of type 2 diabetes (T2D) following Roux-en-Y gastric bypass (RYGB) surgery. Specifically, diabetic patients had lower FGF19 circulating levels but postoperative FGF19 and BA levels were higher in diabetic patients that experience remission of T2D, as compared to non-diabetic patients and diabetic patients that do not experience remission. It has been proposed that this may be due to the direct flow of digestate-free bile acids into the ileum benefiting mostly T2D patients without severe diabetes. METHODS/RESULTS: We used a human colorectal cell line (LS174T) that endogenously expresses FGF19, real time PCR, and Elisas for precise quantitation of FGF19 mRNA and secreted protein levels. We report here that BA and fractions of BA stimulated FGF19 in vitro but this effect was partially blocked when BA were pre-incubated with a lipoprotein mix which emulates digested food. In addition, we show that FGF19 mRNA was stimulated by meal replacement drinks (Ensure, Glucerna, SlimFast), non-fat milk, and coffee which has been linked with reduced risk for developing diabetes. Pure caffeine and the 5-hour Energy drink, on the other hand, decreased FGF19 mRNA. CONCLUSIONS: In summary, FGF19 expression in vitro is modifiable by popular drinks suggesting that such approaches could potentially be used for modulating FGF19 expression in humans. PMID- 24465601 TI - Cognitive loading affects motor awareness and movement kinematics but not locomotor trajectories during goal-directed walking in a virtual reality environment. AB - The primary purpose of this study was to investigate the effects of cognitive loading on movement kinematics and trajectory formation during goal-directed walking in a virtual reality (VR) environment. The secondary objective was to measure how participants corrected their trajectories for perturbed feedback and how participants' awareness of such perturbations changed under cognitive loading. We asked 14 healthy young adults to walk towards four different target locations in a VR environment while their movements were tracked and played back in real-time on a large projection screen. In 75% of all trials we introduced angular deviations of +/-5 degrees to +/-30 degrees between the veridical walking trajectory and the visual feedback. Participants performed a second experimental block under cognitive load (serial-7 subtraction, counter-balanced across participants). We measured walking kinematics (joint-angles, velocity profiles) and motor performance (end-point-compensation, trajectory-deviations). Motor awareness was determined by asking participants to rate the veracity of the feedback after every trial. In-line with previous findings in natural settings, participants displayed stereotypical walking trajectories in a VR environment. Our results extend these findings as they demonstrate that taxing cognitive resources did not affect trajectory formation and deviations although it interfered with the participants' movement kinematics, in particular walking velocity. Additionally, we report that motor awareness was selectively impaired by the secondary task in trials with high perceptual uncertainty. Compared with data on eye and arm movements our findings lend support to the hypothesis that the central nervous system (CNS) uses common mechanisms to govern goal-directed movements, including locomotion. We discuss our results with respect to the use of VR methods in gait control and rehabilitation. PMID- 24465602 TI - Platelet turnover in stable coronary artery disease - influence of thrombopoietin and low-grade inflammation. AB - BACKGROUND: Newly formed platelets are associated with increased aggregation and adverse outcomes in patients with coronary artery disease (CAD). The mechanisms involved in the regulation of platelet turnover in patients with CAD are largely unknown. AIM: To investigate associations between platelet turnover parameters, thrombopoietin and markers of low-grade inflammation in patients with stable CAD. Furthermore, to explore the relationship between platelet turnover parameters and type 2 diabetes, prior myocardial infarction, smoking, age, gender and renal insufficiency. METHODS: We studied 581 stable CAD patients. Platelet turnover parameters (immature platelet fraction, immature platelet count, mean platelet volume, platelet distribution width and platelet large cell-ratio) were determined using automated flow cytometry (Sysmex XE-2100). Furthermore, we measured thrombopoietin and evaluated low-grade inflammation by measurement of high-sensitive CRP and interleukin-6. RESULTS: We found strong associations between the immature platelet fraction, immature platelet count, mean platelet volume, platelet distribution width and platelet large cell ratio (r = 0.61-0.99, p<0.0001). Thrombopoietin levels were inversely related to all of the platelet turnover parameters (r = -0.17--0.25, p<0.0001). Moreover, thrombopoietin levels were significantly increased in patients with diabetes (p = 0.03) and in smokers (p = 0.003). Low-grade inflammation evaluated by high-sensitive CRP correlated significantly, yet weakly, with immature platelet count (r = 0.10, p = 0.03) and thrombopoietin (r = 0.16, p<0.001). Also interleukin-6 correlated with thrombopoietin (r = 0.10, p = 0.02). CONCLUSION: In stable CAD patients, thrombopoietin was inversely associated with platelet turnover parameters. Furthermore, thrombopoietin levels were increased in patients with diabetes and in smokers. However, low-grade inflammation did not seem to have a substantial impact on platelet turnover parameters. PMID- 24465603 TI - Settlement of planulae of the Moon jellyfish Aurelia aurita onto hydrophilic polycarbonate plates modified by atmospheric plasma treatment. AB - It has been reported that planula larvae of some jellyfish prefer artificial substrates for settlement. This research focused on the relationship between the settlement of planulae and the wettability of artificial substrate surfaces. We used atmospheric plasmas to change the wettability of the surfaces of polycarbonate (PC) plates because plasma treatment has no chemical side effects. The treatment made the surfaces hydrophilic, as evidenced by the decrease of contact angle from 85 degrees to 35 degrees . X-ray photoelectron spectroscopy revealed that the change of wettability of the PC plates could be attributed to N2, which was probably ionized in the air above the plates. Scanning electron microscopy revealed no difference in the surface morphology of the plates before and after plasma treatment. Results of bioassays using treated PC plates showed that planulae tended to preferentially settle on hydrophobic surfaces. PMID- 24465604 TI - Synergistic anti-cancer effect of phenformin and oxamate. AB - Phenformin (phenethylbiguanide; an anti-diabetic agent) plus oxamate [lactate dehydrogenase (LDH) inhibitor] was tested as a potential anti-cancer therapeutic combination. In in vitro studies, phenformin was more potent than metformin, another biguanide, recently recognized to have anti-cancer effects, in promoting cancer cell death in the range of 25 times to 15 million times in various cancer cell lines. The anti-cancer effect of phenformin was related to complex I inhibition in the mitochondria and subsequent overproduction of reactive oxygen species (ROS). Addition of oxamate inhibited LDH activity and lactate production by cells, which is a major side effect of biguanides, and induced more rapid cancer cell death by decreasing ATP production and accelerating ROS production. Phenformin plus oxamate was more effective than phenformin combined with LDH knockdown. In a syngeneic mouse model, phenformin with oxamate increased tumor apoptosis, reduced tumor size and (18)F-fluorodeoxyglucose (FDG) uptake on positron emission tomography/computed tomography compared to control. We conclude that phenformin is more cytotoxic towards cancer cells than metformin. Furthermore, phenformin and oxamate have synergistic anti-cancer effects through simultaneous inhibition of complex I in the mitochondria and LDH in the cytosol, respectively. PMID- 24465605 TI - Fatigue effect on low-frequency force fluctuations and muscular oscillations during rhythmic isometric contraction. AB - Continuous force output containing numerous intermittent force pulses is not completely smooth. By characterizing force fluctuation properties and force pulse metrics, this study investigated adaptive changes in trajectory control, both force-generating capacity and force fluctuations, as fatigue progresses. Sixteen healthy subjects (20-24 years old) completed rhythmic isometric gripping with the non-dominant hand to volitional failure. Before and immediately following the fatigue intervention, we measured the gripping force to couple a 0.5 Hz sinusoidal target in the range of 50-100% maximal voluntary contraction. Dynamic force output was off-line decomposed into 1) an ideal force trajectory spectrally identical to the target rate; and 2) a force pulse trace pertaining to force fluctuations and error-correction attempts. The amplitude of ideal force trajectory regarding to force-generating capacity was more suppressed than that of the force pulse trace with increasing fatigue, which also shifted the force pulse trace to lower frequency bands. Multi-scale entropy analysis revealed that the complexity of the force pulse trace at high time scales increased with fatigue, contrary to the decrease in complexity of the force pulse trace at low time scales. Statistical properties of individual force pulses in the spatial and temporal domains varied with muscular fatigue, concurrent with marked suppression of gamma muscular oscillations (40-60 Hz) in the post-fatigue test. In conclusion, this study first reveals that muscular fatigue impairs the amplitude modulation of force pattern generation more than it affects the amplitude responsiveness of fine-tuning a force trajectory. Besides, motor fatigue results disadvantageously in enhancement of motor noises, simplification of short-term force-tuning strategy, and slow responsiveness to force errors, pertaining to dimensional changes in force fluctuations, scaling properties of force pulse, and muscular oscillation. PMID- 24465606 TI - Comparison of antiviral activity between IgA and IgG specific to influenza virus hemagglutinin: increased potential of IgA for heterosubtypic immunity. AB - Both IgA and IgG antibodies are known to play important roles in protection against influenza virus infection. While IgG is the major isotype induced systemically, IgA is predominant in mucosal tissues, including the upper respiratory tract. Although IgA antibodies are believed to have unique advantages in mucosal immunity, information on direct comparisons of the in vitro antiviral activities of IgA and IgG antibodies recognizing the same epitope is limited. In this study, we demonstrate differences in antiviral activities between these isotypes using monoclonal IgA and IgG antibodies obtained from hybridomas of the same origin. Polymeric IgA-producing hybridoma cells were successfully subcloned from those originally producing monoclonal antibody S139/1, a hemaggulutinin (HA) specific IgG that was generated against an influenza A virus strain of the H3 subtype but had cross-neutralizing activities against the H1, H2, H13, and H16 subtypes. These monoclonal S139/1 IgA and IgG antibodies were assumed to recognize the same epitope and thus used to compare their antiviral activities. We found that both S139/1 IgA and IgG antibodies strongly bound to the homologous H3 virus in an enzyme-linked immunosorbent assay, and there were no significant differences in their hemagglutination-inhibiting and neutralizing activities against the H3 virus. In contrast, S139/1 IgA showed remarkably higher cross binding to and antiviral activities against H1, H2, and H13 viruses than S139/1 IgG. It was also noted that S139/1 IgA, but not IgG, drastically suppressed the extracellular release of the viruses from infected cells. Electron microscopy revealed that S139/1 IgA deposited newly produced viral particles on the cell surface, most likely by tethering the particles. These results suggest that anti HA IgA has greater potential to prevent influenza A virus infection than IgG antibodies, likely due to increased avidity conferred by its multivalency, and that this advantage may be particularly important for heterosubtypic immunity. PMID- 24465607 TI - The fiber walk: a model of tip-driven growth with lateral expansion. AB - Tip-driven growth processes underlie the development of many plants. To date, tip driven growth processes have been modeled as an elongating path or series of segments, without taking into account lateral expansion during elongation. Instead, models of growth often introduce an explicit thickness by expanding the area around the completed elongated path. Modeling expansion in this way can lead to contradictions in the physical plausibility of the resulting surface and to uncertainty about how the object reached certain regions of space. Here, we introduce fiber walks as a self-avoiding random walk model for tip-driven growth processes that includes lateral expansion. In 2D, the fiber walk takes place on a square lattice and the space occupied by the fiber is modeled as a lateral contraction of the lattice. This contraction influences the possible subsequent steps of the fiber walk. The boundary of the area consumed by the contraction is derived as the dual of the lattice faces adjacent to the fiber. We show that fiber walks generate fibers that have well-defined curvatures, and thus enable the identification of the process underlying the occupancy of physical space. Hence, fiber walks provide a base from which to model both the extension and expansion of physical biological objects with finite thickness. PMID- 24465608 TI - Grimontia indica AK16(T), sp. nov., isolated from a seawater sample reports the presence of pathogenic genes similar to Vibrio genus. AB - Grimontia indica strain AK16(T) sp. nov. is the type strain of G. indica sp. nov. a new species within the genus Grimontia. This strain, whose genome is described here, was isolated from seawater sample collected from southeast coast of Palk Bay, India. G. indica AK16(T) is a Gram-negative, facultative aerobic rod shaped bacterium. There are only two other strains in the genus Grimontia one of which, Grimontia hollisae CIP 101886(T), is a reported human pathogen isolated from human stool sample while the other, 'Grimontia marina IMCC5001(T)', was isolated from a seawater sample. As compared to the pathogenic strain Grimontia hollisae CIP 101886(T), the strain AK16(T) lacks some genes for pathogenesis like the accessory colonization factors AcfA and AcfD, which are required for the colonization of the bacterium in the host body. While it carries some pathogenesis genes like OmpU, which are related to pathogenesis of Vibrio strains. This suggests that the life cycle of AK16(T) may include some pathogenic interactions with marine animal(s), or it may be an opportunistic pathogen. Study of the Grimontia genus is important because of the severe pathogenic traits exhibited by a member of the genus with only three species reported in total. The study will provide some vital information which may be useful in future clinical studies on the genus. PMID- 24465610 TI - Effects of climatic factors and ecosystem responses on the inter-annual variability of evapotranspiration in a coniferous plantation in subtropical China. AB - Because evapotranspiration (ET) is the second largest component of the water cycle and a critical process in terrestrial ecosystems, understanding the inter annual variability of ET is important in the context of global climate change. Eight years of continuous eddy covariance measurements (2003-2010) in a subtropical coniferous plantation were used to investigate the impacts of climatic factors and ecosystem responses on the inter-annual variability of ET. The mean and standard deviation of annual ET for 2003-2010 were 786.9 and 103.4 mm (with a coefficient of variation of 13.1%), respectively. The inter-annual variability of ET was largely created in three periods: March, May-June, and October, which are the transition periods between seasons. A set of look-up table approaches were used to separate the sources of inter-annual variability of ET. The annual ETs were calculated by assuming that (a) both the climate and ecosystem responses among years are variable (Vcli-eco), (b) the climate is variable but the ecosystem responses are constant (Vcli), and (c) the climate is constant but ecosystem responses are variable (Veco). The ETs that were calculated under the above assumptions suggested that the inter-annual variability of ET was dominated by ecosystem responses and that there was a negative interaction between the effects of climate and ecosystem responses. These results suggested that for long-term predictions of water and energy balance in global climate change projections, the ecosystem responses must be taken into account to better constrain the uncertainties associated with estimation. PMID- 24465609 TI - Genomic analyses reveal broad impact of miR-137 on genes associated with malignant transformation and neuronal differentiation in glioblastoma cells. AB - miR-137 plays critical roles in the nervous system and tumor development; an increase in its expression is required for neuronal differentiation while its reduction is implicated in gliomagenesis. To evaluate the potential of miR-137 in glioblastoma therapy, we conducted genome-wide target mapping in glioblastoma cells by measuring the level of association between PABP and mRNAs in cells transfected with miR-137 mimics vs. controls via RIPSeq. Impact on mRNA levels was also measured by RNASeq. By combining the results of both experimental approaches, 1468 genes were found to be negatively impacted by miR-137--among them, 595 (40%) contain miR-137 predicted sites. The most relevant targets include oncogenic proteins and key players in neurogenesis like c-KIT, YBX1, AKT2, CDC42, CDK6 and TGFbeta2. Interestingly, we observed that several identified miR-137 targets are also predicted to be regulated by miR-124, miR-128 and miR-7, which are equally implicated in neuronal differentiation and gliomagenesis. We suggest that the concomitant increase of these four miRNAs in neuronal stem cells or their repression in tumor cells could produce a robust regulatory effect with major consequences to neuronal differentiation and tumorigenesis. PMID- 24465611 TI - Nuclear hormone receptor expression in mouse kidney and renal cell lines. AB - Nuclear hormone receptors (NHRs) are transcription factors that regulate carbohydrate and lipid metabolism, immune responses, and inflammation. Although several NHRs, including peroxisome proliferator-activated receptor-gamma (PPARgamma) and PPARalpha, demonstrate a renoprotective effect in the context of diabetic nephropathy (DN), the expression and role of other NHRs in the kidney are still unrecognized. To investigate potential roles of NHRs in the biology of the kidney, we used quantitative real-time polymerase chain reaction to profile the expression of all 49 members of the mouse NHR superfamily in mouse kidney tissue (C57BL/6 and db/m), and cell lines of mesangial (MES13), podocyte (MPC), proximal tubular epithelial (mProx24) and collecting duct (mIMCD3) origins in both normal and high-glucose conditions. In C57BL/6 mouse kidney cells, hepatocyte nuclear factor 4alpha, chicken ovalbumin upstream promoter transcription factor II (COUP-TFII) and COUP-TFIII were highly expressed. During hyperglycemia, the expression of the NHR 4A subgroup including neuron-derived clone 77 (Nur77), nuclear receptor-related factor 1, and neuron-derived orphan receptor 1 significantly increased in diabetic C57BL/6 and db/db mice. In renal cell lines, PPARdelta was highly expressed in mesangial and proximal tubular epithelial cells, while COUP-TFs were highly expressed in podocytes, proximal tubular epithelial cells, and collecting duct cells. High-glucose conditions increased the expression of Nur77 in mesangial and collecting duct cells, and liver x receptor alpha in podocytes. These data demonstrate NHR expression in mouse kidney cells and cultured renal cell lines and suggest potential therapeutic targets in the kidney for the treatment of DN. PMID- 24465612 TI - Grey matter changes in cognitively impaired Parkinson's disease patients. AB - BACKGROUND: Cortical changes associated with cognitive decline in Parkinson's disease (PD) are not fully explored and require investigations with established diagnostic classification criteria. OBJECTIVE: We used MRI source-based morphometry to evaluate specific differences in grey matter volume patterns across 4 groups of subjects: healthy controls (HC), PD with normal cognition (PD NC), PD with mild cognitive impairment (MCI-PD) and PD with dementia (PDD). METHODS: We examined 151 consecutive subjects: 25 HC, 75 PD-NC, 29 MCI-PD, and 22 PDD at an Italian and Czech movement disorder centre. Operational diagnostic criteria were applied to classify MCI-PD and PDD. All structural MRI images were processed together in the Czech centre. The spatial independent component analysis was used to assess group differences of local grey matter volume. RESULTS: We identified two independent patterns of grey matter volume deviations: a) Reductions in the hippocampus and temporal lobes; b) Decreases in fronto parietal regions and increases in the midbrain/cerebellum. Both patterns differentiated PDD from all other groups and correlated with visuospatial deficits and letter verbal fluency, respectively. Only the second pattern additionally differentiated PD-NC from HC. CONCLUSION: Grey matter changes in PDD involve areas associated with Alzheimer-like pathology while fronto-parietal abnormalities are possibly an early marker of PD cognitive decline. These findings are consistent with a non-linear cognitive progression in PD. PMID- 24465613 TI - The prevalence and endemic nature of dengue infections in Guangdong, South China: an epidemiological, serological, and etiological study from 2005-2011. AB - OBJECTIVES: Frequent outbreaks of dengue are considered to be associated with an increased risk for endemicity of the disease. The occurrence of a large number of indigenous dengue cases in consecutive years indicates the possibility of a changing dengue epidemic pattern in Guangdong, China. METHODS: To have a clear understanding of the current dengue epidemic, a retrospective study of epidemiological profile, serological response, and virological features of dengue infections from 2005-2011 was conducted. Case data were collected from the National Notifiable Infectious Diseases Reporting Network. Serum samples were collected and prepared for serological verification and etiological confirmation. Incidence, temporal and spatial distribution, and the clinical manifestation of dengue infections were analyzed. Pearson's Chi-Square test was used to compare incidences between different age groups. A seroprevalence survey was implemented in local healthy inhabitants to obtain the overall positive rate for the specific immunoglobulin (Ig) G antibody against dengue virus (DENV). RESULTS: The overall annual incidence rate was 1.87/100000. A significant difference was found in age specific incidence (Pearson's Chi-Square value 498.008, P<0.001). Children under 5 years of age had the lowest incidence of 0.28/100000. The vast majority of cases presented with a mild manifestation typical to dengue fever. The overall seroprevalence of dengue IgG antibody in local populations was 2.43% (range 0.28% 5.42%). DENV-1 was the predominant serotype in circulation through the years, while all 4 serotypes were identified in indigenous patients from different outbreak localities since 2009. CONCLUSIONS: A gradual change in the epidemic pattern of dengue infection has been observed in recent years in Guangdong. With the endemic nature of dengue infections, the transition from a monotypic to a multitypic circulation of dengue virus in the last several years will have an important bearing on the prevention and control of dengue in the province and in the neighboring districts. PMID- 24465614 TI - Expression pattern and biochemical properties of zebrafish N-acetylglutamate synthase. AB - The urea cycle converts ammonia, a waste product of protein catabolism, into urea. Because fish dispose ammonia directly into water, the role of the urea cycle in fish remains unknown. Six enzymes, N-acetylglutamate synthase (NAGS), carbamylphosphate synthetase III, ornithine transcarbamylase, argininosuccinate synthase, argininosuccinate lyase and arginase 1, and two membrane transporters, ornithine transporter and aralar, comprise the urea cycle. The genes for all six enzymes and both transporters are present in the zebrafish genome. NAGS (EC 2.3.1.1) catalyzes the formation of N-acetylglutamate from glutamate and acetyl coenzyme A and in zebrafish is partially inhibited by L-arginine. NAGS and other urea cycle genes are highly expressed during the first four days of zebrafish development. Sequence alignment of NAGS proteins from six fish species revealed three regions of sequence conservation: the mitochondrial targeting signal (MTS) at the N-terminus, followed by the variable and conserved segments. Removal of the MTS yields mature zebrafish NAGS (zfNAGS-M) while removal of the variable segment from zfNAGS-M results in conserved NAGS (zfNAGS-C). Both zfNAGS-M and zfNAGS-C are tetramers in the absence of L-arginine; addition of L-arginine decreased partition coefficients of both proteins. The zfNAGS-C unfolds over a broader temperature range and has higher specific activity than zfNAGS-M. In the presence of L-arginine the apparent Vmax of zfNAGS-M and zfNAGS-C decreased, their Km(app) for acetyl coenzyme A increased while the Km(app) for glutamate remained unchanged. The expression pattern of NAGS and other urea cycle genes in developing zebrafish suggests that they may have a role in citrulline and/or arginine biosynthesis during the first day of development and in ammonia detoxification thereafter. Biophysical and biochemical properties of zebrafish NAGS suggest that the variable segment may stabilize a tetrameric state of zfNAGS M and that under physiological conditions zebrafish NAGS catalyzes formation of N acetylglutamate at the maximal rate. PMID- 24465615 TI - Genome-wide analysis of long noncoding RNA (lncRNA) expression in hepatoblastoma tissues. AB - Long noncoding RNAs (lncRNAs) have crucial roles in cancer biology. We performed a genome-wide analysis of lncRNA expression in hepatoblastoma tissues to identify novel targets for further study of hepatoblastoma. Hepatoblastoma and normal liver tissue samples were obtained from hepatoblastoma patients. The genome-wide analysis of lncRNA expression in these tissues was performed using a 4*180 K lncRNA microarray and Sureprint G3 Human lncRNA Chips. Quantitative RT-PCR (qRT PCR) was performed to confirm these results. The differential expressions of lncRNAs and mRNAs were identified through fold-change filtering. Gene Ontology (GO) and pathway analyses were performed using the standard enrichment computation method. Associations between lncRNAs and adjacent protein-coding genes were determined through complex transcriptional loci analysis. We found that 2736 lncRNAs were differentially expressed in hepatoblastoma tissues. Among these, 1757 lncRNAs were upregulated more than two-fold relative to normal tissues and 979 lncRNAs were downregulated. Moreover, in hepatoblastoma there were 420 matched lncRNA-mRNA pairs for 120 differentially expressed lncRNAs, and 167 differentially expressed mRNAs. The co-expression network analysis predicted 252 network nodes and 420 connections between 120 lncRNAs and 132 coding genes. Within this co-expression network, 369 pairs were positive, and 51 pairs were negative. Lastly, qRT-PCR data verified six upregulated and downregulated lncRNAs in hepatoblastoma, plus endothelial cell-specific molecule 1 (ESM1) mRNA. Our results demonstrated that expression of these aberrant lncRNAs could respond to hepatoblastoma development. Further study of these lncRNAs could provide useful insight into hepatoblastoma biology. PMID- 24465616 TI - Development and application of an immunoaffinity column enzyme immunoassay for mycotoxin zearalenone in complicated samples. AB - The zearalenone (ZEA) monoclonal antibody (mAb) 2D3, one of the highest sensitivity antibodies, was developed. Based on this mAb, it was established of an immunoaffinity column (IAC) coupled with an indirect competitive enzyme-linked immunosorbent assay (icELISA). After optimization, the icELISA allowed an IC50 against ZEA of 0.02 ug L(-1). The mAb 2D3 exhibited a high recognition of ZEA (100%) and beta-zearalenol (beta-ZOL, 88.2%). Its cross-reactivity with alpha zearalenol (alpha-ZOL) and beta-zearalanol (beta-ZAL) were found to be 4.4% and 4.6%, respectively. The IAC-icELISA method was employed to analyze ZEA contamination in food samples, compared with high-performance liquid chromatography (HPLC). The spiked assay for ZEA demonstrated the considerable recoveries for IAC-icELISA (83-93%) and HPLC (94-108%) methods. Results showed that the mAb 2D3 and IAC-icELISA method posed potential applications in sensitively determination of ZEA in maize. PMID- 24465617 TI - Micronutrient deficiency and treatment adherence in a randomized controlled trial of micronutrient supplementation in ART-naive persons with HIV. AB - INTRODUCTION: The MAINTAIN study is an on-going RCT comparing high-dose micronutrient and anti-oxidant supplementation versus recommended daily allowance (RDA) vitamins in slowing HIV immune deficiency progression in ART-naive people with HIV infection. OBJECTIVE: We planned analysis of the first 127 participants to determine the baseline prevalence of serum micronutrient deficiencies and correlates, as well as tolerance and adherence to study interventions. METHODS: Participants receive eight capsules twice daily of 1) high-dose or 2) RDA supplements for two years and are followed-up quarterly for measures of immune deficiency progression, safety and tolerability. Regression analysis was used to identify correlates of micronutrient levels at baseline. Adherence was measured by residual pill count, self-report using the General Treatment Scale (GTS) and short-term recall HIV Adherence Treatment Scale (HATS). RESULTS: Prior micronutrient supplementation (within 30 days) was 27% at screening and 10% of study population, and was not correlated with baseline micronutrient levels. Low levels were frequent for carotene (24%<1 nmol/L), vitamin D (24%<40 nmol/L) and serum folate (20%<15 nmol/L). The proportion with B12 deficiency (<133 pmol/L) was 2.4%. Lower baseline levels of B12 correlated lower baseline CD4 count (r = 0.21, p = 0.02) with a 21 pmol/L reduction in B12 per 100 cells/uL CD4. Vitamin D levels were higher in men (p<0.001). After a median follow-up of 1.63 years, there were 19 (15%) early withdrawals from the study treatment. Mean treatment adherence using pill count was 88%. Subjective adherence by the GTS was 81% and was moderately but significantly correlated with pill count (r = 0.29, p<0.001). Adherence based on short-term recall (HATS) was >80% in 75% of participants. CONCLUSION: Micronutrient levels in asymptomatic HIV+ persons are in keeping with population norms, but micronutrient deficiencies are frequent. Adherence levels are high, and will permit a valid evaluation of treatment effects. TRIAL REGISTRATION: ClinicalTrials.gov NCT00798772. PMID- 24465618 TI - Saliva from obese individuals suppresses the release of aroma compounds from wine. AB - BACKGROUND: Recent evidence suggests that a lower extent of the retronasal aroma release correspond to a higher amount of ad libitum food intake. This has been regarded as one of the bases of behavioral choices towards food consumption in obese people. In this pilot study we investigated the hypothesis that saliva from obese individuals could be responsible for an alteration of the retro-nasal aroma release. We tested this hypothesis in vitro, by comparing the release of volatiles from a liquid food matrix (wine) after its interaction with saliva from 28 obese (O) and 28 normal-weight (N) individuals. METHODS AND FINDINGS: Amplicon sequencing of the 16S rRNA V4 region indicated that Firmicutes and Actinobacteria were more abundant in O, while Proteobacteria and Fusobacteria dominated in N. Streptococcaceae were significantly more abundant in the O subjects and constituted 34% and 19% on average of the saliva microbiota of O and N subjects, respectively. The Total Antioxidant Capacity was higher in O vs N saliva samples. A model mouth system was used to test whether the in-mouth wine aroma release differs after the interaction with O or N saliva. In O samples, a 18% to 60% significant decrease in the mean concentration of wine volatiles was detected as a result of interaction with saliva, compared with N. This suppression was linked to biochemical differences in O and N saliva composition, which include protein content. CONCLUSION: Microbiological and biochemical differences were found in O vs N saliva samples. An impaired retronasal aroma release from white wine was detected in vitro and linked to compositional differences between saliva from obese and normal-weight subjects. Additional in vivo investigations on diverse food matrices could contribute to understanding whether a lower olfactory stimulation due to saliva composition can be a co-factor in the development/maintenance of obesity. PMID- 24465619 TI - Composition and function of T cell subpopulations are slow to change despite effective antiretroviral treatment of HIV disease. AB - The ability to reconstitute a normal immune system with antiretroviral therapy in the setting of HIV infection remains uncertain. This study aimed to characterize quantitative and qualitative aspects of various T cell subpopulations that do not improve despite effective ART. CD4?CD8 ratio was evaluated in HIV-infected subjects with viral loads >10,000 copies/ul ("non-controllers", n = 42), those with undetectable viral loads on ART ("ART-suppressed", n = 53), and HIV uninfected subjects (n = 22). In addition, T cell phenotype and function were examined in 25 non-controllers, 18 ART-suppressed, and 7 HIV-uninfected subjects. CD4?CD8 ratio in non-controllers, ART-suppressed, and HIV-uninfected subjects was 0.25, 0.48, and 1.95 respectively (P<0.0001 for all comparisons). The increased ratio in ART-suppressed compared to non-controllers was driven by an increase of CD4+ T cells, with no change in the expanded CD8+ T cell population. Expansion of differentiated (CD28-CD27-CD45RA+/-CCR7-) T cell subpopulations persisted despite ART and minimal changes were noted in naive T cell frequencies over time. Increased number of CD8+CD28- T cells and increased CD8+ CMV-specific T cell responses were associated with a decreased CD4?CD8 ratio. Measures of T cell function demonstrated persistence of high frequencies of CD8+ T cells producing IFN-gamma. Lastly, though all CD8+ subpopulations demonstrated significantly lower Ki67 expression in ART-suppressed subjects, CD4+ T cell subpopulations did not consistently show this decrease, thus demonstrating different proliferative responses in the setting of T cell depletion. In summary, this study demonstrated that CD4?CD8 ratios remained significantly decreased and naive T cell numbers were slow to increase despite long-term viral suppression on ART. In addition, there is a evidence of differential regulation of the CD4+ and CD8+ T cell subpopulations, suggesting independent homeostatic regulation of the two compartments. PMID- 24465620 TI - Prediction of the number of activated genes in multiple independent Cd(+2)- and As(+3)-induced malignant transformations of human urothelial cells (UROtsa). AB - BACKGROUND: Many toxic environmental agents such as cadmium and arsenic are found to be epidemiologically linked to increasing rates of cancers. In vitro studies show that these toxic agents induced malignant transformation in human cells. It is not clear whether such malignant transformation induced by a single toxic agent is driven by a common set of genes. Although the advancement of high throughput technology has facilitated the profiling of global gene expression, it remains a question whether the sample size is sufficient to identify this common driver gene set. RESULTS: We have developed a statistical method, SOFLR, to predict the number of common activated genes using a limited number of microarray samples. We conducted two case studies, cadmium and arsenic transformed human urothelial cells. Our method is able to precisely predict the number of stably induced and repressed genes and the number of samples to identify the common activated genes. The number of independent transformed isolates required for identifying the common activated genes is also estimated. The simulation study further validated our method and identified the important parameters in this analysis. CONCLUSIONS: Our method predicts the degree of similarity and diversity during cell malignant transformation by a single toxic agent. The results of our case studies imply the existence of common driver and passenger gene sets in toxin-induced transformation. Using a pilot study with small sample size, this method also helps microarray experimental design by determining the number of samples required to identify the common activated gene set. PMID- 24465621 TI - SDF1-a facilitates Lin-/Sca1+ cell homing following murine experimental cerebral ischemia. AB - BACKGROUND: Hematopoietic stem cells mobilize to the peripheral circulation in response to stroke. However, the mechanism by which the brain initiates this mobilization is uncharacterized. METHODS: Animals underwent a murine intraluminal filament model of focal cerebral ischemia and the SDF1-A pathway was evaluated in a blinded manner via serum and brain SDF1-A level assessment, Lin-/Sca1+ cell mobilization quantification, and exogenous cell migration confirmation; all with or without SDF1-A blockade. RESULTS: Bone marrow demonstrated a significant increase in Lin-/Sca1+ cell counts at 24 hrs (272 +/- 60%; P<0.05 vs sham). Mobilization of Lin-/Sca1+ cells to blood was significantly elevated at 24 hrs (607 +/- 159%; P<0.05). Serum SDF1-A levels were significant at 24 hrs (Sham (103 +/- 14), 4 hrs (94 +/- 20%, p = NS) and 24 hrs (130 +/- 17; p<0.05)). Brain SDF1 A levels were significantly elevated at both 4 hrs and 24 hrs (113 +/- 7 pg/ml and 112 +/- 10 pg/ml, respectively; p<0.05 versus sham 76 +/- 11 pg/ml). Following administration of an SDF1-A antibody, Lin-/Sca1+ cells failed to mobilize to peripheral blood following stroke, despite continued up regulation in bone marrow (stroke bone marrow cell count: 536 +/- 65, blood cell count: 127 +/- 24; p<0.05 versus placebo). Exogenously administered Lin-/Sca1+ cells resulted in a significant reduction in infarct volume: 42 +/- 5% (stroke alone), versus 21 +/ 15% (Stroke+Lin-/Sca1+ cells), and administration of an SDF1-A antibody concomitant to exogenous administration of the Lin-/Sca1+ cells prevented this reduction. Following stroke, exogenously administered Lin-/Sca1+ FISH positive cells were significantly reduced when administered concomitant to an SDF1-A antibody as compared to without SDF1-A antibody (10 +/- 4 vs 0.7 +/- 1, p<0.05). CONCLUSIONS: SDF1-A appears to play a critical role in modulating Lin-/Sca1+ cell migration to ischemic brain. PMID- 24465622 TI - Little evidence of avian or equine influenza virus infection among a cohort of Mongolian adults with animal exposures, 2010-2011. AB - Avian (AIV) and equine influenza virus (EIV) have been repeatedly shown to circulate among Mongolia's migrating birds or domestic horses. In 2009, 439 Mongolian adults, many with occupational exposure to animals, were enrolled in a prospective cohort study of zoonotic influenza transmission. Sera were drawn upon enrollment and again at 12 and 24 months. Participants were contacted monthly for 24 months and queried regarding episodes of acute influenza-like illnesses (ILI). Cohort members confirmed to have acute influenza A infections, permitted respiratory swab collections which were studied with rRT-PCR for influenza A. Serologic assays were performed against equine, avian, and human influenza viruses. Over the 2 yrs of follow-up, 100 ILI investigations in the cohort were conducted. Thirty-six ILI cases (36%) were identified as influenza A infections by rRT-PCR; none yielded evidence for AIV or EIV. Serological examination of 12 mo and 24 mo annual sera revealed 37 participants had detectable antibody titers (>=1?10) against studied viruses during the course of study follow-up: 21 against A/Equine/Mongolia/01/2008(H3N8); 4 against an avian A/Teal/Hong Kong/w3129(H6N1), 11 against an avian-like A/Hong Kong/1073/1999(H9N2), and 1 against an avian A/Migrating duck/Hong Kong/MPD268/2007(H10N4) virus. However, all such titers were <1?80 and none were statistically associated with avian or horse exposures. A number of subjects had evidence of seroconversion to zoonotic viruses, but the 4-fold titer changes were again not associated with avian or horse exposures. As elevated antibodies against seasonal influenza viruses were high during the study period, it seems likely that cross-reacting antibodies against seasonal human influenza viruses were a cause of the low-level seroreactivity against AIV or EIV. Despite the presence of AIV and EIV circulating among wild birds and horses in Mongolia, there was little evidence of AIV or EIV infection in this prospective study of Mongolians with animal exposures. PMID- 24465623 TI - Identification of mutations in the PYRIN-containing NLR genes (NLRP) in Head and Neck Squamous Cell Carcinoma. AB - Head and Neck Squamous Cell Carcinoma (HNSCC) encompasses malignancies that arise in the mucosa of the upper aerodigestive tract. Recent high throughput DNA sequencing revealed HNSCC genes mutations that contribute to several cancer cell characteristics, including dysregulation of cell proliferation and death, intracellular proinflammatory signaling, and autophagy. The PYRIN-domain containing NLR (Nucleotide-binding domain, Leucine rich Repeats - containing) proteins have recently emerged as pivotal modulators of cell death, autophagy, inflammation, and metabolism. Their close physiologic association with cancer development prompted us to determine whether mutations within the NLRP (PYRIN containing NLR) gene family were associated with HNSCC genome instability and their clinicopathologic correlations. Catastrophic mutational events underlie cancer cell genome instability and mark a point-of-no-return in cancer cell development and generation of heterogeneity. The mutation profiles of 62 patients with primary conventional type HNSCC excluding other histologic variants were analyzed. Associations were tested using Fisher's Exact test or Mann-Whitney U test. Mutations in NLRP were associated with elevated genome instability as characterized by higher mutation rates. Clinically, NLRP mutations were more frequently found in HNSCC arising in the floor of mouth (50.0%) in comparison with HNSCC at other head and neck locations (14.8%). These mutations were clustered at the leucine rich repeats region of NLRP proteins, and affected NLRP genes were mostly localized at chromosomes 11p15.4 and 19q13.42-19q13.43. Twenty novel NLRP mutations were identified in HNSCC, and mutations in this group of genes were correlated with increased cancer cell genome mutation rates, and such features could be a potential molecular biomarker of HNSCC genome instability. PMID- 24465624 TI - Levofloxacin-based first-line therapy versus standard first-line therapy for Helicobacter pylori eradication: meta-analysis of randomized controlled trials. AB - BACKGROUND: First-line levofloxacin-based treatments eradicate Helicobacter pylori with varying success. We examined the efficacy and safety of first-line levofloxacin-based treatment in comparison to standard first-line therapy for H pylori eradication. MATERIALS AND METHODS: We searched literature databases from Medline, EMBASE, and the Cochrane Register of Randomized Controlled Trials through March 2013 for randomized controlled trials comparing first-line levofloxacin and standard therapy. We included randomized controlled trials conducted only on naive H pylori infected patients in adults. A systematic review was conducted. Meta-analysis was performed with Review Manager 5.2. Treatment effect was determined by relative risk with a random or fixed model by the Mantel Haenszel method. RESULTS: Seven trials were identified with 888 patients receiving 7 days of first-line levofloxacin and 894 treated with standard therapy (Amoxicillin, Clarithromycin and proton pump inhibitor) for 7 days. The overall crude eradication rate in the Levofloxacin group was 79.05% versus 81.4% in the standard group (risk ratio 0.97; 95% CI; 0.93, 1.02). The overall dropout was 46 (5.2%) in the levofloxacin group and 52 (5.8%) for standard therapy. The dizziness was more common among group who took Levofloxacin based treatment and taste disturbance was more common among group who took standard therapy. Meta analysis of overall adverse events were similar between the two groups with a relative risk of 1.06 (95% CI 0.72, 1.57). CONCLUSION: Helicobacter pylori eradication with 7 days of Levofloxacin-based first line therapy was safe and equal compared to 7 days of standard first-line therapy. PMID- 24465625 TI - Bacillus pumilus reveals a remarkably high resistance to hydrogen peroxide provoked oxidative stress. AB - Bacillus pumilus is characterized by a higher oxidative stress resistance than other comparable industrially relevant Bacilli such as B. subtilis or B. licheniformis. In this study the response of B. pumilus to oxidative stress was investigated during a treatment with high concentrations of hydrogen peroxide at the proteome, transcriptome and metabolome level. Genes/proteins belonging to regulons, which are known to have important functions in the oxidative stress response of other organisms, were found to be upregulated, such as the Fur, Spx, SOS or CtsR regulon. Strikingly, parts of the fundamental PerR regulon responding to peroxide stress in B. subtilis are not encoded in the B. pumilus genome. Thus, B. pumilus misses the catalase KatA, the DNA-protection protein MrgA or the alkyl hydroperoxide reductase AhpCF. Data of this study suggests that the catalase KatX2 takes over the function of the missing KatA in the oxidative stress response of B. pumilus. The genome-wide expression analysis revealed an induction of bacillithiol (Cys-GlcN-malate, BSH) relevant genes. An analysis of the intracellular metabolites detected high intracellular levels of this protective metabolite, which indicates the importance of bacillithiol in the peroxide stress resistance of B. pumilus. PMID- 24465626 TI - A cross-sectional analytic study of postpartum health care service utilization in the Philippines. AB - BACKGROUND: The maternal mortality ratio in the Philippines remains high; thus, it will be difficult to achieve the Millennium Development Goals 5 by 2015. Approximately two-thirds of all maternal deaths occur during the postpartum period. Therefore, we conducted the present study to examine the current state of postpartum health care service utilization in the Philippines, and identify challenges to accessing postpartum care. METHODS: A questionnaire and knowledge test were distributed to postpartum women in the Philippines. The questionnaire collected demographical characteristics and information about their utilization of health care services during pregnancy and the postpartum period. The knowledge test consisted of 11 questions regarding 6 topics related to possible physical and mental symptoms after delivery. Sixty-four questionnaires and knowledge tests were analyzed. RESULTS: The mean time of first postpartum health care visit was 5.1 +/- 5.2 days after delivery. Postpartum utilization of health care services was significantly correlated with delivery location (P<0.01). Women who delivered at home had a lower rate of postpartum health care service utilization than women who delivered at medical facilities. The majority of participants scored low on the knowledge test. CONCLUSION: We found inadequate postpartum health care service utilization, especially for women who delivered at home. Our results also suggest that postpartum women lack knowledge about postpartum health concerns. In the Philippines, Barangay health workers may play a role in educating postpartum women regarding health care service utilization to improve their knowledge of possible concerns and their overall utilization of health care services. PMID- 24465627 TI - On the value of intra-motif dependencies of human insulator protein CTCF. AB - The binding affinity of DNA-binding proteins such as transcription factors is mainly determined by the base composition of the corresponding binding site on the DNA strand. Most proteins do not bind only a single sequence, but rather a set of sequences, which may be modeled by a sequence motif. Algorithms for de novo motif discovery differ in their promoter models, learning approaches, and other aspects, but typically use the statistically simple position weight matrix model for the motif, which assumes statistical independence among all nucleotides. However, there is no clear justification for that assumption, leading to an ongoing debate about the importance of modeling dependencies between nucleotides within binding sites. In the past, modeling statistical dependencies within binding sites has been hampered by the problem of limited data. With the rise of high-throughput technologies such as ChIP-seq, this situation has now changed, making it possible to make use of statistical dependencies effectively. In this work, we investigate the presence of statistical dependencies in binding sites of the human enhancer-blocking insulator protein CTCF by using the recently developed model class of inhomogeneous parsimonious Markov models, which is capable of modeling complex dependencies while avoiding overfitting. These findings lead to a more detailed characterization of the CTCF binding motif, which is only poorly represented by independent nucleotide frequencies at several positions, predominantly at the 3' end. PMID- 24465628 TI - Long-term exposure of mice to nucleoside analogues disrupts mitochondrial DNA maintenance in cortical neurons. AB - Nucleoside analogue reverse transcriptase inhibitor (NRTI), an integral component of highly active antiretroviral therapy (HAART), was widely used to inhibit HIV replication. Long-term exposure to NRTIs can result in mitochondrial toxicity which manifests as lipoatrophy, lactic acidosis, cardiomyopathy and myopathy, as well as polyneuropathy. But the cerebral neurotoxicity of NRTIs is still not well known partly due to the restriction of blood-brain barrier (BBB) and the complex microenvironment of the central nervous system (CNS). In this study, the Balb/c mice were administered 50 mg/kg stavudine (D4T), 100 mg/kg zidovudine (AZT), 50 mg/kg lamivudine (3TC) or 50 mg/kg didanosine (DDI) per day by intraperitoneal injection, five days per week for one or four months, and primary cortical neurons were cultured and exposed to 25 uM D4T, 50 uM AZT, 25 uM 3TC or 25 uM DDI for seven days. Then, single neuron was captured from mouse cerebral cortical tissues by laser capture microdissection. Mitochondrial DNA (mtDNA) levels of the primary cultured cortical neurons, and captured neurons or glial cells, and the tissues of brains and livers and muscles were analyzed by relative quantitative real-time PCR. The data showed that mtDNA did not lose in both NRTIs exposed cultured neurons and one month NRTIs treated mouse brains. In four months NRTIs treated mice, brain mtDNA levels remained unchanged even if the mtDNA levels of liver (except for 3TC) and muscle significantly decreased. However, mtDNA deletion was significantly higher in the captured neurons from mtDNA unchanged brains. These results suggest that long-term exposure to NRTIs can result in mtDNA deletion in mouse cortical neurons. PMID- 24465629 TI - The temporal evolution and global spread of Cauliflower mosaic virus, a plant pararetrovirus. AB - Cauliflower mosaic virus (CaMV) is a plant pararetrovirus with a double-stranded DNA genome. It is the type member of the genus Caulimovirus in the family Caulimoviridae. CaMV is transmitted by sap inoculation and in nature by aphids in a semi-persistent manner. To investigate the patterns and timescale of CaMV migration and evolution, we sequenced and analyzed the genomes of 67 isolates of CaMV collected mostly in Greece, Iran, Turkey, and Japan together with nine published sequences. We identified the open-reading frames (ORFs) in the genomes and inferred their phylogeny. After removing recombinant sequences, we estimated the substitution rates, divergence times, and phylogeographic patterns of the virus populations. We found that recombination has been a common feature of CaMV evolution, and that ORFs I-V have a different evolutionary history from ORF VI. The ORFs have evolved at rates between 1.71 and 5.81*10(-4) substitutions/site/year, similar to those of viruses with RNA or ssDNA genomes. We found four geographically confined lineages. CaMV probably spread from a single population to other parts of the world around 400-500 years ago, and is now widely distributed among Eurasian countries. Our results revealed evidence of frequent gene flow between populations in Turkey and those of its neighboring countries, with similar patterns observed for Japan and the USA. Our study represents the first report on the spatial and temporal spread of a plant pararetrovirus. PMID- 24465630 TI - Generation and characterization of functional cardiomyocytes derived from human T cell-derived induced pluripotent stem cells. AB - Induced pluripotent stem cells (iPSCs) have been proposed as novel cell sources for genetic disease models and revolutionary clinical therapies. Accordingly, human iPSC-derived cardiomyocytes are potential cell sources for cardiomyocyte transplantation therapy. We previously developed a novel generation method for human peripheral T cell-derived iPSCs (TiPSCs) that uses a minimally invasive approach to obtain patient cells. However, it remained unknown whether TiPSCs with genomic rearrangements in the T cell receptor (TCR) gene could differentiate into functional cardiomyocyte in vitro. To address this issue, we investigated the morphology, gene expression pattern, and electrophysiological properties of TiPSC-derived cardiomyocytes differentiated by floating culture. RT-PCR analysis and immunohistochemistry showed that the TiPSC-derived cardiomyocytes properly express cardiomyocyte markers and ion channels, and show the typical cardiomyocyte morphology. Multiple electrode arrays with application of ion channel inhibitors also revealed normal electrophysiological responses in the TiPSC-derived cardiomyocytes in terms of beating rate and the field potential waveform. In this report, we showed that TiPSCs successfully differentiated into cardiomyocytes with morphology, gene expression patterns, and electrophysiological features typical of native cardiomyocytes. TiPSCs-derived cardiomyocytes obtained from patients by a minimally invasive technique could therefore become disease models for understanding the mechanisms of cardiac disease and cell sources for revolutionary cardiomyocyte therapies. PMID- 24465631 TI - Sexual behavior among persons living with HIV in Uganda: implications for policy and practice. AB - INTRODUCTION: HIV epidemics are sustained and propagated by new cases of infection which result from transmission from infected persons to uninfected susceptible individuals. People living with HIV (PLHIV) play a critical role in prevention if they adopt safer sexual behaviors. This study estimated the prevalence of and factors associated with safer sexual behaviors among PLHIV seeking care from civil society organizations (CSOs). METHODS: In a cross sectional study PLHIV were interviewed about their sexual practices, use of alcohol, HIV status of their regular sexual partners, desire for more children and about their socio-demographic characteristics. We calculated the proportion of PLHIV who abstained and consistently used condoms in the previous twelve months. Independent associations between safer sex and other variables were estimated using adjusted prevalence ratios (aPR) and their 95% confidence intervals (CI). RESULTS: Of the 939 PLHIV, 54% (508) were either abstaining or using condoms consistently and 291 (31%) desired more children. The prevalence of consistent condom use among the sexually active was 41.3% (300/731). Consistent condom use was higher among PLHIV who: didn't use alcohol (aPR 1.30, CI 1.03 1.63); were educated about re-infection with a new strain of HIV (aPR 1.84, CI 1.08-3.12) and had regular sexual partner who was HIV negative (aPR 1.29, CI 1.05 1.57). Prevalence of abstinence was 22.2% (208/939). Abstinence increased with age from 9.4% among PLHIV <25 years to 40.5% among those >50 years. Abstinence was extremely low (2.5%) among PLHIV who were married. CONCLUSIONS: Effective interventions that reduce alcohol consumption among PLHIV are needed to avert HIV transmission, prevent acquisition of new HIV strains and STIs. In addition, strategies are needed to address needs of PLHIV who desire more children. PMID- 24465632 TI - Multiple pigment cell types contribute to the black, blue, and orange ornaments of male guppies (Poecilia reticulata). AB - The fitness of male guppies (Poecilia reticulata) highly depends on the size and number of their black, blue, and orange ornaments. Recently, progress has been made regarding the genetic mechanisms underlying male guppy pigment pattern formation, but we still know little about the pigment cell organization within these ornaments. Here, we investigate the pigment cell distribution within the black, blue, and orange trunk spots and selected fin color patterns of guppy males from three genetically divergent strains using transmission electron microscopy. We identified three types of pigment cells and found that at least two of these contribute to each color trait. Further, two pigment cell layers, one in the dermis and the other in the hypodermis, contribute to each trunk spot. The pigment cell organization within the black and orange trunk spots was similar between strains. The presence of iridophores in each of the investigated color traits is consistent with a key role for this pigment cell type in guppy color pattern formation. PMID- 24465633 TI - RNA polymerase III transcriptomes in human embryonic stem cells and induced pluripotent stem cells, and relationships with pluripotency transcription factors. AB - Recent genomic approaches have revealed that the repertoire of RNA Pol III transcribed genes varies in different human cell types, and that this variation is likely determined by a combination of the chromatin landscape, cell-specific DNA-binding transcription factors, and collaboration with RNA Pol II. Although much is known about this regulation in differentiated human cells, there is presently little understanding of this aspect of the Pol III system in human ES cells. Here, we determine the occupancy profiles of Pol III components in human H1 ES cells, and also induced pluripotent cells, and compare to known profiles of chromatin, transcription factors, and RNA expression. We find a relatively large fraction of the Pol III repertoire occupied in human embryonic stem cells (hESCs) and induced pluripotent stem cells (iPSCs). In ES cells we find clear correlations between Pol III occupancy and active chromatin. Interestingly, we find a highly significant fraction of Pol III-occupied genes with adjacent binding events by pluripotency factors in ES cells, especially NANOG. Notably, in human ES cells we find H3K27me3 adjacent to but not overlapping many active Pol III loci. We observe in all such cases, a peak of H3K4me3 and/or RNA Pol II, between the H3K27me3 and Pol III binding peaks, suggesting that H3K4me3 and Pol II activity may "insulate" Pol III from neighboring repressive H3K27me3. Further, we find iPSCs have a larger Pol III repertoire than their precursors. Finally, the active Pol III genome in iPSCs is not completely reprogrammed to a hESC like state and partially retains the transcriptional repertoire of the precursor. Together, our correlative results are consistent with Pol III binding and activity in human ES cells being enabled by active/permissive chromatin that is shaped in part by the pluripotency network of transcription factors and RNA Pol II activity. PMID- 24465634 TI - Genome-wide transcriptome and antioxidant analyses on gamma-irradiated phases of deinococcus radiodurans R1. AB - Adaptation of D. radiodurans cells to extreme irradiation environments requires dynamic interactions between gene expression and metabolic regulatory networks, but studies typically address only a single layer of regulation during the recovery period after irradiation. Dynamic transcriptome analysis of D. radiodurans cells using strand-specific RNA sequencing (ssRNA-seq), combined with LC-MS based metabolite analysis, allowed an estimate of the immediate expression pattern of genes and antioxidants in response to irradiation. Transcriptome dynamics were examined in cells by ssRNA-seq covering its predicted genes. Of the 144 non-coding RNAs that were annotated, 49 of these were transfer RNAs and 95 were putative novel antisense RNAs. Genes differentially expressed during irradiation and recovery included those involved in DNA repair, degradation of damaged proteins and tricarboxylic acid (TCA) cycle metabolism. The knockout mutant crtB (phytoene synthase gene) was unable to produce carotenoids, and exhibited a decreased survival rate after irradiation, suggesting a role for these pigments in radiation resistance. Network components identified in this study, including repair and metabolic genes and antioxidants, provided new insights into the complex mechanism of radiation resistance in D. radiodurans. PMID- 24465635 TI - Water-pipe smoking and albuminuria: new dog with old tricks. AB - Water-pipe (WP) smoking is on rise worldwide for the past few years, particularly among younger individuals. Growing evidence indicates that WP smoking is as harmful as cigarette smoking. To date, most of the research has focused on acute health effects of WP smoking, and evidence remains limited when it comes to chronic health effects in relation to long-term WP smoking. Therefore, the aim of this study was to examine the association between WP smoking and albuminuria in apparently healthy individuals. This analysis was conducted on data of a population-based cross-sectional study--the Urban Rural Chronic Diseases Study (URCDS). The study sample was recruited from three sites in Pakistan. Trained nurses carried out individual interviews and obtained the information on demographics, lifestyle factors, and past and current medical history. Measurements of complete blood count, lipid profile, fasting glucose level, and 24-hour albuminuria were also made by using blood and urine samples. Albumin excretion was classified into three categories using standard cut-offs: normal excretion, high-normal excretion and microalbuminuria. Multiple logistic regression models were used to examine the relationship between WP smoking and albuminuria. The final analysis included data from 1,626 health individuals, of which 829 (51.0%) were males and 797 (49.0%) females. Of 1,626 individuals, 267 (16.4%) were current WP smokers and 1,359 (83.6%) were non-WP smokers. WP smoking was significantly associated with high-normal albuminuria (OR = 2.33, 95% CI 1.68-3.22, p-value <0.001) and microalbuminuria (OR = 1.75, 95% CI 1.18-2.58, p value 0.005) after adjustment for age, sex, BMI, social class, hypertension, and diabetes mellitus. WP smoking was significantly associated with high-normal albuminuria and microalbuminuria when analysis was stratified on hypertension and diabetes mellitus categories. WP smoking has a strong association with albuminuria in apparently healthy individuals. More research is warranted to evaluate the temporality of this association between WP smoking and albuminuria. PMID- 24465636 TI - Detecting changes in retinal function: Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement (ANSWERS). AB - Visual fields measured with standard automated perimetry are a benchmark test for determining retinal function in ocular pathologies such as glaucoma. Their monitoring over time is crucial in detecting change in disease course and, therefore, in prompting clinical intervention and defining endpoints in clinical trials of new therapies. However, conventional change detection methods do not take into account non-stationary measurement variability or spatial correlation present in these measures. An inferential statistical model, denoted 'Analysis with Non-Stationary Weibull Error Regression and Spatial enhancement' (ANSWERS), was proposed. In contrast to commonly used ordinary linear regression models, which assume normally distributed errors, ANSWERS incorporates non-stationary variability modelled as a mixture of Weibull distributions. Spatial correlation of measurements was also included into the model using a Bayesian framework. It was evaluated using a large dataset of visual field measurements acquired from electronic health records, and was compared with other widely used methods for detecting deterioration in retinal function. ANSWERS was able to detect deterioration significantly earlier than conventional methods, at matched false positive rates. Statistical sensitivity in detecting deterioration was also significantly better, especially in short time series. Furthermore, the spatial correlation utilised in ANSWERS was shown to improve the ability to detect deterioration, compared to equivalent models without spatial correlation, especially in short follow-up series. ANSWERS is a new efficient method for detecting changes in retinal function. It allows for better detection of change, more efficient endpoints and can potentially shorten the time in clinical trials for new therapies. PMID- 24465637 TI - Alarming proportions of methicillin-resistant Staphylococcus aureus (MRSA) in wound samples from companion animals, Germany 2010-2012. AB - Staphylococcus (S.) aureus is an important cause of wound infections in companion animals, and infections with methicillin-resistant S. aureus (MRSA) are of particular concern due to limited treatment options and their zoonotic potential. However, comparable epidemiological data on MRSA infections in dogs, cats and horses is scarce, also limiting the knowledge about possible links to MRSA isolates from human populations. To gain more knowledge about the occurrence and genotypic variation of MRSA among wound swabs of companion animal origin in Germany we performed a survey (2010-2012) including 5,229 samples from 1,170 veterinary practices. S. aureus was identified in 201 (5.8%) canine, 140 (12.2%) feline and 138 (22.8%) equine swabs from a total of 3,479 canine, 1,146 feline and 604 equine wounds, respectively. High MRSA rates were identified with 62.7%, 46.4% and 41.3% in S. aureus of canine, feline and equine origin, respectively. Further genotyping including spa typing and multilocus sequence typing (MLST) revealed a comparable distribution of spa types among canine and feline MRSA with CC22 (47.6%; 49.2%) and CC5 (30.2%; 29.2%) as predominant lineages followed by CC398 (13.5%; 7.7%) and CC8 (4.0%; 9.2%). In contrast, the majority of equine MRSA belonged to CC398 (87.7%). Our data highlight the importance of S. aureus and MRSA as a cause of wound infections, particularly in cats and horses in Germany. While "human-associated" MRSA lineages were most common in dogs and cats, a remarkable number of CC398-MRSA was detected in horses, indicating a replacement of CC8-MRSA as the predominant lineage within horses in Germany. These data enforce further longitudinal epidemiological approaches to examine the diversity and temporal relatedness of MRSA populations in humans and animals to assess probable sources of MRSA infections. This would enable a sound risk assessment and establishment of intervention strategies to limit the additional spread of MRSA. PMID- 24465638 TI - Does an eye-hand coordination test have added value as part of talent identification in table tennis? A validity and reproducibility study. AB - This study investigated the added value, i.e. discriminative and concurrent validity and reproducibility, of an eye-hand coordination test relevant to table tennis as part of talent identification. Forty-three table tennis players (7-12 years) from national (n = 13), regional (n = 11) and local training centres (n = 19) participated. During the eye-hand coordination test, children needed to throw a ball against a vertical positioned table tennis table with one hand and to catch the ball correctly with the other hand as frequently as possible in 30 seconds. Four different test versions were assessed varying the distance to the table (1 or 2 meter) and using a tennis or table tennis ball. 'Within session' reproducibility was estimated for the two attempts of the initial tests and ten youngsters were retested after 4 weeks to estimate 'between sessions' reproducibility. Validity analyses using age as covariate showed that players from the national and regional centres scored significantly higher than players from the local centre in all test versions (p<0.05). The tests at 1 meter demonstrated better discriminative ability than those at 2 meter. While all tests but one had a positive significant association with competition outcome, which were corrected for age influences, the version with a table tennis ball at 1 meter showed the highest association (r = 0.54; p = 0.001). Differences between the first and second attempts were comparable for all test versions (between -8 and +7 repetitions) with ICC's ranging from 0.72 to 0.87. The smallest differences were found for the test with a table tennis ball at 1 meter (between 3 and +3 repetitions). Best test version as part of talent identification appears to be the version with a table tennis ball at 1 meter regarding the psychometric characteristics evaluated. Longitudinal studies are necessary to evaluate the predictive value of this test. PMID- 24465639 TI - Detection of colorectal serrated polyps by stool DNA testing: comparison with fecal immunochemical testing for occult blood (FIT). AB - OBJECTIVES: Precursors to 1/3 of colorectal cancer (CRC), serrated polyps have been under-detected by screening due to their inconspicuous, non-hemorrhagic, and proximal nature. A new multi-target stool DNA test (multi-target sDNA) shows high sensitivity for both CRC and advanced adenomas. Screen detection of serrated polyps by this approach requires further validation. We sought to assess and compare noninvasive detection of sessile serrated polyps (SSP) >= 1 cm by sDNA and an occult blood fecal immunochemical test (FIT). METHODS: In a blinded prospective study, a single stool sample used for both tests was collected from 456 asymptomatic adults prior to screening or surveillance colonoscopy (criterion standard). All 29 patients with SSP >= 1 cm were included as cases and all 232 with no neoplastic findings as controls. Buffered stool samples were processed and frozen on receipt; Exact Sciences performed sDNA in batches using optimized analytical methods. The sDNA multi-marker panel targets methylated BMP3 (mBMP3) and NDRG4, mutant KRAS, beta-actin, and hemoglobin. FIT (Polymedco OC-FIT Check) was performed in separate lab <= 2 days post defecation and evaluated at cutoffs of 50 (FIT-50) and 100 ng/ml (FIT-100). RESULTS: MEDIAN AGES: cases 61 (range 57 77), controls 62 (52-70), p = NS. Women comprised 59% and 51%, p = NS, respectively. SSP median size was 1.2 cm (1-3 cm), 93% were proximal, and 64% had synchronous diminutive polyps. Among multi-target sDNA markers, mBMP3 proved highly discriminant for detection of SSP >= 1 cm (AUC = 0.87, p<0.00001); other DNA markers provided no incremental sensitivity. Hemoglobin alone showed no discrimination (AUC = 0.50, p = NS). At matched specificities, detection of SSP >= 1 cm by stool mBMP3 was significantly greater than by FIT-50 (66% vs 10%, p = 0.0003) or FIT-100 (63% vs 0%, p<0.0001). CONCLUSIONS: In a screening and surveillance setting, SSP >= 1 cm can be detected noninvasively by stool assay of exfoliated DNA markers, especially mBMP3. FIT appears to have no value in SSP detection. PMID- 24465640 TI - Geographical constraints are stronger than invasion patterns for European urban floras. AB - Understanding the mechanisms that affect invasion success of alien species is an important prerequisite for the effective management of present and future aliens. To gain insight into this matter we asked the following questions: Are the geographical patterns of species distributions in urban floras different for native compared with alien plant species? Does the introduction of alien species contribute to the homogenization of urban floras? We used a Mantel test on Jaccard dissimilarity matrices of 30 urban floras across the British Isles, Italy and central Europe to compare the spatial distribution of native species with four classes of alien species: archaeophytes, all neophytes, non-invasive neophytes, and invasive neophytes. Archaeophytes and neophytes are species that were introduced into Europe before and after 1500 AD, respectively. To analyze the homogenizing effect of alien species on the native urban floras, we tested for differences in the average dissimilarity of individual cities from their group centroid in ordination space. Our results show that the compositional patterns of native and alien species seem to respond to the same environmental drivers, such that all four classes of alien species were significantly related to native species across urban floras. In this framework, alien species may have an impact on biogeographic patterns of urban floras in ways that reflect their history of introduction and expansion: archaeophytes and invasive neophytes tended to homogenize, while non-invasive neophytes tended to differentiate urban floras. PMID- 24465641 TI - Differential immune response associated to malaria outcome is detectable in peripheral blood following Plasmodium yoelii infection in mice. AB - Malaria infection in humans elicits a wide range of immune responses that can be detected in peripheral blood, but we lack detailed long-term follow-up data on the primary and subsequent infections that lead to naturally acquired immunity. Studies on antimalarial immune responses in mice have been based on models yielding homogenous infection profiles. Here, we present a mouse model in which a heterogeneous course of Plasmodium yoelii lethal malaria infection is produced in a non-congenic ICR strain to allow comparison among different immunological and clinical outcomes. Three different disease courses were observed ranging from a fatal outcome, either early or late, to a self-resolved infection that conferred long-term immunity against re-infection. Qualitative and quantitative changes produced in leukocyte subpopulations and cytokine profiles detected in peripheral blood during the first week of infection revealed that monocytes, dendritic cells and immature B cells were the main cell subsets present in highly-parasitized mice dying in the first week after infection. Besides, CD4(+)CD25(high) T cells expanded at an earlier time point in early deceased mice than in surviving mice and expressed higher levels of intracellular Foxp3 protein. In contrast, survivors showed a limited increase of cytokines release and stable circulating innate cells. From the second week of infection, mice that would die or survive showed similar immune profiles, although CD4(+)CD25(high) T cells number increased earlier in mice with the worst prognosis. In surviving mice the expansion of activated circulating T cell and switched-class B cells with a long term protective humoral response from the second infection week is remarkable. Our results demonstrate that the follow-up studies of immunological blood parameters during a malaria infection can offer information about the course of the pathological process and the immune response. PMID- 24465642 TI - Chronic proliferative dermatitis in Sharpin null mice: development of an autoinflammatory disease in the absence of B and T lymphocytes and IL4/IL13 signaling. AB - SHARPIN is a key regulator of NFKB and integrin signaling. Mice lacking Sharpin develop a phenotype known as chronic proliferative dermatitis (CPDM), typified by progressive epidermal hyperplasia, apoptosis of keratinocytes, cutaneous and systemic eosinophilic inflammation, and hypoplasia of secondary lymphoid organs. Rag1(-/-) mice, which lack mature B and T cells, were crossed with Sharpin(-/-) mice to examine the role of lymphocytes in CDPM. Although inflammation in the lungs, liver, and joints was reduced in these double mutant mice, dermatitis was not reduced in the absence of functional lymphocytes, suggesting that lymphocytes are not primary drivers of the inflammation in the skin. Type 2 cytokine expression is increased in CPDM. In an attempt to reduce this aspect of the phenotype, Il4ra(-/-) mice, unresponsive to both IL4 and IL13, were crossed with Sharpin(-/-) mice. Double homozygous Sharpin(-/-) , Il4ra(-/-) mice developed an exacerbated granulocytic dermatitis, acute system inflammation, as well as hepatic necrosis and mineralization. High expression of CHI3L4, normally seen in CPDM skin, was abolished in Sharpin(-/-) , Il4ra(-/-) double mutant mice indicating the crucial role of IL4 and IL13 in the expression of this protein. Cutaneous eosinophilia persisted in Sharpin(-/-) , Il4ra(-/-) mice, although expression of Il5 mRNA was reduced and the expression of Ccl11 and Ccl24 was completely abolished. TSLP and IL33 were both increased in the skin of Sharpin(-/ ) mice and this was maintained in Sharpin(-/-) , Il4ra(-/-) mice suggesting a role for TSLP and IL33 in the eosinophilic dermatitis in SHARPIN-deficient mice. These studies indicate that cutaneous inflammation in SHARPIN-deficient mice is autoinflammatory in nature developing independently of B and T lymphocytes, while the systemic inflammation seen in CPDM has a strong lymphocyte-dependent component. Both the cutaneous and systemic inflammation is enhanced by loss of IL4 and IL13 signaling indicating that these cytokines normally play an anti inflammatory role in SHARPIN-deficient mice. PMID- 24465643 TI - Prediction of monomer isomery in Florine: a workflow dedicated to nonribosomal peptide discovery. AB - Nonribosomal peptides represent a large variety of natural active compounds produced by microorganisms. Due to their specific biosynthesis pathway through large assembly lines called NonRibosomal Peptide Synthetases (NRPSs), they often display complex structures with cycles and branches. Moreover they often contain non proteogenic or modified monomers, such as the D-monomers produced by epimerization. We investigate here some sequence specificities of the condensation (C) and epimerization (E) domains of NRPS that can be used to predict the possible isomeric state (D or L) of each monomer in a putative peptide. We show that C- and E- domains can be divided into 2 sub-regions called Up-Seq and Down-Seq. The Up-Seq region corresponds to an InterPro domain (IPR001242) and is shared by C- and E-domains. The Down-Seq region is specific to the enzymatic activity of the domain. Amino-acid signatures (represented as sequence logos) previously described for complete C-and E-domains have been restricted to the Down-Seq region and amplified thanks to additional sequences. Moreover a new Down-Seq signature has been found for Ct-domains found in fungi and responsible for terminal cyclization of the peptides. The identification of these signatures has been included in a workflow named Florine, aimed to predict nonribosomal peptides from NRPS sequence analyses. In some cases, the prediction of isomery is guided by genus-specific rules. Florine was used on a Pseudomonas genome to allow the determination of the type of pyoverdin produced, the update of syringafactin structure and the identification of novel putative products. PMID- 24465644 TI - Assessing fishing and marine biodiversity changes using fishers' perceptions: the Spanish Mediterranean and Gulf of Cadiz case study. AB - BACKGROUND: The expansion of fishing activities has intensively transformed marine ecosystems worldwide. However, available time series do not frequently cover historical periods. METHODOLOGY: Fishers' perceptions were used to complement data and characterise changes in fishing activity and exploited ecosystems in the Spanish Mediterranean Sea and Gulf of Cadiz. Fishers' interviews were conducted in 27 fishing harbours of the area, and included 64 fishers from ages between 20 to >70 years old to capture the experiences and memories of various generations. Results are discussed in comparison with available independent information using stock assessments and international convention lists. PRINCIPAL FINDINGS: According to fishers, fishing activity substantially evolved in the area with time, expanding towards deeper grounds and towards areas more distant from the coast. The maximum amount of catch ever caught and the weight of the largest species ever captured inversely declined with time. Fishers (70%) cited specific fishing grounds where depletion occurred. They documented ecological changes of marine biodiversity during the last half of the century: 94% reported the decline of commercially important fish and invertebrates and 61% listed species that could have been extirpated, with frequent mentions to cartilaginous fish. Declines and extirpations were in line with available quantitative evaluations from stock assessments and international conventions, and were likely linked to fishing impacts. Conversely, half of interviewed fishers claimed that several species had proliferated, such as cephalopods, jellyfish, and small-sized fish. These changes were likely related to trophic cascades due to fishing and due to climate change effects. The species composition of depletions, local extinctions and proliferations showed differences by region suggesting that regional dynamics are important when analysing biodiversity changes. CONCLUSIONS/SIGNIFICANCE: Using fishers' perceptions, fishing and ecological changes in the study area were documented. The recovery of local ecological knowledge provides valuable information complementing quantitative monitoring and evaluation surveys. PMID- 24465645 TI - Antenatal glucocorticoid treatment affects hippocampal development in mice. AB - Synthetic glucocorticoids are administered to pregnant women at risk for preterm delivery, to enhance fetal lung maturation. The benefit of this treatment is well established, however caution is necessary because of possible unwanted side effects on development of different organ systems, including the brain. Actions of glucocorticoids are mediated by corticosteroid receptors, which are highly expressed in the hippocampus, a brain structure involved in cognitive functions. Therefore, we analyzed the effects of a single antenatal dexamethasone treatment on the development of the mouse hippocampus. A clinically relevant dose of dexamethasone (0.4 mg/kg) was administered to pregnant mice at embryonic day 15.5 and the hippocampus was analyzed from embryonic day 16 until adulthood. We investigated the effects of dexamethasone treatment on anatomical changes, apoptosis and proliferation in the hippocampus, hippocampal volume and on total body weight. Our results show that dexamethasone treatment reduced body weight and hippocampal volume transiently during development, but these effects were no longer detected at adulthood. Dexamethasone treatment increased the number of apoptotic cells in the hippocampus until birth, but postnatally no effects of dexamethasone treatment on apoptosis were found. During the phase with increased apoptosis, dexamethasone treatment reduced the number of proliferating cells in the subgranular zone of the dentate gyrus. The number of proliferative cells was increased at postnatal day 5 and 10, but was decreased again at the adult stage. This latter long-term and negative effect of antenatal dexamethasone treatment on the number of proliferative cells in the hippocampus may have important implications for hippocampal network function. PMID- 24465646 TI - Effect of mixed transplantation of autologous and allogeneic microskin grafts on wound healing in a rat model of acute skin defect. AB - The treatment of extensive thermal injuries with insufficient autologous skin remains a great challenge to burn surgeons. In this study, we investigated the influence of the ratio of autologous and allogeneic tissue in mixed microskin grafts on wound healing in order to develop an effective method for using limited donor skin to cover a large open wound. Four different mixtures were tested: autologous microskin at an area expansion ratio of 10?1 with allogeneic microskin at an area expansion ratio of 10?1 or 10?3 and autologous microskin at an expansion ratio of 20?1 with allogeneic microskin at an expansion ratio of 20?3 or 20?6. Wound healing, wound contraction, and integrin beta1 expression were measured. Mixed microskin grafting facilitated wound healing substantially. The mixture of autologous microskin at an expansion ratio of 10?1 with the same amount of allogeneic microskin achieved the most satisfactory wound healing among the 4 tested mixtures. Histological examination revealed the presence of obviously thickened epidermis and ectopic integrin beta1 expression. Keratinocytes expressing integrin beta1 were scattered in the suprabasal layer. Higher levels of integrin beta1 expression were associated with faster wound healing, implying that ectopic expression of integrin beta1 in keratinocytes may play a pivotal role in wound healing. In conclusion, this study proves that this new skin grafting technique may improve wound healing. PMID- 24465647 TI - Let my people go (home) to Spain: a genealogical model of Jewish identities since 1492. AB - The Spanish government recently announced an official fast-track path to citizenship for any individual who is Jewish and whose ancestors were expelled from Spain during the inquisition-related dislocation of Spanish Jews in 1492. It would seem that this policy targets a small subset of the global Jewish population, that is, restricted to individuals who retain cultural practices associated with ancestral origins in Spain. However, the central contribution of this manuscript is to demonstrate how and why the policy is far more likely to apply to a very large fraction (i.e., the vast majority) of Jews. This claim is supported using a series of genealogical models that include transmissible "identities" and preferential intra-group mating. Model analysis reveals that even when intra-group mating is strong and even if only a small subset of a present-day population retains cultural practices typically associated with that of an ancestral group, it is highly likely that nearly all members of that population have direct genealogical links to that ancestral group, given sufficient number of generations have elapsed. The basis for this conclusion is that not having a link to an ancestral group must be a property of all of an individual's ancestors, the probability of which declines (nearly) superexponentially with each successive generation. These findings highlight unexpected incongruities induced by genealogical dynamics between present-day and ancestral identities. PMID- 24465648 TI - Perspective-taking increases willingness to engage in intergroup contact. AB - The current research explored whether perspective-taking increases willingness to engage in contact with stereotyped outgroup members. Across three studies, we find that perspective-taking increases willingness to engage in contact with negatively-stereotyped targets. In Study 1, perspective-takers sat closer to, whereas stereotype suppressors sat further from, a hooligan compared to control participants. In Study 2, individual differences in perspective-taking tendencies predicted individuals' willingness to engage in contact with a hooligan, having effects above and beyond those of empathic concern. Finally, Study 3 demonstrated that perspective-taking's effects on intergroup contact extend to the target's group (i.e., another homeless man), but not to other outgroups (i.e., a man of African descent). Consistent with other perspective-taking research, our findings show that perspective-taking facilitates the creation of social bonds by increasing contact with stereotyped outgroup members. PMID- 24465649 TI - Genomic data and disease forecasting: application to type 2 diabetes (T2D). AB - A general approach is presented for the extraction of a classifier of disease risk that is latent in large scale disease/control databases. Novel features are the following: (1) a data reorganization into a regularized standard form that emphasizes individual alleles instead of the single nucleotide polymorphism (Snp) allele pair to which they belong; (2) from this a procedure that significantly enhances the discovery of high value genomic loci; (3) an investigative analysis based on the hypothesis that disease represents a very small signal (small signal to-noise) that is latent in the data. The resulting analyses applied to the FUSION T2D database leads to the polling of thousands of genomic loci to classify disease. This large genomic kernel of loci is shared by non-diabetics at nearly the same high level; but a small well defined separation exists and it is speculated that this might be due to unconventional disease mechanisms. Another analysis demonstrates that the FUSION database size limits its disease predictability, and only one third of the resulting classifier loci are estimated to relate to T2D. The remainder is associated with hidden features that might contrast the disease and control populations and that more data would eliminate. PMID- 24465650 TI - Pch2 prevents Mec1/Tel1-mediated Hop1 phosphorylation occurring independently of Red1 in budding yeast meiosis. AB - A prominent feature of meiosis in most sexually reproducing organisms is interhomolog recombination whereby a significant fraction of the programmed meiotic double-strand breaks are repaired using intact homologous non-sister chromatids rather than sister chromatids. Budding yeast DNA damage checkpoint kinases Mec1 and Tel1 act together with the axial element protein Red1 to promote interhomolog recombination by phosphorylating another axial element protein Hop1. Mec1 and Tel1 also phosphorylate gammaH2A and the synaptonemal complex protein Zip1 independently of Red1 to facilitate premeiotic DNA replication and to destabilize homology-independent centromere pairing, respectively. It has been unclear why Hop1 phosphorylation is Red1-dependent. Here, we report that the pachytene checkpoint protein 2 (Pch2) specifically prevents Red1-independent Hop1 phosphorylation. Our findings reveal a new function for Pch2 in linking two axial element proteins Red1 and Hop1 thus coordinating their effects in meiotic recombination and the checkpoint network. PMID- 24465651 TI - No association of cryptococcal antigenemia with poor outcomes among antiretroviral therapy-experienced HIV-infected patients in Addis Ababa, Ethiopia. AB - INTRODUCTION: There are limited data on clinical outcomes of ART-experienced patients with cryptococcal antigenemia. We assessed clinical outcomes of a predominantly asymptomatic, ART-experienced cohort of HIV+ patients previously found to have a high (8.4%) prevalence of cryptococcal antigenemia. METHODS: The study took place at All Africa Leprosy, Tuberculosis and Rehabilitative Training Centre and Black Lion Hospital HIV Clinics in Addis Ababa, Ethiopia. A retrospective study design was used to perform 12-month follow-up of 367 mostly asymptomatic HIV-infected patients (CD4<200 cells/ul) with high levels of antiretroviral therapy use (74%) who were previously screened for cryptococcal antigenemia. Medical chart abstraction was performed approximately one year after initial screening to obtain data on clinic visit history, ART use, CD4 count, opportunistic infections, and patient outcome. We evaluated the association of cryptococcal antigenemia and a composite poor outcome of death and loss to follow up using logistic regression. RESULTS: Overall, 323 (88%) patients were alive, 8 (2%) dead, and 36 (10%) lost to follow-up. Among the 31 patients with a positive cryptococcal antigen test (titers >=1?8) at baseline, 28 were alive (all titers <=1?512), 1 dead and 2 lost to follow-up (titers >=1?1024). In multivariate analysis, cryptococcal antigenemia was not predictive of a poor outcome (aOR = 1.3, 95% CI 0.3-4.8). A baseline CD4 count <100 cells/ul was associated with an increased risk of a poor outcome (aOR 3.0, 95% CI 1.4-6.7) while an increasing CD4 count (aOR 0.1, 95% CI 0.1-0.3) and receiving antiretroviral therapy at last follow-up visit (aOR 0.1, 95% CI 0.02-0.2) were associated with a reduced risk of a poor outcome. CONCLUSIONS: Unlike prior ART-naive cohorts, we found that among persons receiving ART and with CD4 counts <200 cells/ul, asymptomatic cryptococcal antigenemia was not predictive of a poor outcome. PMID- 24465652 TI - Blood vessels pattern heparan sulfate gradients between their apical and basolateral aspects. AB - A hallmark of immune cell trafficking is directional guidance via gradients of soluble or surface bound chemokines. Vascular endothelial cells produce, transport and deposit either their own chemokines or chemokines produced by the underlying stroma. Endothelial heparan sulfate (HS) was suggested to be a critical scaffold for these chemokine pools, but it is unclear how steep chemokine gradients are sustained between the lumenal and ablumenal aspects of blood vessels. Addressing this question by semi-quantitative immunostaining of HS moieties around blood vessels with a pan anti-HS IgM mAb, we found a striking HS enrichment in the basal lamina of resting and inflamed post capillary skin venules, as well as in high endothelial venules (HEVs) of lymph nodes. Staining of skin vessels with a glycocalyx probe further suggested that their lumenal glycocalyx contains much lower HS density than their basolateral extracellular matrix (ECM). This polarized HS pattern was observed also in isolated resting and inflamed microvascular dermal cells. Notably, progressive skin inflammation resulted in massive ECM deposition and in further HS enrichment around skin post capillary venules and their associated pericytes. Inflammation-dependent HS enrichment was not compromised in mice deficient in the main HS degrading enzyme, heparanase. Our results suggest that the blood vasculature patterns steep gradients of HS scaffolds between their lumenal and basolateral endothelial aspects, and that inflammatory processes can further enrich the HS content nearby inflamed vessels. We propose that chemokine gradients between the lumenal and ablumenal sides of vessels could be favored by these sharp HS scaffold gradients. PMID- 24465653 TI - An eye tracking investigation of developmental change in bottom-up attention orienting to faces in cluttered natural scenes. AB - This study examined the contribution of visual salience to bottom-up attention orienting to faces in cluttered natural scenes across development. We eye tracked participants 4 months to 24 years of age as they freely viewed 16 natural scenes, all of which had faces in them. In half, the face was also the winner-take-all salient area in the display as determined by the MATLAB SaliencyToolbox. In the other half, a random location was the winner-take-all salient area in the display and the face was visually non-salient. We found that proportion of attended faces, in the first second of scene viewing, improved after the first year. Visually salient faces attracted bottom-up attention orienting more than non salient faces reliably and robustly only after infancy. Preliminary data indicate that this shift to use of visual salience to guide bottom-up attention orienting after infancy may be a function of stabilization of visual skills. Moreover, sociodemographic factors including number of siblings in the home and family income were agents of developmental change in orienting to faces in cluttered natural scenes in infancy. PMID- 24465654 TI - A quinoxaline derivative as a potent chemotherapeutic agent, alone or in combination with benznidazole, against Trypanosoma cruzi. AB - BACKGROUND: Chagas' disease is a condition caused by the protozoan Trypanosoma cruzi that affects millions of people, mainly in Latin America where it is considered endemic. The chemotherapy for Chagas disease remains a problem; the standard treatment currently relies on a single drug, benznidazole, which unfortunately induces several side effects and it is not successful in the cure of most of the chronic patients. In order to improve the drug armamentarium against Chagas' disease, in the present study we describe the synthesis of the compound 3-chloro-7-methoxy-2-(methylsulfonyl) quinoxaline (quinoxaline 4) and its activity, alone or in combination with benznidazole, against Trypanosoma cruzi in vitro. METHODOLOGY/PRINCIPAL FINDINGS: Quinoxaline 4 was found to be strongly active against Trypanosoma cruzi Y strain and more effective against the proliferative forms. The cytotoxicity against LLCMK2 cells provided selective indices above one for all of the parasite forms. The drug induced very low hemolysis, but its anti-protozoan activity was partially inhibited when mouse blood was added in the experiment against trypomastigotes, an effect that was specifically related to blood cells. A synergistic effect between quinoxaline 4 and benznidazole was observed against epimastigotes and trypomastigotes, accompanied by an antagonistic interaction against LLCMK2 cells. Quinoxaline 4 induced several ultrastructural alterations, including formations of vesicular bodies, profiles of reticulum endoplasmic surrounding organelles and disorganization of Golgi complex. These alterations were also companied by cell volume reduction and maintenance of cell membrane integrity of treated-parasites. CONCLUSION/SIGNIFICANCE: Our results demonstrated that quinoxaline 4, alone or in combination with benznidazole, has promising effects against all the main forms of T. cruzi. The compound at low concentrations induced several ultrastructural alterations and led the parasite to an autophagic-like cell death. Taken together these results may support the further development of a combination therapy as an alternative more effective in Chagas' disease treatment. PMID- 24465655 TI - A functional genetic variant (N521D) in natriuretic peptide receptor 3 is associated with diastolic dysfunction: the prevalence of asymptomatic ventricular dysfunction study. AB - OBJECTIVES: To evaluate the impact of a functional genetic variant in the natriuretic peptide clearance receptor, NPR3, on circulating natriuretic peptides (NPs) and myocardial structure and function in the general community. BACKGROUND: NPR3 plays an important role in the clearance of NPs and through direct signaling mechanisms modulates smooth muscle cell function and cardiac fibroblast proliferation. A NPR3 nonsynonymous single nucleotide polymorphism (SNP) rs2270915, resulting in a N521D substitution in the intracellular catalytic domain that interacts with Gi could affect receptor function. Whether this SNP is associated with alterations in NPs levels and altered cardiac structure and function is unknown. METHODS: DNA samples of 1931 randomly selected residents of Olmsted County, Minnesota were genotyped. Plasma NT-proANP1-98, ANP1-28, proBNP1 108, NT-proBNP1-76, BNP1-32 and BNP3-32 levels were measured. All subjects underwent comprehensive echocardiography. RESULTS: Genotype frequencies for rs2270915 were as follows: (A/A 60%, A/G 36%, G/G 4%). All analyses performed were for homozygotes G/G versus wild type A/A plus the heterozygotes A/G. Diastolic dysfunction was significantly more common (p = 0.007) in the homozygotes G/G (43%) than the A/A+A/G (28%) group. Multivariate regression adjusted for age, sex, body mass index and hypertension demonstrated rs2270915 to be independently associated with diastolic dysfunction (odds ratio 1.94, p = 0.03). There was no significant difference in NPs levels between the 2 groups suggesting that the clearance function of the receptor was not affected. CONCLUSIONS: A nonsynonymous NPR3 SNP is independently associated with diastolic dysfunction and this association does not appear to be related to alterations in circulating levels of natriuretic peptides. PMID- 24465656 TI - Genetic resistance to Bacillus thuringiensis alters feeding behaviour in the cabbage looper, Trichoplusia ni. AB - Evolved resistance to xenobiotics and parasites is often associated with fitness costs when the selection pressure is absent. Resistance to the widely used microbial insecticide Bacillus thuringiensis (Bt) has evolved in several insect species through the modification of insect midgut binding sites for Bt toxins, and reports of costs associated with Bt resistance are common. Studies on the costs of Bt-resistance restrict the insect to a single artificial diet or host plant. However, it is well documented that insects can self-select appropriate proportions of multiple nutritionally unbalanced foods to optimize life-history traits. Therefore, we examined whether Bt-resistant and susceptible cabbage loopers Trichoplusia ni differed in their nutrient intake and fitness costs when they were allowed to compose their own protein:carbohydrate diet. We found that Bt-resistant T. ni composed a higher ratio of protein to carbohydrate than susceptible T. ni. Bt-resistant males exhibited no fitness cost, while the fitness cost (reduced pupal weight) was present in resistant females. The absence of the fitness cost in resistant males was associated with increased carbohydrate consumption compared to females. We demonstrate a sex difference in a fitness cost and a new behavioural outcome associated with Bt resistance. PMID- 24465657 TI - Ecoinformatics reveals effects of crop rotational histories on cotton yield. AB - Crop rotation has been practiced for centuries in an effort to improve agricultural yield. However, the directions, magnitudes, and mechanisms of the yield effects of various crop rotations remain poorly understood in many systems. In order to better understand how crop rotation influences cotton yield, we used hierarchical Bayesian models to analyze a large ecoinformatics database consisting of records of commercial cotton crops grown in California's San Joaquin Valley. We identified several crops that, when grown in a field the year before a cotton crop, were associated with increased or decreased cotton yield. Furthermore, there was a negative association between the effect of the prior year's crop on June densities of the pest Lygus hesperus and the effect of the prior year's crop on cotton yield. This suggested that some crops may enhance L. hesperus densities in the surrounding agricultural landscape, because residual L. hesperus populations from the previous year cannot continuously inhabit a focal field and attack a subsequent cotton crop. In addition, we found that cotton yield declined approximately 2.4% for each additional year in which cotton was grown consecutively in a field prior to the focal cotton crop. Because L. hesperus is quite mobile, the effects of crop rotation on L. hesperus would likely not be revealed by small plot experimentation. These results provide an example of how ecoinformatics datasets, which capture the true spatial scale of commercial agriculture, can be used to enhance agricultural productivity. PMID- 24465658 TI - Characterization of a novel hemolytic activity of human IgG fractions arising from diversity in protein and oligosaccharide components. AB - Human IgG is a well-established multifunctional antigen specific immunoglobulin molecule of the adaptive immune system. However, an antigen nonspecific immunological function of human IgG has never been reported. In this study, human IgG was isolated using ammonium sulfate fractional precipitation and diethylaminoethanol (DEAE) cellulose 52 ion exchange chromatography, from which h IgG and hs-IgG fractions were purified on the basis of their differential binding to rabbit anti-shrimp hemocyanin antibody (h) and rabbit anti-shrimp hemocyanin's small subunit antibody (hs), respectively. We found that h-IgG had a higher hemolytic activity than hs-IgG against erythrocytes from humans, rabbits, mice and chickens, whereas the control IgG showed negligible activity. h-IgG could interact directly with erythrocyte membranes, and this interaction was suppressed by high molecular weight osmoprotectants, showing that it may follow a colloid osmotic mechanism. In comparative proteomics and glycomics studies, h-IgG and hs IgG yielded 20 and 5 significantly altered protein spots, respectively, on a 2-D gel. The mean carbohydrate content of h-IgG and hs-IgG was approximately 3.6- and 2-fold higher than that of IgG, respectively, and the alpha-d-mannose/alpha-d glucose content was in the order of h-IgG>hs-IgG>IgG. In this study, a novel antigen nonspecific immune property of human IgG was investigated, and the diversity in the protein constituents and glycosylation levels may have functional signficance. PMID- 24465660 TI - Dated phylogenies of the sister genera Macaranga and Mallotus (Euphorbiaceae): congruence in historical biogeographic patterns? AB - Molecular phylogenies and estimates of divergence times within the sister genera Macaranga and Mallotus were estimated using Bayesian relaxed clock analyses of two generic data sets, one per genus. Both data sets were based on different molecular markers and largely different samples. Per genus three calibration points were utilised. The basal calibration point (crown node of all taxa used) was taken from literature and used for both taxa. The other three calibrations were based on fossils of which two were used per genus. We compared patterns of dispersal and diversification in Macaranga and Mallotus using ancestral area reconstruction in RASP (S-DIVA option) and contrasted our results with biogeographical and geological records to assess accuracy of inferred age estimates. A check of the fossil calibration point showed that the Japanese fossil, used for dating the divergence of Mallotus, probably had to be attached to a lower node, the stem node of all pioneer species, but even then the divergence time was still younger than the estimated age of the fossil. The African (only used in the Macaranga data set) and New Zealand fossils (used for both genera) seemed reliably placed. Our results are in line with existing geological data and the presence of stepping stones that provided dispersal pathways from Borneo to New Guinea-Australia, from Borneo to mainland Asia and additionally at least once to Africa and Madagascar via land and back to India via Indian Ocean island chains. The two genera show congruence in dispersal patterns, which corroborate divergence time estimates, although the overall mode and tempo of dispersal and diversification differ significantly as shown by distribution patterns of extant species. PMID- 24465659 TI - Clinical oxidative stress during leprosy multidrug therapy: impact of dapsone oxidation. AB - This study aims to assess the oxidative stress in leprosy patients under multidrug therapy (MDT; dapsone, clofazimine and rifampicin), evaluating the nitric oxide (NO) concentration, catalase (CAT) and superoxide dismutase (SOD) activities, glutathione (GSH) levels, total antioxidant capacity, lipid peroxidation, and methemoglobin formation. For this, we analyzed 23 leprosy patients and 20 healthy individuals from the Amazon region, Brazil, aged between 20 and 45 years. Blood sampling enabled the evaluation of leprosy patients prior to starting multidrug therapy (called MDT 0) and until the third month of multidrug therapy (MDT 3). With regard to dapsone (DDS) plasma levels, we showed that there was no statistical difference in drug plasma levels between multibacillary (0.518+/-0.029 ug/mL) and paucibacillary (0.662+/-0.123 ug/mL) patients. The methemoglobin levels and numbers of Heinz bodies were significantly enhanced after the third MDT-supervised dose, but this treatment did not significantly change the lipid peroxidation and NO levels in these leprosy patients. In addition, CAT activity was significantly reduced in MDT-treated leprosy patients, while GSH content was increased in these patients. However, SOD and Trolox equivalent antioxidant capacity levels were similar in patients with and without treatment. These data suggest that MDT can reduce the activity of some antioxidant enzyme and influence ROS accumulation, which may induce hematological changes, such as methemoglobinemia in patients with leprosy. We also explored some redox mechanisms associated with DDS and its main oxidative metabolite DDS-NHOH and we explored the possible binding of DDS to the active site of CYP2C19 with the aid of molecular modeling software. PMID- 24465661 TI - A novel 2006 Indian outbreak strain of Chikungunya virus exhibits different pattern of infection as compared to prototype strain. AB - BACKGROUND: The recent re-emergence of Chikungunya virus (CHIKV) in India after 32 years and its worldwide epidemics with unprecedented magnitude raised a great public health concern. METHODS AND FINDINGS: In this study, a biological comparison was carried out between a novel 2006 Indian CHIKV outbreak strain, DRDE-06 and the prototype strain S-27 in mammalian cells in order to understand their differential infection pattern. Results showed that S-27 produced maximum number of progenies (2.43E+06 PFU/ml) at 20 to 24 hours post infection whereas DRDE-06 produced more than double number of progenies around 8 hours post infection in mammalian cells. Moreover, the observation of cytopathic effect, detection of viral proteins and viral proliferation assay confirmed the remarkably faster and significantly higher replication efficiency of DRDE-06. Moreover, our mutational analysis of whole genome of DRDE-06 revealed the presence of nineteen mutations as compared to S-27, whereas the analysis of 273 global isolates showed the consistent presence of fifteen out of nineteen mutations in almost all outbreak isolates. Further analysis revealed that ~46% of recent outbreak strains including DRDE-06 do not contain the E1-A226V mutation which was earlier shown to be associated with the adaptation of CHIKV in a new vector species, Aedes albopictus. CONCLUSIONS: A novel 2006 Indian CHIKV outbreak strain, DRDE-06 exhibits different pattern of infection as compared to prototype strain, S-27. This might be associated to some specific mutations observed in genome wide mutational analysis in DRDE-06 which emphasizes the need of future experimental investigation. PMID- 24465662 TI - Maternal biomarkers of endothelial dysfunction and preterm delivery. AB - BACKGROUND: Endothelial dysfunction is key to the development of atherosclerosis. Preterm delivery foreshadows later maternal cardiovascular disease (CVD), but it is not known if endothelial dysfunction also occurs. We prospectively measured circulating biomarkers of endothelial dysfunction in pregnant women with preterm or term delivery. METHODS: We conducted a case-control study nested within a large prospective epidemiological study of young, generally healthy pregnant women. Women who delivered preterm (<37 completed weeks gestation, n = 240) and controls who delivered at term (n = 439) were included. Pregnancies complicated by preeclampsia were analyzed separately. Circulating endothelial dysfunction biomarkers included soluble intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1) and soluble E-selectin (sE-selectin). RESULTS: Elevated levels of sICAM-1 and sVCAM-1 were positively associated with preterm delivery independent of usual risk factors. At entry (~16 wks), the adjusted odds ratio (AOR) was 1.73 (95% confidence interval (CI) 1.09-2.74) for the highest quartile of sICAM-1 versus the lowest quartile and for sVCAM-1 the AOR was 2.17 (95% CI 1.36-3.46). When analysis was limited to cases with a spontaneous preterm delivery, the results were unchanged. Similar results were obtained for the 3rd trimester (~30 wks). Elevated sE-selectin was increased only in preterm delivery complicated by preeclampsia; risk was increased at entry (AOR 2.32, 95% CI 1.22 4.40) and in the 3rd trimester (AOR 3.37, 95% CI 1.78-6.39). CONCLUSIONS: Impaired endothelial function as indicated by increased levels of soluble molecules commonly secreted by endothelial cells is a pathogenic precursor to CVD that is also present in women with preterm delivery. Our findings underscore the need for follow-up studies to determine if improving endothelial function prevents later CVD risk in women. PMID- 24465663 TI - Retinal nerve fiber layer thickness changes in Parkinson disease: a meta analysis. AB - BACKGROUND: Parkinson disease (PD) is a neurodegenerative process that leads to a selective loss of dopaminergic neurons, mainly in the basal ganglia of the brain. Numerous studies have analyzed the ability of optical coherence tomography (OCT) to detect retinal nerve fiber layer (RNFL) thickness abnormalities and changes in PD, but the results have not always been consistent. Therefore, we carried out a meta-analysis to evaluate the RNFL thickness measured with OCT in PD. METHODS AND FINDINGS: Case-control studies were selected through an electronic search of the Cochrane Controlled Trials Register, PUBMED and EMBASE. For the continuous outcomes, we calculated the weighted mean difference (WMD) and 95% confidence interval (CI). The statistical analysis was performed by RevMan 5.0 software. Thirteen case-control studies were included in the present meta-analysis, containing a total of 644 eyes in PD patients and 604 eyes in healthy controls. The results of our study showed that there was a significant reduction in average RNFL thickness in patients with PD compared to healthy controls (WMD = -5.76, 95% CI: -8.99 to -2.53, P = 0.0005). Additionally, differences of RNFL thickness in superior quadrant (WMD = -4.44, 95% CI: -6.93 to -1.94, P = 0.0005), inferior quadrant (WMD = -7.56, 95% CI: -11.33 to -3.78, P<0.0001), nasal quadrant (WMD = 3.12, 95% CI: -5.63 to -0.61, P = 0.01) and temporal quadrant (WMD = -4.63, 95% CI: -7.20 to -2.06, P = 0.0004) were all significant between the two groups. CONCLUSION: In view of these results and the noninvasive nature of OCT technology, we surmise that OCT could be a useful tool for evaluating the progression of the Parkinson disease. TRIAL REGISTRATION: ClinicalTrials.gov NCT01928212. PMID- 24465664 TI - The GG genotype of telomerase reverse transcriptase at genetic locus rs2736100 is associated with human atherosclerosis risk in the Han Chinese population. AB - A single nucleotide polymorphism (SNP) in the second intron of human TERT (hTERT), rs2736100, acts as a critical factor in hTERT synthesis and activation. The rs2736100 SNP was found to be associated with susceptibility to many cancers. Recently, inhibition of telomerase and marked telomere shortening were determined to be closely associated with the increasing severity of atherosclerosis. The association between the SNP of rs2736100 and the presence of atherosclerosis was evaluated in 84 atherosclerosis patients and 257 healthy controls using multivariate logistic regression analyses. The proportion of the GG genotype in atherosclerosis patients (17.9%) was significantly higher than in the control group (9.7%). Eight variables, including age, gender, cholesterol, high density lipoprotein, homocysteine, total bilirubin, indirect bilirubin, and rs2736100 GG genotype, were associated with atherosclerosis with odds ratios of 1.88, 2.11, 1.66, 0.23, 1.27, 1.29, 1.53, and 1.74, respectively, using multivariate logistic regression analyses. Homozygous GG was demonstrated to be associated with the presence of atherosclerosis in our population. PMID- 24465665 TI - Proper PIN1 distribution is needed for root negative phototropism in Arabidopsis. AB - Plants can be adapted to the changing environments through tropic responses, such as light and gravity. One of them is root negative phototropism, which is needed for root growth and nutrient absorption. Here, we show that the auxin efflux carrier PIN-FORMED (PIN) 1 is involved in asymmetric auxin distribution and root negative phototropism. In darkness, PIN1 is internalized and localized to intracellular compartments; upon blue light illumination, PIN1 relocalize to basal plasma membrane in root stele cells. The shift of PIN1 localization induced by blue light is involved in asymmetric auxin distribution and root negative phototropic response. Both blue-light-induced PIN1 redistribution and root negative phototropism is mediated by a BFA-sensitive trafficking pathway and the activity of PID/PP2A. Our results demonstrate that blue-light-induced PIN1 redistribution participate in asymmetric auxin distribution and root negative phototropism. PMID- 24465666 TI - NOS2 is critical to the development of emphysema in Sftpd deficient mice but does not affect surfactant homeostasis. AB - RATIONALE: Surfactant protein D (SP-D) has important immuno-modulatory properties. The absence of SP-D results in an inducible NO synthase (iNOS, coded by NOS2 gene) related chronic inflammation, development of emphysema-like pathophysiology and alterations of surfactant homeostasis. OBJECTIVE: In order to test the hypothesis that SP-D deficiency related abnormalities in pulmonary structure and function are a consequence of iNOS induced inflammation, we generated SP-D and iNOS double knockout mice (DiNOS). METHODS: Structural data obtained by design-based stereology to quantify the emphysema-like phenotype and disturbances of the intracellular surfactant were correlated to invasive pulmonary function tests and inflammatory markers including activation markers of alveolar macrophages and compared to SP-D (Sftpd(-/-)) and iNOS single knockout mice (NOS2(-/-)) as well as wild type (WT) littermates. MEASUREMENTS AND RESULTS: DiNOS mice had reduced inflammatory cells in BAL and BAL-derived alveolar macrophages showed an increased expression of markers of an alternative activation as well as reduced inflammation. As evidenced by increased alveolar numbers and surface area, emphysematous changes were attenuated in DiNOS while disturbances of the surfactant system remained virtually unchanged. Sftpd(-/-) demonstrated alterations of intrinsic mechanical properties of lung parenchyma as shown by reduced stiffness and resistance at its static limits, which could be corrected by additional ablation of NOS2 gene in DiNOS. CONCLUSION: iNOS related inflammation in the absence of SP-D is involved in the emphysematous remodeling leading to a loss of alveoli and associated alterations of elastic properties of lung parenchyma while disturbances of surfactant homeostasis are mediated by different mechanisms. PMID- 24465667 TI - Glycerophospholipid and sphingolipid species and mortality: the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. AB - Vascular and metabolic diseases cause half of total mortality in Europe. New prognostic markers would provide a valuable tool to improve outcome. First evidence supports the usefulness of plasma lipid species as easily accessible markers for certain diseases. Here we analyzed association of plasma lipid species with mortality in the Ludwigshafen Risk and Cardiovascular Health (LURIC) study. Plasma lipid species were quantified by electrospray ionization tandem mass spectrometry and Cox proportional hazards regression was applied to assess their association with total and cardiovascular mortality. Overall no differences were detected between total and cardiovascular mortality. Highly polyunsaturated phosphatidylcholine species together with lysophosphatidylcholine species and long chain saturated sphingomyelin and ceramide species seem to be associated with a protective effect. The predominantly circulating phosphatidylcholine-based as well as phosphatidylethanolamine-based ether species and phosphatidylethanolamine species were positively associated with total and cardiovascular mortality. Saturated and monounsaturated phosphatidylcholine species, especially phosphatidylcholine 32?0 (most probably dipalmitoyl phosphatidylcholine) and palmitate containing sphingomyelin and ceramide species showed together with 24?1 containing sphingomyelin and ceramide species strongest positive association with mortality. A quotient of the sums of the six most protective species and the six species with the strongest positive mortality association indicated an almost 3-fold increased risk of mortality, which was higher than the hazard ratio for known risk factors in our cohort. Plasma lipid species levels and especially ratios of certain species may be valuable prognostic marker for cardiovascular and total mortality. PMID- 24465668 TI - Oscillatory behavior of neutrophils under opposing chemoattractant gradients supports a winner-take-all mechanism. AB - Neutrophils constitute the largest class of white blood cells and are the first responders in the innate immune response. They are able to sense and migrate up concentration gradients of chemoattractants in search of primary sites of infection and inflammation through a process known as chemotaxis. These chemoattractants include formylated peptides and various chemokines. While much is known about chemotaxis to individual chemoattractants, far less is known about chemotaxis towards many. Previous studies have shown that in opposing gradients of intermediate chemoattractants (interleukin-8 and leukotriene B4), neutrophils preferentially migrate toward the more distant source. In this work, we investigated neutrophil chemotaxis in opposing gradients of chemoattractants using a microfluidic platform. We found that primary neutrophils exhibit oscillatory motion in opposing gradients of intermediate chemoattractants. To understand this behavior, we constructed a mathematical model of neutrophil chemotaxis. Our results suggest that sensory adaptation alone cannot explain the observed oscillatory motion. Rather, our model suggests that neutrophils employ a winner-take-all mechanism that enables them to transiently lock onto sensed targets and continuously switch between the intermediate attractant sources as they are encountered. These findings uncover a previously unseen behavior of neutrophils in opposing gradients of chemoattractants that will further aid in our understanding of neutrophil chemotaxis and the innate immune response. In addition, we propose a winner-take-all mechanism allows the cells to avoid stagnation near local chemical maxima when migrating through a network of chemoattractant sources. PMID- 24465669 TI - Application of a genetically encoded biosensor for live cell imaging of L-valine production in pyruvate dehydrogenase complex-deficient Corynebacterium glutamicum strains. AB - The majority of biotechnologically relevant metabolites do not impart a conspicuous phenotype to the producing cell. Consequently, the analysis of microbial metabolite production is still dominated by bulk techniques, which may obscure significant variation at the single-cell level. In this study, we have applied the recently developed Lrp-biosensor for monitoring of amino acid production in single cells of gradually engineered L-valine producing Corynebacterium glutamicum strains based on the pyruvate dehydrogenase complex deficient (PDHC) strain C. glutamicum DeltaaceE. Online monitoring of the sensor output (eYFP fluorescence) during batch cultivation proved the sensor's suitability for visualizing different production levels. In the following, we conducted live cell imaging studies on C. glutamicum sensor strains using microfluidic chip devices. As expected, the sensor output was higher in microcolonies of high-yield producers in comparison to the basic strain C. glutamicum DeltaaceE. Microfluidic cultivation in minimal medium revealed a typical Gaussian distribution of single cell fluorescence during the production phase. Remarkably, low amounts of complex nutrients completely changed the observed phenotypic pattern of all strains, resulting in a phenotypic split of the population. Whereas some cells stopped growing and initiated L-valine production, others continued to grow or showed a delayed transition to production. Depending on the cultivation conditions, a considerable fraction of non-fluorescent cells was observed, suggesting a loss of metabolic activity. These studies demonstrate that genetically encoded biosensors are a valuable tool for monitoring single cell productivity and to study the phenotypic pattern of microbial production strains. PMID- 24465670 TI - Signal intensities derived from different NMR probes and parameters contribute to variations in quantification of metabolites. AB - We discovered that serious issues could arise that may complicate interpretation of metabolomic data when identical samples are analyzed at more than one NMR facility, or using slightly different NMR parameters on the same instrument. This is important because cross-center validation metabolomics studies are essential for the reliable application of metabolomics to clinical biomarker discovery. To test the reproducibility of quantified metabolite data at multiple sites, technical replicates of urine samples were assayed by 1D-(1)H-NMR at the University of Alberta and the University of Michigan. Urine samples were obtained from healthy controls under a standard operating procedure for collection and processing. Subsequent analysis using standard statistical techniques revealed that quantitative data across sites can be achieved, but also that previously unrecognized NMR parameter differences can dramatically and widely perturb results. We present here a confirmed validation of NMR analysis at two sites, and report the range and magnitude that common NMR parameters involved in solvent suppression can have on quantitated metabolomics data. Specifically, saturation power levels greatly influenced peak height intensities in a frequency-dependent manner for a number of metabolites, which markedly impacted the quantification of metabolites. We also investigated other NMR parameters to determine their effects on further quantitative accuracy and precision. Collectively, these findings highlight the importance of and need for consistent use of NMR parameter settings within and across centers in order to generate reliable, reproducible quantified NMR metabolomics data. PMID- 24465671 TI - Sleep dissolves illusion: sleep withstands learning of visuo-tactile proprioceptive integration induced by repeated days of rubber hand illusion training. AB - Multisensory integration is a key factor in establishing bodily self consciousness and in adapting humans to novel environments. The rubber hand illusion paradigm, in which humans can immediately perceive illusory ownership to an artificial hand, is a traditional technique for investigating multisensory integration and the feeling of illusory ownership. However, the long-term learning properties of the rubber hand illusion have not been previously investigated. Moreover, although sleep contributes to various aspects of cognition, including learning and memory, its influence on illusory learning of the artificial hand has not yet been assessed. We determined the effects of daily repetitive training and sleep on learning visuo-tactile-proprioceptive sensory integration and illusory ownership in healthy adult participants by using the traditional rubber hand illusion paradigm. Subjective ownership of the rubber hand, proprioceptive drift, and galvanic skin response were measured to assess learning indexes. Subjective ownership was maintained and proprioceptive drift increased with daily training. Proprioceptive drift, but not subjective ownership, was significantly attenuated after sleep. A significantly greater reduction in galvanic skin response was observed after wakefulness compared to after sleep. Our results suggest that although repetitive rubber hand illusion training facilitates multisensory integration and physiological habituation of a multisensory incongruent environment, sleep corrects illusional integration and habituation based on experiences in a multisensory incongruent environment. These findings may increase our understanding of adaptive neural processes to novel environments, specifically, bodily self-consciousness and sleep-dependent neuroplasticity. PMID- 24465672 TI - Comparative study of efficacy of dopaminergic neuron differentiation between embryonic stem cell and protein-based induced pluripotent stem cell. AB - In patients with Parkinson's disease (PD), stem cells can serve as therapeutic agents to restore or regenerate injured nervous system. Here, we differentiated two types of stem cells; mouse embryonic stem cells (mESCs) and protein-based iPS cells (P-iPSCs) generated by non-viral methods, into midbrain dopaminergic (mDA) neurons, and then compared the efficiency of DA neuron differentiation from these two cell types. In the undifferentiated stage, P-iPSCs expressed pluripotency markers as ES cells did, indicating that protein-based reprogramming was stable and authentic. While both stem cell types were differentiated to the terminally matured mDA neurons, P-iPSCs showed higher DA neuron-specific markers' expression than ES cells. To investigate the mechanism of the superior induction capacity of DA neurons observed in P-iPSCs compared to ES cells, we analyzed histone modifications by genome-wide ChIP sequencing analysis and their corresponding microarray results between two cell types. We found that Wnt signaling was up regulated, while SFRP1, a counter-acting molecule of Wnt, was more suppressed in P-iPSCs than in mESCs. In PD rat model, transplantation of neural precursor cells derived from both cell types showed improved function. The present study demonstrates that P-iPSCs could be a suitable cell source to provide patient specific therapy for PD without ethical problems or rejection issues. PMID- 24465673 TI - Why muscle is an efficient shock absorber. AB - Skeletal muscles power body movement by converting free energy of ATP hydrolysis into mechanical work. During the landing phase of running or jumping some activated skeletal muscles are subjected to stretch. Upon stretch they absorb body energy quickly and effectively thus protecting joints and bones from impact damage. This is achieved because during lengthening, skeletal muscle bears higher force and has higher instantaneous stiffness than during isometric contraction, and yet consumes very little ATP. We wish to understand how the actomyosin molecules change their structure and interaction to implement these physiologically useful mechanical and thermodynamical properties. We monitored changes in the low angle x-ray diffraction pattern of rabbit skeletal muscle fibers during ramp stretch compared to those during isometric contraction at physiological temperature using synchrotron radiation. The intensities of the off meridional layer lines and fine interference structure of the meridional M3 myosin x-ray reflection were resolved. Mechanical and structural data show that upon stretch the fraction of actin-bound myosin heads is higher than during isometric contraction. On the other hand, the intensities of the actin layer lines are lower than during isometric contraction. Taken together, these results suggest that during stretch, a significant fraction of actin-bound heads is bound non-stereo-specifically, i.e. they are disordered azimuthally although stiff axially. As the strong or stereo-specific myosin binding to actin is necessary for actin activation of the myosin ATPase, this finding explains the low metabolic cost of energy absorption by muscle during the landing phase of locomotion. PMID- 24465674 TI - Rapid and unambiguous detection of DNase I hypersensitive site in rare population of cells. AB - DNase I hypersensitive (DHS) sites are important for understanding cis regulation of gene expression. However, existing methods for detecting DHS sites in small numbers of cells can lead to ambiguous results. Here we describe a simple new method, in which DNA fragments with ends generated by DNase I digestion are isolated and used as templates for two PCR reactions. In the first PCR, primers are derived from sequences up- and down-stream of the DHS site. If the DHS site exists in the cells, the first PCR will not produce PCR products due to the cuts of the templates by DNase I between the primer sequences. In the second PCR, one primer is derived from sequence outside the DHS site and the other from the adaptor. This will produce a smear of PCR products of different sizes due to cuts by DNase I at different positions at the DHS site. With this design, we detected a DHS site at the CD4 gene in two CD4 T cell populations using as few as 2*10(4) cells. We further validated this method by detecting a DHS site of the IL-4 gene that is specifically present in type 2 but not type 1 T helper cells. Overall, this method overcomes the interference by genomic DNA not cut by DNase I at the DHS site, thereby offering unambiguous detection of DHS sites in the cells. PMID- 24465675 TI - Audio-tactile integration and the influence of musical training. AB - Perception of our environment is a multisensory experience; information from different sensory systems like the auditory, visual and tactile is constantly integrated. Complex tasks that require high temporal and spatial precision of multisensory integration put strong demands on the underlying networks but it is largely unknown how task experience shapes multisensory processing. Long-term musical training is an excellent model for brain plasticity because it shapes the human brain at functional and structural levels, affecting a network of brain areas. In the present study we used magnetoencephalography (MEG) to investigate how audio-tactile perception is integrated in the human brain and if musicians show enhancement of the corresponding activation compared to non-musicians. Using a paradigm that allowed the investigation of combined and separate auditory and tactile processing, we found a multisensory incongruency response, generated in frontal, cingulate and cerebellar regions, an auditory mismatch response generated mainly in the auditory cortex and a tactile mismatch response generated in frontal and cerebellar regions. The influence of musical training was seen in the audio-tactile as well as in the auditory condition, indicating enhanced higher-order processing in musicians, while the sources of the tactile MMN were not influenced by long-term musical training. Consistent with the predictive coding model, more basic, bottom-up sensory processing was relatively stable and less affected by expertise, whereas areas for top-down models of multisensory expectancies were modulated by training. PMID- 24465676 TI - mUbiSiDa: a comprehensive database for protein ubiquitination sites in mammals. AB - MOTIVATION: Protein ubiquitination is one of the important post-translational modifications by attaching ubiquitin to specific lysine (K) residues in target proteins, and plays important regulatory roles in many cell processes. Recent studies indicated that abnormal protein ubiquitination have been implicated in many diseases by degradation of many key regulatory proteins including tumor suppressor, oncoprotein, and cell cycle regulator. The detailed information of protein ubiquitination sites is useful for scientists to investigate the mechanism of many cell activities and related diseases. RESULTS: In this study we established mUbiSida for mammalian Ubiquitination Site Database, which provides a scientific community with a comprehensive, freely and high-quality accessible resource of mammalian protein ubiquitination sites. In mUbiSida, we deposited about 35,494 experimentally validated ubiquitinated proteins with 110,976 ubiquitination sites from five species. The mUbiSiDa can also provide blast function to predict novel protein ubiquitination sites in other species by blast the query sequence in the deposit sequences in mUbiSiDa. The mUbiSiDa was designed to be a widely used tool for biologists and biomedical researchers with a user-friendly interface, and facilitate the further research of protein ubiquitination, biological networks and functional proteomics. The mUbiSiDa database is freely available at http://reprod.njmu.edu.cn/mUbiSiDa. PMID- 24465677 TI - Do preschool children learn to read words from environmental prints? AB - Parents and teachers worldwide believe that a visual environment rich with print can contribute to young children's literacy. Children seem to recognize words in familiar logos at an early age. However, most of previous studies were carried out with alphabetic scripts. Alphabetic letters regularly correspond to phonological segments in a word and provide strong cues about the identity of the whole word. Thus it was not clear whether children can learn to read words by extracting visual word form information from environmental prints. To exclude the phonological-cue confound, this study tested children's knowledge of Chinese words embedded in familiar logos. The four environmental logos were employed and transformed into four versions with the contextual cues (i.e., something apart from the presentation of the words themselves in logo format like the color, logo and font type cues) gradually minimized. Children aged from 3 to 5 were tested. We observed that children of different ages all performed better when words were presented in highly familiar logos compared to when they were presented in a plain fashion, devoid of context. This advantage for familiar logos was also present when the contextual information was only partial. However, the role of various cues in learning words changed with age. The color and logo cues had a larger effect in 3- and 4- year-olds than in 5-year-olds, while the font type cue played a greater role in 5-year-olds than in the other two groups. Our findings demonstrated that young children did not easily learn words by extracting their visual form information even from familiar environmental prints. However, children aged 5 begin to pay more attention to the visual form information of words in highly familiar logos than those aged 3 and 4. PMID- 24465679 TI - Test-retest reliability of the 40 Hz EEG auditory steady-state response. AB - Auditory evoked steady-state responses are increasingly being used as a marker of brain function and dysfunction in various neuropsychiatric disorders, but research investigating the test-retest reliability of this response is lacking. The purpose of this study was to assess the consistency of the auditory steady state response (ASSR) across sessions. Furthermore, the current study aimed to investigate how the reliability of the ASSR is impacted by stimulus parameters and analysis method employed. The consistency of this response across two sessions spaced approximately 1 week apart was measured in nineteen healthy adults using electroencephalography (EEG). The ASSR was entrained by both 40 Hz amplitude-modulated white noise and click train stimuli. Correlations between sessions were assessed with two separate analytical techniques: a) channel-level analysis across the whole-head array and b) signal-space projection from auditory dipoles. Overall, the ASSR was significantly correlated between sessions 1 and 2 (p<0.05, multiple comparison corrected), suggesting adequate test-retest reliability of this response. The current study also suggests that measures of inter-trial phase coherence may be more reliable between sessions than measures of evoked power. Results were similar between the two analysis methods, but reliability varied depending on the presented stimulus, with click train stimuli producing more consistent responses than white noise stimuli. PMID- 24465678 TI - Multiple modes of impulsivity in Parkinson's disease. AB - Cognitive problems are a major factor determining quality of life of patients with Parkinson's disease. These include deficits in inhibitory control, ranging from subclinical alterations in decision-making to severe impulse control disorders. Based on preclinical studies, we proposed that Parkinson's disease does not cause a unified disorder of inhibitory control, but rather a set of impulsivity factors with distinct psychological profiles, anatomy and pharmacology. We assessed a broad set of measures of the cognitive, behavioural and temperamental/trait aspects of impulsivity. Sixty adults, including 30 idiopathic Parkinson's disease patients (Hoehn and Yahr stage I-III) and 30 healthy controls, completed a neuropsychological battery, objective behavioural measures and self-report questionnaires. Univariate analyses of variance confirmed group differences in nine out of eleven metrics. We then used factor analysis (principal components method) to identify the structure of impulsivity in Parkinson's disease. Four principal factors were identified, consistent with four different mechanisms of impulsivity, explaining 60% of variance. The factors were related to (1) tests of response conflict, interference and self assessment of impulsive behaviours on the Barrett Impulsivity Scale, (2) tests of motor inhibitory control, and the self-report behavioural approach system, (3) time estimation and delay aversion, and (4) reflection in hypothetical scenarios including temporal discounting. The different test profiles of these four factors were consistent with human and comparative studies of the pharmacology and functional anatomy of impulsivity. Relationships between each factor and clinical and demographic features were examined by regression against factor loadings. Levodopa dose equivalent was associated only with factors (2) and (3). The results confirm that impulsivity is common in Parkinson's disease, even in the absence of impulse control disorders, and that it is not a unitary phenomenon. A better understanding of the structure of impulsivity in Parkinson's disease will support more evidence-based and effective strategies to treat impulsivity. PMID- 24465680 TI - Noninvasive quantification of in vitro osteoblastic differentiation in 3D engineered tissue constructs using spectral ultrasound imaging. AB - Non-destructive monitoring of engineered tissues is needed for translation of these products from the lab to the clinic. In this study, non-invasive, high resolution spectral ultrasound imaging (SUSI) was used to monitor the differentiation of MC3T3 pre-osteoblasts seeded within collagen hydrogels. SUSI was used to measure the diameter, concentration and acoustic attenuation of scatterers within such constructs cultured in either control or osteogenic medium over 21 days. Conventional biochemical assays were used on parallel samples to determine DNA content and calcium deposition. Construct volume and morphology were accurately imaged using ultrasound. Cell diameter was estimated to be approximately 12.5-15.5 um using SUSI, which corresponded well to measurements of fluorescently stained cells. The total number of cells per construct assessed by quantitation of DNA content decreased from 5.6+/-2.4*10(4) at day 1 to 0.9+/ 0.2*10(4) at day 21. SUSI estimation of the equivalent number of acoustic scatters showed a similar decreasing trend, except at day 21 in the osteogenic samples, which showed a marked increase in both scatterer number and acoustic impedance, suggestive of mineral deposition by the differentiating MC3T3 cells. Estimation of calcium content by SUSI was 41.7+/-11.4 ug/ml, which agreed well with the biochemical measurement of 38.7+/-16.7 ug/ml. Color coded maps of parameter values were overlaid on B-mode images to show spatiotemporal changes in cell diameter and calcium deposition. This study demonstrates the use of non destructive ultrasound imaging to provide quantitative information on the number and differentiated state of cells embedded within 3D engineered constructs, and therefore presents a valuable tool for longitudinal monitoring of engineered tissue development. PMID- 24465681 TI - Overexpression of cohesion establishment factor DSCC1 through E2F in colorectal cancer. AB - Ctf18-replication factor C complex including Dscc1 (DNA replication and sister chromatid cohesion 1) is implicated in sister chromatid cohesion, DNA replication, and genome stability in S. cerevisiae and C. elegans. We previously performed gene expression profiling in primary colorectal cancer cells in order to identify novel molecular targets for the treatment of colorectal cancer. A feature of the cancer-associated transcriptional signature revealed from this effort is the elevated expression of the proto-oncogene DSCC1. Here, we have interrogated the molecular basis for deviant expression of human DSCC1 in colorectal cancer and its ability to promote survival of cancer cells. Quantitative PCR and immunohistochemical analyses corroborated that the expression level of DSCC1 is elevated in 60-70% of colorectal tumors compared to their matched noncancerous colonic mucosa. An in silico evaluation of the presumptive DSCC1 promoter region for consensus DNA transcriptional regulatory elements revealed a potential role for the E2F family of DNA-binding proteins in controlling DSCC1 expression. RNAi-mediated reduction of E2F1 reduced expression of DSCC1 in colorectal cancer cells. Gain- and loss-of-function experiments demonstrated that DSCC1 is involved in the viability of cancer cells in response to genotoxic stimuli. We reveal that E2F-dependent expression of DSCC1 confers anti-apoptotic properties in colorectal cancer cells, and that its suppression may be a useful option for the treatment of colorectal cancer. PMID- 24465682 TI - "People over profits": retailers who voluntarily ended tobacco sales. AB - BACKGROUND: Tobacco retailers are key players in the ongoing tobacco epidemic. Tobacco outlet density is linked to a greater likelihood of youth and adult smoking and greater difficulty quitting. While public policy efforts to address the tobacco problem at the retail level have been limited, some retailers have voluntarily ended tobacco sales. A previous pilot study examined this phenomenon in California, a state with a strong tobacco program focused on denormalizing smoking and the tobacco industry. We sought to learn what motivated retailers in other states to end tobacco sales and how the public and media responded. METHODS: We conducted interviews with owners, managers, or representatives of six grocery stores in New York and Ohio that had voluntarily ended tobacco sales since 2007. We also conducted unobtrusive observations at stores and analyzed media coverage of each retailer's decision. RESULTS: Grocery store owners ended tobacco sales for two reasons, alone or in combination: health or ethics-related, including a desire to send a consistent health message to employees and customers, and business-related, including declining tobacco sales or poor fit with the store's image. The decision to end sales often appeared to resolve troubling contradictions between retailers' values and selling deadly products. New York retailers attributed declining sales to high state tobacco taxes. All reported largely positive customer reactions and most received media coverage. Forty-one percent of news items were letters to the editor or editorials; most (69%) supported the decision. CONCLUSION: Voluntary decisions by retailers to abandon tobacco sales may lay the groundwork for mandatory policies and further denormalize tobacco. Our study also suggests that high tobacco taxes may have both direct and indirect effects on tobacco use. Highlighting the contradictions between being a responsible business and selling deadly products may support voluntary decisions by retailers to end tobacco sales. PMID- 24465683 TI - Thyroid hormone upregulates zinc-alpha2-glycoprotein production in the liver but not in adipose tissue. AB - Overproduction of zinc-alpha2-glycoprotein by adipose tissue is crucial in accounting for the lipolysis occurring in cancer cachexia of certain malignant tumors. The main aim of this study was to explore whether thyroid hormone could enhance zinc-alpha2-glycoprotein production in adipose tissue. In addition, the regulation of zinc-alpha2-glycoprotein by thyroid hormone in the liver was investigated. We performed in vitro (HepG2 cells and primary human adipocytes) and in vivo (C57BL6/mice) experiments addressed to examine the effect of thyroid hormone on zinc-alpha2-glycoprotein production (mRNA and protein levels) in liver and visceral adipose tissue. We also measured the zinc-alpha2-glycoprotein serum levels in a cohort of patients before and after controlling their hyperthyroidism. Our results showed that thyroid hormone up-regulates zinc-alpha2 glycoprotein production in HepG2 cells in a dose-dependent manner. In addition, the zinc-alpha2-glycoprotein proximal promoter contains functional thyroid hormone receptor binding sites that respond to thyroid hormone treatment in luciferase reporter gene assays in HepG2 cells. Furthermore, zinc-alpha2 glycoprotein induced lipolysis in HepG2 in a dose-dependent manner. Our in vivo experiments in mice confirmed the up-regulation of zinc-alpha2-glycoprotein induced by thyroid hormone in the liver, thus leading to a significant increase in zinc-alpha2-glycoprotein circulating levels. However, thyroid hormone did not regulate zinc-alpha2-glycoprotein production in either human or mouse adipocytes. Finally, in patients with hyperthyroidism a significant reduction of zinc-alpha2 glycoprotein serum levels was detected after treatment but was unrelated to body weight changes. We conclude that thyroid hormone up-regulates the production of zinc-alpha2-glycoprotein in the liver but not in the adipose tissue. The neutral effect of thyroid hormones on zinc-alpha2-glycoprotein expression in adipose tissue could be the reason why zinc-alpha2-glycoprotein is not related to weight loss in hyperthyroidism. PMID- 24465684 TI - Functional and evolutionary characterization of the CONSTANS gene family in short day photoperiodic flowering in soybean. AB - CONSTANS (CO) plays a central role in photoperiodic flowering control of plants. However, much remains unknown about the function of the CO gene family in soybean and the molecular mechanisms underlying short-day photoperiodic flowering of soybean. We identified 26 CO homologs (GmCOLs) in the soybean genome, many of them previously unreported. Phylogenic analysis classified GmCOLs into three clades conserved among flowering plants. Two homeologous pairs in Clade I, GmCOL1a/GmCOL1b and GmCOL2a/GmCOL2b, showed the highest sequence similarity to Arabidopsis CO. The mRNA abundance of GmCOL1a and GmCOL1b exhibited a strong diurnal rhythm under flowering-inductive short days and peaked at dawn, which coincided with the rise of GmFT5a expression. In contrast, the mRNA abundance of GmCOL2a and GmCOL2b was extremely low. Our transgenic study demonstrated that GmCOL1a, GmCOL1b, GmCOL2a and GmCOL2b fully complemented the late flowering effect of the co-1 mutant in Arabidopsis. Together, these results indicate that GmCOL1a and GmCOL1b are potential inducers of flowering in soybean. Our data also indicate rapid regulatory divergence between GmCOL1a/GmCOL1b and GmCOL2a/GmCOL2b but conservation of their protein function. Dynamic evolution of GmCOL regulatory mechanisms may underlie the evolution of photoperiodic signaling in soybean. PMID- 24465685 TI - Cell-penetrating peptide-mediated delivery of TALEN proteins via bioconjugation for genome engineering. AB - Transcription activator-like (TAL) effector nucleases (TALENs) have enabled the introduction of targeted genetic alterations into a broad range of cell lines and organisms. These customizable nucleases are comprised of programmable sequence specific DNA-binding modules derived from TAL effector proteins fused to the non specific FokI cleavage domain. Delivery of these nucleases into cells has proven challenging as the large size and highly repetitive nature of the TAL effector DNA-binding domain precludes their incorporation into many types of viral vectors. Furthermore, viral and non-viral gene delivery methods carry the risk of insertional mutagenesis and have been shown to increase the off-target activity of site-specific nucleases. We previously demonstrated that direct delivery of zinc-finger nuclease proteins enables highly efficient gene knockout in a variety of mammalian cell types with reduced off-target effects. Here we show that conjugation of cell-penetrating poly-Arg peptides to a surface-exposed Cys residue present on each TAL effector repeat imparted cell-penetrating activity to purified TALEN proteins. These modifications are reversible under reducing conditions and enabled TALEN-mediated gene knockout of the human CCR5 and BMPR1A genes at rates comparable to those achieved with transient transfection of TALEN expression vectors. These findings demonstrate that direct protein delivery, facilitated by conjugation of chemical functionalities onto the TALEN protein surface, is a promising alternative to current non-viral and viral-based methods for TALEN delivery into mammalian cells. PMID- 24465686 TI - Top-down influences of the medial olivocochlear efferent system in speech perception in noise. AB - One of the putative functions of the medial olivocochlear (MOC) system is to enhance signal detection in noise. The objective of this study was to elucidate the role of the MOC system in speech perception in noise. In normal-hearing human listeners, we examined (1) the association between magnitude of MOC inhibition and speech-in-noise performance, and (2) the association between MOC inhibition and the amount of contralateral acoustic stimulation (CAS)-induced shift in speech-in-noise acuity. MOC reflex measurements in this study considered critical measurement issues overlooked in past work by: recording relatively low-level, linear click-evoked otoacoustic emissions (CEOAEs), adopting 6 dB signal-to-noise ratio (SNR) criteria, and computing normalized CEOAE differences. We found normalized index to be a stable measure of MOC inhibition (mean = 17.21%). MOC inhibition was not related to speech-in-noise performance measured without CAS. However, CAS in a speech-in-noise task caused an SNRSP enhancement (mean = 2.45 dB), and this improvement in speech-in-noise acuity was directly related to their MOC reflex assayed by CEOAEs. Individuals do not necessarily use the available MOC-unmasking characteristic while listening to speech in noise, or do not utilize unmasking to the extent that can be shown by artificial MOC activation. It may be the case that the MOC is not actually used under natural listening conditions and the higher auditory centers recruit MOC-mediated mechanisms only in specific listening conditions-those conditions remain to be investigated. PMID- 24465687 TI - Expression variants of the lipogenic AGPAT6 gene affect diverse milk composition phenotypes in Bos taurus. AB - Milk is composed of a complex mixture of lipids, proteins, carbohydrates and various vitamins and minerals as a source of nutrition for young mammals. The composition of milk varies between individuals, with lipid composition in particular being highly heritable. Recent reports have highlighted a region of bovine chromosome 27 harbouring variants affecting milk fat percentage and fatty acid content. We aimed to further investigate this locus in two independent cattle populations, consisting of a Holstein-Friesian x Jersey crossbreed pedigree of 711 F2 cows, and a collection of 32,530 mixed ancestry Bos taurus cows. Bayesian genome-wide association mapping using markers imputed from the Illumina BovineHD chip revealed a large quantitative trait locus (QTL) for milk fat percentage on chromosome 27, present in both populations. We also investigated a range of other milk composition phenotypes, and report additional associations at this locus for fat yield, protein percentage and yield, lactose percentage and yield, milk volume, and the proportions of numerous milk fatty acids. We then used mammary RNA sequence data from 212 lactating cows to assess the transcript abundance of genes located in the milk fat percentage QTL interval. This analysis revealed a strong eQTL for AGPAT6, demonstrating that high milk fat percentage genotype is also additively associated with increased expression of the AGPAT6 gene. Finally, we used whole genome sequence data from six F1 sires to target a panel of novel AGPAT6 locus variants for genotyping in the F2 crossbreed population. Association analysis of 58 of these variants revealed highly significant association for polymorphisms mapping to the 5'UTR exons and intron 1 of AGPAT6. Taken together, these data suggest that variants affecting the expression of AGPAT6 are causally involved in differential milk fat synthesis, with pleiotropic consequences for a diverse range of other milk components. PMID- 24465688 TI - Current clinical evidence on the effect of general anesthesia on neurodevelopment in children: an updated systematic review with meta-regression. AB - BACKGROUND: Several epidemiological studies have been conducted to address the later effect of anesthesia on neurodevelopment in children. However, the results are still inconclusive. METHODS: We here conducted a systematic review and meta analysis to summarize the currently available clinical and epidemiologic evidence on the association of anesthesia/surgery with neurodevelopmental outcomes in children by searching PubMed, EMBASE, and Web of Science database (from January-1 2000 to February-1, 2013). The evaluation of neurodevelopment includes language and learning disabilities, cognition, behavioral development, and academic performance. Both retrospective and prospective studies were included. Data were abstracted from seven eligible studies. We estimated the synthesized hazard ratios (HR) and 95% confidence interval (CI) according to inter-study heterogeneity. RESULTS: The pooled HR for the association of anesthesia/surgery with an adverse behavioral or developmental outcome was 1.25 (95% CI, 1.13-1.38, P<0.001; random-effects model) in children undergoing the first anesthesia before the age of 4-year. Then we analyzed the factors for this association using meta regression method. It showed that it was the number of times of exposure (HR = 1.75, 95% CI 1.31-2.33; P<0.001) rather than the time at exposure before 4-year (HR = 1.08, 95% CI 0.87-1.34 for the effect of per 1-year early exposure; P = 0.47) is a risk factor for neurodevelopmental impairment. CONCLUSION: The current clinical evidence suggests modestly elevated risk of adverse neurodevelopmental outcomes in children who were exposed to anesthesia/surgery during early childhood, especially for those with multiple times of exposure. Due to limitation of retrospective studies, prospective investigations are needed to determine whether anesthesia/surgery is causative. PMID- 24465689 TI - CKIP-1 is an intrinsic negative regulator of T-cell activation through an interaction with CARMA1. AB - The transcription factor NF-kappaB plays a key regulatory role in lymphocyte activation and generation of immune response. Stimulation of T cell receptor (TCR) induces phosphorylation of CARMA1 by PKCtheta, resulting in formation of CARMA1-Bcl10-MALT1 (CBM) complex at lipid rafts and subsequently leading to NF kappaB activation. While many molecular events leading to NF-kappaB activation have been reported, it is less understood how this activation is negatively regulated. We performed a cell-based screening for negative regulators of TCR mediated NF-kappaB activation, using mutagenesis and complementation cloning strategies. Here we show that casein kinase-2 interacting protein-1 (CKIP-1) suppresses PKCtheta-CBM-NF-kappaB signaling. We found that CKIP-1 interacts with CARMA1 and competes with PKCtheta for association. We further confirmed that a PH domain of CKIP-1 is required for association with CARMA1 and its inhibitory effect. CKIP-1 represses NF-kappaB activity in unstimulated cells, and inhibits NF-kappaB activation induced by stimulation with PMA or constitutively active PKCtheta, but not by stimulation with TNFalpha. Interestingly, CKIP-1 does not inhibit NF-kappaB activation induced by CD3/CD28 costimulation, which caused dissociation of CKIP-1 from lipid rafts. These data suggest that CKIP-1 contributes maintenance of a resting state on NF-kappaB activity or prevents T cells from being activated by inadequate signaling. In conclusion, we demonstrate that CKIP-1 interacts with CARMA1 and has an inhibitory effect on PKCtheta-CBM-NF kappaB signaling. PMID- 24465690 TI - Oviposition site-selection by Bactrocera dorsalis is mediated through an innate recognition template tuned to gamma-octalactone. AB - Innate recognition templates (IRTs) in insects are developed through many years of evolution. Here we investigated olfactory cues mediating oviposition behavior in the oriental fruit fly, Bactrocera dorsalis, and their role in triggering an IRT for oviposition site recognition. Behavioral assays with electrophysiologically active compounds from a preferred host, mango, revealed that one of the volatiles tested, gamma-octalactone, had a powerful effect in eliciting oviposition by gravid B. dorsalis females. Electrophysiological responses were obtained and flies clearly differentiated between treated and untreated substrates over a wide range of concentrations of gamma-octalactone. It triggered an innate response in flies, overriding inputs from other modalities required for oviposition site evaluation. A complex blend of mango volatiles not containing gamma-octalactone elicited low levels of oviposition, whereas gamma octalactone alone elicited more oviposition response. Naive flies with different rearing histories showed similar responses to gamma-octalactone. Taken together, these results indicate that oviposition site selection in B. dorsalis is mediated through an IRT tuned to gamma-octalactone. Our study provides empirical data on a cue underpinning innate behavior and may also find use in control operations against this invasive horticultural pest. PMID- 24465691 TI - Targeting GRP75 improves HSP90 inhibitor efficacy by enhancing p53-mediated apoptosis in hepatocellular carcinoma. AB - Heat shock protein 90 (HSP90) inhibitors are potential drugs for cancer therapy. The inhibition of HSP90 on cancer cell growth largely through degrading client proteins, like Akt and p53, therefore, triggering cancer cell apoptosis. Here, we show that the HSP90 inhibitor 17-AAG can induce the expression of GRP75, a member of heat shock protein 70 (HSP70) family, which, in turn, attenuates the anti growth effect of HSP90 inhibition on cancer cells. Additionally, 17-AAG enhanced binding of GRP75 and p53, resulting in the retention of p53 in the cytoplasm. Blocking GRP75 with its inhibitor MKT-077 potentiated the anti-tumor effects of 17-AAG by disrupting the formation of GRP75-p53 complexes, thereby facilitating translocation of p53 into the nuclei and leading to the induction of apoptosis related genes. Finally, dual inhibition of HSP90 and GRP75 was found to significantly inhibit tumor growth in a liver cancer xenograft model. In conclusion, the GRP75 inhibitor MKT-077 enhances 17-AAG-induced apoptosis in HCCs and increases p53-mediated inhibition of tumor growth in vivo. Dual targeting of GRP75 and HSP90 may be a useful strategy for the treatment of HCCs. PMID- 24465692 TI - Identification of differentially expressed proteins in porcine alveolar macrophages infected with virulent/attenuated strains of porcine reproductive and respiratory syndrome virus. AB - The highly pathogenic porcine reproductive and respiratory syndrome virus (HP PRRSV) is still a serious threat to the swine industry. However, the pathogenic mechanism of HP-PRRSV remains unclear. We infected host porcine alveolar macrophages (PAMs) with the virulent HuN4 strain and the attenuated HuN4-F112 strain and then utilized fluorescent two-dimensional difference gel electrophoresis (2D-DIGE) to screen for intracellular proteins that were differentially expressed in host cells infected with the two strains. There were 153 proteins with significant different expression (P<0.01) observed, 42 of which were subjected to mass spectrometry, and 24 proteins were identified. PAM cells infected with the virulent strain showed upregulated expression of pyruvate kinase M2 (PKM2), heat shock protein beta-1 (HSPB1), and proteasome subunit alpha type 6 (PSMA6), which were downregulated in cells infected with the attenuated strain. The upregulation of PKM2 provides sufficient energy for viral replication, and the upregulation of HSPB1 inhibits host cell apoptosis and therefore facilitates mass replication of the virulent strain, while the upregulation of PSMA6 facilitates the evasion of immune surveillance by the virus. Studying on those molecules mentioned above may be able to help us to understand some unrevealed details of HP-PRRSV infection, and then help us to decrease its threat to the swine industry in the future. PMID- 24465693 TI - Human variants in the neuronal basic helix-loop-helix/Per-Arnt-Sim (bHLH/PAS) transcription factor complex NPAS4/ARNT2 disrupt function. AB - Neuronal Per-Arnt-Sim homology (PAS) Factor 4 (NPAS4) is a neuronal activity dependent transcription factor which heterodimerises with ARNT2 to regulate genes involved in inhibitory synapse formation. NPAS4 functions to maintain excitatory/inhibitory balance in neurons, while mouse models have shown it to play roles in memory formation, social interaction and neurodegeneration. NPAS4 has therefore been implicated in a number of neuropsychiatric or neurodegenerative diseases which are underpinned by defects in excitatory/inhibitory balance. Here we have explored a broad set of non synonymous human variants in NPAS4 and ARNT2 for disruption of NPAS4 function. We found two variants in NPAS4 (F147S and E257K) and two variants in ARNT2 (R46W and R107H) which significantly reduced transcriptional activity of the heterodimer on a luciferase reporter gene. Furthermore, we found that NPAS4.F147S was unable to activate expression of the NPAS4 target gene BDNF due to reduced dimerisation with ARNT2. Homology modelling predicts F147 in NPAS4 to lie at the dimer interface, where it appears to directly contribute to protein/protein interaction. We also found that reduced transcriptional activation by ARNT2 R46W was due to disruption of nuclear localisation. These results provide insight into the mechanisms of NPAS4/ARNT dimerisation and transcriptional activation and have potential implications for cognitive phenotypic variation and diseases such as autism, schizophrenia and dementia. PMID- 24465694 TI - The impact of height during childhood on the national prevalence rates of overweight. AB - BACKGROUND: It is known that height and body mass index (BMI) are correlated in childhood. However, its impact on the (trend of) national prevalence rates of overweight and obesity has never been investigated. The aim of our study is to investigate the relation between height and national prevalence rates of overweight and obesity in childhood between 1980, 1997, and 2009, and to calculate which fixed value of p (2.0,2.1, ...,3.0) in kg/m(p) during childhood is most accurate in predicting adult overweight. METHODS AND FINDINGS: Cross sectional growth data of children from three Dutch nationwide surveys in 1980, 1997, and 2009, and longitudinal data from the Terneuzen Birth Cohort and the Harpenden Growth Study were used. Relative risks (RR) and 95% confidence intervals (CI) were calculated. Our study showed that tall (>1 standard deviation (SD)) girls aged 5.0-13.9 y were more often overweight (RR = 3.5,95%CI:2.8-4.4) and obese (RR = 3.9,95%CI:2.1-7.4) than short girls (<-1 SD). Similar results were found in boys aged 5.0-14.9 y (RR = 4.4,95%CI:3.4-5.7 and RR = 5.3,95%CI:2.6 11.0). No large differences were found in the other age groups and in comparison with children with an average stature. Tall boys aged 2.0-4.9 y had a significantly higher positive trend in overweight between 1980 and 1997 compared to short boys (RR = 4.0,95%CI:1.38-11.9). For other age groups and in girls, no significant trends were found. The optimal Area Under the Curve (AUC) to predict adult overweight was found for p = 2.0. CONCLUSIONS AND SIGNIFICANCE: Tall girls aged 5.0-13.9y and tall boys aged 5.0-14.9y have much higher prevalence rates of overweight and obesity than their shorter peers. We suggest taking into account the impact of height when evaluating trends and variations of BMI distributions in childhood, and to use BMI to predict adult overweight. PMID- 24465695 TI - Elevated peripheral frequencies of Th22 cells: a novel potent participant in obesity and type 2 diabetes. AB - OBJECTIVE: Chronic low-grade inflammation has long been recognized as the central link between obesity and type 2 diabetes (T2D). The novel subset of T helper (Th) cells, Th22, plays an emerging role in chronic inflammation. We investigated the potential association between Th22 and the pathogenesis of obesity and T2D. METHODS: Ninety T2D inpatients (T2D group), 30 healthy participants with BMI ranged from 19 to 23.9 kg/m2 (CTL group) and 30 metabolically healthy obese controls with BMI >= 30 kg/m2 (MHO group) were employed in our study. Peripheral frequencies of Th22 and Th1 and Th17 cells were determined by flow cytometry based on their specific cytokine patterns. Cytokine levels in fresh plasma were quantified by ELISA. RESULTS: Compared to that in CTL group (1.18+/-0.06%, n = 28), peripheral frequency of Th22 cells was significantly increased in MHO group (1.88+/-0.10%, n = 30) and in T2D group (2.247+/-0.10%, n = 89). There was a consistent notable increase in plasma interleukin (IL)-22 of T2D patients [47.56 (30.55-76.89) pg/mL] as compared with that of MHO group [36.65 (29.52-55.70) pg/ml; *P<0.0001] and CTLs [36.33 (31.93-40.62) pg/mL; *P<0.0001]. Furthermore, other than Th1/Th17, previously frequently described participants in obesity and T2D, there was a strong correlation between Th22 frequency and the homeostasis model of assessment for insulin resistance index (r = 0.6771, *P<0.0001) and HOMA for beta-cell function (r = -0.7264, *P<0.0001). CONCLUSIONS: There were increased Th22 frequencies and IL-22 levels in obesity and T2D. Elevated Th22 and IL-22 also aided in the differentiation of MHO from T2D patients. The notable correlation implied that Th22 might play a more determinant role in both insulin resistance and beta-cell impairment. PMID- 24465696 TI - Autophagy inhibition contributes to the synergistic interaction between EGCG and doxorubicin to kill the hepatoma Hep3B cells. AB - (-)-Epigallocatechin-3-O-gallate(EGCG), the highest catechins from green tea, has promisingly been found to sensitize the efficacy of several chemotherapy agents like doxorubicin (DOX) in hepatocellular carcinoma (HCC) treatment. However, the detailed mechanisms by which EGCG augments the chemotherapeutic efficacy remain unclear. Herein, this study was designed to determine the synergistic impacts of EGCG and DOX on hepatoma cells and particularly to reveal whether the autophagic flux is involved in this combination strategy for the HCC. Electron microscopy and fluorescent microscopy confirmed that DOX significantly increased autophagic vesicles in hepatoma Hep3B cells. Western blot and trypan blue assay showed that the increasing autophagy flux by DOX impaired about 45% of DOX-induced cell death in these cells. Conversely, both qRT-PCR and western blotting showed that EGCG played dose-dependently inhibitory role in autophagy signaling, and that markedly promoted cellular growth inhibition. Amazingly, the combined treatment caused a synergistic effect with 40 to 60% increment on cell death and about 45% augmentation on apoptosis versus monotherapy pattern. The DOX-induced autophagy was abolished by this combination therapy. Rapamycin, an autophagic agonist, substantially impaired the anticancer effect of either DOX or combination with EGCG treatment. On the other hand, using small interference RNA targeting chloroquine autophagy-related gene Atg5 and beclin1 to inhibit autophagy signal, hepatoma cell death was dramatically enhanced. Furthermore, in the established subcutaneous Hep3B cells xenograft tumor model, about 25% reduction in tumor growth as well as 50% increment of apoptotic cells were found in combination therapy compared with DOX alone. In addition, immunohistochemistry analysis indicated that the suppressed tendency of autophagic hallmark microtubule associated protein light chain 3 (LC3) expressions was consistent with thus combined usage in vitro. Taken together, the current study suggested that EGCG emerges as a chemotherapeutic augmenter and synergistically enhances DOX anticancer effects involving autophagy inhibition in HCC. PMID- 24465697 TI - Fructooligosacharides reduce Pseudomonas aeruginosa PAO1 pathogenicity through distinct mechanisms. AB - Pseudomonas aeruginosa is ubiquitously present in the environment and acts as an opportunistic pathogen on humans, animals and plants. We report here the effects of the prebiotic polysaccharide inulin and its hydrolysed form FOS on this bacterium. FOS was found to inhibit bacterial growth of strain PAO1, while inulin did not affect growth rate or yield in a significant manner. Inulin stimulated biofilm formation, whereas a dramatic reduction of the biofilm formation was observed in the presence of FOS. Similar opposing effects were observed for bacterial motility, where FOS inhibited the swarming and twitching behaviour whereas inulin caused its stimulation. In co-cultures with eukaryotic cells (macrophages) FOS and, to a lesser extent, inulin reduced the secretion of the inflammatory cytokines IL-6, IL-10 and TNF-alpha. Western blot experiments indicated that the effects mediated by FOS in macrophages are associated with a decreased activation of the NF-kappaB pathway. Since FOS and inulin stimulate pathway activation in the absence of bacteria, the FOS mediated effect is likely to be of indirect nature, such as via a reduction of bacterial virulence. Further, this modulatory effect is observed also with the highly virulent ptxS mutated strain. Co-culture experiments of P. aeruginosa with IEC18 eukaryotic cells showed that FOS reduces the concentration of the major virulence factor, exotoxin A, suggesting that this is a possible mechanism for the reduction of pathogenicity. The potential of these compounds as components of antibacterial and anti-inflammatory cocktails is discussed. PMID- 24465698 TI - Illusory changes in body size modulate body satisfaction in a way that is related to non-clinical eating disorder psychopathology. AB - Historically, body size overestimation has been linked to abnormal levels of body dissatisfaction found in eating disorders. However, recently this relationship has been called into question. Indeed, despite a link between how we perceive and how we feel about our body seeming intuitive, until now lack of an experimental method to manipulate body size has meant that a causal link, even in healthy participants, has remained elusive. Recent developments in body perception research demonstrate that the perceptual experience of the body can be readily manipulated using multisensory illusions. The current study exploits such illusions to modulate perceived body size in an attempt to influence body satisfaction. Participants were presented with stereoscopic video images of slimmer and wider mannequin bodies viewed through head-mounted displays from first person perspective. Illusory ownership was induced by synchronously stroking the seen mannequin body with the unseen real body. Pre and post-illusion affective and perceptual measures captured changes in perceived body size and body satisfaction. Illusory ownership of a slimmer body resulted in participants perceiving their actual body as slimmer and giving higher ratings of body satisfaction demonstrating a direct link between perceptual and affective body representations. Change in body satisfaction following illusory ownership of a wider body, however, was related to degree of (non-clinical) eating disorder psychopathology, which can be linked to fluctuating body representations found in clinical samples. The results suggest that body perception is linked to body satisfaction and may be of importance for eating disorder symptomology. PMID- 24465699 TI - Early quick acuity score provides more complete data on emergency department walkouts. AB - INTRODUCTION: Many prior studies have compared the acuity of Emergency Department (ED) patients who have Left Without Being Seen (LWBS) against non-LWBS patients. A weakness in these studies is that patients may walk out prior to the assignment of a triage score, biasing comparisons. We report an operational change whereby acuity was assessed immediately upon patient arrival. We hypothesized more patients would receive acuity scores with EQAS. We also sought to compare LWBS and non-LWBS patient characteristics with reduced bias. METHODS: SETTING: urban, academic medical center. Retrospective cohort study, electronic chart review, collecting data on all ED patients presenting between 4/1/2010 and 10/31/2011 ("Traditional Acuity Score" period, TAS) and from 11/1/2011 to 3/31/2012 ("Early Quick Acuity Score" period, EQAS). We recorded disposition (LWBS versus non LWBS), acuity and demographics. For each subject during the EQAS period, we calculated how many prior ED visits and how many prior walkouts the subject had had during the TAS period. RESULTS: Acuity was recorded in 92,275 of 94,526 patients (97.6%) for TAS period, and 25,577 of 25,760 patients (99.3%) for EQAS period, a difference of 1.7% (1.5%, 1.8%). LWBS patients had acuity scores recorded in 5,180 of 7,040 cases (73.6%) during TAS period, compared with 897 of 1,010 cases (88.8%) during the EQAS period, a difference of 15.2% (14.8%, 15.7%). LWBS were more likely than non-LWBS to be male, were younger and had lower acuity scores. LWBS averaged 5.3 prior ED visits compared with 2.8 by non-LWBS, a difference of 2.5 (1.5, 3.5). LWBS averaged 1.3 prior ED walkouts compared with 0.2 among non-LWBS, a difference of 1.1 (0.8, 1.3). CONCLUSIONS: EQAS resulted in a higher proportion of patients receiving acuity scores, particularly among LWBS. This offers more complete data when comparing LWBS and non-LWBS patient characteristics. The comparison reinforced findings from prior studies. PMID- 24465700 TI - Spatial genetic structure patterns of phenotype-limited and boundary-limited expanding populations: a simulation study. AB - Range expansions may create a unique spatial genetic pattern characterized by alternate genetically homogeneous domains and allele frequency clines. Previous attempts to model range expansions have mainly focused on the loss of genetic diversity during expansions. Using individual-based models, we examined spatial genetic patterns under two expansion scenarios, boundary-limited range expansions (BLRE) and phenotype-limited range expansions (PhLRE). Our simulation revealed that the genetic diversity within populations lost quickly during the range expansion, while the genetic difference accumulated between populations. Consequently, accompanying the expansions, the overall diversity featured a slow decrease. Specifically, during BLREs, high speed of boundary motion facilitated the maintenance of total genetic diversity and sharpened genetic clines. Very slight constraints on boundary motion of BLREs drastically narrowed the homogeneous domains and increased the allele frequency fluctuations from those levels exhibited by PhLREs. Even stronger constraints, however, surprisingly brought the width of homogeneous domains and the allele frequency fluctuations back to the normal levels of PhLREs. Furthermore, high migration rates maintained a higher total genetic diversity than low ones did during PhLREs. Whereas, the total genetic diversities during BLREs showed a contrary pattern: higher when migration was low than those when migration was high. Besides, the increase of migration rates helped maintain a greater number of homogeneous domains during PhLREs, but their effects on the number of homogeneous domains during BLREs were not monotonous. Previous studies have showed that the homogenous domains can merge to form a few broad domains as the expansion went on, leading to fewer homogeneous domains. Our simulations, meanwhile, revealed that the range expansions could also rebuild homogeneous domains from the clines during the range expansion. It is possible that that the number of homogeneous domains was determined by the interaction of merging and newly emerging homogeneous domains. PMID- 24465701 TI - Characterization and interactome study of white spot syndrome virus envelope protein VP11. AB - White spot syndrome virus (WSSV) is a large enveloped virus. The WSSV viral particle consists of three structural layers that surround its core DNA: an outer envelope, a tegument and a nucleocapsid. Here we characterize the WSSV structural protein VP11 (WSSV394, GenBank accession number AF440570), and use an interactome approach to analyze the possible associations between this protein and an array of other WSSV and host proteins. Temporal transcription analysis showed that vp11 is an early gene. Western blot hybridization of the intact viral particles and fractionation of the viral components, and immunoelectron microscopy showed that VP11 is an envelope protein. Membrane topology software predicted VP11 to be a type of transmembrane protein with a highly hydrophobic transmembrane domain at its N-terminal. Based on an immunofluorescence assay performed on VP11 transfected Sf9 cells and a trypsin digestion analysis of the virion, we conclude that, contrary to topology software prediction, the C-terminal of this protein is in fact inside the virion. Yeast two-hybrid screening combined with co immunoprecipitation assays found that VP11 directly interacted with at least 12 other WSSV structural proteins as well as itself. An oligomerization assay further showed that VP11 could form dimers. VP11 is also the first reported WSSV structural protein to interact with the major nucleocapsid protein VP664. PMID- 24465702 TI - Imaging mitochondrial flux in single cells with a FRET sensor for pyruvate. AB - Mitochondrial flux is currently accessible at low resolution. Here we introduce a genetically-encoded FRET sensor for pyruvate, and methods for quantitative measurement of pyruvate transport, pyruvate production and mitochondrial pyruvate consumption in intact individual cells at high temporal resolution. In HEK293 cells, neurons and astrocytes, mitochondrial pyruvate uptake was saturated at physiological levels, showing that the metabolic rate is determined by intrinsic properties of the organelle and not by substrate availability. The potential of the sensor was further demonstrated in neurons, where mitochondrial flux was found to rise by 300% within seconds of a calcium transient triggered by a short theta burst, while glucose levels remained unaltered. In contrast, astrocytic mitochondria were insensitive to a similar calcium transient elicited by extracellular ATP. We expect the improved resolution provided by the pyruvate sensor will be of practical interest for basic and applied researchers interested in mitochondrial function. PMID- 24465703 TI - Diabetes and risk of Parkinson's disease: an updated meta-analysis of case control studies. AB - BACKGROUND: Whether diabetes increases the risk of Parkinson's disease (PD) is still inconclusive. The objective of this updated meta-analysis is to synthesize evidence from case-control studies that evaluated the association between diabetes and the risk of PD. METHODS: Seven databases were searched to identify case-control studies that evaluated the association between diabetes and PD. The methodological quality of included studies was assessed using Newcastle-Ottawa scale. All data were analyzed using Review Manager 5.1 software. Subgroup analyses were also adopted, according to stratification on gender, geographic location, source of the control group, smoking, anti-diabetes drug prescription and duration of DM. RESULTS: Fourteen studies fulfilled inclusion criteria for meta-analysis, yielding a total of 21395 PD patients and 84579 control subjects. Individuals with diabetes were found to have a negative association with future PD (OR 0.75; 95% CI 0.58-0.98) in spite of significant heterogeneity. In subgroup analyses, the negative correlation was still found in studies from North America, non-PD control groups from general population, never smoking individuals, and DM ascertainment based on questionnaire or self-report. Stratification of gender and DM duration showed no significant association. No association was also found in European and Asian individuals, hospital-based controls, ever smoking subjects, DM assessment by medical record or physician diagnosis, and insulin prescription for DM. CONCLUSION: Evidence from case-control studies suggested that diabetic individuals may have a decreased incidence of PD despite significant heterogeneity. More researches are warranted to clarify an understanding of the association between diabetes and risk of PD. PMID- 24465704 TI - Ologen implant versus mitomycin C for trabeculectomy: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the application of the Ologen implant compared to mitomycin C (MMC) on the outcome of trabeculectomy and to examine the balance of risks and benefits. METHODS: A systematic literature search (Pubmed, Embase, the Cochrane Library, and the Chinese Biomedicine Database) was performed. Randomized controlled trials comparing the Ologen implant with MMC in trabeculectomy were selected. The efficacy measures were the weighted mean differences (WMDs) for the intraocular pressure reduction (IOPR), the reduction in glaucoma medications, and the relative risks (RRs) for success rates. The tolerability measures were RRs for adverse events. The pooled effects were calculated using the random-effects model. RESULTS: Seven randomized controlled trials including 227 eyes were included in this meta-analysis. The WMDs of the IOPR comparing the Ologen group with the MMC group were -2.98 (95% Cl: -5.07 to -0.89) at one month, -1.41 (-3.72 to 0.91) at three months, -1.69 (-3.68 to 0.30) at six months, -1.94 (-3.88 to 0.01) at 12 months, and 0.65 (-2.17 to 0.47) at 24 months. There was no statistically significance except at one and 12 months after surgery. No significant difference in the reduction in glaucoma medications or complete and qualified success rates were found. The rates of adverse events also did not differ significantly between Ologen and MMC. CONCLUSIONS: The Ologen implant is comparable with MMC for trabeculectomy in IOP-lowering efficacy, reduction in the number of glaucoma medications, success rates, and tolerability. However, the results should be interpreted cautiously since relevant evidence is still limited, although it is accumulating. Further large-scale, well-designed randomized controlled trials are urgently needed. PMID- 24465705 TI - Pulsed irradiation improves target selectivity of infrared laser-evoked gene operator for single-cell gene induction in the nematode C. elegans. AB - Methods for turning on/off gene expression at the experimenter's discretion would be useful for various biological studies. Recently, we reported on a novel microscope system utilizing an infrared laser-evoked gene operator (IR-LEGO) designed for inducing heat shock response efficiently in targeted single cells in living organisms without cell damage, thereby driving expression of a transgene under the control of a heat shock promoter. Although the original IR-LEGO can be successfully used for gene induction, several limitations hinder its wider application. Here, using the nematode Caenorhabditis elegans (C. elegans) as a subject, we have made improvements in IR-LEGO. For better spatial control of heating, a pulsed irradiation method using an optical chopper was introduced. As a result, single cells of C. elegans embryos as early as the 2-cell stage and single neurons in ganglia can be induced to express genes selectively. In addition, the introduction of site-specific recombination systems to IR-LEGO enables the induction of gene expression controlled by constitutive and cell type specific promoters. The strategies adopted here will be useful for future applications of IR-LEGO to other organisms. PMID- 24465706 TI - Mechanisms of Ghrelin anti-heart failure: inhibition of Ang II-induced cardiomyocyte apoptosis by down-regulating AT1R expression. AB - BACKGROUND: Ghrelin is a novel growth hormone-releasing peptide administered to treat chronic heart failure (CHF). However, the underlying mechanism of its protective effects against heart failure (HF) remains unclear. METHODS AND RESULTS: A total of 68 patients with CHF and 20 healthy individuals were included. The serum levels of Angiotensin II (Ang II) and ghrelin were measured using ELISA. The results showed that Ang II and ghrelin were both significantly increased in CHF patients and that the ghrelin levels were significantly positively correlated with Ang II. The left anterior descending coronary artery was ligated to establish a rat model of CHF, and cultured cardiomyocytes from neonatal rats were stimulated with Ang II to explore the role of ghrelin in CHF. The results showed that ghrelin inhibited cardiomyocyte apoptosis both in vivo and in vitro. Furthermore, caspase-3 expression was examined, and the results revealed that Ang II induces cardiomyocyte apoptosis through the caspase-3 pathway, whereas ghrelin inhibits this action. Lastly, to further elucidate the mechanism by which ghrelin inhibits Ang II action, the expression of the AT1 and AT2 receptors was evaluated; the results showed that Ang II up-regulates the AT1 and AT2 receptors in cardiomyocytes, whereas ghrelin inhibits AT1 receptor up regulation but does not affect AT2 receptor expression. CONCLUSIONS: These data suggest that the serum levels of ghrelin are significantly positively correlated with Ang II in CHF patients and that ghrelin can inhibit Ang II-induced cardiomyocyte apoptosis by down-regulating AT1R, thereby playing a role in preventing HF. PMID- 24465707 TI - Seaweed-coral interactions: variance in seaweed allelopathy, coral susceptibility, and potential effects on coral resilience. AB - Tropical reefs are in global decline with seaweeds commonly replacing corals. Negative associations between macroalgae and corals are well documented, but the mechanisms involved, the dynamics of the interactions, and variance in effects of different macroalgal-coral pairings are poorly investigated. We assessed the frequency, magnitude, and dynamics of macroalgal-coral competition involving allelopathic and non-allelopathic macroalgae on three, spatially grouped pairs of no-take Marine Protected Areas (MPAs) and non-MPAs in Fiji. In non-MPAs, biomass of herbivorous fishes was 70-80% lower, macroalgal cover 4-9 fold higher, macroalgal-coral contacts 5-15 fold more frequent and 23-67 fold more extensive (measured as % of colony margin contacted by macroalgae), and coral cover 51-68% lower than in MPAs. Coral contacts with allelopathic macroalgae occurred less frequently than expected by chance across all sites, while contact with non allelopathic macroalgae tended to occur more frequently than expected. Transplants of allelopathic macroalgae (Chlorodesmis fastigiata and Galaxaura filamentosa) against coral edges inflicted damage to Acropora aspera and Pocillopora damicornis more rapidly and extensively than to Porites cylindrica and Porites lobata, which appeared more resistant to these macroalgae. Montipora digitata experienced intermediate damage. Extent of damage from macroalgal contact was independent of coral colony size for each of the 10 macroalgal-coral pairings we established. When natural contacts with Galaxaura filamentosa were removed in the field, recovery was rapid for Porites lobata, but Pocillopora damicornis did not recover and damage continued to expand. As macroalgae increase on overfished tropical reefs, allelopathy could produce feedbacks that suppress coral resilience, prevent coral recovery, and promote the stability of algal beds in habitats previously available to corals. PMID- 24465708 TI - Detrended fluctuation analysis and adaptive fractal analysis of stride time data in Parkinson's disease: stitching together short gait trials. AB - Variability indicates motor control disturbances and is suitable to identify gait pathologies. It can be quantified by linear parameters (amplitude estimators) and more sophisticated nonlinear methods (structural information). Detrended Fluctuation Analysis (DFA) is one method to measure structural information, e.g., from stride time series. Recently, an improved method, Adaptive Fractal Analysis (AFA), has been proposed. This method has not been applied to gait data before. Fractal scaling methods (FS) require long stride-to-stride data to obtain valid results. However, in clinical studies, it is not usual to measure a large number of strides (e.g., [Formula: see text][Formula: see text] strides). Amongst others, clinical gait analysis is limited due to short walkways, thus, FS seem to be inapplicable. The purpose of the present study was to evaluate FS under clinical conditions. Stride time data of five self-paced walking trials ([Formula: see text] strides each) of subjects with PD and a healthy control group (CG) was measured. To generate longer time series, stride time sequences were stitched together. The coefficient of variation (CV), fractal scaling exponents [Formula: see text] (DFA) and [Formula: see text] (AFA) were calculated. Two surrogate tests were performed: A) the whole time series was randomly shuffled; B) the single trials were randomly shuffled separately and afterwards stitched together. CV did not discriminate between PD and CG. However, significant differences between PD and CG were found concerning [Formula: see text] and [Formula: see text]. Surrogate version B yielded a higher mean squared error and empirical quantiles than version A. Hence, we conclude that the stitching procedure creates an artificial structure resulting in an overestimation of true [Formula: see text]. The method of stitching together sections of gait seems to be appropriate in order to distinguish between PD and CG with FS. It provides an approach to integrate FS as standard in clinical gait analysis and to overcome limitations such as short walkways. PMID- 24465709 TI - Bluetongue virus nonstructural protein NS3/NS3a is not essential for virus replication. AB - Orbiviruses form the largest genus of the family Reoviridae consisting of at least 23 different virus species. One of these is the bluetongue virus (BTV) and causes severe hemorrhagic disease in ruminants, and is transmitted by bites of Culicoides midges. BTV is a non-enveloped virus which is released from infected cells by cell lysis and/or a unique budding process induced by nonstructural protein NS3/NS3a encoded by genome segment 10 (Seg-10). Presence of both NS3 and NS3a is highly conserved in Culicoides borne orbiviruses which is suggesting an essential role in virus replication. We used reverse genetics to generate BTV mutants to study the function of NS3/NS3a in virus replication. Initially, BTV with small insertions in Seg-10 showed no CPE but after several passages these BTV mutants reverted to CPE phenotype comparable to wtBTV, and NS3/NS3a expression returned by repair of the ORF. These results show that there is a strong selection for functional NS3/NS3a. To abolish NS3 and/or NS3a expression, Seg-10 with one or two mutated start codons (mutAUG1, mutAUG2 and mutAUG1+2) were used to generate BTV mutants. Surprisingly, all three BTV mutants were generated and the respective AUG(Met)->GCC(Ala) mutations were maintained. The lack of expression of NS3, NS3a, or both proteins was confirmed by westernblot analysis and immunostaining of infected cells with NS3/NS3a Mabs. Growth of mutAUG1 and mutAUG1+2 virus in BSR cells was retarded in both insect and mammalian cells, and particularly virus release from insect cells was strongly reduced. Our findings now enable research on the role of RNA sequences of Seg-10 independent of known gene products, and on the function of NS3/NS3a proteins in both types of cells as well as in the host and insect vector. PMID- 24465710 TI - Chemo-immunotherapy with oxaliplatin and interleukin-7 inhibits colon cancer metastasis in mice. AB - Combination of immunotherapy and chemotherapy has shown promise for cancer. Interleukin-7 (IL-7) can potentially enhance immune responses against tumor, while oxaliplatin (OXP), a platinum-based drug, can promote a favorable immune microenvironment and stimulate anticancer immune responses. We evaluated the anti tumor activity of IL-7 combining OXP against a murine colon carcinoma in vitro and in vivo and studied the tumor immune microenvironment to investigate whether the combined treatment affects on the local immune cell populations. Utilizing lung and abdomen metastasis models by inoculation of CT26 mice colon cancer cells, we evaluated the anti-tumor efficacy of combining IL-7 and OXP in mice models. Tumor immune microenvironment was evaluated by flow cytometric analysis and immunohistochemical staining. Our study showed that the in vivo administration of IL-7 combined with OXP markedly inhibited the growth of tumors in lung and abdomen metastasis models of colon cancer. IL-7 alone had no effect on tumor growth in mice and IL-7 did not alter cell sensitivity to OXP in culture. The antitumor effect of combining IL-7 and OXP correlated with a marked increase in the number of tumor-infiltrating activated CD8+ T cells and a marked decrease in the number of regulatory T (Treg) cells in spleen. Our data suggest that OXP plus IL-7 treatment inhibits tumor cell growth by immunoregulation rather than direct cytotoxicity. Our findings justify further evaluation of combining IL-7 and chemotherapy as a novel experimental cancer therapy. PMID- 24465711 TI - Cooperative integration and representation underlying bilateral network of fly motion-sensitive neurons. AB - How is binocular motion information integrated in the bilateral network of wide field motion-sensitive neurons, called lobula plate tangential cells (LPTCs), in the visual system of flies? It is possible to construct an accurate model of this network because a complete picture of synaptic interactions has been experimentally identified. We investigated the cooperative behavior of the network of horizontal LPTCs underlying the integration of binocular motion information and the information representation in the bilateral LPTC network through numerical simulations on the network model. First, we qualitatively reproduced rotational motion-sensitive response of the H2 cell previously reported in vivo experiments and ascertained that it could be accounted for by the cooperative behavior of the bilateral network mainly via interhemispheric electrical coupling. We demonstrated that the response properties of single H1 and Hu cells, unlike H2 cells, are not influenced by motion stimuli in the contralateral visual hemi-field, but that the correlations between these cell activities are enhanced by the rotational motion stimulus. We next examined the whole population activity by performing principal component analysis (PCA) on the population activities of simulated LPTCs. We showed that the two orthogonal patterns of correlated population activities given by the first two principal components represent the rotational and translational motions, respectively, and similar to the H2 cell, rotational motion produces a stronger response in the network than does translational motion. Furthermore, we found that these population-coding properties are strongly influenced by the interhemispheric electrical coupling. Finally, to test the generality of our conclusions, we used a more simplified model and verified that the numerical results are not specific to the network model we constructed. PMID- 24465713 TI - Population assessment of future trajectories in coronary heart disease mortality. AB - BACKGROUND: Coronary heart disease (CHD) mortality rates have been decreasing in Iceland since the 1980s, largely reflecting improvements in cardiovascular risk factors. The purpose of this study was to predict future CHD mortality in Iceland based on potential risk factor trends. METHODS AND FINDINGS: The previously validated IMPACT model was used to predict changes in CHD mortality between 2010 and 2040 among the projected population of Iceland aged 25-74. Calculations were based on combining: i) data on population numbers and projections (Statistics Iceland), ii) population risk factor levels and projections (Refine Reykjavik study), and iii) effectiveness of specific risk factor reductions (published meta analyses). Projections for three contrasting scenarios were compared: (1) If the historical risk factor trends of past 30 years were to continue, the declining death rates of past decades would level off, reflecting population ageing. (2) If recent trends in risk factors (past 5 years) continue, this would result in a death rate increasing from 49 to 70 per 100,000. This would reflect a recent plateau in previously falling cholesterol levels and recent rapid increases in obesity and diabetes prevalence. 3) Assuming that in 2040 the entire population enjoys optimal risk factor levels observed in low risk cohorts, this would prevent almost all premature CHD deaths before 2040. CONCLUSIONS: The potential increase in CHD deaths with recent trends in risk factor levels is alarming both for Iceland and probably for comparable Western populations. However, our results show considerable room for reducing CHD mortality. Achieving the best case scenario could eradicate premature CHD deaths by 2040. Public health policy interventions based on these predictions may provide a cost effective means of reducing CHD mortality in the future. PMID- 24465712 TI - pTyr421 cortactin is overexpressed in colon cancer and is dephosphorylated by curcumin: involvement of non-receptor type 1 protein tyrosine phosphatase (PTPN1). AB - Cortactin (CTTN), first identified as a major substrate of the Src tyrosine kinase, actively participates in branching F-actin assembly and in cell motility and invasion. CTTN gene is amplified and its protein is overexpressed in several types of cancer. The phosphorylated form of cortactin (pTyr(421)) is required for cancer cell motility and invasion. In this study, we demonstrate that a majority of the tested primary colorectal tumor specimens show greatly enhanced expression of pTyr(421)-CTTN, but no change at the mRNA level as compared to healthy subjects, thus suggesting post-translational activation rather than gene amplification in these tumors. Curcumin (diferulolylmethane), a natural compound with promising chemopreventive and chemosensitizing effects, reduced the indirect association of cortactin with the plasma membrane protein fraction in colon adenocarcinoma cells as measured by surface biotinylation, mass spectrometry, and Western blotting. Curcumin significantly decreased the pTyr(421)-CTTN in HCT116 cells and SW480 cells, but was ineffective in HT-29 cells. Curcumin physically interacted with PTPN1 tyrosine phosphatases to increase its activity and lead to dephosphorylation of pTyr(421)-CTTN. PTPN1 inhibition eliminated the effects of curcumin on pTyr(421)-CTTN. Transduction with adenovirally-encoded CTTN increased migration of HCT116, SW480, and HT-29. Curcumin decreased migration of HCT116 and SW480 cells which highly express PTPN1, but not of HT-29 cells with significantly reduced endogenous expression of PTPN1. Curcumin significantly reduced the physical interaction of CTTN and pTyr(421)-CTTN with p120 catenin (CTNND1). Collectively, these data suggest that curcumin is an activator of PTPN1 and can reduce cell motility in colon cancer via dephosphorylation of pTyr(421)-CTTN which could be exploited for novel therapeutic approaches in colon cancer therapy based on tumor pTyr(421)-CTTN expression. PMID- 24465714 TI - A 50-m forest cover map in Southeast Asia from ALOS/PALSAR and its application on forest fragmentation assessment. AB - Southeast Asia experienced higher rates of deforestation than other continents in the 1990s and still was a hotspot of forest change in the 2000s. Biodiversity conservation planning and accurate estimation of forest carbon fluxes and pools need more accurate information about forest area, spatial distribution and fragmentation. However, the recent forest maps of Southeast Asia were generated from optical images at spatial resolutions of several hundreds of meters, and they do not capture well the exceptionally complex and dynamic environments in Southeast Asia. The forest area estimates from those maps vary substantially, ranging from 1.73*10(6) km(2) (GlobCover) to 2.69*10(6) km(2) (MCD12Q1) in 2009; and their uncertainty is constrained by frequent cloud cover and coarse spatial resolution. Recently, cloud-free imagery from the Phased Array Type L-band Synthetic Aperture Radar (PALSAR) onboard the Advanced Land Observing Satellite (ALOS) became available. We used the PALSAR 50-m orthorectified mosaic imagery in 2009 to generate a forest cover map of Southeast Asia at 50-m spatial resolution. The validation, using ground-reference data collected from the Geo-Referenced Field Photo Library and high-resolution images in Google Earth, showed that our forest map has a reasonably high accuracy (producer's accuracy 86% and user's accuracy 93%). The PALSAR-based forest area estimates in 2009 are significantly correlated with those from GlobCover and MCD12Q1 at national and subnational scales but differ in some regions at the pixel scale due to different spatial resolutions, forest definitions, and algorithms. The resultant 50-m forest map was used to quantify forest fragmentation and it revealed substantial details of forest fragmentation. This new 50-m map of tropical forests could serve as a baseline map for forest resource inventory, deforestation monitoring, reducing emissions from deforestation and forest degradation (REDD+) implementation, and biodiversity. PMID- 24465715 TI - Parathyroid hormone related-protein promotes epithelial-to-mesenchymal transition in prostate cancer. AB - Parathyroid hormone-related protein (PTHrP) possesses a variety of physiological and developmental functions and is also known to facilitate the progression of many common cancers, notably their skeletal invasion, primarily by increasing bone resorption. The purpose of this study was to determine whether PTHrP could promote epithelial-to-mesenchymal transition (EMT), a process implicated in cancer stem cells that is critically involved in cancer invasion and metastasis. EMT was observed in DU 145 prostate cancer cells stably overexpressing either the 1-141 or 1-173 isoform of PTHrP, where there was upregulation of Snail and vimentin and downregulation of E-cadherin relative to parental DU 145. By contrast, the opposite effect was observed in PC-3 prostate cancer cells where high levels of PTHrP were knocked-down via lentiviral siRNA transduction. Increased tumor progression was observed in PTHrP-overexpressing DU 145 cells while decreased progression was observed in PTHrP-knockdown PC-3 cells. PTHrP overexpressing DU 145 formed larger tumors when implanted orthoptopically into nude mice and in one case resulted in spinal metastasis, an effect not observed among mice injected with parental DU 145 cells. PTHrP-overexpressing DU 145 cells also caused significant bone destruction when injected into the tibiae of nude mice, while parental DU 145 cells caused little to no destruction of bone. Together, these results suggest that PTHrP may work through EMT to promote an aggressive and metastatic phenotype in prostate cancer, a pathway of importance in cancer stem cells. Thus, continued efforts to elucidate the pathways involved in PTHrP-induced EMT as well as to develop ways to specifically target PTHrP signaling may lead to more effective therapies for prostate cancer. PMID- 24465716 TI - Fructose-bisphosphate aldolase a is a potential metastasis-associated marker of lung squamous cell carcinoma and promotes lung cell tumorigenesis and migration. AB - Fructose-bisphosphate aldolase A (ALDOA) is a key enzyme in glycolysis and is responsible for catalyzing the reversible conversion of fructose-1,6-bisphosphate to glyceraldehydes-3-phosphate and dihydroxyacetone phosphate. ALDOA contributes to various cellular functions such as muscle maintenance, regulation of cell shape and mobility, striated muscle contraction, actin filament organization and ATP biosynthetic process. Here, we reported that ALDOA is a highly expressed in lung squamous cell carcinoma (LSCC) and its expression level is correlated with LSCC metastasis, grades, differentiation status and poor prognosis. Depletion of ALDOA expression in the lung squamous carcinoma NCI-H520 cells reduces the capabilities of cell motility and tumorigenesis. These data suggest that ALDOA could be a potential marker for LSCC metastasis and a therapeutic target for drug development. PMID- 24465717 TI - Scrutinizing virus genome termini by high-throughput sequencing. AB - Analysis of genomic terminal sequences has been a major step in studies on viral DNA replication and packaging mechanisms. However, traditional methods to study genome termini are challenging due to the time-consuming protocols and their inefficiency where critical details are lost easily. Recent advances in next generation sequencing (NGS) have enabled it to be a powerful tool to study genome termini. In this study, using NGS we sequenced one iridovirus genome and twenty phage genomes and confirmed for the first time that the high frequency sequences (HFSs) found in the NGS reads are indeed the terminal sequences of viral genomes. Further, we established a criterion to distinguish the type of termini and the viral packaging mode. We also obtained additional terminal details such as terminal repeats, multi-termini, asymmetric termini. With this approach, we were able to simultaneously detect details of the genome termini as well as obtain the complete sequence of bacteriophage genomes. Theoretically, this application can be further extended to analyze larger and more complicated genomes of plant and animal viruses. This study proposed a novel and efficient method for research on viral replication, packaging, terminase activity, transcription regulation, and metabolism of the host cell. PMID- 24465718 TI - Angiopoietin-like 4 confers resistance to hypoxia/serum deprivation-induced apoptosis through PI3K/Akt and ERK1/2 signaling pathways in mesenchymal stem cells. AB - Angiopoietin-like 4 (ANGPTL4) is a potential anti-apoptotic agent for various cells. We examined the protective effect of ANGPTL4 on hypoxia/serum deprivation (SD)-induced apoptosis of MSCs, as well as the possible mechanisms. MSCs were obtained from rat bone marrow and cultured in vitro. Apoptosis was induced by hypoxia/SD for up to 24 hr, and assessed by flow cytometry and TUNEL assay. Expression levels of Akt, ERK1/2, focal adhesion kinase (FAK), Src, Bcl-2, Bax, cytochrome C and cleaved caspase-3 were detected by Western blotting. Integrin beta1 mRNA was detected by qRT-PCR. Mitochondrial membrane potential was assayed using a membrane-permeable dye. Hypoxia/SD-induced apoptosis was significantly attenuated by recombinant rat ANGPTL4 in a concentration dependent manner. Moreover, ANGPTL4 decreased the hypoxia/SD-induced caspase-3 cleavage and the cytochrome C release, but increased the Bcl-2/Bax ratio and the mitochondrial membrane potential. Decreased expression of integrin beta1, the ANGPTL4 receptor was observed during hypoxia/SD conditions, however, such decrease was reversed by ANGPTL4. In addition, ANGPTL4 induced integrin beta1-associated FAK and Src phosphorylation, which was blocked by anti-integrin beta1 antibody. ANGPTL4 also reversed the hypoxia/SD-induced decrease of Akt and ERK 1/2 phosphorylation, and the effect of ANGPTL4 was abolished by inhibitors of either integrins, ERK1/2, or phosphatidylinositol 3-kinase (PI3K). Blocking integrinbeta1, Akt or ERK largely attenuated anti-apoptotic effect of ANGPTL4. ANGPTL4 protects MSCs from hypoxia/SD-induced apoptosis by interacting with integrins to stimulate FAK complex, leading to downstream ERK1/2 and PI3K/Akt signaling pathways and mimicking the pathway in which MSCs contact with the extracellular matrix. PMID- 24465719 TI - Instruments to assess secondhand smoke exposure in large cohorts of never smokers: the smoke scales. AB - THE OBJECTIVES OF THIS STUDY WERE TO: (i) to develop questionnaires that can identify never-smoking children and adults experiencing increased exposure to secondhand smoke (SHS+), (ii) to determine their validity against hair nicotine, and (iii) assess their reliability. A sample of 191 children (85 males; 106 females; 7-18 years) and 95 adult (23 males; 72 females; 18-62 years) never smokers consented to hair nicotine analysis and answered a large number of questions assessing all sources of SHS. A randomly-selected 30% answered the questions again after 20-30 days. Prevalence of SHS+ in children and adults was 0.52+/-0.07 and 0.67+/-0.10, respectively (p<0.05). The Smoke Scale for Children (SS-C) and the Smoke Scale for Adults (SS-A) were developed via factor analysis and included nine questions each. Positivity criteria for SS-C and SS-A via receiver operating characteristics curve analysis were identified at >16.5 and >16, respectively. Significant Kappa agreement (p<0.05) was confirmed when comparing the SS-C and SS-A to hair nicotine concentration. Reliability analyses demonstrated that the SS-C and SS-A scores obtained on two different days are highly correlated (p<0.001) and not significantly different (p>0.05). Area under the curve and McNemar's Chi-square showed no pair-wise differences in sensitivity and specificity at the cutoff point between the two different days for SS-C and SS-A (p>0.05). We conclude that the SS-C and the SS-A represent valid, reliable, practical, and inexpensive instruments to identify children and adult never smokers exposed to increased SHS. Future research should aim to further increase the validity of the two questionnaires. PMID- 24465720 TI - Does computer survey technology improve reports on alcohol and illicit drug use in the general population? A comparison between two surveys with different data collection modes in France. AB - BACKGROUND: Previous studies have shown that survey methodology can greatly influence prevalence estimates for alcohol and illicit drug use. The aim of this article is to assess the effect of data collection modes on alcohol misuse and drug use reports by comparing national estimates from computer-assisted telephone interviews (CATI) and audio-computer-assisted self interviews (A-CASI). METHODS: DESIGN: Two national representative surveys conducted in 2005 in France by CATI (n = 24,674) and A-CASI (n = 8,111). PARTICIPANTS: French-speaking individuals aged [18]-[64] years old. MEASUREMENTS: Alcohol misuse according to the CAGE test, cannabis use (lifetime, last year, 10+ in last month) and experimentation with cocaine, LSD, heroin, amphetamines, ecstasy, were measured with the same questions and wordings in the two surveys. Multivariate logistic regressions controlling for sociodemographic characteristics (age, educational level, marital status and professional status) were performed. Analyses were conducted on the whole sample and stratified by age (18-29 and 30-44 years old) and gender. 45-64 years old data were not analysed due to limited numbers. RESULTS: Overall national estimates were similar for 9 out of the 10 examined measures. However, after adjustment, A-CASI provided higher use for most types of illicit drugs among the youngest men (adjusted odds ratio, or OR, of 1.64 [1.08-2.49] for cocaine, 1.62 [1.10-2.38] for ecstasy, 1.99 [1.17-3.37] for LSD, 2.17 [1.07-4.43] for heroin, and 2.48 [1.41-4.35] for amphetamines), whereas use amongst women was similar in CATI and A-CASI, except for LSD in the 30-44 age group (OR = 3.60 [1.64-7.89]). Reported alcohol misuse was higher with A-CASI, for all ages and genders. CONCLUSIONS: Although differences in the results over the whole population were relatively small between the surveys, the effect of data collection mode seemed to vary according to age and gender. PMID- 24465721 TI - Biview learning for human posture segmentation from 3D points cloud. AB - Posture segmentation plays an essential role in human motion analysis. The state of-the-art method extracts sufficiently high-dimensional features from 3D depth images for each 3D point and learns an efficient body part classifier. However, high-dimensional features are memory-consuming and difficult to handle on large scale training dataset. In this paper, we propose an efficient two-stage dimension reduction scheme, termed biview learning, to encode two independent views which are depth-difference features (DDF) and relative position features (RPF). Biview learning explores the complementary property of DDF and RPF, and uses two stages to learn a compact yet comprehensive low-dimensional feature space for posture segmentation. In the first stage, discriminative locality alignment (DLA) is applied to the high-dimensional DDF to learn a discriminative low-dimensional representation. In the second stage, canonical correlation analysis (CCA) is used to explore the complementary property of RPF and the dimensionality reduced DDF. Finally, we train a support vector machine (SVM) over the output of CCA. We carefully validate the effectiveness of DLA and CCA utilized in the two-stage scheme on our 3D human points cloud dataset. Experimental results show that the proposed biview learning scheme significantly outperforms the state-of-the-art method for human posture segmentation. PMID- 24465722 TI - Evolutionary and biotechnological implications of robust hydrogenase activity in halophilic strains of Tetraselmis. AB - Although significant advances in H2 photoproduction have recently been realized in fresh water algae (e.g. Chlamydomonas reinhardtii), relatively few studies have focused on H2 production and hydrogenase adaptations in marine or halophilic algae. Salt water organisms likely offer several advantages for biotechnological H2 production due to the global abundance of salt water, decreased H2 and O2 solubility in saline and hypersaline systems, and the ability of extracellular NaCl levels to influence metabolism. We screened unialgal isolates obtained from hypersaline ecosystems in the southwest United States and identified two distinct halophilic strains of the genus Tetraselmis (GSL1 and QNM1) that exhibit both robust fermentative and photo H2-production activities. The influence of salinity (3.5%, 5.5% and 7.0% w/v NaCl) on H2 production was examined during anoxic acclimation, with the greatest in vivo H2-production rates observed at 7.0% NaCl. These Tetraselmis strains maintain robust hydrogenase activity even after 24 h of anoxic acclimation and show increased hydrogenase activity relative to C. reinhardtii after extended anoxia. Transcriptional analysis of Tetraselmis GSL1 enabled sequencing of the cDNA encoding the FeFe-hydrogenase structural enzyme (HYDA) and its maturation proteins (HYDE, HYDEF and HYDG). In contrast to freshwater Chlorophyceae, the halophilic Tetraselmis GSL1 strain likely encodes a single HYDA and two copies of HYDE, one of which is fused to HYDF. Phylogenetic analyses of HYDA and concatenated HYDA, HYDE, HYDF and HYDG in Tetraselmis GSL1 fill existing knowledge gaps in the evolution of algal hydrogenases and indicate that the algal hydrogenases sequenced to date are derived from a common ancestor. This is consistent with recent hypotheses that suggest fermentative metabolism in the majority of eukaryotes is derived from a common base set of enzymes that emerged early in eukaryotic evolution with subsequent losses in some organisms. PMID- 24465723 TI - Actin filaments at the leading edge of cancer cells are characterized by a high mobile fraction and turnover regulation by profilin I. AB - Cellular motility is the basis for cancer cell invasion and metastasis. In the case of breast cancer, the most common type of cancer among women, metastasis represents the most devastating stage of the disease. The central role of cellular motility in cancer development emphasizes the importance of understanding the specific mechanisms involved in this process. In this context, tumor development and metastasis would be the consequence of a loss or defect of the mechanisms that control cytoskeletal remodeling. Profilin I belongs to a family of small actin binding proteins that are thought to assist in actin filament elongation at the leading edge of migrating cells. Traditionally, Profilin I has been considered to be an essential control element for actin polymerization and cell migration. Expression of Profilin I is down-regulated in breast and various other cancer cells. In MDA-MB-231 cells, a breast cancer cell line, further inhibition of Profilin I expression promotes hypermotility and metastatic spread, a finding that contrasts with the proposed role of Profilin in enhancing polymerization. In this report, we have taken advantage of the fluorescence recovery after photobleaching (FRAP) of GFP-actin to quantify and compare actin dynamics at the leading edge level in both cancer and non-cancer cell models. Our results suggest that (i) a high level of actin dynamics (i.e., a large mobile fraction of actin filaments and a fast turnover) is a common characteristic of some cancer cells; (ii) actin polymerization shows a high degree of independence from the presence of extracellular growth factors; and (iii) our results also corroborate the role of Profilin I in regulating actin polymerization, as raising the intracellular levels of Profilin I decreased the mobile fraction ratio of actin filaments and slowed their polymerization rate; furthermore, increased Profilin levels also led to reduced individual cell velocity and directionality. PMID- 24465724 TI - Amino acid isotope incorporation and enrichment factors in Pacific bluefin tuna, Thunnus orientalis. AB - Compound specific isotopic analysis (CSIA) of amino acids has received increasing attention in ecological studies in recent years due to its ability to evaluate trophic positions and elucidate baseline nutrient sources. However, the incorporation rates of individual amino acids into protein and specific trophic discrimination factors (TDFs) are largely unknown, limiting the application of CSIA to trophic studies. We determined nitrogen turnover rates of individual amino acids from a long-term (up to 1054 days) laboratory experiment using captive Pacific bluefin tuna, Thunnus orientalis (PBFT), a large endothermic pelagic fish fed a controlled diet. Small PBFT (white muscle delta(15)N~11.50/00) were collected in San Diego, CA and transported to the Tuna Research and Conservation Center (TRCC) where they were fed a controlled diet with high delta(15)N values relative to PBFT white muscle (diet delta(15)N~13.90/00). Half lives of trophic and source amino acids ranged from 28.6 to 305.4 days and 67.5 to 136.2 days, respectively. The TDF for the weighted mean values of amino acids was 3.0 0/00, ranging from 2.2 to 15.8 0/00 for individual combinations of 6 trophic and 5 source amino acids. Changes in the delta(15)N values of amino acids across trophic levels are the underlying drivers of the trophic (15)N enrichment. Nearly all amino acid delta(15)N values in this experiment changed exponentially and could be described by a single compartment model. Significant differences in the rate of (15)N incorporation were found for source and trophic amino acids both within and between these groups. Varying half-lives of individual amino acids can be applied to migratory organisms as isotopic clocks, determining the length of time an individual has spent in a new environment. These results greatly enhance the ability to interpret compound specific isotope analyses in trophic studies. PMID- 24465725 TI - DEspR roles in tumor vasculo-angiogenesis, invasiveness, CSC-survival and anoikis resistance: a 'common receptor coordinator' paradigm. AB - A priori, a common receptor induced in tumor microvessels, cancer cells and cancer stem-like cells (CSCs) that is involved in tumor angiogenesis, invasiveness, and CSC anoikis resistance and survival, could underlie contemporaneous coordination of these events rather than assume stochasticity. Here we show that functional analysis of the dual endothelin1/VEGFsignal peptide receptor, DEspR, (formerly named Dear, Chr.4q31.2) supports the putative common receptor paradigm in pancreatic ductal adenocarcinoma (PDAC) and glioblastoma (GBM) selected for their invasiveness, CD133+CSCs, and polar angiogenic features. Unlike normal tissue, DEspR is detected in PDAC and GBM microvessels, tumor cells, and CSCs isolated from PDAC-Panc1 and GBM-U87 cells. DEspR-inhibition decreased angiogenesis, invasiveness, CSC-survival and anoikis resistance in vitro, and decreased Panc1-CSC and U87-CSC xenograft tumor growth, vasculo angiogenesis and invasiveness in nude(nu/nu) rats, suggesting that DEspR activation would coordinate these tumor progression events. As an accessible, cell-surface 'common receptor coordinator', DEspR-inhibition defines a novel targeted-therapy paradigm for pancreatic cancer and glioblastoma. PMID- 24465726 TI - Malaria-infected female collared flycatchers (Ficedula albicollis) do not pay the cost of late breeding. AB - Life-history theory predicts that the trade-off between parasite defense and other costly traits such as reproduction may be most evident when resources are scarce. The strength of selection that parasites inflict on their host may therefore vary across environmental conditions. Collared flycatchers (Ficedula albicollis) breeding on the Swedish island Oland experience a seasonal decline in their preferred food resource, which opens the possibility to test the strength of life-history trade-offs across environmental conditions. We used nested-PCR and quantitative-PCR protocols to investigate the association of Haemosporidia infection with reproductive performance of collared flycatcher females in relation to a seasonal change in the external environment. We show that despite no difference in mean onset of breeding, infected females produced relatively more of their fledglings late in the season. This pattern was also upheld when considering only the most common malaria lineage (hPHSIB1), however there was no apparent link between the reproductive output and the intensity of infection. Infected females produced heavier-than-average fledglings with higher-than expected recruitment success late in the season. This reversal of the typical seasonal trend in reproductive output compensated them for lower fledging and recruitment rates compared to uninfected birds earlier in the season. Thus, despite different seasonal patterns of reproductive performance the overall number of recruits was the same for infected versus uninfected birds. A possible explanation for our results is that infected females breed in a different microhabitat where food availability is higher late in the season but also is the risk of infection. Thus, our results suggest that another trade-off than the one we aimed to test is more important for explaining variation in reproductive performance in this natural population: female flycatchers appear to face a trade off between the risk of infection and reproductive success late in the season. PMID- 24465727 TI - Identification of proteins related to epigenetic regulation in the malignant transformation of aberrant karyotypic human embryonic stem cells by quantitative proteomics. AB - Previous reports have demonstrated that human embryonic stem cells (hESCs) tend to develop genomic alterations and progress to a malignant state during long-term in vitro culture. This raises concerns of the clinical safety in using cultured hESCs. However, transformed hESCs might serve as an excellent model to determine the process of embryonic stem cell transition. In this study, ITRAQ-based tandem mass spectrometry was used to quantify normal and aberrant karyotypic hESCs proteins from simple to more complex karyotypic abnormalities. We identified and quantified 2583 proteins, and found that the expression levels of 316 proteins that represented at least 23 functional molecular groups were significantly different in both normal and abnormal hESCs. Dysregulated protein expression in epigenetic regulation was further verified in six pairs of hESC lines in early and late passage. In summary, this study is the first large-scale quantitative proteomic analysis of the malignant transformation of aberrant karyotypic hESCs. The data generated should serve as a useful reference of stem cell-derived tumor progression. Increased expression of both HDAC2 and CTNNB1 are detected as early as the pre-neoplastic stage, and might serve as prognostic markers in the malignant transformation of hESCs. PMID- 24465728 TI - Inhibition of oxygen-induced ischemic retinal neovascularization with adenoviral 15-lipoxygenase-1 gene transfer via up-regulation of PPAR-gamma and down regulation of VEGFR-2 expression. AB - 15-lipoxygenase-1 (15-LOX-1) plays an important role in angiogenesis, but how it works still remains a controversial subject. The aims of our study are focused on determining whether or not 15-LOX-1 inhibiting oxygen-induced ischemic retinal neovascularization (RNV) and the underlying regulatory mechanism involving of 15 LOX-1, peroxisome proliferator-activated receptor gamma (PPAR-gamma) and vascular endothelial growth factor receptor 2 (VEGFR-2) in oxygen-induced retinopathy (OIR). Recombinant adenoviral vectors that expressing the 15-LOX-1 gene (Ad-15 LOX-1-GFP) or the green fluorescence protein gene (Ad-GFP) were intravitreous injected into the OIR mice at postnatal day 12 (P12), the mice were sacrificed 5 days later (P17). Retinal 15-LOX-1 expression was significantly increased at both mRNA and protein levels after 15-LOX-1 gene transfer. Immunofluorescence staining of retinal sections revealed 15-LOX-1 expression was primarily in the outer plexiform layer (OPL), inner nuclear layer (INL) and ganglion cell layer (GCL) retina. Meanwhile, RNV was significantly inhibited indicated by fluorescein retinal angiography and quantification of the pre-retinal neovascular cells. The expression levels of PPAR-gamma were significantly up-regulated while VEGFR-2 were significantly down-regulated both in mRNA and protein levels. Our results suggested 15-LOX-1 gene transfer inhibited RNV in OIR mouse model via up regulation of PPAR-gamma and further down-regulation of VEGFR-2 expression. This could be a potentially important regulatory mechanism involving 15-LOX-1, PPAR gamma and VEGFR-2 during RNV in OIR. In conclusion, 15-LOX-1 may be a new therapeutic target for treating neovascularization diseases. PMID- 24465729 TI - Electrical resonance in the theta frequency range in olfactory amygdala neurons. AB - The cortical amygdala receives direct olfactory inputs and is thought to participate in processing and learning of biologically relevant olfactory cues. As for other brain structures implicated in learning, the principal neurons of the anterior cortical nucleus (ACo) exhibit intrinsic subthreshold membrane potential oscillations in the theta-frequency range. Here we show that nearly 50% of ACo layer II neurons also display electrical resonance, consisting of selective responsiveness to stimuli of a preferential frequency (2-6 Hz). Their impedance profile resembles an electrical band-pass filter with a peak at the preferred frequency, in contrast to the low-pass filter properties of other neurons. Most ACo resonant neurons displayed frequency preference along the whole subthreshold voltage range. We used pharmacological tools to identify the voltage dependent conductances implicated in resonance. A hyperpolarization-activated cationic current depending on HCN channels underlies resonance at resting and hyperpolarized potentials; notably, this current also participates in resonance at depolarized subthreshold voltages. KV7/KCNQ K+ channels also contribute to resonant behavior at depolarized potentials, but not in all resonant cells. Moreover, resonance was strongly attenuated after blockade of voltage-dependent persistent Na+ channels, suggesting an amplifying role. Remarkably, resonant neurons presented a higher firing probability for stimuli of the preferred frequency. To fully understand the mechanisms underlying resonance in these neurons, we developed a comprehensive conductance-based model including the aforementioned and leak conductances, as well as Hodgkin and Huxley-type channels. The model reproduces the resonant impedance profile and our pharmacological results, allowing a quantitative evaluation of the contribution of each conductance to resonance. It also replicates selective spiking at the resonant frequency and allows a prediction of the temperature-dependent shift in resonance frequency. Our results provide a complete characterization of the resonant behavior of olfactory amygdala neurons and shed light on a putative mechanism for network activity coordination in the intact brain. PMID- 24465730 TI - Binding mode analyses and pharmacophore model development for stilbene derivatives as a novel and competitive class of alpha-glucosidase inhibitors. AB - Stilbene urea derivatives as a novel and competitive class of non-glycosidic alpha-glucosidase inhibitors are effective for the treatment of type II diabetes and obesity. The main purposes of our molecular modeling study are to explore the most suitable binding poses of stilbene derivatives with analyzing the binding affinity differences and finally to develop a pharmacophore model which would represents critical features responsible for alpha-glucosidase inhibitory activity. Three-dimensional structure of S. cerevisiae alpha-glucosidase was built by homology modeling method and the structure was used for the molecular docking study to find out the initial binding mode of compound 12, which is the most highly active one. The initial structure was subjected to molecular dynamics (MD) simulations for protein structure adjustment at compound 12-bound state. Based on the adjusted conformation, the more reasonable binding modes of the stilbene urea derivatives were obtained from molecular docking and MD simulations. The binding mode of the derivatives was validated by correlation analysis between experimental Ki value and interaction energy. Our results revealed that the binding modes of the potent inhibitors were engaged with important hydrogen bond, hydrophobic, and pi-interactions. With the validated compound 12-bound structure obtained from combining approach of docking and MD simulation, a proper four featured pharmacophore model was generated. It was also validated by comparison of fit values with the Ki values. Thus, these results will be helpful for understanding the relationship between binding mode and bioactivity and for designing better inhibitors from stilbene derivatives. PMID- 24465732 TI - Prey vulnerability limits top-down control and alters reciprocal feedbacks in a subsidized model food web. AB - Resource subsidies increase the productivity of recipient food webs and can affect ecosystem dynamics. Subsidies of prey often support elevated predator biomass which may intensify top-down control and reduce the flow of reciprocal subsidies into adjacent ecosystems. However, top-down control in subsidized food webs may be limited if primary consumers posses morphological or behavioral traits that limit vulnerability to predation. In forested streams, terrestrial prey support high predator biomass creating the potential for strong top-down control, however armored primary consumers often dominate the invertebrate assemblage. Using empirically based simulation models, we tested the response of stream food webs to variations in subsidy magnitude, prey vulnerability, and the presence of two top predators. While terrestrial prey inputs increased predator biomass (+12%), the presence of armored primary consumers inhibited top-down control, and diverted most aquatic energy (~75%) into the riparian forest through aquatic insect emergence. Food webs without armored invertebrates experienced strong trophic cascades, resulting in higher algal (~50%) and detrital (~1600%) biomass, and reduced insect emergence (-90%). These results suggest prey vulnerability can mediate food web responses to subsidies, and that top-down control can be arrested even when predator-invulnerable consumers are uncommon (20%) regardless of the level of subsidy. PMID- 24465731 TI - Metabolic maturation of white matter is altered in preterm infants. AB - Significant physiological switches occur at birth such as the transition from fetal parallel blood flow to a two-circuit serial system with increased arterial oxygenation of blood delivered to all organs including the brain. In addition, the extra-uterine environment exposes premature infants to a host of stimuli. These events could conceivably alter the trajectory of brain development in premature infants. We used in vivo magnetic resonance spectroscopy to measure absolute brain metabolite concentrations in term and premature-born infants without evidence of brain injury at equivalent post-conceptional age. Prematurity altered the developmental time courses of N-acetyl-aspartate, a marker for axonal and neuronal development, creatine, an energy metabolite, and choline, a membrane metabolite, in parietal white matter. Specifically, at term-equivalency, metabolic maturation in preterm infants preceded development in term infants, but then progressed at a slower pace and trajectories merged at ~340-370 post conceptional days. In parieto/occipital grey matter similar trends were noticed but statistical significance was not reached. The timing of white matter development and synchronization of white matter and grey matter maturation in premature-born infants is disturbed. This may contribute to the greater risk of long-term neurological problems of premature infants and to their higher risk for white matter injury. PMID- 24465733 TI - Homocysteine level and risk of abdominal aortic aneurysm: a meta-analysis. AB - OBJECTIVES: Previous studies have reported inconsistent findings regarding the association between elevated plasma homocysteine (Hcy) levels and abdominal aortic aneurysm (AAA). We investigated this association between Hcy levels in patients with AAA and unaffected controls by conducting a meta-analysis and systematic review. METHODS: We conducted a systematic literature search (up to August 2013) of the PubMed database and Embase. We selected observational studies that evaluated Hcy levels in subjects with AAA compared to unaffected controls. Criteria for inclusion were the assessment of baseline Hcy and risk of AAA as an outcome. The results were presented as odd ratio (OR) and corresponding 95% confidence intervals (CI) comparing AAA patients to the control subjects. RESULTS: 7 studies with 6,445 participants were identified and analyzed. Overall, elevated plasma Hcy was associated with an increased risk of AAA (3.29; 95% CI 1.66-6.51). The pooled adjusted OR from a random effect model of only men participants in the AAA compared with the control group was 2.36 (95% CI 0.63 8.82). CONCLUSION: This meta-analysis and systematic review suggested that Hcy significantly increased the risk of AAA. PMID- 24465734 TI - Immunosuppressive drugs modulate the replication of hepatitis B virus (HBV) in a hydrodynamic injection mouse model. AB - Hepatitis B virus (HBV) reactivation and recurrence are common in patients under immunosuppression and can be controlled by hepatitis B immunoglobulin, antivirals, and hepatitis B vaccine. However, the detailed analysis of HBV infection under immunosuppression is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV replication and T cell responses were analyzed in a HBV-transfected mouse model under immunosuppressive therapy. During the treatment, HBV replication was at a high level in mice treated with dexamethasone, cyclosporine, and cyclophosphamide, whereas was terminated in mice treated with mycophenolate mofetil. After the withdrawal, HBV replication was at low or high levels in the dexamethasone-treated mice or in both cyclosporine- and cyclophosphamide-treated mice. The early withdrawal of cyclosporine allowed the recovery of suppressed T cell responses and led to subsequent HBV clearance, while the adoptive immune transfer to the mice with HBV persistence led to HBV suppression. Taken together, long-term HBV persistence under immunosuppression depends on the immunosuppressive drugs used and on the treatment duration and is mediated by the suppressed intrahepatic CD8 T cell response. These data may be helpful for individualized immunosuppressive therapy in patients with high risk of HBV reactivation and recurrence, and the mouse system is suitable for studying HBV reactivation and recurrence under immunosuppression. PMID- 24465735 TI - Btk regulates macrophage polarization in response to lipopolysaccharide. AB - Bacterial Lipopolysaccharide (LPS) is a strong inducer of inflammation and does so by inducing polarization of macrophages to the classic inflammatory M1 population. Given the role of Btk as a critical signal transducer downstream of TLR4, we investigated its role in M1/M2 induction. In Btk deficient (Btk (-?-)) mice we observed markedly reduced recruitment of M1 macrophages following intraperitoneal administration of LPS. Ex vivo analysis demonstrated an impaired ability of Btk(-/-) macrophages to polarize into M1 macrophages, instead showing enhanced induction of immunosuppressive M2-associated markers in response to M1 polarizing stimuli, a finding accompanied by reduced phosphorylation of STAT1 and enhanced STAT6 phosphorylation. In addition to STAT activation, M1 and M2 polarizing signals modulate the expression of inflammatory genes via differential activation of transcription factors and regulatory proteins, including NF-kappaB and SHIP1. In keeping with a critical role for Btk in macrophage polarization, we observed reduced levels of NF-kappaB p65 and Akt phosphorylation, as well as reduced induction of the M1 associated marker iNOS in Btk(-/-) macrophages in response to M1 polarizing stimuli. Additionally enhanced expression of SHIP1, a key negative regulator of macrophage polarisation, was observed in Btk(-/-) macrophages in response to M2 polarizing stimuli. Employing classic models of allergic M2 inflammation, treatment of Btk (-/-) mice with either Schistosoma mansoni eggs or chitin resulted in increased recruitment of M2 macrophages and induction of M2-associated genes. This demonstrates an enhanced M2 skew in the absence of Btk, thus promoting the development of allergic inflammation. PMID- 24465736 TI - Toxicity assessment of silica coated iron oxide nanoparticles and biocompatibility improvement by surface engineering. AB - We have studied in vitro toxicity of iron oxide nanoparticles (NPs) coated with a thin silica shell (Fe3O4/SiO2 NPs) on A549 and HeLa cells. We compared bare and surface passivated Fe3O4/SiO2 NPs to evaluate the effects of the coating on the particle stability and toxicity. NPs cytotoxicity was investigated by cell viability, membrane integrity, mitochondrial membrane potential (MMP), reactive oxygen species (ROS) assays, and their genotoxicity by comet assay. Our results show that NPs surface passivation reduces the oxidative stress and alteration of iron homeostasis and, consequently, the overall toxicity, despite bare and passivated NPs show similar cell internalization efficiency. We found that the higher toxicity of bare NPs is due to their stronger in-situ degradation, with larger intracellular release of iron ions, as compared to surface passivated NPs. Our results indicate that surface engineering of Fe3O4/SiO2 NPs plays a key role in improving particles stability in biological environments reducing both cytotoxic and genotoxic effects. PMID- 24465737 TI - In vitro and in vivo activity of a novel antifungal small molecule against Candida infections. AB - Candida is the most common fungal pathogen of humans worldwide and has become a major clinical problem because of the growing number of immunocompromised patients, who are susceptible to infection. Moreover, the number of available antifungals is limited, and antifungal-resistant Candida strains are emerging. New and effective antifungals are therefore urgently needed. Here, we discovered a small molecule with activity against Candida spp. both in vitro and in vivo. We screened a library of 50,240 small molecules for inhibitors of yeast-to-hypha transition, a major virulence attribute of Candida albicans. This screening identified 20 active compounds. Further examination of the in vitro antifungal and anti-biofilm properties of these compounds, using a range of Candida spp., led to the discovery of SM21, a highly potent antifungal molecule (minimum inhibitory concentration (MIC) 0.2-1.6 ug/ml). In vitro, SM21 was toxic to fungi but not to various human cell lines or bacterial species and was active against Candida isolates that are resistant to existing antifungal agents. Moreover, SM21 was relatively more effective against biofilms of Candida spp. than the current antifungal agents. In vivo, SM21 prevented the death of mice in a systemic candidiasis model and was also more effective than the common antifungal nystatin at reducing the extent of tongue lesions in a mouse model of oral candidiasis. Propidium iodide uptake assay showed that SM21 affected the integrity of the cell membrane. Taken together, our results indicate that SM21 has the potential to be developed as a novel antifungal agent for clinical use. PMID- 24465738 TI - Aging of non-visual spectral sensitivity to light in humans: compensatory mechanisms? AB - The deterioration of sleep in the older population is a prevalent feature that contributes to a decrease in quality of life. Inappropriate entrainment of the circadian clock by light is considered to contribute to the alteration of sleep structure and circadian rhythms in the elderly. The present study investigates the effects of aging on non-visual spectral sensitivity to light and tests the hypothesis that circadian disturbances are related to a decreased light transmittance. In a within-subject design, eight aged and five young subjects were exposed at night to 60 minute monochromatic light stimulations at 9 different wavelengths (420-620 nm). Individual sensitivity spectra were derived from measures of melatonin suppression. Lens density was assessed using a validated psychophysical technique. Although lens transmittance was decreased for short wavelength light in the older participants, melatonin suppression was not reduced. Peak of non-visual sensitivity was, however, shifted to longer wavelengths in the aged participants (494 nm) compared to young (484 nm). Our results indicate that increased lens filtering does not necessarily lead to a decreased non-visual sensitivity to light. The lack of age-related decrease in non-visual sensitivity to light may involve as yet undefined adaptive mechanisms. PMID- 24465739 TI - Characterization of the structure and immunostimulatory activity of a vaccine adjuvant, de-O-acylated lipooligosaccharide. AB - Lipopolysaccharide (LPS) is a major component of the outer membrane of Gram negative bacteria. LPS elicits strong immunopathological responses during bacterial infection, and the lipid A moiety of LPS is responsible for this immunostimulatory activity. Lipid A exerts its biological activity by sending signals via TLR4 present on immune cells, and TLR4 agonists have been a target for vaccine adjuvant. Previously, we demonstrated an adjuvant activity of deacylated lipooligosaccharide (dLOS) to viral and bacterial antigens. In this study, we characterized the chemical structure of dLOS and evaluated its immunostimulatory activity on mouse and human immune cells in comparison with monophosphoryl lipid A (MPL). dLOS consists of the R3-type core, a glucosamine disaccharide with two phosphate groups, and two N-linked acyl groups [corrected], and two N-linked acyl groups. dLOS was similar to MPL in induction of cytokine production in mouse peritoneal macrophages, but was a more potent activator in human monocytes and dendritic cells (DCs). Results of an analysis of allogeneic T cell responses revealed that dLOS induces Th1, Th2, and Th17-type immune responses in a dose-dependent manner. The immunostimulatory activities of dLOS were completely abrogated in TLR4(-/-) mice, which confirms its TLR4-dependency. These results suggest that in the presence of the core oligosaccharide, O-linked acyl groups of LPS are dispensable for activating the TLR4 signaling pathway. dLOS did not cause any pathological effects or death at 0.25, 0.5, or 1 mg per kg body weight in mice in the acute toxicity tests. This result suggests that dLOS has a low toxicity. dLOS should be considered for further development as a safe and effective adjuvant for human vaccines. PMID- 24465740 TI - Compartmental and temporal dynamics of chronic inflammation and airway remodelling in a chronic asthma mouse model. AB - BACKGROUND: Allergic asthma is associated with chronic airway inflammation and progressive airway remodelling. However, the dynamics of the development of these features and their spontaneous and pharmacological reversibility are still poorly understood. We have therefore investigated the dynamics of airway remodelling and repair in an experimental asthma model and studied how pharmacological intervention affects these processes. METHODS: Using BALB/c mice, the kinetics of chronic asthma progression and resolution were characterised in absence and presence of inhaled corticosteroid (ICS) treatment. Airway inflammation and remodelling was assessed by the analysis of bronchoalveolar and peribronichal inflammatory cell infiltrate, goblet cell hyperplasia, collagen deposition and smooth muscle thickening. RESULTS: Chronic allergen exposure resulted in early (goblet cell hyperplasia) and late remodelling (collagen deposition and smooth muscle thickening). After four weeks of allergen cessation eosinophilic inflammation, goblet cell hyperplasia and collagen deposition were resolved, full resolution of lymphocyte inflammation and smooth muscle thickening was only observed after eight weeks. ICS therapy when started before the full establishment of chronic asthma reduced the development of lung inflammation, decreased goblet cell hyperplasia and collagen deposition, but did not affect smooth muscle thickening. These effects of ICS on airway remodelling were maintained for a further four weeks even when therapy was discontinued. CONCLUSIONS: Utilising a chronic model of experimental asthma we have shown that repeated allergen exposure induces reversible airway remodelling and inflammation in mice. Therapeutic intervention with ICS was partially effective in inhibiting the transition from acute to chronic asthma by reducing airway inflammation and remodelling but was ineffective in preventing smooth muscle hypertrophy. PMID- 24465741 TI - Embryonic morphogen nodal is associated with progression and poor prognosis of hepatocellular carcinoma. AB - BACKGROUND: Nodal, a TGF-beta-related embryonic morphogen, is involved in multiple biologic processes. However, the expression of Nodal in hepatocellular carcinoma (HCC) and its correlation with tumor angiogenesis, epithelial mesenchymal transition, and prognosis is unclear. METHODS: We used real-time PCR and Western blotting to investigate Nodal expression in 6 HCC cell lines and 1 normal liver cell line, 16 pairs of tumor and corresponding paracarcinomatous tissues from HCC patients. Immunohistochemistry was performed to examine Nodal expression in HCC and corresponding paracarcinomatous tissues from 96 patients. CD34 and Vimentin were only examined in HCC tissues of patients mentioned above. Nodal gene was silenced by shRNA in MHCC97H and HCCLM3 cell lines, and cell migration and invasion were detected. Statistical analyses were applied to evaluate the prognostic value and associations of Nodal expression with clinical parameters. RESULTS: Nodal expression was detected in HCC cell lines with high metastatic potential alone. Nodal expression is up-regulated in HCC tissues compared with paracarcinomatous and normal liver tissues. Nodal protein was expressed in 70 of the 96 (72.9%) HCC tumors, and was associated with vascular invasion (P = 0.000), status of metastasis (P = 0.004), AFP (P = 0.049), ICGR15 (indocyanine green retention rate at 15 min) (P = 0.010) and tumor size (P = 0.000). High Nodal expression was positively correlated with high MVD (microvessal density) (P = 0.006), but not with Vimentin expression (P = 0.053). Significantly fewer migrated and invaded cells were seen in shRNA group compared with blank group and negative control group (P<0.05). High Nodal expression was found to be an independent factor for predicting overall survival of HCC. CONCLUSIONS: Our study demonstrated that Nodal expression is associated with aggressive characteristics of HCC. Its aberrant expression may be a predictive factor of unfavorable prognosis for HCC after surgery. PMID- 24465742 TI - Adaptation to changes in higher-order stimulus statistics in the salamander retina. AB - Adaptation in the retina is thought to optimize the encoding of natural light signals into sequences of spikes sent to the brain. While adaptive changes in retinal processing to the variations of the mean luminance level and second-order stimulus statistics have been documented before, no such measurements have been performed when higher-order moments of the light distribution change. We therefore measured the ganglion cell responses in the tiger salamander retina to controlled changes in the second (contrast), third (skew) and fourth (kurtosis) moments of the light intensity distribution of spatially uniform temporally independent stimuli. The skew and kurtosis of the stimuli were chosen to cover the range observed in natural scenes. We quantified adaptation in ganglion cells by studying linear-nonlinear models that capture well the retinal encoding properties across all stimuli. We found that the encoding properties of retinal ganglion cells change only marginally when higher-order statistics change, compared to the changes observed in response to the variation in contrast. By analyzing optimal coding in LN-type models, we showed that neurons can maintain a high information rate without large dynamic adaptation to changes in skew or kurtosis. This is because, for uncorrelated stimuli, spatio-temporal summation within the receptive field averages away non-gaussian aspects of the light intensity distribution. PMID- 24465743 TI - Acute NMDA receptor antagonism disrupts synchronization of action potential firing in rat prefrontal cortex. AB - Antagonists of N-methyl-D-aspartate receptors (NMDAR) have psychotomimetic effects in humans and are used to model schizophrenia in animals. We used high density electrophysiological recordings to assess the effects of acute systemic injection of an NMDAR antagonist (MK-801) on ensemble neural processing in the medial prefrontal cortex of freely moving rats. Although MK-801 increased neuron firing rates and the amplitude of gamma-frequency oscillations in field potentials, the synchronization of action potential firing decreased and spike trains became more Poisson-like. This disorganization of action potential firing following MK-801 administration is consistent with changes in simulated cortical networks as the functional connections among pyramidal neurons become less clustered. Such loss of functional heterogeneity of the cortical microcircuit may disrupt information processing dependent on spike timing or the activation of discrete cortical neural ensembles, and thereby contribute to hallucinations and other features of psychosis induced by NMDAR antagonists. PMID- 24465744 TI - Fate of articles that warranted retraction due to ethical concerns: a descriptive cross-sectional study. AB - OBJECTIVE: To study journals' responses to a request from the State Medical Association of Rheinland-Pfalz, Germany, to retract 88 articles due to ethical concerns, and to check whether the resulting retractions followed published guidelines. DESIGN: Descriptive cross-sectional study. POPULATION: 88 articles (18 journals) by the anaesthesiologist Dr. Boldt, that warranted retraction. METHOD: According to the recommendations of the Committee on Publication Ethics, we regarded a retraction as adequate when a retraction notice was published, linked to the retracted article, identified the title and authors of the retracted article in its heading, explained the reason and who took responsibility for the retraction, and when the retracted article was freely accessible and marked using a transparent watermark that preserved original content. Two authors extracted data independently (January 2013) and contacted editors-in-chief and publishers for clarification in cases of inadequate retraction. RESULTS: Five articles (6%) fulfilled all criteria for adequate retraction. Nine (10%) were not retracted (no retraction notice published, full text article not marked). 79 (90%) retraction notices were published, 76 (86%) were freely accessible, but only 15 (17%) were complete. 73 (83%) full text articles were marked as retracted, of which 14 (16%) had an opaque watermark hiding parts of the original content, and 11 (13%) had all original content deleted. 59 (67%) retracted articles were freely accessible. One editor-in-chief stated personal problems as a reason for incomplete retractions, eight blamed their publishers. Two publishers cited legal threats from Dr. Boldt's co-authors which prevented them from retracting articles. CONCLUSION: Guidelines for retracting articles are incompletely followed. The role of publishers in the retraction process needs to be clarified and standards are needed on marking retracted articles. It remains unclear who should check that retractions are done properly. Legal safeguards are required to allow retraction of articles against the wishes of authors. PMID- 24465745 TI - Individual globular domains and domain unfolding visualized in overstretched titin molecules with atomic force microscopy. AB - Titin is a giant elastomeric protein responsible for the generation of passive muscle force. Mechanical force unfolds titin's globular domains, but the exact structure of the overstretched titin molecule is not known. Here we analyzed, by using high-resolution atomic force microscopy, the structure of titin molecules overstretched with receding meniscus. The axial contour of the molecules was interrupted by topographical gaps with a mean width of 27.7 nm that corresponds well to the length of an unfolded globular (immunoglobulin and fibronectin) domain. The wide gap-width distribution suggests, however, that additional mechanisms such as partial domain unfolding and the unfolding of neighboring domain multimers may also be present. In the folded regions we resolved globules with an average spacing of 5.9 nm, which is consistent with a titin chain composed globular domains with extended interdomain linker regions. Topographical analysis allowed us to allocate the most distal unfolded titin region to the kinase domain, suggesting that this domain systematically unfolds when the molecule is exposed to overstretching forces. The observations support the prediction that upon the action of stretching forces the N-terminal beta-sheet of the titin kinase unfolds, thus exposing the enzyme's ATP-binding site and hence contributing to the molecule's mechanosensory function. PMID- 24465746 TI - Pro-inflammatory mediators and apoptosis correlate to rt-PA response in a novel mouse model of thromboembolic stroke. AB - BACKGROUND: A recent study suggests that patients with persistent occlusion of the middle cerebral artery (MCA) following treatment with recombinant tissue plasminogen activator (rt-PA) have better outcomes than patients with MCA occlusion not receiving rt-PA. We performed a study to elucidate possible mechanisms of this finding in a new model of thromboembolic stroke closely mimicking human pathophysiology. METHODS: Thromboembolic stroke was induced by local injection of thrombin directly into the right MCA of C57 black/6J mice. Rt PA was administered 20 and 40 min after clot formation. The efficiency of rt-PA to induce thrombolysis was measured by laser Doppler. After 24 h, all animals were euthanized and interleukin (IL)-6, tumor necrosis factor-alpha (TNF-alpha), matrix metalloproteinase (MMP)-9, Caspase-3, hsp 32 and hsp 70 protein levels were investigated by immunofluorescence. Presence of hemorrhage was verified and infarct volume was measured using histology. RESULTS: Thrombin injection resulted in clot formation giving rise to cortical brain infarction. Early rt-PA treatment starting at 20 min after the clot formation resulted in 100% recanalization. However, rt-PA-induced thrombolysis dissolved the clot in only 38% of the animals when administered 40 min after clot formation. Protein levels of IL-6, TNF-alpha, MMP-9, Caspase-3, hsp 32 and hsp 70 were increased after MCAO, whereas treatment with rt-PA attenuated the expressions of inflammatory markers in those animals where the thrombolysis was successful. In addition, the infarct size was significantly reduced with rt-PA treatment compared to non-treated MCAO, regardless of whether MCA thrombolysis was successful. CONCLUSIONS: The present study demonstrates a clear correlation of the protein expression of inflammatory mediators, apoptosis and stress genes with the recanalization data after rt-PA treatment. In this model rt-PA treatment decreases the infarct size regardless of whether vessel recanalization is successful. PMID- 24465747 TI - Mechanism of deep-sea fish alpha-actin pressure tolerance investigated by molecular dynamics simulations. AB - The pressure tolerance of monomeric alpha-actin proteins from the deep-sea fish Coryphaenoides armatus and C. yaquinae was compared to that of non-deep-sea fish C. acrolepis, carp, and rabbit/human/chicken actins using molecular dynamics simulations at 0.1 and 60 MPa. The amino acid sequences of actins are highly conserved across a variety of species. The actins from C. armatus and C. yaquinae have the specific substitutions Q137K/V54A and Q137K/L67P, respectively, relative to C. acrolepis, and are pressure tolerant to depths of at least 6000 m. At high pressure, we observed significant changes in the salt bridge patterns in deep-sea fish actins, and these changes are expected to stabilize ATP binding and subdomain arrangement. Salt bridges between ATP and K137, formed in deep-sea fish actins, are expected to stabilize ATP binding even at high pressure. At high pressure, deep-sea fish actins also formed a greater total number of salt bridges than non-deep-sea fish actins owing to the formation of inter-helix/strand and inter-subdomain salt bridges. Free energy analysis suggests that deep-sea fish actins are stabilized to a greater degree by the conformational energy decrease associated with pressure effect. PMID- 24465748 TI - Global distribution of two fungal pathogens threatening endangered sea turtles. AB - Nascent fungal infections are currently considered as one of the main threats for biodiversity and ecosystem health, and have driven several animal species into critical risk of extinction. Sea turtles are one of the most endangered groups of animals and only seven species have survived to date. Here, we described two pathogenic species, i.e., Fusarium falciforme and Fusarium keratoplasticum, that are globally distributed in major turtle nesting areas for six sea turtle species and that are implicated in low hatch success. These two fungi possess key biological features that are similar to emerging pathogens leading to host extinction, e.g., high virulence, and a broad host range style of life. Their optimal growth temperature overlap with the optimal incubation temperature for eggs, and they are able to kill up to 90% of the embryos. Environmental forcing, e.g., tidal inundation and clay/silt content of nests, were correlated to disease development. Thus, these Fusarium species constitute a major threat to sea turtle nests, especially to those experiencing environmental stressors. These findings have serious implications for the survival of endangered sea turtle populations and the success of conservation programs worldwide. PMID- 24465749 TI - Rapid molecular characterization of Acinetobacter baumannii clones with rep-PCR and evaluation of carbapenemase genes by new multiplex PCR in Hospital District of Helsinki and Uusimaa. AB - Multidrug-resistant Acinetobacter baumannii (MDRAB) is an increasing problem worldwide. Prevalence of carbapenem resistance in Acinetobacter spp. due to acquired carbapenemase genes is not known in Finland. The purpose of this study was to examine prevalence and clonal spread of multiresistant A. baumannii group species, and their carbapenemase genes. A total of 55 Acinetobacter isolates were evaluated with repetitive PCR (DiversiLab) to analyse clonality of isolates, in conjunction with antimicrobial susceptibility profile for ampicillin/sulbactam, colistin, imipenem, meropenem, rifampicin and tigecycline. In addition, a new real-time PCR assay, detecting most clinically important carbapenemase genes just in two multiplex reactions, was developed. The assay detects genes for KPC, VIM, IMP, GES-1/-10, OXA-48, NDM, GIM-1, SPM-1, IMI/NMC-A, SME, CMY-10, SFC-1, SIM-1, OXA-23-like, OXA-24/40-like, OXA-58 and ISAbaI-OXA-51-like junction, and allows confident detection of isolates harbouring acquired carbapenemase genes. There was a time-dependent, clonal spread of multiresistant A. baumannii strongly correlating with carbapenamase gene profile, at least in this geographically restricted study material. The new carbapenemase screening assay was able to detect all the genes correctly suggesting it might be suitable for epidemiologic screening purposes in clinical laboratories. PMID- 24465750 TI - The effect of approach/avoidance training on alcohol consumption is mediated by change in alcohol action tendency. AB - Training people to respond to alcohol images by making avoidance joystick movements can affect subsequent alcohol consumption, and has shown initial efficacy as a treatment adjunct. However, the mechanisms that underlie the training's efficacy are unknown. The present study aimed to determine 1) whether the training's effect is mediated by a change in action tendency or a change in selective attention, and 2) whether the training's effect is moderated by individual differences in working memory capacity (WMC). Three groups of social drinkers (total N = 74) completed either approach-alcohol training, avoid-alcohol training or a sham-training on the Approach-Avoidance Task (AAT). Participants' WMC was assessed prior to training, while their alcohol-related action tendency and selective attention were assessed before and after the training on the recently developed Selective-Attention/Action Tendency Task (SA/ATT), before finally completing an alcohol taste-test. There was no significant main effect of approach/avoidance training on alcohol consumption during the taste-test. However, there was a significant indirect effect of training on alcohol consumption mediated by a change in action tendency, but no indirect effect mediated by a change in selective attention. There was inconsistent evidence of WMC moderating training efficacy, with moderation found only for the effect of approach-alcohol training on the AAT but not on the SA/ATT. Thus approach/avoidance training affects alcohol consumption specifically by changing the underlying action tendency. Multiple training sessions may be required in order to observe more substantive changes in drinking behaviour. PMID- 24465751 TI - Complex intra-operonic dynamics mediated by a small RNA in Streptomyces coelicolor. AB - Streptomyces are predominantly soil-dwelling bacteria that are best known for their multicellular life cycle and their prodigious metabolic capabilities. They are also renowned for their regulatory capacity and flexibility, with each species encoding >60 sigma factors, a multitude of transcription factors, and an increasing number of small regulatory RNAs. Here, we describe our characterization of a conserved small RNA (sRNA), scr4677. In the model species Streptomyces coelicolor, this sRNA is located in the intergenic region separating SCO4677 (an anti-sigma factor-encoding gene) and SCO4676 (a putative regulatory protein-encoding gene), close to the SCO4676 translation start site in an antisense orientation. There appears to be considerable genetic interplay between these different gene products, with wild type expression of scr4677 requiring function of the anti-sigma factor SCO4677, and scr4677 in turn influencing the abundance of SCO4676-associated transcripts. The scr4677-mediated effects were independent of RNase III (a double stranded RNA-specific nuclease), with RNase III having an unexpectedly positive influence on the level of SCO4676-associated transcripts. We have shown that both SCO4676 and SCO4677 affect the production of the blue-pigmented antibiotic actinorhodin under specific growth conditions, and that this activity appears to be independent of scr4677. PMID- 24465752 TI - On the eyes of male coffee berry borers as rudimentary organs. AB - The coffee berry borer, Hypothenemus hampei, is the most damaging insect pest of coffee worldwide. Like males in other species in the genus, male coffee berry borers have a lower number of facets in the compound eyes than females. The rudimentary eyes in male coffee berry borers could be an evolutionary response to their cryptic life habit, whereby they are born inside a coffee berry and never leave the berry. The main objective of the study was to determine if the differences in the number of facets translates into differences in visual acuity. We used low-temperature scanning electron microscopy to visualize and quantify the number of facets in the compound eyes. There was a significantly lower (p<0.0001) number of facets in males (19.1 +/- 4.10) than in females (127.5 +/- 3.88). To assess visual acuity, we conducted optomotor response experiments, which indicate that females respond to movement, while males did not respond under the conditions tested. The coffee berry borer is an example of an insect whereby disuse of an organ has led to a rudimentary compound eye. This is the first study that has experimentally tested responses to movement in bark beetles. PMID- 24465753 TI - The dimethylsulfide cycle in the eutrophied Southern North Sea: a model study integrating phytoplankton and bacterial processes. AB - We developed a module describing the dimethylsulfoniopropionate (DMSP) and dimethylsulfide (DMS) dynamics, including biological transformations by phytoplankton and bacteria, and physico-chemical processes (including DMS air-sea exchange). This module was integrated in the MIRO ecological model and applied in a 0D frame in the Southern North Sea (SNS). The DMS(P) module is built on parameterizations derived from available knowledge on DMS(P) sources, transformations and sinks, and provides an explicit representation of bacterial activity in contrast to most of existing models that only include phytoplankton process (and abiotic transformations). The model is tested in a highly productive coastal ecosystem (the Belgian coastal zone, BCZ) dominated by diatoms and the Haptophyceae Phaeocystis, respectively low and high DMSP producers. On an annual basis, the particulate DMSP (DMSPp) production simulated in 1989 is mainly related to Phaeocystis colonies (78%) rather than diatoms (13%) and nanoflagellates (9%). Accordingly, sensitivity analysis shows that the model responds more to changes in the sulfur:carbon (S:C) quota and lyase yield of Phaeocystis. DMS originates equally from phytoplankton and bacterial DMSP-lyase activity and only 3% of the DMS is emitted to the atmosphere. Model analysis demonstrates the sensitivity of DMS emission towards the atmosphere to the description and parameterization of biological processes emphasizing the need of adequately representing in models both phytoplankton and bacterial processes affecting DMS(P) dynamics. This is particularly important in eutrophied coastal environments such as the SNS dominated by high non-diatom blooms and where empirical models developed from data-sets biased towards open ocean conditions do not satisfactorily predict the timing and amplitude of the DMS seasonal cycle. In order to predict future feedbacks of DMS emissions on climate, it is needed to account for hotspots of DMS emissions from coastal environments that, if eutrophied, are dominated not only by diatoms. PMID- 24465754 TI - The interaction of the atm genotype with inflammation and oxidative stress. AB - In ataxia-telangiectasia (A-T) the death of neurons is associated with the loss of neuronal cell cycle control. In most Atm(-/-) mouse models, however, these cell cycle anomalies are present but the phenotype of neuronal cell loss found in humans is not. Mouse Atm(-/-) neurons re-enter a cell cycle and replicate their DNA, but they do not die--even months after initiating the cycle. In the current study, we explore whether systemic inflammation or hypoxia-induced oxidative stress can serve as second stressors that can promote cell death in ATM-deficient neurons. We find that after either immune or hypoxic challenge, the levels of cell cycle proteins--PCNA, cyclin A and cyclin B--are significantly elevated in cerebellar Purkinje cells. Both the number of cells that express cell cycle proteins as well as the intensity of the expression levels in each cell is increased in the stressed animals. The cell cycle-positive neurons also increasingly express cell death markers such as activated caspase-3, gamma-H2AX and TUNEL staining. Interestingly, nuclear HDAC4 localization is also enhanced in Atm(-/-) Purkinje neurons after the immune challenge suggesting that both genetic and epigenetic changes in Atm(-/-) mice respond to environmental challenges. Our findings support the hypothesis that multiple insults are needed to drive even genetically vulnerable neurons to die a cell cycle-related cell death and point to either inflammation or oxidative stressors as potential contributors to the A T disease process. PMID- 24465755 TI - Spatially reciprocal inhibition of inhibition within a stimulus selection network in the avian midbrain. AB - Reciprocal inhibition between inhibitory projection neurons has been proposed as the most efficient circuit motif to achieve the flexible selection of one stimulus among competing alternatives. However, whether such a motif exists in networks that mediate selection is unclear. Here, we study the connectivity within the nucleus isthmi pars magnocellularis (Imc), a GABAergic nucleus that mediates competitive selection in the midbrain stimulus selection network. Using laser photostimulation of caged glutamate, we find that feedback inhibitory connectivity is global within the Imc. Unlike typical lateral inhibition in other circuits, intra-Imc inhibition remains functionally powerful over long distances. Anatomically, we observed long-range axonal projections and retrograde somatic labeling from focal injections of bi-directional tracers in the Imc, consistent with spatial reciprocity of intra-Imc inhibition. Together, the data indicate that spatially reciprocal inhibition of inhibition occurs throughout the Imc. Thus, the midbrain selection circuit possesses the most efficient circuit motif possible for fast, reliable, and flexible selection. PMID- 24465756 TI - Determining the relative contribution and hierarchy of hha and qseBC in the regulation of flagellar motility of Escherichia coli O157:H7. AB - In recent studies, we demonstrated that a deletion of hha caused increased secretion of locus of enterocyte encoded adherence proteins and reduced motility of enterohemorrhagic Escherichia coli (EHEC) O157:H7. In addition to the importance of hha in positive regulation of motility, a two-component quorum sensing pathway encoded by the qseBC genes has been shown to activate bacterial motility in response to mammalian stress hormones epinephrine and norepinephrine as well as bacterially produced autoinducer-3. In this study, we compared regulatory contribution and hierarchy of hha, a member of the Hha/YmoA family of nucleoid-associated proteins, to that of qseBC in the expression of EHEC O157:H7 motility. Since norepinephrine affects motility of EHEC O157:H7 through a qseBC encoded two-component quorum sensing signaling, we also determined whether the hha-mediated regulation of motility is affected by norepinephrine and whether this effect is qseBC dependent. We used single (Deltahha or DeltaqseC) and double (Deltahha DeltaqseC) deletion mutants to show that hha exerts a greater positive regulatory effect in comparison to qseBC on the expression of motility by EHEC O157:H7. We also show that Hha is hierarchically superior in transcriptional regulation of motility than QseBC because transcription of qseC was significantly reduced in the hha deletion mutant compared to that in the parental and the hha complemented mutant strains. These results suggest that hha regulates motility of EHEC O157:H7 directly as well as indirectly by controlling the transcription of qseBC. PMID- 24465757 TI - Hip arthrodesis with the anterolateral plate: an innovating technique for an orphaned procedure. AB - BACKGROUND: In developing countries hip osteoarthritis constitutes a major public health issue as it is highly prevalent in all age ranges of population, including the young. It often remains untreated because of the low accessibility of total hip prostheses. Hip arthrodesis still represents a major treatment option, but, for several reasons which are discussed in this paper, is nowadays infrequently performed. By means of reporting the results of a new simple technique, using a self-devised plate, the relevancy of hip arthrodesis in this particular environment is emphasized. METHODS AND FINDINGS: Our series included 35 patients with painful hip osteoarthritis who underwent a hip fusion with the anterolateral arthrodesis plate. Two of them had a concurrent femoral osteotomy for correction of a vicious position of the limb and another patient had a femoral diaphysis osteotomy and placement of a Wagner elongating device in order to proceed with a limb lengthening by callotasis. The follow-up period averaged 16,9 months (9 to 34). All hips, except two, achieved solid fusion between 6 and 15 months after surgery. One failure of fusion was in the oldest patient, who presented a loosening of plate and screws due to an advanced degree of osteoporosis; the other was in a young patient who admitted having walked on his leg too soon. Patient satisfaction was high. We concluded that this technique is reliable and effective. CONCLUSIONS: The results of this study should convince the hesitant surgeon and patient to consider hip arthrodesis an acceptable treatment option for disabling hip arthritis, compared to no treatment at all. PMID- 24465758 TI - Strong depth-related zonation of megabenthos on a rocky continental margin (~700 4000 m) off southern Tasmania, Australia. AB - Assemblages of megabenthos are structured in seven depth-related zones between ~700 and 4000 m on the rocky and topographically complex continental margin south of Tasmania, southeastern Australia. These patterns emerge from analysis of imagery and specimen collections taken from a suite of surveys using photographic and in situ sampling by epibenthic sleds, towed video cameras, an autonomous underwater vehicle and a remotely operated vehicle (ROV). Seamount peaks in shallow zones had relatively low biomass and low diversity assemblages, which may be in part natural and in part due to effects of bottom trawl fishing. Species richness was highest at intermediate depths (1000-1300 m) as a result of an extensive coral reef community based on the bioherm-forming scleractinian Solenosmilia variabilis. However, megabenthos abundance peaked in a deeper, low diversity assemblage at 2000-2500 m. The S. variabilis reef and the deep biomass zone were separated by an extensive dead, sub-fossil S. variabilis reef and a relatively low biomass stratum on volcanic rock roughly coincident with the oxygen minimum layer. Below 2400 m, megabenthos was increasingly sparse, though punctuated by occasional small pockets of relatively high diversity and biomass. Nonetheless, megabenthic organisms were observed in the vast majority of photographs on all seabed habitats and to the maximum depths observed--a sandy plain below 3950 m. Taxonomic studies in progress suggest that the observed depth zonation is based in part on changing species mixes with depth, but also an underlying commonality to much of the seamount and rocky substrate biota across all depths. Although the mechanisms supporting the extraordinarily high biomass in 2000-2500 m depths remains obscure, plausible explanations include equatorwards lateral transport of polar production and/or a response to depth stratified oxygen availability. PMID- 24465759 TI - Dopamine signaling regulates fat content through beta-oxidation in Caenorhabditis elegans. AB - The regulation of energy balance involves an intricate interplay between neural mechanisms that respond to internal and external cues of energy demand and food availability. Compelling data have implicated the neurotransmitter dopamine as an important part of body weight regulation. However, the precise mechanisms through which dopamine regulates energy homeostasis remain poorly understood. Here, we investigate mechanisms through which dopamine modulates energy storage. We showed that dopamine signaling regulates fat reservoirs in Caenorhabditis elegans. We found that the fat reducing effects of dopamine were dependent on dopaminergic receptors and a set of fat oxidation enzymes. Our findings reveal an ancient role for dopaminergic regulation of fat and suggest that dopamine signaling elicits this outcome through cascades that ultimately mobilize peripheral fat depots. PMID- 24465760 TI - Crystal structure of the lamprey variable lymphocyte receptor C reveals an unusual feature in its N-terminal capping module. AB - Jawless vertebrates represented by lampreys and hagfish use variable lymphocyte receptors (VLRs) as antigen receptors to mount adaptive immune responses. VLRs generate diversity that is comparable to immunoglobulins and T-cell receptors by a gene conversion-like mechanism, which is mediated by cytosine deaminases. Currently, three types of VLRs, VLRA, VLRB, and VLRC, have been identified in lampreys. Crystal structures of VLRA and VLRB in complex with antigens have been reported recently, but no structural information is available for VLRC. Here, we present the first crystal structure of VLRC from the Japanese lamprey (Lethenteron japonicum). Similar to VLRA and VLRB, VLRC forms a typical horseshoe like solenoid structure with a variable concave surface. Strikingly, its N terminal cap has a long loop with limited sequence variability that protrudes toward the concave surface, which is the putative antigen-binding surface. Furthermore, as predicted previously, its C-terminal cap lacks a highly variable protruding loop that plays an important role in antigen recognition by lamprey VLRA and VLRB. Recent work suggests that VLRC+ lymphocytes in jawless vertebrates might be akin to gammadelta T cells in jawed vertebrates. Structural features of lamprey VLRC described here suggest that it may recognize antigens in a unique manner. PMID- 24465761 TI - Effect of intermittent cold exposure on brown fat activation, obesity, and energy homeostasis in mice. AB - Homeotherms have specific mechanisms to maintain a constant core body temperature despite changes in thermal environment, food supply, and metabolic demand. Brown adipose tissue, the principal thermogenic organ, quickly and efficiently increases heat production by dissipating the mitochondrial proton motive force. It has been suggested that activation of brown fat, via either environmental (i.e. cold exposure) or pharmacologic means, could be used to increase metabolic rate and thus reduce body weight. Here we assess the effects of intermittent cold exposure (4 degrees C for one to eight hours three times a week) on C57BL/6J mice fed a high fat diet. Cold exposure increased metabolic rate approximately two fold during the challenge and activated brown fat. In response, food intake increased to compensate fully for the increased energy expenditure; thus, the mice showed no reduction in body weight or adiposity. Despite the unchanged adiposity, the cold-treated mice showed transient improvements in glucose homeostasis. Administration of the cannabinoid receptor-1 inverse agonist AM251 caused weight loss and improvements in glucose homeostasis, but showed no further improvements when combined with cold exposure. These data suggest that intermittent cold exposure causes transient, meaningful improvements in glucose homeostasis, but without synergy when combined with AM251. Since energy expenditure is significantly increased during cold exposure, a drug that dissociates food intake from metabolic demand during cold exposure may achieve weight loss and further metabolic improvements. PMID- 24465762 TI - Secondary metabolism and biotrophic lifestyle in the tomato pathogen Cladosporium fulvum. AB - Cladosporium fulvum is a biotrophic fungal pathogen that causes leaf mould of tomato. Analysis of its genome suggested a high potential for production of secondary metabolites (SM), which might be harmful to plants and animals. Here, we have analysed in detail the predicted SM gene clusters of C. fulvum employing phylogenetic and comparative genomic approaches. Expression of the SM core genes was measured by RT-qrtPCR and produced SMs were determined by LC-MS and NMR analyses. The genome of C. fulvum contains six gene clusters that are conserved in other fungal species, which have undergone rearrangements and gene losses associated with the presence of transposable elements. Although being a biotroph, C. fulvum has the potential to produce elsinochrome and cercosporin toxins. However, the corresponding core genes are not expressed during infection of tomato. Only two core genes, PKS6 and NPS9, show high expression in planta, but both are significantly down regulated during colonization of the mesophyll tissue. In vitro SM profiling detected only one major compound that was identified as cladofulvin. PKS6 is likely involved in the production of this pigment because it is the only core gene significantly expressed under these conditions. Cladofulvin does not cause necrosis on Solanaceae plants and does not show any antimicrobial activity. In contrast to other biotrophic fungi that have a reduced SM production capacity, our studies on C. fulvum suggest that down regulation of SM biosynthetic pathways might represent another mechanism associated with a biotrophic lifestyle. PMID- 24465763 TI - Arctigenin inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways. AB - Arctigenin, a lignan-derived compound, is a constituent of the seeds of Arctium lappa. Arctigenin was previously shown to inhibit osteoclastogenesis; however, this inhibitory mechanism has yet to be elucidated. Here, we showed that arctigenin inhibited the action of nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1), a key transcription factor for osteoclastogenesis. NFATc1 in osteoclast precursors was activated through two distinct pathways: the calcineurin-dependent and osteoblastic cell-dependent pathways. Among the several lignan-derived compounds examined, arctigenin most strongly inhibited receptor activator of nuclear factor kappaB ligand (RANKL)-induced osteoclast-like cell formation in mouse bone marrow macrophage (BMM) cultures, in which the calcineurin-dependent NFATc1 pathway was activated. Arctigenin suppressed neither the activation of nuclear factor kappaB and mitogen-activated protein kinases nor the up-regulation of c-Fos expression in BMMs treated with RANKL. However, arctigenin suppressed RANKL-induced NFATc1 expression. Interestingly, the treatment of osteoclast-like cells with arctigenin converted NFATc1 into a lower molecular weight species, which was translocated into the nucleus even in the absence of RANKL. Nevertheless, arctigenin as well as cyclosporin A (CsA), a calcineurin inhibitor, suppressed the NFAT-luciferase reporter activity induced by ionomycin and phorbol 12-myristate 13-acetate in BMMs. Chromatin immunoprecipitation analysis confirmed that arctigenin inhibited the recruitment of NFATc1 to the promoter region of the NFATc1 target gene. Arctigenin, but not CsA suppressed osteoclast-like cell formation in co-cultures of osteoblastic cells and bone marrow cells, in which the osteoblastic cell-dependent NFATc1 pathway was activated. The forced expression of constitutively active NFATc1 rescued osteoclastogenesis in BMM cultures treated with CsA, but not that treated with arctigenin. Arctigenin also suppressed the pit-forming activity of osteoclast-like cells cultured on dentin slices. These results suggest that arctigenin induces a dominant negative species of NFATc1, which inhibits osteoclast differentiation and function by suppressing both calcineurin-dependent and osteoblastic cell-dependent NFATc1 pathways. PMID- 24465764 TI - Developing clinical strength-of-evidence approach to define HIV-associated malignancies for cancer registration in Kenya. AB - BACKGROUND: Sub-Saharan Africa cancer registries are beset by an increasing cancer burden further exacerbated by the AIDS epidemic where there are limited capabilities for cancer-AIDS match co-registration. We undertook a pilot study based on a "strength-of-evidence" approach using clinical data that is abstracted at the time of cancer registration for purposes of linking cancer diagnosis to AIDS diagnosis. METHODS/FINDINGS: The standard Nairobi Cancer Registry form was modified for registrars to abstract the following clinical data from medical records regarding HIV infection/AIDS in a hierarchal approach at time of cancer registration from highest-to-lowest strength-of-evidence: 1) documentation of positive HIV serology; 2) antiretroviral drug prescription; 3) CD4+ lymphocyte count; and 4) WHO HIV clinical stage or immune suppression syndrome (ISS), which is Kenyan terminology for AIDS. Between August 1 and October 31, 2011 a total of 1,200 cancer cases were registered. Of these, 171 cases (14.3%) met clinical strength-of-evidence criteria for association with HIV infection/AIDS; 69% (118 cases were tumor types with known HIV association - Kaposi's sarcoma, cervical cancer, non-Hodgkin's and Hodgkin's lymphoma, and conjunctiva carcinoma) and 31% (53) were consistent with non-AIDS defining cancers. Verifiable positive HIV serology was identified in 47 (27%) cases for an absolute seroprevalence rate of 4% among the cancer registered cases with an upper boundary of 14% among those meeting at least one of strength-of-evidence criteria. CONCLUSIONS/SIGNIFICANCE: This pilot demonstration of a hierarchal, clinical strength-of-evidence approach for cancer-AIDS registration in Kenya establishes feasibility, is readily adaptable, pragmatic, and does not require additional resources for critically under staffed cancer registries. Cancer is an emerging public health challenge, and African nations need to develop well designed population-based studies in order to better define the impact and spectrum of malignant disease in the backdrop of HIV infection. PMID- 24465765 TI - LIM domain only-2 (LMO2) induces T-cell leukemia by two distinct pathways. AB - The LMO2 oncogene is deregulated in the majority of human T-cell leukemia cases and in most gene therapy-induced T-cell leukemias. We made transgenic mice with enforced expression of Lmo2 in T-cells by the CD2 promoter/enhancer. These transgenic mice developed highly penetrant T-ALL by two distinct patterns of gene expression: one in which there was concordant activation of Lyl1, Hhex, and Mycn or alternatively, with Notch1 target gene activation. Most strikingly, this gene expression clustering was conserved in human Early T-cell Precursor ALL (ETP ALL), where LMO2, HHEX, LYL1, and MYCN were most highly expressed. We discovered that HHEX is a direct transcriptional target of LMO2 consistent with its concordant gene expression. Furthermore, conditional inactivation of Hhex in CD2 Lmo2 transgenic mice markedly attenuated T-ALL development, demonstrating that Hhex is a crucial mediator of Lmo2's oncogenic function. The CD2-Lmo2 transgenic mice offer mechanistic insight into concordant oncogene expression and provide a model for the highly treatment-resistant ETP-ALL subtype. PMID- 24465766 TI - A lifespan observation of a novel mouse model: in vivo evidence supports abeta oligomer hypothesis. AB - Transgenic mouse models are powerful tools in exploring the mechanisms of AD. Most current transgenic models of AD mimic the memory impairment and the main pathologic features, among which the formation of beta-amyloid (Abeta) plaques is considered a dominant pathologic event. Recently, Abeta oligomers have been identified as more neurotoxic than Abeta plaques. However, no ideal transgenic mouse model directly support Abeta oligomers as a neurotoxic species due to the puzzling effects of amyloid plaques in the more widely-used models. Here, we constructed a single-mutant transgenic (Tg) model harboring the PS1V97L mutation and used Non-Tg littermates as a control group. Employing the Morris water maze, electrophysiology, immunohistochemistry, biochemistry, and electron microscopy, we investigated behavioral changes and pathology progression in our single-mutant transgenic model. We discovered the pathological alteration of intraneuronal accumulation of Abeta oligomers without Abeta plaques in the PS1V97L-Tg mouse model, which might be the result of PS1 gene mutation. Following Abeta oligomers, we detected synaptic alteration, tau hyperphosphorylation and glial activation. This model supports an initial role for Abeta oligomers in the onset of AD and suggests that Abeta plaques may not be the only prerequisite. This model provides a useful tool for studying the role of Abeta oligomers in AD pathogenesis. PMID- 24465767 TI - Soluble expression of disulfide bond containing proteins FGF15 and FGF19 in the cytoplasm of Escherichia coli. AB - Fibroblast growth factor 19 (FGF19) is the human ortholog of mouse FGF15, and both proteins function as an endocrine signal to regulate various liver functions. FGF15/FGF19 protein contains two disulfide bonds. It is unfavorable to form disulfide bonds in Escherichia coli (E. coli) cytoplasm because of the bacterial cytoplasmic reducing environment. Modification of the cytoplasmic reducing environment and/or co-expression of protein chaperones are common strategies to express disulfide bond containing proteins in E. coli. In the current study, we report a method to produce soluble FGF15/FGF19 protein in cytoplasm of E. coli. Several commercial available strains with the disruption of thiol-redox pathways, and/or co-expression of redoxase or refolding chaperones were used to develop this novel method for expression of FGF15/FGF19 in E. coli. Mutation of the thiol-disulfide bond reducing pathway in E. coli or N-terminal fusion of thioredox (TRX) alone is not enough to support disulfide bond formation in FGF15/19 proteins. However, TRX fusion protein improved FGF19 solubility in strains of thiol-redox system mutants. In addition, DsbC co-expressed in thiol redox system mutants alone improved and further enhanced FGF19 solubility with combination of TRX fusion tag. The soluble FGF19 proteins were easily purified through Ni-NTA affinity chromatography and anion exchange chromatography, and the purified protein maintained its biological activities, confirmed by suppressing hepatic Cyp7a1 gene transcription in mice and by activating ERK1/2 signaling pathway in HepG2 cells. In contrast, soluble FGF15 protein in cytoplasm remained very low using these strategies. In summary, we have successfully developed a method to express functional FGF19 protein in prokaryotic cells, and this strategy may be adapted for the expression of other disulfide-containing proteins. PMID- 24465768 TI - Olmesartan potentiates the anti-angiogenic effect of sorafenib in mice bearing Ehrlich's ascites carcinoma: role of angiotensin (1-7). AB - Local renin-angiotensin systems exist in various malignant tumor tissues; this suggests that the main effector peptide, angiotensin II, could act as a key factor in tumor growth. The underlying mechanisms for the anti-angiogenic effect of angiotensin II type 1 receptor blockers need to be further evaluated. The present study was carried out to investigate the anti-angiogenic effect of olmesartan alone or in combination with sorafenib, an angiotensin (1-7) agonist or an angiotensin (1-7) antagonist in Ehrlich's ascites carcinoma-bearing mice. The tumor was induced by intradermal injection of Ehrlich's ascites carcinoma cells into mice. Tumor discs were used to evaluate the microvessel density; the serum levels of vascular endothelial growth factor (VEGF) and serum insulin-like growth factor I (IGF-I); and their intratumoral receptors, VEGF receptor-2 and IGF-I receptor, respectively. All parameters were determined following the treatment course, which lasted for 21 days post-inoculation. Monotherapy with olmesartan and its combination with sorafenib resulted in a significant reduction in microvessel density and serum levels of VEGF and IGF-I, as well as their intratumoral receptors. In addition, the combination of olmesartan (30 mg/kg) with an angiotensin (1-7) agonist reduced the microvessel density, IGF-I serum levels and the levels of its intratumoral receptor. In conclusion, olmesartan reduced the levels of the angiogenesis markers IGF-I and VEGF and down-regulated the intratumoral expression of their receptors in a dose-dependent manner, and these effects were dependent on the angiotensin (1-7) receptor. These results suggest that olmesartan is a promising adjuvant to sorafenib in the treatment of cancer. PMID- 24465769 TI - Smoking modifies the associated increased risk of future cardiovascular disease by genetic variation on chromosome 9p21. AB - AIMS: Genetic predisposition for cardiovascular disease (CVD) is likely to be modified by environmental exposures. We tested if the associated risk of CVD and CVD-mortality by the single nucleotide polymorphism rs4977574 on chromosome 9p21 is modified by life-style factors. METHODS AND RESULTS: A total of 24,944 middle aged subjects (62% females) from the population-based Malmo-Diet-and-Cancer Cohort were genotyped. Smoking, education and physical activity-levels were recorded. Subjects were followed for 15 years for incidence of coronary artery disease (CAD; N = 2309), ischemic stroke (N = 1253) and CVD-mortality (N = 1156). Multiplicative interactions between rs4977574 and life-style factors on endpoints were tested in Cox-regression-models. We observed an interaction between rs4977574 and smoking on incident CAD (P = 0.035) and CVD-mortality (P = 0.012). The hazard ratios (HR) per risk allele of rs4977574 were highest in never smokers (N = 9642) for CAD (HR = 1.26; 95% CI 1.13-1.40; P<0.001) and for CVD-mortality (HR = 1.40; 95% CI 1.20-1.63; P<0.001), whereas the risk increase by rs4977574 was attenuated in current smokers (N = 7000) for both CAD (HR = 1.05; 95%CI 0.95 1.16; P = 0.326) and CVD-mortality (HR = 1.08; 95%CI 0.94-1.23; P = 0.270). A meta-analysis supported the finding that the associated increased risk of CAD by the risk-allele was attenuated in smokers. Neither education nor physical activity-levels modified the associated risk of CAD, ischemic stroke and CVD mortality conferred by rs4977574. CONCLUSION: Smoking may modify the associated risk of CAD and CVD-mortality conferred by genetic variation on chromosome 9p21. Whether the observed attenuation of the genetic risk reflects a pathophysiological mechanism or is a result of smoking being such a strong risk factor that it may eliminate the associated genetic effect, requires further investigation. PMID- 24465770 TI - Bisphenol A exposure alters developmental gene expression in the fetal rhesus macaque uterus. AB - Bisphenol A (BPA) exposure results in numerous developmental and functional abnormalities in reproductive organs in rodent models, but limited data are available regarding BPA effects in the primate uterus. To determine if maternal oral BPA exposure affects fetal uterine development in a non-human primate model, pregnant rhesus macaques carrying female fetuses were exposed orally to 400 ug/kg BPA or vehicle control daily from gestation day (GD) 50-100 or GD100-165. Fetal uteri were collected at the completion of treatment (GD100 or GD165); tissue histology, cell proliferation, and expression of estrogen receptor alpha (ERalpha) and progesterone receptor (PR) were compared to that of controls. Gene expression analysis was conducted using rhesus macaque microarrays. There were no significant differences in histology or in the percentage of cells expressing the proliferation marker Ki-67, ERalpha, or PR in BPA-exposed uteri compared to controls at GD100 or GD165. Minimal differences in gene expression were observed between BPA-exposed and control GD100 uteri. However, at GD165, BPA-exposed uteri had significant differences in gene expression compared to controls. Several of the altered genes, including HOXA13, WNT4, and WNT5A, are critical for reproductive organ development and/or adult function. We conclude that second or third trimester BPA exposure does not significantly affect fetal uterus development based on morphological, proliferation, and steroid hormone receptor assessments. However, differences in expression of key developmental genes after third trimester exposure suggest that BPA could alter transcriptional signals influencing uterine function later in life. PMID- 24465771 TI - KRAS early testing: consensus initiative and cost-effectiveness evaluation for metastatic colorectal patients in an Italian setting. AB - KRAS testing is relevant for the choice of the most appropriate first-line therapy of metastatic colorectal cancer (CRC). Strategies for preventing unequal access to the test should be implemented, but their relevance in the practice is related to economic sustainability. The study adopted the Delphi technique to reach a consensus on several topics. Issues related to execution of KRAS testing were identified by an expert's board and proposed to 108 Italian oncologists and pathologists through two subsequent questionnaires. The emerging proposal was evaluated by decision analyses models employed by technology assessment agencies in order to assess cost-effectiveness. Alternative therapeutic strategies included most commonly used chemotherapy regimens alone or in combination with cetuximab or bevacizumab. The survey indicated that time interval for obtaining KRAS test should not exceed 15 days, 10 days being an optimal interval. To assure the access to proper treatment, a useful strategy should be to anticipate the test after radical resection in patients at high risk of relapse. Early KRAS testing in high risk CRC patients generates incremental cost-effectiveness ratios between 6,000 and 13,000 Euro per quality adjusted life year (QALY) gained. In extensive sensitivity analyses ICER's were always below 15,000 Euro per QALY gained, far within the threshold of 60,000 Euro/QALY gained accepted by regulatory institutions in Italy. In metastatic CRC a time interval higher than 15 days for result of KRAS testing limits access to therapeutic choices. Anticipating KRAS testing before the onset of metastatic disease in patients at high risk does not affect the sustainability and cost-effectiveness profile of cetuximab in first-line mCRC. Early KRAS testing may prevent this inequality in high-risk patients, whether they develop metastases, and is a cost-effective strategy. Based on these results, present joined recommendations of Italian societies of Oncology and Pathology should be updated including early KRAS testing. PMID- 24465772 TI - Neural epidermal growth factor-like like protein 2 (NELL2) promotes aggregation of embryonic carcinoma P19 cells by inducing N-cadherin expression. AB - NELL2 was first identified as a mammalian homolog of chick NEL (Neural EGF-like) protein. It is almost exclusively expressed in neurons of the rat brain and has been suggested to play a role in neural differentiation. However, there is still no clear evidence for the detailed function of NELL2 in the differentiation of neurons. In this study, we identified NELL2 function during neural differentiation of mouse embryonic carcinoma P19 cells. Endogenous expression of NELL2 in the P19 cells increased in parallel with the neuronal differentiation induced by retinoic acid (RA). We found that the mouse NELL2 promoter contains RA response elements (RAREs) and that treatment with RA increased NELL2 promoter activity. Transfection of P19 cells with NELL2 expression vectors induced a dramatic increase in cell aggregation, resulting in the facilitation of neural differentiation. Moreover, NELL2 significantly increased N-cadherin expression in the P19 cell. These data suggest that NELL2 plays an important role in the regulation of neuronal differentiation via control of N-cadherin expression and cell aggregation. PMID- 24465773 TI - Comparative analysis of rs12979860 SNP of the IFNL3 gene in children with hepatitis C and ethnic matched controls using 1000 Genomes Project data. AB - The rs12979860 single nucleotide polymorphism located on chromosome 19q13.13 near the interferon L3 gene (formerly and commonly known as interleukin 28B gene) has been associated in adults with both spontaneous and treatment induced clearance of hepatitis C virus. Although the exact mechanism of these associations remains unclear, it suggests that variation in genes involved in the immune response against the virus favours viral clearance. Limited and preliminary data are available on this issue in children. The aim of the present study was to evaluate, in a representative cohort of children with perinatal infection, the potential association between rs12979860 single nucleotide polymorphism and the outcome of hepatitis C virus infection. Alleles and genotypes frequencies were evaluated in 30 children who spontaneously cleared the virus and in 147 children with persistent infection and were compared with a population sample of ethnically matched controls with unknown hepatitis C status obtained using the 1000 Genomes Project data. The C allele and the C/C genotype showed greater frequencies in the clearance group (76.7% and 56.7%, respectively) when compared with both children with viral persistence (C allele 56.5%, p = 0.004; C/C genotype 32.7%, p = 0.02) and with the ethnically matched individuals (C allele 59.7%, p = 0.02; C/C genotype 34.7%, p = 0.03). Children with the C/C genotype were 2 times more likely to clear hepatitis C virus relative to children with the C/T and T/T genotypes combined (odds ratio: 2.7; 90% confidence intervals: 1.3 5.8). The present study provides the evidence that the rs12979860 single nucleotide polymorphism influences the natural history of hepatitis C virus in children. PMID- 24465774 TI - Functional connectivity in the brain estimated by analysis of gamma events. AB - It is known that gamma activity is generated by local networks. In this paper we introduced a new approach for estimation of functional connectivity between neuronal networks by measuring temporal relations between peaks of gamma event amplitudes. We have shown in freely moving rats that gamma events recorded between electrodes 1.5 mm apart in the majority of cases, are generated by different neuronal modules interfering with each other. The map of functional connectivity between brain areas during the resting state, created based on gamma event temporal relationships is in agreement with anatomical connections and with maps described by fMRI methods during the resting state. The transition from the resting state to exploratory activity is accompanied by decreased functional connectivity between most brain areas. Our data suggest that functional connectivity between interhemispheric areas depends on GABAergic transmission, while intrahemispheric functional connectivity is kainate receptor dependent. This approach presents opportunities for merging electrographic and fMRI data on brain functional connectivity in normal and pathological conditions. PMID- 24465775 TI - Evaluating the use of multilocus variable number tandem repeat analysis of Shiga toxin-producing Escherichia coli O157 as a routine public health tool in England. AB - Multilocus variable number tandem repeat analysis (MLVA) provides microbiological support for investigations of clusters of cases of infection with Shiga toxin producing E. coli (STEC) O157. All confirmed STEC O157 isolated in England and submitted to the Gastrointestinal Bacteria Reference Unit (GBRU) during a six month period were typed using MLVA, with the aim of assessing the impact of this approach on epidemiological investigations. Of 539 cases investigated, 341 (76%) had unique (>2 single locus variants) MLVA profiles, 12% of profiles occurred more than once due to known household transmission and 12% of profiles occurred as part of 41 clusters, 21 of which were previously identified through routine public health investigation of cases. The remaining 20 clusters were not previously detected and STEC enhanced surveillance data for associated cases were retrospectively reviewed for epidemiological links including shared exposures, geography and/or time. Additional evidence of a link between cases was found in twelve clusters. Compared to phage typing, the number of sporadic cases was reduced from 69% to 41% and the diversity index for MLVA was 0.996 versus 0.782 for phage typing. Using MLVA generates more data on the spatial and temporal dispersion of cases, better defining the epidemiology of STEC infection than phage typing. The increased detection of clusters through MLVA typing highlights the challenges to health protection practices, providing a forerunner to the advent of whole genome sequencing as a diagnostic tool. PMID- 24465776 TI - Genome wide expression analysis suggests perturbation of vascular homeostasis during high altitude pulmonary edema. AB - BACKGROUND: High altitude pulmonary edema (HAPE) is a life-threatening form of non-cardiogenic edema which occurs in unacclimatized but otherwise normal individuals within two to four days after rapid ascent to altitude beyond 3000 m. The precise pathoetiology and inciting mechanisms regulating HAPE remain unclear. METHODOLOGY/PRINCIPLE FINDINGS: We performed global gene expression profiling in individuals with established HAPE compared to acclimatized individuals. Our data suggests concurrent modulation of multiple pathways which regulate vascular homeostasis and consequently lung fluid dynamics. These pathways included those which regulate vasoconstriction through smooth muscle contraction, cellular actin cytoskeleton rearrangements and endothelial permeability/dysfunction. Some notable genes within these pathways included MYLK; rho family members ARGEF11, ARHGAP24; cell adhesion molecules such as CLDN6, CLDN23, PXN and VCAM1 besides other signaling intermediates. Further, several important regulators of systemic/pulmonary hypertension including ADRA1D, ECE1, and EDNRA were upregulated in HAPE. We also observed significant upregulation of genes involved in paracrine signaling through chemokines and lymphocyte activation pathways during HAPE represented by transcripts of TNF, JAK2, MAP2K2, MAP2K7, MAPK10, PLCB1, ARAF, SOS1, PAK3 and RELA amongst others. Perturbation of such pathways can potentially skew vascular homeostatic equilibrium towards altered vascular permeability. Additionally, differential regulation of hypoxia-sensing, hypoxia response and OXPHOS pathway genes in individuals with HAPE were also observed. CONCLUSIONS/SIGNIFICANCE: Our data reveals specific components of the complex molecular circuitry underlying HAPE. We show concurrent perturbation of multiple pathways regulating vascular homeostasis and suggest multi-genic nature of regulation of HAPE. PMID- 24465777 TI - Microbiota of cow's milk; distinguishing healthy, sub-clinically and clinically diseased quarters. AB - The objective of this study was to use pyrosequencing of the 16S rRNA genes to describe the microbial diversity of bovine milk samples derived from clinically unaffected quarters across a range of somatic cell counts (SCC) values or from clinical mastitis, culture negative quarters. The obtained microbiota profiles were used to distinguish healthy, subclinically and clinically affected quarters. Two dairy farms were used for the collection of milk samples. A total of 177 samples were used. Fifty samples derived from healthy, culture negative quarters with a SCC of less than 20,000 cells/ml (group 1); 34 samples derived from healthy, culture negative quarters, with a SCC ranging from 21,000 to 50,000 cells/ml (group 2); 26 samples derived from healthy, culture negative quarters with a SCC greater than 50,000 cells/ml (group 3); 34 samples derived from healthy, culture positive quarters, with a SCC greater than 400,000 (group 4, subclinical); and 33 samples derived from clinical mastitis, culture negative quarters (group 5, clinical). Bacterial DNA was isolated from these samples and the 16S rRNA genes were individually amplified and pyrosequenced. All samples analyzed revealed great microbial diversity. Four bacterial genera were present in every sample obtained from healthy quarters (Faecalibacterium spp., unclassified Lachnospiraceae, Propionibacterium spp. and Aeribacillus spp.). Discriminant analysis models showed that samples derived from healthy quarters were easily discriminated based on their microbiota profiles from samples derived from clinical mastitis, culture negative quarters; that was also the case for samples obtained from different farms. Staphylococcus spp. and Streptococcus spp. were among the most prevalent genera in all groups while a general multivariable linear model revealed that Sphingobacterium and Streptococcus prevalences were associated with increased 10 log SCC. Conversely, Nocardiodes and Paenibacillus were negatively correlated, and a higher percentage of the genera was associated with a lower 10 log SCC. PMID- 24465778 TI - The incidence of liver injury in Uyghur patients treated for TB in Xinjiang Uyghur autonomous region, China, and its association with hepatic enzyme polymorphisms nat2, cyp2e1, gstm1 and gstt1. AB - BACKGROUND AND OBJECTIVE: Of three first-line anti-tuberculosis (anti-TB) drugs, isoniazid is most commonly associated with hepatotoxicity. Differences in INH induced toxicity have been attributed to genetic variability at several loci, NAT2, CYP2E1, GSTM1and GSTT1, that code for drug-metabolizing enzymes. This study evaluated whether the polymorphisms in these enzymes were associated with an increased risk of anti-TB drug-induced hepatitis in patients and could potentially be used to identify patients at risk of liver injury. METHODS AND DESIGN: In a cross-sectional study, 2244 tuberculosis patients were assessed two months after the start of treatment. Anti-TB drug-induced liver injury (ATLI) was defined as an ALT, AST or bilirubin value more than twice the upper limit of normal. NAT2, CYP2E1, GSTM1 and GSTT1 genotypes were determined using the PCR/ligase detection reaction assays. RESULTS: 2244 patients were evaluated, there were 89 cases of ATLI, a prevalence of 4% 9 patients (0.4%) had ALT levels more than 5 times the upper limit of normal. The prevalence of ATLI was greater among men than women, and there was a weak association with NAT2*5 genotypes, with ATLI more common among patients with the NAT2*5*CT genotype. The sensitivity of the CT genotype for identifying patients with ATLI was 42% and the positive predictive value 5.9%. CT ATLI was more common among slow acetylators (prevalence ratio 2.0 (95% CI 0.95,4.20) )compared to rapid acetylators. There was no evidence that ATLI was associated with CYP2E1 RsaIc1/c1genotype, CYP2E1 RsaIc1/c2 or c2/c2 genotypes, or GSTM1/GSTT1 null genotypes. CONCLUSIONS: In Xinjiang Uyghur TB patients, liver injury was associated with the genetic variant NAT2*5, however the genetic markers studied are unlikely to be useful for screening patients due to the low sensitivity and low positive predictive values for identifying persons at risk of liver injury. PMID- 24465779 TI - Effect of Sfrp5 on cytokine release and insulin action in primary human adipocytes and skeletal muscle cells. AB - Secreted frizzled-related protein 5 (Sfrp5) is an adipokine with anti inflammatory and insulin-sensitizing properties in mice. However, the mechanism of Sfrp5 action, especially in humans, is largely unknown. Therefore, cytokine release and insulin signaling were analyzed to investigate the impact of Sfrp5 on inflammation and insulin signaling in primary human adipocytes and skeletal muscle cells (hSkMC). Sfrp5 neither affected interleukin (IL)-6, monocyte chemoattractant protein-1 (MCP-1) and adiponectin release from human adipocytes, nor IL-6 and IL-8 release from hSkMC. In tumor necrosis factor (TNF) alpha treated adipocytes, Sfrp5 reduced IL-6 release by 49% (p<0.05), but did not affect MCP-1 and adiponectin release. In MCP-1-treated hSkMC, Sfrp5 did not affect cytokine secretion. In untreated adipocytes, Sfrp5 decreased the insulin mediated phosphorylation of Akt-Ser473, Akt-Thr308, GSK3alpha-Ser21 and PRAS40 Thr246 by 34% (p<0.01), 31% (p<0.05), 37% (p<0.05) and 34% (p<0.01), respectively, and the stimulation of glucose uptake by 25% (p<0.05). Incubation with TNFalpha increased the phosphorylation of JNK and NFkappaB, and impaired insulin signaling. When Sfrp5 and TNFalpha were combined, there was no additional effect on insulin signaling and JNK phosphorylation, but phosphorylation of NFkappaB was reversed to basal levels. Sfrp5 had no effect on insulin signaling in untreated or in MCP-1 treated hSkMC. Thus, Sfrp5 lowered IL-6 release and NFkappaB phosphorylation in cytokine-treated human adipocytes, but not under normal conditions, and decreased insulin signaling in untreated human adipocytes. Sfrp5 did not act on hSkMC. Therefore, the cellular actions of Sfrp5 seem to depend on the type of tissue as well as its inflammatory and metabolic state. PMID- 24465780 TI - Reliable single cell array CGH for clinical samples. AB - BACKGROUND: Disseminated cancer cells (DCCs) and circulating tumor cells (CTCs) are extremely rare, but comprise the precursors cells of distant metastases or therapy resistant cells. The detailed molecular analysis of these cells may help to identify key events of cancer cell dissemination, metastatic colony formation and systemic therapy escape. METHODOLOGY/PRINCIPAL FINDINGS: Using the Ampli1TM whole genome amplification (WGA) technology and high-resolution oligonucleotide aCGH microarrays we optimized conditions for the analysis of structural copy number changes. The protocol presented here enables reliable detection of numerical genomic alterations as small as 0.1 Mb in a single cell. Analysis of single cells from well-characterized cell lines and single normal cells confirmed the stringent quantitative nature of the amplification and hybridization protocol. Importantly, fixation and staining procedures used to detect DCCs showed no significant impact on the outcome of the analysis, proving the clinical usability of our method. In a proof-of-principle study we tracked the chromosomal changes of single DCCs over a full course of high-dose chemotherapy treatment by isolating and analyzing DCCs of an individual breast cancer patient at four different time points. CONCLUSIONS/SIGNIFICANCE: The protocol enables detailed genome analysis of DCCs and thereby assessment of the clonal evolution during the natural course of the disease and under selection pressures. The results from an exemplary patient provide evidence that DCCs surviving selective therapeutic conditions may be recruited from a pool of genomically less advanced cells, which display a stable subset of specific genomic alterations. PMID- 24465781 TI - The assessment of the quality of reporting of systematic reviews/meta-analyses in diagnostic tests published by authors in China. AB - BACKGROUND: The quality of reporting in systematic reviews (SRs)/meta-analyses (MAs) of diagnostic tests published by authors in China has not been evaluated. The aims of present study are to evaluate the quality of reporting in diagnostic SRs/MAs using the PRISMA statement and determine the changes in the quality of reporting over time. METHODS: According to the inclusion and exclusion criteria, we searched five databases including Chinese Biomedical Literature Database, PubMed, EMBASE, the Cochrane Library, and Web of knowledge, to identify SRs/MAs on diagnostic tests. The searches were conducted on July 14, 2012 and the cut off for inclusion of the SRs/MAs was December 31(st) 2011. The PRISMA statement was used to assess the quality of reporting. Analysis was performed using Excel 2003, RevMan 5. RESULTS: A total of 312 studies were included. Fifteen diseases systems were covered. According to the PRISMA checklist, there had been serious reporting flaws in following items: structured summary (item 2, 22.4%), objectives (item 4, 18.9%), protocol and registration (item 5, 2.6%), risk of bias across studies (item 15, 26.3%), funding (item 27, 28.8%). The subgroup analysis showed that there had been some statistically significant improvement in total compliance for 9 PRISMA items after the PRISMA was released, 6 items were statistically improved regarding funded articles, 3 items were statistically improved for CSCD articles, and there was a statistically significant increase in the proportion of reviews reporting on 22 items for SCI articles (P<0.050). CONCLUSION: The numbers of diagnostic SRs/MAs is increasing annually. The quality of reporting has measurably been improved over the previous years. Unfortunately, there are still many deficiencies in the reporting including protocol and registration, search, risk of bias across studies, and funding. Future Chinese reviewers should address issues on these aspects. PMID- 24465782 TI - The behavior of organic phosphorus under non-point source wastewater in the presence of phototrophic periphyton. AB - To understand the role of ubiquitous phototrophic periphyton in aquatic ecosystem on the biogeochemical cycling of organic phosphorus, the conversion and removal kinetic characteristics of organic phosphorus (Porg) such as adenosine triphosphate (ATP) were investigated in the presence of the periphyton cultured in artificial non-point source wastewater. The preliminary results showed that the periphyton was very powerful in converting Porg evidenced by the fact that inorganic phosphorus (Pinorg) content in solution increased from about 0.7 to 14.3 mg P L(-1) in 48 hours in the presence of 0.6 g L(-1) periphyton. This was because the periphyton could produce abundant phosphatases that benefited the conversion of Porg to Pinrog. Moreover, this conversion process was described more suitable by the pseudo-first-order kinetic model. The periphyton was also effective in removing Porg, which showed that the Porg can be completely removed even when the initial Porg concentration was as high as 13 mg P L(-1) in 48 hours in the presence of 1.6 g L(-1) periphyton. Furthermore, it was found that biosorption dominated the Porg removal process and exhibited the characteristics of physical adsorption. However, this biosorption process by the periphyton was significantly influenced by biomass (absorbent dosage) and temperature. This work provides insights into Porg biogeochemical circulation of aquatic ecosystem that contained the periphyton or similar microbial aggregates. PMID- 24465783 TI - Isolation of highly suppressive CD25+FoxP3+ T regulatory cells from G-CSF mobilized donors with retention of cytotoxic anti-viral CTLs: application for multi-functional immunotherapy post stem cell transplantation. AB - Previous studies have demonstrated the effective control of cytomegalovirus (CMV) infections post haematopoietic stem cell transplant through the adoptive transfer of donor derived CMV-specific T cells (CMV-T). Strategies for manufacturing CMV immunotherapies has involved a second leukapheresis or blood draw from the donor, which in the unrelated donor setting is not always possible. We have investigated the feasibility of using an aliquot of the original G-CSF-mobilized graft as a starting material for manufacture of CMV-T and examined the activation marker CD25 as a targeted approach for identification and isolation following CMVpp65 peptide stimulation. CD25+ cells isolated from G-CSF-mobilized apheresis revealed a significant increase in the proportion of FoxP3 expression when compared with conventional non-mobilized CD25+ cells and showed a superior suppressive capacity in a T cell proliferation assay, demonstrating the emergence of a population of Tregs not present in non-mobilized apheresis collections. The expansion of CD25+ CMV-T in short-term culture resulted in a mixed population of CD4+ and CD8+ T cells with CMV-specificity that secreted cytotoxic effector molecules and lysed CMVpp65 peptide-loaded phytohaemagglutinin-stimulated blasts. Furthermore CD25 expanded cells retained their suppressive capacity but did not maintain FoxP3 expression or secrete IL-10. In summary our data indicates that CD25 enrichment post CMV stimulation in G-CSF-mobilized PBMCs results in the simultaneous generation of both a functional population of anti-viral T cells and Tregs thus illustrating a potential single therapeutic strategy for the treatment of both GvHD and CMV reactivation following allogeneic haematopoietic stem cell transplantation. The use of G-CSF-mobilized cells as a starting material for cell therapy manufacture represents a feasible approach to alleviating the many problems incurred with successive donations and procurement of cells from unrelated donors. This approach may therefore simplify the clinical application of adoptive immunotherapy and broaden the approach for manufacturing multi functional T cells. PMID- 24465784 TI - Mitochondrial and nuclear DNA survey of Zootoca vivipara across the eastern Italian Alps: evolutionary relationships, historical demography and conservation implications. AB - The European common lizard Zootoca vivipara exhibits reproductive bimodality, with populations being either viviparous or oviparous. In the central-eastern Italian Alps oviparous populations (Z. v. carniolica) and viviparous populations (Z. v. vivipara) partly overlap geographically. Studying the evolutionary relationship between these taxa presents an interesting opportunity to gain insight into the evolution of this trait. We aim to: i) test whether Z. v. carniolica, which is endangered, constitutes an ESU (Evolutionary Significant Unity); ii) infer mtDNA divergence time between the Z. v. carniolica clade and all the other Z. vivipara subspecies with the aid of an external calibration point; and iii) describe the phylogeographical and demographic scenarios in the area. To do so we sequenced about 200 individuals for mitochondrial variation; 64 of them were also analysed for three nuclear genes. Furthermore, we analysed the same nuclear markers in 17 individuals from the other oviparous subspecies Z. v. louislantzi and 11 individuals of Z. v. vivipara from widespread geographical origins. The mtDNA and nDNA loci that we examined supported the monophyly of Z. v. carniolica. The mtDNA-based estimate of divergence time between Z. v. carniolica and all the other subspecies indicated a separation at 4.5 Mya (95% CI 6.1-2.6), with about 5% of sequence divergence. Considering that Z. v. carniolica harbours higher genetic diversity, while Z. v. vivipara from central-eastern Alps shows a signature of recent population and spatial expansion, we argue that Z. v. carniolica represents a distinct evolutionary unit, with a presumably long-term evolutionary history of separation. Z. v. carniolica populations, occurring at higher latitudes and altitudes than insofar supposed, live in peat bogs, a seriously threatened habitat: taking into account also its evolutionary distinctness, specific conservation measures should be considered. PMID- 24465785 TI - Neural network of body representation differs between transsexuals and cissexuals. AB - Body image is the internal representation of an individual's own physical appearance. Individuals with gender identity disorder (GID), commonly referred to as transsexuals (TXs), are unable to form a satisfactory body image due to the dissonance between their biological sex and gender identity. We reasoned that changes in the resting-state functional connectivity (rsFC) network would neurologically reflect such experiential incongruence in TXs. Using graph theory based network analysis, we investigated the regional changes of the degree centrality of the rsFC network. The degree centrality is an index of the functional importance of a node in a neural network. We hypothesized that three key regions of the body representation network, i.e., the primary somatosensory cortex, the superior parietal lobule and the insula, would show a higher degree centrality in TXs. Twenty-three pre-treatment TXs (11 male-to-female and 12 female-to-male TXs) as one psychosocial group and 23 age-matched healthy cissexual control subjects (CISs, 11 males and 12 females) were recruited. Resting-state functional magnetic resonance imaging was performed, and binarized rsFC networks were constructed. The TXs demonstrated a significantly higher degree centrality in the bilateral superior parietal lobule and the primary somatosensory cortex. In addition, the connectivity between the right insula and the bilateral primary somatosensory cortices was negatively correlated with the selfness rating of their desired genders. These data indicate that the key components of body representation manifest in TXs as critical function hubs in the rsFC network. The negative association may imply a coping mechanism that dissociates bodily emotion from body image. The changes in the functional connectome may serve as representational markers for the dysphoric bodily self of TXs. PMID- 24465786 TI - A CARD9 polymorphism is associated with decreased likelihood of persistent conjugated hyperbilirubinemia in intestinal failure. AB - Recently, genetic associations have been described in intestinal transplants. Namely, Crohn's disease susceptibility gene NOD2 polymorphisms have been reported to be more prevalent in patients with graft failure following intestinal transplantation (IT). Therefore, we sought to determine if polymorphisms in the NOD2 signaling cascade, including NOD2, CARD9, RAC1 and ATG16L1 are associated with intestinal failure (IF) or its complications. We carried out a cross sectional study of 59 children with IF and 500 healthy Caucasian controls. Using the Taqman platform we determined the prevalence of NOD2 as well as ATG16L1, RAC1 and CARD9 SNPs. NOD2 pathway polymorphisms were evaluated in relation to outcomes of episodes of sepsis, ICU admissions, hyperbilirubinemia and need for IT. We found that the minor allele of a CARD9 SNP was associated with protection from developing IF when compared to healthy controls and was also associated with decreased odds of sustained conjugated hyperbilirubinemia. Therefore, IF patients with CARD9 polymorphism are less likely to develop progressive liver disease and suggests that host innate immunity may play a role in IF associated liver disease. PMID- 24465787 TI - Regenerative therapies for equine degenerative joint disease: a preliminary study. AB - Degenerative joint disease (DJD) is a major cause of reduced athletic function and retirement in equine performers. For this reason, regenerative therapies for DJD have gained increasing interest. Platelet-rich plasma (PRP) and mesenchymal stem cells (MSCs) were isolated from a 6-year-old donor horse. MSCs were either used in their native state or after chondrogenic induction. In an initial study, 20 horses with naturally occurring DJD in the fetlock joint were divided in 4 groups and injected with the following: 1) PRP; 2) MSCs; 3) MSCs and PRP; or 4) chondrogenic induced MSCs and PRP. The horses were then evaluated by means of a clinical scoring system after 6 weeks (T1), 12 weeks (T2), 6 months (T3) and 12 months (T4) post injection. In a second study, 30 horses with the same medical background were randomly assigned to one of the two combination therapies and evaluated at T1. The protein expression profile of native MSCs was found to be negative for major histocompatibility (MHC) II and p63, low in MHC I and positive for Ki67, collagen type II (Col II) and Vimentin. Chondrogenic induction resulted in increased mRNA expression of aggrecan, Col II and cartilage oligomeric matrix protein (COMP) as well as in increased protein expression of p63 and glycosaminoglycan, but in decreased protein expression of Ki67. The combined use of PRP and MSCs significantly improved the functionality and sustainability of damaged joints from 6 weeks until 12 months after treatment, compared to PRP treatment alone. The highest short-term clinical evolution scores were obtained with chondrogenic induced MSCs and PRP. This study reports successful in vitro chondrogenic induction of equine MSCs. In vivo application of (induced) MSCs together with PRP in horses suffering from DJD in the fetlock joint resulted in a significant clinical improvement until 12 months after treatment. PMID- 24465788 TI - Comprehensive model of Jumbo squid Dosidicus gigas trophic ecology in the Northern Humboldt current system. AB - The jumbo squid Dosidicus gigas plays an important role in marine food webs both as predator and prey. We investigated the ontogenetic and spatiotemporal variability of the diet composition of jumbo squid in the northern Humboldt Current system. For that purpose we applied several statistical methods to an extensive dataset of 3,618 jumbo squid non empty stomachs collected off Peru from 2004 to 2011. A total of 55 prey taxa was identified that we aggregated into eleven groups. Our results evidenced a large variability in prey composition as already observed in other systems. However, our data do not support the hypothesis that jumbo squids select the most abundant or energetic taxon in a prey assemblage, neglecting the other available prey. Indeed, multinomial model predictions showed that stomach fullness increased with the number of prey taxa, while most stomachs with low contents contained one or two prey taxa only. Our results therefore question the common hypothesis that predators seek locally dense aggregations of monospecific prey. In addition D. gigas consumes very few anchovy Engraulis ringens in Peru, whereas a tremendous biomass of anchovy is potentially available. It seems that D. gigas cannot reach the oxygen unsaturated waters very close to the coast, where the bulk of anchovy occurs. Indeed, even if jumbo squid can forage in hypoxic deep waters during the day, surface normoxic waters are then required to recover its maintenance respiration (or energy?). Oxygen concentration could thus limit the co-occurrence of both species and then preclude predator-prey interactions. Finally we propose a conceptual model illustrating the opportunistic foraging behaviour of jumbo squid impacted by ontogenetic migration and potentially constrained by oxygen saturation in surface waters. PMID- 24465789 TI - Phylogeography of Pinus armandii and its relatives: heterogeneous contributions of geography and climate changes to the genetic differentiation and diversification of Chinese white pines. AB - Geographic barriers and Quaternary climate changes are two major forces driving the evolution, speciation, and genetic structuring of extant organisms. In this study, we used Pinus armandii and eleven other Asian white pines (subsection Strobus, subgenus Pinus) to explore the influences of geographic factors and Pleistocene climatic oscillations on species in South China, a region known to be centers of plant endemism and biodiversity hotspots. Range-wide patterns of genetic variation were investigated using chloroplast and mitochondrial DNA markers, with extensive sampling throughout the entire range of P. armandii. Both cpDNA and mtDNA revealed that P. armandii exhibits high levels of genetic diversity and significant population differentiation. Three geographically distinct subdivisions corresponding to the Qinling-Daba Mountains (QDM), Himalaya Hengduan Mountains (HHM) and Yungui Plateau (YGP) were revealed in mainland China by cpDNA. Their break zone was located in the southeastern margin of the Qinghai Tibetan Plateau (QTP). A series of massive mountains, induced by the QTP uplift, imposed significant geographic barriers to genetic exchange. The disjunct distribution patterns of ancestral haplotypes suggest that a large continuous population of the white pines may have existed from southwest to subtropical China. Repeated range shifts in response to the Pleistocene glaciations led to the isolation and diversification of the subtropical species. The two Taiwanese white pines share a common ancestor with the species in mainland China and obtain their chloroplasts via long-distance pollen dispersal from North Asian pines. Distinct genetic patterns were detected in populations from the Qinling-Daba Mountains, Yungui Plateau, Himalaya-Hengduan Mountains, and subtropical China, indicating significant contributions of geographic factors to the genetic differentiation in white pines. Our study depicts a clear picture of the evolutionary history of Chinese white pines and highlights the heterogeneous contributions of geography and Pleistocene climatic fluctuations to the extremely high plant species diversity and endemism in South China. PMID- 24465790 TI - Reduction of advanced-glycation end products levels and inhibition of RAGE signaling decreases rat vascular calcification induced by diabetes. AB - Advanced-glycation end products (AGEs) were recently implicated in vascular calcification, through a process mediated by RAGE (receptor for AGEs). Although a correlation between AGEs levels and vascular calcification was established, there is no evidence that reducing in vivo AGEs deposition or inhibiting AGEs-RAGE signaling pathways can decrease medial calcification. We evaluated the impact of inhibiting AGEs formation by pyridoxamine or elimination of AGEs by alagebrium on diabetic medial calcification. We also evaluated if the inhibition of AGEs-RAGE signaling pathways can prevent calcification. Rats were fed a high fat diet during 2 months before receiving a low dose of streptozotocin. Then, calcification was induced with warfarin. Pyridoxamine was administered at the beginning of warfarin treatment while alagebrium was administered 3 weeks after the beginning of warfarin treatment. Results demonstrate that AGEs inhibitors prevent the time-dependent accumulation of AGEs in femoral arteries of diabetic rats. This effect was accompanied by a reduced diabetes-accelerated calcification. Ex vivo experiments showed that N-methylpyridinium, an agonist of RAGE, induced calcification of diabetic femoral arteries, a process inhibited by antioxidants and different inhibitors of signaling pathways associated to RAGE activation. The physiological importance of oxidative stress was demonstrated by the reduction of femoral artery calcification in diabetic rats treated with apocynin, an inhibitor of reactive oxygen species production. We demonstrated that AGE inhibitors prevent or limit medial calcification. We also showed that diabetes-accelerated calcification is prevented by antioxidants. Thus, inhibiting the association of AGE-RAGE or the downstream signaling reduced medial calcification in diabetes. PMID- 24465792 TI - Confidence intervals for population allele frequencies: the general case of sampling from a finite diploid population of any size. AB - The estimation of population allele frequencies using sample data forms a central component of studies in population genetics. These estimates can be used to test hypotheses on the evolutionary processes governing changes in genetic variation among populations. However, existing studies frequently do not account for sampling uncertainty in these estimates, thus compromising their utility. Incorporation of this uncertainty has been hindered by the lack of a method for constructing confidence intervals containing the population allele frequencies, for the general case of sampling from a finite diploid population of any size. In this study, we address this important knowledge gap by presenting a rigorous mathematical method to construct such confidence intervals. For a range of scenarios, the method is used to demonstrate that for a particular allele, in order to obtain accurate estimates within 0.05 of the population allele frequency with high probability (> or = 95%), a sample size of > 30 is often required. This analysis is augmented by an application of the method to empirical sample allele frequency data for two populations of the checkerspot butterfly (Melitaea cinxia L.), occupying meadows in Finland. For each population, the method is used to derive > or = 98.3% confidence intervals for the population frequencies of three alleles. These intervals are then used to construct two joint > or = 95% confidence regions, one for the set of three frequencies for each population. These regions are then used to derive a > or = 95%% confidence interval for Jost's D, a measure of genetic differentiation between the two populations. Overall, the results demonstrate the practical utility of the method with respect to informing sampling design and accounting for sampling uncertainty in studies of population genetics, important for scientific hypothesis-testing and also for risk-based natural resource management. PMID- 24465791 TI - Local and systemic immune mechanisms underlying the anti-colitis effects of the dairy bacterium Lactobacillus delbrueckii. AB - Several probiotic bacteria have been proposed for treatment or prevention of inflammatory bowel diseases (IBD), showing a protective effect in animal models of experimental colitis and for some of them also in human clinical trials. While most of these probiotic bacteria are isolated from the digestive tract, we recently reported that a Lactobacillus strain isolated from cheese, L. delbrueckii subsp. lactis CNRZ327 (Lb CNRZ327), also possesses anti-inflammatory effects in vitro and in vivo, demonstrating that common dairy bacteria may be useful in the treatment or prevention of IBD. Here, we studied the mechanisms underlying the protective effects of Lb CNRZ327 in vivo, in a mouse dextran sodium sulfate (DSS) colitis model. During colitis, Lb CNRZ327 modulated the production of TGF-beta, IL-6, and IL-12 in colonic tissue and of TGF-beta and IL 6 in the spleen, and caused an expansion of CD4+Foxp3+ regulatory T cells in the cecal lymph nodes. Moreover, a strong tendency to CD4+Foxp3+ expansion was also observed in the spleen. The results of this study for the first time show that orally administered dairy lactobacilli can not only modulate mucosal but also systemic immune responses and constitute an effective treatment of IBD. PMID- 24465793 TI - Cardiovascular risk factor profiles for peripheral artery disease and carotid atherosclerosis among Chinese older people: a population-based study. AB - OBJECTIVES: Epidemiological data concerning atherosclerotic disease among older people in rural China are sparse. We seek to determine prevalence and cardiovascular risk factor profiles for peripheral artery disease (PAD) and carotid atherosclerosis (CAS) among Chinese older people living in a rural community. METHODS: This cross-sectional study included 1499 participants (age >=60 years, 59.0% women) of the Confucius Hometown Aging Project in Shandong, China. From June 2010-July 2011, data were collected through interviews, clinical examinations, and laboratory tests. PAD was defined as an ankle-brachial index <=0.9. Carotid intima-media thickness (cIMT) and carotid artery stenosis were assessed by ultrasonography. We defined moderate stenosis as carotid stenosis >=50%, and severe stenosis as carotid stenosis >=70%. cIMT>=1.81 mm was considered as an increased cIMT (a measure of CAS). Data were analyzed with multiple logistic models. RESULTS: The prevalence was 5.7% for PAD, 8.9% for moderate stenosis, 1.8% for severe stenosis, and 11.2% for increased cIMT. After controlling for multiple potential confounders, diabetes, an increased low density lipoprotein cholesterol (LDL-C)/high-density lipoprotein cholesterol (HDL C) ratio, and hypertension were significantly or marginally associated with PAD. Ever smoking, hypertension, and an increased LDL-C/HDL-C ratio were significantly associated with an increased likelihood of increased cIMT. An increasing number of those cardiovascular risk factors were significantly associated with an increasing odds ratio of PAD and increased cIMT, respectively (p for linear trend <0.001). CONCLUSION: Among Chinese older people living in a rural community, PAD, carotid artery stenosis, and an increased cIMT are relatively uncommon. Cardiovascular risk factor profiles for PAD and CAS are slightly different, with hypertension and an increased LDL-C/HDL-C ratio being associated with an increased likelihood of both PAD and increased cIMT. PMID- 24465794 TI - Windowed correlation: a suitable tool for providing dynamic fMRI-based functional connectivity neurofeedback on task difficulty. AB - The goal of neurofeedback training is to provide participants with relevant information on their ongoing brain processes in order to enable them to change these processes in a meaningful way. Under the assumption of an intrinsic brain behavior link, neurofeedback can be a tool to guide a participant towards a desired behavioral state, such as a healthier state in the case of patients. Current research in clinical neuroscience regarding the most robust indicators of pathological brain processes in psychiatric and neurological disorders indicates that fMRI-based functional connectivity measures may be among the most important biomarkers of disease. The present study therefore investigated the general potential of providing fMRI neurofeedback based on functional correlations, computed from short-window time course data at the level of single task periods. The ability to detect subtle changes in task performance with block-wise functional connectivity measures was evaluated based on imaging data from healthy participants performing a simple motor task, which was systematically varied along two task dimensions representing two different aspects of task difficulty. The results demonstrate that fMRI-based functional connectivity measures may provide a better indicator for an increase in overall (motor) task difficulty than activation level-based measures. Windowed functional correlations thus seem to provide relevant and unique information regarding ongoing brain processes, which is not captured equally well by standard activation level-based neurofeedback measures. Functional connectivity markers, therefore, may indeed provide a valuable tool to enhance and monitor learning within an fMRI neurofeedback setup. PMID- 24465795 TI - Tolerogenic dendritic cells derived from donors with natural rubber latex allergy modulate allergen-specific T-cell responses and IgE production. AB - Natural rubber latex (NRL; Hevea brasiliensis) allergy is an IgE-mediated reaction to latex proteins. When latex glove exposure is the main sensitizing agent, Hev b 5 is one of the major allergens. Dendritic cells (DC), the main antigen presenting cells, modulated with pharmacological agents can restore tolerance in several experimental models, including allergy. In the current study, we aimed to generate DC with tolerogenic properties from NRL-allergic patients and evaluate their ability to modulate allergen-specific T and B cell responses. Here we show that dexamethasone-treated DC (dxDC) differentiated into a subset of DC, characterized by low expression of MHC class II, CD40, CD80, CD86 and CD83 molecules. Compared with LPS-matured DC, dxDC secreted lower IL-12 and higher IL-10 after CD40L activation, and induced lower alloantigenic T cell proliferation. We also show that dxDC pulsed with the dominant Hev b 5 T-cell epitope peptide, Hev b 5(46-65), inhibited both proliferation of Hev b 5-specific T-cell lines and the production of Hev b 5-specific IgE. Additionally, dxDC induced a subpopulation of IL-10-producing regulatory T cells that suppressed proliferation of Hev b 5-primed T cells. In conclusion, dxDC generated from NRL allergic patients can modulate allergen-specific T-cell responses and IgE production, supporting their potential use in allergen-specific immunotherapy. PMID- 24465796 TI - Physiological normoxia and absence of EGF is required for the long-term propagation of anterior neural precursors from human pluripotent cells. AB - Widespread use of human pluripotent stem cells (hPSCs) to study neuronal physiology and function is hindered by the ongoing need for specialist expertise in converting hPSCs to neural precursor cells (NPCs). Here, we describe a new methodology to generate cryo-preservable hPSC-derived NPCs that retain an anterior identity and are propagatable long-term prior to terminal differentiation, thus abrogating regular de novo neuralization. Key to achieving passagable NPCs without loss of identity is the combination of both absence of EGF and propagation in physiological levels (3%) of O2. NPCs generated in this way display a stable long-term anterior forebrain identity and importantly retain developmental competence to patterning signals. Moreover, compared to NPCs maintained at ambient O2 (21%), they exhibit enhanced uniformity and speed of functional maturation, yielding both deep and upper layer cortical excitatory neurons. These neurons display multiple attributes including the capability to form functional synapses and undergo activity-dependent gene regulation. The platform described achieves long-term maintenance of anterior neural precursors that can give rise to forebrain neurones in abundance, enabling standardised functional studies of neural stem cell maintenance, lineage choice and neuronal functional maturation for neurodevelopmental research and disease-modelling. PMID- 24465797 TI - The rapid growth of fibroids during early pregnancy. AB - Several studies aimed to disentangle whether pregnancy influences the growth of uterine fibroids but results were inconsistent. In this study, we speculated that fibroid enlargement during pregnancy may not be linear and we hypothesized that this phenomenon may mainly occur during initial pregnancy. To test this hypothesis, we set up a prospective cohort study of women with fibroids undergoing IVF. Cases were women achieving a viable pregnancy. Controls were the subsequent women with fibroids but failing to become pregnant. Twenty-five cases and 25 controls were recruited. The total number of fibroids in the two groups was 46 and 41, respectively. The mean +/- SD diameter of the fibroids was 17 +/- 10 and 20 +/- 11 mm, respectively (p = 0.18). A statistically significant enlargement emerged exclusively in pregnant women. The median (Interquartile Range) modification of the diameter of the lesions in cases and controls was +34% (+6%/+65%) and +2% (-6%/+12%), respectively (p<0.001). The median (Interquartile Range) modification of the volume of the lesions was +140% (+23%/+357%) and 0% ( 18%/+37%), respectively (p<0.001). In pregnant women, we failed to document any significant correlation between the magnitude of the growth and ovarian responsiveness to hyper-stimulation, suggesting that steroids hormones are not the unique factors involved. In conclusion, fibroids undergo a rapid and remarkable growth during initial pregnancy. Reasons behind this phenomenon remain to be clarified. The early rise in steroids hormones during early pregnancy may not be sufficient to explain the process. Other pregnancy-related hormones and proteins may play also key roles. PMID- 24465798 TI - MSLN gene silencing has an anti-malignant effect on cell lines overexpressing mesothelin deriving from malignant pleural mesothelioma. AB - Genes involved in the carcinogenetic mechanisms underlying malignant pleural mesothelioma (MPM) are still poorly characterized. So far, mesothelin (MSLN) has aroused the most interest. It encodes for a membrane glycoprotein, frequently over-expressed in various malignancies such as MPM, and ovarian and pancreatic cancers. It has been proposed as a diagnostic and immunotherapeutic target with promising results. However, an alternative therapeutic approach seems to rise, whereby synthetic molecules, such as antisense oligonucleotides, could be used to inhibit MSLN activity. To date, such a gene-level inhibition has been attempted in two studies only, both on pancreatic and ovarian carcinoma cell lines, with the use of silencing RNA approaches. With regard to MPM, only one cell line (H2373) has been employed to study the effects of MSLN depletion. Indeed, the knowledge on the role of MSLN in MPM needs expanding. Accordingly, we investigated the expression of MSLN in a panel of three MPM cell lines, i.e., NCI H28, Mero-14, and IstMes2; one non-MPM cell line was used as reference (Met5A). MSLN knock-down experiments on MSLN-overexpressing cells were also performed through silencing RNA (siRNA) to verify whether previous findings could be generalized to a different set of cell cultures. In agreement with previous studies, transient MSLN-silencing caused decreased proliferation rate and reduced invasive capacity and sphere formation in MSLN-overexpressing Mero-14 cells. Moreover, MSLN-siRNA combined with cisplatin, triggered a marked increase in apoptosis and a decrease in proliferation as compared to cells treated with each agent alone, thereby suggesting a sensitizing effect of siRNA towards cisplatin. In summary, our findings confirm that MSLN should be considered a key molecular target for novel gene-based targeted therapies of cancer. PMID- 24465799 TI - ADAM-12 as a diagnostic marker for the proliferation, migration and invasion in patients with small cell lung cancer. AB - Small cell lung cancer (SCLC) is highly aggressive and is characterized by malignant metastasis. Approximately 90% of patients die due to extensive metastasis. The extracellular matrix (ECM) is a natural barrier that can prevent cellular invasion and metastasis. Therefore, degradation of the ECM must take place in order for extensive metastasis to occur. A disintegrin and metalloprotease (ADAM) is a multi-domain protease that plays an important role in tumorigenesis, as well as tumor development, invasion and metastasis. However, there have been few reports on the expression and role of ADAMs in SCLC. In the current study, the expression and role of ADAMs in SCLC proliferation, invasion and metastasis was investigated. A total of 150 SCLC tissue samples were examined by immunohistochemistry for ADAMs expression. ADAM-12 was found to be abundantly expressed in 72.67% samples and other ADAMs were found to be expressed in 10% to 40% of samples. ADAM-12 levels in serum and urine, from 70 SCLC patients and 40 normal controls, were also measured using ELISA. ADAM-12 expression was significantly higher in SCLC patients than in healthy controls and in patients with extensive disease compared to those with more limited disease. Silencing the expression of ADAM-12 in H1688 cells through the use of specific siRNA significantly reduced cellular proliferation, invasion and metastasis. Supplementing the expression of ADAM-12-L or -S in H345 cells, significantly enhanced cellular proliferation, invasion and metastasis. Animal models with metastatic SCLC also exhibited increased expression of ADAM-12 along with enhanced invasion and metastasis. In brief, ADAM-12 is an independent prognostic factor and diagnostic marker, and is involved in the proliferation, invasion and metastasis of SCLC. PMID- 24465800 TI - Inverse agonism of SQ 29,548 and Ramatroban on Thromboxane A2 receptor. AB - G protein-coupled receptors (GPCRs) show some level of basal activity even in the absence of an agonist, a phenomenon referred to as constitutive activity. Such constitutive activity in GPCRs is known to have important pathophysiological roles in human disease. The thromboxane A2 receptor (TP) is a GPCR that promotes thrombosis in response to binding of the prostanoid, thromboxane A2. TP dysfunction is widely implicated in pathophysiological conditions such as bleeding disorders, hypertension and cardiovascular disease. Recently, we reported the characterization of a few constitutively active mutants (CAMs) in TP, including a genetic variant A160T. Using these CAMs as reporters, we now test the inverse agonist properties of known antagonists of TP, SQ 29,548, Ramatroban, L-670596 and Diclofenac, in HEK293T cells. Interestingly, SQ 29,548 reduced the basal activity of both, WT-TP and the CAMs while Ramatroban was able to reduce the basal activity of only the CAMs. Diclofenac and L-670596 showed no statistically significant reduction in basal activity of WT-TP or CAMs. To investigate the role of these compounds on human platelet function, we tested their effects on human megakaryocyte based system for platelet activation. Both SQ 29,548 and Ramatroban reduced the platelet hyperactivity of the A160T genetic variant. Taken together, our results suggest that SQ 29,548 and Ramatroban are inverse agonists for TP, whereas, L-670596 and Diclofenac are neutral antagonists. Our findings have important therapeutic applications in the treatment of TP mediated pathophysiological conditions. PMID- 24465801 TI - Adipokines and obesity are associated with colorectal polyps in adult males: a cross-sectional study. AB - BACKGROUND: Obesity increases the risk of colon cancer. It is also known that most colorectal cancers develop from adenomatous polyps. However, the effects of obesity and adipokines on colonic polyp formation are unknown. METHODS: To determine if BMI, waist circumference or adipokines are associated with colon polyps in males, 126 asymptomatic men (48-65 yr) were recruited at time of colonoscopy, and anthropometric measures as well as blood were collected. Odds ratios were determined using polytomous logistic regression for polyp number (0 or >=3) and polyp type (no polyp, hyperplastic polyp, tubular adenoma). RESULTS: 41% of the men in our study were obese (BMI >=30). The odds of an obese individual having >=3 polyps was 6.5 (CI: 1.3-33.0) times greater than those of a lean (BMI<25) individual. Additionally, relative to lean individuals, obese individuals were 7.8 (CI: 2.0-30.8) times more likely to have a tubular adenoma than no polyp. As BMI category increased, participants were 2.9 (CI: 1.5-5.4) times more likely to have a tubular adenoma than no polyps. Serum leptin, IP-10 and TNF-alpha were significantly associated with tubular adenoma presence. Serum leptin and IP-10 were significantly associated with increased likelihood of >=3 polyps, and TNF-alpha showed a trend (p = 0.09). CONCLUSIONS: Obese men are more likely to have at least three polyps and adenomas. This cross-sectional study provides evidence that colonoscopy should be recommended for obese, white males. PMID- 24465802 TI - Biomarkers of TGF-beta signaling pathway and prognosis of pancreatic cancer. AB - BACKGROUND: Transforming growth factor (TGF)-beta signaling pathway, may act both as a tumor suppressor and as a tumor promoter in pancreatic cancer, depending on tumor stage and cellular context. TGF-beta pathway has been under intensive investigation as a potential therapeutic target in the treatment of cancer. We hypothesized a correlation between TGF-betaR2/SMAD4 expression in the tumor, plasma TGF-beta1 ligand level, genetic variation in TGF-B pathway and prognosis of pancreatic cancer. METHOD: We examined TGF-betaR2 and SMAD4 protein expression in biopsy or surgical samples from 91 patients with pancreatic ductal adenocarcinoma (PDAC) using immunohistochemistry. Plasma level of TGF-beta1 was measured in 644 patients with PDAC using ELISA. Twenty-eight single nucleotide polymorphisms (SNP) of the TGF-beta1, TGF-beta2, TGF-beta3, TGF-betaR1, TGF betaR2, and SMAD4 genes were determined in 1636 patients with PDAC using the Sequenom method. Correlation between protein expression in the tumor, plasma TGF beta1 level, and genotypes with overall survival (OS) was evaluated with Cox proportional regression models. RESULTS: The expression level of TGF-betaR2 and SMAD4 as an independent marker was not associated with OS. However, patients with both low nuclear staining of TGF-betaR2 and high nuclear staining of SMAD4 may have better survival (P = 0.06). The mean and median level of TGF-beta1 was 15.44 (SD: 10.99) and 12.61 (interquartile range: 8.31 to 19.04) ng/ml respectively. Patients with advanced disease and in the upper quartile range of TGF-beta1 level had significantly reduced survival than those with low levels (P = 0.02). A significant association of SMAD4 SNP rs113545983 with overall survival was observed (P<0.0001). CONCLUSION: Our data provides valuable baseline information regarding the TGF-beta pathway in pancreatic cancer, which can be utilized in targeted therapy clinical trials. High TGF-beta1 plasma level, SMAD4 SNP or TGF betaR2/SMAD4 tumor protein expression may suggest a dependence on this pathway in patients with advanced pancreatic cancer. PMID- 24465803 TI - Heparanase interacts with resistin and augments its activity. AB - In an attempt to isolate a heparanase receptor, postulated to mediate non enzymatic functions of the heparanase protein, we utilized human urine collected from healthy volunteers. Affinity chromatography of this rich protein source on immobilized heparanase revealed resistin as a heparanase binding protein. Co immunoprecipitation and ELISA further confirmed the interaction between heparanase and resistin. Importantly, we found that heparanase potentiates the bioactivity of resistin in its standard bioassay in which monocytic human leukemia cell line, THP1, differentiates into adherent macrophage-like foam cells. It is thus conceivable that this newly identified complex of heparanase and resistin exerts a stimulatory effect also in various inflammatory conditions known to be affected by the two proteins. PMID- 24465804 TI - Elevated levels of plasma phenylalanine in schizophrenia: a guanosine triphosphate cyclohydrolase-1 metabolic pathway abnormality? AB - BACKGROUND: Phenylalanine and tyrosine are precursor amino acids required for the synthesis of dopamine, the main neurotransmitter implicated in the neurobiology of schizophrenia. Inflammation, increasingly implicated in schizophrenia, can impair the function of the enzyme Phenylalanine hydroxylase (PAH; which catalyzes the conversion of phenylalanine to tyrosine) and thus lead to elevated phenylalanine levels and reduced tyrosine levels. This study aimed to compare phenylalanine, tyrosine, and their ratio (a proxy for PAH function) in a relatively large sample of schizophrenia patients and healthy controls. METHODS: We measured non-fasting plasma phenylalanine and tyrosine in 950 schizophrenia patients and 1000 healthy controls. We carried out multivariate analyses to compare log transformed phenylalanine, tyrosine, and phenylalanine:tyrosine ratio between patients and controls. RESULTS: Compared to controls, schizophrenia patients had higher phenylalanine (p<0.0001) and phenylalanine: tyrosine ratio (p<0.0001) but tyrosine did not differ between the two groups (p = 0.596). CONCLUSIONS: Elevated phenylalanine and phenylalanine:tyrosine ratio in the blood of schizophrenia patients have to be replicated in longitudinal studies. The results may relate to an abnormal PAH function in schizophrenia that could become a target for novel preventative and interventional approaches. PMID- 24465805 TI - Phosphomimetic modulation of eNOS improves myocardial reperfusion and mimics cardiac postconditioning in mice. AB - OBJECTIVE: Myocardial infarction resulting from ischemia-reperfusion injury can be reduced by cardiac postconditioning, in which blood flow is restored intermittently prior to full reperfusion. Although key molecular mechanisms and prosurvival pathways involved in postconditioning have been identified, a direct role for eNOS-derived NO in improving regional myocardial perfusion has not been shown. The objective of this study is to measure, with high temporal and spatial resolution, regional myocardial perfusion during ischemia-reperfusion and postconditioning, in order to determine the contribution of regional blood flow effects of NO to infarct size and protection. METHODS AND RESULTS: We used myocardial contrast echocardiography to measure regional myocardial blood flow in mice over time. Reperfusion after myocardial ischemia-reperfusion injury is improved by postconditioning, as well as by phosphomimetic eNOS modulation. Knock in mice expressing a phosphomimetic S1176D form of eNOS showed improved myocardial reperfusion and significantly reduced infarct size. eNOS knock-out mice failed to show cardioprotection from postconditioning. The size of the no reflow zone following ischemia-reperfusion is substantially reduced by postconditioning and by the phosphomimetic eNOS mutation. CONCLUSIONS AND SIGNIFICANCE: Using myocardial contrast echocardiography, we show that temporal dynamics of regional myocardial perfusion restoration contribute to reduced infarct size after postconditioning. eNOS has direct effects on myocardial blood flow following ischemia-reperfusion, with reduction in the size of the no-reflow zone. These results have important implications for ongoing clinical trials on cardioprotection, because the degree of protective benefit may be significantly influenced by the regional hemodynamic effects of eNOS-derived NO. PMID- 24465806 TI - Are sample sizes clear and justified in RCTs published in dental journals? AB - Sample size calculations are advocated by the CONSORT group to justify sample sizes in randomized controlled trials (RCTs). The aim of this study was primarily to evaluate the reporting of sample size calculations, to establish the accuracy of these calculations in dental RCTs and to explore potential predictors associated with adequate reporting. Electronic searching was undertaken in eight leading specific and general dental journals. Replication of sample size calculations was undertaken where possible. Assumed variances or odds for control and intervention groups were also compared against those observed. The relationship between parameters including journal type, number of authors, trial design, involvement of methodologist, single-/multi-center study and region and year of publication, and the accuracy of sample size reporting was assessed using univariable and multivariable logistic regression. Of 413 RCTs identified, sufficient information to allow replication of sample size calculations was provided in only 121 studies (29.3%). Recalculations demonstrated an overall median overestimation of sample size of 15.2% after provisions for losses to follow-up. There was evidence that journal, methodologist involvement (OR = 1.97, CI: 1.10, 3.53), multi-center settings (OR = 1.86, CI: 1.01, 3.43) and time since publication (OR = 1.24, CI: 1.12, 1.38) were significant predictors of adequate description of sample size assumptions. Among journals JCP had the highest odds of adequately reporting sufficient data to permit sample size recalculation, followed by AJODO and JDR, with 61% (OR = 0.39, CI: 0.19, 0.80) and 66% (OR = 0.34, CI: 0.15, 0.75) lower odds, respectively. Both assumed variances and odds were found to underestimate the observed values. Presentation of sample size calculations in the dental literature is suboptimal; incorrect assumptions may have a bearing on the power of RCTs. PMID- 24465807 TI - Host-specificity and dynamics in bacterial communities associated with Bloom forming freshwater phytoplankton. AB - Many freshwater phytoplankton species have the potential to form transient nuisance blooms that affect water quality and other aquatic biota. Heterotrophic bacteria can influence such blooms via nutrient regeneration but also via antagonism and other biotic interactions. We studied the composition of bacterial communities associated with three bloom-forming freshwater phytoplankton species, the diatom Aulacoseira granulata and the cyanobacteria Microcystis aeruginosa and Cylindrospermopsis raciborskii. Experimental cultures incubated with and without lake bacteria were sampled in three different growth phases and bacterial community composition was assessed by 454-Pyrosequencing of 16S rRNA gene amplicons. Betaproteobacteria were dominant in all cultures inoculated with lake bacteria, but decreased during the experiment. In contrast, Alphaproteobacteria, which made up the second most abundant class of bacteria, increased overall during the course of the experiment. Other bacterial classes responded in contrasting ways to the experimental incubations causing significantly different bacterial communities to develop in response to host phytoplankton species, growth phase and between attached and free-living fractions. Differences in bacterial community composition between cyanobacteria and diatom cultures were greater than between the two cyanobacteria. Despite the significance, major differences between phytoplankton cultures were in the proportion of the OTUs rather than in the absence or presence of specific taxa. Different phytoplankton species favoring different bacterial communities may have important consequences for the fate of organic matter in systems where these bloom forming species occur. The dynamics and development of transient blooms may also be affected as bacterial communities seem to influence phytoplankton species growth in contrasting ways. PMID- 24465808 TI - Volumetric breast density estimation from full-field digital mammograms: a validation study. AB - OBJECTIVES: To objectively evaluate automatic volumetric breast density assessment in Full-Field Digital Mammograms (FFDM) using measurements obtained from breast Magnetic Resonance Imaging (MRI). MATERIAL AND METHODS: A commercially available method for volumetric breast density estimation on FFDM is evaluated by comparing volume estimates obtained from 186 FFDM exams including mediolateral oblique (MLO) and cranial-caudal (CC) views to objective reference standard measurements obtained from MRI. RESULTS: Volumetric measurements obtained from FFDM show high correlation with MRI data. Pearson's correlation coefficients of 0.93, 0.97 and 0.85 were obtained for volumetric breast density, breast volume and fibroglandular tissue volume, respectively. CONCLUSIONS: Accurate volumetric breast density assessment is feasible in Full-Field Digital Mammograms and has potential to be used in objective breast cancer risk models and personalized screening. PMID- 24465809 TI - Processes underpinning development and maintenance of diversity in rice in West Africa: evidence from combining morphological and molecular markers. AB - We assessed the interplay of artificial and natural selection in rice adaptation in low-input farming systems in West Africa. Using 20 morphological traits and 176 molecular markers, 182 farmer varieties of rice (Oryza spp.) from 6 West African countries were characterized. Principal component analysis showed that the four botanical groups (Oryza sativa ssp. indica, O. sativa ssp. japonica, O. glaberrima, and interspecific farmer hybrids) exhibited different patterns of morphological diversity. Regarding O. glaberrima, morphological and molecular data were in greater conformity than for the other botanical groups. A clear difference in morphological features was observed between O. glaberrima rices from the Togo hills and those from the Upper Guinea Coast, and among O. glaberrima rices from the Upper Guinea Coast. For the other three groups such clear patterns were not observed. We argue that this is because genetic diversity is shaped by different environmental and socio-cultural selection pressures. For O. glaberrima, recent socio-cultural selection pressures seemed to restrict genetic diversity while this was not observed for the other botanical groups. We also show that O. glaberrima still plays an important role in the selection practices of farmers and resulting variety development pathways. This is particularly apparent in the case of interspecific farmer hybrids where a relationship was found between pericarp colour, panicle attitude and genetic diversity. Farmer varieties are the product of long and complex trajectories of selection governed by local human agency. In effect, rice varieties have emerged that are adapted to West African farming conditions through genotype * environment * society interactions. The diversity farmers maintain in their rice varieties is understood to be part of a risk-spreading strategy that also facilitates successful and often serendipitous variety innovations. We advocate, therefore, that farmers and farmer varieties should be more effectively involved in crop development. PMID- 24465810 TI - Geographic patterns of genetic variation in a broadly distributed marine vertebrate: new insights into loggerhead turtle stock structure from expanded mitochondrial DNA sequences. AB - Previous genetic studies have demonstrated that natal homing shapes the stock structure of marine turtle nesting populations. However, widespread sharing of common haplotypes based on short segments of the mitochondrial control region often limits resolution of the demographic connectivity of populations. Recent studies employing longer control region sequences to resolve haplotype sharing have focused on regional assessments of genetic structure and phylogeography. Here we synthesize available control region sequences for loggerhead turtles from the Mediterranean Sea, Atlantic, and western Indian Ocean basins. These data represent six of the nine globally significant regional management units (RMUs) for the species and include novel sequence data from Brazil, Cape Verde, South Africa and Oman. Genetic tests of differentiation among 42 rookeries represented by short sequences (380 bp haplotypes from 3,486 samples) and 40 rookeries represented by long sequences (~800 bp haplotypes from 3,434 samples) supported the distinction of the six RMUs analyzed as well as recognition of at least 18 demographically independent management units (MUs) with respect to female natal homing. A total of 59 haplotypes were resolved. These haplotypes belonged to two highly divergent global lineages, with haplogroup I represented primarily by CC A1, CC-A4, and CC-A11 variants and haplogroup II represented by CC-A2 and derived variants. Geographic distribution patterns of haplogroup II haplotypes and the nested position of CC-A11.6 from Oman among the Atlantic haplotypes invoke recent colonization of the Indian Ocean from the Atlantic for both global lineages. The haplotypes we confirmed for western Indian Ocean RMUs allow reinterpretation of previous mixed stock analysis and further suggest that contemporary migratory connectivity between the Indian and Atlantic Oceans occurs on a broader scale than previously hypothesized. This study represents a valuable model for conducting comprehensive international cooperative data management and research in marine ecology. PMID- 24465811 TI - A prospective study: current problems in radiotherapy for nasopharyngeal carcinoma in yogyakarta, indonesia. AB - INTRODUCTION: Nasopharyngeal carcinoma (NPC) has a high incidence in Indonesia. Previous study in Yogyakarta revealed a complete response of 29% and a median overall survival of less than 2 years. These poor treatment outcome are influenced by the long diagnose-to-treatment interval to radiotherapy (DTI) and the extended overall treatment time of radiotherapy (OTT). This study reveals insight why the OTT and DTI are prolonged. METHOD: All patients treated with curative intent radiotherapy for NPC between July 2011 until October 2012 were included. During radiotherapy a daily diary was kept, containing information on DTI, missed radiotherapy days, the reason for missing and length of OTT. RESULTS: Sixty-eight patients were included. The median DTI was 106 days (95% CI: 98-170). Fifty-nine patients (87%) finished the treatment. The median OTT for radiotherapy was 57 days (95% CI: 57-65). The main reason for missing days was an inoperative radiotherapy machine (36%). Other reasons were patient's poor condition (21%), public holidays (14%), adjustment of the radiation field (7%), power blackout (3%), inoperative treatment planning system (2%) and patient related reasons (9%). Patient's insurance type was correlated to DTI in disadvantage for poor people. CONCLUSION: Yogyakarta has a lack of sufficient radiotherapy units which causes a delay of 3-4 months, besides the OTT is extended by 10-12 days. This influences treatment outcome to a great extend. The best solution would be creating sufficient radiotherapy units and better management in health care for poor patients. The growing economy in Indonesia will expectantly in time enable these solutions, but in the meantime solutions are needed. Solutions can consist of radiation outside office hours, better maintenance of the facilities and more effort from patient, doctor and nurse to finish treatment in time. These results are valuable when improving cancer care in low and middle income countries. PMID- 24465812 TI - Spatial and seasonal dynamic of abundance and distribution of guanaco and livestock: insights from using density surface and null models. AB - Monitoring species abundance and distribution is a prerequisite when assessing species status and population viability, a difficult task to achieve for large herbivores at ecologically meaningful scales. Co-occurrence patterns can be used to infer mechanisms of community organization (such as biotic interactions), although it has been traditionally applied to binary presence/absence data. Here, we combine density surface and null models of abundance data as a novel approach to analyze the spatial and seasonal dynamics of abundance and distribution of guanacos (Lama guanicoe) and domestic herbivores in northern Patagonia, in order to visually and analytically compare the dispersion and co-occurrence pattern of ungulates. We found a marked seasonal pattern in abundance and spatial distribution of L. guanicoe. The guanaco population reached its maximum annual size and spatial dispersion in spring-summer, decreasing up to 6.5 times in size and occupying few sites of the study area in fall-winter. These results are evidence of the seasonal migration process of guanaco populations, an increasingly rare event for terrestrial mammals worldwide. The maximum number of guanacos estimated for spring (25,951) is higher than the total population size (10,000) 20 years ago, probably due to both counting methodology and population growth. Livestock were mostly distributed near human settlements, as expected by the sedentary management practiced by local people. Herbivore distribution was non-random; i.e., guanaco and livestock abundances co-varied negatively in all seasons, more than expected by chance. Segregation degree of guanaco and small livestock (goats and sheep) was comparatively stronger than that of guanaco and large-livestock, suggesting a competition mechanism between ecologically similar herbivores, although various environmental factors could also contribute to habitat segregation. The new and compelling combination of methods used here is highly useful for researchers who conduct counts of animals to simultaneously estimate population sizes, distributions, assess temporal trends and characterize multi-species spatial interactions. PMID- 24465813 TI - Distractor interference during a choice limb reaching task. AB - According to action-centered models of attention, the patterns of distractor interference that emerge in selective reaching tasks are related to the time and effort required to resolve a race for activation between competing target and non target response producing processes. Previous studies have only used unimanual aiming tasks and, as such, only examined the effects of competition that occurs within a limb. The results of studies using unimanual aiming movements often reveal an "ipsilateral effect"--distractors on the same side of space as the effector cause greater interference than distractors on the opposite side of space. The cost of the competition when response selection is between the limbs has yet to be addressed. Participants in the present study executed reaching movements to 1 of 4 (2 left, 2 right) possible target locations with and without a distractor. Participants made ipsilateral reaches (left hand to left targets, right hand to right targets). In contrast to studies using unimanual aiming movements, a "contralateral effect" was observed; distractors affording responses for the other hand (in contralateral space) caused more interference than distractors affording responses for the same hand. The findings from the present research demonstrate that when certain portions of response planning must be resolved prior to response initiation, distractors that code for that dimension cause the greatest interference. PMID- 24465815 TI - The proximate causes of sexual size dimorphism in Phrynocephalus przewalskii. AB - Sexual size dimorphism (SSD) is a common phenomenon and is a central topic in evolutionary biology. Recently, the importance of pursuing an ontogenetic perspective of SSD has been emphasized, to elucidate the proximate physiological mechanisms leading to its evolution. However, such research has seldom focused on the critical periods when males and females diverge. Using mark-recapture data, we investigated the development of SSD, sex-specific survivorship, and growth rates in Phrynocephalus przewalskii (Agamidae). We demonstrated that both male and female lizards are reproductively mature at age 10-11 months (including 5 months hibernation). Male-biased SSD in snout-vent length (SVL) was only found in adults and was fully expressed at age 11 months (June of the first full season of activity), just after sexual maturation. However, male-biased SSD in tail length (TL), hind-limb length (LL), and head width (HW) were fully expressed at age 9-10 months, just before sexual maturation. Analysis of age-specific linear growth rates identified sexually dimorphic growth during the fifth growth month (age 10 11 months) as the proximate cause of SSD in SVL. The males experienced higher mortality than females in the first 2 years and only survived better than females after SSD was well developed. This suggests that the critical period of divergence in the sizes of male and female P. przewalskii occurs between 10 and 11 months of age (May to June during the first full season of activity), and that the sexual difference in growth during this period is the proximate cause. However, the sexual difference in survivorship cannot explain the male-biased SSD in SVL. Our results indicate that performance-related characteristics, such as TL, HW, and LL diverged earlier than SVL. The physiological mechanisms underlying the different growth patterns of males and females may reflect different energy allocations associated with their different reproductive statuses. PMID- 24465814 TI - A nonsense mutation in mouse Tardbp affects TDP43 alternative splicing activity and causes limb-clasping and body tone defects. AB - Mutations in TARDBP, encoding Tar DNA binding protein-43 (TDP43), cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Attempts to model TDP43 dysfunction in mice have used knockouts or transgenic overexpressors, which have revealed the difficulties of manipulating TDP43, whose level is tightly controlled by auto-regulation. In a complementary approach, to create useful mouse models for the dissection of TDP43 function and pathology, we have identified a nonsense mutation in the endogenous mouse Tardbp gene through screening an N-ethyl-N-nitrosourea (ENU) mutant mouse archive. The mutation is predicted to cause a Q101X truncation in TDP43. We have characterised Tardbp(Q101X) mice to investigate this mutation in perturbing TDP43 biology at endogenous expression levels. We found the Tardbp(Q101X) mutation is homozygous embryonic lethal, highlighting the importance of TDP43 in early development. Heterozygotes (Tardbp(+/Q101X) ) have abnormal levels of mutant transcript, but we find no evidence of the truncated protein and mice have similar full-length TDP43 protein levels as wildtype littermates. Nevertheless, Tardbp(+/Q101X) mice have abnormal alternative splicing of downstream gene targets, and limb-clasp and body tone phenotypes. Thus the nonsense mutation in Tardbp causes a mild loss-of function phenotype and behavioural assessment suggests underlying neurological abnormalities. Due to the role of TDP43 in ALS, we investigated potential interactions with another known causative gene, mutant superoxide dismutase 1 (SOD1). Tardbp(+/Q101X) mice were crossed with the SOD1(G93Adl) transgenic mouse model of ALS. Behavioural and physiological assessment did not reveal modifying effects on the progression of ALS-like symptoms in the double mutant progeny from this cross. In summary, the Tardbp(Q101X) mutant mice are a useful tool for the dissection of TDP43 protein regulation, effects on splicing, embryonic development and neuromuscular phenotypes. These mice are freely available to the community. PMID- 24465816 TI - Fluorodeoxyuridine improves Caenorhabditis elegans proteostasis independent of reproduction onset. AB - Protein homeostasis (proteostasis) networks are dynamic throughout the lifespan of an organism. During Caenorhabditis elegans adulthood, the maintenance of metastable proteins and the activation of stress responses are inversely associated with germline stem cell proliferation. Here, we employed the thymidylate synthase inhibitor 5-fluoro-2'-deoxyuridine (FUdR) to chemically inhibit reproduction, thus allowing for examination of the interplay between reproduction and somatic proteostasis. We found that treatment with FUdR modulates proteostasis decline both before and after reproduction onset, such that effective induction of the heat shock response was maintained during adulthood and that metastable temperature-sensitive mutant phenotypes were rescued under restrictive conditions. However, FUdR treatment also improved the folding capacity of germline- and gonadogenesis-defective mutants, suggesting that proteostasis modulation by FUdR is independent of germline stem cell proliferation or inhibition of reproduction. Our data, therefore, indicate that FUdR converges on alternative regulatory signals that modulate C. elegans proteostasis capacity during development and adulthood. PMID- 24465817 TI - Hyperbaric oxygen preconditioning induces tolerance against oxidative injury and oxygen-glucose deprivation by up-regulating heat shock protein 32 in rat spinal neurons. AB - OBJECTIVE: Hyperbaric oxygen (HBO) preconditioning (HBO-PC) has been testified to have protective effects on spinal cord injury (SCI). However, the mechanisms remain enigmatic. The present study aimed to explore the effects of HBO-PC on primary rat spinal neurons against oxidative injury and oxygen-glucose deprivation (OGD) and the relationship with heat shock proteins (HSPs). METHODS: Primary rat spinal neurons after 7 days of culture were used in this study. HSPs were detected in rat spinal neurons following a single exposure to HBO at different time points by Western blot. Using lactate dehydrogenase release assay and cell counting kit-8 assay, the injuries induced by hydrogen peroxide (H2O2) insult or OGD were determined and compared among neurons treated with HBO-PC with or without HSP inhibitors. RESULTS: The results of Western blot showed that HSP27, HSP70 and HSP90 have a slight but not significant increase in primary neurons following HBO exposure. However, HSP32 expression significantly increased and reached highest at 12 h following HBO exposure. HBO-PC significantly increased the cell viability and decreased the medium lactate dehydrogenase content in cultures treated with H2O2 or OGD. Pretreatment with zinc protoporphyrin IX, a specific inhibitor of HSP32, significantly blocked the protective effects of HBO-PC. CONCLUSIONS: These results suggest that HBO-PC could protect rat spinal neurons in vitro against oxidative injury and OGD mostly by up-regulating of HSP32 expression. PMID- 24465818 TI - A simple and sensitive approach for ochratoxin A detection using a label-free fluorescent aptasensor. AB - Ochratoxin A(OTA) is found to be one of the predominant contaminating mycotoxins in a wide variety of food commodities. To avoid the risk of OTA consumption, the detection and quantitation of OTA level are of great significance. Based on the fact that ssDNA aptamer has the ability to form a double-strand structure with its complementary sequence, a simple and rapid aptamer-based label-free approach for highly sensitive and selective fluorescence detection of OTA was developed by using ultra-sensitive double-strand DNA specific dyes PicoGreen. The results showed that as low as 1 ng/mL of OTA could be detected with a dynamic range of more than 5 orders of magnitude which satisfies the requirements for OTA maximum residue limit in various food regulated by European Commission. With the specificity of aptamer, the assay exhibited high selectivity for OTA against two other analogues (N-acetyl-l-phenylalanine and zearalenone). We also tested the aptasensor practicability using real sample of 1% beer spiked with a series of concentration of OTA and the results show good tolerance to matrix effect. All detections could be achieved in less than 30 min, which provides a simple, quick and sensitive detection method for OTA screening in food safety and could be easily extend to other small molecular chemical compounds detection which aptamer has been selected. PMID- 24465819 TI - Risk factors for healthcare-associated extensively drug-resistant Acinetobacter baumannii infections: a case-control study. AB - The emergence of extensively drug-resistant Acinetobacter baumannii (XDRAB) is a serious threat to hospitalized patients. From 2008 to 2010, surveillance detected 25 hospital-acquired infection (HAI) cases caused by XDRAB at a medical center in Taipei. The site of XDRAB infection was bloodstream (n = 8), urinary tract (n = 12), lower respiratory tract (n = 3), surgical site (n = 1), and cardiovascular (n = 1). The isolates were resistant to all currently available antibiotics except for colistin. The XDRAB isolates are genetically diverse, shown by pulsed field gel electrophoresis, but 23 of 25 harbored class 1 integron with a 2.3-kb gene cassette. Most of these isolates carry OXA-23 (n = 21) and OXA-51-like carbapenemase genes (n = 25). To identify the risk factors, a case-control study was conducted. The 25 cases were compared with 100 controls randomly selected from hospitalized patients without XDRAB-HAIs, matched by the onset date, ward, and age, at a ratio of 1?4. Prior use of imipenem, meropenem, piperacillin/tazobactam or fourth-generation cephalosporins (adjusted OR: 3.2, 95% CI: 1.03-10.2, P = 0.04) and >30 days bed-ridden (adjusted OR: 6.0, 95% CI: 1.3-27.6, P = 0.02) were found to be the independent risk factors for XDRAB-HAIs. These findings highlight that, even in the absence of clonal dissemination, XDRAB can emerge under the selective pressure of broad-spectrum antibiotics and causes subsequent HAIs in compromised hosts. An appropriate response to the XDRAB threat therefore should include a component of prudent use of broad-spectrum antibiotics active against gram-negative bacteria. PMID- 24465820 TI - Autochthonous leptospirosis in South-East Austria, 2004-2012. AB - BACKGROUND: Leptospirosis is one of the world's mostly spread zoonoses causing acute fever. Over years, leptospirosis has been reported to occur rarely in Austria and Germany (annual incidence of 0.06/100,000 in Germany). Only imported cases have been on the increase. Objectives of this case-series study were to retrospectively assess epidemiologic and clinical characteristics of leptospirosis illnesses in South-East Austria, to describe risk exposures for autochthonous infections, and to compare patients with imported versus autochthonous infection. METHODOLOGY/PRINCIPAL FINDINGS: During the 9-year period between 2004 and 2012, 127 adult patients (49 females, 78 males) who tested positive by rapid point-of-care test for Leptospira-specific IgM (Leptocheck(r)) were identified through electronic hospital databases. Follow-up telephone interviews were conducted with 82 patients. A total of 114 (89.8%) of the 127 patients enrolled had acquired leptospirosis within Austria and 13 (10.2%) had potentially imported infections. Most autochthonous cases were diagnosed during the months of June and July, whereas fewest were diagnosed during the winter months. Exposure to rodents, recreational activities in woods or wet areas, gardening, cleaning of basements or huts were the most common risk exposures found in autochthonous infection. Serogroups Australis (n = 23), Sejroe (n = 22), and Icterohaemorrhagiae (n = 11) were identified most frequently by MAT testing in autochthonous infections. Patients with imported leptospirosis were significantly younger, less likely to be icteric and had significantly lower liver transaminase levels (p = 0.004) than those with autochthonous infections. CONCLUSIONS/SIGNIFICANCE: Leptospirosis is endemic in South-East Austria. In contrast to reports from other countries we found a relatively high proportion of leptospirosis cases to be female (39% vs. ~ 10%), likely the result of differing risk exposures for South-East Austria. PMID- 24465821 TI - Hippocampal Homer1 levels influence motivational behavior in an operant conditioning task. AB - Loss of motivation and learning impairments are commonly accepted core symptoms of psychiatric disorders such as depression and schizophrenia. Reward-motivated learning is dependent on the hippocampal formation but the molecular mechanisms that lead to functional incentive motivation in this brain region are still largely unknown. Recent evidence implicates neurotransmission via metabotropic glutamate receptors and Homer1, their interaction partner in the postsynaptic density, in drug addiction and motivational learning. As previous reports mainly focused on the prefrontal cortex and the nucleus accumbens, we now investigated the role of hippocampal Homer1 in operant reward learning in the present study. We therefore tested either Homer1 knockout mice or mice that overexpress Homer1 in the hippocampus in an operant conditioning paradigm. Our results show that deletion of Homer1 leads to a diverging phenotype that either displays an inability to perform the task or outstanding hyperactivity in both learning and motivational sessions. Due to the apparent bimodal distribution of this phenotype, the overall effect of Homer1 deletion in this paradigm is not significantly altered. Overexpression of hippocampal Homer1 did not lead to a significantly altered learning performance in any stage of the testing paradigm, yet may subtly contribute to emerging motivational deficits. Our results indicate an involvement of Homer1-mediated signaling in the hippocampus in motivation based learning tasks and encourage further investigations regarding the specific molecular underpinnings of the phenotypes observed in this study. We also suggest to cautiously interpret the results of this and other studies regarding the phenotype following Homer1 manipulations in animals, since their behavioral phenotype appears to be highly diverse. Future studies would benefit from larger group sizes that would allow splitting the experimental groups in responders and non-responders. PMID- 24465822 TI - Detecting fat content of food from a distance: olfactory-based fat discrimination in humans. AB - The desire to consume high volumes of fat is thought to originate from an evolutionary pressure to hoard calories, and fat is among the few energy sources that we can store over a longer time period. From an ecological perspective, however, it would be beneficial to detect fat from a distance, before ingesting it. Previous results indicate that humans detect high concentrations of fatty acids by their odor. More important though, would be the ability to detect fat content in real food products. In a series of three sequential experiments, using study populations from different cultures, we demonstrated that individuals are able to reliably detect fat content of food via odors alone. Over all three experiments, results clearly demonstrated that humans were able to detect minute differences between milk samples with varying grades of fat, even when embedded within a milk odor. Moreover, we found no relation between this performance and either BMI or dairy consumption, thereby suggesting that this is not a learned ability or dependent on nutritional traits. We argue that our findings that humans can detect the fat content of food via odors may open up new and innovative future paths towards a general reduction in our fat intake, and future studies should focus on determining the components in milk responsible for this effect. PMID- 24465823 TI - CADM1 controls actin cytoskeleton assembly and regulates extracellular matrix adhesion in human mast cells. AB - CADM1 is a major receptor for the adhesion of mast cells (MCs) to fibroblasts, human airway smooth muscle cells (HASMCs) and neurons. It also regulates E cadherin and alpha6beta4 integrin in other cell types. Here we investigated a role for CADM1 in MC adhesion to both cells and extracellular matrix (ECM). Downregulation of CADM1 in the human MC line HMC-1 resulted not only in reduced adhesion to HASMCs, but also reduced adhesion to their ECM. Time-course studies in the presence of EDTA to inhibit integrins demonstrated that CADM1 provided fast initial adhesion to HASMCs and assisted with slower adhesion to ECM. CADM1 downregulation, but not antibody-dependent CADM1 inhibition, reduced MC adhesion to ECM, suggesting indirect regulation of ECM adhesion. To investigate potential mechanisms, phosphotyrosine signalling and polymerisation of actin filaments, essential for integrin-mediated adhesion, were examined. Modulation of CADM1 expression positively correlated with surface KIT levels and polymerisation of cortical F-actin in HMC-1 cells. It also influenced phosphotyrosine signalling and KIT tyrosine autophosphorylation. CADM1 accounted for 46% of surface KIT levels and 31% of F-actin in HMC-1 cells. CADM1 downregulation resulted in elongation of cortical actin filaments in both HMC-1 cells and human lung MCs and increased cell rigidity of HMC-1 cells. Collectively these data suggest that CADM1 is a key adhesion receptor, which regulates MC net adhesion, both directly through CADM1-dependent adhesion, and indirectly through the regulation of other adhesion receptors. The latter is likely to occur via docking of KIT and polymerisation of cortical F-actin. Here we propose a stepwise model of adhesion with CADM1 as a driving force for net MC adhesion. PMID- 24465824 TI - Size-dependent antimicrobial effects of novel palladium nanoparticles. AB - Investigating the interactions between nanoscale materials and microorganisms is crucial to provide a comprehensive, proactive understanding of nanomaterial toxicity and explore the potential for novel applications. It is well known that nanomaterial behavior is governed by the size and composition of the particles, though the effects of small differences in size toward biological cells have not been well investigated. Palladium nanoparticles (Pd NPs) have gained significant interest as catalysts for important carbon-carbon and carbon-heteroatom reactions and are increasingly used in the chemical industry, however, few other applications of Pd NPs have been investigated. In the present study, we examined the antimicrobial capacity of Pd NPs, which provides both an indication of their usefulness as target antimicrobial compounds, as well as their potency as potential environmental pollutants. We synthesized Pd NPs of three different well constrained sizes, 2.0 +/- 0.1 nm, 2.5 +/- 0.2 nm and 3.1 +/- 0.2 nm. We examined the inhibitory effects of the Pd NPs and Pd(2+) ions toward gram negative Escherichia coli (E. coli) and gram positive Staphylococcus aureus (S. aureus) bacterial cultures throughout a 24 hour period. Inhibitory growth effects of six concentrations of Pd NPs and Pd(2+) ions (2.5 * 10(-4), 10(-5), 10(-6), 10(-7), 10(-8), and 10(-9) M) were examined. Our results indicate that Pd NPs are generally much more inhibitory toward S. aureus than toward E. coli, though all sizes are toxic at >= 10(-5) M to both organisms. We observed a significant difference in size-dependence of antimicrobial activity, which differed based on the microorganism tested. Our work shows that Pd NPs are highly antimicrobial, and that fine-scale (<1 nm) differences in size can alter antimicrobial activity. PMID- 24465825 TI - Common variants on cytotoxic T lymphocyte antigen-4 polymorphisms contributes to type 1 diabetes susceptibility: evidence based on 58 studies. AB - In the past decade, a number of case-control studies have been carried out to investigate the relationship between the CTLA4 gene polymorphisms and type 1 diabetes (T1D). However, these studies have yielded contradictory results. To investigate this inconsistency, we performed a meta-analysis of all available studies dealing with the relationship between the CTLA4 polymorphism and T1D. In total, 58 association studies on two CTLA4 polymorphisms (G49A and C60T) and risk of T1D, including a total of 30,723 T1D cases and 45,254 controls were included. In a combined analysis, the summary per-allele odds ratio (OR) for T1D of the G49A and C60T polymorphism was 1.42 [95% confidence interval (CI): 1.31-1.53, P<10(-5)] and 1.23 (95% CI: 1.18-1.29, P<10(-5)), respectively. Significant results were also observed using dominant or recessive genetic model. In the subgroup analysis by ethnicity and sample size, significantly increased risks were also found for these polymorphisms. This meta-analysis demonstrated that the G49A and C60T polymorphism of CTLA4 is a risk factor associated with increased T1D susceptibility, but these associations vary in different ethnic populations. PMID- 24465827 TI - Potential impacts of climate change on insect communities: a transplant experiment. AB - Climate change will have profound impacts on the distribution, abundance and ecology of all species. We used a multi-species transplant experiment to investigate the potential effects of a warmer climate on insect community composition and structure. Eight native Australian plant species were transplanted into sites approximately 2.5 degrees C (mean annual temperature) warmer than their native range. Subsequent insect colonisation was monitored for 12 months. We compared the insect communities on transplanted host plants at the warmer sites with control plants transplanted within the species' native range. Comparisons of the insect communities were also made among transplanted plants at warmer sites and congeneric plant species native to the warmer transplant area. We found that the morphospecies composition of the colonising Coleoptera and Hemiptera communities differed markedly between transplants at the control compared to the warmer sites. Community structure, as described by the distribution of feeding guilds, was also found to be different between the controls and transplants when the entire Coleoptera and Hemiptera community, including non-herbivore feeding guilds, was considered. However, the structure of the herbivorous insect community showed a higher level of consistency between plants at control and warm sites. There were marked differences in community composition and feeding guild structure, for both herbivores and non-herbivores, between transplants and congenerics at the warm sites. These results suggest that as the climate warms, considerable turnover in the composition of insect communities may occur, but insect herbivore communities may retain elements of their present-day structure. PMID- 24465826 TI - Accumulation of metal-specific T cells in inflamed skin in a novel murine model of chromium-induced allergic contact dermatitis. AB - Chromium (Cr) causes delayed-type hypersensitivity reactions possibly mediated by accumulating T cells into allergic inflamed skin, which are called irritants or allergic contact dermatitis. However, accumulating T cells during development of metal allergy are poorly characterized because a suitable animal model is not available. This study aimed to elucidate the skewing of T-cell receptor (TCR) repertoire and cytokine profiles in accumulated T cells in inflamed skin during elucidation of Cr allergy. A novel model of Cr allergy was induced by two sensitizations of Cr plus lipopolysaccharide solution into mouse groin followed by single Cr challenge into the footpad. TCR repertoires and nucleotide sequences of complementary determining region 3 were assessed in accumulated T cells from inflamed skin. Cytokine expression profiles and T-cell phenotypes were determined by qPCR. CD3+CD4+ T cells accumulated in allergic footpads and produced increased T helper 1 (Th1) type cytokines, Fas, and Fas ligand in the footpads after challenge, suggesting CD4+ Th1 cells locally expanded in response to Cr. Accumulated T cells included natural killer (NK) T cells and Cr-specific T cells with VA11-1/VB14-1 usage, suggesting metal-specific T cells driven by invariant NKT cells might contribute to the pathogenesis of Cr allergy. PMID- 24465828 TI - Isolation and characterization of a rhizobacterial antagonist of root-knot nematodes. AB - The rhizobacterial strain Jdm2 was isolated from the rhizosphere of the traditional Chinese medicinal herb Trichosanthes kirilowii in Jiangsu province, China, and was identified as Bacillus subtilis. Exposure of cell-free filtrate of the strain to the root-knot nematode Meloidogyne incognita under in vitro conditions caused substantial mortality of the second stage juvenile (J2) and significantly reduced egg hatchability. A greenhouse trial demonstrated that 56 days after treatment with Jdm2, the number of galls associated with M. incognita infection in the tomato (Solanum lycopersicum) roots was significantly reduced compared to controls, and the disease severity of infected plants was lower in treated plants (36%) compared to water control (75%). Consistently, in the field trial, the biocontrol efficacy of Jdm2 reached 69%, 51% and 48% after 30, 60 and 90 days post-transplantation, respectively. As indicated by PCR-DGGE analysis, inoculation with Jdm2 strain had an effect on the bacterial community of the tomato rhizosphere at the first stage, but was not able to imperil the bacterial community stability for long time. The novel bacterial strain Jdm2 enhances plant growth and inhibits nematode activity, and has the potential to be a safe and effective microbial pesticide. PMID- 24465829 TI - Modeling the effects of light and sucrose on in vitro propagated plants: a multiscale system analysis using artificial intelligence technology. AB - BACKGROUND: Plant acclimation is a highly complex process, which cannot be fully understood by analysis at any one specific level (i.e. subcellular, cellular or whole plant scale). Various soft-computing techniques, such as neural networks or fuzzy logic, were designed to analyze complex multivariate data sets and might be used to model large such multiscale data sets in plant biology. METHODOLOGY AND PRINCIPAL FINDINGS: In this study we assessed the effectiveness of applying neuro fuzzy logic to modeling the effects of light intensities and sucrose content/concentration in the in vitro culture of kiwifruit on plant acclimation, by modeling multivariate data from 14 parameters at different biological scales of organization. The model provides insights through application of 14 sets of straightforward rules and indicates that plants with lower stomatal aperture areas and higher photoinhibition and photoprotective status score best for acclimation. The model suggests the best condition for obtaining higher quality acclimatized plantlets is the combination of 2.3% sucrose and photonflux of 122 130 umol m(-2) s(-1). CONCLUSIONS: Our results demonstrate that artificial intelligence models are not only successful in identifying complex non-linear interactions among variables, by integrating large-scale data sets from different levels of biological organization in a holistic plant systems-biology approach, but can also be used successfully for inferring new results without further experimental work. PMID- 24465830 TI - Cerebellar damage impairs executive control and monitoring of movement generation. AB - Executive control of motor responses is a psychological construct of the executive system. Several studies have demonstrated the involvement of the cerebral cortex, basal ganglia, and thalamus in the inhibition of actions and monitoring of performance. The involvement of the cerebellum in cognitive function and its functional interaction with basal ganglia have recently been reported. Based on these findings, we examined the hypothesis of cerebellar involvement in executive control by administering a countermanding task in patients with focal cerebellar damage. The countermanding task requires one to make a movement in response to a 'go' signal and to halt it when a 'stop' signal is presented. The duration of the go process (reaction time; RT), the duration of the stop process (stop signal reaction time; SSRT), and their relationship, expressed by a psychometric function, are recorded as measures of executive control. All patients had longer go process duration in general and in particular, as a proactive control, as demonstrated by the increase in RT after erroneously performed stop trials. Further, they were defective in the slope of the psychometric function indicating a difficulty on triggering the stop process, although the SSRT did not differ from controls. Notably, their performance was worse when lesions affected deep cerebellar nuclei. Our results support the hypothesis that the cerebellum regulates the executive control of voluntary actions. We speculate that its activity is attributed to specific cerebellar influence over the cortico-striatal loop. PMID- 24465831 TI - Comparison of droplet digital PCR and seminested real-time PCR for quantification of cell-associated HIV-1 RNA. AB - Cell-associated (CA) HIV-1 RNA is considered a potential marker for assessment of viral reservoir dynamics and antiretroviral therapy (ART) response in HIV infected patients. Recent studies employed sensitive seminested real-time quantitative (q)PCR to quantify CA HIV-1 RNA. Digital PCR has been recently described as an alternative PCR-based technique for absolute quantification with higher accuracy compared to qPCR. Here, a comparison was made between the droplet digital PCR (ddPCR) and the seminested qPCR for quantification of unspliced (us) and multiply spliced (ms) CA HIV-1 RNA. Synthetic RNA standards and CA HIV-1 RNA from infected patients on and off ART (N = 34) were quantified with both methods. Correlations were observed between the methods both for serially diluted synthetic standards (usRNA: R2 = 0.97, msRNA: R2 = 0.92) and patient-derived samples (usRNA: R2 = 0.51, msRNA: R2 = 0.87). Seminested qPCR showed better quantitative linearity, accuracy and sensitivity in the quantification of synthetic standards than ddPCR, especially in the lower quantification ranges. Both methods demonstrated equally high detection rate of usRNA in patient samples on and off ART (91%), whereas ddPCR detected msRNA in larger proportion of samples from ART-treated patients (p = 0.13). We observed an average agreement between the methods for usRNA quantification in patient samples, albeit with a large standard deviation (bias = 0.05+/-0.75 log10). However, a bias of 0.94+/ 0.36 log10 was observed for msRNA. No-template controls were consistently negative in the seminested qPCR, but yielded a positive ddPCR signal for some wells. Therefore, the false positive signals may have affected the detection power of ddPCR in this study. Digital PCR is promising for HIV nucleic acid quantification, but the false positive signals need further attention. Quantitative assays for CA HIV RNA have the potential to improve monitoring of patients on ART and to be used in clinical studies aimed at HIV eradication, but should be cross-validated by multiple laboratories prior to wider use. PMID- 24465832 TI - Canadians' perceptions of food, diet, and health--a national survey. AB - BACKGROUND: Poor nutrition is harmful to one's health as it can lead to overweight and obesity and a number of chronic diseases. Understanding consumer perceptions toward diet and nutrition is critical to advancing nutrition-related population health interventions to address such issues. The purpose of this paper was to examine Canadians' perceived health and diet status, compared to their actual health status, and general concern about their own diet and beliefs about health. Also analyzed were some of the perceived barriers to eating "healthy" foods, with a focus on the availability of "healthy" processed foods. METHODS: Two surveys were administered online to a group of Canadian panelists from all ten provinces during May 2010 to January 2011. Thirty thousand were invited; 6,665 completed the baseline survey and 5,494 completed the second survey. Panelists were selected to be nationally representative of the Canadian adult population by age, sex, province and education level, according to 2006 census data. RESULTS: Approximately one third of Canadians perceived their health or diet to be very good while very few Canadians perceived their health or diet to be very poor. While the majority of Canadians believed food and nutrition to be very important for improving one's health, fewer Canadians were concerned about their own diets. The majority of Canadians reported difficulty finding "healthy" processed foods (low in salt and sugar and with sufficient vitamins and minerals). Many also reported difficulty finding healthy foods that are affordable. CONCLUSION: Although consumers believe that nutrition is one of the most important factors for maintaining health, there are still a number of attitudinal and perceived environmental barriers to healthy eating. PMID- 24465833 TI - Optimization of landscape services under uncoordinated management by multiple landowners. AB - Landscapes are often patchworks of private properties, where composition and configuration patterns result from cumulative effects of the actions of multiple landowners. Securing the delivery of services in such multi-ownership landscapes is challenging, because it is difficult to assure tight compliance to spatially explicit management rules at the level of individual properties, which may hinder the conservation of critical landscape features. To deal with these constraints, a multi-objective simulation-optimization procedure was developed to select non spatial management regimes that best meet landscape-level objectives, while accounting for uncoordinated and uncertain response of individual landowners to management rules. Optimization approximates the non-dominated Pareto frontier, combining a multi-objective genetic algorithm and a simulator that forecasts trends in landscape pattern as a function of management rules implemented annually by individual landowners. The procedure was demonstrated with a case study for the optimum scheduling of fuel treatments in cork oak forest landscapes, involving six objectives related to reducing management costs (1), reducing fire risk (3), and protecting biodiversity associated with mid- and late successional understories (2). There was a trade-off between cost, fire risk and biodiversity objectives, that could be minimized by selecting management regimes involving ca. 60% of landowners clearing the understory at short intervals (around 5 years), and the remaining managing at long intervals (ca. 75 years) or not managing. The optimal management regimes produces a mosaic landscape dominated by stands with herbaceous and low shrub understories, but also with a satisfactory representation of old understories, that was favorable in terms of both fire risk and biodiversity. The simulation-optimization procedure presented can be extended to incorporate a wide range of landscape dynamic processes, management rules and quantifiable objectives. It may thus be adapted to other socio-ecological systems, particularly where specific patterns of landscape heterogeneity are to be maintained despite imperfect management by multiple landowners. PMID- 24465834 TI - Effect of hematoporphyrin monomethyl ether-sonodynamic therapy (HMME-SDT) on hypertrophic scarring. AB - OBJECTIVE: The aim of the present study was to explore the potential for hematoporphyrin monomethyl ether-Sonodynamic Therapy (HMME-SDT) treatment of hypertrophic scars within rabbit ears. METHODS: 60 white rabbits were randomly divided into five groups: (1) untreated controls, (2) lesioned, (3) lesioned + HMME, (4) lesioned + US (Ultrasound), and (5) lesioned +HMME-SDT. After induction of a lesion upon the ears of the rabbits, hypertrophic scars were assessed at 14, 28, 42 and 56 days post-lesion +/- treatment. Assessments consisted of visual inspection in the change of the skin, scar formation pathological morphology by hematoxylin and eosin (HE) staining technique with optical microscopy, calculation of a hypertrophic index, fibroblastic density measures, and observation of collagen changes in the scar tissue by Van Gieson's (VG)Stain along with calculation of collagen area density. RESULTS: With continued HMME-SDT treatment there was a gradual improvement in all parameters over the duration of the experiment. The lesion-induced scars of rabbits receiving HMME-SDT treatment were soft, the size was reduced, hyperplasia was flat and the color pale. The fibroblasts and collagens were reduced and the collagens were light red, sparse and orderly. The hypertrophic index was reduced, since the fibroblastic density was lowered and collagen area density was decreased. CONCLUSION: HMME is an effective sonosensitizer and the combination of HMME-SDT treatment can exert significant benefits in reducing the formation of hypertrophic scars. PMID- 24465835 TI - Nuclear DNA content variation in life history phases of the Bonnemasoniaceae (Rhodophyta). AB - Nuclear DNA content in gametophytes and sporophytes or the prostrate phases of the following species of Bonnemaisoniaceae (Asparagopsis armata, Asparagopsis taxiformis, Bonnemaisonia asparagoides, Bonnemaisonia clavata and Bonnemaisonia hamifera) were estimated by image analysis and static microspectrophotometry using the DNA-localizing fluorochrome DAPI (4', 6-diamidino-2-phenylindole, dilactate) and the chicken erythrocytes standard. These estimates expand on the Kew database of DNA nuclear content. DNA content values for 1C nuclei in the gametophytes (spermatia and vegetative cells) range from 0.5 pg to 0.8 pg, and for 2C nuclei in the sporophytes or the prostrate phases range from 1.15-1.7 pg. Although only the 2C and 4C values were observed in the sporophyte or the prostrate phase, in the vegetative cells of the gametophyte the values oscillated from 1C to 4C, showing the possible start of endopolyploidy. The results confirm the alternation of nuclear phases in these Bonnemaisoniaceae species, in those that have tetrasporogenesis, as well as those that have somatic meiosis. The availability of a consensus phylogenetic tree for Bonnemaisoniaceae has opened the way to determine evolutionary trends in DNA contents. Both the estimated genome sizes and the published chromosome numbers for Bonnemaisoniaceae suggest a narrow range of values consistent with the conservation of an ancestral genome. PMID- 24465836 TI - Genetic association of human leukocyte antigens with chronicity or resolution of hepatitis B infection in thai population. AB - BACKGROUND: Previous studies showed that single nucleotide polymorphisms (SNPs) in the HLA-DP, TCF19 and EHMT2 genes may affect the chronic hepatitis B (CHB). To predict the degree of risk for chronicity of HBV, this study determined associations with these SNPs. METHODS: The participants for this study were defined into 4 groups; HCC (n = 230), CHB (n = 219), resolved HBV infection (n = 113) and HBV uninfected subjects (n = 123). The HLA-DP SNPs (rs3077, rs9277378 and rs3128917), TCF19 SNP (rs1419881) and EHMT2 SNP (rs652888) were genotyped. RESULTS: Due to similar distribution of genotype frequencies in HCC and CHB, we combined these two groups (HBV carriers). The genotype distribution in HBV carriers relative to those who resolved HBV showed that rs3077 and rs9277378 were significantly associated with protective effects against CHB in minor dominant model (OR = 0.45, p<0.001 and OR = 0.47, p<0.001). The other SNPs rs3128917, rs1419881 and rs652888 were not associated with HBV carriers. CONCLUSIONS: Genetic variations of rs3077 and rs9277378, but not rs3128917, rs1419881 and rs652888, were significantly associated with HBV carriers relative to resolved HBV in Thai population. PMID- 24465837 TI - Single echo MRI. AB - PURPOSE: Previous nonlinear gradient research has focused on trajectories that reconstruct images with a minimum number of echoes. Here we describe sequences where the nonlinear gradients vary in time to acquire the image in a single readout. The readout is designed to be very smooth so that it can be compressed to minimal time without violating peripheral nerve stimulation limits, yielding an image from a single 4 ms echo. THEORY AND METHODS: This sequence was inspired by considering the code of each voxel, i.e. the phase accumulation that a voxel follows through the readout, an approach connected to traditional encoding theory. We present simulations for the initial sequence, a low slew rate analog, and higher resolution reconstructions. RESULTS: Extremely fast acquisitions are achievable, though as one would expect, SNR is reduced relative to the slower Cartesian sampling schemes because of the high gradient strengths. CONCLUSIONS: The prospect that nonlinear gradients can acquire images in a single <10 ms echo makes this a novel and interesting approach to image encoding. PMID- 24465838 TI - The bacterial amyloid curli is associated with urinary source bloodstream infection. AB - Urinary tract infections are the most common cause of E. coli bloodstream infections (BSI) but the mechanism of bloodstream invasion is poorly understood. Some clinical isolates have been observed to shield themselves with extracellular amyloid fibers called curli at physiologic temperature. We hypothesize that curli fiber assembly at 37 degrees C promotes bacteremic progression by urinary E. coli strains. Curli expression by cultured E. coli isolates from bacteriuric patients in the presence and absence of bacteremia were compared using Western blotting following amyloid fiber disruption with hexafluoroisopropanol. At 37 degrees C, urinary isolates from bacteremic patients were more likely to express curli than those from non-bacteremic patients [16/22 (73%) vs. 7/21 (33%); p = 0.01]. No significant difference in curli expression was observed at 30 degrees C [86% (19/22) vs. 76% (16/21); p = 0.5]. Isolates were clonally diverse between patients, indicating that this phenotype is distributed across multiple lineages. Most same-patient urine and blood isolates were highly related, consistent with direct invasion of urinary bacteria into the bloodstream. 37 degrees C curli expression was associated with bacteremic progression of urinary E. coli isolates in this population. These findings suggest new future diagnostic and virulence targeting therapeutic approaches. PMID- 24465839 TI - Crystallographic and biochemical analysis of the mouse poly(ADP-ribose) glycohydrolase. AB - Protein poly(ADP-ribosyl)ation (PARylation) regulates a number of important cellular processes. Poly(ADP-ribose) glycohydrolase (PARG) is the primary enzyme responsible for hydrolyzing the poly(ADP-ribose) (PAR) polymer in vivo. Here we report crystal structures of the mouse PARG (mPARG) catalytic domain, its complexes with ADP-ribose (ADPr) and a PARG inhibitor ADP-HPD, as well as four PARG catalytic residues mutants. With these structures and biochemical analysis of 20 mPARG mutants, we provide a structural basis for understanding how the PAR polymer is recognized and hydrolyzed by mPARG. The structures and activity complementation experiment also suggest how the N-terminal flexible peptide preceding the PARG catalytic domain may regulate the enzymatic activity of PARG. This study contributes to our understanding of PARG catalytic and regulatory mechanisms as well as the rational design of PARG inhibitors. PMID- 24465840 TI - Immunomodulation stimulates the innervation of engineered tooth organ. AB - The sensory innervation of the dental mesenchyme is essential for tooth function and protection. Sensory innervation of the dental pulp is mediated by axons originating from the trigeminal ganglia and is strictly regulated in time. Teeth can develop from cultured re-associations between dissociated dental epithelial and mesenchymal cells from Embryonic Day 14 mouse molars, after implantation under the skin of adult ICR mice. In these conditions however, the innervation of the dental mesenchyme did not occur spontaneously. In order to go further with this question, complementary experimental approaches were designed. Cultured cell re-associations were implanted together with trigeminal ganglia for one or two weeks. Although axonal growth was regularly observed extending from the trigeminal ganglia to all around the forming teeth, the presence of axons in the dental mesenchyme was detected in less than 2.5% of samples after two weeks, demonstrating a specific impairment of their entering the dental mesenchyme. In clinical context, immunosuppressive therapy using cyclosporin A was found to accelerate the innervation of transplanted tissues. Indeed, when cultured cell re associations and trigeminal ganglia were co-implanted in cyclosporin A-treated ICR mice, nerve fibers were detected in the dental pulp, even reaching odontoblasts after one week. However, cyclosporin A shows multiple effects, including direct ones on nerve growth. To test whether there may be a direct functional relationship between immunomodulation and innervation, cell re associations and trigeminal ganglia were co-implanted in immunocompromised Nude mice. In these conditions as well, the innervation of the dental mesenchyme was observed already after one week of implantation, but axons reached the odontoblast layer after two weeks only. This study demonstrated that immunodepression per se does stimulate the innervation of the dental mesenchyme. PMID- 24465841 TI - Sequencing, De Novo assembly and annotation of the Colorado Potato Beetle, Leptinotarsa decemlineata, Transcriptome. AB - BACKGROUND: The Colorado potato beetle (Leptinotarsa decemlineata) is a major pest and a serious threat to potato cultivation throughout the northern hemisphere. Despite its high importance for invasion biology, phenology and pest management, little is known about L. decemlineata from a genomic perspective. We subjected European L. decemlineata adult and larval transcriptome samples to 454 FLX massively-parallel DNA sequencing to characterize a basal set of genes from this species. We created a combined assembly of the adult and larval datasets including the publicly available midgut larval Roche 454 reads and provided basic annotation. We were particularly interested in diapause-specific genes and genes involved in pesticide and Bacillus thuringiensis (Bt) resistance. RESULTS: Using 454-FLX pyrosequencing, we obtained a total of 898,048 reads which, together with the publicly available 804,056 midgut larval reads, were assembled into 121,912 contigs. We established a repository of genes of interest, with 101 out of the 108 diapause-specific genes described in Drosophila montana; and 621 contigs involved in insecticide resistance, including 221 CYP450, 45 GSTs, 13 catalases, 15 superoxide dismutases, 22 glutathione peroxidases, 194 esterases, 3 ADAM metalloproteases, 10 cadherins and 98 calmodulins. We found 460 putative miRNAs and we predicted a significant number of single nucleotide polymorphisms (29,205) and microsatellite loci (17,284). CONCLUSIONS: This report of the assembly and annotation of the transcriptome of L. decemlineata offers new insights into diapause-associated and insecticide-resistance-associated genes in this species and provides a foundation for comparative studies with other species of insects. The data will also open new avenues for researchers using L. decemlineata as a model species, and for pest management research. Our results provide the basis for performing future gene expression and functional analysis in L. decemlineata and improve our understanding of the biology of this invasive species at the molecular level. PMID- 24465842 TI - Using quality measures for quality improvement: the perspective of hospital staff. AB - RESEARCH OBJECTIVE: This study examines the perspectives of a range of key hospital staff on the use, importance, scientific background, availability of data, feasibility of data collection, cost benefit aspects and availability of professional personnel for measurement of quality indicators among Iranian hospitals. The study aims to facilitate the use of quality indicators to improve quality of care in hospitals. STUDY DESIGN: A cross-sectional study was conducted over the period 2009 to 2010. Staff at Iranian hospitals completed a self administered questionnaire eliciting their views on organizational, clinical process, and outcome (clinical effectiveness, patient safety and patient centeredness) indicators. POPULATION STUDIED: 93 hospital frontline staff including hospital/nursing managers, medical doctors, nurses, and quality improvement/medical records officers in 48 general and specialized hospitals in Iran. PRINCIPAL FINDINGS: On average, only 69% of respondents reported using quality indicators in practice at their affiliated hospitals. Respondents varied significantly in their reported use of organizational, clinical process and outcome quality indicators. Overall, clinical process and effectiveness indicators were reported to be least used. The reported use of indicators corresponded with their perceived level of importance. Quality indicators were reported to be used among clinical staff significantly more than among managerial staff. In total, 74% of the respondents reported to use obligatory indicators, while this was 68% for voluntary indicators (p<0.05). CONCLUSIONS: There is a general awareness of the importance and usability of quality indicators among hospital staff in Iran, but their use is currently mostly directed towards external accountability purposes. To increase the formative use of quality indicators, creation of a common culture and feeling of shared ownership, alongside an increased uptake of clinical process and effectiveness indicators is needed to support internal quality improvement processes at hospital level. PMID- 24465844 TI - Reading proficiency and adaptability in orthographic processing: an examination of the effect of type of orthography read on brain activity in regular and dyslexic readers. AB - Regular readers were found to adjust the routine of reading to the demands of processing imposed by different orthographies. Dyslexic readers may lack such adaptability in reading. This hypothesis was tested among readers of Hebrew, as Hebrew has two forms of script differing in phonological transparency. Event related potentials were recorded from 24 regular and 24 dyslexic readers while they carried out a lexical decision task in these two forms of script. The two forms of script elicited distinct amplitudes and latencies at ~165 ms after target onset, and these effects were larger in regular than in dyslexic readers. These early effects appeared not to be merely a result of the visual difference between the two forms of script (the presence of diacritics). The next effect of form of script was obtained on amplitudes elicited at latencies associated with orthographic-lexical processing and the categorization of stimuli, and these appeared earlier in regular readers (~340 ms) than in dyslexic readers (~400 ms). The behavioral measures showed inferior reading skills of dyslexic readers compared to regular readers in reading of both forms of script. Taken together, the results suggest that although dyslexic readers are not indifferent to the type of orthography read, they fail to adjust the routine of reading to the demands of processing imposed by both a transparent and an opaque orthography. PMID- 24465843 TI - Toll-like receptor 4 stimulation before or after Streptococcus pneumoniae induced sepsis improves survival and is dependent on T-cells. AB - INTRODUCTION: Endotoxin tolerance improves outcomes from gram negative sepsis but the underlying mechanism is not known. We determined if endotoxin tolerance before or after pneumococcal sepsis improved survival and the role of lymphocytes in this protection. METHODS: Mice received lipopolysaccharide (LPS) or vehicle before or after a lethal dose of Streptococcus pneumoniae. Survival, quantitative bacteriology, liver function, and cytokine concentrations were measured. We confirmed the necessity of Toll-like receptor 4 (TLR4) for endotoxin tolerance using C3H/HeN (TLR4 replete) and C3H/HeJ (TLR4 deficient) mice. The role of complement was investigated through A/J mice deficient in C5 complement. CBA/CaHN Btk(xid/)/J mice with dysfunctional B cells and Rag-1 knockout (KO) mice deficient in T and B cells delineated the role of lymphocytes. RESULTS: Endotoxin tolerance improved survival from pneumococcal sepsis in mice with TLR4 that received LPS pretreatment or posttreatment. Survival was associated with reduced bacterial burden and serum cytokine concentrations. Death was associated with abnormal liver function and blood glucose concentrations. Endotoxin tolerance improved survival in A/J and CBA/CaHN-Btk(xid/)/J mice but not Rag-1 KO mice. CONCLUSIONS: TLR4 stimulation before or after S. pneumoniae infection improved survival and was dependent on T-cells but did not require an intact complement cascade or functional B cells. PMID- 24465845 TI - Semi-automated, occupationally safe immunofluorescence microtip sensor for rapid detection of Mycobacterium cells in sputum. AB - An occupationally safe (biosafe) sputum liquefaction protocol was developed for use with a semi-automated antibody-based microtip immunofluorescence sensor. The protocol effectively liquefied sputum and inactivated microorganisms including Mycobacterium tuberculosis, while preserving the antibody-binding activity of Mycobacterium cell surface antigens. Sputum was treated with a synergistic chemical-thermal protocol that included moderate concentrations of NaOH and detergent at 60 degrees C for 5 to 10 min. Samples spiked with M. tuberculosis complex cells showed approximately 10(6)-fold inactivation of the pathogen after treatment. Antibody binding was retained post-treatment, as determined by analysis with a microtip immunosensor. The sensor correctly distinguished between Mycobacterium species and other cell types naturally present in biosafe-treated sputum, with a detection limit of 100 CFU/mL for M. tuberculosis, in a 30-minute sample-to-result process. The microtip device was also semi-automated and shown to be compatible with low-cost, LED-powered fluorescence microscopy. The device and biosafe sputum liquefaction method opens the door to rapid detection of tuberculosis in settings with limited laboratory infrastructure. PMID- 24465846 TI - Microarray analysis of rat pancreas reveals altered expression of Alox15 and regenerating islet-derived genes in response to iron deficiency and overload. AB - It is well known that iron overload can result in pancreatic iron deposition, beta-cell destruction, and diabetes in humans. Recent studies in animals have extended the link between iron status and pancreatic function by showing that iron depletion confers protection against beta-cell dysfunction and diabetes. The aim of the present study was to identify genes in the pancreas that are differentially expressed in response to iron deficiency or overload. Weanling male Sprague-Dawley rats (n = 6/group) were fed iron-deficient, iron-adequate, or iron-overloaded diets for 3 weeks to alter their iron status. Total RNA was isolated from the pancreases and pooled within each group for microarray analyses in which gene expression levels were compared to those in iron-adequate controls. In iron-deficient pancreas, a total of 66 genes were found to be differentially regulated (10 up, 56 down), whereas in iron-overloaded pancreas, 164 genes were affected (82 up, 82 down). The most up-regulated transcript in iron-deficient pancreas was arachidonate 15-lipoxygenase (Alox15), which has been implicated in the development of diabetes. In iron-overloaded pancreas, the most upregulated transcripts were Reg1a, Reg3a, and Reg3b belonging to the regenerating islet derived gene (Reg) family. Reg expression has been observed in response to pancreatic stress and is thought to facilitate pancreatic regeneration. Subsequent qRT-PCR validation indicated that Alox15 mRNA levels were 4 times higher in iron-deficient than in iron-adequate pancreas and that Reg1a, Reg3a, and Reg3b mRNA levels were 17-36 times higher in iron-overloaded pancreas. The elevated Alox15 mRNA levels in iron-deficient pancreas were associated with 8 fold higher levels of Alox15 protein as indicated by Western blotting. Overall, these data raise the possibility that Reg expression may serve as a biomarker for iron-related pancreatic stress, and that iron deficiency may adversely affect the risk of developing diabetes through up-regulation of Alox15. PMID- 24465847 TI - Neural correlates of own name and own face detection in autism spectrum disorder. AB - Autism spectrum disorder (ASD) is a heterogeneous neurodevelopmental condition clinically characterized by social interaction and communication difficulties. To date, the majority of research efforts have focused on brain mechanisms underlying the deficits in interpersonal social cognition associated with ASD. Recent empirical and theoretical work has begun to reveal evidence for a reduced or even absent self-preference effect in patients with ASD. One may hypothesize that this is related to the impaired attentional processing of self-referential stimuli. The aim of our study was to test this hypothesis. We investigated the neural correlates of face and name detection in ASD. Four categories of face/name stimuli were used: own, close-other, famous, and unknown. Event-related potentials were recorded from 62 electrodes in 23 subjects with ASD and 23 matched control subjects. P100, N170, and P300 components were analyzed. The control group clearly showed a significant self-preference effect: higher P300 amplitude to the presentation of own face and own name than to the close-other, famous, and unknown categories, indicating preferential attentional engagement in processing of self-related information. In contrast, detection of both own and close-other's face and name in the ASD group was associated with enhanced P300, suggesting similar attention allocation for self and close-other related information. These findings suggest that attention allocation in the ASD group is modulated by the personal significance factor, and that the self-preference effect is absent if self is compared to close-other. These effects are similar for physical and non-physical aspects of the autistic self. In addition, lateralization of face and name processing is attenuated in ASD, suggesting atypical brain organization. PMID- 24465848 TI - Increased tea consumption is associated with decreased arterial stiffness in a Chinese population. AB - BACKGROUND: Tea has attracted considerable attention for its potential cardioprotective effects. The primary chemical components of tea are thought to have a beneficial effect by reducing arterial stiffness. The objective of this study was to assess the association between tea consumption and brachial-ankle pulse wave velocity (baPWV) in a relatively healthy Chinese population. METHODS: We enrolled 3,135 apparently healthy subjects from October 2006 to August 2009. Subjects taking medication for diabetes, hypertension, or hyperlipidemia, or with a history of cardiovascular disease, were excluded from the study. The subjects were categorized into three groups according to their tea-drinking habits: (1) none to low (n = 1615), defined as non-habitual tea drinkers, or drinking for <1 year, or drinking <=150 mL per day for >=1 year ; (2) moderate tea consumption, defined as drinking for >=1 year and consumption between 151 and 450 mL per day; and (3) heavy tea consumption, defined as a drinking for >=1 year and consumption >450 mL per day. Multiple logistic regression was used to determine whether different levels of consumption were independently associated with the highest quartile of baPWV values, defined as >=1428.5 cm/s. RESULTS: Of the 3,135 subjects, 48.5% had drunk >150 mL of tea per day for at least 1 year. In multivariate regression analysis with adjustment for co-variables, including, age, sex, current smoking, alcohol use, habitual exercise, total cholesterol/high density lipoprotein cholesterol (TC/HDL-C) ratio >5, obesity, newly diagnosed hypertension and diabetes, subjects with high tea consumption had a decreased risk of highest quartile of baPWV by 22% (odds ratio = 0.78, 95% confidence interval = 0.62-0.98, p = 0.032), while subjects with moderate tea consumption did not (p = 0.742), as compared subjects with none to low tea consumption. CONCLUSIONS: High, but not moderate, habitual tea consumption may decrease arterial stiffness. PMID- 24465849 TI - Uncovering patterns of inter-urban trip and spatial interaction from social media check-in data. AB - The article revisits spatial interaction and distance decay from the perspective of human mobility patterns and spatially-embedded networks based on an empirical data set. We extract nationwide inter-urban movements in China from a check-in data set that covers half a million individuals within 370 cities to analyze the underlying patterns of trips and spatial interactions. By fitting the gravity model, we find that the observed spatial interactions are governed by a power law distance decay effect. The obtained gravity model also closely reproduces the exponential trip displacement distribution. The movement of an individual, however, may not obey the same distance decay effect, leading to an ecological fallacy. We also construct a spatial network where the edge weights denote the interaction strengths. The communities detected from the network are spatially cohesive and roughly consistent with province boundaries. We attribute this pattern to different distance decay parameters between intra-province and inter province trips. PMID- 24465850 TI - The first mitochondrial genome for the superfamily Hagloidea and implications for its systematic status in Ensifera. AB - Hagloidea Handlirsch, 1906 was an ancient group of Ensifera, that was much more diverse in the past extending at least into the Triassic, apparently diminishing in diversity through the Cretaceous, and now only represented by a few extant species. In this paper, we report the complete mitochondrial genome (mitogenome) of Tarragoilus diuturnus Gorochov, 2001, representing the first mitogenome of the superfamily Hagloidea. The size of the entire mitogenome of T. diuturnus is 16144 bp, containing 13 protein-coding genes (PCGs), 2 ribosomal RNA (rRNA) genes, 22 transfer RNA (tRNA) genes and one control region. The order and orientation of the gene arrangement pattern is identical to that of D. yakuba and most ensiferans species. A phylogenomic analysis was carried out based on the concatenated dataset of 13 PCGs and 2 rRNA genes from mitogenome sequences of 15 ensiferan species, comprising four superfamilies Grylloidea, Tettigonioidae, Rhaphidophoroidea and Hagloidea. Both maximum likelihood and Bayesian inference analyses strongly support Hagloidea T. diuturnus and Rhaphidophoroidea Troglophilus neglectus as forming a monophyletic group, sister to the Tettigonioidea. The relationships among four superfamilies of Ensifera were (Grylloidea, (Tettigonioidea, (Hagloidea, Rhaphidophoroidea))). PMID- 24465851 TI - Effect of dietary components on larval life history characteristics in the medfly (Ceratitis capitata: Diptera, Tephritidae). AB - BACKGROUND: The ability to respond to heterogenous nutritional resources is an important factor in the adaptive radiation of insects such as the highly polyphagous Medfly. Here we examined the breadth of the Medfly's capacity to respond to different developmental conditions, by experimentally altering diet components as a proxy for host quality and novelty. METHODOLOGY/PRINCIPAL FINDINGS: We tested responses of larval life history to diets containing protein and carbohydrate components found in and outside the natural host range of this species. A 40% reduction in the quantity of protein caused a significant increase in egg to adult mortality by 26.5%+/-6% in comparison to the standard baseline diet. Proteins and carbohydrates had differential effects on larval versus pupal development and survival. Addition of a novel protein source, casein (i.e. milk protein), to the diet increased larval mortality by 19.4%+/-3% and also lengthened the duration of larval development by 1.93+/-0.5 days in comparison to the standard diet. Alteration of dietary carbohydrate, by replacing the baseline starch with simple sugars, increased mortality specifically within the pupal stage (by 28.2%+/-8% and 26.2%+/-9% for glucose and maltose diets, respectively). Development in the presence of the novel carbohydrate lactose (milk sugar) was successful, though on this diet there was a decrease of 29.8+/-1.6 ug in mean pupal weight in comparison to pupae reared on the baseline diet. CONCLUSIONS: The results confirm that laboratory reared Medfly retain the ability to survive development through a wide range of fluctuations in the nutritional environment. We highlight new facets of the responses of different stages of holometabolous life histories to key dietary components. The results are relevant to colonisation scenarios and key to the biology of this highly invasive species. PMID- 24465852 TI - Structural basis of thermal stability of the tungsten cofactor synthesis protein MoaB from Pyrococcus furiosus. AB - Molybdenum and tungsten cofactors share a similar pterin-based scaffold, which hosts an ene-dithiolate function being essential for the coordination of either molybdenum or tungsten. The biosynthesis of both cofactors involves a multistep pathway, which ends with the activation of the metal binding pterin (MPT) by adenylylation before the respective metal is incorporated. In the hyperthermophilic organism Pyrococcus furiosus, the hexameric protein MoaB (PfuMoaB) has been shown to catalyse MPT-adenylylation. Here we determined the crystal structure of PfuMoaB at 2.5 A resolution and identified key residues of alpha3-helix mediating hexamer formation. Given that PfuMoaB homologues from mesophilic organisms form trimers, we investigated the impact on PfuMoaB hexamerization on thermal stability and activity. Using structure-guided mutagenesis, we successfully disrupted the hexamer interface in PfuMoaB. The resulting PfuMoaB-H3 variant formed monomers, dimers and trimers as determined by size exclusion chromatography. Circular dichroism spectroscopy as well as chemical cross-linking coupled to mass spectrometry confirmed a wild-type-like fold of the protomers as well as inter-subunits contacts. The melting temperature of PfuMoaB-H3 was found to be reduced by more than 15 degrees C as determined by differential scanning calorimetry, thus demonstrating hexamerization as key determinant for PfuMoaB thermal stability. Remarkably, while a loss of activity at temperatures higher than 50 degrees C was observed in the PfuMoaB-H3 variant, at lower temperatures, we determined a significantly increased catalytic activity. The latter suggests a gain in conformational flexibility caused by the disruption of the hexamerization interface. PMID- 24465853 TI - Dosage and cell line dependent inhibitory effect of bFGF supplement in human pluripotent stem cell culture on inactivated human mesenchymal stem cells. AB - Many different culture systems have been developed for expanding human pluripotent stem cells (hESCs and hiPSCs). In general, 4-10 ng/ml of bFGF is supplemented in culture media in feeder-dependent systems regardless of feeder cell types, whereas in feeder-free systems, up to 100 ng/ml of bFGF is required for maintaining long-term culture on various substrates. The amount of bFGF required in native hESCs growth niche is unclear. Here we report using inactivated adipose-derived human mesenchymal stem cells as feeder cells to examine long-term parallel cultures of two hESCs lines (H1 and H9) and one hiPSCs line (DF19-9-7T) in media supplemented with 0, 0.4 or 4 ng/ml of bFGF for up to 23 passages, as well as parallel cultures of H9 and DF19 in media supplemented with 4, 20 or 100 ng/ml bFGF for up to 13 passages for comparison. Across all cell lines tested, bFGF supplement demonstrated inhibitory effect over growth expansion, single cell colonization and recovery from freezing in a dosage dependent manner. In addition, bFGF exerted differential effects on different cell lines, inducing H1 and DF19 differentiation at 4 ng/ml or higher, while permitting long-term culture of H9 at the same concentrations with no apparent dosage effect. Pluripotency was confirmed for all cell lines cultured in 0, 0.4 or 4 ng/ml bFGF excluding H1-4 ng, as well as H9 cultured in 4, 20 and 100 ng/ml bFGF. However, DF19 demonstrated similar karyotypic abnormality in both 0 and 4 ng/ml bFGF media while H1 and H9 were karyotypically normal in 0 ng/ml bFGF after long-term culture. Our results indicate that exogenous bFGF exerts dosage and cell line dependent effect on human pluripotent stem cells cultured on mesenchymal stem cells, and implies optimal use of bFGF in hESCs/hiPSCs culture should be based on specific cell line and its culture system. PMID- 24465854 TI - Reference genes for real-time PCR quantification of messenger RNAs and microRNAs in mouse model of obesity. AB - Obesity and metabolic syndrome is increasing health problem worldwide. Among other ways, nutritional intervention using phytochemicals is important method for treatment and prevention of this disease. Recent studies have shown that certain phytochemicals could alter the expression of specific genes and microRNAs (miRNAs) that play a fundamental role in the pathogenesis of obesity. For study of the obesity and its treatment, monosodium glutamate (MSG)-injected mice with developed central obesity, insulin resistance and liver lipid accumulation are frequently used animal models. To understand the mechanism of phytochemicals action in obese animals, the study of selected genes expression together with miRNA quantification is extremely important. For this purpose, real-time quantitative PCR is a sensitive and reproducible method, but it depends on proper normalization entirely. The aim of present study was to identify the appropriate reference genes for mRNA and miRNA quantification in MSG mice treated with green tea catechins, potential anti-obesity phytochemicals. Two sets of reference genes were tested: first set contained seven commonly used genes for normalization of messenger RNA, the second set of candidate reference genes included ten small RNAs for normalization of miRNA. The expression stability of these reference genes were tested upon treatment of mice with catechins using geNorm, NormFinder and BestKeeper algorithms. Selected normalizers for mRNA quantification were tested and validated on expression of NAD(P)H: quinone oxidoreductase, biotransformation enzyme known to be modified by catechins. The effect of selected normalizers for miRNA quantification was tested on two obesity- and diabetes- related miRNAs, miR-221 and miR-29b, respectively. Finally, the combinations of B2M/18S/HPRT1 and miR-16/sno234 were validated as optimal reference genes for mRNA and miRNA quantification in liver and 18S/RPlP0/HPRT1 and sno234/miR-186 in small intestine of MSG mice. These reference genes will be used for mRNA and miRNA normalization in further study of green tea catechins action in obese mice. PMID- 24465856 TI - Standardized loads acting in knee implants. AB - The loads acting in knee joints must be known for improving joint replacement, surgical procedures, physiotherapy, biomechanical computer simulations, and to advise patients with osteoarthritis or fractures about what activities to avoid. Such data would also allow verification of test standards for knee implants. This work analyzes data from 8 subjects with instrumented knee implants, which allowed measuring the contact forces and moments acting in the joint. The implants were powered inductively and the loads transmitted at radio frequency. The time courses of forces and moments during walking, stair climbing, and 6 more activities were averaged for subjects with I) average body weight and average load levels and II) high body weight and high load levels. During all investigated activities except jogging, the high force levels reached 3,372 4,218N. During slow jogging, they were up to 5,165N. The peak torque around the implant stem during walking was 10.5 Nm, which was higher than during all other activities including jogging. The transverse forces and the moments varied greatly between the subjects, especially during non-cyclic activities. The high load levels measured were mostly above those defined in the wear test ISO 14243. The loads defined in the ISO test standard should be adapted to the levels reported here. The new data will allow realistic investigations and improvements of joint replacement, surgical procedures for tendon repair, treatment of fractures, and others. Computer models of the load conditions in the lower extremities will become more realistic if the new data is used as a gold standard. However, due to the extreme individual variations of some load components, even the reported average load profiles can most likely not explain every failure of an implant or a surgical procedure. PMID- 24465855 TI - PEP-1-PON1 protein regulates inflammatory response in raw 264.7 macrophages and ameliorates inflammation in a TPA-induced animal model. AB - Paraoxonase 1 (PON1) is an antioxidant enzyme which plays a central role in various diseases. However, the mechanism and function of PON1 protein in inflammation are poorly understood. Since PON1 protein alone cannot be delivered into cells, we generated a cell permeable PEP-1-PON1 protein using protein transduction domains, and examined whether it can protect against cell death in lipopolysaccharide (LPS) or hydrogen peroxide (H2O2)-treated Raw 264.7 cells as well as mice with 12-O-tetradecanoyl phorbol-13-acetate (TPA)-induced skin inflammation. We demonstrated that PEP-1-PON1 protein transduced into Raw 264.7 cells and markedly protected against LPS or H2O2-induced cell death by inhibiting cellular reactive oxygen species (ROS) levels, the inflammatory mediator's expression, activation of mitogen-activated protein kinases (MAPKs) and cellular apoptosis. Furthermore, topically applied PEP-1-PON1 protein ameliorates TPA treated mice skin inflammation via a reduction of inflammatory response. Our results indicate that PEP-1-PON1 protein plays a key role in inflammation and oxidative stress in vitro and in vivo. Therefore, we suggest that PEP-1-PON1 protein may provide a potential protein therapy against oxidative stress and inflammation. PMID- 24465857 TI - Comprehensive transcriptome assembly of Chickpea (Cicer arietinum L.) using sanger and next generation sequencing platforms: development and applications. AB - A comprehensive transcriptome assembly of chickpea has been developed using 134.95 million Illumina single-end reads, 7.12 million single-end FLX/454 reads and 139,214 Sanger expressed sequence tags (ESTs) from >17 genotypes. This hybrid transcriptome assembly, referred to as Cicer arietinumTranscriptome Assembly version 2 (CaTA v2, available at http://data.comparative legumes.org/transcriptomes/cicar/lista_cicar-201201), comprising 46,369 transcript assembly contigs (TACs) has an N50 length of 1,726 bp and a maximum contig size of 15,644 bp. Putative functions were determined for 32,869 (70.8%) of the TACs and gene ontology assignments were determined for 21,471 (46.3%). The new transcriptome assembly was compared with the previously available chickpea transcriptome assemblies as well as to the chickpea genome. Comparative analysis of CaTA v2 against transcriptomes of three legumes - Medicago, soybean and common bean, resulted in 27,771 TACs common to all three legumes indicating strong conservation of genes across legumes. CaTA v2 was also used for identification of simple sequence repeats (SSRs) and intron spanning regions (ISRs) for developing molecular markers. ISRs were identified by aligning TACs to the Medicago genome, and their putative mapping positions at chromosomal level were identified using transcript map of chickpea. Primer pairs were designed for 4,990 ISRs, each representing a single contig for which predicted positions are inferred and distributed across eight linkage groups. A subset of randomly selected ISRs representing all eight chickpea linkage groups were validated on five chickpea genotypes and showed 20% polymorphism with average polymorphic information content (PIC) of 0.27. In summary, the hybrid transcriptome assembly developed and novel markers identified can be used for a variety of applications such as gene discovery, marker-trait association, diversity analysis etc., to advance genetics research and breeding applications in chickpea and other related legumes. PMID- 24465858 TI - A novel evolutionary strategy revealed in the phaeoviruses. AB - Phaeoviruses infect the brown algae, which are major contributors to primary production of coastal waters and estuaries. They exploit a Persistent evolutionary strategy akin to a K- selected life strategy via genome integration and are the only known representatives to do so within the giant algal viruses that are typified by r- selected Acute lytic viruses. In screening the genomes of five species within the filamentous brown algal lineage, here we show an unprecedented diversity of viral gene sequence variants especially amongst the smaller phaeoviral genomes. Moreover, one variant shares features from both the two major sub-groups within the phaeoviruses. These phaeoviruses have exploited the reduction of their giant dsDNA genomes and accompanying loss of DNA proofreading capability, typical of an Acute life strategist, but uniquely retain a Persistent life strategy. PMID- 24465859 TI - Socio-demographic inequalities in the prevalence, diagnosis and management of hypertension in India: analysis of nationally-representative survey data. AB - BACKGROUND: Hypertension is a major contributing factor to the current epidemic of cardiovascular disease in India. Small studies suggest high, and increasing, prevalence especially in urban areas, with poor detection and management, but national data has been lacking. The aim of the current study was to use nationally-representative survey data to examine socio-demographic inequalities in the prevalence, diagnosis and management of hypertension in Indian adults. METHODS: Using data on self-reported diagnosis and treatment, and blood pressure measurement, collected from 12,198 respondents aged 18+ in the 2007 WHO Study on Global Ageing and Adult Health in India, factors associated with prevalence, diagnosis and treatment of hypertension were investigated. RESULTS: 22% men and 26% women had hypertension; prevalence increased steeply with body mass index (<18.5 kg/m(2): 18% men, 21% women; 25-29.9 kg/m(2): 35% men, 35% women), was higher in the least poor vs. poorest (men: odds ratio (95%CI) 1.82 (1.20 to 2.76); women: 1.40 (1.08 to 1.81)), urban vs. rural men (1.64 (1.19 to 2.25)), and men recently vs. never using alcohol (1.96 (1.40 to 2.76)). Over half the hypertension in women, and 70% in men, was undetected with particularly poor detection rates in young urban men, and in poorer households. Two-thirds of men and women with detected hypertension were treated. Two-thirds of women treated had their hypertension controlled, irrespective of urban/rural setting or wealth. Adequate blood pressure control was sub-optimal in urban men. CONCLUSION: Hypertension is very common in India, even among underweight adults and those of lower socioeconomic position. Improved detection is needed to reduce the burden of disease attributable to hypertension. Levels of treatment and control are relatively good, particularly in women, although urban men require more careful attention. PMID- 24465860 TI - Ex-PRESS implantation versus trabeculectomy in open-angle glaucoma: a meta analysis of randomized controlled clinical trials. AB - OBJECTIVE: To evaluate the efficacy and safety of Ex-PRESS implantation (Ex PRESS) compared to trabeculectomy in the treatment of patients with open-angle glaucoma (OAG). METHODS: A comprehensive literature search using the Cochrane Methodology Register to identify randomized controlled clinical trials (RCCTs) comparing Ex-PRESS to trabeculectomy in patients with OAG. Efficacy estimates were measured by weighted mean difference (WMD) for the percentage intraocular pressure reduction (IOPR%) from baseline to end-point, and odds ratios (OR) for the complete success rate and postoperative interventions. Safety estimates were measured by OR for postoperative complications. Statistical analysis was performed using the RevMan 5.1 software. RESULTS: A total of four RCCTs were selected for this meta-analysis, including 215 eyes of 200 patients (110 eyes in the Ex-PRESS group, 105 eyes in the trabeculectomy group). There was no significant difference between Ex-PRESS and trabeculectomy in the IOPR% (WMD = 3.15; 95% confidence interval (CI), -6.17-12.47; P = 0.51). The pooled OR comparing Ex-PRESS to trabeculectomy for the complete success rate at one year after surgery were in favor of Ex-PRESS (OR = 2.93; 95% CI, 1.39-6.16; P = 0.005). The Ex-PRESS procedure was found to be associated with lower number of postoperative interventions (OR = 0.23; 95% CI, 0.07-0.81; P = 0.02) and with a significantly lower frequency of hyphema than trabeculectomy (OR = 0.21; 95% CI, 0.05-0.85; P = 0.03), whereas other complications did not differ statistically. CONCLUSION: In OAG, Ex-PRESS and trabeculectomy provided similar IOP control, but Ex-PRESS was more likely to achieve complete success, with fewer postoperative interventions. Complication rates were similar for the two types of surgery, except for a lower frequency of hyphema in the Ex-PRESS group. PMID- 24465861 TI - Prevalence, risk factors and social context of active pulmonary tuberculosis among prison inmates in Tajikistan. AB - SETTING: Tuberculosis (TB) is highly prevalent in prisons of the former Soviet Union. OBJECTIVE: To understand the behavioral, demographic and biological factors placing inmates in Tajikistan at risk for active TB. DESIGN: We administered a behavioral and demographic survey to 1317 inmates in two prison facilities in Sughd province, Tajikistan along with radiographic screening for pulmonary TB. Suspected cases were confirmed bacteriologically. Inmates undergoing TB treatment were also surveyed. In-depth interviews were conducted with former prisoners to elicit relevant social and behavioral characteristics. RESULTS: We identified 59 cases of active pulmonary TB (prevalence 4.5%). Factors independently associated with increased prevalence of active TB were: HIV infection by self-report (PR 7.88; 95%CI 3.40-18.28), history of previous TB (PR 10.21; 95%CI 6.27-16.63) and infrequent supplemental nutrition beyond scheduled meals (PR 3.00; 95%CI 1.67-5.62). Access to supplemental nutrition was associated with frequency of visits from friends and family and ability to rely on other inmates for help. CONCLUSION: In prison facilities of Tajikistan, HIV-infection, injection drug use and low access to supplemental nutrition were associated with prevalent cases of active pulmonary TB. Policies that reduce HIV transmission among injection drug users and improve the nutritional status of socially isolated inmates may alleviate the TB burden in Tajikistan's prisons. PMID- 24465862 TI - The effect of Diel temperature and light cycles on the growth of nannochloropsis oculata in a photobioreactor matrix. AB - A matrix of photobioreactors integrated with metabolic sensors was used to examine the combined impact of light and temperature variations on the growth and physiology of the biofuel candidate microalgal species Nannochloropsis oculata. The experiments were performed with algal cultures maintained at a constant 20 degrees C versus a 15 degrees C to 25 degrees C diel temperature cycle, where light intensity also followed a diel cycle with a maximum irradiance of 1920 umol photons m(-2) s(-1). No differences in algal growth (Chlorophyll a) were found between the two environmental regimes; however, the metabolic processes responded differently throughout the day to the change in environmental conditions. The variable temperature treatment resulted in greater damage to photosystem II due to the combined effect of strong light and high temperature. Cellular functions responded differently to conditions before midday as opposed to the afternoon, leading to strong hysteresis in dissolved oxygen concentration, quantum yield of photosystem II and net photosynthesis. Overnight metabolism performed differently, probably as a result of the temperature impact on respiration. Our photobioreactor matrix has produced novel insights into the physiological response of Nannochloropsis oculata to simulated environmental conditions. This information can be used to predict the effectiveness of deploying Nannochloropsis oculata in similar field conditions for commercial biofuel production. PMID- 24465863 TI - Chronic treatment with novel small molecule Hsp90 inhibitors rescues striatal dopamine levels but not alpha-synuclein-induced neuronal cell loss. AB - Hsp90 inhibitors such as geldanamycin potently induce Hsp70 and reduce cytotoxicity due to alpha-synuclein expression, although their use has been limited due to toxicity, brain permeability, and drug design. We recently described the effects of a novel class of potent, small molecule Hsp90 inhibitors in cells overexpressing alpha-synuclein. Screening yielded several candidate compounds that significantly reduced alpha-synuclein oligomer formation and cytotoxicity associated with Hsp70 induction. In this study we examined whether chronic treatment with candidate Hsp90 inhibitors could protect against alpha synuclein toxicity in a rat model of parkinsonism. Rats were injected unilaterally in the substantia nigra with AAV8 expressing human alpha-synuclein and then treated with drug for approximately 8 weeks by oral gavage. Chronic treatment with SNX-0723 or the more potent, SNX-9114 failed to reduce dopaminergic toxicity in the substantia nigra compared to vehicle. However, SNX 9114 significantly increased striatal dopamine content suggesting a positive neuromodulatory effect on striatal terminals. Treatment was generally well tolerated, but higher dose SNX-0723 (6-10 mg/kg) resulted in systemic toxicity, weight loss, and early death. Although still limited by potential toxicity, Hsp90 inhibitors tested herein demonstrate oral efficacy and possible beneficial effects on dopamine production in a vertebrate model of parkinsonism that warrant further study. PMID- 24465864 TI - Genetic and DNA methylation changes in cotton (Gossypium) genotypes and tissues. AB - In plants, epigenetic regulation is important in normal development and in modulating some agronomic traits. The potential contribution of DNA methylation mediated gene regulation to phenotypic diversity and development in cotton was investigated between cotton genotypes and various tissues. DNA methylation diversity, genetic diversity, and changes in methylation context were investigated using methylation-sensitive amplified polymorphism (MSAP) assays including a methylation insensitive enzyme (BsiSI), and the total DNA methylation level was measured by high-performance liquid chromatography (HPLC). DNA methylation diversity was greater than the genetic diversity in the selected cotton genotypes and significantly different levels of DNA methylation were identified between tissues, including fibre. The higher DNA methylation diversity (CHG methylation being more diverse than CG methylation) in cotton genotypes suggest epigenetic regulation may be important for cotton, and the change in DNA methylation between fibre and other tissues hints that some genes may be epigenetically regulated for fibre development. The novel approach using BsiSI allowed direct comparison between genetic and epigenetic diversity, and also measured CC methylation level that cannot be detected by conventional MSAP. PMID- 24465865 TI - Tracking molecular recognition at the atomic level with a new protein scaffold based on the OB-fold. AB - The OB-fold is a small, versatile single-domain protein binding module that occurs in all forms of life, where it binds protein, carbohydrate, nucleic acid and small-molecule ligands. We have exploited this natural plasticity to engineer a new class of non-immunoglobulin alternatives to antibodies with unique structural and biophysical characteristics. We present here the engineering of the OB-fold anticodon recognition domain from aspartyl tRNA synthetase taken from the thermophile Pyrobaculum aerophilum. For this single-domain scaffold we have coined the term OBody. Starting from a naive combinatorial library, we engineered an OBody with 3 nM affinity for hen egg-white lysozyme, by optimising the affinity of a naive OBody 11,700-fold over several affinity maturation steps, using phage display. At each maturation step a crystal structure of the engineered OBody in complex with hen egg-white lysozyme was determined, showing binding elements in atomic detail. These structures have given us an unprecedented insight into the directed evolution of affinity for a single antigen on the molecular scale. The engineered OBodies retain the high thermal stability of the parental OB-fold despite mutation of up to 22% of their residues. They can be expressed in soluble form and also purified from bacteria at high yields. They also lack disulfide bonds. These data demonstrate the potential of OBodies as a new scaffold for the engineering of specific binding reagents and provide a platform for further development of future OBody-based applications. PMID- 24465867 TI - Haul-out behaviour of the world's northernmost population of harbour seals (Phoca vitulina) throughout the year. AB - The harbour seal population in Svalbard occurs at the northernmost limit of the species' range. It experiences environmental extremes far beyond the norm for this species, including an extended period of polar night and extensive sea ice cover. In 2009 and 2010, 60 harbour seals (30 pups + 30 immature/mature seals) from this population were equipped with Satellite-Relay Data Loggers (SRDLs) to study their haul-out behaviour, with a special focus on the winter period. Using a combination of Generalized Additive Mixed Models and Cox Proportional Hazard models, the influences of sex, maturity, temporal, spatial and environmental factors on haul-out behaviour were explored. All of the seals continued to haul out even through the coldest periods during the polar night, though clear seasonality in the time spent hauled out daily was displayed by both immature and mature seals. Time spent hauled out daily decreased from ~5.2 hrs in September to ~1.2 hrs in February in these age groups, while pups displayed less seasonality (~2.4 hrs/day throughout most of the year). The average at-sea period also exhibited seasonality, increasing to a maximum of ~1.6 days in February (monthly maxima for individual animals ranged from 7 to 19 days). The seals showed a strong preference to haul out at low tide when hauling out on land but not when using sea ice as a haul-out platform. A diel rhythm in haul-out behaviour was present during the months with day-night cycling and midnight sun but not during the polar night. Haul-out behaviour was impacted to a greater extent by air pressure, through its effect on wind speed, than by absolute temperature values. The extreme environment in Svalbard likely causes some physiological challenges that might impact survival rates negatively, particularly among pups. Climate warming is likely to have positive effects on Svalbard's harbour seal population. PMID- 24465866 TI - The molecular basis of conformational instability of the ecdysone receptor DNA binding domain studied by in silico and in vitro experiments. AB - The heterodimer of the ecdysone receptor (EcR) and ultraspiracle (Usp), members of the nuclear receptors superfamily, regulates gene expression associated with molting and metamorphosis in insects. The DNA binding domains (DBDs) of the Usp and EcR play an important role in their DNA-dependent heterodimerization. Analysis of the crystal structure of the UspDBD/EcRDBD heterocomplex from Drosophila melanogaster on the hsp27 gene response element, suggested an appreciable similarity between both DBDs. However, the chemical denaturation experiments showed a categorically lower stability for the EcRDBD in contrast to the UspDBD. The aim of our study was an elucidation of the molecular basis of this intriguing instability. Toward this end, we mapped the EcRDBD amino acid sequence positions which have an impact on the stability of the EcRDBD. The computational protein design and in vitro analyses of the EcRDBD mutants indicate that non-conserved residues within the alpha-helix 2, forming the EcRDBD hydrophobic core, represent a specific structural element that contributes to instability. In particular, the L58 appears to be a key residue which differentiates the hydrophobic cores of UspDBD and EcRDBD and is the main reason for the low stability of the EcRDBD. Our results might serve as a benchmark for further studies of the intricate nature of the EcR molecule. PMID- 24465868 TI - Temporal dynamics of religion as a determinant of HIV infection in East Zimbabwe: a serial cross-sectional analysis. AB - BACKGROUND: Religion is an important underlying determinant of HIV spread in sub Saharan Africa. However, little is known about how religion influences changes in HIV prevalence and associated sexual behaviours over time. OBJECTIVES: To compare changes in HIV prevalence between major religious groups in eastern Zimbabwe during a period of substantial HIV risk reduction (1998-2005) and to investigate whether variations observed can be explained by differences in behaviour change. METHODS: We analysed serial cross-sectional data from two rounds of a longitudinal population survey in eastern Zimbabwe. Univariate and multivariate logistic regression models were developed to compare differences in sexual behaviour and HIV prevalence between religious groups and to investigate changes over time controlling for potential confounders. RESULTS: Christian churches were the most popular religious grouping. Over time, Spiritualist churches increased in popularity and, for men, Traditional religion and no religion became less and more common, respectively. At baseline (1998-2000), HIV prevalence was higher in Traditionalists and in those with no religion than in people in Christian churches (men 26.7% and 23.8% vs. 17.5%, women: 35.4% and 37.5% vs. 24.1%). These effects were explained by differences in socio-demographic characteristics (for Traditional and men with no religion) or sexual behaviour (women with no religion). Spiritualist men (but not women) had lower HIV prevalence than Christians, after adjusting for socio-demographic characteristics (14.4% vs. 17.5%, aOR = 0.8), due to safer behaviour. HIV prevalence had fallen in all religious groups at follow-up (2003-2005). Odds of infection in Christians reduced relative to those in other religious groups for both sexes, effects that were mediated largely by greater reductions in sexual-risk behaviour and, possibly, for women, by patterns of conversion between churches. CONCLUSION: Variation in behavioural responses to HIV between the major church groupings has contributed to a change in the religious pattern of infection in eastern Zimbabwe. PMID- 24465869 TI - Genetic variants in microRNA target sites of 37 selected cancer-related genes and the risk of cervical cancer. AB - OBJECTIVES: Single nucleotide polymorphisms (SNPs) in putative microRNA binding sites (miRSNPs) modulate cancer susceptibility via affecting miRNA binding. Here, we sought to investigate the association between miRSNPs and cervical cancer risk. METHODS: We first genotyped 41 miRSNPs of 37 cancer-related genes in 338 patients and 334 controls (Study 1), and replicated the significant associations in 502 patients and 600 controls (Study 2). We tested the effects of miRSNPs on microRNA-mRNA interaction by luciferase reporter assay. RESULTS: Five SNPs displayed notable association with cervical cancer risk in Study 1. Only IL-16 rs1131445 maintained a significant association with cervical cancer (CT/CC vs. TT, adjusted OR = 1.51, P = 0.001) in Study 2. This association was more evident in the combined data of two studies (adjusted OR = 1.49, P = 0.00007). We also found that miR-135b mimics interacted with IL-16 3'-UTR to reduce gene expression and that the rs1131445 T to C substitution within the putative binding site impaired the interaction of miR-135b with IL-16 3'-UTR. An ELISA indicated that the serum IL-16 of patients with cervical cancer was elevated (vs. controls, P = 0.001) and correlated with the rs1131445 genotype. Patients who carried the rs1131445 C allele had higher serum IL-16 than non-carriers (P<0.001). CONCLUSIONS: These results support our hypothesis that miRSNPs constitute a susceptibility factor for cervical cancers. rs1131445 affects IL-16 expression by interfering with the suppressive function of miR135b and this variant is significantly associated with cervical cancer risk. PMID- 24465870 TI - Oral delivery of exenatide via microspheres prepared by cross-linking of alginate and hyaluronate. AB - Exenatide is an FDA-approved glucose-lowering peptide drug for the treatment of type 2 diabetes by subcutaneous injection. To address the issues on the inconvenience for patient use and the difficulty of oral administration of peptide drugs, chemical cross-linking of two pH-responsive biomaterials, alginate and hyaluronate, was carried out to prepare a new material for the encapsulation of exenatide as a form of microspheres. The exenatide-loaded microspheres exhibited spherical structures with excellent loading and release behaviors in the simulated gastrointestinal tract environments. After oral administration of the microspheres in db/db mice, maximum plasma concentration of exenatide appeared at 4 hours, and blood glucose was effectively reduced to a normal level within 2 hours and maintained for another 4 hours. The bioavailability of the exenatide-loaded microspheres, relative to subcutaneous injection of exenatide, reached 10.2%. Collectively, the present study demonstrated the feasibility of orally delivering exenatide with the new cross-linked biomaterial and formulation, and showed therapeutic potential for clinical applications. PMID- 24465871 TI - Reference intervals for serum cystatin C and factors influencing cystatin C levels other than renal function in the elderly. AB - OBJECTIVE: The present study aimed to establish reference intervals for serum cystatin C (Scys-C) stratified by stages of chronic kidney disease, explore factors influencing Scys-C and compare the performance of Scys-C with serum creatinine (Scr) in the young and elderly. METHODS: A total of 800 participants, 516 young (<60 years) and 284 old (>=60 years) subjects were included in this study. Scys-C and Scr were assayed by the partical-enhanced immunoturbidimetry method and enzymatic method respectively. 95% reference interval was adopted to evaluate reference intervals. Influencing factors were characterized by multivariate linear regression analysis. Relationship between reference glomerular filtration rate (rGFR) and Scys-C or Scr was determined by correlation coefficient. RESULTS: Reference intervals for Scys-C were calculated to be 0.71 1.38 mg/L, 0.83-1.67 mg/L, 1.02-2.61 mg/L, 1.32-4.48 mg/L, 1.95-6.11 mg/L in the aged in CKD G1, G2, G3a, G3b and G4-5 stages, respectively. Body mass index(BMI), nephritis, kidney neoplasm and hypertension were demonstrated as factors affecting Scys-C in the elderly while gender, nephritis and kidney neoplasm were clarified as influencing factors in the young group. Scr levels were affected by more factors, such as body surface area and hematological disease. Correlation coefficient between rGFR and Scys-C or Scr showed that serum Scys-C was superior to Scr, especially in the subjects with mildly decreased renal function (-0.593 vs. -0.520). CONCLUSIONS: Factors other than renal function influenced Scys-C when applying to evaluate glomerular filtration rate (GFR), such as BMI, nephritis, kidney neoplasm and hypertension, and Scys-C had higher correlation with GFR than Scr in the elderly. PMID- 24465872 TI - Peptide detection of fungal functional amyloids in infected tissue. AB - Many fungal cell adhesion proteins form functional amyloid patches on the surface of adhering cells. The Candida albicans Agglutinin-like sequence (Als) adhesins are exemplars for this phenomenon, and have amyloid forming sequences that are conserved between family members. The Als5p amyloid sequence mediates amyloid fibril formation and is critical for cell adhesion and biofilm formation, and is also present in the related adhesins Als1p and Als3p. We have developed a fluorescent peptide probe containing the conserved Als amyloid-forming sequence. This peptide bound specifically to yeast expressing Als5p, but not to cells lacking the adhesin. The probe bound to both yeast and hyphal forms of C. albicans. Deltaals1/Deltaals3 single and double deletion strains exhibited reduced fluorescence, indicating that probe binding required expression of these proteins. Additionally, the Als peptide specifically stained fungal cells in abscesses in autopsy sections. Counterstaining with calcofluor white showed colocalization with the amyloid peptide. In addition, fungi in autopsy sections derived from the gastrointestinal tract showed colocalization of the amyloid specific dye thioflavin T and the fluorescent peptide. Collectively, our data demonstrate that we can exploit amyloid sequence specificity for detection of functional amyloids in situ. PMID- 24465873 TI - fMRI of retina-originated phosphenes experienced by patients with Leber congenital amaurosis. AB - A phenomenon characterized by the experience of seeing light without any light actually entering the eye is called phosphenes or photopsias. Phosphenes can occur spontaneously or via induction by external stimuli. Previous reports regarding phosphenes have primarily focused on externally induced phosphenes such as by applying alternating or direct current to the cortex. A few of these reports used functional magnetic resonance (fMRI) to study activations induced by cortical phosphenes. However, there are no fMRI reports on spontaneous phosphenes originating from the retina and the resulting pattern of cortical activations. We performed fMRI during a reversing checkerboard paradigm in three LCA patients who underwent unilateral gene therapy and reported experiencing frequent phosphene on a daily basis. We observed bilateral cortical activation covering the entire visual cortices when patients reported experiencing phosphenes. In contrast, in the absence of phosphenes, activation was regulated by patient's visual ability and demonstrated improved cortical activation due to gene therapy. These fMRI results illustrate the potential impact of phosphene perception on visual function and they may explain some of the variability that clinicians find in visual function testing in retinal degeneration. Although we did not perform correlations between visual function and phosphenes, we hope data presented here raises awareness of this phenomenon and its potential effect on visual function and the implications for clinical testing. We recommend a thorough history for phosphene experiences be taken in patients with retinal disease who are candidates for gene or molecular therapy. Lastly, these data illustrate the potential power of fMRI as an outcome measure of gene therapy and the negative impact phosphenes may have on vision testing. fMRI has proven to be a sensitive, non-invasive, and reproducible test paradigm for these purposes and can complement standard visual function testing. PMID- 24465874 TI - IFNalpha serum levels are associated with endothelial progenitor cells imbalance and disease features in rheumatoid arthritis patients. AB - INTRODUCTION: IFNalpha has been largely implicated in the ethiopathogenesis of autoimmune diseases but only recently it has been linked to endothelial damage and accelerated atherosclerosis in autoimmunity. In addition, proinflammatory conditions are supposed to be implicated in the cardiovascular status of these patients. Since a role for IFNalpha in endothelial damage and impaired Endothelial Progenitor Cell (EPC) number and function has been reported in other diseases, we aimed to evaluate the potential associations of IFNalpha serum levels on EPC populations and cytokine profiles in Rheumatoid Arthritis (RA) patients. METHODS: pre-EPC, EPC and mature EPC (mEPC) populations were quantified by flow cytometry analyzing their differential CD34, CD133 and VEGFR2 expression in blood samples from 120 RA patients, 52 healthy controls (HC), and 83 systemic lupus erythematosus (SLE) patients as disease control. Cytokine serum levels were measured by immunoassays and clinical and immunological data, including cardiovascular (CV) events and CV risk factors, were retrospectively obtained by reviewing clinical records. RESULTS: Long-standing, but not recent onset RA patients displayed a significant depletion of all endothelial progenitor populations, unless high IFNalpha levels were present. In fact, the IFN(high) RA patient group (n = 40, 33%), showed increased EPC levels, comparable to SLE patients. In addition, high IFNalpha serum levels were associated with higher disease activity (DAS28), presence of autoantibodies, higher levels of IL-1beta, IL-6, IL-10 and MIP-1alpha, lower amounts of TGF-beta, and increased mEPC/EPC ratio, thus suggesting higher rates of endothelial damage and an endothelial repair failure. Finally, the relationship between high IFNalpha levels and occurrence of CV events observed in RA patients seems to support this hypothesis. CONCLUSIONS: IFNalpha serum marker could be used to identify a group of RA patients with increased disease activity, EPC imbalance, enhanced proinflammatory profile and higher cardiovascular risk, probably due, at least in part, to an impaired endothelial repair. PMID- 24465875 TI - Multicountry burden of chronic hepatitis C viral infection among those aware of their diagnosis: a patient survey. AB - BACKGROUND: The World Health Organization has called for global and regional assessments of the burden of hepatitis C (HCV) along with country-specific patient profiles to better inform healthcare policy. The present investigated the characteristics and burden of patients reporting a diagnosis of HCV infection in the US, France, Germany, Italy, Spain, the UK, urban China, and Japan using a consistent methodology of patient-reported surveys. METHODS: The 2010 5EU (N = 57,805), 2009 US (N = 75,000), 2008/2009 Japan (N = 37,683), and 2009/2010 urban China (N = 33,261) waves of the National Health and Wellness Survey were used as the data source. Within each country, patients with a self-reported diagnosis of HCV were compared with those who did not report a diagnosis of HCV on sociodemographics, health behaviors, comorbidities, and health outcomes (e.g., Short Form-12v2). The effect of HCV was examined using regression analysis applying sampling weights. RESULTS: The prevalence of HCV ranged from 0.26% (China) to 1.42% (Italy). Patients in Japan and Italy (61.60 and 61.02 years, respectively) were the oldest, while patients in the US were the most likely to be obese (39.31%) and have concomitant anxiety (38.43%) and depression (46.05%) compared with other countries. Pooling countries and adjusting for sociodemographics, health behaviors, and comorbidities, HCV was associated with significantly lower physical component summary scores (b = -2.51) and health utilities (b = -0.04) and greater overall work impairment (b = 8.79), physician visits (b = 2.91), and emergency department visits (b = 0.30) (all p<.05). The effects on health status were strongest in the US and UK while the effects on healthcare resource use were strongest in Japan. CONCLUSIONS: HCV was associated with a significant humanistic and economic burden. These results suggest that the manifestation of the HCV burden, and the profile of the patients themselves, varied dramatically by country. Successful disease management should be cognizant of region-specific unmet needs. PMID- 24465877 TI - Spatio-temporal patterns of beaked whale echolocation signals in the North Pacific. AB - At least ten species of beaked whales inhabit the North Pacific, but little is known about their abundance, ecology, and behavior, as they are elusive and difficult to distinguish visually at sea. Six of these species produce known species-specific frequency modulated (FM) echolocation pulses: Baird's, Blainville's, Cuvier's, Deraniyagala's, Longman's, and Stejneger's beaked whales. Additionally, one described FM pulse (BWC) from Cross Seamount, Hawai'i, and three unknown FM pulse types (BW40, BW43, BW70) have been identified from almost 11 cumulative years of autonomous recordings at 24 sites throughout the North Pacific. Most sites had a dominant FM pulse type with other types being either absent or limited. There was not a strong seasonal influence on the occurrence of these signals at any site, but longer time series may reveal smaller, consistent fluctuations. Only the species producing BWC signals, detected throughout the Pacific Islands region, consistently showed a diel cycle with nocturnal foraging. By comparing stranding and sighting information with acoustic findings, we hypothesize that BWC signals are produced by ginkgo-toothed beaked whales. BW43 signal encounters were restricted to Southern California and may be produced by Perrin's beaked whale, known only from Californian waters. BW70 signals were detected in the southern Gulf of California, which is prime habitat for Pygmy beaked whales. Hubb's beaked whale may have produced the BW40 signals encountered off central and southern California; however, these signals were also recorded off Pearl and Hermes Reef and Wake Atoll, which are well south of their known range. PMID- 24465876 TI - The productive entry pathway of HIV-1 in macrophages is dependent on endocytosis through lipid rafts containing CD4. AB - Macrophages constitute an important reservoir of HIV-1 infection, yet HIV-1 entry into these cells is poorly understood due to the difficulty in genetically manipulating primary macrophages. We developed an effective genetic approach to manipulate the sub-cellular distribution of CD4 in macrophages, and investigated how this affects the HIV-1 entry pathway. Pluripotent Stem Cells (PSC) were transduced with lentiviral vectors designed to manipulate CD4 location and were then differentiated into genetically modified macrophages. HIV-1 infection of these cells was assessed by performing assays that measure critical steps of the HIV-1 lifecycle (fusion, reverse transcription, and expression from HIV-1 integrants). Expression of LCK (which tethers CD4 to the surface of T cells, but is not normally expressed in macrophages) in PSC-macrophages effectively tethered CD4 at the cell surface, reducing its normal endocytic recycling route, and increasing surface CD4 expression 3-fold. This led to a significant increase in HIV-1 fusion and reverse transcription, but productive HIV-1 infection efficiency (as determined by reporter expression from DNA integrants) was unaffected. This implies that surface-tethering of CD4 sequesters HIV-1 into a pathway that is unproductive in macrophages. Secondly, to investigate the importance of lipid rafts (as detergent resistant membranes - DRM) in HIV-1 infection, we generated genetically modified PSC-macrophages that express CD4 mutants known to be excluded from DRM. These macrophages were significantly less able to support HIV 1 fusion, reverse-transcription and integration than engineered controls. Overall, these results support a model in which productive infection by HIV-1 in macrophages occurs via a CD4-raft-dependent endocytic uptake pathway. PMID- 24465878 TI - Validity and reproducibility of a Spanish dietary history. AB - OBJECTIVE: To assess the validity and reproducibility of food and nutrient intake estimated with the electronic diet history of ENRICA (DH-E), which collects information on numerous aspects of the Spanish diet. METHODS: The validity of food and nutrient intake was estimated using Pearson correlation coefficients between the DH-E and the mean of seven 24-hour recalls collected every 2 months over the previous year. The reproducibility was estimated using intraclass correlation coefficients between two DH-E made one year apart. RESULTS: The correlations coefficients between the DH-E and the mean of seven 24-hour recalls for the main food groups were cereals (r = 0.66), meat (r = 0.66), fish (r = 0.42), vegetables (r = 0.62) and fruits (r = 0.44). The mean correlation coefficient for all 15 food groups considered was 0.53. The correlations for macronutrients were: energy (r = 0.76), proteins (r= 0.58), lipids (r = 0.73), saturated fat (r = 0.73), monounsaturated fat (r = 0.59), polyunsaturated fat (r = 0.57), and carbohydrates (r = 0.66). The mean correlation coefficient for all 41 nutrients studied was 0.55. The intraclass correlation coefficient between the two DH-E was greater than 0.40 for most foods and nutrients. CONCLUSIONS: The DH E shows good validity and reproducibility for estimating usual intake of foods and nutrients. PMID- 24465879 TI - Isolation and characteristics of Shiga toxin 2f-producing Escherichia coli among pigeons in Kyushu, Japan. AB - An increasing number of Shiga toxin 2f-producing Escherichia coli (STEC2f) infections in humans are being reported in Europe, and pigeons have been suggested as a reservoir for the pathogen. In Japan, there is very little information regarding carriage of STEC2f by pigeons, prompting the need for further investigation. We collected 549 samples of pigeon droppings from 14 locations in Kyushu, Japan, to isolate STEC2f and to investigate characteristics of the isolates. Shiga toxin stx 2f gene fragments were detected by PCR in 16 (2.9%) of the 549 dropping samples across four of the 14 locations. We obtained 23 STEC2f-isolates from seven of the original samples and from three pigeon dropping samples collected in an additional sampling experiment (from a total of seven locations across both sampling periods). Genotypic and phenotypic characteristics were then examined for selected isolates from each of 10 samples with pulsed-field gel electrophoresis profiles. Eight of the stx 2f gene fragments sequenced in this study were homologous to others that were identified in Europe. Some isolates also contained virulence-related genes, including lpfA O26, irp 2, and fyuA, and all of the 10 selected isolates maintained the eae, astA, and cdt genes. Moreover, five of the 10 selected isolates contained sfpA, a gene that is restricted to Shiga toxin-producing E. coli O165:H2 and sorbitol fermenting Shiga toxin-producing E. coli O157:NM. We document serotypes O152:HNM, O128:HNM, and O145:H34 as STEC2f, which agrees with previous studies on pigeons and humans. Interestingly, O119:H21 was newly described as STEC2f. O145:H34, with sequence type 722, was described in a German study in humans and was also isolated in the current study. These results revealed that Japanese zoonotic STEC2f strains harboring several virulence-related factors may be of the same clonal complexes as some European strains. These findings provide useful information for public health-related disease management strategies in Japan. PMID- 24465880 TI - Association between the IL1B (-511), IL1B (+3954), IL1RN (VNTR) polymorphisms and Graves' disease risk: a meta-analysis of 11 case-control studies. AB - BACKGROUND: Data on the association between the interleukin-1 (IL-1) gene polymorphisms and Graves' disease (GD) risk were conflicting. A meta-analysis was undertaken to assess this association. METHODS: We searched for case-control studies investigating the association between the IL1B (-511), IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk. We extracted data using standardized forms and calculated odds ratios (OR) with 95% confidence intervals (CI). RESULTS: A total of 11 case-control studies were included in this meta-analysis. Available data indicated that the IL1B (-511) polymorphism was associated with GD risk in the overall populations (Caucasians and Asians) in homozygote model (TT vs. CC, OR = 0.86, 95% CI: 0.76-0.97, Pz = 0.015), but not in dominant and recessive models (TT+TC vs. CC: OR = 0.95, 95% CI: 0.81-1.12, Pz = 0.553 and TT vs. TC+CC: OR = 0.82, 95% CI: 0.60-1.12, Pz = 0.205, respectively). No association between the IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk was found in the overall populations in any of the genetic models. In subgroup analyses according to ethnicity, the IL1B (-511) polymorphism was associated with GD risk in Asians in recessive and homozygote models (TT vs. TC+CC: OR = 0.68, 95% CI: 0.55-0.84, Pz < 0.001 and TT vs. CC: OR = 0.81, 95% CI: 0.70-0.93, Pz = 0.003, respectively), but not in dominant model (TT+TC vs. CC: OR = 0.92, 95% CI: 0.77-1.11, Pz = 0.389). No association between the IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk was indicated in Asians, and we found no association between the IL1B (-511), IL1B (+3954), IL1RN (VNTR) polymorphisms and GD risk in Caucasians in any of the genetic models. CONCLUSION: The IL1B (-511) polymorphism, but not the IL1B (+3954) and IL1RN (VNTR) polymorphisms was associated with GD risk in Asians. There was no association between these polymorphisms and GD risk in Caucasians. PMID- 24465881 TI - Release of tensile strain on engineered human tendon tissue disturbs cell adhesions, changes matrix architecture, and induces an inflammatory phenotype. AB - Mechanical loading of tendon cells results in an upregulation of mechanotransduction signaling pathways, cell-matrix adhesion and collagen synthesis, but whether unloading removes these responses is unclear. We investigated the response to tension release, with regard to matrix proteins, pro inflammatory mediators and tendon phenotypic specific molecules, in an in vitro model where tendon-like tissue was engineered from human tendon cells. Tissue sampling was performed 1, 2, 4 and 6 days after surgical de-tensioning of the tendon construct. When tensile stimulus was removed, integrin type collagen receptors showed a contrasting response with a clear drop in integrin subunit alpha11 mRNA and protein expression, and an increase in alpha2 integrin mRNA and protein levels. Further, specific markers for tendon cell differentiation declined and normal tendon architecture was disturbed, whereas pro-inflammatory molecules were upregulated. Stimulation with the cytokine TGF-beta1 had distinct effects on some tendon-related genes in both tensioned and de-tensioned tissue. These findings indicate an important role of mechanical loading for cellular and matrix responses in tendon, including that loss of tension leads to a decrease in phenotypical markers for tendon, while expression of pro-inflammatory mediators is induced. PMID- 24465882 TI - Non-equilibrium dynamics contribute to ion selectivity in the KcsA channel. AB - The ability of biological ion channels to conduct selected ions across cell membranes is critical for the survival of both animal and bacterial cells. Numerous investigations of ion selectivity have been conducted over more than 50 years, yet the mechanisms whereby the channels select certain ions and reject others are not well understood. Here we report a new application of Jarzynski's Equality to investigate the mechanism of ion selectivity using non-equilibrium molecular dynamics simulations of Na(+) and K(+) ions moving through the KcsA channel. The simulations show that the selectivity filter of KcsA adapts and responds to the presence of the ions with structural rearrangements that are different for Na(+) and K(+). These structural rearrangements facilitate entry of K(+) ions into the selectivity filter and permeation through the channel, and rejection of Na(+) ions. A mechanistic model of ion selectivity by this channel based on the results of the simulations relates the structural rearrangement of the selectivity filter to the differential dehydration of ions and multiple-ion occupancy and describes a mechanism to efficiently select and conduct K(+). Estimates of the K(+)/Na(+) selectivity ratio and steady state ion conductance for KcsA from the simulations are in good quantitative agreement with experimental measurements. This model also accurately describes experimental observations of channel block by cytoplasmic Na(+) ions, the "punch through" relief of channel block by cytoplasmic positive voltages, and is consistent with the knock-on mechanism of ion permeation. PMID- 24465883 TI - Association between kidney function and Framingham global cardiovascular disease risk score: a Chinese longitudinal study. AB - BACKGROUND: Chronic kidney disease (CKD) is generally considered an independent risk factor for cardiovascular disease (CVD) development, but rates in individuals with estimated glomerular filtration rate (eGFR) >60 ml/min/1.73 m(2) are uncertain. The Framingham global CVD risk score (FRS) equation is a widely accepted tool used to predict CVD risk in the general population. The purpose of the present study was to examine whether an association exists between eGFR and FRS in a Chinese population with no CKD or CVD. METHODS: A total of 333 participants were divided into three groups based on FRS. The Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and CKD-EPI equation for Asians (CKD-EPI-ASIA) were used to measure eGFR. RESULTS: A significant inverse association between eGFR and FRS was confirmed with Pearson correlation coefficients of -0.669, -0.698 (eGFR(CKD-EPI), P<0.01) and -0.658, -0.690 (eGFR(CKD-EPI)-ASIA, P<0.01). This association gradually diminished with progression from the low- to high-risk groups (eGFR(CKD-EPI), r = -0.615, -0.282, -0.197, P<0.01, P<0.01, P>0.05; similar results according to the CKD-EPI-ASIA equation). In the low- or moderate-risk new-groups, this association became stronger with increased FRS (eGFR(CKD-EPI)-ASIA, r = -0557, -0.622 or -0.326, 0.329, P<0.01). In contrast to the results from 2008, eGFR was independently associated with FRS following adjustment for traditional cardiovascular risk factors (P<0.05). CONCLUSION: Renal function has multiple influences on predicting CVD risk in various populations. With increasing FRS and decreasing eGFR, it is also independently associated with CVD, even in individuals with eGFR >60 ml/min/1.73 m(2). PMID- 24465884 TI - Critical amino acids within the human immunodeficiency virus type 1 envelope glycoprotein V4 N- and C-terminals contribute to virus entry. AB - The importance of the fourth variable (V4) region of the human immunodeficiency virus 1 (HIV-1) envelope glycoprotein (Env) in virus infection has not been well clarified, though the polymorphism of this region has been found to be associated with disease progression to acquired immunodeficiency syndrome (AIDS). In the present work, we focused on the correlation between HIV-1 gp120 V4 region polymorphism and the function of the region on virus entry, and the possible mechanisms for how the V4 region contributes to virus infectivity. Therefore, we analyzed the differences in V4 sequences along with coreceptor usage preference from CCR5 to CXCR4 and examined the importance of the amino acids within the V4 region for CCR5- and CXCR4-tropic virus entry. In addition, we determined the influence of the V4 amino acids on Env expression and gp160 processing intracellularly, as well as the amount of Env on the pseudovirus surface. The results indicated that V4 tended to have a shorter length, fewer potential N linked glycosylation sites (PNGS), greater evolutionary distance, and a lower negative net charge when HIV-1 isolates switched from a coreceptor usage preference for CCR5 to CXCR4. The N- and C-terminals of the HIV-1 V4 region are highly conserved and critical to maintain virus entry ability, but only the mutation at position 417 in the context of ADA (a R5-tropic HIV-1 strain) resulted in the ability to utilize CXCR4. In addition, 390L, 391F, 414I, and 416L are critical to maintain gp160 processing and maturation. It is likely that the hydrophobic properties and the electrostatic surface potential of gp120, rather than the conformational structure, greatly contribute to this V4 functionality. The findings provide information to aid in the understanding of the functions of V4 in HIV-1 entry and offer a potential target to aid in the development of entry inhibitors. PMID- 24465885 TI - Cadherin-23 may be dynamic in hair bundles of the model sea anemone Nematostella vectensis. AB - Cadherin 23 (CDH23), a component of tip links in hair cells of vertebrate animals, is essential to mechanotransduction by hair cells in the inner ear. A homolog of CDH23 occurs in hair bundles of sea anemones. Anemone hair bundles are located on the tentacles where they detect the swimming movements of nearby prey. The anemone CDH23 is predicted to be a large polypeptide featuring a short exoplasmic C-terminal domain that is unique to sea anemones. Experimentally masking this domain with antibodies or mimicking this domain with free peptide rapidly disrupts mechanotransduction and morphology of anemone hair bundles. The loss of normal morphology is accompanied, or followed by a decrease in F-actin in stereocilia of the hair bundles. These effects were observed at very low concentrations of the reagents, 0.1-10 nM, and within minutes of exposure. The results presented herein suggest that: (1) the interaction between CDH23 and molecular partners on stereocilia of hair bundles is dynamic and; (2) the interaction is crucial for normal mechanotransduction and morphology of hair bundles. PMID- 24465886 TI - A test of Rensch's rule in greater horseshoe bat (Rhinolophus ferrumequinum) with female-biased sexual size dimorphism. AB - Sexual size dimorphism (SSD) is widespread within the animal kingdom. Rensch's rule describes a relationship between SSD and body size: SSD increases with body size when males are the larger sex, and decreases with body size when females are the larger sex. Rensch's rule is well supported for taxa that exhibit male-biased SSD but patterns of allometry among taxa with female-biased size dimorphism are mixed, there is evidence both for and against the rule. Furthermore, most studies have investigated Rensch's rule across a variety of taxa; but among-population studies supporting Rensch's rule are lacking, especially in taxa that display only slight SSD. Here, we tested whether patterns of intraspecific variation in SSD in greater horseshoe bats conform to Rensch's rule, and evaluated the contribution of latitude to Rensch's rule. Our results showed SSD was consistently female-biased in greater horseshoe bats, although female body size was only slightly larger than male body size. The slope of major axis regression of log10 (male) on log10 (female) was significantly different from 1. Forearm length for both sexes of greater horseshoe bats was significantly negatively correlated with latitude, and males displayed a slightly but nonsignificant steeper latitudinal cline in body size than females. We suggest that variation in patterns of SSD among greater horseshoe bat populations is consistent with Rensch's rule indicating that males were the more variable sex. Males did not have a steeper body size-latitude relationship than females suggesting that sex specific latitudinal variation in body size may not be an important contributing factor to Rensch's rule. Future research on greater horseshoe bats might best focus on more comprehensive mechanisms driving the pattern of female-biased SSD variation. PMID- 24465887 TI - Complex collagen fiber and membrane morphologies of the whole porcine aortic valve. AB - OBJECTIVES: Replacement aortic valves endeavor to mimic native valve function at the organ, tissue, and in the case of bioprosthetic valves, the cellular levels. There is a wealth of information about valve macro and micro structure; however, there presently is limited information on the morphology of the whole valve fiber architecture. The objective of this study was to provide qualitative and quantitative analyses of whole valve and leaflet fiber bundle branching patterns using a novel imaging system. METHODS: We developed a custom automated microscope system with motor and imaging control. Whole leaflets (n = 25) were imaged at high resolution (e.g., 30,000*20,000 pixels) using elliptically polarized light to enhance contrast between structures without the need for staining or other methods. Key morphologies such as fiber bundle size and branching were measured for analyses. RESULTS: The left coronary leaflet displayed large asymmetry in fiber bundle organization relative to the right coronary and non-coronary leaflets. We observed and analyzed three main patterns of fiber branching; tree like, fan-like, and pinnate structures. High resolution images and quantitative metrics are presented such as fiber bundle sizes, positions, and branching morphological parameters. SIGNIFICANCE: To our knowledge there are currently no high resolution images of whole fresh leaflets available in the literature. The images of fiber/membrane structures and analyses presented here could be highly valuable for improving the design and development of more advanced bioprosthetic and/or bio-mimetic synthetic valve replacements. PMID- 24465889 TI - Lateralization of travelling wave response in the hearing organ of bushcrickets. AB - Travelling waves are the physical basis of frequency discrimination in many vertebrate and invertebrate taxa, including mammals, birds, and some insects. In bushcrickets (Tettigoniidae), the crista acustica is the hearing organ that has been shown to use sound-induced travelling waves. Up to now, data on mechanical characteristics of sound-induced travelling waves were only available along the longitudinal (proximal-distal) direction. In this study, we use laser Doppler vibrometry to investigate in-vivo radial (anterior-posterior) features of travelling waves in the tropical bushcricket Mecopoda elongata. Our results demonstrate that the maximum of sound-induced travelling wave amplitude response is always shifted towards the anterior part of the crista acustica. This lateralization of the travelling wave response induces a tilt in the motion of the crista acustica, which presumably optimizes sensory transduction by exerting a shear motion on the sensory cilia in this hearing organ. PMID- 24465888 TI - ARP2, a novel pro-apoptotic protein expressed in epithelial prostate cancer LNCaP cells and epithelial ovary CHO transformed cells. AB - Neoplastic epithelial cells generate the most aggressive types of cancers such as those located in the lung, breast, colon, prostate and ovary. During advanced stages of prostate cancer, epithelial cells are associated to the appearance of androgen-independent tumors, an apoptotic-resistant phenotype that ultimately overgrows and promotes metastatic events. We have previously identified and electrophysiologically characterized a novel Ca(2+)-permeable channel activated during apoptosis in the androgen-independent prostate epithelial cancer cell line, LNCaP. In addition, we reported for the first time the cloning and characterization of this channel-like molecule named apoptosis regulated protein 2 (ARP2) associated to a lethal influx of Ca(2+) in Xenopus oocytes. In the present study, LNCaP cells and Chinese hamster ovary cells (CHO cell line) transfected with arp2-cDNA are induced to undergo apoptosis showing an important impact on cell viability and activation of caspases 3 and 7 when compared to serum deprived grown cells and ionomycin treated cells. The subcellular localization of ARP2 in CHO cells undergoing apoptosis was studied using confocal microscopy. While apoptosis progresses, ARP2 initially localized in the peri nuclear region of cells migrates with time towards the plasma membrane region. Based on the present results and those of our previous studies, the fact that ARP2 constitutes a novel cation channel is supported. Therefore, ARP2 becomes a valuable target to modulate the influx and concentration of calcium in the cytoplasm of epithelial cancer cells showing an apoptotic-resistant phenotype during the onset of an apoptotic event. PMID- 24465890 TI - Bronchodilatory and anti-inflammatory effects of ASM-024, a nicotinic receptor ligand, developed for the treatment of asthma. AB - Conventional asthma and COPD treatments include the use of bronchodilators, mainly beta2-adrenergic agonists, muscarinic receptor antagonists and corticosteroids or leukotriene antagonists as anti-inflammatory agents. These active drugs are administered either separately or given as a fixed-dose combination medication into a single inhaler. ASM-024, a homopiperazinium compound, derived from the structural modification of diphenylmethylpiperazinium (DMPP), has been developed to offer an alternative mechanism of action that could provide symptomatic control through combined anti-inflammatory and bronchodilator properties in a single entity. A dose-dependent inhibition of cellular inflammation in bronchoalveolar lavage fluid was observed in ovalbumin-sensitized mice, subsequently treated for 3 days by nose-only exposure with aerosolized ASM 024 at doses up to 3.8 mg/kg (ED50 = 0.03 mg/kg). The methacholine ED250 values indicated that airway hyperresponsivenness (AHR) to methacholine decreased following ASM-024 administration by inhalation at a dose of 1.5 mg/kg, with a value of 0.145 +/- 0.032 mg/kg for ASM 024-treated group as compared to 0.088 +/- 0.023 mg/kg for untreated mice. In in vitro isometric studies, ASM-024 elicited dose-dependent relaxation of isolated mouse tracheal, human, and dog bronchial preparations contracted with methacholine and guinea pig tracheas contracted with histamine. ASM-024 showed also a dose and time dependant protective effect on methacholine-induced contraction. Overall, with its combined anti-inflammatory, bronchodilating and bronchoprotective properties, ASM-024 may represent a new class of drugs with a novel pharmacological approach that could prove useful for the chronic maintenance treatment of asthma and, possibly, COPD. PMID- 24465891 TI - The relationship between child maltreatment and emotion recognition. AB - Child abuse and neglect affect the development of social cognition in children and inhibit social adjustment. The purpose of this study was to compare the ability to identify the emotional states of others between abused and non-abused children. The participants, 129 children (44 abused and 85 non-abused children), completed a children's version of the Reading the Mind in the Eyes Test (RMET). Results showed that the mean accuracy rate on the RMET for abused children was significantly lower than the rate of the non-abused children. In addition, the accuracy rates for positive emotion items (e.g., hoping, interested, happy) were significantly lower for the abused children, but negative emotion and neutral items were not different across the groups. This study found a negative relationship between child abuse and the ability to understand others' emotions, especially positive emotions. PMID- 24465892 TI - Venous thromboembolism after community-acquired bacteraemia: a 20-year danish cohort study. AB - BACKGROUND: Infections may increase the risk for venous thromboembolism (VTE), but little is known about VTE risk associated with community-acquired bacteraemia (CAB). We examined the risk for VTE within one year of CAB in comparison to that in matched controls. METHODS: We conducted a population-based cohort study in North Denmark 1992-2011, using data from high-quality health-care databases. We included 4,213 adult CAB patients who had positive blood cultures drawn on the day of hospital admission, 20,084 matched hospitalised controls admitted for other acute medical illness, and 41,121 matched controls from the general population. We computed 0-90 and 91-365 day absolute risks for hospital-diagnosed VTE and used regression analyses with adjustment for confounding factors to compare the risk for VTE in bacteraemia patients and controls. RESULTS: Among CAB patients, 1.1% experienced VTE within 90 days of admission and 0.5% during 91-365 days after admission. The adjusted 90-day odds ratio (OR) for VTE was 1.9 (95% CI 1.4-2.7) compared with hospitalised controls, and 23.4 (95% CI 12.9-42.6) compared with population controls. During 91-365 days after CAB admission, the VTE risk remained moderately increased (adjusted hazard ratio vs. hospitalised controls, 1.4; 95% CI 0.8-2.5, and vs. population controls, 1.9; 95% CI 1.0-3.3). Compared to hospitalised controls, the 90-day VTE risk increase was greater for Gram-positive infection (adjusted OR 2.5; 95% CI 1.6-4.1) than for Gram-negative infection (adjusted OR, 1.2; 95% CI 0.7-2.1), partly due to a high risk after Staphylococcus aureus infection (3.6%). CONCLUSION: The risk for VTE is substantially increased within 90 days after community-acquired bacteraemia when compared to hospitalised controls and population controls. However, the absolute risk of VTE following CAB is low. PMID- 24465893 TI - The contributory role of angiotensin receptor-like 1 gene multiple polymorphisms in hypertension among northeastern Han Chinese. AB - BACKGROUND AND OBJECTIVE: Via direct sequencing, we have recently identified six common polymorphisms in angiotensin receptor-like 1 (AGTRL1) gene, and found only two polymorphisms were significantly associated with hypertension in a family based analysis on 1,015 southern Han Chinese. Extending our previous work and considering the ubiquity of epistasis in determining disease susceptibility, we, in this study, sought to explore the potential interaction of AGTRL1 gene six polymorphisms with hypertension in a large northeastern Han Chinese population. METHODS AND RESULTS: This was a case-control study involving 1,009 sporadic hypertensive patients and 756 normotensive controls. Data were analyzed by Haplo.Stats and multifactor dimensionality reduction (MDR) softwares. There were no deviations from Hardy-Weinberg equilibrium for all polymorphisms. The genotypes and alleles of rs7119675 and rs11544374 differed significantly between the two groups (P<0.0005), even after the Bonferroni correction. Under three genetic models, significant association was consistently observed for rs7119675 and rs11544374, and this association was independent of confounding factors. Taking rs7119375 as an example, the odds of having hypertension was 2.46 (95% confidence interval (95% CI): 2.06-2.94), 2.82 (95% CI: 2.29-3.46) and 3.97 (95% CI: 2.37-6.64) under additive, dominant and recessive models (P<0.001), respectively, whereas the adjusted risk estimates were slightly attenuated but still significant. The frequencies of most derived haplotypes differed significantly between patients and controls. Haplotype-phenotype analyses indicated marginal association for triglyceride (P(Sim) = 0.011) and total cholesterol (P(Sim) = 0.025) in patients and for triglyceride in controls (P(Sim) = 0.023). The overall best MDR model included rs11544374, rs7119375 and rs948847 with the maximal testing accuracy of 0.737 and cross-validation consistency of 10 out of 10 (P<0.0001). Further interaction entropy graph suggested that the interaction of rs7119375 with rs11544374 and rs948847 was strongly antagonized. CONCLUSIONS: Our findings demonstrate that AGTRL1 genetic polymorphisms might contribute to the development of hypertension independently and/or through complex interaction. PMID- 24465894 TI - Two-step synthesis and hydrolysis of cyclic di-AMP in Mycobacterium tuberculosis. AB - Cyclic di-AMP is a recently discovered signaling molecule which regulates various aspects of bacterial physiology and virulence. Here we report the characterization of c-di-AMP synthesizing and hydrolyzing proteins from Mycobacterium tuberculosis. Recombinant Rv3586 (MtbDisA) can synthesize c-di-AMP from ATP through the diadenylate cyclase activity. Detailed biochemical characterization of the protein revealed that the diadenylate cyclase (DAC) activity is allosterically regulated by ATP. We have identified the intermediates of the DAC reaction and propose a two-step synthesis of c-di-AMP from ATP/ADP. MtbDisA also possesses ATPase activity which is suppressed in the presence of the DAC activity. Investigations by liquid chromatography -electrospray ionization mass spectrometry have detected multimeric forms of c-di-AMP which have implications for the regulation of c-di-AMP cellular concentration and various pathways regulated by the dinucleotide. We have identified Rv2837c (MtbPDE) to have c-di-AMP specific phosphodiesterase activity. It hydrolyzes c-di-AMP to 5' AMP in two steps. First, it linearizes c-di-AMP into pApA which is further hydrolyzed to 5'-AMP. MtbPDE is novel compared to c-di-AMP specific phosphodiesterase, YybT (or GdpP) in being a soluble protein and hydrolyzing c-di AMP to 5'-AMP. Our results suggest that the cellular concentration of c-di-AMP can be regulated by ATP concentration as well as the hydrolysis by MtbPDE. PMID- 24465895 TI - A novel method to identify routes of hepatitis C virus transmission. AB - BACKGROUND: We propose a new approach based on genetic distances among viral strains to infer about risk exposures and location of transmission at population level. METHODS: We re-analysed 133 viral sequences obtained during a cross sectional survey of 4020 subjects living in a hepatitis C virus (HCV) endemic area in 2002. A permutation test was used to analyze the correlation between matrices of genetic distances in the NS5b region of all pairwise combinations of the 133 viral strains and exposure status (jointly exposed or not) to several potential HCV risk factors. RESULTS: Compared to subjects who did not share the same characteristics or iatrogenic exposures, the median Kimura genetic distances of viral strains were significantly smaller between brothers and sisters (0.031 versus 0.102, P<0.001), mother and child (0.044 versus 0.102, P<0.001), father and child (0.045 versus 0.102, P<0.001), or subjects exposed to periodontal treatment (0.084 versus 0.102, P = 0.02). Conversely, viral strains were more divergent between subjects exposed to blood transfusions (0.216 versus 0.102, P = 0.04) or tooth filling or extraction (0.108, versus 0.097, P = 0.05), suggesting acquisition of the virus outside of the village. CONCLUSION: This method provided insights on where infection took place (household, village) for several socio demographic characteristics or iatrogenic procedures, information of great relevance for targeting prevention interventions. This method may have interesting applications for virologists and epidemiologists studying transmission networks in health-care facilities or among intravenous drug users. PMID- 24465896 TI - Maize yield response to water supply and fertilizer input in a semi-arid environment of Northeast China. AB - Maize grain yield varies highly with water availability as well as with fertilization and relevant agricultural management practices. With a 311-A optimized saturation design, field experiments were conducted between 2006 and 2009 to examine the yield response of spring maize (Zhengdan 958, Zea mays L) to irrigation (I), nitrogen fertilization (total nitrogen, urea-46% nitrogen,) and phosphorus fertilization (P2O5, calcium superphosphate-13% P2O5) in a semi-arid area environment of Northeast China. According to our estimated yield function, the results showed that N is the dominant factor in determining maize grain yield followed by I, while P plays a relatively minor role. The strength of interaction effects among I, N and P on maize grain yield follows the sequence N+I >P+I>N+P. Individually, the interaction effects of N+I and N+P on maize grain yield are positive, whereas that of P+I is negative. To achieve maximum grain yield (10506.0 kg . ha(-1)) for spring maize in the study area, the optimum application rates of I, N and P are 930.4 m(3) . ha(-1), 304.9 kg . ha(-1) and 133.2 kg . ha( 1) respectively that leads to a possible economic profit (EP) of 10548.4 CNY . ha(-1) (CNY, Chinese Yuan). Alternately, to obtain the best EP (10827.3 CNY . ha( 1)), the optimum application rates of I, N and P are 682.4 m(3) . ha(-1), 241.0 kg . ha(-1) and 111.7 kg . ha(-1) respectively that produces a potential grain yield of 10289.5 kg . ha(-1). PMID- 24465897 TI - Genome-wide gene expression profiles in lung tissues of pig breeds differing in resistance to porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome (PRRS) caused by PRRS virus (PRRSV) is an infectious disease characterized by severe reproductive deficiency in pregnant sows, typical respiratory symptoms in piglets, and high mortality rate of piglets. In this study, we employed an Affymetrix microarray chip to compare the gene expression profiles of lung tissue samples from Dapulian (DPL) pigs (a Chinese indigenous pig breed) and Duroc*Landrace*Yorkshire (DLY) pigs after infection with PRRSV. During infection with PRRSV, the DLY pigs exhibited a range of clinical features that typify the disease, whereas the DPL pigs showed only mild signs of the disease. Overall, the DPL group had a lower percentage of CD4(+) cells and lower CD4(+)/CD8(+)ratios than the DLY group (p<0.05). For both IL-10 and TNF-alpha, the DLY pigs had significantly higher levels than the DPL pigs (p<0.01). The DLY pigs have lower serum IFN-gamma levels than the DPL pigs (p<0.01). The serum IgG levels increased slightly from 0 dpi to 7 dpi, and peaked at 14 dpi (p<0.0001). Microarray data analysis revealed 16 differentially expressed (DE) genes in the lung tissue samples from the DLY and DPL pigs (q<=5%), of which LOC100516029 and LOC100523005 were up-regulated in the PRRSV infected DPL pigs, while the other 14 genes were down-regulated in the PRRSV infected DPL pigs compared with the PRRSV-infected DLY pigs. The mRNA expression levels of 10 out of the 16 DE genes were validated by real-time quantitative RT PCR and their fold change was consistent with the result of microarray data analysis. We further analyzed the mRNA expression level of 8 differentially expressed genes between the DPL and DLY pigs for both uninfected and infected groups, and found that TF and USP18 genes were important in underlying porcine resistance or susceptibility to PRRSV. PMID- 24465898 TI - The role of factor inhibiting HIF (FIH-1) in inhibiting HIF-1 transcriptional activity in glioblastoma multiforme. AB - Glioblastoma multiforme (GBM) accounts for about 38% of primary brain tumors in the United States. GBM is characterized by extensive angiogenesis induced by vascular growth factors and cytokines. The transcription of these growth factors and cytokines is regulated by the Hypoxia-Inducible-Factor-1(HIF-1), which is a key regulator mediating the cellular response to hypoxia. It is known that Factor Inhibiting HIF-1, or FIH-1, is also involved in the cellular response to hypoxia and has the capability to physically interact with HIF-1 and block its transcriptional activity under normoxic conditions. Delineation of the regulatory role of FIH-1 will help us to better understand the molecular mechanism responsible for tumor growth and progression and may lead to the design of new therapies targeting cellular pathways in response to hypoxia. Previous studies have shown that the chromosomal region of 10q24 containing the FIH-1 gene is often deleted in GBM, suggesting a role for the FIH-1 in GBM tumorigenesis and progression. In the current study, we found that FIH-1 is able to inhibit HIF mediated transcription of GLUT1 and VEGF-A, even under hypoxic conditions in human glioblastoma cells. FIH-1 has been found to be more potent in inhibiting HIF function than PTEN. This observation points to the possibility that deletion of 10q23-24 and loss or decreased expression of FIH-1 gene may lead to a constitutive activation of HIF-1 activity, an alteration of HIF-1 targets such as GLUT-1 and VEGF-A, and may contribute to the survival of cancer cells in hypoxia and the development of hypervascularization observed in GBM. Therefore FIH-1 can be potential therapeutic target for the treatment of GBM patients with poor prognosis. PMID- 24465899 TI - p120RasGAP is a mediator of rho pathway activation and tumorigenicity in the DLD1 colorectal cancer cell line. AB - KRAS is mutated in ~40% of colorectal cancer (CRC), and there are limited effective treatments for advanced KRAS mutant CRC. Therefore, it is crucial that downstream mediators of oncogenic KRAS continue to be studied. We identified p190RhoGAP as being phosphorylated in the DLD1 CRC cell line, which expresses a heterozygous KRAS G13D allele, and not in DKO4 in which the mutant allele has been deleted by somatic recombination. We found that a ubiquitous binding partner of p190RhoGAP, p120RasGAP (RasGAP), is expressed in much lower levels in DKO4 cells compared to DLD1, and this expression is regulated by KRAS. Rescue of RasGAP expression in DKO4 rescued Rho pathway activation and partially rescued tumorigenicity in DKO4 cells, indicating that the combination of mutant KRAS and RasGAP expression is crucial to these phenotypes. We conclude that RasGAP is an important effector of mutant KRAS in CRC. PMID- 24465900 TI - Molecular dynamics simulation of the allosteric regulation of eIF4A protein from the open to closed state, induced by ATP and RNA substrates. AB - BACKGROUND: Eukaryotic initiation factor 4A (eIF4A) plays a key role in the process of protein translation initiation by facilitating the melting of the 5' proximal secondary structure of eukaryotic mRNA for ribosomal subunit attachment. It was experimentally postulated that the closed conformation of the eIF4A protein bound by the ATP and RNA substrates is coupled to RNA duplex unwinding to promote protein translation initiation, rather than an open conformation in the absence of ATP and RNA substrates. However, the allosteric process of eIF4A from the open to closed state induced by the ATP and RNA substrates are not yet fully understood. METHODOLOGY: In the present work, we constructed a series of diplex and ternary models of the eIF4A protein bound by the ATP and RNA substrates to carry out molecular dynamics simulations, free energy calculations and conformation analysis and explore the allosteric properties of eIF4A. RESULTS: The results showed that the eIF4A protein completes the conformational transition from the open to closed state via two allosteric processes of ATP binding followed by RNA and vice versa. Based on cooperative allosteric network analysis, the ATP binding to the eIF4A protein mainly caused the relative rotation of two domains, while the RNA binding caused the proximity of two domains via the migration of RNA bases in the presence of ATP. The cooperative binding of ATP and RNA for the eIF4A protein plays a key role in the allosteric transition. PMID- 24465901 TI - A potential role of myeloid DAP12-associating lectin (MDL)-1 in the regulation of inflammation in rheumatoid arthritis patients. AB - The pathogenic roles of myeloid DAP12-associating lectin-1(MDL-1) and DAP12 in human rheumatoid arthritis (RA) remain unknown. Frequencies of MDL-1-expressing monocytes in 22 active RA patients, 16 inactive RA patients, 12 osteoarthritis (OA) patients and 10 healthy controls (HC) were determined by flow-cytometry analysis. The mRNA expression levels of MDL-1 and DAP12 on PBMCs were evaluated by quantitative PCR, and their protein expression levels in the synovium were examined by immunohistochemistry. Significantly higher median percentages of circulating MDL-1-expressing monocytes were observed in active RA patients (53.6%) compared to inactive RA patients (34.1%), OA patients (27.9%), and HC (21.2%). Levels of MDL-1 and DAP12 gene expression in PBMCs and their protein expression in the synovium were significantly higher in active RA patients than in inactive RA or OA patients. MDL-1 levels were positively correlated with parameters of disease activity, articular damage, and levels of proinflammatory cytokines. MDL-1 activator (Dengue virus type 2 antigen) stimulation on PBMCs resulted in significantly enhanced levels of proinflammatory cytokines in RA patients compared to those in OA patients or HC, indicating that MDL-1 activation is functional. Frequencies of MDL-1-expressing monocytes and levels of MDL-1 and DAP12 gene expression significantly decreased after effective therapy. Concordant overexpression of MDL-1 and DAP12 were correlated with increased production of proinflammatory cytokines in RA patients, suggesting their roles in regulating articular inflammation. PMID- 24465902 TI - Galectin-9 enhances cytokine secretion, but suppresses survival and degranulation, in human mast cell line. AB - Galectin-9 (Gal-9), a lectin having a beta-galactoside-binding domain, can induce apoptosis of Th1 cells by binding to TIM-3. In addition, Gal-9 inhibits IgE/Ag mediated degranulation of mast cell/basophilic cell lines by binding to IgE, thus blocking IgE/Ag complex formation. However, the role of Gal-9 in mast cell function in the absence of IgE is not fully understood. Here, we found that recombinant Gal-9 directly induced phosphorylation of Erk1/2 but not p38 MAPK in a human mast cell line, HMC-1, which does not express FcepsilonRI. Gal-9 induced apoptosis and inhibited PMA/ionomycin-mediated degranulation of HMC-1 cells. On the other hand, Gal-9 induced cytokine and/or chemokine production by HMC-1 cells, dependent on activation of ERK1/2 but not p38 MAPK. In addition, the lectin activity of Gal-9 was required for Gal-9-mediated cytokine secretion by HMC-1 cells. These observations suggest that Gal-9 has dual properties as both a regulator and an activator of mast cells. PMID- 24465903 TI - Influence of the temperature and the genotype of the HSP90AA1 gene over sperm chromatin stability in Manchega Rams. AB - The present study addresses the effect of heat stress on males' reproduction ability. For that, we have evaluated the sperm DNA fragmentation (DFI) by SCSA of ejaculates incubated at 37 degrees C during 0, 24 and 48 hours after its collection, as a way to mimic the temperature circumstances to which spermatozoa will be subject to in the ewe uterus. The effects of temperature and temperature humidity index (THI) from day 60 prior collection to the date of semen collection on DFI were examined. To better understand the causes determining the sensitivity of spermatozoa to heat, this study was conducted in 60 males with alternative genotypes for the SNP G/C-660 of the HSP90AA1 promoter, which encode for the Hsp90alpha protein. The Hsp90alpha protein predominates in the brain and testis, and its role in spermatogenesis has been described in several species. Ridge regression analyses showed that days 29 to 35 and 7 to 14 before sperm collection (bsc) were the most critical regarding the effect of heat stress over DFI values. Mixed model analyses revealed that DFI increases over a threshold of 30 degrees C for maximum temperature and 22 for THI at days 29 to 35 and 7 to 14 bsc only in animals carrying the GG-660 genotype. The period 29-35 bsc coincide with the meiosis I process for which the effect of the Hsp90alpha has been described in mice. The period 7-14 bsc may correspond with later stages of the meiosis II and early stages of epididymal maturation in which the replacement of histones by protamines occurs. Because of GG-660 genotype has been associated to lower levels of HSP90AA1 expression, suboptimal amounts of HSP90AA1 mRNA in GG-660 animals under heat stress conditions make spermatozoa DNA more susceptible to be fragmented. Thus, selecting against the GG-660 genotype could decrease the DNA fragmentation and spermatozoa thermal susceptibility in the heat season, and its putative subsequent fertility gains. PMID- 24465904 TI - Biological exposure indices of pyrrole adducts in serum and urine for hazard assessment of n-hexane exposure. AB - BACKGROUND: Pyrrole adducts might be used as a biomarker for monitoring occupational exposure to n-hexane, but the Biological Exposure Indices of pyrrole adducts in serum and urine are still unknown. The current study was designed to investigate the biological exposure limit of pyrrole adducts for hazard assessment of n-hexane. METHODS: Male Wistar rats were given daily dose of 500, 1000, 1500, 2000, 4000 mg/kg bw n-hexane by gavage for 24 weeks. The levels of pyrrole adducts in serum and urine were determined at 8, 24 hours postdose once a week. The Biological Exposure Indices was evaluated by neurological evaluation and the levels of pyrrole adducts. The difference in pyrrole adducts formation between humans and rats were estimated by using in vitro test. RESULTS: Dose dependent effects were observed between the doses of n-hexane and pyrrole adducts in serum and urine, and the levels of pyrrole adduct in serum and urine approached a plateau at week 4. There was a significantly negative correlation between the time to paralysis and the level of pyrrole adducts in serum and urine, while a positive correlation between gait score and levels of pyrrole adducts in serum and urine was observed. In vitro, pyrrole adducts formed in human serum was about two times more than those in rat serum at the same level of 2,5-HD. CONCLUSION: It was concluded that the BEIs of pyrrole adducts in humans were 23.1 +/- 5.91 nmol/ml in serum 8 h postdose, 11.7 +/- 2.64 nmol/ml in serum 24 h postdose, 253.8 +/- 36.3 nmol/ml in urine 8 h postdose and 54.6 +/- 15.42 nmol/ml in urine 24 h postdose. PMID- 24465905 TI - Intellectual disability among Dutch homeless people: prevalence and related psychosocial problems. AB - BACKGROUND: There is a higher prevalence of intellectual disability (ID) among homeless people than in the general population. However, little is known about the additional psychosocial problems faced by homeless people with ID. We describe the prevalence of ID in a cohort of homeless people in the Netherlands, and report relationships between ID and psychosocial problems in terms of psychological distress, substance (mis)use and dependence, as well as demographic characteristics in this cohort. METHODS: This cross-sectional study is part of a cohort study among homeless people in the four major cities of the Netherlands. Data were derived from 387 homeless people who were interviewed and screened for ID six months after the baseline measurement. Multivariate logistic regression analyses and chi2 tests were performed to analyze relationships between ID, psychosocial problems and demographic characteristics. FINDINGS: Of all cohort members, 29.5% had a suspected ID. Participants with a suspected ID had a higher mean age, were more likely to be male and to fall in the lowest category of education than participants without a suspected ID. Having a suspected ID was related to general psychological distress (OR = 1.56, p<0.05), somatization (OR = 1.84, p<0.01), depression (OR = 1.58, p<0.05) and substance dependence (OR = 1.88, p<0.05). No relationships were found between a suspected ID and anxiety, regular substance use, substance misuse and primary substance of use. CONCLUSION: The prevalence of ID among Dutch homeless people is higher than in the general population, and is related to more psychosocial problems than among homeless people without ID. Homeless people with a suspected ID appear to be a vulnerable subgroup within the homeless population. This endorses the importance of the extra attention required for this subgroup. PMID- 24465907 TI - Scanning behavior in the medicinal leech Hirudo verbana. AB - While moving through their environment, medicinal leeches stop periodically and wave their head or body back and forth. This activity has been previously described as two separate behaviors: one called 'head movement' and another called 'body waving'. Here, we report that these behaviors exist on a continuum, and provide a detailed description of what we now call 'scanning'. Scanning related behavior has been thought to be involved in orientation; its function has never before been assessed. While previous studies suggested an involvement of scanning in social behavior, or sucker placement, our behavioral studies indicate that scanning is involved in orienting the leech towards prey stimuli. When such stimuli are present, scanning behavior is used to re-orient the leech in the direction of a prey-like stimulus. Scanning, however, occurs whether or not prey is present, but in the presence of prey-like stimuli scanning becomes localized to the stimulus origin. Most likely, this behavior helps the leech to gain a more detailed picture of its prey target. The display of scanning, regardless of the presence or absence of prey stimuli, is suggestive of a behavior that is part of an internally driven motor program, which is not released by the presence of sensory stimuli. The data herein include first steps to understanding the neural mechanisms underlying this important behavior. PMID- 24465906 TI - Multiscale, converging defects of macro-porosity, microstructure and matrix mineralization impact long bone fragility in NF1. AB - Bone fragility due to osteopenia, osteoporosis or debilitating focal skeletal dysplasias is a frequent observation in the Mendelian disease Neurofibromatosis type 1 (NF1). To determine the mechanisms underlying bone fragility in NF1 we analyzed two conditional mouse models, Nf1Prx1 (limb knock-out) and Nf1Col1 (osteoblast specific knock-out), as well as cortical bone samples from individuals with NF1. We examined mouse bone tissue with micro-computed tomography, qualitative and quantitative histology, mechanical tensile analysis, small-angle X-ray scattering (SAXS), energy dispersive X-ray spectroscopy (EDX), and scanning acoustic microscopy (SAM). In cortical bone of Nf1Prx1 mice we detected ectopic blood vessels that were associated with diaphyseal mineralization defects. Defective mineral binding in the proximity of blood vessels was most likely due to impaired bone collagen formation, as these areas were completely devoid of acidic matrix proteins and contained thin collagen fibers. Additionally, we found significantly reduced mechanical strength of the bone material, which was partially caused by increased osteocyte volume. Consistent with these observations, bone samples from individuals with NF1 and tibial dysplasia showed increased osteocyte lacuna volume. Reduced mechanical properties were associated with diminished matrix stiffness, as determined by SAM. In line with these observations, bone tissue from individuals with NF1 and tibial dysplasia showed heterogeneous mineralization and reduced collagen fiber thickness and packaging. Collectively, the data indicate that bone fragility in NF1 tibial dysplasia is partly due to an increased osteocyte-related micro porosity, hypomineralization, a generalized defect of organic matrix formation, exacerbated in the regions of tensional and bending force integration, and finally persistence of ectopic blood vessels associated with localized macro porotic bone lesions. PMID- 24465908 TI - Natural forest biomass estimation based on plantation information using PALSAR data. AB - Forests play a vital role in terrestrial carbon cycling; therefore, monitoring forest biomass at local to global scales has become a challenging issue in the context of climate change. In this study, we investigated the backscattering properties of Advanced Land Observing Satellite (ALOS) Phased Array L-band Synthetic Aperture Radar (PALSAR) data in cashew and rubber plantation areas of Cambodia. The PALSAR backscattering coefficient (sigma0) had different responses in the two plantation types because of differences in biophysical parameters. The PALSAR sigma0 showed a higher correlation with field-based measurements and lower saturation in cashew plants compared with rubber plants. Multiple linear regression (MLR) models based on field-based biomass of cashew (C-MLR) and rubber (R-MLR) plants with PALSAR sigma0 were created. These MLR models were used to estimate natural forest biomass in Cambodia. The cashew plant-based MLR model (C MLR) produced better results than the rubber plant-based MLR model (R-MLR). The C MLR-estimated natural forest biomass was validated using forest inventory data for natural forests in Cambodia. The validation results showed a strong correlation (R2 = 0.64) between C-MLR-estimated natural forest biomass and field based biomass, with RMSE = 23.2 Mg/ha in deciduous forests. In high-biomass regions, such as dense evergreen forests, this model had a weaker correlation because of the high biomass and the multiple-story tree structure of evergreen forests, which caused saturation of the PALSAR signal. PMID- 24465909 TI - An estimation of the prevalence and progression of chronic kidney disease in a rural diabetic cambodian population. AB - BACKGROUND: To date, there are no known estimates of the prevalence of chronic kidney disease within Cambodia, the vast majority of whose citizens live in rural areas with limited access to renal replacement therapy. METHODS: Observational analysis of patients from the Takeo province in Cambodia who presented to MoPoTsyo, a non-governmental organization, for screening and management of diabetes mellitus between 2010 and 2012 (n = 402; 75% females). Estimated glomerular filtration rate (eGFR) was calculated using the CKD-Epi equation. RESULTS: On average, women were younger, with a higher percentage of hypercholesterolemia but also high-density lipoprotein level. Men had a higher serum creatinine level (1.31 mg/dl) than that of women (1.13 mg/dl) at 95% CI. More than half of all screened patients had a reduced eGFR; 60% (95% CI 55%, 65%) had an eGFR<60 ml/min/1.73 m(2); 54% (49%, 59%) had an eGFR 30-60 ml/min/1.73 m(2), and 5.7% (3.4%, 8.0%) with eGFR 15-30 ml/min/1.73 m(2). Women had a greater prevalence of stage 3 CKD (57% women vs. 47% men) and stage 4 CKD (7.0% vs. 2.0%). The adjusted odds ratio for females compared to males having an eGFR <60 ml/min/1.73 m(2) was 3.19 (95% CI 1.78, 5.43; p value<0.001). Thirty-two percent of patients lost >= 5 ml/min/1.73 m2 eGFR during median follow-up time of 433 days (IQR 462 days) days. CONCLUSIONS: Over one-half of Cambodians with diabetes mellitus had reduced eGFR, implying a point-prevalence of chronic kidney disease of 1.2% in among adult Cambodians within the country. This high burden of kidney disease in a society that lacks universal access to renal replacement therapy underscores the importance of early diagnosis - a largely unmet need in Cambodia. PMID- 24465910 TI - Role of mitochondria in parvovirus pathology. AB - Proper functioning of the mitochondria is crucial for the survival of the cell. Viruses are able to interfere with mitochondrial functions as they infect the host cell. Parvoviruses are known to induce apoptosis in infected cells, but the role of the mitochondria in parvovirus induced cytopathy is only partially known. Here we demonstrate with confocal and electron microscopy that canine parvovirus (CPV) associated with the mitochondrial outer membrane from the onset of infection. During viral entry a transient depolarization of the mitochondrial transmembrane potential and increase in ROS level was detected. Subsequently, mitochondrial homeostasis was normalized shortly, as detected by repolarization of the mitochondrial membrane and decrease of ROS. Indeed, activation of cell survival signalling through ERK1/2 cascade was observed early in CPV infected cells. At 12 hours post infection, concurrent with the expression of viral non structural protein 1, damage to the mitochondrial structure and depolarization of its membrane were apparent. Results of this study provide additional insight of parvovirus pathology and also more general information of virus-mitochondria association. PMID- 24465911 TI - The interaction between selection, demography and selfing and how it affects population viability. AB - Population extinction due to the accumulation of deleterious mutations has only been considered to occur at small population sizes, large sexual populations being expected to efficiently purge these mutations. However, little is known about how the mutation load generated by segregating mutations affects population size and, eventually, population extinction. We propose a simple analytical model that takes into account both the demographic and genetic evolution of populations, linking population size, density dependence, the mutation load, and self-fertilisation. Analytical predictions were found to be relatively good predictors of population size and probability of population viability when verified using an explicit individual based stochastic model. We show that initially large populations do not always reach mutation-selection balance and can go extinct due to the accumulation of segregating deleterious mutations. Population survival depends not only on the relative fitness and demographic stochasticity, but also on the interaction between the two. When deleterious mutations are recessive, self-fertilisation affects viability non-monotonically and genomic cold-spots could favour the viability of outcrossing populations. PMID- 24465912 TI - Blocking approach for identification of rare variants in family-based association studies. AB - With the advent of next-generation sequencing technology, rare variant association analysis is increasingly being conducted to identify genetic variants associated with complex traits. In recent years, significant effort has been devoted to develop powerful statistical methods to test such associations for population-based designs. However, there has been relatively little development for family-based designs although family data have been shown to be more powerful to detect rare variants. This study introduces a blocking approach that extends two popular family-based common variant association tests to rare variants association studies. Several options are considered to partition a genomic region (gene) into "independent" blocks by which information from SNVs is aggregated within a block and an overall test statistic for the entire genomic region is calculated by combining information across these blocks. The proposed methodology allows different variants to have different directions (risk or protective) and specification of minor allele frequency threshold is not needed. We carried out a simulation to verify the validity of the method by showing that type I error is well under control when the underlying null hypothesis and the assumption of independence across blocks are satisfied. Further, data from the Genetic Analysis Workshop [Formula: see text] are utilized to illustrate the feasibility and performance of the proposed methodology in a realistic setting. PMID- 24465913 TI - The social modulation of imitation fidelity in school-age children. AB - Children copy the actions of others with high fidelity, even when they are not causally relevant. This copying of visibly unnecessary actions is termed overimitation. Many competing theories propose mechanisms for overimitation behaviour. The present study examines these theories by studying the social factors that lead children to overimitate actions. Ninety-four children aged 5- to 8-years each completed five trials of an overimitation task. Each trial provided the opportunity to overimitate an action on familiar objects with minimal causal reasoning demands. Social cues (live or video demonstration) and eye contact from the demonstrator were manipulated. After the imitation, children's ratings of action rationality were collected. Substantial overimitation was seen which increased with age. In older children, overimitation was higher when watching a live demonstrator and when eye contact was absent. Actions rated as irrational were more likely to be imitated than those rated as rational. Children overimitated actions on familiar objects even when they rated those actions as irrational, suggesting that failure of causal reasoning cannot be driving overimitation. Our data support social explanations of overimitation and show that the influence of social factors increases with age over the 5- to 8 year-old age range. PMID- 24465915 TI - Impacts of climate-change-driven sea level rise on intertidal rocky reef habitats will be variable and site specific. AB - Intertidal rocky reefs are complex and rich ecosystems that are vulnerable to even the smallest fluctuations in sea level. We modelled habitat loss associated with sea level rise for intertidal rocky reefs using GIS, high-resolution digital imagery, and LIDAR technology at fine-scale resolution (0.1 m per pixel). We used projected sea levels of +0.3 m, +0.5 m and +1.0 m above current Mean Low Tide Level (0.4 m). Habitat loss and changes were analysed for each scenario for five headlands in the Solitary Islands Marine Park (SIMP), Australia. The results indicate that changes to habitat extent will be variable across different shores and will not necessarily result in net loss of area for some habitats. In addition, habitat modification will not follow a regular pattern over the projected sea levels. Two of the headlands included in the study currently have the maximum level of protection within the SIMP. However, these headlands are likely to lose much of the habitat known to support biodiverse assemblages and may not continue to be suitable sanctuaries into the future. The fine-scale approach taken in this study thus provides a protocol not only for modelling habitat modification but also for future proofing conservation measures under a scenario of changing sea levels. PMID- 24465914 TI - Identification of novel thymic epithelial cell subsets whose differentiation is regulated by RANKL and Traf6. AB - Thymic epithelial cells (TECs) are critical for the normal development and function of the thymus. Here, we examined the developmental stages of TECs using quantitative assessment of the cortical and medullary markers Keratin 5 and Keratin 8 (K5 and K8) respectively, in normal and gain/loss of function mutant animals. Gain of function mice overexpressed RANKL in T cells, whereas loss of function animals lacked expression of Traf6 in TECs (Traf6DeltaTEC). Assessment of K5 and K8 expression in conjunction with other TEC markers in wild type mice identified novel cortical and medullary TEC populations, expressing different combinations of these markers. RANKL overexpression led to expansion of all medullary TECs (mTECs) and enlargement of the thymic medulla. This in turn associated with a block in thymocyte development and loss of CD4+ CD8+, CD4+ and CD8+ thymocytes. In contrast, Traf6 deletion inhibited the production of most TEC populations including cortical TECs (cTECs), defined by absence of UEA-1 binding and LY51 expression, but had no apparent effect on thymocyte development. These results reveal a large degree of heterogeneity within the TEC compartment and the existence of several populations exhibiting concomitant expression of cortical, medullary and epithelial markers and whose production is regulated by RANKL and Traf6. PMID- 24465916 TI - Circular polarization of transmitted light by sapphirinidae copepods. AB - Circularly polarized light, rare in the animal kingdom, has thus far been documented in only a handful of animals. Using a rotating circular polarization (CP) analyzer we detected CP in linearly polarized light transmitted through epipelagic free living Sapphirina metallina copepods. Both left and right handedness of CP was detected, generated from specific organs of the animal's body, especially on the dorsal cephalosome and prosome. Such CP transmittance may be generated by phase retardance either in the muscle fibers or in the multilayer membrane structure found underneath the cuticle. Although the role, if any, played by circularly polarized light in Sapphirinidae has yet to be clarified, in other animals it was suggested to take part in mate choice, species recognition, and other forms of communication. HIGHLIGHTS: Planktonic Sapphirinidae copepods were found to circularly polarize the light passing through them. Circular polarization may be created by unique, multilayered features of the membrane structure found under their cuticle or by organized muscle fibers. PMID- 24465917 TI - Abundance and survival rates of the Hawai'i Island associated spinner dolphin (Stenella longirostris) stock. AB - Reliable population estimates are critical to implement effective management strategies. The Hawai'i Island spinner dolphin (Stenella longirostris) is a genetically distinct stock that displays a rigid daily behavioural pattern, foraging offshore at night and resting in sheltered bays during the day. Consequently, they are exposed to frequent human interactions and disturbance. We estimated population parameters of this spinner dolphin stock using a systematic sampling design and capture-recapture models. From September 2010 to August 2011, boat-based photo-identification surveys were undertaken monthly over 132 days (>1,150 hours of effort; >100,000 dorsal fin images) in the four main resting bays along the Kona Coast, Hawai'i Island. All images were graded according to photographic quality and distinctiveness. Over 32,000 images were included in the analyses, from which 607 distinctive individuals were catalogued and 214 were highly distinctive. Two independent estimates of the proportion of highly distinctive individuals in the population were not significantly different (p = 0.68). Individual heterogeneity and time variation in capture probabilities were strongly indicated for these data; therefore capture-recapture models allowing for these variations were used. The estimated annual apparent survival rate (product of true survival and permanent emigration) was 0.97 SE +/- 0.05. Open and closed capture-recapture models for the highly distinctive individuals photographed at least once each month produced similar abundance estimates. An estimate of 221 +/- 4.3 SE highly distinctive spinner dolphins, resulted in a total abundance of 631 +/- 60.1 SE, (95% CI 524-761) spinner dolphins in the Hawai'i Island stock, which is lower than previous estimates. When this abundance estimate is considered alongside the rigid daily behavioural pattern, genetic distinctiveness, and the ease of human access to spinner dolphins in their preferred resting habitats, this Hawai'i Island stock is likely more vulnerable to negative impacts from human disturbance than previously believed. PMID- 24465918 TI - Liquidity spillover in international stock markets through distinct time scales. AB - This paper identifies liquidity spillovers through different time scales based on a wavelet multiscaling method. We decompose daily data from U.S., British, Brazilian and Hong Kong stock markets indices in order to calculate the scale correlation between their illiquidities. The sample is divided in order to consider non-crisis, sub-prime crisis and Eurozone crisis. We find that there are changes in correlations of distinct scales and different periods. Association in finest scales is smaller than in coarse scales. There is a rise on associations in periods of crisis. In frequencies, there is predominance for significant distinctions involving the coarsest scale, while for crises periods there is predominance for distinctions on the finest scale. PMID- 24465919 TI - Arginase-1 deficiency regulates arginine concentrations and NOS2-mediated NO production during endotoxemia. AB - RATIONALE AND OBJECTIVE: Arginase-1 is an important component of the intricate mechanism regulating arginine availability during immune responses and nitric oxide synthase (NOS) activity. In this study Arg1(fl/fl)/Tie2-Cre(tg/-) mice were developed to investigate the effect of arginase-1 related arginine depletion on NOS2- and NOS3-dependent NO production and jejunal microcirculation under resting and endotoxemic conditions, in mice lacking arginase-1 in endothelial and hematopoietic cells. METHODS AND RESULTS: Arginase-1-deficient mice as compared with control mice exhibited higher plasma arginine concentration concomitant with enhanced NO production in endothelial cells and jejunal tissue during endotoxemia. In parallel, impaired jejunal microcirculation was observed in endotoxemic conditions. Cultured bone-marrow-derived macrophages of arginase-1 deficient animals also presented a higher inflammatory response to endotoxin than control littermates. Since NOS2 competes with arginase for their common substrate arginine during endotoxemia, Nos2 deficient mice were also studied under endotoxemic conditions. As Nos2(-/-) macrophages showed an impaired inflammatory response to endotoxin compared to wild-type macrophages, NOS2 is potentially involved. A strongly reduced NO production in Arg1(fl/fl)/Tie2-Cre(tg/-) mice following infusion of the NOS2 inhibitor 1400W further implicated NOS2 in the enhanced capacity to produce NO production Arg1(fl/fl)/Tie2-Cre(tg/-) mice. CONCLUSIONS: Reduced arginase-1 activity in Arg1(fl/fl)/Tie2-Cre(tg/-) mice resulted in increased inflammatory response and NO production by NOS2, accompanied by a depressed microcirculatory flow during endotoxemia. Thus, arginase-1 deficiency facilitates a NOS2-mediated pro-inflammatory activity at the expense of NOS3-mediated endothelial relaxation. PMID- 24465920 TI - Age-dependent prevalence of nasopharyngeal carriage of streptococcus pneumoniae before conjugate vaccine introduction: a prediction model based on a meta analysis. AB - INTRODUCTION: Data on the prevalence of nasopharyngeal carriage of S.pneumoniae in all age groups are important to help predict the impact of introducing pneumococcal conjugate vaccines (PCV) into routine infant immunization, given the important indirect effect of the vaccine. Yet most carriage studies are limited to children under five years of age. We here explore the association between carriage prevalence and serotype distribution in children aged >=5 years and in adults compared to children. METHODS: We conducted a systematic review of studies providing carriage estimates across age groups in healthy populations not previously exposed to PCV, using MEDLINE and Embase. We used Bayesian linear meta regression models to predict the overall carriage prevalence as well as the prevalence and distribution of vaccine and nonvaccine type (VT and NVT) serotypes in older age groups as a function of that in <5 y olds. RESULTS: Twenty-nine studies compromising of 20,391 individuals were included in the analysis. In all studies nasopharyngeal carriage decreased with increasing age. We found a strong positive linear association between the carriage prevalence in pre-school childen (<5 y) and both that in school aged children (5-17 y olds) and in adults. The proportion of VT serotypes isolated from carriers was consistently lower in older age groups and on average about 73% that of children <5 y among 5-17 y olds and adults respectively. We provide a prediction model to infer the carriage prevalence and serotype distribution in 5-17 y olds and adults as a function of that in children <5 years of age. CONCLUSION: Such predictions are helpful for assessing the potential population-wide effects of vaccination programmes, e.g. via transmission models, and thus assist in the design of future pneumococcal conjugate vaccination strategies. PMID- 24465921 TI - The PPARgamma locus makes long-range chromatin interactions with selected tissue specific gene loci during adipocyte differentiation in a protein kinase A dependent manner. AB - Differentiation signaling results in reprogramming of cellular gene expression that leads to morphological changes and functional specialization of a precursor cell. This global change in gene expression involves temporal regulation of differentiation-specific genes that are located throughout the genome, raising the idea that genome structure may also be re-organized during cell differentiation to facilitate regulated gene expression. Using in vitro adipocyte differentiation as a model, we explored whether gene organization within the nucleus is altered upon exposure of precursor cells to signaling molecules that induce adipogenesis. The peroxisome proliferator-activated receptor gamma (PPARgamma) nuclear hormone receptor is a master determinant of adipogenesis and is required for adipose differentiation. We utilized the chromosome conformation capture (3C) assay to determine whether the position of the PPARgamma locus relative to other adipogenic genes is changed during differentiation. We report that the PPARgamma2 promoter is transiently positioned in proximity to the promoters of genes encoding adipokines and lipid droplet associated proteins at 6 hours post-differentiation, a time that precedes expression of any of these genes. In contrast, the PPARgamma2 promoter was not in proximity to the EF1alpha promoter, which drives expression of a constitutively active, housekeeping gene that encodes a translation elongation factor, nor was the PPARgamma2 promoter in proximity to the promoter driving the expression of the C/EBPalpha regulatory protein. The formation of the long-range, intergenic interactions involving the PPARgamma2 promoter required the regulatory factor C/EBPbeta, elevated cyclic AMP (cAMP) levels, and protein kinase A (PKA) signaling. We conclude that genome organization is dynamically remodeled in response to adipogenic signaling, and we speculate that these transient inter-genic interactions may be formed for the purposes of selecting some of the transcriptionally silent tissue-specific loci for subsequent transcriptional activation. PMID- 24465922 TI - A self-report risk index to predict occurrence of dementia in three independent cohorts of older adults: the ANU-ADRI. AB - BACKGROUND AND AIMS: The Australian National University AD Risk Index (ANU-ADRI, http://anuadri.anu.edu.au) is a self-report risk index developed using an evidence-based medicine approach to measure risk of Alzheimer's disease (AD). We aimed to evaluate the extent to which the ANU-ADRI can predict the risk of AD in older adults and to compare the ANU-ADRI to the dementia risk index developed from the Cardiovascular Risk Factors, Aging and Dementia (CAIDE) study for middle aged cohorts. METHODS: This study included three validation cohorts, i.e., the Rush Memory and Aging Study (MAP) (n = 903, age >=53 years), the Kungsholmen Project (KP) (n = 905, age >=75 years), and the Cardiovascular Health Cognition Study (CVHS) (n = 2496, age >=65 years) that were each followed for dementia. Baseline data were collected on exposure to the 15 risk factors included in the ANU-ADRI of which MAP had 10, KP had 8 and CVHS had 9. Risk scores and C statistics were computed for individual participants for the ANU-ADRI and the CAIDE index. RESULTS: For the ANU-ADRI using available data, the MAP study c statistic was 0.637 (95% CI 0.596-0.678), for the KP study it was 0.740 (0.712 0.768) and for the CVHS it was 0.733 (0.691-0.776) for predicting AD. When a common set of risk and protective factors were used c-statistics were 0.689 (95% CI 0.650-0.727), 0.666 (0.628-0.704) and 0.734 (0.707-0.761) for MAP, KP and CVHS respectively. Results for CAIDE ranged from c-statistics of 0.488 (0.427-0.554) to 0.595 (0.565-0.625). CONCLUSION: A composite risk score derived from the ANU ADRI weights including 8-10 risk or protective factors is a valid, self-report tool to identify those at risk of AD and dementia. The accuracy can be further improved in studies including more risk factors and younger cohorts with long term follow-up. PMID- 24465923 TI - Identification of human disease genes from interactome network using graphlet interaction. AB - Identifying genes related to human diseases, such as cancer and cardiovascular disease, etc., is an important task in biomedical research because of its applications in disease diagnosis and treatment. Interactome networks, especially protein-protein interaction networks, had been used to disease genes identification based on the hypothesis that strong candidate genes tend to closely relate to each other in some kinds of measure on the network. We proposed a new measure to analyze the relationship between network nodes which was called graphlet interaction. The graphlet interaction contained 28 different isomers. The results showed that the numbers of the graphlet interaction isomers between disease genes in interactome networks were significantly larger than random picked genes, while graphlet signatures were not. Then, we designed a new type of score, based on the network properties, to identify disease genes using graphlet interaction. The genes with higher scores were more likely to be disease genes, and all candidate genes were ranked according to their scores. Then the approach was evaluated by leave-one-out cross-validation. The precision of the current approach achieved 90% at about 10% recall, which was apparently higher than the previous three predominant algorithms, random walk, Endeavour and neighborhood based method. Finally, the approach was applied to predict new disease genes related to 4 common diseases, most of which were identified by other independent experimental researches. In conclusion, we demonstrate that the graphlet interaction is an effective tool to analyze the network properties of disease genes, and the scores calculated by graphlet interaction is more precise in identifying disease genes. PMID- 24465924 TI - The maternal ITPK1 gene polymorphism is associated with neural tube defects in a high-risk Chinese population. AB - BACKGROUND: Epidemiological surveys and animal studies have revealed that inositol metabolism is associated with NTDs, but the mechanisms are not clear. Inositol 1,3,4-trisphosphate 5/6-kinase (ITPK1) is a pivotal regulatory enzyme in inositol metabolic pathway. The objective was to assess the potential impact of the maternal ITPK1 genotypes on the inositol parameter and on the NTD risk in a NTD high-risk area in China. METHODOLOGY/RESULTS: A case-control study of pregnant women affected with NTDs (n = 200) and controls (n = 320) was carried out. 13 tag SNPs of ITPK1 were selected and genotyped by the Sequenom MassArray system. We found that 4 tag SNPs were statistically significant in spina bifida group (P<0.05). MACH was used to impute the un-genotyped SNPs in ITPK1 locus and showed that 3 meaningful SNPs in the non-coding regions were significant. We also predicted the binding capacity of transcription factors in the positive SNPs using the bioinformatics method and found that only rs3783903 was located in the conserved sequence of activator protein-1 (AP-1). To further study the association between biochemical values and genotypes, maternal plasma inositol hexakisphosphate (IP6) levels were also assessed using LC-MS. The maternal plasma IP6 concentrations in the spina bifida subgroup were 7.1% lower than control (136.67 vs. 147.05 ng mL(-1), P<0.05), and significantly lower in rs3783903 GG genotype than others (P<0.05). EMSA showed a different allelic binding capacity of AP-1 in rs3783903, which was affected by an A->G exchange. The RT-PCR suggested the ITPK1 expression was decreased significantly in mutant-type of rs3783903 compared with wild-type in the 60 healthy pregnancies (P<0.05). CONCLUSIONS/SIGNIFICANCE: These results suggested that the maternal rs3783903 of ITPK1 might be associated with spina bifida, and the allele G of rs3783903 might affect the binding of AP-1 and the decrease of maternal plasma IP6 concentration in this Chinese population. PMID- 24465926 TI - Plasma concentrations of the vasoactive peptide fragments mid-regional pro adrenomedullin, C-terminal pro-endothelin 1 and copeptin in hemodialysis patients: associated factors and prediction of mortality. AB - Vasopressin, endothelin and adrenomedullin are vasoactive peptides that regulate vascular tone and might play a role in hypertensive diseases. Recently, laboratory assays have been developed to measure stable fragments of vasopressin, endothelin and adrenomedullin. Little is known about their diagnostic and prognostic value in hemodialysis patients. In this study, we measured the plasma concentration of copeptin, mid-regional-pro-adrenomedullin (MR-pro-ADM) and C terminal pro-endothelin 1 (CT-pro-ET1) in stable ambulatory hemodialysis patients (n = 239) and investigated their associations with clinical factors and mortality. In all patients enrolled, the plasma concentrations of copeptin, MR pro-ADM and CT-pro-ET1 were largely elevated with a median concentration of 132 pmol/L (interquartile range [IQR] 78-192) for copeptin, 1.26 nmol/L (IQR 1.02 1.80) for MR-pro-ADM and 149 pmol/L (IQR 121-181) for CT-pro-ET1. The plasma concentrations of all vasoactive peptide fragments correlated with time on dialysis and plasma beta2-microglobulin concentration and were negatively correlated to residual diuresis. The plasma concentration of MR-pro-ADM was a strong predictor of all-cause (univariate hazard ratio for a 10-fold increase 9.94 [3.14;32], p<0.0001) and cardiovascular mortality (hazard ratio 34.87 [5.58;217], p = 0.0001) within a 3.8-year follow-up. The associations remained stable in models adjusted for dialysis specific factors and were attenuated in a full model adjusted for all prognostic factors. Plasma copeptin concentration was weakly associated with cardiovascular mortality (only in univariate analysis) and CT-pro-ET1 was not associated with mortality at all. In conclusion, vasoactive peptide fragments are elevated in hemodialysis patients because of accumulation and, most likely, increased release. Increased concentrations of MR-pro-ADM are predictive of mortality. PMID- 24465925 TI - From a traditional medicinal plant to a rational drug: understanding the clinically proven wound healing efficacy of birch bark extract. AB - BACKGROUND: Birch bark has a long lasting history as a traditional medicinal remedy to accelerate wound healing. Recently, the efficacy of birch bark preparations has also been proven clinically. As active principle pentacyclic triterpenes are generally accepted. Here, we report a comprehensive study on the underlying molecular mechanisms of the wound healing properties of a well-defined birch bark preparation named as TE (triterpene extract) as well as the isolated single triterpenes in human primary keratinocytes and porcine ex-vivo wound healing models. METHODOLOGY/PRINCIPAL FINDINGS: We show positive wound healing effects of TE and betulin in scratch assay experiments with primary human keratinocytes and in a porcine ex-vivo wound healing model (WHM). Mechanistical studies elucidate that TE and betulin transiently upregulate pro-inflammatory cytokines, chemokines and cyclooxygenase-2 on gene and protein level. For COX-2 and IL-6 this increase of mRNA is due to an mRNA stabilizing effect of TE and betulin, a process in which p38 MAPK and HuR are involved. TE promotes keratinocyte migration, putatively by increasing the formation of actin filopodia, lamellipodia and stress fibers. Detailed analyses show that the TE components betulin, lupeol and erythrodiol exert this effect even in nanomolar concentrations. Targeting the actin cytoskeleton is dependent on the activation of Rho GTPases. CONCLUSION/SIGNIFICANCE: Our results provide insights to understand the molecular mechanism of the clinically proven wound healing effect of birch bark. TE and betulin address the inflammatory phase of wound healing by transient up-regulation of several pro-inflammatory mediators. Further, they enhance migration of keratinocytes, which is essential in the second phase of wound healing. Our results, together with the clinically proven efficacy, identify birch bark as the first medical plant with a high potential to improve wound healing, a field which urgently needs effective remedies. PMID- 24465927 TI - Knockdown of miR-214 promotes apoptosis and inhibits cell proliferation in nasopharyngeal carcinoma. AB - MicroRNA-214 (MiR-214) is aberrantly expressed in several human tumors such as ovarian cancer and breast cancer. However, the role of miR-214 in nasopharyngeal carcinoma (NPC) is still unknown. In this study, we report that miR-214 was overexpressed in NPC cell lines and tissues. Silencing of miR-214 by LNA-antimiR 214 in NPC cells resulted in promoting apoptosis and suppressing cell proliferation in vitro, and suppressed tumor growth in nude mice in vivo. Luciferase reporter assay was performed to identify Bim as a direct target of miR 214. Furthermore, this study showed that low Bim expression in NPC tissues correlated with poor survival of NPC patients. Taken together, our findings suggest that miR-214 plays an important role in NPC carcinogenesis. PMID- 24465928 TI - Identification and profiling of microRNAs in the embryonic breast muscle of pekin duck. AB - MicroRNAs (miRNAs) regulate gene expression by fully or partially binding to complementary sequences and play important roles in skeletal muscle development. However, the roles of miRNAs in embryonic breast muscle of duck are unclear. In this study, we analyzed the miRNAs profiling in embryonic breast muscle of Pekin duck at E13 (the 13(th) day of hatching), E19, and E27 by high-throughput sequencing. A total of 382 miRNAs including 359 preciously identified miRNAs 23 novel miRNA candidates were obtained. The nucleotide bias analysis of identified miRNAs showed that the miRNAs in Pekin duck was high conserved. The expression of identified miRNAs were significantly different between E13 and E19 as well as between E27 and E19. Fifteen identified miRNAs validated using stem-loop qRT-PCR can be divided into three groups: those with peak expression at E19, those with minimal expression at E19, and those with continuous increase from E11 to E27. Considering that E19 is the fastest growth stage of embryonic Pekin duck breast muscle, these three groups of miRNAs might be the potential promoters, the potential inhibitors, and the potential sustainer for breast muscle growth. Among the 23 novel miRNAs, novel-miRNA-8 and novel-miRNA-14 had maximal expression at some stages. The stem-loop qRT-PCR analysis of the two novel miRNAs and their two targets (MAP2K1 and PPARalpha) showed that the expression of novel-mir-8 and PPARalpha reached the lowest points at E19, while that of novel-mir-14 and MAP2K1 peaked at E19, suggesting novel-miRNA-8 and novel-miRNA-14 may be a potential inhibitor and a potential promoter for embryonic breast muscle development of duck. In summary, these results not only provided an overall insight into the miRNAs landscape in embryonic breast muscle of duck, but also a basis for the further investigation of the miRNAs roles in duck skeletal muscle development. PMID- 24465930 TI - Domestic dogs in rural communities around protected areas: conservation problem or conflict solution? AB - Although domestic dogs play many important roles in rural households, they can also be an important threat to the conservation of wild vertebrates due to predation, competition and transmission of infectious diseases. An increasing number of studies have addressed the impact of dogs on wildlife but have tended to ignore the motivations and attitudes of the humans who keep these dogs and how the function of dogs might influence dog-wildlife interactions. To determine whether the function of domestic dogs in rural communities influences their interactions with wildlife, we conducted surveys in rural areas surrounding protected lands in the Valdivian Temperate Forests of Chile. Sixty percent of farm animal owners reported the use of dogs as one of the primary means of protecting livestock from predators. The probability of dog-wild carnivore interactions was significantly associated with the raising of poultry. In contrast, dog-wild prey interactions were not associated with livestock presence but had a significant association with poor quality diet as observed in previous studies. Dog owners reported that they actively encouraged the dogs to chase off predators, accounting for 25-75% of the dog-wild carnivore interactions observed, depending on the predator species. Humans controlled the dog population by killing pups and unwanted individuals resulting in few additions to the dog population through breeding; the importation of predominantly male dogs from urban areas resulted in a sex ratios highly dominated by males. These results indicate that dog interactions with wildlife are related to the role of the dog in the household and are directly influenced by their owners. To avoid conflict with local communities in conservation areas, it is important to develop strategies for managing dogs that balance conservation needs with the roles that dogs play in these rural households. PMID- 24465929 TI - Improved anchorage of Ti6Al4V orthopaedic bone implants through oligonucleotide mediated immobilization of BMP-2 in osteoporotic rats. AB - The aim of the present study was to test the biocompatibility and functionality of orthopaedic bone implants with immobilized oligonucleotides serving as anchor stands for rhBMP-2 and rhVEGF-A conjugated with complementary oligonucleotides in an osteoporotic rat model. Al2O3-blasted acid etched Ti6Al4V implants, carrying oligonucleotide anchor strands and hybridized with rhBMP-2 or rhVEGF-A through complementary 31-mer oligonucleotide stands were inserted into the proximal tibia of ovariectomized rats. At the time of surgery (15 weeks after ovariectomy) microCT analysis showed significantly lower bone mineral density compared to non ovariectomized animals. Bone-implant contact (BIC) and pullout-force were not negatively affected by non-hybridized anchor strands. Twelve weeks after surgery, a significantly higher pullout force was found for BMP-2 hybridized to the anchor strands compared to non-hybridized anchor strands or native samples, and on histomorphometric analysis BIC was highest in the BMP group. Thus, we could show the biocompatibility and in vivo functionality of this modular, self-organizing system for immobilization and subsequent release of BMP-2 in vivo. PMID- 24465931 TI - Chronic kidney disease is characterized by "double trouble" higher pulse pressure plus night-time systolic blood pressure and more severe cardiac damage. AB - BACKGROUND: Hypertension plays a key role in chronic kidney disease (CKD), but CKD itself affects the blood pressure (BP) profile. The aim of this study was to assess the association of BP profile with CKD and the presence of cardiac organ damage. METHODS: We studied 1805 patients, referred to our Hypertension Centre, in whom ABPM, blood tests, and echocardiography were clinically indicated. The glomerular filtration rate was estimated (eGFR) using the MDRD equation and CKD was defined as eGFR<60 mL/min/1.73 m(2). Cardiac organ damage was evaluated by echocardiography. RESULTS: Among patients with CKD there were higher systolic blood pressure (SBP) during the night-time, greater prevalence of non-dippers (OR: 1.8) and increased pulse pressure (PP) during 24-hour period, daytime and night-time (all p<0.001). Patients with CKD had a greater LVM/h(2.7) index, and a higher prevalence of left ventricular hypertrophy and diastolic dysfunction (all p<0.001). Nocturnal SBP and PP correlated more strongly with cardiac organ damage (p<0.001). Patients with CKD had a greater Treatment Intensity Score (p<0.001) in the absence of a significantly greater BP control. CONCLUSIONS: CKD patients have an altered night-time pressure profile and higher PP that translate into a more severe cardiac organ damage. In spite of a greater intensity of treatment in most patients with CKD, BP control was similar to patients without CKD. Our findings indicate the need of a better antihypertensive therapy in CKD, better selected drugs, dosages and posology to provide optimal coverage of 24 hours and night time BP. PMID- 24465932 TI - Pirate stealth or inattentional blindness? The effects of target relevance and sustained attention on security monitoring for experienced and naive operators. AB - Closed Circuit Television (CCTV) operators are responsible for maintaining security in various applied settings. However, research has largely ignored human factors that may contribute to CCTV operator error. One important source of error is inattentional blindness--the failure to detect unexpected but clearly visible stimuli when attending to a scene. We compared inattentional blindness rates for experienced (84 infantry personnel) and naive (87 civilians) operators in a CCTV monitoring task. The task-relevance of the unexpected stimulus and the length of the monitoring period were manipulated between participants. Inattentional blindness rates were measured using typical post-event questionnaires, and participants' real-time descriptions of the monitored event. Based on the post event measure, 66% of the participants failed to detect salient, ongoing stimuli appearing in the spatial field of their attentional focus. The unexpected task irrelevant stimulus was significantly more likely to go undetected (79%) than the unexpected task-relevant stimulus (55%). Prior task experience did not inoculate operators against inattentional blindness effects. Participants' real-time descriptions revealed similar patterns, ruling out inattentional amnesia accounts. PMID- 24465933 TI - Gratitude depends on the relational model of communal sharing. AB - We studied the relation between benefits, perception of social relationships and gratitude. Across three studies, we provide evidence that benefits increase gratitude to the extent to which one applies a mental model of a communal relationship. In Study 1, the communal sharing relational model, and no other relational models, predicted the amount of gratitude participants felt after imagining receiving a benefit from a new acquaintance. In Study 2, participants recalled a large benefit they had received. Applying a communal sharing relational model increased feelings of gratitude for the benefit. In Study 3, we manipulated whether the participant or another person received a benefit from an unknown other. Again, we found that the extent of communal sharing perceived in the relationship with the stranger predicted gratitude. An additional finding of Study 2 was that communal sharing predicted future gratitude regarding the relational partner in a longitudinal design. To conclude, applying a communal sharing model predicts gratitude regarding concrete benefits and regarding the relational partner, presumably because one perceives the communal partner as motivated to meet one's needs. Finally, in Study 3, we found in addition that being the recipient of a benefit without opportunity to repay directly increased communal sharing, and indirectly increased gratitude. These circumstances thus seem to favor the attribution of communal norms, leading to a communal sharing representation and in turn to gratitude. We discuss the importance of relational models as mental representations of relationships for feelings of gratitude. PMID- 24465934 TI - Spatial distribution of excitatory synapses on the dendrites of ganglion cells in the mouse retina. AB - Excitatory glutamatergic inputs from bipolar cells affect the physiological properties of ganglion cells in the mammalian retina. The spatial distribution of these excitatory synapses on the dendrites of retinal ganglion cells thus may shape their distinct functions. To visualize the spatial pattern of excitatory glutamatergic input into the ganglion cells in the mouse retina, particle mediated gene transfer of plasmids expressing postsynaptic density 95-green fluorescent fusion protein (PSD95-GFP) was used to label the excitatory synapses. Despite wide variation in the size and morphology of the retinal ganglion cells, the expression of PSD95 puncta was found to follow two general rules. Firstly, the PSD95 puncta are regularly spaced, at 1-2 um intervals, along the dendrites, whereby the presence of an excitatory synapse creates an exclusion zone that rules out the presence of other glutamatergic synaptic inputs. Secondly, the spatial distribution of PSD95 puncta on the dendrites of diverse retinal ganglion cells are similar in that the number of excitatory synapses appears to be less on primary dendrites and to increase to a plateau on higher branch order dendrites. These observations suggest that synaptogenesis is spatially regulated along the dendritic segments and that the number of synaptic contacts is relatively constant beyond the primary dendrites. Interestingly, we also found that the linear puncta density is slightly higher in large cells than in small cells. This may suggest that retinal ganglion cells with a large dendritic field tend to show an increased connectivity of excitatory synapses that makes up for their reduced dendrite density. Mapping the spatial distribution pattern of the excitatory synapses on retinal ganglion cells thus provides explicit structural information that is essential for our understanding of how excitatory glutamatergic inputs shape neuronal responses. PMID- 24465935 TI - Peripheral blood mononuclear cells derived from grand multigravidae display a distinct cytokine profile in response to P. falciparum infected erythrocytes. AB - Immunopathology of placental malaria is most significant in women in their first pregnancy especially in endemic areas, due to a lack of protective immunity to Plasmodium falciparum, which is acquired in successive pregnancies. In some studies (but not all), grand multigravidae (defined as 5 or more pregnancies, G5 7) are more susceptible to poor birth outcomes associated with malaria compared to earlier gravidities. By comparing peripheral cellular responses in primigravidae (G1), women in their second to fourth pregnancy (G2-4) and grand multigravidae we sought to identify key components of the dysregulated immune response. PBMC were exposed to CS2-infected erythrocytes (IE) opsonised with autologous plasma or unopsonised IE, and cytokine and chemokine secretion was measured. Higher levels of opsonising antibody were present in plasma derived from multigravid compared to primigravid women. Significant differences in the levels of cytokines and chemokines secreted in response to IE were observed. Less IL-10, IL-1beta, IL-6 and TNF but more CXCL8, CCL8, IFNgamma and CXCL10 were detected in G5-7 compared to G2-4 women. Our study provides fresh insight into the modulation of peripheral blood cell function and effects on the balance between host protection and immunopathology during placental malaria infection. PMID- 24465936 TI - Reduced fetal telomere length in gestational diabetes. AB - Gestational diabetes mellitus (GDM) is an important complication of pregnancy that poses significant threats to women and their offspring. Telomere length shortens as cellular damage increases and is associated with metabolic diseases. Telomere length in fetal leucocytes was determined in 82 infants of women with GDM (N = 82) and 65 normal pregnant women (N = 65). Women with preeclampsia (N = 45) and gestational hypertension (N = 23) were also studied. In the GDM group, telomere length was significantly shorter than normal pregnancy (P = 0.028), but there were no significant differences in fetal telomere length between preeclampsia and normal pregnancy (P = 0.841) and between gestational hypertension and normal pregnancy (P = 0.561). Regression analysis revealed that fetal telomere length was significantly associated with intrauterine exposure to GDM (P = 0.027 after adjustment for maternal age, gestational age at delivery, birth weight and fetal gender). Shortened telomere length may increase the risk of metabolic diseases in adulthood of GDM offspring. PMID- 24465937 TI - Genetic instability persists in non-neoplastic urothelial cells from patients with a history of urothelial cell carcinoma. AB - Bladder cancer is one of the most common genitourinary neoplasms in industrialized countries. Multifocality and high recurrence rates are prominent clinical features of this disease and contribute to its high morbidity. Therefore, more sensitive and less invasive techniques could help identify individuals with asymptomatic disease. In this context, we used the micronucleus assay to evaluate whether cytogenetic alterations could be used as biomarkers for monitoring patients with a history of urothelial cell carcinoma (UCC). We determined the frequency of micronucleated urothelial cells (MNC) in exfoliated bladder cells from 105 patients with (n = 52) or without (n = 53) a history of UCC, all of whom tested negative for neoplasia by cytopathological and histopathological analyses. MNC frequencies were increased in patients with a history of UCC (non-smoker and smoker/ex-smoker patients vs non-smoker and smoker/ex-smoker controls; p<0.001), in non-smoker UCC patients (vs non-smoker controls; p<0.01), and in smoker/ex-smoker controls (vs non-smoker controls; p<0.001). Patients with a history of recurrent disease also demonstrated a higher MNC frequency compared to patients with non-recurrent neoplasia. However, logistic regression using smoking habits, age and gender as confounding factors did not confirm MNC frequency as a marker for UCC recurrence. Fluorescent in situ hybridization analysis (using a pan-centromeric probe) showed that micronuclei (MN) arose mainly from clastogenic events regardless of UCC and/or smoking histories. In conclusion, our results confirm previous indications that subjects with a history of UCC harbor genetically unstable cells in the bladder urothelium. Furthermore, these results support using the micronucleus assay as an important tool for monitoring patients with a history of UCC and tumor recurrence. PMID- 24465938 TI - Effects of clear-fell harvest on bat home range. AB - We investigated effects of roost loss due to clear-fell harvest on bat home range. The study took place in plantation forest, inhabited by the New Zealand long-tailed bat (Chalinolobus tuberculatus), in which trees are harvested between the ages 26-32 years. We determined home ranges by radiotracking different bats in areas that had and had not been recently clear-fell harvested. Home ranges were smaller in areas that had been harvested. Adult male bats selected 20-25 year old stands within home ranges before and after harvest. Males selected edges with open unplanted areas when harvest had not occurred but no longer selected these at proportions greater than their availability post harvest, probably because they were then readily available. This is the first radiotracking study to demonstrate a change in home range size and selection concomitant with felling of large areas of plantation forest, and thus quantify negative effects of forestry operations on this speciose group. The use of smaller home ranges post harvest may reflect smaller colony sizes and lower roost availability, both of which may increase isolation of colonies and vulnerability to local extinction. PMID- 24465939 TI - Liver, but not muscle, has an entrainable metabolic memory. AB - Hyperglycemia in the hospitalized setting is common, especially in patients that receive nutritional support either continuously or intermittently. As the liver and muscle are the major sites of glucose disposal, we hypothesized their metabolic adaptations are sensitive to the pattern of nutrient delivery. Chronically catheterized, well-controlled depancreatized dogs were placed on one of three isocaloric diets: regular chow diet once daily (Chow) or a simple nutrient diet (ND) that was given either once daily (ND-4) or infused continuously (ND-C). Intraportal insulin was infused to maintain euglycemia. After 5 days net hepatic (NHGU) and muscle (MGU) glucose uptake and oxidation were assessed at euglycemia (120 mg/dl) and hyperglycemia (200 mg/dl) in the presence of basal insulin. While hyperglycemia increased both NHGU and MGU in Chow, NHGU was amplified in both groups receiving ND. The increase was associated with enhanced activation of glycogen synthase, glucose oxidation and suppression of pyruvate dehydrogenase kinase-4 (PDK-4). Accelerated glucose-dependent muscle glucose uptake was only evident with ND-C. This was associated with a decrease in PDK-4 expression and an increase in AMP-activated protein kinase (AMPK) phosphorylation. Interestingly, ND-C markedly increased hepatic FGF-21 expression. Thus, augmentation of carbohydrate disposal in the liver, as opposed to the muscle, is not dependent on the pattern of nutrient delivery. PMID- 24465940 TI - Influenza virus-induced lung inflammation was modulated by cigarette smoke exposure in mice. AB - Although smokers have increased susceptibility and severity of seasonal influenza virus infection, there is no report about the risk of 2009 pandemic H1N1 (pdmH1N1) or avian H9N2 (H9N2/G1) virus infection in smokers. In our study, we used mouse model to investigate the effect of cigarette smoke on pdmH1N1 or H9N2 virus infection. Mice were exposed to cigarette smoke for 21 days and then infected with pdmH1N1 or H9N2 virus. Control mice were exposed to air in parallel. We found that cigarette smoke exposure alone significantly upregulated the lung inflammation. Such prior cigarette smoke exposure significantly reduced the disease severity of subsequent pdmH1N1 or H9N2 virus infection. For pdmH1N1 infection, cigarette smoke exposed mice had significantly lower mortality than the control mice, possibly due to the significantly decreased production of inflammatory cytokines and chemokines. Similarly, after H9N2 infection, cigarette smoke exposed mice displayed significantly less weight loss, which might be attributed to lower cytokines and chemokines production, less macrophages, neutrophils, CD4+ and CD8+ T cells infiltration and reduced lung damage compared to the control mice. To further investigate the underlying mechanism, we used nicotine to mimic the effect of cigarette smoke both in vitro and in vivo. Pre treating the primary human macrophages with nicotine for 72 h significantly decreased their expression of cytokines and chemokines after pdmH1N1 or H9N2 infection. The mice subcutaneously and continuously treated with nicotine displayed significantly less weight loss and lower inflammatory response than the control mice upon pdmH1N1 or H9N2 infection. Moreover, alpha7 nicotinic acetylcholine receptor knockout mice had more body weight loss than wild-type mice after cigarette smoke exposure and H9N2 infection. Our study provided the first evidence that the pathogenicity of both pdmH1N1 and H9N2 viruses was alleviated in cigarette smoke exposed mice, which might partially be attributed to the immunosuppressive effect of nicotine. PMID- 24465941 TI - Incidence of and mortality from Type I diabetes in Taiwan from 1999 through 2010: a nationwide cohort study. AB - OBJECTIVE: To evaluate the secular trend in incidence of and mortality from Type 1 diabetes mellitus (T1DM) in Taiwan, 1999-2010. METHODS: All 7,225 incident cases of T1DM were retrospectively retrieved from Taiwan's National Health Insurance Research Database from 1999 to 2010. Trend of bi-annual age- and sex specific incidence rates of T1DM was calculated and tested with Poisson regression model. Standardized mortality ratios (SMRs) were calculated, using age , sex-, and calendar years-specific mortality rates of the general population as the reference, to estimate the relative mortality risk of T1DM. RESULTS: The number of male and female T1DM was 3,471 (48%) and 3,754 (52%), respectively. The annual number of incident T1DM increased from 543 in 1999 to 737 in 2010. The overall bi-annual incidence rate rose from 1999-00 to 2003-04 and mildly declined thereafter rose to 2009-10, with an insignificant trend (P = 0.489) over the study period. Regardless of gender, the higher age-specific incidence rate was noted in the younger groups (<30 years) and highest at <15 years. The incidence rates in younger groups were constantly higher in female population than in male one. The SMR from all causes was significantly increased at 3.00 (95% Confidence Interval (CI) 2.83-3.16) in patients with T1DM. The sex-specific SMR was 2.66 (95% CI 2.46-2.85) and 3.58 (95% CI 3.28-3.87) for male and female patients, respectively. For both sexes, the age-specific SMR peaked at 15-29 years. CONCLUSIONS: Among T1DM patients in Taiwan, there were significant increasing trends in males and female aged <15 years. We also noted a significantly increased overall and sex-specific SMR from all causes in patients with TIDM which suggests a need for improvements in treatment and care of patients with T1DM. PMID- 24465942 TI - Targeting cancer cells with reactive oxygen and nitrogen species generated by atmospheric-pressure air plasma. AB - The plasma jet has been proposed as a novel therapeutic method for cancer. Anticancer activity of plasma has been reported to involve mitochondrial dysfunction. However, what constituents generated by plasma is linked to this anticancer process and its mechanism of action remain unclear. Here, we report that the therapeutic effects of air plasma result from generation of reactive oxygen/nitrogen species (ROS/RNS) including H2O2, Ox, OH-, *O2, NOx, leading to depolarization of mitochondrial membrane potential and mitochondrial ROS accumulation. Simultaneously, ROS/RNS activate c-Jun NH2-terminal kinase (JNK) and p38 kinase. As a consequence, treatment with air plasma jets induces apoptotic death in human cervical cancer HeLa cells. Pretreatment of the cells with antioxidants, JNK and p38 inhibitors, or JNK and p38 siRNA abrogates the depolarization of mitochondrial membrane potential and impairs the air plasma induced apoptotic cell death, suggesting that the ROS/RNS generated by plasma trigger signaling pathways involving JNK and p38 and promote mitochondrial perturbation, leading to apoptosis. Therefore, administration of air plasma may be a feasible strategy to eliminate cancer cells. PMID- 24465943 TI - Circadian rhythmicity and light sensitivity of the zebrafish brain. AB - Traditionally, circadian clocks have been thought of as a neurobiological phenomenon. This view changed somewhat over recent years with the discovery of peripheral tissue circadian oscillators. In mammals, however, the suprachiasmatic nucleus (SCN) in the hypothalamus still retains the critical role of a central synchronizer of biological timing. Zebrafish, in contrast, have always reflected a more highly decentralized level of clock organization, as individual cells and tissues contain directly light responsive circadian pacemakers. As a consequence, clock function in the zebrafish brain has remained largely unexplored, and the precise organization of rhythmic and light-sensitive neurons within the brain is unknown. To address this issue, we used the period3 (per3)-luciferase transgenic zebrafish to confirm that multiple brain regions contain endogenous circadian oscillators that are directly light responsive. In addition, in situ hybridization revealed localised neural expression of several rhythmic and light responsive clock genes, including per3, cryptochrome1a (cry1a) and per2. Adult brain nuclei showing significant clock gene expression include the teleost equivalent of the SCN, as well as numerous hypothalamic nuclei, the periventricular grey zone (PGZ) of the optic tectum, and granular cells of the rhombencephalon. To further investigate the light sensitive properties of neurons, expression of c-fos, a marker for neuronal activity, was examined. c-fos mRNA was upregulated in response to changing light conditions in different nuclei within the zebrafish brain. Furthermore, under constant dark (DD) conditions, c fos shows a significant circadian oscillation. Taken together, these results show that there are numerous areas of the zebrafish central nervous system, which contain deep brain photoreceptors and directly light-entrainable circadian pacemakers. However, there are also multiple brain nuclei, which possess neither, demonstrating a degree of pacemaker complexity that was not previously appreciated. PMID- 24465944 TI - A functional variant in the stearoyl-CoA desaturase gene promoter enhances fatty acid desaturation in pork. AB - There is growing public concern about reducing saturated fat intake. Stearoyl-CoA desaturase (SCD) is the lipogenic enzyme responsible for the biosynthesis of oleic acid (18 ? 1) by desaturating stearic acid (18 ? 0). Here we describe a total of 18 mutations in the promoter and 3' non-coding region of the pig SCD gene and provide evidence that allele T at AY487830:g.2228T>C in the promoter region enhances fat desaturation (the ratio 18 ? 1/18 ? 0 in muscle increases from 3.78 to 4.43 in opposite homozygotes) without affecting fat content (18 ? 0+18 ? 1, intramuscular fat content, and backfat thickness). No mutations that could affect the functionality of the protein were found in the coding region. First, we proved in a purebred Duroc line that the C-T-A haplotype of the 3 single nucleotide polymorphisms (SNPs) (g.2108C>T; g.2228T>C; g.2281A>G) of the promoter region was additively associated to enhanced 18 ? 1/18 ? 0 both in muscle and subcutaneous fat, but not in liver. We show that this association was consistent over a 10-year period of overlapping generations and, in line with these results, that the C-T-A haplotype displayed greater SCD mRNA expression in muscle. The effect of this haplotype was validated both internally, by comparing opposite homozygote siblings, and externally, by using experimental Duroc-based crossbreds. Second, the g.2281A>G and the g.2108C>T SNPs were excluded as causative mutations using new and previously published data, restricting the causality to g.2228T>C SNP, the last source of genetic variation within the haplotype. This mutation is positioned in the core sequence of several putative transcription factor binding sites, so that there are several plausible mechanisms by which allele T enhances 18 ? 1/18 ? 0 and, consequently, the proportion of monounsaturated to saturated fat. PMID- 24465945 TI - Astrocytes play a key role in Drosophila mushroom body axon pruning. AB - Axon pruning is an evolutionarily conserved strategy used to remodel neuronal connections during development. The Drosophila mushroom body (MB) undergoes neuronal remodeling in a highly stereotypical and tightly regulated manner, however many open questions remain. Although it has been previously shown that glia instruct pruning by secreting a TGF-beta ligand, myoglianin, which primes MB neurons for fragmentation and also later engulf the axonal debris once fragmentation has been completed, which glia subtypes participate in these processes as well as the molecular details are unknown. Here we show that, unexpectedly, astrocytes are the major glial subtype that is responsible for the clearance of MB axon debris following fragmentation, even though they represent only a minority of glia in the MB area during remodeling. Furthermore, we show that astrocytes both promote fragmentation of MB axons as well as clear axonal debris and that this process is mediated by ecdysone signaling in the astrocytes themselves. In addition, we found that blocking the expression of the cell engulfment receptor Draper in astrocytes only affects axonal debris clearance. Thereby we uncoupled the function of astrocytes in promoting axon fragmentation to that of clearing axonal debris after fragmentation has been completed. Our study finds a novel role for astrocytes in the MB and suggests two separate pathways in which they affect developmental axon pruning. PMID- 24465947 TI - Habitat selection of a large carnivore along human-wildlife boundaries in a highly modified landscape. AB - When large carnivores occupy peripheral human lands conflict with humans becomes inevitable, and the reduction of human-carnivore interactions must be the first consideration for those concerned with conflict mitigation. Studies designed to identify areas of high human-bear interaction are crucial for prioritizing management actions. Due to a surge in conflicts, against a background of social intolerance to wildlife and the prevalent use of lethal control throughout Japan, Asiatic black bears (Ursus thibetanus) are now threatened by high rates of mortality. There is an urgent need to reduce the frequency of human-bear encounters if bear populations are to be conserved. To this end, we estimated the habitats that relate to human-bear interactions by sex and season using resource selection functions (RSF). Significant seasonal differences in selection for and avoidance of areas by bears were estimated by distance-effect models with interaction terms of land cover and sex. Human-bear boundaries were delineated on the basis of defined bear-habitat edges in order to identify areas that are in most need of proactive management strategies. Asiatic black bears selected habitats in close proximity to forest edges, forest roads, rivers, and red pine and riparian forests during the peak conflict season and this was correctly predicted in our human-bear boundary maps. Our findings demonstrated that bears selected abandoned forests and agricultural lands, indicating that it should be possible to reduce animal use near human lands by restoring season-specific habitat in relatively remote areas. Habitat-based conflict mitigation may therefore provide a practical means of creating adequate separation between humans and these large carnivores. PMID- 24465946 TI - Structure-function analysis of the C-clamp of TCF/Pangolin in Wnt/beta-catenin signaling. AB - The evolutionarily conserved Wnt/beta-catenin (Wnt/beta-cat) pathway plays an important role in animal development in metazoans. Many Wnt targets are regulated by members of the TCF/LEF1 (TCF) family of transcription factors. All TCFs contain a High Mobility Group (HMG) domain that bind specific DNA sequences. Invertebrate TCFs and some vertebrate TCF isoforms also contain another domain, called the C-clamp, which allows TCFs to recognize an additional DNA motif known as the Helper site. While the C-clamp has been shown to be important for regulating several Wnt reporter genes in cell culture, its physiological role in regulating Wnt targets is less clear. In addition, little is known about this domain, except that two of the four conserved cysteines are functionally important. Here, we carried out a systematic mutagenesis and functional analysis of the C-clamp from the Drosophila TCF/Pangolin (TCF/Pan) protein. We found that the C-clamp is a zinc-binding domain that is sufficient for binding to the Helper site. In addition to this DNA-binding activity, the C-clamp also inhibits the HMG domain from binding its cognate DNA site. Point mutations were identified that specifically affected DNA-binding or reduced the inhibitory effect. These mutants were characterized in TCF/Pan rescue assays. The specific DNA-binding activity of the C-clamp was essential for TCF/Pan function in cell culture and in patterning the embryonic epidermis of Drosophila, demonstrating the importance of this C clamp activity in regulating Wnt target gene expression. In contrast, the inhibitory mutation had a subtle effect in cell culture and no effect on TCF/Pan activity in embryos. These results provide important information about the functional domains of the C-clamp, and highlight its importance for Wnt/beta-cat signaling in Drosophila. PMID- 24465948 TI - bHLH003, bHLH013 and bHLH017 are new targets of JAZ repressors negatively regulating JA responses. AB - Cell reprogramming in response to jasmonates requires a tight control of transcription that is achieved by the activity of JA-related transcription factors (TFs). Among them, MYC2, MYC3 and MYC4 have been described as activators of JA responses. Here we characterized the function of bHLH003, bHLH013 and bHLH017 that conform a phylogenetic clade closely related to MYC2, MYC3 and MYC4. We found that these bHLHs form homo- and heterodimers and also interact with JAZ repressors in vitro and in vivo. Phenotypic analysis of JA-regulated processes, including root and rosette growth, anthocyanin accumulation, chlorophyll loss and resistance to Pseudomonas syringae, on mutants and overexpression lines, suggested that these bHLHs are repressors of JA responses. bHLH003, bHLH013 and bHLH017 are mainly nuclear proteins and bind DNA with similar specificity to that of MYC2, MYC3 and MYC4, but lack a conserved activation domain, suggesting that repression is achieved by competition for the same cis-regulatory elements. Moreover, expression of bHLH017 is induced by JA and depends on MYC2, suggesting a negative feed-back regulation of the activity of positive JA-related TFs. Our results suggest that the competition between positive and negative TFs determines the output of JA-dependent transcriptional activation. PMID- 24465949 TI - Species radiation of carabid beetles (broscini: mecodema) in new zealand. AB - New Zealand biodiversity has often been viewed as Gondwanan in origin and age, but it is increasingly apparent from molecular studies that diversification, and in many cases origination of lineages, postdate the break-up of Gondwanaland. Relatively few studies of New Zealand animal species radiations have as yet been reported, and here we consider the species-rich genus of carabid beetles, Mecodema. Constrained stratigraphic information (emergence of the Chatham Islands) and a substitution rate for Coleoptera were separately used to calibrate Bayesian relaxed molecular clock date estimates for diversification of Mecodema. The inferred timings indicate radiation of these beetles no earlier than the mid Miocene with most divergences being younger, dating to the Plio-Pleistocene. A shallow age for the radiation along with a complex spatial distribution of these taxa involving many instances of sympatry implicates recent ecological speciation rather than a simplistic allopatric model. This emphasises the youthful and dynamic nature of New Zealand evolution that will be further elucidated with detailed ecological and population genetic analyses. PMID- 24465950 TI - Investigation of complement component C4 copy number variation in human longevity. AB - Genetic factors have been estimated to account for about 25% of the variation in an adult's life span. The complement component C4 with the isotypes C4A and C4B is an effector protein of the immune system, and differences in the overall C4 copy number or gene size (long C4L; short C4S) may influence the strength of the immune response and disease susceptibilities. Previously, an association between C4B copy number and life span was reported for Hungarians and Icelanders, where the C4B*Q0 genotype, which is defined by C4B gene deficiency, showed a decrease in frequency with age. Additionally, one of the studies indicated that a low C4B copy number might be a genetic trait that is manifested only in the presence of the environmental risk factor "smoking". These observations prompted us to investigate the role of the C4 alleles in our large German longevity sample (~ 700 cases; 94-110 years and ~ 900 younger controls). No significant differences in the number of C4A, C4B and C4S were detected. Besides, the C4B*Q0 carrier state did not decrease with age, irrespective of smoking as an interacting variable. However, for C4L*Q0 a significantly different carrier frequency was observed in the cases compared with controls (cases: 5.08%; controls: 9.12%; p = 0.003). In a replication sample of 714 German cases (91-108 years) and 890 controls this result was not replicated (p = 0.14) although a similar trend of decreased C4L*Q0 carrier frequency in cases was visible (cases: 7.84%; controls: 10.00%). PMID- 24465951 TI - Microbial diversity of Emalahleni mine water in South Africa and tolerance ability of the predominant organism to vanadium and nickel. AB - The present study aims firstly at determining the microbial diversity of mine water collected in Emalahleni, South Africa and secondly isolating and characterizing the most dominant bacterial species found in the mine water in terms of its resistance to both V(5+) and Ni(2+) in a modified wastewater liquid media. The results revealed a microbial diversity of 17 orders, 27 families and 33 genera were found in the mine-water samples with Marinobacteria (47.02%) and Anabaena (17.66%) being the most abundant genera. Considering their abundance in the mine-water samples, a species of the Marinobacter genera was isolated, identified, and characterised for metal tolerance and removal ability. The MWI-1 isolate (Marinobacter sp. MWI-1 [AB793286]) was found to be closely related to Marinobacter goseongensis at 97% of similarity. The isolate was exposed to various concentrations of Ni(2+) and V(5+) in wastewater liquid media and its tolerance to metals was also assessed. The MWI-1 isolate could tolerate V(5+) and Ni(2+) separately at concentrations (in terms of MIC) up to 13.41 +/- 0.56 mM and 5.39 +/- 0.5 mM at pH 7, whereas at pH 3, the tolerance limit decrease to 11.45 +/- 0.57 mM and 2.67 +/- 0.1 mM, respectively. The removal of V(5+) and Ni(2+) in liquid media was noted to gradually decrease with a gradual increase of the test metals. A significant difference (p<0.05) between V(5+) and Ni(2+) removal was noted. Marinobacter sp. MWI-1 achieved the maximum permissible limit of 0.1 mg V(5+)/L prescribed by UN-FAO at 100 mg/L, while at 200 mg/L only V(5+) was removed at approximately 95% and Ni(2+) at 47%. This study suggests that mine water indigenous microorganisms are the best solution for the remediation of polluted mine water. PMID- 24465952 TI - Cucumber SUPERMAN has conserved function in stamen and fruit development and a distinct role in floral patterning. AB - The Arabidopsis SUPERMAN (SUP) gene encodes a C2H2 type zinc finger protein that is required for maintaining the boundaries between stamens and carpels, and for regulating development of ovule outer integument. Orthologs of SUP have been characterized in bisexual flowers as well as dioecious species, but it remains elusive in monoecious plants with unisexual flowers on the same individual. Here we isolate the SUP ortholog in Cucumis sativus L (CsSUP), a monoecious vegetable. CsSUP is predominantly expressed in female specific organs: the female flower buds and ovules. Ectopic expression of CsSUP in Arabidopsis can partially complement the fruit development in sup-5 mutant, and its over-expression in wide type leads to reduced silique length, suppressed stamen development and distorted petal patterning. Our data suggest that CsSUP plays conserved as well as distinct roles during flower and fruit development, and it may function in the boundaries and ovules to balance petal patterning, stamen and ovule development in Arabidopsis. PMID- 24465953 TI - Growth arrest specific 2 is up-regulated in chronic myeloid leukemia cells and required for their growth. AB - Although the generation of BCR-ABL is the molecular hallmark of chronic myeloid leukemia (CML), the comprehensive molecular mechanisms of the disease remain unclear yet. Growth arrest specific 2 (GAS2) regulates multiple cellular functions including cell cycle, apoptosis and calpain activities. In the present study, we found GAS2 was up-regulated in CML cells including CD34+ progenitor cells compared to their normal counterparts. We utilized RNAi and the expression of dominant negative form of GAS2 (GAS2DN) to target GAS2, which resulted in calpain activity enhancement and growth inhibition of both K562 and MEG-01 cells. Targeting GAS2 also sensitized K562 cells to Imatinib mesylate (IM). GAS2DN suppressed the tumorigenic ability of MEG-01 cells and impaired the tumour growth as well. Moreover, the CD34+ cells from CML patients and healthy donors were transduced with control and GAS2DN lentiviral vectors, and the CD34+ transduced (YFP+) progeny cells (CD34+YFP+) were plated for colony-forming cell (CFC) assay. The results showed that GAS2DN inhibited the CFC production of CML cells by 57+/ 3% (n = 3), while affected those of normal hematopoietic cells by 31+/-1% (n = 2). Next, we found the inhibition of CML cells by GAS2DN was dependent on calpain activity but not the degradation of beta-catenin. Lastly, we generated microarray data to identify the differentially expressed genes upon GAS2DN and validated that the expression of HNRPDL, PTK7 and UCHL5 was suppressed by GAS2DN. These 3 genes were up-regulated in CML cells compared to normal control cells and the growth of K562 cells was inhibited upon HNRPDL silence. Taken together, we have demonstrated that GAS2 is up-regulated in CML cells and the inhibition of GAS2 impairs the growth of CML cells, which indicates GAS2 is a novel regulator of CML cells and a potential therapeutic target of this disease. PMID- 24465954 TI - The intracellular bacteria Chlamydia hijack peroxisomes and utilize their enzymatic capacity to produce bacteria-specific phospholipids. AB - Chlamydia trachomatis is an obligate intracellular pathogen responsible for loss of eyesight through trachoma and for millions of cases annually of sexually transmitted diseases. The bacteria develop within a membrane-bounded inclusion. They lack enzymes for several biosynthetic pathways, including those to make some phospholipids, and exploit their host to compensate. Three-dimensional fluorescence microscopy demonstrates that small organelles of the host, peroxisomes, are translocated into the Chlamydia inclusion and are found adjacent to the bacteria. In cells deficient for peroxisome biogenesis the bacteria are able to multiply and give rise to infectious progeny, demonstrating that peroxisomes are not essential for bacterial development in vitro. Mass spectrometry-based lipidomics reveal the presence in C. trachomatis of plasmalogens, ether phospholipids whose synthesis begins in peroxisomes and have never been described in aerobic bacteria before. Some of the bacterial plasmalogens are novel structures containing bacteria-specific odd-chain fatty acids; they are not made in uninfected cells nor in peroxisome-deficient cells. Their biosynthesis is thus accomplished by the metabolic collaboration of peroxisomes and bacteria. PMID- 24465955 TI - The biphasic effects of moderate alcohol consumption with a meal on ambiance induced mood and autonomic nervous system balance: a randomized crossover trial. AB - BACKGROUND: The pre-drinking mood state has been indicated to be an important factor in the mood effects of alcohol. However, for moderate alcohol consumption there are no controlled studies showing this association. Also, the mood effects of consuming alcohol combined with food are largely unknown. The aim of this study was to investigate the effects of moderate alcohol combined with a meal on ambiance-induced mood states. Furthermore effects on autonomic nervous system activity were measured to explore physiological mechanisms that may be involved in changes of mood state. METHODS: In a crossover design 28 women (age 18-45 y, BMI 18.5-27 kg/m2) were randomly allocated to 4 conditions in which they received 3 glasses of sparkling white wine (30 g alcohol) or alcohol-free sparkling white wine while having dinner in a room with either a pleasant or unpleasant created ambiance. Subjects filled out questionnaires (B-BAES, POMS and postprandial wellness questionnaire) at different times. Skin conductance and heart rate variability were measured continuously. RESULTS: Moderate alcohol consumption increased happiness scores in the unpleasant, but not in the pleasant ambiance. Alcohol consumption increased happiness and stimulation feelings within 1 hour and increased sedative feelings and sleepiness for 2.5 hour. Skin conductance was increased after alcohol within 1 hour and was related to happiness and stimulation scores. Heart rate variability was decreased after alcohol for 2 hours and was related to mental alertness. CONCLUSION: Mood inductions and autonomic nervous system parameters may be useful to evaluate mood changes by nutritional interventions. Moderate alcohol consumption elevates happiness scores in an unpleasant ambiance. However, drinking alcohol during a pleasant mood results in an equally positive mood state. TRIAL REGISTRATION: Clinicaltrials.gov NCT01426022. PMID- 24465956 TI - HIV pre-exposure prophylaxis interest among female sex workers in Guangxi, China. AB - OBJECTIVES: Acceptability of pre-exposure prophylaxis (PrEP) and willingness to participate in a clinical trial for both safety and efficacy of PrEP were investigated among female sex workers (FSWs) in Guangxi, China. METHODS: A cross sectional study was performed in three cities in Guangxi. Structured, self administered questionnaires were used to assess the acceptability of PrEP and the willingness to participate in a clinical trial. Multivariable logistic regression models were fitted to identify predictors. RESULTS: Among 405 participants, 15.1% had heard of PrEP. If PrEP was deemed to be effective, safe and provided for free, 85.9% reported that they would accept it, and 54.3% of those who accepted PrEP said that they would participate in a clinical trial. The increased acceptability of PrEP was associated with working in male dominated venues, higher income, a poor family relationship, better HIV/AIDS knowledge, not realizing HIV risk from unfamiliar clients, not being forced to use condoms by the gatekeepers, consistent use of condoms, and use of drugs to prevent STD infection. The increased willingness to participate in a clinical trial was associated with a poor family relationship, better HIV/AIDS knowledge, not realizing HIV risk from unfamiliar clients, a willingness to adhere to daily PreP use, and not being concerned about discrimination by others. The main reason for rejecting PrEP or participating in a clinical trial was the concern about the side effects of PrEP. CONCLUSIONS: Acceptability of PrEP among Guangxi FSWs is relatively high, indicating that PrEP intervention programs may be feasible for Chinese FSWs. Given the fact that most of the participants had never heard of PrEP before, and that family, gatekeepers, and social discrimination could significantly affect its acceptability, a comprehensive mix of multiple interventions is necessary for the successful implementation of a PrEP program among this population in Guangxi. PMID- 24465957 TI - Robust single trial identification of conscious percepts triggered by sensory events of variable saliency. AB - The neural correlates of visual awareness are elusive because of its fleeting nature. Here we have addressed this issue by using single trial statistical "brain reading" of neurophysiological event related (ERP) signatures of conscious perception of visual attributes with different levels of saliency. Behavioral reports were taken at every trial in 4 experiments addressing conscious access to color, luminance, and local phase offset cues. We found that single trial neurophysiological signatures of target presence can be observed around 300 ms at central parietal sites. Such signatures are significantly related with conscious perception, and their probability is related to sensory saliency levels. These findings identify a general neural correlate of conscious perception at the single trial level, since conscious perception can be decoded as such independently of stimulus salience and fluctuations of threshold levels. This approach can be generalized to successfully detect target presence in other individuals. PMID- 24465959 TI - Pectoral fin of the megamouth shark: skeletal and muscular systems, skin histology, and functional morphology. AB - This is the first known report on the skeletal and muscular systems, and the skin histology, of the pectoral fin of the rare planktivorous megamouth shark Megachasma pelagios. The pectoral fin is characterized by three features: 1) a large number of segments in the radial cartilages; 2) highly elastic pectoral fin skin; and 3) a vertically-rotated hinge joint at the pectoral fin base. These features suggest that the pectoral fin of the megamouth shark is remarkably flexible and mobile, and that this flexibility and mobility enhance dynamic lift control, thus allowing for stable swimming at slow speeds. The flexibility and mobility of the megamouth shark pectoral fin contrasts with that of fast-swimming sharks, such as Isurus oxyrhinchus and Lamna ditropis, in which the pectoral fin is stiff and relatively immobile. PMID- 24465958 TI - Improving ambulatory saliva-sampling compliance in pregnant women: a randomized controlled study. AB - OBJECTIVE: Noncompliance with scheduled ambulatory saliva sampling is common and has been associated with biased cortisol estimates in nonpregnant subjects. This study is the first to investigate in pregnant women strategies to improve ambulatory saliva-sampling compliance, and the association between sampling noncompliance and saliva cortisol estimates. METHODS: We instructed 64 pregnant women to collect eight scheduled saliva samples on two consecutive days each. Objective compliance with scheduled sampling times was assessed with a Medication Event Monitoring System and self-reported compliance with a paper-and-pencil diary. In a randomized controlled study, we estimated whether a disclosure intervention (informing women about objective compliance monitoring) and a reminder intervention (use of acoustical reminders) improved compliance. A mixed model analysis was used to estimate associations between women's objective compliance and their diurnal cortisol profiles, and between deviation from scheduled sampling and the cortisol concentration measured in the related sample. RESULTS: Self-reported compliance with a saliva-sampling protocol was 91%, and objective compliance was 70%. The disclosure intervention was associated with improved objective compliance (informed: 81%, noninformed: 60%), F(1,60) = 17.64, p<0.001, but not the reminder intervention (reminders: 68%, without reminders: 72%), F(1,60) = 0.78, p = 0.379. Furthermore, a woman's increased objective compliance was associated with a higher diurnal cortisol profile, F(2,64) = 8.22, p<0.001. Altered cortisol levels were observed in less objective compliant samples, F(1,705) = 7.38, p = 0.007, with delayed sampling associated with lower cortisol levels. CONCLUSIONS: The results suggest that in pregnant women, objective noncompliance with scheduled ambulatory saliva sampling is common and is associated with biased cortisol estimates. To improve sampling compliance, results suggest informing women about objective compliance monitoring but discourage use of acoustical reminders. PMID- 24465960 TI - Impact of the CYP3A5, CYP3A4, COMT, IL-10 and POR genetic polymorphisms on tacrolimus metabolism in Chinese renal transplant recipients. AB - Tacrolimus is a widely used immunosuppressive drug for preventing the rejection of solid organ transplants. The efficacy of tacrolimus shows considerable variability, which might be related to genetic variation among recipients. We conducted a retrospective study of 240 Chinese renal transplant recipients receiving tacrolimus as immunosuppressive drug. The retrospective data of all patients were collected for 40 days after transplantation. Seventeen SNPs of CYP3A5, CYP3A4, COMT, IL-10 and POR were identified by the SNaPshot assay. Tacrolimus blood concentrations were obtained on days 1-3, days 6-8 and days 12 14 after transplantation, as well as during the period of the predefined therapeutic concentration range. Kruskal-Wallis test was used to examine the effect of genetic variation on the tacrolimus concentration/dose ratio (C 0/D) at different time points. Chi-square test was used to compare the proportions of patients who achieved the target C 0 range in the different genotypic groups at weeks 1, 2, 3 and 4 after transplantation. After correction for multiple testing, there was a significant association of C 0/D with CYP3A5*3, CYP3A4*1G and CYP3A4 rs4646437 T>C at different time points after transplantation. The proportion of patients in the IL-10 rs1800871-TT group who achieved the target C 0 range was greater (p = 0.004) compared to the IL-10 rs1800871-CT and IL-10 rs1800871-CC groups at week 3 after transplantation. CYP3A5*3, CYP3A4 *1G, CYP3A4 rs4646437 T>C and IL-10 rs1800871 C>T might be potential polymorphisms affecting the interindividual variability in tacrolimus metabolism among Chinese renal transplant recipients. PMID- 24465961 TI - Ureter smooth muscle cell orientation in rat is predominantly longitudinal. AB - In ureter peristalsis, the orientation of the contracting smooth muscle cells is essential, yet current descriptions of orientation and composition of the smooth muscle layer in human as well as in rat ureter are inconsistent. The present study aims to improve quantification of smooth muscle orientation in rat ureters as a basis for mechanistic understanding of peristalsis. A crucial step in our approach is to use two-photon laser scanning microscopy and image analysis providing objective, quantitative data on smooth muscle cell orientation in intact ureters, avoiding the usual sectioning artifacts. In 36 rat ureter segments, originating from a proximal, middle or distal site and from a left or right ureter, we found close to the adventitia a well-defined longitudinal smooth muscle orientation. Towards the lamina propria, the orientation gradually became slightly more disperse, yet the main orientation remained longitudinal. We conclude that smooth muscle cell orientation in rat ureter is predominantly longitudinal, though the orientation gradually becomes more disperse towards the proprial side. These findings do not support identification of separate layers. The observed longitudinal orientation suggests that smooth muscle contraction would rather cause local shortening of the ureter, than cause luminal constriction. However, the net-like connective tissue of the ureter wall may translate local longitudinal shortening into co-local luminal constriction, facilitating peristalsis. Our quantitative, minimally invasive approach is a crucial step towards more mechanistic insight into ureter peristalsis, and may also be used to study smooth muscle cell orientation in other tube-like structures like gut and blood vessels. PMID- 24465962 TI - Interspecific aggression and habitat partitioning in garter snakes. AB - Defense of a limited resource, such as space or food, has recently been discovered in snakes and has been widely documented in lizards. Garter snakes (Thamnophis spp.) are historically considered generalist predators such that food is not a limiting resource. However, in this study we show that the common garter snake (Thamnophis sirtalis) and the aquatic garter snake (Thamnophis atratus) show a strong preference for amphibians as their primary food source at the Santa Lucia Preserve (SLP), Monterey County, California. This food preference forces these snake species at SLP to exploit aquatic habitats. Our principle goal was to investigate the aggressive behavior of T. sirtalis and the potential that this aggression displaces T. atratus from its preferred habitat. We found that when individuals from either species are alone, a 100% preference for aquatic or near aquatic habitat is observed. In contrast, when these species are together, T. sirtalis occupy the aquatic habitat and T. atratus occupy an area far removed from water. Thamnophis sirtalis often physically force T. atratus from the aquatic habitat through repeated biting and other displays of aggression. PMID- 24465963 TI - How does pollen chemistry impact development and feeding behaviour of polylectic bees? AB - Larvae and imagos of bees rely exclusively on floral rewards as a food source but host-plant range can vary greatly among bee species. While oligolectic species forage on pollen from a single family of host plants, polylectic bees, such as bumblebees, collect pollen from many families of plants. These polylectic species contend with interspecific variability in essential nutrients of their host plants but we have only a limited understanding of the way in which chemicals and chemical combinations influence bee development and feeding behaviour. In this paper, we investigated five different pollen diets (Calluna vulgaris, Cistus sp., Cytisus scoparius, Salix caprea and Sorbus aucuparia) to determine how their chemical content affected bumblebee colony development and pollen/syrup collection. Three compounds were used to characterise pollen content: polypeptides, amino acids and sterols. Several parameters were used to determine the impact of diet on micro-colonies: (i) Number and weight of larvae (total and mean weight of larvae), (ii) weight of pollen collected, (iii) pollen efficacy (total weight of larvae divided by weight of the pollen collected) and (iv) syrup collection. Our results show that pollen collection is similar regardless of chemical variation in pollen diet while syrup collection is variable. Micro colonies fed on S. aucuparia and C. scoparius pollen produced larger larvae (i.e. better mates and winter survivors) and fed less on nectar compared to the other diets. Pollen from both of these species contains 24-methylenecholesterol and high concentrations of polypeptides/total amino acids. This pollen nutritional "theme" seems therefore to promote worker reproduction in B. terrestris micro colonies and could be linked to high fitness for queenright colonies. As workers are able to selectively forage on pollen of high chemical quality, plants may be evolutionarily selected for their pollen content, which might attract and increase the degree of fidelity of generalist pollinators, such as bumblebees. PMID- 24465964 TI - Longitudinal profiling of the tissue-specific expression of genes related with insulin sensitivity in dairy cows during lactation focusing on different fat depots. AB - In dairy cows the milk associated energy output in early lactation exceeds the input via voluntary feed intake. To spare glucose for mammary lactose synthesis, peripheral insulin sensitivity (IS) is reduced and fat mobilization is stimulated. For these processes a link between IS and the endocrine functions of adipose tissue (AT) is likely; we thus aimed to characterise the mRNA expression from bovine AT derived proteins and receptors that are related to IS according to the literature in metabolically active tissues plus systemic IS throughout lactation. Conjugated linoleic acids (CLA) reduce milk fat thus decreasing the milk drain of energy and potentially dampening lipolysis, but may also affect IS. Subcutaneous (s.c.) AT and liver from pluriparous cows receiving either control fat or CLA supplement (100 g/day from 1 to 182 days in milk each) were biopsied covering week -3 to 36 relative to parturition. In an additional trial with primiparous cows treated analogously and slaughtered on days in milk 1, 42 or 105, samples from liver, udder, skeletal muscle and 3 visceral and 3 s.c. AT were obtained and assayed for mRNA abundance of adiponectin, its receptors, leptin, leptin receptor, PPARgamma, PPARgamma2, IL-6, and TNF-alpha. In pluriparous animals, the mRNA abundance of most of the target genes decreased after parturition in s.c. AT but increased in liver. In primiparous cows, AT depot specific differences were mostly related to retroperitoneal AT; adiponectin receptor 1 and TNF-alpha were affected predominantly. CLA effects in primiparous cows were largely limited to decreased PPARgamma2 mRNA abundance in udder tissue. In pluriparous cows, insulin secretion was increased by CLA resulting in decreased systemic IS but without consistent changes in tissue target mRNA abundance. The temporal gene expression profiles from the adipokines and related receptors support their coactive function in adapting to the needs of lactation. PMID- 24465965 TI - Rules from words: a dynamic neural basis for a lawful linguistic process. AB - Listeners show a reliable bias towards interpreting speech sounds in a way that conforms to linguistic restrictions (phonotactic constraints) on the permissible patterning of speech sounds in a language. This perceptual bias may enforce and strengthen the systematicity that is the hallmark of phonological representation. Using Granger causality analysis of magnetic resonance imaging (MRI)-constrained magnetoencephalography (MEG) and electroencephalography (EEG) data, we tested the differential predictions of rule-based, frequency-based, and top-down lexical influence-driven explanations of processes that produce phonotactic biases in phoneme categorization. Consistent with the top-down lexical influence account, brain regions associated with the representation of words had a stronger influence on acoustic-phonetic regions in trials that led to the identification of phonotactically legal (versus illegal) word-initial consonant clusters. Regions associated with the application of linguistic rules had no such effect. Similarly, high frequency phoneme clusters failed to produce stronger feedforward influences by acoustic-phonetic regions on areas associated with higher linguistic representation. These results suggest that top-down lexical influences contribute to the systematicity of phonological representation. PMID- 24465966 TI - Protection genes in nucleus accumbens shell affect vulnerability to nicotine self administration across isogenic strains of adolescent rat. AB - Classical genetic studies show the heritability of cigarette smoking is 0.4-0.6, and that multiple genes confer susceptibility and resistance to smoking. Despite recent advances in identifying genes associated with smoking behaviors, the major source of this heritability and its impact on susceptibility and resistance are largely unknown. Operant self-administration (SA) of intravenous nicotine is an established model for smoking behavior. We recently confirmed that genetic factors exert strong control over nicotine intake in isogenic rat strains. Because the processing of afferent dopaminergic signals by nucleus accumbens shell (AcbS) is critical for acquisition and maintenance of motivated behaviors reinforced by nicotine, we hypothesized that differential basal gene expression in AcbS accounts for much of the strain-to-strain variation in nicotine SA. We therefore sequenced the transcriptome of AcbS samples obtained by laser capture microdissection from 10 isogenic adolescent rat strains and compared all RNA transcript levels with behavior. Weighted gene co-expression network analysis, a systems biology method, found 12 modules (i.e., unique sets of genes that covary across all samples) that correlated (p<0.05) with amount of self-administered nicotine; 9 of 12 correlated negatively, implying a protective role. PCR confirmed selected genes from these modules. Chilibot, a literature mining tool, identified 15 genes within 1 module that were nominally associated with cigarette smoking, thereby providing strong support for the analytical approach. This is the first report demonstrating that nicotine intake by adolescent rodents is associated with the expression of specific genes in AcbS of the mesolimbic system, which controls motivated behaviors. These findings provide new insights into genetic mechanisms that predispose or protect against tobacco addiction. PMID- 24465967 TI - Roles of gibberellin catabolism and signaling in growth and physiological response to drought and short-day photoperiods in Populus trees. AB - Survival and productivity of perennial plants in temperate zones are dependent on robust responses to prolonged and seasonal cycles of unfavorable conditions. Here we report whole-genome microarray, expression, physiological, and transgenic evidence in hybrid poplar (Populus tremula * Populus alba) showing that gibberellin (GA) catabolism and repressive signaling mediates shoot growth inhibition and physiological adaptation in response to drought and short-day (SD) induced bud dormancy. Both water deprivation and SDs elicited activation of a suite of poplar GA2ox and DELLA encoding genes. Poplar transgenics with up regulated GA 2-oxidase (GA2ox) and DELLA domain proteins showed hypersensitive growth inhibition in response to both drought and SDs. In addition, the transgenic plants displayed greater drought resistance as evidenced by increased pigment concentrations (chlorophyll and carotenoid) and reductions in electrolyte leakage (EL). Comparative transcriptome analysis using whole-genome microarray showed that the GA-deficiency and GA-insensitivity, SD-induced dormancy, and drought response in poplar share a common regulon of 684 differentially-expressed genes, which suggest GA metabolism and signaling plays a role in plant physiological adaptations in response to alterations in environmental factors. Our results demonstrate that GA catabolism and repressive signaling represents a major route for control of growth and physiological adaptation in response to immediate or imminent adverse conditions. PMID- 24465968 TI - The Not4 E3 ligase and CCR4 deadenylase play distinct roles in protein quality control. AB - Eukaryotic cells control their proteome by regulating protein production and protein clearance. Protein production is determined to a large extent by mRNA levels, whereas protein degradation depends mostly upon the proteasome. Dysfunction of the proteasome leads to the accumulation of non-functional proteins that can aggregate, be toxic for the cell, and, in extreme cases, lead to cell death. mRNA levels are controlled by their rates of synthesis and degradation. Recent evidence indicates that these rates have oppositely co evolved to ensure appropriate mRNA levels. This opposite co-evolution has been correlated with the mutations in the Ccr4-Not complex. Consistently, the deadenylation enzymes responsible for the rate-limiting step in eukaryotic mRNA degradation, Caf1 and Ccr4, are subunits of the Ccr4-Not complex. Another subunit of this complex is a RING E3 ligase, Not4. It is essential for cellular protein solubility and has been proposed to be involved in co-translational quality control. An open question has been whether this role of Not4 resides strictly in the regulation of the deadenylation module of the Ccr4-Not complex. However, Not4 is important for proper assembly of the proteasome, and the Ccr4-Not complex may have multiple functional modules that participate in protein quality control in different ways. In this work we studied how the functions of the Caf1/Ccr4 and Not4 modules are connected. We concluded that Not4 plays a role in protein quality control independently of the Ccr4 deadenylase, and that it is involved in clearance of aberrant proteins at least in part via the proteasome. PMID- 24465969 TI - Tick-borne encephalitis virus infects rat astrocytes but does not affect their viability. AB - Tick-borne encephalitis virus (TBEV) causes one of the most dangerous human neuroinfections in Europe and Asia. To infect neurons it must cross the blood brain-barrier (BBB), and presumably also cells adjacent to the BBB, such as astrocytes, the most abundant glial cell type. However, the knowledge about the viral infection of glial cells is fragmental. Here we studied whether TBEV infects rat astrocytes. Rats belong to an animal group serving as a TBEV amplifying host. We employed high resolution quantitative fluorescence microscopy to investigate cell entry and cytoplasmic mobility of TBEV particles along with the effect on the cell cytoskeleton and cell survival. We report that infection of astrocytes with TBEV increases with time of exposure to TBEV and that with post-infection time TBEV particles gained higher mobility. After several days of infection actin cytoskeleton was affected, but cell survival was unchanged, indicating that rat astrocytes resist TBEV-mediated cell death, as reported for other mammalian cells. Therefore, astrocytes may present an important pool of dormant TBEV infections and a new target for therapeutic intervention. PMID- 24465970 TI - Responses to telomere erosion in plants. AB - In striking contrast to animals, plants are able to develop and reproduce in the presence of significant levels of genome damage. This is seen clearly in both the viability of plants carrying knockouts for key recombination and DNA repair genes, which are lethal in vertebrates, and in the impact of telomere dysfunction. Telomerase knockout mice show accelerated ageing and severe developmental phenotypes, with effects on both highly proliferative and on more quiescent tissues, while cell death in Arabidopsis tert mutants is mostly restricted to actively dividing meristematic cells. Through phenotypic and whole transcriptome RNAseq studies, we present here an analysis of the response of Arabidopsis plants to the continued presence of telomere damage. Comparison of second-generation and seventh-generation tert mutant plants has permitted separation of the effects of the absence of the telomerase enzyme and the ensuing chromosome damage. In addition to identifying a large number of genes affected by telomere damage, many of which are of unknown function, the striking conclusion of this study is the clear difference observed at both cellular and transcriptome levels between the ways in which mammals and plants respond to chronic telomeric damage. PMID- 24465971 TI - SMART: a spatially explicit bio-economic model for assessing and managing demersal fisheries, with an application to italian trawlers in the strait of sicily. AB - Management of catches, effort and exploitation pattern are considered the most effective measures to control fishing mortality and ultimately ensure productivity and sustainability of fisheries. Despite the growing concerns about the spatial dimension of fisheries, the distribution of resources and fishing effort in space is seldom considered in assessment and management processes. Here we propose SMART (Spatial MAnagement of demersal Resources for Trawl fisheries), a tool for assessing bio-economic feedback in different management scenarios. SMART combines information from different tasks gathered within the European Data Collection Framework on fisheries and is composed of: 1) spatial models of fishing effort, environmental characteristics and distribution of demersal resources; 2) an Artificial Neural Network which captures the relationships among these aspects in a spatially explicit way and uses them to predict resources abundances; 3) a deterministic module which analyzes the size structure of catches and the associated revenues, according to different spatially-based management scenarios. SMART is applied to demersal fishery in the Strait of Sicily, one of the most productive fisheries of the Mediterranean Sea. Three of the main target species are used as proxies for the whole range exploited by trawlers. After training, SMART is used to evaluate different management scenarios, including spatial closures, using a simulation approach that mimics the recent exploitation patterns. Results evidence good model performance, with a noteworthy coherence and reliability of outputs for the different components. Among others, the main finding is that a partial improvement in resource conditions can be achieved by means of nursery closures, even if the overall fishing effort in the area remains stable. Accordingly, a series of strategically designed areas of trawling closures could significantly improve the resource conditions of demersal fisheries in the Strait of Sicily, also supporting sustainable economic returns for fishermen if not applied simultaneously for different species. PMID- 24465972 TI - Observing single enzyme molecules interconvert between activity states upon heating. AB - In this paper, we demonstrate that single enzyme molecules of beta-galactosidase interconvert between different activity states upon exposure to short pulses of heat. We show that these changes in activity are the result of different enzyme conformations. Hundreds of single beta-galactosidase molecules are trapped in femtoliter reaction chambers and the individual enzymes are subjected to short heating pulses. When heating pulses are introduced into the system, the enzyme molecules switch between different activity states. Furthermore, we observe that the changes in activity are random and do not correlate with the enzyme's original activity. This study demonstrates that different stable conformations play an important role in the static heterogeneity reported previously, resulting in distinct long-lived activity states of enzyme molecules in a population. PMID- 24465973 TI - The success of the horse-chestnut leaf-miner, Cameraria ohridella, in the UK revealed with hypothesis-led citizen science. AB - Citizen science is an increasingly popular way of undertaking research and simultaneously engaging people with science. However, most emphasis of citizen science in environmental science is on long-term monitoring. Here, we demonstrate the opportunities provided by short-term hypothesis-led citizen science. In 2010, we ran the 'Conker Tree Science' project, in which over 3500 people in Great Britain provided data at a national scale of an insect (horse-chestnut leaf mining moth, Cameraria ohridella) undergoing rapid range-expansion. We addressed two hypotheses, and found that (1) the levels of damage caused to leaves of the horse-chestnut tree, Aesculus hippocastanum, and (2) the level of attack by parasitoids of C. ohridella larvae were both greatest where C. ohridella had been present the longest. Specifically there was a rapid rise in leaf damage during the first three years that C. ohridella was present and only a slight rise thereafter, while estimated rates of parasitism (an index of true rates of parasitism) increased from 1.6 to 5.9% when the time C. ohridella had been present in a location increased from 3 to 6 years. We suggest that this increase is due to recruitment of native generalist parasitoids, rather than the adaptation or host-tracking of more specialized parasitoids, as appears to have occurred elsewhere in Europe. Most data collected by participants were accurate, but the counts of parasitoids from participants showed lower concordance with the counts from experts. We statistically modeled this bias and propagated this through our analyses. Bias-corrected estimates of parasitism were lower than those from the raw data, but the trends were similar in magnitude and significance. With appropriate checks for data quality, and statistically correcting for biases where necessary, hypothesis-led citizen science is a potentially powerful tool for carrying out scientific research across large spatial scales while simultaneously engaging many people with science. PMID- 24465975 TI - Molecular insights into the pH-dependent adsorption and removal of ionizable antibiotic oxytetracycline by adsorbent cyclodextrin polymers. AB - Effects of pH on adsorption and removal efficiency of ionizable organic compounds (IOCs) by environmental adsorbents are an area of debate, because of its dual mediation towards adsorbents and adsorbate. Here, we probe the pH-dependent adsorption of ionizable antibiotic oxytetracycline (comprising OTCH2 (+), OTCH(+/ ), OTC(-), and OTC(2-)) onto cyclodextrin polymers (CDPs) with the nature of molecular recognition and pH inertness. OTCH(+/-) commonly has high adsorption affinity, OTC(-) exhibits moderate affinity, and the other two species have negligible affinity. These species are evidenced to selectively interact with structural units (e.g., CD cavity, pore channel, and network) of the polymers and thus immobilized onto the adsorbents to different extents. The differences in adsorption affinity and mechanisms of the species account for the pH-dependent adsorption of OTC. The mathematical equations are derived from the multiple linear regression (MLR) analysis of quantitatively relating adsorption affinity of OTC at varying pH to adsorbent properties. A combination of the MLR analysis for OTC and molecular recognition of adsorption of the species illustrates the nature of the pH-dependent adsorption of OTC. Based on this finding, gamma-HP-CDP is chosen to adsorb and remove OTC at pH 5.0 and 7.0, showing high removal efficiency and strong resistance to the interference of coexisting components. PMID- 24465974 TI - Design and characterization of a 52K SNP chip for goats. AB - The success of Genome Wide Association Studies in the discovery of sequence variation linked to complex traits in humans has increased interest in high throughput SNP genotyping assays in livestock species. Primary goals are QTL detection and genomic selection. The purpose here was design of a 50-60,000 SNP chip for goats. The success of a moderate density SNP assay depends on reliable bioinformatic SNP detection procedures, the technological success rate of the SNP design, even spacing of SNPs on the genome and selection of Minor Allele Frequencies (MAF) suitable to use in diverse breeds. Through the federation of three SNP discovery projects consolidated as the International Goat Genome Consortium, we have identified approximately twelve million high quality SNP variants in the goat genome stored in a database together with their biological and technical characteristics. These SNPs were identified within and between six breeds (meat, milk and mixed): Alpine, Boer, Creole, Katjang, Saanen and Savanna, comprising a total of 97 animals. Whole genome and Reduced Representation Library sequences were aligned on >10 kb scaffolds of the de novo goat genome assembly. The 60,000 selected SNPs, evenly spaced on the goat genome, were submitted for oligo manufacturing (Illumina, Inc) and published in dbSNP along with flanking sequences and map position on goat assemblies (i.e. scaffolds and pseudo chromosomes), sheep genome V2 and cattle UMD3.1 assembly. Ten breeds were then used to validate the SNP content and 52,295 loci could be successfully genotyped and used to generate a final cluster file. The combined strategy of using mainly whole genome Next Generation Sequencing and mapping on a contig genome assembly, complemented with Illumina design tools proved to be efficient in producing this GoatSNP50 chip. Advances in use of molecular markers are expected to accelerate goat genomic studies in coming years. PMID- 24465976 TI - Has pollination mode shaped the evolution of ficus pollen? AB - BACKGROUND: The extent to which co-evolutionary processes shape morphological traits is one of the most fascinating topics in evolutionary biology. Both passive and active pollination modes coexist in the fig tree (Ficus, Moraceae) and fig wasp (Agaonidae, Hymenoptera) mutualism. This classic obligate relationship that is about 75 million years old provides an ideal system to consider the role of pollination mode shifts on pollen evolution. METHODS AND MAIN FINDINGS: Twenty-five fig species, which cover all six Ficus subgenera, and are native to the Xishuangbanna region of southwest China, were used to investigate pollen morphology with scanning electron microscope (SEM). Pollination mode was identified by the Anther/Ovule ratio in each species. Phylogenetic free regression and a correlated evolution test between binary traits were conducted based on a strong phylogenetic tree. Seventeen of the 25 fig species were actively pollinated and eight species were passively pollinated. Three pollen shape types and three kinds of exine ornamentation were recognized among these species. Pollen grains with ellipsoid shape and rugulate ornamentation were dominant. Ellipsoid pollen occurred in all 17 species of actively pollinated figs, while for the passively pollinated species, two obtuse end shapes were identified: cylinder and sphere shapes were identified in six of the eight species. All passively pollinated figs presented rugulate ornamentation, while for actively pollinated species, the smoother types - psilate and granulate-rugulate ornamentations - accounted for just five and two among the 17 species, respectively. The relationship between pollen shape and pollination mode was shown by both the phylogenetic free regression and the correlated evolution tests. CONCLUSIONS: Three pollen shape and ornamentation types were found in Ficus, which show characteristics related to passive or active pollination mode. Thus, the pollen shape is very likely shaped by pollination mode in this unique obligate mutualism. PMID- 24465977 TI - Free and cued recall memory in Parkinson's disease associated with amnestic mild cognitive impairment. AB - The hypothesis has been advanced that memory disorders in individuals with Parkinson's disease (PD) are related to either retrieval or consolidation failure. However, the characteristics of the memory impairments of PD patients with amnestic mild cognitive impairment have not been clarified. This study was aimed at investigating whether memory deficits in PD patients with amnestic mild cognitive impairment (PDaMCI) are due to failure of retrieval or consolidation processes. Sixteen individuals with PDaMCI, 20 with amnestic mild cognitive impairment without PD (aMCINPD), and 20 healthy controls were recruited. Participants were administered the Free and Cued Selective Reminding Test. An index of cueing was computed for each subject to capture the advantage in retrieval of cued compared to free recall. Individuals with PDaMCI performed worse than healthy controls on the free recall (p<0.01) but not the cued recall (p>0.10) task, and they performed better than aMCINPD subjects on both recall measures (p<0.01). The index of cueing of subjects with PD was comparable to that of healthy controls (p>0.10) but it was significantly higher than that of the aMCINPD sample (p<0.01). Moreover, PD patients' performance on free recall trials was significantly predicted by scores on a test investigating executive functions (i.e., the Modified Card Sorting Test; p = 0.042). Findings of the study document that, in subjects with amnestic mild cognitive impairment associated to PD, episodic memory impairment is related to retrieval rather than to consolidation failure. The same data suggest that, in these individuals, memory deficits might be due to altered frontal-related executive functioning. PMID- 24465978 TI - Genetic variations in the androgen receptor are associated with steroid concentrations and anthropometrics but not with muscle mass in healthy young men. AB - OBJECTIVE: The relationship between serum testosterone (T) levels, muscle mass and muscle force in eugonadal men is incompletely understood. As polymorphisms in the androgen receptor (AR) gene cause differences in androgen sensitivity, no straightforward correlation can be observed between the interindividual variation in T levels and different phenotypes. Therefore, we aim to investigate the relationship between genetic variations in the AR, circulating androgens and muscle mass and function in young healthy male siblings. DESIGN: 677 men (25-45 years) were recruited in a cross-sectional, population-based sibling pair study. METHODS: Relations between genetic variation in the AR gene (CAGn, GGNn, SNPs), sex steroid levels (by LC-MS/MS), body composition (by DXA), muscle cross sectional area (CSA) (by pQCT), muscle force (isokinetic peak torque, grip strength) and anthropometrics were studied using linear mixed-effect modelling. RESULTS: Muscle mass and force were highly heritable and related to age, physical activity, body composition and anthropometrics. Total T (TT) and free T (FT) levels were positively related to muscle CSA, whereas estradiol (E2) and free E2 (FE2) concentrations were negatively associated with muscle force. Subjects with longer CAG repeat length had higher circulating TT, FT, and higher E2 and FE2 concentrations. Weak associations with TT and FT were found for the rs5965433 and rs5919392 SNP in the AR, whereas no association between GGN repeat polymorphism and T concentrations were found. Arm span and 2D:4D finger length ratio were inversely associated, whereas muscle mass and force were not associated with the number of CAG repeats. CONCLUSIONS: Age, physical activity, body composition, sex steroid levels and anthropometrics are determinants of muscle mass and function in young men. Although the number of CAG repeats of the AR are related to sex steroid levels and anthropometrics, we have no evidence that these variations in the AR gene also affect muscle mass or function. PMID- 24465979 TI - Mineralocorticoid receptors guide spatial and stimulus-response learning in mice. AB - Adrenal corticosteroid hormones act via mineralocorticoid (MR) and glucocorticoid receptors (GR) in the brain, influencing learning and memory. MRs have been implicated in the initial behavioral response in novel situations, which includes behavioral strategies in learning tasks. Different strategies can be used to solve navigational tasks, for example hippocampus-dependent spatial or striatum dependent stimulus-response strategies. Previous studies suggested that MRs are involved in spatial learning and induce a shift between learning strategies when animals are allowed a choice between both strategies. In the present study, we further explored the role of MRs in spatial and stimulus-response learning in two separate circular holeboard tasks using female mice with forebrain-specific MR deficiency and MR overexpression and their wildtype control littermates. In addition, we studied sex-specific effects using male and female MR-deficient mice. First, we found that MR-deficient compared to control littermates and MR overexpressing mice display altered exploratory and searching behavior indicative of impaired acquisition of novel information. Second, female (but not male) MR deficient mice were impaired in the spatial task, while MR-overexpressing female mice showed improved performance in the spatial task. Third, MR-deficient mice were also impaired in the stimulus-response task compared to controls and (in the case of females) MR-overexpressing mice. We conclude that MRs are important for coordinating the processing of information relevant for spatial as well as stimulus-response learning. PMID- 24465980 TI - Untangling the influences of voluntary running, environmental complexity, social housing and stress on adult hippocampal neurogenesis. AB - Environmental enrichment (EE) exerts powerful effects on brain physiology, and is widely used as an experimental and therapeutic tool. Typical EE paradigms are multifactorial, incorporating elements of physical exercise, environmental complexity, social interactions and stress, however the specific contributions of these variables have not been separable using conventional housing paradigms. Here, we evaluated the impacts of these individual variables on adult hippocampal neurogenesis by using a novel "Alternating EE" paradigm. For 4 weeks, adult male CD1 mice were alternated daily between two enriched environments; by comparing groups that differed in one of their two environments, the individual and combinatorial effects of EE variables could be resolved. The Alternating EE paradigm revealed that (1) voluntary running for 3 days/week was sufficient to increase both mitotic and post-mitotic stages of hippocampal neurogenesis, confirming the central importance of exercise; (2) a complex environment (comprised of both social interactions and rotated inanimate objects) had no effect on neurogenesis itself, but enhanced depolarization-induced c-Fos expression (attributable to social interactions) and buffered stress-induced plasma corticosterone levels (attributable to inanimate objects); and (3) neither social isolation, group housing, nor chronically increased levels of plasma corticosterone had a prolonged impact on neurogenesis. Mouse strain, handling and type of running apparatus were tested and excluded as potential confounding factors. These findings provide valuable insights into the relative effects of key EE variables on adult neurogenesis, and this "Alternating EE" paradigm represents a useful tool for exploring the contributions of individual EE variables to mechanisms of neural plasticity. PMID- 24465982 TI - The negatively charged regions of lactoferrin binding protein B, an adaptation against anti-microbial peptides. AB - Lactoferrin binding protein B (LbpB) is a bi-lobed membrane bound lipoprotein that is part of the lactoferrin receptor complex in a variety of Gram-negative pathogens. Despite high sequence diversity among LbpBs from various strains and species, a cluster of negatively charged amino acids is invariably present in the protein's C-terminal lobe in all species except Moraxella bovis. The function of LbpB in iron acquisition has yet to be experimentally demonstrated, whereas in vitro studies have shown that LbpB confers protection against lactoferricin, a short cationic antimicrobial peptide released from the N- terminus of lactoferrin. In this study we demonstrate that the negatively charged regions can be removed from the Neisseria meningitidis LbpB without compromising stability, and this results in the inability of LbpB to protect against the bactericidal effects of lactoferricin. The release of LbpB from the cell surface by the autotransporter NalP reduces the protection against lactoferricin in the in vitro killing assay, attributed to removal of LbpB during washing steps, but is unlikely to have a similar impact in vivo. The protective effect of the negatively charged polysaccharide capsule in the killing assay was less than the protection conferred by LbpB, suggesting that LbpB plays a major role in protection against cationic antimicrobial peptides in vivo. The selective release of LbpB by NalP has been proposed to be a mechanism for evading the adaptive immune response, by reducing the antibody binding to the cell surface, but may also provide insights into the primary function of LbpB in vivo. Although TbpB and LbpB have been shown to be major targets of the human immune response, the selective release of LbpB suggests that unlike TbpB, LbpB may not be essential for iron acquisition, but important for protection against cationic antimicrobial peptides. PMID- 24465981 TI - Alteration of daily and circadian rhythms following dopamine depletion in MPTP treated non-human primates. AB - Disturbances of the daily sleep/wake cycle are common non-motor symptoms of Parkinson's disease (PD). However, the impact of dopamine (DA) depletion on circadian rhythms in PD patients or non-human primate (NHP) models of the disorder have not been investigated. We evaluated alterations of circadian rhythms in NHP following MPTP lesion of the dopaminergic nigro-striatal system. DA degeneration was assessed by in vivo PET ([(11)C]-PE2I) and post-mortem TH and DAT quantification. In a light?dark cycle, control and MPTP-treated NHP both exhibit rest-wake locomotor rhythms, although DA-depleted NHP show reduced amplitude, decreased stability and increased fragmentation. In all animals, 6 sulphatoxymelatonin peaks at night and cortisol in early morning. When the circadian system is challenged by exposure to constant light, controls retain locomotor rest-wake and hormonal rhythms that free-run with stable phase relationships whereas in the DA-depleted NHP, locomotor rhythms are severely disturbed or completely abolished. The amplitude and phase relations of hormonal rhythms nevertheless remain unaltered. Use of a light-dark masking paradigm shows that expression of daily rest-wake activity in MPTP monkeys requires the stimulatory and inhibitory effects of light and darkness. These results suggest that following DA lesion, the central clock in the SCN remains intact but, in the absence of environmental timing cues, is unable to drive downstream rhythmic processes of striatal clock gene and dopaminergic functions that control locomotor output. These findings suggest that the circadian component of the sleep-wake disturbances in PD is more profoundly affected than previously assumed. PMID- 24465983 TI - Stability of lysozyme in aqueous extremolyte solutions during heat shock and accelerated thermal conditions. AB - The purpose of this study was to investigate the stability of lysozyme in aqueous solutions in the presence of various extremolytes (betaine, hydroxyectoine, trehalose, ectoine, and firoin) under different stress conditions. The stability of lysozyme was determined by Nile red Fluorescence Spectroscopy and a bioactivity assay. During heat shock (10 min at 70 degrees C), betaine, trehalose, ectoin and firoin protected lysozyme against inactivation while hydroxyectoine, did not have a significant effect. During accelerated thermal conditions (4 weeks at 55 degrees C), firoin also acted as a stabilizer. In contrast, betaine, hydroxyectoine, trehalose and ectoine destabilized lysozyme under this condition. These findings surprisingly indicate that some extremolytes can stabilize a protein under certain stress conditions but destabilize the same protein under other stress conditions. Therefore it is suggested that for the screening extremolytes to be used for protein stabilization, an appropriate storage conditions should also be taken into account. PMID- 24465984 TI - Atrial Fibrillation associated chromosome 4q25 variants are not associated with PITX2c expression in human adult left atrial appendages. AB - Atrial Fibrillation (AF), the most common sustained arrhythmia, has a strong genetic component, but the mechanism by which common genetic variants lead to increased AF susceptibility is unknown. Genome-wide association studies (GWAS) have identified that the single nucleotide polymorphisms (SNPs) most strongly associated with AF are located on chromosome 4q25 in an intergenic region distal to the PITX2 gene. Our objective was to determine whether the AF-associated SNPs on chromosome 4q25 were associated with PITX2c expression in adult human left atrial appendages. Analysis of a lone AF GWAS identified four independent AF risk SNPs at chromosome 4q25. Human adult left atrial appendage tissue was obtained from 239 subjects of European Ancestry and used for SNP analysis of genomic DNA and determination of PITX2c RNA expression levels by quantitative PCR. Subjects were divided into three groups based on their history of AF and pre-operative rhythm. AF rhythm subjects had higher PITX2c expression than those with history of AF but in sinus rhythm. PITX2c expression was not associated with the AF risk SNPs in human adult left atrial appendages in all subjects combined or in each of the three subgroups. However, we identified seven SNPs modestly associated with PITX2c expression located in the introns of the ENPEP gene, ~54 kb proximal to PITX2. PITX2c expression in human adult left atrial appendages is not associated with the chromosome 4q25 AF risk SNPs; thus, the mechanism by which these SNPs are associated with AF remains enigmatic. PMID- 24465985 TI - Effects of elevated CO2 on litter chemistry and subsequent invertebrate detritivore feeding responses. AB - Elevated atmospheric CO2 can change foliar tissue chemistry. This alters leaf litter palatability to macroinvertebrate detritivores with consequences for decomposition, nutrient turnover, and food-web structure. Currently there is no consensus on the link between CO2 enrichment, litter chemistry, and macroinvertebrate-mediated leaf decomposition. To identify any unifying mechanisms, we presented eight invertebrate species from aquatic and terrestrial ecosystems with litter from Alnus glutinosa (common alder) or Betula pendula (silver birch) trees propagated under ambient (380 ppm) or elevated (ambient +200 ppm) CO2 concentrations. Alder litter was largely unaffected by CO2 enrichment, but birch litter from leaves grown under elevated CO2 had reduced nitrogen concentrations and greater C/N ratios. Invertebrates were provided individually with either (i) two litter discs, one of each CO2 treatment ('choice'), or (ii) one litter disc of each CO2 treatment alone ('no-choice'). Consumption was recorded. Only Odontocerum albicorne showed a feeding preference in the choice test, consuming more ambient- than elevated-CO2 birch litter. Species' responses to alder were highly idiosyncratic in the no-choice test: Gammarus pulex and O. albicorne consumed more elevated-CO2 than ambient-CO2 litter, indicating compensatory feeding, while Oniscus asellus consumed more of the ambient-CO2 litter. No species responded to CO2 treatment when fed birch litter. Overall, these results show how elevated atmospheric CO2 can alter litter chemistry, affecting invertebrate feeding behaviour in species-specific ways. The data highlight the need for greater species-level information when predicting changes to detrital processing-a key ecosystem function-under atmospheric change. PMID- 24465986 TI - DNA content variation and its significance in the evolution of the genus Micrasterias (Desmidiales, Streptophyta). AB - It is now clear that whole genome duplications have occurred in all eukaryotic evolutionary lineages, and that the vast majority of flowering plants have experienced polyploidisation in their evolutionary history. However, study of genome size variation in microalgae lags behind that of higher plants and seaweeds. In this study, we have addressed the question whether microalgal phylogeny is associated with DNA content variation in order to evaluate the evolutionary significance of polyploidy in the model genus Micrasterias. We applied flow-cytometric techniques of DNA quantification to microalgae and mapped the estimated DNA content along the phylogenetic tree. Correlations between DNA content and cell morphometric parameters were also tested using geometric morphometrics. In total, DNA content was successfully determined for 34 strains of the genus Micrasterias. The estimated absolute 2C nuclear DNA amount ranged from 2.1 to 64.7 pg; intraspecific variation being 17.4-30.7 pg in M. truncata and 32.0-64.7 pg in M. rotata. There were significant differences between DNA contents of related species. We found strong correlation between the absolute nuclear DNA content and chromosome numbers and significant positive correlation between the DNA content and both cell size and number of terminal lobes. Moreover, the results showed the importance of cell/life cycle studies for interpretation of DNA content measurements in microalgae. PMID- 24465987 TI - Calcium-dependent calcium decay explains STDP in a dynamic model of hippocampal synapses. AB - It is widely accepted that the direction and magnitude of synaptic plasticity depends on post-synaptic calcium flux, where high levels of calcium lead to long term potentiation and moderate levels lead to long-term depression. At synapses onto neurons in region CA1 of the hippocampus (and many other synapses), NMDA receptors provide the relevant source of calcium. In this regard, post-synaptic calcium captures the coincidence of pre- and post-synaptic activity, due to the blockage of these receptors at low voltage. Previous studies show that under spike timing dependent plasticity (STDP) protocols, potentiation at CA1 synapses requires post-synaptic bursting and an inter-pairing frequency in the range of the hippocampal theta rhythm. We hypothesize that these requirements reflect the saturation of the mechanisms of calcium extrusion from the post-synaptic spine. We test this hypothesis with a minimal model of NMDA receptor-dependent plasticity, simulating slow extrusion with a calcium-dependent calcium time constant. In simulations of STDP experiments, the model accounts for latency dependent depression with either post-synaptic bursting or theta-frequency pairing (or neither) and accounts for latency-dependent potentiation when both of these requirements are met. The model makes testable predictions for STDP experiments and our simple implementation is tractable at the network level, demonstrating associative learning in a biophysical network model with realistic synaptic dynamics. PMID- 24465988 TI - The adaptive remodeling of endothelial glycocalyx in response to fluid shear stress. AB - The endothelial glycocalyx is vital for mechanotransduction and endothelial barrier integrity. We previously demonstrated the early changes in glycocalyx organization during the initial 30 min of shear exposure. In the present study, we tested the hypothesis that long-term shear stress induces further remodeling of the glycocalyx resulting in a robust layer, and explored the responses of membrane rafts and the actin cytoskeleton. After exposure to shear stress for 24 h, the glycocalyx components heparan sulfate, chondroitin sulfate, glypican-1 and syndecan-1, were enhanced on the apical surface, with nearly uniform spatial distributions close to baseline levels that differed greatly from the 30 min distributions. Heparan sulfate and glypican-1 still clustered near the cell boundaries after 24 h of shear, but caveolin-1/caveolae and actin were enhanced and concentrated across the apical aspects of the cell. Our findings also suggest the GM1-labelled membrane rafts were associated with caveolae and glypican 1/heparan sulfate and varied in concert with these components. We conclude that remodeling of the glycocalyx to long-term shear stress is associated with the changes in membrane rafts and the actin cytoskeleton. This study reveals a space- and time- dependent reorganization of the glycocalyx that may underlie alterations in mechanotransduction mechanisms over the time course of shear exposure. PMID- 24465989 TI - Hilar somatostatin interneurons contribute to synchronized GABA activity in an in vitro epilepsy model. AB - Epilepsy is a disorder characterized by excessive synchronized neural activity. The hippocampus and surrounding temporal lobe structures appear particularly sensitive to epileptiform activity. Somatostatin (SST)-positive interneurons within the hilar region have been suggested to gate hippocampal activity, and therefore may play a crucial role in the dysregulation of hippocampal activity. In this study, we examined SST interneuron activity in the in vitro 4 aminopyridine (4-AP) model of epilepsy. We employed a multi-disciplinary approach, combining extracellular multi-electrode array (MEA) recordings with patch-clamp recordings and optical imaging using a genetically encoded calcium sensor. We observed that hilar SST interneurons are strongly synchronized during 4-AP-induced local field potentials (LFPs), as assayed by Ca(2+) imaging as well as juxtacellular or intracellular recording. SST interneurons were particularly responsive to GABA-mediated LFPs that occurred in the absence of ionotropic glutamatergic transmission. Our results present evidence that the extensive synchronized activity of SST-expressing interneurons contribute to the generation of GABAergic LFPs in an in vitro model of temporal lobe seizures. PMID- 24465990 TI - Ancient DNA analysis reveals high frequency of European lactase persistence allele (T-13910) in medieval central europe. AB - Ruminant milk and dairy products are important food resources in many European, African, and Middle Eastern societies. These regions are also associated with derived genetic variants for lactase persistence. In mammals, lactase, the enzyme that hydrolyzes the milk sugar lactose, is normally down-regulated after weaning, but at least five human populations around the world have independently evolved mutations regulating the expression of the lactase-phlorizin-hydrolase gene. These mutations result in a dominant lactase persistence phenotype and continued lactase tolerance in adulthood. A single nucleotide polymorphism (SNP) at C/T 13910 is responsible for most lactase persistence in European populations, but when and where the T-13910 polymorphism originated and the evolutionary processes by which it rose to high frequency in Europe have been the subject of strong debate. A history of dairying is presumed to be a prerequisite, but archaeological evidence is lacking. In this study, DNA was extracted from the dentine of 36 individuals excavated at a medieval cemetery in Dalheim, Germany. Eighteen individuals were successfully genotyped for the C/T-13910 SNP by molecular cloning and sequencing, of which 13 (72%) exhibited a European lactase persistence genotype: 44% CT, 28% TT. Previous ancient DNA-based studies found that lactase persistence genotypes fall below detection levels in most regions of Neolithic Europe. Our research shows that by AD 1200, lactase persistence frequency had risen to over 70% in this community in western Central Europe. Given that lactase persistence genotype frequency in present-day Germany and Austria is estimated at 71-80%, our results suggest that genetic lactase persistence likely reached modern levels before the historic population declines associated with the Black Death, thus excluding plague-associated evolutionary forces in the rise of lactase persistence in this region. This new evidence sheds light on the dynamic evolutionary history of the European lactase persistence trait and its global cultural implications. PMID- 24465992 TI - Evolutionary conservation of divergent pro-inflammatory and homeostatic responses in Lamprey phagocytes. AB - In higher vertebrates, phagocytosis plays a critical role in development and immunity, based on the internalization and removal of apoptotic cells and invading pathogens, respectively. Previous studies describe the effective uptake of these particles by lower vertebrate and invertebrate phagocytes, and identify important molecular players that contribute to this internalization. However, it remains unclear if individual phagocytes mediate internalization processes in these ancient organisms, and how this impacts the balance of pro-inflammatory and homeostatic events within their infection sites. Herein we show that individual phagocytes of the jawless vertebrate Petromyzon marinus (sea lamprey), like those of teleost fish and mice, display the capacity for divergent pro-inflammatory and homeostatic responses following internalization of zymosan and apoptotic cells, respectively. Professional phagocytes (macrophages, monocytes, neutrophils) were the primary contributors to the internalization of pro-inflammatory particles among goldfish (C. auratus) and lamprey (P. marinus) hematopoietic leukocytes. However, goldfish showed a greater ability for zymosan phagocytosis when compared to their jawless counterparts. Coupled to this increase was a significantly lower sensitivity of goldfish phagocytes to homeostatic signals derived from apoptotic cell internalization. Together, this translated into a significantly greater capacity for induction of antimicrobial respiratory burst responses compared to lamprey phagocytes, but also a decreased efficacy in apoptotic cell-driven leukocyte homeostatic mechanisms that attenuate this pro-inflammatory process. Overall, our results show the long-standing evolutionary contribution of intrinsic phagocyte mechanisms for the control of inflammation, and illustrate one effective evolutionary strategy for increased responsiveness against invading pathogens. In addition, they highlight the need for development of complementary regulatory mechanisms of inflammation to ensure continued maintenance of host integrity amidst increasing challenges from invading pathogens. PMID- 24465991 TI - Altered response hierarchy and increased T-cell breadth upon HIV-1 conserved element DNA vaccination in macaques. AB - HIV sequence diversity and potential decoy epitopes are hurdles in the development of an effective AIDS vaccine. A DNA vaccine candidate comprising of highly conserved p24(gag) elements (CE) induced robust immunity in all 10 vaccinated macaques, whereas full-length gag DNA vaccination elicited responses to these conserved elements in only 5 of 11 animals, targeting fewer CE per animal. Importantly, boosting CE-primed macaques with DNA expressing full-length p55(gag) increased both magnitude of CE responses and breadth of Gag immunity, demonstrating alteration of the hierarchy of epitope recognition in the presence of pre-existing CE-specific responses. Inclusion of a conserved element immunogen provides a novel and effective strategy to broaden responses against highly diverse pathogens by avoiding decoy epitopes, while focusing responses to critical viral elements for which few escape pathways exist. PMID- 24465993 TI - A dietary test of putative deleterious sterols for the aphid Myzus persicae. AB - The aphid Myzus persicae displays high mortality on tobacco plants bearing a transgene which results in the accumulation of the ketosteroids cholestan-3-one and cholest-4-en-3-one in the phloem sap. To test whether the ketosteroids are the basis of the plant resistance to the aphids, M. persicae were reared on chemically-defined diets with different steroid contents at 0.1-10 ug ml(-1). Relative to sterol-free diet and dietary supplements of the two ketosteroids and two phytosterols, dietary cholesterol significantly extended aphid lifespan and increased fecundity at one or more dietary concentrations tested. Median lifespan was 50% lower on the diet supplemented with cholest-4-en-3-one than on the cholesterol-supplemented diet. Aphid feeding rate did not vary significantly across the treatments, indicative of no anti-feedant effect of any sterol/steroid. Aphids reared on diets containing equal amounts of cholesterol and cholest-4-en-3-one showed fecundity equivalent to aphids on diets containing only cholesterol. Aphids were reared on diets that reproduced the relative steroid abundance in the phloem sap of the control and modified tobacco plants, and their performance on the two diet formulations was broadly equivalent. We conclude that, at the concentrations tested, plant ketosteroids support weaker aphid performance than cholesterol, but do not cause acute toxicity to the aphids. In plants, the ketosteroids may act synergistically with plant factors absent from artificial diets but are unlikely to be solely responsible for resistance of modified tobacco plants. PMID- 24465994 TI - Association of structural global brain network properties with intelligence in normal aging. AB - Higher general intelligence attenuates age-associated cognitive decline and the risk of dementia. Thus, intelligence has been associated with cognitive reserve or resilience in normal aging. Neurophysiologically, intelligence is considered as a complex capacity that is dependent on a global cognitive network rather than isolated brain areas. An association of structural as well as functional brain network characteristics with intelligence has already been reported in young adults. We investigated the relationship between global structural brain network properties, general intelligence and age in a group of 43 cognitively healthy elderly, age 60-85 years. Individuals were assessed cross-sectionally using Wechsler Adult Intelligence Scale-Revised (WAIS-R) and diffusion-tensor imaging. Structural brain networks were reconstructed individually using deterministic tractography, global network properties (global efficiency, mean shortest path length, and clustering coefficient) were determined by graph theory and correlated to intelligence scores within both age groups. Network properties were significantly correlated to age, whereas no significant correlation to WAIS-R was observed. However, in a subgroup of 15 individuals aged 75 and above, the network properties were significantly correlated to WAIS-R. Our findings suggest that general intelligence and global properties of structural brain networks may not be generally associated in cognitively healthy elderly. However, we provide first evidence of an association between global structural brain network properties and general intelligence in advanced elderly. Intelligence might be affected by age associated network deterioration only if a certain threshold of structural degeneration is exceeded. Thus, age-associated brain structural changes seem to be partially compensated by the network and the range of this compensation might be a surrogate of cognitive reserve or brain resilience. PMID- 24465995 TI - A role for topographic cues in the organization of collagenous matrix by corneal fibroblasts and stem cells. AB - Human corneal fibroblasts (HCF) and corneal stromal stem cells (CSSC) each secrete and organize a thick stroma-like extracellular matrix in response to different substrata, but neither cell type organizes matrix on tissue-culture polystyrene. This study compared cell differentiation and extracellular matrix secreted by these two cell types when they were cultured on identical substrata, polycarbonate Transwell filters. After 4 weeks in culture, both cell types upregulated expression of genes marking differentiated keratocytes (KERA, CHST6, AQP1, B3GNT7). Absolute expression levels of these genes and secretion of keratan sulfate proteoglycans were significantly greater in CSSC than HCF. Both cultures produced extensive extracellular matrix of aligned collagen fibrils types I and V, exhibiting cornea-like lamellar structure. Unlike HCF, CSSC produced little matrix in the presence of serum. Construct thickness and collagen organization was enhanced by TGF-beta3. Scanning electron microscopic examination of the polycarbonate membrane revealed shallow parallel grooves with spacing of 200-300 nm, similar to the topography of aligned nanofiber substratum which we previously showed to induce matrix organization by CSSC. These results demonstrate that both corneal fibroblasts and stromal stem cells respond to a specific pattern of topographical cues by secreting highly organized extracellular matrix typical of corneal stroma. The data also suggest that the potential for matrix secretion and organization may not be directly related to the expression of molecular markers used to identify differentiated keratocytes. PMID- 24465996 TI - Variability in seroprevalence of rabies virus neutralizing antibodies and associated factors in a Colorado population of big brown bats (Eptesicus fuscus). AB - In 2001-2005 we sampled permanently marked big brown bats (Eptesicus fuscus) at summer roosts in buildings at Fort Collins, Colorado, for rabies virus neutralizing antibodies (RVNA). Seroprevalence was higher in adult females (17.9%, n = 2,332) than males (9.4%, n = 128; P = 0.007) or volant juveniles (10.2%, n = 738; P<0.0001). Seroprevalence was lowest in a drought year with local insecticide use and highest in the year with normal conditions, suggesting that environmental stress may suppress RVNA production in big brown bats. Seroprevalence also increased with age of bat, and varied from 6.2 to 26.7% among adult females at five roosts sampled each year for five years. Seroprevalence of adult females at 17 other roosts sampled for 1 to 4 years ranged from 0.0 to 47.1%. Using logistic regression, the only ranking model in our candidate set of explanatory variables for serological status at first sampling included year, day of season, and a year by day of season interaction that varied with relative drought conditions. The presence or absence of antibodies in individual bats showed temporal variability. Year alone provided the best model to explain the likelihood of adult female bats showing a transition to seronegative from a previously seropositive state. Day of the season was the only competitive model to explain the likelihood of a transition from seronegative to seropositive, which increased as the season progressed. We found no rabies viral RNA in oropharyngeal secretions of 261 seropositive bats or in organs of 13 euthanized seropositive bats. Survival of seropositive and seronegative bats did not differ. The presence of RVNA in serum of bats should not be interpreted as evidence for ongoing rabies infection. PMID- 24465997 TI - Associations between quantitative mobility measures derived from components of conventional mobility testing and Parkinsonian gait in older adults. AB - OBJECTIVE: To provide objective measures which characterize mobility in older adults assessed in the community setting and to examine the extent to which these measures are associated with parkinsonian gait. METHODS: During conventional mobility testing in the community-setting, 351 ambulatory non-demented Memory and Aging Project participants wore a belt with a whole body sensor that recorded both acceleration and angular velocity in 3 directions. We used measures derived from these recordings to quantify 5 subtasks including a) walking, b) transition from sit to stand, c) transition from stand to sit, d) turning and e) standing posture. Parkinsonian gait and other mild parkinsonian signs were assessed with a modified version of the original Unified Parkinson's Disease Rating Scale (mUPDRS). RESULTS: In a series of separate regression models which adjusted for age and sex, all 5 mobility subtask measures were associated with parkinsonian gait and accounted for 2% to 32% of its variance. When all 5 subtask measures were considered in a single model, backward elimination showed that measures of walking sit to stand and turning showed independent associations with parkinsonian gait and together accounted for more than 35% of its variance. Cross validation using data from a 2(nd) group of 258 older adults showed similar results. In similar analyses, only walking was associated with bradykinesia and sway with tremor. INTERPRETATION: Quantitative mobility subtask measures vary in their associations with parkinsonian gait scores and other parkinsonian signs in older adults. Quantifying the different facets of mobility has the potential to facilitate the clinical characterization and understanding the biologic basis for impaired mobility in older adults. PMID- 24465998 TI - Evaluating the status of African wild dogs Lycaon pictus and cheetahs Acinonyx jubatus through tourist-based photographic surveys in the Kruger National Park [corrected]. AB - The Kruger National Park is a stronghold for African wild dog Lycaon pictus and cheetah Acinonyx jubatus conservation in South Africa. Tourist photographic surveys have been used to evaluate the minimum number of wild dogs and cheetahs alive over the last two decades. Photographic-based capture-recapture techniques for open populations were used on data collected during a survey done in 2008/9. Models were run for the park as a whole and per region (northern, central, southern). A total of 412 (329-495; SE 41.95) cheetahs and 151 (144-157; SE 3.21) wild dogs occur in the Kruger National Park. Cheetah capture probabilities were affected by time (number of entries) and sex, whereas wild dog capture probabilities were affected by the region of the park. When plotting the number of new individuals identified against the number of entries received, the addition of new wild dogs to the survey reached an asymptote at 210 entries, but cheetahs did not reach an asymptote. The cheetah population of Kruger appears to be acceptable, while the wild dog population size and density are of concern. The effectiveness of tourist-based surveys for estimating population sizes through capture-recapture analyses is shown. PMID- 24465999 TI - Glycerol affects root development through regulation of multiple pathways in Arabidopsis. AB - Glycerol metabolism has been well studied biochemically. However, the means by which glycerol functions in plant development is not well understood. This study aimed to investigate the mechanism underlying the effects of glycerol on root development in Arabidopsis thaliana. Exogenous glycerol inhibited primary root growth and altered lateral root development in wild-type plants. These phenotypes appeared concurrently with increased endogenous glycerol-3-phosphate (G3P) and H2O2 contents in seedlings, and decreased phosphate levels in roots. Upon glycerol treatment, G3P level and root development did not change in glycerol kinase mutant gli1, but G3P level increased in gpdhc1 and fad-gpdh mutants, which resulted in more severely impaired root development. Overexpression of the FAD GPDH gene attenuated the alterations in G3P, phosphate and H2O2 levels, leading to increased tolerance to exogenous glycerol, which suggested that FAD-GPDH plays an important role in modulating this response. Free indole-3-acetic acid (IAA) content increased by 46%, and DR5pro::GUS staining increased in the stele cells of the root meristem under glycerol treatment, suggesting that glycerol likely alters normal auxin distribution. Decreases in PIN1 and PIN7 expression, beta glucuronidase (GUS) staining in plants expressing PIN7pro::GUS and green fluorescent protein (GFP) fluorescence in plants expressing PIN7pro::PIN7-GFP were observed, indicating that polar auxin transport in the root was downregulated under glycerol treatment. Analyses with auxin-related mutants showed that TIR1 and ARF7 were involved in regulating root growth under glycerol treatment. Glycerol-treated plants showed significant reductions in root meristem size and cell number as revealed by CYCB1;1pro::GUS staining. Furthermore, the expression of CDKA and CYCB1 decreased significantly in treated plants compared with control plants, implying possible alterations in cell cycle progression. Our data demonstrated that glycerol treatment altered endogenous levels of G3P, phosphate and ROS, affected auxin distribution and cell division in the root meristem, and eventually resulted in modifications of root development. PMID- 24466000 TI - Participation of Candida albicans transcription factor RLM1 in cell wall biogenesis and virulence. AB - Candida albicans cell wall is important for growth and interaction with the environment. RLM1 is one of the putative transcription factors involved in the cell wall integrity pathway, which plays an important role in the maintenance of the cell wall integrity. In this work we investigated the involvement of RLM1 in the cell wall biogenesis and in virulence. Newly constructed C. albicans Delta/Deltarlm1 mutants showed typical cell wall weakening phenotypes, such as hypersensitivity to Congo Red, Calcofluor White, and caspofungin (phenotype reverted in the presence of sorbitol), confirming the involvement of RLM1 in the cell wall integrity. Additionally, the cell wall of C. albicans Delta/Deltarlm1 showed a significant increase in chitin (213%) and reduction in mannans (60%), in comparison with the wild-type, results that are consistent with cell wall remodelling. Microarray analysis in the absence of any stress showed that deletion of RLM1 in C. albicans significantly down-regulated genes involved in carbohydrate catabolism such as DAK2, GLK4, NHT1 and TPS1, up-regulated genes involved in the utilization of alternative carbon sources, like AGP2, SOU1, SAP6, CIT1 or GAL4, and genes involved in cell adhesion like ECE1, ALS1, ALS3, HWP1 or RBT1. In agreement with the microarray results adhesion assays showed an increased amount of adhering cells and total biomass in the mutant strain, in comparison with the wild-type. C. albicans mutant Delta/Deltarlm1 strain was also found to be less virulent than the wild-type and complemented strains in the murine model of disseminated candidiasis. Overall, we showed that in the absence of RLM1 the modifications in the cell wall composition alter yeast interaction with the environment, with consequences in adhesion ability and virulence. The gene expression findings suggest that this gene participates in the cell wall biogenesis, with the mutant rearranging its metabolic pathways to allow the use of alternative carbon sources. PMID- 24466001 TI - Protein kinase C phosphomimetics alter thin filament Ca2+ binding properties. AB - Adrenergic stimulation modulates cardiac function by altering the phosphorylation status of several cardiac proteins. The Troponin complex, which is the Ca(2+) sensor for cardiac contraction, is a hot spot for adrenergic phosphorylation. While the effect of beta-adrenergic related PKA phosphorylation of troponin I at Ser23/24 is well established, the effects of alpha-adrenergic induced PKC phosphorylation on multiple sites of TnI (Ser43/45, Thr144) and TnT (Thr194, Ser198, Thr203 and Thr284) are much less clear. By utilizing an IAANS labeled fluorescent troponin C, TnC(IAANS)(T53C), we systematically examined the site specific effects of PKC phosphomimetic mutants of TnI and TnT on TnC's Ca(2+) binding properties in the Tn complex and reconstituted thin filament. The majority of the phosphomemetics had little effect on the Ca(2+) binding properties of the isolated Tn complex. However, when incorporated into the thin filament, the phosphomimetics typically altered thin filament Ca(2+) sensitivity in a way consistent with their respective effects on Ca(2+) sensitivity of skinned muscle preparations. The altered Ca(2+) sensitivity could be generally explained by a change in Ca(2+) dissociation rates. Within TnI, phosphomimetic Asp and Glu did not always behave similar, nor were Ala mutations (used to mimic non-phosphorylatable states) benign to Ca(2+) binding. Our results suggest that Troponin may act as a hub on the thin filament, sensing physiological stimuli to modulate the contractile performance of the heart. PMID- 24466002 TI - Weight loss and premature death: the 1946 British birth cohort study. AB - OBJECTIVE: The relationship between weight loss and mortality has important clinical and public health significance but has proved to be complex. Evidence is mixed and particularly limited on the association between weight loss in mid-life and premature death (i.e. before 65 years of age), a small albeit important segment of total mortality. We aimed to study the association between midlife weight change and mortality accounting for health and lifestyle characteristics, and also considering potential bias due to preexisting chronic diseases and smoking status. DESIGN: Longitudinal, population-based, 'the 1946 British' birth cohort study. SUBJECTS AND MEASURES: In 2750 men and women, mortality from age 53 through 65 years was analyzed according to categories of measured 10 year weight change between 43 and 53 years. Cox's hazard ratios (HR) were progressively adjusted for socio-demographic, lifestyle and health characteristics. RESULTS: Nearly 20% of participants lost weight and over 50% gained 5 kg or more in midlife. There were 164 deaths. Compared to those who gained between 2 and 5 kg, those who lost 5 kg or more had an increased risk of premature death independently of midlife physical activity, socio-economic circumstances and educational attainment. This association was unaltered when highest weight loss (lost more than 15 Kg) (p = 0.04) and early deaths were excluded (p<0.001), but was no longer significant after adjustment for cardiovascular risk factors and health status (HR = 1.8; 95% CI: 0.9 to 3.5). CONCLUSION: The inverse association between weight loss in midlife and higher risk of premature death may be explained by vascular risk factors and ill health. In consideration of the burden of premature death, closer monitoring of weight loss in mid-life is warranted. PMID- 24466004 TI - Severity-based adaptation with limited data for ASR to aid dysarthric speakers. AB - Automatic speech recognition (ASR) is currently used in many assistive technologies, such as helping individuals with speech impairment in their communication ability. One challenge in ASR for speech-impaired individuals is the difficulty in obtaining a good speech database of impaired speakers for building an effective speech acoustic model. Because there are very few existing databases of impaired speech, which are also limited in size, the obvious solution to build a speech acoustic model of impaired speech is by employing adaptation techniques. However, issues that have not been addressed in existing studies in the area of adaptation for speech impairment are as follows: (1) identifying the most effective adaptation technique for impaired speech; and (2) the use of suitable source models to build an effective impaired-speech acoustic model. This research investigates the above-mentioned two issues on dysarthria, a type of speech impairment affecting millions of people. We applied both unimpaired and impaired speech as the source model with well-known adaptation techniques like the maximum likelihood linear regression (MLLR) and the constrained-MLLR(C-MLLR). The recognition accuracy of each impaired speech acoustic model is measured in terms of word error rate (WER), with further assessments, including phoneme insertion, substitution and deletion rates. Unimpaired speech when combined with limited high-quality speech-impaired data improves performance of ASR systems in recognising severely impaired dysarthric speech. The C-MLLR adaptation technique was also found to be better than MLLR in recognising mildly and moderately impaired speech based on the statistical analysis of the WER. It was found that phoneme substitution was the biggest contributing factor in WER in dysarthric speech for all levels of severity. The results show that the speech acoustic models derived from suitable adaptation techniques improve the performance of ASR systems in recognising impaired speech with limited adaptation data. PMID- 24466003 TI - Prenatal adversities and Latino children's autonomic nervous system reactivity trajectories from 6 months to 5 years of age. AB - The purpose of the study was to determine whether mothers' adversities experienced during early pregnancy are associated with offspring's autonomic nervous system (ANS) reactivity trajectories from 6 months to 5 years of age. This cohort study of primarily Latino families included maternal interviews at 13 14 weeks gestation about their experience of a range of adversities: father's absence, general social support, poverty level, and household density. ANS measures of heart rate, respiratory sinus arrhythmia (parasympathetic nervous system) and preejection period (sympathetic nervous system) were collected during resting and challenging conditions on children at 6 months and 1, 3.5 and 5 years of age. Reactivity measures were calculated as the mean of the responses to challenging conditions minus a resting condition. Fixed effects models were conducted for the 212 children with two or more timepoints of ANS measures. Interactions between maternal prenatal adversity levels and child age at time of ANS protocol were included in the models, allowing the calculation of separate trajectories or slopes for each level of adversity. Results showed no significant relations between mothers' prenatal socioeconomic or social support adversity and offspring's parasympathetic nervous system trajectories, but there was a statistically significant relationship between social support adversity and offspring's heart rate trajectories (p<.05) and a borderline significant relationship between socioeconomic adversity and offspring's sympathetic nervous system trajectories (p = .05). Children whose mothers experienced one, not two, social support adversity had the smallest increases in heart rate reactivity compared to children whose mothers experienced no adversity. The children whose mothers experienced no social support and no socioeconomic adversity had the largest increases in heart rate and preejection period respectively from 6 months to 5 years showing the most plasticity. Mothers' prenatal adverse experiences may program their children's physiologic trajectory to dampen their heart rate or sympathetic responsivity to challenging conditions. PMID- 24466005 TI - Mutation prevalence of cerebral cavernous malformation genes in Spanish patients. AB - OBJECTIVE: To study the molecular genetic and clinical features of cerebral cavernous malformations (CCM) in a cohort of Spanish patients. METHODS: We analyzed the CCM1, CCM2, and CCM3 genes by MLPA and direct sequencing of exons and intronic boundaries in 94 familial forms and 41 sporadic cases of CCM patients of Spanish extraction. When available, RNA studies were performed seeking for alternative or cryptic splicing. RESULTS: A total of 26 pathogenic mutations, 22 of which predict truncated proteins, were identified in 29 familial forms and in three sporadic cases. The repertoire includes six novel non-sense and frameshift mutations in CCM1 and CCM3. We also found four missense mutations, one of them located at the third NPXY motif of CCM1 and another one that leads to cryptic splicing of CCM1 exon 6. We found four genomic deletions with the loss of the whole CCM2 gene in one patient and a partial loss of CCM1and CCM2 genes in three other patients. Four families had mutations in CCM3. The results include a high frequency of intronic variants, although most of them localize out of consensus splicing sequences. The main symptoms associated to clinical debut consisted of cerebral haemorrhage, migraines and epileptic seizures. The rare co occurrence of CCM with Noonan and Chiari syndromes and delayed menarche is reported. CONCLUSIONS: Analysis of CCM genes by sequencing and MLPA has detected mutations in almost 35% of a Spanish cohort (36% of familial cases and 10% of sporadic patients). The results include 13 new mutations of CCM genes and the main clinical symptoms that deserves consideration in molecular diagnosis and genetic counselling of cerebral cavernous malformations. PMID- 24466006 TI - Ungulate browsing maintains shrub diversity in the absence of episodic disturbance in seasonally-arid conifer forest. AB - Ungulates exert a strong influence on the composition and diversity of vegetation communities. However, little is known about how ungulate browsing pressure interacts with episodic disturbances such as fire and stand thinning. We assessed shrub responses to variable browsing pressure by cattle and elk in fuels treated (mechanical removal of fuels followed by prescribed burning) and non-fuels treated forest sites in northeastern Oregon, US. Seven treatment paddocks were established at each site; three with cattle exclusion and low, moderate and high elk browsing pressure, three with elk exclusion and low, moderate and high cattle browsing pressure, and one with both cattle and elk exclusion. The height, cover and number of stems of each shrub species were recorded at multiple plots within each paddock at the time of establishment and six years later. Changes in shrub species composition over the six year period were explored using multivariate analyses. Generalized Linear Mixed Models were used to determine the effect of browsing pressure on the change in shrub diversity and evenness. Vegetation composition in un-browsed paddocks changed more strongly and in different trajectories than in browsed paddocks at sites that were not fuels treated. In fuels treated sites, changes in composition were minimal for un-browsed paddocks. Shrub diversity and evenness decreased strongly in un-browsed paddocks relative to paddocks with low, moderate and high browsing pressure at non-fuels treated sites, but not at fuels treated sites. These results suggest that in the combined absence of fire, mechanical thinning and ungulate browsing, shrub diversity is reduced due to increased dominance by certain shrub species which are otherwise suppressed by ungulates and/or fuels removal. Accordingly, ungulate browsing, even at low intensities, can be used to suppress dominant shrub species and maintain diversity in the absence of episodic disturbance events. PMID- 24466007 TI - Secreted proteins from the helminth Fasciola hepatica inhibit the initiation of autoreactive T cell responses and prevent diabetes in the NOD mouse. AB - Infections with helminth parasites prevent/attenuate auto-inflammatory disease. Here we show that molecules secreted by a helminth parasite could prevent Type 1 Diabetes (T1D) in nonobese diabetic (NOD) mice. When delivered at 4 weeks of age (coincident with the initiation of autoimmunity), the excretory/secretory products of Fasciola hepatica (FhES) prevented the onset of T1D, with 84% of mice remaining normoglycaemic and insulitis-free at 30 weeks of age. Disease protection was associated with suppression of IFN-gamma secretion from autoreactive T cells and a switch to the production of a regulatory isotype (from IgG2a to IgG1) of autoantibody. Following FhES injection, peritoneal macrophages converted to a regulatory M2 phenotype, characterised by increased expression levels of Ym1, Arg-1, TGFbeta and PD-L1. Expression of these M2 genetic markers increased in the pancreatic lymph nodes and the pancreas of FhES-treated mice. In vitro, FhES-stimulated M2 macrophages induced the differentiation of Tregs from splenocytes isolated from naive NOD mice. Collectively, our data shows that FhES contains immune-modulatory molecules that mediate protection from autoimmune diabetes via the induction and maintenance of a regulatory immune environment. PMID- 24466008 TI - Near infrared spectroscopy study of the frontopolar hemodynamic response and depressive mood in children with major depressive disorder: a pilot study. AB - AIM: The aim of this study was to evaluate the frontopolar hemodynamic response and depressive mood in children with mild or moderate major depressive disorder during six weeks treatment without medication. METHODS: The subjects were 10 patients with mild or moderate depression. They were depressive drug-naive children and adolescents. The scores of Depression Self Rating Scale (DSRS), the results of the Verbal Fluency Test (VFT), and the concentrations of oxy hemoglobin (Oxy-Hb) of frontal pole brain assessed by two-channel near infrared spectroscopy (NIRS) after six weeks of treatment was compared with those of initial treatment. RESULTS: The score of DSRS was significantly reduced after six weeks of initial treatment (p<0.001, t-test). The word number of VFT was not significantly changed after six weeks of treatment. The oxy-Hb concentration significantly increased after six weeks of treatment (p<0.001, t-test). CONCLUSIONS: This study demonstrated that the concentration of oxy-Hb of frontopolar cortex in children with mild and moderate depression improved along with their depressive mood. These results suggested that concentration of oxy-Hb using NIRS may be used as the state maker for change in depressive mood of children having depression, similar to that in adults. PMID- 24466009 TI - Parrotfish size: a simple yet useful alternative indicator of fishing effects on Caribbean reefs? AB - There is great need to identify simple yet reliable indicators of fishing effects within the multi-species, multi-gear, data-poor fisheries of the Caribbean. Here, we investigate links between fishing pressure and three simple fish metrics, i.e. average fish weight (an estimate of average individual fish size), fish density and fish biomass, derived from (1) the parrotfish family, a ubiquitous herbivore family across the Caribbean, and (2) three fish groups of "commercial" carnivores including snappers and groupers, which are widely-used as indicators of fishing effects. We hypothesize that, because most Caribbean reefs are being heavily fished, fish metrics derived from the less vulnerable parrotfish group would exhibit stronger relationships with fishing pressure on today's Caribbean reefs than those derived from the highly vulnerable commercial fish groups. We used data from 348 Atlantic and Gulf Rapid Reef Assessment (AGRRA) reef-surveys across the Caribbean to assess relationships between two independent indices of fishing pressure (one derived from human population density data, the other from open to fishing versus protected status) and the three fish metrics derived from the four aforementioned fish groups. We found that, although two fish metrics, average parrotfish weight and combined biomass of selected commercial species, were consistently negatively linked to the indices of fishing pressure across the Caribbean, the parrotfish metric consistently outranked the latter in the strength of the relationship, thus supporting our hypothesis. Overall, our study highlights that (assemblage-level) average parrotfish size might be a useful alternative indicator of fishing effects over the typical conditions of most Caribbean shallow reefs: moderate-to-heavy levels of fishing and low abundance of highly valued commercial species. PMID- 24466010 TI - LcMYB1 is a key determinant of differential anthocyanin accumulation among genotypes, tissues, developmental phases and ABA and light stimuli in Litchi chinensis. AB - The red coloration of litchi fruit depends on the accumulation of anthocyanins. The anthocyanins level in litchi fruit varies widely among cultivars, developmental stages and environmental stimuli. Previous studies on various plant species demonstrate that anthocyanin biosynthesis is controlled at the transcriptional level. Here, we describe a litchi R2R3-MYB transcription factor gene, LcMYB1, which demonstrates a similar sequence as other known anthocyanin regulators. The transcription levels of the LcMYB1 and anthocyanin biosynthetic genes were investigated in samples with different anthocyanin levels. The expression of LcMYB1 was strongly associated with tissue anthocyanin content. LcMYB1 transcripts were only detected in anthocyanin-accumulating tissues and were positively correlated with anthocyanin accumulation in the pericarps of 12 genotypes. ABA and sunlight exposure promoted, whereas CPPU and bagging inhibited the expression of LcMYB1 and anthocyanin accumulation in the pericarp. Cis elements associated with light responsiveness and abscisic acid responsiveness were identified in the promoter region of LcMYB1. Among the 6 structural genes tested, only LcUFGT was highly correlated with LcMYB1. These results suggest that LcMYB1 controls anthocyanin biosynthesis in litchi and LcUFGT might be the structural gene that is targeted and regulated by LcMYB1. Furthermore, the overexpression of LcMYB1 induced anthocyanin accumulation in all tissues in tobacco, confirming the function of LcMYB1 in the regulation of anthocyanin biosynthesis. The upregulation of NtAn1b in response to LcMYB1 overexpression seems to be essential for anthocyanin accumulation in the leaf and pedicel. In the reproductive tissues of transgenic tobacco, however, increased anthocyanin accumulation is independent of tobacco's endogenous MYB and bHLH transcriptional factors, but associated with the upregulation of specific structural genes. PMID- 24466011 TI - Long non-coding RNA H19 promotes glioma cell invasion by deriving miR-675. AB - H19 RNA has been characterized as an oncogenic long non-coding RNA (lncRNA) in breast and colon cancer. However, the role and function of lncRNA H19 in glioma development remain unclear. In this study, we identified that H19/miR-675 signaling was critical for glioma progression. By analyzing glioma gene expression data sets, we found increased H19 in high grade gliomas. H19 depletion via siRNA inhibited invasion in glioma cells. Further, we found H19 positively correlated with its derivate miR-675 expression and reduction of H19 inhibited miR-675 expression. Bioinformatics and luciferase reporter assays showed that miR 675 modulated Cadherin 13 expression by directly targeting the binding site within the 3' UTR. Finally, introduction of miR-675 abrogated H19 knockdown induced cell invasion inhibition in glioma cells. To our knowledge, it is first time to demonstrate that H19 regulates glioma development by deriving miR-675 and provide important clues for understanding the key roles of lncRNA-miRNA functional network in glioma. PMID- 24466012 TI - Transcriptomic analysis of liquid non-sporulating Streptomyces coelicolor cultures demonstrates the existence of a complex differentiation comparable to that occurring in solid sporulating cultures. AB - Streptomyces species produce many clinically relevant secondary metabolites and exhibit a complex development that includes hyphal differentiation and sporulation in solid cultures. Industrial fermentations are usually performed in liquid cultures, conditions in which Streptomyces strains generally do not sporulate, and it was traditionally assumed that no differentiation took place. The aim of this work was to compare the transcriptomes of S. coelicolor growing in liquid and solid cultures, deepening the knowledge of Streptomyces differentiation. Microarrays demonstrated that gene expression in liquid and solid cultures were comparable and data indicated that physiological differentiation was similar for both conditions. Eighty-six percent of all transcripts showed similar abundances in liquid and solid cultures, such as those involved in the biosynthesis of actinorhodin (actVA, actII-4) and undecylprodigiosin (redF); activation of secondary metabolism (absR1, ndsA); genes regulating hydrophobic cover formation (aerial mycelium) (bldB, bldC, bldM, bldN, sapA, chpC, chpD, chpE, chpH, ramA, ramC, ramS); and even some genes regulating early stages of sporulation (wblA, whiG, whiH, whiJ). The two most important differences between transcriptomes from liquid and solid cultures were: first, genes related to secondary metabolite biosynthesis (CDA, CPK, coelichelin, desferrioxamine clusters) were highly up-regulated in liquid but not in solid cultures; and second, genes involved in the final stages of hydrophobic cover/spore maturation (chpF, rdlA, whiE, sfr) were up-regulated in solid but not in liquid cultures. New information was also provided for several non characterized genes differentially expressed in liquid and solid cultures which might be regulating, at least in part, the metabolic and developmental differences observed between liquid and solid cultures. PMID- 24466013 TI - Reduced renal alpha-Klotho expression in CKD patients and its effect on renal phosphate handling and vitamin D metabolism. AB - Renal alpha-Klotho (alpha-KL) plays a fundamental role as a co-receptor for fibroblast growth factor 23 (FGF23), a phosphaturic hormone and regulator of 1,25(OH)2 vitamin D3 (1,25VitD3). Disruption of FGF23-alpha-KL signaling is thought to be an early hallmark of chronic kidney disease (CKD) involving reduced renal alpha-KL expression and a reciprocal rise in serum FGF23. It remains unclear, however, whether the rise in FGF23 is related to the loss of renal alpha KL. We evaluated alpha-KL expression in renal biopsy samples and measured levels of several parameters of mineral metabolism, as well as soluble alpha-KL (sKL), in serum and urinary samples from CKD patients (n = 236). We found that although renal alpha-KL levels were significantly reduced and serum FGF23 levels were significantly elevated in early and intermediate CKD, serum phosphate levels remained within the normal range. Multiple regression analysis showed that the increases in FGF23 were significantly associated with reduced renal function and elevated serum phosphate, but were not associated with loss of renal alpha-KL. Moreover, despite falling renal alpha-KL levels, the increase in FGF23 enhanced urinary fractional excretion of phosphate and reduced serum 1,25VitD3 levels in early and intermediate CKD, though not in advanced CKD. Serum sKL levels also fell significantly over the course of CKD, and renal alpha-KL was a significant independent determinant of sKL. These results demonstrate that FGF23 levels rise to compensate for renal failure-related phosphate retention in early and intermediate CKD. This enables FGF23-alpha-KL signaling and a neutral phosphate balance to be maintained despite the reduction in alpha-KL. In advanced CKD, however, renal alpha-KL declines further. This disrupts FGF23 signaling, and serum phosphate levels significantly increase, stimulating greater FGF23 secretion. Our results also suggest the serum sKL concentration may be a useful marker of renal alpha-KL expression levels. PMID- 24466014 TI - Judging the difference between attractiveness and health: does exposure to model images influence the judgments made by men and women? AB - Recent research has shown facial adiposity (apparent weight in the face) to be a significant predictor of both attractiveness and health, thus making it an important determinant of mate selection. Studies looking at the relationship between attractiveness and health have shown that individuals differentiate between the two by preferring a lower weight for attractiveness than for health in female faces. However, these studies have either been correlational studies, or have investigated weight perceived from only the face. These differences have been discussed with regard to sociocultural factors such as pressure from parents, peers and also media, which has been seen to have the highest influence. While exposure to media images has been shown to influence women's own-body image, no study has yet directly tested the influence of these factors on people's preferred weight in other women's bodies. Here we examine how a short exposure to images of models influences men's and women's judgments of the most healthy looking and attractive BMI in Malaysian Chinese women's bodies by comparing differences in preferences (for attractiveness and health) between groups exposed to images of models of varying attractiveness and body weight. Results indicated that participants preferred a lower weight for attractiveness than for health. Further, women's but not men's preferred BMI for attractiveness, but not health, was influenced by the type of media images to which they were exposed, suggesting that short term exposure to model images affect women's perceptions of attractiveness but not health. PMID- 24466015 TI - Immuno-histochemical analysis of rod and cone reaction to RPE65 deficiency in the inferior and superior canine retina. AB - Mutations in the RPE65 gene are associated with autosomal recessive early onset severe retinal dystrophy. Morphological and functional studies indicate early and dramatic loss of rod photoreceptors and early loss of S-cone function, while L and M cones remain initially functional. The Swedish Briard dog is a naturally occurring animal model for this disease. Detailed information about rod and cone reaction to RPE65 deficiency in this model with regard to their location within the retina remains limited. The aim of this study was to analyze morphological parameters of cone and rod viability in young adult RPE65 deficient dogs in different parts of the retina in order to shed light on local disparities in this disease. In retinae of affected dogs, sprouting of rod bipolar cell dendrites and horizontal cell processes was dramatically increased in the inferior peripheral part of affected retinae, while central inferior and both superior parts did not display significantly increased sprouting. This observation was correlated with photoreceptor cell layer thickness. Interestingly, while L/M cone opsin expression was uniformly reduced both in the superior and inferior part of the retina, S-cone opsin expression loss was less severe in the inferior part of the retina. In summary, in retinae of young adult RPE65 deficient dogs, the degree of rod bipolar and horizontal cell sprouting as well as of S-cone opsin expression depends on the location. As the human retinal pigment epithelium (RPE) is pigmented similar to the RPE in the inferior part of the canine retina, and the kinetics of photoreceptor degeneration in humans seems to be similar to what has been observed in the inferior peripheral retina in dogs, this area should be studied in future gene therapy experiments in this model. PMID- 24466016 TI - Genetic structure, linkage disequilibrium and association mapping of Verticillium wilt resistance in elite cotton (Gossypium hirsutum L.) germplasm population. AB - Understanding the population structure and linkage disequilibrium in an association panel can effectively avoid spurious associations and improve the accuracy in association mapping. In this study, one hundred and fifty eight elite cotton (Gossypium hirsutum L.) germplasm from all over the world, which were genotyped with 212 whole genome-wide marker loci and phenotyped with an disease nursery and greenhouse screening method, were assayed for population structure, linkage disequilibrium, and association mapping of Verticillium wilt resistance. A total of 480 alleles ranging from 2 to 4 per locus were identified from all collections. Model-based analysis identified two groups (G1 and G2) and seven subgroups (G1a-c, G2a-d), and differentiation analysis showed that subgroup having a single origin or pedigree was apt to differentiate with those having a mixed origin. Only 8.12% linked marker pairs showed significant LD (P<0.001) in this association panel. The LD level for linked markers is significantly higher than that for unlinked markers, suggesting that physical linkage strongly influences LD in this panel, and LD level was elevated when the panel was classified into groups and subgroups. The LD decay analysis for several chromosomes showed that different chromosomes showed a notable change in LD decay distances for the same gene pool. Based on the disease nursery and greenhouse environment, 42 marker loci associated with Verticillium wilt resistance were identified through association mapping, which widely were distributed among 15 chromosomes. Among which 10 marker loci were found to be consistent with previously identified QTLs and 32 were new unreported marker loci, and QTL clusters for Verticillium wilt resistanc on Chr.16 were also proved in our study, which was consistent with the strong linkage in this chromosome. Our results would contribute to association mapping and supply the marker candidates for marker-assisted selection of Verticillium wilt resistance in cotton. PMID- 24466017 TI - Genome-wide DNA polymorphisms in seven rice cultivars of temperate and tropical japonica groups. AB - Elucidation of the rice genome is expected to broaden our understanding of genes related to the agronomic characteristics and the genetic relationship among cultivars. In this study, we conducted whole-genome sequencings of 6 cultivars, including 5 temperate japonica cultivars and 1 tropical japonica cultivar (Moroberekan), by using next-generation sequencing (NGS) with Nipponbare genome as a reference. The temperate japonica cultivars contained 2 sake brewing (Yamadanishiki and Gohyakumangoku), 1 landrace (Kameji), and 2 modern cultivars (Koshihikari and Norin 8). Almost >83% of the whole genome sequences of the Nipponbare genome could be covered by sequenced short-reads of each cultivar, including Omachi, which has previously been reported to be a temperate japonica cultivar. Numerous single nucleotide polymorphisms (SNPs), insertions, and deletions were detected among the various cultivars and the Nipponbare genomes. Comparison of SNPs detected in each cultivar suggested that Moroberekan had 5 fold more SNPs than the temperate japonica cultivars. Success of the 2 approaches to improve the efficacy of sequence data by using NGS revealed that sequencing depth was directly related to sequencing coverage of coding DNA sequences: in excess of 30* genome sequencing was required to cover approximately 80% of the genes in the rice genome. Further, the contigs prepared using the assembly of unmapped reads could increase the value of NGS short-reads and, consequently, cover previously unavailable sequences. These approaches facilitated the identification of new genes in coding DNA sequences and the increase of mapping efficiency in different regions. The DNA polymorphism information between the 7 cultivars and Nipponbare are available at NGRC_Rices_Build1.0 (http://www.nodai genome.org/oryza_sativa_en.html). PMID- 24466018 TI - Population pharmacodynamic modeling and simulation of the respiratory effect of acetazolamide in decompensated COPD patients. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) patients may develop metabolic alkalosis during weaning from mechanical ventilation. Acetazolamide is one of the treatments used to reverse metabolic alkalosis. METHODS: 619 time respiratory (minute ventilation, tidal volume and respiratory rate) and 207 time PaCO2 observations were obtained from 68 invasively ventilated COPD patients. We modeled respiratory responses to acetazolamide in mechanically ventilated COPD patients and then simulated the effect of increased amounts of the drug. RESULTS: The effect of acetazolamide on minute ventilation and PaCO2 levels was analyzed using a nonlinear mixed effect model. The effect of different ventilatory modes was assessed on the model. Only slightly increased minute ventilation without decreased PaCO2 levels were observed in response to 250 to 500 mg of acetazolamide administered twice daily. Simulations indicated that higher acetazolamide dosage (>1000 mg daily) was required to significantly increase minute ventilation (P<.001 vs pre-acetazolamide administration). Based on our model, 1000 mg per day of acetazolamide would increase minute ventilation by >0.75 L min(-1) in 60% of the population. The model also predicts that 45% of patients would have a decrease of PaCO2>5 mmHg with doses of 1000 mg per day. CONCLUSIONS: Simulations suggest that COPD patients might benefit from the respiratory stimulant effect after the administration of higher doses of acetazolamide. PMID- 24466019 TI - Comparison of classifiers for decoding sensory and cognitive information from prefrontal neuronal populations. AB - Decoding neuronal information is important in neuroscience, both as a basic means to understand how neuronal activity is related to cerebral function and as a processing stage in driving neuroprosthetic effectors. Here, we compare the readout performance of six commonly used classifiers at decoding two different variables encoded by the spiking activity of the non-human primate frontal eye fields (FEF): the spatial position of a visual cue, and the instructed orientation of the animal's attention. While the first variable is exogenously driven by the environment, the second variable corresponds to the interpretation of the instruction conveyed by the cue; it is endogenously driven and corresponds to the output of internal cognitive operations performed on the visual attributes of the cue. These two variables were decoded using either a regularized optimal linear estimator in its explicit formulation, an optimal linear artificial neural network estimator, a non-linear artificial neural network estimator, a non-linear naive Bayesian estimator, a non-linear Reservoir recurrent network classifier or a non-linear Support Vector Machine classifier. Our results suggest that endogenous information such as the orientation of attention can be decoded from the FEF with the same accuracy as exogenous visual information. All classifiers did not behave equally in the face of population size and heterogeneity, the available training and testing trials, the subject's behavior and the temporal structure of the variable of interest. In most situations, the regularized optimal linear estimator and the non-linear Support Vector Machine classifiers outperformed the other tested decoders. PMID- 24466020 TI - Clinical characteristics and treatment outcomes of patients with low- and high concentration isoniazid-monoresistant tuberculosis. AB - BACKGROUND: Isoniazid (INH) resistance is now the most common type of tuberculosis (TB) infection resistance worldwide. The aim of this study was to evaluate the clinical characteristics and treatment outcomes of patients with low and high-concentration INH-monoresistant TB. METHODS: One hundred and thirty four patients with culture-confirmed INH-monoresistant TB during 2006 January to 2007 December were retrospectively enrolled. INH resistance was classified as either low-concentration or high-concentration resistance according to the critical concentrations of 0.2 ug/mL or 1 ug/mL of INH, respectively. The patients' clinical outcomes, treatment regimens, and treatment duration were analyzed. RESULTS: The treatment success rates between low- and high concentration INH-resistant TB were similar (81.8% vs. 86.7%). The treatment regimens and treatment duration were similar between both groups. Only a minor percentage of the patients in both groups received 6-month treatment regimens (low vs. high concentration resistance, 9.1% vs. 13.3%; respectively, p = 0.447) The most common reason for treatment duration longer than 6 months was pyrazinamide given for less than 6 months, followed by a delay in clinical response to treatment. Multivariable analysis showed that prior tuberculosis treatment (Odds ratio, 2.82, 95% C.I., 1.02-7.77, p = 0.045) was the only independent risk factor for unsuccessful treatment outcome. CONCLUSION: Different levels of INH resistance did not affect the treatment outcomes of patients with INH-monoresistant tuberculosis. Prolonged Rifampin-containing regimens may achieve those good outcomes in patients with low- and high-concentration INH monoresistant TB. PMID- 24466021 TI - CoryneBase: Corynebacterium genomic resources and analysis tools at your fingertips. AB - Corynebacteria are used for a wide variety of industrial purposes but some species are associated with human diseases. With increasing number of corynebacterial genomes having been sequenced, comparative analysis of these strains may provide better understanding of their biology, phylogeny, virulence and taxonomy that may lead to the discoveries of beneficial industrial strains or contribute to better management of diseases. To facilitate the ongoing research of corynebacteria, a specialized central repository and analysis platform for the corynebacterial research community is needed to host the fast-growing amount of genomic data and facilitate the analysis of these data. Here we present CoryneBase, a genomic database for Corynebacterium with diverse functionality for the analysis of genomes aimed to provide: (1) annotated genome sequences of Corynebacterium where 165,918 coding sequences and 4,180 RNAs can be found in 27 species; (2) access to comprehensive Corynebacterium data through the use of advanced web technologies for interactive web interfaces; and (3) advanced bioinformatic analysis tools consisting of standard BLAST for homology search, VFDB BLAST for sequence homology search against the Virulence Factor Database (VFDB), Pairwise Genome Comparison (PGC) tool for comparative genomic analysis, and a newly designed Pathogenomics Profiling Tool (PathoProT) for comparative pathogenomic analysis. CoryneBase offers the access of a range of Corynebacterium genomic resources as well as analysis tools for comparative genomics and pathogenomics. It is publicly available at http://corynebacterium.um.edu.my/. PMID- 24466022 TI - On the heat stability of amyloid-based biological activity: insights from thermal degradation of insulin fibrils. AB - Formation of amyloid fibrils in vivo has been linked to disorders such as Alzheimer's disease and prion-associated transmissible spongiform encephalopathies. One of the characteristic features of amyloid fibrils is the high thermodynamic stability relative both to native and disordered states which is also thought to underlie the perplexingly remarkable heat resistance of prion infectivity. Here, we are comparing high-temperature degradation of native and fibrillar forms of human insulin. Decomposition of insulin amyloid has been studied under helium atmosphere and in the temperature range from ambient conditions to 750 degrees C using thermogravimetry and differential scanning calorimetry coupled to mass spectrometry. While converting native insulin into amyloid does upshift onset of thermal decomposition by ca. 75 degrees C, fibrils remain vulnerable to covalent degradation at temperatures below 300 degrees C, as reflected by mass spectra of gases released upon heating of amyloid samples, as well as morphology and infrared spectra of fibrils subjected to incubation at 250 degrees C. Mass spectra profiles of released gases indicate that degradation of fibrils is much more cooperative than degradation of native insulin. The data show no evidence of water of crystallization trapped within insulin fibrils. We have also compared untreated and heated amyloid samples in terms of capacity to seed daughter fibrils. Kinetic traces of seed-induced insulin fibrillation have shown that the seeding potency of amyloid samples decreases significantly already after exposure to 200 degrees C, even though corresponding electron micrographs indicated persisting fibrillar morphology. Our results suggest that amyloid-based biological activity may not survive extremely high temperature treatments, at least in the absence of other stabilizing factors. PMID- 24466023 TI - Aggregation of human recombinant monoclonal antibodies influences the capacity of dendritic cells to stimulate adaptive T-cell responses in vitro. AB - Subvisible proteinaceous particles which are present in all therapeutic protein formulations are in the focus of intense discussions between health authorities, academics and biopharmaceutical companies in the context of concerns that such particles could promote unwanted immunogenicity via anti-drug antibody formation. In order to provide further understanding of the subject, this study closely examines the specific biological effects proteinaceous particles may exert on dendritic cells (DCs) as the most efficient antigen-presenting cell population crucial for the initiation of the adaptive immune response. Two different model IgG antibodies were subjected to three different types of exaggerated physical stress to generate subvisible particles in far greater concentrations than the ones typical for the currently marketed biotherapeutical antibodies. The aggregated samples were used in in vitro biological assays in order to interrogate the early DC-driven events that initiate CD4 T-cell dependent humoral adaptive immune responses--peptide presentation capacity and co-stimulatory activity of DCs. Most importantly, antigen presentation was addressed with a unique approach called MHC-associated Peptide Proteomics (MAPPs), which allows for identifying the sequences of HLA-DR associated peptides directly from human dendritic cells. The experiments demonstrated that highly aggregated solutions of two model mAbs generated under controlled conditions can induce activation of human monocyte-derived DCs as indicated by upregulation of typical maturation markers including co-stimulatory molecules necessary for CD4 T-cell activation. Additional data suggest that highly aggregated proteins could induce in vitro T cell responses. Intriguingly, strong aggregation-mediated changes in the pattern and quantity of antigen-derived HLA-DR associated peptides presented on DCs were observed, indicating a change in protein processing and presentation. Increasing the amounts of subvisible proteinaceous particles correlated very well with the pronounced increase in the peptide number and clusters presented in the context of class II HLA-DR molecules, suggesting a major involvement of a mass-action mechanism of altering the presentation. PMID- 24466024 TI - Impact of stakeholders influence, geographic level and risk perception on strategic decisions in simulated foot and mouth disease epizootics in France. AB - Comparison of control strategies against animal infectious diseases allows determining optimal strategies according to their epidemiological and/or economic impacts. However, in real life, the choice of a control strategy does not always obey a pure economic or epidemiological rationality. The objective of this study was to analyze the choice of a foot and mouth disease (FMD) control strategy as a decision-making process in which the decision-maker is influenced by several stakeholders (government, agro-food industries, public opinion). For each of these, an indicator of epizootic impact was quantified to compare seven control strategies. We then determined how, in France, the optimal control strategy varied according to the relative weights of stakeholders and to the perception of risk by the decision-maker (risk-neutral/risk-averse). When the scope of decision was national, whatever their perception of risk and the stakeholders' weights, decision-makers chose a strategy based on vaccination. This consensus concealed marked differences between regions, which were connected with the regional breeding characteristics. Vaccination-based strategies were predominant in regions with dense cattle and swine populations, and in regions with a dense population of small ruminants, combined with a medium density of cattle and swine. These differences between regions suggested that control strategies could be usefully adapted to local breeding conditions. We then analyzed the feasibility of adaptive decision-making processes depending on the date and place where the epizootic starts, or on the evolution of the epizootic over time. The initial conditions always explained at least half of the variance of impacts, the remaining variance being attributed to the variability of epizootics evolution. However, the first weeks of this evolution explained a large part of the impacts variability. Although the predictive value of the initial conditions for determining the optimal strategy was weak, adaptive strategies changing dynamically according to the evolution of the epizootic appeared feasible. PMID- 24466025 TI - Novel therapeutic approaches for various cancer types using a modified sleeping beauty-based gene delivery system. AB - Successful gene therapy largely depends on the selective introduction of therapeutic genes into the appropriate target cancer cells. One of the most effective and promising approaches for targeting tumor tissue during gene delivery is the use of viral vectors, which allow for high efficiency gene delivery. However, the use of viral vectors is not without risks and safety concerns, such as toxicities, a host immune response towards the viral antigens or potential viral recombination into the host's chromosome; these risks limit the clinical application of viral vectors. The Sleeping Beauty (SB) transposon based system is an attractive, non-viral alternative to viral delivery systems. SB may be less immunogenic than the viral vector system due to its lack of viral sequences. The SB-based gene delivery system can stably integrate into the host cell genome to produce the therapeutic gene product over the lifetime of a cell. However, when compared to viral vectors, the non-viral SB-based gene delivery system still has limited therapeutic efficacy due to the lack of long-lasting gene expression potential and tumor cell specific gene transfer ability. These limitations could be overcome by modifying the SB system through the introduction of the hTERT promoter and the SV40 enhancer. In this study, a modified SB delivery system, under control of the hTERT promoter in conjunction with the SV40 enhancer, was able to successfully transfer the suicide gene (HSV-TK) into multiple types of cancer cells. The modified SB transfected cancer cells exhibited a significantly increased cancer cell specific death rate. These data suggest that our modified SB-based gene delivery system can be used as a safe and efficient tool for cancer cell specific therapeutic gene transfer and stable long term expression. PMID- 24466026 TI - Functional connectivity between face-movement and speech-intelligibility areas during auditory-only speech perception. AB - It has been proposed that internal simulation of the talking face of visually known speakers facilitates auditory speech recognition. One prediction of this view is that brain areas involved in auditory-only speech comprehension interact with visual face-movement sensitive areas, even under auditory-only listening conditions. Here, we test this hypothesis using connectivity analyses of functional magnetic resonance imaging (fMRI) data. Participants (17 normal participants, 17 developmental prosopagnosics) first learned six speakers via brief voice-face or voice-occupation training (<2 min/speaker). This was followed by an auditory-only speech recognition task and a control task (voice recognition) involving the learned speakers' voices in the MRI scanner. As hypothesized, we found that, during speech recognition, familiarity with the speaker's face increased the functional connectivity between the face-movement sensitive posterior superior temporal sulcus (STS) and an anterior STS region that supports auditory speech intelligibility. There was no difference between normal participants and prosopagnosics. This was expected because previous findings have shown that both groups use the face-movement sensitive STS to optimize auditory-only speech comprehension. Overall, the present findings indicate that learned visual information is integrated into the analysis of auditory-only speech and that this integration results from the interaction of task-relevant face-movement and auditory speech-sensitive areas. PMID- 24466028 TI - Mitochondrial genome of the stonefly Kamimuria wangi (Plecoptera: Perlidae) and phylogenetic position of plecoptera based on mitogenomes. AB - This study determined the mitochondrial genome sequence of the stonefly, Kamimuria wangi. In order to investigate the relatedness of stonefly to other members of Neoptera, a phylogenetic analysis was undertaken based on 13 protein coding genes of mitochondrial genomes in 13 representative insects. The mitochondrial genome of the stonefly is a circular molecule consisting of 16,179 nucleotides and contains the 37 genes typically found in other insects. A 10-bp poly-T stretch was observed in the A+T-rich region of the K. wangi mitochondrial genome. Downstream of the poly-T stretch, two regions were located with potential ability to form stem-loop structures; these were designated stem-loop 1 (positions 15848-15651) and stem-loop 2 (15965-15998). The arrangement of genes and nucleotide composition of the K. wangi mitogenome are similar to those in Pteronarcys princeps, suggesting a conserved genome evolution within the Plecoptera. Phylogenetic analysis using maximum likelihood and Bayesian inference of 13 protein-coding genes supported a novel relationship between the Plecoptera and Ephemeroptera. The results contradict the existence of a monophyletic Plectoptera and Plecoptera as sister taxa to Embiidina, and thus requires further analyses with additional mitogenome sampling at the base of the Neoptera. PMID- 24466027 TI - Effects of varying degrees of intermittent hypoxia on proinflammatory cytokines and adipokines in rats and 3T3-L1 adipocytes. AB - OBJECTIVES: Intermittent hypoxia (IH), resulted from recurring episodes of upper airway obstruction, is the hallmark feature and the most important pathophysiologic pathway of obstructive sleep apnea (OSA). IH is believed to be the most important factor causing systemic inflammation. Studies suggest that insulin resistance (IR) is positively associated with OSA. In this study, we hypothesized that the recurrence of IH might result in cellular and systemic inflammation, which was manifested through the levels of proinflammatory cytokines and adipokines after IH exposure, and because IR is linked with inflammation tightly, this inflammatory situation may implicate an IR status. METHODS: We developed an IH 3T3-L1 adipocyte and rat model respectively, recapitulating the nocturnal oxygen profile in OSA. In IH cells, nuclear factor kappa B (NF-kappaB) DNA binding reactions, hypoxia-inducible factor-1alpha (HIF 1alpha), glucose transporter-1 (Glut-1), necrosis factor alpha (TNF-alpha), interleukin (IL) -6, leptin, adiponectin mRNA transcriptional activities and protein expressions were measured. In IH rats, blood glucose, insulin, TNF-alpha, IL-6, leptin and adiponectin levels were analyzed. RESULTS: The insulin and blood glucose levels in rats and NF-kappaB DNA binding activities in cells had significantly statistical results described as severe IH>moderate IH>mild IH>sustained hypoxia>control. The mRNA and protein levels of HIF-1alpha and Glut 1 in severe IH group were the highest. In cellular and animal models, both the mRNA and protein levels of TNF-alpha, IL-6 and leptin were the highest in severe IH group, when the lowest in severe IH group for adiponectin. CONCLUSIONS: Oxidative stress and the release of pro-inflammatory cytokines/adipokines, which are the systemic inflammatory markers, are associated with IH closely and are proportional to the severity of IH. Because IR and glucose intolerance are linked with inflammation tightly, our results may implicate the clinical relationships between OSA and IR. PMID- 24466029 TI - Investigation of radiosensitivity gene signatures in cancer cell lines. AB - Intrinsic radiosensitivity is an important factor underlying radiotherapy response, but there is no method for its routine assessment in human tumours. Gene signatures are currently being derived and some were previously generated by expression profiling the NCI-60 cell line panel. It was hypothesised that focusing on more homogeneous tumour types would be a better approach. Two cell line cohorts were used derived from cervix [n = 16] and head and neck [n = 11] cancers. Radiosensitivity was measured as surviving fraction following irradiation with 2 Gy (SF2) by clonogenic assay. Differential gene expression between radiosensitive and radioresistant cell lines (SF2 median) was investigated using Affymetrix GeneChip Exon 1.0ST (cervix) or U133A Plus2 (head and neck) arrays. There were differences within cell line cohorts relating to tissue of origin reflected by expression of the stratified epithelial marker p63. Of 138 genes identified as being associated with SF2, only 2 (1.4%) were congruent between the cervix and head and neck carcinoma cell lines (MGST1 and TFPI), and these did not partition the published NCI-60 cell lines based on SF2. There was variable success in applying three published radiosensitivity signatures to our cohorts. One gene signature, originally trained on the NCI-60 cell lines, did partially separate sensitive and resistant cell lines in all three cell line datasets. The findings do not confirm our hypothesis but suggest that a common transcriptional signature can reflect the radiosensitivity of tumours of heterogeneous origins. PMID- 24466030 TI - SHP-1 arrests mouse early embryo development through downregulation of Nanog by dephosphorylation of STAT3. AB - Src-homology protein tyrosine phosphatase-1 (SHP-1) is a protein tyrosine phosphatase that is implicated in the regulation of growth, differentiation, survival, apoptosis and proliferation of hematopoietic cells and other cell types. Here, we found that SHP-1 is involved in regulation of early embryonic development. Embryos overexpressing SHP-1 were mainly arrested at the 8-cell stage, and Nanog mRNA expression was first observed in the morulae that showed down-regulation of SHP-1. These results suggested an antagonistic relationship between SHP-1 and Nanog during early embryonic development. Next, the specific mechanism was examined in mouse F9 embryonal carcinoma cells. We confirmed that signal transducer and activator of transcription 3 (STAT3) was a substrate for SHP-1 by co-immunoprecipitation. Using overexpression and knockdown strategies, we found that SHP-1 participated in regulation of Nanog expression. Furthermore, site mutation of STAT3 was performed to confirm that SHP-1 was responsible for rapid STAT3 dephosphorylation and a decrease of Nanog expression in F9 cells. These findings suggest that SHP-1 plays a crucial role during early embryonic development. Thus, SHP-1 may function as a key regulator for Nanog that specifically demarcates the nascent epiblast, coincident with the domain of X chromosome reprogramming. PMID- 24466031 TI - The influence of topographic and dynamic cyclic variables on the distribution of small cetaceans in a shallow coastal system. AB - The influence of topographic and temporal variables on cetacean distribution at a fine-scale is still poorly understood. To study the spatial and temporal distribution of harbour porpoise Phocoena phocoena and the poorly known Risso's dolphin Grampus griseus we carried out land-based observations from Bardsey Island (Wales, UK) in summer (2001-2007). Using Kernel analysis and Generalized Additive Models it was shown that porpoises and Risso's appeared to be linked to topographic and dynamic cyclic variables with both species using different core areas (dolphins to the West and porpoises to the East off Bardsey). Depth, slope and aspect and a low variation in current speed (for Risso's) were important in explaining the patchy distributions for both species. The prime temporal conditions in these shallow coastal systems were related to the tidal cycle (Low Water Slack and the flood phase), lunar cycle (a few days following the neap tidal phase), diel cycle (afternoons) and seasonal cycle (peaking in August) but differed between species on a temporary but predictable basis. The measure of tidal stratification was shown to be important. Coastal waters generally show a stronger stratification particularly during neap tides upon which the phytoplankton biomass at the surface rises reaching its maximum about 2-3 days after neap tide. It appeared that porpoises occurred in those areas where stratification is maximised and Risso's preferred more mixed waters. This fine scale study provided a temporal insight into spatial distribution of two species that single studies conducted over broader scales (tens or hundreds of kilometers) do not achieve. Understanding which topographic and cyclic variables drive the patchy distribution of porpoises and Risso's in a Headland/Island system may form the initial basis for identifying potentially critical habitats for these species. PMID- 24466032 TI - Reduced peripheral expression of the glucocorticoid receptor alpha isoform in individuals with posttraumatic stress disorder: a cumulative effect of trauma burden. AB - BACKGROUND: Posttraumatic stress disorder (PTSD) is a serious psychiatric condition that was found to be associated with altered functioning of the hypothalamic-pituitary-adrenal (HPA) axis and changes in glucocorticoid (GC) responsiveness. The physiological actions of GCs are primarily mediated through GC receptors (GR) of which isoforms with different biological activities exist. This study aimed to investigate whether trauma-experience and/or PTSD are associated with altered expression of GR splice variants. METHODS: GRalpha and GRbeta mRNA expression levels were determined by real-time quantitative PCR in whole blood samples of individuals with chronic and severe forms of PTSD (n = 42) as well as in ethnically matched reference subjects (non-PTSD, n = 35). RESULTS: Individuals suffering from PTSD exhibited significantly lower expression of the predominant and functionally active GRalpha isoform compared to non-PTSD subjects. This effect remained significant when accounting for gender, smoking, psychotropic medication or comorbid depression. Moreover, the GRalpha expression level was significantly negatively correlated with the number of traumatic event types experienced, both in the whole sample and within the PTSD patient group. Expression of the less abundant and non-ligand binding GRbeta isoform was comparable between patient and reference groups. CONCLUSIONS: Reduced expression of the functionally active GRalpha isoform in peripheral blood cells of individuals with PTSD seems to be a cumulative effect of trauma burden rather than a specific feature of PTSD since non-PTSD subjects with high trauma load showed an intermediate phenotype between PTSD patients and individuals with no or few traumatic experiences. PMID- 24466033 TI - Effect of calcitonin gene-related peptide on the neurogenesis of rat adipose derived stem cells in vitro. AB - Calcitonin gene-related peptide (CGRP) promotes neuron recruitment and neurogenic activity. However, no evidence suggests that CGRP affects the ability of stem cells to differentiate toward neurogenesis. In this study, we genetically modified rat adipose-derived stem cells (ADSCs) with the CGRP gene (CGRP-ADSCs) and subsequently cultured in complete neural-induced medium. The formation of neurospheres, cellular morphology, and proliferative capacity of ADSCs were observed. In addition, the expression of the anti-apoptotic protein Bcl-2 and special markers of neural cells, such as Nestin, MAP2, RIP and GFAP, were evaluated using Western blot and immunocytochemistry analysis. The CGRP-ADSCs displayed a greater proliferation than un-transduced (ADSCs) and Vector transduced (Vector-ADSCs) ADSCs (p<0.05), and lower rates of apoptosis, associated with the incremental expression of Bcl-2, were also observed for CGRP ADSCs. Moreover, upon neural induction, CGRP-ADSCs formed markedly more and larger neurospheres and showed round cell bodies with more branching extensions contacted with neighboring cells widely. Furthermore, the expression levels of Nestin, MAP2, and RIP in CGRP-ADSCs were markedly increased, resulting in higher levels than the other groups (p<0.05); however, GFAP was distinctly undetectable until day 7, when slight GFAP expression was detected among all groups. Wnt signals, primarily Wnt 3a, Wnt 5a and beta-catenin, regulate the neural differentiation of ADSCs, and CGRP gene expression apparently depends on canonical Wnt signals to promote the neurogenesis of ADSCs. Consequently, ADSCs genetically modified with CGRP exhibit stronger potential for differentiation and neurogenesis in vitro, potentially reflecting the usefulness of ADSCs as seed cells in therapeutic strategies for spinal cord injury. PMID- 24466034 TI - Enhanced expression of WD repeat-containing protein 35 via nuclear factor-kappa B activation in bupivacaine-treated Neuro2a cells. AB - The family of WD repeat proteins comprises a large number of proteins and is involved in a wide variety of cellular processes such as signal transduction, cell growth, proliferation, and apoptosis. Bupivacaine is a sodium channel blocker administered for local infiltration, nerve block, epidural, and intrathecal anesthesia. Recently, we reported that bupivacaine induces reactive oxygen species (ROS) generation and p38 mitogen-activated protein kinase (MAPK) activation, resulting in an increase in the expression of WD repeat-containing protein 35 (WDR35) in mouse neuroblastoma Neuro2a cells. It has been shown that ROS activate MAPK through phosphorylation, followed by activation of nuclear factor-kappa B (NF-kappaB) and activator protein 1 (AP-1). The present study was undertaken to test whether NF-kappaB and c-Jun/AP-1 are involved in bupivacaine induced WDR35 expression in Neuro2a cells. Bupivacaine activated both NF-kappaB and c-Jun in Neuro2a cells. APDC, an NF-kappaB inhibitor, attenuated the increase in NF-kappaB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. GW9662, a selective peroxisome proliferator-activated receptor-gamma antagonist, enhanced the increase in NF-kappaB activity and WDR35 protein expression in bupivacaine-treated Neuro2a cells. In contrast, c-Jun siRNA did not inhibit the bupivacaine-induced increase in WDR35 mRNA expression. These results indicate that bupivacaine induces the activation of transcription factors NF kappaB and c-Jun/AP-1 in Neuro2a cells, while activation of NF-kappaB is involved in bupivacaine-induced increases in WDR35 expression. PMID- 24466035 TI - Human and mouse CD137 have predominantly different binding CRDs to their respective ligands. AB - Monoclonal antibodies (mAbs) to CD137 (a.k.a. 4-1BB) have anti-tumor efficacy in several animal models and have entered clinical trials in patients with advanced cancer. Importantly, anti-CD137 mAbs can also ameliorate autoimmunity in preclinical models. As an approach to better understand the action of agonistic and antagonistic anti-CD137 mAbs we have mapped the binding region of the CD137 ligand (CD137L) to human and mouse CD137. By investigating the binding of CD137L to cysteine rich domain II (CRDII )and CRDIII of CD137, we found that the binding interface was limited and differed between the two species in that mouse CD137L mainly combined with CRDII and human CD137L mainly combined with CRDIII. PMID- 24466036 TI - Fisetin inhibits human melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFkappaB signaling pathways. AB - Malignant melanoma is responsible for approximately 75% of skin cancer-related deaths. BRAF plays an important role in regulating the mitogen-activated protein kinase (MAPK) signaling cascade in melanoma with activating mutations in the serine/threonine kinase BRAF occurring in 60-70% of malignant melanomas. The BRAF MEK-ERK (MAPK) pathway is a key regulator of melanoma cell invasion. In addition, activation of NFkappaB via the MAPK pathway is regulated through MEK-induced activation of IKK. These pathways are potential targets for prevention and treatment of melanoma. In this study, we investigated the effect of fisetin, a phytochemical present in fruits and vegetables, on melanoma cell invasion and epithelial-mesenchymal transition, and delineated the underlying molecular mechanism. Treatment of multiple human malignant melanoma cell lines with fisetin (5-20 uM) resulted in inhibition of cell invasion. BRAF mutated melanoma cells were more sensitive to fisetin treatment, and this was associated with a decrease in the phosphorylation of MEK1/2 and ERK1/2. In addition, fisetin inhibited the activation of IKK leading to a reduction in the activation of the NFkappaB signaling pathway. Treatment of cells with an inhibitor of MEK1/2 (PD98059) or of NFkappaB (caffeic acid phenethyl ester) also reduced melanoma cell invasion. Furthermore, treatment of fisetin promoted mesenchymal to epithelial transition in melanoma cells, which was associated with a decrease in mesenchymal markers (N cadherin, vimentin, snail and fibronectin) and an increase in epithelial markers (E-cadherin and desmoglein). Employing three dimensional skin equivalents consisting of A375 cells admixed with normal human keratinocytes embedded onto a collagen-constricted fibroblast matrix, we found that treatment of fisetin reduced the invasive potential of melanoma cells into the dermis and increased the expression of E-cadherin with a concomitant decrease in vimentin. These results indicate that fisetin inhibits melanoma cell invasion through promotion of mesenchymal to epithelial transition and by targeting MAPK and NFkappaB signaling pathways. PMID- 24466037 TI - Low structural variation in the host-defense peptide repertoire of the dwarf clawed frog Hymenochirus boettgeri (Pipidae). AB - THE skin secretion of many amphibians contains peptides that are able to kill a broad range of microorganisms (antimicrobial peptides: AMPs) and potentially play a role in innate immune defense. Similar to the toxin arsenals of various animals, amphibian AMP repertoires typically show major structural variation, and previous studies have suggested that this may be the result of diversifying selection in adaptation to a diverse spectrum of pathogens. Here we report on transcriptome analyses that indicate a very different pattern in the dwarf clawed frog H. boettgeri. Our analyses reveal a diverse set of transcripts containing two to six tandem repeats, together encoding 14 distinct peptides. Five of these have recently been identified as AMPs, while three more are shown here to potently inhibit the growth of gram-negative bacteria, including multi-drug resistant strains of the medically important Pseudomonas aeruginosa. Although the number of predicted peptides is similar to the numbers of related AMPs in Xenopus and Silurana frog species, they show significantly lower structural variation. Selection analyses confirm that, in contrast to the AMPs of other amphibians, the H. boettgeri peptides did not evolve under diversifying selection. Instead, the low sequence variation among tandem repeats resulted from purifying selection, recent duplication and/or concerted gene evolution. Our study demonstrates that defense peptide repertoires of closely related taxa, after diverging from each other, may evolve under differential selective regimes, leading to contrasting patterns of structural diversity. PMID- 24466038 TI - Spastic paraplegia type 7 is associated with multiple mitochondrial DNA deletions. AB - Spastic paraplegia 7 is an autosomal recessive disorder caused by mutations in the gene encoding paraplegin, a protein located at the inner mitochondrial membrane and involved in the processing of other mitochondrial proteins. The mechanism whereby paraplegin mutations cause disease is unknown. We studied two female and two male adult patients from two Norwegian families with a combination of progressive external ophthalmoplegia and spastic paraplegia. Sequencing of SPG7 revealed a novel missense mutation, c.2102A>C, p.H 701P, which was homozygous in one family and compound heterozygous in trans with a known pathogenic mutation c.1454_1462del in the other. Muscle was examined from an additional, unrelated adult female patient with a similar phenotype caused by a homozygous c.1047insC mutation in SPG7. Immunohistochemical studies in skeletal muscle showed mosaic deficiency predominantly affecting respiratory complex I, but also complexes III and IV. Molecular studies in single, microdissected fibres showed multiple mitochondrial DNA deletions segregating at high levels (38-97%) in respiratory deficient fibres. Our findings demonstrate for the first time that paraplegin mutations cause accumulation of mitochondrial DNA damage and multiple respiratory chain deficiencies. While paraplegin is not known to be directly associated with the mitochondrial nucleoid, it is known to process other mitochondrial proteins and it is possible therefore that paraplegin mutations lead to mitochondrial DNA deletions by impairing proteins involved in the homeostasis of the mitochondrial genome. These studies increase our understanding of the molecular pathogenesis of SPG7 mutations and suggest that SPG7 testing should be included in the diagnostic workup of autosomal recessive, progressive external ophthalmoplegia, especially if spasticity is present. PMID- 24466039 TI - Orphan nuclear receptor Errgamma induces C-reactive protein gene expression through induction of ER-bound Bzip transmembrane transcription factor CREBH. AB - The orphan nuclear receptor estrogen-related receptor-gamma (ERRgamma) is a constitutively active transcription factor regulating genes involved in several important cellular processes, including hepatic glucose metabolism, alcohol metabolism, and the endoplasmic reticulum (ER) stress response. cAMP responsive element-binding protein H (CREBH) is an ER-bound bZIP family transcription factor that is activated upon ER stress and regulates genes encoding acute-phase proteins whose expression is increased in response to inflammation. Here, we report that ERRgamma directly regulates CREBH gene expression in response to ER stress. ERRgamma bound to the ERRgamma response element (ERRE) in the CREBH promoter. Overexpression of ERRgamma by adenovirus significantly increased expression of CREBH as well as C-reactive protein (CRP), whereas either knockdown of ERRgamma or inhibition of ERRgamma by ERRgamma specific inverse agonist, GSK5182, substantially inhibited ER stress-mediated induction of CREBH and CRP. The transcriptional coactivator PGC1alpha was required for ERRgamma mediated induction of the CREBH gene as demonstrated by the chromatin immunoprecipitation (ChIP) assay showing binding of both ERRgamma and PGC1alpha on the CREBH promoter. The ChIP assay also revealed that histone H3 and H4 acetylation occurred at the ERRgamma and PGC1alpha binding site. Moreover, chronic alcoholic hepatosteatosis, as well as the diabetic obese condition significantly increased CRP gene expression, and this increase was significantly attenuated by GSK5182 treatment. We suggest that orphan nuclear receptor ERRgamma directly regulates the ER-bound transcription factor CREBH in response to ER stress and other metabolic conditions. PMID- 24466040 TI - A biochemical approach to study the role of the terminal oxidases in aerobic respiration in Shewanella oneidensis MR-1. AB - The genome of the facultative anaerobic gamma-proteobacterium Shewanella oneidensis MR-1 encodes for three terminal oxidases: a bd-type quinol oxidase and two heme-copper oxidases, a A-type cytochrome c oxidase and a cbb 3-type oxidase. In this study, we used a biochemical approach and directly measured oxidase activities coupled to mass-spectrometry analysis to investigate the physiological role of the three terminal oxidases under aerobic and microaerobic conditions. Our data revealed that the cbb 3-type oxidase is the major terminal oxidase under aerobic conditions while both cbb 3-type and bd-type oxidases are involved in respiration at low-O2 tensions. On the contrary, the low O2-affinity A-type cytochrome c oxidase was not detected in our experimental conditions even under aerobic conditions and would therefore not be required for aerobic respiration in S. oneidensis MR-1. In addition, the deduced amino acid sequence suggests that the A-type cytochrome c oxidase is a ccaa 3-type oxidase since an uncommon extra C terminal domain contains two c-type heme binding motifs. The particularity of the aerobic respiratory pathway and the physiological implication of the presence of a ccaa 3-type oxidase in S. oneidensis MR-1 are discussed. PMID- 24466041 TI - Transcriptome and biochemical analyses revealed a detailed proanthocyanidin biosynthesis pathway in brown cotton fiber. AB - Brown cotton fiber is the major raw material for colored cotton industry. Previous studies have showed that the brown pigments in cotton fiber belong to proanthocyanidins (PAs). To clarify the details of PA biosynthesis pathway in brown cotton fiber, gene expression profiles in developing brown and white fibers were compared via digital gene expression profiling and qRT-PCR. Compared to white cotton fiber, all steps from phenylalanine to PA monomers (flavan-3-ols) were significantly up-regulated in brown fiber. Liquid chromatography mass spectrometry analyses showed that most of free flavan-3-ols in brown fiber were in 2, 3-trans form (gallocatechin and catechin), and the main units of polymeric PAs were trihydroxylated on B ring. Consistent with monomeric composition, the transcript levels of flavonoid 3', 5'-hydroxylase and leucoanthocyanidin reductase in cotton fiber were much higher than their competing enzymes acting on the same substrates (dihydroflavonol 4-reductase and anthocyanidin synthase, respectively). Taken together, our data revealed a detailed PA biosynthesis pathway wholly activated in brown cotton fiber, and demonstrated that flavonoid 3', 5'-hydroxylase and leucoanthocyanidin reductase represented the primary flow of PA biosynthesis in cotton fiber. PMID- 24466043 TI - A robot-assisted surgical system using a force-image control method for pedicle screw insertion. AB - OBJECTIVE: To introduce a robot-assisted surgical system for spinal posterior fixation that can automatically recognize the drilling state and stop potential cortical penetration with force and image information and to further evaluate the accuracy and safety of the robot for sheep vertebra pedicle screw placement. METHODS: The Robotic Spinal Surgery System (RSSS) was composed of an optical tracking system, a navigation and planning system, and a surgical robot equipped with a 6-DOF force/torque sensor. The robot used the image message and force signals to sense the different operation states and to prevent potential cortical penetration in the pedicle screw insertion operation. To evaluate the accuracy and safety of the RSSS, 32 screw insertions were conducted. Furthermore, six trajectories were deliberately planned incorrectly to explore whether the robot could recognize the different drilling states and immediately prevent cortical penetration. RESULTS: All 32 pedicle screws were placed in the pedicle without any broken pedicle walls. Compared with the preoperative planning, the average deviations of the entry points in the axial and sagittal views were 0.50 +/- 0.33 and 0.65 +/- 0.40 mm, and the average deviations of the angles in the axial and sagittal views were 1.9 +/- 0.82 degrees and 1.48 +/- 1.2 degrees . The robot successfully recognized the different drilling states and prevented potential cortical penetration. In the deliberately incorrectly planned trajectory experiments, the robot successfully prevented the cortical penetration. CONCLUSION: These results verified the RSSS's accuracy and safety, which supported its potential use for the spinal surgery. PMID- 24466042 TI - The Nogo-C2/Nogo receptor complex regulates the morphogenesis of zebrafish lateral line primordium through modulating the expression of dkk1b, a Wnt signal inhibitor. AB - The fish lateral line (LL) is a mechanosensory system closely related to the hearing system of higher vertebrates, and it is composed of several neuromasts located on the surface of the fish. These neuromasts can detect changes in external water flow, to assist fish in maintaining a stationary position in a stream. In the present study, we identified a novel function of Nogo/Nogo receptor signaling in the formation of zebrafish neuromasts. Nogo signaling in zebrafish, like that in mammals, involves three ligands and four receptors, as well as three co-receptors (TROY, p75, and LINGO-1). We first demonstrated that Nogo-C2, NgRH1a, p75, and TROY are able to form a Nogo-C2 complex, and that disintegration of this complex causes defective neuromast formation in zebrafish. Time-lapse recording of the CldnB::lynEGFP transgenic line revealed that functional obstruction of the Nogo-C2 complex causes disordered morphogenesis, and reduces rosette formation in the posterior LL (PLL) primordium during migration. Consistent with these findings, hair-cell progenitors were lost from the PLL primordium in p75, TROY, and Nogo-C2/NgRH1a morphants. Notably, the expression levels of pea3, a downstream marker of Fgf signaling, and dkk1b, a Wnt signaling inhibitor, were both decreased in p75, TROY, and Nogo-C2/NgRH1a morphants; moreover, dkk1b mRNA injection could rescue the defects in neuromast formation resulting from knockdown of p75 or TROY. We thus suggest that a novel Nogo-C2 complex, consisting of Nogo-C2, NgRH1a, p75, and TROY, regulates Fgf signaling and dkk1b expression, thereby ensuring stable organization of the PLL primordium. PMID- 24466044 TI - Carbon dioxide and fruit odor transduction in Drosophila olfactory neurons. What controls their dynamic properties? AB - We measured frequency response functions between odorants and action potentials in two types of neurons in Drosophila antennal basiconic sensilla. CO2 was used to stimulate ab1C neurons, and the fruit odor ethyl butyrate was used to stimulate ab3A neurons. We also measured frequency response functions for light induced action potential responses from transgenic flies expressing H134R channelrhodopsin-2 (ChR2) in the ab1C and ab3A neurons. Frequency response functions for all stimulation methods were well-fitted by a band-pass filter function with two time constants that determined the lower and upper frequency limits of the response. Low frequency time constants were the same in each type of neuron, independent of stimulus method, but varied between neuron types. High frequency time constants were significantly slower with ethyl butyrate stimulation than light or CO2 stimulation. In spite of these quantitative differences, there were strong similarities in the form and frequency ranges of all responses. Since light-activated ChR2 depolarizes neurons directly, rather than through a chemoreceptor mechanism, these data suggest that low frequency dynamic properties of Drosophila olfactory sensilla are dominated by neuron specific ionic processes during action potential production. In contrast, high frequency dynamics are limited by processes associated with earlier steps in odor transduction, and CO2 is detected more rapidly than fruit odor. PMID- 24466045 TI - CD4+ T-cell help is required for effective CD8+ T cell-mediated resolution of acute viral hepatitis in mice. AB - Cytotoxic CD8+ T cells are essential for the control of viral liver infections, such as those caused by HBV or HCV. It is not entirely clear whether CD4+ T-cell help is necessary for establishing anti-viral CD8+ T cell responses that successfully control liver infection. To address the role of CD4+ T cells in acute viral hepatitis, we infected mice with Lymphocytic Choriomeningitis Virus (LCMV) of the strain WE; LCMV-WE causes acute hepatitis in mice and is cleared from the liver by CD8+ T cells within about two weeks. The role of CD4+ T-cell help was studied in CD4+ T cell-lymphopenic mice, which were either induced by genetic deficiency of the major histocompatibility (MHC) class II transactivator (CIITA) in CIITA-/- mice, or by antibody-mediated CD4+ cell depletion. We found that CD4+ T cell-lymphopenic mice developed protracted viral liver infection, which seemed to be a consequence of reduced virus-specific CD8+ T-cell numbers in the liver. Moreover, the anti-viral effector functions of the liver-infiltrating CD8+ T cells in response to stimulation with LCMV peptide, notably the IFN-gamma production and degranulation capacity were impaired in CIITA-/- mice. The impaired CD8+ T-cell function in CIITA-/- mice was not associated with increased expression of the exhaustion marker PD-1. Our findings indicate that CD4+ T-cell help is required to establish an effective antiviral CD8+ T-cell response in the liver during acute viral infection. Insufficient virus control and protracted viral hepatitis may be consequences of impaired initial CD4+ T-cell help. PMID- 24466046 TI - New MADS-box gene in fern: cloning and expression analysis of DfMADS1 from Dryopteris fragrans. AB - MADS genes encode a family of transcription factors, some of which control the identities of floral organs in flowering plants. Most of the MADS-box genes in fern have been cloned and analyzed in model plants, such as Ceratopteris richardii and Ceratopteris pteridoides. In this study, a new MADS-box gene, DfMADS1(GU385475), was cloned from Dryopteris fragrans (L.) Schott to better understand the role of MADS genes in the evolution of floral organs. The full length DfMADS1 cDNA was 973 bp in length with a 75 bp 5'-UTR and a 169 bp 3'-UTR. The DfMADS1 protein was predicted to contain a typical MIKC-type domain structure consisting of a MADS domain, a short I region, a K domain, and a C-terminal region. The DfMADS1 protein showed high homology with MADS box proteins from other ferns. Phylogenetic analysis revealed that DfMADS1 belongs to the CRM1-like subfamily. RT-PCR analysis indicated that DfMADS1 is expressed in both the gametophytes and the sporophytes of D. fragrans. PMID- 24466047 TI - 9beta Polymorphism of the glucocorticoid receptor gene appears to have limited impact in patients with Addison's disease. AB - BACKGROUND: Addison's disease (AD) has been associated with an increased risk of cardiovascular disease. Glucocorticoid receptor polymorphisms that alter glucocorticoid sensitivity may influence metabolic and cardiovascular risk factors in patients with AD. The 9beta polymorphism of the glucocorticoid receptor gene is associated with relative glucocorticoid resistance and has been reported to increase the risk of myocardial infarction in the elderly. We explored the impact of this polymorphism in patients with AD. MATERIALS AND METHODS: 147 patients with AD and 147 age, gender and ethnicity matched healthy controls were recruited. Blood was taken in a non-fasted state for plasma lipid determination, measurement of cardiovascular risk factors and DNA extraction. RESULTS: Genotype data for the 9beta polymorphism was available for 139 patients and 146 controls. AD patients had a more atherogenic lipid profile characterized by an increase in the prevalence of small dense LDL (p = 0.003), increased triglycerides (p = 0.002), reduced HDLC (p<0.001) an elevated highly sensitive C reactive protein (p = 0.01), compared with controls. The 9beta polymorphism (at least one G allele) was found in 28% of patients and controls respectively. After adjusting for age, gender, ethnicity, BMI and hydrocortisone dose per metre square of body surface area in patients, there were no significant metabolic associations with this polymorphism and hydrocortisone doses were not higher in patients with the polymorphism. CONCLUSIONS: This study did not identify any associations between the 9beta polymorphism and cardiovascular risk factors or hydrocortisone dose and determination of this polymorphism is therefore unlikely to be of clinical benefit in the management of patients with AD. PMID- 24466048 TI - The urokinase receptor takes control of cell migration by recruiting integrins and FPR1 on the cell surface. AB - The receptor (uPAR) of the urokinase-type plasminogen activator (uPA) is crucial in cell migration since it concentrates uPA proteolytic activity at the cell surface, binds vitronectin and associates to integrins. uPAR cross-talk with receptors for the formylated peptide fMLF (fMLF-Rs) has been reported; however, cell-surface uPAR association to fMLF-Rs on the cell membrane has never been explored in detail. We now show that uPAR co-localizes at the cell-surface and co immunoprecipitates with the high-affinity fMLF-R, FPR1, in uPAR-transfected HEK 293 (uPAR-293) cells. uPAR/beta1 integrin and FPR1/beta1 integrin co-localization was also observed. Serum or the WKYMVm peptide (W Pep), a FPR1 ligand, strongly increased all observed co-localizations in uPAR-293 cells, including FPR1/beta1 integrin co-localization. By contrast, a low FPR1/beta1 integrin co-localization was observed in uPAR-negative vector-transfected HEK-293 (V-293) cells, that was not increased by serum or W Pep stimulations. The role of uPAR interactions in cell migration was then explored. Both uPAR-293 and V-293 control cells efficiently migrated toward serum or purified EGF. However, cell treatments impairing uPAR interactions with fMLF-Rs or integrins, or inhibiting specific cell-signaling mediators abrogated uPAR-293 cell migration, without exerting any effect on V-293 control cells. Accordingly, uPAR depletion by a uPAR-targeting siRNA or uPAR blocking with an anti-uPAR polyclonal antibody in cells constitutively expressing high uPAR levels totally impaired their migration toward serum. Altogether, these results suggest that both uPAR-positive and uPAR negative cells are able to migrate toward serum; however, uPAR expression renders cell migration totally and irreversibly uPAR-dependent, since it is completely inhibited by uPAR blocking. We propose that uPAR takes control of cell migration by recruiting fMLF-Rs and beta1 integrins, thus promoting their co-localization at the cell-surface and driving pro-migratory signaling pathways. PMID- 24466050 TI - Pollinator interactions with yellow starthistle (Centaurea solstitialis) across urban, agricultural, and natural landscapes. AB - Pollinator-plant relationships are found to be particularly vulnerable to land use change. Yet despite extensive research in agricultural and natural systems, less attention has focused on these interactions in neighboring urban areas and its impact on pollination services. We investigated pollinator-plant interactions in a peri-urban landscape on the outskirts of the San Francisco Bay Area, California, where urban, agricultural, and natural land use types interface. We made standardized observations of floral visitation and measured seed set of yellow starthistle (Centaurea solstitialis), a common grassland invasive, to test the hypotheses that increasing urbanization decreases 1) rates of bee visitation, 2) viable seed set, and 3) the efficiency of pollination (relationship between bee visitation and seed set). We unexpectedly found that bee visitation was highest in urban and agricultural land use contexts, but in contrast, seed set rates in these human-altered landscapes were lower than in natural sites. An explanation for the discrepancy between floral visitation and seed set is that higher plant diversity in urban and agricultural areas, as a result of more introduced species, decreases pollinator efficiency. If these patterns are consistent across other plant species, the novel plant communities created in these managed landscapes and the generalist bee species that are favored by human altered environments will reduce pollination services. PMID- 24466049 TI - Porphyromonas Gingivalis and E-coli induce different cytokine production patterns in pregnant women. AB - OBJECTIVE: Pregnant individuals of many species, including humans, are more sensitive to various bacteria or their products as compared with non-pregnant individuals. Pregnant individuals also respond differently to different bacteria or their products. Therefore, in the present study, we evaluated whether the increased sensitivity of pregnant women to bacterial products and their heterogeneous response to different bacteria was associated with differences in whole blood cytokine production upon stimulation with bacteria or their products. METHODS: Blood samples were taken from healthy pregnant and age-matched non pregnant women and ex vivo stimulated with bacteria or LPS from Porphyromonas Gingivalis (Pg) or E-coli for 24 hrs. TNFalpha, IL-1beta, IL-6, IL-12 and IL-10 were measured using a multiplex Luminex system. RESULTS: We observed a generally lower cytokine production after stimulation with Pg bacteria or it's LPS as compared with E-coli bacteria. However, there was also an effect of pregnancy upon cytokine production: in pregnant women the production of IL-6 upon Pg stimulation was decreased as compared with non-pregnant women. After stimulation with E-coli, the production of IL-12 and TNFalpha was decreased in pregnant women as compared with non-pregnant women. CONCLUSION: Our results showed that cytokine production upon bacterial stimulation of whole blood differed between pregnant and non-pregnant women, showing that the increased sensitivity of pregnant women may be due to differences in cytokine production. Moreover, pregnancy also affected whole blood cytokine production upon Pg or E-coli stimulation differently. Thus, the different responses of pregnant women to different bacteria or their products may result from variations in cytokine production. PMID- 24466051 TI - Deletion of individual Ku subunits in mice causes an NHEJ-independent phenotype potentially by altering apurinic/apyrimidinic site repair. AB - Ku70 and Ku80 form a heterodimer called Ku that forms a holoenzyme with DNA dependent-protein kinase catalytic subunit (DNA-PKCS) to repair DNA double strand breaks (DSBs) through the nonhomologous end joining (NHEJ) pathway. As expected mutating these genes in mice caused a similar DSB repair-defective phenotype. However, ku70(-/-) cells and ku80(-/-) cells also appeared to have a defect in base excision repair (BER). BER corrects base lesions, apurinic/apyrimidinic (AP) sites and single stand breaks (SSBs) utilizing a variety of proteins including glycosylases, AP endonuclease 1 (APE1) and DNA Polymerase beta (Pol beta). In addition, deleting Ku70 was not equivalent to deleting Ku80 in cells and mice. Therefore, we hypothesized that free Ku70 (not bound to Ku80) and/or free Ku80 (not bound to Ku70) possessed activity that influenced BER. To further test this hypothesis we performed two general sets of experiments. The first set showed that deleting either Ku70 or Ku80 caused an NHEJ-independent defect. We found ku80(-/-) mice had a shorter life span than dna-pkcs(-/-) mice demonstrating a phenotype that was greater than deleting the holoenzyme. We also found Ku70 deletion induced a p53 response that reduced the level of small mutations in the brain suggesting defective BER. We further confirmed that Ku80-deletion impaired BER via a mechanism that was not epistatic to Pol beta. The second set of experiments showed that free Ku70 and free Ku80 could influence BER. We observed that deletion of either Ku70 or Ku80, but not both, increased sensitivity of cells to CRT0044876 (CRT), an agent that interferes with APE1. In addition, free Ku70 and free Ku80 bound to AP sites and in the case of Ku70 inhibited APE1 activity. These observations support a novel role for free Ku70 and free Ku80 in altering BER. PMID- 24466052 TI - Stressful events and continued smoking and continued alcohol consumption during mid-pregnancy. AB - AIM: to examine whether the severity of different categories of stressful events is associated with continued smoking and alcohol consumption during mid pregnancy. Also, we explored the explanation of these associations by anxiety and depressive symptoms during pregnancy. Finally, we studied whether the severity of stressful events was associated with the amount of cigarettes and alcohol used by continued users. METHOD: We conducted a cross-sectional analysis using data from a population-based prospective cohort study. Pregnant women were recruited via midwifery practices throughout The Netherlands. We analyzed women who continued smoking (n = 113) or quit (n = 290), and women who continued alcohol consumption (n = 124) or quit (n = 1403) during pregnancy. Smoking, alcohol consumption, and perceived severity of stressful events were measured at 19 weeks of gestation. The State Trait Anxiety Inventory and the Edinburgh Postnatal Depression Scale were filled out at 14 weeks of gestation. Odds ratios were calculated as association measures and indicated the relative increase for the odds of continuation of smoking and alcohol consumption for the maximum severity score compared to the minimum score. FINDINGS: Severity of the following stressful event categories was associated with continued alcohol consumption: 'conflict with loved ones' (OR = 10.4, p<0.01), 'crime related' (OR= 35.7, p<0.05), 'pregnancy-specific' (OR = 13.4, p<0.05), and the total including all events (OR = 17.2, p<0.05). Adjustment for potential confounders (age, parity and educational level) did not notably change the estimates. There was no association of anxiety and depressive symptoms with continued smoking or alcohol consumption. No associations emerged for continued smoking and severity of stressful events. The amount of cigarettes and alcohol consumption among continued users was not associated with severity of stressful events. CONCLUSIONS: Our findings may be relevant for health care providers, in particular midwives and general practitioners. The impact of stressful events may be considered when advising pregnant women on smoking and alcohol consumption. PMID- 24466053 TI - Endothelin receptor B2 (EDNRB2) is responsible for the tyrosinase-independent recessive white (mo(w) ) and mottled (mo) plumage phenotypes in the chicken. AB - A mutation that confers white plumage with black eyes was identified in the Minohiki breed of Japanese native chicken (Gallus gallus domesticus). The white plumage, with a few partially pigmented feathers, was not associated with the tyrosinase gene, and displayed an autosomal recessive mode of inheritance against the pigmented phenotype. All F1 offspring derived from crosses with mottled chickens (mo/mo), which show characteristic pigmented feathers with white tips, had plumage with a mottled-like pattern. This result indicates that the white plumage mutation is a novel allele at the mo locus; we propose the gene symbol mo(w) for this mutant allele. Furthermore, the F1 hybrid between the mo(w) /mo(w) chicken and the panda (s/s) mutant of Japanese quail (Coturnix japonica), whose causative gene is the endothelin receptor B2 (EDNRB2) gene, showed a mo(w)/mo(w) chicken-like plumage, suggesting the possibility that the mutations in parental species are alleles of the same gene, EDNRB2. Nucleotide sequencing of the entire coding region of EDNRB2 revealed a non-synonymous G1008T substitution, which causes Cys244Phe amino acid substitution in exon 5 (which is part of the extracellular loop between the putative fourth and fifth transmembrane domains of EDNRB2) in the mutant chicken. This Cys244Phe mutation was also present in individuals of four Japanese breeds with white plumage. We also identified a non synonymous substitution leading to Arg332His substitution that was responsible for the mottled (mo/mo) plumage phenotype. These results suggest that the EDN3 (endothelin 3)-EDNRB2 signaling is essential for normal pigmentation in birds, and that the mutations of EDNRB2 may cause defective binding of the protein with endothelins, which interferes with melanocyte differentiation, proliferation, and migration. PMID- 24466054 TI - Functional MRI of the olfactory system in conscious dogs. AB - We depend upon the olfactory abilities of dogs for critical tasks such as detecting bombs, landmines, other hazardous chemicals and illicit substances. Hence, a mechanistic understanding of the olfactory system in dogs is of great scientific interest. Previous studies explored this aspect at the cellular and behavior levels; however, the cognitive-level neural substrates linking them have never been explored. This is critical given the fact that behavior is driven by filtered sensory representations in higher order cognitive areas rather than the raw odor maps of the olfactory bulb. Since sedated dogs cannot sniff, we investigated this using functional magnetic resonance imaging of conscious dogs. We addressed the technical challenges of head motion using a two pronged strategy of behavioral training to keep dogs' head as still as possible and a single camera optical head motion tracking system to account for residual jerky movements. We built a custom computer-controlled odorant delivery system which was synchronized with image acquisition, allowing the investigation of brain regions activated by odors. The olfactory bulb and piriform lobes were commonly activated in both awake and anesthetized dogs, while the frontal cortex was activated mainly in conscious dogs. Comparison of responses to low and high odor intensity showed differences in either the strength or spatial extent of activation in the olfactory bulb, piriform lobes, cerebellum, and frontal cortex. Our results demonstrate the viability of the proposed method for functional imaging of the olfactory system in conscious dogs. This could potentially open up a new field of research in detector dog technology. PMID- 24466055 TI - Antimicrobial properties and membrane-active mechanism of a potential alpha helical antimicrobial derived from cathelicidin PMAP-36. AB - Antimicrobial peptides (AMPs), which present in the non-specific immune system of organism, are amongst the most promising candidates for the development of novel antimicrobials. The modification of naturally occurring AMPs based on their residue composition and distribution is a simple and effective strategy for optimization of known AMPs. In this study, a series of truncated and residue substituted derivatives of antimicrobial peptide PMAP-36 were designed and synthesized. The 24-residue truncated peptide, GI24, displayed antimicrobial activity comparable to the mother peptide PMAP-36 with MICs ranging from 1 to 4 uM, which is lower than the MICs of bee venom melittin. Although GI24 displayed high antimicrobial activity, its hemolytic activity was much lower than melittin, suggesting that GI24 have optimal cell selectivity. In addition, the crucial site of GI24 was identified through single site-mutation. An amino acid with high hydrophobicity at position 23 played an important role in guaranteeing the high antimicrobial activity of GI24. Then, lipid vesicles and whole bacteria were employed to investigate the membrane-active mechanisms. Membrane-simulating experiments showed that GI24 interacted strongly with negatively charged phospholipids and weakly with zwitterionic phospholipids, which corresponded well with the data of its biological activities. Membrane permeabilization and flow cytometry provide the evidence that GI24 killed microbial cells by permeabilizing the cell membrane and damaging membrane integrity. GI24 resulted in greater cell morphological changes and visible pores on cell membrane as determined using scanning electron microscopy (SEM) and transmission electron microscope (TEM). Taken together, the peptide GI24 may provide a promising antimicrobial agent for therapeutic applications against the frequently-encountered bacteria. PMID- 24466056 TI - Human lactate dehydrogenase a inhibitors: a molecular dynamics investigation. AB - Lactate dehydrogenase A (LDHA) is an important enzyme in fermentative glycolysis, generating most energy for cancer cells that rely on anaerobic respiration even under normal oxygen concentrations. This renders LDHA a promising molecular target for the treatment of various cancers. Several efforts have been made recently to develop LDHA inhibitors with nanomolar inhibition and cellular activity, some of which have been studied in complex with the enzyme by X-ray crystallography. In this work, we present a molecular dynamics (MD) study of the binding interactions of selected ligands with human LDHA. Conventional MD simulations demonstrate different binding dynamics of inhibitors with similar binding affinities, whereas steered MD simulations yield discrimination of selected LDHA inhibitors with qualitative correlation between the in silico unbinding difficulty and the experimental binding strength. Further, our results have been used to clarify ambiguities in the binding modes of two well-known LDHA inhibitors. PMID- 24466057 TI - Calcitonin gene-related peptide regulates type IV hypersensitivity through dendritic cell functions. AB - Dendritic cells (DCs) play essential roles in both innate and adaptive immune responses. In addition, mutual regulation of the nervous system and immune system is well studied. One of neuropeptides, calcitonin gene-related peptide (CGRP), is a potent regulator in immune responses; in particular, it has anti-inflammatory effects in innate immunity. For instance, a deficiency of the CGRP receptor component RAMP 1 (receptor activity-modifying protein 1) results in higher cytokine production in response to LPS (lipopolysaccharide). On the other hand, how CGRP affects DCs in adaptive immunity is largely unknown. In this study, we show that CGRP suppressed Th1 cell differentiation via inhibition of IL-12 production in DCs using an in vitro co-culture system and an in vivo ovalbumin induced delayed-type hypersensitivity (DTH) model. CGRP also down-regulated the expressions of chemokine receptor CCR2 and its ligands CCL2 and CCL12 in DCs. Intriguingly, the frequency of migrating CCR2(+) DCs in draining lymph nodes of RAMP1-deficient mice was higher after DTH immunization. Moreover, these CCR2(+) DCs highly expressed IL-12 and CD80, resulting in more effective induction of Th1 differentiation compared with CCR2(-) DCs. These results indicate that CGRP regulates Th1 type reactions by regulating expression of cytokines, chemokines, and chemokine receptors in DCs. PMID- 24466058 TI - RNA-Seq analysis provides insights for understanding photoautotrophic polyhydroxyalkanoate production in recombinant Synechocystis Sp. AB - The photosynthetic cyanobacterium, Synechocystis sp. strain 6803, is a potential platform for the production of various chemicals and biofuels. In this study, direct photosynthetic production of a biopolymer, polyhydroxyalkanoate (PHA), in genetically engineered Synechocystis sp. achieved as high as 14 wt%. This is the highest production reported in Synechocystis sp. under photoautotrophic cultivation conditions without the addition of a carbon source. The addition of acetate increased PHA accumulation to 41 wt%, and this value is comparable to the highest production obtained with cyanobacteria. Transcriptome analysis by RNA-seq coupled with real-time PCR was performed to understand the global changes in transcript levels of cells subjected to conditions suitable for photoautotrophic PHA biosynthesis. There was lower expression of most PHA synthesis-related genes in recombinant Synechocystis sp. with higher PHA accumulation suggesting that the concentration of these enzymes is not the limiting factor to achieving high PHA accumulation. In order to cope with the higher PHA production, cells may utilize enhanced photosynthesis to drive the product formation. Results from this study suggest that the total flux of carbon is the possible driving force for the biosynthesis of PHA and the polymerizing enzyme, PHA synthase, is not the only critical factor affecting PHA-synthesis. Knowledge of the regulation or control points of the biopolymer production pathways will facilitate the further use of cyanobacteria for biotechnological applications. PMID- 24466059 TI - eRF3b, a biomarker for hepatocellular carcinoma, influences cell cycle and phosphoralation status of 4E-BP1. AB - BACKGROUND: Hepatitis B virus (HBV) infection and its sequelae are now recognized as serious problems globally. Our aime is to screen hepatocellular carcinoma (HCC) from chronic hepatitis B (CHB) and identify the characteristics of proteins involved. METHODOLOGY/PRINCIPAL FINDINGS: We affinity-purified sample serum with weak cation-exchange (WCX) magnetic beads and matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) analysis to search for potential markers. The 4210 Da protein, which differed substantially between HCC and CHB isolates, was later identified to be eukaryotic peptide chain release factor GTP-binding subunit eRF3b. Further research showed that eRF3b/GSPT2 was positively expressed in liver tissues. GSPT2 mRNA was, however differentially expressed in blood. Compared with normal controls, the relative expression of GSPT2/18s rRNA was higher in CHB patients than in patients with either LC or HCC (P = 0.035 for CHB vs. LC; P = 0.020 for CHB vs. HCC). The data of further research showed that eRF3b/GSPT2 promoted the entrance of the HepG2 cells into the S-phase and that one of the substrates of the mTOR kinase, 4E-BP1, was hyperphosphorylated in eRF3b-overexpressing HepG2 cells. CONCLUSIONS: Overall, the differentially expressed protein eRF3b, which was discovered as a biomarker for HCC, could change the cell cycle and influence the phosphorylation status of 4E-BP1 on Ser65 in HepG2. PMID- 24466060 TI - Maturation of induced pluripotent stem cell derived hepatocytes by 3D-culture. AB - Induced pluripotent stem cell derived hepatocytes (IPSC-Heps) have the potential to reduce the demand for a dwindling number of primary cells used in applications ranging from therapeutic cell infusions to in vitro toxicology studies. However, current differentiation protocols and culture methods produce cells with reduced functionality and fetal-like properties compared to adult hepatocytes. We report a culture method for the maturation of IPSC-Heps using 3-Dimensional (3D) collagen matrices compatible with high throughput screening. This culture method significantly increases functional maturation of IPSC-Heps towards an adult phenotype when compared to conventional 2D systems. Additionally, this approach spontaneously results in the presence of polarized structures necessary for drug metabolism and improves functional longevity to over 75 days. Overall, this research reveals a method to shift the phenotype of existing IPSC-Heps towards primary adult hepatocytes allowing such cells to be a more relevant replacement for the current primary standard. PMID- 24466061 TI - Endocytosis of Fgf8 is a double-stage process and regulates spreading and signaling. AB - Tightly controlled concentration gradients of morphogens provide positional information and thus regulate tissue differentiation and morphogenesis in multicellular organisms. However, how such morphogenetic fields are formed and maintained remains debated. Here we show that fibroblast growth factor 8 (Fgf8) morphogen gradients in zebrafish embryos are established and maintained by two essential mechanisms. Firstly, Fgf8 is taken up into the cell by clathrin mediated endocytosis. The speed of the uptake rate defines the range of the morphogenetic gradient of Fgf8. Secondly, our data demonstrate that after endocytosis the routing of Fgf8 from the early endosome to the late endosome shuts down signaling. Therefore, intracellular endocytic transport regulates the intensity and duration of Fgf8 signaling. We show that internalization of Fgf8 into the early endosome and subsequent transport towards the late endosome are two independent processes. Therefore, we hypothesize that Fgf8 receiving cells control both, the propagation width and the signal strength of the morphogen. PMID- 24466062 TI - Estimation of a common effect parameter from follow-up data when there is no mechanistic interaction. AB - In a stratified analysis, the results from different strata if homogeneity assumption is met are pooled together to obtain a single summary estimate for the common effect parameter. However, the effect can appear homogeneous across strata using one measure but heterogeneous using another. Consequently, two researchers analyzing the same data can arrive at conflicting conclusions if they use different effect measures. In this paper, the author draws on the sufficient component cause model to develop a stratified-analysis method regarding a particular effect measure, the 'peril ratio'. When there is no mechanistic interaction between the exposure under study and the stratifying variable (i.e., when they do not work together to complete any sufficient cause), the peril ratio is constant across strata. The author presents formulas for the estimation of such a common peril ratio. Three real data are re-analyzed for illustration. When the data is consistent with peril-ratio homogeneity in a stratified analysis, researchers can use the formulas in this paper to pool the strata. PMID- 24466063 TI - Evidence from a mouse model that epithelial cell migration and mesenchymal epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation. AB - BACKGROUND: In women dynamic changes in uterine tissue architecture occur during each menstrual cycle. Menses, characterised by the shedding of the upper functional layer of the endometrium, is the culmination of a cascade of irreversible changes in tissue function including stromal decidualisation, inflammation and production of degradative enzymes. The molecular mechanisms that contribute to the rapid restoration of tissue homeostasis at time of menses are poorly understood. METHODOLOGY: A modified mouse model of menses was developed to focus on the events occurring within the uterine lining during endometrial shedding/repair. Decidualisation, vaginal bleeding, tissue architecture and cell proliferation were evaluated at 4, 8, 12, and 24 hours after progesterone (P4) withdrawal; mice received a single injection of bromodeoxyuridine (BrdU) 90 mins before culling. Expression of genes implicated in the regulation of mesenchymal to epithelial transition (MET) was determined using a RT2 PCR profiler array, qRTPCR and bioinformatic analysis. PRINCIPAL FINDINGS: Mice exhibited vaginal bleeding between 4 and 12 hours after P4 withdrawal, concomitant with detachment of the decidualised cell mass from the basal portion of the endometrial lining. Immunostaining for BrdU and pan cytokeratin revealed evidence of epithelial cell proliferation and migration. Cells that appeared to be in transition from a mesenchymal to an epithelial cell identity were identified within the stromal compartment. Analysis of mRNAs encoding genes expressed exclusively in the epithelial or stromal compartments, or implicated in MET, revealed dynamic changes in expression, consistent with a role for reprogramming of mesenchymal cells so that they could contribute to re-epithelialisation. CONCLUSIONS/SIGNIFICANCE: These studies have provided novel insights into the cellular processes that contribute to re-epithelialisation post-menses implicating both epithelial cell migration and mesenchymal cell differentiation in restoration of an intact epithelial cell layer. These insights may inform development of new therapies to induce rapid healing in the endometrium and other tissues and offer hope to women who suffer from heavy menstrual bleeding. PMID- 24466064 TI - Vestibular-somatosensory interactions: effects of passive whole-body rotation on somatosensory detection. AB - Vestibular signals are strongly integrated with information from several other sensory modalities. For example, vestibular stimulation was reported to improve tactile detection. However, this improvement could reflect either a multimodal interaction or an indirect interaction driven by vestibular effects on spatial attention and orienting. Here we investigate whether natural vestibular activation induced by passive whole-body rotation influences tactile detection. In particular, we assessed the ability to detect faint tactile stimuli to the fingertips of the left and right hand during spatially congruent or incongruent rotations. We found that passive whole-body rotations significantly enhanced sensitivity to faint shocks, without affecting response bias. Critically, this enhancement of somatosensory sensitivity did not depend on the spatial congruency between the direction of rotation and the hand stimulated. Thus, our results support a multimodal interaction, likely in brain areas receiving both vestibular and somatosensory signals. PMID- 24466065 TI - Seabird nutrient subsidies benefit non-nitrogen fixing trees and alter species composition in South American coastal dry forests. AB - Marine-derived nutrients can increase primary productivity and change species composition of terrestrial plant communities in coastal and riverine ecosystems. We hypothesized that sea nutrient subsidies have a positive effect on nitrogen assimilation and seedling survival of non-nitrogen fixing species, increasing the relative abundance of non-nitrogen fixing species close to seashore. Moreover, we proposed that herbivores can alter the effects of nutrient supplementation by preferentially feeding on high nutrient plants. We studied the effects of nutrient fertilization by seabird guano on tree recruitment and how these effects can be modulated by herbivorous lizards in the coastal dry forests of northwestern Peru. We combined field studies, experiments and stable isotope analysis to study the response of the two most common tree species in these forests, the nitrogen-fixing Prosopis pallida and the non-nitrogen-fixing Capparis scabrida. We did not find differences in herbivore pressure along the sea-inland gradient. We found that the non-nitrogen fixing C. scabrida assimilates marine-derived nitrogen and is more abundant than P. pallida closer to guano-rich soil. We conclude that the input of marine-derived nitrogen through guano deposited by seabirds feeding in the Pacific Ocean affects the two dominant tree species of the coastal dry forests of northern Peru in contrasting ways. The non-nitrogen fixing species, C. scabrida may benefit from sea nutrient subsidies by incorporating guano-derived nitrogen into its foliar tissues, whereas P. pallida, capable of atmospheric fixation, does not. PMID- 24466066 TI - High pressure freezing/freeze substitution fixation improves the ultrastructural assessment of Wolbachia endosymbiont-filarial nematode host interaction. AB - BACKGROUND: Wolbachia alpha-proteobacteria are essential for growth, reproduction and survival for many filarial nematode parasites of medical and veterinary importance. Endobacteria were discovered in filarial parasites by transmission electron microscopy in the 1970's using chemically fixed specimens. Despite improvements of fixation and electron microscopy techniques during the last decades, methods to study the Wolbachia/filaria interaction on the ultrastructural level remained unchanged and the mechanisms for exchange of materials and for motility of endobacteria are not known. METHODOLOGY/PRINCIPAL FINDING: We used high pressure freezing/freeze substitution to improve fixation of Brugia malayi and its endosymbiont, and this led to improved visualization of different morphological forms of Wolbachia. The three concentric, bilayer membranes that surround the endobacterial cytoplasm were well preserved. Vesicles with identical membrane structures were identified close to the endobacteria, and multiple bacteria were sometimes enclosed within a single outer membrane. Immunogold electron microscopy using a monoclonal antibody directed against Wolbachia surface protein-1 labeled the membranes that enclose Wolbachia and Wolbachia-associated vesicles. High densities of Wolbachia were observed in the lateral chords of L4 larvae, immature, and mature adult worms. Extracellular Wolbachia were sometimes present in the pseudocoelomic cavity near the developing female reproductive organs. Wolbachia-associated actin tails were not observed. Wolbachia motility may be explained by their residence within vacuoles, as they may co-opt the host cell's secretory pathway to move within and between cells. CONCLUSIONS/SIGNIFICANCE: High pressure freezing/freeze substitution significantly improved the preservation of filarial tissues for electron microscopy to reveal membranes and sub cellular structures that could be crucial for exchange of materials between Wolbachia and its host. PMID- 24466067 TI - Sequencing biological and physical events affects specific frequency bands within the human premotor cortex: an intracerebral EEG study. AB - Evidence that the human premotor cortex (PMC) is activated by cognitive functions involving the motor domain is classically explained as the reactivation of a motor program decoupled from its executive functions, and exploited for different purposes by means of a motor simulation. In contrast, the evidence that PMC contributes to the sequencing of non-biological events cannot be explained by the simulationist theory. Here we investigated how motor simulation and event sequencing coexist within the PMC and how these mechanisms interact when both functions are executed. We asked patients with depth electrodes implanted in the PMC to passively observe a randomized arrangement of images depicting biological actions and physical events and, in a second block, to sequence them in the correct order. This task allowed us to disambiguate between the simple observation of actions, their sequencing (recruiting different motor simulation processes), as well as the sequencing of non-biological events (recruiting a sequencer mechanism non dependant on motor simulation). We analysed the response of the gamma, alpha and beta frequency bands to evaluate the contribution of each brain rhythm to the observation and sequencing of both biological and non biological stimuli. We found that motor simulation (biological>physical) and event sequencing (sequencing>observation) differently affect the three investigated frequency bands: motor simulation was reflected on the gamma and, partially, in the beta, but not in the alpha band. In contrast, event sequencing was also reflected on the alpha band. PMID- 24466068 TI - Prediction of mortality using on-line, self-reported health data: empirical test of the RealAge score. AB - OBJECTIVE: We validate an online, personalized mortality risk measure called "RealAge" assigned to 30 million individuals over the past 10 years. METHODS: 188,698 RealAge survey respondents were linked to California Department of Public Health death records using a one-way cryptographic hash of first name, last name, and date of birth. 1,046 were identified as deceased. We used Cox proportional hazards models and receiver operating characteristic (ROC) curves to estimate the relative scales and predictive accuracies of chronological age, the RealAge score, and the Framingham ATP-III score for hard coronary heart disease (HCHD) in this data. To address concerns about selection and to examine possible heterogeneity, we compared the results by time to death at registration, underlying cause of death, and relative health among users. RESULTS: THE REALAGE SCORE IS ACCURATELY SCALED (HAZARD RATIOS: age 1.076; RealAge-age 1.084) and more accurate than chronological age (age c-statistic: 0.748; RealAge c-statistic: 0.847) in predicting mortality from hard coronary heart disease following survey completion. The score is more accurate than the Framingham ATP-III score for hard coronary heart disease (c-statistic: 0.814), perhaps because self-reported cholesterol levels are relatively uninformative in the RealAge user sample. RealAge predicts deaths from malignant neoplasms, heart disease, and external causes. The score does not predict malignant neoplasm deaths when restricted to users with no smoking history, no prior cancer diagnosis, and no indicated health interest in cancer (p-value 0.820). CONCLUSION: The RealAge score is a valid measure of mortality risk in its user population. PMID- 24466069 TI - The heterodimeric glycoprotein hormone, GPA2/GPB5, regulates ion transport across the hindgut of the adult mosquito, Aedes aegypti. AB - A family of evolutionarily old hormones is the glycoprotein cysteine knot-forming heterodimers consisting of alpha- (GPA) and beta-subunits (GPB), which assemble by noncovalent bonds. In mammals, a common glycoprotein hormone alpha-subunit (GPA1) pairs with unique beta-subunits that establish receptor specificity, forming thyroid stimulating hormone (GPA1/TSHbeta) and the gonadotropins luteinizing hormone (GPA1/LHbeta), follicle stimulating hormone (GPA1/FSHbeta), choriogonadotropin (GPA1/CGbeta). A novel glycoprotein heterodimer was identified in vertebrates by genome analysis, called thyrostimulin, composed of two novel subunits, GPA2 and GPB5, and homologs occur in arthropods, nematodes and cnidarians, implying that this neurohormone system existed prior to the emergence of bilateral metazoans. In order to discern possible physiological roles of this hormonal signaling system in mosquitoes, we have isolated the glycoprotein hormone genes producing the alpha- and beta-subunits (AedaeGPA2 and AedaeGPB5) and assessed their temporal expression profiles in the yellow and dengue-fever vector, Aedes aegypti. We have also isolated a putative receptor for this novel mosquito hormone, AedaeLGR1, which contains features conserved with other glycoprotein leucine-rich repeating containing G protein-coupled receptors. AedaeLGR1 is expressed in tissues of the alimentary canal such as the midgut, Malpighian tubules and hindgut, suggesting that this novel mosquito glycoprotein hormone may regulate ionic and osmotic balance. Focusing on the hindgut in adult stage A. aegypti, where AedaeLGR1 was highly enriched, we utilized the Scanning Ion-selective Electrode Technique (SIET) to determine if AedaeGPA2/GPB5 modulated cation transport across this epithelial tissue. Our results suggest that AedaeGPA2/GPB5 does indeed participate in ionic and osmotic balance, since it appears to inhibit natriuresis and promote kaliuresis. Taken together, our findings imply this hormone may play an important role in ionic balance when levels of Na(+) are limited and levels of K(+) are in excess--such as during the digestion and assimilation of erythrocytes following vertebrate blood-feeding by females. PMID- 24466070 TI - Tomato genomic resources database: an integrated repository of useful tomato genomic information for basic and applied research. AB - Tomato Genomic Resources Database (TGRD) allows interactive browsing of tomato genes, micro RNAs, simple sequence repeats (SSRs), important quantitative trait loci and Tomato-EXPEN 2000 genetic map altogether or separately along twelve chromosomes of tomato in a single window. The database is created using sequence of the cultivar Heinz 1706. High quality single nucleotide polymorphic (SNP) sites between the genes of Heinz 1706 and the wild tomato S. pimpinellifolium LA1589 are also included. Genes are classified into different families. 5' upstream sequences (5'-US) of all the genes and their tissue-specific expression profiles are provided. Sequences of the microRNA loci and their putative target genes are catalogued. Genes and 5'-US show presence of SSRs and SNPs. SSRs located in the genomic, genic and 5'-US can be analysed separately for the presence of any particular motif. Primer sequences for all the SSRs and flanking sequences for all the genic SNPs have been provided. TGRD is a user-friendly web accessible relational database and uses CMAP viewer for graphical scanning of all the features. Integration and graphical presentation of important genomic information will facilitate better and easier use of tomato genome. TGRD can be accessed as an open source repository at http://59.163.192.91/tomato2/. PMID- 24466071 TI - The effect of intra-arterial angiotensin II on the hepatic tumor to non-tumor blood flow ratio for radioembolization: a systematic review. AB - PURPOSE: Treatment efficacy of intra-arterial radioembolization for liver tumors depends on the selective targeting of tumorous tissue. Recent investigations have demonstrated that tumors may receive inadequate doses of radioactivity after radioembolization, due to unfavorable tumor to non-tumor (T/N) uptake ratios of radioactive microspheres. Hepatic arterial infusion of the vasoconstrictor angiotensin II (AT-II) is reported to increase the T/N blood flow ratio. The purpose of this systematic review was to provide a comprehensive overview of the effect of hepatic arterial AT-II on T/N blood flow ratio in patients with hepatic malignancies, and determine its clinical value for radioembolization. METHODS: This review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. A structured search was performed in the PubMed, EMBASE and Cochrane databases. Only studies that presented data on T/N ratios before and after infusion of AT-II into the hepatic artery, in human patients with hepatic malignancies, were selected. Median T/N ratios before, during and after AT-II infusion, and the median T/N ratio improvement factor were extracted from the selected articles. All data on systemic blood pressure measurements and clinical symptoms were also extracted. RESULTS: The search identified 524 titles of which 5 studies, including a total of 71 patients were considered relevant. Median T/N ratios before infusion of AT II ranged from 0.4 to 3.4. All studies observed a substantial improvement of the T/N ratio after AT-II infusion, with median improvement factors ranging from 1.8 to 3.1. A transitory increase of systemic blood pressure was observed during AT II infusion. CONCLUSIONS: Infusion of AT-II into the hepatic artery leads to an increase of the tumor to non-tumor blood flow ratio, as measured by T/N uptake ratios. Clinical trials are warranted to assess safety aspects, optimal administration strategy and impact on treatment efficacy during radioembolization. PMID- 24466072 TI - Chronic allopurinol treatment during the last trimester of pregnancy in sows: effects on low and normal birth weight offspring. AB - Low-birth-weight (LBW) children are born with several risk factors for disease, morbidity and neonatal mortality, even if carried to term. Placental insufficiency leading to hypoxemia and reduced nutritional supply is the main cause for LBW. Brain damage and poor neurological outcome can be the consequence. LBW after being carried to term gives better chances for survival, but these children are still at risk for poor health and the development of cognitive impairments. Preventive therapies are not yet available. We studied the risk/efficacy of chronic prenatal treatment with the anti-oxidative drug allopurinol, as putative preventive treatment in piglets. LBW piglets served as a natural model for LBW. A cognitive holeboard test was applied to study the learning and memory abilities of these allopurinol treated piglets after weaning. Preliminary analysis of the plasma concentrations in sows and their piglets suggested that a daily dose of 15 mg.kg(-1) resulted in effective plasma concentration of allopurinol in piglets. No adverse effects of chronic allopurinol treatment were found on farrowing, birth weight, open field behavior, learning abilities, relative brain, hippocampus and spleen weights. LBW piglets showed increased anxiety levels in an open field test, but cognitive performance was not affected by allopurinol treatment. LBW animals treated with allopurinol showed the largest postnatal compensatory body weight gain. In contrast to a previous study, no differences in learning abilities were found between LBW and normal-birth-weight piglets. This discrepancy might be attributable to experimental differences. Our results indicate that chronic prenatal allopurinol treatment during the third trimester of pregnancy is safe, as no adverse side effects were observed. Compensatory weight gain of treated piglets is a positive indication for the chronic prenatal use of allopurinol in these animals. Further studies are needed to assess the possible preventive effects of allopurinol on brain functions in LBW piglets. PMID- 24466073 TI - Risk factors for chronic and recurrent otitis media-a meta-analysis. AB - Risk factors associated with chronic otitis media (COM) and recurrent otitis media (ROM) have been investigated in previous studies. The objective of this study was to integrate the findings and determine the possible risk factors for COM/ROM based on our meta-analysis. A comprehensive search of electronic bibliographic databases (PubMed, Embase, CNKI and Wanfang database) from 1964 to Dec 2012, as well as a manual search of references of articles, was performed. A total of 2971 articles were searched, and 198 full-text articles were assessed for eligibility; 24 studies were eligible for this meta-analysis. Regarding risk factors for COM/ROM, there were two to nine different studies from which the odds ratios (ORs) could be pooled. The presence of allergy or atopy increased the risk of COM/ROM (OR, 1.36; 95% CI, 1.13-1.64; P = 0.001). An upper respiratory tract infection (URTI) significantly increased the risk of COM/ROM (OR, 6.59; 95% CI, 3.13-13.89; P<0.00001). Snoring appeared to be a significant risk factor for COM/ROM (OR, 1.96; 95% CI, 1.78-2.16; P<0.00001). A patient history of acute otitis media (AOM)/ROM increased the risk of COM/ROM (OR, 11.13; 95% CI, 1.06 116.44; P = 0.04). Passive smoke significantly increased the risk of COM/ROM (OR, 1.39; 95% CI, 1.02-1.89 P = 0.04). Low social status appeared to be a risk factor for COM/ROM (OR, 3.82; 95% CI, 1.11-13.15; P = 0.03). Our meta-analysis identified reliable conclusions that allergy/atopy, URTI, snoring, previous history of AOM/ROM, Second-hand smoke and low social status are important risk factors for COM/ROM. Other unidentified risk factors need to be identified in further studies with critical criteria. PMID- 24466074 TI - Experts and novices use the same factors--but differently--to evaluate pearl quality. AB - Well-trained experts in pearl grading have been thought to evaluate pearls according to their glossiness, interference color, and shape. However, the characteristics of their evaluations are not fully understood. Using pearl grading experiments, we investigate the consistency of novice (i.e., without knowledge of pearl grading) and expert participants' pearl grading skill and then compare the novices' grading with that of experts; furthermore, we discuss the relationship between grading, interference color, and glossiness. We found that novices' grading was significantly less concordant with experts average grading than was experts' grading; more than half of novices graded pearls the opposite of how experts graded those same pearls. However, while experts graded pearls more consistently than novices did, novices' consistency was relatively high. We also found differences between the groups in regression analyses that used interference color and glossiness as explanatory variables and were conducted for each trial. Although the regression coefficient was significant in 60% of novices' trials, there were fewer significant trials for the experts (20%). This indicates that novices can also make use of these two factors, but that their usage is simpler than that of the experts. These results suggest that experts and novices share some values about pearls but that the evaluation method is elaborated for experts. PMID- 24466076 TI - Response suppression delays the planning of subsequent stimulus-driven saccades. AB - The completion of an antisaccade selectively increases the reaction tiME (RT) of a subsequent prosaccade: a result that has been interpreted to reflect the residual inhibition of stimulus-driven saccade networks [1], [2]. In the present investigation we sought to determine whether the increase in prosaccade RT is contingent on the constituent antisaccade planning processes of response suppression and vector inversion or is limited to response suppression. To that end, in one block participants alternated between pro- and antisaccades after every second trial (task-switching block), and in another block participants completed a series of prosaccades that were randomly (and infrequently) interspersed with no-go catch-trials (go/no-go block). Notably, such a design provides a framework for disentangling whether response suppression and/or vector inversion delays the planning of subsequent prosaccades. As expected, results for the task-switching block showed that antisaccades selectively increased the RTs of subsequent prosaccades. In turn, results for the go/no-go block showed that prosaccade RTs were increased when preceded by a no-go catch-trial. Moreover, the magnitude of the RT 'cost' was equivalent across the task-switching and go/no-go blocks. That prosaccades preceded by an antisaccade or a no-go catch-trial produced equivalent RT costs indicates that the conjoint processes of response suppression and vector inversion do not drive the inhibition of saccade planning mechanisms. Rather, the present findings indicate that a general consequence of response suppression is a residual inhibition of stimulus-driven saccade networks. PMID- 24466075 TI - Adiponectin expression protects against angiotensin II-mediated inflammation and accelerated atherosclerosis. AB - Adiponectin (APN), an adipocytokine produced by adipose tissue, exerts pleiotropic actions regulating inflammation, metabolism and vascular homeostasis. APN levels are inversely correlated with obesity, type-2 diabetes, hypertension and cardiovascular disease. Although renin angiotensin system (RAS) activation in these interrelated metabolic syndrome components increases angiotensin II (AngII) levels leading to vascular damage, it is unknown whether APN under these conditions provides atheroprotection. We investigated whether increasing plasma APN provides atheroprotection in a hypertensive and accelerated atherosclerosis model. Using adenoviral gene transfer, sustained APN expression increased plasma levels of total and high-molecular weight APN, leading to a significant elevation of plasma HDL-cholesterol (HDL-C). Elevated APN levels were strongly atheroprotective, yet had no impact on blood pressure. Notably, gene expression analyses revealed that APN significantly inhibited the expression of pro inflammatory and atherogenic genes while it increased the expression of the anti inflammatory cytokine, IL-10 and the cholesterol efflux transporters, ABCA1 and ABCG1 in the artery wall. These findings suggest that increasing APN levels may be an effective therapeutic strategy to inhibit vascular inflammation and accelerated atherosclerosis associated with RAS activation in the metabolic syndrome. PMID- 24466078 TI - Peptide binding properties of the three PDZ domains of Bazooka (Drosophila Par 3). AB - The Par complex is a conserved cell polarity regulator. Bazooka/Par-3 is scaffold for the complex and contains three PDZ domains in tandem. PDZ domains can act singly or synergistically to bind the C-termini of interacting proteins. Sequence comparisons among Drosophila Baz and its human and C. elegans Par-3 counterparts indicate a divergence of the peptide binding pocket of PDZ1 and greater conservation for the pockets of PDZ2 and PDZ3. However, it is unclear whether the domains from different species share peptide binding preferences, or if their tandem organization affects their peptide binding properties. To investigate these questions, we first used phage display screens to identify unique peptide binding profiles for each single PDZ domain of Baz. Comparisons with published phage display screens indicate that Baz and C. elegans PDZ2 bind to similar peptides, and that the peptide binding preferences of Baz PDZ3 are more similar to C. elegans versus human PDZ3. Next we quantified the peptide binding preferences of each Baz PDZ domain using single identified peptides in surface plasmon resonance assays. In these direct binding studies, each peptide had a binding preference for a single PDZ domain (although the peptide binding of PDZ2 was weakest and the least specific). PDZ1 and PDZ3 bound their peptides with dissociation constants in the nM range, whereas PDZ2-peptide binding was in the uM range. To test whether tandem PDZ domain organization affects peptide binding, we examined a fusion protein containing all three PDZ domains and their normal linker regions. The binding strengths of the PDZ-specific peptides to single PDZ domains and to the PDZ domain tandem were indistinguishable. Thus, the peptide binding pockets of each PDZ domain in Baz are not obviously affected by the presence of neighbouring PDZ domains, but act as isolated modules with specific in vitro peptide binding preferences. PMID- 24466077 TI - Multilocus detection of wolf x dog hybridization in italy, and guidelines for marker selection. AB - Hybridization and introgression can impact the evolution of natural populations. Several wild canid species hybridize in nature, sometimes originating new taxa. However, hybridization with free-ranging dogs is threatening the genetic integrity of grey wolf populations (Canis lupus), or even the survival of endangered species (e.g., the Ethiopian wolf C. simensis). Efficient molecular tools to assess hybridization rates are essential in wolf conservation strategies. We evaluated the power of biparental and uniparental markers (39 autosomal and 4 Y-linked microsatellites, a melanistic deletion at the beta defensin CBD103 gene, the hypervariable domain of the mtDNA control-region) to identify the multilocus admixture patterns in wolf x dog hybrids. We used empirical data from 2 hybrid groups with different histories: 30 presumptive natural hybrids from Italy and 73 Czechoslovakian wolfdogs of known hybrid origin, as well as simulated data. We assessed the efficiency of various marker combinations and reference samples in admixture analyses using 69 dogs of different breeds and 99 wolves from Italy, Balkans and Carpathian Mountains. Results confirmed the occurrence of hybrids in Italy, some of them showing anomalous phenotypic traits and exogenous mtDNA or Y-chromosome introgression. Hybridization was mostly attributable to village dogs and not strictly patrilineal. The melanistic beta-defensin deletion was found only in Italian dogs and in putative hybrids. The 24 most divergent microsatellites (largest wolf-dog FST values) were equally or more informative than the entire panel of 39 loci. A smaller panel of 12 microsatellites increased risks to identify false admixed individuals. The frequency of F1 and F2 was lower than backcrosses or introgressed individuals, suggesting hybridization already occurred some generations in the past, during early phases of wolf expansion from their historical core areas. Empirical and simulated data indicated the identification of the past generation backcrosses is always uncertain, and a larger number of ancestry-informative markers is needed. PMID- 24466080 TI - Aboveground feeding by soybean aphid, Aphis glycines, affects soybean cyst nematode, Heterodera glycines, reproduction belowground. AB - Heterodera glycines is a cyst nematode that causes significant lost soybean yield in the U.S. Recent studies observed the aphid Aphis glycines and H. glycines interacting via their shared host, soybean, Glycine max. A greenhouse experiment was conducted to discern the effect of A. glycines feeding on H. glycines reproduction. An H. glycines-susceptible cultivar, Kenwood 94, and a resistant cultivar, Dekalb 27-52, were grown in H. glycines-infested soil for 30 and 60 d. Ten days after planting, plants were infested with either zero, five, or ten aphids. At 30 and 60 d, the number of H. glycines females and cysts (dead females) and the number of eggs within were counted. In general, H. glycines were less abundant on the resistant than the susceptible cultivar, and H. glycines abundance increased from 30 to 60 d. At 30 d, 33% more H. glycines females and eggs were produced on the resistant cultivar in the ten-aphid treatment compared to the zero-aphid treatment. However, at 30 d the susceptible cultivar had 50% fewer H. glycines females and eggs when infested with ten aphids. At 60 d, numbers of H. glycines females and cysts and numbers of eggs on the resistant cultivar were unaffected by A. glycines feeding, while numbers of both were decreased by A. glycines on the susceptible cultivar. These results indicate that A. glycines feeding improves the quality of soybean as a host for H. glycines, but at higher herbivore population densities, this effect is offset by a decrease in resource quantity. PMID- 24466079 TI - HCV genotypes, characterization of mutations conferring drug resistance to protease inhibitors, and risk factors among blood donors in Sao Paulo, Brazil. AB - BACKGROUND: Hepatitis C virus (HCV) infection is a global health problem estimated to affect almost 200 million people worldwide. The aim of this study is to analyze the subtypes and existence of variants resistant to protease inhibitors and their association with potential HCV risk factors among blood donors in Brazil. METHODS: Repeat anti-HCV reactive blood donors are systematically asked to return for retest, notification, and counseling in which they are interviewed for risk factors for transfusion-transmitted diseases. We analyzed 202 donors who returned for counseling from 2007 to 2010 and presented enzyme immunoassay- and immunoblot-reactive results. The HCV genotypes and resistance mutation analyses were determined by the direct sequencing of the NS5b and NS3 regions, respectively. The HCV viral load was determined using an in house real-time PCR assay targeting the 5'-NCR. RESULTS: HCV subtypes 1b, 1a, and 3a were found in 45.5%, 32.0%, and 18.0% of the donors, respectively. The mean viral load of genotype 1 was significantly higher than that of the genotype 3 isolates. Subtype 1a was more frequent among young donors and 3a was more frequent among older donors. Protease inhibitor-resistant variants were detected in 12.8% of the sequenced samples belonging to genotype 1, and a higher frequency was observed among subtype 1a (20%) in comparison to 1b (8%). There was no difference in the prevalence of HCV risk factors among the genotypes or drug resistant variants. CONCLUSIONS: We found a predominance of subtype 1b, with an increase in the frequency of subtype 1a, in young subjects. Mutations conferring resistance to NS3 inhibitors were frequent in treatment-naive blood donors, particularly those infected with subtype 1a. These variants were detected in the major viral population of HCV quasispecies, have replicative capacities comparable to nonresistant strains, and could be important for predicting the response to antiviral triple therapy. PMID- 24466081 TI - Oral administration of Lactobacillus plantarum strain AYA enhances IgA secretion and provides survival protection against influenza virus infection in mice. AB - The mucosal immune system provides the first line of defense against inhaled and ingested pathogenic microbacteria and viruses. This defense system, to a large extent, is mediated by the actions of secretory IgA. In this study, we screened 140 strains of lactic acid bacteria for induction of IgA production by murine Peyer's patch cells. We selected one strain and named it Lactobacillus plantarum AYA. We found that L. plantarum AYA-induced production of IL-6 in Peyer's patch dendritic cells, with this production promoting IgA(+) B cells to differentiate into IgA-secreting plasma cells. We also observed that oral administration of L. plantarum AYA in mice caused an increase in IgA production in the small intestine and lung. This production of IgA correlated strongly with protective ability, with the treated mice surviving longer than the control mice after lethal influenza virus infection. Our data therefore reveals a novel immunoregulatory role of the L. plantarum AYA strain which enhances mucosal IgA production and provides protection against respiratory influenza virus infection. PMID- 24466082 TI - Tuberculin skin test distribution following a change in BCG vaccination policy. AB - BACKGROUND: Epidemiologic data regarding tuberculin skin test (TST) responses are an important basis for TB control strategies. This study analyzed TST responses in Korea, which experienced a rapid change in BCG vaccination status. METHODS: TST responses in young adults were examined over 5 years. Participants with active TB lesions were excluded. RESULTS: A total of 5,552 participants were enrolled with median age of 21 years. When an induration diameter >=10 mm was used as the criterion for a positive test, TST positivity fell (from 28.0% in 2005 to 15.3% in 2009); however, they remained steady when the criterion was >=15 20 mm. A positive TST was associated with a personal or family of TB, the presence of a Bacille Calmette-Guerin (BCG) scar, and age (odds ratio [95% confidence interval] = 4.03 [2.61-6.22], 2.91 [1.80-4.71], 1.50 [1.31-1.72], and 1.15 [1.09-1.20], respectively). Among these factors, the decrease of participants with BCG scars was the most prominent change, which appeared to be associated with the change of TST positivity rate. CONCLUSION: Overall, the rate of TST positivity in Korea decreased. However, this trend seems associated with the change of BCG vaccination strategy rather than successful control of LTBI. This study showed that change in BCG vaccination strategy can have great impact on TB epidemiologic survey based on TST. PMID- 24466083 TI - High-resolution 1H NMR spectroscopy of fish muscle, eggs and small whole fish via Hadamard-encoded intermolecular multiple-quantum coherence. AB - BACKGROUND AND PURPOSE: Nuclear magnetic resonance (NMR) spectroscopy has become an important technique for tissue studies. Since tissues are in semisolid-state, their high-resolution (HR) spectra cannot be obtained by conventional NMR spectroscopy. Because of this restriction, extraction and high-resolution magic angle spinning (HR MAS) are widely applied for HR NMR spectra of tissues. However, both of the methods are subject to limitations. In this study, the feasibility of HR (1)H NMR spectroscopy based on intermolecular multiple-quantum coherence (iMQC) technique is explored using fish muscle, fish eggs, and a whole fish as examples. MATERIALS AND METHODS: Intact salmon muscle tissues, intact eggs from shishamo smelt and a whole fish (Siamese algae eater) are studied by using conventional 1D one-pulse sequence, Hadamard-encoded iMQC sequence, and HR MAS. RESULTS: When we use the conventional 1D one-pulse sequence, hardly any useful spectral information can be obtained due to the severe field inhomogeneity. By contrast, HR NMR spectra can be obtained in a short period of time by using the Hadamard-encoded iMQC method without shimming. Most signals from fatty acids and small metabolites can be observed. Compared to HR MAS, the iMQC method is non-invasive, but the resolution and the sensitivity of resulting spectra are not as high as those of HR MAS spectra. CONCLUSION: Due to the immunity to field inhomogeneity, the iMQC technique can be a proper supplement to HR MAS, and it provides an alternative for the investigation in cases with field distortions and with samples unsuitable for spinning. The acquisition time of the proposed method is greatly reduced by introduction of the Hadamard-encoded technique, in comparison with that of conventional iMQC method. PMID- 24466084 TI - Comparison of medial temporal measures between Binswanger's disease and Alzheimer's disease. AB - Binswanger's disease (BD) is a common cause of vascular dementia in elderly patients; however, few studies have investigated the medial temporal lobe (MTL) atrophy in BD, and the differences in the atrophic patterns between BD and Alzheimer's disease (AD) remain largely unknown. Such knowledge is essential for understanding the pathologic basis of dementia. In this study, we collected structural magnetic resonance imaging (MRI) data from 16 normal controls, 14 patients with AD and 14 patients with BD. The volumes of the hippocampus and amygdala, and morphologic parameters (volume, surface area, cortical thickness and mean curvature) of the entorhinal cortex (ERC) and perirhinal cortex (PRC) were calculated using an automated approach. Volume reduction of the hippocampus, amygdala and ERC, and disturbance of the PRC curvature was found in both AD and BD patients compared with the controls (p<0.05, uncorrected). There were no significant differences among all the structural measures between the AD and BD patients. Finally, partial correlation analyses revealed that cognitive decline could be attributed to ERC thinning in AD and volume reduction of PRC in BD. We conclude that AD and BD exhibit similar atrophy patterns in the medial temporal cortices and deep gray matter but have distinct pathologic bases for cognitive impairments. Although atrophy of the MTL structures is a sensitive biomarker for AD, it is not superior for discrimination between AD and BD. PMID- 24466085 TI - Dystrophic changes in extraocular muscles after gamma irradiation in mdx:utrophin(+/-) mice. AB - Extraocular muscles (EOM) have a strikingly different disease profile than limb skeletal muscles. It has long been known that they are spared in Duchenne (DMD) and other forms of muscular dystrophy. Despite many studies, the cause for this sparing is not understood. We have proposed that differences in myogenic precursor cell properties in EOM maintain normal morphology over the lifetime of individuals with DMD due to either greater proliferative potential or greater resistance to injury. This hypothesis was tested by exposing wild type and mdx:utrophin(+/-) (het) mouse EOM and limb skeletal muscles to 18 Gy gamma irradiation, a dose known to inhibit satellite cell proliferation in limb muscles. As expected, over time het limb skeletal muscles displayed reduced central nucleation mirrored by a reduction in Pax7-positive cells, demonstrating a significant loss in regenerative potential. In contrast, in the first month post-irradiation in the het EOM, myofiber cross-sectional areas first decreased, then increased, but ultimately returned to normal compared to non-irradiated het EOM. Central nucleation significantly increased in the first post-irradiation month, resembling the dystrophic limb phenotype. This correlated with decreased EECD34 stem cells and a concomitant increase and subsequent return to normalcy of both Pax7 and Pitx2-positive cell density. By two months, normal het EOM morphology returned. It appears that irradiation disrupts the normal method of EOM remodeling, which react paradoxically to produce increased numbers of myogenic precursor cells. This suggests that the EOM contain myogenic precursor cell types resistant to 18 Gy gamma irradiation, allowing return to normal morphology 2 months post-irradiation. This supports our hypothesis that ongoing proliferation of specialized regenerative populations in the het EOM actively maintains normal EOM morphology in DMD. Ongoing studies are working to define the differences in the myogenic precursor cells in EOM as well as the cellular milieu in which they reside. PMID- 24466086 TI - VAMP7 modulates ciliary biogenesis in kidney cells. AB - Epithelial cells elaborate specialized domains that have distinct protein and lipid compositions, including the apical and basolateral surfaces and primary cilia. Maintaining the identity of these domains is required for proper cell function, and requires the efficient and selective SNARE-mediated fusion of vesicles containing newly synthesized and recycling proteins with the proper target membrane. Multiple pathways exist to deliver newly synthesized proteins to the apical surface of kidney cells, and the post-Golgi SNAREs, or VAMPs, involved in these distinct pathways have not been identified. VAMP7 has been implicated in apical protein delivery in other cell types, and we hypothesized that this SNARE would have differential effects on the trafficking of apical proteins known to take distinct routes to the apical surface in kidney cells. VAMP7 expressed in polarized Madin Darby canine kidney cells colocalized primarily with LAMP2 positive compartments, and siRNA-mediated knockdown modulated lysosome size, consistent with the known function of VAMP7 in lysosomal delivery. Surprisingly, VAMP7 knockdown had no effect on apical delivery of numerous cargoes tested, but did decrease the length and frequency of primary cilia. Additionally, VAMP7 knockdown disrupted cystogenesis in cells grown in a three-dimensional basement membrane matrix. The effects of VAMP7 depletion on ciliogenesis and cystogenesis are not directly linked to the disruption of lysosomal function, as cilia lengths and cyst morphology were unaffected in an MDCK lysosomal storage disorder model. Together, our data suggest that VAMP7 plays an essential role in ciliogenesis and lumen formation. To our knowledge, this is the first study implicating an R-SNARE in ciliogenesis and cystogenesis. PMID- 24466087 TI - Increased metabolite levels of glycolysis and pentose phosphate pathway in rabbit atherosclerotic arteries and hypoxic macrophage. AB - AIMS: Inflammation and possibly hypoxia largely affect glucose utilization in atherosclerotic arteries, which could alter many metabolic systems. However, metabolic changes in atherosclerotic plaques remain unknown. The present study aims to identify changes in metabolic systems relative to glucose uptake and hypoxia in rabbit atherosclerotic arteries and cultured macrophages. METHODS: Macrophage-rich or smooth muscle cell (SMC)-rich neointima was created by balloon injury in the iliac-femoral arteries of rabbits fed with a 0.5% cholesterol diet or a conventional diet. THP-1 macrophages stimulated with lipopolysaccharides (LPS) and interferon-gamma (INFgamma) were cultured under normoxic and hypoxic conditions. We evaluated comprehensive arterial and macrophage metabolism by performing metabolomic analyses using capillary electrophoresis-time of flight mass spectrometry. We evaluated glucose uptake and its relationship to vascular hypoxia using (18)F-fluorodeoxyglucose ((18)F-FDG) and pimonidazole, a marker of hypoxia. RESULTS: The levels of many metabolites increased in the iliac-femoral arteries with macrophage-rich neointima, compared with those that were not injured and those with SMC-rich neointima (glycolysis, 4 of 9; pentose phosphate pathway, 4 of 6; tricarboxylic acid cycle, 4 of 6; nucleotides, 10 of 20). The uptake of (18)F-FDG in arterial walls measured by autoradiography positively correlated with macrophage- and pimonidazole-immunopositive areas (r = 0.76, and r = 0.59 respectively; n = 69 for both; p<0.0001). Pimonidazole immunoreactivity was closely localized with the nuclear translocation of hypoxia inducible factor 1alpha and hexokinase II expression in macrophage-rich neointima. The levels of glycolytic (8 of 8) and pentose phosphate pathway (4 of 6) metabolites increased in LPS and INFgamma stimulated macrophages under hypoxic but not normoxic condition. Plasminogen activator inhibitor-1 protein levels in the supernatant were closely associated with metabolic pathways in the macrophages. CONCLUSION: Infiltrative macrophages in atherosclerotic arteries might affect metabolic systems, and hypoxia but not classical activation might augment glycolytic and pentose phosphate pathways in macrophages. PMID- 24466088 TI - Estimating respiratory and heart rates from the correntropy spectral density of the photoplethysmogram. AB - The photoplethysmogram (PPG) obtained from pulse oximetry measures local variations of blood volume in tissues, reflecting the peripheral pulse modulated by heart activity, respiration and other physiological effects. We propose an algorithm based on the correntropy spectral density (CSD) as a novel way to estimate respiratory rate (RR) and heart rate (HR) from the PPG. Time-varying CSD, a technique particularly well-suited for modulated signal patterns, is applied to the PPG. The respiratory and cardiac frequency peaks detected at extended respiratory (8 to 60 breaths/min) and cardiac (30 to 180 beats/min) frequency bands provide RR and HR estimations. The CSD-based algorithm was tested against the Capnobase benchmark dataset, a dataset from 42 subjects containing PPG and capnometric signals and expert labeled reference RR and HR. The RR and HR estimation accuracy was assessed using the unnormalized root mean square (RMS) error. We investigated two window sizes (60 and 120 s) on the Capnobase calibration dataset to explore the time resolution of the CSD-based algorithm. A longer window decreases the RR error, for 120-s windows, the median RMS error (quartiles) obtained for RR was 0.95 (0.27, 6.20) breaths/min and for HR was 0.76 (0.34, 1.45) beats/min. Our experiments show that in addition to a high degree of accuracy and robustness, the CSD facilitates simultaneous and efficient estimation of RR and HR. Providing RR every minute, expands the functionality of pulse oximeters and provides additional diagnostic power to this non-invasive monitoring tool. PMID- 24466089 TI - Application of microarray and functional-based screening methods for the detection of antimicrobial resistance genes in the microbiomes of healthy humans. AB - The aim of this study was to screen for the presence of antimicrobial resistance genes within the saliva and faecal microbiomes of healthy adult human volunteers from five European countries. Two non-culture based approaches were employed to obviate potential bias associated with difficult to culture members of the microbiota. In a gene target-based approach, a microarray was employed to screen for the presence of over 70 clinically important resistance genes in the saliva and faecal microbiomes. A total of 14 different resistance genes were detected encoding resistances to six antibiotic classes (aminoglycosides, beta-lactams, macrolides, sulphonamides, tetracyclines and trimethoprim). The most commonly detected genes were erm(B), blaTEM, and sul2. In a functional-based approach, DNA prepared from pooled saliva samples was cloned into Escherichia coli and screened for expression of resistance to ampicillin or sulphonamide, two of the most common resistances found by array. The functional ampicillin resistance screen recovered genes encoding components of a predicted AcrRAB efflux pump. In the functional sulphonamide resistance screen, folP genes were recovered encoding mutant dihydropteroate synthase, the target of sulphonamide action. The genes recovered from the functional screens were from the chromosomes of commensal species that are opportunistically pathogenic and capable of exchanging DNA with related pathogenic species. Genes identified by microarray were not recovered in the activity-based screen, indicating that these two methods can be complementary in facilitating the identification of a range of resistance mechanisms present within the human microbiome. It also provides further evidence of the diverse reservoir of resistance mechanisms present in bacterial populations in the human gut and saliva. In future the methods described in this study can be used to monitor changes in the resistome in response to antibiotic therapy. PMID- 24466090 TI - Exogenous GA3 application can compensate the morphogenetic effects of the GA responsive dwarfing gene Rht12 in bread wheat. AB - The most common dwarfing genes in wheat, Rht-B1b and Rht-D1b, classified as gibberellin-insensitive (GAI) dwarfing genes due to their reduced response to exogenous GA, have been verified as encoding negative regulators of gibberellin signaling. In contrast, the response of gibberellin-responsive (GAR) dwarfing genes, such as Rht12, to exogenous GA is still unclear and the role of them, if any, in GA biosynthesis or signaling is unknown. The responses of Rht12 to exogenous GA3 were investigated on seedling vigour, spike phenological development, plant height and other agronomic traits, using F2 ? 3 and F3 ? 4 lines derived from a cross between Ningchun45 and Karcagi-12 in three experiments. The application of exogenous GA3 significantly increased coleoptile length and seedling leaf 1 length and area. While there was no significant difference between the dwarf and the tall lines at the seedling stage in the responsiveness to GA3, plant height was significantly increased, by 41 cm (53%) averaged across the three experiments, in the GA3-treated Rht12 dwarf lines. Plant height of the tall lines was not affected significantly by GA3 treatment (<10 cm increased). Plant biomass and seed size of the GA3-treated dwarf lines was significantly increased compared with untreated dwarf plants while there was no such difference in the tall lines. GA3-treated Rht12 dwarf plants with the dominant Vrn-B1 developed faster than untreated plants and reached double ridge stage 57 days, 11 days and 50 days earlier and finally flowered earlier by almost 7 days while the GA3-treated tall lines flowering only 1-2 days earlier than the untreated tall lines. Thus, it is clear that exogenous GA3 can break the masking effect of Rht12 on Vrn-B1 and also restore other characters of Rht12 to normal. It suggested that Rht12 mutants may be deficient in GA biosynthesis rather than in GA signal transduction like the GA-insensitive dwarfs. PMID- 24466091 TI - Canonical WNT signaling inhibits follicle stimulating hormone mediated steroidogenesis in primary cultures of rat granulosa cells. AB - Beta-catenin (CTNNB1), a key component of wingless-type mouse mammary tumor virus integration site family (WNT) signaling, participates in follicle stimulated hormone-mediated regulation of estrogen (E2) production. The purpose of these studies was to determine if CTNNB1's contribution to FSH-mediated steroidogenesis in primary rat granulosa cells was due in part to extracellular stimulation of the canonical WNT signaling pathway. To achieve this purpose, primary cultures of rat granulosa cells were exposed to vehicle or a canonical member of the WNT signaling pathway, WNT3A, before co-culture and in the presence or absence of FSH for 24 h. Activation of the canonical WNT signaling pathway was determined by dose-dependent induction of Axin2 mRNA expression and stimulation of the CTNNB1/T cell factor promoter-reporter TOPflash. WNT pathway induction was demonstrated at doses of 50 and 500 ng/mL of WNT3A. Granulosa cells treated with WNT3A in combination with FSH had enhanced CTNNB1/T cell factor transcriptional activity above cells treated with WNT3A alone. Steroidogenic enzymes and ovarian differentiation factor mRNAs were quantified via quantitative PCR. Expression of steroidogenic enzyme mRNAs aromatase (Cyp19a1), P450 side chain cleavage (Cyp11a1), and steroidogenic acute regulatory protein (Star) were increased following FSH treatment. Co-incubation of WNT3A and FSH reduced the ability of FSH to stimulate steroidogenic enzymes and subsequent E2 and progesterone (P4) production. Concomitant activation of FSH and WNT pathways results in marked reduction of ovarian differentiation factors, LH receptor (Lhcgr) and inhibin alpha (Inha). Therefore, WNT inhibits FSH target genes and steroid production associated with maturation and differentiation of the ovarian follicle. PMID- 24466092 TI - Biosynthetic enhancement of the detection of bacteria by the polymerase chain reaction. AB - Molecular viability testing (MVT) was previously reported to specifically detect viable bacterial cells in complex samples. In MVT, brief nutritional stimulation induces viable cells, but not non-viable cells, to produce abundant amounts of species-specific ribosomal RNA precursors (pre-rRNA). Quantitative polymerase chain reaction (qPCR) is used to quantify specific pre-rRNAs in a stimulated aliquot relative to a non-stimulated control. In addition to excluding background signal from non-viable cells and from free DNA, we report here that MVT increases the analytical sensitivity of qPCR when detecting viable cells. Side-by-side limit-of-detection comparisons showed that MVT is 5-fold to >10-fold more sensitive than standard (static) DNA-targeted qPCR when detecting diverse bacterial pathogens (Aeromonas hydrophila, Acinetobacter baumannii, Listeria monocytogenes, Mycobacterium avium, and Staphylococcus aureus) in serum, milk, and tap water. Sensitivity enhancement may come from the elevated copy number of pre-rRNA relative to genomic DNA, and also from the ratiometric measurement which reduces ambiguity associated with weak or borderline signals. We also report that MVT eliminates false positive signals from bacteria that have been inactivated by moderately elevated temperatures (pasteurization), a condition that can confound widely-used cellular integrity tests that utilize membrane-impermeant compounds such as propidium iodide (PI) or propidium monoazide (PMA) to differentiate viable from inactivated bacteria. MVT enables the sensitive and specific detection of very small numbers of viable bacteria in complex matrices. PMID- 24466093 TI - Cardiac sympathetic modulation in response to apneas/hypopneas through heart rate variability analysis. AB - Autonomic dysfunction is recognized to contribute to cardiovascular consequences in obstructive sleep apnea/hypopnea syndrome (OSAHS) patients who present predominant cardiovascular sympathetic activity that persists during wakefulness. Here, we examined 1) the factors that influence sympathetic cardiac modulation in response to apneas/hypopneas; and 2) the influence of autonomic activity during apneas/hypopneas on CA. Sixteen OSAHS patients underwent in-hospital polysomnography. RR interval (RR) and RR spectral analysis using wavelet transform were used to study parasympathetic (high frequency power: HF(WV)) and sympathetic (low frequency power: LF(WV) and LF(WV)/HF(WV) ratio) activity before and after apnea/hypopnea termination. Autonomic cardiac modulations were compared according to sleep stage, apnea/hypopnea type and duration, arterial oxygen saturation, and presence of CA. At apnea/hypopnea termination, RR decreased (p<0.001) while LF(WV) (p = 0.001) and LF(WV)/HF(WV) ratio (p = 0.001) increased. Only RR and LF(WV)/HF(WV) ratio changes were higher when apneas/hypopneas produced CA (p = 0.030 and p = 0.035, respectively) or deep hypoxia (p = 0.023 and p = 0.046, respectively). Multivariate statistical analysis showed that elevated LF(WV) (p = 0.006) and LF(WV)/HF(WV) ratio (p = 0.029) during apneas/hypopneas were independently related to higher CA occurrence. Both the arousal and hypoxia processes may contribute to sympathetic cardiovascular overactivity by recurrent cardiac sympathetic modulation in response to apneas/hypopneas. Sympathetic overactivity also may play an important role in the acute central response to apneas/hypopneas, and in the sleep fragmentation. PMID- 24466094 TI - CYB5D2 requires heme-binding to regulate HeLa cell growth and confer survival from chemotherapeutic agents. AB - The cytochrome b5 domain containing 2 (CYB5D2; Neuferricin) protein has been reported to bind heme, however, the critical residues responsible for heme binding are undefined. Furthermore, the relationship between heme-binding and CYB5D2-mediated intracellular functions remains unknown. Previous studies examining heme-binding in two cytochrome b5 heme-binding domain-containing proteins, damage-associated protein 1 (Dap1; Saccharomyces cerevisiae) and human progesterone receptor membrane component 1 (PGRMC1), have revealed that conserved tyrosine (Y) 73, Y79, aspartic acid (D) 86, and Y127 residues present in human CYB5D2 may be involved in heme-binding. CYB5D2 binds to type b heme, however, only the substitution of glycine (G) at D86 (D86G) within its cytochrome b5 heme binding (cyt-b5) domain abolished its heme-binding ability. Both CYB5D2 and CYB5D2(D86G) localize to the endoplasmic reticulum. Ectopic CYB5D2 expression inhibited cell proliferation and anchorage-independent colony growth of HeLa cells. Conversely, CYB5D2 knockdown and ectopic CYB5D2(D86G) expression increased cell proliferation and colony growth. As PGRMC1 has been reported to regulate the expression and activities of cytochrome P450 proteins (CYPs), we examined the role of CYB5D2 in regulating the activities of CYPs involved in sterol synthesis (CYP51A1) and drug metabolism (CYP3A4). CYB5D2 co-localizes with cytochrome P450 reductase (CYPOR), while CYB5D2 knockdown reduced lanosterol demethylase (CYP51A1) levels and rendered HeLa cells sensitive to mevalonate. Additionally, knockdown of CYB5D2 reduced CYP3A4 activity. Lastly, CYB5D2 expression conferred HeLa cell survival from chemotherapeutic agents (paclitaxel, cisplatin and doxorubicin), with its ability to promote survival being dependent on its heme binding ability. Taken together, this study provides evidence that heme-binding is critical for CYB5D2 in regulating HeLa cell growth and survival, with endogenous CYB5D2 being required to modulate CYP activities. PMID- 24466095 TI - Identification of immunity-related genes in Ostrinia furnacalis against entomopathogenic fungi by RNA-seq analysis. AB - BACKGROUND: The Asian corn borer (Ostrinia furnacalis (Guenee)) is one of the most serious corn pests in Asia. Control of this pest with entomopathogenic fungus Beauveria bassiana has been proposed. However, the molecular mechanisms involved in the interactions between O. furnacalis and B. bassiana are unclear, especially under the conditions that the genomic information of O. furnacalis is currently unavailable. So we sequenced and characterized the transcriptome of O. furnacalis larvae infected by B. bassiana with special emphasis on immunity related genes. METHODOLOGY/PRINCIPAL FINDINGS: Illumina Hiseq2000 was used to sequence 4.64 and 4.72 Gb of the transcriptome from water-injected and B. bassiana-injected O. furnacalis larvae, respectively. De novo assembly generated 62,382 unigenes with mean length of 729 nt. All unigenes were searched against Nt, Nr, Swiss-Prot, COG, and KEGG databases for annotations using BLASTN or BLASTX algorithm with an E-value cut-off of 10(-5). A total of 35,700 (57.2%) unigenes were annotated to at least one database. Pairwise comparisons resulted in 13,890 differentially expressed genes, with 5,843 up-regulated and 8,047 down regulated. Based on sequence similarity to homologs known to participate in immune responses, we totally identified 190 potential immunity-related unigenes. They encode 45 pattern recognition proteins, 33 modulation proteins involved in the prophenoloxidase activation cascade, 46 signal transduction molecules, and 66 immune responsive effectors, respectively. The obtained transcriptome contains putative orthologs for nearly all components of the Toll, Imd, and JAK/STAT pathways. We randomly selected 24 immunity-related unigenes and investigated their expression profiles using quantitative RT-PCR assay. The results revealed variant expression patterns in response to the infection of B. bassiana. CONCLUSIONS/SIGNIFICANCE: This study provides the comprehensive sequence resource and expression profiles of the immunity-related genes of O. furnacalis. The obtained data gives an insight into better understanding the molecular mechanisms of innate immune processes in O. furnacalis larvae against B. bassiana. PMID- 24466096 TI - Comparison of the white-nose syndrome agent Pseudogymnoascus destructans to cave dwelling relatives suggests reduced saprotrophic enzyme activity. AB - White-nose Syndrome (WNS) is an emerging infectious mycosis that has impacted multiple species of North American bats since its initial discovery in 2006, yet the physiology of the causal agent, the psychrophilic fungus Pseudogymnoascus destructans ( = Geomyces destructans), is not well understood. We investigated the ability of P. destructans to secrete enzymes that could permit environmental growth or affect pathogenesis and compared enzyme activity across several Pseudogymnoascus species isolated from both hibernating bats and cave sediments. We found that P. destructans produced enzymes that could be beneficial in either a pathogenic or saprotrophic context, such as lipases, hemolysins, and urease, as well as chitinase and cellulases, which could aid in saprotrophic growth. The WNS pathogen showed significantly lower activity for urease and endoglucanase compared to con-generic species (Pseudogymnoascus), which may indicate a shift in selective pressure to the detriment of P. destructans' saprotrophic ability. Based on the positive function of multiple saprotrophic enzymes, the causal agent of White-nose Syndrome shows potential for environmental growth on a variety of substrates found in caves, albeit at a reduced level compared to environmental strains. Our data suggest that if P. destructans emerged as an opportunistic infection from an environmental source, co-evolution with its host may have led to a reduced capacity for saprotrophic growth. PMID- 24466098 TI - Seasonal predictability of the East Atlantic pattern from sea surface temperatures. AB - This study analyzes the influence of sea surface temperatures (SSTs) on the second mode of atmospheric variability in the north Atlantic/European sector, namely the East-Atlantic (EA) pattern, for the period 1950-2012. For this purpose, lead-lag relationships between SSTs and the EA pattern, ranging from 0 to 3 seasons, were assessed. As a main result, anomalies of the EA pattern in boreal summer and autumn are significantly related to SST anomalies in the Indo Pacific Ocean during the preceding seasons. A statistical forecasting scheme based on multiple linear regression was used to hindcast the EA-anomalies with a lead-time of 1 to 2 months. The results of a one-year-out cross-validation approach indicate that the phases of the EA in summer and autumn can be properly hindcast. PMID- 24466097 TI - Distinct effects of Abelson kinase mutations on myocytes and neurons in dissociated Drosophila embryonic cultures: mimicking of high temperature. AB - Abelson tyrosine kinase (Abl) is known to regulate axon guidance, muscle development, and cell-cell interaction in vivo. The Drosophila primary culture system offers advantages in exploring the cellular mechanisms mediated by Abl with utilizing various experimental manipulations. Here we demonstrate that single-embryo cultures exhibit stage-dependent characteristics of cellular differentiation and developmental progression in neurons and myocytes, as well as nerve-muscle contacts. In particular, muscle development critically depends on the stage of dissociated embryos. In wild-type (WT) cultures derived from embryos before stage 12, muscle cells remained within cell clusters and were rarely detected. Interestingly, abundant myocytes were spotted in Abl mutant cultures, exhibiting enhanced myocyte movement and fusion, as well as neuron-muscle contacts even in cultures dissociated from younger, stage 10 embryos. Notably, Abl myocytes frequently displayed well-expanded lamellipodia. Conversely, Abl neurons were characterized with fewer large veil-like lamellipodia, but instead had increased numbers of filopodia and darker nodes along neurites. These distinct phenotypes were equally evident in both homo- and hetero-zygous cultures (Abl/Abl vs. Abl/+) of different alleles (Abl(1) and Abl(4) ) indicating dominant mutational effects. Strikingly, in WT cultures derived from stage 10 embryos, high temperature (HT) incubation promoted muscle migration and fusion, partially mimicking the advanced muscle development typical of Abl cultures. However, HT enhanced neuronal growth with increased numbers of enlarged lamellipodia, distinct from the characteristic Abl neuronal morphology. Intriguingly, HT incubation also promoted Abl lamellipodia expansion, with a much greater effect on nerve cells than muscle. Our results suggest that Abl is an essential regulator for myocyte and neuron development and that high-temperature incubation partially mimics the faster muscle development typical of Abl cultures. Despite the extensive alterations by Abl mutations, we observed myocyte fusion events and nerve-muscle contact formation between WT and Abl cells in mixed WT and Abl cultures derived from labeled embryos. PMID- 24466099 TI - Climatic control on plant and soil delta(13)C along an altitudinal transect of Lushan mountain in subtropical china: characteristics and interpretation of soil carbon dynamics. AB - Decreasing temperature and increasing precipitation along altitude gradients are typical mountain climate in subtropical China. In such a climate regime, identifying the patterns of the C stable isotope composition (delta(13)C) in plants and soils and their relations to the context of climate change is essential. In this study, the patterns of delta(13)C variation were investigated for tree leaves, litters, and soils in the natural secondary forests at four altitudes (219, 405, 780, and 1268 m a.s.l.) in Lushan Mountain, central subtropical China. For the dominant trees, both leaf and leaf-litter delta(13)C decreased as altitude increased from low to high altitude, whereas surface soil delta(13)C increased. The lower leaf delta(13)C at high altitudes was associated with the high moisture-related discrimination, while the high soil delta(13)C is attributed to the low temperature-induced decay. At each altitude, soil delta(13)C became enriched with soil depth. Soil delta(13)C increased with soil C concentrations and altitude, but decreased with soil depth. A negative relationship was also found between O-alkyl C and delta(13)C in litter and soil, whereas a positive relationship was observed between aromatic C and delta(13)C. Lower temperature and higher moisture at high altitudes are the predominant control factors of delta(13)C variation in plants and soils. These results help understand C dynamics in the context of global warming. PMID- 24466100 TI - Concentrations, source and risk assessment of polycyclic aromatic hydrocarbons in soils from midway atoll, north pacific ocean. AB - This study was designed to determine concentrations of polycyclic aromatic hydrocarbons (PAHs) in soil samples collected from Midway Atoll and evaluate their potential risks to human health. The total concentrations of 16 PAHs ranged from 3.55 to 3200 ug kg(-1) with a mean concentration of 198 ug kg(-1). Higher molecular weight PAHs (4-6 ring PAHs) dominated the PAH profiles, accounting for 83.3% of total PAH mass. PAH diagnostic ratio analysis indicated that primary sources of PAHs in Midway Atoll could be combustion. The benzo[a]pyrene equivalent concentration (BaPeq) in most of the study area (86.5%) was less than 40 ug kg(-1) BaPeq and total incremental lifetime cancer risks of PAHs ranged from 1.00*10(-10) to 9.20*10(-6) with a median value of 1.24*10(-7), indicating a minor carcinogenic risk of PAHs in Midway Atoll. PMID- 24466101 TI - Is gene transcription involved in seed dry after-ripening? AB - Orthodox seeds are living organisms that survive anhydrobiosis and may display dormancy, an inability to germinate at harvest. Seed germination potential can be acquired during a prolonged period of dry storage called after-ripening. The aim of this work was to determine if gene transcription is an underlying regulatory mechanism for dormancy alleviation during after-ripening. To identify changes in gene transcription strictly associated with the acquisition of germination potential but not with storage, we used seed storage at low relative humidity that maintains dormancy as control. Transcriptome profiling was performed using DNA microarray to compare change in gene transcript abundance between dormant (D), after-ripened non-dormant (ND) and after-ripened dormant seeds (control, C). Quantitative real-time polymerase chain reaction (qPCR) was used to confirm gene expression. Comparison between D and ND showed the differential expression of 115 probesets at cut-off values of two-fold change (p<0.05). Comparisons between both D and C with ND in transcript abundance showed that only 13 transcripts, among 115, could be specific to dormancy alleviation. qPCR confirms the expression pattern of these transcripts but without significant variation between conditions. Here we show that sunflower seed dormancy alleviation in the dry state is not related to regulated changes in gene expression. PMID- 24466102 TI - The combined effects of hospital and surgeon volume on short-term survival after hepatic resection in a population-based study. AB - BACKGROUND: The influence of different hospital and surgeon volumes on short-term survival after hepatic resection is not clearly clarified. By taking the known prognostic factors into account, the purpose of this study is to assess the combined effects of hospital and surgeon volume on short-term survival after hepatic resection. METHODS: 13,159 patients who underwent hepatic resection between 2002 and 2006 were identified in the Taiwan National Health Insurance Research Database. Data were extracted from it and short-term survivals were confirmed through 2006. The Cox proportional hazards model was used to assess the relationship between survival and different hospital, surgeon volume and caseload combinations. RESULTS: High-volume surgeons in high-volume hospitals had the highest short-term survivals, following by high-volume surgeons in low-volume hospitals, low-volume surgeons in high-volume hospitals and low-volume surgeons in low-volume hospitals. Based on Cox proportional hazard models, although high volume hospitals and surgeons both showed significant lower risks of short-term mortality at hospital and surgeon level analysis, after combining hospital and surgeon volume into account, high-volume surgeons in high-volume hospitals had significantly better outcomes; the hazard ratio of other three caseload combinations ranging from 1.66 to 2.08 (p<0.001) in 3-month mortality, and 1.28 to 1.58 (p<0.01) in 1-year mortality. CONCLUSIONS: The combined effects of hospital and surgeon volume influenced the short-term survival after hepatic resection largely. After adjusting for the prognostic factors in the case mix, high-volume surgeons in high-volume hospitals had better short-term survivals. Centralization of hepatic resection to few surgeons and hospitals might improve patients' prognosis. PMID- 24466103 TI - Arsenic trioxide induces apoptosis in human platelets via C-Jun NH2-terminal kinase activation. AB - Arsenic trioxide (ATO), one of the oldest drugs in both Western and traditional Chinese medicine, has become an effective anticancer drug, especially in the treatment of acute promyelocytic leukemia (APL). However, thrombocytopenia occurred in most of ATO-treated patients with APL or other malignant diseases, and the pathogenesis remains unclear. Here we show that ATO dose-dependently induces depolarization of mitochondrial inner transmembrane potential (DeltaPsim), up-regulation of Bax and down-regulation of Bcl-2 and Bcl-XL, caspase-3 activation, and phosphotidylserine (PS) exposure in platelets. ATO did not induce surface expression of P-selectin and PAC-1 binding, whereas, obviously reduced collagen, ADP, and thrombin induced platelet aggregation. ATO dose dependently induced c-Jun NH2-terminal kinase (JNK) activation, and JNK specific inhibitor dicumarol obviously reduced ATO-induced DeltaPsim depolarization in platelets. Clinical therapeutic dosage of ATO was intraperitoneally injected into C57 mice, and the numbers of circulating platelets were significantly reduced after five days of continuous injection. The data demonstrate that ATO induces caspase-dependent apoptosis via JNK activation in platelets. ATO does not incur platelet activation, whereas, it not only impairs platelet function but also reduces circulating platelets in vivo, suggesting the possible pathogenesis of thrombocytopenia in patients treated with ATO. PMID- 24466104 TI - AT1 receptor blockade attenuates insulin resistance and myocardial remodeling in rats with diet-induced obesity. AB - BACKGROUND: Although obesity has been associated with metabolic and cardiac disturbances, the carrier mechanisms for these responses are poorly understood. This study analyzed whether angiotensin II blockade attenuates metabolic and cardiovascular disorders in rats with diet-induced obesity. MATERIAL AND METHODS: Wistar-Kyoto (n = 40) rats were subjected to control (C; 3.2 kcal/g) and hypercaloric diets (OB; 4.6 kcal/g) for 30 weeks. Subsequently, rats were distributed to four groups: C, CL, OB, and OBL. L groups received Losartan (30 mg/kg/day) for five weeks. After this period we performed in vivo glucose tolerance and insulin tolerance tests, and measured triacylglycerol, insulin, angiotensin-converting enzyme activity (ACE), and leptin levels. Cardiovascular analyzes included systolic blood pressure (SBP), echocardiography, myocardial morphometric study, myosin heavy chain composition, and measurements of myocardial protein levels of angiotensin, extracellular signal-regulated (ERK1/2), c-Jun amino-terminal kinases (JNK), insulin receptor subunit beta (betaIR), and phosphatidylinositol 3-kinase (PI3K) by Western Blot. RESULTS: Glucose metabolism, insulin, lipid, and ACE activity disorders observed with obesity were minimized by Losartan. Moreover, obesity was associated with increased SBP, myocardial hypertrophy, interstitial fibrosis and improved systolic performance; these effects were also minimized with Losartan. On a molecular level, OB exhibited higher ERK, Tyr-phosphorylated betaIR, and PI3K expression, and reduced myocardial angiotensin and JNK expression. ERK and JNK expression were regulated in the presence of Losartan, while angiotensin, Tyr betaRI, total and Tyr-phosphorylated PI3K expression were elevated in the OBL group. CONCLUSION: Angiotensin II blockade with Losartan attenuates obesity induced metabolic and cardiovascular changes. PMID- 24466105 TI - Sweet taste receptor deficient mice have decreased adiposity and increased bone mass. AB - Functional expression of sweet taste receptors (T1R2 and T1R3) has been reported in numerous metabolic tissues, including the gut, pancreas, and, more recently, in adipose tissue. It has been suggested that sweet taste receptors in these non gustatory tissues may play a role in systemic energy balance and metabolism. Smaller adipose depots have been reported in T1R3 knockout mice on a high carbohydrate diet, and sweet taste receptors have been reported to regulate adipogenesis in vitro. To assess the potential contribution of sweet taste receptors to adipose tissue biology, we investigated the adipose tissue phenotypes of T1R2 and T1R3 knockout mice. Here we provide data to demonstrate that when fed an obesogenic diet, both T1R2 and T1R3 knockout mice have reduced adiposity and smaller adipocytes. Although a mild glucose intolerance was observed with T1R3 deficiency, other metabolic variables analyzed were similar between genotypes. In addition, food intake, respiratory quotient, oxygen consumption, and physical activity were unchanged in T1R2 knockout mice. Although T1R2 deficiency did not affect adipocyte number in peripheral adipose depots, the number of bone marrow adipocytes is significantly reduced in these knockout animals. Finally, we present data demonstrating that T1R2 and T1R3 knockout mice have increased cortical bone mass and trabecular remodeling. This report identifies novel functions for sweet taste receptors in the regulation of adipose and bone biology, and suggests that in these contexts, T1R2 and T1R3 are either dependent on each other for activity or have common independent effects in vivo. PMID- 24466106 TI - A multidisciplinary intervention to reduce infections of ESBL- and AmpC producing, gram-negative bacteria at a University Hospital. AB - In response to a considerable increase in the infections caused by ESBL/AmpC producing Klebsiella pneumonia in 2008, a multidisciplinary intervention, with a main focus on antimicrobial stewardship, was carried out at one university hospital. Four other hospitals were used as controls. Stringent guidelines for antimicrobial treatment and prophylaxis were disseminated throughout the intervention hospital; cephalosporins were restricted for prophylaxis use only, fluoroquinolones for empiric use in septic shock only, and carbapenems were selected for penicillin-allergic patients, infections due to ESBL/AmpC-producing and other resistant bacteria, in addition to their use in severe sepsis/septic shock. Piperacillin-tazobactam +/- gentamicin was recommended for empiric treatments of most febrile conditions. The intervention also included education and guidance on infection control, as well as various other surveillances. Two year follow-up data on the incidence rates of patients with selected bacterial infections, outcomes, and antibiotic consumption were assessed, employing before and-after analysis and segmented regression analysis of interrupted time series, using the other hospitals as controls. The intervention led to a sustained change in antimicrobial consumption, and the incidence of patients infected with ESBL producing K. pneumoniae decreased significantly (p<0.001). The incidences of other hospital-associated infections also declined (p's<0.02), but piperacillin tazobactam-resistant Pseudomonas aeruginosa and Enterococcus faecium infections increased (p's<0.033). In wards with high antimicrobial consumption, the patient gut carrier rate of ESBL-producing bacteria significantly decreased (p = 0.023). The unadjusted, all-cause 30-day mortality rates of K. pneumoniae and E. coli were unchanged over the four-year period, with similar results in all five hospitals. Although not statistically significant, the 30-day mortality rate of patients with ESBL-producing K. pneumoniae decreased, from 35% in 2008-2009, to 17% in 2010-2011. The two-year follow-up data indicated that this multidisciplinary intervention led to a statistically significant decrease in the incidence of ESBL/AmpC-resistant K. pneumoniae infections, as well as in the incidences of other typical hospital-associated bacterial infections. PMID- 24466107 TI - Hyposensitivity of C-fiber afferents at the distal extremities as an indicator of early stages diabetic bladder dysfunction in type 2 diabetic women. AB - PURPOSE: To investigate the relationship between distal symmetric peripheral neuropathy and early stages of autonomic bladder dysfunction in type 2 diabetic women. MATERIALS AND METHODS: A total of 137 diabetic women with minimal coexisting confounders of voiding dysfunction followed at a diabetes clinic were subject to the following evaluations: current perception threshold (CPT) tests on myelinated and unmyelinated nerves at the big toe for peroneal nerve and middle finger for median nerve, uroflowmetry, post-void residual urine volume, and overactive bladder (OAB) symptom score questionnaire. Patients presenting with voiding difficulty also underwent urodynamic studies and intravesical CPT tests. RESULTS: Based on the OAB symptom score and urodynamic studies, 19% of diabetic women had the OAB syndrome while 24.8% had unrecognized urodynamic bladder dysfunction (UBD). The OAB group had a significantly greater mean 5 Hz CPT test value at the big toe by comparison to those without OAB. When compared to diabetic women without UBD, those with UBD showed greater mean 5 Hz CPT test values at the middle finger and big toe. The diabetic women categorized as C fiber hyposensitivity at the middle finger or big toe by using CPT test also had higher odds ratios of UBD. Among diabetic women with UBD, the 5 Hz CPT test values at the big toe and middle finger were significantly associated with intravesical 5 Hz CPT test values. CONCLUSIONS: Using electrophysiological evidence, our study revealed that hyposensitivity of unmyelinated C fiber afferents at the distal extremities is an indicator of early stages diabetic bladder dysfunction in type 2 diabetic women. The C fiber dysfunction at the distal extremities seems concurrent with vesical C-fiber neuropathy and may be a sentinel for developing early diabetic bladder dysfunction among female patients. PMID- 24466108 TI - Plasma D-dimer levels are associated with stroke subtypes and infarction volume in patients with acute ischemic stroke. AB - BACKGROUND: It has been suggested that modestly elevated circulating D-dimer values may be associated with acute ischemic stroke (AIS). Thus, the purpose of this study was to investigate the association between plasma D-dimer level at admission and AIS in Chinese population. METHODS: In a prospective observational study, plasma D-dimer levels were measured using a particle-enhanced, immunoturbidimetric assay on admission in 240 Chinese patients with AIS. The National Institutes of Health Stroke Scale (NIHSS) score was assessed on admission blinded to D-dimer levels. RESULTS: Plasma median D-dimer levels were significantly (P = 0.000) higher in AIS patients as compared to healthy controls (0.88; interquartiler range [IQR], 0.28-2.11 mg/L and 0.31; IQR, 0.17-0.74 mg/L). D-dimer levels increased with increasing severity of stroke as defined by the NIHSS score(r = 0.179, p = 0.005) and infarct volume(r = 0.425, p = 0.000). Those positive trends still existed even after correcting for possible confounding factors (P = 0.012, 0.000; respectively). Based on the Receiver operating characteristic (ROC) curve, the optimal cut-off value of plasma D-dimer levels as an indicator for diagnosis of cardioembolic strokes was projected to be 0.91 mg/L, which yielded a sensitivity of 83.7% and a specificity of 81.5%, the area under the curve was 0.862(95% confidence interval [CI], 0.811-0.912). CONCLUSION: We had shown that plasma D-dimer levels increased with increasing severity of stroke as defined by the NIHSS score and infarct volume. These associations were independent other possible variables. In addition, cardioembolic strokes can be distinguished from other stroke etiologies by measuring plasma D-dimer levels very early (0-48 hours from stroke symptom onset). PMID- 24466109 TI - Correlates of 25-hydroxyvitamin D among Chinese breast cancer patients. AB - BACKGROUND: Few studies have investigated vitamin D status in association with modifiable lifestyle factors and clinical characteristics among breast cancer patients, with no studies among Chinese women, who may be at higher risk of vitamin D deficiency. We aimed to evaluate circulating 25-hydroxyvitamin D (25(OH)D) levels in association with clinical and lifestyle factors among 1,940 Chinese breast cancer patients. METHODS: Participants included breast cancer cases aged 22-77 from a population-based case-control study conducted in Shanghai, China during 1996-1998 (n = 1,044) and 2002-2005 (n = 896). Circulating 25(OH)D levels were measured in plasma samples (95% collected <=6 months post diagnosis). Prevalence ORs and 95% CIs were derived from multinomial logistic regression models, adjusting for age, season, and other factors. RESULTS: About 23% and 48% of women were vitamin D deficient (<30 nmol/L) or insufficient (30-50 nmol/L), respectively. Tumor characteristics were not associated with vitamin D status. Higher BMI was associated with increased odds of vitamin D deficiency (ORs (95% CIs): 1 (reference), 1.12 (0.85,1.47), and 1.57 (1.02,2.42), for <23, 23-<27.5, and >=27.5 kg/m(2), respectively, Ptrend <0.06). Total physical activity was associated with reduced odds of vitamin D deficiency (ORs (95% CIs):1 (reference), 0.84 (0.59,1.20), 0.65 (0.45,0.93), and 0.69 (0.48,1.00), for <7.65, 7.65-<10.6, 10.6-<13.5, >=13.5 MET-hours/day, respectively, Ptrend <0.02). Smoking was associated with vitamin D insufficiency and deficiency (ORs (95% CIs): 2.50 (1.07,5.84) and 2.78 (1.11,6.95), respectively). CONCLUSIONS: In the largest study to date, the prevalence of low vitamin D status was high among Chinese breast cancer patients and associated with higher BMI, smoking, and lower physical activity. Our findings support careful monitoring of vitamin D status and recommendations for supplementation and other lifestyle modifications that may improve vitamin D status in breast cancer patients. PMID- 24466110 TI - Bayesian dynamical systems modelling in the social sciences. AB - Data arising from social systems is often highly complex, involving non-linear relationships between the macro-level variables that characterize these systems. We present a method for analyzing this type of longitudinal or panel data using differential equations. We identify the best non-linear functions that capture interactions between variables, employing Bayes factor to decide how many interaction terms should be included in the model. This method punishes overly complicated models and identifies models with the most explanatory power. We illustrate our approach on the classic example of relating democracy and economic growth, identifying non-linear relationships between these two variables. We show how multiple variables and variable lags can be accounted for and provide a toolbox in R to implement our approach. PMID- 24466112 TI - In vivo evolution of a catalytic RNA couples trans-splicing to translation. AB - How does a non-coding RNA evolve in cells? To address this question experimentally we evolved a trans-splicing variant of the group I intron ribozyme from Tetrahymena over 21 cycles of evolution in E.coli cells. Sequence variation was introduced during the evolution by mutagenic and recombinative PCR, and increasingly active ribozymes were selected by their repair of an mRNA mediating antibiotic resistance. The most efficient ribozyme contained four clustered mutations that were necessary and sufficient for maximum activity in cells. Surprisingly, these mutations did not increase the trans-splicing activity of the ribozyme. Instead, they appear to have recruited a cellular protein, the transcription termination factor Rho, and facilitated more efficient translation of the ribozyme's trans-splicing product. In addition, these mutations affected the expression of several other, unrelated genes. These results suggest that during RNA evolution in cells, four mutations can be sufficient to evolve new protein interactions, and four mutations in an RNA molecule can generate a large effect on gene regulation in the cell. PMID- 24466111 TI - Fibroblast growth factor receptor 3 interacts with and activates TGFbeta activated kinase 1 tyrosine phosphorylation and NFkappaB signaling in multiple myeloma and bladder cancer. AB - Cancer is a major public health problem worldwide. In the United States alone, 1 in 4 deaths is due to cancer and for 2013 a total of 1,660,290 new cancer cases and 580,350 cancer-related deaths are projected. Comprehensive profiling of multiple cancer genomes has revealed a highly complex genetic landscape in which a large number of altered genes, varying from tumor to tumor, impact core biological pathways and processes. This has implications for therapeutic targeting of signaling networks in the development of treatments for specific cancers. The NFkappaB transcription factor is constitutively active in a number of hematologic and solid tumors, and many signaling pathways implicated in cancer are likely connected to NFkappaB activation. A critical mediator of NFkappaB activity is TGFbeta-activated kinase 1 (TAK1). Here, we identify TAK1 as a novel interacting protein and target of fibroblast growth factor receptor 3 (FGFR3) tyrosine kinase activity. We further demonstrate that activating mutations in FGFR3 associated with both multiple myeloma and bladder cancer can modulate expression of genes that regulate NFkappaB signaling, and promote both NFkappaB transcriptional activity and cell adhesion in a manner dependent on TAK1 expression in both cancer cell types. Our findings suggest TAK1 as a potential therapeutic target for FGFR3-associated cancers, and other malignancies in which TAK1 contributes to constitutive NFkappaB activation. PMID- 24466113 TI - Clostridium perfringens phospholipase C induced ROS production and cytotoxicity require PKC, MEK1 and NFkappaB activation. AB - Clostridium perfringens phospholipase C (CpPLC), also called alpha-toxin, is the most toxic extracellular enzyme produced by this bacteria and is essential for virulence in gas gangrene. At lytic concentrations, CpPLC causes membrane disruption, whereas at sublytic concentrations this toxin causes oxidative stress and activates the MEK/ERK pathway, which contributes to its cytotoxic and myotoxic effects. In the present work, the role of PKC, ERK 1/2 and NFkappaB signalling pathways in ROS generation induced by CpPLC and their contribution to CpPLC-induced cytotoxicity was evaluated. The results demonstrate that CpPLC induces ROS production through PKC, MEK/ERK and NFkappaB pathways, the latter being activated by the MEK/ERK signalling cascade. Inhibition of either of these signalling pathways prevents CpPLC's cytotoxic effect. In addition, it was demonstrated that NFkappaB inhibition leads to a significant reduction in the myotoxicity induced by intramuscular injection of CpPLC in mice. Understanding the role of these signalling pathways could lead towards developing rational therapeutic strategies aimed to reduce cell death during a clostridialmyonecrosis. PMID- 24466114 TI - Influence of ATP-binding cassette transporter 1 R219K and M883I polymorphisms on development of atherosclerosis: a meta-analysis of 58 studies. AB - BACKGROUND: Numerous epidemiological studies have evaluated the associations between ATP-binding cassette transporter 1 (ABCA1) R219K (rs2230806) and M883I (rs4149313) polymorphisms and atherosclerosis (AS), but results remain controversial. The purpose of the present study is to investigate whether these two polymorphisms facilitate the susceptibility to AS using a meta-analysis. METHODS: PubMed, Embase, Web of Science, Medline, Cochrane database, Clinicaltrials.gov, Current Controlled Trials, Chinese Clinical Trial Registry, CBMdisc, CNKI, Google Scholar and Baidu Library were searched to get the genetic association studies. All statistical analyses were done with Stata 11.0. RESULTS: Forty-seven articles involving 58 studies were included in the final meta analysis. For the ABCA1 R219K polymorphism, 42 studies involving 12,551 AS cases and 19,548 controls were combined showing significant association between this variant and AS risk (for K allele vs. R allele: OR = 0.77, 95% CI = 0.71-0.84, P<0.01; for K/K vs. R/R: OR = 0.60, 95% CI = 0.51-0.71, P<0.01; for K/K vs. R/K+R/R: OR = 0.69, 95% CI = 0.60-0.80, P<0.01; for K/K+R/K vs. R/R: OR = 0.74, 95% CI = 0.66-0.83, P<0.01). For the ABCA1 M883I polymorphism, 16 studies involving 4,224 AS cases and 3,462 controls were combined. There was also significant association between the variant and AS risk (for I allele vs. M allele: OR = 0.85, 95% CI = 0.77-0.95, P<0.01). CONCLUSIONS: The present meta analysis suggested that the ABCA1 R219K and M883I polymorphisms were associated with the susceptibility to AS. However, due to the high heterogeneity in the meta analysis, the results should be interpreted with caution. PMID- 24466115 TI - Recombinant production of the amino terminal cytoplasmic region of dengue virus non-structural protein 4A for structural studies. AB - BACKGROUND: Dengue virus (DENV) is a mosquito-transmitted positive single strand RNA virus belonging to the Flaviviridae family. DENV causes dengue fever, currently the world's fastest-spreading tropical disease. Severe forms of the disease like dengue hemorrhagic fever and dengue shock syndrome are life threatening. There is no specific treatment and no anti-DENV vaccines. Our recent data suggests that the amino terminal cytoplasmic region of the dengue virus non structural protein 4A (NS4A) comprising amino acid residues 1 to 48 forms an amphipathic helix in the presence of membranes. Its amphipathic character was shown to be essential for viral replication. NMR-based structure-function analysis of the NS4A amino terminal region depends on its milligram-scale production and labeling with NMR active isotopes. METHODOLOGY/PRINCIPAL FINDINGS: This report describes the optimization of a uniform procedure for the expression and purification of the wild type NS4A(1-48) peptide and a peptide derived from a replication-deficient mutant NS4A(1-48; L6E, M10E) with disrupted amphipathic nature. A codon-optimized, synthetic gene for NS4A(1-48) was expressed as a fusion with a GST-GB1 dual tag in E. coli. Tobacco etch virus (TEV) protease mediated cleavage generated NS4A(1-48) peptides without any artificial overhang. Using the described protocol up to 4 milligrams of the wild type or up to 5 milligrams of the mutant peptide were obtained from a one-liter culture. Isotopic labeling of the peptides was achieved and initial NMR spectra were recorded. CONCLUSIONS/SIGNIFICANCE: Small molecules targeting amphipathic helices in the related Hepatitis C virus were shown to inhibit viral replication, representing a new class of antiviral drugs. These findings highlight the need for an efficient procedure that provides large quantities of the amphipathic helix containing NS4A peptides. The double tag strategy presented in this manuscript answers these needs yielding amounts that are sufficient for comprehensive biophysical and structural studies, which might reveal new drug targets. PMID- 24466116 TI - Land use compounds habitat losses under projected climate change in a threatened California ecosystem. AB - Given the rapidly growing human population in mediterranean-climate systems, land use may pose a more immediate threat to biodiversity than climate change this century, yet few studies address the relative future impacts of both drivers. We assess spatial and temporal patterns of projected 21(st) century land use and climate change on California sage scrub (CSS), a plant association of considerable diversity and threatened status in the mediterranean-climate California Floristic Province. Using a species distribution modeling approach combined with spatially-explicit land use projections, we model habitat loss for 20 dominant shrub species under unlimited and no dispersal scenarios at two time intervals (early and late century) in two ecoregions in California (Central Coast and South Coast). Overall, projected climate change impacts were highly variable across CSS species and heavily dependent on dispersal assumptions. Projected anthropogenic land use drove greater relative habitat losses compared to projected climate change in many species. This pattern was only significant under assumptions of unlimited dispersal, however, where considerable climate-driven habitat gains offset some concurrent climate-driven habitat losses. Additionally, some of the habitat gained with projected climate change overlapped with projected land use. Most species showed potential northern habitat expansion and southern habitat contraction due to projected climate change, resulting in sharply contrasting patterns of impact between Central and South Coast Ecoregions. In the Central Coast, dispersal could play an important role moderating losses from both climate change and land use. In contrast, high geographic overlap in habitat losses driven by projected climate change and projected land use in the South Coast underscores the potential for compounding negative impacts of both drivers. Limiting habitat conversion may be a broadly beneficial strategy under climate change. We emphasize the importance of addressing both drivers in conservation and resource management planning. PMID- 24466117 TI - Evaluation of reference genes for accurate normalization of gene expression for real time-quantitative PCR in Pyrus pyrifolia using different tissue samples and seasonal conditions. AB - We have evaluated suitable reference genes for real time (RT)-quantitative PCR (qPCR) analysis in Japanese pear (Pyrus pyrifolia). We tested most frequently used genes in the literature such as beta-Tubulin, Histone H3, Actin, Elongation factor-1alpha, Glyceraldehyde-3-phosphate dehydrogenase, together with newly added genes Annexin, SAND and TIP41. A total of 17 primer combinations for these eight genes were evaluated using cDNAs synthesized from 16 tissue samples from four groups, namely: flower bud, flower organ, fruit flesh and fruit skin. Gene expression stabilities were analyzed using geNorm and NormFinder software packages or by DeltaCt method. geNorm analysis indicated three best performing genes as being sufficient for reliable normalization of RT-qPCR data. Suitable reference genes were different among sample groups, suggesting the importance of validation of gene expression stability of reference genes in the samples of interest. Ranking of stability was basically similar between geNorm and NormFinder, suggesting usefulness of these programs based on different algorithms. DeltaCt method suggested somewhat different results in some groups such as flower organ or fruit skin; though the overall results were in good correlation with geNorm or NormFinder. Gene expression of two cold-inducible genes PpCBF2 and PpCBF4 were quantified using the three most and the three least stable reference genes suggested by geNorm. Although normalized quantities were different between them, the relative quantities within a group of samples were similar even when the least stable reference genes were used. Our data suggested that using the geometric mean value of three reference genes for normalization is quite a reliable approach to evaluating gene expression by RT-qPCR. We propose that the initial evaluation of gene expression stability by DeltaCt method, and subsequent evaluation by geNorm or NormFinder for limited number of superior gene candidates will be a practical way of finding out reliable reference genes. PMID- 24466118 TI - Nucleic acid content in crustacean zooplankton: bridging metabolic and stoichiometric predictions. AB - Metabolic and stoichiometric theories of ecology have provided broad complementary principles to understand ecosystem processes across different levels of biological organization. We tested several of their cornerstone hypotheses by measuring the nucleic acid (NA) and phosphorus (P) content of crustacean zooplankton species in 22 high mountain lakes (Sierra Nevada and the Pyrenees mountains, Spain). The P-allocation hypothesis (PAH) proposes that the genome size is smaller in cladocerans than in copepods as a result of selection for fast growth towards P-allocation from DNA to RNA under P limitation. Consistent with the PAH, the RNA:DNA ratio was >8-fold higher in cladocerans than in copepods, although 'fast-growth' cladocerans did not always exhibit higher RNA and lower DNA contents in comparison to 'slow-growth' copepods. We also showed strong associations among growth rate, RNA, and total P content supporting the growth rate hypothesis, which predicts that fast-growing organisms have high P content because of the preferential allocation to P-rich ribosomal RNA. In addition, we found that ontogenetic variability in NA content of the copepod Mixodiaptomus laciniatus (intra- and interstage variability) was comparable to the interspecific variability across other zooplankton species. Further, according to the metabolic theory of ecology, temperature should enhance growth rate and hence RNA demands. RNA content in zooplankton was correlated with temperature, but the relationships were nutrient-dependent, with a positive correlation in nutrient-rich ecosystems and a negative one in those with scarce nutrients. Overall our results illustrate the mechanistic connections among organismal NA content, growth rate, nutrients and temperature, contributing to the conceptual unification of metabolic and stoichiometric theories. PMID- 24466119 TI - Honey bees avoid nectar colonized by three bacterial species, but not by a yeast species, isolated from the bee gut. AB - The gut microflora of the honey bee, Apis mellifera, is receiving increasing attention as a potential determinant of the bees' health and their efficacy as pollinators. Studies have focused primarily on the microbial taxa that appear numerically dominant in the bee gut, with the assumption that the dominant status suggests their potential importance to the bees' health. However, numerically minor taxa might also influence the bees' efficacy as pollinators, particularly if they are not only present in the gut, but also capable of growing in floral nectar and altering its chemical properties. Nonetheless, it is not well understood whether honey bees have any feeding preference for or against nectar colonized by specific microbial species. To test whether bees exhibit a preference, we conducted a series of field experiments at an apiary using synthetic nectar inoculated with specific species of bacteria or yeast that had been isolated from the bee gut, but are considered minor components of the gut microflora. These species had also been found in floral nectar. Our results indicated that honey bees avoided nectar colonized by the bacteria Asaia astilbes, Erwinia tasmaniensis, and Lactobacillus kunkeei, whereas the yeast Metschnikowia reukaufii did not affect the feeding preference of the insects. Our results also indicated that avoidance of bacteria-colonized nectar was caused not by the presence of the bacteria per se, but by the chemical changes to nectar made by the bacteria. These findings suggest that gut microbes may not only affect the bees' health as symbionts, but that some of the microbes may possibly affect the efficacy of A. mellifera as pollinators by altering nectar chemistry and influencing their foraging behavior. PMID- 24466120 TI - Neural plasticity in human brain connectivity: the effects of long term deep brain stimulation of the subthalamic nucleus in Parkinson's disease. AB - BACKGROUND: Positive clinical outcomes are now well established for deep brain stimulation, but little is known about the effects of long-term deep brain stimulation on brain structural and functional connectivity. Here, we used the rare opportunity to acquire pre- and postoperative diffusion tensor imaging in a patient undergoing deep brain stimulation in bilateral subthalamic nuclei for Parkinson's Disease. This allowed us to analyse the differences in structural connectivity before and after deep brain stimulation. Further, a computational model of spontaneous brain activity was used to estimate the changes in functional connectivity arising from the specific changes in structural connectivity. RESULTS: We found significant localised structural changes as a result of long-term deep brain stimulation. These changes were found in sensory motor, prefrontal/limbic, and olfactory brain regions which are known to be affected in Parkinson's Disease. The nature of these changes was an increase of nodal efficiency in most areas and a decrease of nodal efficiency in the precentral sensory-motor area. Importantly, the computational model clearly shows the impact of deep brain stimulation-induced structural alterations on functional brain changes, which is to shift the neural dynamics back towards a healthy regime. The results demonstrate that deep brain stimulation in Parkinson's Disease leads to a topological reorganisation towards healthy bifurcation of the functional networks measured in controls, which suggests a potential neural mechanism for the alleviation of symptoms. CONCLUSIONS: The findings suggest that long-term deep brain stimulation has not only restorative effects on the structural connectivity, but also affects the functional connectivity at a global level. Overall, our results support causal changes in human neural plasticity after long-term deep brain stimulation and may help to identify the underlying mechanisms of deep brain stimulation. PMID- 24466121 TI - Environmental smoking and smoking onset in adolescence: the role of dopamine related genes. Findings from two longitudinal studies. AB - Although environmental smoking (i.e., paternal and maternal smoking, sibling smoking, and peer smoking) is one of the most important factors for explaining adolescent smoking behavior, not all adolescents are similarly affected. The extent to which individuals are vulnerable to smoking in their environment might depend on genetic factors. The aim of this study was to examine the interplay between environmental smoking and genes encoding components of the dopaminergic system (i.e., dopamine receptor D2, D4, and dopamine transporter DAT1) in adolescent smoking onset. Data from two longitudinal studies were used. Study 1 consisted of 991 non-smoking early adolescents (mean age = 12.52, SD = .57) whereas study 2 consisted of 365 non-smoking middle to late adolescents (mean age = 14.16, SD = 1.07) who were followed for 16 and 48 months, respectively. Logistic regression analyses were conducted using Mplus. In study 1, we found positive associations between parents' and friends' smoking at the first measurement and smoking status 16 months later. In study 2 we found a positive association between friends' smoking and smoking onset 48 months later. Neither study demonstrated any interaction effects of the DRD2, DRD4, or DAT1 genotypes. In conclusion, the effects of environmental smoking on smoking onset are similar for adolescent carriers and non-carriers of these specific genes related to the dopaminergic system. PMID- 24466122 TI - Salicylic acid, a plant defense hormone, is specifically secreted by a molluscan herbivore. AB - Slugs and snails are important herbivores in many ecosystems. They differ from other herbivores by their characteristic mucus trail. As the mucus is secreted at the interface between the plants and the herbivores, its chemical composition may play an essential role in plant responses to slug and snail attack. Based on our current knowledge about host-manipulation strategies employed by pathogens and insects, we hypothesized that mollusks may excrete phytohormone-like substances into their mucus. We therefore screened locomotion mucus from thirteen molluscan herbivores for the presence of the plant defense hormones jasmonic acid (JA), salicylic acid (SA) and abscisic acid (ABA). We found that the locomotion mucus of one slug, Deroceras reticulatum, contained significant amounts of SA, a plant hormone that is known to induce resistance to pathogens and to suppress plant immunity against herbivores. None of the other slugs and snails contained SA or any other hormone in their locomotion mucus. When the mucus of D. reticulatum was applied to wounded leaves of A. thaliana, the promotor of the SA-responsive gene pathogenesis related 1 (PR1) was activated, demonstrating the potential of the mucus to regulate plant defenses. We discuss the potential ecological, agricultural and medical implications of this finding. PMID- 24466123 TI - Putting actions in context: visual action adaptation aftereffects are modulated by social contexts. AB - The social context in which an action is embedded provides important information for the interpretation of an action. Is this social context integrated during the visual recognition of an action? We used a behavioural visual adaptation paradigm to address this question and measured participants' perceptual bias of a test action after they were adapted to one of two adaptors (adaptation after-effect). The action adaptation after-effect was measured for the same set of adaptors in two different social contexts. Our results indicate that the size of the adaptation effect varied with social context (social context modulation) although the physical appearance of the adaptors remained unchanged. Three additional experiments provided evidence that the observed social context modulation of the adaptation effect are owed to the adaptation of visual action recognition processes. We found that adaptation is critical for the social context modulation (experiment 2). Moreover, the effect is not mediated by emotional content of the action alone (experiment 3) and visual information about the action seems to be critical for the emergence of action adaptation effects (experiment 4). Taken together these results suggest that processes underlying visual action recognition are sensitive to the social context of an action. PMID- 24466124 TI - Selection and evaluation of potential reference genes for gene expression analysis in the brown planthopper, Nilaparvata lugens (Hemiptera: Delphacidae) using reverse-transcription quantitative PCR. AB - The brown planthopper (BPH), Nilaparvata lugens (Hemiptera, Delphacidae), is one of the most important rice pests. Abundant genetic studies on BPH have been conducted using reverse-transcription quantitative real-time PCR (qRT-PCR). Using qRT-PCR, the expression levels of target genes are calculated on the basis of endogenous controls. These genes need to be appropriately selected by experimentally assessing whether they are stably expressed under different conditions. However, such studies on potential reference genes in N. lugens are lacking. In this paper, we presented a systematic exploration of eight candidate reference genes in N. lugens, namely, actin 1 (ACT), muscle actin (MACT), ribosomal protein S11 (RPS11), ribosomal protein S15e (RPS15), alpha 2-tubulin (TUB), elongation factor 1 delta (EF), 18S ribosomal RNA (18S), and arginine kinase (AK) and used four alternative methods (BestKeeper, geNorm, NormFinder, and the delta Ct method) to evaluate the suitability of these genes as endogenous controls. We examined their expression levels among different experimental factors (developmental stage, body part, geographic population, temperature variation, pesticide exposure, diet change, and starvation) following the MIQE (Minimum Information for publication of Quantitative real time PCR Experiments) guidelines. Based on the results of RefFinder, which integrates four currently available major software programs to compare and rank the tested candidate reference genes, RPS15, RPS11, and TUB were found to be the most suitable reference genes in different developmental stages, body parts, and geographic populations, respectively. RPS15 was the most suitable gene under different temperature and diet conditions, while RPS11 was the most suitable gene under different pesticide exposure and starvation conditions. This work sheds light on establishing a standardized qRT-PCR procedure in N. lugens, and serves as a starting point for screening for reference genes for expression studies of related insects. PMID- 24466125 TI - Molecular and cellular characterization of the tomato pollen profilin, LePro1. AB - Profilin is an actin-binding protein involved in the dynamic turnover and restructuring of the actin cytoskeleton in all eukaryotic cells. We previously cloned a profilin gene, designated as LePro1 from tomato pollen. To understand its biological role, in the present study, we investigated the temporal and spatial expression of LePro1 during pollen development and found that the transcript was only detected at late stages during microsporogenesis and pollen maturation. Using antisense RNA, we successfully knocked down the expression of LePro1 in tomato plants using stable transformation, and obtained two antisense lines, A2 and A3 showing significant down-regulation of LePro1 in pollen resulting in poor pollen germination and abnormal pollen tube growth. A disorganized F-actin distribution was observed in the antisense pollen. Down regulation of LePro1 also appeared to affect hydration of pollen deposited on the stigma and arrested pollen tube elongation in the style, thereby affecting fertilization. Our results suggest that LePro1 in conjunction with perhaps other cytoskeletal proteins, plays a regulatory role in the proper organization of F actin in tomato pollen tubes through promoting actin assembly. Down-regulation of LePro1 leads to interruption of actin assembly and disorganization of the actin cytoskeleton thus arresting pollen tube growth. Based on the present and previous studies, it is likely that a single transcript of profilin gives rise to multiple forms displaying multifunctionality in tomato pollen. PMID- 24466126 TI - IHF is required for the transcriptional regulation of the Desulfovibrio vulgaris Hildenborough orp operons. AB - Transcriptional activation of sigma(54)-dependent promoters is usually tightly regulated in response to environmental cues. The high abundance of potential sigma(54)-dependent promoters in the anaerobe bacteria, Desulfovibrio vulgaris Hildenborough, reflects the high versatility of this bacteria suggesting that sigma(54) factor is the nexus of a large regulatory network. Understanding the key players of sigma(54)-regulation in this organism is therefore essential to gain insights into the adaptation to anaerobiosis. Recently, the D. vulgaris orp genes, specifically found in anaerobe bacteria, have been shown to be transcribed by the RNA polymerase coupled to the sigma(54) alternative sigma factor. In this study, using in vitro binding experiments and in vivo reporter fusion assays in the Escherichia coli heterologous host, we showed that the expression of the divergent orp promoters is strongly dependent on the integration host factor IHF. Bioinformatic and mutational analysis coupled to reporter fusion activities and mobility shift assays identified two functional IHF binding site sequences located between the orp1 and orp2 promoters. We further determined that the D. vulgaris DVU0396 (IHFalpha) and DVU1864 (IHFbeta) subunits are required to control the expression of the orp operons suggesting that they form a functionally active IHF heterodimer. Interestingly results obtained from the in vivo inactivation of DVU0396, which is required for orp operons transcription, suggest that several functionally IHF active homodimer or heterodimer are present in D. vulgaris. PMID- 24466127 TI - Microsatellite evidence for high frequency of multiple paternity in the marine gastropod Rapana venosa. AB - BACKGROUND: Inferring of parentage in natural populations is important in understanding the mating systems of a species, which have great effects on its genetic structure and evolution. Muricidae, a large group (approximately 1,600 species) of marine gastropods, are poorly investigated in patterns of multiple paternity and sperm competition based on molecular techniques. The veined Rapa whelk, Rapana venosa, a commercially important muricid species with internal fertilization, is an ideal species to study the occurrence and frequency of multiple paternity and to facilitate understanding of their reproductive strategies. METHODOLOGY/PRINCIPAL FINDINGS: We developed five highly polymorphic microsatellites in R. venosa and applied them to identify multiple paternity in 19 broods (1381 embryos) collected from Dandong, China. Multiple paternity was detected in 17 (89.5%) of 19 broods. The number of sires per brood ranged from 1 to 7 (4.3 on average). Of the 17 multiply sired broods, 16 (94.1%) were significantly skewed from equal paternal contributions, and had a dominant sire which was also dominant in each assayed capsule. CONCLUSIONS: Our results indicate that a high level of multiple paternity occurs in the wild population of R. venosa. Similar patterns of multiple paternity in the 2-6 assayed capsules from each brood imply that fertilization events within the body of a female occur mostly (but not entirely) as random draws from a "well-but-not-perfectly blended sperm pool" of her several mates. Strongly skewed distributions of fertilization success among sires also suggest that sperm competition and/or cryptic female choice might be important for post-copulatory paternity biasing in this species. PMID- 24466128 TI - Divergent phenotypes in mutant TDP-43 transgenic mice highlight potential confounds in TDP-43 transgenic modeling. AB - The majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis are pathologically defined by the cleavage, cytoplasmic redistribution and aggregation of TAR DNA binding protein of 43 kDa (TDP-43). To examine the contribution of these potentially toxic mechanisms in vivo, we generated transgenic mice expressing human TDP-43 containing the familial amyotrophic lateral sclerosis-linked M337V mutation and identified two lines that developed neurological phenotypes of differing severity and progression. The first developed a rapid cortical neurodegenerative phenotype in the early postnatal period, characterized by fragmentation of TDP-43 and loss of endogenous murine Tdp-43, but entirely lacking aggregates of ubiquitin or TDP-43. A second, low expressing line was aged to 25 months without a severe neurodegenerative phenotype, despite a 30% loss of mouse Tdp-43 and accumulation of lower molecular weight TDP-43 species. Furthermore, TDP-43 fragments generated during neurodegeneration were not C-terminal, but rather were derived from a central portion of human TDP-43. Thus we find that aggregation is not required for cell loss, loss of murine Tdp-43 is not necessarily sufficient in order to develop a severe neurodegenerative phenotype and lower molecular weight TDP-43 positive species in mouse models should not be inherently assumed to be representative of human disease. Our findings are significant for the interpretation of other transgenic studies of TDP-43 proteinopathy. PMID- 24466129 TI - Reliability and validity of a point-of-care sural nerve conduction device for identification of diabetic neuropathy. AB - BACKGROUND: Confirmation of diabetic sensorimotor polyneuropathy (DSP) relies on standard nerve conduction studies (NCS) performed in specialized clinics. We explored the utility of a point-of-care device (POCD) for DSP detection by nontechnical personnel and a validation of diagnostic thresholds with those observed in a normative database. RESEARCH DESIGN AND METHODS: 44 subjects with type 1 and type 2 diabetes underwent standard NCS (reference method). Two nontechnical examiners measured sural nerve amplitude potential (SNAP) and conduction velocity (SNCV) using the POCD. Reliability was determined by intraclass correlation coefficients (ICC [2], [1]). Validity was determined by Bland-Altman analysis and receiver operating characteristic curves. RESULTS: The 44 subjects (50% female) with mean age 56 +/- 18 years had mean SNAP and SNCV of 8.0 +/- 8.6 uV and 41.5 +/- 8.2 m/s using standard NCS and 8.0 +/- 8.2 uV and 49.9 +/- 11.1 m/s using the POCD. Intrarater reproducibility ICC values were 0.97 for SNAP and 0.94 for SNCV while interrater reproducibility values were 0.83 and 0.79, respectively. Mean bias of the POCD was -0.1 +/- 3.6 uV for SNAP and +8.4 +/- 6.4 m/s for SNCV. A SNAP of <=6 uV had 88% sensitivity and 94% specificity for identifying age-and height-standardized reference NCS values, while a SNCV of <=48 m/s had 94% sensitivity and 82% specificity [corrected].. Abnormality in one or more of these thresholds was associated with 95% sensitivity and 71% specificity for identification of DSP according to electrophysiological criteria. CONCLUSIONS: The POCD demonstrated excellent reliability and acceptable accuracy. Threshold values for DSP identification validated those of published POCD normative values. We emphasize the presence of measurement bias--particularly for SNCV--that requires adjustment of threshold values to reflect those of standard NCS. PMID- 24466130 TI - CD90+ mesothelial-like cells in peritoneal fluid promote peritoneal metastasis by forming a tumor permissive microenvironment. AB - The peritoneal cavity is a common target of metastatic gastrointestinal and ovarian cancer cells, but the mechanisms leading to peritoneal metastasis have not been fully elucidated. In this study, we examined the roles of cells in peritoneal fluids on the development of peritoneal metastasis. We found that a minor subset of human intraperitoneal cells with CD90(+)/CD45(-) phenotype vigorously grew in culture with mesothelial-like appearance. The mesothelial-like cells (MLC) displayed the characteristics of mesenchymal stem cell, such as differentiating into adipocytes, osteocytes, and chondrocytes, and suppressing T cell proliferation. These cells highly expressed type I collagen, vimentin, alpha smooth muscle actin and fibroblast activated protein-alpha by the stimulation with TGF-beta, which is characteristic of activated myofibroblasts. Intraperitoneal co-injection of MLCs with the human gastric cancer cell line, MKN45, significantly enhanced the rate of metastatic formation in the peritoneum of nude mice. Histological examination revealed that many MLCs were engrafted in metastatic nodules and were mainly located at the fibrous area. Dasatinib, a potent tyrosine kinase inhibitor, strongly inhibited the proliferation of MLCs but not MKN45 in vitro. Nevertheless, oral administration of Dasatinib significantly inhibited the development of peritoneal metastasis of MKN45, and resulted in reduced fibrillar formation of metastatic nodules. These results suggest floating MLCs in the peritoneal fluids support the development of peritoneal metastasis possibly through the production of the permissive microenvironment, and thus the functional blockade of MLCs is a reasonable strategy to treat recurrent abdominal malignancies. PMID- 24466131 TI - Human insulin does not increase bladder cancer risk. AB - BACKGROUND: Whether human insulin can induce bladder cancer is rarely studied. METHODS: The reimbursement databases of all Taiwanese diabetic patients from 1996 to 2009 were retrieved from the National Health Insurance. An entry date was set at 1 January 2004 and a total of 785,234 patients with type 2 diabetes were followed up for bladder cancer incidence until the end of 2009. Users of pioglitazone were excluded and the period since the initiation of insulin glargine (marketed after the entry date in Taiwan) was not included in the calculation of follow-up. Incidences for ever-users, never-users and subgroups of human insulin exposure (using tertile cutoffs of time since starting insulin, duration of therapy and cumulative dose) were calculated and the hazard ratios were estimated by Cox regression. RESULTS: There were 87,940 ever-users and 697,294 never-users, with respective numbers of incident bladder cancer of 454 (0.52%) and 3,330 (0.48%), and respective incidence of 120.49 and 94.74 per 100,000 person-years. The overall hazard ratios (95% confidence intervals) indicated a significant association with insulin in the age-sex-adjusted models [1.238 (1.122-1.366)], but not in the model adjusted for all covariates [1.063 (0.951-1.187)]. There was also a significant trend for the hazard ratios for the different categories of the dose-response parameters in the age-sex-adjusted models, which became insignificant when all covariates were adjusted. CONCLUSIONS: This study relieves the concern of a bladder cancer risk associated with human insulin. Appropriate adjustment for confounders is important in the evaluation of cancer risk associated with a medication. PMID- 24466132 TI - Merging metabolism and power: development of a novel photobioelectric device driven by photosynthesis and respiration. AB - Generation of renewable energy is one of the grand challenges facing our society. We present a new bio-electric technology driven by chemical gradients generated by photosynthesis and respiration. The system does not require pure cultures nor particular species as it works with the core metabolic principles that define phototrophs and heterotrophs. The biology is interfaced with electrochemistry with an alkaline aluminum oxide cell design. In field trials we show the system is robust and can work with an undefined natural microbial community. Power generated is light and photosynthesis dependent. It achieved a peak power output of 33 watts/m(2) electrode. The design is simple, low cost and works with the biological processes driving the system by removing waste products that can impede growth. This system is a new class of bio-electric device and may have practical implications for algal biofuel production and powering remote sensing devices. PMID- 24466134 TI - Angiopoietin-2 primes infection-induced preterm delivery. AB - Current knowledge on the participation of angiopoietin-2 (Ang-2) in the inflammatory process and on the importance of bacterial endotoxins (LPS) in the induction of preterm delivery (PTD) led us to investigate the role of Ang-2/LPS interplay in the pathogenesis of PTD. At a first stage, Ang-2 was measured at the end of the first trimester of pregnancy in the serum of 50 women who delivered prematurely; of 88 women well-matched for age and parity who delivered full-term; and of 20 non-pregnant healthy women. Ang-2 was greater in pregnant than in non pregnant women. The time until delivery was shorter among those with Ang-2 greater than 4 ng/ml (odds ratio for delivery until week 34; p: 0.040). To further investigate the role of Ang-2 for PTD, an experimental model of PTD induced by the intraperitoneal injection of LPS in mice was used. Ang-2 was administered intraperitoneally before LPS on day 14 of pregnancy. When Ang-2 was administered before the LPS diluent, all mice delivered full-term. However, administration of Ang-2 prior LPS accelerated further the time until delivery. Sacrifice experiments showed that the effect of Ang-2 was accompanied by decrease of the penetration of Evans Blue in the embryos and by increase of its penetration in maternal tissues. In parallel, the concentration of tumour necrosis factor-alpha in the maternal circulation, in fetal tissues and in the placentas was significantly decreased. Results indicate that Ang-2 accelerated the phenomena of PTD induced by LPS. This is related with deprivation of fetal perfusion. PMID- 24466133 TI - Complex regulation of PKCbeta2 and PDK-1/AKT by ROCK2 in diabetic heart. AB - OBJECTIVES: The RhoA/ROCK pathway contributes to diabetic cardiomyopathy in part by promoting the sustained activation of PKCbeta2 but the details of their interaction are unclear. The purpose of this study was to investigate if over activation of ROCK in the diabetic heart leads to direct phosphorylation and activation of PKCbeta2, and to determine if their interaction affects PDK-1/Akt signaling. METHODS: Regulation by ROCK of PKCbeta2 and related kinases was investigated by Western blotting and co-immunoprecipitation in whole hearts and isolated cardiomyocytes from 12 to 14-week diabetic rats. Direct ROCK2 phosphorylation of PKCbeta2 was examined in vitro. siRNA silencing was used to confirm role of ROCK2 in PKCbeta2 phosphorylation in vascular smooth muscle cells cultured in high glucose. Furthermore, the effect of ROCK inhibition on GLUT4 translocation was determined in isolated cardiomyocytes by confocal microscopy. RESULTS: Expression of ROCK2 and expression and phosphorylation of PKCbeta2 were increased in diabetic hearts. A physical interaction between the two kinases was demonstrated by reciprocal immunoprecipitation, while ROCK2 directly phosphorylated PKCbeta2 at T641 in vitro. ROCK2 siRNA in vascular smooth muscle cells or inhibition of ROCK in diabetic hearts reduced PKCbeta2 T641 phosphorylation, and this was associated with attenuation of PKCbeta2 activity. PKCbeta2 also formed a complex with PDK-1 and its target AKT, and ROCK inhibition resulted in upregulation of the phosphorylation of PDK-1 and AKT, and increased translocation of glucose transporter 4 (GLUT4) to the plasma membrane in diabetic hearts. CONCLUSION: This study demonstrates that over-activation of ROCK2 contributes to diabetic cardiomyopathy by multiple mechanisms, including direct phosphorylation and activation of PKCbeta2 and interference with the PDK-1 mediated phosphorylation and activation of AKT and translocation of GLUT4. This suggests that ROCK2 is a critical node in the development of diabetic cardiomyopathy and may be an effective target to improve cardiac function in diabetes. PMID- 24466135 TI - Mapping genetic variants underlying differences in the central nitrogen metabolism in fermenter yeasts. AB - Different populations within a species represent a rich reservoir of allelic variants, corresponding to an evolutionary signature of withstood environmental constraints. Saccharomyces cerevisiae strains are widely utilised in the fermentation of different kinds of alcoholic beverages, such as, wine and sake, each of them derived from must with distinct nutrient composition. Importantly, adequate nitrogen levels in the medium are essential for the fermentation process, however, a comprehensive understanding of the genetic variants determining variation in nitrogen consumption is lacking. Here, we assessed the genetic factors underlying variation in nitrogen consumption in a segregating population derived from a cross between two main fermenter yeasts, a Wine/European and a Sake isolate. By linkage analysis we identified 18 main effect QTLs for ammonium and amino acids sources. Interestingly, majority of QTLs were involved in more than a single trait, grouped based on amino acid structure and indicating high levels of pleiotropy across nitrogen sources, in agreement with the observed patterns of phenotypic co-variation. Accordingly, we performed reciprocal hemizygosity analysis validating an effect for three genes, GLT1, ASI1 and AGP1. Furthermore, we detected a widespread pleiotropic effect on these genes, with AGP1 affecting seven amino acids and nine in the case of GLT1 and ASI1. Based on sequence and comparative analysis, candidate causative mutations within these genes were also predicted. Altogether, the identification of these variants demonstrate how Sake and Wine/European genetic backgrounds differentially consume nitrogen sources, in part explaining independently evolved preferences for nitrogen assimilation and representing a niche of genetic diversity for the implementation of practical approaches towards more efficient strains for nitrogen metabolism. PMID- 24466136 TI - Preferred and actual relative height among homosexual male partners vary with preferred dominance and sex role. AB - Previous research has shown repeatedly that human stature influences mate preferences and mate choice in heterosexuals. In general, it has been shown that tall men and average height women are most preferred by the opposite sex, and that both sexes prefer to be in a relationship where the man is taller than the woman. However, little is known about such partner preferences in homosexual individuals. Based on an online survey of a large sample of non-heterosexual men (N = 541), we found that the majority of men prefer a partner slightly taller than themselves. However, these preferences were dependent on the participant's own height, such that taller men preferred shorter partners, whereas shorter men preferred taller partners. We also examined whether height preferences predicted the preference for dominance and the adoption of particular sexual roles within a couple. Although a large proportion of men preferred to be in an egalitarian relationship with respect to preferred dominance (although not with respect to preferred sexual role), men that preferred a more dominant and more "active" sexual role preferred shorter partners, whereas those that preferred a more submissive and more "passive" sexual role preferred taller partners. Our results indicate that preferences for relative height in homosexual men are modulated by own height, preferred dominance and sex role, and do not simply resemble those of heterosexual women or men. PMID- 24466137 TI - Licochalcone A suppresses migration and invasion of human hepatocellular carcinoma cells through downregulation of MKK4/JNK via NF-kappaB mediated urokinase plasminogen activator expression. AB - Hepatocellular cell carcinoma (HCC) is one of the most commonly diagnosed cancers worldwide and in Taiwan. Chemoprevention of cancer with dietary bioactive compounds could potentially reverse, suppress, or prevent cancer progression. Licochalcone A (LicA) is a characteristic chalcone of licorice, which is the root of Glycyrrhiza inflate. It had been reported that LicA has anti-inflammatory, anti-microbial, and anti-tumor properties. However, the effects of LicA on the migration and invasion of human HCC cells have not yet been reported. In the present study, it was found that LicA inhibits the migratory and invasion ability of SK-Hep-1 and HA22T/VGH cells in a dose-dependent manner, as assessed by the cell migration and Matrigel cell invasion assay. Using casein zymography, Western blotting, reverse transcriptase polymerase chain reaction, and an immunofluorescence assay, it was found that LicA induces a dose-dependent inhibition of uPA activity and expression, as well as reduces mRNA levels in SK Hep-1 and HA22T/VGH cells. LicA was also found to inhibit the expression of phosphor-JNK and phosphor-MKK4 in SK-Hep-1 cells. Furthermore, LicA significantly decreased uPA levels in SP600125-treated or si-MKK4-transfected cells alongside a marked reduction in cell migration and invasion, which supports the notion that an inhibition of MKK4/JNK results in anti-metastatic effects. Moreover, LicA inhibited the expression of nuclear NF-kappaB, as well as the binding ability of NF-kappaB to the uPA promoter. These findings further our understanding of the role of LicA in suppressing tumor metastasis and its underlying molecular mechanisms, as well as suggest that LicA may be a promising anti-metastatic agent. PMID- 24466138 TI - Loss of CD34 expression in aging human choriocapillaris endothelial cells. AB - Structural and gene expression changes in the microvasculature of the human choroid occur during normal aging and age-related macular degeneration (AMD). In this study, we sought to determine the impact of aging and AMD on expression of the endothelial cell glycoprotein CD34. Sections from 58 human donor eyes were categorized as either young (under age 40), age-matched controls (> age 60 without AMD), or AMD affected (>age 60 with early AMD, geographic atrophy, or choroidal neovascularization). Dual labeling of sections with Ulex europaeus agglutinin-I lectin (UEA-I) and CD34 antibodies was performed, and the percentage of capillaries labeled with UEA-I but negative for anti-CD34 was determined. In addition, published databases of mouse and human retinal pigment epithelium choroid were evaluated and CD34 expression compared between young and old eyes. Immunohistochemical studies revealed that while CD34 and UEA-I were colocalized in young eyes, there was variable loss of CD34 immunoreactivity in older donor eyes. While differences between normal aging and AMD were not significant, the percentage of CD34 negative capillaries in old eyes, compared to young eyes, was highly significant (p = 3.8*10(-6)). Endothelial cells in neovascular membranes were invariably CD34 positive. Published databases show either a significant decrease in Cd34 (mouse) or a trend toward decreased CD34 (human) in aging. These findings suggest that UEA-I and endogenous alkaline phosphatase activity are more consistent markers of aging endothelial cells in the choroid, and suggest a possible mechanism for the increased inflammatory milieu in the aging choroid. PMID- 24466139 TI - Fuzi attenuates diabetic neuropathy in rats and protects schwann cells from apoptosis induced by high glucose. AB - Radix aconite lateralis preparata (Fuzi), a folk medicine, has long been used for the treatment of diabetes and paralysis in China. We examined the effect of Fuzi alone on diabetic rats and Schwann cells in high glucose and the components responsible for its activity. The major constituents of FZE were identified by HPLC-MS/MS data. Male Sprague Dawley rats (n = 36) were randomly divided into control, diabetic, FZE 1.75 g/kg, FZE 3.50 g/kg, FZE 7.00 g/kg, and methylcobalamin groups. After two weeks treatment, nerve conduction velocity and paw withdrawal latency were measured. In vitro, the Schwann cells were grouped according to exposure: normal glucose (NG), normal glucose plus mannitol (NG+M), high glucose (HG), and HG plus different concentrations of FZE (0.1 ug/ml, 1.0 ug/ml, and 10.0 ug/ml). Oxygen free radicals and apoptosis were evaluated through DCFH2DA, DHE and annexin-PE/7-AAD assay, respectively. Apoptosis factors (Bax, Bcl-2, CytoC, caspase-3, and caspase-9) were analyzed using immunofluorescence. Nine alkaloids were identified. The results from animal model showed that FZE was effective in accelerating nerve conduction velocity and shortening paw withdrawal latency in diabetic rats. And in vitro, FZE was also found to protect Schwann cells against high glucose injury. FZE could significantly decrease the apoptotic ratio, superoxide anion and peroxide level. Furthermore, the apoptosis factors, including Bax, Bcl-2, CytoC, caspase-3, and caspase-9 were ameliorated in FZE treated groups. The HPLC-MS(n) method is simple and suitable for the identification of alkaloids in Fuzi. FZE has a protective effect in diabetic neuropathic rats, which is probably achieved by the antiapoptotic effect of FZE on Schwann cells. Apoptosis factor data imply that FZE protected Schwann cells through the mitochondria pathway. Alkaloids are major components contributing to the protective effect. PMID- 24466140 TI - Structure of Utp21 tandem WD domain provides insight into the organization of the UTPB complex involved in ribosome synthesis. AB - Assembly of the eukaryotic ribosome requires a large number of trans-acting proteins and small nucleolar RNAs that transiently associate with the precursor rRNA to facilitate its modification, processing and binding with ribosomal proteins. UTPB is a large evolutionarily conserved complex in the 90S small subunit processome that mediates early processing of 18S rRNA. UTPB consists of six proteins Utp1/Pwp1, Utp6, Utp12/Dip2, Utp13, Utp18 and Utp21 and has abundant WD domains. Here, we determined the crystal structure of the tandem WD domain of yeast Utp21 at 2.1 A resolution, revealing two open-clamshell-shaped beta propellers. The bottom faces of both WD domains harbor several conserved patches that potentially function as molecular binding sites. We show that residues 100 190 of Utp18 bind to the tandem WD domain of Utp21. Structural mapping of previous crosslinking data shows that the WD domains of Utp18 and Utp1 are organized on two opposite sides of the Utp21 WD domains. This study reports the first structure of a UTPB component and provides insight into the structural organization of the UTPB complex. PMID- 24466141 TI - Overexpression of IL-10 in C2D macrophages promotes a macrophage phenotypic switch in adipose tissue environments. AB - Adipose tissue macrophages are a heterogeneous collection of classically activated (M1) and alternatively activated (M2) macrophages. Interleukin 10 (IL 10) is an anti-inflammatory cytokine, secreted by a variety of cell types including M2 macrophages. We generated a macrophage cell line stably overexpressing IL-10 (C2D-IL10) and analyzed the C2D-IL10 cells for several macrophage markers after exposure to adipocytes compared to C2D cells transfected with an empty vector (C2D-vector). C2D-IL10 macrophage cells expressed more CD206 when co-cultured with adipocytes than C2D-vector cells; while the co-cultured cell mixture also expressed higher levels of Il4, Il10, Il1beta and Tnf. Since regular C2D cells traffic to adipose tissue after adoptive transfer, we explored the impact of constitutive IL-10 expression on C2D-IL10 macrophages in adipose tissue in vivo. Adipose tissue-isolated C2D-IL10 cells increased the percentage of CD206(+), CD301(+), CD11c(-)CD206(+) (M2) and CD11c(+)CD206(+) (M1b) on their cell surface, compared to isolated C2D-vector cells. These data suggest that the expression of IL-10 remains stable, alters the C2D-IL10 macrophage cell surface phenotype and may play a role in regulating macrophage interactions with the adipose tissue. PMID- 24466142 TI - The role of contrast adaptation in saccadic suppression in humans. AB - The idea of retinal and ex-retinal sources of saccadic suppression has long been established in previous studies. However, how they are implemented in local circuit remains unknown. Researchers have suggested that saccadic suppression was probably achieved by contrast gain control, but this possibility has never been directly tested. In this study, we manipulated contrast gain control by contrast adapting observers with sinusoidal gratings of different contrasts. Presaccadic and fixational contrast thresholds were measured and compared to give estimates of saccadic suppression at different adaptation states. Our results reconfirmed the selective saccadic suppression in achromatic condition, and further showed that, achromatic saccadic suppression diminished as contrast adaptation was accentuated, whereas no significant chromatic saccadic suppression was induced by greater contrast adaptation. Our data provided evidence for the involvement of contrast gain control in saccadic suppression in achromatic channel. We also discussed how the negative correlation between contrast adaptation and saccadic suppression could be interpreted with contrast gain control. PMID- 24466143 TI - Effect of neoadjuvant chemotherapy in patients with resectable colorectal liver metastases. AB - BACKGROUND: Whether patients with resectable colorectal liver metastases (CRLM) receive survival benefit from neoadjuvant chemotherapy remains controversial. METHODS: We retrospectively analyzed 466 patients with resectable CRLM between 2000 and 2010. Patient characteristics and survival data were recorded. RESULTS: The patients were divided into one group with neoadjuvant chemotherapy (group NC, n = 121) and another without (group WN, n = 345). There was no difference in 5 year survival (52% vs. 48%) between the two groups. No significant differences were identified between the two groups in terms of 30-day mortality (1.7% vs. 1.2%) or morbidity (33.9% vs. 25.8%). A primary tumor at stage T4, >=4 liver metastases, the largest liver metastasis >=5 cm in diameter, and a serum CEA level >=5 ng/ml were independent prognostic factors. By assigning one point to each, the patients were divided into a low-risk group (0-2) and a high-risk (3 4). The patients in the low-risk group received no survival benefit from neoadjuvant chemotherapy, whereas those in the high-risk group received survival benefit (5-year survival, 39% vs. 33%, P = 0.028). CONCLUSIONS: Preoperative neoadjuvant chemotherapy did not increase mortality or complications. Not all resectable patients, only those with >2 independent risk factors, received survival benefit from neoadjuvant chemotherapy. PMID- 24466144 TI - Ohmic-rectifying conversion of Ni contacts on ZnO and the possible determination of ZnO thin film surface polarity. AB - The current-voltage characteristics of Ni contacts with the surfaces of ZnO thin films as well as single crystal (0001) ZnO substrate are investigated. The ZnO thin film shows a conversion from Ohmic to rectifying behavior when annealed at 800 degrees C. Similar findings are also found on the Zn-polar surface of (0001) ZnO. The O-polar surface, however, only shows Ohmic behavior before and after annealing. The rectifying behavior observed on the Zn-polar and ZnO thin film surfaces is associated with the formation of nickel zinc oxide (Ni1-xZnxO, where x = 0.1, 0.2). The current-voltage characteristics suggest that a p-n junction is formed by Ni1-xZnxO (which is believed to be p-type) and ZnO (which is intrinsically n-type). The rectifying behavior for the ZnO thin film as a result of annealing suggests that its surface is Zn-terminated. Current-voltage measurements could possibly be used to determine the surface polarity of ZnO thin films. PMID- 24466145 TI - Time- and behavioral state-dependent changes in posterior hypothalamic GABAA receptors contribute to the regulation of sleep. AB - Sleep-wake behavior is regulated by a circadian rhythm, homeostatically and by additional mechanisms that determine the timing of slow-wave sleep and rapid eye movement sleep (REMS) episodes. The posterior hypothalamus coordinates the neural and humoral signals with the rest-activity cycle. It contains wake-active neurons, and is a site where stimulation of inhibitory GABAA receptors promotes sleep, whereas their antagonism enhances wakefulness. We explored whether GABAergic mechanisms present in the posterior hypothalamus contribute to the homeostatic and other aspects of sleep-wake regulation. Using micropunches of tissue extracted from either the perifornical (PF) or dorsomedial (DM) regions of the posterior hypothalamus of rats, we determined that mRNA levels for selected subunits of GABAA receptors (beta1, beta3 and epsilon) were higher at the end of the active period or following sleep deprivation, when the need for sleep is high, than after several hours of sleep, when sleep need is partially fulfilled. Such a pattern was present in the PF region only, and was consistent with changes in beta1 subunit and GABA synthesizing enzyme (GAD) protein levels. In contrast, in the DM region, the levels of GABAA receptor subunit mRNAs and proteins (alpha1, alpha2, beta1) and GAD varied with circadian time, but were not responsive to sleep deprivation. Separate experiments with sleep-wake monitoring and local perfusion of the PF region with the GABAA receptor antagonist bicuculline revealed that the antagonist had a weaker sleep-reducing effect when sleep need was enhanced by sleep deprivation and that the increased amount of REMS characteristic of the late sleep period was dependent on endogenous GABAergic inhibition. These results support the concept that a varying magnitude of GABAergic inhibition exerted within the PF region contributes to the homeostatic regulation of sleep and shapes its temporal pattern, whereas GABAergic mechanisms in the DM region contribute to circadian regulation. PMID- 24466146 TI - Cardiac pathology and molecular epidemiology by avian leukosis viruses in Japan. AB - Epidemiological studies suggest that retroviruses, including human immunodeficiency virus type 1, are associated with cardiomyopathy and myocarditis, but a causal relationship remains to be established. We encountered unusual cardiomyocyte hypertrophy and mitosis in Japanese native fowls infected with subgroup A of the avian leukosis viruses (ALVs-A), which belong to the genus Alpharetrovirus of the family Retroviridae and mainly induce lymphoid neoplasm in chickens. The affected hearts were evaluated by histopathology and immunohistochemistry, viral isolation, viral genome sequencing and experimental infection. There was non-suppurative myocarditis in eighteen fowls and seven of them had abnormal cardiomyocytes, which were distributed predominantly in the left ventricular wall and showed hypertrophic cytoplasm and atypical large nuclei. Nuclear chains and mitosis were frequently noted in these cardiomyocytes and immunohistochemistry for proliferating cell nuclear antigen supported the enhancement of mitotic activity. ALVs were isolated from all affected cases and phylogenic analysis of envSU genes showed that the isolates were mainly classified into two different clusters, suggesting viral genome diversity. In ovo experimental infection with two of the isolates was demonstrated to cause myocarditis and cardiomyocyte hypertrophy similar to those in the naturally occurring lesions and cardiac hamartoma (rhabdomyoma) in a shorter period of time (at 70 days of age) than expected. These results indicate that ALVs cause myocarditis as well as cardiomyocyte abnormality in chickens, implying a pathogenetic mechanism different from insertional mutagenesis and the existence of retrovirus-induced heart disorder. PMID- 24466147 TI - Allosteric regulation of the Hsp90 dynamics and stability by client recruiter cochaperones: protein structure network modeling. AB - The fundamental role of the Hsp90 chaperone in supporting functional activity of diverse protein clients is anchored by specific cochaperones. A family of immune sensing client proteins is delivered to the Hsp90 system with the aid of cochaperones Sgt1 and Rar1 that act cooperatively with Hsp90 to form allosterically regulated dynamic complexes. In this work, functional dynamics and protein structure network modeling are combined to dissect molecular mechanisms of Hsp90 regulation by the client recruiter cochaperones. Dynamic signatures of the Hsp90-cochaperone complexes are manifested in differential modulation of the conformational mobility in the Hsp90 lid motif. Consistent with the experiments, we have determined that targeted reorganization of the lid dynamics is a unifying characteristic of the client recruiter cochaperones. Protein network analysis of the essential conformational space of the Hsp90-cochaperone motions has identified structurally stable interaction communities, interfacial hubs and key mediating residues of allosteric communication pathways that act concertedly with the shifts in conformational equilibrium. The results have shown that client recruiter cochaperones can orchestrate global changes in the dynamics and stability of the interaction networks that could enhance the ATPase activity and assist in the client recruitment. The network analysis has recapitulated a broad range of structural and mutagenesis experiments, particularly clarifying the elusive role of Rar1 as a regulator of the Hsp90 interactions and a stability enhancer of the Hsp90-cochaperone complexes. Small-world organization of the interaction networks in the Hsp90 regulatory complexes gives rise to a strong correspondence between highly connected local interfacial hubs, global mediator residues of allosteric interactions and key functional hot spots of the Hsp90 activity. We have found that cochaperone-induced conformational changes in Hsp90 may be determined by specific interaction networks that can inhibit or promote progression of the ATPase cycle and thus control the recruitment of client proteins. PMID- 24466148 TI - 2-O-alpha-D-glucosylglycerol phosphorylase from Bacillus selenitireducens MLS10 possessing hydrolytic activity on beta-D-glucose 1-phosphate. AB - The glycoside hydrolase family (GH) 65 is a family of inverting phosphorylases that act on alpha-glucosides. A GH65 protein (Bsel_2816) from Bacillus selenitireducens MLS10 exhibited inorganic phosphate (Pi)-dependent hydrolysis of kojibiose at the rate of 0.43 s(-1). No carbohydrate acted as acceptor for the reverse phosphorolysis using beta-D-glucose 1-phosphate (betaGlc1P) as donor. During the search for a suitable acceptor, we found that Bsel_2816 possessed hydrolytic activity on betaGlc1P with a k cat of 2.8 s(-1); moreover, such significant hydrolytic activity on sugar 1-phosphate had not been reported for any inverting phosphorylase. The H2 (18)O incorporation experiment and the anomeric analysis during the hydrolysis of betaGlc1P revealed that the hydrolysis was due to the glucosyl-transferring reaction to a water molecule and not a phosphatase-type reaction. Glycerol was found to be the best acceptor to generate 2-O-alpha-D-glucosylglycerol (GG) at the rate of 180 s(-1). Bsel_2816 phosphorolyzed GG through sequential Bi-Bi mechanism with a k cat of 95 s(-1). We propose 2-O-alpha-D-glucopyranosylglycerol: phosphate beta-D-glucosyltransferase as the systematic name and 2-O-alpha-D-glucosylglycerol phosphorylase as the short name for Bsel_2816. This is the first report describing a phosphorylase that utilizes polyols, and not carbohydrates, as suitable acceptor substrates. PMID- 24466149 TI - Near isometric biomass partitioning in forest ecosystems of China. AB - Based on the isometric hypothesis, belowground plant biomass (MB) should scale isometrically with aboveground biomass (MA) and the scaling exponent should not vary with environmental factors. We tested this hypothesis using a large forest biomass database collected in China. Allometric scaling functions relating MB and MA were developed for the entire database and for different groups based on tree age, diameter at breast height, height, latitude, longitude or elevation. To investigate whether the scaling exponent is independent of these biotic and abiotic factors, we analyzed the relationship between the scaling exponent and these factors. Overall MB was significantly related to MA with a scaling exponent of 0.964. The scaling exponent of the allometric function did not vary with tree age, density, latitude, or longitude, but varied with diameter at breast height, height, and elevation. The mean of the scaling exponent over all groups was 0.986. Among 57 scaling relationships developed, 26 of the scaling exponents were not significantly different from 1. Our results generally support the isometric hypothesis. MB scaled near isometrically with MA and the scaling exponent did not vary with tree age, density, latitude, or longitude, but increased with tree size and elevation. While fitting a single allometric scaling relationship may be adequate, the estimation of MB from MA could be improved with size-specific scaling relationships. PMID- 24466150 TI - Respiratory tract epithelial cells express retinaldehyde dehydrogenase ALDH1A and enhance IgA production by stimulated B cells in the presence of vitamin A. AB - Morbidity and mortality due to viral infections are major health concerns, particularly when individuals are vitamin A deficient. Vitamin A deficiency significantly impairs mucosal IgA, a first line of defense against virus at its point of entry. Previous reports have suggested that CD11c(Hi) dendritic cells (DCs) of the gastrointestinal tract produce retinaldehyde dehydrogenase (ALDH1A), which metabolizes vitamin A precursors to retinoic acid to support normal mucosal immunity. Given that the upper respiratory tract (URT) and gastrointestinal tract share numerous characteristics, we asked if the CD11c(Hi) DCs of the URT might also express ALDH1A. To address this question, we examined both CD11c(Hi) test cells and CD11c(Lo/neg) control cells from nasal tissue. Surprisingly, the CD11c(Lo/neg) cells expressed more ALDH1A mRNA per cell than did the CD11c(Hi) cells. Further evaluation of CD11c(Lo/neg) populations by PCR and staining of respiratory tract sections revealed that epithelial cells were robust producers of both ALDH1A mRNA and protein. Moreover, CD11c(Lo/neg) cells from nasal tissue (and a homogeneous respiratory tract epithelial cell line) enhanced IgA production by lipopolysaccharide (LPS)-stimulated splenocyte cultures in the presence of the retinoic acid precursor retinol. Within co-cultures, there was increased expression of MCP-1, IL-6, and GM-CSF, the latter two of which were necessary for IgA upregulation. All three cytokines/chemokines were expressed by the LPS-stimulated respiratory tract epithelial cell line in the absence of splenocytes. These data demonstrate the autonomous potential of respiratory tract epithelial cells to support vitamin A-mediated IgA production, and encourage the clinical testing of intranasal vitamin A supplements in vitamin A deficient populations to improve mucosal immune responses toward respiratory tract pathogens and vaccines. PMID- 24466151 TI - Perturbation of human coronary artery endothelial cell redox state and NADPH generation by methylglyoxal. AB - Diabetes is associated with elevated plasma glucose, increased reactive aldehyde formation, oxidative damage, and glycation/glycoxidation of biomolecules. Cellular detoxification of, or protection against, such modifications commonly requires NADPH-dependent reducing equivalents (e.g. GSH). We hypothesised that reactive aldehydes may modulate cellular redox status via the inhibition of NADPH generating enzymes, resulting in decreased thiol and NADPH levels. Primary human coronary artery endothelial cells (HCAEC) were incubated with high glucose (25 mM, 24 h, 37 degrees C), or methylglyoxal (MGO), glyoxal, or glycolaldehyde (100 500 uM, 1 h, 37 degrees C), before quantification of intracellular thiols and NADPH-generating enzyme activities. Exposure to MGO, but not the other species examined, significantly (P<0.05) decreased total thiols (~35%), further experiments with MGO showed significant losses of GSH (~40%) and NADPH (~10%); these changes did not result in an immediate loss of cell viability. Significantly decreased (~10%) NADPH-producing enzyme activity was observed for HCAEC when glucose-6-phosphate or 2-deoxyglucose-6-phosphate were used as substrates. Cell lysate experiments showed significant MGO-dose dependent inhibition of glucose-6-phosphate-dependent enzymes and isocitrate dehydrogenase, but not malic enzyme. Analysis of intact cell or lysate proteins showed that arginine-derived hydroimidazolones were the predominant advanced glycation end product (AGE) formed; lower levels of N(epsilon)-(carboxyethyl)lysine (CEL) and N(epsilon)-(carboxymethyl)lysine (CML) were also detected. These data support a novel mechanism by which MGO exposure results in changes in redox status in human coronary artery endothelial cells, via inhibition of NADPH-generating enzymes, with resultant changes in reduced protein thiol and GSH levels. These changes may contribute to the endothelial cell dysfunction observed in diabetes-associated atherosclerosis. PMID- 24466152 TI - Evaluation of the prevalence and production of Escherichia coli common pilus among avian pathogenic E. coli and its role in virulence. AB - Avian pathogenic Escherichia coli (APEC) strains cause systemic and localized infections in poultry, jointly termed colibacillosis. Avian colibacillosis is responsible for significant economic losses to the poultry industry due to disease treatment, decrease in growth rate and egg production, and mortality. APEC are also considered a potential zoonotic risk for humans. Fully elucidating the virulence and zoonotic potential of APEC is key for designing successful strategies against their infections and their transmission. Herein, we investigated the prevalence of a newly discovered E. coli common pilus (ECP) for the subunit protein of the ECP pilus (ecpA) and ECP expression amongst APEC strains as well as the role of ECP in virulence. A PCR-based ecpA survey of a collection of 167 APEC strains has shown that 76% (127/167) were ecpA+. An immunofluorescence assay using anti-EcpA antibodies, revealed that among the ecpA+ strains, 37.8% (48/127) expressed ECP when grown in DMEM +0.5% Mannose in contact with HeLa cells at 37 degrees C and/or in biofilm at 28 degrees C; 35.4% (17/48) expressed ECP in both conditions and 64.6% (31/48) expressed ECP in biofilm only. We determined that the ecp operon in the APEC strain chi7122 (ecpA+, ECP-) was not truncated; the failure to detect ECP in some strains possessing non-truncated ecp genes might be attributed to differential regulatory mechanisms between strains that respond to specific environmental signals. To evaluate the role of ECP in the virulence of APEC, we generated ecpA and/or ecpD deficient mutants from the strain chi7503 (ecpA+, ECP+). Deletion of ecpA and/or ecpD abolished ECP synthesis and expression, and reduced biofilm formation and motility in vitro and virulence in vivo. All together our data show that ecpA is highly prevalent among APEC isolates and its expression could be differentially regulated in these strains, and that ECP plays a role in the virulence of APEC. PMID- 24466153 TI - Estimating the delay between host infection and disease (incubation period) and assessing its significance to the epidemiology of plant diseases. AB - Knowledge of the incubation period of infectious diseases (time between host infection and expression of disease symptoms) is crucial to our epidemiological understanding and the design of appropriate prevention and control policies. Plant diseases cause substantial damage to agricultural and arboricultural systems, but there is still very little information about how the incubation period varies within host populations. In this paper, we focus on the incubation period of soilborne plant pathogens, which are difficult to detect as they spread and infect the hosts underground and above-ground symptoms occur considerably later. We conducted experiments on Rhizoctonia solani in sugar beet, as an example patho-system, and used modelling approaches to estimate the incubation period distribution and demonstrate the impact of differing estimations on our epidemiological understanding of plant diseases. We present measurements of the incubation period obtained in field conditions, fit alternative probability models to the data, and show that the incubation period distribution changes with host age. By simulating spatially-explicit epidemiological models with different incubation-period distributions, we study the conditions for a significant time lag between epidemics of cryptic infection and the associated epidemics of symptomatic disease. We examine the sensitivity of this lag to differing distributional assumptions about the incubation period (i.e. exponential versus Gamma). We demonstrate that accurate information about the incubation period distribution of a pathosystem can be critical in assessing the true scale of pathogen invasion behind early disease symptoms in the field; likewise, it can be central to model-based prediction of epidemic risk and evaluation of disease management strategies. Our results highlight that reliance on observation of disease symptoms can cause significant delay in detection of soil-borne pathogen epidemics and mislead practitioners and epidemiologists about the timing, extent, and viability of disease control measures for limiting economic loss. PMID- 24466154 TI - Ion channel gene expression in lung adenocarcinoma: potential role in prognosis and diagnosis. AB - Ion channels are known to regulate cancer processes at all stages. The roles of ion channels in cancer pathology are extremely diverse. We systematically analyzed the expression patterns of ion channel genes in lung adenocarcinoma. First, we compared the expression of ion channel genes between normal and tumor tissues in patients with lung adenocarcinoma. Thirty-seven ion channel genes were identified as being differentially expressed between the two groups. Next, we investigated the prognostic power of ion channel genes in lung adenocarcinoma. We assigned a risk score to each lung adenocarcinoma patient based on the expression of the differentially expressed ion channel genes. We demonstrated that the risk score effectively predicted overall survival and recurrence-free survival in lung adenocarcinoma. We also found that the risk scores for ever-smokers were higher than those for never-smokers. Multivariate analysis indicated that the risk score was a significant prognostic factor for survival, which is independent of patient age, gender, stage, smoking history, Myc level, and EGFR/KRAS/ALK gene mutation status. Finally, we investigated the difference in ion channel gene expression between the two major subtypes of non-small cell lung cancer: adenocarcinoma and squamous-cell carcinoma. Thirty ion channel genes were identified as being differentially expressed between the two groups. We suggest that ion channel gene expression can be used to improve the subtype classification in non-small cell lung cancer at the molecular level. The findings in this study have been validated in several independent lung cancer cohorts. PMID- 24466155 TI - Impact of the controlled release of a connexin 43 peptide on corneal wound closure in an STZ model of type I diabetes. AB - The alpha-carboxy terminus 1 (alphaCT1) peptide is a synthetically produced mimetic modified from the DDLEI C-terminus sequence of connexin 43 (Cx43). Previous research using various wound healing models have found promising therapeutic effects when applying the drug, resulting in increased wound healing rates and reduced scarring. Previous data suggested a rapid metabolism rate in vitro, creating an interest in long term release. Using a streptozotocin (STZ) type I diabetic rat model with a surgically induced corneal injury, we delivered alphaCT1 both directly, in a pluronic gel solution, and in a sustained system, using polymeric alginate-poly-l-ornithine (A-PLO) microcapsules (MC). Fluorescent staining of wound area over a 5 day period indicated a significant increase in wound closure rates for both alphaCT1 and alphaCT1 MC treated groups, withalphaCT1 MC groups showing the most rapid wound closure overall. Analysis of inflammatory reaction to the treatment groups indicated significantly lower levels of both Interferon Inducible T-Cell Alpha Chemoattractant (ITAC) and Tumor Necrosis Factor Alpha (TNFalpha) markers using confocal quantification and ELISA assays. Additional analysis examining genes selected from the EMT pathway using RT-PCR and Western blotting suggested alphaCT1 modification of Transforming Growth Factor Beta 2 (TGFbeta2), Keratin 8 (Krt8), Estrogen Receptor 1 (Esr1), and Glucose Transporter 4 (Glut4) over a 14 day period. Combined, this data indicated a possible suppression of the inflammatory response by alphaCT1, leading to increased wound healing rates. PMID- 24466156 TI - Induction of neutralizing antibodies against four serotypes of dengue viruses by MixBiEDIII, a tetravalent dengue vaccine. AB - The worldwide expansion of four serotypes of dengue virus (DENV) poses great risk to global public health. Several vaccine candidates are under development. However, none is yet available for humans. In the present study, a novel strategy to produce tetravalent DENV vaccine based on envelope protein domain III (EDIII) was proposed. Tandem EDIIIs of two serotypes (type 1-2 and type 3-4) of DENV connected by a Gly-Ser linker ((Gly4Ser)3) were expressed in E. coli, respectively. Then, the two bivalent recombinant EDIIIs were equally mixed to form the tetravalent vaccine candidate MixBiEDIII, and used to immunize BALB/c mice. The results showed that specific IgG and neutralizing antibodies against all four serotypes of DENV were successfully induced in the MixBiEDIII employing Freund adjuvant immunized mice. Furthermore, in the suckling mouse model, sera from mice immunized with MixBiEDIII provided significant protection against four serotypes of DENV challenge. Our data demonstrated that MixBiEDIII, as a novel form of subunit vaccine candidates, might have the potential to be further developed as a tetravalent dengue vaccine in the near future. PMID- 24466157 TI - Protective effects of membrane-anchored and secreted DNA vaccines encoding fatty acid-binding protein and glutathione S-transferase against Schistosoma japonicum. AB - In order to explore the high performance bivalent DNA-based vaccine against schistosomes, SjFABP and Sj26GST were selected and used to construct a vaccine. Two strategies were used to construct the bivalent DNA vaccine. In the first strategy, a plasmid encoding antigen in the secreted form was used, while in the other, a plasmid encoding a truncated form of SjFABP and Sj26GST targeted to the cell surface was used. Various parameters, including antibody and cytokine response, proliferation, histopathological examination, and characterization of T cell subsets were used to evaluate the type of immune response and the level of protection against challenge infection. Injection with secreted pIRES-sjFABP sj26GST significantly increased the levels of antibody, splenocyte proliferation, and production of IFN-gamma, compared with membrane-anchored groups. Analysis of splenic T cell subsets showed that the secreted vaccine significantly increased the percentage of CD3(+)CD4(+) and CD3(+)CD8(+) T cells. Liver immunopathology (size of liver granulomas) was significantly reduced in the secreted group compared with the membrane-anchored groups. Moreover, challenge experiments showed that the worm and egg burdens were significantly reduced in animals immunized with recombinant vaccines. Most importantly, secreted Sj26GST-SjFABP markedly enhanced protection, by reducing worm and egg burdens by 31.8% and 24.78%, respectively, while the membrane-anchored group decreased worm and egg burdens by 24.80% and 18.80%, respectively. Taken together, these findings suggest that the secretory vaccine is more promising than the membrane-anchored vaccine, and provides support for the development and application of this vaccine. PMID- 24466158 TI - Joint entropy for space and spatial frequency domains estimated from psychometric functions of achromatic discrimination. AB - We used psychometric functions to estimate the joint entropy for space discrimination and spatial frequency discrimination. Space discrimination was taken as discrimination of spatial extent. Seven subjects were tested. Gabor functions comprising unidimensionalsinusoidal gratings (0.4, 2, and 10 cpd) and bidimensionalGaussian envelopes (1 degrees ) were used as reference stimuli. The experiment comprised the comparison between reference and test stimulithat differed in grating's spatial frequency or envelope's standard deviation. We tested 21 different envelope's standard deviations around the reference standard deviation to study spatial extent discrimination and 19 different grating's spatial frequencies around the reference spatial frequency to study spatial frequency discrimination. Two series of psychometric functions were obtained for 2%, 5%, 10%, and 100% stimulus contrast. The psychometric function data points for spatial extent discrimination or spatial frequency discrimination were fitted with Gaussian functions using the least square method, and the spatial extent and spatial frequency entropies were estimated from the standard deviation of these Gaussian functions. Then, joint entropy was obtained by multiplying the square root of space extent entropy times the spatial frequency entropy. We compared our results to the theoretical minimum for unidimensional Gabor functions, 1/4pi or 0.0796. At low and intermediate spatial frequencies and high contrasts, joint entropy reached levels below the theoretical minimum, suggesting non-linear interactions between two or more visual mechanisms. We concluded that non-linear interactions of visual pathways, such as the M and P pathways, could explain joint entropy values below the theoretical minimum at low and intermediate spatial frequencies and high contrasts. These non-linear interactions might be at work at intermediate and high contrasts at all spatial frequencies once there was a substantial decrease in joint entropy for these stimulus conditions when contrast was raised. PMID- 24466159 TI - Identification of two Wnt-responsive elements in the intron of RING finger protein 43 (RNF43) gene. AB - RING finger protein 43 (RNF43), an E3-type ubiquitin ligase, is frequently up regulated in human colorectal cancer. It has been shown that expression of RNF43 is regulated by the Wnt-signaling pathway. However the regulatory region(s) for its transcriptional activation has not been clarified. In this study, we have shown for the first time that RNF43 is a direct target of TCF4/beta-catenin complex, and that its expression is regulated by a regulatory region containing two Wnt-responsive elements (WREs) in intron2. A reporter gene assay revealed that nucleotide substitutions in the WREs decreased the reporter activity in colon cancer cells, suggesting that both WREs are involved in the transcriptional activation. Knockdown of beta-catenin by siRNA suppressed the reporter activity. In addition, ChIP assay showed that both elements associate with TCF4/beta catenin complex in colon cancer cells. These data indicate that expression of RNF43 is regulated by the canonical Wnt/beta-catenin pathway through binding of the WREs with TCF4/beta-catenin complex. These findings should be useful for the understanding of the regulatory mechanism of RNF43 and may contribute to the clarification of signaling pathways regulated by RNF43. PMID- 24466160 TI - Heterogeneity of tumor vasculature and antiangiogenic intervention: insights from MR angiography and DCE-MRI. AB - PURPOSE: Solid tumor vasculature is highly heterogeneous, which presents challenges to antiangiogenic intervention as well as the evaluation of its therapeutic efficacy. The aim of this study is to evaluate the spatial tumor vascular changes due to bevacizumab/paclitaxel therapy using a combination approach of MR angiography and DCE-MRI method. EXPERIMENTAL DESIGN: Tumor vasculature of MCF-7 breast tumor mouse xenografts was studied by a combination of MR angiography and DCE-MRI with albumin-Gd-DTPA. Tumor macroscopic vasculature was extracted from the early enhanced images. Tumor microvascular parameters were obtained from the pharmacokinetic modeling of the DCE-MRI data. A spatial analysis of the microvascular parameters based on the macroscopic vasculature was used to evaluate the changes of the heterogeneous vasculature induced by a 12 day bevacizumab/paclitaxel treatment in mice bearing MCF-7 breast tumor. RESULTS: Macroscopic vessels that feed the tumors were not affected by the bevacizumab/paclitaxel combination therapy. A higher portion of the tumors was within close proximity of these macroscopic vessels after the treatment, concomitant with tumor growth retardation. There was a significant decrease in microvascular permeability and vascular volume in the tumor regions near these vessels. CONCLUSION: Bevacizumab/paclitaxel combination therapy did not block the blood supply to the MCF-7 breast tumor. Such finding is consistent with the modest survival benefits of adding bevacizumab to current treatment regimens for some types of cancers. PMID- 24466161 TI - Human chondrocytes respond discordantly to the protein encoded by the osteoarthritis susceptibility gene GDF5. AB - A genetic deficit mediated by SNP rs143383 that leads to reduced expression of GDF5 is strongly associated with large-joint osteoarthritis. We speculated that this deficit could be attenuated by the application of exogenous GDF5 protein and as a first step we have assessed what effect such application has on primary osteoarthritis chondrocyte gene expression. Chondrocytes harvested from cartilage of osteoarthritic patients who had undergone joint replacement were cultured with wildtype recombinant mouse and human GDF5 protein. We also studied variants of GDF5, one that has a higher affinity for the receptor BMPR-IA and one that is insensitive to the GDF5 antagonist noggin. As a positive control, chondrocytes were treated with TGF-beta1. Chondrocytes were cultured in monolayer and micromass and the expression of genes coding for catabolic and anabolic proteins of cartilage were measured by quantitative PCR. The expression of the GDF5 receptor genes and the presence of their protein products was confirmed and the ability of GDF5 signal to translocate to the nucleus was demonstrated by the activation of a luciferase reporter construct. The capacity of GDF5 to elicit an intracellular signal in chondrocytes was demonstrated by the phosphorylation of intracellular Smads. Chondrocytes cultured with TGF-beta1 demonstrated a consistent down regulation of MMP1, MMP13 and a consistent upregulation of TIMP1 and COL2A1 with both culture techniques. In contrast, chondrocytes cultured with wildtype GDF5, or its variants, did not show any consistent response, irrespective of the culture technique used. Our results show that osteoarthritis chondrocytes do not respond in a predictable manner to culture with exogenous GDF5. This may be a cause or a consequence of the osteoarthritis disease process and will need to be surmounted if treatment with exogenous GDF5 is to be advanced as a potential means to overcome the genetic deficit conferring osteoarthritis susceptibility at this gene. PMID- 24466162 TI - Evidence of diel vertical migration in Mnemiopsis leidyi. AB - The vertical distribution and migration of plankton organisms may have a large impact on their horizontal dispersal and distribution, and consequently on trophic interactions. In this study we used video-net profiling to describe the fine scale vertical distribution of Mnemiopsis leidyi in the Kattegat and Baltic Proper. Potential diel vertical migration was also investigated by frequent filming during a 24-hour cycle at two contrasting locations with respect to salinity stratification. The video profiles revealed a pronounced diel vertical migration at one of the locations. However, only the small and medium size classes migrated, on average 0.85 m h(-1), corresponding to a total migration distance of 10 m during 12 h. Larger individuals (with well developed lobes, approx. >27 mm) stay on average in the same depth interval at all times. Biophysical data suggest that migrating individuals likely responded to light, and avoided irradiance levels higher than approx. 10 umol quanta m(-2) s(-1). We suggest that strong stratification caused by low surface salinity seemed to prohibit vertical migration. PMID- 24466163 TI - Shifting baselines on a tropical forest frontier: extirpations drive declines in local ecological knowledge. AB - The value of local ecological knowledge (LEK) to conservation is increasingly recognised, but LEK is being rapidly lost as indigenous livelihoods change. Biodiversity loss is also a driver of the loss of LEK, but quantitative study is lacking. In our study landscape in SW China, a large proportion of species have been extirpated. Hence, we were interested to understand whether species extirpation might have led to an erosion of LEK and the implications this might have for conservation. So we investigated peoples' ability to name a selection of birds and mammals in their local language from pictures. Age was correlated to frequency of forest visits as a teenager and is likely to be closely correlated to other known drivers of the loss of LEK, such as declining forest dependence. We found men were better at identifying birds overall and that older people were better able to identify birds to the species as compared to group levels (approximately equivalent to genus). The effect of age was also stronger among women. However, after controlling for these factors, species abundance was by far the most important parameter in determining peoples' ability to name birds. People were unable to name any locally extirpated birds at the species level. However, contrary to expectations, people were better able to identify extirpated mammals at the species level than extant ones. However, extirpated mammals tend to be more charismatic species and several respondents indicated they were only familiar with them through TV documentaries. Younger people today cannot experience the sights and sounds of forest animals that their parents grew up with and, consequently, knowledge of these species is passing from cultural memory. We suggest that engaging older members of the community and linking the preservation of LEK to biodiversity conservation may help generate support for conservation. PMID- 24466164 TI - Porphyromonas gingivalis infection reduces regulatory T cells in infected atherosclerosis patients. AB - Increasing evidence has shown periodontal pathogen Porphyromonas gingivalis (P.gingivalis) infection contributes to atherosclerosis (AS) progression. P.gingivalis fimbriae act as an important virulence factor in AS. Regulatory T cells (Tregs) may play a crucial role in autoimmune response during this process. However, whether P.gingivalis infection is associated with Tregs dysregulation during AS is still unknown and the prevalence of different P.gingivalis FimA genotypes during this process is unclear. Here we analyzed the distribution of Tregs and in P.gingivalis-infected atherosclerotic patients to reveal the relationship between P.gingivalis infection and Tregs reduction/dysfunction and to elucidate their role in periodontitis-AS interaction. FimA genotype was also examined to determine the prevalence of fimbriae. Our results showed that P.gingivalis infection reduced Tregs in atherosclerotic patients compared with non-atherosclerotic patients and health controls. Concentration of TGF-beta1, which plays an important role in the development of Tregs, also decreased in P.gingivalis infected patients. Furthermore, type II FimA seems to show higher prevalence than the other five detected types. The population of Tregs further decreased in patients with type II FimA compared with the other types. P.gingivlias FimA genotype II was the dominant type associated with decreased Treg population. These results indicate that P.gingivalis infection may be associated with Tregs dysregulation in AS; type II FimA may be a predominant genotype in this process. PMID- 24466165 TI - Effects of extrinsic mortality on the evolution of aging: a stochastic modeling approach. AB - The evolutionary theories of aging are useful for gaining insights into the complex mechanisms underlying senescence. Classical theories argue that high levels of extrinsic mortality should select for the evolution of shorter lifespans and earlier peak fertility. Non-classical theories, in contrast, posit that an increase in extrinsic mortality could select for the evolution of longer lifespans. Although numerous studies support the classical paradigm, recent data challenge classical predictions, finding that high extrinsic mortality can select for the evolution of longer lifespans. To further elucidate the role of extrinsic mortality in the evolution of aging, we implemented a stochastic, agent-based, computational model. We used a simulated annealing optimization approach to predict which model parameters predispose populations to evolve longer or shorter lifespans in response to increased levels of predation. We report that longer lifespans evolved in the presence of rising predation if the cost of mating is relatively high and if energy is available in excess. Conversely, we found that dramatically shorter lifespans evolved when mating costs were relatively low and food was relatively scarce. We also analyzed the effects of increased predation on various parameters related to density dependence and energy allocation. Longer and shorter lifespans were accompanied by increased and decreased investments of energy into somatic maintenance, respectively. Similarly, earlier and later maturation ages were accompanied by increased and decreased energetic investments into early fecundity, respectively. Higher predation significantly decreased the total population size, enlarged the shared resource pool, and redistributed energy reserves for mature individuals. These results both corroborate and refine classical predictions, demonstrating a population-level trade-off between longevity and fecundity and identifying conditions that produce both classical and non-classical lifespan effects. PMID- 24466166 TI - Social networking smartphone applications and sexual health outcomes among men who have sex with men. AB - Several smartphone applications (apps) designed to help men who have sex with men (MSM) find casual sexual partners have appeared on the market recently. Apps of this nature have the potential to impact sexual health and behavior by providing constant access to a large supply of available partners. In this study, the sexual health history, behavior, and personality of MSM who use these apps was compared to MSM who meet partners in other ways. A sample of 110 adult MSM was recruited online to complete a cross-sectional survey. All participants were either single or involved in a non-exclusive romantic relationship. There were no statistically significant differences between app users and non-users in frequency of insertive or receptive anal sex without a condom. However, app users reported significantly more sexual partners and had a higher prevalence of ever being diagnosed with an STI than did non-users. App users did not differ from non users on any demographic or personality variables (including erotophilia, sensation seeking, and self-control); however, when adjusting lifetime total sex partners for those met specifically through apps, app users still had significantly more partners. This pattern of results suggests that app users may be more sexually active in general. More work is needed to fully understand the association between this emerging technology and potential sexual health risks. PMID- 24466167 TI - Land-use history and contemporary management inform an ecological reference model for longleaf pine woodland understory plant communities. AB - Ecological restoration is frequently guided by reference conditions describing a successfully restored ecosystem; however, the causes and magnitude of ecosystem degradation vary, making simple knowledge of reference conditions insufficient for prioritizing and guiding restoration. Ecological reference models provide further guidance by quantifying reference conditions, as well as conditions at degraded states that deviate from reference conditions. Many reference models remain qualitative, however, limiting their utility. We quantified and evaluated a reference model for southeastern U.S. longleaf pine woodland understory plant communities. We used regression trees to classify 232 longleaf pine woodland sites at three locations along the Atlantic coastal plain based on relationships between understory plant community composition, soils (which broadly structure these communities), and factors associated with understory degradation, including fire frequency, agricultural history, and tree basal area. To understand the spatial generality of this model, we classified all sites together and for each of three study locations separately. Both the regional and location-specific models produced quantifiable degradation gradients-i.e., progressive deviation from conditions at 38 reference sites, based on understory species composition, diversity and total cover, litter depth, and other attributes. Regionally, fire suppression was the most important degrading factor, followed by agricultural history, but at individual locations, agricultural history or tree basal area was most important. At one location, the influence of a degrading factor depended on soil attributes. We suggest that our regional model can help prioritize longleaf pine woodland restoration across our study region; however, due to substantial landscape-to-landscape variation, local management decisions should take into account additional factors (e.g., soil attributes). Our study demonstrates the utility of quantifying degraded states and provides a series of hypotheses for future experimental restoration work. More broadly, our work provides a framework for developing and evaluating reference models that incorporate multiple, interactive anthropogenic drivers of ecosystem degradation. PMID- 24466168 TI - Detection of novel visible-light region absorbance peaks in the urine after alkalization in patients with alkaptonuria. AB - BACKGROUND: Alkaptonuria, caused by a deficiency of homogentisate 1,2 dioxygenase, results in the accumulation of homogentisic acid (2,5 dihydroxyphenylacetic acid, HGA) in the urine. Alkaptonuria is suspected when the urine changes color after it is left to stand at room temperature for several hours to days; oxidation of homogentisic acid to benzoquinone acetic acid underlies this color change, which is accelerated by the addition of alkali. In an attempt to develop a facile screening test for alkaptonuria, we added alkali to urine samples obtained from patients with alkaptonuria and measured the absorbance spectra in the visible light region. METHODS: We evaluated the characteristics of the absorption spectra of urine samples obtained from patients with alkaptonuria (n = 2) and compared them with those of urine specimens obtained from healthy volunteers (n = 5) and patients with phenylketonuria (n = 3), and also of synthetic homogentisic acid solution after alkalization. Alkalization of the urine samples and HGA solution was carried out by the addition of NaOH, KOH or NH4OH. The sample solutions were incubated at room temperature for 1 min, followed by measurement of the absorption spectra. RESULTS: Addition of alkali to alkaptonuric urine yielded characteristic absorption peaks at 406 nm and 430 nm; an identical result was obtained from HGA solution after alkalization. The absorbance values at both 406 nm and 430 nm increased in a time-dependent manner. In addition, the absorbance values at these peaks were greater in strongly alkaline samples (NaOH- KOH-added) as compared with those in weakly alkaline samples (NH4OH-added). In addition, the peaks disappeared following the addition of ascorbic acid to the samples. CONCLUSIONS: We found two characteristic peaks at 406 nm and 430 nm in both alkaptonuric urine and HGA solution after alkalization. This new quick and easy method may pave the way for the development of an easy method for the diagnosis of alkaptonuria. PMID- 24466169 TI - A chromosomal region on ECA13 is associated with maxillary prognathism in horses. AB - Hereditary variations in head morphology and head malformations are known in many species. The most common variation encountered in horses is maxillary prognathism. Prognathism and brachygnathism are syndromes of the upper and lower jaw, respectively. The resulting malocclusion can negatively affect teeth wear, and is considered a non-desirable trait in breeding programs. We performed a case control analysis for maxillary prognathism in horses using 96 cases and 763 controls. All horses had been previously genotyped with a commercially available 50 k SNP array. We analyzed the data with a mixed-model considering the genomic relationships in order to account for population stratification. Two SNPs within a region on the distal end of chromosome ECA 13 reached the Bonferroni corrected genome-wide significance level. There is no known prognathism candidate gene located within this region. Therefore, our findings in the horse offer the possibility of identifying a novel gene involved in the complex genetics of prognathism that might also be relevant for humans and other livestock species. PMID- 24466170 TI - Selenium protects neonates against neurotoxicity from prenatal exposure to manganese. AB - Manganese (Mn) exposure can affect brain development. Whether Selenium (Se) can protect neonates against neurotoxicity from Mn exposure remains unclear. We investigated this issue in 933 mother-newborn pairs in Shanghai, China, from 2008 through 2009. Umbilical cord serum concentrations of Mn and Se were measured and Neonatal Behavioral Neurological Assessment (NBNA) tests were conducted. The scores <37 were defined as the low NBNA. The median concentrations of cord serum Mn and Se were 4.0 ug/L and 63.1 ug/L, respectively. After adjusting for potential confounders, the interaction between Se and Mn was observed. Cord blood Mn levels had different effects on NBNA scores stratified by different cord blood Se levels. With Se= P50 (>= 63.1 ug/L) (NBNA: adjusted beta = 0.1, 95% CI: -0.3 to 0.5, p = 0.746; Low NBNA: adjusted OR = 4.5, 95% CI: 0.4 to 46.7, p = 0.205). Furthermore, the high Mn exposure group with a low Se level [Mn >= P75 (9.1 ug/L) and Se= P75 (9.1 ug/L) and Se >= P50 (63.1 ug/L)] (38.0 +/- 1.6 & 39.5 +/- 0.9, p<0.001). Mn/Se ratio and NBNA scores were moderately correlated (r = 0.41, p<0.001). Our findings suggest that Se has a protective effect on neonates' brain development against neurotoxicity from prenatal exposure to Mn. Se supplementation should be considered during pregnancy, especially in areas with low natural Se. PMID- 24466171 TI - CCAAT-enhancer binding protein-beta expression and elevation in Alzheimer's disease and microglial cell cultures. AB - CCAAT-enhancer binding proteins are transcription factors that help to regulate a wide range of inflammatory mediators, as well as several key elements of energy metabolism. Because C/EBPs are expressed by rodent astrocytes and microglia, and because they are induced by pro-inflammatory cytokines that are chronically upregulated in the Alzheimer's disease (AD) cortex, we have investigated whether C/EBPs are expressed and upregulated in the AD cortex. Here, we demonstrate for the first time that C/EBPbeta can be detected by Western blots in AD and nondemented elderly (ND) cortex, and that it is significantly increased in AD cortical samples. In situ, C/EBPbeta localizes immunohistochemically to microglia. In microglia cultured from rapid autopsies of elderly patient's brains and in the BV-2 murine microglia cell line, we have shown that C/EBPbeta can be upregulated by C/EBP-inducing cytokines or lipopolysaccharide and exhibits nuclear translocation possibly indicating functional activity. Given the known co regulatory role of C/EBPs in pivotal inflammatory mechanisms, many of which are present in AD, we propose that upregulation of C/EBPs in the AD brain could be an important orchestrator of pathogenic changes. PMID- 24466172 TI - H-NST induces LEE expression and the formation of attaching and effacing lesions in enterohemorrhagic Escherichia coli. AB - BACKGROUND: Enteropathogenic E. coli (EPEC) and enterohemorrhagic E. coli are important causes of morbidity and mortality worldwide. These enteric pathogens contain a type III secretion system (T3SS) responsible for the attaching and effacing (A/E) lesion phenotype. The T3SS is encoded by the locus of enterocyte effacement (LEE) pathogenicity island. The H-NS-mediated repression of LEE expression is counteracted by Ler, the major activator of virulence gene expression in A/E pathogens. A regulator present in EPEC, H-NST, positively affects expression of H-NS regulon members in E. coli K-12, although the effect of H-NST on LEE expression and virulence of A/E pathogens has yet-to-be determined. RESULTS: We examine the effect of H-NST on LEE expression and A/E lesion formation on intestinal epithelial cells. We find that H-NST positively affects the levels of LEE-encoded proteins independently of ler and induces A/E lesion formation. We demonstrate H-NST binding to regulatory regions of LEE1 and LEE3, the first report of DNA-binding by H-NST. We characterize H-NST mutants substituted at conserved residues including Ala16 and residues Arg60 and Arg63, which are part of a potential DNA-binding domain. The single mutants A16V, A16L, R60Q and the double mutant R60Q/R63Q exhibit a decreased effect on LEE expression and A/E lesion formation. DNA mobility shift assays reveal that these residues are important for H-NST to bind regulatory LEE DNA targets. H-NST positively affects Ler binding to LEE DNA in the presence of H-NS, and thereby potentially helps Ler displace H-NS bound to DNA. CONCLUSIONS: H-NST induces LEE expression and A/E lesion formation likely by counteracting H-NS-mediated repression. We demonstrate that H-NST binds to DNA and identify arginine residues that are functionally important for DNA-binding. Our study suggests that H-NST provides an additional means for A/E pathogens to alleviate repression of virulence gene expression by H-NS to promote virulence capabilities. PMID- 24466173 TI - Cyclophosphamide alters the gene expression profile in patients treated with high doses prior to stem cell transplantation. AB - BACKGROUND: Hematopoietic stem cell transplantation is a curative treatment for several haematological malignancies. However, treatment related morbidity and mortality still is a limiting factor. Cyclophosphamide is widely used in condition regimens either in combination with other chemotherapy or with total body irradiation. METHODS: We present the gene expression profile during cyclophosphamide treatment in 11 patients conditioned with cyclophosphamide for 2 days followed by total body irradiation prior to hematopoietic stem cell transplantation. 299 genes were identified as specific for cyclophosphamide treatment and were arranged into 4 clusters highly down-regulated genes, highly up-regulated genes, early up-regulated but later normalized genes and moderately up-regulated genes. RESULTS: Cyclophosphamide treatment down-regulated expression of several genes mapped to immune/autoimmune activation and graft rejection including CD3, CD28, CTLA4, MHC II, PRF1, GZMB and IL-2R, and up-regulated immune related receptor genes, e.g. IL1R2, IL18R1, and FLT3. Moreover, a high and significant expression of ANGPTL1 and c-JUN genes was observed independent of cyclophosphamide treatment. CONCLUSION: This is the first investigation to provide significant information about alterations in gene expression following cyclophosphamide treatment that may increase our understanding of the cyclophosphamide mechanism of action and hence, in part, avoid its toxicity. Furthermore, ANGPTL1 remained highly expressed throughout the treatment and, in contrast to several other alkylating agents, cyclophosphamide did not influence c JUN expression. PMID- 24466174 TI - Human placenta-derived adherent cell treatment of experimental stroke promotes functional recovery after stroke in young adult and older rats. AB - BACKGROUND: Human Placenta-Derived Adherent Cells (PDAC(r)) are a novel mesenchymal-like cell population derived from normal human placental tissue. PDA 001 is a clinical formulation of PDAC(r) developed for intravenous administration. In this study, we investigated the efficacy of PDA-001 treatment in a rat model of transient middle cerebral artery occlusion (MCAo) in young adult (2-3 month old) and older rats (10-12 months old). METHODS: To evaluate efficacy and determine the optimal number of transplanted cells, young adult Wistar rats were subjected to MCAo and treated 1 day post MCAo with 1*10(6), 4*10(6) or 8*10(6) PDA-001 cells (i.v.), vehicle or cell control. 4*10(6) or 8*10(6) PDA-001 cells were also tested in older rats after MCAo. Treatment response was evaluated using a battery of functional outcome tests, consisting of adhesive-removal test, modified Neurological Severity Score (mNSS) and foot-fault test. Young adult rats were sacrificed 56 days after MCAo, older rats were sacrificed 29 days after MCAo, and lesion volumes were measured using H&E. Immunohistochemical stainings for bromodeoxyuridine (BrdU) and von Willebrand Factor (vWF), and synaptophysin were performed. RESULTS: In young adult rats, treatment with 4*10(6) PDA-001 cells significantly improved functional outcome after stroke (p<0.05). In older rats, significant functional improvement was observed with PDA-001 cell therapy in both of the 4*10(6) and 8*10(6) treatment groups. Functional benefits in young adult and older rats were associated with significant increases in the number of BrdU immunoreactive endothelial cells, vascular density and perimeter in the ischemic brain, as well as significantly increased synaptophysin expression in the ischemic border zone (p<0.05). CONCLUSION: PDA-001 treatment significantly improved functional outcome after stroke in both young adult and older rats. The neurorestorative effects induced by PDA-001 treatment may be related to increased vascular density and synaptic plasticity. PMID- 24466175 TI - Relationship between meditative practice and self-reported mindfulness: the MINDSENS composite index. AB - Mindfulness has been described as an inherent human capability that can be learned and trained, and its improvement has been associated with better health outcomes in both medicine and psychology. Although the role of practice is central to most mindfulness programs, practice-related improvements in mindfulness skills is not consistently reported and little is known about how the characteristics of meditative practice affect different components of mindfulness. The present study explores the role of practice parameters on self reported mindfulness skills. A total of 670 voluntary participants with and without previous meditation experience (n = 384 and n = 286, respectively) responded to an internet-based survey on various aspects of their meditative practice (type of meditation, length of session, frequency, and lifetime practice). Participants also completed the Five Facets Mindfulness Questionnaire (FFMQ), and the Experiences Questionnaire (EQ). The group with meditation experience obtained significantly higher scores on all facets of FFMQ and EQ questionnaires compared to the group without experience. However different effect sizes were observed, with stronger effects for the Observing and Non-Reactivity facets of the FFMQ, moderate effects for Decentering in EQ, and a weak effect for Non-judging, Describing, and Acting with awareness on the FFMQ. Our results indicate that not all practice variables are equally relevant in terms of developing mindfulness skills. Frequency and lifetime practice--but not session length or meditation type--were associated with higher mindfulness skills. Given that these 6 mindfulness aspects show variable sensitivity to practice, we created a composite index (MINDSENS) consisting of those items from FFMQ and EQ that showed the strongest response to practice. The MINDSENS index was able to correctly discriminate daily meditators from non-meditators in 82.3% of cases. These findings may contribute to the understanding of the development of mindfulness skills and support trainers and researchers in improving mindfulness oriented practices and programs. PMID- 24466176 TI - Detection and localisation of the abalone probiotic Vibrio midae SY9 and its extracellular protease, VmproA, within the digestive tract of the South African abalone, Haliotis midae. AB - Probiotics have been widely reported to increase the growth rate of commercially important fish and shellfish by enhancing the digestion of ingested feed through the production of extracellular enzymes such as proteases and alginases. In order to investigate this further, the objective of this study was to localise the bacterial probiont Vibrio midae SY9 and one of the extracellular proteases it produces in the digestive tract of the South African abalone Haliotis midae. This was accomplished by inserting a promotorless gfp gene into the chromosome of the bacterium which was incorporated in an artificial, fishmeal-based abalone feed. In situ histological comparison of abalone fed either a basal diet or the basal diet supplemented with V. midae SY9::Tn10.52 using a cocktail of DNA probes to the gfp gene localised the probiont to the crop/stomach and intestinal regions of the H. midae digestive tract. Generally, the ingested probiotic bacterium occurred in association with feed and particulate matter within the crop/stomach and intestinal regions, as well as adhered to the wall of the crop/stomach. Histological immunohistochemical examination using polyclonal anti-VmproA antibodies localised an extracellular protease produced by V. midae SY9 to the H. midae crop/stomach and intestine where it appeared to be associated with feed and/or other particulate matter in the abalone gut. Thus the data suggests that V. midae SY9 colonises and/or adheres to the mucous lining of the abalone gut. Furthermore, the close association observed between the bacterium, its extracellular protease and ingested feed particles supports the theory that V. midae SY9 elevates in situ digestive enzyme levels and thus enhances feed digestion in farmed abalone. PMID- 24466177 TI - Structural alteration of the dorsal visual network in DLB patients with visual hallucinations: a cortical thickness MRI study. AB - Visual hallucinations (VH) represent one of the core features in discriminating dementia with Lewy bodies (DLB) from Alzheimer's Disease (AD). Previous studies reported that in DLB patients functional alterations of the parieto-occipital regions were correlated with the presence of VH. The aim of our study was to assess whether morphological changes in specific cortical regions of DLB could be related to the presence and severity of VH. We performed a cortical thickness analysis on magnetic resonance imaging data in a cohort including 18 DLB patients, 15 AD patients and 14 healthy control subjects. Relatively to DLB group, correlation analysis between the cortical thickness and the Neuropsychiatric Inventory (NPI) hallucination item scores was also performed. Cortical thickness was reduced bilaterally in DLB compared to controls in the pericalcarine and lingual gyri, cuneus, precuneus, superior parietal gyrus. Cortical thinning was found bilaterally in AD compared to controls in temporal cortex including the superior and middle temporal gyrus, part of inferior temporal cortex, temporal pole and insula. Inferior parietal and supramarginal gyri were also affected bilaterally in AD as compared to controls. The comparison between DLB and AD evidenced cortical thinning in DLB group in the right posterior regions including superior parietal gyrus, precuneus, cuneus, pericalcarine and lingual gyri. Furthermore, the correlation analysis between cortical thickness and NPI hallucination item scores showed that the structural alteration in the dorsal visual regions including superior parietal gyrus and precuneus closely correlated with the occurrence and severity of VH. We suggest that structural changes in key regions of the dorsal visual network may play a crucial role in the physiopathology of VH in DLB patients. PMID- 24466178 TI - Visualization of acute liver damage induced by cycloheximide in rats using PET with [(18)F]FEDAC, a radiotracer for translocator protein (18 kDa). AB - Liver damage induced by drug toxicity is an important concern for both medical doctors and patients. The aim of this study was to noninvasively visualize acute liver damage using positron emission tomography (PET) with N-benzyl-N-methyl-2 [7,8-dihydro-7-(2-[(18)F]fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ([(18)F]FEDAC), a radiotracer specific for translocator protein (18 kDa, TSPO) as a biomarker for inflammation, and to determine cellular sources enriching TSPO expression in the liver. A mild acute liver damage model was prepared by a single intraperitoneal injection of cycloheximide (CHX) into rats. Treatment with CHX induced apoptosis and necrotic changes in hepatocytes with slight neutrophil infiltration. The uptake of radioactivity in the rat livers was measured with PET after injection of [(18)F]FEDAC. The uptake of [(18)F]FEDAC increased in livers damaged from treatment with CHX compared to the controls. Presence of TSPO was examined in the liver tissue using quantitative reverse transcriptase-polymerase chain reaction and immunohistochemical assays. mRNA expression of TSPO was elevated in the damaged livers compared to the controls, and the level was correlated with the [(18)F]FEDAC uptake and severity of damage. TSPO expression in the damaged liver sections was mainly found in macrophages (Kupffer cells) and neutrophils, but not in hepatocytes. The elevation of TSPO mRNA expression was derived from the increase of the number of macrophages with TSPO and neutrophils with TSPO in damaged livers. From this study we considered that PET imaging with [(18)F]FEDAC represented the mild liver damage through the enhanced TSPO signal in inflammatory cells. We conclude that this method may be a useful tool for diagnosis in early stage of acute liver damage. PMID- 24466179 TI - Bcl2 deficiency activates FoxO through Akt inactivation and accelerates osteoblast differentiation. AB - Osteoblast apoptosis plays an important role in bone development and maintenance, and is in part responsible for osteoporosis in sex steroid deficiency, glucocorticoid excess, and aging. Although Bcl2 subfamily proteins, including Bcl2 and Bcl-XL, inhibit apoptosis, the physiological significance of Bcl2 in osteoblast differentiation has not been fully elucidated. To investigate this, we examined Bcl2-deficient (Bcl2(-/-)) mice. In Bcl2(-/-) mice, bromodeoxyuridine (BrdU)-positive osteoblasts were reduced in number, while terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive osteoblasts were increased. Unexpectedly, osteoblast differentiation was accelerated in Bcl2(-/-) mice as shown by the early appearance of osteocalcin positive osteoblasts. Osteoblast differentiation was also accelerated in vitro when primary osteoblasts were seeded at a high concentration to minimize the reduction of the cell density by apoptosis during culture. FoxO transcription factors, whose activities are negatively regulated through the phosphorylation by Akt, play important roles in multiple cell events, including proliferation, death, differentiation, longevity, and stress response. Expressions of FasL, Gadd45a, and Bim, which are regulated by FoxOs, were upregulated; the expression and activity of FoxOs were enhanced; and the phosphorylation of Akt and that of FoxO1 and FoxO3a by Akt were reduced in Bcl2(-/-) calvariae. Further, the levels of p53 mRNA and protein were increased, and the expression of p53-target genes, Pten and Igfbp3 whose proteins inhibit Akt activation, was upregulated in Bcl2(-/ ) calvariae. However, Pten but not Igfbp3 was upregulated in Bcl2(-/-) primary osteoblasts, and p53 induced Pten but not Igfbp3 in vitro. Silencing of either FoxO1 or FoxO3a inhibited and constitutively-active FoxO3a enhanced osteoblast differentiation. These findings suggest that Bcl2 deficiency induces and activates FoxOs through Akt inactivation, at least in part, by upregulating Pten expression through p53 in osteoblasts, and that the enhanced expression and activities of FoxOs may be one of the causes of accelerated osteoblast differentiation in Bcl2(-/-) mice. PMID- 24466180 TI - The discovery of phiAGATE, a novel phage infecting Bacillus pumilus, leads to new insights into the phylogeny of the subfamily Spounavirinae. AB - The Bacillus phage phiAGATE is a novel myovirus isolated from the waters of Lake Goreckie (a eutrophic lake in western Poland). The bacteriophage infects Bacillus pumilus, a bacterium commonly observed in the mentioned reservoir. Analysis of the phiAGATE genome (149844 base pairs) resulted in 204 predicted protein-coding sequences (CDSs), of which 53 could be functionally annotated. Further investigation revealed that the bacteriophage is a member of a previously undescribed cluster of phages (for the purposes of this study we refer to it as "Bastille group") within the Spounavirinae subfamily. Here we demonstrate that these viruses constitute a distinct branch of the Spounavirinae phylogenetic tree, with limited similarity to phages from the Twortlikevirus and Spounalikevirus genera. The classification of phages from the Bastille group into any currently accepted genus proved extremely difficult, prompting concerns about the validity of the present taxonomic arrangement of the subfamily. PMID- 24466181 TI - Counterproductive effect of saccadic suppression during attention shifts. AB - During saccadic eye movements, the processing of visual information is transiently interrupted by a mechanism known as "saccadic suppression" [1] that is thought to ensure perceptual stability [2]. If, as proposed in the premotor theory of attention [3], covert shifts of attention rely on sub-threshold recruitment of oculomotor circuits, then saccadic suppression should also occur during covert shifts. In order to test this prediction, we designed two experiments in which participants had to orient towards a cued letter, with or without saccades. We analyzed the time course of letter identification score in an "attention" task performed without saccades, using the saccadic latencies measured in the "saccade" task as a marker of covert saccadic preparation. Visual conditions were identical in all tasks. In the "attention" task, we found a drop in perceptual performance around the predicted onset time of saccades that were never performed. Importantly, this decrease in letter identification score cannot be explained by any known mechanism aligned on cue onset such as inhibition of return, masking, or microsaccades. These results show that attentional allocation triggers the same suppression mechanisms as during saccades, which is relevant during eye movements but detrimental in the context of covert orienting. PMID- 24466182 TI - Effects of age, gender, BMI, and anatomical site on skin thickness in children and adults with diabetes. AB - OBJECTIVE: We aimed to assess the effects of age, sex, body mass index (BMI), and anatomical site on skin thickness in children and adults with diabetes. METHODS: We studied 103 otherwise healthy children and adolescents with type 1 diabetes aged 5-19 years, and 140 adults with type 1 and type 2 diabetes aged 20-85 years. The thicknesses of both the dermis and subcutis were assessed using ultrasound with a linear array transducer, on abdominal and thigh skin. RESULTS: There was an age-related thickening of both dermis (p<0.0001) and subcutis (p = 0.013) in children and adolescents. Girls displayed a substantial pubertal increase in subcutis of the thigh (+54%; p = 0.048) and abdomen (+68%; p = 0.009). Adults showed an age-related decrease in dermal (p = 0.021) and subcutis (p = 0.009) thicknesses. Pubertal girls had a thicker subcutis than pubertal boys in both thigh (16.7 vs 7.5 mm; p<0.0001) and abdomen (16.7 vs 8.8 mm; p<0.0001). Men had greater thigh dermal thickness than women (1.89 vs 1.65 mm; p = 0.003), while the subcutis was thicker in women in thigh (21.3 vs 17.9 mm; p = 0.012) and abdomen (17.7 vs 9.8 mm; p<0.0001). In boys, men, and women, both dermis and subcutis were thicker on the abdomen compared to thigh; in girls this was only so for dermal thickness. In both children and adults, the skin (dermis and subcutis) became steadily thicker with increasing BMI (p<0.0001). CONCLUSIONS: Skin thickness is affected by age, pubertal status, gender, BMI, and anatomical site. Such differences may be important when considering appropriate sites for dermal/subcutaneous injections and other transdermal delivery systems. PMID- 24466183 TI - Dynamics and sources of soil organic C following afforestation of croplands with poplar in a semi-arid region in northeast China. AB - Afforestation of former croplands has been proposed as a promising way to mitigate rising atmospheric CO2 concentration in view of the commitment to the Kyoto Protocol. Central to this C sequestration is the dynamics of soil organic C (SOC) storage and stability with the development of afforested plantations. Our previous study showed that SOC storage was not changed after afforestation except for the 0-10 cm layer in a semi-arid region of Keerqin Sandy Lands, northeast China. In this study, soil organic C was further separated into light and heavy fractions using the density fractionation method, and their organic C concentration and (13)C signature were analyzed to investigate the turnover of old vs. new SOC in the afforested soils. Surface layer (0-10 cm) soil samples were collected from 14 paired plots of poplar (Populus * xiaozhuanica W. Y. Hsu & Liang) plantations with different stand basal areas (the sum of the cross sectional area of all live trees in a stand), ranging from 0.2 to 32.6 m(2) ha( 1), and reference maize (Zea mays L.) croplands at the same sites as our previous study. Soil DeltaC stocks (DeltaC refers to the difference in SOC content between a poplar plantation and the paired cropland) in bulk soil and light fraction were positively correlated with stand basal area (R (2) = 0.48, p<0.01 and R (2) = 0.40, p = 0.02, respectively), but not for the heavy fraction. SOCcrop (SOC derived from crops) contents in the light and heavy fractions in poplar plantations were significantly lower as compared with SOC contents in croplands, but tree-derived C in bulk soil, light and heavy fraction pools increased gradually with increasing stand basal area after afforestation. Our study indicated that cropland afforestation could sequester new C derived from trees into surface mineral soil, but did not enhance the stability of SOC due to a fast turnover of SOC in this semi-arid region. PMID- 24466184 TI - The evolutionary divergence of psbA gene in Synechococcus and their myoviruses in the East China Sea. AB - Marine Synechococcus is a principal component of the picophytoplankton and makes an important contribution to primary productivity in the ocean. Synechophages, infecting Synechococcus, are believed to have significant influences on the distribution and abundance of their hosts. Extensive previous ecological studies on cyanobacteria and viruses have been carried out in the East China Sea (ECS). Here we investigate the diversity and divergence of Synechococcus and their myoviruses (Synechomyoviruses) based on their shared photosynthesis psbA gene. Synechococcus is dominated by subclades 5.1A I, 5.1A II and 5.1A IV in the ECS, and clades I and II are the dominant groups in the Synechomyoviruses. As two phylogenetically independent clades, there is much higher diversity of the Synechomyoviruses than Synechococcus. Obvious partitioning characteristics of GC and GC3 (the GC content at the third codon position) contents are obtained among different picophytoplankton populations and their phages. The GC3 content causes the psbA gene in Synechococcus to have a higher GC content, while the opposite is true in the Synechomyoviruses. Analyzing more than one-time difference of the codon usage frequency of psbA sequences, the third position nucleotides of preferred codons for Synechococcus are all G and C, while most Synechomyoviral sequences (72.7%) have A and T at the third position of their preferred codons. This work shed light on the ecology and evolution of phage-host interactions in the environment. PMID- 24466185 TI - Applications of self-organizing maps for ecomorphological investigations through early ontogeny of fish. AB - We propose a new graphical approach to the analysis of multi-temporal morphological and ecological data concerning the life history of fish, which can typically serves models in ecomorphological investigations because they often undergo significant ontogenetic changes. These changes can be very complex and difficult to describe, so that visualization, abstraction and interpretation of the underlying relationships are often impeded. Therefore, classic ecomorphological analyses of covariation between morphology and ecology, performed by means of multivariate techniques, may result in non-exhaustive models. The Self Organizing map (SOM) is a new, effective approach for pursuing this aim. In this paper, lateral outlines of larval stages of gilthead sea bream (Sparus aurata) and dusky grouper (Epinephelus marginatus) were recorded and broken down using by means of Elliptic Fourier Analysis (EFA). Gut contents of the same specimens were also collected and analyzed. Then, shape and trophic habits data were examined by SOM, which allows both a powerful visualization of shape changes and an easy comparison with trophic habit data, via their superimposition onto the trained SOM. Thus, the SOM provides a direct visual approach for matching morphological and ecological changes during fish ontogenesis. This method could be used as a tool to extract and investigate relationships between shape and other sinecological or environmental variables, which cannot be taken into account simultaneously using conventional statistical methods. PMID- 24466186 TI - Association between 3801T>C polymorphism of CYP1A1 and idiopathic male infertility risk: a systematic review and meta-analysis. AB - BACKGROUND: Epidemiological studies have evaluated the association between 3801T>C polymorphism of CYP1A1 gene and the risk for idiopathic male infertility, but the results are inconclusive. We aimed to derive a more precise estimation of the relationship by conducting a meta-analysis of case-control studies. METHODS: This study conformed to Preferred Reporting Items for Systematic Reviews and Meta Analyses guidelines. PubMed, Embase and CNKI databases were searched through November 2013 to identify relevant studies. Pooled odds ratios with 95% confidence intervals were used to assess the strength of the association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Q-test was performed to evaluate between-study heterogeneity and publication bias was appraised using funnel plots. Sensitivity analyses were conducted to evaluate the robustness of meta-analysis findings. RESULTS: Six studies involving 1,060 cases and 1,225 controls were included in this meta-analysis. Overall, significant associations between 3801T>C polymorphism and idiopathic male infertility risk were observed in allelic comparison (OR = 1.36, 95% CI: 1.01-1.83), homozygous model (OR = 2.18, 95% CI: 1.15-4.12), and recessive model (OR = 1.86, 95% CI: 1.09-3.20), with robust findings according to sensitivity analyses. However, subgroup analyses did not further identify the susceptibility to idiopathic male infertility in all comparisons. Funnel plot inspections did not reveal evidence of publication bias. CONCLUSIONS: The current meta-analysis provides evidence of a significant association between CYP1A1 3801T>C polymorphism and idiopathic male infertility risk. Considering the limitation inherited from the eligible studies, further confirmation in large-scale and well-designed studies is needed. PMID- 24466187 TI - Influence of perturbation velocity on balance control in Parkinson's disease. AB - Underlying somatosensory processing deficits of joint rotation velocities may cause patients with Parkinson's disease (PD) to be more unstable for fast rather than slow balance perturbations. Such deficits could lead to reduced proprioceptive amplitude feedback triggered by perturbations, and thereby to smaller or delayed stabilizing postural responses. For this reason, we investigated whether support surface perturbation velocity affects balance reactions in PD patients. We examined postural responses of seven PD patients (OFF medication) and eight age-matched controls following backward rotations of a support-surface platform. Rotations occurred at three different speeds: fast (60 deg/s), medium (30 deg/s) or slow (3.8 deg/s), presented in random order. Each subject completed the protocol under eyes open and closed conditions. Full body kinematics, ankle torques and the number of near-falls were recorded. Patients were significantly more unstable than controls following fast perturbations (26% larger displacements of the body's centre of mass; P<0.01), but not following slow perturbations. Also, more near-falls occurred in patients for fast rotations. Balance correcting ankle torques were weaker for patients than controls on the most affected side, but were stronger than controls for the least affected side. These differences were present both with eyes open and eyes closed (P<0.01). Fast support surface rotations caused greater instability and discriminated Parkinson patients better from controls than slow rotations. Although ankle torques on the most affected side were weaker, patients partially compensated for this by generating larger than normal stabilizing torques about the ankle joint on the least affected side. Without this compensation, instability may have been greater. PMID- 24466188 TI - The neutron structure of urate oxidase resolves a long-standing mechanistic conundrum and reveals unexpected changes in protonation. AB - Urate oxidase transforms uric acid to 5-hydroxyisourate without the help of cofactors, but the catalytic mechanism has remained enigmatic, as the protonation state of the substrate could not be reliably deduced. We have determined the neutron structure of urate oxidase, providing unique information on the proton positions. A neutron crystal structure inhibited by a chloride anion at 2.3 A resolution shows that the substrate is in fact 8-hydroxyxanthine, the enol tautomer of urate. We have also determined the neutron structure of the complex with the inhibitor 8-azaxanthine at 1.9 A resolution, showing the protonation states of the K10-T57-H256 catalytic triad. Together with X-ray data and quantum chemical calculations, these structures allow us to identify the site of the initial substrate protonation and elucidate why the enzyme is inhibited by a chloride anion. PMID- 24466189 TI - Evidence that a psychopathology interactome has diagnostic value, predicting clinical needs: an experience sampling study. AB - BACKGROUND: For the purpose of diagnosis, psychopathology can be represented as categories of mental disorder, symptom dimensions or symptom networks. Also, psychopathology can be assessed at different levels of temporal resolution (monthly episodes, daily fluctuating symptoms, momentary fluctuating mental states). We tested the diagnostic value, in terms of prediction of treatment needs, of the combination of symptom networks and momentary assessment level. METHOD: Fifty-seven patients with a psychotic disorder participated in an ESM study, capturing psychotic experiences, emotions and circumstances at 10 semi random moments in the flow of daily life over a period of 6 days. Symptoms were assessed by interview with the Positive and Negative Syndrome Scale (PANSS); treatment needs were assessed using the Camberwell Assessment of Need (CAN). RESULTS: Psychotic symptoms assessed with the PANSS (Clinical Psychotic Symptoms) were strongly associated with psychotic experiences assessed with ESM (Momentary Psychotic Experiences). However, the degree to which Momentary Psychotic Experiences manifested as Clinical Psychotic Symptoms was determined by level of momentary negative affect (higher levels increasing probability of Momentary Psychotic Experiences manifesting as Clinical Psychotic Symptoms), momentary positive affect (higher levels decreasing probability of Clinical Psychotic Symptoms), greater persistence of Momentary Psychotic Experiences (persistence predicting increased probability of Clinical Psychotic Symptoms) and momentary environmental stress associated with events and activities (higher levels increasing probability of Clinical Psychotic Symptoms). Similarly, the degree to which momentary visual or auditory hallucinations manifested as Clinical Psychotic Symptoms was strongly contingent on the level of accompanying momentary paranoid delusional ideation. Momentary Psychotic Experiences were associated with CAN unmet treatment needs, over and above PANSS measures of psychopathology, similarly moderated by momentary interactions with emotions and context. CONCLUSION: The results suggest that psychopathology, represented as an interactome at the momentary level of temporal resolution, is informative in diagnosing clinical needs, over and above traditional symptom measures. PMID- 24466190 TI - Depression and anxiety trajectories among women who undergo an elective cesarean section. AB - BACKGROUND: Depression and anxiety are important mood changes in childbearing women. However, changes in depression and anxiety over time in women who undergo an elective cesarean section (CS) have not yet been elucidated. We aimed to characterize the trajectories of depressive and anxiety symptoms, and patterns of co-occurrence, and examined the associated predictors of depression and anxiety courses. METHODS: A prospective longitudinal study of childbearing women (N = 139) who underwent a CS was conducted. Depressive and anxiety symptoms were respectively assessed using the Edinburgh Postnatal Depression Scale and State Anxiety Inventory, in the third trimester and at 1 day, 1 week, and 1 and 6 months postpartum. RESULTS: Group-based modeling identified three distinct trajectories of depressive symptoms: group 1 (low, 30.9%), group 2 (mild, 41.7%), and group 3 (high, 27.3%). Four group trajectories of anxiety symptoms were identified: group 1 (low, 19.4%), group 2 (mild, 44.6%), group 3 (high, 28.8%), and group 4 (very high, 7.2%). Mild symptoms of both depression and anxiety were the most common joint trajectory. Depression trajectories were significantly related to anxiety trajectories (p<0.001). Predictors of the joint trajectory included the pre-pregnant body mass index (odds ratio (OR): 2.42, 95% confidence interval (CI): 1.1 ~ 6.3) and a poor sleep score (OR: 3.2, 95% CI: 1.4 ~ 7.3) in the third trimester. CONCLUSIONS: Distinctive trajectories and co-occurrence patterns of depressive and anxiety symptoms were identified. Our findings suggest a need for greater attention to continuous assessment of psychological well-being among women who undergo an elective CS. PMID- 24466191 TI - Comparison of CpG island methylator phenotype (CIMP) frequency in colon cancer using different probe- and gene-specific scoring alternatives on recommended multi-gene panels. AB - BACKGROUND: In colorectal cancer a distinct subgroup of tumours demonstrate the CpG island methylator phenotype (CIMP). However, a consensus of how to score CIMP is not reached, and variation in definition may influence the reported CIMP prevalence in tumours. Thus, we sought to compare currently suggested definitions and cut-offs for methylation markers and how they influence CIMP classification in colon cancer. METHODS: Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA), with subsequent fragment analysis, was used to investigate methylation of tumour samples. In total, 31 CpG sites, located in 8 different genes (RUNX3, MLH1, NEUROG1, CDKN2A, IGF2, CRABP1, SOCS1 and CACNA1G) were investigated in 64 distinct colon cancers and 2 colon cancer cell lines. The Ogino gene panel includes all 8 genes, in addition to the Weisenberger panel of which only 5 of the 8 genes included were investigated. In total, 18 alternative combinations of scoring of CIMP positivity on probe-, gene-, and panel-level were analysed and compared. RESULTS: For 47 samples (71%), the CIMP status was constant and independent of criteria used for scoring; 34 samples were constantly scored as CIMP negative, and 13 (20%) consistently scored as CIMP positive. Only four of 31 probes (13%) investigated showed no difference in the numbers of positive samples using the different cut-offs. Within the panels a trend was observed that increasing the gene-level stringency resulted in a larger difference in CIMP positive samples than increasing the probe-level stringency. A significant difference between positive samples using 'the most stringent' as compared to 'the least stringent' criteria (20% vs 46%, respectively; p<0.005) was demonstrated. CONCLUSIONS: A statistical significant variation in the frequency of CIMP depending on the cut-offs and genes included in a panel was found, with twice as many positives samples by least compared to most stringent definition used. PMID- 24466192 TI - The monocyte to macrophage transition in the murine sterile wound. AB - The origin of wound repair macrophages is incompletely defined and was examined here in sterile wounds using the subcutaneous polyvinyl alcohol sponge implantation model in mice. Phenotypic analysis identified F4/80(+)Ly6C(hi)CD64(+)MerTK(-) monocytes and F4/80(+)Ly6C(low)CD64(+)MerTK(+) macrophages in the wound. Circulating monocytes were the precursors of inflammatory Ly6C(hi) wound monocytes. Ly6C(low)MerTK(+) macrophages appeared later, expressed CD206, CD11c, and MHC class II, produced cytokines consistent with repair function, and lacked a gene expression profile compatible with mesenchymal transition or fibroblastic transdifferentiation. Data also demonstrated that Ly6C(hi) wound cells were precursors of Ly6C(low) macrophages, although monocytes did not undergo rapid maturation but rather persisted in the wound as Ly6C(hi)MerTK(-) cells. MerTK-deficient mice were examined to determine whether MerTK-dependent signals from apoptotic cells regulated the maturation of wound macrophages. MerTK-deficient mice had day 14 cell compositions that resembled more immature wounds, with a smaller proportion of F4/80(+) cells and higher frequencies of Ly6G(+) neutrophils and Ly6C(hi) monocytes. The cytokine profile and number of apoptotic cells in day 14 wounds of MerTK-deficient mice was unaffected despite the alterations in cell composition. Overall, these studies identified a differentiation pathway in response to sterile inflammation in which monocytes recruited from the circulation acquire proinflammatory function, persist in the wound, and mature into repair macrophages. PMID- 24466193 TI - Neural mechanisms by which attention modulates the comparison of remembered and perceptual representations. AB - Attention is important for effectively comparing incoming perceptual information with the contents of visual short-term memory (VSTM), such that any differences can be detected. However, how attentional mechanisms operate upon these comparison processes remains largely unknown. Here we investigate the underlying neural mechanisms by which attention modulates the comparisons between VSTM and perceptual representations using functional magnetic resonance imaging (fMRI). Participants performed a cued change detection task. Spatial cues were presented to orient their attention either to the location of an item in VSTM prior to its comparison (retro-cues), or simultaneously (simultaneous-cues) with the probe array. A no-cue condition was also included. When attention cannot be effectively deployed in advance (i.e. following the simultaneous-cues), we observed a distributed and extensive activation pattern in the prefrontal and parietal cortices in support of successful change detection. This was not the case when participants can deploy their attention in advance (i.e. following the retro cues). The region-of-interest analyses confirmed that neural responses for successful change detection versus correct rejection in the visual and parietal regions were significantly different for simultaneous-cues compared to retro cues. Importantly, we found enhanced functional connectivity between prefrontal and parietal cortices when detecting changes on the simultaneous-cue trials. Moreover, we demonstrated a close relationship between this functional connectivity and d' scores. Together, our findings elucidate the attentional and neural mechanisms by which items held in VSTM are compared with incoming perceptual information. PMID- 24466194 TI - Evaluation of epidemiological cut-off values indicates that biocide resistant subpopulations are uncommon in natural isolates of clinically-relevant microorganisms. AB - To date there are no clear criteria to determine whether a microbe is susceptible to biocides or not. As a starting point for distinguishing between wild-type and resistant organisms, we set out to determine the minimal inhibitory concentration (MIC) and minimal bactericidal concentration (MBC) distributions for four common biocides; triclosan, benzalkonium chloride, chlorhexidine and sodium hypochlorite for 3319 clinical isolates, with a particular focus on Staphylococcus aureus (N = 1635) and Salmonella spp. (N = 901) but also including Escherichia coli (N = 368), Candida albicans (N = 200), Klebsiella pneumoniae (N = 60), Enterobacter spp. (N = 54), Enterococcus faecium (N = 53), and Enterococcus faecalis (N = 56). From these data epidemiological cut-off values (ECOFFs) are proposed. As would be expected, MBCs were higher than MICs for all biocides. In most cases both values followed a normal distribution. Bimodal distributions, indicating the existence of biocide resistant subpopulations were observed for Enterobacter chlorhexidine susceptibility (both MICs and MBCs) and the susceptibility to triclosan of Enterobacter (MBC), E. coli (MBC and MIC) and S. aureus (MBC and MIC). There is a concern on the potential selection of antibiotic resistance by biocides. Our results indicate however that resistance to biocides and, hence any potential association with antibiotic resistance, is uncommon in natural populations of clinically relevant microorganisms. PMID- 24466195 TI - CD9 negatively regulates CD26 expression and inhibits CD26-mediated enhancement of invasive potential of malignant mesothelioma cells. AB - CD26/dipeptidyl peptidase IV is a cell surface glycoprotein which consists of multiple functional domains beside its ectopeptidase site. A growing body of evidence indicates that elevated expression of CD26 correlates with disease aggressiveness and invasive potential of selected malignancies. To further explore the molecular mechanisms involved in this clinical behavior, our current work focused on the interaction between CD26 and CD9, which were recently identified as novel markers for cancer stem cells in malignant mesothelioma. We found that CD26 and CD9 co-modulated and co-precipitated with each other in the malignant mesothelioma cell lines ACC-MESO1 and MSTO-211H. SiRNA study revealed that depletion of CD26 led to increased CD9 expression, while depletion of CD9 resulted in increased CD26 expression. Consistent with these findings was the fact that gene transfer of CD26 into CD26-negative MSTO-211H cells reduced CD9 expression. Cell invasion assay showed that overexpression of CD26 or gene depletion of CD9 led to enhanced invasiveness, while CD26 gene depletion resulted in reduced invasive potential. Furthermore, our work suggested that this enhanced invasiveness may be partly mediated by alpha5beta1 integrin, since co precipitation studies demonstrated an association between CD26 and alpha5beta1 integrin. Finally, gene depletion of CD9 resulted in elevated protein levels and tyrosine phosphorylation of FAK and Cas-L, which are downstream of beta1 integrin, while depletion of CD26 led to a reduction in the levels of these molecules. Collectively, our findings suggest that CD26 potentiates tumor cell invasion through its interaction with alpha5beta1 integrin, and CD9 negatively regulates tumor cell invasion by reducing the level of CD26-alpha5beta1 integrin complex through an inverse correlation between CD9 and CD26 expression. Our results also suggest that CD26 and CD9 serve as potential biomarkers as well as promising molecular targets for novel therapeutic approaches in malignant mesothelioma and other malignancies. PMID- 24466196 TI - Resistance to inhibitors of cholinesterase (Ric)-8A and Galphai contribute to cytokinesis abscission by controlling vacuolar protein-sorting (Vps)34 activity. AB - Resistance to inhibitors of cholinesterase (Ric)-8A is a guanine nucleotide exchange factor for Galphai, Galphaq, and Galpha12/13, which is implicated in cell signaling and as a molecular chaperone required for the initial association of nascent Galpha subunits with cellular membranes. Ric-8A, Galphai subunits, and their regulators are localized at the midbody prior to abscission and linked to the final stages of cell division. Here, we identify a molecular mechanism by which Ric-8A affects cytokinesis and abscission by controlling Vps34 activity. We showed that Ric-8A protein expression is post-transcriptionally controlled during the cell cycle reaching its maximum levels at mitosis. A FRET biosensor created to measure conformational changes in Ric-8A by FLIM (Fluorescence Lifetime Imaging Microscopy) revealed that Ric-8A was in a close-state during mitosis and particularly so at cytokinesis. Lowering Ric-8A expression delayed the abscission time of dividing cells, which correlated with increased intercellular bridge length and multinucleation. During cytokinesis, Ric-8A co-localized with Vps34 at the midbody along with Galphai and LGN, where these proteins functioned to regulate Vps34 phosphatidylinositol 3-kinase activity. PMID- 24466197 TI - Long-term changes in species composition and relative abundances of sharks at a provisioning site. AB - Diving with sharks, often in combination with food baiting/provisioning, has become an important product of today's recreational dive industry. Whereas the effects baiting/provisioning has on the behaviour and abundance of individual shark species are starting to become known, there is an almost complete lack of equivalent data from multi-species shark diving sites. In this study, changes in species composition and relative abundances were determined at the Shark Reef Marine Reserve, a multi-species shark feeding site in Fiji. Using direct observation sampling methods, eight species of sharks (bull shark Carcharhinus leucas, grey reef shark Carcharhinus amblyrhynchos, whitetip reef shark Triaenodon obesus, blacktip reef shark Carcharhinus melanopterus, tawny nurse shark Nebrius ferrugineus, silvertip shark Carcharhinus albimarginatus, sicklefin lemon shark Negaprion acutidens, and tiger shark Galeocerdo cuvier) displayed inter-annual site fidelity between 2003 and 2012. Encounter rates and/or relative abundances of some species changed over time, overall resulting in more individuals (mostly C. leucas) of fewer species being encountered on average on shark feeding dives at the end of the study period. Differences in shark community composition between the years 2004-2006 and 2007-2012 were evident, mostly because N. ferrugineus, C. albimarginatus and N. acutidens were much more abundant in 2004-2006 and very rare in the period of 2007-2012. Two explanations are offered for the observed changes in relative abundances over time, namely inter-specific interactions and operator-specific feeding protocols. Both, possibly in combination, are suggested to be important determinants of species composition and encounter rates, and relative abundances at this shark provisioning site in Fiji. This study, which includes the most species from a spatially confined shark provisioning site to date, suggests that long-term provisioning may result in competitive exclusion among shark species. PMID- 24466198 TI - Systematic identification and evolutionary analysis of catalytically versatile cytochrome p450 monooxygenase families enriched in model basidiomycete fungi. AB - Genome sequencing of basidiomycetes, a group of fungi capable of degrading/mineralizing plant material, revealed the presence of numerous cytochrome P450 monooxygenases (P450s) in their genomes, with some exceptions. Considering the large repertoire of P450s found in fungi, it is difficult to identify P450s that play an important role in fungal metabolism and the adaptation of fungi to diverse ecological niches. In this study, we followed Sir Charles Darwin's theory of natural selection to identify such P450s in model basidiomycete fungi showing a preference for different types of plant components degradation. Any P450 family comprising a large number of member P450s compared to other P450 families indicates its natural selection over other P450 families by its important role in fungal physiology. Genome-wide comparative P450 analysis in the basidiomycete species, Phanerochaete chrysosporium, Phanerochaete carnosa, Agaricus bisporus, Postia placenta, Ganoderma sp. and Serpula lacrymans, revealed enrichment of 11 P450 families (out of 68 P450 families), CYP63, CYP512, CYP5035, CYP5037, CYP5136, CYP5141, CYP5144, CYP5146, CYP5150, CYP5348 and CYP5359. Phylogenetic analysis of the P450 family showed species-specific alignment of P450s across the P450 families with the exception of P450s of Phanerochaete chrysosporium and Phanerochaete carnosa, suggesting paralogous evolution of P450s in model basidiomycetes. P450 gene-structure analysis revealed high conservation in the size of exons and the location of introns. P450s with the same gene structure were found tandemly arranged in the genomes of selected fungi. This clearly suggests that extensive gene duplications, particularly tandem gene duplications, led to the enrichment of selective P450 families in basidiomycetes. Functional analysis and gene expression profiling data suggest that members of the P450 families are catalytically versatile and possibly involved in fungal colonization of plant material. To our knowledge, this is the first report on the identification and comparative-evolutionary analysis of P450 families enriched in model basidiomycetes. PMID- 24466199 TI - The E2-like conjugation enzyme Atg3 promotes binding of IRG and Gbp proteins to Chlamydia- and Toxoplasma-containing vacuoles and host resistance. AB - Cell-autonomous immunity to the bacterial pathogen Chlamydia trachomatis and the protozoan pathogen Toxoplasma gondii is controlled by two families of Interferon (IFN)-inducible GTPases: Immunity Related GTPases (IRGs) and Guanylate binding proteins (Gbps). Members of these two GTPase families associate with pathogen containing vacuoles (PVs) and solicit antimicrobial resistance pathways specifically to the intracellular site of infection. The proper delivery of IRG and Gbp proteins to PVs requires the autophagy factor Atg5. Atg5 is part of a protein complex that facilitates the transfer of the ubiquitin-like protein Atg8 from the E2-like conjugation enzyme Atg3 to the lipid phosphatidylethanolamine. Here, we show that Atg3 expression, similar to Atg5 expression, is required for IRG and Gbp proteins to dock to PVs. We further demonstrate that expression of a dominant-active, GTP-locked IRG protein variant rescues the PV targeting defect of Atg3- and Atg5-deficient cells, suggesting a possible role for Atg proteins in the activation of IRG proteins. Lastly, we show that IFN-induced cell-autonomous resistance to C. trachomatis infections in mouse cells depends not only on Atg5 and IRG proteins, as previously demonstrated, but also requires the expression of Atg3 and Gbp proteins. These findings provide a foundation for a better understanding of IRG- and Gbp-dependent cell-autonomous resistance and its regulation by Atg proteins. PMID- 24466201 TI - Inter-regional performance of the public health system in a high-inequality country. AB - Previous cross-country studies have revealed a relationship between health and socio-economic factors. However, multinational studies that use aggregate figures could obfuscate the actual situation in each individual region, or even in each individual federal unit, mainly in a developing country that spans a continent and has large socioeconomic inequalities. We conducted a within-country study, in Brazil, of health system performance that examined data in the four perspectives that most strongly affect the performance of public health systems: financial, customer, internal processes and learning&growth. After estimating the interregional health system performance from each perspective, we identified the determinants of inefficiency (i.e., the factors that have the greatest potential for improvement in each region). The results showed that the major determinants of inefficiency in the less efficient regions (N and NE) are concentrated in the perspective of learning&growth (the number of health professionals and the number of graduates with a health-related undergraduate degree) and, in the regions with the best performance (S and SE) the major determinants of inefficiency are concentrated in the financial perspective (spending on health care and the amount paid for hospitalization). PMID- 24466200 TI - The gastroprotective effect of menthol: involvement of anti-apoptotic, antioxidant and anti-inflammatory activities. AB - The aim of this research was to investigate the anti-apoptotic, antioxidant and anti-inflammatory properties of menthol against ethanol-induced gastric ulcers in rats. Wistar rats were orally treated with vehicle, carbenoxolone (100 mg/kg) or menthol (50 mg/kg) and then treated with ethanol to induce gastric ulcers. After euthanasia, stomach samples were prepared for histological slides and biochemical analyses. Immunohistochemical analyses of the cytoprotective and anti-apoptotic heat-shock protein-70 (HSP-70) and the apoptotic Bax protein were performed. The neutrophils were manually counted. The activity of the myeloperoxidase (MPO) was measured. To determine the level of antioxidant functions, the levels of glutathione (GSH), glutathione peroxidase (GSH-Px), glutathione reductase (GR) and superoxide dismutase (SOD) were measured using ELISA. The levels of the pro inflammatory cytokines tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) and the anti-inflammatory cytokine interleukin-10 (IL-10) were assessed using ELISA kits. The menthol treated group presented 92% gastroprotection compared to the vehicle-treated group. An increased immunolabeled area was observed for HSP-70, and a decreased immunolabeled area was observed for the Bax protein in the menthol treated group. Menthol treatment induced a decrease in the activity of MPO and SOD, and the protein levels of GSH, GSH-Px and GR were increased. There was also a decrease in the levels of TNF-alpha and IL-6 and an increase in the level of IL-10. In conclusion, oral treatment with menthol displayed a gastroprotective activity through anti-apoptotic, antixidant and anti inflammatory mechanisms. PMID- 24466202 TI - Genome-wide identification and evolutionary analysis of the SBP-box gene family in castor bean. AB - Genes in the SQUAMOSA promoter-binding-protein (SBP-box) gene family encode transcriptional regulators and perform a variety of regulatory functions that involved in the developmental and physiological processes of plants. In this study, a comprehensive computational analysis identified 15 candidates of the SBP box gene family in the castor bean (Ricinus communis). The phylogenetic and domain analysis indicated that these genes were divided into two groups (group I and II). The group II was a big branch and was further classified into three subgroups (subgroup II-1 to 3) based on the phylogeny, gene structures and conserved motifs. It was observed that the genes of subgroup II-1 had distinct evolutionary features from those of the other two subgroups, however, were more similar to those of group I. Therefore, we inferred that group I and subgroup II 1 might retain ancient signals, whereas the subgroup II-2 and 3 exhibited the divergence during evolutionary process. Estimation of evolutionary parameters (dN and dN/dS) further supported our hypothesis. At first, the group I was more constrained by strong purifying selection and evolved slowly with a lower substitution rate than group II. As regards the three subgroups, subgroup II-1 had the lowest rate of substitution and was under strong purifying selection. By contrast, subgroups II-2 and 3 evolved more rapidly and experienced less purifying selection. These results indicated that the different evolutionary rates and selection strength caused the different evolutionary patterns of the members of SBP-box genes in castor bean. Taken together, these results provide better insights into understanding evolutionary divergence of the members of SBP box gene family in castor bean and provide a guide for future functional diverse analyses of this gene family. PMID- 24466203 TI - Beta-catenin is vital for the integrity of mouse embryonic stem cells. AB - beta-Catenin mediated Wnt-signaling is assumed to play a major function in embryonic stem cells in maintaining their stem cell character and the exit from this unique trait. The complexity of beta-catenin action and conflicting results on the role of beta-catenin in maintaining the pluripotent state have made it difficult to understand its precise cellular and molecular functions. To attempt this issue we have generated new genetically modified mouse embryonic stem cell lines allowing for the deletion of beta-catenin in a controlled manner by taking advantage of the Cre-ER-T2 system and analyzed the effects in a narrow time window shortly after ablation. By using this approach, rather then taking long term cultured beta-catenin null cell lines we demonstrate that beta-catenin is dispensable for the maintenance of pluripotency associated genes. In addition we observed that the removal of beta-catenin leads to a strong increase of cell death, the appearance of multiple clustered functional centrosomes most likely due to a mis-regulation of the polo-like-kinase 2 and furthermore, alterations in chromosome segregation. Our study demonstrates the importance of beta-catenin in maintaining correct cellular functions and helps to understand its role in embryonic stem cells. PMID- 24466204 TI - Increased adenovirus Type 5 mediated transgene expression due to RhoB down regulation. AB - Adenovirus type 5 (Ad5) is a non-enveloped DNA virus frequently used as a gene transfer vector. Efficient Ad5 cell entry depends on the availability of its primary receptor, coxsackie and adenovirus receptor, which is responsible for attachment, and integrins, secondary receptors responsible for adenovirus internalization via clathrin-mediated endocytosis. However, efficacious adenovirus-mediated transgene expression also depends on successful trafficking of Ad5 particles to the nucleus of the target cell. It has been shown that changes occurring in tumor cells during development of resistance to anticancer drugs can be beneficial for adenovirus mediated transgene expression. In this study, using an in vitro model consisting of a parental cell line, human laryngeal carcinoma HEp2 cells, and a cisplatin-resistant clone CK2, we investigated the cause of increased Ad5-mediated transgene expression in CK2 as compared to HEp2 cells. We show that the primary cause of increased Ad5-mediated transgene expression in CK2 cells is not modulation of receptors on the cell surface or change in Ad5wt attachment and/or internalization, but is rather the consequence of decreased RhoB expression. We propose that RhoB plays an important role in Ad5 post-internalization events and more particularly in Ad5 intracellular trafficking. To the best of our knowledge, this is the first study showing changed Ad5 trafficking pattern between cells expressing different amount of RhoB, indicating the role of RhoB in Ad5 intracellular trafficking. PMID- 24466205 TI - Peripheral erythrocytes decrease upon specific respiratory challenge with grass pollen allergen in sensitized mice and in human subjects. AB - BACKGROUND AND AIMS: Specific hyper-responsiveness towards an allergen and non specific airway hyperreactivity both impair quality of life in patients with respiratory allergic diseases. We aimed to investigate cellular responses following specific and non-specific airway challenges locally and systemically in i) sensitized BALB/c mice challenged with grass pollen allergen Phl p 5, and in ii) grass pollen sensitized allergic rhinitis subjects undergoing specific airway challenge in the Vienna Challenge Chamber (VCC). METHODS AND RESULTS: BALB/c mice (n = 20) were intraperitoneally immunized with grass pollen allergen Phl p 5 and afterwards aerosol challenged with either the specific allergen Phl p 5 (n = 10) or the non-specific antigen ovalbumin (OVA) (n = 10). A protocol for inducing allergic asthma as well as allergic rhinitis, according to the united airway concept, was used. Both groups of exposed mice showed significantly reduced physical activity after airway challenge. Specific airway challenge further resulted in goblet cell hyperplasia, enhanced mucous secretion, intrapulmonary leukocyte infiltration and lymphoid follicle formation, associated with significant expression of IL-4, IL-5 and IL-13 in splenocytes and also partially in lung tissue. Concerning circulating blood cell dynamics, we observed a significant drop of erythrocyte counts, hemoglobin and hematocrit levels in both mouse groups, challenged with allergen or OVA. A significant decrease in circulating erythrocytes and hematocrit levels after airway challenges with grass pollen allergen was also found in grass pollen sensitized human rhinitis subjects (n = 42) at the VCC. The effects on peripheral leukocyte counts in mice and humans however were opposed, possibly due to the different primary inflammation sites. CONCLUSION: Our data revealed that, besides significant leukocyte dynamics, particularly erythrocytes are involved in acute hypersensitivity reactions to respiratory allergens. A rapid recruitment of erythrocytes to the lungs to compensate for hypoxia is a possible explanation for these findings. PMID- 24466206 TI - The use of high-throughput DNA sequencing in the investigation of antigenic variation: application to Neisseria species. AB - Antigenic variation occurs in a broad range of species. This process resembles gene conversion in that variant DNA is unidirectionally transferred from partial gene copies (or silent loci) into an expression locus. Previous studies of antigenic variation have involved the amplification and sequencing of individual genes from hundreds of colonies. Using the pilE gene from Neisseria gonorrhoeae we have demonstrated that it is possible to use PCR amplification, followed by high-throughput DNA sequencing and a novel assembly process, to detect individual antigenic variation events. The ability to detect these events was much greater than has previously been possible. In N. gonorrhoeae most silent loci contain multiple partial gene copies. Here we show that there is a bias towards using the copy at the 3' end of the silent loci (copy 1) as the donor sequence. The pilE gene of N. gonorrhoeae and some strains of Neisseria meningitidis encode class I pilin, but strains of N. meningitidis from clonal complexes 8 and 11 encode a class II pilin. We have confirmed that the class II pili of meningococcal strain FAM18 (clonal complex 11) are non-variable, and this is also true for the class II pili of strain NMB from clonal complex 8. In addition when a gene encoding class I pilin was moved into the meningococcal strain NMB background there was no evidence of antigenic variation. Finally we investigated several members of the opa gene family of N. gonorrhoeae, where it has been suggested that limited variation occurs. Variation was detected in the opaK gene that is located close to pilE, but not at the opaJ gene located elsewhere on the genome. The approach described here promises to dramatically improve studies of the extent and nature of antigenic variation systems in a variety of species. PMID- 24466207 TI - Interspecific small molecule interactions between clinical isolates of Pseudomonas aeruginosa and Staphylococcus aureus from adult cystic fibrosis patients. AB - Pseudomonas aeruginosa and Staphylococcus aureus are the most prevalent pathogens in airway infections of cystic fibrosis (CF) patients. We studied how these pathogens coexist and interact with each other. Clinical isolates of both species were retrieved from adult CF patients. Culture supernatants from 63 P. aeruginosa isolates triggered a wide range of biofilm-stimulatory activities when added to the culture of a control S. aureus strain. The extent of biofilm formation by S. aureus was positively correlated to the levels of the 2-alkyl-4-(1H)-quinolones (AQs) Pseudomonas Quinolone Signal (PQS) and 2-heptyl-4-hydroxy quinoline N-oxide (HQNO) produced by the P. aeruginosa isolates. Supernatants from P. aeruginosa isogenic mutants deficient in PQS and HQNO production stimulated significantly less biofilm formation by S. aureus than that seen with the parental strain PA14. When studying co-isolated pairs of P. aeruginosa and S. aureus retrieved from patients showing both pathogens, P. aeruginosa supernatants stimulated less biofilm production by the S. aureus counterparts compared to that observed using the control S. aureus strain. Accordingly, some P. aeruginosa isolates produced low levels of exoproducts and also some of the clinical S. aureus isolates were not stimulated by their co-isolates or by PA14 despite adequate production of HQNO. This suggests that colonization of the CF lungs promotes some type of strain selection, or that co-existence requires specific adaptations by either or both pathogens. Results provide insights on bacterial interactions in CF. PMID- 24466208 TI - Distinct and site-specific phosphorylation of the retinoblastoma protein at serine 612 in differentiated cells. AB - The retinoblastoma susceptibility protein (pRB) is a phosphoprotein that regulates cell cycle progression at the G1/S transition. In quiescent and early G1 cells, pRB predominantly exists in the active hypophosphorylated form. The cyclin/cyclin-dependent protein kinase complexes phosphorylate pRB at the late G1 phase to inactivate pRB. This event leads to the dissociation and activation of E2F family transcriptional factors. At least 12 serine/threonine residues in pRB are phosphorylated in vivo. Although there have been many reports describing bulk phosphorylation of pRB, detail research describing the function of each phosphorylation site remains unknown. Besides its G1/S inhibitory function, pRB is involved in differentiation, prevention of cell death and control of tissue fate. To uncover the function of phosphorylation of pRB in various cellular conditions, we have been investigating phosphorylation of each serine/threonine residue in pRB with site-specific phospho-serine/threonine antibodies. Here we demonstrate that pRB is specifically phosphorylated at Ser612 in differentiated cells in a known kinase-independent manner. We also found that pRB phosphorylated at Ser612 still associates with E2F-1 and tightly binds to nuclear structures including chromatin. Moreover, expression of the Ser612Ala mutant pRB failed to induce differentiation. The findings suggest that phosphorylation of Ser612 provides a distinct function that differs from the function of phosphorylation of other serine/threonine residues in pRB. PMID- 24466210 TI - Effect of proton pump inhibitors on in vitro activity of tigecycline against several common clinical pathogens. AB - In this study, we evaluated the effect of proton pump inhibitors (PPIs) on in vitro antimicrobial activity of tigecycline against several species of clinical pathogens. Clinical non-duplicate isolates of Acinetobacter baumannii, Staphylococcus aureus, Enterococcus faecalis and three species of Enterobacteriaceae (Escherichia coli, Klebsiella pneumonia and Enterobacter cloacae) were collected from a tertiary hospital and their MICs of tigecycline alone and in combination with PPIs (omeprazole, lansoprazole and pantoprazole) were determined. With one randomly selected isolate of each bacterial species, an in vitro time-kill study was performed for the confirmation of the effect of PPIs on tigecycline activity. The MIC changes after PPIs addition correlated with the PPIs concentrations in the test media. Compared with tigecycline alone, the addition of 5 mg/L PPIs could increase the MICs of tigecycline by 0 to 2-fold and the addition of 50 mg/L PPIs could increase the MICs of tigecycline by 4 to >128 fold. The time-kill study confirmed that the addition of PPIs could affect the in vitro activity of tigecycline. Even at low concentration (5 mg/L) of omeprazole and pantoprazole, antagonistic effect could be observed in E. cloacae and E. faecalis strains. We conclude that In vitro activity of tigecycline can be influenced by the presence of PPIs in a concentration-dependent manner. PMID- 24466209 TI - Early colonoscopy confers survival benefits on colon cancer patients with pre existing iron deficiency anemia: a nationwide population-based study. AB - This study aimed to examine the prognostic significance of pre-existing iron deficiency anemia (IDA) and the benefits of early colonoscopy in patients with colon cancer, since these have not been clearly established to date. Using the Taiwanese National Health Insurance Research Database, we retrieved and retrospectively reviewed the records of patients aged >= 55 years who were diagnosed with colon cancer between 2000 and 2005. The patient cohort was divided into two groups: patients with (n = 1,260) or without (n = 15,912) an IDA diagnosis during <= 18 months preceding the date of colon cancer diagnosis. We found that diabetes (27.9% vs. 20.3%, p<0.0001), cardiovascular disease (61.6% vs. 54.7%, p<0.001), and chronic kidney disease (4.6% vs. 2.2%, p<0.0001) were more common among patients with IDA than among those without IDA. The median overall survival times for patients with IDA and those without IDA were 4.6 and 5.7 years, respectively (p = 0.002). Patients who underwent colonoscopy <= 30 days, 31-90, and >= 91 days after IDA diagnosis showed median overall survival times of 5.79, 4.43, and 4.04 years, respectively (p = 0.003). Delayed colonoscopy was an independent factor associated with poor overall survival (adjusted hazard ratio, 1.28; 95% confidence interval, 1.07-1.53; p = 0.01). In conclusion, colon cancer patients with IDA were more likely to experience comorbidities than were those without IDA. Pre-existing IDA was a poor prognostic factor in adult men and postmenopausal women who had colon cancer. Early colonoscopy could improve overall survival possibly by facilitating early diagnosis and treatment. PMID- 24466211 TI - Variability of the QuantiFERON(r)-TB gold in-tube test using automated and manual methods. AB - BACKGROUND: The QuantiFERON(r)-TB Gold In-Tube test (QFT-GIT) detects Mycobacterium tuberculosis (Mtb) infection by measuring release of interferon gamma (IFN-gamma) when T-cells (in heparinized whole blood) are stimulated with specific Mtb antigens. The amount of IFN-gamma is determined by enzyme-linked immunosorbent assay (ELISA). Automation of the ELISA method may reduce variability. To assess the impact of ELISA automation, we compared QFT-GIT results and variability when ELISAs were performed manually and with automation. METHODS: Blood was collected into two sets of QFT-GIT tubes and processed at the same time. For each set, IFN-gamma was measured in automated and manual ELISAs. Variability in interpretations and IFN-gamma measurements was assessed between automated (A1 vs. A2) and manual (M1 vs. M2) ELISAs. Variability in IFN-gamma measurements was also assessed on separate groups stratified by the mean of the four ELISAs. RESULTS: Subjects (N = 146) had two automated and two manual ELISAs completed. Overall, interpretations were discordant for 16 (11%) subjects. Excluding one subject with indeterminate results, 7 (4.8%) subjects had discordant automated interpretations and 10 (6.9%) subjects had discordant manual interpretations (p = 0.17). Quantitative variability was not uniform; within subject variability was greater with higher IFN-gamma measurements and with manual ELISAs. For subjects with mean TB Responses +/-0.25 IU/mL of the 0.35 IU/mL cutoff, the within-subject standard deviation for two manual tests was 0.27 (CI95 = 0.22-0.37) IU/mL vs. 0.09 (CI95 = 0.07-0.12) IU/mL for two automated tests. CONCLUSION: QFT-GIT ELISA automation may reduce variability near the test cutoff. Methodological differences should be considered when interpreting and using IFN-gamma release assays (IGRAs). PMID- 24466212 TI - In vivo measurement of hippocampal GABAA/cBZR density with [18F]-flumazenil PET for the study of disease progression in an animal model of temporal lobe epilepsy. AB - PURPOSE: Imbalance of inhibitory GABAergic neurotransmission has been proposed to play a role in the pathogenesis of temporal lobe epilepsy (TLE). This study aimed to investigate whether [(18)F]-flumazenil ([(18)F]-FMZ) PET could be used to non invasively characterise GABAA/central benzodiazepine receptor (GABAA/cBZR) density and affinity in vivo in the post-kainic acid status epilepticus (SE) model of TLE. METHODS: Dynamic [(18)F]-FMZ -PET scans using a multi-injection protocol were acquired in four male wistar rats for validation of the partial saturation model (PSM). SE was induced in eight male Wistar rats (10 weeks of age) by i.p. injection of kainic acid (7.5-25 mg/kg), while control rats (n = 7) received saline injections. Five weeks post-SE, an anatomic MRI scan was acquired and the following week an [(18)F]-FMZ PET scan (3.6-4.6 nmol). The PET data was co-registered to the MRI and regions of interest drawn on the MRI for selected structures. A PSM was used to derive receptor density and apparent affinity from the [(18)F]-FMZ PET data. KEY FINDINGS: The PSM was found to adequately model [(18)F]-FMZ binding in vivo. There was a significant decrease in hippocampal receptor density in the SE group (p<0.01), accompanied by an increase in apparent affinity (p<0.05) compared to controls. No change in cortical receptor binding was observed. Hippocampal volume reduction and cell loss was only seen in a subset of animals. Histological assessment of hippocampal cell loss was significantly correlated with hippocampal volume measured by MRI (p<0.05), but did not correlate with [(18)F]-FMZ binding. SIGNIFICANCE: Alterations to hippocampal GABAA/cBZR density and affinity in the post-kainic acid SE model of TLE are detectable in vivo with [(18)F]-FMZ PET and a PSM. These changes are independent from hippocampal cell and volume loss. [(18)F]-FMZ PET is useful for investigating the role that changes GABAA/cBZR density and binding affinity play in the pathogenesis of TLE. PMID- 24466213 TI - CRP-cyclic AMP dependent inhibition of the xylene-responsive sigma(54)-promoter Pu in Escherichia coli. AB - The expression of sigma(54)-dependent Pseudomonas putida Pu promoter is activated by XylR activator when cells are exposed to a variety of aromatic inducers. In this study, the transcriptional activation of the P. putida Pu promoter was recreated in the heterologous host Escherichia coli. Here we show that the cAMP receptor protein (CRP), a well-known carbon utilization regulator, had an inhibitory effect on the expression of Pu promoter in a cAMP-dependent manner. The inhibitory effect was not activator specific. In vivo KMnO4 and DMS footprinting analysis indicated that CRP-cAMP poised the RNA polymerase at Pu promoter, inhibiting the isomerization step of the transcription initiation even in the presence of an activator. Therefore, the presence of PTS-sugar, which eliminates cAMP, could activate the poised RNA polymerase at Pu promoter to transcribe. Moreover, the activation region 1 (AR1) of CRP, which interacts directly with the alphaCTD (C-terminal domain of alpha-subunit) of RNA polymerase, was found essential for the CRP-mediated inhibition at Pu promoter. A model for the above observations is discussed. PMID- 24466214 TI - Prediction of aptamer-target interacting pairs with pseudo-amino acid composition. AB - Aptamers are oligonucleic acid or peptide molecules that bind to specific target molecules. As a novel and powerful class of ligands, aptamers are thought to have excellent potential for applications in the fields of biosensing, diagnostics and therapeutics. In this study, a new method for predicting aptamer-target interacting pairs was proposed by integrating features derived from both aptamers and their targets. Features of nucleotide composition and traditional amino acid composition as well as pseudo amino acid were utilized to represent aptamers and targets, respectively. The predictor was constructed based on Random Forest and the optimal features were selected by using the maximum relevance minimum redundancy (mRMR) method and the incremental feature selection (IFS) method. As a result, 81.34% accuracy and 0.4612 MCC were obtained for the training dataset, and 77.41% accuracy and 0.3717 MCC were achieved for the testing dataset. An optimal feature set of 220 features were selected, which were considered as the ones that contributed significantly to the interacting aptamer-target pair predictions. Analysis of the optimal feature set indicated several important factors in determining aptamer-target interactions. It is anticipated that our prediction method may become a useful tool for identifying aptamer-target pairs and the features selected and analyzed in this study may provide useful insights into the mechanism of interactions between aptamers and targets. PMID- 24466217 TI - Premature attraction of pollinators to inaccessible figs of Ficus altissima: a search for ecological and evolutionary consequences. AB - Adult life spans of only one or two days characterise life cycles of the fig wasps (Agaonidae) that pollinate fig trees (Ficus spp., Moraceae). Selection is expected to favour traits that maximise the value of the timing of encounters between such mutualistic partners, and fig wasps are usually only attracted to their hosts by species- and developmental-stage specific volatiles released from figs at the time when they are ready to be entered, oviposited in and pollinated. We found that Ficus altissima is exceptional, because it has persistent tight fitting bud covers that prevent its Eupristina altissima pollinator (and a second species of 'cheater' agaonid) from entering its figs for several days after they start to be attracted. We examined the consequences of delayed entry for the figs and fig wasps and tested whether delayed entry has been selected to increase adult longevity. We found that older pollinators produced fewer and smaller offspring, but seed production was more efficient. Pollinator offspring ratios also varied depending on the age of figs they entered. The two agaonids from F. altissima lived slightly longer than six congeners associated with typical figs, but this was explainable by their larger body sizes. Delayed entry generates reproductive costs, especially for the pollinator. This opens an interesting perspective on the coevolution of figs and their pollinators and on the nature of mutualistic interactions in general. PMID- 24466215 TI - Identification of neural networks that contribute to motion sickness through principal components analysis of fos labeling induced by galvanic vestibular stimulation. AB - Motion sickness is a complex condition that includes both overt signs (e.g., vomiting) and more covert symptoms (e.g., anxiety and foreboding). The neural pathways that mediate these signs and symptoms are yet to identified. This study mapped the distribution of c-fos protein (Fos)-like immunoreactivity elicited during a galvanic vestibular stimulation paradigm that is known to induce motion sickness in felines. A principal components analysis was used to identify networks of neurons activated during this stimulus paradigm from functional correlations between Fos labeling in different nuclei. This analysis identified five principal components (neural networks) that accounted for greater than 95% of the variance in Fos labeling. Two of the components were correlated with the severity of motion sickness symptoms, and likely participated in generating the overt signs of the condition. One of these networks included neurons in locus coeruleus, medial, inferior and lateral vestibular nuclei, lateral nucleus tractus solitarius, medial parabrachial nucleus and periaqueductal gray. The second included neurons in the superior vestibular nucleus, precerebellar nuclei, periaqueductal gray, and parabrachial nuclei, with weaker associations of raphe nuclei. Three additional components (networks) were also identified that were not correlated with the severity of motion sickness symptoms. These networks likely mediated the covert aspects of motion sickness, such as affective components. The identification of five statistically independent component networks associated with the development of motion sickness provides an opportunity to consider, in network activation dimensions, the complex progression of signs and symptoms that are precipitated in provocative environments. Similar methodology can be used to parse the neural networks that mediate other complex responses to environmental stimuli. PMID- 24466216 TI - Population level analysis of evolved mutations underlying improvements in plant hemicellulose and cellulose fermentation by Clostridium phytofermentans. AB - BACKGROUND: The complexity of plant cell walls creates many challenges for microbial decomposition. Clostridium phytofermentans, an anaerobic bacterium isolated from forest soil, directly breaks down and utilizes many plant cell wall carbohydrates. The objective of this research is to understand constraints on rates of plant decomposition by Clostridium phytofermentans and identify molecular mechanisms that may overcome these limitations. RESULTS: Experimental evolution via repeated serial transfers during exponential growth was used to select for C. phytofermentans genotypes that grow more rapidly on cellobiose, cellulose and xylan. To identify the underlying mutations an average of 13,600,000 paired-end reads were generated per population resulting in ~300 fold coverage of each site in the genome. Mutations with allele frequencies of 5% or greater could be identified with statistical confidence. Many mutations are in carbohydrate-related genes including the promoter regions of glycoside hydrolases and amino acid substitutions in ABC transport proteins involved in carbohydrate uptake, signal transduction sensors that detect specific carbohydrates, proteins that affect the export of extracellular enzymes, and regulators of unknown specificity. Structural modeling of the ABC transporter complex proteins suggests that mutations in these genes may alter the recognition of carbohydrates by substrate-binding proteins and communication between the intercellular face of the transmembrane and the ATPase binding proteins. CONCLUSIONS: Experimental evolution was effective in identifying molecular constraints on the rate of hemicellulose and cellulose fermentation and selected for putative gain of function mutations that do not typically appear in traditional molecular genetic screens. The results reveal new strategies for evolving and engineering microorganisms for faster growth on plant carbohydrates. PMID- 24466218 TI - Structural basis for binding of fluorinated glucose and galactose to Trametes multicolor pyranose 2-oxidase variants with improved galactose conversion. AB - Each year, about six million tons of lactose are generated from liquid whey as industrial byproduct, and optimally this large carbohydrate waste should be used for the production of value-added products. Trametes multicolor pyranose 2 oxidase (TmP2O) catalyzes the oxidation of various monosaccharides to the corresponding 2-keto sugars. Thus, a potential use of TmP2O is to convert the products from lactose hydrolysis, D-glucose and D-galactose, to more valuable products such as tagatose. Oxidation of glucose is however strongly favored over galactose, and oxidation of both substrates at more equal rates is desirable. Characterization of TmP2O variants (H450G, V546C, H450G/V546C) with improved D galactose conversion has been given earlier, of which H450G displayed the best relative conversion between the substrates. To rationalize the changes in conversion rates, we have analyzed high-resolution crystal structures of the aforementioned mutants with bound 2- and 3-fluorinated glucose and galactose. Binding of glucose and galactose in the productive 2-oxidation binding mode is nearly identical in all mutants, suggesting that this binding mode is essentially unaffected by the mutations. For the competing glucose binding mode, enzyme variants carrying the H450G replacement stabilize glucose as the alpha-anomer in position for 3-oxidation. The backbone relaxation at position 450 allows the substrate-binding loop to fold tightly around the ligand. V546C however stabilize glucose as the beta-anomer using an open loop conformation. Improved binding of galactose is enabled by subtle relaxation effects at key active-site backbone positions. The competing binding mode for galactose 2-oxidation by V546C stabilizes the beta-anomer for oxidation at C1, whereas H450G variants stabilize the 3-oxidation binding mode of the galactose alpha-anomer. The present study provides a detailed description of binding modes that rationalize changes in the relative conversion rates of D-glucose and D-galactose and can be used to refine future enzyme designs for more efficient use of lactose-hydrolysis byproducts. PMID- 24466219 TI - Reconstruction of the carotenoid biosynthetic pathway of Cronobacter sakazakii BAA894 in Escherichia coli. AB - Cronobacter sakazakii could form yellow-pigmented colonies. However, the chemical structure and the biosynthetic pathway of the yellow pigments have not been identified. In this study, the yellow pigments of C. sakazakii BAA894 were purified and analyzed. The major components of the yellow pigments were confirmed as zeaxanthin-monoglycoside and zeaxanthin-diglycoside. A gene cluster containing seven genes responsible for the yellow pigmentation in C. sakazakii BAA894 was identified. The seven genes of C. sakazakii BAA894 or parts of them were reconstructed in a heterologous host Escherichia coli DH5alpha. The pigments formed in these E. coli strains were isolated and analyzed by thin layer chromatography, UV-visible spectroscopy, high performance liquid chromatography, and electron spray ionization-mass spectrometry. These redesigned E. coli strains could produce different carotenoids. E. coli strain expressing all the seven genes could produce zeaxanthin-monoglycoside and zeaxanthin-diglycoside; E. coli strains expressing parts of the seven genes could produce lycopene, beta carotene, cryptoxanthin or zeaxanthin. This study identified the gene cluster responsible for the yellow pigmentation in C. sakazakii BAA894. PMID- 24466220 TI - RNA viral metagenome of whiteflies leads to the discovery and characterization of a whitefly-transmitted carlavirus in North America. AB - Whiteflies from the Bemisia tabaci species complex have the ability to transmit a large number of plant viruses and are some of the most detrimental pests in agriculture. Although whiteflies are known to transmit both DNA and RNA viruses, most of the diversity has been recorded for the former, specifically for the Begomovirus genus. This study investigated the total diversity of DNA and RNA viruses found in whiteflies collected from a single site in Florida to evaluate if there are additional, previously undetected viral types within the B. tabaci vector. Metagenomic analysis of viral DNA extracted from the whiteflies only resulted in the detection of begomoviruses. In contrast, whiteflies contained sequences similar to RNA viruses from divergent groups, with a diversity that extends beyond currently described viruses. The metagenomic analysis of whiteflies also led to the first report of a whitefly-transmitted RNA virus similar to Cowpea mild mottle virus (CpMMV Florida) (genus Carlavirus) in North America. Further investigation resulted in the detection of CpMMV Florida in native and cultivated plants growing near the original field site of whitefly collection and determination of its experimental host range. Analysis of complete CpMMV Florida genomes recovered from whiteflies and plants suggests that the current classification criteria for carlaviruses need to be reevaluated. Overall, metagenomic analysis supports that DNA plant viruses carried by B. tabaci are dominated by begomoviruses, whereas significantly less is known about RNA viruses present in this damaging insect vector. PMID- 24466221 TI - Response of the unicellular diazotrophic cyanobacterium Crocosphaera watsonii to iron limitation. AB - Iron (Fe) is widely suspected as a key controlling factor of N2 fixation due to the high Fe content of nitrogenase and photosynthetic enzymes complex, and to its low concentrations in oceanic surface seawaters. The influence of Fe limitation on the recently discovered unicellular diazotrophic cyanobacteria (UCYN) is poorly understood despite their biogeochemical importance in the carbon and nitrogen cycles. To address this knowledge gap, we conducted culture experiments on Crocosphaera watsonii WH8501 growing under a range of dissolved Fe concentrations (from 3.3 to 403 nM). Overall, severe Fe limitation led to significant decreases in growth rate (2.6-fold), C, N and chlorophyll a contents per cell (up to 4.1-fold), N2 and CO2 fixation rates per cell (17- and 7-fold) as well as biovolume (2.2-fold). We highlighted a two phased response depending on the degree of limitation: (i) under a moderate Fe limitation, the biovolume of C. watsonii was strongly reduced, allowing the cells to keep sufficient energy to maintain an optimal growth, volume-normalized contents and N2 and CO2 fixation rates; (ii) with increasing Fe deprivation, biovolume remained unchanged but the entire cell metabolism was affected, as shown by a strong decrease in the growth rate, volume-normalized contents and N2 and CO2 fixation rates. The half saturation constant for growth of C. watsonii with respect to Fe is twice as low as that of the filamentous Trichodesmium indicating a better adaptation of C. watsonii to poor Fe environments than filamentous diazotrophs. The physiological response of C. watsonii to Fe limitation was different from that previously shown on the UCYN Cyanothece sp, suggesting potential differences in Fe requirements and/or Fe acquisition within the UCYN community. These results contribute to a better understanding of how Fe bioavailability can control the activity of UCYN and explain the biogeography of diverse N2 fixers in ocean. PMID- 24466222 TI - Characteristics of networks of interventions: a description of a database of 186 published networks. AB - Systematic reviews that employ network meta-analysis are undertaken and published with increasing frequency while related statistical methodology is evolving. Future statistical developments and evaluation of the existing methodologies could be motivated by the characteristics of the networks of interventions published so far in order to tackle real rather than theoretical problems. Based on the recently formed network meta-analysis literature we aim to provide an insight into the characteristics of networks in healthcare research. We searched PubMed until end of 2012 for meta-analyses that used any form of indirect comparison. We collected data from networks that compared at least four treatments regarding their structural characteristics as well as characteristics of their analysis. We then conducted a descriptive analysis of the various network characteristics. We included 186 networks of which 35 (19%) were star shaped (treatments were compared to a common comparator but not between themselves). The median number of studies per network was 21 and the median number of treatments compared was 6. The majority (85%) of the non-star shaped networks included at least one multi-arm study. Synthesis of data was primarily done via network meta-analysis fitted within a Bayesian framework (113 (61%) networks). We were unable to identify the exact method used to perform indirect comparison in a sizeable number of networks (18 (9%)). In 32% of the networks the investigators employed appropriate statistical methods to evaluate the consistency assumption; this percentage is larger among recently published articles. Our descriptive analysis provides useful information about the characteristics of networks of interventions published the last 16 years and the methods for their analysis. Although the validity of network meta-analysis results highly depends on some basic assumptions, most authors did not report and evaluate them adequately. Reviewers and editors need to be aware of these assumptions and insist on their reporting and accuracy. PMID- 24466224 TI - ArchiLD: hierarchical visualization of linkage disequilibrium in human populations. AB - Linkage disequilibrium (LD) is an essential metric for selecting single nucleotide polymorphisms (SNPs) to use in genetic studies and identifying causal variants from significant tag SNPs. The explosion in the number of polymorphisms that can now be genotyped by commercial arrays makes the interpretation of triangular correlation plots, commonly used for visualizing LD, extremely difficult in particular when large genomics regions need to be considered or when SNPs in perfect LD are not adjacent but scattered across a genomic region. We developed ArchiLD, a user-friendly graphical application for the hierarchical visualization of LD in human populations. The software provides a powerful framework for analyzing LD patterns with a particular focus on blocks of SNPs in perfect linkage as defined by r(2). Thanks to its integration with the UCSC Genome Browser, LD plots can be easily overlapped with additional data on regulation, conservation and expression. ArchiLD is an intuitive solution for the visualization of LD across large or highly polymorphic genomic regions. Its ease of use and its integration with the UCSC Genome Browser annotation potential facilitates the interpretation of association results and enables a more informed selection of tag SNPs for genetic studies. PMID- 24466223 TI - Integrative genetic characterization and phenotype correlations in pheochromocytoma and paraganglioma tumours. AB - BACKGROUND: About 60% of Pheochromocytoma (PCC) and Paraganglioma (PGL) patients have either germline or somatic mutations in one of the 12 proposed disease causing genes; SDHA, SDHB, SDHC, SDHD, SDHAF2, VHL, EPAS1, RET, NF1, TMEM127, MAX and H-RAS. Selective screening for germline mutations is routinely performed in clinical management of these diseases. Testing for somatic alterations is not performed on a regular basis because of limitations in interpreting the results. AIM: The purpose of the study was to investigate genetic events and phenotype correlations in a large cohort of PCC and PGL tumours. METHODS: A total of 101 tumours from 89 patients with PCC and PGL were re-sequenced for a panel of 10 disease causing genes using automated Sanger sequencing. Selected samples were analysed with Multiplex Ligation-dependent Probe Amplification and/or SNParray. RESULTS: Pathogenic genetic variants were found in tumours from 33 individual patients (37%), 14 (16%) were discovered in constitutional DNA and 16 (18%) were confirmed as somatic. Loss of heterozygosity (LOH) was observed in 1/1 SDHB, 11/11 VHL and 3/3 NF1-associated tumours. In patients with somatic mutations there were no recurrences in contrast to carriers of germline mutations (P = 0.022). SDHx/VHL/EPAS1 associated cases had higher norepinephrine output (P = 0.03) and lower epinephrine output (P<0.001) compared to RET/NF1/H-RAS cases. CONCLUSION: Somatic mutations are frequent events in PCC and PGL tumours. Tumour genotype may be further investigated as prognostic factors in these diseases. Growing evidence suggest that analysis of tumour DNA could have an impact on the management of these patients. PMID- 24466225 TI - Regulatory T cell ablation causes acute T cell lymphopenia. AB - Regulatory T (Treg) cells enforce T cell homeostasis and maintain peripheral T cell tolerance. Here we report a previously unappreciated phenomenon of acute T cell lymphopenia in secondary lymphoid organs and non-lymphoid tissues triggered by Treg cell depletion that precedes the expansion of self-reactive T cells. Lymphopenia affects both neonates and adults indicating a dominant role of Treg cells in maintaining peripheral T cell numbers regardless of the developmental stage. The lymphopenia was neither triggered by caspase-dependent apoptosis nor macrophage-mediated clearance of T cells, nor diminished survival of naive or recently activated T cells due to paucity of IL-7. It is possible that transient lymphopenia associated with congenital or acute Treg cell deficiency may contribute to the development of T cell mediated autoimmune disorders. PMID- 24466226 TI - The iron-sulphur cluster biosynthesis regulator IscR contributes to iron homeostasis and resistance to oxidants in Pseudomonas aeruginosa. AB - IscR is a global transcription regulator responsible for governing various physiological processes during growth and stress responses. The IscR-mediated regulation of the Pseudomonas aeruginosa isc operon, which is involved in iron sulphur cluster ([Fe-S]) biogenesis, was analysed. The expression of iscR was highly induced through the exposure of the bacteria to various oxidants, such as peroxides, redox-cycling drugs, intracellular iron-chelating agents, and high salts. Two putative type 1 IscR-binding sites were found around RNA polymerase recognition sites, in which IscR-promoter binding could preclude RNA polymerase from binding to the promoter and resulting in repression of the isc operon expression. An analysis of the phenotypes of mutants and cells with altered gene expression revealed the diverse physiological roles of this regulator. High-level IscR strongly inhibited anaerobic, but not aerobic, growth. iscR contributes significantly to the bacteria overall resistance to oxidative stress, as demonstrated through mutants with increased sensitivity to oxidants, such as peroxides and redox-cycling drugs. Moreover, the regulator also plays important roles in modulating intracellular iron homeostasis, potentially through sensing the levels of [Fe-S]. The increased expression of the isc operon in the mutant not only diverts iron away from the available pool but also reduces the total intracellular iron content, affecting many iron metabolism pathways leading to alterations in siderophores and haem levels. The diverse expression patterns and phenotypic changes of the mutant support the role of P. aeruginosa IscR as a global transcriptional regulator that senses [Fe-S] and directly represses or activates the transcription of genes affecting many physiological pathways. PMID- 24466227 TI - Patterns of the non-indigenous isopod Cirolana harfordi in Sydney Harbour. AB - Biological introductions can alter the ecology of local assemblages and are an important driver of global environmental change. The first step towards understanding the impact of a non-indigenous species is to study its distribution and associations in the invaded area. In Sydney Harbour, the non-indigenous isopod Cirolana harfordi has been reported in densities up to 0.5 individuals per cm(2) in mussel-beds. Abundances of this species have, however, been largely overlooked in other key habitats. The first aim of this study was to evaluate the abundances and distribution of C. harfordi across different habitats representative of Sydney Harbour. Results showed that C. harfordi occurred in oyster and mussel-beds, being particularly abundant in oyster-beds. We also aimed to determine the role of C. harfordi as a predator, scavenger and detritus feeder by investigating the relationships between densities of C. harfordi and (i) the structure of the resident assemblages, and (ii) deposited organic matter in oyster-beds. Densities of C. harfordi were not related to the structure of the assemblages, nor amounts of deposited organic matter. These findings suggested little or no ecological impacts of C. harfordi in oyster-beds. These relationships may, however, affect other variables such as growth of individuals, or be disguised by high variability of assemblages among different locations. Future studies should, therefore, test the impacts of C. harfordi on the size of organisms in the assemblage and use manipulative experiments to control for spatial variation. This study is the first published work on the ecology of the invasion of C. harfordi and provides the starting-point for the study of the impacts of this species in Sydney Harbour. PMID- 24466228 TI - Complex I function and supercomplex formation are preserved in liver mitochondria despite progressive complex III deficiency. AB - Functional oxidative phosphorylation requires appropriately assembled mitochondrial respiratory complexes and their supercomplexes formed mainly of complexes I, III and IV. BCS1L is the chaperone needed to incorporate the catalytic subunit, Rieske iron-sulfur protein, into complex III at the final stage of its assembly. In cell culture studies, this subunit has been considered necessary for supercomplex formation and for maintaining the stability of complex I. Our aim was to assess the importance of fully assembled complex III for supercomplex formation in intact liver tissue. We used our transgenic mouse model with a homozygous c.232A>G mutation in Bcs1l leading to decreased expression of BCS1L and progressive decrease of Rieske iron-sulfur protein in complex III, resulting in hepatopathy. We studied supercomplex formation at different ages using blue native gel electrophoresis and complex activity using high-resolution respirometry. In isolated liver mitochondria of young and healthy homozygous mutant mice, we found similar supercomplexes as in wild type. In homozygotes aged 27-29 days with liver disorder, complex III was predominantly a pre-complex lacking Rieske iron-sulfur protein. However, the main supercomplex was clearly detected and contained complex III mainly in the pre-complex form. Oxygen consumption of complex IV was similar and that of complex I was twofold compared with controls. These complexes in free form were more abundant in homozygotes than in controls, and the mRNA of complex I subunits were upregulated. In conclusion, when complex III assembly is deficient, the pre-complex without Rieske iron-sulfur protein can participate with available fully assembled complex III in supercomplex formation, complex I function is preserved, and respiratory chain stability is maintained. PMID- 24466229 TI - Predictive validity of the Suicide Trigger Scale (STS-3) for post-discharge suicide attempt in high-risk psychiatric inpatients. AB - BACKGROUND: The greatly increased risk of suicide after psychiatric hospitalization is a critical problem, yet we are unable to identify individuals who would attempt suicide upon discharge. The Suicide Trigger Scale v.3 (STS-3), was designed to measure the construct of an affective 'suicide trigger state' hypothesized to precede a suicide attempt (SA). This study aims to test the predictive validity of the STS-3 for post-discharge SA on a high-risk psychiatric inpatient sample. METHODS: The STS-3, and a psychological test battery measuring suicidality, mood, impulsivity, trauma history, and attachment style were administered to 161 adult psychiatric patients hospitalized following suicidal ideation (SI) or SA. Receiver Operator Characteristic and logistic regression analyses were used to assess prediction of SA in the 6-month period following discharge from hospitalization. RESULTS: STS-3 scores for the patients who made post-discharge SA followed a bimodal distribution skewed to high and low scores, thus a distance from median transform was applied to the scores. The transformed score was a significant predictor of post-discharge SA (AUC 0.731), and a subset of six STS-3 scale items was identified that produced improved prediction of post discharge SA (AUC 0.814). Scores on C-SSRS and BSS were not predictive. Patients with ultra-high (90(th) percentile) STS-3 scores differed significantly from ultra-low (10(th) percentile) scorers on measures of affective intensity, depression, impulsiveness, abuse history, and attachment security. CONCLUSION: STS-3 transformed scores at admission to the psychiatric hospital predict suicide attempts following discharge among the high-risk group of suicidal inpatients. Patients with high transformed scores appear to comprise two clinically distinct groups; an impulsive, affectively intense, fearfully attached group with high raw STS-3 scores and a low-impulsivity, low affect and low trauma-reporting group with low raw STS-3 scores. These groups may correspond to low-plan and planned suicide attempts, respectively, but this remains to be established by future research. PMID- 24466230 TI - Photoreceptor degeneration in two mouse models for congenital stationary night blindness type 2. AB - Light-dependent conductance changes of voltage-gated Cav1.4 channels regulate neurotransmitter release at photoreceptor ribbon synapses. Mutations in the human CACNA1F gene encoding the alpha1F subunit of Cav1.4 channels cause an incomplete form of X-linked congenital stationary night blindness (CSNB2). Many CACNA1F mutations are loss-of-function mutations resulting in non-functional Cav1.4 channels, but some mutations alter the channels' gating properties and, presumably, disturb Ca(2+) influx at photoreceptor ribbon synapses. Notably, a CACNA1F mutation (I745T) was identified in a family with an uncommonly severe CSNB2-like phenotype, and, when expressed in a heterologous system, the mutation was shown to shift the voltage-dependence of channel activation, representing a gain-of-function. To gain insight into the pathomechanism that could explain the severity of this disorder, we generated a mouse model with the corresponding mutation in the murine Cacna1f gene (I756T) and compared it with a mouse model carrying a loss-of-function mutation (DeltaEx14-17) in a longitudinal study up to eight months of age. In DeltaEx14-17 mutants, the b-wave in the electroretinogram was absent, photoreceptor ribbon synapses were abnormal, and Ca(2+) responses to depolarization of photoreceptor terminals were undetectable. In contrast, I756T mutants had a reduced scotopic b-wave, some intact rod ribbon synapses, and a strong, though abnormal, Ca(2+) response to depolarization. Both mutants showed a progressive photoreceptor loss, but degeneration was more severe and significantly enhanced in the I756T mutants compared to the DeltaEx14-17 mutants. PMID- 24466231 TI - The correlation between peripartum cardiomyopathy and autoantibodies against cardiovascular receptors. AB - BACKGROUND: Peripartum cardiomyopathy (PPCM) is characterized by left ventricular systolic dysfunction and heart failure. However, its pathogenesis is not clear. Our preliminary study revealed that autoantibodies against beta1-adrenergic receptors (beta1R-AABs) and M2-muscarinic receptors (M2R-AABs) participated in heart failure regardless of primary heart disease. Whether beta1R-AABs and M2R AABs participate in the pathogenesis of PPCM is still unknown. METHODS: Totally 37 diagnosed PPCM patients and 36 normal pregnant women were enrolled in this study. Clinical assessment and 2-dimensional echocardiographic studies as well as the measurement of beta1R-AABs or M2R-AABs by enzyme linked immunosorbent assay (ELISA) were performed. RESULTS: The positive rates for beta1R-AABs and M2R-AABs were 59.5% (22/37) and 45.9% (17/37) in PPCM patients, and 19.4% (7/36) (P<0.001) and 16.67% (6/36) (P<0.001) in normal pregnant women, respectively. Both beta1R AABs and M2R-AABs had a positive correlation with serum expression level of NT proBNP, left ventricular dimension and NYHA FC (rs: 0.496-0.892, P<0.01). In addition, a negative correlation between the activity of beta1R-AABs and M2R-AABs and LVEF, LVFS was observed (rs: -0.488-0.568, P<0.01). Moreover, autoantibodies against cardiovascular receptors increased the risk of the onset of PPCM (OR = 18.786, 95% confidence interval 1.926-183.262, P = 0.012). CONCLUSIONS: The beta1R-AABs and M2R-AABs reveal a significant elevation and are correlated with the increased left ventricular dimension and worse cardiac contraction function. The autoantibodies of cardiovascular receptors are independent risk factors for the onset of PPCM. PMID- 24466232 TI - Purified dendritic cell-tumor fusion hybrids supplemented with non-adherent dendritic cells fraction are superior activators of antitumor immunity. AB - BACKGROUND: Strong evidence supports the DC-tumor fusion hybrid vaccination strategy, but the best fusion product components to use remains controversial. Fusion products contain DC-tumor fusion hybrids, unfused DCs and unfused tumor cells. Various fractions have been used in previous studies, including purified hybrids, the adherent cell fraction or the whole fusion mixture. The extent to which the hybrids themselves or other components are responsible for antitumor immunity or which components should be used to maximize the antitumor immunity remains unknown. METHODS: Patient-derived breast tumor cells and DCs were electro fused and purified. The antitumor immune responses induced by the purified hybrids and the other components were compared. RESULTS: Except for DC-tumor hybrids, the non-adherent cell fraction containing mainly unfused DCs also contributed a lot in antitumor immunity. Purified hybrids supplemented with the non-adherent cell population elicited the most powerful antitumor immune response. After irradiation and electro-fusion, tumor cells underwent necrosis, and the unfused DCs phagocytosed the necrotic tumor cells or tumor debris, which resulted in significant DC maturation. This may be the immunogenicity mechanism of the non-adherent unfused DCs fraction. CONCLUSIONS: The non-adherent cell fraction (containing mainly unfused DCs) from total DC/tumor fusion products had enhanced immunogenicity that resulted from apoptotic/necrotic tumor cell phagocytosis and increased DC maturation. Purified fusion hybrids supplemented with the non-adherent cell population enhanced the antitumor immune responses, avoiding unnecessary use of the tumor cell fraction, which has many drawbacks. Purified hybrids supplemented with the non-adherent cell fraction may represent a better approach to the DC-tumor fusion hybrid vaccination strategy. PMID- 24466233 TI - Associations of serum 25-hydroxyvitamin D3 levels with visceral adipose tissue in Chinese men with normal glucose tolerance. AB - OBJECTIVE: Decreased serum vitamin D level is a common observation in obese adults. Since no Chinese population-based study has yet evaluated the relationship between serum vitamin D levels and the accurate adiposity variables, this study investigated the association of serum vitamin D (assessed by 25 hydroxyvitamin D3 [25(OH)D3]) levels with precise body fat content and distribution in a cohort of Chinese men. METHODS: Serum samples were collected from a total of 567 men with normal glucose tolerance (NGT) for assessment by electrochemiluminescence immunoassay to measure 25(OH)D3 levels. In addition, each participant underwent bioelectrical impedance analysis to quantify total body fat and magnetic resonance imaging to measure visceral fat area (VFA) and subcutaneous fat area (SFA). RESULTS: Overweight/obese (BMI >=25 kg/m(2)) subjects had significantly lower serum 25(OH)D3 levels than non-overweight/non obese (BMI <25 kg/m(2)) subjects (P = 0.029). Greater fat mass and VFA were accompanied by a downward trend in serum 25(OH)D3 levels (P for trend <0.01). Among overweight/obese subjects, those with body fat percent >=25% also had significantly lower serum 25(OH)D3 levels (P <0.05). Moreover, participants with VFA >=80 cm(2) had significantly lower serum 25(OH)D3 (P <0.05), regardless of BMI value. VFA was independently correlated with serum 25(OH)D3 levels (beta = 0.023, P <0.001), even after adjustments for confounding factors. In addition, serum 25(OH)D3 levels were found to decrease by 0.26 ng/mL per 10 cm(2) increment of VFA. CONCLUSIONS: Serum 25(OH)D3 levels were inversely associated with VFA in Chinese men with NGT. PMID- 24466234 TI - Matrix metalloproteinase-20 over-expression is detrimental to enamel development: a Mus musculus model. AB - BACKGROUND: Matrix metalloproteinase-20 (Mmp20) ablated mice have enamel that is thin and soft with an abnormal rod pattern that abrades from the underlying dentin. We asked if introduction of transgenes expressing Mmp20 would revert this Mmp20 null phenotype back to normal. Unexpectedly, for transgenes expressing medium or high levels of Mmp20, we found opposite enamel phenotypes depending on the genetic background (Mmp20(-/-) or Mmp20(+/+) ) in which the transgenes were expressed. METHODOLOGY/PRINCIPAL FINDINGS: Amelx-promoter-Mmp20 transgenic founder mouse lines were assessed for transgene expression and those expressing low, medium or high levels of Mmp20 were selected for breeding into the Mmp20 null background. Regardless of expression level, each transgene brought the null enamel back to full thickness. However, the high and medium expressing Mmp20 transgenes in the Mmp20 null background had significantly harder more mineralized enamel than did the low transgene expresser. Strikingly, when the high and medium expressing Mmp20 transgenes were present in the wild-type background, the enamel was significantly less well mineralized than normal. Protein gel analysis of enamel matrix proteins from the high and medium expressing transgenes present in the wild-type background demonstrated that greater than normal amounts of cleavage products and smaller quantities of higher molecular weight proteins were present within their enamel matrices. CONCLUSIONS/SIGNIFICANCE: Mmp20 expression levels must be within a specific range for normal enamel development to occur. Creation of a normally thick enamel layer may occur over a wider range of Mmp20 expression levels, but acquisition of normal enamel hardness has a narrower range. Since over-expression of Mmp20 results in decreased enamel hardness, this suggests that a balance exists between cleaved and full-length enamel matrix proteins that are essential for formation of a properly hardened enamel layer. It also suggests that few feedback controls are present in the enamel matrix to prevent excessive MMP20 activity. PMID- 24466235 TI - Velocity and directionality of the electrohysterographic signal propagation. AB - OBJECTIVE: The initiation of treatment for women with threatening preterm labor requires effective distinction between true and false labor. The electrohysterogram (EHG) has shown great promise in estimating and classifying uterine activity. However, key issues remain unresolved and no clinically usable method has yet been presented using EHG. Recent studies have focused on the propagation velocity of the EHG signals as a potential discriminator between true and false labor. These studies have estimated the propagation velocity of individual spikes of the EHG signals. We therefore focus on estimating the propagation velocity of the entire EHG burst recorded during a contraction in two dimensions. STUDY DESIGN: EHG measurements were performed on six women in active labor at term, and a total of 35 contractions were used for the estimation of propagation velocity. The measurements were performed using a 16-channel two dimensional electrode grid. The estimates were calculated with a maximum likelihood approach. RESULTS: The estimated average propagation velocity was 2.18 (+/-0.68) cm/s. No single preferred direction of propagation was found. CONCLUSION: The propagation velocities estimated in this study are similar to those reported in other studies but with a smaller intra- and inter-patient variation. Thus a potential tool has been established for further studies on true and false labor contractions. PMID- 24466236 TI - An assessment of survival among Korean elderly patients initiating dialysis: a national population-based study. AB - BACKGROUND: Although the proportion of the elderly patients with incident end stage renal disease (ESRD) patients has been increasing in Korea, there has been a lack of information on outcomes of dialysis treatment. This study aimed to assess the survival rate and to elucidate predictors for all-cause mortality among elderly Korean patients initiating dialysis. METHODS: We analyzed 11,301 patients (6,138 men) aged 65 years or older who had initiated dialysis from 2005 to 2008 and had followed up (median, 37.8 months; range, 3-84 months). Baseline demographics, comorbidities and mortality data were obtained using the database from the Health Insurance Review & Assessment Service. RESULTS: The unadjusted 5 year survival rate was 37.6% for all elderly dialysis patients, and the rate decreased with increasing age categories; 45.9% (65~69), 37.5% (70~74), 28.4% (75~79), 24.1% (80~84), and 13.7% (>=85 years). The multivariate Cox proportional hazard model revealed that age, sex, dialysis modality, the type of insurance, and comorbidities such as diabetes mellitus, myocardial infarction, congestive heart failure, peripheral vascular disease, cerebrovascular disease, dementia, chronic pulmonary disease, hemiparesis, liver disease, and any malignancy were independent predictors for mortality. In addition, survival rate was significantly higher in patients on hemodialysis compared to patients on peritoneal dialysis during the whole follow-up period in the intention-to-treat analysis. CONCLUSIONS: Survival rate was significantly associated with age, sex, and various comorbidities in Korean elderly patients initiating dialysis. The results of our study can help to provide relevant guidance on the individualization strategy in elderly ESRD patients requiring dialysis. PMID- 24466238 TI - A multi-clade test supports the intermediate dispersal model of biogeography. AB - BACKGROUND: Biogeography models typically focus on explaining patterns through island properties, such as size, complexity, age, and isolation. Such models explain variation in the richness of island biotas. Properties of the organisms themselves, such as their size, age, and dispersal abilities, in turn may explain which organisms come to occupy, and diversify across island archipelagos. Here, we restate and test the intermediate dispersal model (IDM) predicting peak diversity in clades of relatively intermediate dispersers. METHODOLOGY: We test the model through a review of terrestrial and freshwater organisms in the western Indian Ocean examining the correlation among species richness and three potential explanatory variables: dispersal ability quantified as the number of estimated dispersal events, average body size for animals, and clade age. CONCLUSIONS: Our study supports the IDM with dispersal ability being the best predictor of regional diversity among the explored variables. We find a weaker relationship between diversity and clade age, but not body size. Principally, we find that richness strongly and positively correlates with dispersal ability in poor to good dispersers while a prior study found a strong decrease in richness with increased dispersal ability among excellent dispersers. Both studies therefore support the intermediate dispersal model, especially when considered together. We note that many additional variables not here considered are at play. For example, some taxa may lose dispersal ability subsequent to island colonization and some poor dispersers have reached high diversity through within island radiations. Nevertheless, our findings highlight the fundamental importance of dispersal ability in explaining patterns of biodiversity generation across islands. PMID- 24466237 TI - Collagen XVI induces expression of MMP9 via modulation of AP-1 transcription factors and facilitates invasion of oral squamous cell carcinoma. AB - Collagen XVI belongs to the family of fibril-associated collagens with interrupted triple helices (FACIT). It is overexpressed during the progression of oral squamous cell carcinoma (OSCC). The present data show a strong collagen XVI dependent induction of MMP9 and an increase in OSCC cell invasion. We found activated integrin-linked kinase (ILK) in a complex with kindlin-1 and activation of protein kinase B (PKB/Akt) to be responsible for MMP9 induction. Inhibition of the formation of focal adhesions reduced MMP9 expression. Moreover, collagen XVI overexpressing OSCC cell clones (COLXVI cell clones) transfected with vectors containing different MMP9 promoter fragments adjacent to a luciferase reporter revealed an increase in luciferase signal dependent on AP-1 binding sites. Deletion of the AP-1 binding site 98 bp upstream of the reported transcription start site and inhibition of AP-1 with Tanshinone IIA resulted in decreased MMP9 expression. The AP-1 subunit JunB showed differential expression between COLXVI cell clones and mock control cells. Additionally, mass spectrometric analysis of immunoprecipitates revealed that c-Fos interacted strongly with dyskerin in COLXVI cell clones compared to mock controls. PMID- 24466239 TI - Function, structure, and stability of enzymes confined in agarose gels. AB - Research over the past few decades has attempted to answer how proteins behave in molecularly confined or crowded environments when compared to dilute buffer solutions. This information is vital to understanding in vivo protein behavior, as the average spacing between macromolecules in the cell cytosol is much smaller than the size of the macromolecules themselves. In our study, we attempt to address this question using three structurally and functionally different model enzymes encapsulated in agarose gels of different porosities. Our studies reveal that under standard buffer conditions, the initial reaction rates of the agarose encapsulated enzymes are lower than that of the solution phase enzymes. However, the encapsulated enzymes retain a higher percentage of their activity in the presence of denaturants. Moreover, the concentration of agarose used for encapsulation had a significant effect on the enzyme functional stability; enzymes encapsulated in higher percentages of agarose were more stable than the enzymes encapsulated in lower percentages of agarose. Similar results were observed through structural measurements of enzyme denaturation using an 8 anilinonaphthalene-1-sulfonic acid fluorescence assay. Our work demonstrates the utility of hydrogels to study protein behavior in highly confined environments similar to those present in vivo; furthermore, the enhanced stability of gel encapsulated enzymes may find use in the delivery of therapeutic proteins, as well as the design of novel strategies for biohybrid medical devices. PMID- 24466241 TI - Environmental correlates of H5N2 low pathogenicity avian influenza outbreak heterogeneity in domestic poultry in Italy. AB - Italy has experienced recurrent incursions of H5N2 avian influenza (AI) viruses in different geographical areas and varying sectors of the domestic poultry industry. Considering outbreak heterogeneity rather than treating all outbreaks of low pathogenicity AI (LPAI) viruses equally is important given their interactions with the environment and potential to spread, evolve and increase pathogenicity. This study aims at identifying potential environmental drivers of H5N2 LPAI outbreak occurrence in time, space and poultry populations. Thirty-four environmental variables were tested for association with the characteristics of 27 H5N2 LPAI outbreaks (i.e. time, place, flock type, number and species of birds affected) occurred among domestic poultry flocks in Italy in 2010-2012. This was done by applying a recently proposed analytical approach based on a combined non metric multidimensional scaling, clustering and regression analysis. Results indicated that the pattern of (dis)similarities among the outbreaks entailed an underlying structure that may be the outcome of large-scale, environmental interactions in ecological dimension. Increased densities of poultry breeders, and increased land coverage by industrial, commercial and transport units were associated with increased heterogeneity in outbreak characteristics. In areas with high breeder densities and with many infrastructures, outbreaks affected mainly industrial turkey/layer flocks. Outbreaks affecting ornamental, commercial and rural multi-species flocks occurred mainly in lowly infrastructured areas of northern Italy. Outbreaks affecting rural layer flocks occurred mainly in areas with low breeder densities in south-central Italy. In savannah-like environments, outbreaks affected mainly commercial flocks of galliformes. Suggestive evidence that ecological ordination makes sense genetically was also provided, as virus strains showing high genetic similarity clustered into ecologically similar outbreaks. Findings were informed by hypotheses about how ecological interactions among poultry populations, viruses and their environments can be related to the observed patterns of H5N2 LPAI occurrence. This may prove useful in enhancing future interventions by developing site-specific, ecologically-grounded strategies. PMID- 24466240 TI - Effects of sulforaphane and 3,3'-diindolylmethane on genome-wide promoter methylation in normal prostate epithelial cells and prostate cancer cells. AB - Epigenetic changes, including aberrant DNA methylation, result in altered gene expression and play an important role in carcinogenesis. Phytochemicals such as sulforaphane (SFN) and 3,3'-diindolylmethane (DIM) are promising chemopreventive agents for the treatment of prostate cancer. Both have been shown to induce re expression of genes, including tumor suppressor genes silenced in cancer cells, via modulation of epigenetic marks including DNA methylation. However, it remained unclear the effects SFN and DIM on DNA methylation at a genomic scale. The goal of this study was to determine the genome-wide effects of SFN and DIM on promoter methylation in normal prostate epithelial cells and prostate cancer cells. Both SFN and DIM treatment decreased DNA methyltransferase expression in normal prostate epithelial cells (PrEC), and androgen-dependent (LnCAP) and androgen-independent (PC3) prostate cancer cells. The effects of SFN and DIM on promoter methylation profiles in normal PrEC, LnCAP and PC3 prostate cancer cells were determined using methyl-DNA immunoprecipitation followed by genome-wide DNA methylation array. We showed widespread changes in promoter methylation patterns, including both increased and decreased methylation, in all three prostate cell lines in response to SFN or DIM treatments. In particular, SFN and DIM altered promoter methylation in distinct sets of genes in PrEC, LnCAP, and PC3 cells, but shared similar gene targets within a single cell line. We further showed that SFN and DIM reversed many of the cancer-associated methylation alterations, including aberrantly methylated genes that are dysregulated or are highly involved in cancer progression. Overall, our data suggested that both SFN and DIM are epigenetic modulators that have broad and complex effects on DNA methylation profiles in both normal and cancerous prostate epithelial cells. Results from our study may provide new insights into the epigenetic mechanisms by which SFN and DIM exert their cancer chemopreventive effects. PMID- 24466242 TI - In vivo and in vitro evidence for placental DNA damage in preeclampsia. AB - Preeclampsia (PE) is an idiopathic multisystem disease affecting 5-7% of pregnant women. Placental oxidative stress is a characteristic feature of PE and occurs when the production of reactive oxygen species (ROS) within the placenta overwhelms the intrinsic anti-oxidant defenses. We hypothesize that excessive oxidative DNA damage at the fetal-maternal interface coupled with a defective DNA damage/repair response is causally related to PE. Here we demonstrate that gammaH2AX (a sensitive marker of DNA damage) is expressed in the maternal decidua but not trophoblast of normal placentas, and that expression is significantly higher in PE placental tissues in vivo. Using primary in vitro cultures of maternal decidual stromal cells (DSCs) and fetal cytotrophoblast cells (CTs), we show an increase in gammaH2AX foci in DSCs cultured with vs without H2O2 (70.6% vs 11.6%; P<0.0001) or under hypoxia-reperfusion vs normoxia (20- vs 3-fold; P = 0.01); no foci were seen in CTs. We further demonstrate that Base Excision Repair (BER) intermediates are significantly increased in DSCs (not CTs) under these same conditions. Our data show that DNA damage is significantly more common in PE placentas, and that this DNA damage is localized to the maternal and not fetal side of the placenta. CTs may be selectively resistant to DNA damage in an effort to protect the fetus. PMID- 24466243 TI - Inverse immunological responses induced by allergic rhinitis and head and neck squamous cell carcinoma. AB - Several epidemiological studies have investigated the relation between allergy and cancer with contradicting conclusions, and reports on immunological differences are scarce. By focusing on inflammation, the present study was designed to compare the immune response induced by allergic rhinitis (AR) and head and neck squamous cell carcinoma (HNSCC). Blood and serum was obtained from patients with symptomatic seasonal AR, and newly detected HNSCC, as well as healthy controls. Peripheral blood mononuclear cells (PBMC) and polymorphonuclear leukocytes (PMN) were isolated and cultured with or without the toll-like receptor ligands, Pam3CSK4, LPS, R837, and CpG. Cellular activation and cytokine release were assessed with ELISA, Luminex Multiplex Immunoassay, flow cytometry, and real-time RT-PCR. Sera from HNSCC patients showed elevated levels of innate immune cytokines, and exhibited a response profile consistent with an increased innate immune reaction. In contrast, sera and stimulated PBMC from AR patients displayed increased concentrations of T cell related cytokines, consistent with an adaptive immune response. The presented data demonstrate that AR and HNSCC induce two distinct immunological processes, indicating an inverse association between the immunological responses seen in patients with allergy and cancer of the upper airway. PMID- 24466244 TI - Prediction of severe neonatal hyperbilirubinemia using cord blood hydrogen peroxide: a prospective study. AB - BACKGROUND: We hypothesized that cord blood hydrogen peroxide (H2O2) could be utilized to predict the severity of neonatal hyperbilirubinemia. METHODS: We prospectively enrolled term or near-term healthy neonates. Cord blood and capillary blood at three days of age were measured for hydrogen peroxide and bilirubin concentrations. For newborns with hyperbilirubinemia, further blood samples were obtained at five and seven days of age. Newborns were divided into severe or less severe hyperbilirubinemic groups (peak bilirubin >=17 mg/dL or not). The sensitivity, specificity, and negative predictive values were determined. RESULTS: There were 158 neonates enrolled. The incidence of neonatal hyperbilirubinemia was 30.5% for a concentration >=15 mg/dl. The rising patterns were similar among bilirubin concentrations and hydrogen peroxide levels during the first few days of life. There was a strong positive correlation between bilirubin concentrations and hydrogen peroxide levels after correlation analysis. The rate of severe hyperbilirubinemia was 13.3%. It revealed that a cord blood hydrogen peroxide signal level of 2500 counts/10 seconds was an appropriate cut off for predicting severe hyperbilirubinemia. Sensitivity and the negative predictive value were 76.2% and 93.3%, respectively. CONCLUSIONS: Our findings confirm that hydrogen peroxide levels and bilirubin concentrations in cord and neonatal blood are closely related. A cord blood hydrogen peroxide level above 2500 counts/10 seconds associated with a high predictive value for severe hyperbilirubinemia. This method provides information about which neonate should be closely followed after discharge from the nursery. PMID- 24466245 TI - Chloroquine is grossly under dosed in young children with malaria: implications for drug resistance. AB - BACKGROUND: Plasmodium falciparum malaria is treated with 25 mg/kg of chloroquine (CQ) irrespective of age. Theoretically, CQ should be dosed according to body surface area (BSA). The effect of dosing CQ according to BSA has not been determined but doubling the dose per kg doubled the efficacy of CQ in children aged <15 years infected with P. falciparum carrying CQ resistance causing genes typical for Africa. The study aim was to determine the effect of age on CQ concentrations. METHODS AND FINDINGS: Day 7 whole blood CQ concentrations were determined in 150 and 302 children treated with 25 and 50 mg/kg, respectively, in previously conducted clinical trials. CQ concentrations normalised for the dose taken in mg/kg of CQ decreased with decreasing age (p<0.001). CQ concentrations normalised for dose taken in mg/m(2) were unaffected by age. The median CQ concentration in children aged <2 years taking 50 mg/kg and in children aged 10 14 years taking 25 mg/kg were 825 (95% confidence interval [CI] 662-988) and 758 (95% CI 640-876) nmol/l, respectively (p = 0.67). The median CQ concentration in children aged 10-14 taking 50 mg/kg and children aged 0-2 taking 25 mg/kg were 1521 and 549 nmol/l. Adverse events were not age/concentration dependent. CONCLUSIONS: CQ is under-dosed in children and should ideally be dosed according to BSA. Children aged <2 years need approximately double the dose per kg to attain CQ concentrations found in children aged 10-14 years. Clinical trials assessing the efficacy of CQ in Africa are typically performed in children aged <5 years. Thus the efficacy of CQ is typically assessed in children in whom CQ is under dosed. Approximately 3 fold higher drug concentrations can probably be safely given to the youngest children. As CQ resistance is concentration dependent an alternative dosing of CQ may overcome resistance in Africa. PMID- 24466246 TI - Use of peptide nucleic acids to manipulate gene expression in the malaria parasite Plasmodium falciparum. AB - One of the major concerns in treating malaria by conventional small drug molecules is the rapid emergence of drug resistance. Specific silencing of essential genes by antisense oliogomers has been proposed as an alternative approach that may result in antimalarial activity which is not associated with drug resistance. In addition, such an approach could be an important biological tool for studying many genes' function by reverse genetics. Here we present a novel methodology of using peptide nucleic acids (PNAs) as a useful tool for gene silencing in Plasmodium falciparum. PNAs, designed as specific antisense molecules, were conjugated to a cell penetrating peptide (CPP); namely, octa-D lysine via the C-terminus, to allow facile delivery through cell membranes. PNAs added to P. falciparum cultures were found exclusively in infected erythrocytes and were eventually localized in nuclei of the parasites at all stages of intra erythrocytic development. We show that these PNAs specifically down regulated both a stably expressed transgene as well as an endogenous essential gene, which significantly reduced parasites' viability. This study paves the way for a simple approach to silence a variety of P. falciparum genes as means of deciphering their function and potentially to develop highly specific and potent antimalarial agents. PMID- 24466247 TI - In vitro screening for anti-cholinesterase and antioxidant activity of methanolic extracts of ayurvedic medicinal plants used for cognitive disorders. AB - Inhibition of Acetylcholinesterase (AChE) is still considered as the main therapeutic strategy against Alzheimer's disease (AD). Many plant derived phytochemicals have shown AChE inhibitory activity in addition to the currently approved drugs for AD. In the present study, methanolic extracts of 20 plants used in Indian Ayurvedic system of medicine for improving cognitive function were screened for acetylcholinesterase inhibitory activity by Ellman's microplate colorimetric method. Out of 20 extracts, Emblica officinalis, Nardostachys jatamansi, Nelumbo nucifera, Punica granatum and Raulfia Serpentina showed IC50 values <100 ug/ml for acetylcholinesterase inhibitory activity. Antioxidant activities of these plants were assessed by DPPH scavenging assay. Among the extracts used, antioxidant activity was highest for Terminalia chebula and Emblica officinalis with IC50 values <10 ug/ml. Considering the complex multifactorial etiology of AD, these plant extracts will be safer and better candidates for the future disease modifying therapies against this devastating disease. PMID- 24466248 TI - Training set selection for the prediction of essential genes. AB - Various computational models have been developed to transfer annotations of gene essentiality between organisms. However, despite the increasing number of microorganisms with well-characterized sets of essential genes, selection of appropriate training sets for predicting the essential genes of poorly-studied or newly sequenced organisms remains challenging. In this study, a machine learning approach was applied reciprocally to predict the essential genes in 21 microorganisms. Results showed that training set selection greatly influenced predictive accuracy. We determined four criteria for training set selection: (1) essential genes in the selected training set should be reliable; (2) the growth conditions in which essential genes are defined should be consistent in training and prediction sets; (3) species used as training set should be closely related to the target organism; and (4) organisms used as training and prediction sets should exhibit similar phenotypes or lifestyles. We then analyzed the performance of an incomplete training set and an integrated training set with multiple organisms. We found that the size of the training set should be at least 10% of the total genes to yield accurate predictions. Additionally, the integrated training sets exhibited remarkable increase in stability and accuracy compared with single sets. Finally, we compared the performance of the integrated training sets with the four criteria and with random selection. The results revealed that a rational selection of training sets based on our criteria yields better performance than random selection. Thus, our results provide empirical guidance on training set selection for the identification of essential genes on a genome wide scale. PMID- 24466249 TI - Transport rankings of non-steroidal antiinflammatory drugs across blood-brain barrier in vitro models. AB - The aim of this work was to conduct a comprehensive study about the transport properties of NSAIDs across the blood-brain barrier (BBB) in vitro. Transport studies with celecoxib, diclofenac, ibuprofen, meloxicam, piroxicam and tenoxicam were accomplished across Transwell models based on cell line PBMEC/C1-2, ECV304 or primary rat brain endothelial cells. Single as well as group substance studies were carried out. In group studies substance group compositions, transport medium and serum content were varied, transport inhibitors verapamil and probenecid were added. Resulted permeability coefficients were compared and normalized to internal standards diazepam and carboxyfluorescein. Transport rankings of NSAIDs across each model were obtained. Single substance studies showed similar rankings as corresponding group studies across PBMEC/C1-2 or ECV304 cell layers. Serum content, glioma conditioned medium and inhibitors probenecid and verapamil influenced resulted permeability significantly. Basic differences of transport properties of the investigated NSAIDs were similar comparing all three in vitro BBB models. Different substance combinations in the group studies and addition of probenecid and verapamil suggested that transporter proteins are involved in the transport of every tested NSAID. Results especially underlined the importance of same experimental conditions (transport medium, serum content, species origin, cell line) for proper data comparison. PMID- 24466250 TI - A leech capable of surviving exposure to extremely low temperatures. AB - It is widely considered that most organisms cannot survive prolonged exposure to temperatures below 0 degrees C, primarily because of the damage caused by the water in cells as it freezes. However, some organisms are capable of surviving extreme variations in environmental conditions. In the case of temperature, the ability to survive subzero temperatures is referred to as cryobiosis. We show that the ozobranchid leech, Ozobranchus jantseanus, a parasite of freshwater turtles, has a surprisingly high tolerance to freezing and thawing. This finding is particularly interesting because the leach can survive these temperatures without any acclimation period or pretreatment. Specifically, the leech survived exposure to super-low temperatures by storage in liquid nitrogen (-196 degrees C) for 24 hours, as well as long-term storage at temperatures as low as -90 degrees C for up to 32 months. The leech was also capable of enduring repeated freeze thaw cycles in the temperature range 20 degrees C to -100 degrees C and then back to 20 degrees C. The results demonstrated that the novel cryotolerance mechanisms employed by O. jantseanus enable the leech to withstand a wider range of temperatures than those reported previously for cryobiotic organisms. We anticipate that the mechanism for the observed tolerance to freezing and thawing in O. jantseanus will prove useful for future studies of cryopreservation. PMID- 24466251 TI - Expression and functional characterization of Smyd1a in myofibril organization of skeletal muscles. AB - BACKGROUND: Smyd1, the founding member of the Smyd family including Smyd-1, 2, 3, 4 and 5, is a SET and MYND domain containing protein that plays a key role in myofibril assembly in skeletal and cardiac muscles. Bioinformatic analysis revealed that zebrafish genome contains two highly related smyd1 genes, smyd1a and smyd1b. Although Smyd1b function is well characterized in skeletal and cardiac muscles, the function of Smyd1a is, however, unknown. METHODOLOGY/PRINCIPAL FINDINGS: To investigate the function of Smyd1a in muscle development, we isolated smyd1a from zebrafish, and characterized its expression and function during muscle development via gene knockdown and transgenic expression approaches. The results showed that smyd1a was strongly expressed in skeletal muscles of zebrafish embryos. Functional analysis revealed that knockdown of smyd1a alone had no significant effect on myofibril assembly in zebrafish skeletal muscles. However, knockdown of smyd1a and smyd1b together resulted in a complete disruption of myofibril organization in skeletal muscles, a phenotype stronger than knockdown of smyd1a or smyd1b alone. Moreover, ectopic expression of zebrafish smyd1a or mouse Smyd1 transgene could rescue the myofibril defects from the smyd1b knockdown in zebrafish embryos. CONCLUSION/SIGNIFICANCE: Collectively, these data indicate that Smyd1a and Smyd1b share similar biological activity in myofibril assembly in zebrafish embryos. However, Smyd1b appears to play a major role in this process. PMID- 24466252 TI - A new tumorsphere culture condition restores potentials of self-renewal and metastasis of primary neuroblastoma in a mouse neuroblastoma model. AB - Tumorsphere culture enriches and expands tumor cells, thus providing important resources for cancer studies. However, as compared with metastatic tissues, primary tumors in the nervous system rarely give rise to long-surviving tumorspheres, thereby seriously limiting studies on these cancers. This might be due to the limited self-renewal capability of tumor cells and/or to inappropriate culture conditions. The growth and maintenance of tumor cells may depend on microenvironments and/or cell origins (e.g., primary or metastatic; stem cell like or progenitor-like). Here, we attempted to establish a tumorsphere culture condition for primary neuroblastoma (NB). Primary tumors in MYCN transgenic mice, a NB model, could be serially transplanted, suggesting that these tumors contain cells with a high self-renewal potential. However, primary tumors did not give rise to tumorspheres under a serum-free neurosphere culture condition. The newly established culture condition (named PrimNeuS) contained two critical ingredients: fetal bovine serum and beta-mercaptoethanol were essential for tumorsphere formation as well as indefinite passages. The spheres could be passaged more than 20 times without exhaustion under this condition, exhibited a property of differentiation and formed tumors in vivo. Unexpectedly, PrimNeuS revealed that the MYCN transgenic mice had bone marrow metastasis. Furthermore, subcutaneous tumors derived from tumorspheres of primary tumors showed bone marrow metastasis. Taken together, PrimNeuS provides resources for the study of NB and can be used as a powerful tool for the detection of minimal residual disease and for in vitro evaluation prior to personalized therapy. PMID- 24466253 TI - Regional distribution shifts help explain local changes in wintering raptor abundance: implications for interpreting population trends. AB - Studies of multiple taxa across broad-scales suggest that species distributions are shifting poleward in response to global climate change. Recognizing the influence of distribution shifts on population indices will be an important part of interpreting trends within management units because current practice often assumes that changes in local populations reflect local habitat conditions. However, the individual- and population-level processes that drive distribution shifts may occur across a large, regional scale and have little to do with the habitats within the management unit. We examined the latitudinal center of abundance for the winter distributions of six western North America raptor species using Christmas Bird Counts from 1975-2011. Also, we considered whether population indices within western North America Bird Conservation Regions (BCRs) were explained by distribution shifts. All six raptors had significant poleward shifts in their wintering distributions over time. Rough-legged Hawks (Buteo lagopus) and Golden Eagles (Aquila chrysaetos) showed the fastest rate of change, with 8.41 km yr(-1) and 7.74 km yr(-1) shifts, respectively. Raptors may be particularly responsive to warming winters because of variable migration tendencies, intraspecific competition for nesting sites that drives males to winter farther north, or both. Overall, 40% of BCR population trend models were improved by incorporating information about wintering distributions; however, support for the effect of distribution on BCR indices varied by species with Rough-legged Hawks showing the most evidence. These results emphasize the importance of understanding how regional distribution shifts influence local scale population indices. If global climate change is altering distribution patterns, then trends within some management units may not reflect changes in local habitat conditions. The methods used to monitor and manage bird populations within local BCRs will fundamentally change as species experience changes in distribution in response to climate change. PMID- 24466254 TI - Pollen and phytolith evidence for rice cultivation and vegetation change during the mid-late holocene at the Jiangli site, Suzhou, East China. AB - Pollen and phytolith analyses were undertaken at the Jiangli site in Suzhou, Jiangsu Province, combined with studies on macrofossils by flotation. The concentration of pollen decreased while the percentage of Poaceae pollen in the profile increased from the late phase of the Majiabang Culture to the Songze Culture suggesting that human impact on the local environment intensified gradually. The discovery of rice paddy implies a relatively advanced rice cultivation in this area during the middle-late Holocene. Other than phytoliths, the high percentage of Oryza-type Poaceae pollen (larger than 40 um) supplied robust evidence for the existence of rice paddy. Moreover, the fact that the farther from the rice paddy, the lower the concentration and percentage of Poaceae pollen also proves that the dispersal and deposition of pollen is inversely proportional to the distance. PMID- 24466255 TI - Primary school teachers' assessment profiles in mathematics education. AB - The aim of this study was to contribute to knowledge about classroom assessment by identifying profiles of teachers' assessment of their students' understanding of mathematics. For carrying out this study we used data of a nationwide teacher survey (N = 960) in the Netherlands. The data were collected by an online questionnaire. Through exploratory factor analyses the underlying structure of what is measured by this questionnaire was uncovered as consisting of five factors: Goal centeredness of assessment, Authentic nature of assessment, Perceived usefulness of assessment, Diversity of assessment problem format, and Allocated importance of assessing skills and knowledge. By using a latent class analysis four different assessment profiles of teachers were identified: Enthusiastic assessors, Mainstream assessors, Non-enthusiastic assessors, and Alternative assessors. The findings suggest that teachers with particular assessment profiles have qualitatively different assessment practices. The paper concludes with discussing theoretical implications of these assessment profiles and indications these profiles can offer both for designing material for professional development in classroom assessment and for evaluating changes in teachers' classroom assessment practice. PMID- 24466256 TI - Frequency specificity of regional homogeneity in the resting-state human brain. AB - Resting state-fMRI studies have found that the inter-areal correlations in cortical networks concentrate within ultra-low frequencies (0.01-0.04 Hz) while long-distance connections within subcortical networks distribute over a wider frequency range (0.01-0.14 Hz). However, the frequency characteristics of regional homogeneity (ReHo) in different areas are still unclear. To examine the ReHo properties in different frequency bands, a data-driven method, Empirical Mode Decomposition (EMD), was adopted to decompose the time series of each voxel into several components with distinct frequency bands. ReHo values in each of the components were then calculated. Our results showed that ReHo in cortical areas were higher and more frequency-dependent than those in the subcortical regions. BOLD oscillations of 0.02-0.04 Hz mainly contributed to the cortical ReHo, whereas the ReHo in limbic areas involved a wider frequency range and were dominated by higher-frequency BOLD oscillations (>0.08 Hz). The frequency characteristics of ReHo are distinct between different parts of the striatum, with the frequency band of 0.04-0.1 Hz contributing the most to ReHo in caudate nucleus, and oscillations lower than 0.02 Hz contributing more to ReHo in putamen. The distinct frequency-specific ReHo properties of different brain areas may arise from the assorted cytoarchitecture or synaptic types in these areas. Our work may advance the understanding of the neural-physiological basis of local BOLD activities and the functional specificity of different brain regions. PMID- 24466257 TI - Chromosomal polymorphism in the Sporothrix schenckii complex. AB - Sporotrichosis is a polymorphic disease caused by a complex of thermodimorphic fungi including S. brasiliensis, S. schenckii sensu stricto (s. str.), S. globosa and S. luriei. Humans and animals can acquire the disease through traumatic inoculation of propagules into the subcutaneous tissue. Despite the importance of sporotrichosis as a disease that can take epidemic proportions there are just a few studies dealing with genetic polymorphisms and genomic architecture of these pathogens. The main objective of this study was to investigate chromosomal polymorphisms and genomic organization among different isolates in the S. schenckii complex. We used pulsed field gel electrophoresis (PFGE) to separate chromosomal fragments of isolated DNA, followed by probe hybridization. Nine loci (beta-tubulin, calmodulin, catalase, chitin synthase 1, Internal Transcribed Spacer, Pho85 cyclin-dependent kinase, protein kinase C Ss-2, G protein alpha subunit and topoisomerase II) were mapped onto chromosomal bands of Brazilian isolates of S. schenckii s. str. and S. brasiliensis. Our results revealed the presence of intra and interspecies polymorphisms in chromosome number and size. The gene hybridization analysis showed that closely related species in phylogenetic analysis had similar genetic organizations, mostly due to identification of synteny groups in chromosomal bands of similar sizes. Our results bring new insights into the genetic diversity and genome organization among pathogenic species in the Sporothrix schenckii complex. PMID- 24466259 TI - Response of insect relative growth rate to temperature and host-plant phenology: estimation and validation from field data. AB - Between 1975 to 2011, aphid Relative Growth Rates (RGR) were modelled as a function of mean outdoor temperature and host plant phenology. The model was applied to the grain aphid Sitobion avenae using data on aphid counts in winter wheat at two different climate regions in France (oceanic climate, Rennes (western France); continental climate, Paris). Mean observed aphid RGR was higher in Paris compared to the Rennes region. RGR increased with mean temperature, which is explained by aphid reproduction, growth and development being dependent on ambient temperature. From the stem extension to the heading stage in wheat, there was either a plateau in RGR values (Rennes) or an increase with a maximum at heading (Paris) due to high intrinsic rates of increase in aphids and also to aphid immigration. From the wheat flowering to the ripening stage, RGR decreased in both regions due to the low intrinsic rate of increase in aphids and high emigration rate linked to reduced nutrient quality in maturing wheat. The model validation process showed that the fitted models have more predictive power in the Paris region than in the Rennes region. PMID- 24466258 TI - Identification and characterization of microRNAs in ovary and testis of Nile tilapia (Oreochromis niloticus) by using solexa sequencing technology. AB - MicroRNAs (miRNAs) are endogenous non-coding small RNAs which play important roles in the regulation of gene expression by cleaving or inhibiting the translation of target gene transcripts. Thereinto, some specific miRNAs show regulatory activities in gonad development via translational control. In order to further understand the role of miRNA-mediated posttranscriptional regulation in Nile tilapia (Oreochromis niloticus) ovary and testis, two small RNA libraries of Nile tilapia were sequenced by Solexa small RNA deep sequencing methods. A total of 9,731,431 and 8,880,497 raw reads, representing 5,407,800 and 4,396,281 unique sequences were obtained from the sexually mature ovaries and testes, respectively. After comparing the small RNA sequences with the Rfam database, 1,432,210 reads in ovaries and 984,146 reads in testes were matched to the genome sequence of Nile tilapia. Bioinformatic analysis identified 764 mature miRNA, 209 miRNA-5p and 202 miRNA-3p were found in the two libraries, of which 525 known miRNAs are both expressed in the ovary and testis of Nile tilapia. Comparison of expression profiles of the testis, miR-727, miR-129 and miR-29 families were highly expressed in tilapia ovary. Additionally, miR-132, miR-212, miR-33a and miR-135b families, showed significant higher expression in testis compared with that in ovary. Furthermore, the expression patterns of the miRNAs were analyzed in different developmental stages of gonad. The result showed different expression patterns were observed during development of testis and ovary. In addition, the identification and characterization of differentially expressed miRNAs in the ovaries and testis of Nile tilapia provides important information on the role of miRNA in the regulation of the ovarian and testicular development and function. This data will be helpful to facilitate studies on the regulation of miRNAs during teleosts reproduction. PMID- 24466260 TI - Psychiatrists' attitudes toward metabolic adverse events in patients with schizophrenia. AB - BACKGROUND: There is growing concern about the metabolic abnormalities in patients with schizophrenia. AIMS: The aim of this study was to assess the attitudes of psychiatrists toward metabolic adverse events in patients with schizophrenia. METHOD: A BRIEF QUESTIONNAIRE WAS CONSTRUCTED TO COVER THE FOLLOWING BROAD AREAS: the psychiatrists' recognition of the metabolic risk of antipsychotic therapy, pattern of monitoring patients for physical risks, practice pattern for physical risks, and knowledge of metabolic disturbance. In March 2012, the questionnaire was mailed to 8,482 psychiatrists who were working at hospitals belonging to the Japan Psychiatric Hospitals Association. RESULTS: The overall response rate was 2,583/8,482 (30.5%). Of the respondents, 85.2% (2,200/2,581) reported that they were concerned about prescribing antipsychotics that have a risk of elevating blood sugar; 47.6% (1,201/2,524) stated that their frequency of monitoring patients under antipsychotic treatment was based on their own experiences; and only 20.6% (5,22/2,534) of respondents answered that the frequency with which they monitored their patients was sufficient to reduce the metabolic risks. CONCLUSIONS: Psychiatrists practicing in Japan were generally aware and concerned about the metabolic risks for patients being treated with antipsychotics. Although psychiatrists should monitor their patients for metabolic abnormalities to balance these risks, a limited number of psychiatrists answered that the frequency with which they monitored patients to reduce the metabolic risks was sufficient. Promotion of the best practices of pharmacotherapy and monitoring is needed for psychiatrists treating patients with schizophrenia. PMID- 24466261 TI - Diversity of virulence phenotypes among type III secretion negative Pseudomonas aeruginosa clinical isolates. AB - Pseudomonas aeruginosa is a frequent cause of acute infections. The primary virulence factor that has been linked to clinical disease is the type III secretion system, a molecular syringe that delivers effector proteins directly into host cells. Despite the importance of type III secretion in dictating clinical outcomes and promoting disease in animal models of infections, clinical isolates often do not express the type III secretion system in vitro. Here we screened 81 clinical P. aeruginosa isolates for secretion of type III secretion system substrates by western blot. Non-expressing strains were also subjected to a functional test assaying the ability to intoxicate epithelial cells in vitro, and to survive and cause disease in a murine model of corneal infection. 26 of 81 clinical isolates were found to be type III secretion negative by western blot. 17 of these 26 non-expressing strains were tested for their ability to cause epithelial cell rounding. Of these, three isolates caused epithelial cell rounding in a type III secretion system dependent manner, and one strain was cytotoxic in a T3SS-independent manner. Five T3SS-negative isolates were also tested for their ability to cause disease in a murine model of corneal infection. Of these isolates, two strains caused severe corneal disease in a T3SS independent manner. Interestingly, one of these strains caused significant disease (inflammation) despite being cleared. Our data therefore show that P. aeruginosa clinical isolates can cause disease in a T3SS-independent manner, demonstrating the existence of novel modifiers of clinical disease. PMID- 24466262 TI - Disagreement between human papillomavirus assays: an unexpected challenge for the choice of an assay in primary cervical screening. AB - We aimed to determine the disagreement in primary cervical screening between four human papillomavirus assays: Hybrid Capture 2, cobas, CLART, and APTIMA. Material from 5,064 SurePath samples of women participating in routine cervical screening in Copenhagen, Denmark, was tested with the four assays. Positive agreement between the assays was measured as the conditional probability that the results of all compared assays were positive given that at least one assay returned a positive result. Of all 5,064 samples, 1,679 (33.2%) tested positive on at least one of the assays. Among these, 41% tested positive on all four. Agreement was lower in women aged >= 30 years (30%, vs. 49% at <30 years), in primary screening samples (29%, vs. 38% in follow-up samples), and in women with concurrent normal cytology (22%, vs. 68% with abnormal cytology). Among primary screening samples from women aged 30-65 years (n = 2,881), 23% tested positive on at least one assay, and 42 to 58% of these showed positive agreement on any compared pair of the assays. While 4% of primary screening samples showed abnormal cytology, 6 to 10% were discordant on any pair of assays. A literature review corroborated our findings of considerable disagreement between human papillomavirus assays. This suggested that the extent of disagreement in primary screening is neither population- nor storage media-specific, leaving assay design differences as the most probable cause. The substantially different selection of women testing positive on the various human papillomavirus assays represents an unexpected challenge for the choice of an assay in primary cervical screening, and for follow up of in particular HPV positive/cytology normal women. PMID- 24466263 TI - Autophagy is involved in the cardioprotection effect of remote limb ischemic postconditioning on myocardial ischemia/reperfusion injury in normal mice, but not diabetic mice. AB - BACKGROUND: Recent animal study and clinical trial data suggested that remote limb ischemic postconditioning (RIPostC) can invoke potent cardioprotection. However, during ischemia reperfusion injury (IR), the effect and mechanism of RIPostC on myocardium in subjects with or without diabetes mellitus (DM) are poorly understood. Autophagy plays a crucial role in alleviating myocardial IR injury. The aim of this study was to determine the effect of RIPostC on mice myocardial IR injury model with or without DM, and investigate the role of autophagy in this process. METHODOLOGY AND RESULTS: Streptozocin (STZ) induced DM mice model and myocardial IR model were established. Using a noninvasive technique, RIPostC was induced in normal mice (ND) and DM mice by three cycles of ischemia (5 min) and reperfusion (5 min) in the left hindlimb. In ND group, RIPostC significantly reduced infarct size (32.6+/-3.0% in ND-RIPostC vs. 50.6+/ 2.4% in ND-IR, p<0.05) and improved cardiac ejection fraction (49.70+/-3.46% in ND-RIPostC vs. 31.30+/-3.95% in ND-IR, p<0.05). However, in DM group, no RIPostC mediated cardioprotetion effect was observed. To analyze the role of autophagy, western blot and immunohistochemistry was performed. Our data showed that a decreased sequestosome 1 (SQSTM1/p62) level, an increased Beclin-1 level, and higher ratio of LC3-II/LC3-I were observed in ND RIPostC group, but not DM RIPostC group. CONCLUSIONS: The current study suggested that RIPostC exerts cardioprotection effect on IR in normal mice, but not DM mice, and this difference is via, at least in part, the up-regulation of autophagy. PMID- 24466264 TI - MAP1S controls breast cancer cell TLR5 signaling pathway and promotes TLR5 signaling-based tumor suppression. AB - Targeting TLR5 signaling in breast cancer represents a novel strategy in cancer immunotherapy. However, the underlying mechanism by which TLR5 signaling inhibits cancer cell proliferation and tumor growth has not been elucidated. In this study, we found TLR5 agonist flagellin inhibited the cell state of activation and induced autophagy, and reported that autophagy protein MAP1S regulated the flagellin/TLR5 signaling pathway in breast cancer cells through enhancement of NF kappaB activity and cytokine secretion. Remarkably, MAP1S played a critical role in tumor suppression induced by flagellin, and knockdown of MAP1S almost completely abrogated the suppression of tumor growth and migration by flagellin treatment. In addition, elevated expression of MAP1S in response to flagellin feed-back regulated tumor inflammatory microenvironment in the late stages of TLR5 signaling through degradation of MyD88 in autophagy process. These results indicate a mechanism of antitumor activity that involves MAP1S-controlled TLR5 signaling in breast cancer. PMID- 24466265 TI - Visualizing Vpr-induced G2 arrest and apoptosis. AB - Vpr is an accessory protein of human immunodeficiency virus type 1 (HIV-1) with multiple functions. The induction of G2 arrest by Vpr plays a particularly important role in efficient viral replication because the transcriptional activity of the HIV-1 long terminal repeat is most active in G2 phase. The regulation of apoptosis by Vpr is also important for immune suppression and pathogenesis during HIV infection. However, it is not known whether Vpr-induced apoptosis depends on the ability of Vpr to induce G2 arrest, and the dynamics of Vpr-induced G2 arrest and apoptosis have not been visualized. We performed time lapse imaging to examine the temporal relationship between Vpr-induced G2 arrest and apoptosis using HeLa cells containing the fluorescent ubiquitination-based cell cycle indicator2 (Fucci2). The dynamics of G2 arrest and subsequent long term mitotic cell rounding in cells transfected with the Vpr-expression vector were visualized. These cells underwent nuclear mis-segregation after prolonged mitotic processes and then entered G1 phase. Some cells subsequently displayed evidence of apoptosis after prolonged mitotic processes and nuclear mis segregation. Interestingly, Vpr-induced apoptosis was seldom observed in S or G2 phase. Likewise, visualization of synchronized HeLa/Fucci2 cells infected with an adenoviral vector expressing Vpr clearly showed that Vpr arrests the cell cycle at G2 phase, but does not induce apoptosis at S or G2 phase. Furthermore, time lapse imaging of HeLa/Fucci2 cells expressing SCAT3.1, a caspase-3-sensitive fusion protein, clearly demonstrated that Vpr induces caspase-3-dependent apoptosis. Finally, to examine whether the effects of Vpr on G2 arrest and apoptosis were reversible, we performed live-cell imaging of a destabilizing domain fusion Vpr, which enabled rapid stabilization and destabilization by Shield1. The effects of Vpr on G2 arrest and subsequent apoptosis were reversible. This study is the first to characterize the dynamics of the morphological changes that occur during Vpr-induced G2 arrest and apoptosis. PMID- 24466266 TI - Hsp90 binds directly to fibronectin (FN) and inhibition reduces the extracellular fibronectin matrix in breast cancer cells. AB - Heat shock protein 90 (Hsp90) has been identified in the extracellular space and has been shown to chaperone a finite number of extracellular proteins involved in cell migration and invasion. We used chemical cross-linking and immunoprecipitation followed by tandem mass spectrometry (MS/MS) to isolate a complex containing Hsp90 and the matrix protein fibronectin (FN) from breast cancer cells. Further analysis showed direct binding of Hsp90 to FN using an in vitro co-immunoprecipitation assay, a solid phase binding assay and surface plasmon resonance (SPR) spectroscopy. Confocal microscopy showed regions of co localisation of Hsp90 and FN in breast cancer cell lines. Exogenous Hsp90beta was shown to increase the formation of extracellular FN matrix in the Hs578T cell line, whilst knockdown or inhibition of Hsp90 led to a reduction in the levels of both soluble and insoluble FN and could be partially rescued by addition of exogenous Hsp90beta. Treatment of cells with novobiocin led to internalization of FN into vesicles that were positive for the presence of the lysosomal marker, LAMP-1. Taken together, the direct interaction between FN and Hsp90, as well as the decreased levels of both soluble and insoluble FN upon Hsp90 inhibition or knockdown, suggested that FN may be a new client protein for Hsp90 and that Hsp90 was involved in FN matrix assembly and/or stability. The identification of FN as a putative client protein of Hsp90 suggests a role for Hsp90 in FN matrix stability, which is important for a number of fundamental cellular processes including embryogenesis, wound healing, cell migration and metastasis. PMID- 24466267 TI - STAT3 but not STAT1 is required for astrocyte differentiation. AB - The JAK-STAT signaling pathway has been implicated in astrocyte differentiation. Both STAT1 and STAT3 are expressed in the central nervous system and are thought to be important for glial differentiation, as mainly demonstrated in vitro; however direct in vivo evidence is missing. We investigated whether STAT1 and STAT3 are essential for astrocyte development by testing the STAT responsiveness of astrocyte progenitors. STAT3 was absent in the ventricular zone where glial progenitors are born but begins to appear at the marginal zone at E16.5. At E18.5, both phospho-STAT1 and phospho-STAT3 were present in glial fibrillary acidic protein (GFAP)-expressing white matter astrocytes. Overexpression of STAT3 by electroporation of chicks in ovo induced increased numbers of astrocyte progenitors in the spinal cord. Likewise, elimination of STAT3 in Stat3 conditional knockout (cKO) mice resulted in depletion of white matter astrocytes. Interestingly, elimination of STAT1 in Stat1 null mice did not inhibit astrocyte differentiation and deletion of Stat1 failed to aggravate the glial defects in Stat3 cKO mice. Measuring the activity of STAT binding elements and the gfap promoter in the presence of various STAT mutants revealed that transactivation depended on the activity of STAT3 not STAT1. No synergistic interaction between STAT1 and STAT3 was observed. Cortical progenitors of Stat1 null; Stat3 cKO mice generated astrocytes when STAT3 or the splice variant Stat3beta was supplied, but not when STAT1 was introduced. Together, our results suggest that STAT3 is necessary and sufficient for astrocyte differentiation whereas STAT1 is dispensable. PMID- 24466268 TI - Genome-wide investigation and expression analyses of WD40 protein family in the model plant foxtail millet (Setaria italica L.). AB - WD40 proteins play a crucial role in diverse protein-protein interactions by acting as scaffolding molecules and thus assisting in the proper activity of proteins. Hence, systematic characterization and expression profiling of these WD40 genes in foxtail millet would enable us to understand the networks of WD40 proteins and their biological processes and gene functions. In the present study, a genome-wide survey was conducted and 225 potential WD40 genes were identified. Phylogenetic analysis categorized the WD40 proteins into 5 distinct sub-families (I-V). Gene Ontology annotation revealed the biological roles of the WD40 proteins along with its cellular components and molecular functions. In silico comparative mapping with sorghum, maize and rice demonstrated the orthologous relationships and chromosomal rearrangements including duplication, inversion and deletion of WD40 genes. Estimation of synonymous and non-synonymous substitution rates revealed its evolutionary significance in terms of gene-duplication and divergence. Expression profiling against abiotic stresses provided novel insights into specific and/or overlapping expression patterns of SiWD40 genes. Homology modeling enabled three-dimensional structure prediction was performed to understand the molecular functions of WD40 proteins. Although, recent findings had shown the importance of WD40 domains in acting as hubs for cellular networks during many biological processes, it has invited a lesser research attention unlike other common domains. Being a most promiscuous interactors, WD40 domains are versatile in mediating critical cellular functions and hence this genome-wide study especially in the model crop foxtail millet would serve as a blue-print for functional characterization of WD40s in millets and bioenergy grass species. In addition, the present analyses would also assist the research community in choosing the candidate WD40s for comprehensive studies towards crop improvement of millets and biofuel grasses. PMID- 24466269 TI - Effects of red-backed salamanders on ecosystem functions. AB - Ecosystems provide a vast array of services for human societies, but understanding how various organisms contribute to the functions that maintain these services remains an important ecological challenge. Predators can affect ecosystem functions through a combination of top-down trophic cascades and bottom up effects on nutrient dynamics. As the most abundant vertebrate predator in many eastern US forests, woodland salamanders (Plethodon spp.) likely affect ecosystems functions. We examined the effects of red-backed salamanders (Plethodon cinereus) on a variety of forest ecosystem functions using a combined approach of large-scale salamander removals (314-m(2) plots) and small-scale enclosures (2 m(2)) where we explicitly manipulated salamander density (0, 0.5, 1, 2, 4 m(-2)). In these experiments, we measured the rates of litter and wood decomposition, potential nitrogen mineralization and nitrification rates, acorn germination, and foliar insect damage on red oak seedlings. Across both experimental venues, we found no significant effect of red-backed salamanders on any of the ecosystem functions. We also found no effect of salamanders on intraguild predator abundance (carabid beetles, centipedes, spiders). Our study adds to the already conflicting evidence on effects of red-backed salamander and other amphibians on terrestrial ecosystem functions. It appears likely that the impact of terrestrial amphibians on ecosystem functions is context dependent. Future research would benefit from explicitly examining terrestrial amphibian effects on ecosystem functions under a variety of environmental conditions and in different forest types. PMID- 24466270 TI - Ubiquitin-related modifiers of Arabidopsis thaliana influence root development. AB - Ubiquitins are small peptides that allow for posttranslational modification of proteins. Ubiquitin-related modifier (URM) proteins belong to the class of ubiquitin-like proteins. A primary function of URM proteins has been shown to be the sulfur transfer reaction leading to thiolation of tRNAs, a process that is important for accurate and effective protein translation. Recent analyses revealed that the Arabidopsis genome codes for two URM proteins, URM11 and URM12, which both are active in the tRNA thiolation process. Here, we show that URM11 and URM12 have overlapping expression patterns and are required for tRNA thiolation. The characterization of urm11 and urm12 mutants reveals that the lack of tRNA thiolation induces changes in general root architecture by influencing the rate of lateral root formation. In addition, they synergistically influence root hair cell growth. During the sulfur transfer reaction, URM proteins of different organisms interact with a thiouridylase, a protein-protein interaction that also takes place in Arabidopsis, since URM11 and URM12 interact with the Arabidopsis thiouridylase ROL5. Hence, the sulfur transfer reaction is conserved between distantly related species such as yeast, humans, and plants, and in Arabidopsis has an impact on root development. PMID- 24466271 TI - Reversible modulation of myofibroblast differentiation in adipose-derived mesenchymal stem cells. AB - Unregulated activity of myofibroblasts, highly contractile cells that deposit abundant extracellular matrix (ECM), leads to fibrosis. To study the modulation of myofibroblast activity, we used human adipose-derived mesenchymal stem cells (ADSCs), which have much potential in regenerative medicine. We found that ADSCs treated with TGF-beta developed a myofibroblastic phenotype with increases in alpha-smooth muscle actin (alpha-SMA), a myofibroblast marker, and ECM proteins type I collagen and fibronectin. In contrast, treatment with bFGF had the opposite effect. bFGF-differentiated ADSCs showed marked down-regulation of alpha SMA expression, collagen I, and fibronectin, and loss of focal adhesions and stress fibers. Functionally, bFGF-differentiated ADSCs were significantly more migratory, which correlated with up-regulation of tenascin-C, an anti-adhesive ECM protein, and vimentin, a pro-migratory cytoskeletal protein. On the other hand, TGF-beta-differentiated ADSCs were significantly more contractile than bFGF differentiated cells. Interestingly, cells completely reversed their morphologies, marker expression, signaling pathways, and contractility versus migratory profiles when switched from culture with one growth factor to the other, demonstrating that the myofibroblast differentiation process is not terminal. Cell differentiation was associated with activation of Smad2 downstream of TGF-beta and of ERK/MAP kinase downstream of bFGF. Reversibility of the TGF beta-induced myofibroblastic phenotype depends, in part, on bFGF-induced ERK/MAP kinase signaling. These findings show that ADSC differentiation into myofibroblasts and re-differentiation into fibroblast-like cells can be manipulated with growth factors, which may have implications in the development of novel therapeutic strategies to reduce the risk of fibrosis. PMID- 24466272 TI - Cardiovascular responses induced by obstructive apnea are enhanced in hypertensive rats due to enhanced chemoreceptor responsivity. AB - Spontaneously hypertensive rats (SHR), like patients with sleep apnea, have hypertension, increased sympathetic activity, and increased chemoreceptor drive. We investigated the role of carotid chemoreceptors in cardiovascular responses induced by obstructive apnea in awake SHR. A tracheal balloon and vascular cannulas were implanted, and a week later, apneas of 15 s each were induced. The effects of apnea were more pronounced in SHR than in control rats (Wistar Kyoto; WKY). Blood pressure increased by 57+/-3 mmHg during apnea in SHR and by 28+/-3 mmHg in WKY (p<0.05, n = 14/13). The respiratory effort increased by 53+/-6 mmHg in SHR and by 34+/-5 mmHg in WKY. The heart rate fell by 209+/-19 bpm in SHR and by 155+/-16 bpm in WKY. The carotid chemoreceptors were then inactivated by the ligation of the carotid body artery, and apneas were induced two days later. The inactivation of chemoreceptors reduced the responses to apnea and abolished the difference between SHR and controls. The apnea-induced hypertension was 11+/-4 mmHg in SHR and 8+/-4 mmHg in WKY. The respiratory effort was 15+/-2 mmHg in SHR and 15+/-2 mmHg in WKY. The heart rate fell 63+/-18 bpm in SHR and 52+/-14 bpm in WKY. Similarly, when the chemoreceptors were unloaded by the administration of 100% oxygen, the responses to apnea were reduced. In conclusion, arterial chemoreceptors contribute to the responses induced by apnea in both strains, but they are more important in SHR and account for the exaggerated responses of this strain to apnea. PMID- 24466273 TI - CUSHAW3: sensitive and accurate base-space and color-space short-read alignment with hybrid seeding. AB - The majority of next-generation sequencing short-reads can be properly aligned by leading aligners at high speed. However, the alignment quality can still be further improved, since usually not all reads can be correctly aligned to large genomes, such as the human genome, even for simulated data. Moreover, even slight improvements in this area are important but challenging, and usually require significantly more computational endeavor. In this paper, we present CUSHAW3, an open-source parallelized, sensitive and accurate short-read aligner for both base space and color-space sequences. In this aligner, we have investigated a hybrid seeding approach to improve alignment quality, which incorporates three different seed types, i.e. maximal exact match seeds, exact-match k-mer seeds and variable length seeds, into the alignment pipeline. Furthermore, three techniques: weighted seed-pairing heuristic, paired-end alignment pair ranking and read mate rescuing have been conceived to facilitate accurate paired-end alignment. For base-space alignment, we have compared CUSHAW3 to Novoalign, CUSHAW2, BWA-MEM, Bowtie2 and GEM, by aligning both simulated and real reads to the human genome. The results show that CUSHAW3 consistently outperforms CUSHAW2, BWA-MEM, Bowtie2 and GEM in terms of single-end and paired-end alignment. Furthermore, our aligner has demonstrated better paired-end alignment performance than Novoalign for short reads with high error rates. For color-space alignment, CUSHAW3 is consistently one of the best aligners compared to SHRiMP2 and BFAST. The source code of CUSHAW3 and all simulated data are available at http://cushaw3.sourceforge.net. PMID- 24466274 TI - MiR-26a promotes ovarian cancer proliferation and tumorigenesis. AB - MicroRNAs (miRNAs) important for posttranscriptional gene expression are involved in the initiation and progression of human cancer. In this study, we reported that miR-26a was over-expressed in human EOC specimens and the expression level of extracellular miR-26a in plasma can distinguish patients from healthy controls in EOC. Ectopic expression of miR-26a in ovarian cancer (OC) cells increased cell proliferation and clonal formation. This growth promoting effect of OC cell growth was mediated by miR-26a inhibition of the posttranscription of ER-alpha. Furthermore, inhibition of miR-26a suppressed the tumor formation generated by injecting OC cells in nude mice. Our results suggest that aberrantly expressed miR-26a may contribute to OC development. PMID- 24466275 TI - miR-122 targets pyruvate kinase M2 and affects metabolism of hepatocellular carcinoma. AB - In contrast to normal differentiated cells that depend on mitochondrial oxidative phosphorylation for energy production, cancer cells have evolved to utilize aerobic glycolysis (Warburg's effect), with benefit of providing intermediates for biomass production. MicroRNA-122 (miR-122) is highly expressed in normal liver tissue regulating a wide variety of biological processes including cellular metabolism, but is reduced in hepatocellular carcinoma (HCC). Overexpression of miR-122 was shown to inhibit cancer cell proliferation, metastasis, and increase chemosensitivity, but its functions in cancer metabolism remains unknown. The present study aims to identify the miR-122 targeted genes and to investigate the associated regulatory mechanisms in HCC metabolism. We found the ectopic overexpression of miR-122 affected metabolic activities of HCC cells, evidenced by the reduced lactate production and increased oxygen consumption. Integrated gene expression analysis in a cohort of 94 HCC tissues revealed miR-122 level tightly associated with a battery of glycolytic genes, in which pyruvate kinase (PK) gene showed the strongest anti-correlation coefficient (Pearson r = -0.6938, p = <0.0001). In addition, reduced PK level was significantly associated with poor clinical outcomes of HCC patients. We found isoform M2 (PKM2) is the dominant form highly expressed in HCC and is a direct target of miR-122, as overexpression of miR-122 reduced both the mRNA and protein levels of PKM2, whereas PKM2 re-expression abrogated the miR-122-mediated glycolytic activities. The present study demonstrated the regulatory role of miR-122 on PKM2 in HCC, having an implication of therapeutic intervention targeting cancer metabolic pathways. PMID- 24466276 TI - Chromosome Y centromere array deletion leads to impaired centromere function. AB - The centromere is an essential chromosomal structure that is required for the faithful distribution of replicated chromosomes to daughter cells. Defects in the centromere can compromise the stability of chromosomes resulting in segregation errors. We have characterised the centromeric structure of the spontaneous mutant mouse strain, BALB/cWt, which exhibits a high rate of Y chromosome instability. The Y centromere DNA array shows a de novo interstitial deletion and a reduction in the level of the foundation centromere protein, CENP-A, when compared to the non-deleted centromere array in the progenitor strain. These results suggest there is a lower threshold limit of centromere size that ensures full kinetochore function during cell division. PMID- 24466277 TI - Flock house virus RNA polymerase initiates RNA synthesis de novo and possesses a terminal nucleotidyl transferase activity. AB - Flock House virus (FHV) is a positive-stranded RNA virus with a bipartite genome of RNAs, RNA1 and RNA2, and belongs to the family Nodaviridae. As the most extensively studied nodavirus, FHV has become a well-recognized model for studying various aspects of RNA virology, particularly viral RNA replication and antiviral innate immunity. FHV RNA1 encodes protein A, which is an RNA-dependent RNA polymerase (RdRP) and functions as the sole viral replicase protein responsible for RNA replication. Although the RNA replication of FHV has been studied in considerable detail, the mechanism employed by FHV protein A to initiate RNA synthesis has not been determined. In this study, we characterized the RdRP activity of FHV protein A in detail and revealed that it can initiate RNA synthesis via a de novo (primer-independent) mechanism. Moreover, we found that FHV protein A also possesses a terminal nucleotidyl transferase (TNTase) activity, which was able to restore the nucleotide loss at the 3'-end initiation site of RNA template to rescue RNA synthesis initiation in vitro, and may function as a rescue and protection mechanism to protect the 3' initiation site, and ensure the efficiency and accuracy of viral RNA synthesis. Altogether, our study establishes the de novo initiation mechanism of RdRP and the terminal rescue mechanism of TNTase for FHV protein A, and represents an important advance toward understanding FHV RNA replication. PMID- 24466278 TI - Predicting human protein subcellular locations by the ensemble of multiple predictors via protein-protein interaction network with edge clustering coefficients. AB - One of the fundamental tasks in biology is to identify the functions of all proteins to reveal the primary machinery of a cell. Knowledge of the subcellular locations of proteins will provide key hints to reveal their functions and to understand the intricate pathways that regulate biological processes at the cellular level. Protein subcellular location prediction has been extensively studied in the past two decades. A lot of methods have been developed based on protein primary sequences as well as protein-protein interaction network. In this paper, we propose to use the protein-protein interaction network as an infrastructure to integrate existing sequence based predictors. When predicting the subcellular locations of a given protein, not only the protein itself, but also all its interacting partners were considered. Unlike existing methods, our method requires neither the comprehensive knowledge of the protein-protein interaction network nor the experimentally annotated subcellular locations of most proteins in the protein-protein interaction network. Besides, our method can be used as a framework to integrate multiple predictors. Our method achieved 56% on human proteome in absolute-true rate, which is higher than the state-of-the art methods. PMID- 24466279 TI - Cloning and characterization of a 7 transmembrane receptor from the adherent cells of chicken peripheral blood mononuclear cells. AB - A cDNA encoding a 7 transmembrane (7TM) receptor gene from the adherent cells of chicken peripheral blood mononuclear cells (PBMC) was cloned and characterized. The open reading frame of the chicken-7TM (Ch-7TM) receptor gene was 1008 nucleotides long, encoding a protein of 335 amino acid residues with a molecular mass of approximately 37.1 kDa. Hydrophobic stretches indicated the presence of 7 TM domains. Moreover, the complete nucleotide sequences encoding 7TM of duck (Du 7TM) and goose (Go-7TM), corresponding to the open reading frame of Ch-7TM, were determined. Each of the Du- and Go-7TM encoding regions comprised 990 nucleotides, representing an 18-nucleotide deletion in alignment with the Ch-7TM encoding region, resulting in a 6-amino-acid deletion at the 3'-end. No signal peptides were predicted. Six phosphorylation sites were predicted and conserved for all three 7TMs. The proteins of the three 7TMs were similar, with 11 conserved cysteine residues. No glycosylation sites could be predicted. The results of the pairwise comparisons indicated that the Ch-7TM encoding region and Ch-7TM protein were the least similar to those of Du- and Go-7TMs. These results were in accordance with those of the phylogenetic analysis, which indicated that the Du- and Go-7TM encoding regions clustered, but were separated from the Ch-7TM encoding region. Monoclonal antibody B28D5 was prepared from spleens of mice immunized with the bacterially expressed N-terminal (55 amino acid residues) region of the Ch-7TM protein for further use. Double staining with B28D5 and KUL01 suggested that Ch-7TM was expressed in subsets of the adherent cells, among which a subset that was recognized with both antibodies was likely of monocyte and macrophage lineage. However, the fluorescence intensities of B28D5 and, particularly, KUL01 decreased after the adherent cells were incubated for additional 48 h. PMID- 24466281 TI - Simple patchy-based simulators used to explore pondscape systematic dynamics. AB - Thousands of farm ponds disappeared on the tableland in Taoyuan County, Taiwan since 1920s. The number of farm ponds that have disappeared is 1,895 (37%), 2,667 ponds remain (52%), and only 537 (11%) new ponds were created within a 757 km(2) area in Taoyuan, Taiwan between 1926 and 1960. In this study, a geographic information system (GIS) and logistic stepwise regression model were used to detect pond-loss rates and to understand the driving forces behind pondscape changes. The logistic stepwise regression model was used to develop a series of relationships between pondscapes affected by intrinsic driving forces (patch size, perimeter, and patch shape) and external driving forces (distance from the edge of the ponds to the edges of roads, rivers, and canals). The authors concluded that the loss of ponds was caused by pond intrinsic factors, such as pond perimeter; a large perimeter increases the chances of pond loss, but also increases the possibility of creating new ponds. However, a large perimeter is closely associated with circular shapes (lower value of the mean pond-patch fractal dimension [MPFD]), which characterize the majority of newly created ponds. The method used in this study might be helpful to those seeking to protect this unique landscape by enabling the monitoring of patch-loss problems by using simple patchy-based simulators. PMID- 24466280 TI - Use of the delta neutrophil index as a prognostic factor of mortality in patients with spontaneous bacterial peritonitis: implications of a simple and useful marker. AB - BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a common and life threatening infection in patients with advanced cirrhosis. The prognostic value of a novel marker, the delta neutrophil index (DNI), was investigated relative to mortality in patients with SBP. MATERIALS & METHODS: Seventy-five patients with SBP were studied from April 2010 to May 2012. DNI at initial diagnosis of SBP was determined and compared with 30-day mortality rates. RESULTS: Of the patients, 87.7% were men, and the median age of all patients was 59.0 yrs. The area under the receiver-operating characteristic (ROC) curve of DNI for 30-day mortality was 0.701 (95% confidence interval [CI], 0.553-0.849; p = 0.009), which was higher than that of C-reactive protein (0.640, 95% CI, 0.494-0.786; p = 0.076) or the model for end-stage liver disease score (0.592, 95% CI, 0.436-0.748; p = 0.235). From the ROC curve, with the sum of sensitivity and specificity, the cutoff value of DNI was determined to be 5.7%. In the high-DNI group (DNI >=5.7%), septic shock and 30-day mortality were more prevalent compared with the low-DNI group (84.2% vs. 48.2%, p = 0.007; 57.9% vs. 14.3%, p<0.001, respectively). Patients with an elevated DNI had a higher risk of 30-day mortality compared with those with a low DNI (4.225, 95% CI, 1.631-10.949; p = 0.003). CONCLUSION: A higher DNI at the time of SBP diagnosis is an independent predictor of 30-day mortality in patients with SBP. PMID- 24466282 TI - 4D-analysis of left ventricular heart cycle using procrustes motion analysis. AB - The aim of this study is to investigate human left ventricular heart morphological changes in time among 17 healthy subjects. Preliminarily, 2 patients with volumetric overload due to aortic insufficiency were added to our analyses. We propose a special strategy to compare the shape, orientation and size of cardiac cycle's morphological trajectories in time. We used 3D data obtained by Speckle Tracking Echocardiography in order to detect semi-automated and homologous landmarks clouds as proxies of left ventricular heart morphology. An extended Geometric Morphometrics toolkit in order to distinguish between intra and inter-individual shape variations was used. Shape of trajectories with inter individual variation were compared under the assumption that trajectories attributes, estimated at electrophysiologically homologous times are expressions of left ventricular heart function. We found that shape analysis as commonly applied in Geometric Morphometrics studies fails in identifying a proper morpho space to compare the shape of morphological trajectories in time. To overcome this problem, we performed a special type of Riemannian Parallel Transport, called "linear shift". Whereas the two patients with aortic insufficiency were not differentiated in the static shape analysis from the healthy subjects, they set apart significantly in the analyses of motion trajectory's shape and orientation. We found that in healthy subjects, the variations due to inter individual morphological differences were not related to shape and orientation of morphological trajectories. Principal Component Analysis showed that volumetric contraction, torsion and twist are differently distributed on different axes. Moreover, global shape change appeared to be more correlated with endocardial shape change than with the epicardial one. Finally, the total shape variation occurring among different subjects was significantly larger than that observable across properly defined morphological trajectories. PMID- 24466283 TI - ParABS system in chromosome partitioning in the bacterium Myxococcus xanthus. AB - Chromosome segregation is an essential cellular function in eukaryotic and prokaryotic cells. The ParABS system is a fundamental player for a mitosis-like process in chromosome partitioning in many bacterial species. This work shows that the social bacterium Myxococcus xanthus also uses the ParABS system for chromosome segregation. Its large prokaryotic genome of 9.1 Mb contains 22 parS sequences near the origin of replication, and it is shown here that M. xanthus ParB binds preferentially to a consensus parS sequence in vitro. ParB and ParA are essential for cell viability in M. xanthus as in Caulobacter crescentus, but unlike in many other bacteria. Absence of ParB results in anucleate cells, chromosome segregation defects and loss of viability. Analysis of ParA subcellular localization shows that it clusters at the poles in all cells, and in some, in the DNA-free cell division plane between two chromosomal DNA masses. This ParA localization pattern depends on ParB but not on FtsZ. ParB inhibits the nonspecific interaction of ParA with DNA, and ParA colocalizes with chromosomal DNA only when ParB is depleted. The subcellular localization of ParB suggests a single ParB-parS complex localized at the edge of the nucleoid, next to a polar ParA cluster, with a second ParB-parS complex migrating after the replication of parS takes place to the opposite nucleoid edge, next to the other polar ParA cluster. PMID- 24466284 TI - Platelet glycoproteins and fibrinogen in recovery from idiopathic sudden hearing loss. AB - BACKGROUND: The pathomechanism and location of idiopathic sudden sensorineural hearing loss (ISSHL) is unclear. In a previous case-control study, we found elevated fibrinogen concentrations and a higher prevalence of T allele carriers of the glycoprotein (Gp) Ia C807T polymorphism in ISSHL patients. METHODOLOGY: 127 patients with ISSHL (mean age 53.3 years, 48.8% females), who underwent a standard therapy with high dose steroids, pentoxifyllin and sterofundine over 8 days were included. We examined the influence of GpIa genotype and fibrinogen (BclI-, A312-, HaeIII-) genotype and fibrinogen plasma levels on hearing recovery after 8 weeks (change from baseline: 0 dB = no recovery, >0 to 10 dB = moderate recovery, >10 dB = good recovery). In a subsample of 59 patients with ISSHL, we further studied the association of platelet glycoprotein GpIa, Ib and IIIa densities on hearing recovery as well as the possible effect-modification of platelet glycoproteins on hearing recovery by plasma fibrinogen. RESULTS: In univariate analysis, neither the GpIa genotype nor fibrinogen genotype (all p>0.1) but lower fibrinogen levels (p = 0.029), less vertigo (p = 0.002) and lower GpIIIa receptor density (p = 0.037, n = 59) were associated with hearing recovery. In multivariate analysis, fibrinogen significantly modified the effect of GPIa receptor density on good hearing recovery (effect-modification on multiplicative scale OR = 0.45 (95% confidence interval (0.21-0.94)), p = 0.03). GPIb receptor density below the mean was associated with a 2-fold increase in good hearing recovery both in patients with fibrinogen levels above (p = 0.04) as well as in patients with fibrinogen levels below the mean (p = 0.06). There was no indication for an effect-modification (p = 0.97). CONCLUSIONS: The findings suggest a vascular/rheological origin of ISSHL with unique features of thrombosis in the inner ear artery that may include complex interrelationships among platelet glycoproteins and plasma fibrinogen. PMID- 24466285 TI - Soluble HIV-1 envelope immunogens derived from an elite neutralizer elicit cross reactive V1V2 antibodies and low potency neutralizing antibodies. AB - We evaluated four gp140 Envelope protein vaccine immunogens that were derived from an elite neutralizer, subject VC10042, whose plasma was able to potently neutralize a wide array of genetically distinct HIV-1 isolates. We sought to determine whether soluble Envelope proteins derived from the viruses circulating in VC10042 could be used as immunogens to elicit similar neutralizing antibody responses by vaccination. Each gp140 was tested in its trimeric and monomeric forms, and we evaluated two gp140 trimer vaccine regimens in which adjuvant was supplied at all four immunizations or at only the first two immunizations. Interestingly, all four Envelope immunogens elicited high titers of cross reactive antibodies that recognize the variable regions V1V2 and are potentially similar to antibodies linked with a reduced risk of HIV-1 acquisition in the RV144 vaccine trial. Two of the four immunogens elicited neutralizing antibody responses that neutralized a wide array of HIV-1 isolates from across genetic clades, but those responses were of very low potency. There were no significant differences in the responses elicited by trimers or monomers, nor was there a significant difference between the two adjuvant regimens. Our study identified two promising Envelope immunogens that elicited anti-V1V2 antibodies and broad, but low potency, neutralizing antibody responses. PMID- 24466286 TI - Resurgence of persisting non-cultivable Borrelia burgdorferi following antibiotic treatment in mice. AB - The agent of Lyme borreliosis, Borrelia burgdorferi, evades host immunity and establishes persistent infections in its varied mammalian hosts. This persistent biology may pose challenges to effective antibiotic treatment. Experimental studies in dogs, mice, and non-human primates have found persistence of B. burgdorferi DNA following treatment with a variety of antibiotics, but persisting spirochetes are non-cultivable. Persistence of B. burgdorferi DNA has been documented in humans following treatment, but the significance remains unknown. The present study utilized a ceftriaxone treatment regimen in the C3H mouse model that resulted in persistence of non-cultivable B. burgdorferi in order to determine their long-term fate, and to examine their effects on the host. Results confirmed previous studies, in which B. burgdorferi could not be cultured from tissues, but low copy numbers of B. burgdorferi flaB DNA were detectable in tissues at 2, 4 and 8 months after completion of treatment, and the rate of PCR positive tissues appeared to progressively decline over time. However, there was resurgence of spirochete flaB DNA in multiple tissues at 12 months, with flaB DNA copy levels nearly equivalent to those found in saline-treated mice. Despite the continued non-cultivable state, RNA transcription of multiple B. burgdorferi genes was detected in host tissues, flaB DNA was acquired by xenodiagnostic ticks, and spirochetal forms could be visualized within ticks and mouse tissues by immunofluorescence and immunohistochemistry, respectively. A number of host cytokines were up- or down-regulated in tissues of both saline- and antibiotic treated mice in the absence of histopathology, indicating host response to the presence of non-cultivable, despite the lack of inflammation in tissues. PMID- 24466287 TI - High-resolution satellite imagery is an important yet underutilized resource in conservation biology. AB - Technological advances and increasing availability of high-resolution satellite imagery offer the potential for more accurate land cover classifications and pattern analyses, which could greatly improve the detection and quantification of land cover change for conservation. Such remotely-sensed products, however, are often expensive and difficult to acquire, which prohibits or reduces their use. We tested whether imagery of high spatial resolution (<=5 m) differs from lower resolution imagery (>=30 m) in performance and extent of use for conservation applications. To assess performance, we classified land cover in a heterogeneous region of Interior Atlantic Forest in Paraguay, which has undergone recent and dramatic human-induced habitat loss and fragmentation. We used 4 m multispectral IKONOS and 30 m multispectral Landsat imagery and determined the extent to which resolution influenced the delineation of land cover classes and patch-level metrics. Higher-resolution imagery more accurately delineated cover classes, identified smaller patches, retained patch shape, and detected narrower, linear patches. To assess extent of use, we surveyed three conservation journals (Biological Conservation, Biotropica, Conservation Biology) and found limited application of high-resolution imagery in research, with only 26.8% of land cover studies analyzing satellite imagery, and of these studies only 10.4% used imagery <=5 m resolution. Our results suggest that high-resolution imagery is warranted yet under-utilized in conservation research, but is needed to adequately monitor and evaluate forest loss and conversion, and to delineate potentially important stepping-stone fragments that may serve as corridors in a human-modified landscape. Greater access to low-cost, multiband, high-resolution satellite imagery would therefore greatly facilitate conservation management and decision making. PMID- 24466288 TI - Association between air pollution and general outpatient clinic consultations for upper respiratory tract infections in Hong Kong. AB - BACKGROUND AND OBJECTIVES: Many studies have shown the adverse effects of air pollution on respiratory health, but few have examined the effects of air pollution on service utilisation in the primary care setting. The aim of this study was to examine the association between air pollution and the daily number of consultations due to upper respiratory tract infections (URTIs) in general outpatient clinics (GOPCs) in Hong Kong. METHODS: Daily data on the numbers of consultations due to URTIs in GOPCs, the concentrations of major air pollutants, and the mean values of metrological variables were retrospectively collected over a 3-year period (2008-2010, inclusive). Generalised additive models were constructed to examine the association between air pollution and the daily number of consultations, and to derive the relative risks and 95% confidence intervals (95% CI) of GOPC consultations for a unit increase in the concentrations of air pollutants. RESULTS: The mean daily consultations due to URTIs in GOPCs ranged from 68.4 to 253.0 over the study period. The summary relative risks (and 95% CI) of daily consultations in all GOPCs for the air pollutants PM10, NO2, O3, and SO2 were 1.005 (1.002, 1.009), 1.010 (1.006, 1.013), 1.009 (1.006, 1.012), and 1.004 (1.000, 1.008) respectively, per 10 ug/m(3) increase in the concentration of each pollutant. CONCLUSION: Significant associations were found between the daily number of consultations due to URTIs in GOPCs and the concentrations of air pollutants, implying that air pollution incurs a substantial morbidity and increases the burden of primary health care services. PMID- 24466289 TI - Gram-stain plus MALDI-TOF MS (Matrix-Assisted Laser Desorption Ionization-Time of Flight Mass Spectrometry) for a rapid diagnosis of urinary tract infection. AB - Microbiological confirmation of a urinary tract infection (UTI) takes 24-48 h. In the meantime, patients are usually given empirical antibiotics, sometimes inappropriately. We assessed the feasibility of sequentially performing a Gram stain and MALDI-TOF MS mass spectrometry (MS) on urine samples to anticipate clinically useful information. In May-June 2012, we randomly selected 1000 urine samples from patients with suspected UTI. All were Gram stained and those yielding bacteria of a single morphotype were processed for MALDI-TOF MS. Our sequential algorithm was correlated with the standard semiquantitative urine culture result as follows: Match, the information provided was anticipative of culture result; Minor error, the information provided was partially anticipative of culture result; Major error, the information provided was incorrect, potentially leading to inappropriate changes in antimicrobial therapy. A positive culture was obtained in 242/1000 samples. The Gram stain revealed a single morphotype in 207 samples, which were subjected to MALDI-TOF MS. The diagnostic performance of the Gram stain was: sensitivity (Se) 81.3%, specificity (Sp) 93.2%, positive predictive value (PPV) 81.3%, negative predictive value (NPV) 93.2%, positive likelihood ratio (+LR) 11.91, negative likelihood ratio (-LR) 0.20 and accuracy 90.0% while that of MALDI-TOF MS was: Se 79.2%, Sp 73.5, +LR 2.99, -LR 0.28 and accuracy 78.3%. The use of both techniques provided information anticipative of the culture result in 82.7% of cases, information with minor errors in 13.4% and information with major errors in 3.9%. Results were available within 1 h. Our serial algorithm provided information that was consistent or showed minor errors for 96.1% of urine samples from patients with suspected UTI. The clinical impacts of this rapid UTI diagnosis strategy need to be assessed through indicators of adequacy of treatment such as a reduced time to appropriate empirical treatment or earlier withdrawal of unnecessary antibiotics. PMID- 24466290 TI - Cerebellar abnormalities contribute to disability including cognitive impairment in multiple sclerosis. AB - The cerebellum is known to be involved not only in motor but also cognitive and affective processes. Structural changes in the cerebellum in relation to cognitive dysfunction are an emerging topic in the field of neuro-psychiatric disorders. In Multiple Sclerosis (MS) cerebellar motor and cognitive dysfunction occur in parallel, early in the onset of the disease, and the cerebellum is one of the predilection sites of atrophy. This study is aimed at determining the relationship between cerebellar volumes, clinical cerebellar signs, cognitive functioning and fatigue in MS. Cerebellar volumetry was conducted using T1 weighted MPRAGE magnetic resonance imaging of 172 MS patients. All patients underwent a clinical and brief neuropsychological assessment (information processing speed, working memory), including fatigue testing. Patients with and without cerebellar signs differed significantly regarding normalized cerebellar total volume (nTCV), normalized brain volume (nBV) and whole brain T2 lesion volume (LV). Patients with cerebellar dysfunction likewise performed worse in cognitive tests. A regression analysis indicated that age and nTCV explained 26.3% of the variance in SDMT (symbol digit modalities test) performance. However, only age, T2 LV and nBV remained predictors in the full model (r(2) = 0.36). The full model for the prediction of PASAT (Paced Auditory Serial Addition Test) scores (r(2) = 0.23) included age, cerebellar and T2 LV. In the case of fatigue, only age and nBV (r(2) = 0.17) emerged as significant predictors. These data support the view that cerebellar abnormalities contribute to disability, including cognitive impairment in MS. However, this contribution does not seem to be independent of, and may even be dominated by wider spread MS pathology as reflected by nBV and T2 LV. PMID- 24466291 TI - LABEL: fast and accurate lineage assignment with assessment of H5N1 and H9N2 influenza A hemagglutinins. AB - The evolutionary classification of influenza genes into lineages is a first step in understanding their molecular epidemiology and can inform the subsequent implementation of control measures. We introduce a novel approach called Lineage Assignment By Extended Learning (LABEL) to rapidly determine cladistic information for any number of genes without the need for time-consuming sequence alignment, phylogenetic tree construction, or manual annotation. Instead, LABEL relies on hidden Markov model profiles and support vector machine training to hierarchically classify gene sequences by their similarity to pre-defined lineages. We assessed LABEL by analyzing the annotated hemagglutinin genes of highly pathogenic (H5N1) and low pathogenicity (H9N2) avian influenza A viruses. Using the WHO/FAO/OIE H5N1 evolution working group nomenclature, the LABEL pipeline quickly and accurately identified the H5 lineages of uncharacterized sequences. Moreover, we developed an updated clade nomenclature for the H9 hemagglutinin gene and show a similarly fast and reliable phylogenetic assessment with LABEL. While this study was focused on hemagglutinin sequences, LABEL could be applied to the analysis of any gene and shows great potential to guide molecular epidemiology activities, accelerate database annotation, and provide a data sorting tool for other large-scale bioinformatic studies. PMID- 24466292 TI - Bone loss at implant with titanium abutments coated by soda lime glass containing silver nanoparticles: a histological study in the dog. AB - The aim of the present study was to evaluate bone loss at implants connected to abutments coated with a soda-lime glass containing silver nanoparticles, subjected to experimental peri-implantitis. Also the aging and erosion of the coating in mouth was studied. Five beagle dogs were used in the experiments. Three implants were placed in each mandible quadrant: in 2 of them, Glass/n-Ag coated abutments were connected to implant platform, 1 was covered with a Ti mechanized abutment. Experimental peri-implantitis was induced in all implants after the submarginal placement of cotton ligatures, and three months after animals were euthanatized. Thickness and morphology of coating was studied in abutment cross-sections by SEM. Histology and histo-morphometric studies were carried on in undecalfied ground slides. After the induced peri-implantitis: 1.The abutment coating shown losing of thickness and cracking. 2. The histometry showed a significant less bone loss in the implants with glass/n-Ag coated abutments. A more symmetric cone of bone resorption was observed in the coated group. There were no significant differences in the peri-implantitis histological characteristics between both groups of implants. Within the limits of this in vivo study, it could be affirmed that abutments coated with biocide soda-lime glass-silver nanoparticles can reduce bone loss in experimental peri-implantitis. This achievement makes this coating a suggestive material to control peri implantitis development and progression. PMID- 24466293 TI - Bilateral versus single internal mammary coronary artery bypass grafting in Sweden from 1997-2008. AB - BACKGROUND: Prior observational studies have suggested better outcomes in patients who receive bilateral internal mammary arteries (BIMA) during coronary artery bypass grafting (CABG) compared with patients who receive a single internal mammary artery (SIMA). The aim of this study was to analyze the association between BIMA use and long-term survival in patients who underwent primary isolated CABG. METHODS AND RESULTS: Patients who underwent primary isolated non-emergent CABG in Sweden between 1997 and 2008 were identified. The SWEDEHEART registry and other national Swedish registers were used to acquire information about patient characteristics and outcomes. Unadjusted and multivariable adjusted regression models were used to estimate the association between BIMA use and early mortality, long-term survival, and a composite of death from any cause or rehospitalization for myocardial infarction, heart failure, or stroke in the overall cohort and in a propensity score-matched cohort. The study population consisted of 49702 patients who underwent CABG with at least one internal mammary artery, and 559 (1%) of those had BIMA grafting. In the adjusted analyses, BIMA use was not associated with better survival compared with SIMA use in the overall cohort (hazard ratio (HR) for death: 1.16, 95% confidence interval (CI): 0.97 to 1.37) or in the matched cohort (HR: 1.04, 95% CI: 0.78 to 1.40). The results were similar for early mortality and the composite endpoint. Reoperation for sternal wound complications was more common among BIMA patients (odds ratio: 1.71, 95% CI: 1.01 to 2.88). CONCLUSIONS: BIMA grafting was performed infrequently and was not associated with better outcomes compared with SIMA grafting in patients undergoing non-emergent primary isolated CABG in Sweden during 1997-2008. PMID- 24466294 TI - Isolation and characterization of numerous novel phages targeting diverse strains of the ubiquitous and opportunistic pathogen Achromobacter xylosoxidans. AB - The clinical relevance of nosocomially acquired infections caused by multi resistant Achromobacter strains is rapidly increasing. Here, a diverse set of 61 Achromobacter xylosoxidans strains was characterized by MultiLocus Sequence Typing and Phenotype MicroArray technology. The strains were further analyzed in regard to their susceptibility to 35 antibiotics and to 34 different and newly isolated bacteriophages from the environment. A large proportion of strains were resistant against numerous antibiotics such as cephalosporines, aminoglycosides and quinolones, whereas piperacillin-tazobactam, ticarcillin, mezlocillin and imipenem were still inhibitory. We also present the first expanded study on bacteriophages of the genus Achromobacter that has been so far a blank slate with respect to phage research. The phages were isolated mainly from several waste water treatment plants in Germany. Morphological analysis of all of these phages by electron microscopy revealed a broad diversity with different members of the order Caudovirales, including the families Siphoviridae, Myoviridae, and Podoviridae. A broad spectrum of different host ranges could be determined for several phages that lysed up to 24 different and in part highly antibiotic resistant strains. Molecular characterisation by DNA restriction analysis revealed that all phages contain linear double-stranded DNA. Their restriction patterns display distinct differences underlining their broad diversity. PMID- 24466295 TI - Comparative analysis of alphaB-crystallin expression in heat-stressed myocardial cells in vivo and in vitro. AB - Relationships between alphaB-crystallin expression patterns and pathological changes of myocardial cells after heat stress were examined in vitro and in vivo in this study using the H9C2 cell line and Sprague-Dawley rats, respectively. Histopathological lesions, characterized by acute degeneration, karyopyknosis and loss of a defined nucleus, became more severe in rat hearts over the course of heat stress treatment from 20 min to 100 min. The expression of alphaB-crystallin in rat hearts showed a significant decrease (P<0.05) throughout the heat stress treatment period, except at the 40 min time point. Likewise, decreased alphaB crystallin expression was also observed in the H9C2 cell line exposed to a high temperature in vitro, although its expression recovered to normal levels at later time points (80 and 100 min) and the cellular damage was less severe. The results suggest that alphaB-crystallin is mobilized early after exposure to a high temperature to interact with damaged proteins but that the myocardial cells cannot produce sufficient alphaB-crystallin for protection against heat stress. Lower alphaB-crystallin expression levels were accompanied by obvious cell/tissue damage, suggesting that the abundance of this protein is associated with protective effects in myocardial cells in vitro and in vivo. Thus, alphaB crystallin is a potential biomarker of heat stress. PMID- 24466296 TI - Development of central nervous system autoimmunity is impaired in the absence of Wiskott-Aldrich syndrome protein. AB - Wiskott-Aldrich Syndrome protein (WASP) is a key regulator of the actin cytoskeleton in hematopoietic cells. Defective expression of WASP leads to multiple abnormalities in different hematopoietic cells. Despite severe impairment of T cell function, WAS patients exhibit a high prevalence of autoimmune disorders. We attempted to induce EAE, an animal model of organ specific autoimmunity affecting the CNS that mimics human MS, in Was(-/-) mice. We describe here that Was(-/-) mice are markedly resistant against EAE, showing lower incidence and milder score, reduced CNS inflammation and demyelination as compared to WT mice. Microglia was only poorly activated in Was(-/-) mice. Antigen-induced T-cell proliferation, Th-1 and -17 cytokine production and integrin-dependent adhesion were increased in Was(-/-) mice. However, adoptive transfer of MOG-activated T cells from Was(-/-) mice in WT mice failed to induce EAE. Was(-/-) mice were resistant against EAE also when induced by adoptive transfer of MOG-activated T cells from WT mice. Was(+/-) heterozygous mice developed an intermediate clinical phenotype between WT and Was(-/-) mice, and they displayed a mixed population of WASP-positive and -negative T cells in the periphery but not in their CNS parenchyma, where the large majority of inflammatory cells expressed WASP. In conclusion, in absence of WASP, T-cell responses against a CNS autoantigen are increased, but the ability of autoreactive T cells to induce CNS autoimmunity is impaired, most probably because of an inefficient T-cell transmigration into the CNS and defective CNS resident microglial function. PMID- 24466297 TI - Detection of circulating B cells producing anti-GPIb autoantibodies in patients with immune thrombocytopenia. AB - BACKGROUND: We previously reported that an enzyme-linked immunospot (ELISPOT) assay for detecting anti-GPIIb/IIIa antibody-secreting B cells is a sensitive method for identifying patients with immune thrombocytopenia (ITP). Here we assessed the clinical significance of measuring circulating B cells producing antibodies to GPIb, another major platelet autoantigen. METHODS: Anti-GPIb and anti-GPIIb/IIIa antibody-producing B cells were simultaneously measured using ELISPOT assays in 32 healthy controls and 226 consecutive thrombocytopenic patients, including 114 with primary ITP, 25 with systemic lupus erythematosus (SLE), 30 with liver cirrhosis, 39 with post-hematopoietic stem cell transplantation (post-HSCT), and 18 non-ITP controls (aplastic anemia and myelodysplastic syndrome). RESULTS: There were significantly more circulating anti-GPIb and anti-GPIIb/IIIa antibody-producing B cells in primary ITP, SLE, liver cirrhosis, and post-HSCT patients than in healthy controls (P<0.05 for all comparisons). For diagnosing primary ITP, the anti-GPIb ELISPOT assay had 43% sensitivity and 89% specificity, whereas the anti-GPIIb/IIIa ELISPOT assay had 86% sensitivity and 83% specificity. When two tests were combined, the sensitivity was slightly improved to 90% without a reduction in specificity. In primary ITP patients, the anti-GPIb antibody response was associated with a low platelet count, lack of Helicobacter pylori infection, positive anti-nuclear antibody, and poor therapeutic response to intravenous immunoglobulin. CONCLUSION: The ELISPOT assay for detecting anti-GPIb antibody-secreting B cells is useful for identifying patients with ITP, but its utility for diagnosing ITP is inferior to the anti-GPIIb/IIIa ELISPOT assay. Nevertheless, detection of the anti-GPIb antibody response is useful for subtyping patients with primary ITP. PMID- 24466298 TI - Mucosa-associated bacterial microbiome of the gastrointestinal tract of weaned pigs and dynamics linked to dietary calcium-phosphorus. AB - Dietary composition largely influences pig's gastrointestinal microbiota and represents a useful prophylactic tool against enteric disturbances in young pigs. Despite the importance for host-microbe interactions and bacterial colonization, dietary responses of the mucosa-associated bacterial communities are less well investigated. In the present study, we characterized the mucosa-associated bacterial communities at the Pars non-glandularis of the stomach, ileum and colon, and identified shifts in these communities in response to different dietary calcium-phosphorus (Ca-P) contents (100% versus 190% of the Ca and P requirements) in combination with two basal diets (wheat-barley- or corn-based) in weaned pigs. Pyrosequencing of 16S rRNA genes from 93 mucosal samples yielded 447,849 sequences, clustering into 997 operational taxonomic units (OTUs) at 97% similarity level. OTUs were assigned to 198 genera belonging to 14 different phyla. Correlation-based networks revealed strong interactions among OTUs at the various gastrointestinal sites. Our data describe a previously not reported high diversity and species richness at the Pars non-glandularis of the stomach in weaned pigs. Moreover, high versus adequate Ca-P content significantly promoted Lactobacillus by 14.9% units (1.4 fold change) at the gastric Pars non glandularis (P = 0.035). Discriminant analysis revealed dynamic changes in OTU composition in response to dietary cereals and Ca-P contents at all gastrointestinal sites which were less distinguishable at higher taxonomic levels. Overall, this study revealed a distinct mucosa-associated bacterial community at the different gut sites, and a strong effect of high Ca-P diets on the gastric community, thereby markedly expanding our comprehension on mucosa associated microbiota and their diet-related dynamics in weaned pigs. PMID- 24466299 TI - An Asp7Gly substitution in PPARG is associated with decreased transcriptional activation activity. AB - As the master regulator of adipogenesis, peroxisome proliferator-activated receptor gamma (PPARG) is required for the accumulation of adipose tissue and hence contributes to obesity. A previous study showed that the substitution of +20A>G in PPARG changed the 7(th) amino acid from Asp to Gly, creating a mutant referred to as PPARG Asp7Gly. In this study, association analysis indicated that PPARG Asp7Gly was associated with lower body height, body weight and heart girth in cattle (P<0.05). Overexpression of PPARG in NIH3T3-L1 cells showed that the Asp7Gly substitution may cause a decrease in its adipogenic ability and the mRNA levels of CIDEC (cell death-inducing DFFA-like effector c) and aP2, which are all transcriptionally activated by PPARG during adipocyte differentiation. A dual luciferase reporter assay was used to analyze the promoter activity of CIDEC. The results confirmed that the mutant PPARG exhibited weaker transcriptional activation activity than the wild type (P<0.05). These findings likely explain the associations between the Asp7Gly substitution and the body measurements. Additionally, the Asp7Gly mutation may be used in molecular marker assisted selection (MAS) of cattle breeding in the future. PMID- 24466300 TI - Mechanisms of the scaffold subunit in facilitating protein phosphatase 2A methylation. AB - The function of the biologically essential protein phosphatase 2A (PP2A) relies on formation of diverse heterotrimeric holoenzymes, which involves stable association between PP2A scaffold (A) and catalytic (C or PP2Ac) subunits and binding of variable regulatory subunits. Holoenzyme assembly is highly regulated by carboxyl methylation of PP2Ac-tail; methylation of PP2Ac and association of the A and C subunits are coupled to activation of PP2Ac. Here we showed that PP2A specific methyltransferase, LCMT-1, exhibits a higher activity toward the core enzyme (A-C heterodimer) than free PP2Ac, and the A-subunit facilitates PP2A methylation via three distinct mechanisms: 1) stabilization of a proper protein fold and an active conformation of PP2Ac; 2) limiting the space of PP2Ac-tail movement for enhanced entry into the LCMT-1 active site; and 3) weak electrostatic interactions between LCMT-1 and the N-terminal HEAT repeats of the A-subunit. Our results revealed a new function and novel mechanisms of the A subunit in PP2A methylation, and coherent control of PP2A activity, methylation, and holoenzyme assembly. PMID- 24466301 TI - Nonlinear dynamics analysis of a self-organizing recurrent neural network: chaos waning. AB - Self-organization is thought to play an important role in structuring nervous systems. It frequently arises as a consequence of plasticity mechanisms in neural networks: connectivity determines network dynamics which in turn feed back on network structure through various forms of plasticity. Recently, self-organizing recurrent neural network models (SORNs) have been shown to learn non-trivial structure in their inputs and to reproduce the experimentally observed statistics and fluctuations of synaptic connection strengths in cortex and hippocampus. However, the dynamics in these networks and how they change with network evolution are still poorly understood. Here we investigate the degree of chaos in SORNs by studying how the networks' self-organization changes their response to small perturbations. We study the effect of perturbations to the excitatory-to excitatory weight matrix on connection strengths and on unit activities. We find that the network dynamics, characterized by an estimate of the maximum Lyapunov exponent, becomes less chaotic during its self-organization, developing into a regime where only few perturbations become amplified. We also find that due to the mixing of discrete and (quasi-)continuous variables in SORNs, small perturbations to the synaptic weights may become amplified only after a substantial delay, a phenomenon we propose to call deferred chaos. PMID- 24466302 TI - Activation of duck RIG-I by TRIM25 is independent of anchored ubiquitin. AB - Retinoic acid inducible gene I (RIG-I) is a viral RNA sensor crucial in defense against several viruses including measles, influenza A and hepatitis C. RIG-I activates type-I interferon signalling through the adaptor for mitochondrial antiviral signaling (MAVS). The E3 ubiquitin ligase, tripartite motif containing protein 25 (TRIM25), activates human RIG-I through generation of anchored K63 linked polyubiquitin chains attached to lysine 172, or alternatively, through the generation of unanchored K63-linked polyubiquitin chains that interact non covalently with RIG-I CARD domains. Previously, we identified RIG-I of ducks, of interest because ducks are the host and natural reservoir of influenza viruses, and showed it initiates innate immune signaling leading to production of interferon-beta (IFN-beta). We noted that K172 is not conserved in RIG-I of ducks and other avian species, or mouse. Because K172 is important for both mechanisms of activation of human RIG-I, we investigated whether duck RIG-I was activated by TRIM25, and if other residues were the sites for attachment of ubiquitin. Here we show duck RIG-I CARD domains are ubiquitinated for activation, and ubiquitination depends on interaction with TRIM25, as a splice variant that cannot interact with TRIM25 is not ubiquitinated, and cannot be activated. We expressed GST-fusion proteins of duck CARD domains and characterized TRIM25 modifications of CARD domains by mass spectrometry. We identified two sites that are ubiquitinated in duck CARD domains, K167 and K193, and detected K63 linked polyubiquitin chains. Site directed mutagenesis of each site alone, does not alter the ubiquitination profile of the duck CARD domains. However, mutation of both sites resulted in loss of all attached ubiquitin and polyubiquitin chains. Remarkably, the double mutant duck RIG-I CARD still interacts with TRIM25, and can still be activated. Our results demonstrate that anchored ubiquitin chains are not necessary for TRIM25 activation of duck RIG-I. PMID- 24466303 TI - Association between fat mass- and obesity-associated (FTO) gene polymorphism and polycystic ovary syndrome: a meta-analysis. AB - AIMS: Many studies have investigated the relationship between FTO gene polymorphism and polycystic ovary syndrome (PCOS) susceptibility but revealed mixed results. In this study, we aimed to perform a meta-analysis to clarify this association. METHODS: Published literature from PubMed, Embase and CNKI was retrieved. Meta-analysis was performed to calculate pooled odds ratio (OR) with 95% confidence interval (CI) using the random- or fix- effects model. RESULTS: A total of 5 studies (4778 cases and 4272 controls) were included in our meta analysis. The results suggested that FTO rs9939609 polymorphism (or its proxy) was marginally associated with PCOS risk after adjustment for body mass index (BMI) (OR = 1.26; 95%CI: 1.02-1.55). However, the marginal association was not stable after sensitivity analysis. In the subgroup analysis by ethnicity, the association was significant in East Asians (OR = 1.43, 95%CI = 1.30-1.59) but not in Caucasians (OR = 1.04, 95%CI = 0.85-1.29). CONCLUSIONS: Our present meta analysis indicated that FTO rs9939609 polymorphism (or its proxy) might not be associated with risk of PCOS in overall population. However, in East Asians, there might be a direct association between FTO variant and PCOS risk, which is independent of BMI (adiposity). PMID- 24466304 TI - Sirtuin 1 (SIRT1) activation mediates sildenafil induced delayed cardioprotection against ischemia-reperfusion injury in mice. AB - BACKGROUND: It has been well documented that phosphodiesterase-5 inhibitor, sildenafil (SIL) protects against myocardial ischemia/reperfusion (I-R) injury. SIRT1 is part of the class III Sirtuin family of histone deacetylases that deacetylates proteins involved in cellular stress response including those related to I-R injury. OBJECTIVE/HYPOTHESIS: We tested the hypothesis that SIL induced cardioprotection may be mediated through activation of SIRT1. METHODS: Adult male ICR mice were treated with SIL (0.7 mg/kg, i.p.), Resveratrol (RSV, 5 mg/kg, a putative activator of SIRT1 used as the positive control), or saline (0.2 mL). The hearts were harvested 24 hours later and homogenized for SIRT1 activity analysis. RESULTS: Both SIL- and RSV-treated mice had increased cardiac SIRT1 activity (P<0.001) as compared to the saline-treated controls 24 hours after drug treatment. In isolated ventricular cardiomyocytes, pretreatment with SIL (1 uM) or RSV (1 uM) for one hour in vitro also upregulated SIRT1 activity (P<0.05). We further examined the causative relationship between SIRT1 activation and SIL-induced late cardioprotection. Pretreatment with SIL (or RSV) 24 hours prior to 30 min ischemia and 24 hours of reperfusion significantly reduced infarct size, which was associated with a significant increase in SIRT1 activity (P<0.05). Moreover, sirtinol (a SIRT1 inhibitor, 5 mg/kg, i.p.) given 30 min before I-R blunted the infarct-limiting effect of SIL and RSV (P<0.001). CONCLUSION: Our study shows that activation of SIRT1 following SIL treatment plays an essential role in mediating the SIL-induced cardioprotection against I-R injury. This newly identified SIRT1-activating property of SIL may have enormous therapeutic implications. PMID- 24466305 TI - Resveratrol inhibits cisplatin-induced epithelial-to-mesenchymal transition in ovarian cancer cell lines. AB - BACKGROUND: Many patients diagnosed with ovarian cancer experience recurrence and metastasis, two aspects that will often cause their demise. Epithelial-to mesenchymal transition (EMT) is a key process involved in cancer progression. With increasing evidence linking Cisplatin and EMT, we wanted to identify a compound able to counter EMT progression when cancer cells are treated with Cisplatin. METHODOLOGY/PRINCIPAL FINDINGS: Cell death was evaluated by cytometry with Annexin V/PI staining in A2780 and A2780CP cells. Ovarian cancer cell lines were treated with Cisplatin (24 h, 10 uM) and different concentrations of Resveratrol to evaluate its effect on Cisplatin-induced EMT using Western Blot and RT-PCR analysis. Morphological studies and wound healing assay to evaluate cell motility were performed using 72 h Cisplatin treatment with A2780 and A2780CP cells. Densitometry was done on Western Blot and PCR results, and statistical significance was determined using One-Way ANOVA followed by Tukey post-hoc test. Our results show that Cisplatin induced EMT-associated morphological changes in the A2780 ovarian cancer cell line and to a lesser extent in its Cisplatin-resistant counterpart A2780CP. Resveratrol caused cell death in A2780 and A2780CP cell lines in an apoptotic-independent manner. Resveratrol inhibited Cisplatin-induced Snail expression by reducing the Erk pathway activation, reverted morphological changes induced by Cisplatin and decreased cell migration. CONCLUSIONS: These results indicate that Resveratrol has interesting potential to prevent Cisplatin-induced EMT in ovarian cancer cells. By increasing cell death, it also represents an inviting approach as adjuvant therapy to be used with chemotherapy. Using Erk pathway inhibitors could also prove helpful in ovarian cancer treatment to reduce the risk of metastasis. PMID- 24466306 TI - Regulation of tyrosine phosphatase STEP61 by protein kinase A during motor skill learning in mice. AB - Recently, striatal-enriched protein tyrosine phosphatase (STEP) and its upstream regulator protein kinase A (PKA) have been suspected to play a role in the intracellular mechanisms of fear conditioning and spatial memory. However, whether they contribute to the learning and memory of motor skills is totally unknown. In this study, we have investigated the role of STEP and PKA activities during motor skill learning associated with the accelerating rotarod task. We observed that learning the rotarod task differentially modulated the levels of phosphorylated STEP61 at serine 221, a site directly regulated by PKA, in the hippocampus, motor cortex and striatum. In a second set of experiments, we have pharmacologically inhibited PKA by the injection of Rp-cAMPS directly into the dorsal striatum of mice before rotarod trainings. PKA phosphorylation of STEP prevents the dephosphorylation of STEP substrates, whereas inhibition of PKA promotes STEP activity. Striatal PKA inhibitions dose-dependently impaired mice performances on the accelerating rotarod task. General motor abilities testing revealed an intact motor control in mice treated with 5 and 20 ug of Rp-cAMPS, but not at the highest dose of 40 ug. This suggested that motor learning was selectively affected by PKA inhibition at lower doses. Most notably, striatal inhibition of PKA reduced the levels of phosphorylated STEP61 at serine 221. Our data support that inactivation of STEP61 by the PKA activity is part of the molecular process associated with motor skill learning. PMID- 24466307 TI - Expression and purification of chaperone-active recombinant clusterin. AB - Clusterin was the first described secreted mammalian chaperone and is implicated as being a key player in both intra- and extracellular proteostasis. Its unique combination of structural features and biological chaperone activity has, however, previously made it very challenging to express and purify the protein in a correctly processed and chaperone-active form. While there are multiple reports in the literature describing the use of recombinant clusterin, all of these reports suffer from one or more of the following shortcomings: details of the methods used to produce the protein are poorly described, the product is incompletely (if at all) characterised, and purity (if shown) is in many cases inadequate. The current report provides the first well validated method to economically produce pure chaperone-active recombinant clusterin. The method was developed after trialling expression in cultured bacterial, yeast, insect and mammalian cells, and involves the expression of recombinant clusterin from stably transfected HEK293 cells in protein-free medium. The product is expressed at between 7.5 and 10 ug/ml of culture, and is readily purified by a combination of immunoaffinity, cation exchange and size exclusion chromatography. The purified product was shown to be glycosylated, correctly proteolytically cleaved into alpha- and beta-subunits, and have chaperone activity similar to that of human plasma clusterin. This new method creates the opportunity to use mutagenesis and metabolic labelling approaches in future studies to delineate functionally important sites within clusterin, and also provides a theoretically unlimited supply of recombinant clusterin which may in the future find applications in the development of therapeutics. PMID- 24466308 TI - Metamorphosis of a butterfly-associated bacterial community. AB - Butterflies are charismatic insects that have long been a focus of biological research. They are also habitats for microorganisms, yet these microbial symbionts are little-studied, despite their likely importance to butterfly ecology and evolution. In particular, the diversity and composition of the microbial communities inhabiting adult butterflies remain uncharacterized, and it is unknown how the larval (caterpillar) and adult microbiota compare. To address these knowledge gaps, we used Illumina sequencing of 16S rRNA genes from internal bacterial communities associated with multiple life stages of the neotropical butterfly Heliconius erato. We found that the leaf-chewing larvae and nectar- and pollen-feeding adults of H. erato contain markedly distinct bacterial communities, a pattern presumably rooted in their distinct diets. Larvae and adult butterflies host relatively small and similar numbers of bacterial phylotypes, but few are common to both stages. The larval microbiota clearly simplifies and reorganizes during metamorphosis; thus, structural changes in a butterfly's bacterial community parallel those in its own morphology. We furthermore identify specific bacterial taxa that may mediate larval and adult feeding biology in Heliconius and other butterflies. Although male and female Heliconius adults differ in reproductive physiology and degree of pollen feeding, bacterial communities associated with H. erato are not sexually dimorphic. Lastly, we show that captive and wild individuals host different microbiota, a finding that may have important implications for the relevance of experimental studies using captive butterflies. PMID- 24466309 TI - Controlled administration of penicillamine reduces radiation exposure in critical organs during 64Cu-ATSM internal radiotherapy: a novel strategy for liver protection. AB - PURPOSE: (64)Cu-diacetyl-bis (N (4)-methylthiosemicarbazone) ((64)Cu-ATSM) is a promising theranostic agent that targets hypoxic regions in tumors related to malignant characteristics. Its diagnostic usefulness has been recognized in clinical studies. Internal radiotherapy (IRT) with (64)Cu-ATSM is reportedly effective in preclinical studies; however, for clinical applications, improvements to reduce radiation exposure in non-target organs, particularly the liver, are required. We developed a strategy to reduce radiation doses to critical organs while preserving tumor radiation doses by controlled administration of copper chelator penicillamine during (64)Cu-ATSM IRT. METHODS: Biodistribution was evaluated in HT-29 tumor-bearing mice injected with (64)Cu ATSM (185 kBq) with or without oral penicillamine administration. The appropriate injection interval between (64)Cu-ATSM and penicillamine was determined. Then, the optimal penicillamine administration schedule was selected from single (100, 300, and 500 mg/kg) and fractionated doses (100 mg/kg*3 at 1- or 2-h intervals from 1 h after (64)Cu-ATSM injection). PET imaging was performed to confirm the effect of penicillamine with a therapeutic (64)Cu-ATSM dose (37 MBq). Dosimetry analysis was performed to estimate human absorbed doses. RESULTS: Penicillamine reduced (64)Cu accumulation in the liver and small intestine. Tumor uptake was not affected by penicillamine administration at 1 h after (64)Cu-ATSM injection, when radioactivity was almost cleared from the blood and tumor uptake had plateaued. Of the single doses, 300 mg/kg was most effective. Fractionated administration at 2-h intervals further decreased liver accumulation at later time points. PET indicated that penicillamine acts similarly with the therapeutic (64)Cu-ATSM dose. Dosimetry demonstrated that appropriately scheduled penicillamine administration reduced radiation doses to critical organs (liver, ovaries, and red marrow) below tolerance levels. Laxatives reduced radiation doses to the large intestine. CONCLUSIONS: We developed a novel strategy to reduce radiation exposure in critical organs during (64)Cu-ATSM IRT, thus promoting its clinical applications. This method could be beneficial for other (64)Cu-labeled compounds. PMID- 24466310 TI - Regulation of MYC expression and differential JQ1 sensitivity in cancer cells. AB - High level MYC expression is associated with almost all human cancers. JQ1, a chemical compound that inhibits MYC expression is therapeutically effective in preclinical animal models in midline carcinoma, and Burkitt's lymphoma (BL). Here we show that JQ1 does not inhibit MYC expression to a similar extent in all tumor cells. The BL cells showed a ~90% decrease in MYC transcription upon treatment with JQ1, however, no corresponding reduction was seen in several non-BL cells. Molecularly, these differences appear due to requirements of Brd4, the most active version of the Positive Transcription Elongation Factor B (P-TEFb) within the Super Elongation Complex (SEC), and transcription factors such as Gdown1, and MED26 and also other unknown cell specific factors. Our study demonstrates that the regulation of high levels of MYC expression in different cancer cells is driven by unique regulatory mechanisms and that such exclusive regulatory signatures in each cancer cells could be employed for targeted therapeutics. PMID- 24466311 TI - Quantitative assessment of the influence of TP63 gene polymorphisms and lung cancer risk: evidence based on 93,751 subjects. AB - BACKGROUND: Several genome-wide association studies on lung cancer (LC) have reported similar findings of a new susceptibility locus, 3q28. After that, a number of studies reported that the rs10937405, and rs4488809 polymorphism in chromosome 3q28 has been implicated in LC risk. However, the studies have yielded contradictory results. METHODS: PubMed, ISI web of science, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between rs10937405, rs4488809 polymorphism at 3q28 and susceptibility to LC. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Heterogeneity and publication bias were also tested. RESULTS: A total of 9 studies including 35,961 LC cases and 57,790 controls were involved in this meta-analysis. An overall random-effects per-allele OR of1.19 (95% CI: 1.14-1.25; P<10(-5)) and 1.19 (95% CI: 1.13-1.25; P<10(-5)) was found for the rs10937405 and rs4488809 polymorphism respectively. Similar results were also observed using dominant or recessive genetic model. After stratified by ethnicity, significant associations were found among East Asians (per-allele OR = 1.22, 95% CI: 1.17-1.27; P<10(-5)); whereas no significant associations were found among Caucasians for rs10937405. In the sub group analysis by sample size, significantly increased risks were found for these polymorphisms in all genetic models. When analyzed according to histological type, the effects of rs10937405, and rs4488809 at 3q28 on the risk of lung cancer were significant mostly for lung adenocarcinoma. CONCLUSIONS: Our findings demonstrated that rs10937405-G allele and rs4488809-G allele might be risk conferring factors for the development of lung cancer, especially for East Asian populations. PMID- 24466312 TI - Schmallenberg virus circulation in culicoides in Belgium in 2012: field validation of a real time RT-PCR approach to assess virus replication and dissemination in midges. AB - Indigenous Culicoides biting midges are suggested to be putative vectors for the recently emerged Schmallenberg virus (SBV) based on SBV RNA detection in field caught midges. Furthermore, SBV replication and dissemination has been evidenced in C. sonorensis under laboratory conditions. After SBV had been detected in Culicoides biting midges from Belgium in August 2011, it spread all over the country by the end of 2011, as evidenced by very high between-herd seroprevalence rates in sheep and cattle. This study investigated if a renewed SBV circulation in midges occurred in 2012 in the context of high seroprevalence in the animal host population and evaluated if a recently proposed realtime RT-PCR approach that is meant to allow assessing the vector competence of Culicoides for SBV and bluetongue virus under laboratory conditions was applicable to field-caught midges. Therefore midges caught with 12 OVI traps in four different regions in Belgium between May and November 2012, were morphologically identified, age graded, pooled and tested for the presence of SBV RNA by realtime RT-PCR. The results demonstrate that although no SBV could be detected in nulliparous midges caught in May 2012, a renewed but short lived circulation of SBV in parous midges belonging to the subgenus Avaritia occured in August 2012 at all four regions. The infection prevalence reached up to 2.86% in the south of Belgium, the region where a lower seroprevalence was found at the end of 2011 than in the rest of the country. Furthermore, a frequency analysis of the Ct values obtained for 31 SBV-S segment positive pools of Avaritia midges showed a clear bimodal distribution with peaks of Ct values between 21-24 and 33-36. This closely resembles the laboratory results obtained for SBV infection of C. sonorensis and implicates indigenous midges belonging to the subgenus Avaritia as competent vectors for SBV. PMID- 24466313 TI - Toll-like receptor 9 signaling delays neutrophil apoptosis by increasing transcription of Mcl-1. AB - Neutrophils detect bacterial constituents, including bacterial DNA (CpG DNA), which elicits innate immunity and prolongs the functional life span of neutrophils through suppression of apoptosis. Both the anti-apoptotic protein Mcl 1 and activation of NF-kappaB have been implicated in neutrophil survival, but there is no evidence that these are linked in neutrophils. We hypothesized that CpG DNA could simultaneously activate these pathways. High purity CpG DNA (0.4 3.2 ug/ml) extended the life span of human neutrophils in vitro by delaying apoptosis through altering the rate of Mcl-1 turnover. CpG DNA slightly decreased Mcl-1 protein level in the presence of cyclohexmide and the proteasome inhibitor MG132 had little effect on Mcl-1 expression in CpG DNA-treated neutrophils. In contrast, CpG DNA evoked rapid increases in DNA binding by NF-kappaB/p65 and Mcl 1 mRNA. NF-kappaB inhibitors and the telomere-derived TLR9 inhibitory oligonucleotide 5'-TTT AGG GTT AGG GTT AGG G-3' markedly reduced Mcl-1 protein levels and subsequently abrogated suppression of apoptosis by CpG DNA. Furthermore, CpG DNA attenuated the decreases in Mcl-1 in both cell lysate and nucleus of neutrophils undergoing spontaneous apoptosis and increased Mcl-1 translocation to the mitochondria, leading to preservation of mitochondrial transmembrane potential. These results demonstrate that CpG DNA through toll-like receptor 9 links two survival signaling pathways by delaying apoptosis through induction of NF-kappaB-mediated Mcl-1 gene transcription and promoting Mcl-1 translocation to the mitochondria. PMID- 24466314 TI - Specific expression of DR5 promoter in rice roots using a tCUP derived promoter reporter system. AB - Variation of transgene expression caused by either position effect at the insertion site or the promoter/enhancer elements employed for the expression of selectable marker genes has complicated phenotype characterization and caused misinterpretation. We have developed a reporter system in rice to analyze the influence of vector configuration, spacer and selectable marker gene promoter on the expression of the promoterless GUS reporter and DR5 promoter. Our results indicate that a spacer inserted between the reversed 35S promoter and the GUS reporter could reduce leaky expression of the reporter but was unable to block the nonspecific expression of DR5::GUS. Stacking the selectable marker unit in head to tail with the GUS reporter aided the gene specific expression of the GUS reporter under the DR5 promoter even when the 35S promoter is used for expression of the selectable marker. Compared to 35S under this configuration, a quick and distinctive expression of DR5::GUS was observed in the root cap, quiescent center and xylem cells in the root apical meristem by using the tCUP derived promoter (tCUP1) for selection, that is similar to the pattern obtained by a sensitive DR5 variant (DR5rev) in Arabidopsis. These data suggest a conserved property of the tCUP promoter in preventing enhancer-promoter interactions in rice as it does in Arabidopsis, and also demonstrate that an analogous distal auxin maximum exists in roots of rice. Therefore, the tCUP promoter based selection system provides a new strategy for specific expression of transgenes in rice. PMID- 24466316 TI - Importance of the CEP215-pericentrin interaction for centrosome maturation during mitosis. AB - At the onset of mitosis, the centrosome undergoes maturation, which is characterized by a drastic expansion of the pericentriolar material (PCM) and a robust increase in microtubule-organizing activity. CEP215 is one of the major PCM components which accumulates at the centrosome during mitosis. The depletion phenotypes indicate that CEP215 is essential for centrosome maturation and bipolar spindle formation. Here, we performed a series of knockdown-rescue experiments to link the protein-protein interaction properties of CEP215 to its biological functions. The results showed that CEP215 and pericentrin, another major PCM component, is interdependent for their accumulation at the spindle poles during mitosis. As a result, The CEP215-pericentrin interaction is required for centrosome maturation and subsequent bipolar spindle formation during mitosis. On the other hand, CEP215 interaction with gamma-tubulin is dispensable for centrosome maturation. Our results provide an insight how PCM components are assembled to form a spindle pole during mitosis. PMID- 24466315 TI - Regulation of amyloid precursor protein processing by serotonin signaling. AB - Proteolytic processing of the amyloid precursor protein (APP) by the beta- and gamma-secretases releases the amyloid-beta peptide (Abeta), which deposits in senile plaques and contributes to the etiology of Alzheimer's disease (AD). The alpha-secretase cleaves APP in the Abeta peptide sequence to generate soluble APPalpha (sAPPalpha). Upregulation of alpha-secretase activity through the 5 hydroxytryptamine 4 (5-HT4) receptor has been shown to reduce Abeta production, amyloid plaque load and to improve cognitive impairment in transgenic mouse models of AD. Consequently, activation of 5-HT4 receptors following agonist stimulation is considered to be a therapeutic strategy for AD treatment; however, the signaling cascade involved in 5-HT4 receptor-stimulated proteolysis of APP remains to be determined. Here we used chemical and siRNA inhibition to identify the proteins which mediate 5-HT4d receptor-stimulated alpha-secretase activity in the SH-SY5Y human neuronal cell line. We show that G protein and Src dependent activation of phospholipase C are required for alpha-secretase activity, while, unexpectedly, adenylyl cyclase and cAMP are not involved. Further elucidation of the signaling pathway indicates that inositol triphosphate phosphorylation and casein kinase 2 activation is also a prerequisite for alpha-secretase activity. Our findings provide a novel route to explore the treatment of AD through 5-HT4 receptor-induced alpha-secretase activation. PMID- 24466317 TI - Effects of Escherichia coli subtilase cytotoxin and Shiga toxin 2 on primary cultures of human renal tubular epithelial cells. AB - Shiga toxin (Stx)-producing Escherichia coli (STEC) cause post-diarrhea Hemolytic Uremic Syndrome (HUS), which is the most common cause of acute renal failure in children in many parts of the world. Several non-O157 STEC strains also produce Subtilase cytotoxin (SubAB) that may contribute to HUS pathogenesis. The aim of the present work was to examine the cytotoxic effects of SubAB on primary cultures of human cortical renal tubular epithelial cells (HRTEC) and compare its effects with those produced by Shiga toxin type 2 (Stx2), in order to evaluate their contribution to renal injury in HUS. For this purpose, cell viability, proliferation rate, and apoptosis were assayed on HRTEC incubated with SubAB and/or Stx2 toxins. SubAB significantly reduced cell viability and cell proliferation rate, as well as stimulating cell apoptosis in HRTEC cultures in a time dependent manner. However, HRTEC cultures were significantly more sensitive to the cytotoxic effects of Stx2 than those produced by SubAB. No synergism was observed when HRTEC were co-incubated with both SubAB and Stx2. When HRTEC were incubated with the inactive SubAA272B toxin, results were similar to those in untreated control cells. Similar stimulation of apoptosis was observed in Vero cells incubated with SubAB or/and Stx2, compared to HRTEC. In conclusion, primary cultures of HRTEC are significantly sensitive to the cytotoxic effects of SubAB, although, in a lesser extent compared to Stx2. PMID- 24466318 TI - Non-Gaussian analysis of diffusion weighted imaging in head and neck at 3T: a pilot study in patients with nasopharyngeal carcinoma. AB - PURPOSE: To technically investigate the non-Gaussian diffusion of head and neck diffusion weighted imaging (DWI) at 3 Tesla and compare advanced non-Gaussian diffusion models, including diffusion kurtosis imaging (DKI), stretched exponential model (SEM), intravoxel incoherent motion (IVIM) and statistical model in the patients with nasopharyngeal carcinoma (NPC). MATERIALS AND METHODS: After ethics approval was granted, 16 patients with NPC were examined using DWI performed at 3T employing an extended b-value range from 0 to 1500 s/mm(2). DWI signals were fitted to the mono-exponential and non-Gaussian diffusion models on primary tumor, metastatic node, spinal cord and muscle. Non-Gaussian parameter maps were generated and compared to apparent diffusion coefficient (ADC) maps in NPC. RESULTS: Diffusion in NPC exhibited non-Gaussian behavior at the extended b value range. Non-Gaussian models achieved significantly better fitting of DWI signal than the mono-exponential model. Non-Gaussian diffusion coefficients were substantially different from mono-exponential ADC both in magnitude and histogram distribution. CONCLUSION: Non-Gaussian diffusivity in head and neck tissues and NPC lesions could be assessed by using non-Gaussian diffusion models. Non Gaussian DWI analysis may reveal additional tissue properties beyond ADC and holds potentials to be used as a complementary tool for NPC characterization. PMID- 24466319 TI - The antidepressant 5-HT2A receptor antagonists pizotifen and cyproheptadine inhibit serotonin-enhanced platelet function. AB - There is considerable interest in defining new agents or targets for antithrombotic purposes. The 5-HT2A receptor is a G-protein coupled receptor (GPCR) expressed on many cell types, and a known therapeutic target for many disease states. This serotonin receptor is also known to regulate platelet function. Thus, in our FDA-approved drug repurposing efforts, we investigated the antiplatelet activity of cyproheptadine and pizotifen, two antidepressant 5-HT2A Receptor antagonists. Our results revealed that cyproheptadine and pizotifen reversed serotonin-enhanced ADP-induced platelet aggregation in vitro and ex vivo. And the inhibitory effects of these two agents were found to be similar to that of EMD 281014, a 5-HT2A Receptor antagonist under development. In separate experiments, our studies revealed that these 5-HT2A receptor antagonists have the capacity to reduce serotonin-enhanced ADP-induced elevation in intracellular calcium levels and tyrosine phosphorylation. Using flow cytometry, we also observed that cyproheptadine, pizotifen, and EMD 281014 inhibited serotonin enhanced ADP-induced phosphatidylserine (PS) exposure, P-selectin expression, and glycoprotein IIb-IIIa activation. Furthermore, using a carotid artery thrombosis model, these agents prolonged the time for thrombotic occlusion in mice in vivo. Finally, the tail-bleeding time was investigated to assess the effect of cyproheptadine and pizotifen on hemostasis. Our findings indicated prolonged bleeding time in both cyproheptadine- and pizotifen-treated mice. Notably, the increases in occlusion and bleeding times associated with these two agents were comparable to that of EMD 281014, and to clopidogrel, a commonly used antiplatelet drug, again, in a fashion comparable to clopidogrel and EMD 281014. Collectively, our data indicate that the antidepressant 5-HT2A antagonists, cyproheptadine and pizotifen do exert antiplatelet and thromboprotective effects, but similar to clopidogrel and EMD 281014, their use may interfere with normal hemostasis. PMID- 24466320 TI - Over-expression of TRESK K(+) channels reduces the excitability of trigeminal ganglion nociceptors. AB - TWIK-related spinal cord K(+) (TRESK) channel is abundantly expressed in trigeminal ganglion (TG) and dorsal root ganglion neurons and is one of the major background K(+) channels in primary afferent neurons. Mutations in TRESK channels are associated with familial and sporadic migraine. In rats, both chronic nerve injury and inflammation alter the expression level of TRESK mRNA. Functional studies indicate that reduction of endogenous TRESK channel activity results in hyper-excitation of primary afferent neurons, suggesting that TRESK is a potential target for the development of new analgesics. However, whether and how enhancing TRESK channel activity would decrease the excitability of primary afferent neurons has not been directly tested. Here, we over-expressed TRESK subunits in cultured mouse TG neurons by lipofectamine-mediated transfection and investigated how this altered the membrane properties and the excitability of the small-diameter TG population. To account for the heterogeneity of neurons, we further divided small TG neurons into two groups, based on their ability to bind to fluorescently-labeled isolectin B (IB4). The transfected TG neurons showed a 2 fold increase in the level of TRESK proteins. This was accompanied by a significant increase in the fraction of lamotrigine-sensitive persistent K(+) currents as well as the size of total background K(+) currents. Consequently, both IB4-positive and IB4-negative TG neurons over-expressing TRESK subunits exhibited a lower input resistance and a 2-fold increase in the current threshold for action potential initiation. IB4-negative TG neurons over-expressing TRESK subunits also showed a significant reduction of the spike frequency in response to supra-threshold stimuli. Importantly, an increase in TRESK channel activity effectively inhibited capsaicin-evoked spikes in TG neurons. Taken together, our results suggest that potent and specific TRESK channel openers likely would reduce the excitability of primary afferent neurons and therefore are potential therapeutics for the treatment of migraine and other chronic pain symptoms. PMID- 24466321 TI - Tumor vasculature-targeted recombinant mutated human TNF-alpha enhanced the antitumor activity of doxorubicin by increasing tumor vessel permeability in mouse xenograft models. AB - OBJECTIVE: Increasing evidence suggests that, when used in combination, tumor necrosis factor-alpha (TNF-alpha) synergizes with traditional chemotherapeutic drugs to exert a heightened antitumor effect. The present study investigated the antitumor efficacy of recombinant mutated human TNF-alpha specifically targeted to the tumor vasculature (RGD-rmhTNF-alpha) combined with the chemotherapeutic agent doxorubicin in 2 murine allografted tumor models. METHODS: Mice bearing hepatoma or sarcoma allografted tumors were treated with various doses of RGD rmhTNF-alpha alone or in combination with doxorubicin (2 mg/kg). We then evaluated tumor growth and tumor vessel permeability as well as intratumoral levels of RGD-rmhTNF-alpha and doxorubicin. RESULTS: RGD-rmhTNF-alpha treatment enhanced the permeability of the tumor vessels and increased intratumoral doxorubicin levels. In addition, intratumoral RGD-rmhTNF-alpha levels were significantly higher than that of rmhTNF-alpha. In both of the tested tumor models, administering RGD-rmhTNF-alpha in combination with doxorubicin resulted in an enhanced antitumor response compared to either treatment alone. Double agent combination treatment of doxorubicin with 50,000 IU/kg RGD-rmhTNF-alpha induced stronger antitumor effects on H22 allografted tumor-bearing mice than the single doxorubicin agent alone. Moreover, doxorubicin with 10,000 IU/kg RGD rmhTNF-alpha synergized to inhibit tumor growth in S180 allografted tumor-bearing mice. CONCLUSIONS: These results suggest that targeted delivery of low doses of RGD-rmhTNF-alpha into the tumor vasculature increases the antitumor efficacy of chemotherapeutic drugs. PMID- 24466322 TI - Human liver cell trafficking mutants: characterization and whole exome sequencing. AB - The HuH7 liver cell mutant Trf1 is defective in membrane trafficking and is complemented by the casein kinase 2alpha subunit CK2alpha''. Here we identify characteristic morphologies, trafficking and mutational changes in six additional HuH7 mutants Trf2-Trf7. Trf1 cells were previously shown to be severely defective in gap junction functions. Using a Lucifer yellow transfer assay, remarkable attenuation of gap junction communication was revealed in each of the mutants Trf2-Trf7. Electron microscopy and light microscopy of thiamine pyrophosphatase showed that several mutants exhibited fragmented Golgi apparatus cisternae compared to parental HuH7 cells. Intracellular trafficking was investigated using assays of transferrin endocytosis and recycling and VSV G secretion. Surface binding of transferrin was reduced in all six Trf2-Trf7 mutants, which generally correlated with the degree of reduced expression of the transferrin receptor at the cell surface. The mutants displayed the same transferrin influx rates as HuH7, and for efflux rate, only Trf6 differed, having a slower transferrin efflux rate than HuH7. The kinetics of VSV G transport along the exocytic pathway were altered in Trf2 and Trf5 mutants. Genetic changes unique to particular Trf mutants were identified by exome sequencing, and one was investigated in depth. The novel mutation Ile34Phe in the GTPase RAB22A was identified in Trf4. RNA interference knockdown of RAB22A or overexpression of RAB22AI34F in HuH7 cells caused phenotypic changes characteristic of the Trf4 mutant. In addition, the Ile34Phe mutation reduced both guanine nucleotide binding and hydrolysis activities of RAB22A. Thus, the RAB22A Ile34Phe mutation appears to contribute to the Trf4 mutant phenotype. PMID- 24466323 TI - Are immigrants and nationals born to immigrants at higher risk for delayed or no lifetime breast and cervical cancer screening? The results from a population based survey in Paris metropolitan area in 2010. AB - OBJECTIVES: This study aims to compare breast cancer screening (BCS) and cervical cancer screening (CCS) practices of French women born to French parents with those of immigrants and nationals born to immigrants, taking their socioeconomic status into account. METHODS: The study is based on data collected in 2010 in the Paris metropolitan area among a representative sample of 3000 French-speaking adults. For women with no history of breast or cervical cancer, multivariate logistic regressions and structural equation models were used to investigate the factors associated with never having undergone BCS or CCS. RESULTS: We confirmed the existence of a strong gradient, with respect to migration origin, for delaying or never having undergone BCS or CCS. Thus, being a foreign immigrant or being French of immigrant parentage were risk factors for delayed and no lifetime screening. Interestingly, we found that this gradient persisted (at least partially) after adjusting for the women's socioeconomic characteristics. Only the level of income seemed to play a mediating role, but only partially. We observed differences between BCS and CCS which suggest that organized CCS could be effective in reducing socioeconomic and/or ethnic inequities. CONCLUSION: Socioeconomic status partially explained the screening nonparticipation on the part of French women of immigrant origin and foreign immigrants. This was more so the case with CCS than with BCS, which suggests that organized prevention programs might reduce social inequalities. PMID- 24466324 TI - Activation of p38/JNK pathway is responsible for embelin induced apoptosis in lung cancer cells: transitional role of reactive oxygen species. AB - The natural product embelin has been demonstrated to possess a wide range of therapeutic properties, however, the mechanisms by which it exerts anticancer effects are not yet clear. By monitoring the molecular changes associated during early apoptotic phase, we have identified the crucial role of oxidative stress induced MAP kinase signalling as a predominant mechanism for its anticancer effects. Treatment of A549 lung cancer cells with embelin resulted in the enhancement of phospho-p38 and phospho-JNK levels as early as 4h. Pretreatment of cells with specific inhibitors of p38 (PD169316) and JNK (SP600125) abrogated embelin-induced caspase-3 activation. Studies employing embelin in the presence or absence of specific MAP kinase inhibitors indicated that the observed changes in phosphorylation levels of p38, JNK and ERK 1/2 are solely due to embelin and not because of cross-talk between MAP kinases. Reactive oxygen species (ROS) play a crucial role in embelin induced alterations in MAP kinase phosphorylation and apoptosis as pretreatment of cells with FeTMPyP mitigated this effect. The observed changes are not due to the inhibitory effect of embelin on XIAP as cells treated with SMAC-N7-Ant peptide, a specific inhibitor of XIAP's BIR3 domain did not mimic embelin induced apoptotic effects. The findings of the present study clearly indicate the crucial role of p38 and JNK pathways in embelin induced apoptosis and provide us with new clues for improving its therapeutic efficacy. PMID- 24466325 TI - TRAIL/DR5 signaling promotes macrophage foam cell formation by modulating scavenger receptor expression. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/Apo2L) has been shown to have protective effects against atherosclerosis. However, whether TRAIL has any effects on expression of macrophage scavenger receptors and lipid uptake has not yet been studied. Macrophage lines RAW264.7 and THP-1, and mouse primary peritoneal macrophages, were cultured in vitro and treated with recombinant human TRAIL. Real-time PCR and western blot were performed to measure mRNA and protein expressions. Foam cell formation was assessed by internalization of acetylated and oxidized low-density lipoproteins (LDL). Apoptosis was measured by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. We found that TRAIL treatment increased expression of scavenger receptor (SR)-AI and SR-BI in a time- and dose-dependent manner, and this effect was accompanied by increased foam cell formation. These effects of TRAIL were abolished by a TRAIL neutralizing antibody or in DR5 receptor-deficient macrophages. The increased LDL uptake by TRAIL was blocked by SR-AI gene silencing or the SR-AI inhibitor poly(I:C), while SR-BI blockade with BLT-1 had no effect. TRAIL-induced SR-AI expression was blocked by the inhibitor of p38 mitogen-activated protein kinase, but not by inhibitors of ERK1/2 or JNK. TRAIL also induced apoptosis in macrophages. In contrast to macrophages, TRAIL showed little effects on SR expression or apoptosis in vascular smooth muscle cells. In conclusion, our results demonstrate that TRAIL promotes macrophage lipid uptake via SR-AI upregulation through activation of the p38 pathway. PMID- 24466326 TI - Anti-oxidative effects of Rooibos tea (Aspalathus linearis) on immobilization induced oxidative stress in rat brain. AB - Exposure to chronic psychological stress may be related to increased reactive oxygen species (ROS) or free radicals, and thus, long-term exposure to high levels of oxidative stress may cause the accumulation of oxidative damage and eventually lead to many neurodegenerative diseases. Compared with other organs, the brain appears especially susceptible to excessive oxidative stress due to its high demand for oxygen. In the case of excessive ROS production, endogenous defense mechanisms against ROS may not be sufficient to suppress ROS-associated oxidative damage. Dietary antioxidants have been shown to protect neurons against a variety of experimental neurodegenerative conditions. In particular, Rooibos tea might be a good source of antioxidants due to its larger proportion of polyphenolic compounds. An optimal animal model for stress should show the features of a stress response and should be able to mimic natural stress progression. However, most animal models of stress, such as cold-restraint, electric foot shock, and burn shock, usually involve physical abuse in addition to the psychological aspects of stress. Animals subjected to chronic restraint or immobilization are widely believed to be a convenient and reliable model to mimic psychological stress. Therefore, in the present study, we propose that immobilization-induced oxidative stress was significantly attenuated by treatment with Rooibos tea. This conclusion is demonstrated by Rooibos tea's ability to (i) reverse the increase in stress-related metabolites (5-HIAA and FFA), (ii) prevent lipid peroxidation (LPO), (iii) restore stress-induced protein degradation (PD), (iv) regulate glutathione metabolism (GSH and GSH/GSSG ratio), and (v) modulate changes in the activities of antioxidant enzymes (SOD and CAT). PMID- 24466328 TI - Pitch and timbre interfere when both are parametrically varied. AB - Pitch and timbre perception are both based on the frequency content of sound, but previous perceptual experiments have disagreed about whether these two dimensions are processed independently from each other. We tested the interaction of pitch and timbre variations using sequential comparisons of sound pairs. Listeners judged whether two sequential sounds were identical along the dimension of either pitch or timbre, while the perceptual distances along both dimensions were parametrically manipulated. Pitch and timbre variations perceptually interfered with each other and the degree of interference was modulated by the magnitude of changes along the un-attended dimension. These results show that pitch and timbre are not orthogonal to each other when both are assessed with parametrically controlled variations. PMID- 24466327 TI - Novel analogue of colchicine induces selective pro-death autophagy and necrosis in human cancer cells. AB - Colchicine, a natural product of Colchicum autumnae currently used for gout treatment, is a tubulin targeting compound which inhibits microtubule formation by targeting fast dividing cells. This tubulin-targeting property has lead researchers to investigate the potential of colchicine and analogs as possible cancer therapies. One major study conducted on an analogue of allocolchicine, ZD 6126, was halted in phase 2 clinical trials due to severe cardio-toxicity associated with treatment. This study involves the development and testing of novel allocolchicine analogues that hold non-toxic anti-cancer properties. Currently we have synthesized and evaluated the anti-cancer activities of two analogues; N-acetyl-O-methylcolchinol (NSC 51046 or NCME), which is structurally similar to ZD 6126, and (S)-3,8,9,10-tetramethoxyallocolchicine (Green 1), which is a novel derivative of allocolchicine that is isomeric in the A ring. NSC 51046 was found to be non-selective as it induced apoptosis in both BxPC-3 and PANC-1 pancreatic cancer cells and in normal human fibroblasts. Interestingly, we found that Green 1 was able to modestly induce pro-death autophagy in these pancreatic cancer cells and E6-1 leukemia cells but not in normal human fibroblasts. Unlike colchicine and NSC 51046, Green 1 does not appear to affect tubulin polymerization indicating that it has a different molecular target. Green 1 also caused increased reactive oxygen species (ROS) production in mitochondria isolated from pancreatic cancer cells. Furthermore, in vivo studies revealed that Green 1 was well tolerated in mice. Our findings suggest that a small change in the structure of colchicine has apparently changed the mechanism of action and lead to improved selectivity. This may lead to better selective treatments in cancer therapy. PMID- 24466329 TI - Fibroblasts from type 1 diabetics exhibit enhanced Ca(2+) mobilization after TNF or fat exposure. AB - The effects of cytokine and fatty acid treatment on signal transduction in dermal fibroblasts from type 1 diabetics and matched controls were compared. Chronic exposure to TNF, accentuated Ca(2+) mobilization in response to bradykinin (BK) in cells from both controls and diabetics; responses were three-fold greater in cells from diabetics than in controls. Similarly, with chronic exposure to IL 1beta, BK-induced Ca(2+) mobilization was accentuated in cells from type 1 diabetics compared to the controls. Pretreatment with the protein synthesis inhibitor cycloheximide or the protein kinase C inhibitor calphostin C prior to the addition of TNF completely abrogated the TNF-induced increment in peak bradykinin response. Ca(2+) transients induced by depleting endoplasmic reticulum (ER) Ca(2+) with thapsigargin were also greater in TNF treated fibroblasts than in untreated cells, with greater increases in cells from diabetics. Exposing fibroblasts for 48 hours to 2 mM oleate also increased both the peak bradykinin response and the TNF-induced increment in peak response, which were significantly greater in diabetics than controls. These data indicate that cells from diabetic patients acquire elevated ER Ca(2+) stores in response to both cytokines and free fatty acids,and thus exhibit greater sensitivity to environmental inflammatory stimuli and elevated lipids. PMID- 24466330 TI - Reassessment of the psychometric characteristics and factor structure of the 'Perceived Stress Questionnaire' (PSQ): analysis in a sample of dental students. AB - BACKGROUND: The training to become a dentist can create psychological distress. The present study evaluates the structure of the 'Perceived Stress Questionnaire' (PSQ), its internal consistency model and interrelatedness with burnout, anxiety, depression and resilience among dental students. METHODS: The study employed a cross-sectional design. A sample of Spanish dental students (n = 314) completed the PSQ, the 'Goldberg Anxiety and Depression Scale' (GADS), 'Connor-Davidson Resilience Scale' (10-item CD-RISC) and 'Maslach Burnout Inventory-Student Survey' (MBI-SS). The structure was estimated using Parallel Analysis from polychoric correlations. Unweighted Least Squares was the method for factor extraction, using the Item Response Theory to evaluate the discriminative power of items. Internal consistency was assessed by squaring the correlation between the latent true variable and the observed variable. The relationships between the PSQ and the other constructs were analysed using Spearman's coefficient. RESULTS: The results showed a PSQ structure through two sub-factors ('frustration' and 'tenseness') with regard to one general factor ('perceived stress'). Items that did not satisfy discriminative capacity were rejected. The model fit were acceptable (GFI = 0.98; RSMR = 0.06; AGFI = 0.98; NFI = 0.98; RFI = 0.98). All the factors showed adequate internal consistency as measured by the congeneric model (>=0.91). High and significant associations were observed between perceived stress and burnout, anxiety, depression and resilience. CONCLUSIONS: The PSQ showed a hierarchical bi-factor structure among Spanish dental students. Using the questionnaire as a uni-dimensional scale may be useful in perceived stress level discrimination, while the sub-factors could help us to refine perceived stress analysis and improve therapeutic processes. PMID- 24466332 TI - Mapping cold-water coral habitats at different scales within the Northern Ionian Sea (Central Mediterranean): an assessment of coral coverage and associated vulnerability. AB - In this study, we mapped the distribution of Cold-Water Coral (CWC) habitats on the northern Ionian Margin (Mediterranean Sea), with an emphasis on assessing coral coverage at various spatial scales over an area of 2,000 km(2) between 120 and 1,400 m of water depth. Our work made use of a set of data obtained from ship based research surveys. Multi-scale seafloor mapping data, video inspections, and previous results from sediment samples were integrated and analyzed using Geographic Information System (GIS)-based tools. Results obtained from the application of spatial and textural analytical techniques to acoustic meso-scale maps (i.e. a Digital Terrain Model (DTM) of the seafloor at a 40 m grid cell size and associated terrain parameters) and large-scale maps (i.e. Side-Scan Sonar (SSS) mosaics of 1 m in resolution ground-truthed using underwater video observations) were integrated and revealed that, at the meso-scale level, the main morphological pattern (i.e. the aggregation of mound-like features) associated with CWC habitat occurrences was widespread over a total area of 600 km(2). Single coral mounds were isolated from the DTM and represented the geomorphic proxies used to model coral distributions within the investigated area. Coral mounds spanned a total area of 68 km(2) where different coral facies (characterized using video analyses and mapped on SSS mosaics) represent the dominant macro-habitat. We also mapped and classified anthropogenic threats that were identifiable within the examined videos, and, here, discuss their relationship to the mapped distribution of coral habitats and mounds. The combined results (from multi-scale habitat mapping and observations of the distribution of anthropogenic threats) provide the first quantitative assessment of CWC coverage for a Mediterranean province and document the relevant role of seafloor geomorphology in influencing habitat vulnerability to different types of human pressures. PMID- 24466331 TI - Pre- and neonatal exposure to lipopolysaccharide or the enteric metabolite, propionic acid, alters development and behavior in adolescent rats in a sexually dimorphic manner. AB - Alterations in the composition of the gut microbiome and/or immune system function may have a role in the development of autism spectrum disorders (ASD). The current study examined the effects of prenatal and early life administration of lipopolysaccharide (LPS), a bacterial mimetic, and the short chain fatty acid, propionic acid (PPA), a metabolic fermentation product of enteric bacteria, on developmental milestones, locomotor activity, and anxiety-like behavior in adolescent male and female offspring. Pregnant Long-Evans rats were subcutaneously injected once a day with PPA (500 mg/kg) on gestation days G12-16, LPS (50 ug/kg) on G15-16, or vehicle control on G12-16 or G15-16. Male and female offspring were injected with PPA (500 mg/kg) or vehicle twice a day, every second day from postnatal days (P) 10-18. Physical milestones and reflexes were monitored in early life with prenatal PPA and LPS inducing delays in eye opening. Locomotor activity and anxiety were assessed in adolescence (P40-42) in the elevated plus maze (EPM) and open-field. Prenatal and postnatal treatments altered behavior in a sex-specific manner. Prenatal PPA decreased time spent in the centre of the open-field in males and females while prenatal and postnatal PPA increased anxiety behavior on the EPM in female rats. Prenatal LPS did not significantly influence those behaviors. Evidence for the double hit hypothesis was seen as females receiving a double hit of PPA (prenatal and postnatal) displayed increased repetitive behavior in the open-field. These results provide evidence for the hypothesis that by-products of enteric bacteria metabolism such as PPA may contribute to ASD, altering development and behavior in adolescent rats similar to that observed in ASD and other neurodevelopmental disorders. PMID- 24466333 TI - Enigma prevents Cbl-c-mediated ubiquitination and degradation of RETMEN2A. AB - The Cbl proteins (Cbl, Cbl-b, and Cbl-c) are a highly conserved family of RING finger ubiquitin ligases (E3s) that function as negative regulators of tyrosine kinases in a wide variety of signal transduction pathways. In this study, we identify a new Cbl-c interacting protein, Enigma (PDLIM7). This interaction is specific to Cbl-c as Enigma fails to bind either of its closely related homologues, Cbl and Cbl-b. The binding between Enigma and Cbl-c is mediated through the LIM domains of Enigma as removal of all three LIM domains abrogates this interaction, while only LIM1 is sufficient for binding. Here we show that Cbl-c binds wild-type and MEN2A isoforms of the receptor tyrosine kinase, RET, and that Cbl-c enhances ubiquitination and degradation of activated RET. Enigma blocks Cbl-c-mediated RETMEN2A ubiquitination and degradation. Cbl-c decreased downstream ERK activation by RETMEN2A and co-expression of Enigma blocked the Cbl c-mediated decrease in ERK activation. Enigma showed no detectable effect on Cbl c-mediated ubiquitination of activated EGFR suggesting that this effect is specific to RET. Through mapping studies, we show that Cbl-c and Enigma bind RETMEN2A at different residues. However, binding of Enigma to RETMENA prevents Cbl-c recruitment to RETMEN2A. Consistent with these biochemical data, exploratory analyses of breast cancer patients with high expression of RET suggest that high expression of Cbl-c correlates with a good outcome, and high expression of Enigma correlates with a poor outcome. Together, these data demonstrate that Cbl-c can ubiquitinate and downregulate RETMEN2A and implicate Enigma as a positive regulator of RETMEN2A through blocking of Cbl-mediated ubiquitination and degradation. PMID- 24466334 TI - Eye movements discriminate fatigue due to chronotypical factors and time spent on task--a double dissociation. AB - Systematic differences in circadian rhythmicity are thought to be a substantial factor determining inter-individual differences in fatigue and cognitive performance. The synchronicity effect (when time of testing coincides with the respective circadian peak period) seems to play an important role. Eye movements have been shown to be a reliable indicator of fatigue due to sleep deprivation or time spent on cognitive tasks. However, eye movements have not been used so far to investigate the circadian synchronicity effect and the resulting differences in fatigue. The aim of the present study was to assess how different oculomotor parameters in a free visual exploration task are influenced by: a) fatigue due to chronotypical factors (being a 'morning type' or an 'evening type'); b) fatigue due to the time spent on task. Eighteen healthy participants performed a free visual exploration task of naturalistic pictures while their eye movements were recorded. The task was performed twice, once at their optimal and once at their non-optimal time of the day. Moreover, participants rated their subjective fatigue. The non-optimal time of the day triggered a significant and stable increase in the mean visual fixation duration during the free visual exploration task for both chronotypes. The increase in the mean visual fixation duration correlated with the difference in subjectively perceived fatigue at optimal and non-optimal times of the day. Conversely, the mean saccadic speed significantly and progressively decreased throughout the duration of the task, but was not influenced by the optimal or non-optimal time of the day for both chronotypes. The results suggest that different oculomotor parameters are discriminative for fatigue due to different sources. A decrease in saccadic speed seems to reflect fatigue due to time spent on task, whereas an increase in mean fixation duration a lack of synchronicity between chronotype and time of the day. PMID- 24466335 TI - Sampling strategies in antimicrobial resistance monitoring: evaluating how precision and sensitivity vary with the number of animals sampled per farm. AB - Because antimicrobial resistance in food-producing animals is a major public health concern, many countries have implemented antimicrobial monitoring systems at a national level. When designing a sampling scheme for antimicrobial resistance monitoring, it is necessary to consider both cost effectiveness and statistical plausibility. In this study, we examined how sampling scheme precision and sensitivity can vary with the number of animals sampled from each farm, while keeping the overall sample size constant to avoid additional sampling costs. Five sampling strategies were investigated. These employed 1, 2, 3, 4 or 6 animal samples per farm, with a total of 12 animals sampled in each strategy. A total of 1,500 Escherichia coli isolates from 300 fattening pigs on 30 farms were tested for resistance against 12 antimicrobials. The performance of each sampling strategy was evaluated by bootstrap resampling from the observational data. In the bootstrapping procedure, farms, animals, and isolates were selected randomly with replacement, and a total of 10,000 replications were conducted. For each antimicrobial, we observed that the standard deviation and 2.5-97.5 percentile interval of resistance prevalence were smallest in the sampling strategy that employed 1 animal per farm. The proportion of bootstrap samples that included at least 1 isolate with resistance was also evaluated as an indicator of the sensitivity of the sampling strategy to previously unidentified antimicrobial resistance. The proportion was greatest with 1 sample per farm and decreased with larger samples per farm. We concluded that when the total number of samples is pre-specified, the most precise and sensitive sampling strategy involves collecting 1 sample per farm. PMID- 24466336 TI - Ubiquitin-specific peptidase 22, a histone deubiquitinating enzyme, is a novel poor prognostic factor for salivary adenoid cystic carcinoma. AB - Salivary Adenoid Cystic Carcinoma (SACC) is characterized by a high rate of local recurrence and infiltration, strong invasion to peripheral nerves or late distant metastasis. Our aim was to investigate the expression of Ubiquitin-specific protease 22 (USP22) in SACC patients and its possible relationship to the outcome of the disease. A total of 135 SACC tissues and adjacent non-cancerous tissues which were diagnosed between 2002 and 2007 were enrolled in this study. Immunohistochemistry was used to compare the expression pattern of USP22 in SACC and adjacent non-cancerous groups, and the prognostic significance was assessed by Kaplan-Meier analysis and Cox proportional hazards regression in SACC patients. The rate of high expression of USP22 was significantly higher in SACC group than that in adjacent non-cancerous group. High expression of USP22 was significantly correlated with histological subtype, lymph node metastasis, grade, Ki-67 and SOX2 expression. Furthermore, USP22 acts as an oncogene by regulation the BMI-1 pathway and c-Myc pathway. SACC patients with high USP22 expression showed the poorer overall survival (OS) and disease-free survival (DFS) than those patients with low USP22 expression. In multivariate analysis, only lymph node metastasis and USP22 expression were the independent prognostic factors for OS and DFS in SACC. Our study provides evidence that USP22 expression is an independent prognostic factor for SACC patients. PMID- 24466337 TI - Disruptive colouration and perceptual grouping. AB - Camouflage is the primary defence of many animals and includes multiple strategies that interfere with figure-ground segmentation and object recognition. While matching background colours and textures is widespread and conceptually straightforward, less well explored are the optical 'tricks', collectively called disruptive colouration, that exploit perceptual grouping mechanisms. Adjacent high contrast colours create false edges, but this is not sufficient for an object's shape to be broken up; some colours must blend with the background. We test the novel hypothesis that this will be particularly effective when the colour patches on the animal appear to belong to, not merely different background colours, but different background objects. We used computer-based experiments where human participants had to find cryptic targets on artificial backgrounds. Creating what appeared to be bi-coloured foreground objects on bi-coloured backgrounds, we generated colour boundaries that had identical local contrast but either lay within or between (illusory) objects. As predicted, error rates for targets matching what appeared to be different background objects were higher than for targets which had otherwise identical local contrast to the background but appeared to belong to single background objects. This provides evidence for disruptive colouration interfering with higher-level feature integration in addition to previously demonstrated low-level effects involving contour detection. In addition, detection was impeded in treatments where targets were on or in close proximity to multiple background colour or tone boundaries. This is consistent with other studies which show a deleterious influence of visual 'clutter' or background complexity on search. PMID- 24466338 TI - Unilateral auditory cortex lesions impair or improve discrimination learning of amplitude modulated sounds, depending on lesion side. AB - A fundamental principle of brain organization is bilateral symmetry of structures and functions. For spatial sensory and motor information processing, this organization is generally plausible subserving orientation and coordination of a bilaterally symmetric body. However, breaking of the symmetry principle is often seen for functions that depend on convergent information processing and lateralized output control, e.g. left hemispheric dominance for the linguistic speech system. Conversely, a subtle splitting of functions into hemispheres may occur if peripheral information from symmetric sense organs is partly redundant, e.g. auditory pattern recognition, and therefore allows central conceptualizations of complex stimuli from different feature viewpoints, as demonstrated e.g. for hemispheric analysis of frequency modulations in auditory cortex (AC) of mammals including humans. Here we demonstrate that discrimination learning of rapidly but not of slowly amplitude modulated tones is non-uniformly distributed across both hemispheres: While unilateral ablation of left AC in gerbils leads to impairment of normal discrimination learning of rapid amplitude modulations, right side ablations lead to improvement over normal learning. These results point to a rivalry interaction between both ACs in the intact brain where the right side competes with and weakens learning capability maximally attainable by the dominant left side alone. PMID- 24466339 TI - High incidence of diabetes after stroke in young adults and risk of recurrent vascular events: the FUTURE study. AB - BACKGROUND: Diabetes diagnosed prior to stroke in young adults is strongly associated with recurrent vascular events. The relevance of impaired fasting glucose (IFG) and incidence of diabetes after young stroke is unknown. We investigated the long-term incidence of diabetes after young stroke and evaluated the association of diabetes and impaired fasting glucose with recurrent vascular events. METHODS: This study was part of the FUTURE study. All consecutive patients between January 1, 1980, and November 1, 2010 with TIA or ischemic stroke, aged 18-50, were recruited. A follow-up assessment was performed in survivors between November 1, 2009 and January 1, 2012 and included an evaluation for diabetes, fasting venous plasma glucose and recurrent vascular events. The association of diabetes and IFG with recurrent vascular events was assessed by logistic regression analysis, adjusted for age, sex and follow-up duration. RESULTS: 427 survivors without a medical history of diabetes were included in the present analysis (mean follow-up of 10.1 (SD 8.4) years; age 40.3 (SD 7.9) years). The incidence rate of diabetes was 7.9 per 1000 person-years and the prevalence of IFG was 21.1%. Patients with diabetes and IFG were more likely to have experienced any vascular event than those with normal fasting glucose values (OR 3.5 (95%CI 1.5-8.4) for diabetes and OR 2.5 (95%CI 1.3-4.8) for IFG). CONCLUSIONS: Diabetes or IFG in young stroke survivors is frequent and is associated with recurrent vascular events. Regular screening for IFG and diabetes in this population, yields potential for secondary prevention. PMID- 24466340 TI - Histone deacetylase inhibitors selectively target homology dependent DNA repair defective cells and elevate non-homologous endjoining activity. AB - BACKGROUND: We have previously used the ATAD5-luciferase high-throughput screening assay to identify genotoxic compounds with potential chemotherapeutic capabilities. The successful identification of known genotoxic agents, including the histone deacetylase inhibitor (HDACi) trichostatin A (TSA), confirmed the specificity of the screen since TSA has been widely studied for its ability to cause apoptosis in cancer cells. Because many cancers have acquired mutations in DNA damage checkpoints or repair pathways, we hypothesized that these cancers may be susceptible to treatments that target compensatory pathways. Here, we used a panel of isogenic chicken DT40 B lymphocyte mutant and human cell lines to investigate the ability of TSA to define selective pathways that promote HDACi toxicity. RESULTS: HDACi induced a DNA damage response and reduced viability in all repair deficient DT40 mutants although ATM-nulls were least affected. The most dramatic sensitivity was observed in mutants lacking the homology dependent repair (HDR) factor BLM or the non-homologous end-joining (NHEJ) and HDR factors, KU/RAD54, suggesting an involvement of either HDR or NHEJ in HDACi-induced cell death. To extend these findings, we measured the frequencies of HDR and NHEJ after HDACi treatment and monitored viability in human cell lines comparably deficient in HDR or NHEJ. Although no difference in HDR frequency was observed between HDACi treated and untreated cells, HDR-defective human cell lines were clearly more sensitive than wild type. Unexpectedly, cells treated with HDACis showed a significantly elevated NHEJ frequency. CONCLUSIONS: HDACi targeting drugs induced significant increases in NHEJ activity in human cell lines but did not alter HDR frequency. Moreover, HDR is required for cellular resistance to HDACi therapy; therefore, NHEJ does not appear to be a critical axis for HDACi resistance. Rather, HDACi compounds induced DNA damage, most likely double strand breaks (DSBs), and HDR proficiency is correlated with cell survival. PMID- 24466342 TI - Molecular mechanisms of exopolysaccharide from Aphanothece halaphytica (EPSAH) induced apoptosis in HeLa cells. AB - The present study aims to investigate the pharmacological effect of the exopolysaccharides from Aphanothece halophytica GR02 (EPSAH) on the HeLa human cervical cancer cell line. HeLa cells were cultured in RPMI-1640-10% FBS medium containing with or without different concentrations of EPSAH. Cell viability was assessed by methylthiazol tetrazolium (MTT) assay. Cell apoptosis was elevated with Wright-Giemsa staining, AO/EB double staining, and DNA fragmentation assay. Apoptosis-associated molecules from cultured HeLa cells were quantified using Western blot analysis. Our results suggest that EPASH induces apoptosis in HeLa cells by targeting a master unfolded protein response (UPR) regulator Grp78. Grp78 further promotes the expression of CHOP and downregulates expression of survivin, which leads to activate mitochondria-mediated downstream molecules and p53-survivin pathway, resulting in caspase-3 activation and causing apoptosis. These findings provide important clues for further evaluating the potential potency of EPSAH for use in cancer therapy. PMID- 24466341 TI - Nrf1 and Nrf2 transcription factors regulate androgen receptor transactivation in prostate cancer cells. AB - Despite androgen deprivation therapy (ADT), persistent androgen receptor (AR) signaling enables outgrowth of castration resistant prostate cancer (CRPC). In prostate cancer (PCa) cells, ADT may enhance AR activity through induction of oxidative stress. Herein, we investigated the roles of Nrf1 and Nrf2, transcription factors that regulate antioxidant gene expression, on hormone mediated AR transactivation using a syngeneic in vitro model of androgen dependent (LNCaP) and castration resistant (C4-2B) PCa cells. Dihydrotestosterone (DHT) stimulated transactivation of the androgen response element (ARE) was significantly greater in C4-2B cells than in LNCaP cells. DHT-induced AR transactivation was coupled with higher nuclear translocation of p65-Nrf1 in C4 2B cells, as compared to LNCaP cells. Conversely, DHT stimulation suppressed total Nrf2 levels in C4-2B cells but elevated total Nrf2 levels in LNCaP cells. Interestingly, siRNA mediated silencing of Nrf1 attenuated AR transactivation while p65-Nrf1 overexpression enhanced AR transactivation. Subsequent studies showed that Nrf1 physically interacts with AR and enhances AR's DNA-binding activity, suggesting that the p65-Nrf1 isoform is a potential AR coactivator. In contrast, Nrf2 suppressed AR-mediated transactivation by stimulating the nuclear accumulation of the p120-Nrf1 which suppressed AR transactivation. Quantitative RT-PCR studies further validated the inductive effects of p65-Nrf1 isoform on the androgen regulated genes, PSA and TMPRSS2. Therefore, our findings implicate differential roles of Nrf1 and Nrf2 in regulating AR transactivation in PCa cells. Our findings also indicate that the DHT-stimulated increase in p65-Nrf1 and the simultaneous suppression of both Nrf2 and p120-Nrf1 ultimately facilitates AR transactivation in CRPC cells. PMID- 24466343 TI - Regulation of eukaryotic initiation factor 4AII by MyoD during murine myogenic cell differentiation. AB - Gene expression during muscle cell differentiation is tightly regulated at multiple levels, including translation initiation. The PI3K/mTOR signalling pathway exerts control over protein synthesis by regulating assembly of eukaryotic initiation factor (eIF) 4F, a heterotrimeric complex that stimulates recruitment of ribosomes to mRNA templates. One of the subunits of eIF4F, eIF4A, supplies essential helicase function during this phase of translation. The presence of two cellular eIF4A isoforms, eIF4AI and eIF4AII, has long thought to impart equivalent functions to eIF4F. However, recent experiments have alluded to distinct activities between them. Herein, we characterize distinct regulatory mechanisms between the eIF4A isoforms during muscle cell differentiation. We find that eIF4AI levels decrease during differentiation whereas eIF4AII levels increase during myofiber formation in a MyoD-dependent manner. This study characterizes a previously undefined mechanism for eIF4AII regulation in differentiation and highlights functional differences between eIF4AI and eIF4AII. Finally, RNAi-mediated alterations in eIF4AI and eIF4AII levels indicate that the myogenic process can tolerate short term reductions in eIF4AI or eIF4AII levels, but not both. PMID- 24466344 TI - NADPH oxidase 4 deficiency reduces aquaporin-2 mRNA expression in cultured renal collecting duct principal cells via increased PDE3 and PDE4 activity. AB - The final control of renal water reabsorption occurs in the collecting duct (CD) and relies on regulated expression of aquaporin-2 (AQP2) in principal CD cells. AQP2 transcription is primarily induced by type 2 vasopressin receptor (V2R)-cAMP protein kinase A (PKA) signaling but also by other factors, including TonEBP and NF-kappaB. NAPDH oxidase 4 (NOX4) represents a major source of reactive oxygen species (ROS) in the kidney. Because NOX-derived ROS may alter PKA, TonEBP and NF kappaB activity, we examined the effects of NOX4 depletion on AQP2 expression. Depleted NOX4 expression by siRNA (siNOX4) in mpkCCDcl4 cells attenuated increased AQP2 mRNA expression by arginine vasopressin (AVP) but not by hypertonicity, which induces both TonEBP and NF-kappaB activity. AVP-induced AQP2 expression was similarly decreased by the flavoprotein inhibitor diphenyleneiodonium. siNOX4 altered neither TonEBP nor NF-kappaB activity but attenuated AVP-inducible cellular cAMP concentration, PKA activity and CREB phosphorylation as well as AQP2 mRNA expression induced by forskolin, a potent activator of adenylate cyclase. The repressive effect of siNOX4 on AVP-induced AQP2 mRNA expression was abolished by the non-selective phosphodiesterase (PDE) inhibitor 3-isobutyl-1-methylxanthine (IBMX) and was significantly decreased by selective PDE antagonists cilostamide and rolipram, but not vinpocetine, which respectively target PDE3, PDE4 and PDE1. Thus, by inhibiting PDE3 and PDE4 activity NOX4-derived ROS may contribute to V2R-cAMP-PKA signaling and enhance AQP2 transcription. PMID- 24466346 TI - Hydrogen sulfide offers neuroprotection on traumatic brain injury in parallel with reduced apoptosis and autophagy in mice. AB - Hydrogen sulfide (H2S), a novel gaseous mediator, has been recognized as an important neuromodulator and neuroprotective agent in the central nervous system. The present study was undertaken to study the effects of exogenous H2S on traumatic brain injury (TBI) and the underlying mechanisms. The effects of exogenous H2S on TBI were examined by using measurement of brain edema, behavior assessment, propidium iodide (PI) staining, and Western blotting, respectively. Compared to TBI groups, H2S pretreatment had reduced brain edema, improved motor performance and ameliorated performance in Morris water maze test after TBI. Immunoblotting results showed that H2S pretreatment reversed TBI-induced cleavage of caspase-3 and decline of Bcl-2, suppressed LC3-II, Beclin-1 and Vps34 activation and maintained p62 level in injured cortex and hippocampus post TBI. The results suggest a protective effect and therapeutic potential of H2S in the treatment of brain injury and the protective effect against TBI may be associated with regulating apoptosis and autophagy. PMID- 24466345 TI - A novel immunomodulatory hemocyanin from the limpet Fissurella latimarginata promotes potent anti-tumor activity in melanoma. AB - Hemocyanins, the huge oxygen-transporting glycoproteins of some mollusks, are used as immunomodulatory proteins with proven anti-cancer properties. The biodiversity of hemocyanins has promoted interest in identifying new anti-cancer candidates with improved immunological properties. Hemocyanins promote Th1 responses without known side effects, which make them ideal for long-term sustained treatment of cancer. In this study, we evaluated a novel hemocyanin from the limpet/gastropod Fissurella latimarginata (FLH). This protein has the typical hollow, cylindrical structure of other known hemocyanins, such as the keyhole limpet hemocyanin (KLH) and the Concholepas hemocyanin (CCH). FLH, like the KLH isoforms, is composed of a single type of polypeptide with exposed N- and O-linked oligosaccharides. However, its immunogenicity was significantly greater than that of KLH and CCH, as FLH induced a stronger humoral immune response and had more potent anti-tumor activity, delaying tumor growth and increasing the survival of mice challenged with B16F10 melanoma cells, in prophylactic and therapeutic settings. Additionally, FLH-treated mice demonstrated increased IFN gamma production and higher numbers of tumor-infiltrating CD4(+) lymphocytes. Furthermore, in vitro assays demonstrated that FLH, but not CCH or KLH, stimulated the rapid production of pro-inflammatory cytokines (IL-6, IL-12, IL-23 and TNF-alpha) by dendritic cells, triggering a pro-inflammatory milieu that may explain its enhanced immunological activity. Moreover, this effect was abolished when deglycosylated FLH was used, suggesting that carbohydrates play a crucial role in the innate immune recognition of this protein. Altogether, our data demonstrate that FLH possesses increased anti-tumor activity in part because it activates a more potent innate immune response in comparison to other known hemocyanins. In conclusion, FLH is a potential new marine adjuvant for immunization and possible cancer immunotherapy. PMID- 24466347 TI - Inhibitory effects of Japanese herbal medicines sho-saiko-to and juzen-taiho-to on nonalcoholic steatohepatitis in mice. AB - Although Japanese herbal medicines (JHMs) are widely used in Japan, only a few studies have investigated their effects on nonalcoholic steatohepatitis (NASH). In the present study, we examined the effect of 4 kinds of JHMs [sho-saiko-to (TJ 9), inchin-ko-to (TJ-135), juzen-taiho-to (TJ-48), and keishi-bukuryo-gan (TJ 25)] on a mouse model of NASH. Db/db mice were divided into 6 groups: control diet (control), methionine- and choline-deficient diet (MCD), and MCD diet supplemented with TJ-9, TJ-135, TJ-48, and TJ-25 (TJ-9, TJ-135, TJ-48, and TJ-25, respectively). All mice were sacrificed after 4 weeks of treatment, and biochemical, pathological, and molecular analyses were performed. Serum alanine aminotransferase levels and liver histology, including necroinflammation and fibrosis, were significantly alleviated in the TJ-9 and TJ-48 groups compared with the MCD group. The expression level of transforming growth factor (TGF) beta1 mRNA in the liver was significantly suppressed by TJ-48. Although the differences were not statistically significant, the expression levels of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 were lower, and those of peroxisome proliferators-activated receptor (PPAR)gamma were higher in the TJ-9 and/or TJ-48 groups than in the MCD group. Similarly, even though the results were not statistically significant, malondialdehyde levels in liver tissues were lower in the TJ-9 and TJ-48 groups than in the MCD group. We showed that JHMs, especially TJ-9 and TJ-48, inhibited the necroinflammation and fibrosis in the liver of a mouse model of NASH, even though the mechanisms were not fully elucidated. Further studies are needed in the future to investigate the possibility of clinical application of these medicines in the treatment for NASH. PMID- 24466348 TI - Characterization of the staphylococcal cassette chromosome composite island of Staphylococcus haemolyticus SH32, a methicillin-resistant clinical isolate from China. AB - Staphylococcal cassette chromosome (SCC) elements contribute considerably to virulence and resistance to antibiotic agents in staphylococci. SCC elements in coagulase-negative staphylococci (CoNS) are highly diverse and there is evidence suggesting that they serve as a reservoir for antibiotic resistance genes in methicillin-resistant Staphylococcus aureus (MRSA). However, only a small number of SCC elements have been characterized in CoNS and their exact roles in the emergence and evolution of MRSA remain to be demonstrated. Here, we determined the structure of an SCC composite island (CISH32) found in the clinical Staphylococcus haemolyticus isolate SH32 by whole-genome DNA sequencing. CISH32 was 48 kb in length and mainly composed of two imperfect SCC elements, namely (i) a PsiSCCmec(SH32) part containing a class C1 mec gene complex but lacking ccr genes and (ii) a SCCSH32 part with a ccrA5B3 gene complex but lacking mec genes. In addition, CISH32 contained a type III restriction-modification system and several resistance loci, for example genes conferring resistance to cadmium and arsenic. PsiSCCmec(SH32) is almost entirely identical to a pseudo SCCmec element found in S. haemolyticus WCH1 and shares pronounced sequence similarity to a PsiSCCmec element of S. haemolyticus JCSC1435. However, staphylococci other than S. haemolyticus, including S. aureus and S. epidermidis, contain homologs of SCCSH32 that are more similar to SCCSH32 than those elements found in S. haemolyticus, suggesting that CISH32 of S. haemolyticus SH32 was assembled in recent evolutionary events. Moreover, the composite structure of CISH32 indicates that the detection of class C1 mec and ccrA5B3 gene complexes in S. haemolyticus does not always indicate the existence of a UT9-type SCCmec element, which has remained questionable. PMID- 24466349 TI - Vinculin and Rab5 complex is required [correction of requited]for uptake of Staphylococcus aureus and interleukin-6 expression. AB - Vinculin, a 116-kDa membrane cytoskeletal protein, is an important molecule for cell adhesion; however, little is known about its other cellular functions. Here, we demonstrated that vinculin binds to Rab5 and is required for Staphylococcus aureus (S. aureus) uptake in cells. Viunculin directly bound to Rab5 and enhanced the activation of S. aureus uptake. Over-expression of active vinculin mutants enhanced S. aureus uptake, whereas over-expression of an inactive vinculin mutant decreased S. aureus uptake. Vinculin bound to Rab5 at the N-terminal region (1 258) of vinculin. Vinculin and Rab5 were involved in the S. aureus-induced phosphorylation of MAP kinases (p38, Erk, and JNK) and IL-6 expression. Finally, vinculin and Rab5 knockdown reduced infection of S. aureus, phosphorylation of MAPKs and IL-6 expression in murine lungs. Our results suggest that vinculin binds to Rab5 and that these two molecules cooperatively enhance bacterial infection and the inflammatory response. PMID- 24466351 TI - Biotic vs. abiotic control of decomposition: a comparison of the effects of simulated extinctions and changes in temperature. AB - The loss of species is known to have significant effects on ecosystem functioning, but only recently has it been recognized that species loss might rival the effects of other forms of environmental change on ecosystem processes. There is a need for experimental studies that explicitly manipulate species richness and environmental factors concurrently to determine their relative impacts on key ecosystem processes such as plant litter decomposition. It is crucial to understand what factors affect the rate of plant litter decomposition and the relative magnitude of such effects because the rate at which plant litter is lost and transformed to other forms of organic and inorganic carbon determines the capacity for carbon storage in ecosystems and the rate at which greenhouse gasses such as carbon dioxide are outgassed. Here we compared how an increase in water temperature of 5 degrees C and loss of detritivorous invertebrate and plant litter species affect decomposition rates in a laboratory experiment simulating stream conditions. Like some prior studies, we found that species identity, rather than species richness per se, is a key driver of decomposition, but additionally we showed that the loss of particular species can equal or exceed temperature change in its impact on decomposition. Our results indicate that the loss of particular species can be as important a driver of decomposition as substantial temperature change, but also that predicting the relative consequences of species loss and other forms of environmental change on decomposition requires knowledge of assemblages and their constituent species' ecology and ecophysiology. PMID- 24466350 TI - The RhoGAP activity of myosin IXB is critical for osteoclast podosome patterning, motility, and resorptive capacity. AB - Osteoclasts are large, multinucleated cells of the monocyte-macrophage lineage that generate specialized substrate adhesion complexes to facilitate their function as bone-degrading cells. The patterning and function of these actin based complexes, podosomes and sealing zones, are regulated by the small GTPase Rho. Myosin IXB (Myo9b) is a unique actin-based motor protein that contains a RhoGAP domain, which, like other RhoGAPs, is inhibitory to Rho signaling. In this study, Myo9b is shown to be expressed in osteoclasts and act as a critical regulator of podosome patterning and osteoclast function. SiRNA-mediated knockdown of Myo9b results in increased activity of Rho but not Rac in osteoclasts. Knockdown in osteoclasts on glass results in altered podosome patterning and decreased motility, and this effect is reversed by addition of a Rho inhibitor. SiRNA-mediated suppression of Myo9b expression in osteoclasts on bone results in a dramatic loss of resorptive capacity even though sealing zones appear normal. This loss of resorption is also reversible with addition of a Rho inhibitor. Cells with diminished Myo9b levels display mislocalization and suppressed activation of Src, a tyrosine kinase with critical effects on osteoclast actin cytoskeletal rearrangement and function. In addition, siRNA treated cells display poorly formed microtubule networks and a lack of tubulin acetylation, a marker of microtubule stability. However, short-term addition of TNFalpha to cells with suppressed Myo9b levels overcomes or circumvents these defects and causes increased sealing zone size and resorptive capacity. These results indicate that the RhoGAP activity of Myo9b plays a key role in regulating the actin-based structures necessary for osteoclast motility and resorption, and confirms that Myo9b can act as a motorized signaling molecule that links Rho signaling to the dynamic actin cytoskeleton. PMID- 24466352 TI - Acute high fat diet consumption activates the mesolimbic circuit and requires orexin signaling in a mouse model. AB - Overconsumption of palatable energy-dense foods has negative health implications and it is associated with obesity and several eating disorders. Currently, little is known about the neuronal circuitries activated by the acute ingestion of a rewarding stimulus. Here, we used a combination of immunohistochemistry, pharmacology and neuronal tracing analyses to examine the role of the mesolimbic system in general, and the orexin neurons in particular, in a simple experimental test in which naive mice are allowed to spontaneously eat a pellet of a high fat diet (HFD) for 2 h. We found that acute HFD activates c-Fos expression in several reward-related brain areas, including the ventral tegmental area (VTA), nucleus accumbens, central amygdala and lateral hypothalamic area. We also found that: i- HFD-mediated orosensory stimulation was required for the mesolimbic pathway activation, ii- acute HFD differentially activates dopamine neurons of the paranigral, parabrachial pigmented and interfascicular sub-regions of the VTA, and iii- orexin neurons of the lateral hypothalamic area are responsive to acute HFD. Moreover, orexin signaling blockade, with the orexin 1 receptor antagonist SB-334867, reduces acute HFD consumption and c-Fos induction in the VTA but not in the other mesolimbic nuclei under study. Finally, we found that most orexin neurons responsive to acute HFD innervate the VTA. Our results show that acute HFD consumption recruits the mesolimbic system and that the full manifestation of this eating behavior requires the activation of orexin signaling. PMID- 24466353 TI - Mouse model reveals the role of RERE in cerebellar foliation and the migration and maturation of Purkinje cells. AB - Nuclear receptors and their coregulators play a critical role in brain development by regulating the spatiotemporal expression of their target genes. The arginine-glutamic acid dipeptide repeats gene (Rere) encodes a nuclear receptor coregulator previously known as Atrophin 2. In the developing cerebellum, RERE is expressed in the molecular layer, the Purkinje cell layer and the granule cell layer but not in granule cell precursors. To study RERE's role in cerebellar development, we used RERE-deficient embryos bearing a null allele (om) and a hypomorphic allele (eyes3) of Rere (Rere(om/eyes3)). In contrast to wild-type embryos, formation of the principal fissures in these RERE-deficient embryos was delayed and the proliferative activity of granule cell precursors (GCPs) was reduced at E18.5. This reduction in proliferation was accompanied by a decrease in the expression of sonic hedgehog (SHH), which is secreted from Purkinje cells and is required for normal GCP proliferation. The maturation and migration of Purkinje cells in Rere(om/eyes3) embryos was also delayed with decreased numbers of post-migratory Purkinje cells in the cerebellum. During the postnatal period, RERE depletion caused incomplete division of lobules I/II and III due to truncated development of the precentral fissure in the cerebellar vermis, abnormal development of lobule crus I and lobule crus II in the cerebellar hemispheres due to attenuation of the intercrural fissure, and decreased levels of Purkinje cell dendritic branching. We conclude that RERE deficiency leads to delayed development of the principal fissures and delayed maturation and migration of Purkinje cells during prenatal cerebellar development and abnormal cerebellar foliation and Purkinje cell maturation during postnatal cerebellar development. PMID- 24466355 TI - Perceptions of neighborhood safety and asthma among children and adolescents in Los Angeles: a multilevel analysis. AB - BACKGROUND: Research examining the impact of neighborhoods on asthma has shown an increased interest in the role of the psychosocial environment. We examined the associations between various measures of neighborhood safety, individual and family characteristics, and asthma outcomes among children in Los Angeles. METHODS: Multilevel logistic regression models were used to analyze data on 3,114 children across 65 neighborhoods from Wave 1 of the Los Angeles Family and Neighborhood Survey (2000 to 2002). Primary caregivers reported asthma outcome and all individual covariates; home environmental characteristics were observed by the interviewer. RESULTS: In fully adjusted models, parents who reported their neighborhood fairly safe or somewhat dangerous had lower odds of reported lifetime asthma compared to those who reported their neighborhood completely safe (OR 0.71; 95% CI 0.52-0.96 and OR 0.60; 95% CI 0.42-0.88 respectively). Conversely, parents who reported they could not trust their neighbors to keep their children safe had a nearly 40% increase in lifetime asthma compared to those who reported they could trust their neighbors to keep their children safe (OR 1.39; 95% CI 1.07-1.81). CONCLUSIONS: The study demonstrates a complex pattern between various measures of neighborhood safety and asthma and suggests that these relationships may operate differently in Los Angeles. As an increasing proportion of children are growing up in newer Western and Southwestern cities, which have different physical layouts and residential segregation patterns compared to Northeast and Midwestern cities, future studies should continue to examine neighborhood psychosocial stressors and asthma in diverse contexts. PMID- 24466354 TI - Regulation of the Hsp104 middle domain activity is critical for yeast prion propagation. AB - Molecular chaperones play a significant role in preventing protein misfolding and aggregation. Indeed, some protein conformational disorders have been linked to changes in the chaperone network. Curiously, in yeast, chaperones also play a role in promoting prion maintenance and propagation. While many amyloidogenic proteins are associated with disease in mammals, yeast prion proteins, and their ability to undergo conformational conversion into a prion state, are proposed to play a functional role in yeast biology. The chaperone Hsp104, a AAA+ ATPase, is essential for yeast prion propagation. Hsp104 fragments large prion aggregates to generate a population of smaller oligomers that can more readily convert soluble monomer and be transmitted to daughter cells. Here, we show that the middle (M) domain of Hsp104, and its mobility, plays an integral part in prion propagation. We generated and characterized mutations in the M-domain of Hsp104 that are predicted to stabilize either a repressed or de-repressed conformation of the M domain (by analogy to ClpB in bacteria). We show that the predicted stabilization of the repressed conformation inhibits general chaperone activity. Mutation to the de-repressed conformation, however, has differential effects on ATP hydrolysis and disaggregation, suggesting that the M-domain is involved in coupling these two activities. Interestingly, we show that changes in the M domain differentially affect the propagation of different variants of the [PSI+] and [RNQ+] prions, which indicates that some prion variants are more sensitive to changes in the M-domain mobility than others. Thus, we provide evidence that regulation of the M-domain of Hsp104 is critical for efficient prion propagation. This shows the importance of elucidating the function of the M-domain in order to understand the role of Hsp104 in the propagation of different prions and prion variants. PMID- 24466356 TI - Ketoconazole inhibits the cellular uptake of anandamide via inhibition of FAAH at pharmacologically relevant concentrations. AB - BACKGROUND: The antifungal compound ketoconazole has, in addition to its ability to interfere with fungal ergosterol synthesis, effects upon other enzymes including human CYP3A4, CYP17, lipoxygenase and thromboxane synthetase. In the present study, we have investigated whether ketoconazole affects the cellular uptake and hydrolysis of the endogenous cannabinoid receptor ligand anandamide (AEA). METHODOLOGY/PRINCIPAL FINDINGS: The effects of ketoconazole upon endocannabinoid uptake were investigated using HepG2, CaCo2, PC-3 and C6 cell lines. Fatty acid amide hydrolase (FAAH) activity was measured in HepG2 cell lysates and in intact C6 cells. Ketoconazole inhibited the uptake of AEA by HepG2 cells and CaCo2 cells with IC50 values of 17 and 18 uM, respectively. In contrast, it had modest effects upon AEA uptake in PC-3 cells, which have a low expression of FAAH. In cell-free HepG2 lysates, ketoconazole inhibited FAAH activity with an IC50 value (for the inhibitable component) of 34 uM. CONCLUSIONS/SIGNIFICANCE: The present study indicates that ketoconazole can inhibit the cellular uptake of AEA at pharmacologically relevant concentrations, primarily due to its effects upon FAAH. Ketoconazole may be useful as a template for the design of dual-action FAAH/CYP17 inhibitors as a novel strategy for the treatment of prostate cancer. PMID- 24466357 TI - Structural Stability and Binding Strength of a Designed Peptide-Carbon Nanotube Hybrid. AB - Biological polymers hybridized with single-walled carbon nanotubes (SWCNTs) have elicited much interest recently for applications in SWCNT-based sorting as well as biomedical imaging, sensing, and drug delivery. Recently, de novo designed peptides forming a coiled-coil structure have been engineered to selectively disperse SWCNT of a certain diameter. Here we report on a study of the binding strength and structural stability of the hybrid between such a "HexCoil-Ala" peptide and the (6,5)-SWCNT. Using the competitive binding of a surfactant, we find that affinity strength of the peptide ranks in comparison to that of two single-stranded DNA sequences as (GT)30-DNA > HexCoil-Ala > (TAT)4T-DNA. Further, using replica exchange molecular dynamics (REMD), we show that the hexamer peptide complex has both similarities with and differences from the original design. While one of two distinct helix-helix interfaces of the original model was largely retained, a second interface showed much greater variability. These conformational differences allowed an aromatic tyrosine residue designed to lie along the solvent-exposed surface of the protein instead to penetrate between the two helices and directly contact the SWCNT. These insights will inform future designs of SWCNT-interacting peptides. PMID- 24466358 TI - Metformin in Diabetic Patients with Heart Failure: Safe and Effective? AB - Management of diabetic patients with heart failure is a complex endeavor. The initial reluctance to use metformin in these patients has given way to a broader acceptance after clinical trials and meta-analyses have revealed that some of the insulin-sensitizing agents lead to adverse cardiovascular events. We have proposed that an increase of substrate uptake by the insulin-resistant heart is detrimental because the heart is already flooded with fuel. In light of this evidence, metformin offers a unique safety profile in the patient with diabetes and heart failure. Our article expands on the use of metformin in patients with heart failure. We propose that the drug targets both the source as well as the destination (in this case the heart) of excess fuel. We consider treatment of diabetic heart failure patients with metformin both safe and effective. PMID- 24466359 TI - A scoping review and prevalence analysis of soil-transmitted helminth infections in Honduras. AB - BACKGROUND: Honduras is endemic for soil-transmitted helminth (STH) infections, but critical information gaps still remain on the prevalence and intensity of these infections as well as on their spatial distribution at subnational levels. OBJECTIVES: Firstly, to review the research activity on STH infections in Honduras and secondly, to carry out a national prevalence analysis and map the geographical distribution of these infections in children. METHODS: A systematic search was conducted of the published and grey literature to identify scientific work on the impact and prevalence of STH infections done between May 1930 and June 30, 2012. International databases and Honduran journals were searched. Grey literature was gleaned from local libraries and key informants. Select studies conducted between 2001 and 2012 were used to produce prevalence maps and to investigate association between STH prevalence and socio-economic and environmental factors. RESULTS: Of 257 identified studies, 211 (21.4% peer reviewed) were retained for analysis and categorized as clinical research (10.9%), treatment efficacy studies (8.1%) or epidemiological studies (81%). Prevalence analysis and geographical mapping included 36 epidemiological studies from Honduras's 18 departments and 23% of its municipalities. Overall STH prevalence was >50% in 40.6% of municipalities. Prevalences above 20% for each trichuriasis, ascariasis, and hookworm infection were found in 68%, 47.8%, and 7.2% of studied municipalities, respectively. Municipalities with lower human development index, less access to of potable water, and with higher annual precipitation showed higher STH prevalences. CONCLUSIONS: This is the first study to provide a comprehensive historic review of STH research activity and prevalence in Honduras, revealing important knowledge gaps related to infection risk factors, disease burden, and anti-parasitic drug efficacy, among others. Our decade-long prevalence analysis reveals geographical differences in STH prevalence and these findings suggest that differential intervention strategies might be necessary in Honduras for the control of these infections. PMID- 24466360 TI - The changing epidemiology of Murray Valley encephalitis in Australia: the 2011 outbreak and a review of the literature. AB - Murray Valley encephalitis virus (MVEV) is the most serious of the endemic arboviruses in Australia. It was responsible for six known large outbreaks of encephalitis in south-eastern Australia in the 1900s, with the last comprising 58 cases in 1974. Since then MVEV clinical cases have been largely confined to the western and central parts of northern Australia. In 2011, high-level MVEV activity occurred in south-eastern Australia for the first time since 1974, accompanied by unusually heavy seasonal MVEV activity in northern Australia. This resulted in 17 confirmed cases of MVEV disease across Australia. Record wet season rainfall was recorded in many areas of Australia in the summer and autumn of 2011. This was associated with significant flooding and increased numbers of the mosquito vector and subsequent MVEV activity. This paper documents the outbreak and adds to our knowledge about disease outcomes, epidemiology of disease and the link between the MVEV activity and environmental factors. Clinical and demographic information from the 17 reported cases was obtained. Cases or family members were interviewed about their activities and location during the incubation period. In contrast to outbreaks prior to 2000, the majority of cases were non-Aboriginal adults, and almost half (40%) of the cases acquired MVEV outside their area of residence. All but two cases occurred in areas of known MVEV activity. This outbreak continues to reflect a change in the demographic pattern of human cases of encephalitic MVEV over the last 20 years. In northern Australia, this is associated with the increasing numbers of non Aboriginal workers and tourists living and travelling in endemic and epidemic areas, and also identifies an association with activities that lead to high mosquito exposure. This outbreak demonstrates that there is an ongoing risk of MVEV encephalitis to the heavily populated areas of south-eastern Australia. PMID- 24466361 TI - Strong association between serological status and probability of progression to clinical visceral leishmaniasis in prospective cohort studies in India and Nepal. AB - INTRODUCTION: Asymptomatic persons infected with the parasites causing visceral leishmaniasis (VL) usually outnumber clinically apparent cases by a ratio of 4-10 to 1. We assessed the risk of progression from infection to disease as a function of DAT and rK39 serological titers. METHODS: We used available data on four cohorts from villages in India and Nepal that are highly endemic for Leishmania donovani. In each cohort two serosurveys had been conducted. Based on results of initial surveys, subjects were classified as seronegative, moderately seropositive or strongly seropositive using both DAT and rK39. Based on the combination of first and second survey results we identified seroconvertors for both markers. Seroconvertors were subdivided in high and low titer convertors. Subjects were followed up for at least one year following the second survey. Incident VL cases were recorded and verified. RESULTS: We assessed a total of 32,529 enrolled subjects, for a total follow-up time of 72,169 person years. Altogether 235 incident VL cases were documented. The probability of progression to disease was strongly associated with initial serostatus and with seroconversion; this was particularly the case for those with high titers and most prominently among seroconvertors. For high titer DAT convertors the hazard ratio reached as high as 97.4 when compared to non-convertors. The strengths of the associations varied between cohorts and between markers but similar trends were observed between the four cohorts and the two markers. DISCUSSION: There is a strongly increased risk of progressing to disease among DAT and/or rK39 seropositives with high titers. The options for prophylactic treatment for this group merit further investigation, as it could be of clinical benefit if it prevents progression to disease. Prophylactic treatment might also have a public health benefit if it can be corroborated that these asymptomatically infected individuals are infectious for sand flies. PMID- 24466362 TI - L925I mutation in the Para-type sodium channel is associated with pyrethroid resistance in Triatoma infestans from the Gran Chaco region. AB - BACKGROUND: Chagas' disease is an important public health concern in Latin America. Despite intensive vector control efforts using pyrethroid insecticides, the elimination of Triatoma infestans has failed in the Gran Chaco, an ecoregion that extends over Argentina, Paraguay, Bolivia and Brazil. The voltage-gated sodium channel is the target site of pyrethroid insecticides. Point mutations in domain II region of the channel have been implicated in pyrethroid resistance of several insect species. METHODS AND FINDINGS: In the present paper, we identify L925I, a new pyrethroid resistance-conferring mutation in T. infestans. This mutation has been found only in hemipterans. In T. infestans, L925I mutation occurs in a resistant population from the Gran Chaco region and is associated with inefficiency in the control campaigns. We also describe a method to detect L925I mutation in individuals from the field. CONCLUSIONS AND SIGNIFICANCE: The findings have important implications in the implementation of strategies for resistance management and in the rational design of campaigns for the control of Chagas' disease transmission. PMID- 24466363 TI - Serum hepatitis B surface antigen (HBsAg) kinetics in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B. AB - BACKGROUND: We investigated the differences in HBsAg kinetics at different levels of viremia in hepatitis B e antigen (HBeAg)-negative chronic hepatitis B (CHB). METHODS: We compared HBsAg levels among HBeAg-negative CHB patients with persistently undetectable HBV DNA (<=20 IU/mL; Group A, n = 100), HBV DNA 20 2,000 IU/mL (Group B, n = 100), and HBV DNA >2,000 IU/mL (Group C, n = 100). HBsAg and HBV DNA levels were measured at three consecutive time points during follow-up (median 21.4 months). RESULTS: Median HBsAg levels were significantly lower in Group A than in Groups B and C at all time points (p < 0.001). HBV DNA and HBsAg levels were weakly correlated (r = 0.180 and 0.151 for Groups B and C, respectively). Among patients with HBsAg <100 IU/mL, Group A patients had the greatest median serum HBsAg reduction (0.341 log IU/mL/year; Group B, 0.122 log IU/mL/year; Group C, 0.057 log IU/mL/year; p = 0.002). Among Group A patients with HBsAg <100 IU/mL, baseline HBsAg achieved an AUROC of 0.876 in predicting >1 log annual HBsAg reduction; 10-100 IU/mL HBsAg was the optimal level for prediction (sensitivity 90 %; specificity 74.6 %). Serum HBsAg/HBV DNA ratios were significantly higher in Group B than in Groups A and C (p < 0.05). CONCLUSIONS: HBV DNA and HBsAg were weakly correlated. Only patients with undetectable HBV DNA showed decline in HBsAg levels during follow-up. The greatest reduction in HBsAg levels occurred in patients with baseline HBsAg <100 IU/mL. PMID- 24466364 TI - Accelerated partial breast irradiation for breast cancer: a meta-analysis. AB - To evaluate the long-term effect of breast conservation with accelerated partial breast irradiation (APBI) for early-stage breast cancer, PubMed, EMBASE, Cochrane Library, Web of Science, Chinese Biomedical Literature Database, Chinese Scientific Journals Full-text Database, and China Journal Full-text Database were searched to identify relevant original published trials. Randomized controlled trials in any language comparing APBI with whole-breast radiotherapy in patients with early-stage breast cancer were included. RevMan 5 software was used for statistical analysis. Four trials involving 919 patients were included. The rate of 5- and 7-year excellent/good cosmetic results was significant {odds ratio (OR) = 2.09 [95% confidence interval (CI) = 1.21-3.62]} between two groups. The 5- and 8-year overall survival had no significant difference [OR = 1.76 (95% CI = 0.67 4.62) and OR = 0.86 (95% CI = 0.44-1.66)]. The 10-year overall survival had significant differences [OR = 0.56 (95% CI = 0.35-0.91)]. There were no differences in the 5-year local recurrence (LR)-free survival [OR = 0.65 (95% CI = 0.18-2.34)], cancer-specific survival [OR = 1.67 (95% CI = 0.39-7.12)], disease free survival [OR = 0.84 (95% CI = 0.38-1.84)], LR [OR = 1.36 (95% CI = 0.46 3.99)], the rate of contralateral breast cancer [OR = 2.82 (95% CI = 0.73 10.89)], and distant metastasis [OR = 0.71 (95% CI = 0.22-2.31)]. APBI significantly improved the rate of excellent/good cosmetic results anywhere in the breast, shortened the treatment time, alleviated the pain, and improved the quality of life. Future large-scale, high-quality, and double-blind trials are needed. PMID- 24466365 TI - In vivo imaging of tissue-remodeling activity involving infiltration of macrophages by a systemically administered protease-activatable probe in colon cancer tissues. AB - This study evaluated the detection of tumors using in vivo imaging with a commercially available and systemically administered protease-activatable fluorescent probe, ProSense. To this end, we analyzed the delivery and uptake of ProSense as well as the target protease and its cellular source in a mouse xenograft tumor model. In vivo and ex vivo multi wavelength imaging revealed that ProSense signals accumulated within tumors, with preferential distribution in the vascular leakage area that correlates with vasculature development at the tumor periphery. Immunohistochemically, cathepsin B, which is targeted by ProSense, was specifically localized in macrophages. The codistribution of tenascin C immunoreactivity and gelatinase activity provided evidence of tissue-remodeling at the tumor periphery. Furthermore, in situ zymography revealed extracellular ProSense cleavage in such areas. Colocalization of cathepsin B expression and ProSense signals showing reduction by addition of cathepsin B inhibitor was confirmed in cultured macrophage-derived RAW264.7 cells. These results suggest that increased tissue-remodeling activity involving infiltration of macrophages is a mechanism that may be responsible for the tumor accumulation of ProSense signals in our xenograft model. We further confirmed ProSense signals at the tumor margin showing cathepsin B(+) macrophage infiltration in a rat colon carcinogenesis model. Together, these data demonstrate that systemically administered protease-activatable probes can effectively detect cancer invasive fronts, where tissue-remodeling activity is high to facilitate neoplastic cell invasion. PMID- 24466366 TI - Ionizing radiation and glioblastoma exosomes: implications in tumor biology and cell migration. AB - Exosomes are nanometer-sized lipid vesicles released ubiquitously by cells, which have been shown to have a normal physiological role, as well as influence the tumor microenvironment and aid metastasis. Recent studies highlight the ability of exosomes to convey tumor-suppressive and oncogenic mRNAs, microRNAs, and proteins to a receiving cell, subsequently activating downstream signaling pathways and influencing cellular phenotype. Here, we show that radiation increases the abundance of exosomes released by glioblastoma cells and normal astrocytes. Exosomes derived from irradiated cells enhanced the migration of recipient cells, and their molecular profiling revealed an abundance of molecules related to signaling pathways important for cell migration. In particular, connective tissue growth factor (CTGF) mRNA and insulin-like growth factor binding protein 2 (IGFBP2) protein levels were elevated, and coculture of nonirradiated cells with exosomes isolated from irradiated cells increased CTGF protein expression in the recipient cells. Additionally, these exosomes enhanced the activation of neurotrophic tyrosine kinase receptor type 1 (TrkA), focal adhesion kinase, Paxillin, and proto-oncogene tyrosine-protein kinase Src (Src) in recipient cells, molecules involved in cell migration. Collectively, our data suggest that radiation influences exosome abundance, specifically alters their molecular composition, and on uptake, promotes a migratory phenotype. PMID- 24466367 TI - Antidiabetic Drug Metformin Prevents Progression of Pancreatic Cancer by Targeting in Part Cancer Stem Cells and mTOR Signaling. AB - Epidemiologic studies have shown that diabetes mellitus is associated positively with increased risk of pancreatic ductal adenocarcinoma (PDAC), and recent meta analysis studies showed that metformin, reduces the risk of pancreatic cancer (PC). We tested the effects of metformin on pancreatic intraepithelial neoplasia (PanIN) and their progression to PDAC in p48Cre/+.LSL-KrasG12D/+ transgenic mice. Mice fed control diet showed 80% and 62% incidence of PDAC in males and females, respectively. Male mice showed 20% and 26%, and female mice showed 7% and 0% PDAC incidence with 1000- and 2000-ppm metformin treatments, respectively. Both doses of metformin decreased pancreatic tumor weights by 34% to 49% (P < 0.03-0.001). The drug treatment caused suppression of PanIN 3 (carcinoma in situ) lesions by 28% to 39% (P < .002) and significant inhibition of carcinoma spread in the pancreas. The pancreatic tissue and/or serum of mice fed metformin showed a significant inhibition of mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), phosphorylated extracellular signal-regulated kinases (pErk), and insulin-like growth factor 1 (IGF-1) with an increase in phosphorylated 5' adenosine monophosphate kinase (pAMPK), tuberous sclerosis complex 1 (TSC1, TSC2), C-protein and an autophagy related protein 2 (ATG2). The cancer stem cell (CSC) markers were significantly decreased (P < 0.04-0.0002) in the pancreatic tissue. These results suggest that biologic effects of metformin are mediated through decreased CSC markers cluster of differentiation 44 (CD44 and CD133), aldehyde dehydrogenase isoform 1 (ALDH1), and epithelial cell adhesion molecule (EPCAM) and modulation of the mTOR signaling pathway. Our preclinical data indicate that metformin has significant potential for use in clinical trials for PC chemoprevention. PMID- 24466368 TI - Effects of tyrosine kinase inhibitors and CXCR4 antagonist on tumor growth and angiogenesis in rat glioma model: MRI and protein analysis study. AB - The aim of the study was to determine the antiangiogenic efficacy of vatalanib, sunitinib, and AMD3100 in an animal model of human glioblastoma (GBM) by using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and tumor protein expression analysis. Orthotopic GBM-bearing animals were randomly assigned either to control group or vatalanib, sunitinib, and AMD3100 treatment groups. Following 2 weeks of drug treatment, tumor growth and vascular parameters were measured using DCE-MRI. Expression of different angiogenic factors in tumor extracts was measured using a membrane-based human antibody array kit. Tumor angiogenesis and invasion were determined by immunohistochemistry. DCE-MRI showed a significant increase in tumor size after vatalanib treatment. AMD3100-treated group showed a significant decrease in a number of vascular parameters determined by DCE-MRI. AMD3100 significantly decreased the expression of different angiogenic factors compared to sunitinib or vatalanib; however, there were no significant changes in vascular density among the groups. Sunitinib-treated animals showed significantly higher migration of the invasive cells, whereas in both vatalanib- and AMD3100 treated animals the invasive cell migration distance was significantly lower compared to that of control. Vatalanib and sunitinib resulted in suboptimal therapeutic effect, but AMD3100 treatment resulted in a significant reduction in tumor growth, permeability, interstitial space volume, and invasion of tumor cells in an animal model of GBM. PMID- 24466369 TI - Accurate prediction of nodal status in preoperative patients with pancreatic ductal adenocarcinoma using next-gen nanoparticle. AB - OBJECTIVE: The objective of this study is to assess lymphotropic nanoparticle enhanced magnetic resonance imaging (LNMRI) in identifying malignant nodal involvement in patients with pancreatic ductal adenocarcinoma. METHODS: Magnetic resonance imaging was performed in 13 patients with known or high index of suspicion of pancreatic cancer and who were scheduled for surgical resection. Protocols included T2*-weighted imaging before and after administration of Ferumoxytol (Feraheme) for the evaluation of lymph node involvement. Eleven of the 13 patients underwent a Whipple procedure and lymph node dissection. Nodes that lacked contrast uptake were deemed malignant, and those that demonstrated homogeneous uptake were deemed benign. RESULTS: A total of 264 lymph nodes were resection, of which 17 were malignant. The sensitivity and specificity of LNMRI was 76.5% and 98.4% at a nodal level and 83.3% and 80% at a patient level. CONCLUSION: LNMRI demonstrated high sensitivity and specificity in patients with pancreatic ductal adenocarcinoma. PMID- 24466370 TI - EV20, a Novel Anti-ErbB-3 Humanized Antibody, Promotes ErbB-3 Down-Regulation and Inhibits Tumor Growth In Vivo. AB - ErbB-3 (HER-3) receptor is involved in tumor progression and resistance to therapy. Development of specific inhibitors impairing the activity of ErbB-3 is an attractive tool for cancer therapeutics. MP-RM-1, a murine monoclonal antibody targeting human ErbB-3, has shown anticancer activity in preclinical models. With the aim to provide novel candidates for clinical use, we have successfully generated a humanized version of MP-RM-1. The humanized antibody, named EV20, abrogates both ligand-dependent and ligand-independent receptor signaling of several tumor cell types, strongly promotes ErbB-3 down-regulation, and efficiently and rapidly internalizes into tumor cells. Furthermore, treatment with EV20 significantly inhibits growth of xenografts originating from prostatic, ovarian, and pancreatic cancers as well as melanoma in nude mice. In conclusion, we provide a novel candidate for ErbB-3-targeted cancer therapy. PMID- 24466371 TI - Testing of SNS-032 in a Panel of Human Neuroblastoma Cell Lines with Acquired Resistance to a Broad Range of Drugs. AB - Novel treatment options are needed for the successful therapy of patients with high-risk neuroblastoma. Here, we investigated the cyclin-dependent kinase (CDK) inhibitor SNS-032 in a panel of 109 neuroblastoma cell lines consisting of 19 parental cell lines and 90 sublines with acquired resistance to 14 different anticancer drugs. Seventy-three percent of the investigated neuroblastoma cell lines and all four investigated primary tumor samples displayed concentrations that reduce cell viability by 50% in the range of the therapeutic plasma levels reported for SNS-032 (<754 nM). Sixty-two percent of the cell lines and two of the primary samples displayed concentrations that reduce cell viability by 90% in this concentration range. SNS-032 also impaired the growth of the multidrug resistant cisplatin-adapted UKF-NB-3 subline UKF-NB-3(r)CDDP(1000) in mice. ABCB1 expression (but not ABCG2 expression) conferred resistance to SNS-032. The antineuroblastoma effects of SNS-032 did not depend on functional p53. The antineuroblastoma mechanism of SNS-032 included CDK7 and CDK9 inhibition-mediated suppression of RNA synthesis and subsequent depletion of antiapoptotic proteins with a fast turnover rate including X-linked inhibitor of apoptosis (XIAP), myeloid cell leukemia sequence 1 (Mcl-1), baculoviral IAP repeat containing 2 (BIRC2; cIAP-1), and survivin. In conclusion, CDK7 and CDK9 represent promising drug targets and SNS-032 represents a potential treatment option for neuroblastoma including therapy-refractory cases. PMID- 24466372 TI - Folate receptor-positive circulating tumor cells as a novel diagnostic biomarker in non-small cell lung cancer. AB - The study aims to determine the efficacy and feasibility of a novel folate receptor (FR)-based circulating tumor cell (CTC) detection method in the diagnosis of non-small cell lung cancer (NSCLC). CTCs were collected from 3 ml of blood based on negative enrichment by immunomagnetic beads and then labeled by a conjugate of a tumor-specific ligand folate and an oligonucleotide. After washing off redundant conjugates, the bound conjugates were removed and analyzed by quantitative polymerase chain reaction. The captured cells were validated as tumor cells by immunofluorescence staining. In the evaluation of clinical utility, the results showed that the CTC levels of 153 patients with NSCLC were significantly higher than the controls (49 healthy donors and 64 patients with benign lung diseases; P < .001). With a threshold of 8.64 CTC units, the method showed a sensitivity of 73.2% and a specificity of 84.1% in the diagnosis of NSCLC, especially a sensitivity of 67.2% in stage I disease. Compared with the existing clinical biomarkers such as neuron-specific enolase (NSE), carcinoembryonic antigen (CEA), cancer antigen 125 (CA125), cyfra21-1, and squamous cell carcinoma antigen (SCC Ag), the method showed the highest diagnostic efficiency (area under the curve, 0.823; 95% confidence interval, 0.773-0.874). Together, our results demonstrated that FR-positive CTCs were feasible diagnostic biomarkers in patients with NSCLC, as well as in early-stage tumors. PMID- 24466373 TI - Epithelial ovarian cancer-induced angiogenic phenotype of human omental microvascular endothelial cells may occur independently of VEGF signaling. AB - Epithelial ovarian cancer (EOC) metastasizes transcoelomically to the peritoneum and omentum, and despite surgery and chemotherapy, recurrent disease is likely. Metastasis requires the induction of proangiogenic changes in the omental microenvironment and EOC-induced omental angiogenesis is currently a key therapeutic target. In particular, antiangiogenic therapies targeting the vascular endothelial growth factor A (VEGFA) pathway are commonly used, although, with limited effects. Here, using human omental microvascular endothelial cells (HOMECs) and ovarian cancer cell lines as an in vitro model, we show that factors secreted from EOC cells increased proliferation, migration, and tube-like structure formation in HOMECs. However, EOC-induced angiogenic tube-like formation and migration were unaffected by inhibition of tyrosine kinase activity of VEGF receptors 1 and 2 (Semaxanib; SU5416) or neutralization of VEGFA (neutralizing anti-VEGFA antibody), although VEGFA165-induced HOMEC migration and tube-like structure formation were abolished. Proteomic investigation of the EOC secretome identified several alternative angiogenesis-related proteins. We screened these for their ability to induce an angiogenic phenotype in HOMECs, i.e., proliferation, migration, and tube-like structure formation. Hepatocyte growth factor (HGF) and insulin-like growth factor binding protein 7 (IGFBP-7) increased all three parameters, and cathepsin L (CL) increased migration and tubule formation. Further investigation confirmed expression of the HGF receptor c-Met in HOMECs. HGF- and EOC-induced proliferation and angiogenic tube structure formation were blocked by the c-Met inhibitor PF04217903. Our results highlight key alternative angiogenic mediators for metastatic EOC, namely, HGF, CL, and IGFBP-7, suggesting that effective antiangiogenic therapeutic strategies for this disease require inhibition of multiple angiogenic pathways. PMID- 24466374 TI - Cytosine 5-Hydroxymethylation of the LZTS1 Gene Is Reduced in Breast Cancer. AB - Change of DNA cytosine methylation (5mC) is an early event in the development of cancer, and the recent discovery of a 5-hydroxymethylated form (5hmC) of cytosine suggests a regulatory epigenetic role that might be different from 5 methylcytosine. Here, we aimed at elucidating the role of 5hmC in breast cancer. To interrogate the 5hmC levels of the leucine zipper, putative tumor suppressor 1 (LZTS1) gene in detail, we analyzed 75 primary breast cancer tissue samples from initial diagnosis and 12 normal breast tissue samples derived from healthy persons. Samples were subjected to 5hmC glucosyltransferase treatment followed by restriction digestion and segment-specific amplification of 11 polymerase chain reaction products. Nine of the 11 5'LZTS1 fragments showed significantly lower (fold change of 1.61-6.01, P < .05) 5hmC content in primary breast cancer tissue compared to normal breast tissue samples. No significant differences were observed for 5mC DNA methylation. Furthermore, both LZTS1 and TET1 mRNA expressions were significantly reduced in tumor samples (n = 75, P < .001, Student's t test), which correlated significantly with 5hmC levels in samples. 5hmC levels in breast cancer tissues were associated with unfavorable histopathologic parameters such as lymph node involvement (P < .05, Student's t test). A decrease of 5hmC levels of LZTS1, a classic tumor suppressor gene known to influence metastasis in breast cancer progression, is correlated to down regulation of LZTS1 mRNA expression in breast cancer and might epigenetically enhance carcinogenesis. The study provides support for the novel hypothesis that suggests a strong influence of 5hmC on mRNA expression. Finally, one may also consider 5hmC as a new biomarker. PMID- 24466375 TI - Theranostic gold nanoparticles modified for durable systemic circulation effectively and safely enhance the radiation therapy of human sarcoma cells and tumors. AB - Radiation therapy (RT) is an integral component of the treatment of many sarcomas and relies on accurate targeting of tumor tissue. Despite conventional treatment planning and RT, local failure rates of 10% to 28% at 5 years have been reported for locally advanced, unresectable sarcomas, due in part to limitations in the cumulative RT dose that may be safely delivered. We describe studies of the potential usefulness of gold nanoparticles modified for durable systemic circulation (through polyethylene glycosylation; hereinafter "P-GNPs") as adjuvants for RT of sarcomas. In studies of two human sarcoma-derived cell lines, P-GNP in conjunction with RT caused increased unrepaired DNA damage, reflected by approximately 1.61-fold increase in gamma-H2AX (histone phosphorylated on Ser(139)) foci density compared with RT alone. The combined RT and P-GNP also led to significantly reduced clonogenic survival of tumor cells, compared to RT alone, with dose-enhancement ratios of 1.08 to 1.16. In mice engrafted with human sarcoma tumor cells, the P-GNP selectively accumulated in the tumor and enabled durable imaging, potentially aiding radiosensitization as well as treatment planning. Mice pretreated with P-GNP before targeted RT of their tumors exhibited significantly improved tumor regression and overall survival, with long-term survival in one third of mice in this treatment group compared to none with RT only. Interestingly, prior RT of sarcoma tumors increased subsequent extravasation and in-tumor deposition of P-GNP. These results together suggest P GNP may be integrated into the RT of sarcomas, potentially improving target imaging and radiosensitization of tumor while minimizing dose to normal tissues. PMID- 24466376 TI - Age-Dependent Association between Protein Expression of the Embryonic Stem Cell Marker Cripto-1 and Survival of Glioblastoma Patients. AB - Exploring the re-emergence of embryonic signaling pathways may reveal important information for cancer biology. Nodal is a transforming growth factor-beta (TGF beta)-related morphogen that plays a critical role during embryonic development. Nodal signaling is regulated by the Cripto-1 co-receptor and another TGF-beta member, Lefty. Although these molecules are poorly detected in differentiated tissues, they have been found in different human cancers. Poor prognosis of glioblastomas justifies the search for novel signaling pathways that can be exploited as potential therapeutic targets. Because our intracranial glioblastoma rat xenograft model has revealed importance of gene ontology categories related to development and differentiation, we hypothesized that increased activity of Nodal signaling could be found in glioblastomas. We examined the gene expressions of Nodal, Cripto-1, and Lefty in microarrays of invasive and angiogenic xenograft samples developed from four patients with glioblastoma. Protein expression was evaluated by immunohistochemistry in 199 primary glioblastomas, and expression levels were analyzed for detection of correlations with available clinical information. Gene expression of Nodal, Lefty, and Cripto-1 was detected in the glioblastoma xenografts. Most patient samples showed significant levels of Cripto 1 detected by immunohistochemistry, whereas only weak to moderate levels were detected for Nodal and Lefty. Most importantly, the higher Cripto-1 scores were associated with shorter survival in a subset of younger patients. These findings suggest for the first time that Cripto-1, an important molecule in developmental biology, may represent a novel prognostic marker and therapeutic target in categories of younger patients with glioblastoma. PMID- 24466377 TI - Correlation of MicroRNA 132 Up-regulation with an Unfavorable Clinical Outcome in Patients with Primary Glioblastoma Multiforme Treated with Radiotherapy Plus Concomitant and Adjuvant Temozolomide Chemotherapy. AB - BACKGROUND: MicroRNA 132 (miR-132) is dysregulated in a range of human malignancies; however, its role in glioma has not been reported. The aim of this study was to profile miR-132 expression in a cohort of patients with primary glioblastoma multiforme (GBM) treated with the Stupp regimen and to correlate microRNA levels with patient outcome. METHODS: miR-132 levels relative to RNU44 were assessed by quantitative reverse transcription-polymerase chain reaction in 43 GBMs and normal brain tissue. The cohort comprised patients less than 72 years of age with Eastern Cooperative Oncology Group (ECOG) scores between 0 and 2 who had undergone 6-week concomitant radiation and temozolomide followed by adjuvant temozolomide. Survival data were available for all cases. Tumors were characterized for O6-methylguanine-DNA methyltransferase (MGMT) methylation and isocitrate dehydrogenase (IDH) 1/2 mutation status. Associations between miR-132 expression and clinical indicators were analyzed. RESULTS: Tumor miR-132 levels ranged from 0.07- to 40.4-fold increase (mean = 5.5-fold increase) relative to normal brain. High-level miR-132 (above the mean) independently predicted for a significantly shorter overall survival (P = .008). miR-132 was a stronger prognostic indicator than ECOG score (P = .012) and age at diagnosis (P = .026) but did not correlate with MGMT methylation status or extent of tumor resection. Cox regression analysis confirmed high miR-132 as the strongest predictor of outcome (P = .010) with a hazard ratio of 2.8. CONCLUSIONS: This study identified high miR-132 expression as a biomarker of poor prognosis in patients with primary GBM treated with the Stupp regimen. PMID- 24466378 TI - Three-dimensional Nuclear Telomere Organization in Multiple Myeloma. AB - Multiple myeloma (MM) is preceded by monoclonal gammopathy of undetermined significance (MGUS). Up to date, it is difficult to predict an individual's time to disease progression and the treatment response. To examine whether the nuclear telomeric architecture will unravel some of these questions, we carried out. Three-dimensional (3D) telomere analysis on samples from patients diagnosed with MGUS and MM, as well as from patients who went into relapse. Telomere signal intensity, number of telomere aggregates, nuclear volume, and the overall nuclear telomere distribution (a/c ratio) were analyzed. The telomeric profiles allowed for the differentiation of the disease stages. The telomeric profiles of myeloma cells obtained from blood and bone marrow aspirates were identical. Based on this study, we discuss the use of 3D telomere profiling as a potential future tool for risk stratification and personalized treatment decisions. PMID- 24466379 TI - Plasma metabolomic profiles in breast cancer patients and healthy controls: by race and tumor receptor subtypes. AB - BACKGROUND: A few studies in the last several years have shown that metabolomics, the study of metabolites and small intermediate molecules, may help better understand the breast carcinogenesis. However, breast cancer is a heterogeneous disease with different subtypes. Additionally, there is a significant racial difference in terms of breast cancer incidence and mortality. Few, if any, metabolomics studies in breast cancer have considered race and tumor subtypes in the study design. METHODS: We performed a global metabolomic profiling using mass spectrometry and samples from 60 breast cancer cases and 60 matched controls. RESULTS: A total of 375 named metabolites were observed, with 117 metabolites whose levels were significantly different between African American and Caucasian American women (P < .05 and q < 0.10) and 78 that differed between breast cancer cases and healthy controls (P < .05 and q < 0.10). Most of those differentiated metabolites belong to amino acids, fatty acids, and lysolipids. In the pathway based analysis, we found that plasma levels of many amino acids were statistically significantly lower in patients with breast cancer, especially those with triple-negative breast cancer, than healthy controls. However, plasma levels of many FAs related to beta-oxidation were statistically significantly higher in patients with breast cancer than healthy controls, suggesting the possibility of altered FA beta-oxidation in patients with breast cancer. CONCLUSIONS: Because of small sample size, the clinical usage of the metabolites from this study is unclear. Further validation of those significant metabolites is warranted, especially with the consideration of racial difference. PMID- 24466380 TI - Impact of perfusion map analysis on early survival prediction accuracy in glioma patients. AB - Studies investigating dynamic susceptibility contrast magnetic resonance imaging determined relative cerebral blood volume (rCBV) maps as a metric of treatment response assessment have generated conflicting results. We evaluated the potential of various analytical techniques to predict survival of patients with glioma treated with chemoradiation. rCBV maps were acquired in patients with high grade gliomas at 0, 1, and 3 weeks into chemoradiation therapy. Various analytical techniques were applied to the same cohort of serial rCBV data for early assessment of survival. Three different methodologies were investigated: 1) percentage change of whole tumor statistics (i.e., mean, median, and percentiles), 2) physiological segmentation (low rCBV, medium rCBV, or high rCBV), and 3) a voxel-based approach, parametric response mapping (PRM). All analyses were performed using the same tumor contours, which were determined using contrast-enhanced T1-weighted and fluid attenuated inversion recovery images. The predictive potential of each response metric was assessed at 1-year and overall survival. PRM was the only analytical approach found to generate a response metric significantly predictive of patient 1-year survival. Time of acquisition and contour volume were not found to alter the sensitivity of the PRM approach for predicting overall survival. We have demonstrated the importance of the analytical approach in early response assessment using serial rCBV maps. The PRM analysis shows promise as a unified early and robust imaging biomarker of treatment response in patients diagnosed with high-grade gliomas. PMID- 24466381 TI - Combined Injection of (18)F-Fluorodeoxyglucose and 3'-Deoxy-3' [(18)F]fluorothymidine PET Achieves More Complete Identification of Viable Lung Cancer Cells in Mice and Patients than Individual Radiopharmaceutical: A Proof-of Concept Study. AB - PURPOSE: The objective is to validate the combination of 3'-deoxy-3' [(18)F]fluorothymidine ((18)F-FLT) and (18)F-fluorodeoxyglucose ((18)F-FDG) as a "novel" positron emission tomography (PET) tracer for better visualization of cancer cell components in solid cancers than individual radiopharmaceutical. METHODS: Nude mice with subcutaneous xenografts of human non-small cell lung cancer A549 and HTB177 cells and patients with lung cancer were included. In ex vivo study, intratumoral radioactivity of (18)F-FDG, (18)F-FLT, and the cocktail of (18)F-FDG and (18)F-FLT detected by autoradiography was compared with hypoxia (by pimonidazole) and proliferation (by bromodeoxyuridine) in tumor section. In in vivo study, first, (18)F-FDG PET and (18)F-FLT PET were conducted in the same subjects (mice and patients) 10 to 14 hours apart. Second, PET scan was also performed 1 hour after one tracer injection; subsequently, the other was administered and followed the second PET scan in the mouse. Finally, (18)F-FDG and (18)F-FLT cocktail PET scan was also performed in the mouse. RESULTS: When injected individually, (18)F-FDG highly accumulated in hypoxic zones and high (18)F-FLT in proliferative cancer cells. In case of cocktail injection, high radioactivity correlated with hypoxic regions and highly proliferative and normoxic regions. PET detected that intratumoral distribution of (18)F-FDG and (18)F-FLT was generally mismatched in both rodents and patients. Combination of (18)F-FLT and (18)F-FDG appeared to map more cancer tissue than single-tracer PET. CONCLUSIONS: Combination of (18)F-FDG and (18)F-FLT PET imaging would give a more accurate representation of total viable tumor tissue than either tracer alone and would be a powerful imaging strategy for cancer management. PMID- 24466382 TI - CCR5 Antagonism by Maraviroc Reduces the Potential for Gastric Cancer Cell Dissemination. AB - The chemokine (C-C motif) receptor 5 (CCR5) that belongs to the family of G protein-coupled receptors is exploited by macrophage tropic (R5) human immunodeficiency virus type 1 (HIV-1) to enter cells. Maraviroc, a small molecule CCR antagonist, is used as a part of combination antiretroviral therapy to treat persons infected by R5 HIV-1. CCR5 is expressed in various cancers, and its level of expression is a negative predictor of patients' survival in gastric cancers. Here, we report MKN45, MKN74, and KATOIII cells, three human gastric cancer cell lines with different stages of differentiation, which express CCR5 as detected by flow cytometry and reverse transcription-polymerase chain reaction (RT-PCR), and its ligand RANTES. In vitro experiments demonstrate that CCR5 antagonism reduces gastric cancer cell migration induced by macrophage inflammatory protein 1alpha (MIP-1alpha), MIP-1beta, and RANTES and adhesion to the ex-planted murine peritoneum. Administration of maraviroc from days 3 to 10 after MKN45 cell inoculation to severe combined immunodeficient (SCID) mice effectively reduced the extent of peritoneal disease and increased survival. Maraviroc treatment also reduced the tumor burden in a xenograft model. Gene expression and RT-PCR analyses revealed that CCR5 antagonism in vivo modulates the expression of genes known for their role in cancer growth including interleukin-10 receptor B; hepatocyte growth factor receptor (MET); the homolog of the atypical cadherin gene, FAT1; Nm23-H1; and lymphotoxin beta receptor. In summary, we have shown that CCR5 is mechanistically involved in dissemination of gastric cancer cells, suggesting that small molecule inhibitors of CCR5 might be exploited for their anticancer potential. PMID- 24466385 TI - Understanding Primary Nonadherence. PMID- 24466384 TI - Noninvasive prenatal testing: the future is now. AB - Prenatal detection of chromosome abnormalities has been offered for more than 40 years, first by amniocentesis in the early 1970s and additionally by chorionic villus sampling (CVS) in the early 1980s. Given the well-recognized association between increasing maternal age and trisomy,1-3 the primary utilization of prenatal testing has been by older mothers. This has drastically reduced the incidence of aneuploid children born to older mothers.4 Although younger women have relatively low risks of conceiving a child with aneuploidy, the majority of pregnant women are in their late teens, 20s, and early 30s. As such, most viable aneuploid babies are born to these younger mothers.5 Invasive prenatal diagnosis (CVS and amniocentesis) is not a feasible option for all low-risk mothers, as these procedures carry a small but finite risk and would ultimately cause more miscarriages than they would detect aneuploidy. For this reason, a number of noninvasive tests have been developed-including first-trimester risk assessment at 11 to 14 weeks, maternal serum analyte (quad) screening at 15 to 20 weeks, and sonographic fetal structural survey at 18 to 22 weeks-all of which are designed to give a woman an adjusted (more accurate) estimate of having an aneuploid fetus using as baseline her a priori age-related risk. Ultrasound and maternal serum analysis are considered screening procedures and both require follow up by CVS or amniocentesis in screen-positive cases for a definitive diagnosis of a chromosome abnormality in the fetus. The ability to isolate fetal cells and fetal DNA from maternal blood during pregnancy has opened up exciting opportunities for improved noninvasive prenatal testing (NIPT). Direct analysis of fetal cells from maternal circulation has been challenging given the scarcity of fetal cells in maternal blood (1:10,000-1:1,000,000) and the focus has shifted to the analysis of cell free fetal DNA, which is found at a concentration almost 25 times higher than that available from nucleated blood cells extracted from a similar volume of whole maternal blood. There have now been numerous reports on the use of cell free DNA (cfDNA) for NIPT for chromosomal aneuploidies-especially trisomy (an extra copy of a chromosome) or monosomy (a missing chromosome)-and a number of commercial products are already being marketed for this indication. This article reviews the various techniques being used to analyze cell-free DNA in the maternal circulation for the prenatal detection of chromosome abnormalities and the evidence in support of each. A number of areas of ongoing controversy are addressed, including the timing of maternal blood sampling, the need for genetic counseling, and the use of confirmatory invasive testing. Future applications for this technology are also reviewed. PMID- 24466386 TI - Propolis and its Active Component, Caffeic Acid Phenethyl Ester (CAPE), Modulate Breast Cancer Therapeutic Targets via an Epigenetically Mediated Mechanism of Action. AB - Alternative remedies for cancer treatment is a multi-billion dollar industry. In particular, breast cancer (BC) patients use alternative and natural remedies more frequently than patients with other malignancies. Propolis is an example of a honeybee-produced naturopathic formulation, contents of which differ by geographic location. It is readily available, affordable, and in use safely since ancient times globally. Caffeic acid phenethyl ester (CAPE) is a major active component in propolis and is thought to be responsible for its varied properties, including antibacterial, antiviral, antifungal, antioxidant, anti-inflammatory and anticancer. CAPE is effective in many models of human cancer, including BC as we have previously shown. CAPE affects genes associated with tumor cell growth and survival, angiogenesis and chemoresistance. We demonstrate that these are related in part to CAPE's role as a histone deacetylase inhibitor, a class of drugs designated as epigenetic agents that modulate the activities of oncogenes and tumor suppressor genes. CAPE and propolis, cause an accumulation of acetylated histone proteins in MCF-7 (ER+) and MDA-MB-231 (ER-/PR-/Her2-) cells with associated decreases in ER and PR in MCF-7 cells, and upregulation of ER and decrease in EGFR in MDA-231 cells. In addition, these products reduced activated phosphorylated Her2 protein in SKBR3 (Her2 +) cells. Interestingly, propolis, when normalized for CAPE content, appears to be more potent than CAPE alone similarly to the greater effects of complete foods than isolated components. These data provide a potential mechanistic basis for one of the oldest naturopathic agents used in medicine and cancer treatment. PMID- 24466388 TI - Effects of End Group Termination on Salting-Out Constants for Triglycine. AB - Salting out constants for triglycine were calculated for a series of Hofmeister salts using molecular dynamics simulations. Three variants of the peptide were considered with both termini capped, just the N-terminus capped, and without capping. The simulations were supported by NMR and FTIR measurements. The data provide strong evidence that earlier experimental values of salting out constants assigned to the fully capped peptide (as previously assumed) should have been assigned to the half-capped peptide instead. Therefore, these values cannot be used to directly establish Hofmeister ordering of ions at the peptide backbone, since they are strongly influenced by interactions of the ions with the negatively charged C-terminus. PMID- 24466387 TI - L-Edge X-ray Absorption Spectroscopy of Dilute Systems Relevant to Metalloproteins Using an X-ray Free-Electron Laser. AB - L-edge spectroscopy of 3d transition metals provides important electronic structure information and has been used in many fields. However, the use of this method for studying dilute aqueous systems, such as metalloenzymes, has not been prevalent because of severe radiation damage and the lack of suitable detection systems. Here we present spectra from a dilute Mn aqueous solution using a high transmission zone-plate spectrometer at the Linac Coherent Light Source (LCLS). The spectrometer has been optimized for discriminating the Mn L-edge signal from the overwhelming O K-edge background that arises from water and protein itself, and the ultrashort LCLS X-ray pulses can outrun X-ray induced damage. We show that the deviations of the partial-fluorescence yield-detected spectra from the true absorption can be well modeled using the state-dependence of the fluorescence yield, and discuss implications for the application of our concept to biological samples. PMID- 24466389 TI - Taking a great leap forward on a blue horse. PMID- 24466390 TI - Laparoendoscopic management of midureteral strictures. AB - The incidence of ureteral strictures has increased worldwide owing to the widespread use of laparoscopic and endourologic procedures. Midureteral strictures can be managed by either an endoscopic approach or surgical reconstruction, including open or minimally invasive (laparoscopic/robotic) techniques. Minimally invasive surgical ureteral reconstruction is gaining in popularity in the management of midureteral strictures. However, only a few studies have been published so far regarding the safety and efficacy of laparoscopic and robotic ureteral reconstruction procedures. Nevertheless, most of the studies have reported at least equivalent outcomes with the open approach. In general, strictures more than 2 cm, injury strictures, and strictures associated either with radiation or with reduced renal function of less than 25% may be managed more appropriately by minimally invasive surgical reconstruction, although the evidence to establish these recommendations is not yet adequate. Defects of 2 to 3 cm in length may be treated with laparoscopic or robot-assisted uretero-ureterostomy, whereas defects of 12 to 15 cm may be managed either via ureteral reimplantation with a Boari flap or via transuretero-ureterostomy in case of low bladder capacity. Cases with more extended defects can be reconstructed with the incorporation of the ileum in ureteral repair. PMID- 24466392 TI - Risk factors for postoperative hemorrhage after partial nephrectomy. AB - PURPOSE: To evaluate the frequency and clinical characteristics of postoperative hemorrhage as a complication of partial nephrectomy. MATERIALS AND METHODS: The demographics, physical statistics, tumor size, R.E.N.A.L. nephrometry score, operative method, warm ischemic time, and presence of postoperative hemorrhage and its severity and method of intervention were examined in 300 partial nephrectomy patients in two medical centers (Stanford Medical Center and Kyung Hee University Medical Center) between March 2000 and March 2012. RESULTS: Of the 300 subjects, 13 (4.3%) experienced postoperative hemorrhage severe enough to require intervention more invasive than transfusion (Clavien grade III or higher). Univariate analysis of the bleeding and nonbleeding groups showed that whereas age, ischemic time, tumor size and stage, body mass index, American Society of Anesthesiologists class, and operative method did not differ significantly, the exophyticity (E) score was significantly higher for severe postoperative hemorrhage (p=0.04). However, multivariate analysis showed none of the factors to differ significantly. In most of the cases requiring intervention, selective embolization was sufficient, but in one case explorative laparotomy and nephrectomy were required. Clinical characteristics varied significantly among severe hemorrhage cases, with time of onset ranging from the first to the 30th postoperative day and symptoms presenting in a diverse manner, such as gross hematuria and pleuritic chest pain. Computed tomography and angiographic findings were consistent with either arteriovenous fistula or pseudoaneurysms. CONCLUSIONS: Severe hemorrhage after partial nephrectomy is rare. Nonetheless, with the great variability in presenting symptoms and time of onset after surgery, surgeons should exercise great vigilance during the postoperative care of partial nephrectomy patients. PMID- 24466391 TI - Hypogonadism in human immunodeficiency virus-positive men. AB - In recent years, the life expectancy for those living with human immunodeficiency virus (HIV) with access to combined antiretroviral therapy (cART) has increased. As men live longer, the role testosterone plays in sexual function as well as in general well-being is becoming increasingly important. Here we discuss the available literature concerning androgens and HIV disease. A review was undertaken by using a PubMed search with the umbrella terms HIV or AIDS and testosterone or androgens spanning 1985 to 2011. Significant articles found in references in the primary search were also included. The reported prevalence of androgen deficiency appears to be greater in HIV-infected males than in the general population. Androgen deficiency is usually associated with low luteinizing hormone and follicle-stimulating hormone and is sensitive to the type of measurement of testosterone used. Rates of hypogonadism may be falling since the advent of cART. Causes of low testosterone levels have been attributed to chronic illness, HIV replication, cART, opportunistic infections, comorbidities and coinfections, wasting, and normal age-related declines. Studies of testosterone treatment in HIV-positive men are lacking in standardization and outcome measures. PMID- 24466393 TI - Interfraction prostate movement in bone alignment after rectal enema for radiotherapy. AB - PURPOSE: To assess the effect of a rectal enema on interfraction prostate movement in bone alignment (BA) for prostate radiotherapy (RT), we analyzed the spatial difference in prostates in a bone-matched setup. MATERIALS AND METHODS: We performed BA retrospectively with data from prostate cancer patients who underwent image-guided RT (IGRT). The prostate was identified with implanted fiducial markers. The setup for the IGRT was conducted with the matching of three fiducial markers on RT planning computed tomography images and those on two oblique kV x-ray images. Offline BA was performed at the same position. The coordinates of a virtual prostate in BA and a real prostate were obtained by use of the ExaxTrac/NovalisBody system, and the distance between them was calculated as the spatial difference. Interfraction prostate displacement was drawn from the comparison of the spatial differences. RESULTS: A total of 15 patients with localized prostate cancer treated with curative hypofractionated IGRT were enrolled. A total of 420 fractions were analyzed. The mean of the interfraction prostate displacements after BA was 3.12+/-2.00 mm (range, 0.20-10.53 mm). The directional difference was profound in the anterior-posterior and supero-inferior directions (2.14+/-1.73 mm and 1.97+/-1.44 mm, respectively) compared with the right-left direction (0.26+/-0.22 mm, p<0.05). The required margin around the clinical target volume was 4.97 mm with the formula of van Herk et al. CONCLUSIONS: The interfraction prostate displacement was less frequent when a rectal enema was performed before the procedure. A rectal enema can be used to reduce interfraction prostate displacement and resulting clinical target volume to-planning target volume margin. PMID- 24466394 TI - Hand-assisted retroperitoneoscopic nephroureterectomy with bladder cuffing after preperitoneal and retroperitoneal perivesical ballooning. AB - PURPOSE: We aimed to describe the surgical technique of hand-assisted retroperitoneoscopic nephroureterectomy (HARNU) with bladder cuffing after preperitoneal and retroperitoneal perivesical ballooning. MATERIALS AND METHODS: From March 2008 to September 2012, we performed HARNU and open bladder cuffing in 28 consecutive series of patients with upper urinary tract urothelial carcinoma. We performed HARNU according to the following procedure: (1) a camera port incision was made on the posterior axillary line; (2) multiple, repeated, preperitoneal and retroperitoneal ballooning was performed on both the posterior axillary line and in the umbilicus; (3) a 7.0 cm skin incision was made from the suprapubic to the lower inguinal with the balloon present in the extraperitoneal area; (4) hand-assisted laparoscopic retroperitoneal nephroureterectomy; (5) cessation of gas insufflation; and (6) extravesical cuffing as an open surgical procedure. RESULTS: The mean estimated blood loss was 250 mL. The mean operation time was 240 minutes. The mean time to oral intake and ambulation was 1.0 day and two days, respectively. As for postoperative complications due to the hand assisted device, one patient developed febrile urinary tract infection within three weeks postoperatively and was hospitalized again to receive parenteral antibiotics. CONCLUSIONS: We made a low Gibson incision for a route for the hand assisted procedure as well as a window for open surgery in dissecting the distal ureter and extracting the surgical specimens. Thus, our results indicate that the HARNU might be a feasible surgical modality. PMID- 24466395 TI - The effect of terpene combination on ureter calculus expulsion after extracorporeal shock wave lithotripsy. AB - PURPOSE: Terpene combination (Rowatinex) is known to help with the expulsion of urinary stones. The aim of this study was to determine how Rowatinex affects the expulsion of remnant stones after shock wave lithotripsy (SWL). MATERIALS AND METHODS: Clinical data were collected retrospectively from 499 patients with a diagnosis of ureteral stones who underwent SWL from January 2009 to August 2012. Ureteral stones were diagnosed in all patients by kidney, ureter, and bladder x ray and abdominal computed tomography (CT). The progress of patients was documented every 2 weeks to confirm remnant stones after SWL. The patients with remnant stones underwent SWL again. Group 1 consisted of patients who were prescribed an analgesic, Tamsulosin 0.2 mg, and Rowatinex. Group 2 consisted of patients who were prescribed only an analgesic and Tamsulosin 0.2 mg. The expulsion rate of urinary stones was compared between groups. RESULTS: The expulsion rate of urinary stones was not significantly different between the two groups after 2 weeks. However, after 4 weeks, group 1 had a significantly higher expulsion rate (72.2% compared with 61.1%, p=0.022). Fifteen patients (10.2%) in group 1 and 40 (11.4%) in group 2 had to undergo ureteroscopic removal of the stone (p=0.756). Acute pyelonephritis occurred in one patient (0.7%) in group 1 and in one patient (0.3%) in group 2 (p=0.503). CONCLUSIONS: The long-term administration of Rowatinex for 4 weeks increased the expulsion rate of urinary stones after SWL. PMID- 24466396 TI - An Analytical Comparison of Short-term Effectiveness and Safety Between Thulium:YAG Laser Vaporesection of the Prostate and Bipolar Transurethral Resection of the Prostate in Patients With Benign Prostatic Hyperplasia. AB - PURPOSE: In recent years, laser surgery has been widely used to treat benign prostatic hyperplasia (BPH). A thulium:yttrium-aluminium-garnet (Tm:YAG) laser was recently introduced for BPH surgery. We compared the effectiveness and safety of Tm:YAG laser vaporesection of the prostate (ThuVaRP) with that of bipolar transurethral resection of the prostate (TURP). MATERIALS AND METHODS: From January 2010 to December 2012, 86 patients underwent surgical treatment for symptomatic BPH by a single surgeon. We retrospectively analyzed and compared the medical records of 43 patients who underwent ThuVaRP and 43 patients who underwent bipolar TURP. All patients were assessed by using the International Prostate Symptom Score, transrectal ultrasonography, the serum prostate-specific antigen (PSA) level, uroflowmetry, and postvoid residual volume before and 1 month after surgery. All complications were compared between the two groups. RESULTS: ThuVaRP was superior to TURP in catheterization time (p<0.001) and length of hospital stay (p<0.001). However, operation time was longer with ThuVaRP than with TURP (p<0.001). In patients with a large prostate (>50 g), operation time was much longer with ThuVaRP. One month after surgery, the decrease in PSA was greater (p=0.045) with ThuVaRP than with TURP, and the increase in maximal urine flow rate was greater (p<0.001) with ThuVaRP than with TURP. The postoperative complication transient urinary incontinence was significantly different between the ThuVaRP group (nine cases, 20.9%) and the TURP group (two cases, 4.7%). Other complications were comparable between groups. CONCLUSIONS: The effectiveness and safety of ThuVaRP and TURP were comparable. ThuVaRP is a promising alternative surgical technique to TURP for BPH. PMID- 24466397 TI - Changes in bladder wall thickness and detrusor wall thickness after surgical treatment of benign prostatic enlargement in patients with lower urinary tract symptoms: a preliminary report. AB - PURPOSE: The purpose of the present study was to evaluate the perioperative changes in bladder wall thickness and detrusor wall thickness after transurethral prostatectomy. MATERIALS AND METHODS: Fifty-one men who were treated for benign prostatic hyperplasia/lower urinary tract symptoms with transurethral prostatectomy were prospectively analyzed from May 2012 to July 2013. Prostate size, detrusor wall thickness, and bladder wall thickness were assessed by transrectal and transabdominal ultrasonography perioperatively. All postoperative evaluations were performed 1 month after the surgery. RESULTS: The patients' mean age was 69.0 years, the mean prostate-specific antigen concentration was 8.1 ng/mL, and the mean prostate volume was 63.2 mL. The mean bladder wall thickness was 5.1 mm (standard deviation [SD], +/-1.6), 5.1 mm (SD, +/-1.6), and 5.0 mm (SD, +/-1.4) preoperatively and 4.5 mm (SD, +/-1.5), 4.5 mm (SD, +/-1.3), and 4.6 mm (SD, +/-1.2) postoperatively in the anterior wall, dome, and trigone, respectively (p=0.178, p=0.086, and p=0.339, respectively). The mean detrusor wall thickness was 0.9 mm (SD, +/-0.4) preoperatively and 0.7 mm (SD, +/-0.3) postoperatively (p=0.001). A subgroup analysis stratifying patients into a large prostate group (weight, >=45 g) and a high Abrams-Griffiths number group (>30) showed a significant decrease in detrusor wall thickness (p=0.002, p=0.018). CONCLUSIONS: There was a decrease in detrusor wall thickness after transurethral prostatectomy. The large prostate group and the high Abrams-Griffiths number group showed a significant decrease in detrusor wall thickness after surgery. PMID- 24466398 TI - Clinical effects of discontinuing 5-alpha reductase inhibitor in patients with benign prostatic hyperplasia. AB - PURPOSE: To assess changes in lower urinary tract symptoms (LUTS), prostate volume, and serum prostate-specific antigen (PSA) after discontinuation of 5 alpha reductase inhibitor (5ARI) combination therapy in patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: From December 2003 to December 2012, data were collected retrospectively from 81 men more than 40 years of age with moderate to severe BPH symptoms (International Prostate Symptom Score [IPSS]>=8). The men were classified into group 1 (n=42) and group 2 (n=39) according to the use of 5ARI therapy. A combination of dutasteride 0.5 mg with tamsulosin 0.2 mg was given daily to all patients for 1 year. For the next 1 year, group 1 (n=42) received the combination therapy and group 2 (n=39) received tamsulosin 0.2 mg monotherapy only. The IPSS, prostate volume, and PSA level were measured at baseline and at 12 and 24 months according to the use of dutasteride. RESULTS: Discontinuation of dutasteride led to significant deterioration of LUTS, increased prostate volume, and increased PSA level. The repeated-measures analysis of variance showed that the changes in IPSS, prostate volume, and PSA level over time also differed significantly between groups 1 and 2 (p<0.001). CONCLUSIONS: Withdrawal of 5ARI during combination therapy resulted in prostate regrowth and deterioration of LUTS. The PSA level is also affected by the use of 5ARI. Therefore, regular check-up of the IPSS and PSA level may be helpful for all patients who either continue or discontinue the use of 5ARI. PMID- 24466399 TI - Urologists' Perceptions and Practice Patterns in Peyronie's Disease: A Korean Nationwide Survey Including Patient Satisfaction. AB - PURPOSE: A nationwide survey was conducted of Korean urologists to illustrate physicians' perceptions and real practical patterns regarding Peyronie disease (PD). MATERIALS AND METHODS: A specially designed questionnaire exploring practice characteristics and attitudes regarding PD, as well as patient satisfaction with each treatment modality, was e-mailed to 2,421 randomly selected urologists. RESULTS: Responses were received from 385 practicing urologists (15.9%) with a median time after certification as an urologist of 12 years. Regarding the natural course, 87% of respondents believed that PD is a progressive disease, and 82% replied that spontaneous healing in PD occurred in fewer than 20% of patients. Regarding diagnosis of PD, the methods used were, in order, history taking with physical examination (98%), International Index of Erectile Function questionnaires (40%), intracavernous injection and stimulation (35%), and duplex sonography (28%). Vitamin E was most preferred as an initial medical management (80.2%), followed by phosphodiesterase-5 inhibitors (27.4%) and Potaba (aminobenzoate potassium, 20.1%). For urologists who administered intralesional injection, the injected agent was, in order, corticosteroid (72.2%), verapamil (45.1%), and interferon (3.2%). The most frequently performed surgical procedure was plication (84.1%), followed by excision and graft (42.9%) and penile prosthesis implantation (14.2%). Among the most popular treatments in each modality, the urologists' perceptions regarding the suitability of treatment and patient satisfaction were significantly different, favoring plication surgery. CONCLUSIONS: The practice pattern of urologists depicted in this survey is in line with currently available Western guidelines, which indicates the need for development of further local guidelines based on solid clinical data. PMID- 24466400 TI - Which patients are at higher risk for residual valves after posterior urethral valve ablation? AB - PURPOSE: To find patients at high risk of obstructive remnant leaflets after valve ablation among boys with posterior urethral valve (PUV), we evaluated any possible relationship between preoperative findings in our patients and residual obstructive leaflets after valve ablation. MATERIALS AND METHODS: We retrospectively reviewed the medical records of 55 patients with PUV that was treated by the same surgeon between 2008 and 2012. Of these, 37 patients (67.3%) had no obstructive remnant leaflets (group A) and 18 patients (32.7%) had obstructive remnant leaflets (group B) in follow-up cystoscopy. Preoperative clinical and radiological findings were evaluated and compared between the groups. RESULTS: AMONG ALL THE PREOPERATIVE DATA WE EXAMINED, THE ANALYSIS REVEALED THAT AGE AT THE TIME OF SURGERY (MEDIAN AGE: group A, 15 months; group B, 7 months; p=0.017), echogenicity of kidneys (p<0.05), presence of vesicoureteral reflux (p<0.05), and grade of reflux (p<0.05) were significantly different between the groups. Method of valve ablation, anterior-posterior diameters of the renal pelvis, renal cortical thickness, bladder wall thickening, and scarring on the dimercaptosuccinic acid scan showed no significant differences between the two groups. CONCLUSIONS: In our patients, younger age at surgery time, hyperechogenicity of renal parenchyma, presence of vesicoureteral reflux, and grade 4 or 5 reflux before surgery had a significant relationship with residual valves. More studies may result in enhanced management of patients at high risk of residual valves after PUV ablation, because the sooner the obstruction is resolved entirely, the better the outcome. PMID- 24466401 TI - Reasons for delayed orchiopexies in a korean tertiary care hospital. AB - PURPOSE: Since the 1990s, it has been well known that orchiopexies should be performed by no later than 2 years of age. Nevertheless, studies from other countries report a substantial number of delayed orchiopexies. On the basis of an analysis of a tertiary care hospital database, we aimed to investigate the incidence of delayed orchiopexies performed in patients after 5 years of age and to understand the causes of such delays and the possible consequences. MATERIALS AND METHODS: We retrospectively analyzed the surgical database of Seoul National University Hospital between 2004 and 2012 and detected patients who underwent orchiopexy later than 5 years of age. Reasons for delayed orchiopexies were studied and the possible consequences of delayed orchiopexies were assessed with respect to surgical difficulty and testicular volume. RESULTS: We found 160 cases of delayed orchiopexies, which accounted for about 15% of all orchiopexies performed. Two major reasons for delay were related to the parents of the child: parental delay and parental request for the treatment of persistent retractile testis. Acquired cryptorchidism was found in 21 cases (13.1%), mainly associated with hypospadias. Surgical difficulty, especially owing to a short testicular cord, was encountered in 48 cases (30.2%), and a comparison with age-matched normative values showed substantially smaller testicular volume. CONCLUSIONS: Despite well-established guidelines for the optimal age of surgery, 15% of orchiopexies were not performed at a proper time. Improved propagation of an optimal age limit is necessary to reduce the rate of delayed orchiopexies considering increases in surgical difficulty and potential testicular growth retardation. PMID- 24466402 TI - Intolerance to sunitinib treatment in hemodialysis patients with metastatic renal cell carcinoma. AB - Sunitinib is a multiple tyrosine kinase receptor inhibitor that is approved for the treatment of metastatic renal cell carcinoma (RCC). However, neither an appropriate dose nor dosing schedule of sunitinib has yet been established for patients with metastatic RCC who are on hemodialysis. Here, we report on two hemodialysis patients who received sunitinib to treat metastatic RCC. Sunitinib was planned to be administered at a dosage of 25 mg/d for 4 of every 6 weeks. Although sunitinib toxicity was manageable in one patient, disease progression occurred after 4 months of treatment. In the second patient, acute pulmonary edema, caused by uncontrolled hypertension, developed on the 15th day of sunitinib therapy and the drug had to be discontinued. Sunitinib is thus not well tolerated in a hemodialysis setting. Close monitoring of toxicity and dose manipulation may be required if such therapy is attempted. PMID- 24466403 TI - Ureteral substitution using appendix for a ureteral defect caused by a retroperitoneal rhabdomyosarcoma in a child. AB - A 7-year-old boy was diagnosed with a recurrent embryonal rhabdomyosarcoma in the retroperitoneum. After resection of the mass, direct end-to-end anastomosis of the ureter was not possible owing to the length of the resected segment. Accordingly, we performed ureteral substitution by using the appendix to repair the ureteral defect. PMID- 24466404 TI - The p53-MDM2/MDMX axis - A chemotype perspective. AB - The protein-protein interaction (PPI) of the tumor suppressor p53 and its negative regulator MDM2 consists of the most intense studied PPI with a group of small molecular weight antagonists described and many more disclosed in patent literature. Due to the A-level structural insight into p53 interaction with MDM2 there is a reasonable understanding of the requirements of the molecules to bind. In contrast and despite the very close homology and 3-D similarity no potent MDMX antagonist has been disclosed up to date. The current review summarizes the different disclosed chemotypes for MDM2 including a discussion of the cocrystal structures. Structures and approaches to reconstitute functional p53 from mutated p53 are presented. Finally new screening methods and recent biotech deals based on p53 are discussed. PMID- 24466405 TI - The structure-activity relationships of L3MBTL3 inhibitors: flexibility of the dimer interface. AB - We recently reported the discovery of UNC1215, a potent and selective chemical probe for the L3MBTL3 methyllysine reader domain. In this article, we describe the development of structure-activity relationships (SAR) of a second series of potent L3MBTL3 antagonists which evolved from the structure of the chemical probe UNC1215. These compounds are selective for L3MBTL3 against a panel of methyllysine reader proteins, particularly the related MBT family proteins, L3MBTL1 and MBTD1. A co-crystal structure of L3MBTL3 and one of the most potent compounds suggests that the L3MBTL3 dimer rotates about the dimer interface to accommodate ligand binding. PMID- 24466406 TI - Bridged tetrahydroisoquinolines as selective NADPH oxidase 2 (Nox2) inhibitors. AB - (1SR,4RS)-3,3-Dimethyl-1,2,3,4-tetrahydro-1,4-(epiminomethano)naphthalenes were synthesized in 2-3 steps from commercially available materials and assessed for specificity and effectiveness across a range of Nox isoforms. The N-pentyl and N methylenethiophene substituted analogs 11g and 11h emerged as selective Nox2 inhibitors with cellular IC50 values of 20 and 32 MUM, respectively. PMID- 24466407 TI - Polymer waveguide grating sensor integrated with a thin-film photodetector. AB - This paper presents a planar waveguide grating sensor integrated with a photodetector (PD) for on-chip optical sensing systems which are suitable for diagnostics in the field and in-situ measurements. III-V semiconductor-based thin film PD is integrated with a polymer based waveguide grating device on a silicon platform. The fabricated optical sensor successfully discriminates optical spectral characteristics of the polymer waveguide grating from the on-chip PD. In addition, its potential use as a refractive index sensor is demonstrated. Based on a planar waveguide structure, the demonstrated sensor chip may incorporate multiple grating waveguide sensing regions with their own optical detection PDs. In addition, the demonstrated processing is based on a post-integration process which is compatible with silicon complementary metal-oxide semiconductor (CMOS) electronics. Potentially, this leads a compact, chip-scale optical sensing system which can monitor multiple physical parameters simultaneously without need for external signal processing. PMID- 24466409 TI - Rickets before the discovery of vitamin D. AB - The story of rickets leading to the discovery of vitamin D is an extraordinary tale, spread over many centuries and involving some remarkable characters with much speculation and a few mysteries, before reaching an exciting climax. It would be wrong to credit a single person as discovering rickets or being the first to describe its features, for reasons that will be set out here. Yet the emergence of the term 'rickets' is as important as the discovery of vitamin D itself and the possible causes of its deficiency. It permitted identification of a hitherto ill-defined disease entity, typically occurring in infants and children. It also provided a way for deciding if features of diseases that had been described earlier in the history of medicine could be seen as the symptoms and signs of related conditions. PMID- 24466408 TI - Treatment of Nausea and Vomiting During Chemotherapy. AB - Nausea and vomiting are two of the most troubling side effects patients experience during chemotherapy. While newly available treatments have improved our ability to manage nausea and vomiting, anticipatory and delayed nausea and vomiting are still a major problem for patients receiving chemotherapy. Many cancer patients will delay or refuse future chemotherapy treatments and contemplate stopping chemotherapy altogether because of their fear of experiencing further nausea and vomiting. The purpose of this article is to provide an overview of the patho-psychophysiology of chemotherapy-induced nausea and vomiting and the recommended guidelines for treatment. PMID- 24466410 TI - History of the discovery of vitamin D and its active metabolites. AB - Before the twentieth century, it was not possible to describe the essentials of a diet that could support life, growth and reproduction of higher animals. The discovery of vitamin A by McCollum and Davis in 1913 ushered in the era of accessory food substances culminating in the achievement of that goal. It included the discovery of vitamin D and its production in skin caused by ultraviolet light. This was followed by a description of its actions at the physiological level that resulted in a healthy skeleton and beyond. To carry out these functions, vitamin D is converted to a hormone that acts through a nuclear receptor. The findings leading to this concept and their importance to biology and medicine are presented. PMID- 24466411 TI - Vitamin D: calcium and bone homeostasis during evolution. AB - Vitamin D3 is already found early in the evolution of life but essentially as inactive end products of the photochemical reaction of 7-dehydrocholestol with ultraviolet light B. A full vitamin D (refers to vitamin D2 and D3) endocrine system, characterized by a specific VDR (vitamin D receptor, member of the nuclear receptor family), specific vitamin D metabolizing CYP450 enzymes regulated by calciotropic hormones and a dedicated plasma transport-protein is only found in vertebrates. In the earliest vertebrates (lamprey), vitamin D metabolism and VDR may well have originated from a duplication of a common PRX/VDR ancestor gene as part of a xenobiotic detoxification pathway. The vitamin D endocrine system, however, subsequently became an important regulator of calcium supply for an extensive calcified skeleton. Vitamin D is essential for normal calcium and bone homeostasis as shown by rickets in vitamin D-deficient growing amphibians, reptiles, birds and mammals. From amphibians onward, bone is gradually more dynamic with regulated bone resorption, mainly by combined action of PTH and 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) on the generation and function of multinucleated osteoclasts. Therefore, bone functions as a large internal calcium reservoir, under the control of osteoclasts. Osteocytes also display a remarkable spectrum of activities, including mechanical sensing and regulating mineral homeostasis, but also have an important role in global nutritional and energy homeostasis. Mineralization from reptiles onward is under the control of well-regulated SIBLING proteins and associated enzymes, nearly all under the control of 1,25(OH)2D3. The vitamin D story thus started as inert molecule but gained an essential role for calcium and bone homeostasis in terrestrial animals to cope with the challenge of higher gravity and calcium-poor environment. PMID- 24466414 TI - A hypoxia-inducible factor stabilized by estrogen: its role in osteoporosis. PMID- 24466412 TI - Coupling the activities of bone formation and resorption: a multitude of signals within the basic multicellular unit. AB - Coupling between bone formation and bone resorption refers to the process within basic multicellular units in which resorption by osteoclasts is met by the generation of osteoblasts from precursors, and their bone-forming activity, which needs to be sufficient to replace the bone lost. There are many sources of activities that contribute to coupling at remodeling sites, including growth factors released from the matrix, soluble and membrane products of osteoclasts and their precursors, signals from osteocytes and from immune cells and signaling taking place within the osteoblast lineage. Coupling is therefore a process that involves the interaction of a wide range of cell types and control mechanisms. As bone remodeling occurs at many sites asynchronously throughout the skeleton, locally generated activities comprise very important control mechanisms. In this review, we explore the potential roles of a number of these factors, including sphingosine-1-phosphate, semaphorins, ephrins, interleukin-6 (IL-6) family cytokines and marrow-derived factors. Their interactions achieve the essential tight control of coupling within individual remodeling units that is required for control of skeletal mass. PMID- 24466415 TI - A factor that couples bone formation to bone resorption. PMID- 24466413 TI - Regulation of gene expression by 1,25-dihydroxyvitamin D3 in bone cells: exploiting new approaches and defining new mechanisms. AB - The biological actions of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) serve both to orchestrate calcium and phosphorus homeostasis in higher vertebrates and to regulate a diverse set of cellular functions unrelated to control of mineral metabolism. With regard to bone, mesenchymal lineage cells, including both early and late osteoblasts as well as osteocytes represent classic targets of the vitamin D hormone. Accordingly, much of the early information regarding our current understanding of the mechanism of action of 1,25(OH)2D3, of which gene regulation is central, derives from a broad array of studies in these cell types. Indeed, a gene that provided both the earliest and perhaps the most extensive information regarding this and additional mechanisms was that of osteoblast specific osteocalcin. Subsequent work has provided much additional detail as to how 1,25(OH)2D3, through the vitamin D receptor (VDR), mediates the modulation of many bone cell genes. In recent years, however, a series of technical advances involving the coupling of chromatin immunoprecipitation (ChIP) to unbiased methodologies that involve next-generation DNA sequencing techniques (ChIP-seq) have opened new avenues in the study of gene regulation. In this review, we summarize early work and then focus on more recent studies that have used ChIP seq analysis and other approaches to provide insight into not only the regulation of specific genes such as the VDR, TNFSF11 (RANKL), LRP5, CBS and CYP24a1, but overarching genome-wide principles of gene regulation as well. The results of these studies highlight the value of these new approaches and the increased insight that can be gained. PMID- 24466416 TI - Lamin-A in the cell nucleus regulates tissue stiffness, driving differentiation. PMID- 24466417 TI - Pregnancy-associated osteoporosis: clues to a possible genetic origin. PMID- 24466418 TI - Schnurri-3 and its interaction with ERK and WNT signaling. PMID- 24466419 TI - Denosumab prevents bone metastasis in men with castration-resistant prostate cancer. PMID- 24466420 TI - Atrasentan of no benefit to men with metastatic prostate cancer. PMID- 24466421 TI - Role of the bone marrow microenvironment in CML and AML. PMID- 24466422 TI - Fat metabolism is under the control of osteocytes. PMID- 24466423 TI - The link between arterial calcification and low bone mass in mice. PMID- 24466424 TI - Exploring interactions between dietary calcium, genetics and bone remodeling. PMID- 24466425 TI - Influenza and pneumococcal vaccinations in dialysis patients in a London district general hospital. AB - BACKGROUND: Patients on dialysis mount reduced immune responses compared with the general population. The Department of Health advises that these patients receive influenza and pneumococcal vaccinations at regular intervals-once yearly and every five years, respectively. This article investigates the uptake of these vaccinations in this patient population and seeks to examine factors that may influence vaccination status such as patient's language and presence of a general practitioner (GP) electronic vaccination reminder system. It also explores preferred site of vaccination for patients and GPs as these are primary care vaccinations yet patients have more frequent contact with their dialysis unit than their GP, blurring the boundaries between primary and specialized care. METHODS: This is a retrospective study of all patients registered as dialysing at the North Middlesex University Hospital NHS Trust (NMUH) in September 2011. Information was obtained through GP letters, GP and patient questionnaires. RESULTS: Of 154 patients, 133 were included in the data analysis. Nineteen per cent were up-to-date with both vaccinations and 67% with their influenza vaccination. Fifty per cent had received the influenza vaccination in the last two consecutive years. Thirty per cent were not up-to-date with either vaccination. There was no evidence of a difference in uptake in 2009 (P = 0.7564) and in 2010 (P = 0.7435) among those who could and could not speak English. Twenty-five per cent of GPs and 58.6% of patients preferred vaccination to occur in the dialysis unit. Unfortunately a high number of GPs did not provide information on whether they used an electronic vaccination reminder but the analysis from the information provided by the few respondents did not reveal any correlation between the presence of an electronic reminder and vaccination status. CONCLUSION: Most dialysis patients were not up-to-date with both vaccinations. They were, however, more up-to-date with their influenza than their pneumococcal vaccination. Non-English speakers did not appear to be disadvantaged. GP electronic reminder systems may have influenced influenza uptake but this study did not demonstrate a correlation and this is likely due to the lack of GP respondents; the effectiveness of electronic reminders merits further studies as a tool to improve vaccination rates in at-risk populations. Most patients visited their GP at least annually but preferred to receive their vaccinations at the hospital. Vaccinating in the dialysis unit and maintaining an electronic record accessible to GPs or generating a letter for GPs may help fill the vaccination gap in these patients. Overall, more evidence is required for the effectiveness of such vaccinations and their frequency, but in the meantime UK national guidelines were not being followed with a large proportion of patients remaining unvaccinated against influenza and in particular pneumococcal disease. This audit highlights the importance of local data collection, discussions around correlations influencing outcomes and publication of results to improve standards of care at a national level. PMID- 24466426 TI - Presensitization revisited: pitfalls of vascular allografts in transplant candidates. AB - Vascular allografts in end-stage renal disease (ESRD) patients represent a particular immunological challenge. A broad HLA immunization led us to study in depth the history of two patients with vascular allografts. In Case 1 the allograft was added to a Gore-Tex graft used for haemodialysis access and no immunosuppression was administered. In Case 2 the allograft was used to prolong a renal artery from living donor and immunosuppression was suboptimal. In vascular surgery, immunosuppression is mainly used to improve graft patency. ESRD patients are potential organ recipients and immunosuppression should therefore be tailored to reduce HLA immunization. PMID- 24466427 TI - Social networks, time homeless, and social support: A study of men on Skid Row. AB - Homeless men are frequently unsheltered and isolated, disconnected from supportive organizations and individuals. However, little research has investigated these men's social networks. We investigate the structure and composition of homeless men's social networks, vis-a-vis short- and long-term homelessness with a sample of men drawn randomly from meal lines on Skid Row in Los Angeles. Men continuously homeless for the past six months display networks composed of riskier members when compared to men intermittently homeless during that time. Men who report chronic, long-term homelessness display greater social network fragmentation when compared to non-chronically homeless men. While intermittent homelessness affects network composition in ways that may be addressable with existing interventions, chronic homelessness fragments networks, which may be more difficult to address with those interventions. These findings have implications for access to social support from network members which, in turn, impacts the resources homeless men require from other sources such as the government or NGOs. PMID- 24466429 TI - Editorial introduction - European journal of microbiology and immunology. PMID- 24466428 TI - Rapid Prototyping of Heterotypic Cell-Cell Contacts. AB - Disparities in cellular behaviour between cultures of a single cell type and heterogeneous co-cultures require constructing spatially-defined arrays of multiple cell types. Such arrays are critical for investigating cellular properties as they exist in vivo. Current methods rely upon covalent surface modification or external physical micromanipulation to control cellular organization on a limited range of substrates. Here, we report a direct approach for creating co-cultures of different cell types by microcontact printing a photosensitive cell resist. The cell-resistant polymer converts to cell adhesive 0 with light exposure, thus the initial copolymer pattern dictates the position of both cell types. This strategy enables straightforward preparation of tailored heterotypic cell-cell contacts on materials ranging from polymers to metallic substrates. PMID- 24466430 TI - Welcome - "How immunology has won in Hungary". PMID- 24466431 TI - Parasite dissemination and the pathogenesis of toxoplasmosis. PMID- 24466432 TI - New insights into host-pathogen interactions during Entamoeba histolytica liver infection. AB - Amoebiasis is the third worldwide disease due to a parasite. The causative agent of this disease, the unicellular eukaryote Entamoeba histolytica, causes dysentery and liver abscesses associated with inflammation and human cell death. During liver invasion, before entering the parenchyma, E. histolytica trophozoites are in contact with liver sinusoidal endothelial cells (LSEC). We present data characterizing human LSEC responses to interaction with E. histolytica and identifying amoebic factors involved in the process of cell death in this cell culture model potentially relevant for early steps of hepatic amoebiasis. E. histolytica interferes with host cell adhesion signalling and leads to diminished adhesion and target cell death. Contact with parasites induces disruption of actin stress fibers and focal adhesion complexes. We conclude that interference with LSEC signalling may result from amoeba-triggered changes in the mechanical forces in the vicinity of cells in contact with parasites, sensed and transmitted by focal adhesion complexes. The study highlights for the first time the potential role in the onset of hepatic amoebiasis of the loss of liver endothelium integrity by disturbance of focal adhesion function and adhesion signalling. Among the amoebic factors required for changed LSEC adherence properties we identified the Gal/GalNAC lectin, cysteine proteases and KERP1. PMID- 24466433 TI - Intestinal dendritic cell and macrophage subsets: Tipping the balance to Crohn's disease? AB - Dendritic cells and macrophages play an essential role in immune homeostasis in the intestine. They have the critical task of maintaining the balance between tolerance to the intestinal microflora and potential food antigens while retaining the ability to initiate immunity against pathogens. For patients with Crohn's Disease, the tolerance/immunity balance is disturbed and these individuals suffer from chronic intestinal inflammation driven by aberrant T cell reactivity to intestinal bacteria. As antigen presenting cells are required for T cell activation, intestinal phagocytes with the capacity to present antigens from intestinal bacteria to T cells are likely involved in initiating and propagating Crohn's Disease. Recent data describe unique subsets of human intestinal phagocytes that may be involved in the aberrant reactivity to commensal flora that drives Crohn's Disease pathogenesis. This review summarizes the current knowledge of phagocyte subsets in the intestine and mesenteric lymph nodes in healthy individuals and Crohn's Disease patients. Deciphering the function of intestinal phagocytes in health and disease is crucial to advance our understanding of the cellular mechanisms underlying this debilitating disease, provides a potential way to improve treatment for patients with inflammatory bowel disease. PMID- 24466436 TI - Imported parasitic infections in Serbia. AB - BACKGROUND: Travel to the tropics is associated with a risk of parasitic infection, which is increasing in parallel with the rise in travel to these areas. We thus examined the prevalence and trend in the occurrence of parasitic infections in Serbian travelers. METHODS: A retrospective analysis of the medical records of all travelers returning from tropical and subtropical areas, who presented at the Institute for Infectious and Tropical Diseases in Belgrade between January 2001 and January 2008, was performed. RESULTS: Of a total of 2440 travelers, 169 (6.9%) were diagnosed with a parasitic infection, including malaria in 79, intestinal parasites in 84 (pathogenic species in 30 and non pathogenic in 54), filariasis in four, and visceral leishmaniasis and fascioliasis in one patient each. Importantly, of the whole series only 583 (23.9%) were symptomatic, of which 19.4% were found to be infected with a parasite. The single pathogenic parasite occurring in asymptomatic patients was Giardia intestinalis. CONCLUSIONS: Parasitic infection causing symptomatic disease among travelers returning from tropical areas to Serbia is not infrequent. In view of the expected increase in travel to the tropics, diagnostic protocols for tropical parasitic diseases should take these data into account. PMID- 24466435 TI - Gingipains from Porphyromonas gingivalis - Complex domain structures confer diverse functions. AB - Gingipains, a group of arginine or lysine specific cysteine proteinases (also known as RgpA, RgpB and Kgp), have been recognized as major virulence factors in Porphyromonas gingivalis. This bacterium is one of a handful of pathogens that cause chronic periodontitis. Gingipains are involved in adherence to and colonization of epithelial cells, haemagglutination and haemolysis of erythrocytes, disruption and manipulation of the inflammatory response, and the degradation of host proteins and tissues. RgpA and Kgp are multi-domain proteins composed of catalytic domains and haemagglutinin/adhesin (HA) regions. The structure of the HA regions have previously been defined by a gingipain domain structure hypothesis which is a set of putative domain boundaries derived from the sequences of fragments of these proteins extracted from the cell surface. However, multiple sequence alignments and hidden Markov models predict an alternative domain architecture for the HA regions of gingipains. In this alternate model, two or three repeats of the so-called "cleaved adhesin" domains (and one other undefined domain in some strains) are the modules which constitute the substructure of the HA regions. Recombinant forms of these putative cleaved adhesin domains are indeed stable folded protein modules and recently determined crystal structures support the hypothesis of a modular organisation of the HA region. Based on the observed K2 and K3 structures as well as multiple sequence alignments, it is proposed that all the cleaved adhesin domains in gingipains will share the same beta-sandwich jelly roll fold. The new domain model of the structure for gingipains and the haemagglutinin (HagA) proteins of P. gingivalis will guide future functional studies of these virulence factors. PMID- 24466434 TI - C-type lectins with a sweet spot for Mycobacterium tuberculosis. AB - The pattern of receptors sensing pathogens onto host cells is a key factor that can determine the outcome of the infection. This is particularly true when such receptors belong to the family of pattern recognition receptors involved in immunity. Mycobacterium tuberculosis, the etiologic agent of tuberculosis interacts with a wide range of pattern-recognition receptors present on phagocytes and belonging to the Toll-like, Nod-like, scavenger and C-type lectin receptor families. A complex scenario where those receptors can establish cross talks in recognizing pathogens or microbial determinants including mycobacterial components in different spatial and temporal context starts to emerge as a key event in the outcome of the immune response, and thus, the control of the infection. In this review, we will focus our attention on the family of calcium dependent carbohydrate receptors, the C-type lectin receptors, that is of growing importance in the context of microbial infections. Members of this family appear to be key innate immune receptors of mycobacteria, capable of cross-talk with other pattern recognition receptors to induce or modulate the inflammatory context upon mycobacterial infection. PMID- 24466437 TI - Is the Campylobacter jejuni secretory protein Cj0069 a suitable antigen for serodiagnostics? AB - Campylobacter spp. is the most common bacterial pathogen of gastroenteritis worldwide. Poultry is the main reservoir and consequently the main origin of infections for humans. As a consequence of a primary Campylobacter infection which typically manifests as diarrhea, there is an increased risk to suffer from post-infectious complications such as reactive arthritis, neuropathia, myositis or a Guillain-Barre Syndrome. Usually the verification of acute campylobacteriosis is made by stool culture. In contrast, post-infectious complications can be diagnosed by serological assays. Since most of them are based on whole cell lysates, an insufficient specificity results from cross reactions between related species. Therefore, the use of recombinant antigens becomes more and more favorable. Campylobacter is able to secrete a number of proteins, which are amongst others necessary for cell invasion and therefore play a crucial role for virulence. One of these, Cj0069, has a similar specificity and sensitivity in the detection of anti-Campylobacter jejuni IgG compared to the well-established antigens OMP18 and P39. This makes it a suitable antigen for diagnosing C. jejuni post-infectious complications. PMID- 24466439 TI - Atypical manifestation of gastroesophageal reflux disease: a disease with a thousand faces. PMID- 24466438 TI - The Making of a CYP3A Biomarker Panel for Guiding Drug Therapy. AB - CYP3A ranks among the most abundant cytochrome P450 enzymes in the liver, playing a dominant role in metabolic elimination of clinically used drugs. A main member in CYP3A family, CYP3A4 expression and activity vary considerably among individuals, attributable to genetic and non-genetic factors, affecting drug dosage and efficacy. However, the extent of genetic influence has remained unclear. This review assesses current knowledge on the genetic factors influencing CYP3A4 activity. Coding region CYP3A4 polymorphisms are rare and account for only a small portion of inter-person variability in CYP3A metabolism. Except for the promoter allele CYP3A4*1B with ambiguous effect on expression, common CYP3A4 regulatory polymorphisms were thought to be lacking. Recent studies have identified a relatively common regulatory polymorphism, designated CYP3A4*22 with robust effects on hepatic CYP3A4 expression. Combining CYP3A4*22 with CYP3A5 alleles *1, *3 and *7 has promise as a biomarker predicting overall CYP3A activity. Also contributing to variable expression, the role of polymorphisms in transcription factors and microRNAs is discussed. PMID- 24466440 TI - Are there any differences in sleep disorder, quality of life and gastric motility among subtypes of functional dyspepsia? PMID- 24466441 TI - New and future drug development for gastroesophageal reflux disease. AB - Medical therapy remains the most popular treatment for gastroesophageal reflux disease (GERD). Whilst interest in drug development for GERD has declined over the last few years primarily due to the conversion of most proton pump inhibitor (PPI)'s to generic and over the counter compounds, there are still numerous areas of unmet needs in GERD. Drug development has been focused on potent histamine type 2 receptor antagonist's, extended release PPI's, PPI combination, potassium competitive acid blockers, transient lower esophageal sphincter relaxation reducers, prokinetics, mucosal protectants and esophageal pain modulators. It is likely that the aforementioned compounds will be niched for specific areas of unmet need in GERD, rather than compete with the presently available anti-reflux therapies. PMID- 24466442 TI - The 5-hydroxytryptamine 4 Receptor Agonist-induced Actions and Enteric Neurogenesis in the Gut. AB - We explored a novel effect of 5-hydroxytryptamine 4 receptor (5-HT4R) agonists in vivo to reconstruct the enteric neural circuitry that mediates a fundamental distal gut reflex. The neural circuit insult was performed in guinea pigs and rats by rectal transection and anastomosis. A 5-HT4R-agonist, mosapride citrate (MOS) applied orally and locally at the anastomotic site for 2 weeks promoted the regeneration of the impaired neural circuit or the recovery of the distal gut reflex. MOS generated neurofilament-, 5-HT4R- and 5-bromo-2'-deoxyuridine positive cells and formed neural network in the granulation tissue at the anastomosis. Possible neural stem cell markers increased during the same time period. These novel actions by MOS were inhibited by specific 5-HT4R-antagonist such as GR113808 (GR) or SB-207266. The activation of enteric neural 5-HT4R promotes reconstruction of an enteric neural circuit that involves possibly neural stem cells. We also succeeded in forming dense enteric neural networks by MOS in a gut differentiated from mouse embryonic stem cells. GR abolished the formation of enteric neural networks. MOS up-regulated the expression of mRNA of 5-HT4R, and GR abolished this upregulation, suggesting MOS differentiated enteric neural networks, mediated via activation of 5-HT4R. In the small intestine in H line: Thy1 promoter green fluorescent protein (GFP) mice, we obtained clear 3 dimensional imaging of enteric neurons that were newly generated by oral application of MOS after gut transection and anastomosis. All findings indicate that treatment with 5-HT4R-agonists could be a novel therapy for generating new enteric neurons to rescue aganglionic disorders in the whole gut. PMID- 24466443 TI - Methanogens, methane and gastrointestinal motility. AB - Anaerobic fermentation of the undigested polysaccharide fraction of carbohydrates produces hydrogen in the intestine which is the substrate for methane production by intestinal methanogens. Hydrogen and methane are excreted in the flatus and in breath giving the opportunity to indirectly measure their production using breath testing. Although methane is detected in 30%-50% of the healthy adult population worldwide, its production has been epidemiologically and clinically associated with constipation related diseases, like constipation predominant irritable bowel syndrome and chronic constipation. While a causative relation is not proven yet, there is strong evidence from animal studies that methane delays intestinal transit, possibly acting as a neuromuscular transmitter. This evidence is further supported by the universal finding that methane production (measured by breath test) is associated with delayed transit time in clinical studies. There is also preliminary evidence that antibiotic reduction of methanogens (as evidenced by reduced methane production) predicts the clinical response in terms of symptomatic improvement in patients with constipation predominant irritable bowel syndrome. However, we have not identified yet the mechanism of action of methane on intestinal motility, and since methane production does not account for all constipation associated cases, there is need for high quality clinical trials to examine methane as a biomarker for the diagnosis or as a biomarker that predicts antibiotic treatment response in patients with constipation related disorders. PMID- 24466444 TI - Dietary glutamate: interactions with the enteric nervous system. AB - BACKGROUND/AIMS: Digestion of dietary protein elevates intraluminal concentrations of glutamate in the small intestine, some of which gain access to the enteric nervous system (ENS). Glutamate, in the central nervous system (CNS), is an excitatory neurotransmitter. A dogma that glutamatergic neurophysiology in the ENS recapitulates CNS glutamatergic function persists. We reassessed the premise that glutamatergic signaling in the ENS recapitulates its neurotransmitter role in the CNS. METHODS: Pharmacological analysis of actions of receptor agonists and antagonists in concert with immunohistochemical localization of glutamate transporters and receptors was used. Analysis focused on intracellularly-recorded electrical and synaptic behavior of ENS neurons, on stimulation of mucosal secretion by secretomotor neurons in the submucosal plexus and on muscle contractile behavior mediated by musculomotor neurons in the myenteric plexus. RESULTS: Immunoreactivity for glutamate was expressed in ENS neurons. ENS neurons expressed immunoreactivity for the EAAC-1 glutamate transporter. Neither L-glutamate nor glutamatergic receptor agonists had excitatory actions on ENS neurons. Metabotropic glutamatergic receptor agonists did not directly stimulate neurogenic mucosal chloride secretion. Neither L glutamate nor the metabotropic glutamatergic receptor agonist, aminocyclopentane 1,3-dicarboxylic acid (ACPD), changed the mean amplitude of spontaneously occurring contractions in circular or longitudinal strips of intestinal wall from either guinea pig or human small intestinal preparations. CONCLUSIONS: Early discoveries, for excitatory glutamatergic neurotransmission in the CNS, inspired enthusiasm that investigation in the ENS would yield discoveries recapitulating the CNS glutamatergic story. We found this not to be the case. PMID- 24466445 TI - Regional Differences in Chronic Stress-induced Alterations in Mast Cell and Protease-activated Receptor-2-positive Cell Numbers in the Colon of Ws/Ws Rats. AB - BACKGROUND/AIMS: There have been no reports on the effect of chronic psychological stress on colonic immune cells or the regional differences. We aimed to investigate the effect of chronic psychological stress on the number of mast cells and protease-activated receptor (PAR)-2-positive cells in the rat colonic mucosa. METHODS: Six-week-old and 14-week-old Ws/Ws rats, which lack mast cells after 10 weeks, were used as control and mast cell-deficient groups, respectively. The rats were divided into stress and sham-treated groups. Rats in the stressed group were exposed to water avoidance stress (WAS, 1 hour/day) for 13 days. Fecal pellet output and the number of mast cells and PAR-2-positive cells in colonic mucosa were compared between the WAS and sham groups. RESULTS: In 6-week-old rats, the WAS group showed a significantly higher number of mast cells compared to the sham group. In 14-week-old rats, mast cells were nearly absent in the colonic mucosa. WAS significantly increased PAR-2-positive cells in 14-week-old rats, but not in 6-week-old rats. Indirect estimation of PAR-2 positive mast cells in 6-week-old rats suggested that the majority of increased mast cells following WAS did not express PAR-2. WAS increased mast cells and PAR 2-positive cells mainly in the proximal colon. Fecal pellet output was continuously higher in the WAS group than in the sham group, and the difference was significant for both 6-week-old and 14-week-old rats. CONCLUSIONS: Chronic psychological stress increased the number of mast cells and PAR-2-positive cells in rat colonic mucosa, and these increases were more prominent in the proximal colon. PMID- 24466447 TI - Utilizing intrabolus pressure and esophagogastric junction pressure to predict transit in patients with Dysphagia. AB - BACKGROUND/AIMS: High-resolution manometry (HRM), with a greatly increased number of recording sites and decreased spacing between sites, allows evaluation of the dynamic simultaneous relationship between intrabolus pressure (IBP) and esophagogastric junction (EGJ) relaxation pressure. We hypothesized that bolus transit may occur when IBP overcomes integrated relaxation pressure (IRP) and analyzed the relationships between peristalsis pattern and the discrepancy between IBP and IRP in patients with dysphagia. METHODS: Twenty-two dysphagia patients with normal EGJ relaxation were examined with a 36-channel HRM assembly. Each of the 10 examinations was performed with 20 and 30 mmHg pressure topography isobaric contours, and findings were categorized based on the Chicago classification. We analyzed the relationships between peristalsis pattern and the discrepancy between IBP and IRP. RESULTS: Twenty-two patients were classified by the Chicago classification: 1 patient with normal EGJ relaxation and normal peristalsis, 8 patients with intermittent hypotensive peristalsis and 13 patients with frequent hypotensive peristalsis. A total of 220 individual swallows were analyzed. There were no statistically significant relationships between peristalsis pattern and the discrepancy between IBP and IRP on the 20 or 30 mmHg isobaric contours. CONCLUSIONS: Peristalsis pattern was not associated with bolus transit in patients with dysphagia. However, further controlled studies are needed to evaluate the relationship between bolus transit and peristalsis pattern using HRM with impedance. PMID- 24466446 TI - Relief of Night-time Symptoms Associated With Gastroesophageal Reflux Disease Following 4 Weeks of Treatment With Pantoprazole Magnesium: The Mexican Gastroesophageal Reflux Disease Working Group. AB - BACKGROUND/AIMS: To evaluate the effectiveness of pantoprazole magnesium (pantoprazole-Mg) 40 mg in the relief of esophageal and extra-esophageal symptoms of gastroesophageal reflux disease (GERD), particularly night-time symptoms. METHODS: Patients (aged 18-50 years) with 3-month history of heartburn and/or acid regurgitation plus at least one other symptom in the last week were enrolled in a nationwide, prospective and observational study in Mexico. Patients received pantoprazole-Mg 40 mg once daily during 4 weeks. Symptoms were assessed through a physician-administered structured interview and the patient-completed ReQuest in PracticeTM questionnaire. Night-time GERD was defined as arousal from sleep during the night due to GERD-associated symptoms. RESULTS: Out of 4,343 patients included at basal visit, 3,665 were considered for the effectiveness per protocol analysis. At baseline, patients had a median of 8 GERD related symptoms. Patients with night-time GERD symptoms (42.7%) were more likely to have extra-esophageal symptoms (P < 0.001) than other GERD patients. Pantoprazole-Mg 40 mg once daily for 4 weeks improved a broad range of GERD-associated symptoms from baseline (80% reduction on physicians assessments; 68-77% reduction on ReQuest in PracticeTM dimensions), including both day- and night-time GERD symptoms; improvements were the greatest for extra-esophageal symptoms in patients with night-time symptoms. Pantoprazole-Mg was well tolerated. CONCLUSIONS: Pantoprazole-Mg 40 mg significantly improved a broad range of esophageal and extra-esophageal GERD related symptoms including sleep disturbances, as well as well-being, in patients with daytime or night-time GERD, making it a good option for patients with GERD, especially when extra-esophageal and night-time symptoms are present. PMID- 24466448 TI - Effect of Cold Water on Esophageal Motility in Patients With Achalasia and Non obstructive Dysphagia: A High-resolution Manometry Study. AB - BACKGROUND/AIMS: Swallowing of cold liquids decreases amplitude and velocity of peristalsis in healthy subjects, using standard manometry. Patients with achalasia and non obstructive dysphagia may have degeneration of sensory neural pathways, affecting motor response to cooling. To elucidate this point, we used high-resolution manometry. METHODS: Fifteen healthy subjects, 15 non-obstructive dysphagia and 15 achalasia patients, after pneumatic dilation, were studied. The 3 groups underwent eight 5 mL single swallows, two 20 mL multiple rapid swallows and 50 mL intraesophageal water infusion (1 mL/sec), using both water at room temperature and cold water, in a randomized order. RESULTS: In healthy subjects, cold water reduced distal contractile integral in comparison with water at room temperature during single swallows, multiple rapid swallows and intraesophageal infusion (ratio cold/room temperature being 0.67 [95% CI, 0.48-0.85], 0.56 [95% CI, 0.19-0.92] and 0.24 [95% CI, 0.12-0.37], respectively). A similar effect was seen in non-obstructive dysphagia patients (0.68 [95% CI, 0.51-0.84], 0.69 [95% CI, 0.40-0.97] and 0.48 [95% CI, 0.20-0.76], respectively), whereas no changes occurred in achalasia patients (1.06 [95% CI, 0.83-1.29], 1.05 [95% CI, 0.77 1.33] and 1.41 [95% CI, 0.84-2.00], respectively). CONCLUSIONS: Our data suggest impairment of esophageal reflexes induced by cold water in patients with achalasia, but not in those with non obstructive dysphagia. PMID- 24466449 TI - Prevalence of Extraesophageal Symptoms in Patients With Gastroesophageal Reflux Disease: A Multicenter Questionnaire-based Study in Korea. AB - BACKGROUND/AIMS: Many patients with gastroesophageal reflux disease (GERD) also present with extraesophageal symptoms (EESs). This study sought to determine the prevalence of concomitant EESs and to evaluate quality of life (QOL) impairment in a Korean population with GERD. METHODS: This questionnaire-based study was carried out from 64 hospitals in Korea between October 2008 and March 2009. Patients with typical GERD symptoms of heartburn or acid regurgitation were recruited for study. Participants filled out questionnaire consisting of GerdQ questions and EES questions. All participants underwent endoscopy and were divided into patients with erosive reflux disease (ERD) and with non-erosive reflux disease (NERD). RESULTS: A total of 1,712 patients were included in this study. Of these, 697 (40.7%) patients had ERD and 1,015 (59.3%) NERD. The prevalence of EES was 90.3%. The most prevalent EES was epigastric burning (73.2%), followed by globus (51.8%), chest pain (48.4%), cough (32.0%), hoarseness (24.2%) and wheezing (17.3%). Individual EES was more prevalent in patients with ERD than in those with NERD. Regarding QOL, 701 patients (41.0%) had sleep disturbance and 676 (37.7%) had taken additional over-the-counter medication for heartburn and/or regurgitation, which were more prevalent in patients with ERD than in those with NERD (49.5% vs. 35.1% and 45.8% vs. 32.2%, respectively; all P < 0.001). CONCLUSIONS: The prevalence of EES is high in Korean patients with symptomatic GERD. Individual EES is more prevalent in patients with ERD than in those with NERD. QOL impairment is observed less frequently than previous studies. PMID- 24466450 TI - Analysis on Awareness of Functional Dyspepsia and Rome Criteria Among Japanese Internists by the Self-administered Questionnaires. AB - BACKGROUND/AIMS: Functional dyspepsia (FD) is one of the commonest diseases in the field of Internal Medicine. The Japanese Society of Gastroenterology (JSGE) has been enlightening the term and concept of FD. Aim of this survey was to elucidate the understanding status of FD and Rome criteria and attitude toward FD among Japanese internists. METHODS: Data were collected at the time of lifelong education course for certified members of Japanese Society of Internal Medicine. Self-administered questionnaires were delivered to the medical doctors prior to the lectures. RESULTS: Analysis subjects were 1,623 (24-90 years old) internists among 1,660 medical doctors out of 4,264 attendees. The terms related to FD were known in 62.0-68.9% of internists, whereas 95.5% understood chronic gastritis. Internists who had been taking care of FD patients informed them as chronic gastritis (50.0%), FD in Japanese Kanji character (50.8%) and FD in Kanji and Katakana (18.6%). Logistic linear regression analysis revealed that positive factors for the understanding of FD and intensive care for FD patients were practitioner, caring many patients and certified physician by JSGE. Existence of Rome criteria was known in 39.9% of internists, and 31.8% out of them put it to practical use. The certified physician by JSGE was a positive factor for awareness, but not for utilization. CONCLUSIONS: The results suggest the needs of enlightening the medical term FD in Japan and revision of Rome criteria for routine clinical practice. Precise recognition of FD may enhance efficient patient-based clinical practice. PMID- 24466451 TI - Impact of sleep disorders, quality of life and gastric emptying in distinct subtypes of functional dyspepsia in Japan. AB - BACKGROUND/AIMS: The association between clinical symptoms, gastric emptying, quality of life and sleep disorders in distinct functional dyspepsia (FD) patients has not been studied yet in detail. METHODS: We enrolled 79 FD patients (postprandial distress syndrome [PDS], n = 65; epigastric pain syndrome [EPS], n = 47; EPS-PDS overlap, n = 33) and 44 healthy volunteers. Gastric motility was evaluated. We used Rome III criteria to evaluate clinical symptoms and State Trait Anxiety Inventory (STAI) scores to determine anxiety status. Sleep disorder was evaluated using the Pittsburgh Sleep Quality Index scores. RESULTS: There were no significant differences in age, sex and Helicobacter pylori positivity between FD subtypes and healthy volunteers. The scores of Glasgow dyspepsia severity scores (GDSS), SF-8 and Pittsburgh Sleep Quality Index (PSQI) in distinct subtypes of FD patients were significantly different from those in healthy volunteers. However, there were not significant differences in these scores, Tmax and T1/2 among 3 subtypes of FD patients. PSQI score was significantly (P = 0.027, P = 0.002 and P = 0.039, respectively) associated with GDSS among EPS, PDS and EPS-PDS overlap patients. In addition, 8-item short form health survey (SF-8; Physical Component Score and Mental Component Score) was significantly associated with global PSQI score in PDS and EPS-PDS overlap patients. In contrast, SF-8 (Mental Component Score) only was significantly linked to global PSQI score in EPS patients. CONCLUSIONS: Prevalences for sleep disorders, gastric motility and quality of life in 3 subtypes of FD patients were similar levels. In PDS and EPS-PDS overlap patients, SF-8 was significantly associated with global PSQI score. PMID- 24466453 TI - Hypercontractile esophagus with atypical symptoms. PMID- 24466452 TI - Efficacy and Safety of Tiropramide in the Treatment of Patients With Irritable Bowel Syndrome: A Multicenter, Randomized, Double-blind, Non-inferiority Trial, Compared With Octylonium. AB - BACKGROUND/AIMS: Antispasmodics such as octylonium are widely used to manage irritable bowel syndrome (IBS) symptoms. However, the efficacy and safety of another antispasmodic, tiropramide, remain uncertain. We aimed to evaluate the efficacy and safety of tiropramide compared with octylonium in patients with IBS. METHODS: In this multicenter, randomized, non-inferiority trial, 287 patients with IBS (143 receiving tiropramide and 144 octylonium) were randomly allocated to either tiropramide 100 mg or octylonium 20 mg t.i.d (means 3 times a day) for 4 weeks. Primary endpoint was the mean change of abdominal pain from baseline assessed by visual analogue scales (VAS) score after 4 weeks of treatment. Secondary endpoints were the changes in abdominal pain from baseline at week 2 and in abdominal discomfort at weeks 2 and 4, using VAS scores, patient-reported symptom improvement including stool frequency and consistency, using symptom diaries, IBS-quality of life (IBS-QoL), and depression and anxiety, at week 4. RESULTS: The VAS scores of abdominal pain at week 4, were significantly decreased in both tiropramide and octylonium groups, but the change from baseline did not differ between the 2 groups (difference,-0.26 mm; 95% CI,-4.33-3.82; P = 0.901). Abdominal pain and discomfort assessed using VAS scores, diaries, and IBS-QoL were also improved by both treatments, and the changes from baseline did not differ. The incidence of adverse events was similar in the 2 groups, and no severe adverse events involving either drug were observed. CONCLUSIONS: Tiropramide is as effective as octylonium in managing abdominal pain in IBS, with a similar safety profile. PMID- 24466454 TI - Does Bile Reflux Influence the Progression of Barrett's Esophagus to Adenocarcinoma? (Gastroenterology 2013;145:1300-1311). PMID- 24466455 TI - The Physiologic Roles of the Subepithelial Platelet-derived Growth Factor Receptor alpha-positive Cells in the Colon (Am J Physiol Gastrointest Liver Physiol 2013;304:G823-G834). PMID- 24466456 TI - Not All Patients With Non-erosive Reflux Disease Share Psychological Distress as Main Mechanism of Disease. PMID- 24466457 TI - Not All Patients With Non-erosive Reflux Disease Share Psychological Distress as Main Mechanism of Disease: Author's Reply. PMID- 24466458 TI - Abnormal gastric myoelectrical activity and delayed gastric emptying in asthmatics: what is clinical significance? PMID- 24466459 TI - The influences of obesity on central and peripheral gastrointestinal responses. PMID- 24466460 TI - More than the significance of conventional urinalysis. PMID- 24466461 TI - Paper-based analytical device for quantitative urinalysis. AB - Paper-based analytical devices are fluidic chips fabricated with extremely inexpensive materials, namely paper, thereby allowing their use as a zero-cost analytical device in third-world countries that lack access to expensive diagnostic infrastructures. The aim of this review is to discuss: (1) microfluidic paper-based analytical devices (uPADs) for quantitative analysis, (2) fabrication of two- or three-dimensional uPADs, (3) analytical methods of uPADs, and (4) our opinions regarding the future applications of uPADs for quantitative urinalysis. PMID- 24466462 TI - Acute dose-related differential effects of methylphenidate on murine cystometric parameters. AB - PURPOSE: Methylphenidate is the most widely used central nervous system stimulant in patients with attention deficit hyperactivity disorder. However, few studies have assessed its effects on voiding. Various doses of methylphenidate were investigated for their effects on cystometric parameters in conscious mice. METHODS: Ten male C57BL/6 mice, weighing between 20 and 23 g, were used in this study. To compare the acute drug responses before and after the oral medication was administered in the awake condition, we injected the solution through a catheter inserted into the stomach. Methylphenidate (1.25, 2.5, and 5 mg/kg) in an injection volume of 0.05 mL was administered. RESULTS: Four mice that received high doses of methylphenidate (2.5 and 5 mg/kg) showed no voiding contraction, with urine leakage. Six mice that received a low dose of methylphenidate (1.25 mg/kg) showed typical micturition cycles before and after administration. The micturition pressure decreased and bladder capacity increased without an increased residual volume after administration. CONCLUSIONS: Methylphenidate has differential, dose-dependent effects on the function of the lower urinary tract, due to the dependent relationship between the brain and lower urinary tract. Especially at higher doses, this drug may interfere with normal micturition. Therefore, more detailed clinical or experimental studies are warranted in the future. PMID- 24466463 TI - Association of a Missense ALDH2 Single Nucleotide Polymorphism (Glu504Lys) With Benign Prostate Hyperplasia in a Korean Population. AB - PURPOSE: Aldehyde dehydrogenase 2 (ALDH2) is a well-known gene involved in alcohol and aldehyde metabolism. Moreover, recent studies have reported associations between ALDH2 and age-related disorders. Benign prostate hyperplasia (BPH) is an age-related disorder and genetic factors may contribute to its onset. In this study, we investigated the association of a well-studied ALDH2 single nucleotide polymorphism (SNP), rs671, with the onset and clinical features of BPH. METHODS: A total of 222 BPH patients and 214 control subjects were genotyped. The clinical features of the BPH patients (prostate volume, prostate specific antigen level, and International Prostatic Symptom Score) were analyzed. RESULTS: The results show that rs671 was only associated with the volume of BPH in genotype and allele frequencies (P<0.05). CONCLUSION: We propose that rs671 is an Asian-specific SNP in ALDH2 that may affect the disease progression of BPH in the Korean population. PMID- 24466464 TI - Overexpression of aquaporin-1 and caveolin-1 in the rat urinary bladder urothelium following bladder outlet obstruction. AB - PURPOSE: This study was designed to investigate the effect of detrusor overactivity induced by partial bladder outlet obstruction (BOO) on the expression of aquaporin 1 (AQP1) and caveolin 1 (CAV1) in the rat urinary bladder, and to determine the role of these molecules in detrusor overactivity. METHODS: Female Sprague-Dawley rats were divided into control (n=30) and experimental (n=30) groups. The BOO group underwent partial BOO, and the control group underwent a sham operation. After 4 weeks, an urodynamic study was performed to measure the contraction interval and contraction pressure. The expression and cellular localization of AQP1 and CAV1 were determined by western blot and immunofluorescence experiments in the rat urinary bladder. RESULTS: In cystometrograms, the contraction interval was significantly lower in the BOO group (2.9+/-1.5 minutes) than in the control group (6.7+/-1.0 minutes) (P<0.05). Conversely, the average contraction pressure was significantly higher in the BOO group (21.2+/-3.3 mmHg) than in the control group (13.0+/-2.5 mmHg) (P<0.05). AQP1 and CAV1 were coexpressed in the capillaries, arterioles, and venules of the suburothelial layer. AQP1 and CAV1 protein expression was significantly increased in the BOO rats compared to the control rats (P<0.05). CONCLUSIONS: Detrusor overactivity induced by BOO causes a significant increase in the expression of AQP1 and CAV1, which were coexpressed in the suburothelial microvasculature. This finding suggests that AQP1 and CAV1 might be closely related to bladder signal activity and may have a functional role in BOO-associated detrusor overactivity. PMID- 24466465 TI - Lower urinary tract symptoms and erectile dysfunction in men with type 2 diabetes mellitus. AB - PURPOSE: To assess the prevalence of lower urinary tract symptoms (LUTS) and erectile dysfunction (ED) and the relationships between LUTS, ED, depression, and other factors in Korean men with type 2 diabetes mellitus (T2DM). METHODS: This cross-sectional study included 124 male patients with T2DM who attended a university hospital diabetes clinic between October 2010 and April 2012. Data were collected using structured interviews and chart reviews. LUTS were measured using the International Prostate Symptom Score (IPSS), ED using the five-item Korean version of the International Index of Erectile Function (IIEF), depression using the Center for Epidemiologic Studies Depression Scale, and glycosylated hemoglobin level from clinical data. RESULTS: The IPSS score was 9.2+/-6.6. The total IPSS scores indicated that 53.3% of the subjects had either moderate or severe symptoms. The mean IIEF score was 7.3+/-8.6, indicating the severity of ED to be mild, mild to moderate, moderate, and severe in 10.5%, 9.7%, 1.6%, and 66.9% of the participants, respectively. LUTS showed a significant negative correlation with ED (r=-0.26, P=0.003) and a significant positive correlation with depression (r=0.33, P<0.001). ED was negatively correlated with age (r= 0.44, P<0.001), duration of diabetes (r=-0.26, P=0.004), and depression (r=-0.24, P=0.008). CONCLUSIONS: LUTS and ED were found to have a high prevalence among Korean men with T2DM. More severe ED was associated with worse LUTS, whereas more severe depressive symptoms were found to be associated with more severe ED and LUTS. PMID- 24466466 TI - Incontinence pad usage in medical welfare facilities in Korea. AB - PURPOSE: The prevalence of urinary incontinence and the usage of incontinence pads by elderly residents in Korean medical welfare facilities were investigated. METHODS: From a total of 1,832 facilities, 33 medical welfare facilities in the capital area were randomly selected; all nursing homes were excluded. All data were collected by questionnaires to investigate the residents' age and sex, the presence or absence of urinary incontinence, incontinence pad usage per month, and management methods for urinary incontinence. Surveys were also conducted from January 2010 to August 2010. RESULTS: A total number of residents in medical welfare facilities were 2,783, and all of them were selected for this study. Approximately, 65.3% of residents (1,816 individuals) had incontinence. The mean usage was 75 incontinence pads per month. Only 15.6% of residents received proper management for urinary incontinence, while the remaining 84.4% of residents did not have any experience in evaluating or managing their urinary symptoms. CONCLUSIONS: The prevalence of urinary incontinence in medical welfare facilities in Korea was about 65.3%. However, the management of urinary incontinence was insufficient. Urologists should make further efforts for the proper management of urinary incontinence in elders in these facilities. PMID- 24466467 TI - Maintenance of the therapeutic effect of two high-dosage antimuscarinics in the management of overactive bladder in elderly women. AB - PURPOSE: To improve the long-term efficiency of the pharmacologic management of overactive bladder (OAB) in elderly women. METHODS: The study comprised 229 women (mean age, 66.3 years; range, 65-77 years) with urodynamically and clinically confirmed OAB. All patients received the most effective treatment regimen based on the data obtained in the initial part of the study (trospium 60 mg/day + solifenacin 40 mg/day, for 6 weeks), and positive results similar to those in the first phase were obtained. They were then divided into four groups, based on the maintenance therapy: group A (59 women), trospium (60 mg/day) + solifenacin (40 mg/day) for 1 month; group B (51 women), electrical stimulation of the detrusor muscle for 1 month; group C (63 women), laser puncture for 1 month; group D (56 women), placebo. Maintenance therapy was administered 2.5 months after completion of primary treatment. The patients' condition was monitored through the OAB questionnaire for 1 year and by urodynamic examination at months 6 and 7 from the start of the study. RESULTS: In group A, the clinical and urodynamic results achieved after the initial + main treatment phase (two high-dosage antimuscarinics of different generations, trospium and solifenacin, for a total of 2.5 months) were maintained for at least 7 months. Electrical stimulation of the urinary bladder as a method of maintenance therapy proved to be less effective. In groups C and D, deterioration in results was observed at 6-8 months, which led us to conclude that laser puncture was an inefficient method of maintenance therapy in elderly women with OAB. CONCLUSIONS: Maintenance treatment of OAB in elderly women with a combination of high-dosage antimuscarinics is an effective method for reducing the risk of recurrence of the disease. PMID- 24466468 TI - Anterior urethrectomy for primary carcinoma of the female urethra mimicking a urethral caruncle. AB - Here we report a case of primary carcinoma of the female urethra. A 52-year-old woman presented with a palpable urethral mass associated with intermittent pain that she first experienced a few months prior. Clinical examination showed a urethral mass that appeared to be a caruncle; therefore, simple carunclectomy was performed. However, on histological examination, the mass was revealed to be a squamous cell carcinoma; therefore, anterior urethrectomy was performed. During a 4-year follow-up period, the patient has been well with no dysuria, dyspareunia, or incontinence. PMID- 24466469 TI - Adjustment on the Type I Error Rate for a Clinical Trial Monitoring for both Intermediate and Primary Endpoints. AB - In many clinical trials, a single endpoint is used to answer the primary question and forms the basis for monitoring the experimental therapy. Many trials are lengthy in duration and investigators are interested in using an intermediate endpoint for an accelerated approval, but will rely on the primary endpoint (such as, overall survival) for the full approval of the drug by the Food and Drug Administration. We have designed a clinical trial where both intermediate (progression-free survival, (PFS)) and primary endpoints (overall survival, (OS)) are used for monitoring the trial so the overall type I error rate is preserved at the pre-specified alpha level of 0.05. A two-stage procedure is used. In the first stage, the Bonferroni correction was used where the global type I error rate was allocated to each of the endpoints. In the next stage, the O'Brien Fleming approach was used to design the boundary for the interim and final analysis for each endpoint. Data were generated assuming several parametric copulas with exponential marginals. Different degrees of dependence, as measured by Kendall's tau, between OS and PFS were assumed: 0 (independence) 0.3, 0.5 and 0.70. This approach is applied to an example in a prostate cancer trial. PMID- 24466470 TI - Philosophical Analysis in Modeling Polarization: Notes from a Work in Progress. PMID- 24466471 TI - 0.5 gigapixel microscopy using a flatbed scanner. AB - The capability to perform high-resolution, wide field-of-view (FOV) microscopy imaging is highly sought after in biomedical applications. In this paper, we report a wide FOV microscopy system that uses a closed-circuit-television (CCTV) lens for image relay and a flatbed scanner for data acquisition. We show that such an imaging system is capable of capturing a 10 mm * 7.5 mm FOV image with 0.78 um resolution, resulting in more than 0.5 billion pixels across the entire image. The resolution and field curve of the proposed system were characterized by imaging a USAF resolution target and a hole-array target. To demonstrate its application, 0.5 gigapixel images of histology slides were acquired using this system. PMID- 24466472 TI - In vivo optical spectroscopy for improved detection of pancreatic adenocarcinoma: a feasibility study. AB - Pancreatic adenocarcinoma has a five-year survival rate of less than 6%. This low survival rate is attributed to the lack of accurate detection methods, which limits diagnosis to late-stage disease. Here, an in vivo pilot study assesses the feasibility of optical spectroscopy to improve clinical detection of pancreatic adenocarcinoma. During surgery on 6 patients, we collected spectrally-resolved reflectance and fluorescence in vivo. Site-matched in vivo and ex vivo data agreed qualitatively and quantitatively. Quantified differences between adenocarcinoma and normal tissues in vivo were consistent with previous results from a large ex vivo data set. Thus, optical spectroscopy is a promising method for the improved diagnosis of pancreatic cancer in vivo. PMID- 24466473 TI - Towards a bimodal proximity sensor for in situ neurovascular bundle detection during dental implant surgery. AB - Proof of concept results are presented towards an in situ bimodal proximity sensor for neurovascular bundle detection during dental implant surgery using combined near infrared absorption (NIR) and optical coherence tomography (OCT) techniques. These modalities are shown to have different sensitivity to the proximity of optical contrast from neurovascular bundles. NIR AC and DC signals from the pulsing of an artery enable qualitative ranging of the bundle in the millimeter range, with best sensitivity around 0.5-3mm distance in a custom phantom setup. OCT provides structural mapping of the neurovascular bundle at sub millimeter distances in an ex vivo human jaw bone. Combining the two techniques suggests a novel ranging system for the surgeon that could be implemented in a "smart drill." The proximity to the neurovascular bundle can be tracked in real time in the range of a few millimeters with NIR signals, after which higher resolution imaging OCT to provide finer ranging in the sub-millimeter distances. PMID- 24466474 TI - Age-dependence of the average and equivalent refractive indices of the crystalline lens. AB - Lens average and equivalent refractive indices are required for purposes such as lens thickness estimation and optical modeling. We modeled the refractive index gradient as a power function of the normalized distance from lens center. Average index along the lens axis was estimated by integration. Equivalent index was estimated by raytracing through a model eye to establish ocular refraction, and then backward raytracing to determine the constant refractive index yielding the same refraction. Assuming center and edge indices remained constant with age, at 1.415 and 1.37 respectively, average axial refractive index increased (1.408 to 1.411) and equivalent index decreased (1.425 to 1.420) with age increase from 20 to 70 years. These values agree well with experimental estimates based on different techniques, although the latter show considerable scatter. The simple model of index gradient gives reasonable estimates of average and equivalent lens indices, although refinements in modeling and measurements are required. PMID- 24466475 TI - Verification of a two-layer inverse Monte Carlo absorption model using multiple source-detector separation diffuse reflectance spectroscopy. AB - A two-layer Monte Carlo lookup table-based inverse model is validated with two layered phantoms across physiologically relevant optical property ranges. Reflectance data for source-detector separations of 370 MUm and 740 MUm were collected from these two-layered phantoms and top layer thickness, reduced scattering coefficient and the top and bottom layer absorption coefficients were extracted using the inverse model and compared to the known values. The results of the phantom verification show that this method is able to accurately extract top layer thickness and scattering when the top layer thickness ranges from 0 to 550 MUm. In this range, top layer thicknesses were measured with an average error of 10% and the reduced scattering coefficient was measured with an average error of 15%. The accuracy of top and bottom layer absorption coefficient measurements was found to be highly dependent on top layer thickness, which agrees with physical expectation; however, within appropriate thickness ranges, the error for absorption properties varies from 12-25%. PMID- 24466476 TI - Radiative transport in large arteries. AB - A refined model for the photon energy distribution in a living artery is established by solving the radiative transfer equation in a cylindrical geometry, using the Monte Carlo method. Combining this model with the most recent experimental values for the optical properties of flowing blood and the biomechanics of a blood-filled artery subject to a pulsatile pressure, we find that the optical intensity transmitted through large arteries decreases linearly with increasing arterial distension. This finding provides a solid theoretical foundation for measuring photoplethysmograms. PMID- 24466477 TI - High-resolution visualization of mouse cardiac microvasculature using optical histology. AB - Cardiovascular disease typically is associated with dysfunction of the coronary vasculature and microvasculature. The study of cardiovascular disease typically involves imaging of the large coronary vessels and quantification of cardiac blood perfusion. These methods, however, are not well suited for imaging of the cardiac microvasculature. We used the optical histology method, which combines chemical optical clearing and optical imaging, to create high-resolution, wide field maps of the cardiac microvasculature in ventral slices of mouse heart. We have demonstrated the ability of the optical histology method to enable wide field visualization of the cardiac microvasculature in high-resolution and anticipate that optical histology may have significant impact in studying cardiovascular disease. PMID- 24466478 TI - Towards clinically translatable NIR fluorescence molecular guidance for colonoscopy. AB - White-light surveillance colonoscopy is the standard of care for the detection and removal of premalignant lesions to prevent colorectal cancer, and the main screening recommendation following treatment for recurrence detection. However, it lacks sufficient diagnostic yield, exhibits unacceptable adenoma miss-rates and is not capable of revealing functional and morphological information of the detected lesions. Fluorescence molecular guidance in the near-infrared (NIR) is expected to have outstanding relevance regarding early lesion detection and heterogeneity characterization within and among lesions in these interventional procedures. Thereby, superficial and sub-surface tissue biomarkers can be optimally visualized due to a minimization of tissue attenuation and autofluorescence by comparison with the visible, which simultaneously enhance tissue penetration and assure minimal background. At present, this potential is challenged by the difficulty associated with the clinical propagation of disease specific contrast agents and the absence of a commercially available endoscope that is capable of acquiring wide-field, NIR fluorescence at video-rates. We propose two alternative flexible endoscopic fluorescence imaging methods, each based on a CE certified commercial, clinical grade endoscope, and the employment of an approved monoclonal antibody labeled with a clinically applicable NIR fluorophore. Pre-clinical validation of these two strategies that aim at bridging NIR fluorescence molecular guidance to clinical translation is demonstrated in this study. PMID- 24466479 TI - Feasibility testing of a pre-clinical coded aperture phase contrast imaging configuration using a simple fast Monte Carlo simulator. AB - A simple method of simulating possible coded aperture phase contrast X-ray imaging apparatus is presented. The method is based on ray tracing, with the rays treated ballistically within a voxelized sample and with the phase-shift-induced angular deviations and absorptions applied at a plane in the middle of the sample. For the particular case of a coded aperture phase contrast configuration suitable for small animal pre-clinical imaging we present results obtained using a high resolution voxel array representation of a mathematically-defined 'digital' mouse. At the end of the article a link to the software is supplied. PMID- 24466480 TI - Motion artifact and speckle noise reduction in polarization sensitive optical coherence tomography by retinal tracking. AB - We present a novel polarization sensitive optical coherence tomography (PS-OCT) system with an integrated retinal tracker. The tracking operates at up to 60 Hz, correcting PS-OCT scanning positions during the acquisition to avoid artifacts caused by eye motion. To demonstrate the practical performance of the system, we imaged several healthy volunteers and patients with AMD both with B-scan repetitions for frame averaging and with 3D raster scans. Under large retinal motions with up to 1 mm amplitude at 0.5 ~a few Hz frequency range, motion artifact suppression in the PS-OCT images as well as standard deviation noise reduction in the frame averaged retardation images are presented. PMID- 24466481 TI - Laser speckle contrast imaging with extended depth of field for in-vivo tissue imaging. AB - This work presents, to our knowledge, the first demonstration of the Laser Speckle Contrast Imaging (LSCI) technique with extended depth of field (DOF). We employ wavefront coding on the detected beam to gain quantitative information on flow speeds through a DOF extended two-fold compared to the traditional system. We characterize the system in-vitro using controlled microfluidic experiments, and apply it in-vivo to imaging the somatosensory cortex of a rat, showing improved ability to image flow in a larger number of vessels simultaneously. PMID- 24466482 TI - Imaging deep skeletal muscle structure using a high-sensitivity ultrathin side viewing optical coherence tomography needle probe. AB - We have developed an extremely miniaturized optical coherence tomography (OCT) needle probe (outer diameter 310 um) with high sensitivity (108 dB) to enable minimally invasive imaging of cellular structure deep within skeletal muscle. Three-dimensional volumetric images were acquired from ex vivo mouse tissue, examining both healthy and pathological dystrophic muscle. Individual myofibers were visualized as striations in the images. Degradation of cellular structure in necrotic regions was seen as a loss of these striations. Tendon and connective tissue were also visualized. The observed structures were validated against co registered hematoxylin and eosin (H&E) histology sections. These images of internal cellular structure of skeletal muscle acquired with an OCT needle probe demonstrate the potential of this technique to visualize structure at the microscopic level deep in biological tissue in situ. PMID- 24466483 TI - Characterization of a synthetic bioactive polymer by nonlinear optical microscopy. AB - Tissue Engineering is a new emerging field that offers many possibilities to produce three-dimensional and functional tissues like ligaments or scaffolds. The biocompatibility of these materials is crucial in tissue engineering, since they should be integrated in situ and should induce a good cell adhesion and proliferation. One of the most promising materials used for tissue engineering are polyesters such as Poly-epsilon-caprolactone (PCL), which is used in this work. In our case, the bio-integration is reached by grafting a bioactive polymer (pNaSS) on a PCL surface. Using nonlinear microscopy, PCL structure is visualized by SHG and proteins and cells by two-photon excitation autofluorescence generation. A comparative study between grafted and nongrafted polymer films is provided. We demonstrate that the polymer grafting improves the protein adsorption by a factor of 75% and increase the cell spreading onto the polymer surface. Since the spreading is directly related to cell adhesion and proliferation, we demonstrate that the pNaSS grafting promotes PCL biocompatibility. PMID- 24466484 TI - Label-free multimodal nonlinear optical microscopy reveals fundamental insights of skeletal muscle development. AB - We developed a label-free nonlinear optical (NLO) microscope integrating the stimulated Raman scattering, multi-color two-photon excited fluorescence and second harmonic generation. The system produces multimodal images of protein content, mitochondria distribution and sarcomere structure of fresh muscle samples. With the advanced imaging technique, we studied the mal-development of skeletal muscle caused by sarcomeric gene deficiency. In addition, important development processes of normal muscle from neonatal to adult stage were also clearly revealed based on the changing sarcomere structure, mitochondria distribution and muscle fiber size. The results demonstrate that the newly developed multimodal NLO microscope is a powerful tool to assess the muscle integrity and function. PMID- 24466485 TI - Dual-band Fourier domain optical coherence tomography with depth-related compensations. AB - Dual-band Fourier domain optical coherence tomography (FD-OCT) provides depth resolved spectroscopic imaging that enhances tissue contrast and reduces image speckle. However, previous dual-band FD-OCT systems could not correctly give the tissue spectroscopic contrast due to depth-related discrepancy in the imaging method and attenuation in biological tissue samples. We designed a new dual-band full-range FD-OCT imaging system and developed an algorithm to compensate depth related fall-off and light attenuation. In our imaging system, the images from two wavelength bands were intrinsically overlapped and their intensities were balanced. The processing time of dual-band OCT image reconstruction and depth related compensations were minimized by using multiple threads that execute in parallel. Using the newly developed system, we studied tissue phantoms and human cancer xenografts and muscle tissues dissected from severely compromised immune deficient mice. Improved spectroscopic contrast and sensitivity were achieved, benefiting from the depth-related compensations. PMID- 24466486 TI - Toward nodal staging of axillary lymph node basins through intradermal administration of fluorescent imaging agents. AB - As part of a proof-of-concept study for future delivery of targeted near-infrared fluorescent (NIRF) tracers, we sought to assess the delivery of micrograms of indocyanine green to all the axillary lymph nodes following intraparenchymal breast injections and intradermal arm injections in 20 subjects with advanced breast carcinoma and undergoing complete axillary lymph node dissection. Lymphatic vessels and nodes were assessed in vivo. Ex vivo images demonstrated that 87% of excised lymph nodes, including 81% of tumor-positive lymph nodes, were fluorescent. Future clinical studies using microdose amounts of tumor targeting NIRF contrast agents may demonstrate improved surgical intervention with reduced morbidity. PMID- 24466487 TI - Tethered confocal endomicroscopy capsule for diagnosis and monitoring of eosinophilic esophagitis. AB - Eosinophilic esophagitis (EoE) is an allergic condition that is characterized by eosinophils infiltrating the esophageal wall. The treatment of the disease may require multiple follow up sedated endoscopies and biopsies to confirm elimination of eosinophils. These procedures are expensive, time consuming, and may be difficult for patients to tolerate. Here we report on the development of a confocal microscopy capsule for diagnosis and monitoring of EoE. The swallowable capsule implements a high-speed fiber-based reflectance confocal microscopy technique termed Spectrally Encoded Confocal Microscopy (SECM). SECM scans the sample in one dimension without moving parts by using wavelength swept source illumination and a diffraction grating at the back plane of the objective lens. As the wavelength of the source is tuned, the SECM optics within the 7 x 30 mm capsule are rotated using a driveshaft enclosed in a 0.8 mm flexible tether. A single rotation of the optics covered a field of view of 22 mm x 223 um. The lateral and axial resolutions of the device were measured to be 2.1 and 14 um, respectively. Images of Acetic Acid stained swine esophagus obtained with the capsule ex vivo and in vivo clearly showed squamous epithelial nuclei, which are smaller and less reflective than eosinophils. Imaging of esophageal biopsies from EoE patients ex vivo demonstrated the capability of this technology to visualize individual eosinophils. Based on the results of this study, we believe that this capsule will be a simpler and more effective device for diagnosing EoE and monitoring the therapeutic response of this disease. PMID- 24466488 TI - Pulsetrain-burst mode, ultrafast-laser interactions with 3D viable cell cultures as a model for soft biological tissues. AB - A 3D living-cell culture in hydrogel has been developed as a standardized low tensile-strength tissue proxy for study of ultrafast, pulsetrain-burst laser tissue interactions. The hydrogel is permeable to fluorescent biomarkers and optically transparent, allowing viable and necrotic cells to be imaged in 3D by confocal microscopy. Good cell-viability allowed us to distinguish between typical cell mortality and delayed subcellular tissue damage (e.g., apoptosis and DNA repair complex formation), caused by laser irradiation. The range of necrosis depended on laser intensity, but not on pulsetrain-burst duration. DNA double strand breaks were quantified, giving a preliminary upper limit for genetic damage following laser treatment. PMID- 24466489 TI - High frame-rate intravascular optical frequency-domain imaging in vivo. AB - Intravascular optical frequency-domain imaging (OFDI), a second-generation optical coherence tomography (OCT) technology, enables imaging of the three dimensional (3D) microstructure of the vessel wall following a short and nonocclusive clear liquid flush. Although 3D vascular visualization provides a greater appreciation of the vessel wall and intraluminal structures, a longitudinal imaging pitch that is several times bigger than the optical imaging resolution of the system has limited true high-resolution 3D imaging, mainly due to the slow scanning speed of previous imaging catheters. Here, we demonstrate high frame-rate intravascular OFDI in vivo, acquiring images at a rate of 350 frames per second. A custom-built, high-speed, and high-precision fiber-optic rotary junction provided uniform and high-speed beam scanning through a custom made imaging catheter with an outer diameter of 0.87 mm. A 47-mm-long rabbit aorta was imaged in 3.7 seconds after a short contrast agent flush. The longitudinal imaging pitch was 34 MUm, comparable to the transverse imaging resolution of the system. Three-dimensional volume-rendering showed greatly enhanced visualization of tissue microstructure and stent struts relative to what is provided by conventional intravascular imaging speeds. PMID- 24466490 TI - Imaging and modeling collagen architecture from the nano to micro scale. AB - The collagen meshwork plays a central role in the functioning of a range of tissues including cartilage, tendon, arteries, skin, bone and ligament. Because of its importance in function, it is of considerable interest for studying development, disease and regeneration processes. Here, we have used second harmonic generation (SHG) to image human tissues on the hundreds of micron scale, and developed a numerical model to quantitatively interpret the images in terms of the underlying collagen structure on the tens to hundreds of nanometer scale. Focusing on osteoarthritic changes in cartilage, we have demonstrated that this combination of polarized SHG imaging and numerical modeling can estimate fibril diameter, filling fraction, orientation and bundling. This extends SHG microscopy from a qualitative to quantitative imaging technique, providing a label-free and non-destructive platform for characterizing the extracellular matrix that can expand our understanding of the structural mechanisms in disease. PMID- 24466491 TI - Improved localization accuracy in stochastic super-resolution fluorescence microscopy by K-factor image deshadowing. AB - Localization of a single fluorescent particle with sub-diffraction-limit accuracy is a key merit in localization microscopy. Existing methods such as photoactivated localization microscopy (PALM) and stochastic optical reconstruction microscopy (STORM) achieve localization accuracies of single emitters that can reach an order of magnitude lower than the conventional resolving capabilities of optical microscopy. However, these techniques require a sparse distribution of simultaneously activated fluorophores in the field of view, resulting in larger time needed for the construction of the full image. In this paper we present the use of a nonlinear image decomposition algorithm termed K-factor, which reduces an image into a nonlinear set of contrast-ordered decompositions whose joint product reassembles the original image. The K-factor technique, when implemented on raw data prior to localization, can improve the localization accuracy of standard existing methods, and also enable the localization of overlapping particles, allowing the use of increased fluorophore activation density, and thereby increased data collection speed. Numerical simulations of fluorescence data with random probe positions, and especially at high densities of activated fluorophores, demonstrate an improvement of up to 85% in the localization precision compared to single fitting techniques. Implementing the proposed concept on experimental data of cellular structures yielded a 37% improvement in resolution for the same super-resolution image acquisition time, and a decrease of 42% in the collection time of super-resolution data with the same resolution. PMID- 24466492 TI - Quantitative assessment of oral mucosa and labial minor salivary glands in patients with Sjogren's syndrome using swept source OCT. AB - Three-dimensional imaging of the mucosa of the lower lip and labial minor salivary glands is demonstrated in vivo using swept source optical coherence tomography (OCT) system at 1310 nm with modified interface. Volumetric data sets of the inner surface of the lower lip covering ~230 mm(2) field are obtained from patients with Sjogren's syndrome and a control group. OCT enables high-resolution visualization of mucosal architecture using cross-sectional images as well as en face projection images. Comprehensive morphometry of the labial minor salivary glands is performed, and statistical significance is assessed. Statistically significant differences in morphometric parameters are found when subgroups of patients with Sjogren's syndrome are analyzed. PMID- 24466493 TI - In vitro glucose measurement using tunable mid-infrared laser spectroscopy combined with fiber-optic sensor. AB - Because mid-infrared (mid-IR) spectroscopy is not a promising method to noninvasively measure glucose in vivo, a method for minimally invasive high precision glucose determination in vivo by mid-IR laser spectroscopy combined with a tunable laser source and small fiber-optic attenuated total reflection (ATR) sensor is introduced. The potential of this method was evaluated in vitro. This research presents a mid-infrared tunable laser with a broad emission spectrum band of 9.19 to 9.77[Formula: see text](1024~1088 cm(-1)) and proposes a method to control and stabilize the laser emission wavelength and power. Moreover, several fiber-optic ATR sensors were fabricated and investigated to determine glucose in combination with the tunable laser source, and the effective sensing optical length of these sensors was determined for the first time. In addition, the sensitivity of this system was four times that of a Fourier transform infrared (FT-IR) spectrometer. The noise-equivalent concentration (NEC) of this laser measurement system was as low as 3.8 mg/dL, which is among the most precise glucose measurements using mid-infrared spectroscopy. Furthermore, a partial least-squares regression and Clarke error grid were used to quantify the predictability and evaluate the prediction accuracy of glucose concentration in the range of 5 to 500 mg/dL (physiologically relevant range: 30~400 mg/dL). The experimental results were clinically acceptable. The high sensitivity, tunable laser source, low NEC and small fiber-optic ATR sensor demonstrate an encouraging step in the work towards precisely monitoring glucose levels in vivo. PMID- 24466494 TI - Polarimetric study of birefringent turbid media with three-dimensional optic axis orientation. AB - Recent approaches to the analysis of biological samples with three-dimensional linear birefringence orientation require numerical methods to estimate the best fit parameters from experimental measures. We present a novel analytical method for characterizing the intrinsic retardance and the three-dimensional optic axis orientation of uniform and uniaxial turbid media. It is based on a model that exploits the recently proposed differential generalized Jones calculus, remarkably suppressing the need for numerical procedures. The method is applied to the analysis of samples modeled with polarized sensitive Monte Carlo. The results corroborate its capacity to successfully characterize 3D linear birefringence in a straightforward way. PMID- 24466495 TI - Handheld ultrahigh speed swept source optical coherence tomography instrument using a MEMS scanning mirror. AB - We developed an ultrahigh speed, handheld swept source optical coherence tomography (SS-OCT) ophthalmic instrument using a 2D MEMS mirror. A vertical cavity surface-emitting laser (VCSEL) operating at 1060 nm center wavelength yielded a 350 kHz axial scan rate and 10 um axial resolution in tissue. The long coherence length of the VCSEL enabled a 3.08 mm imaging range with minimal sensitivity roll-off in tissue. Two different designs with identical optical components were tested to evaluate handheld OCT ergonomics. An iris camera aided in alignment of the OCT beam through the pupil and a manual fixation light selected the imaging region on the retina. Volumetric and high definition scans were obtained from 5 undilated normal subjects. Volumetric OCT data was acquired by scanning the 2.4 mm diameter 2D MEMS mirror sinusoidally in the fast direction and linearly in the orthogonal slow direction. A second volumetric sinusoidal scan was obtained in the orthogonal direction and the two volumes were processed with a software algorithm to generate a merged motion-corrected volume. Motion corrected standard 6 x 6 mm(2) and wide field 10 x 10 mm(2) volumetric OCT data were generated using two volumetric scans, each obtained in 1.4 seconds. High definition 10 mm and 6 mm B-scans were obtained by averaging and registering 25 B scans obtained over the same position in 0.57 seconds. One of the advantages of volumetric OCT data is the generation of en face OCT images with arbitrary cross sectional B-scans registered to fundus features. This technology should enable screening applications to identify early retinal disease, before irreversible vision impairment or loss occurs. Handheld OCT technology also promises to enable applications in a wide range of settings outside of the traditional ophthalmology or optometry clinics including pediatrics, intraoperative, primary care, developing countries, and military medicine. PMID- 24466496 TI - Optical imaging of subacute airway remodeling and adipose stem cell engraftment after airway injury. AB - Acquired airway injury is frequently caused by endotracheal intubations, long term tracheostomies, trauma, airway burns, and some systemic diseases. An effective and less invasive technique for both the early assessment and the early interventional treatment of acquired airway stenosis is therefore needed. Optical coherence tomography (OCT) has been proposed to have unique potential for early monitoring from the proliferative epithelium to the cartilage in acute airway injury. Additionally, stem cell therapy using adipose stem cells is being investigated as an option for early interventional treatment in airway and lung injury. Over the past decade, it has become possible to monitor the level of injury using OCT and to track the engraftment of stem cells using stem cell imaging in regenerative tissue. The purpose of this study was to assess the engraftment of exogenous adipose stem cells in injured tracheal epithelium with fluorescent microscopy and to detect and monitor the degree of airway injury in the same tracheal epithelium with OCT. OCT detected thickening of both the epithelium and basement membrane after tracheal scraping. The engraftment of adipose stem cells was successfully detected by fluorescent staining in the regenerative epithelium of injured tracheas. OCT has the potential to be a high resolution imaging modality capable of detecting airway injury in combination with stem cell imaging in the same tracheal mucosa. PMID- 24466497 TI - Depth-resolved model-based reconstruction of attenuation coefficients in optical coherence tomography. AB - We present a method, based on a single scattering model, to calculate the attenuation coefficient of each pixel in optical coherence tomography (OCT) depth profiles. Numerical simulations were used to determine the model's response to different depths and attenuation coefficients. Experiments were performed on uniform and layered phantoms with varying attenuation coefficients. They were measured by a 1300 nm OCT system and their attenuation coefficients were evaluated by our proposed method and by fitting the OCT slope as the gold standard. Both methods showed largely consistent results for the uniform phantoms. On the layered phantom, only our proposed method accurately estimated the attenuation coefficients. For all phantoms, the proposed method largely reduced the variability of the estimated attenuation coefficients. The method was illustrated on an in-vivo retinal OCT scan, effectively removing common imaging artifacts such as shadowing. By providing localized, per-pixel attenuation coefficients, this method enables tissue characterization based on attenuation coefficient estimates from OCT data. PMID- 24466498 TI - MicroRNA Regulatory Networks Provide Feedback Mechanisms for Steroid Receptor Signaling. PMID- 24466499 TI - Long-term Culture of Human SSEA-4 Positive Spermatogonial Stem Cells (SSCs). AB - Recently we and two other groups have shown that human spermatogonial stem cells (SSCs) have the potential to become pluripotent in vitro in defined culture conditions and to differentiate into cells of the three embryonic germ layers. This discovery could open new avenues for autologous cell-based therapy in degenerative diseases, bypassing the ethical and immunological problems related to the human embryonic stem cells. In addition, human SSCs could be used to treat infertility in cancer survival children. However, in order to reprogram SSCs into pluripotency, or to preserve them for repopulation of infertile testes, the first and limiting step is to have access to a highly purified human SSC population that could be multiplied and efficiently cultured in vitro maintaining their molecular and cellular characteristics. Although various studies have attempted to identify molecular markers of human SSCs, to date there is still limited information related to the specific markers that could be used for their isolation and optimized purification that allows long-term in vitro culture of isolated human SSCs. Here using SSEA-4 as an optimal marker for isolation of a subpopulation of SSCs, we show that SSEA-4 positive cells express the highest level of SSC genes compared to other subpopulations isolated with different markers, and can be maintained in culture for over 14 passages which we were unable to obtain with other SSCs markers including GPR125 and ITGA6. In addition, we have established a new technology for cell sorting and long-term culture of human SSC-SSEA-4 positive cells that maximizes the purity and viability of the sorted cells. Our findings are crucial and could be used for the most efficient isolation, purification and long-term culture of SSCs for clinical applications in regenerative medicine, or for preparation of human SSCs for autologous treatment of infertility in cancer survival children. PMID- 24466500 TI - CONSTRAINED SPECTRAL CLUSTERING FOR IMAGE SEGMENTATION. AB - Constrained spectral clustering with affinity propagation in its original form is not practical for large scale problems like image segmentation. In this paper we employ novelty selection sub-sampling strategy, besides using efficient numerical eigen-decomposition methods to make this algorithm work efficiently for images. In addition, entropy-based active learning is also employed to select the queries posed to the user more wisely in an interactive image segmentation framework. We evaluate the algorithm on general and medical images to show that the segmentation results will improve using constrained clustering even if one works with a subset of pixels. Furthermore, this happens more efficiently when pixels to be labeled are selected actively. PMID- 24466501 TI - Exosomes in Plasma of Patients with Ovarian Carcinoma: Potential Biomarkers of Tumor Progression and Response to Therapy. AB - BACKGROUND: In patients with Ovarian Cancer (OvCa) exosomes released by tumor cells are present in the plasma and could be involved in tumor progression. This study examines the association between the exosome presence/protein content in plasma of OvCa patients and disease outcome, response to standard therapy and/or tumorresistance to therapies in patients studied at diagnosis and also serially during and after therapy. DESIGN AND METHODS: Exosomes were purified from OvCa patients' plasma (n=22), patients with benign tumors (n=10) or (n=10) healthy controls (NC) using ultracentrifugation. Exosomes were visualized by scanning electron microscopy. Their protein content was measured. The presence of MAGE 3/6 and TGF-beta1 in exosomes was evaluated in Western blots. RESULTS: The OvCa patients' plasma contained higher levels of exosomal proteins (p<0.05) compared to those isolated from plasma of patients with benign tumors or NC. Exosomes isolated from OvCa patients's plasma carried TGF-beta1 and MAGE3/6, which distinguished OvCa patients from those with benign tumors and NC. High protein levels of exosomes were seen in newly diagnosed patients; however in advanced stages of OvCa patients the protein content of isolated exosomes was significantly higher than that of early stages. The exosome levels variably changed during/after chemotherapy, and correlations between the changes in exosomal protein levels and clinical data suggested that the protein content of exosomes might be useful in predicting responses to therapy and prognosis in OvCa patients. CONCLUSION: Analysis of plasma exosomes levels offers a novel approach to diagnosis and monitoring response to therapies in OvCa patients. PMID- 24466502 TI - Dietary Cholesterol and Plasma Lipoprotein Profiles: Randomized-Controlled Trials. AB - Early work suggested that dietary cholesterol increases plasma total cholesterol concentrations in humans. Given the relationship between elevated plasma cholesterol concentrations and cardiovascular disease risk dietary guidelines have consistently recommended limiting food sources of cholesterol. Current intakes are approaching recommended levels. Recently there have been calls to reassess the importance of continuing to recommend limiting dietary cholesterol. Over the past 10 years there have been a limited number of studies addressing this issue. Striking among these studies is the high degree of variability in background diet, subject characteristics and study design. Within the context of current levels of dietary cholesterol intake, the effect on plasma lipids concentrations, with primary interest in LDL-C cholesterol concentrations, is modest and appears to be limited to population subgroups. In these cases, restrictions in dietary cholesterol intake are likely warranted. The biological determinants of inter-individual variability remain a relatively understudied area. PMID- 24466504 TI - Uncertainty Visualization in HARDI based on Ensembles of ODFs. AB - In this paper, we propose a new and accurate technique for uncertainty analysis and uncertainty visualization based on fiber orientation distribution function (ODF) glyphs, associated with high angular resolution diffusion imaging (HARDI). Our visualization applies volume rendering techniques to an ensemble of 3D ODF glyphs, which we call SIP functions of diffusion shapes, to capture their variability due to underlying uncertainty. This rendering elucidates the complex heteroscedastic structural variation in these shapes. Furthermore, we quantify the extent of this variation by measuring the fraction of the volume of these shapes, which is consistent across all noise levels, the certain volume ratio. Our uncertainty analysis and visualization framework is then applied to synthetic data, as well as to HARDI human-brain data, to study the impact of various image acquisition parameters and background noise levels on the diffusion shapes. PMID- 24466503 TI - Caloric Restriction to Moderate Senescence: Mechanisms and Clinical Utility. AB - As life expectancy in the United States continues to increase, the maintenance of physical independence among older Americans has emerged as a major clinical and public health priority. Therefore, there is an urgent need to identify interventions that can maintain or enhance cognitive and physical function with the goal of preventing or delaying the onset of disability. To date, caloric restriction (CR) is the only method that has been consistently found to increase lifespan and delay the onset of age-associated diseases such as cancer and diabetes across multiple species. The promise of calorie restriction as an intervention to improve health and/or maintain function in humans, however, only holds if individuals are able to adhere to this intervention over the long-term. Unfortunately, long-term adherence to CR regimens is notoriously poor likely due to complex interactions between behavioral, physiological, psychological, and environmental variables. Thus, a current challenge for both researchers and clinicians is to identify methods that can assist individuals in maintaining CR over the long-term. PMID- 24466505 TI - Sociodemographic Characteristics, Distance to the Clinic, and Breast Cancer Screening Results. AB - Timely detection and follow-up of abnormal cellular changes can aid in early diagnosis of breast cancer, thus leading to better treatment outcomes. However, despite substantial breast cancer screening initiatives, the proportion of female breast cancer cases diagnosed at late stages remains high. Distance to screening clinics may affect access to care, particularly for women living in impoverished areas with limited means of reliable transportation. Utilizing breast cancer screening data collected by the Illinois Breast and Cervical Cancer Program between 1996 and 2010, we examined the effect of travel distance to the clinic from which women received breast cancer screening tests on stage of diagnosis. The proportion of abnormal mammograms in White women (1.6%) was higher than in Black women (1.1%) or Hispanic women (0.5%). The average distance traveled to a clinic was also farthest among White women (6.7 mi) than for Hispanic (5.3 mi) or Black women (4.4 mi). Distance to a clinic was significantly associated with increased odds of having abnormal results. When distance to clinic was controlled for, the observed disparity in odds of having an abnormal mammogram between White and Black women was no longer statistically significant. Individual and neighborhood sociodemographic characteristics were significantly associated with distance to clinic, but were not associated with increased odds of having an abnormal mammogram, controlling for distance to the clinic. Findings showed that individual and neighborhood sociodemographic characteristics are directly and indirectly associated with abnormal mammogram results, and that distance to a clinic may mediate, in part, the effects of individual characteristics and neighborhood disadvantage on the probability of having an abnormal mammogram. PMID- 24466506 TI - Surface plasmon resonance applied to G protein-coupled receptors. AB - G protein-coupled receptors (GPCR) are integral membrane proteins that transmit signals from external stimuli to the cell interior via activation of GTP-binding proteins (G proteins) thereby mediating key sensorial, hormonal, metabolic, immunological, and neurotransmission processes. Elucidating their structure and mechanism of interaction with extracellular and intracellular binding partners is of fundamental importance and highly relevant to rational design of new effective drugs. Surface plasmon resonance (SPR) has become a method of choice for studying biomolecular interactions at interfaces because measurements take place in real time and do not require labeling of any of the interactants. However, due to the particular challenges imposed by the high hydrophobicity of membrane proteins and the great diversity of receptor-stimulating ligands, the application of this technique to characterize interactions of GPCR is still in the developmental phase. Here we give an overview of the principle of SPR and analyze current approaches for the preparation of the sensor chip surface, capture and stabilization of GPCR, and experimental design to characterize their interaction with ligands, G proteins and specific antibodies. PMID- 24466507 TI - A fiber-optic system for dual-modality photoacoustic microscopy and confocal fluorescence microscopy using miniature components. AB - Imaging of the cells and microvasculature simultaneously is beneficial to the study of tumor angiogenesis and microenvironments. We designed and built a fiber optic based photoacoustic microscopy (PAM) and confocal fluorescence microscopy (CFM) dual-modality imaging system. To explore the feasibility of this all optical device for future endoscopic applications, a microelectromechanical systems (MEMS) scanner, a miniature objective lens, and a small size optical microring resonator as an acoustic detector were employed trying to meet the requirements of miniaturization. Both the lateral resolutions of PAM and CFM were quantified to be 8.8 MUm. Axial resolutions of PAM and CFM were experimentally measured to be 19 MUm and 53 MUm, respectively. The experiments on ex vivo animal bladder tissues demonstrate the good performance of this system in imaging not only microvasculature but also cellular structure, suggesting that this novel imaging technique holds potential for improved diagnosis and guided treatment of bladder cancer. PMID- 24466508 TI - Role of p53 in regulating tissue response to radiation by mechanisms independent of apoptosis. AB - Radiation exposure leads to diverse outcomes in vivo across different tissues and even within the same cell lineage. The diversity of radiation response in vivo is at least partially attributable to the status of the tumor suppressor p53, a master regulator of cellular response to stress, and activation of its transcriptional targets. In certain cells, such as hematopoietic progenitors and transit amplifying cells in the gastrointestinal epithelium, activation of p53 by radiation triggers the intrinsic pathway of apoptosis. However, in many other cells, activation of p53 by radiation does not result in apoptosis, which underscores the importance of understanding the role of p53 in regulating radiation response through alternative mechanisms. In this review, we summarize recent studies using genetically engineered mice to dissect the role of p53 in 1) cells where its activation is dissociated from the intrinsic pathway of apoptosis, such as hematopoietic stem cells and vascular endothelial cells and 2) tissues where activation of the intrinsic pathway of apoptosis does not promote the acute radiation syndrome, such as the gastrointestinal epithelium. We highlight findings showing that the apoptosis-independent response of p53 to radiation in vivo can contribute to death or survival in a cell-type dependent manner, which underscores the complexity by which p53 regulates the cellular and tissue response to radiation. PMID- 24466509 TI - Potential Autoepitope within the Extracellular Region of Contactin-Associated Protein-like 2 in Mice. AB - AIMS: Implicated in autoimmune encephalitis, neuromyotonia and genetic forms of autism, here we report that contactin-associated protein-like 2 (CNTNAP2) contains a potential autoepitope within the extracellular region. METHODOLOGY: CNTNAP2 sequence-similar regions (CSSRs) from human pathogens were identified. Sera from autistic and control children were obtained and analyzed for the presence of antibodies able to bind CSSRs. One such candidate CSSR was evaluated for evidence of autoimmune responses to CNTNAP2 in a mouse model of acute infection. RESULTS: Autistic and control children sera contained antibodies able to discrete regions of CNTNAP2. In a murine model of acute infection, a CSSR derived from the N-terminal extracellular region of CNTNAP2 resulted in anti CNTNAP2 antibody production, proinflammatory cytokine elevation, cerebellar and cortical white matter T-cell infiltration as well as motor dysfunction. CONCLUSION: Taken together, these data suggest that CNTNAP2 contains a potential autoepitope within the extracellular region. PMID- 24466510 TI - Effect of transcranial direct current stimulation on postural stability and lower extremity strength in hemiplegic stroke patients. AB - OBJECTIVE: To evaluate the effect of anodal transcranial direct current stimulation (tDCS) over the lesioned leg motor cortex, which can enhance the strength and coordination of the contralateral lower extremity and furthermore, enhance the postural stability of the hemiplegic subject. METHODS: Anodal or sham stimulation on the lesioned cortex of a lower extremity was delivered to 11 ambulatory hemiplegic patients. The stimulation intensity was 2 mA. All subjects took part in two 10-minute tDCS sessions consisting of anodal stimulation and sham stimulation. The interval period between real and sham stimulation was 48 hours. The order was counter-balanced among the subjects. Before and after each stimulation session, static postural stability was evaluated with eyes opened and closed. Also, the isometric strength of the hemiplegic side of the treated knee was measured before and after each stimulation session. Repeated measure ANOVA was used to determine the statistical significance of improvements in postural stability and strength. RESULTS: There was significant improvement for overall stability index with eyes opened and closed after anodal tDCS (p<0.05). Isometric strength of the lesioned quadriceps tended to increase after anodal tDCS (p<0.05). Postural stability and quadriceps strength were not changed after sham stimulation. CONCLUSION: Anodal tDCS has potential value in hemiplegic stroke patients to improve balance and strengthen the affected lower extremity. PMID- 24466511 TI - Randomized, sham controlled trial of transcranial direct current stimulation for painful diabetic polyneuropathy. AB - OBJECTIVE: To investigate the analgesic effect of transcranial direct current stimulation (tDCS) over the primary motor (M1), dorsolateral prefrontal cortex (DLPFC), and sham tDCS in patients with painful diabetic polyneuropathy (PDPN). METHODS: Patients with PDPN (n=60) were divided randomly into the three groups (n=20 per group). Each group received anodal tDCS with the anode centered over the left M1, DLPFC, or sham stimulation for 20 minutes at intensity of 2 mA for 5 consecutive days. A blinded physician rated the patients' pain using a visual analog scale (VAS), Clinical Global Impression (CGI) score, anxiety score, sleep quality, Beck Depression Inventory (BDI), and the pain threshold (PT) to pressure. RESULTS: After the tDCS sessions, the M1 group showed a significantly greater reduction in VAS for pain and PT versus the sham and DLPFC groups (p<0.001). The reduction in VAS for pain was sustained after 2 and 4 weeks of follow-up in the M1 group compared with the sham group (p<0.001, p=0.007). Significant differences were observed among the three groups over time in VAS for pain (p<0.001), CGI score (p=0.01), and PT (p<0.001). No significant difference was observed among the groups in sleep quality, anxiety score, or BDI score immediately after tDCS. CONCLUSION: Five daily sessions of tDCS over the M1 can produce immediate pain relief, and relief 2- and 4-week in duration in patients with PDPN. Our findings provide the first evidence of a beneficial effect of tDCS on PDPN. PMID- 24466512 TI - Threshold of Clinical Severity of Cervical Dystonia for Positive (18)F-FDG PET/CT. AB - OBJECTIVE: To examine whether the clinical severity of cervical dystonia (CD) significantly correlates with (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) findings as well as to determine the threshold of the clinical severity of CD for positive (18)F-FDG PET/CT study findings. METHODS: Forty-seven subjects with torticollis as one of the symptoms of CD were included. The clinical severity of CD was evaluated with the Toronto Western Spasmodic Torticollis Rating Scale (TWSTRS) at the time of (18)F-FDG PET/CT. The correlation between the clinical severity of CD and the highest SUVmax was examined. The threshold of the clinical severity of CD necessary for positive (18)F-FDG PET/CT findings was determined using receiver operating characteristics curve analysis. RESULTS: Thirty-three of the 47 subjects (70.21%) showed positive (18)F-FDG PET/CT findings. The ipsilateral splenius capitis/cervicis, oblique capitis inferior, and longus colli/capitis were the rotators most frequently involved. The highest SUVmax of (18)F-FDG PET/CT was significant correlated with the TWSTRS. Subjects with a total TWSTRS exceeding 39 showed positive (18)F-FDG PET/CT findings, with those having a total TWSTRS <=22 showing negative (18)F-FDG PET/CT results. The cutoff value of the total TWSTRS for positive (18)F-FDG PET/CT findings was set at 27.5 with 90.9% sensitivity and 64.3% specificity. CONCLUSION: A significant correlation was evident between the clinical severity of CD and (18)F-FDG PET/CT findings, providing a threshold of the clinical severity of CD for acquisition of positive (18)F-FDG PET/CT findings. PMID- 24466513 TI - Comparison of helmet therapy and counter positioning for deformational plagiocephaly. AB - OBJECTIVE: To compare effectiveness on correcting cranial and ear asymmetry between helmet therapy and counter positioning for deformational plagiocephaly (DP). METHODS: Retrospective data of children diagnosed with DP who visited our clinic from November 2010 to October 2012 were reviewed. Subjects <=10 months of age who showed >=10 mm of diagonal difference were included for analysis. For DP treatment, information on both helmet therapy and counter positioning was given and either of the two was chosen by each family. Head circumference, cranial asymmetry measurements including diagonal difference, cranial vault asymmetry index, radial symmetry index, and ear shift were obtained by 3-dimensional head surface laser scan at the time of initiation and termination of therapy. RESULTS: Twenty-seven subjects were included: 21 had helmet therapy and 6 underwent counter positioning. There was no significant difference of baseline characteristics, head circumferences and cranial asymmetry measurements at the initiation of therapy. The mean duration of therapy was 4.30+/-1.27 months in the helmet therapy group and 4.08+/-0.95 months in the counter positioning group (p=0.770). While cranial asymmetry measurements improved in both groups, significantly more improvement was observed with helmet therapy. There was no significant difference of the head circumference growth between the two groups at the end of therapy. CONCLUSION: Helmet therapy resulted in more favorable outcomes in correcting cranial and ear asymmetry than counter positioning on moderate to severe DP without compromising head growth. PMID- 24466514 TI - Botulinum toxin in the treatment of drooling in tetraplegic patients with brain injury. AB - OBJECTIVE: To investigate the effect of botulinum toxin type A (BTA) injection into the salivary gland and to evaluate the changes of drooling in varied postures in tetraplegic patients with brain injury. METHODS: Eight tetraplegic patients with brain injury were enrolled. BTA was injected into each parotid and submandibular gland of both sides under ultrasonographic guidance. Drooling was measured by a questionnaire-based scoring system for drooling severity and frequency, and the sialorrhea was measured by a modified Schirmer test for the patients before the injection, 3 weeks and 3 months after the injection. Drooling was evaluated in each posture, such as supine, sitting, and tilt table standing, and during involuntary mastication, before and after the injection. RESULTS: The severity and frequency of drooling and the modified Schirmer test improved significantly at 3 weeks and 3 months after the injection (p<0.05). Drooling was more severe and frequent in tilt table standing than in the sitting position and in sitting versus supine position (p<0.05). The severity of drooling was significantly increased in the patients with involuntary mastication (p<0.05). CONCLUSION: Salivary gland injection of BTA in patients with tetraplegia resulting from brain injury who had drooling and sialorrhea could improve the symptoms for 3 months without complications. The severity and frequency of drooling were dependent on posture and involuntary mastication. Proper posture and involuntary mastication of the patients should be taken into account in planning drooling treatment. PMID- 24466515 TI - Effects of abdominal hollowing during stair climbing on the activations of local trunk stabilizing muscles: a cross-sectional study. AB - OBJECTIVE: To examine using surface electromyography whether stair climbing with abdominal hollowing (AH) is better at facilitating local trunk muscle activity than stair climbing without AH. METHODS: Twenty healthy men with no history of low back pain participated in the study. Surface electrodes were attached to the multifidus (MF), lumbar erector spinae, thoracic erector spinae, transverse abdominus - internal oblique abdominals (TrA-IO), external oblique abdominals (EO), and the rectus abdominis. Amplitudes of electromyographic signals were measured during stair climbing. Study participants performed maximal voluntary contractions (MVC) for each muscle in various positions to normalize the surface electromyography data. RESULTS: AH during stair climbing resulted in significant increases in normalized MVCs in both MFs and TrA-IOs (p<0.05). Local trunk muscle/global trunk muscle ratios were higher during stair climbing with AH as compared with stair climbing without AH. Especially, right TrA-IO/EO and left TrA IO/EO were significantly increased (p<0.05). CONCLUSION: Stair climbing with AH activates local trunk stabilizing muscles better than stair climbing without AH. The findings suggest that AH during stair climbing contributes to trunk muscle activation and trunk stabilization. PMID- 24466516 TI - Reliability and validity of the korean version of the pain disability questionnaire. AB - OBJECTIVE: To translate the English version of the Pain Disability Questionnaire (PDQ) into Korean and to investigate the reliability and validity of the Korean version of the PDQ (K-PDQ) in patients suffering chronic disabling musculoskeletal disorders (CDMDs). METHODS: The English version of the PDQ was translated into Korean. Ten patients with CDMDs were randomly selected for a pilot study to assess the comprehensibility of the pre-final version. One hundred and thirty-nine patients suffering from CDMDs for more than 3 months were enrolled in this study. Follow-up questionnaires were obtained to examine the test-retest reliability. Concurrent validity was evaluated by comparing the K-PDQ with the visual analogue scale (VAS). Construct validity was evaluated by comparing the K-PDQ with the brief form of the World Health Organization quality of life assessment instrument (WHOQOL-BREF) using Pearson correlation coefficient. Reliability was assessed using the intraclass correlation coefficient (ICC), and internal consistency was determined by Cronbach's alpha. RESULTS: Test-retest reliability was assessed in 70 patients, with an average time interval of 12 days. The ICC was 0.958 (p<0.001). Internal consistency reached Cronbach's alpha of 0.933 for the functional component and 0.870 for the psychosocial component. The correlation coefficient for the K-PDQ when compared with the VAS was 0.834 in the first assessment and 0.831 in the second assessment. All domains of the WHOQOL-BREF showed a significant negative correlation with the K-PDQ. CONCLUSION: The K-PDQ is a reliable and valid instrument for measuring disability and can be used to assess disability and treatment outcomes in Korean patients with CDMD. PMID- 24466517 TI - Efficacy of epidural neuroplasty versus transforaminal epidural steroid injection for the radiating pain caused by a herniated lumbar disc. AB - OBJECTIVE: To compare the treatment effects of epidural neuroplasty (NP) and transforaminal epidural steroid injection (TFESI) for the radiating pain caused by herniated lumbar disc. METHODS: Thirty-two patients diagnosed with herniated lumbar disc through magnetic resonance imaging or computed tomography were included in this study. Fourteen patients received an epidural NP and eighteen patients had a TFESI. The visual analogue scale (VAS) and functional rating index (FRI) were measured before the treatment, and at 2 weeks, 4 weeks and 8 weeks after the treatment. RESULTS: In the epidural NP group, the mean values of the VAS before the treatment, and at 2 weeks, 4 weeks and 8 weeks after the treatment were 7.00+/-1.52, 4.29+/-1.20, 2.64+/-0.93, 1.43+/-0.51 and those of FRI were 23.57+/-3.84, 16.50+/-3.48, 11.43+/-2.44, 7.00+/-2.15. In the TFESI group, the mean values of the VAS before the treatment, and at 2 weeks, 4 weeks and 8 weeks after the treatment were 7.22+/-2.05, 4.28+/-1.67, 2.56+/-1.04, 1.33+/-0.49 and those of FRI were 22.00+/-6.64, 16.22+/-5.07, 11.56+/-4.18, 8.06+/-1.89. During the follow-up period, the values of VAS and FRI within each group were significantly reduced (p<0.05) after the treatment. But there were no significant differences between the two groups statistically. CONCLUSION: Epidural NP and TFESI are equally effective treatments for the reduction of radiating pain and for improvement of function in patients with a herniated lumbar disc. We recommend that TFESI should be primarily applied to patients who need interventional spine treatment, because it is easier and more cost-effective than epidural NP. PMID- 24466518 TI - Generalized joint hypermobility in healthy female koreans: prevalence and age related differences. AB - OBJECTIVE: Objective To evaluate the prevalence of generalized joint hypermobility (GJH) in healthy female Koreans and to determine whether the degree of GJH differs between children and adults. METHODS: Two groups of females were enrolled, a group of girls from an elementary school (n=404) and women from a call center (n=266). GJH was diagnosed using the Beighton score, which is composed of an evaluation of bilateral knees, elbows, thumbs, and fifth fingers as well as thoracolumbar joint. The GJH and localized hypermobility of each joint was compared between the two groups, and the pattern of hypermobility according to age and dominant hand was investigated. RESULTS: Total prevalence of GJH was 50.0% (335/750), and it was more frequently observed in the group of girls (58.9%, 238/404) than women (36.5%, 97/266). The degree of GJH expressed in terms of Beighton score was inversely correlated with age (p<0.05). Significant differences in localized hypermobility of the thumb and fifth finger were found between the two groups and were postulated as the cause for the decline in GJH with age. The pattern of decreased mobility proportional to aging differed between the two joints. Decreased mobility occurred equally on both sides of the thumb but was biased toward the fifth finger of the dominant side (mostly the right). CONCLUSION: The female Koreans appeared to have a high prevalence of GJH. The incidence of GJH decreased as age increased as a result of decreased mobility of the fifth finger on the dominant side. PMID- 24466519 TI - Electrophysiologic investigation during facial motor neuron suppression in patients with hemifacial spasm: possible pathophysiology of hemifacial spasm: a pilot study. AB - OBJECTIVE: To evaluate the pathophysiological mechanism of hemifacial spasm (HFS), we performed electrophysiological examinations, such as supraorbital nerve stimulation with orbicularis oris muscle recording and lateral spread tests, after suppressing the patient's central nervous system by administering intravenous diazepam. METHODS: Six patients with HFS were recruited. Supraorbital nerve stimulation with orbicularis oris muscle recording and the lateral spread test were performed, followed by intravenous application of 10 mg diazepam to achieve facial motor neuron suppression. Subsequently, we repeated the two electrophysiological experiments mentioned above at 10 and 20 minutes after the patients had received the diazepam intravenously. RESULTS: Orbicularis oris muscle responses were observed in all patients after supraorbital nerve stimulation and lateral spread tests. After the diazepam injection, no orbicularis oris muscle response to supraorbital nerve stimulation was observed in one patient, and the latencies of this response were evident as a slowing tendency with time in the remaining five patients. However, the latencies of the orbicularis oris muscle responses were observed consistently in all patients in the lateral spread test. CONCLUSION: Our results suggest that ectopic excitation/ephaptic transmission contributes to the pathophysiological mechanisms of HFS. This is because the latencies of the orbicularis oris muscle responses in the lateral spread test were observed consistently in the suppressed motor neuron in our patients. PMID- 24466520 TI - Disparity in the Fear of Falling Between Urban and Rural Residents in Relation With Socio-economic Variables, Health Issues, and Functional Independency. AB - OBJECTIVE: To investigate disparities in the fear of falling between urban and rural communities in relation to socio-demographics, health status, and functional level. METHODS: A total of 974 subjects aged 40 years or older participated in this study (335 urban residents and 639 rural). They completed a questionnaire about socio-demographics, health-related variables, and experience with falls. We employed both direct questioning and the Korean version of Falls Efficacy Scale-International (KFES-I) to investigate fear of falling in terms of perceptive fear and higher level of concern over falling during daily activities. The Korean version of Instrumental Activities of Daily Living was used to assess functional independency. RESULTS: Aging, female gender, fall history, and the presence of chronic medical problems were independently associated with higher prevalence for the fear of falling. Both perceptive fear of falling and a higher level of concern over falling were more prevalent in the rural senior population compared with those in the urban population when they had the following characteristics: lower income or educational background, physical laborer or unemployed, no chronic medical morbidity, or functional independency in daily activities. CONCLUSION: The disparity in the fear of falling between the two areas is thought to be related to age structure, and it may also exist in healthy or functionally independent senior populations under the influence of socio environmental factors. A senior population with lower socio-economic status residing in a rural area might be related with a greater vulnerability to the fear of falling. We should consider regional characteristics when we design fall related studies or develop fall-prevention programs at the community level. PMID- 24466521 TI - The effects of visual and haptic vertical stimulation on standing balance in stroke patients. AB - OBJECTIVE: To explore the effect of visual and haptic vertical stimulation on standing balance in post-stroke patients. METHODS: Twenty-five post-stroke patients were recruited. We measured left/right standing pressure differences and the center of pressure (COP) parameters for each patient under three different conditions: no stimulation, visual, and haptic stimulated conditions. First, patients stood on a posturography platform with their eyes blindfolded. After a rest period, the patients stood on the same platform with their eyes fixed to a 1.5-m luminous rod, which was placed at a vertical position in front of the patients. After another rest period, the patients again stood touching a vertically placed long rod in their non-hemiplegic hand with their eyes blindfolded. We collected the signals from the feet in each condition and obtained the balance indices. RESULTS: Compared with the no stimulation condition, significant improvements were observed for most of the COP parameters including COP area, length, and velocity for both the visual and haptic vertical stimulation conditions (p<0.01). Additionally, when we compared visual and haptic vertical stimulation, visual vertical stimulation was superior to haptic stimulation for all COP parameters (p<0.01). Left/right standing pressure differences, increased, although patients bore more weight on their paretic side when vertical stimulation was applied (p>0.01). CONCLUSION: Both visual and haptic vertical stimulation improved standing steadiness of post-stroke patients. Notably, visual vertical stimulation was more effective than haptic stimulation. PMID- 24466522 TI - Trial of oral metoclopramide on diurnal bruxism of brain injury. AB - Bruxism is a diurnal or nocturnal parafunctional activity that includes tooth clenching, bracing, gnashing, and grinding. The dopaminergic system seems to be the key pathophysiology of bruxism and diminution of dopaminergic transmission at the prefrontal cortex seems to induce it. We report two patients with diurnal bruxism in whom a bilateral frontal lobe injury resulted from hemorrhagic stroke or traumatic brain injury. These patients' bruxism was refractory to bromocriptine but responded to low-dose metoclopramide therapy. We propose that administering low doses of metoclopramide is possibly a sound method for treating bruxism in a brain injury patient with frontal lobe hypoperfusion on positron emission tomography imaging. PMID- 24466523 TI - Successful surgery for scoliosis supported by pulmonary rehabilitation in a duchenne muscular dystrophy patient with forced vital capacity below 10%. AB - Low vital capacity is a risk factor for scoliosis correction operation in Duchenne muscular dystrophy (DMD) patients, but pulmonary rehabilitation, including noninvasive intermittent positive pressure ventilator application, air stacking exercise, and assisted coughing technique, reduces the pulmonary complications and perioperative mortality risk. In this case, the patient's preoperative forced vital capacity (FVC) was 8.6% of normal predicted value in sitting position and 9.4% in supine position. He started pulmonary rehabilitation before the operation and continued right after the operation. Scoliosis correction operation was successful without any pulmonary complications, and his discomfort in sitting position was improved. If pulmonary rehabilitative support is provided properly, FVC below 10% of normal predicted value is not a contraindication of scoliosis correction operation in DMD patients. PMID- 24466524 TI - Diffusion tensor tractography in two cases of kernohan-woltman notch phenomenon. AB - Kernohan-Woltman notch phenomenon (KWP) is an ipsilateral motor weakness due to compression of the contralateral cerebral peduncle. We report two cases of KWP following traumatic brain injury. In case 1, ipsilateral hemiplegia was noted after right subdural hemorrhage. Although magnetic resonance imaging showed no abnormal signal changes on cerebral peduncle, diffusion tensor tractography (DTT) revealed interruption of corticospinal tract (CST) at lower level of the midbrain level. In case 2, there was abnormal signal change of the right cerebral peduncle contralateral to the primary lesion and we could not reconstruct right CST. Case 1 showed unsatisfactory motor recovery even after 15 months, and follow-up DTT showed no change. In case 2, follow-up DTT was not performed, but her ipsilateral hemiparesis had almost disappeared during the 15 months. DTT would be useful in detecting ipsilateral hemiparesis due to KWP and the clinical course may differ according to the lesion characteristics. PMID- 24466525 TI - Sciatic nerve injury caused by a stretching exercise in a trained dancer. AB - Sciatic nerve injury after stretching exercise is uncommon. We report a case of an 18-year-old female trained dancer who developed sciatic neuropathy primarily involving the tibial division after routine stretching exercise. The patient presented with dysesthesia and weakness of the right foot during dorsiflexion and plantarflexion. The mechanism of sciatic nerve injury could be thought as hyperstretching alone, not caused by both hyperstretching and compression. Electrodiagnostic tests and magnetic resonance imaging revealed evidence of the right sciatic neuropathy from the gluteal fold to the distal tibial area, and partial tear of the left hamstring origin and fluid collection between the left hamstring and ischium without left sciatic nerve injury. Recovery of motor weakness was obtained by continuous rehabilitation therapy and some evidence of axonal regeneration was obtained by follow-up electrodiagnostic testing performed at 3, 5, and 12 months after injury. PMID- 24466526 TI - Management of severe bilateral ptosis in a patient with midbrain infarction: a case report. AB - Ptosis could be caused by oculomotor nerve palsy in the midbrain infarction. Bilateral ptosis has been reported in several reports, which focused on clinical characteristics of midbrain infarction. Little research attention has been paid to the treatment of patients with bilateral ptosis in midbrain infarction. We experienced a case of severe bilateral ptosis occurring after midbrain infarction. The patient could not open her eyes, perform basic activities or achieve effective rehabilitation. Neurogenic ptosis can improved after the underlying cause is treated. However, in this case, bilateral ptosis was not improved after conservative care for 6 months and the patient remained limited in activities of daily living and mobility. Surgical correction of bilateral ptosis was done by the resection of both Muller's muscles. After surgical correction, the bilateral ptosis was much improved and the effect persisted for at least 6 months. PMID- 24466527 TI - Thoracic outlet syndrome caused by schwannoma of brachial plexus. AB - Schwannomas are benign, usually slow-growing tumors that originate from Schwann cells surrounding peripheral, cranial, or autonomic nerves. The most common form of these tumors is acoustic neuroma. Schwannomas of the brachial plexus are quite rare, and symptomatic schwannomas of the brachial plexus are even rarer. A 47 year-old woman presented with a 1-year history of dysesthesia, neuropathic pain, and mild weakness of the right upper limb. Results of physical examination and electrodiagnostic studies supported a diagnosis as thoracic outlet syndrome. Conservative treatment did not relieve her symptoms. After 9 months, a soft mass was found at the upper margin of the right clavicle. Magnetic resonance imaging showed a 3.0*1.8*1.7 cm ovoid mass between the inferior trunk and the anterior division of the brachial plexus. Surgical mass excision and biopsy were performed. Pathological findings revealed the presence of schwannoma. After schwannoma removal, the right hand weakness did not progress any further and neuropathic pain gradually reduced. However, dysesthesia at the right C8 and T1 dermatome did not improve. PMID- 24466529 TI - Diagnosis with manometry and treatment with repetitive transcranial magnetic stimulation in Dysphagia. AB - Videofluoroscopic swallowing study (VFSS) used for the diagnosis of dysphagia has limitations in objectively assessing the contractility of the pharyngeal muscle or the degree of the upper esophageal sphincter relaxation. With a manometer, however, it is possible to objectively assess the pressure changes in the pharynx caused by pharyngeal muscle contraction during swallowing or upper esophageal sphincter relaxation, hence remedying the limitations of VFSS. The following case report describes a patient diagnosed with lateral medullar infarction presenting a 52-year-old male who had dysphagia. We suggested that the manometer could be used to assess the specific site of dysfunction in patients with dysphagia complementing the limitations of VFSS. We also found that repetitive transcranial magnetic stimulation was effective in treating patients refractory to traditional dysphagia rehabilitation. PMID- 24466528 TI - Atypical supernumerary phantom limb and phantom limb pain in a patient with spinal cord injury: case report. AB - Supernumerary phantom limb (SPL) resulting from spinal cord lesions are very rare, with only sporadic and brief descriptions in the literature. Furthermore, the reported cases of SPL typically occurred in neurologically incomplete spinal cord patients. Here, we report a rare case of SPL with phantom limb pain that occurred after traumatic spinal cord injury in a neurologically complete patient. After a traffic accident, a 43-year-old man suffered a complete spinal cord injury with a C6 neurologic level of injury. SPL and associated phantom limb pain occurred 6 days after trauma onset. The patient felt the presence of an additional pair of legs that originated at the hip joints and extended medially, at equal lengths to the paralyzed legs. The intensity of SPL and associated phantom limb pain subsequently decreased after visual-tactile stimulation treatment, in which the patient visually identified the paralyzed limbs and then gently tapped them with a wooden stick. This improvement continued over the 2 months of inpatient treatment at our hospital and the presence of the SPLs was reduced to 20% of the real paralyzed legs. This is the first comprehensive report on SPLs of the lower extremities after neurologically complete spinal cord injury. PMID- 24466530 TI - Medial antebrachial cutaneous nerve injury after brachial plexus block: two case reports. AB - Medial antebrachial cutaneous (MABC) nerve injury associated with iatrogenic causes has been rarely reported. Local anesthesia may be implicated in the etiology of such injury, but has not been reported. Two patients with numbness and painful paresthesia over the medial aspect of the unilateral forearm were referred for electrodiagnostic study, which revealed MABC nerve lesion in each case. The highly selective nature of the MABC nerve injuries strongly suggested that they were the result of direct nerve injury by an injection needle during previous brachial plexus block procedures. Electrodiagnostic studies can be helpful in evaluating cases of sensory disturbance after local anesthesia. To our knowledge, these are the first documented cases of isolated MABC nerve injury following ultrasound-guided axillary brachial plexus block. PMID- 24466531 TI - What is the role of hand-assisted laparoscopic surgery in the single-port surgery era? PMID- 24466532 TI - Safe distal resection margin in patients with t3 mid and distal rectal cancer who underwent a sphincter-saving resection without preoperative radiotherapy. PMID- 24466533 TI - Preemptive analgesia in single-incision laparoscopic surgery. PMID- 24466534 TI - What matters in colonoscopy? PMID- 24466535 TI - Sham feeding? Same feeding? PMID- 24466536 TI - Clinical outcomes of 103 hand-assisted laparoscopic surgeries for left-sided colon and rectal cancer: single institutional review. AB - PURPOSE: The laparoscopic colectomy is avoided principally because of its technical difficulty, steep learning curve, and increased operative time. Hand assisted laparoscopic surgery (HALS) is an alternative technique that addresses these problems while preserving the short-term benefits of a laparoscopic colectomy. Our study was aimed to describe the characteristics of patients admitted due to left-sided colon and rectal cancer for HALS. METHODS: A prospectively maintained database was used to identify patients who underwent HALS at the Institute of Oncology, Vilnius University, from July 1, 2009, to October 1, 2012. RESULTS: One hundred-three HALS colorectal resections were performed. The patients' mean age was 64 +/- 13.4 years. There were 46 male and 57 female patients. The body mass index was 27.3 +/- 5.8 kg/m(2). Forty-three patients (41.8%) had experienced prior abdominal surgery. The mean HALS time was 105 minutes (range, 55-85 minutes). The conversion rate was 2.7% (3/103). The median of return of gastrointestinal function was 2.5 days (range, 2.2-4.5 days). The median length of hospital stay was 9 days. The postoperative complication and mortality rates were 10.7% and 0.97%, respectively. Four incisional hernias (3.9%) were seen at a mean follow-up of 7.0 +/- 3.4 months. None of the patients had a trocar or a hand-port site recurrence. CONCLUSION: A HALS colorectal resection is a safe and effective technique, and it provides all the benefits of minimally invasive surgery. PMID- 24466537 TI - Association between a close distal resection margin and recurrence after a sphincter-saving resection for t3 mid- or low-rectal cancer without radiotherapy. AB - PURPOSE: To maintain the patient's quality of life, surgeons strive to preserve the sphincter during rectal cancer surgery. This study evaluated the oncologic safety of a sphincter-saving resection with a distal resection margin (DRM) <1 cm without radiotherapy in T3, mid- or low-rectal cancer. METHODS: This retrospective study enrolled 327 patients who underwent a sphincter-saving resection for proven T3 rectal cancer located <10 cm from the anal verge and without radiotherapy between January 1995 and December 2011. The oncologic outcomes included the 5-year cancer-specific survival, the local recurrence, and the systemic recurrence rates. RESULTS: In groups A (DRM <=1 cm) and B (DRM >1 cm), the 5-year cancer-specific survival rates were 81.57% and 80.03% (P = 0.8543), the 5-year local recurrence rates were 6.69% and 9.52% (P = 0.3981), and the 5-year systemic recurrence rates were 19.46% and 23.11% (P = 0.5750), respectively. CONCLUSION: This study showed that the close DRM itself should not be a contraindication for a sphincter-saving resection for T3 mid- or low-rectal cancer without radiotherapy. However, a prospective randomized controlled trial including the effect of adjuvant therapy will be needed. PMID- 24466538 TI - Postoperative pain relief using wound infiltration with 0.5% bupivacaine in single-incision laparoscopic surgery for an appendectomy. AB - PURPOSE: Recently, single-incision laparoscopic surgery (SILS) has been popular for minimally invasive surgery and cosmetic improvement. However, some papers have reported that SILS for an appendectomy (SILS-A) has had the more postoperative complaints of pain. We investigated postoperative pain relief using wound infiltration with 0.5% bupivacaine in SILS-A and compared the result with that for conventional SILS-A. METHODS: Between July 2010 and September 2012, 75 patients who underwent SILS-A were enrolled in this study. The patients were randomly assigned to two groups: conventional SILS-A group (C-SILS-A) or wound infiltrated with 0.5% bupivacaine in SILS-A group (W-SILS-A). Forty-five patients were in the C-SILS-A, and 30 patients were in the W-SILS-A. Patients with perforated appendicitis were excluded. The clinical outcomes were compared between the groups by using the verbal numerical rating scale (VNRS). RESULTS: Clinical outcomes were similar in both study groups except for the pain score. The W-SILS-A group showed significantly lower numbers of additional pain killers and lower VNRS scores 1, 6, and 12 hours after surgery than the C-SILS-A group. CONCLUSION: W-SILS-A is a technically simple and effective method of reducing early postoperative pain. It may be applicable in SILS-A for pain control system. PMID- 24466539 TI - Importance of Early Follow-up Colonoscopy in Patients at High Risk for Colorectal Polyps. AB - PURPOSE: Minimizing the polyp miss rate during colonoscopy is important for patients at high risk for colorectal polyps. We investigated the polyp miss rate and the factors associated with it in high-risk patients. METHODS: The medical records of 163 patients who underwent follow-up colonoscopy between January 2001 and April 2010, which was within 9 months after a polypectomy, because the index colonoscopy had shown multiple (more than 3) adenomas or advanced adenoma were retrospectively reviewed. Miss rates were calculated for all polyps, for neoplastic polyps and for advanced adenomas. Factors associated with the miss rates in these patients, such as the location, shape and size of the polyp, were analyzed. RESULTS: The miss rates for polyps, adenomas, adenomas <5 mm, adenomas >=5 mm and advanced adenomas were 32.6%, 20.9%, 17.7%, 3.2%, and 0.9%, respectively. No carcinoma, except for one small carcinoid tumor, was missed. Flat shape and small size (<5 mm) were significantly associated with adenoma miss rate. The miss rate was significantly higher for flat-type advanced adenomas than for protruded-type advanced adenomas (27.7% vs 4.1%). CONCLUSION: The polyp miss rate in patients at high risk for colorectal polyps was higher than expected. Efforts are needed to reduce miss rates and improve the quality of colonoscopy. Also, early follow-up colonoscopy is mandatory, especially in patients at high risk. PMID- 24466540 TI - Effect of gum chewing on the recovery from laparoscopic colorectal cancer surgery. AB - PURPOSE: We aimed to examine the effect of gum chewing after laparoscopic colorectal cancer surgery. METHODS: We reviewed the medical records of patients who underwent laparoscopic colorectal cancer surgery in Incheon St. Mary's Hospital, The Catholic University of Korea School of Medicine. We divided the patients into 2 groups: group A consisted of 67 patients who did not chew gum; group B consisted of 65 patients who chewed gum. We analyzed the short-term clinical outcomes between the two groups to evaluate the effect of gum chewing. RESULTS: The first passage of gas was slightly earlier in group B, but the difference was not significant. However, the length of hospital stay was 6.7 days in group B, which was significantly shorter than that in group A (7.3 days, P = 0.018). CONCLUSION: This study showed that length of postoperative hospital stay was shorter in the gum-chewing group. In future studies, we expect to elucidate the effect of gum chewing on the postoperative recovery more clearly. PMID- 24466541 TI - Rhabdoid carcinoma of the rectum. AB - Rhabdoid colonic tumors are very rare lesions with just a few publications describing such neoplasms. Even more unusual for these lesions are their primary rectal locations, with only two brief case reports having been published on that subject to date. We present a case of a composite rhabdoid rectal carcinoma in a 49-year-old male. The tumor behaved very aggressively, with rapid patient demise despite radical surgery and intensive postoperative chemotherapy (FOLFIRI [folinic acid {leucovorin}, fluorouracil {5-fluorouracil}, and irinotecan] and FOLFOX4 [folinic acid {leucovorin}, fluorouraci {5-fluorouracil}, and oxaliplatin]). Pathologic examination was supportive of a rhabdoid carcinoma, with a compatible immunohistochemical profile, demonstrating synchronous expression of vimentin and epithelial markers in the tumor cells. In addition, BRAF V600E gene mutation, together with a wild-type KRAS gene, was identified, and no evidence of microsatellite instability based on MLH1, MSH2, MSH6, and PMS2 immunophenotypes, i.e., no loss of expression for all 4 markers, was observed. Our reported case confirms previously published observations of the clinical aggressiveness and the poor therapeutic response for rhabdoid tumors. PMID- 24466542 TI - Pneumoretroperitoneum after procedure for prolapsed hemorrhoid. AB - Procedure for prolapsed hemorrhoid (PPH) is well recognized alternative to the traditional hemorrhoidectomy, and is associated with reduced pain and earlier return to normal activity. Over the past decade, there have been reports of severe life-threatening complications after a PPH, although the incidence is very low. Rectal perforation due to staple-line dehiscence is one of the serious complications that can cause severe pelvic sepsis or a pneumoretroperitoneum. Here, the first Korean case of a pneumoretroperitoneum due to staple-line dehiscence is described. PMID- 24466543 TI - Attempts to treat patients with hemophilia, the "royal disease". PMID- 24466544 TI - A new paradigm in the diagnosis of hereditary hemolytic anemia. PMID- 24466545 TI - Relapsed intravascular large B-cell lymphoma. PMID- 24466546 TI - Chronic myeloid leukemia with marked splenomegaly and pseudo-Gaucher cells. PMID- 24466547 TI - Next generation sequencing: new tools in immunology and hematology. AB - One of the hallmarks of the adaptive immune system is the specificity of B and T cell receptors. Thanks to somatic recombination, a large repertoire of receptors can be generated within an individual that guarantee the recognition of a vast number of antigens. Monoclonal antibodies have limited applicability, given the high degree of diversity among these receptors, in BCR and TCR monitoring. Furthermore, with regard to cancer, better characterization of complex genomes and the ability to monitor tumor-specific cryptic mutations or translocations are needed to develop better tailored therapies. Novel technologies, by enhancing the ability of BCR and TCR monitoring, can help in the search for minimal residual disease during hematological malignancy diagnosis and follow-up, and can aid in improving bone marrow transplantation techniques. Recently, a novel technology known as next generation sequencing has been developed; this allows the recognition of unique sequences and provides depth of coverage, heterogeneity, and accuracy of sequencing. This provides a powerful tool that, along with microarray analysis for gene expression, may become integral in resolving the remaining key problems in hematology. This review describes the state of the art of this novel technology, its application in the immunological and hematological fields, and the possible benefits it will provide for the hematology and immunology community. PMID- 24466548 TI - Comparison of laboratory characteristics between acute promyelocytic leukemia and other subtypes of acute myeloid leukemia with disseminated intravascular coagulation. AB - BACKGROUND: Acute promyelocytic leukemia (APL) is an acute myeloid leukemia (AML) subtype with distinctive cell morphology, molecular presentation, clinical course, and treatment. About 90% of APL patients present with hemorrhagic complications due to disseminated intravascular coagulation (DIC). When APL is suspected, all-trans retinoic acid (ATRA) treatment is recommended even before confirmation by molecular tests. Specific criteria for differentiating unconfirmed APL from other AML subtypes with DIC are currently lacking. We aimed to achieve the early diagnosis of APL from other AML types with DIC by restricting the DIC criteria. METHODS: We retrospectively analyzed 29 patients newly diagnosed with AML accompanied by DIC from January 2005 to January 2013. RESULTS: Fibrin degradation products (FDP) (77.7 ug/mL vs. 23.7 ug/mL, p=0.026), D-dimer (7,376.2 ng/mL vs. 1,315.2 ng/mL, p=0.018), and TIBC (264.4 ug/dL vs. 206.8 ug/dL, P=0.046) were higher, while fibrinogen (133.8 mg/dL vs. 373.2 mg/dL, p<0.001), WBC (14.988*10(9)/L vs. 70.755*10(9)/L, p=0.015), and ESR (7.1 mm/h vs. 50.0 mm/h, p <0.001) were lower in APL patients than in the patients with other AML subtypes. FDP >=27 ug/mL, D-dimer >=2,071 ng/mL, and fibrinogen <=279 mg/dL were our threshold values. These markers may be characteristic to APL and helpful in presumptive diagnosis. CONCLUSION: APL may be differentiated from other AML subtypes by core markers of DIC (FDP, D-dimer, and fibrinogen). We suggest that clinicians set new diagnostic thresholds by restricting the DIC criteria. These findings support the early initiation of ATRA, prior to confirmation by PML-RARA molecular testing. PMID- 24466549 TI - Clinical characteristics of hemophagocytic lymphohistiocytosis following Kawasaki disease: differentiation from recurrent Kawasaki disease. AB - BACKGROUND: Our aim was to investigate the clinical pattern of hemophagocytic lymphohistiocytosis following Kawasaki disease (HLH-KD), to enable differentiation of HLH from recurrent or refractory KD and facilitate early diagnosis. METHODS: We performed a nationwide retrospective survey and reviewed the clinical characteristics of patients with HLH-KD, including the interval between KD and HLH, clinical and laboratory findings, treatment responses, and outcomes, and compared them with historical data for both diseases. RESULTS: Twelve patients with HLH-KD, including 5 previously reported cases, were recruited. The median age was 6.5 years (range, 9 months-14.7 years). Eight patients were male and 4 were female. The median interval between the first episode of KD and the second visit with recurrent fever was 12 days (3-22 days). Of the 12 children, 2 were initially treated with intravenous IgG (IVIG) for recurrent KD when they presented at the hospital with recurrent fever. Eventually, 10 children received chemotherapy under an HLH protocol and 2 received supportive treatment. Two patients died of combined infections during chemotherapy, 1 was lost to follow up, and 9 remain alive. The overall survival rate at 4 years was 81.1% with a median follow up of 45.1 months. CONCLUSION: A diagnosis of HLH-KD should be considered when symptoms similar to recurrent KD develop within 1 month of the first episode of KD. Our findings will help physicians differentiate between HLH and the recurrent form of KD. PMID- 24466550 TI - Posterior reversible encephalopathy syndrome in pediatric patients undergoing treatment for hemophagocytic lymphohistiocytosis: clinical outcomes and putative risk factors. AB - BACKGROUND: Hemophagocytic lymphohistiocytosis (HLH) is a rare multiorgan disease of toxic immune activation caused by the interaction of cytotoxic T cells and innate immune cells and frequently involves the central nervous system (CNS). Posterior reversible encephalopathy syndrome (PRES) might develop during treatment with the HLH-2004 protocol from the Histiocyte Society. The aims of this study were to evaluate clinical outcomes and putative risk factors for prediction of PRES related to HLH. METHODS: We reviewed the medical records of 28 patients with HLH who were treated between April 2005 and April 2012. We compared various clinical and laboratory parameters in patients without or with PRES to evaluate putative risk factors related to development of PRES. RESULTS: Six (21.4%) of the patients experienced PRES during treatment with the HLH-2004 protocol. Clinical and laboratory manifestations were not different compared with other conditions causing PRES. The main mechanism of PRES may be related to the HLH-2004 protocol and a high pro-inflammatory state. Most patients recovered quickly from neurologic manifestations without significant long-term sequelae. Preceding hypertension, an increase in ferritin level >50% compared with 1 week before development of PRES and hyponatremia were statistically significant factors. CONCLUSION: PRES is clinically reversible and has a favorable outcome in patients with HLH. Awareness of PRES and a differential diagnosis of other causes of neurologic complications, including CNS involvement of HLH, can help avoid unnecessary treatment or delayed management. Patients with preceding hypertension, hyponatremia, and rising ferritin levels during HLH treatment should be closely monitored for PRES. PMID- 24466551 TI - Prognostic value of immunohistochemical algorithms in gastrointestinal diffuse large B-cell lymphoma. AB - BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous clinicopathological entity, and its molecular classification into germinal center B cell-like (GCB) and activated B cell-like (ABC) subtypes using gene expression profile analysis has been shown to have prognostic significance. Recent attempts have been made to find an association between immunohistochemical findings and molecular subgroup, although the clinical utility of immunohistochemical classification remains uncertain. METHODS: The clinicopathological features and follow-up data of 68 cases of surgically resected gastrointestinal DLBCL were analyzed. Using the immunohistochemical findings on tissue microarray, the cases were categorized into GCB and non-GCB subtypes according to the algorithms proposed by Hans, Muris, Choi, and Tally. RESULTS: The median patient age was 56 years (range, 26-77 years). Of the 68 cases included, 39.7% (27/68) involved the stomach, and 60.3% (41/68) involved the intestines. The GCB and non-GCB groups sorted according to Hans, Choi, and Tally algorithms, but not the Muris algorithm, were closely concordant (Hans vs. Choi, kappa=0.775, P<0.001; Hans vs. Tally, kappa=0.724, P<0.001; Choi vs. Tally, kappa=0.528, P<0.001). However, there was no prognostic difference between the GCB and non-GCB subtypes, regardless of the algorithm used. On univariate survival analyses, international prognostic index risk group and depth of tumor invasion both had prognostic significance. CONCLUSION: The Hans, Choi, and Tally algorithms might represent identical DLBCL subgroups, but this grouping did not correlate with prognosis. Further studies may delineate the association between immunohistochemical subgroups and prognosis. PMID- 24466552 TI - Sequential chemotherapy followed by radiotherapy versus concurrent chemoradiotherapy in patients with stage I/II extranodal natural killer/T-cell lymphoma, nasal type. AB - BACKGROUND: The purpose of this report is to summarize our clinical experience of patients with stage I/II extranodal natural killer (NK)/T-cell lymphoma, nasal type, treated using sequential chemotherapy followed by radiotherapy (SCRT) or concurrent chemoradiotherapy (CCRT). METHODS: Forty-three patients with stage I/II extranodal NK/T-cell lymphoma, nasal type, who received SCRT (16 patients) or CCRT (27 patients) were included in the present analysis. RESULTS: The median follow-up time was 39 months (range, 4-171 months) for all patients, 77 months (range, 4-171 months) for the SCRT group, and 31 months (range, 6-132 months) for the CCRT group. There were no statistically significant differences between the SCRT and CCRT groups with regard to the 3-year progression-free survival (PFS) (56% vs. 41%, P=0.823) and 3-year overall survival (OS) (75% vs. 59%, P=0.670). Univariate analysis revealed that patients with tumors confined to the nasal cavity and patients achieved complete remission had better PFS and OS rates, regardless of the treatment sequence. Multivariate analysis revealed that patients with tumors confined to the nasal cavity and patients aged <=60 years had better OS rates. CONCLUSION: The effect of SCRT and CCRT are similar in terms of survival outcomes of patients with stage I/II extranodal NK/T-cell lymphoma, nasal type. Our results show that tumors confined to the nasal cavity and an age <=60 years were associated with a better prognosis. PMID- 24466553 TI - Sequential therapy with activated prothrombin complex concentrates and recombinant activated factor VII to treat unresponsive bleeding in patients with hemophilia and inhibitors: a single center experience. AB - BACKGROUND: Currently, the greatest challenge in hemophilia treatment is managing hemophilia patients with inhibitors. The two main bypassing agents that are used to treat hemophilia patients with inhibitors are activated prothrombin complex concentrates (APCC) and recombinant factor VIIa (rFVIIa). Hemophilia patients with inhibitors can develop bleeding episodes, that are refractory to monotherapy with either APCC or rFVIIa and thus are often difficult to manage. METHODS: This report describes a retrospective chart review of four hospitalized patients with severe hemophilia and inhibitors who were treated with sequential therapy of APCC and rFVIIa for refractory bleeding. Sequential therapy was defined as the administration of both rFVIIa and APCC within 12 h. RESULTS: In 5 episodes experienced by 4 patients with inhibitors, bleeding was not controlled by single bypass treatment, but it was controlled when two agents were sequentially administered. Sequential therapy was administered by alternating one APCC dose to 1 to 2 rFVIIa doses, with dosing intervals ranging from 3 to 6 h. All bleeding episodes were controlled within 12 to 24 h. Sequential therapy was discontinued after 2 to 5 days. No adverse clinical events, such as thrombosis, were observed. CONCLUSION: Sequential therapy with APCC and rFVIIa was efficacious without adverse events; however, attention on thrombosis is needed. In addition, a prospective clinical trial is needed to provide further evidence for this treatment. PMID- 24466554 TI - Nodular lymphoid hyperplasia of the stomach in a patient with multiple submucosal tumors. AB - Nodular lymphoid hyperplasia of the stomach is a rare lymphoproliferative disorder. Here, we report a 38-year-old man who presented with multiple submucosal tumors of the stomach. Histologically, the lesions were characterized by multiple discrete submucosal nodules of lymphoid cells. The infiltrates between the lymphoid follicles were composed mainly of medium-sized lymphoid cells with abundant clear cytoplasm, as well as a few large cells with vesicular nuclei. The gastric mucosa exhibited multifocal lymphoid aggregates and some of the epithelial cells were infiltrated by small lymphocytes mimicking lymphoepithelial lesions. Histopathology was consistent with mucosa-associated lymphoid tissue lymphoma. However, the infiltrating lymphoid cells were positive for CD2, CD3, CD5, and CD7. In addition, polymerase chain reaction analysis of the immunoglobulin heavy chain and T-cell receptor gene rearrangements demonstrated polyclonality. This case was diagnosed as reactive lymphoid hyperplasia of the stomach. PMID- 24466555 TI - Primary mixed-type autoimmune hemolytic anemia concomitant with acute splanchnic venous thrombosis of idiopathic origin in a young woman: an unexplained association. PMID- 24466556 TI - Successful treatment of steroid resistant hypereosinophilic syndrome with low dose CsA. PMID- 24466557 TI - Primary diffuse large B-cell lymphoma of the bone marrow in a frail and elderly patient successfully treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone. PMID- 24466558 TI - Late but effective long-term response to splenectomy in the treatment of immune thrombocytopenia. PMID- 24466559 TI - Acute promyelocytic leukemia with an unusual presentation of secondary postpartum hemorrhage. PMID- 24466560 TI - Lymphoplasmacytic non-Hodgkin lymphoma/Waldenstrom's macroglobulinemia with CD5+, CD23+, and CD10-. PMID- 24466561 TI - Analysis of fast boundary-integral approximations for modeling electrostatic contributions of molecular binding. AB - We analyze and suggest improvements to a recently developed approximate continuum electrostatic model for proteins. The model, called BIBEE/I (boundary-integral based electrostatics estimation with interpolation), was able to estimate electrostatic solvation free energies to within a mean unsigned error of 4% on a test set of more than 600 proteins-a significant improvement over previous BIBEE models. In this work, we tested the BIBEE/I model for its capability to predict residue-by-residue interactions in protein-protein binding, using the widely studied model system of trypsin and bovine pancreatic trypsin inhibitor (BPTI). Finding that the BIBEE/I model performs surprisingly less well in this task than simpler BIBEE models, we seek to explain this behavior in terms of the models' differing spectral approximations of the exact boundary-integral operator. Calculations of analytically solvable systems (spheres and tri-axial ellipsoids) suggest two possibilities for improvement. The first is a modified BIBEE/I approach that captures the asymptotic eigenvalue limit correctly, and the second involves the dipole and quadrupole modes for ellipsoidal approximations of protein geometries. Our analysis suggests that fast, rigorous approximate models derived from reduced-basis approximation of boundary-integral equations might reach unprecedented accuracy, if the dipole and quadrupole modes can be captured quickly for general shapes. PMID- 24466562 TI - Koch Institute Symposium on Cancer Immunology and Immunotherapy. AB - The 12th annual summer symposium of The Koch Institute for Integrative Cancer Research at MIT was held in Cambridge, MA, on June 14th, 1023. The symposium entitled "Cancer Immunology and Immunotherapy" focused on recent advances in preclinical research in basic immunology and biomedical engineering, and their clinical application in cancer therapies. The day-long gathering also provided a forum for discussion and potential collaborations between engineers and clinical investigators. The major topics presented include: (i) enhancement of adoptive cell therapy by engineering to improve the ability and functionality of T-cells against tumor cells; (ii) current therapies using protein and antibody therapeutics to modulate endogenous anti-tumor immunity; and (iii) new technologies to identify molecular targets and assess therapeutic efficacy, and devices to control and target drug delivery more effectively and efficiently. PMID- 24466564 TI - Virtual Reality Arm Supported Training Reduces Motor Impairment In Two Patients with Severe Hemiparesis. PMID- 24466563 TI - Selective ROCK2 Inhibition In Focal Cerebral Ischemia. AB - OBJECTIVE: Rho-associated kinase (ROCK) is a key regulator of numerous processes in multiple cell types relevant in stroke pathophysiology. ROCK inhibitors have improved outcome in experimental models of acute ischemic or hemorrhagic stroke. However, the relevant ROCK isoform (ROCK1 or ROCK2) in acute stroke is not known. METHODS: We characterized the pharmacodynamic and pharmacokinetic profile, and tested the efficacy and safety of a novel selective ROCK2 inhibitor KD025 (formerly SLx-2119) in focal cerebral ischemia models in mice. RESULTS: KD025 dose-dependently reduced infarct volume after transient middle cerebral artery occlusion. The therapeutic window was at least 3 hours from stroke onset, and the efficacy was sustained for at least 4 weeks. KD025 was at least as efficacious in aged, diabetic or female mice, as in normal adult males. Concurrent treatment with atorvastatin was safe, but not additive or synergistic. KD025 was also safe in a permanent ischemia model, albeit with diminished efficacy. As one mechanism of protection, KD025 improved cortical perfusion in a distal middle cerebral artery occlusion model, implicating enhanced collateral flow. Unlike isoform nonselective ROCK inhibitors, KD025 did not cause significant hypotension, a dose limiting side effect in acute ischemic stroke. INTERPRETATION: Altogether, these data show that KD025 is efficacious and safe in acute focal cerebral ischemia in mice, implicating ROCK2 as the relevant isoform in acute ischemic stroke. Data suggest that selective ROCK2 inhibition has a favorable safety profile to facilitate clinical translation. PMID- 24466565 TI - County-level estimates of human papillomavirus vaccine coverage among young adult women in Texas, 2008. AB - PURPOSE: The purpose of this study is to describe the county-level geographic distribution of human papillomavirus (HPV) vaccine coverage among young women aged 18-26 in Texas using multilevel, small area estimation. METHODS: Multilevel (individual, county, public health region) random-intercept logit models were fit to HPV vaccination data (receipt of >= 1 dose Gardasil(r)) from the 2008 Behavioral Risk Factor Surveillance System and a number of secondary sources. Using the parameters from the final model, we simulated HPV vaccine coverage in each county. RESULTS: Indirect county-level estimates ranged from 1.9-23.8%, with a weighted state average of 11.4%. The counties with the highest and lowest coverage estimates were Orange County, TX and Webb County, TX respectively. Significant correlations were observed between HPV vaccination and age, Hispanic ethnicity, and the percentage of uninsured at the county and public health region levels. CONCLUSIONS: Small area analyses have been used in a variety of settings to assess a variety of health outcomes, and as shown in this study, can be used to highlight geographic disparities and opportunities for intervention in HPV vaccine coverage. PMID- 24466566 TI - The Human and Economic Burden of Cervical Cancer in Texas. AB - The goal of this study was to quantify the burden of cervical cancer in Texas and provide information about the health care needs of survivors. Data from multiple sources including the Texas Cancer Registry, Behavioral Risk Factor Surveillance System, and Texas Medicare claims were used in this effort. In 2009, there were over 100,000 cervical cancer survivors in Texas. Our descriptive analysis revealed that these women consumed less fruit and vegetables, were more often smokers, and had worse physical and mental health than women without a history of cancer. Survivors aged 65 and older cost Medicare over $15 million in inpatient, outpatient, and hospice care in 2009 alone, or $9,827 per cervical cancer survivor - nearly a third more than the average Medicare enrollee in Texas that year. Providers and public health practitioners can play an integral role in reducing the human and economic burden of cervical cancer in Texas through smoking cession and healthy lifestyle counseling for survivors, recommending the HPV vaccine to males and females aged 9-26, and continuing to offer cervical cancer screening for women up to age 65. PMID- 24466567 TI - Fluorescent sensors for selective detection of thiols: expanding the intramolecular displacement based mechanism to new chromophores. AB - Biological thiols, including cysteine (Cys), homocystein (Hcy) and glutathione (GSH), play crucial roles in maintaining the appropriate redox status of biological systems. An abnormal level of biothiols is associated with different diseases, therefore, the discrimination between them is of great importance. Herein, we present two fluorescent sensors for selective detection of biothiols based on our recently reported intramolecular displacement mechanism. We expanded this mechanism to commercially available chromophores, 4-chloro-7-nitro-2,1,3 benzoxadiazole (NBD-Cl) and heptamethine cyanine dye IR-780. The sensors operate by undergoing displacement of chloride by thiolate. The amino groups of Cys/Hcy further replace the thiolate to form amino-substituted products, which exhibit dramatically different photophysical properties compared to sulfur-substituted products from the reaction with GSH. NBD-Cl is highly selective towards Cys/Hcy and exhibits significant fluorescence enhancement. IR-780 showed a variation in its fluorescence ratio towards Cys over other thiols. Both of the sensors can be used for live-cell imaging of Cys. The wide applicability of the mechanism may provide a powerful tool for developing novel fluorescent sensors for selective detection of biothiols. PMID- 24466568 TI - Colorimetric and ultra-sensitive fluorescence resonance energy transfer determination of H2O2 and glucose by multi-functional Au nanoclusters. AB - Ultra-sensitive colorimetric determination of H2O2 is accomplished based on the intrinsic peroxidase-like activity of Au nanoclusters (AuNCs) stabilized by glutathione (GSH). The color change of 3,3,5,5-tetramethylbenzidine (TMB) catalyzed by AuNCs offers an indirect method to measure glucose. This sensing platform makes use of a dual optical signal change, including the color change in an aqueous solution under visible light illumination and an ultra-sensitive fluorescent assay arising from efficient fluorescence resonance energy transfer (FRET) between the AuNCs and oxidized TMB. The detection limits of H2O2 and glucose are 4.9 * 10(-13) M and 1.0 * 10(-11) M, respectively. In addition, enhanced fluorescence is observed from the AuNCs due to the use of ethanol which produces clear changes in the quantum yield and lifetime of the AuNCs. The quantum yield of AuNCs is enhanced from ~12.5% as an isolated fluorophore to 38.9% in an AuNCs-ethanol complex. The enhanced fluorescence lowers the detection limits of H2O2 and glucose by 2 orders of magnitude compared to those attained from the original AuNCs. PMID- 24466570 TI - Resonance-Raman spectro-electrochemistry of intermediates in molecular artificial photosynthesis of bimetallic complexes. AB - The sequential order of photoinduced charge transfer processes and accompanying structure changes were analyzed by UV-vis and resonance-Raman spectroscopy of intermediates of a Ru(ii) based photocatalytic hydrogen evolving system obtained by electrochemical reduction. PMID- 24466569 TI - Extension of the broadband single-mode integrated optical waveguide technique to the ultraviolet spectral region and its applications. AB - We report here the fabrication, characterization, and application of a single mode integrated optical waveguide (IOW) spectrometer capable of acquiring optical absorbance spectra of surface-immobilized molecules in the visible and ultraviolet spectral region down to 315 nm. The UV-extension of the single-mode IOW technique to shorter wavelengths was made possible by our development of a low-loss single-mode dielectric waveguide in the UV region based on an alumina film grown by atomic layer deposition (ALD) over a high quality fused silica substrate, and by our design/fabrication of a broadband waveguide coupler formed by an integrated diffraction grating combined with a highly anamorphic optical beam of large numerical aperture. As an application of the developed technology, we report here the surface adsorption process of bacteriochlorophyll a on different interfaces using its Soret absorption band centred at 370 nm. The effects of different chemical compositions at the solid-liquid interface on the adsorption and spectral properties of bacteriochlorophyll a were determined from the polarized UV-Vis IOW spectra acquired with the developed instrumentation. The spectral extension of the single-mode IOW technique into the ultraviolet region is an important advance as it enables extremely sensitive studies in key characteristics of surface molecular processes (e.g., protein unfolding and solvation of aromatic amino-acid groups under surface binding) whose spectral features are mainly located at wavelengths below the visible spectrum. PMID- 24466571 TI - Meeting of the Strategic Advisory Group of Experts on immunization, November 2013 -- conclusions and recommendations. PMID- 24466572 TI - Children with cochlear implants: cognitive skills, adaptive behaviors, social and emotional skills. AB - OBJECTIVE: The aim of this study is to examine cognitive skills, adaptive behavior, social and emotional skills in deaf children with cochlear implant (CI) compared to normal hearing children. METHODS: The study included twenty children affected by profound hearing loss implanted with a CI compared to 20 healthy children matched to chronological age and gender. RESULTS: Results of this study indicated that 55% of children with CI showed a score in the normal range of nonverbal intelligence (IQ > 84), 40% in the borderline range (71 < IQ < 84) and 5% were in mild range(50 < IQ < 70). No significant differences were found after comparison with normal hearing children.Children with CI reported more abnormalities in emotional symptoms (p = .018) and peer problems(p = .037) than children with normal hearing. Age of CI was negatively correlated with IQ (p = .002),positively correlated with emotional symptoms (p = .04) and with peer problems (p = .02). CONCLUSIONS: CI has a positive effect on the lives of deaf children, especially if it is implanted in much earlier ages. PMID- 24466573 TI - Effects of novel brominated flame retardants on steroidogenesis in primary porcine testicular cells. AB - Brominated flame retardants are chemicals with fire quenching properties which are extensively used in manufacturing. Historically, less regulated use of legacy brominated flame retardants (BFRs) for a number of years has resulted in ubiquitous contamination of the environment. As a result, some of the more persistent BFRs have been phased out and are being replaced by a next generation of brominated compounds for which there is little toxicological data. The study investigated effects of 2-ethylhexyl tetrabromobenzoate (TBB), 1,2,5,6 tetrabromocyclooctane (TBCO), and bis-(2-ethylhexyl) tetrabromophthalate (TBPH)on steroidogenesis in a porcine primary testicular cell model. TBB did not affect sex-steroid production in this cell model; rather the data suggest a flux towards synthesis of aldosterone and cortisol via up-regulation of CYP21A2. At the greatest concentrations of TBCO and TBPH tested greater production of sex hormones testosterone (T) and estradiol (E2) was observed. Effects were mediated by regulation of multiple molecular targets in the steroidogenesis pathway; CYP11A in the case of TBPH and CYP17A1 in the case of TBCO. This investigation is the first of its kind to use a testicular mixed population cell model to investigate mechanism(s) of action of three chemically diverse compounds currently used in commercial fire retardants. PMID- 24466574 TI - Inflammation and gene expression in the rat lung after instillation of silica nanoparticles: effect of size, dispersion medium and particle surface charge. AB - We investigated the effects of silica particles and nanoparticles (NPs) (50 nm and 200 nm) with a neutral and positively charged surface when dispersed in saline, bovine serum albumin (BSA) or lung lining fluid (LLF) 24 h post instillation into the lungs of rats. There was a significant increase in the recruitment of neutrophils in animals instilled with 50 nm plain and aminated NPs compared with 200 nm particles when dispersed in saline or BSA, but not when dispersed in LLF. There was no evidence of toxicity or an increase in the albumin content of the bronchoalveolar lavage fluid. Immunostaining for the transcription factor Nrf2 in BAL cells indicated that there was a significant increase in nuclear colocalisation in animals treated with plain and aminated 50 nm NPs compared with plain and aminated 200 nm particles when dispersed in saline, but no difference was observed between 50 nm and 200 nm aminated particles when dispersed in BSA. There was no difference in nuclear colocalisation with any of the particle types dispersed in LLF.This study suggests that low dose intratracheal exposure to silica nanoparticles can produce an acute inflammatory response and that the dispersion medium may influence the magnitude of this response. PMID- 24466575 TI - Synthetic mammalian gene circuits for biomedical applications. AB - Synthetic biology is the science of reassembling cataloged and standardized biological items in a systematic and rational manner to create and engineer functional biological designer devices, systems and organisms with novel and useful, preferably therapeutic functions. Synthetic biology has significantly advanced the design of complex genetic networks that can reprogram metabolic activities in mammalian cells and provide novel therapeutic strategies for future gene-based and cell-based therapies. Synthetic biology-inspired therapeutic strategies provide new opportunities for improving human health in the 21st century. This review covers the most recent synthetic mammalian circuits designed for therapy of diseases such as metabolic disorders, cancer, and immune disorders. We conclude by discussing current challenges and future perspectives for biomedical applications of synthetic mammalian gene networks. PMID- 24466576 TI - Computational protein design of ligand binding and catalysis. AB - The vision of custom-made proteins by computation appears closer than ever. Computational methods have advanced rapidly in recent years and proteins have been designed to catalyze new reactions. A number of second-generation enzyme designs analyzed possible bottlenecks and started tackling emergent problems. Detailed experimental analysis combined with structure determination and molecular dynamics simulations as well as design optimization with directed evolution techniques have led to important insights. While ligand recognition seems to be particularly problematic, new approaches focus on this design aspect and promising improvements have been made. PMID- 24466577 TI - Constructing arrays of proteins. AB - The construction of crystalline arrays allows proteins to be presented in a dense, oriented and functional way that also facilitates determination of their structure. Rational design of these supramolecular structures is becoming increasingly tractable with recent successes exploiting both innate protein symmetry and advances in protein-protein interface design. Pre-existing symmetry minimizes the number of non-native interfaces that must be produced, and the use of symmetric interfaces facilitates protein alignment. Arrays in which metal coordination or peptide binding are responsible for the inter-particle associations show particular promise due to the malleable and reversible nature of these interactions. Cross-pollination of the principles that underlie successful strategies is likely to produce rapid advances in this field and consequent benefits to both nanotechnology and structural biology. PMID- 24466578 TI - Membrane proteins by accident or design. AB - Protein design is a valuable tool to create bespoke proteins with desired properties as well as for investigating sequence, structure and function relationships. Membrane protein design is a burgeoning field that is hampered by the lack of high-resolution structural information. In spite of these shortcomings, computational methods have offered a route towards blueprints for these hydrophobic proteins. Advances in structural scoring and sampling methods are enabling more accurate predictions of a folded structure from the primary amino acid sequence. This review highlights a number of novel studies focusing on the methods and information used to successfully design membrane proteins. PMID- 24466579 TI - Structural investigation of multivalent carbohydrate-protein interactions using synthetic biomolecules. AB - Understanding multivalent carbohydrate-protein interactions at the molecular level requires access to structural details of these important biological recognition processes. Recent developments toward this goal comprise the use of conformationally defined molecular rulers in combination with binding assays, crystallographic investigation of complexes of multivalent ligands and their target proteins, and distance measurements in the nanometer range by EPR spectroscopy. PMID- 24466580 TI - Context and complexity: the next big thing in synthetic glycobiology. AB - Complex glycans participate in many essential life processes. Studies of glycan mediated biological events have traditionally employed structurally defined fragments of the more elaborate natural molecules. However, it is now clear that this approach may sometimes be insufficient and this realization has prompted a desire to synthesize glycans of similar size and complexity to those found in nature. We highlight here recent work describing the synthesis of such molecules. PMID- 24466582 TI - Is there a role for novel oral anticoagulants in patients with an acute coronary syndrome? A review of the clinical trials. AB - The novel oral anticoagulant drugs, comprising dabigatran, rivaroxaban, and apixaban, have emerged as compelling alternatives to vitamin K antagonists for stroke prevention in atrial fibrillation, and low-molecular-weight heparin for thromboprophylaxis following hip and knee arthroplasty. Rivaroxaban has also been approved for treatment of venous thromboembolism. However, the role of these drugs for the management of patients with an acute coronary syndrome (ACS) is less certain. The purpose of this review was to summarize the randomized trials evaluating novel oral anticoagulants in patients with an ACS and consider the reasons why these drugs have not been incorporated into routine clinical practice. In addition, the situation involving rivaroxaban, which has been approved for use in patients with an acute coronary syndrome in Europe but not in North America, is discussed. PMID- 24466581 TI - Synthetic carbohydrate antigens for HIV vaccine design. AB - The heavy glycosylation of HIV envelope constitutes a strong defense mechanism for the virus to evade host immune response, which accounts for a major barrier for HIV vaccine development. Nevertheless, the identification of a number of glycan-dependent broadly HIV-neutralizing antibodies from HIV-infected individuals, including 2G12, PG9, PG16, PGT121-123, PGT125-128, and PGT135, strongly suggests that the defensive viral 'glycan shield' can be important targets of vaccines. The novel glycan recognition mode exhibited by these antibodies provides new templates for immunogen design. This review highlights recent work on the characterization of the glycan-dependent epitopes of these neutralizing antibodies and recent advances in the synthesis of the relevant carbohydrate antigens for HIV vaccine design. PMID- 24466583 TI - Eriodictyol-7-O-glucoside activates Nrf2 and protects against cerebral ischemic injury. AB - Stroke is a complex disease that may involve oxidative stress-related pathways in its pathogenesis. The nuclear factor erythroid-2-related factor 2/antioxidant response element (Nrf2/ARE) pathway plays an important role in inducing phase II detoxifying enzymes and antioxidant proteins and thus has been considered a potential target for neuroprotection in stroke. The aim of the present study was to determine whether eriodictyol-7-O-glucoside (E7G), a novel Nrf2 activator, can protect against cerebral ischemic injury and to understand the role of the Nrf2/ARE pathway in neuroprotection. In primary cultured astrocytes, E7G increased the nuclear localization of Nrf2 and induced the expression of the Nrf2/ARE-dependent genes. Exposure of astrocytes to E7G provided protection against oxygen and glucose deprivation (OGD)-induced oxidative insult. The protective effect of E7G was abolished by RNA interference-mediated knockdown of Nrf2 expression. In vivo administration of E7G in a rat model of focal cerebral ischemia significantly reduced the amount of brain damage and ameliorated neurological deficits. These data demonstrate that activation of Nrf2/ARE signaling by E7G is directly associated with its neuroprotection against oxidative stress-induced ischemic injury and suggest that targeting the Nrf2/ARE pathway may be a promising approach for therapeutic intervention in stroke. PMID- 24466584 TI - Retraction: Crucial role of interleukin-7 in T helper type 17 survival and expansion in autoimmune disease. PMID- 24466585 TI - First issue of 2014, Current Medicinal Chemistry. PMID- 24466586 TI - Etiology and outcome of iliopsoas muscle abscess in Korea; changes over a decade. AB - OBJECTIVES: Iliopsoas muscle abscess (IPA) is considered a rare disease whose etiology has changed depending on the country and antibiotic selection pressure. This study evaluates the changes in etiology, clinical outcome, and risk factors for mortality for IPA. METHODS: We reviewed the medical records of a total of 116 patients with IPA who were admitted to 4 university hospitals in Korea over the 11 years, and compared the etiology between 2001 and 2006 (period 1, n = 44) and 2007-2012 (period 2, n = 72). RESULTS: Among 75 cases with a definitive microbial diagnosis, the predominant etiological organisms were Staphylococcus aureus (45.3%), followed by Mycobacterium tuberculosis (14.7%) and Klebsiella pneumoniae (9.3%). The percentage of MRSA in period 2 increased remarkably compared to period 1, from 25% to 44.4%, and incidence of M. tuberculosis from 7.1% to 19.1%, although these were not statistically significant. The overall mortality was 6.8% in period 1, and 13.9% in period 2, and sepsis as an initial manifestation (OR 293.5, CI 7.1-12,034.4, P = 0.003) and serum creatinine level (OR 0.43, CI 0.23 0.80, P = 0.008) were independent predictors of mortality. Invasive procedure improved the prognosis in cases with microbiologic confirmed pyogenic psoas abscess (46/50 [92%] vs. 9/14 [64.3%], P = 0.008). CONCLUSION: The incidence of MRSA as a cause of IPA is on the increase. Although the overall prevalence of tuberculosis is decreasing, tuberculosis is still an important cause of IPA. Initial clinical status and invasive intervention can lead to favorable outcomes. PMID- 24466587 TI - Surveillance snapshot: Bacterial meningitis among beneficiaries of the military health system, 1998-2013. PMID- 24466588 TI - Surveillance snapshot: Age and gender distribution of service members, active component, U.S. Armed Forces, compared to the U.S. population, 2011. PMID- 24466589 TI - The effects of body mass index and sex on impact force and effective pelvic stiffness during simulated lateral falls. AB - BACKGROUND: The incidence of hip fractures is highest for underweight females with low body mass index (BMI). However, it is unknown how these factors influence impact dynamics during in-vivo lateral hip impacts.We used a pelvis release paradigm to compare: (1) absolute and normalized forces applied to the femur-pelvis system across sex and BMI groups; (2) the force-prediction accuracy of vibration-based versus force-deflection-based estimates of effective pelvic stiffness; and (3) effective pelvic stiffness between BMI and sex groups. METHODS: Twenty-eight persons participated (7 low-BMI females, 7 low-BMI males, 7 high-BMI females, 7 high-BMI males,with BMI criteria of <22.5 and >28 for low- and high-BMI groups respectively). The participant's pelvis was released from heights of 0 to 5 cm. A force plate measured impact loads, while a motion capture system measured pelvic deflection. FINDINGS: Peak impact forces were 22.6% higher, while normalized peak forces were 31.2% lower, for high- compared to low BMI participants. Accuracy of peak force predictions improved by 25% for the force-deflection versus the vibration-based stiffness estimation method. Effective pelvic stiffness was greater for males than females, but no significant differences were observed between BMI groups. INTERPRETATION: This study adds to clinical understanding of the effects of sex and BMI on impact dynamics during falls on the hip, and raises questions about the biomechanical mechanisms underlying the protective role of high BMI on hip fracture risk. Understanding the relationship between impact mechanics and faller characteristics should lead to more effective prevention of hip fractures. PMID- 24466590 TI - [Informed consent in surgery. Distance between theory and practice]. PMID- 24466591 TI - Searching for a successful HDL-based treatment strategy. AB - Despite strong evidence that HDL-cholesterol levels predict atherosclerotic events in a population, attempts at using and HDL-based treatment strategy have not yet been successful. Most of the efforts to date have focused on raising plasma HDL-cholesterol levels. This brief review focuses on a different strategy, which is based on the use of 18-amino acid apoA-I-mimetic peptides. The story of these peptides spans decades and illustrates the remarkable complexity of HDL based treatment strategies, but suggests that such a strategy may still be successful. PMID- 24466592 TI - Resident Rounds. Part III. A case of dermatomyositis presenting with eyelid nodules. PMID- 24466593 TI - Discovery research in neuropsychiatry - anxiety, depression and schizophrenia in focus. Editorial. PMID- 24466594 TI - Restoration of spatial memory dysfunction of human APP transgenic mice by transplantation of neuronal precursors derived from human iPS cells. AB - PDGF promoter driven amyloid precursor protein (PDAPP) transgenic mice were accompanied by age dependent amyloid beta deposition and progressive spatial memory dysfunction which emerges within a few months of age. We conducted transplantation of neuronal precursors of cholinergic neuron phenotype which were derived from human iPS (hiPS) cells into bilateral hippocampus of PDAPP mice. We first generated neuronal precursors with cholinergic neuron phenotype from hiPS cells by culturing them with retinoic acid (RA), sonic hedgehog (SHH) and noggin Fc (NOG). Spatial memory function of PDAPP mice was significantly impaired compared to that of nontransgenic littermates at age 8 weeks. After neuronal precursor transplantation, subsequent memory dysfunction of PDAPP mice was significantly improved, compared to that of vehicle injected PDAPP mice. We observed choline acetyltransferase (ChAT) positive cholinergic human neurons and vesicle GABA transporter (VGAT) positive GABAergic human neurons in PDAPP mouse hippocampus 45 days after the transplantation. Neuronal precursors with cholinergic neuron phenotype derived from hiPS cells survived in PDAPP mouse hippocampus and their spatial memory loss was improved. hiPS cells may become applicable for the treatment of patients with dementia. PMID- 24466595 TI - Facilitation of late somatosensory evoked potentials by electrical train stimuli. AB - Somatosensory evoked potentials (SSEP) may reflect synaptic events and could be suitable to characterise the short-time plasticity of synaptic potentials (SP). For this purpose, the left superficial radial nerve was stimulated in 7 subjects with single or trains of 3 stimuli (C4' against Fz, time interval 500 ms, 1 Hz or 0.4 Hz). The within train interstimulus intervals (ISI) were varied from 2 ms to 10 ms. N20, N1 and N2 displayed a significant gain in amplitude following train stimuli compared with single stimuli. Short ISIs of 2-4 ms led to higher amplitudes of N20, N1 and N2 compared with longer ISIs of 7-10 ms. In general, larger amplitude values were observed with 0.4 Hz stimulus repetition compared with 1.0 Hz. This data reflects synaptic facilitation and refractoriness/habituation. Our results could be helpful to non-invasevely investigate synaptic decay dynamics by late SSEP in diseases of the central nervous system such as migraine or epilepsy. PMID- 24466596 TI - Asymmetrical loading during non-visual navigation. AB - Since previous studies showed that loading influences posture and gait, the aim of the present study was to determine the effect of asymmetrical loading on locomotion. The following questions were posed: is there a habituation to asymmetrical loading and what is the effect of immediate unloading? Nine healthy subjects (4 males and 5 females) were tested. They had to memorize visually a triangle drawn on the floor and then to walk clockwise and counterclockwise along it in darkness and blindfolded under the following conditions: baseline, loading of right shoulder with 20% of the body weight, after 30 min of habituation to the weight, and immediately after unloading. The turns in degrees around the angles and the distance of the path in cm were measured. The present study demonstrated that asymmetrical loading, which leads to changes in the somatosensory afferentation, affects the human locomotor pattern. There is a habituation effect as well as an unloading effect. There was also a difference between the changes in clockwise and counterclockwise locomotion. Several hypotheses are discussed to explain the results obtained under all conditions. PMID- 24466597 TI - Expression of proline-rich coiled-coil 2B protein in developing rat brains. AB - The proline-rich coiled coil 2B (prrc2b) is a conservative gene which is found in the genomes of most vertebrates. However, its function and expression pattern remains unknown. This study describes the spatio-temporal expression patterns of the PRRC2B protein in the rat brain with a view to inferring its function. The expression of PRRC2B protein was determined at embryonic day 18 (E18), postnatal day 1 (P1), postnatal day 7 (P7), postnatal day 15 (P15) and adulthood rats by Western blotting and immunohistochemical staining. Western blot results showed that the PRRC2B highly expressed in the whole brain tissues at E18, P1 and P7 but lowly expressed at P15 and adulthood. Immunohistochemical staining showed that the PRRC2B was located in the plasma and neurites of neurons with big size. The PRRC2B positive neurons widely distributed in most brain regions, including olfactory bulb, cerebral cortex, cerebellar cortex, hippocampus, thalamus, hypothalamus, superior colliculus, inferior colliculus, midbrain, pons and medulla oblongata, etc. Interestingly, there were obvious morphological differences between positive neurons in mature and immature rat brains. At P1 and P7 the protein highly expressed in the neuronic plasma, especially in the prominences and branches; while at P15 and adulthood, it only weakly expressed in the plasma. Above findings comprehensively revealed the expression pattern of PRRC2B protein in the whole rat brain at various stages for the first time, which should benefit to explore its function. PMID- 24466598 TI - A short message service (SMS) intervention to prevent diabetes in Chinese professional drivers with pre-diabetes: a pilot single-blinded randomized controlled trial. AB - AIM: To determine the efficacy of delivering short-message service (SMS) to provide diabetes-related information in reducing the risk of developing diabetes in Chinese professional drivers with pre-diabetes. METHODS: A pilot single blinded randomized controlled trial was conducted in Hong Kong between 05/2009 and 04/2012. Professional drivers with impaired glucose tolerance (IGT) were randomly allocated to either a SMS group receiving messages comprising knowledge and lifestyle modification on diabetes or to a control group with usual care. Primary outcomes were the incidence rate of diabetes mellitus over 12 and 24 months period. RESULTS: Fifty-four, out of 104 professional drivers recruited, were randomly allocated to intervention group. Fewer subjects developed diabetes at 12 months in intervention group (5.56%) compared to control group (16.00%). Relative risk (RR) of diabetes onset was 0.35 (95%CI: 0.10-1.24) and the number needed to treat (NNT) for preventing one diabetes was 9.57. At 24 months, RR increased to 0.62 (95%CI: 0.24-1.61) with a NNT of 10.58. Logistic regression showed a significant odds ratio of 0.04 (P = 0.021) for intervention group compared to control group at 12-month follow-up for completers and a non significant odds ratio of 0.34 (P = 0.303) at 24-month follow-up. CONCLUSIONS: The SMS program proved to have potential to reduce the risk of developing diabetes at 12 months but additional measures should be integrated to prevent or delay disease progression. PMID- 24466599 TI - Emergency department management of patients on novel oral anticoagulant agents. AB - The era in which vitamin K antagonists were the only option for long-term anticoagulation has ended. Patients now have multiple treatment options for prophylaxis for nonvalvular atrial fibrillation and prevention and treatment for venous thromboembolism. Novel oral anticoagulants, consisting of direct thrombin inhibitors and factor Xa inhibitors, are a diverse group of agents that have reduced medication and food interactions compared to warfarin, and they eliminate the need for frequent monitoring. However, patients presenting with novel oral anticoagulant-associated bleeding emergencies represent a diagnostic and therapeutic challenge due to the lack of access to appropriate laboratory testing modalities or well-validated reversal agents. Following the treatment path appropriate for vitamin K antagonists is ineffective and potentially harmful, making novel assays and antidotes necessary. This review examines the evidence on the use and risks of enriched clotting factor preparations as well as the clinical and laboratory evaluation that will guide their management. PMID- 24466601 TI - [Targeted organ damage of H-type hypertension in elderly patients]. PMID- 24466600 TI - [Analysis on the epidemic feature of iodine deficiency disorders in Xinjiang Uygur Autonomous Region, 2005 and 2009]. PMID- 24466602 TI - [Epidemiological investigation on the first case of human avian influenza A (H7N9) virus infection in Beijing, 2013]. PMID- 24466603 TI - [A cross-sectional study on the occupational injuries among fishermen in Haikou, Hainan province]. PMID- 24466604 TI - [Not Available]. PMID- 24466605 TI - [Not Available]. PMID- 24466606 TI - [Not Available]. PMID- 24466608 TI - [Not Available]. PMID- 24466607 TI - [Not Available]. PMID- 24466609 TI - Effects of the angiotensin receptor blocker Valsartan (Valsacor(r)) on arterial pressure, indices of myocardial diastolic function and global longitudinal strain in patients with uncontrolled arterial hypertension. AB - The objective of this study was to evaluate the effects of Valsartan (Valsacor(r)) on arterial pressure (AP) and indices of myocardial diastolic and global function in patients with uncontrolled arterial hypertension (AH). MATERIAL AND METHODS: 60 patients (39 men and 21 women, mean age 63.9 +/- 10.8 years, P > 140/90 mmHg with a background of combined antihypertensive therapy) were involved in the study. Valsartan (Valsacor(r)) was added to the standard therapy. The follow-up continued for three months, with clinical visits at initiation and completion of the study. The echocardiographic (EchoCG) evaluation included measurements of left ventricular and left atrial dimensions and function via longitudinal strain and Doppler-analysis of the transmitral blood flow. RESULTS: The administration of Valsartan (Valsacor(r)) resulted in a significant improvement in the antihypertensive control in the studied patients. The mean values of the baseline systolic blood (SBP) and diastolic blood (DBP) pressure in the studied group of patients were 174.9 +/- 17.9 (range 150-230) mmHg and 97.5 +/- 6.4 (range 85-110) mmHg, respectively. The mean SBP and DBP values at the end of the third month of the follow-up period were 139.1 +/- 10.9 (range 120-180) mmHg and 84.9 +/- 6.2 mmHg, respectively, at p < 0.05, compared to the baseline. The results of the echocardiographic analysis revealed significant differences in the dynamic performance of the indices: telesystolic dimension of the left ventricle, deceleration time (DT), E', E/E' ratio and values of longitudinal strain. The observed dynamic performance reflects favour-able responses of the indices for diastolic function and longitudinal strain in the studied patients. CONCLUSION: Valsartan (Valsacor(r)), used as an adjunct to the standard antihypertensive therapy in patients with insufficiently controlled AH, leads to optimisation of the AP values and improvement of the indices of diastolic and global myocardial function, with a very good safety profile. PMID- 24466610 TI - [Not Available]. PMID- 24466611 TI - [The significance of heart arrhythmias, their diagnosis and treatment. 1913. H.E. Hering]. PMID- 24466612 TI - [Engagement of p38 mitogen-activated protein kinase in regulation of epithelial barrier of acute respiratory distress syndrome]. AB - OBJECTIVE: To observe airway epithelial barrier dysfunction in acute respiratory distress syndrome (ARDS), and the possible regulatory role of p38 mitogen activated protein kinase (p38MAPK). METHODS: The primary human trachea-bronchial epithelial cells were incubated either in 1 f.Lg/mL lipopolysaccharide (LPS) , I J.Lg/mLLPS + 10 nmol/L p38MAPK inhibitor (SB203580), or in control medium. Cells were harvested at 3, 6, 24 and 48 hours after incubation. The cell count, trans epithelial electrical resistance (TER) , macromolecular permeability (fluorescence staining), and proteomics were measured at different time points. RESULTS: Compared with control group,the amount of airway epithelial cells in LPS group was significantly lowered at 24 hours and 48 hours [24 hours: (62.5 +/- 12.0)% vs. (85.0 +/- 15.0)% , 1'=-5.681, P=0.001 ; 48 hours: (67.5 +/- 17.0)% vs. (79.0 +/- 20.0)% , 1'=-4.260,P=0.00 1 J, TER was also significantly decreased at 3 hours and 48 hours (D/cm2 , 3 hours: 307 +/- 108 vs. 376 +/- 60,1'=-3.606, P=0.049; 48 hours: 290 +/- 86 vs. 371 +/- 43, 1'=6.971, P=0.037), and the macromolecular permeability was shown to he increased in LPS group [48 hours: (122.2 +/- 22.0)% vs. (100.0 +/- 18.0)%, 1'=3.182, P=0.036]; and phosphorylation p38MAPK p-p38MAPK) was increased (relative intensity: 0.34 +/- 0.16 vs. 0.28 +/- 0.10,1'=4.303, P=0.029). However, SB203580 attenuated the damages induced by LPS both in the amount of epithelial cells [24 hours: (82.5+/-22.0)% vs. (62.5+/ 25.0)%, 1'=-6.124, P=0.010; 48 hours: (79.5+/-28.0)% vs. (67.5 +/- 16.0)% , 1'= 3.860, P=0.039 J, and TER of epithelial cells (Diem', 48 hours: 411 +/- 118 vs. 290 +/- 97,1'=3.560, P=0.022) . In addition, the down-regulation of expression of p-p38MAPK as induced hy LPS was significantly alleviate by SB203580 (relative intensity: 0.04 +/-0.01 vs. 0.34 +/-0.16, 1'=3.840; P=0.011). CONCLUSION: LPS induced airway epithelial barrier dysfunction in ARDS, and p38MAPK may be involved in the pathway of LPS induced airway epithelial barrier dysfunction. PMID- 24466613 TI - Reflections on relationships between national and world events and development of dermatology. Venezuela as a model. AB - From a personal vantage, the author tries to understand evolution of medicine and dermatology as relating to political, ideological,and economic factors.He analyzes the evolution of Venezuelan Dermatology research and practice from 1936 to present, relating it to the events that have taken place in that country during this period and integrating the latter to events in the world. There is a close relationship between Venezuelan and US history particularly since the late nineteen-thirties.Physicians in general and dermatologists in particular should not dismiss or just bear the events that take place in the society as a whole. They should try to influence them by acting in harmony with forces that propitiate freedom, rule of law, free inquiry, and meritocracy. PMID- 24466614 TI - Putting the ethics into aesthetic dentistry. PMID- 24466615 TI - Taking a look at aesthetic dentistry. PMID- 24466616 TI - FGDP(UK) policy update: gauging directional challenges: the new GDC. PMID- 24466617 TI - Amalgam and minimal intervention: an incompatible relationship. PMID- 24466618 TI - Current thinking in the examination and management of the TMJ. PMID- 24466619 TI - Blanket occupational restrictions lifted for HIV positive dentists. PMID- 24466620 TI - Using reflective learning in the dental practice setting. PMID- 24466621 TI - Photoinitiators in dentistry: a review. AB - Polymerization of Resin Based Composites (RBCs) initiated by a light curing unit activating photoinitiators. Different RBCs require different light energy levels for proper curing. Manufacturers are now producing RBCs with more than one initiator and not all of these will be properly polymerised with blue LED lights. An added problem is that manufacturers do not always indicate the type of photoinitiators in their materials. This review discusses the importance of matching the spectral output of LCUs to the absorption spectra of RBCs and the consequences of spectral mismatch. Resin based composites (RBCs) were first introduced in the 1960s and with development of effective and reliable dentine bonding systems2, have been used routinely as a filling material for both anterior and posterior teeth. The early RBCs were either chemically cured two component materials or photo-initiated materials that used UV initiators in the beginning and then transitioned to visible light initiators such as camphorquinine which was introduced in 1978.3 The first report of a light curing material was of an ultraviolet (UV) cured fissure sealant. However, due to the limited penetration depth of the UV light and the potential health hazards, this system was quickly abandoned. The advancement of science yielded light curing materials which contributed to a significant clinical progress over the UV and chemically cured RBCs. Additional advancements to direct RBC restoration materials included luting agents for ceramic restorations, pit and fissure sealants and resin modified glass ionomers. Polymerization in an RBC is initiated by a light curing unit (LCU); this technology is based on the use of photoreactive systems that absorb light irradiation from the LCUs at appropriate wavelength. Then the photoinitiators contained in the RBCs, absorb the incoming photons from the LCU and the monomers in the molecular structure become excited and in that active state, there is a change from monomers into a polymer network. The success of this technology hinges on matching the spectral emission of the LCU with the requirements of the photoinitiator system to convert the monomers into a polymer network. The amount of activated photo initiator depends on the concentration of photoinitiator in the material, the number of photons to which the material is exposed and the energy of the photons (wavelength), the latter depending on the curing light.The most common photoinitiator in dental materials today is camphorquinone, which has a peak activity around 470 nanometres. The factors affecting polymerization include filler type, size and loading, the thickness and shade of the restorative material, the effectiveness of light transmission (eg. light guide tips being free from debris and scratches), exposure time, distance of the light source from the restorative material and light intensity. It is important to note that the photoinitiator activation occurs at specific wavelengths, in other words, the optimum efficiency is obtained when the peak absorptivity of the photoinitiator corresponds with the spectral emission from the LCU. Commercially available curing units have different light intensities and light sources, with energy levels in QTH, LED and other LCUs ranging from 300 to more than 2000 mW/cm. PMID- 24466622 TI - Can historical specimens be applied to modern research? PMID- 24466623 TI - Smile design: rules, tools and strategies to help plan aesthetic restorative dentistry. AB - This article is intended to provide dentists with a framework to help in objectively assessing upper anterior aesthetic restorations. Not all of the areas discussed will be equally important in all cases, and a degree of subjectivity, based on clinical experience, is essential. There has been a huge increase in settlements in cases when aesthetic treatment has not led to patient satisfaction. The author hopes that this type of approach, in conjunction with good patient communication and detailed records, will minimise the potential for litigation, should problems arise. Success or failure is largely defined during the planning stage. PMID- 24466624 TI - Dento-legal aspects of cosmetic dentistry. PMID- 24466625 TI - Implant placement in the aesthetic zone following an autogenous bone graft from an intraoral site: a case study. AB - AIMS: In the front of the mouth, the treatment of such a bony defect carries the risk of a poor aesthetic outcome. High patient expectations, combined with the difficulty of recreating a large mass of viable bone in which a dental implant will be biomechanically stable is a real challenge. PURPOSE OF TREATMENT: The intention of this treatment was to replace the patient's chronically infected upper right incisor with a dental implant that was both biomechanically and aesthetically stable for the long term. METHOD: Four months after extraction of the upper right central incisor, under local anaesthetic, a bone block was harvested from the right retromolar area of the patient's mandible and grafted into the defect. This was secured with a single bone screw. Small deficiencies between the block and the host site were filled in using bovine derived particulate bone (Bio Oss, Geistlich Biomaterials, Wolhuser, Germany). A resorbable porcine derived membrane (Bio-Gide, Geistlich Biomaterials, Wolhuser, Germany), held in position by two bone tacks (Frios, Friadent, Mannheim, Germany), was used to stabilse the graft. Following close clinical and radiographic monitoring of graft maturation, the bone screw was removed at three months and one week later the implant placed. A bone level impression was taken at surgery, and the implant left submerged for four months before exposure and abutment connection. After a further period of two months to facilitate soft tissue contouring the definitive crown was cemented. CONCLUSION: The implant tooth has been in trouble free function for eighteen months. In that period, the marginal bone levels and gingival margin around the implant have remained stable and aesthetically satisfactory. PMID- 24466626 TI - Conservative treatment of tooth wear to improve function and aesthetics. PMID- 24466627 TI - Improving patients' oral health-related quality of life with aesthetic dentistry. PMID- 24466628 TI - The use of digital photography for shade communication. PMID- 24466629 TI - Taking on tooth whitening: changes to legislation for dental hygienists and therapists. PMID- 24466630 TI - Mediating objects: scientific and public functions of models in nineteenth century biology. AB - The aim of this article is to examine the scientific and public functions of two- and three-dimensional models in the context of three episodes from nineteenth century biology. I argue that these models incorporate both data and theory by presenting theoretical assumptions in the light of concrete data or organizing data through theoretical assumptions. Despite their diverse roles in scientific practice, they all can be characterized as mediators between data and theory. Furthermore, I argue that these different mediating functions often reflect their different audiences that included specialized scientists, students, and the general public. In this sense, models in nineteenth-century biology can be understood as mediators between theory, data, and their diverse audiences. PMID- 24466631 TI - Monod before Monod: enzymatic adaptation, Lwoff, and the legacy of general biology. AB - For most of his scientific career, Jacques Monod appeared to be a man of a single problem: the formation of enzymes and the regulation of their properties. His ability to produce theoretical models led him to play a major role in both the discovery of the operon regulation and the model of allosteric transitions. The successes of Monod, from the 1950s to the Noble Prize (1965), are already well documented. In this paper, I will focus on the Monod before Monod, that is, the Monod who, during the 1940s, tried to explain the fundamental phenomenon of enzymatic adaptation. To begin with, however, I will survey how this phenomenon was discovered and explained by French Pasteurians at the very beginning of the twentieth century. This first explanation took place amidst an entrenched Lamarckian atmosphere in French thought, which was still alive during the 1920s and the 1930s, when Monod commenced the study of biology at the Sorbonne. Because of his will to construct a scientific biology free from teleology, Monod always tried to break from the legacy of this traditional background of Lamarckism, and he consequently developed ways of thinking that, in the main, were not part of the French biological tradition. Nevertheless, one point did link Monod to French history: his fruitful interactions with Andre Lwoff. As we shall see, these interactions were necessary for the development of Monod's science, both technically and intellectually speaking. PMID- 24466632 TI - Exaptation, adaptation, and evolutionary psychology. AB - One of the most well known methodological criticisms of evolutionary psychology is Gould's claim that the program pays too much attention to adaptations, and not enough to exaptations. Almost as well known is the standard rebuttal of that criticism: namely, that the study of exaptations in fact depends on the study of adaptations. However, as I try to show in this paper, it is premature to think that this is where this debate ends. First, the notion of exaptation that is commonly used in this debate is different from the one that Gould and Vrba originally defined. Noting this is particularly important, since, second, the standard reply to Gould's criticism only works if the criticism is framed in terms of the former notion of exaptation, and not the latter. However, third, this ultimately does not change the outcome of the debate much, as evolutionary psychologists can respond to the revamped criticism of their program by claiming that the original notion of exaptation is theoretically and empirically uninteresting. By discussing these issues further, I also seek to determine, more generally, which ways of approaching the adaptationism debate in evolutionary biology are useful, and which not. PMID- 24466633 TI - Natural selection among replicators, interactors and transactors. AB - In evolutionary biology and ecology, ontological and epistemological perspectives based on the replicator and the interactor have become the background that makes it possible to transcend traditional biological levels of organization and to achieve a unified view of evolution in which replication and interaction are fundamental operating processes. Using the transactional perspective proposed originally by John Dewey and Arthur Fisher Bentley, a new ontological and methodological category is proposed here: the transactor. The transactional perspective, based on the concept of the transactor, bridges the dichotomy between organisms and environment that characterizes the interactional perspective on evolution and provides epistemological support for the emergentist, systemic view of evolutionary and developmental processes. PMID- 24466634 TI - Immunology's theories of cognition. AB - Contemporary immunology has established its fundamental theory as a biological expression of personal identity, wherein the "immune self" is defended by the immune system. Protection of this agent putatively requires a cognitive capacity by which the self and the foreign are perceived and thereby discriminated; from such information, discernment of the environment is achieved and activation of pathways leading to an immune response may be initiated. This so-called cognitive paradigm embeds such functions as "perception," "recognition," "learning," and "memory" to characterize immune processes, but the conceptual character of such functions has meanings that vary with the particular theory adopted. When different formulations of cognition are considered, immunology's conceptual infrastructure shifts: Extensions of conventional psychological understanding of representational cognition based on a subject-object dichotomy support notions of immune agency; alternatively, formulations of perception that dispense with representations and attendant notions of agency reconfigure the predicate epistemology dominating current immune theory. Reviewing immunological literature of the past five decades, these two understandings of perception- representational and non-representational (considered here from ecological, enactivist, and autopoietic perspectives)--offer competing views of immune cognitive functions. These, in turn, provide competing philosophical understandings of immunology's conceptual foundations, which reflect parallel controversies dominating current debates in philosophy of mind and attendant discussions about personal identity. PMID- 24466635 TI - Mayr's recollections of Haldane: a document with brief commentary. PMID- 24466636 TI - Did Tutankhamun suffer from hypophosphatasia?--A hypothetical approach. AB - Between 2005 and 2010 new efforts have been undertaken to shed light on the life and death of Tutankhamun--for the first time with the aid of modern scientific methods like CT scans and DNA analysis. The publication of a paper in the Journal of the American Medical Association in February 2010, that stated the famous pharaoh died of a combination of Malaria and Kohler's disease II, provoked objections from various sides. Based on new and existing findings, the author has developed the theory that Tutankhamun might, instead, have suffered from hypophosphatasia, an inherited metabolic disorder that affects especially the musculo-skeletal system in many ways. Hypophosphatasia (HPP) can be highly variable in its clinical manifestations and can be difficult to diagnose. The author has compiled both medical and archaeological findings to support his theory and suggests that existing DNA samples of Tutankhamun and other members of his family should be tested for defects on the ALPL gene. PMID- 24466637 TI - Diffuse idiopathic skeletal hyperostosis from Roman Hungary. AB - This paper deals with cases of diffuse idiopathic skeletal hyperostosis (DISH) found at the Late Roman Age necropolis in Pecs, Hungary (4th century AD). The skeletal remains of two male individuals, aged between 60-70 years and 45-55 years, displayed right-sided ossification of the anterior longitudinal ligament with extra-spinal manifestations typical in DISH cases. It is presumed that both male individuals were middle-class citizens. Their social status was supplemented with trace element analysis in order to reconstruct the dietary habits of the urban population. Concentrations of Sr and Zn indicated a predominantly vegetal diet. Potential DISH risk factors and associations were subsequently discussed and compared with our findings. PMID- 24466638 TI - Schleswig: medieval leprosy on the boundary between Germany and Denmark. AB - Leprosy was a well-recognized and dreaded disease in medieval Europe. The disease is reported to have reached Germany with the Roman invasion and it was present in Scandinavia in the first centuries AD. This paper estimates and analyzes the frequency of leprosy among adult people buried in one of five medieval cemeteries in the city of Schleswig. Seven different dichotomous osteological lesions indicative of leprosy were analyzed, and it was possible to score at least one of these conditions on 350 adult skeletons (aged 15 or older). The scores were transformed to a statistic indicating the likelihood that the person to whom the skeleton belonged suffered from leprosy. It was found that the frequency of leprosy in the five cemeteries varied between 9 and 44%. Four of the five cemeteries showed frequencies ranging from 35 and 44% and with no statistically significant differences among them. The fifth cemetery showed a significantly lower frequency of leprosy (9%). The distribution of female age at death does not appear to be affected by leprosy status. This means that females experienced a considerably elevated risk of dying once they had contracted leprosy as the disease usually has a mid-adulthood age of onset. In four of the five cemeteries males with leprosy died in higher ages than men without leprosy--in two of the cemeteries the difference was statistically significant. This indicates that leprosy usually added less to the risk of dying among men than among women in medieval Schleswig. PMID- 24466639 TI - Local and foreign males in a late Bronze Age cemetery at Neckarsulm, south western Germany: strontium isotope investigations. AB - The cemetery of Neckarsulm in southwestern Germany was discovered in 2001 and contained the inhumation graves of 50 individuals in 32 graves. The cemetery was in use for about 50 years during the Late Bronze Age (Urnfield culture, Hallstatt A1 period). The individuals who could confidently be identified were almost exclusively adult males. The majority of the skeletal remains exhibit specialized facets that most likely resulting from horseback riding. Several characteristics make this cemetery very unusual: The inhumations in contrast to normal cremation in this time period, the large number of multiple burials, the uniform sex and age of the deceased. There is no information concerning the cause of death of the individuals from the cemetery. Isotopic analysis was used for diet and mobility investigation. Diet for these individuals was relatively homogeneous and included both terrestrial and freshwater species. Tooth enamel from 37 individuals was analysed for strontium and oxygen isotopes. Almost one-third of the individuals in the sample exhibited non-local strontium isotope ratios and likely came from different areas in southwest Germany. PMID- 24466640 TI - Close genetic relationships in vast territories: autosomal and X chromosome Alu diversity in Yakuts from Siberia. AB - Twelve autosomal and 8 X chromosome Alu markers were genotyped for the first time in 161 Central and West Yakuts to test their ability to reconstruct the genetic history of these populations, the northernmost Turkic-speaker ethnic group living in Siberia. Autosomal data revealed that both groups showed extremely close genetic distances to other populations of Siberian origins that occupied areas from Lake Baikal, the ancestral place of origin of Yakuts, to North Siberia, their current territories. Autosomal and X chromosome data revealed some discrepancies on the genetic differentiation and the effective sizes of Central and West Yakuts. Such discrepancies could be related to the patrilineal and occasionally polygamous structure of these populations. Autosomal and X Alu markers are informative markers to reconstruct population past demography and history, but their utility is limited by the available data. This study represents a contribution for further investigations on these populations. PMID- 24466641 TI - Association between BMI and height in girls aged 7-18 years--a longitudinal study. AB - OBJECTIVE: Several studies indicated that there is a significant relationship between BMI and body height, however, the nature of this relationship is not fully explained. The aim of the study is to evaluate cross relationships between height, BMI and the pace of biological development in girls. SUBJECT: 1008 schoolgirls aged 16-18 years for whom earlier data on weight and height were available. MEASUREMENTS: The tests involved body height and weight measurements and obtaining information on the age at menarche. Body height and weight data at earlier age were collected from schools' medical records. Each girl had been measured at the age of 7, 9 and 14 years by qualified school nurses. Age at menarche was used for assessing the pace of biological development. RESULTS: Differences in mean BMI depending on body height category (very short, short, average, tall, very tall) were observed only in younger age groups. BMI values increase along with an increase in body height at the age of 7 and 9 years. No statistically significant differences in the age at menarche between respective body height categories were ascertained. An analogy analysis was performed for BMI categories (underweight, normal weight, overweight). Overweight girls were taller than normal-weight and underweight girls up to the age of 14 years. The age at menarche was the earliest for girls, who were at 7 years or at 9 years overweight. At the age of 16-18 years the shortest height and the earliest onset of menarche were reported in the case of overweight subjects. CONCLUSION: Overweight girls were more advanced in growth and development than their peers. Taller body height in overweight children is noted before reaching puberty and it is a consequence of rapid growth and maturation. PMID- 24466642 TI - Dental age estimation and different predictive ability of various tooth types in the Czech population: data mining methods. AB - Dental development is frequently used to estimate age in many anthropological specializations. The aim of this study was to extract an accurate predictive age system for the Czech population and to discover any different predictive ability of various tooth types and their ontogenetic stability during infancy and adolescence. A cross-sectional panoramic X-ray study was based on developmental stages assessment of mandibular teeth (Moorrees et al. 1963) using 1393 individuals aged from 3 to 17 years. Data mining methods were used for dental age estimation. These are based on nonlinear relationships between the predicted age and data sets. Compared with other tested predictive models, the GAME method predicted age with the highest accuracy. Age-interval estimations between the 10th and 90th percentiles ranged from -1.06 to +1.01 years in girls and from 1.13 to +1.20 in boys. Accuracy was expressed by RMS error, which is the average deviation between estimated and chronological age. The predictive value of individual teeth changed during the investigated period from 3 to 17 years. When we evaluated the whole period, the second molars exhibited the best predictive ability. When evaluating partial age periods, we found that the accuracy of biological age prediction declines with increasing age (from 0.52 to 1.20 years in girls and from 0.62 to 1.22 years in boys) and that the predictive importance of tooth types changes, depending on variability and the number of developmental stages in the age interval. GAME is a promising tool for age-interval estimation studies as they can provide reliable predictive models. PMID- 24466643 TI - Secular trends in parental age in Croatia from 1985-2009. AB - BACKGROUND: In developed countries general living conditions and living standard have grown, leading to reproductive and other secular changes. During the past decade in Croatia living conditions and living standard have improved. OBJECTIVE: The aim of this study was to determine changes in reproductive secular trend in our country similar to trends in developed countries considering different and improved living conditions in Croatia. METHODS: 2414 parents and their newborns during 25 years were examined. The study was conducted in University Hospital Center "Sisters of mercy", Zagreb, Croatia. The study was randomized and included only healthy singleton pregnancies. The information was taken from medical data. Anthropological parameters of pregnant women regarding the place of residence, educational level, marital status and parity were examined. The results were statistically analyzed using nonparametric tests, parametric tests, and if necessary additional post hoc tests. RESULTS: The age of mothers during the study period significantly increased especially in primiparas and secundiparas. The percentage of highly educated mothers and fathers increased. The age of the fathers also increased. Women living in the cities deliver later. Older women deliver heavier and longer children. The share of under-aged mothers during the 25 year period did not change significantly. In the group of older fathers somewhat more common are boys. The proportion of babies with a specified mass is significantly different regarding the maternal age. The proportion of babies of certain length is significantly different with respect to the maternal age only when all periods are considered. CONCLUSION: Our data show a secular trend in reproductive health similar to developed countries. PMID- 24466644 TI - Comparison of pitching kinematics between youth and adult baseball pitchers: a meta-analytic approach. AB - Coaches teach proper mechanics at a young age in an effort to increase pitching efficiency (i.e., proper pitching mechanics). Unfortunately, the mechanics taught to beginning pitchers are based on the findings from adult pitchers and may result in techniques that are detrimental to younger pitchers. The purpose of this study was to compare kinematics published for pitchers across various ages in an effort to determine whether the pitching techniques vary across developmental periods. A meta-analysis of papers published describing pitching kinematics for youth and adult pitchers was conducted. Maximal rotational velocity of the trunk and maximum external rotation of the shoulder were observed during the arm cocking phase. Peak magnitudes for abduction, horizontal adduction, and shoulder internal rotation were observed during the deceleration phase of the movement. In addition, by comparing previously published data across youth and adult pitchers, valuable insight into the differences in mechanics was gained. The results demonstrated that there are some distinct differences between youth and adult pitching mechanics. This finding may allow increased focus to be applied to those parameters observed to differ across age, increasing the knowledge base available for coaches to properly instruct youth pitchers. PMID- 24466645 TI - Trunk axial rotation in baseball pitching and batting. AB - The purpose of this study was to quantify trunk axial rotation and angular acceleration in pitching and batting of elite baseball players. Healthy professional baseball pitchers (n = 40) and batters (n = 40) were studied. Reflective markers attached to each athlete were tracked at 240 Hz with an eight camera automated digitizing system. Trunk axial rotation was computed as the angle between the pelvis and the upper trunk in the transverse plane. Trunk angular acceleration was the second derivative of axial rotation. Maximum trunk axial rotation (55 +/- 6 degrees) and angular acceleration (11,600 +/- 3,100 degrees/s2) in pitching occurred before ball release, approximately at the instant the front foot landed. Maximum trunk axial rotation (46 +/- 9 degrees) and angular acceleration (7,200 +/- 2,800 degrees/s2) in batting occurred in the follow-through after ball contact. Thus, the most demanding instant for the trunk and spine was near front foot contact for pitching and after ball contact for batting. PMID- 24466646 TI - Shear cushions reduce the impact loading rate during walking and running. AB - In addition to vertical ground reaction force (GRF), anterior-posterior GRF with a greater external moment arm may be another repetitive impact force that contributes to overuse running injuries. In this study, a shear cushion device was placed between the sole of a shoe and the ground to reduce not only the vertical loading, but also the anterior-posterior loading while walking and running. For this study, 15 healthy male runners classified as heel strikers (height: 173.2 +/- 4.7 cm, mass: 68.5 +/- 5.6 kg) were recruited. Participants were required to walk (2.5 m/s), jog (3.5 m/s), and run (4.2 m/s) while wearing shoes with three different sole groove designs (conventional, straight groove, and 45 degrees groove). Both the straight and 45 degrees groove soles provided significant shear shift during walking, jogging, and running, as well as delayed the time to first peak anterior-posterior GRF during walking. The straight groove sole reduced the vertical loading rate during jogging (p = 0.010) and running (p = 0.010), and delayed the time to first peak vertical GRF in all gait conditions. These findings suggest that the vertical loading rate and the time to the first peak anterior-posterior GRF can be changed by the sole groove design under various gait conditions. PMID- 24466647 TI - Is outcome related to movement variability in golf? AB - The aim of this study was to develop a method to quantify movement variability in the backswing and downswing phase of the golf swing and statistically assess whether there was any relationship between movement variability and outcome variability. Sixteen highly skilled golfers each performed 10 swings wearing retro-reflective markers which were tracked by a three-dimensional (3D) motion analysis system operating at 400 Hz. Ball launch conditions were captured using a launch monitor. Performance variability was calculated for each body marker based on a scalene ellipsoid volume concept which produced a score representative of the 3D variability over the 10 trials. Outcome variability was quantified as the coefficient of variation of ball velocity for the 10 trials. The statistical analysis revealed no significant correlations between performance variability for each marker trajectory and outcome variability. Performance variability in the backswing or downswing was not related to ball velocity variability. It was postulated that individual players used their own strategies in order to control their performance variability, such that it had no effect on outcome variability. PMID- 24466648 TI - Changes in performance and poling kinetics during cross-country sprint skiing competition using the double-poling technique. AB - In this study, changes in skiing performance and poling kinetics during a simulated cross-country sprint skiing competition were investigated. Twelve elite male cross-country skiers performed simulated sprint competition (4 x 1,150 m heat with 20 min recovery between the heats) using the double-poling technique. Vertical and horizontal pole forces and cycle characteristics were measured using a force plate system (20-m long) during the starting spurt, racing speed, and finishing spurt of each heat. Moreover, heat and 20-m phase velocities were determined. Vertical and horizontal pole impulses as well as mean cycle length were calculated. The velocities of heats decreased by 2.7 +/- 1.7% (p = 0.003) over the simulated competition. The 20-m spurting velocity decreased by 16 +/- 5% (p < 0.002) and poling time increased by 18 +/- 9% (p < 0.003) in spurt phases within heats. Vertical and horizontal poling impulses did not change significantly during the simulation; however, the mean forces decreased (p < 0.039) (vertical by 24 +/- 11% and horizontal by 20 +/- 10%) within heats but not between the heats. Decreased heat velocities over the simulated sprint and spurting velocities within heats indicated fatigue among the skiers. Fatigue was also manifested by decreased pole force production and increased poling time. PMID- 24466649 TI - Mechanical behaviour of cross-country ski racing poles during double poling. AB - The purpose of this study was to evaluate the behaviour of cross-country ski poles during double poling on a treadmill using three-dimensional kinematics. The results were compared with standard laboratory tests of the pole manufacturers. A total of 18 skiers were analysed at two speeds (85% and 95% of the maximal speed) at grades of 1.5% and 7%. Variables describing cycle characteristics, bending stiffness, bending behaviour, and trajectories of the pole markers were analysed. Triangular-shaped poles demonstrated the greatest stiffness and lowest variability in maximal bending. Softer poles demonstrated greater variability in bending behaviour and lost ground contact at high skiing speeds, which for some skiers resulted in failure to complete high-speed tests. Considerable variations in pole behaviour for similar poles between skiers were observed, which might be attributed to differences in technique, indicating that mechanical properties of the poles did not exclusively determine pole behaviour in the dynamic situation. The greatest magnitude of pole bending was in the middle part of the pole, which differed from the standard static pole analysis of the manufacturer. Increases in grade demonstrated the greatest effect on pole bending. Distinct differences from the pole manufacturers' laboratory measures were apparent, suggesting that basic pole testing might be adapted. PMID- 24466650 TI - Effects of target distance on select biomechanical parameters in taekwondo roundhouse kick. AB - The aim of this study was to investigate the effects of target distance on temporal and impact force parameters that are important performance factors in taekwondo kicks. Forty-nine taekwondo athletes (age = 24.5 +/- 5.9 years; mass = 79.9 +/- 10.8 kg) were recruited: 13 male experts, 21 male novices, 8 female experts, and 6 female novices. Impact force, reaction time, and execution time were computed. Three-way repeated measure ANOVAs revealed significant 'distance' effect on impact force, reaction time, and execution time (p = 0.001). Comparisons between distance conditions revealed that taekwondo athletes kicked with higher impact force from short distance (17.6 +/- 7.5 N/kg) than from long distance (13.1 +/- 5.7 N/kg) (p < 0.001), had lower reaction time from short distance (498 +/- 90 ms) and normal distance (521 +/- 111 ms) than from long distance (602 +/- 121 ms) (p < 0.001), and had lower execution time from short distance (261 +/- 69 ms/m) than from normal distance (306 +/- 105 ms/m) or from long distance (350 +/- 106 ms/m) (p = 0.003 and p < 0.001, respectively). In conclusion, target distance affected the kick performance; as distance increases, impact force decreased and reaction time increased. Therefore, when reaction to a simple visual stimulus is needed, kicking from a long distance is not recommended, as longer time is required to respond. PMID- 24466651 TI - The effects of surface traction characteristics on frictional demand and kinematics in tennis. AB - The interaction between footwear and surfaces influences the forces experienced by tennis players. The purpose of this study was to investigate traction demand and kinematic adaptation during tennis-specific movements with changes in traction characteristics of surfaces. We hypothesised that players would increase the utilised coefficient of friction (horizontal to vertical ground reaction force ratio) when the shoe surface combination had a high coefficient of friction and flex their knee after contact to facilitate braking. Eight participants performed two separate movements, side jump out of stance and running forehand. Ground reaction force was measured and three-dimensional kinematic data were recorded. Clay surface and cushioned acrylic hard court (low vs. high shoe surface friction) were used. The peak utilised coefficient of friction was greater on clay than the hard court. The knee was less flexed at impact on clay ( 5.6 +/- 10.2 degrees) and at peak flexion (-13.1 +/- 12.0 degrees) during the running forehand. Our results indicate that tennis players adapt the level ofutilised friction according to the characteristics of the surface, and this adaptation favours sliding on the low friction surface. Less knee flexion facilitates sliding on clay, whereas greater knee flexion contributes to braking on the hard court. PMID- 24466652 TI - Validity of an upper-body-mounted accelerometer to measure peak vertical and resultant force during running and change-of-direction tasks. AB - This study assessed the validity of a tri-axial accelerometer worn on the upper body to estimate peak forces during running and change-of-direction tasks. Seventeen participants completed four different running and change-of-direction tasks (0 degrees, 45 degrees, 90 degrees, and 180 degrees; five trials per condition). Peak crania-caudal and resultant acceleration was converted to force and compared against peak force plate ground reaction force (GRF) in two formats (raw and smoothed). The resultant smoothed (10 Hz) and crania-caudal raw (except 180 degrees) accelerometer values were not significantly different to resultant and vertical GRF for all running and change-of-direction tasks, respectively. Resultant accelerometer measures showed no to strong significant correlations (r = 0.00-0.76) and moderate to large measurement errors (coefficient of variation [CV] = 11.7-23.9%). Crania-caudal accelerometer measures showed small to moderate correlations (r = -0.26 to 0.39) and moderate to large measurement errors (CV = 15.0-20.6%). Accelerometers, within integrated micro-technology tracking devices and worn on the upper body, can provide a relative measure of peak impact force experienced during running and two change-of-direction tasks (45 degrees and 90 degrees) provided that resultant smoothed values are used. PMID- 24466653 TI - [Basic aspects of medical particle accelerators-a grounding in ion acceleration and beam transport]. PMID- 24466654 TI - [Accelerator beam data commissioning equipment and procedures: report of the TG 106 of the therapy physics committee of the AAPM]. PMID- 24466655 TI - Template electrodeposition of catalytic nanomotors. AB - The combination of nanomaterials with electrode materials has opened new horizons in electroanalytical chemistry, and in electrochemistry in general. Over the past two decades we have witnessed an enormous activity aimed at designing new electrochemical devices based on nanoparticles, nanotubes or nanowires, and towards the use of electrochemical routes--particularly template-assisted electrodeposition--for preparing nanostructured materials. The power of template assisted electrochemical synthesis is demonstrated in this article towards the preparation and the realization of self-propelled catalytic nanomotors, ranging from Pt-Au nanowire motors to polymer/Pt microtube engines. Design considerations affecting the propulsion behavior of such catalytic nanomotors are discussed along with recent bioanalytical and environmental applications. Despite recent major advances, artificial nanomotors have a low efficiency compared to their natural counterparts. Hopefully, the present Faraday Discussion will stimulate other electrochemistry teams to contribute to the fascinating area of artificial nanomachines. PMID- 24466656 TI - Microelectrochemical visualization of oxygen consumption of single living cells. AB - The detection of cellular respiration activity is important for the assessment of the status of a biological cell. Due to its non-invasive character and high spatial resolution scanning electrochemical microscopy (SECM) is a powerful tool for single cell measurements. Common limitations of respiration studies performed by SECM are discussed and strategies provided to further adapt SECM detection schemes to the specific requirements for the investigation of single cell respiration. In particular the combination of a potential pulse technique in the redox competition mode of SECM with a shearforce-based constant-distance positioning of the SECM tip is proposed for characterising the impact of the tip reaction during SECM imaging. The adjustment of the driving force of the tip reaction and the selection of the time for data acquisition after applying the potential pulse allowed a successful visualization of cell respiration activity. PMID- 24466657 TI - Vesicular release of neurotransmitters: converting amperometric measurements into size, dynamics and energetics of initial fusion pores. AB - Amperometric currents displaying a pre-spike feature (PSF) may be treated so as to lead to precise information about initial fusion pores, viz., about the crucial event initiating neurotransmitter vesicular release in neurons and medullary glands. However, amperometric data alone are not self-sufficient, so their full exploitation requires external calibration to solve the inverse problem. For this purpose we resorted to patch-clamp measurements published in the literature on chromaffin cells. Reported pore radii were thus used to evaluate the diffusion rate of neurotransmitter cations in the partially altered matrix located near the fusion pore entrance. This allowed an independent determination of each initial fusion pore radius giving rise to a single PSF event. The statistical distribution of the radii thus obtained provided for the first time an experimental access to the potential energy well governing the thermodynamics of such systems. The shape of the corresponding potential energy well strongly suggested that, after their creation, initial fusion pores are essentially controlled by the usual physicochemical laws describing pores formed in bilayer lipidic biological membranes, i.e., they have an essentially lipidic nature. PMID- 24466658 TI - Potential-dependent single molecule blinking dynamics for flavin adenine dinucleotide covalently immobilized in zero-mode waveguide array of working electrodes. AB - Single molecules exhibit a set of behaviors that are characteristic and distinct from larger ensembles. Blinking is one such behavior that involves episodic transitions between luminescent and dark states. In addition to the common blinking mechanisms, flavin adenine dinucleotide (FAD), a cofactor in many common redox enzymes, exhibits blinking by cycling between a highly fluorescent oxidized state and a dark reduced state. In contrast to its behavior in flavoenzymes, where the transitions are coupled to chemical redox events, here we study single FAD molecules that are chemically immobilized to the Au region of a zero-mode waveguide (ZMW) array through a pyrroloquinoline quinone (PQQ) linker. In this structure, the Au functions both to confine the optical field in the ZMW and as the working electrode in a potentiostatically controlled 3-elecrode system, thus allowing potential-dependent blinking to be studied in single FAD molecules. The subset of ZMW nanopores housing a single molecule were identified statistically, and these were subjected to detailed study. Using equilibrium potential, E(eq), values determined from macroscopic planar Au electrodes, single molecule blinking behavior was characterized at potentials E < E(eq), E - E(eq), and E > E(eq). The probability of observing a reduced (oxidized) state is observed to increase (decrease) as the potential is scanned cathodic of E(eq). This is understood to reflect the potential-dependent probability of electron transfer for single FAD molecules. Furthermore, the observed transition rate reaches a maximum near E(eq) and decreases to either anodic or cathodic values, as expected, since the rate is dependent on having significant probabilities for both redox states, a condition that is obtained only near E(eq). PMID- 24466659 TI - Networks of DNA-templated palladium nanowires: structural and electrical characterisation and their use as hydrogen gas sensors. AB - Electroless templating on DNA is established as a means to prepare high aspect ratio nanowires via aqueous reactions at room temperature. In this report we show how Pd nanowires with extremely small grain sizes (< 2 nm) can be prepared by reduction of PdCl4(2-) in the presence of lambda-DNA. In AFM images the wires are smooth and uniform in appearance, but the grain size estimated by the Scherrer treatment of line broadening in X-ray diffraction is less than the diameter of the wires from AFM (of order 10 nm). Electrical characterisation of single nanowires by conductive AFM shows ohmic behaviour, but with high contact resistances and a resistivity (-10(-2) omega cm) much higher than the bulk value for Pd metal (-10(-5) cm @ 20 degrees C). These observations can be accounted for by a model of the nanowire growth mechanism which naturally leads to the formation of a granular metal. Using a simple combing technique with control of the surface hydrophilicity, DNA-templated Pd nanowires have also been prepared as networks on an Si/SiO2 substrate. These networks are highly convenient for the preparation of two-terminal electronic sensors for the detection of hydrogen gas. The response of these hydrogen sensors is presented and a model of the sensor response in terms of the diffusion of hydrogen into the nanowires is described. The granular structure of the nanowires makes them relatively poor conductors, but they retain a useful sensitivity to hydrogen gas. PMID- 24466660 TI - Anodic TiO2 nanotubes: double walled vs. single walled. AB - Electrochemical formation of self-organized TiO2 nanotube layers has been a highly active research field for more than 10 years. In the present manuscript we investigate the formation of two distinctly different anodic TiO2 nanotube morphologies, 'single walled' and 'double walled' tubes, which are formed mainly depending on the nature of the anodization electrolyte. While the widest used electrolytes are ethylene glycol (EG) based, forming double walled structures, tubes formed in dimethyl sulfoxide (DMSO) based electrolytes show a single tube walled morphology. Here we provide reasons for the formation of double walled tubes, characterize tubes for their composition, structure and certain properties, and give measures to suppress or minimize double wall formation. Except for the fact that in DMSO single walled tubes are formed, we also show that they grow sufficiently slowly to allow partial crystallization of the tubes during growth--this, in turn drastically influences their electronic properties. Finally we discuss the effects and potential consequences of double or single wall growth for TiO2 nanotube applications. PMID- 24466661 TI - The simplest model of charge storage in single file metallic nanopores. AB - The problem of voltage controlled accumulation of ions in a narrow nanopore, which can accommodate just one row of ions of an ionic liquid and is filled with ions when the electrode is unpolarised, is mapped on an exactly solvable one dimensional two state lsing model. Analytical solution of this, presumably simplest, statistical mechanical model reveals the dependence of the electrical capacitance on voltage, pore radius, and temperature. The voltage dependence of capacitance has the character of a smeared resonance, whose position and height is affected by a tiny change of the pore radius. Consequently, even the slightest dispersion of pore radii in the whole electrode, unavoidable in any real system, softens the voltage dependence. PMID- 24466662 TI - Carbon nanotube based electrochemical sensor for the sensitive detection of valacyclovir. AB - An electrochemical sensor for the sensitive detection of valacyclovir has been developed, which is based on single-walled carbon nanotube (SWCNT)-modified glassy carbon electrodes. The electrochemical oxidation of valacyclovir at the SWCNT-modified glassy carbon electrodes has been investigated using cyclic voltammetry and differential pulse voltammetry. Our experimental results show that the SWCNT-modified glassy carbon electrode possesses high activity toward the electrochemical oxidation of valacyclovir. In a 0.1 M phosphate buffer (pH = 7.4), valacyclovir exhibited an irreversible oxidation peak at -0.91 V. The effects of pH of and the amount of SWCNT deposited on the glassy carbon electrode on the activity of the sensor have also been studied. Under optimized conditions, the sensor demonstrates a linear response range from 5 x 10(-9) to 5.5 x 10(-8) M valacyclovir. The detection and quantification limits were found to be 1.80 x 10( 9) M and 6.02 x 10(-9) M, respectively. The selectivity, stability and reproducibility of the proposed sensor were examined as well. To validate its real world application, the electrochemical sensor has been successfully utilized in the detection of valacyclovir in human blood plasma and pharmaceutical samples. Thus, the electrochemical sensor developed in this study has strong potential to be employed in the quality control testing of pharmaceutical products and also for therapeutic drug monitoring in hospitals. PMID- 24466663 TI - Electroanalysis using modified hierarchical nanoporous carbon materials. AB - The role of the electrode nanoporosity in electroanalytical processes is discussed and specific phenomena (slow double layer charging, local pH effects) which can be present in porous electrode are described. Hierarchical porous carbon (HPC) materials are synthesized using a hard template method. The three dimensional carbon porosity is examined using scanning electron microscopy on flat surfaces cut using a focused ion beam (FIB-SEM). The electrochemical properties of the HPC are measured using cyclic voltammetry, AC impedance, chronoamperometry and Probe Beam Deflection (PBD) techniques. Chronoamperometry measurements of HPC seems to fit a transmission line model. PBD data show evidence of local pH changes inside the pores, during double layer charging. The HPC are modified by in situ (chemical or electrochemical) formation of metal (Pt/Ru) or metal oxide (CoOx, Fe3O4) nanoparticles. Additionally, HPC loaded with Pt decorated magnetite (Fe3O4) nanoparticles is produced by galvanic displacement. The modified HPC materials are used for the electroanalysis of different substances (CO, O2, AsO3(-3)). The role of the nanoporous carbon substrate in the electroanalytical data is evaluated. PMID- 24466664 TI - Pd@Au core-shell nanocrystals with concave cubic shapes: kinetically controlled synthesis and electrocatalytic properties. AB - A new type of concave cubic Pd@Au core-shell nanocrystals is synthesized through a kinetically controlled growth process. Pd nanocubes of 56 nm are used as the inner core, and CTAC and Br(-) are used as the capping agent and selective adsorbent, respectively. A suitable ratio of HAuCl4 and cubic Pd seeds and the presence of Br(-) anions are critical to the growth of the concave cubic Pd@Au core-shell nanocrystals. The fast deposition rate on the corners of the cubic Pd seeds promotes the overgrowth of the Au outer shell along the <111> direction, leading to the formation of concave cubic nanostructures. The reduction process is monitored by the surface plasmon resonance spectra of the nanocrystals, and the extinction band became broader and red shifted as the nanocrystals became larger. The electrocatalytic properties of the concave cubic Pd@Au core-shell nanocrystals were investigated with the cathodic electrochemiluminescence reaction of luminol and H2O2. A possible electrocatalytic mechanism was proposed and analyzed. PMID- 24466665 TI - Electrochemical mechanical micromachining based on confined etchant layer technique. AB - The confined etchant layertechnique (CELT) has been proved an effective electrochemical microfabrication method since its first publication at Faraday Discussions in 1992. Recently, we have developed CELT as an electrochemical mechanical micromachining (ECMM) method by replacing the cutting tool used in conventional mechanical machining with an electrode, which can perform lathing, planing and polishing. Through the coupling between the electrochemically induced chemical etching processes and mechanical motion, ECMM can also obtain a regular surface in one step. Taking advantage of CELT, machining tolerance and surface roughness can reach micro- or nano-meter scale. PMID- 24466666 TI - Decoration of active sites to create bimetallic surfaces and its implication for electrochemical processes. AB - The creation of electrocatalysts based on noble metals has received a significant amount of research interest due to their extensive use as fuel cell catalysts and electrochemical sensors. There have been many attempts to improve the activity of these metals through creating nanostructures, as well as post-synthesis treatments based on chemical, electrochemical, sonochemical and thermal approaches. In many instances these methods result in a material with active surface states, which can be considered to be adatoms or clusters of atoms on the surface that have a low lattice co-ordination number making them more prone to electrochemical oxidation at a wide range of potentials that are significantly less positive than those of their bulk metal counterparts. This phenomenon has been termed pre-monolayer oxidation and has been reported to occur on a range of metallic surfaces. In this work we present findings on the presence of active sites on Pd that has been: evaporated as a thin film; electrodeposited as nanostructures; as well as commercially available Pd nanoparticles supported on carbon. Significantly, advantage is taken of the low oxidation potential of these active sites whereby bimetallic surfaces are created by the spontaneous deposition of Ag from AgNO3 to generate Pd/Ag surfaces. Interestingly this approach does not increase the surface area of the original metal but has significant implications for its further use as an electrode material. It results in the inhibition or promotion of electrocatalytic activity which is highly dependent on the reaction of interest. As a general approach the decoration of active catalytic materials with less active metals for a particular reaction also opens up the possibility of investigating the role of the initially present active sites on the surface and identifying the degree to which they are responsible for electrocatalytic activity. PMID- 24466667 TI - Mapping fluxes of radicals from the combination of electrochemical activation and optical microscopy. AB - The coating of gold (Au) electrode surfaces with nitrophenyl (NP) layers is studied by combination of electrochemical actuation and optical detection. The electrochemical actuation of the reduction of the nitrobenzenediazonium (NBD) precursor is used to generate NP radicals and therefore initiate the electrografting. The electrografting process is followed in situ and in real time by light reflectivity microscopy imaging, allowing for spatio-temporal imaging with sub-micrometer lateral resolution and sub-nanometer thickness sensitivity of the local growth of a transparent organic coating onto a reflecting Au electrode. The interest of the electrochemical actuation resides in its ability to finely control the grafting rate of the NP layer through the electrode potential. Coupling the electrochemical actuation with microscopic imaging of the electrode surface allows quantitative estimates of the local grafting rates and subsequently a real time and in situ mapping of the reacting fluxes of NP radicals on the surface. Over the 2 orders of magnitude range of grafting rates (from 0.04 to 4 nm s(-1)), it is demonstrated that the edge of Au electrodes are grafted -1.3 times more quickly than their centre, illustrating the manifestation of edge-effects on flux distribution at an electrode. A model is proposed to explain the observed edge-effect, it relies on the short lifetime of the intermediate NP radical species. PMID- 24466668 TI - Electrochemically assisted self-assembly of ordered and functionalized mesoporous silica films: impact of the electrode geometry and size on film formation and properties. AB - Surfactant-templated mesoporous silica thin films can be deposited onto solid electrode surfaces by electrochemically assisted self-assembly (EASA). The method involves a cathodically triggered self-assembly of cationic surfactants (cetyltrimethyl ammonium bromide, CTAB) and local pH increase leading to the polycondensation of silica precursors (i.e., tetraethoxysilane, alone or in the presence of (3-mercaptopropyl) trimethoxysilane (MPTMS)) and concomitant growth of the ordered mesoporous silica or organosilica film. The present work shows that the EASA method can be applied to film deposition on electrode supports of various morphologies, geometries and sizes (large and flat discs or non-flat streaked supports, i.e., gold CD-trodes, as well as several kinds of ultramicroelectrodes, including carbon fibers, platinum wires, and platinum microdiscs). Galvanostatic conditions were mainly preferred to potentiostatic conditions to avoid problems related to various overpotentials and surface areas experienced with the various working electrodes used here. The results indicate that film deposition was possible on each electrode support but also that both the film formation and properties were dependent on the experimental conditions for EASA. For example, passing from large electrodes to ultramicroelectrodes required the application of larger current densities to ensure film deposition, which can be due to faster loss of the hydroxyl species in solution in the case of radial or spherical diffusion, in comparison to the linear. Highly porous deposits were obtained after template removal, as ascertained by cyclic voltammetry using Ru(NH3)6(3+) as a redox probe. The advantage of better signal to-background current ratios for ultramicroelectrodes relative to the macroscopic ones was maintained after film deposition, also resulting in higher sensitivity when used in conditions of preconcentration electroanalysis (using silver(I) or mercury(II) as a probe being accumulated by complexation to MPTMS-based films). PMID- 24466669 TI - Metallic impurities availability in reduced graphene is greatly enhanced by its ultrasonication. AB - Ultrasonication is an inherent part of the major routes for preparation of reduced graphene. It is used to exfoliate graphite oxide to graphene oxide with consequent reduction to reduced graphenes. Metallic impurities in graphenes, originating from the starting material, graphite, have a profound influence on many properties of graphene, such as the electrochemical, catalytic and electronic properties. We show here that ultrasonication greatly enhances the redox availability of metallic impurities within reduced graphenes. Such findings will have a dramatic influence on future graphene processing methodology and applications of graphene. PMID- 24466670 TI - Highly sensitive detection of nitroaromatic explosives at discrete nanowire arrays. AB - We show a photolithography technique that permits gold nanowire array electrodes to be routinely fabricated at reasonable cost. Nanowire electrode arrays offer the potential for enhancements in electroanalysis such as increased signal-to noise ratio and increased sensitivity while also allowing quantitative detection at much lower concentrations. We explore application of nanowire array electrodes to the detection of different nitroaromatic species. Characteristic reduction peaks of nitro groups are not observed at nanowire array electrodes using sweep voltammetric methods. By contrast, clear and well-defined reduction peaks are resolved using potential step square wave voltammetry. A Principle Component Analysis technique is employed to discriminate between nitroaromatic species including structural isomers of DNT. The analysis indicates that all compounds are successfully discriminated by unsupervised cluster analysis. Finally, the magnitude of the reduction peak at -671 mV for different concentrations of TNT exhibited excellent linearity with increasing concentrations enabling sub-150 ng mL(-1) limits of detection. PMID- 24466671 TI - A systematic study of the influence of nanoelectrode dimensions on electrode performance and the implications for electroanalysis and sensing. AB - Micron resolution photolithography has been employed to make microsquare nanoband edge electrode (MNEE) arrays with reproducible and systematic control of the crucial dimensional parameters, including array element size and spacing and nanoelectrode thickness. The response of these arrays, which can be reproducibly fabricated on a commercial scale, is first established. The resulting characteristics (including high signal and signal-to-noise, low limit of detection, insensitivity to external convection and fast, steady-state, reproducible and quantitative response) make such nanoband electrode arrays of real interest as enhanced electroanalytical devices. In particular, the nanoelectrode response is presented and analysed as a function of nanometre scale electrode dimension, to assess the impact and relative contributions of previously postulated nanodimensional effects on the resulting response. This work suggests a significant contribution of migration at the band edges to mass transfer, which affects the resulting electroanalytical response even at ionic strengths as large as 0.7 mol dm(-3) and for electrodes as wide as 50 nm. For 5 nm nanobands, additional nanoeffects, which are thought to arise from the fact that the size of the redox species is comparable to the band width, are also observed to attenuate the observed current. The fundamental insight this gives into electrode performance is discussed along with the consequent impact on using such electrodes of nanometre dimension. PMID- 24466672 TI - Double layer effects at nanosized electrodes. AB - This paper discusses numerical simulations of double layer effects at shrouded electrodes with dimensions below 100 nm. Special focus is given to the surface charge on the shrouding material. The Poisson-Nernst-Planck equations are solved to study the effects on the limiting current arising from the electrical double layer of the shrouding. PMID- 24466673 TI - Pulse electroanalysis at gold-gold micro-trench electrodes: chemical signal filtering. AB - Bipotentiostatic control of micro- and nano-trench sensor systems provides new opportunities for enhancing signals (employing feedback currents) and for improved selectivity (by "chemical filtering"). In this study both phenomena are exploited with a gold-gold micro-trench electrode with ca. 70 microm width and ca. 800 microm trench depth. In "generator-collector mode", feedback current enhancement is demonstrated for the hydroquinone/ benzoquinone redox system. Next, a "modulator-sensor mode" experiment is developed in which one electrode potential is stepped into the negative potential region (employing the normal pulse voltammetry method) to induce an oscillating pH change locally in the micro trench. The resulting shift in the hydroquinone/benzoquinone reversible potential causes a Faradaic sensor signal (employing chronoamperometry). This method provides a "chemical filter" by selecting pH-sensitive redox processes only, and by showing enhanced sensitivity in the region of low buffer capacity. The results for the chemically reversible hydroquinone/benzoquinone system are contrasted to the detection of the chemically irreversible ammonia oxidation. PMID- 24466674 TI - Effects of adsorption and confinement on nanoporous electrochemistry. AB - Characteristic molecular dynamics of reactant molecules confined in the space of the nanometer scale augments the frequency of collisions with the electrified surface so that a given faradaic reaction can be enhanced at nanoporous electrodes, the so-called nano-confinement effect. Since this effect is grounded on diffusion inside nanopores, it is predicted that adsorption onto the surface will seriously affect the enhancement by nano-confinement. We experimentally explored the correlation between adsorption and the confinement effect by examining the oxidation of butanol isomers at platinum and gold nanoporous electrodes. The results showed that electrooxidation of 2-butanol, which is a non adsorption reaction, was enhanced more than that of 1-butanol, which is an adsorption reaction, at nanoporous platinum in acidic media. In contrast, the nanoporous gold electrode, on which 1-butanol is less adsorptive than it is on platinum, enhanced the electrooxidation of 1-butanol greatly. Furthermore, the electrocatalytic activity of nanoporous gold for oxygen reduction reaction was improved so much as to be comparable with that of flat Pt. These findings show that the nano-confinement effect can be appreciable for electrocatalytic oxygen reduction as well as alcohol oxidation unless the adsorption is extensive, and suggests a new strategy in terms of material design for innovative non-noble metal electrocatalysts. PMID- 24466675 TI - Gold nanowire electrodes in array: simulation study and experiments. AB - Recent developments in nanofabrication have enabled fabrication of robust and reproducible nanoelectrodes with enhanced performance, when compared to microelectrodes. A hybrid electron beam/photolithography technique is shown that permits discrete gold nanowire electrode arrays to be routinely fabricated at reasonable cost. Fabricated devices include twelve gold nanowire working electrode arrays, an on-chip gold counter electrode and an on-chip platinum pseudo reference electrode. Using potential sweep techniques, when diffusionally independent, these nanowires exhibit measurable currents in the nanoAmpere regime and display steady-state voltammograms even at very high scan rates (5000 mV s( 1)) indicative of fast analyte mass transport to the electrode. Nanowire electrode arrays offer the potential for enhancements in electroanalysis including increased signal to noise ratio and increased sensitivity while also allowing quantitative detection at much lower concentrations. However, to achieve this goal a full understanding of the diffusion profiles existing at nanowire arrays is required. To this end, we simulate the effects of altering inter electrode separations on analyte diffusion for a range of scan rates at nanowire electrode arrays, and perform the corresponding experiments. We show that arrays with diffusionally independent concentration profiles demonstrate superior electrochemical performance compared to arrays with overlapping diffusion profiles when employing sweep voltammetric techniques. By contrast, we show that arrays with diffusionally overlapping profiles exhibit enhanced performance when employing step voltammetric techniques. PMID- 24466676 TI - Nanoscale control of interfacial processes for latent fingerprint enhancement. AB - Latent fingerprints on metal surfaces may be visualized by exploiting the insulating characteristics of the fingerprint deposit as a "mask" to direct electrodeposition of an electroactive polymer to the bare metal between the fingerprint ridges. This approach is complementary to most latent fingerprint enhancement methods, which involve physical or chemical interaction with the fingerprint residue. It has the advantages of sensitivity (a nanoscale residue can block electron transfer) and, using a suitable polymer, optimization of visual contrast. This study extends the concept in two significant respects. First, it explores the feasibility of combining observation based on optical absorption with observation based on fluorescence. Second, it extends the methodology to materials (here, polypyrrole) that may undergo post-deposition substitution chemistry, here binding of a fluorophore whose size and geometry preclude direct polymerization of the functionalised monomer. The scenario involves a lateral spatial image (the whole fingerprint, first level detail) at the centimetre scale, with identification features (minutiae, second level detail) at the 100-200 microm scale and finer features (third level detail) at the 10-50 microm scale. However, the strategy used requires vertical spatial control of the (electro)chemistry at the 10-100 nm scale. We show that this can be accomplished by polymerization of pyrrole functionalised with a good leaving group, ester-bound FMOC, which can be hydrolysed and eluted from the deposited polymer to generate solvent "voids". Overall the "void" volume and the resulting effect on polymer dynamics facilitate entry and amide bonding of Dylight 649 NHS ester, a large fluorophore. FTIR spectra demonstrate the spatially integrated compositional changes. Both the hydrolysis and fluorophore functionalization were followed using neutron reflectivity to determine vertical spatial composition variations, which control image development in the lateral direction. PMID- 24466677 TI - Closing remarks: looking back and ahead at 'nano' electroanalytical chemistry. PMID- 24466678 TI - [Selected data of acute poisonings with ethylene glycol and methanol in Poland in the year 2010]. AB - There are no reliable studies in Poland evaluating the scale of acute intoxications with different type of xenobiotics. The aim of the study was to evaluate selected problems referring to the patients intoxicated with ethylene glycol and methanol, who were given the medical treatment in all Toxicological (TUs) and Intensive Care Units (ICUs), having contract with Polish National Fund of Health, in the year 2010. All cases of acute intoxications treated in polish hospitals in 2010 and reported to the Polish National Fund of Health were included to the analysis. To further analysis were chosen only those patients, whose main diagnosis or co-morbidities were coded as T 51.1 or T 52.3, according to the International Statistical Classification of Diseases and Related Health Problems 10th Revision and, according to the state of health, patients were treated in TUs and ICUs. All the cases, in which intoxication was not the main health problem were excluded. RESULTS: There were 85 230 acute poisonings in Poland in 2010, 503 of them referred to ethylene glycol and methanol poisonings. 220 patients were treated in TUs and ICUs. The most common methods of therapy in those units were extracorporeal toxin removal (53.22% in TUs and 52.08% in ICUs) and conservative treatment (46.78% in TUs and 47.92% in ICUs). The mortality rate in ethylene glycol and methanol poisonings in TUs and ICUs were 20.97% and 48.96% respectively. In the conservatively treated group the mortality rates in TUs and ICUs were 15.52% and 54.35% respectively, while in extracorporeal toxin removal group the mortality rates in TUs and ICUs were 25.76% and 44.00% respectively. The authors also observed one region (Makow Mazowiecki), in which the amount of ethylene glycol and methanol poisonings was much higher than in the rest part of the country. CONCLUSIONS: 1. All the cases of acute intoxications of glycol and methanol should be consulted with Polish Poison Control Centers. 2. It is necessary to establish diagnostic and treatment protocols for intoxicated patients in Poland. 3. There is a strong need for popularization of the modern methods of glycol and methanol poisonings therapy and increasing the availability of modern antidotes. 4. It is necessary to continue monitoring and evaluation of different ways of treatment glycol and methanol intoxications. 5. The cases of abnormally high rate of glycol and methanol intoxications in some hospitals should be investigated. PMID- 24466679 TI - [Fatal poisoning in the Department of Toxicology in Poznarn in 2008-2012- preliminary analysis]. AB - This paper presents the results of a preliminary analysis of deaths from acute poisoning, which occurred in the Department of Toxicology in Poznan in 2008-2012. During this period, recorded 31 cases of fatal poisoning, representing 0.38% of all treated cases. In subsequent years the percentage of poisoning deaths ranged from 0.25 to 0.49%. Throughout the period leading cause of fatal poisoning were drugs (38.71%) and non-consumptive alcohols (methanol or ethylene glycol) (38.71%). In subsequent years, however, a decrease in the percentage of drug poisoning (from 75 to 0%) and an increase in the percentage of nonconsumptive alcohol poisoning (from 0% to 100%) were observed. In fatal cases were diagnosed among others olanzapine, carbamazepine, pseudoephedrine, tramadol, benzodiazepines, clozapine, morphine and benzodiazepines, insulin, verapamil, carbon monoxide and smoke fire, cyanide, Amanita phalloides, ethanol and a mixture of drugs with ethanol poisoning. The most common fatal poisoning occurred in people addicted (45.16%), mainly in alcohol dependence syndrome (35.48%). Suicidal poisoning was the cause of 32.26% of the deaths, while accidental of 19.35%. In nine cases, the procedure of diagnosis of death from irreversible cessation of brain stem function was performed in order to qualify donors of organs for transplantation or to terminate the therapy. One of the dead was liver and kidneys, and two were kidneys donors. PMID- 24466680 TI - [Medical analytical toxicology in Poland in year 2012]. AB - There are 12 centers of acute poisoning treatment and 9 round the clock toxicological laboratories. Most of the laboratories access evidence of activity run by National Clinical Toxicology Consultant. The paper presents actual status of medical toxicology laboratories in Poland and summarizes activity of the laboratories in the year 2012. In 2012 toxicological laboratories reported 113,719 assays. There were diagnosed 63.8% men and 34.8% women. The toxicological laboratories determine most substances and markers of exposition to chemical compounds important for diagnosis and treatment of acute poisonings (i.e. ethanol, methanol, ethylene glycol, acetaminophen, salicylates, anticonvulsants, carboxyhemoglobin, methemoglobin). There is not possible to determine heavy metals, all medicines and "designed" drugs of abuse in all laboratories. Limited access to reference methods, that enable to confirm results obtained by screening methods (immunological cassette and strip tests) is also a problem. PMID- 24466681 TI - [Acute ethylene glycol poisoning among patients of Nofer Institute of Occupational Medicine in Lodz, Toxicology Unit, hospitalized in the years 2000 2009]. AB - Acute poisonings with ethylene glycol pose real challenge in the clinical toxicology. The main objective of this study is an analysis of clinical features and identification of prognostic factors in poisoning with ethylene glycol of patients hospitalized in the Toxicology Unit in the years 2000-2009. The medical records of the patients were identified and separated. In the years 2000-2009, 102 patients were hospitalized due to ethylene glycol poisoning, what accounted for 0.38% of total admissions to the unit (26.801 hospitalized people). The mean age of patients amounted 48.05 +/- 12.55 years, the history positive for chronic alcohol abuse was present in 63 (61.76%) cases. Mean values of ethylene glycol concentration were as: in serum 173.14 mg/dl, in urine 6576.46 mg/l. Patients condition on admission varied, with 63 (61.76%) cases described as the severe state. The most frequently noted pathologies were consciousness disturbances and tachycardia. 14 patients died within the analysed group and 63 (61.76%) developed single or multiorgan complications in the course of disease. The most commonly encountered complication were: acute renal failure, anaemia, pneumonia and central nervous system damage. Such parameters as: BE and HCO3 measured on admission should be considered as the prognostic factors, determining the course of the disease and the outcomes of treatment. Poor prognosis may be associated with such clinical features on admission, as: respiratory and circulatory disturbances and cerebral sequelae. The importance of acute poisoning of ethylene glycol is determined both by high frequency of immediate life threatening conditions and by the risk of complications leading to permanent organs damage. PMID- 24466682 TI - [Confirmed poisonings with ethylene glycol and methanol in south Poland in the years 2010-2012 based on results from toxicological laboratories in Krakow and Sosnowiec]. AB - The purpose of the research was to present the number of ethylene glycol and methanol poisonings in south Poland in the years 2010-2012, based on data from toxicological laboratories in Krakow and Sosnowiec. Total numbers of positive determinations of the toxic alcohols were 380-ethylene glycol and 152-methanol. Most of the patients poisoned with the toxic alcohols were men (87.4%), the mean age of the patients was 48.1 years. Mean ethylene glycol concentration in samples from poisoned patients was 57.5 mg/dl in serum and 286.2 mg/dl in urine; mean blood methanol concentration was 1.4 g/l. Samples collected from poisoned patients treated on the area of whole voivodeship were determined in toxicology laboratories. According to information about orderers of ethylene glycol and methanol tests, positive results of the toxic alcohols were the most often in big cities and in cities, where department of toxicology were located (Krakow and Sosnowiec). In many cases patients were treated in hospitals in small cities, and samples collected from patients were transported to perform toxicological determination. The study shows, that intoxications with ethylene glycol and methanol are a big problem in Poland and the number of methanol poisonings markedly increased in the years 2010-2012. PMID- 24466683 TI - [Determination of ethylene glycol in biological fluids--propylene glycol interferences]. AB - Many laboratories in Poland do not use gas chromatography (GC) method for determination of ethylene glycol (EG) and methanol in blood of poisoned patients, they use non specific spectrophotometry methods. One of the interfering substances is propylene glycol (PG)--compound present in many medical and cosmetic products: drops, air freshens, disinfectants, electronic cigarettes and others. In Laboratory of Analytical Toxicology and Drug Monitoring in Krakow determination of EG is made by GC method. The method enables to distinguish and make resolution of (EG) and (PG) in biological samples. In the years 2011-2012 in several serum samples from diagnosed patients PG was present in concentration from several to higher than 100 mg/dL. The aim of the study was to estimate PG interferences of serum EG determination by spectrophotometry method. Serum samples containing PG and EG were used in the study. The samples were analyzed by two methods: GC and spectrophotometry. Results of serum samples spiked with PG with no EG analysed by spectrophotometry method were improper ("false positive"). The results were correlated to PG concentration in samples. Calculated cross reactivity of PG in the method was 42%. Positive results of EG measured by spectrophotometry method must be confirmed by reference GC method. Spectrophotometry method shouldn't be used for diagnostics and monitoring of patients poisoned by EG. PMID- 24466684 TI - [Kidney transplants from donors burdened metabolic acidosis in the course of poisoning with methanol and carbon monoxide]. AB - The question of obtaining organs from donors who died of methanol poisoning has been discussed in the medical literature for many years. The results of such transplants published so far are very optimistic. However, the possibility of permanent and significant injury to transplanted organs caused by poisons or its metabolites raises serious concerns regarding the procedure. The long-term effects of intensive treatment of poisoning need to be considered as well. Metabolic acidosis and high blood osmolality are agents with recognized damaging potential impairing organ function at cellular level. The study traced the fate of kidney transplants from 13 donors who died of methanol poisoning and one isoned with carbon monoxide. The donors group consisted of 12 men and 2 women, of mean age 49 years (SD +/- 7.93). The kidneys were transplanted 20 men and 8 women. The mean age of recipients was 50.29 years (SD +/- 12.9). At the time of admission to the Department of Toxicology all donors presented with profound metabolic acidosis and high plasma osmolality (mean 434.71 mOsm/kg H2O (SD +/- 73.29). Metabolic acidosis was treated high doses of sodium bicarbonate (mean infusion volume of was 409 ml) before the HD procedure. Blood methanol levels were between 125 and 470 mg% (mean 317.23 SD +/- 136.83). The carboxyhaemoglobin concentration of in the donor poisoned with carbon monoxide was 47.2%. Transplantation was performed after confirmation of the brain death, the period of cold ischemia (CIT) ranged from 6 to 22 hours (mean 16.06 hours; SD +/- 3.99). Kidneys have taken function immediately after transplantation in 21 recipients. In seven cases, patients required two or three HD procedures. A total of 16 dialysis were performed post-transplants. In the group of patients, the mean glomerular filtration rate (GFR) at 3 months after transplantation was 46.71 ml/min/1.73m2 (SD +/- 10.89). During the 18 months follow-up a constant upward trend to the mean GFR 50.55 was noticed. In the group of donors, the mean blood urea concentration (BUN) 3 months after transplantation was 61.43 mg/dL, including 7 patients with BUN within the range of 80-100 mg/dL. At 18 months post transplant, the average concentration was 42.36 mg/dL, with no cases exceeding 55 mg/dL. Similarly, serum creatinine level normalized with the mean value of 3.01 mg/dL at 3 months and 1.68 mg/dL at 18 months post the procedure. There was no case exceeding 2 mg/dL. One recipient died of a heart attack after a period of more than 18 months after transplantation. However, the transplant was efficiently active at all times (GFR 56-60 ml). PMID- 24466685 TI - [Acute novel drugs poisoning among patients of Nofer Institute of Occupational Medicine in Lodz, Toxicology Unit, hospitalized in the years 2008-2012- epidemiology, clinical state]. AB - Intoxication with novel recreational drugs poses significant challenge for medical staff due to diagnostic difficulties, complex clinical pattern, resulting from polyethiology of poisoning and potential risk of life threatening complications. OBJECTIVES: Description of clinical pattern novel drug intoxication. METHODS: retrospective review of medical records patients hospitalized in the Toxicology Unit (TU) with diagnosis of intoxication with novel recreational drugs. RESULTS: During the period from 2008-2010--431 patients were admitted to TU with mentioned above diagnosis. 159 (36.9%) patients were positive for ethanol with its average concentration in blood 150 mg%. Presence of other substances like amphetamine, cannabinoids, atropine, ephedrine, carbamazepine, benzodiazepines and dextrometorphan was confirmed. The most frequent clinical symptoms observed on admission were: anxiety, agitation, complaints associated with circulatory system and vertigo Average pulse rate and both: diastolic and systolic pressure were within normal limits, however authors noted slight tendency toward tachycardia. One patients died due to multiorgan failure. Average period of hospitalization amounted 2.24 days. Co-poisoning with ethanol was associated with higher frequency of circulatory system disturbances. RESULTS: Clinical pattern of poisoning with novel drugs could partially correspond with mild sympathomime. tic syndrome. PMID- 24466686 TI - [Recreational usage of dextromethorphan--analysis based on internet users experiences]. AB - In the last decade we have observed a considerable increase in nonmedical usage of dextromethorphan (DXM) among young age groups, especially school children between 13 and 16 yrs. We analysed the "trip reports" after use of DXM, available on a website: www.hyperreal.info in the years 1999-2013. The data collected by authors were analysed according to: age, sex, symptoms, dose of DXM, a reason and a place of using the drug. A review of 124 "trip reports" showed that the majority of their writers are male (M 90.3%, F 9.7%). Young people, aged 16-20 (80.4%), dominated among the study population. The most common place of using DXM was a flat of a drug user (70.2%), and the reason of using a willingness to experiment with new psychoactive substances (41.9%) as well as the desire of "get high" (25.8%). The majority of users used DXM at least once again in their lives (56.5%). A single dose of the ingested drug ranged from 120 mg to 1575 mg (mean 539.25 mg). Most often received doses were 450 mg (30.4%), 300 mg (12%), 900 mg (11.2%). DXM was positively assessed by the internauts as a recreational psychoactive substance (84.7%). The most common clinical symptoms described by internauts were: difficulties with walking (74.2%), visual illusions (73.4%), altered sense of time (41.9%), feeling of exteriorisation (35.5%), euphoria (33.1%), nausea and vomiting (32.3%), auditory illusions (30.6%) and pruritus (29.8%). CONCLUSIONS: 1. DXM is the popular psychoactive substance which has gained a positive opinion among the Internet users. 2. Easy accessibility of DXM may pose a serious threat to health of young people who experiment with psychoactive substances. 3. The improvement of DXM sales control should be considered. PMID- 24466687 TI - [Children and adolescents toxic exposure in 2010-2012--data of Poison Information Centre and Laboratory of Analytical Toxicology and Drug Monitoring Jagiellonian University Medical College]. AB - A telephone inquires to Poison Information Centre and data from toxicological laboratory of Jagiellonian University Medical College related to cases below 19 years of age in 2010 -2012 were analyzed. 37.3% of 3692 information given were related to children and adolescent toxic exposure. Most telephone inquires concerned youngest children (below 6 years); toxicological analysis were ordered in the oldest group (13-19 years) mostly. PMID- 24466688 TI - [Acute poisonings in children in the years 2010-2012--single-centre study in Poznan]. AB - Poisoning is a clinical syndrome caused by the poison, which entered into the body. Poison is every substance that taken in the specified amounts may cause adverse effects. OBJECTIVE: Statistical analysis of acute poisoning in children in the years 2010-2012. MATERIAL AND METHODS: The study group consisted of 308 children who went to the Admissions Room of the Specialized Health Care Mother and Child in Poznan because acute poisoning suspicion or diagnosis, in the period from 1 January 2010 to 31 December 2012. RESULTS: In the group of 308 children, girls accounted for 57.14% and 42.86% boys. Children age ranged from 5 day old to 215 months of age (average 122 +/- 74). Toxic substances, which children have been exposed were drugs in 144 patients, ethyl alcohol in 75 children, carbon monoxide - 55 injured and chemicals in 34. The most commonly acute poisoning occurred in October (11.69%), December (11.04%) and September (10.71%). Of the 308 admitted children, 278 (90.26%) were hospitalized, including 11 patients (3.57%) in the Intensive Care Unit (ICU). In study population poisonings with drugs were dominated and related to 63.89% of girls and 36.11% of boys, aged from 2 to 213 months of age (average 120 +/- 75). In 50.69% of children intentional poisoning was diagnosed, in 18 patients (12.5%) mixture of different drugs was ingested, in five of them together ethyl alcohol. At 4.86% of the children reported a suicide attempt. This group accounted for girls with an average age of 178 +/- 8 months. Ethyl alcohol poisoning related to 56% of girls and 44% of boys between the ages of 152 to 215 months, giving an average age of 184 +/- 17 months. At 5.33% of the patients reported alcohol consumption along with medication, and 2.66% in addition took psychoactive substances. Because carbon monoxide poisoning aid granted to 50.91% girls and 49.09% boys between the ages of five day old to 209 months of age (mean 96 +/- 64). Poisoning with household chemicals related to 58.82% of boys and 41.18% of girls (mean age 32 +/- 36 months). Detergents were the most frequent ingested chemicals in 50% of children with an average age of 3 years. CONCLUSIONS: Acute poisoning with the exception of household products ingestion were more common in girls than in boys. The most common cause of poisoning in children were drugs overdose and ethanol ingestion. Cases of suicidal poisoning target group included only female sex. Accidental poisoning were observed mainly in young children and usually caused by chemicals. PMID- 24466689 TI - [Therapeutic misuses as a reason of telephone inquiries to Poison Information Centre of the Jagiellonian University Medical College in 2012]. AB - The aim of the study was the analysis of exposure due to therapeutic mi. suse registered in Poison Information Centre in 2012. Of all 3084 telephone inquiries 87 were related to therapeutic misuse. The equal gender proportion were noted. More than 50% of calls registered were taken from a lay public. A most common therapeutic misuse was administration of medicine dose higher than recommended, to children of 1-6 y interval and younger, mostly by parents. PMID- 24466690 TI - [Osteopontin level in the serum of patients with alcoholic liver disease, treated for alcohol withdrawal syndrome--a preliminary report]. AB - Alcoholic liver disease (ALD) is consequence of alcohol addiction, that increase morbidity and mortality of those group of patients. Induction of the inflammatory process in alcohol injured liver is a turning point in ALD, can cause acute liver damage symptoms or cirrhosis with increase of hepatic fibrosis intensity and portal hypertension. Osteopontin (OPN)--a protein associated with early inflammatory process and remodeling of damaged tissues with intensification of hepatic fibrogenesis process, is considered to be a biomarker of hepatic inflammation and fibrosis. A group of 12 patients with mean age--44 years, mean alcohol addiction time--16 years, hospitalized because of alcohol withdrawal symptoms were examined in the preliminary report. ALD was diagnosed in all patients, steatosis--in 4, inflammatory--in 3, cirrhosis--in 5. Control group were 19 healthy patients with no alcohol addiction and liver disease in medical history. Serum OPN level was measured by ELISA method using reagents from Raybiotech. Serum OPN level in control group ranged 0-35,955 pg/ml, in examined group ranged 0-338,280 pg/ml. OPN levels in serum of patients with hepatic steatosis were under limit of detection (< 50 pg/ml). OPN serum level increase was correlated to ALD progression. The highest OPN levels (> 100,000 pg/ml) were observed in patients with symptoms of the liver decompensation due to severe hepatitis and advanced cirrhosis. PMID- 24466692 TI - [Recent life events preceding suicide attempt by drug overdose]. AB - Recent stressful life events (ASLE) are considered to be one of the factors precipitating suicidal behavior. They precede a suicide attempt in most cases and according to research occur more often during the month or week before the suicide attempt. Interpersonal events are most common. The article presents an analysis of ASLE timing and incidence of events from specific categories during the month preceding suicide attempt by drug overdose. 124 patients admitted to the hospital because of suicidal intoxication were included in the study. Data regarding ASLE were collected with the use of a structured interview. Majority of patients attempting suicide by drug overdose experience a stressful event during the month prior to the suicide attempt. Nearly 4 out of 10 study subjects experience a stressful event on the day of the attempt or on the preceding day. Most common events that occur during the month prior to the attempt and immediately before the attempt are interpersonal events and most of them are related to relationships with spouses or partners. PMID- 24466691 TI - [Alcohol use and health-risk behaviours among academic students in Podkarpackie]. AB - Alcohol over-use is one of the risk behaviour and has harmful effects on health. In the whole European Region ever forth death among 15-29 years old people is caused by alcohol over. use. The aim of the paper is to present the degree of alcohol consumption propagation among academic stu. dents in Podkarpackie, as well as estimate the occurrence of hazardous drinking. Anonymous questionnaire survey was conducted among academic students in 2010. Chi-square test was used for statistical analysis. There is statistical difference regarding alcohol use between women and men. Men report to drink more and more frequent. Regular alcohol use was declared by 11.9% of men and 2.3% of women. Hazardous drinking was reported by 20.7% students. Age does not statistically differ the occurrence of hazardous drinking. However, it is interesting that although among the group of 19 years old, every seventh student reports hazardous drinking, among the other groups it was reported by every fifth student. More students from urban areas (24%), than from rural areas (18%) report hazardous drinking. Students living in dormitory almost twice more frequent are at the risk of hazardous drinking (29%), than those living with parents (17%). Among female students hazardous drinking was reported by the following faculties: touristic and recreation (24%), law(13%), medical (14%) and mathematic-environmental (15%). Among men students hazardous drinking was highly reported by law and administration faculty students (33%). Among hazardous drinking students as many as 45% regularly smoke cigarettes. PMID- 24466693 TI - [The analysis of early stressful life events and parental relationships among patients after suicide attempts]. AB - A lot of data in literature shows the importance of early stressful life events for the later existence and possible difficulties including suicide behaviours in adult life. The aim of the study was to identify the intensity of traumatic events in childhood and adolescence and distinguish the most significant categories of those events. Remarkable is the fact that the patients who experienced in the childhood situations of emotional abuse focused on the negative attitude of the environment (79%) and physical violence (78%) represented the largest proportion of subjects. Specific difficulties during childhood and adolescence among patients after suicide attempts were proven. Patients after suicide attempts in a large extent early experienced situations connected with emotional distance, negative feedback from the environment, manifestations of rejection and humiliation and misunderstanding. Males more than females declared experiencing situations classified as physical violence, low economic status of the family, interpersonal loss and general trauma. Comparatively often both groups pointed at perilous parents' acts. Females more often pointed at events concerning sexual domain. Very strong emotions assisted stressful life events, particularly significant among females and characterized by anxiety and helplessness. Patients after suicide attempts most often described their fathers as over controlling, demanding and intrusive with the deficiency of care and protectiveness. This pattern was equally distinct in the group of females and males. PMID- 24466694 TI - [Pregnant women and strategies of coping with stress and attachment styles]. AB - In the year 2013 a study of the assessment strategies of coping with stress and attachment styles among pregnant women which were married or in relationship were done. There were 57 females participated in the study, including 30 pregnant women. Mini-COPE Coping Inventory) was used for the diagnosis of strategies to cope with stress, and QAS (Questionnaire of Attachment Styles) was used to assessment attachment styles. CONCLUSIONS: Pregnant women which are married or in relationship more often use adaptability of coping strategies under stress. Pregnant women which are married or in relationship reveal more often secure attachment. Female, which show safe attachment use in stressful situation strategies such as active coping, planning, sense of humor, seeking the emotional and instrumental support. PMID- 24466695 TI - [How pupils of a secondary school cope with difficult situations?]. AB - In the year 2013 a study of the assessment of dispositional and situational coping in difficult situations, among pupils of a secondary school, was done. 176 respondents of a secondary school, form the first and third class, were involved into a study. The analysis was based on the anonymous scale "How do you cope?". CONCLUSIONS: Girls more often than boys cope with stress by focusing on emotions. With increasing the age from 13 to 16 years-old the strategy of active coping and seeking social support were dominant. Among students aged 17 there were significantly reduced rank of concentration on emotions. Pupils who achieved a higher grade point more often used an active coping with the stress. For the assessment of situational coping the result indicates that the severity of the strategy of concentration on emotions is higher among girls than boys. PMID- 24466696 TI - [The perception of social support by students of the 2nd year nursing faculty of the Medical University of Gdansk]. AB - In the year 2012, a study of the assessment of social support after traumatic and/or stressful life events among 85 students of nursing faculty of Medical University of Gdansk was done. The Berlin Social Support Scale was used. Nursing students after traumatic and/or stressful life events often look for the help of other people than students who had not suffered those experiences. Respondents who had partners often feel the need to use support from them after traumatic and/or stressful life events. For respondents who were in close relationship important was not only to receive support from partners, but also to give support to others. PMID- 24466697 TI - [Electronic poison information management system]. AB - We describe deployment of electronic toxicological information database in poison control center of Pomeranian Center of Toxicology. System was based on Google Apps technology, by Google Inc., using electronic, web-based forms and data tables. During first 6 months from system deployment, we used it to archive 1471 poisoning cases, prepare monthly poisoning reports and facilitate statistical analysis of data. Electronic database usage made Poison Center work much easier. PMID- 24466698 TI - [Consciousness disturbances during poisonings: pathophysiology, clinical picture, and basic principles of diagnosis and management]. AB - Consciousness is the physiological state of the central nervous system, during which an individual maintain arousal (level of consciousness, vigilance) and realize the internal thoughts as well as the external stimuli (awareness, consciousness content). The toxicity of multiple xenobiotics may lead to impairment of both consciousness categories, presenting clinically as consciousness disturbances, quantitative and qualitative, respectively. Based on the behavioral criteria, different consciousness disorders are diagnosed, among others: brain death, coma, vegetative state, minimally conscious state, akinetic mutism. In the present paper, pathophysiology, clinical picture, as well as basic diagnostic and therapeutic principles of conscious disturbances are described, especially in poisoned patients. PMID- 24466699 TI - [Brain death and transplantological issues in patients deceased due to poisonings]. AB - The classical definition of human death, based on the statement of the definitive cessation of blood circulation, is still in use except the cases, where the death took the brain, but the blood circulation remained active for some time. In these cases, a "new definition of death" based on the statement of brain death, should be used. The diagnosis of brain death is made by performing of clinical tests and ancillary investigations in order to confirm patient's irreversible coma, lack of brainstem reflexes, lack of motor activity and apnea. Brain death results from the massive damage of brain tissue caused by various pathological processes including the direct and indirect effects of xenobiotics poisoning. Patients who deceased due to poisoning can be donors of tissues and organs for transplantation. PMID- 24466700 TI - [Toxicant-induced and drug-induced coma neurotoxicological issues of general anesthesia]. AB - Coma is a pathological condition of unconsciousness in which the patient cannot be awaken by any stimuli (lack of arousal), whose eyes are closed and who has no awareness of self or environment (lack of content of consciousness). Toxic coma is usually transient and disappears after elimination of xenobiotic, and possibly its active metabolites, from the body. Authors present the etiological factors, clinical features and principles of diagnosis and management of toxic coma. Additionally, mechanisms of altered consciousness induced iatrogenically by general anesthetics as well as a brief description of their toxicity are presented. PMID- 24466701 TI - [Consciousness disorders: vegetative state and minimally conscious state]. AB - Brain injury due to hypoxia, trauma, stroke, poisoning, and other pathological conditions may result in chronic disorders of consciousness in the form of vegetative state (VS) or minimally conscious state (MCS). VS is a condition defining patients who have awaken from coma, open eyes spontaneously or on command, but still are not aware of themselves or their environment, showing only a reflex motor responses. MCS is a condition in which patients are not able to communicate consistently, but they are not already in the VS, because of evident signs of awareness of themselves and the environment. The paper discusses the diagnostic criteria, etiology as well as diagnostic procedures and treatment of VS and MCS PMID- 24466702 TI - [Xenobiotic-induced seizures and epileptic states as a cause of consciousness disturbances]. AB - Poisoning with many xenobiotics may result in seizures, which are usually generalized. Seizures leading to unexplained disturbances of consciousness are usually generalized tonic-clonic, absence seizures and complex partial seizures Prolonged seizures without recovery of consciousness during interictal period are called status epilepticus. This paper presents the etiology, patomechanism, clinical characteristics, as well as diagnostic and therapeutic principles of toxic seizures. Additionally, the clinical description of nonepileptic psychogenic seizures is given, which often need to be differentiated with true seizures. PMID- 24466703 TI - [Rare consciousness disturbances in toxicological practice: akinetic mutism, somnambulism, locked-in syndrome, and psychogenic coma]. AB - The toxicity of xenobiotics can result inrare disorders of consciousness, such as akinetic mutism and somnambulism as well as syndromes mimicking consciousness disturbances, such as locked-in syndrome and psychogenic coma. Akinetic mutism is a condition characterized by a lack of spontaneous movements and little or no vocalization. Somnambulism include performing of complex motor activity in an automatic manner during deep sleep, without any awareness of its execution. The locked-in syndrome is a state with quadriplegia coexisting with cranial nerves palsies and mutism, but with fully preserved consciousness. Psychogenic coma is a condition in which the patient has preserved level of consciousness and awareness, but does not communicate with theenvironment and does not exhibit the external manifestations of consciousness. This paper presents the etiology, clinical characteristics, as well as diagnostic and therapeutic issues for the above syndromes. PMID- 24466704 TI - [Encephalopathy caused by intravenous potassium permanganate used for illegal production of methcathinone (ephedrone) from medicines containing pseudoephedrine]. AB - Encephalopathy caused by manganese compounds used for illicit production of ephedrone (methcathinone) is described. The onset of disease could be observed after some months of regular intravenous use of ephedrone contaminated with manganese. In clinical picture dominate neurological signs and symptoms, mainly extrapyramidal syndromes: parkinsonism, tremor, muscle distonia, pro- and retropulsion. Some other symptoms may be observed: hypophonia or dysarthria, gain disturbances, impairment of precise movement, and micrographia. In cranial NMR often appears bilaterally an increase of an intensity of T1 signal in globus pallidus and in some other brain structures. Elimination of manganese with the use of chelating therapy as well as symptomatic treatment, mainly with the antyparkinsonic drugs, seems to be ineffective. PMID- 24466705 TI - [Transient and permanent damage to the heart in the course of acute poisoning]. AB - Transient and permanent myocardial damage is a vital element of toxicological practice. This applies both to poisonings in which heart injury is typical and to those in which it is only a rare complication. Vital signs of poisoned patients, especially unconscious ones, must be carefully monitored, because the consequences of late diagnosis or improper treatment can be potentially fatal. The following paper discusses the mechanisms leading to heart damage in the course of acute poisoning. It also presents clinical symptoms, treatment options and prognosis for myocardial injury in selected poisonings. PMID- 24466706 TI - [Heart injury secondary to carbon monoxide poisoning--the use of imaging techniques]. AB - The heart muscle is particularly sensitive to the toxic effects of carbon monoxide. Cardiovascular complications are present in 30-40% poisoned patients. Currently, multiple ECG records and at least two-time determination of cardiac markers' concentration (mainly troponin I) are known as the gold standard practice in the diagnosis of cardiac injury especially with regard to medium and severe poisoning. So far there have not been any recommendations for further diagnostic steps in case of abnormalities in these examinations. This paper presents a review of cardiac imaging techniques as well as the analysis of their usefulness in carbon monoxide poisoning. According to the authors echocardiography is considered to be an extremely important examination which, thanks to its accessibility and non-invasive nature, should be performed on all patients with myocardium injury suspicion made on the basis of clinical image, ECG records and biochemical markers. PMID- 24466707 TI - [Nanopaticles cardiotoxity--review of the literature]. AB - Nanoparticles are structures with at least one demension smaller than 100 nm. The rapid development of nanotechnology means that each day comes new nanostructures and also new opportunities for their use. However it should be remembered, that nanotechnology is not only benefits and progress, but the risk of side effects. Due to the unique properties of nanoparticles linked to their size and also large active surface, the nanoparticles interact virtually the entire human body, causing a variety of adverse effects also at the cellular level. The paper presents the general characteristics of the nanoparticles, their use, route of exposure and reports of their cardiotoxicity. PMID- 24466708 TI - [Management of chemical burns and inhalation poisonings in acute medical care procedures of the State Fire Service]. AB - Emergency Medical Services (EMS) were founded by the government to perform tasks aimed at providing people with help in life-threatening conditions. The system comprises two constituent parts. The first one is public administrative bodies which are to organise, plan, coordinate and supervise the completion of the tasks. The other constituent is EMS units which keep people, resources and units in readiness. Supportive services, which include: the State Fire Service (SFS) and the National Firefighting and Rescue System (NFRS), are of great importance for EMS because they are eligible for providing acute medical care (professional first aid). Acute medical care covers actions performed by rescue workers to help people in life-threatening conditions. Rescue workers provide acute medical care in situations when EMS are not present on the spot and the injured party can be accessed only with the use of professional equipment by trained workers of NFRS. Whenever necessary, workers of supportive services can assist paramedics' actions. Cooperation of all units of EMS and NFRS is very important for rescue operations in the integrated rescue system. Time is a key aspect in delivering first aid to a person in life-threatening conditions. Fast and efficient first aid given by the accident's witness, as well as acute medical care performed by a rescue worker can prevent death and minimise negative effects of an injury or intoxication. It is essential that people delivering first aid and acute medical care should act according to acknowledged and standardised procedures because only in this way can the process of decision making be sped up and consequently, the number of possible complications following accidents decreased. The present paper presents an analysis of legal regulations concerning the management of chemical burn and inhalant intoxication in acute medical care procedures of the State Fire Service. It was observed that the procedures for rescue workers entitled to provide acute medical care should be correlated with the procedures for emergency medical teams. PMID- 24466709 TI - [On a border of toxicology and medical physics--atypical radiation accidents]. AB - The paper reviews less known radiation accidents in the history, from deadly ones to those with short-term effects. Many of them were diagnosed with notable delay, particularly ones linked to lack of knowledge or criminal actions. In physician's life, the probability to examine the victim of radiation accident is extremely low, but still exists. Therefore an adequate amount of knowledge of radiation consequences should be provided in a training curricula of medical studies and medical specialization programmes, particularly those of internal medicine and clinical toxicology, also in ones of environmental protection, environmental health and medical physics. PMID- 24466710 TI - [The most popular poisons from Graeco-Roman world]. AB - Article presents the most popular antique poisons. Information from encyclopaedic literature and literary texts of the Roman Empire period has been compared with the etymology of the names of some poisons of plant and animal origin. PMID- 24466711 TI - [Cosmetics as source of xenoestrogens exposure]. AB - The estrogens play important role in the health and disease, therefore environmental contaminants interacting with estrogen receptors and exert similar effects may disrupt functions of endocrine system. Xenoestrogens are present as contaminants virtually everywhere: in water, soil, food and air, exposure to xenoestrogens occurs through household products, however also very often occupational exposures take place. Xenoestrogens exposure may cause problems with fertility; they are also known factors playing a role in estrogen dependent cancer development. Exposure to xenoestrogens is particularly dangerous during 'critical periods' of life, such as intrauterine, or puberty periods. One of the important source of xenoestrogen exposure are cosmetics. In the paper the main groups of xenoestrogenic compounds present in cosmetics such as phatalates, parabens and aluminium are described. PMID- 24466712 TI - [Quod medicina aliis, aliis est acre venenum**--venoms as a source of anticancer agents]. AB - Natural product derived from plants and animals were used in folk medicine for centuries. The venoms produced by animals for hunting of self-defence are rich in bioactive compounds with broad spectrum of biological activity. The papers presents the most promising compounds isolated from venoms of snakes, scorpions and toads. For these compounds both: mechanism of anticancer activity as well as possibilities of clinical use are presented. PMID- 24466713 TI - Fatal suicidal poisoning with antituberculosis agents with ST elevation and acute coronary syndrome symptoms--a case report. AB - A 19-years old, previously healthy male, ingested the higher amount of rifampicin, isoniazyd, pyrazinamide, ketoprofene and alcohol. Within less than 20 hours he developed dyspnoe, pruritus, red man syndrome, and ECG changes suggesting acute coronary syndrome appeared - ST interval elevation. In the next few hours chest pain appeared and troponin I concentration was elevated (13.54 ng/ml). The performed echocardiography revealed global hypokinesis with the decreased left ventricular ejection fraction (approx. 30%). There was no significant pathological changes in coronarography, except for slowed blood flow. Further patient developed cardiogenic shock, pulmonary oedema and died within 32 hours from medication overdose. PMID- 24466714 TI - [Metformin poisoning--clinical features, diagnostics and treatment--case presentations]. AB - Metformin has been used for many years as oral anti-hyperglycaemic agent in the treatment of type 2 diabetes mellitus either in Poland or in the world. Metformin is the most commonly prescribed agent, but acute poisonings of this agent are rare. A review of our experience indicates, that poisoning with this agent may lead to life-threatening or fatal metformin toxicity. The authors of this publication postulate, that each patient with metformin exposure should be hospitalized. Physician must be vigilant to recognize anti-hyperglycaemic agent poisonings like biguanides when hypoglycaemia and acidosis are present in laboratory results. We present patients with metformin toxicity, some of them with fatal course. PMID- 24466715 TI - [MR imaging late changes of brain after carbon monoxide poisoning--case report]. AB - We present the case of 28 years old patient hospitalized at the Regional Center of Clinical Toxicology in Lublin after carbon monoxide poisoning. The level of carboxyhemoglobin was 33.3%. Because of neurological symptoms MR of brain was performed with normal result. During hospitalization the progression of clinical symptoms was observed and the patient underwent control MR of brain. The result was abnormal and show changes bilaterally in white matter. PMID- 24466716 TI - [Acute poisoning with sertindole--a case report]. AB - The paper presents a case of acute, accidental sertindole poisoning. Intoxication had a stormy clinical course with symptoms of cardiovascular, respiratory and nervous system. A relatively small dose of ingested preparation and severe overdose course may indicate a low therapeutic drug index. PMID- 24466717 TI - [Acute methoxetamine intoxication--a case report with serum and urine concentrations]. AB - Methoxetamine (MXE) is a novel synthetic drug, structurally related to phencyclidine, with ketamine-like properties. Available in Poland since 2010, with no legal control, is adverti. sed as the "ideal dissociation drug". The aim of this study was to present a case of nasal methoxetamine acute poisoning in a 28-year-old man, the course of treatment, and the method of identification of this substance in serum and urine. In the course of this intoxication extreme agitation and aggression with slight response to benzodiazepines were observed. The patient was confused, hallucinated. In addition, the physical examination re. vealed tachycardia 120/min and normal blood pressure (130/80 mm Hg). The period of acute poisoning was covered by amnesia. The MXE concentrations in serum and urine were determined using liquid chromatography-mass spectrometry (LC-MS-MS) method, and were respectively 270 ng/ml and 660 ng/ml. Confirmed MXE poisoning increases our knowledge about this new substance, providing relevant clinical and analytical data. PMID- 24466718 TI - [Acute poisonings and organ donation--case reports and literature review]. AB - Poland is one of the European countries where serious problem of shortage of organ donors is observed. Organ donation from victims following fatal acute intoxications is extremely rare, and there's only several such case reports published in Poland. There's a need to establish guidelines of instrumental confirmatory tests of brain death determination according to acute poisonings. Authors present two cases of poisoned donors following acute poisonings with drugs. Current opinions concerning poisoned patients as a potential organ donors are also described. Case 1: A 36-years old male poisoned intentionally with insulin was admitted to Toxicology Department in Poznan. Patient was unconscious (GCS:3), hypoglycemic (glycaemia: 0). In 3rd day of treatment brain death was determined using clinical tests and instrumental confirmatory test (transcranial Doppler ultrasonography). Both kidneys were procured for transplantation. Case 2: A 23-years old male after prehospital sudden cardiac arrest in the course of suicidal carbamazepine intoxication was admitted to Toxicology Department. During whole hospitalization patient was unconscious, unresponsive to the pain (GCS:3), with circulatory and respiratory insufficiency. Despite intense treatment and decrease of carbamazepine level to therapeutic values there were no signs of patient recovery on the 9th day of treatment. After brain death determination patient was qualified as a kidneys and liver donor. Each patient diagnosed of brain death in the course of acute intoxication should be considered as a potential organ donor. Brain death determination in poisoned patients requires consultation by clinical toxicologist to exclude influence of neurotoxic xenobiotics on the central nervous system. Standards of instrumental confirmatory tests in victims following fatal poisonings should be established. Introduction of guidelines concerning donors intensive care procedures that allows successful organ procurement. All organ donations and transplantations from poisoned donors should be registered in national and/or international databases to provide an exchange of experiences and improve understanding of such cases. PMID- 24466719 TI - [Corneal donation from a victim of methanol poisoning--case report]. AB - Cases were corneas have been collected from poisoned patients are extremely rare. Globally, no more than a dozen or so such instances have been reported, with the decided majority concerning cyanide poisonings. The present study outlines a case of severe methanol poisoning, the course of which resulted in the brain death, and the female patient was duly qualified as a potential donor of corneas and kidneys. Due to the suspicion of a neoplastic process in the abdominal cavity, collection of the kidneys was desisted from. According to the knowledge of the authors of the work, this is the first case of transplantation of corneas collected from a person poisoned with methanol in Poland. PMID- 24466720 TI - [Acute-onset thrombocytopenia following single inhalation xylene exposure--a case report]. AB - Bone marrow damage is a well known consequence of chronic exposure to benzene and its homologues, which include xylene. Anemia dominates in the clinical picture and isolated thrombocytopenia is a rare symptom. We have not found reports of isolated thrombocytopenia in the course of acute xylene poisoning. A 56-years old man with thrombocytopenia, was admitted, after two days of work with concrete floor paint containing up to 17% xylene. The thrombocytes' nadir (29 x 10(9)/L) occurred on the fourth day from the exposure. After treatment with dexamethasone the platelet count normalized. There were no signs of hemorrhagic diathesis. Clinicians should be aware of the possibility of thrombocytopenia in patients acutely exposed to xylene. PMID- 24466721 TI - [Rhabdomyolysis as an unspecyfic symptom of mushroom poisoning--a case report]. AB - Since 2001 a number of cases of mushroom poisoning with concomitant rhabdomyolysis have been described. Among the edible mushrooms growing in Europe, these reports concerned only Tricholoma equestre. The results of animal studies suggest that rhabdomyolysis could be a consequence of consumption of other edible fungi, and its occurrence depends on the amount of ingested mushrooms and individual sensitivity. To the best of our knowledge, this is the first report of rhabdomyolysis associated with the consumption of edible mushrooms from Leccinum and Boletus species. A 57-years old man was admitted to the hospital due to severe pain and weakness of thigh muscles with a high serum creatine kinase activity -3811 U/L. Within two days before hospitalization he consumed repeatedly large quantities of stewed Leccinum and Boletus mushrooms. Clinical signs of toxicity and biochemical changes subsided after several days of hospitalization. Rhabdomyolysis after ingestion of a large amount of mushrooms can be an unspecific symptom, unrelated to fungi species. PMID- 24466722 TI - [Accidental poisoning with peach seeds used as anticancer therapy--report of two cases]. AB - We described two cases of poisoning with amygdalin. Clinical signs presented by two females were mild and lasted up to 5 hours. CONCLUSIONS: The usage of amygdalin may be connected with serious side effects. The cyanide and prussic acid which are deliberated in digestive system are responsible for toxicity in such cases. The rarity of poisoning with amygdalin as well as high cost of analysis are responsible for the reason that most labs are not prepare for such procedure. PMID- 24466723 TI - [Hepatoxic effect of a noni juice consumption--a case report]. AB - Noni juice of an Indian mulberry fruit has recently become a very popular remedy for several diseases. The paper presents the case of hepatotoxic action of Noni juice in a previously healthy 55-years old female patient. After symptomatic therapy and cessation of exposure to the juice all symptoms dissapeared. CONCLUSIONS: 1. Indian mulberry formulations may, in some cases, lead to liver toxicity. 2. Treatment consists of cessation of exposure to preparations containing Indian mulberry fruits and a symptomatic therapy. 3 There is an urgent need to examine the therapeutic and toxic effects of commonly used herbal specifics. PMID- 24466724 TI - [Acute intoxication with nutmeg used as a recreational purpose--a case report]. AB - We present a case of acute nutmeg poisoning used for recreational purposes. Poisoning had a stormy clinical course with symptoms of gastrointestinal, cardiovascular and nervous system. The widespread availability of nutmeg suggests that real number of these poisonings may be underestimated in our country. PMID- 24466725 TI - [Intoxication or false-positive acetaminophen result of toxicological determinations? Two case reports]. AB - The aim of this study was to show the diagnostic procedure used in the two cases with false-positive serum acetaminophen results in suspected acetaminophen poisoning. The determination of serum acetaminophen were carried out using a UV/VIS spectrophotometer (Specord 40 Analytik Jena), coupled with an analytic computer station WinASPECT. The employed method of determination was based on the acetaminophen reaction with sodium nitrite, which yields yellow colour of solution in the presence of sodium hydrate. The intensity of the yellow colour depends on the concentration of acetaminophen in serum. The relationship between absorbance and concentration was linear at concentrations in the range 50-600 microg/mL, with relative standard deviation of +/- 2.1% and detection limit of 30 microg/mL. To confirm or reject the doubtful results of colorimetric assays, the serums of patients were measured with high performance liquid chromatography with mass spectrometry detection and gas chromatography with mass spectrometry detection. The analysis of presented cases leads to a conclusion that acetaminophen results should be confirmed either by scanning urine for p aminophenol presence (which is a routine procedure in our laboratory) or by using a different method of measuring acetaminophen serum levels. PMID- 24466726 TI - [The treatment of septic shock with continuous venovenous hemodialysis using high cut-off dialyzer in patient after immediate circulatory arrest]. AB - The decreased immunity which occurs frequently in severely intoxicated patients may led to sepsis. The sepsis may be caused by bacterial toxins in unconscious patients with toxic coma which generate decreased immunity. Apart from the wide spectrum antibiotic therapy, crystalloids, colloids, vasopressin and corticosteroids, the renal replacement therapy may be useful in treatment of sepsis due to its complexes pathophysiology. Taking into account the role of cytokines in sepsis pathomechanism, the trials of treatment using high cut-off (HCO) membranes were performed in the recent years. These membranes remove molecules with mass up to 60 kDa, including cytokines typical for severe sepsis. The usefulness of continuous veno-venous hemodialysis--CVVHD with HCO dialyzer in the treatment of patient in septic shock and multiorgan damage--including damage caused by cardiac arrest was presented in the study. The concentration of IL-1P, IL-2, IL-4, IL-6, IL-10, IL-12, INF-alpha, INF-gamma, TGF-alpha in blood were determined before and after the 24-hours procedure. After the procedure the most evident decrease was observed for IL-4, 6, 10, 12 (17.3%, 31.8%, 83.4% i 22.3% respectively). During the following days the general status of patient improved gradually. The patient was discharged from the hospital after 20 days of hospitalization. His general condition was good, the values of inflammatory parameters were normal and the renal function was correct. There are very few studies describing HCO membranes effectiveness and they were performed on limited populations of patients. The presented case study may contribute to the discussion on the usefulness of dialysis with HCO membranes in the treatment of severely intoxicated patients complicated by serious sepsis resistant to standard antibiotic therapy. PMID- 24466727 TI - [Professor of pharmaceutical subjects, Jerzy Orlowski (1940-2010)--in memoriam]. PMID- 24466728 TI - [Genetic mechanisms of the Bacillus adaptation]. PMID- 24466729 TI - [The detection of Azospirillum thiophilum ability for lithotrophy during oxidation of reduced sulfur compounds]. PMID- 24466730 TI - [Glucose usage and carbon isotopes fractionation by microorganism cells, immobilized on solid phase surface ]. PMID- 24466731 TI - [Kluyveromyces lactis mycocin is active at neutral pH]. PMID- 24466732 TI - [One method for isolation of the DNA-containing shells from vegetative and resting bacterial cells for their efficient detection by PCR]. PMID- 24466733 TI - [Bacterial endophytes from Sphagnum mosses as a promising objects for agricultural microbiology]. PMID- 24466735 TI - [The study of phase-structural condition of the phospholipid fractions in Actinobacteria based on the storage terms]. PMID- 24466734 TI - [Interaction of anoxygenic phototrophic Rhodopseudomonas sp. with kaolinite ]. PMID- 24466736 TI - [ Biodiversity of magnetotactic bacteria from river Ol'khovka]. PMID- 24466737 TI - [Microbial diversity in the late Pleistocene permafrost samples in Siberia]. PMID- 24466738 TI - [The ability of rhizobacteria Azospirillum brasilense to the selenium (IV) reduction to selenium(0)]. PMID- 24466739 TI - [The discovery of phages in the bacterial population in lake Untersee (Antarctica)]. PMID- 24466740 TI - [The detection of microcystin-producing cyanobacteria in the Upper Volga watersheds]. PMID- 24466741 TI - [Thermophilic bacteria from genus Geobacillus from the permafrost volcanic sediments]. PMID- 24466742 TI - [Phylogenetic position and phosphate solubilizing activity of the lactic acid bacteria associated with different plants]. PMID- 24466743 TI - [Non-coding RNAs and diseases]. AB - With the completion of large scale genomic sequencing, a great number of non conding RNAs (ncRNAs) have been discovered and capture the attention of the biological sciences community. All known ncRNAs may be divided into two groups, namely: i) small ncRNAs, which comprise microRNAs (miRNAs), PIWI-interacting RNAs (piRNAs) and short interfering RNAs (siRNAs), and ii) several thousands of long ncRNAs (IncRNAs). NcRNAs were shown to be involved in eukaryotic growth and development, cell proliferation and differentiation, apoptosis, epigenetic modifications, and also the complex control and pathogenesis of various diseases. In this paper, knowledge on the ncRNAs, which functioning is associated with human diseases, has been summarized. PMID- 24466744 TI - [Possibilities and effects of telomerase activation]. AB - In this review we briefly describe recent knowledge of telomerase (predominately human telomerase) activity regulation mechanisms. We also point telomerase complex components localization in cells and discuss the enzyme activities that are independent of telomere elongation. The paper includes the overview of human diseases correlating with reduced telomerase activity, short telomeres and rapid telomeres shortening. We describe in details the possibilities of exogenous hTERTgene transcription activation by different natural and synthetic compounds as well as hTERTgene transfection effects. Such exogenous activation cause increasing proliferative potential of the cells and might be used in cell therapy. It must be noticed that elevated hTERT gene expression, especially in the case of hTERTgene transfection, might be the cause of cell malignesation. In this regard strict constraining criteria in medical application of different methods of telomerase activation must be developed. PMID- 24466745 TI - [Biosyinthesis and mechanism of selenocysteine incorporation into synthesized proteins]. AB - Universal genetic code provides the ability to encode only twenty "canonical" amino acids, whereas the twenty first amino acid--selenocysteine (Sec), is encoded by one of three well-known stop codon (UGA). In terms of molecular biology, selenocysteine is of exceptional interest, the mechanism of its incorporation into synthesized polypeptide chains is very different from that of the other typical 20 amino acids. This process involves some cis- and trans active factors, such as the SECIS element (Selenocystein insertion sequence), a structure located in the 3'-untranslated region of eukaryotic mRNA, and in the open reading frame immediately after the UGA-selenocysteine codon in bacteria, which, in turn, leads to differences in the mechanism of selenocysteine incorporation in these domains of life. The trans-factors include Sec tRNA([Ser]Sec) that has a unique system of biosynthesis, Sec-specific elongation factor EFsec and SBP2--Sec binding protein. Thus, for realization of the selenocysteine incorporation process during translation a large number of additional molecules must be synthesized in the cell, this fact makes the selenocysteine containing proteins rather "expensive" and emphasizes their crucial role in metabolism. PMID- 24466746 TI - [Characterization of some thiol oxidoreductase family members]. AB - There are no doubt about the important role of free radicals and reactive oxygen species in the processes of cell activity. The disturbances of intracellular redox processes are often accompanied with the development of such common pathologies as diabetes, myocardial infarction, neurodegeneration, broncho pulmonary diseases, cancer, etc. To date, there are a large number of antioxidant enzymes related to different redox biology systems, the key role among them is played by enzymes belong to the thiol oxidoreductases superfamily, which consists of thioredoxin, glutaredoxin, peroxiredoxin, protein disulfidizomeraz, glutathione peroxidase families, and a number of other proteins. In addition to the antioxidant function, thiol oxidoreductases display the ability to recycle of hydroperoxide to form specific disulfide bonds within and between proteins that significantly extends the range of their functionality. Therefore, biochemical characterization and elucidation of functional mechanisms of the superfamily proteins is a highly actual problem of redox biology. PMID- 24466747 TI - [Establishment of a new method to detect gene expression by laser capture microdissection-assisted single-cell real time RT-PCR without RNA purification]. AB - Laser capture microdissection (LCM) combined with real time RT-PCR represents a powerful method for analyzing gene expression levels in selected cell types. To avoid degradation of RNA by endogenous and exogenous RNases and to ensure selection of target cells only, we designed a protocol in which the inactivation of exogenous and endogenous RNases by RNaseZap and RNA later is combined with immunofluorescent labeling, and labeled cells in sections used for subsequent LCM and real time RT-PCR. Immunolabelled neurons were captured onto the caps of RNase free microcentrifuge tubes using LCM and lysed with 3% NP-40 without prior RNA purification. Subsequent reverse transcription for cDNA synthesis was performed in situ on the cap surface to avoid mRNA loss due to transfer between tubes. Applying this protocol, we determined immunoglobulin G (IgG), nerve growth factor (NGF) and GAPDH mRNA levels into small numbers of captured neurons with real time RT-PCR. Thus, this novel method combining LCM with real time RT-PCR without RNA purification appears to be an effective tool for the analysis of cell-specific target gene transcription in small numbers of cells isolated from RNA later treated tissues. PMID- 24466748 TI - [Overexpression of the glutathione S-transferase gene from Pyrus pyrifolia fruit improves tolerance to abiotic stress in transgenic tobacco plants]. AB - Glutathione S-transferases (GSTs) are ubiquitous enzymes in animals and plants, and they are multifunctional proteins encoded by a large gene family. GSTs are involved in response to the oxidative stress including drought, salt, heavy metals, and so on. Under oxidative stress, the excessive reactive oxygen species (ROS) induce an increase in GST levels, and then the GSTs metabolize the toxic products of lipid peroxidation, damaged DNA and other molecules. Previously, a full-length cDNA of a novel zeta GST gene, PpGST, was characterized from fruit of Pyrus pyrifolia Nakai cv Huobali. In the present study, a constitutive plant expression vector of PpGSTwas constructed and transferred into tobacco (Nicotiana tabacum L. cv Xanthi) to verify the function of PpGST. As a result, the PpGSTgene was successfully integrated into the genome of the transgenic tobacco lines and expressed as expected in the transformants through Southern blotting and quantitative reverse transcription-polymerase chain reaction analysis. Growth of T1 generation plants of PpGST transgenic lines and WT under non-stressful conditions was similar, however, the transgenic tobacco lines showed relatively normal growth under drought, NaCl, and cadmium (Cd) stresses. Furthermore, the T1 transgenic tobacco lines showed significantly slower superoxide anion production rate than the WT under abiotic stress. Simultaneously, the MDA content of each T1 transgenic tobacco plant was only slightly increased and significantly lower than that of the WT under drought, salt and Cd stress. Together with the GST activity of the transgenic tobacco lines, which was significantly increased under stressful conditions, as compared with that in WT, overexpression of PpGSTin tobacco enhanced the tolerance of transgenic tobacco lines to oxidative damage caused by drought, NaCl, and Cd stresses. PMID- 24466749 TI - [Molecular-genetic analysis of DNA pol and TK of HSV-1 population using NGS technology]. AB - It was determined the ratio of viral DNA and DNA from Vero cells using the polymerase chain reaction in real time in Vero cell lysate, infected with L2 strain of the herpes simplex virus type 1. Copy number of the virus reached a maximum after 24 hours of incubation of infection. Total DNA was isolated and sequenced using NGS technology by Ion Torrent device. Nucleotide sequences of the thymidine kinase gene (UL23) and DNA polymerase (UL30) were determined for a population of HSV-1 strain L2. Comparison of the primary structure of these genes with the corresponding nucleotide sequences of known strains of HSV-1 KOS and 17 was conducted. Differences in the structure of genes UL23 and UL30 between strain L2 and reference strains KOS and 17 are not important, because changes are found in non-conservative regions. PMID- 24466750 TI - [The identification of Saccharomyces cerevisiae genes leading to synthetic lethality of prion [PSI+] with Sup45 mutations]. AB - Previously, we proposed a test system allowing to perform search for genes that influence the properties of the Sup35 and Sup45 protein. This test is based on the phenomenon of lethality of diploids that combine mutations in SUP45 gene with [PSI+] prion. Lethality of this combination depends on the type of sup45 mutation, and the properties of the prion. [PSI+] variant, which is a strong suppressor ([PSI+]s), showing synthetic lethality with all the nonsense mutations and some missense sup45 mutations in the heterozygote state. The presence of extra copies of a gene under test that affects the phenotypic manifestation of prion [PSI+] or translation termination factors properties, leads to the increase or decrease in diploid lethality. Gene library screening using this test system allowed us to establish the effect of ten fragments of genomic DNA of yeast on synthetic lethality. Deletion analysis of these regions has led to the identification of the HLJ1 and TEF2 genes, as affecting Sup35 protein prionization and/or the efficiency of translation termination. PMID- 24466751 TI - [Recovery from parkinsonism with N-acetylcysteine-differentiated neurons]. AB - The upregulation of dopaminergic neuronal differentiation is necessary for stem cell therapy in Parkinson's disease (PD). In this study, neuronal differentiation efficiency increased by more than 2 times in P19 embryonic stem cells (ESCs) induced by N-acetylcysteine (NAC) and retinoic acid (RA) as compared to RA alone, with suppressed glial differentiation. The majority of NAC-treated stem cells grafted into brains of PD mice differentiated into dopaminergic neurons and persisted well for 6 weeks. Parkinsonism was also greatly improved after grafting NAC-treated cells in comparison to cells treated with only RA. Our results strongly suggest that NAC treatment may be an effective strategy for generating stem cells fated to become dopaminergic neurons for PD clinical therapy. PMID- 24466752 TI - [Macrophage migration inhibitory factor in mud crab Scylla paramamosain: molecular cloning, expression profiles in various tissues and under Vibrio challenge]. AB - As one of the first found cytokines, macrophage migration inhibitory factor (MIF) plays AN important role in several physiological processes in crabs. In this study, a full-length MIF cDNA (GenBank accession number: JX131610) from mud crab Scylla paramamosain (Sp) was cloned based on a sequence of S. paramamosain cDNA library. The full length of SpMIF was 734 bp consisting of a 363 bp open reading frame encoding the SpMIF, a 120 amino acid peptide chain. The molecular weight of SpMIF was 13.46 kDa with the pI of 6.82. The alignment analysis showed that SpMIF appeared to be closely related to the counterpart from crab Eriocheir sinensis (68%). Quantitative real-time PCR analysis revealed that SpMIF was highly expressed in hepatopancreas and hemocytes. In addition, the expression level of SpMIF was increased significantly after a 6-h challenge by Vibrio parahaemolyticus (4.00 x 10(6) CFU/mL), peaked at 8 h, and then declined to the common level in 48 h. This data indicated that SpMIF was cloned successfully, and suggested that it participated in the immune system of mud crabs. PMID- 24466753 TI - [The new isoform of Oct-1 transcription factor is transcribed from alternative promoter]. AB - The Oct-1 transcription factor belongs to the family of highly conserved POU domain proteins that participate in regulation of housekeeping and tissue specific gene expression. Several isoforms of Oct-1 were described previously. We have found the new alternative promoter of Oct-1 gene and the corresponding mRNA Oct-1X. This mRNA encodes the alternative Oct-1 isoform that has truncated N terminus comparing to isoforms Oct-1A and Oct-1L. We explored the abundance of this isoform in human tissues and cell lines and demonstrated that it is ubiquitously expressed but its expression strongly varies in different tissues. By co-transfection and double luciferase assay we have demonstrated that Oct-1X is the activator of housekeeping (histone H2B) and tissue-specific genes (B29) transcription. PMID- 24466754 TI - [Apoptosis and neutrophils on the regulation of proliferation and differentiation ex vifo of myeloid cells with Ph-chromosome]. AB - Human myeloid cells with Ph chromosome (Ph+ cells) from chronic myeloid leukemia (CML) in the course of proliferation and differentiation ex vivo are regulated under alternation of cell proliferation and neutrophil maturation stages by consecutive blocking and inducing apoptosis with of neutrophils participation as well bcr/abl, bax and bcl2 genes expression. Apoptosis regulation of three main Ph+ cells types from CML patients depends on alternation sequences of proliferation (1) and maturation (2) cell stages and realized by two ways. The first one is performed by consecutive blocking and inducing apoptosis under 2/1/2 stage alternation. The way is not described early. Neutrophils accumulation correlates with apoprosis blocking. Apoptosis level enhances under neutrophils exhausted. Apoptosis blockage allows cells to proliferate and, thus, to form new portion of neutrophils with consecutive regular their death as well a consequent alternation of apoptosis blocking and inducing. This way regulates proliferation efficiency indexes P/D that reflect Ph+ cells proliferating potential and performs cycle completion for proliferation and differentiation. The second way of apoptosis regulation starts from proliferation stage and performs for 1/2/1 alternations under diminished content of neutrophils and a little increase under next maturation. It leads to resistant depressed apoptosis levels that, at maximal points, are 3-8 times lower than those under alternation 2/1/2. Resistant apoptosis blocking is observed in the Ph+ cells with prolong proliferation or maturation stages, when blasts and myelosytes are accumulated under enhanced bcr/abl and bcl2 > box gene expression and remain under next maturation. Stable apoptosis blocking is accompanied by increasing amounts of blasts and myelocytes and enhancing bcr/abl and bcl 2 > bax expression. This is observed under CML progression. Ph+ cells cultivation may be useful for more distinct diagnostics of CML phases of individual CML patients and optimization of the treatment. PMID- 24466755 TI - [Dose-response effect of steroid hormones on the Gfi1 and U2afil4 gene expression in T lymphocytes at different stages of differentiation]. AB - Alternative splicing of Ptprc gene is a key event in memory T cell differentiation. This gene encodes transmembrane tyrosine phosphatase CD45. One of potential mechanisms of alternative splicing regulation is based on antagonistic effects of auxiliary splicing factor U2AF26 and transcription factor Gfi1. These two proteins regulate antigen-dependent T cell activation. We have shown that steroid hormones have different effects on U2af1l4 and Gfi1 transcription regulation in dissimilar differentiation stage cell culture, subjected to antigen-independent stimulation. Low concentrations of glucocorticoid (Dex) and female sex hormone (Est) can activate expression of U2af1l4 in re-stimulated cells that probably induce terminal receptor CD45 isoforms formation mechanism, whereas high doses of hormones inhibit the process. In the same conditions Dex in a wide range of concentrations (10(-5)-10(-7) M) and Est (10(-6) and 10(-7) M) activate U2af1l4 gene expression that probably leads to "surrogate memory T cells" formation. Dose dependent testosterone (Test) effect is opposite to Est and Dex effect on priming (CD45RO+) and naive (CD45RA+) lymphocytes. The role of steroid hormones in memory T cell differentiation in antigen-independent stimulation conditions is of great interest for the understanding of chronic hormonal and immune disbalance mechanisms. PMID- 24466756 TI - [The family 28 carbohydrate-binding module of the thermostable endo-1,4-beta glucanase CelD Caldicellulosiruptor bescii maximizes the enzyme's activity and binds irreversibly to amorphous cellulose]. AB - The nucleotide sequence of a chromosome fragment of the thermophilic anaerobic bacterium Caldicellulosiruptor bescii (syn. Anaerocellum thermophilum) has been determined. The fragment contains four open reading frames with the second one of 749 aa encoding a multimodular endo-1,4-beta-glucanase CelD (85019 Da). N terminal region of the protein includes the signal peptide and the catalytic module of glycoside hydrolase family 5 (GH5), followed by the substrate-binding module of family 28 (CBM28). The C-terminal region bears three SLH modules. The recombinant endoglucanase and its two separate modules, the catalytic one and CBM28, were produced in E. coli cells and purified to homogeneity. Analysis of the catalytic properties showed CelD to be endo-1,4-beta-glucanase whose maximum activity was exhibited on beta-glucan of barley at pH 6.2 and 70 degrees C. The enzyme was stable at 50 degrees C for 30 days. Upon removal of the C-terminal CBM28, the activity of GH5 decreased on cellulose substrates, and its thermostability was dropped. Binding of CBM28 to amorphous cellulose was almost irreversible as it could not be removed from this substrate in a range of pH 4 11, temperatures--of 0-75 degrees C, and NaCl concentration--of 0-5 M. Only 100% formamide or 1% SDS were able to remove the protein. PMID- 24466757 TI - [Markers of apoptotic dysfunction in schizophrenia]. AB - According to modern concepts, alterations of the apoptosis processes and its genetic regulation are involved in etiopathogenesis of schizophrenia. This is observed on the levels of both the brain and peripheral blood. However, studies in this aspect are on initial stage of development, and molecular and cellular mechanisms of abnormalities of apoptosis in schizophrenia are not clear. In the present study we determined the levels of apoptotic markers, annexin-A5 and ficolin-H proteins, in the serum of patients with chronic and first-episode schizophrenia and healthy controls. The potential association of functional single nucleotide polymorphism rs11575945 (-1C/T) of "Kozak" consensus sequence in the regulatory region of the annexin-A5 gene with schizophrenia was examined. In this study the enzyme linked immunosorbent assay and polymerase chain reaction with allele-specific primers were used. The results suggest that the pathogenesis of schizophrenia is characterized by increase rate of apoptosis, which is more pronounced in case of first-episode neuroleptic-free patients than in case of chronic patients treated with typical neuroleptic haloperidol. It was also shown that rs11575945 polymorphism of the annexin-A5 gene is associated with schizophrenia, and its minor allele is responsible for higher levels of the annexin-A5 protein in the blood and represent one of the risk factors for this disease. PMID- 24466758 TI - [Finding an "invisible" binding site for low-molecular compounds on a protein molecule and predicting their inhibiting activity]. AB - Current computational methods have not been able to discover an unknown binding site for low-molecular ligands on a protein receptor and predict parameters of their interaction when this binding site is not distinguished by energy of binding or structural features. Authors propose a method to find an unknown, structurally undefined site for binding low-molecular inhibitors with a protein, as well as to predict kinetic parameters for new compounds using x-ray structure of a protein receptor and experimental interaction constants of a training set of inhibitors. The developed method is applied to discover structural and kinetic parameters of binding C1q, a protein from the first component of complement system, to low-molecular ligands that inhibit its interactions with immune complexes. Authors have suggested that these ligands bind to a region of C1q globular head near residues Arg150 of chain B, and Lys160 and His67 of chain C, supposedly inhibiting the classical pathway of complement activation. Ligands that inhibit interaction of C1q with immune complexes can be used in the therapy of pathological conditions that are related to unwanted complement activation: allergic reactions, xenograft rejection, etc. PMID- 24466759 TI - [Genome-wide identification of functional noncoding RNAs,]. AB - Non-coding RNAs (ncRNAs) are functional transcripts that do not encode proteins. They are involved in many regulation pathways. The only general characteristic shared by many (but not all) known RNAs is folding into complex shapes that are crucial to function and thus should be conserved. This fact can be used for genome-wide prediction of ncRNAs. Our approach is based on computing of local base pairing probabilities and further maximizing of probability for a segment with the use of Nussinoff algorithm. We showed that it allows to efficiently predict known ncRNA and possibly some new ncRNAs. PMID- 24466760 TI - Lymphomatoid granulomatosis: a practical review for pathologists dealing with this rare pulmonary lymphoproliferative process. AB - Lymphomatoid granulomatosis (LYG) is a rare B-cell lymphoproliferative disorder predominantly involving the lungs, but poorly-recognized among clinicians and pathologists. It is an Epstein-Barr virus (EBV)-driven disease mimicking several other diseases on clinical and radiological grounds, generally showing multiple, bilateral nodular, ill-defined infiltrates of the lungs tending to coalescence and/or cavitation. LYG often affects middle-aged males with an underlying immunodeficiency and commonly involves skin and central nervous system during disease progression. Diagnosis requires a generous biopsy and careful histologic examination with immunohistochemical staining and molecular demonstration of EBV genome in large atypical B-cells. LYG is graded as I to III based on the number of large EBV-positive B-cells; grades II/III are now considered as a peculiar variant of T-cell rich diffuse large B-cell lymphoma. In this brief review, clinical, radiologic and pathologic features of LYG will be analyzed with focus on differential diagnosis, the most appropriate treatment and prognosis. PMID- 24466761 TI - About the necessity of improving the current nodal classification of non-small cell lung carcinoma. AB - BACKGROUND: The current classification of lymph node status in non-small cell lung carcinoma has not been revised since 1997. This fact has prompted many authors to point out the limits of this classification. METHODS: We tried to explore the prognostic relevance of the current TNM classification in comparison with the nodal classification based on the ratio of metastatic lymph nodes (LNR) and the nodal classification based on the number of metastatic LNs (nLN). Additionally, we tried to explore the recommended number of resected LNs. This was done through a retrospective study of 39 cases. We compared the survival curves of patients using the current, RLN and nLN classifications. In the nLN classification, we grouped patients into three categories: nNO (no metastatic LNs), nN1 (1 to 2 metastatic LNs) and nN2 (> 2 metastatic LN). In the LNR classification, we grouped patients into three categories: rNO (0%), rN1 (< or = 12) and rN2 (> 12). Concerning the total number of the resected LNs, patients were categorized into two groups according to the number of LNs: < 10 versus > or = 10 and < 15 versus > or = 15. RESULTS: Our results showed that the LNR classification highlighted a difference in prognosis between the rN1 and rN2 groups. Moreover, survival of patients seemed to be better when the number of the resected LNs was higher. CONCLUSION: The ratio of metastatic LNs seems to be an important prognostic factor, but further studies are necessary to standardize this classification. PMID- 24466762 TI - Intraparenchymal leiomyoma of the breast: report of a case with emphasis on needle core biopsy-based diagnosis. AB - OBJECTIVE: We report the clinicopathologic features of a rare case of leiomyoma of the breast parenchyma in a 36-year-old female, diagnosed preoperatively at core biopsy. A complete review of the literature on the topic is provided and differential diagnostic problems are discussed. METHODS: Standard histological examination and immunohistochemical analyses using a large panel of antibodies were performed in both the core biopsy and surgical specimen. RESULTS: Ultrasonography revealed a well-circumscribed tumour mass without calcifications. Histological examination of the core biopsy showed proliferation of bland-looking eosinophilic spindle cells arranged in a fascicular growth pattern. Mitoses, pleomorphism and necrosis were absent. Immunohistochemistry, revealing diffuse staining for a-smooth muscle actin, desmin and h-caldesmon, confirmed the leiomiomatous nature of neoplastic cells. Histological and immunohistochemical analyses of the surgical specimen confirmed the definitive diagnosis of leiomyoma. CONCLUSIONS: The present case emphasizes that diagnosis of leiomyoma of the breast parenchyma can be confidentially rendered on needle core biopsy. We believe that correct diagnosis is primarily dependent on the awareness that this tumour can arise in this unusual site on rare occasions. PMID- 24466763 TI - Primary mucinous carcinoma of the thyroid gland: case report with review of the literature. AB - Primary mucinous thyroid carcinoma (PMTC) are extremely rare lesions that are histologically indistinguishable from mucinous carcinoma of other sites. We describe the clinicopathological, histological and immunohistochemical features of this rare tumour with a review of the literature. We describe a case of thyroid tumour, in 56-year-old Tunisian man, composed of small nests and sheets of malignant epithelial cells associated with extensive extracellular mucin that entrapped the follicular parenchyma of thyroid. Thyroglobulin and thyroid specific-transcription factor 1 (TTFl) were focally positive. Follow-up did not reveal another neoplasm at other sites. Based on these features, we classified this tumour as PMTC. Mucinous carcinoma of the thyroid gland can be a cause of pitfall in differential diagnosis. For correct diagnosis, complete clinical history, restricted histological criteria and immunohistochemical panel are necessary. PMID- 24466764 TI - A solitary polypoid gastric metastasis 20 years after renal cell carcinoma: an event to be considered, and a brief review of the literature. AB - BACKGROUND: The incidence of gastric metastasis is 2.6%. Although all primary neoplasms can metastasize to the stomach, most originate from melanoma or breast and lung cancer. Their most common endoscopic appearance is a "volcano-like" polypoid mass covered by normal mucosa that may show a central ulceration. Renal cell carcinoma, clear cell type, is known to spread hematogenously, and isolated metastasis to the stomach is a rare event. CASE PRESENTATION: In this report, we describe a gastric recurrence of RCC, clear-cell type, in a 80-year-old patient who had undergone nephrectomy 20 years before. We also performed a brief review of the literature to update the number of cases described to date. CONCLUSION: Metastatic involvement of the stomach should be suspected in any patient with a previous history of renal cell carcinoma, clear cell type, presenting with gastrointestinal symptoms, even if many years after nephrectomy. The peculiarity of our case is due to the very late presentation of the gastric metastasis. Only two cases of very late gastric metastases from RCC, clear cell type, have been described in the literature, to date. PMID- 24466765 TI - Pinkus tumour: an unusual case. AB - Fibroepithelioma of Pinkus is a rare cutaneous tumour. Its classification is controversial and is considered as a variant of either basal cell carcinoma or trichoblastoma. Its presentation as a multiple tumour is rare. We are reporting such a case occurring in a 55-year-old man presenting with multiple seborrheic keratosis-like lesions corresponding histologically to Pinkus tumours. The clinical diagnosis of Pinkus tumour represents a challenge. Histological examination is extremely useful in aiding in the diagnosis of difficult cases. PMID- 24466766 TI - Mammary myofibroblastoma with leiomyomatous differentiation: case report and literature review. AB - INTRODUCTION: Myofibroblastoma of the breast (MFB) is an unusual benign tumour that belongs to the family of benign spindle cell tumours of the mammary stroma. The detection of smooth muscle cells in MFB is explained by its histogenesis from CD34+ fibroblasts of mammary stroma capable of multidirectional mesenchymal differentiation, including smooth muscle. AIMS: The purpose of this case is to highlight characteristics of this rare neoplasm. Immunohistochemical features, in MFB with predominant leiomyomatous differentiation, are provided to offer a practical approach to a correct diagnosis. CASE REPORT: We report a right MFB in a 60-year-old male. The tumour was unusual due to its morphological features, with predominant leiomyomatous differentiation. Immunohistochemical findings, based on the negativity of h-caldesmon, helped in reaching a diagnosis. CONCLUSION: The detection of leiomyomatous rather than myofibrolastic features in MFB may reflect only the predominant cell types of examined area, and this is not necessarily representative of the remaining tumour which may have a different basic cellular composition. Immunohistochemical expression of h-caldesmon is a reliable marker in distinguishing smooth muscle versus myofibrolastic cellular differentiation in spindle cells lesions of the breast. PMID- 24466767 TI - [Correlation between the changes of oxidation reduction potential values and postmortem interval of heart blood in rabbits after death]. AB - OBJECTIVE: To investigate correlation between the changes of oxidation reduction potential (ORP) values of heart blood in rabbits after death and postmortem interval (PMI) at different temperatures. METHODS: Forty-eight rabbits were randomly divided into 6 groups and sacrificed by air embolism. Blood samples were taken from the right ventricle of each rabbit and stored at different temperatures of 10, 15, 20, 25, 30 and 35 degrees C, respectively. Every 4 hours from 0 h to 132 h postmortem, the ORP values of the blood samples were measured at different intervals by PB-21 electrochemical analyzer. The curvilinear regression equation was established by SPSS 17.0 software. The surface equation and 3D surface diagram were established by MATLAB 7.10.0 software. RESULTS: The ORP values at different temperatures of heart blood in rabbits were highly correlated with the PMI. The ORP values rised obviously when the temperature was high and rised slowly when the temperature was low. The surface equation and 3D surface diagram were obtained. CONCLUSION: The surface equation and 3D surface diagram of ORP values and PMI may be used for PMI estimation at different temperatures. PMID- 24466768 TI - [Apoptosis in adult mouse brain after chronic poisoning of ketamine]. AB - OBJECTIVE: To study the effect of chronic poisoning of ketamine on brain cell apoptosis in adult mouse under different duration and doses. METHODS: The mouse model of chronic poisoning of ketamine was established on adult mouse by tail vein injection of ketamine twice every week with different doses (4, 10, 20 and 30 mg/kg). The mice were sacrificed after continuous injection of ketamine of 1, 2, 4, 8 and 12 weeks. The qualitative assessment of apoptosis was made by transmission electron microscope and the quantitative assessment was made by Caspase-3 immumofluorescence staining method and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) to estimate the time point of apoptosis. All the experimental results were statistically analyzed. RESULTS: The neuron apoptosis was observed in hippocampus and corpus striatum by transmission electron microscope one week after administration, and continued for eight weeks. High level of Caspase-3 expression was observed one week after administration, but with a low level expression after 4 weeks. The number of TUNEL positive cells obviously increased one week after administration and maintained in a high number at 4 weeks. CONCLUSION: Ketamine by tail vein injection could induce neuron apoptosis in adult mouse. PMID- 24466769 TI - [Expression of GAP-43 in midbrain ventral tegmental area of morphine withdrawal rats]. AB - OBJECTIVE: To observe the protein expression of growth associated protein-43 (GAP 43) in midbrain ventral tegmental area in morphine withdrawal rats at different time, and to evaluate the effect of GAP-43 on morphine withdrawal memory. METHODS: Rat models of morphine dependent 1 week, 2 weeks and 4 weeks were established by morphine hydrochloride intraperitoneal injection with increasing doses to establish natural withdrawal. The protein expression of GAP-43 in midbrain ventral tegmental area was observed by immunohistochemical staining and the results were analyzed by Image-Pro Plus 5.1 image analysis system. RESULTS: With prolongation of dependent time, the expression of GAP-43 was decreased then increased in midbrain ventral tegmental area. CONCLUSION: GAP-43 could play a role in morphine withdrawal memory in midbrain ventral tegmental area. PMID- 24466770 TI - [Pathological changes in rats with acute Dysosma versipellis poisoning]. AB - OBJECTIVE: To observe the pathological changes of major organs in rats with acute Dysosma versipellis poisoning and investigate the toxic mechanism and the injuries of target tissues and organs. METHODS: Forty Sprague-Dawley (SD) rats were randomly divided into three experimental groups, which were given the gavage with 0.5, 1.0 and 2.0 LDo doses of Dysosma versipellis decoction, and one control group, which was given the gavage with 1.0 LD0 dose of normal saline. The rats were sacrificed 14 days after Dysosma versipellis poisoning and samples including brain, heart, liver, lung, and kidney were taken. After pathological process, the pathological changes of the major organs and tissues were observed by light microscope and electron microscope. The experimental data were statistical analyzed by chi2 test. RESULTS: The observations of light microscopy: loose cytoplasm of neurons with loss of most Nissl bodies; swelling of myocardial cells with disappearance of intercalated disk and striations; hepatocellular edema with ballooning degeneration; and swelling epithelial cells of renal proximal convoluted tubule with red light coloring protein-like substances in the tube. The observations of electron microscopy: the structures of cell membrane and nuclear membrane of neurons were destroyed; cytoplasm of neurons, obvious edema; and most organelles, destroyed and disappeared. The mortalities of rats after acute poisoning of the four groups increased with doses (P < 0.05). CONCLUSION: Acute Dysosma versipellis poisoning can cause multi-organ pathological changes. There is a positive correlation between the toxic effect and the dosage. The target tissues and organs are brain (neurons), heart, liver and kidney. PMID- 24466771 TI - [Change rules of quantity and species of diatoms in Hunhe River in Shenyang]. AB - OBJECTION: To observe the change rules of quantity and species of diatoms in Hunhe River in Shenyang and to provide technology and scientific evidence for drowning identification and the location of drowning in forensic investigation. METHODS: In 2011, different locations for collecting water samples were chosen in Hunhe River in Shenyang. Water samples were collected and variation of quantity and species of diatoms were observed every month. And variation of dominant species of diatoms was observed every week. RESULTS: The quantity, species and dominant species of diatoms in Hunhe River in Shenyang varied with different time and locations. The quantity and species of diatoms were lowest from December to February and gradually increased, reaching peak in May and second peak in October, and then gradually decreased. The dominant species of diatoms varied significantly adjacent two weeks at same location from April to November, but had little changes at different locations in same week from July to August. CONCLUSION: The change rules of quantity and species of diatoms are complicated and affected by various factors such as environment and hydrology. The change rules of species and quantity of diatoms should be considered in forensic investigation of drowning identification and the location of drowning. PMID- 24466772 TI - [Mathematical models of the teenager's skeletal age evaluation based on CT scan and imaging reconstruction of medial clavicular epiphysis]. AB - OBJECTIVE: To explore the correlation between CT volume rendering (VR) statistics and living age and to build the mathematical models for skeletal age evaluation based on the growth rules of medial clavicular epiphysis of teenagers in China. METHODS: The thin layer CT scan and VR 3D imaging reconstruction of both sides of sternal ends of clavicles were examined for 684 teenagers aged from 15 to 25 in East and South China. The parameters of sternal end of clavicle including the longest diameter of epiphysis, the longest diameter of metaphysis, their length radio, area of epiphysis, area of metaphysic, their area ratio, and other data were measured and calculated in order to establish mathematical models of skeletal age evaluation. Fifty trained subjects were tested to verify the accuracy of the mathematical models. RESULTS: In the same age group, the length ratio and the area ratio had significant difference in genders (P < 0.05). The established mathematical models showed that the growth rules of medial clavicular epiphysis were highly correlated with the living ages. The accuracies of these models were higher than 70.5% +/- 1.0 year) and 82.5% (+/- 1.5 year). CONCLUSION: The mathematical models have easy operability and high accuracy. It can be used to confirm and sustain the conclusion of atlas method. Meanwhile, it is of great significance to study the other single skeletal age evaluation in the future. PMID- 24466773 TI - [Stature estimation for Sichuan Han nationality female based on X-ray technology with measurement of lumbar vertebrae]. AB - OBJECTIVE: To establish the mathematical models of stature estimation for Sichuan Han female with measurement of lumbar vertebrae by X-ray to provide essential data for forensic anthropology research. METHODS: The samples, 206 Sichuan Han females, were divided into three groups including group A, B and C according to the ages. Group A (206 samples) consisted of all ages, group B (116 samples) were 20-45 years old and 90 samples over 45 years old were group C. All the samples were examined lumbar vertebrae through CR technology, including the parameters of five centrums (L1-L5) as anterior border, posterior border and central heights (x1-x15), total central height of lumbar spine (x16), and the real height of every sample. The linear regression analysis was produced using the parameters to establish the mathematical models of stature estimation. Sixty-two trained subjects were tested to verify the accuracy of the mathematical models. RESULTS: The established mathematical models by hypothesis test of linear regression equation model were statistically significant (P<0.05). The standard errors of the equation were 2.982-5.004 cm, while correlation coefficients were 0.370-0.779 and multiple correlation coefficients were 0.533-0.834. The return tests of the highest correlation coefficient and multiple correlation coefficient of each group showed that the highest accuracy of the multiple regression equation, y = 100.33 + 1.489 x3 - 0.548 x6 + 0.772 x9 + 0.058 x12 + 0.645 x15, in group A were 80.6% (+/- lSE) and 100% (+/- 2SE). CONCLUSION: The established mathematical models in this study could be applied for the stature estimation for Sichuan Han females. PMID- 24466774 TI - [Gene detection of GPD1-L and the association with sudden unexplained death syndrome in young adults]. AB - OBJECTIVE: To analyze the variations of glycerol-3-phosphate dehydrogenase 1 like gene (GPD1-L) and address the association with sudden manhood death syndrome (SMDS). METHODS: The genomic DNA was extracted from blood samples of the SMDS group and the normal control group. The exons, exon-intron boundaries and 3'-UTRs of coding region of GPD1-L were PCR amplified and DNA sequenced directly to confirm the types of variations. The genotype frequency and allele frequency were analyzed statistically. RESULTS: There were two variants in the SMDS group, c.465C>T and c.*18G>T, the latter existed certain degree difference of genotype distribution and allele frequency between the SMDS group and the control group, but there was no statistically significant (P > 0.05). CONCLUSION: The relation between gene mutation of GPD1-L and the occurrence of Chinese SMDS deserves a further research. PMID- 24466775 TI - [Analysis of deaths caused by secondary damages of road traffic accidents: 17 fatal cases]. AB - OBJECTIVE: To explore the forensic identification points of deaths caused by secondary damages of road traffic accidents. METHODS: Seventeen deaths caused by secondary damages of road traffic accidents were collected. Through scene investigation and necropsy, the basic information of the accidents, distribution and property of the injuries, and other information were collected. According to the collected data, the scene was reconstructed in order to confirm the injury process, analyze the way, mechanism and severity of injury, distinguish antemortem injury from postmortem injury, and determine the cause of deaths. RESULTS: Certain features such as serious injuries, multiple traumas, combined injuries, co-existence of antemortem and postmortem injuries, multiple causes of wounds, complex injury mechanism, as well as the mutual damaging and overlapping injuries were quite characteristically noted in these secondary traffic accident cases. CONCLUSION: Forensic assessment of deaths caused by secondary damages of road traffic accidents should be synthetically analyzed and judged through scene investigation and necropsy. PMID- 24466776 TI - [Comparative analysis between diatom nitric acid digestion method and plankton 16S rDNA PCR method]. AB - OBJECTIVE: To compare and explore the application value of diatom nitric acid digestion method and plankton 16S rDNA PCR method for drowning identification. METHODS: Forty drowning cases from 2010 to 2011 were collected from Department of Forensic Medicine of Wenzhou Medical University. Samples including lung, kidney, liver and field water from each case were tested with diatom nitric acid digestion method and plankton 16S rDNA PCR method, respectively. The Diatom nitric acid digestion method and plankton 16S rDNA PCR method required 20 g and 2 g of each organ, and 15 mL and 1.5 mL of field water, respectively. The inspection time and detection rate were compared between the two methods. RESULTS: Diatom nitric acid digestion method mainly detected two species of diatoms, Centriae and Pennatae, while plankton 16S rDNA PCR method amplified a length of 162 bp band. The average inspection time of each case of the Diatom nitric acid digestion method was (95.30 +/- 2.78) min less than (325.33 +/- 14.18) min of plankton 16S rDNA PCR method (P < 0.05). The detection rates of two methods for field water and lung were both 100%. For liver and kidney, the detection rate of plankton 16S rDNA PCR method was both 80%, higher than 40% and 30% of diatom nitric acid digestion method (P < 0.05), respectively. CONCLUSION: The laboratory testing method needs to be appropriately selected according to the specific circumstances in the forensic appraisal of drowning. Compared with diatom nitric acid digestion method, plankton 16S rDNA PCR method has practice values with such advantages as less quantity of samples, huge information and high specificity. PMID- 24466777 TI - [SNP in differentially methylated region upstream of H19 gene in Chinese Korean nationality]. AB - OBJECTIVE: To investigate SNP and distribution of haplotypes in differentially methylated region (DMR) upstream of H19 gene in Chinese Korean nationality in order to provide basic data for forensic application and population genetics research. METHODS: One hundred and one blood samples from unrelated Chinese Korean individuals and 14 blood samples from 5 Chinese Korean intergenerational families which known genetic relationship were collected. The SNP in DMR upstream of H19 gene were investigated by PCR-cycle sequencing and McrBC digestion followed by PCR. The haplotypes detected by parentally imprinted allele (PIA) method and relevant genetic parameters were calculated. RESULTS: Thirteen SNPs (rs10840167, rs2525883, rs12417375, rs4930101, rs2525882, rs2735970, rs2735971, rs11042170, rs2735972, rs10732516, rs2071094, rs2107425, and rs4930098) and five haplotypes were detected in 1 174 bp target product in DMR upstream of H19 gene, with 9 SNPs having high discrimination power as good genetic markers. The average gene diversity (GD) of haplotypes was 0.714. The maternal haplotype was confirmed correctly by PIA method from McrBC-digested products of genomic DNA. CONCLUSION: High polymorphisms exist in DMR upstream of H19 gene in Chinese Korean nationality. And determination of the maternal haplotype could furthermore enhance the forensic identification efficiency of imprinted gene. PMID- 24466778 TI - [Metallothionein-I/II in brain injury repair mechanism and its application in forensic medicine]. AB - Metallothionein (MT) is a kind of metal binding protein. As an important member in metallothionein family, MT-I/II regulates metabolism and detoxication of brain metal ion and scavenges free radicals. It is capable of anti-inflammatory response and anti-oxidative stress so as to protect the brain tissue. During the repair process of brain injury, the latest study showed that MT-I/II could stimulate brain anti-inflammatory factors, growth factors, neurotrophic factors and the expression of the receptor, and promote the extension of axon of neuron, which makes contribution to the regeneration of neuron and has important effect on the recovery of brain injury. Based on the findings, this article reviews the structure, expression, distribution, adjustion, function, mechanism in the repair of brain injury of MT-I/II and its application prospect in forensic medicine. It could provide a new approach for the design and manufacture of brain injury drugs as well as for age estimation of the brain injury. PMID- 24466779 TI - Messenger RNA profiling for forensic body fluid identification: research and applications. AB - Identifying the origin of body fluids left at a crime scene can give a significant insight into crime scene reconstruction by supporting a link between sample donors and actual criminal acts. However, the conventional body fluid identification methods are prone to various limitations, such as time consumption, intensive labor, nonparallel manner, varying degrees of sensitivity and limited specificity. Recently, the analysis of cell-specific messenger RNA expression (mRNA profiling) has been proposed to supplant conventional methods for body fluid identification. Since 2011, the collaborative exercises have been organized by the European DNA Profiling Group (EDNAP) in order to evaluate the robustness and reproducibility of mRNA profiling for body fluid identification. The major advantages of mRNA profiling, compared to the conventional methods, include higher sensitivity, greater specificity, the ability of detecting several body fluids in one multiplex reaction, and compatibility with current DNA extraction and analysis procedure. In the current review, we provided an overview of the present knowledge and detection methodologies of mRNA profiling for forensic body fluid identification and discussed its possible practical application to forensic casework. PMID- 24467155 TI - Li(+)-conductive polymer-embedded nano-Si particles as anode material for advanced Li-ion batteries. AB - Si has been considered as a promising alternative anode for next-generation lithium ion batteries (LIBs), but the commercial application of Si anodes is still limited due to their poor cyclability. In this paper, we propose a new strategy to enhance the long-term cyclability of Si anode by embedding nano-Si particles into a Li(+)-conductive polymer to form a Si/polymer composite with core-shell structure, in which nano-Si cores act as active Li-storage phase and the polymeric matrix serves not only as a strong buffer to accommodate the volume change, but also as a protection barrier to prevent the direct contact of Si surface with electrolyte, so as to maintain the mechanical integrity of Si anode and suppress the repeated destruction and construction of solid electrolyte interphase (SEI) on the Si surface. To realize this strategy, we synthesize a Si/PPP (polyparaphenylene) composite simply by ball-milling the Si nanoparticles with PPP polymer that has n-doping activity. Our experimental results demonstrate that the thus-prepared Si/PPP composite exhibits a high capacity of 3184 mA h g( 1) with an initial coulombic efficiency of 78%, an excellent rate capability with a considerably high capacity of 1670 mA h g(-1) even at a very high rate of 16 A g(-1), and a long-term cyclability with 60% capacity retention over 400 cycles, showing a great prospect for battery application. In addition, this structural design could be adopted to other Li-storable metals or alloys for developing cycle-stable anode materials for Li-ion batteries. PMID- 24467167 TI - Composition-tuned ZnO/Zn(x)Cd(1-x)Te core/shell nanowires array with broad spectral absorption from UV to NIR for hydrogen generation. AB - For highly efficient photoelectrodes, the materials used must have both a broad absorption range and large separation efficiency of photogenerated electron-hole pairs. Type II heterostructures with a ternary shell meet these two requirements and thus are recognized as being an ideal materials system for application in photocatalytic hydrogen production. Here, a ZnO/ZnxCd1-xTe core/shell nanowires array with a broad absorption edge from UV (380 nm) to NIR (855 nm) was fabricated via a chemical vapor-deposition method. More importantly, the ZnO/ZnxCd1-xTe core/shell nanowires array are highly single crystalline, and the composition can be continuously tuned by optimizing the deposition temperature, making the design of the desired photocatalyst possible. As expected, the single crystalline ternary ZnxCd1-xTe shell greatly enhances the charge separation efficiency and prolongs the lifetime of photogenerated charge carriers, which contribute to the high photocatalytic and photoelectrocatalytic activity under light irradiation. In addition, ZnO/ZnxCd1-xTe core/shell structure show remarkable photocatalytic H2-production activity and high H2-production capability because of the synergistic light absorption of the ternary ZnxCd1-xTe shell and the formation of a type II heterostructure at the interface between the ZnO core and ZnxCd1-xTe shell. This work provides a new material platform for the design of highly efficient solar-fuel devices that demonstrate a broad and controllable absorption from the UV to NIR wavelengths. PMID- 24467172 TI - Patterning, characterization, and chemical sensing applications of graphene nanoribbon arrays down to 5 nm using helium ion beam lithography. AB - Bandgap engineering of graphene is an essential step toward employing graphene in electronic and sensing applications. Recently, graphene nanoribbons (GNRs) were used to create a bandgap in graphene and function as a semiconducting switch. Although GNRs with widths of <10 nm have been achieved, problems like GNR alignment, width control, uniformity, high aspect ratios, and edge roughness must be resolved in order to introduce GNRs as a robust alternative technology. Here we report patterning, characterization, and superior chemical sensing of ultranarrow aligned GNR arrays down to 5 nm width using helium ion beam lithography (HIBL) for the first time. The patterned GNR arrays possess narrow and adjustable widths, high aspect ratios, and relatively high quality. Field effect transistors were fabricated on such GNR arrays and temperature-dependent transport measurements show the thermally activated carrier transport in the GNR array structure. Furthermore, we have demonstrated exceptional NO2 gas sensitivity of the 5 nm GNR array devices down to parts per billion (ppb) levels. The results show the potential of HIBL fabricated GNRs for the electronic and sensing applications. PMID- 24467173 TI - Selected organochlorine pesticides and polychlorinated biphenyls in urban atmosphere of Pakistan: concentration, spatial variation and sources. AB - Robust knowledge on the occurrence and distribution of persistent organic pollutants (POPs) in the atmosphere of low-latitude regions is inevitable to forecast their transportation to pristine ecosystem and assess toxicological impacts upon local biota. Despite the earlier revelation of organochlorine pesticides (OCPs) and polychlorinated biphenyls (PCBs) in soils/sediments and water bodies in Pakistan, knowledge about atmospheric levels and sources of these POPs remains limited. For the first time, a network of XAD resin-based passive air samplers (PAS) was established across megacities of Pakistan, i.e., Karachi, the coastal city, and Lahore, lying in an agricultural region. Typical geographical locations of the two cities allowed assessing the influence of source regions on the occurrence and distribution patterns of selected POPs. Average concentrations (ng/PAS) in both cities ranged as endosulfan 39-101, DDTs 63-92, HCHs 33-65, heptachlor 10-26, and PCBs 48-61. High concentrations of endosulfan and lindane as observed throughout Lahore were certainly due to their ongoing applications in surrounding agricultural fields. Lower proportions of parental DDTs as compared to their metabolites were observed in both cities, suggesting inputs of DDTs from older or secondary sources. Owing to ultimate discharge of country's agricultural/industrial waste through river streams in to Arabian Sea, the coastal region of Karachi was found potential source of weathered POPs that could be dissipated at regional/global scales by maritime advections. The study contributes to the pool of information on fate and geographical distribution of POPs in subtropical developing countries. PMID- 24467163 TI - Integrin cytoplasmic tail interactions. AB - Integrins are heterodimeric cell surface adhesion receptors essential for multicellular life. They connect cells to the extracellular environment and transduce chemical and mechanical signals to and from the cell. Intracellular proteins that bind the integrin cytoplasmic tail regulate integrin engagement of extracellular ligands as well as integrin localization and trafficking. Cytoplasmic integrin-binding proteins also function downstream of integrins, mediating links to the cytoskeleton and to signaling cascades that impact cell motility, growth, and survival. Here, we review key integrin-interacting proteins and their roles in regulating integrin activity, localization, and signaling. PMID- 24467174 TI - Rotavirus gastroenteritis in the Czech Republic before the start of vaccination. AB - BACKGROUND: The primary objective of our study was to investigate rotavirus gastroenteritis (RVGE) retrospectively in the Czech Republic (CzR) and try to estimate its significance in the most affected age groups in the prerotavirus vaccine era. METHODS: To analyze the epidemiological data on RVGE in the CzR, two databases were used retrospectively. The first database consisted of regular yearly reports from the laboratories diagnosing rotavirus infections from 1998 to 2006. The second database used was EPIDAT (the official notification system of the hygiene service). The data from 1998 to 2006 was analysed. RESULTS: From 1998 to 2006, the laboratories reported 1,430 to 4,815 cases of RVGE per year. By extrapolation--, in the CR in 2006, there were an estimated 4,076 rotavirus related hospitalizations (696.7/100,000 in the age group < 5 years). The most commonly applied detection systems in 2006 were immunochromatography and latex agglutination. Of the RVGE cases recorded in the Epidat database between 1998 2006, 76.0-89.2% were for children aged less than five years. Seasonality was observed with the highest incidence rates between January and May with most cases usually occurring in March. Over nine years, there were six deaths linked directly to RVGE - three -deaths reported in children under two and three deaths reported in elderly people whose deaths were related to the epidemics in retirement homes. CONCLUSIONS: The estimated incidence rates of RVGE hospitalization in 2006 was higher in the CzR than that reported in other industrialized European countries. Our findings might verify the need for rotavirus vaccine implementation in the Czech Republic and reinforce the importance of rotavirus gastroenteritis surveillance. PMID- 24467175 TI - [Invasive meningococcal disease in the Czech Republic - analysis of the epidemiological situation and vaccination strategy recommendations]. AB - AIMS: Analysis of invasive meningococcal disease (IMD) surveillance data including molecular epidemio-logy data. Vaccination strategy recommendations based on the current epidemiological situation of IMD in the Czech Republic and availability of meningococcal vaccines. MATERIAL AND METHODS: IMD surveillance data are compiled by the National Reference Laboratory for Meningococcal Disease (NRL) from routinely reported data and NRL data after clearing out duplicate data. Neisseria meningitidis (N.m.) isolates referred to the NRL are confirmed and characterized in detail according to internationally validated methods. RESULTS: The current epidemiological situation of IMD is relatively favourable - the incidence rates have been below 1/100,000 population for several years, but show a slightly upward trend over more than 40-year period (1970-2012). A return to the typical prevalence of serogroup B accounting for up to 75% of cases has recently been shown. In this context, the upward trend in IMD caused by serogroup Y associated with a high case fatality rate in the Czech Republic cannot be overseen or even underestimated. The hypervirulent clonal complex cc11 characteristic of N.m.C:2a:P1.2,5 prevailed in this country between 1993 and 2004, but decreased in the following years and currently, hypervirulent clonal complexes characteristic of N.m.B (cc18, cc32, cc41/44, and cc269) are the most common in the Czech Republic. The average overall case fatality rate in the Czech Republic is 10%, but varies between causative serogroups: the highest case fatality rate has been caused by serogroup Y (16.7% ), followed by serogroup C (12.3%), and serogroup W135 (11.7%), while serogroup B only accounts for a case fatality rate of 7.8%. In the age group under one year, the incidence of IMD caused by serogroup B remains three to five times as high as in the age groups 1 4 years and 15-19 years throughout the surveillance period. The highest numbers of IMD cases caused by serogroup B have been reported in 3-7-month-olds. CONCLUSION: Based on the IMD surveillance data from the Czech Republic, the NRL recommends a vaccination strategy to provide an adequate protection to individuals. To induce an immune response as wide as possible, the tetravalent meningococcal conjugate vaccine A,C,Y,W135 in combination with the newly registered MenB vaccine designed by reverse vaccinology should be given. To maintain immunity, subsequent booster doses are required at intervals depending on the primary vaccination age. PMID- 24467176 TI - [Molecular biological and epidemiological -characteristics of the varicella zoster virus (VZV)]. AB - The genetic diversity and epidemiology of VZV results from an interplay of the geographic area, climate conditions, and population factors. Studies of the genetic diversity of VZV can have direct implications for both the epidemiological and evolutionary analyses and identification of the genetic correlates of VZV pathogenicity or resistance to antiviral drugs. PMID- 24467177 TI - [Bacterial contamination of the indoor air in a transplant unit]. AB - For one year (August 2010 to July 2011), microbial contamination of the indoor air in the Transplant Unit of the Haemato-Oncology Clinic, Olomouc University Hospital was monitored monthly. Twenty sampling sites were singled out and a total of 240 indoor air samples were collected. An MAS-100 air sampler (Merck, GER) was used, air flow rate of 100 liters per minute, 1 minute. The measured values of indoor air temperature were stable. The relative air humidity ranged from 17% to 68%. The highest average value of microbial air contamination was found in the "staff entry room" (1170 CFU/m3). The lowest microbial air contamination (150-250 CFU/m3) was measured in the patient isolation units. The most frequently isolated bacterial strains were coagulase-negative staphylococci (94.3%), followed by Micrococcus spp. (67%) and Bacillus subtilis (11%). It can be assumed that the -source of these airborne bacterial strains are both patients and medical staff. They are classified as -opportunistic pathogens and as such can cause hospital infections among haemato-oncology patients. PMID- 24467178 TI - Hierarchically structured microspheres for high-efficiency rutile TiO(2)-based dye-sensitized solar cells. AB - Peachlike rutile TiO2 microsphere films were successfully produced on transparent conducting fluorine-doped tin oxide substrate via a facile, one-pot chemical bath route at low temperature (T = 80-85 degrees C) by introducing polyethylene glycol (PEG) as steric dispersant. The formation of TiO2 microspheres composed of nanoneedles was attributed to the acidic medium for the growth of 1D needle shaped building blocks where the steric interaction of PEG reduced the aggregation of TiO2 nanoneedles and the Ostwald ripening process. Dye-sensitized solar cells (DSSCs) assembled by employing these complex rutile TiO2 microspheres as photoanodes exhibited a light-to-electricity conversion efficiency of 2.55%. It was further improved to a considerably high efficiency of 5.25% upon a series of post-treatments (i.e., calcination, TiCl4 treatment, and O2 plasma exposure) as a direct consequence of the well-crystallized TiO2 for fast electron transport, the enhanced capacity of dye loading, the effective light scattering, and trapping from microstructures. PMID- 24467179 TI - Silica-based materials as drug adsorbents: first principle investigation on the role of water microsolvation on Ibuprofen adsorption. AB - Silica-based materials find applications as excipients and, particularly for those of mesoporous nature, as drug delivery agents for pharmaceutical formulations. Their performance can be crucially affected by water moisture, as it can modify the behavior of these formulations, by limiting their shelf life. Here we describe the role of water microsolvation on the features of ibuprofen adsorbed on a model of amorphous silica surface by means of density functional theory (DFT) simulations. Starting from the results of the simulation of ibuprofen in interaction with a dry hydrophobic amorphous silica surface, a limited number of water molecules has been added to study the configurational landscape of the microsolvated system. Structural and energetics properties, as well as the role of dispersive forces, have been investigated. Our simulations have revealed that the silica surface exhibits a higher affinity for water than for ibuprofen, even if several structures coexist at room temperature, with an active competition of ibuprofen and water for the exposed surface silanols. Dispersive interactions play a key role in this system, as pure DFT fails to correctly describe its potential energy surface. Indeed, van der Waals forces are the leading contribution to adsorption, independently of whether the drug is hydrogen-bonded directly to the surface or via water molecules. PMID- 24467180 TI - Three-dimensional reconstruction volume: a novel method for volume measurement in kidney cancer. AB - BACKGROUND AND PURPOSE: The role of volumetric estimation is becoming increasingly important in the staging, management, and prognostication of benign and cancerous conditions of the kidney. We evaluated the use of three-dimensional reconstruction volume (3DV) in determining renal parenchymal volumes (RPV) and renal tumor volumes (RTV). We compared 3DV with the currently available methods of volume assessment and determined its interuser reliability. PATIENTS AND METHODS: RPV and RTV were assessed in 28 patients who underwent robot-assisted laparoscopic partial nephrectomy for kidney cancer. Patients with a preoperative creatinine level of <1.2 mg/dL with available scans were selected. RPV and RTV were then assessed using 3DV, as well as cylindrical approximation for RPV and spherical approximation for RTV as described previously in the literature. Measures of the same quantity from each method were then compared. In addition, interuser reliability was determined for 3DV. RESULTS: Calculated volumes differed widely in comparison with 3DV. For example, cylindrical volumes for the contralateral kidney pre- and postsurgery overestimated 3D reconstruction volumes by 15% to 102% and 12% to 101%, respectively. In addition, volumes obtained from 3DV displayed high interuser reliability regardless of experience. CONCLUSIONS: 3DV provides a highly reliable way of assessing kidney volumes. Given that 3DV takes into account visible anatomy, the differences observed using previously published methods can be attributed to the failure of geometry to accurately approximate kidney or tumor shape. 3DV provides a more accurate, reproducible, and clinically useful tool for urologists looking to improve patient care using analysis related to volume. PMID- 24467182 TI - Sediment contaminated with the Azo Dye disperse yellow 7 alters cellular stress- and androgen-related transcription in Silurana tropicalis larvae. AB - Azo dyes are the most commonly used type of dye, accounting for 60-70% of all organic dye production worldwide. They are used as direct dyes in the textile, leather, printing ink, and cosmetic industries. The aim of this study was to assess the lethal and sublethal effects of the disazo dye Disperse Yellow 7 (DY7) in frogs to address a knowledge gap regarding mechanisms of toxicity and the potential for endocrine disrupting properties. Larvae of Silurana tropicalis (Western clawed frog) were exposed to DY7-contaminated water (0 to 22 MUg/L) and sediment (0 to 209 MUg/g) during early larval development. The concentrations used included the range of similar azo dyes found in surface waters in Canada. A significant decrease in tadpole survivorship was observed at 209 MUg/g while there was a significant increase in malformations at the two highest concentrations tested in sediment. In the 209 MUg/g treatment, DY7 significantly induced hsp70 (2.5-fold) and hsp90 (2.4-fold) mRNA levels, suggesting that cells required oxidative protection. The same treatment also altered the expression of two androgen-related genes: decreased ar (2-fold) and increased srd5a2 (2.6 fold). Furthermore, transcriptomics generated new hypotheses regarding the mechanisms of toxic action of DY7. Gene network analysis revealed that high concentrations of DY7 in sediment induced cellular stress-related gene transcription and affected genes associated with necrotic cell death, chromosome condensation, and mRNA processing. This study is the first to report on sublethal end points for azo dyes in amphibians, a growing environmental pollutant of concern for aquatic species. PMID- 24467183 TI - Response of the Sensory animal-like cryptochrome aCRY to blue and red light as revealed by infrared difference spectroscopy. AB - Cryptochromes act as blue light sensors in plants, insects, fungi, and bacteria. Recently, an animal-like cryptochrome (aCRY) was identified in the green alga Chlamydomonas reinhardtii by which gene expression is altered in response to not only blue light but also yellow and red light. This unique response of a flavoprotein in vivo has been attributed to the fact that the neutral radical of the flavin chromophore acts as dark form of the sensor, which absorbs in almost the entire visible spectral range (<680 nm). Here, we investigated light-induced processes in the protein moiety of full-length aCRY by UV-vis and Fourier transform infrared spectroscopy. Findings are compared to published results on the homologous (6-4) photolyases, DNA repair enzymes. The oxidized state of aCRY is converted to the neutral radical by blue light. The recovery is strongly dependent on pH and might be catalyzed by a conserved histidine of the (6 4)/clock cluster. The decay is independent of oxygen concentration in contrast to that of other cryptochromes and (6-4) photolyases. This blue light reaction of the oxidized flavin is not accompanied by any detectable changes in secondary structure, in agreement with a role in vivo of an unphysiological preactivation. In contrast, the conversion by red light of the neutral radical to the anionic fully reduced state proceeds with conformational changes in turn elements, which most probably constitute a part of the signaling process. These changes have not been detected in the corresponding transition of (6-4) photolyase, which points to a decisive difference between the sensor and the enzyme. PMID- 24467184 TI - Automated data extraction from in situ protein-stable isotope probing studies. AB - Protein-stable isotope probing (protein-SIP) has strong potential for revealing key metabolizing taxa in complex microbial communities. While most protein-SIP work to date has been performed under controlled laboratory conditions to allow extensive isotope labeling of the target organism(s), a key application will be in situ studies of microbial communities for short periods of time under natural conditions that result in small degrees of partial labeling. One hurdle restricting large-scale in situ protein-SIP studies is the lack of algorithms and software for automated data processing of the massive data sets resulting from such studies. In response, we developed Stable Isotope Probing Protein Extraction Resources software (SIPPER) and applied it for large-scale extraction and visualization of data from short-term (3 h) protein-SIP experiments performed in situ on phototrophic bacterial mats isolated from Yellowstone National Park. Several metrics incorporated into the software allow it to support exhaustive analysis of the complex composite isotopic envelope observed as a result of low amounts of partial label incorporation. SIPPER also enables the detection of labeled molecular species without the need for any prior identification. PMID- 24467187 TI - Normal phenotype in conditional androgen receptor (AR) exon 3-floxed neomycin negative male mice. AB - Androgens (testosterone and dihydrotestosterone) acting via the androgen receptor (AR) are required for male sexual differentiation, and also regulate the development of many other tissues including muscle, fat and bone. We previously generated an AR(lox) mouse line with exon 3 of the AR gene targeted by loxP sites. The deletion of exon 3 is in-frame, so only the DNA binding-dependent actions of the AR are deleted, but non-DNA binding-dependent actions are retained. This line also contained an antibiotic resistance selection cassette, neomycin (neo) in intron 3, which was also flanked by loxP sites. Hemizygous AR(lox) male mice demonstrated a phenotype of hyperandrogenization, with increased mass of androgen-dependent tissues. We hypothesized that this hyperandrogenization was likely to be due to the presence of the neo cassette. In this study, we have generated an AR(lox) neo-negative mouse line, using the EIIa cre deleter mouse line to remove the neo cassette. Hemizygous AR(lox) neo negative male mice have a normal phenotype, with normal body mass and normal mass of androgen-dependent tissues including the testis, seminal vesicles, kidney, spleen, heart and retroperitoneal fat. This neo-negative exon 3-targeted mouse line is the only floxed AR mouse line available to study the DNA binding dependent actions of the AR in a tissue-specific manner, and is suitable for investigation in all tissues. This study demonstrates the importance of removing the selection cassette, which can potentially alter the phenotype of floxed mouse lines even in the absence of detectable effects on target gene expression. PMID- 24467188 TI - Rapidly fatal "congenital lung dysplasia": a case report and review of the literature. AB - Acinar dysplasia congenital alveolar dysplasia and alveolar capillary dysplasia with misalignment of pulmonary veins belong to the diffuse developmental disorders (congenital lung dysplasia), very rare fatal disorders of infancy that occur early in lung development. A case of quickly fatal congenital lung dysplasia in a full-term infant is presented and underlines the necessity to suspect this disease in a newborn suffering from severe and refractory respiratory distress. PMID- 24467189 TI - The sensitivity of T-SPOT.TB assay in diagnosis of pediatric tuberculosis. AB - This study was performed aiming to evaluate the sensitivity of T-SPOT.TB assay in diagnosis of pediatric TB and investigate the association between age and results of T-SPOT.TB assay. Between March 2012 and September 2013, 102 patients, who aged <=15 years old, were enrolled in this retrospective study and then were grouped into three age categories: Group 1, aged <=2 years; Group 2, aged 3 to 12 years; and Group 3, aged 13 to 15 years. The chi(2) test was used to compare the sensitivities of T-SPOT.TB between groups with different ages. The overall sensitivity of T-SPOT.TB assay was 58.8% (95% confidence interval: 49.1-67.9%) and low in diagnosis of pediatric TB. Although the sensitivities varied in the three groups, the difference did not reach statistical significance (p > 0.05). Therefore, in high burden countries, T-SPOT.TB assay wasn't accurate in diagnosis of pediatric TB, and age was not associated with the results of T-SPOT.TB. PMID- 24467190 TI - Efficacy of face shields against cough aerosol droplets from a cough simulator. AB - Health care workers are exposed to potentially infectious airborne particles while providing routine care to coughing patients. However, much is not understood about the behavior of these aerosols and the risks they pose. We used a coughing patient simulator and a breathing worker simulator to investigate the exposure of health care workers to cough aerosol droplets, and to examine the efficacy of face shields in reducing this exposure. Our results showed that 0.9% of the initial burst of aerosol from a cough can be inhaled by a worker 46 cm (18 inches) from the patient. During testing of an influenza-laden cough aerosol with a volume median diameter (VMD) of 8.5 MUm, wearing a face shield reduced the inhalational exposure of the worker by 96% in the period immediately after a cough. The face shield also reduced the surface contamination of a respirator by 97%. When a smaller cough aerosol was used (VMD = 3.4 MUm), the face shield was less effective, blocking only 68% of the cough and 76% of the surface contamination. In the period from 1 to 30 minutes after a cough, during which the aerosol had dispersed throughout the room and larger particles had settled, the face shield reduced aerosol inhalation by only 23%. Increasing the distance between the patient and worker to 183 cm (72 inches) reduced the exposure to influenza that occurred immediately after a cough by 92%. Our results show that health care workers can inhale infectious airborne particles while treating a coughing patient. Face shields can substantially reduce the short-term exposure of health care workers to large infectious aerosol particles, but smaller particles can remain airborne longer and flow around the face shield more easily to be inhaled. Thus, face shields provide a useful adjunct to respiratory protection for workers caring for patients with respiratory infections. However, they cannot be used as a substitute for respiratory protection when it is needed. [Supplementary materials are available for this article. Go to the publisher's online edition of Journal of Occupational and Environmental Hygiene for the following free supplemental resource: tables of the experiments performed, more detailed information about the aerosol measurement methods, photographs of the experimental setup, and summaries of the experimental data from the aerosol measurement devices, the qPCR analysis, and the VPA.]. PMID- 24467192 TI - Delivery of hypoxia and glioma dual-specific suicide gene using dexamethasone conjugated polyethylenimine for glioblastoma-specific gene therapy. AB - Gene therapy has been considered a promising approach for glioblastoma therapy. To avoid side effects and increase the specificity of gene expression, gene expression should be tightly regulated. In this study, glioma and hypoxia dual specific plasmids (pEpo-NI2-SV-Luc and pEpo-NI2-SV-HSVtk) were developed by combining the erythropoietin (Epo) enhancer and nestin intron 2 (NI2). In the in vitro studies, pEpo-NI2-SV-Luc showed higher gene expression under hypoxia than normoxia in a glioblastoma-specific manner. The MTT and caspase assays demonstrated that pEpo-NI2-SV-HSVtk specifically induced caspase activity and cell death in hypoxic glioblastoma cells. For in vivo evaluation, subcutaneous and intracranial glioblastoma models were established. Dexamethasone-conjugated polyethylenimine (PEI-Dexa) was used as a gene carrier, since PEI-Dexa efficiently delivers plasmid to glioblastoma cells and also has an antitumor effect due to the effect of dexamethasone. In the in vivo study in the subcutaneous and intracranial glioblastoma models, the tumor size was reduced more effectively in the pEpo-NI2-SV-HSVtk group than in the control and pSV-HSVtk groups. In addition, higher levels of HSVtk gene expression and TUNEL-positive cells were observed in the pEpo-NI2-SV-HSVtk group compared with the control and pSV-HSVtk groups, suggesting that pEpo-NI2-SV-HSVtk increased the therapeutic efficacy in hypoxic glioblastoma. Therefore, pEpo-NI2-SV-HSVtk/PEI-Dexa complex may be useful for glioblastoma-specific gene therapy. PMID- 24467193 TI - Printable highly catalytic Pt- and TCO-free counter electrode for dye-sensitized solar cells. AB - Here we show that a counter electrode based on carbon network supported Cu2ZnSnS4 nanodots on Mo-coated soda-lime glass for dye-sensitized solar cells can outperform the conventional best electrode with Pt nanoparticles on the fluorine doped SnO2 conducting glass. In the as-developed electrode, all of the elements are of high abundance ratios with low materials cost. The fabrication is scalable because it is conducted by a screen-printing based approach. Therefore, this research lays a solid ground for the large area fabrication of high-performance dye-sensitized solar cell at reduced material cost. PMID- 24467195 TI - Ultrafast C(Spiro)-O dissociation via a conical intersection drives spiropyran to merocyanine photoswitching. AB - The mechanism of the photochemical conversion of spiropyran to merocyanine is investigated theoretically. Calculations were performed at TD-DFT/omegaB97XD/cc pVDZ level of theory, which shows good agreement with the reference RI-CC2 method. A two-dimensional scan of the potential energy surface has been performed along the C-O distance and the central torsion angle in the ground state and in the first excited state, where the reaction takes place. Starting at the Franck Condon geometry, the energy of the first excited state decreases in the direction of the C-O dissociation while the ground-state energy increases. This leads to a barrierless C-O bond dissociation in the first excited state. While relaxing on the S1 PES toward longer C-O distances, the torsion angle hardly changes, but other coordinates start to vary, leading to a conical intersection of the ground state and the first excited state at a C-O distance of about 3.4 A. Passing the conical intersection, the reaction continues on the ground-state PES. At these large C-O distances, either barrierless Cspiro-O rebinding occurs that quenches spiropyran isomerization or rotation around the central torsion angle occurs that leads to merocyanine. For the latter an energy barrier of 0.1 eV must be overcome explaining the low quantum yield of spiropyran to merocyanine photoswitching. PMID- 24467194 TI - Microsomal oxidation of 2,2',3,3',6,6'-hexachlorobiphenyl (PCB 136) results in species-dependent chiral signatures of the hydroxylated metabolites. AB - Chiral polychlorinated biphenyls (PCBs) display variable atropisomeric enrichment in wildlife and animal models, especially at higher trophic levels. These differences in PCBs' chiral signatures are, at least in part, due to species dependent oxidation of PCBs to hydroxylated PCB metabolites (OH-PCBs). Here, we investigate the hypothesis that the cytochrome P450 (P450) enzyme-mediated oxidation of chiral PCBs results in species-dependent differences in the chiral signatures of OH-PCBs (i.e., the direction and extent of OH-PCBs' atropisomeric enrichment). To investigate this hypothesis, we incubated PCB 136, a representative chiral PCB, with pooled human liver microsomes (HLMs) or liver microsomes from male guinea pig, hamster, monkey, mouse, and rabbit or female dog and determined average profiles and chiral signatures of the OH-PCBs. 2,2',3,3',6,6'-Hexachlorobiphenyl-4-ol (4-136) was the major metabolite in incubations with HLMs and monkey and rabbit microsomes. 2,2',3,3',6,6' Hexachlorobiphenyl-5-ol (5-136) was the major metabolite formed by microsomes from all other species. Both 4-136 and 5-136 were formed atropselectively in all microsomal incubations; however, the direction and extent of the atropisomeric enrichment of both OH-PCB metabolites showed considerable differences across microsomal preparations obtained from different species. These differences in OH PCBs' atropisomeric enrichment may not only be toxicologically relevant but may also be useful to study sources and transport of OH-PCBs in the environment. PMID- 24467196 TI - Presence of Epstein-Barr virus-infected B lymphocytes with thyrotropin receptor antibodies on their surface in Graves' disease patients and in healthy individuals. AB - Graves' disease is an autoimmune hyperthyroidism caused by thyrotropin receptor antibodies (TRAbs). Because Epstein-Barr virus (EBV) persists in B cells and is occasionally reactivated, we hypothesized that EBV contributes to TRAbs production in Graves' disease patients by stimulating the TRAbs-producing B cells. In order for EBV to stimulate antibody-producing cells, EBV must be present in those cells but that have not yet been observed. We examined whether EBV-infected (EBV(+)) B cells with TRAbs on their surface (TRAbs(+)) as membrane immunoglobulin were present in peripheral blood of Graves' disease patients. We analyzed cultured or non-cultured peripheral blood mononuclear cells (PBMCs) from 13 patients and 11 healthy controls by flow-cytometry and confocal laser microscopy, and confirmed all cultured PBMCs from 8 patients really had TRAbs(+) EBV(+) double positive cells. We unexpectedly detected TRAbs(+) cells in all healthy controls, and TRAbs(+) EBV(+) double positive cells in all cultured PBMC from eight healthy controls. The frequency of TRAbs(+) cells in cultured PBMCs was significantly higher in patients than in controls (p = 0.021). In this study, we indicated the presence of EBV-infected B lymphocytes with TRAbs on their surface, a possible player of the production of excessive TRAbs, the causative autoantibody for Graves' disease. This is a basic evidence for our hypothesis that EBV contributes to TRAbs production in Graves' disease patients. Our results further suggest that healthy controls have the potential for TRAbs production. This gives us an important insight into the pathogenesis of Graves' disease. PMID- 24467198 TI - Modeling motivation three ways: effects of MI metrics on treatment outcomes among adolescents. AB - The purpose of this study was to determine how three different measures of motivation (cognitive motivation, taking steps, and self-efficacy for change and maintenance) predict substance use outcomes after engaging in a Motivational Interviewing intervention. Participants were 225 high school students enrolled in Project Reducing the Effects of Alcohol and Drugs on Youth (Project READY), a NIDA-funded intervention initially developed with Motivational Interviewing (MI) principles for adolescents identified by schools as having problems with alcohol or other drug use. We measured motivation at multiple time points during the intervention in multiple methods. Cognitive motivation was assessed using a Decisional Balance matrix at Session 3 of treatment. We measured self-efficacy with the Situational Confidence Questionnaire, administered at 4-, 8-, 12-, and 16-week follow-ups. A measure of taking steps (SOCRATES, v. 8) was administered at intake and Session 8. We hypothesized that motivation would follow the Transtheoretical Model (TTM) pathway, and we proposed a model where cognitive motivation would predict self-confidence for change and taking steps toward change, and self-confidence and taking steps would predict substance use outcomes. We tested our model using path analysis in AMOS and found support for a motivational continuum predicting percent days abstinent at 16-week follow-up [chi(2) = 2.75, df = 7, p = .90, CFI = 1, RMSEA (90% confidence interval) = .00 - .03]. This model demonstrates that motivational metrics predict unique outcomes at different time points and serve as important components of intervention. PMID- 24467197 TI - The role of alcohol perceptions as mediators between personality and alcohol related outcomes among incoming college-student drinkers. AB - After high school, college students escalate their drinking at a faster rate than their noncollege-attending peers, and alcohol use in high school is one of the strongest predictors of alcohol use in college. Therefore, an improved understanding of the role of predictors of alcohol use during the critical developmental period when individuals transition to college has direct clinical implications to reduce alcohol-related harms. We used path analysis in the present study to examine the predictive effects of personality (e.g., impulsivity, sensation seeking, hopelessness, and anxiety sensitivity) and three measures of alcohol perception: descriptive norms, injunctive norms, and perceptions regarding the perceived role of drinking in college on alcohol related outcomes. Participants were 490 incoming freshmen college students. Results indicated that descriptive norms, injunctive norms, and the role of drinking largely mediated the effects of personality on alcohol outcomes. In contrast, both impulsivity and hopelessness exhibited direct effects on alcohol related problems. The perceived role of drinking was a particularly robust predictor of outcomes and mediator of the effects of personality traits, including sensation seeking and impulsivity on alcohol outcomes. The intertwined relationships observed in this study between personality factors, descriptive norms, injunctive norms, and the role of drinking highlight the importance of investigating these predictors simultaneously. Findings support the implementation of interventions that target these specific perceptions about the role of drinking in college. PMID- 24467200 TI - Glucocorticoids: structure, signaling and molecular mechanisms in the treatment of diabetic retinopathy and diabetic macular edema. AB - Diabetic retinopathy (DR) is one of the leading causes of blindness in the working population worldwide. Vascular leakage, angiogenesis and neuronal degeneration are key features of DR. Current effective interventions for DR include treatment of systemic risk factors such as elevated blood glucose, blood pressure and dyslipidemia. Ocular treatments include vascular endothelial growth factor A (VEGF-A) inhibitors, laser photocoagulation and surgery. While anti-VEGF therapy has become as first-line treatment for diabetic macular edema (DME) that causes reduced vision, intravitreal glucocorticoids also have been shown to be efficacious in this situation. It has been reported that all the major pathological processes of DR are susceptible to glucocorticoid treatment. The effects of glucocorticoids on vascular leakage and angiogenesis may be mediated through their well established anti-inflammatory role. Alternatively, glucocorticoids may affect other mechanisms known to be activated in DR. Potential mechanisms for the anti-inflammatory effects of glucocorticoids include blockage of cytokine production and inhibition of leukocyte adhesion induced by VEGF-A. Glucocorticoids decrease the expression of VEGF-A directly, and increase the production, or decrease phosphorylation, of tight junction-associated proteins. Glucocorticoids have also been shown to be neuroprotective, in contrast to VEGF-A inhibitors which animal studies suggest may be neurotoxic. This review outlines the biological properties of synthetic glucocorticoids, with particular emphasis on the potential beneficial effect of combining glucocorticoids with anti-VEGF treatment for DME and DR. PMID- 24467201 TI - Computational methods for analysis of dynamic events in cell migration. AB - Cell migration is a complex biological process that involves changes in shape and organization at the sub-cellular, cellular, and supra-cellular levels. Individual and collective cell migration can be assessed in vitro and in vivo starting from the flagellar driven movement of single sperm cells or bacteria, bacterial gliding and swarming, and amoeboid movement to the orchestrated movement of collective cell migration. One key technology to access migration phenomena is the combination of optical microscopy with image processing algorithms. This approach resolves simple motion estimation (e.g. preferred direction of migrating cells or path characteristics), but can also reveal more complex descriptors (e.g. protrusions or cellular deformations). In order to ensure an accurate quantification, the phenomena under study, their complexity, and the required level of description need to be addressed by an adequate experimental setup and processing pipeline. Here, we review typical workflows for processing starting with image acquisition, restoration (noise and artifact removal, signal enhancement), registration, analysis (object detection, segmentation and characterization) and interpretation (high level understanding). Image processing approaches for quantitative description of cell migration in 2- and 3-dimensional image series, including registration, segmentation, shape and topology description, tracking and motion fields are presented. We discuss advantages, limitations and suitability for different approaches and levels of description. PMID- 24467202 TI - Signaling pathways involved in neuron-astrocyte adhesion and migration. AB - Astrocytes in the normal brain possess a stellate shape reflecting their non migratory properties. Alternatively, in neurodegenerative diseases or after injury, astrocytes become "reactive" in a process known as astrocytosis or reactive gliosis, retract their processes, become polarized and acquire front-to rear asymmetry typical of migratory cells. On the other hand, neuronal migration is a common process during embryonic development, but only few types of neurons can migrate and differentiate during adult life in the central nervous system. Those that do migrate follow tracks made by glial cells and mainly give rise to interneurons. In vitro, molecular mechanisms involved in adhesion of cells to and migration on extracellular matrix proteins have been widely studied; however, signal transduction pathways explaining how particularly neurons and astrocytes, mutually modulate adhesion and migration are less well known. In this review, we describe and discuss how ligand/receptor interactions in astrocytes and neurons trigger signaling events leading to actin and microtubule reorganization, changes in cell morphology, as well as cell adhesion and migration. The biological significance these cell-cell interactions and signaling events might have in the brain are discussed. PMID- 24467203 TI - Caveolin-1 in cell migration and metastasis. AB - Caveolin-1 is a member of the caveolin family that has been ascribed a dual role in cancer. In early stages of disease the protein functions predominantly as a tumor suppressor, whereas at later stages, caveolin-1 expression is associated with tumor progression and metastasis. Here, some mechanisms associated with caveolin-1-dependent tumor suppression will be briefly discussed before focusing on the role of this protein and particularly phosphorylation of tyrosine-14 in promoting cell migration, invasion and metastasis. Models are provided summarizing possible explanations for these dramatic changes in function, as well as mechanisms by which this may be achieved. PMID- 24467205 TI - On the role of Rab5 in cell migration. AB - Uncontrolled endosome trafficking is a common feature of certain cancer cells, which has been acknowledged during the last decade. Migration and invasiveness of metastatic tumor cells are both regulated by components of the endocytic machinery, including Rab proteins. Rab GTPases are essential in processes of endosome fusion, as well as targeting, tethering and transport along the cytoskeleton. In addition to this canonical role, some Rabs depict other functions, such as controlling cell proliferation, apoptosis, adhesion and motility. Here, we review our current knowledge on the role of Rab5, a key regulator of early endosome dynamics, in migration of normal and tumor cells. Rab5 promotes cell migration in vitro and in vivo by mechanisms described at different levels. One such mechanism is by controlling the rates of integrin internalization and recycling, thereby affecting its activation and availability at the cell surface. On the other hand, Rab5 promotes focal adhesion disassembly and modulates downstream pathways of integrin signaling, involving proteins such as Ras and Rho family GTPases. In this context, identification of upstream regulators and downstream effectors of Rab5, and their study represents a big challenge in order to understand how cancer cells depend on endosome control, in order to acquire more aggressive traits that lead to metastatic disease. PMID- 24467204 TI - Caspase-8 as a regulator of tumor cell motility. AB - The caspases are a family of ubiquitously expressed cysteine proteases best known for their roles in programmed cell death. However, caspases play a number of other roles in vertebrates. In the case of caspase-8, loss of expression is an embryonic lethal phenotype, and caspase-8 plays roles in suppressing cellular necrosis, promoting differentiation and immune signaling, regulating autophagy, and promoting cellular migration. Apoptosis and migration require localization of caspase-8 in the periphery of the cells, where caspase-8 acts as part of distinct biosensory complexes that either promote migration in appropriate cellular microenvironments, or cell death in inappropriate settings. In the cellular periphery, caspase-8 interacts with components of the focal adhesion complex in a tyrosine-kinase dependent manner, promoting both cell migration in vitro and metastasis in vivo. Mechanistically, caspase-8 interacts with components of both focal adhesions and early endosomes, enhancing focal adhesion turnover and promoting rapid integrin recycling to the cell surface. Clinically, this suggests that the expression of caspase-8 may not always be a positive prognostic sign, and that the role of caspase-8 in cancer progression is likely context-dependent. PMID- 24467207 TI - Wnt signaling and cell-matrix adhesion. AB - Three decades after the beginning of the study of the Wnt signaling pathway, major contributions have been made to elucidate the molecular mechanisms that regulate this signaling pathway and its role in development, homeostasis and disease. However, there is still a lack of understanding about the relationships between Wnt signaling and cell-extracellular matrix (ECM) adhesion. Data gathered in the last years is helping to uncover these relationships. Several ECM proteins are able to regulate components of the Wnt pathway during development and disease, and their misregulation leads to changes in Wnt signaling. Fibronectin, a major ECM protein, regulates non-canonical Wnt signaling during embryogenesis in Xenopus and in muscle regeneration in mouse, whereas it modulates canonical Wnt signaling through modulation of beta-catenin. Integrins, which act as Fibronectin receptors, also modulate Wnt activity, and Syndecan-4, a heparan sulphate proteoglycan, is able to regulate canonical and non-canonical Wnt pathways, notably during embryogenesis. Other secreted ECM proteins have been recently associated to the regulation of Wnt signaling, albeit molecular mechanisms are still unclear. The non-canonical Wnt pathway plays a role in the regulation of the ECM assembly, and modulates focal adhesion dynamics through the involvement of Wnt components, whereas Wnt/beta-catenin signaling regulates the expression of genes encoding ECM proteins. This evidence indicates that Wnt signaling and cell-ECM adhesion are two closely related processes, and alterations in this cross-talk might be involved in disease. PMID- 24467209 TI - Editorial: Signaling in cell migration and disease. PMID- 24467206 TI - RhoGEFs in cell motility: novel links between Rgnef and focal adhesion kinase. AB - Rho guanine exchange factors (GEFs) are a large, diverse family of proteins defined by their ability to catalyze the exchange of GDP for GTP on small GTPase proteins such as Rho family members. GEFs act as integrators from varied intra- and extracellular sources to promote spatiotemporal activity of Rho GTPases that control signaling pathways regulating cell proliferation and movement. Here we review recent studies elucidating roles of RhoGEF proteins in cell motility. Emphasis is placed on Dbl-family GEFs and connections to development, integrin signaling to Rho GTPases regulating cell adhesion and movement, and how these signals may enhance tumor progression. Moreover, RhoGEFs have additional domains that confer distinctive functions or specificity. We will focus on a unique interaction between Rgnef (also termed Arhgef28 or p190RhoGEF) and focal adhesion kinase (FAK), a non-receptor tyrosine kinase that controls migration properties of normal and tumor cells. This Rgnef-FAK interaction activates canonical GEF dependent RhoA GTPase activity to govern contractility and also functions as a scaffold in a GEF-independent manner to enhance FAK activation. Recent studies have also brought to light the importance of specific regions within the Rgnef pleckstrin homology (PH) domain for targeting the membrane. As revealed by ongoing Rgnef-FAK investigations, exploring GEF roles in cancer will yield fundamental new information on the molecular mechanisms promoting tumor spread and metastasis. PMID- 24467208 TI - Regulation of RhoA activity by adhesion molecules and mechanotransduction. AB - The low molecular weight GTP-binding protein RhoA regulates many cellular events, including cell migration, organization of the cytoskeleton, cell adhesion, progress through the cell cycle and gene expression. Physical forces influence these cellular processes in part by regulating RhoA activity through mechanotransduction of cell adhesion molecules (e.g. integrins, cadherins, Ig superfamily molecules). RhoA activity is regulated by guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs) that are themselves regulated by many different signaling pathways. Significantly, the engagement of many cell adhesion molecules can affect RhoA activity in both positive and negative ways. In this brief review, we consider how RhoA activity is regulated downstream from cell adhesion molecules and mechanical force. Finally, we highlight the importance of mechanotransduction signaling to RhoA in normal cell biology as well as in certain pathological states. PMID- 24467212 TI - Source and fate of hydraulic fracturing water in the Barnett Shale: a historical perspective. AB - Considerable controversy continues about water availability for and potential impacts of hydraulic fracturing (HF) of hydrocarbon assets on water resources. Our objective was to quantify HF water volume in terms of source, reuse, and disposal, using the Barnett Shale in Texas as a case study. Data were obtained from commercial and state databases, river authorities, groundwater conservation districts, and operators. Cumulative water use from ~ 18,000 (mostly horizontal) wells since 1981 through 2012 totaled ~ 170,000 AF (210 Mm(3)); ~ 26 000 AF (32 Mm(3)) in 2011, representing 32% of Texas HF water use and ~ 0.2% of 2011 state water consumption. Increase in water use per well by 60% (from 3 to 5 Mgal/well; 0.011-0.019 Mm(3)) since the mid-2000s reflects the near-doubling of horizontal well lengths (2000-3800 ft), offset by a reduction in water-use intensity by 40% (2000-1200 gal/ft; 2.5-1.5 m(3)/m). Water sources include fresh surface water and groundwater in approximately equal amounts. Produced water amount is inversely related to gas production, exceeds HF water volume, and is mostly disposed in injection wells. Understanding the historical evolution of water use in the longest-producing shale play is invaluable for assessing its water footprint for energy production. PMID- 24467211 TI - Glycine decarboxylase is an unusual amino acid decarboxylase involved in tumorigenesis. AB - Glycine decarboxylase (GLDC) is a metabolic oncogene that links glycine metabolism with tumorigenesis. In humans, GLDC is part of a multienzyme complex (which includes the lipoyl-containing H-protein) that couples the decarboxylation of glycine to the biosynthesis of serine. Details of the GLDC-catalyzed glycine decarboxylation reaction are critical to drug development but remain elusive. This is the first report on the mechanism of the GLDC-catalyzed reaction and shows that GLDC is an unusual PLP-containing alpha-amino acid decarboxylase that removes carbon dioxide from the glycine substrate without releasing the expected amine (methylamine, a metabolic precursor of toxic formaldehyde) as a product. In an unusual decarboxylation mechanism, the resulting aminomethyl moiety is instead transferred to an accessory H-protein. This study defines the role of H-protein in GLDC-catalyzed glycine decarboxylation. (1) H-Protein is not required for glycine decarboxylation but, instead, is required for the release of the aminomethyl moiety from the quinonoid adduct. (2) Glycine decarboxylation is reversible and presumably proceeds through a stable quinonoid intermediate. (3) The physiological product of glycine decarboxylation is H-protein-S-aminomethyl dihydrolipoyllysine and not methylamine (in the absence of H-protein, the aminomethyl moiety remains as a quinonoid adduct). Mechanistic insights obtained from this study will inform future efforts for targeted anticancer therapeutic development. PMID- 24467213 TI - Identification of chemoresistance-related cell-surface glycoproteins in leukemia cells and functional validation of candidate glycoproteins. AB - Chemoresistance remains the most significant obstacle to successful chemotherapy for leukemia, and its exact mechanism is still unknown. In this work, we used the cell-surface capturing method together with quantitative proteomics to investigate differences in the glycoproteomes of adriamycin-sensitive and adriamycin-resistant leukemia cells. Two quantitative methods, isotopic dimethyl labeling and SWATH, were used to quantify glycoproteins, and 35 glycoproteins were quantified by both methods. High correlation was observed between the glycoproteins quantified by the above two methods, and 15 glycoproteins displayed a consistent significant change trend in both sets of quantitative results. These 15 proteins included classical multidrug resistance-related glycoproteins such as ABCB1 as well as a set of novel glycoproteins that have not previously been reported to be associated with chemoresistance in leukemia cells. Further validation with quantitative real-time PCR and Western blotting confirmed the proteomic screening results. Subsequent functional experiments based on RNA interference technology showed that CTSD, FKBP10, and SLC2A1 are novel genes that participate in the acquisition and maintenance of the adriamycin-resistant phenotype in leukemia cells. PMID- 24467214 TI - Nitrofurantoin enteric pellets with high bioavailability based on aciform crystalline formation by wet milling. AB - The aim of the present study was to grind nitrofurantoin (NF) with HPMC solution and to determine the dissolution and bioavailability of the enteric pellets prepared with the NF cogrounds and other excipients. During milling, crystalline transformation occurred--the aciform microcrystalline monohydrate II replaced the coarse crystal anhydrate beta and the particle size markedly reduced. In vitro test demonstrated that the enteric pellets prepared with NF cogrounds (4 h) revealed a faster dissolution than the commercial tablet and 50% was released within 30 min in the basic medium. Finally, an in vivo test was conducted in beagle dogs. The Cmax and AUC(0 -> 24) of the pellets were 2.19 +/- 0.74 MUg/ml and 6.73 +/- 4.71 MUg/ml h, respectively, while the corresponding values were 0.49 +/- 0.42 MUg/ml and 1.38 +/- 1.17 MUg/ml h for the tablet. Thus, the bioavailability of the pellets was increased significantly. In conclusion, the wet grinding that reduced the particle size and created the microcrystalline played a major role in the acceleration of the dissolution of NF and, consequently, enhanced the bioavailability, and the wet grinding process offers an alternative approach to improve the dissolution and bioavailability of drugs with poor aqueous solubility. PMID- 24467215 TI - Decreased cholesterol efflux capacity in patients with low cholesteryl ester transfer protein plasma levels. AB - BACKGROUND: Cholesteryl ester transfer protein (CETP) has been considered as a possible target for treatment of cardiovascular disease. However, first clinical studies employing CETP inhibitors have failed to demonstrate clinical benefit. Additionally, we have previously shown that low endogenous plasma levels of CETP are associated with increased mortality in coronary artery disease (CAD) patients. We hypothesized that low CETP plasma levels are associated with decreased high-density lipoprotein (HDL) function. MATERIALS AND METHODS: Serum HDL efflux capacity was measured in 154 patients of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study displaying extremely low (< 0.68 MUg/mL, n = 77) or high (> 2.13 MUg/mL, n = 77) CETP concentrations in their plasma, respectively. The LURIC study is a prospective observational study of patients referred to coronary angiography at baseline with a median follow-up time of 7.75 years. Primary and secondary endpoints were cardiovascular and all-cause mortality, respectively. RESULTS: High CETP patients showed a significant increase in the capacity of their plasma to mediate cholesterol efflux from cholesterol laden macrophages when compared to the efflux capacity observed in low CETP patients (+ 5.4%, P = 0.015). As shown by multiregression analysis, the impact of CETP on cholesterol efflux capacity was independent from classical risk and lifestyle factors, as well as from lipid parameters including HDL cholesterol, LDL cholesterol and triglycerides. CONCLUSIONS: Our findings indicate that low plasma concentrations of CETP might indeed lead to impaired HDL function within the reverse cholesterol transport pointing towards an atheroprotective role of CETP at least in patients with high risk of CAD. PMID- 24467216 TI - Breath testing as a method for detecting lung cancer. AB - Early diagnosis of lung cancer is important due to high mortality in late stages of the disease. An ideal approach for population screening could be the breath analysis, due to its non-invasiveness, simplicity and cheapness. Using sensitive methods of analysis like gas chromatography/mass spectrometry in exhaled air of cancer patients were discovered some volatile organic compounds - possible candidates for cancer markers. However, these compounds were not specific for cancer cells. At the same time, integrative approaches used to analyze the exhaled breath have demonstrated high sensitivity and specificity of this method for lung cancer diagnosis. Such integrative approaches include detection of smell prints by electronic nose or integrated analysis of wide range of volatile organic compounds detected by gas chromatography/mass spectrometry or related methods. Modern statistical pattern recognition systems like logistic regression analysis, support vector machine or analysis by artificial neuronal network may improve diagnostic accuracy. PMID- 24467217 TI - nab-paclitaxel for the management of patients with advanced non-small-cell lung cancer. AB - The 130 nm albumin-bound form of paclitaxel, nab-paclitaxel (Abraxane((r))), was recently approved by the US FDA for the first-line treatment of locally advanced or metastatic non-small-cell lung cancer (NSCLC) in combination with carboplatin in patients who are not candidates for curative surgery or radiation therapy. In a Phase III registrational trial, nab-paclitaxel plus carboplatin demonstrated a significantly improved overall response rate, the primary endpoint, and a trend toward improved survival compared with solvent-based paclitaxel plus carboplatin in patients with advanced NSCLC. Significantly less neutropenia, neuropathy, arthralgia, and myalgia were observed with the nab-paclitaxel regimen, but the solvent-based paclitaxel regimen produced less thrombocytopenia and anemia. The clinical experience with nab-paclitaxel to date and the role of this newly approved therapy in the management of NSCLC will be summarized in this article. PMID- 24467218 TI - Hollow cocoon-like hematite mesoparticles of nanoparticle aggregates: structural evolution and superior performances in lithium ion batteries. AB - We report the facile, fast, and template-free preparation of hollow alpha-Fe2O3 with unique cocoon-like structure by a one-pot hydrothermal method without any surfactants in a short reaction time of 3 h only. In contrast, typical hydrothermal methods to prepare inorganic hollow structures require 24 h or a few days. Templates and/or surfactants are typically used. The hollow alpha-Fe2O3 nanococoon was thoroughly characterized by field-emission scanning electron microscopy (FESEM), transmission electron microscopy (TEM), and X-ray diffraction (XRD). Ex situ analysis of a series of samples prepared at different reaction times clearly revealed the structural evolution and possible formation mechanism. Superior electrochemical performance in terms of cyclability, specific capacity, and high rate was achieved, which could be attributed to its unique hollow cocoon like structure. Structural stability was revealed by analyzing the samples after 120 charge-discharge cycles. The unusual structural stability of the hollow alpha Fe2O3 nanococoons after 120 cycles, which is rarely observed for transition metal oxides of particle aggregates, will guarantee further research investigation. Experimental evidence further demonstrated that hollow nanococoons exceed solid nanococoons in reversible lithium-ion storage. PMID- 24467219 TI - Continuous low-dose cyclophosphamide and prednisone in the treatment of relapsed/refractory multiple myeloma with severe heart failure. AB - Patients with relapsed/refractory (R/R) multiple myeloma (MM) complicated by severe heart failure typically do not tolerate conventional chemotherapy. Our previous study indicated that R/R MM patients with severe comorbidities could benefit from continuous low-dose oral cyclophosphamide and prednisone (CP regimen). We hereby performed a study of 56 R/R MM patients with severe heart failure (New York Heart Association class >= III) receiving the treatment of CP regimen. Among the 54 evaluable patients, clinical benefit was noted in 63.0% (complete response, 3.7%; very good partial response, 7.4%; partial response, 48.1%; stable disease, 3.7%). The median overall survival (OS) and progression free survival (PFS) were 8 and 6 months. The left ventricular ejection fraction (LVEF) and the serum levels of B-type natriuretic peptide (BNP) were improved significantly. Slight adverse events were observed. In summary, the CP regimen is effective in R/R MM patients complicated with severe heart failure. PMID- 24467220 TI - Acute respiratory failure from nilotinib-associated diffuse alveolar hemorrhage. PMID- 24467221 TI - Treatment of de novo acute myeloid leukemia in the United States: a report from the Patterns of Care program. AB - Few US studies have examined patterns of care (POC) for acute myeloid leukemia (AML) in community settings. We examined treatment and survival in 978 adults with AML sampled from Surveillance, Epidemiology, and End Results (SEER) registries through the POC program. Logistic regression was used to evaluate the association between patient/hospital characteristics and receipt of chemotherapy and allogeneic transplant. Survival was examined using proportional hazards models. Treatment with cytarabine/anthracycline occurred in > 80% of patients without acute promeyelocytic leukemia (non-APL) < 60, but only about one-third of older non-APL patients. Ultimately, 27% of those < 60 received an allogeneic transplant. Thirty-seven percent of those < 40 and 4% of those >= 80 were alive at the end of follow-up. About three-quarters of patients with APL received all trans retinoic acid (ATRA) and either an anthracycline or arsenic trioxide, with 71% surviving. Age and APL diagnosis were the strongest predictors of treatment and survival. Trends in dissemination of novel diagnostic tests and treatments and in survival will be monitored by POC in future years. PMID- 24467223 TI - Evaluation of N95 filtering facepiece respirator efficiency with cyclic and constant flows. AB - An increasing demand for protecting workers against harmful inhalable ultrafine particles (UFPs), by means of filtering facepiece respirators (FFRs), necessitates assessing the efficiency of FFRs. This article evaluates the penetration of particles, mostly in the ultrafine range, through one model of N95 FFRs exposed to cyclic and constant flows, simulating breathing for moderate to heavy work loads. The generated particles were poly-dispersed NaCl, within the range of 10-205.4 nm. The tests were performed for several cyclic flows, with mean inhalation flows (MIFs) ranging from 42 to 360 L/min, and constant flows with the same range. The measurements were based on filter penetration and did not consider particle leakage. With the penetrations recorded for the selected constant and cyclic flows, the worst-case scenario penetrations at the most penetrating particle size (MPPS) were obtained. The MPPS penetrations measured with the cyclic and constant flows equivalent to minute volume, MIF and peak inhalation flow (PIF) of the cyclic flows were then compared. It was indicated that the constant flows equivalent to the minute volume or PIF of the cyclic flow could not accurately represent the penetration of the corresponding cyclic flow: the constant flow equal to the minute volume of the cyclic flow significantly underestimated the MPPS penetration of the corresponding cyclic flow, while the constant flow equal to the PIF of the cyclic flow overestimated it. On the other hand, for the constant flow equal to the MIF of the cyclic flow, the MPPS penetrations were almost equal for both the constant and cyclic flows, for the lower flow rates (42 to 170 L/min). For higher flow rates (230 to 360 L/min), however, the MPPS penetration was exceeded under the constant flows, compared with the corresponding cyclic flows. It was therefore concluded that the constant flow equal to the MIF of the cyclic flow could better predict the results of corresponding cyclic flow, since it could provide the MPPS penetrations (worst case scenario) equal to or greater than the MPPS penetrations of the cyclic flow. PMID- 24467222 TI - Epac and the high affinity rolipram binding conformer of PDE4 modulate neurite outgrowth and myelination using an in vitro spinal cord injury model. AB - BACKGROUND AND PURPOSE: cAMP and pharmacological inhibition of PDE4, which degrades it, are promising therapeutic targets for the treatment of spinal cord injury (SCI). Using our previously described in vitro SCI model, we studied the mechanisms by which cAMP modulators promote neurite outgrowth and myelination using enantiomers of the PDE4-specific inhibitor rolipram and other modulators of downstream signalling effectors. EXPERIMENTAL APPROACH: Rat mixed neural cell myelinating cultures were cut with a scalpel and treated with enantiomers of the PDE4-specific inhibitor rolipram, Epac agonists and PKA antagonists. Neurite outgrowth, density and myelination were assessed by immunocytochemistry and cytokine levels analysed by qPCR. KEY RESULTS: Inhibition of the high-affinity rolipram-binding state (HARBS), rather than the low-affinity rolipram binding state (LARBS) PDE4 conformer promoted neurite outgrowth and myelination. These effects were mediated through the activation of Epac and not through PKA. Expression of the chemokine CXCL10, known to inhibit myelination, was markedly elevated in astrocytes after Rho inhibition and this was blocked by inhibition of Rho kinase or PDE4. CONCLUSIONS AND IMPLICATIONS: PDE4 inhibitors targeted at the HARBS conformer or Epac agonists may provide promising novel targets for the treatment of SCI. Our study demonstrates the differential mechanisms of action of these compounds, as well as the benefit of a combined pharmacological approach and highlighting potential promising targets for the treatment of SCI. These findings need to be confirmed in vivo. PMID- 24467224 TI - Focal adhesion protein expression in human diffuse large B-cell lymphoma. AB - AIMS: Focal adhesions have been associated with poor prognosis in multiple cancer types, but their prognostic value in diffuse large B-cell lymphoma (DLBCL) has not been evaluated. The aim of this study was to investigate the expression patterns and the prognostic value of the focal adhesion proteins FAK, Pyk2, p130Cas and HEF1 in DLBCL. METHODS AND RESULTS: Focal adhesion protein expression was examined using immunohistochemistry in normal lymphoid tissues and in 60 DLBCL patient samples. Kaplan-Meier survival and Cox regression analysis were performed to evaluate the correlation of focal adhesion protein expression with patient prognosis. FAK, Pyk2, p130Cas and HEF1 expression was mostly found in the germinal centres of normal human lymphoid tissues. When assessed in DLBCL samples, FAK, Pyk2, p130Cas and HEF1 were highly expressed in 45%, 34%, 42% and 45% of the samples, respectively. Multivariate Cox analysis revealed that decreased FAK expression was a significant independent predictor of poorer disease outcome. CONCLUSIONS: FAK expression is an independent prognostic factor in DLBCL. Our results suggest that the addition of FAK immunostaining to the current immunohistochemical algorithms may facilitate risk stratification of DLBCL patients. PMID- 24467225 TI - Effective connectivity maps in the swine somatosensory cortex estimated from electrocorticography and validated with intracortical local field potential measurements. AB - Macroscopic techniques are increasingly being used to estimate functional connectivity in the brain, which provides valuable information about brain networks. In any such endeavors it is important to understand capabilities and limitations of each technique through direct validation, which is often lacking. This study evaluated a multiple dipole source analysis technique based on electrocorticography (ECOG) data in estimating effective connectivity maps and validated the technique with intracortical local field potential (LFP) recordings. The study was carried out in an animal model (swine) with a large brain to avoid complications caused by spreading of the volume current. The evaluation was carried out for the cortical projections from the trigeminal nerve and corticocortical connectivity from the first rostrum area (R1) in the primary somatosensory cortex. Stimulation of the snout and layer IV of the R1 did not activate all projection areas in each animal, although whenever an area was activated in a given animal, its location was consistent with the intracortical LFP. The two types of connectivity maps based on ECOG analysis were consistent with each other and also with those estimated from the intracortical LFP, although there were small discrepancies. The discrepancies in mean latency based on ECOG and LFP were all very small and nonsignificant: snout stimulation, -1.1 2.0 msec (contralateral hemisphere) and 3.9-8.5 msec (ipsilateral hemisphere); R1 stimulation, -1.4-2.2 msec for the ipsilateral and 0.6-1.4 msec for the contralateral hemisphere. Dipole source analysis based on ECOG appears to be quite useful for estimating effective connectivity maps in the brain. PMID- 24467227 TI - Serum 25-hydroxyvitamin D levels and self-reported allergic rhinitis in Norwegian adults - The HUNT Study. AB - BACKGROUND: The role of low vitamin D status in the development of allergic rhinitis is unclear. We aimed to investigate the relationship between serum 25 hydroxyvitamin D [25(OH)D] and incidence of allergic rhinitis in adults. METHODS: The study included a random sample from an adult population who participated in the second and third surveys of the Nord-Trondelag Health Study (HUNT) in Norway (HUNT2, 1995-1997 and HUNT3, 2006-2008). Serum 25(OH)D levels were measured in blood samples collected at baseline. Among 1351 adults who did not report allergic rhinitis at baseline, incident allergic rhinitis was identified by participant report of having or having had allergic rhinitis or hay fever at follow-up. Adjusted odds ratios (AOR) and 95% confidence intervals (CI) were calculated after adjustment for age, smoking, physical activity, socioeconomic status, family history of allergy, body mass index, and season. The analyses were stratified by sex due to its significant interaction with 25(OH)D levels (P < 0.02). RESULTS: Over an average of 11 years, 9% of men and 15% of women developed allergic rhinitis. Among men, serum 25(OH)D level <50 nM was associated with an increased risk of incident allergic rhinitis (AOR 2.55; 95% CI 1.01-6.49); each 25 nM reduction in 25(OH)D level was associated with an AOR of 1.84 (95% CI 1.18 2.87). In women, however, the association was opposite, with AOR being 0.83 (95% CI 0.66-1.05) for each 25 nM reduction in serum 25(OH)D level. CONCLUSIONS: Vitamin D appears to play different roles in the development of allergic rhinitis among men and women. PMID- 24467226 TI - Inhibiting metastatic breast cancer cell migration via the synergy of targeted, pH-triggered siRNA delivery and chemokine axis blockade. AB - Because breast cancer patient survival inversely correlates with metastasis, we engineered vehicles to inhibit both the C-X-C chemokine receptor type 4 (CXCR4) and lipocalin-2 (Lcn2) mediated migratory pathways. pH-responsive liposomes were designed to protect and trigger the release of Lcn2 siRNA. Liposomes were modified with anti-CXCR4 antibodies to target metastatic breast cancer (MBC) cells and block migration along the CXCR4-CXCL12 axis. This synergistic approach- coupling the CXCR4 axis blockade with Lcn2 silencing--significantly reduced migration in triple-negative human breast cancer cells (88% for MDA-MB-436 and 92% for MDA-MB-231). The results suggested that drug delivery vehicles engineered to attack multiple migratory pathways may effectively slow progression of MBC. PMID- 24467228 TI - Intramolecular vibrational dynamics in free polyatomic molecules with C?O chromophore bond excited by resonant femtosecond IR laser radiation. AB - In nine polyatomic molecules, we have studied the intramolecular redistribution of vibrational energy from chromophore C?O group excited by a resonant femtosecond IR laser radiation at a wavelength of ~5 MUm. All experiments have been performed in the gas phase using the IR-IR pump-probe technique in combination with the spectral analysis of the probe radiation. For molecules with one C?O end group, characteristic times of intramolecular vibrational redistribution (IVR) lie in the range between 2.4 and 20 ps and correlate with the density of four-frequency Fermi resonances. The IVR times in metal carbonyl molecules are anomalously long, being ~1.0 ns for Fe(CO)5 and ~1.5 ns for Cr(CO)6. In the CH3(C?O)OC2H5 and H2CCH(C?O)OC2H5 molecules, it has been observed that there are two characteristic IVR times, which differ by an order of magnitude from each other; this was interpreted in terms of the developed model of "accumulating states". For the ICF2COF molecule, it has been revealed that the IVR time decreases with increasing level of the vibrational excitation of the C?O bond of the molecule. PMID- 24467230 TI - Environmental and health impacts of artificial turf: a review. AB - With significant water savings and low maintenance requirements, artificial turf is increasingly promoted as a replacement for natural grass on athletic fields and lawns. However, there remains the question of whether it is an environmentally friendly alternative to natural grass. The major concerns stem from the infill material that is typically derived from scrap tires. Tire rubber crumb contains a range of organic contaminants and heavy metals that can volatilize into the air and/or leach into the percolating rainwater, thereby posing a potential risk to the environment and human health. A limited number of studies have shown that the concentrations of volatile and semivolatile organic compounds in the air above artificial turf fields were typically not higher than the local background, while the concentrations of heavy metals and organic contaminants in the field drainages were generally below the respective regulatory limits. Health risk assessment studies suggested that users of artificial turf fields, even professional athletes, were not exposed to elevated risks. Preliminary life cycle assessment suggested that the environmental impacts of artificial turf fields were lower than equivalent grass fields. Areas that need further research to better understand and mitigate the potential negative environmental impacts of artificial turf are identified. PMID- 24467231 TI - Thoracic limb alignment in healthy labrador retrievers: evaluation of standing versus recumbent frontal plane radiography. AB - OBJECTIVE: To report thoracic limb alignment values in healthy dogs; to determine if limb alignment values are significantly different when obtained from standing versus recumbent radiographic projections. STUDY DESIGN: Prospective cross sectional study. ANIMALS: Labrador Retrievers (n = 45) >15 months of age. METHODS: Standing and recumbent radiographs were obtained and limb montages were randomized before analysis by a single investigator blinded to dog, limb, and limb position. Twelve limb alignment values were determined using the CORA methodology. Measurements were performed in triplicate and intra-observer variability was evaluated by intra-class correlation coefficient (ICC). Limb alignment values were reported as mean +/- SD and 95% confidence intervals. Linear mixed models were used to determine if significant associations existed between limb alignment values and limb, limb position, gender, age, weight, and body condition score. RESULTS: There were significant differences in standing and recumbent limb alignment values for all values except elbow mechanical axis deviation (eMAD). Limb, gender, age, body weight, and body condition score had no effect. ICC values ranged from 0.522 to 0.758, indicating moderate to substantial agreement for repeated measurements by a single investigator. CONCLUSIONS: Limb alignment values are significantly different when determined from standing versus recumbent radiographs in healthy Labrador Retrievers. PMID- 24467232 TI - Using mass spectrometry to monitor monoclonal immunoglobulins in patients with a monoclonal gammopathy. AB - A monoclonal gammopathy is defined by the detection a monoclonal immunoglobulin (M-protein). In clinical practice, the M-protein is detected by protein gel electrophoresis (PEL) and immunofixation electrophoresis (IFE). We theorized that molecular mass could be used instead of electrophoretic patterns to identify and quantify the M-protein because each light and heavy chain has a unique amino acid sequence and thus a unique molecular mass whose increased concentration could be distinguished from the normal polyclonal background. In addition, we surmised that top-down MS could be used to isotype the M-protein because each immunoglobulin has a constant region with an amino acid sequence unique to each isotype. Our method first enriches serum for immunoglobulins followed by reduction using DTT to separate light chains from heavy chains and then by microflow LC-ESI-Q-TOF MS. The multiply charged light and heavy chain ions are converted to their molecular masses, and reconstructed peak area calculations for light chains are used for quantification. Using this method, we demonstrate how the light chain portion of an M-protein can be monitored by molecular mass, and we also show that in sequential samples from a patient with multiple myeloma the light chain portion of the M-protein was detected in all samples, even those negative by PEL, IFE, and quantitative FLC. We also present top-down MS isotyping of M-protein light chains using a unique isotype-specific fragmentation pattern allowing for quantification and isotype identification in the same run. Our results show that microLC-ESI-Q-TOF MS provides superior sensitivity and specificity compared to conventional methods and shows promise as a viable method of detecting and isotyping an M-protein. PMID- 24467234 TI - Influence of electronic and formulation variables on transdermal iontophoresis of tacrine hydrochloride. AB - Freshly excised rat skin and side-by-side permeation cells were used to study the effect of electronic and formulation variables on transdermal iontophoretic delivery of tacrine. Current strength at 0.1-0.3 mA was observed to be the driving force resulting in tacrine permation flux of 30.3-366.6 MUg/cm(2)/h. Depot formation of tacrine and altered skin permeability resulted in post iontophoretic flux even after termination of applied current. Increase in the duration of current application did not show significant difference in tacrine permeation flux upto 6 h. Tacrine permeation was directly proportional to tacrine concentration upto 10 mg/ml but further increase in concentration (upto 20 mg/ml) exhibited permeation flux plateau. Buffer molarity had an inverse relationship on permeation flux and the presence of co-ions in formulation exhibited reduced permeation flux. Permeation flux decreased when pH of formulation was successively increased from 7.0 to 10.0 suggesting electromigration of tacrine. Alternate buffer systems including HEPES and Tris showed improved tacrine permeation due to their larger ion size compared to phosphate buffer ions. The results of this study show that transdermal tacrine permeation can be controlled by electronic and formulation variables which would be useful for the development of transdermal iontophoretic delivery of tacrine for the treatment of Alzehimer's disease. PMID- 24467235 TI - Anti-inflammatory effects of rosuvastatin in healthy subjects: a prospective longitudinal study. AB - AIMS: The aims of this study were to determine a mechanism and general timeline for statin related anti-inflammatory activity. METHODS: Healthy male subjects received rosuvastatin (20 mg daily) for 3 weeks. Blood samples before and after treatment were collected for clinical laboratories and research procedures. Toll like receptor-4 (tlr-4) expression on blood monocytes was measured using flow cytometry before and after rosuvastatin treatment. Inflammatory molecules were measured before and after rosuvastatin and after blood samples were incubated for 3 hours with or without lipopolysaccharide. Plasma was collected and analyzed for IL-6, TNF-alpha, IL-8, IGF-1, and sCD14. Comparisons were made using Mann-Whitney rank sum test and paired Student's t-test with significance defined as p<=0.05. KEY FINDINGS: The expression oftlr-4on blood monocytes was significantly lower after 3 weeks of rosuvastatin (p = 0.046). Consistent with the reduced expression of tlr-4, the TNF-alpha release from blood receiving LPS trended lower (p = 0.08). None of the other inflammatory markers (IL-8, sCD14, IL-6, IGF-1, C reactive protein) were modified with rosuvastatin treatment. There were significant declines in total cholesterol (p<0.0001), low-density lipoprotein cholesterol (LDL-C) (p<0.0001), and total cholesterol/high-density lipoprotein cholesterol (HDL-C) ratio (p<0.0001) after 3 weeks of treatment. There was no significant effect on triglycerides, very low-density lipoprotein cholesterol (VLDL-C), or HDL-C. SIGNIFICANCE: The decline in tlr-4 expression on blood monocytes and TNF-alpha plasma concentrations after 3 weeks of rosuvastatin treatment suggest a potential mechanism for the anti-inflammatory activity of rosuvastatin. PMID- 24467236 TI - Examining photoinduced energy transfer in Pseudomonas aeruginosa azurin. AB - Pseudomonas aeruginosa azurin has been an important model system for investigating fundamental electron transfer (EleT) in proteins. Early pioneering studies used ruthenium photosensitizers to induce EleT in azurin and this experimental data continues to be used to develop theories for EleT mediated through a protein matrix. In this study we show that putative EleT rates in the P. aeruginosa azurin model system, measured via photoinduced methods, can also be explained by an alternate energy transfer (EngT) mechanism. Investigation of EngT in azurin, conducted in this study, isolates and resolves confounding phenomena- i.e., zinc contamination and excited state emission--that can lead to erroneous kinetic assignments. Here we employ two azurin photosensitizer systems, the previously reported Ru(2,2'-bipyridine)2(imidazole) and an unreported phototrigger, Ru(bpy)2(phen-IA), Ru(2,2'-bipyridine)2(5-iodoacetamido-1,10 phenanthroline), that has a longer lifetime, to better resolve convoluted kinetic observations and allow us to draw clear distinctions between photoinduced EngT and EleT. Extensive metal analysis, in addition to electrochemical and photochemical (photoinduced transfer) measurements, suggests Zn-metalated azurin contamination can result in a biexponential reaction, which can be mistaken for EleT. Namely, upon photoinduction, the observed slow phase is exclusively the contribution from Zn-metalated azurin, not EleT, whereas the fast phase is the result of EngT between the photosensitizer and the Cu-site, rather than simple excited-state decay of the phototrigger. PMID- 24467237 TI - HSA-based anti-inflammatory therapy: a new and improved approach. PMID- 24467238 TI - Realistically, how far are we from a universal malaria drug? PMID- 24467240 TI - Proposing advancement criteria for efficient DMPK triage of new chemical entities. AB - With the goal of refining our discovery DMPK workflow, we conducted a retrospective analysis on internal Celgene compounds by calculating the physicochemical properties and gathering data from several assays including solubility, rat and human liver S9 stability, Caco-2 permeability, and rat intravenous (iv.) and oral pharmacokinetics. Our analysis identified plasma clearance to be most statistically relevant for prediction of oral exposure. In rat, compounds with rat S9 stability of >=70% at 60 min and a plasma clearance of <=43 ml/min/kg had the greatest chance of achieving oral exposures above 3 uM.h. Compounds with the dual advantage of plasma clearance <=43 ml/min/kg and Caco-2 permeability >=8 * 10(-6) cm/s or efflux ratio <=8 were highly likely to achieve those oral exposures. Implementation of these criteria leads to a significant increase in efficiency, good pharmacokinetic properties, cost savings and a reduction in the use of animals. PMID- 24467241 TI - An insight on bacterial cellular targets of photodynamic inactivation. AB - The emergence of microbial resistance is becoming a global problem in clinical and environmental areas. As such, the development of drugs with novel modes of action will be vital to meet the threats created by the rise in microbial resistance. Microbial photodynamic inactivation is receiving considerable attention for its potentialities as a new antimicrobial treatment. This review addresses the interactions between photosensitizers and bacterial cells (binding site and cellular localization), the ultrastructural, morphological and functional changes observed at initial stages and during the course of photodynamic inactivation, the oxidative alterations in specific molecular targets, and a possible development of resistance. PMID- 24467242 TI - Design of inhibitors of ODCase. AB - ODCase is a highly proficient enzyme responsible for the decarboxylation of orotidine monophosphate to generate uridine monophosphate. ODCase has attracted early attention due to its interesting mechanism of catalysis. In order to exploit therapeutic advantages due to the inhibition of ODCase, one must have selective inhibitors of this enzyme from the pathogen, or a dysregulated molecular mechanism involving ODCase. ODCase inhibitors have potential applications as anticancer agents, antiviral agents, antimalarial agents and potentially act against other parasitic diseases. A variety of C6-substituted uridine monophosphate derivatives have shown excellent inhibition of ODCase. 6 iodouridine is a potent inhibitor of the malaria parasite, and its monophosphate form covalently inhibits ODCase. A variety of inhibitors of ODCase with potential applications as therapeutic agents are discussed in this review. PMID- 24467243 TI - Phenotypic screening and fragment-based approaches to the discovery of small molecule bromodomain ligands. AB - Bromodomains are protein modules that bind to acetylated lysine residues and hence facilitate protein-protein interactions. These bromodomain-mediated interactions often play key roles in transcriptional regulation and their dysfunction is implicated in a large number of diseases. The discovery of potent and selective small-molecule bromodomain and extra C-terminal domain bromodomain ligands, which show promising results for the treatment of cancers and atherosclerosis, has promoted intense interest in this area. Here we describe the progress that has been made to date in the discovery of small-molecule bromodomain ligands, with particular emphasis on the roles played by phenotypic screening and fragment-based approaches. In considering the future of the field we discuss the prospects for development of molecular probes and drugs for the non-bromodomain and extra C-terminal domain bromodomains. PMID- 24467244 TI - The therapeutic potential of miRNAs regulated in settings of physiological cardiac hypertrophy. AB - Cardiac hypertrophy is broadly defined as an increase in heart mass. Heart enlargement in a setting of cardiac disease is referred to as pathological hypertrophy and often progresses to heart failure. Physiological hypertrophy refers to heart growth in response to postnatal development, exercise training and pregnancy, and is an adaptive response associated with the activation of cardioprotective signaling cascades. miRNAs have emerged as novel therapeutic targets for numerous pathologies, and miRNA-based therapies have already entered clinical trials. The identification of miRNAs differentially regulated during physiological growth may open up new therapeutic approaches for heart failure. In this review, we present information on miRNAs regulated in models of physiological hypertrophy, describe preclinical cardiac disease studies that have successfully targeted miRNAs regulated in settings of physiological growth (miR 34, miR-15, miR-199b, miR-208a and miR-378), and discuss challenges to overcome for the safe entry of miRNA-based therapies into the clinic for heart failure patients. PMID- 24467245 TI - Therapeutic modulation of prostate cancer metastasis. AB - Targeting prostate cancer metastasis has very high therapeutic potential. Prostate cancer is the second most common cause of cancer death among men in the USA, and death results from the development of metastatic disease. In order to metastasize, cancer cells must complete a series of steps that together constitute the metastatic cascade. Each step therefore offers the opportunity for therapeutic targeting. However, practical limitations have served as limiting roadblocks to successfully targeting the metastatic cascade. They include our still-emerging understanding of the underlying biology, as well as the fact that many of the dysregulated processes have critical functionality in otherwise normal cells. We provide a discussion of the underlying biology, as it relates to therapeutic targeting. Therapeutic inroads are rapidly being made, and we present a series of case studies to highlight key points. Finally, future perspectives related to drug discovery for antimetastatic agents are discussed. PMID- 24467246 TI - Decreased genetic dosage of hepatic Yin Yang 1 causes diabetic-like symptoms. AB - Insulin sensitivity in liver is characterized by the ability of insulin to efficiently inhibit glucose production and fatty acid oxidation as well as promote de novo lipid biosynthesis. Specific dysregulation of glucose and lipid metabolism in liver is sufficient to cause insulin resistance and type 2 diabetes; this is seen by a selective inability of insulin to suppress glucose production while remaining insulin-sensitive to de novo lipid biosynthesis. We have previously shown that the transcription factor Yin Yang 1 (YY1) controls diabetic-linked glucose and lipid metabolism gene sets in skeletal muscle, but whether liver YY1-targeted metabolic genes impact a diabetic phenotype is unknown. Here we show that decreased genetic dosage of YY1 in liver causes insulin resistance, hepatic lipid accumulation, and dyslipidemia. Indeed, YY1 liver-specific heterozygous mice exhibit blunted activation of hepatic insulin signaling in response to insulin. Mechanistically, YY1, through direct recruitment to promoters, functions as a suppressor of genes encoding for metabolic enzymes of the gluconeogenic and lipogenic pathways and as an activator of genes linked to fatty acid oxidation. These counterregulatory transcriptional activities make targeting hepatic YY1 an attractive approach for treating insulin resistant diabetes. PMID- 24467248 TI - Tradeoffs and Synergies between biofuel production and large solar infrastructure in deserts. AB - Solar energy installations in deserts are on the rise, fueled by technological advances and policy changes. Deserts, with a combination of high solar radiation and availability of large areas unusable for crop production are ideal locations for large solar installations. However, for efficient power generation, solar infrastructures use large amounts of water for construction and operation. We investigated the water use and greenhouse gas (GHG) emissions associated with solar installations in North American deserts in comparison to agave-based biofuel production, another widely promoted potential energy source from arid systems. We determined the uncertainty in our analysis by a Monte Carlo approach that varied the most important parameters, as determined by sensitivity analysis. We considered the uncertainty in our estimates as a result of variations in the number of solar modules ha(-1), module efficiency, number of agave plants ha(-1), and overall sugar conversion efficiency for agave. Further, we considered the uncertainty in revenue and returns as a result of variations in the wholesale price of electricity and installation cost of solar photovoltaic (PV), wholesale price of agave ethanol, and cost of agave cultivation and ethanol processing. The life-cycle analyses show that energy outputs and GHG offsets from solar PV systems, mean energy output of 2405 GJ ha(-1) year(-1) (5 and 95% quantile values of 1940-2920) and mean GHG offsets of 464 Mg of CO2 equiv ha(-1) year(-1) (375 562), are much larger than agave, mean energy output from 206 (171-243) to 61 (50 71) GJ ha(-1) year(-1) and mean GHG offsets from 18 (14-22) to 4.6 (3.7-5.5) Mg of CO2 equiv ha(-1) year(-1), depending upon the yield scenario of agave. Importantly though, water inputs for cleaning solar panels and dust suppression are similar to amounts required for annual agave growth, suggesting the possibility of integrating the two systems to maximize the efficiency of land and water use to produce both electricity and liquid fuel. A life-cycle analysis of a hypothetical colocation indicated higher returns per m(3) of water used than either system alone. Water requirements for energy production were 0.22 L MJ(-1) (0.28-0.19) and 0.42 L MJ(-1) (0.52-0.35) for solar PV-agave (baseline yield) and solar PV-agave (high yield), respectively. Even though colocation may not be practical in all locations, in some water-limited areas, colocated solar PV-agave systems may provide attractive economic incentives in addition to efficient land and water use. PMID- 24467247 TI - Inactivation of dust mites, dust mite allergen, and mold from carpet. AB - Carpet is known to be a reservoir for biological contaminants, such as dust mites, dust mite allergen, and mold, if it is not kept clean. The accumulation of these contaminants in carpet might trigger allergies or asthma symptoms in both children and adults. The purpose of this study is to compare methods for removal of dust mites, dust mite allergens, and mold from carpet. Carpets were artificially worn to simulate 1 to 2 years of wear in a four-person household. The worn carpets were inoculated together with a common indoor mold (Cladosporium species) and house dust mites and incubated for 6 weeks to allow time for dust mite growth on the carpet. The carpets were randomly assigned to one of the four treatment groups. Available treatment regimens for controlling carpet contaminants were evaluated through a literature review and experimentation. Four moderately low-hazard, nondestructive methods were selected as treatments: vacuuming, steam-vapor, Neem oil (a natural tree extract), and benzalkonium chloride (a quaternary ammonium compound). Steam vapor treatment demonstrated the greatest dust mite population reduction (p < 0.05) when compared to other methods. The two physical methods, steam vapor and vacuuming, have no statistically significant efficacy in inactivating dust mite allergens (p = 0.084), but have higher efficacy when compared to the chemical method on dust mite allergens (p = 0.002). There is no statistically significant difference in the efficacy for reducing mold in carpet (p > 0.05) for both physical and chemical methods. The steam-vapor treatment effectively killed dust mites and denatured dust mite allergen in the laboratory environment. PMID- 24467249 TI - Co-infection of mallards with low-virulence Newcastle disease virus and low pathogenic avian influenza virus. AB - Waterfowl are considered the natural reservoir of low-virulence Newcastle disease viruses (loNDVs) and low-pathogenic avian influenza viruses (LPAIVs). The objective of this study was to investigate the effect of co-infections with loNDV and LPAIV on the infectivity and excretion of these viruses in mallards. One month-old mallards were inoculated intranasally with 10(6) median embryo infectious doses of a wild-bird-origin loNDV and A/Mallard/MN/199106/99 (H3N8) LPAIV on the same day or received the LPAIV 2 or 5 days after loNDV inoculation. All mallards became infected with both viruses based on detection of seroconversion and viral shedding. Co-infection resulted in a higher number of cloacal swabs detected positive for LPAIV and a lower number of cloacal swabs detected positive for loNDV in some groups, although differences between groups were not statistically significant. Co-infection did not affect replication of LPAIV in epithelial cells of the lower intestine and bursa of Fabricius. In summary, the results of this study indicate that co-infection with LPAIV and loNDV does not affect the ability of mallards to be infected with either virus although it may have minimal effects on patterns (source and timing) of viral shedding. PMID- 24467250 TI - Nonplanar donor-acceptor chiral molecules with large second-order optical nonlinearities: 1,1,4,4-tetracyanobuta-1,3-diene derivatives. AB - We have investigated the chiroptical, linear, and second-order nonlinear optical (NLO) properties of five 1,1,4,4-tetracyanobuta-1,3-diene (TCBD) derivatives and elucidated structure-property relationships from the micromechanism. The experimental UV-vis absorption and circular dichroism (CD) spectra were well reproduced by our calculations at TDB3LYP/6-31+G* level of theory. The electron transition property and chiroptical origin have been assigned and analyzed. The results show that the studied compounds possess large molecular first hyperpolarizabilities, especially for compound 5 which has a value of 35 * 10( 30) esu, which is comparable with the measured value for highly pi-delocalized phenyliminomethyl ferrocene complex and about 200 times larger than the average first hyperpolarizability of the organic urea molecule. Despite the nonplanarity of these compounds, efficient intramolecular charge transfer (CT) from electron donor to electron acceptor moieties was observed, which plays the key role in determining the NLO response. The intramolecular charge transfer cooperativity was also probed. In view of the first hyperpolarizability values, intrinsic noncentrosymmetric electronic structure, and high stability, the studied compounds have the possibility to be excellent second-order NLO materials. PMID- 24467251 TI - Cbln1 downregulates the formation and function of inhibitory synapses in mouse cerebellar Purkinje cells. AB - The formation of excitatory and inhibitory synapses must be tightly coordinated to establish functional neuronal circuitry during development. In the cerebellum, the formation of excitatory synapses between parallel fibers and Purkinje cells is strongly induced by Cbln1, which is released from parallel fibers and binds to the postsynaptic delta2 glutamate receptor (GluD2). However, Cbln1's role, if any, in inhibitory synapse formation has been unknown. Here, we show that Cbln1 downregulates the formation and function of inhibitory synapses between Purkinje cells and interneurons. Immunohistochemical analyses with an anti-vesicular GABA transporter antibody revealed an increased density of interneuron-Purkinje cell synapses in the cbln1-null cerebellum. Whole-cell patch-clamp recordings from Purkinje cells showed that both the amplitude and frequency of miniature inhibitory postsynaptic currents were increased in cbln1-null cerebellar slices. A 3-h incubation with recombinant Cbln1 reversed the increased amplitude of inhibitory currents in Purkinje cells in acutely prepared cbln1-null slices. Furthermore, an 8-day incubation with recombinant Cbln1 reversed the increased interneuron-Purkinje cell synapse density in cultured cbln1-null slices. In contrast, recombinant Cbln1 did not affect cerebellar slices from mice lacking both Cbln1 and GluD2. Finally, we found that tyrosine phosphorylation was upregulated in the cbln1-null cerebellum, and acute inhibition of Src-family kinases suppressed the increased inhibitory postsynaptic currents in cbln1-null Purkinje cells. These findings indicate that Cbln1-GluD2 signaling inhibits the number and function of inhibitory synapses, and shifts the excitatory-inhibitory balance towards excitation in Purkinje cells. Cbln1's effect on inhibitory synaptic transmission is probably mediated by a tyrosine kinase pathway. PMID- 24467252 TI - Autonomy support and responsibility-sharing predict blood glucose monitoring frequency among youth with diabetes. AB - OBJECTIVE: Adolescence poses a number of special challenges for youth and their families managing the Type 1 diabetes medical regimen. Little is known on how family and youth factors and management of the regimen change over the course of early adolescence and predict adherence to the regimen during this developmental period. METHODS: Youth with Type 1 diabetes (n = 239) and their maternal caregivers completed measures of diabetes-specific autonomy support, diabetes related family conflict, regimen responsibility, and blood glucose monitoring frequency (BGMF) at 4 timepoints over a 3-year period. RESULTS: Autonomy support and BGMF significantly decreased over time and responsibility for the diabetes regimen shifted from the caregiver toward youth over time. Significant changes in perceived family conflict over time differed depending on the reporter. Baseline BGMF, changes in caregiver autonomy support, and changes in responsibility for the regimen significantly predicted changes in BGMF over time. CONCLUSIONS: This study documents changes in autonomy support, youth responsibility for the diabetes regimen, and BGMF during the transition into early adolescence. Higher levels of caregiver autonomy support preserve BGMF during a developmental period in which BGMF typically deteriorates. PMID- 24467253 TI - Where there's a will: can highlighting future youth-targeted marketing increase support for soda taxes? AB - OBJECTIVE: Amid concern about high rates of obesity and related diseases, the marketing of nutritionally poor foods to young people by the food industry has come under heavy criticism by public health advocates, who cite decades of youth targeted marketing in arguing for reforms. In light of recent evidence that the same event evokes stronger emotional reactions when it occurs in the future versus the past, highlighting youth-targeted marketing that has yet to occur may evoke stronger reactions to such practices, and perhaps, greater support for related health policy initiatives. METHOD: In a between-subjects experiment, Web participants (N = 285) read that a major soda company had already launched (past condition) or was planning to launch (future condition) an advertising campaign targeting children. Measures included support for a soda tax and affective responses to the company's actions. RESULTS: Greater support for the soda tax was observed in the future condition than in the past condition. Moreover, participants in the future condition reported heightened negative emotions about the company's actions, which mediated the observed effect on soda tax support. CONCLUSION: The same action undertaken by the food industry (here, marketing soda to children) may evoke stronger negative emotions and greater support for a health policy initiative when it is framed prospectively rather than retrospectively. PMID- 24467255 TI - Age differences in the association of physical activity, sociocognitive engagement, and TV viewing on face memory. AB - OBJECTIVE: Physical and sociocognitive lifestyle activities promote aspects of cognitive function in older adults. Very little is known about the relation between these lifestyle activities and cognitive function in young adults. One aspect of cognitive function that is critical for everyday function is episodic memory. The present study examined the relationship between lifestyle activities and episodic memory in younger and older adults. METHOD: Participants were 62 younger (mean age = 24 years) and older adults (mean age = 74 years). The augmented Victoria Longitudinal Study Activities Questionnaire was used to quantify level of engagement in physical activity, sociocognitive activity, and TV viewing. Episodic memory was assessed using the old-new face recognition paradigm in which memory for younger and older faces was tested. RESULTS: Compared to younger adults, older adults reported being less physically and sociocognitively active while engaging in more passive behaviors such as TV viewing. A positive association was observed between physical activity and episodic memory for young adults but not for older adults. Interestingly, TV viewing was negatively associated with episodic memory in older adults but not younger adults. No relationship was found between sociocognitive activity and episodic memory for either younger or older adults. Although the own-age effect was observed for older adults, face age did not interact with lifestyle activities. CONCLUSION: The positive cognitive benefits of physical activity extend to younger adults; however, the interplay between physical activity and cognition may differ across the life span. Furthermore, TV viewing may be particularly detrimental to cognitive performance later in life. PMID- 24467254 TI - Greater physical activity is associated with better cognitive function in heart failure. AB - OBJECTIVE: Nearly 6 million Americans have heart failure (HF), up to 80% of which exhibit cognitive deficits on testing. Physical inactivity is common in HF, yet little is known about the possible contribution of physical inactivity to cognitive dysfunction in this population. METHOD: Older adults with HF (N = 93; Mage = 68.5 years, 33.7% women) completed neuropsychological testing, as well as cardiac and physical activity assessment as part of a larger protocol. HF severity was measured via impedance cardiography. Physical activity was assessed via an Actigraph accelerometer and operationalized using daily step count and time engaged in moderate-vigorous activity (minutes/day). RESULTS: Linear regression analyses controlling for sex, high blood pressure, diabetes, depressive symptomatology, and HF severity showed that greater physical activity (both step count and minutes spent in moderate-vigorous activity) was associated with better executive function/attention, processing speed, and scores on a screening measure of cognition. CONCLUSIONS: These findings indicate that physical activity is an independent predictor of cognitive function in persons with HF. Future work is needed to clarify the mechanisms by which physical activity benefits cognitive function in HF and determine whether interventions to promote physical activity can attenuate cognitive decline over time. PMID- 24467256 TI - Differential effects of poststressor rumination and distraction on cortisol and C reactive protein. AB - OBJECTIVE: Stress-related physiological activation may last longer for those who ruminate, or dwell, on past stressors. Correlational and quasi-experimental research has linked rumination to immune activity and elevated cortisol. This study's aim was to experimentally test whether rumination (relative to distraction) can sustain stress-induced increases in inflammation and cortisol. Concentrations of poststressor cortisol and inflammatory markers were hypothesized to be greater for those who ruminated compared with those who were distracted. METHOD: Thirty-four healthy young women completed a laboratory speech stressor and were then randomly assigned to either ruminate on the stressor or engage in distraction for 5 minutes. Salivary cortisol and circulating plasma concentrations of C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-alpha) were assessed throughout the 2-hr visit. RESULTS: As predicted, CRP and cortisol responses differed for the rumination and distraction groups. In the distraction group, participants' CRP concentrations increased poststressor and then returned to prestressor levels by the end of the visit. In contrast, participants in the rumination condition demonstrated increases in CRP that did not return to prestressor levels by the end of the visit. Similarly, poststressor cortisol was higher for those who ruminated compared with those who were distracted. Plasma IL-6 and TNF-alpha concentrations increased over the visit, but did not differ by experimental group. CONCLUSIONS: RESULTS suggest that ruminating on stressors may sustain CRP and cortisol responses, whereas distraction may diminish them. Findings have implications for understanding potential risk and protective factors for stress-related activation. PMID- 24467258 TI - Experimental effects of injunctive norms on simulated risky driving among teenage males. AB - OBJECTIVE: Teenage passengers affect teenage driving performance, possibly by social influence. To examine the effect of social norms on driving behavior, male teenagers were randomly assigned to drive in a simulator with a peer-aged confederate to whom participants were primed to attribute either risk-accepting or risk-averse social norms. It was hypothesized that teenage drivers would engage in more risky driving behavior in the presence of peer passengers than no passengers, and with a risk-accepting compared with a risk-averse passenger. METHOD: 66 male participants aged 16 to 18 years holding a provisional driver license were randomized to drive with a risk-accepting or risk-averse passenger in a simulator. Failure to Stop at a red light and percent Time in Red (light) were measured as primary risk-relevant outcomes of interest at 18 intersections, while driving once alone and once with their assigned passenger. RESULTS: The effect of passenger presence on risky driving was moderated by passenger type for Failed to Stop in a generalized linear mixed model (OR = 1.84, 95% CI [1.19, 2.86], p < .001), and percent Time in Red in a mixed model (B = 7.71, 95% CI [1.54, 13.87], p < .05). CONCLUSIONS: Exposure of teenage males to a risk accepting confederate peer increased teenage males' risky simulated driving behavior compared with exposure to a risk-averse confederate peer. These results indicate that variability in teenage risky driving could be partially explained by social norms. PMID- 24467257 TI - Multiple risk-behavior profiles of smokers with serious mental illness and motivation for change. AB - OBJECTIVE: Individuals with serious mental illness (SMI) are dying on average 25 years prematurely. The leading causes are chronic preventable diseases. In the context of a tobacco-treatment trial, this exploratory study examined the behavioral risk profiles of adults with SMI to identify broader interventional needs. METHOD: Recruited from five acute inpatient psychiatry units, participants were 693 adult smokers (recruitment rate = 76%, 50% male, 45% Caucasian, age M = 39, 49% had income < $10,000) diagnosed with mood disorders (71%), substance-use disorders (63%), posttraumatic stress disorder (39%), psychotic disorders (25%), and attention deficit-hyperactivity disorder (25%). The Staging Health Risk Assessment, the primary measure used in this study, screened for risk status and readiness to change 11 health behaviors, referencing the period prior to acute hospitalization. RESULTS: Participants averaged 5.2 (SD = 2.1) risk behaviors, including smoking (100%), high-fat diet (68%), inadequate fruits/vegetables (67%), poor sleep (53%), physical inactivity (52%), and marijuana use (46%). The percent prepared to change ranged from 23% for tobacco and marijuana to 76% for depression management. Latent class analysis differentiated three risk groups: the global higher risk group included patients elevated on all risk behaviors; the global lower risk group was low on all risks; and a mood and metabolic risk group, characterized by inactivity, unhealthy diet, sleep problems, and poor stress and depression management. The global higher risk group (11% of sample) was younger, largely male, and had the greatest number of risk behaviors and mental health diagnoses; had the most severe psychopathologies, addiction treatment histories, and nicotine dependence; and the lowest confidence for quitting smoking and commitment to abstinence. CONCLUSION: Most smokers with SMI engaged in multiple risks. Expanding targets to treat co-occurring risks and personalizing treatment to individuals' multibehavioral profiles may increase intervention relevance, interest, and impact on health. PMID- 24467259 TI - Effects of subtle and explicit health messages on food choice. AB - OBJECTIVE: Explicitly--as opposed to subtly--labeling a food healthy may inadvertently license people to indulge, imply that the food tastes bad, or lead to reactance. We investigated the effects of explicit and subtle health messages on individuals' food selection in two field studies. METHOD: We manipulated the signs on healthy foods such that they explicitly stated that the food was healthy, subtly suggested it with an image, or did not mention health. As participants--attendees at academic conferences--approached registration tables, research assistants recorded the number and type of snacks individuals chose. RESULTS: Participants were more likely to choose the healthy food when it was labeled with the subtle health message than when it was labeled with the explicit health message, which itself was not more effective than the control message. CONCLUSION: Subtle messages may be more useful than explicit health messages in encouraging individuals to make a healthy snack choice. PMID- 24467260 TI - Fluctuations in depression and well-being are associated with sexual risk episodes among HIV-positive men. AB - OBJECTIVE: Research has suggested a weak association between depression and sexual risk behavior in men who have sex with men (MSM). The purpose of this study was to investigate the relationship between within-person fluctuations in depression and well-being and episodes of sexual risk-taking among HIV-positive MSM. METHODS: One hundred six sexually active HIV-positive MSM living in New York City completed a structured weekly survey over 6 weeks. In Weeks 1, 3, and 5, they responded to items assessing their sexual behavior, depression, and well being in the prior week. Multilevel logistic regression analyses were conducted to explore the relationship between changes in levels of depression and well being, and episodes of unprotected anal intercourse (UAI). RESULTS: Within-person deviations from participants' average levels of depression and well-being were associated with the probability of risk. The probability of a risk episode was higher in weeks when depression was higher than participants' average levels (any UAI episode: odd ratio [OR] = 1.71, 95% confidence interval [CI] [1.00, 2.90], p < .05; serodiscordant UAI episode: OR = 2.49, 95% CI [1.31, 4.73], p < .05). The probability of a risk episode was lower in weeks when well-being was higher than participants' average levels (any UAI: OR = 0.40, 95% CI [0.22, 0.74], p < .05; serodiscordant UAI: OR = 0.42, 95% CI [0.22, 0.81], p < .05). Between-person differences in depression and well-being were not associated with risk episodes (ps > .05). CONCLUSION: This study is among the first to examine the association of within-person changes in depression and well-being with sexual risk behavior in a diverse sample. It contributes new evidence to literature exploring the relationship between depression and sexual risk. Future research should employ longitudinal designs to explore pathways linking within-person changes in depression with risk behavior. PMID- 24467262 TI - Diagnostic criteria for ductal adenocarcinoma of the prostate: interobserver variability among 20 expert uropathologists. AB - AIMS: Ductal adenocarcinoma of the prostate (DAC) is clinically important, because its behaviour may differ from that of acinar adenocarcinoma. Our aims were to investigate the interobserver variability of this diagnosis among experts in uropathology and to define diagnostic criteria. METHODS AND RESULTS: Photomicrographs of 21 carcinomas with ductal features were distributed among 20 genitourinary pathologists from eight countries. DAC was diagnosed by 18 observers (mean 13.2 cases, range 6-19). In 11 (52%) cases, a 2/3 consensus was reached for a diagnosis of DAC, and in five (24%) there was consensus against. In DAC, the respondents reported papillary architecture (86%), stratification of nuclei (82%), high-grade nuclear features (54%), tall columnar epithelium (53%), elongated nuclei (52%), cribriform architecture (40%), and necrosis (7%). The most important diagnostic feature reported for DAC was papillary architecture (59%), whereas nuclear and cellular features were considered to be most important in only 2-11% of cases. The most common differential diagnoses were intraductal prostate cancer (52%), high-grade PIN (37%), and acinar adenocarcinoma (17%). The most common reason for not diagnosing DAC was lack of typical architecture (33%). CONCLUSIONS: Papillary architecture was the most useful diagnostic feature of DAC, and nuclear and cellular features were considered to be less important. PMID- 24467261 TI - Comparison and analysis of the animal models used to study the effect of morphine on tumour growth and metastasis. AB - The effect of opioids on tumour growth and metastasis has been debated for many years, with recent emphasis on the possibility that they might influence the rate of disease-free survival after tumour resection when used in the perioperative pain management of cancer surgery patients. The literature presents conflicting and inconclusive in vitro and in vivo data about the potential effect of opioids, especially morphine, on tumour growth and metastasis. To inform clinical practice, appropriate animal models are needed to test whether opioids alter the course of tumour growth and metastasis. Here, we review the literature on animal based studies testing the effect of morphine on cancer so far, and analyse differences between the models used that may explain the discrepancies in published results. Such analysis should elucidate the role of opioids in cancer and help define ideal pre-clinical models to provide definitive answers. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. PMID- 24467263 TI - Coagulation factor and hemostatic protein content of canine plasma after storage of whole blood at ambient temperature. AB - BACKGROUND: Standard practice in canine blood banking is to produce fresh frozen plasma (FFP) by separating and freezing plasma produced from blood within 8 hours of collection. Within canine blood donation programs, this can limit the number of units collected. HYPOTHESIS/OBJECTIVES: The aim was to compare the coagulation factor and hemostatic protein content (CF&HPC) of plasma produced from blood stored at ambient temperature for 8, 12, and 24 hours. Another aim was to compare the CF&HPC between Greyhound types and other breeds. ANIMALS: None. METHODS: In vitro study. A convenience sample of 58 units of canine blood from a blood donor pool was processed to prepare and freeze plasma 8, 12, or 24 hours following collection. RESULTS: Regardless of time of processing, the units contained therapeutic CF&HPC. Frozen plasma prepared after 24 hours had significantly higher factor VIII (P = .014) and factor X (P = .03) when compared with the frozen plasma prepared at 8 hours. Factor X (P < .01), fibrinogen (P < .01), and vWF (P = .04) were significantly lower in plasma collected from Greyhound types than in plasma collected from other breeds. CONCLUSIONS AND CLINICAL IMPORTANCE: Storing whole blood for up to 24 hours is a suitable method for producing FFP. Lower values for some coagulation factors and hemostatic proteins in plasma produced from Greyhound types would not preclude these dogs as FFP donors. PMID- 24467265 TI - Association among different measures of alcohol use across adolescence and emerging adulthood. AB - BACKGROUND AND AIMS: The use of alterative alcohol indices in developmental research may generate conflicting findings in the literature. This study examined the longitudinal associations among four indices of alcohol involvement from ages 15 to 25 years and examined their concurrent associations with alcohol-related problems in emerging adulthood. DESIGN: Data are from the Victoria Healthy Youth Survey, a five-wave multi-cohort study conducted biennially in Victoria, Canada between 2003 and 2011. SETTING AND PARTICIPANTS: This study included a subsample of 637 randomly recruited Canadian adolescents, aged 15-25 years. MEASUREMENTS: Four indices of alcohol use were compared using multivariate piecewise growth modeling: frequency, usual quantity, heavy episodic drinking and volume. FINDINGS: All indices increased on average from ages 15 to 21, peaked at approximately age 21, and gradually declined from ages 21 to 25. Levels of use at age 21 were highly correlated across indices (r = 0.63-0.94, P < 0.001), but correlations among rates of change varied between pairs of indices. Heavy episodic drinking and volume had the strongest correlations over time (r = 0.64 0.81, P < 0.001) and accounted for the greatest variance in alcohol use disorder symptoms (R(2) = 0.35) and social and health consequences (R(2) = 16) in emerging adulthood. Frequency and quantity had the weakest associations during adolescence (r = 0.49, P = 0.001) and were uncorrelated during emerging adulthood (r = 0.23, P = 0.09). CONCLUSIONS: Among Canadian youth aged 15-25 years, measures of heavy episodic drinking and volume are the most strongly correlated over time and account for greater variance in alcohol-related problems in emerging adulthood than either frequency or quantity alone. PMID- 24467264 TI - Human kallistatin administration reduces organ injury and improves survival in a mouse model of polymicrobial sepsis. AB - Kallistatin, a plasma protein, has been shown to exert multi-factorial functions including inhibition of inflammation, oxidative stress and apoptosis in animal models and cultured cells. Kallistatin levels are reduced in patients with sepsis and in lipopolysaccharide (LPS)-induced septic mice. Moreover, transgenic mice expressing kallistatin are more resistant to LPS-induced mortality. Here, we investigated the effects of human kallistatin on organ injury and survival in a mouse model of polymicrobial sepsis. In this study, mice were injected intravenously with recombinant kallistatin (KS3, 3 mg/kg; or KS10, 10 mg/kg body weight) and then rendered septic by caecal ligation and puncture 30 min later. Kallistatin administration resulted in a > 10-fold reduction of peritoneal bacterial counts, and significantly decreased serum tumour necrosis factor-alpha, interleukin-6 and high mobility group box-1 (HMGB1) levels. Kallistatin also inhibited HMGB1 and toll-like receptor-4 gene expression in the lung and kidney. Administration of kallistatin attenuated renal damage and decreased blood urea nitrogen and serum creatinine levels, but increased endothelial nitric oxide synthase and nitric oxide levels in the kidney. In cultured endothelial cells, human kallistatin via its heparin-binding site inhibited HMGB1-induced nuclear factor-kappaB activation and inflammatory gene expression. Moreover, kallistatin significantly reduced apoptosis and caspase-3 activity in the spleen. Furthermore, kallistatin treatment markedly improved the survival of septic mice by 23% (KS3) and 41% (KS10). These results indicate that kallistatin is a unique protecting agent in sepsis-induced organ damage and mortality by inhibiting inflammation and apoptosis, as well as enhancing bacterial clearance in a mouse model of polymicrobial sepsis. PMID- 24467266 TI - Allergen-specific Th2 responses in young children precede sensitization later in life. AB - Allergic sensitization is initiated by allergen-specific Th2-cell responses. Data on early allergen-specific T-cell responses in allergic children are scarce. We hypothesized that allergen-specific Th2-cell responses can be detected preceding sensitization. Therefore, peripheral blood mononuclear cells (PBMC) of nonsensitized, 'not-yet' sensitized or sensitized children were cultured with highly purified allergens. Cytokine levels in supernatant were determined using multiplex assay and GATA3 expression by flow cytometry. PBMC of sensitized children aged 3 and 5 years showed higher production of IL4, IL5 and IL13 and higher expression of GATA3 in response to purified allergens compared to nonsensitized children. PBMC of children that were 'not-yet' sensitized already showed higher levels of IL5 and IL13 and higher GATA3 expression at age 3 years. This shows that allergen-specific in vitro Th2 responses precede the detection of allergen-specific IgE, which can provide a window of opportunity for novel therapeutic interventions. PMID- 24467267 TI - Lifelong exercise training modulates cardiac mitochondrial phosphoproteome in rats. AB - Moderate physical activity has traditionally been associated with the improvement of cardiac function and, consequently, with the extension of life span. Mitochondria play a key role in the adaptation of heart muscle to exercise related metabolic demands. In order to disclose the molecular mechanisms underlying the beneficial effect of lifelong physical activity in cardiac function, we performed label-free quantitative mass spectrometry-based proteomics of Sprague-Dawley rat heart mitochondrial proteome and phosphoproteome. Our data revealed that 54 weeks of moderate treadmill exercise modulates the abundance of proteins involved in the generation of precursor metabolites and cellular respiration, suggesting an increase in carbohydrate oxidation-based metabolism. Moreover, from the 1335 phosphopeptides identified in this study, 6 phosphosites were exclusively assigned to heart mitochondria from sedentary rats and 17 to exercised animals, corresponding to 6 and 16 proteins, respectively. Most proteins exhibiting significant alterations in specific phosphorylation sites were involved in metabolism. Analysis of the acquired data led to the identification of several kinases potentially modulated by exercise training, which were selected for further validation. Indeed, higher protein abundance levels of RAF and p38 in mitochondria were confirmed to be modulated by sustained exercise. Our work describes the plasticity of heart mitochondria in response to long exercise programs manifested by the reprogramming of phosphoproteome and provides evidence for the kinases involved in the regulation of metabolic pathways and mitochondrial maintenance. PMID- 24467268 TI - Discovery of vinyl sulfones as a novel class of neuroprotective agents toward Parkinson's disease therapy. AB - Although the etiology of Parkinson's disease (PD) remains elusive, recent studies suggest that oxidative stress contributes to the cascade leading to dopaminergic (DAergic) neurodegeneration. The Nrf2 signaling is the main pathway responsible for cellular defense system against oxidative stress. Nrf2 is a transcription factor that regulates environmental stress response by inducing expression of antioxidant enzyme genes. We have synthesized novel vinyl sulfone derivatives. They exhibited a broad range of activities in inducing HO-1, whose gene expression is under the control of Nrf2. Among them, compound 12g was confirmed to activate Nrf2 and induce expression of the Nrf2-dependent antioxidant enzymes NQO1, GCLC, GLCM, and HO-1, at both mRNA and protein levels in DAergic neuronal cells. This was accompanied by protection of DAergic neurons in both in vitro and MPTP-induced in vivo models of PD. In addition, compound 12g effectively resulted in attenuation of the PD-associated behavioral deficits in the mouse model. PMID- 24467269 TI - Lower extremity reconstruction after limb-sparing sarcoma resection of the proximal tibia in the pediatric population: case series, with algorithm. AB - Limb salvage surgery (LSS) is the current treatment of choice for bone sarcomas in children. These procedures require composite resection and reconstruction, and are subject to high functional demands. Proximal tibia tumours, in particular, pose a significant challenge to treatment and reconstruction. A retrospective review was performed of all patients undergoing resection of proximal tibia bone sarcomas at a single centre over a 12-year period. Twenty-one patients (14 male, seven female) with an average age of 14.4 years (range = 8.3-19.2 years) underwent resection of a proximal tibial sarcoma. Pathology included osteosarcoma (OS) in 16, and Ewing's sarcoma family of tumours (ESFT) in five. Seventeen patients had bone tumour reconstruction with modular endoprsothesis, one patient with allograft, and three patients with an expandable endoprosthesis. One patient had primary closure; 20 patients had combined gastrocnemius and soleus flap reconstruction; three patients required subsequent bipedicled flap reconstruction, and two patients required subsequent sural artery flap reconstruction. No patients required free flap reconstruction. The average length of tibial osteotomy was 15 cm (range = 12.7-22.5 cm). Median soft tissue mass volume resected was 293 cm(3) (range = 211-1141 cm(3)). Median follow-up was 2.8 years (range = 0.5-6.8 years). Two patients died from metastatic disease. Two patients ultimately required amputation. Nineteen patients were ambulatory at last follow-up. This study presents an algorithm for soft-tissue reconstruction after resection of bone sarcomas of the proximal tibia. These techniques minimise complications, and maximise function in the paediatric population. PMID- 24467270 TI - Highly thermally stable single-component white-emitting silicate glass for organic-resin-free white-light-emitting diodes. AB - Thermal management is still a great challenge for high-power phosphor-converted white-light-emitting diodes (pc-WLEDs) intended for future general lighting. In this paper, a series of single-component white-emitting silicate SiO2-Li2O-SrO Al2O3-K2O-P2O5: Ce(3+), Tb(3+), Mn(2+) (SLSAKP: Ce(3+), Tb(3+), Mn(2+)) glasses that simultaneously play key roles as a luminescent convertor and an encapsulating material for WLEDs were prepared via the conventional melt quenching method, and systematically studied using their absorption spectra, transmittance spectra, photoluminescence excitation and emission spectra in the temperature range 296-498 K, decay curves, and quantum efficiency. The glasses show strong and broad absorption in 250-380 nm region and exhibit intense white emission, produced by in situ mixing of blue-violet, green, and orange-red light from Ce(3+), Tb(3+), and Mn(2+) ions, respectively, in a single glass component. The quantum efficiency of SLSAKP: 0.3%Ce(3+), 2.0%Tb(3+), 2.0%Mn(2+) glass is determined to be 19%. More importantly, this glass shows good thermal stability, exhibiting at 373 and 423 K about 84.56 and 71.02%, respectively, of the observed room temperature (298 K) emission intensity. The chromaticity shift of SLSAKP: 0.3%Ce(3+), 2.0%Tb(3+), 2.0%Mn(2+) is 2.94 * 10(-2) at 498 K, only 57% of the commercial triple-color white-emitting phosphor mixture. Additionally, this glass shows no transmittance loss at the 370 nm emission of a UV-Chip-On-Board (UV-COB) after thermal aging for 240 h, compared with the 82% transmittance loss of epoxy resin. The thermal conductivity of the glass is about 1.07 W/mK, much larger than the 0.17 W/mK of epoxy resin. An organic-resin-free WLEDs device based on SLSAKP: 0.3%Ce(3+), 2.0%Tb(3+), 2.0%Mn(2+) glass and UV-COB is successfully demonstrated. All of our results demonstrate that the presented Ce(3+)/Tb(3+)/Mn(2+) tridoped lithium-strontium-silicate glass may serve as a promising candidate for high power WLEDs. PMID- 24467271 TI - Hospital-based, acute care encounters after radiofrequency ablation of hepatic tumours. AB - BACKGROUND: The use of radiofrequency ablation (RFA) for cancer is increasing; however, post-discharge outcomes have not been well described. The aim of the present study was to determine rates of hospital-based, acute care utilization within 30 days of discharge after RFA. METHODS: Using state-level data from California, patients were identified who were at least 40 years of age who underwent RFA of hepatic tumours without a concurrent liver resection from 2007 2011. Our primary outcome was hospital readmissions or emergency department visits within 30 days of discharge. A multivariable regression model was constructed to identify patient factors associated with these events. RESULTS: The final sample included 1764 patients treated at 100 centres. Hospital readmissions (11.3/100 discharges), emergency department visits (6.0/100 discharges) and overall acute care utilization (17.3/100 discharges) were common. Most encounters occurred within 10 days of discharge for diagnoses related to the procedure. Patients with renal failure [adjusted odds ratio (AOR) = 1.98 (1.11 3.53)], obesity [AOR = 1.69 (1.03-2.77)], drug abuse [AOR = 2.95 (1.40-6.21)] or those experiencing a complication [AOR = 1.52 (1.07-2.15)] were more likely to have a hospital-based acute care encounter within 30 days of discharge. CONCLUSIONS: Hospital-based acute care after RFA is common. Patients should be counselled regarding the potential for acute care utilization and interventions targeted to high-risk populations. PMID- 24467272 TI - Bourdieu at the bedside: briefing parents in a pediatric hospital. AB - The philosophy of family-centered care (FCC) promotes partnerships between families and staff to plan, deliver, and evaluate services for children and has been officially adopted by a majority of pediatric hospitals throughout North America. However, studies indicated that many parents have continued to be dissatisfied with their decision-making roles in their child's care. This is particularly salient for parents of children with chronic ongoing complex health problems. These children are dependent upon medical technology and require frequent hospitalizations during which parents must contribute to difficult decisions regarding their child's care. Given this clinical issue, an alternative theoretical perspective was explored to redress this problem. Pierre Bourdieu's theoretical concepts of field, capital, and habitus were used to analyze the hierarchical relationships in pediatric acute care hospitals and to design a briefing intervention aimed at improving parents' satisfaction with decision making in that health care setting. PMID- 24467273 TI - Simultaneously harvesting electrostatic and mechanical energies from flowing water by a hybridized triboelectric nanogenerator. AB - Flowing water contains not only mechanical kinetic energy, but also the electrostatic energy owing to the triboelectric charges caused by its contact with surrounding media such as air. In this paper, a water wheel hybridized triboelectric nanogenerator (TENG), composed of a water-TENG part and a disk-TENG part, has been developed for simultaneously harvesting the two types of energies from the tap water flowing from a household faucet. The wheel blades of the hybridized TENG are composed by superhydrophobic polytetrafluoroethylene (PTFE) thin films with nanostructures, which are used as water-TENG to harvest the electrostatic energy from the flowing water. In addition, the flowing water impacted on the wheel blades also causes the rotation motion of disk-TENG and can be used to harvest the mechanical kinetic energy. The short-circuit current of the water-TENG and the disk-TENG at a flowing water rate of 54 mL/s can reach 12.9 and 3.8 MUA, respectively. The hybridized TENG is also demonstrated to harvest wind energy and acts as a self-powered sensor to detect the flowing water rate and wind speed. All these results show the potentials of the hybridized TENG for harvesting multiple types of energies from the environment. PMID- 24467275 TI - Evaluation of serum phosphorylated neurofilament subunit NF-H as a prognostic biomarker in dogs with thoracolumbar intervertebral disc herniation. AB - OBJECTIVE: To investigate whether pNF-H is a prognostic biomarker of spinal cord injury (SCI) in paraplegic dogs with thoracolumbar intervertebral disc herniation (IVDH). STUDY DESIGN: Prospective, case-control clinical study ANIMALS: Dogs (n = 60) with SCI from IVDH and 6 healthy dogs. METHODS: Serum from 60 thoracolumbar IVDH dogs (Grade 4: 22 dogs; Grade 5: 38 dogs) collected 1-3 days after injury, and 6 control dogs, was analyzed using enzyme-linked immunosorbent assay (ELISA) against a phosphorylated form of the high-molecular-weight neurofilament subunit NF-H (pNF-H). Serum pNF-H levels were compared between different IVDH grades and their prognostic value was investigated. RESULTS: pNF-H levels were significantly greater in Grade 5 than Grade 4 dogs. There were significant differences in pNF-H levels between dogs that regained voluntarily ambulation and those that did not. All 8 dogs that had high pNF-H levels 1-3 days after injury did not regain the ability to walk after surgery. CONCLUSIONS: Serum pNF-H levels might be a biomarker for predicting prognosis of canine SCI. PMID- 24467274 TI - A broadly applicable NHC-Cu-catalyzed approach for efficient, site-, and enantioselective coupling of readily accessible (pinacolato)alkenylboron compounds to allylic phosphates and applications to natural product synthesis. AB - A set of protocols for catalytic enantioselective allylic substitution (EAS) reactions that allow for additions of alkenyl units to readily accessible allylic electrophiles is disclosed. Transformations afford 1,4-dienes that contain a tertiary carbon stereogenic site and are promoted by 1.0-5.0 mol % of a copper complex of an N-heterocyclic carbene (NHC). Aryl- as well as alkyl-substituted electrophiles bearing a di- or trisubstituted alkene may be employed. Reactions can involve a variety of robust alkenyl-(pinacolatoboron) [alkenyl-B(pin)] compounds that can be either purchased or prepared by various efficient, site-, and/or stereoselective catalytic reactions, such as cross-metathesis or proto boryl additions to terminal alkynes. Vinyl-, E-, or Z-disubstituted alkenyl-, 1,1 disubstituted alkenyl-, acyclic, or heterocyclic trisubstituted alkenyl groups may be added in up to >98% yield, >98:2 SN2':SN2, and 99:1 enantiomeric ratio (er). NHC-Cu-catalyzed EAS with alkenyl-B(pin) reagents containing a conjugated carboxylic ester or aldehyde group proceed to provide the desired 1,4-diene products in good yield and with high enantioselectivity despite the presence of a sensitive stereogenic tertiary carbon center that could be considered prone to epimerization. In most instances, the alternative approach of utilizing an alkenylmetal reagent (e.g., an Al-based species) represents an incompatible option. The utility of the approach is illustrated through applications to enantioselective synthesis of natural products such as santolina alcohol, semburin, nyasol, heliespirone A, and heliannuol E. PMID- 24467277 TI - Impact of air pollution control costs on the cost and spatial arrangement of cellulosic biofuel production in the U.S. AB - Air pollution emissions regulation can affect the location, size, and technology choice of potential biofuel production facilities. Difficulty in obtaining air pollutant emission permits and the cost of air pollution control devices have been cited by some fuel producers as barriers to development. This paper expands on the Geospatial Bioenergy Systems Model (GBSM) to evaluate the effect of air pollution control costs on the availability, cost, and distribution of U.S. biofuel production by subjecting potential facility locations within U.S. Clean Air Act nonattainment areas, which exceed thresholds for healthy air quality, to additional costs. This paper compares three scenarios: one with air quality costs included, one without air quality costs, and one in which conversion facilities were prohibited in Clean Air Act nonattainment areas. While air quality regulation may substantially affect local decisions regarding siting or technology choices, their effect on the system as a whole is small. Most biofuel facilities are expected to be sited near to feedstock supplies, which are seldom in nonattainment areas. The average cost per unit of produced energy is less than 1% higher in the scenarios with air quality compliance costs than in scenarios without such costs. When facility construction is prohibited in nonattainment areas, the costs increase by slightly over 1%, due to increases in the distance feedstock is transported to facilities in attainment areas. PMID- 24467278 TI - Health-related internet habits and health anxiety in university students. AB - Health-related Internet use has grown rapidly, yet little research has considered how health anxious individuals use the Internet for this purpose. Our aim was to examine the relationships between health anxiety and the extent of, reasons for, and consequences of health-related Internet usage in university students (n = 255). Responses on a purpose-made Internet use questionnaire were correlated with health anxiety scores; multiple regression analyses controlling for depression and anxiety were also conducted. Health anxiety positively correlated with (all ps < .01): frequency of health-related searching (r(s) = .163), proportion of health-related information sought (r(s) = .200), time spent online for health purposes (r(s) = .166), and number of searches for both illness (r(s) = .453) and wellness (r(s) = .208) information. Health anxiety further positively correlated with advantages perceived in health-related Internet use (r(s) = .183), heightened tension (r(s) = .364) and relief (r(s) = .174) post-search, and perceived doctor disadvantages (r(s) = .306), yet a greater likelihood to visit a doctor post-search (r(s) = .217). Health anxiety also correlated with six measures of possible addiction to using the Internet for health purposes (r(s) range = .171 to .366, all ps < .01). Some (including several potentially dysfunctional) aspects of health-related Internet use correlate with health anxiety. Research evaluating the possible role of Internet use in the development and maintenance of health anxiety is warranted. PMID- 24467279 TI - Differential role of N-methyl-D-aspartate receptor-mediated glutamate transmission in the nucleus accumbens shell and core in nicotine seeking in rats. AB - Nicotine, a major psychoactive component of tobacco smoke, increases glutamate transmission in the nucleus accumbens (NAcc). However, the role of the N-methyl-D aspartate (NMDA)-mediated glutamatergic neurotransmission in the NAcc shell and core subdivisions in nicotine-dependent behaviors has not been studied. The present study evaluated, in rats, the effects of bilateral administration of the competitive NMDA receptor antagonist LY235959 (0, 0.1, 1, and 10 ng/0.5 MUL/side) into the NAcc shell or core on intravenous nicotine (fixed- and progressive-ratio schedules) and food (fixed-ratio schedule) self-administration, and cue-induced reinstatement of nicotine-seeking behavior. In addition, the effects of LY235959 injections in the NAcc shell were evaluated on nicotine-induced conditioned taste aversion, a procedure that assesses the aversive effects of nicotine. LY235959 injections into the NAcc shell significantly increased nicotine self administration under both fixed- and progressive-ratio schedules, and decreased food self-administration, but had no effect on nicotine-induced conditioned taste aversion or cue-induced nicotine seeking. Furthermore, injections of LY235959 in the lateral septal nucleus, originally intended as an anatomical control site for the NAcc shell, increased nicotine self-administration and decreased food self administration under the fixed-ratio schedule. In contrast, LY235959 injections into the NAcc core increased the cue-induced reinstatement of nicotine seeking and decreased food self-administration, but had no effect on nicotine self administration. The present data suggest that NMDA receptor-mediated glutamatergic neurotransmission in the NAcc shell and core differentially regulates food- and nicotine-maintained responding. Importantly, the data suggest an inhibitory role for NMDA-mediated glutamatergic neurotransmission in the NAcc shell and core in nicotine self-administration and the cue-induced reinstatement of nicotine seeking, respectively. PMID- 24467280 TI - Karl-Friedrich Fischbach's first publications and their impact in the biological sciences. AB - Predictions from the theory of transfection, Karl-Friedrich Fischbach's first paper, were confirmed 20 years later. Also a model, proposed already in 1977 by Karl-Friedrich and colleagues, to explain the nonmonotonous dependence on light intensity of phototaxis in Drosophila, finds support in recent studies of functional neuroanatomy. PMID- 24467281 TI - Pathobiology of avian influenza virus infection in minor gallinaceous species: a review. AB - Susceptibility to avian influenza viruses (AIVs) can vary greatly among bird species. Chickens and turkeys are major avian species that, like ducks, have been extensively studied for avian influenza. To a lesser extent, minor avian species such as quail, partridges, and pheasants have also been investigated for avian influenza. Usually, such game fowl species are highly susceptible to highly pathogenic AIVs and may consistently spread both highly pathogenic AIVs and low pathogenic AIVs. These findings, together with the fact that game birds are considered bridge species in the poultry-wildlife interface, highlight their interest from the transmission and biosecurity points of view. Here, the general pathobiological features of low-pathogenic AIV and highly pathogenic AIV infections in this group of avian species have been covered. PMID- 24467282 TI - Clinical features, intestinal histopathology, and outcome in protein-losing enteropathy in Yorkshire Terrier dogs. AB - BACKGROUND: A poorly understood protein-losing enteropathy (PLE) disorder has been reported in Yorkshire Terrier dogs. OBJECTIVES: To describe clinical features, intestinal histopathology, and outcome in Yorkshire Terrier dogs with PLE, and to identify variables predictive of outcome. ANIMALS: Thirty client owned Yorkshire Terrier dogs with PLE. METHODS: Retrospective study. Records of dogs with a diagnosis of PLE were reviewed. Intestinal histopathology was interpreted using the World Small Animal Veterinary Association gastrointestinal histopathology classification system. Discriminate analysis techniques were used to identify variables predictive of outcome. RESULTS: Females outnumbered males (20/30). Median age was 7 years (range 1-12). Common clinical signs were diarrhea (20/30), vomiting (11), ascites and abdominal distension (11), and respiratory difficulty (8). Histopathologic abnormalities included villous lymphatic dilatation, crypt lesions, villous stunting, and variable increases in cellularity of the lamina propria. All dogs were treated with glucocorticoids. Of 23 dogs with long-term follow-up, 9 had complete, and 3 had partial, resolution of signs, and 11 failed to respond to treatment. Median survival of responders was 44 months and of nonresponders was 12 months, with 4 dogs experiencing peracute death. Vomiting, monocytosis, severity of hypoalbuminemia, low blood urea nitrogen concentration, and villous blunting were predictive of survival <4 months. CONCLUSIONS: In addition to classic GI signs, Yorkshire Terriers with PLE often show clinical signs associated with hypoalbuminemia and low oncotic pressure. Lymphatic dilatation, crypt lesions, and villous stunting are consistent histopathologic findings. Clinical outcomes are variable, but many dogs experience remission of clinical signs and prolonged survival. PMID- 24467284 TI - Qualitative research: quality results? PMID- 24467283 TI - A new histone deacetylase inhibitor improves liver fibrosis in BDL rats through suppression of hepatic stellate cells. AB - BACKGROUND AND PURPOSE: Activation of hepatic stellate cells (HSCs) is a crucial step in the pathogenesis of hepatic fibrosis. Histone deacetylase (HDAC) is an attractive target in liver fibrosis because it plays a key role in gene expression and cell differentiation. We have developed a HDAC inhibitor, N hydroxy-7-(2-naphthylthio)heptanomide (HNHA), and investigated the anti-fibrotic activity of HNHA in vitro and in vivo. EXPERIMENTAL APPROACH: We investigated the anti-fibrotic effect of HNHA on mouse and human HSC activation in vitro and in the liver of bile duct-ligated (BDL) rats in vivo using cell proliferation assays, cell cycle analysis, biochemical assay, immunohistochemistry and Western blots. Liver pathology was assessed with histochemical techniques. KEY RESULTS: HNHA inhibited proliferation and arrested the cell cycle via p21 induction in HSCs. In addition, HNHA induced apoptosis of HSCs, which was correlated with reduced COX-2 expression, NF-kappaB activation and cell death signals. HNHA restored liver function and decreased the accumulation of extracellular matrix in the liver via suppression of HSC activation in BDL rats in vivo. HNHA administration also increased survival in BDL rats. CONCLUSIONS AND IMPLICATIONS: HNHA improved liver function, suppressed liver fibrosis and increased survival of BDL rats, accompanied by reduction of cell growth, activation and survival of HSCs. These findings show that HNHA may be a potent anti-fibrosis agent against hepatic fibrosis because of its multi-targeted inhibition of HSC activity in vivo and in vitro. PMID- 24467285 TI - Effectiveness of tobacco control television advertising in changing tobacco use in England: a population-based cross-sectional study. AB - AIM: To examine whether government-funded tobacco control television advertising shown in England between 2002 and 2010 reduced adult smoking prevalence and cigarette consumption. DESIGN: Analysis of monthly cross-sectional surveys using generalised additive models. SETTING: England. PARTICIPANTS: More than 80 000 adults aged 18 years or over living in England and interviewed in the Opinions and Lifestyle Survey. MEASUREMENTS: Current smoking status, smokers' daily cigarette consumption, tobacco control gross rating points (GRPs-a measure of per capita advertising exposure combining reach and frequency), cigarette costliness, tobacco control activity, socio-demographic variables. FINDINGS: After adjusting for other tobacco control policies, cigarette costliness and individual characteristics, we found that a 400-point increase in tobacco control GRPs per month, equivalent to all adults in the population seeing four advertisements per month (although actual individual-level exposure varies according to TV exposure), was associated with 3% lower odds of smoking 2 months later [odds ratio (OR) = 0.97, 95% confidence interval (CI) = 0.95, 0.999] and accounted for 13.5% of the decline in smoking prevalence seen over this period. In smokers, a 400-point increase in GRPs was associated with a 1.80% (95%CI = 0.47, 3.11) reduction in average cigarette consumption in the following month and accounted for 11.2% of the total decline in consumption over the period 2002-09. CONCLUSION: Government-funded tobacco control television advertising shown in England between 2002 and 2010 was associated with reductions in smoking prevalence and smokers' cigarette consumption. PMID- 24467286 TI - Comparison of means of two lognormal distributions based on samples with multiple detection limits. AB - The problem of comparing the means of two lognormal distributions based on samples with multiple detection limits is considered. Tests and confidence intervals for the ratio of the two means, based on pivotal quantities involving the maximum likelihood estimators, are proposed. The merits of the proposed approaches are evaluated by Monte Carlo simulation. Simulation study indicates that the procedures are satisfactory in terms of coverage probabilities of confidence intervals, and powers of tests. The proposed approach can also be applied to find confidence intervals for the difference between the means of the two lognormal distributions. Illustrative examples with a real data set and with a simulated data set are given. PMID- 24467288 TI - Comprehensive screening for a complete set of Japanese-population-specific filaggrin gene mutations. AB - Mutations in FLG coding profilaggrin cause ichthyosis vulgaris and are an important predisposing factor for atopic dermatitis. Until now, most case-control studies and population-based screenings have been performed only for prevalent mutations. In this study, we established a high-throughput FLG mutation detection system by real-time PCR with a set of two double-dye probes and conducted comprehensive screening for almost all of the Japanese-population-specific FLG mutations (ten FLG mutations). The present comprehensive screening for all ten FLG mutations provided a more precise prevalence rate for FLG mutations (11.1%, n = 820), which seemed high compared with data of previous reports based on screening for limited numbers of FLG mutations. Our comprehensive screening suggested that population-specific FLG mutations may be a significant predisposing factor for hay fever (odds ratio = 2.01 [95% CI: 1.027-3.936, P < 0.05]), although the sample sizes of this study were too small for reliable subphenotype analysis on the association between FLG mutations and hay fever in the eczema patients and the noneczema individuals, and it is not clear whether the association between FLG mutations and hay fever is due to the close association between FLG mutations and hay fever patients with eczema. PMID- 24467287 TI - Structural plasticity of the Semliki Forest virus glycome upon interspecies transmission. AB - Cross-species viral transmission subjects parent and progeny alphaviruses to differential post-translational processing of viral envelope glycoproteins. Alphavirus biogenesis has been extensively studied, and the Semliki Forest virus E1 and E2 glycoproteins have been shown to exhibit differing degrees of processing of N-linked glycans. However the composition of these glycans, including that arising from different host cells, has not been determined. Here we determined the chemical composition of the glycans from the prototypic alphavirus, Semliki Forest virus, propagated in both arthropod and rodent cell lines, by using ion-mobility mass spectrometry and collision-induced dissociation analysis. We observe that both the membrane-proximal E1 fusion glycoprotein and the protruding E2 attachment glycoprotein display heterogeneous glycosylation that contains N-linked glycans exhibiting both limited and extensive processing. However, E1 contained predominantly highly processed glycans dependent on the host cell, with rodent and mosquito-derived E1 exhibiting complex-type and paucimannose-type glycosylation, respectively. In contrast, the protruding E2 attachment glycoprotein primarily contained conserved under-processed oligomannose-type structures when produced in both rodent and mosquito cell lines. It is likely that glycan processing of E2 is structurally restricted by steric-hindrance imposed by local viral protein structure. This contrasts E1, which presents glycans characteristic of the host cell and is accessible to enzymes. We integrated our findings with previous cryo-electron microscopy and crystallographic analyses to produce a detailed model of the glycosylated mature virion surface. Taken together, these data reveal the degree to which virally encoded protein structure and cellular processing enzymes shape the virion glycome during interspecies transmission of Semliki Forest virus. PMID- 24467289 TI - Ecological, historical and evolutionary determinants of modularity in weighted seed-dispersal networks. AB - Modularity is a recurrent and important property of bipartite ecological networks. Although well-resolved ecological networks describe interaction frequencies between species pairs, modularity of bipartite networks has been analysed only on the basis of binary presence-absence data. We employ a new algorithm to detect modularity in weighted bipartite networks in a global analysis of avian seed-dispersal networks. We define roles of species, such as connector values, for weighted and binary networks and associate them with avian species traits and phylogeny. The weighted, but not binary, analysis identified a positive relationship between climatic seasonality and modularity, whereas past climate stability and phylogenetic signal were only weakly related to modularity. Connector values were associated with foraging behaviour and were phylogenetically conserved. The weighted modularity analysis demonstrates the dominating impact of ecological factors on the structure of seed-dispersal networks, but also underscores the relevance of evolutionary history in shaping species roles in ecological communities. PMID- 24467291 TI - The Global Opioid Policy Initiative: a wealth of information, but what is next? AB - Recently, the outcomes were published of the Global Opioid Policy Initiative, evaluating the availability, cost of opioid medicines and the regulatory barriers that are possibly impeding access for the management of cancer pain in developing countries. Other studies have shown that the vast majority of the world population has no access to opioid analgesics. This study shows by country which opioid medicines are available, what they cost to the patient, and investigates the presence of barriers for access to these medicines. Data from the project will be an important resource for those who advocate for improved access to opioid analgesics. Yet, like so often, many more aspects of inadequate opioid analgesic consumption require exploration and reporting, including legislative barriers. The last publication on the project is a "What's next?" that is over focusing on palliative care, forgetting that outside palliative care is also a huge need for opioid analgesics in moderate and severe pain. While promoting access to palliative care and pain management, their recognition as a human right by UN bodies would be of great help. Moreover, WHO's Access to Controlled Medicines Programme, could be an important programme to support the countries in making these improvements. PMID- 24467292 TI - Excellent long-term patient and graft survival are possible with appropriate use of livers from deceased septuagenarian and octogenarian donors. AB - BACKGROUND: Although increasing donor age adversely affects survival after liver transplantation, livers have been used from selected deceased donors older than 70 years. Although there are reports of excellent short-term results, long-term results are unknown. Our experience was reviewed with septuagenarian and octogenarian deceased donors to determine long-term outcomes. METHODS: All primary deceased donor liver transplants performed at our institution between July 1998 and December 2010 were reviewed. Recipients of livers procured after circulatory arrest, split and reduced-size livers and multiple organ transplants were excluded from the study. Patient and graft survival were calculated using the Kaplan-Meier method, and survival comparisons were made with the log-rank test. RESULTS: In total, 780 patients met inclusion criteria, and 109 patients received livers from donors older than 70 years (range = 70-86). There were no differences in long-term patient (P = 0.67) or graft (P = 0.42) survival between hepatitis C negative recipients of livers from older compared with younger donors. In contrast, 7-year survival for HCV-positive recipients of older donor livers was less than half that of HCV-negative recipients. DISCUSSION: Transplantation of livers from septua- and octogenarian donors can achieve excellent long-term patient and graft survival for selected HCV-negative patients. PMID- 24467293 TI - Perception of Spanish primary healthcare nurses about evidence-based clinical practice: a qualitative study. AB - BACKGROUND: Although evidence-based clinical practice constitutes a priority for healthcare services in many countries within the last few years, there is a general lack of implementation of evidence-based clinical practice in nursing care, especially in primary health care. Few qualitative studies concerning the influencing factors on evidence-based clinical practice for community nurses have been carried out. AIM: This study examined the perception of nurses in Spanish primary health care with regard to the knowledge, advantages and barriers within the application process with evidence-based clinical practice. METHODS: We used a descriptive qualitative study with focus groups to collect data. Forty-six primary care nurses took part in this study and they were distributed into five focus groups. RESULTS: Five main topics arose from the results achieved: knowledge and development of evidence-based clinical practice, evidence searching, evidence dissemination, advantages of use of evidence-based clinical practice, and barriers for its application and implementation. Participants had a positive attitude towards evidence-based practice, although they used this infrequently because of lack of competence and organizational support for its application. CONCLUSION: Our participants are increasingly determined to take into account evidence within the decision-making processes in their usual clinical practice. We consider it advisable to develop specialized training strategies as well as provide necessary resources for the implementation of evidence-based clinical practice duly adapted to the field of primary health care. IMPLICATIONS FOR NURSING AND HEALTH POLICY: This study highlights the existing gap in translating knowledge to practice and its potential implications in the effectiveness of nursing interventions and decision making in primary health care, and thus its implications for education policy. PMID- 24467294 TI - Slow magnetic relaxation in trigonal-planar mononuclear Fe(II) and Co(II) bis(trimethylsilyl)amido complexes--a comparative study. AB - Alternating current magnetic investigations on the trigonal-planar high-spin Co(2+) complexes [Li(15-crown-5)] [Co{N(SiMe3)2}3], [Co{N(SiMe3)2}2(THF)] (THF = tetrahydrofuran), and [Co{N(SiMe3)2}2(PCy3)] (Cy = -C6H13 = cyclohexyl) reveal that all three complexes display slow magnetic relaxation at temperatures below 8 K under applied dc (direct current) fields. The parameters characteristic for their respective relaxation processes such as effective energy barriers Ueff (16.1(2), 17.1(3), and 19.1(7) cm(-1)) and relaxation times tau0 (3.5(3) * 10( 7), 9.3(8) * 10(-8), and 3.0(8) * 10(-7) s) are almost the same, despite distinct differences in the ligand properties. In contrast, the isostructural high-spin Fe(2+) complexes [Li(15-crown-5)] [Fe{N(SiMe3)2}3] and [Fe{N(SiMe3)2}2(THF)] do not show slow relaxation of the magnetization under similar conditions, whereas the phosphine complex [Fe{N(SiMe3)2}2(PCy3)] does, as recently reported by Lin et al. (Lin, P.-H.; Smythe, N. C.; Gorelsky, S. I.; Maguire, S.; Henson, N. J.; Korobkov, I.; Scott, B. L.; Gordon, J. C.; Baker, R. T.; Murugesu, M. J. Am. Chem. Soc. 2011, 135, 15806.) Distinctly differing axial anisotropy D parameters were obtained from fits of the dc magnetic data for both sets of complexes. According to density functional theory (DFT) calculations, all complexes possess spatially nondegenerate ground states. Thus distinct spin-orbit coupling effects, as a main source of magnetic anisotropy, can only be generated by mixing with excited states. This is in line with significant contributions of excited determinants for some of the compounds in complete active space self-consistent field (CASSCF) calculations done for model complexes. Furthermore, the calculated energetic sequence of d orbitals for the cobalt compounds as well as for [Fe{N(SiMe3)2}2(PCy3)] differs significantly from the prediction by crystal field theory. Experimental and calculated (time-dependent DFT) optical spectra display characteristic d-d transitions in the visible to near-infrared region. Energies for lowest transitions range from 0.19 to 0.35 eV; whereas, for [Li(15-crown 5)][Fe{N(SiMe3)2}3] a higher value is found (0.66 eV). Zero-field (57)Fe Mobetabauer spectra of the three high-spin iron complexes exhibit a doublet at 3 K with small and similar values of the isomer shifts (delta), ranging between 0.57 and 0.59 mm/s, as well as an unusual small quadrupole splitting (DeltaEQ = 0.60 mm/s) in [Li(15-crown-5)][Fe{N(SiMe3)2}3]. PMID- 24467296 TI - Vascular access-related infection in nocturnal home hemodialysis. AB - Frequent hemodialysis is associated with increased vascular access adverse events. We hypothesized that bacteremia would be more frequent in patients with central venous catheter (CVC) than arteriovenous fistula or arteriovenous graft (AVF/AVG) in nocturnal home hemodialysis (NHHD). We reviewed blood culture reports and concurrent clinical data for a cohort of one hundred eighty-seven NHHD patients between January 1, 2006 and June 30, 2012. The primary outcome was time to first bacteremia, technique failure, or death after commencing NHHD. Types of bacteremia and clinical consequences were analyzed. Analyses were adjusted for a priori defined confounders. One hundred eighty-seven patients were included with a total follow up of six hundred five patient years. Initial vascular access was AVF in seventy-eight (42%) patients, AVG in eleven (6%) patients, and CVC in ninety-eight (52%) patients. A total of 79.3% of patients with a CVC reached the composite endpoint of bacteremia, technique failure, or death in the study period; 44.5% of patients with an AVF or AVG reached this composite endpoint. Adjusted time to first bacteremia, technique failure, or death was significantly shorter in patients with initial CVC access (hazard ratio 2.42, 95% confidence interval 1.50-3.90, p < 0.001). Risk factors for bacteremia were comorbid status quantified by the Charlson Comorbidity Index (p < 0.001) and diabetes (p < 0.001). Coagulase negative staphylococcus was the commonest organism cultured accounting for 51.4% bacteremias. The second commonest organism was staphylococcus aureus (20.3% bacteremias). Patients undergoing NHHD with a CVC have a shorter duration to first infection, technique failure, or death than those with permanent vascular access. PMID- 24467297 TI - Endometrial carcinoma in high-risk populations: is it time to consider a screening policy? AB - Endometrial carcinoma (EC) is the leading female genital tract malignancy in industrialized countries. It will become an important public health problem in the coming years in the USA and Europe, where its incidence is increasing, and next-generation interventions should include periodical screening in high-risk women. In this review, we discuss the importance to gynaecologists of detecting women at high risk and offering an adequate screening programme. Screening for EC is particularly challenging and there is currently no proven programme for the surveillance of women estimated to be at an increased risk of developing this form of cancer. The data in the literature, including this and previous issues of Cytopathology, and personal experience suggest that endometrial liquid-based cytology (LBC) might play an essential role in a screening policy for EC. LBC may enable practitioners to reduce age-adjusted mortality for women at high risk for EC. PMID- 24467298 TI - Enhanced charge transport kinetics in anisotropic, stratified photoanodes. AB - The kinetics of charge transport in mesoporous photoanodes strongly constrains the design and power conversion efficiencies of dye sensitized solar cells (DSSCs). Here, we report a stratified photoanode design with enhanced kinetics achieved through the incorporation of a fast charge transport intermediary between the titania and charge collector. Proof of concept photoanodes demonstrate that the inclusion of the intermediary not only enhances effective diffusion coefficients but also significantly suppresses charge recombination, leading to diffusion lengths two orders of magnitude greater than in standard mesoporous titania photoanodes. The intermediary concept holds promise for higher efficiency DSSCs. PMID- 24467299 TI - Visceral adipose tissue: the link with esophageal adenocarcinoma. AB - OBJECTIVE: There is strong evidence for an association between obesity and esophageal adenocarcinoma (EAC). This study investigated the association between directly measured visceral adipose tissue and the risk of EAC. METHODS: In a case control setting, we measured visceral adipose tissue in patients with EAC and healthy controls. Visceral adipose tissue was determined by abdominal CT. Exclusion criteria were uninterpretable CT scans and severe comorbidity. Controls were healthy volunteers undergoing screening CT colonography. Cross-sectional areas of visceral and subcutaneous adipose tissues were measured in cm(2) at L3/L4. Values of adipose tissue of EAC patients were extrapolated to stage 0 and compared to controls. The association between visceral adipose tissue and EAC was calculated with least-squares regression, adjusted for age, sex and TNM stage. RESULTS: We included 175 EAC patients and 251 controls. While body mass index was similar in EAC patients (26.1 kg/m(2)) and controls (26.2 kg/m(2)), visceral adipose tissue was significantly higher in EAC patients at stage 0 than in controls (276 vs. 231 cm(2); p = 0.015). Regarding subcutaneous adipose tissue, there was no difference. CONCLUSIONS: Patients with EAC have significantly higher visceral adipose tissue than healthy controls. Visceral adipose tissue is a risk factor in the development of EAC and seems to be more important than obesity alone. PMID- 24467300 TI - Real-time detection of redox events in molecular junctions. AB - Redox molecular junctions are promising systems for nanoelectronics applications, and yet they are still only marginally understood. The study of these systems has so far been conducted in solution, utilizing "electrolyte gating" to control their redox states and, as a result, their steady-state transistor-like conductance behavior. Here we explore redox junctions under vacuum at 77 K, and report real time detection of redox events in junctions of the type Au-6 thiohexanethiolferrocene-Au. Redox events are revealed as a two-level fluctuating signal in current-time traces with potential-dependent amplitude and frequency. Using a theoretical model for signals with a telegraph-like noise, the current time traces are analyzed to extract the various molecular parameters which define the dynamics of the system. The presented method, which can be applied to other types of redox molecules, offers a new approach to study the unexplored territory of molecular dynamics in molecular junctions. PMID- 24467302 TI - Transsphenoidal surgery using a high definition video telescope for pituitary adenomas in dogs with pituitary dependent hypercortisolism: methods and results. AB - OBJECTIVE: To (1) establish a technique for transsphenoidal removal of pituitary adenomas in dogs with pituitary dependent hypercortisolism (PDH) using a high definition video telescope, and (2) report initial outcomes. STUDY DESIGN: Prospective case series. ANIMALS: Dogs with pituitary dependent hypercortisolism (PDH; n = 26) with suprasellar masses. METHODS: Pituitary tumors were removed using a modification of a transoral transsphenoidal approach. Surgery was observed using a high definition video telescope (VITOMTM) and localization of the sella was performed by drilling pilot holes in the basisphenoid bone followed by computed tomography (CT). RESULTS: Dogs had PDH confirmed by urinary cortisol to creatinine ratio (UCCR) and endogenous ACTH assays, and tumors confirmed by MRI. There were no postoperative cerebrospinal fluid leaks, wound dehiscence, or surgical site infections. Overall postoperative mortality was 19% with no mortality observed in the last 16 dogs, indicating an initial "learning curve" followed by good surgical results. All dogs that survived the immediate postoperative period (1 week) returned to their owners in good health, on hormonal replacement therapy. Follow-up ranged from 3 to 36 months. Sustained tumor control and hormonal remission based on normalized ACTH and UCCR measurements were observed in 20/21 (95%) dogs at 1-year follow-up. CONCLUSIONS: Modifications of a trans-oral transsphenoidal technique for surgical removal of pituitary tumors provides a safe and effective strategy for long-term remission of PDH with acceptable morbidity and mortality. PMID- 24467301 TI - delta-Opioid receptor agonists inhibit migraine-related hyperalgesia, aversive state and cortical spreading depression in mice. AB - BACKGROUND AND PURPOSE: Migraine is an extraordinarily common brain disorder for which treatment options continue to be limited. Agonists that activate the delta opioid receptor may be promising for the treatment of migraine as they are highly effective for the treatment of chronic rather than acute pain, do not induce hyperalgesia, have low abuse potential and have anxiolytic and antidepressant properties. The aim of this study was to investigate the therapeutic potential of delta-opioid receptor agonists for migraine by characterizing their effects in mouse migraine models. EXPERIMENTAL APPROACH: Mechanical hypersensitivity was assessed in mice treated with acute and chronic doses of nitroglycerin (NTG), a known human migraine trigger. Conditioned place aversion to NTG was also measured as a model of migraine-associated negative affect. In addition, we assessed evoked cortical spreading depression (CSD), an established model of migraine aura, in a thinned skull preparation. KEY RESULTS: NTG evoked acute and chronic mechanical and thermal hyperalgesia in mice, as well as conditioned place aversion. Three different delta-opioid receptor agonists, SNC80, ARM390 and JNJ20788560, significantly reduced NTG-evoked hyperalgesia. SNC80 also abolished NTG-induced conditioned place aversion, suggesting that delta-opioid receptor activation may also alleviate the negative emotional state associated with migraine. We also found that SNC80 significantly attenuated CSD, a model that is considered predictive of migraine preventive therapies. CONCLUSIONS AND IMPLICATIONS: These data show that delta-opioid receptor agonists modulate multiple basic mechanisms associated with migraine, indicating that delta-opioid receptors are a promising therapeutic target for this disorder. PMID- 24467303 TI - Degenerative liver disease in young Beagles with hereditary cobalamin malabsorption because of a mutation in the cubilin gene. PMID- 24467304 TI - Thermoresponsive copolymer brushes possessing quaternary amine groups for strong anion-exchange chromatographic matrices. AB - A thermoresponsive copolymer incorporating a quaternary amine group, poly(N isopropylacrylamide-co-3-acrylamidopropyl trimethylammonium chloride (APTAC)-co tert-butylacrylamide), was conjugated to the surface of silica beads through surface-initiated atom transfer radical polymerization. Prepared copolymer- and copolymer brush-modified beads were characterized by CHN elemental analysis, X ray photoelectron spectroscopy, gel permeation chromatography, and observation of phase transition profiles. Phase transition profiles of the prepared copolymer indicated that 5 mol % APTAC is suitable for enabling thermally modulated property changes in the copolymer. Chromatographic elution behaviors of adenosine nucleotides and proteins were observed using prepared beads as chromatography matrices. Higher retention time of adenosine nucleotides and strong protein adsorption behavior were observed compared with those on beads with tertiary amine groups, because of the strong basic properties. Therefore, copolymer brush modified beads will be useful as thermoresponsive ion-exchange chromatographic matrices. PMID- 24467305 TI - Potential disease interaction reinforced: double-virus-infected escaped farmed Atlantic salmon, Salmo salar L., recaptured in a nearby river. AB - The role of escaped farmed salmon in spreading infectious agents from aquaculture to wild salmonid populations is largely unknown. This is a case study of potential disease interaction between escaped farmed and wild fish populations. In summer 2012, significant numbers of farmed Atlantic salmon were captured in the Hardangerfjord and in a local river. Genetic analyses of 59 of the escaped salmon and samples collected from six local salmon farms pointed out the most likely source farm, but two other farms had an overlapping genetic profile. The escapees were also analysed for three viruses that are prevalent in fish farming in Norway. Almost all the escaped salmon were infected with salmon alphavirus (SAV) and piscine reovirus (PRV). To use the infection profile to assist genetic methods in identifying the likely farm of origin, samples from the farms were also tested for these viruses. However, in the current case, all the three farms had an infection profile that was similar to that of the escapees. We have shown that double-virus-infected escaped salmon ascend a river close to the likely source farms, reinforcing the potential for spread of viruses to wild salmonids. PMID- 24467306 TI - Reliability and validity of the Korean version of Morningness-Eveningness Questionnaire in adults aged 20-39 years. AB - Morningness-Eveningness (ME) can be defined by the difference in individual diurnal preference observed from general behavioral patterns including sleep habits. The Horne & Ostberg Morningness-Eveningness Questionnaire (MEQ) has been used for classifying ME types. We examined the reliability of a Korean version of the MEQ (Korean MEQ) and verified its validity by comparing responses on the Korean MEQ to objectively-recorded sleep-wake rhythms. After translating and back translating the MEQ from English into Korean, we examined the internal consistency of 19 items of the Korean MEQ in 91 subjects, and the test-retest reliability in 21 subjects who took the Korean MEQ twice, 4 weeks apart. The Korean MEQ was then administered to 1022 young adult subjects. A subset of 46 morning, neither, and evening type subjects took part in a validation study in which their rest-activity timing was collected by actigraphy for 7 days. Cosinor analyses on these data were done to obtain the acrophase and amplitude of the sleep-wake rhythm. Cronbach's alpha of the total scores from the Korean MEQ was 0.77, and the test-retest reliability intra-class correlation coefficient was 0.90 (p < 0.0001). There was a significant negative correlation between Korean MEQ score and reported sleep-wake timing among the entire cohort (p < 0.0001). There was a significant difference in bedtime and wake time (on both work and free days), and in the mean sleep-wake rhythm acrophase, between ME types (p < 0.01). In this study, the validity of the Korean MEQ was verified by illustrating the difference in acrophases of the sleep-wake rhythm between the ME types in young adults. PMID- 24467307 TI - Improving clinical learning environments for tomorrow's physicians. PMID- 24467309 TI - Global phosphoproteomic analysis of Daphnia pulex reveals evolutionary conservation of Ser/Thr/Tyr phosphorylation. AB - Reversible protein phosphorylations of serine, threonine, and tyrosine are critical processes in organisms ranging from prokaryotes to eukaryotes. Water fleas (Daphnids) have been used widely in ecologic and ecotoxicological studies, with more than 80% of ecotoxicological publications over the last 10 years involving planktonic genera, including Daphnia. However, the substrate proteins and the functions of phosphorylation in Daphnia remain largely unknown. Here, we report the first global screening of phosphoproteins and their sites of phosphorylation in D. pulex. We identified 103 phosphorylation sites in 91 Daphnia proteins by phosphopeptide enrichment using titanium dioxide isolation technology and an online two-dimensional liquid chromatography (2D-LC) system supported by high accuracy mass spectrometry. The identified Serine/threonine/tyrosine phosphorylation sites showed enrichment in the unstructured regions. Using Gene Ontology analysis, phosphorylated proteins were identified mainly as membrane proteins with essential biological roles such as protein binding, catalytic activity and nucleotide binding. BLASTP searching identified 21 phosphorylated sites in 20 D. pulex proteins that were evolutionally conserved between D. pulex and human. Here, we report the phosphorylation in Daphnia proteins and the predicted biological and functional roles of these phosphorylations. D. pulex might provide a promising model for examining the role of phosphorylation in biological functions. PMID- 24467310 TI - Exposure to airborne culturable microorganisms and endotoxin in two Italian poultry slaughterhouses. AB - Even if slaughterhouses' workers handle large amounts of organic material and are potentially exposed to a wide range of biological agents, relatively little and not recent data are available. The main objective of this study was to characterize indoor concentrations of airborne bacteria, fungi, and endotoxin mod = Im (endotoxin~Gram-negative*plant*filter) in two Italian poultry slaughterhouses. Air samples near air handling units inlets were also collected. Since there are not standardized protocols for endotoxin sampling and extraction procedures, an additional aim of the study was to compare the extraction efficiency of three different filter.. The study was also aimed at determining the correlation between concentrations of Gram-negative bacteria and endotoxin. In Plant A bacterial levels ranged from 17.5 to 2.6*10(3) CFU/m3. The highest concentrations were observed in evisceration area of chickens, between the automatic detachment of the neck and washing offal, and near birds coupling before hair-chilling. The highest mean value of Gram-negative (266.5 CFU/m3) was found near the washing offal of turkeys. In Plant B bacterial concentration ranged from 35 to 8*10(3) CFU/m3. The highest concentration. with the highest value of Gram-negative (248 CFU/m3), was found after defeathering. Fungal concentrations were overall lower than those found for bacteria (range: 0-205 CFU/m3 in Plant A and 0-146.2 CFU/m3 in Plant B). The microbial flora was dominated by Gram-negative and coagulase-negative staphylococci for bacteria and by species belonging to Cladosporium, Penicillium and Aspergillus genera for molds. The highest endotoxin concentrations were measured in washing offal for Plant A (range: 122.7-165.9 EU/m3) and after defeathering for Plant B (range: 0.83-38.85 EU/m3). In this study airborne microorganisms concentrations were lower than those found in similar occupational settings and below the occupational limits proposed by some authors. However, these microorganisms may exert adverse effects on exposed workers, in particular for those engaged in the early slaughtering stages, as evidenced by the presence of pathogenic species. The detection of pathogenic bacteria near AHU inlet may constitute a risk to public health and environmental pollution. PMID- 24467311 TI - Water-molecule-driven vapochromic behavior of a mononuclear platinum(II) system with mixed bipyridine and thioglucose. AB - A mononuclear platinum(II) complex with mixed bpy and H4tg(-) ligands, [Pt(H4tg S)2(bpy)].2H2O (1a; bpy = 2,2'-bipyridine and H5tg = 1-thio-beta-D-glucose), is photoluminescent in the solid state and undergoes facile and reversible removal of solvated water molecules accompanied by changes in its absorption and emission wavelengths. The analogous dmbpy complex, [Pt(H4tg-S)2(dmbpy)].H2O (2a; dmbpy = 4,4'-dimethyl-2,2'-bipyridine), is also emissive in the solid state, but its absorption and emission spectra remain unchanged after dehydration. X-ray crystallographic analyses revealed that the difference in the chromism of 1a and 2a is due to the difference in their hydrogen-bonding networks, which involve solvated water molecules. PMID- 24467313 TI - Lower limb gigantism, lymphedema, and painful varicosities following a thigh vascular access graft. AB - Prosthetic arteriovenous grafts (AVGs) are associated with greater morbidity than autogenous arteriovenous fistulas (AVFs), but their use is indicated when AVF formation is not possible. This report adds to the literature a case of lower limb gigantism, painful varicosities, and lymphedema following long-term use of AVG in the upper thigh. The patient's past medical history included renal transplantation on the same side well before the AVG was inserted and right leg deep vein thrombosis. Suspicion of AVG thrombosis was excluded by Doppler ultrasound, which demonstrated an access flow of 1700 mL/min. A computed tomography (CT) scan of the abdomen and pelvis did not identify the cause of her symptoms. Whereas functional incompetence of the iliac vein valve might be responsible for the varicosities, the extent of hypertrophy in this case raises the suspicion of lymphatic blockage possibly secondary to groin dissection undertaken at the time of graft insertion, in addition to the previous dissection at the time of transplantation. This case highlights the need for minimal groin dissection during AVG insertion, particularly in patients with a history of previous abdominopelvic surgery. PMID- 24467314 TI - Early-career researchers: what's in it for us? PMID- 24467315 TI - Cypriot and Greek nurses' perceptions of the professional practice environment. AB - BACKGROUND: Research evidence supports that the role of the professional practice environment is crucial for the delivery of quality care as it is significantly correlated with patient and nurse outcomes. However, in countries sharing similar cultural and ethnic backgrounds, like Cyprus and Greece, as well as the increased mobility of patients and healthcare workers, there is a lack of information regarding this issue. The aim of this study is to explore and compare Cypriot and Greek nurses' perceptions of their professional practice environment. METHODS: A descriptive comparative survey was employed using a sample of nurses in Cyprus (N = 150) and Greece (N = 147). Information was collected with the Revised Professional Practice Environment Scale (RPPE). RESULTS: The results revealed significant differences between the two countries in three out of eight factors of the RPPE, with Greece's mean value being higher than Cyprus's: Handling Disagreements and Conflicts, Leadership and Autonomy in Clinical Practice, and Teamwork. CONCLUSIONS: The findings generate additional knowledge about the organizational context of care delivery that might help nursing leaders to understand how nurses perceive their work environment and how this influences their work, and consequently the care provided. The results can be utilized by nurse ward managers to improve the quality of nursing care provided. Further research is needed using different approaches to explore nurses' experience in more depth. IMPLICATIONS FOR NURSING OR HEALTH POLICY: Measuring nurses' perceptions of their professional practice environment may assist managers and policymakers in introducing interventions that contribute to a better practice environment and consequently to improved nursing, as well as patient, outcomes. PMID- 24467316 TI - IgG4 overexpression is rare in meningiomas with a prominent inflammatory component: a review of 16 cases. AB - Meningiomas with prominent inflammation are traditionally classified as "lymphoplasmacyte-rich meningioma" (LPM). Both inflammatory and neoplastic meningeal proliferations have recently been linked to IgG4 disease, although a potential association with LPM has not been previously explored. Sixteen meningiomas with inflammatory cells outnumbering tumor cells were further characterized by CD3, CD20, CD68 and/or CD163, CD138, kappa, lambda, IgG and IgG4 immunostains. There were 11 female and 4 male patients, ranging from 22 to 78 (median 59) years of age. Tumors consisted of 10 World Health Organization (WHO) grade I, 5 grade II and 1 grade III LPMs. Immunohistochemically, the most numerous cell type was the macrophage in all cases followed by CD3-positive T cells and fewer CD20-positive B cells. Plasma cells ranged from moderate-marked (N = 5) to rare (N = 7), or absent (N = 4). Maximal numbers of IgG4 plasma cells per high power field (HPF) ranged from 0 to 32, with only two cases having counts exceeding 10/HPF. The IgG4/IgG ratio was increased focally in only two cases (30% and 31%). Additionally, plasma cells represented only a minor component in most examples, whereas macrophages predominated, suggesting that "inflammation-rich meningioma" may be a more accurate term. The inflammatory stimulus for most cases remains to be elucidated. PMID- 24467317 TI - Lupane triterpenoids from the stems of Euonymus carnosus. AB - Fifteen new lupane-type triterpenoids (1-15) and 10 known triterpenoids (16-25) were isolated from the stems of Euonymus carnosus. The structures of the new compounds were elucidated on the basis of spectroscopic analyses, and the absolute configuration of compound 1 was confirmed by X-ray crystallographic analysis using anomalous scattering of Cu Kalpha radiation. In addition, the compounds were tested for their cytotoxic activity against five human cancer cell lines and their ability to inhibit LPS-induced nitric oxide production in the murine microglia BV2 cell line. Compound 11 exhibited moderate cytotoxicity against several human cancer cell lines, and compounds 1, 2, 4, 5, 20, and 25 showed neuritis inhibitory activity against microglial inflammation factor, with IC50 values of 7.39, 7.48, 7.80, 3.48, 2.54, and 6.09 MUM, respectively. PMID- 24467318 TI - Cyanobacteria dominance influences resource use efficiency and community turnover in phytoplankton and zooplankton communities. AB - Freshwater biodiversity loss potentially disrupts ecosystem services related to water quality and may negatively impact ecosystem functioning and temporal community turnover. We analysed a data set containing phytoplankton and zooplankton community data from 131 lakes through 9 years in an agricultural region to test predictions that plankton communities with low biodiversity are less efficient in their use of limiting resources and display greater community turnover (measured as community dissimilarity). Phytoplankton resource use efficiency (RUE = biomass per unit resource) was negatively related to phytoplankton evenness (measured as Pielou's evenness), whereas zooplankton RUE was positively related to phytoplankton evenness. Phytoplankton and zooplankton RUE were high and low, respectively, when Cyanobacteria, especially Microcystis sp., dominated. Phytoplankton communities displayed slower community turnover rates when dominated by few genera. Our findings, which counter findings of many terrestrial studies, suggest that Cyanobacteria dominance may play important roles in ecosystem functioning and community turnover in nutrient-enriched lakes. PMID- 24467319 TI - Healthcare for migrants, participatory health research and implementation science -better health policy and practice through inclusion. The RESTORE project. AB - BACKGROUND: This is a time of unprecedented mobility across the globe. Healthcare systems need to adapt to ensure that primary care is culturally and linguistically appropriate for migrants. Evidence-based guidelines and training interventions for cultural competence and the use of professional interpreters are available across European healthcare settings. However, in real-world practice migrants and their healthcare providers 'get by' with a range of informal and inadequate strategies. RESTORE is an EU FP7 funded project, which is designed to address this translational gap. OBJECTIVES: The objective of RESTORE is to investigate and support the implementation of guidelines and training initiatives to support communication in cross-cultural consultations in selected European primary care settings. DESIGN: RESTORE is a qualitative, participatory health project running from 2011-2015. It uses a novel combination of normalization process theory and participatory learning and action research to follow and shape the implementation journeys of relevant guidelines and training initiatives. Research teams in Ireland, England, the Netherlands, Austria and Greece are conducting similar parallel qualitative case study fieldwork, with a complementary health policy analysis led by Scotland. In each setting, key stakeholders, including migrants, are involved in participatory data generation and analysis. EXPECTED RESULTS: RESTORE will provide knowledge about the levers and barriers to the implementation of guidelines and training initiatives in European healthcare settings and about successful, transferrable strategies to overcome identified barriers. RESTORE will elucidate the role of policy in shaping these implementation journeys; generate recommendations for European policy driving the development of culturally and linguistically appropriate healthcare systems. PMID- 24467321 TI - The role of family, friends and peers in Australian adolescent's alcohol consumption. AB - INTRODUCTION AND AIMS: This study examines factors associated with alcohol related attitudes and behaviours among 888 Australians aged 12 to 17 years. Although these influences have been examined in other countries, notably the USA, Australia's legal drinking age of 18 years is lower and adolescent drinking rates are substantially higher than in the USA. DESIGN AND METHODS: This is a survey of 888 adolescents aged 12-17; they were recruited via a variety of methods (including school based, interception in public places and online) to obtain a cross-section of participants across metropolitan, regional and rural New South Wales. RESULTS: Most respondents believed that people their age regularly consumed alcohol; and more than half believed that their siblings and peers would approve of them drinking. Predictors of frequent alcohol consumption included having a sibling or a friend who consumed alcohol; believing parents, friends and/or siblings approved of drinking; drinking behaviours of parents, friends and/or siblings; and having a higher disposable income. DISCUSSION AND CONCLUSIONS: The results support previous findings from the USA. We find an even stronger effect of family and friends' drinking behaviours and attitudes in a country with a lower legal drinking age and high adult alcohol consumption rates. PMID- 24467322 TI - Robust nonenzymatic hybrid nanoelectrocatalysts for signal amplification toward ultrasensitive electrochemical cytosensing. AB - We have discovered that magnetic Fe3O4 nanoparticles exhibit an intrinsic catalytic activity toward the electrochemical reduction of small dye molecules. Metallic nanocages, which act as efficient signal amplifiers, can be attached to the surface of Fe3O4 beads to further enhance the catalytic electrochemical signals. The Fe3O4@nanocage core-satellite hybrid nanoparticles show significantly more robust electrocatalytic activities than the enzymatic peroxidase/H2O2 system. We have further demonstrated that these nonenzymatic nanoelectrocatalysts can be used as signal-amplifying nanoprobes for ultrasensitive electrochemical cytosensing. PMID- 24467323 TI - Improving the performance of light-emitting electrochemical cells by optical design. AB - The organic light-emitting electrochemical cell (LEC) has emerged as an enabling technology for a wide range of novel and low-cost emissive applications, but its efficiency is still relatively modest. The focus in the field has so far almost exclusively been directed toward limiting internal loss mechanisms, whereas external losses resulting from poor light-outcoupling have been overlooked. Here, we report a straightforward procedure for improving the efficiency and emission quality of LECs. We find that our high-performance glass-encapsulated LECs exhibit a near-ideal Lambertian emission profile but that total internal reflection at the glass/air interface and a concomitant edge emission and self absorption represent a significant loss factor. We demonstrate a 60% improvement in the outcoupled luminance in the forward direction by laminating a light outcoupling film, featuring a hexagonal array of hemispherical microlenses as the surface structure, onto the front side of the device and a large-area metallic reflector onto the back side. With this scalable approach, yellow-emitting LEC devices with a power conversion efficiency of more than 15 lm W(-1) at a luminance of 100 cd m(-2) were realized. Importantly, we find that the same procedure also can mitigate problems with spatial variation in the light-emission intensity, which is a common and undesired feature of large-area LECs. PMID- 24467320 TI - A prospective cohort study of intrathecal versus epidural analgesia for patients undergoing hepatic resection. AB - BACKGROUND: The aim of this prospective observational study was to compare peri/post-operative outcomes of thoracic epidural analgesia (TEA) versus intrathecal morphine and fentanyl patient-controlled analgesia (ITM+fPCA) for patients undergoing a hepatic resection (HR). METHOD: Patients undergoing elective, one-stage, open HR for benign and malignant liver lesions, receiving central neuraxial block as part of the anaesthetic, in a high-volume hepato pancreato-biliary unit, were included in the study. The primary outcome measure was post-operative length of stay (LoS). RESULTS: A total of 73 patients (36 TEA and 37 ITM+fPCA) were included in the study. The median (IQR) post-operative LoS was 13 (11-15) and 11 (9-13) days in the TEA and ITM+fPCA groups, respectively (P = 0.011). There was significantly lower median intra-operative central venous pressure (P < 0.001) and blood loss (P = 0.017) in the TEA group, and a significant reduction in the time until mobilization (P < 0.001), post-operative intra-venous fluid/vasopressor requirement (P < 0.001/P = 0.004) in the ITM+fPCA group. Pain scores were lower at a clinically significant level 12 h post operatively in the TEA group (P < 0.001); otherwise there were no differences out to day five. There were no differences in quality of recovery or postoperative morbidity/mortality between the two groups. CONCLUSION: ITM+fPCA provides acceptable post-operative outcomes for HR, but may also increase the incidence of intra-operative blood loss in comparison to TEA. PMID- 24467325 TI - Elucidation of the molecular mechanism and the efficacy in vivo of a novel 1,4 benzoquinone that inhibits 5-lipoxygenase. AB - BACKGROUND AND PURPOSE: 1,4-Benzoquinones are well-known inhibitors of 5 lipoxygenase (5-LOX, the key enzyme in leukotriene biosynthesis), but the molecular mechanisms of 5-LOX inhibition are not completely understood. Here we investigated the molecular mode of action and the pharmacological profile of the novel 1,4-benzoquinone derivative 3-((decahydronaphthalen-6-yl)methyl)-2,5 dihydroxycyclohexa-2,5-diene-1,4-dione (RF-Id) in vitro and its effectiveness in vivo. EXPERIMENTAL APPROACH: Mechanistic investigations in cell-free assays using 5-LOX and other enzymes associated with eicosanoid biosynthesis were conducted, along with cell-based studies in human leukocytes and whole blood. Molecular docking of RF-Id into the 5-LOX structure was performed to illustrate molecular interference with 5-LOX. The effectiveness of RF-Id in vivo was also evaluated in two murine models of inflammation. KEY RESULTS: RF-Id consistently suppressed 5 LOX product synthesis in human leukocytes and human whole blood. RF-Id also blocked COX-2 activity but did not significantly inhibit COX-1, microsomal PGE2 synthase-1, cytosolic PLA2 or 12- and 15-LOX. Although RF-Id lacked radical scavenging activity, reducing conditions facilitated its inhibitory effect on 5 LOX whereas cell stress impaired its efficacy. The reduced hydroquinone form of RF-Id (RED-RF-Id) was a more potent inhibitor of 5-LOX as it had more bidirectional hydrogen bonds within the 5-LOX substrate binding site. Finally, RF Id had marked anti-inflammatory effects in mice in vivo. CONCLUSIONS AND IMPLICATIONS: RF-Id represents a novel anti-inflammatory 1,4-benzoquinone that potently suppresses LT biosynthesis by direct inhibition of 5-LOX with effectiveness in vivo. Mechanistically, RF-Id inhibits 5-LOX in a non-redox manner by forming discrete molecular interactions within the active site of 5 LOX. PMID- 24467326 TI - Vaginal microbiota of spayed dogs with or without recurrent urinary tract infections. AB - BACKGROUND: Limited information is available regarding the vaginal microbiota of normal spayed dogs and spayed dogs with recurrent UTIs. Vaginal lactic acid producing bacteria (LAB) have been associated with decreased frequency of recurrent urinary tract infection in women and may have a protective role within the urinary tract of female dogs. HYPOTHESIS/OBJECTIVES: Spayed dogs with historical recurrent UTI will have decreased prevalence of LAB and increased prevalence of uropathogenic bacterial populations in the vaginal microbiota when compared with the vaginal microbiota of healthy, spayed dogs. ANIMALS: Twenty-one client-owned adult spayed female dogs with historical recurrent UTI and 23 healthy, spayed female dogs without a history of recurrent UTI. METHODS: Dogs were placed into a recurrent UTI group or control group in this prospective study. Bacterial populations were isolated and characterized from vaginal swabs obtained from each dog. RESULTS: The most common bacterial isolates obtained from the vaginal tract of all dogs were Escherichia coli (11/44) and S. pseudintermedius (13/44). E. coli was isolated from the vaginal tract of 8 of 21 (38%) dogs in the rUTI group and 3 of 23 (13%) dogs in the control group (P = .08). LAB were isolated from 7 of the 44 dogs. Two of these 7 dogs were in the rUTI group and 5 of the 7 dogs were in the control group. CONCLUSIONS AND CLINICAL IMPORTANCE: The vaginal microbiota of spayed female dogs with recurrent UTI was similar to the control population of normal, spayed female dogs. PMID- 24467327 TI - Physico-chemical characteristics of uranium compounds: a review. AB - PURPOSE: To collect values of parameters describing the physico-chemical properties of different uranium compounds in order to quantify their variability and to propose specific parameters for different workplaces and compounds. MATERIAL AND METHODS: The published values of absorption parameters, gastrointestinal absorption fractions, activity median aerodynamic diameters and geometric standard deviations of the particle size activity distribution were collected. RESULTS: Average and median values for each chemical form and workplace were determined for these parameters. These values can be used when no precise information is known for dose assessment following internal contamination by uranium. This review presents and discusses the variability of these parameters for the different uranium chemical forms and workplaces. Finally, sensitivity of the dose coefficients to these parameters was quantified. CONCLUSION: Specific parameter values for different workplaces and compounds were proposed and the variability quantified. PMID- 24467328 TI - Apoptosis induction of cardiomyocytes and subsequent fibrosis after irradiation and neoadjuvant chemotherapy. AB - PURPOSE: Breast cancer treatments can induce important cardiovascular complications. The aim of this study was to evaluate cardiac alterations after irradiation and chemotherapy in an animal model. MATERIAL AND METHODS: Wistar rats were divided into three groups: Control, TC+ IR (received chemotherapy and irradiation) and IR (received only irradiation). After 5 months, echocardiography was performed, the animals were euthanized, and the left ventricle was analyzed using light microscopy techniques and Polymerase Chain Reaction (PCR). RESULTS: Echocardiography showed decreases in ejection fraction and cardiac output, in TC+ IR group. Both TC+ IR and IR showed reduced intramyocardial vessel-to cardiomyocyte ratio, increased connective tissue, cardiomyocyte hypertrophy, increased numbers of apoptotic nuclei and increased Bax/Bcl2 expression. We also observed increased Transforming growth factor (TGF) beta 1 mRNA expression in both groups, but type 1 Procollagen expression was increased in TC+ IR group only. CONCLUSIONS: The study suggests that the induced cardiac remodelling begins with the reduction of intramyocardial vessels in the left ventricle tissue. The main consequence is the loss of cardiomyocytes through apoptosis, leading to the replacement of healthy tissue by fibrous tissue. It was observed that the damage caused by the combination of irradiation and chemotherapy induced functional alterations that did not occur when the animals were only irradiated. PMID- 24467329 TI - Effect of acidic environment on the response of endothelial cells to irradiation: implications for microbeam radiation therapy. AB - PURPOSE: Microbeam radiation therapy (MRT) is a novel experimental radiotherapy regimen, which delivers high doses of synchrotron-generated X-rays in the form of quasi-parallel arrays of microbeam separated by microplanar spaces. The repair or healing of irradiated regions (Peak) via migration of endothelial cells (EC) from unirradiated regions (Valley) plays an important role in the response of tumors and normal tissues to MRT. It is known that intratumor microenvironment is acidic. We investigated the influence of environmental acidity on the response of EC to ionizing radiation. MATERIALS AND METHODS: Effects of irradiation on the viability, clonogenicity and migration rate of endothelial cells were studied using human umbilical vascular endothelial cells and mouse endothelial cells in pH 7.3 and 6.4 environments. RESULTS: An exposure to acidic environment (pH 6.4) for 2-4 days exerted little effect on the viability of EC. On the other hand, acidic environment significantly retarded the migration of control and irradiated EC. The migration of EC into 2000 MUm-wide wound was slower than that into 1000 MUm-side wounds. CONCLUSION: The microenvironmental acidity and the size of beam opening in MRT may greatly affect the repair of irradiated peak regions via migration of EC from unirradiated valley regions. PMID- 24467330 TI - Increased gamma-H2AX by exposure to a 60-Hz magnetic fields combined with ionizing radiation, but not hydrogen peroxide, in non-tumorigenic human cell lines. AB - PURPOSE: Genotoxic effects have been considered the gold standard to determine if an environmental factor is a carcinogen, but the currently available data for extremely low frequency time-varying magnetic fields (ELF-MF) remain controversial. As an environmental stimulus, the effect of ELF-MF on cellular DNA may be subtle. Therefore, a more sensitive method and systematic research strategy are warranted to evaluate genotoxicity. MATERIALS AND METHODS: We investigated the effect of ELF-MF in combination with ionizing radiation (IR) or H(2)O(2) on the DNA damage response of expression of phosphorylated H2AX (gamma H2AX) and production of gamma-H2AX foci in non-tumorigenic human cell systems consisting of human lung fibroblast WI-38 cells and human lung epithelial L132 cells. RESULTS: Exposure to a 60-Hz, 2 mT ELF-MF for 6 h produced increased gamma H2AX expression, as well as gamma-H2AX foci production, a common DNA double strand break (DSB) marker. However, exposure to a 1 mT ELF-MF did not have the same effect. Moreover, 2 mT ELF-MF exposure potentiated the expression of gamma H2AX and gamma-H2AX foci production when combined with IR, but not when combined with H(2)O(2). CONCLUSIONS: ELF-MF could affect the DNA damage response and, in combination with different stimuli, provide different effects on gamma-H2AX. PMID- 24467331 TI - Effect of hypothermia on radiation-induced micronuclei and delay of cell cycle progression in TK6 cells. AB - PURPOSE: Low temperature (hypothermia) during irradiation leads to a reduced frequency of micronuclei in TK6 cells and it has been suggested that perturbation of cell cycle progression is responsible for this effect. The aim of the study was to test this hypothesis. MATERIALS AND METHODS: Human lymphoblastoid TK6 cells were treated by a combination of hypothermia (0.8 degrees C) and ionizing radiation in varying order (hypothermia before, during or after irradiation) and micronuclei were scored. Growth assay and two-dimensional flow cytometry was used to analyze cell cycle kinetics following irradiated of cells at 0.8 degrees C or 37.0 degrees C. RESULTS: The temperature effect was observed at the level of micronuclei regardless of whether cells were cooled during or immediately before or after the radiation exposure. No indication of cell cycle perturbation by combined exposure to hypothermia and radiation could be detected. CONCLUSIONS: The protective effect of hypothermia observed at the level of cytogenetic damage was not due to a modulation of cell cycle progression. A possible alternative mechanism and experiments to test it are discussed. PMID- 24467332 TI - Plate fixation for management of plantar instability of the distal tarsus/proximal metatarsus in 5 horses. AB - OBJECTIVE: To report plate fixation for management of traumatic injuries resulting in plantar instability of the proximal intertarsal (PIT) and tarsometatarsal (TMT) joints. STUDY DESIGN: Case series. MATERIALS AND METHODS: Medical records (October 1988 to August 2007) of horses that had internal fixation of the distal aspect of the tarsus were reviewed. Horses that had a broad dynamic compression plate (DCP) or broad locking compression plate (LCP) applied on the plantar-lateral aspect of the tarsus extending from the proximal calcaneus to the proximal one third of the metatarsus were included. Signalment, clinical signs, radiographic findings, time to surgery, implant type, postoperative management and complications were recorded. Long-term (>1 year) outcome was obtained for 4 horses. RESULTS: Five horses were treated, 4 had DCP fixation and 1 had LCP fixation. Subluxation of the proximal intertarsal joint was treated in 3 horses and 2 horses had fractures of the distal tarsal bones or proximal aspect of the metatarsus. Perioperative complications included peroneus tertius rupture (2 horses) and postoperative infection.(1) Four horses were discharged and 1 year after surgery were considered sound at pasture; 3 horses were sound enough for limited riding. CONCLUSIONS: Plate fixation provides adequate strength and stability for successful management of injuries that result in plantar instability of the tarsus and proximal metatarsus. PMID- 24467333 TI - Initiation of the flexirubin biosynthesis in Chitinophaga pinensis. AB - Bacteria from the Bacteroidetes phylum are known producers of the chemotaxonomic relevant flexirubins. These orange pigments comprise a non-isoprenoid aryl polyene carboxylic acid esterified with a dialkylresorcinol. Herein, we report a gene cluster from Chitinophaga pinensis encoding the biosynthesis of the polyene moiety and the biochemical characterization of a tyrosine ammonia-lyase and a 4 coumarate-CoA ligase responsible for the initiation of the polyene biosynthesis. Additionally, the flexirubin of C. pinensis was characterized by a combination of feeding experiments, high-performance liquid chromatography tandem mass spectrometry and matrix-assisted laser desorption/ionization mass spectrometry. PMID- 24467334 TI - Determination of fullerene scattering length density: a critical parameter for understanding the fullerene distribution in bulk heterojunction organic photovoltaic devices. AB - Fullerene derivatives are commonly used as electron acceptors in combination with (macro)molecular electron donors in bulk heterojunction (BHJ) organic photovoltaic (OPV) devices. Understanding the BHJ structure at different electron donor/acceptor ratios is critical to the continued improvement and development of OPVs. The high neutron scattering length densities (SLDs) of the fullerenes provide effective contrast for probing the distribution of the fullerene within the blend in a nondestructive way. However, recent neutron scattering studies on BHJ films have reported a wide range of SLDs ((3.6-4.4) * 10(-6) A(-2)) for the fullerenes 60-PCBM and 70-PCBM, leading to differing interpretations of their distribution in thin films. In this article, we describe an approach for determining more precisely the scattering length densities of the fullerenes within a polymer matrix in order to accurately quantify their distribution within the active layers of OPV devices by neutron scattering techniques. PMID- 24467335 TI - Delivery of growth factors using a smart porous nanocomposite scaffold to repair a mandibular bone defect. AB - Implantation of a porous scaffold with a large volume into the body in a convenient and safe manner is still a challenging task in the repair of bone defects. In this study, we present a porous smart nanocomposite scaffold with a combination of shape memory function and controlled delivery of growth factors. The shape memory function enables the scaffold with a large volume to be deformed into its temporal architecture with a small volume using hot-compression and can subsequently recover its original shape upon exposure to body temperature after it is implanted in the body. The scaffold consists of chemically cross-linked poly(epsilon-caprolactone) (c-PCL) and hydroxyapatite nanoparticles. The highly interconnected pores of the scaffold were obtained using the sugar leaching method. The shape memory porous scaffold loaded with bone morphogenetic protein-2 (BMP-2) was also fabricated by coating the calcium alginate layer and BMP-2 on the surface of the pore wall. Under both in vitro and in vivo environmental conditions, the porous scaffold displays good shape memory recovery from the compressed shape with deformed pores of 33 MUm in diameter to recover its porous shape with original pores of 160 MUm in diameter. In vitro cytotoxicity based on the MTT test revealed that the scaffold exhibited good cytocompatibility. The in vivo micro-CT and histomorphometry results demonstrated that the porous scaffold could promote new bone generation in the rabbit mandibular bone defect. Thus, our results indicated that this shape memory porous scaffold demonstrated great potential for application in bone regenerative medicine. PMID- 24467336 TI - Therapeutic assessment promotes treatment readiness but does not affect symptom change in patients with personality disorders: findings from a randomized clinical trial. AB - The field of clinical personality assessment is lacking in published empirical evidence regarding its treatment and clinical utility. This article reports on a randomized controlled clinical trial (N = 74) allocating patients awaiting treatment in a specialized clinic for personality disorders to either 4 sessions of (a) therapeutic assessment (TA) or (b) a structured goal-focused pretreatment intervention (GFPTI). In terms of short-term outcome, TA demonstrated superior ability to raise outcome expectancies and patient perceptions of progress toward treatment (Cohen's d = 0.65 and 0.56, respectively) and yielded higher satisfaction (d = 0.68). Moreover, patients reported marginally stronger alliance to the TA clinicians than to GFPT clinicians (d = 0.46), even though therapists perceived the alliance as equally positive in both groups. No differences in symptomatic ratings were observed. Results are discussed with reference to treatment utility in this particular patient group. PMID- 24467338 TI - Photomodulated fluorescence of supramolecular assemblies of sulfonatocalixarenes and tetraphenylethene. AB - Self-assembled fluorescent nanoparticles responding to specific stimuli are highly appealing for applications such as labels, probes, memory devices, and logic gates. However, organic analogues are challenging to prepare, due to unfavorable aggregation-caused quenching. We herein report the preparation of self-assembled fluorescent organic nanoparticles in water by means of calixarene induced aggregation of a tetraphenylethene derivative (QA-TPE) mediated by p sulfonatocalix[4]arenes. The self-assembled nanoparticles showed interesting photoswitching behaviors, and the fluorescence output of the generated nanoparticles was opposite to that of free QA-TPE both before and after irradiation. Free QA-TPE is nonfluorescent, owing to intramolecular rotations of the phenyl rings. In contrast, the self-assembled nanoparticles that formed upon complexation of QA-TPE with p-sulfonatocalix[4]arene exhibited aggregation induced emission fluorescence (lambda(em) = 480 nm, Phi = 14%), as a result of the inhibition of rotations. Upon UV light irradiation, free QA-TPE was cyclized to the corresponding diphenylphenanthrene, which showed typical fluorescence of a pi-conjugated system (lambda(em) = 385 nm, Phi = 9.3%), whereas the nanoparticles were nonfluorescent upon irradiation due to the aggregation-caused quenching. In effect, this system allows programmed modulation of TPE fluorescence at two different emission wavelengths by means of host-guest complexation and irradiation. Relative to a single-mode stimulus-responsive system, our new developed system of highly integrated modes into a single molecular unit that can exhibit modulation of fluorescence by multiple stimulus is expected to be more adaptable for practical applications and to show enhanced multifunctionality. PMID- 24467339 TI - Lessons learned: medical and health care management for emergency workers at the TEPCO Fukushima Daiichi APP accident. AB - During the emergency work at the Fukushima Daiichi Atomic Power Plant (APP), the Tokyo Electric Power Company (TEPCO) and the Japanese government experienced various problems in medical and health care management issues, including special medical examinations, on-site triage and initial treatment, patient transportation, lodging and food, and long-term health care for emergency workers. To resolve these problems, the Ministry of Health, Labor and Welfare (MHLW) issued a series of compulsory directives and provided administrative guidance to TEPCO. Based on the experiences and lessons learned, the MHLW recognized that the proper management and implementation of medical and health care management in response to a similar accident would require sufficient measures and systematic preparation, including the following: 1. In case of large scale nuclear accidents, the government needs to assist in dispatching medical staff to the affected plants. 2. Nuclear facility operators, medical facilities and fire departments should make an agreement to clarify the division of the roles played prior to the accident and should conduct emergency drills periodically with the full attendance of related personnel to identify and resolve the problems. 3. Operators need to develop a support base at a safe distance from the plant and to prepare to develop makeshift lodgings in case of emergency. 4. Operators need to come to an agreement to share food stocks among closely located nuclear plants and prepare cooking equipment that can be used in case of blackout to provide warm foods and drinks to as many workers as possible. 5. It is necessary to conduct long-term follow-up for emergency workers, including health care system, medical examinations and mental health consultations. PMID- 24467340 TI - A critique of concept analysis. PMID- 24467341 TI - Evaluation of standard magnetic resonance characteristics used to differentiate neoplastic, inflammatory, and vascular brain lesions in dogs. AB - Magnetic resonance (MR) imaging characteristics are commonly used to help predict intracranial disease categories in dogs, however, few large studies have objectively evaluated these characteristics. The purpose of this retrospective study was to evaluate MR characteristics that have been used to differentiate neoplastic, inflammatory, and vascular intracranial diseases in a large, multi institutional population of dogs. Medical records from three veterinary teaching hospitals were searched over a 6-year period for dogs that had diagnostic quality brain MR scans and histologically confirmed intracranial disease. Three examiners who were unaware of histologic diagnosis independently evaluated 19 MR lesion characteristics totaling 57 possible responses. A total of 75 dogs with histologically confirmed intracranial disease were included in analyses: 51 with neoplasia, 18 with inflammatory disease, and six with cerebrovascular disease. Only strong contrast enhancement was more common in neoplasia than other disease categories. A multivariable statistical model suggested that extra-axial origin, T2-FLAIR mixed intensity, and defined lesion margins were also predictive of neoplasia. Meningeal enhancement, irregular lesion shape, and multifocal location distinguished inflammatory diseases from the other disease categories. No MR characteristics distinguished vascular lesions and these appeared most similar to neoplasia. These results differed from a previous report describing seven MR characteristics that were predictive of neoplasia in dogs and cats. Findings from the current study indicated that the high performance of MR for diagnosing canine intracranial diseases might be due to evaluator recognition of combinations of MR characteristics vs. relying on any one MR characteristic alone. PMID- 24467342 TI - The level of C-reactive protein in chronic hemodialysis patients: a comparative study between patients with noninfected catheters and arteriovenous fistula in two large Gulf hemodialysis centers. AB - Hemodialysis (HD) patients have greater morbidity and mortality when they have a central venous catheter (CVC) rather than an arteriovenous fistula (AVF) access. Inflammation associated with dialysis catheter use and resultant higher C reactive protein (CRP) levels could have an independent adverse effect on patient outcomes. In this prospective study, we investigated whether HD catheters induce inflammation independent of infection. We compared the mean levels of the inflammatory marker (CRP) in 67 patients on maintenance HD using noninfected catheters with 86 HD patients using AVFs at Prince Salman Center for Kidney Diseases, Saudi Arabia (KSA), and Jahra Hospital, Kuwait, who met our inclusion criteria. C-reactive protein levels were measured every 2 months over a period of 6 months using immunoturbidimetric assay. One hundred fifty-three patients on maintenance HD for more than 6 months were included in the study, with mean age of 52.19 +/- 16.06 years; 66% were males and 34% were females. Serial levels of mean CRP were statistically and significantly higher in group with noninfected catheters (1.33, 1.24, and 1.10 mg/dL) compared to those with AVFs (0.65, 0.59, and 0.68 mg/dL) with P value of 0.000. In our study, we found no relation between CRP level and age, sex, hemoglobin, albumin, calcium, phosphorus, and iPTH level in both groups. Hemodialysis patients with a catheter have a heightened state of inflammation independent of infection, and thus our study supports the avoidance of catheters and a timely conversion to AVFs with catheter removal. PMID- 24467343 TI - Manganese(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid: structure and biological perspectives. AB - Manganese(II) complexes with the non-steroidal anti-inflammatory drug tolfenamic acid (Htolf) with the nitrogen-donor heterocyclic ligands 1,10-phenanthroline (phen), pyridine (py), or 2,2'-bipyridylamine (bipyam) and/or the oxygen-donor ligands H2O or N,N-dimethylformamide (DMF) have been synthesized and characterized. The crystal structures of complexes [Mn(tolf-O)(tolf O,O')(phen)(H2O)], [Mn2(MU2-tolf-O,O')2(tolf-O,O')2(bipyam)2], [Mn2(MU2-H2O)(MU2 tolf-O,O')2(tolf-O)2(py)4].1.5MeOH.py, and [Mn(MU2-tolf-O,O')2(DMF)2]n have been determined by X-ray crystallography. The interaction of the complexes with serum albumin proteins was investigated, and relative high binding constant values were calculated. The ability of the compounds to scavenge 1,1-diphenyl-picrylhydrazyl, 2,2'-azinobis(3-ethylbenzothiazoline-6-sulfonic acid), and hydroxyl radicals was evaluated, and [Mn(tolf)2(phen)(H2O)] was the most active scavenger among the compounds. The compounds have also exhibited noteworthy in vitro inhibitory activity against soybean lipoxygenase. UV titration studies of the interaction of the complexes with calf-thymus (CT) DNA have proved the binding to CT DNA with [Mn(MU2-tolf)2(DMF)2]n exhibiting the highest DNA-binding constant (Kb = 5.21 (+/ 0.35) * 10(5) M(-1)). The complexes bind to CT DNA probably via intercalation as suggested by DNA-viscosity measurements and competitive studies with ethidium bromide (EB), which revealed the ability of the complexes to displace the DNA bound EB. PMID- 24467344 TI - A genotypic difference in primary root length is associated with the inhibitory role of transforming growth factor-beta receptor-interacting protein-1 on root meristem size in wheat. AB - Previously we identified a major quantitative trait locus (QTL) qTaLRO-B1 for primary root length (PRL) in wheat. Here we compare proteomics in the roots of the qTaLRO-B1 QTL isolines 178A, with short PRL and small meristem size, and 178B, with long PRL and large meristem size. A total of 16 differentially expressed proteins were identified: one, transforming growth factor (TGF)-beta receptor-interacting protein-1 (TaTRIP1), was enriched in 178A, while various peroxidases (PODs) were more abundantly expressed in 178B. The 178A roots showed higher TaTRIP1 expression and lower levels of the unphosphorylated form of the brassinosteroid (BR) signaling component BZR1, lower expression of POD genes and reduced POD activity and accumulation of the superoxide anion O2(-) in the root elongation zone compared with the 178B roots. Low levels of 24-epibrassinolide increased POD gene expression and root meristem size, and rescued the short PRL phenotype of 178A. TaTRIP1 directly interacted with the BR receptor TaBRI1 of wheat. Moreover, overexpressing TaTRIP1 in Arabidopsis reduced the abundance of unphosphorylated BZR1 protein, altered the expression of BR-responsive genes, inhibited POD activity and accumulation of the O2(-) in the root tip and inhibited root meristem size. Our data suggested that TaTRIP1 is involved in BR signaling and inhibited root meristem size, possibly by reducing POD activity and accumulation of O2(-) in the root tip. We further demonstrated a negative correlation between the level of TaTRIP1 mRNA and PRL of landraces and modern wheat varieties, providing a valuable insight for better understanding of the molecular mechanism underlying the genotypic differences in root morphology of wheat in the future. PMID- 24467345 TI - Proton clouds to measure long-range contacts between nonexchangeable side chain protons in solid-state NMR. AB - We show that selective labeling of proteins with protonated amino acids embedded in a perdeuterated matrix, dubbed 'proton clouds', provides general access to long-range contacts between nonexchangeable side chain protons in proton-detected solid-state NMR, which is important to study protein tertiary structure. Proton cloud labeling significantly improves spectral resolution by simultaneously reducing proton line width and spectral crowding despite a high local proton density in clouds. The approach is amenable to almost all canonical amino acids. Our method is demonstrated on ubiquitin and the beta-barrel membrane protein BamA. PMID- 24467347 TI - Dual-biomimetic superhydrophobic electrospun polystyrene nanofibrous membranes for membrane distillation. AB - A new type of dual-biomimetic hierarchically rough polystyrene (PS) superhydrophobic micro/nano-fibrous membrane was fabricated via a one-step electrospinning technique at various polymer concentrations from 15 to 30 wt %. The obtained micro/nano-fibers exhibited a nanopapillose, nanoporous, and microgrooved surface morphology that originated from mimicking the micro/nanoscale hierarchical structures of lotus leaf and silver ragwort leaf, respectively. Superhydrophobicity and high porosity of such resultant electrospun nanofibrous membranes make them attractive candidates for membrane distillation (MD) application with low energy water recovery. In this study, two kinds of optimized PS nanofibrous membranes with different thicknesses were applied for desalination via direct contact MD. The membranes maintained a high and stable permeate water vapor flux (104.8 +/- 4.9 kg/m(2).h, 20 g/L NaCl salt feed for a thinner PS nanofibrous membrane with thickness of 60 MUm; 51 +/- 4.5 kg/m(2).h, 35 g/L NaCl salt feed for the thicker sample with thickness of 120 MUm; DeltaT = 50 degrees C) for a test period of 10 h without remarkable membrane pores wetting detected. These results were better than those of typical commercial polyvinylidene fluoride (PVDF) MD membranes or related PVDF nanofibrous membranes reported in literature, suggesting excellent competency of PS nanofibrous membranes for MD applications. PMID- 24467348 TI - Staged invasions across disparate grasslands: effects of seed provenance, consumers and disturbance on productivity and species richness. AB - Exotic plant invasions are thought to alter productivity and species richness, yet these patterns are typically correlative. Few studies have experimentally invaded sites and asked how addition of novel species influences ecosystem function and community structure and examined the role of competitors and/or consumers in mediating these patterns. We invaded disturbed and undisturbed subplots in and out of rodent exclosures with seeds of native or exotic species in grasslands in Montana, California and Germany. Seed addition enhanced aboveground biomass and species richness compared with no-seeds-added controls, with exotics having disproportionate effects on productivity compared with natives. Disturbance enhanced the effects of seed addition on productivity and species richness, whereas rodents reduced productivity, but only in Germany and California. Our results demonstrate that experimental introduction of novel species can alter ecosystem function and community structure, but that local filters such as competition and herbivory influence the magnitude of these impacts. PMID- 24467350 TI - Jung's quest for the Aurora consurgens. AB - The paper focuses on the year 1929 when Jung published 'A European commentary' to Richard Wilhelm's German translation of the Taoist text The Secret of the Golden Flower. This shows that Jung had already started on the track of European alchemy by following up Conrad Waldkirch's preface in Artis Auriferae (1593); and it raises the question of whether this could be the possible missing link to Jung's subsequent research in Alchemy and Hermetic Philosophy in the years to come. It is argued that here was the beginning of Jung's quest for the Aurora consurgens, the publication of which concludes the Mysterium Conuinctionis more than twenty years later. It is further maintained that this choice of the Aurora is a profound expression of Jung's ambition to revitalize the past from within the individual, and helps explain Jung's deep concern with the welfare and future of modern society. PMID- 24467351 TI - From affect to feelings and thoughts: from abuse to care and understanding. AB - The capacity of the infant to bear affect relies on the capacity of the caregiver until it has achieved enough strength to perform this task itself. In the case of neglect the necessary strength to contain, metabolize and think about affect so that it may be converted into differentiated feelings cannot develop because of the absence of a caregiver capable of sustaining the infant in its emotional development. Instead a system of defence against affect arises in which the affect itself is perceived as intrusive and abusive. Because of neglect a confusion between abuse and affect is to be observed, with catastrophic consequences for the growing up child. Furthermore neglected children can be seduced by external abuse in the hope of being protected from affect that threatens to feel abusive from within. Paradoxically these children are drawn toward abusive situations in the hope of finding some ongoing shelter from unmanageable affect. A corollary of this is that actual containment comes to feel abusive to them: if they are made to feel affect, they perceive the other, who put them in touch with affect, as abusive: thus affect, abuse and containment are confused. Clinical material will support this thesis. PMID- 24467352 TI - The spatial metaphor of Utopia in Russian culture and in analysis. AB - The spatial metaphor of Utopia is considered from a Jungian perspective along with its role in Russian culture and in analysis. Such post-Jungian concepts as the cultural complex and the archetypal story pattern of a victim are used in considering the desperate longing for a rescuer in patients' narratives and in Russian society. A clinical vignette is provided to illustrate these ideas. PMID- 24467353 TI - Requiem for analytical psychology: a reflection on Jung's (anti)catastrophic psychology. AB - This article is an interpretation of analytical psychology in the light of the catastrophic vision and dreams that Jung had in 1913 and 1914. It is shown how the guiding spirit of Jung's psychological project is to be found in that psychic material. Then it is proposed that the completion of the symbolic catastrophe displayed in Jung's last vision (1961) points to the end of the psychological foundations upon which analytical psychology is built, and thus to its cultural obsolescence, extensive to any psychology grounded in Jung's notion of 'soul'. PMID- 24467354 TI - The role played by Gerhard Adler in the development of analytical psychology internationally and in the UK. AB - The Jungian analyst Gerhard Adler left Berlin and re-settled in London in 1936. He was closely involved with the professionalization of analytical psychology internationally and in the UK, including the formation of the International Association for Analytical Psychology (IAAP) and The Society of Analytical Psychology (SAP).The tensions that arose within the latter organization led to a split that ended in the formation of the Association of Jungian Analysts (AJA). A further split at AJA resulted in the creation of another organization, the Independent Group of Analytical Psychologists (IGAP). Adler's extensive publications include his role as an editor of Jung's Collected Works and as editor of the C.G. Jung Letters. PMID- 24467355 TI - Jung's views on causes and treatments of schizophrenia in light of current trends in cognitive neuroscience and psychotherapy research I. Aetiology and phenomenology. AB - Jung's writings on schizophrenia are almost completely ignored or forgotten today. The purpose of this paper, along with a follow-up article, is to review the primary themes found in Jung's writings on schizophrenia, and to assess the validity of his theories about the disorder in light of our current knowledge base in the fields of psychopathology, cognitive neuroscience and psychotherapy research. In this article, five themes related to the aetiology and phenomenology of schizophrenia from Jung's writings are discussed:1) abaissement du niveau mental; 2) the complex; 3) mandala imagery; 4) constellation of archetypes and 5) psychological versus toxic aetiology. Reviews of the above areas suggest three conclusions. First, in many ways, Jung's ideas on schizophrenia anticipated much current thinking and data about the disorder. Second, with the recent (re)convergence of psychological and biological approaches to understanding and treating schizophrenia, the pioneering ideas of Jung regarding the importance of both factors and their interaction remain a useful and rich, but still underutilized resource. Finally, a more concerted effort to understand and evaluate the validity of Jung's concepts in terms of evidence from neuroscience could lead both to important advances in analytical psychology and to developments in therapeutic approaches that would extend beyond the treatment of schizophrenia. PMID- 24467360 TI - Hypoxia activates 15-PGDH and its metabolite 15-KETE to promote pulmonary artery endothelial cells proliferation via ERK1/2 signalling. AB - BACKGROUND AND PURPOSE: Dysfunction and injury of endothelial cells in the pulmonary artery play critical roles in the hypertension induced by chronic hypoxia. One consequence of hypoxia is increased activity of 15 hydroxyprostaglandin dehydrogenase (PGDH). Here, we have explored, in detail, the effects of hypoxia on the proliferation of pulmonary artery endothelial cells. EXPERIMENTAL APPROACH: We used bromodeoxyuridine incorporation, cell-cycle analysis, immunohistochemistry and Western blot analysis to study the effects of hypoxia, induced 15-PGDH) activity and its product, 15-keto-6Z, 8Z, 11Z, 13E eicosatetraenoic acid (15-KETE), on endothelial cell proliferation. Scratch-wound and tube formation assays were also used to study migration of endothelial cells. KEY RESULTS: 15-KETE increased DNA synthesis and enhanced the transition from the G0 /G1 phase to the S phase in hypoxia. Inhibition of 15-PGDH or siRNA for 15 PGDH reversed these effects. 15-KETE also activated the ERK1/2 signalling pathway. 15-KETE-induced cell migration and tube formation were reversed by blocking ERK1/2, but not the p38 MAPK pathway. CONCLUSIONS AND IMPLICATIONS: Hypoxia-induced endothelial proliferation and migration, an important underlying mechanism contributing to hypoxic pulmonary vascular remodelling, appears to be mediated by 15-PGDH and 15-KETE, via the ERK1/2 signalling pathway. PMID- 24467362 TI - A new neo-clerodane diterpene from Ajuga decumbens. AB - A new neo-clerodane diterpene, named ajugacumbin J (1), together with 13 known compounds (2-14) was isolated from Ajuga decumbens. The structure of ajugacumbin J (1) was elucidated by 1D and 2D NMR spectra and MS. Ajugacumbin J (1) and ajugacumbin D (5) exhibited inhibition of lipopolysaccharide-induced nitric oxide production in RAW 264.7 macrophages with an IC50 value of 46.2 and 35.9 MUM, respectively. PMID- 24467361 TI - Exclusion of a brain lesion: is intravenous contrast administration required after normal precontrast magnetic resonance imaging? AB - BACKGROUND: No evidence-based guidelines are available for the administration of gadolinium-based contrast media to veterinary patients. OBJECTIVE: To investigate whether administration of intravenous (IV) contrast media alters the likelihood of identifying a brain lesion in dogs and cats. ANIMALS: Four hundred and eighty seven client-owned animals referred for investigation of intracranial disease. METHODS: Two reviewers retrospectively analyzed precontrast transverse and sagittal T1-weighted (T1W), T2-weighted, and fluid-attenuated inversion recovery low-field MRI sequences from each patient for the presence of a clinically relevant brain lesion. All sequences subsequently were reviewed in the same manner with additional access to postcontrast T1W images. RESULTS: Of the 487 precontrast MRI studies, 312 were judged to be normal by 1 or both reviewers. Of these 312 studies, a previously undetected lesion was identified in only 6 cases (1.9%) based on changes observed on postcontrast sequences. Final diagnoses included meningoencephalitis of unknown origin (n = 1), feline infectious peritonitis (n = 1), and neoplasia (n = 2). All 4 of these cases had persistent neurological deficits suggestive of an underlying brain lesion. Contrast enhancement observed in the 2 other cases was considered falsely positive based on the results of further investigations. CONCLUSIONS AND CLINICAL IMPORTANCE: In patients with normal neurological examination and normal precontrast MRI, the subsequent administration of IV gadolinium-based contrast media is highly unlikely to disclose a previously unidentified lesion, calling into question the routine administration of contrast media to these patients. However, administration still should be considered in animals with persistent neurological deficits suggestive of an underlying inflammatory or neoplastic brain lesion. PMID- 24467364 TI - Differential functions of calpain 1 during epithelial cell death and adipocyte differentiation in mammary gland involution. AB - Calpains become activated in the mammary gland early during weaning, cleaving several proteins located mainly in the cell membrane, but also in other organelles such as lysosomes, mitochondria and nuclei. By immunofluorescence and Western blot analysis, we have demonstrated the nuclear translocation of calpain 1 and calpain-2, together with the cleavage of several cytoplasmic nucleoporins in epithelial cells of the lobulo-alveolar compartment. In vivo and in vitro calpain inhibition prevented this nucleoporin degradation. In addition, calpain-1 was also present in the nucleus of non-epithelial mammary tissue cells, concomitant with adipocyte re-differentiation. Calpain-1 was internalized within nuclei and found to be present in the nuclear chromatin-enriched fraction, associated with histone H3. Furthermore, we have demonstrated, both in vivo and in vitro, the cleavage of the N-terminal residue of histone H3 by calpain-1. Calpain-1 co-localized with both H3K4me3 (histone H3 trimethylated at Lys4) and H3K27me3 (histone H3 trimethylated at Lys27) at the nuclear periphery, a bivalent epigenetic signal essential for cell differentiation. Using ChIP assays we could confirm the presence of calpain-1 in the promoters of key genes expressed in adipose tissue, such as Cebpa (CCAAT/enhancer-binding protein alpha) and Lep (leptin). The results of the present study highlight a dual role for calpain-1 in the weaned gland after the pregnancy/lactation cycle, controlling programmed cell death and participating in the epigenetic programme during adipocyte differentiation. PMID- 24467366 TI - Serial plasma deoxyribonucleic acid levels as predictors of outcome in acute traumatic brain injury. AB - Increased plasma deoxyribonucleic acid (DNA) levels may be associated with disease severity after acute traumatic brain injury (TBI). This study posits that increased plasma DNA levels in acute TBI are predictive of outcome. Both serial plasma nuclear DNA (nDNA) and mitochondrial DNA (mtDNA) levels were examined in 88 consecutive patients with acute TBI and 66 control subjects. Additional samples were obtained on day 4 and day 7. Results showed that plasma nDNA and mtDNA on admission were significantly increased in patients with TBI compared with controls. Plasma nDNA, but not plasma mtDNA, levels in patients with acute TBI significantly correlated with Glasgow Coma Scale (GCS) score and Injury Severity Score (ISS) on presentation. Plasma nDNA increased significantly from day 1 to day 7 in patients with poor outcome. Its levels on presentation were independently associated with outcome and higher levels (cutoff value >72.95 ng/mL) were associated with poorer outcomes. These findings suggest plasma nDNA levels reflect the severity of cerebral damage and can be considered a neuropathologic marker of patients with acute TBI. Further studies with bigger patient populations are warranted for better unbiased comparison. PMID- 24467367 TI - Identification of methyl farnesoate from the hemolymph of insects. AB - Methyl farnesoate, [methyl (2E,6E)-3,7,11-trimethyldodeca-2,6,10-trienoate (1)] has not been thought be present in the hemolymph of insects, although it is the immediate biosynthetic precursor of the circulating insect hormone juvenile hormone III (methyl (2E,6E)-10,11-epoxy-3,7,11-trimethyl-2,6-dodecadienoate) (2). Compound 1 was identified from the hemolymph obtained from five orders of insects. Identification of 1 from the American bird grasshopper was facilitated using both electron impact and chemical-ionization GC-MS, GC-FTIR, and 2D NMR techniques. The identifications from other insects were made using GC-MS, and the amounts of all were quantified using LIM-CI-GC-MS. The ratios of 1 and 2 varied in these insects during different developmental stages. The present results underscore the need for further studies on methyl farnesoate (1) as a circulating hormone in insects. PMID- 24467368 TI - Potential for plant growth promotion by a consortium of stress-tolerant 2,4 dinitrotoluene-degrading bacteria: isolation and characterization of a military soil. AB - The presence of explosives in soils and the interaction with drought stress and nutrient limitation are among the environmental factors that severely affect plant growth on military soils. In this study, we seek to isolate and identify the cultivable bacteria of a 2,4-dinitrotoluene (DNT) contaminated soil (DS) and an adjacent grassland soil (GS) of a military training area aiming to isolate new plant growth-promoting (PGP) and 2,4-DNT-degrading strains. Metabolic profiling revealed disturbances in Ecocarbon use in the bare DS; isolation of cultivable strains revealed a lower colony-forming-unit count and a less diverse community associated with DS in comparison with GS. New 2,4-DNT-tolerant strains were identified by selective enrichments, which were further characterized by auxanography for 2,4-DNT use, resistance to drought stress, cold, nutrient starvation and PGP features. By selecting multiple beneficial PGP and abiotic stress-resistant strains, efficient 2,4-DNT-degrading consortia were composed. After inoculation, consortium UHasselt Sofie 3 with seven members belonging to Burkholderia, Variovorax, Bacillus, Pseudomonas and Ralstonia species was capable to successfully enhance root length of Arabidopsis under 2,4-DNT stress. After 9 days, doubling of main root length was observed. Our results indicate that beneficial bacteria inhabiting a disturbed environment have the potential to improve plant growth and alleviate 2,4-DNT stress. PMID- 24467365 TI - Mechanism of nitrogen fixation by nitrogenase: the next stage. PMID- 24467369 TI - Aripiprazole effects on self-administration and pharmacodynamics of intravenous cocaine and cigarette smoking in humans. AB - Aripiprazole is a partial agonist at dopamine (D2) and serotonin (5-HT1a) receptors and 5-HT2 antagonist. Because cocaine affects dopamine and serotonin, this study assessed whether aripiprazole could diminish the reinforcing efficacy of cocaine. Secondary aims evaluated aripiprazole on ad lib cigarette smoking and with a novel 40-hr smoking abstinence procedure. Adults with regular cocaine and cigarette use completed this inpatient double blind, randomized, placebo controlled mixed-design study. A placebo lead-in was followed by randomization to aripiprazole (0, 2 or 10 mg/day/p.o.; n = 7 completed/group). Three sets of test sessions, each consisting of 3 cocaine sample-choice (i.e., self-administration) sessions and 1 dose-response session, were conducted (once during the lead-in and twice after randomization). Sample sessions tested each cocaine dose (0, 20 and 40 mg/70 kg, i.v.) in random order; subjective, observer-rated and physiologic outcomes were collected. Later that day, participants chose between the morning's sample dose or descending amounts of money over 7 trials. In dose response sessions, all doses were given 1 hr apart in ascending order for pharmacodynamic and pharmacokinetic assessment. Two sets of smoking topography sessions were conducted during the lead-in and after randomization; 1 with and 1 without 40 hr of smoking abstinence. Number of ad lib cigarettes smoked during non-session days was collected. Cocaine produced prototypic effects, but aripiprazole did not significantly alter these effects or smoking outcomes. The smoking abstinence procedure reliably produced nicotine withdrawal and craving and increased smoking modestly. These data do not support further investigation of aripiprazole for cocaine or tobacco use disorder treatment. PMID- 24467370 TI - A behavioral economic approach to assessing demand for marijuana. AB - In the United States, marijuana is the most commonly used illicit drug. Its prevalence is growing, particularly among young adults. Behavioral economic indices of the relative reinforcing efficacy (RRE) of substances have been used to examine the appeal of licit (e.g., alcohol) and illicit (e.g., heroin) drugs. The present study is the first to use an experimental, simulated purchasing task to examine the RRE of marijuana. Young-adult (M age = 21.64 years) recreational marijuana users (N = 59) completed a computerized marijuana purchasing task designed to generate demand curves and the related RRE indices (e.g., intensity of demand-purchases at lowest price; Omax-max. spent on marijuana; Pmax-price at which marijuana expenditure is max). Participants "purchased" high-grade marijuana across 16 escalating prices that ranged from $0/free to $160/joint. They also provided 2 weeks of real-time, ecological momentary assessment reports on their marijuana use. The purchasing task generated multiple RRE indices. Consistent with research on other substances, the demand for marijuana was inelastic at lower prices but became elastic at higher prices, suggesting that increases in the price of marijuana could lessen its use. In regression analyses, the intensity of demand, Omax, and Pmax, and elasticity each accounted for significant variance in real-time marijuana use. These results provide support for the validity of a simulated marijuana purchasing task to examine marijuana's reinforcing efficacy. This study highlights the value of applying a behavioral economic framework to young-adult marijuana use and has implications for prevention, treatment, and policies to regulate marijuana use. PMID- 24467372 TI - GSTM1-null genotype as a risk factor for sporadic colorectal cancer in a Romanian population. Association with the NAT2-rapid-acetylator phenotype and exposure to environmental factors. AB - We evaluated the association between the presence of the GSTM1-null genotype and the combined presence of the GSTM1-null genotype/NAT2 rapid acetylator phenotype and the risk of developing sporadic colorectal cancer (CRC), as well as their interaction with environmental risk factors. One hundred and fifty patients with sporadic CRC and 162 controls were genotyped using PCR-RFLP analysis. For testing and quantification of the simple effect (main effect) and of the gene-gene and gene-environment interaction (modification effect), univariate and multivariate logistic regression was used. In the multiplicative model, from the genetic factors, GSTM1-null and NAT2*6B had a statistically significant influence on the risk for CRC, while from the environmental factors, smoking and diet had similar effects. The combination of GSTM1-null/NAT2 rapid acetylator phenotype/smoking behavior or GSTM1-null/NAT2 rapid acetylator phenotype/diet rich in fried red meat was not found to influence the sporadic CRC risk in Romanians, but the GSTM1 null genotype, NAT2 rapid acetylator phenotype influenced the sporadic CRC risk differently depending on the gender of the patient. PMID- 24467371 TI - The effects of mGluR2/3 activation on acute and repeated amphetamine-induced locomotor activity in differentially reared male rats. AB - Environmental stimuli play a key role in affecting the likelihood to abuse drugs. Environmental enrichment can reduce that likelihood. The neurotransmitter glutamate contributes to both drug reward and rearing-induced changes in the brain. The current study investigated the effects of the Group-2 metabotropic glutamate receptor (mGluR2/3) agonist, LY-379268 (0.5, 1.0 mg/kg), on acute and repeated amphetamine-induced locomotor activity in differentially reared male rats. Male Sprague-Dawley rats were randomly assigned to one of 3 environmental conditions postweaning: enriched (EC), isolated (IC), or standard (SC), where they reared for 30 days. The effect of LY-379268 on acute amphetamine-induced locomotor activity was assessed. Rats were injected with either LY-379268 (0.5, 1.0 mg/kg) or saline prior to an amphetamine (0.5 mg/kg) or saline challenge injection. Rats were also administered amphetamine (0.5 mg/kg) or saline injections prior to 5 locomotor sessions. Following a rest period of 14-15 days, the effects of repeated amphetamine exposure were evaluated using LY-379268 (0.5, 1.0 mg/kg) or saline injections 30 min prior to receiving amphetamine (0.5 mg/kg). Results showed that LY-379268 administration dose-dependently attenuated acute amphetamine-induced locomotor activity, with EC rats generally displaying less attenuation than IC or SC rats. After repeated amphetamine administrations, the ability of LY-379268 to attenuate the final expression of amphetamine-induced locomotor activity in differentially reared rats was dose-dependent. The differing effect of LY-379268 observed in EC rats suggests enrichment-induced glutamatergic alterations that may protect against sensitivity to psychostimulants. PMID- 24467373 TI - Physiologic variants, benign processes, and artifacts from 106 canine and feline FDG-PET/computed tomography scans. AB - 18F-Fluoro-deoxyglucose positron emission computed tomography (FDG-PET/CT) is an emerging diagnostic imaging modality in veterinary medicine; however, little published information is available on physiologic variants, benign processes, and artifacts. The purpose of this retrospective study was to describe the number of occurrences of non-neoplastic disease-related FDG-PET/CT lesions in a group of dogs and cats. Archived FDG-PET/CT scans were retrieved and interpreted based on a consensus opinion of two board-certified veterinary radiologists. Non neoplastic disease-related lesions were categorized as physiologic variant, benign activity, or equipment/technology related artifact. If the exact cause of hypermetabolic areas could not be determined, lesions were put into an indeterminate category. A total of 106 canine and feline FDG-PET/CT scans were included in the study. In 104 of the 106 scans, a total of 718 occurrences of physiologic variant, areas of incidental benign activity, and artifacts were identified. Twenty-two of 23 feline scans and 82 of 83 canine scans had at least one artifact. Previously unreported areas of increased radiopharmaceutical uptake included foci associated with the canine gall bladder, linear uptake along the canine mandible, and focal uptake in the gastrointestinal tract. Benign activity was often seen and related to healing, inflammation, and indwelling implants. Artifacts were most often related to injection or misregistration. Further experience in recognizing the common veterinary FDG physiologic variation, incidental radiopharmaceutical uptake, and artifacts is important to avoid misinterpretation and false-positive diagnoses. PMID- 24467374 TI - Internal mammary artery atherosclerosis: an ultrastructural study of two cases. AB - Atherosclerosis of the internal mammary artery (IMA) is generally regarded as a rare (but existent) pathological entity with only a few cases reported in the most recent literature. The only study which to our knowledge has investigated the ultrastructural features of IMA atherosclerosis, demonstrate the presence of endothelial cells loss, defects of internal elastic lamina with no evidence of lipid accumulation. In the present study, we describe two cases of IMA atherosclerosis in which ultrastructural analysis revealed the presence of a typical atherosclerotic plaque morphology with infiltration of inflammatory cells, formation of intraplaque lipid pools, and accumulation of lipid-laden foam cells throughout the thickened intima, never described in this rare lesion before. Microscopically, the lesions were also characterized by intimal thickening, invagination of endothelial cells, migration of smooth muscle cells with splitting, fenestration and/or fragmentation of the elastic sheets. Our observations add new data to the scarce and contradictory literature and to this largely understudied vascular disorder. PMID- 24467375 TI - Waist circumference based abdominal obesity may be helpful as a marker for unmet needs in patients with RA. AB - OBJECTIVES: To assess the impact of abdominal obesity (AO) on disease severity, cardiovascular risk factors, and patient-reported outcomes (PROs) in patients with rheumatoid arthritis (RA). METHOD: Two hundred and thirty consecutive outpatients were cross-sectionally assessed. Waist circumference (WC) with a cut off point of >= 102 cm in men and >= 88 cm in women indicated AO. Clinical assessment included joint counts, radiographs of small joints, and laboratory tests. Comorbidities and medication were verified from the patients' database. Patient questionnaires included sociodemographics, pain intensity, global disease activity, the Beck Depression Inventory (BDI), the Health Assessment Questionnaire (HAQ), physical activity level, and the 36-item Short Form Health Survey (SF-36). Metabolic syndrome (MetS) was defined according to the criteria of National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III). The association of AO with the 28-joint count Disease Activity Score (DAS28) and mental (MCS) and physical component scores (PCS) of the SF-36 and the HAQ was assessed by using regression models with the propensity score as a covariate. RESULTS: The AO prevalence was 52% in the 200 eligible patients. In a univariate analysis, AO was associated with cardiovascular risk factors, low HAQ score, physical inactivity, disease activity parameters, impaired MCS, higher pain, and increased use of biological drugs and antidepressants. In a multivariable model, only poorer DAS28 (p = 0.018) and poorer HAQ score (p = 0.004) remained significantly associated with AO. CONCLUSIONS: AO is highly prevalent in patients with RA. In addition to cardiovascular risk factors, AO is associated with higher disease activity, higher disability, physical inactivity, more patients' perception of pain, and poorer mental health. Multifaceted promotion of lifestyle habits would be beneficial for improving AO-related health outcomes in patients with RA. PMID- 24467376 TI - Anti-proliferative and apoptotic activities of constituents of chloroform extract of Juglans regia leaves. AB - OBJECTIVES: To evaluate anti-proliferative as well as apoptotic activities of compounds identified in chloroform extract of Juglans regia leaves, on human breast and oral cancer cell lines (MCF-7 and BHY). MATERIALS AND METHODS: Column chromatography, MTT assay, flowcytometry and western blotting have all been used in the study. RESULTS: Bioassay-guided fractionation of chloroform extract of J. regia afforded isolation of 5-hydroxy-3,7,4'-trimethoxyflavone [1], lupeol [2], daucosterol [3], 4-hydroxy-alpha-tetralone [4], beta-sitosterol [5], 5,7- dihydroxy-3,4'-dimethoxyflavone [6] and regiolone [7]. Structures of the compounds were established on the basis of spectroscopic analyses [Nuclear magnetic resonance (NMR) and mass]. All compounds inhibited proliferation of MCF 7 (human breast adenocarcinoma) and BHY (human oral squamous carcinoma) cells in a concentration-dependent manner. Compounds 6 and 7 had potent cytotoxic effects on both MCF-7 and BHY cells (IC50 21-51 MUm), yet were not toxic to normal cells. MCF-7 growth inhibition was attributed to apoptosis; population of apoptotic cells increased from 1.12% in controls to 5.64 and 8.1% after 48-h treatment with compounds 6 and 7, indicating their potential at inducing early and late apoptosis. The caspase cascade was not activated, as indicated by only insignificant cleavage of caspase-3. CONCLUSIONS: Our results suggest that compounds 6 and 7 can induce apoptosis in MCF-7 cells through the caspase-3 independent pathway. PMID- 24467377 TI - Molecular and electronic structures of the members of the electron transfer series [Mn(bpy)3]n (n = 2+, 1+, 0, 1-) and [Mn(tpy)2]m (m = 4+, 3+, 2+, 1+, 0). An experimental and density functional theory study. AB - The members of the electron transfer series [Mn(bpy)3](n) (n = 2+, 1+, 0, 1-) and [Mn(tpy)2](m) (m = 2+, 1+, 0) have been investigated using a combination of magnetochemistry, electrochemistry, and UV-vis-NIR spectroscopy; and X-ray crystal structures of [Mn(II)((Me)bpy(*))2((Me)bpy(0))](0), [Li(THF)4][Mn(II)(bpy(*))3], and [Mn(II)(tpy(*))2](0) have been obtained (bpy = 2,2'-bipyridine; (Me)bpy = 4,4'-dimethyl-2,2'-bipyridine; tpy = 2,2':6,2" terpyridine; THF = tetrahydrofuran). It is the first time that the latter complex has been isolated and characterized. Through these studies, the electronic structures of each member of both series of complexes have been elucidated, and their molecular and electronic structures further corroborated by broken symmetry (BS) density functional theoretical (DFT) calculations. It is shown that all one electron reductions that comprise the aforementioned redox series are ligand based. Hence, all species contain a central high-spin Mn(II) ion (SMn = 5/2). In contrast, the analogous series of Tc(II) and Re(II) complexes possess low-spin electron configurations. PMID- 24467380 TI - Curcumin-loaded nanoparticles potently induce adult neurogenesis and reverse cognitive deficits in Alzheimer's disease model via canonical Wnt/beta-catenin pathway. AB - Neurogenesis, a process of generation of new neurons, is reported to be reduced in several neurodegenerative disorders including Alzheimer's disease (AD). Induction of neurogenesis by targeting endogenous neural stem cells (NSC) could be a promising therapeutic approach to such diseases by influencing the brain self-regenerative capacity. Curcumin, a neuroprotective agent, has poor brain bioavailability. Herein, we report that curcumin-encapsulated PLGA nanoparticles (Cur-PLGA-NPs) potently induce NSC proliferation and neuronal differentiation in vitro and in the hippocampus and subventricular zone of adult rats, as compared to uncoated bulk curcumin. Cur-PLGA-NPs induce neurogenesis by internalization into the hippocampal NSC. Cur-PLGA-NPs significantly increase expression of genes involved in cell proliferation (reelin, nestin, and Pax6) and neuronal differentiation (neurogenin, neuroD1, neuregulin, neuroligin, and Stat3). Curcumin nanoparticles increase neuronal differentiation by activating the Wnt/beta-catenin pathway, involved in regulation of neurogenesis. These nanoparticles caused enhanced nuclear translocation of beta-catenin, decreased GSK-3beta levels, and increased promoter activity of the TCF/LEF and cyclin-D1. Pharmacological and siRNA-mediated genetic inhibition of the Wnt pathway blocked neurogenesis-stimulating effects of curcumin. These nanoparticles reverse learning and memory impairments in an amyloid beta induced rat model of AD-like phenotypes, by inducing neurogenesis. In silico molecular docking studies suggest that curcumin interacts with Wif-1, Dkk, and GSK-3beta. These results suggest that curcumin nanoparticles induce adult neurogenesis through activation of the canonical Wnt/beta-catenin pathway and may offer a therapeutic approach to treating neurodegenerative diseases such as AD, by enhancing a brain self-repair mechanism. PMID- 24467381 TI - Neutral color semitransparent microstructured perovskite solar cells. AB - Neutral-colored semitransparent solar cells are commercially desired to integrate solar cells into the windows and cladding of buildings and automotive applications. Here, we report the use of morphological control of perovskite thin films to form semitransparent planar heterojunction solar cells with neutral color and comparatively high efficiencies. We take advantage of spontaneous dewetting to create microstructured arrays of perovskite "islands", on a length scale small enough to appear continuous to the eye yet large enough to enable unattenuated transmission of light between the islands. The islands are thick enough to absorb most visible light, and the combination of completely absorbing and completely transparent regions results in neutral transmission of light. Using these films, we fabricate thin-film solar cells with respectable power conversion efficiencies. Remarkably, we find that such discontinuous films still have good rectification behavior and relatively high open-circuit voltages due to the inherent rectification between the n- and p-type charge collection layers. Furthermore, we demonstrate the ease of "color-tinting" such microstructured perovksite solar cells with no reduction in performance, by incorporation of a dye within the hole transport medium. PMID- 24467382 TI - Arm position during ambulatory blood pressure monitoring: a review of the evidence and clinical guidelines. AB - Ambulatory blood pressure monitoring (ABPM) offers advantages over clinic blood pressure measurement. Supporting the arm at the level of the right atrium has long been standard in clinic blood pressure measurement. In contrast, there is no consensus regarding arm position in the guidelines addressing ABPM. Research studies have used a variety of arm positions during ABPM. Discussed in this review are the merits of ABPM and a review of the several arm positions recommended in ABPM guidelines, suggested by cuff manufacturers, and used in research studies. To address this lack of standardization, a rationale for a clinically reasonable arm position during ABPM is offered. Specifically, the authors recommend advising the patient to keep the arm still and relaxed straight down at the side of the body when the cuff is going to inflate, when safe to do so. PMID- 24467383 TI - Enhancing the tunability of the open-circuit voltage of hybrid photovoltaics with mixed molecular monolayers. AB - The alignment between the energy levels of the constituents of an organic solar cell plays a central role in determining the open-circuit voltage. However, tuning the energy levels of electrodes and/or active components via molecular modifiers placed at interfaces is not straightforward. The morphology of organic materials is commonly controlled by the substrate onto which they are deposited, and differences in morphology often lead to differences in energetics. Such a change in morphology may reduce the effect of surface modifications, as the modified surface is part of an interface with the organic material. Here we show, in an experimental model system, that by using binary molecular monolayers, in which dipolar molecules are buried in a protective nonpolar matrix, we can transform changes in the electrode surface dipole into interface dipole changes without significantly affecting the growth of pentacene onto the molecular layer, thus enabling the use of the full range of dipolar-induced open-circuit-voltage tuning. PMID- 24467386 TI - Enhancing the efficiency of gold nanoparticles treatment of cancer by increasing their rate of endocytosis and cell accumulation using rifampicin. AB - To minimize the toxicity of gold nanoparticles (AuNPs) in cancer treatment, we have developed a technique, which utilizes lesser amount of AuNPs while exhibiting increased treatment efficiency. Rifampicin (RF) is known for its ability to enhance the accumulation of anticancer drugs in multidrug resistant (MDR) cancer cells. In this work we have shown that RF-conjugated AuNPs can greatly enhance the rate as well as efficiency of endocytosis of NPs and hence their concentration inside the cancer cell. Cell viability results showed a remarkable enhancement in the photothermal therapeutic effect of Au nanorods in presence of RF. This is expected to decrease the demand on the overall amount of AuNPs needed for treating cancer and thus decreasing its toxicity. PMID- 24467384 TI - Sex differences in endothelial function in porcine coronary arteries: a role for H2O2 and gap junctions? AB - BACKGROUND AND PURPOSE: Cardiovascular risk is higher in men and postmenopausal women compared with premenopausal women. This may be due to sex differences in endothelial function. Here, sex differences in endothelial function of porcine coronary arteries (PCAs) were investigated. EXPERIMENTAL APPROACH: Distal PCAs were studied under myographic conditions and after precontraction with U46619. Concentration-response curves to bradykinin were constructed in the presence of a range of inhibitors. KEY RESULTS: In male and female PCAs, bradykinin produced comparable vasorelaxant responses. Inhibition of NO and prostanoid synthesis produced greater inhibition in males compared with females. Removing H2 O2 with PEG-catalase reduced the maximum relaxation in the absence, but not the presence of L-NAME and indomethacin in females, and had no effect in males. Blocking gap junctions with 100 uM carbenoxolone or 18alpha-glycyrrhetinic acid further inhibited the endothelium-derived hyperpolarization (EDH)-mediated response in females but not in males. In female PCAs, the maximum EDH-mediated response was reduced by inhibiting SKCa with apamin and by inhibiting IKCa with TRAM-34, or with both. In male PCAs, at maximum bradykinin concentration, the EDH-mediated response was reduced in the presence of apamin but not TRAM-34. Western blot did not detect any differences in connexins 40 or 43 or in IKCa expression between male and female PCAs. CONCLUSIONS AND IMPLICATIONS: H2 O2 mediated some part of endothelium-dependent vasorelaxation in female PCAs and EDH was more important in females, with differences in the contribution of gap junctions and IKCa channels. These findings may contribute to understanding vascular protection in premenopausal women. PMID- 24467388 TI - Happy anniversary Cochrane Collaboration. PMID- 24467387 TI - NF-kappaB inhibitors from Eurycoma longifolia. AB - The roots of Eurycoma longifolia have been used in many countries of Southeast Asia to alleviate various diseases including malaria, dysentery, sexual insufficiency, and rheumatism. Although numerous studies have reported the pharmacological properties of E. longifolia, the mode of action of the anti inflammatory activity has not been elucidated. Bioguided isolation of NF-kappaB inhibitors using an NF-kappaB-driven luciferase reporter gene assay led to the identification of a new quassinoid, eurycomalide C (1), together with 27 known compounds including 11 quassinoids (2-12), six alkaloids (13-18), two coumarins (19, 20), a squalene derivative (21), a triterpenoid (22), and six phenolic compounds (23-28) from the extract of E. longifolia. Evaluation of the biological activity revealed that C19-type and C20-type quassinoids, beta-carboline, and canthin-6-one alkaloids are potent NF-kappaB inhibitors, with IC50 values in the low micromolar range, while C18-type quassinoids, phenolic compounds, coumarins, the squalene derivative, and the triterpenoid turned out to be inactive when tested at a concentration of 30 MUM. Eurycomalactone (2), 14,15beta dihydroklaieanone (7), and 13,21-dehydroeurycomanone (10) were identified as potent NF-kappaB inhibitors with IC50 values of less than 1 MUM. PMID- 24467390 TI - The effects of automated scatter feeders on captive grizzly bear activity budgets. AB - Although captive bears are popular zoo attractions, they are known to exhibit high levels of repetitive behaviors (RBs). These behaviors have also made them particularly popular subjects for welfare research. To date, most research on ursid welfare has focused on various feeding methods that seek to increase time spent searching for, extracting, or consuming food. Prior research indicates an average of a 50% reduction in RBs when attempts are successful and, roughly, a 50% success rate across studies. This research focused on decreasing time spent in an RB while increasing the time spent active by increasing time spent searching for, extracting, and consuming food. The utility of timed, automated scatter feeders was examined for use with captive grizzly bears (Ursis arctos horribilis). Findings include a significant decrease in time spent in RB and a significant increase in time spent active while the feeders were in use. Further, the bears exhibited a wider range of behaviors and a greater use of their enclosure. PMID- 24467389 TI - Epidemiology and ecology of H3N8 canine influenza viruses in US shelter dogs. AB - BACKGROUND: H3N8 canine influenza virus (CIV) infection might contribute to increased duration of shelter stay for dogs. Greater understanding of factors contributing to CIV within shelters could help veterinarians identify control measures for CIV. OBJECTIVES: To assess community to shelter dog CIV transmission, estimate true prevalence of CIV, and determine risk factors associated with CIV in humane shelters. ANIMALS: 5,160 dogs upon intake or discharge from 6 US humane shelters, December 2009 through January 2012. METHODS: A cross-sectional study was performed with prospective convenience sampling of 40 dogs from each shelter monthly. Nasal swabs and serum samples were collected. Hemagglutination inhibition and real-time reverse transcriptase-polymerase chain reaction assays were performed for each nasal and serum sample. True prevalence was estimated by stochastic latent class analysis. Logistic regression was used to identify risk factors associated with CIV shedding and seropositivity. RESULTS: Nasal swabs were positive from 4.4% of New York (NY), 4.7% of Colorado (CO), 3.2% of South Carolina, 1.2% of Florida, and 0% of California and Texas shelter dogs sampled. Seropositivity was the highest in the CO shelter dogs at 10%, and NY at 8.5%. Other shelters had 0% seropositivity. Information-theoretic analyses suggested that CIV shedding was associated with region, month, and year (model weight = 0.95) and comingling/cohousing (model weight = 0.92). CONCLUSIONS AND CLINICAL IMPORTANCE: Community dogs are a likely source of CIV introduction into humane shelters and once CIV has become established, dog-to-dog transmission maintains the virus within a shelter. PMID- 24467391 TI - Longitudinal and prognostic evaluation of mild traumatic brain injury: A 1H magnetic resonance spectroscopy study. AB - In the majority of patients with mild traumatic brain injury (mTBI), brain tissue impairment is undetectable by computed tomography and/or structural magnetic resonance imaging. Even in confirmed cases of head injury, conventional neuroimaging methods lack sensitivity in predicting neuropsychological outcomes of patients. The objectives of this study were to (1) cross-sectionally determine deviations in the neurometabolic profile of patients with mTBI from healthy controls at different stages of mTBI using tightly controlled examination windows, and (2) determine associations between acute neurometabolic markers of mTBI and chronic neurocognitive performance. Patients were examined at the early subacute (n=43; 5.44 +/- 3.15 days post-injury (DPI)), late subacute (n=33; 37.00 +/- 12.26 DPI) and chronic (n=27; 195.30 +/- 19.60 DPI) stages of mTBI. Twenty one neurologically intact subjects were used as controls. Proton magnetic resonance spectroscopy imaging ((1)H-MRSI) was used to obtain metabolic measurements from different brain regions. The Automated Neuropsychological Assessment Metrics (ANAM) was used for cognitive evaluation of patients at the chronic stage of mTBI. Measurements in the thalamus and centrum semiovale (CSV) emerged as the most indicative of injury and were used to predict neurocognitive outcome. The major findings of this study are (1) decreases in Cho/Cre (choline to-creatine ratio) measured in the thalamus (p=0.042) and CSV (p=0.017) at the late subacute stage of mTBI; (2) positive associations of early subacute Cre measurements in the CSV with chronic ANAM scores measuring performance in delayed (r=0.497, p=0.019) and immediate (r=0.391, p=0.072) code substitution. These findings show that metabolic measurements in the thalamus and CSV can potentially serve as diagnostic and prognostic markers of mTBI. PMID- 24467392 TI - Adapting cognitive behavioral therapy for psychosis for case managers: increasing access to services in a community mental health agency. AB - OBJECTIVE: The purpose of this article is twofold: (a) to describe the adaptation of an evidence-based practice and, (b) using a dissemination framework, to describe the process of implementing the practice at a community mental health agency. METHOD: The authors describe the training concept and dissemination framework of implementing an emerging practice: high-yield cognitive behavioral techniques for psychosis, which is rooted in cognitive behavioral therapy. RESULTS: Thirteen case managers who represented teams from across the agency delivered the adapted practice at a community mental health agency. Implementation required buy in from all stakeholders, communication across disciplines, persistence, and flexibility. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: It appears that the use of a dissemination framework that is grounded in the literature, yet flexible, eases the process of implementing an adapted practice. Further research focusing on the effectiveness of this approach, along with the impact of implementing a full spectrum of cognitive behavioral therapy services for individuals with persistent psychotic symptoms, based on cognitive behavioral therapy principles, is indicated. PMID- 24467394 TI - Position-controlled uniform GaAs nanowires on silicon using nanoimprint lithography. AB - We report on the epitaxial growth of large-area position-controlled self catalyzed GaAs nanowires (NWs) directly on Si by molecular beam epitaxy (MBE). Nanohole patterns are defined in a SiO2 mask on 2 in. Si wafers using nanoimprint lithography (NIL) for the growth of positioned GaAs NWs. To optimize the yield of vertical NWs the MBE growth parameter space is tuned, including Ga predeposition time, Ga and As fluxes, growth temperature, and annealing treatment prior to NW growth. In addition, a non-negligible radial growth is observed with increasing growth time and is found to be independent of the As species (i.e., As2 or As4) and the growth temperatures studied. Cross-sectional transmission electron microscopy analysis of the GaAs NW/Si substrate heterointerface reveals an epitaxial growth where NW base fills the oxide hole opening and eventually extends over the oxide mask. These findings have important implications for NW based device designs with axial and radial p-n junctions. Finally, NIL positioned GaAs/AlGaAs core-shell heterostructured NWs are grown on Si to study the optical properties of the NWs. Room-temperature photoluminescence spectroscopy of ensembles of as-grown core-shell NWs reveals uniform and high optical quality, as required for the subsequent device applications. The combination of NIL and MBE thereby demonstrates the successful heterogeneous integration of highly uniform GaAs NWs on Si, important for fabricating high throughput, large-area position controlled NW arrays for various optoelectronic device applications. PMID- 24467393 TI - Serial comprehensive geriatric assessment in elderly head and neck cancer patients undergoing curative radiotherapy identifies evolution of multidimensional health problems and is indicative of quality of life. AB - Head and neck (H&N) cancer is mainly a cancer of the elderly; however, the implementation of comprehensive geriatric assessment (CGA) to quantify functional age in these patients has not yet been studied. We evaluated the diagnostic performance of screening tools [Vulnerable Elders Survey-13 (VES-13), G8 and the Combined Screening Tool 'VES-13 + (17-G8)' or CST], the feasibility of serial CGA, and correlations with health-related quality of life evolution [HRQOL; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires (EORTC QLQ)-C30 and -HN35] during therapy in hundred patients, aged >=65 years, with primary H&N cancer undergoing curative radio(chemo)therapy. Respectively 36.8%, 69.0%, 62.1% and 71.3% were defined vulnerable according to VES-13, G8, CST and CGA at week 0, mostly due to presence of severe grade co morbidities, difficulties in community functioning and nutritional problems. At week 4, significantly more patients were identified vulnerable due to nutritional, functional and emotional deterioration. The CST did not achieve the predefined proportion necessary for validation. Vulnerable patients reported lower function and higher symptom HRQOL scores as compared with fit patients. A comparable deterioration in HRQOL was observed in both groups through therapy. In conclusion, G8 remains the screening tool of choice. Serial CGA identifies the evolution of multidimensional health problems and HRQOL conditions during therapy with potential to guide individualised supportive care. PMID- 24467395 TI - Hypovitaminosis D is a predictor of aromatase inhibitor musculoskeletal symptoms. AB - The aromatase inhibitor (AI)-associated musculoskeletal (MSK) pain symptoms are often debilitating and limit compliance with this important hormonal breast cancer therapy. The etiology of this syndrome is unknown. Hypovitaminosis D has been suggested as a possible risk factor for the development of MSK symptoms in women starting AIs. The objective of this substudy was to define the prevalence of low 25(OH)D in this population, to assess risk of low levels on developing pain and to define a target therapeutic goal for 25(OH)D in this population. This analysis was part of a 6-month prospective cohort study examining the MSK side effects of adjuvant AI therapy in postmenopausal women. Patients were evaluated by a rheumatologist with a joint examination, had 25(OH)D levels measured and completed quality of life questionnaires at baseline, 3 and 6 months. Symptomatic patients were defined as those that self-reported new or worsening MSK symptoms. Of 52 patients, 28 (54%) were symptomatic, and two (3.8%) stopped AIs due to MSK ailments. Thirteen patients had objective evidence of tendonitis on rheumatologic examination. Thirty-three percent of all subjects had baseline 25(OH)D levels <40 ng/mL, 19.2% had levels <30 ng/mL and 5.8% had levels <20 ng/mL. Symptomatic patients were more likely to have had baseline levels below 40 ng/mL, compared with asymptomatic patients (46.4% versus 16.7%, p = 0.037). In multivariate regression analyses, levels <40 ng/mL were associated with developing objective tenosynovitis (p = 0.033) but not with developing nonspecific myalgias. Our findings suggest hypovitaminosis D may be contributing to the AI-associated MSK pain syndrome and in particular to the development of tendonitis. Repletion to 25(OH)D levels >40 ng/mL is advisable. Further research should be carried out on identifying additional modifiable risk factors for this syndrome. PMID- 24467396 TI - The NTP pyrophosphatase DCTPP1 contributes to the homoeostasis and cleansing of the dNTP pool in human cells. AB - The size and composition of dNTP (deoxyribonucleoside triphosphate) pools influence the accuracy of DNA synthesis and consequently the genetic stability of nuclear and mitochondrial genomes. In order to keep the dNTP pool in balance, the synthesis and degradation of DNA precursors must be precisely regulated. One such mechanism involves catabolic activities that convert deoxynucleoside triphosphates into their monophosphate form. Human cells possess an all-alpha NTP (nucleoside triphosphate) pyrophosphatase named DCTPP1 [dCTP pyrophosphatase 1; also known as XTP3-TPA (XTP3-transactivated protein A)]. In the present study, we provide an extensive characterization of this enzyme which is ubiquitously distributed in the nucleus, cytosol and mitochondria. Interestingly, we found that in addition to dCTP, methyl-dCTP and 5-halogenated nucleotides, DCTPP1 hydrolyses 5-formyl-dCTP very efficiently and with the lowest Km value described so far. Because the biological function of mammalian all-alpha NTP pyrophosphatases remains uncertain, we examined the role of DCTPP1 in the maintenance of pyrimidine nucleotide pools and cellular sensitivity to pyrimidine analogues. DCTPP1-deficient cells accumulate high levels of dCTP and are hypersensitive to exposure to the nucleoside analogues 5-iodo-2'-deoxycytidine and 5-methyl-2'-deoxycytidine. The results of the present study indicate that DCTPP1 has a central role in the balance of dCTP and the metabolism of deoxycytidine analogues, thus contributing to the preservation of genome integrity. PMID- 24467398 TI - From policy to action: next steps in achieving population-wide reduction in sodium intake. PMID- 24467399 TI - Coexistence of chronic renal failure, hashimoto thyroiditis and idiopathic hypoparathyroidism: a rare case report. AB - Hypoparathyroidism is an uncommon disease and its coexistence with chronic renal failure is quite rare. Hypocalcemia and hyperphosphatemia are seen in both diseases. Diagnosis of hypoparathyroidism may be overlooked when parathormone response is not evaluated in patients with chronic renal failure. A 19-year-old female patient who had been receiving hemodialysis for 3 years because of chronic renal failure was diagnosed as idiopathic hypoparathyroidism and hashimoto thyroiditis. When her medical records on the first admission and medical history were evaluated, hypoparathyroidism and hashimoto thyroiditis were seen to be present also when she was started hemodialysis. Idiopathic hypoparathyroidism should be suspected in case as absence of parathormone response to hypocalcemia in patients with chronic renal failure. It should be taken into consideration that hashimoto thyroiditis may accompany and required analysis should be done. PMID- 24467400 TI - An experimental test of host specialization in a ubiquitous polar ectoparasite: a role for adaptation? AB - The evolution of host specificity is considered to be an essential mechanism driving parasite diversity. It may be governed by adaptive constraints that lead to host-dependent fitness trade-offs. Alternatively, specificity may arise via transmission constraints that isolate parasite populations, without necessarily involving adaptation per se. Here, we ask whether the repeated observation of host-associated genetic races across the worldwide distribution of the seabird ectoparasite Ixodes uriae is associated with host adaptation. We conducted a field-based experiment to test for adaptive specialisation in host races of I. uriae. We transferred unengorged ticks of two life stages (nymphs and adults) originating from three host species (black-legged kittiwake, common guillemot and Atlantic puffin) onto young kittiwake nestlings and followed attraction and attachment rates, engorgement times and feeding success of the transplanted ticks. All ticks were also typed genetically to match exploitation patterns with genetic differences among races. Ticks from atypical hosts were significantly less attracted to nestlings than ticks from the typical host, and showed lower feeding success and higher mortality. The degree of host specificity matched patterns of neutral genetic variation among races, with puffin ticks being more specific than guillemot ticks. Differences in specificity were also apparent among tick life stages, suggesting that nymphal ticks may be less discriminating of host type than adult ticks. Our results indicate that the genetic divergence previously observed among sympatric I. uriae host races is at least partially linked to adaptive specialisation to the host species and not simply to host mediated transmission. They also suggest that the adaptation process may evolve differently in different life stages based on trade-offs with physiological constraints. The identification of the selective forces acting in host specialization will now be necessary to better characterize these patterns and to understand how transmission interacts with the adaptation process to generate parasite biodiversity. PMID- 24467401 TI - Electrophoretic mobilities of a viral capsid, its capsid protein, and their relation to viral assembly. AB - The self-assembly of many viral capsids is dominated by protein-protein electrostatic interactions. To have a better understanding of this process, it is important to know how the protein and the capsid surface charges vary as a function of the pH and ionic strength. In this work, using phase analysis light scattering, we measured the electrophoretic mobility (EM) of the cowpea chlorotic mottle virus (CCMV), its capsid protein (CP), and a cleaved CP that lacks its basic terminus, as a function of pH and ionic strength. The EM measurements of the CP are difficult to carry out due to its tendency to self-assemble into capsids; we show how to circumvent this problem by appropriately changing the CP concentration. We found that the isoelectric points (pIs) of the virion and of the CP are insensitive to ionic strength. The onset of multishell structures in the phase diagram of the CCMV CP as a function of ionic strength and pH (and its absence in the brome mosaic virus (BMV) CP phase diagram) can be related to the pI of the capsid. We propose that the transition from multiwall shells to nanotube structures is due to a change in the spontaneous curvature of the CP at its pI. A nonzero limit of the EM at high ionic strength is characteristic of a soft colloid, but a near identity of the EMs of empty capsids and those containing RNA indicates that the EM reflects only the charge distribution in the CP. The Henry equation has been used to provide approximate values of the capsid surface charge as a function of pH and I. PMID- 24467402 TI - Carbohydrate-appended tumor targeting iron(III) complexes showing photocytotoxicity in red light. AB - Glucose-appended photocytotoxic iron(III) complexes of a tridentate Schiff base phenolate ligand [Fe(bpyag)(L)](NO3) (1-3), where bpyag is N,N-bis(2 pyridylmethyl)-2-aminoethyl-beta-D-glucopyranoside and H2L is 3-(2 hydroxyphenylimino)-1-phenylbutan-1-one (H2phap) in 1, 3-(2-hydroxyphenylimino)-9 anthrylbutan-1-one (H2anap) in 2, and 3-(2-hydroxyphenylimino)-1-pyrenylbutan-1 one (H2pyap) in 3, were synthesized and characterized. The complex [Fe(dpma)(anap)](NO3) (4), having bis-(2-pyridylmethyl)benzylamine (dpma), in which the glucose moiety of bpyag is substituted by a phenyl group, was used as a control, and the complex [Fe(dpma)(anap)](PF6) (4a) was structurally characterized by X-ray crystallography. The structure shows a FeN4O2 core in a distorted octahedral geometry. The high-spin iron(III) complexes with magnetic moment value of ~5.9 MUB showed a low-energy phenolate-to-Fe(III) charge-transfer (CT) absorption band as a shoulder near 500 nm with a tail extending to 700 nm and an irreversible Fe(III)-Fe(II) redox couple near -0.6 V versus saturated calomel electrode. The complexes are avid binders to calf thymus DNA and showed photocleavage of supercoiled pUC19 DNA in red (647 nm) and green (532 nm) light. Complexes 2 and 3 displayed significant photocytotoxicity in red light, with an IC50 value of ~20 MUM in HeLa and HaCaT cells, and no significant toxicity in dark. The cell death is via an apoptotic pathway, by generation of reactive oxygen species. Preferential internalization of the carbohydrate-appended complexes 2 and 3 was evidenced in HeLa cells as compared to the control complex 4. A 5-fold increase in the cellular uptake was observed for the active complexes in HeLa cells. The photophysical properties of the complexes are rationalized from the density functional theory calculations. PMID- 24467403 TI - The yeast actin cytoskeleton. AB - The actin cytoskeleton is a complex network of dynamic polymers, which plays an important role in various fundamental cellular processes, including maintenance of cell shape, polarity, cell division, cell migration, endocytosis, vesicular trafficking, and mechanosensation. Precise spatiotemporal assembly and disassembly of actin structures is regulated by the coordinated activity of about 100 highly conserved accessory proteins, which nucleate, elongate, cross-link, and sever actin filaments. Both in vivo studies in a wide range of organisms from yeast to metazoans and in vitro studies of purified proteins have helped shape the current understanding of actin dynamics and function. Molecular genetics, genome-wide functional analysis, sophisticated real-time imaging, and ultrastructural studies in concert with biochemical analysis have made yeast an attractive model to understand the actin cytoskeleton, its molecular dynamics, and physiological function. Studies of the yeast actin cytoskeleton have contributed substantially in defining the universal mechanism regulating actin assembly and disassembly in eukaryotes. Here, we review some of the important insights generated by the study of actin cytoskeleton in two important yeast models the budding yeast Saccharomyces cerevisiae and the fission yeast Schizosaccharomyces pombe. PMID- 24467404 TI - Alcohol and crack cocaine use in women: a 14-year cross-sectional study. AB - This article aims to describe the record type for first-time hospital admissions of 761 women at a single institution between 1997 and 2010 according to International Classification of Diseases, 10(th) revision, criteria, for mental and behavioral disorders due to psychoactive substance use (F10-F19). This cross sectional study included a convenience sample of 4,736 patients in the Brazilian public health system, among whom 761 were women. Overall, the rate of alcohol related hospitalizations decreased from 93.6% in 1997 to 50.9% in 2010. In contrast, the rate of crack cocaine-related hospitalizations increased in women from 2.8% in 1997 to 67.8% in 2010. The linear regression was R(2) = 0.8472. These data indicate a new trend in the pattern of psychoactive substance use in women. PMID- 24467405 TI - Towards patient self-triage in the ophthalmic emergency department: sensitivity and specificity of a self-triage instrument. AB - PURPOSE: Trained ophthalmic triage staff may not constantly be available in the emergency department of a specialized ophthalmic hospital, particularly at night. To support the current triage process, the aim of this study was to develop an ophthalmic instrument of patient self-triage (ISET). METHODS: A preliminary ISET, in the form of a pen-and-paper questionnaire, was refined and validated in a two step procedure. In a first explorative step, we compared the results of the ISET with the results of the regular triage process during the day, that is, triage by a trained triage assistant in a specialized ophthalmic hospital. As several patients needed guidance completing the questionnaire, the ISET was subsequently refined. The second step was to test the validity of the refined ISET by again comparing the outcome of this triage with that of the triage assistant in the emergency department. RESULTS: The first explorative step involved 279 patients and the final validation step 298. During the validation step, sensitivity of the ISET was 94.3% and specificity 76.4%. CONCLUSION: The results show that the ISET is a sensitive and specific instrument for ophthalmic triage compared with a trained ophthalmic triage assistant. PMID- 24467406 TI - Preparation and IVIVC evaluation of salvianolic acid B micro-porous osmotic pump pellets. AB - PURPOSE: Salvianolic acid B micro-porous osmotic pump controlled release pellets (SalB-CRPs) with suitable in vitro release profiles and good in vitro and in vivo correlation (IVIVC) were developed. METHOD: Extrusion-spheronization was used to prepare the starter cores containing SalB/MCC/Kollidon(r)CL-SF/Flowlac(r)100 of 30:40:15:15 [w/w, The formulation composition of SalB immediate-release pellets (SalB-IRPs)] and complexed with lactose. The pellets were subsequently coated with Surelease aqueous dispersion to achieve controlled-release properties. Furthermore, a single-dose pharmacokinetics study was carried out in New Zealand White (NZW) rabbits. RESULTS: In the starter cores, the lactose content was 25% based on the SalB-IRPs constituent. The optimal coating polymer ratio of Surelease aqueous dispersion and polyvinyl alcohol-polyethylene glycol (PVA-PEG) graft copolymer (EC/PVA-PEG) was found to be 70:30 (w/w, %) with a coating weight of 5%. The prepared SalB-CRPs had similar in vitro release under three different pH release mediums. A good IVIVC was characterized by a high coefficient of determination (r=0.9801). The in vivo study indicated that the maximum plasma concentration (Cmax) of SalB-CRPs was decreased, peak concentration time (Tmax) and mean residence time (MRT) were all prolonged, as that of SalB-IRPs. In addition, the area under concentration-time curve from 0 to 24 h (AUC0-24 h) and 0 to infinity (AUC0-infinity) were significantly higher, compared with those of SalB-IRPs. CONCLUSION: Collectively, these results manifested that SalB-CRPs were likely to be a more suitable formulation in treating cardiovascular disease with improved in vivo retention, decreased plasma drug concentration fluctuation. PMID- 24467407 TI - Critical attributes of transdermal drug delivery system (TDDS)--a generic product development review. AB - Bioequivalence testing of transdermal drug delivery systems (TDDS) has always been a subject of high concern for generic companies due to the formulation complexity and the fact that they are subtle to even minor manufacturing differences and hence should be clearly qualified in terms of quality, safety and efficacy. In recent times bioequivalence testing of transdermal patches has gained a global attention and many regulatory authorities worldwide have issued recommendations to set specific framework for demonstrating equivalence between two products. These current regulatory procedures demand a complete characterization of the generic formulation in terms of its physicochemical sameness, pharmacokinetics disposition, residual content and/or skin irritation/sensitization testing with respect to the reference formulation. This paper intends to highlight critical in vitro tests in assessing the therapeutic equivalence of products and also outlines their valuable applications in generic product success. Understanding these critical in vitro parameters can probably help to decode the complex bioequivalence outcomes, directing the generic companies to optimize the formulation design in reduced time intervals. It is difficult to summarize a common platform which covers all possible transdermal products; hence few case studies based on this approach has been presented in this review. PMID- 24467408 TI - Room temperature in situ growth of B/BOx nanowires and BOx nanotubes. AB - Despite significant advances in the synthesis of nanostructures, our understanding of the growth mechanisms of nanowires and nanotubes grown from catalyst particles remains limited. In this study we demonstrate a straightforward route to grow coaxial amorphous B/BOx nanowires and BOx nanotubes using gold catalyst particles inside a transmission electron microscope at room temperature without the need of any specialized or expensive accessories. Exceedingly high growth rates (over 7 MUm/min) are found for the coaxial nanowires, and this is attributed to the highly efficient diffusion of B species along the surface of a nanowire by electrostatic repulsion. On the other hand the O species are shown to be relevant to activate the gold catalysts, and this can occur through volatile O species. The technique could be further developed to study the growth of other nanostructures and holds promise for the room temperature growth of nanostructures as a whole. PMID- 24467409 TI - Phosphatidylserine and FVa regulate FXa structure. AB - Human coagulation FXa (Factor Xa) plays a key role in blood coagulation by activating prothrombin to thrombin on 'stimulated' platelet membranes in the presence of its cofactor FVa (Factor Va). PS (phosphatidylserine) exposure on activated platelet membranes promotes prothrombin activation by FXa by allosterically regulating FXa. To identify the structural basis of this allosteric regulation, we used FRET to monitor changes in FXa length in response to (i) soluble short-chain PS [C6PS (dicaproylphosphatidylserine)], (ii) PS membranes, and (iii) FVa in the presence of C6PS and membranes. We incorporated a FRET pair with donor (fluorescein) at the active site and acceptor (Alexa Fluor(r) 555) at the FXa N-terminus near the membrane. The results demonstrated that FXa structure changes upon binding of C6PS to two sites: a regulatory site at the N-terminus [identified previously as involving the Gla (gamma carboxyglutamic acid) and EGFN (N-terminus of epidermal growth factor) domains] and a presumptive protein-recognition site in the catalytic domain. Binding of C6PS to the regulatory site increased the interprobe distance by ~3 A (1 A=0.1 nm), whereas saturation of both sites increased the distance by a further ~6.4 A. FXa binding to a membrane produced a smaller increase in length (~1.4 A), indicating that FXa has a somewhat different structure on a membrane from when bound to C6PS in solution. However, when both FVa2 (a FVa glycoform) and either C6PS- or PS-containing membranes were bound to FXa, the overall change in length was comparable (~5.6-5.8 A), indicating that C6PS- and PS-containing membranes in conjunction with FVa2 have comparable regulatory effects on FXa. We conclude that the similar functional regulation of FXa by C6PS or membranes in conjunction with FVa2 correlates with similar structural regulation. The results demonstrate the usefulness of FRET in analysing structure-function relationships in FXa and in the FXa.FVa2 complex. PMID- 24467410 TI - Cannabinoids inhibit cholinergic contraction in human airways through prejunctional CB1 receptors. AB - BACKGROUND AND PURPOSE: Marijuana smoking is widespread in many countries, and the use of smoked synthetic cannabinoids is increasing. Smoking a marijuana joint leads to bronchodilation in both healthy subjects and asthmatics. The effects of Delta(9) -tetrahydrocannabinol and synthetic cannabinoids on human bronchus reactivity have not previously been investigated. Here, we sought to assess the effects of natural and synthetic cannabinoids on cholinergic bronchial contraction. EXPERIMENTAL APPROACH: Human bronchi isolated from 88 patients were suspended in an organ bath and contracted by electrical field stimulation (EFS) in the presence of the phytocannabinoid Delta(9) -tetrahydrocannabinol, the endogenous 2-arachidonoylglycerol, the synthetic dual CB1 and CB2 receptor agonists WIN55,212-2 and CP55,940, the synthetic, CB2 -receptor-selective agonist JWH-133 or the selective GPR55 agonist O-1602. The receptors involved in the response were characterized by using selective CB1 and CB2 receptor antagonists (SR141716 and SR144528 respectively). KEY RESULTS: Delta(9) tetrahydrocannabinol, WIN55,212-2 and CP55,940 induced concentration-dependent inhibition of cholinergic contractions, with maximum inhibitions of 39, 76 and 77% respectively. JWH-133 only had an effect at high concentrations. 2 Arachidonoylglycerol and O-1602 were devoid of any effect. Only CB1 receptors were involved in the response because the effects of cannabinoids were antagonized by SR141716, but not by SR144528. The cannabinoids did not alter basal tone or contractions induced by exogenous Ach. CONCLUSIONS AND IMPLICATIONS: Activation of prejunctional CB1 receptors mediates the inhibition of EFS-evoked cholinergic contraction in human bronchus. This mechanism may explain the acute bronchodilation produced by marijuana smoking. PMID- 24467412 TI - Esophageal atresia: a critical review of management at a single center in Algeria. AB - The purpose was to study the outcomes and factors affecting the survival of esophageal atresia in our center. A retrospective analysis of 86 cases of esophageal atresia (EA) over a 10-year period was performed with 46 boys and 42 girls. Demographic data, birth weight, gestational age, consanguinity, incidence of associated anomalies, place of delivery, history of feeding, and outcomes were studied. EA with distal tracheoesophageal fistula (TEF) was the commonest type with 58/86 (67%). The percentage of patients with at least one associated anomaly was 52/86 (60%), with 7/86 (8%) who are from consanguineous parents; most commonly associated anomalies were cardiac 13/86 (15%). The average gestational age and birth weight were 36 +/- 2 weeks and 2300 +/- 570 g, respectively. Survival rates for the patients according to the Waterston classification was 80% in group A, 58% in group B, and 25% in group C (three patients died before surgery). Prematurity, the gap between the two ends of the esophagus, and preoperative respiratory status were the most significant factors affecting the survival. Late complication of EA/TEF include respiratory symptoms, especially in the first year, associating tracheomalacia and bronchopulmonary infections in about 24/45 (53%), recurrence of TEF 3/45 (7%), esophageal stricture 26/45 (58%), and gastroesophageal reflux 22/45 (49%). The high incidence of delayed diagnosis, low birth weight, and lack of advanced neonatological management are important contributory factors to the poor outcome. The frequency of late complications highlights the need for multidisciplinary clinics to follow these children's. PMID- 24467397 TI - The mononuclear molybdenum enzymes. PMID- 24467411 TI - Attitudinal barriers to participation in oncology clinical trials: factor analysis and correlates of barriers. AB - Patient participation in cancer clinical trials is low. Little is known about attitudinal barriers to participation, particularly among patients who may be offered a trial during an imminent initial oncology consult. The aims of the present study were to confirm the presence of proposed subscales of a recently developed cancer clinical trial attitudinal barriers measure, describe the most common cancer clinical trials attitudinal barriers, and evaluate socio demographic, medical and financial factors associated with attitudinal barriers. A total of 1256 patients completed a survey assessing demographic factors, perceived financial burden, prior trial participation and attitudinal barriers to clinical trials participation. Results of a factor analysis did not confirm the presence of the proposed four attitudinal barriers subscale/factors. Rather, a single factor represented the best fit to the data. The most highly-rated barriers were fear of side-effects, worry about health insurance and efficacy concerns. Results suggested that less educated patients, patients with non metastatic disease, patients with no previous oncology clinical trial participation, and patients reporting greater perceived financial burden from cancer care were associated with higher barriers. These patients may need extra attention in terms of decisional support. Overall, patients with fewer personal resources (education, financial issues) report more attitudinal barriers and should be targeted for additional decisional support. PMID- 24467414 TI - Copper-catalyzed coupling reaction of arylhydrazines and trialkylphosphites. AB - A novel CuO-catalyzed coupling reaction of arylhydrazines with trialkyl phosphites to afford arylphosphonates is described. The reaction proceeded at 80 degrees C in air without external reductants, oxidants, and ligands. PMID- 24467413 TI - Autologous peripheral blood hematopoietic cell transplantation in dogs with T cell lymphoma. AB - BACKGROUND: Peripheral blood hematopoietic cell transplantation (PBHCT) is a feasible treatment option for dogs with B-cell lymphoma. OBJECTIVE: To examine apheresis and PBHCT outcomes in dogs diagnosed with T-cell lymphoma (TCL). ANIMALS: Fifteen client-owned dogs diagnosed with high-grade TCL. METHODS: After high-dose cyclophosphamide and rhG-colony-stimulating (rhG-CSF) factor treatment, peripheral blood mononuclear cells were collected using cell separators. The harvested cells then were infused after varying doses of total body irradiation (TBI). Postirradiation adverse effects were managed symptomatically and dogs were discharged upon evidence of hematopoietic engraftment. RESULTS: More than 2 * 10(6) CD34+ cells/kg were harvested from 15/15 dogs. Thirteen of 15 (87%) dogs engrafted appropriately, whereas 2 (13%) of the dogs died in the hospital. One dog developed cutaneous B-cell lymphoma 120 days post-PBHCT. The median disease free interval and overall survival (OS) of the 13 dogs transplanted in first remission from the time of PBHCT were 184 and 240 days, respectively. Stage and substage of disease at diagnosis had no effect on OS. Two of 13 (15%) dogs were alive 741 and 772 days post-PBHCT. CONCLUSIONS AND CLINICAL IMPORTANCE: PBHCT may be considered as a treatment option for dogs with TCL. PMID- 24467416 TI - All-solution-processed inverted quantum-dot light-emitting diodes. AB - Quantum dots are a promising new candidate for the emissive material in light emitting devices for display applications. The fabrication of such devices by solution processing allows considerable cost reduction and is therefore very attractive for industrial manufacturers. We report all solution-processed colloidal quantum-dot light-emitting diodes (QLEDs) with an inverted structure. The red, green, and blue devices showed maximum luminances of 12 510, 32 370, and 249 cd/m(2) and turn-on voltages of 2.8, 3.6, and 3.6 V, respectively. We investigate the effect of a surfactant addition in the hole injection layer (HIL), with the aim of facilitating layer deposition and thereby enhancing device performance. We demonstrate that in the device structure presented in this study, a small amount of surfactant in the HIL can significantly improve the performance of the QLED. PMID- 24467417 TI - Conformational dynamics of a seven transmembrane helical protein Anabaena Sensory Rhodopsin probed by solid-state NMR. AB - The ability to detect and characterize molecular motions represents one of the unique strengths of nuclear magnetic resonance (NMR) spectroscopy. In this study, we report solid-state NMR site-specific measurements of the dipolar order parameters and (15)N rotating frame spin-lattice (R1rho) relaxation rates in a seven transmembrane helical protein Anabaena Sensory Rhodopsin reconstituted in lipids. The magnitudes of the observed order parameters indicate that both the well-defined transmembrane regions and the less structured intramembrane loops undergo restricted submicrosecond time scale motions. In contrast, the R1rho rates, which were measured under fast magic angle spinning conditions, vary by an order of magnitude between the TM and exposed regions and suggest the presence of intermediate time scale motions. Using a simple model, which assumes a single exponential autocorrelation function, we estimated the time scales of dominant stochastic motions to be on the order of low tens of nanoseconds for most residues within the TM helices and tens to hundreds of nanoseconds for the extracellular B-C and F-G loops. These relatively slow time scales could be attributed to collective anisotropic motions. We used the 3D Gaussian axial fluctuations model to estimate amplitudes, directions, and time scales of overall motions for helices and the extracellular B-C and F-G loops. Within this model, the TM helices A,B,C,D,E,F undergo rigid body motions on a time scale of tens of nanoseconds, while the time scale for the seventh helix G approaches 100 ns. Similar time scales of roughly 100-200 ns are estimated for the B-C and F-G loops. PMID- 24467418 TI - Communication and professionalism skills of a new graduate: the expectations and experiences of dental foundation trainers. AB - AIM: The aim of this study was to investigate dental foundation year 1 (DF1) trainers' expectations of the dental graduate specifically in relation to non clinical (professionalism and communication) skills and to explore whether these expectations were being met. METHOD: In the UK, dental graduates undertake 1 year of foundation training prior to being permitted to undertake NHS practice. An online survey was distributed to DF1 trainers via all 11 English deaneries and the Northern Ireland deanery. Demographic information and a general view of trainers' expectations of a new trainee were collected. Specific questions relating to six generic trainee problems were followed by 11 ability statements where trainers indicated their expectation of a trainee's ability to perform the skill on a 5-point scale (on own with confidence-unable to undertake). Statements were repeated and trainers were required to respond using the same scale in relation to experience of their current trainee. RESULTS: Five hundred and ten (53%) trainers completed the questionnaire with no missing data. Expectations were high with almost 50% of trainers expecting a new graduate to manage a full list of patients on their own. Experience of new graduates did not always match these expectations. Of concern was the ability to 'keep accurate patient records' and 'self-reflection and knowing when to seek help', where a small proportion of trainers experienced difficulties. CONCLUSIONS: Trainers' expectation and experience in relation to non-clinical skills of a new graduate were investigated. Although they had high expectations, the majority reported only minor problems overall. There were a few areas where concern was raised. PMID- 24467419 TI - In pursuit of progress: promotion motivation and risk preference in the domain of gains. AB - This article examines the role of promotion motivation in decision making in the domain of gains. Using a stock investment paradigm in which individuals believed that they were making decisions that were real and consequential, we found that promotion motivation, and not prevention motivation, predicted the likelihood of switching between risky and conservative choices in the domain of gains. Promotion-focused participants chose a relatively risky option when their stock portfolio remained unchanged (stuck at 0, the status quo) but switched to a relatively conservative option when they had just experienced a large gain (Studies 1-4), both when regulatory focus was measured (Study 1) and manipulated (Studies 2-4). Studies in which progress was manipulated (Study 3) and measured (Study 4) provided evidence that it is perceptions of progress that underlie this tactical switch in risk preferences within the promotion system. We discuss the implications of these findings for decision making and the role of progress in self-regulation. PMID- 24467420 TI - "I cheated, but only a little": partial confessions to unethical behavior. AB - Confessions are people's way of coming clean, sharing unethical acts with others. Although confessions are traditionally viewed as categorical-one either comes clean or not-people often confess to only part of their transgression. Such partial confessions may seem attractive, because they offer an opportunity to relieve one's guilt without having to own up to the full consequences of the transgression. In this article, we explored the occurrence, antecedents, consequences, and everyday prevalence of partial confessions. Using a novel experimental design, we found a high frequency of partial confessions, especially among people cheating to the full extent possible. People found partial confessions attractive because they (correctly) expected partial confessions to be more believable than not confessing. People failed, however, to anticipate the emotional costs associated with partially confessing. In fact, partial confessions made people feel worse than not confessing or fully confessing, a finding corroborated in a laboratory setting as well as in a study assessing people's everyday confessions. It seems that although partial confessions seem attractive, they come at an emotional cost. PMID- 24467421 TI - Speaking from ignorance: not agreeing with others we believe are correct. AB - Values-pragmatics theory (Hodges & Geyer, 2006) predicts that people will sometimes disagree with others they believe are correct, for reasons similar to those explaining agreement with incorrect answers in an Asch (1956) situation. In 3 experiments, we found evidence that people in a position of ignorance sometimes do not agree with the correct answers of others in positions of knowledge. Experiments 1a and 1b found this speaking-from-ignorance (SFI) effect occurred 27% of the time. Experiment 2 introduced experimental controls and self-report data indicating that the SFI effect (30%) was generated by realizing values (e.g., truth, social solidarity) and pragmatic constraints to act cooperatively, rather than by a wide array of alternatives (e.g., normative pressure, reactance). Experiment 3 experimentally manipulated concern for truthfulness, yielding 49% nonagreeing answers, even though there were monetary incentives to give correct, agreeing answers. The overall pattern suggests that people are not so much conformists or independents as they are cooperative truth tellers under social and moral constraints. Results, while surprising for social influence theories, illustrate the dynamics of divergence and convergence that appear across studies in cultural anthropology and developmental psychology, as well as in social psychology. PMID- 24467422 TI - Too much experience: a desensitization bias in emotional perspective taking. AB - People often use their own feelings as a basis to predict others' feelings. For example, when trying to gauge how much someone else enjoys a television show, people might think "How much do I enjoy it?" and use this answer as basis for estimating others' reactions. Although personal experience (such as actually watching the show oneself) often improves empathic accuracy, we found that gaining too much experience can impair it. Five experiments highlight a desensitization bias in emotional perspective taking, with consequences for social prediction, social judgment, and social behavior. Participants who viewed thrilling or shocking images many times predicted first-time viewers would react less intensely (Experiments 1 and 2); participants who heard the same funny joke or annoying noise many times estimated less intense reactions of first-time listeners (Experiments 3 and 4); and further, participants were less likely to actually share good jokes and felt less bad about blasting others with annoying noise after they themselves became desensitized to those events (Experiments 3 5). These effects were mediated by participants' own attenuated reactions. Moreover, observers failed to anticipate this bias, believing that overexposed participants (i.e., repeatedly exposed participants who became desensitized) would make better decisions on their behalf (Experiment 5). Taken together, these findings reveal a novel paradox in emotional perspective taking: If people experience an evocative event many times, they may not become wiser companions but worse, unable to disentangle self-change from other-oriented thinking. Just as lacking exposure to others' experiences can create gaps in empathy and understanding, so may gaining too much. PMID- 24467423 TI - To thine own self be true: psychological adjustment promotes judgeability via personality-behavior congruence. AB - Well-adjusted individuals are highly judgeable in that their personalities tend to be seen more accurately than the personalities of less adjusted individuals (Colvin, 1993a, 1993b; Human & Biesanz, 2011a). The mechanisms behind this effect, however, are not well understood. How does adjustment facilitate judgeability? In the present video-perceptions study, we examined potential mechanisms through which adjustment could promote judgeability at 3 stages of the Realistic Accuracy Model (RAM; Funder, 1995): (a) cue relevance, (b) cue availability, and (c) cue detection. We found that well-adjusted individuals were more judgeable because they provided more relevant cues: Specifically, well adjusted individuals behaved more in line with their distinctive personalities, which in turn led them to be seen more accurately. In contrast, neither cue availability nor detection could sufficiently account for the link between adjustment and judgeability. In sum, well-adjusted individuals are more judgeable because to their own selves, they are true. PMID- 24467424 TI - Self-talk as a regulatory mechanism: how you do it matters. AB - Does the language people use to refer to the self during introspection influence how they think, feel, and behave under social stress? If so, do these effects extend to socially anxious people who are particularly vulnerable to such stress? Seven studies explored these questions (total N = 585). Studies 1a and 1b were proof-of-principle studies. They demonstrated that using non-first-person pronouns and one's own name (rather than first-person pronouns) during introspection enhances self-distancing. Studies 2 and 3 examined the implications of these different types of self-talk for regulating stress surrounding making good first impressions (Study 2) and public speaking (Study 3). Compared with the first-person group, the non-first-person group performed better according to objective raters in both studies. They also displayed less distress (Studies 2 and 3) and engaged in less maladaptive postevent processing (Study 3). Studies 4 and 5 examined how these different forms of self-talk influence the way people appraise social-anxiety-provoking events. They demonstrated that non-first-person language use (compared with first-person language use) leads people to appraise future stressors in more challenging and less threatening terms. Finally, a meta analysis (Study 6) indicated that none of these findings were moderated by trait social anxiety, highlighting their translational potential. Together, these findings demonstrate that small shifts in the language people use to refer to the self during introspection consequentially influence their ability to regulate their thoughts, feelings, and behavior under social stress, even for vulnerable individuals. PMID- 24467425 TI - Low and decreasing self-esteem during adolescence predict adult depression two decades later. AB - Previous studies revealed that low self-esteem is prospectively associated with depression. However, self-esteem has been shown to change over time. We thus hypothesized that not only level but also change in self-esteem affect depression. Using data from a 23-year longitudinal study (N = 1,527), we therefore examined the prospective effects of global and domain-specific self esteem (physical attractiveness, academic competence) level and change on depressive symptoms 2 decades later. Self-esteem was assessed annually from age 12 to 16, and depression was assessed at age 16 and 35. Results from latent growth curve analyses demonstrated that both level and change in self-esteem served as predictors for adult depression. Individuals who entered adolescence with low self-esteem, and/or whose self-esteem declined further during the adolescent years, were more likely to exhibit symptoms of depression 2 decades later as adults; this pattern held both for global and domain-specific self esteem. These findings highlight the importance of adolescent self-esteem development for mental health outcomes in adulthood. PMID- 24467426 TI - Does sociability predict civic involvement and political participation? AB - In contemporary history as well as in political science, a strong associational life known as sociability is thought to explain the roots of modern democracy by establishing a link between the increasing availability of free time to the middle classes, increasing willingness to gather with others in circles or associations, and increasing social capital. In personality psychology, sociability is related to prosocial behavior (i.e., the need for affiliation, agreeableness, openness, and extraversion), whose importance in different political behaviors is increasingly recognized. In the present article, we carried out 5 studies (N = 1,429) that showed that political and associative sociability (a) can be reliably assessed, can have cross-cultural validity, and are properly associated with general social interest measures and personality domains and facets in the five-factor model; (b) do not overlap with similar concepts used in political psychology to account for political participation (political expertise, political interest, political self-efficacy); and (c) predicted political and nonpolitical group membership as well as observable choices in decision-making tasks with political and nonpolitical outcomes. The results are discussed, taking into consideration the extent to which specific facets of sociability can mediate between general personality traits and measures of civic involvement and political participation in a holistic model of political behavior. PMID- 24467427 TI - Turning the tables: the growth of upward bullying in nursing academia. PMID- 24467430 TI - A loss of telocytes accompanies fibrosis of multiple organs in systemic sclerosis. AB - Systemic sclerosis (SSc) is a complex connective tissue disease characterized by fibrosis of the skin and various internal organs. In SSc, telocytes, a peculiar type of stromal (interstitial) cells, display severe ultrastructural damages and are progressively lost from the clinically affected skin. The aim of the present work was to investigate the presence and distribution of telocytes in the internal organs of SSc patients. Archival paraffin-embedded samples of gastric wall, myocardium and lung from SSc patients and controls were collected. Tissue sections were stained with Masson's trichrome to detect fibrosis. Telocytes were studied on tissue sections subjected to CD34 immunostaining. CD34/CD31 double immunofluorescence was performed to unequivocally differentiate telocytes (CD34 positive/CD31-negative) from vascular endothelial cells (CD34-positive/CD31 positive). Few telocytes entrapped in the fibrotic extracellular matrix were found in the muscularis mucosae and submucosa of SSc gastric wall. In the muscle layers and myenteric plexus, the network of telocytes was discontinuous or even completely absent around smooth muscle cells and ganglia. Telocytes were almost completely absent in fibrotic areas of SSc myocardium. In SSc fibrotic lung, few or no telocytes were observed in the thickened alveolar septa, around blood vessels and in the interstitial space surrounding terminal and respiratory bronchioles. In SSc, the loss of telocytes is not restricted to the skin, but it is a widespread process affecting multiple organs targeted by the fibrotic process. As telocytes are believed to be key players in the regulation of tissue/organ homoeostasis, our data suggest that telocyte loss might have important pathophysiological implications in SSc. PMID- 24467432 TI - Crystal structure and vibrational spectra of poly(trimethylene terephthalate) from periodic density functional theory calculations. AB - The crystal structure and the IR spectrum of crystalline poly(trimethylene terephthalate), PTT, have been investigated by means of periodic density functional theory calculations including Grimme's correction for dispersion interactions. Both structural and spectroscopic results have been critically compared to the experimental data taken from the literature, showing very good agreement between theory and the experiments. The previous spectral assignments, based only on experimental investigations, have been revised, and further insights have been obtained. Furthermore, spectroscopic markers of crystallinity or regularity (i.e., of the regular conformation of the polymer chain) have been proposed. In addition to the analysis of the IR spectra, the effect of computational parameters on the crystal structure determination (basis sets and parameters for Grimme's correction) have been analyzed. This work demonstrates that state-of-the-art computational methods can provide an unambiguous description of the structural and vibrational properties of crystalline polymers on the basis of the peculiar intra- and intermolecular interactions occurring in different macromolecular materials. PMID- 24467431 TI - Electrophysiology of human cardiac atrial and ventricular telocytes. AB - Telocytes (TCs) with exceptionally long cellular processes of telopodes have been described in human epicardium to act as structural supporting cells in the heart. We examined myocardial chamber-specific TCs identified in atrial and ventricular fibroblast culture using immunocytochemistry and studied their electrophysiological property by whole-cell patch clamp. Atrial and ventricular TCs with extended telopodes and alternating podoms and podomers that expressed CD34, c-Kit and PDGFR-beta were identified. These cells expressed large conductance Ca2+-activated K+ current (BK(Ca)) and inwardly rectifying K+ current (IK(ir)), but not transient outward K+ current (I(to)) and ATP-sensitive potassium current (K(ATP)). The active channels were functionally competent with demonstrated modulatory response to H2 S and transforming growth factor (TGF) beta1 whereby H2S significantly inhibited the stimulatory effect of TGF-beta1 on current density of both BKCa and IK(ir). Furthermore, H2S attenuated TGF-beta1 stimulated KCa1.1/Kv1.1 (encode BK(Ca)) and Kir2.1 (encode IK(ir)) expression in TCs. Our results show that functionally competent K+ channels are present in human atrial and ventricular TCs and their modulation may have significant implications in myocardial physiopathology. PMID- 24467433 TI - An update on zolpidem abuse and dependence. AB - In 2004, the health authorities (French National Agency for Medicines and Health Products Safety-ANSM) modified the summary of zolpidem characteristics. Particularly it now includes the sentence "a pharmacodependence may materialize." The current article aims to show that despite this modification, zolpidem continues to be associated with problematic drug use, as the official system (Center for Evaluation and Information on Pharmacodependence-Addictovigilance network) providing information on the abuse and dependence potential of drugs informs us. The authors reviewed the literature on this topic and analyzed French data from zolpidem's postmarketing period that were collected by the Addictovigilance network from 2003 to 2010. Postmarketing data and the 30 case reports yielded from the literature review highlight a significant dependence and abuse potential for zolpidem. This survey led to propose in stronger additional rules in France to try to mitigate the abuse potential of zolpidem. PMID- 24467434 TI - Physicochemical analysis of ruthenium(II) sensitizers of 1,2,3-triazole-derived mesoionic carbene and cyclometalating ligands. AB - A series of heteroleptic bis(tridentate) ruthenium(II) complexes bearing ligands featuring 1,2,3-triazolide and 1,2,3-triazolylidene units are presented. The synthesis of the C^N^N-coordinated ruthenium(II) triazolide complex is achieved by direct C-H activation, which is enabled by the use of a 1,5-disubstituted triazole. By postcomplexation alkylation, the ruthenium(II) 1,2,3-triazolide complex can be converted to the corresponding 1,2,3-triazolylidene complex. Additionally, a ruthenium(II) complex featuring a C^N^C-coordinating bis(1,2,3 triazolylidene)pyridine ligand is prepared via transmetalation from a silver(I) triazolylidene precursor. The electronic consequences of the carbanion and mesoionic carbene donors are studied both experimentally and computationally. The presented complexes exhibit a broad absorption in the visible region as well as long lifetimes of the charge-separated excited state suggesting their application in photoredox catalysis and photovoltaics. Testing of the dyes in a conventional dye-sensitized solar cell (DSSC) generates, however, only modest power conversion efficiencies (PCEs). PMID- 24467435 TI - Genetic risk factors for insidious equine recurrent uveitis in Appaloosa horses. AB - Appaloosa horses are predisposed to equine recurrent uveitis (ERU), an immune mediated disease characterized by recurring inflammation of the uveal tract in the eye, which is the leading cause of blindness in horses. Nine genetic markers from the ECA1 region responsible for the spotted coat color of Appaloosa horses, and 13 microsatellites spanning the equine major histocompatibility complex (ELA) on ECA20, were evaluated for association with ERU in a group of 53 Appaloosa ERU cases and 43 healthy Appaloosa controls. Three markers were significantly associated (corrected P-value <0.05): a SNP within intron 11 of the TRPM1 gene on ECA1, an ELA class I microsatellite located near the boundary of the ELA class III and class II regions and an ELA class II microsatellite located in intron 1 of the DRA gene. Association between these three genetic markers and the ERU phenotype was confirmed in a second population of 24 insidious ERU Appaloosa cases and 16 Appaloosa controls. The relative odds of being an ERU case for each allele of these three markers were estimated by fitting a logistic mixed model with each of the associated markers independently and with all three markers simultaneously. The risk model using these markers classified ~80% of ERU cases and 75% of controls in the second population as moderate or high risk, and low risk respectively. Future studies to refine the associations at ECA1 and ELA loci and identify functional variants could uncover alleles conferring susceptibility to ERU in Appaloosa horses. PMID- 24467437 TI - Effects of nitrogen incorporation in HfO(2) grown on InP by atomic layer deposition: an evolution in structural, chemical, and electrical characteristics. AB - We investigated the effects of postnitridation on the structural characteristics and interfacial reactions of HfO2 thin films grown on InP by atomic layer deposition (ALD) as a function of film thickness. By postdeposition annealing under NH3 vapor (PDN) at 600 degrees C, an InN layer formed at the HfO2/InP interface, and ionized NHx was incorporated in the HfO2 film. We demonstrate that structural changes resulting from nitridation of HfO2/InP depend on the film thickness (i.e., a single-crystal interfacial layer of h-InN formed at thin (2 nm) HfO2/InP interfaces, whereas an amorphous InN layer formed at thick (>6 nm) HfO2/InP interfaces). Consequently, the tetragonal structure of HfO2 transformed into a mixture structure of tetragonal and monoclinic because the interfacial InN layer relieved interfacial strain between HfO2 and InP. During postdeposition annealing (PDA) in HfO2/InP at 600 degrees C, large numbers of oxidation states were generated as a result of interfacial reactions between interdiffused oxygen impurities and out-diffused InP substrate elements. However, in the case of the PDN of HfO2/InP structures at 600 degrees C, nitrogen incorporation in the HfO2 film effectively blocked the out-diffusion of atomic In and P, thus suppressing the formation of oxidation states. Accordingly, the number of interfacial defect states (Dit) within the band gap of InP was significantly reduced, which was also supported by DFT calculations. Interfacial InN in HfO2/InP increased the electron barrier height to ~0.6 eV, which led to low-leakage-current density in the gate voltage region over 2 V. PMID- 24467438 TI - Evidence for active atomic defects in monolayer hexagonal boron nitride: a new mechanism of plasticity in two-dimensional materials. AB - We report the formation and motion of 4|8 (square-octagon) defects in monolayer hexagonal boron nitride (h-BN). The 4|8 defects, involving less-favorable B-B and N-N bonds, are mobile within the monolayer at high sample temperature (~ 1000 K) under electron beam irradiation. Gliding of one or two atomic rows along the armchair direction is suggested to be the origin of the defect motion. This represents a completely new mechanism of plasticity in two-dimensional materials. PMID- 24467440 TI - "Rolling" phenomenon in twin screw granulation with controlled-release excipients. AB - The developed knowledge regarding use of twin screw granulators for continuous wet granulation has been primarily limited to immediate release formulations in the literature. The present study highlights an issue previously unreported for wet granulation with twin screw extruders when using formulations containing controlled-release (CR) excipients. Long (3-10 mm), twisted noodle-like granules can be produced in the presence of these excipients that are difficult to control and are anticipated to create complications in downstream unit operations to the granulator. Working with two different CR excipients, METHOCELTM K4M and Kollidon(r) SR, each blended at different ratios with a mixture of 80% alpha lactose monohydrate/20% microcrystalline cellulose, these unique particles were found to be produced in the conveying elements of the extruder, arising from a rolling action at the top of the screw flights. The CR excipients adhesively strengthen the wetted mass, forming this undesired granule shape such that they persisted to the exit of the machine; the shape appeared most strongly affected by screw speed, producing particles of higher aspect ratio as speed was increased. Adjusting the concentration of these CR excipients in the formulation, the flow rate or the type of compression element used in the screws proved ineffective in controlling the problem. Rather, a re-design of the extruder screws was required to prevent generation of these extended-form granules. PMID- 24467436 TI - Arylamine N-acetyltransferases: from drug metabolism and pharmacogenetics to drug discovery. AB - Arylamine N-acetyltransferases (NATs) are polymorphic drug-metabolizing enzymes, acetylating arylamine carcinogens and drugs including hydralazine and sulphonamides. The slow NAT phenotype increases susceptibility to hydralazine and isoniazid toxicity and to occupational bladder cancer. The two polymorphic human NAT loci show linkage disequilibrium. All mammalian Nat genes have an intronless open reading frame and non-coding exons. The human gene products NAT1 and NAT2 have distinct substrate specificities: NAT2 acetylates hydralazine and human NAT1 acetylates p-aminosalicylate (p-AS) and the folate catabolite para aminobenzoylglutamate (p-abaglu). Human NAT2 is mainly in liver and gut. Human NAT1 and its murine homologue are in many adult tissues and in early embryos. Human NAT1 is strongly expressed in oestrogen receptor-positive breast cancer and may contribute to folate and acetyl CoA homeostasis. NAT enzymes act through a catalytic triad of Cys, His and Asp with the architecture of the active site modulating specificity. Polymorphisms may cause unfolded protein. The C-terminus helps bind acetyl CoA and differs among NATs including prokaryotic homologues. NAT in Salmonella typhimurium supports carcinogen activation and NAT in mycobacteria metabolizes isoniazid with polymorphism a minor factor in isoniazid resistance. Importantly, nat is in a gene cluster essential for Mycobacterium tuberculosis survival inside macrophages. NAT inhibitors are a starting point for novel anti-tuberculosis drugs. Human NAT1-specific inhibitors may act in biomarker detection in breast cancer and in cancer therapy. NAT inhibitors for co administration with 5-aminosalicylate (5-AS) in inflammatory bowel disease has prompted ongoing investigations of azoreductases in gut bacteria which release 5 AS from prodrugs including balsalazide. PMID- 24467439 TI - Obesity, diabetes and survival in maintenance hemodialysis patients. AB - Increased body mass index (BMI) confers a survival advantage in maintenance hemodialysis (MHD) patients. Diabetic (diabetes mellitus (DM)) patients undergoing MHD have worse survival. There are limited studies examining the effect of obesity on the risk of death among MHD patients with diabetes. Ninety eight MHD patients were studied for median follow-up time of 33 months. Patients were classified according to the presence of obesity (BMI >= 30 kg/m(2)) or DM. Primary outcome was all-cause mortality. Cox regression was used to evaluate the effect of obesity on time to death. Effect modification and mediation analysis were also performed. Mean age was 49 +/- 13 years, 66% were male, 48% were obese and 34% were diabetic. Mortality rates (per 100 person-years) were: 3.4 for non diabetic obese, 8.6 for non-diabetic non-obese, 14.3 for diabetic non-obese and 18.1 for diabetic obese patients. Log-rank comparing diabetic obese versus non diabetic obese was significant (p=0.007). Diabetes was associated with an increased risk of mortality after adjustment for potential mediators. Effect modification of obesity in the mortality risk was different between patients with and without diabetes. With adjustment for adipokines, a greater effect modification by diabetes was observed; whereas, adjustment for inflammatory marker did not influence the effect modification. Diabetic obese MHD patients have increased mortality risk compared to non-diabetic obese. Obesity does not offer survival benefits in diabetic obese MHD patients and potentially may have detrimental effects. Larger studies evaluating the effect of adipokines and obesity in outcomes in the diabetic MHD population need to be undertaken. PMID- 24467441 TI - Context and psychosocial intervention in mental health. AB - OBJECTIVE: Occupational therapy (OT) services have been provided for people with mental health conditions since the foundation of the profession, but OT practices are not clearly outlined. This paper presents the standard OT practices performed in the mental health area. The aim of the study is to quantitatively characterize domains of OT intervention in mental health. Specifically, OT intervention in community and inpatient-based mental health settings is described, further delineated by age groups and gender. Eighteen occupational therapists (OTs), who work in the area of mental health, participated in the study. Each OT had at least two years of experience, was between the ages of 26 and 40, and documented 2-4 treatment sessions. In total, 70 treatment sessions were recorded; half were recorded in hospitals and the majority of recorded sessions involved clients diagnosed with schizophrenia (n = 47). Significant differences were found in the intervention provided in the different settings. In addition, the intervention focus for men and women, and for age groups, was different. Despite these differences, many aspects of the intervention were similar in all contexts. The study results support previous notions that context influences intervention. PMID- 24467442 TI - Phosphorylation by Akt within the ST loop of AMPK-alpha1 down-regulates its activation in tumour cells. AB - The insulin/IGF-1 (insulin-like growth factor 1)-activated protein kinase Akt (also known as protein kinase B) phosphorylates Ser487 in the 'ST loop' (serine/threonine-rich loop) within the C-terminal domain of AMPK-alpha1 (AMP activated protein kinase-alpha1), leading to inhibition of phosphorylation by upstream kinases at the activating site, Thr172. Surprisingly, the equivalent site on AMPK-alpha2, Ser491, is not an Akt target and is modified instead by autophosphorylation. Stimulation of HEK (human embryonic kidney)-293 cells with IGF-1 caused reduced subsequent Thr172 phosphorylation and activation of AMPK alpha1 in response to the activator A769662 and the Ca2+ ionophore A23187, effects we show to be dependent on Akt activation and Ser487 phosphorylation. Consistent with this, in three PTEN (phosphatase and tensin homologue deleted on chromosome 10)-null tumour cell lines (in which the lipid phosphatase PTEN that normally restrains the Akt pathway is absent and Akt is thus hyperactivated), AMPK was resistant to activation by A769662. However, full AMPK activation could be restored by pharmacological inhibition of Akt, or by re-expression of active PTEN. We also show that inhibition of Thr172 phosphorylation is due to interaction of the phosphorylated ST loop with basic side chains within the alphaC-helix of the kinase domain. Our findings reveal that a previously unrecognized effect of hyperactivation of Akt in tumour cells is to restrain activation of the LKB1 (liver kinase B1)-AMPK pathway, which would otherwise inhibit cell growth and proliferation. PMID- 24467443 TI - Hope for a cure and altruism are the main motives behind participation in phase 3 clinical cancer trials. AB - It is necessary to carry out randomised clinical cancer trials (RCTs) in order to evaluate new, potentially useful treatments for future cancer patients. Participation in clinical trials plays an important role in determining whether a new treatment is the best therapy or not. Therefore, it is important to understand on what basis patients decide to participate in clinical trials and to investigate the implications of this understanding for optimising the information process related to study participation. The aims of this study were to (1) describe motives associated with participation in RCTs, (2) assess if patients comprehend the information related to trial enrolment, and (3) describe patient experiences of trial participation. Questionnaires were sent to 96 cancer patients participating in one of nine ongoing clinical phase 3 trials at the Department of Oncology, Uppsala University Hospital in Sweden. Eighty-eight patients completed the questionnaire (response rate 92%); 95% of these were patients in adjuvant therapy and 5% participated in clinical trials on palliative care. Two main reasons for participation were identified: personal hope for a cure and altruism. Patients show adequate understanding of the information provided to them in the consent process and participation entails high patient satisfaction. PMID- 24467444 TI - Development and evaluation of a questionnaire to assess knowledge, attitudes, and behaviors towards hearing loss prevention. AB - OBJECTIVE: To develop and evaluate a questionnaire assessing knowledge, attitudes, and behaviors (KAB) as they pertain to hearing conservation, using the constructs of the health belief model (HBM). DESIGN: The KAB was completed by 235 participants. Relationships between knowledge and attitudes about hearing and hearing conservation, participation in noisy activities, and use of hearing protection were examined. STUDY SAMPLE: 117 males and 118 females aged between 18 and 80 years (mean = 42.3, SD = 4.1) recruited from the Portland VA Medical Center, local universities, and a community college. RESULTS: Knowledge scores ranged from 15.6% to 93.8%. Factor analyses revealed six attitude factors, interpreted as measuring perceived susceptibility, perceived severity, perceived benefits, perceived barriers, perceived self-efficacy, and cues to action. Over 95% of participants routinely participated in at least one noisy activity but few used hearing protection while doing so. The attitude scores of individuals who used hearing protection differed significantly from the scores of those who did not. CONCLUSIONS: Significant relationships between use of hearing protection and scores on the KAB provide validation that the HBM is a valuable framework for understanding hearing health behaviors, and evidence that the KAB is a valid tool for assessing these attitudes and behaviors. PMID- 24467445 TI - Molecular dynamics shows that ion pairing and counterion anchoring control the properties of triflate micelles: a comparison with triflate at the air/water interface. AB - Micellar properties of dodecyltrimethylammonium triflate (DTA-triflate, DTATf) are very different from those of DTA-bromide (DTAB). DTATf aggregates show high aggregation numbers (Nagg), low degree of counterion dissociation (alpha), disk like shape, high packing, ordering, and low hydration. These micellar properties and the low surface tension of NaTf aqueous solutions point to a high affinity of Tf(-) to the micellar and air/water interfaces. Although the micellar properties of DTATf are well defined, the source of the Tf(-) effect upon the DTA aggregates is unclear. Molecular dynamics (MD) simulations of Tf(-) (and Br(-)) at the air/water interface and as counterion of a DTA aggregate were performed to clarify the nature of Tf(-) preferences for these interfaces. The effect of NaTf or NaBr on surface tension calculated from MD simulations agreed with the reported experimental values. From the MD simulations a high affinity of Tf(-) toward the interface, which occurred in a specific orientation, was calculated. The micellar properties calculated from the MD simulations for DTATf and DTAB were consistent with experimental data: in MD simulations, the DTATf aggregate was more ordered, packed, and dehydrated than the DTAB aggregate. The Tf( )/alkyltrimethylammonium interaction energies, calculated from the MD simulations, suggested ion pair formation at the micellar interface, stabilized by the preferential orientation of the adsorbed Tf(-) at the micellar interface. PMID- 24467446 TI - Degradation of oxalic acid by the mycoparasite Coniothyrium minitans plays an important role in interacting with Sclerotinia sclerotiorum. AB - Coniothyrium minitans (Cm) is a mycoparasite of the phytopathogenic fungus Sclerotinia sclerotiorum (Ss). Ss produces a virulence factor oxalic acid (OA) which is toxic to plants and also to Cm, and Cm detoxifies OA by degradation. In this study, two oxalate decarboxylase genes, Cmoxdc1 and Cmoxdc2, were cloned from Cm strain Chy-1. OA and low pH induced expression of Cmoxdc1, but not Cmoxdc2. Cmoxdc1 was partially responsible for OA degradation, whereas Cmoxdc2 had no effect on OA degradation. Disruption of Cmoxdc1 in Cm reduced its ability to infect Ss in dual cultures where OA accumulated. Compared with Chy-1, the Cmoxdc1-disrupted mutants had reduced expression levels of two mycoparasitism related genes chitinase (Cmch1) and beta-1,3-glucanase (Cmg1), and had no detectable activity of extracellular proteases in the presence of OA. On the other hand, the cultural filtrates of the Cmoxdc1-disrupted mutants in OA-amended media showed enhanced antifungal activity, possibly because of increased production of antifungal substances under acidic pH condition resulted from reduced Cmoxdc1-mediated OA degradation. This study provides direct genetic evidence of OA degradation regulating mycoparasitism and antibiosis of Cm against Ss, and sheds light on the sophisticated strategies of Cm in interacting with metabolically active mycelia and dormant sclerotia of Ss. PMID- 24467447 TI - A pilot investigation of feeding problems in children with esophageal atresia. AB - While many long-term complications of esophageal atresia (EA) have been well investigated, little is known about feeding difficulties in children after surgical correction of EA and its impact on caregivers. This study investigates the feeding behaviors of children with EA through a validated feeding questionnaire. The Montreal Children's Hospital Feeding Scale (MCH-FS) was filled out by the primary caregiver during patient follow-up visits in the multidisciplinary EA clinic. Demographic information, EA subtype, associated anomalies and outcomes were recorded. Results were compared between groups and to a normative sample. Thirty caregivers have completed the MCH-FS; 26 patients had type C atresia (86.7%). In comparison to controls, 17.5% of EA cases are one standard deviation above the mean feeding difficulty score, while 6.7% (n = 2) cases are greater than two standard deviations above normative values. Typical EA patients (type C who were not born <30 weeks) had mean MCH-FS scores in the subclinical range, whereas one extremely premature child and the patients with non-type C EA (n = 4) all had scores in the severe range. Feeding difficulties of patients with typical EA appear mild. Likely explanations include the use of early protocolized care and intensive multidisciplinary care in follow up. Nonetheless, patients with complicated EA (non-type C) and their caregivers tend to experience significant feeding difficulties. Early targeted care may be required for this patient subset, and additional cases will be investigated to confirm these preliminary findings and explore further risk factors of feeding problem in this cohort. PMID- 24467448 TI - Internal adduct formation of active intramolecular C4-bridged frustrated phosphane/borane Lewis pairs. AB - The tetramethylene-bridged PMes2/B(C6F5)2 frustrated Lewis pair (FLP) 8 was prepared by hydroboration of Mes2P-(CH2)2CH?CH2 with HB(C6F5)2. It is an active FLP that splits dihydrogen under mild conditions and, consequently, serves as a metal-free hydrogenation catalyst for a variety of substrates. It also reacts typically with terminal acetylenes. The C4-bridged FLP 23 was prepared by HB(C6F5)2 hydroboration of 1-dimesitylphosphino-2-vinylferrocene. It represents a rare example of a FLP where the equilibrium between the open form and the closed internal P/B adduct form is experimentally observable. It also shows a variety of typical FLP reactions, including dihydrogen splitting. The FLPs 8 and 23 (open form) and many precursors and products were characterized by X-ray diffraction. PMID- 24467449 TI - Commitment to collaboration: rhetorical or real? PMID- 24467450 TI - Laughter and humor therapy in dialysis. AB - Laughter and humor therapy have been used in health care to achieve physiological and psychological health-related benefits. The application of these therapies to the dialysis context remains unclear. This paper reviews the evidence related to laughter and humor therapy as a medical therapy relevant to the dialysis patient population. Studies from other groups such as children, the elderly, and persons with mental health, cancer, and other chronic conditions are included to inform potential applications of laughter therapy to the dialysis population. Therapeutic interventions could range from humorous videos, stories, laughter clowns through to raucous simulated laughter and Laughter Yoga. The effect of laughter and humor on depression, anxiety, pain, immunity, fatigue, sleep quality, respiratory function and blood glucose may have applications to the dialysis context and require further research. PMID- 24467451 TI - Overexpression of STAMP2 suppresses atherosclerosis and stabilizes plaques in diabetic mice. AB - Our research aims to evaluate the function of the STAMP2 gene, an important trigger in insulin resistance (IR), and explore its role in macrophage apoptosis in diabetic atherosclerotic vulnerable plaques. The characteristics of diabetic mice were measured by serial metabolite and pathology tests. The level of STAMP2 was measured by RT-PCR and Western blot. The plaque area, lipid and collagen content of brachiocephalic artery plaques were measured by histopathological analyses, and the macrophage apoptosis was measured by TUNEL. Correlation of STAMP2/Akt signaling pathway and macrophage apoptosis was validated by Ad-STAMP2 transfection and STAMP2 siRNA inhibition. The diabetic mice showed typical features of IR, hyperglycaemia. Overexpression of STAMP2 ameliorated IR and decreased serum glucose level. In brachiocephalic lesions, lipid content, macrophage quantity and the vulnerability index were significantly decreased by overexpression of STAMP2. Moreover, the numbers of apoptotic cells and macrophages in lesions were both significantly decreased. In vitro, both mRNA and protein expressions of STAMP2 were increased under high glucose treatment. P-Akt was highly expressed and caspase-3 was decreased after overexpression of STAMP2. However, expression of p-Akt protein was decreased and caspase-3 was increased when STAMP2 was inhibited by siRNA. STAMP2 overexpression could exert a protective effect on diabetic atherosclerosis by reducing IR and diminishing macrophage apoptosis. PMID- 24467452 TI - Investigation on the mechanism of nanodamage and nanofailure for single ZnO nanowires under an electric field. AB - The electrical service behavior of ZnO nanowires (NWs) with various diameters was investigated by a nanomanipulation technique. The nanodamage and nanofailure phenomena of the ZnO NWs were observed when external voltages were applied. The threshold voltages of the ZnO NWs increased linearly from 15 to 60 V with increasing diameter. The critical current densities were distributed from 19.50 * 10(6) to 56.90 * 10(6) A m(-2), and the reciprocal of the critical current density increased linearly with increasing diameter as well. The thermal core shell model was proposed to explain the nanodamage and nanofailure mechanism of ZnO NWs under an electric field. It can be expected that the investigation on the nanodamage and nanofailure of nanomaterials would have a profound influence on practical applications of photoelectric, electromechanical, and piezoelectric nanodevices. PMID- 24467453 TI - Occupational therapists' experiences of improvement work: a journey towards sustainable evidence-based practice. AB - OBJECTIVE: The aim of this qualitative descriptive study was to describe occupational therapists' experiences of participating in long-term improvement work based on the Occupational Therapy Intervention Process Model. METHOD: Data were collected by focus groups interviewed on two occasions (2006 and 2011). Nineteen occupational therapists participated on each occasion. The data obtained were analysed using a qualitative content analysis. FINDINGS: The long-term improvement work was experienced as a journey towards sustainable and evidence based occupational therapy practice. The journey, guided by the Occupational Therapy Intervention Process Model, led to increased client-centred and occupation-focused practice. The long journey of change involved three intertwined themes. The first theme describes how the occupational therapists transformed their thoughts and actions on an individual and group level. The second theme describes how they dealt with conflicting feelings and faced the duality of change. The third theme describes a shared professional culture, including confidence, clarity, and inter-professional community. CONCLUSION: The study shows how the collective use of an occupational therapy model of practice can lead to an integration of evidence-based knowledge that has long-lasting achievements in practice. PMID- 24467456 TI - Pain, pain catastrophizing, and past legal charges related to drugs. AB - Using a self-report survey methodology in a cross-sectional consecutive primary care sample (N = 238), we examined pain at 3 time points (today, past month, past year), pain catastrophizing using the Pain Catastrophizing Scale, and history of legal charges for 5 drug-related crimes as defined by the Federal Bureau of Investigation. Among the subsample of 185 participants with histories of being prescribed analgesics, 33 reported a history of legal charges for drug-related crimes. Analyses of variance among this subsample confirmed statistically significant relationships between the current level of pain and history of legal charges for drug-related crimes, as well as level of pain catastrophizing and history of legal charges for drug-related crimes. PMID- 24467455 TI - Tenofovir is superior to entecavir for achieving complete viral suppression in HBeAg-positive chronic hepatitis B patients with high HBV DNA. AB - BACKGROUND: Entecavir (ETV) and tenofovir disoproxil fumarate (TDF) are the two first-line anti-viral therapies for chronic hepatitis B (CHB); however, there are limited studies directly comparing their effectiveness. AIM: To compare the effectiveness of ETV and TDF in nucleos(t)ide-naive CHB patients with high hepatitis B virus (HBV) DNA levels, defined as serum HBV DNA greater than 6 log10 IU/mL. METHODS: We performed a retrospective multicentre cohort study of adult CHB patients who were seen between 2009 and 2012 at four Northern California community gastroenterology and hepatology clinics. RESULTS: We identified 59 consecutive patients treated with TDF and 216 patients treated with ETV. Pre treatment characteristics were similar between the two groups. Among HBeAg negative patients, there was no significant difference in viral suppression rates between ETV and TDF (P = 0.72). In contrast, among HBeAg-positive patients, those treated with TDF achieved viral suppression significantly more rapidly than those treated with ETV (P < 0.0001); the Kaplan-Meier estimated probability of complete suppression was 18% vs. 11% at 6 months, 51% vs. 28% at 12 months and 72% vs. 39% at 18 months respectively. Multivariate Cox proportional hazards analysis indicated that treatment with TDF compared to ETV was a significant predictor of viral suppression, but only for HBeAg-positive patients (HR = 2.59; 95% CI 1.58 4.22; P < 0.001). CONCLUSION: Tenofovir is significantly more effective than entecavir for achieving complete viral suppression in HBeAg-positive, nucleos(t)ide-naive chronic hepatitis B patients with HBV DNA greater than 6 log10 IU/mL. PMID- 24467454 TI - Modelling cognitive affective biases in major depressive disorder using rodents. AB - Major depressive disorder (MDD) affects more than 10% of the population, although our understanding of the underlying aetiology of the disease and how antidepressant drugs act to remediate symptoms is limited. Major obstacles include the lack of availability of good animal models that replicate aspects of the phenotype and tests to assay depression-like behaviour in non-human species. To date, research in rodents has been dominated by two types of assays designed to test for depression-like behaviour: behavioural despair tests, such as the forced swim test, and measures of anhedonia, such as the sucrose preference test. These tests have shown relatively good predictive validity in terms of antidepressant efficacy, but have limited translational validity. Recent developments in clinical research have revealed that cognitive affective biases (CABs) are a key feature of MDD. Through the development of neuropsychological tests to provide objective measures of CAB in humans, we have the opportunity to use 'reverse translation' to develop and evaluate whether similar methods are suitable for research into MDD using animals. The first example of this approach was reported in 2004 where rodents in a putative negative affective state were shown to exhibit pessimistic choices in a judgement bias task. Subsequent work in both judgement bias tests and a novel affective bias task suggest that these types of assay may provide translational methods for studying MDD using animals. This review considers recent work in this area and the pharmacological and translational validity of these new animal models of CABs. PMID- 24467457 TI - The first histopathological evidence of trimetazidine for the prevention of contrast-induced nephropathy. AB - AIM: We aimed to investigate the prophylactic effects of trimetazidine (TMZ) against contrast-induced nephropathy (CIN) in rat kidneys. METHODS AND RESULTS: 28 Wistar rats were divided into 4 groups of 7 rats each (control (C), contrast media (CM) TMZ, trimetazidin+contrast media groups (TMZ + CM). The administration of TMZ solution was done on d2, d3 and d4. Fifth day, contrast media was administered at a single dose. On d6 scarification was performed. The oxidant/antioxidant parameters were measured and histopathological scores were performed in kidney tissues. Most of the histopathological scores were significantly higher in the CM group as compared to other groups. Moreover, the scores of the TMZ + CM and C groups were not statistically different. CM group, had significantly higher levels of MDA compared to the C and CM + TMZ groups (562.82 +/- 38.15 vs. 419.15 +/- 49.01 and 507.34 +/- 14.16 01 nmol/mg protein respectively) (p<0.001). CM group had significantly lower levels of SOD as compared to C, CM + TMZ and TMZ groups (p<0.05). CONCLUSION: To the best of our knowledge, this study for the first time, histopathologically demonstrated the effectiveness of TMZ for the prevention of CIN. PMID- 24467459 TI - Evaluation of the jelly processing potential of raspberries adapted in Brazil. AB - Generally raspberry products as jams, jellies, and preserves are made with red raspberry, however, yellow raspberry and especially black raspberry are also fruits adapted in Brazil, presenting even better productivity and quality. Thus, the aim of this study was to evaluate the processing potential of other varieties of raspberry, but the red, in the preparation of jellies through mixture design and response surface methodology (RSM). These techniques were used to optimize the following 3 variables: yellow (Golden Bliss cultivar, Rubus idaeus), black (Rubus niveus), and red raspberries (Batum cultivar, Rubus idaeus) to formulate a mixed raspberry fruit jelly through sensory evaluations. It was found that jelly formulated with a mix of colored raspberries grown in subtropical regions is a viable and alternative way to use yellow and black raspberries. The mixed raspberry jelly must have 0% to 30% yellow raspberries, 25% to 50% black raspberries, and 30% to 75% red raspberries. Within this region, the optimum formulation has ideal characteristics that are often not observed in formulations with 100% black or yellow raspberries. PRACTICAL APPLICATION: The black and yellow raspberries are little explored in fresh consumption and in the development of products such as jams and jellies. From these work, using mixture design and response surface methodology, has been verified that the production of a mixed raspberry jelly seems feasible and is an interesting alternative to use the yellow and black raspberries. The results serve as a guide to the production of jams and jellies from these types of raspberries. PMID- 24467460 TI - Applications of surface-enhanced Raman scattering in advanced bio-medical technologies and diagnostics. AB - In this review of the literature on surface-enhanced Raman scattering (SERS), we describe recent developments of this technique in the medical field. SERS has developed rapidly in the last few years as a result of the fascinating advancements in instrumentation and the ability to interpret complex Raman data using high-processional, computer-aided programs. This technique, has many advantages over ordinary spectroscopic analytical techniques - such as extremely high sensitivity, molecular selectivity, intense signal and great precision - that can be leveraged to address complex medical diagnostics problems. This review focuses on the SERS-active substrate, as well as major advances in cancer and bacteria detection and imaging. Finally, we present a perspective on anticipated future advancements in SERS techniques to address some of the most critical challenges in the areas of diagnostics, detection, and sensing. PMID- 24467461 TI - Role of quantum mechanical tunneling on the gamma-effect of silicon on carbenes in 3-trimethylsilylcyclobutylidene. AB - Quantum mechanical tunneling (QMT) is increasingly being realized as an important phenomenon that can enhance the rate of reactions even at room temperature. Recently, the ability of a trimethylsilane (TMS) group to activate 1,3-H shift to a carbene from a gamma-position has been demonstrated. Direct dynamical calculations (using canonical varitational transition state theory) inclusive of small curvature tunneling (CVT-SCT) show that QMT plays a decisive role in such 1,3-hydrogen migration in both the presence and absence of TMS. The presence of a TMS group reduces the activation energy of 1,3-H shift reaction via 1,3 equatorial interaction of the TMS group with the carbene. Tunneling across the smaller barrier enhances the overall forward rate of the reaction. The Arrhenius plot for the reaction shows substantial curvature in comparison to the CVT mechanism at room temperature. Arrhenius plots for the kinetic isotope effects (KIEs) for the gamma-deuterated and per deuterated 3 trimethylsilylcyclobutylidene also show strong deviations from the classical over the barrier mechanism. The magnitude of the KIE is suggestive of QMT from the vibrational excited states of the carbenes. PMID- 24467462 TI - Fracture and failure of nanoparticle monolayers and multilayers. AB - We present an experimental investigation of fracture in self-assembled gold nanoparticle mono- and multilayers attached to elastomer substrates and subjected to tensile stress. Imaging the fracture patterns down to the scale of single particles provides detailed information about the crack width distribution and allows us to compare the scaling of the average crack spacing as a function of strain with predictions by shear-lag models. With increasing particle size, the fracture strength is found to increase while it decreases as the film thickness is built up layer by layer, indicating stress inhomogeneity in the thickness dimension. PMID- 24467463 TI - Antibiotic intravenous-to-oral switch guidelines: barriers to adherence and possible solutions. AB - OBJECTIVES: To identify reasons for poor adherence to antibiotic intravenous-to oral switch guidelines and to explore the possible solutions. To rate the importance of the barriers and solutions identified, as perceived by a multidisciplinary expert panel. METHODS: Three-round Delphi study in an expert panel comprising doctors, nurses and pharmacists, with concurrent semi-structured interviews. KEY FINDINGS: The three rounds of the Delphi were completed by 13 out of the 30 healthcare professionals invited to participate. No nurses were included in the final round. Consensus was achieved for 28 out of 35 statements, with the most important barrier being that of inappropriate antibiotic review at the weekend, and the most important solution being to raise guideline awareness. The findings from the seven interviews (three doctors, two pharmacists and two nurses) complemented those from the Delphi study, although they provided more specific suggestions on how to improve the adherence to guidelines. CONCLUSION: This study, using a combination of quantitative and qualitative methods, has identified several barriers to explore further and offered many practical solutions to improve practice. The importance of a multidisciplinary approach to address guideline non-adherence was emphasised. Clinical guidelines must be well publicised and well written to prevent a feeling of guideline saturation in the healthcare populous. Novel approaches may have to be investigated in order to further encourage adherence with antibiotic intravenous-to-oral switch guidelines. PMID- 24467465 TI - How academic nursing is being enriched by 'The Thriller Elite'. PMID- 24467464 TI - Endocytoscopic observation of various esophageal lesions at *600: can nuclear abnormality be recognized? AB - Endocytoscopy (ECS) is a novel endoscopic technique that allows detailed diagnostic examination of the gastrointestinal tract at the cellular level. We previously reported that use of ECS at *380 magnification (GIF-Y0002) allowed a pathologist to diagnose esophageal squamous cell carcinoma (ESCC) with high sensitivity (94.9%) but considerably low specificity (46.7%) because this low magnification did not reveal information about nuclear abnormality. In the present study, we used the same magnifying endoscope to observe various esophageal lesions, but employed digital 1.6-fold magnification to achieve an effective magnification of *600, and evaluated whether this improved the diagnostic accuracy in distinguishing neoplastic from non-neoplastic lesions.We examined the morphology of surface cells using vital staining with toluidine blue and compared the histological features of 40 cases, including 19 case of ESCC and 21 non-neoplastic esophageal lesions (18 cases of esophagitis, 1 case of glycogenic acanthosis, 1 case of leiomyoma, and 1 case of normal squamous epithelium). One endoscopist classified the lesions using the type classification, and we consulted one pathologist for judgment of the ECS images as 'neoplastic', 'borderline', or 'non-neoplastic'. At *600 magnification, the pathologist confirmed that nuclear abnormality became evident, in addition to the information about nuclear density provided by observation at *380. The overall sensitivity and specificity with which the endoscopist was able to predict neoplastic lesions using the type classification was 100% (19/19) and 90.5% (19/21), respectively, in comparison with values of 94.7% (18/19 cases) and 76.2% (16/21), respectively, for the pathologist using a magnification of *600. The pathologist diagnosed two non-neoplastic lesions and one case of ESCC showing an apparent increase of nuclear density with weak nuclear abnormality as 'borderline'. Among the 21 non-cancerous lesions, two cases of esophagitis that were misdiagnosed by the endoscopist were also misinterpreted as 'neoplastic' by the pathologist. We have shown, by consultation with a pathologist, that an ECS magnification of *600 (on a 19-inch monitor) is adequate for recognition of nuclear abnormality. We consider that it is feasible to diagnose esophageal neoplasms on the basis of ECS images, and that biopsy histology can be omitted if a combination of increased nuclear density and nuclear abnormality is observed. PMID- 24467466 TI - Personal inhalation exposure to polycyclic aromatic hydrocarbons in urban and rural residents in a typical northern city in China. AB - Personal inhalation exposure samples were collected and analyzed for polycyclic aromatic hydrocarbons (PAHs) for 126 selected volunteers during heating and non heating seasons in a typical northern Chinese city, Taiyuan. Measured personal PAH exposure levels for the urban residents in the heating and non-heating seasons were 690 (540-1051) and 404 (266-544) ng/m(3) , respectively, while, for the rural residents, they were 770 (504-1071) and 312 (201-412) ng/m(3) , respectively. Thus, rural residents are exposed to lower PAH contamination in comparison with the urban residents in the non-heating seasons. In the heating season, personal PAH inhalation exposure levels were comparable between the urban and rural residents, in part owing to the large rate of residential solid fuel consumption in the rural area for household cooking and heating. The estimated incremental lifetime cancer risks (ILCR) due to PAH exposure in Taiyuan were 3.36 * 10(-5) and 2.39 * 10(-5) for the rural and urban residents, respectively, significantly higher than the literature-reported national average level, suggesting an urgent need of PAH pollution control to protect human health. PMID- 24467467 TI - Effect of the method of preparation for consumption on calcium retention, calcium:phosphorus ratio, nutrient density and recommended daily allowance in fourteen vegetables. AB - The aim of this work was to evaluate calcium retention in 14 species of vegetable (from four usable groups). The material investigated consisted of raw and boiled fresh vegetables and two types of frozen product prepared for consumption after 12-month storage: one traditionally produced; the other obtained using the modified method (convenience food). The highest calcium content was found in leafy vegetables, followed (in descending order) by leguminous, root and brassica vegetables. The proportion by weight of Ca to P was highest in leafy vegetables and decreased with calcium retention despite the fact that levels of phosphorus were highest in leguminous and lowest in leafy vegetables. The nutrient density (ND%) of calcium for adults exceeded 100 for each individual vegetable species. The recommended daily allowance (RDA) percentage value varied between 23.04 (kale) and 1.46 (white cauliflower). Of the three types of product, ND and RDA values were generally greater in the frozen convenience products. PMID- 24467468 TI - Women with bipolar disorder: a lifetime challenge from diagnosis to treatment. PMID- 24467469 TI - Effects of the menstrual cycle on bipolar disorder. AB - OBJECTIVES: Several lines of research suggest that reproductive events may affect the course of bipolar disorder (BD) in some women. With respect to the menstrual cycle, the focus has been on dysphoric symptoms [e.g., premenstrual dysphoric disorder (PMDD)], and the exacerbation of depression, in the premenstrual phase. This article reviews the literature on the potential effects of the menstrual cycle on BD. METHODS: A systematic search for published case reports and research studies available through March, 2013 was conducted. Several combinations of search terms were entered into PubMed and PsycInfo. RESULTS: Overall, 25 case reports, ten retrospective studies, and 11 prospective studies were identified. The majority (64%) of case reports involved hypomanic or manic episodes in the premenstrual phase. Retrospective results suggest that 25-77% and 15-27% of women with BD meet the criteria for premenstrual syndrome (PMS) and PMDD, respectively. Menstrual cycle-related mood changes were reported by 64-68% of women with BD in retrospective studies, and were displayed by 44-65% of women in prospective studies. CONCLUSIONS: Although research has focused on the premenstrual phase to the neglect of the periovulatory phase, it appears that a subgroup of women with BD, possibly those with hormonal sensitivity, experience menstrual cycle effects on depressive, hypomanic, and manic episodes. These phase-episode effects appear to be heterogeneous and may have implications for treatment. Whether they might best be described using course specifiers, similar to postpartum onset and rapid cycling, or as diagnostic entities, like PMDD, requires further study. PMID- 24467470 TI - Sex differences in rates of obesity in bipolar disorder: postulated mechanisms. AB - OBJECTIVE: The increased standardized mortality ratio (SMR) from cardiovascular disease (CVD) in women with bipolar disorder (BD), relative to men with BD and individuals of both sexes in the general population, provides the impetus to identify factors that contribute to the differential association of obesity with BD in women. METHODS: We conducted a selective PubMed search of English-language articles published from September 1990 to June 2012. The key search terms were bipolar disorder and metabolic syndrome cross-referenced with gender, sex, obesity, diabetes mellitus, hypertension, and dyslipidemia. The search was supplemented with a manual review of relevant article reference lists. Articles selected for review were based on author consensus, the use of a standardized experimental procedure, validated assessment measures, and overall manuscript quality. RESULTS: It is amply documented that adults with BD are affected by the metabolic syndrome at a rate higher than the general population. Women with BD, when compared to men with BD and individuals of both sexes in the general population, have higher rates of abdominal obesity. The course and clinical presentation of BD manifest differently in men and women, wherein women exhibit a higher frequency of depression predominant illness, a later onset of BD, more seasonal variations in mood disturbance, and increased susceptibility to relapse. Phenomenological factors can be expanded to include differences in patterns of comorbidity between the sexes among patients with BD. Other factors that contribute to the increased risk for abdominal obesity in female individuals with BD include reproductive life events, anamnestic (e.g., sexual and/or physical abuse), lifestyle, and iatrogenic. CONCLUSIONS: A confluence of factors broadly categorized as broad- and sex-based subserve the increased rate of obesity in women with BD. It remains a testable hypothesis that the increased abdominal obesity in women with BD mediates the increased SMR from CVD. A clinical recommendation that emerges from this review is amplified attention to the appearance, or history, of factors that conspire to increase obesity in female patients with BD. PMID- 24467471 TI - Postpartum mania in a man with bipolar disorder: case report and a review of the role of sleep loss. AB - BACKGROUND: In contrast to postpartum mood episodes in women with bipolar disorder, little is known about the risk of recurrence in men with bipolar disorder who have just become fathers. CASE REPORT: We present the case of a man with bipolar disorder who had a manic episode immediately after becoming a father. His spouse had a normal pregnancy, and delivery started during daytime and lasted until the early morning hours. The patient subsequently developed a manic episode, which had a major impact on the family. CONCLUSIONS: There is a well-known relationship between sleep loss and the occurrence of a manic episode. The study of psychopathology in the postpartum period in relation to sleep disturbance refers mainly to women. Disturbance of sleep patterns in the perinatal and postpartum period may also negatively impact the course of bipolar disorder in the father. In cases of pregnancy of a male bipolar disorder patient's spouse, preventive strategies for the postpartum period should be planned in advance. PMID- 24467472 TI - Abundance of four sulfur mustard-DNA adducts ex vivo and in vivo revealed by simultaneous quantification in stable isotope dilution-ultrahigh performance liquid chromatography-tandem mass spectrometry. AB - Sulfur mustard (SM) is a highly reactive alkylating vesicant and causes blisters upon contact with skin, eyes, and respiratory organs. It covalently links with DNAs by forming four mono- or cross-link adducts. In this article, the reference standards of SM-DNA adducts and deuterated analogues were first synthesized with simplified procedures containing only one or two steps and using less toxic chemical 2-(2-chloroethylthio)ethanol or nontoxic chemical thiodiglycol as starting materials. A sensitive and high-throughput simultaneous quantification method of N(7)-[2-[(2-hydroxyethyl)thio]-ethyl]guanine (N(7)-HETEG), O(6)-[2-[(2 hydroxyethyl)thio]-ethyl]guanine (O(6)-HETEG), N(3)-[2-[(2-hydroxyethyl)thio] ethyl]adenine (N(3)-HETEA), and bis[2-(guanin-7-yl)ethyl]sulfide (Bis-G) in the Sprague-Dawley rat derma samples was developed by stable isotope dilution ultrahigh performance liquid chromatography-tandem mass spectrometry (ID-UPLC MS/MS) with the aim of revealing the real metabolic behaviors of four adducts. The method was validated, the limit of detection (S/N ratio greater than 10) was 0.01, 0.002, 0.04, and 0.11 fmol on column for N(7)-HETEG, O(6)-HETEG, Bis-G, and N(3)-HETEA, respectively, and the lower limit of quantification (S/N ratio greater than 20) was 0.04, 0.01, 0.12, and 0.33 fmol on column for N(7)-HETEG, O(6)-HETEG, Bis-G, and N(3)-HETEA, respectively. The accuracy of this method was determined to be 76% to 129% (n = 3), and both the interday (n = 6) and intraday (n = 7) precisions were less than 10%. The method was further applied for the quantifications of four adducts in the derma of adult male Sprague-Dawley rats exposed to SM ex vivo and in vivo, and all adducts had time- and dose-effect relationships. To the best of our knowledge, this is the first time that the real presented status of four DNA adducts was simultaneously revealed by the MS-based method, in which Bis-G showed much higher abundance than the result previously reported and N(3)-HETEA showed much less. It should be noted that since the interstrand cross-linked adduct is believed to stall DNA replication and finally induce a double-strand break, the higher abundance of Bis-G is a great indication of a more serious DNA lesion by SM alkylation. PMID- 24467473 TI - A longitudinal study of nutritional and inflammatory status in patients on dialysis. AB - OBJECTIVE: Several anthropometric, laboratory and bioelectrical impedance parameters of nutritional status and inflammation are often used as prognostic indices in patients on dialysis. Their longitudinal assessment is necessary for the estimation of their true prognostic value. We aim to estimate this prognostic value in better-nourished dialysis patients, which are commonly under-represented in pertinent studies. METHODS: The design is a prospective case series. Pertinent parameters were studied three times during a 20-month period in 47 haemodialysis (HD) and 27 peritoneal dialysis (PD) patients with a low malnutrition inflammation score (MIS). Mortality rate was assessed three years after the initial evaluation. Correlation coefficients were calculated between mortality rate, the studied parameters and their alteration. RESULTS: Serum albumin of less than 40 g/l was strongly correlated with mortality risk. The alteration of studied parameters during a short period of time does not allow for long-term prediction of mortality risk. CONCLUSION: Serum albumin had the strongest predictive value of all the pertinent parameters in the study. Thus, better conjugate clinical and laboratory measurements should be developed for patients on PD, as well as for those with a relatively low MIS. PMID- 24467474 TI - Near-infrared upconversion controls photocaged cell adhesion. AB - Dynamic control of cell-surface interactions with near-infrared (NIR) light is particularly attractive for regeneration medicine and cell-based therapy. Herein we successfully achieve NIR-controlled cell adhesion with upconversion nanoparticles (UCNPs) based programmable substrate. The UCNPs can harvest the biocompatible NIR light and convert it into local UV light, which results in cleavage of the photocaged linkers and on-demand release of adhesive cells. The strategy also enables the feasibility of deep-tissue photocontrol of cell adhesion on substrate. Our work may open a new avenue for design of UCNP-based cell scaffolds to dynamically manipulate cell-matrix and cell-cell interactions. PMID- 24467475 TI - Local control over nucleation of epitaxial thin films by seed layers of inorganic nanosheets. AB - Nanosheets of Ti0.87O2 and Ca2Nb3O10 were synthesized and transferred onto Si substrates by Langmuir-Blodgett deposition. Using pulsed laser deposition, SrRuO3 films were formed on top of these samples. The underlying nanosheets determined both the morphology and crystallographic orientation of the films. SrRuO3 grew preferentially in the [110]pc direction on Ti0.87O2 nanosheets, while growth proceeded in the [001]pc direction on Ca2Nb3O10 nanosheets (pc refers to the pseudocubic unit cell of SrRuO3). Besides macroscopic control over the out-of plane crystal direction, single crystal orientations were measured by electron backscatter diffraction on the level of individual nanosheets, indicating that epitaxial growth was achieved on the nanosheets as imposed by their well-defined crystal lattices. The nanosheets also had a clear effect on the magnetic properties of the films, which showed anisotropic behavior only when a seed layer was used. A monolayer consisting of a mixture of both types of nanosheets was made to locally control the nucleation of SrRuO3. In this context, SrRuO3 was used as model material, as it was used to illustrate that nanosheets can be a unique tool to control the orientation of films on a (sub-)micrometer length scale. This concept may pave the way to the deposition of various other functional materials and the fabrication of devices where the properties are controlled locally by the different crystallographic orientations. PMID- 24467476 TI - Microbial consumption of zero-valence sulfur in marine benthic habitats. AB - Zero-valence sulfur (S degrees ) is a central intermediate in the marine sulfur cycle and forms conspicuous accumulations at sediment surfaces, hydrothermal vents and in oxygen minimum zones. Diverse microorganisms can utilize S degrees , but those consuming S degrees in the environment are largely unknown. We identified possible key players in S degrees turnover on native or introduced S degrees in benthic coastal and deep-sea habitats using the 16S ribosomal RNA approach, (in situ) growth experiments and activity measurements. In all habitats, the epsilonproteobacterial Sulfurimonas/Sulfurovum group accounted for a substantial fraction of the microbial community. Deltaproteobacterial Desulfobulbaceae and Desulfuromonadales were also frequently detected, indicating S degrees disproportionation and S degrees respiration under anoxic conditions. Sulfate production from S degrees particles colonized in situ with Sulfurimonas/Sulfurovum suggested that this group oxidized S degrees . We also show that the type strain Sulfurimonas denitrificans is able to access cyclooctasulfur (S8), a metabolic feature not yet demonstrated for sulfur oxidizers. The ability to oxidize S degrees , in particular S8 , likely facilitates niche partitioning among sulfur oxidizers in habitats with intense microbial sulfur cycling such as sulfidic sediment surfaces. Our results underscore the previously overlooked but central role of Sulfurimonas/Sulfurovum group for conversion of free S degrees at the seafloor surface. PMID- 24467477 TI - Novel GMP-compatible protocol employing an allogeneic B cell bank for clonal expansion of allospecific natural regulatory T cells. AB - The adoptive transfer of natural regulatory T cells (nTreg) is a new option to reshape undesired immune reactivity in autoimmunity and transplantation toward "tolerance." The first clinical trials using adoptive transfer of polyclonal nTreg demonstrated safety and hints of efficacy. However, the low frequencies of antigen-specific cells among the pool of polyclonal nTreg and their broad antigen nonspecific suppression are limitations of this approach regarding efficacy and safety. Recently, the isolation and expansion of (allo)antigen-specific nTreg have successfully been achieved by using Treg-specific activation markers but the yield is relatively low. Here, we describe a novel good manufacturing practice (GMP)-compatible expansion protocol of alloantigen-specific nTreg based on the stimulation of nTreg by allogeneic activated B cells. Their functionality and specificity are superior compared to polyclonal nTreg both in vitro and in vivo. Employing an allogeneic B cell bank, designed to cover the majority of HLA types, allows fast GMP-compliant manufacturing for donor-specific nTreg for clinical application in organ and stem cell transplantation. TCR repertoire analyses by next generation sequencing revealed impressive expansion by several log-steps of even very low-abundance alloantigen-specific nTreg clones. This novel method offers a simple approach for expanding antigen-specific nTreg and is characterized by high replicability and easy transferability to full GMP standards. PMID- 24467478 TI - Marijuana and workplace safety: an examination of urine drug tests. AB - Although the decriminalization of recreational marijuana and medical marijuana laws provide a compassionate answer for treatment-related issues in patients' lives, they leave questions open as to the impact on other realms of life, such as employment and safety. This is a case-control study comparing the proportion of marijuana positive urine specimens for post-accident verses random samples. The marijuana concentration of each sample underwent creatinine normalization to account for in vivo dilution. Any sample that tested positive for one or more substances other than marijuana was eliminated from the study. The prevalence of marijuana violations, the odds ratio and 95% confidence interval of accident involvement and the population attributable risk were calculated. A two-by-two table was created with the remaining data and the data were used to calculate the odds ratio, resulting in a value of 0.814 with a 95% confidence interval between 0.625 and 1.060. The Fisher exact probability test generated a 2-tailed P of .139. The subsequent population attributable risk was found to be -1.83%. These findings fail to reject the null hypothesis, and this study failed to demonstrate a statistically significant difference between the numbers of laboratory positive marijuana urine drug tests for a group of random drug tests compared with a group of post-accident drug tests. PMID- 24467479 TI - Occupational therapists as contributors to health promotion. AB - OBJECTIVE: This study was undertaken to explore the views of occupational therapists concerning their competences in health promotion, and their perceptions of how they apply these competences in their daily work. The study also elicited their views on the contributions that occupational therapists could make to health promotion if given the opportunity. METHODS: Data were collected in five focus-group discussions with 24 occupational therapists. These discussions were tape recorded and transcribed verbatim; data were analysed using qualitative content analysis. RESULTS: The main findings are that the informants took an individualized salutogenic approach in their work and rarely engaged in health promotion on a systemic or societal level. They believed that their patients and collaborating partners, as well as public officials, remained unaware of their competences in health promotion. CONCLUSIONS: The findings of this study could enrich the discussion among occupational therapists on how they could make a more significant contribution to health promotion on a broader level. PMID- 24467480 TI - Rituximab, alkylating agents or combination therapy for gastric mucosa-associated lymphoid tissue lymphoma: a monocentric non-randomised observational study. AB - BACKGROUND: There is no consensus on the standard treatment of gastric mucosa associated lymphoid tissue (MALT) lymphoma for Helicobacter pylori-negative patients and for patients with persistent disease despite H. pylori eradication. AIM: To evaluate the comparative efficacy and safety of alkylating agents and rituximab alone or in combination. METHODS: In this monocentric retrospective study, which included 106 patients who had not been previously treated with anti cancer agents, we evaluated the efficacy and safety of oral alkylating agents monotherapy (n = 48), rituximab monotherapy (n = 28) and the therapy combining both drugs (n = 30). Evaluations were performed at weeks 6 (W6), 25 (W25), and 52 (W52) and after 2 years (W104). RESULTS: After a median follow-up period of 4.9 years (range 0.4-17.2 years), complete remission and overall response were significantly higher in patients in the combination therapy group at W104 (92% and 100% respectively) compared with patients treated with alkylating agents alone (66% and 68%) and rituximab alone (64% and 73%). The 5-year progression free survival probabilities were 68%, 70% and 89% in patients treated with alkylating agents alone, rituximab alone and combination therapy respectively. Haematological adverse events were reported in 32 (30%) patients (mostly grade 1) and were more frequent in the two groups receiving alkylating agents (P = 0.05 and P < 0.001). No toxicity-related death was reported. CONCLUSIONS: The use of anti-cancer systemic therapy is safe and efficient in gastric MALT lymphoma. In this retrospective study, the combination of rituximab plus chlorambucil seems more efficient than rituximab or alkylating agents alone. Rituximab has a better safety profile than regimens containing alkylating agents. PMID- 24467482 TI - Different efficiency of ozonated water washing to inactivate Salmonella enterica typhimurium on green onions, grape tomatoes, and green leaf lettuces. AB - Ozonated water washing is one of the emerging techniques to inactivate foodborne pathogens on produce, and limited information is available to optimize processing parameters (treatment time, temperature, and pH) to improve ozone efficacy on Salmonella inactivation for different produce. The efficacy of ozonated water washing for inactivation of Salmonella enterica Typhimurium on green onions, grape tomatoes and green leaf lettuces were studied in our research. Surface inoculated fresh produce were washed by ozonated water for 1, 5, or 10 min at room temperature and pH 5.60 +/- 0.03. Then efficacy of ozonated water washing at mild heated (50 degrees C) and refrigerated (4 degrees C) temperature for 5 min with pH 5.60 +/- 0.03 was investigated. Salmonella inactivation efficacy under pH 5.60 +/- 0.03 and 2.64 +/- 0.02 with 5 min washing at room temperature were also compared. Our results showed that Salmonella inactivation by ozonated water was time-dependent for 3 fresh produce. Mild heated temperature (50 degrees C) and pH 2.64 +/- 0.02 improved efficacy of ozonated water to inactivate Salmonella on tomatoes and lettuces, but not on green onions. It is suggested that different surface structures of fresh produce significantly impact the antimicrobial efficacy of ozonated water washing operated under various parameters (time, temperature, and pH). PRACTICAL APPLICATION: Washing is the essential step for green onions and lettuces in the packinghouse and grape tomatoes in the restaurants and grocery stores having salad bars. Ozonated water can be used as disinfectant to reduce microbial contamination (FDA). The effectiveness of this disinfectant depends on the type of product and treatment conditions, such as water temperature, acidity, contact time. Our study showed that Salmonella inactivation by ozonated water washing was time-dependent. Mild heat and low pH improved inactivation efficacy on tomatoes and lettuces, but not on green onions. Processors should consider adjustments that are most appropriate for their produce. PMID- 24467484 TI - Temperature-dependent Hall and field-effect mobility in strongly coupled all inorganic nanocrystal arrays. AB - We report on the temperature-dependent Hall effect characteristics of nanocrystal (NC) arrays prepared from colloidal InAs NCs capped with metal chalcogenide complex (MCC) ligands (In2Se4(2-) and Cu7S4(-)). Our study demonstrates that Hall effect measurements are a powerful way of exploring the fundamental properties of NC solids. We found that solution-cast 5.3 nm InAs NC films capped with copper sulfide MCC ligands exhibited high Hall mobility values over 16 cm(2)/(V s). We also showed that the nature of MCC ligands can control doping in NC solids. The comparative study of the temperature-dependent Hall and field-effect mobility values provides valuable insights concerning the charge transport mechanism and points to the transition from a weak to a strong coupling regime in all-inorganic InAs NC solids. PMID- 24467485 TI - Delirious behavior or mild reduction of consciousness mimicking influenza associated encephalopathy. AB - BACKGROUND: During the A/H1N1 pandemic, patients suffered from impaired consciousness. They were suspected of or diagnosed as having influenza-associated encephalopathy (IAE) in an emergency situation. Their symptoms resembled those of a recently described 'unique clinical group', which were reported to have a favorable prognosis. METHODS: We retrospectively examined 46 patients and divided them into two groups. Group IC contained the 26 patients with persisting impaired consciousness. The remainder of the patients were categorized into group R, consisting of patients with only neurological symptoms without impaired consciousness. RESULTS: Male predominance (22 male/four female) was noted in group IC. Patient age ranged from 5 to 12 years old (mean +/- SD, 7.7 +/- 2.3 years). Impaired consciousness such as delirious behavior or mild reduction of consciousness lasted continuously or intermittently from 5 min to 2.5 days. On electroencephalogram, semi-rhythmic high-voltage slow waves in the parieto occipital regions and diffuse high-voltage slow waves were observed in eight and in two patients, respectively. In group R, there was no gender predominance. Patient age ranged from 1 to 9 years old (mean +/- SD, 4.1 +/- 2.5 years). All group R patients were clinically diagnosed with febrile seizure. CONCLUSIONS: Some of the characteristics in group IC resembled those of the unique clinical group, and are part of a continuous clinical spectrum. Some patients may have favorable outcome without specific treatment. PMID- 24467481 TI - Optimizing nanomedicine pharmacokinetics using physiologically based pharmacokinetics modelling. AB - The delivery of therapeutic agents is characterized by numerous challenges including poor absorption, low penetration in target tissues and non-specific dissemination in organs, leading to toxicity or poor drug exposure. Several nanomedicine strategies have emerged as an advanced approach to enhance drug delivery and improve the treatment of several diseases. Numerous processes mediate the pharmacokinetics of nanoformulations, with the absorption, distribution, metabolism and elimination (ADME) being poorly understood and often differing substantially from traditional formulations. Understanding how nanoformulation composition and physicochemical properties influence drug distribution in the human body is of central importance when developing future treatment strategies. A helpful pharmacological tool to simulate the distribution of nanoformulations is represented by physiologically based pharmacokinetics (PBPK) modelling, which integrates system data describing a population of interest with drug/nanoparticle in vitro data through a mathematical description of ADME. The application of PBPK models for nanomedicine is in its infancy and characterized by several challenges. The integration of property-distribution relationships in PBPK models may benefit nanomedicine research, giving opportunities for innovative development of nanotechnologies. PBPK modelling has the potential to improve our understanding of the mechanisms underpinning nanoformulation disposition and allow for more rapid and accurate determination of their kinetics. This review provides an overview of the current knowledge of nanomedicine distribution and the use of PBPK modelling in the characterization of nanoformulations with optimal pharmacokinetics. PMID- 24467486 TI - FOXO3A regulation by miRNA-29a Controls chondrogenic differentiation of mesenchymal stem cells and cartilage formation. AB - Skeletal development and cartilage formation require stringent regulation of gene expression for mesenchymal stem cells (MSCs) to progress through stages of differentiation. Since microRNAs (miRNAs) regulate biological processes, the objective of the present study was to identify novel miRNAs involved in the modulation of chondrogenesis. We performed miRNA profiling and identify miR-29a as being one of the most down-regulated miRNAs during the chondrogenesis. Using chromatin immunoprecipitation, we showed that SOX9 down-regulates its transcription. Moreover, the over-expression of miR-29a strongly inhibited the expression of chondrocyte-specific markers during in vitro chondrogenic differentiation of MSCs. We identified FOXO3A as a direct target of miR-29a and showed a down- and up-regulation of FOXO3a protein levels after transfection of, respectively, premiR- and antagomiR-29a oligonucleotides. Finally, we showed that using the siRNA or premiR approach, chondrogenic differentiation was inhibited to a similar extent. Together, we demonstrate that the down-regulation of miR-29a, concomitantly with FOXO3A up-regulation, is essential for the differentiation of MSCs into chondrocytes and in vivo cartilage/bone formation. The delivery of miRNAs that modulate MSC chondrogenesis may be applicable for cartilage regeneration and deserves further investigation. PMID- 24467487 TI - High-performance reverse osmosis CNT/polyamide nanocomposite membrane by controlled interfacial interactions. AB - Polyamide reverse osmosis (RO) membranes with carbon nanotubes (CNTs) are prepared by interfacial polymerization using trimesoyl chloride (TMC) solutions in n-hexane and aqueous solutions of m-phenylenediamine (MPD) containing functionalized CNTs. The functionalized CNTs are prepared by the reactions of pristine CNTs with acid mixture (sulfuric acid and nitric acid of 3:1 volume ratio) by varying amounts of acid, reaction temperature, and reaction time. CNTs prepared by an optimized reaction condition are found to be well-dispersed in the polyamide layer, which is confirmed from atomic force microscopy, scanning electron microscopy, and Raman spectroscopy studies. The polyamide RO membranes containing well-dispersed CNTs exhibit larger water flux values than polyamide membrane prepared without any CNTs, although the salt rejection values of these membranes are close. Furthermore, the durability and chemical resistance against NaCl solutions of the membranes containing CNTs are found to be improved compared with those of the membrane without CNTs. The high membrane performance (high water flux and salt rejection) and the improved stability of the polyamide membranes containing CNTs are ascribed to the hydrophobic nanochannels of CNTs and well-dispersed states in the polyamide layers formed through the interactions between CNTs and polyamide in the active layers. PMID- 24467489 TI - Characterization of the glass transition of water predicted by molecular dynamics simulations using nonpolarizable intermolecular potentials. AB - Molecular dynamics simulations allow detailed study of the experimentally inaccessible liquid state of supercooled water below its homogeneous nucleation temperature and the characterization of the glass transition. Simple, nonpolarizable intermolecular potentials are commonly used in classical molecular dynamics simulations of water and aqueous systems due to their lower computational cost and their ability to reproduce a wide range of properties. Because the quality of these predictions varies between the potentials, the predicted glass transition of water is likely to be influenced by the choice of potential. We have thus conducted an extensive comparative investigation of various three-, four-, five-, and six-point water potentials in both the NPT and NVT ensembles. The T(g) predicted from NPT simulations is strongly correlated with the temperature of minimum density, whereas the maximum in the heat capacity plot corresponds to the minimum in the thermal expansion coefficient. In the NVT ensemble, these points are instead related to the maximum in the internal pressure and the minimum of its derivative, respectively. A detailed analysis of the hydrogen-bonding properties at the glass transition reveals that the extent of hydrogen-bonds lost upon the melting of the glassy state is related to the height of the heat capacity peak and varies between water potentials. PMID- 24467488 TI - Long-term follow-up of patients with chronic chagas disease and implantable cardioverter-defibrillator. AB - BACKGROUND/OBJECTIVES: Chronic Chagas heart disease (ChHD) is associated with ventricular tachyarrhythmias and an increased risk of sudden cardiac death. Little is known about the effectiveness of implantable cardioverter-defibrillator (ICD) therapy in this population. The objective of this study was to evaluate the efficacy of ICD in patients with ChHD and to identify predictors of mortality and appropriate ICD shocks. METHODS: The cohort study included 65 patients with ChHD and ICD for primary and secondary prevention of sudden death. The Cox model was applied to evaluate the predictors of mortality, and survival was assessed by Kaplan-Meier analysis. RESULTS: The median age was 56 +/- 11.9 years. The median follow-up was 40 +/- 26.8 months. Among the patients 23 (36.5%) had appropriate shocks. A total of 13 (20%) patients died (6.1% of annual mortality rate), and there was no sudden death. In univariate Cox model, functional class IV (hazard ratio [HR] = 1.99; 95% confidence interval [CI], 1.05-3.76; P = 0.034), primary prevention (HR = 0.29; 95% CI, 0.09-0.99; P = 0.048), lower education (HR = 2.51; 95% CI, 1.05-5.99; P = 0.038), and ejection fraction <30% (HR = 2.80; 95% CI, 1.09-7.18; P = 0.032) were predictors of worse prognosis (death). In the multivariate Cox model, an ejection fraction <30% and the low education remained predictors of poor prognosis. Predictors of appropriate shocks were not found. CONCLUSIONS: The ICD was effective for the prevention of sudden cardiac death in patients with chronic ChHD. An ejection fraction <30% and low education were predictors of poor prognosis. PMID- 24467490 TI - The role of clinical pharmacists as perceived by Egyptian physicians. AB - OBJECTIVES: Clinical pharmacists play an important role in ensuring the safe and rational use of medicines; however, physicians in developing countries may not always recognize the wide scope of services that a pharmacist can provide to improve patient safety and achieve clinical outcomes. The aim of this study was to investigate the perceptions and experience of physicians regarding the role of the pharmacists, the pharmacists' ability to perform clinical services, their acceptance of new pharmacist roles and the extent of collaboration that can occur between the two disciplines. METHODS: In this cross-sectional survey, 583 randomly selected physicians from the Grand Cairo area were invited to complete a survey composed of 25 questions designed to determine their perceptions of the role of clinical pharmacists. KEY FINDINGS: The response rate was 53%. Of the 312 physicians who completed the questionnaire, 50.5% reported direct contact with the pharmacists using the pharmacist as a source of information about the name of the medication, side effects, drug interactions or efficacy as the main role. About one-third believed that pharmacists could be a reliable source of clinical information, identify clinically related problems or advise the physicians about medication's cost effectiveness. More than 80% agreed that physicians and clinical pharmacists should have daily cooperation, and face-to-face contact was selected to be the best method of communication. CONCLUSION: Although a wide proportion of the physicians were aware of the clinical pharmacy principle, the service itself is not well promoted or applied. Greater effort needs to be directed towards increasing physicians' awareness and knowledge of the importance of clinical pharmacist and promote the benefit of the clinical pharmacy service. PMID- 24467491 TI - ZnO nanowire-based antireflective coatings with double-nanotextured surfaces. AB - High-aspect-ratio nanotextured surfaces with different morphologies (straight, core-shell type, and core-branch type nanowires) are prepared by a hydrothermal method of ZnO nanowires, followed by means of RF sputtering for core-shell type nanowires and e-beam evaporation for branch-type nanowires. The structural analysis showed that the MgO has highly preferred orientation along the ?111? and ?200? direction, respectively, and the crystalline continuity between the ZnO and MgO layers were also showed. Compared with ZnO nanowires, the MgO/ZnO samples drastically suppress broad and omnidirection reflection, which ascribes to the refractive-index modulation along the lateral direction of nanowires growth as well as the vertical direction. It was also shown that morphology could have a substantial influence on the antireflection property. These results suggest that double-nanotextured surface is one of the promising structures for antireflective surfaces without fine control in nanowire morphology. PMID- 24467492 TI - One and done? Optimal decisions from very few samples. AB - In many learning or inference tasks human behavior approximates that of a Bayesian ideal observer, suggesting that, at some level, cognition can be described as Bayesian inference. However, a number of findings have highlighted an intriguing mismatch between human behavior and standard assumptions about optimality: People often appear to make decisions based on just one or a few samples from the appropriate posterior probability distribution, rather than using the full distribution. Although sampling-based approximations are a common way to implement Bayesian inference, the very limited numbers of samples often used by humans seem insufficient to approximate the required probability distributions very accurately. Here, we consider this discrepancy in the broader framework of statistical decision theory, and ask: If people are making decisions based on samples--but as samples are costly--how many samples should people use to optimize their total expected or worst-case reward over a large number of decisions? We find that under reasonable assumptions about the time costs of sampling, making many quick but locally suboptimal decisions based on very few samples may be the globally optimal strategy over long periods. These results help to reconcile a large body of work showing sampling-based or probability matching behavior with the hypothesis that human cognition can be understood in Bayesian terms, and they suggest promising future directions for studies of resource-constrained cognition. PMID- 24467493 TI - Pharmacokinetics, in vitro and in vivo correlation, and efficacy of exenatide microspheres in diabetic rats. AB - Modeling and simulation are aimed at achieving information about the behaviors of the drugs without the actual measurements and determination. The purpose of this study was to characterize the in vivo behavior of exenatide microspheres using model-based methods. Exenatide is a glucagon-like peptide-1 agonist medication, belonging to the group of incretin mimetics, approved for the treatment of diabetes mellitus type 2. An oil-in-water solvent evaporation method was used to prepare the exenatide microspheres and their physicochemical features were investigated. After subcutaneous injection of exenatide microspheres to streptozotocin-induced diabetic rats, the exenatide concentrations increased and kept increasing and the blood glucose decreased in all diabetic rats. The in vivo release behavior of exenatide from microspheres was described by a transit compartment model. Based on the transit compartment model, the simulation method was proposed for the description of in vivo release. The in vitro and in vivo correlation (IVIVC) was established by the model-based simulation (R(2) = 0.903) and deconvolution (R(2) = 0.922) methods successfully. Using a transit compartment model to characterize the in vivo exenatide release from microspheres is an acceptable approach, and the IVIVC can be estimated reliably with the model based simulation method. PMID- 24467494 TI - Establishing prognosis in alcoholic hepatitis. PMID- 24467495 TI - [Prognostic factors associated with mortality in patients with severe alcoholic hepatitis]. AB - Severe alcoholic hepatitis is associated with high early mortality. This study aimed at identifying prognostic factors associated with in-hospital, medium- and long-term mortality of severe alcoholic hepatitis and to evaluate the different prognostic scoring systems on a cohort of patients in our hospital. To this end, we conducted a retrospective analysis of 66 episodes admitted between 2000 and 2008. Clinical and laboratory data on admission, at 7 days, 1 month, 6 months, and after one year were collected and analyzed, as were the details on the treatment and complications that occurred during hospitalization; the different prognostic indices used in the literature were calculated. Death event associated with an episode of severe alcoholic hepatitis occurs primarily during the first month, with an average mortality rate of 16.9. Infectious complications were associated with lower in-hospital survival. MELD score, urea and bilirubin values one week after admission were independently associated with both in-hospital survival (OR = 1.14, 1.012 and 1.1, respectively), and survival at 6 months (OR = 1, 15; 1.014 and 1.016, respectively). Only MELD score and urea values at 7 days were independent predictors of survival twelve months after the acute hepatitis episode. MELD score, urea, and bilirubin 7 days after admission were the only independent in-hospital survival and also long-term survival factors 6 months and one year after the episode. In our cohort, the MELD score was the best prognostic index to predict mortality associated with an episode of severe alcoholic hepatitis. PMID- 24467496 TI - Periodic gastroenterology and hepatology meetings with primary care. Reasons for consultation. AB - INTRODUCTION: care overload, aging of population, and increased chronic diseases lead to increased referrals from primary care, which may sometimes overload the health system. Thus, different interventions have been carried out attempting to improve these aspects. OBJECTIVES: to assess the most frequent causes of consultation of general physicians, both in joint consultations and clinical sessions held jointly with specialist consultant in primary care, in the urban and rural setting, and the influence on referrals to first consultations of gastroenterology. MATERIAL AND METHODS: a mainly training type of intervention was carried out, consisting of regular meetings in both urban and rural primary care center, to perform joint consultations and clinical sessions on patients and topics related to the specialty of gastroenterology. The intervention period (divided in two subperiods) was compared with a control period. RESULTS: most reasons for consultation were those corresponding to lower gastrointestinal tract, followed by liver disease and upper gastrointestinal tract. Significant differences were only found in distribution of diagnoses between the two centers in joint consultations. There was a relative (percent) decrease in referrals at the global level in both subperiods, only significant in the first (51.45 %), as well as in rural setting (45.24 %). CONCLUSION: common consultations motifs were similar in urban and rural settings, with some relevance of lower gastrointestinal tract disease. Most of them can be solved at primary care, with the help of consultant specialist. There is impact on referrals to the outpatient first consultations of gastroenterology, mainly in rural setting. PMID- 24467497 TI - Safety and effectiveness of gastric balloons associated with hypocaloric diet for the treatment of obesity. AB - INTRODUCTION: intragastric balloons provide early satiety and thereby induce short-term weight loss. The aim of this study was to evaluate safety and short and medium-term effectiveness of gastric balloons associated to hypocaloric diet in obesity. MATERIAL AND METHODS: from May 2004 to June 2011 91 obese patients, body mass index (BMI) 45.2 +/- 7.2 kg/m2 were prospectively followed after endoscopic implantation of a gastric balloon associated to restricted diet. Successful therapy was defined as percent loss of total weight (%LTW) > or = 5 % at six months after balloon placement and 6 and 12 months after their withdrawal. All analyses followed intention-to treat principles considering significant p values < 0.05. RESULTS: we placed 73 fluid-filled balloons (80.2 %) and 18 air filled ones (19.8 %). Compared to baseline values, at 6-month 73.7 % subjects succeeded, showing significant reductions in weight (13.3 +/- 8.8 kg), BMI (5 +/- 3.4 kg/m2) (p < 0.0001), with % LTW 11 +/- 7 %. Six and twelve months after retrieval 45.1 % and 28.6 % patients reached % LTW > or = 5 %. Short-term and medium-term effectiveness was negatively associated to obesity in first-grade relatives (p = 0.003 and p = 0.04). Higher weight loss 6 months after balloon placement independently predicted medium-term effectiveness (p = 0.0001). Mortality was absent but there were two spontaneous deflations of air-filled balloons and severe withdrawal difficulties in 8 patients, leading to surgery in one case. Retrieval complications associated to air-filled balloons (p = 0.0005). CONCLUSIONS: in obesity, effectiveness of gastric balloons associated to hypocaloric diet decreases over time.Complications occurred mainly in the retrieval endoscopic procedure and related to air-filled balloons. PMID- 24467498 TI - Celiac disease and alcohol use disorders: increased length of hospital stay, overexpenditures and attributable mortality. AB - BACKGROUND AND OBJECTIVES: alcohol use disorders are associated with a greater incidence of certain comorbidities in patients with celiac disease. Currently there is no available information about the impact that these disorders may have on length of hospital stays, overexpenditures during hospital stays, and excess mortality in these patients. METHODS: a case-control study was conducted with a selection of patients 18 years and older hospitalized during 2008-2010 in 87 hospitals in Spain. Estimations of excess length of stays, costs, and attributable mortality were calculated using a multivariate analysis of covariance, which included age, gender, hospital group, alcohol use disorders, tobacco related disease and 30 other comorbidities. RESULTS: patients who had both celiac disease and alcohol use disorders had an increased length of hospital stay, an average of 3.1 days longer in women, and 1.7 days longer in men. Excess costs per stay ranged from 838.7 euros in female patients, to 389.1 euros in male patients. Excess attributable mortality was 15.1 % in women, 12.2 % in men. CONCLUSIONS: apart from a gluten-free diet and other medical measures, the prevention of alcohol abuse is indicated in these patients. Patients hospitalized who present these disorders should receive specialized attention after leaving the hospital. Early detection and treatment should be used to prevent the appearance of organic lesions and should not be solely focused on male patients. PMID- 24467499 TI - Endoscopic submucosal dissection in Spain: outcomes and development possibilities. AB - Endoscopic submucosal dissection (ESD) allows endoscopic, curative, en-bloc resection of superficial malignant or premalignant lesions. This procedure was conceived over 10 years ago in Japan, but has not experienced great expansion in Western countries for different reasons. This article reviews ESD indications and outcomes, and reflects on the reasons that prevent ESD from becoming common clinical practice in Western hospitals. Finally, recommendations on ESD training in our setting are made. PMID- 24467500 TI - Gastroduodenal Burkitt's lymphoma in an immunocompetent patient. PMID- 24467501 TI - Radiofrequency ablation: A novel and effective treatment of severe bleeding secondary to actinic proctitis. PMID- 24467502 TI - Sclerosing cholangitis by cytomegalovirus in highly active antiretroviral therapy era. AB - Sclerosing cholangitis (SC) due to cytomegalovirus (CMV) is very rare. It has been described mainly in immunocompromised patients. Currently, in HIV infected patients it is exceptional. The most of cases belong to pre-highly active antiretroviral therapy (pre-HAART) and those cases were in stage AIDS with less than 100 CD4/ microl. The most frequently involved pathogen in pre-HAART period was Cryptosporidium parvum (30-57 %) and CMV (10-30 %); in late HAART period this information are unaware. CMV has been implicated as a possible etiological agent in primary SC partly because of the ability to cause liver damage and its relationship with smooth muscle antibodies. The most effective treatment for SC was the combination of antiretroviral therapy and endoscopic retrograde cholangiopancreatography with sphincterotomy and stent placement.Following, we present the first case of late HAART period which describes a SC extrahepatic without papillary stenosis with CMV as the only cause and clinical presentation of HIV infection in a woman with 177 CD4/microl. PMID- 24467503 TI - Biliary self-expandable metallic stent using single balloon enteroscopy assisted ERCP--overcoming limitations of current accessories. AB - Device assisted enteroscopy (DAE) techniques have been recently developed for the diagnosis and treatment of small bowel diseases. These techniques can also be used to perform endoscopic retrograde cholangiopancreatography (ERCP) in patients with surgically altered anatomies. The main difficulties with DAE-ERCP are related to type of surgery, to the different dimensions and lack of frontal view of the enteroscope and to the resulting limitations with the use of standard accessories, resulting in the need of dedicated accessory devices. Although most ERCP techniques have been successfully performed with DAE-ERCP, biliary self expandable metallic stents (SEMS) have not yet been used, as dedicated biliary SEMS for the enteroscope are lacking. The authors present a case report showing a new method to place standard biliary trough-the-scope SEMS with DAE-ERCP, using a different technique of stent deployment. PMID- 24467504 TI - [Information for the patient. Dysfunction of the Oddi sphinter]. PMID- 24467505 TI - Successful extracorporeal shockwave lithotripsy in chronic calcified pancreatitis management. PMID- 24467506 TI - Endometrioid adenocarcinoma in the lower rectum. PMID- 24467507 TI - Methicillin resistant Staphylococcus aureus liver abscess related with colorectal cancer. PMID- 24467508 TI - Massive upper gastrointestinal bleeding secondary to gastrosplenic fistula. PMID- 24467509 TI - Enterocolic lymphocytic phlebitis preceding the development of inflammatory bowel disease: report of a case. PMID- 24467510 TI - Risk factors for suicidal ideations in patients with bipolar disorder. AB - OBJECTIVE: To identify the risk factors for suicidal ideation in subjects with bipolar depression. METHODS: One-hundred and thirty subjects diagnosed with bipolar depression were evaluated on the following scales: Beck Depression Inventory (BDI), Beck Hopelessness Scale (BHS), Patient Health Questionnaire-15 (PHQ-15), Barrat's Impulsivity Scale (BIS), Irritability, Anxiety, and Depression (IDA) Scale, Young Mania Rating Scale (YMRS), Buss-Durke Hostile Inventory (BDHI), and Brief Psychiatric Rating Scale (BPRS). RESULTS: Based on the BDI suicidal thoughts and wishes item (score of >= 1), the study sample was divided into those with and those without suicidal ideation. Compared to those without suicidal ideations, patients with bipolar depression with suicidal ideation had significantly higher scores on the BDI, YMRS, BPRS total score, IDA total score, PHQ-15, BHS total score, and most of the hostility subscales of the BHI. [corrected]. On binary logistic regression analysis, the odds ratio (OR) for [corrected] presence of suicidal ideations was more than one and was significant for the BHS [OR = 1.53, [corrected] 95% confidence interval (CI): 1.24-1.99], the IDA-irritability directed inwards (OR = 1.48, 95% CI: 1.03-2.13), and the total hostility score (OR = 1.10, 95% CI: 1.02-1.20). Other factors for which the OR was more than one but the difference was not statistically significant were: Hindu religion (OR = 3.13, 95% CI: 0.76-12.99), lifetime mean duration of depressive episodes (OR = 1.08, 95% CI: 0.74-1.57), past history of hospitalization (OR = 1.10, 95% CI: 0.24-6.16), any preceding life events (OR = 1.45, 95% CI: 0.28-7.52), subsyndromal manic symptoms (OR = 1.01, 95% CI:0.53 1.92), presence of psychotic symptoms (OR = 1.06, 95% CI: 0.92-1.22), and irritability directed outwards (OR = 1.14, 95% CI: 0.92-1.41). [corrected]. CONCLUSION: Among the various predictors of suicidal ideations, the severity of hopelessness, irritability directed inwards, and hostility are the most important risk factors for suicidal ideations in patients with bipolar disorder. [corrected]. Hence, patients with these risk factors should be closely monitored to prevent suicide attempts and completed suicides. PMID- 24467511 TI - Systems-level analysis of the metabolic responses of the diatom Phaeodactylum tricornutum to phosphorus stress. AB - Phosphorus is an important macronutrient. To understand the molecular and cellular responses to phosphorus stress better, transcriptome profiling in combination with biochemical investigations was conducted in the model diatom Phaeodactylum tricornutum. Out of 10 402 predicted genes, 2491 and 405 genes were significantly upregulated or downregulated respectively. Unsurprisingly, genes associated with phosphate uptake were upregulated, such as the phosphate transporters and alkaline phosphatases. Genes encoding stress-shock proteins were accordingly upregulated, including genes associated with stress-responsive proteins, signal transduction and secondary metabolism. Additionally, genes related to protein translation, carbon fixation, glycolysis and the citric acid cycle were also upregulated. Genes associated with gene transcription were downregulated, thereby resulting in the upregulation of translation to compensate for the limited supply of messenger RNA. The downregulation of genes related to beta-oxidation could contribute to the accumulation of fatty acids. Accordingly, triacylglycerols, which are important for energy storage, were determined to increase by 1.65-fold. Intracellular membranes, other than chloroplast membranes, tended to be dispersed; this finding was in accordance with the increased transcription of a total of 11 genes encoding putative phospholipases. Taken together, this work revealed the coordination of multiple metabolic pathways and certain key genes in the adaptation of P. tricornutum to phosphorus stress. PMID- 24467512 TI - Optimizing the use of breed types in developing country livestock production systems: a neglected research area. AB - Developing country livestock production systems are diverse and dynamic, and include those where existing indigenous breeds are currently optimal and likely to remain so, those where non-indigenous breed types are already in common use, and systems that are changing, such as by intensification, where the introduction of new breed types represents significant opportunities. These include opportunities to improve the livelihood of the world's poor, increase food and nutrition security and enhance environmental sustainability. At present, very little research has focused on this issue, such that significant knowledge gaps in relation to breed-change interventions remain. The purpose of this study is to raise awareness of this issue and suggests strategic research areas to begin filling these knowledge gaps. Such strategic research would include (i) assessing the impact of differing breed types in developing country livestock productions systems, from a range of viewpoints including intrahousehold livelihood benefit, food and nutrition security at different scales, and environmental sustainability; (ii) identification of specific livestock production systems within developing countries, and the type of livestock keepers within these system, that are most likely to benefit from new breed types; and (iii) identification of new breed types as candidates for in-situ testing within these systems, such as through the use of spatial analysis to identify similar production environments combined with community acceptance studies. Results of these studies would primarily assist stakeholders in agriculture, including both policy makers and livestock keepers, to make informed decisions on the potential use of new breed types. PMID- 24467513 TI - The application of water soluble, mega-Stokes-shifted BODIPY fluorophores to cell and tissue imaging. AB - BODIPY (4,4-difluoro-4-bora-3a,4a-diaza-s-indacene) fluorophores are widely used in bioimaging to label proteins, lipids and nucleotides, but in spite of their attractive optical properties they tend to be prone to self-quenching because of their notably small Stokes shift. Herein, we compare two BODIPY compounds from a recently developed family of naphthyridine substituted BODIPY derivatives, one a visible emitting derivative (BODIPY-VIS) and one a near-infrared emitting fluorophore with a Stokes shift of approximately 165 nm as contrast reagents for live mammalian cells and murine brain tissue. The compounds were rendered water soluble by their conjugation to polyethylene glycol (PEG). Both PEGylated compounds exhibited good cell uptake compared with their parent compounds and confocal fluorescence microscopy revealed all dyes explored to be nuclear excluding, localizing predominantly within the lipophilic organelles; the endoplasmic reticulum and mitochondria. Cytotoxicity studies revealed that these BODIPY derivatives are modestly cytotoxic at concentrations exceeding 10 MUM where they induce apoptosis and necrosis. Although the quantum yield of emission of the visible emitting fluorophore was over an order of magnitude greater than the Mega-Stokes shifted probe, the latter showed considerably reduced tendency to self quench and less interference from autofluorescence. The near-infrared probe also showed good penetrability and staining in live tissue samples. In the latter case similar tendency to exclude the nucleus and to localize in the mitochondria and endoplasmic reticulum was observed as in live cells. This to our knowledge is the first demonstration of such a Mega-Stokes BODIPY probe applied to cell and tissue imaging. PMID- 24467516 TI - Room-temperature ferromagnetism in antiferromagnetic cobalt oxide nanooctahedra. AB - Cobalt oxide octahedra were synthesized by thermal decomposition. Each octahedron shaped nanoparticle consists of an antiferromagnetic CoO core enclosed by eight {111} facets interfaced to a thin (~ 4 nm) surface layer of strained Co3O4. The nearly perfectly octahedral shaped particles with 20, 40, and 85 nm edge length show a weak room-temperature ferromagnetism that can be attributed to ferromagnetic correlations appearing due to strained lattice configurations at the CoO/Co3O4 interface. PMID- 24467515 TI - Cycloisomerization of acetylenic acids to gamma-alkylidene lactones using a palladium(II) catalyst supported on amino-functionalized siliceous mesocellular foam. AB - Cycloisomerization of various gamma-acetylenic acids to their corresponding gamma alkylidene lactones by the use of a heterogeneous Pd(II) catalyst supported on amino-functionalized siliceous mesocellular foam is described. Substrates containing terminal as well as internal alkynes were cyclized in high to excellent yields within 2-24 h under mild reaction conditions. The protocol exhibited high regio- and stereoselectivity, favoring the exo-dig product with high Z selectivity. Moreover, the catalyst displayed excellent stability under the employed reaction conditions, as demonstrated by its good recyclability and low leaching. PMID- 24467514 TI - Quantification of caffeine, trigonelline and nicotinic acid in espresso coffee: the influence of espresso machines and coffee cultivars. AB - Caffeine, trigonelline and nicotinic acid are important bioactive constituents of coffee. In this work, the combination of different water temperatures and pressures in the settings of the espresso coffee (EC) machine was evaluated, to assess how these factors influence how effectively caffeine, trigonelline and nicotinic acid are extracted from both Arabica and Robusta samples. The proposed analytical method, based on a high performance liquid chromatography (HPLC) system coupled to a variable wavelength detector (VWD), showed good linearity (R2> 0.9985) and good recoveries (71-92%); after validation for three monitored compounds, the method was used to analyze 20 commercial samples. The combination of a temperature of 92 degrees C and pressure at 7 or 9 bar seems to be the ideal setting for the most efficient extraction of these compounds and consequently for their intake; the compound extracted in the greatest quantity was caffeine, which was in the range of 116.87-199.68 mg in a 25 ml cup of coffee. PMID- 24467518 TI - Cetuximab inhibits gastric cancer growth in vivo, independent of KRAS status. AB - Mutation status of Kirsten rat sarcoma viral oncogene homolog (KRAS) may serve as a negative predictive marker of Cetuximab in treating colorectal cancer. The present study was to determine the role of KRAS status in EGFR antibody treatment for gastric cancer. KRAS status was clarified in SGC-7901 (wild type) and YCC-2 (G->A mutation) gastric cancer cell lines. Anti-proliferative and pro-apoptotic effects of Cetuximab were tested both in vitro and in vivo, the expression of phosphorylated (p) ERK, a downstream protein in EGFR-RAS-MEK pathway, was also analyzed. No significant in vitro anti-proliferative or pro-apoptotic effects of Cetuximab were observed in both cell lines. The growth of either SGC-7901 or YCC 2 gastric cancer xenograft was significantly inhibited by Cetuximab. Apoptosis was induced in SGC-7901 but not in YCC-2 xenografts after Cetuximab treatment. The expression of pERK was up-regulated in YCC-2 but not SGC-7901 xenografts after Cetuximab treatment. In conclusion, KRAS (G->A) mutation does not affect in vivo anti-cancer efficacy of Cetuximab. PMID- 24467517 TI - Functional selectivity and time-dependence of MU-opioid receptor desensitization at nerve terminals in the mouse ventral tegmental area. AB - BACKGROUND AND PURPOSE: The majority of studies examining desensitization of the MU-opioid receptor (MOR) have examined those located at cell bodies. However, MORs are extensively expressed at nerve terminals throughout the mammalian nervous system. This study is designed to investigate agonist-induced MOR desensitization at nerve terminals in the mouse ventral tegmental area (VTA). EXPERIMENTAL APPROACH: MOR function was measured in mature mouse brain slices containing the VTA using whole-cell patch-clamp electrophysiology. Presynaptic MOR function was isolated from postsynaptic function and the functional selectivity, time-dependence and mechanisms of agonist-induced MOR desensitization were examined. KEY RESULTS: MORs located at GABAergic nerve terminals in the VTA were completely resistant to rapid desensitization induced by the high-efficacy agonists DAMGO and Met-enkephalin. MORs located postsynaptically on GABAergic cell bodies readily underwent rapid desensitization in response to DAMGO. However, after prolonged (>7 h) treatment with Met enkephalin, profound homologous MOR desensitization was observed. Morphine could induce rapid MOR desensitization at nerve terminals when PKC was activated. CONCLUSIONS AND IMPLICATIONS: Agonist-induced MOR desensitization in GABAergic neurons in the VTA is compartment-selective as well as agonist-selective. When MORs are located at cell bodies, higher-efficacy agonists induce greater levels of rapid desensitization than lower-efficacy agonists. However, the converse is true at nerve terminals where agonists that induce MOR desensitization via PKC are capable of rapid agonist-induced desensitization while higher-efficacy agonists are not. MOR desensitization induced by higher-efficacy agonists at nerve terminals only takes place after prolonged receptor activation. LINKED ARTICLES: This article is part of a themed section on Opioids: New Pathways to Functional Selectivity. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2015.172.issue-2. PMID- 24467519 TI - Effects of enuresis nocturna on parents of affected children: case-control study. AB - BACKGROUND: Enuresis nocturna (EN) is a chronic medical disorder that may cause a parent to question their parenting ability and contribute to an inability to perform the parental role. The aim of the study was to investigate the effects of EN on the relationship between parents, and the effect of mood changes in the couples on the children. METHODS: Forty children with EN (group 1) were enrolled in the study, and 44 consecutive healthy children (group 2) were randomly selected from the same school. The clinical diagnosis for the patient group was based on a careful history. Spielberg's State-Trait Anxiety Inventory (STAI), Beck Depression Inventory (BDI), and Dyadic Adjustment Scale (DAS) were applied to all parents, and the answers were recorded. RESULTS: STAI scores differed between the mothers in the two groups in terms of trait anxiety, while significant differences between the fathers in terms of both state and trait anxiety were observed. The BDI scores were similar between the two groups. The scores of dyadic consensus were lower in the mothers, while the affectional expression scores were lower in the EN study group fathers compared with controls. The total DAS scores were significantly lower in the parents of the children with EN. CONCLUSION: The parents of children with EN seem to experience increased levels of anxiety. Their desire to continue the marital relationship, the overall quality of their marital relationship and their comfort as a family may also be negatively affected by having a child with EN. PMID- 24467520 TI - Connective tissue growth factor: a predictor of recurrence after catheter ablation in patients with nonparoxysmal atrial fibrillation. AB - BACKGROUND: Although catheter ablation can effectively eliminate atrial fibrillation (AF), the progression of atrial remodeling increases the risk of recurrence. We, therefore, examined the possibility of determining the postablation prognosis of patients with AF using biomarkers of atrial structural remodeling and serum connective tissue growth factor (CTGF) level, and measured its changes after catheter ablation. METHODS: Subjects were 400 consecutive patients (308 with paroxysmal AF and 92 with nonparoxysmal AF [persistent and long-standing persistent AF]) who underwent catheter ablation for drug-resistant AF. Serum CTGF levels were measured before and 2 months after ablation. RESULTS: During the follow-up period of 20.5 +/- 6.9 (8-30) months, 61 patients (66%) with nonparoxysmal AF and 95 patients (31%) with paroxysmal AF had recurrence after catheter ablation. Recurrence was associated with higher "baseline CTGF level" in patients with nonparoxysmal AF (936.5 +/- 93.1 ng/mL vs 746.3 +/- 56.9 ng/mL, P = 0.007) instead of patients with paroxysmal AF (851.6 +/- 97.6 ng/mL vs 807.6 +/- 99.1 ng/mL, P = 0.921). In nonparoxysmal AF, the recurrence subgroup also had larger left atrial diameter (LAD; 47.1 +/- 5.2 mm vs 39.5 +/- 4.3 mm, P = 0.035) compared with the nonrecurrence subgroup, and "baseline serum CTGF" and LAD were shown to be independent predictors for postablation recurrence by a Cox proportional hazards model. However, the 2-month postablation elevations of CTGF in patients with recurrence were not significantly different from that in patients without recurrence in nonparoxysmal AF. CONCLUSION: Our finding indicates that "baseline serum CTGF level" is an independent predictor for recurrence in patients with nonparoxysmal AF following catheter ablation. Two month postablation elevation in CTGF has no association with recurrence. PMID- 24467521 TI - Impact of dendrimer surface functional groups on the release of doxorubicin from dendrimer carriers. AB - Generation 5 (G5) poly(amidoamine) dendrimers with acetyl (G5.NHAc), glycidol hydroxyl (G5.NGlyOH), and succinamic acid (G5.SAH) terminal groups were used to physically encapsulate an anticancer drug doxorubicin (DOX). Both UV-vis spectroscopy and multiple NMR techniques including one-dimensional NMR and two dimensional NMR were applied to investigate the interactions between different dendrimers and DOX. The influence of the surface functional groups of G5 dendrimers on the DOX encapsulation, release kinetics, and cancer cell inhibition effect was investigated. We show that all three types of dendrimers are able to effectively encapsulate DOX and display therapeutic inhibition effect to cancer cells, which is solely associated with the loaded DOX. The relatively stronger interactions of G5.NHAc or G5.NGlyOH dendrimers with DOX than that of G5.SAH dendrimers with DOX demonstrated by NMR techniques correlate well with the slow release rate of DOX from G5.NHAc/DOX or G5.NGlyOH/DOX complexes. In contrast, the demonstrated weak interaction between G5.SAH and DOX causes a fast release of DOX, suggesting that the G5.SAH/DOX complex may not be a proper option for further in vivo research. Our findings suggest that the dendrimer surface functional groups are crucial for further design of multifunctional dendrimer based drug delivery systems for various biomedical applications. PMID- 24467523 TI - Resin infiltration technique for proximal caries lesions in the permanent dentition: a contrarian viewpoint. PMID- 24467526 TI - Heteroepitaxy of tetragonal BiFeO(3) on hexagonal sapphire(0001). AB - Highly elongated BiFeO3 is epitaxially grown on hexagonal sapphire(0001) substrate within a rather narrow synthesis window. Both X-ray reciprocal space maps and Raman characterizations reveal that it is of true tetragonal symmetry but not the commonly observed MC type monoclinic structure. The tetragonal BiFeO3 film exhibits an island growth mode, with the island edges oriented parallel to the ?10-10? and ?12-30? directions of the sapphire substrate. With increasing deposition time, a transition from square island to elongated island and then to a continuous film is observed. The metastable tetragonal phase can remain on the substrate without relaxation to the thermally stable rhombohedral phase up to a critical thickness of 450 nm, providing an exciting opportunity for practicable lead-free ferroelectrics. These results facilitate a better understanding of the phase stability of BiFeO3 polymorphs and enrich the knowledge about the heteroepitaxial growth mechanism of functional oxides on symmetry-mismatched substrates. PMID- 24467527 TI - THF1 mutations lead to increased basal and wound-induced levels of oxylipins that stimulate anthocyanin biosynthesis via COI1 signaling in Arabidopsis. AB - Mutants defective in chloroplast development or photosynthesis are liable to accumulate higher levels of anthocyanin in photo-oxidative stress. However, regulatory mechanisms of anthocyanin biosynthesis in the mutants remain unclear. Here, we investigated the mechanism by which the deletion of thylakoid formation1 (THF1) leads to an increased level of anthocyanin in Arabidopsis thaliana L. Physiological and genetic evidence showed that the increased level of anthocyanin in thf1 is dependent on coronatine-insensitive1 (COI1) signaling. Our data showed that thf1 had higher levels of basal alpha-linolenic acid (alpha-LeA), and methyl jasmonate (JA)-induced alpha-LeA and 12-oxophytodienoic acid (OPDA) than the wild type (WT). Consistently, expression levels of phospholipase genes including pPLAIIalpha and PLA-Igamma1 were elevated in thf1. Furthermore, inhibition of lipase activity by bromoenol lactone, a specific inhibitor of plant pPLA, led to producing identical levels of anthocyanins in WT and thf1 plants. Interestingly, OPDA biosynthesis was triggered by light illumination in isolated chloroplasts, indicating that new protein import into chloroplasts is not required for OPDA biosynthesis. Thus, we conclude that the elevated anthocyanin accumulation in thf1 is attributed to an increase in JA levels. This JA-mediated signaling to coordinate plant metabolism and growth in stress may be conserved in other photosensitive mutants. PMID- 24467528 TI - Mucoadhesive buccal films containing phospholipid-bile salts-mixed micelles as an effective carrier for Cucurbitacin B delivery. AB - Cucurbitacin B (Cu B), a potent anti-cancer agent, suffers with the problems of water-insoluble, gastrointestinal side effects and non-specific toxicity via oral administration and drawbacks in patient's compliance and acceptance through injections. An integration of nanoscale carriers with mucoadhesive buccal films drug delivery system would resolve these issues effectively with greater therapeutic benefits and clinical significance. Thus, the drug loaded mucoadhesive buccal film was developed and characterized in this study and the carboxymethyl chitosan (CCS) was chosen as a bioadhesive polymer, glycerol was chosen as a plasticizer and phospholipid-bile salts-mixed micelles (PL-BS-MMs) was selected as the nanoscale carriers. The CCS-films containing Cu B loaded PL SDC-MMs was evaluated for the mechanical properties, mucoadhesion properties, in vitro water-uptake, in vitro release and morphological properties, respectively. The optimal CCS-films containing Cu B loaded PL-SDC-MMs was easily reconstituted in a transparent and clear solution with spherical micelles in the submicron range. The in vivo study revealed a greater and more extended release of Cu B from nanoscale CCS-films compared to that from a conventional CCS films (C-CCS films) and oral marketed tablet (Hulusupian). The absorption of Cu B from CCS films containing Cu B loaded PL-SDC-MMs resulted in 2.69-fold increased in bioavailability as compared to conventional tablet formulation and 10.46 times with reference to the C-CCS-films formulation. Thus, this kind of mucoadhesive buccal film might be an alternative safe route for delivery of Cu B with better patient compliance and higher bioavailability for the treatments. PMID- 24467529 TI - Pleiotropic role of HSF1 in neoplastic transformation. AB - HSF1 (Heat Shock transcription Factor 1) is the main transcription factor activated in response to proteotoxic stress. Once activated, it induces an expression of heat shock proteins (HSPs) which enables cells to survive in suboptimal conditions. HSF1 could be also activated by altered kinase signaling characteristic for cancer cells, which is a probable reason for its high activity found in a broad range of tumors. There is rapidly growing evidence that HSF1 supports tumor initiation and growth, as well as metastasis and angiogenesis. It also modulates the sensitivity of cancer cells to therapy. Functions of HSF1 in cancer are connected with HSPs' activity, which generally protects cells from apoptosis, but also are independent of its classical targets. HSF1-dependent regulation of non-HSPs genes plays a role in cell cycle progression, glucose metabolism, autophagy and drug efflux. HSF1 affects the key cell-survival and regulatory pathways, including p53, RAS/MAPK, cAMP/PKA, mTOR and insulin signaling. Although the exact mechanism of HSF1 action is still somewhat obscure, HSF1 is becoming an attractive target in anticancer therapies, whose inhibition could enhance the effects of other treatments. PMID- 24467532 TI - Medicinal herbs in the prevention and treatment of osteoporosis. AB - Osteoporosis is a common disease with wide prevalence, especially in the elderly population. Osteoporosis induced fractures not only decrease the patient's life quality, but also cause heavy financial burden to the society. Although current medications for osteoporosis are effective, numerous adverse effects have been observed accompanying their clinical applications. Effective prevention and therapy strategies with high safety are critical, which benefit both individual patients and the whole society. Traditional Chinese medicines have been used for thousands of years to treat bone related diseases in China and a number of modern preparations have been developed that are currently commercially available. In addition, several medicinal herbs demonstrated therapeutic effects against osteoporosis in animal models. This paper reviewed the anti-osteoporotic effects of traditional Chinese formulas, medicinal herbs and bioactive constituents based on clinical trials and in vivo animal studies. Due to the lack of rigorous studies to compare the effectiveness with conventional interventions, traditional formulas are recommended as alternative medications or supplements to treat osteoporosis at the current stage. Although there are abundant natural resources with anti-osteoporotic effects, either in the form of medicinal herbs or bioactive components, much work need to be accomplished before they are developed into potential drugs. PMID- 24467530 TI - Molecular targeted approaches to cancer therapy and prevention using chalcones. AB - There is an emerging paradigm shift in oncology that seeks to emphasize molecularly targeted approaches for cancer prevention and therapy. Chalcones (1,3 diphenyl-2-propen-1-ones), naturally-occurring compounds with widespread distribution in spices, tea, beer, fruits and vegetables, consist of open-chain flavonoids in which the two aromatic rings are joined by a three-carbon alpha, beta-unsaturated carbonyl system. Due to their structural diversity, relative ease of chemical manipulation and reaction of alpha, beta-unsaturated carbonyl moiety with cysteine residues in proteins, some lead chalcones from both natural products and synthesis have been identified in a variety of screening assays for modulating important pathways or molecular targets in cancers. These pathways and targets that are affected by chalcones include MDM2/p53, tubulin, proteasome, NF kappa B, TRIAL/death receptors and mitochondria mediated apoptotic pathways, cell cycle, STAT3, AP-1, NRF2, AR, ER, PPAR-gamma and beta-catenin/Wnt. Compared to current cancer targeted therapeutic drugs, chalcones have the advantages of being inexpensive, easily available and less toxic; the ease of synthesis of chalcones from substituted benzaldehydes and acetophenones also makes them an attractive drug scaffold. Therefore, this review is focused on molecular targets of chalcones and their potential implications in cancer prevention and therapy. PMID- 24467531 TI - Reporting of critical information in studies of pharmacists in HIV care. AB - OBJECTIVE: To evaluate manuscripts documenting HIV pharmacist interventions and assess adequacy of reporting as defined by CONSORT and STROBE criteria. METHODS: PubMed, EMBASE, Cochrane Library, Web of Science, BIOSIS Previews, and PsycINFO databases were searched from inception - 1 June 2011. Studies were included if pharmacists performed an intervention to improve HIV patient care, and the study evaluated the intervention's impact. Qualitative studies, non-English language reports, abstracts and studies where the pharmacist did not intervene were excluded. Manuscripts were independently evaluated by two reviewers for the presence, absence or lack of applicability of STROBE (observational studies) or CONSORT (randomized studies) criteria, for presence or absence of description of pharmacist's duties, CD4+ cell count, HIV viral load and adherence measurement. Reviewers met to discuss the rationale behind their evaluation; a third arbiter was consulted when reviewers could not agree on a particular criterion. KEY FINDINGS: Twenty-two manuscripts met inclusion criteria. Observational studies of HIV pharmacists (n = 19) included 56% of applicable STROBE criteria. Randomized studies of HIV pharmacists (n = 3) adhered more closely to CONSORT reporting guidelines (average 80% of applicable criteria). Manuscripts published after 2004 more consistently evaluated pharmacist impact on HIV outcomes such as CD4+ and viral load. CONCLUSIONS: Thorough reporting increases the reader's ability to critically evaluate manuscripts of HIV pharmacist services. Increasing pharmacist awareness of manuscript guidelines such as CONSORT and STROBE may improve clarity of reporting in studies of HIV pharmacist interventions and clinical programmes. PMID- 24467534 TI - Traditional Chinese medicine injection for angina pectoris: an overview of systematic reviews. AB - Traditional Chinese medicine (TCM) injection is widely used to treat angina pectoris in China. This overview aims to systematically summarize the general characteristics of systematic reviews (SRs) on TCM injection in treating angina, and assess the methodological and reporting quality of these reviews. We searched PubMed, Embase, the Cochrane Library and four Chinese databases from inception until March 2013. Data were extracted according to a preset form. The AMSTAR and PRISMA checklists were used to explore the methodological quality and reporting characteristics of included reviews, respectively. All data analyses were descriptive. 46 SRs involving over 57,463 participants with angina reviewing 23 kinds of TCM injections were included. The main outcomes evaluated in the reviews were symptoms (43/46, 93.5%), surrogate outcomes (42/46, 91.3%) and adverse events (41/46, 87.0%). Few reviews evaluated endpoints (7/46, 15.2%) and quality of life (1/46, 2.2%). One third of the reviews (16/46, 34.8%) drew definitely positive conclusions while the others (30/46, 65.2%) suggested potential benefits mainly in symptoms, electrocardiogram and adverse events. With many serious flaws such as lack of a protocol and inappropriate data synthesis, the overall methodological and reporting quality of the reviews was limited. While many SRs of TCM injection on the treatment of angina suggested potential benefits or definitely positive effects, stakeholders should not accept the findings of these reviews uncritically due to the limited methodological and reporting quality. Future SRs should be appropriately conducted and reported according to international standards such as AMSTAR and PRISMA, rather than published in large numbers. PMID- 24467533 TI - Phytochemistry and biology of Loranthus parasiticus Merr, a commonly used herbal medicine. AB - Loranthus parasiticus Merr (L. parasiticus) is a member of Loranthaceae family and is an important medicinal plant with a long history of Chinese traditional use. L. parasiticus, also known as Sang Ji Sheng (in Chinese), benalu teh (in Malay) and baso-kisei (in Japanese), is a semiparasitic plant, which is mostly distributed in the southern and southwestern regions of China. This review aims to provide a comprehensive overview of the ethnomedicinal use, phytochemistry and pharmacological activity of L. parasiticus and to highlight the needs for further investigation and greater global development of the plant's medicinal properties. To date, pharmacological studies have demonstrated significant biological activities, which support the traditional use of the plant as a neuroprotective, tranquilizing, anticancer, immunomodulatory, antiviral, diuretic and hypotensive agent. In addition, studies have identified antioxidative, antimutagenic, antiviral, antihepatotoxic and antinephrotoxic activity. The key bioactive constituents in L. parasiticus include coriaria lactone comprised of sesquiterpene lactones: coriamyrtin, tutin, corianin, and coriatin. In addition, two proanthocyanidins, namely, AC trimer and (+)-catechin, have been recently discovered as novel to L. parasiticus. L. parasiticus usefulness as a medicinal plant with current widespread traditional use warrants further research, clinical trials and product development to fully exploit its medicinal value. PMID- 24467535 TI - Therapeutic angiogenesis after ischemic stroke: Chinese medicines, bone marrow stromal cells (BMSCs) and their combinational treatment. AB - Ischemic stroke is a clinical acute disease which causes neurological dysfunction and threatens a patient's life. Because the mechanism of pathology is complicated and most patients miss the best therapeutic window time, the effect of the treatment is not satisfied at present. Numerous studies indicated new vessels not only recuperated blood flow in the ischemic boundary zone, but also facilitated endogenous neurogenesis and improved neurological function after ischemic stroke. Therefore, angiogenesis has been an important research field in neurovascular regeneration. Recently, some Chinese medicines, bone marrow stromal cells (BMSCs) and their combination treatment were demonstrated to have beneficial effects in promoting angiogenesis both in vitro and in vivo. In this review, we summarized the effective mechanisms of Chinese medicines and BMSCs, as well as BMSCs in combination with Chinese medicines on angiogenesis post-stroke. PMID- 24467536 TI - Baicalein protects cardiomyocytes against mitochondrial oxidant injury associated with JNK inhibition and mitochondrial Akt activation. AB - Baicalein, a flavonoid derived from Scutellaria baicalensis Georgi, possesses cardioprotection against oxidant injury by scavenging reactive oxygen species (ROS). Few studies investigate whether baicalein protection is mediated by attenuating mitochondrial ROS and modulating the prosurvival and proapoptotic signaling. Primary cultured chick cardiomyocytes were used to study the role of baicalein in mitochondrial superoxide [Formula: see text] generation and signaling of Akt and JNK. Cells were exposed to H 2 O 2 for 2 h and baicalein was given 2 h prior to and during 2 h of H 2 O 2 exposure. Cell viability was assessed by propidium iodide and DNA fragmentation. H 2 O 2 (500 MUM) significantly induced 45.3 +/- 6.2% of cell death compared to the control (p < 0.001) and resulted in DNA laddering. Baicalein (10, 25 or 50 MUM) dose dependently reduced the cell death to 38.7 +/- 5.6% (p = 0.226); 31.2 +/- 3.9% (p < 0.01); 30.3 +/- 5.3% (p < 0.01), respectively. It also attenuated DNA laddering. Further, baicalein decreased intracellular ROS and mitochondrial [Formula: see text] generation that was confirmed by superoxide dismutase PEG-SOD and mitochondria electron transport chain complex III inhibitor stigmatellin. In addition, baicalein increased Akt phosphorylation and decreased JNK phosphorylation in H 2 O 2-exposed cells. Moreover, baicalein augmented mitochondrial phosphorylation of Akt Thr308 and GSK3beta Ser9, and prevented mitochondrial cytochrome c release assessed by cellular fractionation. Our results suggest that baicalein cardioprotection may involve an attenuation of mitochondrial [Formula: see text] and an increase in mitochondrial phosphorylation of Akt and GSK3beta while decreasing JNK activation. PMID- 24467537 TI - Semen cassiae attenuates myocardial ischemia and reperfusion injury in high-fat diet streptozotocin-induced type 2 diabetic rats. AB - Obese patients with type 2 diabetes mellitus (T2DM), which is characterized by hyperglycemia, are liable to more severe myocardial infarction. Semen Cassiae is proven to reduce serum lipid levels. This study investigated whether the Semen Cassiae extract (SCE) reduces myocardial ischemia and reperfusion (MI/R) injury with or without diabetes and the underlying mechanisms. The high-fat diet-fed streptozotocin (HFD-STZ) rat model was created as a T2DM model. Normal and DM rats received SCE treatment orally (10 mg/kg/day) for one week. Subsequently these animals were subjected to MI/R. Compared with the normal animals, DM rats showed increased plasma total cholesterol (TC) and triacylglycerol (TG), and more severe MI/R injury and cardiac functional impairment. SCE treatment significantly reduced the plasma TC and TG, improved the instantaneous first derivation of left ventricle pressure and reduced infarct size, decreased plasma creatine kinase and lactate dehydrogenase levels, and apoptosis index at the end of reperfusion in diabetic rats. Moreover, SCE treatment increased the antiapoptotic protein Akt and ERK1/2 phosphorylation levels. Pretreatment with a PI3K inhibitor wortmannin or an ERK1/2 inhibitor PD98059 not only blocked Akt and ERK1/2 phosphorylation respectively, but also inhibited the cardioprotective effects of SCE. However, SCE treatment did not show any effects on the MI/R injury in the normal rats. Our data suggest that SCE effectively improves myocardial function and reduces MI/R induced injury in diabetic but not normal animals, which is possibly attributed to the reduced TC/TG levels and the triggered cell survival signaling Akt and ERK1/2. PMID- 24467538 TI - Clinical efficacy of aconitum-containing traditional Chinese medicine for diabetic peripheral neuropathic pain. AB - Diabetic peripheral neuropathy is a common chronic complication of diabetes. Routine clinical management uses analgesics to relieve pain in combination with drugs for nerve repair. The drugs are often not effective for the severe pain cases, and these western medications also have side effects. We report a more effective treatment of diabetic peripheral neuropathic pain using a high dose of a traditional Chinese medicine, aconitum (including both Radix aconite preparata and Radix aconite kusnezoffii), in combination with Huangqi Guizhi Wuwu Tang (i.e., astragalus, cassia twig, white peony root, and spatholobi). In order to achieve stronger analgesic effects, we increased the clinical dosage of aconitum from 15 to 120 g. The aconitum was boiled for 6-8 hours, and licorice was also used to reduce potential toxicities of aconitum. In the four reported cases, the patients' neuropathic pain was remarkably reduced and the EMG profile was also improved with this treatment regimen. Adverse reactions were not observed during the therapy. Thus, aconitum represents a promising and safe treatment for the well-being of patients and their diabetic peripheral neuropathic pain. Future controlled clinical trials using traditional Chinese medicines containing aconitum in treating the neuropathic pain are warranted. PMID- 24467539 TI - Phosphatase-mediated intracellular signaling contributes to neuroprotection by flavonoids of Iris tenuifolia. AB - A variety of flavonoids are suggested to be useful for the treatment of brain related disorders, including dementia and depression. An investigation on the characteristics of the extracted compounds of Iris tenuifolia Pall. (IT) is of much interest, as this plant has been used as a traditional medicine. In the present study, we examined the effect of total flavonoids obtained from IT on cultured cortical neurons under oxidative-stress and found that pretreatment with IT flavonoids significantly inhibited H 2 O 2-induced cell death in cortical neurons. Such a survival-promoting effect by IT flavonoids was partially blocked by inhibitors for extracellular signal-regulated kinase (ERK) and phosphoinositide 3-kinase/Akt (PI3K/Akt) cascades, both of which are known as survival-promoting signaling molecules. Furthermore, the phosphorylation of Src homology-2 (SH2) domain-containing phosphatase2 (Shp2) was induced by IT flavonoids, and the protective effect of IT flavonoids was abolished by NSC87877, an inhibitor for Shp2, suggesting the involvement of Shp2-mediated intracellular signaling in flavonoid-dependent neuroprotection. PMID- 24467540 TI - Effects of carnosine on cyclophosphamide-induced hematopoietic suppression in mice. AB - Cyclophosphamide is one of the most widely used chemotherapeutic agents in treating cancers. Chemotherapy drug-induced oxidative stress produces side effects. The severity of myelosuppression increases with a high dose of cyclophosphamide. Chicken soup or chicken essence, a traditional Chinese aliment, is a popular health supplement for patients with cancers or other diseases in Asia. As a major functional component of chicken meat extract, carnosine (beta alanyl-L-histidine), a dipeptide of the amino acids beta-alanine and histidine, has been shown to have strong antioxidant activities. In the present study, we investigated the effects of carnosine on hematopoietic suppression in mice treated with cyclophosphamide. As expected, we found that cyclophosphamide administration (with a single dose of 150 mg/kg) induced a rapid (within 24 hours) and severe hematopoietic suppression in mice. We further showed that carnosine administration (100 mg/kg/day or 200 mg/kg/day for continuous seven days) could substantially improve suppressed hematopoietic functions and accelerate the recovery of leukocyte counts, bone marrow spontaneous proliferation, colony stimulating activity (CSA) in serum, and production of endogenous cytokines such as interleukin-3 (IL-3) and stem cell factor (SCF). These results indicate that carnosine has the potential to promote the recovery from hematopoietic suppression induced by cyclophosphamide. Our data suggest that carnosine holds a potential in clinical application to minimize the side effects induced by chemotherapeutic agents such as cyclophosphamide and thus will substantially improve the overall anti-tumor effects of the standard chemotherapies. PMID- 24467541 TI - Du-zhong (Eucommia ulmoides) prevents disuse-induced osteoporosis in hind limb suspension rats. AB - Du-Zhong has a long history of being used in traditional Chinese formulas to treat bone related diseases. The objective of the present study is to systematically investigate the effects of Du-Zhong cortex extract (DZCE) on disuse-induced osteoporosis. Rats were randomly divided into four groups, and three groups were treated with hind limb suspension (HLS). Control and HLS group received deionized distilled water, while the other two groups received alendronate (2.0 mg/kg/day) and DZCE (300 mg/kg/day) respectively by intragastric gavage for six weeks (two weeks prior to and during the four weeks of HLS). Dual energy X-ray absorptiometry, assay of biochemical markers, and three-point bending test were employed to determine the effect of various treatments on bone mass, turnover, and strength. The trabecular bone microarchitecture was assessed by microCT analysis. DZCE could effectively prevent the bone loss induced by HLS, which was indicated by decreased levels of bone turnover markers as well as the changes in urinary calcium and phosphorus. The DZCE treatment also enhanced the biomechanical strength of bone and prevented the deterioration of trabecular bone microarchitecture. DZCE administration was able to prevent disuse-induced osteoporosis by regulating the bone metabolism, suggesting that DZCE could be used as an alternative therapy for the prevention of disuse-induced osteoporosis. PMID- 24467542 TI - Withania somnifera attenuates acid production, acid tolerance and extra-cellular polysaccharide formation of Streptococcus mutans biofilms. AB - Withania somnifera (Ashwagandha) is a plant of the Solanaceae family. It has been widely used as a remedy for a variety of ailments in India and Nepal. The plant has also been used as a controlling agent for dental diseases. The aim of the present study was to evaluate the activity of the methanol extract of W. somnifera against the physiological ability of cariogenic biofilms and to identify the components of the extract. To determine the activity of the extract, assays for sucrose-dependent bacterial adherence, glycolytic acid production, acid tolerance, and extracellular polysaccharide formation were performed using Streptococcus mutans biofilms. The viability change of S. mutans biofilms cells was also determined. A phytochemical analysis of the extract was performed using TLC and LC/MS/MS. The extract showed inhibitory effects on sucrose-dependent bacterial adherence (>= 100 MUg/ml), glycolytic acid production (>= 300 MUg/ml), acid tolerance (>= 300 MUg/ml), and extracellular polysaccharide formation (>= 300 MUg/ml) of S. mutans biofilms. However, the extract did not alter the viability of S. mutans biofilms cells in all concentrations tested. Based on the phytochemical analysis, the activity of the extract may be related to the presence of alkaloids, anthrones, coumarines, anthraquinones, terpenoids, flavonoids, and steroid lactones (withanolide A, withaferin A, withanolide B, withanoside IV, and 12-deoxy withastramonolide). These data indicate that W. somnifera may be a potential agent for restraining the physiological ability of cariogenic biofilms. PMID- 24467543 TI - Efficacy comparison of Korean ginseng and American ginseng on body temperature and metabolic parameters. AB - Ginseng has beneficial effects in cancer, diabetes and aging. There are two main varieties of ginseng: Panax ginseng (Korean ginseng) and Panax quinquefolius (American ginseng). There are anecdotal reports that American ginseng helps reduce body temperature, whereas Korean ginseng improves blood circulation and increases body temperature; however, their respective effects on body temperature and metabolic parameters have not been studied. We investigated body temperature and metabolic parameters in mice using a metabolic cage. After administering ginseng extracts acutely (single dose of 1000 mg/kg) or chronically (200 mg/kg/day for four weeks), core body temperature, food intake, oxygen consumption and activity were measured, as well as serum levels of pyrogen-related factors and mRNA expression of metabolic genes. Acute treatment with American ginseng reduced body temperature compared with PBS-treated mice during the night; however, there was no significant effect of ginseng treatment on body temperature after four weeks of treatment. VO 2, VCO 2, food intake, activity and energy expenditure were unchanged after both acute and chronic ginseng treatment compared with PBS treatment. In acutely treated mice, serum thyroxin levels were reduced by red and American ginseng, and the serum prostaglandin E2 level was reduced by American ginseng. In chronically treated mice, red and white ginseng reduced thyroxin levels. We conclude that Korean ginseng does not stimulate metabolism in mice, whereas a high dose of American ginseng may reduce night-time body temperature and pyrogen-related factors. PMID- 24467544 TI - Red cabbage (Brassica oleracea L.) mediates redox-sensitive amelioration of dyslipidemia and hepatic injury induced by exogenous cholesterol administration. AB - The widely used culinary vegetable, red cabbage (Brassica oleracea L. Var. capitata f. rubra), of the Brassicaceae family contains biologically potent anthocyanins and a myriad of antioxidants. Previous studies have shown that the pharmacological effects of red cabbage in vivo are redox-sensitive. The present study explored whether red cabbage modulates various histopathological and biochemical parameters in rats administered with a cholesterol-rich diet (CRD). To this end, prolonged administration of a lyophilized-aqueous extract of red cabbage (250 and 500 mg/kg body weight) significantly blunted the imbalances in lipids, liver enzymes and renal osmolytes induced by the CRD. The effects of red cabbage were compared to simvastatin (30 mg/kg body weight) treated rats. Estimation of malondialdehyde and non-protein sulfhydryls revealed robust antioxidant properties of red cabbage. Histopathological analysis of livers from rats administered with red cabbage showed marked inhibition in inflammatory and necrotic changes triggered by CRD. Similarly, in vitro studies using a 2',7' Dichlorofluorescein-based assay showed that red cabbage conferred cytoprotective effects in cultured HepG2 cells. In conclusion, the present study discloses the potential therapeutic effects of red cabbage in dyslipidemia as well as hepatic injury, that is at least, partly mediated by its antioxidant properties. PMID- 24467545 TI - Induction of Nrf2 and metallothionein as a common mechanism of hepatoprotective medicinal herbs. AB - Many Chinese medicines have the potential to be hepatoprotective and therefore can be used to treat acute and chronic liver diseases. The challenge is to identify the molecular target for their protective mechanism. This study investigated the induction of nuclear factor-erythroid 2(NF-E2)-related factor 2 (Nrf2) antioxidant genes and metallothionein as a common mechanism of hepatoprotective effects of Chinese medicines such as Piper puberulum. Mice were pretreated with Piper puberulum extract (PPE, 500 mg/kg, po) or vehicles for seven days, followed by intoxication with CCl 4 (25 MUl/kg, ip for 16 h), D galactosamine (800 mg/kg, ip for 8 h), or acetaminophen (400 mg/kg, ip for 8 h). Hepatotoprotection was evaluated by serum enzyme activities and histopathology. To determine the mechanism of protection, mice were given PPE (250-1000 mg/kg, po for seven days) and livers were collected to quantify the expression of Nrf2 targeted genes and metallothionein. Nrf2-null mice were also used to determine the role of Nrf2 in PPE-mediated hepatoprotection.PPE pretreatment protected against the hepatotoxicity produced by CCl 4, D-galactosamine, and acetaminophen, as evidenced by decreased serum enzyme activities and ameliorated liver lesions. PPE treatment increased the expression of hepatic Nrf2, NAD(P)H:quinone oxidoreductase1 (Nqo1), heme oxygenase-1 (Ho-1), glutamate-cysteine ligases (Gclc), and metallothionein (MT), at both transcripts and protein levels. PPE protected wild-type mice from CCl 4 and acetaminophen hepatotoxicity, but not Nrf2-null mice, fortifying the Nrf2-dependent protection. In conclusion, induction of the Nrf2 antioxidant pathways and metallothionein appears to be a common mechanism for hepatoprotective herbs such as PPE. PMID- 24467546 TI - Antinociceptive and anti-inflammatory activities of Cuscuta chinensis seeds in mice. AB - The seeds of Cuscuta chinensis, Cuscutae Semen, are commonly used as a medicinal material for treating the aching and weakness of the loins and knees, tonifying the defects of the liver and the kidney, and treating the diarrhea due to hypofunction of the kidney and the spleen. Since aching and inflammation are highly correlated with such diseases, the aim of this study is to investigate the possible antinociceptive and anti-inflammatory mechanisms of the seeds of C. chinensis. The antinociceptive effect of the seeds of C. chinensis was evaluated via the acetic acid-induced writhing response and formalin-induced paw licking methods. The anti-inflammatory effect was evaluated via the lambda-carrageenan induced mouse paw edema method. The results found that 100 and 500 mg/kg of the methanol extract of the seeds of C. chinensis( CC MeOH ) significantly decreased (p < 0.01 and p < 0.001, respectively) the writhing response in the acetic acid assay. Additionally, 20-500 mg/kg of CC MeOH significantly decreased licking time at the early (20 and 100 mg/kg, p < 0.001) and late phases (100 mg/kg, p < 0.01; 500 mg/kg, p < 0.001) of the formalin test, respectively. Furthermore, CC MeOH (100 and 500 mg/kg) significantly decreased (p < 0.01 and p < 0.001, respectively) edema paw volume four hours after lambda-carrageenan had been injected. The results in the following study also revealed that the anti inflammatory mechanism of CC MeOH may be due to declined levels of NO and MDA in the edema paw by increasing the activities of SOD, GPx and GRd in the liver. In addition, CC MeOH also decreased IL-1beta, IL-6, NF-kappaB, TNF-alpha, and COX-2 levels. This is the first study to demonstrate the possible mechanisms for the antinociceptive and anti-inflammatory effects of CC MeOH in vivo. Thus, it provides evidence for the treatment of Cuscutae Semen in inflammatory diseases. PMID- 24467547 TI - Effects of furanodiene on 95-D lung cancer cells: apoptosis, autophagy and G1 phase cell cycle arrest. AB - Furanodiene (FUR) is a natural terpenoid isolated from Rhizoma curcumae, a well known Chinese medicinal herb that presents anti-proliferative activities in several cancer cell lines. Herein, we systematically investigated the effects of FUR on the significant processes of tumor progression with the relatively low concentrations in 95-D lung cancer cells. FUR concentration-dependently inhibited cell proliferation and blocked the cell cycle progressions in G1 phase by down regulating the protein levels of cyclin D1 and CDK6, and up-regulating those of p21 and p27 in 95-D cells. FUR also affected the signaling molecules that regulate apoptosis in 95-D cells revealed by the down-regulation of the protein levels of full PARP, pro-caspase-7, survivin, and Bcl-2, and the up-regulation of cleaved PARP. Further studies showed that FUR enhanced the expression of light chain 3-II (LC3-II) in the protein level, indicating that autophagy is involved in this process. Besides, the adhesion ability of 95-D cells to matrigel and fibronectin was slightly inhibited after FUR treatment for 1 h in our experimental condition. FUR also slightly suppressed cell migration and invasion in 95-D cells according to the data from wound healing and Transwell assays, respectively. Taken together, FUR activated the signal molecules regulating G1 cell cycle arrest, apoptosis and autophagy, while slightly affecting the key steps of cell metastasis in 95-D lung cancer cells in the relatively low concentrations. PMID- 24467548 TI - Smilax riparia reduces hyperuricemia in mice as a potential treatment of gout. AB - The roots and rhizomes of Smilax riparia, called "Niu-Wei-Cai" in traditional Chinese medicine (TCM), are believed to be effective in treating gout symptoms. However, it is not clear if the uricosuric mechanisms of S. riparia support its therapeutic activities. In this study, we examined the efficacy of S. riparia in reducing serum uric acid levels in a potassium oxonate-induced hyperuricemia mouse model. We observed that the total saponins of S. riparia could down regulate renal mURAT1, resulting in the enhancement of urate excretion in the kidney of hyperuricemic mice. These results suggest that S. riparia could be an active anti-gout herbal medicine, which would contribute to the enhancement of uric acid excretion in the kidney. PMID- 24467549 TI - An allopurinol-controlled, multicenter, randomized, double-blind, parallel between-group, comparative study of febuxostat in Chinese patients with gout and hyperuricemia. AB - AIM: Febuxostat, a novel non-purine selective inhibitor of xanthine oxidase, has been identified as a potential alternative to allopurinol in patients with hyperuricemia. The purpose of this study was to compare the urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in Chinese gout patients with hyperuricemia. METHODS: Gout patients (n = 512) with serum uric acid (sUA) concentrations of at least 8.0 mg/dL were randomized to receive daily febuxostat 40 mg or 80 mg or allopurinol 300 mg for 28 weeks. Prophylaxis against gout flares with meloxicam or colchicine was provided during weeks 1 through 8. The primary endpoint was the percentage of subjects achieving a sUA concentration of <6.0 mg/dL at the last three monthly measurements. RESULTS: The primary endpoint was reached in 44.77% of patients receiving 80 mg of febuxostat, 27.33% of those receiving 40 mg of febuxostat, and 23.84% of those receiving allopurinol. The UL efficacy in the febuxostat 80 mg group was higher than in the allopurinol (P < 0.0001) and febuxostat 40 mg (P = 0.0008) groups. The UL efficacy of the febuxostat 40 mg group was statistically non-inferior to that of the allopurinol group. No significant change in the number of tophi was observed during the final visit relative to baseline in each treatment group. The rate of gout flares requiring treatment from weeks 9 through 28 and the incidence of adverse events was similar among treatment groups. CONCLUSIONS: The UL efficacy of daily febuxostat 80 mg was greater than that of febuxostat 40 mg and allopurinol 300 mg, which exhibited comparable UL efficacy. Safety of febuxostat and allopurinol was comparable at the doses tested. PMID- 24467550 TI - A tiered framework for risk-relevant characterization and ranking of chemical exposures: applications to the National Children's Study (NCS). AB - A challenge for large-scale environmental health investigations such as the National Children's Study (NCS), is characterizing exposures to multiple, co occurring chemical agents with varying spatiotemporal concentrations and consequences modulated by biochemical, physiological, behavioral, socioeconomic, and environmental factors. Such investigations can benefit from systematic retrieval, analysis, and integration of diverse extant information on both contaminant patterns and exposure-relevant factors. This requires development, evaluation, and deployment of informatics methods that support flexible access and analysis of multiattribute data across multiple spatiotemporal scales. A new "Tiered Exposure Ranking" (TiER) framework, developed to support various aspects of risk-relevant exposure characterization, is described here, with examples demonstrating its application to the NCS. TiER utilizes advances in informatics computational methods, extant database content and availability, and integrative environmental/exposure/biological modeling to support both "discovery-driven" and "hypothesis-driven" analyses. "Tier 1" applications focus on "exposomic" pattern recognition for extracting information from multidimensional data sets, whereas second and higher tier applications utilize mechanistic models to develop risk relevant exposure metrics for populations and individuals. In this article, "tier 1" applications of TiER explore identification of potentially causative associations among risk factors, for prioritizing further studies, by considering publicly available demographic/socioeconomic, behavioral, and environmental data in relation to two health endpoints (preterm birth and low birth weight). A "tier 2" application develops estimates of pollutant mixture inhalation exposure indices for NCS counties, formulated to support risk characterization for these endpoints. Applications of TiER demonstrate the feasibility of developing risk relevant exposure characterizations for pollutants using extant environmental and demographic/socioeconomic data. PMID- 24467552 TI - Cardiac resynchronization therapy plus coupled pacing improves acutely myocardial function in heart failure patients. AB - BACKGROUND: Coupled pacing (CP), which consists of an additional beat delivered after ventricular refractory period, has been proposed to reduce ventricular rate and increase ventricular contractility. We hypothesized that CP may be added to cardiac resynchronization therapy (CRT) to improve CRT effect in heart failure (HF) patients. METHODS: The study included 20 consecutive HF patients in sinus rhythm referred for CRT-defibrillator (CRT-D) implantation (baseline left ventricular ejection fraction [LVEF] 27 +/- 6%, baseline QRS duration 149 +/- 33 ms, age = 63 +/- 11 years). CP associated with CRT (CRT + CP) was delivered during CRT-D implantation from the right and left ventricular leads simultaneously. Echocardiography data were collected at baseline, during CRT and CRT + CP to assess changes in LVEF, cardiac output (CO), longitudinal global strain assessed by speckle tracking, and LV dyssynchrony (opposing wall delay using tissue Doppler imaging). RESULTS: Compared to the conventional CRT, heart rate (HR) markedly decreased during CRT + CP (79 +/- 20 beats/min vs 51 +/- 8 beats/min, P < 0.0001) and was associated with a significant increase in LVEF (30 +/- 8% vs 35 +/- 8%, P = 0.0002) and peak of longitudinal global strain (-6 +/- 2% vs -8 +/- 2%, P < 0.0001). Importantly, during CRT + CP, CO increased (3.8 +/- 1.0 L/min vs 4.4 +/- 1.4 L/min, P = 0.004) and cardiac synchronicity remained unchanged (38 +/- 24 ms for CRT alone vs 27 +/- 18 ms for CRT + CP, P = 0.1). CONCLUSION: In sinus rhythm HF patients, acute CP application in addition to CRT decreases HR and contributes to myocardial contractility and CO improvement without deleterious impact on ventricular synchronicity. PMID- 24467553 TI - Self-aggregation and optical absorption of stilbazolium merocyanine in chloroform. AB - Dipolar aggregation is in many cases detrimental for the functioning of optical materials. In this study we investigate self-aggregation and optical absorption of stilbazolium merocyanine (SM) in chloroform solution by performing classical Molecular Dynamics (MD) simulations under ambient conditions. The reversal solvatochromic shift, the large bathochromic shift, and the structured absorption band presented by SM in chloroform solution are all aspects of its optical absorption behavior for which the existence of self-aggregation is yet not completely understood. Moreover, the spectroscopic properties of SM oligomers and their occurrence in solvent of low polarity remain a relevant topic that deserves to be investigated. Our analysis of the aggregation behavior of SM in chloroform verified that the majority of the chromophores are involved in the formation of oligomers in solution, where the whole dimer and part of the trimer populations present a stable pi-stacking structure. The optical properties of the monomers and oligomers in solution were evaluated by means of a discrete polarizable embedding quantum mechanical/molecular mechanical (PE-QM/MM) response scheme where the quantum part is described at the level of density functional theory. The visible absorption spectrum of SM in chloroform is simulated using time average values obtained for the monomeric and oligomeric forms of SM from the PE QM/MM calculations performed on uncorrelated configurations extracted from the classical MD simulations. This study shows that the self-aggregation of SM in chloroform may exist, but it is not essential for reproducing the reversal solvatochromic shift in chloroform and that the process does not contribute to enhance the bathochromic shift nor explain the structure observed in its absorption band. Moreover, it is verified that since the electronic transitions of the monomer and oligomers are close together, changes in the interplane separation between the monomeric units of the stacked oligomers substantially affect the spectral resolution of their contribution to the optical absorption spectrum. PMID- 24467554 TI - A tandem reaction of benzyne with functionalized benzylidenephthalan to afford phenanthro[10,1-bc]furan. AB - A tandem reaction of benzyne with functionalized benzylidenephthalan for the synthesis of a variety of phenanthro[10,1-bc]furans has been achieved for the first time in moderate to good yields. The reaction mechanism involves a Diels Alder reaction and an intermolecular nucleophilic addition reaction as the key steps. PMID- 24467551 TI - Microbial ecology of arsenic-mobilizing Cambodian sediments: lithological controls uncovered by stable-isotope probing. AB - Microbially mediated arsenic release from Holocene and Pleistocene Cambodian aquifer sediments was investigated using microcosm experiments and substrate amendments. In the Holocene sediment, the metabolically active bacteria, including arsenate-respiring bacteria, were determined by DNA stable-isotope probing. After incubation with (13) C-acetate and (13) C-lactate, active bacterial community in the Holocene sediment was dominated by different Geobacter spp.-related 16S rRNA sequences. Substrate addition also resulted in the enrichment of sequences related to the arsenate-respiring Sulfurospirillum spp. (13) C-acetate selected for ArrA related to Geobacter spp. whereas (13) C-lactate selected for ArrA which were not closely related to any cultivated organism. Incubation of the Pleistocene sediment with lactate favoured a 16S rRNA-phylotype related to the sulphate-reducing Desulfovibrio oxamicus DSM1925, whereas the ArrA sequences clustered with environmental sequences distinct from those identified in the Holocene sediment. Whereas limited As(III) release was observed in Pleistocene sediment after lactate addition, no arsenic mobilization occurred from Holocene sediments, probably because of the initial reduced state of As, as determined by X-ray Absorption Near Edge Structure. Our findings demonstrate that in the presence of reactive organic carbon, As(III) mobilization can occur in Pleistocene sediments, having implications for future strategies that aim to reduce arsenic contamination in drinking waters by using aquifers containing Pleistocene sediments. PMID- 24467555 TI - Using structured expert judgment to assess invasive species prevention: Asian carp and the Mississippi-Great Lakes hydrologic connection. AB - Recently, authors have theorized that invasive species prevention is more cost effective than control in protecting ecosystem services. However, quantification of the effectiveness of prevention is rare because experiments at field scales are expensive or infeasible. We therefore used structured expert judgment to quantify the efficacy of 17 proposed strategies to prevent Asian carp invasion of the Laurentian Great Lakes via the hydrologic connection between the Mississippi and Great Lakes watersheds. Performance-weighted expert estimates indicated that hydrologic separation would prevent 99% (95,100; median, 5th and 95th percentiles) of Asian carp access, while electric and acoustic-bubble-strobe barriers would prevent 92% (85,95) and 92% (75,95), respectively. For all other strategies, estimated effectiveness was lower, with greater uncertainty. When potential invasions by other taxa are considered, the effectiveness of hydrologic separation increases relative to strategies that are effective primarily for fishes. These results could help guide invasive species management in many waterways globally. PMID- 24467556 TI - Therapeutic options for the treatment of chronic pain in dogs. AB - Chronic pain is a widely recognised problem in humans and is being increasingly recognised as a significant problem in dogs. Whilst a large number of therapies are described and utilised to treat chronic pain in dogs, there is a severe shortage of evidence to guide practitioners in selection of treatments. Until more evidence becomes available, practitioners should adopt a cautious approach, utilising licensed treatments first when possible. Non-pharmacological therapies should be incorporated into the chronic pain management plan whenever possible. Given the probable prevalence of chronic pain in dogs there is an urgent need for research to identify effective treatments. PMID- 24467557 TI - Structural equation modeling: a framework for ocular and other medical sciences research. AB - Structural equation modeling (SEM) is a modeling framework that encompasses many types of statistical models and can accommodate a variety of estimation and testing methods. SEM has been used primarily in social sciences but is increasingly used in epidemiology, public health, and the medical sciences. SEM provides many advantages for the analysis of survey and clinical data, including the ability to model latent constructs that may not be directly observable. Another major feature is simultaneous estimation of parameters in systems of equations that may include mediated relationships, correlated dependent variables, and in some instances feedback relationships. SEM allows for the specification of theoretically holistic models because multiple and varied relationships may be estimated together in the same model. SEM has recently expanded by adding generalized linear modeling capabilities that include the simultaneous estimation of parameters of different functional form for outcomes with different distributions in the same model. Therefore, mortality modeling and other relevant health outcomes may be evaluated. Random effects estimation using latent variables has been advanced in the SEM literature and software. In addition, SEM software has increased estimation options. Therefore, modern SEM is quite general and includes model types frequently used by health researchers, including generalized linear modeling, mixed effects linear modeling, and population average modeling. This article does not present any new information. It is meant as an introduction to SEM and its uses in ocular and other health research. PMID- 24467559 TI - Evaluation of fungal keratitis using a newly developed computer program, Optscore, for grading digital corneal photographs. AB - PURPOSE: To validate computer software developed to assess digital corneal photographs of fungal keratitis in clinical research. METHODS: A cornea specialist and five medical students (after training) graded on two occasions 100 corneal photographs of patients with fungal keratitis using Optscore software. Variables assessed were lesion area, location, degree of opacity, percentage of the ulcer lying within a central 4 mm circle of the cornea. Intraclass correlation coefficients (ICCs) were used to assess intragrader reliability, agreement of the students with the corneal specialist, and the reliability of the group mean of the student raters. The area determined using Optscore was compared to the area estimated from slit lamp and to visual acuity. RESULTS: As a group, medical students achieved an ICC greater than 0.9 for five out of the seven assessed variables. Similar levels of consistency were found after analyzing the graders' individual results compared to the specialist. The area estimated using slit lamp examination was highly correlated with the mean area determined by Optscore, as was the logarithm of the minimum angle of resolution visual acuity at enrollment. CONCLUSIONS: Non-expert graders using Optscore to assess digital photographs of fungal keratitis are self-consistent, agree with an expert grader both as a group and individually, and measurements of ulcer area obtained from Optscore are highly correlated with measurements of the same patients obtained on clinical examination. These observations support the validity of Optscore for assessing corneal pathology associated with fungal keratitis and make it a promising clinical research tool. PMID- 24467558 TI - Harmonizing the classification of age-related macular degeneration in the three continent AMD consortium. AB - PURPOSE: To describe methods to harmonize the classification of age-related macular degeneration (AMD) phenotypes across four population-based cohort studies: the Beaver Dam Eye Study (BDES), the Blue Mountains Eye Study (BMES), the Los Angeles Latino Eye Study (LALES), and the Rotterdam Study (RS). METHODS: AMD grading protocols, definitions of categories, and grading forms from each study were compared to determine whether there were systematic differences in AMD severity definitions and lesion categorization among the three grading centers. Each center graded the same set of 60 images using their respective systems to determine presence and severity of AMD lesions. A common 5-step AMD severity scale and definitions of lesion measurement cutpoints and early and late AMD were developed from this exercise. RESULTS: Applying this severity scale changed the age-sex adjusted prevalence of early AMD from 18.7% to 20.3% in BDES, from 4.7% to 14.4% in BMES, from 14.1% to 15.8% in LALES, and from 7.5% to 17.1% in RS. Age sex adjusted prevalences of late AMD remained unchanged. Comparison of each center's grades of the 60 images converted to the consortium scale showed that exact agreement of AMD severity among centers varied from 61.0-81.4%, and one step agreement varied from 84.7-98.3%. CONCLUSION: Harmonization of AMD classification reduced categorical differences in phenotypic definitions across the studies, resulted in a new 5-step AMD severity scale, and enhanced similarity of AMD prevalence among the four cohorts. Despite harmonization it may still be difficult to remove systematic differences in grading, if present. PMID- 24467560 TI - Prevalence of diabetes and diabetic retinopathy in a Brazilian population. AB - PURPOSE: To evaluate the prevalence of type 2 diabetes mellitus and diabetic retinopathy (DR) in a Brazilian population. METHODS: Population-based, cross sectional study conducted in 9 cities located in the Midwest region of the state of Sao Paulo, Brazil, between 2006 and 2007, including 4690 individuals aged >=30 years. Diabetes was self-reported and DR was assessed by indirect ophthalmoscopy. RESULTS: The prevalence of type 2 diabetes was 8.68% (95% confidence interval, CI, 7.87-9.48%), and DR was present in 7.62% (95% CI 5.02-10.20%) of participants with self-reported type 2 diabetes. Approximately 35.4% of individuals diagnosed with DR did not know they had diabetes prior to DR diagnosis. Prevalences of low vision and blindness were higher among those with diabetes and DR. Cataract was still a major cause of blindness in this population. CONCLUSION: This is the first large population-based study on DR in Brazil. High rates of visual impairment were found in persons with type 2 diabetes, but cataract is still one of the main causes of blindness. Large surveys are necessary for public health policy advocacy in developing countries. PMID- 24467561 TI - Characteristics of undiagnosed primary open-angle glaucoma: the Tajimi Study. AB - PURPOSE: To evaluate the characteristics of patients with previously undiagnosed primary open-angle glaucoma (POAG) in the Tajimi Study. METHODS: Background and ophthalmic examination data from 111 patients previously undiagnosed with POAG from the Tajimi Study, a population-based survey of glaucoma, were analyzed and compared with those of eight patients with previously diagnosed glaucoma. RESULTS: The mean deviation (MD) and vertical cup-to-disc ratio (vC/D) of the worse eye of each patient averaged -5.5 decibels (dB) and 0.72 and -10.4 dB and 0.83, respectively, in undiagnosed and diagnosed POAG. In undiagnosed POAG, arcuate and partial arcuate patterns accounted for 50% of the pattern of the visual field (VF) damage, and 95% of patients presented with intraocular pressure of 21 mmHg or less (normal tension glaucoma). The undiagnosed group had better MD and smaller vC/D values in the worse eye and less involvement of bilateral VFs than the diagnosed group (p = 0.004-0.050 with Bonferroni correction), while other factors, including mean sensitivity of the binocular VF, showed no intergroup difference. CONCLUSION: The characteristics of Japanese patients with previously undiagnosed POAG indicated that bilateral evaluation of the optic disc and VF are important for identifying individuals with glaucoma. PMID- 24467562 TI - Impact of changes in antibiotic prophylaxis on postoperative endophthalmitis in a Spanish hospital. AB - OBJECTIVE: This study aims to assess whether changes in antibiotic prophylaxis used in cataract surgery in the La Mancha Centro General Hospital, Spain, were associated with a reduced incidence of postoperative endophthalmitis (POE). METHODS: The hospital employed two different antibiotic prophylaxis regimens during two clearly differentiated periods. In the first period (January 2000 to April 2003), subconjunctival injections of gentamicin were used while in the second (May 2003 to December 2008), vancomycin and gentamicin were added to the irrigating solution. During both periods, povidone iodine was used at the site of surgery and aminoglycoside eye drops were administered postoperatively. A Poisson regression model was used to evaluate the relationship between the incidence rate of endophthalmitis and variables such as time trends, seasonality, and change in antibiotic prophylaxis regimen. RESULTS: During the period between 2000 and 2008, 26 cases of POE were detected after 14,285 operations for an incidence rate (IR) of 1.8 cases per 1000 procedures (95% confidence interval 1.2-2.7 cases out of 1000 procedures). In the period prior to the change in prophylaxis, 23 cases were detected (IR 4.5 cases/1000 procedures) while only three cases were observed in the period after the change (IR 0.3 cases/1000 procedures). A total of 84% of the microorganisms isolated were gram-positive, and all were sensitive to vancomycin. CONCLUSIONS: The change in antibiotic prophylaxis regimen for cataract surgery was associated with a relevant and significant decrease in the incidence of POE. PMID- 24467564 TI - Age at menarche in a group of French schoolgirls. AB - BACKGROUND: Mean age at menarche in France decreased from 12.78 years in 1979 to 12.6 years in 1994. The aim of this study was to determine mean age at first menstruation in French adolescent girls in order to study the secular trend. METHODS: Age at first menstruation was noted to the nearest month during recording of anthropometric measurements in three secondary schools in the Aisne administrative department, France, in classes in years 7, 8, 9 and 10. A total of 339 girls aged 11-15 1/2 years were examined. The majority were from a social background of workers, employees and middle managerial staff. Mean age at first menses and standard deviation were calculated using the probits method. RESULTS: Mean age was 12.5 +/- 0.08 years (chi(2) gamma=14 = 16.7, P > 0.05), indicating that it had remained stable for more than 15 years. CONCLUSIONS: A secular decline has already been observed in Belgium, Britain, Hungary, Scandinavia and the USA. In all these countries, age at menarche has reached a stable level at around 13 +/- 0.5 years. PMID- 24467563 TI - Aditya Jyot-Diabetic Retinopathy in Urban Mumbai Slums Study (AJ-DRUMSS): study design and methodology - report 1. AB - PURPOSE: To describe the methodology of Aditya Jyot-Diabetic Retinopathy in Urban Mumbai Slums Study (AJ-DRUMSS), which was designed (i) to estimate the prevalence of diabetic retinopathy (DR) in a general population, (ii) to study the risk factors associated with DR in those with type 2 diabetes mellitus (DM), and (iii) to create awareness for early detection and develop timely interventional management for DR. METHODS: AJ-DRUMSS is an ongoing population-based cross sectional study conducted in seven wards of slums in Mumbai, India, wherein eligible subjects from the general population were screened for DR and profiled for their demographic, social and biochemical parameters to study the associations of these factors. RESULTS: To date, nearly 54,000 households have been enumerated for both awareness and DR prevalence in five study areas (out of seven) during 17 awareness campaigns and 78 DR screening camps. Of these, 4295 households were included in AJ-DRUMSS. Nearly 15,000 camp subjects (including subjects from awareness-focused areas who also turned up for the screening camps) were screened from the total enumerated households, of which 16.1% were diagnosed with type 2 DM. A total of 14.5% of these had evidence of DR and 3.5% had sight threatening DR. CONCLUSIONS: A detailed study design of AJ-DRUMSS is described. In the screening camps nearly 3.5% of the diabetic population had sight threatening DR, which needed an active interventional strategy. This study will help in formulating efficient eye care policies, making optimum use of available resources, reorienting healthcare providers and the ignorant within the population regarding the need for periodic ophthalmic surveillance and timely intervention. PMID- 24467565 TI - Insulin degludec's ultra-long pharmacokinetic properties observed in adults are retained in children and adolescents with type 1 diabetes. AB - Insulin degludec (IDeg) is a basal insulin with an ultra-long pharmacokinetic profile in adults that at steady-state produces remarkably flat and stable insulin levels; however, no studies have yet reported on the pharmacokinetic properties of IDeg in subjects younger than 18 years of age. This was a single centre, randomised, single-dose, double-blind, two-period crossover trial conducted in children (6-11 years), adolescents (12-17 years), and adults (18-65 years) with type 1 diabetes. Subjects received a single subcutaneous dose of 0.4 U/kg IDeg or insulin glargine (IGlar), respectively, on two separate dosing visits, with pharmacokinetic blood sampling up to 72-h postdose. A total of 37 subjects (12 children, 13 adolescents, and 12 adults) completed the trial. Total exposure of IDeg after a single dose (AUCIDeg ,0-infinity, SD ) was higher in children compared to adults [estimated ratio children/adults 1.48 (95% confidence interval, CI: 0.98; 2.24)] and in adolescents compared to adults [estimated ratio adolescents/adults 1.33 (95% CI: 1.08; 1.64)]; however, the difference was only statistically significant for the latter comparison. No statistically significant difference in maximum concentration of IDeg (Cmax, IDeg , SD ) was observed. Estimated ratios for Cmax, IDeg , SD were (children/adults) 1.20 (95% CI: 0.90; 1.60) and (adolescents/adults) 1.23 (95% CI: 1.00; 1.51). Simulated mean steady state pharmacokinetic profiles supported a flat and stable IDeg exposure across a 24-h dosing interval. IDeg was detectable in serum for at least 72 h (end of blood sampling period) in all subjects following single dose. In conclusion, the ultra-long pharmacokinetic properties of IDeg observed in adults are preserved in children and adolescents with type 1 diabetes. PMID- 24467566 TI - Biphase stratification approach to three-dimensional dendritic biodegradable mesoporous silica nanospheres. AB - A kind of novel uniform monodispersed three-dimensional dendritic mesoporous silica nanospheres (3D-dendritic MSNSs) has been successfully synthesized for the first time. The 3D-dendritic MSNSs can have hierarchical mesostructure with multigenerational, tunable center-radial, and dendritic mesopore channels. The synthesis was carried out in the heterogeneous oil-water biphase stratification reaction system, which allowed the self-assembly of reactants taking place in the oil-water interface for one-pot continuous interfacial growth. The average pore size of each generation for the 3D-dendritic MSNSs can be adjusted from 2.8 to 13 nm independently, which can be controlled by the varied hydrophobic solvents and concentration of silica source in the upper oil phase. The thickness of each generation can be tuned from ~ 5 to 180 nm as desired, which can be controlled by the reaction time and amount of silica source. The biphase stratification approach can also be used to prepare other core-shell and functional mesoporous materials such as Au nanoparticle@3D-dendritic MSNS and Ag nanocube@3D-dendritic MSNS composites. The 3D-dendritic MSNSs show their unique advantage for protein loading and releasing due to their tunable large pore sizes and smart hierarchical mesostructures. The maximum loading capacity of bovine beta lactoglobulin with 3D-dendritic MSNSs can reach as high as 62.1 wt % due to their large pore volume, and the simulated protein releasing process can be tuned from 24 to 96 h by flexible mesostructures. More importantly, the releasing rates are partly dependent on the hierarchical biodegradation, because the 3D-dendritic MSNSs with larger pore sizes have faster simulated biodegradation rates in simulated body fluid. The most rapid simulated biodegradation can be finished entirely in 24 h, which has been greatly shortened than two weeks for the mesoporous silica reported previously. As the inorganic mesoporous materials, 3D dendritic MSNSs show excellent biocompatibility, and it would have a hopeful prospect in the clinical applications. PMID- 24467567 TI - Increased muscular triglyceride content and hyperglycemia in Goto-Kakizaki rat are decreased by egg white hydrolysate. AB - We investigated the fat metabolic characteristics in non-obese and diabetic Goto Kakizaki (GK) rat and the effects of dietary egg white hydrolysate (EWH) on glucose and fat metabolism. Wistar (W) and GK (G) rats were placed into dietary casein (WC and GC) or EWH (WE and GE) group, and fed their respective diet for six weeks. Triglyceride (TG) content and stearoyl-CoA desaturase (SCD) indices in the soleus muscle were higher in the GC group than WC group in parallel with worsening serum glucose metabolic parameters. The glucose metabolic parameters were significantly improved in the GE group. The TG accumulation and SCD indices in the soleus muscle were also significantly lower in the GE group than in the GC group. In conclusion, dietary EWH not only improved glucose metabolism but also reduced both TG accumulation and SCD indices in the soleus muscle of GK rat. PMID- 24467568 TI - Why is there no morphine concentration-response curve for acute pain? PMID- 24467570 TI - Hunger and thirst numeric rating scales are not valid estimates for gastric content volumes: a prospective investigation in healthy children. AB - AIM: A rating scale for thirst and hunger was evaluated as a noninvasive, simple and commonly available tool to estimate preanesthetic gastric volume, a surrogate parameter for the risk of perioperative pulmonary aspiration, in healthy volunteer school age children. METHOD: Numeric scales with scores from 0 to 10 combined with smileys to rate thirst and hunger were analyzed and compared with residual gastric volumes as measured by magnetic resonance imaging and fasting times in three settings: before and for 2 h after drinking clear fluid (group A, 7 ml/kg), before and for 4 vs 6 h after a light breakfast followed by clear fluid (7 ml/kg) after 2 vs 4 h (crossover, group B), and before and for 1 h after drinking clear fluid (crossover, group C, 7 vs 3 ml/kg). RESULTS: In 30 children aged 6.4-12.8 (median 9.8) years, participating on 1-5 (median two) study days, 496 sets of scores and gastric volumes were determined. Large inter- and intra individual variations were seen at baseline and in response to fluid and food intake. Significant correlations were found between hunger and thirst ratings in all groups, with children generally being more hungry than thirsty. Correlations between scores and duration of fasting or gastric residual volumes were poor to moderate. Receiver operating characteristic (ROC) analysis revealed that thirst and hunger rating scales cannot predict gastric content. CONCLUSION: Hunger and thirst scores vary considerably inter- and intra-individually and cannot predict gastric volume, nor do they correlate with fasting times in school age children. PMID- 24467569 TI - The association between brain injury, perioperative anesthetic exposure, and 12 month neurodevelopmental outcomes after neonatal cardiac surgery: a retrospective cohort study. AB - BACKGROUND: Adverse neurodevelopmental outcomes are observed in up to 50% of infants after complex cardiac surgery. We sought to determine the association of perioperative anesthetic exposure with neurodevelopmental outcomes at age 12 months in neonates undergoing complex cardiac surgery and to determine the effect of brain injury determined by magnetic resonance imaging (MRI). METHODS: Retrospective cohort study of neonates undergoing complex cardiac surgery who had preoperative and 7-day postoperative brain MRI and 12-month neurodevelopmental testing with Bayley Scales of Infant and Toddler Development, Third Edition (Bayley-III). Doses of volatile anesthetics (VAA), benzodiazepines, and opioids were determined during the first 12 months of life. RESULTS: From a database of 97 infants, 59 met inclusion criteria. Mean +/- sd composite standard scores were as follows: cognitive = 102.1 +/- 13.3, language = 87.8 +/- 12.5, and motor = 89.6 +/- 14.1. After forward stepwise multivariable analysis, new postoperative MRI injury (P = 0.039) and higher VAA exposure (P = 0.028) were associated with lower cognitive scores. ICU length of stay (independent of brain injury) was associated with lower performance on all categories of the Bayley-III (P < 0.02). CONCLUSIONS: After adjustment for multiple relevant covariates, we demonstrated an association between VAA exposure, brain injury, ICU length of stay, and lower neurodevelopmental outcome scores at 12 months of age. These findings support the need for further studies to identify potential modifiable factors in the perioperative care of neonates with CHD to improve neurodevelopmental outcomes. PMID- 24467571 TI - A pathfinder technique of laryngeal mask airway placement in an infant with severe contracture of face, neck, and chest. PMID- 24467572 TI - Intranasal clonidine pharmacokinetics. PMID- 24467573 TI - Supraclavicular subclavian vein catheterization is still forgotten. PMID- 24467574 TI - Reply: Sener, supraclavicular subclavian vein catheterization is still forgotten. PMID- 24467575 TI - Central venous catheter placement in children. PMID- 24467576 TI - Epidural blood patch relieves positional diplopia following lumbar punctures. PMID- 24467577 TI - Reply to Breschan et al, re 'central venus catheter placement in children'. PMID- 24467578 TI - The laparoscopic approach in children with cardiopathy: a mosaic still awaiting completion. PMID- 24467579 TI - Intra-operative hypoglycemia and electrolyte imbalance in a child with Apert syndrome during craniosynostosis surgery. PMID- 24467580 TI - External reinforcement for extraoral kinking of tracheal tube during pediatric anesthesia. PMID- 24467581 TI - Ultrasound-guided rectus sheath blocks for open pyloromyotomy: a chance to turn down the gas. PMID- 24467582 TI - Lactoferrin-appended solid lipid nanoparticles of paclitaxel for effective management of bronchogenic carcinoma. AB - Lung cancer is a dreadful disease which claims to be more life threatening as compared to total sum up of colon, prostate and breast cancers. Thus, there is an urgent need to develop an effective delivery approach for its management. Paclitaxel (PTX) is one of the well-known choice as antineoplasitic agent used for the treatment of different types of human cancers such as non-small-cell lung, head and neck cancers, leukemia, breast, ovarian and melanoma. Lactoferrin (Lf), a "multifunctional protein" is crucial for natural immunity which is secreted by exocrine glands. Lf receptors are expressed on the apical surface on bronchial epithelial cells. These over-expressed LF receptors can be utilized for the transportation of Lf-conjugated drug or nanocarrier devices. The present study was aimed to develop PTX-loaded Lf-coupled solid lipid nanoparticles (SLNs) for the treatment of lung cancer. PTX-loaded SLNs were prepared, characterized and then coupled with Lf using carbodiimide chemistry. The formulations were characterized by transmission electron microscopy, particle size, polydispersity index and zeta potential, whereas Lf conjugation was confirmed by FT-IR and 1H NMR and efficiency of prepared system was evaluated by in vitro, ex vivo and in vivo evaluations. The ex vivo cytotoxicity studies on human bronchial epithelial cell lines, BEAS-2B, revealed superior anticancer activity of Lf-coupled SLNs than plain SLNs and free PTX. In vivo biodistribution studies showed higher concentrations of PTX accumulated in lungs via Lf-coupled SLNs than plain SLNs and free PTX. These studies suggested that Lf-coupled PTX-loaded SLNs could be used as potential targeting carrier for delivering anticancer drug to the lungs with the minimal side effects. PMID- 24467583 TI - Colloidal polymers via dipolar assembly of magnetic nanoparticle monomers. AB - In this Spotlight on Applications, we describe our recent progress in the preparation of hierarchical one-dimensional (1-D) materials constructed from polymer-coated ferromagnetic cobalt nanoparticles. We begin with a general discussion of nanoparticles capable of 1-D self-organization to form 1-D assemblies, which we term colloidal polymers. The need for efficient, highly directional interactions prompted our investigation with polymer-coated ferromagnetic nanoparticles, which spontaneously form linear assemblies through coupling of north and south magnetic poles present in these single-domain ferromagnetic nanoparticles. These highly directional N-S interactions and the resulting formation of 1-D assemblies can be understood in the context of traditional polymer-forming reactions. The dipolar assembly of these ferromagnetic nanoparticles into chains and binary assemblies while dispersed in organic media has been investigated as a key foundation to form novel magnetic materials and heterostructured nanocomposites. These studies enabled the fabrication of magnetic nanoactuating systems resembling "artificial cilia and flagella". We then discuss our recent efforts to prepare cobalt oxide nanowires using various nanoparticle conversion reactions through a process termed colloidal polymerization. A series of novel functional "colloidal monomers" based on dipolar cobalt nanoparticles were also prepared, incorporating noble metal or semiconductor nanoinclusions to form heterostructured cobalt oxide nanocomposites. PMID- 24467586 TI - Food additive carrageenan: Part II: A critical review of carrageenan in vivo safety studies. AB - Carrageenan (CGN) is a seaweed-derived high molecular weight (Mw) hydrocolloid, primarily used as a stabilizer and thickener in food. The safety of CGN regarding its use in food is reviewed. Based on experimental studies in animals, ingested CGN is excreted quantitatively in the feces. Studies have shown that CGN is not significantly degraded by low gastric pH or microflora in the gastrointestinal (GI) tract. Due to its Mw, structure and its stability when bound to protein, CGN is not significantly absorbed or metabolized. CGN also does not significantly affect the absorption of nutrients. Subchronic and chronic feeding studies in rodents indicate that CGN at doses up to 5% in the diet does not induce any toxicological effects other than soft stools or diarrhea, which are a common effect for non-digestible high molecular weight compounds. Review of several studies from numerous species indicates that food grade CGN does not produce intestinal ulceration at doses up to 5% in the diet. Effects of CGN on the immune system following parenteral administration are well known, but not relevant to food additive uses. The majority of the studies evaluating the immunotoxicity potential were conducted with CGN administered in drinking water or by oral gavage where CGN exists in a random, open structured molecular conformation, particularly the lambda form; hence, it has more exposure to the intestinal mucosa than when bound to protein in food. Based on the many animal subchronic and chronic toxicity studies, CGN has not been found to affect the immune system, as judged by lack of effects on organ histopathology, clinical chemistry, hematology, normal health, and the lack of target organ toxicities. In these studies, animals consumed CGN at orders of magnitude above levels of CGN in the human diet: >=1000 mg/kg/d in animals compared to 18-40 mg/kg/d estimated in the human diet. Dietary CGN has been shown to lack carcinogenic, tumor promoter, genotoxic, developmental, and reproductive effects in animal studies. CGN in infant formula has been shown to be safe in infant baboons and in an epidemiology study on human infants at current use levels. PMID- 24467585 TI - Heart ischaemia-reperfusion induces local up-regulation of vasoconstrictor endothelin ETB receptors in rat coronary arteries downstream of occlusion. AB - BACKGROUND AND PURPOSE: Endothelins act via two receptor subtypes, ETA and ETB . Under physiological conditions in coronary arteries, ETA receptors expressed in smooth muscle cells mediate vasoconstriction whereas ETB receptors mainly found in endothelial cells mediate vasorelaxation. However, under pathophysiological conditions, ETB receptors may also be expressed in vascular smooth muscle cells mediating vasoconstriction. Here, we have investigated whether vasoconstrictor ETB receptors are up-regulated in coronary arteries after experimental myocardial ischaemia in rats. EXPERIMENTAL APPROACH: Male Sprague-Dawley rats were subjected to either heart ischaemia-reperfusion (15 min ischaemia and 22 h reperfusion), permanent ischaemia (22 h) by ligation of the left anterior descending coronary artery, or sham operation. Using wire myography, the endothelin receptor subtypes mediating vasoconstriction were examined in isolated segments of the left anterior descending and the non-ligated septal coronary arteries. Endothelin receptor-mediated vasoconstriction was examined with cumulative administration of sarafotoxin 6c (ETB receptor agonist) and endothelin-1 (with or without ETA or ETB receptor blockade). The distribution of ETB receptors was localized with immunohistochemistry and quantified by Western blot. KEY RESULTS: Endothelin ETB receptor-mediated vasoconstriction and receptor protein levels were significantly augmented in coronary arteries situated downstream of the occlusion after ischaemia-reperfusion compared with non-ischaemic arteries. In contrast, the ETA receptor-mediated vasoconstriction was unaltered in all groups. CONCLUSIONS AND IMPLICATIONS: Ischaemia-reperfusion induced local up-regulation of ETB receptors in the smooth muscle cells of coronary arteries in the post-ischaemic area. In contrast, in non-ischaemic areas, ETB receptor function was unaltered. PMID- 24467587 TI - Editorial: Assessment of nutritional status in clinical settings. PMID- 24467588 TI - Development and reliability testing of the quality clinical placement evaluation tool. AB - AIMS AND OBJECTIVES: To develop and test the content and face validity, and reliability of the quality clinical placement evaluation tool. BACKGROUND: The importance of clinical experience during undergraduate nursing degrees is undisputed. To date, tools available to measure quality of clinical placements have focused on single perspectives, that of the undergraduate or that of the supervising nurse. The quality clinical placement evaluation tool was proposed to provide an assessment of clinical placement experiences informed by supervising ward nurses and undergraduate stakeholders. DESIGN: The study employed a cross sectional design. METHODS: The internal validity of an existing instrument was evaluated by an expert panel and modified for use in the acute care sector. Surveys were completed by undergraduate students (n = 48) and supervising ward nurses (n = 47). Factor analysis was used to identify themes drawn from the literature and explore redundancy of items. Reliability was assessed using Cronbach's alpha for internal consistency and test-retest (five to seven days apart). RESULTS: Reliability testing showed good internal consistency for the tool; test-retest reliability testing results were moderate to good for students and fair to moderate for nurses. Factor analysis identified three core themes related to supervising ward nurse responses that could also be applied to undergraduate nurses. The domains identified were the following: welcome and belonging; support to meet learning needs; and confidence and competence: reflections on learning. CONCLUSIONS: The quality clinical placement evaluation has shown statistically acceptable levels of reliability and validity for measuring the quality of clinical placement from perspectives of undergraduates and supervising ward nurses. RELEVANCE TO CLINICAL PRACTICE: The tool provides tertiary institutions, acute care facilities, wards and individuals with the means to capture views of the quality of clinical placement which can also be used to undertake comparisons over time and between sites. PMID- 24467589 TI - Commentary on Son H, Thomas SA and Friedmann E (2012) The association between psychological distress and coping patterns in post-MI patients and their partners. Journal of Clinical Nursing 21, 2392-2394. PMID- 24467590 TI - Inference for reaction networks using the linear noise approximation. AB - We consider inference for the reaction rates in discretely observed networks such as those found in models for systems biology, population ecology, and epidemics. Most such networks are neither slow enough nor small enough for inference via the true state-dependent Markov jump process to be feasible. Typically, inference is conducted by approximating the dynamics through an ordinary differential equation (ODE) or a stochastic differential equation (SDE). The former ignores the stochasticity in the true model and can lead to inaccurate inferences. The latter is more accurate but is harder to implement as the transition density of the SDE model is generally unknown. The linear noise approximation (LNA) arises from a first-order Taylor expansion of the approximating SDE about a deterministic solution and can be viewed as a compromise between the ODE and SDE models. It is a stochastic model, but discrete time transition probabilities for the LNA are available through the solution of a series of ordinary differential equations. We describe how a restarting LNA can be efficiently used to perform inference for a general class of reaction networks; evaluate the accuracy of such an approach; and show how and when this approach is either statistically or computationally more efficient than ODE or SDE methods. We apply the LNA to analyze Google Flu Trends data from the North and South Islands of New Zealand, and are able to obtain more accurate short-term forecasts of new flu cases than another recently proposed method, although at a greater computational cost. PMID- 24467591 TI - Selective cyclooxygenase inhibitors: current status. AB - For ages aspirin has established its value as an analgesic, anti-inflammatory drug, but in 1938, it was found to be a causative factor of gastric inflammation (ulcer). Later discovered non-steroidal anti-inflammatory drugs (NSAIDs) were found effective as aspirin but failed to overcome the goal of safer aspirin. As the method of prostaglandin inhibition through COX is a common mechanism to both the wanted and unwanted effects of aspirin and non-aspirin NSAIDs, the COX enzyme becomes a target for drug designers for the development of the "safe aspirin". In the late 1990s, a new class of drug molecules collectively known as selective inhibitors of cyclooxygenase-2(Coxibs) was developed for the treatment of pain and inflammation. Coxibs developed were as efficacious as the common NSAIDs, but they are devoid of major side effect, the gastrointestinal bleeding. This review presents an overview on all the discovered COX-2 inhibitors, their physiological role, side effects and reasons of their withdrawal. PMID- 24467592 TI - Comparative evaluation of aqueous humor viscosity. AB - OBJECTIVE: To evaluate aqueous humor viscosity in the raptor, dog, cat, and horse, with a primary focus on the barred owl (Strix varia). ANIMALS STUDIED: Twenty-six raptors, ten dogs, three cats, and one horse. PROCEDURE: Animals were euthanized for reasons unrelated to this study. Immediately, after horizontal and vertical corneal dimensions were measured, and anterior chamber paracentesis was performed to quantify anterior chamber volume and obtain aqueous humor samples for viscosity analysis. Dynamic aqueous humor viscosity was measured using a dynamic shear rheometer (AR 1000 TA Instruments, New Castle, DE, USA) at 20 degrees C. Statistical analysis included descriptive statistics, unpaired t tests, and Tukey's test to evaluate the mean +/- standard deviation for corneal diameter, anterior chamber volume, and aqueous humor viscosity amongst groups and calculation of Spearman's coefficient for correlation analyses. RESULTS: The mean aqueous humor viscosity in the barred owl was 14.1 centipoise (cP) +/- 9, cat 4.4 cP +/- 0.2, and dog 2.9 cP +/- 1.3. The aqueous humor viscosity for the horse was 1 cP. CONCLUSIONS: Of the animals evaluated in this study, the raptor aqueous humor was the most viscous. The aqueous humor of the barred owl is significantly more viscous than the dog (P < 0.0001). The aqueous humor viscosity of the raptor, dog, cat, and horse can be successfully determined using a dynamic shear rheometer. PMID- 24467594 TI - Reactivity switch enabled by counterion: highly chemoselective dimerization and hydration of terminal alkynes. AB - A counterion-controlled reactivity tuning in Pd-catalyzed highly chemoselective and regioselective dimerization and hydration of terminal alkynes is reported. The use of acetate as counterion favors the formation of an alkenyl alkynyl palladium intermediate which forms hitherto less reported 1,3-diaryl-substituted conjugated enynes after reductive elimination. Using chloride, which is a better leaving group, leads to anion exchange on the alkenylpalladium intermediate with hydroxide which after reductive elimination and tautomerization delivered the hydration products. PMID- 24467593 TI - Accumulation of amikacin in synovial fluid after regional limb perfusion of amikacin sulfate alone and in combination with ticarcillin/clavulanate in horses. AB - OBJECTIVES: To determine the effect of regional limb perfusion (RLP) with amikacin sulfate alone and in combination with ticarcillin/clavulanate on synovial fluid concentration and antimicrobial activity of amikacin. SAMPLE POPULATION: Experimental study. METHODS: RLP with amikacin alone (A; 2.5 g) or amikacin and ticarcillin/clavulanate (AT; 2.5 g amikacin, 7 g ticarcillin/clavulanate) was performed with a tourniquet placed at mid antebrachium in standing, sedated horses. Perfusate blood was collected immediately after injection and again before tourniquet release. Blood from the jugular vein was collected before tourniquet release. Synovial fluid from the middle carpal joint was collected 0, 30, and 60 minutes after tourniquet release. Amikacin concentration and antimicrobial activity of synovial fluid against Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, and Pseudomonas aeruginosa were determined. RESULTS: There was significantly lower amikacin concentration in the middle carpal joint synovial fluid of group AT compared with group A at 30 minutes (AT = median 4.4 ug/mL, IQR 3.0-11.2 ug/mL; A = 17.5 ug/mL, 6.6-80.1 ug/mL) and 60 minutes (AT = median 4.6 ug/mL, IQR 3.1-8.1 ug/mL; A = 15.0 ug/mL, 6.7-61.7 ug/mL) after tourniquet release. Zones of inhibition for ticarcillin-resistant Klebsiella pneumoniae from group AT were significantly smaller than group A from synovial fluid at 30 and 60 minutes after tourniquet release and in the perfusate serum before tourniquet release. CONCLUSIONS: The combination of amikacin with ticarcillin/clavulanate during RLP resulted in significantly lower amikacin synovial concentration and antimicrobial activity on amikacin susceptible and ticarcillin resistant cultures compared with amikacin alone. PMID- 24467595 TI - Molecular dynamics simulations on the frictional behavior of a perfluoropolyether film sandwiched between diamond-like-carbon coatings. AB - We perform molecular dynamics simulations to investigate the nanoscale frictional behavior of a perfluoropolyether (PFPE) film sandwiched between two diamond-like carbon (DLC) coatings. We show that the PFPE films behave like a solid and can perform either a motion-station movement or a continuous motion with fluctuating velocities. The former movement is caused by the alternating stick and slip at the two individual interfaces, while the latter is due to the dynamic sliding motions simultaneously occurring at both interfaces. We reveal that these motion characteristics are governed by the competition between the two interfacial adhesion energies, which are strongly affected by the thermal vibrations and interface roughness fluctuations. We also find that the Amonton's law modified by incorporating the adhesion effect can be used to describe the mean friction traction vs normal pressure relation, but large fluctuations are present at low contact pressures. The magnitude of atomic level friction forces at the interface is found to be highly nonuniform. The directions of atomic level friction forces can even be opposite. With increasing the normal pressure, the nonuniformity of atomic level friction forces decreases first and then increases again. This change can be explained by the concurrent effects from the large difference in material stiffness and the changes in surface roughness under normal pressure. The present work reveals interesting insights into the sliding mechanisms in sandwiched structures and provides useful guidelines for the design of nanoscale lubricant systems. PMID- 24467596 TI - Reaction mechanism of homoprotocatechuate 2,3-dioxygenase with 4-nitrocatechol: implications for the role of substrate. AB - The reaction mechanism of the dioxygen activation by homoprotocatechuate 2,3 dioxygenase (HPCD) with the substrate 4-nitrocatechol was investigated by quantum mechanical/molecular mechanical calculations. Our results demonstrated that the experimentally determined side-on iron-oxygen complex in crystallo is a semiquinone substrate radical (SQ(*))-Fe(III)-hydroperoxo species, which could not act as the reactive species. In fact, the Fe(III)-superoxo species with a hydrogen bond between His200 and the proximal oxygen is the reactive oxygen species. The second-sphere His200 residue was found to play an important role in manipulating the orientation of the superoxide in the Fe-O2 adduct for the further reaction. The rate-limiting step is the attack of the superoxo group on the substrate with a barrier of 17.2 kcal/mol, in good agreement with the experimental value of 16.8 kcal/mol. The reaction mechanism was then compared with the one for HPCD with its native substrate homoprotocatechuate studied recently by the same methods, in which a hybrid SQ(*)-Fe(II)-O2(*-)/Fe(III)-O2(* ) was suggested to be the reactive species. Therefore, our studies suggested that the substrate plays important roles in the dioxygen activation by HPCD. PMID- 24467597 TI - Biochemical effects of salinity on oxygen isotope fractionation during cellulose synthesis. AB - The current isotope tree ring model assumes that 42% of the sucrose oxygen exchanges with stem water during cellulose synthesis and that the oxygen isotope biochemical fractionation is c. 270/00. However, previous studies have indicated that this model can overestimate the cellulose oxygen isotope ratio of plants under salinity or water stress. Saline stress increases soluble carbohydrates and osmolytes, which can alter exchange and biochemical fractionation during cellulose synthesis. To test the effect of salinity as well as the synthesis of osmolytes on exchange and biochemical fractionation, we grew wild-type and a transgenic mannitol synthesizer Arabidopsis thaliana hydroponically with fresh and saline water. We then measured the oxygen isotope ratios of leaf water, stem water and stem cellulose to determine the effects on exchange and biochemical fractionation. Biochemical fractionation did not change, but oxygen isotope exchange was twice as high for plants grown in saline water relative to freshwater-treated plants (0.64 and 0.3, respectively). Mannitol (osmolyte) synthesis did not affect exchange or biochemical fractionation regardless of salinity. Increases in salinity increased oxygen isotope exchange during cellulose synthesis, which may explain the overestimation of cellulose delta(18) O values under saline conditions. PMID- 24467598 TI - Identification of apoptotic bodies in equine semen. AB - Apoptosis in the testis is required to ensure an efficient spermatogenesis. However, sometimes, defective germ cells that are marked for elimination during this process escape elimination in the testes, giving rise to ejaculates with increased percentages of abnormal and apoptotic spermatozoa and a high percentage of apoptotic bodies. Apoptosis markers in the ejaculate have been associated with low fertility, either in animals or humans. Therefore, the goal of this study was to investigate whether fresh equine semen contains apoptotic bodies [initially named Merocyanine 540 (M540) bodies] and to study the relationship between the quantity of these bodies and cell concentration, the volume of ejaculate, viability and motility. Moreover, we also studied whether the presence apoptotic bodies in fresh semen was related to the resistance of the stallion spermatozoa to being incubated at 37 degrees C or being frozen and thawed. Fresh equine semen was stained with fluorescent dyes such as M540 and Annexin-V. Active Caspase 3 was studied in fresh semen through Western blotting and immunofluorescence with a specific antibody. Sperm kinematics was assessed in fresh, incubated and thawed samples using computer-assisted semen analysis, and viability was evaluated with the LIVE/DEAD Sperm Viability Kit. Overall, our results demonstrate for the first time the presence of apoptotic bodies in equine semen. The quantity of apoptotic bodies was highly variable among stallions and was positively correlated with Caspase 3 activity in fresh samples and negatively correlated with the viability and motility of stallion spermatozoa after the cryopreservation process. PMID- 24467599 TI - Drs. Ralph and Harold Roberts I. Linkow invented the blade from dental implant. PMID- 24467600 TI - Design, synthesis, antiviral activity, and structure-activity relationships (SARs) of two types of structurally novel phenanthroindo/quinolizidine analogues. AB - To investigate the influence of the variation of the original skeletons of natural phenanthroindo/quinolizidine alkaloids on antiviral activities, two types of structurally totally novel analogues 7a, 7b, 16a, and 16b were designed, synthesized, and evaluated against tobacco mosaic virus (TMV) for the first time. Bioassay results indicated that all four of the newly designed analogues showed good to excellent antiviral activities, among which analogue 16a dispalyed comparable activity with that of ningnanmycin, perhaps one of the most successful commercial antiviral agents, thus emerging as a potential inhibitor of plant virus and serving as a new lead for further optimization. Further structure activity relationships are also discussed, demonstrating for the first time that the same changes of the original skeletons of phenanthroindolizidine and phenanthroquinolizidine exihibted totally different antiviral activities results, providing some original and useful information about the preferential conformation for maintaining high activities. PMID- 24467601 TI - Nose to brain microemulsion-based drug delivery system of rivastigmine: formulation and ex-vivo characterization. AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder leading to irreversible loss of neurons, cognition and formation of abnormal protein aggregates. Rivastigmine, a reversible cholinesterase inhibitor used for the treatment of AD, undergoes extensive first-pass metabolism, thus limiting its absolute bioavailability to only 36% after 3-mg dose. Due to extreme aqueous solubility, rivastigmine shows poor penetration and lesser concentration in the brain thus requiring frequent oral dosing. This investigation was aimed to formulate microemulsion (ME) and mucoadhesive microemulsions (MMEs) of rivastigmine for nose to brain delivery and to compare percentage drug diffused for both systems using in-vitro and ex-vivo study. Rivastigmine-loaded ME and MMEs were prepared by titration method and characterized for drug content, globule size distribution, zeta potential, pH, viscosity and nasal ciliotoxicity study. Rivastigmine-loaded ME system containing 8% w/w Capmul MCM EP, 44% w/w Labrasol:Transcutol-P (1:1) and 48% w/w distilled water was formulated, whereas 0.3% w/w chitosan (CH) and cetyl trimethyl ammonium bromide (as mucoadhesive agents) were used to formulate MMEs, respectively. ME and MMEs formulations were transparent with drug content, globule size and zeta potential in the range of 98.59% to 99.43%, 53.8 nm to 55.4 nm and -2.73 mV to 6.52 mV, respectively. MME containing 0.3% w/w CH followed Higuchi model (r(2) = 0.9773) and showed highest diffusion coefficient. It was free from nasal ciliotoxicity and stable for three months. However, the potential of developed CH-based MME for nose to brain delivery of rivastigmine can only be established after in-vivo and biodistribution study. PMID- 24467602 TI - Petit suisse from black soybean: bioactive compounds and antioxidant properties during development process. AB - This study aimed to evaluate the antioxidant properties, bioactive compounds and other physico-chemical parameters from black soybean and its derivatives over 30 days under refrigeration at 4 degrees C and develop a probiotic petit suisse produced from black soybean. The soymilk showed the highest levels of isoflavones (109 mg/100 g), total phenolics (600 mg/100 g) and total anthocyanins (388 mg/100 g) with the highest response in the tests with DPPH* and ABTS+* on a dry basis. There was a significant increase (p <= 0.05) in antioxidant activity during storage due to the hydrolysis of isoflavone glycosides to aglycones in soymilk sample, having a strong linear correlation between the concentration of isoflavone aglycones and the antioxidant activity for ABTS+* (R = 0.9437, 0.9624 and 0.9992) and DPPH* (R = 0.9865, 0.9978 and 0.9911), respectively, for soymilk, quark and petit suisse. The conversion of isoflavone was influenced directly by the characteristics of each sample, inhibiting or promoting the action of the enzyme. The petit suisse developed is an alternative for consumers, providing isoflavones and anthocyanins, possessing probiotic average counts (108 CFU g-1) during storage. PMID- 24467604 TI - Environment-sensitive fluorescent supramolecular nanofibers for imaging applications. AB - The combination of an environment-sensitive fluorophore, 4-nitro-2,1,3 benzoxadiazole (NBD), and peptides have yielded supramolecular nanofibers with enhanced cellular uptake, brighter fluorescence, and significant fluorescence responses to external stimuli. We had designed and synthesized NBD-FFYEEGGH that can form supramolecular nanofibers and emit brighter than its counterpart of NBD EEGGH without the self-assembling property. The nanofibers of NBD-FFYEEGGH could specifically bind to Cu(2+), leading to the formation of fluorescence quenched elongated nanofibers. This fluorescence quenching property was enhanced in self assembling nanofibers and could be applied for detection of Cu(2+) in vitro and within cells. In a further step, an enzyme-cleavable DEVD peptide was placed between NBD-FFY and the copper binding tripeptide GGH. The resulting self assembling peptide NBD-FFFDEVDGGH also showed strong fluorescence quenching to Cu(2+). Upon the enzymatic cleavage to remove the Cu(2+)-binding GGH tripeptide from the peptide, the fluorescence was restored. The cellular uptake of nanofibers was better than that of free molecules because of endocytosis. The supramolecular nanofibers with fluorescence turn-on property could therefore be applied for detection of caspase-3 activity in vitro and within cells. We believe that the combination of environment-sensitive fluorescence and fast responses of supramolecular nanostructures would lead to a useful platform to detect many important analytes. PMID- 24467605 TI - The potential role of angiogenic factors in rheumatoid arthritis. AB - Angiogenesis is an important phenomenon in the pathogenesis of some diseases, such as numerous types of tumors and autoimmunity, and also a number of soluble and cell-bound factors may stimulate neovascularization in inflammatory reaction processes. Here, by highlighting the significance of angiogenesis reaction in rheumatoid arthritis (RA), we will mainly focus on the role of various growth factors, cytokines, enzymes, cells, hypoxic conditions and transcription factors in the angiogenic process and we will then explain some therapeutic strategies based on blockage of angiogenesis and modification of the vascular pathology in RA. PMID- 24467603 TI - Genetic variation in the prostaglandin E2 pathway is associated with primary graft dysfunction. AB - RATIONALE: Biologic pathways with significant genetic conservation across human populations have been implicated in the pathogenesis of primary graft dysfunction (PGD). The evaluation of the role of recipient genetic variation in PGD has thus far been limited to single, candidate gene analyses. OBJECTIVES: We sought to identify genetic variants in lung transplant recipients that are responsible for increased risk of PGD using a two-phase large-scale genotyping approach. METHODS: Phase 1 was a large-scale candidate gene association study of the multicenter, prospective Lung Transplant Outcomes Group cohort. Phase 2 included functional evaluation of selected variants and a bioinformatics screening of variants identified in phase 1. MEASUREMENTS AND MAIN RESULTS: After genetic data quality control, 680 lung transplant recipients were included in the analysis. In phase 1, a total of 17 variants were significantly associated with PGD, four of which were in the prostaglandin E2 family of genes. Among these were a coding variant in the gene encoding prostaglandin E2 synthase (PTGES2; P = 9.3 * 10(-5)) resulting in an arginine to histidine substitution at amino acid position 298, and three variants in a block containing the 5' promoter and first intron of the PTGER4 gene (encoding prostaglandin E2 receptor subtype 4; all P < 5 * 10(-5)). Functional evaluation in regulatory T cells identified that rs4434423A in the PTGER4 gene was associated with differential suppressive function of regulatory T cells. CONCLUSIONS: Further research aimed at replication and additional functional insight into the role played by genetic variation in prostaglandin E2 synthetic and signaling pathways in PGD is warranted. PMID- 24467607 TI - Origins of microstructural transformations in charged vesicle suspensions: the crowding hypothesis. AB - It is observed that charged unilamellar vesicles in a suspension can spontaneously deflate and subsequently transition to form bilamellar vesicles, even in the absence of externally applied triggers such as salt or temperature gradients. We provide strong evidence that the driving force for this deflation induced transition is the repulsive electrostatic pressure between charged vesicles in concentrated suspensions, above a critical effective volume fraction. We use volume fraction measurements and cryogenic transmission electron microscopy imaging to quantitatively follow both the macroscopic and microstructural time-evolution of cationic diC18:1 DEEDMAC vesicle suspensions at different surfactant and salt concentrations. A simple model is developed to estimate the extent of deflation of unilamellar vesicles caused by electrostatic interactions with neighboring vesicles. It is determined that when the effective volume fraction of the suspension exceeds a critical value, charged vesicles in a suspension can experience "crowding" due to overlap of their electrical double layers, which can result in deflation and subsequent microstructural transformations to reduce the effective volume fraction of the suspension. Ordinarily in polydisperse colloidal suspensions, particles interacting via a repulsive potential transform into a glassy state above a critical volume fraction. The behavior of charged vesicle suspensions reported in this paper thus represents a new mechanism for the relaxation of repulsive interactions in crowded situations. PMID- 24467606 TI - Structure and expression of a cysteine proteinase gene from Spodoptera litura and its response to biocontrol fungus Nomuraea rileyi. AB - Cysteine proteinases (Cyps) play vital roles in many biological processes, including physiological and pathological reactions. In the present study, we cloned a full cDNA of SlCyp, encoding a 344-amino-acid protein from Spodoptera litura. The putative amino acid sequence shared >75% identity with Cyps from other insects. A phylogenetic analysis revealed that SlCyp is closely related to other known lepidopteran Cyps. Real-time PCR and Western blotting analyses showed that SlCyp is induced by Nomuraea rileyi infection in all the tissues tested. The strongest SlCyp mRNA and protein expression was found in haemocytes, followed by the fat bodies, of unchallenged and N. rileyi-challenged S. litura. A time-course analysis showed that SlCyp mRNA and protein expression levels were upregulated in the haemocytes and fat bodies by N. rileyi infection. Upon N. rileyi infection, the proteolytic activities of SlCyp were also significantly higher in the haemolymph than in normal or phosphate-buffered-saline-challenged controls. These results suggest that SlCyp plays an important role in the innate immunity of S. litura in response to N. rileyi. SlCyp mRNA and protein expression and activities were also elevated during sixth-instar moulting and metamorphosis. Knocking down SlCyp transcripts with double-stranded RNA interference caused prepupal, pupal, and adult phenotypic changes, and SlCyp-silenced mutant larvae displayed a significantly lower survival rate after N. rileyi infection. These facts suggest that SlCyp plays a significant role in resisting N. rileyi infection and an essential role in larval development. Our data should facilitate the development of techniques for S. litura control. PMID- 24467608 TI - Incidence of pain after craniotomy in children. AB - BACKGROUND: There is very few information regarding pain after craniotomy in children. OBJECTIVES: This multicentre observational study assessed the incidence of pain after major craniotomy in children. METHODS: After IRB approval, 213 infants and children who were <10 years old and undergoing major craniotomy were consecutively enrolled in nine Italian hospitals. Pain intensity, analgesic therapy, and adverse effects were evaluated on the first 2 days after surgery. Moderate to severe pain was defined as a median FLACC or NRS score >= 4 points. Severe pain was defined as a median FLACC or NRS score >= 7 points. RESULTS: Data of 206 children were included in the analysis. The overall postoperative median FLACC/NRS scores were 1 (IQR 0 to 2). Twenty-one children (16%) presented moderate to severe pain in the recovery room and 14 (6%) during the first and second day after surgery. Twenty-six children (19%) had severe pain in the recovery room and 4 (2%) during the first and second day after surgery. Rectal codeine was the most common weak opiod used. Remifentanil and morphine were the strong opioids widely used in PICU and in general wards, respectively. Longer procedures were associated with moderate to severe pain (OR 1.30; CI 1.07-1.57) or severe pain (OR 1.41; 1.09-1.84; P < 0.05). There were no significant associations between complications, pain intensity, and analgesic therapy. CONCLUSION: Children receiving multimodal analgesia experience little or no pain after major craniotomy. Longer surgical procedures correlate with an increased risk of having postoperative pain. PMID- 24467610 TI - Bacterial meningitis after sinus surgery in five adult horses. AB - OBJECTIVE: To report meningoencephalitis as a complication after paranasal sinus surgery in 5 horses. STUDY DESIGN: Case series. ANIMALS: Adult horses (n = 5). METHODS: Medical records (2005-2010) of 5 horses that developed neurologic signs after sinus surgery were reviewed to identify potential risk factors, cause(s), or common pathways for infection. RESULTS: Underlying diseases were primary (n = 1) and secondary sinusitis (4) because of apical dental infection (1), sinus cyst (2), or masses in the ethmoturbinate region (2). Horses were treated by conventional surgical approaches and aftercare including repeated sinus lavage. Four horses had undulating pyrexia postoperatively despite antimicrobial therapy. All horses developed neurologic signs, eventually unresponsive to treatment. Suppurative meningoencephalitis was diagnosed macro- and/or microscopically on necropsy in all horses. CONCLUSION: Meningitis is a rare but fatal complication after sinus surgery in horses. PMID- 24467609 TI - Regulatory role of the cannabinoid CB2 receptor in stress-induced neuroinflammation in mice. AB - BACKGROUND AND PURPOSE: Stress exposure produces excitotoxicity and neuroinflammation, contributing to the cellular damage observed in stress-related neuropathologies. The endocannabinoids provide a homeostatic system, present in stress-responsive neural circuits. Here, we have assessed the possible regulatory role of cannabinoid CB2 receptors in stress-induced excitotoxicity and neuroinflammation. EXPERIMENTAL APPROACH: We used wild type (WT), transgenic overexpressing CB2 receptors (CB2xP) and CB2 receptor knockout (CB2-KO) mice exposed to immobilization and acoustic stress (2 h.day(-1) for 4 days). The CB2 receptor agonist JWH-133 was administered daily (2 mg.kg(-1), i.p.) to WT and CB2 KO animals. Glutamate uptake was measured in synaptosomes from frontal cortex; Western blots and RT-PCR were used to measure proinflammatory cytokines, enzymes and mediators in homogenates of frontal cortex. KEY RESULTS: Increased plasma corticosterone induced by stress was not modified by manipulating CB2 receptors. JWH-133 treatment or overexpression of CB2 receptors increased control levels of glutamate uptake, which were reduced by stress back to control levels. JWH-133 prevented the stress-induced increase in proinflammatory cytokines (TNF-alpha and CCL2), in NF-kappaB, and in NOS-2 and COX-2 and in the consequent cellular oxidative and nitrosative damage (lipid peroxidation). CB2xP mice exhibited anti inflammatory or neuroprotective actions similar to those in JWH-133 pretreated animals. Conversely, lack of CB2 receptors (CB2-KO mice) exacerbated stress induced neuroinflammatory responses and confirmed that effects of JWH-133 were mediated through CB2 receptors. CONCLUSIONS AND IMPLICATIONS: Pharmacological manipulation of CB2 receptors is a potential therapeutic strategy for the treatment of stress-related pathologies with a neuroinflammatory component, such as depression. PMID- 24467611 TI - Subtyping of renal cortical neoplasms in fine needle aspiration biopsies using a decision tree based on genomic alterations detected by fluorescence in situ hybridization. AB - OBJECTIVES: To improve the overall accuracy of diagnosis in needle biopsies of renal masses, especially small renal masses (SRMs), using fluorescence in situ hybridization (FISH), and to develop a renal cortical neoplasm classification decision tree based on genomic alterations detected by FISH. PATIENTS AND METHODS: Ex vivo fine needle aspiration biopsies of 122 resected renal cortical neoplasms were subjected to FISH using a series of seven-probe sets to assess gain or loss of 10 chromosomes and rearrangement of the 11q13 locus. Using specimen (nephrectomy)-histology as the 'gold standard', a genomic aberration based decision tree was generated to classify specimens. The diagnostic potential of the decision tree was assessed by comparing the FISH-based classification and biopsy histology with specimen histology. RESULTS: Of the 114 biopsies diagnostic by either method, a higher diagnostic yield was achieved by FISH (92 and 96%) than histology alone (82 and 84%) in the 65 biopsies from SRMs (<4 cm) and 49 from larger masses, respectively. An optimized decision tree was constructed based on aberrations detected in eight chromosomes, by which the maximum concordance of classification achieved by FISH was 79%, irrespective of mass size. In SRMs, the overall sensitivity of diagnosis by FISH compared with histopathology was higher for benign oncocytoma, was similar for the chromophobe renal cell carcinoma subtype, and was lower for clear-cell and papillary subtypes. The diagnostic accuracy of classification of needle biopsy specimens (from SRMs) increased from 80% obtained by histology alone to 94% when combining histology and FISH. CONCLUSION: The present study suggests that a novel FISH assay developed by us has a role to play in assisting in the yield and accuracy of diagnosis of renal cortical neoplasms in needle biopsies in particular, and can help guide the clinical management of patients with SRMs that were non diagnostic by histology. PMID- 24467612 TI - Direct access to alpha-trifluoromethyl enones via efficient copper-catalyzed trifluoromethylation of Meyer-Schuster rearrangement. AB - A novel domino copper-catalyzed trifluoromethylated Meyer-Schuster rearrangement reaction with Togni's reagent was developed, leading to alpha-trifluormethyl (CF3) enone products with moderate to good yields. Furthermore, alpha-CF3 enones can be transformed toward important trifluoromethyl heterocyclic motifs in a one pot version. PMID- 24467613 TI - Bone marrow hypocellularity does not affect tolerance or efficacy of azacitidine in patients with higher-risk myelodysplastic syndromes. AB - The efficacy and tolerance of azacitidine in higher-risk myelodysplasia with hypocellular bone marrow (BM) are unknown. This post hoc AZA-001 trial analysis assessed whether baseline BM cellularity affected the overall survival (OS) advantage demonstrated with azacitidine versus conventional care regimens (CCR). Baseline BM biopsies of <30% cellularity were considered hypocellular with data evaluable from 299 patients (azacitidine n = 154, CCR n = 145); 13% (n = 39) hypocellular, 87% (n = 260) non-hypocellular. Patient characteristics were balanced between cellularity and treatment groups. Most patients (90-100%) had 2 3 cytopenias at baseline. Median (range) azacitidine treatment cycle lengths were 35.5 (28-54) and 33.0 (15-75) d in hypocellular and non-hypocellular groups, respectively. At 33 months, median OS was not reached (NR) [95% confidence interval (CI): 19.2, NR] in hypocellular patients receiving azacitidine versus 16.9 months (95% CI: 11.1, 19.3) with CCR (P = 0.001); and in non-hypocellular patients, it was 21.1 months (95% CI: 16.2, 34.7) versus 15.3 months (95% CI: 9.3, 17.6) (P = 0.012). Azacitidine tolerance was similar regardless of cellularity. Grade 3-4 thrombocytopenia and neutropenia occurred similarly in hypocellular patients treated with azacitidine versus CCR (80% vs. 92% and 88% vs. 75%). Azacitidine OS results are consistent with those from AZA-001, regardless of cellularity, and demonstrate its safety and efficacy in higher-risk myelodysplasia with hypocellular BM. PMID- 24467614 TI - Probing the interactions between ionic liquids and water: experimental and quantum chemical approach. AB - For an adequate choice or design of ionic liquids, the knowledge of their interaction with other solutes and solvents is an essential feature for predicting the reactivity and selectivity of systems involving these compounds. In this work, the activity coefficient of water in several imidazolium-based ionic liquids with the common cation 1-butyl-3-methylimidazolium was measured at 298.2 K. To contribute to a deeper insight into the interaction between ionic liquids and water, COSMO-RS was used to predict the activity coefficient of water in the studied ionic liquids along with the excess enthalpies. The results showed good agreement between experimental and predicted activity coefficient of water in ionic liquids and that the interaction of water and ionic liquids was strongly influenced by the hydrogen bonding of the anion with water. Accordingly, the intensity of interaction of the anions with water can be ranked as the following: [CF3SO3](-) < [SCN](-) < [TFA](-) < Br(-) < [TOS](-) < Cl(-) < [CH3SO3](-) [DMP]( ) < [Ac](-). In addition, fluorination and aromatization of anions are shown to reduce their interaction with water. The effect of temperature on the activity coefficient of water at infinite dilution was measured by inverse gas chromatography and predicted by COSMO-RS. Further analysis based on COSMO-RS provided information on the nature of hydrogen bonding between water and anion as well as the possibility of anion-water complex formation. PMID- 24467615 TI - Charge transfer states in stable neutral and oxidized radical adducts from carbazole derivatives. AB - In this paper we report the spectral properties of the stable radical adducts 1(*)-3(*), which are formed by an electron donor moiety, the carbazole ring, and an electron acceptor moiety, the polychlorotriphenylmethyl radical. The molecular structure of radical adduct 1(*) in the crystalline state shows a torsion angle of approximately 90 degrees between the phenyl and the carbazole rings due to steric interactions. They exhibit a charge transfer band in the visible range of the electronic spectrum. All of them are chemically oxidized with copper(II) perchlorate to the respective cation species, which show a strong charge transfer band into the near-infrared region of the spectrum. Radical adducts 1(*)-3(*) and the corresponding stable oxidized species 1(+)-3(+) are real organic mixed valence compounds due to the open-shell nature of their electronic structure. Charge transfer bands of the cation species are stronger and are bathochromically shifted with respect to those of the neutral species due to the greater acceptor ability of the positively charged central carbon atom of the triphenylmethyl moiety. The cationic species 1(+)-3(+) are diamagnetic, as shown by the absence of a signal in the EPR spectrum in acetonitrile solution at room temperature, but they show an intense and unique band in frozen solutions (183 K). PMID- 24467616 TI - Betalain and betaine composition of greenhouse- or field-produced beetroot ( Beta vulgaris L.) and inhibition of HepG2 cell proliferation. AB - The composition of betalain, red or yellow pigments, and betaine (trimethylglycine or glycinebetaine) of nine beetroot ( Beta vulgaris L.) cultivars produced in the greenhouse or field was studied. Inhibition of HepG2 cell proliferation by betanin and betaine was also tested. Four predominant betalains, two betacyanins (betanin and isobetanin) and two betaxanthins (vulgaxanthin I and miraxanthin V), were isolated and quantified. Betanin and vulgaxanthin I were the major compounds in red and yellow beetroot extracts, respectively, and they comprised >90% of the betalain content in the tested cultivars. The total betalain content of beetroots produced from the field was between 650 and 800 MUg/g fresh weight, approximately 25% higher than those from the greenhouse. The betaine content of the beetroot grown in the field was between 3.0 and 4.8 mg/g fresh weight, approximately 20% higher than in plants from the greenhouse. There was great variation among the cultivars with respect to their contents of betalains and betaine. In vitro cancer cell cytotoxicity was evaluated using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide assay on HepG2 cells after exposure to betanin and betaine at concentrations ranging from 0 to 400 MUg/mL and from 0 to 800 MUg/mL for 48 h, respectively. Betanin resulted in a 49% inhibition of HepG2 cell proliferation at 200 MUg/mL, and betaine yielded a 25% inhibition at 800 MUg/mL, implying a higher cytotoxicity of betanin compared with betaine. The results indicated that the contents of health-beneficial compounds in beetroots, betalains and betaine, could be increased by modifying the growing conditions and that betanin and betaine extracted from beetroots had some anticancer effects against HepG2 cells. PMID- 24467617 TI - Deslorelin implants in pre-pubertal female dogs: short- and long-term effects on the genital tract. AB - Deslorelin acetate is a GnRH agonist used for contraception in dogs. This study aimed to evaluate the treatment of pre-pubertal female dogs with deslorelin acetate implants, to better investigate the primary stimulatory effect of the drug and the long-term effects on the genital tract, throughout repeated treatments. Sicilian hound female dogs (24) were randomly assigned to treated group, control group 1 and control group 2. First group bitches were implanted at 4.5, 9.0 and 13.5 months and monitored clinically, ultrasonographically and endocrinologically, throughout the study period (13.5 months). Control group 1 bitches were not implanted and clinically monitored for the same period. At 18 months, the animals underwent ovariohysterectomy, thus allowing evaluation of the internal genitalia. Control group 2 bitches were ovariohysterectomized at the age of 4.5 months. The suppression of oestrus was obtained in the treated group despite the fact that the first implant caused a modest increase in plasmatic levels of 17-beta estradiol and an evident cornification of the vaginal mucosa cells (50-80%). Estradiol and progesterone were at baseline levels for the remaining study period, in which no other oestrous manifestations were observed. The external genitalia maintained a juvenile appearance. The ovaries, ultrasonographically, showed no follicular structures and stayed the same size. At 18 months, the genital tract was still juvenile with inactive small ovaries and a thin filiform uterus. Deslorelin suppressed ovarian activity in pre pubertal bitches, and oestrous induction was not observed despite the presence of the primary stimulatory effect of the drug. Juvenile genitalia were an expected side effect of the treatment. PMID- 24467618 TI - COX-2 signaling and cancer: new players in old arena. AB - Cancer is a leading cause of death worldwide. The expression of COX-2 and prostaglandins has not only been associated with various types of cancer but is also directly proportional to their aggressiveness including metastasis. Thus, inhibition of COX-2 activity has been one of the preferred targets for cancer reduction. Broad spectrum inhibition of all forms of COX (using NSAIDs) is associated with various side effects ranging from gastric ulceration to renal problems. Even specific COX-2 inhibitors (COXIBs) are associated with side effects like myocardial infarction. Alternative strategies including siRNA technology are also not very victorious due to their off-target associated problems. Thus, there is an urgent need for the development of strategies where COX-2 activity may be reduced without inducing any side effects. One of the approaches for designing novel inhibitors may be to target various molecules downstream of COX-2. In this review, we have tried to cover the basic biology of COX-2 and its association with different types of cancer. Various generations of COX-2 inhibitors have been covered with their merits and demerits. Possible exploitation of novel targets like EP receptors, mPGES and various other downstream molecules which can be utilized for a better COX-2 signaling inhibition and thus efficient cancer reduction with minimal side effects has been discussed. PMID- 24467619 TI - A FluoPol-ABPP PAD2 high-throughput screen identifies the first calcium site inhibitor targeting the PADs. AB - The protein arginine deiminases (PADs) catalyze the post-translational hydrolysis of peptidyl-arginine to form peptidyl-citrulline in a process termed deimination or citrullination. PADs likely play a role in the progression of a range of disease states because dysregulated PAD activity is observed in a host of inflammatory diseases and cancer. For example, recent studies have shown that PAD2 activates ERalpha target gene expression in breast cancer cells by citrullinating histone H3 at ER target promoters. To date, all known PAD inhibitors bind directly to the enzyme active site. PADs, however, also require calcium ions to drive a conformational change between the inactive apo-state and the fully active calcium bound holoenzyme, suggesting that it would be possible to identify inhibitors that bind the apoenzyme and prevent this conformational change. As such, we set out to develop a screen that can identify PAD2 inhibitors that bind to either the apo or calcium bound form of PAD2. Herein, we provide definitive proof of concept for this approach and report the first PAD inhibitor, ruthenium red (Ki of 17 MUM), to preferentially bind the apoenzyme. PMID- 24467620 TI - N-trimethyl chitosan (TMC)-modified microemulsions for improved oral bioavailability of puerarin: preparation and evaluation. AB - The aim of this research was to increase the oral bioavailability of puerarin by N-trimethyl chitosan-modified microemulsions (TMC-MEs) loaded with puerarin. Different concentrations of TMC-modified microemulsions were prepared in our study, and then evaluated for particle size, zeta potential, morphological observation and changes of the microenvironment polarity of inner oil core. It was shown that the zeta potential of the microemulsion was increased with the increasing concentration of TMC, and the peak value was achieved when the concentration of TMC was 3.0 mg/mL. The enhancement of the ratio of I(1)/I(3) (the ratio between the first band and the third band of the emission fluorescence spectrum of pyrene, I(1) = 373 nm, I(3) = 384 nm) indicated that polarity of the inner core of TMC-MEs was increased with the addition of the modifier. Pharmacokinetic studies demonstrated that after oral administration of puerarin N trimethyl chitosan (TMC)-modified microemulsions (PUE-TMEs) and puerarin microemulsions (PUE-MEs) to rats at a dose of 100 mg/kg, relative bioavailability was enhanced about 6.8- and 1.2-fold, respectively, compared to puerarin suspension (PUE-SUS) as control. It indicated that the TMC-MEs could be used as an effective formulation for enhancing the oral bioavailability of puerarin. PMID- 24467621 TI - Blood flukes (Digenea: Aporocotylidae) of elopomorphs: emendation of Paracardicoloides, supplemental observations of Paracardicoloides yamagutii, and a new genus and species from ladyfish, Elops saurus, (Elopiformes: Elopidae) in the Gulf of Mexico. AB - Monotypic Paracardicoloides Martin, 1974 is emended based on supplemental observations of 2 voucher specimens of Paracardicoloides yamagutii Martin, 1974 . Features of the anterior sucker, esophagus, and intestine as well as the male and female genitalia previously attributed to, or omitted from the diagnosis and description of, this fluke are resolved and further detailed herein. The holotype of P. yamagutii, originally deposited in the Allan Hancock Parasitology Collection, apparently has been lost, and Queensland Museum voucher G222650 is designated as the neotype. Elopicola nolancribbi n. gen., n. sp. infects the ladyfish, Elops saurus , (Elopiformes: Elopidae) in the north-central Gulf of Mexico. The new genus resembles Paracardicoloides by having the combination of a bowl-shaped anterior sucker, inverse U-shaped intestine, short posterior ceca, post-cecal ovary, pre-ovarian ootype, compact uterus, and prominent excretory arms and vesicle. It differs from Paracardicoloides by lacking robust tegumental body spines and by having a single testis, post-testicular ovary, and primarily post-testicular uterus. The present study is the first confirmed report of an aporocotylid infecting a member of Elopiformes as well as the first report of an infection in an elopomorph outside of Australia and New Zealand or in marine waters. PMID- 24467622 TI - ER type I signal peptidase subunit (LmSPC1) is essential for the survival of Locusta migratoria manilensis and affects moulting, feeding, reproduction and embryonic development. AB - The endoplasmic reticulum type I signal peptidase complex (ER SPC) is a conserved enzyme that cleaves the signal peptides of secretory or membrane preproteins. The deletion of this enzyme leads to the accumulation of uncleaved proteins in biomembranes and cell death. However, the physiological functions of ER SPC in insects are not fully understood. Here, a catalytic subunit gene of ER SPC, LmSPC1, was cloned from Locusta migratoria manilensis and its physiological functions were analysed by RNA interference (RNAi). The LmSPC1 open reading frame encoded a protein of 178 amino acids with all five conserved regions of signal peptidases. RNAi-mediated knockdown of LmSPC1 resulted in high mortality. Sixty nine per cent of dead nymphs died of abnormal moulting, corresponding to decreased activity of moulting fluid protease. Moreover, insects in the RNAi group experienced a decline in food intake, and a decrease in the secretion of total protein and digestive enzymes from midgut tissues to the midgut lumen. Furthermore, the females produced fewer eggs and eggs with disrupted embryogenesis. These results indicate that LmSPC1 is required for the secretion of secretory proteins, affects physiological functions, including moulting, feeding, reproduction and embryonic development, and is essential for survival. Therefore, LmSPC1 may be a potential target for locust control. PMID- 24467624 TI - Association between urinary adiponectin level and renal involvement in systemic lupus erythematous. AB - AIM: To assess association between urinary levels of adiponectin and severity of renal involvement in SLE patients. Also, this study aims to determine the value of urinary adiponectin levels to discriminate renal involvement in these patients. METHODS: In a multi-center cross-sectional survey, 50 consecutive patients diagnosed as having systemic lupus erythematosus (SLE) according to American College of Rheumatology criteria were classified into two groups with or without renal involvement (microscopic hematuria, reduced glomerular filtration rate < 25% of normal value, and proteinuria > 500 mg/24 h) which was confirmed by renal biopsy. Urinary adiponectin was measured by enzyme-linked immunosorbent assay. SLE disease activity levels were assessed by SLE Disease Activity Index (SLEDAI) score. RESULTS: Comparing urinary levels of adiponectin between the two groups indicated considerable discrepancy in this index between the groups with and without renal involvement (146.33 +/- 258.83 ng/mL vs. 22.96 +/- 44.33 ng/mL, P = 0.023). Also, urinary adiponectin/creatinine ratio was significantly higher in the former group (221.72 +/- 414.58 vs. 19.99 +/- 41.19, P = 0.019). Our study showed a higher mean SLEDAI score in those with renal involvement than others (23.60 +/- 2.53 vs. 9.12 +/- 3.03, P < 0.001). Multivariable linear regression analysis with the presence of potential confounders showed that the level of urinary adiponectin was significantly higher in those with renal involvement than other patients (beta = 0.470, P = 0.023). The optimal cut-off point for urinary adiponectin levels to discriminate renal involvement from normal renal state was 7.5 ng/mL, yielding a sensitivity of 80% and specificity of 52%. CONCLUSION: Urinary levels of adiponectin are significantly elevated in SLE patients with renal involvement. The measurement of this biomarker can be helpful to discriminate impaired from normal renal function in SLE patients. PMID- 24467623 TI - Evaluation of 11 terrestrial carbon-nitrogen cycle models against observations from two temperate Free-Air CO2 Enrichment studies. AB - We analysed the responses of 11 ecosystem models to elevated atmospheric [CO2 ] (eCO2 ) at two temperate forest ecosystems (Duke and Oak Ridge National Laboratory (ORNL) Free-Air CO2 Enrichment (FACE) experiments) to test alternative representations of carbon (C)-nitrogen (N) cycle processes. We decomposed the model responses into component processes affecting the response to eCO2 and confronted these with observations from the FACE experiments. Most of the models reproduced the observed initial enhancement of net primary production (NPP) at both sites, but none was able to simulate both the sustained 10-yr enhancement at Duke and the declining response at ORNL: models generally showed signs of progressive N limitation as a result of lower than observed plant N uptake. Nonetheless, many models showed qualitative agreement with observed component processes. The results suggest that improved representation of above-ground-below ground interactions and better constraints on plant stoichiometry are important for a predictive understanding of eCO2 effects. Improved accuracy of soil organic matter inventories is pivotal to reduce uncertainty in the observed C-N budgets. The two FACE experiments are insufficient to fully constrain terrestrial responses to eCO2 , given the complexity of factors leading to the observed diverging trends, and the consequential inability of the models to explain these trends. Nevertheless, the ecosystem models were able to capture important features of the experiments, lending some support to their projections. PMID- 24467625 TI - Gender differences of cognitive function in migraine patients: evidence from event-related potentials using the oddball paradigm. AB - BACKGROUND: Migraine shows gender-specific incidence and has a higher prevalence in females. Gender plays an important role in the prevalence of migraine, but few studies have investigated the effect of gender on the cognitive functions of migraine patients. This study investigated gender differences in the cognitive function of migraine patients without aura. METHODS: We recruited 29 migraine patients (15 females; mean age 25.4 y) during the interictal period and 28 healthy age-matched participants (14 females; mean age 24.8 y). We used an auditory oddball paradigm to analyze target processing using event-related potentials. RESULTS: We investigated the N2 and P3 components. The P3 amplitude was decreased in patients compared with the control, and this reduction was not modulated by gender. These results of the P3 provided a new evidence for the dysfunction of cognitive function in migraine patients. The N2 amplitude was larger for male than female migraine patients, and this gender effect was not found in the control group. CONCLUSIONS: These results of the P3 provided a new evidence for the dysfunction of cognitive function in migraine patients. And those of N2 may explain that male patients have the super-sensitivity of cerebral function relevant to the early target-selection and response preparation. Our findings emphasize the importance of considering gender when researching the cognitive function of migraine patients. PMID- 24467626 TI - Effect of side-chain carbonyl groups on the interface of vinyl polymers with water. AB - The nature of the polymer-water interface in the poly(methyl 2-propenyl ether) (PMPE)-water model system is investigated by sum-frequency generation spectroscopy, which at the moment gives the best depth resolution among available techniques. PMPE, synthesized via living cationic polymerization, is structurally similar to poly(methyl methacrylate) (PMMA) except for lacking a carbonyl group. We here probe the polymer local conformation as well as the aggregation states of water at the interface. Comparing the results of our measurements to the PMMA water system, the effect of a carbonyl group on the water structure at the interface is discussed. This knowledge should be crucial to the design and construction of highly functionalized polymer interfaces for bioapplications. PMID- 24467628 TI - Separation of parent homopolymers from polystyrene-b-poly(ethylene oxide)-b polystyrene triblock copolymers by means of liquid chromatography: 1. comparison of different methods. AB - Separation of parent homopolymers, polystyrene and poly(ethylene oxide), from the triblock copolymer polystyrene-b-poly(ethylene oxide)-b-polystyrene was investigated by means of liquid chromatography techniques. Overall suitability was evaluated and compared for size exclusion chromatography, (SEC), liquid chromatography under critical conditions of enthalpic interactions (LC CC), and liquid chromatography under limiting conditions of desorption (LC LCD). Among these techniques, LC LCD was the only one able to fully separate block copolymers from both their parent homopolymers in one single run. The efficiency of the separation was proven by (1)H NMR analysis of previously collected fractions. PMID- 24467627 TI - Conditions associated with the cystic fibrosis defect promote chronic Pseudomonas aeruginosa infection. AB - RATIONALE: Progress has been made in understanding how the cystic fibrosis (CF) basic defect produces lung infection susceptibility. However, it remains unclear why CF exclusively leads to chronic infections that are noninvasive and highly resistant to eradication. Although biofilm formation has been suggested as a mechanism, recent work raises questions about the role of biofilms in CF. OBJECTIVES: To learn how airway conditions attributed to CF transmembrane regulator dysfunction could lead to chronic infection, and to determine if biofilm-inhibiting genetic adaptations that are common in CF isolates affect the capacity of Pseudomonas aeruginosa to develop chronic infection phenotypes. METHODS: We studied P. aeruginosa isolates grown in agar and mucus gels containing sputum from patients with CF and measured their susceptibility to killing by antibiotics and host defenses. We also measured the invasive virulence of P. aeruginosa grown in sputum gels using airway epithelial cells and a murine infection model. MEASUREMENTS AND MAIN RESULTS: We found that conditions likely to result from increased mucus density, hyperinflammation, and defective bacterial killing could all cause P. aeruginosa to grow in bacterial aggregates. Aggregated growth markedly increased the resistance of bacteria to killing by host defenses and antibiotics, and reduced their invasiveness. In addition, we found that biofilm-inhibiting mutations do not impede aggregate formation in gel growth environments. CONCLUSIONS: Our findings suggest that conditions associated with several CF pathogenesis hypotheses could cause the noninvasive and resistant infection phenotype, independently of the bacterial functions needed for biofilm formation. PMID- 24467629 TI - Accuracy of manual palpation vs ultrasound for identifying the L3-L4 intervertebral space level in children. AB - BACKGROUND: Insertion of needles into the spinal or epidural space is an important component of modern anesthetic practice. Needles are usually inserted at or below the L3-L4 intervertebral space to minimize the risk of spinal cord injury. Manual palpation is the most common method for identifying intervertebral spaces. However, anesthesiologists are increasingly using ultrasonography to guide the placement of regional, including neuraxial, anesthetic, and analgesic blocks. We undertook an observational study to compare the accuracy of manual palpation and ultrasound for determining the L3-L4 intervertebral space level. METHODS: Thirty children 0-12 years of age undergoing lumbar puncture were enrolled. For each subject, an anesthesiologist, using the landmark palpation method, determined the point on a radio-opaque ruler that corresponded to the L3 L4 intervertebral space. A different anesthesiologist using the ultrasound method repeated this measurement. Fluoroscopy was then used to confirm the accuracy of each technique. The proportion of inaccurate measurements and the effects of anesthesiologists' experience, patient age, and size on the accuracy of each technique were compared. RESULTS: Thirty-seven percent of measurements by the landmark palpation method were inaccurate by >=1 levels cephalad to the L3-L4 intervertebral space. However, less experienced anesthesiologists (residents and fellows) made a disproportionate number of inaccurate measurements compared to consultants. Twenty-three percent of measurements by the ultrasound method were inaccurate by >=1 cephalad levels. The BMI-for-age percentile/weight-for-length percentile was higher in patients in whom either technique was inaccurate. CONCLUSION: This observational study found no difference in the accuracy of landmark palpation, when performed by a consultant anesthesiologist, and ultrasound for determining the L3-L4 intervertebral space in children. PMID- 24467630 TI - Evolution of the Southampton Enhanced Recovery Programme for radical cystectomy and the aggregation of marginal gains. AB - OBJECTIVE: To describe and assess the evolution of an enhanced recovery programme (ERP) for open radical cystectomy. PATIENTS AND METHODS: We introduced a mentored ERP for radical cystectomy in January 2011. The programme underwent service evaluation and multiple changes in August 2012 that we define as marginal gains. We present a retrospective review of 133 consecutive patients undergoing open radical cystectomy, grouped according to the three stages of the ERP from October 2008 to April 2013: (1) non-ERP group (October 2008 to December 2010): n = 69; (2) ERP-1 group (January 2011 to July 2012): n = 37; and (3) ERP-2 group (August 2012 to April 2013): n = 27. Primary outcomes were length of hospital stay (LOS), readmission, morbidity at 90 days using the Clavien classification system and mortality. Secondary outcomes were time to flatus, ileus rates, re-operation rates and oncological outcomes. RESULTS: There were no differences in patient demographics among any of the groups for: age, gender, BMI, American Society of Anesthesiologists score and the use of neoadjuvant chemotherapy. There were no differences in readmission, morbidity and mortality rates. The overall 90-day mortality was six patients (4.5%). There were significant differences in ileus rates between the non-ERP, the ERP-1 and the ERP-2 groups: 44.9% (31 patients), 29.7% (11 patients) and 14.8% (four patients), respectively (P = 0.017). There was a significant difference in the presence of pathological lymphadenopathy in the ERP-2 group: non-ERP group, 10.1%; ERP-1 group, 16.2%; and ERP-2 group, 44.4%; P = 0.002. There was also a difference in the mean (sd) lymph node yield in ERP-2: non-ERP group, 8.4 (5.4) nodes; ERP-1, 8.2 (6.4) nodes; and ERP-2, 16.7 (5.4) nodes (P < 0.001). The median (range) LOS was 14 (7-91) days, 10 (6-55) days and 7 (3-99) days in the non-ERP, ERP-1 and ERP-2 groups, respectively (P < 0.001). CONCLUSIONS: Auditing an already successful ERP and implementing a number of marginal gains has led to a significant decrease in the median LOS for radical cystectomy. The LOS for open radical cystectomy at University Hospital Southampton has halved. In the second phase of our ERP, our median LOS is 7 days. PMID- 24467631 TI - Defining a safe corridor for transcondylar screw insertion across the canine humeral condyle: a comparison of medial and lateral surgical approaches. AB - OBJECTIVES: To (1) develop guidelines for the location of drill entry and exit points when inserting a transcondylar screw across the canine humerus; (2) compare the safe corridor for transcondylar screw insertion when drilling medial to-lateral with drilling lateral-to-medial. STUDY DESIGN: Anatomic study. ANIMALS: Dogs (n = 43). METHODS: The optimum position of a transcondylar screw in 84 elbows was determined using CT multiplanar reconstructions. The positions of drill entry and exit points were defined relative to the epicondyles. Differences in elbow size were accounted for by dividing the measurements by the humeral condylar diameter (HCD), to give normalized measurements. Mean values of normalized measurements were used to develop universal guidelines for the location of drill entry and exit points. These guidelines were then applied to the 84 elbow CT reconstructions. The size of the safe corridor around this calculated drill line was determined, and expressed as tolerance angles in the frontal and transverse planes. The size of the safe corridors for medial-to lateral and lateral-to-medial drilling were compared. RESULTS: The lateral entry/exit point was 0.3 * HCD cranial and 0.3 * HCD distal to the lateral epicondyle. The medial entry/exit point was 0.3 * HCD cranial and 0.2 * HCD distal to the medial epicondyle. Using these guidelines resulted in safe virtual screw placement in all 84 elbows. The tolerance angle in the frontal plane was significantly smaller when drilling medial-to-lateral compared with drilling lateral-to-medial (P < .001). CONCLUSIONS: Medial-to-lateral drilling for transcondylar screw placement carries a higher risk of inadvertently penetrating the joint compared with lateral-to-medial drilling. PMID- 24467633 TI - Intramolecular [1,4]-S- to O-silyl migration: a useful strategy for synthesizing Z-silyl enol ethers with diverse thioether linkages. AB - An intramolecular [1,4]-S- to O-silyl migration has been used to form silyl enol ethers with Z-configurational control. The silyl migration also creates a new anion center at sulfur, which can subsequently react with electrophiles to generate Z-silyl enol ethers with diverse thioether linkages. The synthetic utility of this pathway was demonstrated by modifying the Z-silyl enol ethers with aldehydes via a Mukaiyama aldol reaction or Prins cyclization to generate functionalized organosulfur compounds. PMID- 24467632 TI - Altered intrinsic regional activity and corresponding brain pathways reflect the symptom severity of functional dyspepsia. AB - BACKGROUND: Increasing evidence shows central abnormalities in functional dyspepsia (FD) patients, but whether the symptom severity is directly reflected in altered brain patterns remains unclear. The purpose of this study was to explore how FD affected the resting functional brain patterns for different degrees of symptom severity. METHODS: Functional magnetic resonance imaging was carried out in 40 FD patients and 20 healthy controls. The resting-state brain changes in regional homogeneity (ReHo) and seed correlation analysis were investigated in patients relative to controls. To what degree the brain changes reflected the severity of the disease was assessed by a pattern classification technique. KEY RESULTS: Altered ReHo values (p < 0.05, FDR corrected) were discovered in multiple brain areas in FD patients, and only the anterior cingulate cortex (ACC) and thalamus exhibited significant correlation with the severity of dyspepsia symptoms. Compared with controls, the neural signal changes of the thalamus were not found in the less severe FD patient group but in the relatively more severe group, while the ACC showed aberrations in both groups. Seed-based correlation analysis revealed ACC- and thalamus-related functional connectivity differences between FD patients and controls at a voxel-wise level, and the altered thalamic circuits provided the best performance in distinguishing FD patients with different levels of symptom severity. CONCLUSIONS & INFERENCES: Our results indicated that the functional abnormalities of the ACC and thalamus may occur at different clinical courses in FD. This may help us better understand the progression of FD. PMID- 24467634 TI - The investigational agent MLN2238 induces apoptosis and is cytotoxic to CLL cells in vitro, as a single agent and in combination with other drugs. AB - Chronic lymphocytic leukaemia (CLL) is the most common haematological malignancy in the U.S. The course of the disease has been shown to be negatively impacted by increased levels of BCL2. Strategies to downregulate BCL2 and shift the balance towards cellular demise are actively being explored. Therefore, we examined whether the investigational agent MLN2238 could inhibit the proteasomal machinery and induce CLL cell death while also downregulating BCL2. MLN2238-induced cell death was studied in peripheral blood mononuclear cells from 28 CLL patients. MLN2238 produced a dose-dependent reduction in BCL2 and CLL cell viability with maximum cell death observed at a 50 nmol/l concentration by 48 h. Annexin-V staining, PARP1 and caspase-3 cleavage along with an increase in mitochondrial membrane permeability were noted after cells were treated with MLN2238; however, apoptosis was only partially blocked by the pan-caspase inhibitor z-VAD.fmk. Furthermore, we observed enhanced anti-CLL effects in tumour cells treated with either a combination of MLN2238 and the BH3 mimetic AT-101 or MLN2238 and fludarabine. Together, our data suggest the potential for proteasome inhibitor based therapy in CLL and the rationale design of drug combination strategies based on CLL biology. PMID- 24467635 TI - Interactions between prebiotics, probiotics, polyunsaturated fatty acids and polyphenols: diet or supplementation for metabolic syndrome prevention? AB - The metabolic syndrome can be prevented by the Mediterranean diet, characterized by fiber, omega-3 polyunsaturated fatty acids and polyphenols. However, the composition of the Mediterranean diet, which can be viewed as a natural multiple supplement, is poorly controlled, and its beneficial effects poorly predictable. The metabolic syndrome is associated with intestinal dysbiosis and the gut microbioma seems to be the main target and player in the interactions occurring between probiotics, prebiotics, omega 3 polyunsaturated fatty acids, and polyphenols. From the reviewed evidence, it is reasonable to manage growth and metabolism of gut microflora with specific prebiotics and polyphenols. Even though the healthy properties of functional foods and nutraceuticals still need to be fully elucidated, available data suggest that well-designed supplements, containing the better ratio of omega-3 polyunsaturated fatty acids and antioxidants, specific probiotic strains, and selected polyphenols and prebiotics, could be useful in metabolic syndrome prevention and treatment. PMID- 24467637 TI - Effect of sericin supplementation during in vitro maturation on the maturation, fertilization and development of porcine oocytes. AB - This study aimed to examine the effects of sericin supplementation during in vitro oocyte maturation on the nuclear maturation, fertilization and development of porcine oocytes. Cumulus-oocyte complexes (COCs) were cultured in maturation medium supplemented with 0 (control), 0.1, 0.5, 1.0, 2.5 or 5.0% sericin and were then subjected to in vitro fertilization and embryo culture. More COCs matured with 1.0% sericin underwent germinal vesicle breakdown and reached metaphase II compared with the control COCs matured without sericin (p < 0.01). The proportions of oocytes with DNA-fragmented nuclei did not differ between the groups, regardless of the sericin level. The total fertilization rate of oocytes matured with 1.0% sericin was higher (p < 0.05) than that of oocytes matured with 0.1%, 2.5% and 5.0% sericin. Supplementation with more than 1.0% sericin decreased the DNA fragmentation index of the blastocysts compared with the control group (p < 0.05). However, the supplementation of the maturation medium with sericin had no beneficial effects on the cleavage, development to the blastocyst stage and the total cell number of the embryos. Our findings indicate that supplementation with 1.0% sericin during maturation culture may improve the nuclear maturation and the quality of the embryos but does not affect blastocyst formation. PMID- 24467636 TI - The dual PPARalpha/gamma agonist aleglitazar increases the number and function of endothelial progenitor cells: implications for vascular function and atherogenesis. AB - BACKGROUND AND PURPOSE: Aleglitazar is a dual PPARalpha/gamma agonist but little is known about its effects on vascular function and atherogenesis. Hence, we characterized its effects on circulating angiogenic cells (CAC), neoangiogenesis, endothelial function, arteriogenesis and atherosclerosis in mice. EXPERIMENTAL APPROACH: C57Bl/6 wild-type (WT, normal chow), endothelial NOS (eNOS)(-/-) (normal chow) and ApoE(-/-) (Western-type diet) mice were treated with aleglitazar (10 mg.kg(-1) .day(-1) , i.p.) or vehicle. KEY RESULTS: Aleglitazar enhanced expression of PPARalpha and PPARgamma target genes, normalized glucose tolerance and potently reduced hepatic fat in ApoE(-/-) mice. In WT mice, but not in eNOS(-/-) , aleglitazar up-regulated Sca-1/VEGFR2-positive CAC in the blood and bone marrow and up-regulated diLDL/lectin-positive CAC. Aleglitazar augmented CAC migration and enhanced neoangiogenesis. In ApoE(-/-) mice, aleglitazar up regulated CAC number and function, reduced markers of vascular inflammation and potently improved perfusion restoration after hindlimb ischaemia and aortic endothelium-dependent vasodilatation. This was associated with markedly reduced formation of atherosclerotic plaques. In human cultured CAC from healthy donors and patients with coronary artery disease with or without diabetes mellitus, aleglitazar increased migration and colony-forming units in a concentration dependent manner. Furthermore, oxidative stress-induced CAC apoptosis and expression of p53 were reduced, while telomerase activity and expression of phospho-eNOS and phospho-Akt were elevated. Comparative agonist and inhibitor experiments revealed that aleglitazar's effects on CAC migration and colony forming units were mediated by both PPARalpha and PPARgamma signalling and required Akt. CONCLUSIONS AND IMPLICATIONS: Aleglitazar augments the number, function and survival of CAC, which correlates with improved vascular function, enhanced arteriogenesis and prevention of atherosclerosis in mice. PMID- 24467638 TI - Psychiatric disease in late adolescence and young adulthood. Foetal programming by maternal hypothyroidism? AB - OBJECTIVE: Lack of maternal thyroid hormones during foetal brain development may lead to structural abnormalities in the brain. We hypothesized that maternal hypothyroidism during the pregnancy could programme the foetus to development of psychiatric disease later in life. DESIGN: Danish nationwide register study. PARTICIPANTS: Singletons live-born 1980-1990. MEASUREMENTS: Cox proportional hazards model was used to estimate adjusted hazard ratio (aHR) with 95% confidence interval for offspring redemption of >=2 prescriptions of a psychiatric drug from age 15 to 31 years. RESULTS: Among 542 100 adolescents and young adults included, altogether 3979 (0.7%) were born to mothers with hypothyroidism registered before 1996. In crude analyses, the use of a psychiatric drug was more frequent in late adolescence and young adulthood when the mother had hypothyroidism (P < 0.001); however, several possible confounders had to be taken into account. For example, mothers with hypothyroidism often also had a psychiatric registration (38.5% vs 27.7%, P < 0.001) and the use of psychiatric drugs changed over time. After adjustment for confounders including birth year, maternal age and maternal psychiatric history, maternal hypothyroidism was associated with an increased risk of having redeemed prescriptions of anxiolytics [aHR 1.23 (1.03-1.48)] and antipsychotics [aHR 1.22 (1.03-1.44)] in late adolescence and young adulthood. For antidepressants, aHR was 1.07 (0.98-1.17). CONCLUSIONS: The association between maternal hypothyroidism and the use of a psychiatric drug in late adolescence and young adulthood was partly confounded by maternal psychiatric history, but foetal programming by maternal hypothyroidism may be part of the mechanisms leading to the use of anxiolytics and antipsychotics. PMID- 24467639 TI - Improved stability of trans-resveratrol in aqueous solutions by carboxymethylated (1,3/1,6)-beta-D-glucan. AB - Resveratrol is a polyphenolic compound endowed with multiple health benefits. However, its limited bioavailability and poor stability in solution hamper its use in pharmaceutical applications. Due to its low solubility in water, solvents such as ethanol and dimethyl sulfoxide are often used to dissolve resveratrol. However, these solvents have adverse effects on cultured cells or in vivo. The purpose of this study was to develop an aqueous liquid formulation of resveratrol in combination with a modified glucan, the carboxymethylated (1,3/1,6)-beta-D glucan (CM-glucan). The proposed liquid formulation conferred stability to resveratrol without affecting its antioxidant capability. Shelf-life measurements revealed that resveratrol in aqueous solution is degraded within a few weeks, due to spontaneous oxidation. In contrast, the combination with CM-glucan matrix exerted a strong stabilizing effect in aqueous medium and increased resveratrol stability up to 12 months at 25 degrees C. These data provide evidence of a stable resveratrol formulation in liquid suspensions and support the possible development of pharmaceutical applications of this association in biopharmaceutics and drug delivery. PMID- 24467641 TI - Easily controlled grafting of oligonucleotides on gammaFe2O3 nanoparticles: physicochemical characterization of DNA organization and biological activity studies. AB - We report a one-step process to functionalize superparamagnetic iron oxide nanoparticle (SPIO-NP) surfaces with a controlled number of oligonucleotides. For this study, we use a specific oligonucleotide targeting the signal transducer and activator of transcription 3 (STAT3), a key regulator of cell survival and proliferation. This oligonucleotide is self-complementary and can adopt a hairpin structure. It is labeled with the fluorescein amidite group at the 3'-end. The polyanionic DNA is electrostatically attracted onto the positively charged surface of the bare SPIO-NPs. During synthesis, the molar ratio between the oligonucleotides and nanoparticles was varied from 17.5 to 175. For particles with a mean diameter of 10 nm, a nanoparticle surface saturation is observed corresponding to 70 DNA strands per particle. The increase of DNA density per nanoparticle is correlated to a transition from the hairpin structure adsorbed horizontally on the nanoparticle surface to a vertically ordered surface packing assembly. An in vitro study on human colon carcinoma cell line SW480 shows that the kinetics of internalization and biological activity of the NPs seem to be dependent on the oligonucleotide density. Cell death and the kinetics of internalization are favored by a low density of oligonucleotides. PMID- 24467642 TI - Outcomes in older versus younger patients over 96 weeks in HIV-1- infected patients treated with rilpivirine or efavirenz in ECHO and THRIVE. AB - OBJECTIVES: Increasing life expectancy of HIV-1-infected patients raises interest in how trial results apply to older patients. This post-hoc analysis evaluated potential differences in efficacy and safety in older (>=50 years) versus younger (<50 years) patients in the ECHO and THRIVE trials over 96 weeks. METHODS: HIV infected, treatment-naive adults were randomized to receive rilpivirine (RPV) or efavirenz (EFV), plus a background regimen. Virologic response rates (FDA snapshot analysis; HIV-1 RNA <50 copies/mL) were assessed at Week 96. Total-body bone mineral density was evaluated at baseline and Week 96 by dual-energy X-ray absorptiometry scans. Serum concentrations of 25-hydroxy vitamin D (ECHO trial only) were also measured at baseline, Week 24 and Week 48. RESULTS: 1368 patients were treated. At Week 96, virologic response rates were similar between older (77%) and younger (76%) RPV-treated patients and numerically higher in older (84%) versus younger (76%) EFV-treated patients. No clinically relevant age related differences were observed in immunologic responses. Small differences were noted in older versus younger patients in adverse events (higher rates of depression, insomnia, and rash in older EFV-treated patients), laboratory abnormalities (increased low-density lipoprotein cholesterol and hyperglycemia in older EFV-treated patients and increased amylase in older patients across treatments), bone mineral density (larger decreases in older patients across treatments), and progression to severe vitamin D deficiency (greater in older versus younger EFV-treated patients). CONCLUSION: Efficacy and safety outcomes were generally similar in older versus younger patients in the ECHO and THRIVE trials. PMID- 24467643 TI - Identification and characterization of a sex peptide receptor-like transcript from the western tarnished plant bug Lygus hesperus. AB - Lygus hesperus females exhibit a post-mating behavioural switch that triggers increased egg laying and decreased sexual interest. In Drosophila melanogaster, these changes are controlled by sex peptide (SP) and the sex peptide receptor (DmSPR). In Helicoverpa armigera, SPR (HaSPR) also regulates some post-mating behaviour; however, myoinhibiting peptides (MIPs) have been identified as the SPR ancestral ligand, indicating that SPR is a pleiotropic receptor. In the present study, we identified a transcript, designated L. hesperus SPR (LhSPR), that is homologous to known SPRs and which is expressed throughout development and in most adult tissues. LhSPR was most abundant in female seminal depositories and heads as well as the hindgut/midgut of both sexes. In vitro analyses revealed that fluorescent chimeras of LhSPR, DmSPR and HaSPR localized to the cell surface of cultured insect cells, but only DmSPR and HaSPR bound carboxytetramethylrhodamine-labelled analogues of DmSP21-36 and DmMIP4. Injected DmSP21-36 also failed to have an effect on L. hesperus mating receptivity. Potential divergence in the LhSPR binding pocket may be linked to receptor-ligand co-evolution as 9 of 13 MIPs encoded by a putative L. hesperus MIP precursor exhibit an atypical W-X7 -Wamide motif vs the W-X6 -Wamide and W-X8 -Wamide motifs of Drosophila MIPs and SP. PMID- 24467644 TI - Success or failure of chronic pain rehabilitation: the importance of good interaction - a qualitative study under patients and professionals. AB - AIM: The aim of this study was to explore which factors are associated with a successful treatment outcome in chronic pain patients and professionals participating in a multidisciplinary rehabilitation program, with a specific focus on the patient-professional interaction. METHODS: Patients (n = 16) and professionals (n = 10) were interviewed and/or observed. The transcribed interviews and observations were analyzed and themes were described. RESULTS: Patients with a positive treatment outcome came to a shared understanding of their pain with their professional, demonstrated new learned behavior and were able to continue their learning process at home. Patients with a negative treatment outcome did not reach a shared understanding of their pain with their professional, were not able to change their behavior and wanted more help to achieve this. Both patient groups experienced organizational barriers within the treatment process. Factors associated with a high quality of patient-professional interaction included the patient experience of being taken seriously, the involvement of the professional with the patient, a clear explanation of the pain, and an open interaction between patient and professional. CONCLUSION: This study provides insight into factors which were related to a positively or negatively experienced outcome of pain rehabilitation. A good match within the patient-professional interaction seems essential. IMPLICATIONS OF REHABILITATION: Within chronic pain rehabilitation good didactic skills and a client-centered attitude of the professional may be helpful in order to make the patient feel being taken seriously. An assessment of the patient's learning style might lead to a better fit of the patient education and training according to an individual's learning style. Relapse might be prevented by paying special attention to the integration of new behavior within important life areas as work and sports. PMID- 24467645 TI - Overgeneral autobiographical memory predicts changes in depression in a community sample. AB - This study investigated whether overgeneral autobiographical memory (OGM) predicts the course of symptoms of depression and anxiety in a community sample, after 5, 6, 12 and 18 months. Participants (N=156) completed the Autobiographical Memory Test and the Depression Anxiety Stress Scales-21 (DASS-21) at baseline and were subsequently reassessed using the DASS-21 at four time points over a period of 18 months. Using latent growth curve modelling, we found that OGM was associated with a linear increase in depression. We were unable to detect changes over time in anxiety. OGM may be an important marker to identify people at risk for depression in the future, but more research is needed with anxiety. PMID- 24467646 TI - Reaction-based azide gas sensing with tailored ionic liquids measured by quartz crystal microbalance. AB - On the basis of the strain-promoted [3 + 2] cycloaddition reaction performed at ambient temperature, a label-free, online, and chemospecific gas-phase measurement of organic azides in real time was efficiently achieved on QCM chips thin-coated with tailored ionic liquid TIL 1. PMID- 24467647 TI - The application of esophageal pressure measurement in patients with respiratory failure. AB - This report summarizes current physiological and technical knowledge on esophageal pressure (Pes) measurements in patients receiving mechanical ventilation. The respiratory changes in Pes are representative of changes in pleural pressure. The difference between airway pressure (Paw) and Pes is a valid estimate of transpulmonary pressure. Pes helps determine what fraction of Paw is applied to overcome lung and chest wall elastance. Pes is usually measured via a catheter with an air-filled thin-walled latex balloon inserted nasally or orally. To validate Pes measurement, a dynamic occlusion test measures the ratio of change in Pes to change in Paw during inspiratory efforts against a closed airway. A ratio close to unity indicates that the system provides a valid measurement. Provided transpulmonary pressure is the lung-distending pressure, and that chest wall elastance may vary among individuals, a physiologically based ventilator strategy should take the transpulmonary pressure into account. For monitoring purposes, clinicians rely mostly on Paw and flow waveforms. However, these measurements may mask profound patient-ventilator asynchrony and do not allow respiratory muscle effort assessment. Pes also permits the measurement of transmural vascular pressures during both passive and active breathing. Pes measurements have enhanced our understanding of the pathophysiology of acute lung injury, patient-ventilator interaction, and weaning failure. The use of Pes for positive end-expiratory pressure titration may help improve oxygenation and compliance. Pes measurements make it feasible to individualize the level of muscle effort during mechanical ventilation and weaning. The time is now right to apply the knowledge obtained with Pes to improve the management of critically ill and ventilator-dependent patients. PMID- 24467648 TI - High invasiveness of pneumococcal serotypes included in the new generation of conjugate vaccines. AB - The implementation of the seven-valent pneumococcal conjugate vaccine, PCV7, has resulted in significant changes in the pneumococcal population being carried and causing disease. We aimed to determine the invasive disease potential of serotypes causing invasive paediatric disease in the era of conjugate vaccines in Catalonia, Spain, and their potential coverage by the 13-valent pneumococcal conjugate vaccine, PCV13. As a secondary objective, we evaluated whether implementation of PCV7 had resulted in significant changes in the invasive disease potential of the most frequent serotypes circulating in the area. Two pneumococcal collections obtained from children admitted to the University Hospital Sant Joan de Deu (Barcelona, Spain) between 2007 and 2011 were compared: a first set of 159 invasive disease isolates, and a second set of 209 nasopharyngeal isolates recovered from healthy children admitted for minor surgery. The most common invasive serotypes were 1 (24.5%, n = 39), 19A (21.2%, n = 34), 5 (8.8%, n = 14), 7F (8.8%, n = 14) and 3 (5%, n = 8). The most common serotypes in carriage were 19A (10%, n = 21), 6C (9%, n = 19), 23B (8.1%, n = 17), 6A (7.6%, n = 16) and 19F (6.2%, n = 13). A significantly higher propensity to cause invasive disease was observed for serotypes 1, 3, 5, 7F and 19A, all of which are included in PCV13. After false-discovery-rate correction, the results were robust for serotypes 1, 5, 7F and 19A. Non-PCV13 serotypes had a low invasive disease potential. Our data reinforce the need for continuous surveillance and should encourage efforts to introduce universal vaccination with PCV13 in children in our region. PMID- 24467649 TI - Interleukin-17 and interleukin-23: importance in the pathogenesis of lung impairment in patients with systemic sclerosis. AB - AIM: T cell abnormalities with a focus on Th17 cells have been associated with the pathogenesis of systemic sclerosis (SSc) and interstitial lung disease (ILD). The aim of this study was to evaluate serum levels of interleukin (IL)-17, IL-21 and IL-23 in SSc patients and to assess their relationship with ILD-SSc. METHODS: Thirty-eight patients with SSc and 39 healthy controls were recruited. Serum IL 17, IL-21 and IL-23 levels were examined using enzyme-linked immunosorbent assay (ELISA). Lung involvement of SSc patients was assessed functionally (diffusing capacity of the lung for carbon monoxide [DLCO], body plethysmography) and radiologically (using average disease extent on high resolution computed tomography [HRCT] of the lungs according to the percentage of interstitial changes and quantified with a 30-point Warrick score) in 29 SSc patients. RESULTS: Serum IL-17 and IL-23 levels were significantly decreased and IL-21 levels were elevated in SSc patients when compared with controls (P < 0.001, P < 0.001, P < 0.01, respectively). The level of IL-17 was negatively associated with disease duration (P = 0.01) and positively with HRCT Warrick score (P = 0.03). IL 23 concentration negatively correlated with DLCO (P = 0.04), total lung capacity (TLC) (P = 0.01) and the 6-min walk test distance (P = 0.03). No associations were found between the cytokine levels and the average extent of the disease on HRCT. CONCLUSION: While the relationship between Th17-associated cytokines and ILD-SSc needs to be verified in a larger cohort of patients, the changes in concentrations of IL-17, IL-21 and IL-23 support the hypothesis that these cytokines may play a role in the pathogenesis of SSc. PMID- 24467650 TI - An immunomodulatory role for the Mycobacterium tuberculosis region of difference 1 locus proteins PE35 (Rv3872) and PPE68 (Rv3873). AB - The pathogenesis of Mycobacterium tuberculosis involves the coordinate action of multiple bacillary components that modulate host immune responses to ensure its survival. One such group of factors is the multigenic PE_PPE protein family, several members of which have been implicated in host immune evasion. Here we investigate the function of the PE-PPE gene pair PE35 (Rv3872)-PPE68 (Rv3873), located in the region of difference 1, encoding a specialized mycobacterial secretion system that is deleted in all vaccine strains of Mycobacterium bovis BCG. We report that this gene pair is co-operonic in M. tuberculosis, and demonstrate that its gene products interact with each other. Stimulation of THP-1 macrophages with recombinant PE35 and PPE68, singly or in combination, led to a dose-dependent increase in levels of the anti-inflammatory cytokine interleukin (IL)-10 and the chemokine monocyte chemoattractant protein-1, and caused a reciprocal decrease in levels of the proinflammatory cytokine IL-12. PE35/PPE68 stimulated production of IL-10 and monocyte chemoattractant protein-1 was observed to be dependent on toll-like receptor 2, as receptor blockade caused a significant reduction in their levels. Pharmacological inhibition indicated that this induction involved activation of the mitogen-activated protein kinase signalling axis. In a transwell migration assay, culture supernatants from PE35/PPE68-treated THP-1 cells were observed to stimulate the migration of monocytes. Our findings suggest that the PE35-PPE68 gene pair plays an important immunomodulatory role in regulating the pathophysiology of M. tuberculosis. STRUCTURED DIGITAL ABSTRACT: TLR2 physically interacts with PPE68 by anti bait coimmunoprecipitation (View interaction) PE35 binds to PPE68 by pull down (View interaction) PE35 physically interacts with PPE68 by anti tag coimmunoprecipitation (View interaction) TLR2 physically interacts with PE35 by anti bait coimmunoprecipitation (View interaction) PPE68 and PE35 physically interact by dihydrofolate reductase reconstruction (View interaction). PMID- 24467651 TI - Survival benefit of definitive therapy in patients with clinically advanced prostate cancer: estimations of the number needed to treat based on competing risks analysis. AB - OBJECTIVE: To describe the survival benefit associated with radical prostatectomy (RP), as compared with initial observation, in patients with locally advanced prostate cancer (PCa). PATIENTS AND METHODS: Overall, 1382 patients with locally advanced PCa treated with RP or initial observation between 1995 and 2009 were identified from the Surveillance, Epidemiology and End Results Medicare insurance programme-linked database. Patients were matched using propensity-score methodology, then 10-year cancer-specific mortality (CSM) rates were estimated and the number needed to treat (NNT) was calculated. Competing-risks regression analyses tested the relationship between treatment type and CSM. RESULTS: Overall, the 10-year CSM rates were 11.8 and 19.3% for patients treated with RP and initial observation, respectively (P < 0.001). The corresponding 10-year NNT was 13. The 10-year CSM rates for the same treatment groups were 8.9 vs 13.9%, respectively, for Gleason score <=7, 16.8 vs 27.8%, respectively, for Gleason score 8-10, 10.1 vs 15.8%, respectively, for clinical stage T3a, and 17.0 vs 29.3%, respectively, for T3b/T4, respectively (all P <= 0.04). The corresponding NNTs were 20, 9, 17 and 8, respectively. In multivariable analyses, RP was an independent predictor of more favourable CSM rates in all categories (all P <= 0.04). In separate sensitivity analyses, no differences were recorded when patients treated with radiotherapy were compared with those receiving RP (P = 0.4). Conversely, patients undergoing initial observation had a higher risk of CSM compared with those treated with radiotherapy (P = 0.03). CONCLUSIONS: RP leads to a significant survival advantage compared with observation in patients with locally advanced disease. The highest benefit was observed in patients with T3b/T4 and Gleason score 8-10 disease. PMID- 24467652 TI - Recent advances in molecular recognition based on nanoengineered platforms. AB - Nanoparticles and nanoengineered platforms have great potential for technologies involving biomoleuclar detection or cell-related biosensing, and have provided effective chemical interfaces for molecular recognition. Typically, chemists work on the modification of synthetic polymers or macromolecules, which they link to the nanoparticles by covalent or noncovalent approaches. The motivation for chemical modification is to enhance the selectivity and sensitivity, and to improve the biocompatibility for the in vivo applications. In this Account, we present recent advances in the development and application of chemical interfaces for molecular recognition for nanoparticles and nanoengineered platforms, in particular single-walled carbon nanotubes (SWNTs). We discuss emerging approaches for recognizing small molecules, glycosylated proteins, and serum biomarkers. For example, we compare and discuss detection methods for ATP, NO, H2O2, and monosaccharides for recent nanomaterials. Fluorometric detection appears to have great potential for quantifying concentration gradients and determining their location in living cells. For macromolecular detection, new methods for glycoprofiling using such interfaces appear promising, and benefit specifically from the potential elimination of cumbersome labeling and liberation steps during conventional analysis of glycans, augmenting the currently used mass spectrometry (MS), capillary electrophoresis (CE), and liquid chromatography (LC) methods. In particular, we demonstrated the great potential of fluorescent SWNTs for glycan lectin interactions sensing. In this case, SWNTs are noncovalently functionalized to introduce a chelated nickel group. This group provides a docking site for the His-tagged lectin and acts as the signal modulator. As the nickel proximity to the SWNT surface changes, the fluorescent signal is increased or attenuated. When a free glycan or glycosylated probe interacts with the lectin, the signal increases and they are able to obtain loading curves similar to surface plasmon resonance measurements. They demonstrate the sensitivity and specificity of this platform with two higher-affined glycan-lectin pairs: fucose (Fuc) to PA-IIL and N-acetylglucosamine (GlcNAc) to GafD. Lastly, we discuss how developments in protein biomarker detection in general are benefiting specifically from label free molecular recognition. Electrical field effect transistors, chemi-resistive and fluorometric nanosensors based on various nanomaterials have demonstrated substantial progress in recent years in addressing this challenging problem. In this Account, we compare the balance between sensitivity, selectivity, and nonspecific adsorption for various applications. In particular, our group has utilized SWNTs as fluorescence sensors for label-free protein-protein interaction measurements. In this assay, we have encapsulated each nanotube in a biocompatible polymer, chitosan, which has been further modified to conjugate nitrilotriacetic acid (NTA) groups. After Ni(2+) chelation, NTA Ni(2+) complexes bind to his-tagged proteins, resulting in a local environment change of the SWNT array, leading to optical fluorescence modulation with detection limit down to 100 nM. We have further engineered the platform to monitor single protein binding events, with an even lower detection limit down to 10 pM. PMID- 24467654 TI - Noncontact free-rotating disk triboelectric nanogenerator as a sustainable energy harvester and self-powered mechanical sensor. AB - In this work, we introduced an innovative noncontact, free-rotating disk triboelectric nanogenerator (FRD-TENG) for sustainably scavenging the mechanical energy from rotary motions. Its working principle was clarified through numerical calculations of the relative-rotation-induced potential difference, which serves as the driving force for the electricity generation. The unique characteristic of the FRD-TENG enables its high output performance compared to its working at the contact mode, with an effective output power density of 1.22 W/m(2) for continuously driving 100 light-emitting diodes. Ultrahigh stability of the output and exceptional durability of the device structure were achieved, and the reliable output was utilized for fast/effective charging of a lithium ion battery. Based on the relationship between its output performance and the parameters of the mechanical stimuli, the FRD-TENG could be employed as a self powered mechanical sensor, for simultaneously detecting the vertical displacement and rotation speed. The FRD-TENG has superior advantages over the existing disk triboelectric nanogenerator, and exhibits significant progress toward practical applications of nanogenerators for both energy harvesting and self-powered sensor networks. PMID- 24467653 TI - A biological basis for depression in pancreatic cancer. AB - BACKGROUND: Patients with pancreatic adenocarcinoma frequently present with depression the symptoms of which may precede cancer diagnosis, suggesting that the pathophysiology of depression in pancreatic adenocarcinoma may result from biological changes that are induced by the presence of the tumour itself. The present study was conducted to test a hypothesized relationship with the kynurenine pathway, which has been implicated in both depression and tumour induced immunosuppression. METHODS: 17 patients with pancreatic adenocarcinoma were recruited and completed mood questionnaires (Functional Assessment of Cancer Therapy -Pancreatic Cancer, Beck Depression Inventory and the Beck Anxiety Inventory) and blood testing for serum levels of tryptophan, kynurenine, kynurenic acid and quinolinic acid. Tumour burden was determined from pathology reports (tumour size and nodal involvement). RESULTS: Findings indicated a negative correlation between mood scores and the plasma kynurenic acid : tryptophan ratio in plasma, and a positive correlation between tumour burden and plasma kynurenine level. CONCLUSIONS: This study suggests that pancreatic cancer may influence mood via the kynurenine pathway. The relationship of the kynurenine pathway with pancreatic tumour burden should be explored further in large multicentre studies because a better understanding of this physiology might have significant clinical benefit. PMID- 24467655 TI - Copper-catalyzed double C-S bonds formation via different paths: synthesis of benzothiazoles from N-benzyl-2-iodoaniline and potassium sulfide. AB - A new, highly efficient procedure for the synthesis of benzothiazoles from easily available N-benzyl-2-iodoaniline and potassium sulfide has been developed. The results show copper-catalyzed double C-S bond formation via a traditional cross coupling reaction and an oxidative cross-coupling reaction. PMID- 24467656 TI - Continuity and change in the home literacy environment as predictors of growth in vocabulary and reading. AB - One hundred and ten English-speaking children schooled in French were followed from kindergarten to Grade 2 (Mage : T1 = 5;6, T2 = 6;4, T3 = 6;11, T4 = 7;11). The findings provided strong support for the Home Literacy Model (Senechal & LeFevre, ) because in this sample the home language was independent of the language of instruction. The informal literacy environment at home predicted growth in English receptive vocabulary from kindergarten to Grade 1, whereas parent reports of the formal literacy environment in kindergarten predicted growth in children's English early literacy between kindergarten and Grade 1 and growth in English word reading during Grade 1. Furthermore, 76% of parents adjusted their formal literacy practices according to the reading performance of their child, in support of the presence of a responsive home literacy curriculum among middle-class parents. PMID- 24467657 TI - An increase in adenosine-5'-triphosphate (ATP) content in rostral ventrolateral medulla is engaged in the high fructose diet-induced hypertension. AB - BACKGROUND: The increase in fructose ingestion has been linked to overdrive of sympathetic activity and hypertension associated with the metabolic syndrome. The premotor neurons for generation of sympathetic vasomotor activity reside in the rostral ventrolateral medulla (RVLM). Activation of RVLM results in sympathoexcitation and hypertension. Neurons in the central nervous system are able to utilize fructose as a carbon source of ATP production. We examined in this study whether fructose affects ATP content in RVLM and its significance in the increase in central sympathetic outflow and hypertension induced by the high fructose diet (HFD). RESULTS: In normotensive rats fed with high fructose diet (HFD) for 12 weeks, there was a significant increase in tissue ATP content in RVLM, accompanied by the increases in the sympathetic vasomotor activity and blood pressure. These changes were blunted by intracisternal infusion of an ATP synthase inhibitor, oligomycin, to the HFD-fed animals. In the catecholaminergic containing N2a cells, fructose dose-dependently upregulated the expressions of glucose transporter 2 and 5 (GluT2, 5) and the rate-limiting enzyme of fructolysis, ketohexokinase (KHK), leading to the increases in pyruvate and ATP production, as well as the release of the neurotransmitter, dopamine. These cellular events were significantly prevented after the gene knocking down by lentiviral transfection of small hairpin RNA against KHK. CONCLUSION: These results suggest that increases in ATP content in RVLM may be engaged in the augmented sympathetic vasomotor activity and hypertension associated with the metabolic syndrome induced by the HFD. At cellular level, the increase in pyruvate levels via fructolysis is involved in the fructose-induced ATP production and the release of neurotransmitter. PMID- 24467658 TI - A multicentre study of primary breast diffuse large B-cell lymphoma in the rituximab era. AB - Primary breast diffuse large B-cell lymphoma (DLBCL) is a rare subtype of non Hodgkin lymphoma (NHL) with limited data on pathology and outcome. A multicentre retrospective study was undertaken to determine prognostic factors and the incidence of central nervous system (CNS) relapses. Data was retrospectively collected on patients from 8 US academic centres. Only patients with stage I/II disease (involvement of breast and localized lymph nodes) were included. Histologies apart from primary DLBCL were excluded. Between 1992 and 2012, 76 patients met the eligibility criteria. Most patients (86%) received chemotherapy, and 69% received immunochemotherapy with rituximab; 65% received radiation therapy and 9% received prophylactic CNS chemotherapy. After a median follow-up of 4.5 years (range 0.6-20.6 years), the Kaplan-Meier estimated median progression-free survival was 10.4 years (95% confidence interval [CI] 5.8-14.9 years), and the median overall survival was 14.6 years (95% CI 10.2-19 years). Twelve patients (16%) had CNS relapse. A low stage-modified International Prognostic Index (IPI) was associated with longer overall survival. Rituximab use was not associated with a survival advantage. Primary breast DLBCL has a high rate of CNS relapse. The stage-modified IPI score is associated with survival. PMID- 24467659 TI - Lipid droplet analysis using in vitro bovine oocytes and embryos. AB - The aim of this study was to quantify the content of lipid droplets in bovine oocytes and embryos from Bos indicus (Bi), Bos taurus (Bt) and Bos indicus * Bos taurus (Bi * Bt). Oocytes were aspirated post-mortem and subjected to in vitro maturation, in vitro fertilization and in vitro development; the medium employed at each stage (TCM-199, TALP, SOF) was supplemented with (i) serum replacement (SR), (ii) foetal calf serum (FCS) or (iii) oestrous cow serum (ECS). The structure and distribution of the lipid droplets were established using electron microscopy, but were quantified using an optical microscope on semi-fine toluidine blue-stained sections. The highest percentage of embryos corresponded to those produced with FCS and ECS, which differed from embryos generated with SR (p < 0.05). The highest percentage of morulae and the lowest percentage of blastocysts were obtained with the SR supplement (p < 0.05). The oocytes cultured in FCS demonstrated a higher number of lipid droplets compared to those cultured in SR and ECS (p < 0.05). Less accumulation of lipids was observed in embryos supplemented with SR. The lowest and highest numbers of lipid droplets in oocytes corresponded to the Bi and Bt strain, respectively. The lowest amount of lipid droplets in embryos was observed in Bi (p < 0.05). In conclusion, supplementation of the in vitro development culture medium (synthetic oviduct fluid) with a synthetic substitute serum produced similar results in terms of embryo development compared to those obtained with FCS, but a decreased degree of lipid droplet accumulation was observed in the in vitro-cultured embryos. PMID- 24467661 TI - Gastric dilatation and volvulus in a red panda (Ailurus fulgens). AB - OBJECTIVE: To describe the successful management of gastric dilatation and volvulus (GDV) in a red panda. STUDY DESIGN: Clinical report. ANIMALS: Red panda diagnosed with GDV. RESULTS: A 12-year-old male red panda (Ailurus fulgens) was evaluated for acute onset inappetence, staggering, collapse, and tachypnea. Gastric dilatation and volvulus (GDV) was diagnosed by radiography, abdominal ultrasonography, and exploratory celiotomy. Torsion of the stomach was corrected and an incisional gastropexy performed to prevent recurrence. No organs were devitalized, no other abnormalities detected, and the red panda recovered fully within 72 hours. CONCLUSIONS: GDV should be considered as a differential diagnosis for red pandas presenting with acute onset of unspecific signs such as collapse, inappetence, and abdominal distension. GDV in red pandas can be diagnosed and successfully treated as described in dogs. PMID- 24467662 TI - Structural defects and positronium formation in 40 keV B(+)-implanted polymethylmethacrylate. AB - Slow positron beam and optical absorption measurements are carried out to study structural defects and positronium formation in 40 keV B(+)-implanted polymethylmethacrylate (B:PMMA) with ion doses from 6.25 * 10(14) to 5.0 * 10(16) ions/cm(2). Detailed depth-selective information on defects in implanted samples was obtained by measuring of Doppler broadening of positron annihilation gamma rays as a function of incident positron energy and these experimental results were compared with SRIM (stopping and range of ions in matter) simulation results. Two general processes, appearance of free radicals at lower ion doses (<10(16) ions/cm(2)) and carbonization at higher ion doses (>10(16) ions/cm(2)), are considered from the Doppler S-E and W-E dependences in the framework of the concept of defects formation during radiation damage of polymer structure. Probabilities of ortho-positronium (o-Ps) formation are analyzed using S-W plot and slow positron annihilation lifetime measurements. Dose dependence of o-Ps lifetime tau3 and intensity I3 at the incident positron energy of 2.15 keV correlates well with the dose dependence of S-parameter and seems to account for the existence of the expected two processes, i.e., scission of polymer chains and appearance of free radicals preceding the aggregation of the clusters resulting in the formation of network of conjugated bonds at lower ion doses and carbonization at higher ion doses. The increase of optical absorption observed with increasing ion implantation dose also suggests a formation of carbonaceous phase in the ion-irradiated PMMA. PMID- 24467663 TI - Disrupted rapid eye movement sleep predicts poor declarative memory performance in post-traumatic stress disorder. AB - Successful memory consolidation during sleep depends on healthy slow-wave and rapid eye movement sleep, and on successful transition across sleep stages. In post-traumatic stress disorder, sleep is disrupted and memory is impaired, but relations between these two variables in the psychiatric condition remain unexplored. We examined whether disrupted sleep, and consequent disrupted memory consolidation, is a mechanism underlying declarative memory deficits in post traumatic stress disorder. We recruited three matched groups of participants: post-traumatic stress disorder (n = 16); trauma-exposed non-post-traumatic stress disorder (n = 15); and healthy control (n = 14). They completed memory tasks before and after 8 h of sleep. We measured sleep variables using sleep-adapted electroencephalography. Post-traumatic stress disorder-diagnosed participants experienced significantly less sleep efficiency and rapid eye movement sleep percentage, and experienced more awakenings and wake percentage in the second half of the night than did participants in the other two groups. After sleep, post-traumatic stress disorder-diagnosed participants retained significantly less information on a declarative memory task than controls. Rapid eye movement percentage, wake percentage and sleep efficiency correlated with retention of information over the night. Furthermore, lower rapid eye movement percentage predicted poorer retention in post-traumatic stress disorder-diagnosed individuals. Our results suggest that declarative memory consolidation is disrupted during sleep in post-traumatic stress disorder. These data are consistent with theories suggesting that sleep benefits memory consolidation via predictable neurobiological mechanisms, and that rapid eye movement disruption is more than a symptom of post-traumatic stress disorder. PMID- 24467664 TI - In silico analysis of potential human T Cell antigens from Mycobacterium tuberculosis for the development of subunit vaccines against tuberculosis. AB - In silico analysis was used to predict MHC class I and class II promiscuous epitopes and potential antigens, from 24 novel T cell antigens of Mycobacterium tuberculosis. Majority of the antigens (16/24) had high affinity peptides to both MHC class I and class II alleles and higher population coverage compared to well proven T cell antigens ESAT-6, CFP-10 and Ag85B. Among these, highest population coverage were calculated for three novel T cell antigens Rv0733 (97.24%), Rv0462 (96.9%) and Rv2251 (96.3%). The prediction results were experimentally tested by in vitro stimulation of these novel T cell antigens with blood drawn from QuantiFERON-TB Gold In-Tube (QFT-IT) positive healthy household contacts of tuberculosis patients and pulmonary TB patients. Significantly higher level interferon-gamma (IFN-gamma) was observed, with these novel T cell antigens, in healthy household contacts compared to pulmonary TB subjects (p = 0.0001). In silico analysis also resulted in prediction of 36 promiscuous epitopes from the novel 24 T cell antigens. Population coverage for 4 out of the 36 promiscuous epitopes was >90% [67 VVLLWSPRS (Rv1324), 42 VVGVTTNPS (Rv1448c), 178 MRFLLSAKS (Rv0242c) and 842 IRLMALVEY (Rv3800c)]. Our results shows that these novel antigens and promiscuous epitopes identified from our analysis can further be investigated for their usefulness for subunit vaccine development. PMID- 24467665 TI - Mechanisms of cilia-driven transport in the airways in the absence of mucus. AB - Airway mucus is thought to be required for the clearance of inhaled particles by mucociliary transport, but this view has recently been challenged. To test if mucus is necessary for cilia-driven particle transport, we removed mucus from murine and human ex vivo airway preparations by thorough rinsing with buffer with or without additional dithiothreitol washing. The transport of particles with diameters of 4.5 MUm, 200 nm, and 40 nm and of bacteria was analyzed by video microscopy. Complete removal of mucus was verified by wheat germ agglutinin staining and by scanning electron microscopy. In the absence of mucus, we observed efficient transport of particles and bacteria by direct cilia-mediated propulsion or via fluid flow generated by ciliary beating. Virus-sized particles had the tendency to attach to cilia. Because direct contact of particles with ciliated cells occurs in the absence of mucus, we examined if this direct interaction changes epithelial function. Neither bacteria- nor LPS-induced nuclear translocation of NF-kappaB p65 in ciliated cells occurred, indicating that mere contact between ciliated cells and bacteria during transport does not activate the epithelium. Attachment of virus-sized particles to cilia could induce mucus release and/or increase the ciliary beat frequency. Our results indicate that cilia-driven transport of particles with various sizes is possible in murine and human airways without the presence of mucus. If mucus-free transport fails, the epithelium can react by releasing mucus or increasing the ciliary beat frequency to maintain particle transport. PMID- 24467666 TI - Vertebrate Acyl CoA synthetase family member 4 (ACSF4-U26) is a beta-alanine activating enzyme homologous to bacterial non-ribosomal peptide synthetase. AB - Mammalian ACSF4-U26 (Acyl CoA synthetase family member 4), a protein of unknown function, comprises a putative adenylation domain (AMP-binding domain) similar to those of bacterial non-ribosomal peptide synthetases, a putative phosphopantetheine attachment site, and a C-terminal PQQDH (pyrroloquinoline quinone dehydrogenase)-related domain. Orthologues comprising these three domains are present in many eukaryotes including plants. Remarkably, the adenylation domain of plant ACSF4-U26 show greater identity with Ebony, the insect enzyme that ligates beta-alanine to several amines, than with vertebrate or insect ACSF4 U26, and prediction of its specificity suggests that it activates beta-alanine. In the presence of ATP, purified mouse recombinant ACSF4-U26 progressively formed a covalent bond with radiolabelled beta-alanine. The bond was not formed in a point mutant lacking the phosphopantetheine attachment site. Competition experiments with various amino acids indicated that the reaction was almost specific for beta-alanine, and a KM of ~ 5 MUm was calculated for this reaction. The loaded enzyme was used to study the formation of a potential end product. Among the 20 standard amino acids, only cysteine stimulated unloading of the enzyme. This effect was mimicked by cysteamine and dithiothreitol, and was unaffected by absence of the PQQDH-related domain, suggesting that beta-alanine transfer onto thiols is catalysed by the ACSF4-U26 adenylation domain, but is physiologically irrelevant. We conclude that ACSF4-U26 is a beta-alanine activating enzyme, and hypothesize that it is involved in a rare intracellular reaction, possibly an infrequent post-translational or post-transcriptional modification. PMID- 24467667 TI - Presbyopia: a pilot investigation of the barriers and benefits of near visual acuity correction among a rural Filipino population. AB - BACKGROUND: Presbyopia is the age-related decline in accommodation that diminishes the ability of the eye to focus on near objects. Presbyopia is common and easy to correct; however, many communities lack access to basic eye care. The purpose of this project was to assess the burden of uncorrected presbyopia in a rural Filipino population and to pilot an intervention aimed at increasing access to reading glasses in the community. METHODS: Individuals above the age of 40 who presented to a health outreach in the Philippines were invited to undergo a near vision exam to detect the presence of functional presbyopia and be fitted with ready-made, single-vision glasses. The change in stereoacuity was used as a surrogate measure of functional improvement after near vision correction. A questionnaire was administered to assess this population's perceived barriers and benefits to correcting near vision. RESULTS: The average age of the participants was 57 +/- 11 years, with 87.6% of participants having an uncorrected near visual acuity of <20/50. Reading glasses improved near vision to 20/40 or better in 77.7% of participants having near-vision impairment (uncorrected near visual acuity of <20/40). Over 75% of participants also showed improvement in stereoacuity. Cost, rather than availability, was perceived to be the greater barrier to the procurement of glasses, and 84% of participants reported that the glasses dispensed would greatly improve their ability to earn a living. CONCLUSIONS: Dispensing ready-made, single-vision glasses is a simple and cost effective intervention to improve near vision and enhance depth perception. A greater understanding of the barriers and benefits to correcting near vision will inform the design and execution of a sustainable program to correct presbyopia in developing countries. PMID- 24467668 TI - (99) Tc-methylene diphosphonate improves rheumatoid arthritis disease activity by increasing the frequency of peripheral gammadelta T cells and CD4(+) CD25(+) Foxp3(+) Tregs. AB - AIM: gammadelta T cells exhibit important functions in the pathogenesis of rheumatoid arthritis (RA). In recent years, numerous studies harnessed the gammadelta T cell-activating capacity of aminobiphosphonates for the treatment of malignant tumors. As (99) Tc-methylene diphosphonate ((99) Tc-MDP) has long been widely used for the treatment of RA in China with good efficacy, we are interested in whether this drug exerts its therapeutic effect on RA by modulating peripheral gammadelta T cells of RA patients. OBJECTIVES: To investigate the effect of (99) Tc-MDP on the frequency of gammadelta T cells and CD4(+) CD25(+) Foxp3(+) Tregs in the peripheral blood of patients with active RA. METHODS: Nineteen patients with active RA were treated with (99) Tc-MDP intravenously at a dose of 20 MUg/day consecutively for 10-14 days. Before and after treatment, the main clinical and laboratory parameters for each patient were evaluated. The frequency of CD3(+) gammadelta(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs was detected by flow cytometry. Serum levels of interferon (IFN)-gamma, tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, IL-10 and transforming growth factor (TGF)-beta were measured with enzyme-linked immunosorbent assay. RESULTS: After intravenous (99) Tc-MDP therapy, the frequency of peripheral CD3(+) gammadelta(+) T cells and CD4(+) CD25(+) Foxp3(+) Tregs were significantly elevated, paralleled with decreased serum levels of TNF-alpha and IL-6 and increased level of serum TGF-beta. The elevation of peripheral CD3(+) gammadelta(+) T cells was positively correlated with increased serum TGF-beta and decreased disease activity. CONCLUSION: (99) Tc-MDP may improve the activity of RA through upregulating the frequency of peripheral gammadelta T cells and CD4(+) CD25(+) Foxp3(+) Tregs as well as affecting the serum cytokine environment by increasing TGF-beta and decreasing TNF-alpha and IL-6. PMID- 24467669 TI - Can supervised exercise prevent treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy: a randomised controlled trial. AB - OBJECTIVE: To determine if supervised exercise minimises treatment toxicity in patients with prostate cancer initiating androgen-deprivation therapy (ADT). This is the first study to date that has investigated the potential role of exercise in preventing ADT toxicity rather than recovering from established toxicities. PATIENTS AND METHODS: Sixty-three men scheduled to receive ADT were randomly assigned to a 3-month supervised exercise programme involving aerobic and resistance exercise sessions commenced within 10 days of their first ADT injection (32 men) or usual care (31 men). The primary outcome was body composition (lean and fat mass). Other study outcomes included bone mineral density, physical function, blood biomarkers of chronic disease risk and bone turnover, general and prostate cancer-specific quality of life, fatigue and psychological distress. Outcomes were compared between groups using analysis of covariance adjusted for baseline values. RESULTS: Compared to usual care, a 3 month exercise programme preserved appendicular lean mass (P = 0.019) and prevented gains in whole body fat mass, trunk fat mass and percentage fat with group differences of -1.4 kg (P = 0.001), -0.9 kg (P = 0.008) and -1.3% (P < 0.001), respectively. Significant between-group differences were also seen favouring the exercise group for cardiovascular fitness (peak oxygen consumption 1.1 mL/kg/min, P = 0.004), muscular strength (4.0-25.9 kg, P <= 0.026), lower body function (-1.1 s, P < 0.001), total cholesterol: high-density lipoprotein cholesterol ratio (-0.52, P = 0.028), sexual function (15.2, P = 0.028), fatigue (3.1, P = 0.042), psychological distress (-2.2, P = 0.045), social functioning (3.8, P = 0.015) and mental health (3.6-3.8, P <= 0.022). There were no significant group differences for any other outcomes. CONCLUSION: Commencing a supervised exercise programme involving aerobic and resistance exercise when initiating ADT significantly reduced treatment toxicity, while improving social functioning and mental health. Concurrent prescription of supervised exercise when initiating ADT is therefore advised to minimise morbidity associated with severe hypogonadism. PMID- 24467670 TI - Delta1-Pyrroline-5-carboxylate reductase from Arabidopsis thaliana: stimulation or inhibition by chloride ions and feedback regulation by proline depend on whether NADPH or NADH acts as co-substrate. AB - Delta(1)-pyrroline-5-carboxylate (P5C) reductase (P5CR) catalyses the final step of proline synthesis in plants. In Arabidopsis thaliana, protein levels are correlated neither to the corresponding mRNA copy numbers, nor to intracellular proline concentrations. The occurrence of post-translational regulatory mechanisms has therefore been hypothesized, but never assessed. The purification of A. thaliana P5CR was achieved through either a six-step protocol from cultured cells, or heterologous expression of AtP5CR in Escherichia coli. The protein was characterized with respect to structural, kinetic, and biochemical properties. P5CR was able to use either NADPH or NADH as the electron donor, with contrasting affinities and maximum reaction rates. The presence of equimolar concentrations of NADP(+) completely suppressed the NADH-dependent activity, whereas the NADPH dependent reaction was mildly affected. Proline inhibited only the NADH-dependent reaction. At physiological values, increasing concentrations of salt progressively inhibited the NADH-dependent activity, but were stimulatory of the NADPH-dependent reaction. The biochemical properties of A. thaliana P5CR suggest a complex regulation of enzyme activity by the redox status of the pyridine nucleotide pools, and the concentrations of proline and chloride in the cytosol. Data support a to date underestimated role of P5CR in controlling stress-induced proline accumulation. PMID- 24467671 TI - Mixed germ cell tumour after testotoxicosis. PMID- 24467673 TI - Mini-Emotional State Examination for dementia patients. AB - AIM: Emotional functions, as well as cognitive functions, are critical factors to assess in the care and management for dementia patients. In addition to the Mini Mental State Examination (MMSE), we have developed a Mini-Emotional State Examination (MESE) for the examination of emotional functions in patients with dementia. METHODS: MESE consists of a two-part questionnaire. The first probes emotional functions within the five senses (visual, auditory, tactile, smell and taste). The second explores more complex and comprehensive emotional functions including feelings of tenderness, violence, happiness and sadness, as well as emotional responses to more general human, moral and social phenomena. The questionnaire comprises 30 questions and is scaled to a 30-point healthy maximum. A total of 40 dementia patients in Sendai Tomizawa Hospital were tested with MESE. RESULTS: MESE point scores were roughly parallel to the scores on the MMSE, but MESE scores were widely distributed, independent of MMSE score. MESE scores in nine patients exceeded 23 points. CONCLUSION: The difference in distribution of MMSE and MESE scores show that cognitive and emotional functions are independently affected in dementia, and therefore assessment of both these functions should be cared taken into consideration in the care and management of dementia patients. PMID- 24467672 TI - Radiofrequency vessel-sealing system versus the clamp-crushing technique in liver transection: results of a prospective randomized study on 100 consecutive patients. AB - BACKGROUND: Liver transection is considered a critical factor influencing intra operative blood loss. A increase in the number of complex liver resections has determined a growing interest in new devices able to 'optimize' the liver transection. The aim of this randomized controlled study was to compare a radiofrequency vessel-sealing system with the 'gold-standard' clamp-crushing technique. METHODS: From January to December 2012, 100 consecutive patients undergoing a liver resection were randomized to the radiofrequency vessel-sealing system (LF1212 group; N = 50) or to the clamp-crushing technique (Kelly group, N = 50). RESULTS: Background characteristics of the two groups were similar. There were not significant differences between the two groups in terms of blood loss, transection time and transection speed. In spite of a not-significant larger transection area in the LF1212 group compared with the Kelly group (51.5 versus 39 cm(2) , P = 0.116), the overall and 'per cm(2) ' blood losses were similar whereas the transection speed was better (even if not significantly) in the LF1212 group compared with the Kelly group (1.1 cm(2) /min versus 0.8, P = 0.089). Mortality, morbidity and bile leak rates were similar in both groups. CONCLUSIONS: The radiofrequency vessel-sealing system allows a quick and safe liver transection similar to the gold-standard clamp-crushing technique. PMID- 24467674 TI - Child Engagement in Daily Life: a measure of participation for young children with cerebral palsy. AB - PURPOSE: The objectives of this study were to determine the: (1) internal consistency and test-retest reliability of the Child Engagement in Daily Life measure; (2) construct validity of the measure (known groups methods), that is, the ability of the measure to discriminate participation in family and recreational activities and self-care among young children of varying age and motor ability and between children with and without cerebral palsy, and (3) stability and hierarchical ordering of the items for young children with CP to devise an interval-level scoring system. METHODS: 429 children with CP and their parents and 110 parents of children without CP participated in this methodological study. Parents completed the Child Engagement in Daily Life measure and therapists assessed the children's gross motor function. Rasch analysis was used to create an interval-level measure. RESULTS: Children's frequency in and enjoyment of participation in family and recreational activities and self-care varied by age and gross motor ability. Internal consistency of the domains of the measure was high, Cronbach alpha values ranging from 0.86 to 0.91; test-retest for participation in family and recreational activities was acceptable, ICC = 0.70, and in self-care was high, ICC = 0.96. The items in the measure had a good fit and a logical hierarchical ordering. CONCLUSION: Study results support the validity and reliability of the Child Engagement in Daily Life measure as an assessment of participation in family and recreational activities and self-care for young children with CP. IMPLICATIONS FOR REHABILITATION: Participation in family and recreational activities and self-care for young children with cerebral palsy can be reliably and validly assessed using the Child Engagement in Daily Life measure. Service providers are encouraged to support young children's participation in family and recreational activities and self-care. PMID- 24467675 TI - Is there a relationship between pain and psychological concerns related to falling in community dwelling older adults? A systematic review. AB - PURPOSE: To systematically review and synthesise the research evidence linking pain to psychological concerns about falling in community dwelling older adults. METHODS: A systematic review was conducted in accordance with the preferred reporting items of systematic reviews and meta-analysis statement (PRISMA). Major electronic databases were searched from inception until June 2013. Two authors independently conducted the searches, extracted data and completed methodological quality assessments. Articles were included if they measured one of the psychological concerns related to falling in a sample of community dwelling older adults with pain, or explored the association between the two. RESULTS: Of a potential 892 articles, 12 met the eligibility criteria (n=3398). The methodological quality of the included studies was variable and none of the included studies primary aim was to investigate the relationship between pain and psychological concerns related to falls. Two studies found significant differences in psychological concerns related to falls in older adults with pain and a control group. Nine out of 10 studies reported a significant correlation between pain and psychological concerns related to falls in their sample. CONCLUSION: This review provides provisional evidence that pain is associated with fear of falling (FOF), avoidance of activities due to FOF and falls efficacy in community dwelling older adults. Implications for Rehabilitation Pain is a common and pervasive problem in community dwelling older adults and can affect an individual's mobility, levels of physical activity and increase their falls risk. Psychological concerns related to falls, such as fear of falling (FOF), falls efficacy and balance confidence are also common and troublesome issues in older adults, yet the association with pain has not been investigated with a systematic review. This review provides provisional evidence that pain may increase older adult's risk of developing FOF, avoiding activities due to a FOF and impact their falls efficacy. In recognition of the findings of this review, clinicians working with older adults with pain should consider assessing psychological concerns related to falls and if necessary intervene if they identify an individual at risk. PMID- 24467677 TI - Impact of legal regulations and administrative policies on persons with SCI: identifying potential research priorities through expert interviews. AB - PURPOSE: To identify research gaps and potential research priorities regarding the impact that legal regulations and administrative policies might have on people with spinal cord injury (SCI) living in Switzerland. METHOD: We conducted semi-structured interviews with 14 healthcare professionals working for or being associated with the largest SCI clinic in Switzerland. The transcribed interviews were content analyzed, involving qualitative description, and thematic analysis techniques. RESULTS: Four interrelated clusters of issues were corroborated: (1) social insurance, (2) caregiving, (3) work integration, and (4) aging. In addition, two overarching themes were identified: (1) fairness considerations and (2) unavailability of systematic empirical evidence. Work capacity assessment and family caregiving were deemed to be the most pressing research priority areas. CONCLUSIONS: Legal frameworks do play both a direct and an indirect role in the lives of people with SCI in Switzerland. This is particularly true with regard to various issues related to the social insurance system, such as family caregiving and work capacity assessment. The salience of these topics is closely related to major sociodemographic and political driving forces, i.e. aging and social insurance reforms. Research directly involving people with SCI is needed to further substantiate and refine the findings of this study. IMPLICATIONS FOR REHABILITATION: When dealing with issues related to work reintegration, aging, social insurance, and caregiving, rehabilitation professionals should take existing legal frameworks into account. Eligibility criteria for disability benefits may influence the therapy motivation of rehabilitation clients. PMID- 24467676 TI - A comprehensive assessment of family caregivers of stroke survivors during inpatient rehabilitation. AB - PURPOSE: Stroke caregivers have been identified as a group at high risk for poor outcomes as a result of the suddenness of stroke and a potentially high level of care needed due to significant functional limitations of the patient. However, there is little research on the assessment of family members who will assume the caregiving role prior to patient discharge from rehabilitation. The purpose of this article is to delineate critical assessment domains identified by a subset of spousal stroke caregivers. METHODS: Semi-structured interviews were conducted pre- and post-discharge from rehabilitation as part of a larger study that focused on identifying caregiver and stroke survivor needs as they transitioned home from inpatient rehabilitation. For this study, two semi-structured interviews with 14 spousal caregivers were analyzed using grounded theory methods. RESULTS: Long-term stroke survivor outcomes were dependent upon the commitment, capacity and preparedness of the family caregiver. Twelve domains of assessment were identified and presented. CONCLUSIONS: A comprehensive, systematic caregiver assessment to understand the caregiver's concerns about stroke should be conducted during rehabilitation to help the team to develop a plan to address unmet needs and better prepare family caregivers to take on the caregiving role. IMPLICATIONS FOR REHABILITATION: Stroke is a sudden event that often leaves stroke survivors and their families in crisis. The needs of stroke family caregivers are not often systematically assessed as part of inpatient rehabilitation. Long-term stroke survivor outcomes are dependent upon the commitment, capacity and preparedness of the family caregiver. Stroke caregiver assessment should include the commitment, capacity and preparedness to provide care, and the overall impact of stroke in order to develop discharge plans that will adequately address the needs of the stroke survivor/caregiver dyad. PMID- 24467678 TI - Navigating stroke care: the experiences of younger stroke survivors. AB - PURPOSE: Although stroke is associated with ageing, a significant proportion of strokes occur in younger people. Younger stroke survivors have experienced care available as inappropriate to their needs. However, insufficient attention has been paid to how the social context shapes their experiences of care. We investigated this question with younger stroke survivors in Greater London, UK. METHOD: We conducted in-depth interviews with individuals aged between 24 and 62 years. Interviews were analysed thematically, with interpretation informed by Bourdieu's concepts of field, capital and habitus. RESULTS: In the acute care setting it was implicit for participants that expertise and guidance was to be prioritised and largely this was reported as what was received. Individuals' cultural capital shaped expectations to access information, but health care professionals' symbolic capital meant they controlled its provision. After discharge, professional guidance was still looked for, but many felt it was limited or unavailable. It was here that participants' social, cultural and economic capital became more important in experiences of care. CONCLUSIONS: The field of stroke shaped younger stroke survivors' experiences of care. Navigating stroke care was contingent on accessing different forms of capital. Differences in access to these resources influenced longer term adjustment after stroke. IMPLICATIONS FOR REHABILITATION: Stroke care can be conceptualised as a temporal field of social activity and relationships which shapes variations in experiences of care among younger stroke survivors, and differences in expectations of support at different time points after stroke. On entering the field of stroke participants reported needing health care professional guidance and expertise to manage the acute event, yet difficulties accessing information in hospital limited the agency of some individuals wanting to take an active role in their recovery. After discharge from hospital variations in experiences of care among participants were more evident, with a number still seeking professional guidance, and requiring the capital and agency to navigate the field of stroke. Despite international efforts to improve the quality of acute care, effective models of community stroke care still need to be developed. PMID- 24467679 TI - Disentangling attention from action in the emotional spatial cueing task. AB - In the emotional spatial cueing task, a peripheral cue--either emotional or non emotional--is presented before target onset. A stronger cue validity effect with an emotional relative to a non-emotional cue (i.e., more efficient responding to validly cued targets relative to invalidly cued targets) is taken as an indication of emotional modulation of attentional processes. However, results from previous emotional spatial cueing studies are not consistent. Some studies find an effect at the validly cued location (shorter reaction times compared to a non-emotional cue), whereas other studies find an effect at the invalidly cued location (longer reaction times compared to a non-emotional cue). In the current paper, we explore which parameters affect emotional modulation of the cue validity effect in the spatial cueing task. Results from five experiments in healthy volunteers led to the conclusion that a threatening spatial cue did not affect attention processes but rather indicate that motor processes are affected. A possible mechanism might be that a strong aversive cue stimulus decreases reaction times by means of stronger action preparation. Consequently, in case of a spatially congruent response with the peripheral cue, a stronger cue validity effect could be obtained due to stronger response priming. The implications for future research are discussed. PMID- 24467680 TI - Penis augmentation by application of silicone material: complications and surgical treatment. AB - BACKGROUND: Complications resulting from enlargement of the penis by applications of unknown types of silicone and mineral oils are well described. Surgical removal of the tissue altered by inflammation leads to the development of defects of various sizes, often circular from the glans penis to the scrotum. The options of subsequent surgical treatment described in literature are not very extensive. Most defects are managed with skin grafting, rarely V-Y advancement or bilateral scrotal flaps. METHODS: We present a 36-year-old patient after application of unknown silicone material into the penis for cosmetic enlargement. After the application developed severe inflammation with ulceration and necrosis around the penis. Conservative treatment was not effective, therefore, the infiltrated skin with subcutaneous tissue of the entire penis was surgically removed. The resulting defect was covered by implantation of the penis under the skin of the scrotum. RESULT: There were no complications in the postoperative course, pain that was present before the surgery immediately subsided. Skin suture healed completely within 14 days. Three months after the surgery the patient returned to normal sexual life. CONCLUSIONS: Implantation of the penis under the skin of the scrotum is a fast, safe and effective method that can treat most of the circular skin defects of the penis. Scrotal skin is thin, soft, elastic and creates abundant and good cover around the entire penis. PMID- 24467681 TI - Lipomodelling: an important advance in breast surgery. AB - Based on long-term experiences, the authors consider lipomodelling to be a major advance in plastic, reconstructive and aesthetic surgery of the breast. The technique is now well established and the complication rate is very low. The risk of focal fat necrosis is around 3%. Oncological follow-up (now 14 years for the first patients) shows no increased risk of local recurrence or development of a new cancer. 30-40% of the injected fat is absorbed. Volume of the breast becomes stable in 3 to 4 months and remains definitive if the patient maintains constant weight. Because of very good results obtained and excellent acceptance of the procedure by the patients, this technique has completely modified our indications. In breast reconstruction, lipomodelling with autologous latissimus dorsi flap enables obtaining an entirely autologous breast in the majority of the patients. Analogically, lipomodelling can improve results of implant reconstructions, especially if the expander or the implant is planned to be exchanged. Lipomodelling is an effective tool for correction deformities especially in the decollete after breast reconstruction with abdominal flap (DIEP, SIEA and TRAM). Lipomodelling is also progressively used in the correction of breast and chest wall deformities. In Poland syndrome, this technique appears to be a major advance that will probably revolutionize the treatment of severe cases. This is mainly due to its ability to achieve previously unachievable quality of reconstruction with minimal scaring. The application of lipomodelling in the treatment of pectus excavatum deformities is promising. Lipomodelling represents an advanced therapeutic alternative for tuberous breasts without the need to use an implant, as well as for breast asymmetry due to unilateral hypoplasia. Lipomodelling is an ideal option for cosmetic breast augmentation in patients who wish to achieve moderate, natural enlargement of breasts and who have considerable fat deposits. PMID- 24467682 TI - The interpolation nasolabial flap: the advantageous solution for nasal tip reconstruction in elderly and polymorbid patients. AB - BACKGROUND: Nasal tip is one of the most frequent areas affected by basocellular carcinoma. The treatment must avoid any postsurgical deformity, as the nasal tip is the main part of the facial triangle. Most of these patients are elderly and polymorbid. The surgeon must find a compromise between the cosmetic effect and an acceptable stress for the patient. METHODS: There were five methods of nasal tip reconstruction used on a group of fifty elderly patients with various medical comorbidities: skin graft, bilobed flap, dorsal nasal flap, forehead flap and interpolation nasolabial flap. The resulting cosmetic effect was objectivized by a standardized questionnaire and the advantages and disadvantages of each method were discussed. RESULTS: According to the characteristics that were considered (good vascular supply, matching skin color and texture, sufficient amount of material, possibility to cover exposed cartilage or to combine it with cartilaginous graft; scars of minimal visibility, perfect aesthetic outcome, use of local anesthesia, short surgical time, and technical simplicity) was the interpolation nasolabial flap found as the most appropriate. CONCLUSION: Interpolation nasolabial flap is an easy and effective method for treatment of smaller and middle-sized defects of the nasal tip with minimal stress for the patient. LEVEL OF EVIDENCE: Level III. PMID- 24467683 TI - Epileptics and burns. AB - BACKGROUND: The aim of this paper is to ascertain the number of patients with a burn injury sustained during an epileptic seizure treated in our facility, to identify the characteristics of these types of injuries and to suggest preventive measures, which could reduce the frequency and morbidity of such injuries. PATIENTS AND METHODS: We performed a retrospective study, identifying all patients admitted with burns sustained during an epileptic seizure within a period of six years. RESULTS: Totally 7 women with an average age of 45 years were enrolled in this retrospective study. Mean BSAB was 2.4% (range 0.5-6). All burns occurred in a domestic setting during household activities (cooking, ironing). Thermal injury included contact burn (6 patients with deep burns), followed by scald (one patient with superficial burns). 6 of 7 patients (85%) required excision of deep burns and skin grafting procedure. The average duration of hospital stay was 13 days. Collected data were compared with the results and findings of similar studies and analysed. A list of preventive measures is included. CONCLUSION: Patients with epilepsy should be informed about all potential threats at the time of neurological diagnosis including also the risk of serious burn injury, which should be emphasised. PMID- 24467684 TI - Reconstruction of a nasal tip defect using a V-Y island dorsal nasal flap with unilateral vascular supply. A case report. AB - Closure of a nasal tip defect has specific characteristics with regards to the shape, colour, thickness and texture of skin. During the reconstruction it is necessary to observe aesthetic and functional characteristics to achieve an optimal result. There are several methods for closure of a defect in this area. One of the possible techniques is usage of a local flap. In the selection of an optimal procedure it is suitable to consider the aesthetic subunits in the nose. Usage of the V-Y flap is beneficial compared to a rotation flap or a transposition flap, which are associated with significant scaring and deformities, such as a dog-ear. Such conditions may require further corrections later. Ercocen et al. described a V-Y island dorsal nasal flap, which they used to close a nasal tip defect. The blood supply of the flap was based on the terminal branches of angular artery on both sides (1). In our case report we used the aforementioned flap to close a nasal defect. The flap was based on the terminal branches of the angular artery only on one side. PMID- 24467685 TI - On death and dying - an exploratory and evaluative study of a reflective, interdisciplinary course element in undergraduate anatomy teaching. AB - BACKGROUND: Teaching in palliative care aims not only at providing students with specialized knowledge in symptom therapy in advanced disease, but also at developing a professional attitude consistent with the principles and philosophy of palliative care. Reflecting about one's own or the patient's death and dying is considered essential for empathic patient care. In medical education the dissection course is often the first encounter with the issue of death and dying and represents a significant emotional challenge to many medical students.Against this background we implemented a new course element in preparation for the dissection course, offering opportunity to reflect own experiences with death and dying and providing support in finding a balance between authentic empathy and pragmatic action towards deceased persons. We discuss issues such as dignity and professional distance and reason whether guided support for medical students regarding these issues might influence their future attitude as doctors caring for their patients. METHODS: In tandem, we performed a formal evaluation of the seminar and explored the students' experiences with death and dying, their expectations and fears in the run-up to the dissection course and their attitude towards dissection. RESULTS: This article describes the structure and the concept of this new interdisciplinary course element and presents the results of the formal course evaluation as well as the explorative part of the accompanying research. Medical students had broad experiences with death and dying even before the dissection course. 89.1% of students had worried about some kind of emotional stress during the dissection course before, but 61.7% stated to have actually perceived emotional stress afterwards. The willingness to donate one's own body for anatomy purposes decreased significantly during the course. The given room for reflection and discussion was appreciated by the students, who felt that the effects of this seminar might be of use even beyond the dissection course. CONCLUSION: This new course element successfully assisted medical students during the dissection room experience and gave opportunity to reflection and discussion on death and dying. The accompanying research confirmed the demand for support and gave insight into experiences, emotions and attitudes of medical students. PMID- 24467686 TI - Interface effects on the electronic transport properties in highly epitaxial LaBaCo2O(5.5+delta) films. AB - Single-crystalline perovskite LaBaCo2O5.5+delta thin films were grown on a (110) NdGaO3 single-crystal substrate in order to systematically investigate the effect of lattice mismatch on the electrical transport properties in comparison to the films on LaAlO3, SrTiO3, and MgO substrates. Microstructure studies reveal that all of the LaBaCo2O5.5+delta films are of excellent quality with atomically sharp interface structures. The electrical and magnetic transport property studies indicate that the resistivity, magnetoresistance, and magnetic moment of the film are very sensitive to the substrate materials because of the lattice mismatch/interface strain. The Curie temperature, however, is almost independent of the strain imposed by the substrate, probably because of the strong coupling between the nanodomain boundary and interface strain. PMID- 24467687 TI - Non-synonymous variations in cancer and their effects on the human proteome: workflow for NGS data biocuration and proteome-wide analysis of TCGA data. AB - BACKGROUND: Next-generation sequencing (NGS) technologies have resulted in petabytes of scattered data, decentralized in archives, databases and sometimes in isolated hard-disks which are inaccessible for browsing and analysis. It is expected that curated secondary databases will help organize some of this Big Data thereby allowing users better navigate, search and compute on it. RESULTS: To address the above challenge, we have implemented a NGS biocuration workflow and are analyzing short read sequences and associated metadata from cancer patients to better understand the human variome. Curation of variation and other related information from control (normal tissue) and case (tumor) samples will provide comprehensive background information that can be used in genomic medicine research and application studies. Our approach includes a CloudBioLinux Virtual Machine which is used upstream of an integrated High-performance Integrated Virtual Environment (HIVE) that encapsulates Curated Short Read archive (CSR) and a proteome-wide variation effect analysis tool (SNVDis). As a proof-of-concept, we have curated and analyzed control and case breast cancer datasets from the NCI cancer genomics program - The Cancer Genome Atlas (TCGA). Our efforts include reviewing and recording in CSR available clinical information on patients, mapping of the reads to the reference followed by identification of non synonymous Single Nucleotide Variations (nsSNVs) and integrating the data with tools that allow analysis of effect nsSNVs on the human proteome. Furthermore, we have also developed a novel phylogenetic analysis algorithm that uses SNV positions and can be used to classify the patient population. The workflow described here lays the foundation for analysis of short read sequence data to identify rare and novel SNVs that are not present in dbSNP and therefore provides a more comprehensive understanding of the human variome. Variation results for single genes as well as the entire study are available from the CSR website (http://hive.biochemistry.gwu.edu/dna.cgi?cmd=csr). CONCLUSIONS: Availability of thousands of sequenced samples from patients provides a rich repository of sequence information that can be utilized to identify individual level SNVs and their effect on the human proteome beyond what the dbSNP database provides. PMID- 24467689 TI - Trimethylamine/sulfuric acid/water clusters: a matrix isolation infrared study. AB - In continuation of our studies of sulfuric acid H-bonded complexes of atmospheric relevance we report the infrared spectra of the matrix isolated complexes formed between trimethylamine and sulfuric acid. Evidence for proton transfer was anticipated for the present system, as trimethylamine ((CH3)3N) is of strong basic nature. However, the spectra of this system are complicated by the inevitable presence water in the vapor and in the matrix, resulting in matrix layers containing three species capable of forming H-bonded complexes. The complex formed between trimethylamine and sulfuric acid is of ionic character due to proton transfer of the H(+) proton from sulfuric acid to (CH3)3N to form a new N-H bond and the replacement of the intramolecular O-H bond in H2SO4 by a strong intermolecular N-H...O hydrogen bond. The complex is further stabilized by hydration. The skeletal modes show clear bisulfate related bands and are only slightly affected by hydration. The nu(OH) region shows a rich band scheme, best explained by a structure involving (at least) three H2O molecules. A broad spectral feature spanning the 1700-500 cm(-1) is assigned, in analogy to previous studies to a double-well potential quasi-symmetric, Zundel-like, ionic species with a (CH3)3-N...H(+)...N-(CH3)3 configuration. A band in the skeletal S?O stretch spectral region may be assigned to hydrated sulfate as its counterion. PMID- 24467688 TI - Eliciting maltreated and nonmaltreated children's transgression disclosures: narrative practice rapport building and a putative confession. AB - This study tested the effects of narrative practice rapport building (asking open ended questions about a neutral event) and a putative confession (telling the child an adult "told me everything that happened and he wants you to tell the truth") on 4- to 9-year-old maltreated and nonmaltreated children's reports of an interaction with a stranger who asked them to keep toy breakage a secret (n = 264). Only one third of children who received no interview manipulations disclosed breakage; in response to a putative confession, one half disclosed. Narrative practice rapport building did not affect the likelihood of disclosure. Maltreated children and nonmaltreated children responded similarly to the manipulations. Neither narrative practice rapport building nor a putative confession increased false reports. PMID- 24467690 TI - Metabolic syndrome and cardiovascular risk among long-term survivors of acute lymphoblastic leukaemia - From the St. Jude Lifetime Cohort. AB - Adult survivors of childhood acute lymphoblastic leukaemia (ALL) have a four-fold excess risk of mortality from cardiovascular disease. This cardiovascular risk has not been fully characterized. ALL survivors [n = 784, median age 31.7 years (18.9-59.1)] in the St. Jude Lifetime Cohort Study underwent evaluation for cardiovascular risk and metabolic syndrome (MetS) according to National Cholesterol Education Program - Adult Treatment Panel III criteria. Comparisons were made to 777 age-, sex-, and race-matched controls from the National Health and Nutrition Examination Survey (NHANES). MetS was identified in 259 survivors (33.6%) and associated with older age in 5-year increments (relative risk [RR] 1.13, 95% confidence interval [CI] 1.06-1.19) and prior cranial radiotherapy (CRT) (with craniospinal radiation: RR 1.88, 95%CI 1.32-2.67; without: RR 1.67, 95%CI 1.26-2.23). Measures of obesity were highly prevalent among female survivors and CRT recipients. Compared to NHANES controls, ALL survivors had a higher risk of MetS (RR 1.43, 95%CI 1.22-1.69), hypertension (RR 2.43, 95%CI 2.06 2.86), low high-density lipoprotein (RR 1.40, 95%CI 1.23-1.59), obesity (RR 1.47, 95%CI 1.29-1.68) and insulin resistance (1.64, 95%CI 1.44-1.86). This large study of clinically evaluated ALL survivors identified a high prevalence of MetS, obesity and cardiovascular risk, particularly in CRT recipients, underscoring the need for screening and aggressive reduction of modifiable risks. PMID- 24467691 TI - Exogenous retinoic acid and cytochrome P450 26B1 inhibitor modulate meiosis associated genes expression in canine testis, an in vitro model. AB - Pharmacological approaches to control spermatogenesis are required to resolve overpopulation in dogs. The objective of the study was to investigate the regulation of meiosis-associated and male germ cell-related genes, stimulated by retinoic acid gene 8 (STRA8), synaptonemal complex protein 3 (SYCP3), dosage suppressor of mck1 (DMC1), doublesex and mab-3 related transcription factor 1 (DMRT1) and deleted in azoospermia-like (DAZL) following exogenous administration of retinoic acid (RA) and after the modulation of endogenous RA by a cytochrome P450, family 26, subfamily B, polypeptide 1 inhibitor (CYP26B1-I; R115866) in an in vitro testis model. Testicles of five healthy, medium-sized and mixed-breed dogs were used for the organotypic cultures. All-trans-RA at 2 MUM, CYP26B1-I at 1 MUM and the control dimethyl sulphoxide (DMSO) were administered to the testes cultures, and the cultures were maintained for 24 h. Genes STRA8, DAZL and DMRT1 were significantly up-regulated as a result of the direct and indirect increase in the RA levels in the testis, subsequent to the exogenous administration of all trans-RA and CYP26B1 inhibitor. Up-regulation of STRA8 was very prominent compared to DAZL and DMRT, and the drastic up-regulation of STRA8 was also observed with CY26B1-I than with all-trans-RA. No significant differences were found with the early meiotic markers, SYCP3 and DMC1 with RA, CY26B1-I and vehicle treatments. Because DAZL encodes a germ cell-specific RNA-binding protein, required for the induction of STRA8 and initiation of meiosis, we might see the expression differences temporally with the stage of spermatogenesis. DMRT1 is a unique gonad- and stage-specific transcription factor, directly activates STRA8 and has the temporal influence on its expression. Protein expression of DAZL and STRA8 was greater in RA- and CYP26B1-I-treated testis culture, whereas DMRT1 showed greater protein expression for RA treatment, but not for CYP26B1-I treatment compared to control. Relative protein expression of STRA8 was greatest for the CYP26B1-I treatment compared to DMSO and RA treatments. In conclusion, pharmacological intervention of spermatogenesis pertinent to RA signalling is plausible, and the effect of modulation differs upon the types of molecules and the key stages of signalling being targeted. PMID- 24467692 TI - In vivo biomechanical evaluation of a novel angle-stable interlocking nail design in a canine tibial fracture model. AB - OBJECTIVE: To compare clinical outcome and callus biomechanical properties of a novel angle stable interlocking nail (AS-ILN) and a 6 mm bolted standard ILN (ILN6b) in a canine tibial fracture model. STUDY DESIGN: Experimental in vivo study. ANIMALS: Purpose-bred hounds (n = 11). METHODS: A 5 mm mid-diaphyseal tibial ostectomy was stabilized with an AS-ILN (n = 6) or an ILN6b (n = 5). Orthopedic examinations and radiographs were performed every other week until clinical union (18 weeks). Paired tibiae were tested in torsion until failure. Callus torsional strength and toughness were statistically compared and failure mode described. Total and cortical callus volumes were computed and statistically compared from CT slices of the original ostectomy gap. Statistical significance was set at P < .05 RESULTS: From 4 to 8 weeks, lameness was less pronounced in AS ILN than ILN6b dogs (P < .05). Clinical union was reached in all AS-ILN dogs by 10 weeks and in 3/5 ILN6b dogs at 18 weeks. Callus mechanical properties were significantly greater in AS-ILN than ILN6b specimens by 77% (failure torque) and 166% (toughness). Failure occurred by acute spiral (control and AS-ILN) or progressive transverse fractures (ILN6b). Cortical callus volume was 111% greater in AS-ILN than ILN6b specimens (P < .05). CONCLUSIONS: Earlier functional recovery, callus strength and remodeling suggest that the AS-ILN provides a postoperative biomechanical environment more conducive to bone healing than a comparable standard ILN. PMID- 24467696 TI - The stories of 'snake children': killing and abuse of children with developmental disabilities in West Africa. AB - BACKGROUND: Killing and abuse of children with disabilities are covert phenomena, occurring in some developing regions, such as in some African countries. Similar to the practice of ritual killing of spirit children in Ghana, the phenomenon of the snake child in Cote d'Ivoire (known as Ivory Coast), is the ritual abandonment or killing of children with intellectual disability (ID). METHOD: This study is a qualitative ethnographic investigation into understanding this phenomenon. Three major questions were of interest: (1) Who are the snake children? (2) How are these children viewed and treated? (3) What are ways of changing negative attitudes towards children with developmental disabilities? RESULTS: The practices of killing, abandonment and abuse of children with disabilities take place in Cote d'Ivoire today, although the extent is not known. CONCLUSION: Killing and abuse of children with ID are explained within the context of indigenous African religions, animism and folk culture. The concept of disability 'otherness' and inferiority is also explored as a framework for reflection and ethical debate. PMID- 24467697 TI - Emotion recognition ability and mild depressive symptoms in late adulthood. AB - BACKGROUND/STUDY CONTEXT: Current evidence suggests that dysphoric mood affects the ability to recognize facial emotion. METHODS: In the present study, older adults with and without mild depressive symptoms were asked to complete a task measuring their ability to identify facial affect representative of six different emotions (happiness, surprise, disgust, fear, anger, and sadness). RESULTS: Consistent with previous findings, results showed that older adults experiencing mild depressive symptoms were less accurate in their ability to recognize facial expressions of fear and anger. No group differences were observed in the recognition of happiness, surprise, disgust, and sadness. CONCLUSION: The present study has contributed to previous research by demonstrating that mild depressive symptoms affect the ability to recognize facial emotion in a sample of older adults. PMID- 24467693 TI - Proteomic profile of Cryptococcus neoformans biofilm reveals changes in metabolic processes. AB - Cryptococcus neoformans, a pathogenic yeast, causes meningoencephalitis, especially in immunocompromised patients, leading in some cases to death. Microbes in biofilms can cause persistent infections, which are harder to treat. Cryptococcal biofilms are becoming common due to the growing use of brain valves and other medical devices. Using shotgun proteomics we determine the differences in protein abundance between biofilm and planktonic cells. Applying bioinformatic tools, we also evaluated the metabolic pathways involved in biofilm maintenance and protein interactions. Our proteomic data suggest general changes in metabolism, protein turnover, and global stress responses. Biofilm cells show an increase in proteins related to oxidation-reduction, proteolysis, and response to stress and a reduction in proteins related to metabolic process, transport, and translation. An increase in pyruvate-utilizing enzymes was detected, suggesting a shift from the TCA cycle to fermentation-derived energy acquisition. Additionally, we assign putative roles to 33 proteins previously categorized as hypothetical. Many changes in metabolic enzymes were identified in studies of bacterial biofilm, potentially revealing a conserved strategy in biofilm lifestyle. PMID- 24467698 TI - Intact episodic retrieval in older adults: evidence from an auditory negative priming task. AB - BACKGROUND/STUDY CONTEXT: The negative priming effect has been traditionally interpreted as the inhibitory aftereffect of distractor processing. According to inhibitory deficit theory, older adults should be more impaired by auditory distractors. Recent studies have shown that episodic retrieval processes are involved in the effect. However, so far there is no direct evidence that this is true for older adults. METHODS: In an auditory four-alternative identification task, young adults (18-30 years), younger seniors (60-67 years), and older seniors (68-78 years) identified target sounds while ignoring distractor sounds. In ignored repetition trials, the prime distractor was repeated as the probe target, whereas there was no stimulus repetition in control trials. Reaction times and errors were analyzed. RESULTS: Negative priming was present in all age groups. Senior groups showed increased negative priming in reaction times. All age groups revealed a comparable increase of probe errors with the former prime response in ignored repetition compared with control trials. There was no age difference in the frequency of responding with the former prime response in control trials. CONCLUSION: An increase in prime response errors in ignored repetition trials is consistent with the involvement of episodic retrieval processes in negative priming in younger and older adults. Inconsistent with both an inhibitory account of negative priming and the inhibitory deficit theory of cognitive aging, older adults neither showed evidence of reduced negative priming nor of impaired restraint control. PMID- 24467699 TI - Distinct functions of social support and cognitive function among older adults. AB - BACKGROUND/STUDY CONTEXT: Social support has been shown to buffer cognitive decline in older adults; however, few studies have examined the association of distinct functions of perceived social support and cognitive function. The current study examined the relations between distinct functions of social support and numerous cognitive domains in older adults. METHODS: Data were derived from a cross-sectional, correlational study of cardiovascular risk factors, cognitive function, and neuroimaging. The participants were 175 older adults with a mean age of 66.32. A number of neuropsychological tests and the Interpersonal Support Evaluation List were administered. Multiple linear regression analyses were conducted to determine cross-sectional relations of social support to cognitive function after controlling for age, gender, education, depressive symptomatology, systolic blood pressure, body mass index, total cholesterol, and fasting glucose. RESULTS: No significant positive relations were found between distinct functions of social support and cognitive function in any domain; however, inverse relations emerged such that greater social support across several functions was associated with poorer nonverbal memory and response inhibition. CONCLUSION: Results suggest that the receipt of social support may be a burden for some older adults. Within the current study, fluid cognitive abilities reflected this phenomenon. The mechanism through which social support is associated with poorer cognitive function in some domains deserves further exploration. PMID- 24467700 TI - Empathy and conversational enjoyment in younger and older adults. AB - BACKGROUND/STUDY CONTEXT: Investigations of empathy across adulthood have yielded mixed findings, yet its contribution to successful social interactions is clear. METHODS: Here, the authors investigate the relationship between empathy and self reported conversation enjoyment in 144 young adults (M age = 19.50) and 120 older adults (M age = 68.75). Participants completed three empathy-related measures (Interpersonal Reactivity Index [IRI], Toronto Empathy Questionnaire [TEQ], and Affect Intensity Measure [AIM]), and rated their enjoyment of recalled conversations with diverse targets. RESULTS: On the IRI, older adults had higher scores than younger adults on Empathic Concern, but lower scores on the Personal Distress and Fantasy subscales. For younger adults, conversations with same-age acquaintances were most enjoyable and conversations with children and older adults were least enjoyable. Older adults reported similar enjoyment across all groups. However, the links between conversation enjoyment and empathy were stronger for older adults. CONCLUSION: These results highlight the importance of a multidimensional view of empathy, and the possibility that empathy influences conversational interactions differentially across the life span. PMID- 24467701 TI - Tactile experience does not ameliorate age-related reductions in sensory function. AB - BACKGROUND/STUDY CONTEXT: Sensory function degrades with age, with well established reductions in tactile spatial acuity, vibrotactile sensitivity, and thermosensation, to name but three aspects of perception. Such age-related losses might be partially stemmed by ongoing experience with tasks requiring high levels of manual dexterity or analogous tactile expertise; individuals who are highly expert in skills that have a fundamental tactile component can show improved tactile function as compared with nonexperts. METHODS: Eighty individuals (17 males, 63 females) in the 18-58 age range were assessed on their tactile experience, as measured by self-assessment on a variety of tasks and competencies, each of which required a high level of skill with the hands. Tactile sensory performance, manual dexterity ("haptic efficiency"), and the subjective response to tactile stimulation were quantified. RESULTS: Degradation in tactile sensory acuity with age was confirmed, but no strong evidence was found for variations in acuity contingent on the tactile expertise of participants. In contrast to the performance measures, differences in tactile experience were associated with differences in the subjective response to touch. Greater tactile experience was associated with the provision of richer descriptions of textured materials manipulated with the digits. CONCLUSION: The range of tactile experience reported in a convenience sample of the population was apparently insufficient to preserve sensory function during aging. PMID- 24467702 TI - Interlimb practice and aging: coding a simple movement sequence. AB - BACKGROUND/STUDY CONTEXT: The purpose was to determine if aging interacts with the coding of a simple spatial-temporal movement sequence. METHODS: An interlimb practice paradigm (24 participants; 12 young adults [age: 23-29]; 12 old adults [age: 65-78]) was designed to determine the coordinate system (visual spatial/motor) that is used to code the movement sequence. Practice was scheduled over 2 days involving either the same visual-spatial or the same motor coordinates. On Day 3, two retention tests (Day 1/Day 2) were conducted. RESULTS: Keeping the motor coordinates the same during acquisition resulted in superior retention only for younger adults. CONCLUSION: The data provide strong evidence that the motor code plays a dominant role in acquiring simple movement sequences for younger adults, but not for older adults. PMID- 24467703 TI - Changes in cerebral oxygenation during early postnatal adaptation in newborns delivered by vacuum extraction measured by near-infrared spectroscopy. AB - BACKGROUND: Newborns delivered by vacuum extraction quite often show clinical signs of a hemodynamic compromise, which is difficult to assess in terms of severity. The conventional means to measure the hemodynamic status are not sensitive enough to appreciate the severity of general, and more specifically of cerebral circulatory imbalance. The aim was to study cerebral tissue oxygenation during postnatal adaptation in these infants using near-infrared spectroscopy. METHODS: The tissue hemoglobin index (THI), tissue oxygenation index (TOI), arterial oxygen saturation (pre-ductal SaO2) and heart rate (HR) were recorded immediately after birth, and again after 12-24 hours of life in 15 newborns delivered by vacuum extraction due to fetal distress. A comparison with 19 healthy newborns delivered by elective cesarean section was performed. RESULTS: Newborns delivered by vacuum extraction had significantly higher THI 10 to 15 minutes after birth. TOI and HR were significantly higher in the first 5 min and SaO2 in the first 10 minutes but then did not differ from those after cesarean section. CONCLUSION: Infants delivered by vacuum extraction following fetal distress show transient deviations in cerebral oxygenation and perfusion after birth which were not detectable after 24 hours. PMID- 24467705 TI - Serosurvey of Rickettsia typhi and Rickettsia felis in HIV-infected patients. AB - Consistent with the effects of HIV on cell-mediated immunity, an increased susceptibility to intracellular microorganisms has been observed. Rickettsiae are obligate intracellular microorganisms. The aim of this study was to examine Rickettsia typhi and Rickettsia felis infections in HIV+ population. Sera of 341 HIV+ patients were evaluated by indirect immunofluorescent assay. Age, sex, residential locality, risk behavior, stage according to criteria of the Center for Disease Control and Prevention, CD4+/CD8+ T cells, Hepatitis B antigen, and Hepatitis C serology were surveyed. Seroprevalences of R. typhi and R. felis infection were 7.6% and 4.4%, respectively. No associations were found between seropositivities and the assessed variables. Findings were similar to those obtained in healthy subjects from the same region. PMID- 24467706 TI - Voltage-operated Ca(2) (+) currents and Ca(2) (+) -activated Cl(-) currents in single interstitial cells of the guinea-pig prostate. AB - OBJECTIVE: To investigate the expression of 'T-type' and 'L-type' voltage operated Ca(2) (+) channels in single interstitial cells of the guinea-pig prostate. MATERIAL AND METHODS: Whole-cell and perforated patch-clamp techniques were applied to prostatic interstitial cells (PICs) dispersed using collagenase. RESULTS: In contrast to prostatic myocytes, PICs under voltage clamp and filled with K(+) (130 mm) were distinguished by the absence of a voltage-operated transient outward K(+) current or spike discharge upon membrane depolarisation when under current clamp. Depolarisation of Cs(+) -filled PICs evoked an inward current at potentials positive to -60 mV, which peaked in amplitude near 0 mV. This inward current increased when Ba(2+) (5 mm) replaced the external Ca(2) (+) (1.5 mm) and displayed a variable sensitivity to the inhibitory actions of conditioning depolarisations to -40 mV applied before the test depolarisation or to 1 MUm nifedipine, the 'L-type' Ca(2) (+) channel blocker. A residual inward current recorded in nifedipine was blocked by 10 MUm Ni(2) (+) . Cs(+) -filled PICs also displayed a slowly inactivating outward current that was little affected by nifedipine, reduced by the Cl(-) channel blocker, niflumic acid (10 MUm) and blocked by Ba(2) (+) or a conditioning depolarisation. CONCLUSION: PICs express both a small 'T-type' Ca(2) (+) channel current (ICa ) and a large 'L type' ICa . Ca(2) (+) influx through 'T-type' ICa was an essential trigger for the activation of a Ca(2) (+) -activated Cl(-) -selective current. The dependence of PIC Ca(2) (+) signalling on 'T-type' and 'L-type' ICa is unique compared with other interstitial cells of the urogenital tract and may well be pharmaceutically exploitable. PMID- 24467704 TI - Breaking barriers. New insights into airway epithelial barrier function in health and disease. AB - Epithelial permeability is a hallmark of mucosal inflammation, but the molecular mechanisms involved remain poorly understood. A key component of the epithelial barrier is the apical junctional complex that forms between neighboring cells. Apical junctional complexes are made of tight junctions and adherens junctions and link to the cellular cytoskeleton via numerous adaptor proteins. Although the existence of tight and adherens junctions between epithelial cells has long been recognized, in recent years there have been significant advances in our understanding of the molecular regulation of junctional complex assembly and disassembly. Here we review the current thinking about the structure and function of the apical junctional complex in airway epithelial cells, emphasizing the translational aspects of relevance to cystic fibrosis and asthma. Most work to date has been conducted using cell culture models, but technical advancements in imaging techniques suggest that we are on the verge of important new breakthroughs in this area in physiological models of airway diseases. PMID- 24467707 TI - Crystal structure of mouse mu-crystallin complexed with NADPH and the T3 thyroid hormone. AB - Mu-crystallin (CRYM), first described as a structural component of the eye lens in marsupials, has been characterized as an NADPH-dependent cytosolic T3 thyroid hormone (triiodothyronine) binding protein. More recently, CRYM has also been associated with ketimine reductase activity. Here, we report three crystal structures: mouse CRYM (mCRYM) in its apo form, in a form complexed with NADPH, and in a form with both NADPH and triiodothyronine bound. Comparison of the apo and NADPH forms reveals a rearrangement of the protein upon NADPH binding that reduces the degrees of freedom of several residues and traps the conformation of the binding pocket in a more T3 competent state. These findings are in agreement with the cooperative mechanism identified using isothermal titration calorimetry. Our structure with T3 reveals for the first time the location of the hormone binding site and shows its detailed interactions. T3 binding involves mainly hydrophobic interactions. Only five residues, either directly or through bridging water molecules, are hydrogen bonded to the hormone. Using in silico docking analysis, a series of ring-containing hydrophobic molecules were identified as potential mCRYM ligands, suggesting that the specificity for the recognition of the hydrophobic part of the hormone might be low. This is in agreement with the ketimine reductase activity that has been identified for ovine CRYM, as it demonstrates how a protein known as a thyroid hormone transporter can accommodate the ringed molecules required for its ketimine reductase activity. In the light of our results, a putative role of CRYM in thyroid hormone metabolism is also discussed. STRUCTURED DIGITAL ABSTRACT: CRYM and CRYM bind by x-ray crystallography (View interaction). PMID- 24467708 TI - The term basal plate of the human placenta as a source of functional extravillous trophoblast cells. AB - BACKGROUND: Extravillous trophoblast (EVT) cells are of pivotal importance in human embryo implantation and homeostasis of the maternal fetal interface. Invasion of the endometrium by EVT contributes to placental anchorage, spiral artery remodeling, immunological defense, tolerogenic responses, and several collaborative cross talks involved in establishing and maintaining a successful pregnancy. We report here an improved protocol for the isolation of fully differentiated EVT cells from the basal plate of the human term placenta. METHODS: The basal plate was carefully dissected from the villous tissue and the amniochorion membrane prior to enzymatic digestion. Term basal EVT cells were isolated using a 30 and 60% Percoll gradient. A panel of markers and characteristics of the isolated cells were used to confirm the specificity and efficiency of the method so that their potential as an investigative tool for placental research could be ascertained. RESULTS: Isolated cells were immunoreactive for cytokeratin-7 (CK-7), placental growth factor, placental alkaline phosphatase, human leukocyte antigen G1 (HLA-G1), and alpha1 and alpha5 integrins, similarly to the EVT markers from first trimester placental villi. Around 95% of the isolated cells labeled positively for CK-7 and 82% for HLA-G1. No significant change in viability was observed during 48 h of EVT culture as indicated by propidium iodide incorporation and trypan blue test exclusion. Genes for metalloproteinases MMP-2 and MMP9 (positive regulators of trophoblast invasiveness) were expressed up to 48 h of culturing, as also the gelatinolytic activity of the isolated cells. Transforming growth factor (TGF)-beta, which inhibits proliferation, migration, and invasiveness of first-trimester EVT cells, also reduced invasion of isolated term EVT cells in transwell assays, whereas epidermal growth factor was a positive modulator. CONCLUSIONS: Term basal plate may be a viable source of functional EVT cells that is an alternative to villous explant-derived EVT cells and cell lines. Isolated term EVT cells may be particularly useful in investigation of the role of trophoblast cells in pathological gestations, in which the precise regulation and interactive ability of extravillous trophoblast has been impaired. PMID- 24467709 TI - Integrated strategies for identifying leads that target the NS3 helicase of the hepatitis C virus. AB - Future treatments for individuals infected by the hepatitis C virus (HCV) will likely involve combinations of compounds that inhibit multiple viral targets. The helicase of HCV is an attractive target with no known drug candidates in clinical trials. Herein we describe an integrated strategy for identifying fragment inhibitors using structural and biophysical techniques. Based on an X-ray structure of apo HCV helicase and in silico and bioinformatic analyses of HCV variants, we identified that one site in particular (labeled 3 + 4) was the most conserved and attractive pocket to target for a drug discovery campaign. Compounds from multiple sources were screened to identify inhibitors or binders to this site, and enzymatic and biophysical assays (NMR and SPR) were used to triage the most promising ligands for 3D structure determination by X-ray crystallography. Medicinal chemistry and biophysical evaluations focused on exploring the most promising lead series. The strategies employed here can have general utility in drug discovery. PMID- 24467710 TI - Internet-based health education in China: a content analysis of websites. AB - BACKGROUND: The Internet is increasingly being applied in health education worldwide; however there is little knowledge of its use in Chinese higher education institutions. The present study provides the first review and highlights the deficiencies and required future advances in Chinese Internet based health education. METHODS: Two authors independently conducted a duplicate Internet search in order to identify information regarding Internet-based health education in China. RESULTS: The findings showed that Internet-based education began in China in September 1998. Currently, only 16 of 150 (10.7%) health education institutions in China offer fee-based online undergraduate degree courses, awarding associates and/or bachelors degrees. Fifteen of the 16 institutions were located in the middle or on the eastern coast of China, where were more developed than other regions. Nursing was the most popular discipline in Internet-based health education, while some other disciplines, such as preventive medicine, were only offered at one university. Besides degree education, Chinese institutions also offered non-degree online training and free resources. The content was mainly presented in the form of PowerPoint slides or videos for self-learning. Very little online interactive mentoring was offered with any of the courses. CONCLUSIONS: There is considerable potential for the further development of Internet-based health education in China. These developments should include a focus on strengthening cooperation among higher education institutions in order to develop balanced online health curricula, and on enhancing distance education in low- and middle-income regions to meet extensive learning demands. PMID- 24467711 TI - Isolated Roux loop pancreaticojejunostomy versus pancreaticogastrostomy after pancreaticoduodenectomy: a prospective randomized study. AB - OBJECTIVES: The optimal strategy for the reconstruction of the pancreas following pancreaticoduodenectomy (PD) is still debated. The aim of this study was to compare the outcomes of isolated Roux loop pancreaticojejunostomy (IRPJ) with those of pancreaticogastrostomy (PG) after PD. METHODS: Consecutive patients submitted to PD were randomized to either method of reconstruction. The primary outcome measure was the rate of postoperative pancreatic fistula (POPF). Secondary outcomes included operative time, day to resumption of oral feeding, postoperative morbidity and mortality, and exocrine and endocrine pancreatic functions. RESULTS: Ninety patients treated by PD were included in the study. The median total operative time was significantly longer in the IRPJ group (320 min versus 300 min; P = 0.047). Postoperative pancreatic fistula developed in nine of 45 patients in the IRPJ group and 10 of 45 patients in the PG group (P = 0.796). Seven IRPJ patients and four PG patients had POPF of type B or C (P = 0.710). Time to resumption of oral feeding was shorter in the IRPJ group (P = 0.03). Steatorrhea at 1 year was reported in nine of 42 IRPJ patients and 18 of 41 PG patients (P = 0.029). Albumin levels at 1 year were 3.6 g/dl in the IRPJ group and 3.3 g/dl in the PG group (P = 0.001). CONCLUSIONS: Isolated Roux loop PJ was not associated with a lower rate of POPF, but was associated with a decrease in the incidence of postoperative steatorrhea. The technique allowed for early oral feeding and the maintenance of oral feeding even if POPF developed. PMID- 24467712 TI - Mitochondrion-to-plastid DNA transfer: it happens. PMID- 24467714 TI - A little bit of Africa in Brazil: ethnobiology experiences in the field of Afro Brazilian religions. AB - This essay, which is the fourth in the series "Recollections, Reflections, and Revelations: Ethnobiologists and Their First Time in the Field", is a personal reflection by the researcher on his first field experience with ethnobiology of so called Afro-Brazilian cults. The author recounts his feelings and concerns associated with initial fieldwork. PMID- 24467713 TI - Large-scale mitochondrial DNA analysis in Southeast Asia reveals evolutionary effects of cultural isolation in the multi-ethnic population of Myanmar. AB - BACKGROUND: Myanmar is the largest country in mainland Southeast Asia with a population of 55 million people subdivided into more than 100 ethnic groups. Ruled by changing kingdoms and dynasties and lying on the trade route between India and China, Myanmar was influenced by numerous cultures. Since its independence from British occupation, tensions between the ruling Bamar and ethnic minorities increased. RESULTS: Our aim was to search for genetic footprints of Myanmar's geographic, historic and sociocultural characteristics and to contribute to the picture of human colonization by describing and dating of new mitochondrial DNA (mtDNA) haplogroups. Therefore, we sequenced the mtDNA control region of 327 unrelated donors and the complete mitochondrial genome of 44 selected individuals according to highest quality standards. CONCLUSION: Phylogenetic analyses of the entire mtDNA genomes uncovered eight new haplogroups and three unclassified basal M-lineages. The multi-ethnic population and the complex history of Myanmar were reflected in its mtDNA heterogeneity. Population genetic analyses of Burmese control region sequences combined with population data from neighboring countries revealed that the Myanmar haplogroup distribution showed a typical Southeast Asian pattern, but also Northeast Asian and Indian influences. The population structure of the extraordinarily diverse Bamar differed from that of the Karen people who displayed signs of genetic isolation. Migration analyses indicated a considerable genetic exchange with an overall positive migration balance from Myanmar to neighboring countries. Age estimates of the newly described haplogroups point to the existence of evolutionary windows where climatic and cultural changes gave rise to mitochondrial haplogroup diversification in Asia. PMID- 24467715 TI - Clinical utility of chromogranin A in SDHx-related paragangliomas. AB - BACKGROUND: Measurement of plasma/urinary catecholamine metabolites--especially normetanephrine (NMN)--represents a gold standard in biochemical detection of succinate dehydrogenase subunit B (SDHB) and D (SDHD)-related pheochromocytomas (PHEO) and paragangliomas (PGL). This study was designed to assess diagnostic utility of chromogranin A (CgA) alone or in combination with NMN in patients with PHEO/PGL related to mutations in SDHB and SDHD. MATERIALS AND METHODS: A retrospective study of SDHB and SDHD NIH patients' cohort, which included 41 patients with SDHB mutation-related PHEO/sPGL and 18 patients with either SDHD or SDHB mutation-related head and neck PGL (HNPGL) with both CgA and NMN measured at the time of diagnosis at NIH. RESULTS: In the SDHB group, CgA showed sensitivity of 73.2% and specificity of 95.9%, while for NMN they were 70.7% and 98.6%, respectively. Elevations in CgA and NMN were complementary in 92.7% of patients with proven tumors. Both tests performed well on receiver operating characteristic curve analysis. CgA levels were elevated in 76.9% of SDHB patients and in 80% of patients with metastatic disease and normal NMN levels. CgA values in patients with HNPGL were significantly lower than in patients with PHEO/sPGL. CONCLUSION: CgA is a valuable complementary biomarker in work-up of SDHB-related PHEO/sPGL. In combination with plasma NMN, CgA further enhances tumor detection by 22.0% with minimal loss in specificity. Although non-specific for PHEO/PGL, CgA may well supplement plasma NMN to facilitate diagnostic evaluation of SDHB related PHEO/sPGL, especially where the measurement of plasma metanephrines could otherwise be delayed by decreased availability or cost restriction. PMID- 24467716 TI - Craniopharyngioma. AB - This report is a review of findings on the diagnosis, treatment, clinical course, and prognosis of craniopharyngioma patients. Craniopharyngiomas are rare, partly cystic and calcified embryonic malformations of the sellar/parasellar region with low histological grade (WHO I degrees ). A bimodal age distribution has been shown, with peak incidence rates in childhood-onset at 5-14 years and adult-onset craniopharyngioma at 50-74 years. Clinical manifestations are related to hypothalamic/pituitary deficiencies, visual impairment, and increased intracranial pressure. If the tumor is favorably localized, the therapy of choice is complete resection, with care taken to preserve optical and hypothalamic functions. In patients with unfavorable tumor localization (i.e., hypothalamic involvement), recommended therapy is a limited hypothalamus-sparing surgical strategy followed by local irradiation. Although overall survival rates are high (92%), recurrences and progressions are frequent. Irradiation has proven effective in reducing recurrences and progression, and timing of postsurgical irradiation in childhood-onset cases is currently under investigation in a randomized multinational trial (KRANIOPHARYNGEOM 2007). Anatomical involvement and/or surgical lesions of posterior hypothalamic areas can result in serious quality of life-compromising sequelae such as hypothalamic obesity, psychopathological symptoms, and/or cognitive problems. It is crucial that craniopharyngioma be managed as a frequently chronic disease, providing ongoing care of pediatric and adult patients' clinical and quality of life consequences by experienced multidisciplinary teams. PMID- 24467717 TI - Chronic myelomonocytic leukaemia: a concise clinical and pathophysiological review. AB - Chronic myelomonocytic leukaemia (CMML) is a clonal haematopoietic stem cell disorder with myelodysplastic and myeloproliferative overlap features, and an inherent tendency to transform to acute myeloid leukaemia. Approximately 30% of patients present with clonal cytogenetic abnormalities, while almost 90% have molecular aberrations involving epigenetic regulation, the spliceosome component machinery, tumour suppressor genes and transcription factors/regulators. Numerous prognostic models exist for CMML, with more recent models incorporating prognostic mutations, such as those involving ASXL1. Other variables that seem to consistently affect outcomes include the degree of leucocytosis/monocytosis, anaemia and thrombocytopenia. Allogeneic stem cell transplant remains the only curative option for CMML, while hypomethylating agents can be used for transplant ineligible patients or those without suitable stem cell sources. Targeting biological pathways activated in CMML offers potential hope for more effective and less toxic therapies. PMID- 24467718 TI - Heart failure monitoring with a cardiac resynchronization therapy device-based cardiac contractility sensor: a case series. AB - INTRODUCTION: The SonR signal has been shown to reflect cardiac contractility. It is recorded with an atrial lead connected to a cardiac resynchronization therapy defibrillator. For the first time, clinical evidence on the use of the SonR signal in the monitoring of the clinical status of heart failure patients implanted with cardiac resynchronization therapy defibrillator are presented through three clinical cases. CASE PRESENTATION: In the two first patients (non Hispanic/Latino white), the SonR amplitude increases concomitantly to clinical status improvement subsequent to cardiac resynchronization therapy defibrillator implantation. In the third patient (non-Hispanic/Latino white), a decrease in SonR amplitude is observed concomitantly to atrial fibrillation and clinical status deterioration. CONCLUSIONS: This case series reports the association between SonR signal amplitude changes and patients' clinical status. Combined with remote monitoring, early SonR signal amplitude remote monitoring could be a promising tool for heart failure patients' management. PMID- 24467720 TI - But consider the alternative: the influence of positive affect on overconfidence. AB - Three studies find evidence that positive affect reduces comparative overconfidence (overplacement). This occurs because positive affect attenuates focalism via decreasing people's tendency to overweight information regarding themselves in the light of information concerning others. Specifically, Study 1 provides evidence that positive affect leads to more realistic estimates of comparative ability and that other-focus partially mediates this effect. Then, Study 2 provides causal evidence that positive affect independently influences other-focus and that other-focus, in turn, influences overplacement. Additionally, Study 2 uses an indirect measure of focalism to better capture this attentional process. Finally, Study 3 explores the influence of negative affect on overplacement. In addition, each study finds that positive affect does not influence overconfidence regarding participant's raw performances (overestimation) as this type of overconfidence is not dependent on self-other comparisons. PMID- 24467719 TI - Polypharmacy and health outcomes among older adults discharged from hospital: results from the CRIME study. AB - AIM: To investigate if older adults using multiple drugs have an increased risk of rehospitalization and mortality after hospital discharge. METHODS: This was a prospective cohort study carried out in acute care hospitals. The primary outcomes of the study were rehospitalization and mortality within 1 year after discharge from acute care hospitals. The study population was categorized in two groups according to the number of drugs prescribed at hospital discharge: no polypharmacy (<8 drugs) and polypharmacy (>=8 drugs). RESULTS: The mean age of 480 participants was 78.6+/-6.8 years ,and half of them (n=238; 49.6%) were using multiple drugs (>=8 drugs). Overall, 65 out of 242 participants (26.9%) in the no polypharmacy group and 92/238 (39.1%) in the polypharmacy group were rehospitalized (P=0.004), and 15 out of 242 (6.2%) in the no polypharmacy and 23 out of 238 (9.7%) in the polypharmacy group died during the 1 year follow up (P=0.16). After adjusting for potential confounders, participants in the polypharmacy group had an increased risk of 1-year rehospitalization as compared with those in the no polypharmacy group (RR=1.81, 95% CI=1.18-2.75). No significant association was observed between mortality and polypharmacy. CONCLUSIONS: Older persons using multiple drugs are at increased risk of rehospitalization. Further studies are required to assess the impact of programs aimed at reducing polypharmacy on health outcomes. PMID- 24467721 TI - The neurobiology of aggression: implications for the pharmacotherapy of aggressive challenging behaviour by people with intellectual disabilities. AB - AIM: The aim of this review is to summarise current understanding of the neurobiology of aggression and within this context to consider the evidence base for the pharmacotherapy of aggressive challenging behaviour by people with intellectual disabilities (ID). EVIDENCE: Aggressive encounters involve a variety of psychological processes and progress has been made in understanding the brain mechanisms involved. However, the role in aggression of the neurotransmitters serotonin, dopamine and gamma-aminobutyric acid is no longer as clear as it once appeared, with the result that predictions cannot be made with confidence about drug effects on aggression. There have been relatively few controlled trials of pharmacotherapy for aggression in people with ID, or, indeed, in the general population, and their outcomes have largely been negative. CONCLUSION: With the possible exception of risperidone, there is no reliable evidence that antidepressant, neuroleptic or anticonvulsant drugs are effective treatments for aggression by people with ID. PMID- 24467722 TI - Enhanced local Foxp3 expression in lung tissue attenuates airway inflammation in a mouse model of asthma. AB - OBJECTIVE: Bronchial asthma is a chronic inflammatory disease of the airway mediated by a Th2 immune response. A great deal of data has demonstrated that regulatory T cells (Tregs) have the ability to suppress Th2 immune responses and the transcription factor fork-head box protein 3 (Foxp3) is indispensable for the development of CD4 + CD25 + Tregs. In this study, we hypothesized that enhanced local Foxp3 expression in lung tissue could suppress Th2-mediated allergic asthma. METHODS: Foxp3/PMX retroviruses containing the mouse Foxp3 gene were constructed and administered into asthmatic mice through intra-tracheal instillation before ovalbumin challenging. Foxp3 expression, airway hyper responsiveness (AHR), bronchoalveolar lavage fluid (BALF) and tissue inflammatory cell and cytokine profiles were characterized. RESULTS: Foxp3 mRNA and protein were increased in the lung tissue of asthmatic mice. Enhanced expression of Foxp3 locally in the lung tissue reduced the airway AHR, inflammatory cell infiltration and mucus production. It also attenuated Th2 and Th17 immune responses as evidenced by reduced IL-4, IL-13 and IL-17 levels. CONCLUSIONS: This study demonstrates that enhanced Foxp3 expression in the airway by intra-tracheally instilled Foxp3/PMX retroviruses alleviates allergic airway inflammation by reducing the Th2 immune response. PMID- 24467723 TI - Effects of the histone methyltransferase inhibitor UNC0638 on histone H3K9 dimethylation of cultured ovine somatic cells and development of resulting early cloned embryos. AB - Aberrant hypermethylation of histone H3 lysine 9 (H3K9) may be involved in the developmental failure of cloned embryos. UNC0638 is a type of small molecule that can specifically inhibit the enzyme activity of histone methyltransferase EHMT2 and reduce the H3K9 dimethylation (H3K9me2) levels in cells. The objective of this study was to investigate the effect of UNC0638 in regulating H3K9me2 and development of cloned embryos. Results showed that UNC0638 could efficiently reduce H3K9me2 levels of cultured sheep foetal fibroblast cells in a concentration-dependent manner. Cloned embryos were subsequently produced from UNC0638-treated donor cells with down-regulated H3K9me2, but their in vitro development was not improved when compared with the control. Our study suggested that revision of the single histone H3K9me2 modification may be not sufficient for rescuing the development of cloned embryos. However, because of its low cellular toxicity, UNC0638 may still be a potential chemical that could be used in regulating epigenetic modification of cloned embryos. PMID- 24467724 TI - Hypopigmented macules secondary to imatinib for the treatment of chronic myeloid leukemia: a histopathologic and immunohistochemical study. AB - BACKGROUND: A few series addressing the cutaneous side effects related to imatinib in the skin have been published, but only one described scarce histopathologic information in seven patients. OBJECTIVE: To characterize these lesions and compare the number of melanocytes between hypopigmented lesions and normal appearing skin. METHODS: We retrieved clinical data of the patients and performed 24 skin biopsies (13 from hypopigmented skin and 11 from normal appearing skin) within a cohort of 41 patients with chronic myeloid leukemia treated with imatinib. We classified the biopsies into three patterns. RESULTS: About 45% of patients presented with periocular hypopigmentation. Perifollicular fibrosis was observed in hypopigmented skin biopsies (76.9%) and in normal appearing skin (45.5%). Epidermal melanin, as determined with Masson-Fontana staining, and melanocyte number, as evaluated with MiTF, Melan A and c-kit immunostains, were lower in hypopigmented skin. CONCLUSIONS: Histopathologic study of hypopigmented macules demonstrates the presence of melanin with a statistically significant decrease in the number of melanocytes. Therefore, these findings differ from vitiligo, as melanocytes are present. Three histopathological patterns may be found, namely (a) perifollicular fibrosis, (b) lichen planopilaris-like and (c) apparently normal skin. One of the most striking histopathologic finding consisted of the presence of perifollicular fibrosis in both hypopigmented lesions and apparently normal skin. PMID- 24467725 TI - Plasticizer contamination of firefighter personal protective clothing--a potential factor in increased health risks in firefighters. AB - Chemical exposures may be responsible for firefighters' elevated incidences of cancer and cardiovascular disease. This study characterized semivolatile chemical contamination on firefighter personal protective clothing to assess exposure of firefighters to these chemicals. Samples from used firefighter protective clothing, including gloves, hood, and one coat wristlet, were extracted with methylene chloride and analyzed by EPA method 8270 for semivolatile contaminants, including 20 polycyclic aromatic hydrocarbons (PAHs) and 6 phthalate diesters. Twenty-two of the chemicals of interest were found on at least one clothing swatch. Only di-(2-ethylhexyl) phthalate (DEHP), a plasticizer, added to polyvinyl chloride (PVC) to increase flexibility, was found on every swatch. DEHP concentrations were the highest of any chemical measured, and were 52 to 875 times higher than any PAH concentration measured. DEHP was also detected on most items of unused firefighter personal protective clothing, although at much lower levels. These findings suggest that firefighters are exposed to high levels of DEHP, a probable human carcinogen, and at levels much higher than PAHs, the semivolatile toxic combustion products most extensively studied historically. Firefighter exposure to DEHP and other phthalate diesters therefore merits further study. PMID- 24467726 TI - Cognitive skills assessment during robot-assisted surgery: separating the wheat from the chaff. AB - OBJECTIVE: To investigate the utility of cognitive assessment during robot assisted surgery (RAS) to define skills in terms of cognitive engagement, mental workload, and mental state; while objectively differentiating between novice and expert surgeons. SUBJECTS AND METHODS: In all, 10 surgeons with varying operative experience were assigned to beginner (BG), combined competent and proficient (CPG), and expert (EG) groups based on the Dreyfus model. The participants performed tasks for basic, intermediate and advanced skills on the da Vinci Surgical System. Participant performance was assessed using both tool-based and cognitive metrics. RESULTS: Tool-based metrics showed significant differences between the BG vs CPG and the BG vs EG, in basic skills. While performing intermediate skills, there were significant differences only on the instrument-to instrument collisions between the BG vs CPG (2.0 vs 0.2, P = 0.028), and the BG vs EG (2.0 vs 0.1, P = 0.018). There were no significant differences between the CPG and EG for both basic and intermediate skills. However, using cognitive metrics, there were significant differences between all groups for the basic and intermediate skills. In advanced skills, there were no significant differences between the CPG and the EG except time (1116 vs 599.6 s), using tool-based metrics. However, cognitive metrics revealed significant differences between both groups. CONCLUSION: Cognitive assessment of surgeons may aid in defining levels of expertise performing complex surgical tasks once competence is achieved. Cognitive assessment may be used as an adjunct to the traditional methods for skill assessment during RAS. PMID- 24467727 TI - Effect of ulnar ostectomy on intra-articular pressure mapping and contact mechanics of the congruent and incongruent canine elbow ex vivo. AB - OBJECTIVE: To determine (1) the effect of elbow incongruity on contact mechanics and (2) the effect of treatment of this incongruity with 1 of 2 ulnar ostectomies in the canine elbow. STUDY DESIGN: Ex vivo biomechanical study. SAMPLE POPULATION: Unpaired cadaveric canine forelimbs (n = 17). METHODS: In a servohydraulic testing frame, thin-film pressure sensors were placed into the lateral and medial compartments of the elbow. Specimens were tested in 135 degrees of elbow joint flexion at 200 N of cyclic axial force, followed by a 20 seconds hold. Intra-articular contact area (CA), mean contact pressure (mCP) and peak contact pressure (pCP) were measured in each compartment. After radial shortening, testing was repeated and limbs randomized into proximal ulnar ostectomy with IM pin (PUO) or sequential distal ulnar ostectomy (DUO), interosseous ligament release (DUO-L), and ulnar attachment of the abductor pollicis longus muscle and interosseous membrane release (DUO-ML). Paired t-tests were used to compare each treatment to baseline values. Differences between treatment groups were evaluated with a mixed model with random effect to adjust for the clustering of limbs within dog. P < .05 was considered significant. RESULTS: Radial shortening resulted in shift of mCP and pCP from the lateral to the medial compartment. The PUO group resulted in normalization of medial compartment mCP and decrease of pCP, whereas in the DUO group return to baseline was achieved only after DUO-ML. CONCLUSION: PUO is effective in unloading medial compartment pCP in an incongruent joint. PMID- 24467728 TI - The association between ANKH promoter polymorphism and chondrocalcinosis is independent of age and osteoarthritis: results of a case-control study. AB - INTRODUCTION: Chondrocalcinosis (CC) most commonly results from calcium pyrophosphate crystal deposition (CPPD). The objective of this study is to examine the association between candidate single-nucleotide polymorphisms (SNPs) and radiographic CC. METHODS: SNPs in ankylosis human (ANKH), high ferritin (HFE), tissue non-specific alkaline phosphatase (TNAP), ecto-neucleotide pyrophosphatase 1 (ENPP1), and transferrin (TE) genes were genotyped in participants of the Genetics of Osteoarthritis and Lifestyle (GOAL) and Nottingham Osteoarthritis Case-Control studies. Adjusted genotype odds ratio (aORGENOTYPE), the OR for association between one additional minor allele and CC, was calculated and adjusted for age, gender, body mass index (BMI), and osteoarthritis (OA) by using binary logistic regression. Statistical significance was set at P <=0.003 after Bonferroni correction for multiple tests. RESULTS: The -4bpG > A polymorphism in the 5' untranslated region (5' UTR) of ANKH associated with CC after Bonferroni correction. This was independent of age, gender, OA, and BMI; aORGENOTYPE (95% confidence interval, or CI) was 1.39 (1.14-1.69) (P = 0.001). rs3045 and rs875525, two other SNPs in ANKH, associated with CC; aORGENOTYPE (95% CI) values were 1.31 (1.09-1.58) (P = 0.005) and 1.18 (1.03 1.35) (P = 0.015), respectively; however, this was non-significant after Bonferroni correction. CONCLUSIONS: This study validates the association between a functional polymorphism in the 5' UTR of ANKH and CC and shows for the first time that this is independent of age and OA - the two key risk factors for CC. It shows that other SNPs in ANKH may also associate with CC. This supports the role of extracellular inorganic pyrophosphate in the pathogenesis of CC. The findings of this hospital-based study require replication in a community-based population. PMID- 24467729 TI - Anxiety and depression in adult patients with familial Mediterranean fever: a study comparing patients living in Germany and Turkey. AB - AIM: To determine the prevalence of anxiety and depression among patients with familial Mediterranean fever (FMF) living in Germany or Turkey a prospective study was conducted. METHODS: Forty FMF patients living in Turkey (T), 40 FMF patients living in Germany (G) and 40 healthy controls living in Germany (C) were included. Patients and controls were of Turkish ancestry. G were compared to T and C. The Hospital Anxiety and Depression Scale (HADS) was used with a cut-off of >= 8 for each subdomain score (HADS-A, HADS-D). RESULTS: Baseline characteristics of G were comparable to T and C except for age (T: 30.5 years, G: 35.2 years, C: 34.6 years; T vs. G P = 0.045), duration of disease (T: 14.4 years, G: 24; P < 0.001), C-reactive protein (T: 0.78 mg/dL, G: 0.78 mg/dL, C: 0.35 mg/dL; G vs. C P = 0.03). Prevalence of anxiety was higher in G compared to C (T: 65%, G: 52.5%, C: 22.5%: G vs. C P < 0.05). No difference was found for the prevalence of depression (T: 30%, G: 35%, C: 20%). The association between FMF and anxiety in subjects living in Germany persisted after adjusting for age and gender in a regression analysis and was robust to an adjustment for coexisting depression. Anxiety and depression did not correlate with FMF disease severity assessed with the Pras score. CONCLUSION: Anxiety, but not depression is more common among FMF patients living in Germany compared to healthy controls. No significant difference could be found between FMF patients living in Germany or Turkey concerning the prevalence of anxiety or depression. PMID- 24467730 TI - Examining the relationship between uterine fibroids and dyspareunia among premenopausal women in the United States. AB - INTRODUCTION: Despite estimates of a high prevalence of deep dyspareunia (DD) among women in the United States, risk factors for this important area of sexual dysfunction have been largely understudied. AIMS: The purpose of this study was to examine the relationship between uterine fibroids and the prevalence of DD. METHODS: We used data from the Uterine Fibroid Study (enrollment 1996-1999 in a U.S. metropolitan area). Participating women were ages 35-49 and were randomly selected from the membership rolls of a prepaid health plan. Women were asked to provide detailed health information including a symptom questionnaire with questions about DD and to have a study ultrasound to screen for fibroids >= 0.5 cm in diameter. The analysis included 827 women, after restriction to participants who were premenopausal with an intact uterus, sexually active, completed the symptom questionnaire, and had fibroid status adequately assessed. Logistic regression was conducted to estimate the adjusted prevalence odds ratio (aPOR) for the association of DD with presence of fibroids after adjusting for age, ethnicity, education, depression, physical activity, parity, and pelvic pathology. MAIN OUTCOME MEASURE: Our main outcome measures were the presence and severity of DD. RESULTS: The presence of fibroids was significantly associated with DD (aPOR = 1.7 95% confidence interval [CI] 1.1, 2.5). The aPOR was stronger for severe DD, DD that interfered with normal activity "some" or "a lot" (aPOR = 3.1 95% CI 1.2, 8.2). However, there was not a significant dose response relationship between fibroid burden (measured by uterine volume) and DD. Fundal fibroids were more strongly associated with DD than other fibroids. Additional factors associated with significantly elevated odds of DD were parity, depression, younger age, and pelvic pathology. CONCLUSION: Our results suggest that fibroids are associated with DD. The association may not be causal but may reflect shared etiology and/or pathologic pathways. PMID- 24467733 TI - Incidence and course of child malnutrition according to clinical or anthropometrical assessment: a longitudinal study from rural DR Congo. AB - BACKGROUND: Longitudinal studies describing incidence and natural course of malnutrition are scarce. Studies defining malnutrition clinically [moderate clinical malnutrition (McM) marasmus, kwashiorkor] rather than anthropometrically are rare. Our aim was to address incidence and course of malnutrition among pre schoolers and to compare patterns and course of clinically and anthropometrically defined malnutrition. METHODS: Using a historical, longitudinal study from Bwamanda, DR Congo, we studied incidence of clinical versus anthropometrical malnutrition in 5,657 preschool children followed 3-monthly during 15 months. RESULTS: Incidence rates were highest in the rainy season for all indices except McM. Incidence rates of McM and marasmus tended to be higher for boys than for girls in the dry season. Malnutrition rates increased from the 0-5 to the 6 - 11 months age category. McM and marasmus had in general a higher incidence at all ages than their anthropometrical counterparts, moderate and severe wasting. Shifts back to normal nutritional status within 3 months were more frequent for clinical than for anthropometrical malnutrition (62.2-80.3% compared to 3.4 66.4.5%). Only a minority of moderately stunted (30.9%) and severely stunted children (3.4%) shifted back to normal status. Alteration from severe to mild malnutrition was more characteristic for anthropometrically than for clinically defined malnutrition. CONCLUSIONS: Our data on age distribution of incidence and course of malnutrition underline the importance of early life intervention to ward off malnutrition. In principle, looking at incidence may yield different findings from those obtained by looking at prevalence, since incidence and prevalence differ approximately differ by a factor "duration". Our findings show the occurrence dynamics of general malnutrition, demonstrating that patterns can differ according to nutritional assessment method. They suggest the importance of applying a mix of clinical and anthropometric methods for assessing malnutrition instead of just one method. Functional validity of characterization of aspects of individual nutritional status by single anthropometric scores or by simple clinical classification remain issues for further investigation. PMID- 24467734 TI - Outcomes among buprenorphine-naloxone primary care patients after Hurricane Sandy. AB - BACKGROUND: The extent of damage in New York City following Hurricane Sandy in October 2012 was unprecedented. Bellevue Hospital Center (BHC), a tertiary public hospital, was evacuated and temporarily closed as a result of hurricane-related damages. BHC's large primary care office-based buprenorphine clinic was relocated to an affiliate public hospital for three weeks. The extent of environmental damage and ensuing service disruption effects on rates of illicit drug, tobacco, and alcohol misuse, buprenorphine medication supply disruptions, or direct resource losses among office-based buprenorphine patients is to date unknown. METHODS: A quantitative and qualitative semi-structured survey was administered to patients in BHC's primary care buprenorphine program starting one month after the hurricane. Survey domains included: housing and employment disruptions; social and economic support; treatment outcomes (buprenorphine adherence and ability to get care), and tobacco, alcohol, and drug use. Open-ended questions probed general patient experiences related to the storm, coping strategies, and associated disruptions. RESULTS: There were 132 patients enrolled in the clinic at the time of the storm; of those, 91 patients were recruited to the survey, and 89 completed (98% of those invited). Illicit opioid misuse was rare, with 7 respondents reporting increased heroin or illicit prescription opioid use following Sandy. Roughly half of respondents reported disruption of their buprenorphine-naloxone medication supply post-event, and self-lowering of daily doses to prolong supply was common. Additional buprenorphine was obtained through unscheduled telephone or written refills from relocated Bellevue providers, informally from friends and family, and, more rarely, from drug dealers. CONCLUSIONS: The findings highlight the relative adaptability of public sector office-based buprenorphine treatment during and after a significant natural disaster. Only minimal increases in self-reported substance use were reported despite many disruptions to regular buprenorphine supplies and previous daily doses. Informal supplies of substitute buprenorphine from family and friends was common. Remote telephone refill support and a temporary back-up location that provided written prescription refills and medication dispensing for uninsured patients enabled some patients to maintain an adequate medication supply. Such adaptive strategies to ensure medication maintenance continuity pre/post natural disasters likely minimize poor treatment outcomes. PMID- 24467732 TI - Socioeconomic factors and mortality in diastolic heart failure. AB - BACKGROUND: Mortality in patients with heart failure with preserved ejection fraction (HFPEF) has remained stable over recent decades. Few studies have explored prognostic characteristics specifically in HFPEF, and none of them has assessed the potential impact of socioeconomic factors. We aimed to evaluate the impact of socioeconomic factors on all-cause and cardiovascular mortality in HFPEF patients. MATERIALS AND METHODS: We used data from the French ODIN cohort. All patients with heart failure and a left ventricular ejection fraction (LVEF) > 45%, included in ODIN between July 2007 and July 2010, were eligible here. Socioeconomic, demographic, clinical, biological and therapeutic data were collected at inclusion. The endpoints were all-cause and cardiovascular mortality between inclusion and 30 September 2011. The impact of patient socioeconomic characteristics on mortality was assessed using Cox regression models. RESULTS: Of 575 HFPEF patients considered, 58.6% were male; their mean age was 71.1 +/- 13.5 years, and their mean LVEF was 58.1 +/- 8.5%. After adjustment for confounders, living alone and limitations on activities of daily living were associated with all-cause mortality [HR = 1.77, 95%CI(1.11-2.81) and 2.61(1.35 5.03), respectively] and cardiovascular mortality [2.26 (1.24-4.10) and 3.16 (1.33-7.54), respectively]. Having a professional occupation was associated with a lower cardiovascular mortality only [0.37(0.15-0.94)]. CONCLUSIONS: Poor social conditions impair survival in patients with HFPEF. These findings may shed new light on how best to detect HFPEF patients with high health-care needs. PMID- 24467735 TI - Good longterm survival after primary living donor liver transplantation for solitary hepatocellular carcinomas up to 8 cm in diameter. AB - OBJECTIVES: There is controversy over whether hepatocellular carcinoma (HCC) should be primarily treated with living donor liver transplantation (LDLT) if liver resection (LR) can be effective. This retrospective study was conducted to compare survival outcomes in patients treated with either modality for solitary HCC measuring <=8 cm in diameter. METHODS: Outcomes in patients with solitary HCC primarily treated by LDLT were analysed. Patients with solitary HCC of similar sizes with or without microvascular invasion primarily treated with LR were selected at a ratio of 6 : 1 for comparison. RESULTS: In-hospital mortality amounted to 0% and 1.3% in the LDLT (n = 50) and LR (n = 300) groups, respectively (P = 0.918). Complication rates were 34% and 20% in the LDLT and LR groups, respectively (P = 0.027). Rates of 1-, 3-, 5- and 10-year overall survival were 98%, 94%, 89% and 83%, respectively, in the LDLT group and 95%, 85%, 76% and 56%, respectively, in the LR group (P = 0.013). Rates of 1-, 3-, 5- and 10-year disease-free survival were 96%, 90%, 87% and 81%, respectively, in the LDLT group and 81%, 64%, 57% and 40%, respectively, in the LR group (P < 0.0001). CONCLUSIONS: Living donor liver transplantation surpassed LR in survival outcomes, achieving a 10-year overall survival rate 1.5 times as high and a 10 year disease-free survival rate twice as high as those facilitated by LR. However, it entailed more complications, in addition to the inevitable risks to the donor. PMID- 24467737 TI - Induction of cervical dilation for transcervical embryo transfer in ewes. AB - BACKGROUND: A major limitation in the application of assisted reproductive technologies in sheep arises from the inability to easily traverse the uterine cervix. The cervix of the non-pregnant ewe is a narrow and rigid structure, with 5-7 spiral folds and crypts that block its lumen. The first two folds closest to the vagina appear to be the greatest obstacle for the instrument insertion into the sheep cervix. Therefore, the dilation of the distal part of the cervix could provide the conformational change necessary to perform non-invasive transcervical procedures. The present study set out to assess the efficacy of Cervidil(r), a patented dinoprostone (PgE2)-containing vaginal insert with a controlled-release mechanism, to safely induce sufficient cervical dilation for the purpose of transcervical embryo transfer (TCET) in cyclic ewes. METHODS: The transfer of frozen-thawed ovine embryos was attempted in 22 cross-bred Rideau Arcott x Polled Dorset ewes, with or without the pre-treatment with Cervidil(r) for 12 or 24 h prior to TCET. RESULTS: Cervical penetration rate was significantly improved after Cervidil(r) pre-treatment, with 55% (6/11) of treated versus 9% (1/11) of control animals successfully penetrated (chi2-test, p < 0.05). Within the treated ewes that were penetrated, 67% (4/6) had been exposed to Cervidil(R) for 24 h and 33% (2/6) had had a 12-h exposure (p > 0.05). Variations in the age, weight, genotype, parity, lifetime lamb production (LLP) and post-partum interval (PPI) between penetrated and non-penetrated ewes were not significant (p > 0.05). The time taken to traverse the uterine cervix was negatively correlated (p < 0.05) with the age, parity, LLP and PPI. Progesterone assays and ultrasonographic examinations performed 25 days after ET confirmed pregnancy in 2 of 7 penetrated ewes, but no fetuses were detected ultrasonographically 55 days post-TCET. CONCLUSIONS: The present results indicate a significant benefit of using Cervidil(r) for inducing cervical dilation during the mid-luteal phase in ewes but the reason(s) for impaired fertility after the transfer of frozen-thawed ovine embryos remains to be elucidated. PMID- 24467739 TI - An ethnobiological study in Kala Chitta hills of Pothwar region, Pakistan: multinomial logit specification. AB - BACKGROUND: This paper constitutes an important ethnobiological survey in the context of utilizing biological resources by residents of Kala Chitta hills of Pothwar region, Pakistan. The fundamental aim of this research endeavour was to catalogue and analyse the indigenous knowledge of native community about plants and animals. The study is distinctive in the sense to explore both ethnobotanical and ethnozoological aspects of indigenous culture, and exhibits novelty, being based on empirical approach of Multinomial Logit Specifications (MLS) for examining ethnobotanical and ethnozoological uses of specific plants and animals. METHODS: To document the ethnobiological knowledge, the survey was conducted during 2011-12 by employing a semi-structured questionnaire and thus 54 informants were interviewed. Plant and animal specimens were collected, photographed and properly identified. Distribution of plants and animals were explored by descriptive and graphical examination. MLS were further incorporated to identify the probability of occurrence of diversified utilization of plants and animals in multipurpose domains. RESULTS: Traditional uses of 91 plant and 65 animal species were reported. Data analysis revealed more medicinal use of plants and animals than all other use categories. MLS findings are also in line with these proportional configurations. They reveal that medicinal and food consumption of underground and perennial plants was more as compared to aerial and annual categories of plants. Likewise, medicinal utilization of wild animals and domestic animals were more commonly observed as food items. However, invertebrates are more in the domain of medicinal and food utilization. Also carnivores are fairly common in the use of medicine while herbivores are in the category of food consumption. CONCLUSION: This study empirically scans a good chunk of ethnobiological knowledge and depicts its strong connection with indigenous traditions. It is important to make local residents beware of conservation status of species and authentication of this knowledge needs to be done in near future. Moreover, Statistically significant findings impart novelty in the existing literature in the field of ethnobiology. Future conservation, phytochemical and pharmacological studies are recommended on these identified plants and animals in order to use them in a more sustainable and effective way. PMID- 24467738 TI - Metabolic consequences of microRNA-122 inhibition in rainbow trout, Oncorhynchus mykiss. AB - BACKGROUND: MicroRNAs (miRNAs) are small regulatory molecules which post transcriptionally regulate mRNA stability and translation. Several microRNAs have received attention due to their role as key metabolic regulators. In spite of the high evolutionary conservation of several miRNAs, the role of miRNAs in lower taxa of vertebrates has not been studied with regard to metabolism. The liver specific and highly abundant miRNA-122 is one of the most widely studied miRNA in mammals, where it has been implicated in the control of hepatic lipid metabolism. Following our identification of acute postprandial, nutritional and endocrine regulation of hepatic miRNA-122 isomiRNA expression in rainbow trout, we used complementary in silico and in vivo approaches to study the role of miRNA-122 in rainbow trout metabolism. We hypothesized that the role of miRNA-122 in regulating lipid metabolism in rainbow trout is conserved to that in mammals and that modulation of miRNA-122 function would result in altered lipid homeostasis and secondarily altered glucose homeostasis, since lipogenesis has been suggested to act as glucose sink in trout. RESULTS: Our results show that miRNA-122 was functionally inhibited in vivo in the liver. Postprandial glucose concentrations increased significantly in rainbow trout injected with a miRNA-122 inhibitor, and this effect correlated with decreases in hepatic FAS protein abundance, indicative of altered lipogenic potential. Additionally, miRNA-122 inhibition resulted in a 20% decrease in plasma cholesterol concentration, an effect associated with increased expression of genes involved in cholesterol degradation and excretion. CONCLUSIONS: Overall evidence suggests that miRNA-122 may have evolved in early vertebrates to support liver-specific metabolic functions. Nevertheless, our data also indicate that metabolic consequences of miRNA-122 inhibition may differ quantitatively between vertebrate species and that distinct direct molecular targets of miRNA-122 may mediate metabolic effects between vertebrate species, indicating that miRNA-122 - mRNA target relationships may have undergone species-specific evolutionary changes. PMID- 24467740 TI - The role of apoptosis in megakaryocytes and platelets. AB - The role of apoptotic pathways in the development and function of the megakaryocyte lineage has generated renewed interest in recent years. This has been driven by the advent of BH3 mimetic drugs that target BCL2 family proteins to induce apoptosis in tumour cells: agents such as ABT-263 (navitoclax, which targets BCL2, BCL-XL [BCL2L1] and BCL2L2) and ABT-199 (a BCL2-specific agent) are showing great promise in early stage clinical trials. However, the major dose limiting toxicity of navitoclax has proven to be thrombocytopenia, an on-target effect of inhibiting BCL-XL . It transpires that the anucleate platelet contains a classical intrinsic apoptosis pathway, which at steady state regulates its life span in the circulation. BCL-XL is the critical pro-survival protein that restrains apoptosis and maintains platelet viability. These findings have paved the way to a deeper understanding of apoptotic pathways and processes in platelets, and their precursor cell, the megakaryocyte. PMID- 24467741 TI - Leptin deficiency in rats results in hyperinsulinemia and impaired glucose homeostasis. AB - Leptin, an adipocyte-derived hormone, has well-established anorexigenic effects but is also able to regulate glucose homeostasis independent of body weight. Until recently, the ob/ob mouse was the only animal model of global leptin deficiency. Here we report the effects of leptin deficiency on glucose homeostasis in male and female leptin knockout (KO) rats. Leptin KO rats developed obesity by 6 to 7 weeks of age, and lipid mass was increased by more than 2-fold compared with that of wild-type (WT) littermates at 18 weeks of age. Hyperinsulinemia and insulin resistance were evident in both males and females and were sustained with aging. Male KO rats experienced transient mild fasting hyperglycemia between 14 and 25 weeks of age, but thereafter fasting glucose levels were comparable to those of WT littermates up to 36 weeks of age. Fasting glucose levels of female KO rats were similar to those of WT littermates. Male KO rats exhibited a 3-fold increase in the proportion of beta-cell area relative to total pancreas at 36 weeks of age. Islets from 12-week-old KO rats secreted more insulin when stimulated than islets from WT littermates. Leptin replacement via miniosmotic pump (100 MUg/d) reduced food intake, attenuated weight gain, normalized glucose tolerance, and improved glucose-stimulated insulin secretion and insulin sensitivity. Together, these data demonstrate that the absence of leptin in rats recapitulates some of the phenotype previously observed in ob/ob mice including development of hyperinsulinemia, obesity, and insulin resistance. PMID- 24467743 TI - IL-6 up-regulates the expression of rat LH receptors during granulosa cell differentiation. AB - IL-6 is produced in granulosa cells under normal physiological conditions, including during ovulation. However, the roles of IL-6 in ovarian function, including regulation of LH receptor (LHR) expression in granulosa cells, have not been explored in detail. The aim of this study was to identify the mechanism underlying the effect of IL-6 on LHR expression in the granulosa cells of female Wistar rats. Our results indicated that IL-6 clearly enhanced the FSH-induced LHR mRNA expression in a dose-dependent manner and did not stimulate cAMP accumulation by itself. The membrane protein level of LHR, assessed by a binding assay, was increased by FSH and was further enhanced by association with IL-6. Results of the luciferase assay, using promoter constructs of LHR 281 bp upstream of the translational start site, revealed that IL-6 increased the promoter activity induced by FSH, but this effect was not observed with treatment by IL-6 alone. This ability of IL-6 to enhance FSH-induced LHR mRNA expression was blocked by the Janus tyrosine kinase (JAK) pathway inhibitor, but not by the ERK1/2 inhibitor. Thus, we speculated that this IL-6 activity might be mediated by the JAK/signal transducer and activator of transcription pathway. In addition, IL-6 augmented FSH-induced IL-6 receptor alpha mRNA expression and FSH elevated IL-6 production in granulosa cells, which indicates that IL-6 may positively regulate paracrine and autocrine actions in granulosa cells. These results suggest that IL-6 up-regulates FSH-induced LHR production by increasing mRNA transcription, and JAK/signal transducer and activator of transcription 3 signaling is required for up-regulation by IL-6 in granulosa cells. PMID- 24467742 TI - Knockdown of type 3 iodothyronine deiodinase severely perturbs both embryonic and early larval development in zebrafish. AB - Exposure to appropriate levels of thyroid hormones (THs) at the right time is of key importance for normal development in all vertebrates. Type 3 iodothyronine deiodinase (D3) is the prime TH-inactivating enzyme, and its expression is highest in the early stages of vertebrate development, implying that it may be necessary to shield developing tissues from overexposure to THs. We used antisense morpholino knockdown to examine the role of D3 during early development in zebrafish. Zebrafish possess 2 D3 genes, dio3a and dio3b. Here, we show that both genes are expressed during development and both contribute to in vivo D3 activity. However, dio3b mRNA levels in embryos are higher, and the effects of dio3b knockdown on D3 activity and on the resulting phenotype are more severe. D3 knockdown induced an overall delay in development, as determined by measurements of otic vesicle length, eye and ear size, and body length. The time of hatching was also severely delayed in D3-knockdown embryos. Importantly, we also observed a severe disturbance of several aspects of development. Swim bladder development and inflation was aberrant as was the development of liver and intestine. Furthermore, D3-knockdown larvae spent significantly less time moving, and both embryos and larvae exhibited perturbed escape responses, suggesting that D3 knockdown affects muscle development and/or functioning. These data indicate that D3 is essential for normal zebrafish embryonic and early larval development and show the value of morpholino knockdown in this model to further elucidate the specific role of D3 in some aspects of vertebrate development. PMID- 24467744 TI - Sertolin mediates blood-testis barrier restructuring. AB - Two important events that occur during mammalian spermatogenesis are the release of elongated spermatids at late stage VIII of the seminiferous epithelial cycle and the restructuring of the blood-testis barrier (BTB) during stages VIII-XI. Still, it is not completely understood how these cellular events are accomplished within the seminiferous epithelium. In the present study, we investigate how sertolin, a protein that was initially identified, cloned, and partially characterized by our laboratory, functions in these critical events. Sertolin was found at the BTB, as well as at the apical ectoplasmic specialization and apical tubulobulbar complex, where it colocalized with epidermal growth factor receptor kinase substrate 8 and actin-related protein 3, two actin-regulatory proteins. Knockdown of sertolin by RNA interference showed Sertoli cell barrier function to be enhanced when assessed by transepithelial electrical resistance measurements and immunolocalization experiments. By contrast, the integrity of the BTB was disrupted when sertolin was overexpressed in vitro and in vivo. Sertolin overexpression also prompted germ cell loss from the seminiferous epithelium. Taken collectively, these results suggest that sertolin may be involved in coordinating spermatid release and BTB restructuring during spermatogenesis in the rat. PMID- 24467745 TI - Prenatal stress and stress coping style interact to predict metabolic risk in male rats. AB - Both prenatal stress (PNS) exposure and a passive stress-coping style have been identified as risk factors for insulin resistance in rats. In the current study, we test the hypothesis that PNS and stress-coping style may interact in predicting susceptibility for metabolic disease. To test this hypothesis, adult male control and PNS offspring were behaviorally characterized using a defensive burying test to have either a passive or proactive stress-coping style. In adulthood, all rats were fed either a standard chow or a high-fat diet for 3 weeks. After 3 weeks of diet exposure, glucose and insulin levels were assessed during an oral glucose tolerance test. Under high-fat diet conditions, PNS rats display elevated glucose and insulin responses to the oral glucose tolerance test, indicative of glucose intolerance. Interestingly, these effects of PNS were far more pronounced in rats characterized by a passive stress-coping style. Additionally, the passively coping PNS rats also gained more weight on the high fat diet than all other rats tested. This observation suggests that a stressful prenatal environment in combination with a passive stress-coping strategy may prime an individual to be sensitive to diet-induced obesity and type 2 diabetes. PMID- 24467746 TI - GLP-1 receptor localization in monkey and human tissue: novel distribution revealed with extensively validated monoclonal antibody. AB - Glucagon-like peptide 1 (GLP-1) analogs are increasingly being used in the treatment of type 2 diabetes. It is clear that these drugs lower blood glucose through an increase in insulin secretion and a lowering of glucagon secretion; in addition, they lower body weight and systolic blood pressure and increase heart rate. Using a new monoclonal antibody for immunohistochemistry, we detected GLP-1 receptor (GLP-1R) in important target organs in humans and monkeys. In the pancreas, GLP-1R was predominantly localized in beta-cells with a markedly weaker expression in acinar cells. Pancreatic ductal epithelial cells did not express GLP-1R. In the kidney and lung, GLP-1R was exclusively expressed in smooth muscle cells in the walls of arteries and arterioles. In the heart, GLP-1R was localized in myocytes of the sinoatrial node. In the gastrointestinal tract, the highest GLP-1R expression was seen in the Brunner's gland in the duodenum, with lower level expression in parietal cells and smooth muscle cells in the muscularis externa in the stomach and in myenteric plexus neurons throughout the gut. No GLP 1R was seen in primate liver and thyroid. GLP-1R expression seen with immunohistochemistry was confirmed by functional expression using in situ ligand binding with (125)I-GLP-1. In conclusion, these results give important new insight into the molecular mode of action of GLP-1 analogs by identifying the exact cellular localization of GLP-1R. PMID- 24467747 TI - Effects of parathyroid hormone on bone mass, bone strength, and bone regeneration in male rats with type 2 diabetes mellitus. AB - Type 2 diabetes mellitus (T2DM) is associated with increased skeletal fragility and impaired fracture healing. Intermittent PTH therapy increases bone strength; however, its skeletal and metabolic effects in diabetes are unclear. We assessed whether PTH improves skeletal and metabolic function in rats with T2DM. Subcritical femoral defects were created in diabetic fa/fa and nondiabetic +/+ Zucker Diabetic Fatty (ZDF) rats and internally stabilized. Vehicle or 75 MUg/kg/d PTH(1-84) was sc administered over 12 weeks. Skeletal effects were evaluated by MUCT, biomechanical testing, histomorphometry, and biochemical markers, and defect regeneration was analyzed by MUCT. Glucose homeostasis was assessed using glucose tolerance testing and pancreas histology. In diabetic rats, bone mass was significantly lower in the distal femur and vertebrae, respectively, and increased after PTH treatment by up to 23% in nondiabetic and up to 18% in diabetic rats (P < .0001). Diabetic rats showed 23% lower ultimate strength at the spine (P < .0005), which was increased by PTH by 36% in normal and by 16% in diabetic rats (P < .05). PTH increased the bone formation rate by 3 fold in normal and by 2-fold in diabetic rats and improved defect regeneration in normal and diabetic rats (P < .01). PTH did not affect serum levels of undercarboxylated osteocalcin, glucose tolerance, and islet morphology. PTH partially reversed the adverse skeletal effects of T2DM on bone mass, bone strength, and bone defect repair in rats but did not affect energy metabolism. The positive skeletal effects were generally more pronounced in normal compared with diabetic rats. PMID- 24467748 TI - A systematic review of the epidemiology of unrecorded alcohol consumption and the chemical composition of unrecorded alcohol. AB - BACKGROUND AND AIMS: Unrecorded alcohol constitutes about 30% of all alcohol consumed globally. The aims of this systematic review were to determine the epidemiology (occurrence, types, prevalence) of unrecorded alcohol consumption in different countries/regions, analyse the chemical composition of unrecorded alcohol and examine health outcomes caused by the consumption of unrecorded alcohol, based on either epidemiology or toxicology. METHODS: A systematic search for, and qualitative analysis of, papers with empirical results on the different categories of unrecorded alcohol, based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: Unrecorded alcohol was widespread in all regions of the world. Artisanal fermented beverages and spirits were the most common categories of unrecorded alcohol globally, and were available on all continents. In India, industrially produced spirits (country spirits) were most prevalent. In Russia and countries of the former Soviet Union, surrogate alcohols complemented artisanal spirits. Cross-border shopping was the most prevalent method of obtaining unrecorded alcohol in parts of Europe. Ethanol was the most harmful ingredient of unrecorded alcohol, and health consequences due to other ingredients found in unrecorded alcohol were scarce. However, as unrecorded alcohol is usually the least expensive form of alcohol available in many countries, it may contribute to higher rates of chronic and irregular heavy drinking. CONCLUSIONS: Very large amounts of alcohol are produced globally that go unrecorded. The primary harm from this kind of alcohol arises from the fact that it is typically much cheaper than licit alcohol. PMID- 24467749 TI - Anatomy of the vestibule of the omental bursa and epiploic foramen in the horse. AB - REASONS FOR PERFORMING STUDY: Epiploic foramen entrapment (EFE) is a common cause of colic in horses and available anatomical descriptions of this foramen and the associated vestibule of the omental bursa tend to be inconsistent, contradictory and inaccurate. OBJECTIVES: To describe the anatomy of the vestibule of the omental bursa and epiploic foramen. STUDY DESIGN: Dissection of 21 fresh equine cadavers shortly after euthanasia. METHODS: The anatomy of the vestibule of the omental bursa, epiploic foramen and related structures in the cranial abdomen were examined in situ and after removal from the abdomen. Photographs were taken and illustrations rendered to bring the relationship of the different folds, ligaments and organs involved into a 3D concept. RESULTS: The entrance into the vestibule and the passageway through it to the epiploic foramen is bounded by the gastropancreatic fold dorsally, caudally and ventrally. This fold constitutes the caudoventral boundary of the epiploic foramen along with the portal vein cranially and ventrally. The craniodorsal boundary of the epiploic foramen is formed by the caudate lobe of the liver. CONCLUSIONS: The gastropancreatic fold plays a more important role in the anatomy of the vestibule of the omental bursa and the epiploic foramen than has been documented in the most widely used anatomy textbooks written in English. Because of the importance of EFE in horses, information from this study about the relevant anatomy could provide a first step towards improved methods for treatment and laparoscopic prevention of these diseases. PMID- 24467750 TI - Fulminant systemic capillary leak syndrome due to C1 inhibitor deficiency complicating acute dermatomyositis: a case report. AB - INTRODUCTION: Dermatomyositis is a chronic inflammatory disorder characterized by muscular and dermatologic symptoms with variable internal organ involvement. This is the first report on a patient with acute dermatomyositis and fulminant systemic capillary leak syndrome. CASE PRESENTATION: A 69-year-old Caucasian woman with chronic dermatomyositis presented with clinical signs of severe hypovolemic shock and pronounced hemoconcentration (hematocrit, 69%). Her colloid osmotic pressure was 4.6mmHg. Following a bolus dose of prednisolone (500mg), fluid resuscitation was initiated. During volume loading, anasarca and acute respiratory distress rapidly developed. Echocardiography revealed an underfilled, hypokinetic, diastolic dysfunctional left ventricle with pericardial effusion but no signs of tamponade. Despite continued fluid resuscitation and high-dosed catecholamine therapy, the patient died from refractory shock 12 hours after intensive care unit admission. A laboratory analysis of her complement system suggested the presence of C1 inhibitor deficiency as the cause for systemic capillary leakage. The post-mortem examination revealed bilateral pleural, pericardial and peritoneal effusions as well as left ventricular hypertrophy with patchy myocardial fibrosis. Different patterns of endomysial/perimysial lymphocytic infiltrations adjacent to degenerated cardiomyocytes in her myocardium and necrotic muscle fibers in her right psoas major muscle were found in the histological examination. CONCLUSIONS: This case report indicates that acute exacerbation of chronic dermatomyositis can result in a fulminant systemic capillary leak syndrome with intense hemoconcentration, hypovolemic shock and acute heart failure. In the presented patient, the cause for diffuse capillary leakage was most probably acquired angioedema, a condition that has been associated with both lymphoproliferative and autoimmunologic disorders. PMID- 24467751 TI - Asymptomatic mirror right aortic arch. PMID- 24467752 TI - Foundations for modeling the dynamics of gene regulatory networks: a multilevel perspective review. AB - A promising alternative for unraveling the principles under which the dynamic interactions among genes lead to cellular phenotypes relies on mathematical and computational models at different levels of abstraction, from the molecular level of protein-DNA interactions to the system level of functional relationships among genes. This review article presents, under a bottom-up perspective, a hierarchy of approaches to modeling gene regulatory network dynamics, from microscopic descriptions at the single-molecule level in the spatial context of an individual cell to macroscopic models providing phenomenological descriptions at the population-average level. The reviewed modeling approaches include Molecular Dynamics, Particle-Based Brownian Dynamics, the Master Equation approach, Ordinary Differential Equations, and the Boolean logic abstraction. Each of these frameworks is motivated by a particular biological context and the nature of the insight being pursued. The setting of gene network dynamic models from such frameworks involves assumptions and mathematical artifacts often ignored by the non-specialist. This article aims at providing an entry point for biologists new to the field and computer scientists not acquainted with some recent biophysically-inspired models of gene regulation. The connections promoting intuition between different abstraction levels and the role that approximations play in the modeling process are highlighted throughout the paper. PMID- 24467753 TI - Repertoire of protein kinases encoded in the genome of zebrafish shows remarkably large population of PIM kinases. AB - In recent times, zebrafish has garnered lot of popularity as model organism to study human cancers. Despite high evolutionary divergence from humans, zebrafish develops almost all types of human tumors when induced. However, mechanistic details of tumor formation have remained largely unknown. Present study is aimed at analysis of repertoire of kinases in zebrafish proteome to provide insights into various cellular components. Annotation using highly sensitive remote homology detection methods revealed "substantial expansion" of Ser/Thr/Tyr kinase family in zebrafish compared to humans, constituting over 3% of proteome. Subsequent classification of kinases into subfamilies revealed presence of large number of CAMK group of kinases, with massive representation of PIM kinases, important for cell cycle regulation and growth. Extensive sequence comparison between human and zebrafish PIM kinases revealed high conservation of functionally important residues with a few organism specific variations. There are about 300 PIM kinases in zebrafish kinome, while human genome codes for only about 500 kinases altogether. PIM kinases have been implicated in various human cancers and are currently being targeted to explore their therapeutic potentials. Hence, in depth analysis of PIM kinases in zebrafish has opened up new avenues of research to verify the model organism status of zebrafish. PMID- 24467754 TI - ODEion--a software module for structural identification of ordinary differential equations. AB - In the systems biology field, algorithms for structural identification of ordinary differential equations (ODEs) have mainly focused on fixed model spaces like S-systems and/or on methods that require sufficiently good data so that derivatives can be accurately estimated. There is therefore a lack of methods and software that can handle more general models and realistic data. We present ODEion, a software module for structural identification of ODEs. Main characteristic features of the software are: * The model space is defined by arbitrary user-defined functions that can be nonlinear in both variables and parameters, such as for example chemical rate reactions. * ODEion implements computationally efficient algorithms that have been shown to efficiently handle sparse and noisy data. It can run a range of realistic problems that previously required a supercomputer. * ODEion is easy to use and provides SBML output. We describe the mathematical problem, the ODEion system itself, and provide several examples of how the system can be used. Available at: http://www.odeidentification.org. PMID- 24467755 TI - Protein sub-cellular localization prediction for special compartments via optimized time series distances. AB - Predicting the sub-cellular localization of proteins is an important task in bioinformatics, for which many standard prediction tools are available. While these tools are powerful in general and capable of predicting protein localization for the most common compartments, their performance strongly depends on the organism of interest. More importantly, there are special compartments, such as the apicoplast of apicomplexan parasites, for which these tools cannot provide a prediction at all. In the absence of a highly conserved targeting signal, even motif searches may not be able to provide a lead for the accurate prediction of protein localization for a compartment of interest. In order to approach difficult cases of that kind, we propose an alternative method that complements existing approaches by using a more targeted protein sequence model. Moreover, our method makes use of (weighted) measures for time series comparison. To demonstrate its performance, we use this method for predicting localization in special compartments of three different species, for which existing methods yield only sub-optimal results. As shown experimentally, our method is indeed capable of producing reliable predictions of sub-cellular localization for difficult cases, i.e. if training data is scarce and a potential protein targeting signal may not be well conserved. PMID- 24467756 TI - Is protein folding problem really a NP-complete one? First investigations. AB - To determine the 3D conformation of proteins is a necessity to understand their functions or interactions with other molecules. It is commonly admitted that, when proteins fold from their primary linear structures to their final 3D conformations, they tend to choose the ones that minimize their free energy. To find the 3D conformation of a protein knowing its amino acid sequence, bioinformaticians use various models of different resolutions and artificial intelligence tools, as the protein folding prediction problem is a NP complete one. More precisely, to determine the backbone structure of the protein using the low resolution models (2D HP square and 3D HP cubic), by finding the conformation that minimizes free energy, is intractable exactly. Both proofs of NP completeness and the 2D prediction consider that acceptable conformations have to satisfy a self-avoiding walk (SAW) requirement, as two different amino acids cannot occupy a same position in the lattice. It is shown in this document that the SAW requirement considered when proving NP-completeness is different from the SAW requirement used in various prediction programs, and that they are different from the real biological requirement. Indeed, the proof of NP completeness and the predictions in silico consider conformations that are not possible in practice. Consequences of this fact are investigated in this research work. PMID- 24467757 TI - Exhaustive computation of exact duplications via super and non-nested local maximal repeats. AB - We propose and implement a method to obtain all duplicated sequences (repeats) from a chromosome or whole genome. Unlike existing approaches our method makes it possible to simultaneously identify and classify repeats into super, local, and non-nested local maximal repeats. Computation verification demonstrates that maximal repeats for a genome of several gigabases can be identified in a reasonable time, enabling us to identified these maximal repeats for any sequenced genome. The algorithm used for the identification relies on enhanced suffix array data structure to achieve practical space and time efficiency, to identify and classify the maximal repeats, and to perform further post-processing on the identified duplicated sequences. The simplicity and effectiveness of the implementation makes the method readily extendible to more sophisticated computations. Maxmers can be exhaustively accounted for in few minutes for genome sequences of dozen megabases in length and in less than a day or two for genome sequences of few gigabases in length. One application of duplicated sequence identification is to the study of duplicated sequence length distributions, which our found to exhibit for large lengths a persistent power-law behavior. Variation of estimated exponents of this power law are studied among different species and successive assembly release versions of the same species. This makes the characterization of the power-law regime of sequenced genomes via maximal repeats identification and classification, an important task for the derivation of models that would help us to elucidate sequence duplication and genome evolution. PMID- 24467758 TI - Functional understanding of the diverse exon-intron structures of human GPCR genes. AB - The GPCR genes have a variety of exon-intron structures even though their proteins are all structurally homologous. We have examined all human GPCR genes with at least two functional protein isoforms, totaling 199, aiming to gain an understanding of what may have contributed to the large diversity of the exon intron structures of the GPCR genes. The 199 genes have a total of 808 known protein splicing isoforms with experimentally verified functions. Our analysis reveals that 1301 (80.6%) adjacent exon-exon pairs out of the total of 1,613 in the 199 genes have either exactly one exon skipped or the intron in-between retained in at least one of the 808 protein splicing isoforms. This observation has a statistical significance p-value of 2.051762 * e(-09), assuming that the observed splicing isoforms are independent of the exon-intron structures. Our interpretation of this observation is that the exon boundaries of the GPCR genes are not randomly determined; instead they may be selected to facilitate specific alternative splicing for functional purposes. PMID- 24467759 TI - Probabilistic non-negative matrix factorization: theory and application to microarray data analysis. AB - Non-negative matrix factorization (NMF) has proven to be a useful decomposition technique for multivariate data, where the non-negativity constraint is necessary to have a meaningful physical interpretation. NMF reduces the dimensionality of non-negative data by decomposing it into two smaller non-negative factors with physical interpretation for class discovery. The NMF algorithm, however, assumes a deterministic framework. In particular, the effect of the data noise on the stability of the factorization and the convergence of the algorithm are unknown. Collected data, on the other hand, is stochastic in nature due to measurement noise and sometimes inherent variability in the physical process. This paper presents new theoretical and applied developments to the problem of non-negative matrix factorization (NMF). First, we generalize the deterministic NMF algorithm to include a general class of update rules that converges towards an optimal non negative factorization. Second, we extend the NMF framework to the probabilistic case (PNMF). We show that the Maximum a posteriori (MAP) estimate of the non negative factors is the solution to a weighted regularized non-negative matrix factorization problem. We subsequently derive update rules that converge towards an optimal solution. Third, we apply the PNMF to cluster and classify DNA microarrays data. The proposed PNMF is shown to outperform the deterministic NMF and the sparse NMF algorithms in clustering stability and classification accuracy. PMID- 24467761 TI - Accurate discrimination of outer membrane proteins using secondary structure element alignment and support vector machine. AB - Outer membrane proteins (OMPs) play critical roles in many cellular processes and discriminating OMPs from other types of proteins is very important for OMPs identification in bacterial genomic proteins. In this study, a method SSEA_SVM is developed using secondary structure element alignment and support vector machine. Moreover, a novel kernel function is designed to utilize secondary structure information in the support vector machine classifier. A benchmark dataset, which consists of 208 OMPs, 673 globular proteins, and 206 alpha-helical membrane proteins, is used to evaluate the performance of SSEA_SVM. A high accuracy of 97.7% with 0.926 MCC is achieved while SSEA_SVM is applied to discriminating OMPs and non-OMPs. In comparison with existing methods in the literature, SSEA_SVM is also highly competitive. We suggest that SSEA_SVM is a much more promising method to identify OMPs in genomic proteins. A web server that implements SSEA_SVM is freely available at http://bioinfo.tmmu.edu.cn/SSEA_SVM/. PMID- 24467760 TI - Dynafold: a dynamic programming approach to protein backbone structure determination from minimal sets of Residual Dipolar Couplings. AB - Residual Dipolar Couplings (RDCs) are a source of NMR data that can provide a powerful set of constraints on the orientation of inter-nuclear vectors, and are quickly becoming a larger part of the experimental toolset for molecular biologists. However, few reliable protocols exist for the determination of protein backbone structures from small sets of RDCs. DynaFold is a new dynamic programming algorithm designed specifically for this task, using minimal sets of RDCs collected in multiple alignment media. DynaFold was first tested utilizing synthetic data generated for the N--H , C(alpha)--H(alpha), and C--N vectors of 1BRF, 1F53, 110M, and 3LAY proteins, with up to +/-1 Hz error in three alignment media, and was able to produce structures with less than 1.9 A of the original structures. DynaFold was then tested using experimental data, obtained from the Biological Magnetic Resonance Bank, for proteins PDBID:1P7E and 1D3Z using RDC data from two alignment media. This exercise yielded structures within 1.0 A of their respective published structures in segments with high data density, and less than 1.9 A over the entire protein. The same sets of RDC data were also used in comparisons with traditional methods for analysis of RDCs, which failed to match the accuracy of DynaFold's approach to structure determination. PMID- 24467762 TI - Distance-wise pathway discovery from protein-protein interaction networks weighted by semantic similarity. AB - Reconstruction of signaling pathways is crucial for understanding cellular mechanisms. A pathway is represented as a path of a signaling cascade involving a series of proteins to perform a particular function. Since a protein pair involved in signaling and response have a strong interaction, putative pathways can be detected from protein-protein interaction (PPI) networks. However, predicting directed pathways from the undirected genome-wide PPI networks has been challenging. We present a novel computational algorithm to efficiently predict signaling pathways from PPI networks given a starting protein and an ending protein. Our approach integrates topological analysis of PPI networks and semantic analysis of PPIs using Gene Ontology data. An advanced semantic similarity measure is used for weighting each interacting protein pair. Our distance-wise algorithm iteratively selects an adjacent protein from a PPI network to build a pathway based on a distance condition. On each iteration, the strength of a hypothetical path passing through a candidate edge is estimated by a local heuristic. We evaluate the performance by comparing the resultant paths to known signaling pathways on yeast. The results show that our approach has higher accuracy and efficiency than previous methods. PMID- 24467763 TI - PhD7Faster: predicting clones propagating faster from the Ph.D.-7 phage display peptide library. AB - Phage display can rapidly discover peptides binding to any given target; thus, it has been widely used in basic and applied research. Each round of panning consists of two basic processes: Selection and amplification. However, recent studies have showed that the amplification step would decrease the diversity of phage display libraries due to different propagation capacity of phage clones. This may induce phages with growth advantage rather than specific affinity to appear in the final experimental results. The peptides displayed by such phages are termed as propagation-related target-unrelated peptides (PrTUPs). They would mislead further analysis and research if not removed. In this paper, we describe PhD7Faster, an ensemble predictor based on support vector machine (SVM) for predicting clones with growth advantage from the Ph.D.-7 phage display peptide library. By using reduced dipeptide composition (ReDPC) as features, an accuracy (Acc) of 79.67% and a Matthews correlation coefficient (MCC) of 0.595 were achieved in 5-fold cross-validation. In addition, the SVM-based model was demonstrated to perform better than several representative machine learning algorithms. We anticipate that PhD7Faster can assist biologists to exclude potential PrTUPs and accelerate the finding of specific binders from the popular Ph.D.-7 library. The web server of PhD7Faster can be freely accessed at http://immunet.cn/sarotup/cgi-bin/PhD7Faster.pl. PMID- 24467764 TI - Fertility in dairy cows after artificial insemination using sex-sorted sperm or conventional semen. AB - The aim of this study was to compare pregnancy per artificial insemination (P/AI) after timed AI with sex-sorted sperm (SS) or conventional semen (CS) in lactating dairy cows. Cyclic cows (n = 302) were synchronized by Ovsynch and randomly assigned into two groups at the time of AI. Cows with a follicle size between 12 and 18 mm and clear vaginal discharge at the time of AI were inseminated with either frozen-thawed SS (n = 148) or CS (n = 154) of the same bull. A shallow uterine insemination was performed into the uterine horn ipsilateral to the side of probable impending ovulation. Pregnancy per AI on Day 31 tended (p = 0.09) to be less for SS (31.8%) than CS (40.9%). Similarly, P/AI on Day 62 was less (p = 0.01) for cows inseminated with SS (25.7%) compared with CS (39.0%). The increased difference in fertility between treatments from Days 31 to 62 was caused by the greater (p = 0.02) pregnancy loss for cows receiving SS (19.2%) than CS (4.8%). Cow parity (p = 0.02) and season (p < 0.01) when AI was performed were additional factors affecting fertility. Primiparous cows had greater P/AI than multiparous cows both on Day 31 (41.7% vs 25.0% in SS and 53.0% vs 31.8% in CS groups) and on Day 62 (33.3% vs 20.5% in SS and 48.5% vs 31.8% in CS groups). During the hot season of the year, P/AI on Day 31 was reduced (p = 0.01) in the SS group (19.6%) when compared with the rates during the cool season (38.1%). In conclusion, sex-sorted sperm produced lower fertility results compared to conventional semen even after using some selection criteria to select most fertile cows. PMID- 24467765 TI - Comparison of tensile strength and early healing of acute repeat celiotomy through a ventral median or a right ventral paramedian approach. AB - OBJECTIVE: To compare tensile strength, failure location, and histologic features after acute repeat celiotomy through a ventral median (RVM) or a right ventral paramedian (RVP) celiotomy in horses. STUDY DESIGN: Ex vivo experimental study. ANIMALS: Adult horses (N = 18). METHODS: Twelve adult horses had original ventral median (OVM) celiotomy. Repeat celiotomy was performed 72 hours postoperatively through the original ventral median (RVM, N = 6) or a RVP (N = 6) celiotomy. Celiotomies were scored daily for edema, drainage, and dehiscence. Fourteen days after repeat celiotomy, horses were euthanatized and abdominal wall containing celiotomy(ies) were collected for biomechanical and histological evaluation. The abdominal wall of control horses (N = 6; no celiotomy) was collected for biomechanical testing. Vital sign variables, incisional edema, and histologic scores were compared using a Wilcoxon signed-rank test. Incisional fibrotic depth and tensile strength per unit length (N/cm) was compared using repeated measures ANOVA. RESULTS: RVM and RVP horses had significantly less tensile strength compared to control horses, but no differences were observed between RVM and RVP horses. No differences in healing, inflammation, infection, or necrosis of repeat celiotomies was observed, but RVP horses accumulated more fibrin and hemorrhage within the incision. RVP horses had significantly greater incisional edema scores, but incisional drainage was more frequent in RVM horses. CONCLUSIONS: Acute repeat celiotomy through a RVM incision results in similar incisional healing and tensile strength compared with repeat celiotomy through a RVP incision. PMID- 24467766 TI - Comparison of plasma vitamin D levels in patients with Sjogren's syndrome and healthy subjects. AB - AIM: Sjogren's syndrome (SS) is a systemic autoimmune disease characterized by chronic inflammation of the salivary and lacrimal glands. There is increasing evidence indicating that vitamin D is important in the initiation and propogation of a range of autoimmune diseases which may include SS. The aim of the present study was to evaluate plasma vitamin D (vit D) levels in patients with SS and to compare this with a control group. METHOD: One hundred and seven SS patients (97 [90.7%] female and 10 [9.3%] male) and 74 healthy controls (64 [86.5%] female and 10 [13.5%] male) were included into the study. Plasma baseline 25-hydroxy-vit D levels were measured by high-powered liquid chromatography method using an Agilent 1100 liquid chromatograph. RESULTS: Plasma vit D levels in SS patients (20.5 +/- 10.5 MUg/L) were significantly lower than in the control group (28.4 +/ 15.2 MUg/L) (P < 0.001). Female SS patients had significanly lower vit D levels (19.3 +/- 9.3 MUg/L) than controls (28.3 +/- 15.8 MUg/L) (P < 0.001) but this difference was not present among the male patients and controls. There was no correlation between plasma vit D levels and erythrocyte sedimentation rate and C reactive protein in SS patients. CONCLUSION: Vit D deficiency was frequent in patients with SS. In particular, female SS patients had the risk of vit D deficiency. It may be convenient to look for vit D deficiency and to correct vit D nutritional status in SS patients. PMID- 24467767 TI - CuidaCare: effectiveness of a nursing intervention on the quality of life's caregiver: cluster-randomized clinical trial. AB - BACKGROUND: In Spain, family is the main source of care for dependent people. Numerous studies suggest that providing informal (unpaid) care during a prolonged period of time results in a morbidity-generating burden. Caregivers constitute a high-risk group that experiences elevated stress levels, which reduce their quality of life.Different strategies have been proposed to improve management of this phenomenon in order to minimize its impact, but definitive conclusions regarding their effectiveness are lacking. METHODS/DESIGN: A community clinical trial is proposed, with a 1-year follow-up period, that is multicentric, controlled, parallel, and with randomized allocation of clusters in 20 health care centers within the Community of Madrid. The study's objective is to evaluate the effectiveness of a standard care intervention in primary health care (intervention CuidaCare) to improve the quality of life of the caregivers, measured at 0, 6, and 12 months after the intervention.One hundred and forty two subjects (71 from each group) >=65 years, identified by the nurse as the main caregivers, and who provide consent to participate in the study will be included.The main outcome variable will be perceived quality of life as measured by the Visual Analogue Scale (VAS) of EuroQol-5D (EQ-5D). The secondary outcome variables will be EQ-5D Dimensions, EQ-5D Index, nursing diagnosis, and Zarit's test. Prognostic variables will be recorded for the dependent patient and the caregiver.The principle analysis will be done by comparing the average change in EQ-5D VAS value before and after intervention between the two groups. All statistical tests will be performed as intention-to-treat. Prognostic factors' estimates will be adjusted by mixed-effects regression models. Possible confounding or effect-modifying factors will be taken into account. DISCUSSION: Assistance for the caregiver should be integrated into primary care services. In order to do so, incorporating standard, effective interventions with relevant outcome variables such as quality of life is necessary. Community care nurses are at a privileged position to develop interventions like the proposed one. TRIAL REGISTRATION: This trial has been registered in ClinicalTrials.gov under code number NCT 01478295. PMID- 24467768 TI - Co-expression of HER3 and MUC1 is associated with a favourable prognosis in patients with bladder cancer. AB - OBJECTIVES: To investigate the functional impact of the interaction of MUC1 with the epidermal growth factor receptors HER3 and HER4 in patients with bladder cancer. PATIENTS AND METHODS: Using reverse transcription quantitative polymerase chain reaction, we examined MUC1 expression in 82 bladder cancer biopsies previously examined for the expression of HER3. RESULTS: Patients expressing high MUC1 had a favourable survival when the expression of HER3 was also high compared with when the expression of HER3 was low (P = 0.004). When MUC1 expression was low, HER3 co-expression did not influence the prognostic value of MUC1 (P = 0.488). MUC1 expression had no correlation with survival, tumour stage or grade, or to the prognostic value of HER4. CONCLUSIONS: A high MUC1 expression was associated with a favourable prognosis in patients with bladder cancer when the expression of HER3 was also high. This suggests an involvement of HER3 in MUC1 function in bladder cancer. PMID- 24467769 TI - Developmental screening in a Canadian First Nation (Mohawk): psychometric properties and adaptations of ages & stages questionnaires (2nd edition). AB - BACKGROUND: The need for early intervention tools adapted to the First Nation culture is well documented. However, standards derived from First Nation communities are absent from the literature. This study examines the psychometric properties of an adaptation of a caregiver-completed screening tool, the Ages & Stages Questionnaires (ASQ), for the Mohawk population. METHODS: Participants who completed the questionnaires include 17 teachers, along with the parents of 282 children (130 girls and 152 boys) between the ages of 9 and 66 months who attend the Child and Family Center Mohawk Territory, Quebec. RESULTS: For the internal consistency of the four questionnaires (36-, 42-, 48- and 54-month intervals), Cronbach's alphas varied between .61 and .84. Five results were below 0.60: "gross motor" (Q36 and Q42), "problem solving" (Q36) and "personal-social" (Q36 and Q42). A comparison of the results shows that parents and teachers agreed in 85% of the cases concerning the referral of the child for further evaluation. Moreover, the group discussion with the parents revealed that the use of the questionnaire was appreciated and was deemed appropriate for use within the community. CONCLUSION: The results show that the ASQ is a screening test that may be appropriate for use with children from communities that are seemingly very different in terms of geographic, climatic and cultural backgrounds. This preliminary study with the Child and Family Center appears to support further study and the use of the ASQ with the Mohawk population. PMID- 24467770 TI - Continuous quality improvement (CQI) in addiction treatment settings: design and intervention protocol of a group randomized pilot study. AB - BACKGROUND: Few studies have designed and tested the use of continuous quality improvement approaches in community based substance use treatment settings. Little is known about the feasibility, costs, efficacy, and sustainment of such approaches in these settings. METHODS/DESIGN: A group-randomized trial using a modified stepped wedge design is being used. In the first phase of the study, eight programs, stratified by modality (residential, outpatient) are being randomly assigned to the intervention or control condition. In the second phase, the initially assigned control programs are receiving the intervention to gain additional information about feasibility while sustainment is being studied among the programs initially assigned to the intervention. DISCUSSION: By using this design in a pilot study, we help inform the field about the feasibility, costs, efficacy and sustainment of the intervention. Determining information at the pilot stage about costs and sustainment provides value for designing future studies and implementation strategies with the goal to reduce the time between intervention development and translation to real world practice settings. PMID- 24467771 TI - Development of medium-size half-mask facepiece for male workers at a shipyard and its fit performance in Korea. AB - Ten years ago, three differently sized half-mask facepiece prototypes were constructed from silicon using computer graphics and statistical analysis to fit them according to Korean facial dimensions. The purpose of this study was to complete the medium-size half-mask respirator based on the prototype, which would provide an adequate fit performance for male workers at a shipyard, Hyundai Samho Heavy Industry Co., in Korea. The complete respirator--the hardness 55--was manufactured with existing accessories such as a filter, exhalation valve, and strap attached. The fit performance test was conducted by performing a quantitative fit-test on 48 male subjects: workers who usually wear half-mask respirators (Dobulife Tech Co., Model DM-911, Gwangju, Gyeonggi-do, Korea). The results showed that the hardness 55 provided male subject workers with much better fit performance than the existing mask constructed by the same company. Because softness of the material of the facepiece, in particular the inner part, influenced faceseal leakage, further research on developing better-fit respirator facepieces should consider carefully the fine control of material softness. PMID- 24467772 TI - Assessment of androgen replacement therapy for erectile function in rats with type 2 diabetes mellitus by examining nitric oxide-related and inflammatory factors. AB - INTRODUCTION: Type 2 diabetes mellitus (T2DM) has become a major public health issue and is considered a risk factor for erectile dysfunction (ED). T2DM is also associated with androgen deficiency. However, there have been few basic studies on androgen replacement therapy (ART) for ED treatment in T2DM animal models, and the mechanism underlying the effect of ART on T2DM-induced ED is unclear. AIM: To investigate the effect of ART on ED in T2DM rats by examining inflammatory and nitric oxide (NO)-related factors. METHODS: Otsuka Long-Evans Tokushima Fatty (OLETF) rats and their controls, Long-Evans Tokushima Otsuka (LETO) rats, were distributed into three groups: LETO, OLETF, and ART. In the ART group, OLETF rats were treated daily with testosterone (3 mg/kg/day, subcutaneously) from 20 to 25 weeks of age; LETO and OLETF rats received vehicle only. MAIN OUTCOME MEASURES: We measured erectile function by using measurements of the ratio between intracavernosal pressure (ICP) and mean arterial pressure (MAP) following electrical stimulation of the cavernous nerve and by evaluating the endothelial function of the corpus cavernosum in an isometric tension study. Expression of endothelial NO synthase (eNOS), inducible NO synthase (iNOS), sirtuin-1 (Sirt1), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF-alpha) mRNA was detected using polymerase chain reaction. RESULTS: The ICP/MAP ratio in the OLETF group was significantly decreased and that in the ART group was significantly improved (P < 0.01). The response to acetylcholine was significantly decreased in the OLETF group and improved in the ART group (P < 0.01). Although expression of eNOS and Sirt1 mRNA was decreased and that of iNOS, IL-6, and TNF-alpha mRNA was increased in the OLETF group, ART improved mRNA expression. CONCLUSIONS: ART suppressed inflammation in rats with T2DM and metabolic disorders and improved their endothelial and erectile functions. ART could be effective for T2DM-induced ED and may be considered a potential ED treatment method. PMID- 24467773 TI - Expression of tumor necrosis factor-like weak inducer of apoptosis and fibroblast growth factor-inducible 14 in patients with polymyositis and dermatomyositis. AB - INTRODUCTION: The aim of this study was to investigate the expression of tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) in patients with polymyositis (PM) and dermatomyositis (DM), and their relation to clinical manifestations. METHODS: Serum levels of TWEAK were detected in 98 PM/DM patients and 37 healthy controls by using the ELISA method. Total RNA isolated from fresh-frozen muscle tissue samples of 36 PM/DM patients and 10 healthy controls were used for analyzing the mRNA levels of TWEAK and Fn14 by quantitative reverse transcription polymerase chain reaction (RT-PCR). Immunofluorescence staining of TWEAK and Fn14 was conducted on muscle biopsy specimens from 23 PM/DM patients and seven healthy controls. RESULTS: Serum levels of TWEAK were significantly decreased in the PM/DM patients compared to those in the healthy controls (P < 0.001), and serum TWEAK levels negatively correlated with serum CD163 levels in PM/DM patients (r = -0.49, P < 0.001). The expression of Fn14 mRNA was significantly increased in the muscle tissue of PM/DM patients than in the muscle tissue of healthy controls (P < 0.01), whereas the expression of TWEAK mRNA in PM/DM patients was not statistically different from that of the healthy controls (P > 0.05). Fn14 mRNA levels in muscle tissue positively correlated with muscle disease activity (r = 0.512, P < 0.01). Patients with oropharyngeal dysphagia had significantly higher Fn14 mRNA levels than patients without oropharyngeal dysphagia (P < 0.05). The results of immunofluorescence staining showed that 19 out of 23 PM/DM patients were TWEAK-positive, and 20 out of 23 PM/DM patients were Fn14-positive. No detectable expressions of TWEAK or Fn14 were observed in the healthy controls. CONCLUSIONS: TWEAK-Fn14 axis may be involved in the pathogenesis of PM/DM. Further understanding of TWEAK-Fn14 function in PM/DM may help to define therapeutic targets for PM/DM. PMID- 24467774 TI - Interleukin 10 and clustering of metabolic syndrome components in pediatrics. AB - BACKGROUND: Interleukin 10 (IL-10) has multifaceted anti-inflammatory properties that are known to regulate insulin sensitivity and atherosclerotic development. However, studies in children are limited and have yielded conflicting results. The aim of this study was to evaluate whether changes in this circulating anti inflammatory cytokine is a marker for metabolic syndrome. MATERIALS AND METHODS: This cross-sectional study involved children and young adolescents from eight elementary schools and two junior high schools located in Taipei and New Taipei City. A total of 553 children ages 8, 11 and 13 years old were included in the analysis. Parameters for obesity, anti- and pro-inflammatory cytokines, and metabolic risk profiles were evaluated. RESULTS: Overweight/obese children had lower serum IL-10 concentrations compared with normal weight children in the same age group (all P < 0.001). IL-10 quartiles were negatively associated with body mass index (BMI) and percentage (%) body fat (all P < 0.05). Multivariate regression analysis showed significant inverse relationship between IL-10 concentrations and % body fat (beta = -0.009, P < 0.0001), and total cholesterol (beta = -0.726, P = 0.003), and a small positive correlation between IL-10 and systolic blood pressure (beta = 0.980, P = 0.027). In normal weight children, IL 10 concentrations were independently associated with fasting plasma insulin (beta = 0.2912, P = 0.001) and waist circumference (beta = 0.0069, P = 0.022). By contrast, % body fat (beta = -0.016, P = 0.0009) was independently associated with IL-10 concentrations in overweight and obese children. Association between IL-10 and fasting plasma insulin concentrations was weaker in overweight/obese children compared with normal weight (beta = 0.283, P = 0.011 vs. beta = 0.2912, P = 0.001). CONCLUSION: Our data indicate that changes in circulating IL-10 concentrations are marker of metabolic risk in children. PMID- 24467775 TI - Mycosis fungoides with CD20 expression: report of two cases and review of the literature. AB - CD20 expression is exceedingly rare in T-cell lymphomas. Most published cases have been diagnosed as peripheral T-cell lymphomas, not otherwise specified. Only 18 cases of CD20-positive mycosis fungoides (MF) have been previously reported. Here, we describe two cases of CD20-positive MF. Patient 1 was an 84-year-old woman who presented with a 5-year history of multiple pruritic erythematous papules coalescing into thin plaques over 80% of her body surface area. She expired after developing tumors and large cell transformation. Patient 2 was a 67 year-old woman with a long-standing history of tumor stage MF with large cell transformation. She developed a nodular plaque while receiving topical and systemic therapy. In both cases, the neoplastic T-cells demonstrated a CD4 positive immunophenotype with loss of pan-T-cell markers and a monoclonal T-cell receptor gamma gene rearrangement. CD20 was expressed by a significant population of the neoplastic T-cells, but these T-cells lacked expression of other B-cell markers, including CD79a, CD19 and PAX5. This report adds to and summarizes the small body of literature describing CD20-positive MF, and discusses diagnostic and clinical implications. PMID- 24467776 TI - The public sector nursing workforce in Kenya: a county-level analysis. AB - BACKGROUND: Kenya's human resources for health shortage is well documented, yet in line with the new constitution, responsibility for health service delivery will be devolved to 47 new county administrations. This work describes the public sector nursing workforce likely to be inherited by the counties, and examines the relationships between nursing workforce density and key indicators. METHODS: National nursing deployment data linked to nursing supply data were used and analyzed using statistical and geographical analysis software. Data on nurses deployed in national referral hospitals and on nurses deployed in non-public sector facilities were excluded from main analyses. The densities and characteristics of the public sector nurses across the counties were obtained and examined against an index of county remoteness, and the nursing densities were correlated with five key indicators. RESULTS: Of the 16,371 nurses in the public non-tertiary sector, 76% are women and 53% are registered nurses, with 35% of the nurses aged 40 to 49 years. The nursing densities across counties range from 1.2 to 0.08 per 1,000 population. There are statistically significant associations of the nursing densities with a measure of health spending per capita (P value = 0.0028) and immunization rates (P value = 0.0018). A higher county remoteness index is associated with explaining lower female to male ratio of public sector nurses across counties (P value <0.0001). CONCLUSIONS: An overall shortage of nurses (range of 1.2 to 0.08 per 1,000) in the public sector countrywide is complicated by mal-distribution and varying workforce characteristics (for example, age profile) across counties. All stakeholders should support improvements in human resources information systems and help address personnel shortages and mal-distribution if equitable, quality health-care delivery in the counties is to be achieved. PMID- 24467777 TI - Factors affecting ethnobotanical knowledge in a mestizo community of the Sierra de Huautla Biosphere Reserve, Mexico. AB - BACKGROUND: Worldwide, mestizo communities' ethnobotanical knowledge has been poorly studied. Based on a mestizo group in Mexico, this study assesses a) the use value (UV) of the local flora, b) gendered differences in plant species, and c) the association between socio-economic variables and ethnobotanical knowledge. METHODS: To assess the degree of knowledge of plant resources, we conducted 41 interviews collecting information on knowledge of local plant resources and the socio-economic situation of the informant. We also collected free listings of useful plants by category of use to identify the UV of each species. With the support of key informants, we photographed and collected the plant material recorded during the interviews and free listings on five different habitats. Paired t-tests and a Wilcoxon signed rank test were used to determine differences in the number of species known by men and women. Differences in distribution were analyzed by means of the Shapiro-Wilk's W normality tests. To determine the association of socio-economic factors and ethnobotanical knowledge, we used a non metric multidimensional scaling analysis (NMDS). RESULTS: Informants listed 185 species. Medicinal plants constituted the most diverse group (90 species). Tropical deciduous forest is the habitat that concentrates the highest proportion of plant resources (80 species). The use-values were classified into three groups: A (4-6 UV; three species), B (0.35-1.37 UV; 39 species) and C (0-0.29 UV; 143 species). High-quality wood species and those associated to religious ceremonies had the highest UV. Women's and men's knowledge of plant species showed statistically significant differences at the interspecific and the intracategorical levels (Student's test, T15 = 4.8, p < 0.001). Occupation, gender and age were statistically significant associated to ethnobotanical knowledge (p < 0.05), whereas income, education level, and place of origin were not. CONCLUSION: This research improves our understanding of the socio-economic activities associated with the intracultural distribution of ethnobotanical knowledge among mestizo Mexican communities. It also provides information on plant resources and habitats and how local peasants value them. This information could help in the development of proposals to improve biocultural conservation and strengthen traditional knowledge systems for effective forest management. PMID- 24467778 TI - Production of a reference transcriptome and transcriptomic database (EdwardsiellaBase) for the lined sea anemone, Edwardsiella lineata, a parasitic cnidarian. AB - BACKGROUND: The lined sea anemone Edwardsiella lineata is an informative model system for evolutionary-developmental studies of parasitism. In this species, it is possible to compare alternate developmental pathways leading from a larva to either a free-living polyp or a vermiform parasite that inhabits the mesoglea of a ctenophore host. Additionally, E. lineata is confamilial with the model cnidarian Nematostella vectensis, providing an opportunity for comparative genomic, molecular and organismal studies. DESCRIPTION: We generated a reference transcriptome for E. lineata via high-throughput sequencing of RNA isolated from five developmental stages (parasite; parasite-to-larva transition; larva; larva to-adult transition; adult). The transcriptome comprises 90,440 contigs assembled from >15 billion nucleotides of DNA sequence. Using a molecular clock approach, we estimated the divergence between E. lineata and N. vectensis at 215-364 million years ago. Based on gene ontology and metabolic pathway analyses and gene family surveys (bHLH-PAS, deiodinases, Fox genes, LIM homeodomains, minicollagens, nuclear receptors, Sox genes, and Wnts), the transcriptome of E. lineata is comparable in depth and completeness to N. vectensis. Analyses of protein motifs and revealed extensive conservation between the proteins of these two edwardsiid anemones, although we show the NF-kappaB protein of E. lineata reflects the ancestral structure, while the NF-kappaB protein of N. vectensis has undergone a split that separates the DNA-binding domain from the inhibitory domain. All contigs have been deposited in a public database (EdwardsiellaBase), where they may be searched according to contig ID, gene ontology, protein family motif (Pfam), enzyme commission number, and BLAST. The alignment of the raw reads to the contigs can also be visualized via JBrowse. CONCLUSIONS: The transcriptomic data and database described here provide a platform for studying the evolutionary developmental genomics of a derived parasitic life cycle. In addition, these data from E. lineata will aid in the interpretation of evolutionary novelties in gene sequence or structure that have been reported for the model cnidarian N. vectensis (e.g., the split NF-kappaB locus). Finally, we include custom computational tools to facilitate the annotation of a transcriptome based on high-throughput sequencing data obtained from a "non-model system." PMID- 24467780 TI - Expanded use of aggressive therapies improves survival in early and intermediate hepatocellular carcinoma. AB - BACKGROUND: Despite the increasing annual incidence of hepatocellular carcinoma (HCC) in the USA, now estimated at 2.7 cases per 100 000 population, only a small proportion of patients receive treatment and 5-year survival rates range from 9% to 17%. OBJECTIVES: The present study examines the effects of multimodal treatment on survival in a mixed-stage HCC cohort, focusing on the impact of radical therapy in patients with Barcelona Clinic Liver Cancer (BCLC) stage B disease. METHODS: A retrospective review of the medical records of 254 patients considered for HCC treatment between 2003 and 2011 at a large tertiary referral centre was conducted. RESULTS: A total of 195 (76.8%) patients were treated with a median of two liver-directed interventions. Median survival time was 16 months. In proportional hazards analysis, radiofrequency ablation (RFA) and resection were associated with significantly improved 1- and 5-year survival among patients with BCLC stage 0-A disease. In patients with BCLC stage B disease, RFA conferred a survival benefit at 1 year and resection was associated with significantly improved survival at 5 years. CONCLUSIONS: As one of few studies to track the complete course of sequential HCC therapies, the findings of the present study suggest that HCC patients with intermediate-stage (BCLC stage B) disease may benefit from aggressive interventions not currently included in societal guidelines. PMID- 24467781 TI - A waitlist-controlled trial of group cognitive behavioural therapy for depression and anxiety in Parkinson's disease. AB - BACKGROUND: The aim of this study was to evaluate the efficacy of a group Cognitive Behavioural Therapy (CBT) treatment for depression and anxiety in Parkinson's disease (PD). METHODS: A waitlist-controlled trial design was used. Eighteen adults with PD and a comorbid DSM-IV-TR diagnosis of depression and/or anxiety were randomised to either Intervention (8-week group CBT treatment) or Waitlist (8-week clinical monitoring preceding treatment). The Depression, Anxiety, Stress Scale-21 (DASS-21) was the primary outcome. Assessments were completed at Time 1 (pretreatment), Time 2 (posttreatment/post-waitlist) and 1 month and 6-month follow-ups. RESULTS: At Time 2, participants who received CBT reported greater reductions in depression (M(change) = -2.45) than Waitlist participants (M(change) = .29) and this effect was large, d = 1.12, p = .011. Large secondary effects on anxiety were also observed for CBT participants, d = .89, p = .025. All treatment gains were maintained and continued to improve during the follow-up period. At 6-month follow-up, significant and large effects were observed for both depression (d = 2.07) and anxiety (d = 2.26). CONCLUSIONS: Group CBT appears to be an efficacious treatment approach for depression and anxiety in PD however further controlled trials with larger numbers of participants are required. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (Trial ID: ACTRN12610000455066). PMID- 24467783 TI - Acute polyarthritis immediately after kidney transplantation: a medication induced rheumatoid arthritis flare? AB - A patient with known steroid-dependent rheumatoid arthritis (RA) developed an acute symmetrical polyarthropathy of small and medium-sized joints associated with markedly elevated inflammatory markers suggestive of RA flare, on day 4 after deceased-donor renal transplantation. The patient received standard induction immunosuppression with methylprednisolone and basiliximab, and had commenced prednisolone, tacrolimus and mycophenolate mofetil. Serological investigations and joint aspirate to exclude infective causes and crystal arthropathy were unremarkable. High-dose prednisolone (50 mg daily) resulted in partial but unsustained symptomatic improvement. On suspicion of a medication related adverse event, tacrolimus and mycophenolate mofetil were changed to cyclosporine A and azathioprine on day 16. This was followed by rapid improvement in symptoms and normalization of inflammatory markers. Unexpected sequelae in the early post-transplantation period create diagnostic and management challenges. Medication-related adverse events are not uncommon, and we speculate in this case on the potential for medication-induced immune system dysregulation stimulating disease activity in a chronic autoimmune condition after introduction of new immunosuppressants. PMID- 24467782 TI - Developmental cues for the maturation of metabolic, electrophysiological and calcium handling properties of human pluripotent stem cell-derived cardiomyocytes. AB - Human pluripotent stem cells (hPSCs), including embryonic and induced pluripotent stem cells, are abundant sources of cardiomyocytes (CMs) for cell replacement therapy and other applications such as disease modeling, drug discovery and cardiotoxicity screening. However, hPSC-derived CMs display immature structural, electrophysiological, calcium-handling and metabolic properties. Here, we review various biological as well as physical and topographical cues that are known to associate with the development of native CMs in vivo to gain insights into the development of strategies for facilitated maturation of hPSC-CMs. PMID- 24467784 TI - Atypical gunshot injury to the right side of the face with the bullet lodged in the carotid sheath: a case report. AB - INTRODUCTION: Gunshot injuries of the head and neck from the AK-47 rifle (a common assault rifle, submachine gun type) are a significant contributor to morbidity and mortality among civilians in Sub-Saharan Africa. They may cause significant damage to the closely arranged structures in this region, and the bullet's trajectory can be very difficult to determine. We present an unusual case of gunshot injury with an atypical bullet entry wound, profound injury to the face, lodgment in the right carotid sheath, and 'wandering'; a first of its kind in East Africa. CASE PRESENTATION: A 27-year-old African-Ugandan woman of Nilotic ethnicity was referred to the Accident and Emergency Department of a tertiary hospital in Uganda, having sustained complex injuries due to an inadvertent AK-47 rifle gunshot injury. The gunshot injury was to the right side of her face with a large ragged entry wound and no exit wound. Prior basic wound care and radiological imaging showed a comminuted fracture of her mandible with lodgment of the bullet in her neck, anterior to her sixth and seventh cervical vertebrae. Standard debridement of her wound was done. A computed tomography scan showed an apparent cephalad shift ('wandering') of the bullet, leaving it lying partially anterior to her fifth cervical vertebra as well as within her carotid sheath. Other injuries were to her facial and trigeminal nerves, and her middle ear. The 'wandering' bullet was successfully removed surgically. It had caused no damage to any part of her neck structure. CONCLUSION: AK-47 rifle bullet injuries may present with uncharacteristically large entry wounds and cause complex structural injuries at the area of impact. The consequent trajectory is difficult to predict making regional examination and radiological investigations essential in management. Bullets may be retained, leaving no exit wound. Securing the airway, controlling hemorrhage and identifying other injuries are the first vital steps. This case illustrates all these interventions and the important decision to extract the entrapped bullet from the patient's neck because it had started to 'wander' and could have caused grave injury over time with further migration. Maxillofacial, plastic, trauma, general and military surgeons, otorhinolaryngologists and emergency physicians can gain from this experience because it calls for a multidisciplinary team approach. PMID- 24467785 TI - Performance selection for Thoroughbreds racing in Hong Kong. AB - REASONS FOR PERFORMING STUDY: Different indicators of racing performance are commonly used in the racing industry to assess the genetic superiority of racing Thoroughbreds. However, how well these indicators predict the performance of future progeny or siblings varies depending on the population and circumstances in which the indicators were recorded or achieved. OBJECTIVES: To identify heritable indicators of racing performance for horses racing in Hong Kong. STUDY DESIGN: Heritability analysis of racing performance traits. METHODS: Performance data on the population of Thoroughbreds racing in Hong Kong between 3 September 2000 and 12 March 2011 (n = 4947) were acquired and used to estimate the heritabilities and probability values of fixed effects and covariates for a range of racing performance traits. Heritabilities for all performance traits were estimated using a single trait animal model. Each model included, as a minimum, the effects of sex, region of origin and trainer. RESULTS: Heritability estimates for traits relating to finish position ranged from 0.01 to 0.06. Average handicap weight had a heritability of 0.07 +/- 0.03. The effects of sex (fixed) and trainer (random) were significant (P<0.05) for all performance traits relating to earnings measures, handicap weights and finish positions. The heritability of win time at 1600 m was 0.52 +/- 0.06 and was the only significant estimate of heritability for win time in the current study. CONCLUSIONS: Although significantly affected by multiple environmental factors, certain indicators of Hong Kong racing performance can be reliably used to predict the performance of the individual's progeny or siblings. However, despite Hong Kong's controlled racing environment, these indicators appear to be no more heritable than in other less controlled racing environments. PMID- 24467793 TI - Institution specific risk factors for 30 day readmission at a community hospital: a retrospective observational study. AB - BACKGROUND: As of October 1, 2012, hospitals in the United States with excess readmissions based on the Centers for Medicare and Medicaid Services (CMS) risk adjusted ratio began being penalized. Given the impact of high readmission rates to hospitals nationally, it is important for individual hospitals to identify which patients may be at highest risk of readmission. The objective of this study was to assess the association of institution specific factors with 30-day readmission. METHODS: The study is a retrospective observational study using administrative data from January 1, 2009 through December 31, 2010 conducted at a 257 bed community hospital in Massachusetts. The patients included inpatient medical discharges from the hospitalist service with the primary diagnoses of congestive heart failure, pneumonia or chronic obstructive pulmonary disease. The outcome was 30-day readmission rates. After adjusting for known factors that impact readmission, provider associated factors (i.e. hours worked and census on the day of discharge) and hospital associated factors (i.e. floor of discharge, season) were compared. RESULTS: Over the study time period, there were 3774 discharges by hospitalists, with 637 30-day readmissions (17% readmission rate). By condition, readmission rates were 19.6% (448/2284) for congestive heart failure, 13.0% (141/1083) for pneumonia, and 14.7% (200/1358) for chronic obstructive lung disease. After adjusting for known risk factors (gender, age, length of stay, Elixhauser sum score, admission in the previous year, insurance, disposition, primary diagnosis), we found that patients discharged in the winter remained significantly more likely to be readmitted compared to the summer (OR 1.54, p = 0.0008). Patients discharged from the cardiac floor had a trend toward decreased readmission compared a medical/oncology floor (OR 0.85, p = 0.08). Hospitalist work flow factors (census and hours on the day of discharge) were not associated with readmission. CONCLUSIONS: We found that 30 day hospital readmissions may be associated with institution specific risk factors, even after adjustment for patient factors. These institution specific risk factors may be targets for interventions to prevent readmissions. PMID- 24467794 TI - The relationship between lateral meniscus shape and joint contact parameters in the knee: a study using data from the Osteoarthritis Initiative. AB - INTRODUCTION: The meniscus has an important role in force transmission across the knee, but a detailed three-dimensional (3D) morphometric shape analysis of the lateral meniscus to elucidate subject-specific function has not been conducted. The aim of this study was to perform 3D morphometric analyses of the lateral meniscus in order to correlate shape variables with anthropometric parameters, thereby gaining a better understanding of the relationship between lateral meniscus shape and its load-bearing function. METHODS: The lateral meniscus (LM) was manually segmented from magnetic resonance images randomly selected from the Osteoarthritis Initiative (OAI) non-exposed control subcohort. A 3D statistical shape model (SSM) was constructed to extract the principal morphological variations (PMV) of the lateral meniscus for 50 subjects (25 male and 25 female). Correlations between the principal morphological variations and anthropometric parameters were tested. Anthropometric parameters that were selected included height, weight, body mass index (BMI), femoral condyle width and axial rotation. RESULTS: The first principal morphological variation (PMV) was found to correlate with height (r = 0.569), weight (r = 0.647), BMI (r = 0.376), and femoral condyle width (r = 0.622). The third PMV was found to correlate with height (r = 0.406), weight (r = 0.312), and femoral condyle width (r = 0.331). The percentage of the tibial plateau covered by the lateral meniscus decreases as anthropometric parameters relating to size of the subject increase. Furthermore, when the size of the subject increases, the posterior and anterior horns become proportionally longer and wider. CONCLUSION: The correlations discovered suggest that variations in meniscal shape can be at least partially explained by the levels of loads transmitted across the knee on a regular basis. Additionally, as the size of the subject increases and body weight rises, the coverage percentage of the meniscus is reduced, suggesting that there would be an increase in the load-bearing by the cartilage. However, this reduced coverage percentage is compensated by the proportionally wider and longer meniscal horn. PMID- 24467796 TI - Chain of commercialization of Podocnemis spp. turtles (Testudines: Podocnemididae) in the Purus River, Amazon basin, Brazil: current status and perspectives. AB - BACKGROUND: Consumption of turtles by natives and settlers in the Amazon and Orinoco has been widely studied in scientific communities. Accepted cultural customs and the local dietary and monetary needs need to be taken into account in conservation programs, and when implementing federal laws related to consumption and fishing methods. This study was conducted around the Purus River, a region known for the consumption and illegal trade of turtles. The objective of this study was to quantify the illegal turtle trade in Tapaua and to understand its effect on the local economy. METHODS: This study was conducted in the municipality of Tapaua in the state of Amazonas, Brazil. To estimate turtle consumption, interviews were conducted over 2 consecutive years (2006 and 2007) in urban areas and isolated communities. The experimental design was randomized with respect to type of household. To study the turtle fishery and trade chain, we used snowball sampling methodology. RESULTS: During our study period, 100% of respondents reported consuming at least three species of turtles (Podocnemis spp.). Our estimates indicate that about 34 tons of animals are consumed annually in Tapaua along the margins of a major fishing river in the Amazon. At least five components related to the chain of commercialization of turtles on the Purus River are identified: Indigenous Apurina and (2) residents of bordering villages (communities); (3) of local smugglers buy and sell turtles to the community in exchange for manufactured goods, and (4) regional smugglers buy in Tapaua, Labrea, and Beruri to sell in Manaus and Manacapuru; Finally, (5) there are professional fishermen. CONCLUSIONS: We quantify the full impact of turtle consumption and advocate the conservation of the region's turtle populations. The Brazilian government should initiate a new turtle consumption management program which involves the opinions of consumers. With these measures the conservation of freshwater turtles in the Brazilian Amazon, is possible. PMID- 24467795 TI - Serum proteomic analysis identifies sex-specific differences in lipid metabolism and inflammation profiles in adults diagnosed with Asperger syndrome. AB - BACKGROUND: The higher prevalence of Asperger Syndrome (AS) and other autism spectrum conditions in males has been known for many years. However, recent multiplex immunoassay profiling studies have shown that males and females with AS have distinct proteomic changes in serum. METHODS: Here, we analysed sera from adults diagnosed with AS (males = 14, females = 16) and controls (males = 13, females = 16) not on medication at the time of sample collection, using a combination of multiplex immunoassay and shotgun label-free liquid chromatography mass spectrometry (LC-MSE). The main objective was to identify sex-specific serum protein changes associated with AS. RESULTS: Multiplex immunoassay profiling led to identification of 16 proteins that were significantly altered in AS individuals in a sex-specific manner. Three of these proteins were altered in females (ADIPO, IgA, APOA1), seven were changed in males (BMP6, CTGF, ICAM1, IL 12p70, IL-16, TF, TNF-alpha) and six were changed in both sexes but in opposite directions (CHGA, EPO, IL-3, TENA, PAP, SHBG). Shotgun LC-MSE profiling led to identification of 13 serum proteins which had significant sex-specific changes in the AS group and, of these, 12 were altered in females (APOC2, APOE, ARMC3, CLC4K, FETUB, GLCE, MRRP1, PTPA, RN149, TLE1, TRIPB, ZC3HE) and one protein was altered in males (RGPD4). The free androgen index in females with AS showed an increased ratio of 1.63 compared to controls. CONCLUSION: Taken together, the serum multiplex immunoassay and shotgun LC-MSE profiling results indicate that adult females with AS had alterations in proteins involved mostly in lipid transport and metabolism pathways, while adult males with AS showed changes predominantly in inflammation signalling. These results provide further evidence that the search for biomarkers or novel drug targets in AS may require stratification into male and female subgroups, and could lead to the development of novel targeted treatment approaches. PMID- 24467797 TI - What do popular Spanish women's magazines say about caesarean section? A 21-year survey. AB - OBJECTIVES: Caesarean section (CS) rates are increasing worldwide and maternal request is cited as one of the main reasons for this trend. Women's preferences for route of delivery are influenced by popular media, including magazines. We assessed the information on CS presented in Spanish women's magazines. DESIGN: Systematic review. SETTING: Women's magazines printed from 1989 to 2009 with the largest national distribution. SAMPLE: Articles with any information on CS. METHODS: Articles were selected, read and abstracted in duplicate. Sources of information, scientific accuracy, comprehensiveness and women's testimonials were objectively extracted using a content analysis form designed for this study. MAIN OUTCOME MEASURES: Accuracy, comprehensiveness and sources of information. RESULTS: Most (67%) of the 1223 selected articles presented exclusively personal opinion/birth stories, 12% reported the potential benefits of CS, 26% mentioned the short-term and 10% mentioned the long-term maternal risks, and 6% highlighted the perinatal risks of CS. The most frequent short-term risks were the increased time for maternal recovery (n = 86), frustration/feelings of failure (n = 83) and increased post-surgical pain (n = 71). The most frequently cited long-term risks were uterine rupture (n = 57) and the need for another CS in any subsequent pregnancy (n = 42). Less than 5% of the selected articles reported that CS could increase the risks of infection (n = 53), haemorrhage (n = 31) or placenta praevia/accreta in future pregnancies (n = 6). The sources of information were not reported by 68% of the articles. CONCLUSIONS: The portrayal of CS in Spanish women's magazines is not sufficiently comprehensive and does not provide adequate important information to help the readership to understand the real benefits and risks of this route of delivery. PMID- 24467798 TI - The need for a comprehensive approach to managing confined space entry: summary of the literature and recommendations for next steps. AB - Despite all the regulatory and standard-setting efforts that have been made in North America, judging from the most recent statistics many fatal incidents related to work in confined spaces still occur. In Canada, fatal incidents in the province of Quebec reveal failures in and absence of the identification and preparation of work situations in confined spaces and in risk management. In this study, we performed a literature review consisting of 77 documents on existing hazards and risk assessment for confined spaces. Moreover, we formulated proposals regarding the design of specific and improved tools for assessing such risks. We found that atmospheric hazards monopolized attention in the literature on confined spaces, while risk estimation specific to confined space interventions received little practical coverage overall, apart from atmospheric hazards. The parameters used to establish classes or groupings of confined spaces in existing tools were imprecise. The development of a risk analysis process that is (i) more systematic and based on the concepts recognized in risk management standards, (ii) multidisciplinary, and (iii) adapted to the specific characteristics of confined spaces is therefore needed. Such a process will better support managers and occupational health and safety (OH&S) personnel in their efforts to prioritize and reduce risks. Suggestions on such a risk analysis tool and categorization of interventions in confined spaces are proposed in this article. Lastly, risk analysis tools adapted to confined space interventions are needed to ensure the inherently safe design of these spaces. PMID- 24467799 TI - [The new classification criteria for systemic lupus erythematosus (SLICC)]. PMID- 24467800 TI - Successful treatment of enterohemorrhagic Escherichia coli O111-induced acute encephalopathy and hemolytic-uremic syndrome with plasma diafiltration. PMID- 24467801 TI - Finger soft tissue myoepithelioma: a rare entity. PMID- 24467802 TI - Effectiveness of a worksite mindfulness-based multi-component intervention on lifestyle behaviors. AB - INTRODUCTION: Overweight and obesity are associated with an increased risk of morbidity. Mindfulness training could be an effective strategy to optimize lifestyle behaviors related to body weight gain. The aim of this study was to evaluate the effectiveness of a worksite mindfulness-based multi-component intervention on vigorous physical activity in leisure time, sedentary behavior at work, fruit intake and determinants of these behaviors. The control group received information on existing lifestyle behavior- related facilities that were already available at the worksite. METHODS: In a randomized controlled trial design (n = 257), 129 workers received a mindfulness training, followed by e coaching, lunch walking routes and fruit. Outcome measures were assessed at baseline and after 6 and 12 months using questionnaires. Physical activity was also measured using accelerometers. Effects were analyzed using linear mixed effect models according to the intention-to-treat principle. Linear regression models (complete case analyses) were used as sensitivity analyses. RESULTS: There were no significant differences in lifestyle behaviors and determinants of these behaviors between the intervention and control group after 6 or 12 months. The sensitivity analyses showed effect modification for gender in sedentary behavior at work at 6-month follow-up, although the main analyses did not. CONCLUSIONS: This study did not show an effect of a worksite mindfulness-based multi-component intervention on lifestyle behaviors and behavioral determinants after 6 and 12 months. The effectiveness of a worksite mindfulness-based multi-component intervention as a health promotion intervention for all workers could not be established. PMID- 24467803 TI - The future in the past: Hildegard Peplau and interpersonal relations in nursing. AB - Researchers, educators and clinicians have long recognized the profound influence of the mid-twentieth century focus on interpersonal relations and relationships on nursing. Today, in nursing, as well as in medicine and other social sciences, neuroanatomy, neurobiology and neurophysiology have replaced interpersonal dynamics as keys to understanding human behavior. Yet concerns are being raised that the teaching, research and practice of the critical importance of healing relationships have been overridden by a biological focus on the experiences of health and illness. As a way to move forward, we return to Hildegard Peplau's seminal ideas about the transformative power of relationships in nursing. We propose that Peplau's formulations and, in particular, her seminal Interpersonal Relations in Nursing can provide direction. We do not propose that her formulations or her book be simply transposed from the 1950s to today's classroom and clinic. But we do believe that her ideas and writings are dynamic documents containing concepts and derived operations that can be brought to life in clinical practice. Finally, we explore Peplau's transformative idea that nursing is, at its core, an interpersonal process both to acknowledge an idea that has shaped our past and can guide us into our future. PMID- 24467806 TI - Maxillary sinus atelectasis (silent sinus syndrome): treatment with balloon sinuplasty. AB - INTRODUCTION: Maxillary sinus atelectasis is a form of chronic rhinosinusitis of uncertain aetiology. Previously, the conventional treatment for this condition has been standard endoscopic surgery. There are no reports in the literature of successful treatment using balloon sinuplasty. METHODS: A case of a patient with right maxillary sinus atelectasis is presented, who was treated using the balloon sinuplasty technique. RESULTS: The patient's right maxillary sinus atelectasis was successfully treated using balloon sinuplasty. Three-month follow-up evaluation documented retention of the remodelled form of the uncinate process, and of maxillary sinus os patency. CONCLUSION: This is the first report of successful use of the balloon sinuplasty technique for the treatment of maxillary sinus atelectasis. Follow up demonstrated resolution of the underlying pathophysiology. Further study of the balloon sinuplasty technique for the treatment of maxillary sinus atelectasis is required to determine whether it has widespread applicability, given the current standard treatment. PMID- 24467804 TI - ABO-incompatible living donor liver transplantation without graft local infusion and splenectomy. AB - BACKGROUND: Graft local infusion and splenectomy in ABO-incompatible (ABO-I) living donor liver transplantation (LDLT) are associated with high rates of operative complications. METHODS: Consecutive ABO-I LDLT patients treated at the National Cancer Centre between January 2012 and February 2013 were identified. The protocol for ABO-I LDLT at the study centre included the administration of rituximab (300 mg/m(2)) at 2 weeks preoperatively, followed by plasma exchanges (target isoagglutinin titre: <= 1:8), basiliximab (20 mg on the day of surgery and on postoperative day 4), and i.v. immunoglobulin (0.8 g/kg on postoperative days 1 and 4) without graft local infusion or splenectomy. RESULTS: Fifteen patients (11 men and four women) who underwent transplantation for liver cirrhosis (n = 3) or hepatocellular carcinoma (n = 12) were identified. These included 13 patients with hepatitis B virus infection, one with hepatitis C virus infection and one with alcoholic cirrhosis. The mean age, mean Model for End stage Liver Disease (MELD) score and mean graft-to-recipient weight ratio (GRWR) of these patients was 51.8 years, 11.5 and 0.84, respectively. The median isoagglutinin titre before plasma exchange was 1:32 (range: 1:4 to 1:256). There were no hyperacute or antibody-mediated rejections. No bacterial or fungal infections were observed. Complications included herpes zoster viral infection in one patient, postoperative bleeding in one patient and extrahepatic biliary stricture in three patients. CONCLUSIONS: This simplified ABO-I LDLT protocol showed good graft outcomes without immunologic failure or serious infections. PMID- 24467805 TI - The global effect of follicle-stimulating hormone and tumour necrosis factor alpha on gene expression in cultured bovine ovarian granulosa cells. AB - BACKGROUND: Oocytes mature in ovarian follicles surrounded by granulosa cells. During follicle growth, granulosa cells replicate and secrete hormones, particularly steroids close to ovulation. However, most follicles cease growing and undergo atresia or regression instead of ovulating. To investigate the effects of stimulatory (follicle-stimulating hormone; FSH) and inhibitory (tumour necrosis factor alpha; TNFalpha) factors on the granulosa cell transcriptome, bovine ovaries were obtained from a local abattoir and pools of granulosa cells were cultured in vitro for six days under defined serum-free conditions with treatments present on days 3-6. Initially dose-response experiments (n = 4) were performed to determine the optimal concentrations of FSH (0.33 ng/ml) and TNFalpha (10 ng/ml) to be used for the microarray experiments. For array experiments cells were cultured under control conditions, with FSH, with TNFalpha, or with FSH plus TNFalpha (n = 4 per group) and RNA was harvested for microarray analyses. RESULTS: Statistical analysis showed primary clustering of the arrays into two groups, control/FSH and TNFalpha/TNFalpha plus FSH. The effect of TNFalpha on gene expression dominated that of FSH, with substantially more genes differentially regulated, and the pathways and genes regulated by TNFalpha being similar to those of FSH plus TNFalpha treatment. TNFalpha treatment reduced the endocrine activity of granulosa cells with reductions in expression of FST, INHA, INBA and AMH. The top-ranked canonical pathways and GO biological terms for the TNFalpha treatments included antigen presentation, inflammatory response and other pathways indicative of innate immune function and fibrosis. The two most significant networks also reflect this, containing molecules which are present in the canonical pathways of hepatic fibrosis/hepatic stellate cell activation and transforming growth factor beta signalling, and these were up regulated. Upstream regulator analyses also predicted TNF, interferons gamma and beta1 and interleukin 1beta. CONCLUSIONS: In vitro, the transcriptome of granulosa cells responded minimally to FSH compared with the response to TNFalpha. The response to TNFalpha indicated an active process akin to tissue remodelling as would occur upon atresia. Additionally there was reduction in endocrine function and induction of an inflammatory response to TNFalpha that displays features similar to immune cells. PMID- 24467807 TI - Reducing symptoms of major depressive disorder through a systematic training of general emotion regulation skills: protocol of a randomized controlled trial. AB - BACKGROUND: Major Depressive Disorder is one of the most challenging mental health problems of our time. Although effective psychotherapeutic treatments are available, many patients fail to demonstrate clinically significant improvements. Difficulties in emotion regulation have been identified as putative risk and maintaining factors for Major Depressive Disorder. Systematically enhancing adaptive emotion regulation skills should thus help reduce depressive symptom severity. However, at this point, no study has systematically evaluated effects of increasing adaptive emotion regulation skills application on symptoms of Major Depressive Disorder. In the intended study, we aim to evaluate stand-alone effects of a group-based training explicitly and exclusively targeting general emotion regulation skills on depressive symptom severity and assess whether this training augments the outcome of subsequent individual cognitive behavioral therapy for depression. METHODS/DESIGN: In the evaluation of the Affect Regulation Training, we will conduct a prospective randomized-controlled trial. Effects of the Affect Regulation Training on depressive symptom severity and outcomes of subsequent individual therapy for depression will be compared with an active, common factor based treatment and a waitlist control condition. The study sample will include 120 outpatients meeting criteria for Major Depressive Disorder. Depressive symptom severity as assessed by the Hamilton Rating Scale will serve as our primary study outcome. Secondary outcomes will include further indicators of mental health and changes in adaptive emotion regulation skills application. All outcomes will be assessed at intake and at 10 points in time over the course of the 15-month study period. Measures will include self-reports, observer ratings, momentary ecological assessments, and will be complemented in subsamples by experimental investigations and the analysis of hair steroids. DISCUSSION: If findings should support the hypothesis that enhancing regulation skills reduces symptom severity in Major Depressive Disorder, systematic emotion regulation skills training can enhance the efficacy and efficiency of current treatments for this severe and highly prevalent disorder. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov, number NCT01330485. PMID- 24467808 TI - Ruptured aneurysm at the fenestration of the middle cerebral artery detected by magnetic resonance angiography in a patient with systemic lupus erythematosus and renal failure: a case report. AB - INTRODUCTION: A cerebral aneurysm arising at the fenestration of the middle cerebral artery is extremely rare, with one report describing subarachnoid hemorrhage due to this type of lesion. There have been no reports of this type of lesion occurring in a patient with systemic lupus erythematosus. CASE PRESENTATION: A 47-year-old Japanese woman with 23 years' history of systemic lupus erythematosus and chronic renal failure had sudden onset of subarachnoid hemorrhage. We avoided using contrast medium due to her chronic renal failure. Magnetic resonance angiography showed her ruptured aneurysm arising at the site of fenestration of her middle cerebral artery. Successful clipping, perioperative management avoiding the cerebral vasospasm, renal dialysis initiated after the acute phase and placement of a ventriculoperitoneal shunt were performed, and she was discharged home with no complications. CONCLUSIONS: This is the first report of ruptured aneurysm associated with middle cerebral artery fenestration in a patient with systemic lupus erythematosus as detected by magnetic resonance angiography. The presence and anatomical relationship of fenestration accompanied by aneurysm could be noninvasively and accurately evaluated preoperatively using three-dimensional time-of-flight magnetic resonance angiography with the volume rendering method in a case in which contrast medium was contraindicated. PMID- 24467809 TI - Fucosyltransferase 1 mediates angiogenesis, cell adhesion and rheumatoid arthritis synovial tissue fibroblast proliferation. AB - INTRODUCTION: We previously reported that sialyl Lewis(y), synthesized by fucosyltransferases, is involved in angiogenesis. Fucosyltransferase 1 (fut1) is an alpha(1,2)-fucosyltransferase responsible for synthesis of the H blood group and Lewis(y) antigens. However, the angiogenic involvement of fut 1 in the pathogenesis of rheumatoid arthritis synovial tissue (RA ST) has not been clearly defined. METHODS: Assay of alpha(1,2)-linked fucosylated proteins in RA was performed by enzyme-linked lectin assay. Fut1 expression was determined in RA ST samples by immunohistological staining. We performed angiogenic Matrigel assays using a co-culture system of human dermal microvascular endothelial cells (HMVECs) and fut1 small interfering RNA (siRNA) transfected RA synovial fibroblasts. To determine if fut1 played a role in leukocyte retention and cell proliferation in the RA synovium, myeloid THP-1 cell adhesion assays and fut1 siRNA transfected RA synovial fibroblast proliferation assays were performed. RESULTS: Total alpha(1,2)-linked fucosylated proteins in RA ST were significantly higher compared to normal (NL) ST. Fut1 expression on RA ST lining cells positively correlated with ST inflammation. HMVECs from a co-culture system with fut1 siRNA transfected RA synovial fibroblasts exhibited decreased endothelial cell tube formation compared to control siRNA transfected RA synovial fibroblasts. Fut1 siRNA also inhibited myeloid THP-1 adhesion to RA synovial fibroblasts and RA synovial fibroblast proliferation. CONCLUSIONS: These data show that alpha(1,2)-linked fucosylated proteins are upregulated in RA ST compared to NL ST. We also show that fut1 in RA synovial fibroblasts is important in angiogenesis, leukocyte-synovial fibroblast adhesion, and synovial fibroblast proliferation, all key processes in the pathogenesis of RA. PMID- 24467810 TI - Association of early-onset dementia with activities of daily living (ADL) in middle-aged adults with intellectual disabilities: the caregiver's perspective. AB - Few studies have investigated in detail which factors influence activities of daily living (ADL) in adults with intellectual disabilities (ID) comorbid with/without dementia conditions. The objective of the present study was to describe the relation between early onset dementia conditions and progressive loss of ADL capabilities and to examine the influence of dementia conditions and other possible factors toward ADL scores in adults with ID. This study was part of the "Healthy Aging Initiatives for Persons with an Intellectual Disability in Taiwan: A Social Ecological Approach" project. We analyzed data from 459 adults aged 45 years or older with an ID regarding their early onset symptoms of dementia and their ADL profile based on the perspective of the primary caregivers. Results show that a significant negative correlation was found between dementia score and ADL score in a Pearson's correlation test (r=-0.28, p<0.001). The multiple linear regression model reported that factors of male gender (beta=4.187, p<0.05), marital status (beta=4.79, p<0.05), education level (primary: beta=5.544, p<0.05; junior high or more: beta=8.147, p<0.01), Down's syndrome (beta=-9.290, p<0.05), severe or profound disability level (beta=-6.725, p<0.05; beta=-15.773, p<0.001), comorbid condition (beta=-4.853, p<0.05) and dementia conditions (beta=-9.245, p<0.001) were variables that were able to significantly predict the ADL score (R(2)=0.241) after controlling for age. Disability level and comorbidity can explain 10% of the ADL score variation, whereas dementia conditions can only explain 3% of the ADL score variation in the study. The present study highlights that future studies should scrutinize in detail the reasons for the low explanatory power of dementia for ADL, particularly in examining the appropriateness of the measurement scales for dementia and ADL in aging adults with ID. PMID- 24467811 TI - Onset aging conditions of adults with an intellectual disability associated with primary caregiver depression. AB - Caregivers of adults with an intellectual disability experience depressive symptoms, but the aging factors of the care recipients associated with the depressive symptoms are unknown. The objective of this study was to analyze the onset aging conditions of adults with an intellectual disability that associated with the depression scores of their primary caregivers. A cross-sectional survey was administered to gather information from 455 caregivers of adults with an intellectual disability about their symptoms of depression which assessed by a 9 item Patient Health Questionnaire (PHQ-9). The 12 aging conditions of adults with an intellectual disability include physical and mental health. The results indicate that 78% of adults with an intellectual disability demonstrate aging conditions. Physical conditions associated with aging include hearing decline (66.3%), vision decline (63.6%), incontinence (44%), articulation and bone degeneration (57.9%), teeth loss (80.4), physical strength decline (81.2%), sense of taste and smell decline (52.8%), and accompanied chronic illnesses (74.6%). Mental conditions associated with aging include memory loss (77%), language ability deterioration (74.4%), poor sleep quality (74.2%), and easy onset of depression and sadness (50.3%). Aging conditions of adults with an intellectual disability (p<0.001) was one factor that significantly affected the presence of depressive symptom among caregivers after controlling demographic characteristics. Particularly, poor sleep quality of adults with an intellectual disability (yes vs. no, OR=3.807, p=0.002) was statistically correlated to the occurrence of significant depressive symptoms among their caregivers. This study suggests that the authorities should reorient community services and future policies toward the needs of family caregivers to decrease the burdens associated with caregiving. PMID- 24467812 TI - Ethnopharmacological practices by livestock farmers in Uganda: survey experiences from Mpigi and Gulu districts. AB - BACKGROUND: There is continued reliance on conventional veterinary drugs including anthelmintics, to some of which resistance has developed. Loss of indigenous technical knowledge (ITK) from societies affects the opportunities for utilization of ethnopharmacological practices unless properly documented. This study was conducted to identify common traditional practices using medicinal plants against helminthosis and other livestock diseases in Mpigi and Gulu districts of Uganda. METHODS: Seven focus group discussions with ten farmers per group plus 18 key informant interviews were held in each district from August to November 2011. Ranking was used to quantify disease burdens and to identify priority livestock and breeds. Samples of each plant were submitted to Makerere University herbarium for identification and documentation. The local name, relative availability and International Union for Conservation of Nature (IUCN) status were recorded. RESULTS: Seventy six farmers in Mpigi and 74 in Gulu were interviewed. Theileriosis and helminthosis were the most common disease conditions in cattle and goats, respectively. Forty plant species within 34 genera from 22 botanical families were identified, with 20 of these used against helminthosis. Other plants treated wounds and ecto-parasites, theileriosis, retained placenta and bovine ephemeral fever. Non-plant practices (7) and plants cited were used in combination depending on availability. Males older than 40 years had most ethnopharmacological knowledge. Most plants (75%, n = 40) were common, but 10 were rare. IUCN status was not evaluated for 95% of these plants. Conventional and traditional drug use in Gulu and Mpigi districts was different (chi2 = 24; p < 0.001). The scientific, English, Luganda and Acholi names of all plants and their availability within the communities are documented herein. CONCLUSION: This is the first detailed livestock-related ethnopharmacological study in Gulu district. Farmers in Uganda are still using a variety of practices to treat livestock ailments. Scientific validation and evaluation of conservation status are urgently needed to ensure future availability and knowledge about these plant resources. PMID- 24467813 TI - Assessing the validity of prospective hazard analysis methods: a comparison of two techniques. AB - BACKGROUND: Prospective Hazard Analysis techniques such as Healthcare Failure Modes and Effects Analysis (HFMEA) and Structured What If Technique (SWIFT) have the potential to increase safety by identifying risks before an adverse event occurs. Published accounts of their application in healthcare have identified benefits, but the reliability of some methods has been found to be low. The aim of this study was to examine the validity of SWIFT and HFMEA by comparing their outputs in the process of risk assessment, and comparing the results with risks identified by retrospective methods. METHODS: The setting was a community-based anticoagulation clinic, in which risk assessment activities had been previously performed and were available. A SWIFT and an HFMEA workshop were conducted consecutively on the same day by experienced experts. Participants were a mixture of pharmacists, administrative staff and software developers. Both methods produced lists of risks scored according to the method's procedure. Participants' views about the value of the workshops were elicited with a questionnaire. RESULTS: SWIFT identified 61 risks and HFMEA identified 72 risks. For both methods less than half the hazards were identified by the other method. There was also little overlap between the results of the workshops and risks identified by prior root cause analysis, staff interviews or clinical governance board discussions. Participants' feedback indicated that the workshops were viewed as useful. CONCLUSIONS: Although there was limited overlap, both methods raised important hazards. Scoping the problem area had a considerable influence on the outputs. The opportunity for teams to discuss their work from a risk perspective is valuable, but these methods cannot be relied upon in isolation to provide a comprehensive description. Multiple methods for identifying hazards should be used and data from different sources should be integrated to give a comprehensive view of risk in a system. PMID- 24467815 TI - Testing the accuracy of the two-dimensional object model in HAADF STEM. AB - In high-angle annular dark-field scanning transmission electron microscopy (HAADF STEM) the two-dimensional (2D) object-function approximation and image convolution model is often used to describe the recorded image data from on-axis crystalline samples. In this model the sample, represented by an object function with sharp peaks at the atomic column positions, is convolved with the 2D point spread function (PSF) of the focussed STEM illumination. In this work the validity of the assumption that the object can be considered as 2D is evaluated experimentally through the use of HAADF-STEM focal-series from MgO smoke cubes. The intensity of laterally resolved image-information is evaluated using Fourier transforms and is tracked with respect to defocus. The experimental results are compared with the expected depth resolution capabilities of simulated STEM probes to yield the normalised or 'apparent thickness' of the samples. The 2D object function and image convolution models are found to hold for sample thicknesses of up to 250 nm. As the 2D object model holds true for each individual frame in a recorded focal series, we can hence express the focal-series as a whole as the convolution of a 2D object function with a 3D probe function with implications for both the diagnosis of remnant aberrations and also image reconstruction. PMID- 24467814 TI - Identification of rare DNA sequence variants in high-risk autism families and their prevalence in a large case/control population. AB - BACKGROUND: Genetics clearly plays a major role in the etiology of autism spectrum disorders (ASDs), but studies to date are only beginning to characterize the causal genetic variants responsible. Until recently, studies using multiple extended multi-generation families to identify ASD risk genes had not been undertaken. METHODS: We identified haplotypes shared among individuals with ASDs in large multiplex families, followed by targeted DNA capture and sequencing to identify potential causal variants. We also assayed the prevalence of the identified variants in a large ASD case/control population. RESULTS: We identified 584 non-conservative missense, nonsense, frameshift and splice site variants that might predispose to autism in our high-risk families. Eleven of these variants were observed to have odds ratios greater than 1.5 in a set of 1,541 unrelated children with autism and 5,785 controls. Three variants, in the RAB11FIP5, ABP1, and JMJD7-PLA2G4B genes, each were observed in a single case and not in any controls. These variants also were not seen in public sequence databases, suggesting that they may be rare causal ASD variants. Twenty-eight additional rare variants were observed only in high-risk ASD families. Collectively, these 39 variants identify 36 genes as ASD risk genes. Segregation of sequence variants and of copy number variants previously detected in these families reveals a complex pattern, with only a RAB11FIP5 variant segregating to all affected individuals in one two-generation pedigree. Some affected individuals were found to have multiple potential risk alleles, including sequence variants and copy number variants (CNVs), suggesting that the high incidence of autism in these families could be best explained by variants at multiple loci. CONCLUSIONS: Our study is the first to use haplotype sharing to identify familial ASD risk loci. In total, we identified 39 variants in 36 genes that may confer a genetic risk of developing autism. The observation of 11 of these variants in unrelated ASD cases further supports their role as ASD risk variants. PMID- 24467816 TI - Epidemiology of human adenovirus and molecular characterization of human adenovirus 55 in China, 2009-2012. AB - BACKGROUND: Human adenovirus 55 (HAdV-55) has caused recent outbreaks of acute respiratory disease (ARD) among adults and military trainees. The active surveillance for HAdV infections was sparse in China, and current knowledge on the HAdV-type distributions and its molecular evolution is lacking. OBJECTIVES: To acquire better understanding on the prevalence and molecular evolution of HAdV 55 strains in China, for an informed strategy for disease control and prevention. POPULATION/METHODS: Nasopharyngeal aspirates were collected from hospitalized children with ARTI in Chongqing during 2009-2012. The genotype of HAdV isolates were determined by sequencing the partial hexon and fiber genes. Whole genome sequences of HAdV-55 were obtained for molecular evolution analysis. RESULTS: About 191 (8.55%) HAdV were detected in 2234 children, including 92 (48.2%) with HAdV-7, 72 (37.7%) with HAdV-3, 6 (3.1%) with HAdV-55, 5 (2.6%) with HAdV-5, 4 (2.1%) with HAdV-1, 1 (0.5%) with HAdV-2, and 11(5.8%) with untyped HAdV. Four of these children developed pneumonia, two of whom were diagnosed with severe pneumonia and/or encephalopathy. HAdV-55 isolates clustered with HAdV-11 sequences based on the hexon gene and clustered with HAdV-14 sequences based on the fiber gene and the whole genome. The overall evolutionary rates of hexon gene, fiber gene, and whole genome of HAdV-55 were estimated at 6.2 * 10(-5) s/s/y, 8.0 * 10(-5 ) s/s/y, and 1.7 * 10(-5) s/s/y, respectively. CONCLUSIONS: This study suggested HAdV-55 as an emerging infectious disease pathogen has conserved genetic structure and is closely related to each other. Further molecular investigation based on HAdV-55 of wider origin might facilitate understanding its diversity, dissemination, and transmission in China. PMID- 24467817 TI - Hypomania and mania related to dopamine replacement therapy in Parkinson's disease. AB - OBJECTIVES: To investigate hypomania and mania related to dopamine replacement therapy (DRT) in Parkinson's disease (PD). METHODS: We recruited 108 non-demented PD patients without deep brain stimulation from a movement disorders in and outpatient clinic. Forty-five age- and gender-matched controls were also included. Disease characteristics, cognitive functioning, comorbid psychiatric diseases, dopaminergic and psychiatric medication were evaluated. Diagnosis of DRT-related hypomania and mania was based on DSM-IV-TR criteria with supplementary assessment of two mania self-rating scales. First, patients and controls were compared. Patients with DRT-related hypomania or mania were then compared to the remaining patients. A binary logistic regression analysis was performed to identify correlates of DRT-related hypomania. RESULTS: Patients scored significantly higher on mania self-rating scales than controls. Twelve patients (11.1%) had DRT-related hypomania and six patients (5.6%) had DRT related mania. Both groups had significantly higher self-rating mania-scores than patients without these mood states. DRT-related hypomania was significantly related to younger age, younger age at PD onset, dyskinesias, higher levodopa equivalent daily dose, dopamine dysregulation, and amantadine treatment. In contrast, DRT-related mania was significantly associated with hallucinations and delusions, history of levodopa-induced psychosis, quetiapine treatment, higher depression and daily levodopa dose, and cognitive deficits. Regression analysis revealed dopamine dysregulation, dyskinesias, amantadine treatment, and younger age at PD onset as significant correlates of DRT-related hypomania. CONCLUSION: DRT-related hypomania and mania are relevant comorbidities in PD. DRT-related hypomania may exist as a distinct psychiatric symptom complex in young patients with early disease onset. Different patient profiles likely underlie DRT-related hypomania and mania. PMID- 24467818 TI - Cognitive functions in Parkinson's disease: relation to disease severity and hallucination. AB - OBJECTIVE: We wished to relate severity of Parkinson's disease (PD) with cognitive function in relation to cerebral blood flow (CBF). METHODS: Eighty-one consecutive PD patients were enrolled in this study. We used Mini-Mental State Examination (MMSE) and Wechsler Adult Intelligence Scale-Third edition (WAIS-III) to evaluate cognitive functions, and three-dimensional stereotactic ROI template (3DSRT) and Statistical Parametric Mapping (SPM) 8 to evaluate single photon emission CT (SPECT) recordings of regional CBF. RESULTS: The mean MMSE score of PD patients was 27.4 +/- 2.4. The scores of most patients were higher than 23/30. On the other hand, the mean Full-scale IQ of PD patients was 88.4 +/- 17.3 in WAIS-III, which was lower than that of normal controls. In particular, visuospatial function score of most patients was lower. There was significant correlation between cognitive scores and Hoehn & Yahr stage and hallucinatory episodes. PD Patients with stage III and IV showed significant deterioration in cognitive functions compared to stage II patients. Analysis of CBF revealed relative reductions in perfusion in the cerebral cortex relative to that in normal control. SPM 8 showed that cognitive functions in PD patients were positively correlated with rCBF in the thalamus and cingulate gyrus. CONCLUSIONS: This is the study to demonstrate the cognitive impairments in PD patients using WAIS-III. Visuospatial dysfunction might be caused by decrease in rCBF in the parietal and occipital lobes and dorsolateral prefrontal cortex. The severity of cognitive impairments in PD patients was correlated with disease severity and hallucinatory episodes. PMID- 24467819 TI - Serosurvey of Schmallenberg Virus Infection in the Highest Goat-Specialized Region of France. AB - The monitoring of both the spread and clinical impact of Schmallenberg virus (SBV) infection within its full host range is important for the control of the epidemic and potential new outbreaks. In France, a national surveillance plan based on voluntary notifications of congenital malformations in newborn ruminants revealed that goats were the less affected host species. However, seroprevalence studies only targeted sheep and cattle, preventing accurate estimations of the real impact of SBV infection in goats. Here, a serological survey was conducted in the highest goat-specialized region of France between June 2012 and January 2013. A total of 1490 goat sera from 50 herds were analysed by ELISA. The between herd and within-herd prevalences were estimated at 62% and 13.1%, respectively. Seroprevalence was not uniformly distributed throughout the territory and markedly differed between intensive and extensive herds. The low within-herd seroprevalence demonstrates that a large fraction of the French goat population remains susceptible to SBV infection. PMID- 24467820 TI - Familial myelodysplastic syndrome/acute leukemia syndromes: a review and utility for translational investigations. AB - The familial myelodysplastic (MDS)/acute leukemia (AL) predisposition syndromes are inherited disorders that lead to significantly increased lifetime risks of MDS and AL development. At present, four recognized syndromes have Clinical Laboratory Improvement Amendments--certified testing for their respective germ line mutations: telomere biology disorders due to mutation of TERC or TERT, familial acute myeloid leukemia (AML) with mutated CEBPA, familial MDS/AML with mutated GATA2, and familial platelet disorder with propensity to myeloid malignancy. These disorders are heterogeneous with regard to their causative genetic mutations, clinical presentation, and progression to MDS/AL. However, as a group, they all share the unique requirement for a high index of clinical suspicion to allow appropriate genetic counseling, genetic testing, and mutation specific clinical management. In addition, translational investigations of individuals and families with these syndromes provide a rare opportunity to understand key pathways underlying susceptibility and progression to MDS/AL and allow the possibility of novel strategies for the prevention and treatment of both familial and sporadic forms of MDS/AL. PMID- 24467821 TI - Survivin-responsive conditionally replicating adenovirus kills rhabdomyosarcoma stem cells more efficiently than their progeny. AB - BACKGROUND: Effective methods for eradicating cancer stem cells (CSCs), which are highly tumorigenic and resistant to conventional therapies, are urgently needed. Our previous studies demonstrated that survivin-responsive conditionally replicating adenoviruses regulated with multiple factors (Surv.m-CRAs), which selectively replicate in and kill a broad range of cancer-cell types, are promising anticancer agents. Here we examined the therapeutic potentials of a Surv.m-CRA against rhabdomyosarcoma stem cells (RSCs), in order to assess its clinical effectiveness and usefulness. METHODS: Our previous study demonstrated that fibroblast growth factor receptor 3 (FGFR3) is a marker of RSCs. We examined survivin mRNA levels, survivin promoter activities, relative cytotoxicities of Surv.m-CRA in RSC-enriched (serum-minus) vs. RSC-exiguous (serum-plus) and FGFR3 positive vs. FGFR3-negative sorted rhabdomyosarcoma cells, and the in vivo therapeutic effects of Surv.m-CRAs on subcutaneous tumors in mice. RESULTS: Both survivin mRNA levels and survivin promoter activities were significantly elevated under RSC-enriched relative to RSC-exiguous culture conditions, and the elevation was more prominent in FGFR3-positive vs. FGFR3-negative sorted cells than in RSC enriched vs. RSC-exiguous conditions. Although Surv.m-CRA efficiently replicated and potently induced cell death in all populations of rhabdomyosarcoma cells, the cytotoxic effects were more pronounced in RSC-enriched or RSC-purified cells than in RSC-exiguous or progeny-purified cells. Injections of Surv.m-CRAs into tumor nodules generated by transplanting RSC-enriched cells induced significant death of rhabdomyosarcoma cells and regression of tumor nodules. CONCLUSIONS: The unique therapeutic features of Surv.m-CRA, i.e., not only its therapeutic effectiveness against all cell populations but also its increased effectiveness against CSCs, suggest that Surv.m-CRA is promising anticancer agent. PMID- 24467822 TI - Nursing under the skin: a netnographic study of metaphors and meanings in nursing tattoos. AB - The aims of this study were to present themes in nursing motifs as depicted in tattoos and to describe how it reflects upon nursing in popular culture as well as within professional nursing culture. An archival and cross-sectional observational study was conducted online to search for images of nursing tattoos that were freely available, by utilizing the netnographic methodology. The 400 images were analyzed in a process that consisted of four analytical steps focusing on metaphors and meanings in the tattoos. The findings present four themes: angels of mercy and domination; hegemonic nursing technology; embodying the corps; and nurses within the belly of the monster. The tattoos serve as a mirror of popular culture and the professional culture of nurses and nursing practice within the context of body art. Body art policy statements have been included in nursing personnel dress code policies. Usually these policies prohibit tattoos that are sexist, symbolize sex or could contribute and reproduce racial oppression. The results show that the tattoos can be interpreted according to several layers of meanings in relation to such policies. We therefore stress that this is an area highly relevant for further analyses in nursing research. PMID- 24467823 TI - [Epidemiology of type 1 diabetes mellitus in children in Spain]. AB - INTRODUCTION: Epidemiological studies in many regions and countries have contributed to determining the epidemiology of type 1 diabetes (T1DM) in children less than 15 years old. Studies in many regions of Spain have been published, but the national incidence is not really known. MATERIAL AND METHODS: A review was made of the publications on the epidemiology of T1DM in Spain, selecting the references on patients less than 15 years old. RESULTS: Many epidemiological studies on T1DM in almost all regions in Spain have been published. The methodology of these studies is heterogeneous, with variations in geographical definition, duration, period of study, limit of age, and data collection. The incidence rates are variable, from 11.5 cases per 100,000/year in Asturias to 27.6 in Castilla-La Mancha. Some studies report the percentage of diabetic ketoacidosis at the time of diagnosis, which is usually in the range of 25-40%. CONCLUSIONS: Although there have been various epidemiological studies on T1DM in almost all regions in Spain, the methodology is heterogeneous. The mean incidence of T1DM in children less than 15 years old in Spain, stimated from the selected studies is 17,69 cases per 100,000/year. T1DM registers need to be created and updated, using standardized methodology, to get more reliable data of the epidemiology of T1DM in Spain in the near future. PMID- 24467824 TI - ["Hourglass" image due to a post-surgical hiatal hernia]. PMID- 24467825 TI - [Chorea as a first sign of anti-phospholipid syndrome]. PMID- 24467827 TI - Legionnaires' disease after using an industrial pressure test pump: a case report. AB - INTRODUCTION: Legionnaires' disease is an acute pneumonia caused by inhalation or aspiration of aerosols contaminated with Legionella bacteria. The majority (>90%) of Legionnaires' disease cases are caused by the species Legionella pneumophila, and about 85% more specifically by L. pneumophila serogroup 1 that can be detected by a fast and easy to perform urinary antigen test. Previously reported sources of infection include cooling towers, plumbing systems of hospitals, and whirlpool spas, but for the majority of cases of Legionnaires' disease the source of infection remains unknown. CASE PRESENTATION: A 52-year-old Caucasian man was admitted to a Dutch hospital with pneumonia, where a culture of the available bronchial lavage was found positive for L. pneumophila serogroup 3, confirming the diagnosis of Legionnaires' disease. An environmental investigation identified a manually operated pressure test pump at the metal processing company where he worked as the source of infection: the water sample from the pump contained 9.8*103 colony forming units/L L. pneumophila, and sequence-based typing showed the same sequence type (ST93) for both the clinical and environmental strains. CONCLUSION: This case shows that Legionnaires' disease can be acquired by exposure to relatively rare sources that are not considered in regular control and prevention measures. PMID- 24467826 TI - Combining metabolomics and transcriptomics to characterize tanshinone biosynthesis in Salvia miltiorrhiza. AB - BACKGROUND: Plant natural products have been co-opted for millennia by humans for various uses such as flavor, fragrances, and medicines. These compounds often are only produced in relatively low amounts and are difficult to chemically synthesize, limiting access. While elucidation of the underlying biosynthetic processes might help alleviate these issues (e.g., via metabolic engineering), investigation of this is hindered by the low levels of relevant gene expression and expansion of the corresponding enzymatic gene families. However, the often inducible nature of such metabolic processes enables selection of those genes whose expression pattern indicates a role in production of the targeted natural product. RESULTS: Here, we combine metabolomics and transcriptomics to investigate the inducible biosynthesis of the bioactive diterpenoid tanshinones from the Chinese medicinal herb, Salvia miltiorrhiza (Danshen). Untargeted metabolomics investigation of elicited hairy root cultures indicated that tanshinone production was a dominant component of the metabolic response, increasing at later time points. A transcriptomic approach was applied to not only define a comprehensive transcriptome (comprised of 20,972 non-redundant genes), but also its response to induction, revealing 6,358 genes that exhibited differential expression, with significant enrichment for up-regulation of genes involved in stress, stimulus and immune response processes. Consistent with our metabolomics analysis, there appears to be a slower but more sustained increased in transcript levels of known genes from diterpenoid and, more specifically, tanshinone biosynthesis. Among the co-regulated genes were 70 transcription factors and 8 cytochromes P450, providing targets for future investigation. CONCLUSIONS: Our results indicate a biphasic response of Danshen terpenoid metabolism to elicitation, with early induction of sesqui- and tri- terpenoid biosynthesis, followed by later and more sustained production of the diterpenoid tanshinones. Our data provides a firm foundation for further elucidation of tanshinone and other inducible natural product metabolism in Danshen. PMID- 24467829 TI - Video-assisted thoracoscopic surgery for large Zenker's diverticulum: report of two cases. AB - INTRODUCTION: Zenker's diverticulum is a propulsion diverticulum in the pharynx. Current practice for the management of symptomatic pharyngeal pouches includes endoscopic pharyngeal stapling, performed trans-orally, and external approaches via a cervical incision. There is no published recommendation on how to approach diverticula with extension into the mediastinum, which may not be adequately treated with the above methods. CASES: We describe two cases in which thoracoscopic mobilisation of Zenker's diverticulum was performed using video assisted thoracoscopic surgery together with traditional transcervical mobilisation and excision of the pouch. This allowed safe surgical access to the inferior limit of the pouch, and delivery of the sac into the neck incision following division of any inferior adhesions (to the great vessels in one case). DISCUSSION: In the first report of this technique, we describe a thorough, safe method of dissecting large diverticula that extend into the mediastinum, which minimises the risk to mediastinal structures. PMID- 24467828 TI - PIK3CA mutations, phosphatase and tensin homolog, human epidermal growth factor receptor 2, and insulin-like growth factor 1 receptor and adjuvant tamoxifen resistance in postmenopausal breast cancer patients. AB - INTRODUCTION: Inhibitors of the phosphatidylinositol-3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) pathway can overcome endocrine resistance in estrogen receptor (ER) alpha-positive breast cancer, but companion diagnostics indicating PI3K/AKT/mTOR activation and consequently endocrine resistance are lacking. PIK3CA mutations frequently occur in ERalpha-positive breast cancer and result in PI3K/AKT/mTOR activation in vitro. Nevertheless, the prognostic and treatment-predictive value of these mutations in ERalpha-positive breast cancer is contradictive. We tested the clinical validity of PIK3CA mutations and other canonic pathway drivers to predict intrinsic resistance to adjuvant tamoxifen. In addition, we tested the association between these drivers and downstream activated proteins. METHODS: Primary tumors from 563 ERalpha positive postmenopausal patients, randomized between adjuvant tamoxifen (1 to 3 years) versus observation were recollected. PIK3CA hotspot mutations in exon 9 and exon 20 were assessed with Sequenom Mass Spectometry. Immunohistochemistry was performed for human epidermal growth factor receptor 2 (HER2), phosphatase and tensin homolog (PTEN), and insulin-like growth factor 1 receptor (IGF-1R). We tested the association between these molecular alterations and downstream activated proteins (like phospho-protein kinase B (p-AKT), phospho-mammalian target of rapamycin (p-mTOR), p-ERK1/2, and p-p70S6K). Recurrence-free interval improvement with tamoxifen versus control was assessed according to the presence or absence of canonic pathway drivers, by using Cox proportional hazard models, including a test for interaction. RESULTS: PIK3CA mutations (both exon 9 and exon 20) were associated with low tumor grade. An enrichment of PIK3CA exon 20 mutations was observed in progesterone receptor- positive tumors. PIK3CA exon 20 mutations were not associated with downstream-activated proteins. No significant interaction between PIK3CA mutations or any of the other canonic pathway drivers and tamoxifen-treatment benefit was found. CONCLUSION: PIK3CA mutations do not have clinical validity to predict intrinsic resistance to adjuvant tamoxifen and may therefore be unsuitable as companion diagnostic for PI3K/AKT/mTOR inhibitors in ERalpha- positive, postmenopausal, early breast cancer patients. PMID- 24467830 TI - Intradialytic hypotension: frequency, sources of variation and correlation with clinical outcome. AB - Intradialytic hypotension (IH) is a frequent complication of hemodialysis (HD) and is associated with increased patient mortality and cardiovascular events. We studied IH to determine its variability, correlates, and clinical impact in 13 outpatient HD facilities. Blood pressure was captured by machine download. IH was defined as >30 mmHg decrease in systolic blood pressure to <90 mmHg. Risk factors were assessed by logistic regression and hospitalization by Poisson regression. Time to death and first hospitalization were assessed using Kaplan-Meier analysis in patients completing >20 HD treatments. We studied IH in 44,801 treatments (Tx) in 1137 patients. IH was frequent (17.2% of treatments) and highly variable by patient (0-100% Tx) and dialysis facility (11.1-25.8% Tx). 25.1% of patients had no IH (0% Tx) and 16.2% had IH on >35% Tx. Increased IH frequency was associated with age, female gender, diabetes, Hispanic origin, longer end stage renal disease vintage, higher body mass index, higher ultrafiltration volume, the second and third weekly Tx, lower pre-HD systolic blood pressure, higher difference between prescribed and achieved post-HD weight, and higher dialysate temperature. Dialysis facility was an independent predictor of IH frequency. Patients with >35% IH treatments had poorer survival (P = 0.036), and more frequent and longer hospitalization (P = 0.04, P = 0.002, respectively) than patients without IH. In conclusion, IH frequency was highly variable, associated with individual facilities, patient and treatment characteristics, and correlated with mortality and hospitalization. Identifying practice patterns associated with IH coupled with routine reporting of IH will facilitate medical management and may result in the prevention of IH, decreased mortality, and decreased hospitalization. PMID- 24467831 TI - Wireless substitution: state-level estimates from the National Health Interview Survey, 2012. AB - OBJECTIVES: This report updates subnational estimates of the percentage of adults and children living in households that do not have a landline telephone but have at least one wireless telephone (i.e., wireless-only households). State-level estimates for 2012 are presented, along with estimates for selected U.S. counties and groups of counties, for other household telephone service use categories (e.g., those that had only landlines and those that had landlines yet received all or almost all calls on wireless telephones), and for one earlier 12-month period (July 2011-June 2012). METHODS: Small-area statistical modeling techniques were used to estimate the prevalence of adults and children living in households with various household telephone service types for 93 disjoint geographic areas that make up the United States. This modeling was based on 2007-2012 data from the National Health Interview Survey, 2006-2011 data from the American Community Survey, and auxiliary information on the number of listed telephone lines per capita in 2007-2012. RESULTS: The prevalence of wireless-only adults and children varied substantially across states. State-level estimates for 2012 ranged from 19.4% (New Jersey) to 52.3% (Idaho) of adults and from 20.6% (New Jersey) to 63.4% (Mississippi) of children. PMID- 24467832 TI - Mental health policy in Eastern Europe: a comparative analysis of seven mental health systems. AB - BACKGROUND: The objective of this international comparative study is to describe and compare the mental health policies in seven countries of Eastern Europe that share their common communist history: Bulgaria, the Czech Republic, Hungary, Moldova, Poland, Romania, and Slovakia. METHODS: The health policy questionnaire was developed and the country-specific information was gathered by local experts. The questionnaire includes both qualitative and quantitative information on various aspects of mental health policy: (1) basic country information (demography, health, and economic indicators), (2) health care financing, (3) mental health services (capacities and utilisation, ownership), (4) health service purchasing (purchasing organisations, contracting, reimbursement of services), and (5) mental health policy (policy documents, legislation, civic society). RESULTS: The social and economic transition in the 1990s initiated the process of new mental health policy formulation, adoption of mental health legislation stressing human rights of patients, and a strong call for a pragmatic balance of community and hospital services. In contrast to the development in the Western Europe, the civic society was suppressed and NGOs and similar organizations were practically non-existent or under governmental control. Mental health services are financed from the public health insurance as any other health services. There is no separate budget for mental health. We can observe that the know-how about modern mental health care and about direction of needed reforms is available in documents, policies and programmes. However, this does not mean real implementation. CONCLUSIONS: The burden of totalitarian history still influences many areas of social and economic life, which also has to be taken into account in mental health policy. We may observe that after twenty years of health reforms and reforms of health reforms, the transition of the mental health systems still continues. In spite of many reform efforts in the past, a balance of community and hospital mental health services has not been achieved in this part of the world yet. PMID- 24467833 TI - A sheeppox outbreak in Morocco: isolation and identification of virus responsible for the new clinical form of disease. AB - BACKGROUND: Sheeppoxvirus (SPPV) is a member of the Capripoxvirus genus of the Poxviridae family, which causes significant economic losses in Morocco. The resurgence of the sheeppox disease during 2010 was characterized by an emergence of a classical nodular form for the first time in Morocco. However, little is known about the virus strain responsible for nodular form. In this study, thirty three sheep, from the eastern region of Morocco, clinically infected were examined and dead animals were autopsied.A rapid diagnostic assay for SPPV using different type of clinical samples would be useful for outbreak management. The aim of this work was to isolate the virus strain responsible for nodular form and we identified and compared by phylogenetic analysis the field strain with Moroccan vaccine strain targeting the thymidine kinase (TK) gene and the chemokine analogue receptor of interleukin (IL8) gene. Further, it was important to investigate and validate a real-time PCR using different clinical and post mortem samples to manage epidemic sheeppox disease. RESULTS: The nodular form of sheeppox disease observed in Morocco was clinically characterized by fever, depression, lacrimation, diarrhea in lambs and nodule. At necropsy, the most affected organ was the lung. The etiological strain was successfully isolated from lung nodule in a dead lamb and was identified by using real-time PCR that has been tested and validated on different types of clinical and post mortem samples from naturally infected animals. Sequence and phylogenetic analysis of TK and IL8 gene showed that there was a very close relationship between field and vaccine strain. They were clustered within other SPPV strains. CONCLUSION: In the current study, we show for the first time the nodular form of sheeppox in Morocco. We demonstrate a robust real-time PCR-based diagnostic assay to detect the sheeppox virus in multiple sample that can be implemented to efficiently manage the disease outbreak. Our study also offers the prospect for future molecular studies to understand the clinical forms. PMID- 24467835 TI - What to publish in the official journal of NANDA-I. PMID- 24467834 TI - Limited family members/staff communication in intensive care units in the Czech and Slovak Republics considerably increases anxiety in patients' relatives--the DEPRESS study. AB - BACKGROUND: Symptoms of anxiety and depression are common among family members of ICU patients and are culturally dependent. The aim of the study was to assess the prevalence of symptoms of anxiety and depression and associated factors in family members of ICU patients in two Central European countries. METHODS: We conducted a prospective multicenter study involving 22 ICUs (250 beds) in the Czech and Slovak Republics. The Hospital Anxiety and Depression Scale (HADS) was used to assess symptoms of anxiety and depression in family members of ICU patients. Family member understanding of the patient's condition was assessed using a structured interview and a questionnaire was used to assess satisfaction with family member/ICU staff communication. RESULTS: Twenty two intensive care units (both adult and pediatric) in academic medical centers and community hospitals participated in the study. During a 6 month period, 405 family members of 293 patients were enrolled. We found a high prevalence of anxiety and depression symptoms - 78% and 54%, respectively. Information leaflets distributed to family members did not lower incidences of anxiety/depression. Family members with symptoms of depression reported higher levels of satisfaction according to the modified Critical Care Family Needs Inventory. Extended contact between staff and family members was the only related factor associated with anxiety reduction (p = 0.001). CONCLUSION: Family members of ICU patients in East European countries suffer from symptoms of anxiety and depression. We identified limited family member/ICU staff communication as an important health care professional-related factor associated with a higher incidence of symptoms of anxiety. This factor is potentially amenable to improvement and may serve as a target for proactive intervention proactive intervention. PMID- 24467836 TI - Barriers to patient-centered care: a thematic analysis study. AB - PURPOSE: To explore nurses' attitudes and experience toward the barriers to achieving patient-centered care in the critical care setting. METHODS: A qualitative exploratory design with thematic analysis approach was used to collect and analyze data, and identify barriers to patient-centered care. Data collection was based on in-depth semi-structured interviews. FINDINGS: Data analyses resulted in the identification of three themes: (a) lack of common understanding of teamwork, (b) individual barriers, and (c) organizational barriers. CONCLUSION: This study goes beyond reporting problems with patient centered care to try to understand why patients do not always receive high quality care. IMPLICATION FOR NURSING PRACTICE: For achieving patient-centered care, not only nurses' individual efforts in following up-to-date evidence-based practice and having a holistic view are necessary, but also team coordination, organizational support, and elimination of nursing job problems. PMID- 24467837 TI - Pathogen-free, plasma-poor platelet lysate and expansion of human mesenchymal stem cells. AB - BACKGROUND: Supplements to support clinical-grade cultures of mesenchymal stem cells (MSC) are required to promote growth and expansion of these cells. Platelet lysate (PL) is a human blood component which may replace animal serum in MSC cultures being rich in various growth factors. Here, we describe a plasma poor pathogen-free platelet lysate obtained by pooling 12 platelet (PLT) units, to produce a standardized and safe supplement for clinical-grade expansion of MSC. METHODS: PL lots were obtained by combining 2 6-unit PLT pools in additive solution (AS) following a transfusional-based procedure including pathogen inactivation (PI) by Intercept technology and 3 cycles of freezing/thawing, followed by membrane removal. Three PI-PL and 3 control PL lots were produced to compare their ability to sustain bone marrow derived MSC selection and expansion. Moreover, two further PL, subjected to PI or not, were also produced starting from the same initial PLT pools to evaluate the impact of PI on growth factor concentration and capacity to sustain cell growth. Additional PI-PL lots were used for comparison with fetal bovine serum (FBS) on MSC expansion. Immunoregulatory properties of PI-PL-generated MSC were documented in vitro by mixed lymphocyte culture (MLC) and peripheral blood mononuclear cells (PBMC) mitogen induced proliferation. RESULTS: PI-PL and PL control lots had similar concentrations of 4 well-described growth factors endowed with MSC stimulating ability. Initial growth and MSC expansion by PI-PL and PL controls were comparable either using different MSC populations or in head to head experiments. Moreover, PI-PL and PL control sustained similar MSC growth of frozen/thawed MSC. Multilineage differentiation of PI-derived and PI-PL-derived MSC were maintained in any MSC cultures as well as their immunoregulatory properties. Finally, no direct impact of PI on growth factor concentration and MSC growth support was observed, whereas the capacity of FBS to sustain MSC expansion in basic medium was irrelevant as compared to PL and PI-PL. CONCLUSION: The replacement of animal additives with human supplements is a basic issue in MSC ex vivo production. PI PL represents a standardized, plasma-poor, human preparation which appears as a safe and good candidate to stimulate MSC growth in clinical-scale cultures. PMID- 24467838 TI - Role of LET and chromatin structure on chromosomal inversion in CHO10B2 cells. AB - BACKGROUND: In this study we evaluated the effect of linear energy transfer (LET) and chromatin structure on the induction of chromosomal inversion. High LET radiation causes more complex DNA damage than low LET radiation; this "dirty" damage is more difficult to repair and may result in an increase in inversion formation. CHO10B2 cells synchronized in either G1 or M phase were exposed 0, 1, or 2 Gy of 5 mm Al and Cu filters at 200 kVp and 20 mA X-rays or 500 MeV/nucleon of initial energy and 200 keV/MU m Fe ion radiation. In order to increase the sensitivity of prior techniques used to study inversions, we modified the more traditional Giemsa plus fluorescence technique so that cells were only allowed to incorporate BrdU for a single cycle verses 2 cycles. The BrdU incorporated DNA strand was labeled using a BrdU antibody and an Alexa Fluor 488 probe. This modified technique allowed us to observe inversions smaller than 0.6 megabases (Mb). RESULTS: In this study we have shown that high LET radiation induces significantly more inversions in G1 cells than in M phase cells. Additionally, we have shown that the sizes of the induced inversions not only differ between Fe ion and X-rays, but also between G1 and M phase cells exposed to Fe ions. CONCLUSION: We have effectively shown that both radiation quality and chromosome structure interact to alter not only the number of inversions induced, but also the size of the inversions. PMID- 24467839 TI - Contributions of pharmacogenetics and transcriptomics to the understanding of the hypersensitivity drug reactions. AB - Hypersensitivity drug reactions (HDRs) represent a large and important health problem, affecting many patients and leading to a variety of clinical entities, some of which can be life-threatening. The culprit drugs include commonly used medications including antibiotics and NSAIDs. Nontherapeutical agents, such as contrast media, are also involved. Because the pathophysiological mechanisms are not well known and the current diagnostic procedures are somewhat insufficient, new approaches are needed for understanding the complexity of HDRs. Histochemical and molecular biology studies have enabled us to classify these reactions more precisely. Pharmacogenetics has led to the identification of several genes, involved mainly in T-cell-dependent responses, with a number of markers being replicated in different studies. These markers are now being considered as potential targets for reducing the number of HDRs. Transcriptomic approaches have also been used to investigate HDRs by identifying genes that show different patterns of expression in a number of clinical entities. This information can be of value for further elucidation of the mechanisms involved. Although first studies were performed using RT-PCR analysis to monitor the acute phase of the reaction, nowadays high-density expression platforms represent a more integrative way for providing a complete view of gene expression. By combining a detailed and precise clinical description with information obtained by these approaches, we will obtain a better understanding and management of patients with HDRs. PMID- 24467840 TI - Anesthetic management in a patient with giant growing teratoma syndrome: a case report. AB - INTRODUCTION: Growing teratoma syndrome is a rare occurrence with an ovarian tumor. Anesthesia has been reported to be difficult in cases of growing teratoma syndrome of the cystic type due to the pressure exerted by the tumor. However, there have been no similar reports with the solid mass type. Here, we report our experience of anesthesia in a case of growing teratoma syndrome of the solid type. CASE PRESENTATION: The patient was a 30-year-old Japanese woman who had been diagnosed with an ovarian immature teratoma at age 12 and had undergone surgery and chemotherapy. However, she dropped out of treatment. She presented to our hospital with a 40cm giant solid mass and severe respiratory failure, and was scheduled for an operation. We determined that we could not obtain a sufficient tidal volume without spontaneous respiration. Therefore, we chose to perform awake intubation and not to use a muscle relaxant before the operation. At the start of the operation, when muscle relaxant was first administered, we could not obtain a sufficient tidal volume. An abdominal midline incision was performed immediately and her tidal volume recovered. Her resected tumor weighed 10.5kg. After removal of her tumor, her tidal volume was maintained at a level consistent with that under spontaneous respiration to avoid occurrence of re-expansion pulmonary edema. CONCLUSIONS: We performed successful anesthetic management of a case of growing teratoma syndrome with a giant abdominal tumor. Respiratory management was achieved by avoiding use of a muscle relaxant before the operation to maintain spontaneous respiration and by maintaining a relatively low tidal volume, similar to that during spontaneous respiration preoperatively, after removal of the tumor to prevent re-expansion pulmonary edema. PMID- 24467841 TI - Comprehensive analysis of beta-catenin target genes in colorectal carcinoma cell lines with deregulated Wnt/beta-catenin signaling. AB - BACKGROUND: Deregulation of Wnt/beta-catenin signaling is a hallmark of the majority of sporadic forms of colorectal cancer and results in increased stability of the protein beta-catenin. beta-catenin is then shuttled into the nucleus where it activates the transcription of its target genes, including the proto-oncogenes MYC and CCND1 as well as the genes encoding the basic helix-loop helix (bHLH) proteins ASCL2 and ITF-2B. To identify genes commonly regulated by beta-catenin in colorectal cancer cell lines, we analyzed beta-catenin target gene expression in two non-isogenic cell lines, DLD1 and SW480, using DNA microarrays and compared these genes to beta-catenin target genes published in the PubMed database and DNA microarray data presented in the Gene Expression Omnibus (GEO) database. RESULTS: Treatment of DLD1 and SW480 cells with beta catenin siRNA resulted in differential expression of 1501 and 2389 genes, respectively. 335 of these genes were regulated in the same direction in both cell lines. Comparison of these data with published beta-catenin target genes for the colon carcinoma cell line LS174T revealed 193 genes that are regulated similarly in all three cell lines. The overlapping gene set includes confirmed beta-catenin target genes like AXIN2, MYC, and ASCL2. We also identified 11 Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways that are regulated similarly in DLD1 and SW480 cells and one pathway - the steroid biosynthesis pathway - was regulated in all three cell lines. CONCLUSIONS: Based on the large number of potential beta-catenin target genes found to be similarly regulated in DLD1, SW480 and LS174T cells as well as the large overlap with confirmed beta-catenin target genes, we conclude that DLD1 and SW480 colon carcinoma cell lines are suitable model systems to study Wnt/beta-catenin signaling and associated colorectal carcinogenesis. Furthermore, the confirmed and the newly identified potential beta-catenin target genes are useful starting points for further studies. PMID- 24467842 TI - Significant overlap between human genome-wide association-study nominated breast cancer risk alleles and rat mammary cancer susceptibility loci. AB - INTRODUCTION: Human population-based genome-wide association (GWA) studies identify low penetrance breast cancer risk alleles; however, GWA studies alone do not definitively determine causative genes or mechanisms. Stringent genome- wide statistical significance level requirements, set to avoid false-positive associations, yield many false-negative associations. Laboratory rats (Rattus norvegicus) are useful to study many aspects of breast cancer, including genetic susceptibility. Several rat mammary cancer associated loci have been identified using genetic linkage and congenic strain based-approaches. Here, we sought to determine the amount of overlap between GWA study nominated human breast and rat mammary cancer susceptibility loci. METHODS: We queried published GWA studies to identify two groups of SNPs, one that reached genome-wide significance and one comprised of SNPs failing a validation step and not reaching genome- wide significance. Human genome locations of these SNPs were compared to known rat mammary carcinoma susceptibility loci to determine if risk alleles existed in both species. Rat genome regions not known to associate with mammary cancer risk were randomly selected as control regions. RESULTS: Significantly more human breast cancer risk GWA study nominated SNPs mapped at orthologs of rat mammary cancer loci than to regions not known to contain rat mammary cancer loci. The rat genome was useful to predict associations that had met human genome-wide significance criteria and weaker associations that had not. CONCLUSIONS: Integration of human and rat comparative genomics may be useful to parse out false-negative associations in GWA studies of breast cancer risk. PMID- 24467843 TI - Is one better than another?: A randomized clinical trial of manual therapy for patients with chronic neck pain. AB - Our purpose was to compare the effectiveness of three manual therapy techniques: high velocity, low amplitude (HVLA), mobilization (Mob) and sustained natural apophyseal glide (SNAG) in patients with chronic neck pain (CNP). The randomized controlled trial included patients with mechanically reproducible CNP, who were randomized to the treatment group. Outcome measures were the Visual Analogue scale (VAS), Neck Disability Index (NDI), Global Rating of Change (GROC) and Cervical Range of Motion (CROM). Two-way repeated measures analysis of variance compared outcomes at baseline, at the end of treatment and 1, 2 and 3 months after treatment. A total of 51 subjects completed the trial. No significant differences were found between HVLA, Mob and SNAG at the end of treatment and during the follow-up in any of the analysed outcomes. There were no differences in satisfaction for all techniques. The results lead to the conclusion that there is no long-term difference between the application of HVLA, Mob and SNAG in pain, disability and cervical range of motion for patients with CNP. PMID- 24467844 TI - The effects of clinically relevant doses of amphetamine and methylphenidate on signal detection and DRL in rats. AB - Low dose amphetamine (AMPH) and methylphenidate (MPH, Ritalin((r))) are the most widely prescribed and most effective pharmacotherapy for attention deficit/hyperactivity disorder (ADHD). Certain low, clinically relevant doses of MPH improve sustained attention and working memory in normal rats, in contrast to higher doses that impair cognitive ability and induce locomotor activity. However, the effects of AMPH of MPH on sustained attention and behavioral inhibition remain poorly characterized. The present experiments examined the actions of AMPH (0.1 and 0.25 mg/kg) and MPH (0.5 and 1.0 mg/kg) in a rat model of 1) sustained attention, where signal and blank trials were interspersed randomly and occurred at unpredictable times, and 2) behavioral inhibition, using a differential reinforcement of low rate (DRL) schedule. In a signal detection paradigm, both 0.5 mg/kg and 1.0 mg/kg MPH and 0.25 mg/kg AMPH improve sustained attention, however neither AMPH nor MPH improve behavioral inhibition on DRL. Taken together with other recent studies, it appears that clinically-relevant doses of AMPH and MPH may preferentially improve attention-related behavior while having little effect on behavioral inhibition. These observations provide additional insight into the basic behavioral actions of low-dose psychostimulants and further suggest that the use of sustained attention tasks may be important in the development of novel pharmacological treatments for ADHD. PMID- 24467846 TI - Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena. AB - N-type calcium channels play important roles in the control of neurotransmission release and transmission of pain signals to the central nervous system. Their selective inhibitors are believed to be potential drugs for treating chronic pain. In this study, a novel neurotoxin named Huwentoxin-XVI (HWTX-XVI) specific for N-type calcium channels was purified and characterized from the venom of Chinese tarantula Ornithoctonus huwena. HWTX-XVI is composed of 39 amino acid residues including six cysteines that constitute three disulfide bridges. HWTX XVI could almost completely block the twitch response of rat vas deferens to low frequency electrical stimulation. Electrophysiological assay indicated that HWTX XVI specifically inhibited N-type calcium channels in rat dorsal root ganglion cells (IC50 ~60 nM). The inhibitory effect of HWTX-XVI on N-type calcium channel currents was dose-dependent and similar to that of CTx-GVIA and CTx-MVIIA. However, the three peptides exhibited markedly different degrees of reversibility after block. The toxin had no effect on voltage-gated T-type calcium channels, potassium channels or sodium channels. Intraperitoneal injection of the toxin HWTX-XVI to rats elicited significant analgesic responses to formalin-induced inflammation pain. Toxin treatment also changed withdrawal latency in hot plate tests. Intriguingly, we found that intramuscular injection of the toxin reduced mechanical allodynia induced by incisional injury in Von Frey test. Thus, our findings suggest that the analgesic potency of HWTX-XVI and its greater reversibility could contribute to the design of a novel potential analgesic agent with high potency and low side effects. PMID- 24467845 TI - Differences in amyloid-beta clearance across mouse and human blood-brain barrier models: kinetic analysis and mechanistic modeling. AB - Alzheimer's disease (AD) has a characteristic hallmark of amyloid-beta (Abeta) accumulation in the brain. This accumulation of Abeta has been related to its faulty cerebral clearance. Indeed, preclinical studies that used mice to investigate Abeta clearance showed that efflux across blood-brain barrier (BBB) and brain degradation mediate efficient Abeta clearance. However, the contribution of each process to Abeta clearance remains unclear. Moreover, it is still uncertain how species differences between mouse and human could affect Abeta clearance. Here, a modified form of the brain efflux index method was used to estimate the contribution of BBB and brain degradation to Abeta clearance from the brain of wild type mice. We estimated that 62% of intracerebrally injected (125)I-Abeta40 is cleared across BBB while 38% is cleared by brain degradation. Furthermore, in vitro and in silico studies were performed to compare Abeta clearance between mouse and human BBB models. Kinetic studies for Abeta40 disposition in bEnd3 and hCMEC/D3 cells, representative in vitro mouse and human BBB models, respectively, demonstrated 30-fold higher rate of (125)I-Abeta40 uptake and 15-fold higher rate of degradation by bEnd3 compared to hCMEC/D3 cells. Expression studies showed both cells to express different levels of P glycoprotein and RAGE, while LRP1 levels were comparable. Finally, we established a mechanistic model, which could successfully predict cellular levels of (125)I Abeta40 and the rate of each process. Established mechanistic model suggested significantly higher rates of Abeta uptake and degradation in bEnd3 cells as rationale for the observed differences in (125)I-Abeta40 disposition between mouse and human BBB models. In conclusion, current study demonstrates the important role of BBB in the clearance of Abeta from the brain. Moreover, it provides insight into the differences between mouse and human BBB with regards to Abeta clearance and offer, for the first time, a mathematical model that describes Abeta clearance across BBB. PMID- 24467847 TI - mGluR1 within the nucleus accumbens regulates alcohol intake in mice under limited-access conditions. AB - Idiopathic or alcohol-induced increases in the expression and function of the Group1 metabotropic glutamate receptor subtype 1 (mGluR1) within the extended amygdala are theorized to contribute to an individual's propensity to consume excessive amounts of alcohol. In the past, the detailed study of the functional relevance of mGluR1 for alcoholism-related behaviors in animal models was hampered by the poor solubility and non-specific side effects of available inhibitors; however, the advent of the highly potent and soluble mGluR1 negative allosteric modulator JNJ-16259685 [(3,4-Dihydro-2H-pyrano[2,3-b]quinolin-7-yl) (cis-4-methoxycyclohexyl)-methanone] has instigated a re-examination of the role for this mGluR subtype in mediating the behavioral effects of alcohol. In this regard, systemic pretreatment with JNJ-16259685 was proven effective at reducing alcohol reinforcement and motivation for the drug. mGluR1 is a Galphaq/o-coupled receptor, the stimulation of which activates phospholipase C (PLC). Thus, the present study investigated potential neuroanatomical substrates and intracellular molecules involved in the ability of JNJ-16259685 to reduce alcohol intake. JNJ 16259685 (0-30 pg/side) was infused into the shell subregion of the nucleus accumbens (NAC) of C57BL/6J and Homer2 knock-out (KO) mice, either alone or in combination with the PLC inhibitor U-73122 (5.8 fg/side). Alcohol intake was then assessed under Drinking-in-the-Dark (DID) procedures. Intra-NAC JNJ-16259685 infusion dose-dependently reduced alcohol consumption by C57BL/6J mice; this effect was not additive with that produced by U-73122, nor was it present in Homer2 KO animals. These data provide novel evidence in support of a critical role for mGluR1-PLC signaling, scaffolded by Homer2, within the NAC shell, in maintaining alcohol consumption under limited access procedures. Such findings have relevance for both the pharmacotherapeutics and pharmacogenetics of risky alcohol drinking and alcoholism. PMID- 24467848 TI - A signal peptide missense mutation associated with nicotine dependence alters alpha2*-nicotinic acetylcholine receptor function. AB - A cytosine to thymidine (C -> T) missense mutation in the signal peptide (SP) sequence (rs2472553) of the nicotinic acetylcholine receptor (nAChR) alpha2 subunit produces a threonine-to-isoleucine substitution (T22I) often associated with nicotine dependence (ND). We assessed effects on function of alpha2*-nAChR ('*'indicates presence of additional subunits) of this mutation, which could alter SP cleavage, RNA/protein secondary structure, and/or efficiency of transcription, translation, subunit assembly, receptor trafficking or cell surface expression. Two-electrode voltage clamp analyses indicate peak current responses to ACh or nicotine are decreased 2.8-5.8-fold for putative low sensitivity (LS; 10:1 ratio of alpha:beta subunit cRNAs injected) alpha2beta2- or alpha2beta4-nAChR and increased for putative high sensitivity (HS; 1:10 alpha:beta subunit ratio) alpha2beta2- (5.7-15-fold) or alpha2beta4- (1.9-2.2 fold) nAChR as a result of the mutation. Agonist potencies are decreased 1.6-4 fold for putative LS or HS alpha2(T22I)beta2-nAChR or for either alpha2*-nAChR subtype formed in the presence of equal amounts of subunit cRNA, slightly decreased for LS alpha2(T22I)beta4-nAChR, but increased 1.4-2.4-fold for HS alpha2(T22I)beta4-nAChR relative to receptors containing wild-type alpha2 subunits. These effects suggest that the alpha2 subunit SP mutation generally favors formation of LS receptor isoforms. We hypothesize that lower sensitivity of human alpha2*-nAChR to nicotine could contribute to increased susceptibility to ND. To our knowledge this is the first report of a SP mutation having a functional effect in a member of cys-loop family of ligand-gated ion channels. PMID- 24467849 TI - Critical role of cholinergic transmission from the laterodorsal tegmental nucleus to the ventral tegmental area in cocaine-induced place preference. AB - Conditioned place preference (CPP) is widely used to investigate the rewarding properties of cocaine. Various brain regions and neurotransmitters are involved in developing cocaine CPP. However, the contribution of cholinergic transmission in the ventral tegmental area (VTA) to cocaine CPP remains largely unexplored. Here, we examined the role of cholinergic input arising from the laterodorsal tegmental nucleus (LDT) to the VTA in the acquisition and expression of cocaine CPP in rats. Intra-LDT injection of carbachol, which hyperpolarizes LDT neurons, and of NMDA and AMPA receptor antagonists before cocaine conditioning blocked and attenuated cocaine CPP, respectively, indicating the necessity of LDT activity for acquiring the CPP. Additionally, intra-VTA injection of scopolamine or mecamylamine before cocaine conditioning also attenuated cocaine CPP, demonstrating the contribution of cholinergic transmission via muscarinic and nicotinic acetylcholine receptors in CPP acquisition. Furthermore, intra-VTA injection of scopolamine or mecamylamine immediately before the test attenuated cocaine CPP, indicating that cholinergic signaling is also associated with the expression of CPP. These results suggest that cholinergic transmission from the LDT to the VTA is critically involved in both acquiring and retrieving cocaine associated memories in cocaine CPP. PMID- 24467850 TI - Depression-related behavior and mechanical allodynia are blocked by 3-(4 fluorophenylselenyl)-2,5-diphenylselenophene in a mouse model of neuropathic pain induced by partial sciatic nerve ligation. AB - Clinically, it is suggested that chronic pain might induce mood disorders like depression and anxiety. Based on this antidepressant drugs have emerged as a new therapy for pain. In this study, the effect of acute and subchronic treatments with 3-(4-fluorophenylselenyl)-2,5-diphenylselenophene (F-DPS) on behavioral changes induced by partial sciatic nerve ligation (PSNL) was evaluated. At the 4th week after surgery, PSNL caused a significant depression-like behavior in mice evaluated in the forced swimming test (FST) and the tail suspension test (TST), which was accompanied by increased pain sensitivity. The anxiety-like behavior assessed in the light-dark test (LDT) was not modified by PSNL. Acute treatment with F-DPS, at a dose of 1 mg/kg, intragastrically (i.g.) administered 30 min before the FST, produced a significant anti-immobility effect in PSNL mice. The antidepressant drug paroxetine showed acute antidepressant-like action at a dose 10 times higher than F-DPS. Subchronic treatment with F-DPS (0.1 mg/kg, i.g.) reversed depression-like behavior of sciatic nerve-ligated mice in the TST and FST and produced a significant anxiolytic-like action in both sham-operated and PSNL animals. Although the acute F-DPS treatment did not produce anti allodynic effect, F-DPS subchronic treatment significantly reduced pain sensitivity in PSNL mice. These findings demonstrated that F-DPS blocked behavioral changes induced by neuropathic pain, suggesting that it might be attractive in the pharmacological approach of pain-emotion diseases. PMID- 24467852 TI - Fathers' involvement with their children: United States, 2006-2010. AB - OBJECTIVE: This report measures fathers' involvement with their children. Father involvement is measured by how often a man participated in a set of activities in the last 4 weeks with children who were living with him and with children who were living apart from him. Involvement is measured separately for children aged 0-4 years and children aged 5-18 years. Increased involvement of fathers in their children's lives has been associated with a range of positive outcomes for the children. METHODS: The analyses presented in this report are based on a nationally representative sample of 10,403 men aged 15-44 years in the household population of the United States. The father-involvement measures are based on 2,200 fathers of children under age 5-1,790 who live with their children and 410 who live apart from their children, and on 3,166 fathers of children aged 5-18 2,091 who live with their children and 1,075 who live apart from their children. RESULTS: Statistics are presented on the frequency with which fathers took part in a set of age-specific activities in their children's lives. Differences in percent distributions are found by whether the father lives with or apart from his children, and by his demographic characteristics. In general, fathers living with their children participated in their children's lives to a greater degree than fathers who live apart from their children. Differences in fathers' involvement with their children were also found by the father's age, marital or cohabiting status, education, and Hispanic origin and race. PMID- 24467851 TI - Pseudoginsenoside-F11 (PF11) exerts anti-neuroinflammatory effects on LPS activated microglial cells by inhibiting TLR4-mediated TAK1/IKK/NF-kappaB, MAPKs and Akt signaling pathways. AB - Pseudoginsenoside-F11 (PF11), an ocotillol-type ginsenoside, has been shown to possess significant neuroprotective activity. Since microglia-mediated inflammation is critical for induction of neurodegeneration, this study was designed to investigate the effect of PF11 on activated microglia. PF11 significantly suppressed the release of ROS and proinflammatory mediators induced by LPS in a microglial cell line N9 including NO, PGE2, IL-1beta, IL-6 and TNF alpha. Moreover, PF11 inhibited interaction and expression of TLR4 and MyD88 in LPS-activated N9 cells, resulting in an inhibition of the TAK1/IKK/NF-kappaB signaling pathway. PF11 also inhibited the phosphorylation of Akt and MAPKs induced by LPS in N9 cells. Importantly, PF11 significantly alleviated the death of SH-SY5Y neuroblastoma cells and primary cortical neurons induced by the conditioned-medium from activated microglia. At last, the effect of PF11 on neuroinflammation was confirmed in vivo: PF11 mitigated the microglial activation and proinflammatory factors expression obviously in both cortex and hippocampus in mice injected intrahippocampally with LPS. These findings indicate that PF11 exerts anti-neuroinflammatory effects on LPS-activated microglial cells by inhibiting TLR4-mediated TAK1/IKK/NF-kappaB, MAPKs and Akt signaling pathways, suggesting its therapeutic implication for neurodegenerative disease associated with neuroinflammation. PMID- 24467853 TI - Structure and taxonomic composition of free-living nematode and macrofaunal assemblages in a eutrophic subtropical harbour, Hong Kong. AB - The spatial and seasonal taxonomic composition patterns of macrofauna and nematodes in a eutrophic subtropical harbour, previously suffered from sewage pollution, were studied in relation to a number of sediment parameters. In the polluted, inner-harbour area, levels of organic contents and heavy metals were high, whereas species number, abundance and diversity of nematodes and macrofauna were the lowest in comparison to the cleaner, outer-harbour area. Different taxonomic composition patterns of nematodes and macrofaunal assemblages were found between inner-harbour and outer-harbour area, which was highly correlated with sediment nutrient levels. Different responses of macrofaunal and nematode communities to sewage pollution suggested that macrofauna might be more tolerant than nematodes to eutrophic conditions due to their ability to modify the sediment. The present findings indicated the usefulness of studying both nematode and macrofaunal communities, in order to reveal different aspects of the benthic ecosystems in response to organic enrichment. PMID- 24467854 TI - Seasonal variations of epipelic algal community in relation to environmental factors in the Istanbul Strait (the Bosphorus), Turkey. AB - This study was implemented to investigate the species composition, abundance, seasonal variations and diversity of epipelic algae, to determine environmental variables affecting them and to reveal the accumulation of total organic carbon in the sediment in the coastal zone of the Istanbul Strait, Turkey. Epipelic algal community consisted of 44 taxa with a low diversity. The sediment structure which is highly unstable due to the high hydrodynamism of the zone played a dominant role as the main factor in the epipelic algal flora along the coasts of Istanbul Strait. Low TOC and high carbonate values also support this result. The dominance of cyanobacteria in some periods and, as a result of this, the record of the lowest diversity index values indicated the effect of nutrient enrichment and the risk of coastal eutrophication. High dominance of cyanobacteria may also be explicated by climate changes considering its effect in the other areas. PMID- 24467855 TI - Mandating responsible flagging practices as a strategy for reducing the risk of coastal oil spills. AB - As human civilization is becoming more aware of the negative impact our actions can inflict upon the natural world, the intensification of fossil fuel extraction and industrial development is being met with increasing opposition. In Western Canada, proposals that would increase the volume of petroleum transported by pipelines and by tankers through the coastal waters of British Columbia have engaged the province in debate. To ease public concern on the risk of a coastal oil spill, there are additional commitments that involved parties could make. There is evidence to show that the practice of registering vessels under foreign flags of states that have exhibited failure in compliance with international obligations is more common amongst petroleum tankers that have been involved in large-scale oil spills. To prove that they are committed to reducing the risk of oil spills, businesses need to stop registering their vessels under flags of foreign, non-compliant states. PMID- 24467856 TI - Occurrence, distribution and partitioning of nonionic surfactants and pharmaceuticals in the urbanized Long Island Sound Estuary (NY). AB - This work deals with the environmental distribution of nonionic surfactants (nonylphenol and alcohol ethoxylates), their metabolites (NP, nonylphenol; NPEC, nonylphenol ethoxycarboxylates; and PEG, polyethylene glycols) and a selection of 64 pharmaceuticals in the Long Island Sound (LIS) Estuary which receives important sewage discharges from New York City (NYC). Most target compounds were efficiently removed (>95%) in one wastewater treatment plant monitored, with the exception of NPEC and some specific drugs (e.g., hydrochlorothiazide). Concentrations of surfactants (1.4-4.5 MUg L(-1)) and pharmaceuticals (0.1-0.3 MUg L(-1)) in seawater were influenced by tides and sampling depth, consistent with salinity differences. Surfactants levels in suspended solids samples were higher than 1 MUg g(-1), whereas only most hydrophobic or positively charged pharmaceuticals could be found (e.g., tamoxifen, clarithromycin). Maximum levels of target compounds in LIS sediments (PEG at highest concentrations, 2.8 MUg g( 1)) were measured nearest NYC, sharply decreasing with distance from major sewage inputs. PMID- 24467857 TI - Glyphosate persistence in seawater. AB - Glyphosate is one of the most widely applied herbicides globally but its persistence in seawater has not been reported. Here we quantify the biodegradation of glyphosate using standard "simulation" flask tests with native bacterial populations and coastal seawater from the Great Barrier Reef. The half life for glyphosate at 25 degrees C in low-light was 47 days, extending to 267 days in the dark at 25 degrees C and 315 days in the dark at 31 degrees C, which is the longest persistence reported for this herbicide. AMPA, the microbial transformation product of glyphosate, was detected under all conditions, confirming that degradation was mediated by the native microbial community. This study demonstrates glyphosate is moderately persistent in the marine water under low light conditions and is highly persistent in the dark. Little degradation would be expected during flood plumes in the tropics, which could potentially deliver dissolved and sediment-bound glyphosate far from shore. PMID- 24467858 TI - Diving associated coral breakage in Hong Kong: differential susceptibility to damage. AB - We conducted the first quantitative assessment of coral breakage along a gradient of diving activities in Hong Kong, the most densely populated city in southern China. A survey of six 1 * 25 m transects at seven sites revealed a total of 81 broken corals, among which 44% were branching, 44% plate-like and 12% massive. There were 3-19 broken colonies per site. At most study sites, the percentage of broken corals exceeded the recommended no-action threshold of 4%, suggesting that management intervention is justified. There was a significant positive correlation between the number of broken coral colonies and the number of divers visiting the site. The branching Acropora and the plate-like Montipora suffered from much higher frequency of damage than their relative abundance, raising the concern that the cumulative impact of such differential susceptibility to breakage may affect coral community composition. PMID- 24467859 TI - Metallothioneins pattern during ontogeny of coastal dolphin, Pontoporia blainvillei, from Argentina. AB - Metallothioneins are signals of metal exposure and widely used in biomonitoring. Franciscana dolphin is an endemic cetacean from the Southwestern Atlantic Ocean, classified as Vulnerable A3d by the IUCN. Metallothionein, copper and zinc in Franciscana were assessed in two geographic groups; one inhabits La Plata River estuary, anthropogenically impacted, and the other inhabits marine coastal ecosystems, with negligible pollution. Despite the environment, hepatic and renal MT concentrations were similar, but there was a declining trend from early to later developmental stages. Metallothionein K/L, Cu and Zn levels corresponded to normal reported ranges. MT was not related with Cd. Fetal concentrations were higher than its mother. These results and the health status of dolphins are suggesting that MT correspond to physiological ranges for the species, and they are closely to homeostasis of Zn and Cu, according to its ontogenetic changes. The information constitutes the first MT information on Franciscana dolphin and can be considered as baseline for the species conservation. PMID- 24467860 TI - The increasing impact of food production on nutrient export by rivers to the Bay of Bengal 1970-2050. AB - The objective of this study is to assess the impact of food production on river export of nutrients to the coastal waters of the Bay of Bengal in the past (1970 and 2000) and the future (2030 and 2050), and the associated potential for coastal eutrophication. We model nutrient export from land to sea, using the Global NEWS (Nutrient Export from WaterSheds) approach. We calculate increases in river export of N and P over time. Agricultural sources account for about 70-80% of the N and P in rivers. The coastal eutrophication potential is high in the Bay. In 2000, nutrient discharge from about 85% of the basin area of the Bay drains into coastal seas contributes to the risk of coastal eutrophication. By 2050, this may be 96%. We also present an alternative scenario in which N and P inputs to the Bay are 20-35% lower than in the baseline. PMID- 24467861 TI - Effectiveness and cost-effectiveness of meaning-centered group psychotherapy in cancer survivors: protocol of a randomized controlled trial. AB - BACKGROUND: Meaning-focused coping may be at the core of adequate adjustment to life after cancer. Cancer survivors who experience their life as meaningful are better adjusted, have better quality of life and psychological functioning. Meaning-Centered Group Psychotherapy for Cancer Survivors (MCGP-CS) was designed to help patients to sustain or enhance a sense of meaning and purpose in their lives. The aim of the proposed study is to evaluate the effectiveness and cost effectiveness of MCGP-CS. METHODS/DESIGN: Survivors diagnosed with cancer in the last 5 years and treated with curative intent, are recruited via several hospitals in the Netherlands. After screening, 168 survivors are randomly assigned to one of the three study arms: 1. Meaning-Centered Group Psychotherapy (MCGP-CS) 2. Supportive group psychotherapy (SGP) 3. Care as usual (CAU). Baseline assessment takes place before randomisation, with follow up assessments post-intervention and at 3, 6 and 12 months follow-up. Primary outcome is meaning making (PMP, PTGI, SPWB). Secondary outcome measures address quality of life (EORTC-30), anxiety and depression (HADS), hopelessness (BHS), optimism (LOT-R), adjustment to cancer (MAC), and costs (TIC-P, EQ-5D, PRODISQ). DISCUSSION: Meaning-focused coping is key to adjustment to life after cancer, however, there is a lack of evidence based psychological interventions in this area. Many cancer survivors experience feelings of loneliness and alienation, and have a need for peer support, therefore a group method in particular, can be beneficial for sustaining or enhancing a sense of meaning. If this MCGP-CS is effective for cancer survivors, it can be implemented in the practice of psycho-oncology care. TRIAL REGISTRATION: Netherlands Trial Register, NTR3571. PMID- 24467862 TI - The methodology of population surveys of headache prevalence, burden and cost: principles and recommendations from the Global Campaign against Headache. AB - The global burden of headache is very large, but knowledge of it is far from complete and needs still to be gathered. Published population-based studies have used variable methodology, which has influenced findings and made comparisons difficult. Among the initiatives of the Global Campaign against Headache to improve and standardize methods in use for cross-sectional studies, the most important is the production of consensus-based methodological guidelines. This report describes the development of detailed principles and recommendations. For this purpose we brought together an expert consensus group to include experience and competence in headache epidemiology and/or epidemiology in general and drawn from all six WHO world regions. The recommendations presented are for anyone, of whatever background, with interests in designing, performing, understanding or assessing studies that measure or describe the burden of headache in populations. While aimed principally at researchers whose main interests are in the field of headache, they should also be useful, at least in parts, to those who are expert in public health or epidemiology and wish to extend their interest into the field of headache disorders. Most of all, these recommendations seek to encourage collaborations between specialists in headache disorders and epidemiologists. The focus is on migraine, tension-type headache and medication-overuse headache, but they are not intended to be exclusive to these. The burdens arising from secondary headaches are, in the majority of cases, more correctly attributed to the underlying disorders. Nevertheless, the principles outlined here are relevant for epidemiological studies on secondary headaches, provided that adequate definitions can be not only given but also applied in questionnaires or other survey instruments. PMID- 24467863 TI - Experiences of nurses as postgraduate students of pharmacology and therapeutics: a multiple case narrative study. AB - BACKGROUND: Pharmacology and therapeutics are essential components of educational programmes in prescribing, yet little is known about students' experiences in studying these subjects for a prescribing role. OBJECTIVE: To investigate the views and experiences of nurses as postgraduate students who were studying pharmacology and therapeutics in preparation for a prescribing role. DESIGN: Qualitative study using a multiple case narrative approach. SETTINGS: The participants were undertaking or had recently completed a Master's degree programme; they worked in a range of clinical areas and services in the Auckland region. PARTICIPANTS: Twenty nurses, with advanced clinical backgrounds and experience engaged in postgraduate studies in pharmacology and therapeutics. METHODS: A semi-structured interview of approximately 1h was undertaken with each participant. Transcripts were analysed within and across cases using Narralizer software to support thematic analysis. RESULTS: There were four broad thematic areas. In the first, 'prescribing in the context of advanced nursing practice', participants reflected on why prescribing authority was important to them. In the second theme, 'adequacy of prior pharmacology knowledge' they discussed the relative lack of pharmacology in their undergraduate programmes and in nursing practice. In the third, 'drawing on clinical experience in acquiring pharmacology knowledge', participants discussed how, as they grappled with new pharmacological science, they drew on clinical experience which facilitated their learning. In the fourth theme, 'benefits of increased pharmacology knowledge' they discussed how their studies improved their interactions with patients, medical colleagues and as members of multi-disciplinary teams. CONCLUSIONS: All nurses viewed their studies in pharmacology as fundamental to their roles as prescribers, through knowledge development and an increase in confidence. Although pharmacology theory was new to many participants, their learning was facilitated because they were able to reflect on previous clinical experience and apply this to theory. PMID- 24467864 TI - Attitudes toward Video-Assisted Debriefing after simulation in undergraduate nursing students: an application of Q methodology. AB - BACKGROUND: Video-Assisted Debriefing (VAD) provides an affirmative self reflection through reviewing what went right, what went wrong, what had to be done, and what should be done in the future. OBJECTIVE: To identify attitudes toward Video-Assisted Debriefing after a simulation in undergraduate nursing students. DESIGN: Q-methodology, which has been identified as a method for the analysis of subjective viewpoints and to have the strengths of both qualitative and quantitative methods, was used. SETTING: College of Nursing in Seoul. PARTICIPANTS: A convenience P-sample consisting of 44 third-year undergraduate nursing students. METHODS: Thirty-nine selected Q-statements from each of 44 participants (P-sample) were classified into the shape of a normal distribution using a 9-point bipolar scale from -4 for strongly disagree to +4 for strongly agree. The collected data were analyzed using the pc-QUANL program. RESULTS: Three discrete factors emerged: Factor I (VAD helps self-reflection; strategic view), Factor II (VAD makes us tired and humiliated; reluctant view), and Factor III (VAD boosts self-confidence; forward view). CONCLUSION: The findings could be used as a cornerstone for application of customized debriefing method to undergraduate nursing students. Debriefing techniques considering student's individual learning style. PMID- 24467865 TI - The personal development tutor role: an exploration of student and lecturer experiences and perceptions of that relationship. AB - This exploratory study formed part of the Leadership in Compassionate Care Programme (LCCP) that considered embedding the principles of person-centred compassionate care within an undergraduate nursing curriculum. Currently, there is a lack of literature regarding compassionate care in relation to the student personal development tutor (PDT) relationship. The aim of the study was to explore the current personal development tutor role, within a pre-registration adult nursing programme, in relation to the support provided to students by PDTs and from this, establish what was important in the role from the student and lecturer perspectives, within the context of the LCCP. A qualitative approach utmilising participant interviews was employed. Six undergraduate nursing students on a Bachelor of Nursing adult programme and five PDTs participated in the study and Emotional Touchpoint technique was used to elicit participant experiences. Data were analysed using an adapted version of the Senses Framework, originally proposed by Nolan et al. (2006). The results demonstrate the importance that students and their PDTs attach to the relationship and how elements of care arising from the Senses Framework are fundamental to developing and sustaining this relationship. Further, it is apparent that role modelling in relation to care is considered an important element of the PDT role which has relevance to nurse education and practice. In light of these findings a range of strategies are proposed to enhance the PDT relationship by utilising a modified version of the Senses Framework as a model for PDT and student interaction. PMID- 24467866 TI - The case for reforming the EU regulatory system for GMOs. PMID- 24467868 TI - Treatment of hemopericardium caused by mitral balloon valvuloplasty with activated factor VII: a case report. AB - INTRODUCTION: The use of mitral balloon valvuloplasty as a percutaneous intervention for mitral stenosis has been shown to be efficacious. Cardiac tamponade is a rare but serious complication of this procedure. Despite the low incidence of this event, cardiac tamponade is well-reported in the literature. The management strategy of this complication involves pericardial drainage and correction of coagulopathy, followed by surgical exploration if these interventions fail. With this case report, we demonstrate the successful application of activated factor VII in the management of bleeding after balloon valvuloplasty that persisted despite the standard treatments described above. CASE PRESENTATION: Our patient was a 31-year-old Yemenite man with no significant past medical history, who presented with progressively worsening dyspnea on exertion and limited functional capacity over the last few years. A transesophageal echocardiogram revealed severe mitral stenosis, which was treated with a mitral valve valvuloplasty. The procedure was complicated by significant mediastinal bleeding that did not respond to routine maneuvers, which included pericardiocentesis and correction of coagulopathy. Our patient was evaluated for surgical intervention but responded to treatment with activated factor VII. CONCLUSION: Factor VII may be used in the treatment of refractory mediastinal bleeding secondary to mitral valvuloplasty prior to attempting surgical repair, and therefore may spare the patient the morbidity associated with surgery. PMID- 24467867 TI - Transcription analysis of recombinant industrial and laboratory Saccharomyces cerevisiae strains reveals the molecular basis for fermentation of glucose and xylose. AB - BACKGROUND: There has been much research on the bioconversion of xylose found in lignocellulosic biomass to ethanol by genetically engineered Saccharomyces cerevisiae. However, the rate of ethanol production from xylose in these xylose utilizing yeast strains is quite low compared to their glucose fermentation. In this study, two diploid xylose-utilizing S. cerevisiae strains, the industrial strain MA-R4 and the laboratory strain MA-B4, were employed to investigate the differences between anaerobic fermentation of xylose and glucose, and general differences between recombinant yeast strains, through genome-wide transcription analysis. RESULTS: In MA-R4, many genes related to ergosterol biosynthesis were expressed more highly with glucose than with xylose. Additionally, these ergosterol-related genes had higher transcript levels in MA-R4 than in MA-B4 during glucose fermentation. During xylose fermentation, several genes related to central metabolic pathways that typically increase during growth on non fermentable carbon sources were expressed at higher levels in both strains. Xylose did not fully repress the genes encoding enzymes of the tricarboxylic acid and respiratory pathways, even under anaerobic conditions. In addition, several genes involved in spore wall metabolism and the uptake of ammonium, which are closely related to the starvation response, and many stress-responsive genes mediated by Msn2/4p, as well as trehalose synthase genes, increased in expression when fermenting with xylose, irrespective of the yeast strain. We further observed that transcript levels of genes involved in xylose metabolism, membrane transport functions, and ATP synthesis were higher in MA-R4 than in MA-B4 when strains were fermented with glucose or xylose. CONCLUSIONS: Our transcriptomic approach revealed the molecular events underlying the response to xylose or glucose and differences between MA-R4 and MA-B4. Xylose-utilizing S. cerevisiae strains may recognize xylose as a non-fermentable carbon source, which induces a starvation response and adaptation to oxidative stress, resulting in the increased expression of stress-response genes. PMID- 24467869 TI - A systematic search for discriminating sites in the 16S ribosomal RNA gene. AB - BACKGROUND: The 16S rRNA is by far the most common genomic marker used for prokaryotic classification, and has been used extensively in metagenomic studies over recent years. Along the 16S gene there are regions with more or less variation across the kingdom of bacteria. Nine variable regions have been identified, flanked by more conserved parts of the sequence. It has been stated that the discriminatory power of the 16S marker lies in these variable regions. In the present study we wanted to examine this more closely, and used a supervised learning method to search systematically for sites that contribute to correct classification at either the phylum or genus level. RESULTS: When classifying phyla the site selection algorithm located 50 discriminative sites. These were scattered over most of the alignments and only around half of them were located in the variable regions. The selected sites did, however, have an entropy significantly larger than expected, meaning they are sites of large variation. We found that the discriminative sites typically have a large entropy compared to their closest neighbours along the alignments. When classifying genera the site selection algorithm needed around 80% of the sites in the 16S gene before the classification error reached a minimum. This means that all variation, in both variable and conserved regions, is needed in order to separate genera. CONCLUSIONS: Our findings does not support the statement that the discriminative power of the 16S gene is located only in the variable regions. Variable regions are important, but just as many discriminative sites are found in the more conserved parts. The discriminative power is typically found in sites of large variation located inside shorter regions of higher conservation. PMID- 24467870 TI - A novel, computed tomography guided, trans-cutaneous approach to treat refractory autophony in a patient with a patulous eustachian tube. AB - OBJECTIVE: We report a novel, computed tomography guided treatment for autophony associated with a patulous eustachian tube. METHODS: Case report and literature review of the management of patulous eustachian tube. RESULTS: A 36-year-old woman presented with disabling autophony. Otoscopic examination revealed a poorly mobile right tympanic membrane. High resolution temporal bone computed tomography excluded superior semicircular canal dehiscence. The patient was diagnosed with patulous eustachian tube but failed to achieve therapeutic benefit from conventional endoscopic placement of a silicone elastomer suspension implant adjacent to the eustachian tube. Subsequently, she underwent further silicone elastomer suspension implant placement via a trans-cutaneous, computed tomography guided approach. The patient achieved prompt symptomatic relief and remained symptom-free at six-month follow up. CONCLUSION: This is the first published description of treatment of patulous eustachian tube using a computed tomography guided, trans-cutaneous approach. It serves to highlight to otolaryngologists the fact that computed tomography guided treatment of patulous eustachian tube may control disabling symptoms in patients who have failed to respond to convention endoscopic management. PMID- 24467871 TI - The biomechanical aspects of reconstruction for segmental defects of the mandible: a finite element study to assess the optimisation of plate and screw factors. AB - A bone plate is required to restore the load-bearing capacity of the mandible following a segmental resection. A good understanding of the underlying principles is crucial for developing a reliable reconstruction. A finite element analysis (FEA) technique has been developed to study the biomechanics of the clinical scenarios managed after surgical resection of a tumour or severe trauma to assist in choosing the optimal hardware elements. A computer aided design (CAD) model of an edentulous human mandible was created. Then 4 common segmental defects were simulated. A single reconstruction plate was designed to span the defects. The hardware variations studied were: monocortical or bicortical screw fixation and non-locking or locking plate design. A standardized load was applied to mimic the human bite. The von Mises stress and strain, spatial changes at the screw-bone interfaces were analysed. In general, the locking plate and monocortical screw fixation systems were most effective. Non-locking plating systems produced larger screw "pull-out" displacements, especially at the hemimandible (up to 5% strain). Three screws on either side of the defect were adequate for all scenarios except extensive unilateral defects when additional screws and an increased screw diameter are recommended. The simplification of screw geometry may underestimate stress levels and factors such as poor adaptation of the plate or reduced bone quality are likely to be indications for bicortical locking screw fixation. The current model provides a good basis for understanding the complex biomechanics and developing future refinements in plate or scaffold design. PMID- 24467872 TI - The effects of chronic ethanol self-administration on hippocampal 5-HT1A receptors in monkeys. AB - BACKGROUND: Chronic alcohol consumption reduces brain serotonin and alters the synaptic mechanisms involved in memory formation. Hippocampal 5-HT1A receptors modulate these mechanisms, but the neuroadaptive response of 5HT1A receptors to chronic alcohol self-administration is not well understood. METHODS: Hippocampal tissue from monkeys that voluntarily self-administered ethanol for 12 months (n=9) and accompanying controls (n=8) were prepared for in vitro receptor autoradiography and laser capture microdissection. The 5-HT1A receptor antagonist, [(3)H]MPPF, and the agonist, [(3)H]8-OH-DPAT, were used to measure total and G-protein coupled 5-HT1A receptors respectively. The expression of the genes encoding the 5-HT1A receptor and its trafficking protein Yif1B was measured in microdissected dentate gyrus (DG) granule cells and CA1 pyramidal neurons. RESULTS: An increase in G-protein coupled, but not total, receptors was observed in the posterior pyramidal cell layer of CA1 in ethanol drinkers compared to controls. Chronic ethanol self-administration was also associated with an up regulation of total and G-protein coupled 5-HT1A receptors in the posterior DG polymorphic layer. Changes in receptor binding were not associated with concomitant changes in 5-HT1A receptor mRNA expression. Chronic ethanol self administration was associated with a significant increase in Yif1B gene expression in posterior CA1 pyramidal neurons. CONCLUSIONS: Chronic, ethanol self administration up-regulates hippocampal 5-HT1A receptor density in a region specific manner that does not appear to be due to alterations at the level of transcription but instead may be due to increased receptor trafficking. Further exploration of the mechanisms mediating chronic ethanol-induced 5-HT1A receptor up-regulation and how hippocampal neurotransmission is altered is warranted. PMID- 24467874 TI - The impact of melancholia versus non-melancholia on resting-state, EEG alpha asymmetry: electrophysiological evidence for depression heterogeneity. AB - While depression has been associated with relatively greater right than left frontal cortical activity - a neurophysiological marker reflecting greater activation of the withdrawal system - contradictory findings have been reported. It was hypothesised that melancholia would be associated with relative right frontal activation, in comparison to non-melancholia and controls. We collected 2 min of resting-state, eyes closed, electroencephalographic activity from a total of 237 participants including 117 patients with major depressive disorder (57 with melancholia, 60 with non-melancholia) and 120 healthy controls. In contrast to hypotheses, patients with non-melancholia displayed relative left frontal activation in comparison to controls and those with melancholia. These findings were associated with a small to moderate effect size (Cohen's d=0.30-0.34). Critically, patients with melancholic subtype did not differ from controls despite increased severity - relative to those with non-melancholia - on clinical measures. These results may reflect an increase in approach tendencies in patients with non-melancholia including reassurance seeking, anger or irritable aggression. Findings highlight the need for further research on the heterogeneity MDD. PMID- 24467873 TI - The profile of executive function in OCD hoarders and hoarding disorder. AB - Hoarding disorder is a new mental disorder in DSM-5. It is classified alongside OCD and other presumably related disorders in the Obsessive-Compulsive and Related Disorders chapter. We examined cognitive performance in two distinct groups comprising individuals with both OCD and severe hoarding, and individuals with hoarding disorder without comorbid OCD. Participants completed executive function tasks assessing inhibitory control, cognitive flexibility, spatial planning, probabilistic learning and reversal and decision making. Compared to a matched healthy control group, OCD hoarders showed significantly worse performance on measures of response inhibition, set shifting, spatial planning, probabilistic learning and reversal, with intact decision making. Despite having a strikingly different clinical presentation, individuals with only hoarding disorder did not differ significantly from OCD hoarders on any cognitive measure suggesting the two hoarding groups have a similar pattern of cognitive difficulties. Tests of cognitive flexibility were least similar across the groups, but differences were small and potentially reflected subtle variation in underlying brain pathology together with psychometric limitations. These results highlight both commonalities and potential differences between OCD and hoarding disorder, and together with other lines of evidence, support the inclusion of the new disorder within the new Obsessive-Compulsive and Related Disorders chapter in DSM-5. PMID- 24467875 TI - A group-mediated, home-based physical activity intervention for patients with peripheral artery disease: effects on social and psychological function. AB - BACKGROUND: PAD is a disabling, chronic condition of the lower extremities that affects approximately 8 million people in the United States. The purpose of this study was to determine whether an innovative home-based walking exercise program for patients with peripheral artery disease (PAD) improves self-efficacy for walking, desire for physical competence, satisfaction for physical functioning, social functioning, and acceptance of PAD related pain and discomfort. METHODS: The design was a 6-month randomized controlled clinical trial of 194 patients with PAD. Participants were randomized to 1 of 2 parallel groups: a home-based group-mediated cognitive behavioral walking intervention or an attention control condition. RESULTS: Of the 194 participants randomized, 178 completed the baseline and 6-month follow-up visit. The mean age was 70.66 (+/-9.44) and was equally represented by men and women. Close to half of the cohort was African American. Following 6-months of treatment, the intervention group experienced greater improvement on self-efficacy (p = .0008), satisfaction with functioning (p = .0003), pain acceptance (p = .0002), and social functioning (p = .0008) than the control group; the effects were consistent across a number of potential moderating variables. Change in these outcomes was essentially independent of change in 6-minute walk performance. TRIAL REGISTRATION: [ClinicalTrials.gov Identifier: NCT00693940]. PMID- 24467876 TI - Investigation of variability in image acquisition and contouring during 3D ultrasound guidance for partial breast irradiation. AB - BACKGROUND: Three-dimensional ultrasound (3DUS) at simulation compared to 3DUS at treatment is an image guidance option for partial breast irradiation (PBI). This study assessed if user dependence in acquiring and contouring 3DUS (operator variability) contributed to variation in seroma shifts calculated for breast IGRT. METHODS: Eligible patients met breast criteria for current randomized PBI studies. 5 Operators participated in this study. For each patient, 3 operators were involved in scan acquisitions and 5 were involved in contouring. At CT simulation (CT1), a 3DUS (US1) was performed by a single radiation therapist (RT). 7 to 14 days after CT1 a second CT (CT2) and 3 sequential 3DUS scans (US2a,b,c) were acquired by each of 3 RTs. Seroma shifts, between US1 and US2 scans were calculated by comparing geometric centers of the seromas (centroids). Operator contouring variability was determined by comparing 5 RT's contours for a single image set. Scanning variability was assessed by comparing shifts between multiple scans acquired at the same time point (US1-US2a,b,c). Shifts in seromas contoured on CT (CT1-CT2) were compared to US data. RESULTS: From an initial 28 patients, 15 had CT visible seromas, met PBI dosimetric constraints, had complete US data, and were analyzed. Operator variability contributed more to the overall variability in seroma localization than the variability associated with multiple scan acquisitions (95% confidence mean uncertainty of 6.2 mm vs. 1.1 mm). The mean standard deviation in seroma shift was user dependent and ranged from 1.7 to 2.9 mm. Mean seroma shifts from simulation to treatment were comparable to CT. CONCLUSIONS: Variability in shifts due to different users acquiring and contouring 3DUS for PBI guidance were comparable to CT shifts. Substantial inter observer effect needs to be considered during clinical implementation of 3DUS IGRT. PMID- 24467877 TI - [New treatments of anemia in chronic renal failure]. PMID- 24467878 TI - A single-blinded randomised clinical trial of permissive underfeeding in patients requiring parenteral nutrition. AB - BACKGROUND & AIMS: The importance of adequate nutritional support is well established, but characterising what 'adequate nutrition' represents remains contentious. In recent years there has been increasing interest in the concept of 'permissive underfeeding' where patients are intentionally prescribed less nutrition than their calculated requirements. The aim of this study was to evaluate the effect of permissive underfeeding on septic and nutrition related morbidity in patients requiring short term parenteral nutrition (PN). METHODS: This was a single-blinded randomised clinical trial of 50 consecutive patients requiring parenteral nutritional support. Patients were randomized to receive either normocaloric or hypocaloric feeding (respectively 100% vs. 60% of estimated requirements). The primary end point was septic complications. Secondary end points included the metabolic, physiological and clinical outcomes to the two feeding protocols. RESULTS: Permissive underfeeding was associated with fewer septic complications (3 vs. 12 patients; p = 0.003), and a lower incidence of the systemic inflammatory response syndrome (9 vs. 16 patients; p = 0.017). Permissively underfed patients had fewer feed related complications (2 vs. 9 patients; p = 0.016). CONCLUSION: Permissive underfeeding in patients requiring short term PN appears to be safe and may results in reduced septic and feed-related complications. TRIAL REGISTRATION: NCT01154179 TRIAL REGISTRY: http://clinicaltrials.gov/ct2/show/NCT01154179. PMID- 24467880 TI - Trends in musical theatre voice: an analysis of audition requirements for singers. AB - OBJECTIVES: The American musical theatre industry is a multibillion dollar business in which the requirements for singers are varied and complex. This study identifies the musical genres and voice requirements that are currently most requested at professional auditions to help voice teachers, pedagogues, and physicians who work with musical theatre singers understand the demands of their clients' business. STUDY DESIGN: Frequency count. METHODS: One thousand two thirty-eight professional musical theatre audition listings were gathered over a 6-month period, and information from each listing was categorized and entered into a spreadsheet for analysis. RESULTS: The results indicate that four main genres of music were requested over a wide variety of styles, with more than half of auditions requesting genre categories that may not be served by traditional or classical voice technique alone. CONCLUSIONS: To adequately prepare young musical theatre performers for the current job market and keep the performers healthily making the sounds required by the industry, new singing styles may need to be studied and integrated into voice training that only teaches classical styles. PMID- 24467879 TI - Inferring the relation between transcriptional and posttranscriptional regulation from expression compendia. AB - BACKGROUND: Publicly available expression compendia that measure both mRNAs and sRNAs provide a promising resource to simultaneously infer the transcriptional and the posttranscriptional network. To maximally exploit the information contained in such compendia, we propose an analysis flow that combines publicly available expression compendia and sequence-based predictions to infer novel sRNA target interactions and to reconstruct the relation between the sRNA and the transcriptional network. RESULTS: We relied on module inference to construct modules of coexpressed genes (sRNAs). TFs and sRNAs were assigned to these modules using the state-of-the-art inference techniques LeMoNe and Context Likelihood of Relatedness (CLR). Combining these expressions with sequence-based sRNA-target interactions allowed us to predict 30 novel sRNA-target interactions comprising 14 sRNAs. Our results highlight the role of the posttranscriptional network in finetuning the transcriptional regulation, e.g. by intra-operonic regulation. CONCLUSION: In this work we show how strategies that combine expression information with sequence-based predictions can help unveiling the intricate interaction between the transcriptional and the posttranscriptional network in prokaryotic model systems. PMID- 24467881 TI - Physical activity and sleep profiles in Finnish men and women. AB - BACKGROUND: Physical activity (PA) and sleep are related to cardiovascular diseases (CVD) and their risk factors. The interrelationship between these behaviors has been studied, but there remain questions regarding the association of different types of PA, such as occupational, commuting, and leisure time to sleep, including quality, duration and sufficiency. It is also unclear to what extent sleep affects peoples' PA levels and patterns. Our aim is to investigate the interrelationship between PA and sleep behaviors in the Finnish population, including employment status and gender. METHODS: The study comprised population based data from the FINRISK 2012 Study. A stratified, random sample of 10,000 Finns, 25 to 74 years-old, were sent a questionnaire and an invitation to a health examination. The participation rate was 64% (n = 6,414). Latent class analysis was used to search for different underlying profiles of PA and sleep behavior in men and women, respectively. Models with one through five latent profiles were fitted to the data. Based on fit indicators, a four-class model for men and women, respectively, was decided to be the best fitted model. RESULTS: Four different profiles of PA and sleep were found in both men and women. The most common profile of men comprised 45% of the total participants, and in women, 47%. These profiles were distinguished by probabilities for high leisure time PA and sleep, subjectively rated as sufficient, as well as sleep duration of 7-7.9 hours. The least common profiles represented 5% (men) and 11% (women) of the population, and were characterized by probabilities for physical inactivity, short sleep, and evening type for women and morning type for men. There was also one profile in both genders characterized by likelihood for both high occupational PA and subjectively experienced insufficient sleep. CONCLUSIONS: The use of latent class analysis in investigating the interrelationship between PA and sleep is a novel perspective. The method provides information on the clustering of behaviors in people and the profiles found suggest an accumulative nature of leisure time PA, and better sleep. Our data also suggest that high levels of occupational PA are associated with shorter and poorer sleep. PMID- 24467882 TI - The impact of the use of the Early Warning Score (EWS) on patient outcomes: a systematic review. AB - BACKGROUND: Acute deterioration in critical ill patients is often preceded by changes in physiological parameters, such as pulse, blood pressure, temperature and respiratory rate. If these changes in the patient's vital parameters are recognized early, excess mortality and serious adverse events (SAEs) such as cardiac arrest may be prevented. The Early Warning Score (EWS) is a scoring system which assists with the detection of physiological changes and may help identify patients at risk of further deterioration. OBJECTIVES: The aim of this systematic review is to evaluate the impact of the use of the Early Warning Score (EWS) on particular patient outcomes, such as in-hospital mortality, patterns of intensive care unit admission and usage, length of hospital stay, cardiac arrests and other serious adverse events of adult patients on general wards and in medical admission units. DESIGN AND SETTING: Systematic review of studies identified from the bibliographic databases of PubMed, EMBASE.com and The Cochrane Library. SELECTION CRITERIA: All controlled studies which measured in hospital mortality, ICU mortality, serious adverse events (SAEs), cardiopulmonary arrest, length of stay and documentation of physiological parameters which used a EWS on the ward or the emergency department to identify patients at risk were included in the review. DATA COLLECTION AND ANALYSIS: Three reviewers (NA, AT and EH) independently screened all potentially relevant titles and abstracts for eligibility, by using a standardized data-worksheet. Meta-analysis was not possible due to heterogeneity. MAIN RESULTS: Seven studies met the inclusion criteria. The results of our included studies were mixed, with a positive trend towards better clinical outcomes following the introduction of the EWS chart, sometimes coupled with an outreach service. Six of the seven included studies used mortality as an endpoint: two of these studies reported no significant difference in in-hospital mortality rate; two found a significant reduction of in hospital mortality; two other studies described a trend towards improved survival. Although, both ICU mortality and serious adverse events were not significantly improved, there was a trend towards reduction of these endpoints after introduction of the EWS. However only two studies looked respectively at each endpoint. There were conflicting results concerning cardiopulmonary arrests. One study found a reduction in the incidence of cardiac arrest calls as well as in the mortality of patients who underwent CPR, while another one found an increased incidence of cardio-pulmonary arrests. Neither study met all methodological quality criteria. CONCLUSION: The EWS itself is a simple and easy to use tool at the bedside, which may be of help in recognizing patients with potential for acute deterioration. Coupled with an outreach service, it may be used to timely initiate adequate treatment upon recognition, which may influence the clinical outcomes positively. However, the use of adapted forms of the EWS together with different thresholds, poor or inadequate methodology makes it difficult in drawing comparisons. A general conclusion can thus not be generated from the lack of use of a single standardized score and the use of different populations. In future large multi-centre trials using one standardized score are needed also in order to facilitate comparison. PMID- 24467884 TI - The Mental Health Leadership and Advocacy Program (mhLAP): a pioneering response to the neglect of mental health in Anglophone West Africa. AB - Developing countries in Africa and other regions share a similar profile of insufficient human resources for mental health, poor funding, a high unmet need for services and a low official prioritisation of mental health. This situation is worsened by misconceptions about the causes of mental disorders, stigma and discrimination that frequently result in harmful practices against persons with mental illness. Previous explorations of the required response to these challenges have identified the need for strong leadership and consistent advocacy as potential drivers of the desired change. The Mental Health Leadership and Advocacy Program (mhLAP) is a project that aims to provide and enhance the acquisition of skills in mental health leadership, service development, advocacy and policy planning and to build partnerships for action. Launched in 2010 to serve the Anglophone countries of The Gambia, Ghana, Liberia, Nigeria, Sierra Leone, this paper describes the components of the program, the experience gained since its initiation, and the achievements made during the three years of its implementation. These achievements include: 1) the annual training in mental health leadership and advocacy which has graduated 96 participants from 9 different African countries and 2) the establishment of a broad coalition of service user groups, non-governmental organizations, media practitioners and mental health professionals in each participating country to implement concerted mental health advocacy efforts that are focused on country-specific priorities. PMID- 24467883 TI - Concordance between survey report of Medicaid enrollment and linked Medicaid administrative records in two national studies. AB - The National Health and Nutrition Examination Survey (NHANES) and the National Health Interview Survey (NHIS) are population-based surveys that have each been linked to administrative data from the Centers for Medicare and Medicaid Services (CMS): the Medicaid Analytic eXtract (MAX) files. These linked data were used to examine, among children under age 18 years, respondent-level concordance between Medicaid or the Children's Health Insurance Program (CHIP) enrollment as reported in each survey (NHANES and NHIS) and as indicated by administrative data from the MAX files. Concordance was defined as having Medicaid/CHIP reported as a health insurance source in the survey questionnaire and having a CMS Medicaid/CHIP administrative record in the same month and year as the interview. Records were also considered concordant if there was no report of Medicaid/CHIP coverage based on the interview response and no match to the CMS administrative records for Medicaid enrollment. Between NHANES and MAX, 88% of observations were concordant with respect to Medicaid or CHIP enrollment, yielding a Kappa of 0.71. Between NHIS and MAX, 89% of observations were concordant with respect to Medicaid or CHIP enrollment, yielding a Kappa of 0.73. These concordance rates provide support for the use of both administrative and NHANES and NHIS as a valuable tool for public health researchers and survey methodologists. PMID- 24467885 TI - Novaferon, a novel recombinant protein produced by DNA-shuffling of IFN-alpha, shows antitumor effect in vitro and in vivo. AB - OBJECTIVE: A recombinant antitumor/antiviral protein (Novaferon, Nova) is a new type of interferon, which is produced by artificial design technology combining DNA-shuffling and High Throughput Screening (HTS). METHODS: The in vitro biological activities, such as anti-tumor activity and antiviral activity of Nova and recombinant human interferon alpha-2b (rhIFN-alpha2b) was performed; in vivo anti-tumor activity in nude mice was also tested. Flow cytometry, histo pathological analysis including HE staining and immunohistochemistry, and surface plasmon resonance assay were performed to investigate the underlying mechanisms analysis. RESULTS: Nova exhibited stronger anti-cancer effects compared to rhIFN alpha2b in vitro and in vivo. The antitumor mechanisms of Nova may be related to S phase arrest, pro-apoptosis, and inhibition of tumor angiogenesis. Moreover, Nova exhibited a higher binding affinity for IFN receptor 2 (IFNR2) than rhIFN alpha2b, which is one of the possible reasons accounting for its stronger actions against tumor cells compared with rhIFN-alpha2b. CONCLUSION: Nova has strong antitumor activity and could be a potentially effective therapeutic drug for cancer. PMID- 24467886 TI - Targeting RET-interleukin-6 crosstalk to impair metastatic dissemination in breast cancer. AB - RET (rearranged during transfection) is a receptor tyrosine kinase overexpressed in a subset of oestrogen receptor (ER)-positive breast cancers whose expression is regulated by ER signalling. The article from the Hynes group has reported for the first time that RET expression can also be regulated by the inflammatory cytokine IL-6. Importantly, RET and IL-6 interact at a functional level to control migration and the metastatic potential of ER-positive breast cancer cells, in a process that is mediated by FAK activation. Further, targeting RET with receptor tyrosine kinase inhibitors was reported to be more effective than endocrine therapies in impairing metastatic dissemination in vivo, thereby indicating a level of RET regulation that is independent of ER. PMID- 24467888 TI - Lateral occipitotemporal cortex and action representation. AB - Representation of body and body movements is essential for identifying others intentions or actions or for learning from them. Over the last 10 years, a large collection of research has demonstrated that body representations are distributed across a widely distributed brain network. In this functional magnetic resonance imaging study, we focus on lateral occipitotemporal cortex (LOTC), a recently identified brain region that could represent the body in a multisensory and dynamic manner. We addressed the question of LOTC involvement in visual processing of others' actions through a factorial analysis that manipulated the meaning of an observed action, completed by a psychophysiological interaction analysis. The results show that only left LOTC was significantly activated in relation to others' actions meaning. In addition, only left LOTC was activated during both action observation and action production but it was more dorsal than the activation related to the meaning of observed actions. Furthermore, the psychophysiological interaction analysis showed that when watching meaningless actions, the more dorsal part of the LOTC (the area active during both action production and action observation) had higher functional connectivity with primary visual areas while the more ventral part (that responded to action meaning) had higher correlation with anterior cingulate and medioprefrontal cortices. Taken together these results plead in favour of a strong implication of left LOTC in action observation and understanding, with a possible functional specialisation between the more ventral and the more dorsal parts of LOTC. PMID- 24467889 TI - The cognitive mechanisms underlying perspective taking between conversational partners: evidence from speakers with Alzheimer's disease. AB - Successful communication requires speakers to consider their listeners' perspectives. Little is known about how this ability changes in Alzheimer's Disease (AD) although such knowledge could reveal the cognitive mechanisms fundamental to perspective-taking ability, and reveal which cognitive deficits are fundamental to communication disorders in AD. Patients with mild to moderate AD and age and education matched controls were tested in a communicative perspective-taking task, and on measures of executive control, general cognitive functioning, and lexical retrieval. Patients' ability to perform the perspective taking task was significantly correlated with performance on measures of general cognitive functioning, visual scanning and construction, response conflict and attention. Measures of lexical retrieval tended not to be correlated with performance on the communication task with one exception: semantic but not letter fluency predicted a derived score of perspective-taking ability. These findings broaden our understanding of the cognitive mechanisms underlying perspective taking, and suggest that impairments in perspective taking in AD occur during utterance planning, and at a relatively early processing stage which involves rapid visual scanning and problem solving, rather than during retrieval of lexical items needed to speak. More broadly, these data reveal executive function and semantic deficits, but not problems with lexical retrieval, as more fundamental to the basis of cognitive changes associated with AD. PMID- 24467890 TI - Enhanced resistance to blast fungus in rice (Oryza sativa L.) by expressing the ribosome-inactivating protein alpha-momorcharin. AB - Rice blast caused by Magnaporthe grisea is one of the three major diseases that seriously affect the rice production. Alpha-momorcharin (alpha-MC), a ribosome inactivating protein (RIP) isolated from Momordica charantia seeds, has antifungal effects in vitro. In this study, the alpha-MC gene was constitutively expressed under the control of the 2*35S promoter in transgenic rice (Oryza sativa L.) using an Agrobacterium tumefaciens-mediated method. The nine transgenic plants were obtained and confirmed by PCR and RT-PCR, and the four (B2, B4, B7 and B9) of them whose copy numbers were 1, 2, 3 and 3, respectively, were shown to express the alpha-MC protein by Western blot. The molecular weight of alpha-MC in transgenic plants was approximately 38 kDa larger than the purified alpha-MC protein (28 kDa) in vitro. When the confirmed T1 generations were inoculated with a suspension of M. grisea spores for ten days, the lesions on leaves of transgenic plants were much lesser than those found on wild type (WT). According to the criteria of International Rice Research Institute standard, the mean values for morbidity and disease index numbers were 29.8% and 14.9%, respectively, which were lower than for WT. It is unclear whether RIPs could impact plant fitness and however our results suggest that the alpha-MC protein is an effective antifungal protein preventing rice blast in transgenic rice. PMID- 24467891 TI - Facultative hyperaccumulation of heavy metals and metalloids. AB - Approximately 500 species of plants are known to hyperaccumulate heavy metals and metalloids. The majority are obligate metallophytes, species that are restricted to metalliferous soils. However, a smaller but increasing list of plants are "facultative hyperaccumulators" that hyperaccumulate heavy metals when occurring on metalliferous soils, yet also occur commonly on normal, non-metalliferous soils. This paper reviews the biology of facultative hyperaccumulators and the opportunities they provide for ecological and evolutionary research. The existence of facultative hyperaccumulator populations across a wide edaphic range allows intraspecific comparisons of tolerance and uptake physiology. This approach has been used to study zinc and cadmium hyperaccumulation by Noccaea (Thlaspi) caerulescens and Arabidopsis halleri, and it will be instructive to make similar comparisons on species that are distributed even more abundantly on normal soil. Over 90% of known hyperaccumulators occur on serpentine (ultramafic) soil and accumulate nickel, yet there have paradoxically been few experimental studies of facultative nickel hyperaccumulation. Several hypotheses suggested to explain the evolution of hyperaccumulation seem unlikely when most populations of a species occur on normal soil, where plants cannot hyperaccumulate due to low metal availability. In such species, it may be that hyperaccumulation is an ancestral phylogenetic trait or an anomalous manifestation of physiological mechanisms evolved on normal soils, and may or may not have direct adaptive benefits. PMID- 24467887 TI - Host matrix metalloproteinases in cerebral malaria: new kids on the block against blood-brain barrier integrity? AB - Cerebral malaria (CM) is a life-threatening complication of falciparum malaria, associated with high mortality rates, as well as neurological impairment in surviving patients. Despite disease severity, the etiology of CM remains elusive. Interestingly, although the Plasmodium parasite is sequestered in cerebral microvessels, it does not enter the brain parenchyma: so how does Plasmodium induce neuronal dysfunction? Several independent research groups have suggested a mechanism in which increased blood-brain barrier (BBB) permeability might allow toxic molecules from the parasite or the host to enter the brain. However, the reported severity of BBB damage in CM is variable depending on the model system, ranging from mild impairment to full BBB breakdown. Moreover, the factors responsible for increased BBB permeability are still unknown. Here we review the prevailing theories on CM pathophysiology and discuss new evidence from animal and human CM models implicating BBB damage. Finally, we will review the newly described role of matrix metalloproteinases (MMPs) and BBB integrity. MMPs comprise a family of proteolytic enzymes involved in modulating inflammatory response, disrupting tight junctions, and degrading sub-endothelial basal lamina. As such, MMPs represent potential innovative drug targets for CM. PMID- 24467892 TI - Cellular changes during Medicago truncatula hypocotyl growth depend on temperature and genotype. AB - Hypocotyl growth is a key characteristic for plant emergence, influenced by environmental conditions, particularly temperature, and varying among genotypes. Cellular changes in Medicago truncatula hypocotyl were characterized to study the impact of the environment on heterotrophic growth and analyze differences between genotypes. The number and length of epidermal cells, ploidy levels, and sugar contents were measured in hypocotyls grown in the dark at 20 degrees C and 10 degrees C using two genotypes with contrasting maximum hypocotyl length. Hypocotyl elongation in the dark was due to cell elongation and not to an increase in cell number. A marked increase in cell ploidy level was observed just after germination and until mid elongation of the hypocotyl under all treatments. Larger ploidy levels were also observed in the genotype with the shorter hypocotyl and in cold conditions, but they were associated with larger cells. The increase in ploidy level and in cell volume was concomitant with a marked increase in glucose and fructose contents in the hypocotyl. Finally, differences in hypocotyl length were mainly due to different number of epidermal cells in the seed embryo, shown as a key characteristic of genotypic differences, whereas temperature during hypocotyl growth affected cell volume. PMID- 24467894 TI - Shedding (far-red) light on phytochrome mechanisms and responses in land plants. AB - In order to monitor ambient light conditions, plants rely on functionally diversified photoreceptors. Among these, phytochromes perceive red (R) and far red (FR) light. FR light does not constitute a photosynthetic energy source; it however influences adaptive and developmental processes. In seed plants, phytochrome A (phyA) acts as FR receptor and mediates FR high irradiance responses (FR-HIRs). It exerts a dual role by promoting e.g. germination and seedling de-etiolation in canopy shade and by antagonising shade avoidance growth. Even though cryptogam plants such as mosses and ferns do not have phyA, they show FR-induced responses. In the present review we discuss the mechanistic basis of phyA-dependent FR-HIRs as well as their dual role in seed plants. We compare FR responses in seed plants and cryptogam plants and conclude on different potential concepts for the detection of canopy shade. Scenarios for the evolution of FR perception and responses are discussed. PMID- 24467893 TI - Genistein production in rice seed via transformation with soybean IFS genes. AB - To produce genistein in rice, the isoflavone synthase (IFS) genes, SpdIFS1 and SpdIFS2 were cloned from the Korean soybean cultivar, Sinpaldalkong II as it has a higher genistein content than other soybean varieties. SpdIFS1 and SpdIFS2 show a 99.6% and 98.2% identity at the nucleotide level and 99.4% and 97.9% identity at the amino acid level, respectively, with IFS1 and IFS2 from soybean (GenBank accession Nos. AF195798 and AF195819). Plant expression vectors were constructed harboring SpdIFS1 or SpdIFS2 under the control of a rice globulin promoter that directs seed specific expression, and used to transform two rice varieties, Heugnam, a black rice, and Nakdong, a normal rice cultivar without anthocyanin pigment. Because naringenin, the substrate of SpdIFS1 and SpdIFS2, is on the anthocyanin biosynthesis pathway, the relative production rate of genistein was compared between SpdIFS-expressing transgenic Heugnam and Nakdong. Southern blot analysis of eight of the resulting transgenic rice plants revealed that the T0 plants had one to three copies of the SpdIFS1 or SpdIFS2 gene. The highest level of genistein content found in rice seeds was 103 MUg/g. These levels were about 30-fold higher in our transgenic rice lines than the genistein aglycon content of a non-leguminous IFS-expressing transgenic tobacco petal, equaling about 12% of total genistein content of Sinpaldalkong II. There were no significant differences found between the genistein content in Heugnam and Nakdong transgenic rice plants. PMID- 24467895 TI - SNP discovery and high-density genetic mapping in faba bean (Vicia faba L.) permits identification of QTLs for ascochyta blight resistance. AB - Ascochyta blight, caused by the fungus Ascochyta fabae Speg., is a common and destructive disease of faba bean (Vicia faba L.) on a global basis. Yield losses vary from typical values of 35-40% to 90% under specific environmental conditions. Several sources of resistance have been identified and used in breeding programs. However, introgression of the resistance gene determinants into commercial cultivars as a gene pyramiding approach is reliant on selection of closely linked genetic markers. A total of 14,552 base variants were identified from a faba bean expressed sequence tag (EST) database, and were further quality assessed to obtain a set of 822 high-quality single nucleotide polymorphisms (SNPs). Sub-sets of 336 EST-derived simple sequence repeats (SSRs) and 768 SNPs were further used for high-density genetic mapping of a biparental faba bean mapping population (Icarus*Ascot) that segregates for resistance to ascochyta blight. The linkage map spanned a total length of 1216.8 cM with 12 linkage groups (LGs) and an average marker interval distance of 2.3 cM. Comparison of map structure to the genomes of closely related legume species revealed a high degree of conserved macrosynteny, as well as some rearrangements. Based on glasshouse evaluation of ascochyta blight resistance performed over two years, four genomic regions controlling resistance were identified on Chr-II, Chr VI and two regions on Chr-I.A. Of these, one (QTL-3) may be identical with quantitative trait loci (QTLs) identified in prior studies, while the others (QTL 1, QTL-2 and QTL-4) may be novel. Markers in close linkage to ascochyta blight resistance genes identified in this study can be further validated and effectively implemented in faba bean breeding programs. PMID- 24467896 TI - Sex determination in flowering plants: papaya as a model system. AB - Unisexuality in flowering plants evolved from a hermaphrodite ancestor. Transition from hermaphrodite to unisexual flowers has occurred multiple times across the different lineages of the angiosperms. Sexuality in plants is regulated by genetic, epigenetic and physiological mechanisms. The most specialized mechanism of sex determination is sex chromosomes. The sex chromosomes ensure the stable segregation of sexual phenotypes by preventing the recombination of sex determining genes. Despite continuous efforts, sex determining genes of dioecious plants have not yet been cloned. Concerted efforts with various model systems are necessary to understand the complex mechanism of sex determination in plants. Papaya (Carica papaya L.) is a tropical fruit tree with three sex forms, male, hermaphrodite, and female. Sexuality in papaya is determined by an XY chromosome system that is in an early evolutionary stage. The male and hermaphrodite of papaya are controlled by two different types of Y chromosomes: Y and Y(h). Large amounts of information in the area of genetics, genomics, and epigenetics of papaya have been accumulated over the last few decades. Relatively short lifecycle, small genome size, and readily available genetic and genomic resources render papaya an excellent model system to study sex determination and sex chromosomes in flowering plants. PMID- 24467897 TI - Overexpression of the receptor-like protein kinase genes AtRPK1 and OsRPK1 reduces the salt tolerance of Arabidopsis thaliana. AB - AtRPK1 (AT1G69270) is a leucine-rich repeat receptor-like protein kinase (LRR RLK) gene in Arabidopsis thaliana. The rice gene Os07g0602700 (OsRPK1) is the homolog of AtRPK1. AtRPK1 and OsRPK1 were overexpressed and the expression of AtRPK1 was inhibited by RNAi in A. thaliana. The functional results showed that the degrees of salt tolerance of the 35S:RPK1 A. thaliana plants were significantly lower than that of the control plants. The AtRPK1-RNAi A. thaliana plants exhibited higher salt tolerance than the wild-type plants (Col). The subcellular localisation results showed that the RPK1 proteins were mainly distributed on the cell membrane and that the overexpressed AtRPK1 proteins exhibited a significantly clustered distribution. The physiological analyses revealed that the overexpression of the RPK1 genes increased the membrane permeability in the transgenic A. thaliana plants. In response to salt stress, these plants exhibited an increased Na(+) flux into the cell, which caused greater damage to the cell. The real-time quantitative PCR analysis showed that the expression of the P5CS1 gene was inhibited and the SOS signalling pathway was blocked in the 35S:AtRPK1 A. thaliana plants. These effects at least partially contribute to the salt-sensitive phenotype of the 35S:RPK1 plants. PMID- 24467898 TI - New challenges in plant aquaporin biotechnology. AB - Recent advances concerning genetic manipulation provide new perspectives regarding the improvement of the physiological responses in herbaceous and woody plants to abiotic stresses. The beneficial or negative effects of these manipulations on plant physiology are discussed, underlining the role of aquaporin isoforms as representative markers of water uptake and whole plant water status. Increasing water use efficiency and the promotion of plant water retention seem to be critical goals in the improvement of plant tolerance to abiotic stress. However, newly uncovered mechanisms, such as aquaporin functions and regulation, may be essential for the beneficial effects seen in plants overexpressing aquaporin genes. Under distinct stress conditions, differences in the phenotype of transgenic plants where aquaporins were manipulated need to be analyzed. In the development of nano-technologies for agricultural practices, multiple-walled carbon nanotubes promoted plant germination and cell growth. Their effects on aquaporins need further investigation. PMID- 24467899 TI - Changes in carbohydrate content in zucchini fruit (Cucurbita pepo L.) under low temperature stress. AB - The postharvest handling of zucchini fruit includes low-temperature storage, making cold stress unavoidable. We have investigated the changes of soluble carbohydrates under this stress and its relation with weight loss and chilling injury in zucchini fruit during postharvest storage at 4 degrees C and 20 degrees C for up to 14 days. Two varieties with different degrees of chilling tolerance were compared: Natura, the more tolerant variety, and Sinatra, the variety that suffered more severe chilling-injury symptoms and weight loss. In both varieties, total soluble carbohydrates, reducing soluble carbohydrates and polyols content was generally higher during storage at 4 degrees C than at 20 degrees C, thus these parameters are related to the physiological response of zucchini fruit to cold stress. However, the raffinose content increased in Natura and Sinatra fruits during storage at 4 degrees C and 20 degrees C, although at 20 degrees C the increase in raffinose was more remarkable than at 4 degrees C in both varieties, so that the role of raffinose could be more likely related to dehydration than to chilling susceptibility of zucchini fruit. Glucose, fructose, pinitol, and acid invertase activity registered opposite trends in both varieties against chilling, increasing in Natura and decreasing in Sinatra. The increase in acid invertase activity in Natura fruit during cold storage could contribute in part to the increase of these reducing sugars, whose metabolism could be involved in the adaptation to postharvest cold storage. PMID- 24467900 TI - Transcriptome and metabolome analysis of citrus fruit to elucidate puffing disorder. AB - A systems-level analysis reveals details of molecular mechanisms underlying puffing disorder in Citrus fruit. Flavedo, albedo and juice sac tissues of normal fruits and fruits displaying symptoms of puffing disorder were studied using metabolomics at three developmental stages. Microarrays were used to compare normal and puffed fruits for each of the three tissues. A protein-protein interaction network inferred from previous work on Arabidopsis identified hub proteins whose transcripts show significant changes in expression. Glycolysis, the backbone of primary metabolism, appeared to be severely affected by the disorder, based on both transcriptomic and metabolomic results. Significantly less citric acid was observed consistently in puffed fruits. Gene set enrichment analysis suggested that glycolysis and carbohydrate metabolism were significantly altered in puffed samples in both albedo and flavedo. Expression of invertases and genes for sucrose export, amylose-starch and starch-maltose conversion was higher in puffed fruits. These changes may significantly alter source-sink communications. Genes associated with gibberellin and cytokinin signaling were downregulated in symptomatic albedo tissues, suggesting that these hormones play key roles in the disorder. Findings may be applied toward the development of early diagnostic methods based on host response genes and metabolites (i.e. citric acid), and toward therapeutics based on hormones. PMID- 24467901 TI - Nitrate affects sensu-stricto germination of after-ripened Sisymbrium officinale seeds by modifying expression of SoNCED5, SoCYP707A2 and SoGA3ox2 genes. AB - The influence of nitrate upon the germination of Sisymbrium officinale seeds is not entirely controlled by after-ripening (AR), a process clearly influenced by nitrate. Recently, we have reported that nitrate affects sensu-stricto germination of non-AR (AR0) seeds by modifying the expression of crucial genes involved in the metabolism of GA and ABA. In this study, we demonstrate that nitrate affects also the germination of AR seeds because: (i) the AR negatively alters the ABA sensitivity being the seed more ABA-sensible as the AR is farthest from optimal (AR0 and AR20 versus AR7); in the presence of diniconazole (DZ), a competitive inhibitor of ABA 8'-hydroxylase, testa rupture is affected while the endosperm rupture is not. (ii) AR7 seed-coat rupture is not inhibited by paclobutrazol (PBZ) suggesting that nitrate can act by a mechanism GA independent. (iii) The germination process is accelerated by nitrate, most probably by the increase in the expression of SoNCED5, SoCYP707A2 and SoGA3ox2 genes. Taken together, these and previous results demonstrate that nitrate promotes germination of AR and non-AR seeds through transcriptional changes of different genes involved in ABA and GA metabolism. PMID- 24467902 TI - Identification and validation of promoters and cis-acting regulatory elements. AB - Studies of promoters that largely regulate gene expression at the transcriptional level are crucial for improving our basic understanding of gene regulation and will expand the toolbox of available promoters for use in plant biotechnology. In this review, we present a comprehensive analysis of promoters and their underlying mechanisms in transcriptional regulation, including epigenetic marks and chromatin-based regulation. Large-scale prediction of promoter sequences and their contributing cis-acting elements has become routine due to recent advances in transcriptomic technologies and genome sequencing of several plants. However, predicted regulatory sequences may or may not be functional and demonstration of the contribution of the element to promoter activity is essential for confirmation of regulatory sequences. Synthetic promoters and introns provide useful approaches for functional validation of promoter sequences. The development and improvement of gene expression tools for rapid, efficient, predictable, and high-throughput analysis of promoter components will be critical for confirmation of the functional regulatory element sequences identified through transcriptomic and genomic analyses. PMID- 24467903 TI - Controlled free radical attack in the apoplast: a hypothesis for roles of O, N and S species in regulatory and polysaccharide cleavage events during rapid abscission by Azolla. AB - Shedding of organs by abscission is a key terminal step in plant development and stress responses. Cell wall (CW) loosening at the abscission zone can occur through a combination chain breakage of apoplastic polysaccharides and tension release of cellulose microfibrils. Two distinctly regulated abscission cleavage events are amenable to study in small water ferns of the genus Azolla; one is a rapid abscission induced by environmental stimuli such as heat or chemicals, and the other is an ethylene-induced process occurring more slowly through the action of hydrolytic enzymes. Although free radicals are suggested to be involved in the induction of rapid root abscission, its mechanism is not fully understood. The apoplast contains peroxidases, metal-binding proteins and phenolic compounds that potentially generate free radicals from H2O2 to cleave polysaccharides in the CW and middle lamella. Effects of various thiol-reactive agents implicate the action of apoplastic peroxidases having accessible cysteine thiols in rapid abscission. The Ca(2+) dependency of rapid abscission may reflect the stabilization Ca(2+) confers to peroxidase structure and binding to pectin. To spur further investigation, we present a hypothetical model for small signaling molecules H2O2 and NO and their derivatives in regulating, via modification of putative protein thiols, free radical attack of apoplastic polysaccharides. PMID- 24467904 TI - Inheritance of evolved resistance to a novel herbicide (pyroxasulfone). AB - Agricultural weeds have rapidly adapted to intensive herbicide selection and resistance to herbicides has evolved within ecological timescales. Yet, the genetic basis of broad-spectrum generalist herbicide resistance is largely unknown. This study aims to determine the genetic control of non-target-site herbicide resistance trait(s) that rapidly evolved under recurrent selection of the novel lipid biosynthesis inhibitor pyroxasulfone in Lolium rigidum. The phenotypic segregation of pyroxasulfone resistance in parental, F1 and back-cross (BC) families was assessed in plants exposed to a gradient of pyroxasulfone doses. The inheritance of resistance to chemically dissimilar herbicides (cross resistance) was also evaluated. Evolved resistance to the novel selective agent (pyroxasulfone) is explained by Mendelian segregation of one semi-dominant allele incrementally herbicide-selected at higher frequency in the progeny. In BC families, cross-resistance is conferred by an incompletely dominant single major locus. This study confirms that herbicide resistance can rapidly evolve to any novel selective herbicide agents by continuous and repeated herbicide use. The results imply that the combination of herbicide options (rotation, mixtures or combinations) to exploit incomplete dominance can provide acceptable control of broad-spectrum generalist resistance-endowing monogenic traits. Herbicide diversity within a set of integrated management tactics can be one important component to reduce the herbicide selection intensity. PMID- 24467905 TI - Is Ca2+ involved in the signal transduction pathway of boron deficiency? New hypotheses for sensing boron deprivation. AB - Plants sense and transmit nutrient-deprivation signals to the nucleus. This increasingly interesting research field advances knowledge of signal transduction pathways for mineral deficiencies. The understanding of this topic for most micronutrients, especially boron (B), is more limited. Several hypotheses have been proposed to explain how a B deprivation signal would be conveyed to the nucleus, which are briefly summarized in this review. These hypotheses do not explain how so many metabolic and physiological processes quickly respond to B deficiency. Short-term B deficiency affects the cytosolic Ca(2+) levels as well as root expression of genes involved in Ca(2+) signaling. We propose and discuss that Ca(2+) and Ca(2+)-related proteins - channels/transporters, sensor relays, and sensor responders - might have major roles as intermediates in a transduction pathway triggered by B deprivation. This hypothesis may explain how plants sense and convey the B-deprivation signal to the nucleus and modulate physiological responses. The possible role of arabinogalactan-proteins in the B deficiency signaling pathway is also taken into account. PMID- 24467906 TI - Senescence, dormancy and tillering in perennial C4 grasses. AB - Perennial, temperate, C4 grasses, such as switchgrass and miscanthus have been tabbed as sources of herbaceous biomass for the production of green fuels and chemicals based on a number of positive agronomic traits. Although there is important literature on the management of these species for biomass production on marginal lands, numerous aspects of their biology are as yet unexplored at the molecular level. Perenniality, a key agronomic trait, is a function of plant dormancy and winter survival of the below-ground parts of the plants. These include the crowns, rhizomes and meristems that will produce tillers. Maintaining meristem viability is critical for the continued survival of the plants. Plant tillers emerge from the dormant crown and rhizome meristems at the start of the growing period in the spring, progress through a phase of vegetative growth, followed by flowering and eventually undergo senescence. There is nutrient mobilization from the aerial portions of the plant to the crowns and rhizomes during tiller senescence. Signals arising from the shoots and from the environment can be expected to be integrated as the plants enter into dormancy. Plant senescence and dormancy have been well studied in several dicot species and offer a potential framework to understand these processes in temperate C4 perennial grasses. The availability of latitudinally adapted populations for switchgrass presents an opportunity to dissect molecular mechanisms that can impact senescence, dormancy and winter survival. Given the large increase in genomic and other resources for switchgrass, it is anticipated that projected molecular studies with switchgrass will have a broader impact on related species. PMID- 24467907 TI - Induction of phytic acid synthesis by abscisic acid in suspension-cultured cells of rice. AB - A pathway of phytic acid (PA) synthesis in plants has been revealed via investigations of low phytic acid mutants. However, the regulation of this pathway is not well understood because it is difficult to control the environments of cells in the seeds, where PA is mainly synthesized. We modified a rice suspension culture system in order to study the regulation of PA synthesis. Rice cells cultured with abscisic acid (ABA) accumulate PA at higher levels than cells cultured without ABA, and PA accumulation levels increase with ABA concentration. On the other hand, higher concentrations of sucrose or inorganic phosphorus do not affect PA accumulation. Mutations in the genes RINO1, OsMIK, OsIPK1 and OsLPA1 have each been reported to confer low phytic acid phenotypes in seeds. Each of these genes is upregulated in cells cultured with ABA. OsITPK4 and OsITPK6 are upregulated in cells cultured with ABA and in developing seeds. These results suggest that the regulation of PA synthesis is similar between developing seeds and cells in this suspension culture system. This system will be a powerful tool for elucidating the regulation of PA synthesis. PMID- 24467908 TI - Proteomics changes during the incompatible interaction between cowpea and Colletotrichum gloeosporioides (Penz.) Penz and Sacc. AB - Anthracnose represents an important disease of cowpea [Vigna unguiculata L. (Walp.)] caused by the hemibiothrophic fungus Colletotrichum gloeosporioides that drastically reduces cowpea field production. In this study we investigated some biochemical aspects underlying the incompatible interaction between a resistant cowpea genotype and C. gloeosporioides using a proteomic approach. Analyses of two-dimensional gel electrophoresis patterns and protein identification indicate C. gloeosporioides infection-dependent cowpea leaf proteome changes associated with metabolism, photosynthesis, response to stress, oxidative burst and scavenging, defense signaling, and pathogenesis-related proteins. Moreover the C. gloeosporioides responsive proteins interaction network in cowpea revealed the interconnected modulation of key cellular processes involving particularly antioxidants proteins, photosynthetic apparatus forming proteins and proteins of the energetic metabolism that interact with each other suggesting that their expression changes are also important for resistance of cowpea to C. gloeosporioides. PMID- 24467909 TI - Molecular subtyping of Blastocystis spp. using a new rDNA marker from the mitochondria-like organelle genome. AB - Blastocystis spp. are common anaerobic intestinal protozoa found in both human and animals. They are characterized by a high genetic diversity with at least 17 subtypes (STs) that have been described on the basis of a 600 bp 'barcoding region' from the 18S rDNA gene. However, analysis of the recently sequenced genome of a Blastocystis ST7 isolate (strain B) revealed the presence of multiple variable copies of the 18S rDNA gene, with 17 completely assembled copies. Comparison of the barcoding region from these 17 copies allowed us to classify the 18S rDNA sequences into 6 clusters, each cluster containing identical sequences. Surprisingly, 4 of these clusters had the highest homology with 18S rDNA sequences from 2 other Blastocystis ST7 isolates referred as QQ98-4 and H. These results suggest that the 18S rDNA gene is not the marker of choice to discriminate between strains within STs. In the present study, we identified a single-copy subtyping rDNA marker in the genome of the mitochondria-like organelles (MLOs). Using a partial sequence of the MLO rDNA, we successfully subtyped 66 isolates from both human and animals belonging to Blastocystis ST1 to ST10. Our results also indicate that this mitochondrial marker could be useful to detect co-infections by different isolates of a same ST. PMID- 24467910 TI - The clinical features, diagnosis and classification of dermatomyositis. AB - Dermatomyositis (DM) is an idiopathic inflammatory myopathy (IIM) characterized by an inflammatory infiltrate primarily affecting the skeletal muscle and skin. Most common and peculiar cutaneous lesions include Gottron's papules, Gottron's sign and heliotrope rash. Different DM subsets have been identified until now encompassing classic DM, amyopathic DM, hypomyopathic DM, post-myopathic DM, and DM sine dermatitis. Patients with DM have a higher incidence rate of malignancy than the normal population. In these patients cancer occurs in about 30% of cases with higher occurrence in men and in elderly people. Bohan and Peter's diagnostic criteria, proposed in 1975, have been widely accepted and used until now. In the last ten years muscle immunopathology, myositis specific autoantibodies testing, and the use of new techniques of muscle imaging such as contrast-enhanced ultrasound or Magnetic Resonance Imaging have been introduced in the diagnostic work-up of patients with DM leading to the development of new diagnostic criteria. PMID- 24467912 TI - Reconstruction of the partial pinna using autologous ear cartilage combined with a local sliding skin flap. PMID- 24467913 TI - The evolution of decision rules in complex environments. AB - Models and experiments on adaptive decision-making typically consider highly simplified environments that bear little resemblance to the complex, heterogeneous world in which animals (including humans) have evolved. These studies reveal an array of so-called cognitive biases and puzzling features of behaviour that seem irrational in the specific situation presented to the decision-maker. Here we review an emerging body of work that highlights spatiotemporal heterogeneity and autocorrelation as key properties of most real world environments that may help us understand why these biases evolved. Ecologically rational decision rules adapted to such environments can lead to apparently maladaptive behaviour in artificial experimental settings. We encourage researchers to consider environments with greater complexity to understand better how evolution has shaped our cognitive systems. PMID- 24467914 TI - Increased systemic and adipose tissue inflammation differentiates obese women with T2DM from obese women with normal glucose tolerance. AB - INTRODUCTION: Obesity is strongly related to type-2 diabetes (T2DM), but there is a subset of obese individuals that remains relatively insulin sensitive and metabolically healthy. This study determined to what extent differences in metabolic health in obese women are associated with differences in adipose tissue and/or systemic inflammation. METHODS: The subject group consisted of age comparable lean (n=12) and obese women either with T2DM (n=28) or normal glucose tolerance (NGT; n=26). Number of crown like structures (CLS) and adipocyte size were measured in subcutaneous and visceral adipose tissue of the obese women. Circulating cytokine and free fatty acid (FFA) levels, as well as number and activation status of peripheral leukocytes were determined. RESULTS: Obese T2DM subjects showed higher circulating levels of IL-6, FFA and glycerol as compared to obese NGT subjects. Obese T2DM subjects had higher absolute numbers of peripheral leukocytes which were mainly due to an increase of T helper cells. Activation status of circulating cytotoxic T (CD8+CD25+) and B (CD19+CD38+) cells was significantly increased in obese NGT subjects as compared to lean but was not different between the two obese groups. Subcutaneous adipose tissue of obese T2DM subjects contained more CLS than adipose tissue of obese NGT subjects. CONCLUSION: Obese T2DM subjects show higher FFA levels and adipose tissue macrophage infiltration in addition to higher levels of circulating IL-6 and numbers of CD4+ T cells than obese NGT subjects. Hence, obese T2DM subjects show a higher extent of inflammation at both the systemic and adipose tissue level. PMID- 24467915 TI - Accumulation of adiponectin in inflamed adipose tissues of obese mice. AB - OBJECTIVE: Adipose tissue inflammation plays an important role in the pathogenesis of obesity-associated complications, such as atherosclerosis. Adiponectin secreted from adipocytes has various beneficial effects including anti-inflammatory effect. Obesity often presents with hypoadiponectinemia. However, the mechanism and adiponectin movement in obesity remain uncharacterized. Here we investigated tissue distribution of adiponectin protein in lean and obese mice. METHODS: Adiponectin protein levels were evaluated by enzyme-linked immunosorbent assay and western blotting. Adipose tissues were fractionated into mature adipocyte fraction (MAF) and stromal vascular fraction (SVF). RESULTS: Adiponectin protein was detected not only in MAF but also in SVF, which lacks adiponectin mRNA expression, of adipose tissue remarkably. SVF adiponectin protein level was higher in obese mice than in lean mice. The mechanism of adiponectin accumulation was investigated in adiponectin-deficient (APN-KO) mice after injection of plasma from wild-type mice. These mice showed accumulation of exogenous adiponectin, which derived from wild type mice, in adipose tissues, and the adiponectin was more observed in SVF of diet induced obese APN-KO mice than lean APN-KO mice. Among the adiponectin binding proteins, T-cadherin mRNA and protein levels in SVF of obese mice were remarkably higher than in lean mice. Oxidative stress levels were also significantly higher in SVF of obese mice than lean mice. Mechanistically, H2O2 up-regulated T-cadherin mRNA level in murine macrophages. CONCLUSIONS: The results demonstrated adiponectin targets to adipose SVF of obese mice. These findings should shed a new light on the pathology of adipose tissue inflammation and hypoadiponectinemia of obesity. PMID- 24467916 TI - Breast conserving treatment for breast cancer: dosimetric comparison of different non-invasive techniques for additional boost delivery. AB - BACKGROUND: Today it is unclear which technique for delivery of an additional boost after whole breast radiotherapy for breast conserved patients should be state of the art. We present a dosimetric comparison of different non-invasive treatment techniques for additional boost delivery. METHODS: For 10 different tumor bed localizations, 7 different non-invasive treatment plans were made. Dosimetric comparison of PTV-coverage and dose to organs at risk was performed. RESULTS: The Vero system achieved an excellent PTV-coverage and at the same time could minimize the dose to the organs at risk with an average near-maximum-dose (D2) to the heart of 0.9 Gy and the average volume of ipsilateral lung receiving 5 Gy (V5) of 1.5%. The TomoTherapy modalities delivered an average D2 to the heart of 0.9 Gy for the rotational and of 2.3 Gy for the static modality and an average V5 to the ipsilateral lung of 7.3% and 2.9% respectively. A rotational technique offers an adequate conformity at the cost of more low dose spread and a larger build-up area. In most cases a 2-field technique showed acceptable PTV coverage, but a bad conformity. Electrons often delivered a worse PTV-coverage than photons, with the planning requirements achieved only in 2 patients and with an average D2 to the heart of 2.8 Gy and an average V5 to the ipsilateral lung of 5.8%. CONCLUSIONS: We present advices which can be used as guidelines for the selection of the best individualized treatment. PMID- 24467917 TI - Implementing and evaluating the German adaptation of the "Strengthening Families Program 10 - 14"- a randomized-controlled multicentre study. AB - BACKGROUND: Substance use problems in childhood and adolescence can severely impact youth's physical and mental well-being. When substance use is initiated early, the risk for moving from hazardous substance use to substance use disorders (SUD) is particularly high to developmentally induced biological and psychological vulnerability towards chronic trajectories in youth. Thus, risk factors for developing SUD should be addressed early in life by adequate preventive measures reaching out to children, adolescents, and their families. The study described in this protocol will test the effectiveness of the German adaptation of the Strengthening Families Program for Parents and Youth 10-14 (SFP 10-14) aimed at ten to 14 year old adolescents and their caregivers. METHODS/DESIGN: The study is conducted in four large German cities by counselling centres in the areas of youth welfare, social work and addiction aid. The effectiveness of the manualised group programme "Familien Starken" consisting of seven sessions and four booster-sessions is tested among N = 288 children and participating parents in a multicentre randomised controlled trial with standardised assessment instruments. The control condition receives a minimal 2 hour intervention on parenting delivered in a school setting. Data are collected shortly before and after as well as six and 18 months after the intervention. We expect to replicate the favourable effects of the SFP 10-14 programme in the United States in the area of substance use initiation, family functioning and individual psychosocial adjustment. DISCUSSION: The trial is expected to contribute to the growing literature on family-based preventive interventions, their effectiveness and feasibility. It is in line with several other current European efforts aimed at strengthening families against the detrimental effects of substance abuse in youth. The results of these trials will expand our knowledge on adapting evidence-based interventions and delivering them in diverse cultures and settings. TRIAL REGISTRATION: Current Controlled Trials ISRCTN90251787. PMID- 24467918 TI - Myocardial arterial spin labeling perfusion imaging with improved sensitivity. AB - BACKGROUND: Myocardial arterial spin labeling (ASL) is a noninvasive MRI based technique that is capable of measuring myocardial blood flow (MBF) in humans. It suffers from poor sensitivity to MBF due to high physiological noise (PN). This study aims to determine if the sensitivity of myocardial ASL to MBF can be improved by reducing image acquisition time, via parallel imaging. METHODS: Myocardial ASL scans were performed in 7 healthy subjects at rest using flow sensitive alternating inversion recovery (FAIR) tagging and balanced steady state free precession (SSFP) imaging. Sensitivity encoding (SENSE) with a reduction factor of 2 was used to shorten each image acquisition from roughly 300 ms per heartbeat to roughly 150 ms per heartbeat. A paired Student's t-test was performed to compare measurements of myocardial blood flow (MBF) and physiological noise (PN) from the reference and accelerated methods. RESULTS: The measured PN (mean +/- standard deviation) was 0.20 +/- 0.08 ml/g/min for the reference method and 0.08 +/- 0.05 ml/g/min for the accelerated method, corresponding to a 60% reduction. PN measured from the accelerated method was found to be significantly lower than that of the reference method (p=0.0059). There was no significant difference between MBF measured from the accelerated and reference ASL methods (p=0.7297). CONCLUSIONS: In this study, significant PN reduction was achieved by shortening the acquisition window using parallel imaging with no significant impact on the measured MBF. This indicates an improvement in sensitivity to MBF and may also enable the imaging of subjects with higher heart rates and imaging during systole. PMID- 24467911 TI - Proton-sensitive cation channels and ion exchangers in ischemic brain injury: new therapeutic targets for stroke? AB - Ischemic brain injury results from complicated cellular mechanisms. The present therapy for acute ischemic stroke is limited to thrombolysis with the recombinant tissue plasminogen activator (rtPA) and mechanical recanalization. Therefore, a better understanding of ischemic brain injury is needed for the development of more effective therapies. Disruption of ionic homeostasis plays an important role in cell death following cerebral ischemia. Glutamate receptor-mediated ionic imbalance and neurotoxicity have been well established in cerebral ischemia after stroke. However, non-NMDA receptor-dependent mechanisms, involving acid-sensing ion channel 1a (ASIC1a), transient receptor potential melastatin 7 (TRPM7), and Na(+)/H(+) exchanger isoform 1 (NHE1), have recently emerged as important players in the dysregulation of ionic homeostasis in the CNS under ischemic conditions. These H(+)-sensitive channels and/or exchangers are expressed in the majority of cell types of the neurovascular unit. Sustained activation of these proteins causes excessive influx of cations, such as Ca(2+), Na(+), and Zn(2+), and leads to ischemic reperfusion brain injury. In this review, we summarize recent pre clinical experimental research findings on how these channels/exchangers are regulated in both in vitro and in vivo models of cerebral ischemia. The blockade or transgenic knockdown of these proteins was shown to be neuroprotective in these ischemia models. Taken together, these non-NMDA receptor-dependent mechanisms may serve as novel therapeutic targets for stroke intervention. PMID- 24467919 TI - Infertility service use in the United States: data from the National Survey of Family Growth, 1982-2010. AB - OBJECTIVES: This report presents nationally representative estimates and trends for infertility service use among women aged 15-44 and 25-44 in the United States in 1982-2010. While greater detail on types of infertility service is shown for women, basic data on types of infertility service use, as reported by men aged 25 44, are also presented. METHODS: Data for this report come primarily from the 2006-2010 National Survey of Family Growth (NSFG), consisting of 22,682 interviews with men and women aged 15-44, conducted from June 2006 through June 2010. The response rate for females in the 2006-2010 NSFG was 78%, and for males was 75%. Selected trends are shown based on prior NSFG cycles. RESULTS: Twelve percent of women aged 15-44 in 2006-2010 (7.3 million women), or their husbands or partners, had ever used infertility services. Among women aged 25-44, 17% (6.9 million) had ever used any infertility service, a significant decrease from 20% in 1995. Thirty-eight percent of nulliparous women with current fertility problems in 2006-2010 had ever used infertility services, significantly less than 56% of such women in 1982. In all survey years, ever-use of medical help to get pregnant was highest among older and nulliparous women, non-Hispanic white women, women with current fertility problems, and women with higher levels of education and household income. The most commonly used infertility services among women aged 25-44 in 2006-2010 were advice, testing, medical help to prevent miscarriage, and ovulation drugs. Ever-use of infertility services was reported by 9.4% of men aged 25-44 in 2006-2010, similar to levels seen in 2002. PMID- 24467920 TI - The role of stability measurements of the Baha(r) system in children. AB - OBJECTIVE: Percutaneous bone conduction hearing aids are an established treatment for selected children unable to use conventional hearing aids. Currently in children, loading the implant is delayed for 3-6 months following fixture placement, due to concerns regarding bone quality, bone thickness and subsequent implant stability. Traditionally, such concerns led to children undergoing 2 stage Baha((r)) surgery, with a second operation to attach the abutment after 3-6 months. Bone conduction implant stability can be objectively measured using resonance-frequency analysis (RFA) to generate Implant Stability Quotients (ISQs). We aimed to assess implant stability in children undergoing 1-stage surgery using RFA measurements and investigate the possible implications for earlier loading following surgery. METHODS: We report a case series of consecutive children undergoing Baha((r)) at our tertiary paediatric hospital. The interval to implant loading remained 3-6 months for the duration of this study. RFA measurements were taken peri-operatively, 1 week post-surgery, within 3 months of surgery and then subsequently at follow up appointments. RFA measurements were also measured at loading of the hearing processor and at follow up appointments after loading. RESULTS: Nine children received 10 CochlearTM Baha((r)) BI300 implants (8 unilateral and 1 bilateral) with a mean age of 9 years 4 months (4 years 9 months to 13 years 5 months). The mean time to loading of the hearing processor was 3.3 months (3 to 5 months, n=9) and mean follow up was 9 months (12 weeks to 23 months). Eight children had ISQs that were potentially sufficient to have loaded the implant earlier than 3 months. Implant stability was maintained after loading with the hearing processor. CONCLUSION: This study supports the potential use of RFA measurements to either, guide implant loading following 1-stage surgery in children, or to enable a larger prospective study of early loading (4-6 weeks) in children. PMID- 24467921 TI - 2D immunoblots show differential response of mouse IgG and IgM antibodies to antigens of mammary carcinoma 4 T1 cells. AB - BACKGROUND: Immunosuppression in breast cancer has been reported in women and in the highly metastatic mouse mammary tumor model 4 T1. The immunosuppressive environment complicates the use of the humoral response against the tumor as an immunodiagnostic tool. IgM has not been used in immunodiagnostic in part because its antitumor responses, both innate and adaptive, have not been studied in function of time in breast cancer.We show a new approach to analyzing the mouse humoral immune response, and compare the evolution with time of IgG and IgM responses against the antigens of 4 T1 cells. METHODS: The study is based on 2 dimensional immunoblotting detection of antigens from 4 T1 cells by the IgG and IgM antibodies in the serum of female mice injected with 4 T1 cells. RESULTS: There was a high variability in the intra-and inter-mouse response. Variability in the IgM response was manifested as a pattern of spots that could become a multibinomial variable of 0 and 1, which could represent a signature of the immune response. Different numbers of spots was found in the IgG and IgM responses from week 1 to 5. On average, the IgM had more but the IgG response decrease with the time. The natural IgM at t = 0 responds stronger than w1; the adaptive response of both IgM and IgG were elicited where, with the former being stronger better than the latter. Antigens that are recognized by some female mice in the first week are also recognized by other female mice at time 0. Contamination of the natural IgM makes difficult use the adaptive IgM as a tool for immunodiagnostic. CONCLUSIONS: IgM and IgG response varied with the time and individuals. Spot variation in 2D pattern for the natural IgM could be expressed as a binomial signature, which opens up the way to correlate a particular pattern with resistance or susceptibility. This uncovers a battery of IgMs for each individual to confront cancer or infections. The possibility to differentiate between adaptive IgM antibodies from the natural IgM will allow investigation of the adaptive IgM for early immunodiagnosis. PMID- 24467922 TI - Venous congestion: are we adding insult to kidney injury in sepsis? AB - In critical illness, septic shock is a contributing factor in nearly half of all cases of acute kidney injury (AKI). Traditional approaches to prevention of organ dysfunction in early sepsis have focused on prevention of hypoperfusion by optimisation of systemic haemodynamics, primarily by fluid resuscitation. Fluid administration to a target central venous pressure (CVP) of 8 to 12 mmHg (12 to 15 mmHg in mechanically ventilated patients) is currently recommended for the early resuscitation of septic shock. However, in the previous issue of Critical Care, Legrand and colleagues report that higher CVP in the first 24 hours of ICU admission with septic shock was associated with increased risk for development or persistence of AKI over the next 5 days. This study highlights a potential association between venous congestion and the development of septic AKI, suggesting that CVP-targeted fluid resuscitation in septic shock might not be beneficial for renal function. PMID- 24467923 TI - Providing culturally appropriate mental health first aid to an Aboriginal or Torres Strait Islander adolescent: development of expert consensus guidelines. AB - BACKGROUND: It is estimated that the prevalence of mental illness is higher in Aboriginal and Torres Strait Islander adolescents compared to non-Aboriginal adolescents. Despite this, only a small proportion of Aboriginal youth have contact with mental health services, possibly due to factors such as remoteness, language barriers, affordability and cultural sensitivity issues. This research aimed to develop culturally appropriate guidelines for anyone who is providing first aid to an Australian Aboriginal or Torres Strait Islander adolescent who is experiencing a mental health crisis or developing a mental illness. METHODS: A panel of Australian Aboriginal people who are experts in Aboriginal youth mental health, participated in a Delphi study investigating how members of the public can be culturally appropriate when helping an Aboriginal or Torres Strait Islander adolescent with mental health problems. The panel varied in size across the three sequential rounds, from 37-41 participants. Panellists were presented with statements about cultural considerations and communication strategies via online questionnaires and were encouraged to suggest additional content. All statements endorsed as either Essential or Important by >= 90% of panel members were written into a guideline document. To assess the panel members' satisfaction with the research method, participants were invited to provide their feedback after the final survey. RESULTS: From a total of 304 statements shown to the panel of experts, 194 statements were endorsed. The methodology was found to be useful and appropriate by the panellists. CONCLUSION: Aboriginal and Torres Strait Islander Youth mental health experts were able to reach consensus about what the appropriate communication strategies for providing mental health first aid to an Aboriginal and Torres Strait Islander adolescent. These outcomes will help ensure that the community provides the best possible support to Aboriginal adolescents who are developing mental illnesses or are in a mental health crisis. PMID- 24467924 TI - Microbiome, demystifying the role of microbial communities in the biosphere. AB - The backstory to the motivation for launching Microbiome is a tale of two subdisciplines finding philosophical common ground fueled by substantial technological advancements in DNA sequencing and analysis. Until recently it was possible to neatly divide microbiology into two largely exclusive subdisciplines: clinical microbiology and environmental microbiology. Guided by Koch's postulates for more than a century, clinical microbiologists have excelled in connecting specific microorganisms with disease in animals and plants, and through basic research have suppressed infectious diseases - saving countless lives through disease treatment and prevention and greater food security. Motivated initially by the desire to exploit the biochemical capabilities of microorganisms, environmental microbiologists have uncovered the large diversity of physiological capabilities that allow microorganisms to thrive wherever there exists sufficient free energy to sustain a proton gradient and feed essential biochemical pathways with reducing power. Emergent from these research activities was the discovery of extraordinary diversity of microbial life on Earth that has forever altered our perception of the tree of life. A look back at the five-kingdoms tree illustrated on the inside cover of a circa 1984 freshman biology textbook is clear evidence of how far we have come in our appreciation of microbial diversity; new understanding made possible through basic environmental microbiology research. PMID- 24467926 TI - Timing of food intake and obesity: a novel association. AB - Recent studies link energy regulation to the circadian clock at the behavioral, physiological and molecular levels, emphasizing that the timing of food intake itself may have a significant role in obesity. In this regards, there is emerging literature in animals demonstrating a relationship between the timing of feeding and weight regulation. Unusual feeding time can produce a disruption of the circadian system which might produce unhealthy consequences in humans. In a longitudinal study, we recently showed that the timing of the main meal was predictive of weight loss during a 20-week dietary intervention and that this effect was independent from total 24-h caloric intake. The importance of caloric distribution across the day on weight loss therapy was supported by a recent 12 week experimental study showing that subjects assigned to high caloric intake during breakfast lost significantly more weight than those assigned to high caloric intake during the dinner. Furthermore, one of the most influential discoveries relevant for this area of research in the last years is the presence of an active circadian clock in different organs related to food intake. This is the case for stomach, intestine, pancreas or liver. New data also suggest that there is a temporal component in the regulation of adipose tissue functions. Thus, a specific temporal order in the daily patterns of adipose tissue genes appears to be crucial for adipose tissue to exclusively either accumulate fat or to mobilize fat at the proper time. Taking into account that feeding is the source of energy for adipose tissue, the time of feeding, particularly for high energy content meals, may be decisive, and changes in this timing could have metabolic consequences for the development of obesity and for weight loss. PMID- 24467925 TI - MicroRNA miR-378 promotes BMP2-induced osteogenic differentiation of mesenchymal progenitor cells. AB - BACKGROUND: MicroRNAs (miRNAs) are a family of small, non-coding single-stranded RNA molecules involved in post-transcriptional regulation of gene expression. As such, they are believed to play a role in regulating the step-wise changes in gene expression patterns that occur during cell fate specification of multipotent stem cells. Here, we have studied whether terminal differentiation of C2C12 myoblasts is indeed controlled by lineage-specific changes in miRNA expression. RESULTS: Using a previously generated RNA polymerase II (Pol-II) ChIP-on-chip dataset, we show differential Pol-II occupancy at the promoter regions of six miRNAs during C2C12 myogenic versus BMP2-induced osteogenic differentiation. Overexpression of one of these miRNAs, miR-378, enhances Alp activity, calcium deposition and mRNA expression of osteogenic marker genes in the presence of BMP2. CONCLUSIONS: Our results demonstrate a previously unknown role for miR-378 in promoting BMP2-induced osteogenic differentiation. PMID- 24467927 TI - Characterization of glycidol-hemoglobin adducts as biomarkers of exposure and in vivo dose. AB - Hemoglobin adducts have been used as biomarkers of exposure to reactive chemicals. Glycidol, an animal carcinogen, has been reported to form N-(2,3 dihydroxy-propyl)valine adducts to hemoglobin (diHOPrVal). To support the use of these adducts as markers of glycidol exposure, we investigated the kinetics of diHOPrVal formation and its elimination in vitro and in vivo. Five groups of rats were orally administered a single dose of glycidol ranging from 0 to 75mg/kg bw, and diHOPrVal levels were measured 24h after administration. A dose-dependent increase in diHOPrVal levels was observed with high linearity (R(2)=0.943). Blood sampling at different time points (1, 10, 20, or 40days) from four groups administered glycidol at 12mg/kg bw suggested a linear decrease in diHOPrVal levels compatible with the normal turnover of rat erythrocytes (life span, 61days), with the calculated first-order elimination rate constant (kel) indicating that the diHOPrVal adduct was chemically stable. Then, we measured the second-order rate constant (kval) for the reaction of glycidol with N-terminal valine in rat and human hemoglobin in in vitro experiments with whole blood. The kval was 6.7+/-1.1 and 5.6+/-1.3 (pmol/g globin per MUMh) in rat and human blood, respectively, indicating no species differences. In vivo doses estimated from kval and diHOPrVal levels were in agreement with the area under the (concentration-time) curve values determined in our earlier toxicokinetic study in rats. Our results indicate that diHOPrVal is a useful biomarker for quantification of glycidol exposure and for risk assessment. PMID- 24467928 TI - Shedding of Clostridium difficile PCR ribotype 078 by zoo animals, and report of an unstable metronidazole-resistant isolate from a zebra foal (Equus quagga burchellii). AB - Clostridium difficile is an emerging and potentially zoonotic pathogen, but its prevalence in most animal species, including exhibition animals, is currently unknown. In this study we assessed the prevalence of faecal shedding of C. difficile by zoo animals, and determined the ribotype, toxin profile and antimicrobial susceptibility of recovered isolates. A total of 200 samples from 40 animal species (36.5% of which came from plains zebra, Equus quagga burchellii) were analysed. C. difficile was isolated from 7 samples (3.5% of total), which came from the following animal species: chimpanzee (Pan troglodytes troglodytes), dwarf goat (Capra hircus), and Iberian ibex (Capra pyrenaica hispanica), with one positive sample each; and plains zebra, with 4 positive samples from 3 different individuals. Most recovered isolates (4/7, 57.1%) belonged to the epidemic PCR ribotype 078, produced toxins A and B, and had the genes encoding binary toxin (i.e. A(+)B(+)CDT(+) isolates). The remaining three isolates belonged to PCR ribotypes 039 (A(-)B(-)CDT(-)), 042 (A(+)B(+)CDT(-)) and 110 (A(-)B(+)CDT(-)). Regardless of their ribotype, all isolates displayed high level resistance to the fluoroquinolones ciprofloxacin, enrofloxacin and levofloxacin. Some isolates were also resistant to meropenem and/or ertapenem. A ribotype 078 isolate recovered from a male zebra foal initially showed in vitro resistance to metronidazole (MIC >= 256 MUg/ml), but lost that trait after subculturing on non-selective media. We conclude that zoo animals belonging to different species can carry ribotype 078 and other toxigenic strains of C. difficile showing resistance to antimicrobial compounds commonly used in veterinary and/or human medicine. PMID- 24467929 TI - Recombinant LipL32 stimulates interferon-gamma production in cattle vaccinated with a monovalent Leptospira borgpetersenii serovar Hardjo subtype Hardjobovis vaccine. AB - Leptospira borgpetersenii serovar Hardjo subtype Hardjobovis (Hardjobovis) is the main causative agent of bovine leptospirosis in Australia, New Zealand, North America and elsewhere. Bovine leptospirosis can result in spontaneous abortion, stillbirth and reduced milk output. The organism is shed in the urine of infected animals and contact with contaminated materials can result in zoonotic infections in humans. Protective immunity in cattle against Hardjobovis involves stimulation of a Th1 cell mediated immune response, which can be characterized by the production of IFN-gamma when blood from vaccinated animals is exposed to Hardjobovis antigens. However, the leptospiral components involved in stimulating this response have yet to be identified. In this study, 238 recombinant leptospiral proteins were evaluated for their ability to stimulate IFN-gamma production in blood of cattle vaccinated with a commercial monovalent Hardjobovis vaccine. The conserved lipoprotein LipL32 is the major outer membrane protein of pathogenic Leptospira spp. A pool of soluble recombinant proteins which included LipL32, as well as LipL32 alone, stimulated significant IFN-gamma production in blood of vaccinated cattle. A number of recombinant LipL32 fragments was generated, which identified the amino acids between 20 and 200 as containing the bovine T-cell reactive regions of LipL32. However, whether LipL32 plays a role in stimulating protective immunity in mammals has yet to be conclusively determined. PMID- 24467930 TI - In vivo spread of macrolide-lincosamide-streptogramin B (MLSB) resistance--a model study in chickens. AB - The influence of specific and non-specific antibiotic pressure on in vivo spread of macrolide-lincosamide-streptogramin B (MLSB) resistance was evaluated in this study. Chickens repeatedly inoculated with Enterococcus faecalis harbouring the plasmid pAMbeta1 carrying the erm(B) gene were perorally treated for one week with tylosin, lincomycin (both specific antibiotic pressure) and chlortetracycline (non-specific antibiotic pressure). Antibiotic non-treated but E. faecalis inoculated chickens served as a control. To quantify the erm(B) gene and characterise intestinal microflora, faecal DNA was analysed by qPCR and 454 pyrosequencing. Under the pressure of antibiotics, a significant increase in erm(B) was observed by qPCR. However, at the final stage of the experiment, an increase in erm(B) was also observed in two out of five non-treated chickens. In chickens treated with tylosin and chlortetracycline, the increase in erm(B) was accompanied by an increase in enterococci. However, E. faecalis was at the limit of detection in all animals. This suggests that the erm(B) gene spread among the gut microbiota other than E. faecalis. Pyrosequencing results indicated that, depending on the particular antibiotic pressure, different bacteria could be responsible for the spread of MLSB resistance. Different species of MLSB resistant enterococci and streptococci were isolated from cloacal swabs during and after the treatment. PFGE analysis of MLSB-resistant enterococci revealed four clones, all differing from the challenge strain. All of the MLSB-resistant isolates harboured a plasmid of the same size as pAMbeta1. This study has shown that MLSB resistance may spread within the gut microbiota under specific and non specific pressure and even in the absence of any antimicrobial pressure. Finally, depending on the particular antibiotic pressure, different bacterial species seems to be involved in the spread of MLSB resistance. PMID- 24467931 TI - Altered plasma glutathione levels in bipolar disorder indicates higher oxidative stress; a possible risk factor for illness onset despite normal brain-derived neurotrophic factor (BDNF) levels. AB - BACKGROUND: Oxidative stress and neurotrophic factors have been implicated in the pathophysiology of bipolar disorder. Our objective was to determine whether plasma glutathione or brain-derived neurotrophic factor (BDNF) levels were abnormal in bipolar disorder and therefore useful as possible biomarkers. METHOD: Blood samples were collected from subsyndromal, medicated bipolar I patients (n = 50), recruited from OXTEXT, University of Oxford, and from 50 matched healthy controls. Total and oxidized glutathione levels were measured using an enzymatic recycling method and used to calculate reduced, percentage oxidized, ratio of reduced:oxidized and redox state. BDNF was measured using an enzyme-linked immunoassay. Self-monitored mood scores for the bipolar group were available (Quick Inventory of Depressive Symptomatology and the Altman Self-Rating Mania Scale) over an 8-week period. RESULTS: Compared with controls, bipolar patients had significantly lower levels of total glutathione and it was more oxidized. BDNF levels were not different. Age of illness onset but not current mood state correlated with total glutathione levels and its oxidation status, so that lower levels of total and reduced glutathione were associated with later onset of disease, not length of illness. CONCLUSIONS: Plasma glutathione levels and redox state detect oxidative stress even in subsyndromal patients with normal BDNF. It may relate to the onset and development of bipolar disorder. Plasma glutathione appears to be a suitable biomarker for detecting underlying oxidative stress and for evaluating the efficacy of antioxidant intervention studies. PMID- 24467932 TI - Emergency management of a congenital teratoma of the oral cavity at birth and three-year follow-up. AB - Teratomas are congenital malformations that are rarely located in the head and neck region. We report a case of congenital teratoma of the oral cavity, which was causing an airway obstruction and was treated at the time of birth. This teratoma was discovered at 27 gestational weeks by ultrasonography. A multidisciplinary team was consulted for antenatal diagnosis; the options of therapeutic abortion or management of the birth with the prevention of respiratory distress were debated. However, preterm labour at 32 gestational weeks accelerated the parental and the medical decisions. The parents agreed to the birth. The various disciplines coordinated their work, and the predefined treatment plan for clearing the airway obstruction was applied to manage the birth. The reestablishment of patency of the airway was performed during delivery and removal of the tumour was performed immediately afterwards. The follow-up of this case over 3 years is also presented. PMID- 24467933 TI - Cumulative effect of low-level laser therapy and low-intensity pulsed ultrasound on bone repair in rats. AB - Many studies have assessed the effects of either low-level laser therapy (LLLT) or low-intensity pulsed ultrasound (LIPUS) on bone repair; however, an evaluation of the combination of these modalities (LLLT + LIPUS) has not yet been considered. The aim of this study was to demonstrate the effects of LLLT + LIPUS on bone repair. Male Wistar rats (n = 128; four groups of 32) were used; the animals underwent a partial tibial bone osteotomy. One group had the osteotomized limb treated with LLLT, the second group with LIPUS, and the third group with the combined treatment protocols of the LLLT and LIPUS groups; the fourth group received no further treatment (control). Each group was divided into two subgroups for assessment at two different time-points, 14 and 21 days. After the completion of treatment rats were sacrificed and the tibias submitted to a three point bending test or to histomorphometric analysis. Histological evaluation showed increased bone trabeculae, increased vascularization, and decreased inflammation in the LLLT + LIPUS group. Mechanical evaluation revealed increased biomechanical properties including maximum force, maximum stress, and stiffness, in the LLLT + LIPUS group. Combined LLLT + LIPUS treatment enhanced bone healing both histologically and mechanically, shortening the length of the treatment period, when compared to treatment with LLLT or LIPUS alone. PMID- 24467934 TI - Statistical models of critical phenomena in fuzzy biocognition. AB - A recent line of study exploring statistical models of punctuated global broadcasts associated with attention states has focused on the evolutionary exaptation of the inevitable signal crosstalk between related sets of unconscious cognitive modules (UCM). This work invokes a groupoid treatment of the equivalence classes arising from information sources 'dual', in a formal sense, to the UCM, via a standard spontaneous symmetry breaking/lifting methodology abducted from statistical physics. A related approach involves an index theorem based on a stochastic empirical Onsager-like entropy-analog gradient model. Surprisingly, similar arguments may apply to 'fuzzy groupoid' generalizations likely to better fit biological complexities. PMID- 24467935 TI - Mathematical modeling on bacterial resistance to multiple antibiotics caused by spontaneous mutations. AB - We formulate a mathematical model that describes the population dynamics of bacteria exposed to multiple antibiotics simultaneously, assuming that acquisition of resistance is through mutations due to antibiotic exposure. Qualitative analysis reveals the existence of a free-bacteria equilibrium, resistant-bacteria equilibrium and an endemic equilibrium where both bacteria coexist. PMID- 24467936 TI - Therapeutic aspects of the inflammation mediated oral carcinogenesis. PMID- 24467937 TI - Adjuvant chemoradiation therapy with high-dose versus weekly cisplatin for resected, locally-advanced HPV/p16-positive and negative head and neck squamous cell carcinoma. AB - OBJECTIVES: Standard treatment for patients with poor-risk, resected head and neck squamous cell carcinoma (HNSCC) is adjuvant radiation therapy combined with high-dose cisplatin. Many patients are treated with weekly cisplatin; it is not known whether weekly and high-dose cisplatin are equivalent. This study compares the outcomes of patients with locally-advanced HPV-negative HNSCC and HPV/p16 positive oropharynx HNSCC treated with adjuvant chemoradiation therapy with either high-dose or weekly cisplatin. MATERIALS AND METHODS: Retrospective review of patients with Stage III/IV HNSCC who had surgery followed by adjuvant chemoradiation therapy at Mayo Clinic, Rochester. HPV and/or p16 status was available for all oropharynx patients. RESULTS: 104 Patients (51 high-dose, 53 weekly) were analyzed. The 3-year overall survival was 84% and 75% for patients who received high dose and weekly cisplatin, respectively (p=0.30). The 3-year recurrence free survival was 71% and 74% in the high dose and weekly cisplatin group, respectively (p=0.95). Patients with HPV/p16-positive oropharynx cancer who received adjuvant chemoradiation therapy with high-dose and weekly cisplatin had three-year overall survival rates of 91% and 86% (p=0.56), and 3-year recurrence free survival of 84% and 82% (p=0.93). Extracapsular extension did not affect prognosis in either group. CONCLUSIONS: No significant survival difference was seen between patients with locally advanced HNSCC treated with adjuvant chemoradiation therapy with high-dose or weekly cisplatin, although there was a trend for improved survival with high-dose cisplatin. Weekly cisplatin in the adjuvant setting may be a better treatment for patients with HPV-positive oropharynx cancer to preserve survival and minimize toxicity. PMID- 24467938 TI - CD133+ renal stem cells always co-express CD24 in adult human kidney tissue. PMID- 24467940 TI - Cultural practices and sexual risk behaviour among adolescent orphans and non orphans: a qualitative study on perceptions from a community in Western Kenya. AB - BACKGROUND: This study explored community perceptions of cultural beliefs and practices that may increase sexual risk behaviour of adolescents, to understand more about meaning they hold within the culture and how they expose adolescent orphans and non-orphans to higher risks in a high HIV and teenage pregnancy prevalence context. METHODS: Using a qualitative descriptive cross-sectional design 14 focus group discussions were conducted with 78 adolescents and 68 parents/guardians purposively selected to represent their communities. Thirteen key informant interviews were also conducted with community leaders, health care and child welfare workers, and adolescents who were also selected purposively. The two methods were used to explore how cultural beliefs and practices predispose adolescent orphans and non- orphans to risky sexual behaviours. Data were analysed through line-by-line coding, grouped into families and retrieved as themes and sub-themes. RESULTS: Identified cultural practices that predisposed adolescents orphans and non-orphans to risky sexual behaviours included: adolescent sleeping arrangements, funeral ceremonies, replacing a deceased married daughter with her younger sister in marriage, widow inheritance among boys, early marriage among girls, and preference for boys/sons. Cultural risks perceived to equally affect both orphans and non-orphans were sleeping arrangements, funeral ceremonies, and sister replacement. Factors associated more with orphans than non-orphans were widow inheritance among boys and a preference for boy over girl children. CONCLUSIONS: Adolescent sexual risk reduction programs should be developed considering the specific cultural context, using strategies that empower communities to challenge the widely accepted cultural norms that may predispose young people in general to sexual risks while targeting those that unequally influence orphans. PMID- 24467939 TI - Timing and intensity of changes in FDG uptake with symptomatic esophagitis during radiotherapy or chemo-radiotherapy. AB - PURPOSE: To study whether esophageal FDG activity changes by time of mid-course of fractionated radiotherapy (RT), and whether these changes are associated with radiation esophagitis in patients with non-small cell lung cancer (NSCLC). METHODS: Fifty patients with stage I-III NSCLC were enrolled prospectively and, all received >=60 Gy RT. FDG-PET/CT scans were acquired prior to, and during-RT after delivery of 45 Gy. Normalized standardized uptake values (NSUV), defined by the esophageal maximum SUV relative to intravascular background level in the aortic arch, were sampled in the esophagus at the level of the primary tumor, sternal notch, aortic arch, carina, and gastro-esophageal junction. Symptomatic radiation esophagitis was defined as an event. RESULTS: Compared to baseline, esophageal NSUV increased significantly during-RT at the level of the primary tumor (1.09 +/- 0.05 vs.1.28 +/- 0.06, p = 0.001), but did not change at other levels in the esophagus. 16 patients had radiation esophagitis events and these patients had significantly higher during-RT to baseline NSUV ratios than those without esophagitis (1.46 +/- 0.12, 95% CI 1.20-1.71; vs. 1.11 +/- 0.05, 95% CI 1.01-1.21, p = 0.002). Maximum esophageal dose (p = 0.029), concurrent chemotherapy (p = 0.022) and esophageal FDG PET NSUV ratio (during-RT to baseline, p = 0.007), were independent factors associated with esophagitis and area under curves (AUC) were 0.76, 0.70 and 0.78, respectively. Combining esophageal maximum dose and FDG PET NSUV Ratio at the tumor level increased AUC to 0.85 (p = 0.016). CONCLUSION: FDG uptake increased in esophagus during-RT and this increase may predict radiation esphagitis during later course of treatment. PMID- 24467941 TI - Comparison of self-report and structured clinical interview in the identification of depression. AB - BACKGROUND: A self-report method seeking a binary response for assessing depression is a cost-effective and time-efficient way to obtain a psychiatric history, yet the reliability of this method is largely unknown. The aim of the study was to compare and assess the validity of two methods for identifying a past history of depression in a population-based study. METHODS: This study examined data collected from 891 men and 1086 women participating in the Geelong Osteoporosis Study. Self-reports of depression were compared with results obtained using the Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition (SCID-I/NP). RESULTS: Using the SCID-I/NP, 146 (16.4%) men and 285 (26.2%) women met criteria for a lifetime depression. Of those participants, 61.0% (n=263) self-reported a history of depression. The level of agreement between self-reporting depression and the SCID-I/NP depression module was reasonably high; 61% sensitivity, 89.5% specificity and the overall level of agreement (kappa) was 0.5. LIMITATIONS: Results may not be generalizable to other self-report instruments or be suitable for use in clinical samples. CONCLUSION: The SCID-I/NP remains the gold standard for identifying depression; however, given the moderate level of agreement between the self-report questionnaire and SCID-I/NP in our current study, we conclude that simple self-report methods can be used to identify depression with some degree of confidence. PMID- 24467942 TI - Catechol-O-methyltransferase val158met genotype determines effect of reboxetine on emotional memory in healthy male volunteers. AB - BACKGROUND: Catechol-O-methyltransferase (COMT) metabolizes catecholamines in the prefrontal cortex (PFC). A common polymorphism in the COMT gene (COMT val158met) has pleiotropic effects on cognitive and emotional processing. The met allele has been associated with enhanced cognitive processing but impaired emotional processing relative to the val allele. METHODS: We genotyped healthy, white men in relation to the COMT val158met polymorphism. They were given a single 4 mg dose of the selective noradrenaline reuptake inhibitor (NRI) reboxetine or placebo in a randomized, double-blind between-subjects model and then completed an emotional memory task 2 hours later. RESULTS: We included 75 men in the study; 41 received reboxetine and 34 received placebo. In the placebo group, met/met carriers did not demonstrate the usual memory advantage for emotional stimuli that was observed in val carriers. Reboxetine restored this emotional enhancement of memory in met/met carriers, but had no significant effect in val carriers. LIMITATIONS: We studied only men, thus limiting the generalizability of our findings. We also relied on self-reported responses to screening questions to establish healthy volunteer status, and in spite of the double-blind design, participants were significantly better than chance at identifying their intervention allocation. CONCLUSION: Emotional memory is impaired in healthy met homozygotes and selectively improved in this group by reboxetine. This has potential translational implications for the use of reboxetine, which is currently licensed as an antidepressant in several countries, and edivoxetine, a new selective NRI currently in development. PMID- 24467944 TI - Characterization and application of electrospun alumina nanofibers. AB - Alumina nanofibers were prepared by a technique that combined the sol-gel and electrospinning methods. The solution to be electrospun was prepared by mixing aluminum isopropoxide (AIP) in ethanol, which was then refluxed in the presence of an acid catalyst and polyvinylpyrolidone (PVP) in ethanol. The characterization results showed that alumina nanofibers with diameters in the range of 102 to 378 nm were successfully prepared. On the basis of the results of the XRD and FT-IR, the alumina nanofibers calcined at 1,100 degrees C were identified as comprising the alpha-alumina phase, and a series of phase transitions such as boehmite -> gamma-alumina -> alpha-alumina were observed from 500 degrees C to 1,200 degrees C. The pore size of the obtained gamma-alumina nanofibers is approximately 8 nm, and it means that they are mesoporous materials. The kinetic study demonstrated that MO adsorption on alumina nanofibers can be seen that the pseudo-second-order kinetic model fits better than the pseudo-first-order kinetic model. PMID- 24467943 TI - Antipsychotic dosing: found in translation. AB - In the field of schizophrenia research, as in other areas of psychiatry, there is a sense of frustration that greater advances have not been made over the years, calling into question existing research strategies. Arguably, many purported gains claimed by research have been "lost in translation," resulting in limited impact on diagnosis and treatment in the clinical setting. There are exceptions; for example, we would argue that different lines of preclinical and clinical research have substantially altered how we look at antipsychotic dosing. While this story remains a work in progress, advances "found in translation" have played an important role. Detailing these changes, the present paper speaks to a body of evidence that has already shifted clinical practice and raises questions that may further alter the manner in which antipsychotics have been administered over the last 6 decades. PMID- 24467945 TI - The masseteric nerve: a versatile power source in facial animation techniques. AB - The masseteric nerve has many advantages including low morbidity, its proximity to the facial nerve, the strong motor impulse, its reliability, and the fast reinnervation that is achievable in most patients. Reinnervation of a neuromuscular transplant is the main indication for its use, but it has been used for the treatment of recent facial palsies with satisfactory results. We have retrospectively evaluated 60 patients who had facial animation procedures using the masseteric nerve during the last 10 years. The patients included those with recent, and established or congenital, unilateral and bilateral palsies. The masseteric nerve was used for coaptation of the facial nerve either alone or in association with crossfacial nerve grafting, or for the reinnervation of gracilis neuromuscular transplants. Reinnervation was successful in all cases, the mean (range) time being 4 (2-5) months for facial nerve coaptation and 4 (3-7) months for neuromuscular transplants. Cosmesis was evaluated (moderate, n=10, good, n=30, and excellent, n=20) as was functional outcome (no case of impairment of masticatory function, all patients able to smile, and achievement of a smile independent from biting). The masseteric nerve has many uses, including in both recent, and established or congenital, cases. In some conditions it is the first line of treatment. The combination of combined techniques gives excellent results in unilateral palsies and should therefore be considered a valid option. PMID- 24467946 TI - Lessons learned from the use of HRP-2 based rapid diagnostic test in community wide screening and treatment of asymptomatic carriers of Plasmodium falciparum in Burkina Faso. AB - BACKGROUND: Rapid diagnostic tests (RDTs) are immune chromatographic tests targeting antigens of one or more Plasmodium species and offer the potential to extend accurate malaria diagnosis in endemic areas. In this study, the performance of Plasmodium falciparum-specific histidine-rich protein-2 (PfHRP-2) RDT in the detection of asymptomatic carriers from a hyperendemic region of Burkina Faso was compared with microscopy to gain further insight on its relevance in community-based interventions. METHODS: The performance of HRP-2 test was evaluated in terms of sensitivity, specificity, positive and negative predictive values, discordant values, likelihood ratios, accuracy, and precision using microscopy as the 'gold standard'. This analysis was carried out in a controlled, parallel, cluster-randomized (18 clusters; 1:1) study in children and adults. The effect of systematic treatment of P. falciparum asymptomatic carriers during three consecutive monthly community screening campaigns on the incidence of symptomatic malaria episodes over a 12-month period was compared with no treatment of asymptomatic carriers. RESULTS: Sensitivity of HRP-2 test in asymptomatic carriers was higher in campaign 1 (92.4%) when compared to campaign 2 (84.0%) and campaign 3 (77.8%). The sensitivity of HRP-2 test increased as parasite density increased across all the age groups. Highest sensitivity (>=97.0%) was recorded at parasite densities of 1,000-4,999/MUl, except for children aged 10 to 14 years. The specificity of HRP-2 test was comparable across age groups and highest in campaign 3 (95.9%). The negative predictive values were high across the three campaigns (>=92.7%) while the positive predictive values ranged from 23.2 to 73.8%. False-positive and false-negative rates were high in campaign 1 and campaign 3, respectively. CONCLUSION: The performance of HRP-2 test in detecting asymptomatic carriers of P. falciparum varied by age and parasite density. Although the use of HRP-2 test is beneficial for the diagnosis of acute malaria, its low sensitivity in screening asymptomatic carriers may limit its utility in pre-elimination interventional settings. The use of a practical and more sensitive test such as loop-mediated isothermal amplification in combination with a cost effective HRP-2 test may be worth exploring in such settings. PMID- 24467947 TI - Design and analysis of LacI-repressed promoters and DNA-looping in a cyanobacterium. AB - BACKGROUND: Cyanobacteria are solar-powered prokaryotes useful for sustainable production of valuable molecules, but orthogonal and regulated promoters are lacking. The Lac repressor (LacI) from Escherichia coli is a well-studied transcription factor that is orthogonal to cyanobacteria and represses transcription by binding a primary lac operator (lacO), blocking RNA-polymerase. Repression can be enhanced through DNA-looping, when a LacI-tetramer binds two spatially separated lacO and loops the DNA. Ptrc is a commonly used LacI repressed promoter that is inefficiently repressed in the cyanobacterium Synechocystis PCC 6803. Ptrc2O, a version of Ptrc with two lacO, is more efficiently repressed, indicating DNA-looping. To investigate the inefficient repression of Ptrc and cyanobacterial DNA-looping, we designed a Ptrc-derived promoter library consisting of single lacO promoters, including a version of Ptrc with a stronger lacO (Ptrc1O-proximal), and dual lacO promoters with varying inter-lacO distances (the Ptrc2O-library). RESULTS: We first characterized artificial constitutive promoters and used one for engineering a LacI-expressing strain of Synechocystis. Using this strain, we observed that Ptrc1O-proximal is similar to Ptrc in being inefficiently repressed. Further, the Ptrc2O-library displays a periodic repression pattern that remains for both non- and induced conditions and decreases with longer inter-lacO distances, in both E. coli and Synechocystis. Repression of Ptrc2O-library promoters with operators out of phase is less efficient in Synechocystis than in E. coli, whereas repression of promoters with lacO in phase is efficient even under induced conditions in Synechocystis. Two well-repressed Ptrc2O promoters were highly active when tested in absence of LacI in Synechocystis. CONCLUSIONS: The artificial constitutive promoters herein characterized can be utilized for expression in cyanobacteria, as demonstrated for LacI. The inefficient repression of Ptrc and Ptrc1O-proximal in Synechocystis, as compared to E. coli, may be due to insufficient LacI expression, or differences in RNAP subunits. DNA-looping works as a transcriptional regulation mechanism similarly as in E. coli. DNA-looping contributes strongly to Ptrc2O-library repression in Synechocystis, even though they contain the weakly-repressed primary lacO of Ptrc1O-proximal and relatively low levels of LacI/cell. Hence, Synechocystis RNAP may be more sensitive to DNA looping than E. coli RNAP, and/or the chromatin torsion resistance could be lower. Two strong and highly repressed Ptrc2O promoters could be used without induction, or together with an unstable LacI. PMID- 24467949 TI - Selecting age-related functional characteristics in the human gut microbiome. AB - BACKGROUND: Human gut microbial functions are often associated with various diseases and host physiologies. Aging, a less explored factor, is also suspected to affect or be affected by microbiome alterations. By combining functional feature selection with supervised classification, we aim to facilitate identification of age-related functional characteristics in metagenomes from several human gut microbiome studies (MetaHIT, MicroAge, MicroObes, Kurokawa et al.'s and Gill et al.'s dataset). RESULTS: We apply two feature selection methods, term frequency-inverse document frequency (TF-iDF) and minimum redundancy maximum-relevancy (mRMR), to identify functional signatures that differentiate metagenomes by age. After features are reduced, we use a support vector machine (SVM) to predict host age of new metagenomes. Functional features are from protein families (Pfams), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, KEGG ontologies and the Gene Ontology (GO) database. Initial investigations demonstrate that ordination of the functional principal components shows great overlap between different age groups. However, when feature selection is applied, mRMR tightens the ordination cluster for each age group, and TF-iDF offers better linear separation. Both TF-iDF and mRMR were used in conjunction with a SVM classifier and achieved areas under receiver operating characteristic curves (AUCs) 10 to 15% above chance to classify individuals above/below mid-ages (about 38 to 43 years old) using Pfams. Better performance around mid-ages is also observed when using other functional categories and age-balanced dataset. We also identified some age-related Pfams that improved age discrimination at age 65 with another feature selection method called LEfSe, on an age-balanced dataset. The selected functional characteristics identify a broad range of age-relevant metabolisms, such as reduced vitamin B12 synthesis, reduced activity of reductases, increased DNA damage, occurrences of stress responses and immune system compromise, and upregulated glycosyltransferases in the aging population. CONCLUSIONS: Feature selection can yield biologically meaningful results when used in conjunction with classification, and makes age classification of new human gut metagenomes feasible. While we demonstrate the promise of this approach, the data-dependent prediction performance could be further improved. We hypothesize that while the Qin et al. dataset is the most comprehensive to date, even deeper sampling is needed to better characterize and predict the microbiomes' functional content. PMID- 24467948 TI - Methods for comprehensive experimental identification of RNA-protein interactions. AB - The importance of RNA-protein interactions in controlling mRNA regulation and non coding RNA function is increasingly appreciated. A variety of methods exist to comprehensively define RNA-protein interactions. We describe these methods and the considerations required for designing and interpreting these experiments. PMID- 24467950 TI - Ligand-conjugated mesoporous silica nanorattles based on enzyme targeted prodrug delivery system for effective lung cancer therapy. AB - Epidermal growth factor receptor antibody (EGFRAb) conjugated silica nanorattles (SNs) were synthesized and used to develop receptor mediated endocytosis for targeted drug delivery strategies for cancer therapy. The present study determined that the rate of internalization of silica nanorattles was found to be high in lung cancer cells when compared with the normal lung cells. EGFRAb can specifically bind to EGFR, a receptor that is highly expressed in lung cancer cells, but is expressed at low levels in other normal cells. Furthermore, in vitro studies clearly substantiated that the cPLA2alpha activity, arachidonic acid release and cell proliferation were considerably reduced by pyrrolidine-2 loaded EGFRAb-SN in H460 cells. The cytotoxicity, cell cycle arrest and apoptosis were significantly induced by the treatment of pyrrolidine-2 loaded EGFRAb-SN when compared with free pyrrolidine-2 and pyrrolidine-2 loaded SNs in human non small cell lung cancer cells. An in vivo toxicity assessment showed that silica nanorattles and EGFRAb-SN-pyrrolidine-2 exhibited low systemic toxicity in healthy Balb/c mice. The EGFRAb-SN-pyrrolidine-2 showed a much better antitumor activity (38%) with enhanced tumor inhibition rate than the pyrrolidine-2 on the non-small cell lung carcinoma subcutaneous model. Thus, the present findings validated the low toxicity and high therapeutic potentials of EGFRAb-SN pyrrolidine-2, which may provide a convincing evidence of the silica nanorattles as new potential carriers for targeted drug delivery systems. PMID- 24467951 TI - Resveratrol mediated cell death in cigarette smoke transformed breast epithelial cells is through induction of p21Waf1/Cip1 and inhibition of long patch base excision repair pathway. AB - Cigarette smoking is a key factor for the development and progression of different cancers including mammary tumor in women. Resveratrol (Res) is a promising natural chemotherapeutic agent that regulates many cellular targets including p21, a cip/kip family of cyclin kinase inhibitors involved in DNA damage-induced cell cycle arrest and blocking of DNA replication and repair. We have recently shown that cigarette smoke condensate (CSC) prepared from commercially available Indian cigarette can cause neoplastic transformation of normal breast epithelial MCF-10A cell. Here we studied the mechanism of Res mediated apoptosis in CSC transformed (MCF-10A-Tr) cells in vitro and in vivo. Res mediated apoptosis in MCF-10A-Tr cells was a p21 dependent event. It increased the p21 protein expression in MCF-10A-Tr cells and MCF-10A-Tr cells mediated tumors in xenograft mice. Res treatment reduced the tumor size(s) and expression of anti-apoptotic proteins (e.g. PI3K, AKT, NFkappaB) in solid tumor. The expressions of cell cycle regulatory (Cyclins, CDC-2, CDC-6, etc.), BER associated (Pol-beta, Pol-delta, Pol-epsilon, Pol-eta, RPA, Fen-1, DNA-Ligase-I, etc.) proteins and LP-BER activity decreased in MCF-10A-Tr cells but remain significantly unaltered in isogenic p21 null MCF-10A-Tr cells after Res treatment. Interestingly, no significant changes were noted in SP-BER activity in both the cell lines after Res exposure. Finally, it was observed that increased p21 blocks the LP-BER in MCF-10A-Tr cells by increasing its interaction with PCNA via competing with Fen-1 after Res treatment. Thus, Res caused apoptosis in CSC induced cancer cells by reduction of LP-BER activity and this phenomenon largely depends on p21. PMID- 24467953 TI - [Introduction]. PMID- 24467952 TI - GIGANTUS1 (GTS1), a member of Transducin/WD40 protein superfamily, controls seed germination, growth and biomass accumulation through ribosome-biogenesis protein interactions in Arabidopsis thaliana. AB - BACKGROUND: WD40 domains have been found in a plethora of eukaryotic proteins, acting as scaffolding molecules assisting proper activity of other proteins, and are involved in multi-cellular processes. They comprise several stretches of 44 60 amino acid residues often terminating with a WD di-peptide. They act as a site of protein-protein interactions or multi-interacting platforms, driving the assembly of protein complexes or as mediators of transient interplay among other proteins. In Arabidopsis, members of WD40 protein superfamily are known as key regulators of plant-specific events, biologically playing important roles in development and also during stress signaling. RESULTS: Using reverse genetic and protein modeling approaches, we characterize GIGANTUS1 (GTS1), a new member of WD40 repeat protein in Arabidopsis thaliana and provide evidence of its role in controlling plant growth development. GTS1 is highly expressed during embryo development and negatively regulates seed germination, biomass yield and growth improvement in plants. Structural modeling analysis suggests that GTS1 folds into a beta-propeller with seven pseudo symmetrically arranged blades around a central axis. Molecular docking analysis shows that GTS1 physically interacts with two ribosomal protein partners, a component of ribosome Nop16, and a ribosome biogenesis factor L19e through beta-propeller blade 4 to regulate cell growth development. CONCLUSIONS: Our results indicate that GTS1 might function in plant developmental processes by regulating ribosomal structural features, activities and biogenesis in plant cells. Our results suggest that GIGANTUS1 might be a promising target to engineer transgenic plants with higher biomass and improved growth development for plant-based bioenergy production. PMID- 24467954 TI - [Definition, etiology, classification and presentation forms]. AB - Osteoarthritis is defined as a degenerative process affecting the joints as a result of mechanical and biological disorders that destabilize the balance between the synthesis and degradation of joint cartilage, stimulating the growth of subchondral bone; chronic synovitis is also present. Currently, the joint is considered as a functional unit that includes distinct tissues, mainly cartilage, the synovial membrane, and subchondral bone, all of which are involved in the pathogenesis of the disease. Distinct risk factors for the development of osteoarthritis have been described: general, unmodifiable risk factors (age, sex, and genetic makeup), general, modifiable risk factors (obesity and hormonal factors) and local risk factors (prior joint anomalies and joint overload). Notable among the main factors related to disease progression are joint alignment defects and generalized osteoarthritis. Several classifications of osteoarthritis have been proposed but none is particularly important for the primary care management of the disease. These classifications include etiological (primary or idiopathic forms and secondary forms) and topographical (typical and atypical localizations) classifications, the Kellgren and Lawrence classification (radiological repercussions) and that of the American College of Rheumatology for osteoarthritis of the hand, hip and knee. The prevalence of knee osteoarthritis is 10.2% in Spain and shows a marked discrepancy between clinical and radiological findings. Hand osteoarthritis, with a prevalence of symptomatic involvement of around 6.2%, has several forms of presentation (nodal osteoarthritis, generalized osteoarthritis, rhizarthrosis, and erosive osteoarthritis). Symptomatic osteoarthritis of the hip affects between 3.5% and 5.6% of persons older than 50 years and has different radiological patterns depending on femoral head migration. PMID- 24467956 TI - [Diagnosis. History and physical examination]. AB - Family physicians play a key role in the diagnosis and management of patients with osteoarthritis. Diagnosis is mainly clinical and radiological. A complete history should be taken with meticulous physical examination of the joints. The history-taking should aim to detect risk factors and compatible clinical symptoms. Pain characteristics should be identified, distinguishing between mechanical and inflammatory pain, and an exhaustive examination of the joints should be performed, with evaluation of the presence of pain, deformity, mobility restrictions (both active and passive), crepitus, joint effusion, and inflammation. A differential diagnosis should be made with all diseases that affect the joints and/or produce joint stiffness. PMID- 24467955 TI - [Symptoms. Localizations: knee, hip, hands, spine, other localizations]. AB - The symptoms of osteoarthritis vary widely from patient to patient, depending especially on the localization on the disease. There is a poor correlation between radiological involvement and pain. In general, symptom onset is gradual and symptoms increase slowly but progressively. The most commonly affected joints are the knees, hips, hands, and spine. The main signs and symptoms are pain, stiffness, joint deformity, and crepitus. Pain is mechanical and its causes are multifactorial; in the initial phases, pain usually manifests in self-limiting episodes but may subsequently be almost constant. The criteria of the American college of Rheumatology for the classification of osteoarthritis of the knee, hip and hands are an aid to classification and standardization but are not useful for diagnosis. Hip osteoarthritis usually produces inguinal pain in the internal and anterior sections of the muscle extending to the knee and, with progression, tends to limit mobility. Knee osteoarthritis is more frequent in women and is usually associated with hand osteoarthritis and obesity. In hand osteoarthritis, the most commonly affected joints are the distal interphalangeal joints, followed by the proximal interphalangeal joints and the trapeziometacarpal joints; the development of Heberden and Bouchard nodes is common; involvement of the trapeziometacarpal joint is called rhizarthrosis and is one of the forms of osteoarthritis that produces the greatest limitation on hand function. Osteoarthritis of the spine affects the facet joints and the vertebral bodies. Other, less frequent, localizations are the foot, elbow and shoulder, which are generally secondary forms of osteoarthritis. PMID- 24467957 TI - [Diagnosis. Radiological study. Ultrasound, computed tomography and magnetic resonance imaging]. AB - Because of its low cost, availability in primary care and ease of interpretation, simple X-ray should be the first-line imaging technique used by family physicians for the diagnosis and/or follow-up of patients with osteoarthritis. Nevertheless, this technique should only be used if there are sound indications and if the results will influence decision-making. Despite the increase of indications in patients with rheumatological disease, the role of ultrasound in patients with osteoarthritis continues to be limited. Computed tomography (CT) is of some although limited- use in osteoarthritis, especially in the study of complex joints (such as the sacroiliac joint and facet joints). Magnetic resonance imaging (MRI) has represented a major advance in the evaluation of joint cartilage and subchondral bone in patients with osteoarthritis but, because of its high cost and diagnostic-prognostic yield, this technique should only be used in highly selected patients. The indications for ultrasound, CT and MRI in patients with osteoarthritis continue to be limited in primary care and often coincide with situations in which the patient may require hospital referral. Patient safety should be bourne in mind. Patients should be protected from excessive ionizing radiation due to unnecessary repeat X-rays or inadequate views or to requests for tests such as CT, when not indicated. PMID- 24467958 TI - [Diagnosis: synovial fluid analysis]. AB - Synovial fluid analysis in rheumatological diseases allows a more accurate diagnosis in some entities, mainly infectious and microcrystalline arthritis. Examination of synovial fluid in patients with osteoarthritis is useful if a differential diagnosis will be performed with other processes and to distinguish between inflammatory and non-inflammatory forms. Joint aspiration is a diagnostic and sometimes therapeutic procedure that is available to primary care physicians. PMID- 24467959 TI - [Patient evaluation and outcome measures]. AB - Both the initial evaluation and follow-up of patients with osteoarthritis require systematic evaluation of the indicators that provide information on the degree of involvement of the disease and allow its quantification. Reliable measures of disease progression help decision-making by clinicians and provide valid information on treatment response and the effectiveness of the distinct therapeutic interventions. The instruments recommended in research, as outcome measures in osteoarthritis, are pain evaluation, assessment of physical function, and self-reported global evaluation. In studies lasting more than 1 year, structural changes are evaluated through simple X-ray. Self-reported quality of life assessment and physician global assessment are also recommended as options. These indicators should be incorporated into routine clinical practice for adequate evaluation and correct follow-up of patients with osteoarthritis. The recommended pain evaluation method for use in clinical practice is the visual analog scale (VAS). The best instrument to evaluate physical function in patients with hip or knee osteoarthritis is the WOMAC scale (Western Ontario and McMaster Universities Osteoarthritis Index). For patient-reported global assessment in routine practice, the recommended scales are VAS or the SF-12 (12-item short-form health survey). PMID- 24467960 TI - [Treatment of patients with osteoarthritis]. AB - The therapeutic management of patients with osteoarthritis aims to decrease pain and inflammation, improve physical function, and to apply safe and effective treatments. A patient-centered approach implies the active participation of the patient in the design of the treatment plan and in timely and informed decision making at all stages of the disease. The nucleus of treatment is patient education, physical activity and therapeutic exercise, together with weight control in overweight or obese patients. Self-care by the individual and by the family is fundamental in day-to-day patient management. The use of physical therapies, technical aids (walking sticks, etc.) and simple analgesics, opium alkaloids, and antiinflammatory drugs have demonstrated effectiveness in controlling pain, improving physical function and quality of life and their use is clearly indicated in the treatment of osteoarthritis. Conservative surgery and joint replacement is indicated when treatment goals are not achieved in specific patients. PMID- 24467961 TI - [Follow-up of patients with osteoarthritis. Coordinated management and criteria for referral between healthcare levels]. AB - The correct management of osteoarthritis requires an accurate diagnosis, evaluation of its spread and functional repercussions, and the application of comprehensive and effective individually-tailored treatment aimed at relieving pain and improving physical function with a consequent improvement in quality of life; treatment should also aim to prevent or delay disease progression and its effects. In the National Health Service, primary care is the basic level and the first point of access to healthcare; this level guarantees the continuity of care, coordinates patients, and regulates clinical workflow. Family physicians coordinate the healthcare processes related to chronic diseases and are responsible for the management, diagnosis, evaluation, treatment, and follow-up of patients with osteoarthritis. The clinical practice guidelines internationally accepted as the standard of care for the management of osteoarthritis should be adapted by both Spanish health planning strategies and clinical practice guidelines to the Spanish healthcare setting. The comprehensive assessment of osteoarthritis includes evaluation of its effects on the patient's physical function and quality of life; formulating a treatment plan in collaboration with the patient and adapted to his or her comorbidities; providing advice on basic treatments and their risks and benefits; and carrying out an individually tailored periodic review. Referral criteria are based on diagnostic confirmation, poor treatment response, and surgical evaluation. PMID- 24467962 TI - Efficacy of herbal tincture as treatment option for retained placenta in dairy cows. AB - Retained placenta remains therapeutic challenge in cattle. Certain traditional medicines are believed to be able to alleviate retained placenta condition and improve overall fertility in cows. The aim of the present study was to evaluate the efficacy of an herbal tincture for treatment of retained placenta. The herbal tincture was extracted from a combination of Herba Leonuri, Angelicae Sinensis Radix, Flos Carthami, Myrrha and Rhizoma Cyperi by percolation with 70% ethanol to a concentration of 0.5g crude herb/ml. Cows diagnosed with retained placenta (n=48) were randomly divided into one of two treatment groups (A and B), with animals in group A (n=26) receiving herbal tincture orally, and cows in group B (n=22) receiving oxytetracycline infusion into the uterus. Eighty six cows with no clinically visible pathological conditions, given birth alone and with no retained placenta diagnosis were included into control group (C). Retained placenta was expelled within 72h following initial treatment in 19 cows in group A, yet no cows in group B were recorded to expel placenta in the same time. The median number of days to first service (70.0 vs. 102.5 days; P<0.05) and median number of days open (76.0 vs. 134.0 days; P<0.01) were lower in group A than in group B. Percentage of cows pregnant within 100 days postpartum was the highest for animals in group A compared to controls (61.5% vs. 39.5%, P<0.05), and for animals in group B (61.5% vs. 22.7%; P<0.01). Herbal tincture used in the present study might facilitate expulsion of retained placenta and improve subsequent fertility, thus could present effective treatment option for retained placenta in cows. PMID- 24467963 TI - Cognitive/affective and somatic/affective symptoms of depression in patients with heart disease and their association with cardiovascular prognosis: a meta analysis. AB - BACKGROUND: Several prospective longitudinal studies have suggested that somatic/affective depressive symptoms, but not cognitive/affective depressive symptoms, are related to prognosis in patients with heart disease, but findings have been inconsistent. The aim of this study was to investigate the association of cognitive/affective and somatic/affective symptoms of depression with cardiovascular prognosis in patients with heart disease using a meta-analytic perspective. METHOD: A systematic search was performed in PubMed, EMBASE and PsycInfo. Thirteen prospective studies on symptom dimensions of depression and cardiovascular prognosis fulfilled the inclusion criteria, providing data on a total of 11,128 subjects. The risk estimates for each dimension of depressive symptoms, demographic and methodological variables were extracted from the included articles. RESULTS: In least-adjusted analyses, both the somatic/affective [hazard ratio (HR) 1.30, 95% confidence interval (CI) 1.19 1.41, p < 0.001] and cognitive/affective (HR 1.07, 95% CI 1.00-1.15, p = 0.05) dimensions of depressive symptoms were associated with cardiovascular prognosis. In fully adjusted analyses, somatic/affective symptoms were significantly associated with adverse prognosis (HR 1.19, 95% CI 1.10-1.29, p < 0.001) but cognitive/affective symptoms were not (HR 1.04, 95% CI 0.97-1.12, p = 0.25). An increase of one standard deviation (+/-1 s.d.) in the scores of the somatic/affective dimension was associated with a 32% increased risk of adverse outcomes (HR 1.32, 95% CI 1.17-1.48, p < 0.001). CONCLUSIONS: Somatic/affective depressive symptoms were more strongly and consistently associated with mortality and cardiovascular events in patients with heart disease compared with cognitive/affective symptoms. Future research should focus on the mechanisms by which somatic/affective depressive symptoms may affect cardiovascular prognosis. PMID- 24467964 TI - It IS worth the effort: Patient knowledge of reproductive aspects of inflammatory bowel disease improves dramatically after a single group education session. AB - BACKGROUND: Individuals with Inflammatory Bowel Disease (IBD) have poor knowledge regarding the implications of disease for fertility and pregnancy. Previous studies suggest that this poor knowledge adversely influences reproductive decision making. AIM: To examine the effect of a single group education session on IBD-specific reproductive knowledge in subjects with IBD. METHOD: People with IBD attending an educational event were invited to complete the CCPKnow questionnaire, testing reproductive knowledge in IBD, before and after an evidenced based presentation on this topic delivered by a Gastroenterologist. RESULTS: Of 248 attendees, 155 participated; 69% female, mean age 40.3years. CCPKnow scores (maximum 17) were low at baseline and increased significantly post education (mean 5.4 pre vs. 14.5 post education; p<0.0001). A large majority (65.1%) of subjects had "poor" (score <8) knowledge at baseline, compared with only 1.9% after education (p<0.0001). Whilst all subareas of knowledge improved after education, the most important improvement was in attitudes toward medication use in pregnancy: 33.5% of subjects indicated at baseline that women should avoid all drugs in pregnancy compared with only 1.2% post education (p<0.0001). CONCLUSION: A single group-delivered education event focussed on reproductive issues in IBD can dramatically improve patient knowledge. This has the potential to change reproductive behaviour and may reduce voluntary childlessness resulting from misperceptions amongst individuals with IBD. PMID- 24467965 TI - Mevalonate metabolism in cancer. AB - Cancer cells are characterized by sustained proliferative signaling, insensitivity to growth suppressors and resistance to apoptosis as well as by replicative immortality, the capacity to induce angiogenesis and to perform invasive growth. Additional hallmarks of cancer cells include the reprogramming of energy metabolism as well as the ability to evade immune surveillance. The current review focuses on the metabolic reprogramming of cancer cells and on the immune system's capacity to detect such changes in cancer cell metabolism. Specifically, we focus on mevalonate metabolism, which is a target for drug and immune based cancer treatment. PMID- 24467966 TI - mTOR is a promising therapeutical target in a subpopulation of pancreatic adenocarcinoma. AB - Pancreatic ductal adenocarcinoma (PDAC) remains a highly lethal disease, unusually resistant against therapy. It is generally felt that stratification of patients for personalized medicine is the way forward. Here, we report that a subpopulation of PDACs shows strong activation of the mTOR signaling cassette. Moreover, we show that inhibition of mTOR in pancreatic cancer cell lines showing high levels of mTOR signaling is associated with cancer cell death. Finally, we show using fine needle biopsies the existence of a subpopulation of PDAC patients with high activation of the mTOR signaling cassette and provide evidence that inhibition of mTOR might be clinically useful for this group. Thus, our results define an unrecognized subpopulation of PDACs, characterized by high activation of mTOR and show that identification of this specific patient group in the early phase of diagnosis is feasible. PMID- 24467967 TI - Upregulation of beta1-adrenoceptors is involved in the formation of gastric dysmotility in the 6-hydroxydopamine rat model of Parkinson's disease. AB - Gastrointestinal dysmotility is one of the nonmotor symptoms of Parkinson's disease (PD). Gastroparesis and upregulated beta-adrenoceptors (beta-ARs) have been reported in rats with bilateral microinjection of 6-hydroxydopamine (6-OHDA) in the substantia nigra, but the underlying mechanism is unclear. The aim of the current study is to investigate the role of beta-ARs in gastroparesis in 6-OHDA rats. Gastric motility was studied through strain gauge measurement. Immunofluorescence, real-time reverse transcription-polymerase chain reaction and Western blotting were performed to examine the expression of beta-ARs. Norepinephrine (NE) inhibited gastric motility in a dose-dependent fashion in both control and 6-OHDA rats, but much stronger adrenergic reactivity was observed in the 6-OHDA rats. The inhibition of gastric motility by NE in both control and 6-OHDA rats was not affected by tetrodotoxin, a neural sodium channel blocker. Blocking beta1-AR or beta2-AR did not affect the inhibition of strip contraction by NE in control rats, but beta1-AR blockage obviously enhanced the half maximal inhibitory concentration value of NE in 6-OHDA rats. Selective inhibition of beta3-AR blocked the effect of NE significantly in both control and 6-OHDA rats. The protein expression of beta1-AR, but not beta2-AR and beta3-AR in gastric muscularis externa was increased significantly in 6-OHDA rats. In conclusion, beta3-AR involves the regulation of gastric motility in control rats, whereas the upregulation of beta1-AR is responsible for enhanced NE reactivity in 6-OHDA rats and therefore is involved in the formation of gastroparesis. The effect of both beta1-AR and beta3-AR on gastric motility is independent of the enteric nervous system. PMID- 24467968 TI - Biologic therapies in inflammatory bowel disease. AB - Inflammatory bowel disease, including its 2 entities ulcerative colitis and Crohn's disease, is a chronic medical condition characterized by the destructive inflammation of the intestinal tract. Biologics represent a class of therapeutics with immune intervention potential. These agents block the proinflammatory cascade that triggers the activation and proliferation of T lymphocytes at the level of the intestine, therefore reestablishing the balance between the pro- and anti-inflammatory messages. All 7 biologics showing clinical benefits in inflammatory bowel disease are monoclonal antibodies. The following systematic review discusses the pharmacokinetics and efficacy of the tumor necrosis factor blockers infliximab, adalimumab, certolizumab pegol, and golimumab. In addition, we describe the alpha4 integrin inhibitors natalizumab and vedolizumab, which are directed against cell adhesion molecules, as well as the interleukin 12/23 blocker ustekinumab. PMID- 24467969 TI - CYP94B3 activity against jasmonic acid amino acid conjugates and the elucidation of 12-O-beta-glucopyranosyl-jasmonoyl-L-isoleucine as an additional metabolite. AB - The hormonal action of jasmonate in plants is controlled by the precise balance between its biosynthesis and inactivation. Oxidation of jasmonoyl-L-isoleucine at the C-12 position, which is catalyzed by cytochrome P450s CYP94B3 and CYP94C1, is thought to be one of the main inactivation pathways. In this study, an additional function of CYP94B3 was elucidated, as well additional jasmonoyl-L-isoleucine metabolites being investigated. It was found that CYP94B3 also catalyzes the hydroxylation of jasmonoyl-L-valine and jasmonoyl-L-phenylalanine, and that these hydroxyl compounds accumulated after wounding and possessed lower activity than non-hydroxylated compounds. Additionally, 12-O-beta-glucopyranosyl-jasmonoyl-L isoleucine accumulated after wounding, suggesting that it is a metabolite of jasmonoyl-L-isoleucine. PMID- 24467970 TI - The Clinical Biomechanics Award 2012 - presented by the European Society of Biomechanics: large scale simulations of trabecular bone adaptation to loading and treatment. AB - BACKGROUND: Microstructural simulations of bone remodeling are particularly relevant in the clinical management of osteoporosis. Before a model can be applied in the clinics, a validation against controlled in vivo data is crucial. Here we present a strain-adaptive feedback algorithm for the simulation of trabecular bone remodeling in response to loading and pharmaceutical treatment and report on the results of the large-scale validation against in vivo data. METHODS: The algorithm follows the mechanostat principle and incorporates mechanical feedback, based on the local strain-energy density. For the validation, simulations of bone remodeling and adaptation in 180 osteopenic mice were performed. Permutations of the conditions for early (20th week) and late (26th week) loading of 8N or 0N, and treatments with bisphosphonates, or parathyroid hormone were simulated. Static and dynamic morphometry and local remodeling sites from in vivo and in silico studies were compared. FINDINGS: For each study an individual set of model parameters was selected. Trabecular bone volume fraction was chosen as an indicator of the accuracy of the simulations. Overall errors for this parameter were 0.1-4.5%. Other morphometric indices were simulated with errors of less than 19%. Dynamic morphometry was more difficult to predict, which resulted in significant differences from the experimental data. INTERPRETATION: We validated a new algorithm for the simulation of bone remodeling in trabecular bone. The results indicate that the simulations accurately reflect the effects of treatment and loading seen in respective experimental data, and, following adaptation to human data, could be transferred into clinics. PMID- 24467971 TI - Frontal and transverse plane hip kinematics and gluteus maximus recruitment correlate with frontal plane knee kinematics during single-leg squat tests in women. AB - BACKGROUND: Hip muscle dysfunction may be associated with knee valgus that contributes to problems like patellofemoral pain syndrome. The purpose of this study was to (1) compare knee and hip kinematics and hip muscle strength and recruitment between "good" and "poor" performers on a single-leg squat test developed to assess hip muscle dysfunction and (2) examine relationships between hip muscle strength, recruitment and frontal plane knee kinematics to see which variables correlated with knee valgus during the test. METHODS: Forty-one active women classified via visual rating as "good" or "poor" performers on the test participated. Participants completed 5-repetition single-leg squat tests. Isometric hip extension and abduction strength, gluteus maximus and gluteus medius recruitment, and 3-dimensional hip and knee kinematics during the test were compared between groups and examined for their association with frontal plane knee motion. FINDINGS: "Poor" performers completed the test with more hip adduction (mean difference=7.6 degrees ) and flexion (mean difference=6.3 degrees ) than "good" performers. No differences in knee kinematics, hip strength or hip muscle recruitment occurred. However, the secondary findings indicated that increased medial hip rotation (partial r=0.94) and adduction (partial r=0.42) and decreased gluteus maximus recruitment (partial r=0.35) correlated with increased knee valgus. INTERPRETATION: Whereas hip muscle function and knee kinematics did not differ between groups as we'd hypothesized, frontal plane knee motion correlated with transverse and frontal plane hip motions and with gluteus maximus recruitment. Gluteus maximus recruitment may modulate frontal plane knee kinematics during single-leg squats. PMID- 24467972 TI - A retrospective analysis of survival and prognostic factors after stereotactic radiosurgery for aggressive meningiomas. AB - BACKGROUND: While most meningiomas are benign, aggressive meningiomas are associated with high levels of recurrence and mortality. A single institution's Gamma Knife radiosurgical experience with atypical and malignant meningiomas is presented, stratified by the most recent WHO classification. METHODS: Thirty-one patients with atypical and 4 patients with malignant meningiomas treated with Gamma Knife radiosurgery between July 2000 and July 2011 were retrospectively reviewed. All patients underwent prior surgical resection. Overall survival was the primary endpoint and rate of disease recurrence in the brain was a secondary endpoint. Patients who had previous radiotherapy or prior surgical resection were included. Kaplan-Meier and Cox proportional hazards models were used to estimate survival and identify factors predictive of recurrence and survival. RESULTS: Post-Gamma Knife recurrence was identified in 11 patients (31.4%) with a median overall survival of 36 months and progression-free survival of 25.8 months. Nine patients (25.7%) had died. Three-year overall survival (OS) and progression-free survival (PFS) rates were 78.0% and 65.0%, respectively. WHO grade II 3-year OS and PFS were 83.4% and 70.1%, while WHO grade III 3-year OS and PFS were 33.3% and 0%. Recurrence rate was significantly higher in patients with a prior history of benign meningioma, nuclear atypia, high mitotic rate, spontaneous necrosis, and WHO grade III diagnosis on univariate analysis; only WHO grade III diagnosis was significant on multivariate analysis. Overall survival was adversely affected in patients with WHO grade III diagnosis, prior history of benign meningioma, prior fractionated radiotherapy, larger tumor volume, and higher isocenter number on univariate analysis; WHO grade III diagnosis and larger treated tumor volume were significant on multivariate analysis. CONCLUSION: Atypical and anaplastic meningiomas remain difficult tumors to treat. WHO grade III diagnosis and treated tumor volume were significantly predictive of recurrence and survival on multivariate analysis in aggressive meningioma patients treated with radiosurgery. Larger tumor size predicts poor survival, while nuclear atypia, necrosis, and increased mitotic rate are risk factors for recurrence. Clinical and pathologic predictors may help identify patients that are at higher risk for recurrence. PMID- 24467973 TI - Screening for atrial fibrillation in patients with obstructive sleep apnoea to reduce ischaemic strokes. AB - Obstructive sleep apnoea is an independent risk factor for stroke. A number of different mechanisms have been identified which link OSA and stroke including hypertension and oxidative stress. Atrial fibrillation (AF) is likely to play a role in the development of stroke in patients with OSA. Indeed, patients with OSA have a higher incidence of AF than the general population. Given the higher constellation of cardiovascular co-morbidities seen in patients with OSA, we believe that a strategy of actively screening for the presence of AF in patients with OSA and initiating oral anticoagulation therapy when appropriate may reduce the burden of stroke in this population. This is a question that needs to be addressed in a clinical trial. PMID- 24467974 TI - Radial coronary interventions and post-procedural complication rates in the real world: a report from a Japanese multicenter percutaneous coronary intervention registry. PMID- 24467975 TI - China's epidemic of child obesity: an ounce of prevention is better than a pound of treatment. PMID- 24467976 TI - Glutamate neurotoxicity is involved in the neurological damage in patients undergoing extracorporeal circulation. PMID- 24467977 TI - Secondary prevention after myocardial infarction: it takes two (physician and patient) to tango. PMID- 24467978 TI - Increased soluble ST2 is a stronger predictor of long-term cardiovascular death than natriuretic peptides in heart failure patients with reduced ejection fraction. PMID- 24467979 TI - Interleukin-10 in patients with ST-segment elevation myocardial infarction. PMID- 24467980 TI - Letter in response to "acute coronary involvement in acute type A aortic dissection: a subgroup analysis of bicuspid aortic valve and Marfan syndrome". PMID- 24467981 TI - Posterior reversible encephalopathy syndrome in a patient submitted to extracorporeal membrane oxygenation for acute fulminant myocarditis. PMID- 24467982 TI - Do patients with a left ventricular ejection fraction between 30% and 35% benefit from a primary prevention implantable cardioverter defibrillator? PMID- 24467983 TI - Transcatheter aortic valve implantation can potentially impact short-term and long-term functionality: an in vitro study. PMID- 24467984 TI - Forming-free bipolar resistive switching in nonstoichiometric ceria films. AB - The mechanism of forming-free bipolar resistive switching in a Zr/CeOx/Pt device was investigated. High-resolution transmission electron microscopy and energy dispersive spectroscopy analysis indicated the formation of a ZrOy layer at the Zr/CeOx interface. X-ray diffraction studies of CeOx films revealed that they consist of nano-polycrystals embedded in a disordered lattice. The observed resistive switching was suggested to be linked with the formation and rupture of conductive filaments constituted by oxygen vacancies in the CeOx film and in the nonstoichiometric ZrOy interfacial layer. X-ray photoelectron spectroscopy study confirmed the presence of oxygen vacancies in both of the said regions. In the low-resistance ON state, the electrical conduction was found to be of ohmic nature, while the high-resistance OFF state was governed by trap-controlled space charge-limited mechanism. The stable resistive switching behavior and long retention times with an acceptable resistance ratio enable the device for its application in future nonvolatile resistive random access memory (RRAM). PMID- 24467985 TI - Field evaluation of the photo-induced electron transfer fluorogenic primers (PET) real-time PCR for the detection of Plasmodium falciparum in Tanzania. AB - BACKGROUND: Accurate diagnosis of malaria infections remains challenging, especially in the identification of submicroscopic infections. New molecular diagnostic tools that are inexpensive, sensitive enough to detect low-level infections and suitable in laboratory settings of resource-limited countries are required for malaria control and elimination programmes. Here the diagnostic potential of a recently developed photo-induced electron transfer fluorogenic primer (PET) real-time polymerase chain reaction (PCR) called PET-PCR was investigated. This study aimed to (i) evaluate the use of this assay as a method for the detection of both Plasmodium falciparum and other Plasmodium species infections in a developing country's diagnostic laboratory; and, (ii) determine the assay's sensitivity and specificity compared to a nested 18S rRNA PCR. METHODS: Samples used in this study were obtained from a previous study conducted in the region of Iringa, Tanzania. A total of 303 samples from eight health facilities in Tanzania were utilized for this evaluation. All samples were screened using the multiplex PET-PCR assay designed to detect Plasmodium genus and P. falciparum initially in laboratory in Tanzania and then repeated at a reference laboratory at the CDC in the USA. Microscopy data was available for all the 303 samples. A subset of the samples were tested in a blinded fashion to find the sensitivity and specificity of the PET-PCR compared to the nested 18S rRNA PCR. RESULTS: Compared to microscopy, the PET-PCR assay was 59% more sensitive in detecting P. falciparum infections. The observed sensitivity and specificity were 100% (95% confidence interval (CI0.95) = 94-100%) and (CI0.95 = 96-100%), respectively, for the PET-PCR assay when compared to nested 18S rRNA PCR. When compared to 18S rRNA PCR, microscopy had a low sensitivity of 40% (CI0.95 = 23 61%) and specificity of 100% (CI0.95 = 96-100%). The PET-PCR results performed in the field laboratory in Tanzania were in 100% concordance with the results obtained at the reference laboratory in the USA. CONCLUSION: The PET-PCR is a new molecular diagnostic tool with similar performance characteristics as commonly used PCR methods that is less expensive, easy to use, and amiable to large scale surveillance studies in developing country settings. PMID- 24467986 TI - Ensuring good quality RNA for quantitative real-time PCR isolated from renal proximal tubular cells using laser capture microdissection. AB - BACKGROUND: In order to provide gene expression profiles of different cell types, the primary step is to isolate the specific cells of interest via laser capture microdissection (LCM), followed by extraction of good quality total RNA sufficient for quantitative real-time polymerase chain reaction (qPCR) analysis. This LCM-qPCR strategy has allowed numerous gene expression studies on specific cell populations, providing valuable insights into specific cellular changes in diseases. However, such strategy imposed challenges as cells of interests are often available in limited quantities and quality of RNA may be compromised during long periods of time spent on collection of cells and extraction of total RNA; therefore, it is crucial that protocols for sample preparation should be optimised according to different cell populations. FINDINGS: We made several modifications to existing protocols to improve the total RNA yield and integrity for downstream qPCR analyses. A modified condensed hematoxylin and eosin (H&E) staining protocol was developed for the identification of rat renal proximal tubular cells (PTCs). It was then determined that a minimal of eight thousands renal PTCs were required to meet the minimal total RNA yield required for downstream qPCR. RNA integrity was assessed using at every progressive step of sample preparation. Therefore, we decided that the shortened H&E staining, together with microdissection should be performed consecutively within twenty minutes for good quality for gene expression analysis. These modified protocols were later applied on six individual rat samples. A panel of twenty rat renal drug transporters and five housekeeping genes showed Ct values below thirty-five, confirming the expression levels of these drug transporters can be detected. CONCLUSIONS: We had successfully optimized the protocols to achieve sufficient good quality total RNA from microdissected rat renal PTCs for gene expression profiling via qPCR. This protocol may be suitable for researchers who are interested in employing similar applications for gene expression studies. PMID- 24467987 TI - Stool substitute transplant therapy for the eradication of Clostridium difficile infection: 'RePOOPulating' the gut. AB - BACKGROUND: Fecal bacteriotherapy ('stool transplant') can be effective in treating recurrent Clostridium difficile infection, but concerns of donor infection transmission and patient acceptance limit its use. Here we describe the use of a stool substitute preparation, made from purified intestinal bacterial cultures derived from a single healthy donor, to treat recurrent C. difficile infection that had failed repeated standard antibiotics. Thirty-three isolates were recovered from a healthy donor stool sample. Two patients who had failed at least three courses of metronidazole or vancomycin underwent colonoscopy and the mixture was infused throughout the right and mid colon. Pre-treatment and post treatment stool samples were analyzed by 16 S rRNA gene sequencing using the Ion Torrent platform. RESULTS: Both patients were infected with the hyper virulent C. difficile strain, ribotype 078. Following stool substitute treatment, each patient reverted to their normal bowel pattern within 2 to 3 days and remained symptom-free at 6 months. The analysis demonstrated that rRNA sequences found in the stool substitute were rare in the pre-treatment stool samples but constituted over 25% of the sequences up to 6 months after treatment. CONCLUSION: This proof of-principle study demonstrates that a stool substitute mixture comprising a multi-species community of bacteria is capable of curing antibiotic-resistant C. difficile colitis. This benefit correlates with major changes in stool microbial profile and these changes reflect isolates from the synthetic mixture. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION NUMBER: CinicalTrials.gov NCT01372943. PMID- 24467988 TI - PRImary care Streptococcal Management (PRISM) study: in vitro study, diagnostic cohorts and a pragmatic adaptive randomised controlled trial with nested qualitative study and cost-effectiveness study. AB - BACKGROUND: Antibiotics are still prescribed to most patients attending primary care with acute sore throat, despite evidence that there is modest benefit overall from antibiotics. Targeting antibiotics using either clinical scoring methods or rapid antigen detection tests (RADTs) could help. However, there is debate about which groups of streptococci are important (particularly Lancefield groups C and G), and uncertainty about the variables that most clearly predict the presence of streptococci. OBJECTIVE: This study aimed to compare clinical scores or RADTs with delayed antibiotic prescribing. DESIGN: The study comprised a RADT in vitro study; two diagnostic cohorts to develop streptococcal scores (score 1; score 2); and, finally, an open pragmatic randomised controlled trial with nested qualitative and cost-effectiveness studies. SETTING: The setting was UK primary care general practices. PARTICIPANTS: Participants were patients aged >= 3 years with acute sore throat. INTERVENTIONS: An internet program randomised patients to targeted antibiotic use according to (1) delayed antibiotics (control group), (2) clinical score or (3) RADT used according to clinical score. MAIN OUTCOME MEASURES: The main outcome measures were self-reported antibiotic use and symptom duration and severity on seven-point Likert scales (primary outcome: mean sore throat/difficulty swallowing score in the first 2-4 days). RESULTS: The IMI TestPack Plus Strep A (Inverness Medical, Bedford, UK) was sensitive, specific and easy to use. Lancefield group A/C/G streptococci were found in 40% of cohort 2 and 34% of cohort 1. A five-point score predicting the presence of A/C/G streptococci [FeverPAIN: Fever; Purulence; Attend rapidly (<= 3 days); severe Inflammation; and No cough or coryza] had moderate predictive value (bootstrapped estimates of area under receiver operating characteristic curve: 0.73 cohort 1, 0.71 cohort 2) and identified a substantial number of participants at low risk of streptococcal infection. In total, 38% of cohort 1 and 36% of cohort 2 scored <= 1 for FeverPAIN, associated with streptococcal percentages of 13% and 18%, respectively. In an adaptive trial design, the preliminary score (score 1; n = 1129) was replaced by FeverPAIN (n = 631). For score 1, there were no significant differences between groups. For FeverPAIN, symptom severity was documented in 80% of patients, and was lower in the clinical score group than in the delayed prescribing group (-0.33; 95% confidence interval -0.64 to -0.02; p = 0.039; equivalent to one in three rating sore throat a slight rather than moderately bad problem), and a similar reduction was observed for the RADT group (-0.30; -0.61 to 0.00; p = 0.053). Moderately bad or worse symptoms resolved significantly faster (30%) in the clinical score group (hazard ratio 1.30; 1.03 to 1.63) but not the RADT group (1.11; 0.88 to 1.40). In the delayed group, 75/164 (46%) used antibiotics, and 29% fewer used antibiotics in the clinical score group (risk ratio 0.71; 0.50 to 0.95; p = 0.018) and 27% fewer in the RADT group (0.73; 0.52 to 0.98; p = 0.033). No significant differences in complications or reconsultations were found. The clinical score group dominated both other groups for both the cost/quality-adjusted life-years and cost/change in symptom severity analyses, being both less costly and more effective, and cost-effectiveness acceptability curves indicated the clinical score to be the most likely to be cost-effective from an NHS perspective. Patients were positive about RADTs. Health professionals' concerns about test validity, the time the test took and medicalising self-limiting illness lessened after using the tests. For both RADTs and clinical scores, there were tensions with established clinical experience. CONCLUSIONS: Targeting antibiotics using a clinical score (FeverPAIN) efficiently improves symptoms and reduces antibiotic use. RADTs used in combination with FeverPAIN provide no clear advantages over FeverPAIN alone, and RADTs are unlikely to be incorporated into practice until health professionals' concerns are met and they have experience of using them. Clinical scores also face barriers related to clinicians' perceptions of their utility in the face of experience. This study has demonstrated the limitation of using one data set to develop a clinical score. FeverPAIN, derived from two data sets, appears to be valid and its use improves outcomes, but diagnostic studies to confirm the validity of FeverPAIN in other data sets and settings are needed. Experienced clinicians need to identify barriers to the use of clinical scoring methods. Implementation studies that address perceived barriers in the use of FeverPAIN are needed. TRIAL REGISTRATION: Current Controlled Trials ISRCTN32027234. SOURCE OF FUNDING: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 18, No. 6. See the NIHR Journals Library website for further project information. PMID- 24467989 TI - Victimization of Peruvian adolescents and health risk behaviors: Young Lives cohort. AB - BACKGROUND: While extensive research has been conducted on bullying and victimization in western countries, research is lacking in low- and middle-income settings. This study focused on bullying victimization in Peru. It explored the relationship between the caregiver's perception of child victimization and the child's view of selected negative experiences occurring with other children their age. Also, the study examined the association between victimization and adolescent health risk behaviors. METHODS: This study used data from 675 children participating in the Peru cohort of the Young Lives study. Children and caregivers were interviewed in 2002 when children were 8 years of age and again in 2009 when children were 15 years of age. Measures of victimization included perceptions from children and caregivers while measures of health risk behaviors included cigarette smoking, alcohol drinking, and sexual relations among adolescents. RESULTS: Caregivers identified 85 (12.6%) children bullied at ages 8 and 15, 235 (34.8%) bullied at age 8 only, 61 (9.0%) bullied at age 15 only, and 294 (43.6%) not bullied at either age. Children who were bullied at both ages compared with all other children were 1.58 (95% CI 1.00-2.50) times more likely to smoke cigarettes, 1.57 (1.04-2.38) times more likely to drink alcohol, and 2.17 (1.41-3.33) times more likely to have ever had a sexual relationship, after adjusting for gender. The caregiver's assessment of child victimization was significantly associated with child reported bullying from other children their age. Child reported victimization was significantly associated with increased risky behaviors in some cases. CONCLUSION: Long-term victimization from bullying is more strongly associated than less frequent victimization with increased risk of cigarette smoking, alcohol drinking, and sexual relations at age 15. Hence, programs focused on helping children learn how to mitigate and prevent bullying consistently over time may also help reduce risky adolescent health behaviors such as smoking, alcohol consumption, and sexual activity. PMID- 24467990 TI - To be or not to be a piRNA: genomic origin and processing of piRNAs. AB - Piwi-interacting RNAs (piRNAs) originate from genomic regions dubbed piRNA clusters. How cluster transcripts are selected for processing into piRNAs is not understood. We discuss evidence for the involvement of chromatin structure and maternally inherited piRNAs in determining their fate. PMID- 24467991 TI - Predictors of discordance between perceived and objective neighborhood data. AB - PURPOSE: Pathways by which the social and built environments affect health can be influenced by differences between perception and reality. This discordance is important for understanding health impacts of the built environment. This study examines associations between perceived and objective measures of 12 nonresidential destinations, as well as previously unexplored sociodemographic, lifestyle, neighborhood, and urbanicity predictors of discordance. METHODS: Perceived neighborhood data were collected from participants of the Survey of the Health of Wisconsin, using a self-administered questionnaire. Objective data were collected using the Wisconsin Assessment of the Social and Built Environment, an audit-based instrument assessing built environment features around each participant's residence. RESULTS: Overall, there was relatively high agreement, ranging from 50% for proximity to parks to more than 90% for golf courses. Higher education, positive neighborhood perceptions, and rurality were negatively associated with discordance. Associations between discordance and depression, disease status, and lifestyle factors appeared to be modified by urbanicity level. CONCLUSIONS: These data show perceived and objective neighborhood environment data are not interchangeable and the level of discordance is associated with or modified by individual and neighborhood factors, including the level of urbanicity. These results suggest that consideration should be given to including both types of measures in future studies. PMID- 24467992 TI - Photoluminescence properties of the high-brightness Eu(3+)-doped KNaCa2(PO4)2 phosphors. AB - A series of red-emitting phosphors Eu(3+)-doped KNaCa2(PO4)2 were synthesized by solid-state reaction, and the photoluminescence (PL) properties were also investigated. The excitation spectrum is composed of charge-transfer (CT) of Eu-O and excitation lines of Eu(3+) ions. The strongest excitation lines appeared at 393 nm. The emission spectra of KNaCa2(PO4)2:Eu(3+) phosphors exhibit five peaks assigned to the (5)D0-(7)FJ (J=0, 1, 2, 3, 4) transitions of Eu(3+) and have dominating emission peak at 621 nm under 393 nm excitation. The luminescence intensity enhanced with increasing Eu(3+) content and the emission reached the maximum intensity at x=0.02 in KNaCa2-x(PO4)2:xEu(3+). The effect of the charge compensators on the emission intensity of the phosphors was investigated. The integral intensity of the emission spectrum of KNaCa1.96(PO4)2:0.02Eu(3+), 0.02Na(+) excited at 393 nm is about 2.4 times as strong as that of Y2O3:0.05Eu(3+) commercial red phosphor. The color coordinates for KNaCa1.96(PO4)2:0.02Eu(3+),0.02Na(+) were measured. The results indicate that KNaCa2(PO4)2:Eu(3+) might be a promising phosphor for w-LEDs. PMID- 24467994 TI - Quantifying tetrodotoxin levels in the California newt using a non-destructive sampling method. AB - Toxic or noxious substances often serve as a means of chemical defense for numerous taxa. However, such compounds may also facilitate ecological or evolutionary processes. The neurotoxin, tetrodotoxin (TTX), which is found in newts of the genus Taricha, acts as a selection pressure upon predatory garter snakes, is a chemical cue to conspecific larvae, which elicits antipredator behavior, and may also affect macroinvertebrate foraging behavior. To understand selection patterns and how potential variation might affect ecological and evolutionary processes, it is necessary to quantify TTX levels within individuals and populations. To do so has often required that animals be destructively sampled or removed from breeding habitats and brought into the laboratory. Here we demonstrate a non-destructive method of sampling adult Taricha that obviates the need to capture and collect individuals. We also show that embryos from oviposited California newt (Taricha torosa) egg masses can be individually sampled and TTX quantified from embryos. We employed three different extraction techniques to isolate TTX. Using a custom fabricated high performance liquid chromatography (HPLC) system we quantified recovery of TTX. We found that a newly developed micro-extraction technique significantly improved recovery compared to previously used methods. Results also indicate our improvements to the HPLC method have high repeatability and increased sensitivity, with a detection limit of 48 pg (0.15 pmol) TTX. The quantified amounts of TTX in adult newts suggest fine geographic variation in toxin levels between sampling localities isolated by as little as 3 km. PMID- 24467995 TI - Poor alkaloid sequestration by arrow poison frogs of the genus Phyllobates from Costa Rica. AB - Frogs of the genus Phyllobates from Colombia are known to contain the highly toxic alkaloid batrachotoxin, but species from Central America exhibit only very low levels or are entirely free of this toxin. In the present study alcohol extracts from 101 specimens of Phyllobates lugubris and Phyllobates vittatus and 21 of three sympatric species (Dendrobates pumilio, Dendrobates auratus, Dendrobates granuliferus) from Costa Rica were analyzed by gas chromatography mass spectrometry. Whereas the extracts of the Dendrobates species exhibited typical profiles of toxic alkaloids, those of the two Phyllobates species contained low levels of few alkaloids only, batrachotoxin was not detected. Although the feeding pattern of the Dendrobates and Phyllobates species are similar as revealed by examination of their stomach content (mainly ants and mites), the Phyllobates species are poorly sequestering alkaloids from their food source in contrast to the Dendrobates frogs. PMID- 24467993 TI - Effects of paracentesis on hemodynamic parameters and respiratory function in critically ill patients. AB - BACKGROUND: Ascites is a major and common complication of liver cirrhosis. Large or refractory ascites frequently necessitates paracentesis. The aim of our study was to investigate the effects of paracentesis on hemodynamic and respiratory parameters in critically ill patients. METHODS: Observational study comparing hemodynamic and respiratory parameters before and after paracentesis in 50 critically ill patients with advanced hemodynamic monitoring. 28/50 (56%) required mechanical ventilation.Descriptive statistics are presented as mean +/- standard deviation for normally distributed data and median, range, and interquartile range (IQR) for non-normally distributed data. Comparisons of hemodynamic and respiratory parameters before and after paracentesis were performed by Wilcoxon signed-rank tests. Bivariate relations were assessed by Spearman's correlation coefficient and univariate regression analyses. RESULTS: Median amount of ascites removed was 5.99 L (IQR, 3.33-7.68 L). There were no statistically significant changes in hemodynamic parameters except a decrease in mean arterial pressure (-7 mm Hg; p = 0.041) and in systemic vascular resistance index (-116 dyne.sec/cm5/m2; p = 0.016) when measured 2 hours after paracentesis. In all patients, oxygenation ratio (PaO2/FiO2; median, 220 mmHg; IQR, 161-329 mmHg) increased significantly when measured immediately (+58 mmHg; p = 0.001), 2 hours (+9 mmHg; p = 0.004), and 6 hours (+6 mmHg); p = 0.050) after paracentesis. In mechanically ventilated patients, lung injury score (cumulative points without x-ray; median, 6; IQR, 4-7) significantly improved immediately (5; IQR, 4-6; p < 0.001), 2 hours (5; IQR, 4-7; p = 0.003), and 6 hours (6; IQR 4-6; p = 0.012) after paracentesis. CONCLUSION: Paracentesis in critically ill patients is safe regarding circulatory function and is related to immediate and sustained improvement of respiratory function. PMID- 24467996 TI - Infochemicals released by Daphnia magna fed on Microcystis aeruginosa affect mcyA gene expression. AB - Microcystins (MCs) are toxic heptapeptides produced by cyanobacteria during blooms that are noxious to diverse organisms, from bacteria to vertebrates. Specifically in daphnids, they cause reduced growth, a low reproductive rate, and, in extreme cases, death; however, different infochemicals released by cladocerans stimulate MCs synthesis. Ecological cyanobacteria-daphnids interactions are complex and not clear yet. In this study, we evaluated the effects of infochemicals released by Daphnia magna neonates and adults fed with different concentrations of Microcystis aeruginosa on population growth of strains Ch10 and UTEX LB2385 of M. aeruginosa, mcyA gene expression in real time qPCR, and the intracellular concentration of MCs. In addition, we assessed the relation between the cellular diameter and the intracellular concentration of MCs in both strains. Chlorophyll content per cell was affected by the presence of infochemicals from D. magna neonates and adults. mcyA gene was significantly overexpressed in the early stages of population growth (5 days) in all treatments with strain UTEX LB2385, whereas overexpression was observed in strain Ch10 at the end stage of the exponential and stationary phases (10 and 15 days). Intracellular concentration of MCs varied with the tested factor. Results suggest that the increase in mcyA gene expression and in MCs production could be defense mechanisms against the consumption by D. magna. Results also demonstrate the physiological plasticity among Microcystis strains, which could explain the permanence and dominance of this genus in toxic blooms. PMID- 24467998 TI - Effect of carryover and presampling procedures on the results of real-time PCR used for diagnosis of bovine intramammary infections with Streptococcus agalactiae at routine milk recordings. AB - The use of PCR tests as diagnostics for intramammary infections (IMI) based on composite milk samples collected in a non-sterile manner at milk recordings is increasing. Carryover of sample material between cows and non-aseptic PCR sampling may be incriminated for misclassification of IMI with Streptococcus agalactiae (S. agalactiae) in dairy herds with conventional milking parlours. Misclassification may result in unnecessary costs for treatment and culling. The objectives of this study were to (1) determine the effect of carryover on PCR positivity for S. agalactiae at different PCR cycle threshold (Ct) cut-offs by estimating the between-cow correlation while accounting for the milking order, and (2) evaluate the effect of aseptic presampling procedures (PSP) on PCR positivity at the different Ct-value cut-offs. The study was conducted in four herds with conventional milking parlours at routine milk recordings. Following the farmers' routine pre-milking preparation, 411 of 794 cows were randomly selected for the PSP treatment. These procedures included removing the first streams of milk and 70% alcohol teat disinfection. Composite milk samples were then collected from all cows and tested using PCR. Data on milking order were used to estimate the correlation between consecutively milked cows in each milking unit. Factors associated with the PCR-positivity for S. agalactiae were analyzed using generalized estimating equations assuming a binomially-distributed outcome with a logit link function. Presampling procedures were only significant using cut-off 37. A first-order autoregressive correlation structure provided the best correlation between consecutively milked cows. The correlation was 13%, 11%, 9% at cut-offs <40, 37, and 34, respectively. PSP did not reduce the odds of cows being PCR-positive for S. agalactiae. In conclusion, carryover and non-aseptic sampling affected the PCR results and should therefore be considered when samples from routine milk recordings are used. In relative terms, higher cut-offs resulted in higher between-cow correlation, but the absolute amount of carryover may not be affected although this was not tested. PMID- 24467997 TI - Do anxiety symptoms predict major depressive disorder in midlife women? The Study of Women's Health Across the Nation (SWAN) Mental Health Study (MHS). AB - BACKGROUND: In women, anxiety symptoms are common and increase during midlife, but little is known about whether these symptoms predict onsets of major depressive disorder (MDD) episodes. We examined whether anxiety symptoms are associated with subsequent episodes of MDD in midlife African-American and Caucasian women, and whether they confer a different risk for first versus recurrent MDD episodes. METHOD: A longitudinal analysis was conducted using 12 years of data from the Study of Women's Health Across the Nation (SWAN) Mental Health Study (MHS). The baseline sample comprised 425 Caucasian (n=278) and African American (n=147) community-dwelling women, aged 46.1+/-2.5 years. Anxiety symptoms measured annually using a self-report questionnaire were examined in relation to MDD episodes in the subsequent year, assessed with the SCID. Multivariable models were estimated with random effects logistic regression. RESULTS: Higher anxiety symptoms scores were associated with a significantly higher adjusted odds of developing an episode of MDD at the subsequent annual visit [odds ratio (OR) 1.47, p=0.01], specifically for a recurrent episode (OR 1.49, p=0.03) but non-significant for a first episode (OR 1.32, p=0.27). There were no significant racial effects in the association between anxiety symptoms and subsequent MDD episodes. CONCLUSIONS: Anxiety symptoms often precede MDD and may increase the vulnerability of midlife women to depressive episodes, particularly recurrences. Women with anxiety symptoms should be monitored clinically during the ensuing year for the development of an MDD episode. PMID- 24467999 TI - GEOVET 2013: geospatial analysis in veterinary epidemiology and preventive medicine. PMID- 24468000 TI - Microbe observation and cultivation array (MOCA) for cultivating and analyzing environmental microbiota. AB - BACKGROUND: The use of culture-independent nucleic acid techniques, such as ribosomal RNA gene cloning library analysis, has unveiled the tremendous microbial diversity that exists in natural environments. In sharp contrast to this great achievement is the current difficulty in cultivating the majority of bacterial species or phylotypes revealed by molecular approaches. Although recent new technologies such as metagenomics and metatranscriptomics can provide more functionality information about the microbial communities, it is still important to develop the capacity to isolate and cultivate individual microbial species or strains in order to gain a better understanding of microbial physiology and to apply isolates for various biotechnological applications. RESULTS: We have developed a new system to cultivate bacteria in an array of droplets. The key component of the system is the microbe observation and cultivation array (MOCA), which consists of a Petri dish that contains an array of droplets as cultivation chambers. MOCA exploits the dominance of surface tension in small amounts of liquid to spontaneously trap cells in well-defined droplets on hydrophilic patterns. During cultivation, the growth of the bacterial cells across the droplet array can be monitored using an automated microscope, which can produce a real-time record of the growth. When bacterial cells grow to a visible microcolony level in the system, they can be transferred using a micropipette for further cultivation or analysis. CONCLUSIONS: MOCA is a flexible system that is easy to set up, and provides the sensitivity to monitor growth of single bacterial cells. It is a cost-efficient technical platform for bioassay screening and for cultivation and isolation of bacteria from natural environments. PMID- 24468001 TI - Reflections in the clinical practice. AB - The purpose of this article is to analyze some models of expert decision and their impact on the clinical practice. We have analyzed decision-making considering the cognitive aspects (explanatory models, perceptual skills, analysis of the variability of a phenomenon, creating habits and inertia of reasoning and declarative models based on criteria). We have added the importance of emotions in decision making within highly complex situations, such as those occurring within the clinical practice. The quality of the reflective act depends, among other factors, on the ability of metacognition (thinking about what we think). Finally, we propose an educational strategy based on having a task supervisor and rectification scenarios to improve the quality of medical decision making. PMID- 24468002 TI - How to prevent and treat pharmacological hypoglycemias. AB - A 58 year-old woman with type 2 diabetes diagnosed 3 years before came to our clinic. Her treatment was metformin 850 mg every 12 hours and glimepiride 4 mg every 24 hours. After the initiation of glimepiride 9 months before her weight has increased 5 kg, and she suffers frequent hypoglycemias which have affected her while driving. Her BMI is 35.5 kg/m2. She has a normal eye fund exam. She has hypertension treated with telmisartan and hidroclorotiazide with adequate control, and also hypercholesterolemia treated with atorvastatine 40 mg every 24 hours. Her blood test shows an HbA1c of 7.0%, normal values of microalbuminuria, total cholesterol 149 mg/dl, HDL cholesterol 52 mg/dl, LDL cholesterol 98 mg/dl and triglycerides 123 mg/dl. Her blood pressure is 129/81 mmHg, there was no orthostatic hypotension, and her peripheral neurological examination shows normal results. In summary, our case is a young woman with type 2 diabetes and obesity, without chronic complications and which has frequent hypoglycaemia. How must this woman be evaluated and treated? PMID- 24468003 TI - The anticancer antibiotic mithramycin-A inhibits TRPV1 expression in dorsal root ganglion neurons. AB - Activation of peripheral nociceptors by products of inflammation has been shown to be dependent on specific sensory transducing elements such as the capsaicin receptor, TRPV1. The development of high-affinity antagonists to TRPV1 as well as to other receptors capable of detecting noxious stimuli has now become a major focus in analgesic development. Another critical feature of nociception is the relative abundance of a particular pain transducing receptor under normal or pathophysiologic conditions. Increases in expression and/or changes in distribution of nociceptive receptors such as TRPV1 have been correlated with progression of tissue injury and persistence of pain behaviors. Although some details are emerging as to what regulates nociceptor-specific gene expression, compounds that could potentially be used to block or reverse over-expression of nociceptive gene expression are essentially absent. In our efforts to better understand the transcriptional regulation of TRPV1 in sensory neurons, we identified an anticancer agent, mithramycin-A, that decreased TRPV1 expression in primary rat dorsal root ganglion (DRG) neurons. Mithramycin-A dose-dependently (10-50 nM) decreased endogenous TRPV1 mRNA content and appeared to decrease TRPV1 like protein expression in DRG neurons. We also observed that mithramycin-A directed a decrease in the number of capsaicin-responsive DRG neurons without a significant change in the capsaicin-response magnitudes. Interestingly, mithramycin-A also reduced the mRNA encoding Sp1 and Sp4 in DRG neurons, transcription factors previously found to positively regulate TRPV1 expression in sensory neurons. Taken together, we propose that mithramycin-A directs an inhibitory effect on a subpopulation of capsaicin-responsive DRG neurons that utilize Sp1-like factors for TRPV1 expression. Given the therapeutic correlate of mithramycin-A effectiveness in the treatment of certain cancers, small molecule transcriptional inhibitors such as mithramycin-A may serve as useful tools of discovery in pain transduction and possibly future analgesic development. PMID- 24468004 TI - Bone marrow necrosis and fat embolism syndrome in sickle cell disease: increased susceptibility of patients with non-SS genotypes and a possible association with human parvovirus B19 infection. AB - Fat embolism syndrome (FES) due to extensive bone marrow necrosis (BMN) in sickle cell disease (SCD) is a potentially under-diagnosed complication associated with severe morbidity and mortality. We identified 58 cases reported in the world literature to date. Typically, patients presented with a seemingly uncomplicated vaso-occlusive crisis (VOC) and subsequently deteriorated rapidly with a drop in their haemoglobin and platelets, development of respiratory failure, encephalopathy and varying degrees of involvement of other systems. Overall mortality in the reported cases was 64% but differed according to the use of transfusion and was 29%, 61% and 91% for patients receiving exchange, top-up or no transfusion respectively. Patients most at risk appear to be those with a "milder" form of SCD as 81% of patients had a genotype other than HbSS and the majority had no history of significant sickle-related complications. Human parvovirus B19 (HPV B19) infection was documented in 24% of cases. PMID- 24468005 TI - Production and expression of RANTES (CCL5) by human disc cells and modulation by IL-1-beta and TNF-alpha in 3D culture. AB - Chemokines act as important secondary inflammatory mediators which are released by cells in response to a variety of stimuli. Chemokines bind to cell surface receptors and act as second-order cytokines with specialized functions in inflammation. The role of RANTES (Regulated upon Activation, Normal T-cell Expressed, and Secreted) (also called CCL5 (chemokine (C-C motif) ligand 5)) has received little attention to date in disc tissue. Microarray analyses of lumbar disc annulus tissue revealed that RANTES expression was significantly upregulated in more degenerated Thompson grades IV and V discs compared to expression levels in grades I, II and III discs (p=0.032). Immunolocalization confirmed the presence of RANTES in the annulus and nucleus of the disc, and localized the RANTES receptors CCR1, CCR3 and CCR5 to cells in the disc. In vitro studies with IL-1-beta and TNF-alpha challenges, both proinflammatory cytokines resulted in elevated levels of RANTES in conditioned media (p<0.01); TNF-alpha exposure, however, produced significantly greater levels than did IL-1alpha (p<0.0001), suggesting a differential regulation by TNF-alpha. Local production of RANTES in vivo by annulus and nucleus cells, and in vitro induction of RANTES by proinflammatory cytokines suggest that disc cells are primary effector cells as well as target cells, and thus can mediate physiological immune-related processes during disc degeneration by both autocrine and paracrine signaling. PMID- 24468006 TI - Is crystalloid cardioplegia a strong predictor of intra-operative hemodilution? AB - INTRODUCTION: Complications due to hemodilution (hematocrit value less than 22%) after cardiopulmonary bypass inevitably resulted with significantly greater intensive care requirements, long hospital stays, more operative costs, and increased mortality rates. We tried to identify whether crystalloid cardioplegia is the strongest predictor of intraoperative hemodilution or not. MATERIALS AND METHODS: One hundred patients were included into this randomized prospective study. Patients were divided into the two groups. Crystalloid cardioplegia were given to the odd-numbered patients (Group 1, n=50 patients) and blood cardioplegia were given to the even-numbered patients (Group 2, n=50 patients). St. Thomas-II solution was used in Group-1 and Calafiore cold blood cardioplegia was in Group-2. RESULTS: Average intraoperative hematocrit value was 18.4% +/- 2.3 in crystalloid group 24.2% +/- 3.4 in blood cardioplegia group (p<0.001). The lowest hematocrit value was 15% and 20% in two groups respectively (p<0.001). In crystalloid group average intraoperative packed red blood cell (RBC) transfusion was 2.3 +/- 0.41 units, 0.7 +/- 0.6 units blood cardioplegia group (p=0.001). Average transfused RBC was 2.7 +/- 0.8 units in crystalloid group, 0.9 +/- 0.4 units blood cardioplegia group (p<0.001). Multivariate analyses confirmed age (p = 0.005, OR = 3.78), female gender (p = 0.003, OR = 2.91), longer cross-clamp time (>60 minutes) (p = 0.001, OD = 0.97), body surface area <1.6 m2 (p = 0.001, OR = 6.01) and crystalloid cardioplegia (p < 0.001, OR = 0.19) as predictor of intraoperative hemodilution. CONCLUSION: Crystalloid cardioplegia, compared to blood cardioplegia not only causes much more intra-operative hemodilution but also increases the blood transfusion requirement. Hemodilution and increased transfusion increases the intensive care unit and hospital stay, in the early postoperative period. PMID- 24468007 TI - Early parasite clearance following artemisinin-based combination therapy among Ugandan children with uncomplicated Plasmodium falciparum malaria. AB - BACKGROUND: Artemisinin-based combination therapy (ACT) is widely recommended as first-line therapy for uncomplicated Plasmodium falciparum malaria worldwide. Artemisinin resistance has now been reported in Southeast Asia with a clinical phenotype manifested by slow parasite clearance. Although there are no reliable reports of artemisinin resistance in Africa, there is a need to better understand the dynamics of parasite clearance in African children treated with ACT in order to better detect the emergence of artemisinin resistance. METHODS: Data from a cohort of Ugandan children four to five years old, enrolled in a longitudinal, randomized, clinical trial comparing two leading ACT, artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP), were analysed. For all episodes of uncomplicated P. falciparum malaria over a 14-month period, daily blood smears were performed for three days following the initiation of therapy. Associations between pre-treatment variables of interest and persistent parasitaemia were estimated using multivariate, generalized, estimating equations with adjustment for repeated measures in the same patient. RESULTS: A total of 202 children were included, resulting in 416 episodes of malaria treated with AL and 354 episodes treated with DP. The prevalence of parasitaemia on days 1, 2, and 3 following initiation of therapy was 67.6, 5.6 and 0% in those treated with AL, and 52.2, 5.7 and 0.3% in those treated with DP. Independent risk factors for persistent parasitaemia on day 1 included treatment with AL vs DP (RR = 1.34, 95% CI 1.20 1.50, p < 0.001), having a temperature >=38.0 degrees C vs < 37.0 degrees C (RR = 1.19, 95% CI 1.05-1.35, p = 0.007) and having a parasite density >20,000/MUL vs <4,000/MUL (RR = 3.37, 95% CI 2.44-4.49, p < 0.001). Independent risk factors for having persistent parasitaemia on day 2 included elevated temperature, higher parasite density, and being HIV infected. CONCLUSIONS: Among Ugandan children, parasite clearance following treatment with AL or DP was excellent with only one of 752 patients tested having a positive blood slide three days after initiation of therapy. The type of ACT given, pre-treatment temperature, pre-treatment parasite density and HIV status were associated with differences in persistent parasitaemia, one or two days following therapy. TRIAL REGISTRATION: Current Controlled Trials Identifier NCT00527800. PMID- 24468008 TI - Docosatetraenoyl LPA is elevated in exhaled breath condensate in idiopathic pulmonary fibrosis. AB - BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease with no effective medical therapies. Recent research has focused on identifying the biological processes essential to the development and progression of fibrosis, and on the mediators driving these processes. Lysophosphatidic acid (LPA), a biologically active lysophospholipid, is one such mediator. LPA has been found to be elevated in bronchoalveolar lavage (BAL) fluid of IPF patients, and through interaction with its cell surface receptors, it has been shown to drive multiple biological processes implicated in the development of IPF. Accordingly, the first clinical trial of an LPA receptor antagonist in IPF has recently been initiated. In addition to being a therapeutic target, LPA also has potential to be a biomarker for IPF. There is increasing interest in exhaled breath condensate (EBC) analysis as a non-invasive method for biomarker detection in lung diseases, but to what extent LPA is present in EBC is not known. METHODS: In this study, we used liquid chromatography-tandem mass spectrometry (LC-MS/MS) to assess for the presence of LPA in the EBC and plasma from 11 IPF subjects and 11 controls. RESULTS: A total of 9 different LPA species were detectable in EBC. Of these, docosatetraenoyl (22:4) LPA was significantly elevated in the EBC of IPF subjects when compared to controls (9.18 pM vs. 0.34 pM; p = 0.001). A total of 13 different LPA species were detectable in the plasma, but in contrast to the EBC, there were no statistically significant differences in plasma LPA species between IPF subjects and controls. CONCLUSIONS: These results demonstrate that multiple LPA species are detectable in EBC, and that 22:4 LPA levels are elevated in the EBC of IPF patients. Further research is needed to determine the significance of this elevation of 22:4 LPA in IPF EBC, as well as its potential to serve as a biomarker for disease severity and/or progression. PMID- 24468009 TI - [Validation of APACHE II and SOFA scores in 2 cohorts of patients with suspected infection and sepsis, not admitted to critical care units]. AB - OBJECTIVE: To validate the APACHE II and SOFA scores in patients with suspected infection in clinical settings other than intensive care units. MATERIALS AND METHODS: A secondary analysis was performed on 2,530 adult patients participating in 2 cohort studies, with suspected infection as admission diagnosis within the first 24 h of hospitalization. The performance of both scoring systems was studied in order to set calibration and discrimination, respectively, on the outcomes such as mortality, admission to Intensive Care Unit, development of septic shock, or multiple organ dysfunctions. RESULTS: The AUC-ROC values for mortality at discharge and on day 28 in the first cohort were around 0.50 for the SOFA and APACHE II scores; whereas for the second cohort the discrimination value was around 0.70. Calibration of both scoring systems for primary outcomes, according to Hosmer-Lemeshow test, showed p>.05 in the first cohort; while in the second cohort calibration it only showed a p>.05 in the case of the SOFA for mortality at hospital discharge. CONCLUSION: This validation study of SOFA and APACHE II scores in patients with suspected infection in-hospital units other than the Intensive Care Unit, showed no consistent performance for calibration and discrimination. Its application in emergency and in-hospital patients is limited. PMID- 24468010 TI - [Hemophagocytic syndrome associated with Epstein-Barr virus. Presentation of a case and treatment in the Resuscitation Unit]. AB - We report the case of a 17 year old male patient, who was admitted to the Resuscitation Unit with the diagnosis of hemophagocytic syndrome, associated with infection by Epstein-Barr virus with unfavorable outcome. Hemophagocytic syndrome is a pathological immune activation syndrome due to the production/uncontrolled modulation of some cytokines. Its clinical signs and symptoms, defined by consensus criteria HLH-2004, are not pathognomonic, and often appear sequentially, thus suspicion should be followed by aggressive supportive therapy combined with early specific treatment of the triggering factor, as it is the only way to improve survival in patients with multiple organic failure as a result. PMID- 24468011 TI - Changes in cytomegalovirus seroprevalence in pregnant Japanese women-a 10-year single center study. AB - BACKGROUND: Human cytomegalovirus (CMV) causes congenital infections during pregnancy, and seroepidemiological data are important for estimating the risk of infection. However, only a few reports of CMV seroprevalence exist for pregnant Japanese women. OBJECTIVES: The purpose of this study was to assess CMV seroprevalence in pregnant Japanese women. STUDY DESIGN: This cross-sectional study involved pregnant Japanese women who delivered from 2003 to 2012 at our hospital (n=15,616). Among these women, 14,099 (90.3%) underwent tests for the presence of CMV IgG. Those with an equivocal test result were excluded (n=195) from this analysis, leaving a study sample of 13,904 Japanese pregnant women. The prevalence of CMV IgG was also assessed by calendar year, age, and parity. RESULTS: The overall CMV IgG prevalence rate was 66.0%. CMV IgG prevalence significantly decreased over the course of 10 years from 2003 to 2012 (from 69.9% in 2003 to 65.2% in 2012) (p<0.001). Adjusted odds ratios for CMV IgG positivity in women aged <25, 25-30, 35-40, and >40 years were 1.66 (95%CI: 1.25-2.20), 1.20 (95%CI: 1.07-1.35), 1.16 (95%CI: 1.07-1.26), and 1.44 (95%CI: 1.28-1.62), respectively, compared to women aged 30-35 years. Adjusted odds ratios for CMV IgG positivity for a parity of 1, 2, and >=3 were 1.14 (95%CI: 1.06-1.23), 1.52 (95%CI: 1.32-1.77), and 2.54 (95%CI: 2.69-3.84), respectively, compared to nulliparous women. CONCLUSION: We found that 34% of pregnant Japanese women were susceptible to CMV infection. Calendar year, maternal age, and parity were significantly associated with changes in CMV seroprevalence among this population. PMID- 24468012 TI - A comparison of methylation levels in HPV18, HPV31 and HPV33 genomes reveals similar associations with cervical precancers. AB - BACKGROUND: High risk human papillomavirus (HR-HPV) infection is common and only a small minority of infections become persistent and lead to cervical cancers. Women positive for HR-HPV usually require a second test to avoid unnecessary colposcopies and over treatment. Elevated DNA methylation of HR-HPV L1 and L2 genes in high grade disease has emerged as a promising molecular triage tool. OBJECTIVES: Our aim was to accurately measure methylation levels at selected CpG positions in the HPV18, HPV31 and HPV33 genomes. We focused on the L2, L1, URR and E6 regions because these were previously shown to be interesting areas for study. STUDY DESIGN: Pyrosequencing was used to measure methylation in 208 HPV18, 207 HPV31, and 126 HPV33 positive women selected from a London colposcopy referral population. RESULTS: After adjustment for multiple testing, at FDR 5%, elevated methylation was significantly associated with cervical intraepithelial neoplasia grades 2 or worse (CIN2+) in all investigated CpGs in HPV18 L2 and L1. Two of 6 L2 and 12 of 15 L1 sites in HPV31 and 6 of 8 L2 and 3 of 13 L1 sites in HPV33 showed significantly elevated methylation in CIN2+. Methylation of CpG sites in the URR and E6 region of the HPV types was low and most differences were not significant. CONCLUSION: Elevated methylation of CpG sites in the L1 and L2 regions of HPV18, HPV31 and HPV33 is associated with CIN2+ and a panel test may be useful for triage of women with HR-HPV infections. PMID- 24468013 TI - Flowers and weeds: cell-type specific pruning in the developing visual thalamus. AB - In the first weeks of vertebrate postnatal life, neural networks in the visual thalamus undergo activity-dependent refinement thought to be important for the development of functional vision. This process involves pruning of synaptic connections between retinal ganglion cells and excitatory thalamic neurons that relay signals on to visual areas of the cortex. A recent report in Neural Development shows that this does not occur in inhibitory neurons, questioning our current understanding of the development of mature neural circuits. PMID- 24468014 TI - Excitatory/inhibitory equilibrium of the central amygdala nucleus gates anti depressive and anxiolytic states in the hamster. AB - Several studies have pointed to the amygdala as a main limbic station capable of regulating different stressful states such as anxiety and depression. In this work it was our intention to determine the role of the central amygdala nucleus (CeA) on the execution of either anxiolytic and/or anti-depressant behaviors in the hibernating hamster (Mesocricetus auratus) via infusion of CeA with the antagonist, 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX) specific for alpha-amino 3-hydroxy-5-methyl-4-isoxazole propionic acid receptor (AMPAR) plus the specific agonist for alpha4 GABAAR i.e. 4,5,6,7-tetrahydroisoxazolo(5,4-c)pyridin-3-ol (THIP). Treatment with CNQX appeared to mainly prompt anti-depressant effects as shown by the achievements of swimming feats during forced swim test while THIP prevalently accounted for evident bouts of climbing when exposed to the same test. Moreover, even in the presence of the concomitant administration of both of these compounds, hamsters continued to spend more time in swimming despite this significant behavioral effect resulted to be numerically reduced for hamsters treated with only the alpha4 GABAAR agonist. Conversely, when these animals were tested in elevated plus maze (EPM), THIP tended to mostly favor anxiolytic activities as exhibited by stressed animals spending more time entering and remaining in EPM open arms. It was interesting to note that behavioral changes induced by both drugs appeared to be also responsible for glutamate receptor (GluR) expression differences as indicated by CNQX favoring an evident up regulation of GluR2-containing neurons whereas THIP induced an up-regulation, this time of GluR1-containing neurons. Overall, the anti-depressant role of CNQX seems to be mostly attributed to elevated GluR2 levels while an anxiolytic-like effect of THIP was correlated to high GluR1values thereby proposing distinct GluRs as useful therapeutic sites against degenerative diseases such as depression-like behaviors. PMID- 24468016 TI - Morphometric modelling of ageing in the human pubic symphysis: sexual dimorphism in an Australian population. AB - Despite the prominent use of the pubic symphysis for age estimation in forensic anthropology, little has been documented regarding the quantitative morphological and micro-architectural changes of this surface. Specifically, utilising post mortem computed tomography data from a large, contemporary Australian adult population, this study aimed to evaluate sexual dimorphism in the morphology and bone composition of the symphyseal surface; and temporal characterisation of the pubic symphysis in individuals of advancing age. The sample consisted of multi slice computed tomography (MSCT) scans of the pubic symphysis (slice thickness: 0.5mm, overlap: 0.1mm) of 200 individuals of Caucasian ancestry aged 15-70 years, obtained in 2011. Surface rendering reconstruction of the symphyseal surface was conducted in OsiriX((r)) (v.4.1) and quantitative analyses in Rapidform XOSTM and OsteomeasureTM. Morphometric variables including inter-pubic distance, surface area, circumference, maximum height and width of the symphyseal surface and micro architectural assessment of cortical and trabecular bone compositions were quantified using novel automated engineering software capabilities. The major results of this study are correlated with the macroscopic ossification and degeneration pattern of the symphyseal surface, demonstrating significant age related changes in the morphometric and bone tissue variables between 15 and 70 years. Regardless of sex, the overall dimensions of the symphyseal surface increased with age, coupled with a decrease in bone mass in the trabecular and cortical bone compartments. Significant differences between the ventral, dorsal and medial cortical surfaces were observed, which may be correlated to bone formation activity dependent on muscle activity and ligamentous attachments. Our study demonstrates significant sexual dimorphism at this site, with males exhibiting greater surface dimensions than females. These baseline results provide a detailed insight into the changes in the structure of the pubic symphysis with ageing and sexually dimorphic features associated with the cortical and trabecular bone profiles. PMID- 24468015 TI - Antidepressant response to aripiprazole augmentation associated with enhanced FDOPA utilization in striatum: a preliminary PET study. AB - Several double blind, prospective trials have demonstrated an antidepressant augmentation efficacy of aripiprazole in depressed patients unresponsive to standard antidepressant therapy. Although aripiprazole is now widely used for this indication, and much is known about its receptor-binding properties, the mechanism of its antidepressant augmentation remains ill-defined. In vivo animal studies and in vitro human studies using cloned dopamine dopamine D2 receptors suggest aripiprazole is a partial dopamine agonist; in this preliminary neuroimaging trial, we hypothesized that aripiprazole's antidepressant augmentation efficacy arises from dopamine partial agonist activity. To test this, we assessed the effects of aripiprazole augmentation on the cerebral utilization of 6-[(18)F]-fluoro-3,4-dihydroxy-l-phenylalanine (FDOPA) using positron emission tomography (PET). Fourteen depressed patients, who had failed 8 weeks of antidepressant therapy with selective serotonin reuptake inhibitors, underwent FDOPA PET scans before and after aripiprazole augmentation; 11 responded to augmentation. Whole brain, voxel-wise comparisons of pre- and post aripiprazole scans revealed increased FDOPA trapping in the right medial caudate of augmentation responders. An exploratory analysis of depressive symptoms revealed that responders experienced large improvements only in putatively dopaminergic symptoms of lassitude and inability to feel. These preliminary findings suggest that augmentation of antidepressant response by aripiprazole may be associated with potentiation of dopaminergic activity. PMID- 24468017 TI - Yersinia pseudotuberculosis enterocolitis mimicking enteropathic gammadelta T cell lymphoma with abnormal clonality. AB - BACKGROUND: Yersinia pseudotuberculosis generally infects the gastrointestinal tract and causes enteropathy symptoms suggesting infection. Y. pseudotuberculosis infections are often complicated with intraceliac lymphoadenopathy mimicking malignant lymphoma. This is a first case of Yersinia pseudotuberculosis enteropathy mimicking enteropathic gammadelta T-cell lymphoma. This case highlighted the gammadelta T-cell reaction to Yersinia enterocolitis sometimes mimicking malignant lymphoma clinically. CASE PRESENTATION: A 72-year-old female was referred to our institute due to abdominal pain with skin rush, fever and diarrhea. Computed tomography (CT) scanning revealed mucosal swelling of the cecum with enlargement of regional lymph nodes. Laboratory data showed elevated CRP (7.74 mg/dL), an increased level of soluble interleukin-2 receptor (sIL-2R 3095 IU/mL), and CD3+ gammadelta T-cell circulation in peripheral blood and bone marrow (10.9% and 3.9%, respectively). Increased proportions of gammadelta T cells supported the diagnosis of malignant lymphoma. Colonoscopy demonstrated hemorrhagic mucosal erosion with partial ulceration, and the subsequent pathological findings at the inflammation site suggested malignant lymphoma histopathology in the colon. These objective findings were entirely consistent with enteropathic gammadelta T-cell lymphoma. Thereafter, however, the microbiological results of the patient's stool at admission showed Yersinia pseudotuberculosis, and she was diagnosed as having Yersinia enterocolitis. All abnormal findings including subjective symptoms were in remission or mitigated within 2 weeks after her onset. Even the gammadelta T-cell circulation disappeared (0.04% in peripheral blood), and we speculate that those cells were a reaction to the Yersinia infection. CONCLUSION: In this case, a differential diagnosis included infectious enterocolitis from other immunogenic or malignant diseases. Although a measurement of sIL-2R is critical in differentiating malignant lymphoma in patients suffering with lymph adenopathy, that is not confirmative. This patient's case indicates that T cells expressing the gammadelta T-cell receptor might be associated with the acute and late phase reactions, in which T cells play a role in the construction of granulomas and the establishment of sequelae. PMID- 24468018 TI - The mediating role of the environment in explaining participation of children and youth with and without disabilities across home, school, and community. AB - OBJECTIVE: To test the effect of personal and environmental factors on children's participation across 3 different settings (home, school, community); to ascertain the interrelations between these factors; and to propose and test 3 models, 1 for each setting, using structural equation modeling. DESIGN: Survey, cross-sectional study, and model testing. SETTING: Web-based measures were completed by parents residing in North America in their home/community. PARTICIPANTS: Parents (N=576) of children and youth with and without disabilities, (n=282 and n=294, respectively), ages 5 to 17 years (mean age, 11y 2mo), completed the Participation and Environment Measure for Children and Youth (PEM-CY). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The PEM-CY measured levels of participation frequency and involvement, as well as environmental barriers and supports of participation, in each of the following 3 settings: home, school, and community. Information about the child's health condition and functional issues was also collected. RESULTS: All 3 models fit the data well (comparative fit index, .89-.97) and explained 50% to 64% of the variance of participation frequency and involvement. Environmental barriers and supports served as significant mediators between child/personal factors (income, health condition, functional issues) and participation outcomes, across all models. The effect of the environment was most pronounced, however, in the community setting. CONCLUSIONS: Our findings highlight the unique role of the environment in explaining children's participation across different settings and, therefore, support the development of interventions targeting modifiable environmental factors. PMID- 24468019 TI - Simultaneous double-opposing Z-plasty and posterior pharyngeal flap. AB - PURPOSE: Strategies to address severe anteroposterior palatal shortening with velopharyngeal insufficiency include palatal lengthening or manipulation of posterior pharyngeal tissue as a flap or sphincter. In some cases, a single procedure alone is not sufficient to achieve dynamic velopharyngeal closure. The objective of this study was to determine whether double-opposing Z-plasty coupled with a posterior pharyngeal flap would achieve adequate palatal length in severe velopharyngeal dysfunction. MATERIALS AND METHODS: Six patients, 3 with previously unrepaired cleft palate and 3 children with previous straight-line repairs and significant anteroposterior shortening, were included. Demographic and perioperative information was tabulated. Subjective and objective speech data were gathered, if available. Complications, follow-ups, and postoperative nasometric results were compiled. Statistical analysis involved the paired t test. RESULTS: There were no perioperative complications. Follow-up was at least 1 year. No postoperative fistulas or nasal obstruction developed. Hypernasal speech and nasal emission were subjectively improved in all patients. Nasometric data showed a statistically significant improvement in nasal air escape with speech. CONCLUSIONS: Simultaneous double-opposing Z-plasty and posterior pharyngeal flap can be performed effectively. This strategy is useful for severe velopharyngeal dysfunction secondary to anteroposterior palatal shortening or a previously unrepaired cleft palate, and the technique optimizes palatal function and creates a mechanical blockade to nasal air escape. PMID- 24468020 TI - Management of needle breakage using intraoperative navigation following inferior nerve block. PMID- 24468021 TI - Of RNA-binding proteins and their targets: interaction determines expression. AB - Combining the prediction of interactions between mRNAs and RNA-binding proteins with experimental expression profiles uncovers novel regulatory paradigms concerning proliferation and differentiation processes. PMID- 24468022 TI - Behavioral and emotional dysregulation trajectories marked by prefrontal-amygdala function in symptomatic youth. AB - BACKGROUND: Neuroimaging measures of behavioral and emotional dysregulation can yield biomarkers denoting developmental trajectories of psychiatric pathology in youth. We aimed to identify functional abnormalities in emotion regulation (ER) neural circuitry associated with different behavioral and emotional dysregulation trajectories using latent class growth analysis (LCGA) and neuroimaging. METHOD: A total of 61 youth (9-17 years) from the Longitudinal Assessment of Manic Symptoms study, and 24 healthy control youth, completed an emotional face n-back ER task during scanning. LCGA was performed on 12 biannual reports completed over 5 years of the Parent General Behavior Inventory 10-Item Mania Scale (PGBI-10M), a parental report of the child's difficulty regulating positive mood and energy. RESULTS: There were two latent classes of PGBI-10M trajectories: high and decreasing (HighD; n=22) and low and decreasing (LowD; n=39) course of behavioral and emotional dysregulation over the 12 time points. Task performance was >89% in all youth, but more accurate in healthy controls and LowD versus HighD (p<0.001). During ER, LowD had greater activity than HighD and healthy controls in the dorsolateral prefrontal cortex, a key ER region, and greater functional connectivity than HighD between the amygdala and ventrolateral prefrontal cortex (p's<0.001, corrected). CONCLUSIONS: Patterns of function in lateral prefrontal cortical-amygdala circuitry in youth denote the severity of the developmental trajectory of behavioral and emotional dysregulation over time, and may be biological targets to guide differential treatment and novel treatment development for different levels of behavioral and emotional dysregulation in youth. PMID- 24468023 TI - American College of Surgeons/Association for Surgical Education medical student simulation-based surgical skills curriculum needs assessment. AB - BACKGROUND: Simulation can enhance learning effectiveness, efficiency, and patient safety and is engaging for learners. METHODS: A survey was conducted of surgical clerkship directors nationally and medical students at 5 medical schools to rank and stratify simulation-based educational topics. Students applying to surgery were compared with others using Wilcoxon's rank-sum tests. RESULTS: Seventy-three of 163 clerkship directors (45%) and 231 of 872 students (26.5%) completed the survey. Of students, 28.6% were applying for surgical residency training. Clerkship directors and students generally agreed on the importance and timing of specific educational topics. Clerkship directors tended to rank basic skills, such as examination skills, higher than medical students. Students ranked procedural skills, such as lumbar puncture, more highly than clerkship directors. CONCLUSIONS: Surgery clerkship directors and 4th-year medical students agree substantially about the content of a simulation-based curriculum, although 4th year medical students recommended that some topics be taught earlier than the clerkship directors recommended. Students planning to apply to surgical residencies did not differ significantly in their scoring from students pursuing nonsurgical specialties. PMID- 24468024 TI - The impact of brief team communication, leadership and team behavior training on ad hoc team performance in trauma care settings. AB - BACKGROUND: Communication breakdowns and care coordination problems often cause preventable adverse patient care events, which can be especially acute in the trauma setting, in which ad hoc teams have little time for advanced planning. Existing teamwork curricula do not address the particular issues associated with ad hoc emergency teams providing trauma care. METHODS: Ad hoc trauma teams completed a preinstruction simulated trauma encounter and were provided with instruction on appropriate team behaviors and team communication. Teams completed a postinstruction simulated trauma encounter immediately afterward and 3 weeks later, then completed a questionnaire. Blinded raters rated videotapes of the simulations. RESULTS: Participants expressed high levels of satisfaction and intent to change practice after the intervention. Participants changed teamwork and communication behavior on the posttest, and changes were sustained after a 3 week interval, though there was some loss of retention. CONCLUSIONS: Brief training exercises can change teamwork and communication behaviors on ad hoc trauma teams. PMID- 24468025 TI - When surgeons decide to become surgeons: new opportunities for surgical education. AB - BACKGROUND: When surgeons decide to become surgeons has important implications. If the decision is made prior to or early in medical school, surgical education can be more focused on surgical diseases and resident skills. METHODS: To determine when surgeons - compared with their nonsurgical colleagues - decide on their medical path, residents in surgery, internal medicine, obstetrics and gynecology, pediatrics, psychiatry, and emergency medicine were surveyed. Timing of residency choice, demographic data, personal goals, and reason for residency choice were queried. RESULTS: A total of 234 residents responded (53 surgical residents). Sixty-two percent of surgeons reported that they were "fairly certain" of surgery before medical school, 13% decided during their preclinical years, and 25% decided during their clerkship years. This compares with an aggregate 40%, 7%, and 54%, respectively, for the other 5 residency specialties. These differences were statistically significant (P = .001). When the 234 residents were asked about their primary motivation for choosing their field, 51% pointed to expected job satisfaction and 44% to intellectual curiosity, and only 3% mentioned lifestyle, prestige, or income. CONCLUSIONS: General surgery residents decide on surgery earlier than residents in other programs. This may be advantageous, resulting in fast-tracking of these medical students in acquiring surgical knowledge, undertaking surgical research, and early identification for surgical residency programs. Surgical training in the era of the 80-hour work week could be enhanced if medical students bring much deeper knowledge of surgery to their first day of residency. PMID- 24468026 TI - The impact of aptitude on the learning curve for laparoscopic suturing. AB - BACKGROUND: Within surgery, several specialties demand advanced technical skills, specifically in the minimally invasive environment. METHODS: Two groups of 10 medical students were recruited on the basis of their aptitude (visual-spatial ability, depth perception, and psychomotor ability). All subjects were tested consecutively using the ProMIS III simulator until they reached proficiency performing laparoscopic suturing. Simulator metrics, critical error scores, observed structured assessment of technical skills scores, and Fundamentals of Laparoscopic Surgery scores were recorded. RESULTS: Group A (high aptitude) achieved proficiency after a mean of 7 attempts (range, 4-10). In group B (low aptitude), 30% achieved proficiency after a mean of 14 attempts (range, 10-16). In group B, 40% demonstrated improvement but did not attain proficiency, and 30% failed to progress. CONCLUSIONS: Distinct learning curves for laparoscopic suturing can be mapped on the basis of fundamental ability. High aptitude is directly related to earlier completion of the learning curve. A proportion of subjects with low aptitude are unable to reach proficiency despite repeated attempts. PMID- 24468027 TI - Is there a place for medical students as teachers in the education of junior residents? AB - BACKGROUND: The aim of this study was to investigate a novel resident education model that turns the traditional surgical hierarchy upside down, termed a "reverse" peer-assisted learning curriculum. METHODS: Thirty surgical topics were randomized between medical students and chief residents on each clinical team, with 1 topic being presented briefly during morning rounds. An exam evaluating junior residents' knowledge of these topics was administered before and after 1 month of presentations. A questionnaire was distributed to evaluate the junior residents' perceptions of this teaching model. RESULTS: Thirty-four residents participated. There was a significant improvement in the mean examination score (54 vs 74, P < .05). No significant difference was noted in the mean score differentials of topics presented by either the medical students or the chief resident (21 vs 18, P = .22). More than 80% of the residents responded positively about the effectiveness of this exercise and agreed that they would like to see this model used on other services. CONCLUSIONS: This study confirms the hypothesis that medical students can teach surgical topics to junior residents at least as effectively as their chief residents. PMID- 24468028 TI - European validation of a real-time PCR-based method for detection of Listeria monocytogenes in soft cheese. AB - The classical microbiological method for detection of Listeria monocytogenes requires around 7 days for final confirmation, and due to perishable nature of RTE food products, there is a clear need for an alternative methodology for detection of this pathogen. This study presents an international (at European level) ISO 16140-based validation trial of a non-proprietary real-time PCR-based methodology that can generate final results in the following day of the analysis. This methodology is based on an ISO compatible enrichment coupled to a bacterial DNA extraction and a consolidated real-time PCR assay. Twelve laboratories from six European countries participated in this trial, and soft cheese was selected as food model since it can represent a difficult matrix for the bacterial DNA extraction and real-time PCR amplification. The limit of detection observed was down to 10 CFU per 25 of sample, showing excellent concordance and accordance values between samples and laboratories (>75%). In addition, excellent values were obtained for relative accuracy, specificity and sensitivity (82.75%, 96.70% and 97.62%, respectively) when the results obtained for the real-time PCR-based methods were compared to those of the ISO 11290-1 standard method. An interesting observation was that the L. monocytogenes detection by the real-time PCR method was less affected in the presence of Listeria innocua in the contaminated samples, proving therefore to be more reliable than the reference method. The results of this international trial demonstrate that the evaluated real-time PCR based method represents an excellent alterative to the ISO standard since it shows a higher performance as well as reduce the extent of the analytical process, and can be easily implemented routinely by the competent authorities and food industry laboratories. PMID- 24468029 TI - A comparison of muscle strength and endurance, exercise capacity, fatigue perception and quality of life in patients with chronic obstructive pulmonary disease and healthy subjects: a cross-sectional study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) has significant systemic effects that substantially impact quality of life and survival. The purpose of this study was to assess and compare peripheral muscle strength and endurance, exercise capacity, fatigue perception and quality of life between patients with COPD and healthy subjects. METHODS: Twenty COPD patients (mean FEV1 49.3 +/- 19.2%) and 20 healthy subjects were included in the study. Pulmonary function testing and six-minute walk test (6MWT) were performed. Peripheral muscle strength was measured with a hand-held dynamometer, peripheral muscle endurance was evaluated with sit-ups, squats and modified push-ups tests. Fatigue perception was assessed using the Fatigue Impact Scale (FIS) and Fatigue Severity Scale (FSS). General quality of life was determined with the Nottingham Health Profile (NHP), and cough-specific quality of life was evaluated with the Leicester Cough Questionnaire (LCQ). RESULTS: Pulmonary functions, strength of shoulder abductor and flexor muscles, numbers of sit-ups and squats, 6MWT distance and 6MWT% were significantly lower in COPD patients than in healthy subjects (p < 0.05). FIS psychosocial sub-dimension and total scores, NHP scores for all sub-dimensions except pain sub-dimension of the COPD group were significantly higher than those of healthy subjects (p < 0.05). The LCQ physical, psychological and social sub-dimensions and total scores were significantly lower in COPD patients than in healthy subjects (p < 0.05). CONCLUSIONS: Pulmonary functions, peripheral muscle strength and endurance, exercise capacity and quality of life were adversely affected in patients with COPD. There are greater effect of fatigue on psychosocial functioning and general daily life activities and effect of cough on the quality of life in patients with COPD. This study supports the idea that COPD patients must be evaluated in a comprehensive manner for planning pulmonary rehabilitation programs. PMID- 24468030 TI - China launched a pilot project to improve its rare disease healthcare levels. AB - China is facing the great challenge of serving the world's largest rare disease population. It is necessary to develop a specific medical plan to increase the levels of optimal prevention, diagnosis and treatment of rare diseases under the existing clinical service structures in China. In 2013, China launched its first pilot project focused on 20 representative rare diseases. A national network including approximately 100 provincial or municipal medical centers has been established to enable collaboration on rare diseases across China. The main objectives for this project are to develop and apply medical guidelines and clinical pathways for rare diseases, to establish a rare disease patient registry and data repository system, and to promote molecular testing for rare genetic disorders. This project also emphasizes building close links among the collaborative network, clinicians on the frontlines in basic medical services institutions and rare disease patient organizations. Primarily, this project expects to develop an actionable medical services plan to increase the delivery of quality healthcare for individuals and families living with rare diseases in China within five years. PMID- 24468031 TI - Effects of gustatory nerve transection and/or ovariectomy on oral capsaicin avoidance in rats. AB - The incidence of chronic oral pain such as burning mouth syndrome is greater in peri-menopausal females, and was postulated to be associated with gustatory nerve damage. We investigated whether bilateral transection of the chorda tympani, with or without accompanying ovariectomy, affected oral capsaicin avoidance in rats. Female rats had restricted access to 2 bottles, 1 bottle containing capsaicin (concentration range: 0.33-33 MUM/L) and the other vehicle. Percent volume of capsaicin consumption and lick counts were measured. The concentration series was tested before and 0.5, 3, 6, 9, and 12 months after the following surgical procedures: (a) bilateral transection of the chorda tympani (CTx); (b) ovariectomy (OVx); (3) CTx plus OVx; or (4) sham CT surgery. Before surgery there was a concentration-dependent decrease in licks and volume of capsaicin consumed, with a threshold between 0.1 and 0.3 ppm. The majority of drink licks occurred during the first 9 minutes of access. Over the 12-month test period, the CTx group did not exhibit reduced capsaicin consumption, and consumed significantly more capsaicin at 6 and 9 months postsurgery. Rats in the OVx group consistently consumed significantly less capsaicin and exhibited significantly higher counts of capsaicin-evoked Fos-like immunoreactivity in the dorsomedial trigeminal subnucleus caudalis (Vc) compared to all other treatment groups. That CTx, with or without OVx, did not enhance capsaicin avoidance indicates that damage to the gustatory system does not disinhibit trigeminal nociceptive transmission. PMID- 24468032 TI - Support vector machine (SVM) based multiclass prediction with basic statistical analysis of plasminogen activators. AB - BACKGROUND: Plasminogen (Pg), the precursor of the proteolytic and fibrinolytic enzyme of blood, is converted to the active enzyme plasmin (Pm) by different plasminogen activators (tissue plasminogen activators and urokinase), including the bacterial activators streptokinase and staphylokinase, which activate Pg to Pm and thus are used clinically for thrombolysis. The identification of Pg activators is therefore an important step in understanding their functional mechanism and derives new therapies. METHODS: In this study, different computational methods for predicting plasminogen activator peptide sequences with high accuracy were investigated, including support vector machines (SVM) based on amino acid (AC), dipeptide composition (DC), PSSM profile and Hybrid methods used to predict different Pg-activators from both prokaryotic and eukaryotic origins. RESULTS: Overall maximum accuracy, evaluated using the five-fold cross validation technique, was 88.37%, 84.32%, 87.61%, 85.63% in 0.87, 0.83,0.86 and 0.85 MCC with amino (AC) or dipeptide composition (DC), PSSM profile and Hybrid methods respectively. Through this study, we have found that the different subfamilies of Pg-activators are quite closely correlated in terms of amino, dipeptide, PSSM and Hybrid compositions. Therefore, our prediction results show that plasminogen activators are predictable with a high accuracy from their primary sequence. Prediction performance was also cross-checked by confusion matrix and ROC (Receiver operating characteristics) analysis. A web server to facilitate the prediction of Pg-activators from primary sequence data was implemented. CONCLUSION: The results show that dipeptide, PSSM profile, and Hybrid based methods perform better than single amino acid composition (AC). Furthermore, we also have developed a web server, which predicts the Pg-activators and their classification (available online at http://mamsap.it.deakin.edu.au/plas_pred/home.html). Our experimental results show that our approaches are faster and achieve generally a good prediction performance. PMID- 24468033 TI - Microbes in the neonatal intensive care unit resemble those found in the gut of premature infants. AB - BACKGROUND: The source inoculum of gastrointestinal tract (GIT) microbes is largely influenced by delivery mode in full-term infants, but these influences may be decoupled in very low birth weight (VLBW, <1,500 g) neonates via conventional broad-spectrum antibiotic treatment. We hypothesize the built environment (BE), specifically room surfaces frequently touched by humans, is a predominant source of colonizing microbes in the gut of premature VLBW infants. Here, we present the first matched fecal-BE time series analysis of two preterm VLBW neonates housed in a neonatal intensive care unit (NICU) over the first month of life. RESULTS: Fresh fecal samples were collected every 3 days and metagenomes sequenced on an Illumina HiSeq2000 device. For each fecal sample, approximately 33 swabs were collected from each NICU room from 6 specified areas: sink, feeding and intubation tubing, hands of healthcare providers and parents, general surfaces, and nurse station electronics (keyboard, mouse, and cell phone). Swabs were processed using a recently developed 'expectation maximization iterative reconstruction of genes from the environment' (EMIRGE) amplicon pipeline in which full-length 16S rRNA amplicons were sheared and sequenced using an Illumina platform, and short reads reassembled into full-length genes. Over 24,000 full-length 16S rRNA sequences were produced, generating an average of approximately 12,000 operational taxonomic units (OTUs) (clustered at 97% nucleotide identity) per room-infant pair. Dominant gut taxa, including Staphylococcus epidermidis, Klebsiella pneumoniae, Bacteroides fragilis, and Escherichia coli, were widely distributed throughout the room environment with many gut colonizers detected in more than half of samples. Reconstructed genomes from infant gut colonizers revealed a suite of genes that confer resistance to antibiotics (for example, tetracycline, fluoroquinolone, and aminoglycoside) and sterilizing agents, which likely offer a competitive advantage in the NICU environment. CONCLUSIONS: We have developed a high-throughput culture-independent approach that integrates room surveys based on full-length 16S rRNA gene sequences with metagenomic analysis of fecal samples collected from infants in the room. The approach enabled identification of discrete ICU reservoirs of microbes that also colonized the infant gut and provided evidence for the presence of certain organisms in the room prior to their detection in the gut. PMID- 24468034 TI - A novel serum marker for biliary tract cancer: diagnostic and prognostic values of quantitative evaluation of serum mucin 5AC (MUC5AC). AB - BACKGROUND AND AIMS: Mucin 5AC (MUC5AC) is a glycoprotein found in different epithelial cancers, including biliary tract cancer (BTC). The aims of this study were to investigate the role of MUC5AC as serum marker for BTC and its prognostic value after operation with curative intent. PATIENTS AND METHOD: From January 2007 to July 2012, a quantitative assessment of serum MUC5AC was performed with enzyme-linked immunoassay in a total of 88 subjects. Clinical and biochemical data (including CEA and Ca 19-9) of 49 patients with BTC were compared with a control population that included 23 patients with benign biliary disease (BBD) and 16 healthy control subjects (HCS). RESULTS: Serum MUC5AC was greater in BTC patients (mean 17.93 +/- 10.39 ng/mL) compared with BBD (mean 5.95 +/- 5.39 ng/mL; P < .01) and HCS (mean 2.74 +/- 1.35 ng/mL) (P < .01). Multivariate analysis showed that MUC5AC was related with the presence of BTC compared with Ca 19-9 and CEA: P < .01, P = .080, and P = .463, respectively. In the BTC group, serum MUC5AC >= 14 ng/mL was associated with lymph-node metastasis (P = .050) and American Joint Committee on Cancer and International Union for Cancer Control stage IVb disease (P = .047). Moreover, in patients who underwent operation with curative intent, serum MUC5AC >= 14 ng/mL was related to a worse prognosis compared with patients with lesser levels, with 3-year survival rates of 21.5% and 59.3%, respectively (P = .039). CONCLUSION: MUC5AC could be proposed as new serum marker for BTC. Moreover, the quantitative assessment of serum MUC5AC could be related to tumor stage and long-term survival in patients with BTC undergoing operation with curative intent. PMID- 24468035 TI - Perioperative pleiotropic statin effects in general surgery. AB - BACKGROUND: Evidence suggests that statins may decrease inflammation, airway hyperreactivity, and hypercoagulability while improving revascularization mediated by cholesterol-independent pathways. This study evaluated whether the preoperative use of statins is associated with decreased postoperative major noncardiac complications in noncardiac procedures. STUDY DESIGN: This was a single-institution study of noncardiac operations performed from 2005 to 2010. The use of statins was identified from electronic medical records and merged with local National Surgical Quality Improvement Program data. Preoperative statin exposure was defined as statin use before operation, as documented by admission medication reconciliation and outpatient or pharmacy records. The primary end point was major noncardiac complications, and secondary end points included respiratory, infectious (sepsis and organ space infection) and complications of venous thromboembolism (VTE). Multivariable logistic regression was performed for each end point while we controlled for clinical covariates meeting P < .10 on bivariate analysis. RESULTS: Preoperative statin use was present in 10.5% (n = 814) of 7,777 total cases. Procedure type included general operation (n = 2,605, 33.5%), breast/endocrine (n = 739, 9.5%), colorectal (n = 1,533, 19.7%), hepatobiliary/pancreatic (n = 397, 5.1%), orthopedic (n = 205, 2.6%), skin/ear nose- throat (145, 1.9%), thoracic (n = 53, 0.7%), upper gastrointestinal (n = 651, 8.4%), and vascular cases (1,449, 18.6%). On multivariable analysis, the use of statins was associated with decreased major, noncardiac complications (odds ratio [OR] 0.62, 95% confidence interval [95% CI] 0.49-0.92, P < .001), respiratory complications (OR 0.63, 95% CI 0.50-0.79, P = .017), VTE (OR 0.41, 95% CI 0.18-0.98, P = .044), and infectious complications (OR 0.65, 95% CI 0.45 0.94, P = .023). CONCLUSION: The preoperative use of statins is independently associated with decreased risk of major complications. This effect is likely driven by reduction in respiratory, VTE, and infectious complication rates. These results warrant future clinical trials to assess the perioperative benefit of statin use in noncardiac procedures. PMID- 24468036 TI - Prognostic impact of diagnosing colorectal neuroendocrine carcinoma using the World Health Organization 2010 classification. AB - BACKGROUND: Neuroendocrine carcinomas (NECs) arising in the large intestine are rare neoplasms with highly aggressive behavior. The aim of the study was to compare the 2000 and 2010 World Health Organization (WHO) classification of these colorectal NECs. METHODS: We conducted a retrospective study of patients diagnosed with colorectal NECs according to the WHO 2000 classification who underwent surgery at the Asan Medical Center between May 2000 and December 2010. The data were reevaluated to assess their consistency with the WHO 2010 classification. RESULTS: For 20 of the 34 patients (59%), the 2000 and 2010 WHO classifications yielded the same NEC diagnosis (NEC group), whereas for 14 of the 34 patients (41%), the WHO 2010 classification mandated a diagnosis of G1 or G2 neuroendocrine tumors (NETs) rather than NECs (G1/G2 NET group). The NEC group was older than the G1/G2 NET group (64 vs 55 years; P = .05). Tumor differentiation in the NEC group was poorer than in the G1/G2 NET group (percentage of poorly differentiated tumor, 70% vs 7%; P < .001). In both groups based on the 7th American Joint Committee on Cancer staging, most of the tumors were advanced at the time of diagnosis, reaching stage IIIB (6 NEC vs 10 NET) and stage IV (10 NEC vs 3 NET). The 5-year overall survival in the 2 groups was different (P = .02), but not the 5-year disease-free survival (P = .24). CONCLUSION: These results indicate that the WHO 2010 classification of colorectal NEC is more accurate and has better prognostic value than the WHO 2000 classification. PMID- 24468037 TI - Early mortality and long-term survival after abdominal surgery in patients with liver cirrhosis. AB - BACKGROUND: Patients with liver cirrhosis have an increased risk of postoperative mortality. In addition, cirrhotic patients per se have a reduced life expectancy. Little is known about the combined effect of these factors on long-term outcomes after surgery. We thus evaluated early -and long-term survival in patients with cirrhosis who underwent abdominal surgery. METHODS: We evaluated 30- and 90-day mortality as well as long-term survival after 212 general surgical procedures performed in 194 patients with liver cirrhosis. Risk factors for early and late mortality were assessed by uni- and multivariate methods. To avoid multicollinearity of data, different models (Child Turcotte Pugh [CTP], model for end-stage liver disease [MELD], or American Society of Anesthesiologists [ASA] score) were used in multivariate analysis. RESULTS: The 30- and 90-day mortality rates were 20% and 30%, respectively. CTP, MELD, and ASA were all independently associated with 30- and 90-day mortality. Although emergency operations and intraoperative transfusions independently influenced 30-day mortality, 90-day mortality also was influenced by the extent of the procedure and thrombocytopenia. Survival after surgery (n = 180) was 54% after one and 25% after 5 years (median survival 1.24 years). Long-term survival was independently influenced by CTP, MELD, ASA, hyponatremia, emergency operations, thrombocytopenia, and underlying malignancies. Survival in patients discharged after surgery (n = 140) was 69% after 1 and 33% after 5 years (median survival 2.8 years). Survival after discharge was independently influenced by MELD, CTP, hyponatremia, underlying malignant disease, and (partially) by serum creatinine. The inclusion of serum sodium into MELD scores did not further facilitate prediction of early and late mortality. CONCLUSION: A high postoperative mortality as well as a strongly reduced survival even after hospital discharge contribute to the very poor life expectancy in patients with liver cirrhosis requiring general surgery. Postoperative outcome is influenced by liver function, comorbidity and "surgical" factors such as the need for blood transfusion and emergent or major operations. However, after hospital discharge, "surgical" factors did not influence survival. PMID- 24468038 TI - Nontechnical skills performance and care processes in the management of the acute trauma patient. AB - BACKGROUND: Acute trauma management is a complex process, with the effective cooperation among multiple clinicians critical to success. Despite this, the effect of nontechnical skills on performance on outcomes has not been investigated previously in trauma. METHODS: Trauma calls in an urban, level 1 trauma center were observed directly. Nontechnical performance was measured using T-NOTECHS. Times to disposition and completion of assessment care processes were recorded, as well as any delays or errors. Statistical analysis assessed the effect of T-NOTECHS on performance and outcomes, accounting for Injury Severity Scores (ISS) and time of day as potential confounding factors. Meta-analysis was performed for incidence of delays. RESULTS: Fifty trauma calls were observed, with an ISS of 13 (interquartile range [IQR], 5-25); duration of stay 1 (IQR, 1 8) days; T-NOTECHS, 20.5 (IQR, 18-23); time to disposition, 24 minutes (IQR, 18 42). Trauma calls with low T-NOTECHS scores had a greater time to disposition: 35 minutes (IQR, 23-53) versus 20 (IQR, 16-25; P = .046). ISS showed a significant correlation to duration of stay (r = 0.736; P < .001), but not to T-NOTECHS (r = 0.201; P = .219) or time to disposition (r = 0.113; P = .494). There was no difference between "in-hours" and "out-of-hours" trauma calls for T-NOTECHS scores (21 [IQR, 18-22] vs 20 [IQR, 20-23]; P = .361), or time to disposition (34 minutes [IQR, 24-52] vs 17 [IQR, 15-27]; P = .419). Regression analysis revealed T-NOTECHS as the only factor associated with delays (odds ratio [OR], 0.24; 95% confidence interval [CI], 0.06-0.95). CONCLUSION: Better teamwork and nontechnical performance are associated with significant decreases in disposition time, an important marker of quality in acute trauma care. Addressing team and nontechnical skills has the potential to improve patient assessment, treatment, and outcomes. PMID- 24468039 TI - Recurrent laryngeal nerve palsy during surgery for benign thyroid diseases: risk factors and outcome analysis. AB - BACKGROUND: We investigated the risk factors for postoperative recurrent laryngeal nerve (RLN) palsy and related outcomes in patients with benign thyroid diseases. MATERIAL AND METHODS: From 2008 to 2010, 844 thyroidectomies for benign thyroid diseases (benign nodules in 447; Graves' disease in 377; huge goiter attributable to Hashimoto thyroiditis in 20) were performed at Noguchi Thyroid Clinic and Hospital Foundation. The otolaryngologists screened all patients for the presence or absence of RLN palsy by laryngoscope, both pre- and postoperatively. When RLN palsy was present, the patients were checked periodically by laryngoscopy without additional drug therapy until the recovery of vocal cord palsy or loss of contact. RESULTS: A total of 1,374 nerves were at risk during the thyroid surgery (bilateral risk in 530, unilateral risk in 314). No patient exhibited a bilateral RLN palsy. Unilateral postoperative RLN palsies were found in 45 patients (benign nodules in 25, Graves' disease in 19, and Hashimoto thyroiditis in 1). The RLN was involuntarily amputated in five patients during the operation. The incidence of RLN palsy was 5.3% per patient and 3.3% per nerve. The incidence of RLN palsy was greater in patients who underwent complete unilateral thyroid lobe resection compared with partial resection of the lobe (P = .04). The occurrence of RLN palsy was associated with the need for reoperation caused by postoperative bleeding and the reduced weight of the thyroid remnant in Graves' disease (P = .04 and P = .03, respectively). Among 40 patients with RLN palsy and excluding 5 amputated patients, the RLN palsy resolved in 34 patients (85%) within 12 months after the procedure. The remaining 6 patients (15%) were considered to have permanent RLN palsies. CONCLUSION: Complete resection of the thyroid lobe and reoperation for postoperative bleeding are the risk factors for postoperative RLN palsy in patients with benign thyroid nodules. In Graves' disease, smaller weight of the residual thyroid tissue contributes to the occurrence of RLN palsy. Most RLN palsies that do not require amputation of the nerve resolve spontaneously within 12 months after surgery. In this study, the palsy remained in 1.3% (11/844) of patients. PMID- 24468040 TI - Commentary on: does pathologic response of rectal cancer influence postoperative morbidity after neoadjuvant radiochemotherapy and total mesorectal excision? PMID- 24468041 TI - Developing an argument for bundled interventions to reduce surgical site infection in colorectal surgery. AB - BACKGROUND: Surgical site infection (SSI) remains a costly and morbid complication after colectomy. The primary objective of this study was to investigate whether a group of perioperative care measures previously shown to be associated with reduced SSI would have an additive effect in SSI reduction. If so, this would support the use of an "SSI prevention bundle" as a quality improvement intervention. METHODS: Data from 24 hospitals participating in the Michigan Surgical Quality Collaborative were included in the study. The main outcome measure was SSI. Hierarchical logistic regression was used to account for clustering of patients within hospitals. RESULTS: In total, 4,085 operations fulfilled inclusion criteria for the study (Current Procedural Terminology codes 44140, 44160, 44204, and 44205). A "bundle score" was assigned to each operation, based on the number of perioperative care measures followed (appropriate Surgical Care Improvement Project-2 antibiotics, postoperative normothermia, oral antibiotics with bowel preparation, perioperative glycemic control, minimally invasive surgery, and short operative duration). There was a strong stepwise inverse association between bundle score and incidence of SSI. Patients who received all 6 bundle elements had risk-adjusted SSI rates of 2.0% (95% confidence interval [CI], 7.9-0.5%), whereas patients who received only 1 bundle measure had SSI rates of 17.5% (95% CI, 27.1-10.8%). CONCLUSION: This multi institutional study shows that patients who received all 6 perioperative care measures attained a very low, risk-adjusted SSI rate of 2.0%. These results suggest the promise of an SSI reduction intervention for quality improvement; however, prospective research are required to confirm this finding. PMID- 24468042 TI - Development of an ultra low noise, miniature signal conditioning device for vestibular evoked response recordings. AB - BACKGROUND: Inner ear evoked potentials are small amplitude (<1 MUVpk) signals that require a low noise signal acquisition protocol for successful extraction; an existing such technique is Electrocochleography (ECOG). A novel variant of ECOG called Electrovestibulography (EVestG) is currently investigated by our group, which captures vestibular responses to a whole body tilt. The objective is to design and implement a bio-signal amplifier optimized for ECOG and EVestG, which will be superior in noise performance compared to low noise, general purpose devices available commercially. METHOD: A high gain configuration is required (>85 dB) for such small signal recordings; thus, background power line interference (PLI) can have adverse effects. Active electrode shielding and driven-right-leg circuitry optimized for EVestG/ECOG recordings were investigated for PLI suppression. A parallel pre-amplifier design approach was investigated to realize low voltage, and current noise figures for the bio-signal amplifier. RESULTS: In comparison to the currently used device, PLI is significantly suppressed by the designed prototype (by >20 dB in specific test scenarios), and the prototype amplifier generated noise was measured to be 4.8 nV/Hz @ 1 kHz (0.45 MUVRMS with bandwidth 10 Hz-10 kHz), which is lower than the currently used device generated noise of 7.8 nV/Hz @ 1 kHz (0.76 MUVRMS). A low noise (<1 nV/Hz) radio frequency interference filter was realized to minimize noise contribution from the pre-amplifier, while maintaining the required bandwidth in high impedance measurements. Validation of the prototype device was conducted for actual ECOG recordings on humans that showed an increase (p < 0.05) of ~5 dB in Signal-to-Noise ratio (SNR), and for EVestG recordings using a synthetic ear model that showed a ~4% improvement (p < 0.01) over the currently used amplifier. CONCLUSION: This paper presents the design and evaluation of an ultra-low noise and miniaturized bio-signal amplifier tailored for EVestG and ECOG. The increase in SNR for the implemented amplifier will reduce variability associated with bio features extracted from such recordings; hence sensitivity and specificity measures associated with disease classification are expected to increase. Furthermore, immunity to PLI has enabled EVestG and ECOG recordings to be carried out in a non-shielded clinical environment. PMID- 24468043 TI - Short-term rebleeding rates for isolated gastric varices managed by transjugular intrahepatic portosystemic shunt versus balloon-occluded retrograde transvenous obliteration. AB - PURPOSE: To assess the short-term rebleeding rate associated with the use of a transjugular intrahepatic portosystemic shunt (TIPS) compared with balloon occluded retrograde transvenous obliteration (BRTO) for management of gastric varices (GV). MATERIALS AND METHODS: A single-center retrospective comparison of 50 patients with bleeding from GV treated with a TIPS or BRTO was performed. Of 50 patients, 27 (17 men and 10 women; median age, 55 y; range, 31-79 y) received a TIPS with covered stents, and 23 (12 men and 11 women; median age, 52 y; range, 23-83 y) underwent a BRTO procedure with a foam sclerosant. All study subjects had clinical and endoscopic evidence of isolated bleeding GV and were hemodynamically stable at the time of the procedure. Clinical and endoscopic follow-up was performed. Kaplan-Meier analysis was used to evaluate rebleeding rates from the GV. RESULTS: The technical success rate was 100% in the TIPS group and 91% in the BRTO group (P = .21). Major complications occurred in 4% of the patients receiving TIPS and 9% of patients the undergoing BRTO (P = .344). Encephalopathy was reported in 4 of 27 (15%) patients in the TIPS group and in none of the patients in the BRTO group (0%; P = .12). At 12 months, the incidence of rebleeding from a GV source was 11% in the TIPS group and 0% in the BRTO group (P = .25). CONCLUSIONS: BRTO appears to be equivalent to TIPS in the short-term for management of bleeding GV. Further comparative studies are warranted to determine optimal management strategies in individual patients. PMID- 24468044 TI - Drug-eluting beads loaded with antiangiogenic agents for chemoembolization: in vitro sunitinib loading and release and in vivo pharmacokinetics in an animal model. AB - PURPOSE: The combination of embolic beads with a multitargeted tyrosine kinase inhibitor that inhibits tumor vessel growth is suggested as an alternative and improvement to the current standard doxorubicin-eluting beads for use in transarterial chemoembolization. This study demonstrates the in vitro loading and release kinetics of sunitinib using commercially available embolization microspheres and evaluates the in vitro biologic efficacy on cell cultures and the resulting in vivo pharmacokinetics profiles in an animal model. MATERIALS AND METHODS: DC Bead microspheres, 70-150 um and 100-300 um (Biocompatibles Ltd., Farnham, United Kingdom), were loaded by immersion in sunitinib solution. Drug release was measured in saline in a USP-approved flow-through apparatus and quantified by spectrophotometry. Activity after release was confirmed in cell culture. For pharmacokinetics and in vivo toxicity evaluation, New Zealand white rabbits received sunitinib either by intraarterial injection of 100-300 um sized beads or per os. Plasma and liver tissue drug concentrations were assessed by liquid chromatography-tandem mass spectroscopy. RESULTS: Sunitinib loading on beads was close to complete and homogeneous. A total release of 80% in saline was measured, with similar fast-release profiles for both sphere sizes. After embolization, drug plasma levels remained below the therapeutic threshold (< 50 ng/mL), but high concentrations at 6 hours (14.9 ug/g) and 24 hours (3.4 ug/g) were found in the liver tissue. CONCLUSIONS: DC Bead microspheres of two sizes were efficiently loaded with sunitinib and displayed a fast and almost complete release in saline. High liver drug concentrations and low systemic levels indicated the potential of sunitinib-eluting beads for use in embolization. PMID- 24468045 TI - Comparison of characteristics and transarterial chemoembolization outcomes in patients with unresectable hepatocellular carcinoma and different viral etiologies. AB - PURPOSE: To determine any differences in patient characteristics and outcomes after transarterial chemoembolization between different viral etiologies of hepatocellular carcinoma (HCC). METHODS: This retrospective study consisted of 201 patients undergoing first-time transarterial chemoembolization for unresectable HCC from January to December 2009. The patients were divided into four groups: hepatitis B virus (HBV) only (n = 104), hepatitis C virus (HCV) only (n = 63), HBV and HCV (n = 10), and no viral hepatitis (n = 24). The clinical and laboratory data were obtained from electronic medical records, and imaging findings obtained before transarterial chemoembolization were analyzed. Kaplan Meier analyses were used to assess the impact of HBV or HCV status, clinical characteristics, and imaging results on overall survival. RESULTS: After a median follow-up of 28.3 months +/- 16.2, the 1-, 2-, and 3-year overall survival rates were 74.1%, 59.7%, and 53.2%. Patients with HBV had a significant association with younger age (P = .001), higher male-to-female ratio (P = .003), lower alanine aminotransferase levels (P = .018), higher albumin levels (P = .009), and multifocal tumors at diagnosis (P = .04) compared with patients with HCV. Patients with both HBV and HCV had significantly higher serum bilirubin levels compared with the other groups (P = .002). No significant difference was found in overall survival among the different hepatitis groups (P = .943). Multivariate analysis showed that statistically significant determinants for overall survival were Child-Pugh class (P = .002), Barcelona Clinic Liver Cancer stage (P < .001), tumor size (P < .001), and distribution (P < .001). CONCLUSIONS: Viral etiology has no correlation with the outcome of patients with HCC undergoing transarterial chemoembolization. PMID- 24468046 TI - Enhanced stabilization of collagen by furfural. AB - Furfural (2-furancarboxaldehyde), a product derived from plant pentosans, has been investigated for its interaction with collagen. Introduction of furfural during fibril formation enhanced the thermal and mechanical stability of collagen. Collagen films treated with furfural exhibited higher denaturation temperature (Td) (p<0.04) and showed a 3-fold increase in Young's modulus (p<0.04) at higher concentration. Furfural and furfural treated collagen films did not have any cytotoxic effect. Rheological characterization showed an increase in shear stress and shear viscosity with increasing shear rate for treated collagen. Circular dichroism (CD) studies indicated that the furfural did not have any impact on triple helical structure of collagen. Scanning electron microscopy (SEM) of furfural treated collagen exhibited small sized porous structure in comparison with untreated collagen. Thus this study provides an alternate ecologically safe crosslinking agent for improving the stability of collagen for biomedical and industrial applications. PMID- 24468047 TI - Anti-tumour and immunomodulatory activities of oligosaccharides isolated from Panax ginseng C.A. Meyer. AB - Water-soluble ginseng oligosaccharides (WGOS) composed of D-glucose with a degree of polymerisation ranging from 2 to 14 were obtained from Panax ginseng C.A. Meyer. In this study, the anti-tumour and immunoregulatory effects of WGOS were evaluated in Hepatoma-22 (H22)-bearing mice. Treatment with WGOS inhibited tumour growth in vivo and significantly increased relative spleen and thymus weight, serum tumour necrosis factor-alpha level, spleen lymphocyte proliferation, natural killer cell activity, phagocytic function and nitric oxide production secreted by macrophage in H22-bearing mice. However, no direct cytotoxicity was detected. Therefore, the anti-tumour activity of WGOS may be related to their immunomodulatory effects. PMID- 24468048 TI - Structural differences between chitin and chitosan extracted from three different marine sources. AB - Three marine sources of chitin from Tunisia were investigated. Structural differences between alpha-chitin from shrimp (Penaeus kerathurus) waste, crab (Carcinus mediterraneus) shells, and beta-chitin from cuttlefish (Sepia officinalis) bones were studied by the (13)C NMR, FTIR, and XRD diffractograms. The (13)C NMR analysis showed a splitting of the C3 and C5 carbon signals for alpha-chitin, while that of beta-chitin was merged into a single resonance. The bands contour of deconvoluted and curve-fit FTIR spectra showed a more detailed structure of alpha-chitin in the region of O-H, N-H and CO stretching regions. IR and (13)C NMR were used to determine the chitin degree of acetylation (DA). XRD analysis indicated that alpha-chitins were more crystalline polymorph than beta chitin. Shrimp chitin was obtained with a good yield (20% on raw material dry weight) and no residual protein and salts. Chitosans, with a DA lower than 20% and relatively low molecular masses were prepared from the wet chitins in the same experimental conditions. They were perfectly soluble in acidic medium. Nevertheless, chitin and chitosan characteristics were depending upon the chitin source. PMID- 24468050 TI - Attitudes on warfarin pharmacogenetic testing in Chinese patients and public. AB - INTRODUCTION: Genetic factors affecting warfarin maintenance dose have been well established, but patient acceptance is a necessary consideration for the successful clinical implementation of warfarin pharmacogenetic testing (WPGT). In this study, we aimed to determine the attitudes toward WPGT among Singaporean Chinese. METHODS: A total of 194 warfarin patients and 187 members of the public completed a structured survey on paper and the Internet, respectively. Attitudes were expressed as willingness to undergo WPGT (single item with 5-point response) and expectations and concerns about WPGT (two multi-item scales). Relationships between attitudes and socio-demographic and clinical variables were explored using Fisher's exact test, Student's t-test, one-way analysis of variance or Pearson's correlation. RESULTS: Majority of respondents were willing to or neutral about undergoing WPGT. Both patients and public had relatively high expectations (mean [SD]: 3.77 [0.63], and 3.97 [0.55], respectively) and moderately high concerns (mean [SD]: 3.30 [0.69] and 3.33 [0.68], respectively) about WPGT. Willingness to undergo WPGT was associated with gender, educational status, length of warfarin treatment, and number of chronic diseases among warfarin patients, and with history of adverse drug reactions and number of chronic diseases among the public. Higher expectation of WPGT was associated with higher willingness (p < .001 in both populations), while higher concern was associated with lower willingness to undergo WPGT among the public (p = .004) but not among patients (p = .072). CONCLUSION: Patient acceptance is not a major barrier to clinical implementation of WPGT but patient education is necessary and the ethical, social, and legal issues should be addressed. PMID- 24468049 TI - Host insulin stimulates Echinococcus multilocularis insulin signalling pathways and larval development. AB - BACKGROUND: The metacestode of the tapeworm Echinococcus multilocularis is the causative agent of alveolar echinococcosis, a lethal zoonosis. Infections are initiated through establishment of parasite larvae within the intermediate host's liver, where high concentrations of insulin are present, followed by tumour-like growth of the metacestode in host organs. The molecular mechanisms determining the organ tropism of E. multilocularis or the influences of host hormones on parasite proliferation are poorly understood. RESULTS: Using in vitro cultivation systems for parasite larvae we show that physiological concentrations (10 nM) of human insulin significantly stimulate the formation of metacestode larvae from parasite stem cells and promote asexual growth of the metacestode. Addition of human insulin to parasite larvae led to increased glucose uptake and enhanced phosphorylation of Echinococcus insulin signalling components, including an insulin receptor-like kinase, EmIR1, for which we demonstrate predominant expression in the parasite's glycogen storage cells. We also characterized a second insulin receptor family member, EmIR2, and demonstrated interaction of its ligand binding domain with human insulin in the yeast two-hybrid system. Addition of an insulin receptor inhibitor resulted in metacestode killing, prevented metacestode development from parasite stem cells, and impaired the activation of insulin signalling pathways through host insulin. CONCLUSIONS: Our data indicate that host insulin acts as a stimulant for parasite development within the host liver and that E. multilocularis senses the host hormone through an evolutionarily conserved insulin signalling pathway. Hormonal host-parasite cross communication, facilitated by the relatively close phylogenetic relationship between E. multilocularis and its mammalian hosts, thus appears to be important in the pathology of alveolar echinococcosis. This contributes to a closer understanding of organ tropism and parasite persistence in larval cestode infections. Furthermore, our data show that Echinococcus insulin signalling pathways are promising targets for the development of novel drugs. PMID- 24468051 TI - Smaug destroys a huge treasure. AB - Smaug, a protein repressing translation and inducing mRNA decay, directly controls an unexpectedly large number of maternal mRNAs driving early Drosophila development. PMID- 24468052 TI - Risk, adaptation and the functional teenage brain. AB - Over the last decade, the propensity for young people to take risks has been a particular focus of neuroscientific inquiries into human development. Taking population-level data about teenagers' involvement in drinking, smoking, dangerous driving and unprotected sex as indicative, a consensus has developed about the association between risk-taking and the temporal misalignment in the development of reward-seeking and executive regions of the brain. There are epistemological difficulties in this theory. Risk, the brain, and adolescence are different kinds of objects, and bringing them into the same frame for analysis is not unproblematic. In particular, risk is inextricably contextual and value driven. The assessment of adolescent behaviour and decision-making as 'sub optimal', and the implication that the developmental schedule of the teenage brain is dysfunctional, is also reassessed in terms of evolutionary development of the individual, the family and the human community. The paper proposes a view of adolescent development as adaptive, and a focus on young people's capacities in the profile of the needs of the community as a whole. PMID- 24468053 TI - Increased circulating obestatin in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Some peptides, which regulate the metabolic balance, are thought to play important roles in nutritional disorders and systemic inflammation in COPD. Treatment of rats with obestatin decreased body-weight gain. Obestatin was also found to be correlated with inflammation in rheumatoid arthritis. The aims of this study were to investigate the level of circulating obestatin in COPD and to analyze the relationship among obestatin and nutritional status, and systemic inflammation. METHODS: 32 COPD patients with BMI less than 20 kg/m2 and 22 normal controls were included. Body composition was estimated using "foot-to-foot" BIA technology. Circulating obestatin was determined with enzyme-linked immunosorbent assay. Pulmonary function, TNF-alpha and C reactive protein were also measured. RESULTS: The level of circulating obestatin was higher in COPD with underweight than that in normal control (5562.75 +/- 3435.43 pg/ml in COPD, 3663.90 +/- 2313.95 pg/ml in controls, p = 0.028). BMI, Waist circumference, hip circumference, bodyFAT and FAT% in COPD group were lower than those in normal control. Positive correlation was found among circulating C reactive protein, TNF alpha and obestatin. There was no significant correlation among BMI, pulmonary function and obestatin. CONCLUSIONS: This study shows that circulating obestatin is higher in underweight COPD patients, and positively correlated to systemic inflammation, but not to nutritional status. PMID- 24468054 TI - Prevalence of human papillomavirus infection in the oropharynx and urine among sexually active men: a comparative study of infection by papillomavirus and other organisms, including Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma spp., and Ureaplasma spp. AB - BACKGROUND: Oropharyngeal squamous cell carcinoma (OSCC) has shown a gradual increase in male predominance due to the increasing incidence of human papillomavirus (HPV)-associated OSCC. However, the mode of HPV transmission to the oral cavity is poorly understood, and little is known about the epidemiology of oral HPV infection in men. The prevalence rates of HPV, Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma spp., and Ureaplasma spp. were compared in the oropharynx (oral cavity) and urine of male Japanese patients attending a sexually transmitted disease clinic. METHODS: The study population consisted of 213 men aged 16 - 70 years old (mean: 34.4 years old). Oropharyngeal gargles and urine were collected, and sedimented cells were preserved in liquid-based cytology solution. After DNA extraction, beta-globin and infectious organisms were analyzed by a PCR-based method. The HPV genotype was determined by HPV GenoArray test. RESULTS: beta-Globin was positive in 100% and 97.7% of oral and urine samples, respectively. HPV detection rates were 18.8% and 22.1% in oral and urine samples, respectively, suggesting that the prevalence of HPV infection in the oral cavity was similar to that in the urinary tract. N. gonorrhoeae was more prevalent in oral (15.6%) than urine samples (9.1%), whereas C. trachomatis was detected more frequently in urine (15.9%) than oral samples (4.2%). The detection rates of M. genitalium, M. hominis, and Ureaplasma spp. were 5.2%, 10.3%, and 16.0% in oral samples, and 7.7%, 6.3%, and 19.2% in urine, respectively. There were no significant differences in the detection rates of Mycoplasma spp. and Ureaplasma spp. between anatomical locations. The distribution of HPV types were similar in oral and urine samples, and HPV16 was the most common type. The majority of men with HPV infection in both the oral cavity and urine had concordant oral and urinary HPV infection. The presence of urinary HPV infection was an independent risk factor of oral HPV infection, with an odds ratio of 3.39 (95% CI: 1.49 - 7.71), whereas oral gonococcal infection was inversely correlated with oral HPV infection (odds ratio: 0.096; 95% CI: 0.01 - 0.77). CONCLUSIONS: Oral HPV infection commonly occurs in sexually active men, and is significantly correlated with urinary HPV infection. PMID- 24468057 TI - Advancing technology in the echo lab. PMID- 24468055 TI - Multimodality imaging guidelines for patients with repaired tetralogy of fallot: a report from the AmericanSsociety of Echocardiography: developed in collaboration with the Society for Cardiovascular Magnetic Resonance and the Society for Pediatric Radiology. PMID- 24468058 TI - One million vascular screening tests a year: a considered perspective. PMID- 24468059 TI - CD133 facilitates epithelial-mesenchymal transition through interaction with the ERK pathway in pancreatic cancer metastasis. AB - BACKGROUND: Pancreatic cancer is a lethal disease due to the high incidence of metastasis at the time of detection. CD133 expression in clinical pancreatic cancer correlates with poor prognosis and metastasis. However, the molecular mechanism of CD133-regulated metastasis remains unclear. In recent years, epithelial-mesenchymal transition (EMT) has been linked to cancer invasion and metastasis. In the present study we investigated the role of CD133 in pancreatic cancer metastasis and its potential regulatory network. METHODS: A highly migratory pancreatic cancer cell line, Capan1M9, was established previously. After shRNA was stable transducted to knock down CD133 in Capan1M9 cells, gene expression was profiled by DNA microarray. Orthotopic, splenic and intravenous transplantation mouse models were set up to examine the tumorigenesis and metastatic capabilities of these cells. In further experiments, real-time RT-PCR, Western blot and co-immunoprecipitate were conducted to evaluate the interactions of CD133, Slug, N-cadherin, ERK1/2 and SRC. RESULTS: We found that CD133+ human pancreatic cancer cells were prone to generating metastatic nodules in in vivo models using immunodeficient mice. In contrast, CD133 knockdown suppressed cancer invasion and metastasis in vivo. Gene profiling analysis suggested that CD133 modulated mesenchymal characteristics including the expression of EMT-related genes, such as Slug and N-cadherin. These genes were down-regulated following CD133 knockdown. Moreover, CD133 expression could be modulated by the extracellular signal-regulated kinase (ERK)1/2 and SRC signaling pathways. The binding of CD133 to ERK1/2 and SRC acts as an indispensable mediator of N cadherin expression. CONCLUSIONS: These results demonstrate that CD133 plays a critical role in facilitating the EMT regulatory loop, specifically by upregulating N-cadherin expression, leading to the invasion and metastasis of pancreatic cancer cells. Our study provides a novel insight into the function of CD133 in the EMT program and a better understanding of the mechanism underlying the involvement of CD133 in pancreatic cancer metastasis. PMID- 24468060 TI - ["Traffic lights" in pediatrics: what do residents beginning their family residency know about them?]. AB - OBJECTIVES: Pediatric practice is a difficult task requiring physicians to discriminate potentially serious situations among a variety of benign situations. The goal of this study was to assess the knowledge of students beginning their residency in family medicine on these situations. METHODS: One hundred and three students were evaluated on pediatric "traffic lights" using 103 true/false questions. Pediatric and family medicine teachers of the Nantes University Hospital defined "traffic lights" as the fundamentals of pediatrics, misleading situations, and diagnosis and treatment that should not to be missed. Emergency levels were defined by colors, with "red light" corresponding to life-threatening emergencies. RESULTS: Thirty-six percent of the questions (n=103) had a correct response rate below 75%. Thirty-two percent of the questions on emergency situations ("red lights") (n=37) had a response rate below 75%. Fifteen percent of the questions (n=103) had a correct response rate below 50%, half of which were "red light" (e.g., on meningitis, diabetic acidocytosis, or shock). Questions concerning infants (n=24) had significantly fewer correct answers (correct response rate below 50%: 29% versus 10%; P=0.047). All the students answered seven questions correctly. The students' mean score (percentage of good answers) was 76% (+/-6%). No student had 100% or less than 50% good answers. CONCLUSIONS: Some life-threatening situations or situations concerning infants had not been mastered by most of the students. It is therefore essential to optimize the teaching of pediatrics during the second cycle of medical studies. PMID- 24468061 TI - [Inconsolable crying revealing primary erythermalgia in a 6-month-old infant]. AB - Erythermalgia is a peripheral vascular disease triggered by exposure to heat. The primary infantile form is rare. No cases have been described in infants. We report a case in a 6-month-old child revealed by crying bouts associated with erythema of the lower limbs. A 6-month-old child was brought in for consultation for daily crying bouts, occurring six times a day, associated with erythema of the lower limbs. Blood count, abdominal ultrasound and endoscopy were normal, excluding gastroesophageal reflux and intussusception. Attacks disappeared during winter but recurred at high temperatures. The diagnosis was primary infant erythemalgia. Treatment with analgesics and ice packs was established. Erythermalgia is a rare peripheral vascular disease characterized by paroxysmal pain triggered by heat and relieved by cold. The primary form occurs in childhood but has never been reported in infants. The pathophysiology is based on an alteration of sodium channels inducing neuropathy in small-caliber fibers. Genetic mutations have been found in the SNC9 gene on chromosome 2q, with autosomal dominant transmission. Support of this condition is difficult due to resistance to conventional analgesics. The prognosis is sometimes poor with a significant death rate in the pediatric population. PMID- 24468062 TI - Non-invasive mechanical ventilation and mortality in elderly immunocompromised patients hospitalized with pneumonia: a retrospective cohort study. AB - BACKGROUND: Mortality after pneumonia in immunocompromised patients is higher than for immunocompetent patients. The use of non-invasive mechanical ventilation for patients with severe pneumonia may provide beneficial outcomes while circumventing potential complications associated with invasive mechanical ventilation. The aim of our study was to determine if the use of non-invasive mechanical ventilation in elderly immunocompromised patients with pneumonia is associated with higher all-cause mortality. METHODS: In this retrospective cohort study, data were obtained from the Department of Veterans Affairs administrative databases. We included veterans age >=65 years who were immunocompromised and hospitalized due to pneumonia. Multilevel logistic regression analysis was used to determine the relationship between the use of invasive versus non-invasive mechanical ventilation and 30-day and 90-day mortality. RESULTS: Of 1,946 patients in our cohort, 717 received non-invasive mechanical ventilation and 1,229 received invasive mechanical ventilation. There was no significant association between all-cause 30-day mortality and non-invasive versus invasive mechanical ventilation in our adjusted model (odds ratio (OR) 0.85, 95% confidence interval (CI) 0.66-1.10). However, those patients who received non invasive mechanical ventilation had decreased 90-day mortality (OR 0.66, 95% CI 0.52-0.84). Additionally, receipt of guideline-concordant antibiotics in our immunocompromised cohort was significantly associated with decreased odds of 30 day mortality (OR 0.31, 95% CI 0.24-0.39) and 90-day mortality (OR 0.41, 95% CI 0.31-0.53). CONCLUSIONS: Our findings suggest that physicians should consider the use of non-invasive mechanical ventilation, when appropriate, for elderly immunocompromised patients hospitalized with pneumonia. PMID- 24468063 TI - Coexistence of two liquid crystalline phases in dihydrosphingomyelin and dioleoylphosphatidylcholine binary mixtures. AB - Recently, DHSM, a minor constituent in naturally occurring SMs, was indicated to form a raft-like ordered phase more effectively than a naturally occurring form of SM because DHSM has greater potential to induce the intermolecular hydrogen bond. In order to examine the influence of the DHSM-induced hydrogen bond on the phase segregation, the thermal phase behavior of stearoyl-DHSM/DOPC binary bilayers was examined using calorimetry and fluorescence observation and compared with that of SSM/DOPC binary bilayers. Results revealed that the DHSM/DOPC bilayers undergo phase segregation between two L(alpha) phases within a limited compositional range. On the other hand, apparent phase separation was not observed above main transition temperature in SSM/DOPC mixtures. Our monolayer measurements showed that the lipid packing of DHSM is less perturbed than that of SSM by the addition of small amount of DOPC, indicating a stronger hydrogen bond between DHSM molecules. Therefore, in DHSM/DOPC binary bilayers, DHSM molecules may locally accumulate to form a DHSM-rich domain due to a DHSM-induced hydrogen bond. On the other hand, excess accumulation of DHSM should be prevented because the difference in the curvature between DHSM and DOPC assemblies causes elastic constraint at the domain boundary between the DHSM-rich and DOPC-rich domains. Competition between the energetic advantages provided by formation of the hydrogen bond and the energetic disadvantage conferred by elastic constraints likely results in L(alpha)/L(alpha) phase separation within a limited compositional range. PMID- 24468064 TI - Multi-step formation of a hemifusion diaphragm for vesicle fusion revealed by all atom molecular dynamics simulations. AB - Membrane fusion is essential for intracellular trafficking and virus infection, but the molecular mechanisms underlying the fusion process remain poorly understood. In this study, we employed all-atom molecular dynamics simulations to investigate the membrane fusion mechanism using vesicle models which were pre bound by inter-vesicle Ca(2+)-lipid clusters to approximate Ca(2+)-catalyzed fusion. Our results show that the formation of the hemifusion diaphragm for vesicle fusion is a multi-step event. This result contrasts with the assumptions made in most continuum models. The neighboring hemifused states are separated by an energy barrier on the energy landscape. The hemifusion diaphragm is much thinner than the planar lipid bilayers. The thinning of the hemifusion diaphragm during its formation results in the opening of a fusion pore for vesicle fusion. This work provides new insights into the formation of the hemifusion diaphragm and thus increases understanding of the molecular mechanism of membrane fusion. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy. PMID- 24468066 TI - Mitochondrial research in Australia: a major player in worldwide trends. PMID- 24468065 TI - miR-33a is up-regulated in chemoresistant osteosarcoma and promotes osteosarcoma cell resistance to cisplatin by down-regulating TWIST. AB - BACKGROUND: miRNAs are involved in osteosarcoma (OS) chemoresistance, and TWIST reportedly enhances cisplatin-induced OS cell apoptosis by inhibiting multiple signaling pathways. In this study, we profiled miRNAs differentially expressed in chemoresistant OS, with a focus to identify miRNAs that regulate TWIST expression and OS chemoresistance. METHODS: OS patients who showed <90% tumor necrosis after neochemotherapy were defined as poor responders (chemoresistant), and those who showed >=90% tumor necrosis were defined as good responders (control). miRNA microarray analysis was carried out with a discovery cohort (n = 12) of age-, sex and tumor stage-matched chemoresistant and control OS patients. RESULTS: Among the up-regulated miRNAs in chemoresistant OS samples, miR-33a was verified to down-regulate TWIST expression, which was supported by an inverse miRNA-33a/TWIST expression trend in the validation cohort (n = 70), target-sequence-specific inhibition of TWIST-3' untranslated region-luciferase reporter activity by miR 33a, and alteration of TWIST expression by overexpression or inhibition of miR 33a in human OS cell lines. In Saos-2 cells treated with cisplatin, inhibition of miR-33a by antagomir-33a markedly increased cell apoptosis, which was enhanced by overexpression of TWIST. The apoptosis-inducing effect of TWIST overexpression was reversed by overexpression of miR-33a. In MG-63 cells, overexpression of miR 33a significantly decreased cisplatin-induced cell apoptosis, which was enhanced by knockdown of TWIST. Antagomir-33a significantly increased cisplatin-induced cell apoptosis, which was reversed by knockdown of TWIST. CONCLUSIONS: We have demonstrated in this study that miR-33a is up-regulated in chemoresistant OS and that the miR-33a level is negatively correlated with the TWIST protein level in OS. Our in vitro data indicate that miR-33a promotes OS cell resistance to cisplatin by down-regulating TWIST; on the other hand, inhibition of miR-33a by antagomir-33a enhances cisplatin-induced apoptosis in OS cells by up-regulating TWIST expression. The findings suggest that inhibition of miR-33a/TWIST signaling could be a potential new strategy to enhance neoadjuvant chemotherapy for OS. PMID- 24468067 TI - Myosin IIa activation is crucial in breast cancer derived galectin-1 mediated tolerogenic dendritic cell differentiation. AB - BACKGROUND: Tolerogenic dendritic cells (tDCs) play important roles in immune tolerance, autoimmune disease, tissue transplantation, and the tumor micro environment. Factors that induce tDCs have been reported, however the intracellular mechanisms involved are rarely discussed. METHODS: Circulating CD14(+)CD16(+) of breast cancer patients and induced CD14(+)CD16(+) DCs were identified as tDCs by treating CD14(+) monocytes with galectin-1 and cancer cell derived medium combined with IL-4 and GM-CSF. In addition, the 4T1 breast cancer syngeneic xenograft model was used to investigate the effect of galectin-1 in vivo. RESULTS: The CD14(+)CD16(+) tDC population in the breast cancer patients was comparatively higher than that in the healthy donors, and both the MDA-MB-231 conditioned medium and galectin-1 could induce tDC differentiation. In a BALB/c animal model, the 4T1 breast cancer cell line enhanced IL-10 expression in CD11c(+) DCs which was down-regulated after knocking down the galectin-1 expression of 4T1 cells. Analysis of galectin-1 interacting proteins showed that myosin IIa was a major target of galectin-1 after internalization through a caveolin-dependent endocytosis. Myosin IIa specific inhibitor could diminish the effects of galectin-1 on monocyte-derived tDCs and also block the 4T1 cell induced CD11c(+)/Ly6G(+)/IL-10(+) in the BALB/c mice. CONCLUSIONS: Galectin-1 can induce tDCs after internalizing into CD14(+) monocytes through the caveolae dependent pathway and activating myosin IIa. For the breast cancer patients with a high galectin-1 expression, blebbistatin and genistein show potential in immune modulation and cancer immunotherapy. GENERAL SIGNIFICANCE: Myosin IIa activation and galectin-1 endocytosis are important in tumor associated tDC development. PMID- 24468068 TI - Asymmetric training using virtual reality reflection equipment and the enhancement of upper limb function in stroke patients: a randomized controlled trial. AB - BACKGROUND: Asymmetric movements with both hands contributed to the improvement of spatially coupled motion. Thus, the aim of this study was to investigate the effects of an asymmetric training program using virtual reality reflection equipment on upper limb function in stroke patients. METHODS: Twenty-four stroke patients were randomly allocated to an experimental group (n=12) or a control group (n=12). Both groups participated in conventional physical therapy for 2*30 min/d, 5 d/wk, for 4 weeks. The experimental group also participated in an asymmetric training program using virtual reality reflection equipment, and the control group participated in a symmetric training program. Both asymmetric and symmetric programs were conducted for 30 min/d, 5 d/wk, for 4 weeks. To compare upper limb function before and after intervention, the Fugl-Meyer Assessment (FMA), the Box and Block Test (BBT), grip strength, range of motion (ROM), and spasticity were assessed. RESULTS: Both groups showed significant increases in upper limb function, excepting spasticity, after intervention (P<.05, 1-way repeated-measures analysis of variance [ANOVA]). A significant group-time interaction was demonstrated only for shoulder/elbow/wrist items of FMA, BBT, grip strength, and ROM of wrist flexion, extension, and ulnar deviation (P<.05, 2 way repeated-measures ANOVA). CONCLUSIONS: This study confirms that the asymmetric training program using virtual reality reflection equipment is an effective intervention method for improving upper limb function in stroke patients. We consider that an additional study based on a program using virtual reflection, which is more functional than performing simple tasks, and consisting of tasks relevant to the activities of daily living be conducted. PMID- 24468070 TI - Comparison of fast MRI-based individual thrombolysis therapy for patients with superacute infarction. AB - BACKGROUND: The aim of this study is to investigate the outcomes of magnetic resonance imaging (MRI)-based individual thrombolysis therapy using recombinant tissue plasminogen activator (rt-PA) in patients with superacute infarction, comparing the outcome in 1 group of patients treated within 4.5 hours compared with 4.5- to 12-hour window treatment group. METHODS: We studied 135 patients stratified to 2 different groups based on whether they presented with stroke symptoms within 4.5 hours (4.5-hour group, 72 patients) or between 4.5 and 12 hours (4.5- to 12-h group, 63 patients). All patients were treated with rt-PA after MRI confirmed superacute ischemic stroke (hyperintense in diffusion weighted imaging but no hypointense change in T2-weighted image (T2WI) or fluid attenuated inversion recovery). Clinical neurologic deficit was evaluated using the National Institutes of Health Stroke Scale on admission, at 24 hours, and 7 days later. A 90-day clinical outcome was assessed using the modified Rankin Scale (mRS). RESULTS: There was no significant difference in the clinical outcome between the patients treated with thrombolysis within the first 4.5 hours and those treated between 4.5 and 12 hours. The 2 groups both had recanalization, mRS, and favorable outcome at 90 days (P > .05). CONCLUSIONS: Our study suggested that fast MR-based thrombolysis using rt-PA was safe and reliable in superacute infarction within 4.5 hours and 4.5-12 hours poststroke. PMID- 24468069 TI - Racial and gender differences in stroke severity, outcomes, and treatment in patients with acute ischemic stroke. AB - BACKGROUND: Previous research has indicated that women and blacks have worse outcomes after acute ischemic stroke (AIS). Little research has been done to investigate the combined influence of race and gender in the presentation, treatment, and outcome of patients with AIS. We sought to determine the association of race and gender on initial stroke severity, thrombolysis, and functional outcome after AIS. METHODS: AIS patients who presented to 2 academic medical centers in the United States (2004-2011) were identified through prospective registries. In-hospital strokes were excluded. Stroke severity, measured by admission National Institutes of Health Stroke Scale (NIHSS) scores, treatment with tissue plasminogen activator (tPA), neurologic deterioration (defined by a >=2-point increase in NIHSS score), and functional outcome at discharge, measured by the modified Rankin Scale, were investigated. These outcomes were compared across race/gender groups. A subanalysis was conducted to assess race/gender differences in exclusion criteria for tPA. RESULTS: Of the 4925 patients included in this study, 2346 (47.6%) were women and 2310 (46.9%) were black. White women had the highest median NIHSS score on admission (8), whereas white men had the lowest median NIHSS score on admission (6). There were no differences in outcomes between black men and white men. A smaller percentage of black women than white women were treated with tPA (27.6% versus 36.6%, P < .0001), partially because of a greater proportion of white women presenting within 3 hours (51% versus 45.5%, P = .0005). Black women had decreased odds of poor functional outcome relative to white women (odds ratio [OR] = .85, 95% confidence interval [CI] .72-1.00), but after adjustment for baseline differences in age, NIHSS, and tPA use, this association was no longer significant (OR = 1.2, 95% CI .92-1.46, P = .22). Black women with an NIHSS score less than 7 on admission were at lower odds of receiving tPA than the other race/gender groups, even after adjusting for arriving within 3 hours and admission glucose (OR = .66, 95% CI .44-.99, P = .0433). CONCLUSION: Race and gender were not significantly associated with short-term outcome, although black women were significantly less likely to be treated with tPA. Black women had more tPA exclusions than any other group. The primary reason for tPA exclusion in this study was not arriving within 3 hours of stroke symptom onset. Given the growth in incident strokes projected in minority groups in the next 4 decades, identifying factors that contribute to black women not arriving to the emergency department in time are of great importance. PMID- 24468071 TI - Coexisting diseases of moyamoya vasculopathy. AB - BACKGROUND: Several coexisting diseases have been reported in patients with moyamoya vasculopathy (MMV), but studies of quasi-moyamoya disease (quasi-MMD) are rare. This study aims to investigate the frequency of known coexisting diseases in patients with quasi-MMD and to compare quasi-MMD with moyamoya disease (MMD). METHODS: Between 2000 and 2011, we retrospectively screened patients with International Classification of Diseases, Ninth Revision, code of 4375 (MMD) in the Health Information System of our hospital. The vascular images of each patient were confirmed by 2 neurologists and 1 neuroradiologist based on the diagnostic criteria of Japan Ministry of Health and Welfare. We excluded the patients with missing images and erroneous diagnosis. Demographics, coexisting diseases, laboratory data, treatment, and recurrent strokes were recorded. The eligible patients were divided into quasi-MMD and MMD groups according to the presence or absence of coexisting diseases. RESULTS: MMV was found in 90 patients including 37 (41.1%) quasi-MMD and 53 (58.9%) MMD. Atherosclerosis (32.4%) and thyroid disease (29.7%) were the leading coexisting diseases in quasi-MMD. Patients with MMD became symptomatic in a bimodal age distribution, whereas patients with quasi-MMD became symptomatic in a single-peak distribution. The prognosis of recurrent strokes was similar between quasi-MMD and MMD based on Kaplan-Meier analysis. CONCLUSIONS: A bimodal distribution of onset age was noted in MMD, whereas a single-peak distribution was found in quasi-MMD. Coexisting diseases were usually underevaluated but were more common than expected in patients with MMV. Atherosclerosis and thyroid diseases were the leading coexisting diseases in different preferential age. PMID- 24468072 TI - Plant growth-promoting bacterium Acinetobacter calcoaceticus P23 increases the chlorophyll content of the monocot Lemna minor (duckweed) and the dicot Lactuca sativa (lettuce). AB - Acinetobacter calcoaceticus P23 is a plant growth-promoting bacterium that was isolated from the surface of duckweed (Lemna aoukikusa). The bacterium was observed to colonize on the plant surfaces and increase the chlorophyll content of not only the monocotyledon Lemna minor but also the dicotyledon Lactuca sativa in a hydroponic culture. This effect on the Lactuca sativa was significant in nutrient-poor (*1/100 dilution of H2 medium) and not nutrient-rich (*1 or *1/10 dilutions of H2 medium) conditions. Strain P23 has the potential to play a part in the future development of fertilizers and energy-saving hydroponic agricultural technologies. PMID- 24468073 TI - Improved on-line high performance liquid chromatography method for detection of antioxidants in Eucommia ulmoides Oliver flower. AB - Eucommia ulmoides Oliver is a traditional Chinese medicine and material for functional food with a strong antioxidant activity. To investigate antioxidants in E. ulmoides Oliver flower, an improved on-line high performance liquid chromatography method with the radical cation 2,2'-azinobis-(3 ethylbenzothiazoline-6-sulfonate) (ABTS(+)) as a stable model free radical for the detection of radical scavenging ability was developed. The radical concentration, flow rate, and length of reaction coil were optimized with rutin as a model antioxidant. Under the optimized instrumental set-up, a radical solution of 0.32 mM ABTS(+) is delivered by a pump equipped with a superloop at 0.5 mL/min through a reaction coil of 10 m * 0.25 mm. This method showed a high sensitivity since the system noise was reduced by the superloop. The minimum detecting concentration of the method was in the range of 0.03-0.10 MUM for the negative peaks of rutin, quercetin, ascorbic acid, and alpha-tocopherol. Importantly, the method could be not only used for detection of antioxidants in plant extracts but also combined with mass spectrometry to obtain the structural messages of peaks in high performance liquid chromatography profiles. After analysis by the method, nineteen antioxidants were found in E. ulmoides Oliver flower extract, and the main active compound was identified as chlorogenic acid. PMID- 24468074 TI - A novel recurrent mutation in ATP1A3 causes CAPOS syndrome. AB - BACKGROUND: We undertook genetic analysis of three affected families to identify the cause of dominantly-inherited CAPOS (cerebellar ataxia, areflexia, pes cavus, optic atrophy and sensorineural hearing loss) syndrome. METHODS: We used whole exome sequencing to analyze two families affected with CAPOS syndrome, including the original family reported in 1996, and Sanger sequencing to assess familial segregation of rare variants identified in the probands and in a third, apparently unrelated family with CAPOS syndrome. RESULTS: We found an identical heterozygous missense mutation, c.2452G > A (p.(Glu818Lys)), in the Na+/K+ ATPase alpha3(ATP1A3) gene in the proband and his affected sister and mother, but not in either unaffected maternal grandparent, in the first family. The same mutation was also identified in the proband and three other affected members of the second family and in all three affected members of the third family. This mutation was not found in more than 3600 chromosomes from unaffected individuals. CONCLUSION: Other mutations in ATP1A3 have previously been demonstrated to cause rapid-onset dystonia-parkinsonism (also called dystonia-12) or alternating hemiplegia of childhood. This study shows that an allelic mutation in ATP1A3 produces CAPOS syndrome. PMID- 24468075 TI - Proteomic identification of differentially expressed proteins in sea cucumber Apostichopus japonicus coelomocytes after Vibrio splendidus infection. AB - Skin ulceration syndrome (SUS) was the main limitation in the development of Apostichopus japonicus culture industries. To better understand how Vibrio splendidus modulates SUS outbreak, the immune response of A. japonicus coelomocytes after the pathogen challenge were investigated through comparative proteomics approach, and differentially expressed proteins were screened and characterized in the present study. A total of 40 protein spots representing 30 entries were identified at 24, 72 and 96 h post-infection. Of these proteins, 32 were up-regulated and 8 were down-regulated in the V. splendidus challenged samples compared to those of control. These differentially expressed proteins were mainly classified into four categories by GO analysis, in which approximate 33% of proteins showed to be related to immunity response. The mRNA expression levels of 6 differentially expressed proteins were further validated by qRT-PCR. Similar protein-mRNA-level expression patterns were detected in genes of phospholipase (spot 4), G protein (spot 20), annexin (spot 30) and filamin (spot 31). Whilst the levels of ficolin (spot 12) and calumenin (spot 14) transcripts were not corresponded with those of their translation products. These data provide a new insight to understand the molecular immune mechanism of sea cucumber responsive towards pathogen infection. PMID- 24468077 TI - Issues in the conceptualization and assessment of hot executive functions in childhood. AB - Our review examines the current state of the research on hot executive function (EF), as contrasted with cool EF, with regard to the evidence for construct validity. Current theoretical discussions have examined the conceptual overlap among constructs such as hot EF, effortful control, self-control, and self regulation. We explore this emerging literature with a focus on research questions, tasks, and methods. Finally, we consider the unresolved questions facing the study of hot EF, most notably the difficulty in determining the relative "heat" of a given task based on task content, testing context, and the individual differences among the participants. PMID- 24468076 TI - Uncovering by atomic force microscopy of an original circular structure at the yeast cell surface in response to heat shock. AB - BACKGROUND: Atomic Force Microscopy (AFM) is a polyvalent tool that allows biological and mechanical studies of full living microorganisms, and therefore the comprehension of molecular mechanisms at the nanoscale level. By combining AFM with genetical and biochemical methods, we explored the biophysical response of the yeast Saccharomyces cerevisiae to a temperature stress from 30 degrees C to 42 degrees C during 1 h. RESULTS: We report for the first time the formation of an unprecedented circular structure at the cell surface that takes its origin at a single punctuate source and propagates in a concentric manner to reach a diameter of 2-3 MUm at least, thus significantly greater than a bud scar. Concomitantly, the cell wall stiffness determined by the Young's Modulus of heat stressed cells increased two fold with a concurrent increase of chitin. This heat induced circular structure was not found either in wsc1Delta or bck1Delta mutants that are defective in the CWI signaling pathway, nor in chs1Delta, chs3Delta and bni1Delta mutant cells, reported to be deficient in the proper budding process. It was also abolished in the presence of latrunculin A, a toxin known to destabilize actin cytoskeleton. CONCLUSIONS: Our results suggest that this singular morphological event occurring at the cell surface is due to a dysfunction in the budding machinery caused by the heat shock and that this phenomenon is under the control of the CWI pathway. PMID- 24468078 TI - Talcum powder or aqueous gel to aid external cephalic version: a randomised controlled trial. AB - BACKGROUND: External cephalic version (ECV) is offered to reduce the number of Caesarean delivery indicated by breech presentation which occurs in 3-4% of term pregnancies. ECV is commonly performed aided by the application of aqueous gel or talcum powder to the maternal abdomen. We sought to compare gel with powder during ECV on achieving successful version and increasing tolerability. METHOD: We enrolled 95 women (>= 36 weeks gestation) on their attendance for planned ECV. All participants received terbutaline tocolysis. Regional anaesthesia was not used. ECV was performed in the standard fashion after the application of the allocated aid. If the first round (maximum of 2 attempts) of ECV failed, crossover to the opposing aid was permitted. RESULTS: 48 women were randomised to powder and 47 to gel. Self-reported procedure related median [interquartile range] pain scores (using a 10-point visual numerical rating scale VNRS; low score more pain) were 6 [5-9] vs. 8 [7-9] P = 0.03 in favor of gel. ECV was successful in 21/48 (43.8%) vs. 26/47 (55.3%) RR 0.6 95% CI 0.3-1.4 P = 0.3 for powder and gel arms respectively. Crossover to the opposing aid and a second round of ECV was performed in 13/27 (48.1%) following initial failure with powder and 4/21 (19%) after failure with gel (RR 3.9 95% CI 1.0-15 P = 0.07). ECV success rate was 5/13 (38.5%) vs. 1/4 (25%) P = 0.99 after crossover use of gel or powder respectively. Operators reported higher satisfaction score with the use of gel (high score, greater satisfaction) VNRS scores 6 [4.25-8] vs 8 [7-9] P = 0.01. CONCLUSION: Women find gel use to be associated with less pain. The ECV success rate is not significantly different. TRIAL REGISTRATION: The trial is registered with ISRCTN (identifier ISRCTN87231556). PMID- 24468079 TI - Dendritic retraction, but not atrophy, is consistent in amyotrophic lateral sclerosis-comparison between Onuf's neurons and other sacral motor neurons. AB - BACKGROUND: Fundamental cytological changes of amyotrophic lateral sclerosis (ALS) were looked for by comparing relatively preserved Onuf's nucleus (ON) and severely affected neighboring motor neuron groups (dorsolateral alpha motoneurons (DL) and other anterior horn neurons (OAH)). The second sacral segments from 11 ALS patients and 5 controls were initially quadruple-labeled for phosphorylated and non-phosphorylated TAR DNA-binding protein of 43 kDa (TDP43), and p62 with DAPI to identify TDP43-related changes. After digital recording of these fluorescence data encompassing the entire specimen at a high resolution, the same sections were stained with Kluver-Barrera method to obtain their exact bright field counterparts. This novel approach facilitated exact identification of ON. Furthermore, this cell to cell comparison enabled to correlate quantitative indices of the neuronal cell bodies: perimeter, area and circularity index (CI) i.e. the ratio of (perimeter/2pi) divided by the square root of (area/pi), which decreases with dendritic retraction, overall number of neurons and inclusions. RESULTS: In addition to known preservation of ON neuron number relative to DL and OAH, size reduction of ON neurons was not significant even in the advanced stage. Significant size reduction in DL was counteracted in the presence of TDP43 positive inclusions. Early increase of neuronal size in OAH was further enhanced by the presence of TDP43-positive inclusions. Even with these heterogeneous cytopathological changes, a decrease in CI was consistent in all groups at an early phase and was correlated with neuronal loss. CONCLUSIONS: Among variable cytological changes of ALS, a decrease in CI is a consistent early feature shared between non-atrophic ON neurons and other anterior horn neurons with either decreased (DL) or even increased (OAH) size and profounder neuronal loss. This decrease in CI, representative of dendritic retraction, is fundamental to ALS pathogenesis, not necessarily linked to cell size and pathological inclusions. PMID- 24468080 TI - The Queensland high risk foot form (QHRFF) - is it a reliable and valid clinical research tool for foot disease? AB - BACKGROUND: Foot disease complications, such as foot ulcers and infection, contribute to considerable morbidity and mortality. These complications are typically precipitated by "high-risk factors", such as peripheral neuropathy and peripheral arterial disease. High-risk factors are more prevalent in specific "at risk" populations such as diabetes, kidney disease and cardiovascular disease. To the best of the authors' knowledge a tool capturing multiple high-risk factors and foot disease complications in multiple at risk populations has yet to be tested. This study aimed to develop and test the validity and reliability of a Queensland High Risk Foot Form (QHRFF) tool. METHODS: The study was conducted in two phases. Phase one developed a QHRFF using an existing diabetes foot disease tool, literature searches, stakeholder groups and expert panel. Phase two tested the QHRFF for validity and reliability. Four clinicians, representing different levels of expertise, were recruited to test validity and reliability. Three cohorts of patients were recruited; one tested criterion measure reliability (n = 32), another tested criterion validity and inter-rater reliability (n = 43), and another tested intra-rater reliability (n = 19). Validity was determined using sensitivity, specificity and positive predictive values (PPV). Reliability was determined using Kappa, weighted Kappa and intra-class correlation (ICC) statistics. RESULTS: A QHRFF tool containing 46 items across seven domains was developed. Criterion measure reliability of at least moderate categories of agreement (Kappa > 0.4; ICC > 0.75) was seen in 91% (29 of 32) tested items. Criterion validity of at least moderate categories (PPV > 0.7) was seen in 83% (60 of 72) tested items. Inter- and intra-rater reliability of at least moderate categories (Kappa > 0.4; ICC > 0.75) was seen in 88% (84 of 96) and 87% (20 of 23) tested items respectively. CONCLUSIONS: The QHRFF had acceptable validity and reliability across the majority of items; particularly items identifying relevant co-morbidities, high-risk factors and foot disease complications. Recommendations have been made to improve or remove identified weaker items for future QHRFF versions. Overall, the QHRFF possesses suitable practicality, validity and reliability to assess and capture relevant foot disease items across multiple at risk populations. PMID- 24468081 TI - fMRI pain activation in the periaqueductal gray in healthy volunteers during the cold pressor test. AB - The periaqueductal gray (PAG), a brain area belonging to the descending pain modulatory system, plays a crucial role in pain perception. Little information is available on the relationship between PAG activation and perceived pain intensity. In this study, we acquired functional magnetic resonance imaging (fMRI) scans from the PAG during the cold pressor test, a model for tonic pain, in 12 healthy volunteers. fMRI data were acquired with a 12-channel head-coil and a 3-Tesla scanner and analyzed with Statistical Parametric Mapping (SPM8) software. During the cold pressor test, fMRI showed significant activation clusters in pain-related brain areas: bilateral middle and superior frontal gyrus, anterior cingulate cortex and thalamus, left insula, right inferior frontal gyrus, left inferior temporal gyrus and in the bilateral PAG (cluster level corrected threshold p<0.05). PAG activation correlated directly with the pain threshold and inversely with the participant's perceived pain intensity (cluster level corrected threshold (p<0.05). The cold pressor test consistently activated the PAG as well as other pain-related areas in the brain. Our study, showing that the greater the PAG activation the higher the pain threshold and the weaker the pain intensity perceived, highlights the key role of the PAG in inhibiting the pain afferent pathway function. Our findings might be useful for neuroimaging studies investigating PAG activation in patients with chronic idiopathic pain conditions possibly related to dysfunction in the descending pain modulatory system. PMID- 24468082 TI - Building a research career: one grant at a time. PMID- 24468083 TI - A retrospective study of microscopic polyangiitis patients presenting with pulmonary fibrosis in China. AB - BACKGROUND: Pulmonary involvement is a common feature of MPA. Although alveolar hemorrhage is the most common pulmonary manifestation of MPA, a few recent studies have described instances of MPA patients with pulmonary fibrosis. Pulmonary fibrosis was seen to predate, be concomitant with, or occur after the diagnosis of MPA. The goal of this study was to describe the clinical features and prognosis of microscopic polyangiitis (MPA) patients whose initial respiratory presentation was pulmonary fibrosis. METHODS: We conducted a retrospective analysis of 19 MPA patients who presented with pulmonary fibrosis at Peking Union Medical College Hospital between 1990 and 2012. RESULTS: Of 67 total MPA cases, 19 patients presented with pulmonary fibrosis. There were 8 males and 11 females, with a median age of 63.6 years. Common clinical manifestations included fever (89.5%), cough (84.2%), dyspnea (78.9%) and velcro rales (84.2%). Eleven patients experienced weight loss, several had kidney involvement, and most had an increased erythrocyte sedimentation rate and C reactive protein. All were positive for myeloperoxidase-anti-neutrophil cytoplasmic antibody (ANCA), with 6 patients being positive at the time of their initial diagnosis of pulmonary fibrosis. Every patient had typical features of usual interstitial pneumonia on High-resolution CT. All were treated with corticosteroids and cyclophosphamide, which lead to an improvement in twelve cases. One of the remaining patients progressed slowly, whereas six died. CONCLUSIONS: Patients with MPA, who also presented with pulmonary fibrosis in our cohort, were more likely to be older, female, and have extrapulmonic involvement. Most patients had a delayed positive ANCA. Corticosteroids plus cyclophosphamide was the remission-induction treatment scheme for all cases. The current prognosis for MPA patients with pulmonary fibrosis appears to be poor, suggesting that they may be candidates for new therapies. PMID- 24468084 TI - FBI1/Akirin2 promotes tumorigenicity and metastasis of Lewis lung carcinoma cells. AB - The 14-3-3 family of proteins regulates various signaling pathways involved in cell cycle, apoptosis, stress response, and malignant transformation. We previously demonstrated that the beta isoform of the 14-3-3 protein promotes cell growth and tumorigenicity of rat K2 hepatocellular carcinoma cells. We identified fourteen-three-three beta interactant 1 (FBI1)/Akirin2 as a binding partner of 14 3-3beta and showed that the complex of these proteins promotes tumorigenicity and metastasis of K2 cells. In addition, we demonstrated that FBI1/Akirin2 downregulation shortened the duration of MAPK activity. Because 14-3-3beta and FBI1/Akirin2 overexpression is observed in various cancer cell lines, 14-3-3beta FBI1/Akirin2 oncogenic function should be elucidated in different types of cancer. In this study, we used LLC1 Lewis lung carcinoma cells as a model. We established FBI1/Akirin2 knockdown cell clones through transfection of an antisense FBI1/Akirin2 expression vector and assessed the capacity for cell growth in vitro and tumorigenicity and metastasis in vivo. FBI1/Akirin2 downregulation decreased anchorage-independent growth, whereas the growth rate in monolayer culture was not affected. Moreover, an in vivo assay in nude mice showed that FBI1/Akirin2 overexpression is required for LLC1 tumor growth and metastasis. These results suggest that FBI1/Akirin2 plays an important role in oncogenesis of LLC1 lung carcinoma cells, and this protein may also serve as an oncogene in other cancers. PMID- 24468085 TI - P300 binds to and acetylates MTA2 to promote colorectal cancer cells growth. AB - MTA2 is a member of metastasis associated family, which is highly expressed in several solid tumors and associated with tumor cells migration and invasion. Here, we report that MTA2 is acetylated at K152 and histone acetyltransferase p300 binds to and acetylates MTA2. Furthermore, mutation of the MTA2 acetylation site inhibits the growth of colorectal cancer cells and migration and invasion of Rat1 fibroblasts. These results reveal a novel post-translational regulation of MTA2 by the way of p300-dependent acetylation, which is important for tumor cells growth and migration and provides a potential target for clinical cancer research. PMID- 24468086 TI - Role of gamma carboxylated Glu47 in connexin 26 hemichannel regulation by extracellular Ca2+: insight from a local quantum chemistry study. AB - Connexin hemichannels are regulated by several gating mechanisms, some of which depend critically on the extracellular Ca(2+) concentration ([Ca(2+)]e). It is well established that hemichannel activity is inhibited at normal (~1 mM) [Ca(2+)]e, whereas lowering [Ca(2+)]e to micromolar levels fosters hemichannel opening. Atomic force microscopy imaging shows significant and reversible changes of pore diameter at the extracellular mouth of Cx26 hemichannels exposed to different [Ca(2+)]e, however, the underlying molecular mechanisms are not fully elucidated. Analysis of the crystal structure of connexin 26 (Cx26) gap junction channels, corroborated by molecular dynamics (MD) simulations, suggests that several negatively charged amino acids create a favorable environment for low affinity Ca(2+) binding within the extracellular vestibule of the Cx26 hemichannel. In particular a highly conserved glutammic acid, found in position 47 in most connexins, is thought to undergo post translational gamma carboxylation (gammaGlu47), and is thus likely to play an important role in Ca(2+) coordination. gammaGlu47 may also form salt bridges with two conserved arginines (Arg75 and Arg184 in Cx26), which are considered important in stabilizing the structure of the extracellular region. Using a combination of quantum chemistry methods, we analyzed the interaction between gammaGlu47, Arg75 and Arg184 in a Cx26 hemichannel model both in the absence and in the presence of Ca(2+). We show that Ca(2+) imparts significant local structural changes and speculate that these modifications may alter the structure of the extracellular loops in Cx26, and may thus account for the mechanism of hemichannel closure in the presence of mM [Ca(2+)]e. PMID- 24468087 TI - Modeling of Menkes disease via human induced pluripotent stem cells. AB - Menkes disease (MD) is a copper-deficient neurodegenerative disorder that manifests severe neurologic symptoms such as seizures, lethargic states, and hypotonia. Menkes disease is due to a dysfunction of ATP7A, but the pathophysiology of neurologic manifestation is poorly understood during embryonic development. To understand the pathophysiology of neurologic symptoms, molecular and cellular phenotypes were investigated in Menkes disease-derived induced pluripotent stem cells (MD-iPSCs). MD-iPSCs were generated from fibroblasts of a Menkes disease patient. Abnormal reticular distribution of ATP7A was observed in MD-fibroblasts and MD-iPSCs, respectively. MD-iPSCs showed abnormal morphology in appearance during embryoid body (EB) formation as compared with wild type (WT) iPSCs. Intriguingly, aberrant switch of E-cadherin (E-cad) to N-cadherin (N-cad) and impaired neural rosette formation were shown in MD-iPSCs during early differentiation. When extracellular copper was chelated in WT-iPSCs by treatment with bathocuprione sulfate, aberrant switch of E-cad to N-cad and impaired neuronal differentiation were observed, like in MD-iPSCs. Our results suggest that neurological defects in Menkes disease patients may be responsible for aberrant cadherin transition and impaired neuronal differentiation during early developmental stage. PMID- 24468088 TI - Inhibition of miRNA-21 prevents fibrogenic activation in podocytes and tubular cells in IgA nephropathy. AB - Podocytopathy and tubular interstitial fibrosis impact on renal outcomes of IgA nephropathy (IgAN). We found that level of miR-21 was up regulated in both glomerular and tubular-interstitial tissues of patients with IgAN. Enhanced expression of miR-21 mainly located in podocytes and tubular cells. Mesangial cell derived cytokines contributed to the increase of miR-21 in podocytes and HK2 cells. IgA-HMC medium prepared with pIgA from IgAN, lead to obvious fibrogenic activation, evidenced by the loss of Podocin and CD2AP in podocytes, loss of E cadherin and Megalin in HK2 cells and increase of FN and Col I in both cells. miR 21 targeted PTEN in these cells. Expression of PTEN was decreased and phosphorylation of Akt was increased in podocytes and HK2 cells exposed to the medium prepared with pIgA from IgAN. Inhibition of miR-21 preserved the expression of PTEN, prevented the activation of Akt and inhibited the fibrogenic activation in podocytes and HK2 cells exposed to the IgA-HMC medium prepared with pIgA from IgAN. In conclusion, our study suggests that inhibition of miR-21 prevents fibrogenic activation in podocytes and tubular cells by preventing PTEN/Akt pathway activation in IgAN. PMID- 24468089 TI - Axial systems and their actuation: new twists on the ancient body of craniates. AB - Craniate animals--vertebrates and their jawless sister taxa--have evolved a body axis with powerful muscles, a distributed nervous system to control those muscles, and an endoskeleton that starts at the head and ends at the caudal fin. The body axis undulates, bends, twists, or holds firm, depending on the behavior. In this introduction to the special issue on axial systems and their actuation, we provide an overview of the latest research on how the body axis functions, develops, and evolves. Based on this research, we hypothesize that the body axis of craniates has three primary, post-cranial modules: precaudal, caudal, and tail. The term "module" means a portion of the body axis that functions, develops, and evolves in relative independence from other modules; "relative independence" means that structures and processes within a module are more tightly correlated in function, development, and behavior than the same processes are among modules. PMID- 24468090 TI - Salinomycin treatment reduces metastatic tumor burden by hampering cancer cell migration. AB - BACKGROUND: Tumor spreading is the major threat for cancer patients. The recently published anti-cancer drug salinomycin raised hope for an improved treatment by targeting therapy-refractory cancer stem cells. However, an unambiguous role of salinomycin against cancer cell migration and metastasis formation remains elusive. FINDINGS: We report that salinomycin effectively inhibits cancer cell migration in a variety of cancer types as determined by Boyden chamber assays. Additionally, cells were treated with doxorubicin at a concentration causing a comparable low cytotoxicity, emphasizing the anti-migratory potential of salinomycin. Moreover, single-cell tracking by time-lapse microscopy demonstrated a remarkable effect of salinomycin on breast cancer cell motility. Ultimately, salinomycin treatment significantly reduced the metastatic tumor burden in a syngenic mouse tumor model. CONCLUSIONS: Our findings clearly show that salinomycin can strongly inhibit cancer cell migration independent of the induction of cell death. We furthermore demonstrate for the first time that salinomycin treatment reduces metastasis formation in vivo, strengthening its role as promising anti-cancer therapeutic. PMID- 24468091 TI - Repetitive paired-pulse transcranial magnetic stimulation over the visual cortex selectively inhibits focal flash VEPs. AB - BACKGROUND: The human visual system processes different aspects of visual information such as luminance and contrast via multiple channels. We previously used repetitive paired-pulse stimulation (rPPS) over the visual cortex to elicit a disinhibitory effect on the visual recovery function of paired pattern-reversal (PR) visual evoked potentials (VEPs). OBJECTIVE: We tested the hypothesis that different visual channels exhibit diverse response patterns after rPPS over the visual cortex. Thus, we examined how rPPS influenced each channel of the visual cortex. METHODS: We employed rPPS with a 1.5-ms interstimulus interval over the visual cortex at the stimulus intensity of the visual masking effect. Focal flash (FF) and PR-VEPs (check size, 15 min) were recorded to evaluate the response properties of visual channels in 10 healthy subjects. Visual stimuli were presented for the lower half-field that subtended 6 degrees in radius. The amplitudes and latencies of each VEP were compared before and after rPPS for up to 30 min. RESULTS: Following rPPS, N1-P1 and P1-N2 amplitudes of FF-VEPs decreased linearly up to 30 min. In contrast, the amplitudes of PR-VEPs were not significantly changed. Latencies of FF- and PR-VEPs were also unchanged. CONCLUSIONS: Modulation of FF-VEPs by rPPS suggests that rPPS selectively induced an inhibitory effect on the luminance channel. Therefore, rPPS may be a promising tool for exploring plastic changes in the visual cortex. PMID- 24468092 TI - Transcranial magnetic stimulation of the left dorsolateral prefrontal cortex decreases cue-induced nicotine craving and EEG delta power. AB - BACKGROUND: TMS has high potential as smoking cessation treatment. However, the neural mechanisms underlying TMS induced reduction of tobacco craving remain unclear. Electroencephalographic (EEG) delta frequency has been associated with the activity of the dopaminergic brain reward system, which is crucial for nicotine induced effects, and decreases after nicotine admission in smokers. OBJECTIVE: The aim of this study was to investigate EEG delta power changes induced by hf rTMS of the left dorsolateral prefrontal cortex (DLPFC) in nicotine deprived smokers and it's relation to cue-induced nicotine craving. METHODS: Fourteen healthy smokers meeting ICD-10 criteria for tobacco addiction participated in this within-subject sham controlled study. Participants had to abstain from smoking 6 h before the experiment. Effects of high-frequency repetitive TMS (hf rTMS) (10 Hz) for verum (left DLPFC) and sham (vertex) stimulations on cue-induced nicotine craving and resting state EEG delta power were assessed before and three times within 40 min after rTMS. RESULTS: Both craving (P = 0.046) and EEG delta power (P = 0.048) were significantly lower after verum stimulation compared to sham stimulation across the whole post stimulation time period assessed. However, changes of craving ratings and delta power did not correlate. CONCLUSION: Hf rTMS applied to the left DLPFC reduces nicotine craving in short-term abstinent smokers. Changes in delta activity support the idea that stimulation induced effects are mediated by the dopaminergic brain reward system, which presumably plays a prominent, but probably not exclusive, role in this stimulation induced behavioral modulation, making this method a promising smoking cessation treatment candidate. PMID- 24468094 TI - Identification of evolutionarily meaningful information within the mammalian RNA editing landscape. AB - A large comparative genomic sequence study has determined the extent of conservation between RNA editing sites within the mammalian evolutionary tree. PMID- 24468095 TI - Genetic variants for type 2 diabetes and new-onset cancer in Chinese with type 2 diabetes. AB - BACKGROUND: Diabetes is associated with an increased risk of cancer. This study aimed to evaluate associations between recently reported type 2 diabetes (T2D) susceptibility genetic variants and cancer risk in a prospective cohort of Chinese patients with T2D. METHODS: Seven single nucleotide polymorphisms (SNP) in IGF2BP2, CDKAL1, SLC30A8, CDKN2A/B, HHEX and TCF7L2, all identified from genome-wide association studies of T2D, were genotyped in 5900 T2D patients [age mean +/- SD = 57 +/- 13 years, % males = 46] without any known cancer at baseline. Associations between new-onset of cancer and SNPs were tested by Cox proportional hazard models with adjustment of conventional risk factors. RESULTS: During the mean follow-up period of 8.5 +/- 3.3 years, 429 patients (7.3%) developed cancer. Of the T2D-related SNPs, the G-alleles of HHEX rs7923837 (hazard ratio [HR] (95% C.I.) = 1.34 (1.08-1.65); P = 6.7 *10(-3) under dominant model) and TCF7L2 rs290481 (HR (95% C.I.) = 1.16 (1.01-1.33); P = 0.040 under additive model) were positively associated with cancer risk, while the G-allele of CDKAL1 rs7756992 was inversely associated (HR (95% C.I.) = 0.80 (0.65-1.00); P = 0.048 under recessive model). The risk alleles of these significant SNPs exhibited combined effect on increasing cancer risk (per-allele HR (95% C.I.) = 1.25 (1.12-1.39); P = 4.8 * 10(-5)). The adjusted cancer risk was 2.41 (95% C.I. 1.23-4.69) for patients with four risk alleles comparing to patients without risk allele. CONCLUSIONS: T2D-related variants HHEX rs7923837, TCF7L2 rs290481 and CDKAL1 rs7756992 increased cancer risk in patients with diabetes. IMPACT: Our findings provide novel insights into the pathogenesis of cancer in diabetes. PMID- 24468096 TI - The 5-time point oral glucose tolerance test as a predictor of new-onset diabetes after kidney transplantation. AB - AIMS: To evaluate the predictive power of the 5-time point oral glucose tolerance test (OGTT) for new-onset diabetes after kidney transplantation (NODAT). METHODS: We performed a retrospective study of 145 patients without diabetes who received kidney transplantations at our hospital. The 5-time point OGTT was performed before transplantation. The area under a receiver-operating characteristic curve (aROC) was used for evaluating the predictive power of 5-time point OGTT values. RESULTS: Seventeen patients developed NODAT within 1 year after transplantation. All postload plasma glucose (PPG) levels were higher in patients who developed NODAT than in those who did not; fasting plasma glucose levels were not different. The aROC for the area under the glucose concentration-time curve was significantly greater than that for fasting plasma glucose. Univariate and multivariate analyses showed that each PPG level was an independent risk factor for NODAT. Furthermore, patients with normal glucose tolerance (NGT) or impaired glucose tolerance (IGT) could be stratified with a 1-h plasma glucose (1h-PG) cut off point of 8.4 mmol/L. The incidences of NODAT were 23.5%, 16.7%, 9.1%, and 0% for patients with IGT+1h-PG >=8.4 mmol/L,IGT+1h-PG <8.4 mmol/L, NGT+1h-PG >= 8.4 mmol/L, and NGT+1h-PG<8.4 mmol/L, respectively. CONCLUSIONS: The area under the glucose concentration-time curve and each PPG concentration during the 5-time point OGTT are strong predictors of NODAT. A 1h-PG cut-off point of 8.4 mmol/L plus NGT/IGT can be used to identify patients at intermediate and high risk of developing NODAT. PMID- 24468097 TI - Prevalence, trends and risk factors for the diabetes epidemic in China: a systematic review and meta-analysis. AB - AIMS: To describe the prevalence and trends of diabetes and to quantitatively assess its risk factors in mainland China. METHODS: Thirty-one epidemiological studies were identified by a systematic search of four databases. Prevalence estimates were mapped and summarized by meta-analysis in each region of China. The pooled ORs and 95% CIs of risk factors for diabetes were also calculated. RESULTS: There was a large geographical imbalance with regard to the prevalence of diabetes. Region-pooled prevalence was highest in the eastern region (8.0%, 95% CI: 6.1-10.0%) and lowest in the western region (4.6%, 95% CI: 3.3-6.0%), which was consistent with regional levels of economic development. The overall prevalence of diabetes has been increasing since 1980. Traditional risk factors such as age, family history of diabetes, obesity, hypertension and elevated triglycerides were found to be associated with diabetes. In addition, urban residence and being from ethnic minorities were also significantly associated. CONCLUSION: Based on the meta-analyses, we found that the prevalence of diabetes is different in different parts of China but it has been increasing sharply during the last three decades. Some risk factors were quantitatively derived in the study, which are free from the diversity of a single sample. PMID- 24468093 TI - Motor cortex stimulation suppresses cortical responses to noxious hindpaw stimulation after spinal cord lesion in rats. AB - BACKGROUND: Motor cortex stimulation (MCS) is a potentially effective treatment for chronic neuropathic pain. The neural mechanisms underlying the reduction of hyperalgesia and allodynia after MCS are not completely understood. OBJECTIVE: To investigate the neural mechanisms responsible for analgesic effects after MCS. We test the hypothesis that MCS attenuates evoked blood oxygen-level dependent signals in cortical areas involved in nociceptive processing in an animal model of chronic neuropathic pain. METHODS: We used adult female Sprague-Dawley rats (n = 10) that received unilateral electrolytic lesions of the right spinal cord at the level of C6 (SCL animals). In these animals, we performed magnetic resonance imaging (fMRI) experiments to study the analgesic effects of MCS. On the day of fMRI experiment, 14 days after spinal cord lesion, the animals were anesthetized and epidural bipolar platinum electrodes were placed above the left primary motor cortex. Two 10-min sessions of fMRI were performed before and after a session of MCS (50 MUA, 50 Hz, 300 MUs, for 30 min). During each fMRI session, the right hindpaw was electrically stimulated (noxious stimulation: 5 mA, 5 Hz, 3 ms) using a block design of 20 s stimulation off and 20 s stimulation on. A general linear model-based statistical parametric analysis was used to analyze whole brain activation maps. Region of interest (ROI) analysis and paired t-test were used to compare changes in activation before and after MCS in these ROI. RESULTS: MCS suppressed evoked blood oxygen dependent signals significantly (Family-wise error corrected P < 0.05) and bilaterally in 2 areas heavily implicated in nociceptive processing. These areas consisted of the primary somatosensory cortex and the prefrontal cortex. CONCLUSIONS: These findings suggest that, in animals with SCL, MCS attenuates hypersensitivity by suppressing activity in the primary somatosensory cortex and prefrontal cortex. PMID- 24468098 TI - The relation between glycemic control and HDL-C in type 2 diabetes: a preliminary step forward? AB - Low high-density lipoprotein cholesterol (HDL-C) levels are associated with cardiovascular (CV) disease in type 2 diabetes (T2D). Unfortunately available drugs to increase HDL-C have failed to demonstrate a reduction in CV risk. We assessed the effect of improving glycemic control on HDL-C levels. A 6-month intervention resulted in significant improvement in HbA1c but not in HDL-C levels. However, when considering the subgroup of subjects with low levels of HDL C at baseline, we found a significant and inverse relation between improvement in HbA1c and HDL-C levels. PMID- 24468099 TI - A novel mutation of KCNJ11 gene in a patient with permanent neonatal diabetes mellitus. AB - A 4-month-old male baby was diagnosed with Permanent Neonatal Diabetes Mellitus. We identified a novel missense heterogeneous mutation in the KCNJ11 gene at codon 167 (aTC->tTC) in a region that corresponds to a predicted intracellular gate of the ATP-sensitive potassium channel. PMID- 24468101 TI - Childhood narcolepsy with cataplexy: comparison between post-H1N1 vaccination and sporadic cases. AB - OBJECTIVES: We aimed to compare post-Pandemrix vaccination (postvaccine) childhood narcolepsy with cataplexy (NC) vs. sporadic pre-H1N1 pandemic (pre H1N1) cases. METHODS: Clinical, anthropometric, polysomnographic, and cerebrospinal hypocretin 1 (hcrt-1) measurements were collected together with the video recordings of cataplexy in 27 Finnish patients with NC onset after H1N1 Pandemrix vaccination (mean age, 12+/-4 years; 52% boys) and 42 Italian NC patients with NC onset before the H1N1 pandemic (mean age, 11+/-3 years; 48% boys). All subjects carried the HLA-DQB1*0602 allele. RESULTS: Postvaccine subjects were older at NC onset (12+/-3 vs. 9+/-3 years; P=.008) and displayed a shorter mean sleep latency in multiple sleep latency tests (MSLT) (2.3+/-2.2 vs. 3.7+/-2.9 min; P=.026) compared to pre-H1N1 cases. Anthropometric, clinical (core NC symptoms), hcrt-1 deficiency, and polysomnographic data did not differ among groups, but higher disrupted nocturnal sleep was observed in postvaccine subjects. Comparison of cataplexy features at video assessment showed an overlapping picture with the exception for hyperkinetic movements which appeared to be more evident in pre-H1N1 subjects. CONCLUSIONS: The clinical picture of childhood NC was similar in postvaccine and pre-H1N1 children. PMID- 24468100 TI - The levels of plasma growth arrest-specific protein 6 is associated with insulin sensitivity and inflammation in women. AB - AIMS: Vitamin K-dependent growth arrest-specific protein 6 (Gas6) and its receptors of the TAM (TYRO-3/Axl/Mer) family are ubiquitously expressed in immune, cardiovascular, and reproductive systems. They play pivotal roles of regulating tissue homeostasis via anti-inflammatory effects. Recent studies show that the Gas6/TAM system is involved in glucose tolerance-related metabolic disorders. Our aim was to investigate the link between Gas6 protein, insulin sensitivity and inflammatory cytokines in men and women. METHODS: A total of 278 adults (126 men and 152 women) were recruited in this study. Plasma Gas6 concentration and various biochemical, proinflammatory and endothelial markers were measured. Insulin sensitivity was estimated by homeostasis model assessment. RESULTS: Waist, fasting and 2h post-load glucose, and glycated hemoglobin (HbA1C) were significantly lower in women than in men. Age, high-density lipoprotein cholesterol, and highly-sensitive C-reactive protein levels were significantly higher in women than in men. Plasma Gas6 levels were negatively correlated with waist (r = -0.187, P = 0.022), HOMA-IR (r = -0.171, P=0.035), interleukin 6 (r = 0.362, P < 0.001), and E-selectin (r = -0.216, P = 0.008), while they were positively correlated with insulin sensitivity (QUICKI) (r = 0.168, P = 0.039) in women, but not in men. Stepwise multiple regression analysis showed that TNF alpha was independently correlated with plasma Gas6 levels in both the sexes (P < 0.001). CONCLUSION: Plasma Gas6 is associated with obesity, insulin sensitivity, inflammation, and endothelial dysfunction in women and may be a general marker of inflammatory conditions in women. PMID- 24468102 TI - Sleep fragmentation and sleep-disordered breathing in individuals living close to main roads: results from a population-based study. AB - BACKGROUND: Nighttime traffic noise is associated with sleep disturbances, but sleep fragmentation and sleep-disordered breathing (SDB) have not been demonstrated in individuals living near busy roads. METHODS: We asked 1383 participants to answer a health questionnaire and to undergo 24-h electrocardiogram (ECG). Nocturnal ECG records were used to calculate the very low frequency index (VLFI) interval, a surrogate marker of sleep fragmentation. Distances of participants' addresses to roadways were calculated using the VECTOR25(c) Swisstopo roads classification, a traffic noise proxy. Distances of homes within 100 or 50 m of major roads defined proximity to busy roads. Adjusted multivariate logistic regressions analyzed associations between the distance of home to main roads and VLFI or self-reported SDB. RESULTS: Distance of participants' homes to main roads was significantly associated with the VLFI in women (odds ratio [OR], 1.58 [confidence interval {CI}, 1.03-2.42]; P = .038) but not in men (OR, 1.35 [CI, 0.77-2.35]; P = .295). Women under hormonal replacement therapy (HRT) were at higher risk for increased VLFI when living close to main roads (OR, 2.10 [CI, 1.20-3.68]; P = .01) than untreated women (P = .584). Associations with self-reported SDB were not statistically relevant. CONCLUSIONS: In our large population, women living close to main roads were at significantly higher risk for sleep fragmentation than men. The 2-fold higher risk for menopausal women under HRT underscores the vulnerability of this group. PMID- 24468103 TI - Platelet extracts induce growth, migration and invasion in human hepatocellular carcinoma in vitro. AB - BACKGROUND: Thrombocytopenia has been reported to be associated with small size HCCs, and thrombocytosis to be associated with large size HCCs. The aim was to examine the effects of platelets in relation to HCC cell growth. METHODS: The effects of time-expired pooled normal human platelets were examined on human HCC cell line growth and invasion. RESULTS: Blood platelet numbers increased with increasing HCC tumor size and portal vein invasion. Platelet extracts enhanced cell growth in 4 human HCC cell lines, as well as cell migration, medium AFP levels and decreased apoptosis. Cell invasion was significantly enhanced, using a Matrigel-coated trans-well membrane and 3D (Real-Time Imaging) invasion assay. Western blots showed that platelets caused enhanced phospho-ERK and phospho-JNK signaling and anti-apoptotic effect with increase of Bcl-xL (anti-apoptotic marker) and decrease of Bid (pro-apoptotic marker) levels. Their growth effects were blocked by a JNK inhibitor. CONCLUSIONS: Platelets stimulated growth and invasion of several HCC cell lines in vitro, suggesting that platelets or platelet growth factors could be a potential pharmacological target. PMID- 24468105 TI - Medial prefrontal cortex circuit function during retrieval and extinction of associative learning under anesthesia. AB - Associative learning is encoded under anesthesia and involves the medial prefrontal cortex (mPFC). Neuronal activity in mPFC increases in response to a conditioned stimulus (CS+) previously paired with an unconditioned stimulus (US) but not during presentation of an unpaired stimulus (CS-) in anesthetized animals. Studies in conscious animals have shown dissociable roles for different mPFC subregions in mediating various memory processes, with the prelimbic (PL) and infralimbic (IL) cortex involved in the retrieval and extinction of conditioned responding, respectively. Therefore PL and IL may also play different roles in mediating the retrieval and extinction of discrimination learning under anesthesia. Here we used in vivo electrophysiology to examine unit and local field potential (LFP) activity in PL and IL before and after auditory discrimination learning and during later retrieval and extinction testing in anesthetized rats. Animals received repeated presentations of two distinct sounds, one of which was paired with footshock (US). In separate control experiments animals received footshocks without sounds. After discrimination learning the paired (CS+) and unpaired (CS-) sounds were repeatedly presented alone. We found increased unit firing and LFP power in PL and, to a lesser extent, IL after discrimination learning but not after footshocks alone. After discrimination learning, unit firing and LFP power increased in PL and IL in response to presentation of the first CS+, compared to the first CS-. However, PL and IL activity increased during the last CS- presentation, such that activity during presentation of the last CS+ and CS- did not differ. These results confirm previous findings and extend them by showing that increased PL and IL activity result from encoding of the CS+/US association rather than US presentation. They also suggest that extinction may occur under anesthesia and might be represented at the neural level in PL and IL. PMID- 24468104 TI - Puberty in the corpus callosum. AB - Adolescence is an important period for brain development. White matter growth is influenced by sex hormones such as testosterone, and the corpus callosum-the largest white matter structure in the human brain-may change structurally during the hormone-laden period of adolescence. Little is known about puberty's relationship to structural brain development, even though pubertal stage may better predict cognitive and behavioral maturity than chronological age. We therefore aimed to establish the presence and direction of pubertal effects on callosal anatomy. For this purpose, we applied advanced surface-based mesh modeling to map correlations between callosal thickness and pubertal stage in a large and well-matched sample of 124 children and adolescents (62 female and 62 male) aged 5-18years from a normative database. When linking callosal anatomy to pubertal status, only positive correlations reached statistical significance, indicating that callosal growth advances with puberty. In tests of differences in callosal anatomy at different stages of puberty, callosal growth was concentrated in different locations depending on the pubertal stage. Changing levels of circulating sex hormones during different phases of puberty likely contributed to the observed effects, and further research is clearly needed. Direct quantification of sex hormone levels and regional fiber connectivity-ideally using fiber tractography-will reveal whether hormones are the main drivers of callosal change during puberty. These callosal findings may lead to hypotheses regarding cortical changes during puberty, which may promote or result from changes in inter-hemispheric connectivity. PMID- 24468106 TI - Neural basis of economic bubble behavior. AB - Throughout human history, economic bubbles have formed and burst. As a bubble grows, microeconomic behavior ceases to be constrained by realistic predictions. This contradicts the basic assumption of economics that agents have rational expectations. To examine the neural basis of behavior during bubbles, we performed functional magnetic resonance imaging while participants traded shares in a virtual stock exchange with two non-bubble stocks and one bubble stock. The price was largely deflected from the fair price in one of the non-bubble stocks, but not in the other. Their fair prices were specified. The price of the bubble stock showed a large increase and battering, as based on a real stock-market bust. The imaging results revealed modulation of the brain circuits that regulate trade behavior under different market conditions. The premotor cortex was activated only under a market condition in which the price was largely deflected from the fair price specified. During the bubble, brain regions associated with the cognitive processing that supports order decisions were identified. The asset preference that might bias the decision was associated with the ventrolateral prefrontal cortex and the dorsolateral prefrontal cortex (DLPFC). The activity of the inferior parietal lobule (IPL) was correlated with the score of future time perspective, which would bias the estimation of future price. These regions were deemed to form a distinctive network during the bubble. A functional connectivity analysis showed that the connectivity between the DLPFC and the IPL was predominant compared with other connectivities only during the bubble. These findings indicate that uncertain and unstable market conditions changed brain modes in traders. These brain mechanisms might lead to a loss of control caused by wishful thinking, and to microeconomic bubbles that expand, on the macroscopic scale, toward bust. PMID- 24468107 TI - Hyperactivity following unilateral hearing loss in characterized cells in the inferior colliculus. AB - Hyperactivity (increased spontaneous firing rates) following cochlear trauma and hearing loss has been well documented in the inferior colliculus (IC). This hyperactivity is associated with frequency regions in the IC that are closely related to regions of peripheral hearing loss. In other auditory nuclei, notably cochlear nucleus, hyperactivity has been shown to be more prevalent in particular cell types but this has not been investigated in the IC. Single-neuron spontaneous firing rates were recorded in the IC of animals after acoustic trauma (10-kHz tone at 124dB for 2h) and in sham surgery controls. Single-neuron recordings were made 2weeks later. Evoked responses to ipsi- and contralateral sound were used for classification. Classifications were based on peri-stimulus time histograms, input-output functions, frequency response areas and monaural/binaural responses. Results showed increased spontaneous firing rates in the IC following trauma, in regions corresponding to the frequencies at which there was peripheral hearing loss (12-20kHz). Most response categories, with the exception of cells showing an onset response classification, showed a significantly increased average spontaneous firing rate. These data suggest that hyperactivity in the IC is not confined to a particular response type in contrast to findings in the cochlear nucleus. This may be the result of factors intrinsic to the IC, or because of convergent input to the IC from a range of other auditory structures. PMID- 24468109 TI - The trouble with circadian clock dysfunction: multiple deleterious effects on the brain and body. AB - This review consolidates research employing human correlational and experimental work across brain and body with experimental animal models to provide a more complete representation of how circadian rhythms influence almost all aspects of life. In doing so, we will cover the morphological and biochemical pathways responsible for rhythm generation as well as interactions between these systems and others (e.g., stress, feeding, reproduction). The effects of circadian disruption on the health of humans, including time of day effects, cognitive sequelae, dementia, Alzheimer's disease, diet, obesity, food preferences, mood disorders, and cancer will also be discussed. Subsequently, experimental support for these largely correlational human studies conducted in non-human animal models will be described. PMID- 24468108 TI - Experimental mouse model of optic neuritis with inflammatory demyelination produced by passive transfer of neuromyelitis optica-immunoglobulin G. AB - BACKGROUND: Although optic neuritis (ON) is a defining feature of neuromyelitis optica (NMO), appropriate animal models of NMO ON are lacking. Most NMO patients are seropositive for immunoglobulin G autoantibodies (NMO-IgG) against the astrocyte water channel aquaporin-4 (AQP4). METHODS: Several approaches were tested to develop a robust, passive-transfer mouse model of NMO ON, including NMO IgG and complement delivery by: (i) retrobulbar infusion; (ii) intravitreal injection; (iii) a single intracranial injection near the optic chiasm; and (iv) 3-days continuous intracranial infusion near the optic chiasm. RESULTS: Little ON or retinal pathology was seen using approaches (i) to (iii). Using approach (iv), however, optic nerves showed characteristic NMO pathology, with loss of AQP4 and glial fibrillary acidic protein immunoreactivity, granulocyte and macrophage infiltration, deposition of activated complement, demyelination and axonal injury. Even more extensive pathology was created in mice lacking complement inhibitor protein CD59, or using a genetically modified NMO-IgG with enhanced complement effector function, including significant loss of retinal ganglion cells. In control studies, optic nerve pathology was absent in treated AQP4 deficient mice, or in wild-type mice receiving control (non-NMO) IgG and complement. CONCLUSION: Passive transfer of NMO-IgG and complement by continuous infusion near the optic chiasm in mice is sufficient to produce ON with characteristic NMO pathology. The mouse model of NMO ON should be useful in further studies of NMO pathogenesis mechanisms and therapeutics. PMID- 24468110 TI - Competitive adsorption and transport of Cd, Cu, Ni and Zn in a mine soil amended with mussel shell. AB - Batch type and column experiments were used to study competitive adsorption desorption and transport for Cd, Cu, Ni and Zn in a mine soil, both un-amended and amended with mussel shell. Batch type experiments showed that adsorption was affected by the added concentration of the metals, generally following the sequence Cu>Zn>Cd~Ni. Metal desorbed was a function of the dose of metal added, as well as of the dose of shell amendment, being relevant that even when the highest dose of metal (2300 MUM) was added, the 24 g kg(-1) shell amendment caused a drastic diminution in the amount of metal desorbed. Column experiments showed that even the lowest dose of the shell amendment (6 g kg(-1)) caused a strong retention of the 4 heavy metals assayed, whereas using the 24 g kg(-1) shell amendment no metal was detected in the effluent during the time of the experiment. The mass of metal retained in the un-amended soil was very different for the various metals assayed, but the amendment with 6 g kg(-1) shell increased this retention in all cases, and the 24 g kg(-1) amendment caused almost 100% retention for all 4 metals. The retardation factor (R) suffered an overall increase as a function of the shell dose; the profile distribution of the 4 heavy metals was homogeneous through the un-amended soil into the column, but the shell amendment clearly decreased the solute transport affecting these metals, causing its concentration in the first centimeters of the soil profile. PMID- 24468111 TI - A biomarker of contaminant exposure is effective in large scale assessment of ten estuaries. AB - Cost-effective and sensitive measures of anthropogenic stress are necessary tools in any environmental monitoring program. When implementing new monitoring tools in a region, rigorous laboratory and field studies are essential for characterizing the sensitivity and efficacy of the approach. We exposed the oyster Saccostrea glomerata to various individual contaminants through multiple exposure pathways (water- and food-borne) in the laboratory and measured two biomarker responses, lysosomal membrane stability (LMS) and lipid peroxidation (LPO). LMS was sensitive to both contaminant exposure pathways. We subsequently measured this biomarker in oysters which had been experimentally deployed at multiple sites in each of ten estuaries with varying levels of contamination associated with re-suspended sediments. There was a strong association between LMS and metal exposure, despite substantial natural variation in water quality parameters. Our results illustrate the potential use of LMS as a pragmatic indicator of biotic injury in environmental monitoring programs for re-suspended contaminated sediments. PMID- 24468112 TI - Study on effects of temperature, moisture and pH in degradation and degradation kinetics of aldrin, endosulfan, lindane pesticides during full-scale continuous rotary drum composting. AB - Study focused on effects of temperature, moisture and pH on degradation and degradation kinetics of aldrin, endosulfan (alpha), endosulfan (beta) and lindane during vegetable waste composting using full-scale continuous rotary drum composter (FSCRDC). Extraction, concentration and quantification of pesticides were made from waste material at different stages by ultra-sonification, silica gel column and GC-MS analysis. Removal efficiency of aldrin, endosulfan alpha, endosulfan beta and lindane was found 85.67%, 84.95%, 83.20% and 81.36% respectively due to optimum temperature, moisture, pH and enhanced microbial activity. Maximum temperature in inlet zone was found 60-65 degrees C which is most suitable for complex microbial population. After feeding and turning in inlet zone, temperature reduced to 38 degrees C from 60 to 65 degrees C and regained it within 7-8h, and pH reduced to 5.3+/-0.2 from 7.5+/-0.3 in 4h and regained it in 10h. Heterotrophic bacteria Bacillus sp., Pseudomonas sp. and Lactobacillus sp. also decreased from 4.4*10(3) to 7.80*10(2)CFU g(-1) in 2 h due to gradual variation in temperature and pH. No significant temperature change was found in middle and outlet zones during feeding and turning. Degradation of pesticides was observed as first order kinetics and half-life of aldrin, endosulfan alpha, endosulfan beta and lindane was reduced to 25.54, 18.43, 18.43 and 27.43 d from 1095, 60, 270 and 160 d respectively. Thus, the observations in contrast of removal and degradation kinetics of organochlorine pesticides residues in vegetable waste though full-scale rotary drum composting proved it the best suited technique. PMID- 24468113 TI - Reduced sphingosine kinase-1 and enhanced sphingosine 1-phosphate lyase expression demonstrate deregulated sphingosine 1-phosphate signaling in Alzheimer's disease. AB - BACKGROUND: The accumulation of beta amyloid (Abeta) peptides, a hallmark of Alzheimer's disease (AD) is related to mechanisms leading to neurodegeneration. Among its pleiotropic cellular effects, Abeta accumulation has been associated with a deregulation of sphingolipid metabolism. Sphingosine 1-phosphate (S1P) derived from sphingosine is emerging as a critical lipid mediator regulating various biological activities including cell proliferation, survival, migration, inflammation, or angiogenesis. S1P tissue level is low and kept under control through equilibrium between its synthesis mostly governed by sphingosine kinase-1 (SphK1) and its degradation by sphingosine 1-phosphate lyase (SPL). We have previously reported that Abeta peptides were able to decrease the activity of SphK1 in cell culture models, an effect that could be blocked by the prosurvival IGF-1/IGF-1R signaling. RESULTS: Herein, we report for the first time the expression of both SphK1 and SPL by immunohistochemistry in frontal and entorhinal cortices from 56 human AD brains. Immunohistochemical analysis revealed a decreased expression of SphK1 and an increased expression of SPL both correlated to amyloid deposits in the entorhinal cortex. Otherwise, analysis of brain tissue extracts showed a decrease of SphK1 expression in AD brains whereas SPL expression was increased. The content of IGF-1R, an activator of SphK1, was found decreased in AD brains as well as S1P1, the major receptor for S1P. CONCLUSIONS: Collectively, these results highlight the importance of S1P in AD suggesting the existence of a global deregulation of S1P signaling in this disease from its synthesis by SphK1 and degradation by SPL to its signaling by the S1P1 receptor. PMID- 24468114 TI - Higher mortality rates among the elderly with mild traumatic brain injury: a nationwide cohort study. AB - BACKGROUND: It is known that the risk of death in elderly patients with moderate to severe traumatic brain injury is increased. However, the relationship between mild traumatic brain injury and death has never been established. We investigated the mortality rates of older patients with mild traumatic brain injury in Taiwan to evaluate if there is a higher risk of death compared with the general population. METHODS: We utilized a sampled National Health Insurance claims database containing one million beneficiaries. We followed all adult beneficiaries older than 65 years from January 1, 2005 till December 31, 2009 to see if they died. We further identified patients with mild traumatic brain injury and compared their risk of death with the general population. RESULTS: We identified 5997 patients with mild traumatic brain injury and 84,117 patients without mild traumatic brain injury. After controlling for age, gender, urbanization level, socioeconomic status, diabetes, hypertension, history of alcohol intoxication, history of ischemic stroke, history of intracranial hemorrhage, malignancies, dementia and Charlson Comorbidity Index score, the adjusted hazard ratio was 1.25 (95% confidence interval, 1.16-1.34). CONCLUSIONS: Mild traumatic brain injury is an independent significant risk factor for death in the elderly. PMID- 24468115 TI - Muscle fibre type distribution of the thoracolumbar and hindlimb regions of horses: relating fibre type and functional role. AB - BACKGROUND: Although the majority of equine muscles have a mixed fibre type distribution indicative of diverse functional roles, the predominance of a fibre type can indicate the primary function of a muscle. The deep epaxial musculature has an important role in core spinal stability in humans, reflected as a predominantly muscle fibre type (MFT) I or postural fibre type. The fibre type of the deep epaxial musculature has not been determined in horses. The objective of the study was to determine the MFT distribution in selected muscles of thoracolumbar and hindlimb region of horses. This included deep epaxial and hypaxial muscles that were hypothesised to have a postural stabilising role. A second objective was to examine differences in MFT distribution between horses bred for endurance (Arabian) and sprinting (Quarter horse). Muscle biopsy samples were obtained from selected thoracolumbar and hind limb muscles of 5 Quarter horses, 4 Arabians, and 2 Thoroughbreds. The myosin heavy chain distribution was determined by gel electrophoresis. Mann-Whitney rank test was used to compare the proportional MFT and differences between breeds. RESULTS: Mm. sacrocaudalis dorsalis medialis and diaphragm had the highest proportion of MFT-I. The remaining deep epaxial muscles and the hypaxial muscle m. psoas minor had approximately equal MFT I and II proportions. Mm. psoas major, iliocostalis, longissimus dorsi and the hind limb muscles contained mostly MFT-IIX. The fibre type distribution was similar between Arabians and Quarter horses, although Quarter horses had more MFT-IIX fibres in psoas major (P = 0.02) while Arabians had more MFT-I fibres in m. longissimus dorsi (P = 0.03). CONCLUSIONS: The fibre type distribution of the deep epaxial muscles, mm psoas minor and diaphragm varied from approximately equal MFT-I and II proportions to predominantly MFT-I suggesting a postural stabilising role possibly important in core spinal stability. In contrast the fibre type proportions of mm psoas major, iliocostalis, longissimus dorsi and the hind limb muscles were mainly MFT-II suggesting a locomotory role. Knowledge of fibre type distribution in such a clinically important area can direct diagnosis, prevention and treatment of muscular or neuromotor dysfunction. PMID- 24468116 TI - Amplitude control of the track-induced self-excited vibration for a maglev system. AB - The Electromagnet Suspension (EMS) maglev train uses controlled electromagnetic forces to achieve suspension, and self-excited vibration may occur due to the flexibility of the track. In this article, the harmonic balance method is applied to investigate the amplitude of the self-excited vibration, and it is found that the amplitude of the vibration depends on the voltage of the power supplier. Based on this observation, a vibration amplitude control method, which controls the amplitude of the vibration by adjusting the voltage of the power supplier, is proposed to attenuate the vibration. A PI controller is designed to control the amplitude of the vibration at a given level. The effectiveness of this method shows a good prospect for its application to commercial maglev systems. PMID- 24468117 TI - Design and implementation of an internet-based electrical engineering laboratory. AB - This paper describes an internet-based electrical engineering laboratory (IEE Lab) with virtual and physical experiments at Zhejiang University. In order to synthesize the advantages of both experiment styles, the IEE-Lab is come up with Client/Server/Application framework and combines the virtual and physical experiments. The design and workflow of IEE-Lab are introduced. The analog electronic experiment is taken as an example to show Flex plug-in design, data communication based on XML (Extensible Markup Language), experiment simulation modeled by Modelica and control terminals' design. PMID- 24468118 TI - An atypical presentation of intrahepatic perforated cholecystitis: a modern indication to open cholecystectomy. Report of a case. AB - BACKGROUND: Intrahepatic gallbladder perforation with chronic liver abscess formation was anecdotically reported in the literature. The aim of this work is to report a case of intrahepatic gallbladder perforation and its atypical clinical presentation. CASE PRESENTATION: A 62-year-old male patient came to our observation; his medical history showed intermittent fever up to 39-40 degrees C of about 2 weeks and anorexia, with an overall weight loss of about 12 Kg. Physical examination of the abdomen was negative. An ultrasound of the liver and an abdominal CT angiogram detected a disomogeneous hypoechoic-hypodense area in the 5th segment of the liver. Differential diagnosis between hepatic abscess or gallbladder cancer remained open. A surgical exploration was planned. After laparoscopic exploration, a conversion to open procedure with an atypical resection of the 5th hepatic segment was performed. Histologic examination of the specimen showed an intrahepatic chronic perforation of the gallbladder with intrahepatic abscess. CONCLUSION: To the best of our knowledge, 18 cases have been reported in the literature as a Niemeier type I perforation. Clinical presentation, even in its extreme rarity, is more often acute. Differential diagnosis between gallbladder cancer versus liver abscess remains controversial. Open approach is mandatory in such cases. PMID- 24468119 TI - An inpatient rehabilitation program utilizing standardized care pathways after paracorporeal ventricular assist device placement in children. AB - BACKGROUND: Structured rehabilitation programs in adults after ventricular assist device (VAD) placement result in improvements in physical function and exercise capacity, and have been shown to improve survival and accelerate post-transplant recovery. The objective of this study was to determine the safety and feasibility of an acute inpatient rehabilitation program for children utilizing standardized, age-appropriate, family-centered care pathways after paracorporeal VAD placement in both the ICU and acute-care inpatient settings. METHODS: Between November 12, 2010 and March 15, 2013, 17 patients were referred to therapy after VAD implantation, 14 of whom were medically stable enough to participate. Beginning in the ICU, a structured physical and occupational therapy program was implemented utilizing novel age-appropriate, standardized care pathways for infants (age <1 year) and children (age 1 to 12 years). The infant and child pathways consisted of 8 and 10 goals, respectively. Retrospective review was conducted to ascertain the number of phases achieved per patient. Adverse events, defined as bleeding, physiologic instability, stroke, or device disruption during therapy, were also analyzed. RESULTS: The median age was 1.1 (range 0.5 to 14.4) years in the 14 patients considered medically stable enough to participate in rehabilitation. Nine of them were female. Eight patients participated in the infant standardized care pathway (SCP) and 6 participated in the child SCP. Seven patients were on biventricular support. Twelve patients were transplanted and survived. Two patients died while awaiting transplantation. There were 1,473 total days on the VAD (range 40 to 229 days). The median time to extubation was 2 days (range 1 to 8) and the median ICU stay was 6.5 days (range 3 to 152). Eleven patients achieved all goals of the SCP, including all of the patients in the child group. For the infant group, 5 patients achieved all goals of the SCP (range 5 to 8), and all but 1 patient achieved at least 7 goals of the SCP. There were no adverse events related to therapy. CONCLUSIONS: Standardized, family centered inpatient rehabilitation care paths are safe for infants and children after paracorporeal device placement. Structured rehabilitation goals can be achieved by the majority of pediatric patients during VAD support. Early mobilization and inpatient rehabilitation in this cohort promotes normalization of function while awaiting cardiac transplantation. PMID- 24468120 TI - T-regulatory cell treatment prevents chronic rejection of heart allografts in a murine mixed chimerism model. AB - BACKGROUND: The mixed chimerism approach induces donor-specific tolerance in both pre-clinical models and clinical pilot trials. However, chronic rejection of heart allografts and acute rejection of skin allografts were observed in some chimeric animals despite persistent hematopoietic chimerism and tolerance toward donor antigens in vitro. We tested whether additional cell therapy with regulatory T cells (Tregs) is able to induce full immunologic tolerance and prevent chronic rejection. METHODS: We recently developed a murine "Treg bone marrow (BM) transplantation (BMT) protocol" that is devoid of cytoreductive recipient pre-treatment. The protocol consists of a moderate dose of fully mismatched allogeneic donor BM under costimulation blockade, together with polyclonal recipient Tregs and rapamycin. Control groups received BMT under non myeloablative irradiation and costimulation blockade without Treg therapy. Multilineage chimerism was followed by flow cytometry, and tolerance was assessed by donor-specific skin and heart allografts. RESULTS: Durable multilineage chimerism and long-term donor skin and heart allograft survival were successfully achieved with both protocols. Notably, histologic examination of heart allografts at the end of follow-up revealed that chronic rejection is prevented only in chimeras induced with the Treg protocol. CONCLUSIONS: In a mouse model of mixed chimerism, additional Treg treatment at the time of BMT prevents chronic rejection of heart allografts. As the Treg-chimerism protocol also obviates the need for cytoreductive recipient treatment it improves both efficacy and safety over previous non-myeloablative mixed chimerism regimens. These results may significantly impact the development of protocols for tolerance induction in cardiac transplantation. PMID- 24468121 TI - Impact of pancreatic comorbidities in patients with end-stage liver disease on outcome after liver transplantation. AB - BACKGROUND: Diseases leading to end-stage liver disease (ESLD), especially alcoholic liver cirrhosis cause comorbidities of the pancreas, too. The aim of this retrospective study was to determine the impact of pancreatic alterations diagnosed pretransplant on the outcome after liver transplantation (LT). METHODS: In total, data from 372 LT patients were analyzed. Patients were followed up for a mean of 4.2 years. Incidence of chronic pancreatitis (CP), pancreatic cysts (PC) and intraductal papillary mucinous neoplasm (IPMN) was acquired retrospectively from patient's charts. RESULTS: CP, IPMN and PC were rarely diagnosed in LT-recipients [CP (3.8%), PC (1.6%) and IPMN (1.6%)]. There was no significant correlation of IPMN, CP, PC and other patient characteristics. The prevalence of CP (log rank: p=0.315), PC (log rank: p=0.242) and IPMN (log rank: p=0.491) did not influence patient survival. CONCLUSION: Frequency of radiological alterations of the pancreas in LT recipients (such as CP, PC, IPMN) diagnosed by sonography, CT scan or MRI is comparable to the non-transplant population. Short term survival of LT-recipients after transplantation is not reduced for patients with CP, PC and patients with branch-duct IPMN (with a low risk for malignancy according to international consensus guidelines). PMID- 24468122 TI - Fatal myocardial ischemia in a 12-year old secondary to fibromuscular dysplasia. AB - Cardiac causes of chest pain in children are rare; however, they continue to account for 1% to 6% of all cases dependent on the practice setting and patient history. Here we describe the case of a 12-year old with fibromuscular dysplasia that died from an acute myocardial infarction. Although this specific etiology is uncommon, the case illustrates the need for broad differentials when treating children with chest pain in the emergency medicine environment. In particular, even if the specific diagnosis cannot be readily made in the prehospital or emergency department (ED) setting, the possibility of cardiac disease should be considered. PMID- 24468123 TI - Cerebral oxygen saturation monitoring in pediatric altered mental status patients. AB - OBJECTIVES: A pilot study assessing the potential utility of cerebral oximetry (local cerebral oxygen saturation [rcSO2]) in children presenting to the emergency department (ED) with altered mental status (AMS) and no history of trauma. METHODS: Patients who presented to a tertiary pediatric ED with AMS were monitored with left and right cerebral near-infrared spectroscopy probes and the first 30 minutes of rcSO2 data was analyzed. Patients with a history of trauma were excluded. Patients with an abnormal head computed tomography (CT) (n = 146) were compared with those with a negative head CT (n = 45). RESULTS: Mean rcSO2 values were consistent during each time period studied (5, 10, 20, and 30 minutes). In this study population, rcSO2 less than 50% or greater than 80% and increased absolute difference between the left and right rcSO2 measurements were associated with an abnormal CT scan. A difference of 12.2% between the left and right rcSO2 values had a 100% positive predictive value for an abnormal head CT among our patients. Cumulative graphical plots of rcSO2 trends showed that values <50% were associated with subdural hematomas (SDH) and values >80% were associated with epidural hematomas (EDH). CONCLUSIONS: This study demonstrated that cerebral oximetry can noninvasively detect altered cerebral physiology among a selected patient population. The difference between the left and right rcSO2 readings most reliably identified those subjects with altered cerebral physiology. In the future, rcSO2 monitoring has the potential to be used as a screening tool to identify, localize, and characterize intracranial injuries among children with AMS without a history of trauma. PMID- 24468124 TI - Patients in pain that refuse acetaminophen at triage. PMID- 24468125 TI - Outcome from severe accidental hypothermia with cardiac arrest resuscitated with extracorporeal cardiopulmonary resuscitation. AB - PURPOSE: This study aimed to identify factors of neurologic prognosis in severe accidental hypothermic patients with cardiac arrest. BASIC PROCEDURES: This retrospective observational study was performed in a tertiary care university hospital in Sapporo, Japan (January 1994 to December 2012). We investigated 26 patients with accidental hypothermic cardiac arrest resuscitated with extracorporeal cardiopulmonary resuscitation (ECPR). We evaluated the neurologic outcome in patients who were resuscitated with ECPR at discharge from hospital. MAIN FINDINGS: In those 26 patients, their median age was 50.5 years; and 69.2% were male. The cause of hypothermia was exposure to cold air in 46.1%, submersion in 46.1%, and avalanche in 7.8%. Ten (38.5%) of these patients survived to favorable neurological outcome at discharge. Factors associated with favorable neurological outcome were a cardiac rhythm other than asystole (P = .009), nonasphyxial hypothermia (P = .006), higher pH (P = .01), and lower serum lactate (P = .01). In subgroup analyses, the patients with hypothermic cardiac arrest due to submersion or avalanche (asphyxia group) showed no factors associated with good neurological outcome, whereas the nonasphyxia group showed a significantly lower core temperature (P = .02) and a trend towards a lower serum lactate (P = .09). PRINCIPAL CONCLUSIONS: Patients with hypothermic cardiac arrest due to nonasphyxial hypothermia have improved neurologic outcomes when treated with ECPR compared to patients with asphyxial hypothermic cardiac arrest. Further investigation is needed to develop a prediction rule for patients with nonasphyxial hypothermic cardiac arrest to determine which patients would benefit from treatment with ECPR. PMID- 24468126 TI - Acute dysphagia in an octogenarian: an unusual case of tetanus. AB - Tetanus is a major worldwide health problem, and its global incidence has been estimated to be approximately 1 million cases per year. In particular, tetanus is more frequent in the elderly as compared with adults. We report a case of an octogenarian who presented with dysphagia and tremors as the only clinical symptoms. During hospitalization, the patient's clinical conditions worsened rapidly, and, although in absence of the classic clinical presentation (trisma, nuchal rigidity, and opisthotonus), a diagnosis of tetanus was suspected. Thus, the patient underwent a tetanus immunoglobulin immunization and antibiotic therapy with excellent clinical recovery. PMID- 24468127 TI - Longitudinal study of sustained attention in outpatients with bipolar disorder. AB - Individuals with bipolar disorder (BD) may exhibit attentional deficits, however, the extent of impairment and long-term fluctuations in performance in attention are relatively unknown. We investigated the relationship between sustained attention and affective symptoms over time among BD patients. We also examined whether global differences in attentional capacity differed among BD versus normal comparison (NC) subjects. Participants included 106 outpatients with BD and 66 NC subjects who were administered symptom rating scales and a measure of sustained attention (Continuous Performance Test- Identical Pairs). Measures were repeated 6, 12, and 26 weeks post-baseline. Compared to NC subjects, participants with BD showed impairment in sustained attention across time. Within patient increases in manic symptoms were associated with increased false alarms; both manic and depressive symptoms were associated with worse discrimination. Neither manic nor depressive symptoms were related to hit rates. Our results indicate that the ability to inhibit a response to near miss stimuli (i.e., those that are close to but not identical to the target) is globally impaired among BD patients relative to NC subjects, as well as state-dependent, covarying with affective symptoms. Psychosocial interventions requiring high levels of attentional capacity may need to be adapted according to patients' current symptomatology. PMID- 24468128 TI - Foetal aortic flow velocity waveforms in healthy and hypertensive pregnant women. AB - BACKGROUND: The foetal aortic Doppler frequency spectrum is influenced by cardiac output and contractility of the foetal heart as well as vascular compliance, blood viscosity and impedance of the arterial vascular system. The present study aimed at comparing Doppler flow pulsatility (PI) and resistance (RI) indexes of foetal proximal descending aorta (AoF) in the first, second and third trimesters of pregnancy, in low risk women and in those with chronic arterial hypertension, who had normal pregnancy outcomes. METHODS: A longitudinal and prospective study was carried out in 101 singleton pregnancies (71 low-risk pregnancies and 30 with essential hypertension). Multivariate regression had to be considered due to the experiment's nature: two different indexes were read on the same set of individuals, once at each trimester of the pregnancy [1st (11-14 weeks), 2nd (19 22 weeks) and 3rd (28-32 weeks) trimesters]. The response variable was denoted as index d, in a subject with hypertensive status h (hypertensive or normotensive), at continuous time t. RESULTS: In both groups, AoF-PI and AoF-RI showed a small, but significant increase from the first to the second (1.850 +/- 0.339 vs 2.110 +/- 0.242 for PI, and 0.829 +/- 0.068 vs 0.857 +/- 0.038 for RI; p < 0.001) and the first to the third (1.850 +/- 0.339 vs 2.163 +/- 0.282 for PI, and 0.829 +/- 0.068 vs 0.864 +/- 0.037 for RI; p < 0.001) trimesters of pregnancy. The global model showed that while AoF-RI trends were converging as time progressed, the AoF PI values exhibited a divergent trend (p < 0.05). CONCLUSIONS: Chronic stable hypertension in pregnancies with normal outcome, evidences an upward regular trend of foetal descending aorta pulsatility index that is similar to the normotensive condition. PMID- 24468129 TI - Severe asthma exacerbation in an intermediate respiratory care unit: fact or controversy? PMID- 24468130 TI - Can pulse transit time be useful for detecting hypertension in patients in a sleep unit? AB - INTRODUCTION: Pulse transit time (PTT) is the time that a pulse wave takes to travel between two different arterial points, and may be useful in estimating blood pressure. This noninvasive technique, which does not add any cost to the procedure, offers the advantage of avoiding 'arousals' during sleep measurement as occurs with ambulatory blood pressure monitoring (ABPM). We aim to confirm the usefulness of PTT for the detection of hypertension, and to study the correlation between both measurements. METHODS: Prospective observational study in a multidisciplinary sleep unit. We recruited 30consecutive patients attending a sleep clinic and ran a baseline polysomnography followed by an ABPM the following day. Average systolic and diastolic blood pressure (SBP, DBP) by PTT were calculated and compared with ABMP results. In accordance with international guidelines, patients with mean nocturnal ABMP >= 120/70 mmHg were diagnosed as having arterial hypertension. RESULTS: Mean age of 60years; 66% male, 80% suffered from sleep apnoea (OSAS). Taking the ABPM as the reference technique, we found that the diagnostic sensitivity of PTT is 85% with a specificity of 88% in the case of SBP, with a positive predictive value of 85% and negative predictive value of 88%. By studying the relationship between mean SBP measured by ABPM and PTT, we found a linear correlation coefficient (R) of 0.88, showing a distribution of all subjects with a difference of between +/-15mmHg between tests. There is also a positive correlation between mean DBP measured for the two tests, with a weaker linear correlation. CONCLUSIONS: Pulse transit time shows a strong correlation with blood pressure (measured by ABPM). PTT provides continuous, non-invasive, cuffless blood pressure monitoring free of additional cost and could be an alternative for screening hypertension. PMID- 24468132 TI - Cyclin D1 amplification in multiple myeloma is associated with multidrug resistance expression. AB - BACKGROUND: Cyclin D1 is involved in normal regulation of the cell cycle and in neoplasia. Inhibition of cyclin D1 function markedly attenuates the proliferation of fibroblasts of colon, esophageal, lung, and pancreatic cancer. However, the prognostic value of overexpression of cyclin D1 in multiple myeloma is still a point of debate. This study aimed at evaluating the effect of cyclin D1 gene amplification in multiple myeloma on overall survival and response to therapy. PATIENTS AND METHODS: Fifty patients with multiple myeloma were retrospectively studied. Cyclin D1 gene amplification was studied in bone marrow biopsies of these patients using FISH. An immunohistochemical study of the bone marrow biopsies was done to detect MDR1 protein expression. The correlations between the cyclin D1 gene amplification and overall survival and MDR1 expression were studied and analyzed statistically. RESULTS: Cyclin D1 gene amplification was found in 20% of myeloma patients and was associated with higher percentage of plasma cell infiltration of the bone marrow and increased liability for multiple osteolytic lesions. Cyclin D1-positive patients had a significantly lower progression-free and overall survival and higher levels of MDR1 compared with cyclin D1-negative patients. Cyclin D1 levels showed a highly statistically significant positive correlation with MDR1 levels (R, 0.8 and P < .0001). CONCLUSION: We suggest that there is an association between cyclin D1 gene amplification and disease severity, unfavorable prognosis, and increased expression of MDR1 in multiple myeloma patients. PMID- 24468131 TI - Pharmacological profiles of acute myeloid leukemia treatments in patient samples by automated flow cytometry: a bridge to individualized medicine. AB - BACKGROUND: We have evaluated the ex vivo pharmacology of single drugs and drug combinations in malignant cells of bone marrow samples from 125 patients with acute myeloid leukemia using a novel automated flow cytometry-based platform (ExviTech). We have improved previous ex vivo drug testing with 4 innovations: identifying individual leukemic cells, using intact whole blood during the incubation, using an automated platform that escalates reliably data, and performing analyses pharmacodynamic population models. PATIENTS AND METHODS: Samples were sent from 24 hospitals to a central laboratory and incubated for 48 hours in whole blood, after which drug activity was measured in terms of depletion of leukemic cells. RESULTS: The sensitivity of single drugs is assessed for standard efficacy (EMAX) and potency (EC50) variables, ranked as percentiles within the population. The sensitivity of drug-combination treatments is assessed for the synergism achieved in each patient sample. We found a large variability among patient samples in the dose-response curves to a single drug or combination treatment. CONCLUSION: We hypothesize that the use of the individual patient ex vivo pharmacological profiles may help to guide a personalized treatment selection. PMID- 24468133 TI - Novel anti-inflammatory function of NSC95397 by the suppression of multiple kinases. AB - NSC95397 (2,3-bis-[(2-hydroxyethyl)thio]-1,4-naphthoquinone) is a CDC25 inhibitor with anti-cancer properties. Since the anti-inflammatory activity of this compound has not yet been explored, the aim of this study was to examine whether this compound is able to modulate the inflammatory process. Toll like receptor (TLR)-mediated inflammatory responses were induced by lipopolysaccharide (LPS), a TLR4 ligand, and pam3CSK, a TLR2 ligand, in peritoneal macrophages and RAW264.7. The molecular mechanism of NSC95397's anti-inflammatory activity was studied using immunoblotting analysis, nuclear fractionation, immunoprecipitation, overexpression strategies, luciferase reporter gene assays, and kinase assays. NSC95397 dose-dependently suppressed the production of nitric oxide (NO), tumor necrosis factor (TNF)-alpha, and prostaglandin (PG)E2, and diminished the mRNA expression of inflammatory genes such as inducible NO synthase (iNOS), cyclooxygenase (COX)-2, interferon (IFN)-beta, and TNF-alpha in peritoneal macrophages and RAW264.7 cells that were stimulated by LPS and pam3CSK. This compound also clearly blocked the activation of NF-kappaB (p65), AP-1 (c-Fos/c Jun), and IRF-3 in LPS-treated RAW264.7 cells and TRIF- and MyD88-overexpressing HEK293 cells. In addition, biochemical and molecular approaches revealed that this compound targeted AKT, IKKalpha/beta, MKK7, and TBK1. Therefore, these results suggest that the anti-inflammatory function of NSC95397 can be attributed to its inhibition of multiple targets such as AKT, IKKalpha/beta, MKK7, and TBK1. PMID- 24468134 TI - Genomics for clinical utility: the future is near. AB - A REPORT ON THE PRECISION MEDICINE: Personal Genomes and Pharmacogenomics meeting, Cold Spring Harbor Laboratory, USA, November 13-16, 2013. PMID- 24468135 TI - Age-associated cardiovascular risk and metabolomics of mitochondrial dysfunction. PMID- 24468136 TI - Metabolomics signature improves the prediction of cardiovascular events in elderly subjects. AB - AIMS: Age is one of the most important determinants of cardiovascular health, therefore the management of cardiovascular diseases (CVD) in elderly people entails great challenge. A possible explanation of vascular senescence process is the mitochondrial damage and dysfunction. We hypothesized that metabolomic profiling would identify biomarkers predicting major cardiovascular events (MACEs) in elderly people, improving the clinical standard cardiovascular risk factors. METHODS AND RESULTS: Targeted-mass-spectrometry-based profiling of 49 metabolites was performed in a group of very old participants (n = 67, mean age = 85 +/- 3 years) with a high rate of previous CVD (68%). Principal Component Analysis, Random Survival Forest analysis and Cox proportional hazards regression modeling were used to evaluate the relation between the metabolite factors and recurring MACEs. We tested discrimination ability and reclassification of clinical and metabolomic models. At follow-up (median = 3.5 years), 17 MACEs occurred (5 cardiovascular deaths, 1 nonfatal myocardial infarction, 7 nonfatal strokes and 4 peripheral artery surgeries) (incidence = 7.3% person-years). Metabolite factor 1, composed by medium- and long-chain acylcarnitines, and factor 7 (alanine) were independently associated with MACEs, after adjustment for clinical CV covariates [HR = 1.77 (95%CI = 1.11-2.81, p = 0.016) and HR = 2.18 (95%CI = 1.17-4.07, p = 0.014), respectively]. However, only factor 1 significantly increases the prediction accuracy of the Framingham Recurring Coronary-Heart-Disease-Score, with a significant improvement in discrimination (integrated discrimination improvement = 7%, p = 0.01) and correctly reclassifying 41% of events and 37% of non-events resulting in a cNRI = 0.79 (p = 0.005). CONCLUSIONS: Aging mitochondrial dysfunction evaluated by metabolomic profiling is associated with MACEs, independently of standard predictors. PMID- 24468137 TI - Hyperuricemia and risk of stroke: a systematic review and meta-analysis of prospective studies. AB - INTRODUCTION: Hyperuricemia may be associated with an increased risk of stroke, but to date results from prospective studies have been inconsistent. This study aimed to evaluate the association between hyperuricemia and risk of stroke incidence and mortality by performing a meta-analysis. MATERIALS AND METHODS: Studies were identified by searching multiple electronic databases through July 13, 2013, and by reviewing reference lists of obtained articles. Prospective studies reported a multivariate-adjusted estimate, represented as relative risk (RRs) with 95% confidence intervals (CIs) for the association between hyperuricemia and risk of stroke incidence and mortality were eligible. A random effects model was used to compute the pooled risk estimate. RESULTS: A total of fourteen articles including results from 15 prospective studies with 22,571 cases of stroke and 1,042,358 participants were included in the meta-analysis. Overall, presence of hyperuricemia was associated with a significantly greater risk of both stroke incidence (RR, 1.22; 95% CI, 1.02-1.46) and mortality (RR, 1.33; 95% CI, 1.24-1.43). In addition, the pooled estimate of multivariate RRs of stroke incidence and mortality were 1.08 (95% CI: 0.85-1.38); 1.26 (95% CI: 1.14-1.40) among men and 1.25 (95% CI: 1.04-1.46); 1.41 (95% CI: 1.31-1.52) among women respectively. CONCLUSIONS: Results from this meta-analysis indicate that hyperuricemia may modestly increase the risks of both stroke incidence and mortality. Future studies should explore whether hyperuricemia is a modifiable risk factor for stroke. PMID- 24468138 TI - Combination of plaque burden, wall shear stress, and plaque phenotype has incremental value for prediction of coronary atherosclerotic plaque progression and vulnerability. AB - AIMS: Large plaque burden, certain phenotypes, and low wall shear stress (WSS) are associated with adverse outcomes and high WSS with development of plaque vulnerability. We aimed to investigate the incremental value of the combination of plaque burden, WSS and plaque phenotype for prediction of coronary atherosclerotic plaque progression and vulnerability. METHODS: Twenty patients with CAD underwent baseline and 6-month follow-up coronary virtual histology intravascular ultrasound (VH-IVUS) and computational fluid dynamics modeling for calculation of WSS. Low WSS was defined as <10 dynes/cm(2) and high WSS as >=25 dynes/cm(2). Baseline plaque characteristics and WSS were related to plaque progression and vulnerability. RESULTS: In 2249 VH-IVUS frames analyzed, coronary segments with both plaque burden >40% and low WSS had significantly greater change in plaque area at follow-up (+0.68 +/- 1.05 mm(2)), compared to segments with plaque burden >40% without low WSS (-0.28 +/- 1.32 mm(2)) or segments with low WSS and plaque burden <=40% (+0.05 +/- 0.71 mm(2)) (p = 0.047). Among plaque phenotypes, pathologic intimal thickening (PIT) had the greatest increase in necrotic core (NC) area (p = 0.06) and greatest decrease in fibro-fatty (FF) area (p < 0.0001). At follow-up, compared to segments with either plaque burden >60%, PIT, or high WSS, those with a combination of plaque burden >60%, PIT, and high WSS developed greater increase in NC area (p = 0.002), greater decrease in FF (p = 0.004) and fibrous areas (p < 0.0001), and higher frequency of expansive remodeling (p = 0.019). CONCLUSION: Combination of plaque burden, WSS, and plaque phenotype has incremental value for prediction of coronary plaque progression and increased plaque vulnerability in patients with non-obstructive CAD. PMID- 24468140 TI - Low-grade albuminuria is associated with peripheral artery disease in Chinese diabetic patients. AB - BACKGROUND: Increasing studies have suggested that albuminuria might be an important risk factor for peripheral artery disease (PAD). However, studies focusing on the association between low-grade albuminuria and PAD are limited. It would be of great interest to elucidate the association between low-grade albuminuria and PAD in diabetic subjects. METHODS: A cross-sectional study was conducted in 1386 diabetic subjects (age >= 40 years) with normal urinary albumin levels from Shanghai, China. A first voided early morning spot urine sample was obtained for urinary albumin and creatinine measurements. Subjects were divided into three groups according to sex-specific cutoff points of urinary albumin creatinine ratio (UACR) tertiles. Subjects in the upper tertile of UACR were classified as having low-grade albuminuria. PAD was defined by ankle-brachial index (ABI) <0.9 or >1.4. RESULTS: Overall, 106 (7.7%) of the study population had PAD. The prevalence of PAD in tertile 3 of UACR was higher than the prevalence in tertile 2 and tertile 1 (10.2%, 6.4% and 6.4%, respectively; P < 0.05). A fully adjusted logistic regression analysis revealed that compared with subjects in tertile 1 of normal UACR, those in tertile 3 had 1.7-fold increased risk for the presence of PAD. CONCLUSIONS: In diabetic patients, high normal UACR level, which is below the current cutoff point of microalbuminuria, was associated with the increased prevalence of PAD. It suggested that low-grade albuminuria might be an early marker for the detection of PAD in diabetic patients. PMID- 24468139 TI - Flow patterns regulate hyperglycemia-induced subendothelial matrix remodeling during early atherogenesis. AB - OBJECTIVE: Altered subendothelial matrix composition regulates endothelial dysfunction and early atherosclerotic plaque formation. Hyperglycemia promotes endothelial matrix remodeling associated with multiple microvascular complications of diabetes, but a role for altered matrix composition in diabetic atherogenesis has not been described. Therefore, we sought to characterize the alterations in matrix composition during diabetic atherogenesis using both in vitro and in vivo model systems. METHODS AND RESULTS: Streptozotocin-induced diabetes in atherosclerosis-prone ApoE knockout mice promoted transitional matrix expression (fibronectin, thrombospondin-1) and deposition in intima of the aortic arch as determined by qRT-PCR array and immunohistochemistry. Early plaque formation occurs at discrete vascular sites exposed to disturbed blood flow patterns, whereas regions exposed to laminar flow are protected. Consistent with this pattern, hyperglycemia-induced transitional matrix deposition was restricted to regions of disturbed blood flow. Laminar flow significantly blunted high glucose-induced fibronectin expression (mRNA and protein) and fibronectin fibrillogenesis in endothelial cell culture models, whereas high glucose-induced fibronectin deposition was similar between disturbed flow and static conditions. CONCLUSIONS: Taken together, these data demonstrate that flow patterns and hyperglycemia coordinately regulate subendothelial fibronectin deposition during early atherogenesis. PMID- 24468141 TI - Association of chronic kidney disease categories defined with different formulae with major adverse events in patients with peripheral vascular disease. AB - OBJECTIVE: The aim of this study was to compare the ability of eGFR calculated by modification of diet in renal disease (MDRD), Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) and Lund-Malmo formulae in predicting major adverse events in peripheral vascular disease (PVD) patients. METHODS: We prospectively recruited 2137 patients, measured serum creatinine to calculate eGFR using three different formulae and grouped patients into eGFR categories >=90, 60-89, 45-59, 30-44, 15-29 and <15 ml/min/1.73 m(2). Patients were followed up for a median of 1.3 (inter-quartile range 0.3-3.6) years. The primary outcome was the combined incidence of myocardial infarction, stroke or death. The ability of eGFR categories defined with the different formulae to predict outcome was assessed using the net reclassification index. RESULTS: 1450 (67.9%), 1515 (70.9%) and 1813 (84.8%) patients had eGFR <90 ml/min/1.73 m(2) according to the CKD-EPI, MDRD and Lund-Malmo formulae, respectively. Using the CKD-EPI formula 276 (12.9%) patients were reclassified to a different eGFR category in comparison to the MDRD formula and the prediction of outcome was improved (net reclassification index 0.106, p < 0.001). Using the Lund-Malmo formula 563 (26.3%) patients were reclassified to a different eGFR category in comparison to the MDRD formula and the prediction of outcome was improved (net reclassification index 0.108, p < 0.001). Classification using the CKD-EPI and Lund-Malmo formulae was equally effective at predicting outcome (net reclassification index - 0.002, p = 0.397). CONCLUSIONS: eGFR categories determined with the CKD-EPI and Lund-Malmo formulae are equally effective at predicting major adverse events in patients with PVD. PMID- 24468143 TI - Serum lipid concentrations among persons with spinal cord injury - a systematic review and meta-analysis of the literature. AB - BACKGROUND: Lipid optimization comprises a therapeutic cornerstone of primary and secondary cardiovascular disease prevention. This systematic review and meta analysis sought to clarify patterns of lipid profiles in spinal cord injury (SCI) patients compared to able-bodied individuals as well as among subgroups of SCI patients stratified by sex, activity level, race, and level of injury. METHODS: Searches were conducted in PubMed, CINAHL, PsycINFO, and EMBASE. The initial literature search broadly identified peer-reviewed studies that examined cardiovascular risk factors in SCI. A total of 50 studies were ultimately identified that focused on lipid levels in SCI. Demographic data (including subject age, duration of injury, height, weight, and body mass index [BMI]) and lipid values were extracted for able-bodied individuals and subjects with SCI. Statistical analyses included t-testing and analysis of variance (ANOVA). RESULTS: Compared with controls, individuals with SCI had significantly lower total cholesterol (TC) (183.4 mg/dL versus 194.9 mg/dL, p = 0.019) and high density lipoprotein cholesterol (HDL-C) (41.0 mg/dL versus 49.6 mg/dL, p < 0.001) and higher TC/HDL-C ratios (4.5 versus 4.0, p = 0.002), though no significant differences were found for triglyceride (TG) and non-HDL-C values. CONCLUSIONS: SCI represents an increasingly common chronic condition, now secondarily characterized by heightened CVD risk potentially in part due to unique lipid profiles characterized primarily by low HDL-C and an increased TC/HDL-C ratio. As other at-risk patient populations have received increased acknowledgment with more stringent lipid panel screening at earlier ages and increased frequency, we would propose that the same be implemented for the SCI population until more specific CVD risk stratification guidelines are established for this population. PMID- 24468142 TI - Incremental prognostic value of coronary computed tomographic angiography over coronary artery calcium score for risk prediction of major adverse cardiac events in asymptomatic diabetic individuals. AB - BACKGROUND: Coronary artery disease (CAD) diagnosis by coronary computed tomographic angiography (CCTA) is useful for identification of symptomatic diabetic individuals at heightened risk for death. Whether CCTA-detected CAD enables improved risk assessment of asymptomatic diabetic individuals beyond clinical risk factors and coronary artery calcium scoring (CACS) remains unexplored. METHODS: From a prospective 12-center international registry of 27,125 individuals undergoing CCTA, we identified 400 asymptomatic diabetic individuals without known CAD. Coronary stenosis by CCTA was graded as 0%, 1-49%, 50-69%, and >=70%. CAD was judged on a per-patient, per-vessel and per-segment basis as maximal stenosis severity, number of vessels with >=50% stenosis, and coronary segments weighted for stenosis severity (segment stenosis score), respectively. We assessed major adverse cardiovascular events (MACE) - inclusive of mortality, nonfatal myocardial infarction (MI), and late target vessel revascularization >=90 days (REV) - and evaluated the incremental utility of CCTA for risk prediction, discrimination and reclassification. RESULTS: Mean age was 60.4 +/- 9.9 years; 65.0% were male. At a mean follow-up 2.4 +/- 1.1 years, 33 MACE occurred (13 deaths, 8 MI, 12 REV) [8.25%; annualized rate 3.4%]. By univariate analysis, per-patient maximal stenosis [hazards ratio (HR) 2.24 per stenosis grade, 95% confidence interval (CI) 1.61-3.10, p < 0.001], increasing numbers of obstructive vessels (HR 2.30 per vessel, 95% CI 1.75-3.03, p < 0.001) and segment stenosis score (HR 1.14 per segment, 95% CI 1.09-1.19, p < 0.001) were associated with increased MACE. After adjustment for CAD risk factors and CACS, maximal stenosis (HR 1.80 per grade, 95% CI 1.18-2.75, p = 0.006), number of obstructive vessels (HR 1.85 per vessel, 95% CI 1.29-2.65, p < 0.001) and segment stenosis score (HR 1.11 per segment, 95% CI 1.05-1.18, p < 0.001) were associated with increased risk of MACE. Beyond age, gender and CACS (C-index 0.64), CCTA improved discrimination by maximal stenosis, number of obstructive vessels and segment stenosis score (C-index 0.77, 0.77 and 0.78, respectively). Similarly, CCTA findings improved risk reclassification by per-patient maximal stenosis [integrated discrimination improvement (IDI) index 0.03, p = 0.03] and number of obstructive vessels (IDI index 0.06, p = 0.002), and by trend for segment stenosis score (IDI 0.03, p = 0.06). CONCLUSION: For asymptomatic diabetic individuals, CCTA measures of CAD severity confer incremental risk prediction, discrimination and reclassification on a per-patient, per-vessel and per-segment basis. PMID- 24468144 TI - High serum alkaline phosphatase in relation to cerebral small vessel disease. AB - OBJECTIVES: Vascular calcification is related with cerebral small vessel disease. We investigated whether alkaline phosphatase (ALP), a marker of vascular calcificiation, is related to cerebral small vessel disease. METHODS: We included 1082 neurologically healthy subjects who underwent brain magnetic resonance image for a routine health checkup. ALP levels were divided into quartiles. We used quantile regression and logistic regression to evaluate the associations of ALP with white matter hyperintensities (WMH), cerebral infarct and cerebral microbleeds. RESULTS: Subjects with higher ALP were more likely to have a large WMH volume. The adjusted difference of WMH volume between the highest and the lowest quartiles was 0.27 mL (95% confidence interval [CI]; 0.22-0.31 mL). In addition, cerebral infarct was more prevalent in subjects with higher ALP. Compared to the lowest quartile, adjusted odds ratios of having cerebral infarct for the highest quartile was 2.60 (95% CI, 1.10-6.10). No association was found between ALP and cerebral microbleeds. In addition, we found a conjoint effect of ALP and C-reactive protein(CRP) on cerebral small vessel disease. Compared with subjects with low ALP (<=63 IU/L) and low CRP (<=0.5 mg/dl), those with high ALP (>63 IU/L) and high CRP (>0.5 mg/dl) had larger WMH volume (adjusted difference 0.39 mL; 95% CI 0.37-0.42 mL) and a 3-fold (adjusted OR. 3.37; 95% CI, 1.61-7.03) risk of cerebral infarct. CONCLUSION: We found that higher serum levels of ALP are independently associated with WMH and cerebral infarct, but not with cerebral microbleeds. PMID- 24468145 TI - Physical activity, ethnicity and cardio-metabolic health: does one size fit all? AB - A large and consistent body of epidemiological evidence indicates that low levels of physical activity, low levels of cardiorespiratory fitness and high levels of sedentary behaviour are associated with increased risk of cardio-metabolic diseases. However, most such studies have been undertaken in populations of White European descent. The available data from non-White populations suggests that physical activity is also protective in these groups, but the threshold level of activity needed to confer low risk, particularly for type 2 diabetes, may not be the same across all ethnic groups. In patients with impaired glucose regulation, lifestyle interventions, including physical activity as a component (often in combination with weight loss), are effective at reducing risk of incident diabetes across a range of ethnic groups. However, the optimal levels of physical activity for prevention of diabetes and cardiovascular disease amongst the general populations of different ethnic groups have not been firmly established. Emerging data suggest that innate differences in cardiorespiratory fitness levels and capacity for fat oxidation potentially contribute to ethnic differences in the cardio-metabolic risk profile and that ethnicity-specific physical activity guidelines may be conceptually warranted. More study is needed to understand how and why the dose-response relationship between physical activity and cardio metabolic risk differs according to ethnicity and to determine the best approaches to promote physical activity in non-White ethnic groups. PMID- 24468146 TI - Omega-6 and omega-3 polyunsaturated fatty acid levels are reduced in whole blood of Italian patients with a recent myocardial infarction: the AGE-IM study. AB - OBJECTIVE: The relationship between whole blood fatty acids and myocardial infarction (MI) risk has not been analyzed in detail, especially in Mediterranean countries. The AGE-IM (Acidi Grassi Essenziali e Infarto Miocardico) study was planned to examine the relationships between MI, whole blood fatty acids and the diet in an Italian cohort. METHODS: 119 Patients with a recent MI and 103 control subjects were enrolled in the study. The whole blood fatty acid composition was determined; information on anthropometrics, biochemical parameters and blood pressure values were also obtained. Diet composition was assessed using a validated food frequency questionnaire from 86 cases and 72 controls. RESULTS: Total PUFA, omega-6 and omega-3 PUFA (as percentage of whole blood fatty acids) were significantly lower in MI patients than in matched controls, whereas saturated and monounsaturated fatty acids were higher in cases. MI infarction risk significantly and steadily decreased with increasing levels of total PUFA (OR: 0.14) and of total omega-6 and omega-3 (OR: 0.15 and 0.37, respectively). No correlation was identified between dietary fats and MI risk or between whole blood fatty acid levels and dietary nutrients and fats. CONCLUSION: Percentage levels of total PUFA, total omega-3 PUFA and total omega-6 PUFA are lower in MI patients than in matched control subjects in the AGE-IM cohort. These data support a favorable association not only of whole blood percentage levels of total omega-3, but also of total omega-6, with cardiovascular risk. PMID- 24468147 TI - Effect of smoking and other traditional risk factors on the onset of coronary artery calcification: results of the Heinz Nixdorf recall study. AB - BACKGROUND: Coronary artery calcium (CAC) indicates coronary atherosclerosis and can be present in very early stages of the disease. The conversion from no CAC to any CAC reflects an important step of the disease process as cardiovascular risk is increased in persons even with mildly elevated CAC. We sought to identify risk factors that determined incident CAC>0 in men and women from an unselected general population with a special focus on the role of smoking. METHODS: All 4814 persons that were initially studied in the Heinz Nixdorf Recall Study were invited to participate in the follow-up examination after 5.1 +/- 0.3 years. All traditional Framingham risk factors were quantified using standard techniques. Smokers were categorized in never, former and present smokers. The CAC scores were measured from EBCT using the Agatston method. RESULTS: Overall, out of 342 men and 919 women with zero CAC at baseline, 107 (31.3%) men and 210 (22.9%) women had CAC>0 at second examination. In multivariable analysis, age (OR estimate per 5 years: 1.34 (95%CI: 1.21-1.47)), LDL cholesterol (per 10 mg/dL: 1.05 (95%CI: 1.01-1.10)), systolic blood pressure (per 10 mmHg: 1.19 (95%CI: 1.11 1.28)) and current smoking (1.49 (95%CI: 1.04-2.15)) were independent predictors of CAC onset. The probability of CAC onset steadily increased with age from 23.3% (men) and 15.3% (women) at age 45-49 years to 66.7% (men) and 42.9% (women) at age 70-74 years. The difference in age-dependent conversion rates was quantified by years between reaching a given level of CAC onset probability. We found a consistent pattern with respect to smoking status: presently (formerly) smoking middle-aged men convert to positive CAC 10 (5) years earlier than never smokers, for women (middle-aged to elderly) this time span is 8 (5) years. CONCLUSION: Several traditional CVD risk factors are associated with CAC onset during 5 years follow-up. CAC onset is accelerated by approximately 10 (5) years for present (former) compared to never smokers. PMID- 24468149 TI - Advanced atherosclerosis is associated with increased medial degeneration in sporadic ascending aortic aneurysms. AB - OBJECTIVE: The pathogenesis of non-familial, sporadic ascending aortic aneurysms (SAAA) is poorly understood, and the relationship between ascending aortic atherosclerosis and medial degeneration is unclear. We evaluated the prevalence and severity of aortic atherosclerosis and its association with medial degeneration in SAAA. METHODS AND RESULTS: Atherosclerosis was characterized in ascending aortic tissues collected from 68 SAAA patients (mean age, 62.9 +/- 12.0 years) and 15 controls (mean age, 56.6 +/- 11.4 years [P = 0.07]) by using a modified American Heart Association classification system. Upon histologic examination, 97% of SAAA patients and 73% of controls showed atherosclerotic changes. Most SAAA samples had intermediate (types 2 and 3, 35%) or advanced atherosclerosis (types >= 4; 40%), whereas most control samples showed minimal atherosclerosis (none or type 1, 80%; P < 0.001 after adjusting for age). In a separate analysis, we examined the total incidence and grade distribution of medial degenerative changes among SAAA samples according to atherosclerosis grade. Advanced atherosclerosis was associated with higher grades of smooth muscle cell depletion (P < 0.001), elastic fiber depletion (P = 0.02), elastic fiber fragmentation (P < 0.001), and mucopolysaccharide accumulation (P = 0.04). Aortic diameter was larger in SAAA patients with advanced atherosclerosis than in patients with minimal (P = 0.04) or intermediate atherosclerosis (P = 0.04). Immunostaining showed marked CD3+ T-cell and CD68+ macrophage infiltration, MMP-2 and MMP-9 production, and cryopyrin expression in the medial layer adjacent to atherosclerotic plaque. CONCLUSIONS: SAAA tissues exhibited advanced atherosclerosis that was associated with severe medial degeneration and increased aortic diameter. Our findings suggest a role for atherosclerosis in the progression of sporadic ascending aortic aneurysms. PMID- 24468148 TI - Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease. AB - OBJECTIVE: This EAS Consensus Panel critically appraised evidence relevant to the benefit to risk relationship of functional foods with added plant sterols and/or plant stanols, as components of a healthy lifestyle, to reduce plasma low-density lipoprotein-cholesterol (LDL-C) levels, and thereby lower cardiovascular risk. METHODS AND RESULTS: Plant sterols/stanols (when taken at 2 g/day) cause significant inhibition of cholesterol absorption and lower LDL-C levels by between 8 and 10%. The relative proportions of cholesterol versus sterol/stanol levels are similar in both plasma and tissue, with levels of sterols/stanols being 500-/10,000-fold lower than those of cholesterol, suggesting they are handled similarly to cholesterol in most cells. Despite possible atherogenicity of marked elevations in circulating levels of plant sterols/stanols, protective effects have been observed in some animal models of atherosclerosis. Higher plasma levels of plant sterols/stanols associated with intakes of 2 g/day in man have not been linked to adverse effects on health in long-term human studies. Importantly, at this dose, plant sterol/stanol-mediated LDL-C lowering is additive to that of statins in dyslipidaemic subjects, equivalent to doubling the dose of statin. The reported 6-9% lowering of plasma triglyceride by 2 g/day in hypertriglyceridaemic patients warrants further evaluation. CONCLUSION: Based on LDL-C lowering and the absence of adverse signals, this EAS Consensus Panel concludes that functional foods with plant sterols/stanols may be considered 1) in individuals with high cholesterol levels at intermediate or low global cardiovascular risk who do not qualify for pharmacotherapy, 2) as an adjunct to pharmacologic therapy in high and very high risk patients who fail to achieve LDL C targets on statins or are statin- intolerant, 3) and in adults and children (>6 years) with familial hypercholesterolaemia, in line with current guidance. However, it must be acknowledged that there are no randomised, controlled clinical trial data with hard end-points to establish clinical benefit from the use of plant sterols or plant stanols. PMID- 24468150 TI - Family history of coronary heart disease and the incidence and progression of coronary artery calcification: Multi-Ethnic Study of Atherosclerosis (MESA). AB - OBJECTIVE: We evaluated family history as a predictor of incident and progressive coronary artery calcium (CAC) using data from the Multi-Ethnic Study of Atherosclerosis (MESA). BACKGROUND: MESA is a multi-center prospective study of 6814 asymptomatic individuals. The relationship between family history of coronary heart disease (CHD) and CAC incidence or progression has not been described previously. METHODS: A total of 5099 participants had detailed information about family history of CHD (late versus premature and parental versus sibling history). The mean time between CAC scans was 3.1 +/- 1.3 years. The association of late versus premature family history was assessed against CAC change using multivariate regression model adjusted for demographics and cardiac risk factors. RESULTS: A family history of premature CHD was associated with an odds ratio (OR) of 1.55 (p < 0.01) for incident development of CAC after adjusting for risk factors and demographics. A premature family history was associated with 14.4 units (p < 0.01) greater volume scores compared to those with no family history in similarly adjusted models by median regression analysis. A combined parental and sibling family history was associated with the greatest incidence and progression in demographic-adjusted models. Caucasians demonstrated the most consistent predictive relationship between family history of premature CHD and incidence (p < 0.01) and progression (p < 0.05) of CAC, though no significant interaction with ethnicity was noted. CONCLUSIONS: Family history of premature CHD is associated with enhanced development and progression of subclinical disease, independent of other risk factors, in a multiethnic, population-based study. PMID- 24468151 TI - Myeloperoxidase levels predict accelerated progression of coronary atherosclerosis in diabetic patients: insights from intravascular ultrasound. AB - OBJECTIVE: While inflammation has been proposed to contribute to the adverse cardiovascular outcome in diabetic patients, the specific pathways involved have not been elucidated. The leukocyte derived product, myeloperoxidase (MPO), has been implicated in all stages of atherosclerosis. The relationship between MPO and accelerated disease progression observed in diabetic patients has not been studied. METHODS: We investigated the relationship between MPO and disease progression in diabetic patients. 881 patients with angiographic coronary artery disease underwent serial evaluation of atherosclerotic burden with intravascular ultrasound. Disease progression in diabetic (n = 199) and non-diabetic (n = 682) patients, stratified by baseline MPO levels was investigated. RESULTS: MPO levels were similar in patients with and without diabetes (1362 vs. 1255 pmol/L, p = 0.43). No relationship was observed between increasing quartiles of MPO and either baseline (p = 0.81) or serial changes (p = 0.43) in levels of percent atheroma volume (PAV) in non-diabetic patients. In contrast, increasing MPO quartiles were associated with accelerated PAV progression in diabetic patients (p = 0.03). While optimal control of lipid and the use of high-dose statin were associated with less disease progression, a greater benefit was observed in diabetic patients with lower compared with higher MPO levels at baseline. CONCLUSIONS: Increasing MPO levels are associated with greater progression of atherosclerosis in diabetic patients. This finding indicates the potential importance of MPO pathways in diabetic cardiovascular disease. PMID- 24468152 TI - Long-chain n-3 polyunsaturated fatty acids intake and cardiovascular disease mortality risk in Japanese: a 24-year follow-up of NIPPON DATA80. AB - BACKGROUND: Dietary intake of long-chain n-3 PUFA (LCn3FA) among Japanese is generally higher than that in Western populations. However, little is known whether an inverse association of LCn3FA with cardiovascular disease (CVD) risk exists in a population with higher LCn3FA intake. OBJECTIVE: To investigate the association between LCn3FA intake and the long-term risk of CVDs in a Japanese general population. METHODS: We followed-up a total of 9190 individuals (56.2% women, mean age 50.0 years) randomly selected from 300 areas across Japan and free from CVDs at baseline. Dietary LCn3FA intake was estimated using household weighed food records. Cox models were used to calculate multivariate-adjusted hazard ratios (HR) and confidence intervals (CI) according to sex specific quartiles of LCn3FA intake. RESULTS: During 24-year follow-up (192,897 person years), 879 cardiovascular deaths were observed. The median daily intake of LCn3FA was 0.37% kcal (0.86 g/day). Adjusted HR for CVD mortality was lower in the highest quartile of LCn3FA intake (HR 0.80; 95% CI 0.66-0.96) compared with the lowest quartile, and the trend was statistically significant (P = 0.038). The similar but statistically non-significant trends were observed for coronary heart disease death and stroke death. In analyses by age groups, the inverse associations of LCn3FA intake with the risk of total CVD death and stroke death were significant in younger individuals (30-59 years at baseline). CONCLUSION: LCn3FA intake was inversely and independently associated the long-term risk of total CVD mortality in a representative sample of Japanese with high LCn3FA intake. PMID- 24468153 TI - Cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male LDL receptor knockout mice. AB - OBJECTIVE: It is generally assumed that hepatic inflammation in obesity is linked to the pathogenesis of insulin resistance. Several recent studies have shed doubt on this view, which questions the causality of this association. This study focuses on Kupffer cell-mediated hepatic inflammation as a possible driver of insulin resistance in the absence and presence of obesity. METHODS: We used male mice deficient for the low-density lipoprotein receptor (Ldlr(-/-)) and susceptible to cholesterol-induced hepatic inflammation. Whole body and hepatic insulin resistance was measured in mice fed 4 diets for 2 and 15 weeks, i.e., chow, high-fat (HF), HF-cholesterol (HFC; 0.2% cholesterol) and HF without cholesterol (HFnC). Biochemical parameters in plasma and liver were measured and inflammation was determined using immunohistochemistry and RT-PCR. RESULTS: At 2 weeks, we did not find significant metabolic effects in either diet group, except for the mice fed a HFC diet which showed pronounced hepatic inflammation (p < 0.05) but normal insulin sensitivity. At 15 weeks, a significant increase in insulin levels, HOMA-IR, and hepatic insulin resistance was observed in mice fed a HFC, HFnC, and HF diet compared to chow-fed mice (p < 0.05). Regardless of the level of hepatic inflammation (HFC > HF, HFnC; p < 0.05) insulin resistance in mice fed HFC was no worse compared to mice on a HFnC and HF diet. CONCLUSION: These data show that cholesterol-induced hepatic inflammation does not contribute to the development of insulin resistance in male Ldlr(-/-) mice. This study suggests that Kupffer cell-driven hepatic inflammation is a consequence, not a cause, of metabolic dysfunction in obesity. PMID- 24468154 TI - Single sweep three-dimensional carotid ultrasound: reproducibility in plaque and artery volume measurements. AB - BACKGROUND: There is a need for non-invasive and accurate techniques for assessment of severity of atherosclerotic disease in the carotid arteries. Recently an automated single sweep three-dimensional ultrasound (3D US) technique became available. The aims of this study were to evaluate the feasibility and reproducibility of the automated single sweep method in a cohort of patients undergoing clinically indicated carotid ultrasound. METHODS: Consecutive patients with a history of stroke or transient ischemic attack (TIA) and having a plaque in the internal carotid artery (ICA) were recruited for this study. Imaging was performed using a Philips iU 22 ultrasound system equipped with the single sweep volumetric transducer vL 13-5. Analysis was performed offline with software provided by the manufacturer. Two independent observers performed all measurements. RESULTS: Of 137 arteries studied (from 79 patients), plaque and artery volumes could be measured in 106 (77%). Reproducibility of plaque volume measurements was assessed in 82 arteries. Bland-Altman analysis demonstrated good inter-observer reproducibility with limits of agreement -0.06 to +0.07 ml. The mean percentage difference between two observers was 5.6% +/- 6.0%. Reproducibility of artery volume measurement was assessed in 31 cases. Bland Altman analysis demonstrated limits of agreement from -0.15 to +0.15 ml. The mean percentage difference was 6.4 +/- 5.9%. CONCLUSION: The new automated single sweep 3D ultrasound is feasible in the majority of patients. Good reproducibility in plaque and artery volume measurements makes this technique suitable for serial assessment of carotid plaques. PMID- 24468155 TI - Supplementation with carnosine decreases plasma triglycerides and modulates atherosclerotic plaque composition in diabetic apo E(-/-) mice. AB - OBJECTIVE: Carnosine has been shown to modulate triglyceride and glycation levels in cell and animal systems. In this study we investigated whether prolonged supplementation with carnosine inhibits atherosclerosis and markers of lesion stability in hyperglycaemic and hyperlipidaemic mice. METHODS: Streptozotocin induced diabetic apo E(-/-) mice were maintained for 20 weeks, post-induction of diabetes. Half of the animals received carnosine (2g/L) in their drinking water. Diabetes was confirmed by significant increases in blood glucose and glycated haemoglobin, plasma triglyceride and total cholesterol levels, brachiocephalic artery and aortic sinus plaque area; and lower body mass. RESULTS: Prolonged carnosine supplementation resulted in a significant (~20-fold) increase in plasma carnosine levels, and a significant (~23%) lowering of triglyceride levels in the carnosine-supplemented groups regardless of glycaemic status. Supplementation did not affect glycaemic status, blood cholesterol levels or loss of body mass. In the diabetic mice, carnosine supplementation did not diminish measured plaque area, but reduced the area of plaque occupied by extracellular lipid (~60%) and increased both macrophage numbers (~70%) and plaque collagen content (~50%). The area occupied by alpha-actin-positive smooth muscle cells was not significantly increased. CONCLUSIONS: These data indicate that in a well-established model of diabetes-associated atherosclerosis, prolonged carnosine supplementation enhances plasma levels, and has novel and significant effects on atherosclerotic lesion lipid, collagen and macrophage levels. These data are consistent with greater lesion stability, a key goal in treatment of existing cardiovascular disease. Carnosine supplementation may therefore be of benefit in lowering triglyceride levels and suppressing plaque instability in diabetes-associated atherosclerosis. PMID- 24468156 TI - An International Atherosclerosis Society position paper: global recommendations for the management of dyslipidemia: executive summary. PMID- 24468158 TI - Improving the care of high-risk patients: the potential of PCSK9. PMID- 24468157 TI - Corticosterone accelerates atherosclerosis in the apolipoprotein E-deficient mouse. AB - Chronic stress is an important risk factor for atherosclerosis, which is a chief process in the development of cardiovascular disease. Increased circulating levels of corticosterone have been documented in several animal models of chronic stress. However, it remains to be established whether corticosterone is sufficient to exacerbate atherosclerosis. To test this hypothesis, apolipoprotein E (ApoE)-deficient mice were fed a high-fat diet for 13 weeks with exposure to either corticosterone or vehicle in the drinking water (CORT and Con). Corticosterone treatment significantly increased atherosclerotic plaque area at the aortic root. Such exacerbation of atherosclerosis was accompanied by significantly lower levels of circulating white blood cells and serum interleukin 1beta (IL-1beta), and significantly elevated serum concentrations of total cholesterol, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and small dense low-density lipoprotein (sd-LDL) in CORT mice when compared to Con mice. These findings demonstrate that corticosterone is sufficient to exacerbate atherosclerosis in vivo despite its anti-inflammatory properties and that this marked pro-atherogenic phenotype is primarily associated with increased dyslipidaemia. PMID- 24468159 TI - Controlling the depth of anesthesia by a novel positive control strategy. AB - In this paper a positive control law is designed for multi-input positive systems that ensures asymptotic tracking of a desired output reference value. This control law can be viewed as a generalization of another one proposed in the literature for the control of the total mass in SISO compartmental systems, but is suitable for a wider class of positive systems. The controller proposed here is applied to the control of the depth of anesthesia (DoA), by means of the administration of propofol and remifentanil, when using a parameter parsimonious Wiener model recently introduced in the literature. Its performance is illustrated by realistic simulations. PMID- 24468160 TI - Ontology driven decision support for the diagnosis of mild cognitive impairment. AB - In recent years, mild cognitive impairment (MCI) has attracted significant attention as an indicator of high risk for Alzheimer's disease (AD), and the diagnosis of MCI can alert patient to carry out appropriate strategies to prevent AD. To avoid subjectivity in diagnosis, we propose an ontology driven decision support method which is an automated procedure for diagnosing MCI through magnetic resonance imaging (MRI). In this approach, we encode specialized MRI knowledge into an ontology and construct a rule set using machine learning algorithms. Then we apply these two parts in conjunction with reasoning engine to automatically distinguish MCI patients from normal controls (NC). The rule set is trained by MRI data of 187 MCI patients and 177 normal controls selected from Alzheimer's Disease Neuroimaging Initiative (ADNI) using C4.5 algorithm. By using a 10-fold cross validation, we prove that the performance of C4.5 with 80.2% sensitivity is better than other algorithms, such as support vector machine (SVM), Bayesian network (BN) and back propagation (BP) neural networks, and C4.5 is suitable for the construction of reasoning rules. Meanwhile, the evaluation results suggest that our approach would be useful to assist physicians efficiently in real clinical diagnosis for the disease of MCI. PMID- 24468161 TI - Molecular characterization of exosome-like vesicles from breast cancer cells. AB - BACKGROUND: Membrane vesicles released by neoplastic cells into extracellular medium contain potential of carrying arrays of oncogenic molecules including proteins and microRNAs (miRNA). Extracellular (exosome-like) vesicles play a major role in cell-to-cell communication. Thus, the characterization of proteins and miRNAs of exosome-like vesicles is imperative in clarifying intercellular signaling as well as identifying disease markers. METHODS: Exosome-like vesicles were isolated using gradient centrifugation from MCF-7 and MDA-MB 231 cultures. Proteomic profiling of vesicles using liquid chromatography-mass spectrometry (LC MS/MS) revealed different protein profiles of exosome-like vesicles derived from MCF-7 cells (MCF-Exo) than those from MDA-MB 231 cells (MDA-Exo). RESULTS: The protein database search has identified 88 proteins in MDA-Exo and 59 proteins from MCF-Exo. Analysis showed that among all, 27 proteins were common between the two exosome-like vesicle types. Additionally, MDA-Exo contains a higher amount of matrix-metalloproteinases, which might be linked to the enhanced metastatic property of MDA-MB 231 cells. In addition, microarray analysis identified several oncogenic miRNA between the two types vesicles. CONCLUSIONS: Identification of the oncogenic factors in exosome-like vesicles is important since such vesicles could convey signals to non-malignant cells and could have an implication in tumor progression and metastasis. PMID- 24468162 TI - The hidden epidemic of hypertension. AB - The majority of cardiovascular disease (CVD) is caused by risk factors that can be controlled, treated or modified. In terms of attributable deaths, the leading cardiovascular disease risk factor is hypertension. The Australian Health Survey results showed some startling figures-4.6 million adult Australians are hypertensive (>140/90 mmHg). Further, a fifth of the adult population experience hypertension, with more than two out of three not attaining blood pressure target levels. This is despite an estimated cost of $1 billion per annum spent on managing hypertension. It is now well recognised that the level of risk for coronary heart disease is linked to an individual's risk profile. Results indicate that many Australians have multiple risk factors, including hypertension. It could be considered that these numbers provide a proxy indicator of secondary prevention failure. Considerable attention needs to be given to the assessment of the combined risk of those with hypertension enabling effective management of identified, modifiable risk factors. We look forward to presenting the absolute risk profiles when the Australian Health Survey biometric results are released. PMID- 24468163 TI - Aortic annulus rupture during transcatheter aortic valve implantation (TAVI): one ounce of prevention is worth one pound of cure. PMID- 24468165 TI - Diagnostic paracentesis is associated with improved survival among hospitalized patients with cirrhosis. PMID- 24468166 TI - An unusual cause of a pancreatic space-occupying lesion. PMID- 24468167 TI - Azathioprine in early Crohn's disease: time to revisit patient selection and end points for clinical trials and/or azathioprine efficacy? PMID- 24468168 TI - Combination therapy with methotrexate in inflammatory bowel disease: time to COMMIT? PMID- 24468169 TI - Reply: To PMID 23803760. PMID- 24468170 TI - Prevalence of advanced neoplasia in black versus white patients. PMID- 24468171 TI - Microbiome-obesity-liver cancer interaction: senescence of hepatic stellate cells and bile acids play new roles. PMID- 24468172 TI - Broadening the paradigm of mucosal dendritic cell-mediated induction of gut homing on T cells. PMID- 24468173 TI - Right upper quadrant pain in a 21-year-old man. PMID- 24468174 TI - Get the best out of thiopurine therapy. PMID- 24468175 TI - An unusual endoscopic diagnosis. PMID- 24468176 TI - An uncommon cystic lesion of the liver. PMID- 24468177 TI - An uncommon cause of recurrent duodenal intussusception. PMID- 24468178 TI - Shrinking indications for azathioprine in Crohn's disease: a conclusion too premature? PMID- 24468179 TI - Acute dyspnea during diagnostic sigmoidoscopy. PMID- 24468180 TI - Reply: To PMID 23644079. PMID- 24468181 TI - Reply: To PMID 23644079. PMID- 24468182 TI - Early use of azathioprine in Crohn's disease. PMID- 24468183 TI - Differentiating Lynch-like from Lynch syndrome. PMID- 24468184 TI - Hypoglycemia after gastric bypass: the dark side of GLP-1. PMID- 24468185 TI - An exploration of EEG features during recovery following stroke - implications for BCI-mediated neurorehabilitation therapy. AB - BACKGROUND: Brain-Computer Interfaces (BCI) can potentially be used to aid in the recovery of lost motor control in a limb following stroke. BCIs are typically used by subjects with no damage to the brain therefore relatively little is known about the technical requirements for the design of a rehabilitative BCI for stroke. METHODS: 32-channel electroencephalogram (EEG) was recorded during a finger-tapping task from 10 healthy subjects for one session and 5 stroke patients for two sessions approximately 6 months apart. An off-line BCI design based on Filter Bank Common Spatial Patterns (FBCSP) was implemented to test and compare the efficacy and accuracy of training a rehabilitative BCI with both stroke-affected and healthy data. RESULTS: Stroke-affected EEG datasets have lower 10-fold cross validation results than healthy EEG datasets. When training a BCI with healthy EEG, average classification accuracy of stroke-affected EEG is lower than the average for healthy EEG. Classification accuracy of the late session stroke EEG is improved by training the BCI on the corresponding early stroke EEG dataset. CONCLUSIONS: This exploratory study illustrates that stroke and the accompanying neuroplastic changes associated with the recovery process can cause significant inter-subject changes in the EEG features suitable for mapping as part of a neurofeedback therapy, even when individuals have scored largely similar with conventional behavioural measures. It appears such measures can mask this individual variability in cortical reorganization. Consequently we believe motor retraining BCI should initially be tailored to individual patients. PMID- 24468186 TI - Special Section: New developments and applications in the use of algae for monitoring rivers. Foreword. PMID- 24468187 TI - Adaptive traffic management in cities--comparing decision-making methods. AB - Traffic is the dominant source of air pollution in cities. We simulated 'adaptive traffic management' (temporary traffic interventions that are invoked based on preset conditions such as high ambient concentrations) aimed at reducing traffic related air pollution. We compared these results with the effect of permanent temporary traffic interventions (measures that are always invoked for a few hours, irrespective of other criteria). The potential impact of the traffic interventions was assessed using Black Carbon and NOx-concentration observations in a busy urban street in Rotterdam, The Netherlands. Results show that generic traffic information (counts, speed, composition) in combination with general knowledge about the atmospheric conditions, provide sufficient information for operational decision making. However, the results also show that the overall net benefits of temporary measures are very small. The impact of permanent measures such as lowering the traffic density during rush hours is higher than measures taken for short time periods when air pollution is high or expected to be high. PMID- 24468188 TI - Serious long-term health consequences of Q-fever and Legionnaires' disease. AB - BACKGROUND: We assessed and compared the long-term health status of Q-fever patients and patients with Legionnaires' disease. METHODS: Q-fever patients and patients with Legionnaires' disease fulfilling the Dutch notification criteria filled out a questionnaire at one year after onset of illness. The proportion of patients with an abnormal score was calculated for 12 health status subdomains and mean scores for the most relevant subdomains were compared between the patient groups. RESULTS: We included 309 Q-fever patients and 190 patients with Legionnaires' disease in the study. A large proportion of the two patient groups was negatively affected on many of the subdomains, especially 'Fatigue', 'General Quality of Life' and 'Role Physical'. We assessed health status of the patient groups using a multivariate regression analysis and found no significant difference for 'Fatigue' and 'General Quality of Life'. Only for the subdomain 'Role Physical', Q-fever patients scored significantly worse compared to patients with Legionnaires' disease. CONCLUSIONS: Many Q-fever patients and patients with Legionnaires' disease suffer from a severely affected health status on one or more subdomains at one year after onset of illness. We recommend additional support for a large proportion of both patient groups during the first year after onset of illness. PMID- 24468189 TI - Characteristics of nobiletin-induced effects on jejunal contractility. AB - Nobiletin, a citrus polymethoxylated flavone, exhibits multiple biological properties including anti-inflammatory, anti-carcinogenic, and anti-insulin resistance effects. The present study found that nobiletin exerted significant stimulatory effects on the contractility of isolated rat jejunal segments in all 6 different low contractile states, and meanwhile significant inhibitory effects in all 6 different high contractile states, showing characteristics of bidirectional regulation (BR). Nobiletin-exerted BR on jejunal contractility was abolished in the presence of c-kit receptor tyrosine kinase inhibitor imatinib or Ca(2+) channel blocker verapamil. In the presence of neuroxin tetrodotoxin, nobiletin only exerted stimulatory effects on jejunal contractility in both low and high contractile states. Hemicholinium-3 and atropine partially blocked nobiletin-exerted stimulatory effects on jejunal contractility in low-Ca(2+) induced low contractile state. Phentolamine or propranolol or l-NG-nitro-arginine significantly blocked nobiletin-exerted inhibitory effects on jejunal contractility in high-Ca(2+)-induced high contractile state respectively. The effects of nobiletin on myosin light chain kinase (MLCK) mRNA expression, MLCK protein content, and myosin light chain phosphorylation extent were also bidirectional. In summary, nobiletin-exerted BR depends on the contractile states of rat jejunal segments. Nobiletin-exerted BR requires the enteric nervous system, interstitial cell of Cajal, Ca(2+), and myosin phosphorylation-related mechanisms. PMID- 24468190 TI - Dietary flavonoids fisetin and myricetin: dual inhibitors of Plasmodium falciparum falcipain-2 and plasmepsin II. AB - Malaria is one of the most devastating infectious diseases in the developing world. Until now, only one candidate malaria vaccine RTS,S/AS01 has shown modest protection in phase 3 trial in African infants. Hence the treatment of malaria still depends on the current chemotherapeutic drugs. Considering the resistance of malaria parasites to almost all used antimalarial drugs, aiming at multi targets rather than a single target will be a more promising strategy. Previous studies have shown that myricetin and fisetin exhibited in vitro antimalarial activity against Plasmodium falciparum, but very little research focused on the molecular mechanism for their parasiticidal activity. The cysteine protease falcipain-2 and aspartic protease plasmepsin II have long been considered as important antimalarial drug targets, especially combined inhibition of these two proteases. In this study, we determined that myricetin and fisetin are dual inhibitors of falcipain-2 and plasmepsin II, which might account for their antimalarial properties. Overall, the dual inhibition of falcipain-2 and plasmepsin II by myricetin and fisetin has shed light on a possible mechanism for their antimalarial activity and provided a rationale for further development as antimalarial drugs. PMID- 24468191 TI - Baicalein decreases side population proportion via inhibition of ABCG2 in multiple myeloma cell line RPMI 8226 in vitro. AB - OBJECTIVE: To investigate the effect of baicalein on side population in human multiple myeloma cell line RPMI 8226 and the underlying molecular mechanisms in vitro and in silico. METHODS: MTT assay was applied to detect the anti proliferation effect of baicalein. The detection of side population cells is based on the Hoechst 33342 exclusion assay technique and flow cytometric analysis. Western blotting assay was used to explore the expression of ABCG2 protein. Homology modeling and molecular docking were performed with Discovery Studio 2.1. RESULTS: Baicalein decreased both cell viability with IC50=168.5 MUM and the proportion of SP cells in a dose-dependent manner. Correspondingly, it significantly decreased the expression level of ABCG2 protein. Baicalein also shared similar binding sites and modes with fumitremorgin C to the protein. CONCLUSIONS: Baicalein possessed novel anticancer properties, such as anti proliferation and drug efflux inhibition in side population cells, which suggested its potential feature of targeting cancer stem cells of multiple myeloma. PMID- 24468193 TI - Mechanism of metabolic stroke and spontaneous cerebral hemorrhage in glutaric aciduria type I. AB - BACKGROUND: Metabolic stroke is the rapid onset of lasting central neurological deficit associated with decompensation of an underlying metabolic disorder. Glutaric aciduria type I (GA1) is an inherited disorder of lysine and tryptophan metabolism presenting with metabolic stroke in infancy. The clinical presentation includes bilateral striatal necrosis and spontaneous subdural and retinal hemorrhages, which has been frequently misdiagnosed as non-accidental head trauma. The mechanisms underlying metabolic stroke and spontaneous hemorrhage are poorly understood. RESULTS: Using a mouse model of GA1, we show that metabolic stroke progresses in the opposite sequence of ischemic stroke, with initial neuronal swelling and vacuole formation leading to cerebral capillary occlusion. Focal regions of cortical followed by striatal capillaries are occluded with shunting to larger non-exchange vessels leading to early filling and dilation of deep cerebral veins. Blood-brain barrier breakdown was associated with displacement of tight-junction protein Occludin. CONCLUSION: Together the current findings illuminate the pathophysiology of metabolic stroke and vascular compromise in GA1, which may translate to other neurometabolic disorders presenting with stroke. PMID- 24468194 TI - Associations between state regulations, training length, perceived quality and job satisfaction among certified nursing assistants: cross-sectional secondary data analysis. AB - BACKGROUND: In the U.S., there are federal requirements on how much training and annual continuing education a certified nursing assistant must complete in order to be certified. The requirements are designed to enable them to provide competent and quality care to nursing home residents. Many states also require additional training and continuing education hours as improved nursing home quality indicators have been found to be related to increased training. OBJECTIVES: This study investigated the associations among state level regulations, initial training quality and focus, and job satisfaction in certified nursing assistants. DESIGN: Cross-sectional secondary data analysis. SETTINGS: This study used the National Nursing Home Survey and National Nursing Assistant Survey as well as data on state regulations of certified nursing assistant training. PARTICIPANTS: 2897 certified nursing assistants in 580 nursing homes who were currently working at a nursing home facility, who represented 680,846 certified nursing assistants in US. METHODS: State regulations were related to initial training and job satisfaction among certified nursing assistants using chi square tests and binomial logistic regression models. Analyses were conducted using SAS-callable SUDAAN to correct for complex sampling design effects in the National Nursing Home Survey and National Nursing Assistant Survey. Models were adjusted for personal and facility characteristics. RESULTS: Certified nursing assistants reporting high quality training were more likely to work in states requiring additional initial training hours (p=0.02) and were more satisfied with their jobs (OR=1.51, 95% CI=1.09-2.09) than those with low quality training. In addition, those with more training focused on work life skills were 91% more satisfied (OR=1.91, 95% CI=1.41-2.58) whereas no relationship was found between training focused on basic care skills and job satisfaction (OR=1.36, 95% CI=0.99-1.84). CONCLUSIONS: Certified nursing assistants with additional initial training were more likely to report that their training was of high quality, and this was related to job satisfaction. Job satisfaction was also associated with receiving more training that focused on work life skills. Federal training regulations should reconsider additional hours for certified nursing assistant initial training, and include work life skills as a focus. As job satisfaction has been linked to nursing home turnover, attention to training may improve satisfaction, ultimately reducing staff turnover. PMID- 24468196 TI - Comparative evaluation of open source software for mapping between metabolite identifiers in metabolic network reconstructions: application to Recon 2. AB - BACKGROUND: An important step in the reconstruction of a metabolic network is annotation of metabolites. Metabolites are generally annotated with various database or structure based identifiers. Metabolite annotations in metabolic reconstructions may be incorrect or incomplete and thus need to be updated prior to their use. Genome-scale metabolic reconstructions generally include hundreds of metabolites. Manually updating annotations is therefore highly laborious. This prompted us to look for open-source software applications that could facilitate automatic updating of annotations by mapping between available metabolite identifiers. We identified three applications developed for the metabolomics and chemical informatics communities as potential solutions. The applications were MetMask, the Chemical Translation System, and UniChem. The first implements a "metabolite masking" strategy for mapping between identifiers whereas the latter two implement different versions of an InChI based strategy. Here we evaluated the suitability of these applications for the task of mapping between metabolite identifiers in genome-scale metabolic reconstructions. We applied the best suited application to updating identifiers in Recon 2, the latest reconstruction of human metabolism. RESULTS: All three applications enabled partially automatic updating of metabolite identifiers, but significant manual effort was still required to fully update identifiers. We were able to reduce this manual effort by searching for new identifiers using multiple types of information about metabolites. When multiple types of information were combined, the Chemical Translation System enabled us to update over 3,500 metabolite identifiers in Recon 2. All but approximately 200 identifiers were updated automatically. CONCLUSIONS: We found that an InChI based application such as the Chemical Translation System was better suited to the task of mapping between metabolite identifiers in genome-scale metabolic reconstructions. We identified several features, however, that could be added to such an application in order to tailor it to this task. PMID- 24468195 TI - Complement components as potential therapeutic targets for asthma treatment. AB - Asthma is the most common respiratory disorder, and is characterized by distal airway inflammation and hyperresponsiveness. This disease challenges human health because of its increasing prevalence, severity, morbidity, and the lack of a proper and complete cure. Asthma is characterized by T(H)2-skewed inflammation with elevated pulmonary levels of IL-4, IL-5, and IL-13 levels. Although there are early forays into targeting T(H)2 immunity, less-specific corticosteroid therapy remains the immunomodulator of choice. Innate immune injury mediated by complement components also act as potent mediators of the allergic inflammatory responses and offer a new and exciting possibility for asthma immunotherapy. The complement cascade consists of a number of plasma- and membrane-bound proteins, and the cleavage products of these proteins (C3 and C5) regulate the magnitude of adaptive immune responses. Complement protein are responsible for many pathophysiological features of asthma, including inflammatory cell infiltration, mucus secretion, increases in vascular permeability, and smooth muscle cell contraction. This review highlights the complement-mediated injury during asthma inflammation, and how blockade of active complement mediators may have therapeutic application. PMID- 24468197 TI - Tetramer formation in Arabidopsis MADS domain proteins: analysis of a protein protein interaction network. AB - BACKGROUND: MADS domain proteins are transcription factors that coordinate several important developmental processes in plants. These proteins interact with other MADS domain proteins to form dimers, and it has been proposed that they are able to associate as tetrameric complexes that regulate transcription of target genes. Whether the formation of functional tetramers is a widespread property of plant MADS domain proteins, or it is specific to few of these transcriptional regulators remains unclear. RESULTS: We analyzed the structure of the network of physical interactions among MADS domain proteins in Arabidopsis thaliana. We determined the abundance of subgraphs that represent the connection pattern expected for a MADS domain protein heterotetramer. These subgraphs were significantly more abundant in the MADS domain protein interaction network than in randomized analogous networks. Importantly, these subgraphs are not significantly frequent in a protein interaction network of TCP plant transcription factors, when compared to expectation by chance. In addition, we found that MADS domain proteins in tetramer-like subgraphs are more likely to be expressed jointly than proteins in other subgraphs. This effect is mainly due to proteins in the monophyletic MIKC clade, as there is no association between tetramer-like subgraphs and co-expression for proteins outside this clade. CONCLUSIONS: Our results support that the tendency to form functional tetramers is widespread in the MADS domain protein-protein interaction network. Our observations also suggest that this trend is prevalent, or perhaps exclusive, for proteins in the MIKC clade. Because it is possible to retrodict several experimental results from our analyses, our work can be an important aid to make new predictions and facilitates experimental research on plant MADS domain proteins. PMID- 24468198 TI - Effects of diabetes self-management programs on time-to-hospitalization among patients with type 2 diabetes: a survival analysis model. AB - OBJECTIVE: This study compared time-to-hospitalization among subjects enrolled in different diabetes self-management programs (DSMP). We sought to determine whether the interventions delayed the occurrence of any acute event necessitating hospitalization. METHODS: Electronic medical records (EMR) were obtained for 376 adults enrolled in a randomized controlled trial (RCT) of Type 2 diabetes (T2DM) self-management programs. All study participants had uncontrolled diabetes and were randomized into either: personal digital assistant (PDA), Chronic Disease Self-Management Program (CDSMP), combined PDA and CDSMP (COM), or usual care (UC) groups. Subjects were followed for a maximum of two years. Time-to hospitalization was measured as the interval between study enrollment and the occurrence of a diabetes-related hospitalization. RESULTS: Subjects enrolled in the CDSMP-only arm had significantly prolonged time-to-hospitalization (Hazard ratio: 0.10; p=0.002) when compared to subjects in the control arm. Subjects in the PDA-only and combined PDA and CDSMP arms showed no improvements in comparison to the control arm. CONCLUSION: CDSMP can be effective in delaying time-to hospitalization among patients with T2DM. PRACTICE IMPLICATIONS: Reducing unnecessary healthcare utilization, particularly inpatient hospitalization is a key strategy to improving the quality of health care and lowering associated health care costs. The CDSMP offers the potential to reduce time-to hospitalization among T2DM patients. PMID- 24468199 TI - Educational group visits for the management of chronic health conditions: a systematic review. AB - OBJECTIVE: Review the effectiveness of group visits (appointments of multiple patients) on quality of life, function, self-efficacy, utilization, and biophysical outcomes in randomized controlled trials of patients with chronic conditions. METHODS: We searched MEDLINE((r)), Cochrane, CINAHL, and PsycINFO to January 2013 for English-language trials of educational group visits led by non prescribing facilitators (e.g., peer educators). RESULTS: We report on 80 arthritis/falls (n=22), asthma/COPD (n=10), CHF/hypertension (n=12), diabetes (n=29), multiple conditions (n=4), and pain (n=4) studies. We found moderate evidence of improved short-term self-efficacy in patients with arthritis (10 studies) and diabetes (10 studies). We found no consistent evidence of improved quality of life; however a moderately strong body of evidence suggests peer-led community-based programs might improve quality of life and utilization in patients with multiple chronic conditions. Meta-analyses found short- (14 studies; mean change HbA1c=-0.27, CI=-0.44, 0.11) and long-term (10 studies; mean change HbA1c=-0.23, CI=-0.44, -0.02) glycemic improvement. CONCLUSIONS: Group visits may improve self-efficacy and glycemic control. There was little consistent evidence of improved quality of life, functional status, or utilization. PRACTICE IMPLICATIONS: Group visits represent a reasonable alternative for educating patients with chronic illness, though varied participation/retention suggests they should not be the sole alternative. PMID- 24468200 TI - Residents' perceived barriers to communication skills learning: comparing two medical working contexts in postgraduate training. AB - OBJECTIVE: Contextual factors are known to influence the acquisition and application of communication skills in clinical settings. Little is known about residents' perceptions of these factors. This article aims to explore residents' perceptions of contextual factors affecting the acquisition and application of communication skills in the medical workplace. METHOD: We conducted an exploratory study comprising seven focus groups with residents in two different specialities: general practice (n=23) and surgery (n=18). RESULTS: Residents perceive the use of summative assessment checklists that reduce communication skills to behavioural components as impeding the learning of their communication skills. Residents perceive encouragement to deliberately practise in an environment in which the value of communication skills is recognised and support is institutionalised with appropriate feedback from role models as the most important enhancing factors in communication skills learning. CONCLUSION: To gradually realise a clinical working environment in which the above results are incorporated, we propose to use transformative learning theory to guide further studies. PRACTICAL IMPLICATIONS: Provided it is used continuously, an approach that combines self-directed learning with observation and discussion of resident patient consultations seems an effective method for transformative learning of communication skills. PMID- 24468201 TI - Effect on the tensile strength of human acellular dermis (Epiflex(r)) of in-vitro incubation simulating an open abdomen setting. AB - BACKGROUND: The use of human acellular dermis (hAD) to close open abdomen in the treatment process of severe peritonitis might be an alternative to standard care. This paper describes an investigation of the effects of fluids simulating an open abdomen environment on the biomechanical properties of Epiflex(r) a cell-free human dermis transplant. METHODS: hAD was incubated in Ringers solution, blood, urine, upper gastrointestinal (upper GI) secretion and a peritonitis-like bacterial solution in-vitro for 3 weeks. At day 0, 7, 14 and 21 breaking strength was measured, tensile strength was calculated and standard fluorescence microscopy was performed. RESULTS: hAD incubated in all five of the five fluids showed a decrease in mean breaking strength at day 21 when compared to day 0. However, upper GI secretion was the only incubation fluid that significantly reduced the mechanical strength of Epiflex after 21 days of incubation when compared to incubation in Ringer's solution. CONCLUSION: hAD may be a suitable material for closure of the open abdomen in the absence of upper GI leakage and pancreatic fistulae. PMID- 24468202 TI - Prediction for response duration to epidermal growth factor receptor-tyrosine kinase inhibitors in EGFR mutated never smoker lung adenocarcinoma. AB - OBJECTIVES: Among non-small cell lung cancer (NSCLC) patients harboring activating epidermal growth factor receptor (EGFR) mutations, ~ 20-30% exhibit de novo resistance to EGFR-tyrosine kinase inhibitor (TKI). The aim of this study was to examine whether mutations in the EGFR-downstream genes may be associated with de novo resistance to EGFR-TKIs in EGFR mutation-positive patients. MATERIALS AND METHODS: Sixty-eight never-smoker adenocarcinoma patients with an activating EGFR mutation were included in the mutational analysis and 55 patients treated with EGFR-TKIs were analyzed for the treatment outcomes to EGFR-TKIs. We concurrently analyzed mutations in PIK3CA, PTEN, AKT and STK11, which are all EGFR-downstream genes. Mutations in PIK3CA, PTEN, AKT, and STK11 were analyzed by polymerase chain reaction-based sequencing. RESULTS: PIK3CA mutations were detected in 4.4% (3/68) of patients, PTEN mutations in 16.1% (11/68), AKT mutations in 5.9% (4/68), and STK11 mutations in 13.2% (9/68). One patient with an activating exon 21 L858R mutation concomitantly had an exon 20 T790M mutation in EGFR. The proportion of patients who had mutations in EGFR-downstream genes was 32.4% (22/68). When we analyzed the treatment outcome of 55 patients treated with EGFR-TKI, the presence of mutations in EGFR-downstream genes correlated with a poor overall response rate to EGFR-TKIs (63.6 vs.14.5% in patients with mutation in EGFR-downstream gene, P<0.0001), shorter median progression-free survival (12.0 vs. 3.0 months, P=0.060), and shorter median overall survival (18.9 vs. 25.0 months, P=0.048). CONCLUSION: Mutations in the EGFR-downstream genes may confer resistance to EGFR-TKIs and result in poor treatment outcomes in never-smoker adenocarcinoma patients with activating EGFR mutations. PMID- 24468203 TI - Oxytocin's role in anxiety: a critical appraisal. AB - A growing literature suggests that the oxytocin (OT) system may play a role in human anxiety states, anxiety-related traits, and moreover, that this system may be a target for the development of novel anxiolytic treatments. However, studies of OT's acute and chronic effects on various aspects of anxiety have produced mixed results. In this forward-looking review, we discuss the myriad phenomena to which the term "anxiety" is applied in the OT literature and the problem this presents developing a coherent picture of OT's role in anxiety. We then survey several different fields of research that support the role of the OT system in human anxiety, including evolutionary perspectives, translational and neuroimaging research, genetic studies, and clinical trials of intranasal OT. As an outgrowth of this data, we propose a "bowtie" model of OT's role at the interface of social attachment and anxiety. We next direct attention to understudied brain regions and neural circuits which may be important to study in OT experiments in humans anxiety disorders. Finally, we conclude by proposing questions and priorities for studying both the clinical potential of OT in anxiety, as well as mechanisms that may underlie this potential. Crucially, these priorities include targeted proof-of-concept clinical trials of IN OT in certain anxiety disorders, including investigations of individual moderators of OT's anxiolytic effects (i.e. sex, genetic factors, and early experience). This article is part of a Special Issue entitled Oxytocin and Social Behav. PMID- 24468204 TI - Distinct roles of the hippocampus and perirhinal cortex in GABAA receptor blockade-induced enhancement of object recognition memory. AB - It is well known that the hippocampus plays a role in spatial and contextual memory, and that spatial information is tightly regulated by the hippocampus. However, it is still highly controversial whether the hippocampus plays a role in object recognition memory. In a pilot study, the administration of bicuculline, a GABAA receptor antagonist, enhanced memory in the passive avoidance task, but not in the novel object recognition task. In the present study, we hypothesized that these different results are related to the characteristics of each task and the different roles of hippocampus and perirhinal cortex. A region-specific drug treatment model was employed to clarify the role of the hippocampus and perirhinal cortex in object recognition memory. After a single habituation in the novel object recognition task, intra-perirhinal cortical injection of bicuculline increased and intra-hippocampal injection decreased the exploration time ratio to novel object. In addition, when animals were repeatedly habituated to the context, intra-perirhinal cortical administration of bicuculline still increased exploration time ratio to novel object, but the effect of intra-hippocampal administration disappeared. Concurrent increases of c-Fos expression and ERK phosphorylation were observed in the perirhinal cortex of the object with context exposed group either after single or repeated habituation to the context, but no changes were noted in the hippocampus. Altogether, these results suggest that object recognition memory formation requires the perirhinal cortex but not the hippocampus, and that hippocampal activation interferes with object recognition memory by the information encoding of unfamiliar environment. PMID- 24468205 TI - Poor breakfast habits in adolescence predict the metabolic syndrome in adulthood. AB - OBJECTIVE: To analyse whether poor breakfast habits in adolescence predict the metabolic syndrome and its components in adulthood. Previous studies suggest that regular breakfast consumption improves metabolic parameters. DESIGN: Prospective. Breakfast habits and other lifestyle variables at age 16 years were assessed from questionnaires. Poor breakfast habits were defined as skipping breakfast or only drinking or eating something sweet. At age 43 years, the effective sample consisted of 889 participants defined as having the metabolic syndrome or not, using the International Diabetes Federation criteria. Logistic regression was used to calculate odds ratios and confidence intervals. SETTING: The Northern Swedish Cohort, a longitudinal population-based cohort with 27-year follow-up. SUBJECTS: Adolescents (age 16 years). RESULTS: Prevalence of the metabolic syndrome at age 43 years was 27.0 %. Of the participants, 9.9 % were classified with poor breakfast habits at age 16 years. Adjusted odds for the metabolic syndrome at age 43 years was OR = 1.68 (95 % CI 1.01, 2.78) for those with poor breakfast habits at age 16 years compared with breakfast eaters. Looking at the metabolic syndrome components, poor breakfast habits at age 16 years were associated with central obesity (OR = 1.71; 95 % CI 1.00, 2.92) and high fasting glucose (OR = 1.75; 95 % CI 1.01, 3.02) at age 43 years, even after multivariate adjustments. CONCLUSIONS: Poor breakfast habits in adolescence predicted the metabolic syndrome in adulthood. Of the metabolic syndrome components, poor breakfast habits in adolescence predicted central obesity and high fasting glucose in adulthood. Further research is needed to fully understand the relationship between early breakfast habits and adult metabolic syndrome. PMID- 24468207 TI - MRI strain imaging of the carotid artery: present limitations and future challenges. AB - Rupture of atherosclerotic plaques in the carotid artery is a main cause of stroke. Current diagnostics are not sufficient to identify all rupture-prone plaques, and studies have shown that biomechanical factors improve current plaque risk assessment. Strain imaging may be a valuable contribution to this risk assessment. MRI is a versatile imaging technique that offers various methods that are capable of measuring tissue strain. In this review, MR imaging techniques with displacement (DENSE), velocity (PC MRI), or strain (SENC) encoding protocols are discussed, together with post-processing techniques based on time-resolved MRI data. Although several MRI techniques are being developed to improve time resolved MR imaging, current technical limitations related to spatial and temporal resolutions render MRI strain imaging currently unfit for carotid plaque strain evaluation. A novel approach using non-rigid image registration of MR images to determine strain in carotid arteries based on black blood cine MRI is proposed in this review. This and other post-processing techniques based on time resolved MRI data may provide a good estimate of plaque strain, but are also dependent on the spatial and temporal resolution of the MR images. However, they seem to be the most promising approach for MRI based plaque strain analysis in the near future. PMID- 24468208 TI - Influence of plaque calcifications on coronary stent fracture: a numerical fatigue life analysis including cardiac wall movement. AB - Coronary stent fracture is still an unresolved issue in the field of minimally invasive cardiovascular interventions due to its high rate of incidence and uncertain clinical consequences. Recent studies, based on clinical data, proved that there are several factors which can be identified as independently responsible of coronary stent fracture. Among these, calcifications, which increase the local stiffness and heterogeneity of atherosclerotic plaques, seem to play a major role. From a mechanical point of view, stent fracture in coronary arteries is triggered by the cyclic loading of pulsatile blood pressure combined with the movement of cardiac wall. In this context, this study aims at simulating the stent expansion in a model of epicardial atherosclerotic coronary artery and correlating the effects of cyclic blood pressure and cardiac wall movement on the stent fatigue resistance. Two ideal cases of atherosclerotic plaques were modelled: the first one included a localised plaque calcification; the latter one did not include such calcification. Results of stress/strain and fatigue analyses confirmed the influence of the plaque calcification on potential fracture of the devices. In addition, the effects of cardiac wall movement were quantified as more dangerous causes of the stent fatigue fracture with respect to the internal blood pressure oscillations. In conclusion, this study demonstrates the increased risk of coronary stent fracture associated to the presence of localised plaque calcifications. This work also suggests the necessity of more realistic biomechanical models which takes into account the heterogeneity of atherosclerotic plaques in order to assess the mechanical performances of coronary stents. PMID- 24468209 TI - Free-living bodonids and derived parasitic trypanosomatids: but what lies in between? AB - Inclusion of suitable out-group taxa has been of particular importance in accurate reconstruction of evolutionary relationships among trypanosomatids. However, the persistence of researchers focusing on insect trypansomatids appears to have paid off, and a novel, apparently-monoxenous parasite isolated from mosquitoes has recently been characterised. Critically, phylogenetic and phylogenomic analyses robustly position this new species, Paratrypanosoma confusum, between free-living bodonid out-group taxa and other trypanosomatids, thereby overcoming some of the issues associated with previously utilised out groups. PMID- 24468210 TI - Reporting haemostatic protein measurements: the time has come to standardise terminology. PMID- 24468213 TI - Information gathering during contests: the relationship between lateralisation and contestant behaviour during fallow deer fights. AB - One class of model relating to animal contest behaviour assumes that individuals gather information concerning their opponents' competitive ability; these models argue that such a process allows contestants to avoid engaging in dangerous fighting behaviour with a superior opponent. The brain hemispheres of vertebrates are lateralised in that they are specialised for processing different type of information. Within the context of the current study, we might expect that lateralisation would play a role in facilitating the assessment of opponent quality; nevertheless, the degree of lateralisation shown by individuals can vary suggesting that contest behaviour might also vary based on the ability to process information about competitor quality. The current study tests this hypothesis by predicting that the duration that individuals engage in fighting and the rate of aggressive contest actions should decrease as lateralisation increases. There was a positive relationship between two laterality indices and the duration spent in antler contact; thus lateralised individuals experienced greater time costs. Further, lateralised individuals also experienced a greater disparity in contest actions: there was a negative relationship between lateralisation and the difference in the mean number of backward pushes achieved during fights. When only opponent signal rate was considered there was no effect of lateralisation, therefore, there is support for a mutual assessment process. These results suggest that information gathering via lateral displays may be disadvantageous to lateralised individuals during escalated fighting. PMID- 24468212 TI - Behavioural response of European starlings exposed to video playback of conspecific flocks: effect of social context and predator threat. AB - We studied the behavioural response of European starlings to a socially mediated predation event. Adult starlings were exposed to either a video of a flock attacked by a peregrine falcon or a video of a flock not under attack. We investigated whether the social condition affected the anti-predator response under the hypothesis that in such a gregarious species singletons would increase their anti-predator behaviour more than individuals in groups, to compensate for potential increased risk. The video of the flock under attack caused an increase in immobility and vigilance, more marked in singletons, both during and after the exposure. The video of the non-threatened flock caused an increase in activity levels, especially during the exposure. Furthermore, we observed a marked increase in comfort activities in singletons as well as in social interactions and vocalizations in mini-flocks. Only birds in mini-flocks vocalized, which may be explained by an audience effect, a process of social cognition mediated by the social context, and not only by the stimulus. The results are in line with previous field studies, which showed that isolated starlings are exposed to a higher risk of predation compared to individuals in flocks. PMID- 24468211 TI - Inverse association of colorectal cancer prevalence to serum levels of perfluorooctane sulfonate (PFOS) and perfluorooctanoate (PFOA) in a large Appalachian population. AB - BACKGROUND: Perfluorooctanoate (PFOA) and perfluorooctane sulfonate (PFOS) are persistent environmental contaminants that affect metabolic regulation, inflammation, and other factors implicated in the development and progression of colorectal cancer (CRC). However, the link between these compounds and CRC remains unknown. In this cross-sectional study, we investigated the association of CRC diagnosis to PFOA and PFOS blood levels in a large Appalachian population. METHODS: Participants were 47,359 adults >= 21 years of age and residing in six PFOA-contaminated water districts in the mid-Ohio Valley (N = 47,151 cancer-free adults, 208 cases of primary CRC). All participants completed a comprehensive health survey between 2005 and 2006; serum levels of PFOA, PFOS, and a range of other blood markers were also measured. Medical history was assessed via self report and cancer diagnosis confirmed via chart review. RESULTS: CRC showed a strong inverse, dose-response association with PFOS serum levels (odds ratio (OR) adjusted for potential confounders = 0.2, 95% confidence interval (CI) 0.2,0.3) for highest vs. lowest quartile of PFOS, P-trend < 0.00001) and a significant, but more modest inverse association with PFOA (adjusted OR = 0.6 (CI 0.4, 0.9) for highest vs. lowest quartile, P-trend = 0.001). These inverse associations were stronger in those diagnosed within the previous 6 years and resident in the same water district for a minimum of 10-15 years preceding assessment. The relationship between PFOA and CRC was also more pronounced in men and leaner adults, and showed a stronger linear trend at lower exposure levels. CONCLUSIONS: In this large cross-sectional study, we found a strong, inverse association between PFOS and likelihood of CRC diagnosis and a significant, although more modest inverse association between PFOA and CRC. If confirmed in prospective investigations, these findings may aid in identifying new strategies for CRC prevention and treatment and inform future studies regarding mechanisms underlying CRC pathogenesis. PMID- 24468214 TI - On the dynamics of stimulus control during guided skill learning in nonhumans. AB - This study measured skill acquisition in the presence and absence of guiding cues in pigeons. It asked whether the speed of development of autonomy for the motor skill is influenced by the difficulty level of two guiding-cue conditions requiring the same left-right response sequence. The Follow-Red condition required a simple go, no-go discrimination (red=S+, green=S-), whereas the Red Green condition was a more difficult simultaneous chain requiring sensitivity to the serial order of key colors (red=S+, green=S- for the first peck, but red=S-, green=S+ for the second peck). Pigeons exposed to the difficult Red-Green condition displayed significantly higher accuracy levels during no-cues conditions earlier in training than those exposed to the easier Follow-Red condition. A modified Power Law of Practice was used to evaluate the null hypothesis that autonomy develops equally in explicit guiding-cues conditions and no-cues conditions. This hypothesis was retained in the Follow-Red condition but rejected in the Red-Green condition. Practice completing the response sequence in the Follow-Red and no-cues conditions both contributed equally to autonomy. Autonomy developed faster in the Red-Green group in both conditions, and it developed unexpectedly rapidly during the second guiding-cues condition, implying the involvement of a second process for the Red-Green condition. We discuss the implications of these results to prompt dependence in children with learning disabilities, the transfer of stimulus control, and potential behavioral interventions. PMID- 24468215 TI - Association, roost use and simulated disruption of Myotis septentrionalis maternity colonies. AB - How wildlife social and resource networks are distributed on the landscape and how animals respond to resource loss are important aspects of behavioral ecology. For bats, understanding these responses may improve conservation efforts and provide insights into adaptations to environmental conditions. We tracked maternity colonies of northern bats (Myotis septentrionalis) at Fort Knox, Kentucky, USA to evaluate their social and resource networks and space use. Roost and social network structure differed between maternity colonies. Overall roost availability did not appear to be strongly related to network characteristics or space use. In simulations for our two largest networks, roost removal was related linearly to network fragmentation; despite this, networks were relatively robust, requiring removal of >20% of roosts to cause network fragmentation. Results from our analyses indicate that northern bat behavior and space use may differ among colonies and potentially across the maternity season. Simulation results suggest that colony social structure is robust to fragmentation caused by random loss of small numbers of roosts. Flexible social dynamics and tolerance of roost loss may be adaptive strategies for coping with ephemeral conditions in dynamic forest habitats. PMID- 24468217 TI - Effects of space allowance on the behaviour of long-term housed shelter dogs. AB - The aim of this study was to assess the effects of space allowance (4.5 m(2)/head vs. 9 m(2)/head) on the behaviour of shelter dogs (Canis familiaris) at different times of the day (from 10:30 to 13:30 vs. from 14:30 to 17:30), and the dogs' preference between two types of beds (fabric bed vs. plastic basket). Twelve neutered dogs (seven males and five females aged 3-8 years) housed in pairs were observed using a scan sampling recording method every 20 s for a total of 14,592 scans/treatment. An increase in space allowance increased general level of activity (risk ratio (RR)=1.34), standing (RR=1.37), positive social interactions (RR=2.14), visual exploration of the environment (RR=1.21), and vocalisations (RR=2.35). Dogs spent more time in the sitting (RR=1.39) or standing (RR=1.88) posture, in positive interactions (RR=1.85), and active visual exploration (RR=1.99) during the morning than in the afternoon. The dogs were more often observed in the fabric bed than in the plastic basket (53% vs. 15% of total scans, p<0.001). Results suggest that a 9.0 m(2)/head space allowance could be more beneficial to dogs than one of 4.5 m(2). PMID- 24468216 TI - Tactile stimulation and neonatal isolation affect behavior and oxidative status linked to cocaine administration in young rats. AB - We investigated the influence of neonatal handling on cocaine-induced conditioned place preference (CPP), anxiety-like symptoms and oxidative status related to drug abstinence in young rats. Pups were submitted to tactile stimulation (TS) or neonatal isolation (NI10 or NI60) after birth, and then were submitted to CPP performed with cocaine. TS group did not show place preference, while unhandled (UH), NI10 and NI60 rats did. Handling was related to anxiety-like symptoms per se in UH and NI60 groups and this behavior was also observed in the cocaine conditioned rats exposed to the same handlings. Both TS and NI10 pups treated or not with cocaine showed less anxiety-like behavior than animals submitted to other handlings. TS reduced protein carbonyl (PC) in cortex and NI60 increased PC in both striatum and hippocampus of cocaine-treated rats. Among cocaine-treated rats, both times of NI increased plasma lipoperoxidation levels, which was reduced by TS in erythrocytes. TS increased the catalase activity in brain areas, while other handlings did not change this. Both TS and NI10 increased plasma vitamin C levels. These findings indicate that neonatal handling can modify anxiety-like symptoms related to cocaine preference and abstinence, and its protective influence, especially TS, on the antioxidant system. PMID- 24468218 TI - Determinants of individuals' risks to 2009 pandemic influenza virus infection at household level amongst Djibouti city residents--a CoPanFlu cross-sectional study. AB - BACKGROUND: Following the 2009 swine flu pandemic, a cohort for pandemic influenza (CoPanFlu) study was established in Djibouti, the Horn of Africa, to investigate its case prevalence and risk predictors' at household level. METHODS: From the four city administrative districts, 1,045 subjects from 324 households were included during a face-to-face encounter between 11th November 2010 and 15th February 2011. Socio-demographic details were collected and blood samples were analysed in haemagglutination inhibition (HI) assays. Risk assessments were performed in a generalised estimating equation model. RESULTS: In this study, the indicator of positive infection status was set at an HI titre of >= 80, which was a relevant surrogate to the seroconversion criterion. All positive cases were considered to be either recent infections or past contact with an antigenically closely related virus in humans older than 65 years. An overall sero-prevalence of 29.1% and a geometrical mean titre (GMT) of 39.5% among the residents was observed. Youths, <= 25 years and the elderly, >=65 years had the highest titres, with values of 35.9% and 29.5%, respectively. Significantly, risk was high amongst youths <= 25 years, (OR 1.5-2.2), residents of District 4(OR 2.9), students (OR 1.4) and individuals living near to river banks (OR 2.5). Belonging to a large household (OR 0.6), being employed (OR 0.5) and working in open space outdoor (OR 0.4) were significantly protective. Only 1.4% of the cohort had vaccination against the pandemic virus and none were immunised against seasonal influenza. CONCLUSION: Despite the limited number of incident cases detected by the surveillance system, A(H1N1)pdm09 virus circulated broadly in Djibouti in 2010 and 2011. Age-group distribution of cases was similar to what has been reported elsewhere, with youths at the greatest risk of infection. Future respiratory infection control should therefore be tailored to reach specific and vulnerable individuals such as students and those working in groups indoors. It is concluded that the lack of robust data provided by surveillance systems in southern countries could be responsible for the underestimation of the epidemiological burden, although the main characteristics are essentially similar to what has been observed in developed countries. PMID- 24468219 TI - Forelimb locomotor rating scale for behavioral assessment of recovery after unilateral cervical spinal cord injury in rats. AB - BACKGROUND: Cervical spinal cord injury (SCI) models in rats have become increasingly useful because of their translational potential. The goal of this study was to design, develop and validate a quick and reliable forelimb locomotor rating scale for adult rats with unilateral cervical SCI injury. NEW METHOD: Adult female rats were subjected to a C5 unilateral mild contusion (n=10), moderate contusion (n=10) or hemisection injury (n=9). Forelimb locomotion was evaluated before injury, four times during the first week (Days 2, 3, 4 and 7) and weekly for up to 8 weeks post-injury. Scoring categories were identified and animals were ranked based on their performance in these categories. The scale was validated for its usefulness by comparing animals with different injury models (dorsolateral funiculotomy C3/4), levels of injury (moderate contusion C4) and sex (male - moderate contusion C3/4) and also by correlating FLS scores with other established behavioral tests (grid walking and kinetic tests). RESULTS AND COMPARISON WITH EXISTING METHODS: Forelimb performance on both the grid-walking and kinetic tests was positively correlated with the forelimb locomotor rating scale (FLS). Histological analysis established a positive correlation between the spared tissue and the observed FLS score. Our results show that the new rating scale can reliably detect forelimb deficits and recovery predicted by other behavioral tests. Furthermore, the new method provides reproducible data between trained and naive examiners. CONCLUSION: In summary, the proposed rating scale is a useful tool for assessment of injury and treatments designed to enhance recovery after unilateral cervical SCI. PMID- 24468220 TI - Effect of food intake on left ventricular wall stress. AB - OBJECTIVE: Left ventricular wall stress has been investigated in a variety of populations, but the effect of food intake has not been evaluated. We assessed whether left ventricular wall stress is affected by food intake in healthy subjects. METHODS: Twenty-three healthy subjects aged 25.6 +/- 4.5 years were investigated. Meridional end-systolic wall stress (ESS) and circumferential end systolic wall stress (cESS) were measured before, 30 minutes after, and 110 minutes after a standardised meal. RESULTS: Both ESS and cESS decreased significantly (P < 0.001) from fasting values 30 minutes after the meal, and had not returned to baseline after 110 minutes. ESS decreased from 65 +/- 16 kdynes/cm2 (fasting) to 44 +/- 12 kdynes/cm2 30 minutes after, and to 58 +/- 13 kdynes/cm2 110 minutes after eating. cESS decreased from 98 +/- 24 kdynes/cm2 to 67 +/- 18 kdynes/cm2 30 minutes after, and to 87 +/- 19 kdynes/cm2 110 minutes after the meal. CONCLUSION: This study shows that left ventricular wall stress is affected by food intake in healthy subjects. PMID- 24468221 TI - An unusual presentation of a swollen arm: a case report. AB - INTRODUCTION: Subclavian vein thrombosis is a rare but potentially fatal condition that most often occurs iatrogenically or in the context of malignancy. Here we report the case of an active, healthy 32-year-old woman who presented with subtle findings of arm pain, paresthesias and skin changes of acute onset and was subsequently diagnosed with upper extremity deep vein thrombosis and subclavian stenosis, and was started on a course of oral antithrombotics. CASE PRESENTATION: A 32-year-old right-handed Caucasian woman presented to her family medicine clinic with left shoulder pain and numbness along her ipsilateral forearm and hand, as well as subtle swelling of the affected limb. Initially diagnosed with medial epicondylitis, she was later diagnosed with subclavian thrombosis caused by Paget-Schroetter syndrome. CONCLUSION: Presentations such as these are often attributable to soft-tissue injuries that resolve with rest and sometimes physiotherapy. Subclavian thrombosis was a highly unexpected diagnosis in this case; however, family physicians must remain vigilant in considering rare causes of common clinical presentations which could cause patients significant morbidity if left undiagnosed. PMID- 24468222 TI - Risk stratification of 7,732 hepatectomy cases in 2011 from the National Clinical Database for Japan. AB - BACKGROUND: There has been no report on risk stratification for hepatectomy using a nationwide surgical database in Japan. The objective of this study was to evaluate mortality and variables associated with surgical outcomes of hepatectomy at a national level. STUDY DESIGN: We analyzed records of 7,732 patients who underwent hepatectomy for more than 1 segment (MOS) during 2011 in 987 different hospitals, as identified in the National Clinical Database (NCD) of Japan. The NCD captured 30-day morbidity and mortality as well as 90-day in-hospital mortality outcomes, which were submitted through a web-based data entry system. Based on 80% of the population, independent predictors for 30-day mortality and 90-day in-hospital mortality were calculated using a logistic regression model. The risk factors were validated with the remaining 20% of the cohort. RESULTS: The median postoperative length of hospitalization was 16.0 days. The overall patient morbidity rate was 32.1%. Thirty-day mortality and 90-day in-hospital mortality rates were 2.0% and 4.0%, respectively. Totals of 14 and 23 risk factors were respectively identified for 30-day mortality and 90-day in-hospital mortality. Factors associated with risk for 90-day in-hospital mortality were preoperative condition and comorbidity, operative indication (emergency surgery, intrahepatic/perihilar cholangiocarcinoma, or gallbladder cancer), preoperative laboratory data, and extent and location of resected segments (segment 1, 7, or 8). As a performance metric, c-indices of 30-day mortality and 90-day in-hospital mortality were 0.714 and 0.761, respectively. CONCLUSIONS: Here we report the first risk stratification analysis of hepatectomy using a Japanese nationwide surgical database. This system would predict surgical outcomes of hepatectomy and be useful to evaluate and benchmark performance. PMID- 24468224 TI - Functional outcomes and complications after restorative proctocolectomy and ileal pouch anal anastomosis in the pediatric population. AB - BACKGROUND: Data regarding the long-term outcomes of restorative proctocolectomy and ileal pouch anal anastomosis including pouch function and quality of life in the pediatric population are limited in pediatric patients. STUDY DESIGN: Indications for surgery, complications, long-term function, and quality of life were evaluated in pediatric patients undergoing ileal pouch anal anastomosis. Assessment of quality of life was performed using the Cleveland Global Quality of Life score. RESULTS: There were 433 patients with a mean age of 18.04 +/- 2.9 years. Final pathologic diagnoses were ulcerative colitis or indeterminate colitis (78.3%), familial adenomatous polyposis (15.7%), Crohn's disease (5.1%), and others (0.9%). There were 237 patients (54.7%) who underwent total proctocolectomy and ileal pouch anal anastomosis; 196 (45.3%) underwent initial subtotal colectomy followed by completion proctectomy with ileal pouch anal anastomosis. Anastomosis was stapled in 352 patients (81.3%) and hand-sewn in 81 (18.7%) patients. Mean follow-up was 108.5 +/- 78.4 months. At the most recent follow-up, mean Cleveland Global Quality of Life score was 0.8 +/- 0.2 and numbers of daytime and night-time bowel movements were 5.3 +/- 3.1 and 1.6 +/- 1.3, respectively. The majority of the patients (86.8%) were fully continent or only complained of rare incontinence. Most patients had no seepage (day, 84.3%; night, 72.4%) and did not wear any pads (day, 89.3%; night, 84.3%). Most denied dietary (71.3%), social (84.8%), work (85.7%), or sexual restrictions (87.6%) at the time of last follow-up. There were 92.7% of patients who said they would undergo ileal pouch anal anastomosis again and 95.2% would recommend surgery to others. CONCLUSIONS: Restorative proctocolectomy with ileal pouch anal anastomosis can be performed in pediatric patients with acceptable morbidity and is associated with good long-term results in terms of gastrointestinal function, quality of life, and patient satisfaction. PMID- 24468223 TI - Evaluation of initial participation in public reporting of American College of Surgeons NSQIP surgical outcomes on Medicare's Hospital Compare website. AB - BACKGROUND: In October 2012, The Centers for Medicare and Medicaid Services (CMS) began publicly reporting American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) surgical outcomes on its public reporting website, Hospital Compare. Participation in this CMS-NSQIP initiative is voluntary. Our objective was to compare CMS-NSQIP participating hospitals with ACS NSQIP hospitals that elected not to participate. STUDY DESIGN: Hospital Compare and American Hospital Association Annual Survey data were merged to compare CMS-NSQIP participants with nonparticipants. Regression models were developed to assess predictors of participation and to assess if hospitals differed on 32 process, 10 patient experience (Hospital Consumer Assessment of HealthCare Providers and Systems [HCAHPS]), and 16 outcomes (Hospital Compare and Agency for Healthcare Research Quality) measures. Additionally, performance on 2 waves of publicly reported ACS NSQIP surgical outcomes measures was compared. RESULTS: Of the 452 ACS NSQIP hospitals, 80 (18%) participated in CMS-NSQIP public reporting. Participating hospitals had more beds, admissions, operations, and were more often accredited (Commission on Cancer and the Council of Teaching Hospitals [COTH] [p < 0.05]). Only COTH membership remained significant in adjusted analyses (odds ratio 2.45, 95% CI 1.12 to 5.35). Hospital performance on process, HCAHPS, and outcomes measures were not associated with CMS-NSQIP participation for 54 of 58 measures examined. Hospitals with "better-than average" performance were more likely to publicly report the Elderly Surgery measure (p < 0.05). In wave 2, an increased proportion of new participants reported "worse-than-average" outcomes. CONCLUSIONS: There were few measurable differences between CMS-NSQIP participating and nonparticipating hospitals. The decision to voluntarily publicly report may be related to the hospital's culture of quality improvement and transparency. PMID- 24468225 TI - Sex, role models, and specialty choices among graduates of US medical schools in 2006-2008. AB - BACKGROUND: Undergraduate education studies have suggested instructor sex can influence female students to pursue a discipline. We sought to evaluate a similar hypothesis in medical students. STUDY DESIGN: We obtained Association of American Medical Colleges (AAMC) data about the specialization of 2006-2008 graduates of US medical schools, the sex of their faculty and department chairs, and sex of residents in the residency programs in which they enrolled. We used logistic regression to examine associations between faculty and leadership sex and female students' pursuit of 5 surgical specialties along with 3 nonsurgical specialties for context. We used Wilcoxon rank-sum tests to evaluate whether women entered residency programs with a higher proportion of female residents. RESULTS: In 2006 2008, US medical school graduates included 23,642 women. Women were substantially under-represented among residents in neurosurgery, orthopaedics, urology, otolaryngology, general surgery, and radiology; women constituted 47.4% of US graduates specializing in internal medicine and 74.9% in pediatrics. We found no significant associations between exposure to a female department chair and selection of that specialty and no consistent associations with the proportion of female full-time faculty. Compared with male students, female students entered residency programs in their chosen specialty that had significantly higher proportions of women residents in the year before their graduation. CONCLUSIONS: Although we did not detect consistent significant associations between exposure to potential female faculty role models and specialty choice, we observed that female students were more likely than males to enter programs with higher proportions of female residents. Sex differences in students' specialization decisions merit additional investigation. PMID- 24468226 TI - Comparative radiographic analysis of changes in the abdominal wall musculature morphology after open posterior component separation or bridging laparoscopic ventral hernia repair. AB - BACKGROUND: Large ventral hernias are known to induce atrophic changes to the anterior abdominal wall musculature. We have shown that anterior component separation with external oblique (EO) release, with resultant reconstruction of the midline, results in hypertrophy of the rectus muscle (RM), internal oblique (IO), and transversus abdominis (TA). We aimed to compare and contrast the impact of posterior component separation with transversus abdominis release (TAR) and bridging laparoscopic ventral hernia repair (LVHR) on the muscles of the abdominal wall. STUDY DESIGN: Preoperative and at least 6-month postoperative CT scans were analyzed for patients undergoing TAR with midline reconstruction and LVHR without midline reconstruction. A change in the measured area of each abdominal wall muscle was used as the determinant of hypertrophy or atrophy. The areas of the RM, EO, IO, and TA were measured at the L3 to L4 level through the axial plane. RESULTS: Twenty-five consecutive patients with pre- and postoperative images were analyzed in each group. In the TAR group, the RA, EO, and IO demonstrated significant increases in area. In the LVHR group, no muscles demonstrated any significant changes. CONCLUSIONS: Similar to anterior component separation, hernia repair with TAR results in hypertrophy of the rectus abdominis muscle. In addition, we found that TAR was associated with hypertrophy of both external and internal oblique muscles. Bridging repair during LVHR, on the other hand, did not result in any significant changes in any of the abdominal muscles. Our findings provide clear radiologic evidence that re-creation of the midline by means of the TAR leads to improved anatomy of the abdominal wall, in addition to positive compensatory changes of the lateral abdominal wall musculature. PMID- 24468227 TI - Mortality and management of surgical necrotizing enterocolitis in very low birth weight neonates: a prospective cohort study. AB - BACKGROUND: Necrotizing enterocolitis (NEC) is a leading cause of death in very low birth weight (VLBW) neonates. The overall mortality of NEC is well documented. However, those requiring surgery appear to have increased mortality compared with those managed medically. The objective of this study was to establish national birth-weight-based benchmarks for the mortality of surgical NEC and describe the use and mortality of laparotomy vs peritoneal drainage. STUDY DESIGN: There were 655 US centers that prospectively evaluated 188,703 VLBW neonates (401 to 1,500 g) between 2006 and 2010. Survival was defined as living in-hospital at 1-year or hospital discharge. RESULTS: There were 17,159 (9%) patients who had NEC, with mortality of 28%; 8,224 patients did not receive operations (medical NEC, mortality 21%) and 8,935 were operated on (mortality 35%). On multivariable regression, lower birth weight, laparotomy, and peritoneal drainage were independent predictors of mortality (p < 0.0001). In surgical NEC, a plateau mortality of around 30% persisted despite birth weights >750 g; medical NEC mortality fell consistently with increasing birth weight. For example, in neonates weighing 1,251 to 1,500 g, mortality was 27% in surgical vs 6% in medical NEC (odds ratio [OR] 6.10, 95% CI 4.58 to 8.12). Of those treated surgically, 6,131 (69%) underwent laparotomy only (mortality 31%), 1,283 received peritoneal drainage and a laparotomy (mortality 34%), and 1,521 had peritoneal drainage alone (mortality 50%). CONCLUSIONS: Fifty-two percent of VLBW neonates with NEC underwent surgery, which was accompanied by a substantial increase in mortality. Regardless of birth weight, surgical NEC showed a plateau in mortality at approximately 30%. Laparotomy was the more frequent method of treatment (69%) and of those managed by drainage, 46% also had a laparotomy. The laparotomy alone and drainage with laparotomy groups had similar mortalities, while the drainage alone treatment cohort was associated with the highest mortality. PMID- 24468228 TI - Leptin signaling and hyperparathyroidism: clinical and genetic associations. AB - BACKGROUND: The role of leptin in mediating calcium-related metabolic processes is not well understood. STUDY DESIGN: We enrolled patients with hyperparathyroidism undergoing parathyroidectomy in a prospective study to assess postoperative changes to serum leptin and parathyroid hormone levels and to determine the presence of LEPR (leptin receptor) polymorphisms. Patients undergoing hemithyroidectomy under identical surgical conditions were enrolled as controls. Wilcoxon signed-rank test was used to analyze changes in leptin. Pearson correlations and Bland-Altman methods were used to examine the between subject and within-subject correlations in changes in leptin and parathyroid hormone levels. Five single-nucleotide polymorphisms in the LEPR gene were genotyped, and linear regression analysis was performed for each polymorphism. RESULTS: Among the 71 patients included in the clinical study, after-surgery leptin levels decreased significantly in the parathyroid adenoma (p < 0.001) and parathyroid hyperplasia subgroups (p = 0.002) and increased in the control group (p = 0.007). On multivariate analysis, parathyroid disease subtype, baseline leptin levels, age, body mass index, and calcium at diagnosis was associated with changes in leptin. Among the 132 patients included in the genotyping analysis, under a recessive model of inheritance, single-nucleotide polymorphism rs1137101 had a significant association with the largest parathyroid gland and total mass of parathyroid tissue removed (p = 0.045 and p = 0.040, respectively). When analyzing obese patients only, rs1137100 and rs1137101 were significantly associated with total parathyroid size (p = 0.0343 and p = 0.0259, respectively). CONCLUSIONS: Our results suggest a role for the parathyroid gland in regulating leptin production. Genetic contributions from the leptin pathway might predispose to hyperparathyroidism. PMID- 24468229 TI - Effect of a checklist on advanced trauma life support workflow deviations during trauma resuscitations without pre-arrival notification. AB - BACKGROUND: Trauma resuscitations without pre-arrival notification are often initially chaotic, which can potentially compromise patient care. We hypothesized that trauma resuscitations without pre-arrival notification are performed with more variable adherence to ATLS protocol and that implementation of a checklist would improve performance. STUDY DESIGN: We analyzed event logs of trauma resuscitations from two 4-month periods before (n = 222) and after (n = 215) checklist implementation. Using process mining techniques, individual resuscitations were compared with an ideal workflow model of 6 ATLS primary survey tasks performed by the bedside evaluator and given model fitness scores (range 0 to 1). Mean fitness scores and frequency of conformance (fitness = 1) were compared (using Student's t-test or chi-square test, as appropriate) for activations with and without notification both before and after checklist implementation. Multivariable linear regression, controlling for patient and resuscitation characteristics, was also performed to assess the association between pre-arrival notification and model fitness before and after checklist implementation. RESULTS: Fifty-five (12.6%) resuscitations lacked pre-arrival notification (23 pre-implementation and 32 post-implementation; p = 0.15). Before checklist implementation, resuscitations without notification had lower fitness (0.80 vs 0.90; p < 0.001) and conformance (26.1% vs 50.8%; p = 0.03) than those with notification. After checklist implementation, the fitness (0.80 vs 0.91; p = 0.007) and conformance (26.1% vs 59.4%; p = 0.01) improved for resuscitations without notification, but still remained lower than activations with notification. In multivariable analysis, activations without notification had lower fitness both before (b = -0.11, p < 0.001) and after checklist implementation (b = -0.04, p = 0.02). CONCLUSIONS: Trauma resuscitations without pre-arrival notification are associated with a decreased adherence to key components of the ATLS primary survey protocol. The addition of a checklist improves protocol adherence and reduces the effect of notification on task performance. PMID- 24468230 TI - Combined surgical and interventional therapy of acute portal vein thrombosis without cirrhosis: a new effective hybrid approach for recanalization of the portal venous system. PMID- 24468232 TI - Interhospital transfer and adverse outcomes after general surgery: implications for pay for performance. AB - BACKGROUND: Interhospital transfer is frequent, and transferred patients can have worse outcomes than direct admissions. We sought to define the incidence of interhospital transfer in general surgery and evaluate its association with surgical outcomes. STUDY DESIGN: The 2011 American College of Surgeons NSQIP database was used. Transferred patients were compared with urgent, inpatient direct admissions in a series of increasingly complex risk-adjustment models, including multiple regression using modified Poisson and negative binomial models, as well as propensity scores. Primary outcomes were overall complications, mortality, length of stay, and readmission. RESULTS: Overall, 7% of inpatient general surgery cases were transferred in. Among urgent cases, there were 6,197 transferred patients and 47,267 direct admissions. The most common procedures for direct admissions were appendectomy and cholecystectomy, and transfers had a more complex and broader range of procedures. On unadjusted analysis, transferred patients had a much higher risk for complications (risk ratio [RR] = 1.48; 95% CI, 1.45-1.52) and mortality (RR = 2.70; 95% CI, 2.48 2.94), as well as a longer length of stay (1.74 times longer; 95% CI, 1.69-1.78) and higher risk of readmission (RR = 1.31; 95% CI, 1.20-1.44). In the most sophisticated model, the propensity score match, the difference in outcomes for transferred patients was only modestly higher or equivalent (complications: RR = 1.03; 95% CI, 1.00-1.07; mortality: RR = 0.98; 95% CI, 0.88-1.09; length of stay: 1.08 times longer; 95% CI, 1.04-1.11; readmission: RR = 0.97; 95% CI, 0.88-1.08). CONCLUSIONS: Interhospital transfer is frequent in surgery. Worse outcomes seen in transferred patients are largely due to confounding by patient characteristics rather than any true harm from transfer. Pay-for-performance schemes should adjust for transfer status to avoid unfairly penalizing hospitals that frequently accept transfers. PMID- 24468233 TI - Caloric restriction or telmisartan control dyslipidemia and nephropathy in obese diabetic Zucker rats. AB - BACKGROUND: The obese Zucker diabetic fatty male rat (ZDF:GmiTM-fa) is an animal model of type II diabetes associated with obesity and related metabolic disturbances like dyslipidaemia and diabetic nephropathy. In addition, diabetic dyslipidaemia has been linked to vascular and glomerular damage too. Dietary fat restriction is a current strategy to tackle obesity and, telmisartan, as a renoprotective agent, may mediate cholesterol efflux by activating PPARgamma. To test the hypothesis that both therapeutical alternatives may influence dyslipidaemia and nephropathy in the ZDF rat, we studied their effect on development of diabetes. METHODS: Male Zucker Diabetic Fatty (ZDF) rats received a low-calorie diet, vehicle or telmisartan for 9 weeks. Blood samples were obtained for analyses of lipids and lipoproteins, LDL-oxidisability, HDL structural and functional properties. Urinalysis was carried out to estimate albumin loss. At the end of the experimental period, rats were sacrificed, liver extracted and APOA1 mRNA quantified. RESULTS: Results indicated that low-calorie diet and telmisartan can slower the onset of overt hyperglycaemia and renal damage assessed as albuminuria. Both interventions decreased the oxidative susceptibility of LDL and hepatic APOA1 mRNA expression but only dietary restriction lowered hyperlipidaemia. CONCLUSION: Either a dietary or pharmacologic interventions with telmisartan have important beneficial effects in terms of LDL oxidative susceptibility and progression of albuminuria in obesity related type II diabetes. PMID- 24468231 TI - Optimal resources for children's surgical care in the United States. AB - In summary, the Task Force does understand that change is difficult and, in the circumstance of the US health care environment, quite complex. Having acknowledged this, the Task Force firmly believes that if optimal resource standards are clear, providers will act in the best interests of their patients, infants, and children undergoing surgery in this circumstance. We intend to provide evidence to this point, to define optimal resources, and to facilitate this process. The hope and the underlying intent of these recommendations is to insure that every infant and child undergoing a surgical procedure in the United States will receive his or her care in an environment that offers all of the facilities, equipment, and, most especially, access to the professional providers who have the appropriate background and training to provide optimal care. This must be done while balancing the issues of access, staff, and the need to improve the value proposition. The Task Force is unanimous in its intent to advocate for this agenda. PMID- 24468234 TI - Air monitoring of aromatic hydrocarbons during automobile spray painting for developing change schedule of respirator cartridges. AB - In the absence of End of Service Life Indicator (ESLI), a cartridge change schedule should be established for ensuring that cartridges are changed before their end of service life. Factors effecting service life of cartridges were evaluated, including the amount of atmospheric contamination with aromatic hydrocarbon vapors in the workplace, temperature, and relative humidity of the air. A new change schedule was established based on comparing the results of air monitoring and workplace conditions, laboratory experiment, and the NIOSH MultiVapor software. Spray painters were being exposed to aromatic hydrocarbons in a range exceeding occupational exposure limits. The cartridge change schedule was not effective and could no longer provide adequate protection against organic contaminants for sprayers. Change schedules for respirator cartridges should be reduced from 16-24 hours to 4 hours. NIOSH's service life software program could be applied to developing cartridge change schedules. PMID- 24468235 TI - Mobile opioid agonist treatment and public funding expands treatment for disenfranchised opioid-dependent individuals. AB - The New Jersey Medication Assisted Treatment Initiative (NJ-MATI) sought to reduce barriers to treatment by providing free, opioid agonist treatment (OAT, methadone or buprenorphine) via mobile medication units (MMUs). To evaluate barriers to OAT, logistic regression was used to compare opioid dependent patients enrolled in NJ-MATI to those entering treatment at fixed-site methadone clinics or non-medication assisted treatment (non-MAT). Client demographic and clinical data were taken from an administrative database for licensed treatment providers. The MMUs enrolled a greater proportion of African-American, homeless, and uninsured individuals than the fixed-site methadone clinics. Compared to non MAT and traditional methadone clients, NJ-MATI patients were more likely to be injection drug users and daily users but less likely to have a recent history of treatment. These observations suggest that the patient-centered policies associated with NJ-MATI increased treatment participation by high severity, socially disenfranchised patients who were not likely to receive OAT. PMID- 24468236 TI - Hypothalamic ghrelin signalling mediates olanzapine-induced hyperphagia and weight gain in female rats. AB - Excessive weight gain is a major metabolic side effect of second-generation antipsychotics (SGAs) in the treatment of schizophrenia. Ghrelin is an orexigenic hormone secreted mainly from the stomach, which can induce weight gain and hyperphagia through regulating neuropeptides at the hypothalamus. Accumulating evidence implicates a relationship between ghrelin signalling and SGA-induced hyperphagia and weight gain. We report that olanzapine (a SGA with high weight gain liability) potently and time-dependently up-regulate ghrelin and ghrelin signalling, leading to hyperphagia and weight gain in female Sprague-Dawley rats, an action reversed by i.c.v. injection of a ghrelin receptor (GHS-R1a) antagonist. These findings indicate a crucial role of ghrelin signalling in hyperphagia induced by olanzapine, supporting the notion that GHS-R1a antagonist may be useful for pharmacological treatment of SGA-induced weight gain resulted from hyperphagia. PMID- 24468237 TI - Sialendoscopy for the diagnosis and treatment of juvenile recurrent parotitis. AB - PURPOSE: The aim of the current study was to analyze the use of sialendoscopy for the diagnosis and treatment of juvenile recurrent parotitis (JRP), note possible complications, and the rate of disease recurrence. We believe that this cutting edge procedure may be very effective both for the diagnosis and treatment of JRP, with few complications and low rates of recurrence. PATIENTS AND METHODS: A retrospective descriptive case study was conducted on a sample of patients presenting with JRP. Data was collected from the patient's medical records. Diagnostic sialendoscopy was performed to identify and classify the ductal pathology, treated by interventional therapeutic sialendoscopy. We carefully noted all complications and the disease recurrence rates. RESULTS: The patient sample included 50 children presenting with JRP (33 M, 17 F; age range: 2 to 16 years). Seven children presented with bilateral parotitis, the remaining 43 with unilateral parotitis. The study was conducted from 2003 to 2012. There was a statistically significant association between sialendoscopic data and the actual outcome. Seven children underwent additional sialendoscopy because of recurrence. They were all in the group of children presenting with unilateral parotitis. DISCUSSION: Our results validate the expected outcome. Sialendoscopy is an accurate technique for the diagnosis of JPR, and an effective tool for the treatment of JRP, with a low rate of complications and recurrence. PMID- 24468238 TI - Rapid determination of octanol-water partition coefficient using vortex-assisted liquid-liquid microextraction. AB - Vortex-assisted liquid-liquid microextraction (VALLME) coupled with high performance liquid chromatography (HPLC) is proposed here for the rapid determination of octanol-water partitioning coefficients (Kow). VALLME uses vortex agitation, a mild emulsification procedure, to disperse microvolumes of octanol in the aqueous phase thus increasing the interfacial contact area and ensuring faster partitioning rates. With VALLME, 2min were enough to achieve equilibrium conditions between the octanolic and aqueous phases. Upon equilibration, separation was achieved using centrifugation and the octanolic microdrop was collected and analyzed in a HPLC system. Six model compounds with logKow values ranging between ~0.5 and 3.5 were used during the present investigations. The proposed method produced logKow values that were consistent with previously published values and the recorded uncertainty was well within the acceptable log unit range. Overall, the key features of the proposed Kow determination procedure comprised speed, reliability, simplicity, low cost and minimal solvent consumption. PMID- 24468239 TI - A critical overview of non-aqueous capillary electrophoresis. Part I: mobility and separation selectivity. AB - This two-part review critically gives an overview on the theoretical and practical advances in non-aqueous capillary electrophoresis (NACE) achieved over the recent five years. Part I starts out by reviewing the aspects relevant to electromigration in organic solvents and evaluates potential advantages of the latter in comparison to aqueous solvent systems. The crucial role of solubility for the species involved in CE - analytes and back ground electrolyte constituents - is discussed both for ionic and neutral compounds. The impact of organic solvents on the electrophoretic and electroosmotic mobility and on the ionization (pKa values) of weak acids and bases is highlighted. Special emphasis is placed on methanol, acetonitrile and mixtures of these solvents, being the most frequent employed media for NACE applications. In addition, also solvents less commonly used in NACE will be covered, including other alcohols, amides (formamide, N-methylformamide, N,N-dimethylformamide, N,N-dimethylacetamide), propylene carbonate, dimethylsulphoxide, and nitromethane. The discussions address the consequences of dramatic pKa shifts frequently seen for weak acids and bases, and the important contributions of medium-specific electroosmotic flow (EOF) to electromigration in nonaqueous media. Important for NACE, the role of the water content on pKa and mobility is analyzed. Finally, association phenomena rather specific to nonaqueous solvents (ion pairing, homo- and heteroconjugation) will be addressed, along with their potential advantages for the development of NACE separation protocols. It is pointed out that this review is not intended as a listing of all papers that have been published on NACE in the period mentioned above. It rather deals with general aspects of migration and selectivity in organic solvent systems, and discusses - critically - examples from the literature with particular interest to the topic. An analog discussion about the role of the solvent on efficiency will be presented in Part II. PMID- 24468240 TI - Decomposition of size-exclusion chromatography elution curves of complex branched polymers. AB - A new method for the decomposition of non-baseline-resolved multimodal elution curves of SEC with the concentration, light scattering and viscosity detection is presented. The method makes possible the characterization of the polymer-sample components, represented by the peaks forming multimodal elution curves, individually and reduces also the error in the calculation of molecular-weight averages. The procedure is demonstrated on narrow molecular-weight distribution polystyrene standards and their mixture as well as on a grafted polymer sample. PMID- 24468241 TI - Simultaneous determination of volatile and non-volatile nitrosamines in processed meat products by liquid chromatography tandem mass spectrometry using atmospheric pressure chemical ionisation and electrospray ionisation. AB - A sensitive, selective and generic method has been developed for the simultaneous determination of the contents (MUgkg(-1) range) of both volatile nitrosamines (VNA) and non-volatile nitrosamines (NVNA) in processed meat products. The extraction procedure only requires basic laboratory equipment and a small volume of organic solvent. Separation and quantification were performed by the developed LC-(APCI/ESI)MS/MS method. The method was validated using spiked samples of three different processed meat products. Satisfactory recoveries (50-130%) and precisions (2-23%) were obtained for eight VNA and six NVNAs with LODs generally between 0.2 and 1MUgkg(-1), though for a few analyte/matrix combinations higher LODs were obtained (3 to 18MUgkg(-1)). The validation results show that results obtained for one meat product is not always valid for other meat products. We were not able to obtain satisfactory results for N-nitrosohydroxyproline (NHPRO), N-nitrosodibenzylamine (NDBzA) and N-nitrosodiphenylamine (NDPhA). Application of the APCI interface improved the sensitivity of the method, because of less matrix interference, and gave the method a wider scope, as some NAs were ionisable only by APCI. However, it was only possible to ionize N-nitroso-thiazolidine-4 carboxylic acid (NTCA) and N-nitroso-2-methyl-thiazolidine-4-carboxylic acid (NMTCA) by ESI. The validated method was applied for the analysis of processed meat products and contents of N-nitrosodimethylamine (NDMA), N-nitrosopyrrolidine (NPYR), N-nitrosomethylaniline (NMA), N-nitrosoproline (NPRO), NTCA, and NMTCA were found in one or several nitrite cured meat products, whereas none were detected in non-nitrite cured bacon. PMID- 24468243 TI - When more can be less. PMID- 24468244 TI - Mice matter. PMID- 24468245 TI - Aspirin allergy in patients with myocardial infarction: the allergist's role. PMID- 24468242 TI - Hippocampal granule cell pathology in epilepsy - a possible structural basis for comorbidities of epilepsy? AB - Temporal lobe epilepsy in both animals and humans is characterized by abnormally integrated hippocampal dentate granule cells. Among other abnormalities, these cells make axonal connections with inappropriate targets, grow dendrites in the wrong direction, and migrate to ectopic locations. These changes promote the formation of recurrent excitatory circuits, leading to the appealing hypothesis that these abnormal cells may by epileptogenic. While this hypothesis has been the subject of intense study, less attention has been paid to the possibility that abnormal granule cells in the epileptic brain may also contribute to comorbidities associated with the disease. Epilepsy is associated with a variety of general findings, such as memory disturbances and cognitive dysfunction, and is often comorbid with a number of other conditions, including schizophrenia and autism. Interestingly, recent studies implicate disruption of common genes and gene pathways in all three diseases. Moreover, while neuropsychiatric conditions are associated with changes in a variety of brain regions, granule cell abnormalities in temporal lobe epilepsy appear to be phenocopies of granule cell deficits produced by genetic mouse models of autism and schizophrenia, suggesting that granule cell dysmorphogenesis may be a common factor uniting these seemingly diverse diseases. Disruption of common signaling pathways regulating granule cell neurogenesis may begin to provide mechanistic insight into the cooccurrence of temporal lobe epilepsy and cognitive and behavioral disorders. PMID- 24468246 TI - The allergist and the intensivist: not such odd bedfellows. PMID- 24468248 TI - Aeroallergen botany. PMID- 24468247 TI - Drug allergens and food--the cetuximab and galactose-alpha-1,3-galactose story. AB - OBJECTIVE: A novel form of food allergy has been described that initially became apparent from IgE reactivity with the drug cetuximab. Ongoing work regarding the etiology, distribution, clinical management, and cellular mechanisms of the IgE response to the oligosaccharide galactose-alpha-1,3-galactose (alpha-gal) is reviewed. DATA SOURCES: Brief review of the relevant literature in peer-reviewed journals. STUDY SELECTION: Studies on the clinical and immunologic features, pathogenesis, epidemiology, laboratory evaluation, and management of IgE to alpha gal are included in this review. RESULTS: Recent work has identified a novel IgE antibody response to the mammalian oligosaccharide epitope, alpha-gal, that has been associated with 2 distinct forms of anaphylaxis: (1) immediate-onset anaphylaxis during first exposure to intravenous cetuximab and (2) delayed-onset anaphylaxis 3 to 6 hours after ingestion of mammalian food products (eg, beef and pork). Study results have suggested that tick bites are a cause of IgE antibody responses to alpha-gal in the United States. Patients with IgE antibody to alpha gal continue to emerge, and, increasingly, these cases involve children. Nevertheless, this IgE antibody response does not appear to pose a risk for asthma but may impair diagnostic testing in some situations. CONCLUSION: The practicing physician should understand the symptoms, evaluation, and management when diagnosing delayed allergic reactions to mammalian meat from IgE to alpha gal or when initiating treatment with cetuximab in patients who have developed an IgE antibody response to alpha-gal. PMID- 24468249 TI - Biologic targeted therapy in allergic asthma. AB - OBJECTIVE: To review the structure, function, clinical utility, and safety of current biologic targeted therapies being used for the treatment of asthma. DATA SOURCES: Medical literature obtained from PubMed and OVID searches from June to November 2013. STUDY SELECTIONS: Studies were selected based on article impact, relevance, and clinical significance. Particular emphasis was placed on articles discussing therapies targeted at IgE, interleukin (IL)-4, IL-4 receptor, IL-5, IL 13, tumor necrosis factor-alpha, CRTh2, and toll-like receptors 7 and 9. RESULTS: Since the approval of omalizumab in 2003, the development of biologic asthma therapies has grown at a remarkable pace. With approximately 30 drugs currently in clinical trials and dozens more in development, the future of asthma biologic therapies is promising. Despite several well-publicized setbacks, researchers remain focused on elucidating the complex pathophysiology of asthma. The hope is that asthma biologic therapies will eventually be tailored to an individual's asthma phenotype. With more than 300 million people worldwide affected by asthma and with roughly 5% to 10% of this population living with severe, uncontrolled asthma, the need for new biologic therapies is great. CONCLUSION: The introduction of each new biologic therapy into clinical trials has been associated with great anticipation, but the outcome of these trials, in many cases, has led to disappointment. Given the lack of overwhelming positive responses, these results have emphasized that asthma is a complex clinical syndrome with multiple underlying genotypes and clinical phenotypes. It has become abundantly clear that it is very unlikely that there is one "magic bullet" to cure all patients with asthma. PMID- 24468250 TI - Factors associated with levels of adherence to inhaled corticosteroids in minority adolescents with asthma. AB - BACKGROUND: Nonadherence to inhaled corticosteroids (ICS) is a significant risk factor for poor asthma outcomes in minority adolescents with persistent asthma. OBJECTIVE: To identify factors associated with nonadherence to daily ICS in this target population. METHODS: Adolescents 11 to 16 years old, self-identified as African American or Hispanic, diagnosed with persistent asthma and with an active prescription for daily ICS were invited to participate. Participant adherence to ICS was electronically measured during 14 days. Concurrently, participants completed the following assessments: demographic information, asthma history, asthma control, asthma exacerbations, media use, depression, asthma knowledge, ICS knowledge, and ICS self-efficacy. Of the 93 subjects, 68 had low (<48%) adherence and 25 had high (>48%) adherence. RESULTS: Older age and low ICS knowledge each were associated with low (<=48%) adherence (P < .01 for the 2 variables). CONCLUSION: Older age and low ICS knowledge each may be associated with poor adherence to ICS in minority adolescents with persistent asthma. Although older age often is associated with the assignment of increased responsibility for medication-taking behavior, it may not be associated with increased adherence. Continued and expanded efforts at promoting asthma education and specifically knowledge of ICS may increase adherence to ICS. PMID- 24468251 TI - Food-specific serum immunoglobulin E measurements in children presenting with food allergy. AB - BACKGROUND: In children with food allergy, multiple food-specific serum IgE levels to common food allergens are frequently measured. OBJECTIVE: To compare food-specific serum IgE measurements among common food allergens in children with food allergy to determine the characteristics of the measurements, their ability to discriminate between foods associated and not associated with a presenting clinical reaction, and their change over time. METHODS: A retrospective analysis was conducted of food-specific serum IgE to cow's milk, egg white and yolk, peanuts, almond, and soy, for up to 3 subsequent measurements, in 291 children with food allergy. A food-specific serum IgE level lower than 0.35 kU/L was considered a negative measurement. The correlation of IgE measurements with presenting symptoms was conducted for each food in 172 children. RESULTS: Of 1,312 food-specific serum IgE measurements, 69.8% were positive. The median (interquartile range) IgE level for foods associated with the presenting complaint was 7.3 kU/L (2.7-31) and that for foods not associated with a clinical complaint was 2.2 kU/L (0.38-13). The difference was statistically significant (P = .01) only for cow's milk. Specific IgE levels were highest for peanuts, followed by cow's milk, eggs, soy, and almonds, and trended upward over time. CONCLUSION: In children presenting with clinical symptoms of a reaction to a food allergen, measurements of food-specific serum IgE to other common food allergens are commonly positive. An increase in food-specific serum IgE occurs over time. PMID- 24468252 TI - H2-antihistamines for the treatment of anaphylaxis with and without shock: a systematic review. AB - BACKGROUND: Anaphylaxis is a serious allergic or hypersensitivity reaction, which is rapid in onset and sometimes can prove fatal. Although H2-antihistamines are often administered for emergency treatment in anaphylaxis, there is uncertainty about their effectiveness in this disease. OBJECTIVE: To assess the benefits and harms of H2-antihistamines in the treatment of anaphylaxis. METHODS: A systematic review was performed of randomized controlled trials and quasi-randomized controlled trials comparing H2-antihistamines with placebo or no intervention in patients with anaphylaxis. RESULTS: The authors failed to identify any eligible studies for inclusion in this systematic review. CONCLUSION: When H2 antihistamines are recommended for anaphylaxis treatment, the status of the evidence base supporting their use should be described. Well-designed randomized controlled trials investigating the role of H2-antihistamines in anaphylaxis treatment are urgently needed. PMID- 24468253 TI - Perinatal influences on the development of asthma and atopy in childhood. AB - BACKGROUND: In most children with asthma and atopy, onset of disease occurs early in life, indicating a crucial role of in utero and early childhood environment. However, only a small part of this burden of disease established early in life has been explained. OBJECTIVE: To examine the effects of early environmental exposures on the development of asthma and atopy within the setting of an affluent urban population. METHODS: The authors followed 526 German children from birth to 5 years of age. Parental interviews in pregnancy and then yearly assessed the health of the child and environmental characteristics. Endotoxin and allergens in house dust were measured at 3 months. Atopic sensitization was assessed at 1 and 5 years. RESULTS: In atopic mothers, acute atopic symptoms during pregnancy were associated with increased risk of early atopic dermatitis (adjusted odds ratio [aOR] 1.74, 95% confidence interval [CI] 1.00-3.02) and allergic rhinitis at 5 years (aOR 2.11, 95% CI 1.01-4.41). Further, maternal illnesses during pregnancy (ie, repeated common colds) increased the risk of asthma at 5 years (aOR 2.31, 95% CI 1.12-4.78). Endotoxin in the child's mattress was inversely associated with atopic sensitization (aOR 0.79, 95% CI 0.64-0.97) and asthma (aOR 0.71, 95% CI 0.55-0.93). A contrasting effect of early endotoxin and mite exposure was observed for mite sensitization: mite exposure increased the risk of mite sensitization at 5 years (aOR 1.30, 95% CI 1.11-1.53), whereas endotoxin exposure was inversely associated with mite sensitization (aOR 0.73, 95% CI 0.57-0.95). CONCLUSION: Factors affecting the in utero environment, such as maternal atopy and infections, and bacterial exposure in pregnancy or early life may act as immunomodulators enhancing or inhibiting the development of asthma and atopy in childhood. PMID- 24468254 TI - Bla g 3: a novel allergen of German cockroach identified using cockroach-specific avian single-chain variable fragment antibody. AB - BACKGROUND: The IgE response to cockroach allergens is thought to be associated with asthma. German cockroach (GCr) allergen extract is a complex mixture of allergens, and the identification and characterization of immunodominant allergens is important for the effective diagnosis and treatment of GCr-induced asthma. OBJECTIVE: To characterize a novel GCr allergen homologous to the American cockroach allergen Per a 3. METHODS: GCr-specific avian monoclonal antibodies were used for direct immunoprecipitation of specific targets from whole-body GCr extract. Precipitated protein was identified by mass spectrometry and sequence analysis. Putative recombinant protein also was expressed, purified, and used for determination of allergenicity, determined by IgE enzyme-linked immunosorbent assay with serum from 61 GCr-allergic patients. The identified target also was analyzed for heat stability using a bead-based assay. RESULTS: The immunoprecipitated target of monoclonal antibody 2A1 was identified as a novel allergen of GCr homologous to American cockroach allergen Per a 3. This homolog, designated Bla g 3, has an apparent mass of 78 kDa, can be measured in GCr extract using antibody 2A1, and is a heat-stable protein. Screening of 61 serum samples from GCr-allergic patients showed a 22% prevalence of Bla g 3 specific IgE. CONCLUSION: Bla g 3 is a GCr allergen with structural homology to American cockroach allergen Per a 3. PMID- 24468255 TI - Efficacy and safety of grass sublingual immunotherapy tablet, MK-7243: a large randomized controlled trial. AB - BACKGROUND: In North America, few studies have evaluated sublingual immunotherapy for allergic rhinitis with or without conjunctivitis (AR/C); pediatric data are sparse. The authors report findings from the largest published immunotherapy trial yet conducted in adults and children. OBJECTIVE: To evaluate grass sublingual immunotherapy tablet (MK-7243) treatment in subjects with AR/C. METHODS: North American subjects (5-65 years old) with grass allergy were randomized 1:1 to once-daily MK-7243 (2,800 BAU Phleum pratense) or placebo. The first dose was given at the investigator's office; subsequent doses were self administered at home. The primary end point was total combined score (TCS; rhinoconjunctivitis daily symptom score [DSS] plus daily medication score [DMS]) over the entire grass pollen season (GPS). Key secondary end points included entire-season DSS, DMS, peak-season TCS, and rhinoconjunctivitis quality-of-life questionnaire scores. Safety outcomes included adverse events (AEs). RESULTS: One thousand five hundred one subjects were randomized (85% polysensitized, 25% had asthma). MK-7243 yielded improvements vs placebo of 23% in entire-season TCS (median difference -0.98, P < .001), 29% in peak-season TCS (median difference 1.33, P < .001), 20% in entire-season DSS (median difference -0.64, P = .001), 35% in entire-season DMS (mean difference -0.48, P < .001), and 12% in peak season rhinoconjunctivitis quality-of-life questionnaire (median difference 0.13, P = .027). Efficacy between children and adults was similar. Most AEs were transient local application-site reactions, with no serious treatment-related AEs or anaphylactic shock. Three subjects (1 placebo, 2 MK-7243) had moderate systemic allergic reactions. CONCLUSION: MK-7243 was effective in polysensitized grass-allergic North American children and adults with AR/C in this large trial, confirming previous research. PMID- 24468256 TI - Effect of vitamin D on T-helper type 9 polarized human memory cells in chronic persistent asthma. AB - BACKGROUND: Vitamin D suppresses inflammation and vitamin D deficiency is linked to the severity of asthma symptoms. T-helper type 9 (TH9) cells are important in the pathogenesis, yet the effects of vitamin D on this subset of inflammatory T helper cells from patients with chronic asthma is unknown. OBJECTIVE: To determine the effects of vitamin D and dexamethasone on TH9 memory cells from adults with chronic persistent asthma and on a recall response to dust mite allergen. METHODS: T-helper memory cells were cultured with cytokines that drive TH9 polarization with vitamin D and/or dexamethasone. Peripheral blood mononuclear cells (PBMCs) from patients with radioallergosorbent test results for house dust mite were stimulated with allergen in the presence or absence of vitamin D. Intracellular cytokines, transcription factors, and identification of cell surface phenotypic markers were determined by flow cytometry. RESULTS: Vitamin D decreased interleukin (IL)-9, IL-5, and IL-8 but increased IL-13(+) cells in TH9 cultures. Transcription factors PU.1 and interferon regulatory factor 4 were downregulated by vitamin D but not GATA3 and c-MAF. When PBMCs from patients with positive radioallergosorbent test results were stimulated with dust mite allergen, vitamin D decreased IL-9, IL-5, and IL-13 in T-helper cells (CD4(+)). TH9 cells present in a recall response were classically TH2 (CD294(+)), and polarization by transforming growth factor-beta and IL-4 altered that phenotype. CONCLUSION: Vitamin D decreased inflammatory cytokine profiles in TH9 memory cells and CD4(+) cells stimulated with dust mite allergen. Vitamin D is additive with dexamethasone in decreasing inflammatory cytokine production from T cell subsets implicated in asthma. PMID- 24468258 TI - Real-life experiences with omalizumab for the treatment of chronic urticaria. AB - BACKGROUND: Evidence has shown that omalizumab, a subcutaneous anti-IgE monoclonal antibody, is highly effective for the treatment of chronic urticaria. OBJECTIVE: To evaluate omalizumab 150 mg/month in severe, difficult-to-treat, chronic urticaria in a real-life setting. METHODS: This prospective open-label study evaluated of 150 mg of omalizumab in severe urticaria defined by a 7-day urticaria activity score (UAS-7) higher than 30, a history of oral glucocorticoid use, and by suboptimal response to previous treatments. Two subgroups of patients at different centers (Toronto and Quebec City, Canada) were included. The primary efficacy evaluation was a change in UAS-7 from baseline. A quantitative medication score assessed the use of other anti-urticarial medications. RESULTS: Sixty-eight patients were included: 61 with chronic spontaneous urticaria, 6 with cold urticaria, and 1 with urticarial vasculitis. Patients were followed for up to 25 months. In Toronto, mean UAS-7 decreased from 32.2 at baseline to 5.7 after the last omalizumab treatment. Seventy-nine percent achieved complete remission during omalizumab therapy (UAS-7 0) and 6 (18%) showed improvement but never achieved complete remission. The most common maintenance dosing intervals were 1 to 3 months. In Quebec City, from baseline to 18 months, mean UAS-7 decreased from 24.4 to 2.2 and the quantitative medication score decreased from 13.3 to 3.0. All 6 patients with cold urticaria became symptom free, with a significant decrease of their cold stimulation tolerance test. CONCLUSION: Omalizumab 150 mg was effective in difficult to treat patients with severe, chronic urticaria refractory to recommended treatments who usually required prednisone. Omalizumab induced a long-lasting positive response and was well tolerated without side effects. PMID- 24468257 TI - Recombinant human C1-esterase inhibitor relieves symptoms of hereditary angioedema attacks: phase 3, randomized, placebo-controlled trial. AB - BACKGROUND: Hereditary angioedema (HAE), caused by C1 inhibitor (C1INH) deficiency or dysfunction, is characterized by recurrent attacks of tissue swelling affecting multiple anatomic locations. Recombinant human C1INH (rhC1INH) has been shown effective for acute treatment of HAE attacks. OBJECTIVE: To evaluate the efficacy and safety of rhC1INH (50 IU/kg to maximum 4,200 IU/treatment) vs placebo in a larger HAE population. METHODS: Seventy-five patients experiencing peripheral, abdominal, facial, and/or oropharyngeal laryngeal attacks were randomized (3:2) to rhC1INH (n = 44) or placebo (saline; n = 31). Efficacy was assessed by patient responses on a Treatment Effect Questionnaire (TEQ) and visual analog scale (VAS). Safety also was evaluated. RESULTS: Median (95% confidence interval) time to beginning of symptom relief at the primary attack location was 90 minutes (61-150) in rhC1INH-treated patients vs 152 minutes (93, not estimable) in placebo-treated patients (P = .031) based on the TEQ and 75 minutes (60-105) vs 303 minutes (81-720, P = .003) based on a VAS decrease of at least 20 mm. Median time to minimal symptoms was 303 minutes (240-720) in rhC1INH-treated patients vs 483 minutes (300-1,440) in placebo treated patients based on the TEQ (P = .078) and 240 minutes (177-270) vs 362 minutes (240, not estimable; P = .005), based on an overall VAS less than 20 mm. Overall, rhC1INH was safe and well tolerated; no thromboembolic events, anaphylaxis, or neutralizing antibodies were observed. CONCLUSION: Relief of symptoms of HAE attacks was achieved faster with rhC1INH compared with placebo as assessed by the TEQ and VAS, with a positive safety profile. Results are consistent with previous studies showing efficacy and safety of rhC1INH in patients with HAE. PMID- 24468259 TI - Identification of peamaclein as a marker allergen related to systemic reactions in peach allergy. PMID- 24468260 TI - Orolingual angioedema associated with olmesartan use after recombinant tissue plasminogen activator treatment of acute stroke. PMID- 24468261 TI - Evaluating for seasonal variation in angiotensin-converting enzyme inhibitor- and angiotensin receptor blocker-induced angioedema. PMID- 24468262 TI - Urinary triclosan levels and recent asthma exacerbations. PMID- 24468263 TI - Test-retest reliability of the International Study of Asthma and Allergies in Childhood questionnaire for a web-based survey. PMID- 24468264 TI - Urinary biopyrrin: a potential inflammatory marker of atopic dermatitis. PMID- 24468265 TI - Serum IgE assessment in prescribing allergen immunotherapy. PMID- 24468266 TI - Author response. PMID- 24468267 TI - Allergen of the month--grama grass. PMID- 24468268 TI - Oncogenes in melanoma: an update. AB - Melanoma is a highly aggressive tumour with poor prognosis in the metastatic stage. BRAF, NRAS, and KIT are three well-known oncogenes involved in melanoma pathogenesis. Targeting of mutated BRAF kinase has recently been shown to significantly improve overall survival of metastatic melanoma patients, underscoring the particular role of this oncogene in melanoma biology. However, recurrences regularly occur within several months, which supposedly involve further oncogenes. Moreover, oncogenic driver mutations have not been described for up to 30% of all melanomas. In order to obtain a more complete picture of the mutational landscape of melanoma, more recent studies used high-throughput DNA sequencing technologies. A number of new oncogene candidates such as MAPK1/2, ERBB4, GRIN2A, GRM3, RAC1, and PREX2 were identified. Their particular role in melanoma biology is currently under investigation. Evidence for the functional relevance of some of these new oncogene candidates has been provided in in vitro and in vivo experiments. However, these findings await further validation in clinical studies. This review provides an overview on well-known melanoma oncogenes and new oncogene candidates, based on recent high-throughput sequencing studies. The list of genes discussed herein is of course not complete but highlights some of the most significant of recent findings in this area. The new candidates may support more individualized treatment approaches for metastatic melanoma patients in the future. PMID- 24468269 TI - Treatment efficacy and tolerability of intravesical bacillus Calmette-Guerin (BCG)-RIVM strain: induction and maintenance protocol in high grade and recurrent low grade non-muscle invasive bladder cancer (NMIBC). AB - BACKGROUND: BCG-RIVM strain was used in many treatment protocols for non-muscle invasive bladder cancer only as induction courses. Cho et al. (Anticancer Res 2012) compared BCG-RIVM induction and 'standard' maintenance (Lamm et al., J Urol. 2000) to mitomycin C. They found no statistically significant differences regarding disease recurrence and progression. The purpose of our study was to determine the efficacy & tolerability of this specific BCG RIVM strain, using six weekly, induction course and single monthly instillations as maintenance for one year, in high risk recurrent, multifocal low grade and multifocal high grade pTa/pT1, CIS transitional cell carcinoma of bladder. METHODS: From 2003-2012, BCG naive patients treated with intravesical BCG-RIVM for high-risk multifocal NMIBC were identified. Transurethral resection of bladder tumor (TURBT) and re-staging TURBT within six weeks, was done for accurate staging and complete elimination of disease. A six-weekly induction course, started 2-3 weeks after the last TURBT, followed by monthly maintenance protocol for one year. Recurrence, progression, cystectomy free survivals, cancer specific and over-all survival were determined. RESULTS: Sixty evaluable patients--median age 63, median follow-up 3.98 years. Forty-two patients (70%) completed BCG-RIVM treatment as planned. BCG termination was necessary in 18 patients (30%). Recurrence occurred in 16 patients (26.7%) at a median follow-up of 24.2 months while progression occurred in five patients (8.3%) at a median follow-up of 33 months. Recurrence-free survival and progression-free survival rates were 73% and 92% respectively. Cystectomy was performed in seven patients (12%) with a cystectomy-free survival of 88%. There were no cancer specific deaths. Two patients died of other causes (3.3%). The overall survival rate was 97%. CONCLUSIONS: Our study is the first to show the clinical efficacy and tolerability of BCG-RIVM strain in the management of high risk NMIBC when given in a schedule of six-weekly induction with monthly maintenance for one year. Our maintenance protocol, achieved equivalent recurrence-free, progression-free, disease specific survival and overall survival to the reported literature and the more intense three-years South West Oncology Group (SWOG) protocol. PMID- 24468270 TI - First genome sequences of Achromobacter phages reveal new members of the N4 family. AB - BACKGROUND: Multi-resistant Achromobacter xylosoxidans has been recognized as an emerging pathogen causing nosocomially acquired infections during the last years. Phages as natural opponents could be an alternative to fight such infections. Bacteriophages against this opportunistic pathogen were isolated in a recent study. This study shows a molecular analysis of two podoviruses and reveals first insights into the genomic structure of Achromobacter phages so far. METHODS: Growth curve experiments and adsorption kinetics were performed for both phages. Adsorption and propagation in cells were visualized by electron microscopy. Both phage genomes were sequenced with the PacBio RS II system based on single molecule, real-time (SMRT) technology and annotated with several bioinformatic tools. To further elucidate the evolutionary relationships between the phage genomes, a phylogenomic analysis was conducted using the genome Blast Distance Phylogeny approach (GBDP). RESULTS: In this study, we present the first detailed analysis of genome sequences of two Achromobacter phages so far. Phages JWAlpha and JWDelta were isolated from two different waste water treatment plants in Germany. Both phages belong to the Podoviridae and contain linear, double stranded DNA with a length of 72329 bp and 73659 bp, respectively. 92 and 89 putative open reading frames were identified for JWAlpha and JWDelta, respectively, by bioinformatic analysis with several tools. The genomes have nearly the same organization and could be divided into different clusters for transcription, replication, host interaction, head and tail structure and lysis. Detailed annotation via protein comparisons with BLASTP revealed strong similarities to N4-like phages. CONCLUSIONS: Analysis of the genomes of Achromobacter phages JWAlpha and JWDelta and comparisons of different gene clusters with other phages revealed that they might be strongly related to other N4-like phages, especially of the Escherichia group. Although all these phages show a highly conserved genomic structure and partially strong similarities at the amino acid level, some differences could be identified. Those differences, e.g. the existence of specific genes for replication or host interaction in some N4-like phages, seem to be interesting targets for further examination of function and specific mechanisms, which might enlighten the mechanism of phage establishment in the host cell after infection. PMID- 24468271 TI - Expression of recombinant human IL-4 in Pichia pastoris and relationship between its glycosylation and biological activity. AB - Secretory human interleukin 4 (hIL4) is an N-glycosylated pleiotropic cytokine. It is unknown if these N-linked glycans are required and essential for hIL4 protein stability, expression, secretion, and activity in vivo, and hIL4 expressed from Pichia pastoris yeast has not been tested to date. In this study, we successfully expressed human hIL4 in P. pastoris, the methylotrophic yeast, with a yield of 15.0mg/L. Using the site-directed mutagenesis technique, we made two mutant hIL4 cDNA clones (N38A and N105L) and subsequently expressed them in P. pastoris to analyze the relevant function of each N-glycosylation site on hIL4. Our results demonstrate that the glycosylation only occurs at position Asn38, but not Asn105. The glycosylated form of hIL4 unexpectedly has lower biological activity and lower stability when compared to its non-glycosylated form. The implications of this are discussed. PMID- 24468272 TI - Influence of various antioxidants added to TCM-199 on post-thaw bovine sperm parameters, DNA integrity and fertilizing ability. AB - Supplementation of the semen extender with antioxidants did not produce any significant effect on CASA and progressive motilities and sperm motility characteristics, in comparison to the control group (P > 0.05). For sperm acrosome and total abnormalities, TCM-199 supplemented with cysteine (2.60 +/- 0.24% and 4.80 +/- 0.20%), glutamine (2.80 +/- 0.20% and 6.40 +/- 0.40%), carnitine (2.60 +/- 0.24% and 6.00 +/- 0.63%) and methionine (3.40 +/- 0.51% and 9.20 +/- 0.86%) at doses of 2 mM provided a better protective effect, compared to that of the controls (8.00 +/- 0.44 and 15.60 +/- 1.895). As regards sperm membrane integrity, supplementation with 2 mM of glutamine and methionine (56.00 +/- 1.70% and 62.40 +/- 1.78%, respectively) resulted in higher rates, when compared to the control group (41.40 +/- 4.74%). According to the results of the COMET assay, only the use of TCM-199 supplemented with 2 mM of cysteine reduced DNA damage and resulted in percentages of sperm with damaged DNA (2.17 +/- 0.18%) lower than those of the control group (3.16 +/- 0.32%) (P < 0.001). For pregnancy rates, there were no significant differences among the extender groups (P > 0.05). PMID- 24468273 TI - Tributyltin contributes in reducing the vascular reactivity to phenylephrine in isolated aortic rings from female rats. AB - Organotin compounds such as tributyltin (TBT) are used as antifouling paints by shipping companies. TBT inhibits the aromatase responsible for the transformation of testosterone into estrogen. Our hypothesis is that TBT modulates the vascular reactivity of female rats. Female Wistar rats were treated daily (Control; CONT) or TBT (100 ng/kg) for 15 days. Rings from thoracic aortas were incubated with phenylephrine (PHE, 10(-10)-10(-4) M) in the presence and absence of endothelium, and in the presence of N(G)-Nitro-L-Arginine Methyl Ester (L-NAME), tetraethylammonium (TEA) and apocynin. TBT decreased plasma levels of estrogen and the vascular response to PHE. In the TBT group, the vascular reactivity was increased in the absence of endothelium, L-NAME and TEA. The decrease in PHE reactivity during incubation with apocynin was more evident in the TBT group. The sensitivity to acetylcholine (ACh) and sodium nitroprusside (SNP) was reduced in the TBT group. TBT increased collagen, reduced alpha1-smooth muscle actin. Female rats treated with TBT for 15 days showed morphology alteration of the aorta and decreased their vascular reactivity, probably due to mechanisms dependent on nitric oxide (NO) bioavailability, K(+) channels and an increase in oxidative stress. PMID- 24468275 TI - Can hepatitis C virus infection be eradicated in people who inject drugs? AB - People who inject drugs (PWID) represent the core of the hepatitis C virus (HCV) epidemic in many countries and HCV-related disease burden continues to rise. There are compelling data demonstrating that with the appropriate programs, treatment for HCV infection among PWID is successful, with responses to therapy similar those observed in large randomized controlled trials in non-PWID. However, assessment and treatment for HCV infection lags far behind the numbers who could benefit from therapy, related to systems-, provider- and patient related barriers to care. The approaching era of interferon-free directly acting antiviral therapy has the potential to provide one of the great advances in clinical medicine. Simple, tolerable and highly effective therapy will likely address many of these barriers, thereby enhancing the numbers of PWID cured of HCV infection. This commentary will consider why we should strive for the eradication of HCV infection among PWID, whether eradication of HCV infection among PWID is feasible, components that would be needed to achieve eradication of HCV infection in PWID, potential settings and strategies required to establish programs targeted towards eradicating HCV infection among PWID and the feasibility of eradication versus elimination of HCV infection among PWID. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication." PMID- 24468277 TI - What is the future of ribavirin therapy for hepatitis C? AB - With the introduction of direct-acting antiviral (DAA) therapy against hepatitis C virus (HCV) infection, the field is rapidly evolving towards interferon-free regimens with high sustained virologic response (SVR) rates. The ultimate goal of therapy in chronic HCV infection should include an easily dosed all-oral regimen that is highly effective, inexpensive, pan-genotypic, safe and tolerable, with minimal to no resistance. Various investigational DAA regimens are currently under evaluation with and without ribavirin (Rbv). With the projected arrival of improved therapies over the next 5years, the future role of Rbv comes into question. Despite being plagued by the lack of understanding of its mechanism of action and significant side effects such as anemia, Rbv has been a part of the standard-of-care therapies in chronic HCV infection for more than 10years. As we look towards the future HCV therapy, Rbv may still have utility in the care of patients infected with HCV because of its low cost and potentially added value in combination with other DAAs. This article forms part of a symposium in Antiviral Research on "Hepatitis C: next steps toward global eradication." PMID- 24468276 TI - Peptide inhibitor of Japanese encephalitis virus infection targeting envelope protein domain III. AB - Japanese encephalitis virus (JEV) is a major cause of acute viral encephalitis in both humans and animals. Domain III of the virus envelope glycoprotein (E DIII) plays an important role in the interaction of viral particles with host cell receptors to facilitate viral entry. Intervention of the interaction between E DIII and its cognate host cell receptor would provide an important avenue for inhibiting JEV infection. A phage display peptide library was therefore panned against E DIII, which resulted in the identification of several peptides. One peptide, named P3, inhibited JEV infection of BHK-21 cells with an IC50 of ~1 MUM and an IC90 at ~100 MUM. Further characterization revealed that P3 bound to E DIII with a K(d) of 6.06 * 10-6 M and inhibited JEV infection by interfering with viral attachment to cells. Based on in silico prediction by ZDOCK, P3 was found to interact with E DIII via a hydrophobic pocket, which was confirmed by the binding assay of P3 to the V357A mutant. P3 was hypothesized to bind to E DIII by interacting with the sties adjacent to the BC and DE loops, which might interfere with the binding of JEV to cellular receptors, thus impeding viral infection. This newly isolated peptide may represent a new therapeutic candidate for treatment of JEV. PMID- 24468278 TI - Functional outcomes by reconstruction technique following laparoscopic proximal gastrectomy for gastric cancer: double tract versus jejunal interposition. AB - BACKGROUND: For early gastric cancer located in the upper third of the stomach, we have adopted laparoscopic 1/2-proximal gastrectomy (PG) with two types of reconstruction: double tract reconstruction (L-DT) and jejunal interposition reconstruction with crimping of the jejunum on the anal side of the jejunogastrostomy with a knifeless linear stapler (L-JIP). METHODS: Functional outcomes were prospectively compared between these two types of reconstruction following laparoscopic PG. Resection and reconstruction were performed using L-DT (n = 10) and L-JIP (n = 10) alternately. Quality of life was evaluated through a questionnaire and endoscopic examination of the ten patients in each group, and functional evaluations were carried out in five patients of each group. RESULTS: The postoperative/preoperative body weight ratio was significantly higher in the L-JIP group than in the L-DT group. While the incidence of reflux esophagitis was 10% in both groups, the endoscope could reach the remnant stomach in all patients. In the L-DT group, the plasma acetaminophen concentration at 15 minutes and the insulin level at 30 minutes were markedly increased after oral administration, while the increases in the blood sugar level at 30 and 60 minutes were more gradual than in the L-JIP group. CONCLUSIONS: While L-JIP may be thought of as the ideal method for function-preserving gastrectomy, L-DT may be suitable for gastric cancer patients with impaired glucose tolerance. These results raise the possibility of individualized selection of reconstruction for gastric cancer patients with various kinds of preoperative complications. PMID- 24468279 TI - Endometriosis and susceptibility to tuberculosis: is interferon-gamma the critical player? PMID- 24468280 TI - Investigating the clinical significance of mesh peritonization in abdominal vault suspension surgery using a comparative rabbit model. AB - OBJECTIVE: To investigate the clinical significance of mesh peritonization in an experimental rabbit model. STUDY DESIGN: Twenty rabbits were randomly assigned to two groups. A sacrouteropexy operation was performed in both groups using a polypropylene mesh. In the first group, the pelvic peritoneum was not closed over the mesh, and in the second group, the mesh was buried throughout the pelvic retroperitoneal tunnel. One month after mesh implantation, the abdomen was opened and the previous surgical site was explored. The primary outcome was intraabdominal adhesion formation; the secondary outcome was the histologic degree of tissue remodeling. RESULTS: There were no statistically significant differences between the two groups in terms of adhesion scores and collagen organization (P=0.692, P=0.097, respectively). There was a greater degree of inflammation in the second group as identified by significantly higher scores for eosinophils-neutrophils, macrophages-foreign body giant cells and mononuclear cells (P=0.002, P=0.001 and P=0.002, respectively). CONCLUSIONS: Similar adhesion and collagen organization patterns were found in both groups, but indicators of the inflammatory process were significantly higher in the second group. PMID- 24468281 TI - Determination of antibiotic consumption index for animal originated foods produced in animal husbandry in Iran, 2010. AB - The public health concerns over the long-term exposure to antibiotics have risen in different parts of the world. The purpose of this study was to investigate the antibiotic consumption pattern in livestock and poultry and to estimate the quantity of antibiotic active ingredient (mg) consumed per unit weight (Kg) of red meat, milk and egg production in Iran in 2010. A cross-sectional study was designed in charmahal - bakhtiary province-Iran. A questioner has been developed by naming 110 types of antibiotics. Twenty two veterinary clinicians and three livestock pharmaceutical distributor companies were included in the survey to determine the antibiotic prescription and distribution pattern in the farms. Veterinary organization of Iran supplied the information of the total antibiotic consumption in different dosage forms. National and international data on the livestock and poultry production were obtained from the relevant official web sites. Tetracycline class of antibiotics was the most common types of antibacterial prescribed and sold to both livestock and poultry farms. Amino glycoside, penicillin and macrolide in the cattle farms and furofenocole in broiler farms were the second most used groups of antibiotics. The quantity of antibiotic active ingredients consumed per unit weight of animal-originated food products was counted as 107.4 mg/kg for both milk and red meat and 249.5 mg/kg for broiler meat and egg. Totally, it was estimated that 133 mg antibiotic substances was used per kg of milk, meat and egg produced in 2010. In comparison to available data for other countries, consumption of antibiotics in livestock and poultry in Iran is higher than developed countries with an exception of South Korea. The findings of the present study could be alarming for the legislative authorities in food security and safety. More clear evaluation should be carried out as well as implementation of national monitoring and inspective programs in order to reach an added safety regarding animal-originated foods. PMID- 24468282 TI - Expression of proteins associated with adipocyte lipolysis was significantly changed in the adipose tissues of the obese spontaneously hypertensive/NDmcr-cp rat. AB - BACKGROUND: The etiology of the metabolic syndrome is complex, and is determined by the interplay of both genetic and environmental factors. The present study was designed to identify genes and proteins in the adipose tissues with altered expression in the spontaneously hypertensive/NIH -corpulent rat, SHR/NDmcr-cp (CP) and to find possible molecular targets associated with the pathogenesis or progression of obesity related to the metabolic syndrome. METHODS: We extracted RNAs and proteins from the epididymal adipose tissues in CP, SHR/Lean (Lean), and Wistar Kyoto (WKY) rats and performed microarray analysis and two-dimensional difference in gel electrophoresis (2D-DIGE) linked to a matrix-assisted laser desorption ionization time-of-flight tandem mass spectrometry (MALDI-TOF/TOF MS). RESULTS: The results showed different mRNA and protein expression levels in the adipose tissue: oligo DNA microarray identified 33 genes that were significantly (P < 0.01) up-regulated and 17 genes significantly down-regulated in CP compared with WKY and Lean rats at both 6 and 25 weeks of age. The affected genes-proteins were associated with lipolytic enzymes stimulated by peroxisome proliferator activated receptor (PPAR) signaling. Further analysis using the 2D-DIGE connected with MALDI-TOF/TOF analysis, the expression of monoglyceride lipase (MGLL) was significantly up-regulated and that of carboxylesterase 3 (CES3) was significantly down-regulated in 6- and 25-week-old CP compared with age-matched control (WKY and Lean rats). CONCLUSIONS: Our results suggest the possible involvement of proteins associated with adipocyte lipolysis in obesity related to the metabolic syndrome. PMID- 24468283 TI - Follow-up outcomes of hybrid procedures for thoracoabdominal aortic pathologies with special focus on graft patency and late mortality. AB - OBJECTIVE: The purpose of this study was to analyze midterm results of bypass patency and overall and aortic-related mortality rates of hybrid aortic procedures for thoracoabdominal aortic pathologies. METHODS: A retrospective study was performed considering prospectively collected data in two centers. From January 2001 to December 2012, 45 patients (33 men; mean age, 67.8 +/- 7.6 years) received hybrid aortic procedures for thoracoabdominal aortic diseases (31 atherosclerotic aneurysms, 7 chronic expanding type B aortic dissections, 2 penetrating aortic ulcers, and 5 pseudoaneurysms), corresponding to 155 revascularized visceral abdominal arteries. Elective/emergency and staged/simultaneous approaches were 31 of 14 and 28 of 17, respectively. Patient demographics, clinical risk factors, and aortic morphological and procedural data were collected. End points were technical success, 30-day morbidity, reintervention and mortality, bypass graft patency, freedom from reintervention, and overall and aortic-related mortality during midterm follow-up. Mean follow-up was 2.2 +/- 2.4 years. RESULTS: Technical success was achieved in 86.6% (39/45) of patients. Thirty-day morbidity rate was 60% (paraplegia/paraparesis: 13.3%, stroke: 6.7%, renal failure: 31.3%, permanent dialysis: 4.4%). Thirty-day freedom from reintervention rates were 67.1% and 78.5%, respectively. Thirty-day occlusion of revascularized visceral vessels occurred in 11 (7.1%, 11/155) target arteries. In-hospital mortality rate was 24.4%. Primary graft patency after 1, 2, and 4 years was 89.7%, 85.3%, and 79%, respectively. Bypass thrombosis or stenosis developed in nine (6.8%, 9/132) vessels during follow-up. Of these, three patients required reintervention and one died. Freedom from reintervention rates after 1, 2, and 4 years were 45.6%, 45.6%, and 34.2%, respectively. Overall and aortic-related mortality rates after 1, 2, and 4 years were 32.6%, 41.4%, and 45.3% and 9.1%, 13.9%, and 13.9%, respectively. CONCLUSIONS: A hybrid procedure for thoracoabdominal aortic pathologies in high-risk patient is feasible but carries a significant rate of early and midterm reintervention and death. Long term surveillance of the visceral bypass is necessary because one-third of the patients will have bypass-related complications. PMID- 24468284 TI - Assessment of abdominal branch vessel patency after bare-metal stenting of the thoracoabdominal aorta in a human ex vivo model of acute type B aortic dissection. AB - OBJECTIVE: The purpose of this study was to assess the efficiency of bare-metal stenting of the thoracoabdominal aorta in a human ex vivo model of acute type B aortic dissection and the impact of this approach on the patency of the visceral and renal arteries. METHODS: Fifteen human cadaveric aortas were harvested. Type B aortic dissections were surgically initiated 2 cm below the left subclavian artery. Aortas were thereafter connected to a bench top pulsatile flow to induce propagation of the dissection. A 5-mm 30 degrees lens (Richard Wolf, Vernon Hills, Ill) was introduced successively into the false lumen and the true lumen to monitor the propagation of the dissection. Bare-metal stents were deployed into the true lumen from the primary entry tear to the infrarenal aorta. Measurement of systolic pressure was taken within the abdominal branch vessels before and after stenting. A pressure gradient drop of 15 mm Hg or more after bare-metal stenting was considered hemodynamically relevant. RESULTS: Dissection was propagated at least to the renal aorta in 11 cases (73%) and to the infrarenal aorta in 3 cases (20%). Of the 60 abdominal branch vessels studied, 22 (36.7%) were supplied by the false lumen. After extensive aortic bare-metal stenting, complete reattachment of the dissection flap was observed in all cases. Regarding visceral and renal artery patency after bare-metal stenting, a significant pressure gradient drop was reported in 54.5% (n = 12) when these arteries were supplied by the false lumen, whereas those originating from the true lumen had a significantly less common pressure gradient drop (7.9% [n = 3]; P < .0001). CONCLUSIONS: Bare-metal stenting in this model of acute type B aortic dissection was effective in true lumen reexpansion but induced a high (54.5%) rate of significant pressure drop in the visceral and renal arteries when they were supplied by the false lumen. PMID- 24468285 TI - Severe bilateral renal artery stenosis after transluminal radiofrequency ablation of renal sympathetic nerve plexus. AB - Percutaneous renal sympathetic denervation is an evolving therapy for resistant hypertension. Evidence to date demonstrates a reduction of blood pressure in the short term to medium term. Reported complications relate to problems with vascular access vessels and dissection of the renal artery. Renal artery stenosis has not been described in the literature. We present a patient with hypertensive crisis, flash pulmonary edema, and deterioration of renal function, secondary to bilateral renal artery stenosis, 9 months after renal sympathetic radiofrequency ablation denervation. PMID- 24468287 TI - Successful use of extracorporeal membrane oxygenation in the reversal of cardiorespiratory failure induced by atonic uterine bleeding: a case report. AB - INTRODUCTION: Although extracorporeal membrane oxygenation has made sufficient progress to be considered for the management of life-threatening cardiac and respiratory failure, the risk of hemorrhagic complications may outweigh the benefits for patients with bleeding tendencies. We report, to the best of our knowledge, the first case of successful treatment by extracorporeal membrane oxygenation, without any hemorrhagic complications, of postpartum cardiorespiratory failure after massive uterine bleeding. CASE PRESENTATION: A 25 year-old Japanese woman experienced massive atonic bleeding after delivering her second baby. Recovery from hemorrhagic shock was managed by conservative treatments, but she developed decompensated heart failure and refractory hypoxia. Because we could not obtain hemodynamic stability and proper oxygenation even with high doses of catecholamines and maximal ventilator settings, we administered venoarterial extracorporeal membrane oxygenation, whereupon her hemodynamic status immediately stabilized. After 72 hours of support without major bleeding, extracorporeal membrane oxygenation was successfully withdrawn. CONCLUSION: Even in cases of obstetric bleeding, if clotting status is stringently monitored, extracorporeal membrane oxygenation can be considered as an ultimate means of life support. PMID- 24468286 TI - Cilostazol is associated with improved outcomes after peripheral endovascular interventions. AB - OBJECTIVE: Although cilostazol is commonly used as an adjunct after peripheral vascular interventions, its efficacy remains uncertain. We assessed the effect of cilostazol on outcomes after peripheral vascular interventions using meta analytic techniques. METHODS: We searched MEDLINE (1946-2012), Cochrane CENTRAL (1996-2012), and trial registries for studies comparing cilostazol in combination with antiplatelet therapy to antiplatelet therapy alone after peripheral vascular interventions. Treatment effects were reported as pooled risk/hazard ratio (HR) with random-effects models. RESULTS: Two randomized trials and four retrospective cohorts involving 1522 patients met inclusion criteria. Across studies, mean age ranged from 65 to 76 years, and the majority of patients were male (64%-83%); mean follow-up ranged from 18 to 37 months. Most interventions were in the femoropopliteal segment, and overall, 68% of patients had stents placed. Pooled estimates demonstrated that the addition of cilostazol was associated with decreased restenosis (relative risk [RR], 0.71; 95% confidence interval [CI], 0.60-0.84; P < .001), improved amputation-free survival (HR, 0.63; 95% CI, 0.47 0.85; P = .002), improved limb salvage (HR, 0.42; 95% CI, 0.27-0.66; P < .001), and improved freedom from target lesion revascularization (RR, 1.36; 95% CI, 1.14 1.61; P < .001). There was no significant reduction in mortality among those receiving cilostazol (RR, 0.73; 95% CI, 0.45-1.19; P = .21). CONCLUSIONS: The addition of cilostazol to antiplatelet therapy after peripheral vascular interventions is associated with a reduced risk of restenosis, amputation, and target lesion revascularization in our meta-analysis of six studies. Consideration of cilostazol as a medical adjunct after peripheral vascular interventions is warranted, presuming these findings are broadly generalizable. PMID- 24468288 TI - Expression profile of CD44s, CD44v6, and CD44v10 in localized prostate cancer: effect on prognostic outcomes following radical prostatectomy. AB - OBJECTIVES: To investigate the expression of CD44 standard form (CD44s) and 2 major variant exons (CD44v6 and CD44v10) in localized prostate cancer (PC) to determine the prognostic significance of these markers following radical prostatectomy (RP). MATERIALS AND METHODS: Expression levels of CD44s, CD44v6, and CD44v10 in RP specimens from 160 consecutive patients with clinically localized PC were evaluated by immunohistochemical staining. RESULTS: Of these 3 markers, expression level of CD44v6 was closely associated with several conventional prognostic factors. Univariate analysis identified CD44v6 expression in addition to serum prostate-specific antigen level, Gleason score, seminal vesicle invasion, and surgical margin status as significant predictors for biochemical recurrence (BR). Of these significant factors, CD44v6 expression, serum prostate-specific antigen level, and surgical margin status appeared to be independently associated with BR on multivariate analysis. We observed significant differences in BR-free survival according to the positive numbers of these 3 independent factors; i.e., BR occurred in 0 (0%) of 42 patients who had negative results for risk factors, 9 (16.7%) of 54 who had positive results for 1 risk factor, and 31 (48.4%) of 64 who had positive results for 2 or 3 risk factors. CONCLUSIONS: Assessment of the expression levels of CD44v6 in RP specimens in addition to conventional prognostic parameters would contribute to the accurate prediction of the biochemical outcome in patients with localized PC who underwent RP. PMID- 24468289 TI - Structure of MST2 SARAH domain provides insights into its interaction with RAPL. AB - The STE20 kinases MST1 and MST2 are key players in mammalian Hippo pathway. The SARAH domains of MST1/2 act as a platform to mediate homodimerization and hetero interaction with a range of adaptors including RASSFs and Salvador, which also possess SARAH domains. Here, we determined the crystal structure of human MST2 SARAH domain, which forms an antiparallel homodimeric coiled coil. Structural comparison indicates that SARAH domains of different proteins may utilize a shared dimerization module to form homodimer or heterodimer. Structure-guided mutational study identified specific interface residues critical for MST2 homodimerization. MST2 mutations disrupting its homodimerization also impaired its hetero-interaction with RAPL (also named RASSF5 and NORE1), which is mediated by their SARAH domains. Further biochemical and cellular assays indicated that SARAH domain-mediated homodimerization and hetero-interaction with RAPL are required for full activation of MST2 and therefore apoptotic functions in T cells. PMID- 24468290 TI - Automatic cryo-EM particle selection for membrane proteins in spherical liposomes. AB - Random spherically constrained (RSC) single particle reconstruction is a method to obtain structures of membrane proteins embedded in lipid vesicles (liposomes). As in all single-particle cryo-EM methods, structure determination is greatly aided by reliable detection of protein "particles" in micrographs. After fitting and subtraction of the membrane density from a micrograph, normalized cross correlation (NCC) and estimates of the particle signal amplitude are used to detect particles, using as references the projections of a 3D model. At each pixel position, the NCC is computed with only those references that are allowed by the geometric constraint of the particle's embedding in the spherical vesicle membrane. We describe an efficient algorithm for computing this position dependent correlation, and demonstrate its application to selection of membrane protein particles, GluA2 glutamate receptors, which present very different views from different projection directions. PMID- 24468291 TI - Adeno-associated virus type 2 preferentially integrates single genome copies with defined breakpoints. AB - BACKGROUND: Adeno-associated virus (AAV) serotype 2 prevalently infects humans and is the only described eukaryotic virus that integrates site-preferentially. In a recent high throughput study, the genome wide distribution of AAV-2 integrants was determined using Integrant Capture Sequencing (IC-Seq). Additional insight regarding the integration of AAV-2 into human genomic DNA could be gleaned by low-throughput sequencing of complete viral-chromosomal junctions. FINDINGS: In this study, 140 clones derived from Integrant-Capture Sequencing were sequenced. 100 met sequence inclusion criteria, and of these 39 contained validated junction sequences. These unique sequences were analyzed to investigate the structure and location of viral-chromosomal junctions. CONCLUSIONS: Overall the low-throughput analysis confirmed the genome wide distribution profile gathered through the IC-Seq analysis. We found no unidentifiable sequence inserted at AAV-2 chromosomal junctions. Assessing both left and right ends of the AAV genome, viral breakpoints predominantly occurred in one hairpin of the inverted terminal repeat and AAV genomes were preferentially integrated as single copies. PMID- 24468292 TI - Routes of transmission during a nosocomial influenza A(H3N2) outbreak among geriatric patients and healthcare workers. AB - BACKGROUND: Influenza presents a life-threatening infection for hospitalized geriatric patients, who might be nosocomially infected via healthcare workers (HCWs), other patients or visitors. In the 2011/2012 influenza season an influenza A(H3N2) outbreak occurred in the geriatric department at the Hopital Edouard Herriot, Lyon. AIM: To clarify the transmission chain for this influenza A(H3N2) outbreak by sequence analysis and to identify preventive measures. METHODS: Laboratory testing of patients with influenza-like illness in the acute care geriatric department revealed 22 cases of influenza between 19th February and 15th March 2012. Incidences for patients and HCWs were calculated and possible epidemiological links were analysed using a questionnaire. Neuraminidase and haemagglutinin genes of culture-positive samples and community influenza samples were sequenced and clustered to detect patients with identical viral strains. FINDINGS: Sixteen patients and six HCWs were affected, resulting in an attack rate of 24% and 11% respectively. Six nosocomial infections were recorded. The sequence analysis confirmed three independent influenza clusters on three different sections of the geriatric ward. For at least two clusters, an HCW source was determined. CONCLUSION: Epidemiological and microbiological results confirm influenza transmission from HCWs to patients. A higher vaccination rate, isolation measures and better hand hygiene are recommended in order to prevent outbreaks in future influenza seasons. PMID- 24468293 TI - Importance of subject-specific QT/RR curvatures in the design of individual heart rate corrections of the QT interval. PMID- 24468294 TI - Curing kinetics of visible light curing dental resin composites investigated by dielectric analysis (DEA). AB - During the curing process of light curing dental composites the mobility of molecules and molecule segments is reduced leading to a significant increase of the viscosity as well as the ion viscosity. Thus, the kinetics of the curing behavior of 6 different composites was derived from dielectric analysis (DEA) using especially redesigned flat sensors with interdigit comb electrodes allowing for irradiation at the top side and measuring the ion viscosity at the bottom side. As the ion viscosities of dental composites change 1-3 orders of magnitude during the curing process, DEA provides a sensitive approach to evaluate their curing behavior, especially in the phase of undisturbed chain growth. In order to determine quantitative kinetic parameters a kinetic model is presented and examined for the evaluation of the ion viscosity curves. From the obtained results it is seen that DEA might be employed in the investigation of the primary curing process, the quality assurance of ingredients as well as the control of processing stability of the light curing dental composites. PMID- 24468295 TI - INO80-dependent regression of ecdysone-induced transcriptional responses regulates developmental timing in Drosophila. AB - Sequential pulses of the steroid hormone ecdysone regulate the major developmental transitions in Drosophila, and the duration of each developmental stage is determined by the length of time between ecdysone pulses. Ecdysone regulates biological responses by directly initiating target gene transcription. In turn, these transcriptional responses are known to be self-limiting, with mechanisms in place to ensure regression of hormone-dependent transcription. However, the biological significance of these transcriptional repression mechanisms remains unclear. Here we show that the chromatin remodeling protein INO80 facilitates transcriptional repression of ecdysone-regulated genes during prepupal development. In ino80 mutant animals, inefficient repression of transcriptional responses to the late larval ecdysone pulse delays the onset of the subsequent prepupal ecdysone pulse, resulting in a significantly longer prepupal stage. Conversely, increased expression of ino80 is sufficient to shorten the prepupal stage by increasing the rate of transcriptional repression. Furthermore, we demonstrate that enhancing the rate of regression of the mid prepupal competence factor betaFTZ-F1 is sufficient to determine the timing of head eversion and thus the duration of prepupal development. Although ino80 is conserved from yeast to humans, this study represents the first characterization of a bona fide ino80 mutation in any metazoan, raising the possibility that the functions of ino80 in transcriptional repression and developmental timing are evolutionarily conserved. PMID- 24468296 TI - Intraoperative radiological margin assessment in breast-conserving surgery. AB - A prospective study was lead in order to analyze the accuracy of an X-ray device settled in the operating room for margin assessment, when performing breast conserving surgery. PATIENTS AND METHODS: One hundred and seventy patients were included. All lesions were visible on the preoperative mammograms. An intraoperative X-ray of the lumpectomy specimen was systematically performed for margins assessment. Final histological data were collected and the accuracy of intraoperative specimen radiography (IOSR) for margin assessment was analyzed. RESULTS: IOSR allowed an evaluation of margins status in 155 cases (91.2%). After final histological examination, the positive margins rate would have been 6.5% if margin assessment had relied only on IOSR. CONCLUSION: Margin assessment with a two-dimensional X-ray device would have allowed the achievement of negative margins in 93.5% of the cases. Moreover, this procedure allows important time saving and could have a substantial economical impact. PMID- 24468297 TI - Is the health status of female victims poorer than males in the post-disaster reconstruction in China: a comparative study of data on male victims in the first survey and double tracking survey data. AB - BACKGROUND: The health of females is more at risk during disasters. Studies that focus on the comparison of males and time span are few. This article focuses on the health-related quality of life (HRQOL) of female victims in the post-disaster reconstruction in China. We aim to reduce gender health inequalities by comparing and analyzing gender differences in HRQOL. Moreover, we analyze the trends in HRQOL of female victims by using tracking data, and then provide reasonable suggestions to enhance the HRQOL. METHODS: This article explores the HRQOL of women victims in the post-disaster reconstruction from two perspectives: a comparison between males and a time span of six-month intervals. We conducted the first survey, and the double tracking survey in 2013. This study uses data from half a year later sample surveys collected from five counties (Wenchuan, Qingchuan, Mianzhu, Lushan, and Dujiangyan) in Sichuan in 2013 (N = 2000). RESULTS: (1) By calculating the Cronbach's alpha coefficients of the SF-12 scale, we found that that reliability of the scale and the internal consistency are good. (2) Using SF-12 instead of SF-36 to measure the HRQOL of survivors is feasible. (3) The ANOVA and non-parametric testing methods show that significant differences exist between the eight dimensions of HRQOL in different genders after the earthquake. (4) After six months, the HRQOL of female victims in the post-disaster reconstruction has also undergone a significant change. (5) Compared with male victims, we should give more attention to female victims' HRQOL issues in the post-disaster reconstruction in Sichuan. (6) The performances of victims in the post-disaster reconstruction in PCS and MCS affect each other. CONCLUSION: We found that in terms of gender, the male and female victims' HRQOL after the disaster largely varied: (1) In general, significant difference exists between male and female victims in terms of HRQOL. The HRQOL of female victims is poorer than that of male victims. (2) The PCS and MCS of victims affect each other. However, for female victims, the degree of influence of MCS on PCS is larger than that in males. (3) The MCS of female victims is more vulnerable than that of male victims. In terms of time span, the following information was obtained: (1) after six months of rest, victims' HRQOL significantly improved. (2) At this stage, relative to the MCS, the PCS of females should be given more attention. PMID- 24468298 TI - Does obesity interfere with anastrozole treatment? Positive association between body mass index and anastrozole plasma levels. AB - INTRODUCTION: The efficacy of adjuvant endocrine treatment with aromatase inhibitors (AIs), inhibiting the conversion of androgens to estrogen in adipose tissue, might depend on the overall volume of adipose tissue. However, little evidence is available regarding the pharmacokinetic behavior of AIs in women with obesity. The aim of this study was to investigate the interaction between body mass index (BMI) and anastrozole treatment as well as estrogenic activity. PATIENTS AND METHODS: A total of 216 postmenopausal patients with early-stage breast cancer who were receiving AI treatment with anastrozole constituted the final sample included in the analysis. During a regular 3-month after-care check up, sociodemographic and clinical data and BMI were assessed. Blood samples were collected during routine blood testing. Measurement of AI plasma levels was performed by liquid chromatography-tandem mass spectrometry. Follicle stimulating hormone (FSH) and estradiol were measured within the routine blood examination. RESULTS: A median anastrozole plasma concentration of 34.7 ng/mL (mean, 37.4), with a large interindividual variability, was observed (SD, 15.1; range, 5.4 86.5). After age adjustment, it was found that anastrozole plasma concentrations significantly increased with BMI (r = 0.241; P = .001). Anastrozole serum concentrations in women with obesity (BMI >= 30) exceeded those of women with normal weight (BMI <= 25) by 25%. Women with excess weight had lower mean FSH levels, indicating higher estrogenic activity, compared with women with normal weight. CONCLUSION: This study indicates that BMI is a vital factor in anastrozole metabolism, as measured by anastrozole plasma concentration and FSH levels. Further research is mandatory to clarify results on the association of obesity and AI treatment efficacy to allow adapting AI treatment accordingly. PMID- 24468299 TI - Survival and surgical outcomes of cardiac cancer of the remnant stomach in comparison with primary cardiac cancer. AB - BACKGROUND: Although cardiac cancer of the remnant stomach and primary cardiac cancer both occur in the same position, their clinical characteristics and outcomes have not been compared previously. The objective of this study was designed to evaluate the prognosis of cardiac cancer of the remnant stomach in comparison with primary cardiac cancer. METHODS: In this retrospective comparative study, clinical data and prognosis were compared in 48 patients with cardiac cancer of the remnant stomach and 96 patients with primary cardiac cancer who underwent radical resection from January 1995 to June 2007. Clinicopathologic characteristics, survival times, mortality, and complications were analyzed. RESULTS: The 5-year survival rate was significantly higher in patients with primary cardiac cancer than in those with cardiac cancer of the remnant stomach (28.4% vs. 16.7%, P = 0.035). Serosal invasion, lymph node metastasis and tumor location were independent prognostic factors for survival. Subgroup analysis, however, showed similar survival rates in patients with primary cardiac cancer and cardiac cancer of the remnant stomach without serosal invasion (25.0% vs. 43.8%, P = 0.214) and without lymph node metastasis (25.0% vs. 38.8%, P = 0.255), as well as similar complication rates (20.8% vs. 11.5%, P = 0.138). CONCLUSION: Although the survival rates after radical resection in patients with cardiac cancer of the remnant stomach were poorer than in those with primary cardiac cancer, they were similar in survival rates when patients without serosal invasion or lymph node metastasis. Therefore, early detection is an important way to improve overall survival in cardiac cancer of the remnant stomach. PMID- 24468300 TI - [A solitary kidney patient with diarrhea of 2 weeks duration]. AB - The case is presented of a 78 year old woman with a history of congenital right renal, who suffered from diarrhea of approximately 2 weeks duration and discomfort due to cramp in both legs. The laboratory results showed severe hyperkalemia, hyponatremia, and slightly elevated creatinine levels, with no symptoms associated with this finding and with the rest of the normal laboratory results. She was admitted to the intensive care unit for treatment, and when her results returned to normal she was transferred to internal medicine. Among the other tests performed, the ACTH was shown to be high, and a left adrenal adenoma was found in the MR scan. The final diagnosis was Addison's syndrome. She was treated with mineralocorticoids with follow-up by internal medicine as an outpatient. PMID- 24468301 TI - [Persistent backache in a 62 year-old male: mechanical pain?]. AB - The case is presented of a 62 year old man with a history of pulmonary tuberculosis, repeatedly consulting his primary care physician for treatment of analgesic / anti-inflammatory resistant back pain, and usually coincided with physical activity. It was initially diagnosed as mechanical pain, but in the absence of response to rest and treatment a magnetic resonance of the spine was requested, which reported bone metastases. The patient was then referred to Internal Medicine for further tests in hospital. The histopathology ruled out the presence of neoplastic cells, and imaging tests showed radiographic abnormalities in vertebral bodies (osteomyelitis-discitis) associated with epidural abscess, compatible with Pott's disease, a kind of tuberculous arthritis of the intervertebral joints. PMID- 24468302 TI - [Takayasu arteritis and cerebral venous thrombosis: report of a case]. AB - Palpitations, paresthesias and anxiety are very common reasons of consultation in primary care. We report the case of a 40 year-old Caucasian woman who came to the clinic due to these symptoms, and was finally diagnosed with Takayasu arteritis. Later, she had an episode of headache, as the initial manifestation of cerebral venous thrombosis. Takayasu arteritis is a systemic vasculitis affecting medium and large arteries, mainly leacausing stenosis of the aorta and its branches. It most frequently affects Asian women, being much rarer in Europe. The primary care doctor plays a key role in the initial diagnosis and monitoring of patients with rare diseases, such as Takayasu arteritis, and must be a basic support for the patient and family, providing information and advice, and contributing with his work to reduce the vulnerability of this group. PMID- 24468303 TI - [Torsade de pointes in the management of atrial fibrillation]. AB - Torsade de pointes is a frequent cause of sudden death of cardiac origin, with uncertain mechanisms of actions and very diverse origins. A case is presented of a patient with a bronchial condition on pharmacological treatment with macrolides, and who, as well as having atrial fibrillation, suffered an episode of self-limiting torsade de pointes that abated spontaneously with no associated clinical complications. PMID- 24468304 TI - [Dermatoses in pregnancy. Presentation of a case]. AB - Family physicians usually follow up pregnancies in which no special incidences are expected to occur. Cutaneous pruritus is a common symptom in pregnant women, on most occasions without further consequences. However, noteworthy is a group of very rare pathologies known as pregnancy dermatoses, some of which may have potentially severe complications, mainly for the fetus and the pregnancy outcome, and also, to a lesser degree, for the mothers and other future pregnancies. It is essential to know how to manage the pruritus, and how to take an adequate clinical history in order to diagnose these severe conditions. The case of a pregnant woman who consulted for pruriginous dermatoses (pemphigoid gestationis) is presented to illustrate this topic. A description of the diagnostic process, differential diagnosis, treatment and outcome, is included. PMID- 24468305 TI - Ethnobotany, phytochemistry, and bioactivity of the genus Turnera (Passifloraceae) with a focus on damiana--Turnera diffusa. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Half a dozen of the currently accepted 135 Turnera species are used in traditional medicine, most notably Turnera diffusa Willd. ex Schult. which is one of the most highly appreciated plant aphrodisiacs. Other traditional uses of Turnera L. species include the treatment of anaemia, bronchitis, cough, diabetes, fever, fungal disease, gastrointestinal complaints, pain, pulmonary and respiratory diseases, skin disorders, and women's health problems. Additionally, Turnera species are used as abortives, expectorants, and laxatives. PHYTOCHEMISTRY: Flavonoids (22 different compounds), maltol glucoside, phenolics, cyanogenic glycosides (7 different compounds), monoterpenoids, sesquiterpenoids, triterpenoids, the polyterpene ficaprenol-11, fatty acids, and caffeine have been found in the genus Turnera. BIOACTIVITY: Bioactivities experimentally proven for members of the genus Turnera encompass antianxiety, antiaromatase, antibacterial including antimycobacterial, antidiabetic, antioxidant, adapatogenic, antiobesity, antispasmodic, cytotoxic, gastroprotective, hepatoprotective, and aphrodisiac activities. Most of these activities have so far been investigated only in chemical, cell based, or animal assays. In contrast, the antiobesity activity was also investigated in a study on healthy human subjects and with a herbal preparation containing among other ingredients Turnera diffusa leaves. Moreover, the enhancement of female sexual function was assessed in humans; again the product contained besides Turnera diffusa other potentially bioactive ingredients. However, with only few exceptions, most of the traditional uses and the experimentally verified bioactivities can currently not be related to a particular compound or compound class. A notable exception is the flavonoid apigenin, which was identified animal experiments as the antinociceptive principle of Turnera diffusa. CONCLUSION: In this review, the current knowledge on ethnobotanical uses of members of the genus Turnera, the secondary metabolites reported from Turnera, and experimentally documented bioactivities from Turnera extracts and pure compounds derived from Turnera extracts are compiled. Moreover, some of the most interesting avenues for future research projects are being discussed briefly. These include in particular the aphrodisiac activity of Turnera diffusa and the antibiotic activity potentiating effect of Turnera ulmifolia L. against aminoglycoside resistant bacteria. PMID- 24468306 TI - Spectral domain optical coherence tomography findings in acute syphilitic posterior placoid chorioretinitis. AB - BACKGROUND: We describe the spectral domain optical coherence tomography (SD-OCT) findings in three patients with acute syphilitic posterior placoid chorioretinitis (ASPPC). The SD-OCT images demonstrate the pathologic changes in ASPPC with a high level of anatomic detail and may provide information about the pathophysiology of the disease. FINDINGS: We report a series of three consecutive patients seen at the Wilmer Eye Institute in 2012 and 2013 who presented with clinical and laboratory findings consistent with a diagnosis of unilateral ASPPC. Two of the three patients had HIV co-infection with good immune recovery. SD-OCT images from their initial (pre-treatment) presentation demonstrated thickening and hyperreflective nodularity of the choroid-retinal pigment epithelium (RPE) complex, with focal disruption of the overlying photoreceptor inner segment-outer segment junction in the areas corresponding to the retinal lesions seen on clinical examination. These changes improved with intravenous antibiotic treatment over a 3-month period of follow-up. CONCLUSIONS: SD-OCT imaging in ASPPC demonstrates reversible, focal thickening, and nodularity of the RPE with disruption of the overlying photoreceptor inner segment-outer segment junction. We believe that these SD-OCT images support the concept that ASPPC involves an inflammatory process at the level of the choroid-RPE with resultant structural and functional changes in the retinal photoreceptors. Further study with OCT imaging may be helpful in better understanding this disease. PMID- 24468307 TI - Performance assessment of different STPs based on UASB followed by aerobic post treatment systems. AB - This paper present the experiences gained from the study of ten up flow anaerobic sludge blanket (UASB) based sewage treatment plants (STPs) of different cities of India. Presently 37 UASB based STPs were under operation and about 06 UASB based STPs are under construction and commissioning phase at different towns. The nature of sewage significantly varied at each STP. Two STP were receiving sewage with high sulfate and heavy metals due to the mixing of industrial waste. The treatment performance of all UASB reactors in terms of BOD, COD and TSS were observed between 55 to 70% respectively. The post treatment units down flow hanging sponge (DHS) and Aeration followed by activated sludge process (ASP) at two STPs were performing well and enable to achieve the required disposal standards. Results indicate the effluent quality in terms of BOD and SS were less than 30 and 50 mg/L and well below the discharging standards. PMID- 24468308 TI - The effect of opiodergic system and testosterone on anxiety behavior in gonadectomized rats. AB - BACKGROUND AND AIM: Removal of the testes (gonadectomy; GDX), the primary source of androgens, increases anxiety behavior in several tasks. Opioids are known to play a role in mediating the effects of androgen. In the present study, the effect of testosterone and opioidergic system on anxiety behavior was investigated. METHODS: Adult male Wistar rats were bilaterally castrated. The elevated plus maze which is a useful test to investigate the effects of anxiogenic or anxiolytic drugs in rodents was used. RESULTS: The data indicated that there is a decrease, 10 days after castration, in the percentage of OAT (the ratio of time spent in the open arms to total times spent in any arms * 100) and OAE (the ratio of entries into open arms to total entries * 100) but not locomotor activity, showing anxiogenic-like effects of gonadectomy. Intraperitoneal injection of testosterone (200, 300 and 450 mg/kg) and morphine (2.5, 5 and 7.5mg/kg), before testing 10 days after castration, showed an increase in OAT and OAE. Furthermore, injection of naloxone (5 and 7.5mg/kg, i.p.), 5 min before testing 10 days after castration, decreased OAT and OAE. Also, injection of a significant dose of testosterone (300 mg/kg, i.p.), 1h before the injection of different doses of morphine (1, 2.5, 5 and 7.5mg/kg, i.p.), 10 days after castration, did not significantly alter OAT, OAE and locomotor activity. While, administration of a significant dose of testosterone (300 mg/kg, i.p.), 1h before the infusion of different doses of naloxone (1, 2.5, 5 and 7.5mg/kg, i.p.), 10 days after castration, decreased OAT and OAE. CONCLUSION: The results show the involvement of testosterone and opioidergic system in anxiogenic-like behaviors induced by gonadectomy. PMID- 24468309 TI - Early administration of terbutaline in severe pediatric asthma may reduce incidence of acute respiratory failure. AB - BACKGROUND: Severe pediatric asthma, if not immediately and aggressively treated, may progress to acute respiratory failure requiring mechanical ventilation in the pediatric intensive care unit (PICU). Intravenous (IV) terbutaline, a beta2 agonist, is dispensed when the initial treatment does not improve the clinical condition. OBJECTIVE: To investigate the influence of early initiation of IV terbutaline on the incidence of acute respiratory failure requiring mechanical ventilation in severe pediatric asthma. METHODS: A retrospective chart review was conducted of 120 subjects (35 patients from an outside hospital emergency department [ED] with late start of terbutaline and 85 patients from the authors' hospital ED with early initiation of IV terbutaline) admitted to the PICU with severe asthma treated with continuous IV terbutaline. Responses to terbutaline treatment and outcomes were evaluated. RESULTS: Patients transported from outlying hospital EDs had shorter pre-PICU mean durations of IV terbutaline than those transferred from the authors' ED (0.69 +/- 1.38 and 2.91 +/- 2.47 hours, respectively, P = .001). Twenty-one of 35 patients (60%) from outlying EDs required mechanical ventilation compared with 14 of 85 patients (16%) from the authors' ED (P = .001). Durations of pre-PICU terbutaline infusion for patients requiring mechanical ventilation were significantly shorter than those with no such requirement (P = .015). CONCLUSION: The results of the present study, conducted in the largest number of subjects to date, suggest that early administration of continuous terbutaline in the ED may decrease acute respiratory failure and the need for mechanical respiratory (invasive and noninvasive) support in severe pediatric asthma. PMID- 24468310 TI - Management of T-cell lymphomas: overcoming challenges and choosing the best treatment. PMID- 24468312 TI - Chemotherapeutic advancements in peripheral T-cell lymphoma. AB - The peripheral T-cell lymphomas (PTCLs) include a pathologic and clinically heterogeneous group of mature aggressive T-cell lymphomas, with overall inferior prognoses compared with aggressive B-cell lymphomas. Diagnosis by expert pathologic analysis is paramount in differentiating the multiple different clinicopathologic subtypes. The clinical presentations of PTCLs are variable, from that of an indolent nature to an aggressive behavior, although most have natural histories as aggressive lymphomas. First-line treatment for most PTCLs should include multi-agent chemotherapy with consideration of inclusion of etoposide chemotherapy for younger patients, as well as consolidation with autologous stem cell transplantation (SCT) in select cases. For patients with disease relapse, salvage therapy followed by autologous or allogeneic SCT should be considered. Additionally, several novel therapeutic agents have been approved by the US Food and Drug Administration (FDA) for relapsed/refractory PTCL, including romidepsin, pralatrexate, and brentuximab vedotin, the latter specifically for anaplastic large cell lymphoma. Furthermore, there are a number of new, targeted agents being studied. In order to improve outcomes for PTCL, it remains critical to consider these patients for clinical studies. In this article, we examine the recent progress and changing landscape of treatment of PTCL. PMID- 24468311 TI - Pathology of peripheral T-cell lymphomas: where do we stand? AB - Peripheral T-cell lymphomas (PTCLs) are heterogeneous and uncommon malignancies characterized by a usually aggressive clinical course. The current World Health Organization (WHO) classification delineates many entities grouped according to the clinical presentation as predominantly leukemic, cutaneous, extranodal, or nodal diseases. Yet, few genetic lesions serve as entity-defining markers. Using high-throughput methods, new recurrent genetic and molecular alterations are being discovered that are expected to refine the current classification and serve as diagnostic genetic markers and targets for novel therapies. There is increasing evidence that certain cellular subsets, in particular follicular helper T cells and gamma delta T cells, represent important defining markers and/or determinants of the biology of certain entities; nevertheless, the cellular derivation of many PTCL entities remains poorly characterized and there is evidence of plasticity in terms of cellular derivation (alpha-beta, gamma delta, natural killer [NK]) especially in several extranodal entities with a cytotoxic profile. While most clonal NK/T-cell proliferations are in general highly malignant, some more indolent forms of NK or T-cell lympho-proliferations are being identified. PMID- 24468313 TI - The changing landscape of peripheral T-cell lymphoma in the era of novel therapies. AB - Peripheral T-cell lymphomas (PTCLs) are the most common sub-entity of mature T cell lymphomas, and apart from particular presentations, share a poor prognosis with frequent short-term, agressive, and chemorefractory relapses. Because of the rarity and also the heterogeneity of the disease, we lack randomized clinical trials. However, to date, neither intensification of frontline chemotherapy or autologous transplant has led to any improvement of survival, and the standard CHOP (cyclophosphamide, doxorubicine, vincristine, and prednisone) regimen remains the most employed as induction therapy. In the past few years, new chemotherapeutic agents, with the capability to encompass the resistance to conventional chemotherapy, such as pralatrexate or bendamustine, have been evaluated. Furthermore, identification of cell surface molecular markers (CD52, CD30, CCR4) has led to the development of new monoclonal antibodies. Similarly, the better comprehension of physiopathological mechanisms and detection of deregulated intracellular pathways encouraged the use of novel therapies such as histone deacetylase inhibitors or immunomodulatory drugs. Some of these compounds have been approved for relapse, and are currently evaluated upfront in ongoing clinical trials. Despite these efforts, the global prognosis still remains much inferior to those of B-cell lymphomas, highlighting the necessity of multicenter clinical trials. PMID- 24468314 TI - Novel therapeutic strategies for cutaneous T-cell lymphoma in advanced stages. AB - The term cutaneous T-cell lymphoma (CTCL), introduced in 1975, was used to describe a spectrum of skin-based malignant tumors of T-cell origin. Immunological studies identified the complex interaction of cytokines released from infiltrating accessory or malignant cells and how such cytokines aid in the maintenance and proliferation of malignant cells. Though the etiology remains unknown, an association with rare retrovirus in some cases has been described. The mainstay of therapy has been to control the cutaneous presentation with topical therapies in patients with early limited-stage disease. However, a significant number of patients develop refractory disease to skin-directed therapies with or without clinical progression to advanced stages requiring systemic therapy. Over the last two decades a wide number of novel agents such as monoclonal antibodies, small molecule inhibitors, and chemotherapy agents have been developed and are used in patients with advanced disease or those who have exhausted topical treatment options and/or radiation. In this contribution we review the results of clinical studies evaluating emerging therapeutic strategies for patients with CTCL that had developed from ongoing translational research programs focused on understanding the biology of different subtypes of CTCL and identifying disease-specific biomarkers suitable for targeting. PMID- 24468315 TI - Pathogenesis and treatment of extranodal natural killer/T-cell lymphoma. AB - Extranodal natural killer (NK)/T-cell lymphoma, nasal type (ENKL) is one of the uncommon subtypes of malignant lymphoma, and predominantly occurs in the nasal or paranasal areas and less frequently in the skin. Previously, its prognosis was poor due to the expression of P-glycoprotein, which actively exports several anticancer agents outside the lymphoma cells. However, in recent years, novel therapeutic approaches such as simultaneous chemoradiotherapy or l-asparaginase based regimens including SMILE (steroid, methotrexate, ifosfamide, l asparaginase, and etoposide) improved the response to therapy and survival of ENKL patients. Epstein-Barr virus (EBV) is present in lymphoma cells of almost all patients, accounting for the pathogenesis of ENKL. Fragmented EBV-DNA is released from tumor cells, and can be detected in the peripheral blood of patients. The EBV-DNA copy numbers are associated with tumor burden, and can predict the prognosis of ENKL, as well as the toxicity against chemotherapy. Based on this recent progress, ENKL is currently categorized as a lymphoma with intermediate prognosis, but the overall treatment results are not satisfactory. Further improvement of the prognosis of ENKL is therefore warranted, including the optimal use of hematopoietic stem cell transplantation (HSCT). PMID- 24468316 TI - Angioimmunoblastic T-cell lymphoma management. AB - Angioimmunoblastic T-cell lymphoma (AITL) is a frequent subtype of peripheral T cell lymphoma (PTCL) that is clinically characterized by generalized lymphadenopathy, extranodal involvement, advanced stage at presentation, hypergammaglobulinemia, and significant immune dysregulation resulting in infections as the most common cause of death. Recent advances in pathobiology of AITL have improved our understanding of it as a clonal T-cell disorder and of its effect on B cells in the tumor microenvironment. Reponses to first-line therapies have largely been dismal. In this review, we discuss the clinical features, pathobiology, prognostic models, standard therapy, and newer therapeutic agents used and their implications for the future. PMID- 24468317 TI - Autologous stem cell transplantation for T-cell lymphomas. AB - Peripheral T-cell lymphomas (PTCLs) are a rare and heterogeneous group of T-cell malignancies characterized by a very poor outcome. The optimal treatment for PTCLs remains controversial. The role of stem cell transplantation in PTCLs has been investigated; however, no randomized control studies specifically dedicated to PTCLs are currently available. Several retrospective and prospective studies have suggested that high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) may improve the survival in patients with chemosensitive T cell lymphoma, either upfront or as salvage treatment. This review provides a summary of the current literature with the intent to explore the role of ASCT in various clinical scenarios. PMID- 24468318 TI - Allogeneic transplantation in T-cell lymphomas. AB - Except for ALK-positive anaplastic large cell lymphoma (ALCL) and patients with limited disease, mature T- and natural killer (NK) cell lymphomas are disorders with a poor prognosis. Patients with relapsed or refractory ALK-negative ALCL, angioimmunoblastic T-cell lymphoma (AITL), or peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) after allogeneic transplantation of hematopoietic stem cells (alloSCT) achieve long-term survival in 35%-50% of cases. Survival in patients with less frequent subtypes (NK/T-cell lymphoma, cutaneous T-cell lymphomas, acute T-cell leukemia/lymphoma, or hepatosplenic T-cell lymphoma) also seems promising. These results are significantly better than those of any other treatment modality, including the new drugs. Therefore, alloSCT should be considered in patients with relapsed/ refractory T-cell lymphoma. Because of low patient numbers and lack of comparative studies, the optimum conditioning regimen prior to transplantation as well as other details of the transplant procedure remain unknown and await further study. Studies investigating the role of alloSCT as part of first-line therapy in poor-risk T-cell lymphomas are ongoing. At present, data are not sufficient to recommend alloSCT outside of clinical trials. PMID- 24468319 TI - Management of relapses after hematopoietic cell transplantation in T-cell non Hodgkin lymphomas. AB - T-cell non-Hodgkin lymphomas (NHLs) are a heterogeneous group of malignancies that represent 10%-15% of all NHLs. The prognosis of relapsed T-cell NHL is poor, especially for those relapsing after an autologous (auto-) or allogeneic (allo-) hematopoietic cell transplantation (HCT). Disease relapse post auto-HCT is best managed on a clinical trial. In the absence of an investigational protocol, the choice of salvage therapies should take into account patient performance status, eligibility for an allo-HCT, and surface CD30 expression. CD30-directed therapies or aggressive salvage regimens can be used as a bridge to allo-HCT in medically fit patients. In the elderly or more infirm patients, single-agent therapies could be offered, aiming at palliation. Similarly, relapse after an allo-HCT is not uncommon and is a real challenge. Reduction in ongoing immune suppression or donor lymphocyte infusion are often considered in this setting to augment graft versus-lymphoma (GVL) effects and can occasionally provide durable disease control. Clinical trials designed to investigate novel therapeutic agents with immunomodulatory properties to augment GVL effects (eg, histone deacetylase [HDAC] inhibitors, proteasome inhibitor, lenalidomide) or targeted therapies (eg, aurora A kinase inhibitors, anaplastic lymphoma kinase [ALK] inhibitors) are sorely needed to improve the dismal outcomes of T-cell NHL relapsing after an allo-HCT. PMID- 24468320 TI - Basal encephalocele in an adult patient presenting with minor anomalies: a case report. AB - INTRODUCTION: Basal encephalocele is rare in adults. Congenital and acquired cases have been reported with regard to the developmental mechanism, and the pathology has not been elucidated in detail. CASE PRESENTATION: We encountered an adult with basal encephalocele strongly suggesting congenital development because of the presence of minor anomalies: strabismus and ocular hypertelorism. The disease manifested as persistent spontaneous cerebrospinal fluid rhinorrhea and repeated meningitis in a 66-year-old Japanese man. On computed tomography, brain tissue protruded through a part of the ethmoid bone of his right anterior skull base, and it was diagnosed as transethmoidal-type basal encephalocele. Regarding his facial form, the distance between his bilateral eyeballs was large compared to his facial width, and his canthal index (defined as inner to outer inter canthal ratio * 100) was calculated as 38.5, based on which it was judged as ocular hypertelorism. In addition, his right eyeball showed strabismus. A right frontotemporal craniotomy was performed for spontaneous cerebrospinal fluid rhinorrhea, and the defective dura mater region was patched with temporal fascia. CONCLUSIONS: Mild minor anomalies that require no treatment are overlooked in adults, but the presence of several anomalies increases the possibility of congenital disease. Therefore, it may be necessary to examine minor anomalies in cases of adult basal encephalocele when considering the possibility that the disease may be congenital. PMID- 24468321 TI - Balloon dilatation for congenital nasal piriform aperture stenosis (CNPAS): a novel conservative technique. AB - Congenital nasal piriform aperture stenosis (CNPAS) is an uncommon but important cause of nasal obstruction in infants. When it is severe, nasal decongestants or temporary nasal airway devices cannot address the problem adequately. The most common surgical technique used to treat the bony piriform aperture stenosis is the sublabial approach and drill-out of the nasal aperture followed by nasal stenting. This paper describes an infant with bilateral CNPAS who underwent a single successful balloon dilatation and short-term stenting of the nasal piriform apertures without the need for additional procedures. PMID- 24468322 TI - Biosorption: current perspectives on concept, definition and application. AB - Biosorption is a physico-chemical and metabolically-independent process based on a variety of mechanisms including absorption, adsorption, ion exchange, surface complexation and precipitation. Biosorption processes are highly important in the environment and conventional biotreatment processes. As a branch of biotechnology, biosorption has been aimed at the removal or recovery of organic and inorganic substances from solution by biological material which can include living or dead microorganisms and their components, seaweeds, plant materials, industrial and agricultural wastes and natural residues. For decades biosorption has been heralded as a promising cost-effective clean-up biotechnology. Despite significant progress in our understanding of this complex phenomenon and a dramatic increase in publications in this research area, commercialization of biosorption technologies has been limited so far. This article summarizes existing knowledge on various aspects of the fundamentals and applications of biosorption and critically reviews the obstacles to commercial success and future perspectives. PMID- 24468323 TI - The development of a reverse anammox sequencing partial nitrification process for simultaneous nitrogen and COD removal from wastewater. AB - In order to achieve simultaneous removal of nitrogenous and organic pollutants, a novel reverse anammox-partial nitrification nitrogen removal process was developed. During steady operation, the maximum nitrogen and COD (chemical oxygen demand) removal efficiencies were over 90%, with influent NH4(+)-N and COD concentrations of 300 and 100mgL(-1). The optimum recycle ratio of Membrane bioreactor (MBR for partial nitrification) and fixed bed reactor (anammox) for this process was recommended as 3 due to increasingly larger recycle ratio caused slight increase in TN (total nitrogen) removal efficiency. Additionally, the steady nitrogen removal rate was obtained at 0.92-1.03kgNm(-3)day(-1). Considering its great potential in nitrogen removal, this reverse process will be revealing for the study of anammox technique. PMID- 24468324 TI - Antibacterial and antiviral properties of tongue sole (Cynoglossus semilaevis) high mobility group B2 protein are largely independent on the acidic C-terminal domain. AB - High mobility group box (HMGB) proteins are known to be involved in diverse functions in mammalian cells. In teleost, very limited studies on HMGB proteins have been documented. In this study, we reported identification of a HMGB homologue (named CsHMGB2) from tongue sole (Cynoglossus semilaevis) and examined its biological property. CsHMGB2 is 245 residues in length and contains two basic HMG boxes and an acidic C-terminal tail composed of 23 Asp/Glu residues. Quantitative real time RT-PCR (qRT-PCR) analysis showed that CsHMGB2 expression occurred in multiple tissues and was upregulated by bacterial and viral infection in a time-dependent manner. In vitro studies showed that when tongue sole peripheral blood leukocytes were treated with recombinant CsHMGB2 (rCsHMGB2) and the mutant rCsHMGB2M, which bears a deletion of the C-terminal acidic region, significant and comparable increases in cellular resistance against bacterial infection were observed. qRT-PCR detected enhanced expression of proinflammatory cytokines and chemokines in rCsHMGB2-treated cells. In vivo studies showed that when tongues sole were administered with rCsHMGB2 or rCsHMGB2M before being subjected to bacterial and viral infection, the pathogen loads in the spleen and kidney of the fish were significantly reduced. Taken together, these results suggest that CsHMGB2 possesses immunoregulatory properties that promote resistance against bacterial and viral infection in a manner that is largely independent on the highly conserved C-terminal acidic domain. PMID- 24468325 TI - Current trends in rotator cuff repair: surgical technique, setting, and cost. AB - PURPOSE: The purpose of this study was to evaluate national trends in the surgical setting and hospital costs of shoulder arthroscopy and rotator cuff repair (RCR) using the Florida State surgical database and national inpatient database. METHODS: In part I we analyzed population-adjusted shifts in RCR technique (arthroscopic v open) in the Florida surgical database from 2000-2007 and quantified the procedural codes associated with arthroscopic and open RCR. In part II we analyzed the Nationwide Inpatient Sample database from 2001-2009 for the total number of inpatient RCRs, the inpatient hospital type (rural, urban non teaching, or urban teaching), and the cost. RESULTS: Part I showed a 163% increase in outpatient procedures in Florida, with a 353% increase in arthroscopic RCRs. There was a concurrent decrease in open RCRs; however, the overall trend was a 2-fold increase in total RCRs. Associated procedures such as subacromial decompression, distal clavicle resection, and extensive glenohumeral debridement increased by 440%, 589%, and 1,253%, respectively. Part II showed an overall 58.8% decrease in inpatient RCRs that was similar across all hospital settings, with an increase in RCR-associated hospital charges by 144.9%, whereas hospital costs only increased by 85.2%. CONCLUSIONS: The study confirms a shift toward arthroscopic RCR and associated procedures in the outpatient setting. The increased financial cost partly explains the shift; nevertheless, future studies are needed to further examine national trends. CLINICAL RELEVANCE: This study examining RCR trends by hospital type, cost, and setting further elucidates how orthopaedic surgery practice is evolving with the implementation of arthroscopic RCR in the past decade. PMID- 24468326 TI - Clinical and functional outcome after acetabular labral repair in patients aged older than 50 years. AB - PURPOSE: To assess the clinical and functional outcome of labral repair in patients aged older than 50 years. METHODS: We performed a prospective analysis of 20 patients aged older than 50 years who had undergone arthroscopic repair of a torn acetabular labrum (6 men and 14 women; mean age, 58 years). The indication for surgery was groin pain due to various causes with or without associated mechanical symptoms that did not respond to nonoperative treatment for more than 6 months. Intraoperatively, all patients were diagnosed with labral pathology. The mean duration of symptoms was 3.1 years (range, 0.5 to 15 years). The mean follow-up period was 22 months (range, 12 to 35 months). The outcome was prospectively measured with the modified Harris Hip Score (MHHS) and Hip Outcome Score (HOS). RESULTS: The indication for surgery was femoroacetabular impingement (FAI) with cam deformity and a labral tear in 4 patients, FAI with pincer deformity and a labral tear in 1 patient, FAI with both deformities in 1 patient, a gluteus medius tear in 2 patients, and an isolated labral tear in 12 patients. Acetabular chondral lesions were present in 11 patients (55%). The mean preoperative and postoperative MHHS was 62.5 and 87.2, respectively (P < .001); the mean preoperative and postoperative HOS was 42.7 and 86.3, respectively (P < .001); and the mean preoperative and postoperative level of function during usual activities of daily living according to the HOS was 46.0% and 73.7%, respectively (P < .001). No significant difference was identified in MHHS and HOS between gender groups. CONCLUSIONS: Arthroscopic management of FAI and labral repair in patients aged older than 50 years without significant arthritis (Tonnis grade 1 or better) are associated with significant improvement in outcome. Because of the potential importance of the labrum for long-term hip joint integrity, we advocate repair of the labrum in patients aged older than 50 years when possible. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24468327 TI - Using the genetics of Echinococcus multilocularis to trace the history of expansion from an endemic area. AB - Alveolar echinococcosis, caused by the cestode Echinococcus multilocularis, is the most serious parasitic disease for humans in Europe, with a sylvatic life cycle generally between small rodents and red foxes. General expansion of the range of E. multilocularis has been observed across Europe over the last 15years. In France, a westward spread of the known endemic areas of the parasite was described recently. For genotyping, the microsatellite EmsB was used to trace expansion in five French areas. A total of 22 EmsB profiles were identified, with five similar to those previously described in other parts of Europe. An imbalance of genetic diversity was observed between the five areas which also revealed their interconnection with the presence of common profiles, notably the two main profiles both present in all regions except one in the North. These two findings are similar to those described at the European level, highlighting transmission of the parasite by a mainland-island system. A spatio-temporal scenario of the expansion of E. multilocularis can be proposed with spread from the French historical focus in eastern France to the Lorraine, the Champagne-Ardenne and finally the North, while simultaneously another expansion has occurred from the historical focus into the West. The colonization by the parasite into the West and North areas from the historical focus was probably due to the migration of foxes several decades ago. Recent detection of the parasite in new endemic "departements" may be due to more active research rather than a recent spread of the parasite. Regarding the numerous data obtained by the different EmsB analyses, principally across Europe, centralization of all the profiles described in a public databank appears necessary in order to obtain a precise understanding of transmission of the parasite from one country to another. PMID- 24468328 TI - Early corticospinal tract Wallerian degeneration versus mesencephalic substantia nigra degeneration secondary to striatal stroke. PMID- 24468329 TI - Interaction between forest biodiversity and people's use of forest resources in Roviana, Solomon Islands: implications for biocultural conservation under socioeconomic changes. AB - BACKGROUND: In Solomon Islands, forests have provided people with ecological services while being affected by human use and protection. This study used a quantitative ethnobotanical analysis to explore the society-forest interaction and its transformation in Roviana, Solomon Islands. We compared local plant and land uses between a rural village and urbanized village. Special attention was paid to how local people depend on biodiversity and how traditional human modifications of forest contribute to biodiversity conservation. METHODS: After defining locally recognized land-use classes, vegetation surveys were conducted in seven forest classes. For detailed observations of daily plant uses, 15 and 17 households were randomly selected in the rural and urban villages, respectively. We quantitatively documented the plant species that were used as food, medicine, building materials, and tools. RESULTS: The vegetation survey revealed that each local forest class represented a different vegetative community with relatively low similarity between communities. Although commercial logging operations and agriculture were both prohibited in the customary nature reserve, local people were allowed to cut down trees for their personal use and to take several types of non-timber forest products. Useful trees were found at high frequencies in the barrier island's primary forest (68.4%) and the main island's reserve (68.3%). Various useful tree species were found only in the reserve forest and seldom available in the urban village. In the rural village, customary governance and control over the use of forest resources by the local people still functioned. CONCLUSIONS: Human modifications of the forest created unique vegetation communities, thus increasing biodiversity overall. Each type of forest had different species that varied in their levels of importance to the local subsistence lifestyle, and the villagers' behaviors, such as respect for forest reserves and the semidomestication of some species, contributed to conserving diversity. Urbanization threatened this human-forest interaction. Although the status of biodiversity in human-modified landscapes is not fully understood, this study suggested that traditional human modifications can positively affect biodiversity and that conservation programs should incorporate traditional uses of landscapes to be successful. PMID- 24468330 TI - Age-dependent decline in dental pulp regeneration after pulpectomy in dogs. AB - The age-associated decline in the regenerative abilities of mesenchymal stem cells (MSCs) may be due to age-related changes in reduction in number, intrinsic properties of MSCs and extrinsic factors of the extracellular environment (the stem cell niche). The effect of age on the efficacy of MSC transplantation on regeneration, however, has not been clearly demonstrated due to variable methods of isolation of MSCs and variations in stem cell populations. In this study, dental pulp stem cell (DPSC) subsets were isolated from young and aged dog teeth based on their migratory response to granulocyte-colony stimulating factor (G CSF) (MDPSCs). In order to study the age-associated changes, their biological properties and stability were compared and the regenerative potential was examined in a pulpectomized tooth model in aged dogs. MDPSCs from aged dogs were efficiently enriched in stem cells, expressing trophic factors with high proliferation, migration and anti-apoptotic effects as in MDPSCs from young dogs. However, pulp regeneration was retarded 120 days after autologous transplantation of aged MDPSCs. We further demonstrated that isolated periodontal ligament stem cells (PDLSCs) from aged dogs, representative of migrating stem cells from outside of the tooth compartment to regenerate pulp tissue, had lower proliferation, migration and anti-apoptotic abilities. These results therefore provide a better understanding of the mechanisms involved in the age-dependent decline in pulp regeneration, which are attributed to a decrease in the regenerative potential of resident stem cells. PMID- 24468331 TI - T cell receptor-mediated activation is a potent inducer of macroautophagy in human CD8(+)CD28(+) T cells but not in CD8(+)CD28(-) T cells. AB - A key feature of the aged human immune system is the accumulation of highly differentiated CD8(+)CD28(-) T cells, a phenomenon that negatively influences immune function in the elderly. However, the mechanisms that regulate survival or death of CD8(+)CD28(-) T cells remain incompletely understood. Macroautophagy has been shown to protect cells from unfavorable environmental conditions and extend lifespan of various cells and organisms. In this study, we investigated autophagy in CD8(+)CD28(+) and CD8(+)CD28(-) T cells following T cell receptor (TCR) engagement. We demonstrate that TCR-mediated activation led to a potent induction of autophagy in CD8(+)CD28(+) T cells which was accompanied by an increased activity of the mammalian target of rapamycin complex 1 (mTORC1). This was surprising, as mTORC1 is generally perceived as an inhibitor of autophagy. Inhibition of mTORC1 by rapamycin could still enhance activation-induced autophagy. In contrast, CD8(+)CD28(-) T cells induced autophagy to a significantly lower extent in response to TCR engagement compared to CD8(+)CD28(+) T cells and failed to increase autophagy upon mTORC1 inhibition. In conclusion, we describe for the first time the induction of autophagy in human CD8(+) T cells following TCR engagement and the decreased ability of CD8(+)CD28( ) T cells to induce autophagy, suggesting that they cannot meet the metabolic needs of antigen receptor-mediated activation and are therefore unlikely to survive when confronted by their specific antigens. PMID- 24468332 TI - Ignorance or knowledge. PMID- 24468333 TI - A gene knock-in method used to purify plasmid pSPI12 from Salmonella enterica serovar Pullorum and characterization of IpaJ. AB - A small plasmid with 4080 bp long, designated pSPI12, was purified from Salmonella enterica serovar Pullorum using a gene knock-in method by inserting a kanamycin resistance cassette in the plasmid. The G+C content of the plasmid was 51.8%, which is in the range of Salmonella genomic DNA. A sequence analysis revealed that pSPI12 had 99.1% homology to pSFD10, which was first reported in the vaccine strain S. enterica serovar Chloreaesuis C500, but not prevalent among other strains of S. Chloreaesuis. The plasmid has seven open reading frames (ORFs), with one ORF containing a putative virulence-related protein, which had 49% homology with invasion plasmid antigen J protein (IpaJ) secreted by type III secretion system of Shigella flexneri. The putative IpaJ protein was expressed and purified as a His-tagged fusion protein reacted with convalescent sera against S. Pullorum, confirming its identification as an immunogen of the pathogen. In addition, the gene was upregulated for 1h post-infection of HD-11 cells with the pathogen by a quantitative real-time reverse transcription PCR assay. The results suggest that IpaJ may be a virulent protein involved in the early stage of infection by S. Pullorum. PMID- 24468334 TI - Voltammetric determination of sumatriptan based on a graphene/gold nanoparticles/Nafion composite modified glassy carbon electrode. AB - A mixture of graphene oxide and tetrachloroauric acid was electrochemically co reduced directly on a glassy carbon electrode (GCE) surface via cyclic voltammetry so as to form a graphene (Gr)-gold nanoparticles (AuNP) composite. This nanocomposite was then coated with nafion (NAF) film so as to form Gr/AuNP/NAF/GCE. Sumatriptan (SUM) is a drug belonging to the triptan class, used for the treatment of migraine headaches. In this work, an electrochemical method based on the adsorptive stripping differential pulse voltammetry (AdSDPV) employing Gr/AuNP/NAF/GCE has been proposed for the subnanomolar determination of SUM. Characterization of the electrode material has been carried out by UV visible spectrophotometry, X-ray diffraction and scanning electron microscopy. Also the electrode surface has been characterized by means of cyclic voltammetry, electrochemical impedance spectroscopy, chronocoulometry. By employing Gr/AuNP/NAF/GCE at pH 7.0 phosphate buffer, a 20-fold enhancement in the AdSDPV signal was observed as compared to GCE. Under the optimized conditions, Ip (uA) was proportional to the SUM concentration in the range of 1.0*10(-6)-4.12*10(-5) M (R(2)=0.9991) and 2.14*10(-9)-1.0*10(-6) M (R(2)=0.9954) with a detection limit (3*SD/s) of 7.03*10(-10) M. The practical analytical utilities of the modified electrode were demonstrated by the determination of SUM in pharmaceutical formulations, human urine and blood serum samples. This proposed method was validated by HPLC and the results are in agreement at the 95% confidence level. PMID- 24468335 TI - Combined capillary electrophoresis and high performance liquid chromatography studies on the kinetics and mechanism of the hydrogen peroxide-thiocyanate reaction in a weakly alkaline solution. AB - The hydrogen peroxide-thiocyanate reaction has been reinvestigated by means of capillary electrophoresis and high performance liquid chromatography under weakly alkaline conditions at 25.0+/-0.1 degrees C. Concentration-time series of thiocyanate, sulfate and cyanate have been followed by capillary electrophoresis as well as that of thiocyanate and hydrogen peroxide by HPLC. It has been clearly demonstrated that OxSCN(-) (where x=1, 2 and 3) cannot be accumulated in detectable amount in contrast to the results of Christy and Egeberg, hence these species can only be regarded as short-lived intermediates. It has been shown that the overall rate law is first-order with respect to both reactants, but no pH dependence was observed within the pH range of 8.86-10.08. A simple kinetic model has been proposed to fit all the concentration-time curves simultaneously at five different pHs demonstrating the powerful combination of the experimental techniques CE and HPLC with simultaneous evaluation of kinetic curves. It is also enlightened that the quality of the buffer strongly affects the rate of the overall reaction that increases in the order of application of ammonia, phosphate, carbonate and borate, respectively at a constant ionic strength and pH. PMID- 24468336 TI - Polymelamine modified edge plane pyrolytic graphite sensor for the electrochemical assay of serotonin. AB - A sensitive and novel electrochemical method has been developed for the determination of an important neurotransmitter, serotonin, using a polymelamine modified edge plane pyrolytic graphite sensor (EPPGS). Melamine was used for the modification of sensor by electropolymerizing it at the surface of EPPGS in acidic medium to form a layer of conducting polymer. Field emission scanning electron microscopy (FE-SEM) and electrochemical impedance spectroscopy (EIS) were used for the characterization of the surface of polymer modified sensor. The electrochemical measurements were carried out using square wave voltammetry and cyclic voltammetry. The polymelamine modified sensor exhibited excellent electrocatalytic activity towards the electrochemical oxidation of serotonin, exhibiting a larger peak current and shift of peak potential to less positive potentials as compared to the unmodified sensor. The dynamic range for the serotonin determination was found between 1-100 um and 0.1-100 um with detection limit of 492 nM and 30 nM for unmodified and polymer modified sensors, respectively. The determination of serotonin in human blood serum and urine has been carried out. The common metabolites such as ascorbic acid, dopamine, xanthine and hypoxanthine do not interfere in the determination up to 10-fold concentration, revealing good selectivity of the proposed sensor. PMID- 24468337 TI - On-line coupled reversed phase liquid chromatography and gas chromatography: a new sealing design for the TOTAD interface. AB - Total elimination of the eluent resulting from the pre-separation step is the critical point when coupling LC to GC. As a helium flow is applied during transfer to eliminate the solvent, the interface used for linking the two chromatographic systems must be properly sealed to prevent gas leaks and to achieve an effective evaporation of the eluent. The aim of this work was to improve the performance of the Through Oven Transfer Adsorption Desorption (TOTAD) interface to remove the eluent coming from LC by modifying the way in which the injector sealing system is held in place. As with the original design, the new approach makes it possible to transfer high volumes at a high rate, but the proposed modification also simplifies the experimental work because the displacement risk of the sealing system is reduced. Analyses of an ester mixture by RPLC-GC were performed to confirm the applicability of the system modification. In this work, volumes of up to 5 ml, at flow rates as high as 2 ml/min, were transferred from LC to GC with almost complete solvent removal even when working in reversed phase mode in the LC step. PMID- 24468338 TI - A simple recirculating flow system for the calibration of polar organic chemical integrative samplers (POCIS): effect of flow rate on different water pollutants. AB - A calibration system for POCIS was developed and used to calculate the sampling rates of eight analytes belonging to pesticides, non-steroidal anti-inflammatory drugs and perfluorinated compounds: atrazine, propazine, terbutylazine, diclofenac, ibuprofen, ketoprofen, perfluorooctanoic acid and perfluorooctanesulfonate. Experiments with a linear velocity of 2.0, 5.1, 10.2 and 15.3 cm/s were carried out for 96 h using two different analyte concentrations. POCIS extracts were analyzed by liquid chromatography-tandem mass spectrometry (LC-MS/MS), using multiple reaction monitoring to maximize sensitivity. Results highlighted that the calculated sampling rates are rather constant at the considered concentrations and flow rates. Obtained values of sampling rates were then employed to calculate Time-Weighted Average concentration of the analytes in river and drinking waters. PMID- 24468339 TI - A new approach to highly sensitive determination of retinoic acid isomers by preconcentration with CdSe quantum dots. AB - Unusual amounts of retinoic acid (RA) isomers play an important role in abnormal morphological development of mammals; such as rat embryos. Each isomer of RA has a unique function in first steps of embryonic life. In the current study, a new method for preconcentration and simultaneous determination of all-trans retinoic acid, 13-cis retinoic acid, 9-cis retinoic acid and 9,13-di-cis retinoic acid in rat whole rudimentary embryo culture (RWEC) has been developed. RA isomers were extracted from samples by conjugation to appropriate amount of surface modified CdSe quantum dots (QDs) prior to HPLC/UV determination. In order to quickly release of the analytes with unchanged form, separated RA-QD conjugation were irradiated by intensive near infrared wavelength (NIR). Low energy NIR irradiation results in maintaining the primary forms of RA isomers during the release. The conjugation and release mechanisms were described and experimental parameters were investigated in detail. Under optimized conditions, the method was linear in the range of 0.040-34.600 pmol g(-1) for all-trans RA (R(2)=0.9996), 0.070-34.200 pmol g(-1) for 13-cis RA (R(2)=0.9992), 0.050-35.300 pmol g(-1) for 9,13-di-cis RA (R(2)=0.9998) and 0.050-32.900 pmol g(-1) for 9-cis RA (R(2)=0.9990). The present method can be useful for retinoic acid monitoring in clinical studies. PMID- 24468340 TI - Biotin-streptavidin enzyme-linked immunosorbent assay for detecting Tetrabromobisphenol A in electronic waste. AB - Tetrabromobisphenol A (TBBPA) is a widely used brominated flame retardant. A sensitive and selective indirect competitive biotin-streptavidin-amplified enzyme linked immunosorbent assay (BA-ELISA) was developed for detecting TBBPA. The optimal hapten of TBBPA was 2-(2,6-dibromo-4-(2-(3,5-dibromo-4 hydroxyphenly)propan-2-yl)) acetic acid. Several physiochemical factors that influence assay performance, such as optimal coupling concentration of immunogen and antibody, organic solvent, ionic strength, and pH, were studied and optimized. The limit of detection (IC10) was 0.027 ng/mL and the median inhibitory concentration (IC50) was 0.58 ng/mL. The BA-ELISA was highly selective, with low cross-reactivity with TBBPA analogs. Finally, the assay was used to detect TBBPA in electronic waste samples. The results are consistent with those using liquid chromatography, which proves that the proposed immunoassay is accurate and receptive. This BA-ELISA method is suitable for the rapid and sensitive screening of TBBPA in environmental monitoring. PMID- 24468341 TI - Vortex-assisted liquid-liquid microextraction coupled with high performance liquid chromatography for the determination of furfurals and patulin in fruit juices. AB - A fast and simple solvent microextraction technique using salting out-vortex assisted liquid-liquid microextraction (salting out-VALLME) was developed for the extraction of furfurals (2-furfural (2-F), 3-furfural (3-F), 5-methylfurfural (5 MF) and 5-hydroxymethylfurfural (5-HMF)) and patulin (PAT) in fruit juice samples. The optimum extraction conditions for 5 mL sample were: extraction solvent, 1-hexanol; volume of extractant, 200 uL; vortex time, 45 s; salt addition, 20%. The simultaneous determination of the furfurals and PAT were investigated using high performance liquid chromatography coupled with diode array detector (HPLC-DAD). The separation was performed using ODS Hypersil C18 column (4.6 mm i.d * 250 mm, 5 MUm) under gradient elution. The detection wavelengths used for all compounds were 280 nm except for 3-F (210 nm). The furfurals and PAT were successfully separated in less than 9 min. Good linearities (r(2)>0.99) were obtained within the range 1-5000 MUg L(-1) for all compounds except for 3-F (10-5000 ug L(-1)) and PAT (0.5-100 MUg L(-1)). The limits of detection (0.28-3.2 ug L(-1)) were estimated at S/N ratio of 3. The validated salting out-VALLME-HPLC method was applied for the analysis of furfurals and PAT in fruit juice samples (apple, mango and grape). PMID- 24468342 TI - Multidimensional and comprehensive two-dimensional gas chromatography of dichloromethane soluble products from a high sulfur Jordanian oil shale. AB - A high sulfur Jordanian oil shale was converted into liquid hydrocarbons by reaction at 390 degrees C under N2, and the dichloromethane soluble fraction of the products was isolated then analyzed by using gas chromatography (GC). Comprehensive two-dimensional GC (GC*GC) and multidimensional GC (MDGC) were applied for component separation on a polar - non-polar column set. Flame ionization detection (FID) was used with GC*GC for general sample profiling, and mass spectrometry (MS) for component identification in MDGC. Multidimensional GC revealed a range of thiophenes (th), benzothiophenes (bth) and small amounts of dibenzothiophenes (dbth) and benzonaphthothiophenes (bnth). In addition, a range of aliphatic alkanes and cycloalkanes, ethers, polar single ring aromatic compounds and small amounts of polycyclic aromatics were also identified. Some of these compound classes were not uniquely observable by conventional 1D GC, and certainly this is true for many of their minor constituent members. The total number of distinct compounds was very large (ca.>1000). GC*GC was shown to be appropriate for general sample profiling, and MDGC-MS proved to be a powerful technique for the separation and identification of sulfur-containing components and other polar compounds. PMID- 24468343 TI - Analysis of explosives using corona discharge ionization combined with ion mobility spectrometry-mass spectrometry. AB - Corona discharge ionization combined with ion mobility spectrometry-mass spectrometry (IMS-MS) was utilized to investigate five common explosives: cyclonite (RDX), trinitrotoluene (TNT), pentaerythritol tetranitrate (PETN), cyclotetramethylenetetranitramine (HMX), and 2,4-dinitrotoluene (DNT). The MS scan and the selected ion IMS analyses confirmed the identities of the existing ion species and their drift times. The ions observed were RDX.NO3(-), TNT(-), PETN.NO3(-), HMX.NO3(-), and DNT(-), with average drift times of 6.93 ms, 10.20 ms, 9.15 ms, 12.24 ms, 11.30 ms, and 8.89 ms, respectively. The reduced ion mobility values, determined from a standard curve calculated by linear regression of (normalized drift times)(-1) versus literature K0 values, were 2.09, 1.38, 1.55, 1.15, 1.25, and 1.60 cm(2) V(-1) s(-1), respectively. The detection limits were found to be 0.1 ng for RDX, 10 ng for TNT, 0.5 ng for PETN, 5.0 ng for HMX, and 10 ng for DNT. Simplified chromatograms were observed when nitrogen, as opposed to air, was used as the drift gas, but the detection limits were approximately 10 times worse (i.e., less sensitivity of detection). PMID- 24468344 TI - Graphene nanoplatelets as a highly efficient solid-phase extraction sorbent for determination of phthalate esters in aqueous solution. AB - Graphene nanoplatelet (GN) as a solid-phase extraction (SPE) sorbent in combination with high performance liquid chromatography has been used for the determination of five phthalate esters (PAEs) in aqueous solution. The operation parameters affecting the extraction efficiency were optimized. Comparative studies showed that GN was superior to other common SPE sorbents in terms of recovery and adsorption capacity. Under optimization conditions, detection limits of 0.09-0.33 ng mL(-1) were achieved for five PAEs and enrichment factors of 402 711 for the analytes were obtained. The proposed method was successfully applied for the determination of PAEs in tap water and drink samples with recoveries ranging from 87.7% to 100.9%. PMID- 24468345 TI - A facile approach for imprinting protein on the surface of multi-walled carbon nanotubes. AB - This study describes a green, facile and low cost approach for imprinting protein on the surface of multi-walled carbon nanotubes (MWNTs) using papain as the template, dopamine as the functional monomer. By simply mixing MWNTs, dopamine, template protein in weak alkaline aqueous solution, a thin adherent polydopamine (PDA) film imprinted with protein was spontaneously obtained on the surface of MWNTs to produce the imprinted nanomaterials (MWNTs@MIPs). The obtained MWNTs@MIPs were characterized with Fourier transform infrared spectrometer (FT IR), Raman spectroscopy, X-ray photoelectron spectroscopy (XPS), scanning electron microscopy (SEM) and transmission electron microscopy (TEM). The adsorption process of the MWNTs@MIPs towards template protein was investigated in detail. The effects of the concentration of the monomer and template, polymerization time, extraction process were optimized. The prepared MWNTs@MIPs show fast binding kinetics, high binding capacity and acceptable specific recognition behavior towards template proteins. Furthermore, the stability and regeneration were also investigated, which indicated that the MWNTs@MIPs had good reusability. The good recognizing behavior coupled to the low cost and facile one step preparation make the MWNTs@MIPs attractive for separation and specific protein recognition. PMID- 24468346 TI - Development of a pair of differential H/D isotope-coded derivatization reagents d(0)/d(3)-4-(1-methyl-1H-phenanthro[9,10-d]imidazol-2-yl)phenlamine and its application for determination of aldehydes in selected aquatic products by liquid chromatography-tandem mass spectrometry. AB - A new pair of derivatization reagents, d0-4-(1-methyl-1H-phenanthro[9,10 d]imidazol-2-yl)phenlamine (d0-MPIA) and d3-4-(1-methyl-1H-phenanthro[9,10 d]imidazol-2-yl)phenlamine (d3-MPIA) have been designed and synthesized. It was successfully used to label aliphatic aldehydes and the aldehyde derivatives were analyzed by high-performance liquid chromatography-tandem mass spectrometry (HPLC MS/MS). The new isotope-coded reagents could easily label aldehydes under acidic conditions in the presence of NaCNBH3. The target derivatives exhibited intense [M+H](+) and regular product ions with electrospray ionization source in positive mode. The d0/d3-MPIA-aldehydes were monitored by the transitions of [M+H](+)->m/z 322 and [M+H](+)->m/z 165, and the obtained detection limits were in the range of 0.18-15.9 pg/mL at signal to noise ratio of 3. The global isotope internal standard technology was employed for quantification analysis with d3-MPIA aldehyde as internal standard for corresponding d0-MPIA-aldehyde. Excellent linear responses for relative quantification were observed in the range of 1/10 10/1 with coefficients >0.998. The developed method has been applied to the quantification of aliphatic aldehydes in selected aquatic products with RSD<3.6% and recoveries >85.2%. PMID- 24468347 TI - Headspace solid-phase microextraction coupled to gas chromatography for the analysis of aldehydes in edible oils. AB - Oxidation has important effects on the quality of edible oils. In particular, the generation of aldehydes produced by the oxidation of oils is one of the deteriorative factors to their quality. The aim of this study was to develop a method to determine the aldehydes as lipid oxidation markers in edible oils. Seven aldehydes generated from lipid oxidation were studied using headspace solid phase microextraction coupled to gas chromatography with a flame ionization detector. The extraction efficiency of five commercial fibers was investigated and the influence of extraction temperature, extraction time, desorption temperature, and desorption time were optimized. The best result was obtained with 85 MUm carboxen/polydimethylsiloxane, extraction at 50 degrees C for 15 min and desorption in the gas chromatography injector at 250 degrees C for 2 min. Under the optimized conditions, the content of hexanal was the highest of the seven aldehydes in all edible oils. The limits of detection for hexanal in the three oils were found to range from 4.6 to 10.2 ng L(-1). The reproducibility of the method was evaluated and the relative standard deviations were less than 8.9%. This developed approach was successfully applied to analyze hexanal in peanut oil, soy oil, and olive oil samples, and these results were compared with those obtained using the thiobarbituric acid-reactive substances (TBARs) method. PMID- 24468348 TI - Upconversion luminescence nanosensor for TNT selective and label-free quantification in the mixture of nitroaromatic explosives. AB - This paper reports a rapid, sensitive, and selective nanosensor for the detection of 2,4,6-trinitrotoluene (TNT) in the mixture aqueous solution of nitroaromatics independent of immunoassay or molecularly imprinted technology and complicated instruments. Despite many strategies including immunoassay and molecularly imprinted technologies been successfully developed for the detection of TNT, it is not easy to differentiate TNT from 2,4,6-trinitrophenol (TNP) due to their very similar chemical structures and properties. In this work, the amine functionalized NaYF4:Yb(3+)/Er(3+) upconversion luminescence nanoparticles (UCNPs) whose excitation (980 nm) and emission (543 nm) wavelength were far from the absorbance bands of other usual interference nitroaromatics including 2,4 dinitrotoluene (DNT), nitrobenzene (NB), and especially TNP, were utilized as the luminescent nanosensors for TNT luminescence detection. To make these UCNPs highly water stable and render the charge transfer from UCNPs to TNT easier, amino groups were introduced onto the surface of the UCNPs by coating a polymer layer of ethylene glycol dimethacrylate (EGDMA) hybridized with 3 aminopropyltriethoxysilane (APTS). After binding with TNT through amino groups on the UCNPs, the naked eye visible green upconversion luminescence of the UCNPs was dramatically quenched and thus a sensitive UC luminescence nanosensor was developed for TNT detection. However, other nitroaromatics including TNP, DNT, and NB have no influence on the green UC luminescence and thus no influence on the TNT detection. The luminescence intensity is negatively proportional to the concentration of TNT in the range of 0.01-9.0 ug/mL with the 3sigma limit of detection (LOD) of 9.7 ng/mL. The present studies provide a novel and facile strategy to fabricate the upconversion luminescence sensors with highly selective recognition ability in aqueous media and are desirable for label free analysis of TNT in mixed solution independent of immunoassay and molecularly imprinted technology and complicated instruments. PMID- 24468349 TI - Validation and use of a QuEChERS-based gas chromatographic-tandem mass spectrometric method for multiresidue pesticide analysis in blackcurrants including studies of matrix effects and estimation of measurement uncertainty. AB - A triple quadrupole GC-QqQ-MS/MS method was optimized for multiresidue analysis of over 180 pesticides in blackcurrants. The samples were prepared by using a modified quick, easy, cheap, effective, rugged and safe (QuEChERS) analytical protocol. To reduce matrix co-extractives in the final extract, the supernatant was cleaned up by dispersive-solid phase extraction (dispersive-SPE) with a mixture of sorbents: primary secondary amine (PSA), octadecyl (C18) and graphitized carbon black (GCB). The validation results demonstrated fitness for purpose of the streamlined method. The overall recoveries at the three spiking levels of 0.01, 0.05 and 0.2 mg kg(-1) spanned between 70% and 116% (102% on average) with relative standard deviation (RSD) values between 3% and 19% except for chlorothalonil (23%). Response linearity was studied in the range between 0.005 and 0.5 mg kg(-1). The matrix effect for each individual compound was evaluated through the study of ratios of the slopes obtained in solvent and blackcurrant matrix. The optimized method provided small matrix effect (<10%) for 77% of the compounds, whereas only for 14%, 5% and 4% compounds, the matrix effect was 10-20%, 20-30% and >30%, respectively. Following the application of "top-down" approach, the expanded measurement uncertainty was estimated as being 21% on average (coverage factor k=2, confidence level 95%). If compared with samples of other crops, the analyses of blackcurrants revealed a high percentage of exceedance of the legislative maximum residue levels (MRLs), as well as some instances of the detection of pesticides unapproved on this crop. PMID- 24468350 TI - A Process Analytical Technology (PAT) approach to control a new API manufacturing process: development, validation and implementation. AB - Pharmaceutical companies are progressively adopting and introducing Process Analytical Technology (PAT) and Quality-by-Design (QbD) concepts promoted by the regulatory agencies, aiming the building of the quality directly into the product by combining thorough scientific understanding and quality risk management. An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) manufacturing crystallization step during which the API and residual solvent contents need to be precisely determined to reach the predefined seeding point. An original methodology based on the QbD principles was designed to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. On this basis, Partial least squares (PLS) models were developed and optimized using chemometrics methods. The method was fully validated according to the ICH Q2(R1) guideline and using the accuracy profile approach. The dosing ranges were evaluated to 9.0-12.0% w/w for the API and 0.18 1.50% w/w for the residual methanol. As by nature the variability of the sampling method and the reference method are included in the variability obtained for the NIR method during the validation phase, a real-time process monitoring exercise was performed to prove its fit for purpose. The implementation of this in-process control (IPC) method on the industrial plant from the launch of the new API synthesis process will enable automatic control of the final crystallization step in order to ensure a predefined quality level of the API. In addition, several valuable benefits are expected including reduction of the process time, suppression of a rather difficult sampling and tedious off-line analyses. PMID- 24468351 TI - Improvements on bar adsorptive microextraction (BAMUE) technique--application for the determination of insecticide repellents in environmental water matrices. AB - Bar adsorptive microextraction combined with micro-liquid desorption followed by large volume injection-gas chromatography-mass spectrometry operating in the selected-ion monitoring acquisition mode (BAuE-uLD/LVI-GC-MS(SIM)), is proposed for the determination of trace levels of three insecticide repellents (N,N diethyl-meta-toluamide (DEET), cis and trans permethrin (PERM)) in environmental water matrices. By comparing different sorbent coatings (five activated carbons and six polymers) through BAuE, an activated carbon (AC2) proved to be the best compromise between selectivity and efficiency, even against polydimethylsiloxane through stir bar sorptive extraction. The novel improvement proposed on the back extraction stage performed in a single step, by reducing the desorption solvent volume at the microliter level, demonstrated remarkable performance turning possible to save time, making easier the practical manipulation and more environmentally friendly. Assays performed by BAuE(AC2)-uLD/LVI-GC-MS(SIM) on 25 mL of ultrapure water samples spiked at the 1.0 MUg/L level, yielded recoveries ranging from 73.8+/-8.8% (trans-PERM) to 96.4+/-9.9% (DEET), under optimised experimental conditions. The analytical performance showed convenient detection limits (8-20 ng/L) and good linear dynamic ranges (0.04-4.0 ug/L) with suitable determination coefficients (r(2)>0.9963, DEET). Excellent repeatability were also achieved through intraday (RSD<14.9%) and interday (RSD<11.9%) experiments. The novel improvement on downsizing the BAuE device to half-size proved to be either a promising option in forthcoming to reduce still more the desorption solvent volume without losing microextraction efficiency. By using the standard addition methodology, the application of the present analytical approach on tap, ground, river, swimming-pool and estuary water samples revealed good sensitivity at trace level and absence of matrix effects. PMID- 24468352 TI - Visible paper chip immunoassay for rapid determination of bacteria in water distribution system. AB - Paper chips for immunoassay were patterned by screen printing of polydimethylsiloxane (PDMS) or wax pencil drawing. The methods for paper chip patterning are cheap, convenient, rapid and suitable for most laboratories. The whole time for patterning a paper chip is no more than 10 min. Visible immunoassay for the detection of bacteria (Escherichia coli ) has been realized using the paper chip, on which the antibody for capturing E. Coli was immobilized on the detection zones of the paper chip, while the detection antibody was labeled with gold nanoparticles (AuNPs) as a signal reporter. After an immunological reaction, the AuNPs bound on the paper chip can effectively catalyse the reduction of silver ions during the silver enhancing step, generating a visible result that can be read by naked eyes. The quantitative results can be acquired by scanning the silver stained paper chip with a commercial scanner/or digital camera. The density of E. coli in water samples can be measured after calibrating the gray value of silver stained spots with the logarithmic number of bacteria. The time and reagents consumed on the paper chip immunoassay is much smaller than those of conventional ELISA, while the sensitivity of the paper chip immunoassay is comparable to conventional ELISA. The technology proposed in this work displays a great potential in the in-situ analysis when daily monitoring of water quality are required. PMID- 24468353 TI - DNA nanomachines as evolved molecular beacons for in vitro and in vivo detection. AB - Modern biosensors require high sensitivity, great signal enhancement and extensive applicability for detection and diagnostic purposes. Traditional molecular beacons (MBs) do not meet these requirements because of the lack of signal amplification. The current amplification pathways using enzymes, DNAzymes and nanoparticles are usually quite sophisticated and are limited to specific applications. Herein, we developed simple biosensors based on the structure of kissing-hairpin. Through hybridization amplification of these nanomachines, the evolved MBs could greatly enhance the detected signals (approximately 10-fold higher than the signals generated by traditional molecular beacons), reduce the sensing limits for targets and, remarkably, distinguish single-base mismatches specifically for nucleic acid detection. In addition, these new MBs can be directly applied in living cells. By introducing aptamer sequences, these novel sensors can also detect proteins and small molecules. These properties were exemplified by the detection of both the beta-actin gene and thrombin. The simplicity, sensitivity and flexibility of these devices make them appropriate for more expansive applications. PMID- 24468354 TI - Rapid microwave assisted synthesis of graphene nanosheets/polyethyleneimine/gold nanoparticle composite and its application to the selective electrochemical determination of dopamine. AB - In this study, a simple and fast microwave assisted chemical reduction method for the preparation of graphene nanosheet/polyethyleneimine/gold nanoparticle (GNS/PEI/AuNP) composite was developed. PEI, a cationic polymer, was used both as a non-covalent functionalizing agent for the graphene oxide nanosheets (GONSs) through electrostatic interactions in the aqueous medium and also as a stabilizing agent for the formation of AuNPs on PEI wrapped GNSs. This preparation method involves a simple mixing step followed by a simultaneous microwave assisted chemical reduction of the GONSs and gold ions. The prepared composite exhibits the dispersion of high density AuNPs which were densely decorated on the large surface area of the PEI wrapped GNS. X-ray photoelectron spectroscopy, powder X-ray diffraction, high-resolution transmission electron microscopy, field-emission scanning electron microscopy with energy dispersive X ray spectroscopy, and thermo-gravimetric analysis, were used to characterize the properties of the resultant composite. The prepared GNS/PEI/AuNP composite film exhibited excellent electrocatalytical activity towards the selective determination of dopamine in the presence of ascorbic acid, which showed potential application in electrochemical sensors. The applicability of the presented sensor was also demonstrated for the determination of dopamine in human urine samples. PMID- 24468355 TI - Determination of nine benzotriazole UV stabilizers in environmental water samples by automated on-line solid phase extraction coupled with high-performance liquid chromatography-tandem mass spectrometry. AB - A method using automated on-line solid phase extraction coupled with a high performance liquid chromatography-tandem mass spectrometry system was developed for the determination of emerging benzotriazole UV stabilizers (BZTs) in different environmental water matrices including river water, sewage influent and effluent. Water sample was injected directly and the analytes were preconcentrated on a Polar Advantage II on-line SPE cartridge. After cleanup step the target BZTs were eluted in back flush mode and then separated on a liquid chromatography column. Experimental parameters such as sample loading flow rate, SPE cartridge, pH value and methanol ratio in the sample were optimized in detail. The method detection limits ranged from 0.21 to 2.17 ng/L. Recoveries of the target BZTs at 50 ng/L spiking level ranged from 76% to 114% and the inter day RSDs ranged from 1% to 15%. The optimized method was successfully applied to analyze twelve water samples collected from different wastewater treatment plants and rivers, and five BZTs (UV-P, UV-329, UV-350, UV-234 and UV-328) were detected with concentrations up to 37.1 ng/L. The proposed method is simple, sensitive and suitable for simultaneous analysis and monitoring of BZTs in water samples. PMID- 24468356 TI - Rapid determination of eight bioactive alkaloids in Portulaca oleracea L. by the optimal microwave extraction combined with positive-negative conversion multiple reaction monitor (+/-MRM) technology. AB - A rapid and reliable microwave extraction and the triple quadrupole-linear ion trap mass spectrometry method was developed and validated for the determination of eight alkaloids in Portulaca oleracea L. The optimal microwave extraction (MWE) condition was performed at 60 degrees C for 12 min with ethanol-water (70:30, v/v) as the extracting solvent, and the solvent to solid ratio was 30:1. The alkaloids were first detected simultaneously by electrospray ionization tandem mass spectrometry under positive-negative conversion multiple reaction monitor ((+/-)MRM) technique. With investigating three different columns, samples were separated in only 8 min on a Waters ACQUITY UPLC HSS T3 (50 * 2.1 mm(2), 1.8 MUm) column using acetonitrile and formic acid-water solution as a mobile phase with a flow rate at 0.2 mL/min. All calibration curves showed good linearity (r>0.999) within the test ranges. The method developed was validated with acceptable sensitivity, intra- and inter-day precision, reproducibility, and extraction recoveries. It was successfully applied to the determination of eight alkaloids in Portulaca oleracea L. from different sources and different harvest periods. The method also provide a reference for extraction and determination of alkaloids in other complex systems. PMID- 24468357 TI - Development of an electrospray-(63)Ni-differential ion mobility spectrometer for the analysis of aqueous samples. AB - The feasibility of an electrospray coupled with a (63)Ni-differential ion mobility spectrometer (DMS) for the analysis of water samples was proven on examples of 2-hexanone, fluoroacetamide, l-nicotine and 1-phenyl-2-thiourea water solutions. The model substances were selected in order to cover the vapor pressure range of 0.3-1467 Pa. To reduce the inline humidity, which demonstrates a strong influence on the analyte compensation voltage, two units with a desolvation region lengths of 15.5 and 7 mm were examined. The counter gas (heated to 100 degrees C nitrogen) with flow rates of 100 mL min(-1) and 30 mL min(-1) for short and long desolvation units, respectively, was essential for the efficient reduction of humidity. The reduction of water content in the carrier gas to 2.2-2.4 g m(-3) and to 1.8-2.0 g m(-3) for the short and long desolvation unit, respectively, was achieved at an electrospray flow rate of 1000 nL min(-1). With this adjusted experimental setup, the detection of model substances in the water solutions, in the range of 0.1-50 mg L(-1), was performed. No correlation between the vapor pressure and signal area was observed. The high stability of the inline humidity, and the correspondingly stable carrier gas flow rate, were found to be essential for an acceptable reproducibility. PMID- 24468358 TI - Chromatographic analysis with different detectors in the chemical characterisation and dereplication of African propolis. AB - Propolis or bee glue has very diverse composition and is potentially a source of biologically active compounds. Comprehensive chemical profiling was performed on 22 African propolis samples collected from the sub-Saharan region of Africa by using various hyphenated analytical techniques including Liquid Chromatography (LC)-UltraViolet Detection (UV)-Evaporative Light Scattering Detection (ELSD), LC High Resolution Mass Spectrometry (HRMS), Gas Chromatography (GC)-MS and LC-Diode Array Detector (DAD)-HRMS/MS. The diversity of the composition of these African propolis samples could be observed by heat mapping the LC-UV and ELSD data. The characteristic chemical components were uncovered by applying Principal Component Analysis (PCA) to the LC-HRMS data and a preliminary dereplication was carried out by searching their accurate masses in the Dictionary of Natural Products (DNP). A further identification was achieved by comparing their GC-MS or LC-DAD HRMS/MS spectra with previously published data. Generally no clear geographic delineation was observed in the classification of these African propolis samples. Triterpenoids were found as the major chemical components in more than half of the propolis samples analysed in this study and some others were classified as temperate and Eastern Mediterranean type of propolis. Based on the comparative chemical profiling and dereplication studies one uncommon propolis from southern Nigeria stood out from others by presenting prenylated isoflavonoids, which indicated that it was more like Brazilian red propolis, and more significantly a high abundance of stilbenoid compounds which could be novel in propolis. PMID- 24468359 TI - Determination of cyclic and linear siloxanes in wastewater samples by ultrasound assisted dispersive liquid-liquid microextraction followed by gas chromatography mass spectrometry. AB - A fast, simple and environmentally friendly ultrasound-assisted dispersive liquid liquid microextraction (USA-DLLME) procedure has been developed to preconcentrate eight cyclic and linear siloxanes from wastewater samples prior to quantification by gas chromatography-mass spectrometry (GC-MS). A two-stage multivariate optimization approach has been developed employing a Plackett-Burman design for screening and selecting the significant factors involved in the USA-DLLME procedure, which was later optimized by means of a circumscribed central composite design. The optimum conditions were: extractant solvent volume, 13 uL; solvent type, chlorobenzene; sample volume, 13 mL; centrifugation speed, 2300 rpm; centrifugation time, 5 min; and sonication time, 2 min. Under the optimized experimental conditions the method gave levels of repeatability with coefficients of variation between 10 and 24% (n=7). Limits of detection were between 0.002 and 1.4 ug L(-1). Calculated calibration curves gave high levels of linearity with correlation coefficient values between 0.991 and 0.9997. Finally, the proposed method was applied for the analysis of wastewater samples. Relative recovery values ranged between 71 and 116% showing that the matrix had a negligible effect upon extraction. To our knowledge, this is the first time that combines LLME and GC-MS for the analysis of methylsiloxanes in wastewater samples. PMID- 24468360 TI - Gold nanoparticle mediated designing of non-hydrolytic sol-gel cross-linked metformin imprinted polymer network: a theoretical and experimental study. AB - A sensitive and selective electrochemical sensor based on molecularly imprinted polymers was developed for trace level detection of metformin-an antidiabetic drug. For the first time, we have applied non-hydrolytic sol-gel matrix as a cross-linking agent in the field of molecular imprinting. To create the sol-gel matrix and enhance the electro-conductivity of the proposed sensor citrate-capped gold nanoparticle were used. The morphologies and properties of the sensor were characterized by scanning electron microscopy, cyclic voltammetry, electron impedance spectroscopy, chronocoulometry and differential pulse voltammetry. Energy of the HOMO and LUMO orbitals and Mulliken's atomic charges of template molecule were also calculated using density functional theory utilizing B3LYP with 3-21G-basis set. The theoretical results allied to the diagnostic criteria of the cyclic voltammetry indicate that the metformin redox mechanism is associated to the irreversible oxidation process of metformin-imino-group to N hydroxyimino-group. The results demonstrated that the prepared sensor had excellent selectivity and high sensitivity for metformin in the linear range from 0.02 to 80 ng ml(-1) with a detection limit of 0.005 ng ml(-1) (S/N=3). The sensor was also successfully employed to detect metformin in pharmaceutical sample. PMID- 24468361 TI - Ceria nanocubic-ultrasonication assisted dispersive liquid-liquid microextraction coupled with matrix assisted laser desorption/ionization mass spectrometry for pathogenic bacteria analysis. AB - A new ceria (CeO2) nanocubic modified surfactant is used as the basis of a novel nano-based microextraction technique for highly sensitive detection of pathogenic bacteria (Pseudomonas aeruginosa and Staphylococcus aureus). The technique uses ultrasound enhanced surfactant-assisted dispersive liquid-liquid microextraction (UESA-DLLME) with and without ceria (CeO2) followed by matrix assisted laser desorption/ionization mass spectrometry (MALDI-MS). In order to achieve high separation efficiency, we investigated the influential parameters, including extraction time of ultrasonication, type and volume of the extraction solvent and surfactant. Among various surfactants, the cationic surfactants can selectively offer better extraction efficiency on bacteria analysis than that of the anionic surfactants due to the negative charges of bacteria cell membranes. Extractions of the bacteria lysate from aqueous samples via UESA-DLLME-MALDI-MS were successfully achieved by using cetyltrimethyl ammonium bromide (CTAB, 10.0 uL, 1.0*10(-3) M) as surfactants in chlorobenzene (10.0 uL) and chloroform (10.0 uL) as the optimal extracting solvent for P. aeruginosa and S. aureus, respectively. Ceria nanocubic was synthesized, and functionalized with CTAB (CeO2@CTAB) and then characterized using transmission electron microscopy (TEM) and optical spectroscopy (UV and FTIR). CeO2@CTAB demonstrates high extraction efficiency, improve peaks ionization, and enhance resolution. The prime reasons for these improvements are due to the large surface area of nanoparticles, and its absorption that coincides with the wavelength of MALDI laser (337 nm, N2 laser). CeO2@CTAB-based microextraction offers lowest detectable concentrations tenfold lower than that of without nanoceria. The present approach has been successfully applied to detect pathogenic bacteria at low concentrations of 10(4)-10(5) cfu/mL (without ceria) and at 10(3)-10(4) cfu/mL (with ceria) from bacteria suspensions. Finally, the current approach was applied for analyzing the pathogenic bacteria in biological samples (blood and serum). Ceria assist surfactant (CeO2@CTAB) liquid-liquid microextraction (LLME) offers better extraction efficiency than that of using the surfactant in LLME alone. PMID- 24468362 TI - Ultrasensitive enzyme-free electrochemical immunosensor based on hybridization chain reaction triggered double strand DNA@Au nanoparticle tag. AB - An ultrasensitive enzyme-free electrochemical immunoassay was developed for detection of the fg/mL level carcinoembryonic antigen (CEA) by using a double strand DNA@Au nanoparticle (dsDNA@AuNP) tag and hexaammineruthenium(III) chloride (RuHex) as the electroactive indicator. The dsDNA@AuNP was synthesized by one-pot hybrid polymerization of dsDNA on initiator DNA modified AuNPs via hybridization chain reaction. The immunosensor was prepared by covalently cross-linking capture antibody on chitosan/AuNP nanocomposite modified glass carbon electrode. The AuNPs accelerated the electron transfer and led to high detection sensitivity. With a sandwich-type immunoreaction and a biotin-streptavidin affinity reaction, the dsDNA@AuNP tag was conjugated on the immunocomplex to bring a high amount of RuHex to the electrode surface via electrostatic interaction, resulting in an amplified electrochemical signal. Under optimal conditions, the proposed sensing platform showed a wide linear detection range from 10 fg/mL to 10 ng/mL along with a detection limit of 3.2 fg/mL for CEA. The immunosensor exhibited high sensitivity and good stability, showing a promising application in early cancer diagnosis and could be extended to sensitive electrochemical biosensing of other analytes. PMID- 24468363 TI - Design and implementation of an automated liquid-phase microextraction-chip system coupled on-line with high performance liquid chromatography. AB - An automated liquid-phase microextraction (LPME) device in a chip format has been developed and coupled directly to high performance liquid chromatography (HPLC). A 10-port 2-position switching valve was used to hyphenate the LPME-chip with the HPLC autosampler, and to collect the extracted analytes, which then were delivered to the HPLC column. The LPME-chip-HPLC system was completely automated and controlled by the software of the HPLC instrument. The performance of this system was demonstrated with five alkaloids i.e. morphine, codeine, thebaine, papaverine, and noscapine as model analytes. The composition of the supported liquid membrane (SLM) and carrier was optimized in order to achieve reasonable extraction performance of all the five alkaloids. With 1-octanol as SLM solvent and with 25 mM sodium octanoate as anionic carrier, extraction recoveries for the different opium alkaloids ranged between 17% and 45%. The extraction provided high selectivity, and no interfering peaks in the chromatograms were observed when applied to human urine samples spiked with alkaloids. The detection limits using UV-detection were in the range of 1-21 ng/mL for the five opium alkaloids presented in water samples. The repeatability was within 5.0-10.8% (RSD). The membrane liquid in the LPME-chip was regenerated automatically between every third injection. With this procedure the liquid membrane in the LPME-chip was stable in 3-7 days depending on the complexity of sample solutions with continuous operation. With this LPME-chip-HPLC system, series of samples were automatically injected, extracted, separated, and detected without any operator interaction. PMID- 24468364 TI - Flow microcapillary plasma mass spectrometry-based investigation of new Al-Cr-Fe complex metallic alloy passivation. AB - Al-Cr-Fe complex metallic alloys are new intermetallic phases with low surface energy, low friction, and high corrosion resistance down to very low pH values (0 2). Flow microcapillary plasma mass spectrometry under potentiostatic control was used to characterize the dynamic aspect of passivation of an Al-Cr-Fe gamma phase in acidic electrolytes, allowing a better insight on the parameters inducing chemical stability at the oxyhydroxide-solution interface. In sulfuric acid pH 0, low element dissolution rates (in the ug cm(-2) range after 60 min) evidenced the passive state of the Al-Cr-Fe gamma phase with a preferential over-stoichiometric dissolution of Al and Fe cations. Longer air-aging was found to be beneficial for stabilizing the passive film. In chloride-containing electrolytes, ten times higher Al dissolution rates were detected at open-circuit potential (OCP), indicating that the spontaneously formed passive film becomes unstable. However, electrochemical polarization at low passive potentials induces electrical field generated oxide film modification, increasing chemical stability at the oxyhydroxide-solution interface. In the high potential passive region, localized attack is initiated with subsequent active metal dissolution. PMID- 24468365 TI - Reliable classification of moving waste materials with LIBS in concrete recycling. AB - Effective discrimination between different waste materials is of paramount importance for inline quality inspection of recycle concrete aggregates from demolished buildings. The moving targeted materials in the concrete waste stream are wood, PVC, gypsum block, glass, brick, steel rebar, aggregate and cement paste. For each material, up to three different types were considered, while thirty particles of each material were selected. Proposed is a reliable classification methodology based on integration of the LIBS spectral emissions in a fixed time window, starting from the deployment of the laser shot. PLS-DA (multi class) and the hybrid combination PCA-Adaboost (binary class) were investigated as efficient classifiers. In addition, mean centre and auto scaling approaches were compared for both classifiers. Using 72 training spectra and 18 test spectra per material, each averaged by ten shots, only PLS-DA achieved full discrimination, and the mean centre approach made it slightly more robust. Continuing with PLS-DA, the relation between data averaging and convergence to 0.3% average error was investigated using 9-fold cross-validations. Single-shot PLS-DA presented the highest challenge and most desirable methodology, which converged with 59 PC. The degree of success in practical testing will depend on the quality of the training set and the implications of the possibly remaining false positives. PMID- 24468366 TI - Analysis of 7 synthetic musks in cream by supported liquid extraction and solid phase extraction followed by GC-MS/MS. AB - A new method for the simultaneous determination of 7 synthetic musks (musk amberette, musk tibetene, musk moskene, musk ketone, musk xylene, phantolide, and tonalide) in cream by means of supporting liquid extraction (SLE) coupled with LC Alumina-N SPE, then followed by GC-MS/MS has been established. In this study, 7 synthetic musks are extracted and pre-purified by a mixture solution of water and isopropanol from cream, and separated and purified by tandem columns containing SLE column and LC-Alumina-N SPE column, which were seldom reported before. Ultrasonic and mechanical shaking were applied to improve the extraction efficiency. Different experiment conditions, such as the type of extraction solution, extraction time of ultrasonic and mechanical shaking, the type of SLE and SPE column, and matrix effects were optimized and the recoveries of 7 synthetic musks for each part were above 86.61%. In addition, the use of isotope internal standards was systemically discussed. The method showed satisfactory linearity over the range assayed (5-1000 ng g(-1)), and the limits of detections (LODs) ranged from 0.15 to 4.86 ng g(-1), and the limits of quantifications (LOQs) were ranging from 0.49 to 16.21 ng g(-1). The recoveries using this method at three spiked concentration levels (10, 100, and 1000 ng g(-1)) range from 85.6% to 109%. The relative standard deviation was lower than 9.8% in all case. The proposed analytical method has been successfully applied for the analysis of 7 synthetic musks in commercial cream. PMID- 24468367 TI - Hierarchically imprinted mesoporous silica polymer: an efficient solid-phase extractant for bisphenol A. AB - Improving the site accessibility of molecularly imprinted polymer (MIP) is one of the biggest challenges for application of MIP in solid-phase extraction (SPE). Hierarchically imprinted mesoporous silica polymer was prepared with semicovalently bond imprinting methods based on MCM-41 and SBA-15 mesostructures, aiming to improve the site accessibility of MIP and increase the efficiency of molecularly imprinted-SPE. Characterization and performance tests of the obtained products revealed that molecularly imprinted SBA-15 (MIP-SBA-15) not only retained the mesoporous structure of SBA-15, but also displayed excellent selectivity of MIP to the target molecule. As the MIP-SBA-15 were adopted as the adsorbents of solid-phase extraction for detecting bisphenol A in spiked water samples, the recoveries of spiked samples more than 87%, which reveals that the molecularly imprinted SBA-15 were efficient SPE adsorbents for bisphenol A. PMID- 24468368 TI - Preventing UV induced cell damage by scavenging reactive oxygen species with enzyme-mimic Au-Pt nanocomposites. AB - We have prepared enzyme-mimic Au-Pt nanocomposites (NCs) for catalyzing the decomposition of reactive oxygen species. After surface modification, the Au-Pt NCs can be readily internalized and retained by human skin cells and also can effectively reduce cellular oxidative stress. We have demonstrated that the active and biocompatible Au-Pt nanocomposites can be applied for preventing cell damages by scavenging cellular reactive oxygen species induced by ultraviolet irradiation, indicating potential uses for the prevention and therapy of ROS mediated diseases. PMID- 24468369 TI - One-step enrichment and chemiluminescence detection of sodium dodecyl benzene sulfonate in river water using Mg-Al-carbonate layered double hydroxides. AB - In this work, Mg-Al CO3-layered double hydroxides (LDHs) were used as adsorbent materials for sodium dodecyl benzene sulfonate (SDBS) in aqueous solutions, the enriched SDBS can be directly detected by IO4(-)-H2O2 chemiluminescence (CL) system. The commonly existing cations cannot be enriched by Mg-Al CO3-LDHs due to the structurally positively charged layers of LDHs, while other adsorbed anionic interferents had no effect on the IO4(-)-H2O2 CL reaction. The corresponding linear regression equation was established in the range of 0.1-10 MUM for SDBS. The detection limit at a signal-to-noise (S/N) ratio of 3 for SDBS was 0.08 MUM. The relative standard deviation (RSD) for nine repeated measurements of 0.5 MUM SDBS was 2.6%. This proposed method has been successfully applied to the determination of SDBS in river water samples. To the best of our knowledge, we have first time coupled the high enrichment capacity of LDHs towards anions with CL detection for analytes. PMID- 24468370 TI - Complementarity of UV-PLS and HPLC for the simultaneous evaluation of antiemetic drugs. AB - This work was dedicated to the development of a simple and direct multivariate UV spectrophotometric method for the simultaneous determination of three antiemetic drugs (ondansetron, dexamethasone and aprepitant) in a new organogel formulation developed for their simultaneous transdermal administration. This method that does not require separation of the drugs and sophisticated instrument will permit to control quality of this new transdermal form both during the optimization step and for a further routine control of this preparation at the pharmacy department of the hospital. Hence, a partial least squares regression model using the spectral data record from 260 to 288 nm and 5 components, has firstly been validated thanks to the evaluation of the REP% (under 7.9%) and secondly using an accuracy profile approach (acceptance limit of +/-10%). Thereby, the method allows the quantitation of the drugs in the ranges (5-15 mg L(-1)), (4-8 mg L( 1)) and (20-50 mg L(-1)) for ondansetron, dexamethasone and aprepitant, respectively. An HPLC/UV reference method has also been developed. Optimal separation (2.52=4 points for men and >=3 for women are considered positive screens based on US validation studies that compared the AUDIT-C to "gold standard" measures of unhealthy alcohol use from independent, detailed interviews. However, results of screening- positive or negative based on AUDIT-C scores--can be inconsistent with reported drinking on the AUDIT-C questions. For example, individuals can screen positive based on the AUDIT-C score while reporting drinking below US recommended limits on the same AUDIT-C. Alternatively, they can screen negative based on the AUDIT-C score while reporting drinking above US recommended limits. Such inconsistencies could complicate interpretation of screening results, but it is unclear how often they occur in practice. METHODS: This study used AUDIT-C data from respondents who reported past-year drinking on one of two national US surveys: a general population survey (N = 26,610) and a Veterans Health Administration (VA) outpatient survey (N = 467,416). Gender-stratified analyses estimated the prevalence of AUDIT-C screen results--positive or negative screens based on the AUDIT-C score--that were inconsistent with reported drinking (above or below US recommended limits) on the same AUDIT-C. RESULTS: Among men who reported drinking, 13.8% and 21.1% of US general population and VA samples, respectively, had screening results based on AUDIT-C scores (positive or negative) that were inconsistent with reported drinking on the AUDIT-C questions (above or below US recommended limits). Among women who reported drinking, 18.3% and 20.7% of US general population and VA samples, respectively, had screening results that were inconsistent with reported drinking. LIMITATIONS: This study did not include an independent interview gold standard for unhealthy alcohol use and therefore cannot address how often observed inconsistencies represent false positive or negative screens. CONCLUSIONS: Up to 21% of people who drink alcohol had alcohol screening results based on the AUDIT-C score that were inconsistent with reported drinking on the same AUDIT-C. This needs to be addressed when training clinicians to use the AUDIT-C. PMID- 24468407 TI - Left insular cortex and left SFG underlie prismatic adaptation effects on time perception: evidence from fMRI. AB - Prismatic adaptation (PA) has been shown to affect left-to-right spatial representations of temporal durations. A leftward aftereffect usually distorts time representation toward an underestimation, while rightward aftereffect usually results in an overestimation of temporal durations. Here, we used functional magnetic resonance imaging (fMRI) to study the neural mechanisms that underlie PA effects on time perception. Additionally, we investigated whether the effect of PA on time is transient or stable and, in the case of stability, which cortical areas are responsible of its maintenance. Functional brain images were acquired while participants (n=17) performed a time reproduction task and a control-task before, immediately after and 30 min after PA inducing a leftward aftereffect, administered outside the scanner. The leftward aftereffect induced an underestimation of time intervals that lasted for at least 30 min. The left anterior insula and the left superior frontal gyrus showed increased functional activation immediately after versus before PA in the time versus the control task, suggesting these brain areas to be involved in the executive spatial manipulation of the representation of time. The left middle frontal gyrus showed an increase of activation after 30 min with respect to before PA. This suggests that this brain region may play a key role in the maintenance of the PA effect over time. PMID- 24468408 TI - Functional differences in emotion processing during adolescence and early adulthood. AB - Adolescence is a transitional period between childhood and adulthood and is characterized by emotional instability. Underlying this behavior may be an imbalance between the limbic subcortical areas and the prefrontal cortex. Here, we investigated differences in these regions during adolescence and young adulthood. Fifty subjects aged 10 to 24 viewed and rated neutral, negative, and positive pictures (IAPS: International Affective Picture System), while being scanned with functional MRI. Only those trials in which there was a match between the subject's response and the IAPS rating were included in the analyses. Task performance (matching accuracy, reaction times) did not differ across age. Activity in the amygdala and hippocampus decreased with age when processing emotional salient stimuli versus neutral stimuli. In contrast, activation in the ventrolateral prefrontal cortex increased with age. Importantly, we show for the first time that these age-related changes are paralleled by an increase in functional coupling of the amygdala and hippocampus with the orbitofrontal cortex and ventrolateral prefrontal cortex. These findings are in line with the general notion that brain development from childhood to adulthood is characterized by a gradual increase in frontal control over subcortical regions. Understanding these developmental changes is important as these may underlie typical adolescent behavior. PMID- 24468409 TI - Sleep deprivation reduces the rate of rapid picture processing. AB - Object recognition becomes impaired at faster presentation rates and here we show the neuroanatomical foci of where this might be exacerbated by sleep deprivation (SD). Twenty healthy human participants were asked to detect a target house in serially presented house pictures that appeared at 1-15images/s. Temporal response profiles relating fMRI signal magnitude to presentation frequency were derived from task-responsive regions. Following SD, the inverted U-shaped response profile within parahippocampal place area was lower and peaked at a slower presentation rate than when participants slept normally. Contrastingly, SD did not shift the relatively monotonic early visual cortex responses. The intraparietal sulci but not the frontal eye fields or medial frontal region, showed similar shifts in temporal response profiles following SD, suggesting differential contribution of areas mediating attention control towards limiting rapid object processing. As nodes of the default mode network (DMN) continued to show monotonically increasing deactivation at higher presentation frequencies even following SD, the observed state modulations of temporal responses likely represent temporal limitations in object processing as opposed to task disengagement. PMID- 24468410 TI - Periodontal probing of an impacted tooth recovered through a surgical-orthodontic approach: a case report. AB - INTRODUCTION: The aim of this work was to assess the periodontal support of a central upper incisor recovered through a surgical-orthodontic approach compared to the spontaneously erupted contralateral incisor. CASE PRESENTATION: This case study describes an 8-year-old Caucasian female with an impacted upper right central incisor. Surgical-orthodontic treatment was performed to reset the impacted dental element in the arch. Periodontal probing was performed of all sites (mesio-buccal, central-buccal, disto-buccal, mesio-palatal, central-palatal and disto-palatal) of the recovered impacted tooth and the contralateral tooth. The results were compared to determine whether the treated element showed signs of periodontal injury. CONCLUSIONS: Most of the probing results on both her right and left incisors gave values of approximately 3mm, which were not considered pathological. Both dental elements had adequate and physiological osseous attachments. PMID- 24468411 TI - Synthesis of halogenated 4-quinolones and evaluation of their antiplasmodial activity. AB - Treatment of 4-hydroxyquinolines with (2-methyl)allyl bromide in the presence of K2CO3 resulted in the formation of novel N-[(2-methyl)allyl]-4-quinolones through selective N-alkylation. Further reaction of N-(2-methylallyl)-4-quinolones with bromine or N-bromosuccinimide yielded the corresponding 3-bromo-1-(2,3-dibromo-2 methylpropyl)-4-quinolones and 3-bromo-1-(2-methylallyl)-4-quinolones, respectively. Furthermore, a copper-catalyzed C-N coupling of the latter 3-bromo 4-quinolones with (5-chloro)indole afforded novel 3-[(5-chloro)indol-1-yl]-4 quinolone hybrids. Antifungal and antiplasmodial assays of all new 4-quinolones were performed and revealed no antifungal properties but moderate antiplasmodial activities. All 15 compounds displayed micromolar activities against a chloroquine-sensitive strain of Plasmodium falciparum, and the five most potent compounds also showed micromolar activities against a chloroquine-resistant strain of P. falciparum with IC50-values ranging between 4 and 70 MUM. PMID- 24468412 TI - Identification of proton-pump inhibitor drugs that inhibit Trichomonas vaginalis uridine nucleoside ribohydrolase. AB - Trichomonas vaginalis continues to be a major health problem with drug-resistant strains increasing in prevalence. Novel antitrichomonal agents that are mechanistically distinct from current therapies are needed. The NIH Clinical Compound Collection was screened to find inhibitors of the uridine ribohydrolase enzyme required by the parasite to scavenge uracil for its growth. The proton pump inhibitors omeprazole, pantoprazole, and rabeprazole were identified as inhibitors of this enzyme, with IC50 values ranging from 0.3 to 14.5 MUM. This suggests a molecular mechanism for the in vitro antitrichomonal activity of these proton-pump inhibitors, and may provide important insights toward structure-based drug design. PMID- 24468413 TI - Synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition. AB - The synthesis and antifungal activity of ASP9726, a novel echinocandin with potent Aspergillus hyphal growth inhibition and significantly improved MIC against Candida parapsilosis and echinocandin resistant-Candida is described. PMID- 24468414 TI - Synthesis of 2',3',4'-trihydroxyflavone (2-D08), an inhibitor of protein sumoylation. AB - Protein sumoylation is a dynamic posttranslational modification involved in diverse biological processes during cellular homeostasis and development. Recently sumoylation has been shown to play a critical role in cancer, although to date there are few small molecule probes available to inhibit enzymes involved in the SUMO conjugation process. As part of a program to identify and study inhibitors of sumoylation we recently reported the discovery that 2',3',4' trihydroxyflavone (2-D08) is a cell permeable, mechanistically unique inhibitor of protein sumoylation. The work reported herein describes an efficient synthesis of 2-D08 as well as a structurally related but inactive isomer. We also report an unanticipated Wessely-Moser rearrangement that occurs under vigorous methyl ether deprotection conditions. This rearrangement likely gave rise to 2-D08 during a deprotection step, resulting in 2-D08 appearing as a contaminant in a screening well from a commercial supplier. PMID- 24468415 TI - 14th International Congress on Antiphospholipid Antibodies: task force report on antiphospholipid syndrome treatment trends. AB - Antiphospholipid Syndrome (APS) is characterized by vascular thrombosis and/or pregnancy morbidity occurring in patients with persistent antiphospholipid antibodies (aPL). The primary objective of the APS Treatment Trends Task Force, created as part of the 14th International Congress on aPL, was to systematically review the potential future treatment strategies for aPL-positive patients. The task force chose as future clinical research directions: a) determining the necessity for controlled clinical trials in venous thromboembolism with the new oral direct thrombin or anti-factor Xa inhibitors pending the results of the ongoing rivaroxaban in APS (RAPS) trial, and designing controlled clinical trials in other forms of thrombotic APS; b) systematically analyzing the literature as well as aPL/APS registries, and creating specific registries for non warfarin/heparin anticoagulants; c) increasing recruitment for an ongoing primary thrombosis prevention trial, and designing secondary thrombosis and pregnancy morbidity prevention trials with hydroxychloroquine; d) determining surrogate markers to select patients for statin trials; e) designing controlled studies with rituximab and other anti-B-cell agents; f) designing mechanistic and clinical studies with eculizumab and other complement inhibitors; and g) chemically modifying peptide therapy to improve the half-life and minimize immunogenicity. The report also includes recommendations for clinicians who consider using these agents in difficult-to-manage aPL-positive patients. PMID- 24468416 TI - On the relationship between human papilloma virus vaccine and autoimmune diseases. AB - The human papilloma virus (HPV) vaccines were introduced to reduce the incidence of cervical cancer. The bivalent vaccine is effective against HPV-16, -18, -31, 33 and -45 while the quadrivalent vaccine is effective against HPV-16, 18, 31, 6 and 11 types. The immunisation, recommended for adolescent females, has led to high vaccine coverage in many countries. Along with the introduction of the HPV vaccines, several cases of onset or exacerbations of autoimmune diseases following the vaccine shot have been reported in the literature and pharmacovigilance databases, triggering concerns about its safety. This vaccination programme, however, has been introduced in a population that is at high risk for the onset of autoimmune diseases, making it difficult to assess the role of HPV vaccine in these cases and no conclusive studies have been reported thus far. We have thus analysed and reviewed comprehensively all case reports and studies dealing with either the onset of an autoimmune disease in vaccinated subject or the safety in patients with autoimmune diseases to define the role of the HPV vaccines in these diseases and hence its safety. A solid evidence of causal relationship was provided in few cases in the examined studies, and the risk vs. benefit of vaccination is still to be solved. The on-going vigilance for the safety of this vaccine remains thus of paramount importance. PMID- 24468417 TI - Comparison of the prevalence, clinical features, and long-term outcomes of midventricular hypertrophy vs apical phenotype in patients with hypertrophic cardiomyopathy. AB - BACKGROUND: Previous studies on the association between the distribution of left ventricle hypertrophy and the clinical features of hypertrophic cardiomyopathy (HCM) have yielded unclear results. The aim of this study was to investigate the differences in the prevalence, clinical features, management strategies, and long term outcomes between patients with midventricular hypertrophic obstructive cardiomyopathy (MVHOCM) and patients with apical HCM (ApHCM). METHODS: A retrospective study of 60 patients with MVHOCM and 263 patients with ApHCM identified in a consecutive single-centre cohort consisting of 2068 patients with HCM was performed. The prevalence, clinical features, and natural history of the patients in these 2 groups were compared. RESULTS: Compared with ApHCM patients, patients with MVHOCM tended to be much younger and more symptomatic during their initial evaluation. Over a mean follow-up of 7 years, the probability of cardiovascular mortality and that of morbidity was significantly greater in MVHOCM patients compared with ApHCM patients (log-rank, P < 0.001). CONCLUSIONS: Our results suggest that, compared with ApHCM, MVHOCM represents an uncommon presentation of the clinical spectrum of HCM that is characterized by progressive clinical deterioration leading to increased cardiovascular mortality and morbidity. Our results also underscore the importance of the timely recognition of MVHOCM for the prediction of prognosis and the early consideration of appropriate management strategies. PMID- 24468418 TI - Heart failure clinics are still useful (more than ever?). AB - Heart failure (HF) clinics have had an important role in optimal HF management and the effectiveness of these clinics has been studied intensively. A HF clinic is one of the various ways to organize a HF disease management program. There is good evidence that HF disease management can improve outcomes in HF patients, but it is not clear what the optimal components of these programs are and what the relative effectiveness of a HF clinic is compared with other forms of HF management. After initial positive reports on the effect of HF clinics, these clinics were implemented in many countries, although in different formats and of varying quality. In this article we describe the initial need for HF clinics, reflect on their development over time, and discuss the role of HF clinics in context of the current need for HF disease management. PMID- 24468419 TI - Basis for sex-dependent outcomes in acute coronary syndrome. AB - This review aims to provide new insights into the basis for sex differences in acute coronary syndrome (ACS). Sex differences in mortality after ACS depend on age and the type of ACS, with the greatest gap being observed among younger adults and patients with ST-segment elevation myocardial infarction (STEMI). The sex gap diminishes with increasing age and does not appear to exist to the same extent among patients with non-STEMI or unstable angina. Although it is clear that younger women with acute myocardial infarction have higher mortality than do men in the short term; whether this difference is present in the long term remains unclear. Furthermore, women with ACS face delays in diagnosis and treatment, undergo less invasive management, have more bleeding complications, and receive less evidence-based medical therapy than do their male counterparts. Finally, women with ACS consistently report lower health-related quality of life than do men. To date, our understanding of the sex differences in ACS remains limited. The impact of biological factors and nonbiological factors (especially gender roles) need to be explored to elucidate the disparities in health outcomes between men and women. PMID- 24468421 TI - Perceptions of environmental change and use of traditional knowledge to plan riparian forest restoration with relocated communities in Alcantara, Eastern Amazon. AB - BACKGROUND: Riparian forests provide ecosystem services that are essential for human well-being. The Pepital River is the main water supply for Alcantara (Brazil) and its forests are disappearing. This is affecting water volume and distribution in the region. Promoting forest restoration is imperative. In deprived regions, restoration success depends on the integration of ecology, livelihoods and traditional knowledge (TEK). In this study, an interdisciplinary research framework is proposed to design riparian forest restoration strategies based on ecological data, TEK and social needs. METHODS: This study takes place in a region presenting a complex history of human relocation and land tenure. Local populations from seven villages were surveyed to document livelihood (including 'free-listing' of agricultural crops and homegarden tree species). Additionally, their perceptions toward environmental changes were explored through semi-structured interviews (n = 79). Ethnobotanical information on forest species and their uses were assessed by local-specialists (n = 19). Remnants of conserved forests were surveyed to access ecological information on tree species (three plots of 1,000 m2). Results included descriptive statistics, frequency and Smith's index of salience of the free-list results. RESULTS: The local population depends primarily on slash-and-burn subsistence agriculture to meet their needs. Interviewees showed a strong empirical knowledge about the environmental problems of the river, and of their causes, consequences and potential solutions. Twenty four tree species (dbh > 10 cm) were found at the reference sites. Tree density averaged 510 individuals per hectare (stdv = 91.6); and 12 species were considered the most abundant (density > 10ind/ha). There was a strong consensus among plant-specialists about the most important trees. The species lists from reference sites and plant-specialists presented an important convergence. CONCLUSIONS: Slash-and-burn agriculture is the main source of livelihood but also the main driver of forest degradation. Effective restoration approaches must transform problems into solutions by empowering local people. Successional agroforestry combining annual crops and trees may be a suitable transitional phase for restoration. The model must be designed collectively and include species of ecological, cultural, and socioeconomic value. In deprived communities of the Amazon, forest restoration must be a process that combines environmental and social gains. PMID- 24468420 TI - Tumor exosomes induce tunneling nanotubes in lipid raft-enriched regions of human mesothelioma cells. AB - Tunneling nanotubes (TnTs) are long, non-adherent, actin-based cellular extensions that act as conduits for transport of cellular cargo between connected cells. The mechanisms of nanotube formation and the effects of the tumor microenvironment and cellular signals on TnT formation are unknown. In the present study, we explored exosomes as potential mediators of TnT formation in mesothelioma and the potential relationship of lipid rafts to TnT formation. Mesothelioma cells co-cultured with exogenous mesothelioma-derived exosomes formed more TnTs than cells cultured without exosomes within 24-48 h; and this effect was most prominent in media conditions (low-serum, hyperglycemic medium) that support TnT formation (1.3-1.9-fold difference). Fluorescence and electron microscopy confirmed the purity of isolated exosomes and revealed that they localized predominantly at the base of and within TnTs, in addition to the extracellular environment. Time-lapse microscopic imaging demonstrated uptake of tumor exosomes by TnTs, which facilitated intercellular transfer of these exosomes between connected cells. Mesothelioma cells connected via TnTs were also significantly enriched for lipid rafts at nearly a 2-fold higher number compared with cells not connected by TnTs. Our findings provide supportive evidence of exosomes as potential chemotactic stimuli for TnT formation, and also lipid raft formation as a potential biomarker for TnT-forming cells. PMID- 24468422 TI - Enhancing expression of the classical swine fever virus glycoprotein E2 in yeast and its application to a blocking ELISA. AB - Classical swine fever virus (CSFV) infection is a severe swine disease, often causing large economic losses. A Pichia pastoris yeast-expressed CSFV glycoprotein E2 (yE2) has been shown to induce a protective immune response against the virus. To improve the expression level of yE2, the first codon of E2 gene, Arg (CGG), which is the least used in P. pastoris, was optimized to the most favorite codon AGA. The yield of E2 protein was remarkably increased in the codon optimized strain (N342). Three truncated E2 subunits encoding the N terminal 330 (N330), 301 (N301), and 190 (N190) residues, respectively, were also constructed. The immunogenicity of each recombinant E2 subunits was confirmed by immunization of pigs, and all immunized groups demonstrated high neutralizing antibody titers after boost immunization, which lasted for a long period of time. In addition, a monoclonal antibody (MAb), 1B6, specific to yE2, was generated and shown to recognize CSFV-infected cells. A panel of swine sera were tested by peroxidase-conjugated MAb 1B6-based blocking enzyme-linked immunosorbent assay (ELISA) using N330 as coated antigen, and the assay demonstrated high sensitivity and specificity. The recombinant yE2 subunits may provide potential subunit vaccine candidates and useful diagnostic reagents for CSFV with easy manipulation and low cost. PMID- 24468423 TI - Comparing the distress thermometer (DT) with the patient health questionnaire (PHQ)-2 for screening for possible cases of depression among patients newly diagnosed with advanced cancer. AB - OBJECTIVE: Distress screening guidelines call for rapid screening for emotional distress at the time of cancer diagnosis. The purpose of this study was to examine the distress thermometer's (DT) ability to screen in patients in treatment for advanced cancer who may be depressed. METHODS: Using cross sectional data collected from patients within 30 days of diagnosis with advanced cancer, this study used ROC analysis to determine the optimal-cutoff point of the distress thermometer (DT) for screening for depression as measured by the physician health questionnaire (PHQ)-9; inter-test reliability analysis to compare the DT with the PHQ-2 for screening in possible cases of depression, and multivariate analysis to examine associations among the DT emotional problem list (EPL) items with cases of depression. RESULTS: The average age of the 123 patients in the study was 59.9 (12.9) years. Seventy (56.9%) were female. All had Stage 3 or 4 cancers (40% gastrointestinal, 19% gynecologic, 20% head and neck, 21% lung). The mean DT score was 4 (2.7)/10; and 56 (43%) were depressed as measured by the PHQ-9 >= 5. The optimal DT cut-off score to screen in possible cases of depression was >= 2/10, with a sensitivity of .96, compared to a sensitivity of .32 of the PHQ-2 >= 2. Correlation coefficients for the DT >= 2 and the PHQ-2 with the PHQ-9 >= 5 were 0.4 and -0.2, respectively. EPL items associated with cases of depression were Depression (OR = 0.15, 0.02-0.85) and Sadness (OR = 0.21, 0.06-0.72). SIGNIFICANCE OF RESULTS: The optimal DT threshold for identifying possible cases of depression at the time of diagnosis is >= 2; this threshold is more sensitive than the PHQ-2 >= 2. EPL items may be used with the DT score to triage patients for evaluation. PMID- 24468424 TI - The value of anecdote. AB - Anecdote is defined as "a usually short narrative of an interesting, amusing, or biographical incident" and are not often deemed scientifically valuable (www.merriam-webster.com). Anecdotes can be analyzed, however, and those observations can become the initiation of important and groundbreaking work. In this article, we describe aecdotes of several cases which by themselves had seemingly little value. The value was added later, when these concepts were extrapolated to important projects, which expanded into series of experiences, which were reproducible and able to be analyzed and judged as valuable devices and/or methods. The authors recognize that some of the images are old and not of great quality but the information provided is as complete as possible and reliable. PMID- 24468425 TI - Comparison of 1,2-dichloroethane, dichloroethene and vinyl chloride carbon stable isotope fractionation during dechlorination by two Dehalococcoides strains. AB - Carbon stable isotope fractionation during 1,2-dichloroethane (1,2-DCA), dichloroethene (DCE) and vinyl chloride (VC) dechlorination was analysed for two Dehalococcoides strains, Dehalococcoides mccartyi strain 195 (formerly Dehalococcoides ethenogenes strain 195) and D. mccartyi strain BTF08, and used to characterize the reaction. The isotope enrichment factors (epsilonC) determined for 1,2-DCA were -30.8 +/- 1.30/00 and -29.0 +/- 3.00/00 for D. mccartyi strain BTF08 and D. mccartyi strain 195, respectively. Enrichment factors (epsilonC) determined for chlorinated ethenes with strain BTF08 were -28.8 +/- 1.50/00 (VC), -30.5 +/- 1.50/00 (cis-DCE) and -12.4 +/- 1.10/00 (1,1-DCE). Product, ethene, related enrichment factors (epsilonC1,2-DCA-ethene) calculated for 1,2-DCA (-34.1 and -32.30/00 for strain BTF08 and strain 195, respectively) were similar to substrate based enrichment factors (epsilonC1,2-DCA), supporting the hypothesis that ethene is the direct product of 1,2-DCA dichloroelimination but that VC was a side product as result of branching in the reaction. PMID- 24468426 TI - Evaluating hydraulic and disinfection efficiencies of a full-scale ozone contactor using a RANS-based modeling framework. AB - The capability of predicting hydraulic and disinfection efficiencies of ozone disinfection contactors is essential for evaluating existing contactors and improving future designs. Previous attempts based on ideal and non-ideal models for the hydraulics and simplified mechanisms for chemical reaction modeling have resulted in low accuracy and are restricted to contactors with simple geometries. This manuscript develops a modeling framework for the ozonation process by combining computational fluid dynamics (CFD) with a kinetics-based reaction modeling for the first time. This computational framework has been applied to the full-scale ozone contactor operated by the City of Tampa Water Department. Flow fields, residence time distribution, ozone concentration distribution, and concentration-contact time (CT) distribution within the contactor have been predicted via the computational framework. The predictions of ozone and bromate concentrations at sample points agree well with physical experimental data measured in the contactor. The predicted CT values at the contactor outlet demonstrate that the disinfection performance of the ozone contactor operated by the City of Tampa Water Department is sufficient to meet regulation requirements. The impact of seasonal flow rate change on disinfection performance is found to be significant and deserves attention during the management and operation of a water treatment plant. PMID- 24468427 TI - Serum concentrations of eicosanoids and lipids in dogs naturally infected with Babesia canis. AB - Canine babesiosis is a tick-borne disease with world-wide significance caused by intraerythrocytic protozoa of the genus Babesia. The eicosanoids, as inflammatory mediators, are involved in the regulation of the immune response and inflammatory reaction. Metabolism of lipids is of great importance in babesiosis. In this study it was aimed to investigate the dynamics of serum concentration of prostaglandin E2 (PGE2), thromboxane B2 (TxB2), leukotriene B4 (LTB4), triglycerides, total cholesterol (Chol), HDL- and LDL-cholesterol in dogs naturally infected with Babesia canis and healthy dogs. Both groups were measured for all parameters on the admission day and on the first, second and seventh day of the disease. Dogs that were included in this study had systemic inflammatory response syndrome (SIRS) and multiple organ dysfunction syndrome (MODS). It was demonstrated that the level of LTB4, PGE2, TxB2 in dogs naturally infected with B. canis significantly changed during the disease. The level of LTB4 was significantly higher during the study, while the concentration of PGE2 was significantly higher second, third and seventh day of disease in relation with healthy dogs. The level of TxB2 was significantly lower at the beginning of the disease, but after seven days concentration was significantly higher. Both group of patients with SIRS and MODS had significantly higher level of LTB4. Substained high concentrations of PGE2 were observed in dogs with MODS after therapy but not in dogs with SIRS, and LTB4 followed a similar tendency. On the other hand, increases in TxB2 were only significant in dogs with SIRS. The lipid profile in naturally infected dogs with B. canis infection was significantly changed. Further studies are needed to assess the prognostic values of lipid mediators in dogs with B. canis infection, and the ability of these markers to predict the progress of SIRS and MODS. PMID- 24468428 TI - Change in milk production after treatment against gastrointestinal nematodes according to grazing history, parasitological and production-based indicators in adult dairy cows. AB - To investigate future tools for targeted selective treatment against gastrointestinal nematodes (GIN) in adult dairy cows, we evaluated herd and individual cow factors associated with the post-treatment milk production (MP) response over time. A field trial involving 20 pasturing dairy herds in Western France was conducted in autumn 2010 and autumn 2011. In each herd, lactating cows were randomly allocated to a treatment group (fenbendazole) (623 cows), or a control group (631 cows). Daily cow MP was recorded from 2 weeks before until 10 to 14 weeks after treatment. Individual serum anti-Ostertagia antibody levels (expressed as ODR), pepsinogen levels, faecal egg count (FEC), and bulk tank milk ODR were measured at the time of treatment. Moreover, in each herd, information regarding heifers' grazing and treatment history was collected to assess the Time of Effective Contact (TEC, expressed in months) with GIN infective larvae before the first calving. TEC was expected to reflect the development of immunity against GIN, and TEC=8 months was a cautious threshold over which the resistance to re-infection was expected to be established. Daily MP averaged by week was analyzed using linear mixed models with three nested random effects (cow within herd and herd within year). The overall treatment effect was significant but slight (maximum=+0.85 kg/d on week 6 after treatment), and the evolution of treated cows' MP differed significantly according to several factors. At the herd level, cows from low-TEC herds responded better than cows from high-TEC (>= 8 months) herds; cows from herds in which the percentage of positive FEC was >22.6% (median value) responded better than those from herds where it was lower. At the individual cow level, primiparous cows, cows with days in milk (DIM) < or = 100 at the time of treatment, and cows with low individual ODR (< or = 0.38) responded better than multiparous cows, cows with DIM>100, and cows with higher ODR, respectively. These results highlight the variability of the treatment response, suggesting that whole herd anthelmintic treatment are not always appropriate, and propose promising key criteria for targeted selective treatment for GIN in dairy cows. Particularly, the TEC is an original criterion which lends support for a simultaneous on-farm qualitative analysis of grazing management factors. PMID- 24468429 TI - Infant botulism in Andalusia (Southern Spain). AB - BACKGROUND: Infant botulism (IB) is caused by the intestinal colonization by Clostridium botulinum in the first year of life and its subsequent production of neurotoxins. Traditionally, IB has been associated to honey consumption. IB cases tend to cluster in geographic regions. In Europe, IB is a rare disorder. From 1976 through 2006, 65 cases were identified in 13 European countries. In Spain, in the last 15 years, most of the cases have been reported in one region, Andalusia (Southern Spain). A specific treatment for IB type A and type B (BabyBIG) is available outside of the United States since 2005. METHODS: and aims: We performed a retrospective review of IB cases detected in Andalusia since 1997 and compare them with the cases of IB reported in Europe. RESULTS: We identified 11 confirmed cases of IB in Andalusia since 1997, and 14 cases in Spain. Nine out of 11 cases were detected since 2007; none of these infants had been exposed to honey consumption. One case in 1997 and another in 2000 were associated to honey. Two cases were treated with BabyBIG in 2007. In the period 2006-2012 the cases of IB reported in Europe were 54. CONCLUSIONS: We identified a considerable increase in the incidence of IB since 2006. A tendency to a reduction in the number of cases of IB linked to honey consumption has also been identified. An increase in the exposure to these bacteria from the environment could be presumed. Clinicians should maintain a high index of suspicion for this treatable disorder. PMID- 24468430 TI - Individuals' openness to migrate and job mobility. AB - In this article we extend the scope of the interdependence between migration and job mobility: We investigate whether an individual's openness to migrate not only increases the probability of migration but also the likelihood to conduct a job search and exhibit job mobility. Using data from a three-wave panel study, which allows the analysis of temporal links between decision-making and subsequent events regarding migration and job mobility, a joint estimation of multiple equations is performed. We show that considering migration as an option for the future, which is our indicator of individuals' openness to migrate, is positively associated with both migration and job mobility. It even increases job mobility independently of whether migration takes place or not. These findings contribute significantly to our body of knowledge about the interdependence of migration and job mobility. Additionally, they enhance our understanding of the mechanisms behind a common selectivity of migrants and job mobile individuals. PMID- 24468431 TI - School accountability and the black-white test score gap. AB - Since at least the 1960s, researchers have closely examined the respective roles of families, neighborhoods, and schools in producing the black-white achievement gap. Although many researchers minimize the ability of schools to eliminate achievement gaps, the No Child Left Behind Act (NCLB) increased pressure on schools to do so by 2014. In this study, we examine the effects of NCLB's subgroup-specific accountability pressure on changes in black-white math and reading test score gaps using a school-level panel dataset on all North Carolina public elementary and middle schools between 2001 and 2009. Using difference-in difference models with school fixed effects, we find that accountability pressure reduces black-white achievement gaps by raising mean black achievement without harming mean white achievement. We find no differential effects of accountability pressure based on the racial composition of schools, but schools with more affluent populations are the most successful at reducing the black-white math achievement gap. Thus, our findings suggest that school-based interventions have the potential to close test score gaps, but differences in school composition and resources play a significant role in the ability of schools to reduce racial inequality. PMID- 24468432 TI - Relationships of choice: can friendships or fictive kinships explain the race paradox in mental health? AB - African Americans typically exhibit similar or better mental health outcomes than whites, an unexpected pattern given their disproportionate exposure to psychosocial stressors. The "race paradox in mental health" has been attributed to presumed stronger social ties among blacks but there is scarce empirical research in this regard. Using data from the 2001-2003 National Survey of American Life (N=4086), I test whether more abundant and higher quality friendships and fictive kin relationships among African Americans (if they exist) account for the race paradox in mental health. I find few race differences in the quantity and quality of friendships and fictive kinships and these differences did not explain the race paradox in mental health. Future research should investigate other potential resilience mechanisms among African Americans to explain their relatively positive mental health outcomes. PMID- 24468433 TI - The racial foundations of whites' support for child saving. AB - Scholars emphasize that attitudes toward rehabilitation and views about punitive polices are distinct phenomena with seemingly unique etiologies. However, few existing studies examine the sources of public views about juvenile rehabilitation, or "child saving," and none engage a measure of racial attitudes. At the same time, recent theoretical work implicates racial concerns as a central foundation of public opinion about youth justice. This paper thus provides the first assessment of whether whites' perceptions of the racial makeup of delinquents and animosities toward blacks are associated with their views about juvenile rehabilitation. Findings show that whites who more strongly associate delinquency with blacks and those who are racially resentful both tend to be less supportive-in absolute and relative terms-of rehabilitation. The results also suggest that contextual threat moderates the effect of racial typification of delinquency, but not that of racial resentment, on whites' views about rehabilitation. PMID- 24468434 TI - Relational trustworthiness: how status affects intra-organizational inequality in job autonomy. AB - Recent accounts of trustworthiness have moved away from treating it as a stable, individual-level attribute toward viewing it as a variable situated in a relational context, but have not been formalized or supported empirically. We extend status characteristics theory (SCT) to develop formal propositions about relational trustworthiness. We posit that members of task- and collectively oriented groups (non-consciously) infer three qualities from their relative status that are commonly used to determine an individual's trustworthiness: ability, benevolence, and integrity. We apply our formalization to clarify ambiguities regarding intra-organizational job autonomy inequality, thereby linking SCT to broader disparities rooted in job autonomy. We analyze data from a vignette experiment and the General Social Survey to test incrementally how well our propositions generalize across different settings and populations. Results generally support our proposed links between status and intra-organizational job autonomy. We discuss implications for SCT in understanding broader patterns of inequalities. PMID- 24468435 TI - Citizen-making: the role of national goals for socializing children. AB - The ecological, political, religious and economic constraints and opportunities characterizing a nation crystallize to set the agenda for socializing children, its future citizens. Parented accordingly, members of those nations would come to adopt the values, beliefs, skills and attitudes that constitute the requisite human capital to sustain that nation. This study reports on the profiling of 55 nations by two dimensions of the socialization goals for children extracted from the World Values Survey, viz., Self-directedness versus Other-directedness, and Civility versus Practicality. An affluent, less corrupt and more gender-equal society is associated with greater focus on Self-directedness and Civility. Both dimensions show convergent and discriminant validities in their correlation with nation-level psychosocial variables such as citizen subjective well-being, values, beliefs, pace of life and trust of out-groups. These dimensions are also shown to connect a nation's ecological construct to the outcomes of its citizens, adding a psychological-developmental perspective to examine nation-building and cultural transmission. PMID- 24468436 TI - Theories of lean management: an empirical evaluation. AB - Debates within organization theory traditionally argued the relative merits of bureaucracy but today there is broad agreement across different perspectives that bureaucratic organization is inefficient and outmoded. Despite their differences, post-bureaucratic and neo-liberal theories argue that organizations with relatively flat hierarchies and low management overhead are better adapted to current market requirements. Post-bureaucratic theory also argues that employees, as well as firms, benefit from leaner management structures. This paper investigates trends in managerial leanness, proposed explanations for such trends, and the consequences of leanness for firms and employees. Although there is a trend toward flatter management hierarchies, there is only weak support for current claims regarding both the causes and consequences of lean management. PMID- 24468437 TI - Social origins and post-high school institutional pathways: a cumulative dis/advantage approach. AB - The social stratification that takes place during the transition out of high school is traditionally explained with theoretical frameworks such as status attainment and social reproduction. In our paper, we suggest the cumulative dis/advantage hypothesis as an alternative theoretical and empirical approach that explains this divergence in institutional pathways as the result of the dynamic interplay between social institutions (in our case, schools) and individuals' resources. We use data from the NLSY79 in order to compute institutional pathways (defined by educational and occupational status) of 9,200 high school graduates. Optimal Matching Analysis and Cluster Analysis generated a typology of life course pathways. Our results show that both ascribed characteristics and students' high school characteristics and resources are predictors of post-high school pathways. PMID- 24468438 TI - A non-stationary panel data investigation of the unemployment-crime relationship. AB - Many empirical studies of the economics of crime focus solely on the determinants thereof, and do not consider the dynamic and cross-sectional properties of their data. As a response to this, the current paper offers an in-depth analysis of this issue using data covering 21 Swedish counties from 1975 to 2010. The results suggest that the crimes considered are non-stationary, and that this cannot be attributed to county-specific disparities alone, but that there are also a small number of common stochastic trends to which groups of counties tend to revert. In an attempt to explain these common stochastic trends, we look for a long-run cointegrated relationship between unemployment and crime. Overall, the results do not support cointegration, and suggest that previous findings of a significant unemployment-crime relationship might be spurious. PMID- 24468439 TI - The color of juvenile justice: racial disparities in dispositional decisions. AB - Existing research on dispositional decisions typically models the outcome as merely placed or not placed. However, this does not accurately reflect the wide variation in residential options available to juvenile court actors. In this research, we combine data from ProDES, which tracks adjudicated youth in Philadelphia, with data from the Program Design Inventory, which describes over 100 intervention programs, to further examine the factors that influence court actors' decision making in selecting an appropriate program for a juvenile offender. We find that even after controlling for legal and needs-based factors, race continues to exert a significant influence, with decision makers being significantly more likely to commit minority youth to facilities using physical regimen as their primary modality and reserving smaller, therapeutic facilities for their white counterparts. Using focal concerns theory as an explanatory lens, we suggest that court actors in this jurisdiction employ a racialized perceptual shorthand of youthful offenders that attributes both higher levels of blame and lower evaluations of reformability to minority youth. PMID- 24468440 TI - Marital age homogamy in China: a reversal of trend in the reform era? AB - This paper reports on a study of trends in marital age homogamy in China from 1960 to 2005 that uses data from the China 2005 1% Population Inter-census Survey. Instead of a consistent increase in age homogamy, results show an inverted U-shaped trend. One plausible explanation is that intensified economic pressure, rising consumerism, and a shrinking gender gap in education during the post-1990s reform era have acted to increase women's desire to marry men who are more economically established, and thus usually older, than less financially secure men. We argue that age hypergamy maintains status hypergamy, a deeply rooted norm for couples in China. An auxiliary analysis based on the human capital model for earnings supports this interpretation. A continued trend in age hypergamy implies a future "marriage squeeze" for men of low socioeconomic status. PMID- 24468441 TI - Ethnic stratification amid China's economic transition: evidence from the Xinjiang Uyghur Autonomous Region. AB - This paper analyzes a sample from the 2005 mini-census of Xinjiang to examine ethnic stratification in China's labor markets, with a special focus on how ethnic earnings inequality varies by employment sector. We show that Han and Uyghur Chinese dominated different economic sectors. Excluding those in agriculture, Uyghurs were more likely to work in government or institutions than either Han locals or migrants, and also more likely to become self-employed. The Han-Uyghur earnings gap was negligible within government/public institutions, but increased with the marketization of the employment sector. It was the largest among the self-employed, followed by employees in private enterprises and then employees in public enterprises. Han migrants in economic sectors enjoyed particular earnings advantages and hukou registration status had no impact on earnings attainment except in government/public institutions. These findings have important implications for understanding social and economic sources of increasing ethnic conflicts in Xinjiang in recent years. PMID- 24468442 TI - Changes in college attainment and the economic returns to a college degree in urban China, 2003-2010: implications for social equality. AB - Expansion of higher education is expected to reduce social inequality under the conditions that (1) higher education should become increasingly egalitarian; (2) educational attainment should be the main determinant of class destinations; and (3) individuals from different social backgrounds should benefit from higher education homogeneously. Using representative data collected in mainland China from 2003 to 2010, we find (1) social background factors, especially parents' education, are significantly associated with the opportunity of completing college across periods; (2) the economic returns to a college degree have been longitudinally increasing; and (3) for both 2003 and 2010, people from different social origins benefit from higher education attainment in a homogeneous way. An overall assessment of the findings suggests that changes in college attainment and the returns to higher education in urban China are not in favor of the promotion of general social equality, but maintain the existing extent of inequality. PMID- 24468443 TI - Do mother's and father's education condition the impact of parental divorce on child well-being? AB - We use the British Cohort Study to investigate to what extent parental resources moderate the association between parental divorce in childhood and lowered child well-being as indicated by maternal reports of child psychological well-being and by academic test scores (reading and math tests). We argue that children of mothers with more years of education suffer less when their parents split up because better educated mothers may be better able to provide a safe and stable environment for their children after divorce. In addition, we argue that having a better educated father could either aggravate or reduce the effects of parental divorce. This is one of the first studies to simultaneously investigate the role of maternal, and paternal resources, and pre-divorce shared resources. Our analyses indicate that the effect of parental divorce on psychological well-being is reduced for better educated mothers and for families with more pre-divorce economic resources, but increased for better educated fathers. For academic test scores we find a protective effect of having a better educated father and higher pre-divorce social resources. PMID- 24468444 TI - The preferred role and perceived performance of the welfare state: European welfare attitudes from a multidimensional perspective. AB - Welfare state support has two core dimensions: attitudes about what the welfare state should do and beliefs about its actual performance. People can combine any position on one dimension with any position on the other, yielding four opinion clusters: people can combine preferences for a relatively strong role of the welfare state with a perception of a relatively low or high welfare state performance; likewise, people preferring a small role of the welfare state can perceive a high or low performing welfare state. We apply Latent Class Factor Analysis to data of 22 European countries from the 2008/9 European Social Survey. We find that each of the four clusters contains a substantial proportion of respondents that differs between welfare regimes. In addition, cluster membership is also related to covariates that measure people's structural positions and ideological preferences. PMID- 24468445 TI - Online questionnaire development: using film to engage participants and then gather attitudes towards the sharing of genomic data. AB - How can a researcher engage a participant in a survey, when the subject matter may be perceived as 'challenging' or even be totally unfamiliar to the participant? The Genomethics study addressed this via the creation and delivery of a novel online questionnaire containing 10 integrated films. The films documented various ethical dilemmas raised by genomic technologies and the survey ascertained attitudes towards these. Participants were recruited into the research using social media, traditional media and email invitation. The film survey strategy was successful: 11,336 initial hits on the survey website led to 6944 completed surveys. Participants included from those who knew nothing of the subject matter through to experts in the field of genomics (61% compliance rate), 72% of participants answered every single question. This paper summarises the survey design process and validation methods applied. The recruitment strategy and results from the survey are presented elsewhere. PMID- 24468447 TI - Gene expression analysis in gonads and brain of catfish Clarias batrachus after the exposure of malathion. AB - Pesticides like malathion have the potential to disrupt development and reproduction of aquatic organisms including fishes. To investigate the likely consequences of malathion exposure at low doses in juvenile catfish, Clarias batrachus, we studied the expression pattern of genes encoding certain transcription factors, activin A, sex steroid or orphan nuclear receptors and steroidogenic enzymes which are known to be involved in gonadal development along with histological changes. To compare further, we also analyzed certain brain specific genes related to gonadal axis. Fifty days post hatch catfish fingerlings were exposed continuously to 1 and 10 ug/L of malathion for 21 days. Results from these experiments indicated that transcript levels of various genes were altered by the treatments, which may further affect the gonadal development either directly or indirectly through brain. Histological analysis revealed slow progression of spermatogenesis in testis, while in ovary, the oil droplet oocytes were found to be higher after treatment (10 ug/L). Our findings revealed that the exposure of malathion, even at low doses, hinder or modulate early gonadal development differentially by targeting gene expression pattern of transcription factors, activin A, sex steroid or orphan nuclear receptors and steroidogenic enzymes with an evidence on histological changes. Further, some of the genes showed differential expression at the level of brain in male and female sex after the exposure of malathion. PMID- 24468446 TI - Functional DNA nanomaterials for sensing and imaging in living cells. AB - Recent developments in integrating high selectivity of functional DNA, such as DNAzymes and aptamers, with efficient DNA delivery into cells by gold nanoparticles or superior near-infrared optical properties of upconversion nanoparticles are reviewed. Their applications in sensing and imaging small organic metabolites, toxins, metal ions, pH, DNA, RNA, proteins, and pathogens are summarized. The advantages and future directions of these functional DNA materials are discussed. PMID- 24468448 TI - The interconnectedness between landowner knowledge, value, belief, attitude, and willingness to act: policy implications for carbon sequestration on private rangelands. AB - Rangelands can be managed to increase soil carbon and help mitigate emissions of carbon dioxide. This study assessed Utah rangeland owner's environmental values, beliefs about climate change, and awareness of and attitudes towards carbon sequestration, as well as their perceptions of potential policy strategies for promoting carbon sequestration on private rangelands. Data were collected from semi-structured interviews and a statewide survey of Utah rangeland owners, and were analyzed using descriptive and bivariate statistics. Over two-thirds of respondents reported some level of awareness of carbon sequestration and a generally positive attitude towards it, contrasting to their lack of interest in participating in a relevant program in the future. Having a positive attitude was statistically significantly associated with having more "biocentric" environmental values, believing the climate had been changing over the past 30 years, and having a stronger belief of human activities influencing the climate. Respondents valued the potential ecological benefits of carbon sequestration more than the potential financial or climate change benefits. Additionally, respondents indicated a preference for educational approaches over financial incentives. They also preferred to work with a private agricultural entity over a non-profit or government entity on improving land management practices to sequester carbon. These results suggest potential challenges for developing technically sound and socially acceptable policies and programs for promoting carbon sequestration on private rangelands. Potential strategies for overcoming these challenges include emphasizing the ecological benefits associated with sequestering carbon to appeal to landowners with ecologically oriented management objectives, enhancing the cooperation between private agricultural organizations and government agencies, and funneling resources for promoting carbon sequestration into existing land management and conservation programs that may produce carbon benefits. PMID- 24468449 TI - Simulation of batch-operated experimental wetland mesocosms in AQUASIM biofilm reactor compartment. AB - In this study, a mathematical biofilm reactor model based on the structure of the Constructed Wetland Model No.1 (CWM1) coupled to AQUASIM's biofilm reactor compartment has been used to reproduce the sequence of transformation and degradation of organic matter, nitrogen and sulphur observed in a set of constructed wetland mesocosms and to elucidate the development over time of microbial species as well as the biofilm thickness of a multispecies bacterial biofilm in a subsurface constructed wetland. Experimental data from 16 wetland mesocosms operated under greenhouse conditions, planted with three different plant species (Typha latifolia, Carex rostrata, Schoenoplectus acutus) and an unplanted control were used in the calibration of this mechanistic model. Within the mesocosms, a thin (predominantly anaerobic) biofilm was simulated with an initial thickness of 49 MUm (average) and in which no concentration gradients developed. The biofilm density and area, and the distribution of the microbial species within the biofilm were evaluated to be the most sensitive biofilm properties; while the substrate diffusion limitations were not significantly sensitive to influence the bulk volume concentrations. The simulated biofilm density ranging between 105,000 and 153,000 gCOD/m(3) in the mesocosms was observed to vary with temperature, the presence as well as the species of macrophyte. The biofilm modeling was found to be a better tool than the suspended bacterial modeling approach to show the influence of the rhizosphere configuration on the performance of the constructed wetlands. PMID- 24468450 TI - [Colorectal screening makes sense]. PMID- 24468451 TI - [Post treatment follow-up of patients with testicular cancer by primary care physicians]. PMID- 24468454 TI - [Colitis-associated colorectal carcinoma: epidemiology, pathogenesis and early diagnosis]. AB - Colitis-associated colorectal carcinoma (CRC) accounts for about 5% of all CRC and the risk for CRC in inflammatory bowel disease (IBD) patients - according to older meta-analyses - is slightly increased when compared to normal population. Effective anti-inflammatory therapy seems to decrease this risk. Main risk factors for colitis-associated CRC are pancolitis, duration of colitis and presence of primary sclerosing cholangitis. In contrast to sporadic CRC, a characteristic adenoma-carcinoma sequence in the pathogenesis of colitis associated CRC cannot be found. Nevertheless, numerous cell and gene defects occur. Reactive oxygen species also seem to play a pivotal role in the pathogenesis of colitis-associated CRC. Particularly patients with chronically active pancolitis should undergo regular surveillance colonoscopy, since prognosis of colitis-associated CRC is poor. PMID- 24468453 TI - [Recommendations for diagnosis and therapy of behavioral and psychological symptoms in dementia (BPSD)]. AB - In patients with dementia, Behavioral and Psychological Symptoms of Dementia (BPSD) are frequent findings that accompany deficits caused by cognitive impairment and thus complicate diagnostics, therapy and care. BPSD are a burden both for affected individuals as well as care-givers, and represent a significant challenge for therapy of a patient population with high degree of multi morbidity. The goal of this therapy-guideline issued by swiss professional associations is to present guidance regarding therapy of BPSD as attendant symptoms in dementia, based on evidence as well as clinical experience. Here it appears to be of particular importance to take into account professional experience, as at this point for most therapeutic options no sufficiently controlled clinical trials are available. A critical discussion of pharmaco therapeutic intervention is necessary, as this patient-population is particularly vulnerable for medication side-effects. Finally, a particular emphasis is placed on incorporating and systematically reporting psycho-social and nursing options therapeutic intervention. PMID- 24468455 TI - [Heterogeneity of epithelial ovarian carcinomas and their clinical significance]. AB - Epithelial ovarian cancer is one of the most lethal gynecological malignant tumors despite improvement of the treatment. Recent molecular studies show that ovarian cancer is a heterogeneous disease which is reflected by different histologic types. These subtypes differ from their origin, pathogenesis and molecular alterations and can be divided in two major groups. The type I cancer (low grade) evolves from precursor lesions in a step-wise process. In contrast, the type II cancer (high grade) grows rapidly without any identifiable precursors. Among all subtypes is heterogeneity in the biological behavior which has implications in patient prognosis and treatment especially for individualized therapies in the future. PMID- 24468456 TI - [Knee pain of unknown origin after total knee prosthesis in a patient with chronic polyarthritis]. AB - Persisting pain after TKA is a frequent problem. The most frequent differential diagnoses are aseptic loosening, malpositioning or a prosthetic joint infection. Retropatellar pain, functional or psychosomatic cause should be taken into account, too. An acute episode in patients with a rheumatoid arthritis should be ruled out. Insufficiency fractures, which can also be found in the presented case, are more often in patients with rheumatoid arthritis. The insufficiency fracture was detectable in the MRI and shows an uncommon, non-described localization. To prevent a loss of mobility of fractures close to the joint a surgical stabilizing is recommended, leading to quick healing. PMID- 24468458 TI - [Selected indications for antibiotic treatment of sore throat]. PMID- 24468459 TI - [Stress incontinence: first pelvic floor training or direct surgery?]. PMID- 24468461 TI - [CME - rheumatology 1. Ganglion]. PMID- 24468463 TI - [Individuals in the history of medicine. David Bruce]. PMID- 24468464 TI - Intraoperative assessment of margins in breast conserving therapy: a systematic review. AB - Approximately one quarter of patients undergoing breast conserving therapy for breast cancer will require a second operation to achieve adequate clearance of the margins. A number of techniques to assess margins intraoperatively have been reported. This systematic review examines current intraoperative methods for assessing margin status. The final pathology status, statistical measures including accuracy of tumour margin assessment, average time impact on the procedure and second operation rate, were used as criteria for comparison between studies. Although pathological methods, such as frozen section and imprint cytology performed well, they added on average 20-30 min to operation times. An ultrasound probe allows accurate examination of the margins and delivers results in a timely manner, yet it has a limited role with DCIS where calcification is present and in multifocal cancer. Further research is required in other intraoperative margin assessment techniques, such as mammography, radiofrequency spectroscopy and optical coherence tomography. PMID- 24468465 TI - Testing anxiolytic drugs in the C57BL/6J mouse strain. AB - C57BL/6J mice are one of the most commonly used mouse strains in biobehavioral and psychopharmacological research. Prone to variance due to multiple environmental factors, animal neurophenotyping studies rely on using proper experimental protocols, study designs and well-established models and tests. Choosing the dose range for anxiolytic or anxiogenic drugs is key for obtaining valid testing results and correct data interpretation. Here we emphasize the importance of accurate dose selection in rodent anxiety paradigms for concluding whether the mouse strain used is "sensitive" and therefore appropriate for studying anxiety in selected behavioral tests. We also provide further argument in support of using the C57BL/6J mouse strain for testing anxiolytic and anxiogenic compounds. PMID- 24468466 TI - Evaluation of the sensitivity of a new fully implantable telemetry device and the importance of simultaneously measuring cardiac output and left ventricular pressure. AB - INTRODUCTION: The absence of drug-induced changes in heart rate (HR), aortic pressure (AOP) and ECG, the minimum endpoints suggested in ICH S7A, does not necessarily indicate the absence of cardiovascular (CV) pharmacodynamic activity. This potential pitfall can be avoided by prospectively incorporating "follow-up" endpoints in initial evaluations made possible by the advent of new telemetry implants capable of also measuring changes in cardiac output (CO) and left ventricular pressure (LVP). The purpose of this study was (1) to evaluate the sensitivity of a new, fully implantable telemetry device, and (2) to highlight the importance of the device to simultaneously measure cardiac output and left ventricular pressure in order to adequately evaluate the full potential for a drug to impact global cardiovascular function. METHODS: 4 dogs were instrumented with Konigsberg Instruments, Inc. (KI) TU7/T27H series fully implantable telemetry device and recovered for >8weeks. Sotalol (8mg/kg), milrinone (0.2mg/kg), hydralazine (0.2mg/kg) and control were administered 1week apart. Data were collected for 1h pre- and 24h post-treatment and time-averaged to fully characterize the a priori pharmacodynamic effects of interest for each drug. This included PR and QTci (sotalol); HR, AOP and LVP (milrinone); HR, AOP, CO and systemic vascular resistance (SVR) (hydralazine). RESULTS: Expected changes in CV parameters were observed following all drugs with the following detection sensitivities: PR and QTci of 4ms and 3ms, respectively (sotalol); AOP and LVP dP/dt+max of 5mmHg and 232mmHg/s, respectively (milrinone); HR, CO and SVR of 11bpm, 0.302l/min and 5mmHg*min/l, respectively (hydralazine). DISCUSSION: KI TU7/T27H implant detects drug-induced CV changes with statistical significance using a standard, four-subject design. The ability of the TU7/T27H to also measure CO and LVP allowed for full characterization of the CV impact of hydralazine and milrinone, which could have been misinterpreted/missed altogether if these drugs were novel and the endpoints evaluated were prospectively limited to the minimum suggested in ICH S7A. PMID- 24468467 TI - Effect of endothelin antagonism on apnea frequency following chronic intermittent hypoxia. AB - Chronic hypoxia increases the hypoxic ventilatory response (HVR). Augmented HVR contributes to central apneas seen in heart failure and complex sleep apnea. Endothelin receptor (ETR) antagonism decreases carotid body afferent activity following chronic intermittent hypoxia (CIH). We speculated ETR antagonism would reduce HVR and apneas following CIH. HVR and apneas were measured after exposure to CIH and room air sham (SHAM). ETR blocker Ambrisentan was administered via the chow of CIH-exposed animals from days 1 to 12 of CIH (CIH/AMB). A separate crossover group was exposed to CIH and fed normal chow (placebo) days 1-6, and Ambrisentan days 7-12 (CIH/PLA-AMB). SHAM and CIH/PLA animals were fed placebo days 1-12. The CIH/AMB and CIH/PLA-AMB rats had reduced HVR compared to CIH/PLA, similar HVR compared to sham exposed animals, and reduced apnea frequency compared to CIH/PLA animals. The reduced HVR and post-hypoxic apneas resulting from Ambrisentan administration suggests ETR antagonists may have utility in reducing central apneas following CIH. PMID- 24468468 TI - Validation of respiratory inductive plethysmography (LifeShirt) in obesity hypoventilation syndrome. AB - Validation of respiratory inductive plethysmography (LifeShirt system) (RIPLS) for tidal volume (VT), minute ventilation (VE), and respiratory frequency (fB) was performed among people with untreated obesity hypoventilation syndrome (OHS) and controls. Measures were obtained simultaneously from RIPLS and a spirometer during two tests, and compared using Bland Altman analysis. Among 13 OHS participants (162 paired measures), RIPLS-spirometer agreement was unacceptable for VT: mean difference (MD) 3 mL (1%); limits of agreement (LOA) -216 to 220 mL (+/-36%); VE MD 0.1 L min(-1) (2%); LOA -4.1 to 4.3 L min(-1) (+/-36%); and fB: MD 0.2 br min(-1) (2%); LOA -4.6 to 5.0 br min(-1) (+/-27%). Among 13 controls (197 paired measures), RIPLS-spirometer agreement was acceptable for fB: MD -0.1 br min(-1) (-1%); LOA -1.2 to 1.1 br min(-1) (+/-12%), but unacceptable for VT: MD 5 mL (1%); LOA -160 to 169 mL (+/-20%) and VE: MD 0.1 L min(-1) (1%); LOA -1.4 to 1.5 L min(-1) (+/-20%). RIPLS produces valid measures of fB among controls but not OHS patients, and is not valid for quantifying respiratory volumes among either group. PMID- 24468469 TI - Withdrawing performance indicators: retrospective analysis of general practice performance under UK Quality and Outcomes Framework. AB - OBJECTIVES: To investigate the effect of withdrawing incentives on recorded quality of care, in the context of the UK Quality and Outcomes Framework pay for performance scheme. DESIGN: Retrospective longitudinal study. SETTING: Data for 644 general practices, from 2004/05 to 2011/12, extracted from the Clinical Practice Research Datalink. PARTICIPANTS: All patients registered with any of the practices over the study period-13,772,992 in total. INTERVENTION: Removal of financial incentives for aspects of care for patients with asthma, coronary heart disease, diabetes, stroke, and psychosis. MAIN OUTCOME MEASURES: Performance on eight clinical quality indicators withdrawn from a national incentive scheme: influenza immunisation (asthma) and lithium treatment monitoring (psychosis), removed in April 2006; blood pressure monitoring (coronary heart disease, diabetes, stroke), cholesterol concentration monitoring (coronary heart disease, diabetes), and blood glucose monitoring (diabetes), removed in April 2011. Multilevel mixed effects multiple linear regression models were used to quantify the effect of incentive withdrawal. RESULTS: Mean levels of performance were generally stable after the removal of the incentives, in both the short and long term. For the two indicators removed in April 2006, levels in 2011/12 were very close to 2005/06 levels, although a small but statistically significant drop was estimated for influenza immunisation. For five of the six indicators withdrawn from April 2011, no significant effect on performance was seen following removal and differences between predicted and observed scores were small. Performance on related outcome indicators retained in the scheme (such as blood pressure control) was generally unaffected. CONCLUSIONS: Following the removal of incentives, levels of performance across a range of clinical activities generally remained stable. This indicates that health benefits from incentive schemes can potentially be increased by periodically replacing existing indicators with new indicators relating to alternative aspects of care. However, all aspects of care investigated remained indirectly or partly incentivised in other indicators, and further work is needed to assess the generalisability of the findings when incentives are fully withdrawn. PMID- 24468470 TI - Genetic susceptibility to accelerated cognitive decline in the US Health and Retirement Study. AB - Age-related cognitive decline is a major public health concern facing a large segment of the US population. To identify genetic risk factors related to cognitive decline, we used nationally representative longitudinal data from the US Health and Retirement Study to conduct genome-wide association studies with 5765 participants of European ancestry, and 890 participants of African ancestry. Mixed effects models were used to derive cognitive decline phenotypes from data on repeated cognitive assessments and to perform single nucleotide polymorphism based heritability estimation. We found 2 independent associations among European Americans in the 19q13.32 region: rs769449 (APOE intron; p = 3.1 * 10(-20)) and rs115881343 (TOMM40 intron; p = 6.6 * 10(-11)). rs769449 was also associated with cognitive decline among African-Americans (p = 0.005), but rs115881343 was not. Cross-sectional cognitive function showed moderate heritability (15%-32%) across several age strata (50-59, 60-69, 70-79 years), but the cognitive decline heritability estimate was low (~5%). These results indicate that despite multiple association signals for cognitive decline in the 19q13.32 region, inter individual variation is likely influenced substantially by environmental factors. PMID- 24468471 TI - Pinocembrin improves cognition and protects the neurovascular unit in Alzheimer related deficits. AB - Amyloid-beta (Abeta) peptides accumulate in the brain and initiate a cascade of pathologic events in Alzheimer's disease. The receptor for advanced glycation end products (RAGE) has been implicated to mediate Abeta-induced perturbations in the neurovascular unit (NVU). We demonstrated that pinocembrin exhibits neuroprotection through inhibition of the Abeta and/or RAGE pathway, but the therapeutic role and mechanism involved are not ascertained. Here, we report that a 3-month treatment with pinocembrin prevents the cognition decline in APP/PS1 transgenic mice without altering Abeta burden and oxidative stress. Instead, pinocembrin is effective in conferring neurovascular protection through maintenance of neuropil ultrastructure, reduction of glial activation and levels of inflammatory mediators, preservation of microvascular function, improving the cholinergic system by conserving the ERK-CREB-BDNF pathway, and modulation of RAGE-mediated transduction. Furthermore, in an in vitro model, pinocembrin provides the NVU protection against fibrillar Abeta1-42, accompanied by regulation of neurovascular RAGE pathways. Our findings indicate that pinocembrin improves cognition, at least in part, attributable to the NVU protection, and highlights pinocembrin as a potential therapeutic strategy for the prevention and/or treatment of Alzheimer's disease. PMID- 24468472 TI - Association between the CETP polymorphisms and the risk of Alzheimer's disease, carotid atherosclerosis, longevity, and the efficacy of statin therapy. AB - The purpose of this meta-analysis was to detect the association between the cholesteryl ester transfer protein gene polymorphisms and the risk of Alzheimer's disease (AD), carotid atherosclerosis, longevity, and the efficacy of statin therapy. Databases of MEDLINE, EMBASE, BIOSIS, the Cochrane Library, and the Chinese National Knowledge Infrastructure were systematically searched. Thirty two studies were included in this meta-analysis. There was no difference in the I405V, C629A, and Taq1B polymorphisms between AD and control groups. However, stratified analysis showed that AD group had higher B2B2 genotype frequency than control group in Asian populations with APOE4+ in Taq1B. I405V and Taq1B polymorphisms were not associated with the risk of carotid atherosclerosis and longevity. The efficacy of statin therapy was not associated with Taq1B polymorphism. In conclusion, there was no association between cholesteryl ester transfer protein gene polymorphisms and the risk of AD, carotid atherosclerosis, longevity, and the efficacy of statin therapy in the pooled effects of overall population. However, the B2B2 genotype of Taq1B was associated with increased risk of AD in the Asian populations with APOE4+. PMID- 24468474 TI - Radial contrast enhancement on brain magnetic resonance imaging diagnostic of primary angiitis of the central nervous system: a case report and review of the literature. AB - INTRODUCTION: Primary angiitis of the central nervous system is a rare disease of unclear etiology. There is no single test diagnostic of primary angiitis of the central nervous system. We report an unusual pattern on brain magnetic resonance imaging that might be specific for primary angiitis of the central nervous system. CASE PRESENTATION: A 47-year-old Caucasian man developed progressive bilateral hand tremor, difficulty walking, cognitive slowing and headache. A physical examination showed bilateral hand tremor with dysmetria, hyperreflexia and abnormal gait. Magnetic resonance imaging of his brain showed bilateral, symmetrical, increased intensity on T2-weighted images concurrent with linear contrast enhancement in a radial distribution throughout his white matter, sparing subcortical regions in his centrum semiovale, corona radiata, basal ganglia and brainstem. Magnetic resonance spectroscopy demonstrated elevated choline and decreased N-acetyl aspartate. Except for elevated protein and lymphocytic pleocytosis, examination of his cerebrospinal fluid showed no abnormalities. Serological tests for rheumatologic, vasculitic, paraneoplastic, infectious and peroxisomal disorders were negative. A brain biopsy revealed primary angiitis of the central nervous system. Our patient was treated with steroids and intravenous cyclophosphamide, with improvement in signs and symptoms as well as changes on magnetic resonance imaging. CONCLUSION: Bilateral, symmetrical, increased intensity on T2-weighted images concurrent with linear contrast enhancement in a radial distribution throughout the white matter on magnetic resonance imaging of the brain should be recognized as a feature of primary angiitis of the central nervous system, and might avoid the need for a brain biopsy to diagnose primary angiitis of the central nervous system. PMID- 24468473 TI - Regional proton magnetic resonance spectroscopy patterns in dementia with Lewy bodies. AB - Magnetic resonance spectroscopy (MRS) characteristics of dementia with Lewy bodies (DLB) Alzheimer's disease (AD) and cognitively normal controls were compared. DLB (n = 34), AD (n = 35), and cognitively normal controls (n = 148) participated in a MRS study from frontal, posterior cingulate, and occipital voxels. We investigated DLB patients with preserved hippocampal volumes to determine the MRS changes in DLB with low probability of overlapping AD pathology. DLB patients were characterized by decreased N acetylaspartate/creatine (NAA/Cr) in the occipital voxel. AD patients were characterized by lower NAA/Cr in the frontal and posterior cingulate voxels. Normal NAA/Cr levels in the frontal voxel differentiated DLB patients with preserved hippocampal volumes from AD patients. DLB and AD patients had elevated choline/creatine, and myo-Inositol/creatine in the posterior cingulate. MRS abnormalities associated with loss of neuronal integrity localized to the occipital lobes in DLB, and the posterior cingulate gyri and frontal lobes in AD. This pattern of MRS abnormalities may have a role in differential diagnosis of DLB and in distinguishing DLB patients with overlapping AD pathology. PMID- 24468476 TI - Neurotrophic factor expression in denervated motor and sensory Schwann cells: relevance to specificity of peripheral nerve regeneration. PMID- 24468475 TI - Disulfide bond generation in mammalian blood serum: detection and purification of quiescin-sulfhydryl oxidase. AB - A sensitive new plate-reader assay has been developed showing that adult mammalian blood serum contains circulating soluble sulfhydryl oxidase activity that can introduce disulfide bonds into reduced proteins with the reduction of oxygen to hydrogen peroxide. The activity was purified 5000-fold to >90% homogeneity from bovine serum and found by mass spectrometry to be consistent with the short isoform of quiescin-sulfhydryl oxidase 1 (QSOX1). This FAD dependent enzyme is present at comparable activity levels in fetal and adult commercial bovine sera. Thus cell culture media that are routinely supplemented with either fetal or adult bovine sera will contain this facile catalyst of protein thiol oxidation. QSOX1 is present at approximately 25 nM in pooled normal adult human serum. Examination of the unusual kinetics of QSOX1 toward cysteine and glutathione at low micromolar concentrations suggests that circulating QSOX1 is unlikely to significantly contribute to the oxidation of these monothiols in plasma. However, the ability of QSOX1 to rapidly oxidize conformationally mobile protein thiols suggests a possible contribution to the redox status of exofacial and soluble proteins in blood plasma. Recent proteomic studies showing that plasma QSOX1 can be utilized in the diagnosis of pancreatic cancer and acute decompensated heart failure, together with the overexpression of this secreted enzyme in a number of solid tumors, suggest that the robust QSOX assay developed here may be useful in the quantitation of enzyme levels in a wide range of biological fluids. PMID- 24468478 TI - The courage to survive: facing the loss of your soul-mate. PMID- 24468477 TI - High-resolution intravital imaging reveals that blood-derived macrophages but not resident microglia facilitate secondary axonal dieback in traumatic spinal cord injury. AB - After traumatic spinal cord injury, functional deficits increase as axons die back from the center of the lesion and the glial scar forms. Axonal dieback occurs in two phases: an initial axon intrinsic stage that occurs over the first several hours and a secondary phase which takes place over the first few weeks after injury. Here, we examine the secondary phase, which is marked by infiltration of macrophages. Using powerful time-lapse multi-photon imaging, we captured images of interactions between Cx3cr1(+/GFP) macrophages and microglia and Thy-1(YFP) axons in a mouse dorsal column crush spinal cord injury model. Over the first few weeks after injury, axonal retraction bulbs within the lesion are static except when axonal fragments are lost by a blebbing mechanism in response to physical contact followed by phagocytosis by mobile Cx3Cr1(+/GFP) cells. Utilizing a radiation chimera model to distinguish marrow-derived cells from radio-resistant CNS-resident microglia, we determined that the vast majority of accumulated cells in the lesion are derived from the blood and only these are associated with axonal damage. Interestingly, CNS-resident Cx3Cr1(+/GFP) microglia did not increasingly accumulate nor participate in neuronal destruction in the lesion during this time period. Additionally, we found that the blood derived cells consisted mainly of singly labeled Ccr2(+/RFP) macrophages, singly labeled Cx3Cr1(+/GFP) macrophages and a small population of double-labeled cells. Since all axon destructive events were seen in contact with a Cx3Cr1(+/GFP) cell, we infer that the CCR2 single positive subset is likely not robustly involved in axonal dieback. Finally, in our model, deletion of CCR2, a chemokine receptor, did not alter the position of axons after dieback. Understanding the in vivo cellular interactions involved in secondary axonal injury may lead to clinical treatment candidates involving modulation of destructive infiltrating blood monocytes. PMID- 24468479 TI - Attachment styles of Oregonians who request physician-assisted death. AB - OBJECTIVE: Qualitative analyses suggest that requests for physician-assisted death (PAD) may often be the culmination of a person's lifelong pattern of concern with issues such as control, autonomy, self-sufficiency, distrust of others, and avoidance of intimacy. Such characteristics may be measured by attachment style. We compared family members' reports of attachment style in Oregonians who did and did not request PAD. METHOD: Eighty-four family members of terminally ill patients who requested PAD before death and 63 members of a comparison group that included family members of terminally ill Oregonians who died without requesting PAD rated their loved ones' attachment style in a one time survey. RESULTS: Individuals who requested PAD were most often described as having dismissive personality styles (56%) compared to 41% of comparison individuals, and on continuous measures of relational style, the highest mean score among PAD requesters was for dismissive style. There were marginally significant differences in the proportions of each attachment style when comparing the two groups (p = 0.08). SIGNIFICANCE OF RESULTS: Patients' attachment styles may be an important factor in requests for PAD. Recognition of a patient's attachment style may improve the ability of the physician to maintain a constructive relationship with the patient throughout the dying process. PMID- 24468480 TI - Phenomenology of the subtypes of delirium: phenomenological differences between hyperactive and hypoactive delirium. AB - OBJECTIVE: The purpose of this study was to examine the differences in phenomenology between hypoactive and hyperactive subtypes of delirium, and specifically to determine the comparative prevalence of perceptual disturbances (e.g., hallucinations) and delusions in these two subtypes of delirium. METHOD: We conducted an analysis of Memorial Delirium Assessment Scale (MDAS) items in a set of 100 delirium cases evaluated and treated at Memorial Sloan-Kettering Cancer Center (MSKCC) utilizing an MSKCC Institutional Review Board (IRB) approved Clinical Delirium Database. Individual MDAS items, reflecting the phenomenology of delirium, were compared in delirious patients classified as to motoric subtype (hypoactive versus hyperactive based on MDAS item no. 9, psychomotor activity). Particular attention was paid to differences between subtypes as to the prevalence of perceptual disturbances (MDAS item no. 7) and delusions (MDAS item no. 8). RESULTS: Significant differences were found between hyperactive and hypoactive subtypes of delirium for the presence and severity of perceptual disturbances and delusions; with perceptual disturbances (e.g., hallucinations) and delusions being significantly more prevalent in hyperactive than in hypoactive delirium. The prevalence of perceptual disturbances was 50.9% and the prevalence of delusions was 43.4% in patients with hypoactive delirium. In patients with hyperactive delirium, the prevalence of perceptual disturbances was 70.2% and the prevalence of delusions was 78.7%. The prevalence of perceptual disturbances and delusions in both subtypes of delirium was significantly correlated with the presence of moderate-to-severe disturbance of consciousness/arousal (MDAS item no. 1) and attention impairment (MDAS item no. 5), but was not correlated with the presence of moderate-to-severe cognitive impairment (MDAS item nos. 2-4). SIGNIFICANCE OF RESULTS: Contrary to earlier studies, which indicated extremely low prevalence rates of perceptual disturbances (e.g., hallucinations) and delusion in hypoactive delirium, our study demonstrates that the prevalence of perceptual disturbances and delusions in hypoactive delirium is much higher than previously reported (50.9% and 43.4%, respectively), and deserving of clinical attention and intervention. PMID- 24468481 TI - Parent self-efficacy for managing pain in seriously ill children and adolescents nearing end of life. AB - OBJECTIVE: Using data from a multi-site study of parent-child symptom reporting concordance, this secondary analysis explored the role of parent self-efficacy related to pain management for seriously ill school-age children and adolescents. METHOD: In the initial study, 50 children and adolescents who were expected to survive 3 years or less were recruited along with their parent/primary caregiver. Parent self-report data were used in this secondary analysis to describe parent self-efficacy for managing their child's pain, caregiver strain, mood states, and perception of the child's pain; to explore relationships among these variables; and to determine predictors of greater self-efficacy. RESULTS: Parents expressed a wide range of self-efficacy levels (Chronic Pain Self-Efficacy Scale; possible range 10-100, mean 76.2, SD 14.7) and higher levels on average than reported previously by family caregivers of adult patients. Caregiver Strain Index scores were markedly high (possible range 0-13, mean 8.1, SD 3.8) and inversely correlated with self-efficacy (r = -0.44, p = 0.001). On the Profile of Mood States parents reported more negative moods (t = 4.0, p < 0.001) and less vigor (t = -5.0, p < 0.001) than adults in a normative sample, yet vigor rather than mood disturbance predicted self-efficacy. With the exception of child age, self efficacy was not associated with demographics (child gender, ethnicity, household income, parent age, education, family size) or with the diagnostic groups (primarily cardiac and oncologic) comprising the sample. Younger child age, less caregiver strain, more parent vigor, and parent perception that child is without pain predicted more than half of the variance in parent self-efficacy (R2 = 0.51). SIGNIFICANCE OF RESULTS: Findings advance knowledge of parent self efficacy in managing the pain of a child with life-threatening illness. Results can be used to design supportive interventions enhancing parents' caregiving roles during their child's last stages of life. PMID- 24468482 TI - Being a parent and coping with cancer: intervention development. AB - OBJECTIVE: Diagnosis of a parent's cancer has a profound influence on the parent, the children and the child-parent relationship, and puts all family members at risk for psychological distress. This article describes the development and the first attempts at implementation of an intervention aimed at helping people cope with difficulties arising from being both parents and cancer patients. METHODS: Based on themes discussed in focus groups with parents coping with cancer and with professionals in the field, a four-module psychological intervention was developed. The modules are: Telling and Sharing, Children' Responses, Routine and Changes, and Learning and Awareness as a Parent. The techniques used are mainly psycho-educational and cognitive-behavioral. RESULTS: Preliminary experience showed this intervention to be more feasible as a one-day workshop than as a four session intervention. Parents who participated in two workshops reported it to be helpful in empowering them as parents and in imparting learning tools for identifying their children's needs, as well as for communicating with their children. SIGNIFICANCE OF RESULTS: Intervention tailored specifically for parents coping with cancer can be relevant for their special needs. Research is needed to establish the effectiveness of this intervention. PMID- 24468483 TI - Inter-rater reliability of the bereavement risk assessment tool. AB - OBJECTIVE: The Bereavement Risk Assessment Tool (BRAT) was designed to consistently communicate information affecting bereavement outcomes; to predict the risk for difficult or complicated bereavement based on information obtained before the death; to consider resiliency as well as risk; and to assist in the efficacy and consistency of bereavement service allocation. Following initial development of the BRAT's 40 items and its clinical use, this study set out to test the BRAT for inter-rater reliability along with some basic validity measures. METHOD: Case studies were designed based on actual patients and families from a hospice palliative care program. Bereavement professionals were recruited via the internet. Thirty-six participants assessed BRAT items in 10 cases and then estimated one of 5 levels of risk for each case. These were compared with an expert group's assignment of risk. RESULTS: Inter-rater reliability for the 5-level risk scores yielded a Fleiss' kappa of 0.37 and an intra-class correlation (ICC) of 0.68 (95% CI 0.5-0.9). By collapsing scores into low and high risk groups, a kappa of 0.63 and an ICC of 0.66 (95% CI 0.5-0.9) was obtained. Participant-estimated risk scores yielded a kappa of 0.24. Although opinion varied on the tool's length, participants indicated it was well organized and easy to use with potential in assessment and allocation of bereavement services. Limitations of the study include a small sample size and the use of case studies. Limitations of the tool include the subjectivity of some items and ambiguousness of unchecked items. SIGNIFICANCE OF RESULTS: The collapsed BRAT risk levels show moderately good inter-rater reliability over clinical judgement alone. This study provides introductory evidence of a tool that can be used both prior to and following a death and, in conjunction with professional judgment, can assess the likelihood of bereavement complications. PMID- 24468484 TI - Developing the social distress scale for head and neck cancer outpatients in Japan. AB - OBJECTIVE: This study assessed the factor structure, internal consistency, and concurrent and discriminant validity of a scale used to measure social distress in Japanese head and neck cancer outpatients with facial disfigurement. METHOD: The sample included 225 Japanese outpatients with head and neck cancer, including 129 patients with facial disfigurement. Participants' level of social distress was assessed through our scale, the European Organization for Research and Treatment Cancer questionnaire (EORTC) QLQ-H&N35 and the Hospital Anxiety and Depression scale (HADS). RESULTS: Factor analyses confirmed the structure of two subscales of the social distress scale. Social distress was significantly correlated with the social contact subscale of the EORTC QLQ-H&N35 and the HADS. SIGNIFICANCE OF RESULTS: Results demonstrated preliminary reliability and validity of the social distress scale. This scale may extend social adjustment research by revealing its determinants and effects for head and neck cancer with facial disfigurement in Japan. PMID- 24468485 TI - Experiences of truth disclosure in terminally ill cancer patients in palliative home care. AB - OBJECTIVE: The aim of this study was to explore the experiences and preferences of terminally ill cancer patients regarding truth telling in the communication of poor prognoses. METHOD: We recorded and transcribed interviews with 45 patients who knew their cancer was terminal, and analyzed their responses hermeneutically. RESULTS: Patients identified three different modes of truth: (1) the absolute objective truth that they are dying; (2) the partial truth about their condition including some facts but not all of the details; and (3) the desired truth, originating in the patient's own beliefs about a healthy or better life. Coping strategies were related to patients' preferred mode of truth: (1) facing the truth in order to take action; (2) facing some parts of the truth in order to maintain hope; and (3) hovering between facing and avoiding the truth. In their struggle for existential survival, patients used different coping strategies, changing from one to another depending upon the circumstances. SIGNIFICANCE OF RESULTS: Varying use of different coping strategies impacts on patient preferences concerning communication about bad news with their doctors. Truth telling entails more than merely providing information related to the forthcoming death. It also concerns how physicians or other healthcare staff can support the patient's existential survival by fine-tuning the communication of "truth" according to the individuals' preferences. PMID- 24468487 TI - In the midnight hour: Cancer and nightmares. A review of theories and interventions in psycho-oncology. AB - OBJECTIVES: The purposes of this study were: (1) to explore cancer patients' complaints of poor sleep, which often involve a combination of somatic symptoms and nightmares; and (2) to understand these sleep disturbances in the light of modern dream theories and intervention modalities. METHOD: The literature search originated with several major articles (Revonsuo, 2000; Krakow & Zadra, 2006; Hobson, 2009) which then opened up the search through their references. We also used the database PubMed, and employed the following key words: cancer, nightmares/dreams, sleep disturbances, and dream theory. The literature search covered the interval between 1900 (Freud, 1900) and 2009. Our criteria for selecting studies included the most recent major review articles on the neuroscience of sleep and dreams; articles reviewing sleep disturbances in cancer patients and relevant treatments; and articles reviewing interventions for traumatic dreams. Approximately 30 articles were deemed worthy of inclusion. RESULTS: Thirty article/books/chapters met the criteria for relevance related to key theories and clinical interventions related to nightmares and traumatic dreams of cancer patients. Key concepts involve threat simulation theory and imagery rehearsal therapy in regard to theoretical and interventional paradigms significantly generalizable to cancer patients. The dream material included in this article presents patients' attempts to deal with complex threats such as intense dependency/ loss of self-sufficiency, disfigurement, and death. This is especially true with regard to the doctor-patient relationship at all stages of the illness and disease. Imagery rehearsal can facilitate empowerment in light of highly threatening and conflictual cancer-related dreams in which the patient feels helpless and victimized. SIGNIFICANCE OF RESULTS: This review offers a new lens on current dream theories and understanding of sleep disturbance in cancer patients as well as their familes and medical caregivers. Modern theories lead to opportunities for intervention that can both relieve symptoms and improve communication between medical caregivers and patients and families. PMID- 24468486 TI - Palliative care referral practices and perceptions: the divide between metropolitan and non-metropolitan general practitioners. AB - OBJECTIVE: Late or non-referral of patients to specialist palliative care (SPC) services may affect patients' and their carers' quality of care. General practitioners (GPs) are key professionals in linking people with SPC. The aim of this article is to assess GPs' perceptions and SPC referrals for their patients with advanced cancer and differences between metropolitan (M GPs) and non metropolitan GPs (NM GPs). METHOD: Self-report survey mailed to a stratified random sample of 1,680 Australian GPs was used. RESULTS: Thirty-one percent (469) of eligible GPs returned surveys. More M GPs than NM GPs reported referring >60% of their patients for SPC (p = 0.014); and that a more comprehensive range of SPC services was available. The most frequently reported referral prompts were: presence of terminal illness (M GPs, 71%, NM GPs, 66%, ns (not significant)); future need for symptom control (69% vs. 59%, ns) and uncontrolled physical symptoms (63% vs. 54%, ns). Reasons for not referring were: doctor's ability to manage symptoms (62% vs. 68%, ns) and the absence of symptoms (29% vs. 18%, p = 0.025). Higher referral was associated with: having a palliative care physician or consultative service available; agreeing that all patients with advanced cancer should be referred, and agreeing that with SPC, the needs of the family are better met. SIGNIFICANCE OF RESULTS: Referrals for SPC were primarily disease related rather than for psychological and emotional concerns. Measures are needed to encourage referrals based upon psychosocial needs as well as for physical concerns, and to support GPs caring for people with advanced cancer in areas with fewer comprehensive SPC services. PMID- 24468488 TI - Communication contexts about illness, death and dying for people with intellectual disabilities and life-limiting illness. AB - OBJECTIVE: The general population has been involved in considerable debate about communication and awareness within the context of death and dying. However, there has been little research on how matters of communication on this topic are handled for people with life-limiting illness and intellectual disabilities. This qualitative study explored how staff managed communication about death and dying with people with intellectual disabilities in a Health Service Executive area in Ireland. METHOD: Ninety-one individuals took part in 16 focus groups. Interviews were analysed using framework analysis. RESULTS: Participants infrequently discussed death and dying with people with intellectual disabilities. Participants operated most commonly in suspicious awareness environments with people with mild-to-moderate intellectual disabilities, and closed awareness environments with people with severe intellectual disabilities. The majority of participants did not hold absolute opinions that talking about illness, death, and dying with people with intellectual disabilities was "wrong." Rather, they were concerned that their lack of skill and experience in the area would cause harm if they engaged in open conversations. Relatives had an influential role on the process of communication. Participants were strongly motivated to provide quality care and were willing to consider alternative approaches to communication if this would benefit people with intellectual disabilities. SIGNIFICANCE OF RESULTS: Although there has been a shift toward conditional open awareness of death and dying in Western society, people with intellectual disabilities have not been afforded the same opportunity to engage in open discussion of their mortality. This study points to the urgent need to engage in debate about this issue in order to ensure that people with intellectual disabilities receive high quality palliative care toward the end of life. PMID- 24468490 TI - A physician as a cancer of the neck patient: Am I cured? PMID- 24468489 TI - Drug-induced akathisia as a cause of distress in spouse caregivers of cancer patients. AB - OBJECTIVE: Family caregivers of cancer patients suffer from physical, psychological, and social distress and therefore are often referred to as second order patients. Akathisia is a common side effect of antipsychotics and antidepressants that causes great discomfort and even agitation and is often described by patients administered these drugs as the most distressing side effect of their treatment. Several studies of akathisia as a cause of distress in cancer patients have been reported. However, akathisia has not been reported as a cause of distress in family caregivers of cancer patients. METHOD/CASE REPORT: A 74-year-old spouse caregiver who was under treatment for major depressive disorder was not able to visit the hospital where her husband, a terminally ill cancer patient, was being treated. Initially, the spouse caregiver thought that she could not visit the hospital because of the symptoms of her depression and her grief about losing her husband. However, careful clinical examination revealed that she was suffering from akathisia in addition to her grief. RESULTS: Discontinuation of her sulpiride treatment resulted in the disappearance of her akathisia symptoms, and therefore she became able to visit the hospital and care for her terminally ill husband. SIGNIFICANCE OF RESULTS: Drug induced akathisia is a cause of distress in spouse caregivers taking certain drugs. It is important for clinicians to realize that family caregivers might suffer from not only socioeconomic, physical, and psychological problems but also side effects of medication. PMID- 24468491 TI - In the nighttime of your fear: The anatomy of compassion in the healing of the sick. PMID- 24468492 TI - Holding on...and...letting go. PMID- 24468493 TI - Identification and characterization of a distinct banana bunchy top virus isolate of Pacific-Indian Oceans group from North-East India. AB - Banana bunch top virus (BBTV) is considered to be a serious threat to banana production. A new isolate of the virus (BBTV-Umiam) was identified and characterized from local banana mats growing in mid-hills of Meghalaya in North East India. The complete nucleotide sequence analysis revealed the presence of six full-length ssDNA components (DNA R, DNA U3, DNA S, DNA M, DNA C and DNA N) sharing major common region (CR-M) and a stem-loop common region (CR-SL). BBTV Umiam showed a unique deletion of 20 nucleotides in the intergenic region of DNA R, the absence of predicted open reading frame (ORF) in DNA U3 and probability for a small ORF in DNA U3 expecting functional evidence at transcriptional level. Phylogenetic analysis based on 88 complete nucleotide sequence of BBTV DNA R available in GenBank generated two broad clusters of Pacific-Indian Oceans (PIO) and South-East Asian (SEA) groups including BBTV-Umiam within PIO cluster. However, BBTV-Umiam was identified as the most distinct member of the PIO group with 100% bootstrap support. This was further supported by the phylogenetic grouping of each genomic component of BBTV-Umiam at the distant end of PIO group during clustering of 21 complete BBTV sequences. BBTV-Umiam shared relatively less nucleotide identity with PIO group for each genomic component (85.0-95.4%) and corresponding ORF (93.8-97.5%) than that of earlier PIO isolates (91.5-99.6% and 96.0-99.3%, respectively). Recombination analysis revealed two intra component and five inter-component recombination events in BBTV-Umiam, but none of them was unique. Moreover, the isolate was identified as major parental sequence for intra-component recombination event spanning the replication associated protein encoding region in Tongan BBTV DNA R. The current study indicated differential evolution of BBTV in North-East India (Meghalaya). The natural occurrence of hybrids of Musa balbisiana and M. acuminata in this geographically isolated region could be the contributing factor in accumulating genetic distinctiveness in BBTV-Umiam which need further characterization. PMID- 24468494 TI - Novel insights on the progression of intermediate viral forms in the morphogenesis of vaccinia virus. AB - Morphogenesis of vaccinia virus (VACV) is a complex structural process in which the capture of all cytoplasmic stages is difficult due to the rapid transition between the different viral forms. Taking advantage of two VACV mutants (M65 and M101) with defined genetic alterations, we described by transmission electron microscopy (TEM) of ultrathin sections novel potential transition viral forms (Ts) with reorganization of the immature virus (IV) membrane and construction of the internal core, and illustrated the envelopment steps from the mature virus (MV) to the wrapped virus (WV) stages. Our observations allowed us to propose a sequence of structural events for VACV assembly that provides key clues about VACV morphogenesis. PMID- 24468495 TI - [Chronic diseases and complexity: new roles in nursing. Advanced practice nurses and chronic patient]. AB - The increase in chronic diseases and the progressive ageing of the population is a source of concern for the different agencies with responsibility for health care. This has led to the creation of many documents focused on the analysis of the current situation and care of chronic diseases, including the WHO recommendations intended to assist countries and health services design and implement strategies that will address the existing demand, control and prevention of chronic diseases. In addition, there is a need to respond to the demand generated by chronic diseases in every sense, and from the different systems it is becoming more difficult to get enough support from multidisciplinary teams where the nurse has a central importance. While chronic diseases are becoming a threat due to the costs they generate, it is also an opportunity for nursing to be at the forefront for advanced care requirements, performed by professionals with recognized advanced clinical skills and ability for case management while monitoring and controlling complex chronic patients. The different services of the National Health System have introduced nurses that play different roles (cases managers, liaison nurses, advanced practice nurses and so on). However, it could be argued that they are not being trained to a desirable development level. It is therefore time for health care authorities to determine the role of the advanced practice nurse in relation to functional positions, and allow them to make an advance in the development of unified skills for the whole National Health System. From our experience we have learned that the advanced practice nurse is a resource that helps in the sustainability of services, thanks to the efficiency shown in the results obtained from the care given to both chronic and complex chronic patients. PMID- 24468496 TI - [Clinical integration in the chronic patient]. AB - Castilla-La Mancha Health Service is developing the integration of care levels due to the challenge of an aging population in the region. Aging is associated with chronic diseases and an increasing number of concomitant diseases. This poses a major care challenge care, with more fragile patients and new needs. This also requires a sustainable approach: the concurrence of several chronic diseases affects the cost of care, which is especially acute in times of severe economic crisis. One of the pillars of the strategy for dealing with chronic diseases in our region is care integration, in an effort to adapt the organization to the new needs. The Balanced Scorecard or Integrated Scorecard of the integration process was introduced as it has been designed. The integration of primary and hospital care at an organizational level has already been completed, and the development of integrated care processes has also been performed in order to achieve real integration at care level. To help finance this, a prospective capitation system is gradually being implemented, achieving a convergence of per capita costs in the different health areas integrated. Nurses has a key role in this process, their skills as educators and trainers in self-care, in the role of case managers of patients with particularly complex conditions, and the role of professional liaison to improve the transition between care areas and units. PMID- 24468497 TI - [Challenges and opportunities: contributions of the Advanced Practice Nurse in the chronicity. Learning from experiences]. AB - Undoubtedly, our society is facing new economic, political, demographic, social and cultural challenges that require healthcare services able to meet the growing health needs of the population, especially in dealing with chronic conditions. In this new context, some countries such as the United Kingdom have made a firm commitment to develop new models for chronic patients care based on the introduction of new figures of Advanced Practice Nurses, which includes 4 cornerstones of professional practice: advanced clinical skills, clinical management, teaching and research. The implementation of this new figures implies a redefinition of professional competencies and has its own accreditation system and a specific catalogue of services adapted to the population requirements, in order to provide chronic care support from Primary Care settings. This trajectory allows us analysing the process of design and implementation of these new models and the organizational structure where it is integrated. In Spain, there are already experiences in some regions such as Andalucia and the Basque Country, focused on the creation of new advanced nursing roles. At present, it is necessary to consider suitable strategic proposals for the complete development of these models and to achieve the best results in terms of overall health and quality of life of patients with chronic conditions, improving the quality of services and cost-effectiveness through a greater cohesion and performance of healthcare teams towards the sustainability of healthcare services and patient satisfaction. PMID- 24468498 TI - Flow of sewage sludge-borne phthalate esters (PAEs) from human release to human intake: implication for risk assessment of sludge applied to soil. AB - The wide production and use of phthalate esters (PAEs) in both industry and commercial products lead to their ubiquitous existence in the environment. However, understanding flow and pathway of human exposure to PAEs from sources to receptors is necessary and challenging. In this study, we selected final sewage sludge, an inevitable byproduct of wastewater treatment plants (WWTP), as one type of important carrier/sources of PAEs to clarify the flow of PAEs between human and the environment, e.g. the release by human to sludge and in turn ingestion by human after these sludges were disposed as soil amendment. Twenty five sludge samples were collected from 25 wastewater treatment plants (WWTPs) in Shanghai, East China. Of all 16 PAE congeners, di(2-ethylhexyl) phthalate (DEHP) and dibutyl phthalate (DnBP) were predominant with mean concentrations of 97.4 and 22.4 MUg/g dw, respectively, both locating at the high end of the global range. WWTP treating industrial waster generally contained higher PAEs compared to those treating domestic wastewater, but no positive relationship was found between PAE levels with the percentage of industrial wastewater. Principal component analysis (PCA) showed that similar PAE sources for all WWTPs in Shanghai with three exceptions, in which specific PAE products were made. The annual mass loadings via sludge of DEHP, DnBP, and Sigma16PAEs were 31.4, 7.44, and 39.6 tons in Shanghai and 1042, 247, and 1314 tons in China, respectively, only accounting for 0.09% of the total consumption of PAEs in China. If this sludge is applied in soil, human will take 16.4 and 3.8 MUg/kg bw for DEHP and DnBP every day, respectively, via dietary and soil ingestion, which were lower than the toxicological safety parameters. To the best of our knowledge, this is the first report to analyze the flow of sludge-borne PAEs from human release to human intake. PMID- 24468499 TI - Destruction of DDT wastes in two preheater/precalciner cement kilns in China. AB - The destruction of DDT formulations and DDT contaminated soil was conducted by feeding wastes into the flue gas chamber at the kiln inlet of two different preheater/precalciner cement kilns in China. The concentration of DDT, PCDD/PCDFs and HCB were measured in the flue gas of the main stack, in the solid material under baseline conditions and when feeding DDT-wastes. The destruction efficiency and the destruction and removal efficiency for DDT were in the range of 99.9335% 99.9998% and 99.9984%-99.9999%, respectively. The emissions of PCDD/PCDFs and HCB in the flue gas varied in the range of 0.0019-0.0171 ng I-TEQ/Nm(3) and 0.0064 0.0404 MUg/Nm(3), respectively. The emission factor for PCDD/PCDF and HCB varied from 0.0137 to 0.0281 MUg/ton and from 17.32 to 109.34 MUg/ton of clinker, respectively. The concentration of PCDD/PCDFs and HCB in solid samples decreased as follows: cement kiln dust, 4.1-5 ng I-TEQ/kg and 0.70-0.71 MUg/kg, respectively; >raw meal, 0.82-0.97 ng I-TEQ/kg and 0.18 MUg/kg, respectively; >cement clinker, 0.09-0.22 ng I-TEQ/kg and 0.14-0.18 MUg/kg, respectively. This study indicates that the feeding of DDT and POPs-wastes to the lower temperature part of a cement kiln system possibly to create a buildup of trace not-destroyed compounds in the system and might cause emissions; the technical feasibility and the environmental acceptability of this practice need to be investigated thoroughly. PMID- 24468500 TI - Petroleum contamination of soil and water, and their effects on vegetables by statistically analyzing entire data set. AB - Aliphatic hydrocarbons have been used to assess total oil concentrations, petroleum sources, and petroleum degradation. In this study, surface soil, groundwater, surface water, and vegetables were collected from the outskirts of Xi'an, the largest city in northwestern China, and the samples were analyzed for aliphatic hydrocarbon contents. The concentrations of n-alkanes were 1.06-4.01 MUg/g in the soil. The concentrations and the geochemical characteristics of n alkanes showed that the low carbon number hydrocarbons were mainly from petroleum sources, whereas the high carbon number hydrocarbons received more hydrocarbons from herbaceous plants. The concentrations of n-alkanes were 9.20-93.44 MUg/L and 23.74-118.27 MUg/L in the groundwater and the surface water, respectively. The water had characteristics of petroleum and submerged/floating macrophytes and was found in concentrations that would cause chronic disruption of sensitive organisms. The concentrations and geochemical characteristics of n-alkanes in Brassica chinensis L. and Apium graveolens were different, but both were contaminated by petroleum hydrocarbons. The results from principal component analysis (PCA) indicated that the sorption of n-alkanes to soil particles could not be described by linear models. The distributions of n-alkanes in vegetables were positively correlated with those in soil, and the correlation coefficient was up to 0.9310 using the constructed vectors. Therefore, the researchers should pay close attention to the effect of soil contamination on vegetables. PMID- 24468501 TI - Seasonal variation and sediment-water exchange of antibiotics in a shallower large lake in North China. AB - The occurrence of four antibiotics, including oxytetracycline (OTC), tetracycline (TC), norfloxacin (NOR) and ofloxacin (OFL), in surface water, overlying water, pore water and sediment samples were studied in the Baiyangdian Lake from February to November in 2009. The total concentrations of these antibiotics ranged among 17.73-281.82, 22.98-258.45, 22.43-198.95 ng L(-1) and 131.65-750.27 ng g(-1) in surface water, overlying water, pore water and sediments, respectively. Seasonal variation might be impacted by the frequency of different pattern of antibiotics and the water temperatures of different seasons, where the higher concentrations appeared at different seasons. In addition, the regions with significant sewage discharge or human agricultural activities exhibited high concentrations of antibiotics in water and sediments. The highest accumulation rates of the four antibiotics ranged from 11.27 to 29.71%, which indicated that these compounds exhibited strong adsorption to the sediment. However, higher concentrations of antibiotics in pore water and even overlying water may result in the release of these compounds from the sediment acting as a secondary contaminant source in a certain time period, especially for TC. The pseudo partitioning values of fluoroquinolones (FQs) ranged from 4493 to 47,093 L kg(-1) and were much higher than those of tetracyclines (TCs), which ranged from 277 to 1880 L kg(-1) indicating that the FQs are prone to accumulation in the sediment. PMID- 24468502 TI - Effect of ciprofloxacin antibiotic on the partial-nitritation process and bacterial community structure of a submerged biofilter. AB - A partial-nitritation bench-scale submerged biofilter was used for the treatment of synthetic wastewater containing a high concentration of ammonium in order to study the influence of the antibiotic ciprofloxacin on the partial-nitritation process and biodiversity of the bacterial community structure. The influence of ciprofloxacin was evaluated in four partial-nitritation bioreactors working in parallel, which received sterile synthetic wastewater amended with 350 ng/L of ciprofloxacin (Experiment 1), synthetic wastewater without ciprofloxacin (Experiment 2), synthetic wastewater amended with 100 ng/L of ciprofloxacin (Experiment 3) and synthetic wastewater amended with 350 ng/L of ciprofloxacin (Experiment 4). The concentration of 100 ng/L of antibiotics demonstrated that the partial-nitritation process, microbial biomass and bacterial structure generated by tag-pyrosequencing adapted progressively to the conditions in the bioreactor. However, high concentrations of ciprofloxacin (350 ng/L) induced a decay of the partial-nitritation process, while the total microbial biomass was increased. Within the same experiment, the bacterial community experienced sequential shifts with a clear reduction of the ammonium oxidation bacteria (AOB) and an evident increase of Commamonas sp., which have been previously reported to be ciprofloxacin-resistant. Our study suggests the need for careful monitoring of the concentration of antibiotics such as ciprofloxacin in partial-nitritation bioreactors, in order to choose and maintain the most appropriate conditions for the proper operation of the system. PMID- 24468503 TI - The growth and survival of plants in urban green roofs in a dry climate. AB - Green roofs as one of the components of water-sensitive urban design have become widely used in recent years. This paper describes performance monitoring of four prototype-scale experimental green roofs in a northern suburb of Adelaide, South Australia, undertaken over a 1-year period. Four species of indigenous Australian ground cover and grass species comprising Carpobrotus rossii, Lomandra longifolia 'Tanika,' Dianella caerula 'Breeze' and Myoporum parvifolium were planted in extensive and intensive green roof configurations using two different growing media. The first medium consisted of crushed brick, scoria, coir fibre and composted organics while the second comprised scoria, composted pine bark and hydro-cell flakes. Plant growth indices including vertical and horizontal growth rate, leaf succulence, shoot and root biomasses, water use efficiency and irrigation regimes were studied during a 12-month period. The results showed that the succulent species, C. rossii, can best tolerate the hot, dry summer conditions of South Australia, and this species showed a 100% survival rate and had the maximum horizontal growth rate, leaf succulence, shoot biomass and water use efficiency. All of the plants in the intensive green roofs with the crushed brick mix media survived during the term of this study. It was shown that stormwater can be used as a source of irrigation water for green roofs during 8 months of the year in Adelaide. However, supplementary irrigation is required for some of the plants over a full annual cycle. PMID- 24468504 TI - Formulation effects on the release of silica dioxide nanoparticles from paint debris to water. AB - Waterborne paints with integrated nanoparticles have been recently introduced into the market as nanoparticles offer improved or novel functionalities to paints. However, the release of nanoparticles during the life cycle of nano enhanced paint has only been studied to a very limited extent. The paint composition could determine in what quantities and forms the nanoparticles are released. In this work, paint formulations containing the same amount of silicon dioxide (SiO2) nanoparticles but differing in the pigment volume concentration (PVC) and in amount and type of binder and pigment, were studied through leaching test to investigate the influence of these parameters on release of Si from paint. The results indicate greater release of Si, about 1.7 wt.% of the SiO2 nanoparticles in the paint, for paint formulated with higher PVC value (63%), suggesting that the PVC is a crucial factor for release of SiO2 nanoparticles from paints. This hypothesis was also based on the fact that agglomerates of SiO2 nanoparticles were only found in leachates from paint with higher PVC. A paint sample with the higher amount of binder and less calcite filler exhibited a lower release of Si among the paints with a low PVC value (35%), and no SiO2 particles were detected in leachates collected from this paint. This could be due to the fact that a high portion of binder forms a suitable matrix to hold the SiO2 ENPs in paint. The paint sample in which the amount of calcite was partially substituted with TiO2 pigment did not show an important reduction on Si release. Our work suggests that paint debris containing SiO2 nanoparticles may release a limited amount of Si into the environment, and that by adjusting the properties of the binder in combination with common pigments it is possible to reduce the release of SiO2 nanoparticles. PMID- 24468505 TI - Ventilator associated pneumonia in major paediatric burns. AB - More than three-quarters of deaths related to major burns are a consequence of infection, which is frequently ventilator associated pneumonia (VAP). A retrospective study was performed, over a five-year period, of ventilated children with major burns. 92 patients were included in the study; their mean age was 3.5 years and their mean total body surface area burn was 30%. 62% of the patients sustained flame burns, and 31% scalds. The mean ICU stay was 10.6 days (range 2-61 days) and the mean ventilation time was 8.4 days (range 2-45 days). There were 59 documented episodes of pneumonia in 52 patients with a rate of 30 infections per 1000 ventilator days. Length of ventilation and the presence of inhalational injury correlate with the incidence of VAP. 17.4% of the patients died (n=16); half of these deaths may be attributed directly to pneumonia. Streptococcus pneumonia, Pseudomonas aeruginosa, Acinetobacter baumanii and Staphylococcus aureus were the most prominent aetiological organisms. Broncho alveolar lavage was found to be more specific and sensitive at identifying the organism than other methods. This study highlights the importance of implementing strictly enforced strategies for the prevention, detection and management of pneumonia in the presence of major burns. PMID- 24468506 TI - Perioperative visual loss after excision and autografting of a thermal burn to the back. AB - Peri-operative visual loss is an uncommon and poorly understood entity whose severity launched a Practice Advisory to identify peri-operative risk factors including prone positioning, anemia, hypotension, blood loss >44.7% of EBV, and surgical time >4-6.5 h. Contributing co-morbidities are obesity, tobacco, malnutrition, and PAD, which reduce blood flow to the optic nerve. We describe a patient with POVL focusing on the peri-operative course defined as the immediate preoperative assessment through discharge to compare the hospital course with previous reports of POVL in cardiac and spine operations.ss A middle-aged man admitted to the burn unit with 10% deep partial and full thickness burns to the back and neck underwent excision and autografting while prone. He was subsequently diagnosed with ischemic optic neuropathy and blindness. Co morbidities were tobacco, malnutrition (albumin of 2.6 g/dl), and obesity (BMI 30.1). Preoperative risk assessment included anemia and prone positioning. Intra operative hypotension to SBP 75 mmHg was noted. Operative duration was 5 h. Blood loss was estimated to be 43.7% of EBV. Risk factors for POVL are present in many prone burn operations as these patients have long operative times and significant blood loss. Thus, minimization of these factors where possible is advised. PMID- 24468507 TI - Pro-bullying attitudes among incarcerated juvenile delinquents: antisocial behavior, psychopathic tendencies and violent crime. AB - The objective was to evaluate a new scale aimed at assessing antisocial attitudes, the Pro-bullying Attitude Scale (PAS), on a group of 259 voluntarily recruited male juvenile delinquents from a juvenile correctional institution in Arkhangelsk, North-western Russia. Exploratory factor analysis gave a two-factor solution: Factor 1 denoted Callous/Dominance and Factor 2 denoted Manipulativeness/Impulsiveness. Subjects with complete data on PAS and Childhood Psychopathy Scale (CPS) (n=171) were divided into extreme groups (first and fourth quartiles) according to their total scores on PAS and the two factor scores, respectively. The extreme groups of total PAS and PAS Factor 1 differed in CPS ratings and in violent behavior as assessed by the Antisocial Behavior Checklist (ABC). They also differed in the personality dimension Harm Avoidance as measured by use of the Temperament and Character Inventory (TCI), and in delinquent and aggressive behavior as assessed by the Youth Self Report (YSR). The extreme groups of PAS Factor 2, in turn, differed in aggressive behavior as assessed by the YSR, and in the TCI scale Self-Directedness. When PAS was used as a continuous variable, total PAS and PAS Factor 1 (Callous/Dominance) were significantly positively related to registered violent crime. The possible usefulness of PAS in identifying high-risk individuals for bullying tendencies among incarcerated delinquents is discussed. PMID- 24468508 TI - To spike, or when to spike? AB - Recent experimental reports have suggested that cortical networks can operate in regimes were sensory information is encoded by relatively small populations of spikes and their precise relative timing. Combined with the discovery of spike timing dependent plasticity, these findings have sparked growing interest in the capabilities of neurons to encode and decode spike timing based neural representations. To address these questions, a novel family of methodologically diverse supervised learning algorithms for spiking neuron models has been developed. These models have demonstrated the high capacity of simple neural architectures to operate also beyond the regime of the well established independent rate codes and to utilize theoretical advantages of spike timing as an additional coding dimension. PMID- 24468510 TI - Editorial comment. PMID- 24468509 TI - Readmission after robot-assisted radical cystectomy: outcomes and predictors at 90-day follow-up. AB - OBJECTIVE: To characterize the outcomes and predictors of readmission after robot assisted radical cystectomy (RARC) during early (30-day) and late (31-90-day) postoperative periods. METHODS: We retrospectively evaluated our prospectively maintained RARC quality assurance database of 272 consecutive patients operated between 2005 and 2012. We evaluated the relationship of readmission with perioperative outcomes and examined possible predictors during the postoperative period. RESULTS: Overall 30- and 90-day mortality was 0.7% and 4.8%, respectively, with 25.5% patients readmitted within 90 days after RARC (61% of them were readmitted within 30 days and 39% were readmitted between 31-90 days postoperatively). Infection-related problems were the most common cause of readmission during early and late periods. Overall operative time and obesity were significantly associated with readmission (P = .034 and .033, respectively). Body mass index and female gender were independent predictors of 90-day readmission (P = .004 and .014, respectively). Having any type of complication correlated with 90-day readmission (P = .0045); meanwhile, when complications were graded on the basis of Clavien grading system, only grade 1-2 complications statistically correlated with readmission (P = .046). Four patients needed reoperation (2 patients in early "for appendicitis and adhesive small bowel obstruction" and 2 in late "for ureteroenteric stricture" readmission); meanwhile, 6 patients needed percutaneous procedures (4 patients in early "1 for anastomotic leak and 3 for pelvic collections" and 2 "for pelvic collections and ureterocutaneous fistula" in late readmission). CONCLUSION: The rate of readmission within 90 days after RARC is significant. Female gender and body mass index are independent predictors of readmission. Outcomes at 90 days provide more thorough results, essential to proper patient counseling. PMID- 24468511 TI - The role of magnetic resonance imaging in delineating clinically significant prostate cancer. AB - OBJECTIVE: To determine whether multiparametric magnetic resonance imaging might improve the identification of patients with higher risk disease at diagnosis and thereby reduce the incidence of undergrading or understaging. METHODS: We retrospectively reviewed the clinical records of 115 patients who underwent multiparametric magnetic resonance imaging before radical prostatectomy. We used Epstein's criteria of insignificant disease with and without a magnetic resonance imaging (MRI) parameter (apparent diffusion coefficient) to calculate sensitivity, specificity, as well as negative and positive predictive values [NPV and PPV] across varying definitions of clinically significant cancer based on Gleason grade and tumor volume (0.2 mL, 0.5 mL, and 1.3 mL) on whole-mount prostate specimens. Logistic regression analysis was performed to determine the incremental benefit of MRI in delineating significant cancer. RESULTS: The majority had a prostate-specific antigen from 4.1-10.0 (67%), normal rectal examinations (90%), biopsy Gleason score <= 6 (68%), and <= 2 cores positive (55%). Of the 58 patients pathologically staged with Gleason 7 or pT3 disease at prostatectomy, Epstein's criteria alone missed 12 patients (sensitivity of 79% and NPV of 68%). Addition of apparent diffusion coefficient improved the sensitivity and NPV for predicting significant disease at prostatectomy to 93% and 84%, respectively. MRI improved detection of large Gleason 6 (>= 1.3 mL, P = .006) or Gleason >= 7 lesions of any size (P <.001). CONCLUSION: Integration of MRI with existing clinical staging criteria helps identify patients with significant cancer. Clinicians should consider utilizing MRI in the decision making process. PMID- 24468512 TI - Editorial comment. PMID- 24468513 TI - 18F-fluorodeoxyglucose--positron emission tomography/computed tomography aids staging and predicts mortality in patients with muscle-invasive bladder cancer. AB - OBJECTIVE: To investigate the association between extravesical (18)F fluorodeoxyglucose (FDG) avid lesions on FDG-positron emission tomography/computed tomography (PET/CT) and mortality in patients with muscle invasive bladder cancer. METHODS: An international, bi-institutional cohort study of 211 patients with muscle-invasive bladder cancer who underwent staging CT and FDG-PET/CT imaging. On the basis of the presence of extravesical FDG-avid lesions suspicious for malignancy on PET/CT images, patients were divided into a PET/CT positive and PET/CT-negative group. Data on staging and mortality were retrospectively analyzed from prospective databases. Kaplan-Meier analyses were performed to compare overall (OS) and disease-specific survival (DSS) between the groups. Multivariable Cox regression models were used to investigate the association between extravesical PET/CT lesions and mortality. Extravesical lesions suspicious for malignancy on conventional CT were included in the models. RESULTS: Of the 211 patients, 98 (46.4%) had 1 or more extravesical lesions on PET/CT, 113 (53.5%) had a negative PET/CT. Conventional CT revealed extravesical lesions in 51 patients (24.4%). Median follow-up was 18 months. Patients with a positive PET/CT had a significantly shorter OS and DSS (median OS: 14 vs 50 months, P = .001; DSS: 16 vs 50 months, P <.001). In multivariable analysis, the presence of extravesical lesions on PET/CT was an independent prognostic indicator of mortality (OS: hazard ratio = 3.0, confidence interval 95% 1.7-5.1). This association was not statistically significant for conventional CT (hazard ratio = 1.6 (95% confidence interval 0.9-2.7). CONCLUSION: On the basis of our results, the presence of extravesical FDG-avid lesions on PET/CT might be considered an independent indicator of mortality. PMID- 24468514 TI - Editorial comment. PMID- 24468515 TI - Reply: To PMID 24468513. PMID- 24468516 TI - Could the sling position influence the clinical outcome in male patients treated for urinary incontinence? A magnetic resonance imaging study with a 3 tesla system. AB - OBJECTIVE: To analyze the morphologic changes visible on magnetic resonance imaging (MRI) after sling procedure in continent patients and to compare MRI findings with the incontinent ones, to detect possible factors explaining the different clinical outcomes. METHODS: Twenty-seven male patients who were treated with Advance sling for urinary stress incontinence after prostate surgery were enrolled: 16 had clinical recovery, whereas 11 had persistent incontinence. Patients after sling were defined as continent if used 0-1 dry "security pad" or incontinent >1 pad. Magnetic Resonance examinations were performed with a 3 Tesla system and included 3-dimensional T2-weighted sequence. Three readers performed a qualitative (representation of the bulb and indentation of the sling) and a quantitative analysis (length of the bulb posterior to the sling and distance of the sling from a line bisecting the pubic symphysis). RESULTS: The sling was clearly recognizable in all 16 continent patients but only in 2 of 11 incontinent ones. The length of the bulb posterior to the sling was >10 mm (range, 10-28) in all continent patients and in 2 of the incontinent ones. The sling was coincident with a line drawn through the long axis of the pubic bone in 9 of 16 continent patients. A statistically significant association was found between MRI qualitative findings and continence status (P <.0001). CONCLUSION: On the basis of our MRI results, the position of the sling and, in particular, the length of the urethral bulb posterior to the sling seem to be correlated with continence and must be considered in case of treatment failure. PMID- 24468517 TI - A novel 3-dimensional image analysis system for case-specific kidney anatomy and surgical simulation to facilitate clampless partial nephrectomy. AB - OBJECTIVE: To report our initial experience with the novel 3-dimensional (3D) image analysis system Synapse Vincent in clampless partial nephrectomy (PN), describing its advantages with regard to short-term surgical outcomes and its usefulness as an informed consent tool. METHODS: Twenty-six patients with renal cell carcinoma underwent clampless PN navigated with the aid of case-specific 3D anatomic video images of the kidney, after surgical simulation using the same video system. Baseline characteristics were reviewed, and short-term surgical outcomes were recorded. Of the 26, 6 had imperative indications, and 22 were treated with a minimally invasive approach. Before tumor excision, the renal hilar vessels were meticulously dissected, and definite tumor feeders were selectively ligated. Before patients consented to PN, the surgical procedure and perioperative risks were explained to each patient using case-specific 3D video images; subsequently, surgeons asked patients whether the 3D images had helped them understand PN more clearly than 2D images would have. RESULTS: All operations were successfully completed without clamping, with negative surgical margins. No patients required blood transfusions. During PN, the surgeons confirmed the accuracy of the reconstructed 3D images and surgical simulations in all cases. All patients answered that the 3D images had helped them understand their disease status and surgical risks. CONCLUSION: This is the first report on the Synapse Vincent 3D image analysis system for kidney surgery. Its 3D images and surgical simulation helped not only surgeons in their performance of clampless PN but also patients in their understanding of the operation. PMID- 24468518 TI - Editorial comment. PMID- 24468519 TI - Reply: To PMID 24468517. PMID- 24468520 TI - Reply by the authors. PMID- 24468521 TI - Re: Figler et al.: Impact of graft position on failure of single-stage bulbar urethroplasties with buccal mucosa graft. (Urology 2013;82:1166-1170). PMID- 24468522 TI - Re: Pshak et al.: Is tissue interposition always necessary in transvaginal repair of benign, recurrent vesicovaginal fistulae? (Urology 2013;82:707-712). PMID- 24468523 TI - Does crystal deposition in genetic hypercalciuric rat kidney tissue share similarities with bone formation? AB - OBJECTIVE: To address the effect of bone-related factors and 1,25(OH)2D3/vitamin D receptor (VDR) on renal stone formation in idiopathic hypercalciuria using genetic hypercalciuric rats. METHODS: The basal levels of bone-related factors were detected in Sprague-Dawley and genetic hypercalciuric rats. In VDR silenced kidneys, the expression levels of bone morphogenetic protein 2 (BMP2), runt related transcription factor 2 (Runx2), Osterix, and osteopontin (OPN) were measured, respectively. Tubular calcium phosphate deposits in kidneys and renal tubular epithelial cells (RTECs) were assessed using von Kossa stain. Kidneys were stained with immunohistochemical staining for OPN expression. Gene and protein expression levels of BMP2, Runx2, and Osterix were examined in RTECs incubated with 1,25(OH)2D3. RESULTS: The basal levels of BMP2, Runx2, Osterix, and OPN were significantly increased in genetic hypercalciuric rats, whereas there were no differences in the expression levels of msh homeobox homolog 2 and alkaline phosphatase between the genetic hypercalciuric and normal control rats. VDR knockdown in genetic hypercalciuric rats reduced the expression levels of BMP2, Runx2, Osterix, and OPN. Tubular calcium phosphate deposits were also decreased in VDR silenced kidneys. Immunohistochemical staining showed that there was a reduction in OPN expression in RTECs along with reduction in calcification. Gene and protein expression levels of BMP2, Runx2, and Osterix were upregulated in RTECs incubated with 1,25(OH)2D3. The calcium phosphate deposits in RTECs were also increased by elevated 1,25(OH)2D3. CONCLUSION: Our findings indicate that BMP2, Runx2, Osterix, and OPN might play an important role in renal stone formation in idiopathic hypercalciuria, and 1,25(OH)2D3/VDR might be the significant regulator in this process. PMID- 24468524 TI - Cancer-associated changes in the expression of TMPRSS2-ERG, PCA3, and SPINK1 in histologically benign tissue from cancerous vs noncancerous prostatectomy specimens. AB - OBJECTIVE: To investigate whether messenger ribonucleic acid (mRNA) expression of TMPRSS2-ERG fusion gene, a suggested prostate cancer (PCa) biomarker, was specific to cancerous lesions alone and to study the expression of SPINK1 and PCA3 mRNAs in the same cohort to also explore the proposed mutual exclusivity of TMPRSS2-ERG and SPINK1 expression. METHODS: Levels of 2 TMPRSS2-ERG transcripts, PCA3, and SPINK1 mRNAs were measured with highly standardized reverse transcription quantitative polymerase chain reaction assays in cystoprostatectomy specimens from 19 patients with invasive bladder cancer and 174 radical prostatectomy (RP) samples (88 histologically benign prostate [HBP] tissues and 86 from cancerous lesions) from 87 patients with clinically localized PCa. RESULTS: Expression of TMPRSS2-ERG transcripts was detected in 45 of 88 (51%) HBP tissues from RP specimens and more frequently (57 of 86, 66%) found in cancerous lesions. In contrast, TMPRSS2-ERG expression was detected in only 2 of 19 (11%) cystoprostatectomy specimens, both with incidental PCa foci elsewhere in the gland. Similar trends of changes in the expression of PCA3 and SPINK1 were present in HBP tissue from RP compared with cystoprostatectomy specimens. CONCLUSION: Although the expression of TMPRSS2-ERG, SPINK1, and PCA3 mRNA is higher or more frequently found in cancerous lesions, HBP tissues from patients with clinically localized PCa manifest molecular, mRNA level changes that are absent in cystoprostatectomy specimens lacking incidental PCa foci or infrequent in cystoprostatectomy specimens containing incidental PCa. If this finding is replicated, these molecular assays could be used to inform men with negative biopsy results about the likelihood of cancerous lesions in unsampled regions and hence the need for repeat biopsy. PMID- 24468525 TI - Volumetric scale-up of smouldering remediation of contaminated materials. AB - Smouldering remediation is a process that has been introduced recently to address non-aqueous phase liquid (NAPL) contamination in soils and other porous media. Previous work demonstrated this process to be highly effective across a wide range of contaminants and soil conditions at the bench scale. In this work, a suite of 12 experiments explored the effectiveness of the process as operating scale was increased 1000-fold from the bench (0.003m(3)) to intermediate (0.3m(3)) and pilot field-scale (3m(3)) with coal tar and petrochemical NAPLs. As scale increased, remediation efficiency of 97-99.95% was maintained. Smouldering propagation velocities of 0.6-14*10(-5)m/s at Darcy air fluxes of 1.54-9.15cm/s were consistent with observations in previous bench studies, as was the dependence on air flux. The pilot field-scale experiments demonstrated the robustness of the process despite heterogeneities, localised operation, controllability through airflow supply, and the importance of a minimum air flux for self-sustainability. Experiments at the intermediate scale established a minimum-observed, not minimum-possible, initial concentration of 12,000mg/kg in mixed oil waste, providing support for the expectation that lower thresholds for self-sustaining smouldering decreased with increasing scale. Once the threshold was exceeded, basic process characteristics of average peak temperature, destructive efficiency, and treatment velocity were relatively independent of scale. PMID- 24468526 TI - Inactivation of Microcystis aeruginosa by DC glow discharge plasma: Impacts on cell integrity, pigment contents and microcystins degradation. AB - We proposed a method to inactivate M. aeruginosa by using discharge plasma taking at the gas-solution interface supplied by DC power. Multiple analysis techniques including fluorescence excitation-emission matrix (EEM) and flow cytometry (FCM) were used to reveal the inactivation mechanism of M. aeruginosa. The photosynthetic pigment contents including phycocyanin, chlorophyll and metabolites were examined quantitatively. The DC glow discharge plasma caused an increased level of reactive oxygen species (ROS), and the damage of M. aeruginosa cells are mainly attributed to the oxidative stress including OH attack and H2O2 oxidation. Our findings demonstrate that plasma oxidation is a promising technology for inactivation of M. aeruginosa cells with simultaneous removal of microcystins and so it may lead us to a new route to efficient treatment of cyanobacterial blooms. PMID- 24468527 TI - Stabilization/solidification on chromium (III) wastes by C(3)A and C(3)A hydrated matrix. AB - Hazardous wastes are usually used in the Portland cement production in order to save energy, costs and/or stabilize toxic substances and heavy metals inside the clinker. This work focus on the stabilization/solidification on chromium (III) wastes by C(3)A and C(3)A hydrated matrix. The immobilization rate of chromium in C(3)A and the leaching characteristics of the C(3)A hydrated matrixes containing chromium were investigated by ICP-AES. The results indicated that C(3)A had a good solidifying effect on chromium using the clinkering process, however, the Cr leaching content of Cr-doped C(3)A was higher than that of hydrated C(3)A matrix in Cr(NO(3))3 solution and was lower than that of the hydrated C(3)A matrix in K(2)CrO(4) solution, no matter the leachant was sulphuric acid & nitric acid or water. To explain this, C(3)A formation, chemical valence states of chromium in C(3)A, hydration products and Cr distribution in the C(3)A-gypsum hydrated matrixes were studied by XRD, XPS and FESEM-EDS. The investigation showed that part of Cr(3+) was oxidized to Cr(6+) in the clinkering process and identified as the chromium compounds Ca(4)Al(6)O(12)CrO(4) (3CaO.Al(20O(3).CaCrO(4)), which resulted in the higher leaching of hydrated matrix of Cr-doped C(3)A. PMID- 24468528 TI - Evaluation of the phytostabilisation efficiency in a trace elements contaminated soil using soil health indicators. AB - The efficiency of a remediation strategy was evaluated in a mine soil highly contaminated with trace elements (TEs) by microbiological, ecotoxicological and physicochemical parameters of the soil and soil solution (extracted in situ), as a novel and integrative methodology for assessing recovery of soil health. A 2.5 year field phytostabilisation experiment was carried out using olive mill-waste compost, pig slurry and hydrated lime as amendments, and a native halophytic shrub (Atriplex halimus L.). Comparing with non-treated soil, the addition of the amendments increased soil pH and reduced TEs availability, favoured the development of a sustainable vegetation cover (especially the organic materials), stimulated soil microorganisms (increasing microbial biomass, activity and functional diversity, and reducing stress) and reduced direct and indirect soil toxicity (i.e., its potential associated risks). Therefore, under semi-arid conditions, the use of compost and pig slurry with A. halimus is an effective phytostabilisation strategy to improve soil health of nutrient-poor soils with high TEs concentrations, by improving the habitat function of the soil ecosystem, the reactivation of the biogeochemical cycles of essential nutrients, and the reduction of TEs dissemination and their environmental impact. PMID- 24468529 TI - Predicting synergistic toxicity of heavy metals and ionic liquids on photobacterium Q67. AB - Results from three mathematical approaches to predict the toxicity of uniform design mixtures of four heavy metals (HMs) including Cd(II), Ni(II), Cu(II), and Zn(II) and six ionic liquids (ILs) were compared to the observed toxicity of these mixtures on Vibrio qinghaiensis sp.-Q67. Single toxicity analysis indicated that the ILs had greater toxicity than the HMs. Combined toxicities of HMs and ILs were found to be synergistic. The combined toxicities were underestimated by concentration addition (CA) and independent action (IA) models. However, the mixture toxicities were effectively predicted by the integrated CA with IA based on multiple linear regression model (ICIM). We propose that ICIM model can serve as a useful tool for predicting the toxicity of interactive mixtures. PMID- 24468530 TI - Photoconversion of 4-nitrophenol in the presence of hydrazine with AgNPs-TiO2 nanoparticles prepared by the sol-gel method. AB - The photocatalytic properties of functionalized TiO2 with silver nanoparticles (AgNPs) for the conversion of 4-nitrophenol to 4-aminophenol in the presence of hydrazine were investigated. The TiO2 semiconductor synthesized by the sol-gel method was functionalized with AgNPs at different loadings, and their structural and optical properties were characterized by several techniques. The functionalized TiO2 with 1.5wt% AgNPs presented the highest photocatalytic activity for the conversion of 4-nitrophenol with appropriate hydrazine concentrations (0.5M). The photoefficiency enhancement under UV light irradiation was attributed to the electron transfer from the TiO2 semiconductor surface to the adsorbed acceptor reactant (4-nitrophenol) through the deposited AgNPs. PMID- 24468531 TI - Application of polycolloid-releasing substrate to remediate trichloroethylene contaminated groundwater: a pilot-scale study. AB - The objectives of this pilot-scale study were to (1) evaluate the effectiveness of bioremediation of trichloroethylene (TCE)-contaminated groundwater with the supplement of slow polycolloid-releasing substrate (SPRS) (contained vegetable oil, cane molasses, surfactants) under reductive dechlorinating conditions, (2) apply gene analyses to confirm the existence of TCE-dechlorinating genes, and (3) apply the real-time polymerase chain reaction (PCR) to evaluate the variations in TCE-dechlorinating bacteria (Dehalococcoides spp.). Approximately 350L of SPRS solution was supplied into an injection well (IW) and groundwater samples were collected and analyzed from IW and monitor wells periodically. Results show that the SPRS caused a rapid increase of the total organic carbon concentration (up to 5794mg/L), and reductive dechlorination of TCE was significantly enhanced. TCE dechlorination byproducts were observed and up to 99% of TCE removal (initial TCE concentration=1872MUg/L) was observed after 50 days of operation. The population of Dehalococcoides spp. increased from 4.6*10(1) to 3.41*10(7)cells/L after 20 days of operation. DNA sequencing results show that there were 31 bacterial species verified, which might be related to TCE biodegradation. Results demonstrate that the microbial analysis and real-time PCR are useful tools to evaluate the effectiveness of TCE reductive dechlorination. PMID- 24468532 TI - Curcumin and kaempferol prevent lysozyme fibril formation by modulating aggregation kinetic parameters. AB - Interaction of small molecule inhibitors with protein aggregates has been studied extensively, but how these inhibitors modulate aggregation kinetic parameters is little understood. In this work, we investigated the ability of two potential aggregation inhibiting drugs, curcumin and kaempferol, to control the kinetic parameters of aggregation reaction. Using thioflavin T fluorescence and static light scattering, the kinetic parameters such as amplitude, elongation rate constant and lag time of guanidine hydrochloride-induced aggregation reactions of hen egg white lysozyme were studied. We observed a contrasting effect of inhibitors on the kinetic parameters when aggregation reactions were measured by these two probes. The interactions of these inhibitors with hen egg white lysozyme were investigated using fluorescence quench titration method and molecular dynamics simulations coupled with binding free energy calculations. We conclude that both the inhibitors prolong nucleation of amyloid aggregation through binding to region of the protein which is known to form the core of the protein fibril, but once the nucleus is formed the rate of elongation is not affected by the inhibitors. This work would provide insight into the mechanism of aggregation inhibition by these potential drug molecules. PMID- 24468534 TI - Ninety-day morbidity in patients undergoing primary TKA with discontinuation of warfarin and bridging with LMWH. AB - We asked whether patients under long-term warfarin and managed with current guidelines regarding bridging therapy have a higher complications rate within ninety days following total knee arthroplasty. We retrospectively identified 38 patients under long-term warfarin. They were match-paired with 76 control patients. Our results showed a significant increased rate of complications (42.1% vs. 6.9%, P < 0.001) and re-operation (21.1% vs. 5.2%, P < 0.001) in the warfarin group. The difference was related to the number of hematomas requiring surgical evacuation. The warfarin group had a significantly higher rate of blood loss, blood transfusion, and length of hospital stay. Our data suggest that current guidelines for preoperative warfarin management are associated with a high rate of bleeding complications and reoperations following TKA. PMID- 24468533 TI - Global spread of dengue virus types: mapping the 70 year history. AB - Since the first isolation of dengue virus (DENV) in 1943, four types have been identified. Global phenomena such as urbanization and international travel are key factors in facilitating the spread of dengue. Documenting the type-specific record of DENV spread has important implications for understanding patterns in dengue hyperendemicity and disease severity as well as vaccine design and deployment strategies. Existing studies have examined the spread of DENV types at regional or local scales, or described phylogeographic relationships within a single type. Here we summarize the global distribution of confirmed instances of each DENV type from 1943 to 2013 in a series of global maps. These show the worldwide expansion of the types, the expansion of disease hyperendemicity, and the establishment of an increasingly important infectious disease of global public health significance. PMID- 24468535 TI - Mutual inhibition between YAP and SRSF1 maintains long non-coding RNA, Malat1 induced tumourigenesis in liver cancer. AB - Emerging studies have revealed that Malat1 is overexpressed in many malignant diseases, including liver cancer, and contributes to enhancing cell migration or facilitating proliferation. However, the mechanism underlying its regulation has largely remained elusive. Here, we characterised the oncoprotein Yes-associated protein (YAP), which up-regulated metastasis-associated lung adenocarcinoma transcript 1 (Malat1) expression at both transcriptional and post-transcriptional levels, whereas serine/arginine-rich splicing factor 1 (SRSF1) played an opposing role. SRSF1 inhibited YAP activity by preventing its co-occupation with TCF/beta catenin on the Malat1 promoter. In contrast, overexpression of YAP impaired the nuclear retention of both SRSF1 and itself via an interaction with Angiomotin (AMOT). This effect removed the inhibitory role of SRSF1 on Malat1 in the nucleus. Furthermore, higher expression of YAP was consistent with a lower SRSF1 nuclear accumulation in human liver cancer tissues. We also revealed that overexpression of YAP combined with a knockdown of SRSF1 resulted in conspicuously enhanced transwell cell mobility, accelerated tumour growth rate, and loss of body weight in a tail vein-injected mouse models. Taken together, these data provided a novel mechanism underlying the balance between SRSF1, YAP and Malat1 and uncovered a new role of YAP in regulating long non-coding RNA (lncRNA). Thus, disrupting the interaction between YAP and SRSF1 may serve as a crucial therapeutic method in liver cancer. PMID- 24468536 TI - Multifocal central nervous system demyelination and Lhermitte's phenomenon secondary to combination chemotherapy for chronic lymphocytic leukaemia. AB - The CRF regime (cyclophosphamide, rituximab and fludarabine) is used for the treatment of chronic lymphocytic leukaemia. We report a case of diffuse CNS demyelination following treatment with CRF, presenting with Lhermitte's phenomenon, and imaging and neurophysiological evidence of demyelination. Fludarabine is the most likely causative agent, although CNS demyelination has not been previously described in low dose therapy. PMID- 24468537 TI - Tractography of the corticobulbar tract. PMID- 24468538 TI - Waist circumference and waist-to-hip ratio in carpal tunnel syndrome: a case control study. AB - BACKGROUND: The association between carpal tunnel syndrome (CTS) and high body mass index (BMI) and some hand measures is well known. No study has been specifically focused on waist circumference (WC) and waist-to-hip-ratio (WHR). The aim of this prospective case-control study is to evaluate the association between CTS and WC, WHR and other body and hand anthropometric measures. METHODS: We consecutively enrolled one "idiopathic" CTS case for two controls in 3 outpatient electromyography labs. The main anthropometric measures were BMI, WC, WHR, wrist ratio (WR) and hand ratio (HR). We performed univariate and multivariate analyses. RESULTS: Female cases and controls were 250 and 474 and male cases and controls were 120 and 273, respectively. At univariate analysis there were differences in many anthropometric measures between cases and controls. At multivariate logistic regression analyses high BMI, WC and WHR and abnormal HR and WR were independent risk factors for CTS. Crossing two categories between BMI, WC and WHR, the overweight subjects, especially females, were at risk only if they had very high WC or high WHR. The risk increased if they were obese. CONCLUSIONS: High WC/WHR doubles the risk of CTS, the risk further increased if overweight/obese subjects have also very high WC or high WHR. The obese subjects were always at risk regardless of WC and WHR values. Metabolic causes of this association with CTS were hypothesised. BMI is not the only and most powerful body predictor of "idiopathic" CTS, but also WHR and WC should be considered. These measures may not be interchangeable and it may be desirable to consider the utility of their joint use. PMID- 24468539 TI - Predictors for cortical gray matter volume in stroke patients with confluent white matter changes. AB - BACKGROUND AND PURPOSE: Our previous study found that cortical gray matter (cGM) volume predicted vascular cognitive impairment independent of age-related white matter changes (WMC). We aimed to investigate predictors for cGM volume in ischemic stroke patients with confluent WMC. METHODS: One-hundred post-stroke patients with confluent WMC were recruited into the study. All volumetric measures were standardized by intracranial volume as volume ratio. Univariate analyses and multivariate linear regression models were used to test relationship of cGM volume with basic demography, vascular risk factors, APOE status, WMC volume (periventricular and deep WMC), infarct measures (volume, number and location) and microbleed (number, presence and location). RESULTS: After controlling for significant variables in the univariate analyses, multivariate linear regression models found that old age (beta=-0.288, p=0.001), low triglyceride (beta=0.194, p=0.027), periventricular WMC (PVWMC) (beta=-0.392, p<0.001) and presence of thalamic microbleed (beta=-0.197, p=0.041) were independently predictive of less cGM volume ratio. CONCLUSIONS: Age, PVWMC and left thalamic microbleed predict less cGM volume. PMID- 24468540 TI - A case of 3243A>G mutation in mtDNA presenting as apparently idiopathic hyperCKemia. AB - The 3243A>G mutation of mtDNA usually is associated with MELAS syndrome. Here we report a patient with the 3243A>G mutation presenting only recurrent muscle fatigue and elevated levels of serum creatine kinase (CK). The mother of the proband was referred to us for type 2 diabetes mellitus, muscle pain and sensorineural hearing loss. The percentage of mutation load in different tissues was similar in both subjects, except in the urinary epithelium. The mutation load in the son's urinary epithelial cells (UEC) was consistently higher (nearly 50%) than in his muscle (nearly 20%). We conclude that a correlation between the proportion of the UEC mutation load and the severity of the disease was lacking in this pedigree. The use of UEC as the tissue of choice in the noninvasive diagnosis of the 3243A>G mutation offers a very attractive alternative to muscle biopsy. Finally, our data expand the clinical spectrum of the 3243A>G mutation. PMID- 24468541 TI - Magnetic resonance spectroscopy findings as related to fatigue and cognitive performance in multiple sclerosis patients with mild disability. AB - BACKGROUND: The origin of fatigue in multiple sclerosis (MS) remains unclear. Magnetic resonance spectroscopy (MRS) provides an insight into metabolic properties of the brain. OBJECTIVES: The aim of the study was to evaluate brain MRS measurements in MS patients, with regard to fatigue and cognition. METHODS: The study comprised 32 MS patients and 43 controls. Fatigue was assessed using the Fatigue Severity Scale (FSS) and the Modified Fatigue Impact Scale (MFIS) and cognition - using the Brief Repeatable Battery of Neuropsychological Tests (parts of BRBNT). MRS voxels were placed in the parietal white matter (PWM) and the posterior cingulate gyrus (PCG); N-acetyl-aspartate (NAA), choline (Cho) and myoinositol (mI) to creatine (Cr) ratios were determined. Relationships were searched between MRS measurements and fatigue as well as BRBNT results. RESULTS: MS patients in comparison with controls showed decreased NAA/Cr and increased mI/Cr ratios in PCG and PWM, respectively. No significant relationships between MRS parameters and fatigue measures, BRBNT results or MS-related variables were found. CONCLUSIONS: The decrease of NAA and increase of mI within white and gray matters in MS patients do not show a significant relationship with cognitive performance or fatigue. PMID- 24468542 TI - Evaluation of dengue virus strains for human challenge studies. AB - Discordance between the measured levels of dengue virus neutralizing antibody and clinical outcomes in the first-ever efficacy study of a dengue tetravalent vaccine (Lancet, Nov 2012) suggests a need to re-evaluate the process of pre screening dengue vaccine candidates to better predict clinical benefit prior to large-scale vaccine trials. In the absence of a reliable animal model and established correlates of protection for dengue, a human dengue virus challenge model may provide an approach to down-select vaccine candidates based on their ability to reduce risk of illness following dengue virus challenge. We report here the challenge of flavivirus-naive adults with cell culture-passaged dengue viruses (DENV) in a controlled setting that resulted in uncomplicated dengue fever (DF). This sets the stage for proof-of-concept efficacy studies that allow the evaluation of dengue vaccine candidates in healthy adult volunteers using qualified DENV challenge strains well before they reach field efficacy trials involving children. Fifteen flavivirus-naive adult volunteers received 1 of 7 DENV challenge strains (n=12) or placebo (n=3). Of the twelve volunteers who received challenge strains, five (two DENV-1 45AZ5 and three DENV-3 CH53489 cl24/28 recipients) developed DF, prospectively defined as >=2 typical symptoms, >=48h of sustained fever (>100.4 degrees F) and concurrent viremia. Based on our study and historical data, we conclude that the DENV-1 and DENV-3 strains can be advanced as human challenge strains. Both of the DENV-2 strains and one DENV-4 strain failed to meet the protocol case definition of DF. The other two DENV-4 strains require additional testing as the illness approximated but did not satisfy the case definition of DF. Three volunteers exhibited effusions (1 pleural/ascites, 2 pericardial) and 1 volunteer exhibited features of dengue (rash, lymphadenopathy, neutropenia and thrombocytopenia), though in the absence of fever and symptoms. The occurrence of effusions in milder DENV infections counters the long-held belief that plasma leakage syndromes are restricted to dengue hemorrhagic fever/dengue shock syndromes (DHF/DSS). Hence, the human dengue challenge model may be useful not only for predicting the efficacy of vaccine and therapeutic candidates in small adult cohorts, but also for contributing to our further understanding of the mechanisms behind protection and virulence. PMID- 24468544 TI - The effects of alternative pretreatment strategies on anaerobic digestion and methane production from different algal strains. AB - The effect of various pretreatment strategies on methane yields following anaerobic digestion (AD) of five different microalgal strains was investigated. Pavlova_cf sp., Tetraselmis sp. and Thalassiosira weissflogii exhibited substantial methane yields of 0.4-0.5L/g volatile solids (VS) without pretreatment, providing up to 75-80% of theoretical values. In contrast, methane yields from Chlorella sp. and Nannochloropsis sp. were around 0.35L/g VS, or 55 60% of the theoretical values, respectively. Alkali treatment was not effective and thermal pretreatment only enhanced Nannochloropsis methane yields. Thermochemical pretreatment had the strongest impact on biomass solubilization with methane yields increasing by 30% and 40% for Chlorella and Nannochloropsis, respectively. The lipid content had a strong beneficial impact on the theoretical and observed methane yields as compared to protein and carbohydrate content. Other features such as cell-wall composition are also likely to be important factors dictating algal biodegradability and methane yields addressed in part by thermochemical pretreatment. PMID- 24468543 TI - Optimal cut-off value for cardiac troponin I in ruling out Type 5 myocardial infarction. AB - OBJECTIVES: The clinical classification of myocardial infarction (MI) into five types was introduced in 2007 as a component of the universal definition. A Type 5 MI was defined as a MI related to coronary artery bypass surgery. In a setting of patients undergoing elective coronary artery bypass grafting, we set out (i) to describe the pattern of multiple serial cardiac troponin I (cTnI) measurements within 72 h postoperatively and (ii) to determine the optimal cardiac troponin I cut-off value in ruling in or ruling out a Type 5 MI. METHODS: In 2011-2012, patients with two- and three-vessel disease scheduled for elective on-pump coronary artery bypass grafting were considered. Samples for cTnI were drawn before and 0, 2, 4, 6, 12, 24, 48 and 72 h after surgery. Analysis for cardiac troponin I was performed by use of the Abbott Architect c16000 system with an upper reference limit (URL) of 30 ng/l. The diagnosis of a Type 5 MI was prospectively made by a consultant cardiologist and was based on clinical, electrocardiographic and imaging data together with routine sampling and measurements of cTnI, but without knowledge of the results of serial study cTnI measurements. RESULTS: Of the 141 eligible patients, 99 (70%) qualified for final enrollment. In 8 patients (8%), the clinical diagnosis of a Type 5 MI was made. Patients without Type 5 MI (n = 91) had a median cTnI peak value of 7675 ng/l compared with 20 500 ng/l in Type 5 MI patients (P = 0.01). By use of receiver operating characteristic curves, optimal cut-off values for identifying Type 5 MI were defined as 7970 ng/l (corresponding to 266 times the URL) 12 h postoperatively and 9950 ng/l (corresponding to 331 times the URL) 24 h postoperatively. These cut-off values resulted in negative predictive values of 0.99 (12 h) and 0.99 (24 h). Positive predictive values were 0.23 (12 h) and 0.35 (24 h). CONCLUSIONS: In clinically stable patients undergoing elective coronary artery bypass grafting, measurements of cTnI are useful in ruling out a Type 5 MI. PMID- 24468545 TI - BDNF and COMT polymorphisms have a limited association with episodic memory performance or engagement in complex cognitive activity in healthy older adults. AB - Cognitive decline is a major factor in lowering the quality of life in older populations, and contributes substantially to social, economic, and health costs. As humans age, cognitive function decreases differentially, and individual differences in cognitive ageing are likely attributed to a range of causes, including environmental and genetic influences. The current study included 360 participants (240 females and 120 males) aged between 50 and 79years from the Tasmanian Healthy Brain Project. The brain-derived neurotrophic factor (BDNF) Val66Met and Catechol-O-Methyltransferase (COMT) Val158Met polymorphisms were examined for their association with visual and auditory episodic memory performance. The polymorphisms were also investigated for their association with reported life-long engagement in complex cognitive activity using a retrospective questionnaire. Relative to the demographic variables, the gene variations were found to have no association with episodic memory performance, with the exception of the COMT polymorphism on a single measure of auditory memory (RAVLT). Several other studies also demonstrated that these polymorphisms have no, small, or inconsistent effects on memory function. The BDNF Val66Met and COMT Val158Met polymorphisms were also found to be of little significance to active engagement in complex cognitive activity throughout most of the lifespan. An association was detected between BDNF Val66Met and engagement in cognitive activity in early life (p=.04, d=.23), however this did not reach significance when adjusted for multiple comparisons. The biological mechanisms that underlie engagement in cognitive activity are elusive, thus the potential relationship between BDNF Val66Met genotype and early life cognitive engagement warrants further investigation. PMID- 24468546 TI - CCK-58 elicits both satiety and satiation in rats while CCK-8 elicits only satiation. AB - Reduction of food intake by exogenous cholecystokinin (CCK) has been demonstrated primarily for its short molecular form, CCK-8. Mounting evidence, however, implicates CCK-58 as a major physiologically active CCK form, with different neural and exocrine response profiles than CCK-8. In three studies, we compared meal-pattern effects of intraperitoneal injections CCK-8 vs. CCK-58 in undeprived male Sprague-Dawley rats consuming sweetened condensed milk. In study 1, rats (N=10) received CCK-8, CCK-58 (0.45, 0.9, 1.8 and 3.6 nmol/kg) or vehicle before a 4-h test-food presentation. At most doses, both CCK-8 and CCK-58 similarly reduced meal size relative to vehicle. Meal-size reduction prompted a compensatory shortening of the intermeal interval (IMI) after CCK-8, but not after CCK-58, which uniquely increased the satiety ratio (IMI/size of the preceding meal). In the second study, lick patterns were monitored after administration of 0.9 nmol/kg CCK-58, CCK-8 or vehicle. Lick cluster size, lick efficiency and interlick-interval distribution remained unaltered compared to vehicle, implying natural satiation, rather than illness, following both CCK forms. In study 3, threshold satiating doses of the two CCK forms were given at 5 and 30 min after meal termination, respectively. CCK 58, but not CCK-8 increased the intermeal interval and satiety ratio compared to vehicle. In conclusion, while CCK 58 and CCK-8 both stimulate satiation, thereby reducing meal size, CCK 58 consistently exerts a satiety effect, prolonging IMI. Given the physiological prominence of CCK-58, these results suggest that CCK's role in food intake regulation may require re-examination. PMID- 24468547 TI - Urotensin II (U-II), a novel cyclic peptide, possibly associated with the pathophysiology of osteoarthritis. AB - Synovial fibrosis is one of the main outcomes of osteoarthritis. Some authors have reported that urotensin-II (U-II) may cause pathologic fibrosis in cardiovascular system, lung and liver. However there are no previous reports available in the literature about its relationship with the synovial fibrosis in osteoarthritis. The aim of this study was to compare the U-II levels in knee synovial fluids obtained from osteoarthritic and non-osteoarthritic patients. Two groups were created, the osteoarthritis group and non-osteoarthritic control group. The control group was consisted of patients who underwent arthroscopic surgery for other reasons than cartilage disorders. In the osteoarthritis group all patients had grade 4 primer degenerative osteoarthritis and were treated with total knee arthroplasty. Minimum 1 mL knee synovial fluids were obtained during operation. Levels of U-II were measured by using ELISA kit U-II levels were significantly higher in the osteoarthritic group than that in the control group. No correlation was found between U-II levels and age. In conclusion, the significantly high U-II levels in the knee synovial fluid of osteoarthritic patients supported our hypothesis that "U-II may be associated with the synovial fibrosis in osteoarthritis". PMID- 24468548 TI - Characterization of a far-red analog of ghrelin for imaging GHS-R in P19-derived cardiomyocytes. AB - Ghrelin and its receptor, the growth hormone secretagogue receptor (GHS-R), are expressed in the heart, and may function to promote cardiomyocyte survival, differentiation and contractility. Previously, we had generated a truncated analog of ghrelin conjugated to fluorescein isothiocyanate for the purposes of determining GHS-R expression in situ. We now report the generation and characterization of a far-red ghrelin analog, [Dpr(3)(octanoyl), Lys(19)(Cy5)]ghrelin (1-19), and show that it can be used to image changes in GHS R in developing cardiomyocytes. We also generated the des-acyl analog, des-acyl [Lys(19)(Cy5)]ghrelin (1-19) and characterized its binding to mouse heart sections. Receptor binding affinity of Cy5-ghrelin as measured in HEK293 cells overexpressing GHS-R1a was within an order of magnitude of that of fluorescein ghrelin and native human ghrelin, while the des-acyl Cy5-ghrelin did not bind GHS R1a. Live cell imaging in HEK293/GHS-R1a cells showed cell surface labeling that was displaced by excess ghrelin. Interestingly, Cy5-ghrelin, but not the des-acyl analog, showed concentration-dependent binding in mouse heart tissue sections. We then used Cy5-ghrelin to track GHS-R expression in P19-derived cardiomyocytes. Live cell imaging at different time points after DMSO-induced differentiation showed that GHS-R expression preceded that of the differentiation marker aMHC and tracked with the contractility marker SERCA 2a. Our far-red analog of ghrelin adds to the tools we are developing to map GHS-R in developing and diseased cardiac tissues. PMID- 24468550 TI - CART in the brain of vertebrates: circuits, functions and evolution. AB - Cocaine- and amphetamine-regulated transcript peptide (CART) with its wide distribution in the brain of mammals has been the focus of considerable research in recent years. Last two decades have witnessed a steady rise in the information on the genes that encode this neuropeptide and regulation of its transcription and translation. CART is highly enriched in the hypothalamic nuclei and its relevance to energy homeostasis and neuroendocrine control has been understood in great details. However, the occurrence of this peptide in a range of diverse circuitries for sensory, motor, vegetative, limbic and higher cortical areas has been confounding. Evidence that CART peptide may have role in addiction, pain, reward, learning and memory, cognition, sleep, reproduction and development, modulation of behavior and regulation of autonomic nervous system are accumulating, but an integration has been missing. A steady stream of papers has been pointing at the therapeutic potentials of CART. The current review is an attempt at piecing together the fragments of available information, and seeks meaning out of the CART elements in their anatomical niche. We try to put together the CART containing neuronal circuitries that have been conclusively demonstrated as well as those which have been proposed, but need confirmation. With a view to finding out the evolutionary antecedents, we visit the CART systems in sub-mammalian vertebrates and seek the answer why the system is shaped the way it is. We enquire into the conservation of the CART system and appreciate its functional diversity across the phyla. PMID- 24468549 TI - Involvement of adrenomedullin in the attenuation of acute morphine-induced analgesia in rats. AB - Adrenomedullin (AM) is a member of calcitonin gene-related peptide (CGRP) family and a pain-related peptide. We have shown that chronic administration of morphine (20 MUg) upregulates AM activity contributing to morphine tolerance. The present study investigated if AM is involved in acute morphine-induced analgesia. Single intrathecal (i.t.) injection of morphine at a dose of 5 MUg increased the tail flick latency (TFL). This analgesic effect was potentiated by the co administration of the AM receptor antagonist AM22-52 (5 and 10 nmol). Exposure of sensory ganglion culture to morphine increased AM content in the ganglia in concentration (0.33-10 MUM)- and time (10-240 min)-dependent manners. However, treatment with morphine (3.3 MUM) for 30-240 min did not alter AM mRNA levels in the cultured ganglia. Furthermore, exposure of ganglion cultures to morphine (3.3 MUM) for 30-240, but not 10 min induced an increase in AM content in the culture medium. These results reveal that a single morphine treatment potentiates post translational change and the release of AM in sensory ganglia masking morphine induced analgesia. Thus, targeting AM and its receptors should be considered as a novel approach to improve the analgesic potency of opiates during their acute use. PMID- 24468551 TI - A new approach for the characterization of proliferative cells in cestodes. AB - Cestodes show a remarkable proliferative capability that sustains the constant growth and differentiation of proglottids essential for their lifestyle. It is believed that a separate population of undifferentiated stem cells (the so-called germinative cells) are the only cells capable of proliferation during growth and development. The study of this particular cell subpopulation is hampered by the current lack of methods to isolate it. In this work, we developed a reproducible flow cytometry and cell sorting method to quantify and isolate the proliferating cells in the tetrathyridia larvae of the model cestode Mesocestoides corti, based on the DNA content of the cells. The isolated cells display the typical germinative cell morphology, and can be used for RNA isolation with a yield in the ng to MUg range. We expect that this approach may facilitate the characterization of the germinative cells in M. corti and other model tapeworms. PMID- 24468552 TI - The value of urban vacant land to support arthropod biodiversity and ecosystem services. AB - The expansion of urban areas is occurring globally, but not all city neighborhoods are gaining population. Because of economic decline and the recent foreclosure crisis, many U.S. cities are demolishing abandoned residential structures to create parcels of vacant land. In some cities, weak housing markets have, or will likely, recover in the near term, and these parcels will be redeveloped. However, in other cities, large numbers of abandoned parcels have no significant market value and no likelihood of near-term redevelopment. The creation of these vacated green spaces could offer opportunities to preserve declining species, restore ecosystem functions, and support diverse ecosystem services. Arthropods are an important indicator of the ability of urban vacant land to serve multiple functions, from conservation to food production. Across Europe, vacant lands have been found to support a diversity of rare species, and similar examinations of arthropods within this habitat are underway in the United States. In addition, using vacant land as a resource for local food production is growing rapidly worldwide. Arthropods play key roles in the sustainability of food production in cities, and land conversion to farming has been found to influence their community composition and function. A greater focus on quantifying the current ecological value of vacant land and further assessment of how changes in its ecosystem management affect biodiversity and ecosystem processes is clearly needed. Herein, we specifically focus on the role of arthropods in addressing these priorities to advance our ecological understanding of the functional role of vacant land habitats in cities. PMID- 24468553 TI - Dung beetles (Coleoptera: Scarabaeidae) attracted to dung of the largest herbivorous rodent on earth: a comparison with human feces. AB - The capybara, Hydrochoerus hydrochaeris (L.) (Rodentia: Caviidae), is the largest herbivorous rodent on Earth and abundant in the Neotropical region, which can provide a stable food source of dung for dung beetle communities (Coleoptera: Scarabaeidae: Scarabaeinae). However, the use of capybara dung by dung beetles is poorly known. Here, we present data on the structure of the dung beetle community attracted to capybara dung and compare with the community attracted to human feces. Dung beetles were captured with pitfall traps baited with fresh capybara dung and human feces in pastures with exotic grass (Brachiaria spp.), patches of Brazilian savanna (Cerrado), and points of degraded riparian vegetation along the Aquidauana river in Anastacio and Aquidauana, Mato Grosso do Sul, Brazil. In traps baited with human feces, 13,809 individuals of 31 species were captured, and in those baited with capybara dung 1,027 individuals belonging to 26 species were captured. The average number of individuals and species captured by the traps baited with human feces was greater than for capybara dung in all habitats studied. Composition of the communities attracted to human feces and capybara dung formed distinct groups in all habitats. Despite the smaller number of species and individuals captured in capybara dung when compared with human feces, capybara dung was attractive to dung beetles. In Brazil, the legalization of hunting these rodents has been debated, which would potentially affect the community and consequently the ecological functions performed by dung beetles that use the feces of these animals as a resource. In addition, the knowledge of the communities associated with capybaras may be important in predicting the consequences of future management of their populations. PMID- 24468554 TI - Flight phenologies of the southeastern Ips species (Coleoptera: Curculionidae: Scolytinae) and some associated Coleoptera in central and southern Louisiana. AB - A year-long flight phenology study was undertaken from 15 July 2009 to 7 July 2010 in central and southeastern Louisiana to estimate the temporal flight patterns of the three southeastern Ips species: Ips grandicollis (Eichhoff), Ips avulsus (Eichhoff), and Ips calligraphus (Germar) (Coleoptera: Curculionidae: Scolytinae) as well as some of their predatory and phloem-feeding coleopteran associates. The southeastern Ips species play important roles as decomposers in forest ecosystems, but can cause ecological and economic damage during epidemic population phases. In total, 282,761 individuals of the three southeastern Ips species were collected using Ips pheromone-baited multiple funnel traps during the study period. Two major Ips activity peaks were observed during 16 September to 7 October of 2009 and 24 March to 15 April of 2010. In total, 9,139 associated Coleoptera were also collected. Greater than 95% of the total number of associated Coleoptera collected were represented by histerids from the genus Platysoma (4,487; 49.1% of total), the trogossitid Temnoscheila virescens (F.) (2,107; 23.1%), cerambycids from the genus Monochamus (1,013; 11.1%), and Acanthocinus obsoletus (Olivier) (743; 8.1%), and the clerid Thanasimus dubius (F.) (477; 5.2%). Results showed that the associates fell into four temporal groups: the winter and spring active species T. dubius; the spring active species Rhagium inquisitor (L.) and histerids from the genus Platysoma; the spring and summer active species T. virescens, Buprestis lineata F., and Monochamus carolinensis (Olivier); and the summer through fall active species A. obsoletus and Monochamus titillator (F.). PMID- 24468555 TI - Detection and identification of Amylostereum areolatum (Russulales: Amylostereaceae) in the mycangia of Sirex nigricornis (Hymenoptera: Siricidae) in central Louisiana. AB - The woodwasp Sirex noctilio F. (Hymenoptera: Siricidae) has become established in North America. A primary tactic for the management of S. noctilio in the southern hemisphere has been the development of a biological control agent, Deladenus siricidicola Bedding. This nematode has a bicyclic life cycle including a mycetophagous free-living and parasitic cycle. During oviposition, female Sirex woodwasps inject a symbiotic fungus. Because D. siricidicola only develops well on Amylostereum areolatum (Chaillet ex Fries) Boidin (Russulales: Amylostereaceae) and North American woodwasps were thought to all have Amylostereum chailletii (Persoon) Boidin as their fungal symbiont, the risk of unintended impacts from D. siricidicola in North America was considered low. Specific polymerase chain reaction primers were designed to amplify the intergenic spacer region of Amylostereum symbionts in a population of the native woodwasp Sirex nigricornis F. located in central Louisiana (i.e., well outside the known distribution of S. noctilio); identity of the symbiont was confirmed by phylogenetic analyses. Overall, 95 out of 100 fungal isolates obtained from the mycangia of S. nigricornis were identified as Amylostereum species. Contrary to expectations, 60% were identified as A. chailletii (N = 60), while 35% were identified as A. areolatum (N = 35). The remaining 5% of these isolates (N = 5) were identified as Bipolaris papendorfii (Aa) Alcorn, Alternaria alternata (Fr.) Keissl, Penicillium marneffei Segretain, Scytalidium cuboideum (Sacc. & Ellis) Sigler & Kang, and Hyphopichia heimii (Pignal) Kurtzman based on sequencing of the internal transcribed spacer (ITS) region. The five non-Amylostereum isolates were likely contaminants during mycangia-spore extraction process. This study confirms the presence of A. areolatum in a population of the native woodwasp S. nigricornis well outside the known distribution of S. noctilio. PMID- 24468556 TI - Molecular characterization and analysis of bacterial diversity in Aleurocanthus woglumi (Hemiptera: Aleyrodidae). AB - Aleurocanthus woglumi Ashby (Hemiptera: Aleyrodidae), commonly referred to as citrus blackfly, is a sap-sucking hemipteran insect. Although polyphagous, citrus is its most preferred host plant. Samples of this insect were collected from Murraya koenigii (L.). The cytochrome c oxidase subunit I gene (mtCO1)-based analysis by sequencing helped in molecular identification of the insect. Phylogenetic analysis of cytB-nd1-LrDNA showed the coevolution of A. woglumi with its primary bacterial symbiont Portiera. Sequencing a 16S rDNA library from insect DNA revealed three bacterial phylotypes, namely, Portiera, Wolbachia, and Erwinia chrysanthemi. Further, we used fluorescence in situ hybridization to visualize the endosymbionts in a whole mount of A. woglumi. Culturable bacteria were obtained on different media and were classified on the basis of 16S rDNA. In total, 30 bacterial phylotypes belonging to 14 different genera, namely, Bacillus, Kocuria, Micrococcus, Staphylococcus, Paenibacillus, Rhodococcus, Rummellibacillus, Arthrobacter, Curtobacterium, Psychrobacillus, Listeria, Brevibacillus, Bhargavae, and Pantoea, were isolated by culturable methods. PMID- 24468557 TI - Factors affecting establishment and recovery of Sasajiscymnus tsugae (Coleoptera: Coccinellidae), an introduced predator of hemlock woolly adelgid (Hemiptera: Adelgidae) on eastern hemlock (Pinales: Pinaceae). AB - To reduce populations of hemlock woolly adelgid, Adelges tsugae Annand (Hemiptera: Adelgidae), >500,000 Sasajiscymnus tsugae (Sasaji and McClure) (Coleoptera: Coccinellidae) have been released in the Great Smoky Mountains National Park since 2002. To determine factors affecting establishment and recovery of these predatory beetles, 65 single release sites were sampled using beat sheets from 2008 to 2012. Several abiotic and biotic factors were evaluated for their association with establishment and recovery of S. tsugae. Information on predatory beetle releases (location, year of release, number released, and season of release), topographic features (elevation, slope, Beers transformed aspect, and topographic relative moisture index), and temperature data (minimum and maximum temperatures 1 d after release and average minimum and maximum temperatures 7 d after release) were obtained from Great Smoky Mountains National Park personnel. These factors were evaluated using stepwise logistic regression and Pearson correlation. S. tsugae was recovered from 13 sites 2 to 10 yr after release, and the greatest number was recovered from 2002 release sites. Regression indicated establishment and recovery was negatively associated with year of release and positively associated with the average maximum temperature 7 d after release and elevation (generally, recovery increased as temperatures increased). Several significant correlations were found between presence and number of S. tsugae and year of release, season of release, and temperature variables. These results indicate that releases of S. tsugae should be made in warmer (?10-25 degrees C) temperatures and monitored for at least 5 yr after releases to enhance establishment and recovery efforts. PMID- 24468558 TI - Feeding-induced interactions between two rice planthoppers, Nilaparvata lugens and Sogatella furcifera (Hemiptera: Delphacidae): effects on feeding and honeydew excretion. AB - A series of laboratory experiments was conducted using electrical penetration graph, salivary flange, and honeydew measurement to study the effects of feeding induced intra- and interspecific interactions on feeding behavior and honeydew excretion between planthoppers Nilaparvata lugens (Stal) and Sogatela furcifera (Horvath). Feeding-induced intra- and interspecific interactions affected many measures of feeding behavior. The number of salivary flanges, mean duration of pathway activities per insect, and mean duration from first probe to first sustained phloem ingestion for both N. lugens and S. furcifera were significantly shorter on rice plants with feeding-induced conspecific and heterospecific effects than those for planthoppers fed on control plants. Feeding-induced intra- and interspecific interactions also affected the duration per insect of phloem ingestion for both N. lugens and S. furcifera. The durations per insect of phloem ingestion on host plants with feeding-induced conspecific and heterospecific effects were significantly longer than those on control plants. An asymmetric facilitative effect of induced interspecific interactions on the weight of honeydew excreted was detected, because only the honeydew weights of S. furcifera were significantly increased by the induced heterospecific effect on both varieties. The results demonstrated that the facilitative effects on honeydew excretion were consistent with previously documented effects on performance. Both facilitative effects on honeydew excretion and performance were asymmetrical, with more benefits to S. furcifera from N. lugens. Such facilitative effects might be mainly related to altered nutrient status and induced allelochemistry in rice. PMID- 24468559 TI - Pseudococcus maritimus (Hemiptera: Pseudococcidae) and Parthenolecanium corni (Hemiptera: Coccidae) are capable of transmitting grapevine leafroll-associated virus 3 between Vitis x labruscana and Vitis vinifera. AB - The grape mealybug, Pseudococcus maritimus (Ehrhorn), and European fruit lecanium scale, Parthenolecanium corni (Bouche), are the predominant species of Coccoidea in Washington State vineyards. The grape mealybug has been established as a vector of Grapevine leafroll-associated virus 3 (GLRaV-3) between wine grape (Vitis vinifera L.) cultivars, elevating its pest status. The objective of this study was to determine if GLRaV-3 could be transmitted between Vitis x labruscana L. and V. vinifera by the grape mealybug and scale insects. Three transmission experiments were conducted with regard to direction; from V. vinifera to V. x labruscana L., from V. x labruscana L. to V. x labruscana L., and from V. x labruscana L. to V. vinifera. Each experiment was replicated 15 times for each vector species. Crawlers (first-instars) of each vector species were allowed 1-wk acquisition and inoculation access periods. The identities of viral and vector species were confirmed by reverse transcription-polymerase chain reaction, cloning, and sequencing of species-specific DNA fragments. GLRaV-3 was successfully transmitted by both species in all experiments, although Ps. maritimus was a more efficient vector under our experimental conditions. To the best of our knowledge, this study represents the first documented evidence of interspecific transmission of GLRaV-3 between two disparate Vitis species. It also highlights the potential role of V. x labruscana L. in the epidemiology of grapevine leafroll disease as a symptomless source of GLRaV-3 inoculum. PMID- 24468560 TI - Seasonal pheromone trap catches of male Bactrocera oleae (Diptera: Tephritidae) in northern California: asynchrony with host (olive tree) phenology? AB - Bactrocera oleae (Rossi) (Diptera: Tephritidae, Dacinae) is an oligophagous species that feeds only on cultivated olives (Olea europaea L.) and its close relatives. Synchrony of seasonal activity patterns of B. oleae, the olive fruit fly with its host's phenology is therefore expected. The objective of this study was to monitor the male olive fruit fly response to female sex pheromone in the field. White sticky traps were deployed year round for 3 yr in an olive orchard in Oroville, CA. They were checked periodically, and flies captured were counted and sexed. Although males were captured regularly, the numbers of females captured on pheromone traps were negligible. Food-baited traps and water-baited traps were deployed to show the presence of flies in the field. Our hypothesis that males would respond to pheromone when females were available and olive fruits were susceptible for oviposition was partially supported. There were two peaks of high male captures in pheromone traps: spring and fall. In spring, females were available and mature but few acceptable olives were available for oviposition (no new crop olives yet). In fall, females were present but many of the new crop olives were already infested. The food baited traps confirmed the presence of flies in the field even when very few were being captured in the pheromone-baited traps. Traps containing only water caught only two flies showing that water alone or the trap type in itself was not attractive to flies. PMID- 24468561 TI - Cashew volatiles mediate short-range location responses in Pseudotheraptus wayi (Heteroptera: Coreidae). AB - Pseudotheraptus wayi Brown (Heteroptera: Coreidae) is a major pest of cashew in East Africa, but little is known about its chemical ecology. Here, we show by using behavioral assays and chemical analysis that some components of cashew leaf volatiles are attractants for male P. wayi. By using a petri dish arena EthoVision video-tracking assay, males oriented closer to crude cashew leaf odor than females. In coupled gas chromatography-electroantennographic detection analysis, we found that four components of cashew leaf volatiles that were identified by coupled gas chromatography-mass spectrometry and confirmed with authentic standards as (E)- and (Z)-beta-ocimene, allo-ocimene, and (Z)-3-hexenyl butyrate appeared to elicit stronger and more consistent responses in male than female antennae. We recorded electroantennograms from antennae of either sex, which confirmed that antennal responses of males to synthetic components of the cashew leaf odor were stronger than those of females. In the petri dish arena EthoVision video-tracking assay, males oriented closer to the synthetic cashew leaf monoterpenes than females. Our results suggest that specific monoterpenes in cashew leaf volatiles may serve as candidate kairomones for males. PMID- 24468562 TI - Periviable birth: management and counseling issues--part 2. PMID- 24468563 TI - Outcomes following periviable birth. AB - This review is presented in three segments: (1) important background concepts, (2) recent reports from regional geographically defined cohorts, and (3) prognosis research from the National Institutes of Health Neonatal Research Network. Extending the use of intensive care to newborns of lower gestational ages will unavoidably result in a higher proportion and a higher absolute number of survivors with morbidity, unless other changes in practice offset the increased risk associated with decreasing gestational age. In geographically defined cohort studies, the proportion of periviable newborns delivered in perinatal centers and the practices around foregoing and withdrawing intensive care are two important determinants of outcomes following periviable birth. It is much easier to quantify the effect of the former than the latter. Decisions regarding comfort care vs. intensive are frequently based on gestational age as the sole predictor variable, although multiple factors can be readily used to more accurately assess the benefits and burdens of intensive care and facilitate better informed parental counseling and decision making. PMID- 24468564 TI - Initial resuscitation and stabilization of the periviable neonate: the Golden Hour approach. AB - There is a paucity of data to support recommendations for stabilization and resuscitation of the periviable neonate in the delivery room. The importance of delivery at a tertiary center with adequate experience, resuscitation team composition, and training for a periviable birth is reviewed. Evidence for delayed cord clamping, delivery room temperature stabilization, strategies to establish functional residual capacity, and adequate ventilation as well as oxygen use in the delivery room is generally based on expert consensus, physiologic plausibility, as well as data from slightly more mature extremely low gestational-age neonates. Little is known about optimal care in the delivery room of these most fragile infants, and thus the need for research remains critical. PMID- 24468565 TI - Management during the first 72 h of age of the periviable infant: an evidence based review. AB - After NICU admission the extremely immature newborn (EIN) requires evaluation and support of each organ system, and the integration of all those supports in a comprehensive plan of care. In this review, I attempt to analyze the evidence for treatment options after the initial transition, during the first 3 days of life, which have been shown to improve survival or short- or long-term morbidity. This review revealed several things: there is little available evidence from studies that have included significant numbers of EINs; interventions affecting different organ systems need to be co-ordinated as any intervention will have multiple effects; and future advances in treatment of this group of patients will require the installation of permanent research networks to have enough power to perform many studies needed to improve outcomes. PMID- 24468566 TI - Ongoing issues in the intensive care for the periviable infant--nutritional management and prevention of bronchopulmonary dysplasia and nosocomial infections. AB - The focus of this paper is to describe the following: (1) the benefits of implementing feeding guidelines, (2) management practices associated with the prevention of BPD, and (3) management practices associated with prevention of nosocomial infection. PMID- 24468567 TI - End-of-life decisions for extremely low-gestational-age infants: why simple rules for complicated decisions should be avoided. AB - Interventions for extremely preterm infants bring up many ethical questions. Guidelines for intervention in the "periviable" period generally divide infants using predefined categories, such as "futile," "beneficial," and "gray zone" based on completed 7-day periods of gestation; however, such definitions often differ among countries. The ethical justification for using gestational age as the determination of the category boundaries is rarely discussed. Rational criteria used to make decisions regarding life-sustaining interventions must incorporate other important prognostic information. Precise guidelines based on imprecise data are not rational. Gestational age-based guidelines include an implicit judgment of what is deemed to be an unacceptably poor chance of "intact" survival but fail to explore the determination of acceptability. Furthermore, unclear definitions of severe disability, the difficulty, or impossibility, of accurately predicting outcome in the prenatal or immediate postnatal period make such simplistic formulae inappropriate. Similarly, if guidelines for intervention for the newborn are based on the "qualitative futility" of survival, it should be explicitly stated and justified according to established ethical guidelines. They should discuss whether newborn infants are morally different to older individuals or explain why thresholds recommended for intervention are different to recommendations for those in older persons. The aim should be to establish individualized goals of care with families while recognizing uncertainty, rather than acting on labels derived from gestational age categories alone. PMID- 24468569 TI - Teaching antenatal counseling skills to neonatal providers. AB - Counseling a family confronted with the birth of a periviable neonate is one of the most difficult tasks that a neonatologist must perform. The neonatologist's goal is to facilitate an informed, collaborative decision about whether life sustaining therapies are in the best interest of this baby. Neonatologists are trained to provide families with a detailed account of the morbidity and mortality data they believe are necessary to facilitate a truly informed decision. Yet these complicated and intensely emotional conversations require advanced communication and counseling skills that our current fellowship-training strategies are not adequately providing. We review educational models for training neonatology fellows to provide antenatal counseling at the threshold of viability. We believe that training aimed at teaching these skills should be incorporated into the neonatal-perinatal medicine fellowship. The optimal approaches for teaching these skills remain uncertain, and there is a need for continued innovation and outcomes-based research. PMID- 24468568 TI - Communication with parents concerning withholding or withdrawing of life sustaining interventions in neonatology. AB - The nature and content of the conversations between the healthcare team and the parents concerning withholding or withdrawing of life-sustaining interventions for neonates vary greatly. These depend upon the status of the infant; for some neonates, death may be imminent, while other infants may be relatively stable, yet with a potential risk for surviving with severe disability. Healthcare providers also need to communicate with prospective parents before the birth of premature infants or neonates with uncertain outcomes. Many authors recommend that parents of fragile neonates receive detailed information about the potential outcomes of their children and the choices they have provided in an unbiased and empathetic manner. However, the exact manner this is to be achieved in clinical practice remains unclear. Parents and healthcare providers may have different values regarding the provision of life-sustaining interventions. However, parents base their decisions on many factors, not just probabilities. The role of emotions, regret, hope, quality of life, resilience, and relationships is rarely discussed. End-of-life discussions with parents should be individualized and personalized. This article suggests ways to personalize these conversations. The mnemonic "SOBPIE" may help providers have fruitful discussions: (1) What is the Situation? Is the baby imminently dying? Should withholding or withdrawing life sustaining interventions be considered? (2) Opinions and options: personal biases of healthcare professionals and alternatives for patients. (3) Basic human interactions. (4) Parents: their story, their concerns, their needs, and their goals. (5) Information: meeting parental informational needs and providing balanced information. (6) Emotions: relational aspects of decision making which include the following: emotions, social supports, coping with uncertainty, adaptation, and resilience. In this paper, we consider some aspects of this complex process. PMID- 24468570 TI - Peri-viable birth: legal considerations. AB - Peri-viable birth raises an array of complex moral and legal concerns. This article discusses the problem with defining viability, touches on its relationship to abortion jurisprudence, and analyzes a few interesting normative implications of current medical practice at the time of peri-viable birth. PMID- 24468571 TI - Costs and cost-effectiveness of periviable care. AB - With increasing concerns regarding rapidly expanding healthcare costs, cost effectiveness analysis allows assessment of whether marginal gains from new technology are worth the increased costs. Particular methodologic issues related to cost and cost-effectiveness analysis in the area of neonatal and periviable care include how costs are estimated, such as the use of charges and whether long term costs are included; the challenges of measuring utilities; and whether to use a maternal, neonatal, or dual perspective in such analyses. A number of studies over the past three decades have examined the costs and the cost effectiveness of neonatal and periviable care. Broadly, while neonatal care is costly, it is also cost effective as it produces both life-years and quality adjusted life-years (QALYs). However, as the gestational age of the neonate decreases, the costs increase and the cost-effectiveness threshold is harder to achieve. In the periviable range of gestational age (22-24 weeks of gestation), whether the care is cost effective is questionable and is dependent on the perspective. Understanding the methodology and salient issues of cost effectiveness analysis is critical for researchers, editors, and clinicians to accurately interpret results of the growing body of cost-effectiveness studies related to the care of periviable pregnancies and neonates. PMID- 24468572 TI - Clinical outcome of kidney transplantation from deceased donors with acute kidney injury by Acute Kidney Injury Network criteria. AB - PURPOSE: In this study, we investigated the outcome of kidney transplantation (KT) from deceased donors with acute kidney injury (AKI), as defined by the Acute Kidney Injury Network criteria. METHODS: Of 156 deceased donors, kidneys from 43 donors (27.6%) with AKI were transplanted into 57 recipients (AKI group). Another 147 recipients received kidneys from donors without AKI (non-AKI group). We compared the incidence of delayed graft function, allograft function for 1 year after KT, and long-term (5 and 10 years) graft survival rate between the 2 groups. RESULTS: Delayed graft function developed more frequently in the AKI group than in the non-AKI group (42.1% vs 12.2%; P<.05), and allograft function assessed by the modification of diet in renal disease equation-showed a significantly deteriorating pattern at 2 weeks and 1, 3, and 6 months after KT compared with that in the non-AKI group (P<.05 for comparisons at each time point). However, allograft function at 12 months after KT and the long-term allograft and patient survival rates did not differ between the AKI and non-AKI groups. CONCLUSIONS: In KT from deceased donors, the AKI group that received kidneys with AKI, as defined by the Acute Kidney Injury Network criteria, showed a higher delayed graft function rate and lower allograft function for 6 months after KT but no effect on allograft function 1 year after KT and on long-term allograft survival. PMID- 24468573 TI - Bone marrow cell therapy in cardiovascular disease drives us slowly to a better identification of the active cell component. AB - Endothelial progenitor cell therapy and stem cell therapy have been proposed in regeneration of acute myocardial infarction (AMI). In the previous issue of Stem Cell Research & Therapy, Lamirault and colleagues described a strong analysis of progenitors in blood and bone marrow of patients collected after AMI, and correlated these levels to bone marrow mononuclear cell (BM-MNC) therapy efficacy and smoking status. The main results are that BM-MNCs can override smoking alteration in endothelial lineage and confirm that endothelial progenitor cells are probably not by themselves the active component of BM-MNC in AMI. This paper allows one to better appreciate the cellular complexity of cell therapy approach in AMI. PMID- 24468574 TI - Maternal exposure to bisphenol A may increase the risks of Parkinson's disease through down-regulation of fetal IGF-1 expression. AB - So far, the pathogenesis of Parkinson's disease (PD) remains unclear. Current studies implicate environmental toxins may be potential causes of fetal origin of PD. BPA is a member of the family of estrogenic chemicals existing widely in environment. Significant evidences from animal experimentation have demonstrated that BPA interfere with fetal neurodevelopment. Based on previous reports and our research on EB derived from hESCs, we speculate that maternal exposure to low dose BPA during gestational period may decrease IGF-1 expression, thus hinder the development of fetal DA neurons, and finally increase the risks of fetal origin of PD. Our hypothesis may shed new light on the pathogenesis of PD and lead to potential preventive treatments. PMID- 24468575 TI - The role of thyroid hormone in sleep deprivation. AB - Sleep deprivation is a stressful condition, as the subject experiences feelings of inadequate well-being and exhibits impairments in his/her functioning. However, in some circumstances sleep deprivation may be crucial for survival of the individual. Most likely, complex neural circuits and hormones play a role in allowing sleep deprivation to occur. For instance, thyroid hormone activity sharply increases when an individual is in a state of sleep deprivation. We believe that this increase is central to sleep deprivation physiology. During sleep deprivation, the hypothalamic-pituitary-thyroid axis initially increases as a consequence of increased release of thyroid stimulating hormone from the pituitary. Subsequently, as sleep deprivation continues, the sympathetic nervous system is recruited through its anatomical connection with the thyroid gland. While thyroid stimulating hormone levels markedly increase during sleep deprivation, it has been suggested that these increases are secondary to sleep deprivation. However, there is little evidence to support this assumption. We believe that the physiology of the thyroid axis during sleep deprivation and the actions of the effector hormone thyroid hormone suggest that thyroid hormone inhibits sleep and not the contrary. To our knowledge, few studies have addressed the possible neural functions that enable sleep deprivation. In this article, we discuss the hypothesis that an augmentation in the thyroid hormone axis is central to a subject's ability to curtail sleep. PMID- 24468576 TI - Chronotherapeutics: an alternative treatment of juvenile depression. AB - Chronotherapeutic treatments, such as bright light therapy, sleep deprivation and sleep phase advance have successfully been established for the treatment of adults with seasonal and major depression. Today, sleep deprivation is supposed to be the fastest acting antidepressant we know of. Combined with bright light therapy, the antidepressive effect can be sustained. Notwithstanding, the effect of sleep deprivation and bright light therapy has not yet been studied in adolescents suffering from juvenile depression. However, because of its growing prevalence rates and the insufficient outcomes of established treatments, such as medication and psychotherapy, alternative treatments of juvenile depression are urgently needed. Furthermore, a high percentage of patients suffer from sleep disorders. Along with their large positive impact on sleep patterns and antidepressive effects, chronotherapeutics are thought to be powerful interventions for patients with juvenile depression. The present study investigates the additional benefit of sleep deprivation combined with bright light therapy, as compared to mere bright light therapy. We hypothesize that both therapies have a positive impact on depressive symptoms and sleep parameters, but that a combined therapy enhances and sustains outcomes. PMID- 24468577 TI - Relationships between sleep and addiction: the role of drug-environment conditioning. AB - Addiction to cocaine and other amphetamine-like psychostimulants is a chronic relapsing disorder characterized by loss of control over drug taking. Sleep disturbance is common among patients in recovery from drug abuse and can precipitate relapse. It has been widely demonstrated that sleep deprivation and psychostimulants share similar neurobiological effects regarding the dopaminergic system. In addition, the persistence of a drug-environment conditioning induced by repeated psychostimulant treatment, which is deeply related to the dopaminergic neurotransmission, is thought to play a key role in the addictive cycle. In this scenario, we hypothesized that sleep deprivation is a potential detrimental factor to the extinction process of previously established drug environment conditioning. Therefore, sleep deprivation would extend the pairing between the cocaine reinforcing effects and the environmental cues, thereby leading drug abusers to relapse. PMID- 24468578 TI - The Association of Free Testosterone Levels in Men and Lifestyle Factors and Chronic Disease Status: A North Texas Healthy Heart Study. AB - PURPOSE: Hypogonadism is highly prevalent in men older than 45 years and is associated with an increased risk of chronic diseases, including obesity, metabolic syndrome, diabetes, and cardiovascular disease. The objective of this study was to determine whether lifestyle factors such as smoking, diet, and exercise are associated with reduced testosterone levels. METHODS: In this cross sectional study, 147 men older than 44 years were recruited from a collaborative network of primary care clinics in the Dallas/Fort Worth, Texas, metropolitan area. Free testosterone levels were measured in plasma samples via an enzyme linked immunosorbent assay-based method, and analyzed by simple and multiple linear regression in relationship to age, race/ethnicity, smoking, diet, exercise, obesity, diabetes, hypertension, and dyslipidemia. RESULTS: The participants had a mean free testosterone level of 3.1 ng/mL (standard deviation [SD] = 1.5) and mean age of 56.8 years (SD = 7.9). In simple regression analysis, free testosterone levels were associated with increased age (beta = -0.04; P = .02), diet (beta = -0.49; P = .05), diabetes (beta = -0.9; P = .003), and hypertension (beta = -0.55; P = .03) but not with race/ethnicity, smoking, exercise, obesity, or dyslipidemia. In multiple regression analysis, free testosterone values were significantly associated only with age (beta = -0.05; P = .01) and diet (beta = -0.72; P = .01). CONCLUSIONS: This study implicates diet, in addition to advanced age as a possible risk factor in the development of reduced testosterone levels. PMID- 24468579 TI - Health Centers in States With Public Health Agency Support Do Not Have Better Chronic Disease Outcomes. AB - OBJECTIVES: To examine the quality of chronic disease care at federally qualified health centers (FQHCs) as a function of state health agency support. METHODS: We merged data from the 2010 Association of State and Territorial Health Officials Public Health Survey, the 2011 Area Resource File, and the 2010 Uniform Data System. Using ordinary least squares regression, we modeled hypertension and diabetes control among FQHC patients as a function of state public health agency support of FQHCs, including financial support, direct collaboration, and electronic health data exchanges. RESULTS: The rate of hypertension control is 63.4%, while the rate of diabetes control (HbA1c <7%) is 41.3%. Some two thirds of FQHCs (67.1%) are in states whose public health agencies are fully engaged in FQHC-supporting activities, and approximately one third (34.6%) are in states whose public health agencies send and receive electronic health record data with FQHCs. However, none of our measures of public health agency support of FQHCs significantly predicted FQHC-specific chronic disease outcomes. CONCLUSIONS: We find no evidence that state public health agency support of FQHCs affects chronic disease outcomes for FQHC patients. PMID- 24468580 TI - Erectile dysfunction. PMID- 24468581 TI - Biointerface control of electrospun fiber scaffolds for bone regeneration: engineered protein link to mineralized surface. AB - Control over the interface of biomaterials that favors the initial adhesion and subsequent differentiation of stem cells is one of the key strategies in bone tissue engineering. Here we engineer the interface of biopolymer electrospun fiber matrices with a fusion protein of fibronectin 9-10 domain (FNIII9-10) and osteocalcin (OCN), aiming to stimulate mesenchymal stem cell (MSC) functions, including initial adhesion, growth and osteogenic differentiation. In particular, a specific tethering of FNIII9-10-OCN protein was facilitated by the hydroxyapatite (HA) mineralization of the biopolymer surface through a molecular recognition of OCN to the HA crystal lattice. The FNIII9-10-OCN anchorage to the HA-mineralized fiber was observed to be highly specific and tightly bound to preserve stability over a long period. Initial cell adhesion levels, as well as the spreading shape and process, of MSCs within 24h were strikingly different between the fibers linked with and without fusion protein. Significant up regulations in the mRNA expression of adhesion signaling molecules occurred with the fusion protein link, as analyzed by the reverse transcriptase polymerase chain reaction. The expression of a series of osteogenic-related genes at later stages, over 2-3weeks, was significantly improved in the fusion protein-tailored fiber, and the osteogenic protein levels were highly stimulated, as confirmed by immunofluorescence imaging and fluorescence-activated cell sorting analyses. In vivo study in a rat calvarium model confirmed a higher quantity of new bone formation in the fiber linked with fusion protein, and a further increase was noticed when the MSCs were tissue-engineered with the fusion protein-linked fiber. Collectively, these results indicate that FN-OCN fusion protein links via HA mineralization is a facile tool to generate a biointerface with cell attractive and osteogenic potential, and that the engineered fibrous matrix is a potential bone regenerative scaffold. PMID- 24468582 TI - Curcumin-releasing mechanically adaptive intracortical implants improve the proximal neuronal density and blood-brain barrier stability. AB - The cellular and molecular mechanisms by which neuroinflammatory pathways respond to and propagate the reactive tissue response to intracortical microelectrodes remain active areas of research. We previously demonstrated that both the mechanical mismatch between rigid implants and the much softer brain tissue, as well as oxidative stress, contribute to the neurodegenerative reactive tissue response to intracortical implants. In this study, we utilize physiologically responsive, mechanically adaptive polymer implants based on poly(vinyl alcohol) (PVA), with the capability to also locally administer the antioxidant curcumin. The goal of this study is to investigate if the combination of two independently effective mechanisms - softening of the implant and antioxidant release - leads to synergistic effects in vivo. Over the first 4weeks of the implantation, curcumin-releasing, mechanically adaptive implants were associated with higher neuron survival and a more stable blood-brain barrier at the implant-tissue interface than the neat PVA controls. 12weeks post-implantation, the benefits of the curcumin release were lost, and both sets of compliant materials (with and without curcumin) had no statistically significant differences in neuronal density distribution profiles. Overall, however, the curcumin-releasing softening polymer implants cause minimal implant-mediated neuroinflammation, and embody the new concept of localized drug delivery from mechanically adaptive intracortical implants. PMID- 24468583 TI - Enhanced trophic factor secretion by mesenchymal stem/stromal cells with Glycine Histidine-Lysine (GHK)-modified alginate hydrogels. AB - Recombinant proteins and cytokines are under broad preclinical and clinical investigation to promote angiogenesis, but their success is limited by ineffective delivery, lack of long-term stability and excessive cost. Mesenchymal stem/stromal cells (MSC) secrete bioactive trophic factors, and thus, may provide an effective alternative to address these challenges. Glycine-Histidine-Lysine (GHK) is a peptide fragment of osteonectin, a matricellular protein with reported proangiogenic potential. We examined the capacity of GHK to up-regulate secretion of proangiogenic factors from human MSC in culture and when covalently coupled to alginate hydrogels. GHK had no apparent cytotoxic effects on MSC in culture over a wide range of concentrations. We detected a dose-dependent increase in vascular endothelial growth factor (VEGF) concentration in media conditioned by GHK treated MSC, which increased endothelial cell proliferation, migration and tubule formation. We covalently coupled GHK to alginate using carbodiimide chemistry, and human MSC were entrapped in alginate hydrogels to assess VEGF secretion. Similar to monolayer culture, MSC responded to GHK-modified gels by secreting increased concentrations of VEGF and basic fibroblast growth factor compared to unmodified gels. The pre-treatment of MSC with antibodies to alpha6 and beta1 integrins prior to entrapment in GHK-modified gels abrogated VEGF secretion, suggesting that the proangiogenic response of MSC was integrin-mediated. These data demonstrate that the proangiogenic potential of MSC can be significantly increased by the presentation of GHK with a biodegradable carrier, therefore increasing their clinical potential when used for tissue repair. PMID- 24468584 TI - Impact of genetic polymorphisms on the pathogenesis of idiopathic achalasia: Association with IL33 gene variant. AB - AIM: To investigate the association of single nucleotide polymorphisms (SNPs) of genes involved in the regulation of immune responses, IL33, IL1RL1, IL23R, and IL10, with idiopathic achalasia in an Italian cohort of patients. MATERIALS AND METHODS: A panel of eleven polymorphisms were genotyped in 116 unrelated idiopathic achalasic patients and 371 healthy subjects, by using TaqMan genotyping assays. RESULTS: Significant differences of allele (P=0.0065, OR=1.59, CI=1.14-2.22) and genotype (P=0.0097, OR=1.74, CI=1.14-2.65) frequencies of the IL33 rs3939286 variant were found between achalasic patients and controls. No association of the other investigated SNPs was detected. No differences in genotype and allele distribution were found with respect to clinical characteristics of patients. CONCLUSION: We provide for the first time an association between the risk of developing idiopathic achalasia and IL-33 variant, underling the role of cytokines and inflammatory mediators on the pathogenesis of the disease. PMID- 24468585 TI - MiR-20b, -21, and -130b inhibit PTEN expression resulting in B7-H1 over expression in advanced colorectal cancer. AB - Co-inhibitor B7-H1 expresses in various cancers and contributes to cancer immune evasion by inhibiting T cell activation and proliferation, yet the regulatory mechanisms for B7-H1 over-expression in cancers remain largely unknown. Here, the expression of B7-H1 and PTEN proteins were firstly detected by using immunohistochemistry method. B7-H1 immunoreactivities were found in 54.5% (55/101) of the colorectal cancer tissues with no expression in the normal tissues, and the PTEN protein immunoreactivities were observed in 51.5% (52/101) of the colorectal cancer tissues and 72.3% (73/101) of the normal tissues. Statistical analysis results indicated that the B7-H1 expression was negatively correlated to the PTEN expression in colorectal cancer (p=0.001). Then the expressions of microRNAs (miRNAs) in six pairs of colorectal cancer and normal tissues were determined by miRNA array, and 30 up-regulated miRNAs were found in the colorectal cancer tissues. Finally, the impact of these up-regulated miRNAs on PTEN expression was tested by using dual-luciferase reporter assay system, from which the results indicated that miR-20b, -21, and -130b were involved in suppression of PTEN expression. These findings suggest that miR-20b, -21, and 130b, up-regulated in colorectal cancer, through inhibiting the expression of PTEN, result in B7-H1 over-expression in colorectal cancer. PMID- 24468586 TI - IgG antibodies against immunodominant C-terminal epitopes of BP230 do not induce skin blistering in mice. AB - Bullous pemphigoid, the most common autoimmune blistering disease in Western Europe and the USA is characterized by the presence of circulating and tissue bound autoantibodies against the hemidesmosomal proteins BP230 and BP180/collagen XVII. After binding to their target antigens at the basement membrane of the dermal-epidermal junction these autoantibodies are thought to trigger an inflammatory cascade comprising complement- and granulocyte-dependent reactions that result in tissue damage. Whereas the role of anti-BP180 antibodies has been extensively characterized, few and conflicting data is available on the contribution of anti-BP230 antibodies to bullous pemphigoid pathogenesis. Therefore, we addressed in the present study the role of autoantibodies to BP230 in experimental bullous pemphigoid. Rabbit polyclonal antibodies generated against epitopes of the C-terminal fragment of murine BP230 bound to the basement membrane and activated the complement system ex vivo. Affinity-purified antibodies were subsequently subcutaneously transferred into neonatal and adult BALB/c mice. In vivo, we observed a dose-dependent binding of transferred antibodies in the murine skin; however, there was no complement activation and these mice showed no clinical or histological signs of inflammatory disease, in contrast to mice receiving anti-BP180 antibodies. We further conducted ex vivo experiments and demonstrated that rabbit IgG anti-BP230-specific antibodies, in contrast to antibodies from bullous pemphigoid patients or rabbit IgG anti-BP180 antibodies used as positive controls, did not activate human granulocytes to induce dermal-epidermal separation in skin cryosections. Our present findings demonstrate that antibodies against BP230 are non-pathogenic in experimental models of bullous pemphigoid and suggest that proper activation of the complement and granulocytes represent prerequisites for conferring bullous pemphigoid autoantibodies their tissue destructive potential. PMID- 24468587 TI - Evaluation of factors associated with the nutritional mixture leading to liver complications in patients treated by means of parenteral nutrition at home. AB - The major problem of total parenteral treatment consists in the balancing of the source and dose of the nutritional mixture, so as to not deepen malnutrition with a positive impact on the patients' organism. The aim of the study was to evaluate selected factors that induce hepato-biliary complications in patients treated by means of parenteral nutrition at home. MATERIAL AND METHODS: The retrospective study comprised 70 patients with biochemistry performed every three months. Considering statistical analysis patients were allocated to four groups, depending on the period of treatment. Group A analysis results were based on the activity of aminotransferases, group B on the activity of bilirubin. Both groups A and B were additionally divided into group I where we assigned normal values of control lab results, and group II with improper results after treatment. RESULTS: Differences between groups Ia vs IIa were presented on the basis of the daily supply of glucose: mean- 2.52 vs 3.49 g/kg (p=0.000003), glucose/lipids ratio: mean- 3.76 vs 4.90 g/kg (p=0.0001), daily non-protein energy: mean- 16.73 vs 21.06 kcal/kg (p=0.0001). Differences between groups Ib vs IIb were presented on the basis of the daily supply of glucose: mean- 2.76 vs 3.46 g/kg (p=0.0007), glucose/lipids ratio: mean- 3.98 vs 5.13 g/kg (p=0.01), daily non-protein energy: mean-17.96 vs 20.36 kcal/kg (p=0.04). Based on the above-mentioned analysis the main goal in the prevention of hepatic complications should lead to the reduction of the dose of glucose. Increased glucose supply leads to increased number of hepato-biliary complications. CONCLUSIONS: Based on obtained results we were able to conclude that in case of liver complications associated with parenteral nutrition, proper management consists in the modification of nutritional mixtures (reduction in the daily glucose supply and change in the proportions of extra protein energy). Such management has the greatest clinical effect. When determining the composition of the nutritional mixture one should adjust the glucose supply, so as to offset both sources of extra-protein energy. PMID- 24468588 TI - The evaluation of the effectiveness of Tachosil in the treatment of lymphorrhea of the postoperative wound in the selected group of patients, after vascular reconstructive surgeries--preliminary report. AB - Lymphorrhea of a postoperative wound after vascular reconstructive surgeries does not occur frequently but it accounts for a major complication. It should be brought to attention that during the intraoperative period it is impossible to diagnose any damages within the lymphatic system of the operated area. Additionally, the treatment of lymphorrhea with thermal abrasion does not usually bring the desired outcome. Therefore, the extended time of the postoperative wound treatment with the lymphatic drainage constitutes a standard method in such cases. The aim of the study was to evaluate the effectiveness of Tachosil surgical patch in the treatment of lymphorrhea of the postoperative wound in a selected group of patients who have undergone vascular reconstructive surgeries. Additionally, the aim of the study was to analyze the results and draw conclusions pertaining to the validity and effectiveness of the treatment with the use of Tachosil surgical patch. MATERIAL AND METHODS: The observed group included 10 patients with lymphorrhea developed during the postoperative period. 6 of the observed patients have undergone the vascular reconstructive surgery with the implantation of the vascular prosthesis (distal femoropopliteal reconstruction bridge - 3 patients; iliofemoral reconstruction bridge - 1 patient; angioplasty of the common femoral artery (CFA) with the use of the prosthetic patch - 1 patient; the implantation of the bifurcated (type Y) aortofemoral prosthesis - 1 patient). The remaining patients in the observed group have undergone the restoration of patency of the CFA. Additionally, 1 patient has undergone the resection of the pseudo aneurysm in the distal part of the iliofemoral prosthesis. The vascular reconstructive surgery required the denudation and isolation of the common femoral artery from the surrounding tissue as a step 1. The persisting lymphorrhea of the postoperative wound, in the volume of more than 200 ml per day during the first 3 postoperative days, indicated the necessity for the inguinal wound revision. In addition, Tachosil surgical patch was applied at that time. The drain was placed over Tachosil patch. RESULTS: Complete stop of lymphorrhea was shorter by 4.87 days in patients treated with the use of Tachosil in comparison to control group. These patients also had an average hospitalization time shorter by 3.88 days than patients in the control group. CONCLUSIONS: Early intervention in the cases of lymphorrhea of the postoperative wound allows planning and conducting successful treatment. The use of Tachosil surgical patch in the treatment of lymphorrhea of the postoperative wound shortens the treatment and hospitalization periods. The use of Tachosil in the treatment of postoperative lymphorrhea appeared to be significantly more effective than the standard drainage method of treatment. Results obtained through this study pave the way for the research on other possible applications of Tachosil in the cases of lymphorrhea after vascular reconstructive surgeries. PMID- 24468589 TI - Assessment of the accuracy of preoperative imaging methods in the diagnosis of hepatic single-chamber echinococcosis. AB - Echinococcosis is an infectious disease, caused by larval stages of cestode species of the genus Echinococcus. The course of the disease is determined on the basis of the location and larval size. In 80-95% of cases echinococcosis is located in the liver and lungs, rarely in the brain. Symptoms are usually uncharacteristic for an uncomplicated disease. The diagnosis of echinococcosis is based on imaging and immunodiagnostic tests. The aim of the study was to assess the accuracy of preoperative imaging methods in the diagnosis of hepatic single- chamber echinococcosis. MATERIAL AND METHODS: Amongst the 110 patients with hepatic cysts diagnosed during the period between 2000 and 2009, a group of 30 subjects with suspicion of single-chamber echinococcosis (ultrasound and CT) was isolated. The imaging methods visualized structures typical for hydatid cysts: the mother cyst with satellite cysts called " honeycomb appearance", cysts with calcified walls and compartments, and endocyst separation called "water lily sign". The study group comprised 22 female and 8 male patients with an average age of 52+/-16.2 years. The histopathological examination of the excised cyst verified the diagnosis. RESULTS: Single-chamber echinococcosis was finally recognized in 19 cases, while in the 11 remaining cases the parasitic disease was excluded. The sensitivity of imaging methods was estimated at 73.7%, specificity 88.9%, negative predictive value - 61.5%, positive predictive value - 93.3%, Youden's factor - 0.626, and Phi index - 0.586. CONCLUSIONS: In conclusion, the presence of an unilocular cyst with an uniform anechoic content can be a simple cyst or single-chamber echinococcus cyst. The typical, characteristic image of a hydatid cyst, such as the "water lily-sign" is rarely observed during imaging examinations. It has also been shown that cystic calcification, observed during ultrasonography and computed tomography was evidence of the parasitic character of the lesion. PMID- 24468590 TI - Analysis of the reliability of clinical examination in predicting traumatic cerebral lesions and skull fractures in patients with mild and moderate head trauma. AB - The aim of the study was to assess the reliability of neurological examination and other factors in predicting traumatic cerebral lesions and skull fractures in patients with mild and moderate head trauma (GCS 10-15). MATERIAL AND METHODS: Over a one-year period, 227 patients: 145 male and 82 female, aged a mean of 51 years who sustained mild or moderate head trauma (GSC 10-15) were examined neurologically and had performed head CT scans. The neurological examination as a whole and each finding of the neurological examination were tested as predictors of the presence of traumatic abnormalities in the head CT scan. RESULTS: Post traumatic lesions in head CT scan were found in 109 patients (48%): skull fractures in 66 of these and brain injuries in 94; fifty-eight patients had skull fracture combined with brain injury. Seventeen patients required neurosurgical intervention (hematoma evacuation). Abnormal neurological examination showed the highest reliability in identifying patients with brain injuries in CT (sensitivity 87%, specificity 79%). Of single findings, gait abnormalities and consciousness disturbances, present in sober patients, were the strongest predictors of cerebral lesions. Likewise, abnormal neurological examination was the best indicator of skull fractures (sensitivity 77%, specificity 63%). Gait abnormalities and "raccoon eyes" present in alcohol intoxicated patients were the strongest individual predictors of skull fractures. CONCLUSION: Results of our study show neurological abnormalities as the most reliable (although not 100% accurate) in identifying patients who are likely to have brain injuries and/or skull fracture following head trauma. Use of clinical decision rules may reduce the number of head CT scans performed "just in case". PMID- 24468591 TI - Retroperitoneoscopic and laparoscopic removal of periadrenally located bronchogenic cysts--a systematic review. AB - Retroperitoneal bronchogenic cysts (BC) are rare clinical entities and may mimic an adrenal mass. Laparoscopic and retroperitoneoscopic approach is widely-used in adrenal surgery. However minimally-invasive resection of a periadrenally located BC has been reported rarely. MATERIAL AND METHODS: A systematic review of PubMed has been performed using the following search strategy: bronchogenic cyst AND (adrenal OR retroperitoneal OR subdiaphragmatic). 18 BC being removed via minimally invasive approach have been found. Including our own case 7 were removed retroperitoneoscopically and 12 laparoscopically. RESULTS: An index case of a 50 year old male is presented. CT revealed 2 masses above the left adrenal area. A control demonstrated an increase in size. Retroperitoneoscopic resection was performed. Pathologic finding showed a multilocular cystic lesion with a diameter of 4cm. The cysts were lined by pseudostratified ciliated epithelium. The wall contained hyaline cartilage, seromucous glands and smooth muscle. CONCLUSIONS: Because exact preoperative diagnosis of hormonally inactive adrenal masses is not possible surgical resection is recommended in case of tumor growth, symptoms and to obtain definitive histological diagnosis. Minimal invasive approach seems to be a safe way for resection of BC in experienced hands. There is no clear evidence if laparoscopic or retroperitoneoscopic approach is favourable. PMID- 24468593 TI - Unsuccessful replantation of metacarpal hand after venous thrombosis--case report. AB - Trans-metacarpal hand replantation is one of the most complex and difficult procedures in the reconstructive microsurgery. As far as we know the arrangement of the palmar arterial network, the problem lies in the absence of accurate venous maps at the dorsum of the hand. The quality of venous circulation structure at the replanted hand determine the success of the surgery. In this paper we present a case of a failed replantation of a metacarpal hand after early thrombosis at the venous microcirculation system. PMID- 24468592 TI - Evaluation of immature monocyte-derived dendritic cells generated from patients with colorectal cancer. AB - Dendritic cells are heterogeneous population of the leukocytes and most potent APC in activation of naive T lymphocytes. Therefore the DCs generated in vitro are under research for their application in anti-tumor immunotherapy. The aim of the study was generation of the immature dendritic cells from peripheral blood monocytes collected from colorectal cancer patients and comparison of their ability to endocytosis, cytokine production and immunophenotype to DCs generated from healthy donors. MATERIAL AND METHODS: 16 adenocarcinoma stage II patients were included in the study. Dendritic cells were generated in the presence of rhGM-CSF and IL-4. PBMC were isolated from the blood of patients and 16 healthy donors - control group. Immunophenotype, ability of endocytosis of Dextran- FITC as well as intracellular IL-12 expression of the generated dendritic cells was measured using flow cytometry. The cytokines (IL-6, IL-10, IL-12p70, IFN-gamma) concentration in the supernatants of DCs culture was measured by ELISA. RESULTS: The percentage of the immature dendritic cells and expression of CD206 and CD209 antigens was significantly higher in patients group (p <0.05 and p <0.001 respectively). Significantly (p <0.001) higher expression of the antigens which initiate the Th2 immune response (CD80-/CD86 + and B7-H2 + / CD209 +) was in the patients group. There were no differences in endocytosis ability and the cytokines (IL-6, IL-10, IL-12p70, IFN-gamma) concentration between investigated groups. CONCLUSIONS: High immature markers expression on the generated dendritic cells together with identical endocytosis ability in patients group is advantageous in antitumor autologous cells immunotherapy planning. However there is one troubling fact--high expression of markers, which may induce tolerance to particular antigen. It seems to be more reasonable to use the autologous DCs in the antitumor immunotherapy, especially due to the incompatibility in allogenic cells in the context of HLA complex. PMID- 24468594 TI - Spontaneous, idiopathic urinary bladder perforation--case report. AB - Spontaneous, idiopathic urinary bladder rupture is a very rare disease entity, which may face the problem of proper preoperative diagnosis. In many cases the medical history, physical examination, and additional tests raise false suspicion of gastrointestinal perforation. The study presented a case of a female patient with spontaneous urinary bladder perforation, paying particular attention to the diagnostic difficulties associated with the above-mentioned pathology. The aim of the study was to analyse the presence of symptoms and imaging and laboratory results observed in case of spontaneous urinary bladder rupture, as well as differentiate the above-mentioned pathology with gastrointestinal perforation. Whenever diagnosing a patient with acute peritonitis symptoms, in whom the predominating symptoms include sudden abdominal pain, peritoneal cavity fluid presence, hematuria, oliguria, and coexisting increased urea, creatinine, and potassium levels, one should consider the possibility of urinary bladder rupture. PMID- 24468595 TI - Stenosis after sleeve gastrectomy--cause, diagnosis and management strategy. PMID- 24468596 TI - Fat grafts in the reconstruction and treatment of chronic wounds. PMID- 24468597 TI - Women's knowledge and attitude towards pregnancy in a high-income developing country. AB - OBJECTIVE: The aim of this study was to determine the knowledge and attitudes among women in a high-income developing country regarding pregnancy and antenatal care. METHODS: Women who participated in the study were asked to complete a questionnaire. The questionnaire enquired about age, level of education, Internet use, marital status, and employment. It also included questions regarding their knowledge of ultrasound, the effects of sexual activity and other exercise during pregnancy, breast feeding, and premature delivery. The collected data were subjected to statistical analysis using SPSS. RESULTS: The total number of women included in this study was 205. A total of 115 women (56.1%) thought that the most important benefit of ultrasound was to discover fetal abnormalities. Only 75 (36.6%) thought that regular exercise was not harmful during pregnancy. Of the total respondents 116 (56.6%) of 205 thought that sex during pregnancy was harmful to the fetus or did not know. Age (P=0.001), marital status (P=0.001) and working status (P=0.005) were found to significantly affect their knowledge. CONCLUSION: Knowledge about pregnancy among Emirati women is low. There is a need for effective prenatal classes that focus on educating women about issues related to pregnancy and antenatal care. PMID- 24468598 TI - Global education in perinatal medicine: will the bureaucracy or smartocracy prevail? PMID- 24468599 TI - Intestinal invagination in diabetic ketoacidosis: case report. PMID- 24468600 TI - Investigation of adropin and leptin levels in pediatric obesity-related nonalcoholic fatty liver disease. AB - AIM: Nonalcoholic fatty liver disease (NAFLD) is the accumulation of excess fat in the liver in the absence of alcohol consumption, which is commonly associated with obesity and increased risk of atherosclerosis as well as insulin resistance. Adropin is a recently identified protein encoded by the gene related with energy homeostasis, which is expressed in the liver and the brain and has a role in preventing insulin resistance and obesity. The aim of this study was to investigate the serum adropin and leptin levels in obese adolescents and compare the patients with, and without, NAFLD and with healthy controls. METHODS: Sixty four obese adolescents (30 with NAFLD, 34 without NAFLD) and 36 healthy controls were enrolled in the study. Serum adropin and leptin levels were evaluated by sandwich enzyme-linked immunosorbent assay. RESULTS: Serum adropin levels were significantly lower in obese children than healthy controls (3.2+/-1.0 and 9.2+/ 1.2 ng/mL, respectively, p=0.001). Serum leptin levels were significantly higher in patients than in controls (12.4+/-1.1 and 4.1+/-3.1 pg/mL, respectively; p=0.000). Serum adropin levels of patients with NAFLD were significantly lower than in patients without NAFLD (2.9+/-0.5 and 3.5+/-1.2 ng/mL, respectively; p=0.023) and healthy controls (p=0.000). Logistic regression analysis showed that a decrease in adropin levels was the only independent factor for fatty liver disease in obese adolescents (odds ratio: 3.07, 95% confidence interval 1.14-8.2, p=0.026). Leptin, relative weight and HOMA-IR of the patients were not independent risk factors for NAFLD. CONCLUSIONS: In this study, serum adropin levels were significantly lower in obese adolescents with fatty liver disease compared to patients without fatty liver disease and healthy controls. Lower adropin level was an independent risk factor for NAFLD in obese adolescents in logistic regression analysis. Assessment of serum adropin concentrations may provide a reliable indicator of fatty liver disease in obese adolescents. PMID- 24468601 TI - Psychological impact on parents of children with congenital adrenal hyperplasia: a study from Sri Lanka. AB - INTRODUCTION: Congenital adrenal hyperplasia (CAH) is a group of autosomal recessively inherited disorders with significant morbidity. The long-term implications result in immense psychological stress to the parents. This study assessing the psychological impact on the parents is a first in Sri Lanka and one of the few worldwide. OBJECTIVE: Document the presence of depressive symptoms in parents of children with CAH. DESIGN: Study participants were 37 parents of children diagnosed with CAH who were attending an endocrinology clinic of the largest children's hospital in Sri Lanka. Centre for Epidemiological Studies Depression scale (CES-D), a psychometrically sound scale for assessing depressive symptomatology, was used. RESULTS: The study classified 59% of the parents as being affected, and the psychological impact on them did not reduce with time. CONCLUSION: Parents of children with CAH demonstrated symptoms of depression that did not abate with the passage of time. PMID- 24468602 TI - The effect of earlier puberty on cardiometabolic risk factors in Afro-Caribbean children. AB - An earlier onset of puberty is associated with increased cardiometabolic risk. We investigated whether this relation was independent of faster childhood growth or current size in an Afro-Caribbean birth cohort (n=259). Anthropometry was measured at birth and then 6-monthly. Tanner staging started at age 8 years. Cardiometabolic risk factors were measured at mean age 11.5 years. In boys, pubarchal stage and testicular size were associated with lower high-density lipoprotein cholesterol, higher systolic blood pressure, and higher homeostasis model assessment of insulin resistance score, but not after adjusting for current body mass index (BMI) or rate of growth (up to age 8 years). In girls, earlier menarche and greater breast development were associated with higher fasting glucose even after adjusting for current BMI or prior growth. Pubarchal stage was associated with systolic blood pressure, even after adjusting for current BMI and prior growth. We concluded that earlier puberty is independently associated with cardiometabolic risk in girls but not in boys. PMID- 24468603 TI - The heterogeneity of hyperinsulinaemic hypoglycaemia in 19 patients with Beckwith Wiedemann syndrome due to KvDMR1 hypomethylation. AB - Beckwith-Wiedemann syndrome (BWS) is an overgrowth syndrome caused by multiple epigenetic and genetic changes affecting imprinted genes on chromosome 11p15.5. Hypomethylation of KvDMR1 on the maternal allele is the most common genetic cause, and hyperinsulinaemic hypoglycaemia (HH) is the most common biochemical abnormality. We evaluated the correlation between severity of HH and degree of hypomethylation in BWS. Out of the 19 patients with BWS due to KvDMR1 hypomethylation, 10 patients had no HH, 5 had mild transient HH that resolved spontaneously, and 4 required diazoxide therapy for up to 6 months. There was no correlation between the degree of KvDMR1 hypomethylation and severity of HH in the 6 patients studied. All patients also showed marked clinical heterogeneity with respect to the features of BWS. In patients with BWS due to hypomethylation of KvDMR1, the clinical presentation of HH is quite heterogeneous with no correlation with the degree of KvDMR1 hypomethylation. PMID- 24468604 TI - Endocrinological anomalies in a patient with 12q14 microdeletion syndrome. Completing phenotype of this exceptional short stature condition. AB - 12q14 microdeletion syndrome consists of the association of short stature, mental retardation, and osteopoikilosis. Since its first description in 2007, there have been <20 cases reported and each case presented variable phenotypes. We present a girl with 12q14 microdeletion that showed mental retardation and short stature but without osteopoikilosis. She also exhibited precocious puberty and growth hormone deficiency and required treatment for improving final height. This report adds further to the knowledge of the endocrinological anomalies in 12q14 microdeletion syndrome. It is important to perform growth hormone level measurements and pubertal signs to follow-up with these patients and avoid the consequential adult height worsening. PMID- 24468605 TI - Effect of ethosuximide on cortisol metabolism in the treatment of congenital adrenal hyperplasia. AB - BACKGROUND: Antiepileptics may affect cortisol metabolism through CYP3A4. There is little known about ethosuximide. CLINICAL CASE: Our patient is a 12-year-old girl with salt-wasting congenital adrenal hyperplasia (CAH) owing to 21 hydroxylase deficiency. A standard treatment regimen was initiated with satisfactory results until the age of 6 years, when she developed absence seizures treated with ethosuximide. She received such therapy until the age of 12 years, at which point ethosuximide was discontinued. During ethosuximide administration, she experienced worsening control of CAH disease activity that responded to progressive increases in hydrocortisone dose up to 28 mg/m2 per day. Despite high doses of hydrocortisone, she suffered no cushingoid symptoms. Her requirements for high glucocorticoid replacement doses resolved shortly after ethosuximide was discontinued. We provide data over 6 years demonstrating a correlation between adrenal hormone secretion, cortisol requirements and ethosuximide dose. CONCLUSION: This is the first case demonstrating an interaction between ethosuximide and hydrocortisone clearance in the treatment of salt-wasting CAH. PMID- 24468606 TI - Asymmetric dimethyl L-arginine, nitric oxide and cardiovascular disease in adolescent type 1 diabetics. AB - OBJECTIVE: To evaluate asymmetric dimethyl L-arginine (ADMA), nitric oxide (NO) and cardiovascular disease in adolescent type 1 diabetics. METHODS: The study included 62 type 1 diabetic patients and 30 healthy volunteers of the same age and sex. Blood samples were taken for assessment of ADMA, NO, oxidized low density lipoprotein (OxLDL), glycosylated hemoglobin, and lipid profile. Urine samples were taken for assessment of albumin/creatinine ratio. M mode echocardiography and flow mediated dilatation (FMD) via ultrasound were completed; t-test for independent variables, Pearson's correlation, and stepwise multiple regression analysis were used. RESULTS: The mean age of patients was 16.3+/-1.5 years and mean duration of diabetes was 9.4+/-2.9 years. Nitric oxide, ADMA and FMD were significantly lower, while OxLDL and the albumin/creatinine ratio were significantly higher in diabetics. Nitric oxide had a significant negative correlation with left ventricular end-diastolic dimension, left ventricular end-systolic dimension, posterior wall thickness, left ventricular mass, albumin/creatinine ratio, and OxLDL, as well as a positive correlation with ADMA. Albumin/creatinine ratio had a significant positive correlation with OxLDL and negative correlation with ADMA. Stepwise multiple regression analysis revealed that ADMA is the only parameter related to NO, however, albumin/creatinine ratio and OxLDL are related to ADMA. CONCLUSIONS: Type 1 diabetic patients had endothelial and diastolic dysfunction. The reduction in NO, ADMA, and elevation of OxLDL, and its relation to echocardiographic data and albumin/creatinine ratio, may reflect their role in cardiac and renal affection. PMID- 24468607 TI - Identification of a novel insulin receptor gene heterozygous mutation in a patient with type A insulin resistance syndrome. AB - BACKGROUND: Several types of mutations in the insulin receptor gene have been identified in patients with genetic syndromes of insulin resistance. PATIENT REPORT: We describe a 12-year-old girl with type A insulin resistance with hyperandrogenism, hyperinsulinemia, and diabetes mellitus but without the dysmorphic characteristic of leprechaunism or Rabson-Mendenhall syndrome. The proband's mother had hyperinsulinemia and diabetes mellitus but did not show any common clinical features of type A insulin resistance. The proband's brother also had hyperinsulinemia but manifested neither glucose intolerance nor common clinical features of type A insulin resistance. A novel heterozygous mutation, p.Asn1164Thr, of the insulin receptor gene (INSR) was identified in this family. CONCLUSION: These cases illustrate the diversity of clinical phenotypes associated with mutations of the insulin receptor gene. PMID- 24468608 TI - Serum uric acid: relationships with biomarkers in adolescents and changes over 1 year. AB - OBJECTIVES: To (1) elucidate the range of serum uric acid (UA) levels in adolescent sample; (2) examine the relationships of serum UA and 1-year change with gender, anthropometric and cardiometabolic factors. MATERIALS AND METHODS: Measurements (anthropometrics, fasting venipuncture and blood pressure) were performed at the beginning of the seventh and eighth grades. Descriptive data, differences according to weight, correlations and changes over time were examined. FINDINGS: In 77 adolescents, BMI and serum UA had relationships with several cardiometabolic measures. Males had higher serum UA at follow-up compared to baseline; female change was minimal. Time-by-gender interaction was significant, as were the main effects of gender and BMI classification. Males had lower HDL-C at follow-up than at baseline; females had higher HDL-C at follow-up. CONCLUSIONS: Serum UA has importance in cardiometabolic examination of youth risk factors. It should be examined in youth with elevated BMI and/or hypertension. Early adolescence is the period when gender-related metabolic changes occur. PMID- 24468609 TI - A novel activating ABCC8 mutation underlying neonatal diabetes mellitus in an infant presenting with cerebral sinovenous thrombosis. AB - Neonatal diabetes mellitus is a rare clinical condition, which develops most commonly secondary to mutations in KCNJ11 and ABCC8 genes encoding ATP-sensitive K+ channels. Patients are typically diagnosed with hyperglycemia-related symptoms in the first 6 months of life and rarely with ketoacidosis. In this article, we report an infant who presented with focal clonic convulsion and thereafter was diagnosed with neonatal diabetes mellitus and thrombi in cerebral venous sinus. In this patient, after a molecular analysis of the ABCC8 gene revealed a novel heterozygous missense mutation (p.D424V), a successful transition from insulin to sulfonylurea treatment was made. PMID- 24468610 TI - Monoamine modulation of tonic GABAA inhibition. AB - In recent years, it has become evident that many neurotransmitters and endogenous ligands differentially modulate synaptic gamma-aminobutyric acid type A receptors (sGABAARs) and extrasynaptic GABAAR (eGABAARs). In this mini-review, we will summarize the available evidence on the ability of the monoamines serotonin (5 HT), noradrenaline (NA), and, in particular, dopamine (DA) to alter the functional response of eGABAARs, thus either increasing or decreasing tonic GABAA inhibition. Although this field of research is still in its infancy, it has already been demonstrated that eGABAARs show a nucleus-selective and neuronal type-selective regulation by monoamines in a way that differs from that of sGABAARs. Further work will undoubtedly advance our knowledge of the intricate talk between monoamines and eGABAAR and may ultimately provide new leads for the treatment of neurological and neuropsychiatric disorders, where alteration in GABAAR function is one of the underlying causes. PMID- 24468611 TI - Systems medicine, stratified medicine, personalized medicine but not precision medicine. PMID- 24468612 TI - Potential pharmacokinetic interactions of therapeutic cytokines or cytokine modulators on small-molecule drugs: mechanistic understanding via studies using in vitro systems. AB - The potential pharmacokinetic interactions between macromolecules and small molecule drugs have received more and more attention with the increasing development of macromolecule therapeutics. Studies have shown that cytokines can differentially modulate drug-metabolizing enzymes and transporters, which raises concerns on the potential interactions of therapeutic cytokines and cytokine modulators on the disposition of small-molecule drugs. Although many in vitro studies have been conducted to characterize the effects of cytokines on drug metabolizing enzymes and transporters, these studies were limited to only a handful of cytokines, such as interleukin-1 (IL-1), IL-6, tumor necrosis factor alpha, and interferon. It is also challenging to translate these in vitro results to in vivo. In addition, information on the impact of cytokine modulators on drug metabolizing enzymes and transporters is rather limited. More research is needed in this area. The present review is to provide a summary of the in vitro findings on the pharmacokinetic interactions of therapeutic cytokines and cytokine modulators on small-molecule drugs. Discussion on current challenges in assessing these interactions is also included. PMID- 24468613 TI - Antibacterial activity of the body wall extracts of sea cucumber (Invertebrata; Echinodermata) on infectious oral streptococci. AB - Abstract Background: The present study was carried out to test the antibacterial effect of the body wall of the sea cucumber Holothuria leucospilota Brandt on Streptococcus mutans and Streptococcus salivarius. Methods: After sampling sea cucumbers from the Persian Gulf, different extractions were prepared. Then, aqueous, phosphate-buffered saline (PBS, pH 7.8), chloroform, hexane and methanolic extracts from sea cucumber body wall were screened for antibacterial activity against pathogenic bacteria S. mutans and S. salivarius using the disk diffusion method. Results: The PBS extract did not show any antibacterial or inhibitory activity; the chloroform extract, however, demonstrated high levels of antibacterial activity against S. salivarius while exhibiting low levels of activity against S. mutans. The hexane and methanolic extracts were found to show no antibacterial activity against S. mutans, but exhibited antibacterial activity against S. salivarius. Conclusions: In conclusion, the results demonstrated the possibility of utilizing sea cucumbers as a cheap source of potential antibacterial agents and for treating odontogenic diseases. PMID- 24468614 TI - Analgesic, anti-inflammatory, and antipyretic effects of Ixora coccinea. AB - Abstract Background: The present study was carried out to explore the potential of the ethanol extract of Ixora coccinea L. (IC) leaves as analgesic, anti inflammatory and antipyretic agents using the hot-plate, acetic acid-induced writhing, carrageenan-induced paw edema and brewer's yeast-induced pyrexia tests in rodents. Methods: The extract was prepared by soaking the dried powdered leaves of IC in ethanol for 2 days. The filtrate thus obtained by filtration and evaporation was considered as a stock solution and was used in all experimental models. Results: Oral administration of IC (250 and 500 mg/kg) significantly (p<0.05) increased the reaction time in the hot-plate test. Ixora coccinea (250 and 500 mg/kg) produced 56.14% and 63.16% inhibition (p<0.05) in acetic acid induced writhing. It also (250 and 500 mg/kg) produced significant (p<0.05) inhibition of paw edema pronounced at 6 h after carrageenan injection. Intraperitoneal administration of IC (250 and 500 mg/kg) lowered the body temperature in brewer's yeast-induced hyperthermia. Conclusions: Based on the findings, it may be concluded that the IC leaves possessed analgesic, anti inflammatory, and antipyretic activities. Phytochemical constituents of IC leaves such as flavonoids, tannins, and triterpenes in ethanol extract could be correlated with its observed biological activities. PMID- 24468615 TI - Assessment of raloxifene, estradiol-17beta, dl-ormeloxifene and levormeloxifene on thrombin activity. AB - Abstract Background: Cancer is one of the leading causes of morbidity and mortality globally. Cancer-associated thrombosis is well established in clinical settings, and thrombin has been found to induce angiogenesis at cancer sites. This establishes a link between cardiovascular diseases and cancer, where cancer and thrombin have been intricately associated. Various selective estrogen receptor modulators (SERMs) have been reported to exhibit anticancer activity. Therefore, we investigated estradiol-17beta and SERMs dl-ormeloxifene (centchroman), raloxifene and levormeloxifene (l-centchroman) for their anticancer effects and their effect on thrombin activity. Methods: Anticancer activity was assessed against PC-3 cell line by flow cytometry following treatment with estradiol-17beta and SERMs at 10 nM-1 mM concentrations. The cells were stained with propidium iodide and the percentage of cells in the sub-G0/G1 region was considered apoptotic. Thrombin inhibitory effect was evaluated by thrombin inhibition assay in vitro following incubation with 100 nM-3 mM concentrations of estradiol-17beta or various SERMs. Further, the effect of estradiol-17beta and SERMs on endogenous thrombin generation potential (ETP) was assessed by thrombin generation assay on rat plasma in vitro. Results: These compounds exhibited >90% cell death in PC-3 cell lines at 1 mM concentration except estradiol-17beta. Neither estradiol-17beta, dl-ormeloxifene and levormeloxifene showed any thrombin inhibitory or enhancing activity in thrombin inhibition assay, nor did they show any effect on ETP on rat plasma in vitro. However, raloxifene inhibited thrombin activity in a concentration-dependent manner. Raloxifene decreased ETP of the plasma at 3 and 1 mM,which is equivalent to that of 30-100 U/mL of heparin. Interestingly, raloxifene increased thrombin generation at lower concentrations and it inhibited thrombin generation at higher concentrations. Conclusions: These observations suggest that dl-ormeloxifene, estradiol-17beta and levormeloxifene do not possess thrombin inhibitory activity. Raloxifene possesses thrombin modulatory effect in addition to its anticancer activity, and this observation may help us in understanding the thromboembolic complications associated with raloxifene. PMID- 24468616 TI - Chronic ethanol use in alcoholic beverages by HIV-infected patients affects the therapeutic window of stavudine, lamivudine and nevirapine during the 9-month follow-up period: using chronic alcohol-use biomarkers. AB - Abstract Background: Chronic ethanol use is a global problem including among HIV infected patients on stavudine/lamivudine/nevirapine (d4T/3TC/NVP) regimen. The study determined the effect of chronic ethanol use on the therapeutic window of d4T, 3TC and NVP in HIV-infected patients using alcohol-use biomarkers to screen patients for chronic ethanol use. Methods: A case-control study using repeated measures design with serial measurements was used to quantify drugs in plasma. The WHO alcohol use disorder identification test (AUDIT) tool was initially used to screen patients for chronic alcohol use, and then they were further sorted using alcohol-use bioamarkers (gamma-glutamyl transferase >=55.0 IU; mean corpuscular volume, >=96 fl, aspartate amino transferase/alanine aminotransferase ratio >=2.0 value). A total of 41 patients (26 in the alcohol group and 15 in the control group) were followed up for 9 months with blood sampling done at 3-month intervals. Plasma drug concentrations were quantified using a Shimadzu Class-VPTM HPLC data system version 6.1. Data was analyzed using SAS 2003 version 9.1 statistical package with repeated measures fixed model. Means were compared using Student's t-test. Results: The mean steady-state plasma drug concentrations of d4T and 3TC in the alcohol group were lower than that in the control group during the 9-month period of follow-up. For 3TC, there was a statistical difference in the mean steady-state plasma drug concentrations between the alcohol group and the control group (p<=0.05) in the 6- and 9-month period of follow-up. For NVP, in both groups they were within the reference ranges, although the drug plasma concentrations were higher in the alcohol group compared to the control group and were statistically significant (p<0.05) in 0, 3 and 6 months of follow-up. Conclusions: Chronic ethanol use by HIV-infected patients reduced the therapeutic steady-state plasma drug concentrations of d4T and 3TC and increased the NVP drug concentrations in the HIV-infected patients. PMID- 24468617 TI - Sodium valproate, a histone deacetylase inhibitor ameliorates cyclophosphamide induced genotoxicity and cytotoxicity in the colon of mice. AB - Abstract Background: Cyclophosphamide (CP) is an alkylating anticancer drug used for the treatment of various cancer and noncancer disorders. Toxicity of CP is well characterized using different test systems. However, its intestinal genotoxicity and cytotoxicity are the least explored and the mechanism is not fully investigated. Valproic acid (VPA) has been reported as a histone deacetylase (HDAC) inhibitor, which modulates the cytotoxicity of anticancer drugs. The present study aimed to investigate the influence of VPA on CP-induced genotoxicity and cytotoxicity in the colon of mice. Methods: In the 16-day experiment, animals were treated with VPA alone (500 mg/kg/day), CP alone (50 mg/kg, on the 4th, 8th, 12th, and 16th days), and the combination of CP and VPA, while in the 28-day experiment, animals were treated with VPA alone (300 mg/kg/day, 5 days/week), CP alone (100 mg/kg/week), and the combination of low and high dose of VPA (VPA150+CP and VPA300+CP). Animals were sacrificed 24 h after the administration of the last dose. The influence of VPA treatment on CP induced genotoxicity and cytotoxicity was assessed by the evaluation of oxidative stress, DNA damage, histology, and the expression of 8-hydroxy-guanosine and phosphorylated histone H2AX by immunohistochemistry. Results and conclusions: The present study's results demonstrated that VPA treatment significantly decreased the CP-induced DNA damage, cytotoxicity, and expression of gammaH2AX in the colon as revealed by the comet assay and histological as well as immunohistochemical evaluation. VPA treatment significantly ameliorated the CP-induced DNA damage and cytotoxicity in the colon of mice. PMID- 24468618 TI - Preclinical efficacy of melatonin in the amelioration of tenofovir nephrotoxicity by the attenuation of oxidative stress, nitrosative stress, and inflammation in rats. AB - Abstract Background: Nephrotoxicity is a dose-limiting side effect of long-term use of tenofovir, a reverse transcriptase inhibitor that is used for the treatment of human immunodeficiency virus (HIV) infection. Identifying an agent that prevents tenofovir disoproxil fumarate (TDF)-induced renal injury can lead to better tolerance to TDF, and a more effective treatment can be achieved in HIV infected patients. Recent studies show that oxidative stress, nitrosative stress, and inflammation play a role in TDF nephrotoxicity. The present study is aimed at investigating whether melatonin, a potent antioxidant and anti-inflammatory agent, protects against TDF nephrotoxicity in rats. Methods: Adult male rats were used for the study. Some rats received 600 mg/kg body weight TDF by gavage for 35 days, while others received once daily 20 mg/kg body weight melatonin i.p. 2 h before TDF administration. All the rats were sacrificed on the 36th day, after overnight fast. Results: Melatonin pretreatment protected the rats against TDF nephrotoxicity both histologically and biochemically. Biochemically, melatonin pretreatment attenuated TDF-induced renal oxidative stress, nitrosative stress, and inflammation and preserved proximal tubular function. Histologically, melatonin pretreatment prevented TDF-induced proximal tubular injury and mitochondrial injury such as swelling, disruption of cristae, and deposition of amorphous material in the matrix. It restored the lysosomal and mitochondrial numbers in the proximal tubules also. Conclusions: Melatonin pretreatment protects rats from tenofovir-induced damage to proximal tubular mitochondria by attenuating oxidative stress, nitrosative stress, and inflammation. This suggests that it may be useful in ameliorating TDF nephrotoxicity in humans. PMID- 24468619 TI - Antinociceptive and antiedematogenic effect of pecan (Carya illinoensis) nut shell extract in mice: a possible beneficial use for a by-product of the nut industry. AB - Abstract Background: Interest in pecan (Carya illinoensis) nut shells, a by product of the nut industry, has increased due to its anti-inflammatory and antioxidant activities. The goal of this study was to evaluate the antinociceptive and antiedematogenic activity and the mechanisms of the pecan shell aqueous extract (AE). Methods: First, we performed fingerprinting of C. illinoensis AE. The antinociceptive and antiedematogenic effects of AE intragastric (i.g.) administration in mice (male Swiss mice 20-30 g) were evaluated using the acetic acid test or after subcutaneous (s.c.) paw injection of diverse transient receptor potential ankyrin 1 (TRPA1) agonists, including hydrogen peroxide (H2O2), allyl isothiocyanate, or cinnamaldehyde. We also observed AE antinociceptive and antiedematogenic effects after carrageenan s.c. paw injection and measured H2O2 production. Moreover, we observed the development of adverse effects after AE i.g. treatment. Results: The high-performance liquid chromatography fingerprinting of AE showed the presence of rutin. AE or rutin i.g. treatment produced antinociception in the acetic acid test and reduced the nociception and edema mediated by H2O2 s.c. hind paw injection or nociception induced by other TRPA1 agonists. Moreover, AE or rutin reduced the hyperalgesia, edema, and H2O2 production induced by carrageenan s.c. paw injection. No motor, gastric, or toxicological alterations were observed after AE administration. Conclusions: Collectively, the present results show that AE and its constituent rutin produced antinociceptive and antiedematogenic action in models of acute and persistent inflammatory nociception and it seems to be related to the inhibition of TRPA1 receptor activation. PMID- 24468620 TI - PKC-delta isozyme gene silencing restores vascular function in diabetic rat. AB - Abstract Background: Endothelium and K+ channel functionality in smooth muscle cells (SMCs) regulates vascular function and is exposed to damage in diabetes. The regulatory enzyme protein kinase C (PKC) is known to play a key role in vascular tone regulation in health and disease. In this study, we evaluated the effect of PKC-delta gene silencing using small interfering RNAs (siRNAs) on endothelial dysfunction and acquired potassium channelopathy in vascular SMCs in diabetes. Methods: The experimental design comprised diabetes induction by streptozotocin (65 mg/kg) in rats, RNA interference, isolated aortic ring contractile recordings, whole-cell patch-clamp technique, measurements of reactive oxygen species (ROS), and real-time polymerase chain reaction technique. Animals were killed by cervical dislocation following ketamine (45 mg/kg, i.p.) and xylazine (10 mg/kg, i.p.) anesthesia administration on the third month of diabetes and on the seventh day after intravenous injection of siRNAs. Results: The aortas of diabetic rats demonstrated depressed endothelium-dependent relaxation and integral SMCs outward K+ currents as compared with those of controls. On the seventh day, PKC-delta gene silencing effectively restored K+ currents and increased the amplitude of vascular relaxation up to control levels. An increased level of PKC-delta mRNA in diabetic aortas appeared to be reduced after targeted PKC-delta gene silencing. Similarly, the level of ROS production that was increased in diabetes came back to control values after siRNAs administration. Conclusions: The silencing of PKC-delta gene expression using siRNAs led to restoration of vasodilator potential in rats with diabetes mellitus. It is likely that the siRNA technique can be a good therapeutic tool to normalize vascular function in diabetes. PMID- 24468621 TI - Human dyskerin: beyond telomeres. AB - Human dyskerin is an evolutively conserved protein that participates in diverse nuclear complexes: the H/ACA snoRNPs, that control ribosome biogenesis, RNA pseudouridylation, and stability of H/ACA snoRNAs; the scaRNPs, that control pseudouridylation of snRNAs; and the telomerase active holoenzyme, which safeguards telomere integrity. The biological importance of dyskerin is further outlined by the fact that its deficiency causes the X-linked dyskeratosis congenita disease, while its over-expression characterizes several types of cancers and has been proposed as prognostic marker. The role of dyskerin in telomere maintenance has widely been discussed, while its functions as H/ACA sno/scaRNP component has been so far mostly overlooked and represent the main goal of this review. Here we summarize how increasing evidence indicates that the snoRNA/microRNA pathways can be interlaced, and that dyskerin-dependent RNA pseudouridylation represents a flexible mechanism able to modulate RNA function in different ways, including modulation of splicing, change of mRNA coding properties, and selective regulation of IRES-dependent translation. We also propose a speculative model that suggests that the dynamics of pre-assembly and nuclear import of H/ACA RNPs are crucial regulatory steps that can be finely controlled in the cytoplasm in response to developmental, differentiative and stress stimuli. PMID- 24468622 TI - Beyond survival: fostering growth and innovation in doctoral study--a concept analysis of the Ba space. AB - PURPOSE: This concept analysis examines the Ba space in the context of interdisciplinary doctoral study in nursing and healthcare innovation in a minimal residency program. The authors identified Ba in their small, highly diverse, self-selected doctoral study group and believe Ba is an educational innovation that will prove useful to nursing and healthcare educators. BACKGROUND: Ba originates from Japanese philosophy and is foundational to the birth and sustainment of environments fostering knowledge creation. Ba manifests in complex environments where participants are emotionally invested and relies on the tacit knowledge of each participant, allowing for synthesis of rationality and intuition. METHOD: Walker and Avant's concept analysis methodology will explore Ba's centrality to interdisciplinary education. Ba's utility and application in fostering innovation in doctoral study will be illustrated. SIGNIFICANCE: Ba is a true educational innovation, enriching learning environments promoting interdisciplinary collaboration. Ba permits each member a voice and fosters a safe environment where relationships are created and sustained. PMID- 24468624 TI - Botulinum toxin injection technique for axillary hyperhidrosis. PMID- 24468626 TI - [Human immunodeficiency virus testing in emergency departments]. PMID- 24468625 TI - Golgi- and trans-Golgi network-mediated vesicle trafficking is required for wax secretion from epidermal cells. AB - Lipid secretion from epidermal cells to the plant surface is essential to create the protective plant cuticle. Cuticular waxes are unusual secretory products, consisting of a variety of highly hydrophobic compounds including saturated very long-chain alkanes, ketones, and alcohols. These compounds are synthesized in the endoplasmic reticulum (ER) but must be trafficked to the plasma membrane for export by ATP-binding cassette transporters. To test the hypothesis that wax components are trafficked via the endomembrane system and packaged in Golgi derived secretory vesicles, Arabidopsis (Arabidopsis thaliana) stem wax secretion was assayed in a series of vesicle-trafficking mutants, including gnom like1-1 (gnl1-1), transport particle protein subunit120-4, and echidna (ech). Wax secretion was dependent upon GNL1 and ECH. Independent of secretion phenotypes, mutants with altered ER morphology also had decreased wax biosynthesis phenotypes, implying that the biosynthetic capacity of the ER is closely related to its structure. These results provide genetic evidence that wax export requires GNL1- and ECH-dependent endomembrane vesicle trafficking to deliver cargo to plasma membrane-localized ATP-binding cassette transporters. PMID- 24468627 TI - Who and how many of the potential users would be willing to pay the current or a lower price of the HIV self-test? The opinion of participants in a feasibility study of HIV self-testing in Spain. AB - INTRODUCTION: We estimate the proportion of participants willing to pay the US price (?30) or ?20 for an HIV self-test and analyse their associated factors. METHODS: In a street-based testing program, 497 participants in a feasibility self-test study answered the question, "What would be the maximum price you would be willing to pay for a similar test to this one so you can use it at your convenience?" RESULTS: Only 17.9% would pay >=?30, while 40.0%, >=?20. In the logistic regression, paying more was associated with being tested outside the campuses and having paid or been paid for sex. CONCLUSION: In Spain, self-testing would not have an impact unless it became more affordable to potential users. PMID- 24468628 TI - [Human immunodeficiency virus and emergency departments. Reply]. PMID- 24468629 TI - Improved storage stability and immunogenicity of hepatitis B vaccine after spray freeze drying in presence of sugars. AB - The current hepatitis B vaccines need to be stored and transported under refrigerated conditions (2-8 degrees C). This dependence on a cold-chain is highly challenging in areas where hepatitis B virus infections are endemic. To decrease the cold-chain dependency, powder formulations of the hepatitis B surface antigen (HBsAg) without aluminum were prepared by spray-freeze drying in the presence of either inulin or a combination of dextran and trehalose. The stability of HBsAg in the amorphous powder formulations was strongly improved during storage both at room temperature and at an elevated temperature (60 degrees C), compared to a liquid plain and an aluminum hydroxide adjuvanted HBsAg formulation. Immunogenicity studies in mice showed that reconstituted powder formulations induced higher IgG immune responses after intramuscular administration than those induced after administration of unprocessed plain antigen. Although the immune response was not as high as after administration of aluminum adjuvanted HBsAg, the immune response to the reconstituted vaccines shifted towards a more balanced Th1/Th2 response compared to the aluminum containing HBsAg formulation. PMID- 24468630 TI - Synthesis and toxicological studies of in vivo anticoagulant activity of novel 3 (1-aminoethylidene)chroman-2,4-diones and 4-hydroxy-3-(1-iminoethyl)-2H-chromen-2 ones combined with a structure-based 3-D pharmacophore model. AB - Eight synthesized 3-(1-aminoethylidene)chroman-2,4-diones and 4-hydroxy-3-(1 iminoethyl)-2H-chromen-2-ones were evaluated as in vivo anticoagulants by intraperitoneal application to adult male Wistar rats in order to examine their pharmacological potential, evaluate ther toxicity and propose the mechanism of action. Two of them, 2f and 2a, in concentration of 2mg/kg of body weight, presented remarkable activity (PT=130s; PT=90s) upon seven days of continuous application. The results of rat serum and liver biochemical screening, as well those of histopathological studies, proved the compounds to be non-toxic. Activity of the compounds was further examined on the molecular level. Here, molecular docking studies were performed to position the compounds in relation to the active site of VKORC1 and determine the bioactive conformations. Docking results suggested a non-covalent mode of action during which the proton transfer occurs from Cys135 SH towards 4-carbonyl group of anticoagulant. All crucial interactions for anticoagulant activity were confirmed in generated structure based 3-D pharmacophore model, consisted of hydrogen bond acceptor and hydrophobic aromatic features, and quantified by a best correlation coefficient of 0.97. PMID- 24468631 TI - Gabapentin hybrid peptides and bioconjugates. AB - Synthetic approaches to gabapentin bioconjugates that overcome the tendency of gabapentin to cyclize into its gamma-lactam are studied. Gabapentin was converted by N-acylation at its N-terminus into di-, tri-, and tetrapeptides (L-Ala-Gbp, L Val-Gbp, L-Ala-L-Phe-Gbp, Gly-L-Ala-beta-Ala-Gbp). Carboxyl-activated Boc protected gabapentin was used to N-, O-, and S-acylate small peptides and hormones to give conjugates that could also provide prodrugs containing conformationally constrained gabapentin units. PMID- 24468633 TI - Synthesis of 3-tetrazolylmethyl-4H-chromen-4-ones via Ugi-azide and biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis. AB - The synthesis of novel 3-tetrazolylmethyl-4H-chromen-4-ones via an Ugi-azide multicomponent reaction and their biological evaluation against Entamoeba histolytica, Giardia lamblia and Trichomona vaginalis are described. Reported yields are moderate to good and biological results show that these compounds could be considered as candidates to anti-parasitic drugs, especially against G. lamblia. PMID- 24468632 TI - Synthesis and biological evaluation of benzo[4,5]imidazo[1,2-c]pyrimidine and benzo[4,5]imidazo[1,2-a]pyrazine derivatives as anaplastic lymphoma kinase inhibitors. AB - Chromosomal translocations involving anaplastic lymphoma kinase (ALK) are the driving mutations for a range of cancers and ALK is thus considered an attractive therapeutic target. We synthesized a series of functionalized benzo[4,5]imidazo[1,2-c]pyrimidines and benzo[4,5]imidazo[1,2-a]pyrazines by an aza-Graebe-Ullman reaction, followed by palladium-catalyzed cross-coupling reactions. A sequential regioselective cross-coupling route is reported for the synthesis of unsymmetrically disubstituted benzo[4,5]imidazo[1,2-a]pyrazines. The inhibition of ALK was evaluated and compound 19 in particular showed good activity against both the wild type and crizotinib-resistant L1196M mutant in vitro and in ALK-transfected BaF3 cells. PMID- 24468634 TI - Downsides of the recycling process: harmful organic chemicals in children's toys. AB - Most of the materials used in consumer goods contain a number of additives which are meant to improve key properties like plasticity or flame resistance. At the end-of-life of the product, many polymeric materials are recycled and the additives they contain, such as flame retardants (FRs) and plasticizers, are transferred to the newly manufactured goods. We have investigated the occurrence and profiles of FRs, such as polybrominated diphenyl ethers (PBDEs) and phosphate FR (PFRs) and of plasticisers, such as phthalate esters, in 106 toys samples. Low levels and detection frequencies of components of the technical Penta-BDE and Deca-BDE mixtures were found, with BDE 209 being the dominant PBDE in all samples (maximum value was 0.14mg/g or 0.014%). The levels of PFRs and phthalates were up to 10,000 times higher than those of the PBDEs, with triphenyl phosphate and diethylhexyl phthalate being the major representatives of these classes. Maximum values were 1.3 and 6.9%, respectively. The detection frequencies were up to 50% for PFRs and 98% for phthalates. All but one of the toys produced after the REACH regulation went into force complied with its provisions. The samples were grouped according to relevant selection criteria to assess the risk for children of different age groups. Using models in the literature, exposure to these chemicals was tentatively assessed. It is clear that at the levels found in the investigated toys, these additives do not contribute to the intended characteristics of the materials, but in some cases may pose a health hazard to the children. Most likely, recycled materials are an important source of these additives in toys and therefore, their (re)use in products for children should be subject to stricter restrictions. PMID- 24468635 TI - Temporal trends of perfluoroalkane sulfonic acids and their sulfonamide-based precursors in herring from the Swedish west coast 1991-2011 including isomer specific considerations. AB - A method was developed for simultaneous analysis of perfluoroalkane sulfonic acids (PFSAs) and their sulfonamide-based precursors (perfluoroalkane sulfonamidoacetic acids (FASAAs), sulfonamides (FASAs), and sulfonamidoethanols (FASEs)) in fish muscle. Extraction was performed with acetonitrile followed by a clean-up and fractionation step and instrumental analysis by UPLC/MS/MS and GC/MS. Time trends of PFSAs and their precursors in herring muscle samples originating from the Kattegat at the west coast of Sweden were investigated covering the years 1991-2011. The following analytes were detected, all with decreasing or unchanged trends between 1991 and 2011: Perfluorobutane sulfonic acid (PFBS, below the method detection limit (G (+0.14, P=0.04) and CAST:c.1985G>C ( 0.12, P=0.02) had significant effects on juiciness, but no effects on other traits. In contrast, CAPN1:c.1589G>A was associated with meat tenderness (P=0.01) and juiciness (P=0.04). The CAPN1:c.1589G>A (Val530Ile) SNP marker displayed significant effect on the meat tenderness score which is strongly supported by molecular modeling of the CAPN1:c.1589G>A (Val530Ile) variant that inhibits CAST protein from binding more strongly than the wild-type protein, which may explain its effect on meat tenderness. PMID- 24468664 TI - A comparison of the structure of American (Homarus americanus) and European (Homarus gammarus) lobster cuticle with particular reference to shell disease susceptibility. AB - The integument of arthropods is an important first-line defence against the invasion of parasites and pathogens. Once damaged, this can be subject to colonisation by microbial agents from the surrounding environment, which in crustaceans can lead to a condition termed shell disease syndrome. This condition has been reported in several crustacean species, including crabs and lobsters. The syndrome is a progressive condition where the outer cuticle becomes pitted and eroded, and in extreme cases is compromised, leaving animals susceptible to septicaemia. This study examined the susceptibility of juvenile American (Homarus americanus) and European (Homarus gammarus) lobsters to shell disease, as a result of mechanical damage. Scanning electron microscopy was used as a method to identify differences in the cuticle structure and consequences of mechanical damage. Claw regions were aseptically punctured, whilst carapaces were abraded using sterile sandpaper, to mimic natural damage. After a period of between 10 and 12 weeks, lobsters were sacrificed, fixed and stored for later examination. The carapace and claws of juvenile American lobsters were shown to be thinner and more vulnerable to abrasion damage than their European counterparts. In addition, the number and distribution of setal pits and pore canal openings also differed between the two species of lobster. Mechanical damage resulted in the formation of shell disease lesions on the claw and carapace of both lobster species. However, American lobsters, unlike their European counterparts, had extensive bacterial colonisation on the margins of these lesions. Overall, it is concluded that the cuticle of the American lobster is more susceptible to damage and resulting microbial colonisation. This may have implications for susceptibility of both species of lobster to shell disease syndrome. PMID- 24468665 TI - Theoretical 57Fe Mossbauer spectroscopy: isomer shifts of [Fe]-hydrogenase intermediates. AB - Mossbauer spectroscopy is an indispensable spectroscopic technique and analytical tool in iron coordination chemistry. The linear correlation between the electron density at the nucleus ("contact density") and experimental isomer shifts has been used to link calculated contact densities to experimental isomer shifts. Here we have investigated relativistic methods of systematically increasing sophistication, including the eXact 2-Component (X2C) Hamiltonian and a finite nucleus model, for the calculation of isomer shifts of iron compounds. While being of similar accuracy as the full four-component treatment, X2C calculations are far more efficient. We find that effects of spin-orbit coupling can safely be neglected, leading to further speedup. Linear correlation plots using effective densities rather than contact densities versus experimental isomer shift lead to a correlation constant a = -0.294 a0(-3) mm s(-1) (PBE functional) which is close to an experimentally derived value. Isomer shifts of similar quality can thus be obtained both with and without fitting, which is not the case if one pursues a priori a non-relativistic model approach. As an application for a biologically relevant system, we have studied three recently proposed [Fe]-hydrogenase intermediates. The structures of these intermediates were extracted from QM/MM calculations using large QM regions surrounded by the full enzyme and a solvation shell of water molecules. We show that a comparison between calculated and experimentally observed isomer shifts can be used to discriminate between different intermediates, whereas calculated atomic charges do not necessarily correlate with Mossbauer isomer shifts. Detailed analysis reveals that the difference in isomer shifts between two intermediates is due to an overlap effect. PMID- 24468666 TI - Scheuermann's disease: an update. AB - Scheuermann's disease is a juvenile osteochondrosis of the spine. It is a disease of the growth cartilage endplate, probably due to repetitive strain on the growth cartilage weakened by a genetic background. The radiographic aspects are related to the vertebral endplate lesions and include vertebral wedging, irregularity of the vertebral endplate, and Schmorl's node (intraossous disk herniation). Disc alterations are frequent and may be secondary to dysfunction of the disc-vertebra complex. The definitions of Scheuermann's disease are varied; it can refer to the classical form of juvenile kyphosis, described by Scheuermann as well as asymptomatic radiographic abnormalities. Lumbar involvement is probably as frequent as the thoracic form and might be more painful. The first-line treatment is medical and includes rehabilitation and bracing. The earlier the start of treatment, the better the outcome, which highlights the importance of early diagnosis. Surgery is uncommon and must be limited to severe involvement after failure of conservative treatment. The natural history of Scheuermann's disease is unknown, but it might be associated with increased risk of back pain. The evolution of thoracolumbar and lumbar disease is unknown. PMID- 24468667 TI - Abrupt development of Dupuytren's contractures with the BRAF inhibitor vemurafenib. PMID- 24468668 TI - Arthritis of the first metatarsophalangeal joint is not always gout: a prospective cohort study in primary care patients. AB - OBJECTIVES: Arthritis of the first metatarsophalangeal joint has been considered pathognomonic for gout, but it is unknown how frequently other forms of arthritis occur in this joint. The aims were to determine the validity of the general practitioner's clinical diagnosis using joint fluid analysis as the reference test, the prevalence of other diagnoses than gout, and the signs and symptoms that discriminate between gout and non-gout patients. METHODS: This prospective cohort study comprised primary care patients with monoarthritis of the first metatarsophalangeal joint. After patient recruitment by general practitioners, patients' characteristics were collected by a rheumatologist. Joint fluid was analyzed for the presence of monosodium urate-crystals. If crystals were absent, patients entered a follow-up period of 6 years, or until a definite diagnosis. If during follow-up crystals were identified, the patient was classified as already having gout at baseline assessment. RESULTS: One hundred and fifty-nine primary care patients were included. At baseline the clinical diagnosis was gout in 98%. The positive and negative predictive values of the diagnosis of gout were 0.79 and 0.75, respectively. After follow-up 77% had gout, 8% had another rheumatic disease, and 15% had a transient unspecified monoarthritis. Gout patients had discriminating signs and symptoms from non-gout patients. CONCLUSIONS: Gout is an important but certainly not an exclusive cause of arthritis of the first metatarsophalangeal joint. PMID- 24468669 TI - Consanguinity profile in the Gaza Strip of Palestine: large-scale community-based study. AB - Consanguineous marriages which have been practiced throughout history continue to be practiced within different ethnic, religious and social groups to varying degrees with highest prevalences in North Africa, Middle East and central and south Asia. In the Gaza Strip of Palestine, little is known about the consanguinity profile, so the present large-scale study aims to explore the consanguinity profile of two generations using data from the beta-thalassemia premarital screening program. Sociodemographic data analysis included 156,635 (141,200 males and 15,435 females) persons and their parents, representing 141,200 couples who were referred to the Thalassemia and Hemophilia Center for premarital testing. In addition, the consanguinity characteristics of parents of 217 transfusion-dependent beta-thalassemic non-sibling patients were analyzed. Results revealed a significant decrease in the overall prevalence of consanguineous (first- and second-cousin) marriages between the previous (fathers') generation (45.2%) and the current (groom/bride) generation (39.9%). Among the five governorates of the Gaza Strip, records of Gaza Governorate revealed the lowest occurrence (36.9% current generation and 42.1% previous generation) of consanguineous marriages, as compared to all others. Consanguineous marriages are significantly higher in semi-urban areas (41.6%) than in urban areas (39.1%) in the current generation (previous generation, 46.4% vs 44.7%, respectively). Compound consanguinity (two generation) and a single level of consanguinity were seen in 20.7% and 43.7%, respectively, of the cases. The average age of those with first-cousin marriages is significantly lower (22.4+/-4.4 years) than those with second-cousin marriages (24.3+/-6.1 years) and the non-consanguineous (26.5+/-8.2 years). The rate of consanguineous marriages among never married people (42.2%) is significantly much higher than the rate of people with multiple marriages (18.1%). About 74.7% of the non-sibling thalassemic patients of the Gaza Strip are associated with consanguineous parents, of them 54.4% first-cousins and 20.3% second-cousins. In conclusion, although there is a decline in the consanguinity profile in the present compared to previous generation, consanguineous marriages are still a common practice in the Gaza Strip, which rationalizes the necessity for more awareness and counseling efforts about the potential health-related risks of consanguinity on individual lives and the population overall. PMID- 24468670 TI - Standardized ethyl acetate fraction from the roots of Brassica rapa attenuates the experimental arthritis by down regulating inflammatory responses and inhibiting NF-kappaB activation. AB - This study was undertaken to investigate the anti-arthritic potential of a standardized ethyl acetate fraction from the roots of Brassica rapa (EABR) and to explore the molecular mechanisms in adjuvant-induced arthritic rats and macrophages. In AIA-induced arthritic rats, EABR significantly reduced paw swelling, an arthritic index, serum rheumatoid factor, and tissue expression ratio of RANKL/OPG versus vehicle-administered group. This was found to be well correlated with significant suppressions in productions of PGE2, NO, and pro inflammatory cytokines and in activations of NF-kappaB in AIA-induced paw tissues and LPS-induced macrophages. EABR attenuated NF-kappaB activation by reducing the nuclear translocation and phosphorylation of the p65 NF-kappaB, which were accompanied by parallel reductions in the degradation and phosphorylation of IkappaBalpha after blocking the phosphorylation mediated IKK activation. The findings suggest EABR exerts its anti-arthritic and anti-inflammatory properties via NF-kappaB inactivation in vitro and in vivo, and that EABR is a potential therapeutic for the treatment of arthritis and inflammation-associated disorders. PMID- 24468671 TI - Absence of in vitro genotoxicity potential of the mycotoxin deoxynivalenol in bacteria and in human TK6 and HepaRG cell lines. AB - Deoxynivalenol (DON) is the major mycotoxin detected in cereal foods and a risk for human health following DON ingestion could not be excluded due to high level exposure. In this light, the hazard of DON must be carefully evaluated. Therefore, the aim of this study is to perform in vitro genotoxicity tests with DON using the Salmonella typhimurium reverse mutation assay (Ames' test), the comet assay and the micronucleus test in accordance with the OECD test guideline 487 in two human cell lines: the lymphoblastoid TK6 and the hepatoma HepaRG cells. DON gave negative results in the Ames' test performed, both with and without rat liver S9 on three strains TA98, TA100 and TA102. DON elicited cytotoxicity in TK6 and HepaRG cells but did not induce primary DNA damage. DON failed also to induce MN formation in TK6 cells with or without human and rat liver S9. After 24h of treatment, DON induced micronucleus formation in TK6 cells but only at concentrations producing more than 55 +/- 5% cytotoxicity. In HepaRG cells, DON highly increased the caspase-3/7 activity but no micronucleus induction was observed. Taken together, our results suggest that DON could be considered as a non in vitro genotoxin. PMID- 24468672 TI - Urinary excretion of arsenicals following daily intake of various seafoods during a two weeks intervention. AB - The excretion pattern of arsenic (As) species after seafood intake varies widely depending on species ingested and individual handling. We have previously reported the 72 h urinary excretion of arsenicals following a single dose of seafood. Here, we report the excretion patterns in the same 37 subjects following 15 days daily consumption of either 150 g cod, salmon, blue mussels or potato (control), followed by a 72 h period with a low-As diet. In all seafood groups, total As (tAs) in plasma and urinary excretion of tAs, arsenobetaine (AB) and dimethylarsinate (DMA) increased significantly after the intervention. Confirming the single dose study AB and DMA excreted were apparently endogenously formed from other arsenicals ingested. Total tAs excretion was 1386, 763 and 303 MUg in the cod, blue mussel and salmon groups, respectively; about twice the amounts after the single dose study indicating accumulation of arsenicals. In the cod group, rapid excretion after the single dose was associated with lower total As in blood and less accumulation after two weeks with seafood indicating lower accumulation. In the blue mussels group only, inorganic As (iAs) excretion increased significantly, whilst methylarsonate (MA) strongly increased, indicating a possible toxicological concern of repeated mussel consumption. PMID- 24468673 TI - Ameliorative effects of oleanolic acid on fluoride induced metabolic and oxidative dysfunctions in rat brain: Experimental and biochemical studies. AB - Beneficial effects of oleanolic acid on fluoride-induced oxidative stress and certain metabolic dysfunctions were studied in four regions of rat brain. Male Wistar rats were treated with sodium fluoride at a dose of 20 mg/kg b.w./day (orally) for 30 days. Results indicate marked reduction in acidic, basic and neutral protein contents due to fluoride toxicity in cerebrum, cerebellum, pons and medulla. DNA, RNA contents significantly decreased in those regions after fluoride exposure. Activities of proteolytic enzymes (such as cathepsin, trypsin and pronase) were inhibited by fluoride, whereas transaminase enzyme (GOT and GPT) activities increased significantly in brain tissue. Fluoride appreciably elevated brain malondialdehyde level, free amino acid nitrogen, NO content and free OH radical generation. Additionally, fluoride perturbed GSH content and markedly reduced SOD, GPx, GR and CAT activities in brain tissues. Oral supplementation of oleanolic acid (a plant triterpenoid), at a dose of 5mg/kgb.w./day for last 14 days of fluoride treatment appreciably ameliorated fluoride-induced alteration of brain metabolic functions. Appreciable counteractive effects of oleanolic acid against fluoride-induced changes in protein and nucleic acid contents, proteolytic enzyme activities and other oxidative stress parameters indicate that oleanolic acid has potential antioxidative effects against fluoride-induced oxidative brain damage. PMID- 24468674 TI - NP/MS since 1970: from the basement to the bench top. AB - This Highlight explores the evolution of applications of mass spectrometric technologies in the context of natural products research since the 1970's. The central themes are the analysis of mixtures, dereplication (identification) and structure determination. The ascension of HPLC as the method of choice for the analysis of pharmaceuticals was a driving force for the development of interfaces for coupling of HPLC and MS. An example of sequential analysis of fragment ions or MS/MS or MS(n) methods to provide detailed structural information on muraymycins, a family of uridyl-peptide antibiotics, is presented. PMID- 24468675 TI - A facile and versatile methodology for cysteine specific labeling of proteins with octahedral polypyridyl d6 metal complexes. AB - We have synthesized and characterized four octahedral polypyridyl d(6) metal complexes bearing the 5,6-epoxy-5,6-dihydro-[1,10]phenanthroline ligand (L1) as cysteine specific labeling reagents. The proposed synthetic pathways allow the preparation of the metal complexes containing Re(I), Ru(II), Os(II) and Ir(III) while preserving the epoxide functionality. The complexes were characterized by (1)H and (13)C NMR, mass spectrometry, UV-visible and luminescence spectroscopies as well as cyclic voltammetry. As proof of concept, a set of non-native single cysteine P450 BM3 heme domain mutants previously developed in our laboratory was used to study the labeling reaction. We demonstrate that the proposed labels can selectively react, often in high yield, with cysteine residues of the protein via the nucleophilic thiol ring opening of the epoxide moiety. In addition, under basic conditions, subsequent loss of a water molecule led to the aromatization of the phenanthroline ring on the protein-bound label compounds, as observed by mass spectrometry and luminescence measurements. PMID- 24468677 TI - Randomized Controlled Trials and real life studies. Approaches and methodologies: a clinical point of view. AB - Randomized Controlled Trials (RCTs) are the "gold standard" for evaluating treatment outcomes providing information on treatments "efficacy". They are designed to test a therapeutic hypothesis under optimal setting in the absence of confounding factors. For this reason they have high internal validity. The strict and controlled conditions in which they are conducted, leads to low generalizability because they are performed in conditions very different from real life usual care. Conversely, real life studies inform on the "effectiveness" of a treatment, that is, the measure of the extent to which an intervention does what is intended to do in routine circumstances. At variance to RCTs, real life trials have high generalizability, but low internal validity. Recently the number of real life studies has been rapidly growing in different areas of respiratory medicine, particularly in asthma and COPD. The role of such studies is becoming a hot topic in respiratory medicine, attracting research interest and debate. In the first part of this review we discuss some of the advantages and disadvantages of different types of RCTs and analyze the strengths and weaknesses of real life trials, considering the recent examples of some studies conducted in COPD. We then discuss methodological approaches and options to overcome some of the limitations of real life studies. Comparing the conclusions of effectiveness and efficacy trials can provide important pieces of information. Indeed, these approaches can result complementary, and they can guide the interpretation of each other results. PMID- 24468678 TI - Phaseolin: a 47.5kDa protein of red kidney bean (Phaseolus vulgaris L.) plays a pivotal role in hypersensitivity induction. AB - Red kidney bean (Phaseolus vulgaris L.), a protein rich legume, is consumed globally due to its delicacy. This study was aimed to purify, characterize and assess allergenicity of one of its clinically relevant allergens, later identified as phaseolin. This study was carried out using clinical, in vivo and ex vivo approaches. Phaseolin, an abundant protein of red kidney bean, was purified by column chromatography and reverse-phase-HPLC techniques and characterized by peptide mass fingerprinting. The IgE immunoblotting using red kidney bean allergic patients sera showed phaseolin as a major IgE binding protein of red kidney bean. Phaseolin treated mice demonstrated enhanced levels of specific IgE and IgG1, mouse mast cell protease-1, mRNA expressions of IL-4, IL-5, IL-13 and GATA-3 in the lungs, spleen and intestine along with anaphylactic symptoms indicative of allergic responses. Further, flow cytometry analysis and immunohistochemical studies indicated increased levels of IL-4, IL-5, IL-13 and GATA-3, respectively as compared to controls. The level of Foxp3 was found suppressed in the intestine of phaseolin treated mice when compared to the control. Further, phaseolin treated mice showed positive results in type 1 skin test. Bone marrow derived mast cells (BMMCs) and rat basophilic leukemia (RBL 2H3) cells showed enhanced release of allergic mediators like beta hexosaminidase, histamine, cysteinyl leukotrienes and prostaglandin D2. Taken together, phaseolin was found to possess characteristics of a potential allergen that may lead to hypersensitivity responses in the susceptible individuals and this may be one of the major proteins responsible for allergenicity of red kidney bean. PMID- 24468679 TI - Recombinant soluble CD226 protein directly inhibits cancer cell proliferation in vitro. AB - Interactions between CD155 and nectins on tumor cells have been reported to potentially inhibit tumor growth. CD226, a receptor that recognizes CD155 and CD112, is an activation receptor of NK and T cells by which immune cells may attack a tumor. The purpose of this study is to explore whether soluble CD226 (sCD226) directly inhibits tumor growth by binding CD155 or CD112 on tumor cells. We expressed, purified and confirmed the identity of recombinant sCD226 (19aa 248aa) and then examined the effect of sCD226 on tumor cell growth using CD226 ligand (CD155 and CD112)-expressing cancer cell lines (K562, HeLa). After 3days of co-culture with sCD226, we found that the numbers of K562 and HeLa cells were significantly reduced but those of a CD226-blocking mAb specifically attenuated the inhibitory effects of sCD226. We also noted that the sCD226 protein could compete with a PE-conjugated anti-CD112 antibody in flow cytometric analysis and block the binding of the PE-conjugated anti-CD112 antibody to tumor cells. Mechanistic studies using flow cytometric analysis demonstrated that sCD226 inhibited the division of CFSE (carboxyfluorescein diacetate succinimidyl ester) labeled K562 cells by delaying the cell cycle. In addition, we observed that sCD226 might have an impact on the metastatic potential of solid tumors in vitro. These results demonstrated that sCD226 molecule might be a potential biotherapy against tumor for further development. PMID- 24468676 TI - Oxygen sensing strategies in mammals and bacteria. AB - The ability to sense and adapt to changes in pO2 is crucial for basic metabolism in most organisms, leading to elaborate pathways for sensing hypoxia (low pO2). This review focuses on the mechanisms utilized by mammals and bacteria to sense hypoxia. While responses to acute hypoxia in mammalian tissues lead to altered vascular tension, the molecular mechanism of signal transduction is not well understood. In contrast, chronic hypoxia evokes cellular responses that lead to transcriptional changes mediated by the hypoxia inducible factor (HIF), which is directly controlled by post-translational hydroxylation of HIF by the non-heme Fe(II)/alphaKG-dependent enzymes FIH and PHD2. Research on PHD2 and FIH is focused on developing inhibitors and understanding the links between HIF binding and the O2 reaction in these enzymes. Sulfur speciation is a putative mechanism for acute O2-sensing, with special focus on the role of H2S. This sulfur-centered model is discussed, as are some of the directions for further refinement of this model. In contrast to mammals, bacterial O2-sensing relies on protein cofactors that either bind O2 or oxidatively decompose. The sensing modality for bacterial O2-sensors is either via altered DNA binding affinity of the sensory protein, or else due to the actions of a two-component signaling cascade. Emerging data suggests that proteins containing a hemerythrin-domain, such as FBXL5, may serve to connect iron sensing to O2-sensing in both bacteria and humans. As specific molecular machinery becomes identified, these hypoxia sensing pathways present therapeutic targets for diseases including ischemia, cancer, or bacterial infection. PMID- 24468680 TI - PANDER transgenic mice display fasting hyperglycemia and hepatic insulin resistance. AB - PANcreatic-DERived factor (PANDER, FAM3B) is a novel protein that is highly expressed within the endocrine pancreas and to a lesser degree in other tissues. Under glucose stimulation, PANDER is co-secreted with insulin from the beta-cell. Despite prior creation and characterization of acute hepatic PANDER animal models, the physiologic function remains to be elucidated from pancreas-secreted PANDER. To determine this, in this study, a transgenic mouse exclusively overexpressing PANDER from the endocrine pancreas was generated. PANDER was selectively expressed by the pancreatic-duodenal homeobox-1 (PDX1) promoter. The PANDER transgenic (PANTG) mice were metabolically and proteomically characterized to evaluate effects on glucose homeostasis, insulin sensitivity, and lipid metabolism. Fasting glucose, insulin and C-peptide levels were elevated in the PANTG compared with matched WT mice. Younger PANTG mice also displayed glucose intolerance in the absence of peripheral insulin sensitivity. Hyperinsulinemic euglycemic clamp studies revealed that hepatic glucose production and insulin resistance were significantly increased in the PANTG with no difference in either glucose infusion rate or rate of disappearance. Fasting glucagon, corticosterones, resistin and leptin levels were also similar between PANTG and WT. Stable isotope labeling of amino acids in cell culture revealed increased gluconeogenic and lipogenic proteomic profiles within the liver of the PANTG with phosphoenol-pyruvate carboxykinase demonstrating a 3.5-fold increase in expression. This was matched with increased hepatic triglyceride content and decreased p-AMPK and p-acetyl coenzyme A carboxylase-1 signaling in the PANTG. Overall, our findings support a role of pancreatic beta-cell-secreted PANDER in the regulation of hepatic insulin and lipogenenic signaling with subsequent impact on overall glycemia. PMID- 24468682 TI - Influence of indoor and outdoor temperatures on the fingertip blood flow rate. AB - A total of 58 healthy subjects participated to elucidate the influence of indoor and outdoor temperatures on blood flow. After walking outdoors for 20 min, the blood flow rate of a subject was measured. The subject then entered a classroom and studied for 120 min, and afterwards, the blood flow rate was measured again. The subjects were exposed to outdoor temperature ranging from -2.5 to 33.7 degrees C. During the summer, the average blood flow rate after walking outdoors was 45.95 +/- 25.790 TPU (tissue perfusion units); after the class, this decreased to 36.14 +/- 21.837 TPU (p<0.05). During the autumn, the blood flow rate decreased from 27.69 +/- 12.334 TPU to 12.47 +/- 12.255 TPU (p<0.001). When the outside air temperature was below 3 degrees C, the blood flow rate indoors increased significantly from 6.74 +/- 3.540 TPU to 13.95 +/- 11.522 TPU (p<0.05). In a comfortable and healthy environment, the blood flow rate was not constant but fluctuated between 15 TPU and 40 TPU. PMID- 24468681 TI - Kinetic behaviour of the cells touching substrate: the interfacial stiffness guides cell spreading. AB - To describe detailed behaviour of cell spreading under the influence of substrate stiffness, A549 cells cultured on the surfaces of polydimethylsiloxane (PDMS) and polyacrylamide (PAAm) with bulk rigidities ranging from 0.1 kPa to 40 kPa were in situ observed. The spreading behaviour of cells on PAAm presented a positive correlation between spreading speed and substrate stiffness. After computing the deformations of PAAm gels and collagen, the bulk stiffness of PAAm, rather than matrix tethering, determined the cell behaviour. On the other hand, spreading behaviour of the cells was unaffected by varying the bulk stiffness of PDMS. Based on simulation analyses, the elasticity of silica-like layer induced by UV radiation on PDMS surface dominated cell-substrate interaction, rather than the bulk stiffness of the material, indicating that it is the interfacial stiffness that mainly guided the cell spreading. And then the kinetics of cell spreading was for the first time modeled based on absolute rate theory. PMID- 24468684 TI - Comparative analysis of two phenologically divergent populations of the pine processionary moth (Thaumetopoea pityocampa) by de novo transcriptome sequencing. AB - The pine processionary moth Thaumetopoea pityocampa is a Mediterranean lepidopteran defoliator that experiences a rapid range expansion towards higher latitudes and altitudes due to the current climate warming. Its phenology - the time of sexual reproduction - is certainly a key trait for the local adaptation of the processionary moth to climatic conditions. Moreover, an exceptional case of allochronic differentiation was discovered ca. 15 years ago in this species. A population with a shifted phenology (the summer population, SP) co-exists near Leiria, Portugal, with a population following the classical cycle (the winter population, WP). The existence of this population is an outstanding opportunity to decipher the genetic bases of phenology. No genomic resources were so far available for T. pityocampa. We developed a high-throughput sequencing approach to build a first reference transcriptome, and to proceed with comparative analyses of the sympatric SP and WP. We pooled RNA extracted from whole individuals of various developmental stages, and performed a transcriptome characterisation for both populations combining Roche 454-FLX and traditional Sanger data. The obtained sequences were clustered into ca. 12,000 transcripts corresponding to 9265 unigenes. The mean transcript coverage was 21.9 reads per bp. Almost 70% of the de novo assembled transcripts displayed significant similarity to previously published proteins and around 50% of the transcripts contained a full-length coding region. Comparative analyses of the population transcriptomes allowed to investigate genes specifically expressed in one of the studied populations only, and to identify the most divergent homologous SP/WP transcripts. The most divergent pairs of transcripts did not correspond to obvious phenology-related candidate genes, and 43% could not be functionally annotated. This study provides the first comprehensive genome-wide resource for the target species T. pityocampa. Many of the assembled genes are orthologs of published Lepidoptera genes, which allows carrying out gene-specific re sequencing. Data mining has allowed the identification of SNP loci that will be useful for population genomic approaches and genome-wide scans of population differentiation to identify signatures of selection. PMID- 24468683 TI - Influence of pressure-relief insoles developed for loaded gait (backpackers and obese people) on plantar pressure distribution and ground reaction forces. AB - The aims of this study were to test the effects of two pressure relief insoles developed for backpackers and obese people on the ground reaction forces (GRF) and plantar pressure peaks during gait; and to compare the GRF and plantar pressures among normal-weight, backpackers, and obese participants. Based on GRF, plantar pressures, and finite element analysis two insoles were manufactured: flat cork-based insole with (i) corkgel in the rearfoot and forefoot (SLS1) and with (ii) poron foam in the great toe and lateral forefoot (SLS2). Gait data were recorded from 21 normal-weight/backpackers and 10 obese participants. The SLS1 did not influence the GRF, but it relieved the pressure peaks for both backpackers and obese participants. In SLS2 the load acceptance GRF peak was lower; however, it did not reduce the plantar pressure peaks. The GRF and plantar pressure gait pattern were different among the normal-weight, backpackers and obese participants. PMID- 24468685 TI - Texas forced life-support case could happen in Canada. PMID- 24468686 TI - RCT wins CMAJ Bruce Squires Award. PMID- 24468687 TI - Rural premedicine program aims to tackle doctor shortages. PMID- 24468688 TI - Lower urinary tract symptoms in a 66-year-old man. PMID- 24468691 TI - Screening immigrants for latent tuberculosis: do we have the resources? PMID- 24468692 TI - Moving magic as hospitals merge in Montreal. PMID- 24468693 TI - Postmenopausal hormone replacement therapy and risk of acute pancreatitis: a prospective cohort study. AB - BACKGROUND: Several case reports have suggested that women's use of exogenous sex hormones is associated with acute pancreatitis; however, relevant epidemiologic data are sparse. We examined the association between postmenopausal hormone replacement therapy and risk of acute pancreatitis. METHODS: We conducted a prospective study involving 31,494 postmenopausal women (aged 48-83 yr) from the population-based Swedish Mammography Cohort. Participants completed a baseline questionnaire in 1997 assessing their use of hormone replacement therapy. We linked the cohort to the hospital-based Swedish National Patient Register to determine hospital admissions for acute pancreatitis through 2010. Relative risks (RRs) were calculated using Cox proportional hazard models. RESULTS: Over a total follow-up of 389,456 person-years, we identified 237 cases of incident acute pancreatitis. The age-standardized incidence rates per 100,000 person-years were 71 cases among women who had ever used hormone replacement therapy and 52 cases among women who had never used such hormones. Among ever users of hormone replacement therapy, the multivariable-adjusted RR of acute pancreatitis was 1.57 (95% confidence interval [CI] 1.20-2.05) compared with never users. The risk did not differ by current or past use, but it seemed to be higher among women who used systemic therapy (RR 1.92, 95% CI 1.38-2.66) and among those with duration of therapy of more than 10 years (RR 1.87, 95% CI 1.11-3.17). INTERPRETATION: Use of postmenopausal hormone replacement therapy was associated with increased risk of acute pancreatitis. Physicians should consider this potential increase in risk when prescribing such therapy. PMID- 24468695 TI - Gene regulation: Characterizing monoallelic expression. PMID- 24468694 TI - Prevention and treatment of the common cold: making sense of the evidence. PMID- 24468697 TI - Gene expression: Consequences of parent-of-origin effects. PMID- 24468696 TI - Ribosome profiling: new views of translation, from single codons to genome scale. AB - Genome-wide analyses of gene expression have so far focused on the abundance of mRNA species as measured either by microarray or, more recently, by RNA sequencing. However, neither approach provides information on protein synthesis, which is the true end point of gene expression. Ribosome profiling is an emerging technique that uses deep sequencing to monitor in vivo translation. Studies using ribosome profiling have already provided new insights into the identity and the amount of proteins that are produced by cells, as well as detailed views into the mechanism of protein synthesis itself. PMID- 24468698 TI - Disease genetics: Tools to exploit familial data. PMID- 24468699 TI - Rh(III)-catalyzed intramolecular redox-neutral cyclization of alkenes via C-H activation. AB - Biologically interesting fused oligocyclic lactams have been prepared via an intramolecular redox-neutral cyclization process. By the proper choice of the substrates with a wide variety of tethered olefins, the less favored C-H bond can be activated and functionalized. This C-H activation proceeds under mild conditions, obviates the need for external oxidants, and displays a broad scope with respect to the substituents. PMID- 24468702 TI - [Outpatient vaginal hysterectomy, feasibility and morbidity: an observational study on thirty patients]. AB - OBJECTIVE: Outpatient surgery is nowadays a major evolution axis of the surgery in France. Outpatient vaginal hysterectomy is possible with the use of electrosurgical bipolar vessel sealing allowing the reduction of operative time and postoperative pain. Our aim was to study the feasibility and morbidity of outpatient vaginal hysterectomy by assessment of postoperative pain and satisfaction. PATIENTS AND METHODS: Thirty patients were enrolled in this observational study. All patients underwent an outpatient vaginal hysterectomy with a standardized operative technic. Pain was evaluated by administering a 10 cm visual analogic scale (VAS) at the first and second postoperative days. The total duration of analgesic treatment was noticed. Patient's satisfaction was recorded at the postoperative visit one month after the intervention and by a telephonic interview. RESULTS: The mean operative time was 59.3 (25-110) minutes and the mean uterine weight was 170.2 (60-710) grams. No intraoperative complications were reported. Among the thirty patients, 3 (10%) were not discharged the same day. At the first and second postoperative days, the VAS was 4.40 and 4.35 respectively. The mean total duration of analgesic's use was 5 days (3-8 days). Patients were very satisfied of medical care in 36.7% of cases (11/30), satisfied in 53.3% (16/30) and not much satisfied in 10% (3/30). In total, 83.3% (25/30) have agreed to repeat the procedure in the ambulatory sector. DISCUSSION AND CONCLUSION: Outpatient vaginal hysterectomy seems to be a possible and a safe technique with a high patient's satisfaction in France at the present time. PMID- 24468700 TI - Overexpression of gastric leptin precedes adipocyte leptin during high-fat diet and is linked to 5HT-containing enterochromaffin cells. AB - OBJECTIVES: In obesity, while hyperleptinemia highly correlates with excess fat mass, the status of gastric leptin remains unknown. Here, we investigated the expression of leptin in stomach biopsies of obese humans and analyzed the temporal changes of gastric leptin expression in response to diet-induced obesity and its impact on 5-hydroxytryptamine (5HT)-producing cells. METHODS: Enterochromaffin (EC) cells and expression of leptin, PAX4 (critical factor for EC specification), tryptophane hydroxylase-1 (TPH1, the peripheral rate-limiting enzyme for 5HT) and 5HT were examined by immunofluorescence, quantitative real time PCR, radioimmunoassay, respectively, in stomach and duodenum biopsies from 19 obese and 14 normo-weighed individuals, and in mucosa scrapings from C57Bl6/J diet-induced obese mice, leptin-deficient ob/ob mice and intestine-specific leptin receptor isoform B-deficient mice. RESULTS: Gastric mucosa of obese subjects displays an increased expression of leptin (LEP mRNA by fivefold and protein by twofold, P<0.01), TPH1 ((1.75-2.73, 95% confidence interval (CI)) vs (0.38-0.67, 95% CI); P<0.01) and PAX4 ((1.33-2.11, 95%CI) vs (0.62-0.81, 95% CI); P<0.01) as compared with normo-weighed individuals. In diet-induced obese mice, the overexpressions of gastric leptin, antral Pax4, Tph1 and increased EC cell number occurred before the onset of obesity and hyperleptinemia (reflect of adipocyte leptin production). In addition, leptin deficiency was associated with reduced Pax4 mRNA, whereas oral leptin treatment enhanced both Tph1 and Pax4 mRNA. Finally, mice with an intestine-specific deletion of leptin signaling exhibit significant decrease in duodenal mucosa 5HT content. CONCLUSIONS: These data demonstrate that gastric leptin is upregulated in obese individuals. RESULTS from high-fat diet mice showed that overexpression of gastric leptin that is linked to gut '5HT pathway' occurred before the onset of obesity and expansion of fat mass. This may be relevant in the pathophysiology of obesity. PMID- 24468701 TI - Effect of bariatric surgery on microvascular dysfunction associated to metabolic syndrome: a 12-month prospective study. AB - OBJECTIVE: To prospectively evaluate the effect of weight loss after bariatric surgery on microvascular function in morbidly obese patients with and without metabolic syndrome (MetS). METHODS: A cohort of morbidly obese patients with and without MetS was studied before surgery and after 12 months of surgery. Healthy lean controls were also examined. Microvascular function was assessed by postocclusive reactive hyperemia (PORH) at forearm skin evaluated by laser Doppler flowmetry (LDF). Cutaneous vascular conductance (CVC) was calculated from laser-Doppler skin blood flow and blood pressure. Regression analysis was performed to assess the contribution of different clinical, metabolic and biochemical parameters to microvascular function. RESULTS: Before surgery, 62 obese patients, 39 with MetS and 23 without MetS, and 30 lean control subjects were analyzed. The absolute area under the hyperemic curve (AUC(H)) CVC of PORH was significantly decreased in obese patients compared with lean control subjects. One year after surgery, AUC(H) CVC significantly increased in patients free of MetS, including patients that had MetS before surgery. In contrast, AUC(H) CVC did not significantly change in patients in whom MetS persisted after surgery. Stepwise multivariate regression analysis showed that only changes in HDL cholesterol (HDL-C) and oxidized LDL (oxLDL) independently predicted improvement of AUC(H) after surgery. These two variables together accounted for 40.9% of the variability of change in AUC(H) CVC after surgery. CONCLUSIONS: Bariatric surgery could significantly improve microvascular dysfunction in obese patients, but only in patients free of MetS after surgery. Improvement of microvascular dysfunction is strictly associated to postoperative increase in HDL C levels and decrease in oxLDL levels. PMID- 24468703 TI - [Progesterone and preterm delivery: back to the future?]. AB - Progesterone was widely used in France during the 1980s and 1990s to prevent preterm birth until some published cases of cholestasis suddenly stopped its prescription. Since then, multiple randomized controlled trials have emerged and demonstrated the efficiency of the treatment but also its safety at low doses. In order to clarify its indications, we performed a current literature review. We analyzed literature data according to different categories of risk and different routes of administration. Results confirm that progesterone is an efficient treatment to prevent preterm birth in singleton gestation with short cervical length, and in singleton gestation with prior preterm birth with or without short cervical length. Apart from these indications, progesterone, especially 17-alpha hydroxyprogesterone (17OHP), should not be used outside research protocols. PMID- 24468704 TI - High pressure induced changes in beef muscle proteome: correlation with quality parameters. AB - The relationship between pressure induced changes on individual proteins and selected quality parameters in bovine longissimus thoracis et lumborum (LTL) muscle was studied. Pressures ranging from 200 to 600 MPa at 20 degrees C were used. High pressure processing (HPP) at pressures above 200 MPa induced strong modifications of protein solubility, meat colour and water holding capacity (WHC). The protein profiles of non-treated and pressure treated meat were observed using two dimensional electrophoresis. Proteins showing significant differences in abundance among treatments were identified by mass spectrometry. Pressure levels above 200 MPa strongly modified bovine LTL proteome with main effects being insolubilisation of sarcoplasmic proteins and solubilisation of myofibrillar proteins. Sarcoplasmic proteins were more susceptible to HPP effects than myofibrillar. Individual protein changes were significantly correlated with protein solubility, L, b and WHC, providing further insights into the mechanistic processes underlying HPP influence on quality and providing the basis for the future development of protein markers to assess the quality of processed meats. PMID- 24468705 TI - The impact of packaging system and temperature abuse on the shelf life characteristics of ground beef. AB - New ground beef packaging systems have warranted investigation of their spoilage and quality characteristics. Furthermore, analysis of ground beef spoilage in modified atmosphere packaging (MAP) and stored at abusive temperature is lacking. This research aimed to determine the effect of packaging systems and temperature abuse on the sensory and shelf-life characteristics of ground beef. Ground beef patties were packaged using polyvinyl chloride overwrap (OW), HI-OX MAP (80% O2, 20% CO2), LO-OX MAP (30% CO2, 70% N2), CO-MAP (0.4% CO, 30% CO2, 69.6% N2), or vacuum (VAC) prior to color, odor, biochemical, and microbial analyses over display. CO-MAP exhibited more desirable color and consumer acceptability throughout display. Lean discoloration and odor scores were lower for anaerobic packaging than aerobic packaging. Microbial results mirrored sensory preferences for anaerobic packaging. These results indicate anaerobic packaging extends shelf life properties and desirable sensory attributes throughout display and temperature abuse. PMID- 24468706 TI - The enhanced catalytic performance of cobalt catalysts towards butadiene polymerization by introducing a labile donor in a salen ligand. AB - A family of cobalt complexes supported by a tridentate Schiff base ligand with a labile donor (O, S, N) as a pendant arm (Co1-Co12, formulated as CoL2) were synthesized by the treatment of the corresponding ligands with cobalt acetate tetrahydrate. The resultant complexes were well characterized by elemental analysis, FT-IR, magnetic moment as well as EI-MS. The solid-state structures of Co7 and Co12 were determined by X-ray diffraction and both established a distorted octahedron geometry around the cobalt center. The butadiene polymerization capabilities of the 12 complexes were evaluated and compared in representative cases. Diethylaluminum chloride (AlEt2Cl) was found to be the compatible activator resulting in highly active catalysts for producing polybutadiene of 93.8-98.2% cis-1,4 enchainment with negligible 1,2-structure and trans-1,4 units. It appears that a certain degree of lability of the donor is beneficial for high catalytic activity, generally following the order of O > S > N, and the high cis-1,4 selectivity. Moreover, the remarkable thermal stability of these systems has been achieved: the catalytic systems have the ability of conducting a high level of active and selective polymerization, reaching an upper limit of polymerization temperature of about 70 degrees C. The enhanced catalytic performances were further rationalized by the established diene polymerization mechanism, which could shed light on developing highly selective and reactive industrially applicable catalysts with an enhanced thermal stability. PMID- 24468707 TI - FeSe2 films with controllable morphologies as efficient counter electrodes for dye-sensitized solar cells. AB - The FeSe2 films with controllable morphologies (including 3D flower-like and sphere-shaped) have been applied as the counter electrodes (CEs) for dye sensitized solar cells (DSSCs). It is found that 3D flower-like FeSe2 CEs perform comparably to conventional platinum CEs (power conversion efficiencies of 8.00 and 7.87%, respectively). PMID- 24468708 TI - Meeting the fetal requirement for polyunsaturated fatty acids in pregnancy. AB - PURPOSE OF REVIEW: The aim of this review is to summarize recent evidence on the importance of individual long chain polyunsaturated fatty acid (LCPUFA) to the developing fetus and the maternal dietary requirement for these. RECENT FINDINGS: Large-scale randomized controlled trials and innovative genetic and stable isotope studies are providing new insights in this field. SUMMARY: Large randomized controlled trials of LCPUFA supplementation in pregnancy suggest that higher n-3 LCPUFA intake reduces the risk of preterm birth and increases the length of gestation, with secondary effects on birth weight. There is little evidence of an effect on postnatal visual function and cognition, but interpretation is complicated by maternal metabolic adaptations and adipose tissue status in the newborn. The links between polymorphisms in the FADS genes and tissue fatty acid composition suggest that LCPUFA synthesis influences overall availability. Stable isotope studies have also demonstrated the capacity for LCPUFA synthesis in pregnancy, the fact that n-6 synthesis is greater than n 3, metabolic channeling of individual fatty acids to different fates, and selective placental transfer. Studies linking FADS genotype to cognition imply that n-3 LCPUFA synthesis could have an effect on infant cognition, but more large-scale genetic studies are needed. PMID- 24468709 TI - Comprehensive evaluation of hibernating myocardium: use of noninvasive imaging. AB - Ischemic heart failure is probably the most challenging issue in cardiology today, posing an enormous medical and financial burden on our society. Conceptually, it represents a maladaptive cardiac remodeling due to acute and/or chronic coronary artery disease with varying degrees of left ventricular dilatation and dysfunction. Although therapeutic options have improved overall survival over the years, mortality rates remain high, and in daily practice cardiologists not infrequently face the therapeutic dilemma whether a revascularization procedure will lead to symptomatic and prognostic benefit for the patient. Simple, straightforward guidelines are lacking because of the complexity of the disease. Moreover, the issue of viability imaging grounded on observational and retrospective studies has recently been challenged by the publication of prospective, randomized trials (eg, STICH and PARR trial) showing no benefit of revascularization nor of preprocedural viability assessment in those patients. These contradictory findings have obliged us to inquire whether viability imaging is still relevant and what is needed to make it more appropriate. PMID- 24468710 TI - Tuning morphology and photovoltaic properties of diketopyrrolopyrrole-based small molecule solar cells by taloring end-capped aromatic groups. AB - In this article, we selected BDT-DPP-BDT (DPP = diketopyrrolopyrrole and BDT = 4,8-di-2-(2-ethylhexyl)-thienyl-benzo[1,2-b:4,5-b']dithiophene) as the model backbone and end-capped it with hydrogen, octyl 2-cyano-3-(thiophen-2-yl)acrylate (CNR), and 2-hexylbithiophene (HTT), respectively, forming three small molecule donors: BDB, CNRBDB and HTTBDB. Introduction of a polar and planar electron withdrawing unit of CNR to both ends of the BDB backbone enhances the hole mobility from 4.14 * 10(-4) to 7.75 * 10(-3) cm(2) V(-1) s(-1) and raises the fill factor from 27 to 57% when blended with PC71BM. This is associated with the PC71BM phase size decreasing from 70 to 20 nm. When the electron-donating unit of HTT with poorer planarity is linked to both ends of the BDB backbone, both donor and acceptor phase sizes are decreased to 20 nm. The short-circuit current density is greatly improved from 4.22 to 9.66 mA cm(-2), and the fill factor is enhanced to 46%. Overall, this work demonstrates that the end-capped aromatic groups play an important role in tuning the phase size and photovoltaic properties of DPP-based small molecule solar cells. PMID- 24468711 TI - Vasoprotective effects of an endothelin receptor antagonist in ovariectomized female rats. AB - AIMS: The effects of hormone replacement therapy with estrogen on cardiovascular disease in postmenopausal women are still controversial. In the present study, we examined the effects of an endothelin (ET) receptor antagonist (ERA) and/or angiotensin receptor blocker (ARB) on neointimal formation following vascular injury in ovariectomized (OVX) female rats. MAIN METHODS: Female rats were divided into intact female and OVX groups. The right carotid artery was subjected to balloon injury, and harvested 2 weeks later. KEY FINDINGS: In the intact female groups, treatment with ARB (L-158809; 1 mg/kg/day) for two weeks after the injury significantly decreased neointimal formation, whereas treatment with the ERA (J-104132; 10 mg/kg/day) did not affect neointimal formation. On the other hand, the ERA markedly decreased neointimal formation after the injury in the OVX groups; however, neointimal formation was not significantly improved by the ARB treatment. In addition, the combined treatment with 17beta-estradiol (20 MUg/kg/day) or the ERA and ARB markedly suppressed neointimal formation after the balloon injury in the OVX groups, whereas no combinational effects were observed due to the combined treatment with 17beta-estradiol and the ERA. SIGNIFICANCE: These results suggest that ERAs have estrogen-like vasoprotective effects on neointimal formation following balloon injury in OVX rats. ERAs may be useful as an alternative therapy to prevent vascular disease in postmenopausal women. PMID- 24468712 TI - The retrobulbar sinus is superior to the lateral tail vein for the injection of contrast media in small animal cardiac imaging. AB - Cardiac perfusion studies using computed tomography are a common tool in clinical practice. Recent technical advances and the availability of dedicated small animal scanners allow the transfer of these techniques to the preclinical sector in general and to mouse models of cardiac diseases in particular. This necessitates new requirements for contrast injection techniques as a rapid transport of contrast media from the intravenous access to the animal heart. Clinical contrast agents containing high iodine concentrations are used within small animal studies although they exhibit a high viscosity which might limit their transport within the vasculature. The authors provide a comparison of the transport of contrast media following an injection into the lateral tail vein and an injection into the retrobulbar sinus and discuss the anatomy involved. The temporal evolution of a contrast bolus and its in vivo distribution is visualized. It is demonstrated that injecting contrast agents into the lateral tail vein of mice results in a retrograde blood flow to the liver veins and therefore does not deliver a detectable contrast bolus to the heart, and thus it cannot be used for cardiac perfusion studies. By contrast, boli injected into the retrobulbar sinus are rapidly transported to the heart and provide ventricular contrast enabling perfusion studies similar to those in human patients. The results demonstrate that an injection into the retrobulbar sinus is superior to an injection into the lateral tail vein for the delivery of contrast boli to the animal heart, while all drawbacks of an injection into the lateral tail vein are overcome. PMID- 24468713 TI - Chemo- and site-selective derivatizations of natural products enabling biological studies. AB - Bioactive natural products and derivatives remain an enduring starting point for the discovery of new cellular targets for disease intervention and lead compounds for the development of new therapeutic agents. The former goal is accomplished through the synthesis of bioactive cellular probes from natural products, enabling insights into the mechanism of action of these natural products by classical affinity chromatography or more recent proteome profiling methods. However, the direct and selective modification of native natural products for these purposes remains a challenge due to the structural complexity and the wide functional group diversity found in these natural substances. The lack of selective synthetic methods available to directly manipulate unprotected complex small molecules, in particular to perform structure-activity relationship studies and prepare appropriate cellular probes, has recently begun to be addressed, benefitting from the broader emerging area of chemoselective synthetic methodology. Thus, new reagents, catalysts and reaction processes are enabling both chemo- and site-selective modifications of complex, native natural products. In this review, we describe selected recent examples of these functionalization strategies in this emerging area. PMID- 24468714 TI - Effects of tacrolimus and insulin in a liver regeneration model in growing animals with portal vein stenosis: immunohistochemical and molecular studies. AB - The aim of the present investigation was to describe a new model of liver regeneration in growing rats with reduced portal flow. In addition, it was studied whether tacrolimus and insulin could have any pro-regenerative effect under such conditions. Ninety-five rats were divided into five groups: Group 1 (sham), abdominal incision without intervention; Group 2, 70% hepatectomy; Group 3, 70% hepatectomy + PV stenosis; Group 4, 70% hepatectomy + portal vein stenosis + insulin; and Group 5, 70% hepatectomy + portal vein stenosis + tacrolimus. The remnant liver lobes were harvested for analyses. The liver weight decreased in the PV stenosis group and it increased with the use of insulin and tacrolimus. The mitotic activity was higher in the hepatectomy, insulin and tacrolimus groups and this parameter was reduced by portal stenosis. Levels of interleukin 6 (IL-6) were higher in the hepatectomy group compared to the sham and PV stenosis groups. The expression of IL-6 and Ki67 was significantly increased in the insulin and tacrolimus groups compared to the portal stenosis group. A highly reproducible model was standardized to study liver regeneration with portal blood inflow reduction in weaning rats. It was demonstrated that insulin or tacrolimus administration may partially reverse the harmful effects of PV stenosis. PMID- 24468715 TI - Laparoscopic distal pancreatectomy to treat solid pseudopapillary tumors in children: transition from open to laparoscopic approaches in suitable cases. AB - PURPOSE: The aim of this study was to evaluate the outcomes of open and laparoscopic distal pancreatectomy (LDP) in the treatment of solid pseudopapillary tumors (SPT) in children. METHODS: This was a retrospective study of 22 patients under 18 years of age who underwent a distal pancreatectomy for SPT between January 1995 and December 2012. RESULTS: Fourteen patients and eight patients underwent LDP and open distal pancreatectomy (ODP), respectively, and 71.4 % of the LDP and 25.0 % of the ODP procedures were spleen-sparing operations. The median duration of surgery in the LDP group was shorter than that in the ODP group [175 (range 120-540) vs. 257 (range 200-305) min, p = 0.024]. There were no differences in postoperative complications. The LDP patients commenced oral intake earlier than the ODP patients [2.0 (range 1.0-7.0) vs. 4.0 (range 3.0-12.0) days, p = 0.010], and had an earlier discharge from hospital [7.0 (range 5.0-20.0) vs. 13.0 (range 7.0-22.0) days, p = 0.009]. CONCLUSION: LDP treatment for SPT in children is associated with a shorter hospitalization and a shorter time to oral intake compared to ODP. LDP is a safe and feasible option for SPT in select pediatric patients. PMID- 24468716 TI - Tissue-engineered cholecyst-derived extracellular matrix: a biomaterial for in vivo autologous bladder muscular wall regeneration. AB - PURPOSE: To compare the biocompatibility and histological aspects of cholecyst derived extra cellular matrix (CDECM) graft, either alone or with application of autologous detrusor muscles small fragments (ADMSF) on rabbit bladder mucosa for bladder augmentation. METHODS: The gallbladders were acellularized and evaluated for preserved acellular matrix scaffold and biophysical properties. Thirty rabbits were divided into five groups. Rabbits in the control group underwent partial detrusorectomy followed by perivesical fat coverage. Groups I and II underwent the same procedure and bladder mucosa was covered either by acellular rabbit gallbladder (ARG) (group I) or acellular sheep gallbladder (ASG) (group II). Groups III and IV underwent detrusorectomy and the bladder mucosal was seeded by ADMSF and covered by ARG (group III), or ASG (group IV). Biopsies were taken at 4, 12, and 24 weeks postoperatively. RESULTS: Higher expression of CD34 endothelial progenitor cells, CD31 microvessels, alpha-smooth muscle actin, S100, and cytokeratin with more organized muscular wall generation was demonstrated in groups III and IV. Expression of IHC markers was higher in groups III and IV compared with groups I and II in all the time points. CONCLUSION: The current study confirmed that autologous fragment-seeded CDECM can be considered as a reliable natural collagen scaffold for bladder augmentation. PMID- 24468717 TI - A closer look at the immediate trabecula response to combined parathyroid hormone and alendronate treatment. AB - Daily injections of parathyroid hormone (PTH) are the only FDA-approved anabolic treatment for osteoporosis; however PTH is only clinically approved for treatment periods of up to 24months. To enhance its anabolic effect, combining PTH with anti-resorptive therapy was proposed and expected to maximize the effectiveness of PTH. The current study aimed to elucidate structural mechanisms through which combination therapy can further improve bone strength over a limited treatment window of 12days, to more closely examine the early phase of the anabolic window. We examined 30 female rats treated with either vehicle (Veh), alendronate (ALN), PTH, or both PTH and ALN (PTH+ALN). Standard and individual trabecula segmentation (ITS)-based microstructural analyses were performed using in vivo micro-computed tomography. We found an increase in BV/TV in all treatments with the highest in the PTH+ALN group. Tb.Th* increased in both PTH and PTH+ALN groups well beyond that of the Veh or ALN group. SMI decreased in all treatments with PTH+ALN having the greatest tendency toward plate-like structures. ITS confirmed the trend toward more plate-like structures with increased plate Tb.N* and increased plate-to-rod ratio that was most pronounced in the PTH+ALN group. Using image-based finite element analysis, we demonstrated that stiffness increased in all treatment groups, again with the largest increase in the PTH+ALN group, indicating the resulting structural implications of increased plate-like structure. Static and dynamic bone histomorphometry and a serum resorption marker confirmed that PTH+ALN significantly increased bone formation activities and suppressed bone resorption activities. Overall the results indicate that PTH+ALN treatment has an additive effect due to a preferential increase in plate-like structures. PMID- 24468718 TI - Absence of femoral cortical thickening in long-term bisphosphonate users: implications for atypical femur fractures. AB - The radiographs of patients on long term bisphosphonates with atypical femur fractures demonstrate markedly thick cortices at the site of the fracture. We conducted a prospective clinical study to determine if cortical thickening is increased in long term bisphosphonate users. We recruited 43 patients who had taken bisphosphonates for more than 5 years. A group of 45 healthy volunteers and 12 patients recently diagnosed with osteoporosis served as controls. We measured the cortical thickening as the ratio of femoral cortical thickness to diameter of the femur, and looked for cortical beaking. No difference in the cortical thickness ratio was observed between long term bisphosphonate users and osteoporotic controls (0.53 vs. 0.54, p=0.659). No cases of cortical beaking were seen and no increase in thigh pain was observed. The power of the study was 95% to detect a 10% difference in cortical thickness ratio. We conclude that long term bisphosphonate use does not produce a generalized increase in subtrochanteric femoral cortical thickening in the majority of patients. PMID- 24468719 TI - Bone cell-independent benefits of raloxifene on the skeleton: a novel mechanism for improving bone material properties. AB - Raloxifene is an FDA approved agent used to treat bone loss and decrease fracture risk. In clinical trials and animal studies, raloxifene reduces fracture risk and improves bone mechanical properties, but the mechanisms of action remain unclear because these benefits occur largely independent of changes to bone mass. Using a novel experimental approach, machined bone beams, both from mature male canine and human male donors, were depleted of living cells and then exposed to raloxifene ex vivo. Our data show that ex vivo exposure of non-viable bone to raloxifene improves intrinsic toughness, both in canine and human cortical bone beams tested by 4-point bending. These effects are cell-independent and appear to be mediated by an increase in matrix bound water, assessed using basic gravimetric weighing and sophisticated ultrashort echo time magnetic resonance imaging. The hydroxyl groups (OH) on raloxifene were shown to be important in both the water and toughness increases. Wide and small angle X-ray scattering patterns during 4-pt bending show that raloxifene alters the transfer of load between the collagen matrix and the mineral crystals, placing lower strains on the mineral, and allowing greater overall deformation prior to failure. Collectively, these findings provide a possible mechanistic explanation for the therapeutic effect of raloxifene and more importantly identify a cell-independent mechanism that can be utilized for novel pharmacological approaches for enhancing bone strength. PMID- 24468720 TI - Population-based cohort study of warfarin-treated patients with atrial fibrillation: incidence of cardiovascular and bleeding outcomes. AB - OBJECTIVES: Atrial fibrillation (AF) is the most common cardiac rhythm disorder with a significant health burden. The aim of this study was to characterise patients with recently diagnosed AF and to estimate the rates of comorbidities and outcome events requiring hospitalisation in routine clinical practice. DESIGN: Pharmacoepidemiological cohort study using observational data. METHODS/SETTING: This study included 16 513 patients with a first diagnosis of AF between 1 January 2005 and 28 February 2010 (newly diagnosed patients) using data from the UK Clinical Practice Research Datalink (CPRD) linked to Hospital Episode Statistics (HES) and the Office for National Statistics mortality data. Exposure was stratified by vitamin K antagonist (VKA) exposure (non-use, current, recent and past exposure) based on prescriptions and/or international normalised ratio measurements, and followed for outcome events of interest based on diagnosis codes in the databases, that is, vascular outcomes, bleeding events and others. The main focus of the study was on outcome events requiring hospitalisation using the HES data. RESULTS: The incidence of vascular outcome hospitalisations (myocardial infarction (MI), stroke or systemic arterial peripheral embolism) was 3.8 (95% CI 3.5 to 4.0)/100 patient-years. The incidence of stroke was 0.9 (0.8 to 1.1) during current VKA exposure, 2.2 (1.6 to 2.9) for recent, 2.4 (1.9 to 2.9) for past and 3.4 (3.1 to 3.7) during non-use. MI incidence was 0.7 (0.6 to 0.9) for current VKA exposure, 0.7 (0.4 to 1.2) for recent, 1.1 (0.8 to 1.5) for past and 1.9 (1.7 to 2.1) during non-use. The incidence of bleeding event hospitalisations was 3.8 (3.4 to 4.2) for current VKA exposure, 4.5 (3.7 to 5.5) for recent, 2.7 (2.2 to 3.3) for past and 2.9 (2.6 to 3.2) during non-use; 38% of intracranial bleeds and 6% of gastrointestinal bleeds were fatal. CONCLUSIONS: This population-based study from recent years provides a comprehensive characterisation of newly diagnosed patients with AF and incidence estimates of common outcomes with a focus on hospitalised events stratified by VKA exposure. This study will help to place future data on new oral anticoagulants into perspective. PMID- 24468721 TI - Stratified medicine in European Medicines Agency licensing: a systematic review of predictive biomarkers. AB - OBJECTIVES: Stratified medicine is often heralded as the future of clinical practice. Key part of stratified medicine is the use of predictive biomarkers, which identify patient subgroups most likely to benefit (or least likely to experience harm) from an intervention. We investigated how many and what predictive biomarkers are currently included in European Medicines Agency (EMA) licensing. SETTING: EMA licensing. PARTICIPANTS: Indications and contraindications of all drugs considered by the EMA and published in 883 European Public Assessment Reports and Pending Decisions. PRIMARY AND SECONDARY OUTCOME MEASURES: Data were collected on: the type of the biomarker, whether it selected a subgroup of patients based on efficacy or toxicity, therapeutic area, marketing status, date of licensing decision, date of inclusion of the biomarker in the indication or contraindication and on orphan designation. RESULTS: 49 biomarker-indication-drug (B-I-D) combinations were identified over 16 years, which included 37 biomarkers and 41 different drugs. All identified biomarkers were molecular. Six drugs (relating to 10 B-I-D combinations) had an orphan designation at the time of licensing. The identified B-I-D combinations were mainly used in cancer and HIV treatment, and also in hepatitis C and three other indications (cystic fibrosis, hyperlipoproteinaemia type I and methemoglobinaemia). In 45 B-I-D combinations, biomarkers were used as predictive of drug efficacy and in four of drug toxicity. It appeared that there was an increase in the number of B-I-D combinations introduced each year; however, the numbers were too small to identify any trends. CONCLUSIONS: Given the large body of literature documenting research into potential predictive biomarkers and extensive investment into stratified medicine, we identified relatively few predictive biomarkers included in licensing. These were also limited to a small number of clinical areas. This might suggest a need for improvement in methods of translation from laboratory findings to clinical practice. PMID- 24468722 TI - EU member state government contribution to alternative methods. AB - Article 47 of the new EU Directive 2010/63/EU on the protection of animals used for scientific purposes requires national governments to contribute to the development and promotion of alternative methods. A recent survey of EU member states found that reported funding of alternative (3Rs) methods totalled ? 18.7 million in 2013, provided by only seven countries (Austria, Belgium, Denmark, Finland, Germany, Sweden, and the UK). There were indications that the contributions of some of these countries have increased since the implementation of the new Directive. However, funding of alternatives is between 0 and 0.036% of national science R&D expenditure and nearly half of the countries that responded reported that they do not specifically contribute. Data (and, by assumption, financial contribution) remains unavailable from half of the member states across the EU, regardless of the method of collection. PMID- 24468723 TI - In this issue of Gut Microbes. PMID- 24468724 TI - Intermanual transfer and proprioceptive recalibration following training with translated visual feedback of the hand. AB - Reaching with visual feedback that is misaligned with respect to the actual hand's location leads to changes in reach trajectories (i.e., visuomotor adaptation). Previous studies have also demonstrated that when training to reach with misaligned visual feedback of the hand, the opposite hand also partially adapts, providing evidence of intermanual transfer. Moreover, our laboratory has shown that visuomotor adaptation to a misaligned hand cursor, either translated or rotated relative to the hand, also leads to changes in felt hand position (what we call proprioceptive recalibration), such that subjects' estimate of felt hand position relative to both visual and non-visual reference markers (e.g., body midline) shifts in the direction of the visuomotor distortion. In the present study, we first determined the extent that motor adaptation to a translated cursor leads to transfer to the opposite hand, and whether this transfer differs across the dominant and non-dominant hands. Second, we looked to establish whether changes in hand proprioception that occur with the trained hand following adaptation also transfer to the untrained hand. We found intermanual motor transfer to the left untrained (non-dominant) hand after subjects trained their right (dominant) hand to reach with translated visual feedback of their hand. Motor transfer from the left trained to the right untrained hand was not observed. Despite finding changes in felt hand position in both trained hands, we did not find similar evidence of proprioceptive recalibration in the right or left untrained hands. Taken together, our results suggest that unlike visuomotor adaptation, proprioceptive recalibration does not transfer between hands and is specific only to the arm exposed to the distortion. PMID- 24468725 TI - Combining proprioception and touch to compute spatial information. AB - Localising a tactile stimulus in egocentric space involves integrating information from skin receptors with proprioceptive inputs about body posture. We investigated whether body posture automatically influences tactile spatial judgements, even when it is irrelevant to the task. In Experiment 1, participants received two successive tactile stimuli on the forearm and were asked to indicate whether the first or second touch of the pair was closer to an anatomical body landmark, either the wrist or the elbow. The task was administered in three experimental conditions involving different body postures: canonical body posture with extended forearm and hand pointing distally; a non-canonical body posture with forearm and hand pointing vertically up at 90 degrees and a 'reversed' body posture with the elbow fully flexed at 180 degrees , so that the hand pointed proximally. Thus, our task required localising touch on the skin and then relating skin locations to anatomical body landmarks. Critically, both functions are independent of the posture of the body in space. We nevertheless found reliable effects of body posture: judgement errors increased when the canonical forearm posture was rotated through 180 degrees . These results were further confirmed in Experiment 2, in which stimuli were delivered to the finger. However, additionally reversing the canonical posture of the finger, as well as that of the forearm, so that the finger was restored to its canonical orientation in egocentric space, restored performance to normal levels. Our results confirm an automatic process of localising the body in external space underlying the process of tactile perception. This process appears to involve a combination of proprioceptive and tactile information. PMID- 24468726 TI - Detecting subtle fingertip sensory and motor dysfunction in adults with type II diabetes. AB - Although evidence has emerged regarding functional neural impairment of all four limbs with a diagnosis of type II diabetes (T2D), there is conflicting evidence regarding impairment in manual function with the disease. The purpose of the current study was to evaluate hand/fingertip function in T2D as compared to healthy age- and gender-matched controls. Ten adults with T2D and ten healthy age and gender-matched control subjects underwent a battery of clinically validated and laboratory-based evaluations of sensory function, motor function, and quality of life evaluation. The T2D group exhibited sensory dysfunction and altered kinetic output and inconsistent differences in clinically-validated timed performance tasks as compared to age-matched controls. No difference in quality of life was found between the two groups. Sensory dysfunction and some timed evaluations correlated with disease severity. Linear kinetic features did not covary with diminished sensation; however, nonlinear measures did covary with sensation changes. None of the recorded measures were related to clinical diagnosis of peripheral neuropathy. The relationship among exhibited behavioral changes is discussed in terms of small fiber neuropathy, micro-vascular adaptations, and endothelial dysfunction co-occurring with T2D. PMID- 24468727 TI - The effects of nonextensivity on quantum dissipation. AB - Nonextensive dynamics for a quantum dissipative system described by a Caldirola Kanai (CK) Hamiltonian is investigated in SU(1,1) coherent states. To see the effects of nonextensivity, the system is generalized through a modification fulfilled by replacing the ordinary exponential function in the standard CK Hamiltonian with the q-exponential function. We confirmed that the time behavior of the system is somewhat different depending on the value of q which is the degree of nonextensivity. The effects of q on quantum energy dissipation and other parameters are illustrated and discussed in detail. PMID- 24468728 TI - Growth initiation in the geotropic response of the wheat node. AB - The geotropic response in stems of Triticum aestivum occurs at the leaf sheath bases. Growth is initiated in the lower halves of these organs after orientation into the horizontal position. Lateral transport of growth hormone is not involved in the development of curvature. Continuous stimulation is necessary to maintain the response.Growth can be initiated in small pieces of tissue excised from the leaf sheath base but this is entirely dependent upon the precise orientation of the tissue in the gravitational field. Growth occurs only when the segment is orientated horizontally with the outer epidermis facing downwards. IAA is able to initiate growth in nongeo-induced tissue segments of the leaf sheath base but this effect appears to differ from the geo-induced growth. PMID- 24468729 TI - Carrageenans in the gametophytic and sporophytic stages of Chondrus crispus. AB - The morphologically similar sporophytic and gametophytic plants of Chondrus crispus Stackhouse were examined and it was shown that the former contain lambda carrageenan. The gametophytes contain kappa- and two additional carrageenans which are KCl-soluble and may comprise up to 25% of the total carrageenan. After alkaline modification, these KCl-soluble components were separated into a gel and a soluble carrageenan. The gel was indistinguishable from kappa-carrageenan and presumably was derived from MU-carrageenan while the KCl-soluble fraction possessed a unique infrared spectrum easily distinguished from alkali-modified lambda-carrageenan. This appears to represent a third carrageenan in the gametophytes.Our observations suggest that the biologically separate plants of C. crispus exhibit distinctive patterns of sulfation of their galactans. The sporophytes add SO4 (2-) at C2 of the precursor, whereas the gametophytes appear to add it principally at the available C4 positions. Both types of plant are capable of sulfating at C6 of the 4-linked galactose unit. PMID- 24468730 TI - Cytochemical localization and antigenicity of alpha-amylase in barley aleurone tissue. AB - Gibberellic-acid(GA3)-induced alpha-amylase has been localised in barley aleurone layers using cytochemical methods and light microscopy. Evidence obtained from the use of a starch substrate film method as well as immunofluorescence indicated that the first amylase to appear in the cell was associated with aleurone grains, apparently with the outer membrane, and also with the peripheral cytoplasm. In GA3-treated tissue, the amylase distribution was much more diffuse, although patchy, throughout the cytoplasm and it tended to accumulate in the endosperm side of the cell. The possibility that the aleurone grain membrane is the site of gibberellin-induced enzyme synthesis and that it proliferates to become rough endoplasmic reticulum is considered. Immunological information was obtained which supports earlier indications that induced alpha-amylase consists of two different proteins, each with molecular heterogeneity. PMID- 24468731 TI - Cytokinins in Populus x robusta Schneid: A complex in leaves. AB - At least seven cytokinins have been detected in mature leaves of Populus x robusta Schneid after chromatography on Sephadex LH-20. Two of these have similar elution volumes to zeatin and zeatin riboside. A third appears to be a cytokinin glucoside. A fourth is a new, unidentified cytokinin, susceptible to mild oxidation, and yielding two cytokinin active products after acid hydrolysis. This cytokinin complex has been found in fully expanded leaves, a tissue in which cell division is completed. PMID- 24468732 TI - Metabolism of [2-(14)C] acetate to amino acids and proteins in segments of bean seedling roots. AB - (14)C from [2-(14)C] acetate was found to be incorporated into soluble and protein amino acids in substantial amounts by bean root apices. The (14)C was spread through a wide range of amino acids in both these fractions. Glutamic acid was found to be heavily labelled with (14)C in both soluble and protein amino acid fractions. The data are discussed in relation to present ideas on transport and utilization of amino acids in root systems. PMID- 24468733 TI - Effects of hydroxyproline on the growth of excised root segments of Pisum sativum under aseptic conditions. AB - The cis and trans isomers of 4-hydroxy-L-proline stimulated the extension growth of excised 2-4 mm pea root segments during culture. Increase in the uptake and subsequent incorporation of [(14)c]leucine into proteins was inhibited by both L isomers, and so also were changes in chloride uptake capacity and in protein metabolism measured in terms of invertase and peroxidase activities. Changes in [(14)C]proline uptake and incorporation, and in respiration, were unaffected. Proline had no effect on changes in extension growth or protein metabolism but did prevent the effects of both hydroxyproline isomers. Azetidine-2-carboxylic acid inhibited extension growth and all the aspects of protein metabolism studied, the effects again being all prevented by proline. It is suggested that hydroxyproline enhances growth by interfering with protein synthesis in the cell walls. PMID- 24468734 TI - [CO2-Fixation and translocation in benthic marine algae : V. A Histoautoradiographic study of the pathway of (14)C-labelled assimilates in Laminaria hyperborea]. AB - After local assimilation of NaH(14)CO3 by an old frond of Laminaria hyperborea, radioactive photosynthate is translocated to the growing region of the thallus. The pathway of this long-distance transport was studied by histoautoradiography. Cellular localization of the conducting channels was accomplished by new autoradiographic methods including freeze-substitution and 1 MUm-cuttings of epoxy resin embedded tissue. In the autoradiographs, patches of silver grains overlying single trumpet-filaments (=Trompetenzellen) indicated that downward translocation occurs in these cells only. It could be shown that predominantly young trumpetfilaments contain the bulk of labeling. It is concluded that the young filaments rather than the older ones are particularly active in translocation. A lateral movement of labelled material was not observed except in the growing region. PMID- 24468735 TI - [Inhibition of carotenoid synthesis during nitrogen deficiency]. AB - The ability to synthesize carotenoids during normal or strongly reduced nitrogen supply was tested in a higher plant (Hordeum vulgare L.) and in a green alga (Scenedesmus obliquus). Though carotenoids are nitrogenfree, their synthesis is strongly inhibited during nitrogen deficiency. The formation of secondary carotenoids, which apparently proceeds at the expense of the primary carotenoid components, occurs in Scenedesmus but not in Hordeum plants. It is concluded that the dimerisation of geranly-geranyl-pyrophosphate is the limiting step in the carotenoid synthesis during nitrogen deficiency. The synthesis of prenyl chains is less affected by nitrogen deficiency. PMID- 24468736 TI - [Investigations concerning the correlation between the light-dependent and the redox-dependent change of the membrane potential in Griffithsia setacea]. AB - 1. With the red alga Griffithsia setacea in the dark the addition of reduced DCPIP effects a depolarization of the membrane potential. The kinetics of this redox-dependent depolarization is in good conformity with that of the light dependent depolarization. Ascorbate as well as cystein are efficient as reducing substance. 2. By simultaneous application of light and reduced DCPIP it can be demonstrated that the light-dependent and the redox-dependent change of the membrane potential may be involved in the same system. 3. The redox-dependent membrane potential change is a function of the redox potential difference between oxidized and reduced DCPIP. In the linear range of this relation the simultaneously measured light-dependent membrane potential change corresponds to a redox potential difference of 124mV. 4. The redox-dependent membrane potential change, like the light-dependent membrane potential change, is dependent on the pH of the medium. Between pH 9.0 and pH 9.5a transition from a depolarization to a hyperpolarization of the membrane potential can be observed. 5. The results support the hypothesis that the redox level of a component in the photosynthetic electron transport chain may steer the light-dependent and the redox-dependent change of the membrane potential. PMID- 24468738 TI - Rare earth replacement magnets. PMID- 24468739 TI - Distribution of single-walled carbon nanotubes in pyrene containing liquid crystalline asymmetric zinc phthalocyanine matrix. AB - A novel pyrene containing asymmetric Zn(II) phthalocyanine (AB3 type) was synthesized and characterized by various spectroscopic techniques as well as elemental analysis. A symmetric polyoxyethylene substituted Zn(II) phthalocyanine (B4 type) derivative was also prepared in order to compare the properties and determine the effect of the pyrene group on the phthalocyanine molecule. Composites of synthesized zinc(II) phthalocyanine-single wall carbon nanotubes (ZnPc-SWCNTs) containing 1 and 2 wt% carbon nanotubes were prepared by mixing these two components in dichloromethane followed by removal of the solvent and drying under vacuum. The liquid crystalline properties of the pure compounds and their composites were investigated in comparison with symmetric polyoxyethylene substituted Zn(II) phthalocyanine (B4 type) by using polarized optical microscopy, differential scanning calorimetry and X-ray diffraction analysis. The distribution of the SWCNTs in the ordered matrix of the columnar mesophase of these derivatives was studied by the method of polarized Raman spectroscopy and scanning electron microscopy (SEM). It was shown that the nature of the mesophases was not altered in these composites. The I(V) dependencies for the films deposited onto interdigitated electrodes were measured and it was shown that the lateral conductivity tends to increase with increasing SWCNT concentration. PMID- 24468737 TI - Epigenetic regulation of EBV persistence and oncogenesis. AB - Epigenetic mechanisms play a fundamental role in generating diverse and heritable patterns of viral and cellular gene expression. Epstein-Barr virus (EBV) can adopt a variety of gene expression programs that are necessary for long-term viral persistence and latency in multiple host-cell types and conditions. The latent viral genomes assemble into chromatin structures with different histone and DNA modifications patterns that control viral gene expression. Variations in nucleosome organization and chromatin conformations can also influence gene expression by coordinating physical interactions between different regulatory elements. The viral-encoded and host-cell factors that control these epigenetic features are beginning to be understood at the genome-wide level. These epigenetic regulators can also influence viral pathogenesis by expanding tissue tropism, evading immune detection, and driving host-cell carcinogenesis. Here, we review some of the recent findings and perspectives on how the EBV epigenome plays a central role in viral latency and viral-associated carcinogenesis. PMID- 24468740 TI - Occurrence of parotoid glands in tadpoles of the tropical frog, Clinotarsus curtipes and their role in predator deterrence. AB - Tadpoles of the tropical bicolored frog, Clinotarsus curtipes are unique in having parotoid glands secreting a white viscous fluid and are structurally similar to granular glands from other amphibians. To ascertain the involvement of these glands and their secretion in predator deterrence, it was tested against a predatory fish, Clarias gariepinus, using a paired choice behavioral assay. The results showed that the fish avoid eating C. curtipes tadpoles when paired with tadpoles of a sympatric species, Sylvirana temporalis. While the fish fed on C. curtipes tadpoles whose parotoid glands were surgically removed, did not touch those with intact glands, suggesting a role for the parotoid gland secretion in predator deterrence. Histochemical and biochemical analyses of the gland secretion revealed the presence of high concentrations of proteins, lipids, and alkaloids. SDS-PAGE showed the presence of proteins with prominent bands at 17 and 50kDa. The presence of other small molecules (950-2000amu) as detected by LC MS showed the presence of five major peaks. Peaks 1 and 2 are probably tetrodotoxin and/or its analogs. Peaks 3 and 5 are possibly bufalin and argininosuccinic acid, respectively while peak 4 remains unidentified. Thus, secretion of parotoid glands of larval C. curtipes contains chemicals which, either alone or in combination, might be responsible for deterring predators. PMID- 24468741 TI - Huge myoid hamartoma of the breast treated with reduction mammaplasty: report of a case. AB - Breast hamartoma is an uncommon benign tumor characterized by the variety of component tissues. Adipose tissue, mammary glands, and fibrous tissue in various proportions are the main components and form a well-circumscribed mass. Myoid (muscular) hamartoma is an extremely rare subtype of breast hamartoma, which contains an additional smooth muscle component. Inadequate breast contour and nipple-areola complex malposition and expansion can occur after resection of a large myoid hamartoma. Immediate mammaplasty for the affected breast, using the dermoglandular flap technique, is required to provide symmetry of the bilateral breasts. We report a case of myoid hamartoma that was larger than ever documented before. An acceptable aesthetic result was achieved by resection and application of reduction mammaplasty in a single-stage operation. PMID- 24468742 TI - Aortoenteric fistula at the site of esophagojejunostomy after laparoscopic total gastrectomy: report of a case. AB - A fistula between the aorta and the digestive tract is a rare complication of gastrointestinal tract or vascular surgery. There are occasional reports of aortoesophageal fistula as a fatal complication after esophagectomy or esophageal stent implantation and of aortoenteric fistula (AEF) as a complication after aortic or other vascular procedures. However, AEF after gastrointestinal surgery is rare. We report a case of AEF after laparoscopic total gastrectomy for advanced gastric cancer, using the so-called overlap method of esophagojejunal anastomosis. The patient was a 77-year-old Japanese woman who underwent laparoscopic total gastrectomy and esophagojejunal anastomosis with Roux-en-Y reconstruction for advanced gastric cancer. Bacterial peritonitis was diagnosed 5 days after the operation, manifesting as partial necrosis and perforation of the small intestine. The patient was treated successfully with laparoscopic partial resection of the small intestine, but ultimately died of massive hematemesis caused by the AEF 30 days after her primary surgery. PMID- 24468743 TI - Bioactivation of 3-n-butylphthalide via sulfation of its major metabolite 3 hydroxy-NBP: mediated mainly by sulfotransferase 1A1. AB - 3-n-Butylphthalide (NBP) [(+/-)-3-butyl-1(3H)-isobenzofuranone] is an anti cerebral-ischemia drug. Moderate hepatotoxicity has been observed in clinical applications. One of the major metabolites, 3-N-acetylcysteine-NBP, has been detected in human urine, indicating the formation of a reactive metabolite. We elucidated the formation mechanism of the reactive metabolite and its association with the hepatotoxicity of NBP. The in vitro incubations revealed that 3 glutathione-NBP (3-GSH-NBP) was observed only in fresh rat liver homogenate rather than in liver microsomes, liver cytosol, or liver 9,000g supernatant supplemented with NADPH and GSH. We also detected 3-GSH-NBP when 3' phosphoadenosine-5'-phosphosulfate was added in GSH-fortified human liver cytosol (HLC). The formation of 3-GSH-NBP was 39.3-fold higher using 3-hydroxy-NBP (3-OH NBP) as the substrate than NBP. The sulfotransferase (SULT) inhibitors DCNP (2,6 dichloro-4-nitrophenol) and quercetin suppressed 3-GSH-NBP formation in HLC by 75 and 82%, respectively, suggesting that 3-OH-NBP sulfation was involved in 3-GSH NBP formation. Further SULT phenotyping revealed that SULT1A1 is the major isoform responsible for the sulfation. Dose-dependent toxicity was observed in primary rat hepatocytes exposed to 3-OH-NBP, with an IC50 of approximately 168 MUM. Addition of DCNP and quercetin significantly increased cell viability, whereas l-buthionine-sulfoximine (a GSH depleter) decreased cell viability. Overall, our study revealed the underlying mechanism for the bioactivation of NBP is as follows. NBP is first oxidized to 3-OH-NBP and further undergoes sulfation to form 3-OH-NBP sulfate. The sulfate spontaneously cleaves off, generating highly reactive electrophilic cations, which can bind either to GSH to detoxify or to hepatocellular proteins to cause undesirable side effects. PMID- 24468744 TI - Construction of a metal-organic monolayer-semiconductor junction on a hydrogen terminated Si(111) surface via Si-C covalent linkage and its electrical properties. AB - A metal-organic monolayer-semiconductor junction, exhibiting a diode behaviour, was constructed on a hydrogen-terminated n-type Si(111) by sequential surface reactions of (1) formation of an organic monolayer with a thiol terminal group, (2) platinum deposition onto the thiol group via adsorption of a platinum complex followed by chemical reduction, and finally (3) continuous Ag layer formation by electroless deposition. Rectifying behaviour was observed at this interface. PMID- 24468745 TI - Th2 cytokines increase Staphylococcus aureus alpha toxin-induced keratinocyte death through the signal transducer and activator of transcription 6 (STAT6). AB - Atopic dermatitis (AD) is an inflammatory skin disease characterized by increased T-helper type 2 (Th2) cytokine expression. AD skin lesions are often exacerbated by Staphylococcus aureus-mediated secretion of the lytic virulence factor, alpha toxin. In the current study, we report that alpha toxin-induced cell death is greater in the skin from patients with AD compared with controls. Furthermore, we find that keratinocyte differentiation and Th2 cytokine exposure influence sensitivity to S. aureus alpha toxin-induced cell death. Differentiated keratinocytes are protected from cell death, whereas cells treated with Th2 cytokines have increased sensitivity to alpha toxin-induced lethality. Our data demonstrate that the downstream effects mediated by Th2 cytokines are dependent upon host expression of STAT6. We determine that Th2 cytokines induce biochemical changes that decrease levels of acid sphingomyelinase (SMase), an enzyme that cleaves sphingomyelin, an alpha toxin receptor. Furthermore, Th2 cytokines inhibit the production of lamellar bodies, organelles critical for epidermal barrier formation. Finally, we determine that SMase and its enzymatic product, phosphocholine, prevent Th2-mediated increases in alpha toxin-induced cell death. Therefore, our studies may help explain the increased propensity for Th2 cytokines to exacerbate S. aureus-induced skin disease, and provide a potential therapeutic target for treatment of AD. PMID- 24468746 TI - Decreased expression of the chromatin remodeler ATRX associates with melanoma progression. PMID- 24468747 TI - Regulation of the dynamic chromatin architecture of the epidermal differentiation complex is mediated by a c-Jun/AP-1-modulated enhancer. AB - The epidermal differentiation complex (EDC) locus comprises a syntenic and linear cluster of genes whose concomitant expression is a hallmark feature of differentiation in the developing skin epidermis. Many of the EDC proteins are cross-linked together to form the cornified envelope, an essential and discrete unit of the mammalian skin barrier. The mechanism underlying coordinate transcriptional activation of the EDC is unknown. Within the human EDC, we identified an epidermal-specific regulatory enhancer, 923, which responded to the developmental and spatiotemporal cues at the onset of epidermal differentiation in the mouse embryo. Comparative chromosomal conformation capture assays in proliferating and differentiated primary mouse keratinocytes revealed multiple physiologically sensitive chromatin interactions between the 923 enhancer and EDC gene promoters, thus depicting the dynamic chromatin topology of the EDC. We elucidate a mechanistic link between c-Jun/AP-1 and 923, whereby AP-1- and 923 mediated EDC chromatin remodeling are required for functional EDC gene activation. Thus, we identify a critical enhancer/transcription factor axis governing the dynamic regulation of the EDC chromatin architecture and gene expression and provide a framework for future studies toward understanding gene regulation in cutaneous diseases. PMID- 24468748 TI - Intratumoral CD4+ T lymphodepletion sensitizes poorly immunogenic melanomas to immunotherapy with an OX40 agonist. AB - Previous studies have shown that the antitumor effects of OX40 agonists depend on the immunogenicity of the tumor and that poorly immunogenic tumors such as B16F10 melanomas do not respond to OX40 agonist treatment. In this study, we have shown that intratumoral CD4+ T lymphodepletion sensitized poorly immunogenic B16F10 melanomas to immunotherapy with an OX40 agonist. CD4+ T lymphodepletion dramatically altered the tumor immune microenvironment, making it more susceptible to the antitumor effects of an OX40 agonist by enhancing the accumulation of CD8+ T cells and natural killer (NK) cells in tumor tissue. However, unexpectedly, the number of CD11b+ Gr-1(+) myeloid-derived suppressor cells (MDSCs) within tumor tissues also significantly increased as a result of CD4+ T lymphodepletion. As a countermeasure against CD8+ T-cell accumulation, CCR2-positive CD11b+ Gr-1(int) (monocytic) MDSCs predominantly increased. Treatment with an OX40 agonist under CD4+ T lymphodepletion neither reduced MDSCs nor increased CD8+ T cells and NK cells, but further enhanced the expression of cytotoxic molecules from tumor-infiltrating effector cells. Our results suggest that combined immunotherapy using both an OX40 agonist and CD4+ T lymphodepletion could be a promising therapeutic strategy for poorly immunogenic tumors and might be more effective if further combined with a therapeutic strategy targeting MDSCs. PMID- 24468750 TI - Triphenylalanine peptides self-assemble into nanospheres and nanorods that are different from the nanovesicles and nanotubes formed by diphenylalanine peptides. AB - Understanding the nature of the self-assembly of peptide nanostructures at the molecular level is critical for rational design of functional bio-nanomaterials. Recent experimental studies have shown that triphenylalanine(FFF)-based peptides can self-assemble into solid plate-like nanostructures and nanospheres, which are different from the hollow nanovesicles and nanotubes formed by diphenylalanine(FF)-based peptides. In spite of extensive studies, the assembly mechanism and the molecular basis for the structural differences between FFF and FF nanostructures remain poorly understood. In this work, we first investigate the assembly process and the structural features of FFF nanostructures using coarse-grained molecular dynamics simulations, and then compare them with FF nanostructures. We find that FFF peptides spontaneously assemble into solid nanometer-sized nanospheres and nanorods with substantial beta-sheet contents, consistent with the structural properties of hundred-nanometer-sized FFF nano plates characterized by FT-IR spectroscopy. Distinct from the formation mechanism of water-filled FF nanovesicles and nanotubes reported in our previous study, intermediate bilayers are not observed during the self-assembly process of FFF nanospheres and nanorods. The peptides in FFF nanostructures are predominantly anti-parallel-aligned, which can form larger sizes of beta-sheet-like structures than the FF counterparts. In contrast, FF peptides exhibit lipid-like assembly behavior and assemble into bilayered nanostructures. Furthermore, although the self-assembly of FF and FFF peptides is mostly driven by side chain-side chain (SC-SC) aromatic stacking interactions, the main chain-main chain (MC-MC) interactions also play an important role in the formation of fine structures of the assemblies. The delicate interplay between MC-MC and SC-SC interactions results in the different nanostructures formed by the two peptides. These findings provide new insights into the structure and self-assembly pathway of di /tri-phenylalanine peptide assemblies, which might be helpful for the design of bioinspired nanostructures. PMID- 24468749 TI - Role of CRD-BP in the growth of human basal cell carcinoma cells. AB - Although the number of new cases of basal cell carcinoma (BCC) has increased rapidly in the last few decades, the molecular basis of its pathogenesis is not completely understood. Activation of the Hedgehog (Hh) signaling pathway has been shown to be a key factor driving the development of BCC. The Wnt/beta-catenin signaling pathway was also shown to be activated in BCCs and to perhaps modulate the activity of the Hh pathway. We have previously identified a mechanism by which Wnt signaling regulates the transcriptional outcome of the Hh signaling pathway. We demonstrated that coding region determinant-binding protein (CRD-BP), a direct target of the Wnt/beta-catenin signaling, binds to GLI1 mRNA, stabilizes it, and consequently upregulates its levels (mRNA and protein) and activities. We hypothesized that Wnt-induced and CRD-BP-dependent regulation of GLI1 expression and activities is important for the development of BCC. In this study, we show that CRD-BP is overexpressed in BCC and that its expression positively correlates with the activation of both Wnt and Hh signaling pathways. We also describe the generation and characterization of a human BCC cell line. This cell line was utilized to demonstrate the importance of CRD-BP-dependent regulation of GLI1 expression and activities in the development of BCC. PMID- 24468751 TI - Protonic defects in yttria stabilized zirconia: incorporation, trapping and migration. AB - Both classical and quantum mechanical simulation techniques have been applied to investigate the incorporation, migration and potential binding of protonic defects in bulk yttria-stabilised zirconia (YSZ). The calculated redox reaction energies are found to be high, although the reduction energies are lower than those of bulk cubic ZrO2 and are shown to decrease further with increasing Y content. The hydration energies for YSZ are also lower than the values calculated for bulk ZrO2 and are found to be lowest when the oxygen ion is in close proximity to at least one Y ion. Strong binding (proton trapping) energies are observed between the protons and additional acceptor dopants including Sc, Yb and Gd. These energies are found to vary significantly depending on local configuration and again are generally lower than the values for ZrO2. Density functional theory (DFT) calculations are used to determine energy barriers for proton transfers via neighbouring oxygen ions (Grotthuss-type mechanism). Energy barriers of 0.32-0.42 eV are obtained for the pathways with the closest O-O interatomic distances and are found to be very comparable to well-established proton conducting materials. PMID- 24468753 TI - Glucocorticoid-related bone changes from endogenous or exogenous glucocorticoids. AB - PURPOSE OF REVIEW: Glucocorticoids have a negative impact on bone through direct effects on bone cells and indirect effects on calcium absorption. Here, recent findings regarding glucocorticoid-induced osteoporosis, bone changes in patients with endogenous glucocorticoid derangements, and treatment of steroid-induced bone disease are reviewed. RECENT FINDINGS: Although the majority of our understanding arises from the outcomes of patients treated with exogenous steroids, endogenous overproduction appears to be similarly destructive to bone, but these effects are reversible with cure of the underlying disease process. Additionally, there are bone changes that occur in diseases that interrupt adrenal glucocorticoid production, both in response to our inability to perfectly match glucocorticoid replacement and also related to the underlying disease process. More investigation is required to understand which patients with endogenous overproduction or underproduction of glucocorticoid would benefit from osteoporosis treatment. Better understood is the benefit that can be achieved with currently approved treatments for glucocorticoid-induced osteoporosis from exogenous steroids. With growing concern of long-term use of bisphosphonates, however, further investigation into the duration of use and use in certain populations, such as children and premenopausal women, is essential. SUMMARY: Glucocorticoid-induced osteoporosis is a complex disease that is becoming better understood through advances in the study of exogenous and endogenous glucocorticoid exposure. Further advancement of proper treatment and prevention is on the horizon. PMID- 24468752 TI - A rapid and massive gene expression shift marking adolescent transition in C. elegans. AB - Organismal development is the most dynamic period of the life cycle, yet we have only a rough understanding of the dynamics of gene expression during adolescent transition. Here we show that adolescence in Caenorhabditis elegans is characterized by a spectacular expression shift of conserved and highly polymorphic genes. Using a high resolution time series we found that in adolescent worms over 10,000 genes changed their expression. These genes were clustered according to their expression patterns. One cluster involved in chromatin remodelling showed a brief up-regulation around 50 h post-hatch. At the same time a spectacular shift in expression was observed. Sequence comparisons for this cluster across many genotypes revealed diversifying selection. Strongly up-regulated genes showed signs of purifying selection in non-coding regions, indicating that adolescence-active genes are constrained on their regulatory properties. Our findings improve our understanding of adolescent transition and help to eliminate experimental artefacts due to incorrect developmental timing. PMID- 24468754 TI - Male hypogonadism and skeletal health. AB - PURPOSE OF REVIEW: To examine the role of testosterone in skeletal health in men. RECENT FINDINGS: Evidence from recent studies shows that the contributing role of testosterone to osteoporosis is modest and likely trumped by other factors such as estradiol levels. A few studies have documented an association between low testosterone levels and lower bone mineral density (BMD), increased prevalence of osteoporosis of the hip and low bone mass-related fractures. Other studies, however, have found that testosterone levels are not independent predictors of bone resorption or formation markers, BMD at the hip or incident fractures. Curiously, hypogonadism does not account for the increased osteoporosis seen in men with Klinefelter Syndrome. Regardless of hypogonadism status, two recent clinical trials have found fewer new morphometric vertebral fractures in men treated with zoledronic acid and increased BMD in men treated with denosumab. Denosumab was also shown to modestly increase bone-metastasis-free survival in men with castration-resistant prostate cancer. SUMMARY: Although male hypogonadism is associated with osteoporosis, estradiol is likely to be the more important hormone for bone health. Although a few large randomized controlled trials have been conducted in men with low bone density (a subset of whom have hypogonadism), more trials are needed, particularly with fractures as the main outcome. PMID- 24468755 TI - Breast cancer and osteoporosis. AB - PURPOSE OF REVIEW: Over the past few years, a number of studies have examined the relationship between breast cancer and osteoporosis, the effect of breast cancer treatment on bone health, and the effect of osteoporosis therapies on aromatase inhibitor-induced bone loss and breast cancer recurrence. New guidelines have been released on the prevention of osteoporotic fractures in women with breast cancer who are on aromatase inhibitors for adjuvant therapy. RECENT FINDINGS: Despite common factors linking high bone mineral density and increased risk of breast cancer, women with breast cancer are not protected from osteoporosis or osteoporotic fractures. Recent data suggest that aromatase inhibitors have a detrimental effect on bone mineral density and can increase the risk of fractures. Bisphosphonate therapy not only preserves aromatase inhibitor-induced bone loss, but may also improve disease-free survival and decrease risk of death in select women with breast cancer (i.e., postmenopausal women). SUMMARY: Osteoporosis and breast cancer are common in women, especially in postmenopausal women. Current guidelines suggest that we need to pay special attention to those on aromatase inhibitors to prevent adverse bone outcomes. PMID- 24468757 TI - Progress on the road to better medical care for transgender patients. AB - PURPOSE OF REVIEW: In order to improve transgender individuals' access to healthcare, primary care physicians and specialists alike should be knowledgeable about transgender medicine. This review is intended to provide concise transgender hormone treatment guidelines. RECENT FINDINGS: Transgender individuals report that the lack of knowledgeable providers represents the greatest barrier to transgender medical care. Hormone treatments are generally well tolerated and greatly benefit transgender patients. After physicians recognize that gender identity is stable, hormone treatments for transgender patients are often straightforward. A practical target for hormone therapy for transgender men (female to male) is to increase testosterone levels to the normal male physiological range (300-1000 ng/dl) by administering testosterone. A practical target for hormone therapy for transgender women (male to female) is to decrease testosterone levels to the normal female range (30-100 ng/dl) without supra-physiological levels of estradiol (<200 pg/ml) by administering an antiandrogen and estrogen. Patients should be monitored every 3 months for the first year and then every 6-12 months for hormonal effects. SUMMARY: Although more studies are required, recently published transgender medical treatment guidelines provide a good start toward making care of transgender patients more generalized and accessible to healthcare providers. PMID- 24468756 TI - Cystic fibrosis-related bone disease: insights into a growing problem. AB - PURPOSE OF REVIEW: This review will describe the clinical significance, pathogenesis and treatment of cystic fibrosis related bone disease (CFBD). RECENT FINDINGS: CFBD continues to increase as the life expectancy of individuals with cystic fibrosis increases. According to clinical guidelines, individuals with cystic fibrosis should be initially screened at the age of 18 years via dual energy x-ray absorptiometry, if not done so previously. The underlying pathogenesis of CFBD appears to be multifactorial, but increasing data imply a direct impact by the cystic fibrosis transmembrane conductance regulator (CFTR). CFTR deficiency and/or dysfunction impair osteoblast activity and differentiation, and indirectly promote osteoclast formation. Unfortunately, once diagnosed with CFBD, few cystic fibrosis tested medical therapies exist. SUMMARY: CFBD is an increasingly recognized complication that has a significant impact on the overall health of the individual. Recommendations to identify patients with cystic fibrosis who are at risk for fracture using dual-energy x-ray absorptiometry have been established. Therapeutic agents directly studied in patients with cystic fibrosis are limited to bisphosphonates, although other potential treatment agents exist. Finally, an improved understanding of the pathologic mechanisms will aid in the study and development of therapies. PMID- 24468758 TI - Management of juvenile gender dysphoria. AB - PURPOSE OF REVIEW: To describe the treatment of gender dysphoria in adolescents. RECENT FINDINGS: Careful study and evaluation of children with persistent severe gender dysphoria has led to the recommendation that puberty be suppressed at Tanner Stage II. If the dysphoria persists until age 16, treatment with sex steroids of the appropriate gender may begin at age 16 and be followed by gender appropriate surgery. SUMMARY: Protocols and results of treatment of early adolescents have demonstrated that the harmful effects of persistent gender dysphoria can be prevented. Pubertal suppression in early puberty not only prevents the severe distress, but also allows healthy adolescent development living in the appropriate gender. PMID- 24468759 TI - Safety of hormonal treatment in transgenders. AB - PURPOSE OF REVIEW: Discussion of short and long-term issues of cross-hormone treatment of transgender individuals in the light of recent literature. RECENT FINDINGS: Gender nonconformity has been depathologized and replaced by gender dysphoria in the Diagnostic and Statistical Manual of Mental Disorders version V.Safety of cross-sex hormone treatment is still a matter of debate, but the latest findings in literature are quite reassuring about short-term and long-term effects. No dramatic changes in recommendations for treatment have emerged in the past years, and for the most part, clinical work is based on Endocrine Society Clinical Guidelines published in 2009. SUMMARY: Most recent findings agreed on the importance of maintaining cross-sex hormone serum concentration within the physiological range, avoiding or limiting maximum peaks and troughs.Treatment must be highly individualized and transitioning patients need to be engaged in a 'clinical contract' with the physician in order to ensure compliance with prescribed treatments.Although overall mortality appears to be higher among transgender individuals, this in not attributed to hormonal treatment but to other causes mostly related to lifestyle habits. PMID- 24468760 TI - Sex reassignment surgery for transsexuals. AB - PURPOSE OF REVIEW: The purpose of this article is to report on the most recent findings on the current surgical treatments for sex reassignment surgery for both male-to-female and female-to-male transsexuals. RECENT FINDINGS: For male-to female sex reassignment surgery, researches aim to refine the inverted peno scrotal flap surgical technique in order to increase the neovaginal length and width, prevent complications and ameliorate the cosmetic outcome.Bowel segment vaginoplasty, used mainly for secondary cases, is becoming more and more common.For female-to-male sex reassignment surgery, the radial forearm flap is the only procedure that has proved to fulfil most of the patient expectations; however, because of a high complications rate, long recovery time and a large number of the required operations, and the absence of guarantee that patients will be satisfied, the free radial forearm flap is not the best option for every patient. Alternatives such as abdominal/groin flap, thigh flap and metaidoioplasty are very much used. SUMMARY: In order to provide the best care for transsexual patients, centres performing sex reassignment surgery should co operate and implement both the refinements and the new techniques offered and/or requested. PMID- 24468761 TI - Transgenderism and reproduction. AB - PURPOSE OF REVIEW: The development of new reproductive medicine techniques creates opportunities for preserving fertility in transgender persons. Before, losing fertility was accepted as the price to pay for transitioning. RECENT FINDINGS: The desire for children is present in many trans persons, as in the general population. Ethical concerns are sometimes raised against the preservation of fertility; however, the only unique aspect of this group is the gender transition of one of the parents. All other elements such as same sex parenthood, use of donor gametes, social stigma, etc., can be found in other groups of parents. Not all reproductive options for all trans persons are equal because not only the gametes are of importance, but also the sex of the (future) partner. In trans women, the best option to preserve gametes is cryopreservation of sperm by preference initiated before starting hormonal therapy. In trans men, donor sperm is most often used, but in theory, there are three options available to preserve fertility: oocyte banking, embryo banking and banking of ovarian tissue. SUMMARY: Fertility is possible for both trans men and women, but it requires timely cryopreservation of gametes or stopping cross-sex hormones and possible fertility treatments which are costly and may be unpleasant. Centers should elucidate their policy and inform trans persons on the possibilities and limitations. PMID- 24468762 TI - Care of the elderly transgender patient. AB - PURPOSE OF REVIEW: This review examines recent developments regarding the care of the elderly transgender patient. There is scant clinical or other relevant information related to this topic, as the phenomenon of gender incongruity has been largely misunderstood and underreported. It is important that guidelines for appropriate and sensitive care be established, as this population is proliferating due to media attention and greater access to care. RECENT FINDINGS: A preponderance of evidence exists establishing that gender nonconforming elders are subject to discriminatory healthcare treatment. Agencies that serve the elderly are rife with policies and practices that resist acknowledging the needs of this population. Most heathcare and service providers have little experience with this group and limited understanding of non-normative gender identification. Barriers to treatment amplify the challenges of ageing for the transgender person and can lead to nondisclosure of clinically relevant personal information. SUMMARY: Increasing numbers of ageing transgender individuals will be interfacing with health and care providers. Many of these individuals will require medical and surgical interventions for gender dysphoria. Therefore, a concise enunciation of guidelines and standards of care applicable to these elderly, and training of primary care and specialists to provide such care are necessary. Education for nurses, social workers, administrators and others who comprise the comprehensive care system must be mandatory. Finally, institutions and agencies must adapt and become inclusive of the spectrum of diverse individuals found across the changing social landscape. PMID- 24468763 TI - Coordination of healthcare for transsexual persons: a multidisciplinary approach. AB - PURPOSE OF REVIEW: To describe the experience in Spain concerning the public healthcare for transsexual persons using a multidisciplinary approach and to review the relevant literature. Treatment includes social and psychological support, cross-hormone treatment, and sex reassignment surgeries. Although the recommendations of The World Professional Association for Transgender Health are used as guidelines, the application of these standards of care varies considerably, probably because of specific clinical and country factors. RECENT FINDINGS: The sex reassignment process is complex and requires not only coordination of multiple procedures, but also lifetime follow-up of transsexual individuals. Gender units must provide high-quality services, been essential the principle of accessibility to resources together with a protocolized follow-up and anticipation of secondary effects from the clinical surgical treatment. Two recent challenges are juvenile gender dysphoria and gender variants, which increasingly consult professionals. SUMMARY: Transsexualism affects all adaptive physical and psychosocial aspects of a person. As diagnosis is based only on the history and personal perceptions, a broad social debate exists about the need for treatment financed by the public health systems. Some countries restrict the care to transsexuals with private medical policies. Thus, coordination of care also requires participation of the family and associations, with continuous information to the health authorities, the judiciary, and the media of each country. PMID- 24468765 TI - Albuminuria is controlled primarily by proximal tubules. PMID- 24468767 TI - Basic research: the long and the short of it-the temporal effects of renal lithium exposure are beginning to be unravelled. PMID- 24468768 TI - Acute kidney injury: late-onset acute kidney injury-subacute or more of the same? AB - Fujii and colleagues define 'subacute' kidney injury (s-AKI) as AKI that takes >7 days to develop, timed from admission or lowest creatinine measurement after admission. Although s-AKI is unlikely to be a distinct syndrome from AKI, the association with increased mortality highlights the need to monitor patient creatinine levels. PMID- 24468769 TI - Acute kidney injury: SOCS-3 expression detrimental in AKI. PMID- 24468766 TI - The emergence of the glomerular parietal epithelial cell. AB - Glomerular diseases are the leading causes of chronic and end-stage kidney disease. In the 1980s and 1990s, attention was focused on the biology and role of glomerular endothelial and mesangial cells. For the past two decades, seminal discoveries have been made in podocyte biology in health and disease. More recently, the glomerular parietal epithelial cell (PEC)-the fourth resident glomerular cell type-has been under active study, leading to a better understanding and definition of how these cells behave normally, and their potential roles in glomerular disease. Accordingly, this Review will focus on our current knowledge of PECs, in both health and disease. We discuss model systems to study PECs, how PECs might contribute to glomerulosclerosis, crescent and pseudocrescent formation and how PECs handle filtered albumin. These events have consequences on PEC structure and function, and PECs have potential roles as stem or progenitor cells for podocytes in glomerular regeneration, which will also be described. PMID- 24468773 TI - Reply: podocytes are key-although albumin never reaches the slit diaphragm. PMID- 24468774 TI - Safety evaluations under the proposed US Safe Cosmetics and Personal Care Products Act of 2013: animal use and cost estimates. AB - The proposed Safe Cosmetics and Personal Care Products Act of 2013 calls for a new evaluation program for cosmetic ingredients in the US, with the new assessments initially dependent on expanded animal testing. This paper considers possible testing scenarios under the proposed Act and estimates the number of test animals and cost under each scenario. It focuses on the impact for the first 10 years of testing, the period of greatest impact on animals and costs. The analysis suggests the first 10 years of testing under the Act could evaluate, at most, about 50% of ingredients used in cosmetics. Testing during this period would cost about $ 1.7-$ 9 billion and 1-11.5 million animals. By test year 10, alternative, high-throughput test methods under development are expected to be available, replacing animal testing and allowing rapid evaluation of all ingredients. Given the high cost in dollars and animal lives of the first 10 years for only about half of ingredients, a better choice may be to accelerate development of high-throughput methods. This would allow evaluation of 100% of cosmetic ingredients before year 10 at lower cost and without animal testing. PMID- 24468775 TI - Community-onset Escherichia coli infection resistant to expanded-spectrum cephalosporins in low-prevalence countries. AB - By global standards, the prevalence of community-onset expanded-spectrum cephalosporin-resistant (ESC-R) Escherichia coli remains low in Australia and New Zealand. Of concern, our countries are in a unique position, with high extramural resistance pressure from close population and trade links to Asia-Pacific neighbors with high ESC-R E. coli rates. We aimed to characterize the risks and dynamics of community-onset ESC-R E. coli infection in our low-prevalence region. A case-control methodology was used. Patients with ESC-R E. coli or ESC susceptible E. coli isolated from blood or urine were recruited at six geographically dispersed tertiary care hospitals in Australia and New Zealand. Epidemiological data were prospectively collected, and bacteria were retained for analysis. In total, 182 patients (91 cases and 91 controls) were recruited. Multivariate logistic regression identified risk factors for ESC-R among E. coli strains, including birth on the Indian subcontinent (odds ratio [OR]=11.13, 95% confidence interval [95% CI]=2.17 to 56.98, P=0.003), urinary tract infection in the past year (per-infection OR=1.430, 95% CI=1.13 to 1.82, P=0.003), travel to southeast Asia, China, the Indian subcontinent, Africa, and the Middle East (OR=3.089, 95% CI=1.29 to 7.38, P=0.011), prior exposure to trimethoprim with or without sulfamethoxazole and with or without an expanded-spectrum cephalosporin (OR=3.665, 95% CI=1.30 to 10.35, P=0.014), and health care exposure in the previous 6 months (OR=3.16, 95% CI=1.54 to 6.46, P=0.02). Among our ESC-R E. coli strains, the blaCTX-M ESBLs were dominant (83% of ESC-R E. coli strains), and the worldwide pandemic ST-131 clone was frequent (45% of ESC-R E. coli strains). In our low-prevalence setting, ESC-R among community-onset E. coli strains may be associated with both "export" from health care facilities into the community and direct "import" into the community from high-prevalence regions. PMID- 24468776 TI - Breakthrough candidemia due to multidrug-resistant Candida glabrata during prophylaxis with a low dose of micafungin. AB - We identified a case of breakthrough candidemia in a 25-year-old patient receiving micafungin prophylaxis (50 mg/day). Five Candida glabrata isolates were obtained from blood cultures and were classified as multidrug-resistant isolates, since all of them exhibited high MICs for echinocandin and azole drugs. A mutation (S663F) in hot spot 1 of the FKS2 gene was found in all five isolates. This mutation yielded a 1,3-beta-D-glucan synthase enzyme with highly reduced sensitivities to echinocandin drugs. PMID- 24468777 TI - Crystal structure of carbapenemase OXA-58 from Acinetobacter baumannii. AB - Class D beta-lactamases capable of hydrolyzing last-resort carbapenem antibiotics represent a major challenge for treatment of bacterial infections. Wide dissemination of these enzymes in Acinetobacter baumannii elevated this pathogen to the category of most deadly and difficult to treat. We present here the structure of the OXA-58 beta-lactamase, a major class D carbapenemase of A. baumannii, determined to 1.30-A resolution. Unlike two other Acinetobacter carbapenemases, OXA23 and OXA-24, the OXA-58 enzyme lacks the characteristic hydrophobic bridge over the active site, despite conservation of the residues which participate in its formation. The active-site residues in OXA-58 are spatially conserved in comparison to those in other class D beta-lactamases. Lys86, which activates water molecules during the acylation and deacylation steps, is fully carboxylated in the OXA-58 structure. In the absence of a substrate, a water molecule is observed in the active site of the enzyme and is positioned in the pocket that is usually occupied by the 6alpha-hydroxyethyl moiety of carbapenems. A water molecule in this location would efficiently deacylate good substrates, such as the penicillins, but in the case of carbapenems, it would be expelled by the 6alpha-hydroxyethyl moiety of the antibiotics and a water from the surrounding medium would find its way to the vicinity of the carboxylated Lys86 to perform deacylation. Subtle differences in the position of this water in the acyl-enzyme complexes of class D beta lactamases could ultimately be responsible for differences in the catalytic efficiencies of these enzymes against last-resort carbapenem antibiotics. PMID- 24468778 TI - Class D beta-lactamases: are they all carbapenemases? AB - Carbapenem-hydrolyzing class D beta-lactamases (CHDLs) are enzymes of the utmost clinical importance due to their ability to produce resistance to carbapenems, the antibiotics of last resort for the treatment of various life-threatening infections. The vast majority of these enzymes have been identified in Acinetobacter spp., notably in Acinetobacter baumannii. The OXA-2 and OXA-10 enzymes predominantly occur in Pseudomonas aeruginosa and are currently classified as narrow-spectrum class D beta-lactamases. Here we demonstrate that when OXA-2 and OXA-10 are expressed in Escherichia coli strain JM83, they produce a narrow-spectrum antibiotic resistance pattern. When the enzymes are expressed in A. baumannii ATCC 17978, however, they behave as extended-spectrum beta lactamases and confer resistance to carbapenem antibiotics. Kinetic studies of OXA-2 and OXA-10 with four carbapenems have demonstrated that their catalytic efficiencies with these antibiotics are in the same range as those of some recognized class D carbapenemases. These results are in disagreement with the classification of the OXA-2 and OXA-10 enzymes as narrow-spectrum beta lactamases, and they suggest that other class D enzymes that are currently regarded as noncarbapenemases may in fact be CHDLs. PMID- 24468779 TI - Strategy for rapid detection of carbapenemase-producing Enterobacteriaceae. AB - A prospective survey was conducted on 862 Enterobacteriaceae isolates with reduced susceptibility to carbapenems. The Carba NP test, UV spectrophotometry, and a DNA microarray were used to detect carbapenemase producers, and the results were compared to those from PCR and sequencing. The 172 carbapenemase producers were detected using the Carba NP test and UV spectrophotometry, whereas the DNA microarray failed to detect IMI producers. The use of the Carba NP test as a first screening, followed by the use of molecular techniques, has been determined to be an efficient strategy for identifying carbapenemase-producing Enterobacteriaceae. PMID- 24468780 TI - Phase I, open-label, safety and pharmacokinetic study to assess bronchopulmonary disposition of intravenous eravacycline in healthy men and women. AB - This study evaluated the pulmonary disposition of eravacycline in 20 healthy adult volunteers receiving 1.0 mg of eravacycline/kg intravenously every 12 h for a total of seven doses over 4 days. Plasma samples were collected at 0, 1, 2, 4, 6, and 12 h on day 4, with each subject randomized to undergo a single bronchoalveolar lavage (BAL) at 2, 4, 6, or 12 h. Drug concentrations in plasma, BAL fluid, and alveolar macrophages (AM) were determined by liquid chromatography tandem mass spectrometry, and the urea correction method was used to calculate epithelial lining fluid (ELF) concentrations. Pharmacokinetic parameters were estimated by noncompartmental methods. Penetration for ELF and AM was calculated by using a ratio of the area under the concentration time curve (AUC0-12) for each respective parameter against free drug AUC (fAUC0-12) in plasma. The total AUC0-12 in plasma was 4.56+/-0.94 MUg.h/ml with a mean fAUC0-12 of 0.77+/-0.14 MUg.h/ml. The eravacycline concentrations in ELF and AM at 2, 4, 6, and 12 h were means+/-the standard deviations (MUg/ml) of 0.70+/-0.30, 0.57+/-0.20, 0.34+/ 0.16, and 0.25+/-0.13 with a penetration ratio of 6.44 and 8.25+/-4.55, 5.15+/ 1.25, 1.77+/-0.64, and 1.42+/-1.45 with a penetration ratio of 51.63, respectively. The eravacycline concentrations in the ELF and AM achieved greater levels than plasma by 6- and 50-fold, respectively, supporting further study of eravacycline for patients with respiratory infections. PMID- 24468781 TI - OXA-48 carbapenemase-producing Salmonella enterica serovar Kentucky isolate of sequence type 198 in a patient transferred from Libya to Switzerland. AB - Here, we report a case of OXA-48-producing Salmonella enterica serovar Kentucky of sequence type 198 (ST198) from perianal screening cultures of a patient transferred from Libya to Switzerland. The blaOXA-48 gene was carried by Tn1999.2 and located on an ~60-kb IncL/M plasmid. This Salmonella strain also possessed the blaVEB-8, aac(6)-Ib, tet(A), sul1, and mphA resistance genes and substitutions in GyrA (Ser83Phe and Asp87Asn) and ParC (Ser80Ile). This finding emphasizes that prompt screening strategies are essential to prevent the dissemination of carbapenemase producers imported from countries where they are endemic. PMID- 24468782 TI - Sensitive deep-sequencing-based HIV-1 genotyping assay to simultaneously determine susceptibility to protease, reverse transcriptase, integrase, and maturation inhibitors, as well as HIV-1 coreceptor tropism. AB - With 29 individual antiretroviral drugs available from six classes that are approved for the treatment of HIV-1 infection, a combination of different phenotypic and genotypic tests is currently needed to monitor HIV-infected individuals. In this study, we developed a novel HIV-1 genotypic assay based on deep sequencing (DeepGen HIV) to simultaneously assess HIV-1 susceptibilities to all drugs targeting the three viral enzymes and to predict HIV-1 coreceptor tropism. Patient-derived gag-p2/NCp7/p1/p6/pol-PR/RT/IN- and env-C2V3 PCR products were sequenced using the Ion Torrent Personal Genome Machine. Reads spanning the 3' end of the Gag, protease (PR), reverse transcriptase (RT), integrase (IN), and V3 regions were extracted, truncated, translated, and assembled for genotype and HIV-1 coreceptor tropism determination. DeepGen HIV consistently detected both minority drug-resistant viruses and non-R5 HIV-1 variants from clinical specimens with viral loads of >=1,000 copies/ml and from B and non-B subtypes. Additional mutations associated with resistance to PR, RT, and IN inhibitors, previously undetected by standard (Sanger) population sequencing, were reliably identified at frequencies as low as 1%. DeepGen HIV results correlated with phenotypic (original Trofile, 92%; enhanced-sensitivity Trofile assay [ESTA], 80%; TROCAI, 81%; and VeriTrop, 80%) and genotypic (population sequencing/Geno2Pheno with a 10% false-positive rate [FPR], 84%) HIV 1 tropism test results. DeepGen HIV (83%) and Trofile (85%) showed similar concordances with the clinical response following an 8-day course of maraviroc monotherapy (MCT). In summary, this novel all-inclusive HIV-1 genotypic and coreceptor tropism assay, based on deep sequencing of the PR, RT, IN, and V3 regions, permits simultaneous multiplex detection of low-level drug-resistant and/or non-R5 viruses in up to 96 clinical samples. This comprehensive test, the first of its class, will be instrumental in the development of new antiretroviral drugs and, more importantly, will aid in the treatment and management of HIV infected individuals. PMID- 24468783 TI - Ultradeep sequencing study of chronic hepatitis C virus genotype 1 infection in patients treated with daclatasvir, peginterferon, and ribavirin. AB - Direct-acting antivirals (DAAs) are either part of the current standard of care or are in advanced clinical development for the treatment of patients chronically infected with hepatitis C virus (HCV) genotype 1, but concern exists with respect to the patients who fail these regimens with emergent drug-resistant variants. In the present study, ultradeep sequencing was performed to analyze resistance to daclatasvir (DCV), which is a highly selective nonstructural protein 5A (NS5A) inhibitor. Eight patients with HCV genotype 1b, who were either treatment naive or prior nonresponders to pegylated interferon plus ribavirin (Rebetol; Schering Plough) (PEG-IFN/RBV) therapy, were treated with DCV combined with PEG-IFN alpha 2b (Pegintron; Schering-Plough, Kenilworth, NJ) and RBV. To identify the cause of viral breakthrough, the preexistence and emergence of DCV-resistant variants at NS5A amino acids were analyzed by ultradeep sequencing. Sustained virological response (SVR) was achieved in 6 of 8 patients (75%), with viral breakthrough occurring in the other 2 patients (25%). DCV-resistant variant Y93H preexisted as a minor population at higher frequencies (0.1% to 0.5%) in patients who achieved SVR. In patients with viral breakthrough, DCV-resistant variant mixtures emerged at NS5A-31 over time that persisted posttreatment with Y93H. Although enrichment of DCV-resistant variants was detected, the preexistence of a minor population of the variant did not appear to be associated with virologic response in patients treated with DCV/PEG-IFN/RBV. Ultradeep sequencing results shed light on the complexity of DCV-resistant quasispecies emerging over time, suggesting that multiple resistance pathways are possible within a patient who does not rapidly respond to a DCV-containing regimen. (This study has been registered at ClinicalTrials.gov under registration no. NCT01016912.). PMID- 24468784 TI - Evaluation of Acanthamoeba myosin-IC as a potential therapeutic target. AB - Members of the genus Acanthamoeba are facultative pathogens of humans, causing a sight-threatening keratitis and a fatal encephalitis. We have targeted myosin-IC by using small interfering RNA (siRNA) silencing as a therapeutic approach, since it is known that the function of this protein is vital for the amoeba. In this work, specific siRNAs against the Acanthamoeba myosin-IC gene were developed. Treated and control amoebae were cultured in growth and encystment media to evaluate the induced effects after myosin-IC gene knockdown, as we have anticipated that cyst formation may be impaired. The effects of myosin-IC gene silencing were inhibition of cyst formation, inhibition of completion of cytokinesis, inhibition of osmoregulation under osmotic stress conditions, and death of the amoebae. The finding that myosin-IC silencing caused incompletion of cytokinesis is in agreement with earlier suggestions that the protein plays a role in cell locomotion, which is necessary to pull daughter cells apart after mitosis in a process known as "traction-mediated cytokinesis". We conclude that myosin-IC is a very promising potential drug target for the development of much needed antiamoebal drugs and that it should be further exploited for Acanthamoeba therapy. PMID- 24468785 TI - Alkyl galactofuranosides strongly interact with Leishmania donovani membrane and provide antileishmanial activity. AB - We investigated the in vitro effects of four alkyl-galactofuranoside derivatives, i.e., octyl-beta-D-galactofuranoside (compound 1), 6-amino-beta-D galactofuranoside (compound 2), 6-N-acetamido-beta-D-galactofuranoside (compound 3), and 6-azido-beta-D-galactofuranoside (compound 4), on Leishmania donovani. Their mechanism of action was explored using electron paramagnetic resonance spectroscopy (EPR) and nuclear magnetic resonance (NMR), and ultrastructural alterations were analyzed by transmission electron microscopy (TEM). Compound 1 showed the most promising effects by inhibiting promastigote growth at a 50% inhibitory concentration (IC50) of 8.96+/-2.5 MUM. All compounds exhibit low toxicity toward human macrophages. Compound 1 had a higher selectivity index than the molecule used for comparison, i.e., miltefosine (159.7 versus 37.9, respectively). EPR showed that compound 1 significantly reduced membrane fluidity compared to control promastigotes and to compound 3. The furanose ring was shown to support this effect, since the isomer galactopyranose had no effect on parasite membrane fluidity or growth. NMR showed a direct interaction of all compounds (greatest with compound 1, followed by compounds 2, 3, and 4, in descending order) with the promastigote membrane and with octyl-galactopyranose and octanol, providing evidence that the n-octyl chain was primarily involved in anchoring with the parasite membrane, followed by the putative crucial role of the furanose ring in the antileishmanial activity. A morphological analysis of compound 1-treated promastigotes by TEM revealed profound alterations in the parasite membrane and organelles, but this was not the case with compound 3. Quantification of annexin V binding by flow cytometry confirmed that compound 1 induced apoptosis in >90% of promastigotes. The effect of compound 1 was also assessed on intramacrophagic amastigotes and showed a reduction in amastigote growth associated with an increase of reactive oxygen species (ROS) production, thus validating its promising effect. PMID- 24468786 TI - An altered Mycobacterium tuberculosis metabolome induced by katG mutations resulting in isoniazid resistance. AB - The most common form of drug resistance found in tuberculosis (TB)-positive clinical samples is monoresistance to isoniazid. Various genomics and proteomics studies to date have investigated this phenomenon; however, the exact mechanisms relating to how this occurs, as well as the implications of this on the TB causing organisms function and structure, are only partly understood. Considering this, we followed a metabolomics research approach to identify potential new metabolic pathways and metabolite markers, which when interpreted in context would give a holistic explanation for many of the phenotypic characteristics associated with a katG mutation and the resulting isoniazid resistance in Mycobacterium tuberculosis. In order to achieve these objectives, gas chromatography-time of flight mass spectrometry (GCxGC-TOFMS)-generated metabolite profiles from two isoniazid-resistant strains were compared to a wild type parent strain. Principal component analyses showed clear differentiation between the groups, and the metabolites best describing the separation between these groups were identified. It is clear from the data that due to a mutation in the katG gene encoding catalase, the isoniazid-resistant strains experience increased susceptibility to oxidative stress and have consequently adapted to this by upregulating the synthesis of a number of compounds involved in (i) increased uptake and use of alkanes and fatty acids as a source of carbon and energy and (ii) the synthesis of a number of compounds directly involved in reducing oxidative stress, including an ascorbic acid degradation pathway, which to date hasn't been proposed to exist in these organisms. PMID- 24468787 TI - Disuccinyl betulin triggers metacaspase-dependent endonuclease G-mediated cell death in unicellular protozoan parasite Leishmania donovani. AB - The unicellular organism Leishmania undergoes apoptosis-like cell death in response to external stress or exposure to antileishmanial agents. Here, we showed that 3-O,28-O-disuccinyl betulin (DiSB), a potent topoisomerase type IB inhibitor, induced parasitic cell death by generating oxidative stress. The characteristic feature of the death process resembled the programmed cell death (PCD) seen in higher eukaryotes. In the current study, the generation of reactive oxygen species (ROS), followed by the depolarization of mitochondrial membrane potential (DeltaPsim), caused a loss in ATP production in Leishmania parasites. This further gave positive feedback to produce a large amount of ROS, which in turn caused oxidative DNA lesions and genomic DNA fragmentation. The treatment of promastigotes with DiSB induced high expression levels of metacaspase protein that led to cell death in this unicellular organism. The PCD was insensitive to benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk), suggesting that the death process was not associated with the activation of caspases. DiSB treatment translocated Leishmania donovani endonuclease G (LdEndoG) from mitochondria to the nucleus, which was responsible for the DNA degradation process. Conditional antisense knockdown of L. donovani metacaspase (LdMC), as well as EndoG, -subverted death of the parasite and rescued cell cycle arrest in G1 phase. The present study on the effector molecules associated with the PCD pathway of the parasite should help to manifest the mechanisms of PCD and also might be exploited in antileishmanial chemotherapy. PMID- 24468788 TI - New chemical scaffolds for human african trypanosomiasis lead discovery from a screen of tyrosine kinase inhibitor drugs. AB - Human African trypanosomiasis (HAT) is caused by the protozoan Trypanosoma brucei. New drugs are needed to treat HAT because of undesirable side effects and difficulties in the administration of the antiquated drugs that are currently used. In human proliferative diseases, protein tyrosine kinase (PTK) inhibitors (PTKIs) have been developed into drugs (e.g., lapatinib and erlotinib) by optimization of a 4-anilinoquinazoline scaffold. Two sets of facts raise a possibility that drugs targeted against human PTKs could be "hits" for antitrypanosomal lead discoveries. First, trypanosome protein kinases bind some drugs, namely, lapatinib, CI-1033, and AEE788. Second, the pan-PTK inhibitor tyrphostin A47 blocks the endocytosis of transferrin and inhibits trypanosome replication. Following up on these concepts, we performed a focused screen of various PTKI drugs as possible antitrypanosomal hits. Lapatinib, CI-1033, erlotinib, axitinib, sunitinib, PKI-166, and AEE788 inhibited the replication of bloodstream T. brucei, with a 50% growth inhibitory concentration (GI50) between 1.3 MUM and 2.5 MUM. Imatinib had no effect (i.e., GI50>10 MUM). To discover leads among the drugs, a mouse model of HAT was used in a proof-of-concept study. Orally administered lapatinib reduced parasitemia, extended the survival of all treated mice, and cured the trypanosomal infection in 25% of the mice. CI-1033 and AEE788 reduced parasitemia and extended the survival of the infected mice. On the strength of these data and noting their oral bioavailabilities, we propose that the 4-anilinoquinazoline and pyrrolopyrimidine scaffolds of lapatinib, CI 1033, and AEE788 are worth optimizing against T. brucei in medicinal chemistry campaigns (i.e., scaffold repurposing) to discover new drugs against HAT. PMID- 24468790 TI - Zn-BTC MOFs with active metal sites synthesized via a structure-directing approach for highly efficient carbon conversion. AB - Three zinc-trimesic acid (Zn-BTC) MOFs, BIT-101, BIT-102 and BIT-103, have been synthesized via a structure-directing strategy. Interestingly, BIT-102 and -103 exhibit extraordinary catalytic performance (up to Conv. 100% and Sele. 95.2%) in the cycloaddition of CO2 under solvent- and halogen-free conditions without any additives or co-catalysts. PMID- 24468791 TI - Quantum mechanical investigations on the role of C-terminal residue in influencing the structural features of dipeptides containing N-terminal proline. AB - This study investigates the influence of the side chain moiety of C-terminal residue on the structural and molecular properties of seven dipeptides having proline at their N-terminal positions. The C-terminal component of the dipeptides is varied with seven different combinations viz. Ala, Leu, Asp, Thr, Asn, Arg and Sec. The calculations are carried out using B3LYP/6-311++G(d,p) level of theory in gas and implicit aqueous phase. Effects of explicit aqueous environment on the dipeptide structures are also investigated for two systems. The results furnished by this DFT study provide valuable information regarding the role of the side chain groups of C-terminal residues in determining the structural features of the amide planes, values of the psi and f dihedrals, geometry about the alpha-carbon atoms, theoretical IR spectra as well as the number and type of intramolecular H bond interactions existing in the dipeptides, and extend a fine corroboration to the earlier theoretical and experimental observations. In aqueous phase the dipeptide geometries exhibit larger values of total dipole moments, greater HOMO LUMO energy gaps and enhanced thermodynamic stability than those in gas phase. The explicit water molecules are found to modify the geometrical parameters related to the amide planes and vibrational spectra of the dipeptides. PMID- 24468789 TI - Mutations in the Pseudomonas aeruginosa needle protein gene pscF confer resistance to phenoxyacetamide inhibitors of the type III secretion system. AB - The type III secretion system (T3SS) is a clinically important virulence mechanism in Pseudomonas aeruginosa that secretes and translocates effector toxins into host cells, impeding the host's rapid innate immune response to infection. Inhibitors of T3SS may be useful as prophylactic or adjunctive therapeutic agents to augment the activity of antibiotics in P. aeruginosa infections, such as pneumonia and bacteremia. One such inhibitor, the phenoxyacetamide MBX 1641, exhibits very responsive structure-activity relationships, including striking stereoselectivity, in its inhibition of P. aeruginosa T3SS. These features suggest interaction with a specific, but unknown, protein target. Here, we identify the apparent molecular target by isolating inhibitor-resistant mutants and mapping the mutation sites by deep sequencing. Selection and sequencing of four independent mutants resistant to the phenoxyacetamide inhibitor MBX 2359 identified the T3SS gene pscF, encoding the needle apparatus, as the only locus of mutations common to all four strains. Transfer of the wild-type and mutated alleles of pscF, together with its chaperone and cochaperone genes pscE and pscG, to a DeltapscF P. aeruginosa strain demonstrated that each of the single-codon mutations in pscF is necessary and sufficient to provide secretion and translocation that is resistant to a variety of phenoxyacetamide inhibitor analogs but not to T3SS inhibitors with different chemical scaffolds. These results implicate the PscF needle protein as an apparent new molecular target for T3SS inhibitor discovery and suggest that three other chemically distinct T3SS inhibitors interact with one or more different targets or a different region of PscF. PMID- 24468792 TI - Fletcher-Reeves based Particle Swarm Optimization for prediction of molecular structure. AB - The determination of the most stable conformers of a molecule can be formulated as a global optimization problem. Knowing the stable conformers of a molecule is important because it allows us to understand its properties and behavior based on its structure. The most stable conformation is that involving the global minimum of potential energy. The problem of finding this global minimum is highly complex, and is computationally difficult because of the number of local minima, which grows exponentially with molecular size. In this paper, we propose a hybrid approach combining Particle Swarm Optimization (PSO) and the Fletcher-Reeves algorithm to minimize the potential energy function. The proposed hybrid algorithm is applied to a simplified molecular potential energy function in problems with up to 100 degrees of freedom and also to a realistic potential energy function modeling a pseudoethane molecule. The computational results for both the cases show that the proposed method performs significantly better than the other algorithms. PMID- 24468793 TI - Inhibition of TBK1 attenuates radiation-induced epithelial-mesenchymal transition of A549 human lung cancer cells via activation of GSK-3beta and repression of ZEB1. AB - Radiotherapy is an effective treatment method for lung cancer, particularly when the disease is at an advanced stage. However, previous researchers have observed that the majority of patients with conventional radiation therapy develop distant metastases and succumb to the disease. Thus, identifying and understanding novel pathways for the development of new therapeutic targets is a major goal in research on pulmonary neoplasms. Recent studies suggest that epithelial mesenchymal transition (EMT) is the most important contributor to cancer metastasis. Induction of this complex process requires endogenously produced microRNAs; specifically, downregulation of the miRNA-200c causes an induction of EMT. We recently identified the tank-binding kinase-1 (TBK1) as a downstream effector of the miR-200c-driven pathway, but the biological function of TBK1 in EMT remains unknown. In this study, we tested whether TBK1 has a role in radiation-induced EMT and identified associated potential mechanisms. Human alveolar type II epithelial carcinoma A549 cells were irradiated with (60)Co gamma-rays. Western blotting revealed a time- and dose-dependent decrease in E cadherin with a concomitant increase in vimentin after radiation, suggesting that the epithelial cells acquired a mesenchymal-like morphology. TBK1 siRNA significantly inhibited radiation-induced suppression of the epithelial marker E cadherin and upregulation of the mesenchymal marker vimentin. The invasion and migratory potential of lung cancer cells upon radiation treatment was also reduced by TBK1 knockdown. Furthermore, radiation-induced EMT attenuated by TBK1 depletion was partially dependent on transcriptional factor ZEB1 expression. Finally, we found glycogen synthase kinase-3beta (GSK-3beta) is involved in regulation of radiation-induced EMT by TBK1. Thus, our findings reveal that TBK1 signaling regulates radiation-induced EMT by controlling GSK-3beta phosphorylation and ZEB1 expression. TBK1 may therefore constitute a useful target for treatment of radiotherapy-induced metastasis diseases. PMID- 24468795 TI - Syntheses and structural characterization of o-carboranylamides with direct cage amide bond. AB - Reactions of lithio-o-carborane with isocyanates under various conditions were studied, and the structural features of the resulting carboranylamides are described. The reactions of o-carborane (o-C2B10H12), n-BuLi (two equiv.) and two equiv. of (substituted) phenylisocyanate, pentylisocyanate and p ethylphenylthioisocyanate in diethyl ether, respectively, led, after workup, to the corresponding mono-substituted carboranylamide 2a-g and carboranylthioamide 5 in low to moderate yields, and only with RNCO (R = Ph, m-MeOC6H4, pentyl) could disubstituted products 3a-c be isolated. The reaction with phenylisocyanate afforded the mono-amide and di-amide products in a ratio of approximately 1 : 2, whereas in the other two reactions the ratios are approximately 4 : 1 and 3 : 2, respectively. In tetrahydrofuran all the reactions attempted with RNCO (R = Ph, p IC6H4, m-NCC6H4 and pentyl) gave more monoamide products than those in diethyl ether. With phenylisocyanate no diamide product was isolated and with pentylisocyanate the ratio between monoamide and diamide is approximately 3.5 : 1. The new carboranylamides were characterized by means of elemental analyses, IR and NMR spectroscopy and mass spectrometry, as well as single-crystal X-ray diffraction analyses of 2a-f, 3a and 5. PMID- 24468794 TI - Colony-stimulating factor 1 potentiates lung cancer bone metastasis. AB - Colony-stimulating factor 1 (CSF1) is essential for osteoclastogenesis that mediates osteolysis in metastatic tumors. Patients with lung cancer have increased CSF1 in serum and high levels are associated with poor survival. Adenocarcinomas metastasize rapidly and many patients suffer from bone metastasis. Lung cancer stem-like cells sustain tumor growth and potentiate metastasis. The purpose of this study was to determine the role of CSF1 in lung cancer bone metastasis and whether inhibition of CSF1 ameliorates the disease. Human lung adenocarcinoma A549 cells were examined in vitro for CSF1/CSF1R. A549 luc cells were injected intracardiac in NOD/SCID mice and metastasis was assessed. To determine the effect of CSF1 knockdown (KD) in A549 cells on bone metastasis, cells were stably transfected with a retroviral vector containing short-hairpin CSF1 (KD) or empty vector (CT). Results showed that A549 cells express CSF1/CSF1R; CSF1 increased their proliferation and invasion, whereas soluble CSF1R inhibited invasion. Mice injected with A549-luc cells showed osteolytic bone lesions 3.5 weeks after injection and lesions increased over 5 weeks. Tumors recapitulated adenocarcinoma morphology and showed osteoclasts along the tumor/bone interface, trabecular, and cortical bone loss. Analyses of KD cells showed decreased CSF1 protein levels, reduced colony formation in soft agar assay, and decreased fraction of stem-like cells. In CSF1KD mice, the incidence of tumor metastasis was similar to controls, although fewer CSF1KD mice had metastasis in both hind limbs. KD tumors showed reduced CSF1 expression, Ki 67+ cells, and osteoclasts. Importantly, there was a low incidence of large tumors >0.1 mm(2) in CSF1KD mice compared with control mice (10% vs 62.5%). This study established a lung osteolytic bone metastasis model that resembles human disease and suggests that CSF1 is a key determinant of cancer stem cell survival and tumor growth. Results may lead to novel strategies to inhibit CSF1 in lung cancer and improve management of bone metastasis. PMID- 24468796 TI - Impact of intraoperative temperature and humidity on healing of intestinal anastomoses. AB - PURPOSE: Clinical data indicate that laparoscopic surgery has a beneficial effect on intestinal wound healing and is associated with a lower incidence of anastomotic leakage. This observation is based on weak evidence, and little is known about the impact of intraoperative parameters during laparoscopic surgery, e.g., temperature and humidity. METHODS: A small-bowel anastomosis was formed in rats inside an incubator, in an environment of stable humidity and temperature. Three groups of ten Wistar rats were operated: a control group (G1) in an open surgical environment and two groups (G2 and G3) in the incubator at a humidity of 60 % and a temperature of 30 and 37 degrees C (G2 and G3, respectively). After 4 days, bursting pressure and hydroxyproline concentration of the anastomosis were analyzed. The tissue was histologically examined. Serum levels of C-reactive protein (CRP) were measured. RESULTS: No significant changes were seen in the evaluation of anastomotic stability. Bursting pressure was very similar among the groups. Hydroxyproline concentration in G3 (36.3 MUg/g) was lower by trend (p = 0.072) than in G1 (51.7 MUg/g) and G2 (46.4 MUg/g). The histological evaluation showed similar results regarding necrosis, inflammatory cells, edema, and epithelization for all groups. G3 (2.56) showed a distinctly worse score for submucosal bridging (p = 0.061) than G1 (1.68). A highly significant increase (p = 0.008) in CRP was detected in G3 (598.96 ng/ml) compared to G1 (439.49 ng/ml) and G2 (460 ng/ml). CONCLUSION: A combination of high temperature and humidity during surgery induces an increased systemic inflammatory response and seems to be attenuating the early regeneration process in the anastomotic tissue. PMID- 24468797 TI - Effect of an elastic girdle on lung function, intra-abdominal pressure, and pain after midline laparotomy: a randomized controlled trial. AB - PURPOSE: Girdles and abdominal binders may reduce pain and stabilize the abdominal wall after laparotomy, but a risk for increased intra-abdominal pressure and decreased lung function is also hypothesized. The aim of this study was to investigate the effect of an abdominal girdle after midline laparotomy in a randomized controlled trial. METHODS: Twenty-three patients undergoing laparotomy were randomized to wear an elastic girdle postoperatively and 25 were randomized to no girdle. Pulmonary function was evaluated with; forced vital capacity (FVC), forced expiratory volume during one second (FEV1), peak expiratory flow (PEF), and cough PEF. Pain was recorded using a visual analog scale (VAS). All patients completed the ventral hernia pain questionnaire (VHPQ) before surgery and at the end of the study. Intra-abdominal pressure was measured via an indwelling urinary catheter. Wound healing was assessed from photographs. RESULTS: FVC, FEV1, PEF, and cough PEF were reduced by about 30 % after surgery, but there were no differences between patients with or without a girdle (ANOVA). Intra-abdominal pressure and wound healing were the same in both groups. Pain was significantly lower on day 5 in the girdle group (p = 0.004). CONCLUSIONS: An individually fitted elastic girdle used after midline laparotomy was found to be safe, as this did not affect lung function, coughing, intra-abdominal pressure, or wound healing. The immediate decline in lung function after surgery is restrictive and due to anesthesia and the surgical procedure. Pain was significantly decreased in the girdle group. The study is registered at ClinicalTrials.gov, number NCT01517217. PMID- 24468798 TI - Education and employment needs and receipt of services in community and inpatient mental health settings. AB - The interRAI Education and Employment Clinical Assessment Protocol (EdEmp CAP) identifies three groups of individuals in community and inpatient mental health settings: those who are at risk of losing their employment or disrupting their education; those who require support in employment or educational participation; or those for whom interventions related to education and employment are not triggered. The EdEmp CAP was effective in identifying subpopulations who were at risk, but who did not receive any vocational rehabilitation or counseling. The EdEmp CAP can be used in clinical practice to identify individuals who might benefit from specific interventions in these areas. PMID- 24468799 TI - A comparison of tau-MnAl particulates produced via different routes. AB - MnAl alloys are very promising rare-earth-free permanent magnets. Nanocrystalline microstructures can have beneficial effects on the properties of magnetic MnAl alloys. In the present work we examined multiple routes to process MnAl alloys and studied the effects of milling on Mn-46 at.% Al powders. Mn54Al46 was produced via gas atomization, melt spinning, and rapid solidification rate processing. It was then mechanically milled using a water-cooled Union Process attritor for times up to 20 h. X-ray diffraction patterns showed the presence of mostly the high-temperature epsilon-phase with significant amounts of the equilibrium gamma2 and beta phases in both the cast and milled particulates. The powders were annealed for various temperatures and times in order to obtain the ferromagnetic tau-phase. Magnetic measurements of the optimally annealed powders showed a coercivity of 3.62 kOe and saturation magnetization of 59.8 emu g(-1) for mechanically milled gas-atomized powder annealed at 500 degrees C for 30 min. PMID- 24468800 TI - Capacitive performance enhancements of RuO2 nanocrystals through manipulation of preferential orientation growth originated from the synergy of Pluronic F127 trapping and annealing. AB - The capacitive performances of RuO2 prepared by oxidation precipitation of Ru precursors (RuCl3.xH2O) surrounded with tri-block co-polymer, Pluronic F127, in aqueous media can be enhanced through manipulating its preferential orientation growth of nanocrystals. From the heterogeneous surface chemistry viewpoints with the support of structure characterizations, such enhancement originates from the preferential orientation growth of the {101} facet due to the adsorption of the highly polarisable, non-ionic ligands of Pluronic F127 on the high surface energy facets on RuO2 nanocrystallites. In this case, the F127-trapped sample with annealing at 300 degrees C enhances the specific capacitance 1.6-fold in comparison to its counterpart without F127. With the mechanistic insight into the heterogeneous surface crystal growth pathways, our results materialize the development of RuO2 with tuneable capacitive performances. Furthermore, due to the different propagation models of RuO2 with and without F127 trapping, a schematic diagram is proposed to interpret such a unique crystal growth evolution phenomenon. PMID- 24468801 TI - Prospects for magnetic nanoparticles in systemic administration: synthesis and quantitative detection. AB - Methods for the quantitative determination of magnetic nanoparticles in biological matrices, in the frame of biomedical applications, are required to evaluate the particles biodistribution after systemic administration. AC magnetic susceptibility measurements are an alternative method to quantify magnetic nanoparticles in tissues, being able to provide also information on the particle transformations over time and allowing the distinction of the particles from other endogenous species such as the ferritin iron cores. The protocol for particle quantification using AC magnetic susceptibility measurements is described in detail in this article. A summary of synthesis routes towards magnetic nanoparticles is also provided. PMID- 24468802 TI - Nutritional modulation of the metabonome: applications of metabolic phenotyping in translational nutritional research. AB - PURPOSE OF REVIEW: Metabolic profiling technologies provide a global overview of complex dietary processes. Metabonomic analytical approaches have now been translated into multiple areas of clinical nutritional research based on the widespread adoption of high-throughput mass spectrometry and proton nuclear magnetic resonance spectroscopy. This has generated novel insights into the molecular mechanisms that shape the microbiome-dietary-chronic disease axis. RECENT FINDINGS: Metabolome-wide association studies have created a new paradigm in nutritional molecular epidemiology and they have highlighted the importance of gut microbial cometabolic processes in the development of cardiovascular disease and diabetes. Targeted analyses are helping to explain the mechanisms by which high-risk diets (such as red meat) modulate disease risk and they are generating novel biomarkers that will serve to re-define how the efficacy of nutritional interventions is assessed. Nutritional metabonome-microbiome interactions have also been defined in extreme dietary states such as obesity and starvation, and they also serve as important models for understanding how the gut microbiome modifies disease risk. Finally, nutritional systems medicine approaches are creating novel insights into the functional components of our diet, and the mechanisms by which they cause disease. SUMMARY: Diet is an important modulator of the human metabolic phenotype and the analysis of the nutritional metabolome will drive future development of personalized nutritional interventions. PMID- 24468803 TI - The gut microbiota and the metabolic health of the host. AB - PURPOSE OF REVIEW: It is clear that the metabolic activities of the gut microbiota significantly impact upon human health and disease. RECENT FINDINGS: Recent analyses have correlated alterations in microbial community structure with the onset of diabetes, obesity and cardiovascular disease as well as inflammatory conditions of the intestine. This work has demonstrated the influence of diet upon the microbiota in disease states and has identified a number of microbial metabolites that orchestrate the crucial aspects of the host-microbe dialog. The microbial production of short-chain fatty acids, trimethylamine, acetaldehyde and inflammatory mediators has been shown to significantly impact upon the metabolic health of the host through pathways that influence satiety, gut permeability and immune function. In the small intestine, microbial metabolism alters the host bile acid profile affecting the interactions with dedicated bile acid receptors (including FXR and TGR5) to influence both local and systemic cellular responses. Recent findings have, therefore, identified specific microbiota profiles and metabolites as predictors of disease risk as well as determining the microbial species (such as Akkermansia muciniphila and Bilophila wadsworthia) which correlate with health and disease. SUMMARY: This work identifies the microbiota as an important target for new diagnostic and therapeutic approaches in metabolic disease. PMID- 24468804 TI - The evidence for the use of nutritional support in liver disease. AB - PURPOSE OF REVIEW: Although there is a well established association between malnutrition and poorer clinical outcomes in patients with liver disease, that fact alone does not prove that improving the malnutrition will improve outcome. The best way to determine if nutritional interventions are effective is to compare them to untreated control groups in well designed and executed randomized clinical trials. RECENT FINDINGS: A recent systematic review assessed 37 trials that compared parenteral nutrition, enteral nutrition, or nutritional supplements to no nutritional therapy in patients with a variety of liver diseases. Since the publication of that review, an additional three trials have become available. Whereas all but one of the trials did have methodologic shortcomings that may have allowed the introduction of bias (which usually results in an overestimation of benefit), the trials failed to show much, if any, benefit. In fact, the single trial at low risk of bias found that more deaths occurred in the recipients of the supplements. SUMMARY: Although malnutrition may be associated with a poor outcome, the current best evidence indicates that the provision of adjunctive nutritional support (parenteral or enteral nutrition, or nutritional supplements) to patients with a variety of liver diseases (alcoholic hepatitis, cirrhosis, hepatocellular carcinoma, liver surgery, liver transplantation, obstructive jaundice, hepatitis C antiviral treatment) does not improve clinical outcomes. PMID- 24468805 TI - Inappropriate crushing information on ward lists: cytotoxic drugs, capsules, and modified release formulations are gravely neglected. AB - PURPOSE: The aim of this study was to assess the quality of the information sources on the modification of solid medication dosage forms (crushing, suspending) used on the wards of a large university hospital in Germany. METHODS: We performed on-site visits of all 79 wards of the hospital and collected available sources of information on the modification of solid medication dosage forms. To evaluate the quality of such information, we gathered reference information for each listed brand from the respective pharmaceutical company, transferred this information to a knowledge base, and classified it into three categories, i.e., modification not allowed, modification allowed, and modification allowed under certain circumstances. RESULTS: Twenty-two lists of information on drug modification were identified in the 79 wards. Each list contained errors, and on average 17.0 % (range 8.0-32.3 %) of the brands listed had been withdrawn from the market or the information on crushing and/or suspending was inappropriate. Most of the incorrect information either concerned brands containing ingredients that were potentially hazardous to the staff members who prepared the drugs or referred to special dosage forms such as capsules and modified release formulations (e.g., cytotoxic drugs). CONCLUSION: We found that the lists posted on the wards were often outdated and did not take into account the limitations/problems of preparing drugs on the ward. Our results emphasize that lists posted in wards need to be checked regularly and that "ready to-use" lists from third parties might require adaptation to site-specific conditions in order to protect healthcare staff from exposure to potentially hazardous drugs during drug preparation and ensure safe drug application to the patient. PMID- 24468806 TI - Large-scale imaging of subcellular calcium dynamics of cortical neurons with G CaMP6-actin. AB - Understanding the information processing performed by a single neuron requires the monitoring of physiological dynamics from a variety of subcellular compartments including dendrites and axons. In this study, we showed that the expression of a fusion protein, consisting of a Ca2+ indicator protein (G-CaMP6) and a cytoskeleton protein (actin), enabled large-scale recording of Ca2+ dynamics from hundreds of postsynaptic spines and presynaptic boutons in a cortical pyramidal cell. At dendritic spines, G-CaMP6-actin had the potential to detect localized Ca2+ activity triggered by subthreshold synaptic inputs. Back propagating action potentials reliably induced Ca2+ fluorescent increases in all spines. At axonal boutons, G-CaMP6-actin reported action potential trains propagating along axonal collaterals. The detectability of G-CaMP6-actin should contribute toward a deeper understanding of neural network architecture and dynamics at the level of individual synapses. PMID- 24468807 TI - Melt-infiltration of spiro-OMeTAD and thermal instability of solid-state dye sensitized solar cells. AB - A method for achieving complete pore-filling in solid-state dye-sensitized solar cells termed melt-infiltration is presented: after the customary solution processed deposition of spiro-OMeTAD, the device is heated above the glass transition temperature of spiro-OMeTAD to soften the material and allow capillary action to pull additional spiro-OMeTAD from the overlayer reservoir into the pores. The pore-filling fraction increases from 60-65% to 90-100% as a result of melt-infiltration. The organic D-pi-A dye used in this study is found to withstand the thermal treatment without performance loss, unlike ruthenium-based dyes. Through our experiments, we find that the 4-tert-butylpyridine (tBP) additive, commonly used in dye-sensitized solar cells, evaporates from the device during heat treatment at temperatures as low as 85 degrees C. This significantly impacts device performance, potentially excluding its use in commercial applications, and demonstrates the need for a more thermally stable tBP alternative. Melt-infiltration is expected to be a viable method for achieving complete pore-filling in systems where volatile additives are not required for operation. PMID- 24468808 TI - Phyllotaxy and water relations in tobacco. AB - The relative effectiveness of vascular connections between adjacent leaves of tobacco is demonstrated. It is shown that water movement between adjacent leaves is more difficult than between phyllotactically related leaves. Total and specific resistance ratios between adjacent and phyllotactically related leaves are calculated. These figures indicate that vertical water potential profiles need to be interpreted with a full knowledge of the vascular structure and phyllotaxy as well as gross structural and environmental parameters. PMID- 24468809 TI - The effect of CCCP on ion fluxes in the stele and cortex of maize roots. AB - The accumulation of (86)Rb labelled potassium by isolated stelar and cortical tissues from 7-day-old roots of Zea mays has been compared with the levels accumulated by these tissues in the intact root. Cortical tissues have similar uptake eapacities in these two conditions whereas stelar tissues only exhibit an uptake capacity in the intact root system. The uncoupler carbonylcyanide m chlorophenylhydrazone caused a considerable decrease in the uptake of potassium by these tissues. In the intact root system it prevented ions from the bathing medium reaching the stelar tissues. The efflux pattern from preloaded isolated stelar and cortical tissues was considerably altered by the inhibitor, a promotion of the efflux occurring in both of these tissues.It is concluded that stelar tissues only accumulated ions when these are supplied through the root symplasm and that the stelar plasmalemma has only a limited uptake capacity per se. Stelar uptake is thus a reflection of vacuolar accumulation across the tonoplast. There is no evidence in the present study of a carrier-mediated active secretion of ions across the stelar plasmalemma. The fact that the efflux was promoted rather than depressed by the uncoupler supports the postulate that a passive leakage is the final stage in the transport of ions across the plant root. PMID- 24468810 TI - Enzymic activities and galactomannan mobilisation in germinating seeds of fenugreek (Trigonella foenum-graecum L. Leguminosae) : Secretion of alpha galactosidase and beta-mannosidase by the aleurone layer. AB - The activities of alpha-galactosidase, beta-mannosidase and alpha-mannosidase were determined in extracts from the endosperm and from the embryo of fenugreek seeds at different stages of germination. Endosperm homogenates contained little or no activity of the above enzymes in the early stages of germination, before the reserve galactomannan began to be mobilised. The onset of galactomannan breakdown coincided with the appearance of alpha-galactosidase and beta mannosidase activities, which increased throughout the period of galactomannan degradation and then remained constant. A similar rise in alpha-galactosidase and beta-mannosidase activities occurred during galactomannan breakdown in dry isolated endosperms incubated under germination conditions. The increase could be suppressed by metabolic inhibitors which also inhibit galactomannan breakdown. Embryo homogenates contained high alpha-galactosidase, high alpha-mannosidase and some beta-mannosidase activity at all stages of germination.No "oligomannosyl beta-1,4 phosphorylase" activity could be detected either in the endosperm or in the embryo.It is concluded that the galactomannan of fenugreek is broken down by a series of hydrolases secreted by the aleurone layer of the endosperm. They include alpha-galactosidase, beta-mannosidase and probably also endo-beta mannanase. PMID- 24468811 TI - Protein synthesis patterns in barley embryos during germination. AB - The incorporation pattern of [(14)C] amino-acid into protein during the first 8 h of germination in isolated barley embryos (Hordeum vulgare) is described. Two maxima were recognised. The first, at 4 h, was entirely accounted for by scutellum activity and the second, at 8 h, coincided with active radicle elongation. An intervening minimum was situated at 5.5 h. The first peak was insensitive to actinomycin-D but the second showed a partial inhibition by this compound. Only slight changes in enzyme activity were associated with these periods of increased synthesis. Incorporation of [17-(14)C] kaurenoic acid into compounds co-chromatographing with gibberellins was followed over the same period in both embryos and scutella and high activity was found after only 2-4 h. It is concluded that, on the basis of protein synthetic activity, the scutellum is the most probable source of the initial gibberellin stimulus. PMID- 24468812 TI - The mechanism of infection of plant protoplasts by viruses. AB - The process of virus infection of protoplasts isolated from tobacco leaves has been examined by means of electron microscopy. Immediately after inoculation, virus particles appear at two types of site: trapped in complex surface lesions of the plasmalemma, or in peripheral cytoplasmic vesicles. The complex lesions are only visible after treatment of the protoplasts with inocula containing poly L-ornithine. With infection by tobacco mosaic virus and cowpea chlorotic mottle virus, which require poly-L-ornithine, the majority of virus particles occur at lesion sites. Pea enation mosaic virus, which does not require poly-L-ornithine for infection to become established, is found predominantly and in high numbers in peripheral vesicles. The behaviour of these three viruses is discussed in terms of a probable mechanism for infection of the protoplasts. PMID- 24468813 TI - Cavitation studies on whole Ricinus plants by acoustic detection. AB - Acoustic detection has been used to investigate the incidence of cavitation in whole potted Ricinus plants subjected to water stress by withholding water. Cavitation proceeded rather slowly and was detectable before and during wilting. Techniques which restricted water uptake more drastically such as root cooling or overlapping cuts induced more rapid "click" production and wilting; a response already described for excised leaves. When water stress was removed by rewatering, or rewarming a cooled root system, cavitation soon ceased. This response was more sluggish of over-delayed.Cavitation in aging leaves on well watered plants has also been examined. Despite the onset of senescence over many days there was no evidence that dry patches, which often develop extensively, are a consequence of water shortage induced by xylem blockage. Leaves, falling naturally by abscission in still air, were often remarkably turgid with water potentials similar to those of healthy attached leaves. Only after losing water was cavitation apparent, as usual for excised mature leaves. Sometimes more persistent leaves did cavitate in situ, just before abscission, showing that in normal leaves xylem blockage can occasionally precede leaf fall by several hours. PMID- 24468814 TI - [Enzymes of starch metabolism in root cap cells of Zea mays L]. AB - In connection with the problem of the well-known stability of statolith starch, some enzymes of starch metabolism have been investigated qualitatively in the root cap cells of Zea mays L. No activity of granule-bound UDPG- and ADPG transglucosylase (EC 2.4.1.21) could be found. In the soluble enzyme fraction of the root cap cells, on the other hand, activities of phosphorylase (EC 2.4.1.1), sucrose synthetase (EC 2.4.1.13), UDPG-pyrophosphorylase (EC 2.7.7.9), alpha Amylase (EC 3.2.11), Maltase (EC 3.2.1.20), and D-enzyme (EC 2.4.1.25) were clearly shown to be present. However, no measurable activities of ADPG pyrophosphorylase, sucrose-6-phosphate-synthetase (EC 2.4.1.14) and UDPG dehydrogenase (EC 1.1.1.22) could be found. It is concluded that the stability of statolith starch in the root cap cells is not caused by the lack of enzymes of starch metabolism, but perhaps by a dynamic equilibrium between the degradation and the synthesis of starch. The later could proceed by the activity of phosphorylase working in the direction of starch synthesis because of removal of the inorganic phosphate by phosphorylating mitochondria accumulating in the neighbourhood of the statolith amyloplasts. PMID- 24468815 TI - [CAM in Tillandsia usneoides: Studies on the pathway of carbon and the dependency of CO2-exchange on light intensity, temperature and water content of the plant]. AB - Tillandsia usneoides, in the common sense a non-succulent plant, exhibits CO2 exchange characterized by net CO2 dark fixation during the night and depression of CO2 exchange during the day. Malate has been demonstrated to accumulate during CO2 dark fixation and to be converted to carbohydrates in light. Thus, T. usneoides exhibits CAM like typical succulents.Net CO2 uptake during the day is increased with net CO2 output being suppressed in duration of time and extent when light intensity increases. Furthermore, a slight increase in CO2 fixation during the following night can be observed if the plants were treated with high light intensity during the previous day.Curves of CO2 exchange typical for CAM are obtained if T. usneoides is kept at 15 degrees C and 20 degrees C. Lower temperature tend to increase CO2 uptake during the day and to inhibit CO2 dark fixation. Temperatures higher than 20 degrees C favour loss of CO2 by respiration, which becomes apparent during the whole day and night at 30 degrees C and higher temperatures. Thus, T. usneoides gains carbon only at temperatures well below 25 degrees C.Net CO2 uptake during the day occurs only in moist plant material and is inhibited in plants cept under water stress conditions. However, CO2 uptake during the night is clearly favoured if the plants dry out. Therefore dry plants gain more carbon than moist ones.Curves of CO2 exchange typical for CAM were also obtained with 13 other species of the genus Tillandsia.The exhibition of CAM by the non-succulent T. usneoides calls for a new definition of the term "succulence" if it is to remain useful in characterizing this metabolic pathway. Because CO2-fixing cells of T. usneoides possess relatively large vacuoles and are relatively poor in chloroplasts, they resembles the assimilatory cells of typical CAM-exhibiting succulents. Therefore, if "succulence" only means the capacity of big vacuoles to store malate, the assimilatory cells in T. usneoides are succulent. It seems to be useful to investigate parameters which would allow a definition of the term "succulence" on the level of the cell rather than on the level of the whole plant or plant organs. PMID- 24468816 TI - Predictors and outcomes of Candida bloodstream infection: eight-year surveillance, western Saudi Arabia. AB - OBJECTIVES: To assess the epidemiological pattern of Candida bloodstream infection (BSI) over an 8-year period (2002-2009) in King Abdulaziz Medical City, western Saudi Arabia. METHOD: A retrospective chart review was performed. RESULTS: A total of 258 BSI were identified in 134 males (53.2%) and 118 females (46.8%). There were 86 (34.1%) cases of Candida albicans and 166 (65.9%) non albicans Candida species. Malignancy was independently associated with the development of candidemia by non-albicans Candida species (odds ratio 3.24, 95% confidence interval 1.25-8.41). Fluconazole in vitro susceptibility was 38.5% for C. albicans and 52.5% for other Candida species. The overall, crude 12-month mortality rate was 50% for C. albicans and 57.8% for non-albicans Candida species. CONCLUSIONS: The antifungal resistance coinciding with a change in the epidemiologic pattern of candidemia identified in this study is alarming and urges the need for a review of empiric antifungal therapy and potential contributing environmental factors. PMID- 24468817 TI - Metabolomic profiling in multiple sclerosis: insights into biomarkers and pathogenesis. AB - Metabolomics enables the provision of sensitive bio-markers of disease. We performed 800 MHz (1)H-nuclear magnetic resonance (NMR) spectroscopic analyses of cerebrospinal fluid (CSF) specimens to identify biomarkers of multiple sclerosis (MS), yielding reproducible detection of 15 metabolites from MS (n=15) and non-MS (n=17) patients. Mean levels of choline, myo-inositol and threonate were increased, whereas 3-hydroxybutyrate, citrate, phenylalanine, 2 hydroxyisovalerate and mannose were decreased in MS-derived CSF (p<0.05), suggesting alterations to energy and phospholipid metabolism. Multivariate hierarchal cluster analysis indicated a high correlation within the metabolite profiles, significantly clustering samples into the two clinical groups, which was corroborated using principal components analysis. CSF metabolomics have the capacity to yield quantitative biomarkers and insights into the pathogenesis of MS. PMID- 24468818 TI - Comment on 'Fingolimod to treat severe MS after natalizumab-associated progressive multifocal leukoencephalopathy: a valid option?' Maillart et al. PMID- 24468819 TI - Need for the upcoming revision of the current diagnostic criteria for NMO - response to the letter from Zhou et al. PMID- 24468820 TI - Creation of a dental X-ray unit with a contactless exposure control switch. AB - OBJECTIVE: A new dental radiographic unit (DXRU) with a contactless switch for adjusting exposure conditions and a foot-pedal exposure switch was developed to prevent bacterial or viral contamination from patients and was compared with a conventional DXRU with a panel push-button switch with respect to user friendliness. METHODS: 45 fourth-year dental school students carried out intraoral radiography using both types of DXRU. Errors regarding dose shortages of X-rays were compared and a questionnaire completed. RESULTS: 22 (49%) of the 45 students failed to provide the correct radiographic exposure and the number of errors was 32 for the conventional DXRU, and 4 (9%) students failed to provide the correct radiographic exposure and the number of errors was 4 for our new DXRU, at the first stage (p < 0.001). At the second stage, the number of students who failed to provide the correct radiographic exposure and the number of errors decreased to 12 and 16, respectively, for the conventional DXRU (p < 0.05). 37 (82%) of the 45 students preferred our DXRU because of its contactless switch and the push-pedal exposure switch. CONCLUSIONS: These data suggested that our new contactless mechanism should be used for other DXRUs for contamination control. PMID- 24468821 TI - Entangled photons from on-chip slow light. AB - We report the first entanglement generation experiment using an on-chip slow light device. With highly efficient spontaneous four-wave mixing enhanced by the slow light effect in a coupled resonator optical waveguide based on a silicon photonic crystal, we generated 1.5-MUm-band high-dimensional time-bin entangled photon pairs. We undertook two-photon interference experiments and observed the coincidence fringes with visibilities >74%. The present result enables us to realize an on-chip entanglement source with a very small footprint, which is an essential function for quantum information processing based on integrated quantum photonics. PMID- 24468822 TI - Familial risk of epilepsy: a population-based study. AB - Almost all previous studies of familial risk of epilepsy have had potentially serious methodological limitations. Our goal was to address these limitations and provide more rigorous estimates of familial risk in a population-based study. We used the unique resources of the Rochester Epidemiology Project to identify all 660 Rochester, Minnesota residents born in 1920 or later with incidence of epilepsy from 1935-94 (probands) and their 2439 first-degree relatives who resided in Olmsted County. We assessed incidence of epilepsy in relatives by comprehensive review of the relatives' medical records, and estimated age specific cumulative incidence and standardized incidence ratios for epilepsy in relatives compared with the general population, according to proband and relative characteristics. Among relatives of all probands, cumulative incidence of epilepsy to age 40 was 4.7%, and risk was increased 3.3-fold (95% confidence interval 2.75-5.99) compared with population incidence. Risk was increased to the greatest extent in relatives of probands with idiopathic generalized epilepsies (standardized incidence ratio 6.0) and epilepsies associated with intellectual or motor disability presumed present from birth, which we denoted 'prenatal/developmental cause' (standardized incidence ratio 4.3). Among relatives of probands with epilepsy without identified cause (including epilepsies classified as 'idiopathic' or 'unknown cause'), risk was significantly increased for epilepsy of prenatal/developmental cause (standardized incidence ratio 4.1). Similarly, among relatives of probands with prenatal/developmental cause, risk was significantly increased for epilepsies without identified cause (standardized incidence ratio 3.8). In relatives of probands with generalized epilepsy, standardized incidence ratios were 8.3 (95% confidence interval 2.93 15.31) for generalized epilepsy and 2.5 (95% confidence interval 0.92-4.00) for focal epilepsy. In relatives of probands with focal epilepsy, standardized incidence ratios were 1.0 (95% confidence interval 0.00-2.19) for generalized epilepsy and 2.6 (95% confidence interval 1.19-4.26) for focal epilepsy. Epilepsy incidence was greater in offspring of female probands than in offspring of male probands, and this maternal effect was restricted to offspring of probands with focal epilepsy. The results suggest that risks for epilepsies of unknown and prenatal/developmental cause may be influenced by shared genetic mechanisms. They also suggest that some of the genetic influences on generalized and focal epilepsies are distinct. However, the similar increase in risk for focal epilepsy among relatives of probands with either generalized (2.5-fold) or focal epilepsy (2.6-fold) may reflect some coexisting shared genetic influences. PMID- 24468823 TI - Integrating the roles of long and small non-coding RNA in brain function and disease. AB - Regulatory RNA is emerging as the major architect of cognitive evolution and innovation in the mammalian brain. While the protein machinery has remained largely constant throughout animal evolution, the non protein-coding transcriptome has expanded considerably to provide essential and widespread cellular regulation, partly through directing generic protein function. Both long (long non-coding RNA) and small non-coding RNAs (for example, microRNA) have been demonstrated to be essential for brain development and higher cognitive abilities, and to be involved in psychiatric disease. Long non-coding RNAs, highly expressed in the brain and expanded in mammalian genomes, provide tissue- and activity-specific epigenetic and transcriptional regulation, partly through functional control of evolutionary conserved effector small RNA activity. However, increased cognitive sophistication has likely introduced concomitant psychiatric vulnerabilities, predisposing to conditions such as autism and schizophrenia, and cooperation between regulatory and effector RNAs may underlie neural complexity and concomitant fragility in the human brain. PMID- 24468825 TI - Juvenile stress produces long-lasting changes in hippocampal DISC1, GSK3beta and NRG1 expression. PMID- 24468824 TI - Genetic pleiotropy between multiple sclerosis and schizophrenia but not bipolar disorder: differential involvement of immune-related gene loci. AB - Converging evidence implicates immune abnormalities in schizophrenia (SCZ), and recent genome-wide association studies (GWAS) have identified immune-related single-nucleotide polymorphisms (SNPs) associated with SCZ. Using the conditional false discovery rate (FDR) approach, we evaluated pleiotropy in SNPs associated with SCZ (n=21,856) and multiple sclerosis (MS) (n=43,879), an inflammatory, demyelinating disease of the central nervous system. Because SCZ and bipolar disorder (BD) show substantial clinical and genetic overlap, we also investigated pleiotropy between BD (n=16,731) and MS. We found significant genetic overlap between SCZ and MS and identified 21 independent loci associated with SCZ, conditioned on association with MS. This enrichment was driven by the major histocompatibility complex (MHC). Importantly, we detected the involvement of the same human leukocyte antigen (HLA) alleles in both SCZ and MS, but with an opposite directionality of effect of associated HLA alleles (that is, MS risk alleles were associated with decreased SCZ risk). In contrast, we found no genetic overlap between BD and MS. Considered together, our findings demonstrate genetic pleiotropy between SCZ and MS and suggest that the MHC signals may differentiate SCZ from BD susceptibility. PMID- 24468827 TI - An update on pancreatic pathophysiology (do we have to rewrite pancreatic pathophysiology?). AB - This review focuses on seven aspects of physiology and pathophysiology of the exocrine pancreas that have been intensively discussed and studied within the past few years: (1) the role of neurohormonal mechanisms like melatonin, leptin, or ghrelin in the stimulation of pancreatic enzyme secretion; (2) the initiation processes of acute pancreatitis, like fusion of zymogen granules with lysosomes leading to intracellular activation of trypsinogen by the lysosomal enzyme cathepsin B, or autoactivation of trypsinogen; (3) the role of genes in the pathogenesis of acute pancreatitis; (4) the role of alcohol and constituents of alcoholic beverages in the pathogenesis of acute pancreatitis; (5) the role of pancreatic hypertension, neuropathy, and central mechanisms for the pathogenesis of pain in chronic pancreatitis; (6) the relation between exocrine pancreatic function and diabetes mellitus; and (7) pathophysiology, diagnosis and treatment of pancreatic steatorrhea. PMID- 24468828 TI - Preventive medicine: self-assessment of knowledge, skills and attitudes of medical students at the Medical University of Vienna. AB - Prevention and health promotion are gaining importance in modern medical curricula. Aim of this study was to evaluate the self-assessment of knowledge, skills and attitudes of medical students towards health promotion and prevention. In 2012, at the Medical University of Vienna, 27% of the 633 fourth-year medical students (50.3% male and 49.7% female; mean age: 24 years) completed a questionnaire. Results show a high assessment of prevention in most respondents. Knowledge gaps were detected on occupational health and mother-child pass examinations. However, almost all students reported sufficient knowledge on screening and risk assessment of developing cardiovascular diseases. Almost all respondents estimated to be able to identify risky behaviours. Overall, estimation towards prevention of tomorrow's physicians is very positive. However, only 40% believed to have been adequately trained on preventive medicine so far. Relevant preventive aspects were added to the medical curriculum in 2012-2013 with the new block 'Public Health'. PMID- 24468826 TI - FGF-21, a novel metabolic regulator, has a robust neuroprotective role and is markedly elevated in neurons by mood stabilizers. AB - Fibroblast growth factor-21 (FGF-21) is a new member of the FGF super-family and an important endogenous regulator of glucose and lipid metabolism. It has been proposed as a therapeutic target for diabetes and obesity. Its function in the central nervous system (CNS) remains unknown. Previous studies from our laboratory demonstrated that aging primary neurons are more vulnerable to glutamate-induced excitotoxicity, and that co-treatment with the mood stabilizers lithium and valproic acid (VPA) induces synergistic neuroprotective effects. This study sought to identify molecule(s) involved in these synergistic effects. We found that FGF-21 mRNA was selectively and markedly elevated by co-treatment with lithium and VPA in primary rat brain neurons. FGF-21 protein levels were also robustly increased in neuronal lysates and culture medium following lithium-VPA co-treatment. Combining glycogen synthase kinase-3 (GSK-3) inhibitors with VPA or histone deacetylase (HDAC) inhibitors with lithium synergistically increased FGF 21 mRNA levels, supporting that synergistic effects of lithium and VPA are mediated via GSK-3 and HDAC inhibition, respectively. Exogenous FGF-21 protein completely protected aging neurons from glutamate challenge. This neuroprotection was associated with enhanced Akt-1 activation and GSK-3 inhibition. Lithium-VPA co-treatment markedly prolonged lithium-induced Akt-1 activation and augmented GSK-3 inhibition. Akt-1 knockdown markedly decreased FGF-21 mRNA levels and reduced the neuroprotection induced by FGF-21 or lithium-VPA co-treatment. In addition, FGF-21 knockdown reduced lithium-VPA co-treatment-induced Akt-1 activation and neuroprotection against excitotoxicity. Together, our novel results suggest that FGF-21 is a key mediator of the effects of these mood stabilizers and a potential new therapeutic target for CNS disorders. PMID- 24468830 TI - Template-free multicomponent coordination-driven self-assembly of Pd(II)/Pt(II) molecular cages. AB - Recent years have seen a tremendous increase in the interest for constructing hollowed-out molecular frameworks, for their potential uses. Metal-ligand coordination-driven self-assembly has provided multitudes of opportunities in the formation of molecular architectures of desired shapes and sizes, with the help of the information already coded in the components. This article summarizes the recent developments in the construction of multicomponent molecular cages through this process, with a focus on the decreasing relevance of templates, and use of these systems in catalysis/host-guest chemistry. PMID- 24468829 TI - Health care utilisation in subjects with osteoarthritis, chronic back pain and osteoporosis aged 65 years and more: mediating effects of limitations in activities of daily living, pain intensity and mental diseases. AB - Musculoskeletal diseases (MDs) have major consequences for the individual, and also for society and may thus lead to increased use of health care. It was the aim of this study to explore health care utilisation in patients with self reported osteoarthritis, chronic back pain or osteoporosis compared with people of the same age without those diseases, based on data of the Austrian health interview survey including 3,097 subjects aged >= 65 years. Patients with MDs in our study visited a general practitioner (GP) and were hospitalised significantly more often compared with persons without the respective diseases. Problems in the activities of daily living (ADLs), pain intensity and anxiety/depression influenced GP consultations. Complex factors explain the higher health care utilisation in subjects with MDs in our study. Our results indicate that integrated strategies are needed to manage those patients, which should focus on management of ADL problems, pain and mental health. PMID- 24468831 TI - Modulation of heparan sulfate biosynthesis by sodium butyrate in recombinant CHO cells. AB - Sodium butyrate, a histone deacetylase inhibitor, has been used to improve transgene expression in Chinese hamster ovary (CHO) cells. The current study explores the impact of butyrate treatment on heparan sulfate (HS) biosynthesis and structural composition in a recombinant CHO-S cell line expressing enzymes in the heparin (HP)/(HS) biosynthetic pathway (Dual-10 stably expressing NDST2 and HS3st1). Flow cytometric analysis showed that antithrombin binding was increased in Dual-10 cells and basic fibroblast growth factor binding was decreased in response to sodium butyrate treatment. The results were in agreement with the AMAC-LCMS (2-aminoacridine-tagged HS/HP analysis by liquid chromatography mass spectrometry) data that showed that there was an increase in heparan sulfate tri sulfated disaccharides and a decrease in N-sulfated disaccharides in the butyrate treated cells. However, we could not detect any changes in the chondroitin sulfate pathway in Dual-10 cells treated with butyrate. The current study is the first to report the effect of butyrate on glycosaminoglycan profiles. PMID- 24468832 TI - Comparison of plasmid DNA versus PCR amplified gene of insert DNA for nucleofection in Kasumi-1 cells. AB - Plasmid electroporation, or its optimized version nucleofection, is an important technique for gene transfection of cells in suspension. However, substantial cell death and/or low transfection efficiency are still common for some cell lines. By using enhanced green fluorescent protein (EGFP) as a reporter, we compared the use of PCR amplified EGFP (PaEGFP) and its parental plasmid (pEGFP-N2) for nucleofection in Kasumi-1 cells. We found that PaEGFP induced significantly lower cell death but had similar transfection efficiency compared to its parent plasmid (pEGFP-N2). Most importantly, contrary to the pEGFP-N2-nucleofected cells, the PaEGFP-nucleofected cells subsequently grew properly. Tests in other cell lines also implied that PaEGFP indeed induced consistently less cell death, but transfection efficiencies varied, being good in suspension cell lines but lower in adhesive cell lines. We suggest that direct transfection with PCR amplified genes can be a simple and useful approach for optimization of electropulse-based transfection not only of Kasumi-1 cells, but also may be useful for other cell lines that are difficult to transfect in suspension. PMID- 24468833 TI - Proteomic profiling of human placenta-derived mesenchymal stem cells upon transforming LIM mineralization protein-1 stimulation. AB - Human placenta-derived mesenchymal stem cells (hPDMSCs) can differentiate into different types of cells and thus have tremendous potential for cell therapy and tissue engineering. LIM mineralization protein-1 (LMP-1) plays an important role in osteoblast differentiation, maturation and bone formation. To determine a global effect of LMP-1 on hPDMSCs, we designed a study using a proteomic approach combined with adenovirus-mediated gene transfer of LMP-1 to identify LMP-1 induced changes in hPDMSCs on proteome level. We have generated proteome maps of undifferentiated hPDMSCs and LMP-1 induced hPDMSCs. Two dimensional gel electrophoresis revealed 22 spots with at least 2.0-fold changes in expression and 15 differently expressed proteins were successfully identified by MALDI-TOF MS. The proteins regulated by LMP-1 included cytoskeletal proteins, cadmium binding proteins, and metabolic proteins, etc. The expression of some identified proteins was confirmed by further Western blot analyses. Our results will play an important role in better elucidating the underlying molecular mechanism in LMP-1 included hPDMSCs differentiation into osteoblasts. PMID- 24468834 TI - Prevalence of life-limiting conditions in children and young people in England: time trends by area type. AB - Palliative care services in England lack data on the number of children with 'life limiting conditions' (LLCs). Recent research determined that the prevalence of LLCs in children in England was double previous estimates. We build on this by analysing time-trends in the prevalence of LLCs by small area deprivation and geodemographic area types. Prevalence is highest for children aged less than one year but time trends show no increase for the youngest age group but significant increases for older children. These increases are mirrored by a decrease in all cause mortality for children suggesting improved survival. Rates are highest in more deprived areas and those typified by multicultural populations. Increasing prevalence and number of cases over time may require increased paediatric palliative care service provision in the future. PMID- 24468835 TI - Graft-versus-host disease: why have we not made more progress? AB - PURPOSE OF REVIEW: Although allogeneic hematopoietic stem cell transplantation (allo-SCT) is potentially curative for a number of hematologic malignancies, its use is limited by the development of acute and chronic graft-versus-host disease (GVHD). This potentially fatal complication occurs in approximately 50% of allo SCT recipients. RECENT FINDINGS: The pathogenesis of acute and chronic GVHD remains poorly understood, methods to prevent it are largely unchanged over the last two decades, and response to front-line treatment with corticosteroids is suboptimal. For patients with steroid-refractory disease, response to second-line treatment is dismal. The prospective clinical studies evaluating new agents for GVHD have been hampered by the inconsistencies in design, making generalization difficult, and few multicenter studies have been conducted. SUMMARY: Advances have been made over the last decade in grading both acute and chronic GVHD, with the development of biomarkers that provide improved prognostic information in acute GVHD and National Institutes of Health Consensus Criteria for improved grading of chronic GVHD. This, along with the broad understanding of the need to conduct prospective studies with uniform inclusion criteria and endpoints leading to multicenter studies, will hopefully lead to advancements in the prevention of GVHD in the near future. PMID- 24468836 TI - Will FLT3 inhibitors fulfill their promise in acute meyloid leukemia? AB - PURPOSE OF REVIEW: 'FMS'-like tyrosine kinase 3 (FLT3) mutations in acute myeloid leukemia (AML) have been brought from discovery in the early 1990s to clinical targeting in the past 10 years. Despite several promising leads in preclinical models, no agent has yet been approved for clinical use. Here we will review the development of novel therapies for AML with FLT3 mutations. RECENT FINDINGS: Initial clinical development focused on broad kinase inhibitors which were found to have limited clinical activity due to insufficient kinase inhibitory activity and high toxicity. Subsequent development has brought forth narrow-spectrum inhibitors with potent in-vivo activity and reasonable clinical tolerance, but many patients still progress with prolonged use. SUMMARY: The optimal role for targeting FLT3 may depend on multimodality therapy and will likely require hematopoietic transplant. The incorporation of ABL kinase inhibitors into acute lymphoblastic leukemia management should serve as a model for incorporation of FLT3-targeted agents into clinical care. Strategies incorporating FLT3-targeted agents into AML therapy are ongoing, but challenges in trial design, clinical heterogeneity and need for long-term follow-up make these investigations complicated in design and implementation. PMID- 24468837 TI - Effect of dietary selenomethionine on growth performance, tissue burden, and histopathology in green and white sturgeon. AB - A comparative examination of potential differences in selenium (Se) sensitivity was conducted on two sturgeon species indigenous to the San Francisco Bay-Delta. Juvenile green (Acipenser medirostris), recently given a federally threatened status, and white sturgeon (Acipenser transmontanus) were exposed to one of four nominal concentrations of dietary l-selenomethionine (SeMet) (0 (control), 50, 100, or 200 mg SeMet/kg diet) for 8 weeks. Mortality, growth performance, whole body composition, histopathology, and Se burdens of the whole body, liver, kidneys, gills, heart, and white muscle were determined every 2 to 4 weeks. Significant (p<0.05) mortality was observed in green sturgeon fed the highest SeMet diet after 2 weeks, whereas no mortality was observed in white sturgeon. Growth rates were significantly reduced in both species; however, green sturgeon was more adversely affected by the treatment. Dietary SeMet significantly affected whole body composition and most noticeably, in the decline of lipid contents in green sturgeon. Selenium accumulated significantly in all tissues relative to the control groups. After 4 and 8 weeks of exposure, marked abnormalities were observed in the kidneys and liver of both sturgeon species; however, green sturgeon was more susceptible to SeMet than white sturgeon at all dietary SeMet levels. Our results showed that a dietary Se concentration at 19.7 +/- 0.6 mg Se/kg, which is in range with the reported Se concentrations of the benthic macro-vertebrate community of the San Francisco Bay, had adverse effects on both sturgeon species. However, the exposure had a more severe pathological effect on green sturgeon, suggesting that when implementing conservation measures, this federally listed threatened species should be monitored and managed independently from white sturgeon. PMID- 24468838 TI - Transcriptomic responses to heat stress and nickel in the mussel Mytilus galloprovincialis. AB - The exposure of marine organisms to stressing agents may affect the level and pattern of gene expression. Although many studies have examined the ecological effects of heat stress on mussels, little is known about the physiological mechanisms that maybe affected by co-exposure to heat stress and environmental contaminants such as nickel (Ni). In the present work, we investigated the effects of simultaneous changes in temperature and Ni supply on lysosomal membrane stability (LMS) and malondialdehyde accumulation (MDA) in the digestive gland (DG) of the blue mussel Mytilus galloprovincialis (Lam.). To elucidate how the molecular response to environmental stressors is modulated, we employed a cDNA microarray with 1673 sequences to measure relative transcript abundances in the DG of mussels exposed to Ni along with a temperature increase. A two-way ANOVA revealed that temperature and Ni rendered additive effects on LMS and MDA accumulation, increasing the toxic effects of metal cations. Ni loads in the DG were also affected by co-exposure to 26 degrees C. In animals exposed only to heat stress, functional genomics analysis of the microarray data (171 differentially expressed genes (DEGs)) highlighted seven biological processes, largely dominated by the up-regulation of folding protein-related genes and the down-regulation of genes involved in cell migration and cellular component assembly. Exposure to Ni at 18 degrees C and 26 degrees C yielded 188 and 262 DEGs, respectively, exhibiting distinct patterns in terms of biological processes. In particular, the response of mussels exposed to Ni at 26 degrees C was characterized by the up-regulation of proteolysis, ribosome biogenesis, response to unfolded proteins, and catabolic-related genes, as well as the down regulation of genes encoding cellular metabolic processes. Our data provide new insights into the transcriptomic response in mussels experiencing temperature increases and Ni exposure; these data should be carefully considered in view of the biological effects of heat stress, particularly in polluted areas. PMID- 24468839 TI - Targeting of follicle stimulating hormone peptide-conjugated dendrimers to ovarian cancer cells. AB - Ovarian cancer is the most lethal gynecological malignancy. Current treatment modalities include a combination of surgery and chemotherapy, which often lead to loss of fertility in premenopausal women and a myriad of systemic side effects. To address these issues, we have designed poly(amidoamine) (PAMAM) dendrimers to selectively target the follicle stimulating hormone receptor (FSHR), which is overexpressed by tumorigenic ovarian cancer cells but not by immature primordial follicles and other non-tumorigenic cells. Fluorescein-labeled generation 5 (G5) PAMAM dendrimers were conjugated with the binding peptide domain of FSH (FSH33) that has a high affinity to FSHR. The targeted dendrimers exhibited high receptor selectivity to FSHR-expressing OVCAR-3 cells, resulting in significant uptake and downregulation of an anti-apoptotic protein survivin, while showing minimal interactions with SKOV-3 cells that do not express FSHR. The selectivity of the FSH33-targeted dendrimers was further validated in 3D organ cultures of normal mouse ovaries. Immunostaining of the conjugates revealed their selective binding and uptake by ovarian surface epithelium (OSE) cells that express FSHR, while sparing the immature primordial follicles. In addition, an in vivo study monitoring tissue accumulation following a single intraperitoneal (i.p.) injection of the conjugates showed significantly higher accumulation of FSH33 targeted dendrimers in the ovary and oviduct compared to the non-targeted conjugates. These proof-of-concept findings highlight the potential of these FSH33-targeted dendrimers to serve as a delivery platform for anti-ovarian cancer drugs, while reducing their systemic side effects by preventing nonspecific uptake by the primordial follicles. PMID- 24468840 TI - Trending now: future directions in digital media for the public health sector. AB - BACKGROUND: Digital media usage is expanding enormously and is starting to be used as a public health intervention and communication tool. It has an ability to increase the reach of public health research and communication, as well as drive measurable behaviour change. But there is an absence of both deep and wide understanding of the opportunities within digital media, i.e. most people think only of Facebook and Twitter when they think of social media; smart, strategic planning for its widespread use is not common practice and rigorous evaluative studies of its effectiveness are few and far between. METHODS: This paper analyses the published literature on this topic and identifies the top 10 directions that use of digital media is likely to take in the medium term. RESULTS: The analysis strongly supports the position that digital media needs to be taken seriously as a vehicle for public health activity in its own right and not merely as an adjunct to other campaigns. CONCLUSIONS: Digital media will continue to develop and move from being an add-on to existing activity to being the major vehicle for significant elements of research, data collection and advocacy. It is important that public health leaders fully understand and engage in its development and use. PMID- 24468841 TI - Ultrastructure of the hairs of the filamentous green alga Bulbochaete hiloensis (Nordst.) Tiffany: an apoplastidic plant cell with a well developed Golgi apparatus. AB - Bulbochaete hiloensis is a filamentous green alga in the Oedogoniales. It possesses colourless hair cells, the ultrastructure and development of which are unusual in several respects: (1) The initial wall of the hair cell is formed by eversion of a pre-formed pad of cell wall material (Cook, 1962). (2) The hair cells are apoplastidic, even lacking colourless remnants of plastid material. (3) A nucleolus is lacking from young and mature hair cell nuclei, though it is not known whether one is present in the earliest stages. (4) Despite the absence of chloroplasts, starch reserves, and a nucleolus, the ultrastructure of the cytoplasm is characteristic of intensive granulocrine secretory activity. Massed cisternae of rough endoplasmic reticulum and numerous dictyosomes, together with associated transitional and secretory vesicles, are present. Substrate for the biosyntheses in these systems must enter the hairs via plasmodesmata, which exist in the basal wall. The product is probably a mucilage, exported to the exterior through a system of pores which pierce the outer wall of the hair. (5) Microtubules lie in the hair, and in its bulbous base, where some may be interpreted as having a role in anchoring the nucleus. (6) The significance of the apoplastidic and anucleolate condition is discussed. PMID- 24468842 TI - Fine structure of isolated mesophyll protoplasts of tobacco. AB - Protoplasts of palisade cells isolated enzymatically from mature leaves of tobacco were studied with the electron microscope. A cell wall was completely absent, and the chloroplasts contained large inclusion bodies which were believed to be a crystalline form of fraction I protein. The fine structure of the protoplasts was otherwise that of healthy mesophyll cells, indicating that they are in a good physiological state. Some protoplasts were multinucleate as a result of fusion during the isolation process. PMID- 24468843 TI - The influence of genomes on autonomous growth of pith cultures of Nicotiana glauca-Langsdorffii hybrids. AB - A differential influence of the two parental genomes on cell proliferation and morphogenesis in pith tissue explants can be observed among the various tumorous hybrid combinations between Nicotiana glauca Grah. and N. langsdorffii Weinm.: the F1 hybrid (GL), its amphiploid (GGLL), and two different triploids (GGL and GLL). This influence was evident when the explants were cultured in the presence of exogenous auxin (indole-3-acetic acid, 2.5 MUM), supplied either continuously or for a brief period of time. Compared with the F1 and the amphiploid, the higher proportion of N. glauca genomes in GGL cells resulted in greater growth, the higher proportion of N. langsdorffii genomes in GLL cells in lesser growth. In addition, shoots are produced on the GGL callus, while only roots are formed on calli of the other types in the same medium. When, in addition to auxin, a cytokinin [6-(3-methyl-2-butenyl-amino)purine] was added to the culture medium, the differential growth of the different tissue types was less pronounced; at 1.0 MUM of the cytokinin, all tissues grew at about the same rate and remained undifferentiated, regardless of their genomic composition. PMID- 24468844 TI - Synthesis and release of sucrose by the aleurone layer of barley: Regulation by gibberellic acid. AB - Aleurone layers of barley contain large amounts of a soluble oligosaccharide which was identified as sucrose (30-40 MUg/mg fresh weight). Treatment of the layers with gibberellic acid (GA3) causes the release of sucrose from the cells. This release requires the participation of metabolic processes, including protein synthesis. When embryoless half-seeds are incubated sucrose accumulates in the aleurone layers, but when seeds are germinated the sucrose content of the aleurone layers declines. Labeling experiments with radioactive glucose and fructose show that aleurone layers continuously synthesize sucrose and that the release, but not the synthesis of sucrose is enhanced by GA3. PMID- 24468845 TI - The apparent absence of a pathway for synthesis of acetyl coenzyme A in pea chloroplasts: Lack of (14)CO 2 incorporation into lipids by the isolated organelle. AB - We have examined the extent to which isotopic lable derived from photosynthetically fixed (14)CO2 can be transferred to lipids by aqueously isolated chloroplasts of Pisum sativum. Although photosynthetically active, chloroplast preparations incubated with (14)CO2 showed little or no accumulation of label in lipids under any condition tested. Under identical conditions the chloroplasts were readily able to incorporate [(14)C]acetate into the lipid fraction; a fatty-acid synthesizing system was therefore operative in these chloroplasts.The essential failure of the isolated chloroplasts to incorporate label from fixed (14)CO2 into fatty acids supports the view that the organelle itself does not possess a self-contained pathway for the synthesis of acetyl coenzyme A, and favours the possibility that a shuttle mechanism involving the participation of extra-chloroplastic enzymes may be responsible for supplying the chloroplast with acetyl coenzyme A in vivo. PMID- 24468846 TI - Decarboxylation of malate by isolated bundle-sheath cells of certain plants having the C4-dicarboxylic acid cycle of photosynthesis. AB - Bundle-sheath cells isolated by the grinding and filtration procedure of Edwards and Black (1971b) from species of plants having the C4-dicarboxylic acid pathway of photosynthesis were tested for the decarboxylation of malate from the C4 carboxyl position. The bundle-sheath cells, which showed high malic enzyme activity in extracts, decarboxylated 4[(14)C]malate at rates sufficient to be involved in photosynthesis. The malate decarboxylation is dependent on the addition of magnesium or manganese and NADP(+). The activity was increased by raising the temperature from 30 to 50 degrees . The evidence supports the idea that malate may be a carboxyl donor to the reductive pentose-phosphate cycle in bundle-sheath cells in certain C4-dicarboxylic acid pathway plants such as Zea mays L., Sorghum bicolor L., and Digitaria sanguinalis (L.) Scop. PMID- 24468847 TI - Correlative effects of leaf age on reproductive growth in red clover (Trifolium pratense L.). AB - The contribution of individual leaves towards the flowering response in red clover (Trifolium pratense L.) seedlings at the three-leaf stage is described. Removal of the first (oldest) or first and second leaves resulted in large increases (up to 300%) in both the rate of stem extension and the degree of apical differentiation.Removal of the youngest leaves depressed both processes. Application of cycloheximide to specific leaves produced effects similar to defoliation, but chloramphenicol was generally inhibitory and kinetin substantially ineffective. Translocation patterns between leaves and the shoot apex were studied using [(14)C] sucrose and [(3)H] gibberellin A1. There was appreciable movement between leaves, but exposure to long-days depressed the transport of labelled assimilate. Label arriving at the apex was increasingly derived from the younger leaves as floral induction proceeded. PMID- 24468848 TI - [Precursors of ribosomal RNA in freely suspended callus cells of parsley (Petroselinum sativum)]. AB - Six high molecular weight, rapidly labelled RNA species were detected in freely suspended callus cells of Petroselinum sativum by means of isotope labelling and electrophoretic separation in agarose-polyacrylamide gels. On the basis of their migration in the latter the RNA species were calculated to have the following molecular weights: 2.9*10(6), 2,4*10(6), 1.9*10(6), 1.4*10(6), 1.0*10(6) and 0.75*10(6) daltons. Thus they can clearly be distinguished from the two ribosomal RNA species (1.3*10(6) and 0.7*10(6) daltons). During incubation of the cells with [(3)H]methyl-methionine as a methyl donator all six components incorporated radioactivity rapidly. With [(3)H]nucleosides or [(3)H]orotic acid as precursors the 2.9*10(6) and the 2.4*10(6) daltons RNA were labelled within 10 min, while the other high molecular weight species appeared after about 20 min of labelling.Prolongation to 45-120 min resulted in accumulation of radioactivity preferentially in the 1.4*10(6) and 0.75*10(6) daltons RNA and in the ribosomal RNA species. The results of cell fractionation experiments provide evidence that these rapidly labelled high molecular weight RNA species are synthesized in the cell nucleus. The kinetics of their synthesis together with the other data obtained strongly support the suggestion that these RNA species function as precursors in the processing of ribosomal RNA. The possible mechanism of this process is discussed. PMID- 24468849 TI - The photoluminescence and gas sorption properties of three Cd(II) MOFs based on 1,3,5-benzenetribenzoate with -NH2 or -OH groups. AB - The functionalization and modification of the ligand 1,3,5-tris(4 carboxyphenyl)benzene (H3BTB) have been realized with amine (NH2-H3BTB) and hydroxy (HO-H3BTB) groups. Three new Cd(II) compounds based on R-H3BTB ligands (R = -NH2 and -OH) have been synthesized and structurally characterized. Compounds 1 and 2 show pillared-layer frameworks and display strong fluorescence emission ability. Compound 3 features a 3D porous framework with trinuclear Cd units linked by the NH2-BTB ligand. The activated framework of 3 has good gas storage and separation properties for CO2 and hydrocarbons. PMID- 24468850 TI - Insight into the mechanism of nanodiamond catalysed decomposition of methane molecules. AB - Nanodiamond can catalyze the decomposition of methane, and its initial rate is linearly dependent on the number of -CH=CH- defective sites. Thermal treatment improves the ordering of surface atoms, resulting in an inferior activity but a more stable performance over a long period of time, and above 1300 degrees C few layered graphene can be found. PMID- 24468851 TI - Reproducibility of PET measurement for presynaptic dopaminergic functions using L [beta-(11)C]DOPA and [(18)F]FE-PE2I in humans. AB - OBJECTIVE: Recent PET studies have indicated altered presynaptic function and relation with psychotic symptoms in patients with schizophrenia. The L-[beta (11)C]DOPA uptake rate reflects the dopamine synthesis capacity (kref), whereas the nondisplaceable binding potential (BPND) of [(18)F]FE-PE2I reflects the dopamine transporter availability. Although the kref values of L-[beta-(11)C]DOPA and the BPND of [(18)F]FE-PE2I can be potential markers for evaluating the severity of positive symptoms, test-retest reproducibility has not been confirmed. The purpose of this study was to investigate the test-retest reproducibility of kref values of L-[beta-(11)C]DOPA and that of BPND of [(18)F]FE-PE2I in the striatum and midbrain in healthy humans. MATERIALS AND METHODS: Twelve healthy male volunteers underwent two PET studies on separate days. Each PET study comprised two PET scans, one with L-[beta-(11)C]DOPA and the other with [(18)F]FE-PE2I. Volumes of interest were defined for the caudate, putamen, midbrain, and thalamus. Test-retest reproducibility was assessed in terms of intrasubject variability (absolute variability) and reliability [intraclass correlation coefficient (ICC)]. RESULTS: The absolute variability values of kref and BPND were 4.8-25.7% on average for the caudate, putamen, midbrain, and thalamus. The ICC values of the kref values of L-[beta-(11)C]DOPA were 0.78, 0.71, 0.77, and 0.77 for the caudate, putamen, midbrain, and thalamus, respectively. The ICC values of the BPND of [(18)F]FE-PE2I were 0.83, 0.88, 0.71, and 0.70 for the caudate, putamen, midbrain, and thalamus, respectively. CONCLUSION: We found good test-retest reproducibility for the kref values of L [beta-(11)C]DOPA and that for the BPND of [(18)F]FE-PE2I in the striatum and midbrain, indicating the reliability of clinical investigation using PET with L [beta-(11)C]DOPA and [(18)F]FE-PE2I. PMID- 24468852 TI - The diagnostic role of dual-phase (18)F-FDG PET/CT in the characterization of solitary pulmonary nodules. AB - OBJECTIVE: Our objective was to evaluate the diagnostic role of dual-phase (18)F fluorodeoxyglucose ((18)F-FDG) PET/computed tomography (CT) in the characterization of solitary pulmonary nodules (SPNs). PATIENTS AND METHODS: A total of 48 SPNs in 48 patients were included in this retrospective study. The final diagnosis was confirmed histopathologically or by follow-up CT. Two PET/CT scans were performed: the first (early scan) was performed 1 h after injection and the second (delayed scan) was performed 2 h later. Standardized uptake values (SUVs) [early and delayed SUVmax and SUVmean adjusted to body weight, body surface area (BSA), lean body mass (LBM) and blood glucose level (Glc)], retention index and nodule-to-mediastinum (nodule activity/subcarinal region of interest activity) ratios were calculated, along with the receiver operating characteristic curve. Intraobserver and interobserver variabilities among nuclear medicine physicians were analysed for the two phases. RESULTS: Eighteen patients had malignant tumour, whereas 30 had benign lesions. The median (min-max) SUVmax was 1.5 (0.5-4.1) in the benign group and 3.6 (1.3-38) in the malignant group. With the threshold value of early SUVmax as 2.5 and 2.75 using the receiver operating characteristic curve, a sensitivity of 94-75%, specificity of 75-80% and an accuracy of 83-78% were calculated. With the same threshold values for delayed images, 94-100% sensitivity, 77-80% specificity and 83-88% accuracy were obtained. BSA-SUVmax, LBM-SUVmax and Glc-SUVmax did not show any advantage over other quantitative parameters in the SPN characterization. There was no variability in the results obtained between the two nuclear medicine physicians. CONCLUSION: Dual-phase PET/CT may increase the diagnostic potential of PET/CT in the characterization of SPNs. In this particular study group, a threshold value could not be determined for the retention index, but higher retention indices may show higher malignant potential in SPNs. PMID- 24468853 TI - Correcting (18)F-fluoride PET static scan measurements of skeletal plasma clearance for tracer efflux from bone. AB - OBJECTIVE: The aim of the study was to examine whether (18)F-fluoride PET ((18)F PET) static scan measurements of bone plasma clearance (Ki) can be corrected for tracer efflux from bone from the time of injection. MATERIALS AND METHODS: The efflux of tracer from bone mineral to plasma was described by a first-order rate constant kloss. A modified Patlak analysis was applied to 60-min dynamic (18)F PET scans of the spine and hip acquired during trials on the bone anabolic agent teriparatide to find the best-fit values of kloss at the lumbar spine, total hip and femoral shaft. The resulting values of kloss were used to extrapolate the modified Patlak plots to 120 min after injection and derive a sequence of static scan estimates of Ki at 4-min intervals that were compared with the Patlak Ki values from the 60-min dynamic scans. A comparison was made with the results of the standard static scan analysis, which assumes kloss=0. RESULTS: The best-fit values of kloss for the spine and hip regions of interest averaged 0.006/min and did not change when patients were treated with teriparatide. Static scan values of Ki calculated using the modified analysis with kloss=0.006/min were independent of time between 10 and 120 min after injection and were in close agreement with findings from the dynamic scans. In contrast, by 2 h after injection the static scan Ki values calculated using the standard analysis underestimated the dynamic scan results by 20%. CONCLUSION: Using a modified analysis that corrects for F efflux from bone, estimates of Ki from static PET scans can be corrected for time up to 2 h after injection. This simplified approach may obviate the need to perform dynamic scans and hence shorten the scanning procedure for the patient and reduce the cost of studies. It also enables reliable estimates of Ki to be obtained from multiple skeletal sites with a single injection of tracer. PMID- 24468854 TI - Dysprosium-free melt-spun permanent magnets. AB - Melt-spun NdFeB powders can be formed into a number of different types of permanent magnet for a variety of applications in electronics, automotive and clean technology industries. The melt-spinning process produces flake powder with a fine uniform array of nanoscale Nd2Fe14B grains. These powders can be net-shape formed into isotropic polymer-bonded magnets or hot formed into fully dense magnets. This paper discusses the influence of heavy rare earth elements and microstructure on the magnetic performance, thermal stability and material cost of NdFeB magnets. Evidence indicates that melt-spun nanocrystalline NdFeB magnets are less dependent on heavy rare earth elements for high-temperature performance than the alternative coarser-grained sintered NdFeB magnets. In particular, hot pressed melt-spun magnets are an attractive low-cost solution for applications that require thermal stability up to 175-200 degrees C. PMID- 24468855 TI - Local geometric and electronic structures of gasochromic VO(x) films. AB - VOx films were deposited by radio-frequency reactive magnetron sputtering from a vanadium target at room temperature. Local atomic and electronic structures of the films were then modified by thermal annealing. The oxidation state and structural and gasochromic properties of the films were elucidated by X-ray absorption spectroscopy. Analytical results indicate that the as-deposited VOx films were amorphous with mixed V(4+) and V(5+) valences. The amorphous VOx had a disordered and expanded lamellar structure resembling that of polymer intercalated V2O5 gels. VOx films were crystallized into orthorhombic V2O5 at 300 degrees C, and the lamellar structure was eliminated at 400 degrees C. Additionally, the gasochromic reaction reduced the vanadium valence via intervalence transitions between V(5+) and V(3+). Moreover, removing the lamellar structure reduced the gasochromic rate, and the gasochromic reaction transformed the V2O5 crystalline phase irreversibly into an H1.43V2O5 phase. Based on the results of this study, amorphous VOx with a lamellar structure is recommended for use in H2 gas sensors. PMID- 24468856 TI - In vitro studies on organophosphate pesticides induced oxidative DNA damage in rat lymphocytes. AB - Organophosphate (OP) pesticides are widely used for agricultural and household pest control. We studied the genotoxicity of the commonly used OP pesticides chlorpyrifos (CPF), methyl parathion (MPT), and malathion (MLT), individually and in combination, in Wistar rat peripheral blood lymphocytes in vitro. DNA single strand and double-strand breaks were measured by single cell gel electrophoresis (SCGE; comet assay). To test whether the DNA lesions were caused by oxidative stress, the DNA repair enzymes formamidoaminopyrimidineglycosylase (Fpg) and endonuclease (Endo III), which convert base damages to strand breaks, were used. Significant increases in strand breaks and in levels of the reactive oxygen species (ROS) superoxide anion and hydrogen peroxide were observed in lymphocytes treated with pesticides. MPT exposure caused the greatest DNA damage and ROS production, followed by CPF and ML. Our results demonstrate genotoxic potential of these OP pesticides. PMID- 24468857 TI - Light trapping and surface plasmon enhanced high-performance NIR photodetector. AB - Heterojunctions near infrared (NIR) photodetectors have attracted increasing research interests for their wide-ranging applications in many areas such as military surveillance, target detection, and light vision. A high-performance NIR light photodetector was fabricated by coating the methyl-group terminated Si nanowire array with plasmonic gold nanoparticles (AuNPs) decorated graphene film. Theoretical simulation based on finite element method (FEM) reveals that the AuNPs@graphene/CH3-SiNWs array device is capable of trapping the incident NIR light into the SiNWs array through SPP excitation and coupling in the AuNPs decorated graphene layer. What is more, the coupling and trapping of freely propagating plane waves from free space into the nanostructures, and surface passivation contribute to the high on-off ratio as well. PMID- 24468858 TI - A preliminary diffusional kurtosis imaging study of Parkinson disease: comparison with conventional diffusion tensor imaging. AB - INTRODUCTION: Diffusional kurtosis imaging (DKI) is a more sensitive technique than conventional diffusion tensor imaging (DTI) for assessing tissue microstructure. In particular, it quantifies the microstructural integrity of white matter, even in the presence of crossing fibers. The aim of this preliminary study was to compare how DKI and DTI show white matter alterations in Parkinson disease (PD). METHODS: DKI scans were obtained with a 3-T magnetic resonance imager from 12 patients with PD and 10 healthy controls matched by age and sex. Tract-based spatial statistics were used to compare the mean kurtosis (MK), mean diffusivity (MD), and fractional anisotropy (FA) maps of the PD patient group and the control group. In addition, a region-of-interest analysis was performed for the area of the posterior corona radiata and superior longitudinal fasciculus (SLF) fiber crossing. RESULTS: FA values in the frontal white matter were significantly lower in PD patients than in healthy controls. Reductions in MK occurred more extensively throughout the brain: in addition to frontal white matter, MK was lower in the parietal, occipital, and right temporal white matter. The MK value of the area of the posterior corona radiata and SLF fiber crossing was also lower in the PD group. CONCLUSION: DKI detects changes in the cerebral white matter of PD patients more sensitively than conventional DTI. In addition, DKI is useful for evaluating crossing fibers. By providing a sensitive index of brain pathology in PD, DKI may enable improved monitoring of disease progression. PMID- 24468859 TI - Endovascular treatment of head and neck arteriovenous malformations. AB - INTRODUCTION: Head and neck arteriovenous malformations (H&N AVM) are associated with considerable clinical and psychosocial burden and present a significant treatment challenge. We evaluated the presentation, response to treatment, and outcome of patients with H&N AVMs treated by endovascular means at our institution. METHODS: Patients with H&N AVMs treated by endovascular means from 1984 to 2012 were evaluated retrospectively. These included AVMs involving the scalp, orbit, maxillofacial, and upper neck localizations. Patient's clinical files, radiological images, catheter angiograms, and surgical reports were reviewed. RESULTS: Eighty-nine patients with H&N AVMs (46 females, 43 males; 48 small, 41 large) received endovascular therapy. The goals of treatment were curative (n = 30), palliative (n = 34), or presurgical (n = 25). The total number of endovascular treatment sessions was 244 (average of 1.5 per patient). The goal of treatment was met in 92.1 % of cases. Eventual cure was achieved in 42 patients accounting for 58.4 % (52/89) of all patients who underwent treatment for any goal. Twenty-eight of these patients were cured by embolization alone (28/89, 31.4 %) of which 18 were single-hole AVFs. Twenty-four were cured by planned surgical excision after presurgical embolization (24/89, 27 %). Seven patients (7/89, 7.2 %) suffered transient and two (2/89, 2.2 %) permanent endovascular treatment complications. CONCLUSION: Endovascular treatment is effective for H&N AVMs and relatively safe. It is particularly effective for symptom palliation and presurgical aid. Embolization is curative mostly in small lesions and single-hole fistulas. In patients with large non-curable H&N AVMs, endovascular therapy is often the only palliative option. PMID- 24468860 TI - Stability of ischemic core volume during the initial hours of acute large vessel ischemic stroke in a subgroup of mechanically revascularized patients. AB - INTRODUCTION: This study aimed to relate growth of the infarct core with time to recanalization in patients receiving mechanical recanalization in whom the time of recanalization is known. METHODS: We analyzed data from patients with anterior circulation acute ischemic stroke who underwent mechanical recanalization. Demographic and angiographic characteristics, initial apparent diffusion coefficient (ADC) infarct volume, time-to-peak defect volume, revascularization grade, 24-48 h nonenhanced computed tomography (CT) infarct volume, symptom onset to recanalization time, diffusion-weighted imaging to recanalization time, and discharge National Institutes of Health Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores were compared between minimal and substantial infarct growth groups. Substantial infarct growth was defined as an increase of infarct volume >10 cm(3) assessed by subtracting initial ADC infarct core volume from infarct volume at 24-48 h CT. RESULTS: Of 25 patients, 9 had minimal infarct growth (median 0 cm(3), interquartile range (IQR) -3 to 5 cm(3)) and 16 had substantial infarct growth (median 103 cm(3), IQR 48-132 cm(3)). Patients with minimal infarct growth had a median time from symptom onset to recanalization of 329 min (IQR 314-412 min) and a median time from imaging to recanalization of 231 min (IQR 198-309 min). On univariate analysis, minimal infarct growth was related to male gender (p = 0.04), smaller initial ADC volume (p = 0.04), higher recanalization grade (p < 0.001), and lower discharge NIHSS (p = 0.04) and mRS grades (p = 0.04). CONCLUSION: There was no or minimal infarct core growth in at least one third of patients despite an exceptionally long median time from magnetic resonance imaging to recanalization of almost 4 h. PMID- 24468861 TI - Synthesis and enzymatic photo-activity of an O2 tolerant hydrogenase-CdSe@CdS quantum rod bioconjugate. AB - This communication reports on the preparation of stable and photo-active nano heterostructures composed of O2 tolerant [NiFe] hydrogenase extracted from the Aquifex aeolicus bacterium grafted onto hydrophilic CdSe/CdS quantum rods in view of the development of H2/O2 biofuel cells. The resulting complex is efficient towards H2 oxidation, displays good stability and new photosensitive properties. PMID- 24468862 TI - Comment on: current initiatives to improve prudent antibiotic use amongst school aged children. PMID- 24468863 TI - High-throughput informative single nucleotide polymorphism-based typing of Neisseria gonorrhoeae using the Sequenom MassARRAY iPLEX platform. AB - OBJECTIVES: Neisseria gonorrhoeae antimicrobial resistance (AMR) is a global problem heightened by emerging resistance to ceftriaxone. Appropriate molecular typing methods are important for understanding the emergence and spread of N. gonorrhoeae AMR. We report on the development, validation and testing of a Sequenom MassARRAY iPLEX method for multilocus sequence typing (MLST)-style genotyping of N. gonorrhoeae isolates. METHODS: An iPLEX MassARRAY method (iPLEX14SNP) was developed targeting 14 informative gonococcal single nucleotide polymorphisms (SNPs) previously shown to predict MLST types. The method was initially validated using 24 N. gonorrhoeae control isolates and was then applied to 397 test isolates collected throughout Queensland, Australia in the first half of 2012. RESULTS: The iPLEX14SNP method provided 100% accuracy for the control isolates, correctly identifying all 14 SNPs for all 24 isolates (336/336). For the 397 test isolates, the iPLEX14SNP assigned results for 5461 of the possible 5558 SNPs (SNP call rate 98.25%), with complete 14 SNP profiles obtained for 364 isolates. Based on the complete SNP profile data, there were 49 different sequence types identified in Queensland, with 11 of the 49 SNP profiles accounting for the majority (n = 280; 77%) of isolates. AMR was dominated by several geographically clustered sequence types. Using the iPLEX14SNP method, up to 384 isolates could be tested within 1 working day for less than Aus$10 per isolate. CONCLUSIONS: The iPLEX14SNP offers an accurate and high-throughput method for the MLST-style genotyping of N. gonorrhoeae and may prove particularly useful for large-scale studies investigating the emergence and spread of gonococcal AMR. PMID- 24468864 TI - Avibactam activity against extended-spectrum AmpC beta-lactamases. PMID- 24468865 TI - In vitro synergy testing of novel antimicrobial combination therapies against Neisseria gonorrhoeae. AB - BACKGROUND: Antimicrobial-resistant Neisseria gonorrhoeae is a major public health threat. Current CDC treatment guidelines for uncomplicated gonorrhoea recommend only ceftriaxone plus either azithromycin or doxycycline. Additional treatment options are needed. METHODS: We used antibiotic gradient synergy testing (the Etest) to evaluate antimicrobial combinations that included a third generation cephalosporin (cefixime or ceftriaxone) plus azithromycin, doxycycline, gentamicin, rifampicin or fosfomycin. We tested each combination against 28 clinical N. gonorrhoeae isolates and four control strains of varying susceptibility profiles, and compared the results with those obtained using combination antimicrobial testing using agar dilution. We calculated the fractional inhibitory concentration index (FICI) for each combination to determine synergy, the results being interpreted as follows: FICI <= 0.5 = synergy; FICI > 4.0 = antagonism; and FICI > 0.5-4 = indifference. RESULTS: The combinations of a third-generation cephalosporin plus azithromycin, doxycycline, rifampicin, gentamicin or fosfomycin produced FICIs of indifference. The Etest and agar dilution methods produced comparable results. CONCLUSIONS: Combinations of ceftriaxone plus rifampicin, gentamicin or fosfomycin may warrant further clinical investigation as treatments for gonorrhoea. Using the Etest for synergy testing is a viable method that has practical advantages over agar dilution. PMID- 24468866 TI - Zyvox(r) Annual Appraisal of Potency and Spectrum (ZAAPS) program: report of linezolid activity over 9 years (2004-12). AB - OBJECTIVES: To summarize the activity and spectrum of linezolid and comparators tested against 7972 Gram-positive clinical isolates as part of the Zyvox((r)) Annual Appraisal of Potency and Spectrum (ZAAPS) Program for 2012. Moreover, to provide molecular characterization for associated resistance mechanisms and epidemiological typing. METHODS: A total of 7972 isolates were collected from 73 medical centres (33 countries) on five continents. Isolates were tested for susceptibility by broth microdilution following the CLSI M07-A9 document. MIC interpretations were based on CLSI and EUCAST criteria. RESULTS: Linezolid showed MIC50 and MIC90 results of 1 and 2 mg/L, respectively, when tested against Staphylococcus aureus. These isolates were inhibited by linezolid at <=2 mg/L, except for four S. aureus exhibiting higher MIC values (4-8 mg/L), which had cfr and/or target site mutations, including a first detection of cfr in an isolate from Brazil. Coagulase-negative staphylococci (CoNS) were susceptible to linezolid (MIC50/90, 0.5/1 mg/L), with only eight isolates exhibiting high MIC results (16-32 mg/L). These CoNS had cfr and/or single or multiple target site alterations in 23S rRNA and/or ribosomal proteins (L3, L4). The same species of linezolid-resistant CoNS collected from the same hospital were clonally related to those observed in previously surveyed years. Linezolid exhibited stable modal MIC and MIC50 results when tested against enterococci, regardless of the species or vancomycin resistance phenotype; in addition, linezolid inhibited all streptococci at <=2 mg/L. CONCLUSIONS: This surveillance report documents stable linezolid activity and susceptibility rates against a large and longitudinal collection of clinical isolates worldwide. PMID- 24468867 TI - Performance of the Abbott RealTime HIV-1 assay versus the roche amplicor HIV-1 MonitorTM Test, v1.5, UltraSensitive assay for samples with low plasma HIV-1 RNA copy numbers. PMID- 24468868 TI - Anidulafungin dosing in critically ill patients with continuous venovenous haemodiafiltration. AB - BACKGROUND: Anidulafungin is indicated as a first-line treatment for invasive candidiasis in critically ill patients. In the intensive care unit, sepsis is the main cause of acute renal failure, and treatment with continuous renal replacement therapy (CRRT) has increased in recent years. Antimicrobial pharmacokinetics is affected by CRRT, but few studies have addressed the optimal dosage for anidulafungin during CRRT. PATIENTS AND METHODS: We included 12 critically ill patients who received continuous venovenous haemodiafiltration to treat acute renal failure. Anidulafungin was infused on 3 consecutive days, starting with a loading dose (200 mg) on Day 1, and doses of 100 mg on Days 2 and 3. Blood and ultradiafiltrate samples were collected on Day 3 (during steady state) before, and at regular intervals after, the infusion had started. Anidulafungin concentrations were determined with HPLC. RESULTS: On Day 3, peak plasma concentrations with the 100 mg dose were 6.2 +/- 1.7 mg/L and 7.1 +/- 1.9 mg/L in the arterial and venous samples, respectively. The mean, pre-filter trough concentration was 3.0 +/- 0.6 mg/L. The mean AUC0-24 values for plasma anidulafungin were 93.9 +/- 19.4 and 104.1 +/- 20.3mg.h/L in the arterial and venous samples, respectively. There was no adsorption to synthetic surfaces, and the anidulafungin concentration in the ultradiafiltrate was below the limit of detection. CONCLUSION: The influence of CRRT on anidulafungin elimination appeared to be negligible. Therefore, we recommend no adjustments to the anidulafungin dose for patients receiving CRRT. PMID- 24468869 TI - Autoantibodies to transient receptor potential cation channel, subfamily M, member 1 in a Japanese patient with melanoma-associated retinopathy. AB - PURPOSE: To report a case of melanoma-associated retinopathy (MAR) in a Japanese patient found to have autoantibodies to transient receptor potential cation channel, subfamily M, member 1 (TRPM1). CASE: An 82-year-old man presented with blurred vision OS as well as night blindness and photopsia OU. Fundus photography, fluorescein angiography, and spectral domain-optical coherence tomography findings were essentially normal. Goldmann perimetry revealed a relative central scotoma, including the blind spot in the right eye, as well as a relative scotoma around a blind spot OS. The full-field scotopic electroretinograms showed a "negative-type" pattern OU, suggestive of extensive bipolar cell dysfunction. Systemic examination revealed that the patient had malignant melanoma of the anus with lung metastasis. Autoantibodies to TRPM1 were detected in the serum of the patient by immunoblot analysis. Vitreous opacity developed during follow-up. The visual symptoms and vitreous opacity of the patient were markedly improved after oral prednisolone therapy. The patient died as a result of widespread metastasis of the melanoma at 11 months after his first visit. CONCLUSION: The present case is the first reported instance of MAR positive for autoantibodies to TRPM1 in an Asian patient. PMID- 24468870 TI - Clinical features and glaucoma according to optic disc size in a South Korean population: the Namil study. AB - PURPOSE: To assess the proportion of glaucomatous eyes based on the association between optic disc (OD) size and its clinical determinants in the resident population of Namil-myon, Central South Korea. METHODS: Of the 1,532 participants in the Namil study, we included 1,410 Koreans (2,734 eyes) with legible fundus photographs in this study. Following the estimation of OD size on the photographs using Image J software, we corrected for image magnification. Associations between the clinical features, such as age, sex, axial length (AL), spherical equivalent (SE), and central corneal thickness, and the estimated OD size were assessed for individual eyes. After adjusting for the influencing factors, the proportion of glaucoma was compared among three categories of measured OD size (small, medium, and large OD groups). RESULTS: After adjusting for the potential confounders using a linear mixed model, age, sex, AL, and SE were correlated with the OD size estimates (P = 0.003, P = 0.029, P < 0.001, and P < 0.001, respectively). The percentage of glaucomatous eyes was 3.77 % in the small disc group, which was higher than in the other groups (P = 0.054). In particular, normal tension glaucoma (NTG) was statistically significantly more frequent in this group (odds ratio = 1.86, P = 0.042). CONCLUSIONS: These results suggest that clinical features such as age, sex, AL, and SE might need to be considered for an accurate evaluation of the OD. In addition, in individuals with a small OD, the presence of NTG must be carefully investigated in the South Korea population. PMID- 24468873 TI - Neural repair and rehabilitation: new assistive devices for stroke rehabilitation. PMID- 24468877 TI - Extracellular alpha--synuclein-a novel and crucial factor in Lewy body diseases. AB - Misfolding and intracellular aggregation of alpha-synuclein are thought to be crucial factors in the pathogenesis of Lewy body diseases (LBDs), such as Parkinson disease. However, the pathogenic modifications of this protein and the mechanisms underlying its activity have not been fully characterized. Recent studies suggest that small amounts of alpha-synuclein are released from neuronal cells by unconventional exocytosis, and that this extracellular alpha-synuclein contributes to the major pathological features of LBD, such as neurodegeneration, progressive spreading of alpha-synuclein pathology, and neuroinflammation. In this article, we review a rapidly growing body of literature on possible mechanisms by which extracellular alpha-synuclein contributes to LBD pathology, and discuss therapeutic approaches to target this form of alpha-synuclein to halt disease progression. PMID- 24468879 TI - Neuro-oncology: antifungal treatment for glioma? PMID- 24468878 TI - Disorders of consciousness after acquired brain injury: the state of the science. AB - The concept of consciousness continues to defy definition and elude the grasp of philosophical and scientific efforts to formulate a testable construct that maps to human experience. Severe acquired brain injury results in the dissolution of consciousness, providing a natural model from which key insights about consciousness may be drawn. In the clinical setting, neurologists and neurorehabilitation specialists are called on to discern the level of consciousness in patients who are unable to communicate through word or gesture, and to project outcomes and recommend approaches to treatment. Standards of care are not available to guide clinical decision-making for this population, often leading to inconsistent, inaccurate and inappropriate care. In this Review, we describe the state of the science with regard to clinical management of patients with prolonged disorders of consciousness. We review consciousness-altering pathophysiological mechanisms, specific clinical syndromes, and novel diagnostic and prognostic applications of advanced neuroimaging and electrophysiological procedures. We conclude with a provocative discussion of bioethical and medicolegal issues that are unique to this population and have a profound impact on care, as well as raising questions of broad societal interest. PMID- 24468882 TI - Disentangling the heterogeneity of autism spectrum disorder through genetic findings. AB - Autism spectrum disorder (ASD) represents a heterogeneous group of disorders, which presents a substantial challenge to diagnosis and treatment. Over the past decade, considerable progress has been made in the identification of genetic risk factors for ASD that define specific mechanisms and pathways underlying the associated behavioural deficits. In this Review, we discuss how some of the latest advances in the genetics of ASD have facilitated parsing of the phenotypic heterogeneity of this disorder. We argue that only through such advances will we begin to define endophenotypes that can benefit from targeted, hypothesis-driven treatments. We review the latest technologies used to identify and characterize the genetics underlying ASD and then consider three themes-single-gene disorders, the gender bias in ASD, and the genetics of neurological comorbidities-that highlight ways in which we can use genetics to define the many phenotypes within the autism spectrum. We also present current clinical guidelines for genetic testing in ASD and their implications for prognosis and treatment. PMID- 24468884 TI - Fluorescence-guided surgery in high grade gliomas using an exoscope system. AB - BACKGROUND: Fluorescence-guided microsurgical resections of high-grade gliomas using 5-aminolevulinic acid (5-ALA) is superior to conventional microsurgery. An optical device, usually a modified microscope, is needed for these procedures. However, an exoscope may be implemented for fluorescence techniques. We present the use of an exoscope to perform tumor resection guided by 5-ALA fluorescence in 21 consecutive patients with high-grade glioma and two neuronavigation-guided biopsies. METHODS: Twenty-three patients underwent operations. Tumor volume and localization were quantified with pre- and postoperative volumetric MRI in non biopsy cases. RESULTS: In non-biopsy cases, the age range was 20 to 79 years, with a median of 56 (interquartile range = 45-66). Histological analysis indicated that 14 had glioblastoma multiforme, 2 grade-III oligodendrogliomas and 1 anaplastic astrocytoma, 3 metastases and 1 low-grade astrocytoma. Total resection was achieved in 15 cases; subtotal resection was performed in 5 patients. The result was partial resection in one case. There was no perioperative mortality. The median fluorescence intensity, on a scale of 1-5, was 4.5 in the GBM group (IQR = 4-5), 3 (IQR = 2.5-3.5) in anaplastic glioma, and 2.5 (IQR = 2.25-2.75) for oligodendrogliomas. Of the three metastases, one showed fluorescence level 4. As for the two biopsy cases, one was anaplastic astrocytoma and one glioblastoma multiforme. The samples obtained were fluorescent in both cases. CONCLUSIONS: An exoscope can be also used for fluorescence-guided surgery with 5-aminolevulinic acid (5-ALA) and neuronavigation-guided biopsy. With an important advantage of low cost, this allows the surgeon to perform collaborative surgeries and adds agility to the procedure. PMID- 24468885 TI - Effect of simvastatin plus cetuximab/irinotecan for KRAS mutant colorectal cancer and predictive value of the RAS signature for treatment response to cetuximab. AB - PURPOSE: Preclinical data has demonstrated the potential of simvastatin to overcome cetuximab resistance in KRAS mutant CRC patients. Therefore, we designed a study using simvastatin/cetuximab/irinotecan for KRAS mutant CRC patients who are refractory to irinotecan and oxaliplatin-based chemotherapy. PATIENTS AND METHODS: In this phase II study, patients received 500 mg/m(2) cetuximab, 150-180 mg/m(2) (day 1), and 80 mg simvastatin (once daily, days 1-14, every 2 weeks). The primary endpoint was the objective response rate (ORR). Secondary endpoints were progression-free survival (PFS), overall survival (OS), the disease control rate (DCR), and safety. We also analyzed the relationship between the RAS gene expression signature score and treatment response to simvastatin/cetuximab/irinotecan. RESULTS: Fifty-two KRAS mutant CRC patients were enrolled. The ORR (complete response [CR], 0; partial response [PR], 1) was 1.9 % (95 % confidence interval [CI], -1.8-5.6). The DCR (CR, 0; PR, 1; stable disease, 33) was 65.4 % (95 % CI, 52.5-78.3). The median PFS and OS from the time of study drug administration were 7.6 months (95 % CI, 4.4-10.8) and 12.8 months (95 % CI, 9.5-16.2), respectively. The most common grade 3/4 adverse events were anemia (28.8 %), neutropenia (13.5 %), and diarrhea (7.7 %). The RAS signature score was significantly correlated with the maximal change in target lesions from baseline (r = 0.57, P = 0.014). CONCLUSION: The simvastatin/cetuximab/irinotecan regimen showed promising efficacy and safety in KRAS mutant CRC patients who failed irinotecan and oxaliplatin-based chemotherapy. The RAS signature may be a novel predictor of treatment response to cetuximab-combined chemotherapy in CRC patients. PMID- 24468887 TI - Real-world experience with atrial fibrillation ablation: cause for concern. PMID- 24468886 TI - An assessment of the pharmacokinetics, pharmacodynamics, and tolerability of GCPGC, a novel pegylated granulocyte colony-stimulating factor (G-CSF), in healthy subjects. AB - INTRODUCTION: A pegylated recombinant human granulocyte colony-stimulating factor (G-CSF) is effective in reducing the severity and duration of neutropenia. This study was performed to investigate the pharmacokinetics (PK), pharmacodynamics (PD), and tolerability of GCPGC, a new formulation of pegylated G-CSF, in healthy volunteers and to compare them with those of pegfilgrastim (Neulasta(r)). METHODS: Twenty-five healthy Korean male volunteers randomly received a single subcutaneous (SC) GCPGC injection at a dose of 30 (n = 10), 100 (n = 10), or 300 (n = 5) MUg/kg or placebo in a 4:1 ratio in a double-blind manner. Additionally, 8 subjects received a SC dose of pegfilgrastim at 100 MUg/kg. Blood samples were collected up to 14 days after both therapies. The absolute neutrophil count (ANC) and CD34(+) cell counts were the PD markers. RESULTS: After GCPGC administration, 4 different pharmacokinetic phases were identified, indicating target-mediated drug disposition (TMDD) for the elimination of GCPGC, which was slowed down as the dose was increased, resulting in a higher than proportional dose-normalized exposure to GCPGC. Although GCPGC was cleared faster than pegfilgrastim, leading to a 19 % lower systemic exposure to pegylated G-CSF, the increase in ANC and CD34(+) were ~20 % greater by GCPGC at 100 MUg/kg than pegfilgrastim. Thrombocytopenia, splenomegaly, and hemoperitoneum occurred in one subject in the 300 MUg/kg GCPGC group, which resolved completely with appropriate care. CONCLUSIONS: GCPGC showed a non-linear TMDD. The PK-PD characteristics of GCPGC at 30-100 MUg/kg were comparable to those of pegfilgrastim at 100 MUg/kg. GCPGC at 30-100 MUg/kg was well tolerated in healthy Korean males. PMID- 24468888 TI - Activated macrophage-like synoviocytes are resistant to endoplasmic reticulum stress-induced apoptosis in antigen-induced arthritis. AB - OBJECTIVE: To explore the characteristic expression of endoplasmic reticulum (ER) stress protein in antigen-induced arthritis models and the role of ER stress in arthritis. METHODS: Effective animal models of rheumatoid arthritis in rabbits and rats were induced by methylated bovine serum albumin and Freund's complete adjuvant. Pathological changes were assessed by magnetic resonance imaging and histological analysis. The expression and localization of ER stress proteins in synovium and peritoneal macrophages (PMPhi) were analyzed by double immunofluorescence staining. RT-PCR was performed to detect mRNA expression of ER stress-related genes. Tumor necrosis factor alpha (TNF-alpha) and interleukin-1 beta (IL-1beta) levels in synoviocytes were measured by RT-PCR and radioimmunoassay. RESULTS: We found that the ER stress marker BiP was highly up regulated in arthritis synovium and extensively expressed in fibroblast-like synoviocytes (FLS) and macrophage-like synoviocytes (MLS). The expression of the pro-apoptotic factor CHOP/GADD153 was slightly elevated in inflammatory synovium and mainly localized in FLS, but insignificant in MLS. Unexpectedly, increased expression of CHOP was observed in PMPhi in arthritis rats. Likewise, cleaved caspase-3 was rarely expressed in MLS. In addition, induction of ER stress by tunicamycin resulted in significantly increased expression of pro-inflammatory molecules such as IL-1beta and TNF-alpha in cultured inflammatory FLS. CONCLUSION: Differential activation of the ER stress proteins in synovium MLS may contribute to the resistance of synoviocytes to ER stress-induced apoptosis. Furthermore, ER stress is a potential mediator of arthritis inflammation. PMID- 24468889 TI - Vascular barrier protective effects of piperlonguminine in vitro and in vivo. AB - AIM AND OBJECTIVE: The nuclear DNA binding protein known as high-mobility group box 1 (HMGB1) acts as a late mediator of severe vascular inflammatory conditions, such as sepsis and septic shock. Piperlonguminine (PL), an important component of Piper longum fruit, is known to exhibit anti-hyperlipidemic, anti-platelet, and anti-melanogenesis activities. However, little is known about its effects on HMGB1-mediated inflammatory response. METHODS: We investigated the effects of PL on HMGB1-mediated inflammatory response by monitoring the effects of PL on lipopolysaccharide or cecal ligation and puncture (CLP)-mediated release of HMGB1, as well as on the modulation of HMGB1-mediated inflammatory responses. RESULTS: According to our data, PL caused inhibition of the release of HMGB1 and downregulation of HMGB1-dependent inflammatory responses in human endothelial cells. PL also inhibited HMGB1-mediated hyperpermeability and leukocyte migration in mice. In addition, treatment with PL reduced the CLP-induced release of HMGB1 and sepsis-related mortality. CONCLUSION: These results indicate that PL could be a candidate therapeutic agent for various severe vascular inflammatory diseases via inhibition of the HMGB1 signaling pathway. PMID- 24468890 TI - Anti-inflammatory effects of curcumin in experimental spinal cord injury in rats. AB - AIM: Antioxidant transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) has been shown in our previous studies to play an important role in protection against spinal cord injury (SCI) induced inflammatory response. The objective of this study was to test whether curcumin, a novel Nrf2 activator, can protect the spinal cord against SCI-induced inflammatory damage. METHODS: Adult male Sprague-Dawley rats were subjected to laminectomy at T8-T9 and compression with a vascular clip. The spinal cords spanning the injury site about 0.8 cm were collected for testing. There were three groups: (a) sham group; (b) SCI group; and (c) SCI + curcumin group. We measured Nrf2 and nuclear factor kappa B (NF kappaB) binding activities by electrophoretic mobility shift assay, concentrations of tumor necrosis factor-alpha, interleukin-1beta and interleukin 6 by enzyme-linked immunosorbent assay, hindlimb locomotion function by Basso, Beattie, and Bresnahan rating, spinal cord edema by the wet/dry weight method, and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis. RESULTS: Induction of the Nrf2 activity by curcumin markedly decreased NF-kappaB activation and inflammatory cytokines production in the injured spinal cord. Administration of curcumin also significantly ameliorated the secondary spinal cord damage, as shown by decreased severity of locomotion deficit, spinal cord edema, and apoptosis. CONCLUSION: Post-SCI curcumin administration attenuates the inflammatory response in the injured spinal cord, and this may be a mechanism whereby curcumin improves the outcome following SCI. PMID- 24468891 TI - Transcription-related element gene expression pattern differs between microglia and macrophages during inflammation. AB - OBJECTIVE AND DESIGN: Microglia and macrophages play an important role in the innate and adaptive immune systems. Although the resident location of these cells is different, their functions during the polarization response due to various stimuli are very similar. The present study aimed to analyze differences in microglial and macrophage gene expression during inflammation. METHODS: Mouse microglial BV-2 cells were exposed to LPS (10 ng/ml). The levels of gene expression were measured using real-time RT-PCR and whole transcriptome shotgun sequencing. RESULTS: The level of Jmjd3 gene expression in activated microglia showed a similar pattern to that of macrophages. In both cell types, genes associated with the inflammation response were generally increased whereas genes associated with metabolic and biosynthetic processes were decreased. However, the expression of transcription-related elements other than genes encoding histone modification enzymes showed a significantly different pattern between microglia and macrophages. CONCLUSION: Although the function and the gene expression levels of histone modification enzymes showed a similar pattern in microglia and macrophages during inflammation, the expression of transcription-related elements in both cell types showed a completely different pattern. PMID- 24468893 TI - Modelling in concentrated epidemics: informing epidemic trajectories and assessing prevention approaches. AB - PURPOSE OF THE REVIEW: This review summarizes recent mathematical modelling studies conducted among key populations including MSM, people who inject drugs (PWID), and female sex workers (FSWs) in low prevalence settings used as a marker of concentrated epidemics. RECENT FINDINGS: Most recent studies focused on MSM, Asian settings or high-income countries, studied the transmission dynamics or modelled pre-exposure prophylaxis, treatment as prevention or behavioural interventions specific to each key population (e.g., needle exchange programme or use of low-dead space syringes for PWID). Biological interventions were deemed effective and cost-effective, though still expensive, and often deemed unlikely to result in HIV elimination if used alone. Targeting high-risk individuals even within key populations improved efficiency. Some studies made innovative use of models to formally evaluate HIV prevention programmes, to interpret genetic or co infection data, and to address methodological questions and validate epidemiological tools. CONCLUSION: More work is needed to optimize combination prevention focusing on key populations in different settings. The gaps identified include the limited number of studies modelling drug resistance, structural interventions, treatment as prevention among FSWs, and estimating the contribution of key populations to overall transmission in different settings. PMID- 24468892 TI - Role of neurokinin 1 receptors in dextran sulfate-induced colitis: studies with gene-deleted mice and the selective receptor antagonist netupitant. AB - OBJECTIVE AND DESIGN: The function of the neurokinin 1 (NK1) receptor was investigated in the DSS-induced mouse colitis model using NK1 receptor-deficient mice and the selective antagonist netupitant. SUBJECTS: Colitis was induced by oral administration of 20 mg/ml DSS solution for 7 days in C57BL/6 and Tacr1 KO animals (n = 5-7). TREATMENT: During the induction, one-half of the C57BL/6 and Tacr1 KO group received one daily dose of 6 mg/kg netupitant, administered intraperitoneally, the other half of the group received saline, respectively. METHODS: Disease activity index (DAI), on the basis of stool consistency, blood and weight loss, was determined over 7 days. Histological evaluation, myeloperoxidase (MPO) measurement, cytokine concentrations and receptor expression analysis were performed on the colon samples. RESULTS: NK1 receptors are up-regulated in the colon in response to DSS treatment. DSS increased DAI, histopathological scores, BLC, sICAM-1, IFN-gamma, IL-16 and JE in wildtype mice, which were significantly reduced in NK1 receptor-deficient ones. NK1 receptor antagonism with netupitant significantly diminished DAI, inflammatory histopathological alterations, BLC, IFN-gamma, IL-13 and IL-16 in wildtype mice, but not in the NK1-deficient ones. MPO was similarly elevated and netupitant significantly decreased its activity in both groups. CONCLUSIONS: NK1 receptor antagonism could be beneficial for colitis via inhibiting different inflammatory mechanisms. PMID- 24468894 TI - Hypertension and hypertensive heart disease in African women. AB - Hypertension and hypertensive heart disease is one of the main contributors to a growing burden of non-communicable forms of cardiovascular disease around the globe. The recently published global burden of disease series showed a 33 % increase of hypertensive disorders in pregnancy in the past two decades with long term consequences. Africans, particularly younger African women, appear to be bearing the brunt of this increasing public health problem. Hypertensive heart disease is particularly problematic in pregnancy and is an important contributor to maternal case-fatality. European physicians increasingly need to attend to patients from African decent and need to know about unique aspects of disease presentation and pharmacological as well as non-pharmacological care. Reductions in salt consumption, as well as timely detection and treatment of hypertension and hypertensive heart disease remain a priority for effective primary and secondary prevention of CVD (particularly stroke and CHF) in African women. This article reviews the pattern, potential causes and consequences and treatment of hypertension and hypertensive heart disease in African women, identifying the key challenges for effective primary and secondary prevention in this regard. PMID- 24468895 TI - Pre-hospital ultrasound detects pericardial tamponade in young patients with occult blunt trauma: time for preparation? Case report and review of literature. PMID- 24468896 TI - Risk factors for clinical events at 1-year follow-up after drug-eluting stent implantation: results from the prospective multicenter German DES.DE registry. AB - BACKGROUND: Drug-eluting stents (DES) have substantially reduced target vessel revascularization (TVR) after percutaneous coronary interventions. Risk factors for clinical events need to be redefined with this treatment option. METHODS AND RESULTS: In the prospective DES.DE registry, baseline clinical and angiographic characteristics as well as in-hospital and follow-up events were recorded for all enrolled patients. Between October 2005 and May 2009, 21,774 patients receiving DES were enrolled at 98 DES.DE sites. The composite of death, myocardial infarction (MI) and stroke defined as major adverse cardiac and cerebrovascular events (MACCE) and TVR were predefined as primary endpoints. At 1-year follow-up rates for overall death, MI, stroke, MACCE, TVR and definite stent thrombosis were 2.7, 3.1, 1.4, 7.1, 11.5 and 0.6 %, respectively. Aside from well-known risk factors like age, diabetes mellitus and triple-vessel disease, stratification in patients with or without MACCE revealed atrial fibrillation, non-ST-segment elevation myocardial infarction, renal failure, impaired ejection fraction and peripheral vascular disease as strong predictors of MACCE at 1 year. CONCLUSION: Data collected in the DES.DE registry, reflecting the clinical practice in Germany, revealed favorable clinical outcomes after DES implantation in a real world setting but also identifying several high-risk populations. PMID- 24468897 TI - Not left ventricular lead position, but the extent of immediate asynchrony reduction predicts long-term response to cardiac resynchronization therapy. AB - Cardiac resynchronization therapy (CRT) is an effective treatment for a large subgroup of chronic heart failure patients. Various attempts to improve the high non-responder rate of 30 % by preoperative asynchrony assessment have failed. We hypothesized that superior response to CRT is correlated with greater acute reduction of asynchrony and that a concordant left ventricular (LV) lead is beneficial compared to a discordant lead. Hundred and eight consecutive CRT patients from our center were prospectively included. Clinical status and asynchrony parameters were assessed before, 1 day and 6 months after CRT implantation. Super-response was defined as an increase of the LV ejection fraction by >=15 % and a decrease in LV end systolic volume (LVESV) by >=30 %. When the criteria for super-response were not met, average response was given with a decrease of baseline LVESV >=15 %. Sixty eight patients were classified as responders (63 %). Comparing super- (n = 19) and average (n = 49) responders, we found that greater acute reduction of LV asynchrony (change of asynchronous segments under CRT: -1.3 vs. -0.4, p < 0.05; decrease of LV intraventricular delay: -34 ms vs. -16 ms, p < 0.05) is associated with superior reverse remodeling after 6 months. Importantly, asynchrony parameters of super-, average and non-responders were almost identical at baseline. A concordant LV lead (n = 63) was not associated with improved LV reverse remodeling compared to a discordant lead (n = 28): LVEF: +8.6 % vs. +7.8 %, p = 0.91; LVESV: -30.5 ml vs. 23.8 mL, p = 0.84. A greater immediate reduction of LV asynchrony predicts superior response. Preoperative asynchrony parameters do not correlate with outcome. A concordant LV lead is not superior to a discordant lead. PMID- 24468898 TI - Forces and trauma associated with minimally invasive image-guided cochlear implantation. AB - OBJECTIVE: Minimally invasive image-guided cochlear implantation (CI) utilizes a patient-customized microstereotactic frame to access the cochlea via a single drill-pass. We investigate the average force and trauma associated with the insertion of lateral wall CI electrodes using this technique. STUDY DESIGN: Assessment using cadaveric temporal bones. SETTING: Laboratory setup. SUBJECTS AND METHODS: Microstereotactic frames for 6 fresh cadaveric temporal bones were built using CT scans to determine an optimal drill path following which drilling was performed. CI electrodes were inserted using surgical forceps to manually advance the CI electrode array, via the drilled tunnel, into the cochlea. Forces were recorded using a 6-axis load sensor placed under the temporal bone during the insertion of lateral wall electrode arrays (2 each of Nucleus CI422, MED-EL standard, and modified MED-EL electrodes with stiffeners). Tissue histology was performed by microdissection of the otic capsule and apical photo documentation of electrode position and intracochlear tissue. RESULTS: After drilling, CT scanning demonstrated successful access to cochlea in all 6 bones. Average insertion forces ranged from 0.009 to 0.078 N. Peak forces were in the range of 0.056 to 0.469 N. Tissue histology showed complete scala tympani insertion in 5 specimens and scala vestibuli insertion in the remaining specimen with depth of insertion ranging from 360 degrees to 600 degrees . No intracochlear trauma was identified. CONCLUSION: The use of lateral wall electrodes with the minimally invasive image-guided CI approach was associated with insertion forces comparable to traditional CI surgery. Deep insertions were obtained without identifiable trauma. PMID- 24468899 TI - Imaging prevalence of sigmoid sinus dehiscence among patients with and without pulsatile tinnitus. AB - OBJECTIVE: Define the radiographic prevalence of sigmoid sinus diverticulum or dehiscence (SSDD) in patients with and without pulsatile tinnitus (PT). STUDY DESIGN: Case series with chart review. SETTING: Tertiary care university medical center. SUBJECTS: Patients imaged between January 1, 2003, and December 31, 2012. METHODS: Two groups were evaluated for SSDD. The first ("PT") included patients whose radiology report indicated a clinical history of PT (n = 37 symptomatic ears in 30 patients). The second ("non-PT") included all patients undergoing temporal bone high resolution CT (HRCT) between November 2011 and November 2012 (n = 308 ears in 164 patients) for reasons other than pulsatile tinnitus. Primary outcome measure was the radiographic presence of SSDD. Covariates including age, gender, body mass index (BMI), and audiometric data were analyzed by independent t tests and Fisher's exact test. RESULTS: Within the PT group, SSDD was identified in 24% of ears (9/37) and 23% of patients (7/30); all SSDD patients were female (P = .024). Patients with SSDD were significantly younger (P = .037). SSDD more frequently caused objective tinnitus (P = .016). There was no difference in average BMI between those with and those without SSDD. In the non PT group, SSDD was identified in 2 (both female) of 164 patients (1.2%; 0.6% of ears). The difference in SSDD prevalence between groups was significant (P < .0001). CONCLUSIONS: The prevalence of SSDD in patients with PT was 23%. Among patients with PT, those with SSDD were younger, exclusively female, and presented with objective tinnitus. The prevalence of SSDD among asymptomatic patients in 1 year was 1.2%. PMID- 24468900 TI - Ferromagnetic nanoparticles with peroxidase-like activity enhance the cleavage of biological macromolecules for biofilm elimination. AB - Hydrogen peroxide (H2O2) is a "green chemical" that has various cleaning and disinfectant uses, including as an anti-bacterial agent for hygienic and medical treatments. However, its efficacy is limited against biofilm-producing bacteria, because of poor penetration into the protective, organic matrix. Here we show new applications for ferromagnetic nanoparticles (Fe3O4, MNPs) with peroxidase-like activity in potentiating the efficacy of H2O2 in biofilm degradation and prevention. Our data show that MNPs enhanced oxidative cleavage of biofilm components (model nucleic acids, proteins, and oligosaccharides) in the presence of H2O2. When challenged with live, biofilm-producing bacteria, the MNP-H2O2 system efficiently broke down the existing biofilm and prevented new biofilms from forming, killing both planktonic bacteria and those within the biofilm. By enhancing oxidative cleavage of various substrates, the MNP-H2O2 system provides a novel strategy for biofilm elimination, and other applications utilizing oxidative breakdown. PMID- 24468902 TI - The influence of calcium on potassium fluxes across the root of Ricinus communis. AB - The effect of calcium on the flux of potassium to the exudate of detached root systems of Ricinus communis has been investigated. Previous analyses have indicated the presence of a water dependent and a water independent flux of potassium which vary with the concentration of potassium in the bathing medium, in the presence of 0.1 mM CaCl2. In the present study it has been observed that at a higher concentration of calcium in the bathing medium (2.5 mM CaCl2) the water dependent flux of potassium is greatly reduced while the water independent flux is not affected. It is proposed that the differential effect of calcium on these two fluxes is a reflection of the degree of dependence of these fluxes on the permeability of the plasmamembranes within the root. PMID- 24468903 TI - The protective effect of sugars on chloroplast membranes during temperature and water stress and its relationship to frost, desiccation and heat resistance. AB - Freezing, desiccation and high-temperature stress may under certain conditions result in inactivation of electron transport (DCIP reduction) and cyclic photophosphorylation of isolated chloroplast membranes of spinach (Spinacia oleracea L.). When sugars are present during temperature and water stress, the thylakoids may be partially or completely protected. This membrane stabilization depends on the concentration of sugars and their molecular size. The trisaccharide raffinose is, on a molar basis, more effective than the disaccharide sucrose and the latter more than the monosaccharide glucose. An uncoupling effect and a stimulation of electron transport can be observed during freezing, desiccation and heat treatment, e.g. electron transport reactions are less sensitive to temperature and water stress than is photophosphorylation. As sugars are known to accumulate in winter, unspecific membrane stabilization by sugars may help to explain the often reported parallel development of frost, drought and heat resistance in many plants during winter. PMID- 24468901 TI - Lysosomal-mediated waste clearance in retinal pigment epithelial cells is regulated by CRYBA1/betaA3/A1-crystallin via V-ATPase-MTORC1 signaling. AB - In phagocytic cells, including the retinal pigment epithelium (RPE), acidic compartments of the endolysosomal system are regulators of both phagocytosis and autophagy, thereby helping to maintain cellular homeostasis. The acidification of the endolysosomal system is modulated by a proton pump, the V-ATPase, but the mechanisms that direct the activity of the V-ATPase remain elusive. We found that in RPE cells, CRYBA1/betaA3/A1-crystallin, a lens protein also expressed in RPE, is localized to lysosomes, where it regulates endolysosomal acidification by modulating the V-ATPase, thereby controlling both phagocytosis and autophagy. We demonstrated that CRYBA1 coimmunoprecipitates with the ATP6V0A1/V0-ATPase a1 subunit. Interestingly, in mice when Cryba1 (the gene encoding both the betaA3- and betaA1-crystallin forms) is knocked out specifically in RPE, V-ATPase activity is decreased and lysosomal pH is elevated, while cathepsin D (CTSD) activity is decreased. Fundus photographs of these Cryba1 conditional knockout (cKO) mice showed scattered lesions by 4 months of age that increased in older mice, with accumulation of lipid-droplets as determined by immunohistochemistry. Transmission electron microscopy (TEM) of cryba1 cKO mice revealed vacuole-like structures with partially degraded cellular organelles, undigested photoreceptor outer segments and accumulation of autophagosomes. Further, following autophagy induction both in vivo and in vitro, phospho-AKT and phospho-RPTOR/Raptor decrease, while pMTOR increases in RPE cells, inhibiting autophagy and AKT-MTORC1 signaling. Impaired lysosomal clearance in the RPE of the cryba1 cKO mice also resulted in abnormalities in retinal function that increased with age, as demonstrated by electroretinography. Our findings suggest that loss of CRYBA1 causes lysosomal dysregulation leading to the impairment of both autophagy and phagocytosis. PMID- 24468904 TI - A proteinaceous inhibitor of ethylene biosynthesis by etiolated mungbean hypocotyl sections. AB - A protein which reversibly inhibits auxin-induced ethylene synthesis has been isolated and purified from hypocotyls of etiolated mungbean (Phaseolus aureus Roxb.) seedlings. The molecular weight of the inhibitor was estimated to be 112 000 by gel filtration and polyacrylamide gel-electrophoresis. When treated with sodium dodecylsulfate, the inhibitor gave on polyacrylamide gel-electrophoresis a single band corresponding to a molecular weight of 56 000, indicating that it consisted of two subunits with identical molecular weight. The inhibitor does not degrade nor bind indole-3-acetic acid, and has no peroxidase activity. PMID- 24468905 TI - Membrane structures in the integumentary cell walls of the ovule of Nerium oleander. AB - Ultrastructural changes in the integumentary cell walls of Nerium oleander L. were observed, starting with the beginning of nucellus degeneration. The cell walls in direct contact with the nucellus, followed in a regular progression by those of the next 2-3 cell layers, were seen to increase rapidly in thickness and, in contact with the plasmalemma, to develop a peculiar layer characterized by the presence of numerous membrane-like structures. Morphological and cytochemical findings indicate a membraneous nature of these wall structures; the structures exhibit a marked affinity to potassium permanganate, ruthenium red and phosphotungstic acid, and possess a three-layered configuration. Moreover, the structures were found to be disorganized by phospholipase C. Some of the wall structures appear to be pitted, sac-shaped formations; others to be single sheets. Both types exhibit a direct continuity with the plasmalemma after digestion of the wall material by cellulase. The origin and development of these structures are discussed. PMID- 24468906 TI - Cation regulation in Anacystis nidulans. AB - Anacystis nidulans accumulates K(+) in preference to Na(+). The majority of the internal K(+) exchanges with (42)K by a first order process at rates of about 1.3 pequiv.cm(-2).sec(-1) in the light and 0.26 pequiv.cm(-2).sec(-1) in the dark. Although the K(+)/K(+) exchange was stimulated by light and inhibited by 10(-4) M CCCP and 10(-5) M DCMU there are several indications that this cation is passively distributed in Anacystis. Inhibition of the exchange by CCCP and DCMU occurred at concentrations greater than those required to inhibit photosynthesis and the K(+) fluxes were stimulated by low temperatures. Moreover, although valinomycin stimulated the exchange this compound did not induce a net K(+) leak. Assuming K(+) is passively distributed and in free solution within the cytoplasm, as indicated by osmotic studies, would imply that there is an active Na(+) extrusion pump operating in this organism. As yet there are no firm conclusions about the nature of the energy source for this efflux pump. PMID- 24468907 TI - [A cell-free system of protein synthesis from maize seedlings]. AB - An amino acid incorporating system has been prepared from maize seedlings, and it has been characterized with the aid of poly-U and a "mRNA enriched fraction" from the same plant material.The rate of protein synthesis decreases proportionally with the incubation period. It seems to be related to the degradation of polysomes. The optimal Mg(2+) concentration is 20 mM for the poly-U dependent protein synthesis and 10 mM for the synthesis with endogenous polysomes. The poly U directed polyphenylalanine synthesis is increased 12-fold by addition of exogenous sRNA. Under optimal conditions poly-U causes a 40-fold increase of the phenylalanine incorporation.A "mRNA enriched fraction" was prepared from maize seedlings using proteinase K for deproteination of polysomes. The resulting RNA was further fractionated by successive precipitation with LiCl, NaCl and ethanol and characterized by polyacrylamide gel electrophoresis. The addition of 57 MUg of the mRNA-enriched sample increases the incorporation of amino acid into polypeptides by a factor of approximately 2 at a Mg(2+) concentration of 5 mM, and by a factor of 1.5 at 15 mM Mg(2+). The addition of 72 MUg rRNA does not stimulate the incorporation at low Mg(2+) concentration, while at 15 mM Mg(2+) a 1.3-fold increase is observed. PMID- 24468908 TI - [Localization of mannitol biosynthesis in the marine brown alga Fucus serratus]. AB - Tips of fronds of Fucus serratus L. were exposed to H(14)CO3 in the light for periods of 10, 30, 60, and 180s, fixed in petrol ether at-70 degrees C, and subsequently lyophilized. Pheoplasts (=chloroplasts) were isolated using the nonaqueous technique of Thalacker et al. (1959). After extraction and chromatography percentage (14)C activity and distribution of individual photoassimilates between pheoplasts and other compartments of assimilating cells were analyzed. Eighty percent of [(14)C]-phosphate esters were found within the pheoplasts after 10s (14)C-assimilation, whereas only 25% were found there after 30s. After 10s [(14)C] mannitol is almost totally localized within the plastids, but after 180s the major part has been localized outside the pheoplasts. On the basis of these data the pheoplasts are regarded to be the only sites of primary mannitol biosynthesis during photosynthesis in Fucus. PMID- 24468909 TI - Leaf development and phloem transport in Cucurbita pepo: Transition from import to export. AB - The capacity of a growing leaf blade of Cucurbita pepo L. to import (14)C labelled photoassimilate is lost in a basipetal direction. Import into the lamina tip stops when the blade is 10% expanded. Development of the leaf progresses linearly with time and the lamina base stops importing when the blade is 45% expanded. Export capacity also develops basipetally and follows immediately the loss of import capacity, at least in the lamina base. The small amount of material initially exported from the leaf tip is redistributed to the still importing leaf base, delaying export from the lamina until the blade is 35% expanded. Loss of import capacity by the petiole is both basipetal and dorsoventral. The proximal, adaxial portion of the petiole is the last region to cease importing (14)C. Leaves of Beta vulgaris L. and Nicotiana tabacum L. also lose import capacity in a basipetal direction. PMID- 24468910 TI - Hydrazinium lanthanide oxalates: synthesis, structure and thermal reactivity of N2H5[Ln2(C2O4)4(N2H5)].4H2O, Ln = Ce, Nd. AB - New hydrazinium lanthanide oxalates N2H5[Ln2(C2O4)4(N2H5)].4H2O, Ln = Ce (Ce HyOx) and Nd (Nd-HyOx), were synthesized by hydrothermal reaction at 150 degrees C between lanthanide nitrate, oxalic acid and hydrazine solutions. The structure of the Nd compound was determined from single-crystal X-ray diffraction data, space group P21/c with a = 16.315(4), b = 12.127(3), c = 11.430(2) A, beta = 116.638(4) degrees , V = 2021.4(7) A(3), Z = 4, and R1 = 0.0313 for 4231 independent reflections. Two distinct neodymium polyhedra are formed, NdO9 and NdO8N, an oxygen of one monodentate oxalate in the former being replaced by a nitrogen atom of a coordinated hydrazinium ion in the latter. The infrared absorption band at 1005 cm(-1) confirms the coordination of N2H5(+) to the metal. These polyhedra are connected through MU2 and MU3 oxalate ions to form an anionic three-dimensional neodymium-oxalate arrangement. A non-coordinated charge compensating hydrazinium ion occupies, with water molecules, the resulting tunnels. The N-N stretching frequencies of the infrared spectra demonstrate the existence of the two types of hydrazine ions. Thermal reactivity of these hydrazinium oxalates and of the mixed isotypic Ce/Nd (CeNd-HyOx) oxalate were studied by using thermogravimetric and differential thermal analyses coupled with gas analyzers, and high temperature X-ray diffraction. Under air, fine particles of CeO2 and Ce(0.5)Nd(0.5)O(1.75) are formed at low temperature from Ce-HyOx and CeNd-HyOx, respectively, thanks to a decomposition/oxidation process. Under argon flow, dioxymonocyanamides Ln2O2CN2 are formed. PMID- 24468913 TI - Thermal evolution of the submonolayer near-surface alloy of ZnPd on Pd(111). AB - We have performed a high-resolution synchrotron radiation photoelectron spectroscopy study of the initial growth stages of the ZnPd near-surface alloy on Pd(111), complemented by scanning tunnelling microscopy data. We show that the chemical environment for surfaces containing less than half of one monolayer of Zn is chemically distinct from subsequent layers. Surfaces where the deposition is performed at room temperature contain ZnPd islands surrounded by a substrate with dilute Zn substitutions. Annealing these surfaces drives the Zn towards the substrate top-layer, and favours the completion of the first 1 : 1 monolayer before the onset of growth in the next layer. PMID- 24468912 TI - Hijacking common mycorrhizal networks for herbivore-induced defence signal transfer between tomato plants. AB - Common mycorrhizal networks (CMNs) link multiple plants together. We hypothesized that CMNs can serve as an underground conduit for transferring herbivore-induced defence signals. We established CMN between two tomato plants in pots with mycorrhizal fungus Funneliformis mosseae, challenged a 'donor' plant with caterpillar Spodoptera litura, and investigated defence responses and insect resistance in neighbouring CMN-connected 'receiver' plants. After CMN establishment caterpillar infestation on 'donor' plant led to increased insect resistance and activities of putative defensive enzymes, induction of defence related genes and activation of jasmonate (JA) pathway in the 'receiver' plant. However, use of a JA biosynthesis defective mutant spr2 as 'donor' plants resulted in no induction of defence responses and no change in insect resistance in 'receiver' plants, suggesting that JA signalling is required for CMN-mediated interplant communication. These results indicate that plants are able to hijack CMNs for herbivore-induced defence signal transfer and interplant defence communication. PMID- 24468914 TI - Spark plasma sintering of Mn-Al-C hard magnets. AB - Structural and magnetic characterization of isotropic Mn-Al-C bulk samples obtained by spark plasma sintering (SPS) is reported. This technique, to the best of our knowledge, has not been used for preparation of Mn-Al-based permanent magnets previously. Transformation from the parent -phase to the ferromagnetic tau-phase occurred on heating in the process of sintering. The phase constitution of the melt-spun precursors and consolidated samples was determined by x-ray diffraction. Magnetic hysteresis loops were recorded using a vibrating sample magnetometer. The compositional dependence of the coercivity, magnetization and density of the sintered materials is analysed. To combine good magnetic properties with proper densification, further optimization of the production parameters is necessary. PMID- 24468915 TI - Tropism-modified AAV vectors overcome barriers to successful cutaneous therapy. AB - Autologous human keratinocytes (HK) forming sheet grafts are approved as skin substitutes. Genetic engineering of HK represents a promising technique to improve engraftment and survival of transplants. Although efficacious in keratinocyte-directed gene transfer, retro-/lentiviral vectors may raise safety concerns when applied in regenerative medicine. We therefore optimized adeno associated viral (AAV) vectors of the serotype 2, characterized by an excellent safety profile, but lacking natural tropism for HK, through capsid engineering. Peptides, selected by AAV peptide display, engaged novel receptors that increased cell entry efficiency by up to 2,500-fold. The novel targeting vectors transduced HK with high efficiency and a remarkable specificity even in mixed cultures of HK and feeder cells. Moreover, differentiated keratinocytes in organotypic airlifted three-dimensional cultures were transduced following topical vector application. By exploiting comparative gene analysis we further succeeded in identifying alphavbeta8 integrin as a target receptor thus solving a major challenge of directed evolution approaches and describing a promising candidate receptor for cutaneous gene therapy. PMID- 24468916 TI - Tubeless percutaneous nephrolithotomy: yes but when? A multicentre retrospective cohort study. AB - The aim of our study is to determine the predictive factors for placement of percutaneous nephrostomy tube (PNT) in percutaneous nephrolithotomy (PCNL) procedure and to evaluate the optimal cutoff points of the predictive factors. 229 patients, who had undergone percutaneous nephrolithotomy operation between February 2009 and February 2013 were reviewed retrospectively. Five patients were excluded from the study because of solitary kidney. All characteristics of 224 patients, stones and operative data were investigated. Patient and stone-related factors, such as age, BMI, history of previous surgery or SWL, characteristics of the stone, renal parenchymal thickness (RPT), as well as procedural factors, such as percutaneous access number and location were analyzed by univariate and multivariate tests. The continuous variables were analyzed using Receiver operating characteristic curve analysis. There were no differences in sex, age, BMI and hemoglobin decrease between the groups. Previous operation status, RPT, stone size, multiplicity of the stone, stone localization, blood transfusion presence, access points, access number and operation time were found statistically different according to univariate analysis. Multivariate analysis showed that RPT, operation time and stone size were the independent factors that affected the PNT insertion. For RPT, operation time and stone size, the optimal cutoff points for insertion PNT were 13.75 mm, 75.5 min and 890 mm(2), respectively. Tubeless PCNL should be chosen in patients with stone area less than 890 mm(2), and parenchymal thickness thicker than 13.75 mm and procedure with operation period <75.5 min. PMID- 24468917 TI - Supplemental description of Thelohanellus wuhanensis Xiao & Chen, 1993 (Myxozoa: Myxosporea) infecting the skin of Carassius auratus gibelio (Bloch): ultrastructural and histological data. AB - Thelohanellus wuhanensis Xiao & Chen, 1993 infects allogynogenetic gibel carp Carassius auratus gibelio (Bloch) forming numerous plasmodia in the skin, resulting in high mortality of juvenile host fish. Within this paper we supplement the identification of this pathogenic species with information on its ultrastructural and histological characteristics. Measurements of the spores corresponded to the original description, but asymmetry in the spore shape was recorded. Scanning electron microscopy revealed that the spore surface was smooth and the sutural ridge of the anterior end was asymmetric as one side was thinner. In addition, the sutural line was either straight or "S" like. Transmission electron microscopy showed that most spores were surrounded by a membranous sheath, while some sheaths were difficult to observe under light microscopy as the closeness of the sheath to the valves. The small electron-dense granules in the sporoplasm ranged from 0.66 to 1.14 MUm in diameter, but their function was unknown. Histology showed that the plasmodia of T. wuhanensis developed in the stratum spongiosum of skin dermis. The presence of melanocytes around the plasmodia was responsible for the black spots on T. wuhanensis cyst. The plasmodia were curved, perhaps to expand the surface area in contact with adjacent host tissue, facilitating the attainment of nutrients from the host. PMID- 24468918 TI - Highly enantioselective synthesis of alpha-azido-beta-hydroxy methyl ketones catalyzed by a cooperative proline-guanidinium salt system. AB - The combined activity of (S)-proline and an achiral tetraphenylborate TBD-derived guanidinium salt permits the aldol reaction between azidoacetone and aromatic, or heteroaromatic aldehydes. The alpha-azido-beta-hydroxy methyl ketones obtained as products can be isolated in good yield, with high diastereo- and enantioselectivity. PMID- 24468919 TI - Survival after 131I-labeled lipiodol therapy for hepatocellular carcinoma. A single-center study based on a long-term follow-up. AB - This study investigated the efficacy of 131iodine-labeled lipiodol (131I lipiodol) as a palliative therapy, evaluated overall survival (OS) across Barcelona Clinic Liver Cancer (BCLC) stages, and determined the main prognostic factors influencing OS in patients with hepatocellular carcinoma (HCC). PATIENTS, METHODS: We retrospectively analyzed 57 (44 men; mean age, 65.7 years; mean activity per session, 1.6 GBq; mean cumulative activity in patients with >1 sessions, 3.9 GBq) HCC patients who underwent 131I-lipiodol therapy. A majority of patients exhibited Child-Pugh class B (53.6%) disease and a good Eastern Cooperative Oncology Group performance status (0-1; 72%). Multinodular disease was observed in 87.7% patients, bilobar disease in 73%, and portal vein occlusion (PVO) in 54%. Furthermore, 21.1% patients were staged as BCLC B and 59.6 % as BCLC C. All patients were followed until death. RESULTS: The median OS was 6.4 months, which varied significantly with disease stage (median OS for BCLC A, B, C, and D was 29.4, 12.0, 4.6, and 2.7 months, respectively; p = 0.009); Child Pugh score and class; presence of ascites, PVO, or extrahepatic disease; largest lesion size; favourable treatment response; international normalized ratio, baseline albumin and alpha-fetoprotein levels. Patients with a Child-Pugh A liver disease had a longer OS. CONCLUSION: Currently, different treatment modalities for HCC include radioembolization, transarterial chemoembolization, and systemic therapy with sorafenib; however, 131I-lipiodol therapy remains a feasible alternative for patients without a favourable response to other therapies, particularly for patients with Child-Pugh A liver cirrhosis. PMID- 24468920 TI - Sudden gains in internet-based cognitive behaviour therapy for severe health anxiety. AB - OBJECTIVE: A sudden gain is defined as a large and stable individual improvement occurring between two consecutive treatment sessions. Sudden gains have been shown to predict better long-term improvement in several treatment studies, including cognitive behavioural therapy for depression and anxiety disorders, but have not been studied in the treatment of health anxiety or any form of internet based cognitive behavioural therapy. The aim of this study was to investigate the role of sudden gains in internet-based cognitive behavioural therapy for severe health anxiety. METHOD: We examined the occurrence and significance of sudden gains in measures of health anxiety in 81 participants receiving internet-based cognitive behavioural therapy. We compared patients with sudden gains, patients without sudden gains, and patients with gradual gains. RESULTS: Thirteen participants (16%) experienced one sudden gain in health anxiety with individual sudden gains distributed across the treatment. As expected, patients with a sudden gain showed larger improvements than patients without a sudden gain at post-treatment (d = 1.04) and at one-year follow-up (d = 0.91) on measures of health anxiety. CONCLUSIONS: Consistent with previous studies, sudden gains in internet-based cognitive behavioural therapy are associated with significantly larger and stable treatment effects up to one-year follow-up. PMID- 24468921 TI - Relationship between land use pattern and the structure and diversity of soil meso-micro arthropod community. AB - Soil arthropod communities can provide valuable information regarding the impacts of human disturbances on ecosystem structure. Our study evaluated the structure, composition and diversity of soil meso-micro arthropod communities, in six different vegetation types and assessed the impacts of human activity. A completely randomized design, including 3 replicates from 6 sites (mowing steppe, natural grassland, severe degradation grassland, farmland, artificial shelter forest, and wetland) was used. Soil samples from the depth of 0 to 20 cm were collected during May, July, and September 2007. Soil meso-micro arthropod were separated using the Tullgren funnels method, and were identified and counted. Soil pH value, organic matter, and total nitrogen were measured in topsoil (0-20 cm) from each site. A total of 5,602 soil meso-micro arthropod individuals were collected, representing 4 classes, 14 orders, and 57 families. Most soil arthropods were widely distributed; however, some species appeared to be influenced by environment variables, and might serve as bioindicators of adverse human impacts. Canonical correspondence analysis indicated the soil arthropod distribution in the severely degraded grassland, mowing steppe, farmland, and shelter forest differed from the natural grassland. Arthropod density and diversity were greatest in May, and the forestland community was the most stable. Because of the vital role soil arthropods have in maintaining a healthy ecosystem, mechanisms to maintain their abundance and diversity should be further evaluated. PMID- 24468922 TI - Blood lead concentrations in Alaskan tundra swans: linking breeding and wintering areas with satellite telemetry. AB - Tundra swans (Cygnus columbianus) like many waterfowl species are susceptible to lead (Pb) poisoning, and Pb-induced mortality has been reported from many areas of their wintering range. Little is known however about Pb levels throughout the annual cycle of tundra swans, especially during summer when birds are on remote northern breeding areas where they are less likely to be exposed to anthropogenic sources of Pb. Our objective was to document summer Pb levels in tundra swans throughout their breeding range in Alaska to determine if there were population specific differences in blood Pb concentrations that might pose a threat to swans and to humans that may consume them. We measured blood Pb concentrations in tundra swans at five locations in Alaska, representing birds that winter in both the Pacific Flyway and Atlantic Flyway. We also marked swans at each location with satellite transmitters and coded neck bands, to identify staging and wintering sites and determine if winter site use correlated with summer Pb concentrations. Blood Pb levels were generally low (<0.2 MUg/ml) in swans across all breeding areas. Pb levels were lower in cygnets than adults, suggesting that swans were likely exposed to Pb on wintering areas or on return migration to Alaska, rather than on the summer breeding grounds. Blood Pb levels varied significantly across the five breeding areas, with highest concentrations in birds on the North Slope of Alaska (wintering in the Atlantic Flyway), and lowest in birds from the lower Alaska Peninsula that rarely migrate south for winter. PMID- 24468924 TI - Toxicity of phthalate esters exposure to carp (Cyprinus carpio) and antioxidant response by biomarker. AB - To study the toxic effects of phthalate esters on the aquatic creatures, carps were exposed to dibutyl phthalate (DBP) and di-2-ethylhexyl phthalate (DEHP) of six different concentrations for 96 h-LC50 measurements. It shows that the 96 h LC50 is 16.30 and 37.95 mg L(-1), thus the safe concentration (1/10LC(50)) is 1.63 mg L(-1). The activities of xanthine oxidase (XOD) and catalase (CAT) were measured in liver to carp exposure for single or combinations of DBP and DEHP. The quantity of malonic dialdehyde (MDA) was also measured in the same way. XOD, CAT and MDA had shown an evident change while exposure time and concentration increased, combined exposure can aggravate this change. They might be used as early warning indicators and monitors, and have potentials in the ecological risk assessment. PMID- 24468923 TI - Monitoring impacts of air pollution: PIXE analysis and histopathological modalities in evaluating relative risks of elemental contamination. AB - Environmental toxicants invariably affect all biological organisms resulting to sufferings ranging from subclinical to debilitating clinical conditions. This novel research aimed to determine the toxic burdens of increased environmental elements in some vital organs/tissues of the wild animals (starling, owl, crow and pigeon), exposed to air polluted environment were assessed using particle induced X-ray emission and histopathological approaches. The presence of significantly elevated amounts of elemental toxicants namely: Aluminum (Al), Chlorine (Cl), Iron (Fe), Potassium (K), Magnesium (Mg), Manganese (Mn), Silicon (Si) and Vanadium (V) from the skin, muscle, lungs, liver and kidney of sampled animals were in concurrence with the observed histopathological changes. The skin of sampled starling, owl, pigeon and crow spotlighted highly significant increase (P < 0.001) in Al, Cl, Mg and Si. Muscle samples with myodegenerative lesions and mineral depositions highlighted substantial augmentation (P < 0.001) in the amount of Al, Fe, Mn, Si and V. The lungs of starling, owl, and pigeon were severely intoxicated (P < 0.001) with increased amount of Al, Fe, K, Mn and Si producing pulmonary lesions of congestion, edema, pneumonitis and mineral debris depositions. Liver samples revealed that the sampled animals were laden with Cl, Fe, Mg, Mn and V with histopathological profound degenerative changes and hepatic necrosis. Kidney sections presented severe tubular degenerative and necrotic changes that may be attributed to increased amounts of Cl and Fe. These current findings implied that the environmental/elemental toxicants and the accompanying lesions that were discerned in the organs/tissues of sampled birds may as well be afflicting people living within the polluted area. Further assessment to more conclusively demonstrate correlations of current findings to those of the populace within the area is encouraged. PMID- 24468925 TI - Distinct responses of Gulf of Mexico phytoplankton communities to crude oil and the dispersant corexit((r)) Ec9500A under different nutrient regimes. AB - This study examines the potential effects of exposure to South Louisiana sweet crude oil (LSC), Corexit((r)) EC9500A, and dispersed oil on enclosed phytoplankton communities under different nutrient regimes. Three distinct microcosm experiments were conducted for 10 days to assess changes to the structure of natural communities from the Gulf of Mexico as quantified by temporal changes in the biomasses of different phytoplankton groups. Concentration of NO3, Si and PO4 were 0.83, 0.99 and 0.09 MUM for the unenriched treatments and 14.07, 13.01 and 0.94 MUM for the enriched treatments, respectively. Overall, the contaminants LSC and Corexit((r)) EC9500A led to a decrease in the number of sensitive species and an increase in more resistant species. Phytoplankton communities showed more sensitivity to LSC under nutrient limited conditions. The addition of nutrients to initially nutrient-limited treatments lessened the inhibitory effect of LSC in the short term. Centric diatoms benefited most from this enrichment, but pennate diatoms demonstrated considerably greater tolerance to crude oil at low crude oil concentrations in nutrient-enriched treatments. Dinoflagellates showed relatively higher tolerance in nutrient-limited treatments and high crude oil concentrations. Corexit((r)) EC9500A inputs significantly increased the toxicity of crude oil. Corexit((r)) EC9500A alone had a highly inhibitory effect at 63 ppm on phytoplankton communities. This study highlights the fact that different nutrient regimes play a major role in determining the shifts of the phytoplankton community in response to exposure to different concentrations of crude oil and dispersant. Determination of the functional equivalence of shifted phytoplankton groups could complement our research and allow for more pertinent extrapolation to real world conditions. PMID- 24468926 TI - The vertical variation of nutrients in a sediment core of Delong Lake reveals the anthropogenic effect. AB - Phosphorus content and its species were studied for the core sediments of Delong Lake, using the SMT sequential extraction method, and then were correlated to the contents of total nitrogen and organic matter. According to (210)Pb and (137)Cs dating, the historical profiles of 33 cm core sediments were generated. The objective of this study was to understand how nutrients of lake sediments evolved in order to get insights into the effect of human activities on their sedimentary history. The nutrients contents in the core sediments slowly increased after 1957, showing the human activity influence the natural deposition of the lake sediment. From 1978 to 1985, various nutrients in the lake sediment rapid increased, showing that the human activities strengthened. From 2003 to now, most of nutrients in the sediment rapidly increased and significantly modified the natural deposition of the lake sediment. PMID- 24468928 TI - Prognostic impact of circumferential resection margin in rectal cancer treated with preoperative chemoradiotherapy. AB - BACKGROUND: The circumferential resection margin (CRM) is a strong prognostic factor in rectal cancer. The purpose of this study was to investigate the relationship between CRM distance and recurrence in patients with locally advanced rectal cancer who received preoperative chemoradiotherapy (CRT). METHODS: We analyzed data for 561 patients who underwent preoperative CRT and curative surgery for locally advanced rectal cancer between August 2001 and December 2008. CRM was divided into four groups: group 1, CRM > 2 mm; group 2, 1.1-2.0 mm; group 3, 0.1-1.0 mm; and group 4, 0 mm. We assessed the associations of CRM with local recurrence and disease-free survival. RESULTS: Groups 1, 2, 3, and 4 comprised 487, 36, 20, and 18 patients, respectively. The local recurrence rate was highest and the disease-free survival rate was lowest in group 4, followed by groups 3, 2, and 1. Survival was similar between groups 2 and 1. Local recurrence rates were lower in groups 3, 2, and 1 than in group 4 [hazard ratio (HR) 0.28, 95 % confidence interval (CI) 0.09-0.91, P = 0.035; HR 0.11, 95 % CI 0.03-0.46, P = 0.002; HR 0.18, 95 % CI 0.08-0.42, P < 0.0001, respectively]. Disease-free survival rates were higher in groups 3, 2, and 1 than in group 4 (HR 0.32, 95 % CI 0.13-0.75, P = 0.009; HR 0.24, 95 % CI 0.10-0.54, P = 0.001; HR 0.26, 95 % CI 0.14-0.48, P < 0.0001, respectively). CONCLUSIONS: After preoperative CRT, CRM distance provides useful information for risk stratification in the recurrence of rectal cancer. PMID- 24468929 TI - A pipeline for improved QSAR analysis of peptides: physiochemical property parameter selection via BMSF, near-neighbor sample selection via semivariogram, and weighted SVR regression and prediction. AB - In this paper, we present a pipeline to perform improved QSAR analysis of peptides. The modeling involves a double selection procedure that first performs feature selection and then conducts sample selection before the final regression analysis. Five hundred and thirty-one physicochemical property parameters of amino acids were used as descriptors to characterize the structure of peptides. These high-dimensional descriptors then go through a feature selection process given by the binary matrix shuffling filter (BMSF) to obtain a set of important low-dimensional features. Each descriptor that passes the BMSF filtering also receives a weight defined through its contribution to reduce the estimation error. These selected features served as the predictors for subsequent sample selection and modeling. Based on the weighted Euclidean distances between samples, a common range was determined with high-dimensional semivariogram and then used as a threshold to select the near-neighbor samples from the training set. For each sample to be predicted, the QSAR model was established using SVR with the weighted, selected features based on the exclusive set of near-neighbor training samples. Prediction was conducted for each test sample accordingly. The performances of this pipeline are tested with the QSAR analysis of angiotensin converting enzyme inhibitors and HLA-A*0201 data sets. Improved prediction accuracy was obtained in both applications. This pipeline can optimize the QSAR modeling from both the feature selection and sample selection perspectives. This leads to improved accuracy over single selection methods. We expect this pipeline to have extensive application prospect in the field of regression prediction. PMID- 24468930 TI - Synthesis of a cyclic isostere of alpha-methyl homoserine by a stereoselective acylation-alkylation sequence of a chiral gamma-lactam. AB - Starting from a chiral 4-hydroxymethyl pyrrolidin-2-one, an isostere of alpha methyl homoserine tethered on a gamma-lactam ring was prepared exploiting a stereoselective acylation-methylation sequence, followed by Curtius rearrangement, and structural assignment was confirmed by n.O.e. experiments. By reverting the sequence, the 3-carboxy-3-methyl derivative having the opposite configuration at C-3 was obtained with total stereoselection, but Curtius rearrangement invariably afforded only inseparable mixtures of decomposition products. PMID- 24468931 TI - The effect of nitrate assimilation deficiency on the carbon and nitrogen status of Arabidopsis thaliana plants. AB - Carbon (C) and nitrogen (N) metabolism are integrated processes that modulate many aspects of plant growth, development, and defense. Although plants with deficient N metabolism have been largely used for the elucidation of the complex network that coordinates the C and N status in leaves, studies at the whole-plant level are still lacking. Here, the content of amino acids, organic acids, total soluble sugars, starch, and phenylpropanoids in the leaves, roots, and floral buds of a nitrate reductase (NR) double-deficient mutant of Arabidopsis thaliana (nia1 nia2) were compared to those of wild-type plants. Foliar C and N primary metabolism was affected by NR deficiency, as evidenced by decreased levels of most amino acids and organic acids and total soluble sugars and starch in the nia1 nia2 leaves. However, no difference was detected in the content of the analyzed metabolites in the nia1 nia2 roots and floral buds in comparison to wild type. Similarly, phenylpropanoid metabolism was affected in the nia1 nia2 leaves; however, the high content of flavonol glycosides in the floral buds was not altered in the NR-deficient plants. Altogether, these results suggest that, even under conditions of deficient nitrate assimilation, A. thaliana plants are capable of remobilizing their metabolites from source leaves and maintaining the C-N status in roots and developing flowers. PMID- 24468933 TI - Connective tissue diseases: How do autoreactive B cells survive in SLE- autophagy? PMID- 24468932 TI - Hand osteoarthritis-nonpharmacological and pharmacological treatments. AB - Hand osteoarthritis (OA) is a prevalent disease with a high clinical burden. The number of clinical trials in hand OA is limited and, therefore, recommendations for the management of hand OA are mostly expert-based instead of evidence-based, and medication is often prescribed off-label. However, in the past 5 years, this 'forgotten' disease has attracted increasing attention and a number of high quality clinical trials have now been performed, or are ongoing. The results from studies conducted to assess nonpharmacological treatment modalities indicate that educating patients about self-management, the provision of assistive devices and the application of splints for thumb base OA, are effective for pain and disability. For pharmacological management, more high-quality trials are needed, although evidence is available for short-term symptom alleviation of pain by topical and oral NSAIDs. The role of anti-inflammatory medication, such as corticosteroids and biologic agents, is controversial, and the same holds true for the efficacy of symptomatic slow acting drugs for OA. Disease modifying OA drugs (DMOADs) for hand OA are currently not available. The results from the ongoing pharmacological trials will increase our knowledge for evidence-based management of hand OA in the near future. PMID- 24468935 TI - Reply: Gout treatment--more tablets might be needed. PMID- 24468934 TI - The skeletal muscle arachidonic acid cascade in health and inflammatory disease. AB - Muscle atrophy and weakness are often observed in patients with chronic inflammatory diseases, and are the major clinical features of the autoimmune myopathies, polymyositis and dermatomyositis. A general understanding of the pathogenesis of muscle atrophy and the impaired muscle function associated with chronic inflammatory diseases has not been clarified. In this context, arachidonic acid metabolites, such as the prostaglandin and leukotriene subfamilies, are of interest because they contribute to immune and nonimmune processes. Accumulating evidence suggests that prostaglandins and leukotrienes are involved in causing muscular pain and inflammation, and also in myogenesis and the repair of muscles. In this Review, we summarize novel findings that implicate prostaglandins and leukotrienes in the muscle atrophy and weakness that occur in inflammatory diseases of the muscles, with a focus on inflammatory myopathies. We discuss the role of the arachidonic acid cascade in skeletal muscle growth and function, and individual metabolites as potential therapeutic targets for the treatment of inflammatory muscle diseases. PMID- 24468936 TI - Gout treatment: when a tablet is not enough. PMID- 24468937 TI - Imaging: Whole-body MRI in RA: do we still need the rheumatologist? PMID- 24468938 TI - Risk estimation in rheumatoid arthritis: from bench to bedside. AB - The prognosis for patients with rheumatoid arthritis (RA) who were diagnosed in the years since 2010 is much better than for individuals who were diagnosed with the disease 20 years ago. This improvement in the long-term outcome of disease is the result of earlier initiation of therapy, disease-activity-guided modification of treatment and the availability of new, and effective, drugs. Nonetheless, current treatment strategies remain population-based, rather than individualized. Decision-making processes relevant to the provision of individualized treatment require appropriate prognostication with regard to a number of variables. Here, the methods available to evaluate the performance of predictive models are discussed. In addition, I highlight the advances in risk estimation that have been made concerning three treatment decisions relevant to the management of RA that are made daily in the clinic: when to initiate treatment with DMARDs in patients in the early stages of arthritis; the ideal intensity of initial treatment; and the likely responsiveness of the patient to a particular therapy. Apart from a model predicting the development of RA, the majority of prognostic tools derived in arthritis and RA are not accurate or not validated. Hence, personalized treatment decisions in arthritis and RA are still far from bedside. PMID- 24468939 TI - Dietary patterns and the risk of depression in adults: a systematic review of observational studies. AB - PURPOSE: Diet, a modifiable lifestyle factor, may influence the development of depression. We performed a systematic review of observational studies examining the relationship between dietary patterns and depression in healthy adults. METHODS: A literature research was conducted searching various electronic databases up to May 2013. Study selection was based on predefined inclusion and exclusion criteria. Included studies were reviewed, and relevant data were extracted by two independent researchers. Due to a high level of heterogeneity, no meta-analysis was conducted. Therefore, main results are presented in a descriptive way. RESULTS: In total, 16 studies met the inclusion criteria and are part of this review. Dietary patterns most commonly found were traditional/healthy patterns, Western/unhealthy patterns and Mediterranean patterns. The available literature suggests a protective effect of healthy and Mediterranean patterns, as well as a potential positive association of Western patterns and depression. However, comparison of the included studies was difficult, due to differences in relevant study characteristics and methodological limitations. CONCLUSIONS: There are indications that dietary patterns may have influence on the onset of depression, but no firm conclusion can be drawn at this point. Further research is needed to clarify the diet depression relationship, preferably in the form of methodological strong prospective studies using more homogeneous methods. PMID- 24468942 TI - Using modeling to inform international guidelines for antiretroviral treatment. PMID- 24468941 TI - Resveratrol increases brown adipose tissue thermogenesis markers by increasing SIRT1 and energy expenditure and decreasing fat accumulation in adipose tissue of mice fed a standard diet. AB - PURPOSE: Adipose tissue is central to the regulation of energy balance. Two functionally different fat pads are present in mammals: white adipose tissue, the primary site of triglyceride storage, and brown adipose tissue (BAT), which is specialized in heat production. In this context, new strategies capable of modulating the development and function of white and BAT become relevant. In the present study, we analyzed the influence of resveratrol (sirtuin activator) on energy balance and the expression of thermogenesis markers. METHODS: Mice were divided into two groups: standard diet (ST) and standard diet plus resveratrol (ST + RSV). RESULTS: After 2 months of treatment, ST + RSV mice presented significantly decreased fat accumulation in adipose tissue, with diminished total cholesterol and glucose plasma levels. Additionally, increased oxygen consumption was observed in ST + RSV group. Analyses of mRNA of thermogenesis-related genes showed significant increase in UCP1, SIRT1, PTEN and BMP-7 expression in BAT. CONCLUSION: Our data suggest that improved metabolism produced by oral administration of resveratrol is, at least in part, associated with increased thermogenesis followed by high expression of UCP1 and SIRT1, which can mediate higher energy expenditure and decreased fat accumulation in adipose tissue. PMID- 24468940 TI - Maternal diet, bioactive molecules, and exercising as reprogramming tools of metabolic programming. AB - Nutrition and lifestyle, particularly over-nutrition and lack of exercise, promote the progression and pathogenesis of obesity and metabolic diseases. Nutrition is likely the most important environmental factor that modulates the expression of genes involved in metabolic pathways and a variety of phenotypes associated with obesity and diabetes. During pregnancy, diet is a major factor that influences the organ developmental plasticity of the foetus. Experimental evidence shows that nutritional factors, including energy, fatty acids, protein, micronutrients, and folate, affect various aspects of metabolic programming. Different epigenetic mechanisms that are elicited by bioactive factors in early critical developmental ages affect the susceptibility to several diseases in adulthood. The beneficial effects promoted by exercise training are well recognised, and physical exercise may be considered one of the more prominent non pharmacological tools that can be used to attenuate metabolic programming and to consequently ameliorate the illness provoked by metabolic diseases and reduce the prevalence of obesity, type 2 diabetes, and cardiovascular diseases. Literature on the different outcomes of unbalanced diets and the beneficial effects of some bioactive molecules during gestation and lactation on the metabolic health of offspring, as well as the potential mechanisms underlying these effects, was reviewed. The importance of the combined effects of functional nutrition and exercise as reprogramming tools of metabolic programming is discussed in depth. Finally, this review provides recommendations to healthcare providers that may aid in the control of early programming in an attempt to optimise the health of the mother and child. PMID- 24468943 TI - Predicted levels of HIV drug resistance: potential impact of expanding diagnosis, retention, and eligibility criteria for antiretroviral therapy initiation. AB - BACKGROUND: There is concern that the expansion of antiretroviral roll-out may impact future drug resistance levels and hence compromise the benefits of antiretroviral therapy (ART) at an individual and population level. We aimed to predict future drug resistance in South Africa and its long-term effects. METHODS: The previously validated HIV Synthesis model was calibrated to South Africa. Resistance was modeled at the level of single mutations, transmission potential, persistence, and effect on drug activity. RESULTS: We estimate 652 000 people (90% uncertainty range: 543 000-744 000) are living with nonnucleoside reverse transcriptase inhibitor (NNRTIs)-resistant virus in South Africa, 275 000 in majority virus [Non-nucleoside reverse transcriptase inhibitor resistant virus present in majority virus (NRMV)] with an unsuppressed viral load. If current diagnosis and retention in care and eligibility criteria are maintained, in 20 years' time HIV incidence is projected to have declined by 22% (95% confidence interval, CI -23 to -21%), and the number of people carrying NNRTI resistance to be 2.9-fold higher. If enhancements in diagnosis and retention in care occur, and ART is initiated at CD4 cell count less than 500 cells/MUl, HIV incidence is projected to decline by 36% (95% CI: -37 to -36%) and the number of people with NNRTI resistance to be 4.1-fold higher than currently. Prevalence of people with viral load more than 500 copies/ml carrying NRMV is not projected to differ markedly according to future ART initiation policy, given the current level of diagnosis and retention are maintained. CONCLUSION: Prevalence of resistance is projected to increase substantially. However, introduction of policies to increase ART coverage is not expected to lead to appreciably higher prevalence of HIV-positive people with resistance and viral load more than 500 copies/ml. Concern over resistance should not stop expansion of treatment availability. PMID- 24468944 TI - The potential effects of changing HIV treatment policy on tuberculosis outcomes in South Africa: results from three tuberculosis-HIV transmission models. AB - OBJECTIVE(S): Many countries are considering expanding HIV treatment following recent findings emphasizing the effects of antiretroviral therapy (ART) on reducing HIV transmission in addition to already established survival benefits. Given the close interaction of tuberculosis (TB) and HIV epidemics, ART expansion could have important ramifications for TB burden. Previous studies suggest a wide range of possible TB impacts following ART expansion. We used three independently developed TB-HIV models to estimate the TB-related impact of expanding ART in South Africa. DESIGN: We considered two dimensions of ART expansion--improving coverage of pre-ART and ART services, and expanding CD4-based ART eligibility criteria (from CD4 <350 to CD4 <500 or all HIV-positive). METHODS: Three independent mathematical models were calibrated to the same data pertaining to the South African HIV-TB epidemic, and used to assess standardized ART policy changes. Key TB impact indicators were projected from 2014 to 2033. RESULTS: Compared with current eligibility and coverage, cumulative TB incidence was projected to decline by 6-30% over the period 2014-2033 if ART eligibility were expanded to all HIV positive individuals, and by 28-37% if effective ART coverage were additionally increased to 80%. Overall, expanding ART was estimated to avert one TB case for each 10-13 additional person-years of ART. All models showed that TB incidence and mortality reductions would grow over time, but would stabilize towards the end of the projection period. CONCLUSION: ART expansion could substantially reduce TB incidence and mortality in South Africa and could provide a platform for collaborative HIV-TB programs to effectively halt HIV-associated TB. PMID- 24468945 TI - Modeling the impact of early antiretroviral therapy for adults coinfected with HIV and hepatitis B or C in South Africa. AB - OBJECTIVE: There has been discussion about whether individuals coinfected with HIV and hepatitis C virus (HCV) or hepatitis B virus (HBV) (~30% of all people living with HIV) should be prioritized for early HIV antiretroviral therapy (ART). We assess the relative benefits of providing ART at CD4 count below 500 cells/MUl or immediate ART to HCV/HIV or HBV/HIV-coinfected adults compared with HIV-monoinfected adults. We evaluate individual outcomes (HIV/liver disease progression) and preventive benefits in a generalized HIV epidemic setting. METHODS: We modeled disease progression for HIV-monoinfected, HBV/HIV-coinfected, and HCV/HIV-coinfected adults for differing ART eligibility thresholds (CD4 <350 cells/MUl, CD4 <500 cells/MUl, immediate ART eligibility upon infection). We report disability-adjusted life-years averted per 100 person-years on ART (DALYaverted/100PYonART) as a measure of the health benefits generated from incremental changes in ART eligibility. Sensitivity analyses explored impact on sexual HIV and vertical HIV, HCV, and HBV transmission. RESULTS: For HBV/HIV coinfected adults, a switch to ART initiation at CD4 count below 500 cells/MUl from CD4 below 350 cells/MUl generates 9% greater health benefits per year on ART (48 DALYaverted/100PYonART) than for HIV-monoinfected adults (44 DALYaverted/100PYonART). Additionally, ART at CD4 below 500 cells/MUl could prevent 25% and 32% of vertical transmissions of HIV and HBV, respectively. For HCV/HIV-coinfected adults, ART at CD4 below 500 cells/MUl generates 10% fewer health benefits (40 DALYaverted/100PYonART) than for HIV monoinfection, unless ART reduces progression to cirrhosis by more than 70% (33% in base-case). CONCLUSIONS: The additional therapeutic benefits of ART for HBV-related liver disease results in ART generating more health benefits among HBV/HIV-coinfected adults than HIV-monoinfected individuals, whereas less health benefits are generated amongst HCV/HIV coinfection in a generalized HIV epidemic setting. PMID- 24468946 TI - Dropout and re-enrollment: implications for epidemiological projections of treatment programs. AB - OBJECTIVE: EMOD-HIV v0.8 has been used to estimate the potential impact of expanding treatment guidelines to allow earlier initiation of antiretroviral therapy (ART) in sub-Saharan Africa with current or improved treatment coverage. In generating these results, a model must additionally make assumptions about the rates of dropout and re-initiation into ART programs before and after the program change, about which little is known. The objective of this work is to rigorously analyze modeling assumptions and the sensitivity of model results with respect to relevant mechanisms and parameters. METHODS: We varied key model assumptions pertaining to ART dropout and re-enrollment to analyze their effect on the cost, impact, and cost-effectiveness of expanding treatment guidelines, and of expanding coverage via improved testing and linkage to care. Additionally, we performed a sensitivity analysis of 17 relevant model parameters. SETTING: South Africa. RESULTS: Allowing re-initiation of ART irrespective of prior treatment doubled the cost and impact of expanding treatment guidelines, as compared with a scenario in which re-initiation could only be triggered by a health event (AIDS symptoms, diagnosis of a partner, or an antenatal care visit). Increasing the probability of 'voluntary' re-initiation (not triggered by a health event) was the most cost-effective way to improve the treatment program, especially in the short term because it provided immediate benefits to those who would otherwise have delayed re-initiation until the onset of AIDS symptoms. However, the maximum impact of this change was limited compared with expanding coverage through improvements in testing and linkage to care. Beyond improvements in coverage and re-initiation, further gains could be made by improving retention in care. Only with optimal retention in care was expansion of guidelines cost-saving after 20 years due to reductions in transmission. Re-initiation did not reduce transmission sufficiently to make a guideline change cost-effective due to transmission that occurred while patients were away from care. Sensitivity analysis suggested that enormous health benefits could be attained by improving treatment regimens to have higher efficacy at preventing transmission, increasing the proportion of the population with access to improved healthcare, and reducing 'leaks' in the 'cascade of care.' Increasing the proportion of individuals who receive CD4 cell results was particularly cost-effective at baseline levels of coverage, and increasing retention on ART was particularly cost-effective with expanded coverage. CONCLUSION: This analysis provides a sense of the magnitude of uncertainty in program cost and impact that policy-makers could anticipate in the face of uncertain future programmatic changes. Our findings suggest that increasing re-initiation is the most cost-effective means of initial program improvement, especially in the short term, but that improvements in retention are necessary in order to reap the full transmission-blocking benefits of a test-and treat program in the long term. PMID- 24468947 TI - The costs and benefits of Option B+ for the prevention of mother-to-child transmission of HIV. AB - OBJECTIVE: Most countries follow WHO 2010 guidelines for the prevention of mother to-child transmission (PMTCT) of HIV using either Option A or B for women not yet eligible for antiretroviral therapy (ART). Both of these approaches involve the use of antiretrovirals during pregnancy and breastfeeding. Some countries have adopted a new strategy, Option B+, in which HIV-positive pregnant women are started immediately on ART and continued for life. Option B+ is more costly than Options A or B, but provides additional health benefits. In this article, we estimate the additional costs and effectiveness of Option B+. METHODS: We developed a deterministic model to simulate births, breastfeeding, and HIV infection in women in four countries, Kenya, Zambia, South Africa, and Vietnam that differ in fertility rate, birth interval, age at first birth, and breastfeeding patterns, but have similar age at HIV infection. We estimated the total PMTCT costs and new child infections under Options A, B, and B+, and measured cost-effectiveness as the incremental PMTCT-related costs per child infection averted. We included adult sexual transmissions averted from ART, the corresponding costs saved, and estimated the total incremental cost per transmission (child and adult) averted. RESULTS: When considering PMTCT-related costs and child infections, Option B+ was the most cost-effective strategy costing between $6000 and $23 000 per infection averted compared with Option A. Option B+ averted more child infections compared with Option B in all four countries and cost less than Option B in Kenya and Zambia. When including adult sexual transmissions averted, Option B+ cost less and averted more infections than Options A and B. PMID- 24468948 TI - Exploring the population-level impact of antiretroviral treatment: the influence of baseline intervention context. AB - OBJECTIVE: To compare the potential population-level impact of expanding antiretroviral treatment (ART) in HIV epidemics concentrated among female sex workers (FSWs) and clients, with and without existing condom-based FSW interventions. DESIGN: Mathematical model of heterosexual HIV transmission in south India. METHODS: We simulated HIV epidemics in three districts to assess the 10-year impact of existing ART programs (ART eligibility at CD4 cell count <=350) beyond that achieved with high condom use, and the incremental benefit of expanding ART by either increasing ART eligibility, improving access to care, or prioritizing ART expansion to FSWs/clients. Impact was estimated in the total population (including FSWs and clients). RESULTS: In the presence of existing condom-based interventions, existing ART programs (medium-to-good coverage) were predicted to avert 11-28% of remaining HIV infections between 2014 and 2024. Increasing eligibility to all risk groups prevented an incremental 1-15% over existing ART programs, compared with 29-53% when maximizing access to all risk groups. If there was no condom-based intervention, and only poor ART coverage, then expanding ART prevented a larger absolute number but a smaller relative fraction of HIV infections for every additional person-year of ART. Across districts and baseline interventions, for every additional person-year of treatment, prioritizing access to FSWs was most efficient (and resource saving), followed by prioritizing access to FSWs and clients. CONCLUSION: The relative and absolute benefit of ART expansion depends on baseline condom use, ART coverage, and epidemic size. In south India, maximizing FSWs' access to care, followed by maximizing clients' access are the most efficient ways to expand ART for HIV prevention, across baseline intervention context. PMID- 24468949 TI - How do different eligibility guidelines for antiretroviral therapy affect the cost-effectiveness of routine viral load testing in sub-Saharan Africa? AB - BACKGROUND: Increased eligibility guidelines of antiretroviral therapy (ART) may lead to greater routine viral load monitoring. However, in resource-constrained settings, the additional resources required by greater routine viral load monitoring may impair ability to comply with expanded eligibility guidelines for ART. OBJECTIVE: We use a published validated computer simulation of the HIV epidemic in East African countries (expanded to include transmission as well as disease progression) to evaluate the cost-effectiveness of routine viral load monitoring. METHODS: We explored alternative scenarios regarding cost, frequency, and switching threshold of routine viral load monitoring (including every 6 or every 12 months; and switching thresholds of 1000, or 10 000 copies/ml), as well as alternative scenarios regarding ART initiation (200, 350, 500 cells/MUl, and no CD4 cell threshold). For each ART initiation strategy, we sought to identify the viral load monitoring strategy at which the incremental cost-effectiveness ratio (ICER) of more frequent routine viral load testing became more favorable than the ICER of more expansive ART eligibility. Cost inputs were based on data provided by the Academic Model Providing Access to Healthcare (AMPATH), and disease progression inputs were based on prior published work. We used a discount rate of 3%, a time horizon of 20 years, and a payer perspective. RESULTS: Across a wide range of scenarios, and even when considering the beneficial effect of virological monitoring at reducing HIV transmission, earlier ART initiation conferred far greater health benefits for resources spent than routine virological testing, with ICERs of approximately $1000 to $2000 for earlier ART initiation, versus ICERs of approximately $5000 to $25 000 for routine virological monitoring. ICERs of viral load testing were insensitive to the cost of the viral load test, because most of the costs originated from the downstream higher costs of later regimens. ICERs of viral load testing were very sensitive to the relative cost of second-line compared with first-line regimens, assuming favorable value when the costs of these regimens were equal. CONCLUSION: If all HIV patients are not yet treated with ART starting at 500 cells/MUl and costs of second regimens remain substantially more expensive than first-line regimens, resources would buy more population health if they are spent on earlier ART rather than being spent on routine virological testing. PMID- 24468950 TI - The role of mathematical modelling in the development of recommendations in the 2013 WHO consolidated antiretroviral therapy guidelines. AB - Despite the exponential growth in the literature on modelling and simulation studies of impact and cost-effectiveness in different aspects of healthcare, there is no clear consensus on the appropriate role of modelling in the development of recommendations in clinical guidelines. This is compounded both by the lack of a standardised approach to assess the quality of modelling, and lack of clarity on its positioning within the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) method for decision-making in the development of WHO guidelines, that considers both evidence from systematic reviews of randomized clinical trials (RTCs) or observational studies, together with stakeholder values and preferences, resource use, and feasibility issues. In the development of the 2013 WHO Consolidated Guidelines on the use of Antiretroviral drugs for treating and preventing HIV infection, a series of modelling projects were undertaken to inform the recommendations on eligibility criteria for ART initiation, and approaches to monitoring for treatment response. We report our experiences, challenges encountered, and several key considerations to guide the future use of modelling in the development of WHO guidelines. These are: (1) Transparency in the conduct and reporting of model inputs and results; (2) The need for agreed standards for critical appraisal and use of modelling data in healthcare policy making; (3) recognition that modelling of cost effectiveness is only one component of decision-making in development of WHO recommendations and in priority-setting; (4) The need for closer interaction and an ongoing dialogue between modellers and model end-users or decision-makers; (5) the important role of WHO in convening and facilitating comparative assessment of multiple models; and (6) The need to optimize research and data collection to inform modelling studies. PMID- 24468951 TI - Fine structure of P-protein filaments from Ricinus communis. AB - Exudate from the phloem of Ricinus communis L. was negatively stained, examined in the electron microscope, and the filamentous components compared with those in fixed, sectioned material. In the exudate, two main fibrillar components were observed. One component has a diameter of 20+/-0.35 (standard error) nm, the other of 14.1+/-0.34 nm. This second compoent has projections along its length measuring 5 by 14 nm and spaced at intervals of 6.5-10 nm. Fibrils have been found possessing characteristics of both fibril types, suggesting some structural relationship between the two, possibly an interconvertibility. Several other types of fibrils occurred less frequently in the exudate. The exudate also contains torus-shaped structures measuring 13.5-15 nm in diameter. Sections of mature sieve elements of Ricinus and Acer rubrum L. contain fibrils structurally similar to the 14-nm fibrils from the exudate of Ricinus. Ricinus exudate was also fixed and pelleted in the ultracentrifuge. Thin sections of the pellet afforded cross-sectional views of the 20-nm fibrils, and showed that these fibrils apparently have a solid core. Possible models for the structure of the 20 nm filaments are described. PMID- 24468952 TI - Effect of calcium, (2-chloroethyl) phosphonic acid and ethylene on bean leaf abscission. AB - The effects of CaCl2, (2-chloroethyl) phosphonic acid (Ethephon) and ethylene on leaf abscission of debladed and intact bean plants (Phaseolus vulgaris L.) were studied. Ethephon (1000 MUg/l) and ethylene (8 MUl/l) induced abscission in debladed and intact plants in 24-72 h whereas IAA (10(-5)M), cycloheximide (10( 5)M) and CaCl2 (0.068M) delayed abscission in debladed plants. CaCl2 completely inhibited the abscission-enhancing effect of Ethephon in intact bean leaves. When CaCl2 and Ethephon were applied simultaneously to separate halves of the leaf blade, leaves with Ethephon applied closest to the pulvinus abscised rapidly; when CaCl2 was applied closest to the pulvinus, abscission was prevented. Calcium pre-treatment prior to ethylene (8 MUl/l) treatment of debladed plants delayed abscission as compared to those treated with ethylene alone. PMID- 24468953 TI - Fluctuations in leaf water balance, with a period of 1 to 10 minutes. AB - Water uptake into leaves, and water vapour efflux from leaves, were found to show short-term fluctuations. The fluctuations were observed in a number of parameters of leaf water metabolism. It is suggested that this behaviour is a result of time lags in the transmission of changes in water potential through the leaf. PMID- 24468954 TI - Effect of chloramphenicol and cycloheximide on the induction of nitrate reductase and nitrite reductase in bean leaves. AB - In etiolated leaves of Phaseolus vulgaris L. cv. Prelude only low levels of NADH nitrate oxidoreductase (E.C. 1.6.6.2; NAR) and reduced benzyl viologen-nitrite oxidoreductase (E.C. 1.6.6.4; NIR) could be detected, even in the presence of nitrate. When nitrate was available illumination of leaves of 10-day-old etiolated seedlings resulted in an induction of both NAR and NIR. In the absence of nitrate no induction of the enzymes took place, although greening of the leaves was normal. Chloramphenicol (CAP) and cycloheximide (CHI), applied at the beginning of the light period, inhibited the induction of both NAR and NIR. Administered after 24 h of illumination CHI still inhibited the induction of both enzymes whereas CAP was no longer inhibitory. The induction of NAR and NIR by nitrate in green leaves in light was inhibited by CHI but not by CAP. From these results it seems likely that both the enzymes NAR and NIR are synthesized on cytoplasmic ribosomes. Before the enzymes can be manufactured in the cytoplasm some chloroplast development is required. PMID- 24468955 TI - Effects of environmental changes on sugars, tannins, and organized growth in cell suspension cultures of white spruce. AB - Callus from hypocotyls of white spruce (Picea glauca [Moench] Voss) was grown on agar under defined conditions with high levels of calcium nitrate. Transfer of callus to liquid suspension cultures and maintenance of suspensions either under a regime of constant temperature and light or under alternating conditions similar to those of a late spring day, affected the content of free sugars, tannins, and aldehydes. Under the alternating conditions the levels of these substances increased greatly compared to those under the constant environment. By contrast, vascularization of cell clumps, which was comparable to the differentiation of hypocotyls in seedlings, was obtained only under constant conditions. Cells at the centre of the clumps developed secondary wall thickenings and bordered pits, and were surrounded by cambial-like initials. PMID- 24468956 TI - Tannin inclusions in cell suspension cultures of white spruce. AB - Tannins were detected cytochemically in cell suspension cultures of white spruce (Picea glauca [Moench] Voss) and were studied by electron microscopy. Tannin inclusions originated within cytoplasmic vacuoles, possibly derived from the endoplasmic reticulum, and accumulated in the central vacuole through enlargement and coalescence of those cytoplasmic vacuoles. Structural information supported the suggested metabolic relationship between starch and tannin, although tannins did not develop within plastids. Membranous material, resembling myelinlike bodies, was often observed in close association with tannins. PMID- 24468957 TI - The development of haploid embryoids from anther cultures of Atropa belladonna L. AB - Development of haploid embryoids from the microspores of Atropa belladonna occurs with relatively high frequency when anthers are excised from buds in which the petals are shorter than the sepals (at this stage microspores are predominantly uninucleate) and cultured on a medium containing iron as the ferric salt of ethylenediamine-di-O-hydroxyphenylacetic acid (FeEDDHA). Additions of combinations of kinetin, auxin and casamino-acids to the culture medium induce callusing in both haploid and diploid tissues, lead to the origin of embryoids from somatic tissues of the anther and should be avoided. Simple techniques for the maintenance of haploid clones are described.Stages in early embryogenesis in the pollen grains have been observed and these indicate that embryogenesis is most frequently initiated by an equal division in the uninucleate spore. The frequency of grains showing embryoid formation is very low and it is estimated that plantlets are formed from up to 50% of these grains. PMID- 24468958 TI - The use of antibiotics in the culture of non-sterile plant protoplasts. AB - The use of antibiotics to control infections in cultures of protoplasts of leaf mesophyll cells has been examined. The antifungal agents nystatin and amphotericin B were non-toxic to protoplasts at concentrations that controlled fungal growth (25 units and 2.5 MUg/ml respectively). Of the antibacterial agents examined, only carbenicillin and, to a lesser extent, gentamicin were active against the bacteria usually encountered whilst still permitting normal protoplast metabolism and regeneration. The most satisfactory control of contaminating microorganisms was obtained with a combination of nystatin (25 units/ml) or amphotericin B (2.5 MUg/ml) and carbenicillin (250 MUg/ml). PMID- 24468959 TI - The effects of sodium chloride, potassium chloride and glycerol on the activity of nitrate reductase of a salt-tolerant and two non-tolerant plants. AB - The activity of nitrate reductase from the salt-tolerant alga Dunaliella parva is inhibited by sodium chloride and potassium chloride, but not by glycerol. The activity of the enzyme from Chlorella pyrenoidosa Chick 611-8b and from the XD line of tobacco (Nicotiana tabacum L. cv. Xanthi) cells is inhibited by all three solutes. Salt tolerance in Dunaliella parva, which is due to internal formation of glycerol, is accompanied by the adaptation of the activity of the enzyme to elevated glycerol concentrations. PMID- 24468960 TI - The wax glands and wax secretion of Matsucoccus matsumurae at different development stages. AB - In this paper, the wax secretions and wax glands of Matsucoccus matsumurae (Kuwana) at different instars were investigated using light microscopy, scanning electron microscopy and transmission electron microscopy. The first and second instar nymphs were found to secrete wax filaments via the wax glands located in the atrium of the abdominal spiracles, which have a center open and a series of outer ring pores. The wax gland of the abdominal spiracle possesses a large central wax reservoir and several wax-secreting cells. Third-instar male nymphs secreted long and translucent wax filaments from monolocular, biolocular, trilocular and quadrilocular pores to form twine into cocoons. The adult male secreted long and straight wax filaments in bundles from a group of 18-19 wax secreting tubular ducts on the abdominal segment VII. Each tube duct contained five or six wax pores. The adult female has dorsal cicatrices distributed in rows, many biolocular tubular ducts and multilocular disc pores with 8-12 loculi secreting wax filaments that form the egg sac, and a rare type wax pores with 10 loculi secreting 10 straight, hollow wax filaments. The ultrastructure and cytological characteristics of the wax glands include wax-secreting cells with a large nucleus, multiple mitochondria and several rough endoplasmic reticulum. The functions of the wax glands and wax secretions are discussed. PMID- 24468961 TI - Pitaya-like Sn@C nanocomposites as high-rate and long-life anode for lithium-ion batteries. AB - In this article, we report on the preparation of the pitaya-like Sn@C nanocomposite with an aerosol spray pyrolysis and its application as a high-rate and long-life anode material for lithium-ion batteries. The structure and morphology analysis of the as-prepared Sn@C nanocomposite shows that Sn nanoparticles with a size of about 8 nm are homogeneously dispersed in the spherical carbon matrix (denoted as Sn8@C). The Sn8@C nanocomposite exhibits an initial discharge capacity of 1007.1 mA h g(-1) and maintains a reversible capacity of 910 mA h g(-1) after 180 cycles at 200 mA g(-1) (0.305 C). A capacity of 410 mA h g(-1) was obtained after 1000 cycles at 4000 mA g(-1) (6.1 C). Furthermore, the Sn8@C nanocomposite displays a charge-discharge capacity of 205.3 mA h g(-1) at 16 000 mA g(-1) (24.4 C). This high-rate performance is owing to the fact that the ultrasmall tin nanoparticles can effectively alleviate the absolute stress/strain during the lithiation/delithiation process and that the uniformly embedded nanoparticles in the stable carbon framework can accommodate the large volume change with a buffering effect to prevent Sn nanoparticles from aggregating. PMID- 24468962 TI - Hf-Co and Zr-Co alloys for rare-earth-free permanent magnets. AB - The structural and magnetic properties of nanostructured Co-rich transition-metal alloys, Co(100-x)TMx (TM = Hf, Zr and 10 <= x <= 18), were investigated. The alloys were prepared under non-equilibrium conditions using cluster-deposition and/or melt-spinning methods. The high-anisotropy HfCo7 and Zr2Co11 structures were formed for a rather broad composition region as compared to the equilibrium bulk phase diagrams, and exhibit high Curie temperatures of above 750 K. The composition, crystal structure, particle size, and easy-axis distribution were precisely controlled to achieve a substantial coercivity and magnetization in the nanostructured alloys. This translates into high energy products in the range of about 4.3-12.6 MGOe, which are comparable to those of alnico. PMID- 24468963 TI - Enhanced dye-sensitized solar cells performance using anatase TiO2 mesocrystals with the Wulff construction of nearly 100% exposed {101} facets as effective light scattering layer. AB - Anatase TiO2 mesocrystals with a Wulff construction of nearly 100% exposed {101} facets were successfully synthesized by a facile, green solvothermal method. Their morphology, and crystal structure are characterized by powder X-ray diffraction (XRD), Field emission scanning electron microscopy (FESEM) and high resolution transmission electron microscopy (HRTEM). Accordingly, a possible growth mechanism of anatase TiO2 mesocrystals is elucidated in this work. The as prepared single anatase TiO2 mesocrystal's mean center diameter is about 500 nm, and the length is about 1 MUm. They exhibit high light adsorbance, high reflectance and low transmittance in the visible region due to the unique nearly 100% exposed {101} facets. When utilized as the scattering layer in dye sensitized solar cells (DSSCs), such mesocrystals effectively enhanced light harvesting and led to an increase of the photocurrent of the DSSCs. As a result, by using an anatase TiO2 mesocrystal film as a scattering overlayer of a compact commercial P25 TiO2 nanoparticle film, the double layered DSSCs show a power conversion efficiency of 7.23%, indicating a great improvement compared to the DSSCs based on a P25 film (5.39%) and anatase TiO2 mesocrystal films, respectively. The synergetic effect of P25 and the mesocrystals as well as the latters unique feature of a Wulff construction of nearly 100% exposed (101) facets are probably responsible for the enhanced photoelectrical performance. In particular, we explore the possibility of the low surface area and exposed {101} facets as an efficient light scattering layer of DSSCs. Our work suggests that anatase TiO2 mesocrystals with the Wulff construction is a promising candidate as a superior scattering material for high-performance DSSCs. PMID- 24468965 TI - 18F-FLT PET changes during radiotherapy combined with cetuximab in head and neck squamous cell carcinoma patients. AB - AIM: Early treatment response of head and neck cancer to radiotherapy concomitant with cetuximab was monitored by repetitive PET imaging with the proliferation tracer 18F-FLT. PATIENTS, METHODS: Five head and neck cancer patients, treated with radiotherapy and concomitant cetuximab following cetuximab induction, received four 18F-FLT PET-CT scans before and during treatment. Changes in SUVpeak, SUVmean and CT- and PET-segmented gross tumour volumes were evaluated, as were correlations with immunohistochemical staining for Epidermal Growth Factor Receptor (EGFR) and Ki-67 (proliferation marker) in pre-treatment tumour biopsies. RESULTS: 18F-FLT PET measured tumor responses to the induction dose of cetuximab varied from 43% SUVpeak decrease to 47% increase. After start of radiotherapy 18F-FLT PET parameters decreased significantly in all patients. No associations were found between PET parameters and EGFR or Ki-67 expression levels. CONCLUSION: Proliferation of head and neck carcinomas shows a varying response to cetuximab induction, but consistently decreases after addition of radiotherapy. PMID- 24468966 TI - Methylmercury in biota downstream of Arivaca lake, Arizona, USA. AB - Concentrations of total mercury (Hg) and methylmercury (MeHg) were determined in water, sediment, periphyton, spiders, and amphibians from the streams and desert marsh downstream from Arivaca Lake, Arizona, to better understand their distribution and bioaccumulation. Mean concentrations of MeHg in water ranged from 0.09 to 0.93 ng/L, and mean concentrations of total Hg in sediment ranged from 10.4 to 126 MUg/kg. Hg and MeHg in water and sediments downstream from Arivaca Lake were low enough that they did not exceed human health or ecological thresholds. Hg and MeHg between sites ranged from 0.11 to 1.90 MUg/g Hg and 0.01 to 0.3 MUg/g MeHg in periphyton, from 0.09 to 0.25 MUg/g Hg and 0.04 to 0.10 MUg/g MeHg in spiders, and from 0.15 to 0.38 MUg/g Hg and 0.14 to 0.35 MUg/g MeHg in adult bullfrogs. No Hg toxicity data exist for periphyton or spiders, but MeHg concentrations in tadpoles (0.04 +/- 0.005 MUg/g) were lower than those known to cause sublethal effects and subchronic mortality. The mean total Hg concentration in adult bullfrogs in the present study was 0.24 MUg/g, which is slightly lower than the mean (0.37 MUg/g) from an Hg-contaminated wetland in California. MeHg bioaccumulated at each successive trophic level, and MeHg bioconcentration factors from the Arivaca watershed were similar to those for periphyton but greater than amphibians in other studies. Local resource managers can use these data to determine if water should be released from Arivaca Lake to recharge the aquifer downstream or to decrease Hg methylation in the reservoir. PMID- 24468967 TI - Changes to cuticle surface ultrastructure and some biological functions in the nematode Caenorhabditis elegans exposed to excessive copper. AB - Copper is an essential metal, but its toxic effects are pronounced when organisms are exposed to it in excessive amounts. However, information about the effects of chronic copper exposure on the cuticle ultrastructure of organisms is insufficient. Studies of the model organism, Caenorhabditis elegans, could further our understanding of the effect of chronic excessive copper exposure on human health. In this study, the cuticle surface ultrastructure of C. elegans was observed using scanning electron microscopy after excessive copper exposure. In addition to this, some biological functions, such as chemotaxis, reproduction, and development, were also analyzed. After chronic excessive copper exposure, the worms' body surface from vulva to tail was extensively wrinkled and folded along with the annulus. The worm's vulva size was significantly decreased, and the middle ridge of the alae was disrupted. Furthermore, some of the biological functions of nematodes were also affected: the chemotaxis index was partially changed, bags-of-worms were induced, development was delayed, and egg-laying number was decreased by copper treatment. The results of the present study shed new light on the effects of copper on C. elegans cuticle as well as some biological functions. PMID- 24468968 TI - Potential use of low-cost lignocellulosic waste for the removal of direct violet 51 from aqueous solution: equilibrium and breakthrough studies. AB - An efficient biosorbent, sugarcane bagasse was used in native, HCl-treated, and Na-alginate immobilized form for the removal of Direct Violet 51 dye from aqueous solutions. Batch study was performed to optimize important process parameters, such as pH, contact time, biosorbent dose, initial dye concentration, and temperature. Removal of Direct Violet 51 was found to be favorable at pH 2 with the biosorbent dose of 0.05 g. Biosorption process was found to be exothermic in nature. Maximum dye biosorption (39.6 mg/g) was achieved by using HCl-treated biomass. The pseudo-second-order kinetic and Langmuir adsorption isotherm models showed best fitness to the experimental data. Thermodynamic study was also performed to determine the feasibility of biosorption process. Continuous mode study was performed to optimize the important process parameters, such as bed height, flow rate, and initial dye concentration for maximum removal of Direct Violet 51 dye. The higher bed height, low flow rate, and high initial dye concentration were found to be the better conditions for maximum dye biosorption (17.28 mg/g). The linearized form of the Thomas model equation fitted well to the experimental data. The bed depth service time model was used to express the effect of bed height on breakthrough curves. Characterization of biosorbent was performed by scanning electron microscopy and Fourier transform infrared (FT-IR) analysis. The FT-IR spectral analyses showed the involvement of hydroxyl, carbonyl, and carboxyl groups in biosorption process. These results indicated that sugarcane bagasse biomass could be used as a novel biosorbent for the removal of Direct Violet 51 dye from real textile and related industries. PMID- 24468969 TI - Empirical and mechanistic evaluation of NH4(+) release kinetic in calcareous soils. AB - Release, fixation, and distribution of ammonium (NH4(+)) as a source of nitrogen can play an important role in soil fertility and plant nutrition. In this study, ten surface soils, after addition of 1,000 mg NH4(+) kg(-1,) were incubated for 1 week at the field capacity moisture and 25 +/- 2 degrees C temperature, and then NH4(+) release kinetic was investigated by sequential extractions with 10 mM CaCl2. Furthermore, NH4(+) distribution among three fractions, including water soluble, exchangeable, and non-exchangeable, was determined in all soil samples. NH4(+) release was initially rapid followed by a slower reaction, and this was described well with the Elovich equation as an empirical model. The cumulative NH4(+) concentration released in spiked soil samples had a positive significant correlation with sand content and negative ones with pH, exchangeable Ca(2+)m and K(+), cation exchange capacity (CEC), equivalent calcium carbonate (ECC), and clay content. The cation exchange model in the PHREEQC program was successful in mechanistic simulation of the release trend of native and added NH4(+) in all control and spiked soil samples. The results of fractionation experiments showed that the non-exchangeable fraction in control and spiked soil samples was greater than that in water-soluble and exchangeable fractions. Soil properties, such as pH, exchangeable Ca(2+) and K(+), CEC, ECC, and contents of sand and clay, had significant influences on the distribution of NH4(+) among three measured fractions. This study indicated that both native and recently fixed NH4(+), added to soil through the application of fertilizers, were readily available for plant roots during 1 week after exposure. PMID- 24468964 TI - The panorama of miRNA-mediated mechanisms in mammalian cells. AB - MicroRNAs comprise a large family of short, non-coding RNAs that are present in most eukaryotic organisms and are typically involved in downregulating the expression of protein-coding genes. The detailed mechanisms of miRNA functioning in animals and plants have been under investigation for more than decade. In mammalian cells, miRNA guides the effector complex miRISC to bind with partially complementary sequences, usually within the 3'UTR of mRNAs, and inhibit protein synthesis with or without transcript degradation. In addition to these main mechanisms, several other modes of miRNA-mediated gene expression regulation have been described, but their scale and importance remain a matter of debate. In this review, we briefly summarize the pathway of miRNA precursor processing during miRNA biogenesis and continue with the description of the miRISC assembly process. Then, we present the miRNA-mediated mechanisms of gene expression regulation in detail, and we gather information concerning the proteins involved in these processes. In addition, we briefly refer to the current applications of miRNA mechanisms in therapeutic strategies. Finally, we highlight some of the remaining controversies surrounding the regulation of mammalian gene expression by miRNAs. PMID- 24468970 TI - Occurrence of endocrine-disrupting phenols and estrogens in water and sediment of the Songhua river, northeastern China. AB - Concentrations of six phenolic endocrine-disrupting chemicals [4-tert-octylphenol (OP), 4-t-nonylphenol (4-t-NP), 4-n-nonylphenol (4-n-NP), nonylphenol mono- to di ethoxylates (NP1EO, NP2EO), and bisphenol A (BPA)] and five estrogens [estrone (E1), beta-estradiol (E2), estriol (E3) 17alpha-ethynylestradiol (EE2), and diethylstilbestrol (DES)] were determined in surface water and sediment samples collected from the Songhua River in northeast China. Concentrations of sum of five alkylphenols and alkylphenol ethoxylates (SigmaOP, 4-n-NP, 4-t-NP, NP1EO, NP2EO) were 117-1,030 ng L(-1) (mean 296) in water samples and 25.5-386 ng g(-1) (mean 67.3 ng g(-1) dry weight (dw)) in sediments. Concentrations of BPA in water and sediments were 8.24-263 ng L(-1) (mean 52.0) and 1.60-17.3 ng g(-1) dw (mean 4.90 dw), respectively. Concentrations in water were 0.840-20.8 ng L(-1) (mean 5.03) for the sum of three natural steroidal estrogens (SigmaE1, E2, E3) and below detection limit (BDL) at -1.38 ng L(-1) (average 0.200) for the sum of two synthetic estrogens (EE2, SigmaDES). Among estrogens, only E1 was detected in all of the sediment samples in the range of 0.100-3.00 ng g(-1) dw. Concentrations of Sigmaphenolic EDCs and Sigmaestrogens in water and sediments and their correlations with total organic carbon indicated that these contaminants originate from similar sources, such as municipal wastewater. In situ [Formula: see text] values and sediment-water fugacity fraction were calculated for the target chemicals, and the results indicated that these chemicals were, in general, supersaturated in sediments relative to those in water. PMID- 24468971 TI - Preparation of synthetic oligosaccharide-conjugates of poly-beta-(1->6)-N-acetyl glucosamine. AB - Staphylococcus aureus and Staphylococcus epidermidis are prominent bacterial pathogens of nosocomial infections. Both microorganisms colonize medical devices by forming adherent biofilms. Poly-beta-D-(1->6)-N-acetyl-glucosamine (PNAG) is a surface polysaccharide antigen which was found on both S. aureus and S. epidermidis. Animal studies have proved that PNAG can elicit antibodies which protect against staphylococcal infections. We have presented the synthesis of di , tetra- and hexasaccharide fragments of PNAG with formyl-heptyl aglycone and their attachment to bovine serum albumin (BSA) by reductive amination. PMID- 24468972 TI - Designing of a novel dextransucrase efficient in acceptor reactions. AB - Dextransucrase is produced by Leuconostoc, Streptococcus and Lactobacillus Species. The enzyme synthesizes dextran and acceptor products some of which act as prebiotics that are increasingly used in such industries as food, medicine, and cosmetics. B-512F Leuconostoc mesenteroides dextransucrase (DSR-S) is the preferred enzyme in commercial production of dextran and prebiotics. In the present work, a novel dextransucrase which is efficient in prebiotics production was designed. The enzyme was produced at optimal conditions in Escherichia coli by truncation and fusion to glutathione S-transferase (GST) in the gene from Leuconostoc mesenteroides B-512 FMC. The novel enzyme (MW: 119 kDa) was active and carried out dextran biosynthesis and acceptor reactions effectively. The novel dextransucrase (fTDSR-S) was produced by truncating signal, variable, and the glucan-binding regions in the gene and fusion of gst gene at the 5' end. fTDSR-S was characterized in detail and compared to the DSR-S. Truncation and fusion resulted in an increase in fTDSR-S biosynthesis in E. coli BL21 (DE3) by 35 fold. fTDSR-S leads to production of dextran as well as increased acceptor reactions. Due to GST fusion, it was possible to immobilize fTDSR-S covalently onto Eupergit C successfully. It was also found that the size of the active site of dextransucrase is 49 amino acids shorter than that reported previously in the literature. PMID- 24468973 TI - Outdoor air particle-bound trace metals in four selected communities in Ibadan, Nigeria. AB - Trace metal concentrations were determined in particulate matter (PM10) in ambient air of four purposively selected residential areas in Ibadan, Nigeria namely Bodija market (BM), Ojo Park (OP), Oluyole Estate (OE) and University of Ibadan (UI). PM10 was determined in the morning (7-10 a.m.) and afternoon (2-5 p.m.) for 12 weeks in the dry season months of January-March using a volumetric sampler following standard procedures and levels compared with WHO guideline limits. Glass-fibre filter papers exposed to the particulate matter were digested using appropriate acid mixtures, and the digest analysed for trace metals including Ni, Cr, Mn, Zn, and Pb using ICPMS method and levels compared with WHO limits. Data was analysed using ANOVA and Pearson correlation test at 5 % level of significance. The highest mean PM10 concentrations 502.3 +/- 39.9 MUg/m(3) were recorded in the afternoon period at BM, while the lowest concentration 220.6 +/- 69.9 MUg/m(3) was observed in the morning hours at UI. There was a significant difference between the PM10 levels across the various locations (p < 0.05), and all the levels were higher than WHO limit of 50 MUg/m(3). The highest levels of Ni, Zn and Pb were recorded at BM, which also had the highest PM10 burden. The trend in Pb levels across the locations was BM > UI > OP > OE with the highest level 5.70 MUg/m(3) in BM nearly fourfolds WHO limits of 1.5 MUg/m(3). There was a significant correlation between PM10 and Ni (p < 0.05).Urban communities with increased human activities especially motor traffic recorded both higher levels of PM10 and toxic trace metals. There is need to carry out source apportionment to establish the origin of these trace metals in future studies. PMID- 24468974 TI - An amyloid inhibitor octapeptide forms amyloid type fibrous aggregates and affects microtubule motility. AB - An amyloid inhibitor octapeptide simultaneously forms amyloid type fibrous aggregates on its own and interacts with the microtubule lattice three times stronger than a Xenopus Microtubule Associated Protein (XMAP215). PMID- 24468975 TI - Vascularization strategies for bone regeneration. AB - The functional regeneration of thick vascularized tissues such as bone and muscle is complicated by the large volume of lost tissue, challenging biomechanical environment, and the need to reproduce the highly organized structure of both the native tissue extracellular matrix and its vascular support system. Stem cell or progenitor cell delivery approaches, for example, continue to be plagued by low viability and engraftment in part due to the initial absence of a vascular supply. Recognition of diffusion limitations in thick tissues has prompted regenerative strategies that seek to accelerate establishment of a functional vasculature. The successful design of robust regeneration strategies for these challenging clinical scenarios will rely on a thorough understanding of interactions between construct design parameters and host biological and biomechanical factors. Here, we discuss the critical role of vascularization in normal bone tissue homeostasis and repair, vascular network adaptation to the local biomechanical environment, and the future directions of revascularization approaches being developed and integrated with bone regeneration strategies. PMID- 24468976 TI - Validation of an anatomical coordinate system for clinical evaluation of the knee joint in upright and closed MRI. AB - A computerized method to automatically and spatially align joint axes of in vivo knee scans was established and compared to a fixed reference system implanted in a cadaver model. These computational methods to generate geometric models from static MRI images with an automatic coordinate system fitting proved consistent and accurate to reproduce joint motion in multiple scan positions. Two MRI platforms, upright and closed, were used to scan a phantom cadaver knee to create a three-dimensional, geometric model. The knee was subsequently scanned in several positions of knee bending in a custom made fixture. Reference markers fixed to the bone were tracked by an external infrared camera system as well as by direct segmentation from scanned images. Anatomical coordinate systems were automatically fitted to the segmented bone model and the transformations of joint position were compared to the reference marker coordinate systems. The tracked translation and rotation measurements of the automatic coordinate system were found to be below root mean square errors of 0.8 mm and 0.7 degrees . In conclusion, the precision of the translation and rotational tracking is found to be sensitive to the scanning modality, albeit in upright or closed MRI, but still within comparative measures to previously performed studies. The potential to use segmented bone models for patient joint analysis could vastly improve clinical evaluation of disorders of the knee with continual application in future three dimensional computations. PMID- 24468977 TI - Treatment of traumatic lumbosacral spondyloptosis combined with unstable pelvic ring injury. PMID- 24468978 TI - Pre-operative role of BRAF in the guidance of the surgical approach and prognosis of differentiated thyroid carcinoma. AB - OBJECTIVE: The p.V600E BRAF and RAS mutations are found in 30-80% of differentiated thyroid carcinoma (DTC). BRAF mutation has been associated with poor prognosis. This study investigated the role of molecular studies in preoperative diagnosis of DTC and the association of p.V600E mutation with prognostic factors. DESIGN: Prospective study. METHODS: A total of 202 patients with cytological diagnosis of Bethesda III-VI underwent preoperative molecular studies and subsequent thyroidectomy. p.V600E and RAS mutations were studied in the cytology smears, using real-time PCR genotyping technique. The BRAF mutation (BRAF(+) or BRAF(-)) was correlated with histological and clinical findings. RESULTS: Molecular study of 172 nodules with Bethesda III-V cytology improved negative predictive value and accuracy of Bethesda III and IV diagnosis. BRAF mutation was present in 65% of 94 DTC and p.Q61R NRAS in one. Except for age, BRAF(+) and BRAF(-) did not differ in sex, tumor size, histological subtype, multifocality, vascular invasion, extrathyroidal extension, or prognostic staging. Among papillary carcinomas, lymph node (LN) metastasis was diagnosed in 23% BRAF(+) and 37% BRAF(-). Distant metastasis occurred in four BRAF(-). Recurrent or persistent disease was more frequent in BRAF(-) (26.7 vs 3.3% BRAF(+), P=0.002) along follow-up of 29.8+/-10 months. BRAF(+) patients without LN metastasis by pre-operative evaluation submitted to thyroidectomy with central neck dissection (CND) had more frequent LN metastasis (45 vs 5% no CND, P=0.002), but no difference in clinical outcome was observed. CONCLUSIONS: Pre-operative identification of BRAF mutation improved cytological diagnosis of DTC, but it was not associated with poor prognostic factors. Prophylactic CND did not guarantee better outcome in BRAF(+) patients. PMID- 24468979 TI - White, brown and pink adipocytes: the extraordinary plasticity of the adipose organ. AB - In mammals, adipocytes are lipid-laden cells making up the parenchyma of the multi-depot adipose organ. White adipocytes store lipids for release as free fatty acids during fasting periods; brown adipocytes burn glucose and lipids to maintain thermal homeostasis. A third type of adipocyte, the pink adipocyte, has recently been characterised in mouse subcutaneous fat depots during pregnancy and lactation. Pink adipocytes are mammary gland alveolar epithelial cells whose role is to produce and secrete milk. Emerging evidence suggests that they derive from the transdifferentiation of subcutaneous white adipocytes. The functional response of the adipose organ to a range of metabolic and environmental challenges highlights its extraordinary plasticity. Cold exposure induces an increase in the 'brown' component of the organ to meet the increased thermal demand; in states of positive energy balance, the 'white' component expands to store excess nutrients; finally, the 'pink' component develops in subcutaneous depots during pregnancy to ensure litter feeding. At the cell level, plasticity is provided not only by stem cell proliferation and differentiation but also, distinctively, by direct transdifferentiation of fully differentiated adipocytes by the stimuli that induce genetic expression reprogramming and through it a change in phenotype and, consequently function. A greater understanding of adipocyte transdifferentiation mechanisms would have the potential to shed light on their biology as well as inspire novel therapeutic strategies against metabolic syndrome (browning) and breast cancer (pinking). PMID- 24468980 TI - Trends in electrochemical CO2 reduction activity for open and close-packed metal surfaces. AB - We present a theoretical analysis of trends in overpotentials for electrocatalytic CO2 reduction based on density functional theory calculations. The analysis is based on understanding variations in the free energy of intermediates and mapping out the potential at which different elementary steps are exergonic as a measure of the catalytic activity. We study different surface structures and introduce a simple model for including the effect of adsorbate adsorbate interactions. We find that high coverages of CO under typical reaction conditions for the more reactive transition metals affect the catalytic activity towards the CO2 reduction reaction, but the ordering of metal activities is not changed. For the hydrogen evolution reaction, a high CO coverage shifts the maximum activity towards more reactive metals than Pt. PMID- 24468981 TI - Generation of folliculogenic human epithelial stem cells from induced pluripotent stem cells. AB - Epithelial stem cells (EpSCs) in the hair follicle bulge are required for hair follicle growth and cycling. The isolation and propagation of human EpSCs for tissue engineering purposes remains a challenge. Here we develop a strategy to differentiate human iPSCs (hiPSCs) into CD200(+)/ITGA6(+) EpSCs that can reconstitute the epithelial components of the hair follicle and interfollicular epidermis. The hiPSC-derived CD200(+)/ITGA6(+) cells show a similar gene expression signature as EpSCs directly isolated from human hair follicles. Human iPSC-derived CD200(+)/ITGA6(+) cells are capable of generating all hair follicle lineages including the hair shaft, and the inner and outer root sheaths in skin reconstitution assays. The regenerated hair follicles possess a KRT15(+) stem cell population and produce hair shafts expressing hair-specific keratins. These results suggest an approach for generating large numbers of human EpSCs for tissue engineering and new treatments for hair loss, wound healing and other degenerative skin disorders. PMID- 24468982 TI - A simple spectrophotometric method for the determination of arsenic in industrial and environmental samples using 2,4-Dihydroxy benzophenone-2-amino thiophenol. AB - 2,4-Dihydroxy benzophenone-2-amino thiophenol (BPBT) has been proposed as new analytical reagent for the direct non-extractive spectrophotometric determination of arsenic. The reagent reacts with arsenic in acidic medium (pH=6.0, sodium acetate-acetic acid buffer) to form light greenish yellow colored 1:1 (M:L) complex. Maximum absorbance was obtained at 343 nm and remains constant for over 24 h. The molar absorptivity and Sandell's sensitivity of BPBT are found to be 6.01*10(4) L mol(-1)cm(-1) and 0.0016 MUg cm(-2) respectively. The system obeys Beer's law in the range of 0.125-2.637 MUg/ml of As (III). Since BPBT method is more sensitive, it was applied for the determination of arsenic in some environmental water samples. PMID- 24468983 TI - Structural and spectroscopic characterization of a novel potential anti inflammatory agent 3-(adamantan-1-yl)-4-ethyl-1H-1,2,4-triazole-5(4H)thione by first principle calculations. AB - A comprehensive investigation on the molecular structure, electronic properties and vibrational spectra of the 3-(adamantan-1-yl)-4-ethyl-1H-1,2,4-triazole 5(4H)thione, a novel potential anti-inflammatory agent has been done with the hope that the results of present study may be helpful in the prediction of its mechanism of biological activity. The experimentally observed spectral data (FT IR and FT-Raman) of the title compound was compared with the spectral data obtained by DFT/B3LYP method. The (1)H nuclear magnetic resonance (NMR) chemical shifts of the molecule were calculated by the Gauge Including Atomic Orbital method and compared with experimental results. The molecular properties like dipole moment, polarizability, first static hyperpolarizability, the molecular electrostatic potential surface, contour map have been calculated to get a better insight of the properties of the title molecule. Natural bond orbital (NBO) analysis has been applied to study stability of the molecule arising from charge delocalization. UV-Vis spectrum of the title compound was also recorded and the electronic properties, such as Frontier orbitals and band gap energies were calculated by TD-DFT approach. Global and local reactivity descriptors have been computed to predict reactivity and reactive sites on the molecule. PMID- 24468984 TI - A new fluorescent and electrochemical Zn2+ ion sensor based on Schiff base derived from benzil and L-tryptophan. AB - Single molecule acting as both fluorescent and electrochemical sensor for Zn(2+) ion is rare. The product (L) obtained on condensation between benzil and L tryptophan has been characterized by H NMR, ESI-MS and FT-IR spectroscopy. L in 1:1 (v/v) CH3OH:H2O solution shows fluorescence emission in the range 300 nm to 600 nm with lambdamax at 350 nm when is excited with 295 nm photon. Zn(2+) ion could induce a 10-fold enhancement in fluorescent intensity of L. Fluorescence and UV/Visible spectral data analysis shows that the binding ratio between Zn(2+) ion and L is 1:1 with log beta=4.55. Binding of Zn(2+) ion disrupts the photoinduced electron transfer (PET) process in L and causes the fluorescence intensity enhancement. When cyclic voltammogram is recorded for L in 1:1 (v/v) CH3OH:H2O using glassy carbon (GC) electrode, two quasi reversible redox couples at redox potential values -0.630+/-0.005 V and -1.007+/-0.005 V are obtained (Ag AgCl as reference, scan rate 0.1 V s(-1)). Interaction with Zn(2+) ion makes the first redox couple irreversible while the second couple undergoes a 0.089 V positive shift in redox potential. Metal ions - Cd(2+), Cu(2+), Co(2+), Hg(2+), Ag(+), Ni(2+), Fe(2+), Mn(2+), Mg(2+), Ca(2+)and Pb(2+), individually or all together, has no effect on the fluorescent as well as electrochemical property of L. DFT calculations showed that Zn(2+) ion binds to L to form a stable complex. The detection limit for both fluorescence as well as electrochemical detection was 10(-6) M. PMID- 24468985 TI - Combination of best promoter and micellar catalyst for chromic acid oxidation of 1-butanol to 1-butanal in aqueous media at room temperature. AB - In aqueous acidic media, picolinic acid, 2,2'-bipyridine and 1,10-phenanthroline promoted Cr(VI) oxidation of 1-butanol produces 1-butanal. 1-butanal is separated from mixture by fractional distillation. The anionic surfactant (SDS) and neutral surfactant (TX-100) accelerate the process while the cationic surfactant (CPC) retards the reaction. Combination of bipy and SDS is the best choice for chromic acid oxidation of 1-butanol to 1-butanal in aqueous media. PMID- 24468986 TI - Improved photocatalytic activity of CdSe-nanocomposites: effect of Montmorillonite support towards efficient removal of Indigo Carmine. AB - To ascertain the contribution of adsorptive capacity of Montmorillonite (MMT) towards photocatalytic process, CdSe-MMT nanocomposites are explored for adsorptive removal of Indigo Carmine (IC). The nanocomposites are prepared via two approaches: (a) in-situ formation and (b) wet impregnation of CdSe onto MMT support. XRD analysis of composites suggested the proper dispersion of CdSe nanoparticles in MMT clay matrix with spherical morphology of 5-10nm sized CdSe nanoparticles. These nanocomposites are employed for photocatalytic degradation of IC under visible light at various IC concentrations and different amount of catalyst. Kinetics of IC is found to be of pseudo-second order with 10% in-situ and 50% loaded nanocomposites exhibiting better photocatalytic activity at 1.0 g L(-)(1) catalyst and 100 mg L(-)(1)of IC. Dynamics of its adsorptive removal on the composite surface evaluated by employing error estimation tools clearly suggest that Redlich-Peterson and Flory-Huggins adsorption isotherms effectively describe the multi-layer process. It is observed that spontaneous, exothermic chemisorption process occurring on the surface indeed enhances photocatalytic activity. Moreover, such a feature is also found to be associated with diffusion of IC within mesoporous structure of MMT that subsequently favors pore-diffusion controlled adsorption process. IR spectral analysis demonstrated that IC molecule is degraded on the catalyst surface. Light or oxygenated species induced photocorrosion of CdSe is suppressed due to its composite formation with MMT that results in 620 ppm removal of IC during successive cycles; a feature ascribed as improved photocatalytic activity for CdSe nanoparticles. PMID- 24468987 TI - Rapid phytochrome-mediated changes in the uptake by bean roots of sodium acetate [1-(14)C] and their modification by cholinergic drugs. AB - 4 min of red light increases the uptake of sodium acetate[1-(14)C] by excised, etiolated secondary roots of Phaseolus aureus Roxb. 4 min of far-red light reveres this effect. AMO-1618, which inhibits acetylcholinesterase activity, enhances the red-light effect, while d-tubocurarine, which blocks the animal acetylcholine receptor, inhibits it. Red light also increases basipetal translocation of the label. When the metabolic fate of the label was determined in dark-held roots, 36% of the label remained as acetate, 48% evolved as [(14)C]CO2, 3% partitioned with acetylcholine, and 3% effluxed from the roots. The rest of the label was associated with the coarse residue left after extraction. The major effect of red light was to increase the uptake of the label in the acetate fraction.We interpret these observations to mean that the phytochrome mechanism immediately causes an increase in uptake of the label during brief irradiation with red light. Because of our previous demonstration that both red light and acetylcholine increase respiration, it is probable that the increased absorption of the label is a process requiring respiratory energy. These data support the concept of phytochrome as a membrane-bound functional system that in bean roots is mediated by the acetylcholine mechanism. PMID- 24468988 TI - Maternal inheritance, cytology and macromolecular composition of defective chloroplasts in a variegated mutant of Nicotiana tabacum. AB - By phase microscopy of living cells the cause of a maternally-inherited variegated, spontaneous mutation of Nicotiana tabacum L. cv. Turkish Samsun was shown to be the presence of defective chloroplasts. These were intermingled with normal chloroplasts in some of the cells of the mesophyll tissue. In young, expanding leaves, the defective chloroplasts contain traces of chlorophylls a and b in the same ratio as found in normal chloroplasts, but only one-thirtieth of the quantity. As the defective chloroplasts mature, the green pigments disappear. The defective chloroplasts thus appear to be greatly deficient in thylakoid membranes. From their dynamic changes in shape, the defective chloroplasts appear to consist almost entirely of mobile phase, the structure which surrounds the thylakoid system of membranes of normal chloroplasts of higher plants. Consistent with this idea, two constitutents located in the mobile phase of normal chloroplasts-70S ribosomes and Fraction I protein-were detected in defective chloroplasts. The Fraction I protein was unchanged in specific ribulose diphosphate carboxylase activity from enzyme isolated from normal chloroplasts. Speculations are presented that the mutation in chloroplast DNA responsible for the formation of defective chloroplasts cannot be attributed to cistrons coding for the protein of Photosystem II, chloroplast ribosomal RNA or proteins, Fraction I protein, or the DNA-dependent RNA polymerase of chloroplasts. PMID- 24468989 TI - Identification of a mutation in chloroplast DNA correlated with formation of defective chloroplasts in a variegated mutant of Nicotiana tabacum. AB - As in wild-type Nicotiana tabacum L., two satellite DNAs having densities of 1.700 and 1.705 g cm(-3) in CsCl were identified in the organelle fraction of homogenates made from variegated leaves of a cytoplasmic mutant of N. tabacum. As the proportion of white to green tissue increased a great reduction in the 1.700 chloroplast DNA occurred correlated with a concomitant reduction in the total number of defective and normal chloroplasts per cell. At the same time, there was an absolute increase in the 1.705 satellite DNA. Separation of the two satellite DNAs was achieved by one cycle of purification on NaI gradients. When the 1.700 chloroplast DNAs from white and from green tissue of variegated leaves were compared, identical properties were found by the conventional buoyant density, T m and renaturation kinetics measurements. However, using a specially constructed difference melting system, the 1.700 DNA from defective chloroplasts was shown to have an approximately 1% higher GC composition than the DNA from normal chloroplasts. Also, by renaturation of a mixture of alkali denatured normal and defective chloroplast DNAs and subsequent spreading in formamide for electron microscopy, internal regions of mismatching were observed. The nonhomologous region corresponded to about 500-1000 base pairs. No differences in composition of the 1.705 satellite DNA derived from white or green tissues were detected either by difference melting or formation of heteroduplexes. PMID- 24468990 TI - A temperature-dependent source of variability in estimates of germination behaviour of lettuce fruits. AB - Germination of fruits of Lactuca sativa L. cv. "Arctic King" showed a sharp upper temperature maximum at 31+/-1.0 degrees C on an agar substrate in light. In a series of 60 tests carried out over 2 years, above, below and in the region of this maximum it was demonstrated that variability of germination counts was greater in the transition zone around this maximum. This is important when single controlled temperatures are chosen to compare effects of chemical or physical stresses on germination, where the stress causes the transition zone to shift and introduces a factor of greater variability into the results. PMID- 24468991 TI - [Studies on the efflux of malate from the vacuoles of the assimilating cells in Bryophyllum and the possible effects of this process on Crassulacean acid metabolism]. AB - Kinetic studies on the release of [(14)C] malate into unlabelled buffer in tissue slices of Bryophyllum leaves labelled by (14)CO2 dark fixation showed a curve characterized by three phases. According to literature, these phases indicate malate efflux from free space, cytoplasm and vacuoles. From the curves obtained it could be estimated that the cytoplasmatic pool of [(14)C] malate after (14)CO2 dark fixation is higher in "acidified" tissue (i.e. high malate content) than in "deacidified" tissue (i.e. low malate content). Efflux of [(14)C] malate from the vacuoles is also higher in "acidified" tissue. It increases when the malate solution enclosed in the vacuoles becomes more concentrated. This could be demonstrated in experiments in which water was extracted from the labelled tissue by raising the osmotic potential of the buffers in which the tissue slices were suspended. The increase of [(14)C] malate efflux from the vacuoles followed a sigmoid curve when plotted against the osmotic potential of the washing buffer, i.e. agaisnt the degree of dehydratation of the tissue.The osmotic potential of the buffer in which leaf tissue of Bryophyllum was suspended also had an effect on the distribution of radiocarbon among the metabolites when the tissue was allowed to fix (14)CO2 in the light. In deacidified tissue the incorporation of (14)C into malate was inhibited whereas label found in carbohydrates (starch + sucrose) remained nearly unchanged when the osmotic potential of the buffer increased up to 12 atm. This effect is explained in terms of inhibition of PEP carboxylase by a growing cytoplasmic malate pool, which is caused by the increasing malate efflux from the vacuole and by retarded malate flux from cytoplasm into vacuole under these conditions. However, in acidified tissue labelling of malate was already low with no osmotic stress, and no further inhibition of malate synthesis could be observed when the osmotic potential of the buffer was increased.Label found in starch after (14)CO2-fixation decreased in the light under osmotic stress, with more label being transferred into sucrose. This effect could be interpreted as osmoregulation which forces the cells of the leaf tissue to produce osmotically effective substances to balance the higher osmotic potential of the buffer. PMID- 24468992 TI - The three-dimensional structure of primary phloem systems. AB - A method has been developed for staining the phloem so that its ramifications can be observed directly in thick preparations. This method is based on clearing the material with lactic acid, staining with lacmoid and observing it in sodium lactate. Phloem anastomoses between the primary vascular strands of stem internodes were found to be common in many plant species (18 out 26 studied). These anastomoses are possible channels for the lateral distribution of materials in the stem and for movement of assimilates upwards from the leaves. PMID- 24468993 TI - On the volume-flow mechanism of phloem transport. AB - A steady-state model of solution flow in a tubular semipermeable membrane is developed for an arbitrary distribution of solute sources and sinks along the translocation path. It is demonstrated that the volume-flow mechanism of phloem transport depends only on the two assumptions: 1. that the plasmalemma of the sieve tube is a differentially permeable membrane, and 2. that sugars are actively secreted into and absorbed from the lumen of the sieve tube. It is shown that in the absence of a pressure gradient, there is a negligible concentration gradient over most of the translocation path. However, in the presence of a pressure gradient a small concentration gradient develops as a result of the continually changing chemical potential of water along the direction of solution flow. For Poiseuille flow the concentration gradient is approximately proportional to the mean stream velocity. PMID- 24468994 TI - Effect of moisture stress on abscisic acid levels in Ricinus communis L. with particular reference to phloem exudate. AB - Abscisic acid (ABA) increased considerably in stem apices attached to Ricinus plants during a moisture stress but only slightly in stem apices which were detached and then allowed to lose water. A very marked rise in ABA also occurred in phloem-sap of moisture-stressed Ricinus plants. These results suggest that in apices of moisture-stressed plants the increased ABA does not arise in situ but is translocated to the apex after synthesis in the mature leaves. PMID- 24468995 TI - Repeating particles associated with membranes of transfer cells. AB - Freeze etching of unfixed root nodule transfer cells of Trifolium repens reveals regular arrays of 11 nm particles on the fracture face of the plasmalemma associated with wall ingrowths. The particles are arranged in a hexagonal lattice and have a centre-to-centre spacing of 15 nm. Similarly arranged, smaller particles also occur on the bacteroid membrane envelopes. PMID- 24468996 TI - Effect of HIV-1 exposure and antiretroviral treatment strategies in HIV-infected children on immunogenicity of vaccines during infancy. AB - INTRODUCTION: We studied the effect of maternal HIV-exposure and timing of antiretroviral treatment (ART) in HIV-infected infants on antibody responses to combined diphtheria-toxoid-tetanus-toxoid-whole cell pertussis and Haemophilus influenzae type b conjugate vaccine (HibCV) and monovalent hepatitis B vaccine (HBV). METHODS: HIV-uninfected infants born to HIV-infected (HEU) or HIV uninfected (HUU) mothers were enrolled in parallel with HIV-infected children with CD4+ >=25%, who were randomized to initiate ART immediately upon confirmation of HIV-infection (ART-Immed) or when clinically and/or immunologically indicated (ART-Def). Infants received three doses of diphtheria toxoid-tetanus-toxoid -wP-HibC/HBV at 7.3, 11.4 and 15.4 weeks of age. Antibody to diphtheria-toxoid, tetanus-toxoid, pertussis toxin, filamentous hemagglutinin (FHA) and hepatitis B surface antigen (HBsAg) were measured by Luminex multiplex immunoassay and polyribosyl-ribitol phosphate (PRP) antibodies by standard ELISA and bactericidal assay. RESULTS: Prevaccination antibody geometric mean concentrations (GMCs) were higher in HUU than HEU infants for tetanus-toxoid, but lower for HBsAg, diphtheria-toxoid and FHA. Postvaccination GMCs and proportion with seroprotective antibody levels or sero-conversion rates were similar between HUU and HEU infants for all vaccines. Postvaccination GMCs were higher in HUU for tetanus-toxoid, diphtheria-toxoid, HBsAg and FHA than ART-Immed infants; and for tetanus-toxoid, HBsAg and pertussis-toxoid than ART-Def infants. Nevertheless, there was no difference in proportion of HUU and HIV-infected infants who developed sero-protective vaccine-specific antibody levels postvaccination. The timing of ART initiation generally did not affect immune responses to vaccines between HIV-infected groups. CONCLUSION: Vaccination with DTwP-HibCV/HBV of HEU and HIV-infected infants initiated on early-ART confers similar immunity compared with HUU children. PMID- 24468997 TI - Home-based versus clinic-based care for patients starting antiretroviral therapy with low CD4+ cell counts: findings from a cluster-randomized trial. AB - OBJECTIVES: African health services have shortages of clinical staff. We showed previously, in a cluster-randomized trial, that a home-based strategy using trained lay-workers is as effective as a clinic-based strategy. It is not known whether home-based care is suitable for patients with advanced HIV disease. METHODS: The trial was conducted in Jinja, Uganda. One thousand, four hundred and fifty-three adults initiating ART between February 2005 and January 2009 were randomized to receive either home-based care or routine clinic-based care, and followed up for about 3 years. Trained lay workers, supervised by clinical staff based in a clinic, delivered the home-based care. In this sub-analysis, we compared survival between the two strategies for those who presented with CD4+ cell count less than 50 cells/MUl and those who presented with higher CD4+ cell counts. We used Kaplan-Meier methods and Poisson regression. RESULTS: Four hundred and forty four of 1453 (31%) participants had baseline CD4+ cell count less than 50 cells/MUl. Overall, 110 (25%) deaths occurred among participants with baseline CD4+ cell count less than 50 cells/MUl and 87 (9%) in those with higher CD4+ cell count. Among participants with CD4 cell count less than 50 cells/MUl, mortality rates were similar for the home and facility-based arms; adjusted mortality rate ratio 0.80 [95% confidence interval (CI) 0.53-1.18] compared with 1.22 (95% CI 0.78-1.89) for those who presented with higher CD4+ cell count. CONCLUSION: HIV home-based care, with lay workers playing a major role in the delivery of care including providing monthly adherence support, leads to similar survival rates as clinic-based care even among patients who present with very low CD4+ cell count. This emphasises the critical role of adherence to antiretroviral therapy. PMID- 24469000 TI - Option B+ for prevention of mother-to-child transmission of HIV in resource constrained settings: great promise but some early caution. PMID- 24468999 TI - Retention in care under universal antiretroviral therapy for HIV-infected pregnant and breastfeeding women ('Option B+') in Malawi. AB - OBJECTIVE: To explore the levels and determinants of loss to follow-up (LTF) under universal lifelong antiretroviral therapy (ART) for pregnant and breastfeeding women ('Option B+') in Malawi. DESIGN, SETTING, AND PARTICIPANTS: We examined retention in care, from the date of ART initiation up to 6 months, for women in the Option B+ program. We analysed nationwide facility-level data on women who started ART at 540 facilities (n = 21,939), as well as individual-level data on patients who started ART at 19 large facilities (n = 11,534). RESULTS: Of the women who started ART under Option B+ (n = 21,939), 17% appeared to be lost to follow-up 6 months after ART initiation. Most losses occurred in the first 3 months of therapy. Option B+ patients who started therapy during pregnancy were five times more likely than women who started ART in WHO stage 3/4 or with a CD4 cell count 350 cells/MUl or less, to never return after their initial clinic visit [odds ratio (OR) 5.0, 95% confidence interval (CI) 4.2-6.1]. Option B+ patients who started therapy while breastfeeding were twice as likely to miss their first follow-up visit (OR 2.2, 95% CI 1.8-2.8). LTF was highest in pregnant Option B+ patients who began ART at large clinics on the day they were diagnosed with HIV. LTF varied considerably between facilities, ranging from 0 to 58%. CONCLUSION: Decreasing LTF will improve the effectiveness of the Option B+ approach. Tailored interventions, like community or family-based models of care could improve its effectiveness. PMID- 24469001 TI - Abacavir-induced liver toxicity in an HIV-infected patient. PMID- 24468998 TI - Increased incidence of antiretroviral drug discontinuation among patients with viremic hepatitis C virus coinfection and high hyaluronic acid, a marker of liver fibrosis. AB - BACKGROUND: Most antiretroviral drugs are metabolized by the liver; hepatic disease or liver damage as a result of hepatitis C virus (HCV) could impair this metabolism leading to an increased risk of drug toxicity. This study aimed to determine the risk of antiretroviral drug discontinuation among HCV/HIV coinfected patients. METHODS: EuroSIDA patients taking combination antiretroviral therapy were included. Poisson regression identified factors associated with antiretroviral treatment discontinuation. RESULTS: A total of 9535 HIV-positive patients with known HCV status were included (6939 HCVAb-negative; 2596 HCVAb positive at baseline). Viremic HCV infection was associated with a 44% increased risk of antiretroviral drug discontinuation compared with aviremic infection [adjusted incidence rate ratio, aIRR: 1.44 (95% confidence interval, CI 1.22 1.69)]; this relationship was largest among nonnucleoside reverse transcriptase inhibitors [aIRR: 1.59 (95% CI 1.18-2.14)]. In the subset of 935 HIV-positive patients also HCV-positive or HBV-positive with plasma hyaluronic acid measured, hyaluronic acid more than 100 ng/ml was associated with a 37% increased risk of antiretroviral drug discontinuation [aIRR: 1.37 (95% CI 1.08-1.73) vs. hyaluronic acid <=100 ng/ml] and the effect of HCV viremia became nonsignificant; the largest drug association was seen for protease inhibitors [aIRR: 1.40 (95% CI 1.04-1.89)]. CONCLUSION: HCV viremia and high levels of hyaluronic acid predict antiretroviral drug discontinuation. Evidence was also found to suggest a link between impaired liver function and protease inhibitor toxicity. PMID- 24469002 TI - Effect of HIV-2 infection on HIV-1 disease progression and mortality. PMID- 24469003 TI - Effect of HIV-2 infection on HIV-1 disease progression and mortality: reply. PMID- 24469004 TI - Total hospital costs of surgical treatment for adult spinal deformity: an extended follow-up study. AB - BACKGROUND CONTEXT: Whereas the costs of primary surgery, revisions, and selected complications for adult spinal deformity (ASD) have been individually reported in the literature, the total costs over several years after surgery have not been assessed. The determinants of such costs are also not well understood in the literature. PURPOSE: This study analyzes the total hospital costs and operating room (OR) costs of ASD surgery through extended follow-up. STUDY DESIGN/SETTING: Single-center retrospective analysis of consecutive surgical patients. PATIENT SAMPLE: Four hundred eighty-four consecutive patients undergoing surgical treatment for ASD from January 2005 through January 2011 with minimum three levels fused. OUTCOME MEASURES: Costs were collected from hospital administrative data on the total hospital costs incurred for the operation and any related readmissions, expressed in 2010 dollars and discounted at 3.5% per year. Detailed data on OR costs, including implants and biologics, were also collected. METHODS: We performed a series of paired t tests and Wilcoxon signed-rank tests for differences in total hospital costs over different follow-up periods. The goal of these tests was to identify a time period over which average costs plateau and remain relatively constant over time. Generalized linear model regression was used to estimate the effect of patient and surgical factors on hospital inpatient costs, with different models estimated for different follow-up periods. A similar regression analysis was performed separately for OR costs and all other hospital costs. RESULTS: Patients were predominantly women (n=415 or 86%) with an average age of 48 (18-82) years and an average follow-up of 4.8 (2-8) years. Total hospital costs averaged $120,394, with primary surgery averaging $103,143 and total readmission costs averaging $67,262 per patient with a readmission (n=130 or 27% of all patients). Operating room costs averaged $70,514 per patient, constituting the majority (59%) of total hospital costs. Average total hospital costs across all patients significantly increased (p<.01) after primary surgery, from $111,807 at 1-year follow-up to $126,323 at 4-year follow-up. Regression results also revealed physician preference as the largest determinant of OR costs, accounting for $14,780 of otherwise unexplained OR cost differences across patients, with no significant physician effects on all other non-OR costs (p<.05). CONCLUSIONS: The incidence of readmissions increased the average cost of ASD surgery by more than 70%, illustrating the financial burden of revisions/reoperations; however, the cost burden resulting from readmissions appeared to taper off within 5 years after surgery. The estimated impact of physician preference on OR costs also highlights the variation in current practice and the opportunity for large cost reductions via a more standardized approach in the use of implants and biologics. PMID- 24469005 TI - Dimensions of the ascending aorta in conotruncal heart defects. AB - Dilatation of the ascending aorta is an important sequel in conotruncal anomalies, such as tetralogy of Fallot (TOF) or d-transposition of the great arteries (TGA). We measured dimensions and their progression at different levels of the ascending aorta in 80 patients. In TOF patients, mean z-score for aortic annulus was 1.65 (range -3.16-6.47), for sinus 1.93 (range -2.28-5.39), for st junction 4.15 (range 0.0-8.18), and for ascending aorta 3.51 (range -1.23-6.36). Over time, annulus z-scores increased in the univariate analysis [0.07/year, 95 % confidence interval (CI) 0.01-0.14; p = 0.02], and this was unique to male patients (0.08/year, 95 % CI 0.00-0.15; p = 0.05). z-scores of the ascending aorta decreased (-0.1/year, 95 % CI -0.18 to -0.02; p = 0.02), and this was confined to patients without aortic regurgitation (AR; -0.09/year, 95 % CI -0.18 to -0.01; p = 0.04). In TGA, mean z-score for the aortic annulus was 2.13 (range 3.71-8.39), for sinus 1.77 (range -3.04-6.69), for st-junction 1.01 (range -5.44 6.71), and for ascending aorta 0.82 (range -4.91-6.46). In bivariate analysis, annulus z-scores decreased in females (-0.14/year, 95 % CI -0.25 to -0.03; p = 0.01) and in patients without AR (-0.07/year, 95 % CI -0.14-0.0; p = 0.03). z scores of the ascending aorta increased significantly in males (0.08/year, 95 % CI 0.0 to 0.16; p = 0.05) and in patients with AR (0.12/year, 95 % CI 0.03-0.21; p = 0.01). In conclusion, TOF and TGA z-scores of the ascending aorta differ significantly from those of the normal population. Progression of z-scores over time is influenced by diagnosis, sex, and presence of AR. PMID- 24469006 TI - Acute kidney injury: global health alert. AB - Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high-risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, and increase awareness of AKI by governments, the public, general and family physicians and other healthcare professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI. PMID- 24469007 TI - Current world literature. Renal immunology and pathology. PMID- 24469009 TI - Towards high-performance permanent magnets without rare earths. AB - Achieving a very strong magnetic anisotropy in a 3d material is a difficult, but not an impossible task. It is difficult because there is no general recipe (necessary condition) for a strong anisotropy in a band magnet. Several strategies can be pursued in this situation. One of them is to re-examine the less studied 3d compounds, somewhat neglected since the discovery of the Nd-Fe-B magnets 30 years ago. As an example, a single crystal of (Fe0.7Co0.3)2B has been investigated in this work. PMID- 24469010 TI - [Treatment of lipid disorders]. AB - Lipid disorders play an essential role in the pathogenesis of atherosclerotic diseases. An integral part of the clinical evaluation is the estimation of the individual cardiovascular risk using risk scores and patient history. Due to the long established prognostic relevance, reduction of low-density lipoproteins (LDL) using statins remains beyond doubt the central intervention both in primary and secondary prevention of atherosclerotic diseases. Indispensible components of treatment in all patients with elevated triglyceride levels are lifestyle changes contributing to a reduction of accompanying risk factors, in particular physical activity and smoking cessation. PMID- 24469011 TI - Termination of adaptive servoventilation after successful long-term therapy. Case report of a heart failure patient with nocturnal Cheyne-Stokes respiration. PMID- 24469012 TI - Preparation of PCDTBT nanofibers with a diameter of 20 nm and their application to air-processed organic solar cells. AB - A strategy for fabricating organic photovoltaic (OPV) devices based on PCDTBT nanofibers and PC70BM is described. Electrospinning techniques are used to prepare PCDTBT nanofibers and OPV devices in ambient air. The diameters of the PCDTBT nanofibers are approximately twice the exciton diffusion length, 20 nm. The active layer exhibits 100% photoluminescence quenching due to the small nanofiber diameter, indicating that the excitons are efficiently dissociated. The electrospun PCDTBT nanofibers absorb more photons at longer wavelengths, leading to improved photon harvesting. OPV devices composed of PCDTBT nanofibers show a high short circuit current of 11.54 mA cm(-2) and a high power conversion efficiency of 5.82%. The increase in the short circuit current is attributed to enhanced photon harvesting and charge transport. This method may be applied to the fabrication, in ambient air, of large-area active layers composed of other new conjugated polymers to yield high-performance OPV devices. PMID- 24469013 TI - One-step replication and enhanced catalytic activity for cathodic oxygen reduction of the mesostructured Co3O4/carbon composites. AB - Mesostructured Co3O4/C composites of high surface area have been synthesized via a one-step replica route by co-nanocasting cobalt and carbon precursors into mesoporous silica, in which the Co3O4 nanoparticles are homogeneously dispersed in the mesoporous structure of carbon substrates. The mesostructured composites showed relatively high catalytic activities for oxygen reduction reaction (ORR), and that with a Co loading content of 4.3 at% exhibited the best electrochemical performance for ORR. The relatively high catalytic activity is attributed to the effects of the redox couples (Co(3+)/Co(2+)) together with the contribution from the conductive mesoporous carbon substrate. PMID- 24469014 TI - Microbial contamination of dental unit waterlines and effect on quality of indoor air. AB - The microbiological quality in dental unit waterlines (DUWLs) is considered to be important because patients and dental staff with suppressed immune systems are regularly exposed to water and aerosols generated from dental units (DUs). Opportunistic pathogens like Pseudomonas, Legionella, Candida, and Aspergillus can be present in DUWLs, while during consultations, bioaerosols can be dispersed in the air, thus resulting in effects on microbiological quality of indoor air. This present study represents microbiological air and water quality in dental offices (DOs) and also concerns the relationship between the quality of DO air and dental unit water. This study aimed to assess both the microbial quality of dental unit water and the indoor air in 20 DOs and to survey the effect on the quality of the indoor air with the existing microorganisms in dental unit water. Fourteen out of 20 (70 %) DUWLs were found to be contaminated with a high number of aerobic mesophilic heterotrophic bacteria. In terms of bacterial air contamination levels, in 90 % of DOs, a medium level (<500 colony-forming units (CFU)/m(3)) of contamination was determined, while in terms of microfungal air contamination, in all DOs, a low level (<100 CFU/m(3)) of contamination was determined. Potential infection or allergen agents, such as Pseudomonas, Micrococcus, Staphylococcus, Alternaria, Cladosporium, Penicillium, Aspergillus, and Paecilomyces were isolated from water and air samples. This study's determination of contamination sources and evaluation of microbial load in DOs could contribute to the development of quality control methods in the future. PMID- 24469015 TI - Simultaneous measurements of radon and thoron, and their progeny levels in dwellings on anticlinal structures of Assam, India. AB - Radon and thoron, and their progeny concentrations along with equilibrium factors for gas progeny and radiological risks to the residents have been measured in dwellings of Digboi and Mashimpur areas located on anticlines during the winter season. In this present investigation, twin-cup dosemeters fitted with LR-115 (II) nuclear detectors have been employed. The present work has shown that there exist considerable house-to-house variations in values with maximum values in mud houses and minimum values in assam type (AT) houses. It has been found that mean (and geometric standard deviations (GSD)) radon concentrations are 83.8 (1.3), 113.5 (1.1) and 157.2 (1.2) Bq m(-3) in AT, reinforced cement concrete (RCC) and mud houses in Digboi area and 63.0 (1.1), 87.1 (1.4) and 182.1 (1.2) Bq m(-3) in AT, RCC and mud houses in Mashimpur area, respectively. The overall mean radon concentrations in Digboi and Mashimpur are estimated to be 114.4 (1.4) and 100.0 (1.7) Bq m(-3). The mean radon concentrations are found to be less than the lower reference level of 200 Bq m(-3) of the International Commission on Radiological Protection (ICRP 2007). The thoron concentrations in Digboi area are estimated to be 31.1 (1.3), 50.8 (1.4) and 67.0 (1.6) Bq m(-3) in AT, RCC and mud houses, respectively, whereas in Mashimpur area, the thoron concentrations are estimated to be 26.4 (1.3), 44.4 (1.3) and 77.7 (1.3) Bq m(-3) in AT, RCC and mud houses, respectively. The mean annual effective doses in Digboi area are found to be 1.9 (1.3), 2.7 (1.2) and 4.1 (1.4) mSv y(-1) in AT, RCC and mud houses, respectively, while in the case of Mashimpur area, the mean annual effective doses are found to be 1.5 (1.4), 2.2 (1.2) and 4.9 (1.3) mSv y(-1) in AT, RCC and mud houses, respectively. Nevertheless, the obtained results are much lower than the upper reference level of 10 mSv (ICRP 2007). PMID- 24469016 TI - Risk of severe and repetitive traumatic brain injury in persons with epilepsy: a population-based case-control study. AB - BACKGROUND: While traumatic brain injury (TBI) can lead to epilepsy, individuals with preexisting epilepsy or seizure disorder (ESD), depending on the type of epilepsy and the degree of seizure control, may have a greater risk of TBI from seizure activity or medication side effects. The joint occurrence of ESD and TBI can complicate recovery as signs and symptoms of TBI may be mistaken for postictal effects. Those with ESD are predicted to experience more deleterious outcomes either because of having a more severe TBI or because of the cumulative effects of repetitive TBI. METHODS: We conducted a case-control study of all emergency department visits and hospital discharges for TBI from 1998 through 2011 in a statewide population. The severity of TBI, repetitive TBI, and other demographic and clinical characteristics were compared between persons with TBI with preexisting ESD (cases) and those without (controls). Significant differences in proportions were evaluated with confidence intervals. Logistic regression was used to examine the association of the independent variables with ESD. RESULTS: During the study period, 236,164 individuals sustained TBI, 5646 (2.4%) of which had preexisting ESD. After adjustment for demographic and clinical characteristics, cases were more likely to have sustained a severe TBI (OR=1.49; 95% CI=1.38-1.60) and have had repetitive TBI (OR=1.54; 95% CI=1.41 1.69). CONCLUSION: The consequences of TBI may be greater in individuals with ESD owing to the potential for a more severe or repetitive TBI. Seizure control is paramount, and aggressive management of comorbid conditions among persons with ESD and increased awareness of the hazard of repetitive TBI is warranted. Furthermore, future studies are needed to examine the long-term outcomes of cases in comparison with controls to determine if the higher risk of severe or repetitive TBI translates into permanent deficits. PMID- 24469017 TI - A mutarotation mechanism based on dual proton exchange in the amorphous D glucose. AB - It is a well known fact that carbohydrates have unusual chemical and physical properties when they approach the glassy state during the cooling process. Differences between sugar aqueous solutions and their pure anhydrous states are caused mainly by the different intermolecular interactions related to the different hydrogen bond patterns. The mutarotation, a specific reaction in the saccharides, was recently investigated in the supercooled liquid and the glassy state of D-glucose. It was shown that the activation energy of this process in the supercooled liquid state is twice as low as for the same process in aqueous solution. In contrast, the activation energy in the glassy state is twice as high as in the aqueous solution. Herein, we present possible explanations for this phenomenon and propose a universal mechanism for the mutarotation process in the amorphous state of matter. In this work, for the first time, a double proton exchange mechanism in carbohydrates is proposed. PMID- 24469018 TI - Genetic, pathological and physiological determinants of transdermal fentanyl pharmacokinetics in 620 cancer patients of the EPOS study. AB - OBJECTIVE: This study aimed to investigate whether CYP3A4/5 genetic variants, together with clinical and patient factors, influence serum fentanyl and norfentanyl concentrations and their ratio in cancer pain patients receiving transdermal fentanyl. METHODS: CYP3A4*22 and CYP3A5*3 polymorphisms were analysed in 620 cancer pain patients receiving transdermal fentanyl (12.5-700 MUg/h) from the European Pharmacogenetic Opioid Study. Using stepwise linear regression, CYP3A4/5 genetic variability was examined in combination with patient factors relating to organ drug elimination function and ABCB1 genetics for their association with serum fentanyl and norfentanyl concentrations and metabolic ratio (MR) (norfentanyl : fentanyl). RESULTS: Delivery rate-adjusted serum fentanyl concentrations (0.0012-1.1 nmol/l/MUg.h) and MRs (0.08-499) varied widely. Only 43% of variability in serum fentanyl concentrations was accounted for by delivery rate and less than 50% by CYP3A4/5 genotypes and clinical variables (delivery rate, sex, comedications, kidney disease, BMI, serum albumin). CYP3A4*22 and CYP3A5*3 variants, CYP3A inhibitors and variables relating to liver and kidney function (serum albumin, glomerular filtration rate, kidney disease, BMI) were associated with MR, but accounted for only 14% of variability. CONCLUSION: Serum fentanyl concentrations and MR vary considerably between cancer pain patients on transdermal fentanyl patches. CYP3A4*22 and CYP3A5*3 genotypes, and multiple clinical factors, combine to influence transdermal fentanyl pharmacokinetics, but accounted for only a small proportion of variability in this study. Identification of the remaining factors determining serum fentanyl concentrations, and their relationship to efficacy and adverse effects may aid in improving the safety and effectiveness of transdermal fentanyl. PMID- 24469019 TI - Advanced glycation end products of beta2-microglobulin in uremic patients as determined by high resolution mass spectrometry. AB - By using a high resolution top-down and bottom-up approach we identified and characterized the AGEs of beta2-microglobulin (beta2-m) formed by incubating the protein in the presence of glucose and of the main reactive carbonyl species. Glucose induced glycation on the N-terminal residue, while glyoxal (GO) and methylglyoxal (MGO) covalently reacted with Arg3. Carboxymethyl (CM-R) and imidazolinone (R-GO) derivatives were identified in the case of GO and carboxyethyl arginine (CE-R) and methyl-imidazolinone (R-MGO) for MGO. Interestingly, alpha,beta-unsaturated aldehydes [4-hydroxy-2-nonenal (HNE); 4-oxo 2-nonenal (ONE); acrolein (ACR)] did not induce any covalent modifications up to 100MUM. The different reactivity of beta2-m towards the different RCS was then rationalized by molecular modeling studies. The MS method was then applied to fully characterize the AGEs of beta2-m isolated from the urine of uremic subjects. CM-R, CE-R and R-MGO were easily identified on Arg3 and their relative abundance in respect to the native protein determined by a semi-quantitative approach. Overall, the AGEs content of urinary beta2-m ranged from 0.2 to 1% in uremic subjects. The results here reported offer novel insights and technical achievements for a potential biological role of AGEs-beta2-m in pathological conditions. PMID- 24469020 TI - A MU-SPE procedure for the determination of cannabinoids and their metabolites in urine by LC-MS/MS. AB - In this paper the development and validation of a method for the analysis of THC COOH, THC, THC-OH, CBD and CBN in their total form in urine by LC-MS/MS is presented. Tandem hydrolysis, i.e. enzymatic and basic, has been found optimal for the simultaneous analysis of the selected analytes in urine: basic hydrolysis is more effective for the cleavage of THC-COOH glucuronide while enzymatic hydrolysis allows the cleavage of the conjugated cannabinoids possessing ether bonds (THC, THC-OH, CBD). The whole procedure requires a 2h enzymatic hydrolysis using only 90MUL of urine by MU-SPE extraction technique with C18 tips. Clear advantages in terms of time and of enzyme reduction are obtained and the cost of the analysis can be dramatically reduced. Satisfactory recovery values and matrix effect are obtained, and the chromatographic run, performed with a fused-core column, allowed the complete analyte separation in only 3min (total run 5.8min) with a common HPLC system. Furthermore the whole procedure has been validated according to SWGTOX guidelines: LOQs are between 6 and 10ppb, quite lower than the requested cut-off for urine testing; intermediate reproducibility of the selected analytes is below 10% and accuracy is between 85% and 113%, except for CBD, included only for semi-quantitative determination. PMID- 24469022 TI - Smoothened inhibitors in the treatment of advanced basal cell carcinomas. AB - PURPOSE OF REVIEW: The Hedgehog pathway has been identified as a key element in the development of many forms of cancer. Smoothened (Smo) inhibitors are known to beneficially interfere with the Hedgehog pathway and are currently under investigation as anticancer drugs for many tumor entities. Reviewed here are the most recent developments in clinical research on Smo inhibitors for the treatment of advanced basal cell carcinoma (BCC). RECENT FINDINGS: When reviewing the literature of the past 12 months, it is striking to see the rapid evolution of the field. Compounds that have been presented as powerful new drug candidates 12 months ago have now been discontinued, whereas new ones have emerged. Reports on 13 drug candidates have been identified: one marketed, vismodegib, eight currently under development (phase I-II) and four for which clinical investigation for BCC is currently not being pursued. SUMMARY: Smo inhibitors are a promising drug class for the treatment of BCC. To date, most candidates are in early stage development and are expected to enter the market in approximately 5-8 years, if successful. PMID- 24469021 TI - Ligand-induced structural changes in the cyclic nucleotide-modulated potassium channel MloK1. AB - Cyclic nucleotide-modulated ion channels are important for signal transduction and pacemaking in eukaryotes. The molecular determinants of ligand gating in these channels are still unknown, mainly because of a lack of direct structural information. Here we report ligand-induced conformational changes in full-length MloK1, a cyclic nucleotide-modulated potassium channel from the bacterium Mesorhizobium loti, analysed by electron crystallography and atomic force microscopy. Upon cAMP binding, the cyclic nucleotide-binding domains move vertically towards the membrane, and directly contact the S1-S4 voltage sensor domains. This is accompanied by a significant shift and tilt of the voltage sensor domain helices. In both states, the inner pore-lining helices are in an 'open' conformation. We propose a mechanism in which ligand binding can favour pore opening via a direct interaction between the cyclic nucleotide-binding domains and voltage sensors. This offers a simple mechanistic hypothesis for the coupling between ligand gating and voltage sensing in eukaryotic HCN channels. PMID- 24469023 TI - Precision medicine and skin cancer therapy: dealing with a moving target. PMID- 24469024 TI - Thermoelectric properties and electronic structure of the Zintl phase Sr5Al2Sb6. AB - The Zintl phase Sr5Al2Sb6 has a large, complex unit cell and is composed of relatively earth-abundant and non-toxic elements, making it an attractive candidate for thermoelectric applications. The structure of Sr5Al2Sb6 is characterized by infinite oscillating chains of AlSb4 tetrahedra. It is distinct from the structure type of the previously studied Ca5M2Sb6 compounds (M = Al, Ga or In), all of which have been shown to have promising thermoelectric performance. The lattice thermal conductivity of Sr5Al2Sb6 (~0.55 W mK(-1) at 1000 K) was found to be lower than that of the related Ca5M2Sb6 compounds due to its larger unit cell (54 atoms per primitive cell). Density functional theory predicts a relatively large band gap in Sr5Al2Sb6, in agreement with the experimentally determined band gap of E(g) ~ 0.5 eV. High temperature electronic transport measurements reveal high resistivity and high Seebeck coefficients in Sr5Al2Sb6, consistent with the large band gap and valence-precise structure. Doping with Zn(2+) on the Al(3+) site was attempted, but did not lead to the expected increase in carrier concentration. The low lattice thermal conductivity and large band gap in Sr5Al2Sb6 suggest that, if the carrier concentration can be increased, thermoelectric performance comparable to that of Ca5Al2Sb6 could be achieved in this system. PMID- 24469025 TI - Structural, magnetic and electronic state characterization of L1 0-type ordered FeNi alloy extracted from a natural meteorite. AB - To understand the hard magnetism of L10-type ordered FeNi alloy, we extracted the L10-FeNi phase from a natural meteorite, and evaluated its fundamental solid state properties: sample composition, magnetic hysteresis, crystal structure and electronic structure. We executed multidirectional analyses using scanning electron microscopy with an electron probe micro-analyzer (SEM-EPMA), a superconducting quantum interference device (SQUID), x-ray diffraction (XRD) and magnetic circular dichroism (MCD). As a result, we found that the composition was Fe: 50.47 +/- 1.98 at.%, Ni: 49.60 +/- 1.49 at.%, and an obvious superlattice peak is confirmed. The estimated degree of order was 0.608, with lattice constants a = b = 3.582 A and c = 3.607 A. The obtained coercivity was more than 500 Oe. MCD analysis using the K absorption edge suggests that the magnetic anisotropy could originate from the orbital magnetic moment of 3d electrons in Fe; this result is consistent with that in a previous report obtained with synthetic L10-FeNi. PMID- 24469026 TI - Increased levels of asymmetric dimethylarginine are associated with pulmonary arterial hypertension in HIV infection. AB - OBJECTIVE: To examine the relationship between asymmetric dimethylarginine (ADMA) and HIV-associated pulmonary arterial hypertension (PAH). DESIGN: HIV infection is an independent risk factor for PAH, but the underlying pathogenesis remains unclear. Chronic inflammation resulting in nitric oxide-mediated endothelial dysfunction is a key mechanism underlying other types of PAH. ADMA is an endogenous inhibitor of endothelial nitric oxide synthase. Among uninfected individuals, ADMA is associated with PAH and predicts disease-related mortality. METHODS: We measured ADMA, high sensitivity C-reactive protein, interleukin-6 (IL 6), D-dimer, and pulmonary artery systolic pressure (PASP) using echocardiography in HIV-infected individuals. Right heart catheterization (RHC) was performed in individuals with a PASP at least 30 mmHg. We performed multivariable analysis to identify factors associated with high PASP by echocardiogram and PAH by RHC. RESULTS: Among 214 HIV-infected individuals, the median age was 50 years, 82% were men, 71% were on antiretroviral therapy, and 4.2% carried a prior diagnosis of PAH. ADMA and IL-6 were associated with increased values of PASP following multivariable adjustment (7.2% per 0.1 MUmol/l, P = 0.0049 and 3.9% per doubling, P = 0.027, respectively). In adjusted analysis among the 85 participants who underwent RHC, ADMA and IL-6 were associated with higher values of mean PAP (14.2% per 0.1 MUmol/l, P = 0.0014 and 5.8% per doubling, P = 0.038, respectively). However, only ADMA was associated with PAH (prevalence ratio = 1.74, P = 0.029). CONCLUSION: Elevated levels of ADMA are independently associated with PAH among HIV-infected individuals. Our findings suggest that chronic HIV-associated inflammation leading to an accumulation of ADMA and subsequent nitric oxide-mediated endothelial dysfunction may represent a novel mechanism for HIV-associated PAH. PMID- 24469028 TI - Fat-plug myringoplasty of ear lobule vs abdominal donor sites. AB - The purpose of this study is to compare the success rates of fat-graft myringoplasties harvesting adipose grafts from different donor sites (ear lobule vs abdomen). The clinical records of 61 patients (24 males and 37 females) who underwent fat-plug myringoplasty (FPM) were reviewed retrospectively. Fat from ear lobule (FEL) and abdominal fat were used as graft materials. The impact of age, gender, systemic diseases, topography of the perforation, utilization of fat graft materials of different origin on the tympanic membrane closure rate and the effect of FPM on hearing gain was analyzed. Our tympanic membrane (TM) closure rate was 82 %. No statistical significant difference was observed regarding age, gender, comorbidities (septal deviation, hypertension and diabetes mellitus) or habits (smoking). Posterior TM perforations had significantly lower healing rate. The change in TM closure rate considering different adipose tissue donor sites was not statistically significant. The hearing gain of the patients was mostly below 20 dB. Fat-plug myringoplasty (FPM) is a safe, cost-effective and easy operation for selected patients. Abdominal fat graft is as effective as ear lobe fat graft on tympanic membrane healing, has cosmetic advantages and should be taken into consideration when planning fat as the graft source. PMID- 24469027 TI - Inlay butterfly cartilage tympanoplasty in the treatment of dry central perforated chronic otitis media as an effective and time-saving procedure. AB - The aim of this study is to compare the inlay butterfly transcanal cartilage tympanoplasty with the conventional underlay tympanoplasty. Operation time, pre- and postoperative hearing levels, successful closure rate of tympanic membrane (take rate) and long-term re-perforation in dry perforated chronic otitis media were evaluated. The study design consists of case series with a chart review. The study settings are tertiary referral center. Of the 72 patients (age range 14-57 years) with dry perforated chronic otitis media, 29 patients underwent inlay butterfly transcanal cartilage tympanoplasty (group 1) and 43 patients underwent conventional underlay tympanoplasty without mastoidectomy (group 2) between January 2010 and June 2012. The outcome measures were the duration of surgery, "take rate" at the 30th postoperative day and the audiometric results at the 45th postoperative day. Long-term re-perforation was evaluated at least postoperative 1 year. The graft take rate was 96.5 % in group 1 and 90.7 % in group 2 at the 30th postoperative day (p > 0.05). Mean air-bone gap was improved from 18.8 +/- 8.09 to 11.9 +/- 7.12 dB in group 1 and from 21.9 +/- 7.32 to 11.6 +/- 8.43 dB in group 2. The improvement of air-bone gap in both groups was statistically significant (p < 0.05) but the improvement between the groups was not statistically significant (p > 0.05). The average duration of the surgery was 29.9 +/- 5.38 min for inlay tympanoplasty group and 58.9 +/- 12.1 min for underlay tympanoplasty group (p < 0.05). Two patients in group 2 had re perforations after an initial take of the graft in 1-year follow-up period. Inlay butterfly transcanal cartilage tympanoplasty is a good choice in selected cases. Although this technique has the similar take rate and audiological results with conventional underlay tympanoplasty, it is a time-saving procedure. PMID- 24469029 TI - Garden-like perovskite superstructures with enhanced photocatalytic activity. AB - By subjecting amorphous flower-like TiO2 to a facile hydrothermal synthesis in the presence of Sr(2+), garden-like perovskite SrTiO3 superstructures were achieved. The amorphous TiO2 was preformed using ZnO flowers as templates. Different three-dimensional SrTiO3 architectures were coexisted in the garden, including SrTiO3 flowers composed of several hollow sword-shaped petals, many sheet-shaped petals or numerous flake-shaped petals, and SrTiO3 grass consisting of a number of long blades. These SrTiO3 superstructures were simultaneously grown on fluorine-doped tin oxide (FTO) substrates. On the basis of a comprehensive study on the effects of growth time, temperature, initial concentrations of precursor, and pH, the formation of these various hierarchical architectures was attributed primarily to the dissolution of amorphous TiO2 and precipitation of perovskite crystals, followed by the Ostwald ripening process of perovskite nanocrystals and self-organization of perovskite building blocks. Interestingly, this approach can be readily extended to create other perovskite structures, including dendritic BaTiO3 and nest-like CaTiO3, as well as PbTiO3 transformed from plate-like pyrochlore Pb2Ti2O6 after post-thermal treatment. Garden-like SrTiO3 superstructures showed a superior photocatalytic performance when compared to other as-prepared semiconductors and perovskite materials (i.e., ZnO, TiO2, BaTiO3, CaTiO3 and PbTiO3), probably due to their intrinsic photocatalytic activity and special garden-like features with a coexistence of various structures that significantly facilitated the adsorption and diffusion of methyl blue (MB) molecules and oxygen species in the photochemical reaction of MB degradation. PMID- 24469030 TI - Mechanisms and consequences of constitutive NF-kappaB activation in B-cell lymphoid malignancies. AB - The discovery of constitutive nuclear factor-kappaB (NF-kappaB) activation in Hodgkin's lymphoma tumor cells almost two decades ago was one of the first reports that directly connected deregulated NF-kappaB signaling to human cancer. Subsequent studies demonstrated that enhanced NF-kappaB signaling is a common hallmark of many lymphoid malignancies, including Hodgkin lymphoma, mucosa associated lymphoid tissue lymphoma, diffuse large B-cell lymphoma and multiple myeloma. By inducing an anti-apoptotic and pro-proliferative gene program, NF kappaB is involved in lymphoma survival and growth. Identification of somatic mutations that led to activation of oncogenes and inactivation of tumor suppressor genes in the pathway revealed that specific pathogenic mechanisms are responsible for constitutive NF-kappaB activation in different lymphoma entities. Thus, the identification of distinct oncogenic events is reflecting the diverse cellular origins of the different lymphomas. Further, elucidation of the mechanisms that drive NF-kappaB in lymphoma is of high clinical relevance as it will allow the design of target-directed precision therapy. Indeed, a number of drugs that impair constitutive NF-kappaB activation in lymphoid malignancies are currently in preclinical or clinical development. PMID- 24469031 TI - Mitochondrial ion channels as oncological targets. AB - Mitochondria, the key bioenergetic intracellular organelles, harbor a number of proteins with proven or hypothetical ion channel functions. Growing evidence points to the important contribution of these channels to the regulation of mitochondrial function, such as ion homeostasis imbalances profoundly affecting energy transducing processes, reactive oxygen species production and mitochondrial integrity. Given the central role of mitochondria in apoptosis, their ion channels with the potential to compromise mitochondrial function have become promising targets for the treatment of malignancies. Importantly, in vivo evidence demonstrates the involvement of the proton-transporting uncoupling protein, a mitochondrial potassium channel, the outer membrane located porin and the permeability transition pore in tumor progression/control. In this review, we focus on mitochondrial channels that have been assigned a definite role in cell death regulation and possess clear oncological relevance. Overall, based on in vivo and in vitro genetic and pharmacological evidence, mitochondrial ion channels are emerging as promising targets for cancer treatment. PMID- 24469032 TI - A link between inflammation and metastasis: serum amyloid A1 and A3 induce metastasis, and are targets of metastasis-inducing S100A4. AB - S100A4 is implicated in metastasis and chronic inflammation, but its function remains uncertain. Here we establish an S100A4-dependent link between inflammation and metastatic tumor progression. We found that the acute-phase response proteins serum amyloid A (SAA) 1 and SAA3 are transcriptional targets of S100A4 via Toll-like receptor 4 (TLR4)/nuclear factor-kappaB signaling. SAA proteins stimulated the transcription of RANTES (regulated upon activation normal T-cell expressed and presumably secreted), G-CSF (granulocyte-colony-stimulating factor) and MMP2 (matrix metalloproteinase 2), MMP3, MMP9 and MMP13. We have also shown for the first time that SAA stimulate their own transcription as well as that of proinflammatory S100A8 and S100A9 proteins. Moreover, they strongly enhanced tumor cell adhesion to fibronectin, and stimulated migration and invasion of human and mouse tumor cells. Intravenously injected S100A4 protein induced expression of SAA proteins and cytokines in an organ-specific manner. In a breast cancer animal model, ectopic expression of SAA1 or SAA3 in tumor cells potently promoted widespread metastasis formation accompanied by a massive infiltration of immune cells. Furthermore, coordinate expression of S100A4 and SAA in tumor samples from colorectal carcinoma patients significantly correlated with reduced overall survival. These data show that SAA proteins are effectors for the metastasis-promoting functions of S100A4, and serve as a link between inflammation and tumor progression. PMID- 24469033 TI - Targeting the epigenetic machinery of cancer cells. AB - Cancer is characterized by uncontrolled cell growth and the acquisition of metastatic properties. In most cases, the activation of oncogenes and/or deactivation of tumour suppressor genes lead to uncontrolled cell cycle progression and inactivation of apoptotic mechanisms. Although the underlying mechanisms of carcinogenesis remain unknown, increasing evidence links aberrant regulation of methylation to tumourigenesis. In addition to the methylation of DNA and histones, methylation of nonhistone proteins, such as transcription factors, is also implicated in the biology and development of cancer. Because the metabolic cycling of methionine is a key pathway for many of these methylating reactions, strategies to target the epigenetic machinery of cancer cells could result in novel and efficient anticancer therapies. The application of these new epigenetic therapies could be of utility in the promotion of E2F1-dependent apoptosis in cancer cells, in avoiding metastatic pathways and/or in sensitizing tumour cells to radiotherapy. PMID- 24469034 TI - Loss of epithelial p53 and alphav integrin cooperate through Akt to induce squamous cell carcinoma yet prevent remodeling of the tumor microenvironment. AB - Most of the squamous cell carcinomas (SCCs) of the skin and head and neck contain p53 mutations. The presence of p53 mutations in premalignant lesions suggests that they represent early events during tumor progression and additional alterations may be required for SCC development. Here we show that codeletion of the p53 and alphav integrin genes in mouse stratified epithelia induced SCCs in 100% of the mice, more frequently and with much shorter latency than deletion of either gene alone. The SCCs that lacked p53 and alphav in the epithelial tumor cells exhibited high Akt activity, lacked multiple types of infiltrating immune cells, contained a defective vasculature and grew slower than tumors that expressed p53 or alphav. These results reveal that loss of alphav in epithelial cells that lack p53 promotes SCC development, but also prevents remodeling of the tumor microenvironment and delays tumor growth. We observed that Akt inactivation in SCC cells that lack p53 and alphav promoted anoikis. Thus, tumors may arise in these mice as a result of the increased cell survival induced by Akt activation triggered by loss of alphav and p53, and by the defective recruitment of immune cells to these tumors, which may allow immune evasion. However, the defective vasculature and lack of a supportive stroma create a restrictive microenvironment in these SCCs that slows their growth. These mechanisms may underlie the rapid onset and slow growth of SCCs that lack p53 and alphav. PMID- 24469035 TI - Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes. AB - Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-alpha (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER alpha/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer. PMID- 24469036 TI - KSHV vCyclin counters the senescence/G1 arrest response triggered by NF-kappaB hyperactivation. AB - Many oncogenic viruses activate nuclear factor-kappaB (NF-kappaB) as a part of their replicative cycles. We have shown recently that persistent and potentially oncogenic activation of NF-kappaB by the human T-lymphotropic virus 1 (HTLV-1) oncoprotein Tax immediately triggers a host senescence response mediated by cyclin-dependent kinase inhibitors: p21(CIP1/WAF1) (p21) and p27(Kip1) (p27) Here we demonstrate that RelA/NF-kappaB activation by Kaposi sarcoma herpesvirus (KSHV) latency protein vFLIP also leads to p21/p27 upregulation and G1 cell cycle arrest. Remarkably, KSHV vCyclin, another latency protein coexpressed with vFLIP from a bicistronic latency-specific mRNA, was found to prevent the senescence and G1 arrest induced by HTLV-1 Tax and vFLIP, respectively. This is because of the known ability of vCyclin/cyclin-dependent kinase 6 complex to resist p21 and p27 inhibition and cause p27 degradation. In KSHV-transformed BCBL-1 cells, sustained vFLIP expression with small hairpin RNAs-mediated vCyclin depletion resulted in G1 arrest. The functional interdependence of vFLIP and vCyclin explains why they are cotranslated from the same viral mRNA. Importantly, deregulation of the G1 cyclin-dependent kinase can facilitate chronic I-kappaB kinases/NF-kappaB activation. PMID- 24469037 TI - Structural proteins of Kaposi's sarcoma-associated herpesvirus antagonize p53 mediated apoptosis. AB - The tumor suppressor p53 is a central regulatory molecule of apoptosis and is commonly mutated in tumors. Kaposi's sarcoma-associated herpesvirus (KSHV) related malignancies express wild-type p53. Accordingly, KSHV encodes proteins that counteract the cell death-inducing effects of p53. Here, the effects of all KSHV genes on the p53 signaling pathway were systematically analyzed using the reversely transfected cell microarray technology. With this approach we detected eight KSHV-encoded genes with potent p53 inhibiting activity in addition to the previously described inhibitory effects of KSHV genes ORF50, K10 and K10.5. Interestingly, the three most potent newly identified inhibitors were KSHV structural proteins, namely ORF22 (glycoprotein H), ORF25 (major capsid protein) and ORF64 (tegument protein). Validation of these results with a classical transfection approach showed that these proteins inhibited p53 signaling in a dose-dependent manner and that this effect could be reversed by small interfering RNA-mediated knockdown of the respective viral gene. All three genes inhibited p53-mediated apoptosis in response to Nutlin-3 treatment in non-infected and KSHV infected cells. Addressing putative mechanisms, we could show that these proteins could also inhibit the transactivation of the promoters of apoptotic mediators of p53 such as BAX and PIG3. Altogether, we demonstrate for the first time that structural proteins of KSHV can counteract p53-induced apoptosis. These proteins are expressed in the late lytic phase of the viral life cycle and are incorporated into the KSHV virion. Accordingly, these genes may inhibit cell death in the productive and in the early entrance phase of KSHV infection. PMID- 24469038 TI - Wig-1 regulates cell cycle arrest and cell death through the p53 targets FAS and 14-3-3sigma. AB - Wig-1, also known as ZMAT3, is a p53 target gene that encodes an RNA-binding zinc finger protein involved in the regulation of mRNA stability through binding to AU rich elements (AREs). We have used microarray analysis to identify novel Wig-1 target mRNAs. We identified 2447 transcripts with >fourfold differential expression between Wig-1 and control small interfering (si)RNA-treated HCT116 cells. Several p53 target genes were among the deregulated transcripts. We found that Wig-1 regulates FAS and 14-3-3sigma mRNA independently of p53. We show that Wig-1 binds to FAS mRNA 3'-UTR and decreases its stability through an ARE in the 3'-UTR. Depletion of Wig-1 was associated with increased cell death and reduced cell cycle arrest upon DNA damage. Our results suggest a role of Wig-1 as a survival factor that directs the p53 stress response toward cell cycle arrest rather than apoptosis through the regulation of FAS and 14-3-3sigma mRNA levels. PMID- 24469039 TI - Helicobacter pylori might contribute to cancer and/or bone marrow-derived stem cell-related gastrointestinal oncogenesis. PMID- 24469040 TI - Oncogenic Y641 mutations in EZH2 prevent Jak2/beta-TrCP-mediated degradation. AB - EZH2 (enhancer of zeste homolog 2) is a critical enzymatic subunit of the polycomb repressive complex 2 (PRC2), which trimethylates histone H3 (H3K27) to mediate gene repression. Somatic mutations, overexpression and hyperactivation of EZH2 have been implicated in the pathogenesis of several forms of cancer. In particular, recurrent gain-of-function mutations targeting EZH2 Y641 occur most frequently in follicular lymphoma and aggressive diffuse large B-cell lymphoma and are associated with H3K27me3 hyperactivation, which contributes to lymphoma pathogenesis. However, the post-translational mechanisms of EZH2 regulation are not completely understood. Here we show that EZH2 is a novel interactor and substrate of the SCF E3 ubiquitin ligase beta-TrCP (FBXW1). beta-TrCP ubiquitinates EZH2 and Jak2-mediated phosphorylation on Y641 directs beta-TrCP mediated EZH2 degradation. RNA interference-mediated silencing of beta-TrCP or inhibition of Jak2 results in EZH2 stabilization with attendant increase in H3K27 trimethylation activity. Importantly, the EZH2(Y641) mutants recurrently implicated in lymphoma pathogenesis are unable to bind beta-TrCP. Further, endogenous EZH2(Y641) mutants in lymphoma cells exhibit increased EZH2 stability and H3K27me3 hyperactivity. Our studies demonstrate that beta-TrCP has an important role in controlling H3K27 trimethylation activity and lymphoma pathogenesis by targeting EZH2 for degradation. PMID- 24469041 TI - Arf tumor suppressor disrupts the oncogenic positive feedback loop including c Myc and DDX5. AB - Tumor suppressor protein p19(ARF) (Arf; p14(ARF) in humans) functions in both p53 dependent and -independent modes to counteract hyper-proliferative signals caused by proto-oncogene activation, but its p53-independent activities remain poorly understood. Using the tandem affinity purification-tag technique, we purified Arf containing protein complexes and identified p68 DEAD-box protein (DDX5) as a novel interacting protein of Arf. In this study, we found that DDX5 interacts with c-Myc, and harbors essential roles for c-Myc-mediated transcription and its transforming activity. Furthermore, when c-Myc was forcibly expressed, the expression level of DDX5 protein was drastically increased through the acceleration of protein synthesis of DDX5, suggesting the presence of an oncogenic positive feedback loop including c-Myc and DDX5. Strikingly, Arf blocked the physical interaction between DDX5 and c-Myc, and drove away DDX5 from the promoter of c-Myc target genes. These observations most likely indicate the mechanism by which Arf causes p53-independent tumor-suppressive activity. PMID- 24469042 TI - SPRED1, a RAS MAPK pathway inhibitor that causes Legius syndrome, is a tumour suppressor downregulated in paediatric acute myeloblastic leukaemia. AB - Constitutional dominant loss-of-function mutations in the SPRED1 gene cause a rare phenotype referred as neurofibromatosis type 1 (NF1)-like syndrome or Legius syndrome, consisted of multiple cafe-au-lait macules, axillary freckling, learning disabilities and macrocephaly. SPRED1 is a negative regulator of the RAS MAPK pathway and can interact with neurofibromin, the NF1 gene product. Individuals with NF1 have a higher risk of haematological malignancies. SPRED1 is highly expressed in haematopoietic cells and negatively regulates haematopoiesis. SPRED1 seemed to be a good candidate for leukaemia predisposition or transformation. We performed SPRED1 mutation screening and expression status in 230 paediatric lymphoblastic and acute myeloblastic leukaemias (AMLs). We found a loss-of-function frameshift SPRED1 mutation in a patient with Legius syndrome. In this patient, the leukaemia blasts karyotype showed a SPRED1 loss of heterozygosity, confirming SPRED1 as a tumour suppressor. Our observation confirmed that acute leukaemias are rare complications of the Legius syndrome. Moreover, SPRED1 was significantly decreased at RNA and protein levels in the majority of AMLs at diagnosis compared with normal or paired complete remission bone marrows. SPRED1 decreased expression correlated with genetic features of AML. Our study reveals a new mechanism which contributes to deregulate RAS MAPK pathway in the vast majority of paediatric AMLs. PMID- 24469044 TI - The von Hippel-Lindau tumor suppressor regulates programmed cell death 5-mediated degradation of Mdm2. AB - Functional loss of the von Hippel-Lindau (VHL) tumor suppressor protein (pVHL), which is part of an E3-ubiquitin ligase complex, initiates most inherited and sporadic clear-cell renal cell carcinomas (ccRCC). Genetic inactivation of the TP53 gene in ccRCC is rare, suggesting that an alternate mechanism alleviates the selective pressure for TP53 mutations in ccRCC. Here we use a zebrafish model to describe the functional consequences of pVHL loss on the p53/Mdm2 pathway. We show that p53 is stabilized in the absence of pVHL and becomes hyperstabilized upon DNA damage, which we propose is because of a novel in vivo interaction revealed between human pVHL and a negative regulator of Mdm2, the programmed cell death 5 (PDCD5) protein. PDCD5 is normally localized at the plasma membrane and in the cytoplasm. However, upon hypoxia or loss of pVHL, PDCD5 relocalizes to the nucleus, an event that is coupled to the degradation of Mdm2. Despite the subsequent hyperstabilization and normal transcriptional activity of p53, we find that zebrafish vhl(-/-) cells are still as highly resistant to DNA damage-induced cell cycle arrest and apoptosis as human ccRCC cells. We suggest this is because of a marked increase in expression of birc5a, the zebrafish homolog of Survivin. Accordingly, when we knock down Survivin in human ccRCC cells we are able to restore caspase activity in response to DNA damage. Taken together, our study describes a new mechanism for p53 stabilization through PDCD5 upon hypoxia or pVHL loss, and reveals new clinical potential for the treatment of pathobiological disorders linked to hypoxic stress. PMID- 24469043 TI - Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis. AB - The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of nuclear factor (NF)kappaB through Galphai. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2 NFkappaB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis. PMID- 24469045 TI - PRC2-independent chromatin compaction and transcriptional repression in cancer. AB - The silencing of large chromosomal regions by epigenetic mechanisms has been reported to occur frequently in cancer. Epigenetic marks, such as histone methylation and acetylation, are altered at these loci. However, the mechanisms of formation of such aberrant gene clusters remain largely unknown. Here, we show that, in cancer cells, the epigenetic remodeling of chromatin into hypoacetylated domains covered with histone H3K27 trimethylation is paralleled by changes in higher-order chromatin structures. Using fluorescence in situ hybridization, we demonstrate that regional epigenetic silencing corresponds to the establishment of compact chromatin domains. We show that gene repression is tightly correlated to the state of chromatin compaction and not to the levels of H3K27me3-its removal through the knockdown of EZH2 does not induce significant gene expression nor chromatin decompaction. Moreover, transcription can occur with intact high H3K27me3 levels; treatment with histone deacetylase inhibitors can relieve chromatin compaction and gene repression, without altering H3K27me3 levels. Our findings imply that compaction and subsequent repression of large chromatin domains are not direct consequences of PRC2 deregulation in cancer cells. By challenging the role of EZH2 in aberrant gene silencing in cancer, these findings have therapeutical implications, notably for the choice of epigenetic drugs for tumors with multiple regional epigenetic alterations. PMID- 24469046 TI - Casein kinase 1 regulates Sprouty2 in FGF-ERK signaling. AB - Sprouty2 (SPRY2) is a potent negative regulator of receptor tyrosine kinase signaling, and is implicated as a tumor suppressor. SPRY2 inhibits FGF-RAS-ERK signaling by binding to growth factor receptor bound protein 2 (GRB2) during fibroblast growth factor receptor (FGFR) activation, disrupting the GRB2-SOS (son of sevenless) complex that transduces signals from FGFR to RAS. SPRY2 binding to GRB2 is modulated by phosphorylation but the key regulatory kinase(s) are not known. Prior studies identified the frequent presence of CK1 phosphorylation motifs on SPRY2. We therefore tested if CK1 has a role in SPRY2 phosphorylation and function. Loss of CK1 binding and inhibition of CK1 activity by two structurally distinct small molecules abrogated SPRY2 inhibition of FGF-ERK signaling, leading to decreased SPRY2 interaction with GRB2. Moreover, CK1 activity and binding are necessary for SPRY2 inhibition of FGF-stimulated neurite outgrowth in PC12 cells. Consistent with its proposed role as an inhibitor of FGF signaling, we find that CSNK1E transcript abundance negatively correlates with FGF1/FGF7 message in human gastric cancer samples. Modulation of CK1 activity may be therapeutically useful in the treatment of FGF/SPRY2-related diseases. PMID- 24469048 TI - Juvenile myelomonocytic leukaemia-associated mutation in Cbl promotes resistance to apoptosis via the Lyn-PI3K/AKT pathway. AB - Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloproliferative neoplasm in children characterized by granulocyte macrophage colony-stimulating factor (GM-CSF) hypersensitivity and resistance to chemotherapy. We recently identified c-Cbl (henceforth referred to as Cbl) as a GM-CSF receptor (GMR) responsive protein that targets Src for ubiquitin-mediated destruction upon GM CSF stimulation and showed that a loss of negative regulation of Src is pivotal in the hyperactivation of GMR signalling in JMML cells. However, the mechanism regulating the chemoresistant nature of JMML has remained largely unknown. Here, we show that the JMML-associated Cbl mutant in complex with the Src family kinase Lyn promotes Cbl's adapter function, leading to increased association to PI3K regulatory subunit p85 and Lyn-dependent AKT pro-survival signalling. Notably, molecular or pharmacologic inhibition of the Lyn-PI3K/AKT pathway, but not the Ras/mitogen-activated protein kinase signalling axis, markedly increased the sensitivity of the otherwise chemoresistant Cbl mutant-JMML cells to chemotherapeutic agents currently used in the treatment of JMML patients. These results support the potential translational benefit of combining modalities that inhibit Lyn-PI3K/AKT signalling with traditional antileukaemia agents in the management of JMML. PMID- 24469047 TI - Elafin drives poor outcome in high-grade serous ovarian cancers and basal-like breast tumors. AB - High-grade serous ovarian carcinoma (HGSOC) and basal-like breast cancer (BLBC) share many features including TP53 mutations, genomic instability and poor prognosis. We recently reported that Elafin is overexpressed by HGSOC and is associated with poor overall survival. Here, we confirm that Elafin overexpression is associated with shorter survival in 1000 HGSOC patients. Elafin confers a proliferative advantage to tumor cells through the activation of the MAP kinase pathway. This mitogenic effect can be neutralized by RNA interference, specific antibodies and a MEK inhibitor. Elafin expression in patient-derived samples was also associated with chemoresistance and strongly correlates with bcl xL expression. We extended these findings into the examination of 1100 primary breast tumors and six breast cancer cell lines. We observed that Elafin is overexpressed and secreted specifically by BLBC tumors and cell lines, leading to a similar mitogenic effect through activation of the MAP kinase pathway. Here too, Elafin overexpression is associated with poor overall survival, suggesting that it may serve as a biomarker and therapeutic target in this setting. PMID- 24469049 TI - TFAP2C governs the luminal epithelial phenotype in mammary development and carcinogenesis. AB - Molecular subtypes of breast cancer are characterized by distinct patterns of gene expression that are predictive of outcome and response to therapy. The luminal breast cancer subtypes are defined by the expression of estrogen receptor alpha (ERalpha)-associated genes, many of which are directly responsive to the transcription factor activator protein 2C (TFAP2C). TFAP2C participates in a gene regulatory network controlling cell growth and differentiation during ectodermal development and regulating ESR1/ERalpha and other luminal cell-associated genes in breast cancer. TFAP2C has been established as a prognostic factor in human breast cancer, however, its role in the establishment and maintenance of the luminal cell phenotype during carcinogenesis and mammary gland development have remained elusive. Herein, we demonstrate a critical role for TFAP2C in maintaining the luminal phenotype in human breast cancer and in influencing the luminal cell phenotype during normal mammary development. Knockdown of TFAP2C in luminal breast carcinoma cells induced epithelial-mesenchymal transition with morphological and phenotypic changes characterized by a loss of luminal associated gene expression and a concomitant gain of basal-associated gene expression. Conditional knockout of the mouse homolog of TFAP2C, Tcfap2c, in mouse mammary epithelium driven by MMTV-Cre promoted aberrant growth of the mammary tree leading to a reduction in the CD24(hi)/CD49f(mid) luminal cell population and concomitant gain of the CD24(mid)/CD49f(hi) basal cell population at maturity. Our results establish TFAP2C as a key transcriptional regulator for maintaining the luminal phenotype in human breast carcinoma. Furthermore, Tcfap2c influences development of the luminal cell type during mammary development. The data suggest that TFAP2C has an important role in regulated luminal-specific genes and may be a viable therapeutic target in breast cancer. PMID- 24469050 TI - Global identification of genes targeted by DNMT3b for epigenetic silencing in lung cancer. AB - The maintenance cytosine DNA methyltransferase DNMT1 and de novo methyltransferase DNMT3b cooperate to establish aberrant DNA methylation and chromatin complexes to repress gene transcription during cancer development. The expression of DNMT3b was constitutively increased 5-20-fold in hTERT/CDK4 immortalized human bronchial epithelial cells (HBECs) before treatment with low doses of tobacco carcinogens. Overexpression of DNMT3b increased and accelerated carcinogen-induced transformation. Genome-wide profiling of transformed HBECs identified 143 DNMT3b-target genes, many of which were transcriptionally regulated by the polycomb repressive complex 2 (PRC2) complex and silenced through aberrant methylation in non-small-cell lung cancer cell lines. Two genes studied in detail, MAL and OLIG2, were silenced during transformation, initially through enrichment for H3K27me3 and H3K9me2, commonly methylated in lung cancer, and exert tumor suppressor effects in vivo through modulating cancer-related pathways. Re-expression of MAL and OLIG2 to physiological levels dramatically reduced the growth of lung tumor xenografts. Our results identify a key role for DNMT3b in the earliest stages of initiation and provide a comprehensive catalog of genes targeted for silencing by this methyltransferase in non-small-cell lung cancer. PMID- 24469051 TI - Selective killing of lung cancer cells by miRNA-506 molecule through inhibiting NF-kappaB p65 to evoke reactive oxygen species generation and p53 activation. AB - The tumor suppressor p53, nuclear factor-kappaB (NF-kappaB) and reactive oxygen species (ROS) have crucial roles in tumorigenesis, although the mechanisms of cross talk between these factors remain largely unknown. Here we report that miR 506 upregulation occurs in 83% of lung cancer patients (156 cases), and its expression highly correlates with ROS. Ectopic expression of miR-506 inhibits NF kappaB p65 expression, induces ROS accumulation and then activates p53 to suppress lung cancer cell viability, but not in normal cells. Interestingly, p53 promotes miR-506 expression level, indicating that miR-506 mediates cross talk between p53, NF-kappaB p65 and ROS. Furthermore, we demonstrated that miR-506 mimics inhibited tumorigenesis in vivo, implicating that miR-506 might be a potential therapeutic molecule for selective killing of lung cancer cells. PMID- 24469052 TI - p53 suppresses carcinoma progression by inhibiting mTOR pathway activation. AB - Genetic alterations in human cancers and murine models indicate that retinoblastoma (Rb) and p53 have critical tumor suppressive functions in retinoblastoma, a tumor of neural origin, and neuroendocrine tumors including small cell lung cancer and medullary thyroid cancer (MTC). Rb inactivation is the initiating lesion in retinoblastoma and current models propose that induction of apoptosis is a key p53 tumor suppressive function. Genetic studies in mice, however, indicate that other undefined p53 tumor suppressive functions are operative in vivo. How p53 loss cooperates with Rb inactivation to promote carcinogenesis is also not fully understood. In the current study, genetically engineered mice were generated to determine the role of Rb and p53 in MTC pathogenesis and test the hypothesis that p53 suppresses carcinogenesis by inhibiting mammalian target of rapamycin (mTOR) signaling. Conditional Rb ablation resulted in thyroid tumors mimicking human MTC, and additional p53 loss led to rapid tumor progression. p53 suppressed tumorigenesis by inhibiting cell cycle progression, but did not induce apoptosis. On the contrary, p53 loss led to increased apoptosis that had to be overcome for tumor progression. The mTOR activity was markedly increased in p53-deficient tumors and rapamycin treatment suppressed tumor cell growth, identifying mTOR inhibition as a critical p53 tumor suppressive function. Rapamycin treatment did not result in AKT/mitogen-activated protein kinase activation, providing evidence that this feedback mechanism operative in other cancers is not a general response to mTORC1 inhibition. Together, these studies provide mechanistic links between genetic alterations and aberrant signaling pathways critical in carcinogenesis, and identify essential Rb and p53 tumor suppressive functions in vivo. PMID- 24469053 TI - TRIM24 promotes glioma progression and enhances chemoresistance through activation of the PI3K/Akt signaling pathway. AB - The tripartite motif protein TRIM24 (tripartite motif-containing 24) has been found to play distinct roles in tumor development and progression, according to different tumor contexts. However, it remains elusive whether TRIM24 plays a role in malignant gliomas that are the most common and deadly primary brain tumors in adults. We report here that TRIM24 expression is positively correlated with glioma malignancy and is negatively associated with prognosis of patients with newly diagnosed glioblastoma, which is the most malignant form of gliomas but displays highly heterogeneous clinical outcome. The multivariate Cox regression analysis demonstrates the independent predictive value of TRIM24 expression level for overall and progression-free survival. Knockdown of TRIM24 suppresses cell proliferation, cell cycle progression, clone formation and in vivo tumor development, whereas overexpression of TRIM24 promotes cell growth. Chromatin immunoprecipitation, real-time reverse transcription-PCR and mutation analyses demonstrate that TRIM24 binds to the PIK3CA promoter via its PHD-Bromo domain to activate the transcription of PIK3CA gene, thus enhancing phosphatidylinositide 3 kinase (PI3K)/Akt signaling. The pan-PI3K inhibitor LY294002 and small interfering RNA targeting PIK3CA both abrogate the growth-promoting effect of TRIM24. Moreover, TRIM24 regulates the expression of DNA repair enzyme O(6) methylguanine-DNA methyltransferase (MGMT) through PI3K/Akt/nuclear factor-kappaB signaling transduction and enhances resistance to temozolomide, the standard chemotherapeutic agent for glioblastoma. Finally, glioblastoma patients with low TRIM24 expression benefit from chemotherapy, whereas those with high TRIM24 expression do not have such benefit. Our results suggest that TRIM24 might serve as a potential prognostic marker and therapeutic target for the management of malignant gliomas. PMID- 24469054 TI - ASC deficiency suppresses proliferation and prevents medulloblastoma incidence. AB - Apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC) is silenced by promoter methylation in many types of tumors, yet ASC's role in most cancers remains unknown. Here, we show that ASC is highly expressed in a model of medulloblastoma, the most common malignant pediatric brain cancer; ASC is also expressed in human medulloblastomas. Importantly, while ASC deficiency did not affect normal cerebellar development, ASC knockout mice on the Smoothened (ND2:SmoA1) transgenic model of medulloblastoma exhibited a profound reduction in medulloblastoma incidence and a delayed tumor onset. A similar decrease in tumorigenesis with ASC deficiency was also seen in the hGFAP-Cre:SmoM2 mouse model of medulloblastoma. Interestingly, hyperproliferation of the external granule layer (EGL) was comparable at P20 in both wild-type and ASC-deficient SmoA1 mice. However, while the apoptosis and differentiation markers remained unchanged at this age, proliferation makers were decreased, and the EGL was reduced in thickness and area by P60. This reduction in proliferation with ASC deficiency was also seen in isolated SmoA1 cerebellar granule precursor cells in vitro, indicating that the effect of ASC deletion on proliferation was cell autonomous. Interestingly, ASC-deficient SmoA1 cerebella exhibited disrupted expression of genes in the transforming growth factor-beta pathway and increased level of nuclear Smad3. Taken together, these results demonstrate an unexpected role for ASC in Sonic hedgehog-driven medulloblastoma tumorigenesis, thus identifying ASC as a promising novel target for antitumor therapy. PMID- 24469055 TI - Oncogenic RIT1 mutations in lung adenocarcinoma. AB - Lung adenocarcinoma is comprised of distinct mutational subtypes characterized by mutually exclusive oncogenic mutations in RTK/RAS pathway members KRAS, EGFR, BRAF and ERBB2, and translocations involving ALK, RET and ROS1. Identification of these oncogenic events has transformed the treatment of lung adenocarcinoma via application of therapies targeted toward specific genetic lesions in stratified patient populations. However, such mutations have been reported in only ~55% of lung adenocarcinoma cases in the United States, suggesting other mechanisms of malignancy are involved in the remaining cases. Here we report somatic mutations in the small GTPase gene RIT1 in ~2% of lung adenocarcinoma cases that cluster in a hotspot near the switch II domain of the protein. RIT1 switch II domain mutations are mutually exclusive with all other known lung adenocarcinoma driver mutations. Ectopic expression of mutated RIT1 induces cellular transformation in vitro and in vivo, which can be reversed by combined PI3K and MEK inhibition. These data identify RIT1 as a driver oncogene in a specific subset of lung adenocarcinomas and suggest PI3K and MEK inhibition as a potential therapeutic strategy in RIT1-mutated tumors. PMID- 24469056 TI - Akt phosphorylates and activates HSF-1 independent of heat shock, leading to Slug overexpression and epithelial-mesenchymal transition (EMT) of HER2-overexpressing breast cancer cells. AB - Epithelial-mesenchymal transition (EMT) is an essential step for tumor progression, although the mechanisms driving EMT are still not fully understood. In an effort to investigate these mechanisms, we observed that heregulin (HRG) mediated activation of HER2, or HER2 overexpression, resulted in EMT, which is accompanied with increased expression of a known EMT regulator Slug, but not TWIST or Snail. We then investigated how HER2 induced Slug expression and found, for the first time, that there are four consensus HSF sequence-binding elements (HSEs), the binding sites for heat shock factor-1 (HSF-1), located in the Slug promoter. HSF-1 bound to and transactivated the Slug promoter independent of heat shock, leading to Slug expression in breast cancer cells. Mutation of the putative HSEs ablated Slug transcriptional activation induced by HRG or HSF-1 overexpression. Knockdown of HSF-1 expression by siRNA reduced Slug expression and HRG-induced EMT. The positive association between HSF-1 and Slug was confirmed by immunohistochemical staining of a cohort of 100 invasive breast carcinoma specimens. While investigating how HER2 activated HSF-1 independent of heat shock, we observed that HER2 activation resulted in concurrent phosphorylation of Akt and HSF-1. We then observed, also for the first time, that Akt directly interacted with HSF-1 and phosphorylated HSF-1 at S326. Inhibition of Akt using siRNA, dominant-negative Akt mutant, or small molecule inhibitors prevented HRG-induced HSF-1 activation and Slug expression. Conversely, constitutively active Akt induced HSF-1 phosphorylation and Slug expression. HSF 1 knockdown reduced the ability of Akt to induce Slug expression, indicating an essential role that HSF-1 plays in Akt-induced Slug upregulation. Altogether, our study uncovered the existence of a novel Akt-HSF-1 signaling axis that leads to Slug upregulation and EMT, and potentially contributes to progression of HER2 positive breast cancer. PMID- 24469057 TI - Hedgehog acyltransferase as a target in pancreatic ductal adenocarcinoma. AB - Sonic Hedgehog (Shh) is abnormally expressed in pancreatic cancer and is associated with disease onset and progression. Inhibition of Shh signaling is thus an attractive clinical target for therapeutic intervention. Most efforts to block Shh signaling have focused on inhibitors of Smoothened, which target the canonical Shh signaling pathway. These approaches have met with limited success, in part due to development of resistance-conferring mutations and contributions from non-canonical signaling pathways. Here, we show that Hedgehog acyltransferase (Hhat), the enzyme responsible for the attachment of palmitate onto Shh, is a novel target for inhibition of Shh signaling in pancreatic cancer cells. Depletion of Hhat with lentivirally delivered small hairpin RNA decreased both anchorage-dependent and independent proliferation of human pancreatic cancer cells. In vivo, Hhat knockdown led to reduction of tumor growth in a mouse xenograft model of pancreatic cancer. RU-SKI 43, a small molecule inhibitor of Hhat recently developed by our group, reduced pancreatic cancer cell proliferation and Gli-1 activation through Smoothened-independent non-canonical signaling. In addition, RU-SKI 43 treatment inhibited two key proliferative pathways regulated by Akt and mTOR. This work demonstrates that Hhat has a critical role in pancreatic cancer and that a small molecule inhibitor of Hhat can successfully block pancreatic cancer cell proliferation. It also highlights the importance of developing optimized Hhat inhibitors to be used as therapeutics in pancreatic cancer, as well as in other malignancies characterized by Shh overexpression. PMID- 24469058 TI - Growth factor receptor/steroid receptor cross talk in trastuzumab-treated breast cancer. AB - Treatment with tyrosine kinase inhibitors (TKIs) including trastuzumab has revolutionized the management of HER2-positive breast cancer. Recent evaluation of clinical trial data suggests that a subset of HER2/ER double-positive cancers may not receive significant benefit from the TKI therapy. Here we investigate the cross talk between HER2 and ER in breast cancer and monitor the effect of trastuzumab on the tyrosine kinase effector transcription factor Myc. In HER2 positive breast cancer patients treated with neoadjuvant trastuzumab, steroid receptor-negative status (ER and PR negative) of pre-treatment biopsies predicted pathological complete response (pCR) (n=31 patients, P=0.0486), whereas elevated Myc protein inversely associated with pCR (P=0.0446). Liquid chromatography mass spectrometry identified the corepressor SMRT as a novel Myc-interacting protein. Trastuzumab treatment enhanced Myc-SMRT interactions in HER2-overexpressing breast cancer cells (LCC1) and inhibited expression of the Myc target gene survivin. In HER2-low, ER-positive steroid-dominant cells (MCF7), trastuzumab therapy repressed Myc-SMRT interactions and upregulated survivin expression. Trastuzumab treatment induced ER-CBP interactions, enhanced ER transcriptional activity and upregulated expression of the ER target gene pS2. The absence of pS2 expression in pre-treatment biopsies predicted pCR to neoadjuvant trastuzumab in breast cancer patients (n=25, P=0.0089) and pS2 expression associated with residual cancer burden (P=0.0196). Furthermore, metastatic tissues from patients who had failed trastuzumab therapy were pS2 positive. In HER2-overexpressing cells, trastuzumab treatment can repress Myc transcriptional activity and clinical response is favorable. However, with co-expression of the steroid pathway, this inhibition is lost and response to treatment is often poor. PMID- 24469059 TI - A chromatin modifier genetic screen identifies SIRT2 as a modulator of response to targeted therapies through the regulation of MEK kinase activity. AB - Resistance to targeted therapies is a major problem in cancer treatment. The epidermal growth factor receptor (EGFR) antibody drugs are effective in a subset of colorectal cancers, but the molecular mechanisms of resistance are understood poorly. Genes involved in epigenetic regulation are frequently deregulated in cancer, raising the possibility that such genes also contribute to drug resistance. Using a focused RNA interference library for genes involved in epigenetic regulation, we identify sirtuin2 (SIRT2), an NAD(+)-dependent deacetylase, as a modulator of the response to EGFR inhibitors in colon and lung cancer. SIRT2 loss also conferred resistance to BRAF and MEK inhibitors in BRAF mutant melanoma and KRAS mutant colon cancers, respectively. These results warrant further investigation into the potential role of SIRT2 in resistance to drugs that act in the receptor tyrosine kinase-RAS-RAF-MEK-ERK signaling pathway. PMID- 24469060 TI - The stem cell transcription factor ZFP57 induces IGF2 expression to promote anchorage-independent growth in cancer cells. AB - Several common biological properties between cancer cells and embryonic stem (ES) cells suggest the possibility that some genes expressed in ES cells might have important roles in cancer cell growth. The transcription factor ZFP57 is expressed in self-renewing ES cells and its expression level decreases during ES cell differentiation. This study showed that ZFP57 is involved in the anchorage independent growth of human fibrosarcoma HT1080 cells in soft agar. ZFP57 overexpression enhanced, whereas knockdown suppressed, HT1080 tumor formation in nude mice. Furthermore, ZFP57 regulates the expression of insulin-like growth factor 2 (IGF2), which has a critical role in ZFP57-induced anchorage-independent growth. ZFP57 also promotes anchorage-independent growth in ES cells and immortal fibroblasts. Finally, immunohistochemical analysis revealed that ZFP57 is overexpressed in human cancer clinical specimens. Taken together, these results suggest that the ES-specific transcription factor ZFP57 is a novel oncogene. PMID- 24469061 TI - MicroRNA-193a-3p and -5p suppress the metastasis of human non-small-cell lung cancer by downregulating the ERBB4/PIK3R3/mTOR/S6K2 signaling pathway. AB - The metastatic cascade is a complex and multistep process with many potential barriers. Recent evidence has shown that microRNAs (miRNAs) are involved in carcinogenesis and tumor progression in non-small-cell lung cancer (NSCLC). In this study, by comparing the miRNA expression profiles of SPC-A-1sci (high metastatic) and SPC-A-1 (weakly metastatic) cells, we demonstrated that the downregulation and function of miR-193a-3p and miR-193a-5p in NSCLC metastasis and the expression of these miRNAs was suppressed in NSCLC compared with corresponding non-tumorous tissues. Decreased miR-193a-3p/5p expression was significantly associated with tumor node metastasis (TNM) and lymph node metastasis. Furthermore, functional assays showed that the overexpression of miR 193a-3p/5p inhibited NSCLC cell migration, invasion and epithelial-mesenchymal transition (EMT) in vitro and lung metastasis formation in vivo. In addition, we discovered that ERBB4 and S6K2 were the direct targets of miR-193a-3p and that PIK3R3 and mTOR were the direct targets of miR-193a-5p in NSCLC. We also observed that miR-193a-3p/5p could inactivate the AKT/mTOR signaling pathway. Thus, miR 193a-3p/5p functions as a tumor suppressor and has an important role in NSCLC metastasis through ERBB signaling pathway. PMID- 24469062 TI - Janus molecularly imprinted polymer particles. AB - By combining the specific molecular recognition capability of MIPs and the asymmetric structure of Janus particles, the Janus MIP particles which were synthesized via a wax-water Pickering emulsion showed attractive capabilities as self-propelled transporters for controlled drug delivery. PMID- 24469063 TI - Protein conformation as a regulator of cell-matrix adhesion. AB - The dynamic regulation of cell-matrix adhesion is essential for tissue homeostasis and architecture, and thus numerous pathologies are linked to altered cell-extracellular matrix (ECM) interaction and ECM scaffold. The molecular machinery involved in cell-matrix adhesion is complex and involves both sensory and matrix-remodelling functions. In this review, we focus on how protein conformation controls the organization and dynamics of cell-matrix adhesion. The conformational changes in various adhesion machinery components are described, including examples from ECM as well as cytoplasmic proteins. The discussed mechanisms involved in the regulation of protein conformation include mechanical stress, post-translational modifications and allosteric ligand-binding. We emphasize the potential role of intrinsically disordered protein regions in these processes and discuss the role of protein networks and co-operative protein interactions in the formation and consolidation of cell-matrix adhesion and extracellular scaffolds. PMID- 24469064 TI - Differential expression and ligand binding indicate alternative functions for zebrafish polymeric immunoglobulin receptor (pIgR) and a family of pIgR-like (PIGRL) proteins. AB - The polymeric immunoglobulin (Ig) receptor (pIgR) is an integral transmembrane glycoprotein that plays an important role in the mammalian immune response by transporting soluble polymeric Igs across mucosal epithelial cells. Single pIgR genes, which are expressed in lymphoid organs including mucosal tissues, have been identified in several teleost species. A single pigr gene has been identified on zebrafish chromosome 2 along with a large multigene family consisting of 29 pigr-like (PIGRL) genes. Full-length transcripts from ten different PIGRL genes that encode secreted and putative inhibitory membrane-bound receptors have been characterized. Although PIGRL and pigr transcripts are detected in immune tissues, only PIGRL transcripts can be detected in lymphoid and myeloid cells. In contrast to pIgR which binds Igs, certain PIGRL proteins bind phospholipids. PIGRL transcript levels are increased after infection with Streptococcus iniae, suggesting a role for PIGRL genes during bacterial challenge. Transcript levels of PIGRL genes are decreased after infection with Snakehead rhabdovirus, suggesting that viral infection may suppress PIGRL function. PMID- 24469065 TI - Divergence and diversity of ULBP2 genes in rhesus and cynomolgus macaques. AB - Non-human primates such as rhesus macaque and cynomolgus macaque are important animals for medical research fields and they are classified as Old World monkey, in which genome structure is characterized by gene duplications. In the present study, we investigated polymorphisms in two genes for ULBP2 molecules that are ligands for NKG2D. A total of 15 and 11 ULBP2.1 alleles and 11 and 10 ULBP2.2 alleles were identified in rhesus macaques and cynomolgus macaques, respectively. Nucleotide sequences of exons for extra cellular domain were highly polymorphic and more than 70 % were non-synonymous variations in both ULBP2.1 and ULBP2.2. In addition, phylogenetic analyses revealed that the ULBP2.2 was diverged from a branch of ULBP2.1 along with ULBP2s of higher primates. Moreover, when 3D structural models were constructed for the rhesus ULBP2 molecules, residues at presumed contact sites with NKG2D were polymorphic in ULBP2.1 and ULBP2.2 in the rhesus macaque and cynomolgus macaque, respectively. These observations suggest that amino acid replacements at the interaction sites with NKG2D might shape a specific nature of ULBP2 molecules in the Old World monkeys. PMID- 24469067 TI - PKA and Epac activation mediates cAMP-induced vasorelaxation by increasing endothelial NO production. AB - Vascular relaxation induced by 3',5'-cyclic adenosine monophosphate (cAMP) is both endothelium-dependent and endothelium-independent, although the underlying signaling pathways are not fully understood. Aiming to uncover potential mechanisms, we performed contraction-relaxation experiments on endothelium denuded and intact rat aorta rings and measured NO levels in isolated human endothelial cells using single cell fluorescence imaging. The vasorelaxant effect of forskolin, an adenylyl cyclase activator, was decreased after selective inhibitor of protein kinase A (PKA), a cAMP-activated kinase, or L-NAME, an endothelial nitric oxide synthase (eNOS) inhibitor, only in intact aortic rings. Both selective activation of PKA with 6-Bnz-cAMP and exchange protein directly activated by cAMP (Epac) with 8-pCPT-2'-O-Me-cAMP significantly relaxed phenylephrine-induced contractions. The vasorelaxant effect of the Epac activator, but not that of the PKA activator, was reduced by endothelium removal. Forskolin, dibutyryl cAMP (a cAMP analogue), 6-Bnz-cAMP and 8-pCPT-2'-O-Me-cAMP increased NO levels in endothelial cells and the forskolin effect was significantly inhibited by inactivation of both Epac and PKA, and eNOS inhibition. Our results indicate that the endothelium-dependent component of forskolin/cAMP-induced vasorelaxation is partially mediated by an increase in endothelial NO release due to an enhanced eNOS activity through PKA and Epac activation in endothelial cells. PMID- 24469066 TI - Low anticoagulant heparin blocks thrombin-induced endothelial permeability in a PAR-dependent manner. AB - Acute lung injury and acute respiratory distress syndrome are accompanied by thrombin activation and fibrin deposition that enhance lung inflammation, activate endothelial cells and disrupt lung paracellular permeability. Heparin possesses anti-inflammatory properties but its clinical use is limited by hemorrhage and heparin induced thrombocytopenia. We studied the effects of heparin and low anticoagulant 2-O, 3-O desulfated heparin (ODSH) on thrombin induced increases in paracellular permeability of cultured human pulmonary endothelial cells (ECs). Pretreatment with heparin or ODSH blocked thrombin induced decrease in the EC transendothelial electrical resistance (TER), attenuated thrombin-stimulated paracellular gap formation and actin cytoskeletal rearrangement. Our data demonstrated that heparin and ODSH had inhibitory effects on thrombin-induced RhoA activation and intracellular calcium elevation. Thrombin stimulated phosphorylation of the cytoskeletal regulatory proteins, myosin light chain and ezrin/radixin/moesin was also reduced. In these effects, low anticoagulant ODSH was more potent than heparin. Heparin or ODSH alone produced decreases in the EC TER that were abolished by siRNA-mediated depletion of the thrombin receptor, PAR-1. We also demonstrated that, in contrast to heparin, ODSH did not possess thrombin-binding activity. Results suggest that heparin and low anticoagulant ODSH can interfere with thrombin-activated signaling. PMID- 24469068 TI - Freiburg neuropathology case conference: a temporal, partially calcified tumor in a child. PMID- 24469069 TI - CXCL4L1 and CXCL4 signaling in human lymphatic and microvascular endothelial cells and activated lymphocytes: involvement of mitogen-activated protein (MAP) kinases, Src and p70S6 kinase. AB - CXC chemokines influence a variety of biological processes, such as angiogenesis, both in a physiological and pathological context. Platelet factor-4 (PF-4)/CXCL4 and its variant PF-4var/CXCL4L1 are known to favor angiostasis by inhibiting endothelial cell proliferation and chemotaxis. CXCL4L1 in particular is a potent inhibitor of angiogenesis with anti-tumoral characteristics, both through regulation of neovascularization and through attraction of activated lymphocytes. However, its underlying signaling pathways remain to be elucidated. Here, we have identified various intracellular pathways activated by CXCL4L1 in comparison with other CXCR3 ligands, including CXCL4 and interferon-gamma-induced protein 10/CXCL10. Signaling experiments show involvement of the mitogen-activated protein kinase (MAPK) family in CXCR3A-transfected cells, activated lymphocytes and human microvascular endothelial cells (HMVEC). In CXCR3A transfectants, CXCL4 and CXCL4L1 activated p38 MAPK, as well as Src kinase within 30 and 5 min, respectively. Extracellular signal-regulated kinase (ERK) phosphorylation occurred in activated lymphocytes, yet was inhibited in microvascular and lymphatic endothelial cells. CXCL4L1 and CXCL4 counterbalanced the angiogenic chemokine stromal cell-derived factor-1/CXCL12 in both endothelial cell types. Notably, inhibition of ERK signaling by CXCL4L1 and CXCL4 in lymphatic endothelial cells implies that these chemokines might also regulate lymphangiogenesis. Furthermore, CXCL4, CXCL4L1 and CXCL10 slightly enhanced forskolin-stimulated cAMP production in HMVEC. Finally, CXCL4, but not CXCL4L1, induced activation of p70S6 kinase within 5 min in HMVEC. Our findings confirm that the angiostatic chemokines CXCL4L1 and CXCL4 activate both CXCR3A and CXCR3B and bring new insights into the complexity of their signaling cascades. PMID- 24469070 TI - Kawasaki disease hospitalization rate among children younger than 5 years in California, 2003-2010. AB - In California, the 2010 annual Kawasaki disease hospitalization rate for children <5 years of age was higher than the rate in 2003. An increasing trend during 2003 2010 appears to be driven by an increase from 2003 to 2006, whereas the Kawasaki disease hospitalization rate remained stable through 2010. PMID- 24469071 TI - Disseminated tuberculosis in 2 children with inflammatory bowel disease receiving infliximab. AB - Patients with inflammatory bowel disease are predisposed to opportunistic infections. We report 2 cases of disseminated tuberculosis in adolescents receiving a TNF antagonist, infliximab. Both had negative baseline tuberculin skin tests. Multimodal testing using tuberculin skin tests and interferon gamma release assays at the time of inflammatory bowel disease diagnosis and annually may increase the sensitivity of LTBI testing in these high risk children. PMID- 24469072 TI - Highly stretchable and transparent nanomesh electrodes made by grain boundary lithography. AB - Foldable photoelectronics and muscle-like transducers require highly stretchable and transparent electrical conductors. Some conducting oxides are transparent, but not stretchable. Carbon nanotube films, graphene sheets and metal-nanowire meshes can be both stretchable and transparent, but their electrical resistances increase steeply with strain <100%. Here we present highly stretchable and transparent Au nanomesh electrodes on elastomers made by grain boundary lithography. The change in sheet resistance of Au nanomeshes is modest with a one time strain of ~160% (from ~21 Omega per square to ~67 Omega per square), or after 1,000 cycles at a strain of 50%. The good stretchability lies in two aspects: the stretched nanomesh undergoes instability and deflects out-of-plane, while the substrate stabilizes the rupture of Au wires, forming distributed slits. Larger ratio of mesh-size to wire-width also leads to better stretchability. The highly stretchable and transparent Au nanomesh electrodes are promising for applications in foldable photoelectronics and muscle-like transducers. PMID- 24469073 TI - Slowed muscle oxygen uptake kinetics with raised metabolism are not dependent on blood flow or recruitment dynamics. AB - Oxygen uptake kinetics (tauVO2) are slowed when exercise is initiated from a raised metabolic rate. Whether this reflects the recruitment of muscle fibres differing in oxidative capacity, or slowed blood flow (Q) kinetics is unclear. This study determined tauVO2 in canine muscle in situ, with experimental control over muscle activation and Q during contractions initiated from rest and a raised metabolic rate. The gastrocnemius complex of nine anaesthetised, ventilated dogs was isolated and attached to a force transducer. Isometric tetanic contractions (50 Hz; 200 ms duration) via supramaximal sciatic nerve stimulation were used to manipulate metabolic rate: 3 min stimulation at 0.33 Hz (S1), followed by 3 min at 0.67 Hz (S2). Circulation was initially intact (SPON), and subsequently isolated for pump-perfusion (PUMP) above the greatest value in SPON. Muscle VO2 was determined contraction-by-contraction using an ultrasonic flowmeter and venous oximeter, and normalised to tension-time integral (TTI). tauVO2/TTI and tauQ were less in S1SPON (mean +/- s.d.: 13 +/- 3 s and 12 +/- 4 s, respectively) than in S2SPON (29 +/- 19 s and 31 +/- 13 s, respectively; P < 0.05). tauVO2/TTI was unchanged by pump-perfusion (S1PUMP, 12 +/- 4 s; S2PUMP, 24 +/- 6 s; P < 0.001) despite increased O2 delivery; at S2 onset, venous O2 saturation was 21 +/ 4% and 65 +/- 5% in SPON and PUMP, respectively. VO2 kinetics remained slowed when contractions were initiated from a raised metabolic rate despite uniform muscle stimulation and increased O2 delivery. The intracellular mechanism may relate to a falling energy state, approaching saturating ADP concentration, and/or slowed mitochondrial activation; but further study is required. These data add to the evidence that muscle VO2 control is more complex than previously suggested. PMID- 24469074 TI - Prostaglandins induce vasodilatation of the microvasculature during muscle contraction and induce vasodilatation independent of adenosine. AB - Blood flow data from contracting muscle in humans indicates that adenosine (ADO) stimulates the production of nitric oxide (NO) and vasodilating prostaglandins (PG) to produce arteriolar vasodilatation in a redundant fashion such that when one is inhibited the other can compensate. We sought to determine whether these redundant mechanisms are employed at the microvascular level. First, we determined whether PGs were involved in active hyperaemia at the microvascular level. We stimulated four to five skeletal muscle fibres in the anaesthetized hamster cremaster preparation in situ and measured the change in diameter of 2A arterioles (maximum diameter 40 MUm, third arteriolar level up from the capillaries) at a site of overlap with the stimulated muscle fibres before and after 2 min of contraction [stimulus frequencies: 4, 20 and 60 Hz at 15 contractions per minute (CPM) or contraction frequencies of 6, 15 or 60 CPM at 20 Hz; 250 ms train duration]. Muscle fibres were stimulated in the absence and presence of the phospholipase A2 inhibitor quinacrine. Further, we applied a range of concentrations of ADO (10(-7)-10(-5) M) extraluminally, (to mimic muscle contraction) in the absence and presence of L-NAME (NO synthase inhibitor), indomethacin (INDO, cyclooxygenase inhibitor) and L-NAME + INDO and observed the response of 2A arterioles. We repeated the latter experiment on a different level of the cremaster microvasculature (1A arterioles) and on the microvasculature of a different skeletal muscle (gluteus maximus, 2A arterioles). We observed that quinacrine inhibited vasodilatation during muscle contraction at intermediate and high contraction frequencies (15 and 60 CPM). L-NAME, INDO and L-NAME + INDO were not effective at inhibiting vasodilatation induced by any concentration of ADO tested in 2A and 1A arterioles in the cremaster muscle or 2A arterioles in the gluteus maximus muscle. Our data show that PGs are involved in the vasodilatation of the microvasculature in response to muscle contraction but did not obtain evidence that extraluminal ADO causes vasodilatation through NO or PG or both. Thus, we propose that PG-induced microvascular vasodilation during exercise is independent of ADO. PMID- 24469075 TI - Remodelling at the calyx of Held-MNTB synapse in mice developing with unilateral conductive hearing loss. AB - Structure and function of central synapses are profoundly influenced by experience during developmental sensitive periods. Sensory synapses, which are the indispensable interface for the developing brain to interact with its environment, are particularly plastic. In the auditory system, moderate forms of unilateral hearing loss during development are prevalent but the pre- and postsynaptic modifications that occur when hearing symmetry is perturbed are not well understood. We investigated this issue by performing experiments at the large calyx of Held synapse. Principal neurons of the medial nucleus of the trapezoid body (MNTB) are innervated by calyx of Held terminals that originate from the axons of globular bushy cells located in the contralateral ventral cochlear nucleus. We compared populations of synapses in the same animal that were either sound deprived (SD) or sound experienced (SE) after unilateral conductive hearing loss (CHL). Middle ear ossicles were removed 1 week prior to hearing onset (approx. postnatal day (P) 12) and morphological and electrophysiological approaches were applied to auditory brainstem slices taken from these mice at P17-19. Calyces in the SD and SE MNTB acquired their mature digitated morphology but these were structurally more complex than those in normal hearing mice. This was accompanied by bilateral decreases in initial EPSC amplitude and synaptic conductance despite the CHL being unilateral. During high frequency stimulation, some SD synapses displayed short-term depression whereas others displayed short-term facilitation followed by slow depression similar to the heterogeneities observed in normal hearing mice. However SE synapses predominantly displayed short-term facilitation followed by slow depression which could be explained in part by the decrease in release probability. Furthermore, the excitability of principal cells in the SD MNTB had increased significantly. Despite these unilateral changes in short-term plasticity and excitability, heterogeneities in the spiking fidelity among the population of both SD and SE synapses showed similar continuums to those in normal hearing mice. Our study suggests that preservations in the heterogeneity in spiking fidelity via synaptic remodelling ensures symmetric functional stability which is probably important for retaining the capability to maximally code sound localization cues despite moderate asymmetries in hearing experience. PMID- 24469077 TI - Glaucoma in pregnancy. AB - PURPOSE OF REVIEW: Glaucoma management during pregnancy generates numerous therapeutic challenges and potential risks for both the patient and the fetus. Data are limited on this topic given the lack of large, prospective, and randomized clinical trials because of ethical and legal constraints in this patient population. Therefore, many ophthalmologists remain unsure about treating glaucoma during pregnancy and lactation. This review focuses on the importance of preconception planning, the natural course of intraocular pressure during pregnancy, and a discussion of various therapeutic modalities during pregnancy and lactation. RECENT FINDINGS: The risks of glaucoma medications during pregnancy are not well established for the human fetus or infant and are often inferred from animal studies. Some guidelines have been provided by the US Food and Drug Administration (FDA) about medication safety during pregnancy. Currently, brimonidine is classified as a category B medication with presumed safety based on animal studies. Other glaucoma medications (beta blockers, carbonic anhydrase inhibitors, parasympathomimetics, and prostaglandin analogues) are classified as category C medications with uncertain safety from the lack of human studies and reported adverse effects in animal studies. SUMMARY: The treatment of glaucoma during pregnancy and lactation requires careful consideration and understanding of disease status, stage of pregnancy, FDA classification and guidelines, and potential benefits and limitations of various therapeutic modalities. A multidisciplinary team approach is necessary to appropriately balance the risks and benefits of any intervention and to individualize treatment to achieve the best outcomes for both mother and fetus. PMID- 24469076 TI - Sarcoplasmic reticulum Ca2+ uptake and leak properties, and SERCA isoform expression, in type I and type II fibres of human skeletal muscle. AB - The Ca(2+) uptake properties of the sarcoplasmic reticulum (SR) were compared between type I and type II fibres of vastus lateralis muscle of young healthy adults. Individual mechanically skinned muscle fibres were exposed to solutions with the free [Ca(2+)] heavily buffered in the pCa range (-log10[Ca(2+)]) 7.3-6.0 for set times and the amount of net SR Ca(2+) accumulation determined from the force response elicited upon emptying the SR of all Ca(2+). Western blotting was used to determine fibre type and the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) isoform present in every fibre examined. Type I fibres contained only SERCA2 and displayed half-maximal Ca(2+) uptake rate at ~pCa 6.8, whereas type II fibres contained only SERCA1 and displayed half-maximal Ca(2+) uptake rate at ~pCa 6.6. Maximal Ca(2+) uptake rate was ~0.18 and ~0.21 mmol Ca(2+) (l fibre)( 1) s(-1) in type I and type II fibres, respectively, in good accord with previously measured SR ATPase activity. Increasing free [Mg(2+)] from 1 to 3 mM had no significant effect on the net Ca(2+) uptake rate at pCa 6.0, indicating that there was little or no calcium-induced calcium release occurring through the Ca(2+) release channels during uptake in either fibre type. Ca(2+) leakage from the SR at pCa 8.5, which is thought to occur at least in part through the SERCA, was ~2-fold lower in type II fibres than in type I fibres, and was little affected by the presence of ADP, in marked contrast to the larger SR Ca(2+) leak observed in rat muscle fibres under the same conditions. The higher affinity of Ca(2+) uptake in the type I human fibres can account for the higher relative level of SR Ca(2+) loading observed in type I compared to type II fibres, and the SR Ca(2+) leakage characteristics of the human fibres suggest that the SERCAs are regulated differently from those in rat and contribute comparatively less to resting metabolic rate. PMID- 24469078 TI - Glaucoma management in Boston keratoprosthesis type I recipients. AB - PURPOSE OF REVIEW: To review the literature on management of glaucoma in Boston keratoprosthesis type I recipients. RECENT FINDINGS: Glaucoma is a prevalent and important cause of permanent loss of sight in Boston keratoprosthesis recipients. The management of glaucoma is challenging as there are no reliable and accurate means to monitor the intraocular pressure (IOP) in these patients, and no standardized protocols exist regarding management. Because a significant number of patients require glaucoma drainage device placement, further studies are needed to determine ways to reduce the risk of shunt-associated complications. Surgical adjustments including posterior shunt placement, adjunctive corneal patch graft, and selection of a different size bandage contact lens can help reduce shunt-associated complications. Anterior segment optical coherence tomography is useful in elucidating the mechanisms of failure to control IOP. Continual innovations in imaging and IOP measurement technologies will assist surgeons' preoperative planning and postoperative management. SUMMARY: In keratoprosthesis recipients, glaucoma often leads to permanent loss of sight. It is imperative that these patients be monitored with vigilance by a multidisciplinary team to prevent progression. Pooled data from multiple centers and technologic innovations will assist the surgeon to design a surgical approach and postoperative management regimen for the individual recipient. PMID- 24469079 TI - Novel macrocyclic molecules based on 12a-N substituted 16-membered azalides and azalactams as potential antifungal agents. AB - Novel macrocyclic molecules comprising sulfonyl and acyl moiety at the position N 12a of 16-membered azalides (6a-n) and azalactams (10a-r) scaffold were synthesized from cyclododecanone 1 as starting material via 5 steps and 4 steps, respectively. The antifungal activity of these compounds against Sclerotinia sclerotiorum, Pyricularia oryzae, Botrytis cinerea, Rhizoctonia solani and Phytophthora capsici were evaluated and found that compounds possessing alpha exomethylene (6c, 6d, 6e and 6g) showed antifungal activity comparable to commercial fungicide Chlorothalonil against P. oryzae and compounds possessing p chlorobenzoyl exhibited enhanced antifungal activity than those with other substituents against S. sclerotiorum, P. oryzae, and B. cinerea. These findings suggested that the alpha-exomethylene and p-chlorobenzoyl may be two potential pharmacological active groups with antifungal activities. PMID- 24469080 TI - 7-Chloroquinolinotriazoles: synthesis by the azide-alkyne cycloaddition click chemistry, antimalarial activity, cytotoxicity and SAR studies. AB - Twenty-seven 7-chloroquinolinotriazole derivatives with different substituents in the triazole moiety were synthesized via copper-catalyzed cycloaddition (CuAAC) click chemistry between 4-azido-7-chloroquinoline and several alkynes. All the synthetic compounds were evaluated for their in vitro activity against Plasmodium falciparum (W2) and cytotoxicity to Hep G2A16 cells. All the products disclosed low cytotoxicity (CC50 > 100 MUM) and five of them have shown moderate antimalarial activity (IC50 from 9.6 to 40.9 MUM). As chloroquine analogs it was expected that these compounds might inhibit the heme polymerization and SAR studies were performed aiming to explain their antimalarial profile. New structural variations can be designed on the basis of the results obtained. PMID- 24469081 TI - Mycobacterium leprae upregulates IRGM expression in monocytes and monocyte derived macrophages. AB - Leprosy is caused by the infection of Mycobacterium leprae, which evokes a strong inflammatory response and leads to nerve damage. Immunity-related GTPase family M protein (IRGM) plays critical roles in controlling inflammation. The objective of the study was to investigate whether IRGM is involved in the infection of M. leprae. Levels of IRGM were assessed in M. leprae-infected CD4(+) T cells, monocytes, and monocyte-derived macrophages. Data revealed that both protein and mRNA levels of IRGM were increased in monocytes after M. leprae infection. Interestingly, monocyte-derived macrophages showed more prominent IRGM expression with M. leprae infection, whereas the bacteria did not affect IRGM in CD4(+) T cells. Furthermore, we assessed levels of IRGM in CD4(+) T cells and monocytes from 78 leprosy patients and 40 healthy controls, and observed upregulated protein level of IRGM in the monocytes from leprosy patients. Also, IRGM expression was inversely correlated with the severity of the disease. These findings suggested a close involvement of IRGM in M. leprae infection and indicated a potential mechanism of defending M. leprae infection. PMID- 24469082 TI - Fe-Ni composition dependence of magnetic anisotropy in artificially fabricated L1 0-ordered FeNi films. AB - We prepared L10-ordered FeNi alloy films by alternate deposition of Fe and Ni monatomic layers, and investigated their magnetic anisotropy. We employed a non ferromagnetic Au-Cu-Ni buffer layer with a flat surface and good lattice matching to L10-FeNi. An L10-FeNi film grown on Au6Cu51Ni43 showed a large uniaxial magnetic anisotropy energy (Ku = 7.0 * 10(6) erg cm(-)3). Ku monotonically increased with the long-range order parameter (S) of the L10 phase. We investigated the Fe-Ni composition dependence by alternating the deposition of Fe 1 - x and Ni 1 + x monatomic layers (- 0.4 < x < 0.4). Saturation magnetization (Ms) and Ku showed maxima (Ms = 1470 emu cm(-3), Ku = 9.3 * 10(6) erg cm(-3)) for Fe60Ni40 (x = -0.2) while S showed a maximum at the stoichiometric composition (x = 0). The change in the ratio of lattice parameters (c/a) was small for all compositions. We found that enrichment of Fe is very effective to enhance Ku. The large Ms and Ku of Fe60Ni40 indicate that Fe-rich L10-FeNi is promising as a rare earth-free permanent magnet. PMID- 24469083 TI - Nursing theories for the 21st century. PMID- 24469084 TI - No one gets through it OK. PMID- 24469085 TI - Emerging theories for practice critical, participatory, ecological, and user-led: nursing scholarship and knowledge development of the future. PMID- 24469086 TI - Situation-specific theories from the middle-range transitions theory. AB - The purpose of this article was to analyze the theory development process of the situation-specific theories that were derived from the middle-range transitions theory. This analysis aims to provide directions for future development of situation-specific theories. First, transitions theory is concisely described with its history, goal, and major concepts. Then, the approach that was used to retrieve the situation-specific theories derived from transitions theory is described. Next, an analysis of 6 situation-specific theories is presented. Finally, 4 themes reflecting commonalities and variances in the theory development process are discussed with implications for future theoretical development. PMID- 24469087 TI - Uniting postcolonial, discourse, and linguistic theory to explore participation of African Americans in cancer research as an effect of social and historical race relationships. AB - This article uses a historical framework of postcolonialism; discourse analytic concepts (significance, identity, and relationships); and 5 social and cultural linguistic principles of emergence, positionality, indexicality, relationality, and partialness as a theoretical and methodological triangulation approach to data analysis of focus group discussion. Exemplars of focus group data from a study exploring African American participation in research demonstrate the application of this combined framework as a useful tool for analysis. This approach allows for examination of identity and interaction and generates a more rigorous and complete understanding of how individuals use language to construct identity as participants or nonparticipants in research. PMID- 24469088 TI - Cultural competence in health care: an emerging theory. AB - This study examined the current state of cultural competence in health care using a qualitative descriptive design. Interviews were conducted with 20 multidisciplinary experts in culture and cultural competence from the United States and abroad. Findings identified 3 themes; awareness, engagement, and application that crossed 4 domains of cultural competence; intrapersonal, interpersonal, system/organization, and global. PMID- 24469089 TI - Work-integrated learning: a didactic tool to develop praxis in nurse education. AB - Praxis is a concept that is both vague and overused in nursing science. Hence, a more stringent use of the concept praxis could help clarify the connections between theory and practice. The purpose of this theoretical article was to highlight the advantages of developing praxis in nursing education. By using praxis as a dialectic concept, nurse educators can make significant contributions to clinical practice by clarifying that theory and practice are perceived as 2 sides of same coin, leading to a move from "being in praxis" to "being of praxis," a way to develop the profession's autonomy. PMID- 24469091 TI - The association of tumor volume with mortality following radical prostatectomy. AB - BACKGROUND: Data regarding the prognostic significance of tumor volume (TV) in prostate cancer are conflicting. Herein, we evaluated the association of TV with prostate cancer mortality following radical prostatectomy (RP), and assessed the additive prognostic value of TV to an established predictive model. METHODS: We identified 13,687 patients who underwent RP without preoperative therapy between 1987 and 2009. TV was estimated using the prolate ellipsoid formula. Survival was estimated using the Kaplan-Meier method and compared with the log-rank test. Cox proportional hazard regression models were used to evaluate the association of TV with mortality. The ability of TV to enhance the performance of an established prognostic model (Mayo Clinic GPSM (Gleason, PSA, seminal vesicle and margin status) score) was assessed using the c-index. RESULTS: Median TV was 1.57 cm(3) (interquartile range (IQR) 0.48-4.19). Increasing TV was associated with significantly higher risks of seminal vesicle invasion (hazard ratio (HR) 1.58; P<0.0001), positive surgical margins (HR 1.28; P<0.0001) and lymph node involvement (HR 1.26; P<0.0001). Median postoperative follow-up was 9.4 years (IQR 5.0-14.5). Patient grouping into quartiles according to TV resulted in a significant stratification of outcome, as the 15-year cancer-specific survival by TV quartile was 99%, 98%, 95% and 88%, respectively (P<0.0001). Moreover, on multivariate analysis, greater TV remained associated with significantly increased risks of systemic progression (HR 1.27; P<0.0001), death from prostate cancer (HR 1.29; P<0.0001) and all-cause mortality (HR 1.05; P<0.0001). Meanwhile, addition of TV to the GPSM score increased the c-index for the model's prediction of prostate cancer mortality from 0.803 to 0.822. CONCLUSIONS: TV is associated with survival following RP, and enhances, although modestly, the performance of an established prediction model. As such, TV warrants continued assessment in risk stratification tools. PMID- 24469090 TI - Development of a frailty framework among vulnerable populations. AB - Frailty is a public health issue that is experienced by homeless and other vulnerable populations; to date, a frailty framework has not been proposed to guide researchers who study hard-to-reach populations. The Frailty Framework among Vulnerable Populations has been developed from empirical research and consultation with frailty experts in an effort to characterize antecedents, that is, situational, health-related, behavioral, resource, biological, and environmental factors that contribute to physical, psychological, and social frailty domains and impact adverse outcomes. As vulnerable populations continue to age, a greater understanding of frailty will enable the development of nursing interventions. PMID- 24469092 TI - ERG rearrangement and protein expression in the progression to castration resistant prostate cancer. AB - BACKGROUND: Approximately half of the prostate carcinomas are characterized by a chromosomal rearrangement fusing the androgen-regulated gene TMPRSS2 to the oncogenic ETS transcription factor ERG. Aim of this study was to comprehensively analyze the role and impact of the ERG rearrangement and protein expression on the progression to castration-resistant (CR) disease. METHODS: We used a tissue microarray (TMA) constructed from 114 hormone naive (HN) and 117 CR PCs. We analyzed the ERG rearrangement status by fluorescence in situ hybridization and the expression profiles of ERG, androgen receptor (AR) and the proliferation marker Ki67 by immunohistochemistry. RESULTS: Nearly half of the PC tissue specimens (HN: 38%, CR: 46%) harbored a TMPRSS2-ERG gene fusion. HN PCs with positive translocation status showed increased tumor cell proliferation (P<0.05). As expected, TMPRSS2-ERG gene fusion was strongly associated with increased ERG protein expression in HN and CR PCs (both P<0.0001). Remarkably, the study revealed a subgroup (26%) of CR PCs with ERG rearrangement but without any detectable ERG protein expression. This subgroup showed significantly lower levels of AR protein expression and androgen-regulated serum PSA (both P<0.05). CONCLUSIONS: In this study, we identified a subgroup of ERG-rearranged CR PCs without detectable ERG protein expression. Our results suggest that this subgroup could represent CR PCs with a dispensed AR pathway. These tumors might represent a thus far unrecognized subset of patients with AR-independent CR PC who may not benefit from conventional therapy directed against the AR pathway. PMID- 24469093 TI - UHPLC/Q-TOF MS-based plasma metabolic profiling analysis of the bleeding mechanism in a rat model of yeast and ethanol-induced blood heat and hemorrhage syndrome. AB - Blood heat and hemorrhage (BHH) syndrome is the most common bleeding disease in clinic. In this study, a rat model with BHH syndrome was built for the first time. Biochemical study showed the intrinsic coagulation pathways and the platelet aggregation rate in the rat model were inhibited, while extrinsic pathway of coagulation cascade was activated. An UHPLC/Q-TOF MS combined with orthogonal partial least squares-discriminant analysis (OPLS-DA) was employed to construct plasma metabolic profiling of the rat model with BHH syndrome. Twenty four unique metabolites were identified, which were involved in glycerophospholipid metabolism, arachidonic acid metabolism, fatty acid metabolism, amino acid metabolism and cholic acid metabolism. In the end, we concluded that bleeding mechanism of the rat with BHH syndrome may be associated with augmenting blood viscosity, inhibiting platelet aggregation and intrinsic coagulation pathways. PMID- 24469094 TI - Detection of dehalogenation impurities in organohalogenated pharmaceuticals by UHPLC-DAD-HRESIMS. AB - The presence of dehalogenated impurities is often observed in halogen-containing pharmaceuticals, and can present a difficult analytical challenge, as the chromatographic behavior of the halogenated drug and the hydrogen-containing analog can be quite similar. In this study we describe the chromatographic separation and unambiguous identification of dehalogenation impurities or associated isomers in organohalogenated pharmaceuticals using UHPLC with a pentafluorophenyl column coupled with diode-array and high resolution electrospray ionization mass spectrometry detection (UHPLC-DAD-HRESIMS). PMID- 24469095 TI - Simultaneous determination of four alkaloids in mice plasma and brain by LC-MS/MS for pharmacokinetic studies after administration of Corydalis Rhizoma and Yuanhu Zhitong extracts. AB - A sensitive and selective liquid chromatography with tandem mass spectrometry (LC MS/MS) method was developed for simultaneous determination of tetrahydropalmatine, coptisine, palmatine and dehydrocorydaline in mice plasma and brain after intraperitoneal administration of the extracts of Yuanhu Zhitong (YZ) and Corydalis Rhizoma (CR). Biological samples were processed with ethyl acetate extraction. The mobile phase consisted of acetonitrile and water (containing 10mM ammonium acetate, adjusted with acetic acid to pH 4.25) with gradient elution at a flow rate of 0.4mL/min. Detection was performed on a triple quadrupole mass spectrometer using positive ion ESI in the multiple reaction monitoring (MRM) mode. The calibration curves for all analytes had good linearity (r(2)>0.9910). The intra- and inter-day precisions (RSD) were within 13.9%, and accuracy (RE) was between -12.0% and 13.7%. This method was successfully applied to the pharmacokinetic and brain distribution study after administration of the extracts of YZ and CR. The pharmacokinetic study indicated that the AUC of plasma and brain increased, and the CL of the two matrixes decreased after administration of YZ when compared with CR (p<0.05). The four analytes could cross the blood-brain barrier in vivo and elucidate the potentials for the treatment of diseases of the central nervous system. PMID- 24469096 TI - Direct and comprehensive analysis of ginsenosides and diterpene alkaloids in Shenfu injection by combinatory liquid chromatography-mass spectrometric techniques. AB - Shenfu injection (SFI) is a widely used Chinese herbal formulation for cardiac diseases prepared from red ginseng and processed aconite root. Clinical observations and pharmacological effects on SFI have been well investigated. Chemical analysis and quality control studies of this formulation, however, are relatively limited, especially regarding toxic aconite alkaloids. In this work, a high-performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry (HPLC-QTOF MS) method was applied to comprehensive analysis of constituents in SFI. Highly sensitive MS allows direct analysis of injections without additional sample pretreatment required. Using diagnostic ions and fragmentation rules, we identified 23 trace diterpene alkaloids, nineteen ginseng saponins, one panaxytriol, and one 5-hydroxymethylfurfural in SFI. A LC-MS method with selected ion monitoring was then used to quantify 24 major alkaloids and ginsenosides. The method was validated in terms of linearity, accuracy and precision. Especially, the limits of quantification were low to 0.4-18ng/mL for diterpene alkaloids. The total concentrations of saponins and alkaloids were about 676-742MUg/mL and 3-7MUg/mL in five batches of SFI samples, respectively. Finally, cosine ratio and euclidean distance were introduced to evaluate the batch-to-batch reproducibility of SFI samples, and the results demonstrated high quality consistency. Global identification and quantification of complex constituents based on LC-MS promises wide applications in quality control and batch monitoring for herbal products. PMID- 24469097 TI - Stability studies of cefpirome sulfate in the solid state: Identification of degradation products. AB - The process of degradation was studied by using an HPLC-DAD method. Four degradation products were identified with a hybrid ESI-Q-TOF mass spectrometer. The influence of temperature and relative air humidity (RH) on the stability of cefpirome sulfate was investigated. In the solid state the degradation of cefpirome sulfate was a first-order reaction depending on the substrate concentration. The kinetic and thermodynamic parameters of degradation were calculated. PMID- 24469098 TI - Pharmacokinetics difference of multiple active constituents from decoction and maceration of Fuzi Xiexin Tang after oral administration in rat by UPLC-MS/MS. AB - Fuzi Xiexin Tang (FXT) is a classic traditional Chinese medicine formula which has been employed in clinical for more than 1800 years. The distinctive preparation method (maceration) recorded in ancient time is different from one in modern clinical practice (decoction). Aim of this study is to investigate the pharmacokinetic difference of alkaloids, flavones and anthraquinones in rats after oral administration of decoction of FXT (DFXT, 30gkg(-1)), maceration of FXT (MFXT, 30gkg(-1)) and decoction of Aconiti Lateralis Radix Preparata (DAR, 6gkg(-1)) by a validated UPLC-MS/MS method. Plasma concentrations and pharmacokinetic parameters of 16 active constituents (aconitine, hypaconitine, mesaconitine, benzoylaconine, benzoylhypaconine, benzoylmesaconine, berberine, palmatine, jatrorrhizine, coptisine, baicalin, wogonin, wogonoside, emodin, aloe emodin, rhein) in rat were quantified and compared. Different preparative methods resulted in significant difference on exposure and pharmacokinetic characteristics of alkaloids, flavones and anthraquinones from FXT, especially protoberberine alkaloids. Concentrations of monoester-diterpenoid alkaloids were below the LOD in rat plasma after administration of DFXT and MFXT because of the existence of other three herbs from FXT. Maceration could decrease the absorption of flavones while increased the absorption of anthraquinones. Cmax of emodin and rhein were 3.1 and 10.3 times increased, while eliminations of these two constituents were 8.0 and 19.0 times slower after administration of MFXT. Bioavailability of both flavones and anthraquinones increased after administration of MFXT, especially emodin and rhein increasing as much as 13.5 and 20.7 times. Herb-herb interaction between DAR and other three herbs from FXT significantly influenced the exposure of aconitum alkaloids. PMID- 24469100 TI - Composition-dependent Raman modes of Mo(1-x)W(x)S2 monolayer alloys. AB - Two-dimensional (2D) transition-metal dichalcogenide alloys with tunable band gaps have promising applications in nanoelectronics and optoelectronics. Characterization of structures of 2D alloys, such as composition and atom mixing, is of fundamental importance to their applications. Here, we have conducted systematic Raman spectroscopic studies on Mo1-xWxS2 monolayers (0 <=x<= 1). First order Raman modes and second-order Raman modes have been observed in the range of 100-480 cm(-1) in the 2D alloys. The out-of-plane A1' modes and in-plane E' modes showed one-mode and two-mode behaviors, respectively. The broadening of A1' and E' modes in the alloys has been observed. The disorder-related Raman peaks at ~360 cm(-1) were only observed in the 2D alloys but not in the two end materials. Modified random-element-isodisplacement (MREI) model has been adopted to successfully predict mode behaviors of A1' and E' modes in the monolayer alloys. Further, composition-dependent A1' and E' frequencies can be well fitted by the MREI model, giving composition-dependent force constants. PMID- 24469099 TI - Altered brain activation during response inhibition and error processing in subjects with Internet gaming disorder: a functional magnetic imaging study. AB - The aim of the present study was to evaluate the impulsivity and brain correlates of response inhibition and error processing among subjects with Internet gaming disorder (IGD). We evaluated the response inhibition and error processing by functional magnetic resonance imaging (fMRI) in subjects with IGD and controls. Twenty-six men with IGD for at least 2 years and 23 controls with no history of IGD were recruited as the IGD and control groups, respectively. All subjects performed the event-related designed Go/No-go task under fMRI and completed questionnaires related to Internet addiction and impulsivity. The IGD group exhibited a higher score for impulsivity than the control group. The IGD group also exhibited higher brain activation when processing response inhibition over the left orbital frontal lobe and bilateral caudate nucleus than controls. Both the IGD and control groups exhibited activation of the insula and anterior cingulate cortex during error processing. The activation over the right insula was lower in the subjects with IGD than the control group. Our results support the fact that the fronto-striatal network involved in response inhibition, and the salience network, anchored by the anterior cingulate and insula, contributes to error processing. Further, adults with IGD have impaired insular function in error processing and greater activation of the fronto-striatal network in order to maintain their response inhibition performance. PMID- 24469101 TI - Dynamic heteroleptic metal-phenanthroline complexes: from structure to function. AB - Dynamically heteroligated metal centres are auspicious platforms to access multicomponent supramolecular systems, the latter showing unique structures, amazing properties and even emergent functions. The great potential of heteroleptic complexes has materialised after the development of appropriate strategies that warrant quantitative formation in spite of the dynamic character. In this perspective, we discuss our endeavours at developing various heteroleptic self-assembly protocols based on sterically bulky 2,9-diarylphenanthrolines and our work toward self-sorted multicomponent architectures and assemblies with new and useful functions. PMID- 24469102 TI - First-principles study of electric field effects on the structure, decomposition mechanism, and stability of crystalline lead styphnate. AB - The electric field effects on the structure, decomposition mechanism, and stability of crystalline lead styphnate have been studied using density functional theory. The results indicate that the influence of external electric field on the crystal structure is anisotropic. The electric field effects on the distance of the Pb-O ionic interactions are stronger than those on the covalent interactions. However, the changes of most structural parameters are not monotonically dependent on the increased electric field. This reveals that lead styphnate can undergo a phase transition upon the external electric field. When the applied field is increased to 0.003 a.u., the effective band gap and total density of states vary evidently. And the Franz-Keldysh effect yields larger influence on the band gap than the structural change induced by external electric field. Furthermore, lead styphnate has different initial decomposition reactions in the presence and absence of the electric field. Finally, we find that its sensitivity becomes more and more sensitive with the increasing electric field. PMID- 24469104 TI - Improvement of a direct electron transfer-type fructose/dioxygen biofuel cell with a substrate-modified biocathode. AB - The fructose/dioxygen biofuel cell, one of the direct electron transfer (DET) type bioelectrochemical devices, utilizes fructose dehydrogenase (FDH) on the anode and multi-copper oxidase such as bilirubin oxidase (BOD) on the cathode as catalysts. The power density in the literature is limited by the biocathode performance. We show that the DET-type biocathode performance is greatly improved, when bilirubin or some related substances are adsorbed on electrodes before the BOD adsorption. Several data show that the substrate modification induces the appropriate orientation of BOD on the electrode surface for the DET. The substrate-modification method has successfully been applied to air-breathing gas-diffusion-type biocathodes. We have also optimized the conditions of the FDH adsorption on carbon cryogel electrodes. Finally, a one-compartment DET-type biofuel cell without separators has been constructed, and the maximum power density of 2.6 mW cm(-2) was achieved at 0.46 V of cell voltage under quiescent (passive) and air atmospheric conditions. PMID- 24469103 TI - Discovery of novel urokinase plasminogen activator (uPA) inhibitors using ligand based modeling and virtual screening followed by in vitro analysis. AB - Urokinase plasminogen activator (uPA)-a serine protease-is thought to play a central role in tumor metastasis and angiogenesis and, therefore, inhibition of this enzyme could be beneficial in treating cancer. Toward this end, we explored the pharmacophoric space of 202 uPA inhibitors using seven diverse sets of inhibitors to identify high-quality pharmacophores. Subsequently, we employed genetic algorithm-based quantitative structure-activity relationship (QSAR) analysis as a competition arena to select the best possible combination of pharmacophoric models and physicochemical descriptors that can explain bioactivity variation within the training inhibitors (r (2) 162 = 0.74, F statistic = 64.30, r (2) LOO = 0.71, r (2) PRESS against 40 test inhibitors = 0.79). Three orthogonal pharmacophores emerged in the QSAR equation suggesting the existence of at least three binding modes accessible to ligands within the uPA binding pocket. This conclusion was supported by receiver operating characteristic (ROC) curve analyses of the QSAR-selected pharmacophores. Moreover, the three pharmacophores were comparable with binding interactions seen in crystallographic structures of bound ligands within the uPA binding pocket. We employed the resulting pharmacophoric models and associated QSAR equation to screen the national cancer institute (NCI) list of compounds. The captured hits were tested in vitro. Overall, our modeling workflow identified new low micromolar anti-uPA hits. PMID- 24469105 TI - Uml2 is a novel CalB-type lipase of Ustilago maydis with phospholipase A activity. AB - CalB of Pseudozyma aphidis (formerly named Candida antarctica) is one of the most widely applied enzymes in industrial biocatalysis. Here, we describe a protein with 66 % sequence identity to CalB, designated Ustilago maydis lipase 2 (Uml2), which was identified as the product of gene um01422 of the corn smut fungus U. maydis. Sequence analysis of Uml2 revealed the presence of a typical lipase catalytic triad, Ser-His-Asp with Ser125 located in a Thr-Xaa-Ser-Xaa-Gly pentapeptide. Deletion of the uml2 gene in U. maydis diminished the ability of cells to hydrolyse fatty acids from tributyrin or Tween 20/80 substrates, thus demonstrating that Uml2 functions as a lipase that may contribute to nutrition of this fungal pathogen. Uml2 was heterologously produced in Pichia pastoris and recombinant N-glycosylated Uml2 protein was purified from the culture medium. Purified Uml2 released short- and long-chain fatty acids from p-nitrophenyl esters and Tween 20/80 substrates. Furthermore, phosphatidylcholine substrates containing long-chain saturated or unsaturated fatty acids were effectively hydrolysed. Both esterase and phospholipase A activity of Uml2 depended on the Ser125 catalytic residue. These results indicate that Uml2, in contrast to CalB, exhibits not only esterase and lipase activity but also phospholipase A activity. Thus, by genome mining, we identified a novel CalB-like lipase with different substrate specificities. PMID- 24469107 TI - RNA helicase A is a downstream mediator of KIF1Bbeta tumor-suppressor function in neuroblastoma. AB - Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform beta (KIF1Bbeta) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic XIAP associated factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor (NGF) during development. KIF1Bbeta is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1Bbeta expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis. SIGNIFICANCE: KIF1Bbeta has neuroblastoma tumor-suppressor properties and promotes and requires nuclear localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1Bbeta alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation. PMID- 24469106 TI - Response of BRAF-mutant melanoma to BRAF inhibition is mediated by a network of transcriptional regulators of glycolysis. AB - Deregulated glucose metabolism fulfills the energetic and biosynthetic requirements for tumor growth driven by oncogenes. Because inhibition of oncogenic BRAF causes profound reductions in glucose uptake and a strong clinical benefit in BRAF-mutant melanoma, we examined the role of energy metabolism in responses to BRAF inhibition. We observed pronounced and consistent decreases in glycolytic activity in BRAF-mutant melanoma cells. Moreover, we identified a network of BRAF-regulated transcription factors that control glycolysis in melanoma cells. Remarkably, this network of transcription factors, including hypoxia-inducible factor-1alpha, MYC, and MONDOA (MLXIP), drives glycolysis downstream of BRAF(V600), is critical for responses to BRAF inhibition, and is modulated by BRAF inhibition in clinical melanoma specimens. Furthermore, we show that concurrent inhibition of BRAF and glycolysis induces cell death in BRAF inhibitor (BRAFi)-resistant melanoma cells. Thus, we provide a proof-of-principle for treatment of melanoma with combinations of BRAFis and glycolysis inhibitors. SIGNIFICANCE: BRAF is suppress glycolysis and provide strong clinical benefi t in BRAF V600 melanoma. We show that BRAF inhibition suppresses glycolysis via a network of transcription factors that are critical for complete BRAFi responses. Furthermore, we provide evidence for the clinical potential of therapies that combine BRAFis with glycolysis inhibitors. PMID- 24469108 TI - CD74-NRG1 fusions in lung adenocarcinoma. AB - We discovered a novel somatic gene fusion, CD74-NRG1, by transcriptome sequencing of 25 lung adenocarcinomas of never smokers. By screening 102 lung adenocarcinomas negative for known oncogenic alterations, we found four additional fusion-positive tumors, all of which were of the invasive mucinous subtype. Mechanistically, CD74-NRG1 leads to extracellular expression of the EGF like domain of NRG1 III-beta3, thereby providing the ligand for ERBB2-ERBB3 receptor complexes. Accordingly, ERBB2 and ERBB3 expression was high in the index case, and expression of phospho-ERBB3 was specifically found in tumors bearing the fusion (P < 0.0001). Ectopic expression of CD74-NRG1 in lung cancer cell lines expressing ERBB2 and ERBB3 activated ERBB3 and the PI3K-AKT pathway, and led to increased colony formation in soft agar. Thus, CD74-NRG1 gene fusions are activating genomic alterations in invasive mucinous adenocarcinomas and may offer a therapeutic opportunity for a lung tumor subtype with, so far, no effective treatment. SIGNIFICANCE: CD74-NRG1 fusions may represent a therapeutic opportunity for invasive mucinous lung adenocarcinomas, a tumor with no effective treatment that frequently presents with multifocal unresectable disease. PMID- 24469109 TI - Understanding the effects of time on collaborative learning processes in problem based learning: a mixed methods study. AB - Little is known how time influences collaborative learning groups in medical education. Therefore a thorough exploration of the development of learning processes over time was undertaken in an undergraduate PBL curriculum over 18 months. A mixed-methods triangulation design was used. First, the quantitative study measured how various learning processes developed within and over three periods in the first 1,5 study years of an undergraduate curriculum. Next, a qualitative study using semi-structured individual interviews focused on detailed development of group processes driving collaborative learning during one period in seven tutorial groups. The hierarchic multilevel analyses of the quantitative data showed that a varying combination of group processes developed within and over the three observed periods. The qualitative study illustrated development in psychological safety, interdependence, potency, group learning behaviour, social and task cohesion. Two new processes emerged: 'transactive memory' and 'convergence in mental models'. The results indicate that groups are dynamic social systems with numerous contextual influences. Future research should thus include time as an important influence on collaborative learning. Practical implications are discussed. PMID- 24469110 TI - Reconstitution of OmpF membrane protein on bended lipid bilayers: perforated hexagonal mesophases. AB - Membrane proteins have been reconstituted on lipid bilayers with zero mean curvature (cubic phases or vesicles). Here we show that reconstitution of pore forming membrane proteins can also occur on highly curved lipidic bilayers of reverse hexagonal mesophases, for which the mean-curvature is significantly different from zero. We further show that the membrane protein provides unique topological interconnectivities between the aqueous nanochannels, significantly enhancing mesophase transport properties. PMID- 24469111 TI - High-throughput search for new permanent magnet materials. AB - The currently highest-performance Fe-Nd-B magnets show limited cost-effectiveness and lifetime due to their rare-earth (RE) content. The demand for novel hard magnetic phases with more widely available RE metals, reduced RE content or, even better, completely free of RE metals is therefore tremendous. The chances are that such materials still exist given the large number of as yet unexplored alloy systems. To discover such phases, an elaborate concept is necessary which can restrict and prioritize the search field while making use of efficient synthesis and analysis methods. It is shown that an efficient synthesis of new phases using heterogeneous non-equilibrium diffusion couples and reaction sintering is possible. Quantitative microstructure analysis of the domain pattern of the hard magnetic phases can be used to estimate the intrinsic magnetic parameters (saturation polarization from the domain contrast, anisotropy constant from the domain width, Curie temperature from the temperature dependence of the domain contrast). The probability of detecting TM-rich phases for a given system is high, therefore the approach enables one to scan through even higher component systems with one single sample. The visualization of newly occurring hard magnetic phases via their typical domain structure and the correlation existing between domain structure and intrinsic magnetic properties allows an evaluation of the industrial relevance of these novel phases. PMID- 24469112 TI - Nonclassical antifolates, part 5. Benzodiazepine analogs as a new class of DHFR inhibitors: synthesis, antitumor testing and molecular modeling study. AB - A new series of tetrahydro-quinazoline and tetrahydro-1H dibenzo[b,e][1,4]diazepine analogs were synthesized and tested for their DHFR inhibition and in vitro antitumor activity. Compound 35 showed a remarkable DHFR inhibitory potency (IC50, 0.004 MUM) which is twenty fold more active than methotrexate (MTX). Compounds 17 and 23 proved to be fifteen fold more active than the known antitumor 5-FU, with MG-MID GI50, TGI, and LC50 values of 1.5, 46.8, 93.3 and 1.4, 17.4, 93.3 MUM, respectively. Computer modeling studies allowed the identification that methoxy and methyl substituents, the pi-system of the chalcone core, the nitrogen atoms, on the dibenzodiazepine ring as pharmacophoric features essential for activity. These mark points could be used as template model for further future optimization. PMID- 24469113 TI - Carotid intima media thickness in patients with obstructive sleep apnea: comparison with a community-based cohort. AB - BACKGROUND: The impact of obstructive sleep apnea (OSA) on the development of atherosclerotic cardiovascular disease (CVD) in the absence of overt CVD or risk factors is unclear. Our purpose was to assess whether patients with OSA without overt CVD or risk factors have subclinical atherosclerosis as evaluated by carotid intima medial thickness (CIMT) compared to matched controls. METHODS: We measured CIMT in patients >40 years old, who underwent polysomnography for suspected OSA and did not have a history of CVD or risk factors (smoking, hypertension, diabetes, hyperlipidemia). OSA severity was classified according to apnea-hypopnea index. Serum levels of high-sensitivity C-reactive protein, fibrinogen, and lipids were assessed and relationships with OSA severity explored. CIMT measurements from patients with OSA were compared those of to age , gender-, and BMI-matched controls from a community-based cohort without known CVD or OSA. RESULTS: Fifty-one patients were studied. Of these, patients with severe OSA had an increased CIMT compared to patients without OSA, but the relationship was not significant after controlling for age (p = 0.10). However, 37 patients had OSA and were matched to 105 controls. CIMT was significantly increased in OSA patients versus controls (0.77 vs. 0.68 mm, p = 0.03). The difference between patients and controls was greater for patients with severe OSA (0.83 vs. 0.71 mm) than for patients with mild-to-moderate OSA (0.71 vs. 0.67 mm). CONCLUSIONS: Patients with OSA but without a history of or risk factors for CVD have increased CIMT compared to a BMI-, age-, and gender-matched cohort. This provides evidence that OSA is an independent risk factor for the development of CVD. PMID- 24469114 TI - Results of the prospective multicenter Japanese bridge to transplant study with a continuous-flow left ventricular assist device. AB - Continuous-flow left ventricular assist devices (LVADs) are becoming the standard of care for patients with refractory end-stage heart failure. We present the outcomes of patients enrolled in a prospective multicenter clinical study in Japan using the HeartMate II continuous-flow LVAD for bridge to transplantation. The study evaluated 6 inotrope-dependent heart failure patients failing on medical management (3 males and 3 females, age 44.7 +/- 15.8 years, BSA 1.58 +/- 0.17 m(2)) implanted with the HMII LVAD at 5 Japanese centers. Functional status, adverse events and outcomes were determined for the first 6 months with follow-up at 2 years. After implant, functional improvement was evident in 6-min walk distance which increased from 268 +/- 92 m at baseline to 399 +/- 105 m at 6 months, and 100% of patients were in NYHA class I or II at 6 months compared to 0% at baseline. Adverse events included localized non-device-related infection (4/6), arrhythmias (3/6) and percutaneous lead infection (1/6). There were no re thoracotomies for bleeding and no strokes or pump replacements. All patients were alive at 6 months and all were transplanted after 1.96-3.58 years of LVAD support. The results in Japan of the HMII LVAD for BTT are consistent with results from the US pivotal clinical trial. The expanded use of this technology to Japanese heart failure patients is appropriate. PMID- 24469115 TI - Untethered micro-robotic coding of three-dimensional material composition. AB - Complex functional materials with three-dimensional micro- or nano-scale dynamic compositional features are prevalent in nature. However, the generation of three dimensional functional materials composed of both soft and rigid microstructures, each programmed by shape and composition, is still an unsolved challenge. Here we describe a method to code complex materials in three-dimensions with tunable structural, morphological and chemical features using an untethered magnetic micro-robot remotely controlled by magnetic fields. This strategy allows the micro-robot to be introduced to arbitrary microfluidic environments for remote two- and three-dimensional manipulation. We demonstrate the coding of soft hydrogels, rigid copper bars, polystyrene beads and silicon chiplets into three dimensional heterogeneous structures. We also use coded microstructures for bottom-up tissue engineering by generating cell-encapsulating constructs. PMID- 24469116 TI - Effect of change in macular birefringence imaging protocol on retinal nerve fiber layer thickness parameters using GDx VCC in eyes with macular lesions. AB - This study evaluates the effect of two macular birefringence protocols (bow-tie retardation and irregular macular scan) using GDx VCC on the retinal nerve fiber layer (RNFL) thickness parameters in normal eyes and eyes with macular lesions. In eyes with macular lesions, the standard protocol led to significant overestimation of RNFL thickness which was normalized using the irregular macular pattern protocol. In eyes with normal macula, absolute RNFL thickness values were higher in irregular macular pattern protocols with the difference being statistically significant for all parameters except for inferior average thickness. This has implications for monitoring glaucoma patients who develop macular lesions during the course of their follow-up. PMID- 24469117 TI - Ocular manifestations of head injury and incidence of post-traumatic ocular motor nerve involvement in cases of head injury: a clinical review. AB - As the eyes are in close proximity to the skull, they can get simultaneously affected in head injuries. This close association warrants careful ocular examination in all cases of head injury. This is a prospective non-randomized analytical study to evaluate various ocular manifestations in cases of head injury with special reference to ocular motor nerve involvement, correlation between pupillary changes, and survival. A total of 1,184 patients with head injury were screened for ocular manifestations. This study comprises 594 patients with ocular manifestations of head injury. All the relevant data was compiled and analyzed as per proforma. Ocular manifestations were evaluated in each patient and appropriate investigations were carried out. Patients with ocular morbidity were analyzed for age, sex, mode of injury, Glasgow Coma Score, and associated injuries in addition to ophthalmic and neurosurgical evaluations. Of the 594 patients, 81.6 % were male and 18.4 % were female, with a male-to-female ratio of 4:1. The major cause of head injury was road traffic accidents (70.37 %). The most common age group involved was, 21-40-year-olds (67.40 %). Out of 594 patients, ecchymosis was found in 51.85 %, subconjunctival hemorrhage in 44.44 %, lid edema in 41.48 %, lacerated wound in 22.59 %, pupillary involvement in 21.04 %, ptosis in 6.73 %, cranial nerve palsy in 11.62 %, orbital fractures in 10.44 %, optic nerve trauma in 4.04 %, and exposure keratitis in 4.21 %. Patients with bilaterally dilated or pinpoint fixed pupils had a 10 times higher risk of mortality than patients without pupillary involvement. Third nerve involvement was seen 2.85 times more frequently in frontal and parietal region injuries compared to other sites of injury. The involvement of the sixth nerve occurred 4.6 times more frequently in parietal region injuries compared to other sites of injury. PMID- 24469118 TI - [Spatiotemporal expression of ADAM10 during cranial base suture development]. AB - PURPOSE: To explore the expression of a disintegrin and metalloproteinase 10 (ADAM10) during mouse's development of cranial base synchondrosis. METHODS: Histological and biochemical method including alcian blue-alizarin red staining, IHC, ICC and Western blot were applied to observe and analyze the expression of ADAM10 in mouse cranial base. RESULTS: The spheno-occipital synchondrosis and spheno-ethmoid synchondrosis were of similar histological structure, including resting zone, proliferative zone and hypertrophic zone. ADAM10 was expressed widely in synchondrosis,especially in the hypertrophic zone. During development of cranial base, ADAM10 was highly expressed from embryo period to infantile period, while there was a huge decrease when it came to adulthood. As an excellent cell line to mimic chondrogenesis, ATDC5 expressed ADAM10 in cytoplasm, particularly around the nucleus. CONCLUSIONS: The expression of ADAM10 during mouse's development of cranial base synchondrosis is spatiotemprally different. Supported by National Natural Science Foundation of China (10972142), National Science Foundation for Distinguished Young Scholars of China (81000451),Science Foundation for Young Scholars of Shanghai Municipal Public Health Bureau (2010y142), Foundation for Distinguished Youth Teachers of Shanghai Municipal Commission of Education [(2010)83], Key Research Project of Science and Technology Committee of Shanghai Municipality (12JC1405700) and Innovation Team Project of Shanghai Municipal Commission of Education. PMID- 24469119 TI - [Finite element analysis of first maxillary molars restored with different post and core materials]. AB - PURPOSE: To analyze the stress magnitude and distribution of residual dentin in maxillary first molar restored with post and crown using three-dimension finite element methods. METHODS: An intact maxillary first molar was scanned using a 3DX multi-image micro-CT. Three-dimensional finite element models simulated an endodontically treated first maxillary molar restored with post and crown, which were varied in different number and material of post. A load of 480 N, simulating intercuspal occlusion, was applied vertically to the occlusal surface and a load of 240 N simulating mastication was applied to the occlusal surface with a 45 degrees angle to the long axis of the tooth. Von Mises stresses were calculated by MSC.Marc software. RESULTS: The maximum stresses among the post in the radicular portion increased as elastic modulus of the material increased. The stress values of remaining dentin observed in two-post group were lower than those in one post group and three-post group for cast metal post systems. In the test simulating mastication, the peak value of Von Mises stress was higher on remaining dentin among the post in the radicular portion and lower on the outer surface of residual tooth tissue than that in the test simulating intercuspal occlusion. CONCLUSIONS: The number, material of post and occlusal loading have influence on magnitude and distributionn of stress. Supported by Natural Science Foundation of China (81271175) and National Science and Technology Supporting Plan (2012BAI07B01). PMID- 24469120 TI - [Detection of the exogenous gene copy number of the transgenic tomato anti-caries vaccine]. AB - PURPOSE: To detect the exogenous gene copy number of the transgenic tomato anti caries vaccine by using the SYBR Green real-time PCR. METHODS: Recombinant plasmid pEAC10 and pEPC10 were used as standard to detect genome samples of exogenous gene pacA-ctxB and pacP-ctxB by SYBR green fluorescent quantitation, then the average value was calculated as gene copy number. RESULTS: The copy number of the transgenic tomato carrying pacA-ctxB was 1.3 and the pacP-ctxB was 3.2. CONCLUSIONS: The transgenic tomato plants which have high stability are low copy transgenic plants. Supported by National Natural Science Foundation of China (30160086, 81260164), Science and Technical Fund of Guizhou Province (LKZ[2011]41), Project of Technology Innovation Team in Guizhou Province, Leading Academic Discipline Construction Project in Guizhou Province and Excellent Scientific Research Team Cultivation Project in Zunyi Medical College ([2012]12). PMID- 24469121 TI - [Specific markers and ultrastructure of lymphatic vessel in healthy human dental pulp]. AB - PURPOSE: To explore the existence of lymphatic vessels in healthy human dental pulp. METHODS: Thirty healthy human dental pulps were obtained from non-carious premolars removed for orthodontic reasons. Immunohistochemistry was performed using the antibodies specific for lymphatic endothelium such as D2-40 and LYVE-1, and for vascular endothelial cell such as CD31 and CD34. The expression of D2-40 was detected by Western blotting and ultrastructure was examined by transmission electron microscopy. RESULTS: In healthy human dental pulps, we failed to detect any reactivity for the lymphatic markers D2-40 and LYVE-1 in the observed vessels. These vessels were positive stained by blood endothelial markers CD34 and CD31. Odontoblasts were weakly stained with D2-40. Western blotting performed on collagenase-treated human dental pulps did not show a band at 40 kDa, corresponding to the molecular weight of the lymphatic marker D2-40. Transmission electron microscopy indicated that vessels in dental pulp consisted of endothelial monolayer surrounded by pericytes and complete basement membrane, which were typical ultrastructural characteristics of blood vessels rather than lymphatic vessel. CONCLUSIONS: Human dental pulp does not contain true lymphatic vessels under healthy conditions. Whether lymphatic system is involved in dental pulp interstitial fluid circulation during inflammation deserved further study. Supported by National Natural Science Foundation of China (81100768) and Key Project Supported by Medical Science and Technology Development Foundation, Department of Health of Nanjing City (YKK11040 and QRX11123). PMID- 24469122 TI - [Construction of recombinant for generation of Porphyromonas gingivalis minor accessory proteins FimCDE deficient strain]. AB - PURPOSE: To construct a recombinant plasmid containing the upstream of fimC and downstream of fimE of Porphyromonas gingivalis, designated as pPHU281-C-Spec-E, which may be further used to knock out fimCDE gene to determine the role of FimCDE in the infection by P. gingivalis. METHODS: DNA fragments were generated by PCR with the genomic DNA of P. gingivalis strain ATCC 33277 as the template. The upstream fragment of fimC (fragment C) and downstream fragment of fimE (fragment E) were cloned into the suicide plasmid pPHU281 to generate plasmid pPHU281-C-E. The spectinomycin resistance gene was inserted between fragment C and E to construct plasmid Pphu281-C-Spec-E. The recombinant plasmid was verified by restriction enzyme digestion and DNA sequencing. RESULTS: The recombinant plasmid pPHU281-C-Spec-E was successfully constructed, which was ready for generation of FimCDE-knockout mutant of P. gingivalis. CONCLUSIONS: The recombinant plasmid pPHU281-C-Spec-E is a tool for construction of FimCDE deficient mutant of P. gingivalis. Supported by National Natural Science Foundation of China (81070839). Team Project of Medical Leaders in Talent and Innovation of Jiangsu Province (LJ201110), Science and Technology Development Plan of Nanjing City(YKK06115) and Medical Science and Technology Development Project of Nanjing City(ZKX1030). PMID- 24469123 TI - [A comparative study of the cytotoxicity of five dental bonding agents to human periodontal ligament cells]. AB - PURPOSE: To compare the cytotoxicity of 5 different dental bonding agents to human periodontal ligament cells(HPDLCs). METHODS: Primary cultured HPDLCs were exposed to different concentrations (100%,50% and 25%) of Super Bond, Clearfil SE Bond, G-Bond, Single Bond2, and Adper Easy One for different times (24 h, 48 h and 72 h). Cytotoxicity of 5 different agents to HPDLCs were observed by MTT method. The data was analyzed using SPSS 19.0 software package. RESULTS: Cytotoxicity of 5 dentin bonding agents to HPDLCs were Super Bond0.05). CONCLUSIONS: Cytotoxicity of 5 dentin bonding agents are different. Cytotoxicity of Super-bond C&B,G-Bond and Clearfil SE Bond are weak, while cytotoxicity of Single Bond2 is the strongest among the 5 agents. Supported by Medical Leading Talents and Innovation Team Project of Jiangsu Province (LJ201110) and Natural Science Foundation of Jiangsu Province (SBK201340904). PMID- 24469124 TI - [Recombinant hFOXA2 and hPDX1 lentivirus induced dental pulp stem cells from deciduous teeth reprogramming for insulin-producing cells]. AB - PURPOSE: The purpose of this study was to culture and identify dental pulp stem cells(DPSCs) from deciduous teeth in vitro and construct the recombinant hFOXA2 and hPDX1 lentivirus vectors and transfect the DPSCs to induce insulin-producing cells (IPCs). METHODS: DPSCs were separated and cultured by enzyme digest method, and purified by limited dilution method. Flow cytometry was used to determine the surface marker expression of the DPSCs, and the ability of multiple differentiations was determined by specific staining. hFOXA2 and hPDX1 genes were amplified by PCR, and the recombinant hFOXA2 and hPDX1 lentivirus vectors were reconstructed and transfected into 293T cells by lipofectamine2000 for virus packaging. The viral infection efficiency and titer were determined through fluorescence cell count. The recombinant virus was used to infect the DPSCs cells via multiplicity of infection (MOI) and induce the DPSCs reprogramming for IPCs. Immunofluorescence staining was used to measure the expression of proinsulin, FOXA2 and PDX1. ELISA method was used to detect the insulin secretion. The data was analyzed Using SPSS13.0 software package. RESULTS: DPSCs were isolated and cultured successfully. Cell surface highly expressed STRO-1 (98.01%), CDl46 (98.51%), CD34 (99.54%) and CD45 (24.08%). The multi-lineage differentiation capacity into osteoblasts, chondrocytes, and adipose was achieved. The recombinant hFOXA2 and hPDX1 lentivirus vectors were successfully constructed. Double enzyme digestion and sequencing appraisal showed that the sequence was fully consistent with GenBank retrieval. Virus packing efficiency was (96.15+/ 0.17) % and (95.49+/-0.21) % respectively, and the infection titer was about 1.80+/-108 GTU/mL. The best MOI of the virus was 20. After inducing the cells to express proinsulin, FOXA2 and PDX1, insulin secretion volume was about 1.92 MUmol/L. Compared with the uninduced group and control group, insulin secretion increased significantly (P<0.01). CONCLUSIONS: The recombinant transcription factor virus can activate cell reprogramming mechanism, form insulin-producing cells, and can be used for gene therapy of diabetes seed cells. Supported by Science and Technology Research Program of Shaanxi Province (2009K17-06) and Science and Technology Innovation as a Whole Plan Resources Leading Industry Key Technology (Chain) Project of Shaanxi Province (2011KTCL03-24). PMID- 24469125 TI - [Study of the effect of chitosan and its composites on proliferation and differentiation of mouse osteoblasts]. AB - PURPOSE: A mouse osteoblast cell line, MC3T3-E1, was cultivated in the medium that contained chitosan, type I collagen and recombinant human bone morphogenetic protein-2 in vitro to evaluate the effect of chitosan and its composites on proliferation and differentiation of mouse osteoblasts. METHODS: This study was categorized into 4 groups based on the medium used. Group A: alpha-MEM medium; group B: CS, type I collagen and alpha-MEM medium; group C: CS, type I collagen, rhBMP-2 and alpha-MEM medium. alpha-MEM medium containing 1%FBS was used in the control group. Cells of each group were cultivated for 1,3,5 and 7 days. The optical density (OD) value at each time point was evaluated with MTT assay and growth curve was drawn to observe the proliferation of osteoblasts. Differentiation of osteoblasts was determined with alkaline phosphatase (ALP) activity assay, alkaline phosphatase staining and alizarin red staining. Alkaline phosphatase activity of each group was measured at day 1, 3, 5 and 7 days. After 7 days of culture, the cells were stained with alkaline phosphatase, and at day 14, the mineralized nodules were stained with alizarin red. Statistical analysis was performed using SPSS13.0 software package. RESULTS: The MTT assay results showed that the OD value was maximal when osteoblasts were cultured in group C. The difference were statistically significant between group C and others (P<0.05). The ALP activity showed that the result of group C was significantly higher than other groups. The increase of ALP activity was significant between group C and control group (P<0.05). However, no significant difference was found between group C and group B (P>0.05). Compared with the control group, group C had more calcium nodules and blue particles than others. CONCLUSIONS: The incorporation of type I collagen and bone morphogenetic protein-2 into chitosan can promote MC3T3-E1 cell proliferation and differentiation better. Supported by Major Science and Technology Project of Liaoning Province (2010225001). PMID- 24469126 TI - [Effect of overexpressed VEGF165 and TGFbeta1 on the regeneration of dentin-like tissue in rat]. AB - PURPOSE: To transfect recombinant vectors pcDNA3.1hisA-VEGF165 and pcDNA3.1hisA TGFbeta1 in Chinese hamster ovary cell (CHO) and investigate the effect of released VEGF165 and TGFbeta1 proteins by CHO on the regeneration of dentin-like tissues. METHODS: The recombinant plasmids pcDNA3.1hisA-VEGF165 and pcDNA3.1hisA TGFbeta1 were transfected in CHO via liposome. After screen culture by G418, stable transfected CHO cell line was established. The levels of VEGF165 and TGFbeta1 were evaluated by RT - PCR and ELISA. Then the cells were seeded on collagen membranes. The bilateral maxillary first molars of 24 Wistar rats were selected as experimental teeth and the collagen membranes were separately planted over the holes of artificial dental pulp exposure. The cavities were filled with ChemFlex finally. After 8 weeks, specimens from 24 rats were collected and dyed with toluidine blue. Statistical analysis was performed with SPSS 17.0 software package. RESULTS: The results of RT-PCR and ELISA showed that CHO stably expressed VEGF165 and TGFbeta1 mRNAs and proteins after transfection and selection. The result of toluidine blue staining showed that in the group of CHO transfected with pcDNA3.1hisA-VEGF165, the blood capillaries were congestive and inflammatory cells infiltrated obviously under the mechanically exposed pulpal site, but no hard tissue regenerated. In the group of CHO transfected with pcDNA3.1hisA-TGFbeta1, a spot of colored mineralization pellets under the mechanically exposed pulpal site surrounded with hyperplastic fibroblast were observed, no tubular dentin and sporadic inflammatory cells were detected. In the group of CHO transfected with pcDNA3.1hisA-VEGF165 and pcDNA3.1hisA-TGFbeta1, generous colored mineralization pellets almost closed the mechanically exposed pulpal site and columnar odontoblast were arranged orderly, no regular dentin bridge was detected. The hard tissue was not detected in the control group. CONCLUSIONS: TGFbeta1 could promote the formation of mineralization pellets in vivo, and VEGF165 and TGFbeta1 could promote the formation of mineralization pellets better. Supported by Science and Technology Development Foundation of Shandong Province (2010G0020230) and Natural Science Foundation of Shandong Province (Y2006C47). PMID- 24469127 TI - [The experimental study of subcutaneous ectopic ossification with different proportional mixtures of human autologous bone and hydroxyapatite in nude mice]. AB - PURPOSE: To observe the effect of subcutaneous ectopic osteogenesis using different proportional mixtures of hydroxyapatite (HAP) and human mandible in nude mice. METHODS: After obtaining external oblique ridge of mandible, autologous bone was mixed with HAP according to certain proportion. The mixtures were divided into 5 groups (group A: autologous bone/HAP=2/1; Group B: autologous bone/HAP=1/1; Group C: autologous bone/HAP=1/2; Group D: autologous bone/HAP=a quarter; Group E: HAP). The 5 groups of mixtures were respectively implanted into nude mice subcutaneously. After 8 weeks, the specimens were obtained and hard tissue sections were completed. The new bone formation was measured after trinitrophenol staining. The data was analyzed with SPSS 13.0 software package. RESULTS: The hard tissue section showed that new ectopic bone formation area was 9.1% (Group A), 16.1% (Group B), 6.1% (Group C), 3.8% (Group D), and 1.3% (Group E), respectively. New bone formation was the most in group B, while it was the least in group E. Significant differences were found between group B and other groups(P<0.05). However, there was no significant difference between group E and group C or D (P>0.05). The retention rate of HAP was the most in group E (30.3%) and the least (16.3%) in group A. CONCLUSIONS: During 8 weeks, human autologous bone mixed with HAP helps new bone formation in nude mice. The best ratio autologous bone and HAP was 1:1. This study provides certain reference basis for dentist to make lifting surgery outside the maxillary sinus using artificial bone graft. Supported by Science and Technology Project of Ningxia Hui Autonomous Region (2011zys271). PMID- 24469128 TI - [Effect of bonding strength of dentin adhesive agent under 2 kinds of storage temperatures]. AB - PURPOSE: To measure the changes of bonding strength of dentin adhesive agent at different storage temperatures. METHODS: One hundred extracted bicuspids were randomly divided into 10 sets, 10 teeth in each set. Each set was further divided randomly into Group A and Group B, each with 5 teeth. During a 10-week test period, Groups A and B were applied with adhesives labeled A and B. Group A was refrigerated under 4 degrees centigrade and B was stored at room-temperature from the second week on. The first set was stored at the same situation. The shear force of samples were tested by universal material tester at the speed of 1 mm/min. The results were evaluated using one-way ANOVA and LSD t test using SPSS 18.0 software package. RESULTS: According to one-way ANOVA, the shear bond strength of the 2 groups differed significantly (P<0.05). Comparing the sets by LSD t test, the results showed that during the first 5 weeks, there was no significant difference between Group A and B. However, there were measurable differences in performance after 6 weeks. CONCLUSIONS: With time goes on, the bonding strength of both refrigerated and room-temperature adhesives tend to diminish. After 6 weeks, the bonding performance of the 2 groups begins to differ significantly, and the refrigerated adhesives are superior to room-temperature adhesives. PMID- 24469129 TI - [Effect of different surface managements on micro-tensile bond strength of non carious sclerotic dentin to resin]. AB - PURPOSE: To evaluate the micro-tensile bond strength of 3 different surface managements to non-carious sclerotic dentin. METHODS: Fifteen periodontal patients' occlusal wearing molars which were above 3rd degree were selected. The teeth were equally cut into two pieces along the buccolingual direction, and each piece was randomly divided into 3 groups. Group 1 was processed with polishing, group 2 was processed with EX-26 diamond bur and group 3 was processed with 5# round bur. All teeth were subjected to Optibond treatment, and then filled with composite resin (Premisa) and saved in normal artificial saliva (37 degrees centigrade) for 24 hours. At last, fatigue test pieces were made, the micro tensile bond strength was evaluated and every specimen was examined under stero microscope. The micro-tensile bond strength was analyzed with one-way analysis of variance using SPSS17.0 software package. RESULTS: The micro-tensile bond strength of the 3 groups were (10.48+/-1.29) MPa, (21.52+/-0.97) MPa and(16.30+/ 1.02) MPa, respectively. The bond strength of EX-26 diamond bur group was significantly greater than that of the other 2 groups (P<0.05). The bond strength of 5# round bur group was significantly greater than that of polishing group (P<0.05). The breakage mostly happened in adhesive dentine surface. CONCLUSIONS: Non-carious sclerotic dentin which is processed with diamond bur has better micro tensile bonding strength. PMID- 24469130 TI - [Effect of pituitary tumour transforming gene on invasion and metastasis of salivary adenoid cystic carcinoma]. AB - PURPOSE: To study the effect of pituitary tumour transforming gene (PTTG) on invasion and metastasis of salivary adenoid cystic carcinoma. METHODS: The expression of PTTG and bFGF was investigated in 40 salivary adenoid cystic carcinoma tissues and 20 normal salivary tissues by immunohistochemistry. Pearson's Chi-square test and Spearman correlation analysis were used to analyze the data using SPSS 11.5 software package. RESULTS: The expression of PTTG and bFGF were significantly higher in salivary adenoid cystic carcinoma tissues than in normal salivary gland tissues (P<0.01) and their expression levels were positively correlated (P<0.01). CONCLUSIONS: PTTG and bFGF are highly expressed in salivary adenoid cystic carcinoma. The invasion and metastasis of salivary adenoid cystic carcinoma are correlated with the expression of PTTG. Supported by National Natural Science Foundation of China (81102058). PMID- 24469131 TI - [Assessment of mental health status in oral squamous cell carcinoma patients and its correlation with catecholamines level]. AB - PURPOSE: To investigate the relationship between mental health status and catecholamines level in oral squamous cell carcinoma patients. METHODS: Forty patients with oral squamous carcinoma (OSCC) who were diagnosed in West China School of Stomatology between Dec. 2011 and Aug. 2012, were assessed with symptom checklist-90 (the 5-grade scoring of 0 to 4 points was used) independently according to their actual conditions. Blood sample was taken on the second admission day and fresh tumor tissue with the weight of 0.5 g was obtained. A method was developed for determination of catecholamine and glucocorticoid in serum using liquid chromatography-tandem mass spectrometry (HPLC-MS-MS). SPSS19.0 software package was used for statistical analysis. RESULTS: Forty patients were included in the study. Compared with the scores of SCL-90 in national norms, the scores were all higher in oral squamous carcinoma patients except the interpersonal relationship. Epinephrine(E) and norepinephrine(NE) in serum was (70.27+/-34.50) pg/mL and (316.73+/-109.22) pg/mL, respectively. E and NE in tumor tissues was (6.66+/-3.58) pg/mg and (12.67+/-5.27) pg/mg respectively. As the concentrations of NE and E from circulating serum increasing, the stage and grade of oral squamous carcinoma were promoted. CONCLUSIONS: Psychiatric factors have an important impact on OSCC patients. The increased level of catecholamines is closely related to clinical stage and grade of OSCC. Supported by National Natural Science Foundation of China (81172578) and Natural University Students Innovation Training Program (201210610096). PMID- 24469132 TI - [Clinical study on base bonding CAD/CAM customized zirconium abutment]. AB - PURPOSE: To evaluate the clinical application of base bonding customized zirconium abutment. METHODS: A total of 141 base bonding customized zirconium abutments used in 114 implant-supported cases during 2010.6-2012.11 in Hangzhou Stomatology Hospital were involved in the study. To evaluate the efficacy, they were followed up for 3 months to 2 years. RESULTS: Among 141 abutments, 140 were successfully applied to implant prosthesis at first time. During the observation period, partial zirconia exfoliation from bases occurred in 1 abutment. All the patients and dentists were satisfied with the final esthetic outcomes. CONCLUSIONS: The clinical effect of base bonding customized zirconium abutment is acceptable. Supported by Science and Technology Development Project of Hangzhou City(20120633B20) and Science Research Fund Key Specialist of Health and Disease of Hangzhou City(20130633B35). PMID- 24469133 TI - [Abnormal expression of CytC in the labial gland of patients with primary Sjoigren's syndrome]. AB - PURPOSE: To explore the expression of CytC in the labial glands of patients with primary Sjogren's syndrome(pSS). METHODS: Thirty-five cases with pSS and 15 controls were collected. Immunohistochemistry and RT-PCR were used to examine CytC protein and mRNA in labial glands of 2 groups. The integral optical density were measured and the data was analyzed by Mann-Whitney test with SPSS14.0 software package. The correlation between the clinical manifestations and the expression of CytC were calculated by Spearman's analysis. RESULTS: The expression of CytC protein and mRNA in pSS were positively correlated with the disease course and significantly higher than those in control group (P<0.05). There was a positive correlation between the lymphocyte focus score and the expression of CytC, but no correlation with the other clinical parameters. CONCLUSIONS: The expression of CytC in pSS is increased,which is related to the disease course and the lymphocyte focus score. Supported by Science and Technology Research Project of Liaoning Province (2011225020) and College Scientific Research Foundation for Youth in 2013 (K101593-13-39). PMID- 24469134 TI - [Evaluation of upper airway and surrounding structures in patients with obstructive sleep apnea using cephalometry combined with Muller's maneuver]. AB - PURPOSE: To evaluate the upper airway and surrounding structures under intraluminal pressure using cephalometry combined with Muller's maneuver in obstructive sleep apnea and hypopnea syndrome (OSAHS) patients with different severity. METHODS: Thirty-nine male patients were enrolled in our department during June 2011 to February 2012. Polysomnography (PSG) and anthropometric measurements data were recorded prior to the study. The lateral cephalograms of each patient were obtained during both the end-expiration phase and Muller's maneuver phase. The patients enrolled were classified into 3 groups according to the results of apnea-hypopnea index (AHI), including mild group (n=11), moderate group (n=14), and severe group (n=14). Craniofacial and upper airway structures were measured in lateral cephalometry by application of Cassos 2001 computed aided measurement software before and after the patients practicing Muller's maneuver. The data was analysed using SAS 9.13 software package. RESULTS: Muller's maneuver had a great influence on the upper airway and surrounding tissue, including increased thickness of the uvula, reduction in the anteroposterior dimension of retropalatal and increased vertical distance of the hyoid bone to the mandible in all groups (P<0.05). In addition, Muller's maneuver also had an impact on the length of the upper airway, which was more significant in severe cases. CONCLUSIONS: Cephalometry combined with Muller's maneuver can display how the intraluminal pressure function on the upper airway and surrounding tissues, and they also can distinguish some minor differences of the upper airway in patients with different security. Supported by Research Fund of Science and Technology Commission of Shanghai Municipality (11140902001). PMID- 24469135 TI - [Perforator vascular anatomy and clinical application of the anteromedial thigh flap for head and neck reconstruction]. AB - PURPOSE: A clinical study was undertaken to define the vascular anatomy of anteromedial thigh perforator flap (AMT) and evaluate the outcomes of the flap in head and neck reconstruction. METHODS: The sizable perforators of AMT flaps and their origins were prospectively explored in 54 patients. For each patient, we recorded the sizable perforators' location, diameter, source vessel, numbers and anatomical types. Among them, 14 cases underwent head and neck reconstruction with AMT flaps. The complications and functions of donor and recipient sites were recorded and the operative techniques of AMT were described. Statistical analysis was performed with SPSS 13.0 software package. RESULTS: Eight of fifty-four thighs had no sizable AMT perforators. AMT flap was based on the medial branch of descending branch of lateral circumflex femoral artery (d-LCFA) and shared the same vascular pedicle with anterolateral thigh flap (ALT). The total sizable perforators were 56. Among them, 40.9%(25/61) were direct septocutaneous perforators, the remaining perforators were all musculocutaneous. Most of the sizable perforators (58/61, 95.1%) were located in the middle one-third of the thigh, with an average of (3.9+/-0.72) cm medial to a line connecting the anterior superior iliac spine and the superolateral patella and an average of (22.5+/-2.38) cm to anterior superior iliac spine. There was an negtive relationship between the number of sizable perforators of AMT and ALT flaps (P<0.01). 14 flaps survived completely. No complications were observed in recipient and donor site. CONCLUSIONS: The pedicle of AMT flap is the medial branch of d-LCFA. The AMT flap may be useful if ALT flap is without sizable perforators. AMT flap may be as a primary or an alternative choice of anterolateral thigh flap for head and neck reconstruction. PMID- 24469136 TI - [Survey and analysis of dental anxiety in adult outpatients]. AB - PURPOSE: To analyze the prevalence of dental anxiety in outpatients and to discuss the possible correlative factors. METHODS: A questionaire survey was conducted among a total of 1266 adult outpatients in our department from Jan. 2010 to Jun. 2012. All patients were asked to complete the Modified Dental Anxiety Scale to evaluate the level of dental anxiety and the related factors. The data was analyzed by SPSS 13.0 software package. RESULTS: The prevalence rate of dental anxiety in outpatients was 61.37%, Dental anxiety was more likely to occur in female patients, patients of lower education level, and patients who re visit or visit for oral surgery (P<0.05). CONCLUSIONS: The prevalence rate of dental anxiety of adult outpatients is high. Dental anxiety is positively correlated with gender, education level, main complaints, first visit or re visit. PMID- 24469137 TI - [Effect of dexmedetomidine on emergence agitation after oral and maxillofacial surgery]. AB - PURPOSE: To evaluate the effect of dexmedetomidine on emergence agitation after oral and maxillofacial surgery. METHODS: Fifty five patients who went into recovery room after oral and maxillofacial surgery were randomly divided into 2 groups: dexmedetomidine group (n=28) and control group (n=27). Patients in dexmedetomidine group were assigned to receive intravenous dexmedetomidine at a dose of 0.3 MUg/kg when they came into recovery room. Patients in control group were assigned to receive intravenous normal saline. Emergence agitation was assessed and extubation time after operation was recorded. Mean arterial pressure, heart rate, arterial oxygen saturation, Ramsay scale were recorded at the time point of entering the recovery room instantly(T0) and 5 minutes(T1), 15 minutes(T2), 30 minutes(T3), 60 minutes(T4), 120 minutes(T5) after the patient came into recovery room. Statistical analysis was performed using SAS 9.1 software package. RESULTS: The incidence of emergence agitation was significantly lower in the dexmedetomidine group (18%) than in the control group (70%) (P<0.05). The Ramsay scale was significantly higher in dexmedetomidine group than in the control group at the time point of T1, T2, T3, T4 (P<0.05). The heart rate was significantly lower in dexmedetomidine group than in the control group at the time point of T1, T2, T3, T4, T5 (P<0.05). Mean arterial pressure was significantly lower in dexmedetomidine group than in the control group at the time point of T2, T3 (P<0.05). There was no significant difference on extubation time between 2 groups. There was no postoperative respiratory depression in 2 groups. CONCLUSIONS: Intravenous dexmedetomidine at a dose of 0.3 MUg/kg can reduce emergence agitation after oral and maxillofacial surgery with safety and efficacy. PMID- 24469138 TI - [Clinical trail on the effect of nitrous oxide/oxygen inhalation sedation on the treatment of acute pulpitis]. AB - PURPOSE: To evaluate the effectiveness and safety of nitrous oxide/oxygen inhalation sedation in the treatment of acute pulpitis. METHODS: The study population comprised 72 patients of acute pulpitis treated from September 2012 to March 2013. They were randomly divided into 2 groups, which included experimental group (37 cases) and control group (35 cases). Venham clinical anxiety, cooperative behavior level and WHO clinical pain level evaluation were conducted for the patients. Wilcoxon and Chi-square test were used respectively for statistical analysis with SPSS 14.0 software package. RESULTS: In the experimental group, 86.5% cases behaved comfortable, while in the control group the rate was only 42.9%. 94.6% of the patients in the experimental group felt painless after therapy. The proportion of that in the control group was 68.6%. There was significant difference between the 2 groups (P<0.01). CONCLUSIONS: The technique of nitrous oxide/oxygen inhalation sedation provides a safe and effective way to release pain and anxiety during treatment of acute pulpitis, while the long-term clinical result still needs further investigation. PMID- 24469139 TI - [Efficacy of E-max porcelain laminate veneer on esthetic restoration for anterior teeth over 2 years]. AB - PURPOSE: To evaluate the clinical effect of E-max porcelain laminate veneer on esthetic restoration for anterior teeth over 2 years. METHODS: E-max porcelain laminate veneer was used in 45 patients with 120 defective anterior teeth. Improved Ryge veneer reexamination standards including the integrity of ceramic veneer, marginal adaptation, gingival health and color match were adopted to evaluate the of clinical effect during 2 years of follow-up. RESULTS: The average satisfaction rate instantly after treatment, 1 year after treatment and 2 years after treatment was 93%, 95% and 94%, respectively. CONCLUSIONS: E-max porcelain laminate veneer has fewer side effects, better aesthetics and biological characteristics. The treatment is cost-efficient, safe and long-lasting. PMID- 24469140 TI - [A randomized single-blind controlled clinical trial of tacrolimus mouth rinse on erosive oral lichen planus]. AB - PURPOSE: To evaluate the efficacy and safety of tacrolimus mouth rinse on the treatment of erosive and ulcerative oral lichen planus (OLP). METHODS: A randomized single-blind open trial of tacrolimus mouth rinse with dexamethasone as control was designed. The VAS and REU scoring system was utilized to compare the signs and symptoms. The scores and therapeutic effects were analyzed with SPSS 17.0 software package. RESULTS: There was no significant difference in effective rate between the treatment group and control group (X(2)=0.295,0.413, P>0.01) at 4-week and 12-week after treatment. There was significant difference in REU scores between the 2 groups (P<0.01) 4 weeks after treatment. CONCLUSIONS: Tacrolimus mouth rinse effects quickly and is worthy of application in the treatment of erosive and ulcerative OLP. PMID- 24469141 TI - [Application of case-based learning in clinical internship teaching of conservative dentistry and endodontics]. AB - PURPOSE: To investigate the education effect of case-based learning (CBL) pattern on clinical internship of conservative dentistry and endodontics. METHODS: Forty one undergraduates were randomly assigned into CBL group and traditional teaching group. After clinical internship in the department of conservative dentistry and endodontics for 11 weeks, each student in the 2 groups underwent comprehensive examinations including medical record writing, case analysis, academic knowledge, professional skills and the ability of winning the trust of the patients. The scores were compared between the 2 groups using SPSS 13.0 software package. RESULTS: There was no significant difference between the 2 groups with regard to the scores of academic knowledge and profession skills (P>0.05). However, the results of medical record writing, case analysis and the ability of winning the trust of the patients showed significant difference between the 2 groups(P<0.05). CONCLUSIONS: Proper application of CBL in clinical internship of conservative dentistry and endodontics contributes to improve students' ability of clinical thinking, synthetical analysis and adaptability to different patients. PMID- 24469142 TI - [The reasons why 13 MK1 attachment were re-fabricated and some methods for improvement]. AB - PURPOSE: To investigate the reasons why 13 MK1 attachment were re-fabricated and to suggest some improvement methods. METHODS: Mechanics and denture production technology were reviewed in 13 cases with MK1 attachment denture to determine the causes of failure. RESULTS: In some cases, MK1 attachments were poorly designed, while in other cases problems were found during denture design and production process due to limited experiences at the initial stage. MK1 attachments were re done based on the specific cause and the outcome was good after 1-1.5 years of follow-up. CONCLUSIONS: When using MK1 attachment, prosthodontists should be familiar with the characteristics and indications of MK1 attachment. Meanwhile, we should strengthen doctor-patient communication and follow up patients timely to improve the success rate of MK1 attached denture repair. PMID- 24469143 TI - [Use of cone-beam computed tomography to detect atypical vertical root fracture occurring at first left mandibular incisor:report of one case]. AB - The use of cone-beam computed tomography (CBCT) in stomatology was a hot spot in recent years, both to CT researchers and dentists. Vertical root fracture was the fracture occurring in root which didn't spread to the crown. This paper showed how to use CBCT to diagnose a vertical root fracture occurring in incisor correctly. Compared with conventional periapical film, CBCT was more accurate in diagnosing root fracture and had higher clinical application value.Supported by Science and Technology Program of Shandong University (J12LK57). PMID- 24469144 TI - Preoperative renal scar as a risk factor of postoperative metabolic acidosis following ileocystoplasty in patients with neurogenic bladder. AB - OBJECTIVES: We investigated relation of preoperative renal scar to incidence of postoperative metabolic acidosis following ileocystoplasty in patients with neurogenic bladder. PATIENTS: Thirty patients with neurogenic bladder, who underwent ileocystoplasty, were enrolled in the present study. Median age at ileocystoplasty was 13.9 years and median follow-up period after ileocystoplasty was 8.2 years. Metabolic acidosis was defined based on the outlined criteria: base excess (BE) is less than 0 mmol l(-1). Preoperative examination revealed that no apparent renal insufficiency was identified in blood analysis, although preoperative (99m)Tc-DMSA scintigraphy indicated abnormalities such as renal scar in 14 patients (47%). Incidence of postoperative metabolic acidosis was compared between patients with and without preoperative renal scar, which may reflect some extent of renal tubular damage. RESULTS: Postoperative metabolic acidosis was identified in 13 patients (43%). Incidence of postoperative metabolic acidosis was significantly higher in patients with renal scar (11/14, 79%) compared with patients without renal scar (2/16, 13%; P<0.01). Particularly, all eight patients who had bilateral renal scars showed metabolic acidosis postoperatively. Compared with patients without preoperative renal scar, pH (P<0.05) and BE (P<0.01) were significantly lower postoperatively in patients with preoperative renal scar. However, there was no significant difference in PCO2. Hyperchloremia was observed in each patient with or without preoperative renal scar. CONCLUSION: Incidence of postoperative metabolic acidosis was significantly implicated in preoperative renal scar. If renal abnormalities are preoperatively identified in imaging tests, we need to care patients carefully regarding metabolic acidosis and subsequent comorbidities following ileocystoplasty. PMID- 24469145 TI - The association of assistive mobility devices and social participation in people with spinal cord injuries. AB - OBJECTIVE: We assumed that assistive technology in mobility devices (that is, wheelchairs with external power and driving modified vehicle (MV) with or without driving on wheelchair) may facilitate social participation for wheelchairs users who have spinal cord injuries (SCIs). This study examined the relationship between mobility devices and social participation in this population. METHODS: We included 2986 individuals who had received initial rehabilitation at one of 18 regional centers of the Model Spinal Cord Injury System in the United States, had been interviewed between 2004 and 2010, and were wheelchair users (use a wheelchair > or = 40 h per week and cannot ambulate 150 feet at home). We performed secondary panel-data analysis using a mixed-effect model on data from 3498 follow-up interviews. Participation (measured by the Craig Handicap Assessment and Reporting Technique-Short Form (CHART-SF) and employment status) and the use of wheelchair and MV were recorded. RESULTS: Among the participants, 33% drove an MV, and 44% used an external-powered wheelchair. The use of an MV was positively related to employment and CHART-SF score, regardless of driving directly or driving with a wheelchair. People who drove an MV were found to have approximately two more business associates to contact to once a month and ~2 additional days out of home per week compared with those without an MV. No significant association was shown between the type of wheelchair used and participation. CONCLUSION: The use of an MV was found to be positively associated with social participation in an SCI population. PMID- 24469146 TI - Bladder stones in patients with spinal cord injury: a long-term study. AB - STUDY DESIGN: Retrospective follow-up study. OBJECTIVES: To assess the occurrence of bladder stones in patients with spinal cord injury (SCI). SETTING: Single SCI rehabilitation center in Switzerland. METHODS: We searched our database for SCI patients who had undergone surgery due to bladder stones between 2004 and 2012. In all patients retrieved, personal characteristics, bladder management, bladder stone occurrence and time to stone formation/recurrence were recorded. RESULTS: We identified 93 (3.3%) of 2825 patients with bladder stones, 24 women and 69 men, with a mean age 50 years (17-83) years. We observed bladder stones in patients with suprapubic catheter (SPC) in 11% (50/453), transurethral catheter (TC) in 6.6% (5/75), with intermittent catheterization (IC) in 2% (27/1315) and with reflex micturition (RM) in 1.1% (11/982), respectively. The mean time period to stone development was 95 months. The TC group had the shortest time interval (31 months), followed by the SPC group (59 months), individuals performing IC (116 months) and RM (211 months), respectively. Bladder stone recurrence rate was 23%. Recurrences were most frequent in the TC group (40%), followed by SPC (28%) and IC (22%), whereas no recurrences occurred in the RM group. Time to recurrence was shortest in the SPC group (14 months), followed by the IC (26 months) and the TC group (31 months), respectively. CONCLUSION: In SCI patients, bladder management has an important role in the development of bladder stones. Indwelling catheters (TC/SPC) are associated with the highest risk to develop bladder stones and therefore should be avoided if possible. If unavoidable, SPC are superior to TC. PMID- 24469147 TI - The International Spinal Cord Injury Pain Basic Data Set (version 2.0). AB - OBJECTIVES: To revise the International Spinal Cord Injury Pain Basic Data Set (ISCIPBDS) based on new developments in the field and on suggestions from the spinal cord injury (SCI) and pain clinical and research community. SETTING: International. METHODS: The ISCIPBDS working group evaluated suggestions regarding the utility of the ISCIPBDS and made modifications in response to these and to significant developments in the field. The revised ISCIPBDS (version 2.0) was reviewed by members of the Executive Committee of the International SCI Standards and Data Sets, the International Spinal Cord Society (ISCoS) Executive and Scientific Committees, the American Spinal Injury Association and American Pain Society Boards and the Neuropathic Pain Special Interest Group of the International Association for the Study of Pain, individual reviewers and societies and the ISCoS Council. RESULTS: The ISCIPBDS (version 2.0) is significantly shortened but still contains clinically relevant core questions concerning SCI-related pain. The revisions include an updated SCI pain classification, omission of three questions regarding temporal pain pattern and three pain interference questions. The remaining three pain interference questions concern perceived interference with activities, mood and sleep for overall pain rather than for individual pain problems and are scored on a 0 to 10 scale. PMID- 24469148 TI - Long lived BSA Au clusters as a time gated intensity imaging probe. AB - The work presented here reports the use of long lifetime (>1 MUs) BSA Au clusters as a cellular/tissue, time gated, intensity imaging probe. By collecting the emission signal 50 ns post excitation, one can off-gate the intense auto fluorescence background, thereby greatly enhancing the clarity/specificity in fluorescence imaging. PMID- 24469149 TI - Use of dust fall filters as passive samplers for metal concentrations in air for communities near contaminated mine tailings. AB - Mine tailings are a source of metal exposures in many rural communities. Multiple air samples are necessary to assess the extent of exposures and factors contributing to these exposures. However, air sampling equipment is costly and requires trained personnel to obtain measurements, limiting the number of samples that can be collected. Simple, low-cost methods are needed to allow for increased sample collection. The objective of our study was to assess if dust fall filters can serve as passive air samplers and be used to characterize potential exposures in a community near contaminated mine tailings. We placed filters in cylinders, concurrently with active indoor air samplers, in 10 occupied homes. We calculated an estimated flow rate by dividing the mass on each dust fall filter by the bulk air concentration and the sampling duration. The mean estimated flow rate for dust fall filters was significantly different during sampling periods with precipitation. The estimated flow rate was used to estimate metal concentration in the air of these homes, as well as in 31 additional homes in another rural community impacted by contaminated mine tailings. The estimated air concentrations had a significant linear association with the measured air concentrations for beryllium, manganese and arsenic (p < 0.05), whose primary source in indoor air is resuspended soil from outdoors. In the second rural community, our estimated metal concentrations in air were comparable to active air sampling measurements taken previously. This passive air sampler is a simple low-cost method to assess potential exposures near contaminated mining sites. PMID- 24469150 TI - Posterior atlantoaxial dislocation complicating odontoid fracture without neurologic deficit: a case report and review of the literature. AB - Traumatic posterior atlantoaxial dislocation associated with odontoid fracture is extremely rare, with only eight cases reported thus far in the English literature. This report concerns a 47-year-old female who presented with considerable pain and stiffness in the neck without a neurologic deficit after injury due to a fall. Radiographs, computed tomography, and magnetic resonance imaging demonstrated a posterior dislocation of the atlas with respect to the axis with an odontoid fracture. No cord compression or intramedullary cord signal abnormalities were detected at the level of the atlantoaxial dislocation. A pedicle screw fixation/fusion was performed via a posterior approach following successful closed reduction. PMID- 24469151 TI - Necrotizing fasciitis: an urgent diagnosis. AB - Necrotizing fasciitis (NF) is a rare, life-threatening soft-tissue infection and a medical and surgical emergency, with increasing incidence in the last few years. It is characterized by a rapidly spreading, progressive necrosis of the deep fascia and subcutaneous tissue. Necrotizing fasciitis is often underestimated because of the lack of specific clinical findings in the initial stages of the disease. Many adjuncts such as laboratory findings, bedside tests- e.g., the "finger test" or biopsy--and imaging tests have been described as being helpful in the early recognition of the disease. Imaging is very useful to confirm the diagnosis, but also to assess the extent of the disorder, the potential surgical planning, and the detection of underlying etiologies. The presence of gas within the necrotized fasciae is characteristic, but may be lacking. The main finding is thickening of the deep fasciae due to fluid accumulation and reactive hyperemia, best seen on magnetic resonance imaging. PMID- 24469153 TI - Development of human brain cortical network architecture during infancy. AB - The brain's mature functional network architecture has been extensively studied but the early emergence of the brain's network organization remains largely unknown. In this study, leveraging a large sample (143 subjects) with longitudinal rsfMRI scans (333 datasets), we aimed to characterize the important developmental process of the brain's functional network architecture during the first 2 years of life. Based on spatial independent component analysis and longitudinal linear mixed effect modeling, our results unveiled the detailed topology and growth trajectories of nine cortical functional networks. Within networks, our findings clearly separated the brains networks into two categories: primary networks were topologically adult-like in neonates while higher-order networks were topologically incomplete and isolated in neonates but demonstrated consistent synchronization during the first 2 years of life (connectivity increases 0.13-0.35). Between networks, our results demonstrated both network level connectivity decreases (-0.02 to -0.64) and increases (0.05-0.18) but decreasing connections (n = 14) dominated increasing ones (n = 5). Finally, significant sex differences were observed with boys demonstrating faster network level connectivity increases among the two frontoparietal networks (growth rate was 1.63e-4 per day for girls and 2.69e-4 per day for boys, p < 1e-4). Overall, our study delineated the development of the whole brain functional architecture during the first 2 years of life featuring significant changes of both within- and between-network interactions. PMID- 24469154 TI - A perfect storm: Wolf Parkinson White syndrome, Ebstein's anomaly, biventricular non-compaction, and bicuspid aortic valve. PMID- 24469156 TI - Chemical and morphological changes during olivine carbonation for CO2 storage in the presence of NaCl and NaHCO3. AB - The increasing concentrations of CO2 in the atmosphere are attributed to the rising consumption of fossil fuels for energy generation around the world. One of the most stable and environmentally benign methods of reducing atmospheric CO2 is by storing it as thermodynamically stable carbonate minerals. Olivine ((Mg,Fe)2SiO4) is an abundant mineral that reacts with CO2 to form Mg-carbonate. The carbonation of olivine can be enhanced by injecting solutions containing CO2 at high partial pressure into olivine-rich formations at high temperatures, or by performing ex situ mineral carbonation in a reactor system with temperature and pressure control. In this study, the effects of NaHCO3 and NaCl, whose roles in enhanced mineral carbonation have been debated, were investigated in detail along with the effects of temperature, CO2 partial pressure and reaction time for determining the extent of olivine carbonation and its associated chemical and morphological changes. At high temperature and high CO2 pressure conditions, more than 70% olivine carbonation was achieved in 3 hours in the presence of 0.64 M NaHCO3. In contrast, NaCl did not significantly affect olivine carbonation. As olivine was dissolved and carbonated, its pore volume, surface area and particle size were significantly changed and these changes influenced subsequent reactivity of olivine. Thus, for both long-term simulation of olivine carbonation in geologic formations and the ex situ reactor design, the morphological changes of olivine during its reaction with CO2 should be carefully considered in order to accurately estimate the CO2 storage capacity and understand the mechanisms for CO2 trapping by olivine. PMID- 24469155 TI - Radial artery intima-media thickness predicts major cardiovascular events in patients with suspected coronary artery disease. AB - AIMS: In the present study, we investigated the prognostic value of radial artery intima-media thickness (rIMT) in patients with suspected coronary artery disease (CAD). Carotid artery intima-media thickness is a well-known surrogate marker of atherosclerosis. Recently, using very high-resolution ultrasound, we showed rIMT can be imaged with great precision and is related to various cardiovascular risk factors. METHODS AND RESULTS: We recruited a total of 416 patients (62 +/- 9 years, 44% male) with suspected CAD, referred to myocardial perfusion scintigraphy (MPS). Among these patients, 133 underwent coronary angiography on clinical indication. Two-dimensional images of carotid and radial arteries were acquired bilaterally (using 8 and 55 MHz ultrasound, respectively). All patients were followed regarding major adverse cardiovascular events (MACE), including cardiovascular death, myocardial infarction, stroke, and coronary revascularization. A group of 20 healthy subjects (aged 61 +/- 3, 50% male) were recruited for reference. During 3 years of follow-up, 77 MACE occurred. Patients with MACE exhibited significantly thicker rIMT vs. those without (0.35 +/- 0.06 vs. 0.32 +/- 0.07 mm, P < 0.001). Increased rIMT was associated with an increased occurrence of significant coronary artery narrowing, diagnosed by coronary angiography (P = 0.028). Patients with rIMT values above the median had a nearly three-fold increased risk for MACE (hazard ratio 2.8, 95% confidence interval 1.6 4.8). In multivariate analysis, rIMT (P = 0.011) remained a significant predictor of MACE, along with type II diabetes (P = 0.012), body mass index (P = 0.024), and MPS-verified ischaemia (P < 0.001). CONCLUSION: Radial artery IMT, assessed by very high-resolution ultrasound, confers prognostic information in patients with suspected CAD. PMID- 24469157 TI - The effect of radiation on acellular dermal matrix and capsule formation in breast reconstruction: clinical outcomes and histologic analysis. AB - BACKGROUND: The authors compared clinical outcomes to determine whether acellular dermal matrix altered the capsular tissue architecture in irradiated and nonirradiated breasts following matrix-assisted expander reconstruction. METHODS: Part I included all 27 patients who underwent bilateral tissue expander reconstruction with acellular dermal matrix between 2007 and 2012 and subsequent unilateral radiation therapy. Part II included a subset of patients with capsular biopsy specimens taken at the time of implant exchange for histologic analysis. Specimens included irradiated and nonirradiated acellular dermal matrix and irradiated and nonirradiated native capsule. Clinical outcomes were analyzed in relation to capsule architecture and acellular dermal matrix performance. RESULTS: In part I, mean follow-up was 28 months. Grade III/IV contractures were identified in nine patients (all on the irradiated side), and 12 developed noncontracture complications (75 percent on the irradiated side). Nine patients were unable to continue with implant reconstruction and required salvage with autologous tissue. In part II, postirradiation biopsy specimens were taken of the peri-implant capsule in six patients at the time of secondary surgery. Elastin content and the total cellular infiltrate were significantly greater in the irradiated versus nonirradiated native capsules (p = 0.0015). Conversely, the irradiated matrix capsule was composed of similar amounts of cellular infiltrate and collagen as the nonirradiated matrix capsules and nonirradiated native capsules. Irradiated acellular dermal matrix showed the least amount of alpha smooth actin staining but a similar number of blood vessels. CONCLUSION: Acellular dermal matrix appears to limit the elastosis and chronic inflammation seen in irradiated implant reconstructions and is potentially beneficial in these patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24469158 TI - Muscle-sparing TRAM flap does not protect breast reconstruction from postmastectomy radiation damage compared with the DIEP flap. AB - BACKGROUND: Irradiation to free flaps following immediate breast reconstruction has been shown to compromise outcomes. The authors hypothesized that irradiated muscle-sparing free transverse rectus abdominis musculocutaneous (TRAM) flaps experience less fat necrosis than irradiated deep inferior epigastric perforator (DIEP) flaps. METHODS: The authors performed a retrospective study of all consecutive patients undergoing immediate, autologous, abdomen-based free flap breast reconstruction with muscle-sparing free TRAM or DIEP flaps over a 10-year period at their institution. Irradiated flaps (external-beam radiation therapy) after immediate breast reconstruction were compared with nonirradiated flaps. Logistic regression analysis identified potential associations between patient, tumor, and reconstructive characteristics and surgical outcomes. RESULTS: The analysis included 625 flaps: 40 (6.4 percent) irradiated versus 585 (93.6 percent) nonirradiated. Mean follow-up for the irradiated and nonirradiated flaps was 60.0 and 48.5 months, respectively (p = 0.02). Overall complication rates were similar for both the irradiated and nonirradiated flaps. Irradiated flaps (i.e., both DIEP and muscle-sparing free TRAM flaps) developed fat necrosis at a significantly higher rate (22.5 percent) than the nonirradiated flaps (9.2 percent; p = 0.009). There were no differences in fat necrosis rates between the DIEP and muscle-sparing free TRAM flaps in both the irradiated and nonirradiated groups. CONCLUSIONS: Both DIEP and muscle-sparing free TRAM flap reconstructions had much higher rates of fat necrosis when irradiated. Contrary to our hypothesis, the authors found that immediate breast reconstruction with a muscle sparing free TRAM flap does not result in a lower rate of fat necrosis than reconstruction with a DIEP flap. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24469159 TI - Safety of tissue expander/implant versus autologous abdominal tissue breast reconstruction in postmastectomy breast cancer patients: a systematic review and meta-analysis. AB - BACKGROUND: Breast reconstruction after mastectomy for breast cancer should be informed by evidence-based knowledge, such as complication rates. The authors compared the safety of tissue expander/implant reconstruction with that of autologous abdominal tissue reconstruction. METHODS: A systematic literature review identified peer-reviewed studies published from January of 2000 to October of 2012 that compared tissue expander/implant against autologous abdominal tissue reconstruction in the MEDLINE, EMBASE, Cochrane Library, PubMed, and ProQuest Dissertations and Theses databases. Two reviewers independently screened all reports and selected the relevant articles using specific inclusion criteria. Data were extracted from the relevant articles using a standardized abstraction form. RESULTS: Fourteen observational studies were identified that included more than 3000 reconstructed breasts. Significant differences were found between these two approaches. The relative risk associated with reconstructive failure favored autologous abdominal tissue (relative risk, 0.14; 95 percent CI, 0.06 to 0.32; I = 0 percent). Surgical-site infection was significantly lower in autologous abdominal tissue reconstruction compared with tissue expander/implant (relative risk, 0.37; 95 percent CI, 0.25 to 0.55; I = 0 percent), although skin or flap necrosis was higher in autologous abdominal tissue reconstruction compared with tissue expander/implant (relative risk, 2.79; 95 percent CI, 1.87 to 4.17). Studies were of low to moderate quality according to the Newcastle-Ottawa scale. CONCLUSIONS: This study suggests that tissue expander/implant reconstruction has a higher risk of reconstructive failure and surgical-site infection compared with autologous abdominal tissue reconstruction. With the lack of long-term safety studies on different approaches to breast reconstruction, additional long-term comparative studies are needed to support evidence-based decision-making. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24469160 TI - Total breast reconstruction using the thoracodorsal artery perforator flap without implant. AB - BACKGROUND: The thoracodorsal artery perforator flap was described mainly for partial breast reconstruction by Hamdi. The purpose of this article is to describe the use of the pedicled thoracodorsal artery perforator flap for total autologous breast reconstruction without using an implant. METHODS: Between January of 2009 and December of 2011, seven patients underwent total breast reconstruction with a pedicled thoracodorsal artery perforator flap. The mean age of the patients was 53 years (range, 43 to 62 years), and the mean body mass index was 27 kg/m (range, 24 to 32 kg/m). RESULTS: The mean size of the harvested skin paddle was 23.7 * 8.8 cm (range, 15 * 7 cm to 39 * 14 cm). The flaps were based on one to three perforators and successfully transferred with an average operative time of 3 hours. No seroma occurred at the donor site. Average hospital stay was 4 days (range, 3 to 6 days). At an average follow-up of 21.5 months, two patients underwent additional revisions using autologous fat grafting, with overall fat injection volumes of 240 and 280 cc, respectively. CONCLUSION: The pedicled thoracodorsal artery perforator flap offers an alternative for total autologous breast reconstruction in small to medium breasted patients when abdominal tissues are not available. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24469161 TI - Smile analysis in rhinoplasty: a randomized study for comparing resection and transposition of the depressor septi nasi muscle. AB - BACKGROUND: The depressor septi nasi muscle is responsible for smiling deformity. Its manipulation is beneficial in patients with muscle hypertrophy. In addition, it enhances the smile and tip-lip relationship. In this study, depressor septi nasi muscle excision through a transfixion incision is compared with its transposition through an upper labial sulcus incision. METHODS: Two techniques of depressor septi nasi muscle treatment were performed randomly for rhinoplasty cases. Smile analysis in rhinoplasty, consisting of measurements of nasal length, nasal diagonal, tip projection, and upper lip height, and noting transverse upper labial crease in repose and full smile, was performed on preoperative and postoperative photographs. RESULTS: One hundred patients were studied in two equal groups. Preoperatively, tip projection and upper lip height were decreased significantly with smiling. Generally, the effect of smiling on all five parameters was decreased significantly following rhinoplasty. The two different techniques were not significantly different in decreasing the effects of smiling on nasal length, nasal diagonal, tip projection, upper lip height, or transverse crease. CONCLUSIONS: The two different techniques were the same in decreasing the effects of smiling. The authors recommend smile analysis in rhinoplasty, consisting of measurement of nasal length, nasal diagonal, tip projection, and upper lip height, and noting transverse upper labial crease in repose and during smiling, before rhinoplasty for preoperative evaluation and after the operation for outcome assessment. Depressor septi nasi muscle treatment should be considered if a decrease in tip projection or upper lip height with smiling or a transverse upper labial crease during smiling is extraordinary or unsightly. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 24469162 TI - Discussion: smile analysis in rhinoplasty: a randomized study for comparing resection and transposition of the depressor septi nasi muscle. PMID- 24469163 TI - Understanding the fascial supporting network of the breast: key ligamentous structures in breast augmentation and a proposed system of nomenclature. AB - BACKGROUND: The fascial system of the breast has, to date, only been described in general terms. This anatomical study has developed two distinct methods for better defining existing breast structures such as the inframammary fold, as well as defining previously unnamed ligamentous structures. METHODS: The authors harvested and examined 40 frozen, entire chest wall cadavers. Initially, 15 embalmed cadavers were studied with a combination of blunt and sharp dissection, which proved to be inaccurate. A further 20 fresh and five embalmed chest walls were harvested, frozen, and then sectioned with a bandsaw (3-cm slices) and knife (1.5- to 4-cm slices) depending on the area studied. Sagittal, horizontal, and oblique sections along the length of the ribs were created and then dissolved using either sodium hydroxide or alcohol dehydration followed by xylene immersion. Constant fascial connections between the breast parenchyma, superficial fascia, pectoralis muscle (deep) fascia, and bone were observed. RESULTS: Specimens clearly demonstrated internal structures responsible for the surface landmarks of the breast. The precise configuration of the infra mammary fold was clearly visible, and new ligamentous structures were identified and named. CONCLUSIONS: Knowing the location and interrelationship of these structures is particularly important in breast augmentation. Reappraisal of the anatomy in this area has enabled precise identification of ligamentous structures in the breast. Correlation of the findings in this article to specific clinical conditions or modes of treatment can be proven only by a clinical series that scientifically addresses the necessity and efficacy of preserving, releasing, or repositioning any of these structures. PMID- 24469164 TI - Avulsion brachioplasty: technique overview and 5-year experience. AB - BACKGROUND: Popularity of arm-contouring procedures, once coveted by the massive weight loss population, has grown among society at large. The technique has evolved with the goal of producing a predictable and thin scar in a location that is acceptable for interpersonal interaction. METHODS: All consecutive brachioplasty patients from May of 2008 to May of 2013 were reviewed retrospectively at a private surgery center. Data collected included age, body mass index, amount of fat removed by liposuction, weight of resected tissue, hematoma or seroma, wound dehiscence, revision procedures, and length of follow up. RESULTS: The authors reviewed 44 consecutive brachioplasties over 5 years. Average age was 53 years and body mass index was 26. Average amount of liposuctioned fat was 342 ml per arm using 867 ml of tumescent and an average skin specimen weight of 90 g. The follow-up period averaged 446 days. Fourteen patients had wound dehiscence requiring dressing changes. There were no return trips to the operating room for serious concerns such as bleeding or infection. One patient had a seroma. Nine patients underwent scar revision within 1 year. Overall complication rate was 50 percent. Overall revision rate was 21 percent. CONCLUSIONS: Brachioplasty is a rewarding procedure with consistent results and low risk of major complications. The potential for minor complications is substantial, and patients should receive preoperative counseling regarding this risk. In the authors' 5-year study of consecutive patients, 50 percent of patients needed dressing changes for small-wound dehiscence or scar revision within 1 year. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24469165 TI - Lymph node transplantation results in spontaneous lymphatic reconnection and restoration of lymphatic flow. AB - BACKGROUND: Although lymph node transplantation has been shown to improve lymphatic function, the mechanisms regulating lymphatic vessel reconnection and functional status of lymph nodes remains poorly understood. METHODS: The authors developed and used LacZ lymphatic reporter mice to examine the lineage of lymphatic vessels infiltrating transferred lymph nodes. In addition, the authors analyzed lymphatic function, expression of vascular endothelial growth factor (VEGF)-C, maintenance of T- and B-cell zone, and anatomical localization of lymphatics and high endothelial venules. RESULTS: Reporter mice were specific and highly sensitive in identifying lymphatic vessels. Lymph node transfer was associated with rapid return of lymphatic function and clearance of technetium-99 secondary to a massive infiltration of recipient mouse lymphatics and putative connections to donor lymphatics. T- and B-cell populations in the lymph node were maintained. These changes correlated with marked increases in the expression of VEGF-C in the perinodal fat and infiltrating lymphatics. Newly formed lymphatic channels in transferred lymph nodes were in close anatomical proximity to high endothelial venules. CONCLUSIONS: Transferred lymph nodes have rapid infiltration of functional host lymphatic vessels and maintain T- and B-cell populations. This process correlates with increased endogenous expression of VEGF-C in the perinodal fat and infiltrating lymphatics. Anatomical proximity of newly formed lymphatics and high endothelial venules supports the hypothesis that lymph node transfer can improve lymphedema by exchanges with the systemic circulation. PMID- 24469166 TI - Variation in the incidence of distal radius fractures in the U.S. elderly as related to slippery weather conditions. AB - BACKGROUND: Distal radius fractures are costly and debilitating injuries, especially for the elderly. These fractures often occur from falls and commonly occur outdoors. Inclement weather may increase the risk of fall-related injuries. Small studies have reported an increased risk of distal radius fracture caused by inclement winter weather; larger studies are lacking. METHODS: The authors analyzed a sample of 2007 Medicare claims for distal radius fracture. Weather data were collected for the date and location of each distal radius fracture in the authors' analysis cohort. A novel slipperiness score was used as a measure of the severity of slippery outdoor conditions. Negative binomial regression models evaluated the correlation between slipperiness and distal radius fracture occurrence. RESULTS: Risk of distal radius fracture was higher in winter months (incidence rate ratio, 1.2; p < 0.001). Days with average temperature less than or equal to 32 degrees F (incidence rate ratio, 1.36; p < 0.001), snow/ice on the ground at the start of the day (incidence rate ratio, 1.45; p < 0.001), and freezing rain (incidence rate ratio, 1.24; p = 0.025) all had an increased risk of distal radius fracture. The risk of sustaining a distal radius fracture was increased 21 percent on days with a slipperiness score above 4 (incidence rate ratio, 1.21; p = 0.007). For each increase in slipperiness score above 4, the incidence rate ratio of distal radius fracture increased as well. CONCLUSIONS: Weather events that create slippery walking conditions, often in the winter, result in an increased risk of distal radius fracture in the elderly. This finding can be used to support resource allocation and awareness and prevention campaigns. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, IV. PMID- 24469167 TI - Upper extremity replantation: current concepts. AB - BACKGROUND: Upper extremity replantation is a procedure that has revolutionized hand surgery. Since its introduction, a rapid evolution has occurred with a shifting focus from implant survival to optimization of functional outcomes and surgical efficiency. In this review, the current concepts surrounding the indications for replantation, variations in surgical technique, the factors affecting outcomes, and future directions of the specialty are analyzed. METHODS: A literature review was performed of all recent articles pertaining to digit, hand, and upper extremity replantation surgery. Particular emphasis was placed on comparative studies and recent meta-analyses. RESULTS: The indications and contraindications for replantation surgery are largely unchanged, with mechanism of injury remaining one of the most important determinants of implant survival. With advances in surgical technique, improved outcomes have been observed with avulsion injuries. Distal tip replantations appear to be more common with improved microsurgical techniques, and for these distal injuries, digital nerve and vein repair may not be necessary. Cold ischemia time for a digit amputation should not preclude transfer to a replantation facility or significantly affect the decision to perform a replantation. However, transferring physicians should thoroughly review the options with patients to prevent unnecessary transfers, which is an area where telemedicine may be useful. CONCLUSION: This review provides an update on the current concepts of the practice of replantation and the treatment and management of patients with upper extremity amputations. PMID- 24469168 TI - Maxillary hypoplasia in the cleft patient: contribution of orthodontic dental space closure to orthognathic surgery. AB - BACKGROUND: Cleft lip and palate surgery in the developing child is known to be associated with maxillary hypoplasia. However, the effects of nonsurgical manipulations on maxillary growth have not been well investigated. The authors present the contribution of orthodontic dental space closure with canine substitution to maxillary hypoplasia and the need for orthognathic surgery. METHODS: Cleft lip/palate and cleft palate patients older than 15 years of age were reviewed for dental anomalies, orthodontic canine substitution, and Le Fort I advancement. Skeletal relationships of the maxilla to the skull base (SNA), mandible (ANB), and facial height were determined on lateral cephalograms. Logistic regression analyses were performed to estimate odds ratios. RESULTS: Ninety-five patients were reviewed (mean age, 18.1 years). In 65 patients with congenitally missing teeth, 55 percent with patent dental spaces required Le Fort I advancement. In contrast, 89 percent who underwent canine substitution required Le Fort I advancement (p = 0.004). Canine substitution is associated with a statistically significant increase in maxillary retrognathia when compared with dental space preservation on lateral cephalograms (mean SNA, 75.2 and 79.0, respectively; p = 0.006). Adjusting for missing dentition, logistic regression analyses demonstrated that canine substitution is an independent predictor for orthognathic surgery (OR, 6.47) and maxillary retrusion defined by SNA < 78 (OR, 8.100). CONCLUSIONS: The coordination of orthodontia and surgery is essential to cleft care. The authors report a strong association between orthodontic cleft closure using canine substitution with maxillary hypoplasia and subsequent Le Fort I advancement, and suggest systematic criteria for management of cleft related dental agenesis. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24469169 TI - The safe and efficacious use of arch bars in patients during primary and mixed dentition: a challenge to conventional teaching. AB - BACKGROUND: Erich arch bars facilitate intermaxillary fixation, and traditional teaching questions and often argues against the use of arch bars in patients during primary and mixed dentition. Dental anatomy, risk of tooth avulsion, and potential disruption of developing permanent dentition are reasons cited. This study provides the only outcome data on the use of arch bars in children during primary and mixed dentition. METHODS: Patients in primary and mixed dentition presenting with mandible fractures treated with arch bars from 2000 to 2010 were reviewed. Elements collected included demographics, medical history, fracture management, adverse outcomes, and dental health as determined by a pediatric dentist at follow-up. RESULTS: A total of 154 mandible fractures in 79 patients were identified, with 23 patients (48 fractures) meeting inclusion criteria. Average age at injury was 9.10 years (range, 2.70 to 13.49 years), and average follow-up was 32.35 months (range, 0.43 to 131.84 months). Fracture types included condylar head (n = 9), condylar neck (n = 12), angle (n = 10), body (n = 4), and parasymphysis (n = 13) fractures. There were no periodontal defects, tooth avulsions, or disturbances to permanent dentition noted with regard to arch bar use. CONCLUSIONS: These data demonstrate that arch bars can be safely used in children during primary and mixed dentition with no periodontal defects, tooth avulsions, or disturbances to permanent dentition. Despite traditional teaching, the authors demonstrate arch bar use to be efficacious and safe in children during primary or mixed dentition. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24469170 TI - The shifting paradigm in the management of giant congenital melanocytic nevi: review and clinical applications. AB - SUMMARY: Congenital melanocytic nevi remain a subject of controversy with respect to risk of malignant transformation and recommended management. Recent studies indicate a lower malignant risk (0.7 to 2.9 percent) than had previously been estimated. Surgery has not been proven to reduce malignant risk or improve quality of life, and may result in undesirable aesthetic and functional outcomes. In this article, the authors review key controversial issues in the management of congenital melanocytic nevi and re-evaluate indications for surgical treatment. An updated review of controversial topics in the management of congenital melanocytic nevi is presented, and clinical applications are demonstrated through clinical cases. Updates regarding the risks and outcomes of congenital melanocytic nevi patients open a renewed debate with respect to the indications for surgery as well as the extent of surgery that may be suitable. Treatment should be tailored to achieve optimal aesthetic results whereby complete nevus excision is not the goal. As such, nonsurgical management and incomplete nevus excision should be integrated as legitimate parts of any treatment algorithm. PMID- 24469171 TI - Aesthetic and functional facial transplantation: a classification system and treatment algorithm. AB - BACKGROUND: As of July of 2013, 27 facial vascularized composite allotransplantations have been performed. The authors developed a classification system and treatment algorithm that is practical and surgically applicable. METHODS: The majority of the transplants have been described in the surgical literature and the media, and a review of the data was performed. A classification system and a treatment algorithm were designed. Skeletal defects were defined by craniofacial osteotomies and soft-tissue defects by aesthetic facial subunits. The soft-tissue defect was subdivided into the following subunits: oral-nasal (type 1), oronasal-orbital (type 2), and full facial (type 3). The bony defects were subdivided into mandibular involvement (M), Le Fort 1 (A), Le Fort 3 (B), and monobloc (C). RESULTS: The mechanisms of injury included trauma (n = 13), burns (n = 8), congenital deformity (n = 3), oncologic resection (n = 1), and unreported (n = 2). According to the proposed classification system: one was type 1; one was type 1-M; one was type 1-MB; two were type 2; two were type 2-B; two were type 2-MB; six were type 3; one was type 3-B; and three were type 3-MB; eight could not be classified due to a lack of data. The treatment algorithm designed a vascularized composite allotransplantation that addressed the bony and soft-tissue components. CONCLUSIONS: Patient selection for these complicated procedures, currently dependent on lifelong immunosuppression, is crucial to their success. The authors describe a classification system and treatment algorithm for facial defects that may be ideally suited for facial transplantation. The proposed classification and algorithm may help centers define indications and ideally improve patient outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24469172 TI - Discussion: the embrace device significantly decreases scarring following scar revision surgery in a randomized controlled trial. PMID- 24469173 TI - Association between Agent Orange exposure and nonmelanotic invasive skin cancer: a pilot study. AB - BACKGROUND: Agent Orange, or 2,3,7,8-tetrachlorodibenzodioxin, has been shown to cause indirect DNA damage, producing malignancies. However, its connection to nonmelanotic invasive skin cancer is unclear. This study investigated whether 2,3,7,8-tetrachlorodibenzodioxin exposure increases the incidence of this cancer. METHODS: The authors retrospectively reviewed the medical records of 100 consecutive male patients with Fitzpatrick skin types I through IV who enrolled in the Agent Orange registry at the Veterans Affairs Hospital of Washington, D.C., between August of 2009 and January of 2010. RESULTS: The study population's mean age was 65.7 years (range, 56 to 80 years). 2,3,7,8-Tetrachlorodibenzodioxin exposure included living or working in contaminated areas (56 percent), actively spraying it (30 percent), or traveling in contaminated areas (14 percent). Fifty one percent of patients had nonmelanotic invasive skin cancer; 43 percent had chloracne; and 26 percent had other malignancies, such as prostate (14 percent), colon (3 percent), or bladder cancer (2 percent). The nonmelanotic invasive skin cancer incidence rate in the study population (51 percent) was significantly higher than the national age-matched incidence rate (23.8 percent; p < 0.001). High Fitzpatrick skin type score (p = 0.010) and dark eye color (p = 0.036) were associated with a decreased incidence of the cancer. Exposure by means of active spraying (73 percent versus 67 percent; p = 0.003) and presence of chloracne (81 percent versus 28 percent; p < 0.001) were associated with increased nonmelanotic invasive skin cancer incidence rates. CONCLUSIONS: 2,3,7,8 Tetrachlorodibenzodioxin exposure appears to be associated with the development of nonmelanotic invasive skin cancer. Further studies are warranted to determine the relative risk within this patient population and to determine appropriate management strategies. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II. PMID- 24469174 TI - Institutional review boards: what's old? What's new? What needs to change? AB - SUMMARY: Institutional review boards have come under fire for being burdened with work, causing delays in the progress of human subject research without improvements in the protection of human subjects. Over the years, there have been increases in the numbers of clinical trials, the use of multisite studies, and the amount of bureaucracy, but there have been no changes to the system to accommodate these advancements. Proposed changes include the use of a centralized institutional review board for multisite studies and harmonization of reporting requirements among agencies. The purposes of this article are to review the history, structure, and purpose of the institutional review board, to assess the criticisms of the current system, and to discuss solutions for improvement. PMID- 24469175 TI - A plastic surgery application in evolution: three-dimensional printing. AB - BACKGROUND: Three-dimensional printing represents an evolving technology still in its infancy. Currently, individuals and small business entities have the ability to manufacture physical objects from digital renderings, computer-aided design, and open source files. Design modifications and improvements in extrusion methods have made this technology much more affordable. This article explores the potential uses of three-dimensional printing in plastic surgery. METHODS: A review was performed detailing the known uses of three-dimensional printing in medicine. The potential applications of three-dimensional printing in plastic surgery are discussed. RESULTS: Various applications for three-dimensional printing technology have emerged in medicine, including printing organs, printing body parts, bio-printing, and computer-aided tissue engineering. In plastic surgery, these tools offer various prospective applications for surgical planning, resident education, and the development of custom prosthetics. CONCLUSIONS: Numerous applications exist in medicine, including the printing of devices, implants, tissue replacements, and even whole organs. Plastic surgeons may likely find this technology indispensable in surgical planning, education, and prosthetic device design and development in the near future. PMID- 24469176 TI - So ... are we really safe? PMID- 24469177 TI - Advice to the outliers in plastic surgery: write it up. PMID- 24469178 TI - Ten principles for plastic surgeons beginning their careers in cosmetic surgery. PMID- 24469180 TI - Predesigned breast shaping assisted by multidetector-row computed tomographic angiography in autologous breast reconstruction. AB - BACKGROUND: Free abdominal flaps are the first option in autologous breast reconstruction using the multidetector-row computed tomographic angiography for mapping the abdominal perforators. The authors aim to evaluate the impact of using a preoperative design for shaping the new breast symmetrical to the contralateral breast, assisted by multidetector-row computed tomographic angiography. METHODS: Thirty-two consecutive patients who underwent delayed unilateral breast reconstruction with free abdominal flaps were divided into two groups. In group A, the new breast was shaped intraoperatively and inset, whereas in group B, a preoperative design of the new breast was used. All patients underwent multidetector-row computed tomographic angiography before the operation and the flaps were centralized around the selected perforators. Both groups were evaluated for the time spent on flap harvest, time spent on breast shaping and inset, complication rates, and secondary operations required for breast symmetrization. Independent surgeons evaluated the final aesthetic outcome. RESULTS: The mean time spent on harvesting the flap was not significantly different between the two groups (p > 0.05); the mean time spent on breast shaping and inset was significantly shorter in group B (p < 0.001). There were no differences between the two groups regarding complications recorded, whereas symmetrization surgery was significantly less in group B (p < 0.05). At a mean follow-up 17.3 months, the final aesthetic outcome was greater in group B. CONCLUSION: Predesigned breast shaping assisted by multidetector-row computed tomographic angiography promotes a significant reduction in the overall operative time and the need for secondary symmetrization procedures. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 24469181 TI - The potential effects of rhinoplasty on voice. AB - BACKGROUND: Rhinoplasty is one of the most popular cosmetic surgical procedures in Iran. Surgery on the vocal tract can potentially change the voice characteristics. To the best of the authors' knowledge, no study has described voice changes after rhinoplasty, and the results of this study may help physicians to be aware of potential voice alterations following rhinoplasty. METHODS: The authors selected 27 patients for this study. Patients completed Voice Handicap Index questionnaires, and the authors performed perceptual and acoustic analyses before and 5 months after rhinoplasty. RESULTS: The Voice Handicap Index score and its physical and emotional subscales showed a statistically significant increase after rhinoplasty, indicating a worsening of voice quality after rhinoplasty. Blind perceptual analysis by six trained listeners revealed a statistically significant increase in hyponasality after rhinoplasty. Acoustic analysis showed that the frequency of the first and second nasal murmurs increased for the phonemes "m" and "n," while the amplitude of these murmurs decreased significantly after surgery. The same pattern was seen for the phoneme "a" when it was produced between two nasal consonants, as in the word "man." CONCLUSIONS: Rhinoplasty can change vocal characteristics by narrowing the nasal cavity. Rhinoplasty has some effects on the voice, but these changes are problematic in general for most patients. However, for individuals who rely on their voice for professional reasons, the surgeon should preoperatively discuss these changes with the patient and consider more conservative types of surgery. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24469182 TI - Magnetic resonance imaging screening results compared with explantation results in poly implant prothese silicone breast implants, recalled from the European market in 2010. AB - BACKGROUND: In a prospective cohort study, the authors followed 112 women whose Poly Implant Prothese silicone breast implants were recalled. Magnetic resonance imaging results and clinical consequences were previously published. The authors compared magnetic resonance imaging screening with explantation results to study the diagnostic value of magnetic resonance imaging in this unique unselected and nonbiased group. METHODS ONE HUNDRED TWELVE: women with 224 proven Poly Implant Prothese implants after a mean implantation time of 10 years were enrolled in 2011. All women underwent magnetic resonance imaging screening and were offered explantation. The explantation details of 107 women could be compared with magnetic resonance imaging results. RESULTS: Of 107 women, 29 (27 percent) had at least one ruptured implant at explantation, and 44 of 214 explanted implants (21 percent) were ruptured. The magnetic resonance imaging results correctly diagnosed 154 intact and 35 ruptured implants. Sensitivity and specificity were 80 percent and 91 percent, respectively. The positive predictive value was 69 percent, and the negative predictive value was 95 percent. CONCLUSIONS: The accuracy of magnetic resonance imaging is comparable to previously published data from other manufacturers of modern silicone implants but lower than that of some recent validation studies in selected symptomatic women. The authors believe that this study is representative of common daily practice as they followed normal day to-day magnetic resonance imaging protocol without using multiple independent readers. The authors hope that this study will contribute to the ongoing discussion to screen asymptomatic women with modern silicone breast implants. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, II. PMID- 24469183 TI - Changing role of hyaluronidase in plastic surgery. AB - SUMMARY: Soft-tissue augmentation has become an increasingly popular option for facial rejuvenation. Hyaluronic acid fillers are part of the most rapidly expanding segment of this market, largely because of their safe drug profile and temporary nature. Despite their good safety profile, they can and do have complications ranging from superficial placement, uneven placement, granulomatous reactions, and skin necrosis. This article reviews the on- and off-label uses of hyaluronidase and presents several clinical algorithms detailing the effective and safe use of hyaluronidase to manage complications secondary to hyaluronic acid fillers. PMID- 24469184 TI - The neck as a preferred recipient site for vascularized composite allotransplantation in the mouse. AB - BACKGROUND: The mouse is still considered the premier model in basic immunologic and transplant-related research. However, because of its much smaller size, the mouse has proven to be a technically difficult and physiologically fragile model from a surgical standpoint. That is why only a few studies currently use mouse models in vascularized composite allotransplantation. The purpose of this study therefore was to develop a reproducible and reliable surgical technique in the mouse for future vascularized composite allotransplantation studies. METHODS: Forty DBA/2 (H2-D) hindlimb osteomyocutanous flaps were transplanted into the right cervical region of C57BL/6 (H2-D) mice using a nonsuture cuff technique. The donor iliac artery and femoral vein were mounted with polyimide cuffs (inner diameter, 0.404 mm; wall thickness, 0.025 mm) and subsequently anastomosed to the recipient common carotid artery and external jugular vein. Immunosuppressant drugs were used postoperatively. RESULTS: The overall success rate was 85.0 percent (34 of 40). The mortality rate was 12.5 percent (five of 40); all deaths resulted from perioperative bleeding. Only one arterial insufficiency was encountered after transplantation. The operative time was approximately 2 hours. Indefinite allograft survival (>120 days) could be achieved using a specific immunosuppressant regimen. CONCLUSIONS: This novel mouse model allows performing vascularized composite allotransplantation with very high success and survival rates. The advantages over conventional models are multifold. A high-flow common carotid artery keeps the anastomosis patent, and diastolic suction of the heart reduces the risk of venous stasis and thrombus formation. Less destruction because of the heterotopic positioning of the hindlimb graft further reduces the associated mortality and morbidity in this fragile model. PMID- 24469185 TI - Ectopic osteogenesis of allogeneic bone mesenchymal stem cells loading on beta tricalcium phosphate in canines. AB - BACKGROUND: Bone mesenchymal stem cells are progenitor cells for mesenchymal tissues. The objective of this study was to evaluate the subcutaneous ectopic osteogenesis of allogeneic bone mesenchymal stem cells, which were loaded on beta tricalcium phosphate in canines without immunosuppressive therapy. METHODS: Osteoinduced allogeneic bone mesenchymal stem cells were seeded onto a beta tricalcium phosphate scaffold to construct tissue-engineered bone. Four dogs (recipients) in the allogeneic group were subcutaneously implanted with the allogeneic bone mesenchymal stem cells/scaffold; four dogs (donors) in the autogeneic group were implanted with the autogeneic bone mesenchymal stem cells/scaffold complex; and four dogs in the control group were implanted with scaffold alone. Systemic immune responses were evaluated by measuring the T lymphocyte CD4, CD8, and CD4/CD8 subsets of each group. Subcutaneous osteogenesis was compared between the three groups by histologic analysis at week 24 after implantation. RESULTS: Flow cytometry showed no significant differences in the number of CD4 and CD8 T cells and the CD4/CD8 T-cell ratios among the three groups. Histologically, at week 24, both the autogeneic and allogeneic complexes led to subcutaneous osteogenesis, whereas the control group alone did not. There were no significant differences in the percentage of osteogenic area between the allogeneic and the autogeneic complexes on histomorphometric analysis (p > 0.05), which was significantly higher than that produced by the control group alone (p < 0.001). CONCLUSION: The results demonstrate that osteoinduced, allogeneic bone mesenchymal stem cells loaded on beta-tricalcium phosphate enhanced ectopic bone formation in canines without immunosuppressive therapy. PMID- 24469186 TI - Hand tumors: I. skin and soft-tissue tumors of the hand. AB - SUMMARY: Hand tumors of the skin and soft tissue are frequently encountered by plastic surgeons. Although similar to lesions affecting other parts of the body, the presentation, workup, and treatment options often differ in the hand secondary to its complex anatomy and functional significance. The purpose of this article is to provide an overview of those lesions that commonly arise in the hand-including epidermal inclusion cysts, ganglion cysts, and glomus tumors-in addition to tumors such as soft-tissue sarcomas that are rare but nonetheless require astute diagnosis and expedient initiation of treatment. Presenting symptoms and clinical features, recommended workup, and appropriate treatment options are reviewed. PMID- 24469187 TI - A comparison of the dorsal digital island flap with the dorsal branch of the digital nerve versus the dorsal digital nerve for fingertip and finger pulp reconstruction. AB - BACKGROUND: Traumatic fingertip and finger pulp defects can be treated with dorsal digital island flaps. Either the dorsal branch of the digital nerve or the dorsal digital nerve can be included in the flap for sensory reconstruction. However, it is still unclear whether there are differences in the results between the two donor nerves. METHODS: A retrospective study was conducted in 71 patients who had a fingertip or finger pulp defect treated with an innervated dorsal digital island flap from February of 2005 to June of 2011. The patients were divided into two groups based on which donor nerve was chosen. The donor nerve was coaptated to the digital nerve in the defect. At the final follow-up, the two groups were compared for static two-point discrimination, Semmes-Weinstein monofilament scores, pain, cold intolerance of the reconstructed finger, and patient satisfaction. RESULTS: Significant differences were found in static two point discrimination, pain, cold intolerance, and patient satisfaction (p < 0.05). The dorsal branch group presented slightly better discriminatory sensation in the flap and lower incidence of pain and cold intolerance in the injured finger. In addition, the dorsal branch group had a larger degree of satisfaction than the dorsal digital nerve group. No significant differences were found regarding Semmes-Weinstein monofilament flap score and total active motion of the finger. CONCLUSION: When utilizing dorsal digital island flaps to reconstruct traumatic fingertip and finger pulp defects, choosing the dorsal branch rather than the dorsal digital nerve as the donor may attain better outcomes. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III. PMID- 24469188 TI - The mandibular deformity in hemifacial microsomia: a reassessment of the Pruzansky and Kaban classification. AB - BACKGROUND: The authors examined hemifacial microsomia using three-dimensional computed tomography and the Kaban modification of the Pruzansky classification to determine its relationship with traditional evaluation and its reproducibility among evaluators. METHODS: A retrospective review of all patients diagnosed with hemifacial microsomia was performed. Three-dimensional computed tomographic scans were reviewed by expert evaluators and rated according to evaluators' understanding of the Kaban modification of the Pruzansky classification. The clinical Kaban-Pruzansky score was recorded at the time of initial clinical presentation and an in-house score stratified the population into mild (0-I), moderate (IIA), and severe (IIB-III). These two standards and the evaluators' scores were compared. Fleiss's kappa was used to assess interrater variability (p < 0.05). RESULTS: Forty-one patients met inclusion criteria, and 38 had documented clinical Kaban-Pruzansky scores. Sixteen craniofacial surgeons with an average of 15.5 years (range, 6 to 38 years) of experience were surveyed. Fair interrater reproducibility was found among all expert evaluators (Fleiss K = 0.238). When comparing raters' three-dimensional computed tomography-based classification to the clinical Kaban-Pruzansky scores, the average agreement was 39.17 +/- 8.83 percent (average K = 0.257 +/- 0.147) (p = 0.90). When comparing raters' classification to the in-house score, the average agreement was 69.71 +/- 9.42 percent (p = 0.97) (average K = 0.576 +/- 0.140). CONCLUSIONS: The introduction of three-dimensional computed tomography into the diagnostic paradigm highlights the inaccuracy and variability of traditional classification systems. The results question the accuracy and reproducibility of the current clinical paradigm, suggesting the need to reexamine the classification of hemifacial microsomia. CLINICAL QUESTION/LEVEL OF EVIDENCE: Diagnostic, III. PMID- 24469189 TI - Patient-reported quality of life in highest-functioning Apert and Crouzon syndromes: a comparative study. AB - BACKGROUND: Crouzon and Apert syndromes are the most common syndromic forms of craniofacial dysostosis. Apert syndrome has a broad clinical spectrum, including complex craniofacial involvement, as well as limiting deformities of the hands, feet, and other joints that require multiple surgical procedures when compared with Crouzon syndrome, which is generally less severe. The authors hypothesized that the quality of life of Apert syndrome patients is inferior to that of Crouzon syndrome patients. METHODS: The quality of life of Apert (n = 8) and Crouzon (n = 12) syndrome patients was assessed using the World Health Organization Quality of Life-100 questionnaire. The Mann-Whitney test was used to compare the quality-of-life scores between Apert and Crouzon patients. Values were considered significant for a confidence interval of 95 percent (p < 0.05). RESULTS: Apert patients showed an overall higher (score > 60 percent) quality of life in most World Health Organization Quality of Life-100 facets (68 percent) and domains (83.33 percent), with significance (p < 0.05) in three facets (energy and fatigue, mobility, and environment in the home), compared with Crouzon patients. CONCLUSION: Contrary to the authors' initial hypothesis, both the highest-functioning Apert patients and the Crouzon patients presented a satisfactory quality of life, demonstrating that these syndromic patients had acquired the necessary repertoire to manage the adverse daily situations of their lives. PMID- 24469190 TI - The mechanism of vascularized lymph node transfer for lymphedema: natural lymphaticovenous drainage. AB - BACKGROUND: Vascularized lymph node flap transfer for the treatment of upper and lower limb lymphedema has had promising results. This study was performed to investigate the mechanism of lymph drainage of a vascularized lymph node flap both experimentally and clinically. METHODS: In the experimental study, 18 Sprague-Dawley rats were used to create 36 flaps, either a groin lymph node flap or an abdominal cutaneous flap that did not contain lymph nodes. Indocyanine green dye was injected into the edge of 12 lymph node flaps, directly into a lymph node of 12 lymph node flaps, and into the edge of 12 cutaneous flaps. In the clinical study, an identical study design was used, with 24 vascularized lymph node flaps and 12 cutaneous flaps not containing lymph nodes. RESULTS: Experimentally, fluorescence was detected in the pedicle vein after a mean latency period of 153 +/- 129 seconds when the edge of the lymph node flap was injected and 12.8 +/- 8.1 seconds when the lymph node was directly injected. Fluorescence was not detected in the pedicle vein of the cutaneous flaps (p < 0.01). Clinically, fluorescence was detected in the pedicle vein after a mean latency period of 346 +/- 249 seconds when the edge of the lymph node flap was injected and 23.5 +/- 27.1 seconds when the lymph node was directly injected. Fluorescence was not detected in the pedicle vein of the cutaneous flaps (p < 0.01). CONCLUSION: The vascularized lymph node flap drains lymph into the pedicle vein, both experimentally and clinically. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, V. PMID- 24469191 TI - Wound healing: part I. Basic science. AB - LEARNING OBJECTIVES: After studying this article, the participant should be able to: 1. Describe the basic physiologic events in normal wound healing. 2. Understand the differences in healing among skin, bone, cartilage, and tendon. 3. Identify factors that may compromise or delay wound healing. 4. Describe methods for optimal closure of a wound. SUMMARY: Understanding the physiology and pathophysiology of normal wound healing and potential impediments to its end will allow the plastic surgeon to maximize postoperative outcomes and, in some instances, avoid unnecessary surgical interventions. Continuous advancements in our understanding of this process require frequent reviews of available data to permit reliable, evidence-based recommendations for clinical application. This is the first of a two-part article summarizing the science and clinical recommendations necessary for successful wound healing. PMID- 24469192 TI - Does hyperbaric oxygen therapy work in facilitating acute wound healing: a systematic review. AB - BACKGROUND: Adjunctive hyperbaric oxygen therapy is a safe and effective modality with which to increase tissue oxygenation and aid in healing of difficult wounds. The majority of the literature surrounding hyperbaric oxygen therapy supports its use in chronic wounds, but its use in acute wounds, flaps, and grafts is less well supported. METHODS: The authors reviewed the Ovid, PubMed, and Cochrane Library databases, and selected studies, level III and above, using hyperbaric oxygen therapy in the treatment of complicated acute wounds, flaps, and grafts. RESULTS: A total of eight studies were found to meet criteria for evaluation of adjunctive hyperbaric oxygen therapy in the treatment of complicated acute wounds, flaps, and grafts. CONCLUSIONS: When combined with standard wound management principles, hyperbaric oxygen therapy can augment healing in complicated acute wounds. However, it is not indicated in normal wound management. Further investigation is required before it can be recommended as a mainstay in adjuvant wound therapy. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II. PMID- 24469193 TI - Randomized controlled trial comparing health-related quality of life in patients undergoing vertical scar versus inverted T-shaped reduction mammaplasty. PMID- 24469194 TI - Outcomes analysis of patients undergoing autoaugmentation after breast implant removal. PMID- 24469195 TI - Reply: outcomes analysis of patients undergoing autoaugmentation after breast implant removal. PMID- 24469196 TI - Transaxillary totally subfascial breast augmentation with anatomical breast implants: review of 27 cases. PMID- 24469197 TI - The effect of pressure and shear on autologous fat grafting. PMID- 24469198 TI - Reply: the effect of pressure and shear on autologous fat grafting. PMID- 24469199 TI - Donor-Site morbidity of the radial forearm free flap versus the ulnar forearm free flap. PMID- 24469200 TI - Reply: donor-site morbidity of the radial forearm free flap versus the ulnar forearm free flap. PMID- 24469201 TI - A practical guide to free tissue transfer. PMID- 24469202 TI - Are the new changes in our operating rooms really making us safer and better surgeons? PMID- 24469204 TI - Social media use and impact on plastic surgery practice. PMID- 24469203 TI - Reply: are the new changes in our operating rooms really making us safer and better surgeons? PMID- 24469205 TI - Prophylactic mastectomy after planned submuscular breast augmentation. PMID- 24469206 TI - Lambda laser nymphoplasty: retrospective study of 231 cases. PMID- 24469207 TI - The original lift and fill facial rejuvenation. PMID- 24469208 TI - Two-stage breast augmentation-mastopexy: how many return for the mastopexy? PMID- 24469209 TI - Swine sign: a valuable audible sign in liposuction. PMID- 24469210 TI - The composite Moberg flap for reconstruction of complex thumb tip injuries. PMID- 24469211 TI - Infrahyoid myocutaneous flap for reconstruction after robotic transoral surgery for oropharyngeal tumors. PMID- 24469212 TI - A new technique for fixation in the fronto-orbital reconstruction for craniosynostosis using a resorbable mesh. PMID- 24469213 TI - Multilayer integra dermal template for frontal bone contour deformity reconstruction: a novel technique. PMID- 24469214 TI - Lip replantation in an infant after prolonged ischemia: age as a factor affecting success. PMID- 24469215 TI - Use of polyglycolic acid nerve conduit (neurotube) to alleviate pedicle kinking in microvascular anastomosis. PMID- 24469216 TI - The level of evidence published in a partner Journal of Plastic and Reconstructive Surgery: Revista Brasileira de Cirurgia Plastica. PMID- 24469217 TI - Beyond biologics: absorbable mesh as a low-cost, low-complication sling for implant-based breast reconstruction. AB - BACKGROUND: There is an intense push to decrease overall healthcare costs in the United States. Although the use of acellular dermal matrix in implant-based reconstruction has grown significantly over the past decade, potential drawbacks remain a source of debate. Matrices are costly and not universally available across institutions, whereas Vicryl mesh is widely available, relatively inexpensive, and resistant to bacteria biofilm formation. With the intent of maximizing the reconstructive and economic advantages of direct-to-implant breast reconstruction, the authors report the first experience in the literature using an absorbable mesh as an inferolateral sling. METHODS: A retrospective review was performed of the first 50 consecutive patients (76 reconstructions) who underwent implant-based breast reconstruction with Vicryl mesh from August of 2011 until June of 2012. RESULTS: Fifty patients underwent 76 direct-to-implant reconstructions with Vicryl mesh between August of 2011 and June of 2012 (mean follow-up, 1.2 years). Five breasts (6.6 percent) had complications, with only one complication resulting in implant loss (1.3 percent). Implant positioning and contour were excellent, with only two patients [three breasts (3.9 percent)] undergoing revision procedures, for size enlargement. Using costs available at the authors' institution, use of Vicryl mesh instead of acellular dermal matrix resulted in a direct material cost savings of $172,112 in 10 months. CONCLUSIONS: Results to date have been encouraging, with a low complication rate (6.6 percent) and excellent aesthetic results. The technique has resulted in $172,112 in direct material cost savings over 10 months. Continued follow-up is planned to evaluate long-term results. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV. PMID- 24469218 TI - Interventional treatment of ventricular tachycardia and electrical storm: from ablation of substrate and triggers to autonomic modulation by renal denervation. PMID- 24469219 TI - Multidetector computed tomography may be an adequate screening test to reduce periprocedural stroke in atrial fibrillation ablation: a multicenter propensity matched analysis. AB - BACKGROUND: Whether routine transesophageal echocardiography (TEE) in addition to multidetector computed tomography (MDCT) has incremental value in preventing periprocedural stroke before atrial fibrillation (AF) ablation is unclear. OBJECTIVE: The purpose of this study was to evaluate whether screening with MDCT is sufficient for preventing periprocedural stroke. METHODS: From 4 tertiary centers, we enrolled 1147 patients (902 males, age 57 +/- 11 years) with optimal anticoagulation and preserved left ventricular ejection function who had undergone MDCT and routine TEE (group 1, n = 678) or selective TEE (group 2, n = 469) as screening tests before AF ablation. Based on a propensity score analysis, 2 groups with 412 matched pairs were created. RESULTS: Patient baseline characteristics were comparable between the matched groups. In group 1 (n = 412), thrombi were detected in 4 patients (1.0%) on TEE, and ablation was not performed. These patients also showed thrombi (n = 3) or blood stasis (n = 1) on MDCT. For thrombi detection, MDCT had sensitivity and negative predictive value of 100%. In group 2 (n = 412), thrombi were detected in 7 patients (1.7%) on MDCT. Of these patients , 2 (0.5%) also showed thrombi on TEE. Periprocedural stroke incidence did not differ between the groups (0.2% each, P = 1.0). CONCLUSION: The incidence of periprocedural stroke was low and did not differ significantly between the group assigned to routine TEE vs selective TEE screening in AF patients undergoing anticoagulation therapy if the patients had conditions associated with low thrombus risk. Thus, preprocedural TEE may not be necessary before AF ablation in patients who have undergone preprocedural cardiac MDCT that shows no evidence of left atrial appendage thrombus. PMID- 24469220 TI - Serendipitous induction of ventricular tachycardia during pace-mapping: should we ablate? PMID- 24469221 TI - Opportunities for improving partner notification for HIV: results from a community-based participatory research study. AB - To identify actionable opportunities for improving Partner Notification (PN) for HIV among men who have sex with men (MSM), we characterized the perspectives and experiences of PN among Medical Case Managers (case managers), Disease Intervention Specialists (DIS), and MSM. In partnership with an AIDS service organization and the Connecticut State Health Department, we conducted a focus group of case managers (n = 14) and in-depth interviews with DIS (n = 7) and MSM (n = 24). We found differences between MSM's and providers' (case managers and DIS) perspectives regarding (1) determinants of sexual risk behaviors; (2) considerations impacting HIV disclosure; and (3) barriers to trusting relationships between MSM and providers. Factors impacting MSM perspectives on PN were incompletely appreciated by both case managers and DIS. PN may be improved through improving provider understanding of the complexities for MSM regarding sexual risk behaviors and disclosure and transcending barriers to trusting relationships between MSM and providers. PMID- 24469222 TI - Pregnant women living with HIV (WLH) supported at clinics by peer WLH: a cluster randomized controlled trial. AB - Throughout Africa, Peer Mentors who are women living with HIV (WLH) are supporting pregnant WLH at antenatal and primary healthcare clinics (McColl in BMJ 344:e1590, 2012). We evaluate a program using this intervention strategy at 1.5 months post-birth. In a cluster randomized controlled trial in KwaZulu-Natal, South Africa, eight clinics were randomized for their WLH to receive either: standard care (SC), based on national guidelines to prevent mother-to-child transmission (4 clinics; n = 656 WLH); or an enhanced intervention (EI; 4 clinics; n = 544 WLH). The EI consisted of four antenatal and four postnatal small group sessions led by Peer Mentors, in addition to SC. WLH were recruited during pregnancy and 70 % were reassessed at 1.5 months post-birth. EI's effect was ascertained on 16 measures of maternal and infant well-being using random effects regressions to control for clinic clustering. A binomial test for correlated outcomes evaluated EI's overall effectiveness. Among EI WLH reassessed, 87 % attended at least one intervention session (mean 4.1, SD 2.0). Significant overall benefits were found in EI compared to SC using the binomial test. However, it is important to note that EI WLH were significantly less likely to adhere to ARV during pregnancy compared to SC. Secondarily, compared to SC, EI WLH were more likely to ask partners to test for HIV, better protected their infants from HIV transmission, and were less likely to have depressed mood and stunted infants. Adherence to clinic intervention groups was low, yet, there were benefits for maternal and infant health at 1.5 months post-birth. PMID- 24469223 TI - Social network structure and HIV infection among injecting drug users in Lithuania: gatekeepers as bridges of infection. AB - The aim of the study was to assess-while controlling for individual risk characteristics-how certain social network structural characteristics (degree, eigenvector, and betweenness centrality) are related to HIV infections. Injecting drug users (N = 299) in Vilnius, Lithuania were recruited using incentivized chain referral sampling for a cross-sectional study. Sociometric social links were established between participants, and UCINET was used to calculate network measures. HIV prevalence was 10 %, and all except two knew they were infected. Of the five variables that remained significant in the final multivariate model, one showed temporal cumulative infection risk (more years since first drug injecting), three reflected informed altruism (always using condoms, less distributive syringe sharing and having not more than one sex partner), and one pointed to the importance of social network structure (betweenness centrality, indicating bridge populations). Loess regression indicates that betweenness may have the highest impact on HIV prevalence (about 60 vs. 20 % estimated HIV prevalence for the highest betweenness centrality values vs. highest age values). This analysis contributes to existing evidence showing both potential informed altruism (or maybe social desirability bias) in connection with HIV infection, and a link between HIV infection risk and the role of bridges within the social network of injecting drug user populations. These findings suggest the importance of harm reduction activities, including confidential testing and counseling, and of social network interventions. PMID- 24469225 TI - Permanent magnetism of intermetallic compounds between light and heavy transition metal elements. AB - First-principle calculations are used to investigate the intrinsic magnetic properties of intermetallic alloys of the type XMn, where X is a 4d or 5d element and M is Fe or Co. Emphasis is on the hexagonal C14 Laves-phase 1:2 and 1:5 alloys, the latter crystallizing in the CaCu5 structure. These series are of interest in permanent magnetism from fundamental and practical viewpoints, respectively. In the former, the unit cells form a prototypical motif where a heavy atom with high spin-orbit coupling and magnetocrystalline anisotropy is surrounded by many somewhat smaller M atoms with high magnetization, and the latter are Laves-phase derivatives of renewed interest in permanent magnetism. Our DFT calculations predict magnetic moments, magnetizations and anisotropies, as well as formation energies. The results are analyzed across the 4d and 5d series, especially with respect to hybridization effects between 3d and 4d/5d bands. PMID- 24469227 TI - In situ monitoring of the Li-O2 electrochemical reaction on nanoporous gold using electrochemical AFM. AB - The lithium-oxygen (Li-O2) electrochemical reaction on nanoporous gold (NPG) is observed using in situ atomic force microscopy (AFM) imaging coupled with potentiostatic measurement. Dense Li2O2 nanoparticles form a film at 2.5 V, which is decomposed at 3.8-4.0 V in an ether-based electrolyte. PMID- 24469226 TI - State of the art in nail dosimetry: free radicals identification and reaction mechanisms. AB - Until very recently, analysis of bone biopsies by means of the method of electron paramagnetic resonance (EPR) collected after surgery or amputation has been considered as the sole reliable method for radiation dose assessment in hands and feet. EPR measurements in finger- and toenail have been considered for accident dosimetry for a long time. Human nails are very attractive biophysical materials because they are easy to collect and pertinent to whole body irradiation. Information on the existence of a radiation-induced signal in human nails has been reported almost 25 years ago. However, no practical application of EPR dosimetry on nails is known to date because, from an EPR perspective, nails represent a very complex material. In addition to the radiation-induced signal (RIS), parasitic and intense signals are induced by the mechanical stress caused when collecting nail samples (mechanically induced signals-MIS). Moreover, it has been demonstrated that the RIS stability is strongly influenced not only by temperature but also by humidity. Most studies of human nails were carried out using conventional X-band microwave band (9 GHz). Higher frequency Q-band (37 GHz) provides higher spectral resolution which allows obtaining more detailed information on the nature of different radicals in human nails. Here, we present for the first time a complete description of the different EPR signals identified in nails including parasitic, intrinsic and RIS. EPR in both X- and Q-bands was used. Four different MIS signals and five different signals specific to irradiation with ionizing radiation have been identified. The most important outcome of this work is the identification of a stable RIS component. In contrast with other identified (unstable) RIS components, this component is thermally and time stable and not affected by the physical contact of fingernails with water. A detailed description of this signal is provided here. The discovery of stable radiation-induced radical(s) associated with the RIS component mentioned opens a way for broad application of EPR dosimetry in human nails. Consequently, several recent dosimetry assessments of real accident cases have been performed based on the described measurements and analyses of this component. PMID- 24469228 TI - Development of a synovial fluid analogue with bio-relevant rheology for wear testing of orthopaedic implants. AB - The rheological properties of synovial fluid (SF) are crucial to the performance of joint prostheses. During the development of joint prostheses, wear tests are performed, which simulate joint movements in diluted solutions (usually between 25 and 33% v/v) of bovine serum which has very different rheological properties compared with native SF, where rheology is maintained by hyaluronan. Consequently, there is a need to develop a more suitable artificial SF. In this study, we used rheological techniques to understand SF flow properties which provided an insight into the mechanical behaviour required of a practical SF analogue. Steady-shear viscosity measurements were performed to reveal changes as a function of shear rate. To analyse the viscoelastic properties small deformation oscillatory measurements of storage modulus (G') loss modulus (G") and complex viscosity (eta(*)) were made. The rheological properties of the SF where compared with those of the polysaccharides sodium alginate, gellan gum and mixtures of both polymers. Initial results revealed classic shear thinning behaviour for the SF with a small Newtonian plateau at low shear rates with a gradual reduction in viscosity with increasing shear rate. Viscoelasticity measurements also showed that at low frequencies of oscillation there was a viscous response with G" greater than G' and at higher frequencies there was an elastic response. Rheological properties were found to be similar to that of a 50:50 mix of 2% w/v high molecular weight alginate and 0.75% w/v gellan gum. Importantly, the lubricating behaviour of the serum differed significantly from the biopolymer blend over a full range of sliding velocities. The biopolymer blend was shown to lubricate the opposing surfaces more effectively. This difference was attributed to the more rapid alignment of the polysaccharide during shear when compared with the bovine albumin (the most abundant protein in serum), which typically exhibits a globular structure and has a tendency for self association. These results suggest that polysaccharide solutions with bio relevant rheology maybe be suitable as lubricants for in vitro orthopaedic prosthetic wear tests. PMID- 24469229 TI - When trust fails: the relation between children's trust beliefs in peers and their peer interactions in a natural setting. AB - One hundred and forty-nine 8-11 year-old children (86 males; M = 9 years - 4 months and SD = 7 months) from the UK were administered the Trust Beliefs in Peers scale and were observed in the playground over one school year. Quadratic relations were found between trust beliefs in peers and peer interaction, which varied by gender. Compared to girls with the middle range of trust beliefs, girls with very low beliefs and those with very high beliefs (a) were less accepted/more rejected by the peer group (i.e., lower group interaction, and greater negatively received bids), (b) showed greater indirect aggression (engaged in and received), (c) showed greater non-engagement (i.e., being alone), and (d) showed greater concomitant distress. Compared to children with the middle range of trust beliefs, children with those extreme trust beliefs in peers demonstrated greater direct aggression (engaged in and received) and showed passive behavior (for boys only). The findings supported the conclusion that children, primarily girls, who trust peers too little and those who trust too much are at risk for psychosocial maladjustment. PMID- 24469230 TI - ATDC/TRIM29 phosphorylation by ATM/MAPKAP kinase 2 mediates radioresistance in pancreatic cancer cells. AB - Pancreatic ductal adenocarcinoma (PDAC) is characterized by therapeutic resistance for which the basis is poorly understood. Here, we report that the DNA and p53-binding protein ATDC/TRIM29, which is highly expressed in PDAC, plays a critical role in DNA damage signaling and radioresistance in pancreatic cancer cells. Ataxia-telangiectasia group D-associated gene (ATDC) mediated resistance to ionizing radiation in vitro and in vivo in mouse xenograft assays. ATDC was phosphorylated directly by MAPKAP kinase 2 (MK2) at Ser550 in an ATM-dependent manner. Phosphorylation at Ser-550 by MK2 was required for the radioprotective function of ATDC. Our results identify a DNA repair pathway leading from MK2 and ATM to ATDC, suggesting its candidacy as a therapeutic target to radiosensitize PDAC and improve the efficacy of DNA-damaging treatment. PMID- 24469231 TI - Health-related quality of life in children with disorders of sex development (DSD). AB - Disorders of sex development (DSD) are rare genetic conditions resulting in atypical development of the sex organs. While some evidence is available on psychosexual outcomes, much less is known about the quality of life in this population, especially in children. Health-related quality of life (HRQOL) is a widely accepted endpoint for assessment and evaluation of interventions and medical care. Within the German DSD Network study, 86 children aged 8-12 years with several subtypes of DSD were recruited from Germany, Austria and Switzerland. Demographic, medical and psychosocial variables were collected through interviews of the attending physicians, the children and the parents. HRQOL was the primary outcome. It was assessed by the KINDL-R Questionnaire [2001]. Psychosexual determinants included gender identity/gender dysphoria, gender role behaviour, the child's knowledge about the condition and number/timing of genital surgery. A significant reduction of HRQOL was reported in children's self-report (p < 0.001), in particular in the area of self-esteem (p < 0.001), physical well-being (p < 0.01) and school functioning (p < 0.05). Girls with congenital adrenal hyperplasia who experienced gender dysphoria reported lower HRQOL scores compared to the study group at large. Atypical gender role behaviour was not associated with HRQOL. CONCLUSION: Psychosocial support of children with DSD and their families appears to be necessary in at least some cases and must be accessible for all patients. PMID- 24469233 TI - Origami lithium-ion batteries. AB - There are significant challenges in developing deformable devices at the system level that contain integrated, deformable energy storage devices. Here we demonstrate an origami lithium-ion battery that can be deformed at an unprecedented high level, including folding, bending and twisting. Deformability at the system level is enabled using rigid origami, which prescribes a crease pattern such that the materials making the origami pattern do not experience large strain. The origami battery is fabricated through slurry coating of electrodes onto paper current collectors and packaging in standard materials, followed by folding using the Miura pattern. The resulting origami battery achieves significant linear and areal deformability, large twistability and bendability. The strategy described here represents the fusion of the art of origami, materials science and functional energy storage devices, and could provide a paradigm shift for architecture and design of flexible and curvilinear electronics with exceptional mechanical characteristics and functionalities. PMID- 24469234 TI - Achieving glycemic goals with addition of incretin-based therapies to insulin in patients with type 2 diabetes mellitus. AB - As type 2 diabetes mellitus progresses, multiple antihyperglycemic agents are needed to maintain adequate glycemic control. Consensus guidelines recommend combining agents with complementary mechanisms of action. Given that hypoglycemic events increase the risk of cardiovascular disease and that weight gain affects mortality in obese individuals, it is important to control hyperglycemia without inducing hypoglycemia or weight gain. Peer-reviewed clinical trial data from patients requiring insulin-containing combination therapy suggest that insulin may be more effective at controlling hyperglycemia when given with appropriate combination therapy, but insulin is associated with weight gain and hypoglycemia. Some agents should not be combined with insulin because of associated weight gain and edema (ie, thiazolidinediones) or hypoglycemia (ie, sulfonylureas). Conversely, the lack of weight gain and hypoglycemia associated with metformin, glucagon-like peptide-1 agonists and dipeptidyl peptidase-4 inhibitors and suppression of glucagon secretion by both classes of incretin-based therapies suggest that these agents are well suited to combination therapy with insulin. PMID- 24469235 TI - Quantitative passive soil vapor sampling for VOCs--part 1: theory. AB - Volatile organic compounds are the primary chemicals of concern at many contaminated sites and soil vapor sampling and analysis is a valuable tool for assessing the nature and extent of contamination. Soil gas samples are typically collected by applying vacuum to a probe in order to collect a whole-gas sample, or by drawing gas through a tube filled with an adsorbent (active sampling). There are challenges associated with flow and vacuum levels in low permeability materials, and leak prevention and detection during active sample collection can be cumbersome. Passive sampling has been available as an alternative to conventional gas sample collection for decades, but quantitative relationships between the mass of chemicals sorbed, the soil vapor concentrations, and the sampling time have not been established. This paper presents transient and steady state mathematical models of radial vapor diffusion to a drilled hole and considerations for passive sampler sensitivity and practical sampling durations. The results indicate that uptake rates in the range of 0.1 to 1 mL min(-1) will minimize the starvation effect for most soil moisture conditions and provide adequate sensitivity for human health risk assessment with a practical sampling duration. This new knowledge provides a basis for improved passive soil vapour sampler design. PMID- 24469237 TI - The effectiveness and ineffectiveness of complex behavioral interventions: impact of treatment fidelity. AB - There is often wide variability in the reported effects of complex behavioral interventions. Effectiveness can vary across studies, sites, and providers. A factor that has been insufficiently considered is the fidelity of the behavioral treatment that was provided. Low quality practice could be likened to partial doses of a vaccine or antibiotic: the right idea but insufficient strength. Using motivational interviewing (MI) as an example, the authors describe three quality conditions that should be present for a study to be regarded as a trial of a complex behavioral intervention: (1) The treatment should clearly contain the components that are theoretically or empirically related to its efficacy; (2) providers should be trained to an adequate and specified criterion of proficiency before treating trial patients; and (3) the fidelity of treatment should be documented by reliable coding of practice throughout the study and reported in a manner that permits comparison with skill levels in other trials. The authors also discuss bona fide intervention failures despite strong clinical trial methodology, offering recommendations for future outcome research. PMID- 24469239 TI - A functionalized Ge3-compound with a dual character of the central germanium atom. AB - (cAAC)Ge(GeL)2 (1) (cAAC = cyclic alkyl(amino) carbene; L = PhC-(tBuN)2), a functionalized Ge3-compound was prepared. Quantum mechanical studies on 1 show a reciprocal relationship between the electronic state of the central tri coordinated Ge atomand its reactivity towards protons, viz. tetravalent Ge(0) in terms of bonding and divalent Ge(0) in terms of reactivity. Thus the central Ge atomcan be considered as having a hidden but highly reactive lone pair of electrons. However, the terminal Ge atoms can be considered as tri-coordinated divalent Ge(I) with an active lone pair of electrons. PMID- 24469238 TI - Preventing caries in preschoolers: successful initiation of an innovative community-based clinical trial in Navajo Nation Head Start. AB - Navajo Nation children have the greatest prevalence of early childhood caries in the United States. This protocol describes an innovative combination of community based participatory research and clinical trial methods to rigorously test a lay native Community Oral Health Specialists-delivered oral health intervention, with the goal of reducing the progression of disease and improving family knowledge and behaviors. METHODS/DESIGN: This cluster-randomized trial designed by researchers at the Center for Native Oral Health Research at the University of Colorado in conjunction with members of the Navajo Nation community compares outcomes between the manualized 2-year oral health fluoride varnish-oral health promotion intervention and usual care in the community (child-caregiver dyads from 26 Head Start classrooms in each study arm; total of 1016 dyads). Outcome assessment includes annual dental screening and an annual caregiver survey of knowledge, attitudes and behaviors; collection of cost data will support cost benefit analyses. DISCUSSION: The study protocol meets all standards required of randomized clinical trials. Aligned with principles of community-based participatory research, extended interaction between members of the Navajo community and researchers preceded study initiation, and collaboration between project staff and a wide variety of community members informed the study design and implementation. We believe that the benefits of adding CBPR methods to those of randomized clinical studies outweigh the barriers and constraints, especially in studies of health disparities and in challenging settings. When done well, this innovative mix of methods will increase the likelihood of valid results that communities can use. PMID- 24469236 TI - Reducing the burden of acute respiratory distress syndrome: the case for early intervention and the potential role of the emergency department. AB - The mortality for acute respiratory distress syndrome (ARDS) remains unacceptably high. Success in clinical trials has been limited, resulting in a lack of effective therapies to treat the syndrome. The projected increase in mechanically ventilated patients and global need for critical care services suggests that the clinical and research landscape in ARDS can no longer be confined to the intensive care unit. A demonstrable minority of patients present to the emergency department (ED) with ARDS, and ARDS onset typically occurs shortly after intensive care unit admission. Furthermore, the ED is an entry point for many of the highest-risk patients for ARDS development and progression. These facts, combined with prolonged lengths of stay in the ED, suggest that the ED could represent a window of opportunity for treatment and preventive strategies, as well as clinical trial enrollment. This review aims to discuss some of the potential strategies that may prevent or alter the trajectory of ARDS, with a focus on the potential role the ED could play in reducing the burden of this syndrome. PMID- 24469240 TI - Partial deletions of the GRN gene are a cause of frontotemporal lobar degeneration. AB - Mutations in the progranulin gene (GRN) are an important cause of frontotemporal lobar degeneration (FTLD). Most known GRN mutations are null mutations, such as nonsense and frameshift mutations, which create a premature stop codon resulting in loss of function of the progranulin protein. Complete or near-complete genomic GRN deletions have also been found in three families, but heterozygous partial deletions that remove only one or two exons have not been reported to date. In this study, we analysed three unrelated FTLD patients with low plasma progranulin levels but no point GRN mutations by multiplex ligation-dependent probe amplification (MLPA) and quantitative multiplex polymerase chain reaction of short fluorescent fragments (QMPSF). We detected two heterozygous partial GRN deletions in two patients. One deletion removed exon 1 and part of intron 1. The second deletion was complex: it removed 1,410 bp extending from the part of intron 1 to the part of exon 3, with a small 5-bp insertion at the breakpoint junction (c.-7-1121_159delinsGATCA). Our findings illustrate the usefulness of a quantitative analysis in addition to GRN gene sequencing for a comprehensive genetic diagnosis of FTLD, particularly in patients with low plasma progranulin levels. PMID- 24469241 TI - DNA-assisted assembly of carbon nanotubes and MnO2 nanospheres as electrodes for high-performance asymmetric supercapacitors. AB - A DNA-assisted assembly approach is developed to fabricate a capacitor-type electrode material, DNA-functionalized carbon nanotubes (CNTs@DNA), and a battery type electrode material, DNA@CNTs-bridged MnO2 spheres (CNTs@DNA-MnO2), for asymmetric supercapacitors. An energy density of 11.6 W h kg(-1) is achieved at a power density of 185.5 W kg(-1) with a high MnO2 mass loading of 4.2 mg cm(-2). It is found that DNA assembly plays a critical role in the enhanced supercapacitor performance. This is because while DNA molecules functionalize carbon nanotubes (CNTs) via pi-pi stacking, their hydrophilic sugar-phosphate backbones also promote the dispersion of CNTs. The resultant CNTs@DNA chains can link multiple MnO2 spheres to form a networked architecture that facilitates charge transfer and effective MnO2 utilization. The improved performance of the asymmetric supercapacitors indicates that DNA-assisted assembly offers a promising approach to the fabrication of high-performance energy storage devices. PMID- 24469242 TI - Cost-efficient assessment of biomechanical exposure in occupational groups, exemplified by posture observation and inclinometry. AB - OBJECTIVES: This study compared the cost efficiency of observation and inclinometer assessment of trunk and upper-arm inclination in a population of flight baggage handlers, as an illustration of a general procedure for addressing the trade-off between resource consumption and statistical performance in occupational epidemiology. METHODS: Trunk and upper-arm inclination with respect to the line of gravity were assessed for three days on each of 27 airport baggage handlers using simultaneous inclinometer and video recordings. Labor and equipment costs associated with data collection and processing were tracked throughout. Statistical performance was computed from the variance components within and between workers and bias (with inclinometer assumed to produce "correct" inclination angles). The behavior of the trade-off between cost and efficiency with changed sample size, as well as with changed logistics for data collection and processing, was investigated using simulations. RESULTS: At similar total costs, time spent at trunk and arm inclination angles >60 degrees as well as 90 (th)percentile arm inclination were estimated at higher precision using inclinometers, while median inclination and 90th percentile trunk inclination was determined more precisely using observation. This hierarchy remained when the study was reproduced in another population, while inclinometry was more cost-efficient than observation for all three posture variables in a scenario where data were already collected and only needed to be processed. CONCLUSIONS: When statistical performance was measured only in terms of precision, inclinometers were more cost-efficient than observation for two out of three posture metrics investigated. Since observations were biased, inclinometers consistently outperformed observation when both bias and precision were included in statistical performance. This general model for assessing cost efficiency may be used for designing exposure assessment strategies with considerations not only of statistical but also cost criteria. The empirical data provide a specific basis for planning assessments of working postures in occupational groups. PMID- 24469243 TI - Oral contraceptives, human papillomavirus and cervical cancer. AB - Oncogenic human papillomavirus is the key determinant of cervical cancer, but other risk factors interact with it to define individual risk. Among these, there is oral contraceptive (OC) use. A quantitative review of the link between OCs and cervical cancer was performed. Long-term (>5 year) current or recent OC use has been related to an about two-fold excess risk of cervical cancer. Such an excess risk, however, levels off after stopping use, and approaches unity 10 or more years after stopping. The public health implications of OC use for cervical cancer are limited. In any case, such implications are greater in middle-income and low-income countries, as well as in central and eastern Europe and Latin America, where cervical cancer screening and control remain inadequate. PMID- 24469244 TI - Alcohol drinking and multiple myeloma risk--a systematic review and meta-analysis of the dose-risk relationship. AB - The role of alcohol intake in the risk for multiple myeloma (MM) is unclear, although some recent findings suggest an inverse relationship. To summarize the information on the topic, we carried out a systematic review and a dose-risk meta analysis of published data. Through the literature search until August 2013, we identified 18 studies, eight case-control and 10 cohort studies, carried out in a total of 5694 MM patients. We derived pooled meta-analytic estimates using random effects models, taking into account the correlation between estimates, and we carried out a dose-risk analysis using a class of nonlinear random-effects meta regression models. The relative risk for alcohol drinkers versus non/occasional drinkers was 0.97 [95% confidence interval (CI), 0.85-1.10] overall, 0.96 (95% CI, 0.74-1.24) among case-control studies, and 1.00 (95% CI, 0.89-1.13) among cohort studies. Compared with nondrinkers, the pooled relative risks were 0.96 (95% CI, 0.81-1.13) for light (i.e. <= 1 drink/day) and 0.89 (95% CI, 0.74-1.07) for moderate-to-heavy (i.e. >1 drink/day) alcohol drinkers. The dose-risk analysis revealed a model-based MM risk reduction of about 15% at two to four drinks/day (i.e. 25-50 g of ethanol). The present meta-analysis of published data found no strong association between alcohol drinking and MM risk, although a modest favorable effect emerged for moderate-to-heavy alcohol drinkers. PMID- 24469245 TI - Response to the letter to the editor sent by J.M. Broeders and S. Moss on our article entitled 'Pitfalls in using case-control studies for the evaluation of the effectiveness of breast screening programmes' that appeared in the European Journal of Cancer Prevention, issue of 20 December 2012. PMID- 24469246 TI - Multi-functional NaErF4:Yb nanorods: enhanced red upconversion emission, in vitro cell, in vivo X-ray, and T2-weighted magnetic resonance imaging. AB - In this paper, multi-functional hexagonal phase NaErF4:Yb nanorods were synthesized by a facile hydrothermal method. The upconversion luminescence (UCL) intensity and red to green ratio of the multi-functional NaErF4 nanorods can be improved by Yb(3+) doping. More importantly, owing to the decreased distance of Er and Yb, the significant enhancement of red UCL can be obtained, which is different to the usual green UCL of Yb/Er doped NaYF4 host. In addition, the intensity of UCL is strongest when the Yb(3+)-doped concentration reached 30%. The in vitro cell imaging and localized UCL spectra taken from HeLa cells revealed that these NaErF4: 30% Yb(3+) nanorods are ideal nanoprobes with absence of autofluorescence for optical bioimaging. Moreover, these nanorods possess large X-ray absorption ions (Er(3+) and doped Yb(3+)), and were successfully used as contrast agents for in vivo X-ray bioimaging for the first time. In addition to the excellent UCL and X-ray absorption properties, these nanorods present significant paramagnetic properties and can be used as T2-weighted magnetic resonance imaging (MRI) agents. Therefore, these enhanced red UCL NaErF4 nanocrystals with excellent paramagnetic properties and X-ray absorption properties can be used as promising multi-modal nanoprobes for optical bioimaging, MRI, computed X-ray tomography (CT), and may have potential applications in bioseparation. PMID- 24469247 TI - Comprehensive approach to ocular consequences of Stevens Johnson Syndrome - the aftermath of a systemic condition. AB - BACKGROUND: Stevens Johnson Syndrome (SJS) can lead to end stage corneal blindness. This study describes the comprehensive treatment measures and their outcomes in the management of ocular sequelae and complications of SJS. METHODS: Four hundred sixty-four eyes of 232 patients of SJS who underwent surgical intervention (punctal cautery, mucus membrane grafting for lid margin keratinisation, fornix reconstructive procedures, tectonic procedures, keratoplasty and keratoprosthesis) were studied. It was a non-comparative, retrospective, interventional case series. The primary outcome was the change in the best corrected visual acuity (BCVA). Secondary outcome measures included an improvement in the ocular surface status as indicated by corneal epithelial fluorescein staining and Schirmer's I strip wetting. RESULTS: The BCVA and the ocular surface status improved and/or stabilized in > 70 % of eyes following punctal cautery (n = 160) and > 80 % of eyes following lid margin mucus membrane grafting (n = 238). BCVA improved in 50 % of eyes following fornix reconstructive procedures (n = 24) with COMET (n = 6), in 63.9 % eyes with the Prosthetic Replacement of the Ocular Surface Ecosystem (PROSE) lens (n = 36), in 81.8 % of eyes after cataract surgery (n = 22). A BCVA of >=20/200 was achieved in 72.34 % of eyes following keratoprostheses procedures (n = 47). The mean duration of follow up was 53.3 +/- 15.2 months. CONCLUSION: The ocular sequelae of Stevens Johnson Syndrome can be blinding. They need to be identified and addressed early to retard the continued deterioration of the ocular surface. Our study aims to highlight the problem as well as the importance of comprehensive measures in the management of this potentially blinding disorder. PMID- 24469248 TI - [Quality assurance at the interface between anesthesia and transfusion medicine]. AB - BACKGROUND: The current situation in hospitals is characterized by financial limitations and simultaneously by increasing demands on quality and safety. The operative interface between anesthesia and transfusion medicine affects both factors. AIM: A detailed analysis was performed to evaluate the process quality at this operative interface at the University Hospital of Gottingen. The aim of the project was to revise und develop the structures and responsibilities at this interface, to dispose of weak points and to realize the optimization potential in the supply of blood products. MATERIAL AND METHODS: A databank-based electronic data processing solution was established with the clear definition of responsibilities for the various workflow procedures and the written documentation of these definitions in standard operating protocols. In order to guarantee the necessary transparency a routine reporting system to the department of surgery was established. In addition, a continuous further development of the blood supply standard based on electronic report data was implemented. RESULTS: By implementing the above named measures the rate of supplied to transfused blood products could be increased from 43.1 % to 55.7 %. The compliance with the blood supply standard improved continually over the first 18 months from 60.3 % to 92.3 %. The rate of supplied blood product deliveries without subsequent operation could be reduced from 9.0 % to 4.6 %. As a result of this optimization the supply costs in the internal cost allocation were reduced from 9,406 to 3,544 . CONCLUSION: The measures described are appropriate to cost effectively improve quality and patient safety. The optimization measures presented in this article can be implemented in other hospitals to increase quality and safety after individual adjustment to the local circumstances. PMID- 24469249 TI - Trajectories of posttraumatic stress among urban residents. AB - Urban residents experience a wide range of traumatic events and are at increased risk of assaultive violence. Although previous research has examined trajectories of posttraumatic stress (PTS) through latent class growth analysis (LCGA) among persons exposed to the same index events (e.g., a natural disaster), PTS trajectories have not been documented among urban residents. The aims of this study were to conduct LGCA with a sample of trauma survivors from Detroit, Michigan (N = 981), and to explore predictors of trajectory membership. Participants completed three annual telephone surveys, each of which included the posttraumatic stress disorder (PTSD) Checklist-Civilian Version. Four PTS trajectories were detected. Although the majority evidenced a trajectory of consistently few symptoms (Low: 72.5%), 4.6% were in a trajectory of chronic severe PTSD (High), and the remainder were in trajectories of consistently elevated, but generally subclinical, levels of PTS (Decreasing: 12.3%; Increasing: 10.6%). Socioeconomic disadvantage (e.g., lower income), more extensive trauma history (e.g., childhood abuse), and fewer social resources (e.g., lower social support) were associated with membership in higher PTS trajectories, relative to the Low trajectory. The results suggest that efforts to reduce PTS in urban areas need to attend to socioeconomic vulnerabilities in addition to trauma history and risk for ongoing trauma exposure. PMID- 24469250 TI - Have you seen? Shaking up the salt and pepper: origins of cellular heterogeneity in the inner cell mass of the blastocyst. PMID- 24469252 TI - A simple Markov model of sodium channels with a dynamic threshold. AB - Characteristics of action potential generation are important to understanding brain functioning and, thus, must be understood and modeled. It is still an open question what model can describe concurrently the phenomena of sharp spike shape, the spike threshold variability, and the divisive effect of shunting on the gain of frequency-current dependence. We reproduced these three effects experimentally by patch-clamp recordings in cortical slices, but we failed to simulate them by any of 11 known neuron models, including one- and multi-compartment, with Hodgkin Huxley and Markov equation-based sodium channel approximations, and those taking into account sodium channel subtype heterogeneity. Basing on our voltage-clamp data characterizing the dependence of sodium channel activation threshold on history of depolarization, we propose a 3-state Markov model with a closed-to open state transition threshold dependent on slow inactivation. This model reproduces the all three phenomena. As a reduction of this model, a leaky integrate-and-fire model with a dynamic threshold also shows the effect of gain reduction by shunt. These results argue for the mechanism of gain reduction through threshold dynamics determined by the slow inactivation of sodium channels. PMID- 24469251 TI - Miswiring the brain: Delta9-tetrahydrocannabinol disrupts cortical development by inducing an SCG10/stathmin-2 degradation pathway. AB - Children exposed in utero to cannabis present permanent neurobehavioral and cognitive impairments. Psychoactive constituents from Cannabis spp., particularly Delta(9)-tetrahydrocannabinol (THC), bind to cannabinoid receptors in the fetal brain. However, it is unknown whether THC can trigger a cannabinoid receptor driven molecular cascade to disrupt neuronal specification. Here, we show that repeated THC exposure disrupts endocannabinoid signaling, particularly the temporal dynamics of CB1 cannabinoid receptor, to rewire the fetal cortical circuitry. By interrogating the THC-sensitive neuronal proteome we identify Superior Cervical Ganglion 10 (SCG10)/stathmin-2, a microtubule-binding protein in axons, as a substrate of altered neuronal connectivity. We find SCG10 mRNA and protein reduced in the hippocampus of midgestational human cannabis-exposed fetuses, defining SCG10 as the first cannabis-driven molecular effector in the developing cerebrum. CB1 cannabinoid receptor activation recruits c-Jun N terminal kinases to phosphorylate SCG10, promoting its rapid degradation in situ in motile axons and microtubule stabilization. Thus, THC enables ectopic formation of filopodia and alters axon morphology. These data highlight the maintenance of cytoskeletal dynamics as a molecular target for cannabis, whose imbalance can limit the computational power of neuronal circuitries in affected offspring. PMID- 24469253 TI - Risk factors and treatment outcomes of new contralateral upper urinary urothelial carcinoma after nephroureterectomy: the experiences of a large Chinese center. AB - OBJECTIVE: To explore the risk factors and treatment outcomes of contralateral new upper tract urothelial carcinoma (UTUC) after nephroureterectomy in a large single-center cohort of UTUC patients. METHODS: A retrospective analysis of the clinicopathological data of 509 consecutive patients treated by nephroureterectomy from 2000 to 2010 at a high-volume center in China was conducted. RESULTS: Thirty-five patients (6.9%) were found to develop contralateral UTUC. Gross hematuria was a common symptom, and aristolochic acid (AA) containing Chinese herbs was identified as an underlying cause. In multivariate analysis, renal transplant recipients (HR = 16.507) and preoperative renal insufficiency (HR = 2.523) were independent risk factors. No correlation was found in the clinical and pathological characteristics of primary and subsequent contralateral UTUC. A second round of nephroureterectomy should be performed on renal transplant patients, whereas patients who are older, exhibit relatively better renal function, and have tumors that are single, located in the ureter and small size could be treated with nephron-sparing surgery. No survival difference was detected between the two treatment groups, and developing contralateral UTUC was not associated with worse survival. CONCLUSION: Contralateral UTUC is comparatively rare, and gross hematuria is a common symptom. Renal transplant history and renal insufficiency are independent risk factors, and prophylactic contralateral nephroureterectomy is considered for uremic UTUC patients with proper renal replacement treatment or renal transplant recipients. These features are likely related to the mechanisms of multifocality of UTUC, and the potential correlation with AA remains to be elucidated. Tumor characteristics and renal function are informative for the decisions concerning surgical options for contralateral UTUC. PMID- 24469256 TI - Micromagnetic analysis of the hardening mechanisms of nanocrystalline MnBi and nanopatterned FePt intermetallic compounds. AB - The uniaxial intermetallic compounds of L10-FePt and the low temperature NiAs structure of MnBi are suitable alloys for application as high-density recording materials or as high-coercivity permanent magnets. Single domain particles of these materials are characterized by coercive fields above 1 T over a large temperature range. In particular MnBi shows a coercive field of 2 T at 450 K. Its extraordinary magnetic properties in the temperature range up to 600 K are due to an increase of the magnetocrystalline anisotropy constant from 1.2 MJ m(-3) at 300 K to 2.4 MJ m(-3) at 450 K. In spite of the large coercivities obtained for both type of materials their experimental values deviate considerably from the theoretical values Hc = 2K1/Js valid for a homogeneous rotation process in spherical particles. As is well known these discrepancies are due to the deteriorating effects of the microstructure. For an analysis of the coercive fields the Stoner-Wohlfarth theory has to be expanded with respect to higher anisotropy constants and to microstructural effects such as misaligned grains and grain surfaces with reduced anisotropy constants. It is shown that the temperature dependence and the angular dependence of Hc for FePt as well as MnBi can be quantitatively interpreted by taking into account the above mentioned intrinsic and microstructural effects. PMID- 24469254 TI - Cell-surface nucleolin acts as a central mediator for carcinogenic, anti carcinogenic, and disease-related ligands. AB - PURPOSE: Cell-surface nucleolin in human gastric cancer cell lines is a receptor for TNF-alpha-inducing protein (Tipalpha) of Helicobacter pylori. The binding complex of nucleolin and Tipalpha is internalized into the cells and then induces tumor progression of human gastric cancer. Surface nucleolin is also a receptor of human immunodeficiency virus-1, and the anti-HIV pseudopeptide (HB-19) showed anti-carcinogenic activity in vivo. Surface nucleolin has dual functions depending on the ligands: In order to understand the mechanisms of surface nucleolin, it is necessary to review surface nucleolin and its relation to carcinogenic ligands and anti-carcinogenic ligands. Other ligands can be grouped among disease-related ligands, which is an important new topic for the prevention of various ailments. RESULTS AND DISCUSSION: This paper mainly deals with two ligands of surface nucleolin, Tipalpha and pseudopeptide HB-19. The binding complex of nucleolin and Tipalpha induces expression of TNF-alpha and chemokine genes and activates NF-kappaB in gastric cancer cells of humans and mice. However, when human gastric cancer cell line MKN-1 was transfected with nucleolin targeted siRNA, the result was inhibition of cell migration and elongation induced by Tipalpha. The amount of surface nucleolin was reduced in membrane fraction of the nucleolin knockdown MKN-1 cells, but the amount of nucleolin in the cytosol or nuclear fractions of the cells did not change. The results indicate that surface nucleolin acts as a carcinogenic mediator for Tipalpha of H. pylori. In contrast, both the viral external envelop glycoprotein gp120 of HIV and the anti-HIV pseudopeptide HB-19 bind to surface nucleolin. Through this binding, treatment with HB-19 inhibited tumor development in human breast cancer cell line MDA-MB-231 and rhabdoid tumor cell line derived from Wilms's tumor in xenograft nude mouse models. The results show that surface nucleolin acts as an anti-carcinogenic mediator for HB-19. CONCLUSION: Based on these discrete functions of surface nucleolin, the binding complex of carcinogenic ligands and surface nucleolin seems to be competing with that of anti-carcinogenic ligands and surface nucleolin. Moreover, carcinogenic ligands derived from endogenous sources play a significant role in human cancer development, and the interaction of surface nucleolin with disease-related ligands will be a new research subject for the prevention and treatment of various ailments. PMID- 24469255 TI - Does regular zoledronic acid change the bone turnover of the jaw in men with metastatic prostate cancer: a possible clue to the pathogenesis of bisphosphonate related osteonecrosis of the jaw? AB - PURPOSE: To find out whether the most popular pathogenesis hypothesis of the bisphosphonate (BP) related osteonecrosis of the jaw (BRONJ) is comprehensible: (1) is there a higher bone remodeling in the jaw compared with other skeletal sites? (2) Is the bone turnover (BT) of the jaw overly altered after BP intake? (3) Are there gender- or entity-specific differences in BT before and after BP intake? METHODS: Bone scintigraphies of 42 patients with prostate cancer were retrospectively analyzed (n = 21 with BP intake; n = 21 no BP). All patients received bone scintigraphy prior to the therapy and in the course of the treatment (after 12 and 24 months). Data were quantitatively analyzed using six predetermined regions of interest and compared with a breast cancer cohort. RESULTS: The mandible revealed a similar BT as the femur and a significant lower BT compared with the maxilla. All investigated bone regions showed no significant changes under BP administration. Inter-gender differences revealed significantly lower BT values for the prostate cancer compared with the female breast cancer cohort, changes over the course of time could not be found. CONCLUSIONS: The finding that the mandible revealed a significant lower BT than the maxilla and the fact that 2/3 of the BRONJ cases occur in the mandible are inconsistent with the investigated hypothesis. Furthermore, the BT in the jawbone is not overly suppressed by BP. Thus, it seems implausible that a high BT and its over suppression play the key role in the pathomechanism of BRONJ. PMID- 24469257 TI - Highlights of the 26th EANM 2013 congress in Lyon: new horizons and further. AB - The 26th European Association of Nuclear Medicine (EANM) annual congress was held in Lyon, France, under the chairmanship of Professor Dominique LeGuludec. The congress was attended by more than 5,200 participants, with about one-quarter coming from outside Europe. This review summarizes the major scientific contributions which were selected from the more than 1,700 submitted abstracts, and presented in the closing highlights session. They covered the diverse areas of nuclear medicine, with particular focus on oncology, cardiovascular science and neurology. Various innovations were reported regarding imaging methodology, physics, radiopharmaceuticals and chemistry. Novel radionuclide applications in both diagnosis and therapy were investigated and described, triggering strong interest from the many professionals involved. Significant progress has been demonstrated in the clinical use of existing nuclear medicine procedures, and a number of new applications are under development in preclinical and early clinical stages. The congress was a unique opportunity to get a thorough update on this research. PMID- 24469259 TI - Differentiation of HIV-associated lymphoma from HIV-reactive adenopathy using quantitative FDG-PET and symmetry. PMID- 24469258 TI - Differentiation of HIV-associated lymphoma from HIV-associated reactive adenopathy using quantitative FDG PET and symmetry. AB - PURPOSE: To determine the diagnostic accuracy of a semiautomated (18)F-FDG PET/CT measurement of total lesion glycolysis (TLG), maximum and peak standardized uptake value at lean body mass (SUL-Max and SUL-Peak), qualitative estimates of left/right nodal symmetry and FDG uptake for differentiating lymphoma from reactive adenopathy in HIV-infected patients. METHODS: We retrospectively analyzed 41 whole-body (18)F-FDG PET/CT studies performed in HIV-infected patients for clinical reasons. The study received institutional review board approval. Of the 41 patients, 19 had biopsy-proven untreated lymphoma, and 22 with reactive adenopathy without malignancy on follow-up were used as controls. Nodal and extranodal visual qualitative metabolic scores, SUL-Max, SUL-Peak, CT nodal size, and PERCIST 1.0 threshold-based TLG and metabolic tumor volume (MTV) were determined. The qualitative intensity of nodal involvement and symmetry of uptake were compared using receiver operator curve (ROC) analysis. HIV plasma viral RNA measurements were also obtained. RESULTS: All of the quantitative PET metrics performed well in differentiating lymphoma from reactive adenopathy and performed better than qualitative visual intensity scores. The areas under the ROC curves (AUC) were significantly higher for TLG = 0.96, single SUL-Peak = 0.96, single SUL-Max = 0.97, and MTV = 0.96, compared to 0.67 for CT nodal size (p < 0.001). These PET metrics performed best in separating the two populations in aviremic patients, with AUCs of 1 (AUC 0.91 for CT nodal size). TLG, MTV, SUL Peak and SUL-Max were more reliable markers among viremic individuals, with AUCs between 0.84 and 0.93, compared to other metrics. PET metrics were significantly correlated with plasma viral load in HIV-reactive adenopathy controls. Asymmetrical FDG uptake had an accuracy of 90.4 % for differentiating lymphoma from reactive adenopathy in HIV-infected patients. CONCLUSION: Quantitative PET metabolic metrics as well as the qualitative assessment of symmetry of nodal uptake appear to be valuable tools for differentiating lymphoma from reactive adenopathy in HIV-infected patients using FDG PET. These parameters appear more robust in aviremic patients. PMID- 24469260 TI - Dike intrusions during rifting episodes obey scaling relationships similar to earthquakes. AB - As continental rifts evolve towards mid-ocean ridges, strain is accommodated by repeated episodes of faulting and magmatism. Discrete rifting episodes have been observed along two subaerial divergent plate boundaries, the Krafla segment of the Northern Volcanic Rift Zone in Iceland and the Manda-Hararo segment of the Red Sea Rift in Ethiopia. In both cases, the initial and largest dike intrusion was followed by a series of smaller intrusions. By performing a statistical analysis of these rifting episodes, we demonstrate that dike intrusions obey scaling relationships similar to earthquakes. We find that the dimensions of dike intrusions obey a power law analogous to the Gutenberg-Richter relation, and the long-term release of geodetic moment is governed by a relationship consistent with the Omori law. Due to the effects of magma supply, the timing of secondary dike intrusions differs from that of the aftershocks. This work provides evidence of self-similarity in the rifting process. PMID- 24469261 TI - Cesarean section and osteosynthesis of lower limb fractures in the same surgical procedure. AB - INTRODUCTION: Orthopedic trauma during pregnancy can cause serious complications such as premature birth, stillbirth and maternal morbidities. PRESENTATION OF CASE: We report the case of a patient at 38 weeks pregnancy who fractured the left ankle and the right fifth metatarsal after falling. Cesarean section and osteosynthesis were performed in the usual manner in the same surgical procedure. There were no postoperative complications. DISCUSSION: Pregnancy and puerperium are associated with a hypercoagulable state. The early mobilization provided by surgical treatment of the fractures reduced the risks of thromboembolic events. CONCLUSION: The approach adopted may be used as an example for future procedures done in similar situations. PMID- 24469262 TI - Physiologically based pharmacokinetic-pharmacodynamic modeling to the rescue: understanding how resuscitation from local anesthetic overdose with lipid emulsions works. PMID- 24469263 TI - Gastrin: from pathophysiology to cancer prevention and treatment. AB - Gastrin has been identified as the principal effector of gastric secretion, but several studies have demonstrated its role as a biomarker of cancer risk and as a growth factor for colorectal, stomach, liver, and pancreatic cancer. Hypergastrinemia characterizes autoimmune gastritis, with body and fundic gland atrophy and increased risk for both gastric adenocarcinoma and neuroendocrine tumors. Gastric type I carcinoids develop in the context of autoimmune gastritis because of the stimulus exerted by gastrin on enterochromaffin-like cells and remain gastrin-sensitive for long durations because the removal of hypergastrinemia leads to tumor regression. The treatment of gastric carcinoid is still open to debate, but when the disease frequently relapses, or is multicentric or infiltrating, surgery is advocated or, in the alternative, a costly and long-lasting treatment with long-acting somatostatin analogues is prescribed. A technology allowing the preparation of an immunogen eliciting an immune system response with generation of antibodies against G17 has been developed. This vaccine has been tested in patients with colorectal, pancreatic or advanced gastric cancer. The vaccine has also been used in the treatment of gastric type I carcinoids, and the administration of G17DT in patients harboring these lesions leads to carcinoid regression. Antigastrin vaccination in the treatment of gastrointestinal cancer obviously needs validation, but this immunotherapy may well represent a simple, inexpensive, and active 'adjuvant' treatment. PMID- 24469264 TI - Self-sorting of dynamic metallosupramolecular libraries (DMLs) via metal-driven selection. AB - "Metal-driven" selection between finite mononuclear and polymeric metallosupramolecular species can be quantitatively achieved in solution and in a crystalline state via coupled coordination/stacking interactional algorithms within dynamic metallosupramolecular libraries - DMLs. PMID- 24469265 TI - Workers' psychological distress, depression, and burnout symptoms: associations with diurnal cortisol profiles. AB - OBJECTIVE: This study investigated whether self-reported psychological distress and depressive and burnout symptoms were associated with cortisol concentrations among workers. METHODS: Day-shift workers (N=401) employed in 34 diverse workplaces in Canada participated. We administered well-validated questionnaires and collected salivary cortisol concentrations at five time points (awakening, 30 minutes after awakening, 14:00 hours, 16:00 hours, and bedtime) repeated three times a week (Saturday, Tuesday, Thursday) to capture work and non-workday variation. Multilevel regressions models estimated cortisol concentrations at different levels according to time of day, workers, and workplaces. RESULTS: After controlling for awakening time, sex, age, season of sampling, alcohol use, physical activity, psychotropic drugs use, health conditions, and body mass index, results revealed significant associations between psychological distress and depressive and burnout symptoms in relation to cortisol concentrations at different diurnal time points. Specifically, higher levels of psychological distress and depressive symptoms were associated with higher cortisol concentrations at awakening but not 30 minutes afterwards. Starting steadily from 14:00 hours until bedtime, levels of psychological distress and depressive and burnout symptoms were associated with lower cortisol concentrations. Significant cortisol variations were also found between workplaces. Sex did not moderate associations in secondary analyses. CONCLUSIONS: Distinct time points of diurnal cortisol variation were consistently, albeit modestly, associated with increased psychological distress and depressive and burnout symptoms. Our findings therefore link subjective psychometrics with objective biometrics. This research area could potentially lead to the development of refined screening tools that provide correspondence between diurnal cortisol and mental health. PMID- 24469266 TI - Dehydration and crystallization of amorphous calcium carbonate in solution and in air. AB - The mechanisms by which amorphous intermediates transform into crystalline materials are poorly understood. Currently, attracting enormous interest is the crystallization of amorphous calcium carbonate, a key intermediary in synthetic, biological and environmental systems. Here we attempt to unify many contrasting and apparently contradictory studies by investigating this process in detail. We show that amorphous calcium carbonate can dehydrate before crystallizing, both in solution and in air, while thermal analyses and solid-state nuclear magnetic resonance measurements reveal that its water is present in distinct environments. Loss of the final water fraction--comprising less than 15% of the total--then triggers crystallization. The high activation energy of this step suggests that it occurs by partial dissolution/recrystallization, mediated by surface water, and the majority of the particle then crystallizes by a solid-state transformation. Such mechanisms are likely to be widespread in solid-state reactions and their characterization will facilitate greater control over these processes. PMID- 24469267 TI - Spin density distribution after electron transfer from triethylamine to an [Ir(ppy)2(bpy)]+ photosensitizer during photocatalytic water reduction. AB - The photoreduction of the bis(2-phenylpyridinato-)(2,2'-bipyridine)iridium(III) ion ([Ir(ppy)2(bpy)](+)), used as a photosensitizer in photocatalytic water splitting, by triethylamine was studied by means of UV/VIS, XANES, and EPR spectroscopies, supported by theoretical calculations at density functional theory (DFT) and complete active space self-consistent field (CASSCF/CASPT2) levels. The combination of these methods suggests a predominant bpy localization of the spin-density of the unpaired electron with notable delocalization to the Ir center. This is particularly evident from EPR and theoretical results and leads to broad EPR lines and a large anisotropy of the g-factor. PMID- 24469268 TI - RhoA and Rac1 play independent roles in lysophosphatidic acid-induced ovarian cancer chemotaxis. AB - Lysophosphatidic acid (LPA), which is a bioactive phospholipid existing at high level in ascites and plasma of ovarian cancer patients, is known to be involved in cell survival, proliferation, adhesion, and migration. Small guanosine triphosphatases (GTPases) such as RhoA and Rac1 are intracellular signaling molecules which affect morphology and chemotactic behavior of cells. In this research, we first investigated roles of RhoA and Rac1 in the LPA-induced chemotaxis of SKOV3 human ovarian cancer cells using a multilevel microfluidic platform. The multilevel microfluidic device was fabricated by a rapid prototyping method based on soft lithography using multi-layered adhesive tapes. This platform allows us to conduct the on-chip chemotaxis assays in conventional biology laboratories without any huge and expensive equipment for fabrication and fluidic manipulation. Based on image-based analysis of single cell trajectories in the microfluidic device, the chemotaxis of SKOV3 cells could be quantitatively analyzed in two independent parameters-migration speed and directional persistence. Inhibition of the RhoA/ROCK pathways reduced the directional persistence, not the migration speed, of the cells, while only the migration speed was decreased when the activity of Rac1/PAK pathways was suppressed. These results suggest that RhoA and Rac1 signaling pathways potentially play independent roles in the chemotactic migration of SKOV3 ovarian cancer cells in the linear and stable LPA concentration gradient. Our microfluidic platform would provide a rapid, low cost, easy-to-use, and versatile way for research of cancer cell migration which is crucial for tumor metastasis. PMID- 24469269 TI - Genetic diversity of rotavirus strains circulating in environmental water and bivalve shellfish in Thailand. AB - Rotavirus is a common cause of acute diarrhea in young children worldwide. This study investigated the prevalence and molecular characterization of rotavirus in environmental water and oyster samples in Thailand. A total of 114 water samples and 110 oyster samples were collected and tested for group A rotavirus using RT nested PCR. Rotavirus genotype was identified by phylogenetic analysis of the VP7 genetic sequences. Group A rotavirus was detected in 21 water samples (18.4%) and six oyster samples (5.4%). Twenty five rotavirus strains were successfully sequenced and classified into four genotypes; G1, G2, G3, and G9. Rotavirus G1 (three strains), G2 (three strains), and G9 (two strains) demonstrated the genetic sequences similar to human strains (90%-99% nucleotide identity), whereas G3 (17 strains) was closely related to animal strains (84%-98% nucleotide identity). G1 strains belonged to lineages I (sub-lineage c) and II. G2 strains belonged to lineage II. G9 strains belonged to lineages III (sub-lineage b) and IV. G3 strains belonged to lineages I, III (sub-lineage c), and IV with a predominance of lineage I. The present study provides important information on the rotavirus strains circulating in the environment. PMID- 24469270 TI - Comparative phylogenetic analysis of genome-wide Mlo gene family members from Glycine max and Arabidopsis thaliana. AB - Powdery mildew locus O (Mlo) gene family is one of the largest seven transmembrane protein-encoding gene families. The Mlo proteins act as negative regulators of powdery mildew resistance and a loss-of-function mutation in Mlo is known to confer broad-spectrum resistance to powdery mildew. In addition, the Mlo gene family members are known to participate in various developmental and biotic and abiotic stress response-related pathways. Therefore, a genome-wide similarity search using the characterized Mlo protein sequences of Arabidopsis thaliana was carried out to identify putative Mlo genes in soybean (Glycine max) genome. This search identified 39 Mlo domain containing protein-encoding genes that were distributed on 15 of the 20 G. max chromosomes. The putative promoter regions of these Mlo genes contained response elements for different external stimuli, including different hormones and abiotic stresses. Of the 39 GmMlo proteins, 35 were rich (8.7-13.1 %) in leucine, while five were serine-rich (9.2-11.9 %). Furthermore, all the GmMlo members were localized in the plasma membrane. Phylogenetic analysis of the GmMlo and the AtMlo proteins classified them into three main clusters, and the cluster I comprised two sub-clusters. Multiple sequence alignment visualized the location of seven transmembrane domains, and a conserved CaM-binding domain. Some of the GmMlo proteins (GmMlo10, 20, 22, 23, 32, 36, 37) contained less than seven transmembrane domains. The motif analysis yielded 27 motifs; out of these, motif 2, the only motif present in all the GmMlos, was highly conserved and three amino acid residues were essentially invariant. Five of the GmMlo members were much smaller in size; presumably they originated through deletion following a gene duplication event. The presence of a large number of GmMlo members in the G. max genome may be due to its paleopolyploid nature and the large genome size as compared to that of Arabidopsis. The findings of this study may further help in characterization and isolation of individual GmMlo members. PMID- 24469272 TI - Drug-free holiday in patients with rheumatoid arthritis: a qualitative study to explore patients' opinion. AB - Clinical trials have shown that in patients with long-standing low disease activity, tapering and/or stopping antirheumatic medication is a realistic option. The objective of this study is to explore patients' opinion about tapering and discontinuing antirheumatic drugs. This qualitative study is based on interviews with 20 patients with rheumatoid arthritis (RA) about RA treatment and treatment discontinuation through structured interviewing. Interviews were tape-recorded, transcribed verbatim, and screened by three assessors independently for meaning units. Not only positive emotions about drug discontinuation such as hope, happiness, and relief, but also fear and disappointment were mentioned. Some patients expect that drug discontinuation will be possible in other patients and/or themselves, while others do not expect this. The concept of increase in disease activity after discontinuing medication was mentioned, and while patients expect that disease activity will decrease again after restarting medication, they expect that this will take (too much) time. Positive emotions about the option to taper and discontinue antirheumatic medication, with negative expectations is a common combination in these RA patients. In particular, patients expect that disease activity will flare and that improvement upon restarting medication will take time. Patients' expectations and feelings should be addressed before drug tapering is attempted in a clear strategy of continued monitoring of disease activity. PMID- 24469273 TI - Synthesis of wafer-scale uniform molybdenum disulfide films with control over the layer number using a gas phase sulfur precursor. AB - We describe a method for synthesizing large-area and uniform molybdenum disulfide films, with control over the layer number, on insulating substrates using a gas phase sulfuric precursor (H2S) and a molybdenum metal source. The metal layer thickness was varied to effectively control the number of layers (2 to 12) present in the synthesized film. The films were grown on wafer-scale Si/SiO2 or quartz substrates and displayed excellent uniformity and a high crystallinity over the entire area. Thin film transistors were prepared using these materials, and the performances of the devices were tested. The devices displayed an on/off current ratio of 10(5), a mobility of 0.12 cm(2) V(-1) s(-1) (mean mobility value of 0.07 cm(2) V(-1) s(-1)), and reliable operation. PMID- 24469274 TI - Ovarian endometrioma: what the patient needs. PMID- 24469275 TI - Assessment of periodic blood loss: interindividual and intraindividual variations of pictorial blood loss assessment chart registrations. AB - STUDY OBJECTIVE: To explore the interindividual and intraindividual variation of Pictorial Blood Loss Assessment Chart (PBAC) registrations of subjective perception of minimal, normal, and heavy menstrual bleeding in women using their usual sanitary protection. DESIGN: Retrospective study (Canadian Task Force classification II-3). SETTING: University tertiary hospital. PATIENTS: Women who had participated in 4 previously published prospective studies using PBAC as the outcome measure. INTERVENTIONS: Patients underwent hysteroscopic removal of polyps, laparoscopic occlusion of uterine vessels, or uterine artery embolization, and control subjects received no treatment. MEASUREMENTS AND MAIN RESULTS: PBAC scores, hemoglobin concentration, and subjective assessment of periodic blood loss were recorded in 429 women during 1049 menstrual cycles. The median PBAC values in groups of women who assessed their bleeding as light, normal, and heavy were 45.0, 116.0, and 254.5, respectively (p < .001). Sensitivity and specificity for specific PBAC cutoff points were calculated using a receiver operating characteristic curve. The maximum sensitivity for assessment of heavy periodic blood loss (78.5) was reached at a PBAC score of 160. The corresponding specificity was 75.8. At PBAC values below 130, 90% of the women reported normal blood loss, and 91% had hemoglobin values >12.0 g/dL. The reliability of repeated PBAC scores for individual measures was assessed via calculation of the intraclass correlation coefficient, which for repeated PBAC measurements was 0.86 (95% confidence interval, 0.80-0.90) for average measures. CONCLUSION: The interindividual variation was high, and the intraindividual variation was low. A low PBAC score may be used to define treatment end points for clinical use or in trials. PMID- 24469276 TI - Minilaparotomy vs. laparoscopic hysterectomy: comparison of length of hospital stay. AB - STUDY OBJECTIVE: To compare length of hospital stay for minilaparotomy vs laparoscopic hysterectomy. DESIGN: Retrospective cohort study (Canadian Task Force classification II-2). SETTING: Kaiser Permanente Northern California, a large integrated health care delivery system. PATIENTS: Women >18 years of age undergoing laparoscopic or minilaparotomy hysterectomy because of benign indications from June 2009 through January 2010. INTERVENTION: Hysterectomy via minilaparotomy or laparoscopy. MEASUREMENTS AND MAIN RESULTS: Medical records were reviewed for outcomes of interest including length of stay and surgical and demographic data. Parametric and non-parametric analyses were used to compare the 2 groups. The study was powered to detect a difference of 8 hours in length of stay. Two hundred sixty-three cases were identified as hysterectomy via minilaparotomy (n = 100) or laparoscopy (n = 163). The laparoscopy group demonstrated a significantly shorter mean (SD) length of stay (19 [14] hours vs. 42 [20] hours; p < .001) and less blood loss (126 [140] mL vs. 241 [238] mL; p < .001). The minilaparotomy group experienced a shorter procedure time (113 [47] minutes vs. 197 [124] minutes; p < .001). There was no difference between the groups insofar as patient morbidity including intraoperative and postoperative complications, emergency visits, readmissions, or repeat operations. CONCLUSION: Compared with minilaparotomy, laparoscopic hysterectomy is associated with shorter length of hospital stay, longer operating time, and no increased patient morbidity. PMID- 24469277 TI - [Small-area health-care research: where science, practice, and policy meet]. PMID- 24469278 TI - [John E. Wennberg, pioneer of regional health services research: what does he teach us in Germany?]. AB - Using claims data, Wennberg demonstrated regional health-care variation that was not due to differentials in morbidity nor was it preference-based, but was partly supply-sensitive. The structure, processes, and outcomes of care are imperfectly coupled, and more services are not necessarily associated with better outcomes. Feeding data back to the responsible providers, restraining capacities, and fostering patient autonomy are seen as important in reducing unwarranted variation in health-care service delivery. In Germany, regional analyses of claims data and disease registries confirm the heterogeneity of processes and outcomes. A reduction in regional variation is in the interest of patient safety and likely to improve the effectiveness and efficiency of medical care. More health-care delivery science-both analytic and experimental-is needed. PMID- 24469279 TI - [Health-care research from the German Medical Association's perspective on small area analysis]. AB - As early as 2003, the German medical profession realized the necessity of not only forwarding medical research, but also analyzing the process of health care itself. Approved by a decision of the 108th German Medical Assembly in 2005, an initiative on health-care research paid by contributions of the medical profession was launched. Since then several projects have been supported with the results being published continuously. From the perspective of the German Medical Association, the success of the initiative also proves the effective approach of the scientific and medical communities' self-administration. Although the current results from health-care research can be used to support health-care politics and decision making at a macro level, a focus on small-area analysis tends to be an intrinsic attribute of health-care research, keeping a local approach toward changes so as to obtain real effects. Without local settings and without data reflecting the local situation, the"last mile" of a health-care system, which is the core subject of health-care research, will not be comprehensible. PMID- 24469280 TI - [Statistical methods for research on regional health-care services]. AB - Accurate modeling of spatial dependencies between observations is a significant challenge in research on regional health-care services. This article provides insight into current methods of modeling relationships in regional health-care service research, with consideration of spatial dependencies. Spatial dependencies may be triggered by spillover effects between neighboring regions and spatially distributed differences in - e.g., morbidity - which are not observable. If not considered in the model, the results of the analyses may be biased. Spatial dependencies can be added to the regression model as a spatial lag or a spatial error term. Using an example study, we illustrate that failing to consider spatial autocorrelation may lead to biased coefficients and/or standard errors. Research on regional health-care services should, therefore, if possible, test for spatial autocorrelation in the data and adjust the model accordingly. PMID- 24469281 TI - [Data linkage of primary and secondary data: a gain for small-area health-care analysis?]. AB - In Germany, research on health-care services addresses many topics within a regional context, and it predominantly uses a single (typically secondary) data sources for this purpose. The specific disadvantages and methodological challenges associated with these data sources may limit analysis. Various data sources break the data down by region and may be of interest in regional health care research. Linking multiple data sources (data linkage) could therefore expand analysis options in this area. Researchers in this field are currently discussing various approaches for using data linkage to overcome the respective weaknesses of primary and secondary data. This contribution covers the various types of data linkage (on an aggregate or individual level) and their potentials and limitations in small area health services research. The focus lies on individual data linkage, which requires written informed consent. Taking into account methodological and particularly data protection challenges, conclusions are drawn regarding future application areas and options of small area health services research and specific examples are provided. PMID- 24469282 TI - [Does the elicitation of stakeholder attitudes and preferences add valuable information to small-area analyses? A health policy perspective]. AB - Small-area analyses are increasingly valuable for health-policy planning given the observed regional variation in health care. The combination of data from different sources enables researchers to describe and analyze structural, procedural, and outcome-related variation in health care. For variation that cannot be explained by these data, the attitudes, behaviors, and preferences of important stakeholders in health care-physicians and patients-might play an explanatory role. In this paper, we outline why stakeholder preference elicitation appears to be an important addition to small-area health-care analyses. Its inclusion in various decision-making contexts may help to explain and decrease unwarranted variation in health care. At the individual level, this could happen within any decision on health service use that is taken by physicians, patients, or-within a shared decision-making context-by both. At an aggregate level, the elicitation of preferences in guideline or health program development may increase stakeholder acceptance and consistent implementation. Different approaches to the elicitation of stakeholder preferences and potential areas for application within small-area research are outlined. The role of attitudes and preferences in explaining regional variation should be acknowledged by health-care policy makers and initiatives to include these in health-care decision-making at various levels should be supported. PMID- 24469283 TI - [What do functionally defined populations contribute to the explanation of regional differences in medical care?]. AB - Geographic variation in health care is increasingly subject to analysis and health policy aiming at the suitable allocation of resources and the reduction of unwarranted variation for the patient populations concerned. As in the case of area-level indicators, in most cases populations are geographically defined. The concept of geographically defined populations, however, may be self-limiting with respect to identifying the potential for improvement. As an alternative, we explored how a functional definition of populations would support defining the scope for reducing unwarranted geographical variations. Given that patients in Germany have virtually no limits in accessing physicians of their choice, we adapted a method that has been developed in the United States to create virtual networks of physicians based on commonly treated patients. Using the physician claims data under statutory insurance, which covers 90% of the population, we defined 43,006 populations-and networks-in 2010. We found that there is considerable variation between the population in terms of their risk structure and the share of the primary care practice in the total services provided. Moreover, there are marked differences in the size and structure of networks between cities, densely populated regions, and rural regions. We analyzed the variation for two area-level indicators: the proportion of diabetics with at least one HbA1c test per year for diabetics, and the proportion of patients with low back pain undergoing computed tomography and/or magnetic resonance imaging. Variation at the level of functionally defined populations proved to be larger than for geographically defined populations. The pattern of distribution gives evidence on the degree to which consensus targets could be reached and which networks need to be addressed in order to reduce unwarranted regional variation. The concept of functionally defined populations needs to be further developed before implementation. PMID- 24469284 TI - [The Electronic Health Information System (eGIS) of the National Association of Statutory Health Insurance Physicians (KBV): a basis for small-scale analyses of health-care provision]. AB - As one of the main players in the German health system, the National Association of Statutory Health Insurance Physicians (KBV) is heavily involved in issues around research and planning for the current and future provision of medical care. The KBV is particularly concerned with tackling the challenge of establishing a uniform source of data and is working to bridge the"data divide" in the research and planning of medical care. To this end, it has developed the Electronic Health Information System (eGIS). The procedure for setting up the EGIS was as follows: (1) Merging externally available data from the relevant sectors of the German health system with the KBV's own data to form a single database. (2) Merging and aggregating the cross-sector data at a single small scale geographical level. (3) Capturing several years' worth of data in order to be able to carry out time series analyses and identify trends. eGIS provides a single database and uniform evaluation methods, thus ensuring that the principles of homogeneity and comparability are adhered to. The access it gives to the available regionalized data facilitates comprehensive analyses, such as regional, time series and regression analyses, at a small-scale level. The design chosen for the eGIS ensures that its analyses achieve high consistency in answering questions related to the provision of medical care. With the help of the eGIS, an exceptionally broad range of issues in the field of health and medical care can be studied at a regional level. PMID- 24469285 TI - [Learning from regional differences: online platform: http://www.versorgungsatlas.de]. AB - In 2011, the Central Research Institute of Ambulatory Health Care in Germany (ZI) published the website http://www.versorgungsatlas.de, a portal that presents research results from regional health services in Germany. The Web portal provides a publicly accessible source of information and a growing number of selected analyses focusing on regional variation in health care. Each topic is presented in terms of interactive maps, tables, and diagrams and is supplemented by a paper that examines the results in detail and provides an explanation of the findings. The portal has been designed to provide a forum on which health service researchers can publish their results derived from various data sources of different institutions in Germany and can comment on results already available on http://www.versorgungsatlas.de. For health policy actors, the discussion of regional differences offers a new, previously unavailable basis for determining the region-specific treatment needs and for providing health-care management with the goal of high-quality care for each resident. PMID- 24469286 TI - [Significance of regional variations in the prevalence and treatment of depressive disorders and implications for health-care research]. AB - Providing mental health care to patients with depressive disorders is accompanied by deficits in the diagnostics and in the access and adequacy of treatment. Analyzing regional variations in mental health care is of increasing importance in order to detect and explain these supply shortfalls. This paper discusses different explanatory approaches to the regional variations in diagnosed depressive disorders and their treatment. Differences in demographic structures and in patients' attitudes toward mental disorders as well as in their preferences in the choice of treatment may explain regional variation. Furthermore, the number and distribution of care providers between regions may have an effect on variation. In addition to the density and availability of care givers, the quality of care may differ because of factors such as sensitivity to the detection of depressive disorders, coding quality of diagnosis and treatment, guideline-oriented treatment, as well as treatment outcome. Small-area analyses should consider all perspectives in order to understand the complexity of regional variation in the provision of health-care services and to derive recommendations for health-care services that meet people's needs. PMID- 24469287 TI - Rotavirus vaccination: a risk factor for intussusception? AB - Recently published pharmacoepidemiological studies associate the currently authorized Rotavirus (RV) vaccines with intussusception (IS). We aimed at investigating whether, in Germany, there are excess IS cases in RV vaccinees compared with the background incidence before market authorization in 2006. Suspected cases of IS following receipt of RV vaccines reported to the Paul Ehrlich-Institut (PEI) from 2006 to 2010 were reviewed and validated against the criteria of the Brighton Collaboration's definition for IS. An observed-versus expected analysis was conducted using standardized morbidity ratio (SMR) methods based on age-specific incidence rates for IS ranging from 19.2 to 98.5 per 100,000 person-years. A total of 27 cases of suspected IS in RV vaccinees were reported to the PEI. No excess of IS cases could be detected 1-7 days after receipt of either RV vaccine after any dose in the first year of life; however, in infants aged 3-5 months, a significantly increased SMR for IS was found in a risk window of 1-7 days after the first dose of either RV vaccine [SMRs: Rotarix(r) 4.6 (95% CI 1.5-10.7); RotaTeq(r) 5.8 (95% CI 1.2-17.1)]. A significantly increased risk of IS in a risk window of 1-7 days after RV vaccination was not found when the first dose was administered earlier. Therefore, it is recommended to start the vaccination course at 6-12 weeks of age. PMID- 24469289 TI - The impact of eyelid and eye contour factors on a toric soft contact lens fitting in Chinese subjects. AB - PURPOSE: To evaluate eyelid and eye contour factors that can influence the fitting of toric soft contact lenses (TSCLs). METHODS: Thirty-two subjects (64 eyes) were enrolled and fitted with Lo-Torque design TSCLs. One eye of each subject was randomly selected. High-resolution digital images were acquired after the subjects had worn the lens for 20 minutes, and the images were then processed with Adobe Photoshop. The palpebral aperture (PA), various angles of the eyelid, horizontal visible iris diameter (HVID), and lens parameters were obtained. Finally, lens fitting was evaluated. RESULTS: During the assessment of the correlations between the eyelid and eye contour factors and the lens fitting, there were four pairs of significant correlations: (1) the PA and rotational direction of the lens: larger eye PA was associated with a greater possibility of nasal rotation of the corresponding lens (P=0.03); (2) the angle of the central lower lid (theta3) and the rotational stability of the lens: the larger the angle was, the worse the rotational stability was (P=0.02); (3) the lower lid angle of the medial canthus (theta5) and temporal rotational recovery: the smaller the angle was, the more quickly the lens recovered (P=0.05); and (4) HVID and routine fitting assessments: the larger the HVID was, the looser the lens fitting (P=0.00). Finally, when assessing correlations between some lens parameters and the orientation of the lens, we found that lower sphere values were associated with quicker lens recovery (P=0.04). CONCLUSION: Several eye factors, as well as lens characteristics, had impacts on the TSCLs fitting, including the PA, the angle of the central lower lid (theta3), the lower lid angle of the medial canthus (theta5), and the sphere of the lens. These factors should receive particular attention when fitting TSCLs. PMID- 24469291 TI - New permanent magnets; manganese compounds. AB - The exponential growth of maximum energy product that prevailed in the 20th century has stalled, leaving a market dominated by two permanent magnet materials, Nd2Fe14B and Ba(Sr)Fe12O19, for which the maximum theoretical energy products differ by an order of magnitude (515 kJ m(-3) and 45 kJ m(-3), respectively). Rather than seeking to improve on optimized Nd-Fe-B, it is suggested that some research efforts should be devoted to developing appropriately priced alternatives with energy products in the range 100-300 kJ m( 3). The prospects for Mn-based hard magnetic materials are discussed, based on known Mn-based compounds with the tetragonal L10 or D022 structure or the hexagonal B81 structure. PMID- 24469290 TI - Intracarotid transplantation of autologous adipose-derived mesenchymal stem cells significantly improves neurological deficits in rats after MCAo. AB - We aimed to evaluate whether adipose-derived mesenchymal stem cells (ADMSCs) that were transplanted via internal carotid can improve the neurological function after acute ischemic stroke and explore the underlying mechanisms. Total 40 adult Sprague-Dawley rats were subjected to transient (1.5 h) middle cerebral artery occlusion (MCAo) to induce ischemia/reperfusion injury. These rats were randomly divided into two groups with 20 ones in each group, which were intracarotid injected with autologous ADMSCs (2.0 * 10(6)) and saline (control) at day 3 after MCAo, respectively. Behavioral tests (adhesive-removal and modified neurological severity score) were performed before and after MCAo. Histology was used to evaluate the ischemia lesion volume and pathological changes. The apoptosis and astroglial reactivity were determined by TUNEL and glial fibrillary acidic protein (GFAP) staining, respectively. Besides, we applied immunofluorescence to identify the distribution of ADMSCs and the neural makers (NeuN and GFAP) expressed by them under confocal microscope. Significant improvement of neurological deficits was observed in rats transplanted with ADMSCs when compared to controls. But there was no obvious difference on ischemia lesion volume between these two groups. The injected ADMSCs migrated to the brain infarct region and mainly localized in the ischemic core and boundary zone of the lesion, which can express NeuN and GFAP in the brain. In addition, autologous transplantation of ADMSCs significantly attenuated astroglial reactivity, inhibited cellular apoptosis and promoted cellular proliferation. Our data indicated that intracarotid transplantation of autologous ADMSCs had the potential therapeutic application for ischemic stroke. PMID- 24469292 TI - Numerical investigation of three patterns of motion in an electromagnetic pulsatile VAD. AB - Hemolysis and thrombus formation which are critical concerns in designing a long term implantable ventricular assist device (VAD) have impeded the widespread use of VADs. In this study, thus, the three-dimensional fluid domain of blood flow in a small bichamber positive displacement VAD (25 ml) with a magnetically levitated moving pusher plate was simulated by the means of a finite element package called ADINA. To optimize the function of the pump for minimizing shear stress induced blood damage, three different driver patterns (linear, sinusoidal, and Guyton's pulse) were investigated. The first pattern produced a constant flow, whereas the two others created pulsatile flows. The flow pattern and the distribution of shear stress of each pattern were observed for comparison. It was revealed that the three types of motions may induce less than 0.06% red blood cell damage. Moreover, in comparison to the other patterns not only did the sinusoidal motion of the pusher plate cause less risk of hemolysis, but in comparison to the linear pattern, it produced a pulsatile flow which reduced the stagnation areas in chambers, lowering the probability of thrombosis. In addition, this motion eliminates the probability of cavitations as compared with the Guyton's pulse pattern. PMID- 24469293 TI - Beyond heart transplantation: potentials and problems of the shape memory alloy fibers in the treatment of heart failure. AB - Heart failure can be treated with devices that mechanically support the circulation. The improvement of these devices would benefit many patients, especially those refractory to maximal pharmacological treatment and ineligible for heart transplantation. This study examined whether the shape memory alloy (SMA) fibers, which are fibers that contract when electric current flows through them and relax passively when that flow is interrupted, can be wrapped around the failing heart and assist in its pumping action. A band of SMA fibers was wrapped around a silicon cylindrical chamber which simulated a dilated heart and its pumping action was tested in a circulatory mockup. This rudimentary device was innovatively controlled by pulse width modulation. The band was made of only six fibers but yet produced the considerable pressure of 20 mm Hg and a stroke volume of 11.8 ml with modest energy demands. A SMA device could assist a severely failing heart, but there are limiting factors to overcome before designing highly effective devices. PMID- 24469294 TI - Human leukocyte antigen sensitization in pediatric patients exposed to mechanical circulatory support. AB - Human leukocyte antigen (HLA) sensitization of pediatric heart recipients increases their risk of rejection and graft loss. As more children are placed on mechanical circulatory support (MCS) as a bridge to transplant, the risk factors for development of sensitization warrant further study. A single-center retrospective review of 36 children who received MCS identified 22 patients supported with either extracorporeal membrane oxygenation (ECMO) (n = 15) or ECMO ventricular assist device (VAD) (n = 7) with paired (pre-MCS/post-MCS) panel reactive antibodies (PRA) or only negative post-MCS PRAs. Four patients (18%) became sensitized post-MCS (one ECMO-only patient, three ECMO-VAD patients). No difference was found between sensitized and nonsensitized patients in terms of congenital heart disease versus primary cardiomyopathy (p = 0.096), duration of MCS (38 days vs. 14 days, p = 0.233), or volume of blood product transfusions (358.6 ml/kg vs. 612.7 ml/kg, p = not significant). By multivariable analysis, the association of sensitization with older age at MCS (p = 0.076) and history of homograft (p = 0.064) approached significance. Pediatric patients supported with MCS are at low risk of developing HLA sensitization. Diagnosis, MCS duration, and volume of transfused blood products do not appear to be associated with HLA sensitization, but there is a suggestion of an association with older age at MCS and history of a homograft. PMID- 24469295 TI - Ad hoc cost analysis of the new gastrointestinal bleeding algorithm in patients with ventricular assist device. AB - Gastrointestinal bleed (GIB) is a known complication in patients receiving nonpulsatile ventricular assist devices (VAD). Previously, we reported a new algorithm for the workup of GIB in VAD patients using deep bowel enteroscopy. In this new algorithm, patients underwent fewer procedures, received less transfusions, and took less time to make the diagnosis than the traditional GIB algorithm group. Concurrently, we reviewed the cost-effectiveness of this new algorithm compared with the traditional workup. The procedure charges for the diagnosis and treatment of each episode of GIB was ~ $2,902 in the new algorithm group versus ~ $9,013 in the traditional algorithm group (p < 0.0001). Following the new algorithm in VAD patients with GIB resulted in fewer transfusions and diagnostic tests while attaining a substantial cost savings per episode of bleeding. PMID- 24469296 TI - Ventricular assist device thrombosis following recovery of left ventricular function. AB - Although ventricular assist devices (VADs) are lifesaving therapy for patients with severe heart failure, complications such as pump thrombosis can occur. In this report, we present a case of VAD thrombosis following recovery of left ventricular (LV) function. The patient had been supported with a VAD for 8 months, and at the time of presentation, echocardiography revealed near normal native systolic function, aortic valve opening with significant native heart ejection, reduced systolic flow in the outflow and inflow cannulae, and no forward flow through the VAD during diastole. The patient underwent successful VAD explant and examination of the pump revealed thrombus on the rotor. We propose that abnormal flow through the VAD seen with recovery of LV function may contribute to VAD thrombosis. PMID- 24469297 TI - Natural infestation of Hydrochoerus hydrochaeris by Amblyomma dubitatum ticks. AB - Natural infestation of Amblyomma dubitatum in relation to individual specific attributes of Hydrochoerus hydrochaeris such as sex, body mass and body condition was analyzed. The anatomical distribution of A. dubitatum on H. hyrochaeris was also evaluated. Prevalence of adults and nymphs were significantly higher than prevalence of larvae. Non-significant differences in the infestation levels were found among host sex. Multiple regression analysis did not show any statistically significant association among the level of infestation with ticks and body mass and body condition of the host. All parasitic tick stages were collected in all five anatomical areas of the host, but they exhibited significant differences in feeding site preference. Factors associated to the host which determine the high levels of infestation with A. dubitatum could be assigned to a combination of population-level properties of the host as abundance, ubiquity and aggregation, rather than individual specific attributes related to body condition, body mass or sex. PMID- 24469298 TI - Tetrahydro[5]helicene-based imide dyes with intense fluorescence in both solution and solid state. AB - A new kind of tetrahydro[5]helicene-based imide dyes with intense fluorescence and large Stokes shifts in both solution and solid state were developed and theoretically investigated. PMID- 24469299 TI - Correlation between atomic structure evolution and strength in a bulk metallic glass at cryogenic temperature. AB - A model Zr41.25Ti13.75Ni10Cu12.5Be22.5 (at.%) bulk metallic glass (BMG) is selected to explore the structural evolution on the atomic scale with decreasing temperature down to cryogenic level using high energy X-ray synchrotron radiation. We discover a close correlation between the atomic structure evolution and the strength of the BMG and find out that the activation energy increment of the concordantly atomic shifting at lower temperature is the main factor influencing the strength. Our results might provide a fundamental understanding of the atomic-scale structure evolution and may bridge the gap between the atomic scale physics and the macro-scale fracture strength for BMGs. PMID- 24469300 TI - Best investments for health. PMID- 24469301 TI - Process evaluation of a community-based intervention program: Healthy Youth Healthy Communities, an adolescent obesity prevention project in Fiji. AB - Nearly one-half of the adult population in Fiji between the ages of 15-64 years is either overweight or obese; and rates amongst school children have, on average, doubled during the last decade. There is an urgent need to scale up the promotion of healthy behaviors and environments using a multi-sectoral approach. The Healthy Youth Healthy Community (HYHC) project in Fiji used a settings approach in secondary schools and faith-based organizations to increase the capacity of the whole community, including churches, mosques and temples, to promote healthy eating and regular physical activity, and to prevent unhealthy weight gain in adolescents aged 13-18 years. The team consisted of a study manager, project coordinator and four research assistants (RAs) committed to planning, designing and facilitating the implementation of intervention programs in collaboration with other stakeholders, such as the wider school communities, government and non-governmental organizations and business partners. Process data were collected on all intervention activities and analyzed by dose, frequency and reach for each specific strategy. The Fiji Action Plan included nine objectives for the school settings; four were based on nutrition and two on physical activity in schools, plus three general objectives, namely capacity building, social marketing and evaluation. Long-term change in nutritional behavior was difficult to achieve; a key contributor to this was the unhealthy food served in the school canteens. Whilst capacity-building proved to be one of the best mechanisms for intervening, it is important to consider the cultural and social factors influencing health behaviors and affecting specific groups. PMID- 24469302 TI - Is collectivism good for health promotion? Experiences of day labourers in Japan. AB - Collectivist values such as social trust and reciprocity are usually associated with positive health outcomes. Few studies have explored how collectivism influences individual and community capacity to engage health promotion practices. This paper explores how collectivism excludes people who do not conform to societal expectations and negatively affects individuals and communities as they practise health promotion. Data were collected through interviews with day labourers in Japan. Using critical ethnography, participants' accounts were examined focusing on the normative claims, which were principally about what behaviours are proper, appropriate and conventional among day labourers in order to understand the cultural norms and values that influence their behaviours. Findings show that day labourers are often denied public support and their social disadvantages are ignored when they seek support. Day labourers often accept their exclusions as inevitable because they accept the dominant social norms. These findings indicate that collectivist norms prevent individuals and communities from developing their capacities for health promotion practices. Individual needs tend to be obscured when prioritizing collective interests, which are also used as a tool for justifying inadequate social programmes. In a collectivist society, burdens that should be shared equally by all may not be equitably distributed, falling disproportionately on the disadvantaged. An uncritical adoption of a collectivist ethos in examining health promotion is not warranted and more investigation is needed to determine when collectivism is helpful and when harmful. PMID- 24469303 TI - Road accidents: a third burden of 'disease' in sub-Saharan Africa. AB - Road traffic injuries (RTIs) continue to be a major cause of death and disability throughout low- and middle-income countries (LMICs). The aim of this commentary is highlight some of the major causes of RTIs in sub-Saharan Africa and suggests strategies for better road safety as well as suggestions on how to reduce road accidents in LMICs. PMID- 24469306 TI - Functional results and patient satisfaction after arthroscopic capsular release of idiopathic and post-traumatic stiff shoulder. AB - PURPOSE: The purpose of this prospective study was to compare the functional results and patient satisfaction after arthroscopic shoulder capsular release in patients with idiopathic and posttraumatic stiff shoulder. METHODS: The study included 50 patients who underwent arthroscopic capsular release after failure of conservative treatment. The etiology of stiffness was either idiopathic (25 patients) or post-traumatic (25 patients). There were 28 women and 22 men with an average age of 49 years (range, 32-70 years). All patients were treated with physical therapy for a mean of six months (range, 3-12 months) before surgery. Range of motion was measured three times: 48 hours after surgery, then one month and six months after surgery. RESULTS: Constant score showed improvement for both groups of patients in the period of six months after surgery. In the group with idiopathic stiffness the score increased from 36 to 86, while in the group with post-traumatic stiff shoulder the score advanced from 32 to 91. The idiopathic stiff shoulder group had an improved active forward flexion from 90 to 161 degrees , external rotation from 10 to 40 degrees , and internal rotation from L5 to L1. In the post-traumatic stiff shoulder groupthe forward flexion was improved from 95 to 170 degrees , external rotation from 13 to 40 degrees and internal rotation from L4 to L1. CONCLUSION: There was an improvement of range of motions and patients' satisfaction after arthroscopic shoulder capsular release and manipulation under anesthesia, equally in idiopathic and post-traumatic stiff shoulder, compared to the situation before surgery. Post-traumatic contracture patients expressed higher level of satisfaction with their shoulder function than the idiopathic stiff shoulder patients. PMID- 24469307 TI - Percutaneous reclosure of a patent foramen ovale after bioabsorbable device implantation. PMID- 24469309 TI - Electrodeposition from supercritical fluids. AB - Recent studies have shown that it is possible to electrodeposit a range of materials, such as Cu, Ag and Ge, from various supercritical fluids, including hydrofluorocarbons and mixtures of CO2 with suitable co-solvents. In this perspective we discuss the relatively new field of electrodeposition from supercritical fluids. The perspective focuses on some of the underlying physical chemistry and covers both practical and scientific aspects of electrodeposition from supercritical fluids. We also discuss possible applications for supercritical fluid electrodeposition and suggest some key developments that are required to take the field to the next stage. PMID- 24469308 TI - Cell-type-specific roles for COX-2 in UVB-induced skin cancer. AB - In human tumors, and in mouse models, cyclooxygenase-2 (COX-2) levels are frequently correlated with tumor development/burden. In addition to intrinsic tumor cell expression, COX-2 is often present in fibroblasts, myofibroblasts and endothelial cells of the tumor microenvironment, and in infiltrating immune cells. Intrinsic cancer cell COX-2 expression is postulated as only one of many sources for prostanoids required for tumor promotion/progression. Although both COX-2 inhibition and global Cox-2 gene deletion ameliorate ultraviolet B (UVB) induced SKH-1 mouse skin tumorigenesis, neither manipulation can elucidate the cell type(s) in which COX-2 expression is required for tumorigenesis; both eliminate COX-2 activity in all cells. To address this question, we created Cox 2(flox/flox) mice, in which the Cox-2 gene can be eliminated in a cell-type specific fashion by targeted Cre recombinase expression. Cox-2 deletion in skin epithelial cells of SKH-1 Cox-2(flox/flox);K14Cre(+) mice resulted, following UVB irradiation, in reduced skin hyperplasia and increased apoptosis. Targeted epithelial cell Cox-2 deletion also resulted in reduced tumor incidence, frequency, size and proliferation rate, altered tumor cell differentiation and reduced tumor vascularization. Moreover, Cox-2(flox/flox);K14Cre(+) papillomas did not progress to squamous cell carcinomas. In contrast, Cox-2 deletion in SKH 1 Cox-2(flox/flox); LysMCre(+) myeloid cells had no effect on UVB tumor induction. We conclude that (i) intrinsic epithelial COX-2 activity plays a major role in UVB-induced skin cancer, (ii) macrophage/myeloid COX-2 plays no role in UVB-induced skin cancer and (iii) either there may be another COX-2-dependent prostanoid source(s) that drives UVB skin tumor induction or there may exist a COX-2-independent pathway(s) to UVB-induced skin cancer. PMID- 24469310 TI - The ecology of spatial memory in four lemur species. AB - Evolutionary theories suggest that ecology is a major factor shaping cognition in primates. However, there have been few systematic tests of spatial memory abilities involving multiple primate species. Here, we examine spatial memory skills in four strepsirrhine primates that vary in level of frugivory: ruffed lemurs (Varecia sp.), ring-tailed lemurs (Lemur catta), mongoose lemurs (Eulemur mongoz), and Coquerel's sifakas (Propithecus coquereli). We compare these species across three studies targeting different aspects of spatial memory: recall after a long-delay, learning mechanisms supporting memory and recall of multiple locations in a complex environment. We find that ruffed lemurs, the most frugivorous species, consistently showed more robust spatial memory than the other species across tasks-especially in comparison with sifakas, the most folivorous species. We discuss these results in terms of the importance of considering both ecological and social factors as complementary explanations for the evolution of primate cognitive skills. PMID- 24469311 TI - Microfluidic assembly of multistage porous silicon-lipid vesicles for controlled drug release. AB - A reliable microfluidic platform for the generation of stable and monodisperse multistage drug delivery systems is reported. A glass-capillary flow-focusing droplet generation device was used to encapsulate thermally hydrocarbonized porous silicon (PSi) microparticles into the aqueous cores of double emulsion drops, yielding the formation of a multistage PSi-lipid vesicle. This composite system enables a large loading capacity for hydrophobic drugs. PMID- 24469312 TI - Dexamethasone reduces ATDC5 chondrocyte cell viability by inducing autophagy. AB - Prolonged use of glucocorticoids (GCs) for the treatment of chronic inflammatory and autoimmune diseases commonly exerts various side-effects, including impairment of skeletal development. However, the effect of GCs on chondrocytes, which play a key role in skeletal development, has been rarely reported. In the present study, autophagy was induced in the ATDC5 chondrocyte cell line following treatment with dexamethasone (Dex) at doses of 1-100 uM, and that this effect can be inhibited by RU486, a GC antagonist. Autophagy induced by the highest Dex dose (100 uM) was associated with a reduction in ATDC5 cell viability. We conclude that high doses of GC can reduce ATDC5 chondrocyte cell viability by inducing autophagy. PMID- 24469313 TI - iRSpot-TNCPseAAC: identify recombination spots with trinucleotide composition and pseudo amino acid components. AB - Meiosis and recombination are the two opposite aspects that coexist in a DNA system. As a driving force for evolution by generating natural genetic variations, meiotic recombination plays a very important role in the formation of eggs and sperm. Interestingly, the recombination does not occur randomly across a genome, but with higher probability in some genomic regions called "hotspots", while with lower probability in so-called "coldspots". With the ever-increasing amount of genome sequence data in the postgenomic era, computational methods for effectively identifying the hotspots and coldspots have become urgent as they can timely provide us with useful insights into the mechanism of meiotic recombination and the process of genome evolution as well. To meet the need, we developed a new predictor called "iRSpot-TNCPseAAC", in which a DNA sample was formulated by combining its trinucleotide composition (TNC) and the pseudo amino acid components (PseAAC) of the protein translated from the DNA sample according to its genetic codes. The former was used to incorporate its local or short-rage sequence order information; while the latter, its global and long-range one. Compared with the best existing predictor in this area, iRSpot-TNCPseAAC achieved higher rates in accuracy, Mathew's correlation coefficient, and sensitivity, indicating that the new predictor may become a useful tool for identifying the recombination hotspots and coldspots, or, at least, become a complementary tool to the existing methods. It has not escaped our notice that the aforementioned novel approach to incorporate the DNA sequence order information into a discrete model may also be used for many other genome analysis problems. The web-server for iRSpot-TNCPseAAC is available at http://www.jci-bioinfo.cn/iRSpot-TNCPseAAC. Furthermore, for the convenience of the vast majority of experimental scientists, a step-by-step guide is provided on how to use the current web server to obtain their desired result without the need to follow the complicated mathematical equations. PMID- 24469314 TI - Atomistic Monte Carlo simulation of lipid membranes. AB - Biological membranes are complex assemblies of many different molecules of which analysis demands a variety of experimental and computational approaches. In this article, we explain challenges and advantages of atomistic Monte Carlo (MC) simulation of lipid membranes. We provide an introduction into the various move sets that are implemented in current MC methods for efficient conformational sampling of lipids and other molecules. In the second part, we demonstrate for a concrete example, how an atomistic local-move set can be implemented for MC simulations of phospholipid monomers and bilayer patches. We use our recently devised chain breakage/closure (CBC) local move set in the bond-/torsion angle space with the constant-bond-length approximation (CBLA) for the phospholipid dipalmitoylphosphatidylcholine (DPPC). We demonstrate rapid conformational equilibration for a single DPPC molecule, as assessed by calculation of molecular energies and entropies. We also show transition from a crystalline-like to a fluid DPPC bilayer by the CBC local-move MC method, as indicated by the electron density profile, head group orientation, area per lipid, and whole-lipid displacements. We discuss the potential of local-move MC methods in combination with molecular dynamics simulations, for example, for studying multi-component lipid membranes containing cholesterol. PMID- 24469315 TI - Protein a detection based on quantum dots-antibody bioprobe using fluorescence coupled capillary electrophoresis. AB - In this report, fluorescence detection coupled capillary electrophoresis (CE-FL) was used to detect Protein A. Antibody was first labeled with Cy5 and then mixed with quantum dots (QDs) to form QDs-antibody bioprobe. Further, we observed fluorescence resonance energy transfer (FRET) from QDs donor to Cy5 acceptor. The bioprobe was formed and brought QDs and Cy5 close enough to allow FRET to occur. After adding protein A, the FRET system was broken and caused the FRET signal to decrease. Thus, a new method for the determination of protein A was proposed based on the FRET signal changes. This study provides a new trail of thought for the detection of protein. PMID- 24469316 TI - Cell-based in vitro blood-brain barrier model can rapidly evaluate nanoparticles' brain permeability in association with particle size and surface modification. AB - The possibility of nanoparticle (NP) uptake to the human central nervous system is a major concern. Recent reports showed that in animal models, nanoparticles (NPs) passed through the blood-brain barrier (BBB). For the safe use of NPs, it is imperative to evaluate the permeability of NPs through the BBB. Here we used a commercially available in vitro BBB model to evaluate the permeability of NPs for a rapid, easy and reproducible assay. The model is reconstructed by culturing both primary rat brain endothelial cells and pericytes to support the tight junctions of endothelial cells. We used the permeability coefficient (P(app)) to determine the permeability of NPs. The size dependency results, using fluorescent silica NPs (30, 100, and 400 nm), revealed that the Papp for the 30 nm NPs was higher than those of the larger silica. The surface charge dependency results using Qdots(r) (amino-, carboxyl-, and PEGylated-Qdots), showed that more amino Qdots passed through the model than the other Qdots. Usage of serum-containing buffer in the model resulted in an overall reduction of permeability. In conclusion, although additional developments are desired to elucidate the NPs transportation, we showed that the BBB model could be useful as a tool to test the permeability of nanoparticles. PMID- 24469318 TI - Biskyrmion states and their current-driven motion in a layered manganite. AB - The magnetic skyrmion is a topologically stable spin texture in which the constituent spins point to all the directions wrapping a sphere. Generation and control of nanometric magnetic skyrmions have large potential, for example, reduced power consumption, in spintronics device applications. Here we show the real-space observation of a biskyrmion, as defined by a molecular form of two bound skyrmions with the total topological charge of 2, realized under magnetic field applied normal to a thin plate of a bilayered manganite with centrosymmetric structure. In terms of a Lorentz transmission electron microscopy (TEM), we have observed a distorted-triangle lattice of biskyrmion crystal, each composed of two bound skyrmions with oppositely swirling spins (magnetic helicities). Furthermore, we demonstrate that these biskyrmions can be electrically driven with orders of magnitude lower current density (<10(8) A m( 2)) than that for the conventional ferromagnetic domain walls. PMID- 24469317 TI - Exploring the molecular basis for selective binding of homoserine dehydrogenase from Mycobacterium leprae TN toward inhibitors: a virtual screening study. AB - Homoserine dehydrogenase (HSD) from Mycobacterium leprae TN is an antifungal target for antifungal properties including efficacy against the human pathogen. The 3D structure of HSD has been firmly established by homology modeling methods. Using the template, homoserine dehydrogenase from Thiobacillus denitrificans (PDB Id 3MTJ), a sequence identity of 40% was found and molecular dynamics simulation was used to optimize a reliable structure. The substrate and co-factor-binding regions in HSD were identified. In order to determine the important residues of the substrate (L-aspartate semialdehyde (L-ASA)) binding, the ASA was docked to the protein; Thr163, Asp198, and Glu192 may be important because they form a hydrogen bond with HSD through AutoDock 4.2 software. neuraminidaseAfter use of a virtual screening technique of HSD, the four top-scoring docking hits all seemed to cation-pi ion pair with the key recognition residue Lys107, and Lys207. These ligands therefore seemed to be new chemotypes for HSD. Our results may be helpful for further experimental investigations. PMID- 24469319 TI - Visually guided gait modifications for stepping over an obstacle: a bio-inspired approach. AB - There is an increasing interest in conceiving robotic systems that are able to move and act in an unstructured and not predefined environment, for which autonomy and adaptability are crucial features. In nature, animals are autonomous biological systems, which often serve as bio-inspiration models, not only for their physical and mechanical properties, but also their control structures that enable adaptability and autonomy-for which learning is (at least) partially responsible. This work proposes a system which seeks to enable a quadruped robot to online learn to detect and to avoid stumbling on an obstacle in its path. The detection relies in a forward internal model that estimates the robot's perceptive information by exploring the locomotion repetitive nature. The system adapts the locomotion in order to place the robot optimally before attempting to step over the obstacle, avoiding any stumbling. Locomotion adaptation is achieved by changing control parameters of a central pattern generator (CPG)-based locomotion controller. The mechanism learns the necessary alterations to the stride length in order to adapt the locomotion by changing the required CPG parameter. Both learning tasks occur online and together define a sensorimotor map, which enables the robot to learn to step over the obstacle in its path. Simulation results show the feasibility of the proposed approach. PMID- 24469320 TI - Sigma receptor 1 modulates ER stress and Bcl2 in murine retina. AB - Sigma receptor 1 (sigmaR1), a non-opiate transmembrane protein located on endoplasmic reticulum (ER) and mitochondrial membranes, is considered to be a molecular chaperone. Marked protection against cell death has been observed when ligands for sigmaR1 have been used in in vitro and in vivo models of retinal cell death. Mice lacking sigmaR1 (sigmaR1(-/-)) manifest late-onset loss of retinal ganglion cells and retinal electrophysiological changes (after many months). The role of sigmaR1 in the retina and the mechanisms by which its ligands afford neuroprotection are unclear. We therefore used sigmaR1(-/-) mice to investigate the expression of ER stress genes (BiP/GRP78, Atf6, Atf4, Ire1alpha) and proteins involved in apoptosis (BCL2, BAX) and to examine the retinal transcriptome at young ages. Whereas no significant changes occurred in the expression of major ER stress genes (over a period of a year) in neural retina, marked changes were observed in these genes, especially Atf6, in isolated retinal Muller glial cells. BCL2 levels decreased in sigmaR1(-/-) retina concomitantly with decreases in NFkB and pERK1/2. We postulate that sigmaR1 regulates ER stress in retinal Muller cells and that the role of sigmaR1 in retinal neuroprotection probably involves BCL2 and some of the proteins that modify its expression (such as ERK, NFkappaB). Data from the analysis of the retinal transcriptome of sigmaR1 null mice provide new insights into the role of sigmaR1 in retinal neuroprotection. PMID- 24469322 TI - The covariates of parent and youth reporting differences on youth secondary exposure to community violence. AB - Survey data for studying youth's secondary exposure to community violence (i.e., witnessing or hearing violence in the community) come from both parents and their children. There are benefits of considering multiple informants in psychosocial assessments, but parents and youths often disagree about comparable information. These reporting differences present challenges for both researchers and clinicians. To shed new light on the individual, family, and neighborhood factors that contribute to parent and youth reporting differences regarding youth's secondary exposure to community violence, this study analyzed hierarchical item response models on a sample of youth respondents from the Project on Human Development in Chicago Neighborhoods. Participants were aged approximately 9, 12, and 15 years (trimodal distribution; mean age = 12.0 years) at baseline (N = 2,344; 49.6% female). Descriptive analyses indicated that parents significantly underestimated their children's exposure to community violence. Logistic hierarchical item response models indicated that absolute discrepancies between parent and youth reports were a function of youth demographic characteristics (male, Hispanic or African American as compared to white, age, 3rd as compared to 1st generation immigrant), individual difference factors (lower levels of self control, higher levels of violent peer exposure), and family factors (lower household socioeconomic status). Parental under-reporting of youth's exposure to violence was associated with youth demographic characteristics (male, age, 2nd as compared to 3rd generation immigrant), family factors (lower levels of parental supervision), and neighborhood characteristics (higher levels of violence, less access to youth services). The results suggest that a constellation of individual and contextual factors may contribute to the understanding of parent and youth reporting differences. The findings speak to the utility of examining parent and youth reporting differences from a hierarchical lens. PMID- 24469323 TI - Thermal stability of MnBi magnetic materials. AB - MnBi has attracted much attention in recent years due to its potential as a rare earth-free permanent magnet material. It is unique because its coercivity increases with increasing temperature, which makes it a good hard phase material for exchange coupling nanocomposite magnets. MnBi phase is difficult to obtain, partly because the reaction between Mn and Bi is peritectic, and partly because Mn reacts readily with oxygen. MnO formation is irreversible and harmful to magnet performance. In this paper, we report our efforts toward developing MnBi permanent magnets. To date, high purity MnBi (>90%) can be routinely produced in large quantities. The produced powder exhibits 74.6 emu g(-1) saturation magnetization at room temperature with 9 T applied field. After proper alignment, the maximum energy product (BH)max of the powder reached 11.9 MGOe, and that of the sintered bulk magnet reached 7.8 MGOe at room temperature. A comprehensive study of thermal stability shows that MnBi powder is stable up to 473 K in air. PMID- 24469321 TI - Aryl hydrocarbon receptor (AhR) agonists increase airway epithelial matrix metalloproteinase activity. AB - The aryl hydrocarbon receptor (AhR) agonists may upregulate matrix metalloproteinases (MMPs) and contribute to many airway diseases, such as asthma and chronic obstructive pulmonary disease. Elucidation of the detailed molecular mechanisms regulating MMPs may provide the scientific basis for diagnostic and therapeutic opportunities to improve the care of various pulmonary diseases, especially those related to xenobiotic agents. In this study, we investigated the detailed mechanisms of how AhR agonists modulated the expressions and activities of MMPs in bronchial epithelial cells. Treating the cells (Beas-2B or HBE135 E6E7) with 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester or 2,3,7,8-tetrachlorodibenzo-p-dioxin, we found these AhR agonists increased the expression and activity of MMP-1 via a noncanonical AhR pathway and increased the activity of MMP-2 and MMP-9 in an MMP-1-dependent manner. AhR agonists increased the expression of MMP-1 via the activation of mitogen-activated protein kinase (MAPK) pathways by increased cytosolic calcium level and activated calcium/calmodulin-dependent protein kinase II (CaMKII). The activated MAPK pathways phosphorylated c-Jun, c-Fos, and ATF-2, resulting in their nuclear translocation and binding to the activator protein-1 (AP-1) elements of the MMP-1 promoter region. These findings correlated clinically to the significantly higher plasma/serum MMP-1 level in asthmatic patients. In conclusion, the present study demonstrated a novel signaling pathway by which AhR agonists elevated intracellular calcium levels, which activated CaMKII, leading to increased MMP-1 expression through MAPK pathways in bronchial epithelial cell lines. This novel regulatory pathway may serve as a potential target for the treatment of airway remodeling of many pulmonary diseases, such as asthma. KEY MESSAGE: AhR agonists increase MMP-1 expression in bronchial epithelial cells. The underlying AhR pathway involves CaMKII, MAPKs, and AP-1 elements. The upregulated MMP-1 further activated MMP-2 and MMP-9. Asthmatic patients have higher serum MMP-1 level. This novel regulatory pathway is a potential target for treating asthma. PMID- 24469324 TI - Lifestyle modification in cervical cancer survivors: an ongoing need. AB - OBJECTIVE: With the introduction of multimodality therapy for cervical cancer, many women will be long-term survivors in need of comprehensive surveillance care. Our goals were to evaluate patterns of obesity and smoking in a cohort of cervical cancer survivors and to assess the potential influence of these comorbidities on subsequent follow-up. METHODS: We reviewed the records of patients treated for invasive cervical cancer at our institution from 2000 to 2003 who had no evidence of disease for 3 or more years. Demographic and clinical data were collected, including smoking history and anthropometric measurements. Body mass index (BMI) was categorized according to World Health Organization criteria. Logistic regression and Wilcoxon rank sum analyses were performed. RESULTS: Two hundred ninety-eight women had complete follow-up data at 3 years. The median age at diagnosis was 43.5 years (range, 17.6-87.1 years). At diagnosis, 31.9% had a normal BMI, 28.2% were overweight, and 34.6% were obese compared with 31.7%, 21.1%, and 30.2% at 3 years, respectively. Of the 51 women whose BMI categorization changed, 33 (64.7%) had weight gain, and 18 (35.3%) had weight loss. By paired analyses, increase in BMI was significant over the 3-year interval (P < 0.001). Seventy patients actively smoked at diagnosis. Compared with nonsmokers, current smokers had a greater odds of referral to the pain service (odds ratio [OR], 6.56; confidence interval [CI], 6.26-16.43; P < 0.001), physical therapy (OR, 4.74; CI, 1.29-17.36; P = 0.02), and gastroenterology (OR, 2.25; CI, 1.14-4.24; P = 0.02). CONCLUSIONS: Obesity and smoking are significant comorbidities that may complicate care in cervical cancer survivors. Interventions aimed at modifying these risk factors should be routinely undertaken in this population. PMID- 24469325 TI - Effectiveness of chemotherapy in measurable granulosa cell tumors: a retrospective study and review of literature. AB - OBJECTIVE: Patients with irresectable granulosa cell tumors (GCTs) often receive chemotherapy. The effectiveness of this approach, however, is uncertain. The aim of our study was to assess the response rate to chemotherapy for residual and recurrent inoperable GCT. METHODS: All consecutive chemotherapy-naive patients in 3 referral hospitals who were treated with chemotherapy for residual or recurrent GCT between 1968 and 2011 were included. Main outcome was the response according to Response Evaluation Criteria in Solid Tumor criteria. A literature search in MEDLINE through PubMed was performed, from inception to August 19, 2013. RESULTS: Twenty-seven patients with a GCT who received chemotherapy were identified. Eighteen patients were not evaluable because they had either no measurable disease, or no imaging was performed before and after chemotherapy. One of the 9 evaluable patients (11%) had a complete response, and 1 patient (11%) had a partial response, resulting in a response rate of 22% (95% confidence interval, 0%-49%). Seven patients (78%) had stable disease (range, 2-50 months), and none had progressive disease. Fifteen studies that assessed response rates to chemotherapy on measurable disease in a total of 224 patients showed a response rate of 50% (95% confidence interval, 44%-57%). Strict criteria of response, however, were not uniformly applied in the majority of these published series. CONCLUSIONS: In the present study, we present only a moderate beneficial effect of chemotherapy in patients with irresectable GCT with measurable disease. Comparison with previous studies is hampered by a lack of standardized response evaluation in the majority of studies. Given the toxicity of platinum-based chemotherapy, administering this treatment should be a well-considered decision. PMID- 24469326 TI - Radical vaginal trachelectomy after laparoscopic staging and neoadjuvant chemotherapy in women with early-stage cervical cancer over 2 cm: oncologic, fertility, and neonatal outcome in a series of 20 patients. AB - OBJECTIVES: The aim of the study was to assess oncologic and fertility outcome of treatment in patients with cervical cancer of more than 2 cm seeking parenthood. METHODS: The regimen consisted of laparoscopic lymphadenectomy as a staging procedure to confirm no lymph node metastases before neoadjuvant chemotherapy (NACT) consisting of 2 or 3 cycles of paclitaxel/ifosfamide/cisplatin followed by radical vaginal trachelectomy (RVT). Oncologic and fertility outcome was evaluated prospectively. RESULTS: Twenty women were enrolled up to now. The mean age was 32 years (range, 26-41 years), and mean tumor size was 3 cm (range, 2.1 5.0 cm). Lymphadenectomy was performed before NACT without complications. During NACT, hematologic toxicity grade 3 was observed in 2 of 20 patients, and renal toxicity grade 3 in 1 of 20 patients. Radical vaginal trachelectomy was performed in 18 women until now with 2 intraoperative complications (ureter injury and injury of internal iliac vein). There were no severe postoperative or long-term complications. Complete pathologic remission was found in 9 of 18 patients. In 2 of 18 patients, chemoradiation was recommended because of insufficient pathologic response in the RVT specimen. After a mean follow-up of 23 months (range, 1-88 months), 1 relapse was observed. After RVT, 7 women tried to conceive until now. Seven pregnancies occurred in 5 women. Four children were born, 2 of whom were premature (31 weeks 2 days and 33 weeks 4 days of gestation); 1 pregnancy is ongoing. CONCLUSIONS: Laparoscopic lymphadenectomy followed by NACT and RVT in pN0 patients with cervical cancer of more than 2 cm seems to be an oncologically safe procedure with promising fertility outcomes. PMID- 24469327 TI - Continuous synthesis of zinc oxide nanoparticles in a microfluidic system for photovoltaic application. AB - This study describes the synthesis of zinc oxide nanoparticles (ZnO NPs) using a microfluidic system. A continuous and efficient synthetic process was developed based on a microfluidic reactor in which was implemented a time pulsed mixing method that had been optimized using numerical simulations and experimental methods. Numerical simulations revealed that efficient mixing conditions could be obtained over the frequency range 5-15 Hz. This system used ethanol solutions containing 30 mM sodium hydroxide (NaOH) or 10 mM dehydrated zinc acetate (Zn(OAc)2) under 5 Hz pulsed conditions, which provided the optimal mixing performance conditions. The ZnO NPs prepared using the microfluidic synthetic system or batch-processed system were validated by several analytical methods, including transmission electron microscopy (TEM), energy dispersive X-ray spectrometry (EDS), X-ray diffraction (XRD), UV/VIS NIR and zeta (zeta) potential analysis. Bulk-heterojunction organic photovoltaic cells were fabricated with the synthesized ZnO NPs to investigate the practicability and compared with batch process synthesized ZnO NPs. The results showed that microfluidic synthesized ZnO NPs had good preservability and stability in working solution and the synthetic microfluidic system provided a low-cost, environmentally friendly approach to the continuous production of ZnO NPs. PMID- 24469328 TI - Nonsmooth finite-time stabilization of neural networks with discontinuous activations. AB - This paper is concerned with the finite-time stabilization for a class of neural networks (NNs) with discontinuous activations. The purpose of the addressed problem is to design a discontinuous controller to stabilize the states of such neural networks in finite time. Unlike the previous works, such stabilization objective will be realized for neural networks when the activations and controllers are both discontinuous. Based on the famous finite-time stability theorem of nonlinear systems and nonsmooth analysis in mathematics, sufficient conditions are established to ensure the finite-time stability of the dynamics of NNs. Then, the upper bound of the settling time for stabilization can be estimated in two forms due to two different methods of proof. Finally, two numerical examples are given to illustrate the effectiveness of the proposed design method. PMID- 24469329 TI - Positive and negative religious coping, depressive symptoms, and quality of life in people with HIV. AB - The present study examined the relationships of positive and negative types of religious coping with depression and quality of life, and the mediating role of benefit finding in the link between religious coping and psychological outcomes among 198 individuals with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS). The results of multiple hierarchical analyses revealed that negative religious coping was significantly associated with a high level of depressive symptoms and a low level of quality of life, controlling for demographic and clinical variables. On the other hand, positive religious coping was significantly associated with positive domains of outcome measures such as positive affect and life satisfaction, but not with overall depressive symptoms or quality of life. Tests of mediation analyses showed that benefit finding fully mediated the relationship between positive religious coping and the positive sub domains of psychological outcomes. The importance of investigating both positive and negative types of religious coping in their relationships with psychological adaptation in people with HIV was discussed, as well as the significance of benefit finding in understanding the link between religious coping and psychological outcomes. PMID- 24469330 TI - Ars Moriendi; the art of dying well - new insights into the molecular pathways of necroptotic cell death. AB - When our time comes to die most people would probably opt for a quick, peaceful and painless exit. But the manner and timing are rarely under our direct control. Hence the Ars moriendi, literally, "The Art of Dying", two texts written in Latin around the 15th century that offered advice on how to die well according to the Christian ideals of the time. In contrast, for individual cells, the death process is frequently under their control and several signaling pathways that cause cell death, including apoptosis, pyroptosis and necroptosis, have been described. Furthermore the manner in which cells die can have good or bad consequences for the organism. In this review we will discuss how cells die via the necroptotic signaling pathway, with emphasis on recent structural work and place this work in a biological context by discussing relevant studies with knock out animals. PMID- 24469332 TI - Spies, data and research. PMID- 24469333 TI - Dual base-flipping of cytosines in a CpG dinucleotide sequence. AB - Simultaneous flipped-out conformation of two neighboring bases on opposite strands of DNAs has been observed in several X-ray structures. It has also been detected for two cytosines on opposite strands in different contexts of CpG sites. In this paper, we study by MD simulations the dual base flipping of the two cytosines in hemi-methylated CpG site. We calculate the potential of mean force of flipping-out the unmethylated cytosine in three model systems. The first is for DNA bound to the regulatory protein UHRF1. In this case, the methyl cytosine on the complementary strand is flipped-out into the binding pocket of the SRA domain of the protein. The other two systems are for unbound DNAs in which the methyl-cytosine is either intra-helical or extra-helical. We find that when the methyl-cytosine is flipped-out it is easier to flip-out the other (unmethylated) cytosine on the opposite strand by about 14-16kJ/mol. This lower penalty for dual-base flipping is observed for both the bound and unbound states of the DNA. Analyses of the hydrogen bond network and stacking interactions within the CpG site indicate that the lower penalty is due to stabilization of the dual-base flipped-out conformation via interactions involving the orphan guanines. The results presented in this paper suggest that the extra-helical conformation of the methyl-cytosine recognized by UHRF1 can facilitate the base flipping process of the target cytosine to be methylated by Dnmt1. PMID- 24469331 TI - RBR E3-ligases at work. AB - The RING-in-between-RING (RBR) E3s are a curious family of ubiquitin E3-ligases, whose mechanism of action is unusual in several ways. Their activities are auto inhibited, causing a requirement for activation by protein-protein interactions or posttranslational modifications. They catalyse ubiquitin conjugation by a concerted RING/HECT-like mechanism in which the RING1 domain facilitates E2 discharge to directly form a thioester intermediate with a cysteine in RING2. This short-lived, HECT-like intermediate then modifies the target. Uniquely, the RBR ligase HOIP makes use of this mechanism to target the ubiquitin amino terminus, by presenting the target ubiquitin for modification using its distinctive LDD region. PMID- 24469335 TI - Study of the nano-morphological versatility by self-assembly of a peptide mimetic molecule in response to physical and chemical stimuli. AB - A small peptide mimetic molecule can form diverse nanostructures such as nano vesicles, nano-tubes and nano-ribbons/fibrils by self-assembly, in response to various physical and chemical stimulations. PMID- 24469334 TI - Fast and simple scheme for generating NOON states of photons in circuit QED. AB - The generation, manipulation and fundamental understanding of entanglement lies at very heart of quantum mechanics. Among various types of entangled states, the NOON states are a kind of special quantum entangled states with two orthogonal component states in maximal superposition, which have a wide range of potential applications in quantum communication and quantum information processing. Here, we propose a fast and simple scheme for generating NOON states of photons in two superconducting resonators by using a single superconducting transmon qutrit. Because only one superconducting qutrit and two resonators are used, the experimental setup for this scheme is much simplified when compared with the previous proposals requiring a setup of two superconducting qutrits and three cavities. In addition, this scheme is easier and faster to implement than the previous proposals, which require using a complex microwave pulse, or a small pulse Rabi frequency in order to avoid nonresonant transitions. PMID- 24469336 TI - Inspired by nature: investigating tetrataenite for permanent magnet applications. AB - Chemically ordered L10-type FeNi, also known as tetrataenite, is under investigation as a rare-earth-free advanced permanent magnet. Correlations between crystal structure, microstructure and magnetic properties of naturally occurring tetrataenite with a slightly Fe-rich composition (~ Fe55Ni44) obtained from the meteorite NWA 6259 are reported and augmented with computationally derived results. The tetrataenite microstructure exhibits three mutually orthogonal crystallographic variants of the L10 structure that reduce its remanence; nonetheless, even in its highly unoptimized state tetrataenite provides a room-temperature coercivity of 95.5 kA m(-1) (1200 Oe), a Curie temperature of at least 830 K and a largely temperature-independent anisotropy that preliminarily point to a theoretical magnetic energy product exceeding (BH)max = 335 kJ m(-3) (42 MG Oe) and approaching those found in today's best rare-earth-based magnets. PMID- 24469337 TI - Treatment of mechanical aortic valve thrombosis with heparin and eptifibatide. AB - A 75-year old woman with a history of coronary disease status post 3-vessel coronary artery bypass grafting (CABG) 8 years ago and a repeat one-vessel CABG 2 years ago in the setting of aortic valve replacement with a #19 mm St. Jude bileaflet mechanical valve for severe aortic stenosis presented with two to three weeks of progressive dyspnea and increasing substernal chest discomfort. Echocardiography revealed a gradient to 31 mmHg across her aortic valve, increased from a baseline of 13 mmHg five months previously. Fluoroscopy revealed thrombosis of her mechanical aortic valve. She was not a candidate for surgery given her multiple comorbidities, and fibrinolysis was contraindicated given a recent subdural hematoma 1 year prior to presentation. She was treated with heparin and eptifibatide and subsequently demonstrated resolution of her aortic valve thrombosis. We report the first described successful use of eptifibatide in addition to unfractionated heparin for the management of subacute valve thrombosis in a patient at high risk for repeat surgery or fibrinolysis. PMID- 24469338 TI - The pornography craving questionnaire: psychometric properties. AB - Despite the prevalence of pornography use, and recent conceptualization of problematic use as an addiction, we could find no published scale to measure craving for pornography. Therefore, we conducted three studies employing young male pornography users to develop and evaluate such a questionnaire. In Study 1, we had participants rate their agreement with 20 potential craving items after reading a control script or a script designed to induce craving to watch pornography. We dropped eight items because of low endorsement. In Study 2, we revised both the questionnaire and cue exposure stimuli and then evaluated several psychometric properties of the modified questionnaire. Item loadings from a principal components analysis, a high internal consistency reliability coefficient, and a moderate mean inter-item correlation supported interpreting the 12 revised items as a single scale. Correlations of craving scores with preoccupation with pornography, sexual history, compulsive internet use, and sensation seeking provided support for convergent validity, criterion validity, and discriminant validity, respectively. The enhanced imagery script did not impact reported craving; however, more frequent users of pornography reported higher craving than less frequent users regardless of script condition. In Study 3, craving scores demonstrated good one-week test-retest reliability and predicted the number of times participants used pornography during the following week. This questionnaire could be applied in clinical settings to plan and evaluate therapy for problematic users of pornography and as a research tool to assess the prevalence and contextual triggers of craving among different types of pornography users. PMID- 24469339 TI - Adolescent perspectives on social support received in the aftermath of sexual abuse: a qualitative study. AB - The extent and quality of social support provided to young survivors of sexual abuse (SA) have only rarely been examined. This qualitative study aimed to investigate adolescent perspectives on social support received in the aftermath of SA. A total of 26 sexually victimized adolescents (15-18 years old) participated in a qualitative face-to-face, in-depth interview that focused on perceived social support. Qualitative content analysis was conducted as per Mayring (2008) using the qualitative data analysis program ATLAS.ti. In addition, quantitative correlational analyses were conducted to identify characteristics of SA and their associations with perceived social support. Although participants perceived parental support as the most necessary type of support, they were much more satisfied with support from peers. In particular, adolescents stated that they wished they had received more emotional support from their parents in order to better cope with the abuse. About half of participants reported having received counseling, and counseling was seen as very helpful in dealing with the consequences of SA. Only a few adolescents mentioned their school as a source of support. Intra-familial abuse, younger victim age at the time of abuse, an adult perpetrator, and severe abuse were all negatively associated with satisfaction with perceived support. Our results suggest that support for young survivors of SA needs to be improved. Prevention of SA needs particular focus on improving parental reactions to SA, facilitating access to professional support, and raising teacher awareness of the importance of their role in the provision of support for sexually victimized children. PMID- 24469340 TI - Exogenous activation of LKB1/AMPK signaling induces G1 arrest in cells with endogenous LKB1 expression. AB - The tumor suppressor protein LKB1 is a serine/threonine kinase that plays a critical role in cell proliferation, and its inactivation has been linked to tumorigenesis in various cancer types. Current understanding of the LKB1 function is largely restricted to results from experiments on LKB1-deficient cancer cells, while the regulation and activity of endogenous LKB1 has been rarely investigated. In a previous study, we showed that LKB1 knockdown in two healthy cell lines accelerates cell cycle progression through the G1/S checkpoint by inhibition of the p53 and p16 pathways. In the present study, we examined the effects of overexpression of LKB1 on two healthy and one cancer cell line. Administration of exogenous LKB1 activated LKB1/AMPK signaling and arrested the cell cycle at the G1 phase in an LKB1-dependent manner. G1 arrest induced by LKB1 was accompanied by the downregulation of cyclin D1 and cyclin D3, and the upregulation of p53, p21 and p16, while no differences were detected for CDK4, CDK6, cyclin E, p15 and p27. These results indicated that exogenous activation of LKB1/AMPK signaling inhibits the G1/S cell cycle transition, even in cells with an endogenous expression of LKB1. Findings of the present study extend earlier observations on LKB1-inactivated neoplastic cells and provide novel insights into the growth-inhibitory effects of LKB1. PMID- 24469341 TI - Seasonality and facilitation drive tree establishment in a semi-arid floodplain savanna. AB - A popular hypothesis for tree and grass coexistence in savannas is that tree seedlings are limited by competition from grasses. However, competition may be important in favourable climatic conditions when abiotic stress is low, whereas facilitation may be more important under stressful conditions. Seasonal and inter annual fluctuations in abiotic conditions may alter the outcome of tree-grass interactions in savanna systems and contribute to coexistence. We investigated interactions between coolibah (Eucalyptus coolabah) tree seedlings and perennial C4 grasses in semi-arid savannas in eastern Australia in contrasting seasonal conditions. In glasshouse and field experiments, we measured survival and growth of tree seedlings with different densities of C4 grasses across seasons. In warm glasshouse conditions, where water was not limiting, competition from grasses reduced tree seedling growth but did not affect tree survival. In the field, all tree seedlings died in hot dry summer conditions irrespective of grass or shade cover, whereas in winter, facilitation from grasses significantly increased tree seedling survival by ameliorating heat stress and protecting seedlings from herbivory. We demonstrated that interactions between tree seedlings and perennial grasses vary seasonally, and timing of tree germination may determine the importance of facilitation or competition in structuring savanna vegetation because of fluctuations in abiotic stress. Our finding that trees can grow and survive in a dense C4 grass sward contrasts with the common perception that grass competition limits woody plant recruitment in savannas. PMID- 24469342 TI - Computational modeling of single- versus double-anchoring modes in di-branched organic sensitizers on TiO2 surfaces: structural and electronic properties. AB - We present a first-principles DFT investigation of the adsorption geometry on the anatase (101) surface of a prototypical di-branched organic dye based on the extended tetrathiafulvalene moiety, incorporating two anchoring cyanoacrylic acid units. Reduced model systems with one and two anchoring groups have been initially studied to investigate the vibrational frequencies related to TiO2 dye adsorption. Our calculations confirm that the reduced systems can be used as reliable models to study the anchoring modes and that the conclusions extracted from the reduced systems can be extrapolated to the entire molecule. A series of molecular structures have been investigated to simulate the anchoring environment in monodentate- and bidentate-like adsorption modes. The comparison between the theoretical results and the available experimental data suggests a di-anchored monodentate adsorption mode as the most probable adsorption structure. Geometry optimizations of the di-branched model system adsorbed on a periodic slab of anatase (101) allowed us to compare the relative stability of different adsorption conformations and led to a di-anchored monodentate mode as the most stable adsorption structure. Furthermore, ab initio molecular dynamics simulations confirmed this structure as the preferred one, providing additional stabilization by effective hydrogen-bonding to surface oxygens and structure distortion from planarity. The analysis of the partial density of states for the prototypical models confirms that the doubly anchored adsorption provides improved electronic properties compared to the singly anchored structures for dye sensitized solar cell purposes. PMID- 24469343 TI - A remarkable regiocontrol in the palladium-catalyzed silylstannylation of fluoroalkylated alkynes--highly regio- and stereoselective synthesis of multi substituted fluorine-containing alkenes. AB - On treating fluorine-containing internal alkynes with 1.2 equiv. of (trimethylsilyl)tributyltin in the presence of 2.5 mol% of Pd(PPh3)2Cl2 in THF at the reflux temperature for 6 h, the silylstannylation reaction proceeded smoothly to afford the corresponding silylstannylated adducts in high yields in a highly regio- and cis-selective manner. Switching the palladium catalyst from Pd(PPh3)2Cl2 to Pd(t-BuNC)2Cl2 promoted the formation of silylstannylated adducts with opposite regioselectivity. The thus obtained silylstannylated adducts were subjected to Stille cross-coupling reactions to furnish the corresponding fluoroalkylated vinylsilanes whose C-Si bond was converted to a C-C bond by treating with aldehyde in the presence of TBAF and Zn(OTf)2, the corresponding fluoroalkylated tetra-substituted alkenes being afforded in moderate to good yields with a defined stereochemistry. PMID- 24469344 TI - Differences in vessel healing following delivery of everolimus or paclitaxel: a comparative experimental study using identical stent and biodegradable polymer platforms. AB - AIMS: We aimed to compare the vascular effects exclusive to antiproliferative agents by using identical stent and biodegradable polymeric matrices eluting everolimus (BP-EES) (Carlo; Balton) and paclitaxel (BP-PES) (Luc-Chopin2; Balton) in the porcine model of coronary injury. A total of 37 stents were implanted with 110% overstretch in the coronary arteries of 14 domestic pigs: 13 BP-PES, 16 BP EES and eight bare metal stents (BMS) (Chopin2; Balton). Coronary angiography was performed after 28 and 90 days, the animals were sacrificed and the stented segments harvested for histopathological evaluation. At 28 days, BP-PES most effectively limited angiographic late loss (LL PES: 0.15+/-0.1 vs. EES: 0.40+/ 0.3 vs. BMS: 0.5+/-0.2 mm; p=0.04) and neointimal thickness (NT) in histology (PES: 0.12 [0.1-0.2] vs. EES: 0.38 [0.3-0.4] vs. BMS: 0.35 [0.3-0.4] mm; p<0.01). The BP-PES had lower endothelialisation (EES: 100% vs. PES: 40+/-4% vs. BMS: 97.5+/-5%; p<0.01) and slightly higher inflammation scores (EES: 1 vs. PES: 2.1+/ 0.3 vs. BMS: 1; p<0.01). At three months, LL remained unchanged in the EES and BMS groups in contrast to an increase in the PES group (EES: 0.38+/-0.3 vs. PES: 0.52+/-0.4 vs. BMS: 0.51+/-0.3 mm; p=0.69). NT stabilised at 90 days in the EES group in comparison to a fourfold increase in the PES group and a 30% increase in the BMS group (EES: 0.35 [0.3-0.5] vs. PES: 0.53 [0.5-0.8] vs. BMS: 0.46 [0.4 0.5] mm: p=0.07). Stent endothelialisation and inflammation were comparable at 90 days in all groups. Temporal differences in vascular response were seen by the delivery of different antiproliferative agents. In contrast to everolimus, paclitaxel seems to induce a slightly higher degree of inflammation in the short term, potentially leading to further neointimal hyperplasia in the long term. PMID- 24469345 TI - Subcutaneous vs intravenous administration of immunoglobulin in chronic inflammatory demyelinating polyneuropathy: an Italian cost-minimization analysis. AB - Prior researches have suggested that home-based subcutaneous immunoglobulin (SCIG) is equally effective and can be less expensive than hospital-based intravenous immunoglobulin (IVIG) in treating chronic inflammatory demyelinating polyneuropathy (CIDP) patients. This economic evaluation aims at comparing costs of SCIG vs IVIG for CIDP patients in Italy. A 1-year model-based cost minimization analysis basically populated via neurologists' opinion was undertaken from a societal perspective. Health care resources included immunoglobulin; drugs for premedication and complications (rash, headache, and hypertension) management; time of various health care professionals; pump for SCIG self-administration; infusion disposables. Non-health care resources encompassed transport and parking; losses of working and leisure time for patients and caregivers. Unit or yearly costs for resources valuation were mainly obtained from published sources. Costs were expressed in Euro () 2013. An extensive one-way sensitivity analysis (OWSA) and a scenario SA tested the robustness of the base case findings. Overall costs per patient amount to 49,534.75 (SCIG) and 50,895.73 (IVIG); saving in favour of SCIG reaches 1360.98. For both SCIG and IVIG, the cost driver was immunoglobulin (94.06 vs 86.06 % of the overall costs, respectively). Sensitivity analyses confirmed the consistency of the baseline results. SCIG may be a cost-saving therapy for Italian CIDP patients. PMID- 24469346 TI - Lateral medullary infarction with ipsilateral hemiparesis, lemniscal sensation loss and hypoglossal nerve palsy. AB - Here, we present a rare case of a lateral medullary infarction with ipsilateral hemiparesis, lemniscal sensation loss and hypoglossal nerve palsy. In this case, we proved Opalski's hypothesis by diffusion tensor tractography that ipsilateral hemiparesis in a medullary infarction is due to the involvement of the decussated corticospinal tract. We found that the clinical triad of ipsilateral hemiparesis, lemniscal sensation loss and hypoglossal nerve palsy, which had been regarded as a variant of medial medullary syndrome, turned out to be caused by lateral lower medullary infarction. Therefore, this clinical triad does not imply the involvement of the anteromedial part of medulla oblongata, when it is hard to distinguish a massive lateral medullary infarction from a hemimedullary infarction merely from MR images. At last, we suggest that hyperreflexia and Babinski's sign may not be indispensable to the diagnosis of Opalski's syndrome and we propose that "hemimedullary infarction with ipsilateral hemiparesis" is intrinsically a variant of lateral medullary infarction. PMID- 24469347 TI - Coexisting cytotoxic and vasogenic edema in Wernicke encephalopathy. PMID- 24469349 TI - Cardiac myosin binding protein-C: a structurally dynamic regulator of myocardial contractility. AB - Cardiac myosin binding protein-C (cMyBP-C) is a modular protein anchored to the thick filament through interactions mediated by its C-terminal region. The N terminal region of cMyBPC-C regulates myocardial contractility by modifying actin myosin association. Phosphorylation of the N-terminal region diminishes cMyBP-C's capacity to regulate actin-myosin function. Despite a substantial body of literature, many issues remain unclear regarding the structural and functional roles of cMyBP-C. While no high-resolution structures of the intact protein exist, crystallographic and nuclear magnetic resonance (NMR) structures of isolated N-terminal domains provide important molecular details regarding cMyBP C's role in controlling contractility. In this review, we summarize the emerging structural understanding of cMyBP-C with a particular emphasis placed on describing how its dynamic molecular interactions with both thin and thick filament proteins likely contribute to contractile regulation. Furthermore, we discuss the future directions and strategies by which we may improve the mechanistic understanding of its role in modulating cardiac muscle contraction. PMID- 24469350 TI - Non-hysteretic colossal magnetoelectricity in a collinear antiferromagnet. AB - The manipulation of magnetic ordering with applied electric fields is of pressing interest for new magnetoelectric devices and information storage applications. Recently, such magnetoelectric control was realized in multiferroics. However, their magnetoelectric switching is often accompanied by significant hysteresis, resulting from a large barrier, separating different ferroic states. Hysteresis prevents robust switching, unless the applied field overcomes a certain value (coercive field). Here we address the role of a switching barrier on magnetoelectric control, and identify a material, collinear antiferromagnetic and pyroelectric Ni3TeO6, in which magnetoelectric switching occurs without hysteresis. The barrier between two magnetic states in the vicinity of a spin flop transition is almost flat, and thus small changes in external electric/magnetic fields allow to switch the ferroic state through an intermediate state in a continuous manner, resulting in a colossal magnetoelectric response. This colossal magnetoelectric effect resembles the large piezoelectric effect at the morphotropic phase boundary in ferroelectrics. PMID- 24469351 TI - A novel integrated structure with a radial displacement sensor and a permanent magnet biased radial magnetic bearing. AB - In this paper, a novel integrated structure is proposed in order to reduce the axial length of the high speed of a magnetically suspended motor (HSMSM) to ensure the maximum speed, which combines radial displacement sensor probes and the permanent magnet biased radial magnetic bearing in HSMSM. The sensor probes are integrated in the magnetic bearing, and the sensor preamplifiers are placed in the control system of the HSMSM, separate from the sensor probes. The proposed integrated structure can save space in HSMSMs, improve the working frequency, reduce the influence of temperature on the sensor circuit, and improve the stability of HSMSMs. PMID- 24469348 TI - Racial disparities in early mortality in 1,134 young patients with acute stroke. AB - We sought to investigate potential racial disparities in early outcomes of young individuals with stroke in an international multicenter study. We evaluated consecutive patients with first-ever acute stroke aged 18-45 years from prospective databases involving 12 tertiary-care stroke centers in North America (n = 2), Europe (n = 6), and Asia (n = 4). Demographics, vascular risk factors, stroke subtypes, pre-stroke functional status, stroke severity, blood pressure parameters, and serum glucose at hospital admission were documented. The outcome events of interest were 30-day mortality and 30-day favorable functional outcome (FFO) defined as modified-Rankin Scale score of 0-1. A total of 1,134 young adults (mean age 37.4 +/- 7.0 years; 58.8 % men; 48.6 % Whites, 23.9 % Blacks, and 27.5 % Asians; median baseline National Institutes of Health Stroke Scale score 6 points, interquartile range 2-13) were included in the analyses. The 30 day stroke mortality and FFO rates differed (p < 0.001) across races. After adjusting for potential confounders, race was independently associated with 30 day mortality (p = 0.026) and 30-day FFO (p = 0.035). Blacks had a fourfold higher odds of 30-day stroke mortality in comparison to Asians (OR 4.00; 95 % CI 1.38-11.59; p = 0.011). Whites also had an increased likelihood of 30-day stroke mortality in comparison to Asians (OR 3.59; 95 % CI 1.28-10.03; p = 0.015). Blacks had a lower odds of 30-day FFO in comparison to Whites (OR 0.57; 95 % CI 0.35-0.91; p = 0.018). Racial disparities in early outcomes following first-ever stroke in young individuals appear to be independent of other known outcome predictor variables. Whites appear to have higher likelihood of 30-day FFO and Asians have lower odds of 30-day stroke mortality. PMID- 24469352 TI - Foreground segmentation in depth imagery using depth and spatial dynamic models for video surveillance applications. AB - Low-cost systems that can obtain a high-quality foreground segmentation almost independently of the existing illumination conditions for indoor environments are very desirable, especially for security and surveillance applications. In this paper, a novel foreground segmentation algorithm that uses only a Kinect depth sensor is proposed to satisfy the aforementioned system characteristics. This is achieved by combining a mixture of Gaussians-based background subtraction algorithm with a new Bayesian network that robustly predicts the foreground/background regions between consecutive time steps. The Bayesian network explicitly exploits the intrinsic characteristics of the depth data by means of two dynamic models that estimate the spatial and depth evolution of the foreground/background regions. The most remarkable contribution is the depth based dynamic model that predicts the changes in the foreground depth distribution between consecutive time steps. This is a key difference with regard to visible imagery,where the color/gray distribution of the foreground is typically assumed to be constant.Experiments carried out on two different depth based databases demonstrate that the proposed combination of algorithms is able to obtain a more accurate segmentation of the foreground/background than other state-of-the art approaches. PMID- 24469353 TI - Surveillance of a 2D plane area with 3D deployed cameras. AB - As the use of camera networks has expanded, camera placement to satisfy some quality assurance parameters (such as a good coverage ratio, an acceptable resolution constraints, an acceptable cost as low as possible, etc.) has become an important problem. The discrete camera deployment problem is NP-hard and many heuristic methods have been proposed to solve it, most of which make very simple assumptions. In this paper, we propose a probability inspired binary Particle Swarm Optimization (PI-BPSO) algorithm to solve a homogeneous camera network placement problem. We model the problem under some more realistic assumptions: (1) deploy the cameras in the 3D space while the surveillance area is restricted to a 2D ground plane; (2) deploy the minimal number of cameras to get a maximum visual coverage under more constraints, such as field of view (FOV) of the cameras and the minimum resolution constraints. We can simultaneously optimize the number and the configuration of the cameras through the introduction of a regulation item in the cost function. The simulation results showed the effectiveness of the proposed PI-BPSO algorithm. PMID- 24469354 TI - Wearable monitoring devices for assistive technology: case studies in post-polio syndrome. AB - The correct choice and customization of an orthosis are crucial to obtain the best comfort and efficiency. This study explored the feasibility of a multivariate quantitative assessment of the functional efficiency of lower limb orthosis through a novel wearable system. Gait basographic parameters and energetic indexes were analysed during a Six-Minute Walking Test (6-MWT) through a cost-effective, non-invasive polygraph device, with a multichannel wireless transmission, that carried out electro-cardiograph (ECG); impedance-cardiograph (ICG); and lower-limb accelerations detection. Four subjects affected by Post Polio Syndrome (PPS) were recruited. The wearable device and the semi-automatic post-processing software provided a novel set of objective data to assess the overall efficiency of the patient-orthosis system. Despite the small number of examined subjects, the results obtained with this new approach encourage the application of the method thus enlarging the dataset to validate this promising protocol and measuring system in supporting clinical decisions and out of a laboratory environment. PMID- 24469355 TI - Detection of virgin olive oil adulteration using low field unilateral NMR. AB - The detection of adulteration in edible oils is a concern in the food industry, especially for the higher priced virgin olive oils. This article presents a low field unilateral nuclear magnetic resonance (NMR) method for the detection of the adulteration of virgin olive oil that can be performed through sealed bottles providing a non-destructive screening technique. Adulterations of an extra virgin olive oil with different percentages of sunflower oil and red palm oil were measured with a commercial unilateral instrument, the profile NMR-Mouse. The NMR signal was processed using a 2-dimensional Inverse Laplace transformation to analyze the transverse relaxation and self-diffusion behaviors of different oils. The obtained results demonstrated the feasibility of detecting adulterations of olive oil with percentages of at least 10% of sunflower and red palm oils. PMID- 24469356 TI - Energy-efficient data reduction techniques for wireless seizure detection systems. AB - The emergence of wireless sensor networks (WSNs) has motivated a paradigm shift in patient monitoring and disease control. Epilepsy management is one of the areas that could especially benefit from the use of WSN. By using miniaturized wireless electroencephalogram (EEG) sensors, it is possible to perform ambulatory EEG recording and real-time seizure detection outside clinical settings. One major consideration in using such a wireless EEG-based system is the stringent battery energy constraint at the sensor side. Different solutions to reduce the power consumption at this side are therefore highly desired. The conventional approach incurs a high power consumption, as it transmits the entire EEG signals wirelessly to an external data server (where seizure detection is carried out). This paper examines the use of data reduction techniques for reducing the amount of data that has to be transmitted and, thereby, reducing the required power consumption at the sensor side. Two data reduction approaches are examined: compressive sensing-based EEG compression and low-complexity feature extraction. Their performance is evaluated in terms of seizure detection effectiveness and power consumption. Experimental results show that by performing low-complexity feature extraction at the sensor side and transmitting only the features that are pertinent to seizure detection to the server, a considerable overall saving in power is achieved. The battery life of the system is increased by 14 times, while the same seizure detection rate as the conventional approach (95%) is maintained. PMID- 24469357 TI - Polymerization or cyclic dimerization: solvent dependent homo-coupling of terminal alkynes at HOPG surface. AB - Surface reactivity has become one of the most important issues in surface chemistry over the past few years. In this work, we, for the first time, have investigated the homo-coupling of a special terminal alkyne derivative on the highly oriented pyrolitic graphite (HOPG) surface. Using scanning tunneling microscopy (STM) technique, we have found that such coupling reaction seriously depends on the supramolecular assembly of the monomer on the studied substrate, whereas the latter appears an obvious solvent effect. As a result, the reaction in our system undergoes polymerization and cyclic dimerization process in 1 phenyloctane and 1,2,4-trichlorobenzene, respectively. That is to say, the solvent effect can be extended from the two-dimensional (2D) supramolecular self assembly to surface chemical reactions, and the selective homo-coupling has been successfully achieved at the solid/liquid interface. PMID- 24469358 TI - Maternal health literacy progression among rural perinatal women. AB - This research examined changes in maternal health literacy progression among 106 low income, high risk, rural perinatal African American and White women who received home visits by Registered Nurse Case Managers through the Enterprise Community Healthy Start Program. Maternal health literacy progression would enable women to better address intermediate factors in their lives that impacted birth outcomes, and ultimately infant mortality (Lu and Halfon in Mater Child Health J 7(1):13-30, 2003; Sharma et al. in J Natl Med Assoc 86(11):857-860, 1994). The Life Skills Progression Instrument (LSP) (Wollesen and Peifer, in Life skills progression. An outcome and intervention planning instrument for use with families at risk. Paul H. Brookes Publishing Co., Baltimore, 2006) measured changes in behaviors that represented intermediate factors in birth outcomes. Maternal Health Care Literacy (LSP/M-HCL) was a woman's use of information, critical thinking and health care services; Maternal Self Care Literacy (LSP/M SCL) was a woman's management of personal and child health at home (Smith and Moore in Health literacy and depression in the context of home visitation. Mater Child Health J, 2011). Adequacy was set at a score of (>=4). Among 106 women in the study initial scores were inadequate (<4) on LSP/M-HCL (83 %), and on LSP/M SCL (30 %). Significant positive changes were noted in maternal health literacy progression from the initial prenatal assessment to the first (p < .01) postpartum assessment and to the final (p < .01) postpartum assessment using McNemar's test of gain scores. Numeric comparison of first and last gain scores indicated women's scores progressed (LSP/M-HCL; p < .0001) and (LSP/M-SCL; p < .0001). Elevated depression scores were most frequent among women with <4 LSP/M HCL and/or <4 LSP/M-SCL. Visit notes indicated lack or loss of relationship with the father of the baby and intimate partner discord contributed to higher depression scores. PMID- 24469359 TI - Recruiting low income and racially/ethnically diverse adolescents for focus groups. AB - Recruiting and enrolling low income, racially and ethnically diverse adolescents into research studies can be a challenge. This paper details our research team's methodology in the recruitment and enrollment of low income and racially/ethnically diverse adolescents in three cities as part of a broader study to understand adolescent perceptions of a health risks. Our team used Florida's Medicaid and Children's Health Insurance Plan administrative databases to identify a sample of adolescents for focus group participation. Utilizing geographic information systems software we generated maps of racial and ethnic group clusters in three cities and identified community centers within each cluster to hold the focus groups. We mailed initial focus group introduction letters, conducted follow-up phone calls for recruitment and further implemented techniques to optimize participant confidentiality and comfort. We enrolled 35 participants for eight focus groups in three cities at a total cost of $264 per participant, including personnel, materials, travel, and incentives costs. As a result of our efforts, groups were fairly evenly distributed by both race and gender. Administrative databases provide opportunities to identify and recruit low income and racially/ethnically diverse adolescents for focus groups that might not otherwise have the opportunity to participate in research studies. It is important that researchers ensure these populations are represented when conducting health assessment tool evaluations. PMID- 24469360 TI - Association between cyclooxygenase-2 gene polymorphisms and head and neck squamous cell carcinoma risk. AB - Cyclooxygenase-2 (COX-2) is an inducible enzyme that catalyzes prostaglandins through inflammatory response, which may be involved in autoimmune diseases and cancer pathogenesis. Two potentially functional genetic single-nucleotide polymorphisms (COX-2 -1195G>A and 8473T>C) were supposed to contribute to head and neck squamous cell carcinoma (HNSCC) susceptibility. The aim of this study was to determine the association of these polymorphisms with HNSCC susceptibility in a Chinese Han population. In this study, 2 SNPs were genotyped by TaqMan methods in a patient-control study including 260 patients with HNSCC and 1047 cancer-free controls in a Chinese Han population. We found significant difference in the frequency of alcohol consumption between the patients with HNSCC and controls (P < 0.001), but the genotype frequencies of the 2 polymorphisms were not significantly different between the patients and controls. Further stratified analysis indicated that none of the genotypes were associated with increased risk for HNSCC. This research indicated that the COX-2 -1195G>A and 8473T>C polymorphisms may not be involved in the development of HNSCC in the Chinese Han population. However, further perspective studies are warranted to test these findings and further investigate the potential interactions involving the COX-2 polymorphism and HNSCC. PMID- 24469361 TI - Aneurysmal bone cyst of the zygomatic bone. AB - Aneurysmal bone cyst is a rare, non-neoplastic lesion that mostly involves the long bone and the spine, and is characterized by its expansile, vascular, and multi-cystic features. Reports of facial bone lesions are rare, and when it occurs, is usually located in the mandible. Herein, this report is aimed to describe a very rare case of an aneurysmal bone cyst in the zygoma with a brief review of the literature. PMID- 24469362 TI - Reconstruction of an infraorbital defect with deepithelialized forehead flap. PMID- 24469363 TI - A simple aesthetic approach for correction of frontal sinus fracture. AB - PURPOSE: Frontal sinus fracture management remains controversial and involves preserving function whenever possible or obliterating the sinus and duct as required by the fracture pattern. The purpose of this study was to introduce the simple and effective method in the surgical treatment of the anterior wall of frontal sinus fractures. METHODS: All 11 patients who presented with anterior wall fractures of the frontal sinus between 2009 and 2013 were included in this study. Two 7-mm stab incisions were made on each side of the fracture, a titanium screw with an attached wire was fixed to the fractured fragment, and an elevator was used to apply force in the opposite vector. One titanium screw was also fixed to the firm normal frontal bone, and the reduction was conducted by observing the C-arm until the fractured fragment reached the height of the normal side. RESULTS: No patients showed any recurrent displacement or infection during the follow-up period, nor did any patient complain of or demonstrate forehead paresthesia. The surgical scar was less than 3 cm in all 11 patients, and all of them reported satisfaction with the results. CONCLUSION: We obtained the results of an open reduction while using a less invasive method in the surgical treatment of the anterior wall of frontal sinus fractures. PMID- 24469364 TI - An underestimated "ghost" foreign body as an unusual cause of mandibular osseocutaneous fistula formation: impacted spike of a soccer cleat. AB - In this article, the case of a patient with osteocutaneous fistula at the left malar region secondary to impacted spike of a soccer cleat to the mandible is presented. Both the clinical and radiologic diagnoses failed because of an obscure anamnesis of the patient and the unavailability of viewing the spike in orthopantomogram and computed tomography. Surgical extirpation was performed to the 41-year-old man who was injured in a football match 3 months before the presentation and had a swooning history after an accidental booting. There were no early or late complications after the surgery at the end of 9 months. This study shows the importance of both obtaining a definite history of patients and sequential radiologic imaging to make a differential diagnosis between the foreign bodies and cystic or noncystic tumors and inflammatory lesions of the mandible. PMID- 24469365 TI - Construction and validation of the midsagittal reference plane based on the skull base symmetry for three-dimensional cephalometric craniofacial analysis. AB - OBJECTIVE: The objective of this study was to determine the reliable midsagittal (MS) reference plane in practical ways for the three-dimensional craniofacial analysis on three-dimensional computed tomography images. METHODS: Five normal human dry skulls and 20 normal subjects without any dysmorphoses or asymmetries were used. The accuracies and stability on repeated plane construction for almost every possible candidate MS plane based on the skull base structures were examined by comparing the discrepancies in distances and orientations from the reference points and planes of the skull base and facial bones on three dimensional computed tomography images. RESULTS: The following reference points of these planes were stable, and their distribution was balanced: nasion and foramen cecum at the anterior part of the skull base, sella at the middle part, and basion and opisthion at the posterior part. CONCLUSIONS: The candidate reference planes constructed using the aforementioned reference points were thought to be reliable for use as an MS reference plane for the three-dimensional analysis of maxillofacial dysmorphosis. PMID- 24469366 TI - A pulsatile mass in the retropharynx: dangerous aberrations of the cervical carotid artery. AB - Aberrations of the cervical internal carotid artery can be detected in the nasopharynx, oropharynx, and hypopharynx. Most previous literature reviews have focused on an analysis of the anatomic variations. However, clinical symptoms and physical examination findings have been rarely reported. Our clinical study describes a 63-year-old woman who presented with a lumpy and sore throat. We found an obvious protruding pulsatile mass in her retropharynx. Furthermore, an additional head and neck computed tomographic scan showed a variant course of the left common carotid artery and left internal carotid artery in the retropharynx and oropharynx. PMID- 24469367 TI - From "head to heart: " reconstruction of a sternal cleft with split calvarial bone graft in a 15-month-old child. AB - Sternal cleft is a rare anomaly and has been variously managed by using either autogenous tissue or synthetic materials for bony reconstruction. We report the reconstruction of sternal cleft in a 15-month-old child with a single-piece outer table cranial bone graft that was harvested by splitting in situ. The reconstructed sternum was covered with bilateral pectoralis major advancement muscle flaps. PMID- 24469368 TI - A clinical study of various buccinator musculomucosal flaps for palatal fistulae closure after cleft palate surgery. AB - This retrospective study describes various buccinator musculomucosal flaps for the repair of palatal fistulae. Twenty-two palatal fistulae were repaired at our institution between 2002 and 2012 by buccinator musculomucosal flaps with superior-anterior or posterior pedicles. Seventeen patients were treated with posteriorly pedicled flaps, 7 of whom had lengthening of the soft palate and 10 of whom had simultaneously repaired severe lateral palatal scarring. Five patients with anterior or midpalatal fistulae were treated with superior anteriorly pedicled flaps. All but 4 of the 22 patients had satisfactory results. Four patients had recurrent fistulae, 2 resulting from flap tip necrosis and 2 from wound dehiscence. Follow-up was from 5 to 72 months. None of the patients had facial nerve injury, limited mouth opening, or difficulty chewing. We evaluated the factors that could cause complications, such as flap pattern, location of fistula, and size of palate defect. No statistically significant differences were found in the complication rates among different groups. In conclusion, the buccinator musculomucosal flap is reliable and versatile, with rich vascularity and flexible design. The flap is a good option for fistula repair, especially for larger fistulae at the anterior portion of the hard palate or at the junction of hard and soft palate, where surrounding soft tissues are stiff, scarred, and difficult to mobilize. PMID- 24469369 TI - A morphologic study of the transcallosal-interventricular foramen approach in endoscopic third ventriculostomy with magnetic resonance imaging. AB - There is a very wide range of applications in neurosurgery for the treatment of obstructive hydrocephalus by third ventriculostomy. To facilitate the operation, we measured the related data of transcallosal-interventricular foramen approach in endoscopic third ventriculostomy with the magnetic resonance images of the third ventricle from 103 healthy adults. We calculated the mean and standard deviation as well as the 95% confidence interval for the mean value of the measured data, which conformed to normal distribution. We used median and interquartile range to show its concentration and the level of variation when it does not. PMID- 24469370 TI - Using conservative condylectomy for management of a large osteochondroma of the mandibular condyle with 6-year follow-up. AB - Osteochondroma is a hamartomatous proliferation of cartilaginous tissue, which is the most common benign tumor of the long bones, but is relatively rare in the maxillofacial region. Most cases of mandibular condylar osteochondroma manifest with facial asymmetry or malocclusion with limited temporomandibular joint movements. Several approaches for management of this lesion have been proposed, as conservative condylectomy technique. This procedure has been suggested a valid approach to minimize facial asymmetry, contributing to the recovery of occlusion associated with no local tumor recurrence, and without condylar reconstruction procedure. Therefore, this article aims to describe a clinical report of a true osteochondroma of the mandibular condyle in a 35-year-old patient who was successfully treated using conservative condylectomy procedure. PMID- 24469371 TI - Traditional endodontic surgery versus modern technique: a 5-year controlled clinical trial. AB - In this study, we compared outcomes of traditional apicoectomy versus modern apicoectomy, by means of a controlled clinical trial with a 5-year follow-up. The study investigated 938 teeth in 843 patients. On the basis of the procedure performed, the teeth were grouped in 3 groups. Differences between the groups were the method of osteotomy (type of instruments used), type of preparation of retrograde cavity (different apicoectomy angles and instruments used for root-end preparation), and root-end filling material used (gray mineral trioxide aggregate or silver amalgam). Outcome (tooth healing) was estimated after 1 and 5 years, postoperatively. Clinical success rates after 1 year were 67% (306 teeth), 90% (186 teeth), and 94% (256 teeth) according to traditional apicoectomy (group 1), modern microsurgical apicoectomy using burns for osteotomy (group 2) or using piezo-osteotomy (group 3), respectively. After 1 year, group comparison results were statistically significant (P < 0.0001). Linear trend test was also statistically significant (P < 0.0001), pointing out larger healing from group 1 to group 3. After 5 years, teeth were classified into 2 groups on the basis of root-end filling material used. Clinical success was 90.8% (197 teeth) in the silver amalgam group versus 96% (309 teeth) in the mineral trioxide aggregate group (P < 0.00214). Multiple logistic regression analysis found that surgical technique was independently associated to tooth healing. In conclusion, modern apicoectomy resulted in a probability of success more than 5 times higher (odds ratio, 5.20 [95% confidence interval, 3.94-6.92]; P < 0.001) compared with the traditional technique. PMID- 24469372 TI - Local versus systemic antibiotics effectiveness: a comparative study of postoperative oral disability in lower third molar surgery. PMID- 24469373 TI - Evaluation of foramen tympanicum using cone-beam computed tomography in orthodontic malocclusions. AB - The foramen tympanicum is a persistent anatomic formation of the temporal bone due to a defect in ossification normal bone physiology in neonatal or postnatal period. This study determined the occurrence and location of the foramen tympanicum in a Turkish sample using cone-beam computed tomography. Scans of 370 sites in 185 patients were retrospectively analyzed to determine foramen tympanicum occurrence, sizes, and locations according to their orthodontic malocclusions. Measurements were done on axial and sagittal sections to identify the dimensions. Differences in foramen tympanicum incidence by measurements, sex, side, malocclusions, and location were statistically evaluated. Foramen tympanicum was determined in 42 (22.7%) of 185 patients. No statistical difference was found considering location and sex (P > 0.05), but it was found more bilaterally in female patients within significance level at P = 0.024. Mean sizes did not differ significantly by sex but were found to be greater in females. In axial diameter, the average measurement was found wider on the right side of all patients (P = 0.017). The findings showed a greater foramen tympanicum dimension among class II than among class I and III subjects (P < 0.05). Knowledge about these structures is helpful for the interpretation of imaging (especially cone-beam computed tomography) and provides valuable information especially before orthognathic surgery to avoid intraoperative reconstruction and complications. PMID- 24469374 TI - Intraparenchymal hematoma caused by rupture of the traumatic pseudoaneurysm of middle meningeal artery. AB - Rupture of traumatic pseudoaneurysms of the middle meningeal artery (MMA) usually causes extradural hematoma. In rare cases, it may be a possible cause of intraparenchymal hematoma. We present 2 cases of intraparenchymal hematoma caused by rupture of traumatic pseudoaneurysms of MMA. Both patients had definite medical history of head trauma. Imaging examinations indicated temporal hematoma or frontal hematoma caused by rupture of pseudoaneurysm of MMA. After surgical management, both the patients had a favorable prognosis. The formation of the traumatic pseudoaneurysms, imaging findings, and the management were discussed, and we conclude that in the management of traumatic intraparenchymal hematoma, possibility of traumatic pseudoaneurysms must be considered. Surgery may be the prior choice for the treatment of traumatic pseudoaneurysms. PMID- 24469375 TI - Treatment of temporomandibular joint ankylosis by posterior border of mandibular ramus osteotomy. AB - Temporomandibular joint (TMJ) ankylosis (TMJA) is an anatomic and functional alteration of the TMJ surfaces, caused by the fusion of these surfaces by either bone or fibrous tissue. Several techniques are used for the treatment of TMJA. The following case report describes a 5-year-old boy who was diagnosed with TMJA. The treatment of choice is reconstruction of the condyle by sliding the posterior border of the mandibular ramus. Temporomandibular joint ankylosis treatment with vertical ramus osteotomy and mandibular posterior border repositioning offers minimizing the reduction in height or shortening of the mandibular posterior border. The postoperative period requires a multidisciplinary approach with an aggressive physiotherapy. PMID- 24469376 TI - Endoscopic cryotherapy for the treatment of epistaxis due to hereditary hemorrhagic telangiectasia. AB - Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vascular disease, involves mainly skin, mucocutaneous membranes, and viscera. Epistaxis is one of the most common symptoms of HHT, and chronic, frequently relapsing epistaxis can cause symptoms such as iron deficiency anemia, severe crusting, and nasal obstruction that can cause lower quality of life. Treatments for HHT range from medication and conservative management to more aggressive surgeries. None of the treatment options, however, have had satisfactory outcomes until now. We introduced cryotherapy for a patient with HHT and at least a 10-year history of frequent, severe epistaxis. This treatment strategy resulted in successful management of symptoms and no associated complications. We present herein a literature review and the clinical course and symptoms of an HHT patient who underwent cryotherapy. PMID- 24469377 TI - Management of sagittal synostosis: a solution to equipoise. AB - BACKGROUND: In the craniofacial surgery literature, there is a wide disparity of opinions regarding the appropriate treatment of nonsyndromic sagittal synostosis. With the lack of level 1 evidence to support a particular regimen, our study aims to elucidate the current state of practice among craniofacial surgeons with the hope of establishing a standard of care. METHODS: An internet-based survey was sent to 102 craniofacial surgeons in 14 countries on 4 continents. Data were collected regarding the following parameters: primary indication for surgery, preference of timing, and choice of operative intervention for patients presenting with nonsyndromic isolated sagittal synostosis with normative intracranial pressure values. Surgeons were also queried regarding preoperative, intraoperative, and postoperative protocols. RESULTS: After 2 mailings, the response rate was 58% (59/102). For 63% of respondents, skull deformity was the primary indication for treatment of craniosynostosis. Open surgical management of sagittal craniosynostosis was most commonly performed at 6 months (35%) of age. Total cranial vault remodeling was the most commonly performed procedure (37%). Thirty-five percent of craniofacial surgeons chose an endoscopic surgical approach for patients presenting at younger than 4 months. Only 10% of craniofacial surgeons selected spring-assisted strip craniectomy. Seventy-one percent of polled surgeons performed computed tomographic scans of the skull in all cases, irrespective of presentation. CONCLUSION: Our survey demonstrates that there exists a wide disparity of opinion regarding diagnosis and treatment of nonsyndromic sagittal synostosis. When current practice is compared to findings in the literature, significant discrepancies exist. PMID- 24469378 TI - Penetrating maxillary sinus injury caused by a construction nail passing through the orbital cavity. AB - Because of its anatomic position, the orbit is frequently subject to trauma, leading to functional and cosmetic problems. After blunt trauma, orbital fractures can cause functional problems by trapping the periocular tissues without affecting the anatomic integrity of the globe. In comparison, high-energy penetrating injuries can cause serious consequences such as disrupting the lacrimal drainage system and causing loss of vision. In rare cases, however, penetration of the orbit by a foreign body can result in a treatable injury that causes no functional or cosmetic problems.This article presents a patient in whom a nail penetrated the orbit from the inferomedial margin and reached the maxillary sinus without damaging the globe, extraocular muscles, or lacrimal duct system. Reports of similar injuries are reviewed, focusing on the anatomic structures that might be traumatized, to guide the readers in considering the diagnosis and treatment of such injuries. PMID- 24469379 TI - Anterior communicating artery aneurysm surgery: which is the most appropriate head position? AB - Head positioning and the degree of rotation for anterior communicating artery aneurysm surgery is controversial. With this anatomic study, we aimed to give a broad description of head positioning for various aneurysm dome projections. In addition, with the use of a corrosion-cast technique, a three-dimensional arterial tree was demonstrated, an anterior communicating artery region aneurysm model was prepared, and pictures were taken at various angles. According to our observations, 30-degree head rotation was found to be the most suitable position for the anterior and superior projected aneurysms. For posterior projection, aneurysm neck was best viewed with 15-degree head rotation. Aneurysms projecting inferiorly necessitated the greatest rotation at 45 degrees. Each aneurysm dome projection of the anterior communicating artery aneurysm should be individually considered, and the head position should be adjusted accordingly. The use of appropriate head positions during surgery will prevent the development of postoperative ischemic complications and will increase the success of surgery by preventing unnecessary tissue manipulation. PMID- 24469380 TI - Ensemble learning prediction of protein-protein interactions using proteins functional annotations. AB - Protein-protein interactions are important for the majority of biological processes. A significant number of computational methods have been developed to predict protein-protein interactions using protein sequence, structural and genomic data. Vast experimental data is publicly available on the Internet, but it is scattered across numerous databases. This fact motivated us to create and evaluate new high-throughput datasets of interacting proteins. We extracted interaction data from DIP, MINT, BioGRID and IntAct databases. Then we constructed descriptive features for machine learning purposes based on data from Gene Ontology and DOMINE. Thereafter, four well-established machine learning methods: Support Vector Machine, Random Forest, Decision Tree and Naive Bayes, were used on these datasets to build an Ensemble Learning method based on majority voting. In cross-validation experiment, sensitivity exceeded 80% and classification/prediction accuracy reached 90% for the Ensemble Learning method. We extended the experiment to a bigger and more realistic dataset maintaining sensitivity over 70%. These results confirmed that our datasets are suitable for performing PPI prediction and Ensemble Learning method is well suited for this task. Both the processed PPI datasets and the software are available at . PMID- 24469381 TI - [Deep brain stimulation as possible alternative for therapy resistant depression]. AB - There are many fearful prejudices and misunderstandings on the method of deep brain stimulation (DBS), especially in its application to neuropsychiatric diseases. Using the example of the treatment of resistant depression this article will discuss the current state of DBS in an attempt to overcome some of the prejudices and to elaborate on its potential development. The DBS is a straightforward method and has been used clinically for more than 12 years to treat some neurological diseases, such as tremor in Parkinson's disease and other movement disorders. More than 100,000 patients have already been treated worldwide using DBS which is a procedure in which electrodes are placed bilaterally in certain brain regions where they can modulate disease-related dysfunctions. PMID- 24469382 TI - [Clinical course of cerebral sinus venous thrombosis. Data from a monocentric cohort study over 15 years]. AB - INTRODUCTION: Thrombosis of cerebral veins or sinuses (CVST) is a rare condition. In a monocentric retrospective cohort study the clinical characteristics, risk factors, radiological findings as well as course and prognosis of patients over the past 15 years were examined. METHODS: Between January 1998 and March 2013 all patients who were treated as inpatients for CVST at the department of neurology of the University of Heidelberg were systematically registered in a database. Along with all relevant clinical data the modified Rankin scale (MRS) was used to measure the clinical severity. A follow-up visit was performed at three time points. The odds ratios (OR) were calculated to establish predictors of good outcome (MRS 0-2), mortality at discharge and at follow-up. Significant variables after univariate analysis were tested for independency in a multivariate logistic regression model. RESULTS: A total of 143 patients were included in the study. The median age was 43 years (range 17-74 years) and 67.4 % of patients were female. The most common symptoms were headache (70.6 %), seizures (50.4 %) and paresis (37.8 %). The most prominent clinical risk factor was oral contraception (40.4 %). The two most common localizations of thrombosis were the transversal sinus with the sigmoid sinus (66.4 %) and the sagittal superior sinus (47.6 %). On admission 42.7 % of patients suffered additionally from intracerebral hemorrhage and 12.6 % from congestive infarction. Of the patients 9.5 % (10 out of 105) showed a pathologically reduced activated protein C (APC) resistance and 8.4 % (6 out of 94) a prothrombin mutation. All patients were initially treated with heparin and 88.7 % were switched to cumarin during the course of the disease. The median duration of anticoagulation was 15.75 months (range 1-121 months). On discharge 77.7 % had a good outcome and the in-hospital mortality was 4.7 %. The median time to follow-up in 108 patients was 36 months (range 3-132 months), 74.1 % of patients had a good outcome (MRS 0-2) and 18.5 % died. Independent predictors of in-hospital mortality were MRS on admission (OR 2.2, 95 % CI 1.03-4.7) and of mortality at follow-up the presence of a malignant disease (OR 50.2, 6-423) and intracerebral hemorrhage on admission (OR 10.3, 1.7-62.6). DISCUSSION: The results of this study are in line with previously published data on CVST. The most prominent clinical risk factors for CVST were female gender and oral contraception. At discharge from hospital and 3 years after CVST approximately 75 % of patients achieved a good clinical outcome. A severe clinical syndrome and the presence of an intracerebral hemorrhage on admission were independent predictors of mortality. PMID- 24469383 TI - Mining communities from a resilience perspective: managing disturbance and vulnerability in Itabira, Brazil. AB - This paper applies the resilience lens to a social-ecological system characterized by the presence of large-scale mineral extraction operations. The system in question is the Brazilian community of Itabira, Minas Gerais, host to an iron ore operation of Vale, the world's second largest mining corporation. Utilizing a resilience assessment framework, this study describes the various components of the Itabira social-ecological system revealing the challenges brought about by mining's dominance. Data collection included literature reviews and semi-structured interviews with 29 individuals representing different stakeholder groups. Findings revealed that, despite recent efforts by government to regulate the industry, the mine continues to generate press and pulse disturbances that impact the resilience of the community. Operating from the standpoint that resilience depends largely upon the management capacity of stakeholders, the research identifies three ways to improve mining governance in Itabira. First, there is a need for local government to have more power in dealings with the corporation. Concurrent with this power, however, the municipality must demonstrate ownership over its fate, ideally through the creation of a sustainability plan. Finally, all key parties must demonstrate commitment to cooperating to resolve outstanding disturbances, even when these fall outside the regulatory approval process. While Itabira will remain a mining town for the foreseeable future, actions taken now to address challenges will only strengthen community well-being and sustainability moving forward. PMID- 24469384 TI - Dead space reduction by Kolobow's endotracheal tube does not justify the waiving of volume monitoring in small, ventilated lungs. AB - In ventilated preterm infants the flow sensor contributes significantly to the total apparatus dead space, which may impair gas exchange. The aim of the study was to quantify to which extent a dead space reduced Kolobow tube (KB) without flow sensor improves the gas exchange compared with a conventional ventilator circuit with flow sensor [Babylog 8000 (BL)]. In a cross-over trial in 14 tracheotomized, surfactant-depleted (saline lavage) and mechanically ventilated newborn piglets (age <12 h; body weight 705-1200 g) BL and KB was applied alternately for 15 min and blood gases were recorded. The inner diameter of the endotracheal tube was 3.6 mm and the apparatus dead space of BL and KB including the endotracheal tube were 3.0 and 1.34 mL. Despite a 50 % apparatus dead space reduction with KB compared to BL statistically significant improvements were only observed for body weights <900 g. In this weight group median paCO2 was decreased by 5 mmHg (p < 0.01), whereas the improvement decreased with decreasing baseline paCO2. Furthermore, median paO2 was increased by 4 mmHg (p < 0.05) and O2 saturation was increased by 2.5 % (p < 0.05). No significant changes were seen in the circulatory parameters. In very small, ventilated lungs the use of KB improved the gas exchange; however, the improvement was moderate and does not justify the waiving of volume monitoring. PMID- 24469385 TI - Hydrogen bonding in microsolvation: photoelectron imaging and theoretical studies on Au(x)(-)-(H2O)(n) and Au(x)(-)-(CH3OH)(n) (x = 1, 2; n = 1, 2) complexes. AB - We have combined photoelectron velocity-map imaging (VMI) spectroscopy and theoretical calculations to elucidate the geometry and energy properties of Aux( )(Solv)n clusters with x = 1, 2; n = 1, 2; and Solv = H2O and CH3OH. Besides the blue-shifted vertical electron detachment energies (VDEs) of the complexes Au1,2( )(Solv)n with the increase of the solvation number (n), we independently probed two distinct Au(-)(CH3OH)2 isomers, which combined with MP2/aug-cc-pVTZ(pp) calculations represent a competition between O...H-O hydrogen bonds (HBs) and Au...H-O nonconventional hydrogen bonds (NHBs). Complementary calculations provide the total binding energies of the low-energy isomers. Moreover, the relationship between the total binding energies and total VDEshift is discussed. We found that the Au1,2(-) anions exhibit halide-analogous behavior in microsolvation. These findings also demonstrate that photoelectron velocity map imaging spectroscopy with the aid of the ab initio calculations is an effective tool for investigating weak-interaction complexes. PMID- 24469386 TI - Rational design of the exchange-spring permanent magnet. AB - The development of the optimal exchange-spring permanent magnet balances exchange hardening, magnetization enhancement, and the feasibility of scalable fabrication. These requirements can be met with a rational design of the microstructural characteristics. The magnetization processes in several model exchange-spring structures with different geometries have been analyzed with both micromagnetic simulations and nucleation theory. The multilayer geometry and the soft-cylinders-in-hard-matrix geometry have the highest achievable figure of merit (BH)max, while the soft-spheres-in-hard-matrix geometry has the lowest upper limit for (BH)max. The cylindrical geometry permits the soft phase to be larger and does not require strict size control. Exchange-spring permanent magnets based on the cylindrical geometry may be amenable to scaled-up fabrication. PMID- 24469387 TI - Long-term outcomes after pulmonary embolism: current knowledge and future research. AB - In this article, we provide the rationale for the ELOPE (Evaluation of Long-term Outcomes after Pulmonary Embolism) Study, a prospective, observational, multicenter cohort study of patients with a newly diagnosed, first episode of pulmonary embolism (www.clinicaltrials.govNCT01174628) that aims to identify clinical, anatomic, physiologic and biomarker determinants of poor outcome after pulmonary embolism.Pulmonary embolism, the most serious form of venous thromboembolism (VTE), leads to the hospitalization or death of over 30,000 Canadians, 225,000 Americans and 300,000 Europeans each year, numbers that have risen over the past decade. Although numerous studies have evaluated optimal approaches to the diagnosis and treatment of pulmonary embolism, their focus has primarily been on short-term outcomes such as mortality and recurrent VTE in the days, weeks or months after pulmonary embolism diagnosis. However, it is increasingly recognized that pulmonary embolism may have long-lasting sequelae that impact on patients' health. The objective of this article was to review the available evidence on long-term clinical, functional, anatomic and physiologic outcomes after pulmonary embolism, and discuss avenues for research in this field, including the ELOPE Study. Residual pulmonary vascular abnormalities on follow-up imaging and echocardiogram are frequent in pulmonary embolism patients, but the clinical significance of these abnormalities is poorly understood. Whether initial and/or residual clot burden, recurrent pulmonary embolism, altered pulmonary artery or right ventricular hemodynamics or other prognostic factors such as biomarker levels contribute to long-term morbidity after pulmonary embolism is as yet unknown. The ELOPE Study will describe and identify the predictors of long-term outcomes after pulmonary embolism in the setting of a rigorous, multicenter cohort study in which long-term clinical, anatomic, physiologic and functional sequelae such as quality of life, return to work and loss of productivity after pulmonary embolism are systematically evaluated. PMID- 24469388 TI - Acquired factor V inhibitor in a woman following aortic aneurysm surgery. AB - A 67-year-old woman with nephrotic syndrome as a complication of membranous glomerulonephritis associated with chronic active hepatitis B virus infection developed factor V inhibitor following emergency aortic aneurysm surgery followed by massive blood transfusions and haemodialysis. On the second postoperative day, prothrombin time and activated partial thromboplastin time increased and were unresponsive to fresh frozen plasma. Epistaxis and urethral bleeding were observed, followed by mucosal mouth bleeding. A very low factor V activity less than 5% was found and a factor V inhibitor was detected at 7.76 Bethesda Units. Treatment with corticosteroids was successful. In this patient, several conditions known to predispose to the generation of factor V inhibitor occurred simultaneously. Four months later, factor V inhibitor (225 Bethesda Units) recurred and the patient died of intracerebral haemorrhage. PMID- 24469390 TI - Haemostatic trends in HIV-infected individuals in Yaounde, Cameroon: a pilot study. AB - Bleeding disorders are haematological manifestations that are frequently observed during HIV infection. This study intends to describe the haemostatic trends in HIV-infected patients in Cameroon. This cross-sectional descriptive study was carried out at the haematology unit of the Yaounde University Teaching Hospital from March to June 2012. It included consenting HIV-positive patients, aged 18 years and above, naive to antiretroviral treatment or not. The coagulation profile was measured with Stago reagents (Stago Diagnostics, Asnieres sur Seine, France) using a chronometric technique on a semi-automate (Stago Diagnostics). Platelets count was estimated on a human count automate (Human Diagnostics, Wiesbaden, Germany) by flow cytometry. A total of 139 HIV-infected patients were included in this study, out of which 106 were females (76.3%) against 33 (23.7%) males, giving a sex ratio of 0.3 (M/F). Mean age was 38.85 years (range 22-73 years) and median CD4 count was 353 cells/MUl (Interquartile range 200-500 cells/MUl). Hyperfibrinogenaemia was the most frequent bleeding disorder in the studied population [40 of 139 (28.78%)], followed by low prothrombin time (PT) [22 of 139 (15.83%)], thrombocytopenia [19 of 139 (13.67%)], hypofibrinogenaemia [18 of 139 (12.95)], prolonged activated partial thromboplastin time (7.91) and by thrombocytosis which was less frequent [6 of 139 (4.32%)]. Out of the six haemostatic disorders, only low PT was significantly associated with CD4 count (P = 0.02). This study showed that bleeding disorders are very frequent in the HIV infected patients studied. Low PT was significantly associated with CD4 count, hence it may be recommended to systematic screen for bleeding disorders in severe immune-depressed (CD4 <= 200 cells/MUl) HIV-infected patients. PMID- 24469391 TI - Acute thrombotic thrombocytopenic purpura after pneumococcal vaccination. AB - We report the case of a 68-year-old woman with acute thrombotic thrombocytopenic purpura (TTP) that developed after pneumococcal vaccination. She was found in a confusional state with high fever 15 days after vaccination. Laboratory data showed hemolytic anemia and thrombocytopenia, and blood smear showed fragmented erythrocytes. TTP was diagnosed based on the clinical presentation, and was subsequently confirmed by the absence of ADAMTS13 activity and the presence of inhibitor against ADAMTS13 in serum. She was successfully treated using plasma exchange and corticosteroids, and no recurrence has been identified. This appears to represent the first report of TTP following pneumococcal vaccination. PMID- 24469392 TI - Lymphoplasmacytic lymphoma exposed by haemoptysis and acquired von Willebrand syndrome. AB - We report on a 36-year-old man who presented to the emergency department with haemoptysis. Computed tomography (CT) of the thorax showed a pulmonary mass paramediastinal in the right upper lobe, with the density of a haematoma. Laboratory data demonstrated an absolute lymphocytosis of 5.900 * 10/l (normal range, 1.150-3.250 * 10/l) and a prolonged activated partial thromboplastin time (APTT) of 47.7 s (normal range, 28.0-39.0 s). A de novo diagnosis of lymphoplasmacytic lymphoma (Waldenstrom macroglobulinaemia) was made, complicated by an acquired von Willebrand syndrome (aVWS) as demonstrated by further laboratory investigations. In this case report, we present a case of aVWS with markedly prolonged APTT and haemoptysis that revealed an underlying Waldenstrom macroglobulinaemia. PMID- 24469393 TI - Effects of sexual maturation and Salmonella infection on the expression of avian beta-defensin genes in the chicken testis. AB - Rooster infertility is a major concern in the poultry industry and protection of the male reproductive organs from pathogens is an essential aspect of reproductive physiology. During the last years, research on antimicrobial protection has elucidated the critical role of the antimicrobial peptides avian beta-defensins (AvBDs) in the innate immunity in chickens. AvBDs have been reported to be expressed in the hen reproductive organs, providing protection against microbial pathogens including Salmonella Enteritidis (SE). However, mechanisms of antimicrobial protection of rooster reproductive organs and especially the testis, mediated by AvBDs are poorly understood. The aim of this study was to investigate the expression of the complete family of the 14 AvBD genes, in the rooster testis in vivo, to determine whether sexual maturation affects their testicular mRNA abundance and to investigate whether SE infection alters their expression. Expression analysis revealed that 9 members of the AvBD family, namely AvBD1, 2, 4, 5, 6, 9, 10, 12 and 14 were expressed in the testis. Quantitative real-time PCR analysis revealed that the mRNA abundance of three AvBDs was up regulated and of three AvBDs was down regulated with respect to sexual maturation. In addition, SE infection resulted in a significant induction of AvBD4, 10, 12 and 14 in the testis of sexually mature roosters. These findings provide strong evidence to suggest that an AvBD-mediated immune response mechanism exists in the rooster testis providing protection against bacterial pathogens including Salmonella species. PMID- 24469394 TI - Stat5 regulates the phosphatidylinositol 3-kinase/Akt1 pathway during mammary gland development and tumorigenesis. AB - Stat5 (signal transducer and activator of transcription 5) is an essential mediator of cytokine receptor signaling and plays important roles in the proliferation of alveolar progenitors and the survival of functionally differentiated epithelial cells in the mammary gland. A deregulated expression and activation of Stat5 leads to precocious alveolar development in the absence of pregnancy hormones, impaired mammary gland remodeling following the cessation of lactation, and mammary tumor formation. We reported previously that Stat5 induces the transcription of the Akt1 gene from a novel promoter. In this report, we provide experimental evidence that Akt1 is an essential mediator for the biological function of Stat5 as a survival factor. Additionally, Stat5 controls the expression of the regulatory and catalytic subunits of the phosphatidylinositol 3-kinase (PI3K) (p85alpha and p110alpha), thereby greatly augmenting signaling through the prosurvival PI3K/Akt pathway. In agreement with this model, we observed that the constitutive activation of Stat5 cooperates with the loss of function of the tumor suppressor PTEN by accelerating the formation of preneoplastic lesions and mammary tumors. The mammary gland-specific ablation of Stat5 is sufficient to prevent mammary carcinogenesis in a genuine mouse model for Cowden syndrome. Therefore, targeting the Jak2/Stat5 pathway might be a suitable strategy to prevent breast cancer in patients that carry a mutant PTEN allele. PMID- 24469395 TI - Sept6 is required for ciliogenesis in Kupffer's vesicle, the pronephros, and the neural tube during early embryonic development. AB - Septins are conserved filament-forming GTP-binding proteins that act as cellular scaffolds or diffusion barriers in a number of cellular processes. However, the role of septins in vertebrate development remains relatively obscure. Here, we show that zebrafish septin 6 (sept6) is first expressed in the notochord and then in nearly all of the ciliary organs, including Kupffer's vesicle (KV), the pronephros, eye, olfactory bulb, and neural tube. Knockdown of sept6 in zebrafish embryos results in reduced numbers and length of cilia in KV. Consequently, cilium-related functions, such as the left-right patterning of internal organs and nodal/spaw signaling, are compromised. Knockdown of sept6 also results in aberrant cilium formation in the pronephros and neural tube, leading to cilium related defects in pronephros development and Sonic hedgehog (Shh) signaling. We further demonstrate that SEPT6 associates with acetylated alpha-tubulin in vivo and localizes along the axoneme in the cilia of zebrafish pronephric duct cells as well as cultured ZF4 cells. Our study reveals a novel role of sept6 in ciliogenesis during early embryonic development in zebrafish. PMID- 24469396 TI - Rad51-dependent aberrant chromosome structures at telomeres and ribosomal DNA activate the spindle assembly checkpoint. AB - The spindle assembly checkpoint (SAC) monitors defects in kinetochore-microtubule attachment or lack of tension at kinetochores and arrests cells at prometaphase. In fission yeast, the double mutant between pot1Delta and the helicase-dead point mutant of the RecQ helicase Rqh1 gene (rqh1-hd) accumulates Rad51-dependent recombination intermediates at telomeres and enters mitosis with those intermediates. Here, we found that SAC-dependent prometaphase arrest occurred more frequently in pot1Delta rqh1-hd double mutants than in rqh1-hd single mutants. SAC-dependent prometaphase arrest also occurred more frequently in rqh1 hd single mutants after cells were released from DNA replication block compared to the rqh1-hd single mutant in the absence of exogenous insult to the DNA. In both cases, Mad2 foci persisted longer than usual at kinetochores, suggesting a defect in kinetochore-microtubule attachment. In pot1Delta rqh1-hd double mutants and rqh1-hd single mutants released from DNA replication block, SAC-dependent prometaphase arrest was suppressed by the removal of the recombination or replication intermediates. Our results indicate that the accumulation of recombination or replication intermediates induces SAC-dependent prometaphase arrest, possibly by affecting kinetochore-microtubule attachment. PMID- 24469397 TI - Cytoplasmic poly(A) binding protein C4 serves a critical role in erythroid differentiation. AB - The expression of an mRNA is strongly impacted by its 3' poly(A) tail and associated poly(A)-binding proteins (PABPs). Vertebrates encode six PABP isoforms that vary in abundance, distribution, developmental control, and subcellular localization. Here we demonstrate that the minor PABP isoform PABPC4 is expressed in erythroid cells and impacts the steady-state expression of a subset of erythroid mRNAs. Motif analyses reveal a high-value AU-rich motif in the 3' untranslated regions (UTRs) of PABPC4-impacted mRNAs. This motif enhances the association of PABPC4 with mRNAs containing critically shortened poly(A) tails. This association may serve to protect a subset of mRNAs from accelerated decay. Finally, we demonstrate that selective depletion of PABPC4 in an erythroblast cell line inhibits terminal erythroid maturation with corresponding alterations in the erythroid gene expression. These observations lead us to conclude that PABPC4 plays an essential role in posttranscriptional control of a major developmental pathway. PMID- 24469398 TI - 53BP1, BRCA1, and the choice between recombination and end joining at DNA double strand breaks. AB - When DNA double-strand breaks occur, the cell cycle stage has a major influence on the choice of the repair pathway employed. Specifically, nonhomologous end joining is the predominant mechanism used in the G1 phase of the cell cycle, while homologous recombination becomes fully activated in S phase. Studies over the past 2 decades have revealed that the aberrant joining of replication associated breaks leads to catastrophic genome rearrangements, revealing an important role of DNA break repair pathway choice in the preservation of genome integrity. 53BP1, first identified as a DNA damage checkpoint protein, and BRCA1, a well-known breast cancer tumor suppressor, are at the center of this choice. Research on how these proteins function at the DNA break site has advanced rapidly in the recent past. Here, we review what is known regarding how the repair pathway choice is made, including the mechanisms that govern the recruitment of each critical factor, and how the cell transitions from end joining in G1 to homologous recombination in S/G2. PMID- 24469399 TI - Mechanism underlying IkappaB kinase activation mediated by the linear ubiquitin chain assembly complex. AB - The linear ubiquitin chain assembly complex (LUBAC) ligase, consisting of HOIL 1L, HOIP, and SHARPIN, specifically generates linear polyubiquitin chains. LUBAC mediated linear polyubiquitination has been implicated in NF-kappaB activation. NEMO, a component of the IkappaB kinase (IKK) complex, is a substrate of LUBAC, but the precise molecular mechanism underlying linear chain-mediated NF-kappaB activation has not been fully elucidated. Here, we demonstrate that linearly polyubiquitinated NEMO activates IKK more potently than unanchored linear chains. In mutational analyses based on the crystal structure of the complex between the HOIP NZF1 and NEMO CC2-LZ domains, which are involved in the HOIP-NEMO interaction, NEMO mutations that impaired linear ubiquitin recognition activity and prevented recognition by LUBAC synergistically suppressed signal-induced NF kappaB activation. HOIP NZF1 bound to NEMO and ubiquitin simultaneously, and HOIP NZF1 mutants defective in interaction with either NEMO or ubiquitin could not restore signal-induced NF-kappaB activation. Furthermore, linear chain-mediated activation of IKK2 involved homotypic interaction of the IKK2 kinase domain. Collectively, these results demonstrate that linear polyubiquitination of NEMO plays crucial roles in IKK activation and that this modification involves the HOIP NZF1 domain and recognition of NEMO-conjugated linear ubiquitin chains by NEMO on another IKK complex. PMID- 24469400 TI - Insulin stimulates syntaxin4 SNARE complex assembly via a novel regulatory mechanism. AB - Insulin stimulates glucose transport into fat and muscle cells by increasing the exocytic trafficking rate of the GLUT4 facilitative glucose transporter from intracellular stores to the plasma membrane. Delivery of GLUT4 to the plasma membrane is mediated by formation of functional SNARE complexes containing syntaxin4, SNAP23, and VAMP2. Here we have used an in situ proximity ligation assay to integrate these two observations by demonstrating for the first time that insulin stimulation causes an increase in syntaxin4-containing SNARE complex formation in adipocytes. Furthermore, we demonstrate that insulin brings about this increase in SNARE complex formation by mobilizing a pool of syntaxin4 held in an inactive state under basal conditions. Finally, we have identified phosphorylation of the regulatory protein Munc18c, a direct target of the insulin receptor, as a molecular switch to coordinate this process. Hence, this report provides molecular detail of how the cell alters membrane traffic in response to an external stimulus, in this case, insulin. PMID- 24469401 TI - Yin Yang 1 is a repressor of glutamate transporter EAAT2, and it mediates manganese-induced decrease of EAAT2 expression in astrocytes. AB - Impairment of astrocytic glutamate transporter (GLT-1; EAAT2) function is associated with multiple neurodegenerative diseases, including Parkinson's disease (PD) and manganism, the latter being induced by chronic exposure to high levels of manganese (Mn). Mn decreases EAAT2 promoter activity and mRNA and protein levels, but the molecular mechanism of Mn-induced EAAT2 repression at the transcriptional level has yet to be elucidated. We reveal that transcription factor Yin Yang 1 (YY1) is critical in repressing EAAT2 and mediates the effects of negative regulators, such as Mn and tumor necrosis factor alpha (TNF-alpha), on EAAT2. YY1 overexpression in astrocytes reduced EAAT2 promoter activity, while YY1 knockdown or mutation of the YY1 consensus site of the EAAT2 promoter increased its promoter activity and attenuated the Mn-induced repression of EAAT2. Mn increased YY1 promoter activity and mRNA and protein levels via NF kappaB activation. This led to increased YY1 binding to the EAAT2 promoter region. Epigenetically, histone deacetylase (HDAC) classes I and II served as corepressors of YY1, and, accordingly, HDAC inhibitors increased EAAT2 promoter activity and reversed the Mn-induced repression of EAAT2 promoter activity. Taken together, our findings suggest that YY1, with HDACs as corepressors, is a critical negative transcriptional regulator of EAAT2 and mediates Mn-induced EAAT2 repression. PMID- 24469403 TI - Proteasome failure promotes positioning of lysosomes around the aggresome via local block of microtubule-dependent transport. AB - Ubiquitinated proteins aggregate upon proteasome failure, and the aggregates are transported to the aggresome. In aggresomes, protein aggregates are actively degraded by the autophagy-lysosome pathway, but why targeting the aggresome promotes degradation of aggregated species is currently unknown. Here we report that the important factor in this process is clustering of lysosomes around the aggresome via a novel mechanism. Proteasome inhibition causes formation of a zone around the centrosome where microtubular transport of lysosomes is suppressed, resulting in their entrapment and accumulation. Microtubule-dependent transport of other organelles, including autophagosomes, mitochondria, and endosomes, is also blocked in this entrapment zone (E-zone), while movement of organelles at the cell periphery remains unaffected. Following the whole-genome small interfering RNA (siRNA) screen for proteins involved in aggresome formation, we defined the pathway that regulates formation of the E-zone, including the Stk11 protein kinase, the Usp9x deubiquitinating enzyme, and their substrate kinase MARK4. Therefore, upon proteasome failure, targeting of aggregated proteins of the aggresome is coordinated with lysosome positioning around this body to facilitate degradation of the abnormal species. PMID- 24469402 TI - Deregulation of pancreas-specific oxidoreductin ERO1beta in the pathogenesis of diabetes mellitus. AB - A growing body of evidence has underlined the significance of endoplasmic reticulum (ER) stress in the pathogenesis of diabetes mellitus. ER oxidoreductin 1beta (ERO1beta) is a pancreas-specific disulfide oxidase that is known to be upregulated in response to ER stress and to promote protein folding in pancreatic beta cells. It has recently been demonstrated that ERO1beta promotes insulin biogenesis in beta cells and thus contributes to physiological glucose homeostasis, though it is unknown if ERO1beta is involved in the pathogenesis of diabetes mellitus. Here we show that in diabetic model mice, ERO1beta expression is paradoxically decreased in beta cells despite the indications of increased ER stress. However, overexpression of ERO1beta in beta cells led to the upregulation of unfolded protein response genes and markedly enlarged ER lumens, indicating that ERO1beta overexpression caused ER stress in the beta cells. Insulin contents were decreased in the beta cells that overexpressed ERO1beta, leading to impaired insulin secretion in response to glucose stimulation. These data indicate the importance of the fine-tuning of the ER redox state, the disturbance of which would compromise the function of beta cells in insulin synthesis and thus contribute to the pathogenesis of diabetes mellitus. PMID- 24469404 TI - TRF2-tethered TIN2 can mediate telomere protection by TPP1/POT1. AB - The shelterin protein TIN2 is required for the telomeric accumulation of TPP1/POT1 heterodimers and for the protection of telomeres by the POT1 proteins (POT1a and POT1b in the mouse). TIN2 also binds to TRF1 and TRF2, improving the telomeric localization of TRF2 and its function. Here, we ask whether TIN2 needs to interact with both TRF1 and TRF2 to mediate the telomere protection afforded by TRF2 and POT1a/b. Using a TIN2 allele deficient in TRF1 binding (TIN2-L247E), we demonstrate that TRF1 is required for optimal recruitment of TIN2 to telomeres and document phenotypes associated with the TIN2-L247E allele that are explained by insufficient TIN2 loading onto telomeres. To bypass the requirement for TRF1 dependent recruitment, we fused TIN2-L247E to the TRF2-interacting (RCT) domain of Rap1. The RCT-TIN2-L247E fusion showed improved telomeric localization and was fully functional in terms of chromosome end protection by TRF2, TPP1/POT1a, and TPP1/POT1b. These data indicate that when sufficient TIN2 is loaded onto telomeres, its interaction with TRF1 is not required to mediate the function of TRF2 and the TPP1/POT1 heterodimers. We therefore conclude that shelterin can protect chromosome ends as a TRF2-tethered TIN2/TPP1/POT1 complex that lacks a physical connection to TRF1. PMID- 24469405 TI - Role of Thiobacillus thioparus in the biodegradation of carbon disulfide in a biofilter packed with a recycled organic pelletized material. AB - This study reports the biodegradation of carbon disulfide (CS2) in air biofilters packed with a pelletized mixture of composted manure and sawdust. Experiments were carried out in two lab-scale (1.2 L) biofiltration units. Biofilter B was seeded with activated sludge enriched previously on CS2-degrading biomass under batch conditions, while biofilter A was left as a negative inoculation control. This inoculum was characterized by an acidic pH and sulfate accumulation, and contained Achromobacter xylosoxidans as the main putative CS2 biodegrading bacterium. Biofilter operation start-up was unsuccessfully attempted under xerophilic conditions and significant CS2 elimination was only achieved in biofilter A upon the implementation of an intermittent irrigation regime. Sustained removal efficiencies of 90-100 % at an inlet load of up to 12 g CS2 m( 3) h(-1) were reached. The CS2 removal in this biofilter was linked to the presence of the chemolithoautotrophic bacterium Thiobacillus thioparus, known among the relatively small number of species with a reported capacity of growing on CS2 as the sole energy source. DGGE molecular profiles confirmed that this microbe had become dominant in biofilter A while it was not detected in samples from biofilter B. Conventional biofilters packed with inexpensive organic materials are suited for the treatment of low-strength CS2 polluted gases (IL <12 g CS2 m(-3) h(-1)), provided that the development of the adequate microorganisms is favored, either upon enrichment or by inoculation. The importance of applying culture-independent techniques for microbial community analysis as a diagnostic tool in the biofiltration of recalcitrant compounds has been highlighted. PMID- 24469406 TI - Temperature impacts on anaerobic biotransformation of LNAPL and concurrent shifts in microbial community structure. AB - Thermally-enhanced bioremediation is a promising treatment approach for petroleum contamination; however, studies examining temperature effects on anaerobic biodegradation in zones containing light non-aqueous phase liquids (LNAPLs) are lacking. Herein, laboratory microcosm studies were conducted for a former refinery to evaluate LNAPL transformation, sulfate reduction, and methane generation over a one-year period for temperatures ranging from 4 to 40 degrees C, and microbial community shifts were characterized. Temperatures of 22 and 30 degrees C significantly increased total biogas generation compared to lower (4 and 9 degrees C) and higher temperatures (35 and 40 degrees C; p < 0.1). Additionally, at 22 and 30 degrees C methane generation commenced ~6 months earlier than for 35 and 40 degrees C. Statistically significant biodegradation of benzene, toluene and xylenes was observed at elevated temperatures but not at lower temperatures (p < 0.1). Additionally, a novel differential chromatogram approach was developed to overcome challenges associated with resolving losses in complex mixtures of hydrocarbons, and application of this method revealed greater losses of hydrocarbons at 22 and 30 degrees C as compared to lower and higher temperatures. Finally, molecular biology assays revealed that the composition and activity of microbial communities shifted in a temperature-dependent manner. Collectively, results demonstrated that anaerobic biodegradation processes can be enhanced by increasing the temperature of LNAPL-containing soils, but biodegradation does not simply increase as temperature increases likely due to a lack of microorganisms that thrive at temperatures well above the historical high temperatures for a site. Rather, optimal degradation is achieved by holding soils at the high end of, or slightly higher than, their natural range. PMID- 24469407 TI - Folate-polyethylene glycol conjugated carboxymethyl chitosan for tumor-targeted delivery of 5-fluorouracil. AB - Targeted drug delivery has been evolving at an increasing rate due to its potential to reduce the minimum effective dose of a drug and its accompanying side effects. It has shown improved therapeutic efficacy at equivalent plasma concentrations; however, the development of effective targeted delivery systems has remained a major task. In this study, a drug carrier was designed and synthesized by conjugation of folate acid (FA) to carboxymethyl chitosan (CMCS) through a polyethylene glycol (PEG) spacer. The resulting conjugates were confirmed by 1H nuclear magnetic resonance and infrared spectroscopy. The cytotoxicity of CMCS and CMCS-5-fluorouracil (5-FU) was determined by a crystal violet stain assay. The potential of CMCS-PEG-FA for use in the targeted delivery of 5-FU was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide analysis in two cell lines, HeLa and A549, which contain different numbers of folate receptors on their surfaces. The MTT results revealed that in HeLa cells, the cytotoxicity of (CMCS-5-FU)-PEG-FU cells is greater compared with CMCS-5-FU, suggesting that folate receptor-mediated endocytosis may affect the cellular uptake efficiency of 5-FU-loaded CMCS-PEG-FA. The CMCS-PEG-FA conjugates presented in this study show promise as carriers for chemotherapeutic agents due to their solubility at physiological pH, efficiency in carrying chemotherapeutic agents, low cytotoxicity and targeting ability. PMID- 24469408 TI - Diagnosis and treatment of corticobasal degeneration. AB - OPINION STATEMENT: Corticobasal degeneration is a pathologic entity. Presenting clinical phenotypes include corticobasal syndrome (CBS), frontal behavioral spatial syndrome, aphasia, progressive supranuclear palsy-like syndrome (PSPS), and a predominantly cognitive phenotype often mistaken for Alzheimer's disease (AD). Treatment of CBD is symptomatic, particularly given recently negative neuroprotective studies. Given the relentless progression in CBD, all interested patients should be offered the opportunity to enroll in clinical neuroprotective trials as they arise. For symptomatic therapy, treatment options are necessarily based on evidence from other disorders given the lack of studies in CBD. In patients with CBS and PSPS, parkinsonism is treated with levodopa/carbidopa. This generally has modest and transient benefits at best and often results in no improvement. Botulinum toxin injections are the treatment of choice for limb dystonia. Clonazepam and levetiracetam are commonly used for myoclonus. Physical therapy is an important part of motor treatment, particularly for fall prevention strategies and assist device assessment. Whether medications such as cholinesterase inhibitors or memantine have any role in CBD is unclear given the various responses described in related phenotypes and diseases. Treating the behavioral symptoms associated with CBD is critical in an attempt to treat symptoms for which we have good pharmacologic interventions and to hopefully improve quality of life. General supportive care is important, including assessing for sores related to dystonia or immobility, monitoring dysphagia, and identifying needs for support services. Finally, as with other relentlessly progressive neurodegenerative diseases, it is critical to provide family and caregiver support and to assess for when palliative care services will serve the patient best. PMID- 24469409 TI - Identifying aberrant hepatic arteries prior to intra-arterial radioembolization. AB - PURPOSE: Failing to identify aberrant hepatic arteries before radioembolization (RE) may compromise its treatment efficacy due to inadequate biodistribution of radioactive microspheres. The purpose of this study was to evaluate how often aberrant hepatic arteries were identified correctly in clinical practice, with computed tomography (CT), and during angiography in patients with liver tumors who received a workup for RE. METHODS: The presence and vascularization pattern of aberrant (i.e., accessory and replaced) hepatic arteries was assessed on triphasic liver CT in 110 patients. Subsequently, radiological reports on CT and angiographic procedures were reviewed to determine whether aberrant hepatic arteries were identified correctly in clinical practice. The intrahepatic biodistribution of (99m)Tc-MAA and radioactive microspheres was assessed on SPECT/CT and PET/CT in all patients with unidentified aberrant hepatic arteries. RESULTS: Thirty-seven of 110 patients (34%) had aberrant hepatic arteries. In 18 of 37 (49%) patients, the aberrant hepatic arteries were correctly identified on CT and in 32 of 37 (86%) during angiography. Aberrant right hepatic arteries were identified more frequently than aberrant left hepatic arteries on CT (54 vs. 44%) and during angiography (100 vs. 69%, p = 0.007). In five patients (14%), an aberrant left hepatic artery remained unidentified, resulting in a lack of (99m)Tc-MAA and (90)Y activity in the segmental territory of the unidentified aberrant hepatic arteries. CONCLUSIONS: Aberrant left hepatic arteries were the most common unidentified aberrant hepatic arteries, resulting in incomplete radiation coverage. We formulated a practical approach to identify aberrant hepatic arteries correctly before RE. PMID- 24469410 TI - Live cell cytoplasm staining and selective labeling of intracellular proteins by non-toxic cell-permeant thiophene fluorophores. AB - A structurally correlated series of cell-permeant thiophene fluorophores, characterized by intense green or red fluorescence inside live mouse embryonic fibroblasts, was developed. The fluorophores displayed rapid internalization, excellent retention inside the cells, and high optical stability in the cytosolic environment and did not alter cell viability and reproducibility. Depending on the molecular structure, they experienced distinct fate inside the cells: from bright and lasting staining of the cytoplasm to selective tagging of a small set of globular proteins. PMID- 24469411 TI - The cyclic ground state structure of the HF trimer revealed by far infrared jet cooled Fourier transform spectroscopy. AB - The rovibrationally resolved Fourier transform (FT) far infrared (FIR) spectra of two intermolecular librations of (HF)3, namely the in-plane nu6 and out-of-plane nu4 bending fundamentals centered, respectively, at about 494 cm(-1) and 602 cm( 1), have been recorded for the first time under jet-cooled conditions using the supersonic jet of the Jet-AILES apparatus. The simultaneous rotational analysis of 245 infrared transitions belonging to both bands enabled us to determine the ground state (GS), nu6 and nu4 rotational and centrifugal distortion constants. These results provided definite experimental answers to the structure of such a weakly bound trimer: firstly the vibrationally averaged planarity of cyclic (HF)3, also supported by the very small value of the inertia defect obtained in the GS, secondly the slight weakening of the hydrogen bond in the intermolecular excited states evidenced from the center of mass separations of the HF constituents determined in the ground, nu6 = 1 and nu4 = 1 states of (HF)3 as well as the decrease of the fitted rotational constants upon excitation. Finally, lower bounds of about 2 ns on nu6 and nu4 state lifetimes could be derived from the deconvolution of experimental linewidths. Such long lifetimes highlight the interest in probing low frequency intermolecular motions of molecular complexes to get rid of constraints related to the vibrational dynamics of coupled anharmonic vibrations at higher energy, resulting in loss of rotational information. PMID- 24469412 TI - The influence of dinitrophenol on phloem transport along the stolon of Saxifraga sarmentosa. AB - Dinitrophenol in concentrations of 5*10(-3) M applied to the centre 30 cm of 60 70 cm stolons of Saxifraga produces a strong and reversible inhibition of the phloem transport of (137)Cs or (14)C-assimilates. There is every reason to believe that this effect is localised in the sieve tubes; callose formation does not occur. This evidence is very difficult to reconcile with the Munch hypothesis; it seems on the contrary to demand a theory of active pumping. PMID- 24469413 TI - Sodium transport in Na(+)-rich Chlorella cells. AB - The rate of Na(+)/Na(+) exchange as measured with (24)Na(+) in Na(+)-rich cells of Chlorella pyrenoidosa is governed by a single rate constant and saturates with increasing external Na(+) concentration. The K mvalue for this process is 0.8 mM Na(+) and the maximum rate of exchange in illuminated cells is about 5 pmoles cm( 2) sec(-1). These values contrast with a K mof 0.18 mM K(+) and maximum rate of about 17 pmoles K(+).cm(-2).sec(-1) for net K(+) influx. Although the Na(+)/Na(+) exchange was only slightly sensitive to light it was inhibited by the uncouplers CCCP and DNP and by the energy transfer inhibitor DCCD. This inhibition of the rate of Na(+)/Na(+) exchange was not accompanied by a loss of internal Na(+). Both the effect of external K(+) on (24)Na(+) influx into Na(+)-rich cells and the inhibition of net K(+) uptake by the presence of external Na(+) indicates that Na(+)/Na(+) and K(+)/Na(+) exchanges share the same carrier and that the external site of this carrier has a three to four times higher affinity for K(+) over Na(+). PMID- 24469414 TI - Allelopathic compounds, thelypterin A and B in the fern Thelypteris normalis. AB - The growth of Thelypteris normalis (C. Chr.) Moxley gametophytes is inhibited under T. normalis sporophytes. Competition for minerals, light, change in pH, or microbial inhibitors were experimentally eliminated as causes of the inhibition. This is the first demonstration of allelopathy between a sporophyte and gametophyte in a fern. Two inhibitors, thelypterin A and B, which were released from the roots of the Thelypteris sporophyte, were isolated and a bioassay for the inhibitors was devised. Thelypterin A gave an Ehrlich-positive reaction indicative of secondary aromatic amines and an ultraviolet absorption spectrum indicative of a heterocyclic ring. The inhibitors affected the growth of Thelypteris, Pteris and Phlebodium gametophytes. PMID- 24469415 TI - Production of phytosterols by mature Digitalis purpurea L. plants. AB - The relative rates of production by mature Digitalis purpurea plants of cholesterol, campesterol, stigmasterol and sitosterol isolated from the glycoside and lipid fractions of the plant extract, were estimated. Plants were exposed to an atmosphere of (14)CO2 in a growth chamber and the radioactivity of the individual sterols assessed at intervals over 25 days on a gas-liquid radio chemical chromatography (GLRC). Incorporation of (14)CO2 occurred within 12 hours into both fractions of the extract. The 5-ene sterols were produced at a similar rate over a period of 25 days but the lipid fraction was about 100% more radioactive than the glycoside fraction. PMID- 24469416 TI - Effect of nitrite and nitrate on chlorophyll fluorescence in green algae. AB - The influence of nitrite and nitrate on chlorophyll fluorescence, a very sensitive indicator for the redox state of the primary acceptor of photosystem II of photosynthesis, was studied in green algae (several species of Chlorella, and Ankistrodesmus braunii). In phosphate solution under an atmosphere of nitrogen (i.e., in the absence of O2 and CO2, and without nitrite or nitrate), fluorescence shows a pronounced induction and then rises to a high steady-state level. In the presence of nitrite, however, fluorescence decreases after a rather short induction peak to a much lower steady-state. Nitrate, on the other hand, does not have any influence on either induction or steady-state of fluorescence. These results clearly demonstrate that nitrite reduction in the light is very closely coupled to the photosynthetic electron transport system, whereas nitrate is not reduced photosynthetically in vivo. PMID- 24469417 TI - Studies on nitrite reductase in barley. AB - Nitrite reductase from barley seedlings was purified 50-60 fold by ammonium sulphate precipitation and gel filtration. No differences were established in the characteristics of nitrite reductases isolated in this way from either leaf or root tissues. The root enzyme accepted electrons from reduced methyl viologen, ferredoxin, or an unidentified endogenous cofactor. Enzyme activity in both tissues was markedly increased by growth on nitrate. This activity was not associated with sulphite reductase activity. Microbial contamination could not account for the presence of nitrite reductase activity in roots. Nitrite reductase assayed in vitro with reduced methyl viologen as the electron donor was inhibited by 2,4-dinitrophenol but not by arsenate. PMID- 24469418 TI - The appearance of nitrate reductase activity in nitrogen-starved cells of Ankistrodesmus braunii. AB - Nitrate reductase activity was detectable in ammonium-grown cells of Ankistrodesmus braunii after 50 minutes of nitrogen starvation. The rate of formation of nitrate reductase was stimulated by addition of nitrate and inhibited completely by cycloheximide (20 MUg/ml). Nitrogen-starved cells assimilated added nitrate or nitrite rapidly and no nitrite or nitrate was detectable in either cells or culture medium from cultures subjected to nitrogen starvation. It is concluded that nitrate is not obligatory for the formation of nitrate reductase. PMID- 24469419 TI - [Identification and localisation of tryptophan synthetase in seeds of Juglans regia L]. AB - Cell-free extracts from seeds of Juglans regia synthesize tryptophan from L serine and indole. Tryptophan synthetase has maximal activity in the range between pH 7 and 8. The enzyme is associated with a particulate fraction (density 1,210 g/ml) which is separated from the mitochondria (density 1,191 g/ml) after isopycnic density centrifugation on a continuous sucrose gradient. PMID- 24469420 TI - Transcription and translation for carotenoid synthesis in Chlamydomonas reinhardtii. AB - The sites of transcription and translation of carotenoid pigments were studied in synchronously grown cells of Chlamydomonas reinhardtii Dang. Rifampicin, cycloheximide and spectinomycin were used to distinguish between the nuclear cytoplasmic genetic system and the genetic system of the chloroplast. Since rifampicin is without effect, chloroplast DNA appears not to possess information required for the synthesis of carotenoids. Carotenoid synthesis parallels chlorophyll synthesis in these cells. Carotenoid synthesis is dependent on de novo protein synthesis both on cytoplasmic and chloroplast ribosomes, for both cycloheximide and spectinomycin are effective inhibitors. However, the cells are able to form about 40% of the expected increase in carotenoids when cytoplasmic and chloroplast ribosomes are simultaneously inhibited. Of the major carotenoids in C. reinhardtii, lutein appears the least dependent on de novo protein synthesis. The synthesis of beta-carotene and trollein appears to be completely dependent on the function of cytoplasmic ribosomes. PMID- 24469421 TI - The role of ethylene in the induction of apogamous buds in Pteridium gametophytes. AB - The level of induced apogamy in gametophytic colonies of Pteridium aquilinum (L.) Kuhn is altered by varying the number of colonies per culture vessel or by including a constant number of colonies in culture vessels of different volumes. In either case, placing vials of mercuric perchlorate, an absorber of ethylene, within the closed culture vessels reduced the apogamous response to a very low level. Production of ethylene by the gametophytes was demonstrated by gas chromatography. Ethylene supplied in a continuous-flow system promoted the apogamous response above that of an air control. PMID- 24469422 TI - Effects of different cytokinins on the senescence of detached oat leaves. AB - Senescence is delayed (chlorophyll retained) in oat leaf sections by kinetin and benzyladenine, but not by the natural cytokinins, zeatin and isopentenyladenine. PMID- 24469424 TI - Orbital-selective metal-insulator transition and gap formation above TC in superconducting Rb(1-x)Fe(2-y)Se2. AB - Understanding the origin of high-temperature superconductivity in copper- and iron-based materials is one of the outstanding tasks of current research in condensed matter physics. Even the normal metallic state of these materials exhibits unusual properties. Here we report on a hierarchy of temperatures T(c)42 degrees C were 1.7 +/- 1.4 and 2.6 +/- 1.7 in the oesophageal cooling group and the control group, respectively (P = 0.04), and the maximal oesophageal temperature at those sites was 43.0 +/- 0.6 and 44.7 +/- 0.9 degrees C (P < 0.0001). Oesophageal lesions occurred almost equally between the oesophageal cooling group [10 of 50 patients (20%)] and the control group [11 of 50 patients (22%)]. However, the severity of the oesophageal lesions was slightly milder in the oesophageal cooling group (three moderate, seven mild) than in the control group (three severe, one moderate, seven mild). CONCLUSION: Oesophageal cooling may alleviate the severity of oesophageal lesions but does not reduce the incidence of this complication under the specific protocol evaluated here. PMID- 24469437 TI - Urinary schistosomiasis. AB - Schistosomiasis is the second most common socio-economically devastating parasitic disease after malaria, affecting about 240 million residents of developing countries. In Africa, it predominantly manifests as urogenital disease, and the main infective agent is Schistosoma hematobium. Endemicity is propagated by poor socio-economic status and environmental degradation due to rapid urbanization. Recreational swimming is a potent medium for the spread of disease in children and adolescents. Most affected individuals are asymptomatic. The male and female worms are equipped with an extraordinary capacity for immune evasion and are able to co-habit for several decades within the pelvic venous plexus. Eggs deposited in the bladder wall resist elimination by type 1 T lymphocytes. Instead, they are sustained by pro-fibrogenic encapsulation (as modulated by type 2 helper cells). Progressive bladder disease results in obstructive uropathy and predisposes to (mostly) squamous cell carcinoma. Schistosomal glomerulopathy manifests as a clinical spectrum of asymptomatic proteinuria, nephrosis and/or nephritic syndrome. Findings on renal biopsy may be influenced by co-morbidity with Salmonella bacteria, amyloidosis and hepatitis C infection. Potentially fatal Katayama fever and spinal radiculopathy may ensue in tourists visiting an endemic zone. Early detection by urine microscopy is hampered by low urinary excretion rates of the parasite eggs. Although useful in travelers with newly acquired disease, the results of the serological antibody assay may be false positive in residents of an endemic zone. Cystoscopy, however, may be invaluable. Due to its safety, effectiveness and once-daily dosing, praziquantel is the drug of choice. An integrated approach that includes mass chemotherapy, environmental health programs and public health education is the most cost-effective preventive strategy. PMID- 24469438 TI - Extrarenal sequential organ failure assessment score as an outcome predictor of critically ill children on continuous renal replacement therapy. AB - BACKGROUND: The sequential organ failure assessment (SOFA) score is easy to calculate and has been well validated as an outcome predictor in critically ill adult patients. However, its use in children has been limited, mainly because of differences in basal reference levels of serum creatinine. METHODS: Data include 87 patients requiring continuous renal replacement therapy (CRRT) between January 2005 and July 2011. We modified the SOFA score by excluding the renal component to an extrarenal SOFA score, based on the assumption that CRRT may mitigate the renal effect on outcome and investigated the utility in predicting outcome with comparison with pediatric risk of mortality (PRISM) III, pediatric logistic organ dysfunction (PELOD), and SOFA scores. RESULTS: Results showed that 95.4 % (n = 83) had multiple organ dysfunction syndrome with an overall mortality of 50.6 %. The extrarenal SOFA score at CRRT initiation and >=20 % fluid overload were significantly associated with mortality. In comparison with the predictive power of various scoring systems, the extrarenal SOFA score showed the largest area under the receiver operating characteristic curve (extrarenal SOFA 0.774, SOFA 0.770, PRISM III 0.660, and PELOD 0.650). CONCLUSIONS: The extrarenal SOFA score may be a useful prognostic marker in critically ill children treated with CRRT. PMID- 24469439 TI - Maintenance dialysis in developing countries. AB - Patients with end-stage renal disease require renal replacement therapy with maintenance hemodialysis or chronic peritoneal dialysis while awaiting transplantation. In addition to economic issues and limited state funding for advanced health care, the lack of trained medical personnel contributes to scarce dialysis facilities for children in developing countries. The establishment and operation of a hemodialysis unit with multidisciplinary facilities is both cost- and labor-intensive. Hemodialysis is usually carried out three times a week in a hospital setting and affects the curricular and extracurricular activities of the patient. Chronic ambulatory or cyclic peritoneal dialysis is technically simpler and allows better nutrition and growth, but is expensive for the majority of patients who must pay out of their own pocket. Multiple initiatives to enhance the training of pediatricians and nurses in skills related to initiating and managing patients on maintenance dialysis have resulted in the improved survival of children with end-stage renal disease. Support from state governments and philanthropic institutions have helped in establishing pediatric nephrology units that are equipped to provide renal replacement therapy for children. PMID- 24469440 TI - Simple synthesis, self-assembly, and cytotoxicity of novel dimeric cholesterol derivatives. AB - A simple and economic methodology to synthesize three types of novel dimeric cholesterol derivatives (DCDs) was developed. Results obtained from dynamic light scattering and transmission electron microscopy show that spherical and/or angular nano-structural aggregates of DCDs are formed by self-assembly in aqueous solution. The size and morphology of DCD dispersions depend on the spatial arrangement of the substituents and polarity of the head group in the DCD structures. The cytoxicity of DCD dispersions to human keratinocytes (HaCaT) and squamous cell carcinomas (SCC25) cells was also evaluated by a 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The present novel DCD dispersions were not toxic to HaCaT and SCC25 cells at appropriate tested concentrations. PMID- 24469441 TI - A systematic study of chemogenomics of carbohydrates. AB - Chemogenomics focuses on the interactions between biologically active molecules and protein targets for drug discovery. Carbohydrates are the most abundant compounds in natural products. Compared with other drugs, the carbohydrate drugs show weaker side effects. Searching for multi-target carbohydrate drugs can be regarded as a solution to improve therapeutic efficacy and safety. In this work, we collected 60 344 carbohydrates from the Universal Natural Products Database (UNPD) and explored the chemical space of carbohydrates by principal component analysis. We found that there is a large quantity of potential lead compounds among carbohydrates. Then we explored the potential of carbohydrates in drug discovery by using a network-based multi-target computational approach. All carbohydrates were docked to 2389 target proteins. The most potential carbohydrates for drug discovery and their indications were predicted based on a docking score-weighted prediction model. We also explored the interactions between carbohydrates and target proteins to find the pathological networks, potential drug candidates and new indications. PMID- 24469442 TI - Attitudes about internet support groups among adolescents and young adults with neurofibromatosis type 1 and their parents. AB - Youth with neurofibromatosis type 1 (NF1) have multiple, complex symptoms associated with physical, social-emotional, and cognitive difficulties. In addition, caring for a child with NF1 can be extremely challenging for parents. Since research with other chronic illness populations suggests that social support, including internet support groups (ISGs), can be beneficial, this survey study aimed to determine the attitudes and preferences of adolescents and young adults with NF1 and parents of a child with NF1 regarding ISGs. Thirty patients and 30 caregivers completed a 24-item survey about ISGs. Many patients and parents are not aware of any ISGs for NF1, but are interested in using one in the future for a variety of reasons, including to get answers to their questions about NF1, to find out about research studies, and to discuss problems and concerns about NF1. Specific concerns of interest include physical, social emotional, and cognitive aspects of NF1. ISGs have potential as a social support intervention within the NF1 community. ISGs for the NF1 population should include patients with NF1 (or parents of children with NF1) as well as a health professional, and both chat rooms and discussion boards likely would be well received. PMID- 24469443 TI - Adapting genetic counseling training to the genomic era: more an evolution than a revolution. PMID- 24469444 TI - Structural insights into neonatal Fc receptor-based recycling mechanisms. AB - We report the three-dimensional structure of human neonatal Fc receptor (FcRn) bound concurrently to its two known ligands. More particularly, we solved the crystal structure of the complex between human FcRn, wild-type human serum albumin (HSA), and a human Fc engineered for improved pharmacokinetics properties (Fc-YTE). The crystal structure of human FcRn bound to wild-type HSA alone is also presented. HSA domain III exhibits an extensive interface of contact with FcRn, whereas domain I plays a lesser role. A molecular explanation for the HSA recycling mechanism is provided with the identification of FcRn His(161) as the only potential direct contributor to the corresponding pH-dependent process. At last, this study also allows an accurate structural definition of residues considered for decades as important to the human IgG/FcRn interaction and reveals Fc His(310) as a significant contributor to pH-dependent binding. Finally, we explain various structural mechanisms by which several Fc mutations (including YTE) result in increased human IgG binding to FcRn. Our study provides an unprecedented relevant understanding of the molecular basis of human Fc interaction with human FcRn. PMID- 24469445 TI - Mechanistic strategies for catalysis adopted by evolutionary distinct family 43 arabinanases. AB - Arabinanases (ABNs, EC 3.2.1.99) are promising catalysts for environmentally friendly biomass conversion into energy and chemicals. These enzymes catalyze the hydrolysis of the alpha-1,5-linked L-arabinofuranoside backbone of plant cell wall arabinans releasing arabino-oligosaccharides and arabinose, the second most abundant pentose in nature. In this work, new findings about the molecular mechanisms governing activation, functional differentiation, and catalysis of GH43 ABNs are presented. Biophysical, mutational, and biochemical studies with the hyperthermostable two-domain endo-acting ABN from Thermotoga petrophila (TpABN) revealed how some GH43 ABNs are activated by calcium ions via hyperpolarization of the catalytically relevant histidine and the importance of the ancillary domain for catalysis and conformational stability. On the other hand, the two GH43 ABNs from rumen metagenome, ARN2 and ARN3, presented a calcium independent mechanism in which sodium is the most likely substituent for calcium ions. The crystal structure of the two-domain endo-acting ARN2 showed that its ability to efficiently degrade branched substrates is due to a larger catalytic interface with higher accessibility than that observed in other ABNs with preference for linear arabinan. Moreover, crystallographic characterization of the single-domain exo-acting ARN3 indicated that its cleavage pattern producing arabinose is associated with the chemical recognition of the reducing end of the substrate imposed by steric impediments at the aglycone-binding site. By structure-guided rational design, ARN3 was converted into a classical endo enzyme, confirming the role of the extended Arg(203)-Ala(230) loop in determining its action mode. These results reveal novel molecular aspects concerning the functioning of GH43 ABNs and provide new strategies for arabinan degradation. PMID- 24469446 TI - Periostin induces intracellular cross-talk between kinases and hyaluronan in atrioventricular valvulogenesis. AB - Periostin (PN), a novel fasciclin-related matricellular protein, has been implicated in cardiac development and postnatal remodeling, but the mechanism remains unknown. We examined the role of PN in mediating intracellular kinase activation for atrioventricular valve morphogenesis using well defined explant cultures, gene transfection systems, and Western blotting. The results show that valve progenitor (cushion) cells secrete PN into the extracellular matrix, where it can bind to INTEGRINs and activate INTEGRIN/focal adhesion kinase signaling pathways and downstream kinases, PI3K/AKT and ERK. Functional assays with prevalvular progenitor cells showed that activating these signaling pathways promoted adhesion, migration, and anti-apoptosis. Through activation of PI3K/ERK, PN directly enhanced collagen expression. Comparing PN-null to WT mice also revealed that expression of hyaluronan (HA) and activation of hyaluronan synthase 2 (Has2) are also enhanced upon PN/INTEGRIN/focal adhesion kinase-mediated activation of PI3K and/or ERK, an effect confirmed by the reduction of HA synthase-2 in PN-null mice. We also identified in valve progenitor cells a potential autocrine signaling feedback loop between PN and HA through PI3K and/or ERK. Finally, in a three-dimensional assay to simulate normal valve maturation in vitro, PN promoted collagen compaction in a kinase-dependent fashion. In summary, this study provides the first direct evidence that PN can act to stimulate a valvulogenic signaling pathway. PMID- 24469447 TI - Cortactin scaffolds Arp2/3 and WAVE2 at the epithelial zonula adherens. AB - Cadherin junctions arise from the integrated action of cell adhesion, signaling, and the cytoskeleton. At the zonula adherens (ZA), a WAVE2-Arp2/3 actin nucleation apparatus is necessary for junctional tension and integrity. But how this is coordinated with cadherin adhesion is not known. We now identify cortactin as a key scaffold for actin regulation at the ZA, which localizes to the ZA through influences from both E-cadherin and N-WASP. Using cell-free protein expression and fluorescent single molecule coincidence assays, we demonstrate that cortactin binds directly to the cadherin cytoplasmic tail. However, its concentration with cadherin at the apical ZA also requires N-WASP. Cortactin is known to bind Arp2/3 directly (Weed, S. A., Karginov, A. V., Schafer, D. A., Weaver, A. M., Kinley, A. W., Cooper, J. A., and Parsons, J. T. (2000) J. Cell Biol. 151, 29-40). We further show that cortactin can directly bind WAVE2, as well as Arp2/3, and both these interactions are necessary for actin assembly at the ZA. We propose that cortactin serves as a platform that integrates regulators of junctional actin assembly at the ZA. PMID- 24469448 TI - Critical roles for Rictor/Sin1 complexes in interferon-dependent gene transcription and generation of antiproliferative responses. AB - We provide evidence that type I IFN-induced STAT activation is diminished in cells with targeted disruption of the Rictor gene, whose protein product is a key element of mTOR complex 2. Our studies show that transient or stable knockdown of Rictor or Sin1 results in defects in activation of elements of the STAT pathway and reduced STAT-DNA binding complexes. This leads to decreased expression of several IFN-inducible genes that mediate important biological functions. Our studies also demonstrate that Rictor and Sin1 play essential roles in the generation of the suppressive effects of IFNalpha on malignant erythroid precursors from patients with myeloproliferative neoplasms. Altogether, these findings provide evidence for critical functions for Rictor/Sin1 complexes in type I IFN signaling and the generation of type I IFN antineoplastic responses. PMID- 24469449 TI - Transcription of the SCL/TAL1 interrupting Locus (Stil) is required for cell proliferation in adult Zebrafish Retinas. AB - The human oncogene SCL/TAL1 interrupting locus (Stil) is highly conserved in vertebrate species. Previously, we identified a homolog of the Stil gene in zebrafish mutant (night blindness b, nbb), which showed neural defects in the retina (e.g. dopaminergic cell degeneration and/or lack of regeneration). In this research, we examined the roles of Stil in cell proliferation after degeneration in adult zebrafish retinas. We demonstrated that knockdown of Stil gene expression or inhibition of Sonic hedgehog (Shh) signaling transduction decreases the rate of cell proliferation. In contrast, activation of Shh signal transduction promotes cell proliferation. In nbb(+/-) retinas, inhibition of SUFU (a repressor in the Shh pathway) rescues the defects in cell proliferation due to down-regulation of Stil gene expression. The latter data suggest that Stil play a role in cell proliferation through the Shh signal transduction pathway. PMID- 24469450 TI - Isoform- and species-specific control of inositol 1,4,5-trisphosphate (IP3) receptors by reactive oxygen species. AB - Reactive oxygen species (ROS) stimulate cytoplasmic [Ca(2+)] ([Ca(2+)]c) signaling, but the exact role of the IP3 receptors (IP3R) in this process remains unclear. IP3Rs serve as a potential target of ROS produced by both ER and mitochondrial enzymes, which might locally expose IP3Rs at the ER-mitochondrial associations. Also, IP3Rs contain multiple reactive thiols, common molecular targets of ROS. Therefore, we have examined the effect of superoxide anion (O2) on IP3R-mediated Ca(2+) signaling. In human HepG2, rat RBL-2H3, and chicken DT40 cells, we observed [Ca(2+)]c spikes and frequency-modulated oscillations evoked by a O2 donor, xanthine (X) + xanthine oxidase (XO), dose-dependently. The [Ca(2+)]c signal was mediated by ER Ca(2+) mobilization. X+XO added to permeabilized cells promoted the [Ca(2+)]c rise evoked by submaximal doses of IP3, indicating that O2 directly sensitizes IP3R-mediated Ca(2+) release. In response to X+XO, DT40 cells lacking two of three IP3R isoforms (DKO) expressing either type 1 (DKO1) or type 2 IP3Rs (DKO2) showed a [Ca(2+)]c signal, whereas DKO expressing type 3 IP3R (DKO3) did not. By contrast, IgM that stimulates IP3 formation, elicited a [Ca(2+)]c signal in every DKO. X+XO also facilitated the Ca(2+) release evoked by submaximal IP3 in permeabilized DKO1 and DKO2 but was ineffective in DKO3 or in DT40 lacking every IP3R (TKO). However, X+XO could also facilitate the effect of suboptimal IP3 in TKO transfected with rat IP3R3. Although in silico studies failed to identify a thiol missing in the chicken IP3R3, an X+XO-induced redox change was documented only in the rat IP3R3. Thus, ROS seem to specifically sensitize IP3Rs through a thiol group(s) within the IP3R, which is probably inaccessible in the chicken IP3R3. PMID- 24469451 TI - A novel structural unit in the N-terminal region of filamins. AB - Immunoglobulin-like (Ig) domains are a widely expanded superfamily that act as interaction motifs or as structural spacers in multidomain proteins. Vertebrate filamins (FLNs), which are multifunctional actin-binding proteins, consist of 24 Ig domains. We have recently discovered that in the C-terminal rod 2 region of FLN, Ig domains interact with each other forming functional domain pairs, where the interaction with signaling and transmembrane proteins is mechanically regulated by weak actomyosin contraction forces. Here, we investigated if there are similar inter-domain interactions around domain 4 in the N-terminal rod 1 region of FLN. Protein crystal structures revealed a new type of domain organization between domains 3, 4, and 5. In this module, domains 4 and 5 interact rather tightly, whereas domain 3 has a partially flexible interface with domain 4. NMR peptide titration experiments showed that within the three-domain module, domain 4 is capable for interaction with a peptide derived from platelet glycoprotein Ib. Crystal structures of FLN domains 4 and 5 in complex with the peptide revealed a typical beta sheet augmentation interaction observed for many FLN ligands. Domain 5 was found to stabilize domain 4, and this could provide a mechanism for the regulation of domain 4 interactions. PMID- 24469452 TI - F-box only protein 2 (Fbxo2) regulates amyloid precursor protein levels and processing. AB - The amyloid precursor protein (APP) is an integral membrane glycoprotein whose cleavage products, particularly amyloid-beta, accumulate in Alzheimer disease (AD). APP is present at synapses and is thought to play a role in both the formation and plasticity of these critical neuronal structures. Despite the central role suggested for APP in AD pathogenesis, the mechanisms regulating APP in neurons and its processing into cleavage products remain incompletely understood. F-box only protein 2 (Fbxo2), a neuron-enriched ubiquitin ligase substrate adaptor that preferentially binds high-mannose glycans on glycoproteins, was previously implicated in APP processing by facilitating the degradation of the APP-cleaving beta-secretase, beta-site APP-cleaving enzyme. Here, we sought to determine whether Fbxo2 plays a similar role for other glycoproteins in the amyloid processing pathway. We present in vitro and in vivo evidence that APP is itself a substrate for Fbxo2. APP levels were decreased in the presence of Fbxo2 in non-neuronal cells, and increased in both cultured hippocampal neurons and brain tissue from Fbxo2 knock-out mice. The processing of APP into its cleavage products was also increased in hippocampi and cultured hippocampal neurons lacking Fbxo2. In hippocampal slices, this increase in cleavage products was accompanied by a significant reduction in APP at the cell surface. Taken together, these results suggest that Fbxo2 regulates APP levels and processing in the brain and may play a role in modulating AD pathogenesis. PMID- 24469453 TI - Glucose-dependent de novo lipogenesis in B lymphocytes: a requirement for atp citrate lyase in lipopolysaccharide-induced differentiation. AB - Bacterially derived lipopolysaccharide (LPS) stimulates naive B lymphocytes to differentiate into immunoglobulin (Ig)-secreting plasma cells. Differentiation of B lymphocytes is characterized by a proliferative phase followed by expansion of the intracellular membrane secretory network to support Ig production. A key question in lymphocyte biology is how naive B cells reprogram metabolism to support de novo lipogenesis necessary for proliferation and expansion of the endomembrane network in response to LPS. We report that extracellularly acquired glucose is metabolized, in part, to support de novo lipogenesis in response to LPS stimulation of splenic B lymphocytes. LPS stimulation leads to increased levels of endogenous ATP-citrate lyase (ACLY), and this is accompanied by increased ACLY enzymatic activity. ACLY produces cytosolic acetyl-CoA from mitochondrially derived citrate. Inhibition of ACLY activity in LPS-stimulated B cells with the selective inhibitor 2-hydroxy-N-arylbenzenesulfonamide (compound 9; C-9) blocks glucose incorporation into de novo lipid biosynthesis, including cholesterol, free fatty acids, and neutral and acidic phospholipids. Moreover, inhibition of ACLY activity in splenic B cells results in inhibition of proliferation and defective endomembrane expansion and reduced expression of CD138 and Blimp-1, markers for plasma-like B cell differentiation. ACLY activity is also required for LPS-induced IgM production in CH12 B lymphoma cells. These data demonstrate that ACLY mediates glucose-dependent de novo lipogenesis in response to LPS signaling and identify a role for ACLY in several phenotypic changes that define plasma cell differentiation. PMID- 24469454 TI - Modulation of ten-eleven translocation 1 (TET1), Isocitrate Dehydrogenase (IDH) expression, alpha-Ketoglutarate (alpha-KG), and DNA hydroxymethylation levels by interleukin-1beta in primary human chondrocytes. AB - 5-Hydroxymethylcytosine (5-hmC) generated by ten-eleven translocation 1-3 (TET1 3) enzymes is an epigenetic mark present in many tissues with different degrees of abundance. IL-1beta and TNF-alpha are the two major cytokines present in arthritic joints that modulate the expression of many genes associated with cartilage degradation in osteoarthritis. In the present study, we investigated the global 5-hmC content, the effects of IL-1beta and TNF-alpha on 5-hmC content, and the expression and activity of TETs and isocitrate dehydrogenases in primary human chondrocytes. The global 5-hmC content was found to be ~0.1% of the total genome. There was a significant decrease in the levels of 5-hmC and the TET enzyme activity upon treatment of chondrocytes with IL-1beta alone or in combination with TNF-alpha. We observed a dramatic (10-20-fold) decrease in the levels of TET1 mRNA expression and a small increase (2-3-fold) in TET3 expression in chondrocytes stimulated with IL-1beta and TNF-alpha. IL-1beta and TNF-alpha significantly suppressed the activity and expression of IDHs, which correlated with the reduced alpha-ketoglutarate levels. Whole genome profiling showed an erasure effect of IL-1beta and TNF-alpha, resulting in a significant decrease in hydroxymethylation in a myriad of genes including many genes that are important in chondrocyte physiology. Our data demonstrate that DNA hydroxymethylation is modulated by pro-inflammatory cytokines via suppression of the cytosine hydroxymethylation machinery. These data point to new mechanisms of epigenetic control of gene expression by pro-inflammatory cytokines in human chondrocytes. PMID- 24469455 TI - An extended active-site motif controls the reactivity of the thioredoxin fold. AB - Proteins belonging to the thioredoxin (Trx) superfamily are abundant in all organisms. They share the same structural features, arranged in a seemingly simple fold, but they perform a multitude of functions in oxidative protein folding and electron transfer pathways. We use the C-terminal domain of the unique transmembrane reductant conductor DsbD as a model for an in-depth analysis of the factors controlling the reactivity of the Trx fold. We employ NMR spectroscopy, x-ray crystallography, mutagenesis, in vivo functional experiments applied to DsbD, and a comparative sequence analysis of Trx-fold proteins to determine the effect of residues in the vicinity of the active site on the ionization of the key nucleophilic cysteine of the -CXXC- motif. We show that the function and reactivity of Trx-fold proteins depend critically on the electrostatic features imposed by an extended active-site motif. PMID- 24469456 TI - Functional characterization of drim2, the Drosophila melanogaster homolog of the yeast mitochondrial deoxynucleotide transporter. AB - The CG18317 gene (drim2) is the Drosophila melanogaster homolog of the Saccharomyces cerevisiae Rim2 gene, which encodes a pyrimidine (deoxy)nucleotide carrier. Here, we tested if the drim2 gene also encodes for a deoxynucleotide transporter in the fruit fly. The protein was localized to mitochondria. Drosophila S2R(+) cells, silenced for drim2 expression, contained markedly reduced pools of both purine and pyrimidine dNTPs in mitochondria, whereas cytosolic pools were unaffected. In vivo drim2 homozygous knock-out was lethal at the larval stage, preceded by the following: (i) impaired locomotor behavior; (ii) decreased rates of oxygen consumption, and (iii) depletion of mtDNA. We conclude that the Drosophila mitochondrial carrier dRIM2 transports all DNA precursors and is essential to maintain mitochondrial function. PMID- 24469457 TI - Perturbations of the straight transmembrane alpha-helical structure of the amyloid precursor protein affect its processing by gamma-secretase. AB - The amyloid precursor protein (APP) is a widely expressed type I transmembrane (TM) glycoprotein present at the neuronal synapse. The proteolytic cleavage by gamma-secretase of its C-terminal fragment produces amyloid-beta (Abeta) peptides of different lengths, the deposition of which is an early indicator of Alzheimer disease. At present, there is no consensus on the conformation of the APP-TM domain at the biological membrane. Although structures have been determined by NMR in detergent micelles, their conformation is markedly different. Here we show by using molecular simulations that the APP-TM region systematically prefers a straight alpha-helical conformation once embedded in a membrane bilayer. However, APP-TM is highly flexible, and its secondary structure is strongly influenced by the surrounding lipid environment, as when enclosed in detergent micelles. This behavior is confirmed when analyzing in silico the atomistic APP-TM population observed by residual dipolar couplings and double electron-electron resonance spectroscopy. These structural and dynamic features are critical in the proteolytic processing of APP by the gamma-secretase enzyme, as suggested by a series of Gly(700) mutants. Affecting the hydration and flexibility of APP-TM, these mutants invariantly show an increase in the production of Abeta38 compared with Abeta40 peptides, which is reminiscent of the effect of gamma-secretase modulators inhibitors. PMID- 24469458 TI - The mineralocorticoid receptor promotes fibrotic remodeling in atrial fibrillation. AB - We studied the role of the mineralocorticoid receptor (MR) in the signaling that promotes atrial fibrosis. Left atrial myocardium of patients with atrial fibrillation (AF) exhibited 4-fold increased hydroxyproline content compared with patients in sinus rhythm. Expression of MR was similar, as was 11beta hydroxysteroid dehydrogenase type 2 (11beta-HSD2), which also increased. 11beta HSD2 converts cortisol to receptor-inactive metabolites allowing aldosterone occupancy of MR. 11beta-HSD2 was up-regulated by arrhythmic pacing in cultured cardiomyocytes and in a mouse model of spontaneous AF (RacET). In cardiomyocytes, aldosterone induced connective tissue growth factor (CTGF) in the absence but not in the presence of cortisol. Hydroxyproline expression was increased in cardiac fibroblasts exposed to conditioned medium from aldosterone-treated cardiomyocytes but not from cardiomyocytes treated with both cortisol and aldosterone. Aldosterone increased connective tissue growth factor and hydroxyproline expression in cardiac fibroblasts, which were prevented by BR-4628, a dihydropyridine-derived selective MR antagonist, and by spironolactone. Aldosterone activated RhoA GTPase. Rho kinase inhibition by Y-27632 prevented CTGF and hydroxyproline, whereas the RhoA activator CN03 increased CTGF expression. Aldosterone and CTGF increased lysyl oxidase, and aldosterone enhanced miR-21 expression. MR antagonists reduced the aldosterone but not the CTGF effect. In conclusion, MR signaling promoted fibrotic remodeling. Increased expression of 11beta-HSD2 during AF leads to up-regulation of collagen and pro fibrotic mediators by aldosterone, specifically RhoA activity as well as CTGF, lysyl oxidase, and microRNA-21 expression. The MR antagonists BR-4628 and spironolactone prevent these alterations. MR inhibition may, therefore, represent a potential pharmacologic target for the prevention of fibrotic remodeling of the atrial myocardium. PMID- 24469459 TI - Insulin-like growth factor-1 increases synthesis of collagen type I via induction of the mRNA-binding protein LARP6 expression and binding to the 5' stem-loop of COL1a1 and COL1a2 mRNA. AB - Collagen content in atherosclerotic plaque is a hallmark of plaque stability. Our earlier studies showed that insulin-like growth factor-1 (IGF-1) increases collagen content in atherosclerotic plaques of Apoe(-/-) mice. To identify mechanisms we investigated the effect of IGF-1 on the la ribonucleoprotein domain family member 6 (LARP6). LARP6 binds a stem-loop motif in the 5'-UTR of the mRNAs encoding the collagen type I alpha-subunits (alpha1(I) and alpha2(I)), and coordinates their translation into the heterotrimeric collagen type I molecule. In human aortic smooth muscle cells (SMCs), IGF-1 rapidly increased LARP6 expression and the rate of collagen synthesis and extracellular accumulation. IGF 1 increased both LARP6 and collagen type I expression via a post-transcriptional and translation-dependent mechanism involving PI3K/Akt/p70S6k-signaling. Immunoprecipitation of LARP6, followed by qPCR indicated that IGF-1 increased the level of COL1a1 and COL1a2 mRNA bound to LARP6. Mutation of the 5' stem-loop of Col1a1 mRNA, which inhibits binding of LARP6, abolished the ability of IGF-1 to increase synthesis of collagen type I. Furthermore, overexpression of a 5' stem loop RNA molecular decoy that sequesters LARP6, prevented the ability of IGF-1 to increase pro-alpha1(I) and mature alpha1(I) expression in cultured medium. IGF-1 infusion in Apoe(-/-) mice increased expression of LARP6 and pro-alpha1(I) in aortic lysates, and SMC-specific IGF-1-overexpression robustly increased collagen fibrillogenesis in atherosclerotic plaque. In conclusion, we identify LARP6 as a critical mediator by which IGF-1 augments synthesis of collagen type I in vascular smooth muscle, which may play an important role in promoting atherosclerotic plaque stability. PMID- 24469460 TI - Nitration of tyrosine 247 inhibits protein kinase G-1alpha activity by attenuating cyclic guanosine monophosphate binding. AB - The cGMP-dependent protein kinase G-1alpha (PKG-1alpha) is a downstream mediator of nitric oxide and natriuretic peptide signaling. Alterations in this pathway play a key role in the pathogenesis and progression of vascular diseases associated with increased vascular tone and thickness, such as pulmonary hypertension. Previous studies have shown that tyrosine nitration attenuates PKG 1alpha activity. However, little is known about the mechanisms involved in this event. Utilizing mass spectrometry, we found that PKG-1alpha is susceptible to nitration at tyrosine 247 and 425. Tyrosine to phenylalanine mutants, Y247F- and Y425F-PKG-1alpha, were both less susceptible to nitration than WT PKG-1alpha, but only Y247F-PKG-1alpha exhibited preserved activity, suggesting that the nitration of Tyr(247) is critical in attenuating PKG-1alpha activity. The overexpression of WT- or Y247F-PKG-1alpha decreased the proliferation of pulmonary artery smooth muscle cells (SMC), increased the expression of SMC contractile markers, and decreased the expression of proliferative markers. Nitrosative stress induced a switch from a contractile to a synthetic phenotype in cells expressing WT- but not Y247F-PKG-1alpha. An antibody generated against 3-NT-Y247 identified increased levels of nitrated PKG-1alpha in humans with pulmonary hypertension. Finally, to gain a more mechanistic understanding of how nitration attenuates PKG activity, we developed a homology model of PKG-1alpha. This model predicted that the nitration of Tyr(247) would decrease the affinity of PKG-1alpha for cGMP, which we confirmed using a [(3)H]cGMP binding assay. Our study shows that the nitration of Tyr(247) and the attenuation of cGMP binding is an important mechanism regulating in PKG-1alpha activity and SMC proliferation/differentiation. PMID- 24469461 TI - Naphthoquinone-mediated inhibition of lysine acetyltransferase KAT3B/p300, basis for non-toxic inhibitor synthesis. AB - Hydroxynaphthoquinone-based inhibitors of the lysine acetyltransferase KAT3B (p300), such as plumbagin, are relatively toxic. Here, we report that free thiol reactivity and redox cycling properties greatly contribute to the toxicity of plumbagin. A reactive 3rd position in the naphthoquinone derivatives is essential for thiol reactivity and enhances redox cycling. Using this clue, we synthesized PTK1, harboring a methyl substitution at the 3rd position of plumbagin. This molecule loses its thiol reactivity completely and its redox cycling ability to a lesser extent. Mechanistically, non-competitive, reversible binding of the inhibitor to the lysine acetyltransferase (KAT) domain of p300 is largely responsible for the acetyltransferase inhibition. Remarkably, the modified inhibitor PTK1 was a nearly non-toxic inhibitor of p300. The present report elucidates the mechanism of acetyltransferase activity inhibition by 1,4 naphthoquinones, which involves redox cycling and nucleophilic adduct formation, and it suggests possible routes of synthesis of the non-toxic inhibitor. PMID- 24469462 TI - Thermal and solvent effects on the triplet formation in cinnoline. AB - Cinnoline (1,2-diazanaphthalene) is of particular interest among the diazanaphthalenes. Its triplet quantum yield upon photoexcitation depends strongly on the temperature and the solvent environment. At the beginning of this study, the properties of the lowest triplet electronic state were not understood either. To elucidate the photophysics of cinnoline, we implemented algorithms based on the time-dependent approach for calculating intersystem crossing rates and one-photon spectra of thermally equilibrated vibronic levels. Our quantum chemical investigations reveal that the triplet formation in hydrocarbon solutions at low temperatures is an El-Sayed forbidden process. At higher temperatures and in hydroxylic solutions an additional El-Sayed allowed channel opens up, increasing the intersystem crossing rate substantially. Furthermore, we have solved the old puzzle concerning the character of the lowest triplet state of cinnoline. In the gas phase the electronic structure has mainly npi* character with additional contributions from pipi* configurations since the nuclear arrangement in the pyridazine ring is not planar. In hydroxylic solvents, the electronic structure of the T1 state is altered. The simulation of the triplet emission shows that the experimentally observed phosphorescence of cinnoline in ethanol most certainly stems from the (3)(pipi*) emission. PMID- 24469463 TI - pH and thermo-responsive tetronic micelles for the synthesis of gold nanoparticles: effect of physiochemical aspects of tetronics. AB - Micelles of the star shaped block polymers "tetronics" were employed for the synthesis of gold (Au) nanoparticles (NPs) under the effect of pH and temperature variation. The presence of the diamine core in the tetronic macromolecule made its micelles highly pH responsive, thereby dramatically altering the physiochemical properties. Likewise, a high degree of hydration made the micelles temperature sensitive. UV-visible studies, transmission electron microscopy (TEM), gel electrophoresis, and structure optimization by energy minimization were applied to understand the physiochemical aspects of tetronic micelles and their further role in the synthesis of Au NPs. Synthesis of Au NPs was triggered by the surface cavities of the micelles and hence the NPs simultaneously adsorbed on the micelle surface. Low pH induced high hydration and temperature responsive well defined vesicular morphologies bearing Au NPs, while high pH produced mainly large and compact compound micelles carrying NPs. Both pH and temperature responsive behaviors of different tetronics significantly influenced the synthesis of Au NPs and thus demonstrated their ability to act as nanoreactors for the materials synthesis under different experimental conditions. PMID- 24469464 TI - Recombinant lentivirus targeting the pleotrophin gene reduces pleotrophin protein expression in pancreatic cancer cells and inhibits neurite outgrowth of dorsal root ganglion neurons. AB - The objectives of the present study were to construct the recombinant primate lentivirus-short hairpin RNA-pleiotrophin (pLV-shRNA-PTN) vector, to investigate the silencing effect of pLV-shRNA-PTN on PTN expression in MIA PaCa-2 cells and to observe the inhibition efficiency of pLV-shRNA-PTN on neurite outgrowth from dorsal root ganglion (DRG) neurons in vitro. The construction procedure for recombinant lentivirus pLV-shRNA-PTN has been described previously. In the present study, pLV-shRNA-PTN was used to infect MIA PaCa-2 pancreatic cancer cells and the efficiency of the knockdown of the PTN gene on day 7 following infection was analyzed using western blotting. The morphological changes in the cultured DRG neurons were observed by monoculture of DRG neurons and co-culture with MIA PaCa-2 cells in vitro. The recombinant lentivirus pLV-shRNA-PTN was successfully constructed. The western blot analysis showed that the inhibition rates of PTN expression were 46, 80, 20 and 21%, respectively, following pLV shRNA-PTN-A, B, C and D infection. pLV-shRNA-PTN-B showed the highest knockdown efficiency. DRG neurons co-cultured with infected MIA PaCa-2 cells were decreased in size when compared with the control, and there was a significant decrease in the number and length of neurites. The results suggest that efficient and specific knockdown of PTN in MIA PaCa-2 pancreatic cancer cells and the subsequent reduction in PTN expression results in the inhibition of neurite outgrowth from DRG neurons. PMID- 24469465 TI - Complete sequence and phylogenetic analysis of a porcine bocavirus strain swBoV CH437. AB - Porcine bocavirus (PBoV), a member of genus Bocavirus, family Parvoviridae, was first identified in 2009 in Swedish swine herds suffering from postweaning multisystemic wasting syndrome. Up to date, the different species of PBoVs have been reported in different countries. Especially, the virus isolated in China was complicated. In this study, we detected a novel PBoV strain swBoV CH437 from clinical samples collected in Gansu Province, Northwest China. The complete genome of swBoV CH437 was 5,275 nucleotides (nt) in length and contains three ORFs: ORF1 encodes NS1 (2,004 nt, 667 aa), ORF3 encodes NP1 (681 nt, 226 aa), and ORF2 encodes VP1 (2,049 nt, 682 aa) and VP2 (1,641 nt, 546 aa). Sequence analysis demonstrated that the NS1 gene shared 24.2-88.6 % nucleotide sequence identity, the NP1 shared 21.3-89.9 %, less than 95 % nucleotide sequence identity with other PBoV strains. Therefore, we propose that swBoV CH437 should be classified as a novel PBoV species. PMID- 24469466 TI - Susceptibility of muridae cell lines to ecotropic murine leukemia virus and the cationic amino acid transporter 1 viral receptor sequences: implications for evolution of the viral receptor. AB - Ecotropic murine leukemia viruses (Eco-MLVs) infect mouse and rat, but not other mammalian cells, and gain access for infection through binding the cationic amino acid transporter 1 (CAT1). Glycosylation of the rat and hamster CAT1s inhibits Eco-MLV infection, and treatment of rat and hamster cells with a glycosylation inhibitor, tunicamycin, enhances Eco-MLV infection. Although the mouse CAT1 is also glycosylated, it does not inhibit Eco-MLV infection. Comparison of amino acid sequences between the rat and mouse CAT1s shows amino acid insertions in the rat protein near the Eco-MLV-binding motif. In addition to the insertion present in the rat CAT1, the hamster CAT1 has additional amino acid insertions. In contrast, tunicamycin treatment of mink and human cells does not elevate the infection, because their CAT1s do not have the Eco-MLV-binding motif. To define the evolutionary pathway of the Eco-MLV receptor, we analyzed CAT1 sequences and susceptibility to Eco-MLV infection of other several murinae animals, including the southern vole (Microtus rossiaemeridionalis), large Japanese field mouse (Apodemus speciosus), and Eurasian harvest mouse (Micromys minutus). Eco-MLV infection was enhanced by tunicamycin in these cells, and their CAT1 sequences have the insertions like the hamster CAT1. Phylogenetic analysis of mammalian CAT1s suggested that the ancestral CAT1 does not have the Eco-MLV-binding motif, like the human CAT1, and the mouse CAT1 is thought to be generated by the amino acid deletions in the third extracellular loop of CAT1. PMID- 24469467 TI - Molecular evolution of H9N2 avian influenza viruses in Israel. AB - While the previous phylogenetic analyses of AIV H9N2 in Israel had mainly focused on phylogenetics and on describing different virus introductions into the country, for the first time, the H9N2-HA gene evolutionary history has been examined taking into account its origin, evolution and phylodynamics. The present study reveals the Israeli H9N2 molecular evolution rate, the virus molecular clock and skyline plot. The molecular skyline plot showed two major increments in population diversity sizes, the first which had occurred in 2003, the second between the end of 2007 and the first half of 2008. Between 2004 and 2007 the population size had proved to be constant. The two peaks correspond to the appearance of the 3rd and 4th major genetic groups, as well as to the introduction of two H9N2 vaccines. The mean evolution rate was 6.123 E-3 substitutions/site/year, typical of avian influenza viruses. The time interval from the most recent common ancestor was 12.3 years, corresponding to the year 2000, when H9N2 was first isolated in Israel. PMID- 24469468 TI - Modulation of expression in BEAS-2B airway epithelial cells of alpha-L-fucosidase A1 and A2 by Th1 and Th2 cytokines, and overexpression of alpha-L-fucosidase 2. AB - Chronic Th2-driven airway inflammation with excessive mucus production occurs in asthma. The regulation of FUCA1 and FUCA2 gene expression and enzyme activity in response to asthma-associated Th2 cytokines and, for contrast, Th1 cytokine IFN gamma, were investigated in a human airway cell line. BEAS-2B cells were supplemented with Th2-derived cytokines (IL-13, IL-4, IL-5) or/and IFN-gamma. RNA and cell supernatants from stimulated and unstimulated cells were collected over a period of 3 h. Alpha-L-fucosidase A1 and A2 gene expression were assessed using real time RT-PCR, while enzymatic activities were measured using a fluorescent assay. To characterise alpha-L-fucosidase A2, CHO-K1 and BEAS-2B cell lines were transiently transfected, the FUCA2 gene was overexpressed, and the protein was immunoprecipitated. The transcription of FUCA1 was upregulated (p < 0.01) in response to IFN-gamma, suggesting that FUCA1 transcription and fucosidase activity are regulated in a Th1-dependent manner. The gene expression was the highest for 30 min after IFN-gamma stimulation (>twofold induction), whereas secreted enzyme activity in BEAS-2B cells was significantly increased 1 h after IFN-gamma addition. IL-4, IL-5 and IL-13 had no effect on FUCA1 and FUCA2 expression and activity. The IFN-gamma-induced increase in expression and activity was repressed by the presence of the Th2 cytokine IL-5. Enzymatically active alpha-L-fucosidase 2 was immunoprecipitated from BEAS-2B cells, with highest activity at pH 4.9. IL-13, IL-4 and IL-5 have no effect on the expression of FUCA1 and FUCA2, but its expression is upregulated by IFN-gamma, a Th1 cytokine. Active alpha-L-fucosidase 2 was overexpressed in BEAS-2B cells. PMID- 24469469 TI - Silencing heat shock protein 27 (HSP27) inhibits the proliferation and migration of vascular smooth muscle cells in vitro. AB - The objective of this study was to examine the role of heat shock protein 27 (HSP27) in proliferation and migration of vascular smooth muscle cells (VSMCs). Three complementary DNA sequences targeting rat HSP27 gene were designed, synthesized, and subcloned into lentiviral vector. The interfering efficiency was detected by reverse transcriptase-polymerase chain reaction and Western blot. Methyl thiazolyl tetrazolium bromide assay was used for examining cell proliferation. F-actin polymerization was detected by FITC-Phalloidin staining using confocal microscopy. Modified Boyden chamber technique was used to assess VSMCs migration. The recombinant lentivirus containing RNAi targeting HSP27 gene significantly inhibited expression of HSP27 at both mRNA and protein levels. The interfering efficiencies of pNL-HSP27-EGFP-1, pNL-HSP27-EGFP-2, and pNL-HSP27 EGFP-3 were 71 %, 77 %, and 43 %, respectively. Reorganization of actin stimulated by PDGF-BB was markedly blocked by pretreatment with pNL-HSP27-EGFP-2. Proliferation and migration rates of VSMCs induced by PDGF-BB were inhibited by 30.8 % and 45.6 %, respectively, by pNL-HSP27-EGFP-2 (all P < 0.01). To conclude, these data indicate that HSP27 may regulate the proliferation, actin reorganization, and the migration of VSMCs. RNAi targeting at HSP27 may be a potential approach for inhibition of cell migration involved in pathogenesis of proliferative vascular diseases. PMID- 24469470 TI - MiR-96 downregulates RECK to promote growth and motility of non-small cell lung cancer cells. AB - MicroRNAs play critical roles in the development and progression of non-small cell lung cancer (NSCLC). miR-96 acts as an oncogene in some malignancies, while its role in NSCLC is unclear. Here, we validated that miR-96 was significantly increased in both human NSCLC tissues and cell lines. Inhibition of miR-96 expression remarkably reduced cell proliferation, colony formation, migration, and invasion of NSCLC cells. Reversion-inducing-cysteine-rich protein with kazal motifs (RECK) was identified as a target of miR-96 in NSCLC cells. In addition, the expression of RECK was found to be negatively correlated with the expression of miR-96 in NSCLC tissues. Our data suggest that miR-96 might promote the growth and motility of NSCLC cells partially by targeting RECK. PMID- 24469471 TI - Who regulates ethics in the virtual world? AB - This paper attempts to give an insight into emerging ethical issues due to the increased usage of the Internet in our lives. We discuss three main theoretical approaches relating to the ethics involved in the information technology (IT) era: first, the use of IT as a tool; second, the use of social constructivist methods; and third, the approach of phenomenologists. Certain aspects of ethics and IT have been discussed based on a phenomenological approach and moral development. Further, ethical issues related to social networking sites are discussed. A plausible way to make the virtual world ethically responsive is collective responsibility which proposes that society has the power to influence but not control behavior in the virtual world. PMID- 24469472 TI - The disaster of the impact factor. PMID- 24469473 TI - Identification of a robust molecular marker for the detection of the stem rust resistance gene Sr45 in common wheat. AB - KEY MESSAGE: Fine mapping of the Ug99 effective stem rust resistance gene Sr45 introgressed into common wheat from the D -genome goatgrass Aegilops tauschii. Stem rust resistance gene Sr45, discovered in Aegilops tauschii, the progenitor of the D -genome of wheat, is effective against commercially important Puccinia graminis f. sp. tritici races prevalent in Australia, South Africa and the Ug99 race group. A synthetic hexaploid wheat (RL5406) generated by crossing Ae. tauschii accession RL5289 (carrying Sr45 and the leaf rust resistance gene Lr21) with a tetraploid experimental line 'TetraCanthatch' was previously used as the source in the transfer of these rust resistance genes to other hexaploid cultivars. Previous genetic studies on hexaploid wheats mapped Sr45 on the short arm of chromosome 1D with the following gene order: centromere-Sr45-Sr33-Lr21 telomere. To identify closely linked markers, we fine mapped the Sr45 region in a large mapping population generated by crossing CS1D5406 (disomic substitution line with chromosome 1D of RL5406 substituted for Chinese Spring 1D) with Chinese Spring. Closely linked markers based on 1DS-specific microsatellites, expressed sequence tags and AFLP were useful in the delineation of the Sr45 region. Sequences from an AFLP marker amplified a fragment that was linked with Sr45 at a distance of 0.39 cM. The fragment was located in a bacterial artificial chromosome clone of contig (ctg)2981 of the Ae. tauschii accession AL8/78 physical map. A PCR marker derived from clone MI221O11 of ctg2981 amplified 1DS specific sequence that harboured an 18-bp indel polymorphism that specifically tagged the Sr45 carrying haplotype. This new Sr45 marker can be combined with a previously reported marker for Lr21, which will facilitate selecting Sr45 and Lr21 in breeding populations. PMID- 24469474 TI - Clinical outcomes of MitraClip for the treatment of functional mitral regurgitation. AB - AIMS: The aim of this study was to report medium-term outcomes of MitraClip implantation in inoperable or high-risk surgical candidates with functional mitral regurgitation (FMR) in our single-centre experience. From October 2008, 109 consecutive patients with FMR underwent MitraClip implantation (mean age 69+/ 9 years; 82% NYHA Class III-IV). Logistic EuroSCORE was 22+/-16%. Comorbidities included: chronic renal failure (47%), diabetes (22%), COPD (28%). Mean EF was 28+/-11%; LVEDD was 68+/-8 mm. Procedural success was 99% and 30-day mortality was 1.8%. At discharge, 87% patients had MR <=2+. At 12 months, EF was 34.7+/ 10.4% (p=0.002 compared to preoperative value). Actuarial survival at three years was 74.5+/-7%. Actuarial freedom from MR >=3+ at 2.5 years was 70+/-6%. At one year follow-up, 86% of patients were in NYHA Class I-II. Preoperative pro-BNP level >=1,600 pg/ml was identified as an independent risk factor of mortality at follow-up. MitraClip therapy for FMR is a valuable alternative to surgery in high risk patients. Higher preoperative pro-BNP level is a risk factor for mortality at follow-up. Although patients treated in current practice are high-risk, the procedure remains safe and effective in selected patients. PMID- 24469475 TI - Ultrasound diagnosis of varicocele in the adolescent: our experience from Benin. AB - BACKGROUND: The diagnosis of varicocele is clinical. In order to improve diagnosis of varicocele, we compared the clinical with the ultrasound findings in schoolboys with the condition. This is because the conditions can affect testicular growth. PATIENTS AND METHODS: It was a cross-sectional, descriptive study of schoolboys aged from 10 to 19 years who had varicocele. Among 2724 boys examined, 149 had varicocele and only 81 had scrotal (18 with Doppler) and renal ultrasound examination. RESULTS: Among the 81 adolescents who were clinically diagnosed with varicocele and also with the aid of ultrasound scan, 25, 36 and 20 had grade 1, 2 and 3, respectively. Testicular hypotrophy (TH) was clinically noticed in 17 cases. At ultrasonography, varicocele was bilateral in 87.66% and unilateral in 12.34% (P = 0.01) with 32 adolescents (39.51%) showing TH compared with 20.99% being diagnosed with TH using clinical examination alone (P = 0.01). In 50 schoolboys (61.73%) with unilateral varicocele, a subclinical type was discovered at other side. Renal ultrasound revealed abnormalities in 4.93% of cases. Doppler ultrasound helped in finding varicoceles along the top edge of the testis (n = 15) and under tunica albuginea (n = 3). CONCLUSION: TH due to varicocele is better studied by ultrasound. PMID- 24469476 TI - Recurrent intussusception in children and infants. AB - BACKGROUND: Recurrent intussusceptions in child and infants are problematic and there are controversies about its management. The aim of this study is to determine the details of the clinical diagnosis of recurrent intussusception and to determine the aetiology of recurrent intussusceptions. PATIENTS AND METHODS: It's a retrospective study of 28 cases of recurrent intussusception treated in the paediatric surgery department of Monastir (Tunisia) between January 1998 and December 2011. RESULTS: During the study period, 505 patients were treated for 544 episodes of intussusception; there were 39 episodes of recurrent intussusceptions in 28 patients; the rate of patients with recurrence was 5.5%. With comparison to the initial episode, clinical features were similar to the recurrent episode, except bloody stool that was absent in the recurrent group (P = 0,016). Only one patient had a pathologic local point. CONCLUSION: In recurrent intussusception, patients are less symptomatic and consult quickly. Systematic surgical exploration is not needed as recurrent intussusceptions are easily reduced by air or hydrostatic enema and are not associated with a high rate of pathologic leading points. PMID- 24469477 TI - The hidden mortality of imperforate anus. AB - BACKGROUND: Anorectal malformations (ARMs) affect 1 in 4000-5000 births and are a big challenge in western countries. However, little is known about ARMs in Africa. The aim of this study is to evaluate the incidence, treatment and outcome of ARMs in Malawi. MATERIALS AND METHODS: Over a 4-year period (2006-2009), data was extracted from patients up to and including the age of 5 years or less who underwent a colostomy, posterior sagittal anorectoplasty or colostomy closure. RESULTS: Of the data that could be retrieved 46 patients met the criteria of congenital ARMs; 65.2% were female (N = 30) and 34.8% were male (N = 16). The median distance from patient to the hospital was 79 km and the median age at presentation was 24 days. In female patients: The most common ARM was the vestibular fistula (N = 21; 70%), a recto-vaginal fistula was found four times, a cloaca was found three times and a perineal fistula or no fistula were both found once each. The most common ARM among boys was the recto-urethral fistula (N = 10). Two boys had no fistula. A perineal fistula and a recto-vesical fistula were both found once each. Nearly, half of the patients (N = 22) had complications. Complications occurred less often in the group, which lived closest to the Surgical Unit (25%). Associated anomalies were found in one patient. CONCLUSION: This study shows a skewed distribution of age at presentation and type of ARM. The most likely explanations are (1) the distance to the hospital: Because none of the male patients presented after 4 weeks and many may have passed away before arriving at the tertiary care centre; (2) lack of knowledge among primary caregivers since very few patients with rectoperineal fistulas were seen. The rate of complications was high, probably also related to advance age at presentation. Therefore, Malawi needs more awareness for earlier detection and quicker intervention. PMID- 24469478 TI - An evaluation of surgical outcome of bilateral cleft lip surgery using a modified Millard's (Fork Flap) technique. AB - BACKGROUND: The central third of the face is distorted by the bilateral cleft of the lip and palate and restoring the normal facial form is one of the primary goals for the reconstructive surgeons. The history of bilateral cleft lip repair has evolved from discarding the premaxilla and prolabium and approximating the lateral lip elements to a definitive lip and primary cleft nasal repair utilising the underlying musculature. The aim of this study was to review surgical outcome of bilateral cleft lip surgery (BCLS) done at the Lagos University Teaching Hospital. MATERIALS AND METHODS: A review of all cases of BCLS done between January 2007 and December 2012 at the Lagos University Teaching Hospital was done. Data analysis included age and sex of patients, type of cleft deformity and type of surgery (primary or secondary) and whether the cleft deformity was syndromic and non-syndromic. Techniques of repair, surgical outcome and complications were also recorded. RESULTS: A total of 39 cases of BCLS involving 21 males and 18 females were done during the period. This constituted 10% (39/390) of all cases of cleft surgery done during the period. There were 5 syndromic and 34 non-syndromic cases. Age of patients at time of surgery ranged between 3 months and 32 years. There were 24 bilateral cleft lip and palate deformities and 15 bilateral cleft lip deformities. Thirty-one of the cases were primary surgery, while 8 were secondary (revision) surgery. The most common surgical technique employed was modified Fork flap (Millard) technique, which was employed in 37 (95%) cases. CONCLUSION: Bilateral cleft lip deformity is a common cleft deformity seen in clinical practice, surgical repair of which can be a challenge to an experienced surgeon. A modified Fork flap technique for repair of bilateral cleft lip is a reliable and versatile technique associated with excellent surgical outcome. PMID- 24469479 TI - Tunica vaginalis flap cover in repair of recurrent proximal urethrocutaneous fistula: a final solution. AB - BACKGROUND: The objective of this study was to assess the significance of tunica vaginalis flap cover in cases of recurrent proximal penile fistula. MATERIALS AND METHODS: This retrospective study included complicated cases of proximal penile hypospadias with recurrent fistula. Recurrent fistula was defined as fistula after at least two previous attempts of closure. Group 1 included cases with tunica vaginalis flap and Group 2 included cases with local flap. Outcome was assessed at day 10 after stent removal and at first follow-up. Fistula closure was considered successful in case with no leak. RESULTS: Out of 39 cases of recurrent fistulas, 20 cases in Group 1 and 18 cases in Group 2 formed the study group. The mean age at fistula repair was 7.2 +/- 0.9 years (range: 2.1-12 years) and 7.1 +/- 0.7 years (range: 2.3-12 years) in Group 1 and 2 respectively. Leak at the time of stent removal was present in 1/20 (5%) and 3/18 (16.67%) cases in Group 1 and 2 respectively (P = 0.04). Leak at the time of first follow-up was present in 2/20 (10%) and 4/18 (22.22%) cases in Group 1 and 2 respectively (P = 0.03). Complete disruption of fistula closure was present in 1/20 (5%) and 2/18 (11.11%) cases in Group 1 and Group 2 respectively (P = 0.1). The overall success rate in Group 1 and 2 was 16/20 (80%) and 9/18 (50%) respectively (P = 0.01). CONCLUSIONS: Tunica vaginalis flap reinforcement is a viable and reliable option. With proper use cases of recurrent fistula can be managed successfully. PMID- 24469480 TI - Role of damage control enterostomy in management of children with peritonitis from acute intestinal disease. AB - BACKGROUND: Intestinal anastomosis in severely ill children with peritonitis from intestinal perforation, intestinal gangrene or anastomotic dehiscence (acute intestinal disease) is associated with high morbidity and mortality. Enterostomy as a damage control measure may be an option to minimize the high morbidity and mortality. This report evaluates the role of damage control enterostomy in the treatment of these patients. MATERIALS AND METHODS: A retrospective review of 52 children with acute intestinal disease who had enterostomy as a damage control measure in 12 years. RESULTS: There were 34 (65.4%) boys and 18 (34.6%) girls aged 3 days-13 years (median 9 months), comprising 27 (51.9%) neonates and infants and 25 (48.1%) older children. The primary indication for enterostomy in neonates and infants was intestinal gangrene 25 (92.6%) and perforated typhoid ileitis 22 (88%) in older children. Enterostomy was performed as the initial surgery in 33 (63.5%) patients and as a salvage procedure following anastomotic dehiscence in 19 (36.5%) patients. Enterostomy-related complications occurred in 19 (36.5%) patients, including 11 (21.2%) patients with skin excoriations and eight (15.4%) with hypokalaemia. There were four (7.7%) deaths (aged 19 days, 3 months, 31/2 years and 10 years, respectively) directly related to the enterostomy, from hypokalaemia at 4, 12, 20 and 28 days postoperatively, respectively. Twenty other patients died shortly after surgery from their primary disease. Twenty of 28 surviving patients have had their enterostomy closed without complications, while eight are awaiting enterostomy closure. CONCLUSION: Damage-control enterostomy is useful in management of severely ill children with intestinal perforation or gangrene. Careful and meticulous attention to fluid and electrolyte balance, and stoma care, especially in the first several days following surgery, are important in preventing morbidity and mortality. PMID- 24469481 TI - Effect of number of associated anomalies on outcome in oesophageal atresia with or without tracheoesophageal fistula patient. AB - BACKGROUND: The objective of this study was to assess effect of number of associated anomalies on outcome in oesophageal atresia with or without tracheoesophageal fistula patients. MATERIALS AND METHODS: Retrospective analysis of records of neonates admitted with a diagnosis of oesophageal atresia (EA) with or without tracheoesophageal fistula during January 2005 to May 2011. Preoperative investigation included chest X-Ray, ultrasonography of abdomen and echocardiography. Associated anomalies were grouped as minor or major depending on whether life threatening or not. Major anomalies were further sub grouped according to the involvement of single, two or > 2 organ systems. Survival was correlated with the presence of anomalies and the number of systems involved. RESULTS: Out of 301 patients with EA, 240 survived (79.7%). Of these 301, 117 (38.9%) had no associated anomalies. Of the total 61 deaths, 59% (36/61) were in patients with cardiac anomalies and 44% (27/61) were in those with >2 associated anomalies. The mortality rate was highest in those with >2 anomalies 27/34 (79.4%), whereas survival was best in those without any associated anomalies 104/117 (88.9%). CONCLUSIONS: Apart from other factors, an association of more than two system anomalies influence the mortality in oesophageal atresia. PMID- 24469482 TI - Outcome of management of complicated extragonadal teratoma in a resource poor setting. AB - BACKGROUND: Extragonadal teratomas (EXGTs) are ubiquitous in the human body; hence, they have varied presentation. In underdeveloped areas presentation and management are affected by socio-economic, cultural and health facilities factors. The aim of this study was to review the outcome of management of complicated EXGT in a tertiary health centre. MATERIALS AND METHODS: A review data of paediatric patients with EXGT was done between January 1999 and December 2012. Variables reviewed were bio-data, mode of presentation and site of tumour, comorbidity, treatments and outcome. The data was analysed with Statistical Package for Social Sciences (SPSS (R)) version 16.0. RESULTS: There were 21 complicated EXGT (77.8%) among 27 children, age ranges from 4 days to 16 years (median = 2 years). Male:Female ratio of 1:2. The complications per region of the body at presentation were cervical 4 (66.7%), mediastinal 2 (100%), abdominal 3 (75%) and sacrococcygeal 12 (75%). The complications were respiratory distress 6, intestinal obstruction 5, faecal incontinence 2, bladder outlet obstruction 3, malignant transformation 5, ruptured sacrococcygeal teratoma 2, ulcerated tumour 2, anaemia 3 and malnutrition 3. There were 5 (23.8%) progressive disease post excision outside our facility. Excision biopsy was successful in 19 (85%) patients two of which had neoadjuvant cytotoxic therapy. Overall mortality was 5 (23.8%) (septicaemia, anaemia, respiratory distress, renal failure) and post excision mortality was 11.8% (endotracheal tube blockage and progressive disease). CONCLUSION: Delay presentation (due to local belief, ignorance and poverty) malnutrition, sepsis, malignant transformation characterised presentation of children in this study and the lack of paediatric intensive care unit facility and intensivists compromised survival of children with EXGT. PMID- 24469483 TI - Paediatric acute retropharyngeal abscesses: an experience. AB - BACKGROUND: To describe our experience of paediatric patients with acute retropharyngeal abscess in terms of clinical presentation, diagnosis, management and complications. MATERIALS AND METHODS: A prospective study was done for a period of 4 years (Jan 2009 to Jan 2013) on paediatric patients (< 15 years) with acute retropharyngeal abscess at two tertiary hospitals in Srinagar. Diagnosis was made on the basis of X-ray, CECT scan findings and confirmed on incision and drainage. Pus was aspirated from all patients and sent for culture and sensitivity. Data for clinical presentation, X-ray, CECT scan findings, causes, complications, bacteriology and management were collected. Thirty-five abscesses were drained while 5 with small abscesses on CECT were managed conservatively. RESULTS: A total of 40 patients were diagnosed as acute retropharyngeal abscesses. Males were commonly affected, and most of the patients were less than 6 years of age. Most common symptom at presentation was fever (35) followed by neck pain (30) Dysphagia/odynophagia (22), swelling in neck (19). Most common clinical sign observed was oropharyngeal swelling and limitation of neck movements (30), cervical swelling/lymphadenopathy in 22 patients. Torticollosis and drooling were seen in 15 patients. Complications were seen in 8 patients. Most common X-ray finding was pre-vertebral thickening. Success rate with primary surgical drainage was 95% while 3 patients in conservative group failed. CONCLUSION: Children with RPA most commonly present with restricted neck movements, fever and cervical lymphadenopathy, and rarely with respiratory distress or stridor. Surgical intervention is necessary for most of these patients. PMID- 24469484 TI - Omentopexy for patch repair of diaphragmatic defect. AB - BACKGROUND: There are many techniques in the reconstructive of congenital diaphragmatic hernia defect. In this study, we present our results from a prospective, randomised trial of using the omentum (omentopexy) for repair of large diaphragmatic defects. MATERIALS AND METHODS: Twenty white, male, New Zealand rabbits were used to compare incidence and severity of adhesion bands formation in abdominal cavity with/without of omentopexy after repair of diaphragm defect with the non-absorbable patch (Dacron). They were divided in to two groups, GI (10 animals with omentopexy and repair) and GII (10 animals with repair, without omentopexy). On the 60 th day, animals were re-operated. In each case, adhesion band formation and its severity were recorded. RESULTS: The difference between the incidence of adhesion band formation among the two group was statistically significant (P = 0.019).The majority of rabbits in GII (60%) had substantial adhesion bands (Grade >2 or severe score), whereas, in GI, none of rabbits had substantial adhesion bands (P = 0.019). CONCLUSION: Our study showed that the use of omentopexy as a cover in repair of diaphragmatic defect is versatile technique with a good success for decreasing of adhesion band formations at short-term follow-up. PMID- 24469485 TI - Childhood unintentional injuries: supervision and first aid provided. AB - BACKGROUND: The aim of this study was to investigate the circumstances surrounding unintentional injuries of children and the appropriateness of the first aid provided by caregivers. MATERIALS AND METHODS: This prospective study included children with aged range 0-12 years, who presented with an unintentional injury at the Trauma Unit of a hospital in Cape Town, South Africa, over a 3 month period. Caregivers were interviewed about the circumstances of the injury and the first aid provided. Experts classified the first aid as appropriate, appropriate but incomplete, or inappropriate. RESULTS: A total of 313 children were included with a median age of 3.75 years. The most common causes of injury were falls (39.6%, n = 124), burns (23.9%, n = 75) and motor vehicle crashes (10.5%, n = 33). More than a quarter of the children (27.2%, n = 81) had been left under the supervision of another child below the age of 12. When the injury occurred, 7.1% (n = 22) of the children were unattended. First aid was provided in 43.1% (n = 134) of the cases. More than half of these interventions (53%, n = 72) were inappropriate or appropriate but incomplete. CONCLUSIONS: Especially young children are at risk for unintentional injuries. Lack of appropriate supervision increases this risk. Prevention education of parents and children may help to protect children from injuries. First-aid training should also be more accessible to civilians as both the providing of as well as the quality of first aid provided lacked in the majority of cases. PMID- 24469486 TI - Surgical outcome and complications following cleft lip and palate repair in a teaching hospital in Nigeria. AB - BACKGROUND: Measurement of treatment outcome is important in estimating the success of cleft management. The aim of this study was to assess the surgical outcome of cleft lip and palate surgery. PATIENTS AND METHODS: The surgical outcome of 131 consecutive patients with cleft lip and palate surgeries between October 2008 and December 2010 were prospectively evaluated at least 4 weeks postoperatively. Data collected included information about the age, sex, type of cleft defects, and type of surgery performed as well as postoperative complications. For cleft lip repair, the Pennsylvania lip and nose (PLAN) score was used to assess the surgical outcome, while the integrity of the closure was used for cleft palate repair. RESULTS: A total of 92 patients had cleft lip repair and 64 had palate repair. Overall, 68.8% cases of cleft lip and palate repair had good outcomes; 67.9% of lip repairs had good lip and nose scores, while 70.2% of palatal repair had a good surgical outcome. Oro-fistula was observed in 29.8% of cleft palate repairs Inter-rater reliability coefficient was substantially significant. CONCLUSIONS: The fact that 25.7% of those treated were aged >1 year suggests a continued need to enlighten the public on the availability of cleft lip and palate expertise and treatment. Although an overall good treatment outcome was demonstrated in this study, the nasal score was poorer than the lip score. Complication rate of about 14% following surgical repair is consistent with previous reports in the literature. PMID- 24469487 TI - Epidemiology and management of head injury in paediatric age group in North Eastern Nigeria. AB - BACKGROUND: Paediatric head injury (HI) is the single most common cause of death and permanent disability in children world over, and this is increasingly becoming worrisome in our society because of increased risks and proneness to road traffic accidents on our highways and streets. The study set to determine causes and management of HI among children in our society. PATIENTS AND METHODS: A retrospective review of all children aged 0-15 years with traumatic head injury (THIs) who were managed at the University of Maiduguri Teaching Hospital between July, 2006 and August, 2008. RESULTS: A total of 45 children with THIs presented to the casualty unit of the hospital; 30 (66.7%) were boys and 15 (33.3%) were girls. Three (6.7%) children were less than 1 year of age, 21 (46.7%) were between 1 years and 6 years while 16 (35.6%) and 5 (11.0%) were aged 7-11 years and 12-15 years respectively. Thirty six (80.0%) of the children were pedestrians, 6 (13.4%) fell from a height, while 2 (4.4%) and 1 (2.2% were as a result of home accident and assault, respectively. Twenty one patients (46.7%) had mild HI, while 53.3% had moderate to severe category. Forty one (91.1%) of children were managed as in-patients, mostly (95.1%) by conservative non operative management, while 4 (8.9%) were treated on the out-patient basis. The mortality rate was 17.8%. CONCLUSION: H1 among children is of a great concern, because of its incremental magnitude, due to increasing child labour and interstate religious discipleship among children, with attendant high mortality and permanent disabilities. Necessary laws and legislations should be formulated and implemented with organized campaigns and public enlightenment to prevent and mitigate this menace. PMID- 24469488 TI - Soave transanal one-stage endorectal pull-through in the treatment of Hirschsprung's disease of the child above two-year-old: a report of 20 cases. AB - BACKGROUND: The definitive treatment of Hirschsprung's disease is the removal of the aganglionic bowel by a pull-through surgery. In most cases, this surgery is performed in infancy or in the neonatal period as presentation in older children and adulthood is uncommon. MATERIALS AND METHODS: It is a retrospective study of 20 patients above two-year-old who underwent a transanal Soave one-stage endorectal pull-through procedure for Hirschsprung's disease between January 2002 and December 2010. RESULTS: Twenty patients were recruited in this study. Fourteen were males and six were females. Patient ages ranged from 2 to 14 years (median age: five years and three months). All patients presented with persistent constipation and abdominal distension. Two of them had an intestinal obstruction that required colostomy. Ten patients (50%) had a recto-sigmoid Hirschsprung's disease. All patients were operated on using a Soave one-stage endorectal pull through procedure. The laparoscopy was necessary during the pull-through in three cases. The average duration of the intervention was 240 minutes. That represents almost the double of the duration of the same procedure in newborns and infants in our department (130 minutes). Early postoperative complications included one case of anastomosis leakage and one case of intussusception. Late postoperative complications were perineum irritation in five cases (25%), anal stenosis in four cases (20%) and enterocolitis in one case (5%). None of our patients developed fecal incontinence. Soiling was reported in four cases (20%). There was no death. CONCLUSION: Soave transanal one-stage endorectal pull-through is safely feasible in children of more than two years of age. Laparoscopy may be necessary whenever there are difficulties in the pull-through. PMID- 24469489 TI - Childhood injuries in a tertiary institution in north east Nigeria. AB - BACKGROUND: Injury has been recognised as a preventable cause of morbidity and mortality in children. The aim of this study was to determine the aetiology, pattern and location of childhood injuries in north east Nigeria. MATERIALS AND METHODS: This is a 3-year retrospective hospital-based descriptive study. The study included 114 children (77 boys, 37 girls; mean age 6.4 +/- 3.2 years; range 2 months to 15 years) who were admitted for various injuries in the female/paediatric surgical ward from January 2007 to December 2009. Information obtained from their case notes included demographic data, mechanism of injury, location of injury, anatomical site of injury and outcome of treatment. RESULTS: Records for 114 children (77 boys, 37 girls; mean age 6.2 years; range 2 months to 15 years) were available for analysis. The highest number of injuries occurred in the age group 6-10 years. Home was the most common location of injury among the age group 0-5 years while older children sustained most of their injuries outside the home on the street/highways. Burns from hot water was the most common injury among children aged 0-5 years while pedestrian accident accounted for the highest cause of injury among older children. Fall accounted for 20.2% of the injuries. The most common specific anatomic injury was head injury followed by limb fractures. Two mortalities were recorded (1.8%). CONCLUSION: This study provided useful information on the characteristics of childhood injuries in our environment. There is the need for parents and children education about the risks of injury and preventive measures in addition to legislation and policy on environmental modifications and enforcements to significantly reduce childhood injury. PMID- 24469490 TI - Activating transcription factor 3 is not up-regulated in hypospadias patients in Japan. AB - BACKGROUND: The aetiology of hypospadias is largely uncharacterized. Some of the researchers have advocated that activating transcription factor 3 (ATF3), an oestrogen-responsive transcription factor, is up-regulated in patients with hypospadias. The purpose is to evaluate the universality of this fact; we studied the expression of ATF3 protein in prepuce tissue obtained from hypospadias and phimosis patients living in metropolitan Tokyo. MATERIALS AND METHODS: Prepuce tissue was obtained from outer foreskin at the time of surgery, quickly prepared for paraffin-embedded sectioning and stained immunohistochemically for ATF3. Two researchers blindly evaluated immunoreactivity and scored it semi-quantitatively as nil = 0, weak = 1, or strong = 2, to give a final staining intensity score (SIS). Subjects were 18 hypospadias patients and 17 phimosis patients (as controls) who had surgery between January, 2009 and March, 2010. RESULTS: All subjects lived in metropolitan Tokyo, Japan. Mean ages at surgery were 2.9 +/- 1.0 and 3.9 +/- 2.4 years, respectively (P > 0.05). SIS was not statistically different between hypospadias patients (1.4 +/- 0.5) and controls (1.5 +/- 0.5), (P > 0.05). CONCLUSIONS: Our data suggest that ATF3 is not highly associated with hypospadias in metropolitan Tokyo. Differences in ethnicity might have influenced our results. PMID- 24469491 TI - Octreotide treatment in a neonate with non-chylous pleural effusion. AB - Fetal pleural effusion is a rare condition. While it may regress spontaneously, it may also continue up to the post-natal period. This condition may be treated by thoracentesis, thoracoabdominal shunt application and pleurodesis in the intrauterine period while thoracentesis or tube thoracostomy may be used in the post-natal period. In cases where the fluid is defined to represent chylothorax, octreotide, a somatostatin analogue, may be administered for treatment. In this case report, we discussed the outcomes of treatment with octreotide administered in a neonatal case under follow-up due to fetal pleural effusion and with non chylous ascites detected in the post-natal period. PMID- 24469492 TI - Post appendectomy acalculus bilateral ureteric obstruction: a rare entity in children. AB - Bilateral acalculus ureteric obstruction is described as rare sequelae of acute appendicitis in two paediatric patients aged 6 and 11 years presented with features of anuria. Imaging and endoscopic evaluation confirmed bilateral ureteric obstruction secondary to bladder wall oedema as an inflammatory reaction to appendix. Both cases recovered following bilateral ureteric stenting and are doing well. PMID- 24469493 TI - Oesophageal elongation with traction sutures (FOKER procedure) in a newborn baby with long-gap oesophageal atresia (LGEA): maybe too early, maybe too dangerous? AB - In children with long gap oesophageal atresia (LGEA), the FOKER technique (oesophageal elongation with traction sutures) has been criticized for its high complication rate. We advocate analysing such problems to increase the safety in the future. The present case report will focus on timing. A female newborn (3000 g) with LGEA (gap of 5 cm) was delivered in an outward hospital. On day two of life, she received traction sutures on both pouches. By day five, all sutures had torn out, and a primary anastomosis was attempted. However, it leaked severely. Thus, on day ten, the oesophagus was approached from the neck converting the proximal end into a spit fistula and closing the distal end blindly. Furthermore, the gastro-oesophageal (GE-) junction was wrapped with a Teflon sling. When the baby arrived in our institution, she suffered from cavernous oesophageal masses extending from the thoracic inlet down to the diaphragm and fistulas draining them into the neck as well as into the right lung. Moreover, the Teflon sling had dislodged allowing for GE-reflux. In several stages, the oesophageal remnants were resected without any complications. Finally, Prof. Alaa Hamza performed a colonic interposition, which is working well today. In conclusion, the present case aims to caution paediatric surgeons to apply traction sutures for oesophageal elongation in newborns with LGEA. PMID- 24469494 TI - A rare complication of small bowel intussusception: report of a case and review of literature. AB - Volvulus and intussusception are rare conditions in children. We describe an unusual case of intussusception due to a solitary Peutz-Jeghers type hamartomatous polyp complicated by volvulus, which occurred in an 11-year-old girl. A laparotomy allows to successfully treat the pathology. The postoperative course was favourable. We discuss the clinical findings and the values of the preoperative instrumental diagnosis. The literature is reviewed. Identifying a midgut volvulus, as complication of a small bowel intussusception, during the diagnostic phase could help in choosing the most appropriate surgical approach. PMID- 24469495 TI - An unusual complication of ischemic injury to upper pole ureter during lower pole heminephroureterectomy. AB - Lower pole heminephroureterectomy is a common paediatric urology procedure with few reported complications. We report a case of possible vascular ischemic injury to the normal remaining ureter following a lower pole heminephroureterectomy, probably due to both ureters sharing a common blood supply. Extra caution in such procedures is therefore warranted. PMID- 24469496 TI - Massive de-gloving thigh injury treated by vacuum therapy, dermal regeneration matrix and lipografting. AB - Frequently lower limb injuries are caused by road and work accidents. The young age of those affected coupled with the anatomical and functional peculiarities of this part of the body with regards to social life during adolescence make the treatment of the leg wound complex and challenging. We present two cases of young girls, victims of serious road accidents who were treated initially with frequent wound washings, vacuum therapy to stimulate granulation tissue, then dermal regeneration matrix (INTEGRA(r)) and split-thickness skin grafts. After one year, both patients treated with lipofilling have shown improved cosmetic results allowing a new social life. PMID- 24469497 TI - Sigmoid volvulus in a neonate: case report and review of literature. AB - Sigmoid volvulus (SV) is an extremely rare cause of bowel obstruction in the newborn period. We report a neonatal case of SV misdiagnosed as small bowel volvulus. At laparotomy, the classical findings of SV were observed without gangrene. The operative procedure consisted of simple detorsion without sigmoidopexy. PMID- 24469498 TI - Imaging to diagnose acute appendicitis. PMID- 24469499 TI - Total bilirubin in nasogastric aspirate. PMID- 24469501 TI - Abdominal neuroblastoma in children. PMID- 24469500 TI - Acute typhic cholecystitis. PMID- 24469502 TI - Therapy resistance mechanisms in Ewing's sarcoma family tumors. AB - Ewing's sarcoma family tumors are aggressive small round cell malignancies that arise in bone or soft tissues in adolescents and young adults. The addition of chemotherapy to local control measures has remarkably improved the survival of patients with localized disease. However, metastatic tumors are often refractory to conventional chemotherapy and irradiation, and the outcome of patients with metastatic or recurrent disease remains dismal. Despite growing understanding of the molecular biology of this tumor and the discovery of new therapeutic targets such as the insulin growth factor-1 receptor, tumor resistance continues to be a formidable challenge. Numerous adaptive mechanisms have been identified which allow tumor cells to escape the cytotoxic effect of chemotherapeutic agents. This review focuses on these mechanisms in an effort to highlight opportunities for more effective disease control. PMID- 24469504 TI - Iron and zinc binding activity of Escherichia coli topoisomerase I homolog YrdD. AB - YrdD, a homolog of the C-terminal zinc-binding region of Escherichia coli topoisomerase I, is highly conserved among proteobacteria and enterobacteria. However, the function of YrdD remains elusive. Here we report that YrdD purified from E. coli cells grown in LB media contains both zinc and iron. Supplement of exogenous zinc in the medium abolishes the iron binding of YrdD in E. coli cells, indicating that iron and zinc may compete for the same metal binding sites in the protein. While the zinc-bound YrdD is able to bind single-stranded (ss) DNA and protect ssDNA from the DNase I digestion in vitro, the iron-bound YrdD has very little or no binding activity for ssDNA, suggesting that the zinc-bound YrdD may have an important role in DNA repair by interacting with ssDNA in cells. PMID- 24469505 TI - Formation of perfect ohmic contact at indium tin oxide/N,N'-di(naphthalene-1-yl) N,N'-diphenyl-benzidine interface using ReO3. AB - A perfect ohmic contact is formed at the interface of indium tin oxide (ITO) and N,N'-di(naphthalene-1-yl)-N,N'-diphenyl-benzidine (NPB) using ReO3 as the interfacial layer. The hole injection efficiency is close to 100% at the interface, which is much higher than those for interfacial layers of 1,4,5,8,9,11 hexaazatripheylene hexacarbonitrile (HAT-CN) and MoO3. Interestingly, the ReO3 and MoO3 interfacial layers result in the same hole injection barrier, ~0.4 eV, to NPB, indicating that the Fermi level is pinned to the NPB polaron energy level. However, a significant difference is observed in the generated charge density in the NPB layer near the interfacial layer/NPB interface, indicating that charge generation at the interface plays an important role in forming the ohmic contact. PMID- 24469506 TI - Distribution of imported (14)C in developing leaves of eastern cottonwood according to phyllotaxy. AB - Individual leaves of eastern cottonwood (Populus deltoides Bartr.), representing an ontogenetic series from leaf plastochron index (LPI) 3.0 to 8.0, were fed (14)CO2 and harvested after 2-24 h. Importing leaves from LPI-1.0 through 8.0 on each plant were sectioned into 9 parts, and each part was quantitatively assayed for (14)C activity. The highest level of (14)C import was by leaves from LPI 1.0 to 3.0, irrespective of source-leaf age. (14)C was translocated preferentially to either the right or left lamina-half depending on the position of the importing leaf in the phyllotactic sequence and its stage of development. For example, import was high when the importing leaf and the source leaf had two vascular bundles in common, moderately high with one bundle in common, and low with no bundles in common. The distribution of (14)C within young importing leaves was highest in the lamina tip and decreased toward the base. With increasing leaf age, incorporation declined in the lamina tip and increased in the base.It may be concluded that each cottonwood leaf progresses through a continuum of importing and exporting stages as its lamina expands. The photosynthate imported by a given leaf is compartmentalized, with different exporting leaves supplying photosynthate to rather restricted regions of the lamina. Such localization within the importing leaf depends on its vascular connections with each of the exporting leaves, and these are predictable from a knowledge of the phyllotaxy. PMID- 24469503 TI - HSV-2 vaccine: current status and insight into factors for developing an efficient vaccine. AB - Herpes simplex virus type 2 (HSV-2), a globally sexually transmitted virus, and also one of the main causes of genital ulcer diseases, increases susceptibility to HIV-1. Effective vaccines to prevent HSV-2 infection are not yet available, but are currently being developed. To facilitate this process, the latest progress in development of these vaccines is reviewed in this paper. A summary of the most promising HSV-2 vaccines tested in animals in the last five years is presented, including the main factors, and new ideas for developing an effective vaccine from animal experiments and human clinical trials. Experimental results indicate that future HSV-2 vaccines may depend on a strategy that targets mucosal immunity. Furthermore, estradiol, which increases the effectiveness of vaccines, may be considered as an adjuvant. Therefore, this review is expected to provide possible strategies for development of future HSV-2 vaccines. PMID- 24469507 TI - Catabolic ring-cleavage of tyrosine in plant cell cultures. AB - Ten species of plants from 8 families, grown as sterile cell cultures, were examined for their ability to degrade the aromatic ring of L-tyrosine and two of its metabolites, homogentisic acid and 3,4-dihydroxyphenylalanine (DOPA). All cultures showed low levels of tyrosine degradation (0.3-2.6% in 24 h) and high levels of homogentisic acid degradation (9.3-31.0% in 24 h). Cultures of Amaranthus caudatus L. resembled the other nine species in possessing a moderate capacity for DOPA degradation (0.3-11.1% in 24 h). PMID- 24469508 TI - [Organ specific multiple forms of glutamic dehydrogenase in Medicago sativa]. AB - The alteration of the multiple forms of NAD-dependent glutamic dehydrogenase (GDH) during the development of Medicago sativa is investigated by means of polyacrylamide electrophoresis. Seed germination is accompanied by a characteristic change of the GDH-isoenzyme pattern. Seeds contain seven isoenzymes, which gradually decrease in number during germination. At the same time a pattern of new isoenzymes becomes visible. The seed pattern is called GDH I and the later appearing pattern GDH-II. GDH-I is characteristic for the cotyledons, whereas GDH-II is the typical pattern of the root system. Shoots produce a mixed pattern composed of the GDH-II isoenzymes as well as some GDH-I isoenzymes.These isoenzyme patterns are organ specific. No qualitative change occurs during further development of the plants and during growth in the presence of different inorganic and organic N-sources in the culture medium.All the individual isoenzymes are found predominantly in the particulate fraction. They represent stable forms which are not altered by variation of the conditions of enzyme extraction or during enzyme purification. Re-electrophoresis of the individual isoenzymes following elution from the polyacrylamide gels reveals only one specific band. The molecular weights of all the distinctive isoenzymes are identical.There is some evidence that the different isoenzymes represent conformational forms of one enzyme, and it is postulated that the GDH-I isoenzymes are correlated to a normal metabolic (or catabolic) function of the enzyme, whereas the GDH-II isoenzymes are responsible for a primarily anabolic function of glutamic dehydrogenase. PMID- 24469509 TI - [Endogenously and exogenously caused alteration of the isoenzyme pattern of NAD specific glutamic dehydrogenase in shoots of Pisum sativum]. AB - The isoenzymes of NAD-specific glutamic dehydrogenase (GDH) of Pisum sativum, separated by polyacrylamide gel electrophoresis, constitute two patterns, each of which covers seven individual isoenzymes. One pattern (GDH-I) is found in the cotyledons and young shoots. The second one (GDH-II) occurs together with at least some GDH-I isoenzymes in pea roots. In the shoots of older pea plants GDH II isoenzymes become visible in addition to the GDH-I pattern.Section of the cotyledons (but not of the roots) of young pea seedlings causes the formation of the complete GDH-II isoenzyme pattern in the shoots within a few hours. It has been verified that the cotyledons specifically suppress the formation of the GDH II pattern in the young shoot. In older plants which no longer depend on the cotyledons this effect is maintained somewhat less obviously by the root system.In experiments with isolated shoot segments or shoot tips it has been shown that NH 4 (+) reinforces the formation of the GDH-II whereas glucose shows the opposite effect.The formation of the GDH-II isoenzymes in the presence of NH 4 (+) is accompanied by an increase of the specific activity of GDH. Simultaneously the ratio of aminating activity (anabolic reaction) to deaminating activity (catabolic reaction) changes in favor of the anabolic reaction.The results support the supposition that the GDH-I and GDH-II isoenzyme patterns correspond to different molecular forms of one enzyme, the GDH-II representing a form with predominantly anabolic function and the GDH-I a form which has merely metabolic or catabolic function. PMID- 24469510 TI - [Comparative studies on the lipid composition of etioplasts and chloroplasts from Pisum and of chloroplasts from an Aurea mutant of Nicotiana]. AB - Etioplasts and chloroplasts isolated from Pisum sativum differ in lipid composition. The relative amounts of galactolipids, especially of MGD, are higher in the chloroplast. In contrast, the sulfo- and the phospholipids are already present in the etioplasts in higher concentrations. During the formation of the thylakoids with stacked membranes only the galactolipids are synthesized simultaneously with the pigments. It is suggested that the polar lipids are embedded into the membranes after the basic structure has already been formed.A different type of membrane formation has been described for the chloroplasts of an aurea mutant of tobacco.The grana formation was observed when the plants were grown under lower light intensities. The possibility of a parallel synthesis of polar lipids and pigments is discussed on the basis of the lipid analysis. However, the amount of MGD is lower in the chloroplasts with a higher degree of stacking. The low temperature absorbance spectrum is identical in chloroplasts from yellow and green leaves. Since the mutant is lacking in chlorophyll b, the conclusion can be drawn that this pigment and MGD are not involved in the contact of the grana stacks. From the analysis of lipids released from the membranes under hypotonic conditions, it is concluded that MGD is localized at the surface. PMID- 24469511 TI - The effect of acetylcholine on growth and on growth inhibition by CCC in wheat seedlings. AB - The inhibition of the growth of wheat seedlings by 2-chloroethyltrimethylammonium chloride (CCC) was strongly reduced by root application of acetylcholine (Ach). Ach was applied after uptake of CCC by the roots or by the leaves. Ach also stimulated growth of non-CCC-treated seedlings up to 30% when applied to the roots. Growth stimulation appeared to be dependent on pH of the medium and most effective at pH 4.5 and 6. At pH 7.5 Ach did not promote growth of wheat seedlings. PMID- 24469512 TI - Incorporation of different labelled precursors into chloroplast RNA of Chlorella. AB - Radioactive uridine is incorporated by Chlorella strain 211-8b/p into ribosomal subunits and their rapidly labelled RNA comigrates with chloroplast RNA on polycrylamide gels.Ribosomal particles which can be labelled by short pulses of orotic acid cosediment with the particles labelled by uridine pulses and contain the same RNA species as these when separated either on sucrose gradients or on polycrylamide gels. This incorporation is, like that of uridine, sensitive to rifampin and chloramphenicol, but insensitive to cycloheximide.A comparative study of short-time incorporation of uridine, orotic acid and guanosine into the RNA of Chlorella showed that all three precursors were incorporated mainly into RNA of chloroplastic origin. However, guanosine was also partly incorporated into cytoplasmic rRNA. Nitrogen-deficient cells always incorporated part of all three precursors into cytoplasmic rRNA, but the proportions of these were different among the different precursors.These results are consistent with the hypothesis that the described differences in the incorporation of the above mentioned precursors into RNA of different cellular compartments are largely attributable to effects of pool sizes. PMID- 24469513 TI - Phototaxis in a dinoflagellate: Action spectra as evidence for a two-pigment system. AB - Action spectra were determined in the UV region of the spectrum for the first phase of the phototactic response (stop response) and for the phytochrome pigment associated with this response in the dinoflagellate Gyrodinium dorsum Kofoid. Differences between these action spectra indicate the participation of two pigments in phototaxis. Following R (620 nm) irradiation of the phytochrome, the stop response maxima occur at 470 and 280-nm; after FR irradiation they shift to 490 and 300-310 nm. These maxima suggest that the photoreceptor pigment for phototaxis is a carotenoprotein. The action spectrum shift following the different phytochrome conversions may represent a trans to cis isomer change by the carotenoid. The absorption maximum of PR in the UV appears to be at 320 nm, which is consistent with the shift of the R absorption maximum to shorter wavelengths (620 nm) as compared to higher plants. The PFR absorption maximum appears as a broad band between 360 and 390 nm. Comparison of PR to PFR conversions by different intensities of 620-nm and 320-nm light indicates that at lower intensities the logarithm of the threshold for the stop response is inversely proportional to the logarithm of the intensity of the sensitizing light. The ratio of response activation by R and UV light is about 4:1. PMID- 24469514 TI - On the mechanism of the "photo-geo" response in the mesocotyl of oat seedlings. AB - The photo-geo response comes about through the differential inhibition of cell growth on the two curved sides of the mesocotyl. PMID- 24469515 TI - A modified Amaranthus betacyanin bioassay for the rapid determination of cytokinins in plant extracts. AB - Pure cytokinin standards and celery seed extracts containing cytokinin activity were bioassayed using a modified Amaranthus betacyanin bioassay. The assay is very rapid and requires no special sterile precautions. PMID- 24469517 TI - One hundred years of limited impact of Jaspers' General Psychopathology on US psychiatry. AB - Jaspers, a German psychiatrist, published General Psychopathology in 1913. Jaspers, Schneider, and Mayer-Gross were members of the Heidelberg school. General Psychopathology, indirectly through Schneider's and Mayer-Gross' textbooks and directly by its English translation in 1963, led to a narrow set of schizophrenia criteria in the United Kingdom. General Psychopathology had very limited direct impact on US psychiatry, which adopted a broader schizophrenia definition. The difference between UK and US schizophrenia was a key element in the Diagnostic and Statistical Manual of Mental Disorders, Third Edition, and the neo-Kraepelinian revolution. General Psychopathology contains two essential interrelated ideas: a) psychiatry is a hybrid scientific discipline that must combine natural and social science methods that provide an explanation of illness that follows the medical model and an understanding of psychiatric abnormalities that are variations of human living, respectively, and b) psychiatric disorders are heterogeneous. Berrios' ideas on the hybridity of psychiatry in the United Kingdom and McHugh's ideas on psychiatric diagnoses in the United States can be considered neo-Jasperian approaches because they further elaborate these two Jasperian concepts in the late 20th century. PMID- 24469518 TI - The sequelae of our millennial war. PMID- 24469516 TI - Protein profiles associated with context fear conditioning and their modulation by memantine. AB - Analysis of the molecular basis of learning and memory has revealed details of the roles played by many genes and the proteins they encode. Because most individual studies focus on a small number of proteins, many complexities of the relationships among proteins and their dynamic responses to stimulation are not known. We have used the technique of reverse phase protein arrays (RPPA) to assess the levels of more than 80 proteins/protein modifications in subcellular fractions from hippocampus and cortex of mice trained in Context Fear Conditioning (CFC). Proteins include components of signaling pathways, several encoded by immediate early genes or involved in apoptosis and inflammation, and subunits of glutamate receptors. At one hour after training, levels of more than half the proteins had changed in one or more fractions, among them multiple components of the Mitogen-activated protein kinase, MAPK, and Mechanistic Target of Rapamycin, MTOR, pathways, subunits of glutamate receptors, and the NOTCH pathway modulator, NUMB homolog (Drosophila). Levels of 37 proteins changed in the nuclear fraction of hippocampus alone. Abnormalities in levels of thirteen proteins analyzed have been reported in brains of patients with Alzheimer's Disease. We therefore further investigated the protein profiles of mice treated with memantine, a drug approved for treatment of AD. In hippocampus, memantine alone induced many changes similar to those seen after CFC and altered the levels of seven proteins associated with Alzheimer's Disease abnormalities. Lastly, to further explore the relevance of these datasets, we superimposed responses to CFC and memantine onto components of the long term potentiation pathway, a process subserving learning and memory formation. Fourteen components of the long term potentiation pathway and 26 proteins interacting with components responded to CFC and/or memantine. Together, these datasets provide a novel view of the diversity and complexity in protein responses and interactions following normal learning. PMID- 24469519 TI - Psychotic-like experiences, symptom expression, and cognitive performance in combat veterans with posttraumatic stress disorder. AB - Apparent psychotic symptoms are often associated with posttraumatic stress disorder (PTSD), but these symptoms are poorly understood. In a sample of 30 male Vietnam combat veterans with severe and chronic PTSD, we conducted detailed assessments of psychotic symptom endorsement, insight, symptom severity, neurocognitive function, and feigning. Two thirds of the subjects endorsed a psychotic item but did not believe that the experiences were real. Those endorsing psychotic items were higher in PTSD severity, general psychopathology, and dissociation but not depression, functional health, cognitive function, or feigned effort. Severity of psychotic symptoms correlated with dissociation, combat exposure, and attention but not PTSD, depression, or functional health. Those endorsing psychotic items scored higher on a screen but not on a detailed structured interview for malingering. Endorsement of psychotic experiences by combat veterans with PTSD do not seem to reflect psychotic symptoms or outright malingering. PMID- 24469520 TI - Determinants of prospective engagement in mental health treatment among symptomatic Iraq/Afghanistan veterans. AB - There is considerable public and professional concern about the mental health status of veterans deployed to Iraq and Afghanistan as well as how to engage and retain symptomatic veterans in treatment. This study examined demographic, psychiatric, and psychosocial determinants of prospective initiation and retention in mental health services among symptomatic Iraq/Afghanistan veterans. One hundred thirty-seven symptomatic veterans who were referred to mental health screening completed a survey at the time of their first mental health visit. Associations between survey variables and subsequent Veterans Affairs service utilization were evaluated. The most consistent determinants of mental health service initiation and retention were severity of posttraumatic stress disorder (PTSD) and depressive symptoms. Notably, whereas PTSD-related re-experiencing symptoms were independently associated with initiation of mental health treatment, PTSD-related numbing symptoms were independently associated with retention in treatment. Stigma, barriers to care, and beliefs about mental health treatment were not associated with either mental health initiation or retention. PMID- 24469521 TI - Posttraumatic stress symptoms and work-related accomplishment as predictors of general health and medical utilization among Special Operations Forces personnel. AB - Research has established clear links among posttraumatic stress disorder (PTSD), somatic symptoms, and general health among conventional force military personnel. It is possible that the same relationships exist among Special Operations Force (SOF) personnel, but there are very few, if any, studies that examine these relationships. This study investigated correlates of general health and medical visits among SOF personnel and found that the interaction of somatic and PTSD symptoms was associated with worse health and more frequent medical visits. Follow-up analyses indicated that the interaction of avoidance symptoms with somatic symptoms was significantly associated with worse health, whereas the interaction of emotional numbing with somatic symptoms significantly contributed to increased medical visits. In addition, the results suggest that a sense of accomplishment among SOF personnel may serve as a protective factor against poor health. The results suggest developing interactions among SOF personnel that promote a sense of achievement to ultimately improve the health of the force. PMID- 24469522 TI - Personality dysfunction and complex posttraumatic stress disorder among chronically traumatized Bosnian refugees. AB - A proposal for the inclusion of complex posttraumatic stress disorder (CPTSD) in the upcoming ICD-11 has been put forward. Using self-report, we investigated the resemblance between disorders of extreme stress not otherwise specified (DESNOS) and both axis I and II syndromes among 116 treatment-seeking Bosnian refugees. In this sample, the prevalence of DESNOS overlapped to a large degree with the prevalence of schizotypal and paranoid personality disorders (PDs). There was, however, also a large prevalence of axis I syndromes in the group. Thus, DESNOS in the refugees can be categorized as an axis I or II disorder depending on the chronicity and the severity of functional impairment. DESNOS and PD-like states were even observed among the refugees with no history of childhood maltreatment. No large differences were observed between DESNOS and PD regarding sex. The symptom constellation of CPTSD in the ICD-11 is partially supported. However, CPTSD might resemble PD to a considerable degree. PMID- 24469523 TI - Personality disorders in eating disorder not otherwise specified and binge eating disorder: a meta-analysis of comorbidity studies. AB - A meta-analysis was conducted to identify the proportion of comorbid personality disorders (PDs) in patients with eating disorder not otherwise specified (EDNOS) and binge eating disorder (BED). A search identified 20 articles in the period of 1987 to 2010. For EDNOS and BED, the comorbid proportions for any PD were 0.38 and 0.29, respectively; for cluster C PDs, 0.38 and 0.30, respectively (avoidant PD, 0.18 and 0.12, and obsessive-compulsive PD, 0.11 and 0.10, respectively); and for cluster B PDs, 0.25 and 0.11, respectively (borderline, 0.12 and 0.10). This pattern converged with findings on anorexia nervosa and bulimia nervosa, except being lower. Because the comorbidity profiles for EDNOS and BED were highly similar, their underlying PD pathology seems similar. Few moderators were significant, except for interviews yielding lower estimates than that of questionnaires. The variance statistic for any PD comorbidity was wide for EDNOS and narrow for BED, thus partly supporting BED as a distinct eating disorder category and EDNOS as a potentially more severe condition than BED. PMID- 24469524 TI - Optimal social support practices for health care professionals who treat patients managing eating disorders. AB - Research indicates that positive social support leads to positive results in the health of individuals managing eating disorders (e.g., Bertera [J Soc Pers Relat 22:33-48, 2005]). The current study set out to understand the specific qualities of supportive interactions those with eating disorders receive from their health care practitioners and report as beneficial as well as the types of support perceived as unhelpful. Through one-on-one interviews with 34 individuals managing eating disorders, the transcribed data indicate recurring forms of helpful and unhelpful social support received from health care professionals. Helpful forms of social support identified include facilitating treatment, encouraging elaboration, holding accountable, demonstrating compassion, and conveying acceptance. Unhelpful forms of support include lecture, use of coercion, discouragement, and criticism. Descriptive explanations of coded findings and implications for application are discussed. PMID- 24469525 TI - Escitalopram treatment of depression in human immunodeficiency virus/acquired immunodeficiency syndrome: a randomized, double-blind, placebo-controlled study. AB - Depression can be a chronic and impairing illness in people with human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome. Large randomized studies of newer selective serotonin reuptake inhibitors such as escitalopram in the treatment of depression in HIV, examining comparative treatment efficacy and safety, have yet to be done in HIV-positive patients. This was a fixed-dose, placebo-controlled, randomized, double-blind study to investigate the efficacy of escitalopram in HIV-seropositive subjects with Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, major depressive disorder. One hundred two participants were randomly assigned to either 10 mg of escitalopram or placebo for 6 weeks. An analysis of covariance of the completers found that there was no advantage for escitalopram over placebo on the Montgomery-Asberg Depression Rating Scale (p = 0.93). Sixty-two percent responded to escitalopram and 59% responded to placebo on the Clinical Global Impression Scale. Given the relatively high placebo response, future trials in this area need to be selective in participant recruitment and to be adequately powered. PMID- 24469526 TI - Is the residential combined (psychotherapy plus medication) treatment of patients with severe personality disorder effective in terms of suicidality and impulsivity? AB - The aim of this study was to compare the effectiveness of combined treatment medication plus psychodynamic psychotherapy-and psychodynamic psychotherapy alone on the outcome variables of suicidality and impulsivity in a population of adult inpatients with severe personality disorder (SPD). This is a naturalistic empirical (observational) study under the conditions of clinical practice (an intensive specialized inpatient psychotherapeutic program [SIPP]). The sample consisted of 33 inpatients with SPD who were allocated to two subgroups (groups A and B). The patients in group A received psychodynamic psychotherapy and adjunctive pharmacotherapy, whereas the patients in group B received multimodal psychodynamic psychotherapy only. A statistically significant reduction in suicidality score was observed in the patients in group A, whereas a tendency for significant reduction in impulsivity score was observed in group B after the SIPP termination. Pharmacotherapy combined with multimodal psychodynamic psychotherapy, always within the SIPP, seems more effective in the case of suicidality rather than impulsivity. PMID- 24469527 TI - Effectiveness of a brief group cognitive behavioral therapy for auditory verbal hallucinations: a 6-month follow-up study. AB - The current study investigated the effectiveness of a group cognitive behavioral therapy for auditory verbal hallucinations (AVHs), the Voices Group. This consists of seven specific sessions. Forty-one participants with schizophrenic or schizoaffective disorders completed a battery of questionnaires. The severity of psychiatric symptoms, beliefs about voices, quality of life, self-esteem, clinical global impression, and functioning were assessed at baseline, before and after intervention, and at the 6-month follow-up. After intervention, there was a statistically significant reduction in the severity of AVHs. This result remained stable at follow-up. The dropout rate was high. Some differences were found in subjective experience of AVHs between the patients who completed the intervention and those who dropped out. Altogether, these findings suggest that a brief intervention has some positive benefits in patients struggling with voices, which remain stable over time. PMID- 24469528 TI - Symptoms of the anxiety disorders in a perinatal psychiatric sample: a chart review. AB - Symptoms of anxiety are a central feature of perinatal mental health, yet the anxiety disorders have received considerably less attention than depression in both perinatal research and practice. The present investigation involved a retrospective review of the clinical records of 334 patients seen at a psychiatric day hospital program serving pregnant and postpartum women. We examined the frequency with which the patients in this setting reported symptoms of anxiety, clinical correlates of elevated anxiety, and patterns of diagnosis in the clinical record. The results suggest that anxiety symptoms are very common in this population and that the presence of anxiety is associated with a more severe clinical profile, including higher rates of suicidality and increased use of psychotropic medications during pregnancy and postpartum. Although anxiety symptom levels were markedly elevated in this sample, anxiety disorders were diagnosed at relatively low rates. Implications for clinical practice, including discharge and treatment planning, are discussed. PMID- 24469529 TI - Suicide ideation and acceptability among females aged 15 to 34 years in rural China. AB - The suicide rate of females is very close to that of males in China, in contrast to Western societies, in which the rates of male suicide outnumber those of females by three to four times. This study investigated the prevalence of suicidal ideation and prosuicide attitude (acceptability) among females of childbearing age. With the Chinese version of the Scale for Suicide Ideation and the General Social Survey questionnaire, we examined the demographic and psychological risk factors of suicide among Chinese rural young females aged 15 to 34 years. Logistic regression analysis was performed to explore the factors related to suicidal ideation and suicide acceptability. The prevalence rates of suicidal ideation and suicide acceptability among the sampled females are 22.5% and 3.8%, respectively. Education, depression, social support, hopelessness, and negative life events were significantly associated with suicidal ideation. Ethnicity, education, abortion, and depression were significantly associated with suicide acceptability. There is statistical difference between suicide ideation and acceptability. The results indicate that mental disorder remains a major risk factor of suicidal ideation. Sociodemographic and psychological characteristics are associated with suicide acceptability. PMID- 24469530 TI - Impact of sleep complaints and depression outcomes among participants in the standard medical intervention and long-term exercise study of exercise and pharmacotherapy for depression. AB - The aim of this study was to examine the effects of exercise and sertraline on disordered sleep in patients with major depressive disorder (MDD). Methods The Standard Medical Intervention and Long-term Exercise study randomized the patients with MDD (n = 202) to one of four arms: a) supervised exercise, b) home based exercise, c) sertraline therapy, and d) placebo pill. Sleep disturbance was assessed with three sleep-related items from the Hamilton Rating Scale for Depression (HAM-D) before and after 4 months of treatment. The patients were followed for 12 months to assess the prognostic value of sleep disturbance on MDD relapse and recovery.Results Comparison of the active treatment and placebo groups showed no treatment differences in HAM-D sleep complaints after 4 months (p = 0.758). However, residual insomnia symptoms after treatment were strongly associated with elevated depressive symptoms assessed by the HAM-D after 4 months (beta = 0.342, p < 0.0001) and MDD relapse (odds ratio, 1.55; 95% confidence interval, 1.15-2.10; p = 0.004) assessed at 1-year follow-up (16 months after randomization). Neither exercise nor sertraline was associated with greater improvements in sleep disturbance compared with the placebo controls. However, residual symptoms of insomnia after successful treatment of MDD predicted relapse, highlighting the clinical importance of addressing insomnia in patients with MDD. PMID- 24469531 TI - Personality disorder cognitions in the eating disorders. AB - Patients with eating disorder have relatively high rates of comorbid personality disorder diagnoses, including both anxiety-based personality disorders (obsessive compulsive and avoidant) and borderline personality disorder. However, there is preliminary evidence that the core cognitions underlying personality pathology in the eating disorders are those related specifically to anxiety. This article builds on that evidence, replicating and extending the findings with a large sample of patients with eating disorder (N = 374). There were no differences in personality disorder cognitions between eating disorder diagnoses. This study also examines the possibility that there are clusters of patients, differentiated by patterns of personality disorder cognition. Affect-related personality disorder cognitions were key to understanding the role of personality pathology in the eating disorders. It is suggested that those cognitions should be considered when planning psychological treatments. PMID- 24469532 TI - Distinguishing spirituality from other constructs: commentary on Lindeman et al. PMID- 24469533 TI - Spirituality studies are in need of differentia: a reply to Garssen and Visser. PMID- 24469535 TI - M1 macrophages, key contributors to lymphoid neogenesis in atherosclerotic aorta. PMID- 24469536 TI - Interactions between thromboxane A2, thromboxane/prostaglandin (TP) receptors, and endothelium-derived hyperpolarization. AB - Endothelium-dependent smooth muscle hyperpolarization (EDH) increasingly predominates over endothelium-derived nitric oxide (NO) as a participant in vasodilation as vessel size decreases. Its underlying nature is highly variable between vessel types, species, disease states, and exact experimental conditions, and is variably mediated by one or more transferable endothelium-derived hyperpolarizing factors and/or the electrotonic spread of endothelial hyperpolarization into the media via gap junctions. Although generally regarded (and studied) as a mechanism that is independent of NO and prostanoids, evidence has emerged that the endothelium-derived contracting factor and prostanoid thromboxane A2 can modulate several signalling components central to EDH, and therefore potentially curtail vasodilation through mechanisms that are distinct from those putatively involved in direct smooth muscle contraction. Notably, vascular production of thromboxane A2 is elevated in a number of cardiovascular disease states that promote endothelial dysfunction. This review will therefore discuss the mechanisms through which thromboxane A2 interacts with and modulates EDH, and will also consider the implications of such cross-talk in vasodilator control in health and disease. PMID- 24469537 TI - Natural killer (NK) cells augment atherosclerosis by cytotoxic-dependent mechanisms. AB - AIM: Although natural killer (NK) cells, a key component of the innate immune system, have been identified in human and mouse atherosclerotic lesions, their role in atherosclerosis development remains unclear. To determine their role in atherosclerosis, we used both loss- and gain-of-function experiments in ApoE(-/-) mice fed a high-fat diet. METHODS AND RESULTS: Treatment of ApoE(-/-) mice with anti-Asialo-GM1 antibodies depleted NK cells without affecting other lymphocytes, including natural killer T cells, and greatly attenuated atherosclerosis. These effects were independent of plasma lipids. To confirm the atherogenicity of NK cells, these cells were isolated from mouse spleens for adoptive transfer into lymphocyte-deficient ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice. Transfer of NK cells from wild-type mice into ApoE(-/-)Rag2(-/-)IL2rg(-/-) mice doubled lesion size, confirming a pro-atherogenic role for NK cells. To determine whether their atherogenicity was dependent on production of interferon-gamma (IFN-gamma) or cytotoxins, we compared the transfer of NK cells deficient in IFN-gamma, perforin, and granzyme B with the transfer of wild-type NK cells. Transfer of IFN gamma-deficient NK cells increased lesion size in the lymphocyte-deficient ApoE( /-) mice as wild-type NK cells. However, granzyme B- and perforin-deficient NK cells did not affect lesion size. Only wild-type NK cells increased necrotic core size, whereas perforin- and granzyme B-deficient NK cells did not. Plasma lipid levels were largely unaffected by the cell transfer. CONCLUSION: Our loss- and gain-of-function findings provide definitive evidence that NK cells are atherogenic and their production of perforin and granzyme B contributes to atherosclerosis and the expansion of necrotic cores. PMID- 24469538 TI - Inhibiting thrombosis without causing bleeding: can EP3 blockers fulfil the dream? PMID- 24469539 TI - A portable microchip for ultrasensitive and high-throughput assay of thrombin by rolling circle amplification and hemin/G-quadruplex system. AB - In this work, a convenient and high-throughput colorimetric assay was developed on an aptamer-modified microchip for ultrasensitive detection of thrombin using rolling circle amplification and G-quadruplex DNAzyme. This system consisted of an aptamer-modified microchip and a secondary aptamer. The secondary aptamer contained a thrombin aptamer and a primer with a G-quadruplex circular template. RCA technology was used to improve the sensitivity by producing the multiple G quadruplex units. To generate colorimetric signal, G-quadruplex DNAzyme was used to catalyze the H2O2-mediated oxidation of 2,2'-azinobis (3-ethylbenzothiozoline) 6-sulfonic acid. At the optimal conditions, the linear range for thrombin was 0.100-50.000 pg/mL, and the limit of detection was down to 0.083 pg/mL. Moreover, the developed method was successfully applied to detect thrombin from human plasma and serum, indicating that this approach has great potential in clinical diagnosis and medical investigation. PMID- 24469540 TI - A paper disk equipped with graphene/polyaniline/Au nanoparticles/glucose oxidase biocomposite modified screen-printed electrode: toward whole blood glucose determination. AB - In this work, a convenient, fast, low cost, small sample volume and in situ detection of glucose in human whole blood has been developed by using a disposable screen-printed carbon electrode (SPCE) coupled with a paper disk. To perform the assay, the SPCE was modified with graphene/polyaniline/Au nanoparticles/glucose oxidase (Gr/PANI/AuNPs/GOD) biocomposite and then covered by a paper disk impregnated with the sample. After introducing PBS on the paper disk, the electrochemical measurement was carried out. The assay was based on measuring the current decrease of flavin adenine dinucleotide (FAD) in GOD provoked by the enzyme-substrate reaction using differential pulse voltammetry (DPV). The analytical performance was comparable to conventional methods, and covered the full range of clinically relevant concentrations of glucose in whole blood. This new paper-based electrochemical glucose sensor shows promise in applying point-of-care (POC) device in whole blood tests, and particularly being appropriate for use in the developing world and in resource-limited settings. PMID- 24469541 TI - Foxp3 gene expression in oral lichen planus: a clinicopathological study. AB - CD4+CD25+ Forkhead-box protein 3 (Foxp3+) regulatory T cells are important in oral lichen planus (OLP). The present study aimed to investigate Foxp3 expression in CD4+CD25+ T cells of peripheral blood mononuclear cells and oral lesions in patients diagnosed with OLP, who were grouped as OLP subtype, duration and relapse. Using quantitative polymerase chain reaction (qPCR), western blotting and immunohistochemistry, Foxp3 expression levels in explants of oral lesions and CD4+CD25+ T cells from 32 patients with OLP were measured and compared, with 10 healthy subjects as the control group. Foxp3 mRNA expression levels in the explants of oral lesions and circulating CD4+CD25+ T cells in patients with OLP were significantly higher than those in the control group (P<0.05). In patients with clinically erosive lesions, Foxp3 mRNA expression was significantly lower in circulating CD4+CD25+ T cells and tissue explants compared to patients with reticular lesions (P<0.01 and P<0.05, respectively), and lowest in patients with a history of OLP of >1 year or with a history of relapse (P<0.05 and P<0.01, respectively). Foxp3 protein levels in reticular OLP were significantly higher than those in erosive OLP and the control group. The incidence of Foxp3 protein expression in OLP tissues was 36.24+/-18.92 and 10.44+/-6.51% in normal oral mucosa (P=0.019). Atrophic/erosive OLP lesions showed a higher proportion of Foxp3-expressing cells than that of reticular OLP lesions (P<0.05). This study indicated that Foxp3 expression in patients with OLP is associated with the severity and duration of the disorder, suggesting altered immune suppression in the development, clinical course and responsiveness to treatment. PMID- 24469542 TI - First example of quinine-squaramide catalyzed enantioselective addition of diphenyl phosphite to ketimines derived from isatins. AB - A highly enantioselective addition of diphenyl phosphite to ketimines derived from isatins has been achieved using a bifunctional organocatalyst, quinine derived squaramide catalyst. This method works efficiently with several ketimines to produce the corresponding 3-amino-2-oxoindolin-3-yl-phosphonates in excellent yields with high enantioselectivity (up to 98% ee). PMID- 24469543 TI - The substituent effect on benzene dications. AB - It was recently postulated that the benzene ring and its 4n + 2 pi-electron analogues are resistant to the substituent effect due to the fact that such systems tend to retain their delocalized character. Therefore, the 4n pi-electron dicationic form of benzene should appear to be less resistant to the substituent effect, as compared with its parent neutral molecule. For this reason the effect of substitution on the dicationic form of benzene was thoroughly investigated and the consequences of single and double substitution (of para- and meta-type) were assessed by means of several parameters, including various aromaticity indices and the Substituent Effect Stabilization Energy (SESE) parameter. It is shown that, distinct from neutral benzene, its dicationic form is much more sensitive to the substitution. However, the dicationic benzene itself, as a moiety with a significant deficit of electrons, will be considered as a strongly electron withdrawing centre, thus interacting in a cooperative way with electron-donating substituents and in an anticooperative way with electron-withdrawing substituents. Clear differences between singlet- and triplet-state dicationic forms of benzene were also found. Triplet state structures seem to be significantly more delocalized, and as a consequence less sensitive to the substituent effect than the singlet state structures. Finally, the para- and meta type substitution was investigated and it was found that the disubstituted dicationic benzene exhibits significantly different behaviour from that of neutral benzene. Although the difference between para- and meta-substitution can be found for dicationic benzene, the mechanism responsible for such an observation is different from that present in neutral benzene. Finally, it is shown how and why double ionization of benzene reduces its aromatic character in the singlet dication whereas aromaticity is essentially conserved in the triplet dication. The above findings highlight that in the case of charged analogues of benzene the aromaticity indices can be misleading and are to be used with great precaution. PMID- 24469544 TI - Inter-annual variation in the response of leaf-out onset to soil moisture increase in a teak plantation in northern Thailand. AB - To understand the impact of inter-annual climate change on vegetation-atmosphere mass and energy exchanges, it has become necessary to explore changes in leaf-out onset in response to climatic fluctuations. We examined the response of leaf-out and transpiration onset dates to soil moisture in a teak plantation in northern Thailand based on a 12-year leaf area index and sap flow measurements. The date of leaf-out and transpiration onset varied between years by up to 40 days, and depended on the initial date when the relative extractable water in a soil layer of 0-0.6 m (Theta) was greater than 0.2 being consistent with our previous results. Our new finding is that the delay in leaf-out and transpiration onset relative to the initial date when Theta > 0.2 increases linearly as the initial date on which Theta > 0.2 becomes earlier. The delay spans about 20 days in years when Theta > 0.2 occurs in March (the late dry season)-much earlier than usual because of heavy pre-monsoon rainfalls-while there is little delay in years when Theta > 0.2 occurs in May. This delay indicates the influence of additional factors on leaf-out onset, which controls the delay in the response of leaf-out to soil moisture increase. The results increased our knowledge about the pattern and extent of the changes in leaf phenology that occur in response to the inter annual climate variation in tropical regions, where, in particular, such research is needed. PMID- 24469545 TI - Fan-precooling effect on heat strain while wearing protective clothing. AB - This study compared heat strain during walking while wearing impermeable protective suits between fan-precooling and nonprecooling conditions. Six males engaged in 60 min of walking at a moderate speed (~2.5 km/h) in a hot environment (37 degrees C, 40% relative humidity). Fanning using a fan (4.5 m/s) and spraying water over the body before wearing the suits produced significantly lower rectal temperature before the walking (37.3 +/- 0.1 degrees C vs. 37.0 +/- 0.1 degrees C, P < 0.05). In addition, whilst walking, rectal temperature was significantly lower in the precooling condition (maximum difference: 0.4 degrees C at 15 min of walking; 38.0 +/- 0.1 degrees C vs. 37.8 +/- 0.1 degrees C at the end of walking, P < 0.05). Although skin temperature decreased during fanning, no difference was observed during walking. Heart rate was lower in the precooling condition during the early stages of walking. Thermal and fatigue perceptions whilst walking did not differ between the conditions. Body weight loss was significantly lower in the precooling condition. These results may indicate that fan precooling attenuates exertional heat strain while wearing impermeable protective clothing. The fan-cooling method is practical, convenient, and yields lower heat strain during prolonged moderate exertion. PMID- 24469546 TI - Lifestyle intervention and cardiovascular disease risk reduction in low-income Hispanic immigrant women participating in the Illinois WISEWOMAN program. AB - Cardiovascular disease (CVD) is the leading cause of death for Hispanic women in the United States. In 2001, the Illinois Department of Public Health received funding from the Centers for Disease Control and Prevention to implement the enhanced WISEWOMAN program (IWP) to address the disproportionate CVD risk among uninsured and underinsured women enrolled in the Illinois Breast and Cervical Cancer Early Detection Program. This paper presents the results of the Spanish language arm of the IWP. Spanish speaking IWP participants were recruited from two sites, and randomized into either the minimum intervention (MI) or the enhanced intervention (EI) group. Both groups received CVD risk factor screening and educational handouts. The EI group also received an integrated 12-week nutrition and physical activity lifestyle change intervention. Of the 180 Spanish speaking immigrants in this sample, 90 (50%) received the EI and 90 (50%) received the MI. At baseline there were no significant differences between group demographics or clinical values. At post-intervention, the EI group showed improvements in fat intake, fiber intake, moderate intensity physical activity, and total physical activity. At 1 year only the change in fiber intake remained. A significant improvement was also seen in body mass index (BMI) at the 1-year follow-up. The IWP Spanish-language arm was moderately successful in addressing risk factors for CVD in this population. The behavior changes that sustained up to a year were an increase in fiber intake and a decrease in BMI. PMID- 24469547 TI - Isolation and characterization of methane utilizing bacteria from wetland paddy ecosystem. AB - Methylotrophic bacteria which are known to utilize C1 compounds including methane. Research during past few decades increased the interest in finding out novel genera of methane degrading bacteria to efficiently utilize methane to decrease global warming effect. Moreover, evaluation of certain known plant growth promoting strains for their methane degrading potential may open up a new direction for multiple utility of such cultures. In this study, efficient methylotrophic cultures were isolated from wetland paddy fields of Gujarat. From the overall morphological, biochemical and molecular characterization studies, the isolates were identified and designated as Bacillus aerius AAU M 8; Rhizobium sp. AAU M 10; B. subtilis AAU M 14; Paenibacillus illinoisensis AAU M 17 and B. megaterium AAU M 29. Gene specific PCR analysis of the isolates, P. illinoisensis, B. aerius, Rhizobium sp. and B. subtilis showed presence of pmoA gene encoding alpha subunit particulate methane monooxygenase cluster. B. megaterium, P. illinoisensis, Rhizobium sp. and Methylobacterium extrorquens showed presence of mmoX gene encoding alpha subunit of the hydroxylase component of the soluble methane monooxygenase cluster. P. illinoisensis and Rhizobium sp. showed presence mxaF gene encoding alpha subunit region of methanol dehydrogenase gene cluster showing that both isolates are efficient utilizers of methane. To the best of our knowledge, this is the first time report showing presence of methane degradation enzymes and genes within the known PGPB group of organisms from wet land paddy agro-ecosystem, which is considered as one of the leading methane producer. PMID- 24469548 TI - High level expression, purification and immunogenicity analysis of a protective recombinant protein against botulinum neurotoxin type E. AB - Botulinum neurotoxin type E heavy chain consists of two domains: N-terminal half as a translocation domain and C-terminal half (Hcc) as a binding domain. In this research a synthetic gene fragment encoding the binding domain of botulinum neurotoxin type E (BoNT/E-Hcc) was highly expressed in Escherichia coli by pGEX4T 1 vector. After purification, the recombinant BoNT/E-Hcc was evaluated by SDS PAGE and western blot (immunoblot) analysis. Average yields obtained in this research were 3.7 mg recombinant BoNT/E-Hcc per liter of bacterial culture. The recombinant protein was injected in mice for study of its protection ability against botulinum neurotoxin type E challenges. The challenge studies showed that, vaccinated mice were fully protected against 104 * minimum lethal dose of botulinum neurotoxin type E. PMID- 24469549 TI - Comments on "Omentum-preserving gastrectomy for advanced gastric cancer: a propensity-matched retrospective cohort study". PMID- 24469550 TI - The critical residues of helix 5 for in vitro pentamer formation and stability of the papillomavirus capsid protein, L1. AB - The mono-site mutations of the absolutely conserved residues, (464)LGR(466), in the alpha-helix 5 (h5) of HPV16 L1 completely disrupted the pentamer formation. The implication of this finding is the potential usage of a h5-like peptide as the reagent to interfere with the pentamer formation and stability as an anti-HPV reagent. PMID- 24469552 TI - Bright yellow and green Eu(II) luminescence and vibronic fine structures in LiSrH3, LiBaH3 and their corresponding deuterides. AB - The luminescence of Eu(2+) in hydride and deuteride perovskite hosts LiMH3 and LiMD3 (M = Sr, Ba) is reported. Bright yellow (M = Sr) and green (M = Ba) emission is observed and assigned to 4f(6)5d-4f(7) emission from Eu(2+) in the highly symmetric 12-coordinated M(2+) site (m3[combining macron]m). The long wavelength of the emission is explained by the strong covalence and crystal field splitting in europium's coordination by hydride anions. A well-resolved vibrational structure in the emission and excitation spectra of Eu(2+) in the Sr compounds allows for an accurate determination of the energy of the lowest 4f(6)5d state and vibrational frequencies, for both the hydride and deuteride. The isotope effect on the energy of the fd states is small (~70 cm(-1)), as expected. Surprisingly, also the vibrational energies observed in the vibronic progression are similar for the d-f emission spectra in LiSrH3 and LiSrD3. This is explained by strong coupling of the d-f emission with low energy acoustic phonons which, contrary to optical phonons, are not strongly affected by replacing H by D. The present results provide insight into the long wavelength Eu(2+) emission in hydride coordination and the influence of isotope replacement on the luminescence. PMID- 24469551 TI - Outcome after reconstruction of the proximal humerus for tumor resection: a systematic review. AB - BACKGROUND: Tumors of the appendicular skeleton commonly affect the proximal humerus, but there is no consensus regarding the best reconstructive technique after proximal humerus resection for tumors of the shoulder. QUESTIONS/PURPOSES: We wished to perform a systematic review to determine which surgical reconstruction offers the (1) best functional outcome as measured by the Musculoskeletal Tumor Society (MSTS) score, (2) longest construct survival, and (3) lowest complication rate after proximal humerus resection for malignant or aggressive benign tumors of the shoulder. METHODS: We searched the literature up to June 1, 2013, from MEDLINE, EMBASE, and the Cochrane Library. Only studies reporting results in English, Dutch, or German and with followups of 80% or more of the patients at a minimum of 2 years were included. Twenty-nine studies with 693 patients met our criteria, seven studies (24%) were level of evidence III and the remainder were level IV. Studies reported on reconstruction with prostheses (n = 17), osteoarticular allografts (n = 10), and allograft-prosthesis composites (n = 11). Owing to substantial heterogeneity and bias, we narratively report our results. RESULTS: Functional scores in prosthesis studies ranged from 61% to 77% (10 studies, 141 patients), from 50% to 78% (eight studies, 84 patients) in osteoarticular graft studies, and from 57% to 91% (10 studies, 141 patients) in allograft-prosthesis composite studies. Implant survival ranged from 0.38 to 1.0 in the prosthesis group (341 patients), 0.33 to 1.0 in the osteoarticular allograft group (143 patients), and 0.33 to 1.0 in allograft-prosthesis group (132 patients). Overall complications per patient varied between 0.045 and 0.85 in the prosthesis group, 0 and 1.5 in the osteoarticular graft group, and 0.19 and 0.79 in the prosthesis-composite graft group. We observed a higher fracture rate for osteoarticular allografts, but other specific complication rates were similar. CONCLUSIONS: Owing to the limitations of our systematic review, we found that allograft-prosthesis composites and prostheses seem to have similar functional outcome and survival rates, and both seem to avoid fractures that are observed with osteoarticular allografts. Further collaboration in the field of surgical oncology, using randomized controlled trials, is required to establish the superiority of any particular treatment. PMID- 24469553 TI - Approximation of papillary muscles for ischaemic mitral regurgitation combined with coronary artery bypass grafting and left ventricular aneurysmectomy: a case report. AB - A 72-year-old female presented with severe ischaemic mitral regurgitation following a recent myocardial infarction. She had no significant past medical history. Pre-operative echocardiogram assessment demonstrated preserved tendinous cords of the mitral leaflets, a mitral valve annulus measuring 3.2 cm with end systolic coaptation of 0.3 cm, impaired left ventricular function with an ejection fraction of 35% and significant ventricular dilatation. Cardiac magnetic resonance imaging (MRI) showed delayed enhancement in the anterolateral, septal and lateral walls and confirmed the impairment of the left ventricle and a large aneurysmal deformation. On-table transoesophageal echo showed that the distance between the two papillary muscles was over 4 cm. We performed coronary artery bypass grafting combined with a Dor Procedure and papillary muscle approximation using a polytetrafluoroethylene (PTFE) vascular graft as a sling, without the insertion of a mitral annuloplasty ring. Postoperative echo and cardiac MRI showed improved left ventricular systolic function and reduced left ventricle volume associated with mild mitral regurgitation. We conclude that papillary muscles approximation as a method of mitral valve repair is a very effective procedure for functional ischaemic mitral regurgitation. PMID- 24469554 TI - Gender and anti-thrombotic therapy: from biology to clinical implications. AB - Cardiovascular diseases actually remain the leading cause of death and morbidity in Western countries, and it is the most common cause of death in American women accounting for about one third of all deaths. Women remain underrepresented in published trial literature relative to their disease prevalence. Strong evidence do exists demonstrating gender differences in efficacy (ischemic risk) and safety (bleeding risk) associated with antithrombotic treatment, mostly related to different values of body mass, and renal function in women than men. Several data show a higher platelet reactivity in females and a higher prevalence of high platelet reactivity on aspirin and clopidogrel therapy. In primary prevention, the use of aspirin is associated with a higher reduction of risk for ischemic stroke in females and for myocardial infarction in males. In the setting of ACS, female gender is associated with a significantly higher risk of bleeding. In summary, there are some gender-related aspects of guidance in the complex spectrum of the net clinical benefit related to antithrombotic treatment. PMID- 24469556 TI - Prioritizing factors influencing nurses' satisfaction with hospital information systems: a fuzzy analytic hierarchy process approach. AB - Our aim was to use the fuzzy analytic hierarchy process approach to prioritize the factors that influence nurses' satisfaction with a hospital information system. First, we reviewed the related literature to identify and select possible factors. Second, we developed an analytic hierarchy process framework with three main factors (quality of services, of systems, and of information) and 22 subfactors. Third, we developed a questionnaire based on pairwise comparisons and invited 10 experienced nurses who were identified through snowball sampling to rate these factors. Finally, we used Chang's fuzzy extent analysis method to compute the weights of these factors and prioritize them. We found that information quality was the most important factor (58%), followed by service quality (22%) and then system quality (19%). In conclusion, although their weights were not similar, all factors were important and should be considered in evaluating nurses' satisfaction. PMID- 24469555 TI - Translating multilevel theory into multilevel research: challenges and opportunities for understanding the social determinants of psychiatric disorders. AB - INTRODUCTION: The observation that features of the social environment, including family, school, and neighborhood characteristics, are associated with individual level outcomes has spurred the development of dozens of multilevel or ecological theoretical frameworks in epidemiology, public health, psychology, and sociology, among other disciplines. Despite the widespread use of such theories in etiological, intervention, and policy studies, challenges remain in bridging multilevel theory and empirical research. METHODS: This paper set out to synthesize these challenges and provide specific examples of methodological and analytical strategies researchers are using to gain a more nuanced understanding of the social determinants of psychiatric disorders, with a focus on children's mental health. To accomplish this goal, we begin by describing multilevel theories, defining their core elements, and discussing what these theories suggest is needed in empirical work. In the second part, we outline the main challenges researchers face in translating multilevel theory into research. These challenges are presented for each stage of the research process. In the third section, we describe two methods being used as alternatives to traditional multilevel modeling techniques to better bridge multilevel theory and multilevel research. These are (1) multilevel factor analysis and multilevel structural equation modeling; and (2) dynamic systems approaches. CONCLUSIONS: Through its review of multilevel theory, assessment of existing strategies, and examination of emerging methodologies, this paper offers a framework to evaluate and guide empirical studies on the social determinants of child psychiatric disorders as well as health across the life course. PMID- 24469557 TI - Effect of two probiotic strains of Lactobacillus on in vitro adherence of Listeria monocytogenes, Streptococcus agalactiae, and Staphylococcus aureus to vaginal epithelial cells. AB - The lactobacilli probiotics maintain a normal vaginal biota and prevent disease recurrence. This microorganisms form a pellicle on the vaginal epithelium that acts as a biologic barrier against colonization by pathogenic bacteria. In this paper were realized assays of exclusion, competition, and displacement. For these test, vaginal epithelial cells, two strains of lactobacilli and pathogenic bacteria (Staphylococcus aureus, Streptococcus agalactiae and Listeria monocytogenes) were used. The lactobacilli strains showed a great capacity of adherence, with a mean of 83.5 +/- 26.67 Lactobacillus fermentum cells and 56.2 +/- 20.87 Lactobacillus rhamnosus cells per vaginal epithelial cells. L. fermentum and L. rhamnosus were able to reduce the adherence of S. aureus, S. agalactiae and L. monocytogenes in a significant level in this assay (P < 0.01). The lactobacilli used in this study protect the vaginal epithelium through a series of barriers and interference mechanisms. The aim of present study was to assess the ability of vaginal Lactobacillus strains, selected for their probiotic properties, to block the adherence of pathogenic microorganisms in vitro by displacement, competition, and exclusion mechanisms. PMID- 24469558 TI - Correlation between glycated haemoglobin and glucose testing for diabetes mellitus screening. AB - Hemoglobin A1C is used to screen and diagnose diabetes but measurement of glucose in the blood is subject to several limitations, many of which are not widely appreciated. Blood glucose testing should be taken into consideration before taking the patient to be diabetic on the basis of abnormal HbA1c values. PMID- 24469559 TI - Immunocontraception stimulation advantages versus other fertility control methods. AB - The world population with an increase of 75% will be 10 billion by 2050. Current contraception methods have difficulties, and there is no safe and ideal way of contraception. Contraception, which based on immunocontraception stimulation, is a modern method presentation. This study is going to review and examine the response of anti-sperm anti-body in serum and uterus secretions, and resultant infertility induction rate. Despite of current different contradictions in the field of mature sperm protein capability in infertility induction, the results of this study showed that, immunocontraception stimulation is the best way of infertility induction. Antibody response induction is wholly depends on the type of immunogenic element and its method of presentation. Compared with other different methods of presentation, the intramuscular presentation method was efficient than mucous presentation methods. Perhaps the inefficiency of mucous methods is due to the largeness of mature sperm antigen and mucous cells inability in presentation of this antigen to immune system in mucous presentation methods. More studies should be done in future. PMID- 24469561 TI - Prevalence and determining factors of anemia and malnutrition among Egyptian children. AB - BACKGROUND: The first Millennium Development Goal to "eradicate extreme poverty and hunger" implied reducing by 50% the prevalence of underweight status among children younger than five years between 1990 and 2015. AIM OF WORK: This study investigates the prevalence and determining factors of anemia and malnutrition among children of Albasra village, one of the Egyptian villages, to produce directives for a management program. MATERIALS AND METHODS: All inhabitants aged between six months and 15 years (397 children) were subjected to a structured interview, clinical assessment, anthropometric assessment, and laboratory examination. A complete blood picture analysis and a hemoglobin percentage assessment were done. RESULTS: The main prevailing symptom in the two weeks preceding the survey was diarrhea (55%). Complete weaning before the age of 18 months occurred in 20.5% of the below-six children. The children more likely to be anemic were those under the age of two years, children having the first or more than the fourth order among their siblings, and those who suffered a diarrheal attack, vomiting, grunting, or chest in drawing within two weeks preceding the survey, among children completely weaned after the age of 24 months and those from a low socioeconomic level. Stunting was highest among younger children from extended families. Children who suffered a chronic disease were more likely to be wasted (13.2%). CONCLUSION: An understanding of the risk factors for anemia and malnutrition among a population is fundamental to provide efficient preventive and control measures. PMID- 24469560 TI - Autonomic system modification in Zen practitioners. AB - BACKGROUND: Meditation in its various forms is a traditional exercise with a potential benefit on well-being and health. On a psychosomatic level these exercises seem to improve the salutogenetic potential in man.Especially the cardiorespiratory interaction seems to play an important role since most meditation techniques make use of special low frequency breathing patterns regardless of whether they result from a deliberate guidance of breathing or other mechanisms, for example, the recitation of specific verse. During the different exercises of Zen meditation the depth and the duration of each respiratory cycle is determined only by the process of breathing. Respiratory manoeuvres during Zazen meditation may produce HR variability changes similar to those produces during biofeedback. Recognition that the respiratory sinus arrhythmia (RSA) was mediated by efferent vagal activity acting on the sinus node led investigators to attempt to quantify the fluctuations in R-R intervals that were related to breathing. MATERIALS AND METHODS: Nine Zen practitioners with five years of experience took part in the study. Autonomic nervous system function was evaluated by heart rate variability (HRV) analysis during 24-hours ECG recording during zen meditation and at rest. RESULTS: The data of this small observational study confirm that ZaZen breathing falls within the range of low frequency HR spectral bands. Our data suggest that the modification of HR spectral power remained also in normal day when the subject have a normal breathing. CONCLUSION: We suggest that the changes in the breathing rate might modify the chemoreflex and the continuous practice in slow breathing can reduce chemoreflex. This change in the automonic control of respiration can be permanent with a resetting of endogenous circulatory rhythms. PMID- 24469562 TI - Yellow oleander poisoning in eastern province: an analysis of admission and outcome. AB - INTRODUCTION: Cardiac toxicity after self-poisoning from ingestion of yellow oleander seeds is common in Eastern Sri Lanka. OBJECTIVE: To determine the clinical manifestations, cardiac arrhythmias, electrolytes abnormalities and outcome of management using currently available treatment, Poisoning Unit, Tertiary Care Hospital in Eastern Sri Lanka. MATERIALS AND METHODS: We studied 65 patients [Mean age : 23(+/- 0.43)yrs], (Male: Female=27:38) with yellow oleander poisoning (YOP) admitted to a Poisoning Unit, Tertiary Care Hospital in Eastern Sri Lanka from January to December 2011. RESULTS: Most patients are symptomatic who presented with classical symptoms of vomiting, abdominal pain and diarrhea. Cardiac dysrhythmias such as bradycardia or an irregular pulse are the most common findings on examination. Most symptomatic patients had conduction defects affecting the sinus node, the atrioventricular (AV) node, or both. Patients showing cardiac arrhythmias that required transfer for specialised management had significantly higher serum potassium concentrations. Almost all patients were treated with multiple activated charcoal even late presentation. Patients with brad arrhythmias were treated with intravenous boluses of atropine and intravenous infusions of isoprenaline. Temporary cardiac pacing was done for those not responding to drug therapy. There were two deaths (3.07%), both had third-degree heart block. They died even definitive treatment could be instituted. Of the remaining 63 patients, 54 (83.1%) patients required treatment, and 29 were treated with only atropine and/or isoprenaline while one required cardiac pacing in addition. 12 (18.4%) patients had arrhythmias that were considered life threatening (second-degree heart block type II, third-degree heart block and nodal bradycardia). They had good recovery even though they had developed cardiac toxicity. CONCLUSIONS: YOP are common among young females. The cardiac toxicity develops within 24 hrs of ingestion of YO seeds. The risk of toxicity has negative correlation with number of seeds. Most patients have nonspecific symptoms. AV conduction defects are common. Multiple activated charcoals alone were safe and adequate in most cases even late presentation. PMID- 24469563 TI - A 24 year-old male with yellow nail syndrome having bronchiactasis without pleural effusion as a pulmonary manifestation. AB - Yellow nail syndrome is a rare entity of unknown etiology. Classically, it consists of a triad of slow-growing yellow nails of fingers and toes, lymphedema, and pulmonary manifestations mainly pleural effusion. Other pulmonary manifestations also have been described in the literature such as bronchiectasis, recurrent pneumonias, bronchitis, and sinusitis. This paper describes a case of yellow nail syndrome which did not have the classic triad of the condition; he presented with progressive yellow hand and toe nails intermittent lymphedema, bronchctasis, and sinusitis without pleural effusion. PMID- 24469564 TI - Chronic myeloid leukemia with hyperdiploidy: a case report with review of literature. AB - Chronic myeloid leukemia (CML) is a common marrow stem cell neoplasm characterized by the presence of the Philadelphia (Ph) chromosome in more than 90% of patients. Studies have shown that CML can be associated with various other cytogenetic abnormalities. 5-10% of these cases can show complex translocations involving other chromosomes in addition to Ph chromosome. Here, we report a Ph positive CML patient with a hyperdiploid karyotype who presented clinically in chronic phase but progressed to blast crisis in spite of treatment with Imatinib. This case highlights the significance of cytogenetic abnormalities on the prognosis in CML. PMID- 24469565 TI - An unusual formation of sciatic nerve. AB - Sciatic nerve is the largest nerve and a branch of sacral plexus that controls hamstrings and all muscles of the lower limb below the knee. We are reporting a bilateral variant formation of the sciatic nerve found in a male human cadaver. The commencement of single sciatic nerve trunk formation was found to be in the lower gluteal region instead of the pelvic region. All the roots of the sciatic nerve, namely, the lumbosacral trunk (L4, L5), S1, S2, and S3 were observed to remain separate up to the lower part of the gluteal region. Incidence of this variation in general population needs to be investigated so as to create awareness among surgeons and anesthetists about the degree and extent of variation in sciatic nerve formation. Complete sciatic nerve blockages will fail even after multiple punctures and attempts if the sciatic nerve is present as separately sheathed bundles until the lower gluteal level. PMID- 24469566 TI - Levo-tetrahydropalmatine attenuates oxaliplatin-induced mechanical hyperalgesia in mice. AB - Common chemotherapeutic agents such as oxaliplatin often cause neuropathic pain during cancer treatment in patients. Such neuropathic pain is difficult to treat and responds poorly to common analgesics, which represents a challenging clinical issue. Corydalis yanhusuo is an old traditional Chinese medicine with demonstrated analgesic efficacy in humans. However, the potential analgesic effect of its active component, levo-tetrahydropalmatine (l-THP), has not been reported in conditions of neuropathic pain. This study found that l-THP (1-4 mg/kg, i.p.) produced a dose-dependent anti-hyperalgesic effect in a mouse model of chemotherapeutic agent oxaliplatin-induced neuropathic pain. In addition, we found that the anti-hyperalgesic effect of l-THP was significantly blocked by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg), suggesting a dopamine D1 receptor mechanism. In contrast, l-THP did not significantly alter the general locomotor activity in mice at the dose that produced significant anti hyperalgesic action. In summary, this study reported that l-THP possesses robust analgesic efficacy in mice with neuropathic pain and may be a useful analgesic in the management of neuropathic pain. PMID- 24469567 TI - The need of shared diagnostic protocols. PMID- 24469568 TI - Diagnostic flowcharts in osteomyelitis, spondylodiscitis and prosthetic joint infection. AB - Infections of the bone, spine and prosthetic joints are serious and complex conditions to diagnose and to treat. Structured diagnostic workup may very well improve the accuracy and speed of diagnosis, thereby improving the outcome since treatment may very well be more successful and less harmful if timely management is started. Literature shows no uniform advise on diagnosis. The EANM organized a consensus meeting with representatives from the involved disciplines in order to develop common flowcharts for the diagnosis of osteomyelitis, spondylodiscitis and prosthetic joint infections. In this report the proceedings of this consensus meeting, including the proposed flowcharts for diagnosis, are published. PMID- 24469569 TI - Common diagnostic flow charts for diagnosis and management of patients with an inflammatory bowel disease. AB - This paper presents the different views of the gastroenterologist, the radiologist and the nuclear medicine specialist in the management of inflammatory bowel disease. The role of clinical parameters and biochemical marker as well as the progressive use of the different imaging modalities: magnetic resonance, computerized tomography and nuclear medicine techniques is presented. The paper is an effort to combine the published European Crohn's and Colitis Organization, European Society of Gastrointestinal and Abdominal Radiology and European Association of Nuclear Medicine consensus with the conclusions of the multidisciplinary meeting organized in 2012 Milano during the EANM Congress with the objective of find a common diagnostic flowchart. PMID- 24469570 TI - Diagnostic performance of FDG PET or PET/CT in prosthetic infection after arthroplasty: a meta-analysis. AB - AIM: The purpose of this study was to systematically review and perform a meta analysis of published data regarding the diagnostic performance of positron emission tomography (PET) or PET/computed tomography (PET/CT) in prosthetic infection after arthroplasty. METHODS: A comprehensive computer literature search of studies published through May 31, 2012 regarding PET or PET/CT in patients suspicious of prosthetic infection was performed in PubMed/MEDLINE, Embase and Scopus databases. Pooled sensitivity and specificity of PET or PET/CT in patients suspicious of prosthetic infection on a per prosthesis-based analysis were calculated. The area under the receiver-operating characteristic (ROC) curve was calculated to measure the accuracy of PET or PET/CT in patients with suspicious of prosthetic infection. RESULTS: Fourteen studies comprising 838 prosthesis with suspicious of prosthetic infection after arthroplasty were included in this meta analysis. The pooled sensitivity of PET or PET/CT in detecting prosthetic infection was 86% (95% confidence interval [CI] 82-90%) on a per prosthesis-based analysis. The pooled specificity of PET or PET/CT in detecting prosthetic infection was 86% (95% CI 83-89%) on a per prosthesis-based analysis. The area under the ROC curve was 0.93 on a per prosthesis-based analysis. CONCLUSION: In patients suspicious of prosthetic infection, FDG PET or PET/CT demonstrated high sensitivity and specificity. FDG PET or PET/CT are accurate methods in this setting. Nevertheless, possible sources of false positive results and influcing factors should kept in mind. PMID- 24469571 TI - Notch1 silencing inhibits proliferation and invasion in SGC-7901 gastric cancer cells. AB - Downregulation of Notch1 has been shown to exert antineoplastic effects in vivo and in vitro. However, the role of the Notch1 gene in the proliferative and invasive ability of gastric cancer cells is not clear. In this study, we investigated the effect of Notch1 gene silencing on the proliferation and invasion of gastric cancer SGC-7901 cells. Small interfering RNA (siRNA) targeting Notch1 was transfected into SGC-7901 cells using Lipofectamine 2000. Proliferation of SGC-7901 cells was then determined by the MTT assay. Notch1 mRNA expression was determined by reverse transcription-polymerase chain reaction (RT PCR). Invasion of the SGC-7901 cells was detected by the Transwell assay. The protein levels of cyclin D1, cyclin A1 and cyclin-dependent kinase 2 (CDK2) were determined by western blotting. The mRNA levels of matrix metalloproteinase-2 (MMP-2) and cyclooxygenase-2 (COX-2) were determined by RT-PCR. Compared to the control group, the Notch1 mRNA level was significantly decreased following transfection. The growth and invasion rates of SGC-7901 cells were significantly reduced after Notch1 silencing. Additionally, the expression of cyclin D1 and cyclin A1 proteins and of the MMP-2 and COX-2 mRNAs was markedly attenuated. From these results, it was concluded that Notch1 gene silencing inhibits the proliferation of gastric SGC-7901 cells by decreasing the expression of cyclins D1 and A1, and reduces the invasive ability of SGC-7901 cells through the downregulation of MMP-2 and COX-2 genes. Thus, silencing of the Notch1 pathway may be a novel approach in the treatment of gastrointestinal cancer. PMID- 24469572 TI - [Localization of dehydrogenases of energy metabolism in the pholoem of Cucurbita pepo L]. AB - In the stem phloem of Cucurbita pepo the enzymes GAPDH, ADH, MDH, NADP-IDH, NAD IDH, G6PDH and SDH were localized histochemically with the aid of tetrazolium salt (NBT). When the stems were deep-frozen the most intense formation of formazan was found in companion cells, less in phloem parenchyma cells, and very little in sieve tubes.The distribution of enzymes in phloem markedly changes when stems were cut 2 minutes before freezing: 2,5 cm behind the sectional area little formazan was found. Companion cells and parenchyma cells had lost nearly all activity. 15 cm behind the sectional area there was again a higher concentration of formazan in the companion cells and parenchyma cells. In this region an even higher activity was detected in sieve tubes. 25-30 cm behind the sectional area the distribution of formazan was nearly the same as in the intact stems.Apparently activities of the enzymes tested primaily occur in the companion cells and parenchyma cells only. After wounding they are translocated into sieve tubes or exudate. PMID- 24469573 TI - Effect of poly-L-ornithine on isolated tobacco mesophyll protoplasts: Evidence against stimulated pinocytosis. AB - The effects of poly-L-ornithine on the surface membrane of isolated tobacco protoplasts have been examined in the electron microscope using a colloidal metal oxide and a spherical virus as marker substances. No evidence was found to suggest that isolated protoplasts take up either of these markers by a pinocytotic process. Poly-L-ornithine increased the degree of damage observed in fixed preparations, and specifically caused lesions of the plasmalemma which were favoured sites for the binding of both external marker substances. It is suggested that the function of poly-L-ornithine and other treatments used to obtain virus infection of protoplasts is to stress the cell membrane to allow a non-physiological entry of high molecular weight materials. Pinocytosis appears not to occur nor to be necessary for uptake of these materials under conditions of membrane stress. PMID- 24469574 TI - [Localisation of the alpha-amanitin-sensitive RNA-polymerase in nuclei of Acetabularia]. AB - An isolation medium for nuclei of Acetabularia mediterranea is described. The medium offers the possibility to keep nuclei alive (verified by reimplantation) for at least 10 min and to obtain nuclei with radioactively labelled RNA.The influence of alpha-amanitin on nucleolar and nucleoplasmatic RNA-synthesis is investigated autoradiographically. Amanitin inhibits the incorporation of uridine into the nucleoplasmatic RNA, whereas incorporation into the RNA of nucleoli is hardly or not at all influenced.We conclude that, in agreement with findings on animal cells, alpha-amanitin inhibits at least one of the RNA-polymerases localized in the nucleoplasm but does not markedly influence the RNA-polymerase of the nucleoli. PMID- 24469575 TI - Investigations on the growth and metabolism of cultured explants of Daucus carota : V. Effects of trace elements and growth factors on the solutes accumulated. AB - Earlier papers of this series relate to different growth-promoting substances and systems which, singly and in combination, have interacted with trace elements (Mn and Mo) and Fe to induce growth and to affect the metabolism of aseptic cultures of carrot. The solutes of cultured carrot cells (K(+), Na(+), Cl(-), total solutes) are also affected. Two clones were grown in 9 combinations of growth factors and under 4 trace-element regimes (a complete complement including Fe, and this complement lacking either Mn or Mo, or both Mn and Mo), a total of 36 treatments under otherwise standardized experimental conditions. Under the treatments applied the number of cells varied over a 35fold range and their average size over a 7fold range; the concomitant effects on their solutes are expressed in terms of concentrations and of total content per cell. Both growth and the solutes accumulated were variously affected by carrot growth-promoting system I (mediated by inositol), by system II (mediated by IAA), and by coconut milk in the presence of Fe, with and without Mn, Mo, or Mn and Mo.The greatest concentrations of total solutes occurred in tissue cultured in nutrient solutions which lacked the stimuli to rapid cell multiplication and were also limited by the trace elements Mn and Mo. Moreover, specific regulatory effects of the trace elements on solute content, not solely attributable to their effects on cell growth, have been noted. An imbalanced growth-factor regime (zeatin acting alone, i.e. without IAA) shifted the normal preference for K(+) over Na(+) strongly toward Na(+), a trend which could also be induced by certain trace elements and more balanced growth-factor regimes, e.g. in a basal coconut milk medium lacking only Mn.The data are interpreted in the context of views on the de-novo uptake of salts and solutes in cultured cells as they grow. These cells respond to a network, or matrix, of interacting factors by distinctive effects that are attributable to the component parts of the culture medium acting singly and in various combinations. These interactions (involving trace elements and exogenous growth factors) control growth (fresh weight, number and size of cells) and regulate the solutes (organic and inorganic; K(+) vs. Na(+); organic anions vs. Cl(-)) which the cells acquire as they grow and develop. The intensity of the response of the cultures to balanced, or imbalanced, growth factors creates the internal spaces accessible to solutes; and the metabolism, as it is also affected by growth factors and trace elements, determines how these spaces are to be filled at a given osmotic value. The evidence shows the range of factors that affect the accumulation of solutes in cells as they grow and is to be contrasted with conventional observations on mature cells held in steady states under conditions that preclude all growth and when only a single ionic species is followed over a very short interval of time. PMID- 24469576 TI - beta-Glucanases and non-cellulosic glucans in the developing oat plant. AB - The changes in the levels of various beta-glucan hydrolase activities in the second internode of the stem of the developing oat plant have been examined. Concurrent changes in the non-cellulosic beta-glucans contained in the corresponding total hemicelluloses were also studied. Possible relationships between the observed changes and the growth and development of the plant tissue are discussed. PMID- 24469577 TI - In vitro germination and pollen tube growth of maize (Zea mays L.) pollen : VIII. Storage temperature and pollen source effects. AB - Pollen grains from two hybrids, WF9xH55 (W) and K64xK55 (K) were collected and a sample from each was cultured immediately (0 h). The remainder was subdivided and stored at 2, 20, and 35 degrees C. At 3, 6, 12, 24, 36, 48, 72, 96, and 120 h, a sample was cultured. The culture medium contained 15% sucrose, 0.6% bacto-agar, 0.03% calcium nitrate and 0.01% boric acid. Storage at 2 degrees C resulted in a large increase in germination percentage in both W and K reaching a maximum at 24 h and then slowly decreasing with additional storage. No germination was observed at 96 h with W and at 120 h with K. The complete loss of germination occurred during a 24 h period and was very abrupt. At 20 degrees C, a similar but less pronounced pattern was observed. However, after 24 h, aggregates of 50-1 000 pollen grains developed during storage in both W and K. Storage of W at 35 degrees C slightly decreased the germination percentage at 3 h and eliminated it at 6 h. Storage of K at 35 degrees C substantially increased the germination percentage at 3 h with further increases in storage periods resulting in the aggregation of grains. This general pattern of an increase at shorter storage periods followed by a gradual decrease as the storage period was extended, was found for pollen tube length and growth rate. In vitro germination characteristics can be substantially altered by the temperature and length of storage and the response to storage is associated with pollen source. PMID- 24469578 TI - Effects of benzyladenine on the growth of waterlogged tomato plants. AB - Treatment of waterlogged tomato plants with benzyladenine relieved most of the symptoms of flooding injury. The effects of benzyladenine included maintenance of chlorophyll levels, reduced epinastic curvature of petioles, absence of adventitious roots, and stem growth greater than that of waterlogged control plants. PMID- 24469579 TI - The activity of uridine diphosphate-D-glucose-4-epimerase in cambial tissue and differentiating xylem isolated from sycamore (Acer pseudoplatanus) trees. AB - It is demonstrated that, contrary to another report, UDPGlc-4-epimerase is present in both sycamore (Acer pseudoplantanus) cambium and xylem tissue. It is suggested that the enzyme may be localised in the non-lignifying primary-walled cells common to both tissue fractions. PMID- 24469580 TI - Glutamine synthetase in the chloroplasts of Vicia faba. AB - A glutamine synthetase has been localised in the chloroplasts of Vicia faba. The enzyme has requirements for Mg(2+) and ATP in the biosynthetic reaction and in addition will catalyse a gamma-glutamyl transferase reaction in the presence of Mn(2+) and arsenate. The enzyme is inhibited by AMP, CTP, glycine and alanine. These results are discussed in relation to the possible chloroplastic synthesis of nucleotide bases. Estimations of glutamine amide-2-oxoglutarate amino transferase (oxido-reductase) have demonstrated only low levels of activity in the chloroplast extracts. This enzyme is generally active in organisms where GS has an assimilary role. It is coneluded that glutamine synthetase has a biosynthetic and not an assimilatory role in the chloroplast. PMID- 24469581 TI - Growth inhibitor from the root cap of Zea mays. AB - The downward lateral transport of at least one inhibitor produced in or released by the cap of a maize root partly explains differences in growth of the upper and lower sides of roots placed in the horizontal position.The relative activity or level of such a regulator increases with the increase in root length. PMID- 24469582 TI - A fluorene-based material containing triple azacrown ether groups: synthesis, characterization and application in chemosensors and electroluminescent devices. AB - We design a novel multifunctional fluorene-based material containing triple azacrown ether (FTC) not only for application in aqueous solution as a chemosensor towards Fe(3+) but also to enhance the electroluminescence of PLEDs using an environmentally stable aluminum cathode. The photo-physical and sensing properties were investigated by absorption and photoluminescence (PL) spectroscopy. The FTC exhibited specific selectivity and high sensitivity toward Fe(3+), with the Stern-Volmer coefficients (Ksv) being 1.59 * 10(5) M(-1) in a solvent mixture of tetrahydrofuran and water (THF-H2O = 9/1, v/v). The FTC maintained high selectivity toward Fe(3+) in the presence of ten interfering metal cations. The HOMO and LUMO levels were estimated to be -5.88 eV and -2.88 eV, respectively. The FTC significantly enhances the emission performance of PLEDs [ITO/PEDOT:PSS/MEH-PPV/EIL/Al] when used as an electron injection layer (EIL), especially in the presence of metal carbonates. Particularly, the device using K2CO3 doped FTC as the electron-injection layer (EIL) exhibited significantly enhanced performance compared to the one without EIL. The performance was significantly enhanced to 11 630 cd m(-2) and 1.47 cd A(-1), respectively, from 230 cd m(-2) and 0.03 cd A(-1) of the non-FTC device. Current results indicate that multifunctional fluorene-based material FTC is a potential candidate for selective detection of Fe(3+) and as an effective electron injection layer to enhance the performance of MEH-PPV. PMID- 24469583 TI - Agency and ownership are independent components of 'sensing the self' in the auditory-verbal domain. AB - 'Sensing the self' relies on the ability to distinguish self-generated from external stimuli. It requires functioning mechanisms to establish feelings of agency and ownership. Agency is defined causally, where the subjects action is followed by an effect. Ownership is defined by the features of the effect, independent from the action. In our study, we manipulated these qualities separately. 13 right-handed healthy individuals performed the experiment while 76 channel EEG was recorded. Stimuli consisted of visually presented words, read aloud by the subject. The experiment consisted of six conditions: (a) subjects saw a word, read it aloud, heard it in their own voice; (b) like a, but the word was heard in an unfamiliar voice; (c) subject heard a word in his/her own voice without speaking; (d) like c, but the word was heard in an unfamiliar voice; (e) like a, but subjects heard the word with a delay; (f) subjects read without hearing. ERPs and difference maps were computed for all conditions. Effects were analysed topographically. The N100 (86-172 ms) displayed significant main effects of agency and ownership. The topographies of the two effects shared little common variance, suggesting independent effects. Later effects (174-400 ms) of agency and ownership were topographically similar, suggesting common mechanisms. Replicating earlier studies, significant N100 suppression was observed, with a topography resembling the agency effect. 'Sensing the self' appears to recruit from at least two very distinct processes: an agency assessment that represents causality and an ownership assessment that compares stimulus features with memory content. PMID- 24469584 TI - Essential role of Gly33 in a novel organic solvent-tolerant lipase from Serratia marcescens ECU1010 as determined by site-directed mutagenesis. AB - A novel lipase lipB from Serratia marcescens ECU1010 is highly stable in the presence of organic solvents. By sequence and structure comparison with homologous lipase lipA, three amino acid residues were found to be different between them. To identify the residues which increase the organic solvent stability of lipB, residues that potentially provide this stability were mutated to the ones of lipA at equivalent positions. The replacement of Gly at position 33 by Asp obviously decreased its stability in organic solvents. Molecular modeling and structural analysis also suggested that the Gly33 residue is important for the organic solvent stability of lipB. PMID- 24469585 TI - Isolation, characterization and immunolocalization of a seed dominant CaM from finger millet (Eleusine coracana L. Gartn.) for studying its functional role in differential accumulation of calcium in developing grains. AB - To understand the exceptional high grain calcium accumulation in finger millet grains, a calmodulin (CaM) gene that is strongly expressed during developing spikes of high grain calcium genotype was further characterized. Using 5'-3' RACE, the full-length CaM open reading frame (ORF) was isolated and the deduced protein sequence showed the presence of four characteristic EF motifs. Phylogenetic analysis showed that the finger millet CaM (Eleusine coracana calmodulin [EcCaM]) was identical to the rice CaM 1-1. Southern hybridization showed the presence of at least four copies of CaM gene that might be located on different regions of the finger millet "AABB" genome. Immunodetection using monospecific polyclonal anti-EcCaM antibodies revealed that EcCaM is localized in the embryo and aleurone layer and accumulates in higher amounts in high grain calcium genotype compared to the low grain calcium genotype. Furthermore, in silico analysis showed that EcCaM interacts with aquaporin which indicates that calcium is probably delivered to developing spike via mass flow of water. These results indicate that higher expression of CaM might cause greater stimulation of the downstream calcium transport machinery operative in the aleurone layer leading to the higher calcium accumulation in the grains of high grain calcium genotype. PMID- 24469586 TI - Mineral composition of seawater bittern nigari products and their effects on changing of browning and antioxidant activity in the glucose/lysine maillard reaction. AB - Seawater bittern (nigari) is a concentrated solution remaining after the crystallization process of salt that has been used as a coagulant for tofu. Recently, various nigari products are distributed in the East Asia. To clarify the properties of nigari products, major mineral composition of six nigari products was determined. Then, effects of the nigari on the browning and antioxidant activity during the glucose/lysine Maillard reaction were investigated. Though the predominant cation was Mg(2+), the content was varied by each product (0.88-6.49 mol/L). The other major ion contents were also varied. Each 0.5 mol/L of D-glucose and L-lysine were incubated with the nigari (5-50% (v/v)) or nigari-related salts (1 or 2 mol/L). The browning (OD at 465 nm) and antioxidant activity (1,1-diphenyl-2-picrylhydrazyl (DPPH) radical-scavenging capacity and ferrous-reducing power) were increased remarkably by the nigari containing high Mg(2+) content. The browning tended to be high with sulfates (Na2SO4, (NH4)2SO4). On the other hand, high content of MgCl2 decreased slightly the browning and antioxidant activity. These results suggest that the reaction and antioxidant activities were affected not only by salinity and cations but also by anions and other elements in the nigari. PMID- 24469587 TI - Enhanced fumaric acid production from brewery wastewater and insight into the morphology of Rhizopus oryzae 1526. AB - The present work explores brewery wastewater as a novel substrate for fumaric acid production employing the filamentous fungal strain Rhizopus oryzae 1526 through submerged fermentation. The effects of different parameters such as substrate total solid concentrations, fermentation pH, incubation temperature, flask shaking speed, and inoculum size on the fungal morphologies were investigated. Different morphological forms (mycelium clumps, suspended mycelium, and solid/hairy pellets) of R. oryzae 1526 were obtained at different applied fermentation pH, incubation temperature, flask shaking speed, and inoculum size. Among all the obtained morphologies, pellet morphology was found to be the most favorable for enhanced production of fumaric acid for different studied parameters. Scanning electron microscopic investigation was done to reveal the detailed morphologies of the pellets formed under all optimized conditions. With all the optimized growth conditions (pH 6, 25 degrees C, 200 rpm, 5% (v/v) inoculum size, 25 g/L total solid concentration, and pellet diameter of 0.465 +/- 0.04 mm), the highest concentration of fumaric acid achieved was 31.3 +/- 2.77 g/L. The results demonstrated that brewery wastewater could be used as a good substrate for the fungal strain R. oryzae 1526 in submerged fermentation for the production of fumaric acid. PMID- 24469588 TI - Probiotics tailored to the infant: a window of opportunity. AB - Initial neonatal gut colonization is a crucial stage for developing a healthy physiology, beneficially influenced by breast-feeding. Breast milk has been shown not only to provide nutrients and bioactive immunological compounds, but also commensal bacteria, including gut-associated anaerobic bacteria such as Bifidobacterium species. Infant formulas are increasingly supplemented with probiotic bacteria despite uncertainties regarding their efficacy, and lack of mechanistic understanding. Breast milk may be a valuable source of such bacteria which, upon validation of their mechanism of action, might open a window of opportunity for developing probiotic-supplemented infant formula with proven efficacy. PMID- 24469589 TI - Self-reported discrimination, diabetes distress, and continuous blood glucose in women with type 2 diabetes. AB - We investigated whether self-reported racial discrimination was associated with continuous glucose levels and variability in individuals with diabetes, and whether diabetes distress mediated these associations. Seventy-four Black and White women with type 2 diabetes completed the Experience of Discrimination scale, a measure of lifetime racial discrimination, and the Problem Areas in Diabetes, a measure of diabetes distress. Participants wore a continuous glucose monitor for 24 h after 8 h of fasting, a standard meal, and a 4-h run in period. Higher discrimination predicted higher continuous mean glucose and higher standard deviation of glucose. For both mean and standard deviation of glucose, a race * discrimination interaction indicated a stronger relationship between discrimination and glucose for Whites than for Blacks. Diabetes distress mediated the discrimination-mean glucose relationship. Whites who report discrimination may be uniquely sensitive to distress. These preliminary findings suggest that racial discrimination adversely affects glucose control in women with diabetes, and does so indirectly through diabetes distress. Diabetes distress may be an important therapeutic target to reduce the ill effects of racial discrimination in persons with diabetes. PMID- 24469590 TI - Acculturation, gender, and mental health of Southeast Asian immigrant youth in Canada. AB - The relationships between mental health, protective factors and acculturation among Southeast Asian youth were examined in this study using a gender-based analysis. Population-based data from the 2008 British Columbia Adolescent Health Survey were used to examine differences in extreme stress and despair by acculturation. Associations between emotional distress and hypothesized protective factors were examined using logistic regression. Stratified analyses were performed to assess gender-related differences. Recent immigrant youth reported higher odds of emotional distress. Family connectedness and school connectedness were linked to lower odds of extreme stress and despair among girls. Family connectedness was associated with lower odds of extreme stress and despair among boys. Higher cultural connectedness was associated with lower odds of despair among boys but with higher odds of extreme stress among girls. Findings are discussed in relation to acculturation and gender-based patterns in protective factors for mental health among Southeast Asian immigrant youth. PMID- 24469591 TI - Detecting depression in pregnancy: validation of EPDS in British Pakistani mothers. AB - Recent reports suggest that antenatal depression is as prevalent as postnatal depression. The Edinburgh Postnatal Depression Scale (EPDS) is the most widely used tool to detect postnatal depression, which can also detect depression during the antenatal period. Mothers of Pakistani origin have the highest birth rate in the UK. The validity of EPDS has not been assessed in this group. A prospective cohort of 714 women in their third trimester of pregnancy completed the EPDS while waiting for their antenatal visit. Women scoring 12 or more on the EPDS, and a random sample of low scores were assessed with the Schedule for Clinical Assessment in Neuropsychiatry to establish psychiatric diagnosis. A cut-off point of 8 showed the best discrimination with sensitivity = 89.6% and specificity 54.7%. Positive predictive value was 29.4 and negative predictive value was 96.2. The area under the curve (AUC) was 0.72 (0.66-0.78). When language is taken into account the area under the ROC curve for subjects who preferred the Urdu or Punjabi language is slightly higher at 0.79 than those who preferred English (0.61). We have not been able to find a single clear cut-off is a result of the AUCs not being particularly large, and confirms that the EPDS should only be used as a screen and not for diagnostic purposes. The larger AUC for the Urdu/Punjabi speakers than for the English speakers suggests that the EPDS is as good a screen for this group as for the indigenous English population. PMID- 24469592 TI - Dopaminergic contributions to hippocampal pathophysiology in schizophrenia: a computational study. AB - Since the original formulation of the dopamine hypothesis, a number of other cellular-level abnormalities--eg, NMDA receptor hypofunction, GABA system dysfunction, neural connectivity disturbances--have been identified in schizophrenia, but the manner in which these potentially interact with hyperdopaminergia to lead to schizophrenic symptomatology remains uncertain. Previously, we created a neuroanatomically detailed, biophysically realistic computational model of hippocampus in the control (unaffected) and schizophrenic conditions, implemented on a 72-processor supercomputer platform. In the current study, we apply the effects of dopamine (DA), dose-dependently, to both models on the basis of an exhaustive review of the neurophysiologic literature on DA's ion channel and synaptic level effects. To index schizophrenic behavior, we use the specific inability of the model to attune to the 40 Hz (gamma band) frequency, a finding that has been well replicated in the clinical electroencephalography (EEG) and magnetoencephalography literature. In trials using 20 'simulated patients', we find that DA applied to the control model produces modest increases in 40 Hz activity, similar to experimental studies. However, in the schizophrenic model, increasing DA induces a decrement in 40 Hz resonance. This modeling work is significant in that it suggests that DA's effects may vary based on the neural substrate on which it acts, and--via simulated EEG recordings-points to the neurophysiologic mechanisms by which this may occur. We also feel that it makes a methodological contribution, as it exhibits a process by which a large amount of neurobiological data can be integrated to run pharmacologically relevant in silico experiments, using a systems biology approach. PMID- 24469593 TI - mTORC1 inhibition in the nucleus accumbens 'protects' against the expression of drug seeking and 'relapse' and is associated with reductions in GluA1 AMPAR and CAMKIIalpha levels. AB - The mechanistic target of rapamycin complex 1 (mTORC1) is necessary for synaptic plasticity, as it is critically involved in the translation of synaptic transmission-related proteins, such as Ca(2+)/Calmodulin-dependent kinase II alpha (CAMKIIalpha) and AMPA receptor subunits (GluAs). Although recent studies have implicated mTORC1 signaling in drug-motivated behavior, the ineffectiveness of rapamycin, an mTORC1 inhibitor, in suppressing cocaine self-administration has raised questions regarding the specific role of mTORC1 in drug-related behaviors. Here, we examined mTORC1's role in three drug-related behaviors: cocaine taking, withdrawal, and reinstatement of cocaine seeking, by measuring indices of mTORC1 activity and assessing the effect of intra-cerebroventricular rapamycin on these behaviors in rats. We found that withdrawal from cocaine self-administration increased indices of mTORC1 activity in the nucleus accumbens (NAC). Intra cerebroventricular rapamycin attenuated progressive ratio (PR) break points and reduced phospho-p70 ribosomal S6 kinase, GluA1 AMPAR, and CAMKIIalpha levels in the NAC shell (NACsh) and core (NACc). In a subsequent study, we treated rats with intra-NACsh infusions of rapamycin (2.5 MUg/side/day for 5 days) during cocaine self-administration and then tracked the expression of addiction-relevant behaviors through to withdrawal and extinction. Rapamycin reduced drug seeking in signaled non-drug-available periods, PR responding, and cue-induced reinstatement, with these effects linked to reduced mTORC1 activity, total CAMKIIalpha, and GluA1 AMPAR levels in the NACsh. Together, these data highlight a role for mTORC1 in the neural processes that control the expression and maintenance of drug reward, including protracted relapse vulnerability. These effects appear to involve a role for mTORC1 in the regulation of GluA1 AMPARs and CAMKIIalpha in the NACsh. PMID- 24469594 TI - In vivo imaging of cerebral dopamine D3 receptors in alcoholism. AB - Animal studies support the role of the dopamine D3 receptor (DRD3) in alcohol reinforcement or liking. Sustained voluntary alcohol drinking in rats has been associated with an upregulation of striatal DRD3 gene expression and selective blockade of DRD3 reduces ethanol preference, consumption, and cue-induced reinstatement. In vivo measurement of DRD3 in the living human brain has not been possible until recently owing to a lack of suitable tools. In this study, DRD3 status was assessed for the first time in human alcohol addiction. Brain DRD3 availability was compared between 16 male abstinent alcohol-dependent patients and 13 healthy non-dependent age-matched males using the DRD3-preferring agonist positron emission tomography (PET) radioligand [(11)C]PHNO with and without blockade with a selective DRD3 antagonist (GSK598809 60 mg p.o.). In striatal regions of interest, where the [(11)C]PHNO PET signal represents primarily DRD2 binding, no differences were seen in [(11)C]PHNO binding between the groups at baseline. However, baseline [(11)C]PHNO binding was higher in alcohol-dependent patients in hypothalamus (VT: 16.5 +/- 4 vs 13.7 +/- 2.9, p = 0.040), a region in which the [(11)C]PHNO signal almost entirely reflects DRD3 availability. The reductions in regional receptor binding (VT) following a single oral dose of GSK598809 (60 mg) were consistent with those observed in previous studies across all regions. There were no differences in regional changes in VT following DRD3 blockade between the two groups, indicating that the regional fractions of DRD3 are similar in the two groups, and the increased [(11)C]PHNO binding in the hypothalamus in alcohol-dependent patients is explained by elevated DRD3 in this group. Although we found no difference between alcohol-dependent patients and controls in striatal DRD3 levels, increased DRD3 binding in the hypothalamus of alcohol-dependent patients was observed. This may be relevant to the development of future therapeutic strategies to treat alcohol abuse. PMID- 24469595 TI - Current and emerging opportunities for molecular simulations in structure-based drug design. AB - An overview of the current capabilities and limitations of molecular simulation of biomolecular complexes in the context of computer-aided drug design is provided. Steady improvements in computer hardware coupled with more refined representations of energetics are leading to a new appreciation of the driving forces of molecular recognition. Molecular simulations are poised to more frequently guide the interpretation of biophysical measurements of biomolecular complexes. Ligand design strategies emerge from detailed analyses of computed structural ensembles. The feasibility of routine applications to ligand optimization problems hinges upon successful extensive large scale validation studies and the development of protocols to intelligently automate computations. PMID- 24469596 TI - Emergency department CT screening of patients with nontraumatic neurological symptoms referred to the posterior fossa: comparison of thin versus thick slice images. AB - Evaluation of the posterior fossa (PF) on 5-mm-thick helical CT images (current default) has improved diagnostic accuracy compared to 5-mm sequential CT images; however, 5-mm-thick images may not be ideal for PF pathology due to volume averaging of rapid changes in anatomy in the Z-direction. Therefore, we sought to determine if routine review of 1.25-mm-thin helical CT images has superior accuracy in screening for nontraumatic PF pathology. MRI proof of diagnosis was obtained within 6 h of helical CT acquisition for 90 consecutive ED patients with, and 88 without, posterior fossa lesions. Helical CT images were post processed at 1.25 and 5-mm-axial slice thickness. Two neuroradiologists blinded to the clinical/MRI findings reviewed both image sets. Interobserver agreement and accuracy were rated using Kappa statistics and ROC analysis, respectively. Of the 90/178 (51 %) who were MR positive, 60/90 (66 %) had stroke and 30/90 (33 %) had other etiologies. There was excellent interobserver agreement (kappa > 0.97) for both thick and thin slice assessments. The accuracy, sensitivity, and specificity for 1.25-mm images were 65, 44, and 84 %, respectively, and for 5-mm images were 67, 45, and 85 %, respectively. The diagnostic accuracy was not significantly different (p > 0.5). In this cohort of patients with nontraumatic neurological symptoms referred to the posterior fossa, 1.25-mm-thin slice CT reformatted images do not have superior accuracy compared to 5-mm-thick images. This information has implications on optimizing resource utilizations and efficiency in a busy emergency room. Review of 1.25-mm-thin images may help diagnostic accuracy only when review of 5-mm-thick images as current default is inconclusive. PMID- 24469597 TI - An environmental scan of advance care planning decision AIDS for patients undergoing major surgery: a study protocol. AB - BACKGROUND: Patients who undergo major surgery are at risk for perioperative morbidity and mortality. It would be appropriate to initiate advance care planning with patients prior to surgery, but surgeons may experience difficulty initiating such conversations. Rather than focus on changing clinician behavior, advance care planning decision aids can be an innovative vehicle to motivate advance care planning among surgical patients and their families. OBJECTIVE: The purpose of this paper is to describe a study protocol for conducting an environmental scan concerning advance care planning decision aids that may be relevant to patients undergoing high-risk surgery. METHODS/DESIGN: This study will gather information from written or verbal data sources that incorporate professional and lay perspectives: a systematic review, a grey literature review, key informant interviews, and patient and family engagement. It is envisioned that this study will generate three outcomes: a synthesis of current evidence, a summary of gaps in knowledge, and a taxonomy of existing advance care planning decision aids. DISCUSSION: This environmental scan will demonstrate principles of patient-centered outcomes research, and it will exemplify a pioneering approach for reviewing complex interventions. Anticipated limitations are that information will be gathered from a small sample of patients and families, and that potentially relevant information could also be missing from the environmental scan due to the inclusion/exclusion criteria. Outcomes from the environmental scan will inform future patient-centered research to develop and evaluate a new decision aid. PMID- 24469598 TI - A red light-controlled synthetic gene expression switch for plant systems. AB - On command control of gene expression in time and space is required for the comprehensive analysis of key plant cellular processes. Even though some chemical inducible systems showing satisfactory induction features have been developed, they are inherently limited in terms of spatiotemporal resolution and may be associated with toxic effects. We describe here the first synthetic light inducible system for the targeted control of gene expression in plants. For this purpose, we applied an interdisciplinary synthetic biology approach comprising mammalian and plant cell systems to customize and optimize a split transcription factor based on the plant photoreceptor phytochrome B and one of its interacting factors (PIF6). Implementation of the system in transient assays in tobacco protoplasts resulted in strong (95-fold) induction in red light (660 nm) and could be instantaneously returned to the OFF state by subsequent illumination with far-red light (740 nm). Capitalizing on this toggle switch-like characteristic, we demonstrate that the system can be kept in the OFF state in the presence of 740 nm-supplemented white light, opening up perspectives for future application of the system in whole plants. Finally we demonstrate the system's applicability in basic research, by the light-controlled tuning of auxin signalling networks in N. tabacum protoplasts, as well as its biotechnological potential for the chemical-inducer free production of therapeutic proteins in the moss P. patens. PMID- 24469599 TI - Thermal degradation kinetics and decomposition mechanism of PBSu nanocomposites with silica-nanotubes and strontium hydroxyapatite nanorods. AB - Novel poly(butylene succinate) (PBSu) nanocomposites containing 5 and 20 wt% mesoporous strontium hydroxyapatite nanorods (SrHNRs) and silica nanotubes (SiNTs) were prepared by melt-mixing. A systematic investigation of the thermal stability and decomposition kinetics of PBSu was performed using pyrolysis-gas chromatography-mass spectroscopy (Py-GC-MS) and thermogravimetry (TG). Thorough studies of evolving decomposition compounds along with the isoconversional and model-fitting analysis of mass loss data led to the proposal of a decomposition mechanism for PBSu. Moreover, the effects of SrHNRs and SiNTs on the thermal stability and decomposition kinetics of PBSu were also examined in detail. The complementary use of these techniques revealed that the incorporation of SiNTs in PBSu does not induce significant effects neither on its thermal stability nor on its decomposition mechanism. In contrast, the addition of SrHNRs resulted in the catalysis of the initial decomposition steps of PBSu and also in modified decomposition mechanisms and activation energies. The evolving gaseous products of PBSu and their evolution pattern in the SiNT nanocomposites were the same as in neat PBSu, while they were slightly modified for the SrHNR nanocomposites, confirming the findings from thermogravimetric analysis. PMID- 24469600 TI - Prandial effect on the systemic exposure of amisulpride. AB - A substituted benzamide, amisulpride is an atypical antipsychotic and a specific antagonist for dopamine D2 and D3 receptors. The prandial effect on amisulpride absorption remains unclear, therefore, this study was designed to investigate the effect of food on the systemic exposure to amisulpride in healthy volunteers. The study was a randomized, two-way crossed trial in which a single oral dose of amisulpride was administered on two occasions, with 7-days washout period between each drug administration. The volunteers were randomly divided into two groups and received amisulpride (50 mg) with Korean traditional food or under fasting state. Blood was serially taken, and the plasma amisulpride concentrations were measured by LC/MS/MS. At fasting state, amisulpride reached the first peak (37.1 +/- 13.3 ng/ml) at ~2.3 h, and decreased down to 19.4 +/- 4.3 ng/ml until 3.5 h, and then again went up to the second peak (25.3 +/- 5.8 ng/ml) at 5 h followed by a slow decay with 10.6 h of half-life. In contrast, no double peaks were shown when the drug was given with meal. The maximum concentration of amisulpride (56.0 +/- 12.7 ng/ml) was increased by a 1.5-fold compared with that under fasting (p > 0.05), and the time to peak shortened a little (1.7 +/- 0.6 h). PMID- 24469601 TI - Down-regulation of oxidative stress and COX-2 and iNOS expressions by dimethyl lithospermate in aged rat kidney. AB - Oxidative stress has been proposed to be a major cause of aging and many age related diseases. Peroxynitrite (ONOO(-)), formed from the reaction of superoxide ((*)O2 (-)) and nitric oxide (NO), is a cytotoxic species that can oxidize various cellular components, such as proteins, lipids, and DNA. The present study investigated whether dimethyl lithospermate (DML), isolated from Salvia miltiorrhiza, modulates age-related increases of ONOO(-), NO, and reactive species (RS) levels and expressions of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). For this study, 20-month-old rats were intraperitoneally injected with 5 or 10 mg/kg/day of DML, and 6-month-old rats were used as young control animals. Our results indicated that DML reduces ONOO( ) levels in a dose-dependent manner. The data also revealed that DML has significant inhibitory effects on NO metabolites and RS generation in a dose dependent manner during aging. Furthermore, the results of Western blot analysis revealed that DML treatment reduces age-associated increases in COX-2 and iNOS expressions. Thus, this study found that DML caused the decrease of renal oxidative stress and COX-2 and iNOS expressions in aged rats. The significance of the present study is the finding of DML in its potential application against the aging process. PMID- 24469603 TI - Astragaloside IV possesses antiarthritic effect by preventing interleukin 1beta induced joint inflammation and cartilage damage. AB - The saponin astragaloside IV (AST) is one of major active components purified from Astragalus membranaceus (Fisch) Bge, which has been used in traditional Chinese medicine to treat immune disorders including rheumatoid arthritis (RA). The effects of AST on the suppression of experimental arthritis and its possible mechanisms are unknown. We measured the paw swelling of ankle joints, splenocyte proliferation, interleukin 1beta (IL-1beta), tumor necrosis factor alpha (TNFalpha) and nitric oxide (NO) formation by macrophages in rat adjuvant-induced arthritis (AIA). Intraarticular injection of IL-1beta to rat knee joint for inducing the edema and in vitro IL-1beta-stimulated cartilage impairment were examined. The results showed that oral treatment of AST (100 mg/kg/day) suppressed the joint inflammation and inhibited IL-1beta, TNFalpha and NO production in macrophages from AIA rats. Macrophages were one of AST targeted cells, and mediated the reduced splenocyte proliferation in AIA rats. In addition, AST reduced the swelling induced by intraarticular injection of IL 1beta, and protected against IL-1beta-induced damage of cartilage proteoglycan synthesis and chondrocyte proliferation. We conclude that AST possesses antiarthritic effect and prevents IL-1beta-induced joint inflammation and cartilage destruction. These findings suggest that AST may be used for the treatment of RA and other inflammatory joint diseases. PMID- 24469602 TI - Protective effects of 2',4'-dihydroxy-6'-methoxy-3',5'-dimethylchalcone against hydrogen peroxide-induced oxidative stress in hepatic L02 cell. AB - 2',4'-Dihydroxy-6'-methoxy-3',5'-dimethylchalcone (DMC) is a chalcone isolated from the buds of Cleistocalyx operculatus (Roxb.) Merr. et Perry, and the hepatoprotective effects of DMC on Kunming mice have been studied in previous study. However, the effects of DMC on hepatocyte toxicity and corresponding mechanism remain unclear. The aim of this study was to evaluate the hepatoprotective mechanism of DMC in human hepatocytes (L02) treated with H2O2. The results demonstrated that pretreatment with DMC effectively protected H2O2 induced cell viability loss, cell membrane damage (lactate dehydrogenase, nitric oxide production and caspase-3 accumulation. Besides, DMC pretreatment increased the amount of glutathione, decreased malondialdehyde and the percentage of apoptotic L02 cells compared with only H2O2 treated group. Taken together, these results indicated that DMC had hepatoprotective effects against H2O2-induced liver injury by alleviating oxidative stress and apoptosis process in L02 cells, and DMC might be a potential candidate for the intervention of liver diseases. PMID- 24469604 TI - Comparative effectiveness of cycling of tumor necrosis factor-alpha (TNF-alpha) inhibitors versus switching to non-TNF biologics in rheumatoid arthritis patients with inadequate response to TNF-alpha inhibitor using a Bayesian approach. AB - Alternative tumor necrosis factor-alpha (TNF-alpha) inhibitors and non-TNF biologics are available as treatment options for rheumatoid arthritis patients who exhibit inadequate response to TNF-alpha inhibitor (TNF-IR patients). These agents have considerable efficacy compared with placebo, but head-to-head comparisons among these agents have not been performed. The objective of this study was to use Bayesian approach to compare the effectiveness of cycling TNF alpha inhibitors versus switching to non-TNF biologics in TNF-IR patients. A systematic review was conducted using MEDLINE and Cochrane library. Key endpoints were the American College of Rheumatology (ACR) responses of 20/50/70 and the health assessment questionnaire (HAQ) score change at six months. Bayesian outcomes were calculated as the probability that OR is greater than one and HAQ score change difference is less than zero. Compared with TNF-alpha inhibitors, non-TNF biologics were associated with higher ACR response rates; in ACR20, the OR was 1.639 for abatacept [P(OR > 1) = 90.7 %], 1.871 for rituximab [P(OR > 1) = 96.2 %] and 3.52 for tocilizumab [P(OR > 1) = 99.9 %]. Similar trends were shown in the HAQ change comparison; the median differences (MD) were -0.259 for abatacept [P(MD < 0) = 100 %], -0.160 for rituximab [P(MD < 0) = 98.2 %], and 0.200 for tocilizumab [P(MD < 0) = 99.3 %]. In conclusion, switching to non-TNF biologics was more effective than cycling TNF-alpha inhibitor in TNF-IR patients. PMID- 24469605 TI - Sediment quality evolution (2001-2011) in the Ebro River basin (Spain). AB - Spatio-temporal variations in sediment quality (20 sample sites) of the Ebro River basin between 2001 and 2011 have been assessed. The self-organizing map classified the sediment samples according to similarities in their chemical compositions. Its powerful visualization tools helped establish the main pollution contribution on each sample. Most of the samples showed low values of the mean-probable effect concentration quotient through time. However, six samples presented several quality issues related to some trace elements or polycyclic aromatic hydrocarbons. Finally, geoaccumulation index values calculated using estimates of background trace element concentrations suggested anthropogenic influences in more than half of the samples. PMID- 24469606 TI - Sorption of cadmium and zinc in selected species of epigeic mosses. AB - The sorption abilities of seven moss species growing on the area of Bory Stobrawskie forest (southern Poland) were tested in laboratory. Sorption was carried out in solutions of Zn and Cd chlorides. It has been shown that the sorption properties depend on the moss species and increases in the series as follows: Polytrichum commune < Leucobryum glaucum < Eurhynchium praelongum < Thuidium tamtariscifolium <= Dicranum scoparium <= Pleurozium schreberi < Sphagnum sp. With help of microscope images, it was also demonstrated that one of the factors affecting the sorption properties of mosses was the level of their surface development. The determined sorption capacity of Zn varies according to species of mosses from 0.0491 to 0.1287 mmol g(-1), and in relation to Cd from 0.0319 to 0.1335 mmol g(-1). The described results may be important in the process of biomonitoring research design and in the test results interpretation. PMID- 24469607 TI - Controlling exfoliation in order to minimize damage during dispersion of long SWCNTs for advanced composites. AB - We propose an approach to disperse long single-wall carbon nanotubes (SWCNTs) in a manner that is most suitable for the fabrication of high-performance composites. We compare three general classes of dispersion mechanisms, which encompass 11 different dispersion methods, and we have dispersed long SWCNTs, short multi-wall carbon nanotubes, and short SWCNTs in order to understand the most appropriate dispersion methods for the different types of CNTs. From this study, we have found that the turbulent flow methods, as represented by the Nanomizer and high-pressure jet mill methods, produced unique and superior dispersibility of long SWCNTs, which was advantageous for the fabrication of highly conductive composites. The results were interpreted to imply that the biaxial shearing force caused an exfoliation effect to disperse the long SWCNTs homogeneously while suppressing damage. A conceptual model was developed to explain this dispersion mechanism, which is important for future work on advanced CNT composites. PMID- 24469608 TI - Moist exposed burn ointment promotes cutaneous excisional wound healing in rats involving VEGF and bFGF. AB - Cutaneous delayed wounds are a challenging clinical problem, and vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) exhibit key roles in wound healing. Moist exposed burn ointment (MEBO), a Chinese burn ointment with a USA patented formulation, has been reported to promote chronic ischemic and neurogenic ulcer healing in patients; however, the underlying mechanisms remain unclear. In the present study, MEBO significantly promoted the formation of granulation tissue in cutaneous excisional wounds, shortened the time of wound healing, and increased neovascularization and the number of fibroblasts. Furthermore, as well as enhancing the protein expression, MEBO application also increased the gene expression of VEGF and bFGF. The results indicate that MEBO promotes cutaneous excisional wound healing by at least partially enhancing VEGF and bFGF production, implicating the potential uses of MEBO for delayed cutaneous wound healing. PMID- 24469609 TI - Molecular analysis of cluster headache. AB - OBJECTIVES: Cluster headache (CH) is characterized by severe, recurrent, unilateral attacks of extreme intensity and brief duration. Variants in a myriad of genes were studied in sporadic CH patients, often with conflicting results. METHODS: We studied gene mutations in some candidate genes, hypocretin receptor 2, Clock, and alcohol dehydrogenase 4 (ADH4), in 54 unrelated sporadic CH patients and in 200 controls in 8 kindreds/families that included more affected and nonaffected cases. Furthermore, we performed the whole-genome scanning by comparative genomic hybridization, searching for rearrangements associated with DNA gain or loss in a subset of sporadic and familial CH and control participants. RESULTS: The analysis of candidate genes revealed that only allele and genotype frequency of the 2 ADH4 mutations resulted significantly between sporadic CH and controls; the same mutations were homozygous in CH patients from 2 families. The comparative genomic hybridization analysis revealed 2 novel rearrangements that involved the intron regions of thyrotropin-releasing hormone degrading enzyme and neurexin 3 (NRXN3) genes, respectively. The first arrangement was present either in CH or in controls, whereas the second one was specifically found in some sporadic and familial CH cases. CONCLUSIONS: Our data (although obtained on a small number of cases) confirm the genetic heterogeneity of CH, suggesting that mutations in the ADH4 gene and a novel rearrangement involving NRXN3 gene might be related to CH in a subset of cases. PMID- 24469610 TI - Traumatic functional pathology of the masticatory system as being responsible for headaches: an odontologic standpoint. PMID- 24469612 TI - The impact of timing and duration of thiopurine treatment on first intestinal resection in Crohn's disease: national UK population-based study 1989-2010. AB - OBJECTIVES: The efficacy of thiopurines (TPs) in altering the risk of surgery in Crohn's disease (CD) remains controversial. We evaluated the impact of TP therapy, optimal timing, and duration of TP therapy on first intestinal resection rates using a population-based cohort. METHODS: We constructed a population-based cohort of incident cases of CD between 1989 and 2005. We used the Kaplan-Meier analysis to calculate time trends in TP use and first intestinal resection in three groups defined by time period of diagnosis: 1989-1993, 1994-1999, and 2000 2005 groups A, B, and C, respectively. We quantified impact of duration and timing of TP treatment on likelihood of surgery using Cox regression and propensity score matching. RESULTS: We identified 5,640 eligible patients with CD. The 5-year cumulative probability of TP use increased from 12, 18, to 25% ( P<0.0001) while probability of first intestinal resection decreased from 15, 12 to 9% (P<0.001) in groups A, B, and C, respectively. Patients treated with at least 6 months of TP therapy had a 44% reduction in the risk of surgery (hazards ratio (HR): 0.56; 95% confidence interval (CI): 0.37-0.85) and those receiving at least 12 months of TP therapy had a 69% reduction in the risk of surgery (HR: 0.31; 95% CI: 0.22-0.44). Early treatment (<12 months from diagnosis) vs. late treatment with TP showed no additional benefit in reducing risk of surgery (HR: 0.41; 95% CI: 0.27-0.61 vs. 0.21; 95% CI: 0.13-0.34). CONCLUSIONS: Over the past 20 years, TP use has doubled, whereas intestinal surgery has fallen by one-third among the UK population of Crohn's patients. Prolonged exposure is associated with a reduced likelihood of surgery whereby more than 12 months TP therapy reduces the risk of first intestinal surgery two-fold; however, early initiation of TP treatment offered no apparent additional benefit. PMID- 24469611 TI - Cognitive mediators of treatment outcomes in pediatric functional abdominal pain. AB - OBJECTIVES: Cognitive-behavioral (CB) interventions improve outcomes for many pediatric health conditions, but little is known about which mechanisms mediate these outcomes. The goal of this study was to identify whether changes in targeted process variables from baseline to 1 week posttreatment mediate improvement in outcomes in a randomized controlled trial of a brief CB intervention for idiopathic childhood abdominal pain. MATERIALS AND METHODS: Two hundred children with persistent functional abdominal pain and their parents were randomly assigned to 1 of 2 conditions: a 3-session social learning and CB treatment (N=100), or a 3-session educational intervention controlling for time and attention (N=100). Outcomes were assessed at 3-, 6-, and 12-month follow-ups. The intervention focused on altering parental responses to pain and on increasing adaptive cognitions and coping strategies related to pain in both parents and children. RESULTS: Multiple mediation analyses were applied to examine the extent to which the effects of the social learning and CB treatment condition on child gastrointestinal (GI) symptom severity and pain as reported by children and their parents were mediated by changes in targeted cognitive process variables and parents' solicitous responses to their child's pain symptoms. Reductions in parents' perceived threat regarding their child's pain mediated reductions in both parent-reported and child-reported GI symptom severity and pain. Reductions in children's catastrophic cognitions mediated reductions in child-reported GI symptom severity but no other outcomes. Reductions in parental solicitousness did not mediate outcomes. DISCUSSION: Results suggest that reductions in reports of children's pain and GI symptoms after a social learning and CB intervention were mediated at least in part by decreasing maladaptive parent and child cognitions. PMID- 24469613 TI - Adherence and efficacy of screening for low bone mineral density among ulcerative colitis patients treated with corticosteroids. AB - OBJECTIVES: Ulcerative colitis (UC) is associated with an increased risk of metabolic bone disease and fragility fractures. The aim of this study was to assess the adherence to the guidelines issued by the American Gastroenterology Association (AGA) for the screening for low bone density in UC patients and to assess the benefits of dual-energy X-ray absorptiometry (DXA) screening among corticosteroid (CS)-treated UC patients. METHODS: Nationwide Veterans Affairs system (VA) data were obtained. UC patients followed up in the VA between 2001 and 2011 and the occurrence of fragility fractures were identified using International Classification of Diseases, Ninth Revision codes. Exposure to CSs was assessed using pharmacy data. DXA screening was assessed using the VA procedure database. Post DXA screening, medication use was also assessed from the pharmacy database. Cox regression analysis was performed to calculate the hazard ratio (HR) of fragility fractures among those patients who received DXA compared with those who did not. RESULTS: We included 5,736 patients. Among them, 80 (1.4%) patients suffered from fragility fractures during the follow-up period. Overall adherence rate to AGA guidelines was 23%. Adherence rate was highest among postmenopausal women (48%) and lowest among men above 50 years of age (20%). UC patients who received DXA screening were more likely to be started on bisfosfonates (P<0.001), calcitonin (P<0.001), vitamin D, and calcium (P<0.001) compared with those who did not receive screening. Those who received DXA screening were half as likely (HR=0.5, 0.3-0.9, P=0.03) to develop fragility fractures as compared with those who did not receive screening. The benefits were more prominent among those with higher CS exposure. CONCLUSIONS: Rates of DXA screening were low among CS-treated UC patients. Those who received DXA screening were more likely to be started on antiresorptive therapy and supplemental medications and had a 50% reduction in the risk of fragility fractures. More efforts should be directed toward raising the adherence to AGA guidelines and the awareness of DXA benefits. PMID- 24469614 TI - Prospective evaluation of adverse events following lower gastrointestinal tract EUS FNA. AB - OBJECTIVES: There are virtually no data concerning the risk of adverse events (AEs) following lower gastrointestinal (LGI) endoscopic ultrasound (EUS). Our aim was to determine the incidence and factors associated with AEs following LGI EUS fine needle aspiration (FNA). METHODS: We conducted a prospective cohort study at a tertiary referral center. Five hundred and sixty-three patients underwent LGI EUS FNA between 1 January 2004 and 1 January 2012. We analyzed the 502 patients who had complete follow-up. AE severity was graded (1-5) utilizing Common Terminology Criteria or Visual Analog Scale. AEs were assessed during the procedures, in clinical follow-up, during phone interviews conducted at 7-14 days, and final clinical and/or phone interviews at 2-4 months. RESULTS: AEs developed in 103 (20.5%) patients and were classified as grade 1, 2, 3, or 4 in 34 (6.8%), 41 (8.2%), 23 (4.6%), and 5 (1.0%) patients, respectively. Bleeding and pain were the commonest AEs. No deaths occurred. On multivariate analysis, AEs were associated with prior pain (odds ratio (OR): 3.83, 95% confidence interval (CI): 2.35-6.25), FNA from a site other than a lymph node (LN) or gut wall (OR: 2.26, 95% CI: 1.10-4.70), and malignant FNA cytology (OR: 1.80, 95% CI: 1.10-2.97); serious (grade 3-4) AEs were associated with prior pain (OR: 15.21, 95% CI: 5.04-45.85) and FNA from a site other than a LN or gut wall (OR: 3.25, 95% CI: 1.15-9.20). CONCLUSIONS: LGI EUS FNA is associated with a high rate of serious grades 3-4 AEs. This may reflect the total number of associated interventions and the frequency of underlying pathology and symptoms. PMID- 24469615 TI - Systematic review and meta-analysis of the effect of the World Health Organization surgical safety checklist on postoperative complications. AB - BACKGROUND: The World Health Organization (WHO) surgical safety checklist (SSC) was introduced to improve the safety of surgical procedures. This systematic review evaluated current evidence regarding the effectiveness of this checklist in reducing postoperative complications. METHODS: The Cochrane Library, MEDLINE, Embase and CINAHL were searched using predefined inclusion criteria. The systematic review included all original articles reporting a quantitative measure of the effect of the WHO SSC on postoperative complications. Data were extracted for postoperative complications reported in at least two studies. A meta-analysis was conducted to quantify the effect of the WHO SSC on any complication, surgical site infection (SSI) and mortality. Yule's Q contingency coefficient was used as a measure of the association between effectiveness and adherence with the checklist. RESULTS: Seven of 723 studies identified met the inclusion criteria. There was marked methodological heterogeneity among studies. The impact on six clinical outcomes was reported in at least two studies. A meta-analysis was performed for three main outcomes (any complication, mortality and SSI). Risk ratios for any complication, mortality and SSI were 0.59 (95 per cent confidence interval 0.47 to 0.74), 0.77 (0.60 to 0.98) and 0.57 (0.41 to 0.79) respectively. There was a strong correlation between a significant decrease in postoperative complications and adherence to aspects of care embedded in the checklist (Q = 0.82; P = 0.042). CONCLUSION: The evidence is highly suggestive of a reduction in postoperative complications and mortality following implementation of the WHO SSC, but cannot be regarded as definitive in the absence of higher-quality studies. PMID- 24469616 TI - Systematic review of outcomes used to evaluate enhanced recovery after surgery. AB - BACKGROUND: Enhanced recovery pathways (ERPs) aim to improve patient recovery. However, validated outcome measures to evaluate this complex process are lacking. The objective of this review was to identify how recovery is measured in ERP studies and to provide recommendations for the design of future studies. METHODS: A systematic search of MEDLINE, Embase and Cochrane databases was conducted. Prospective studies evaluating ERPs compared with traditional care in abdominal surgery published between 2000 and 2013 were included. All reported outcomes were classified into categories: biological and physiological variables, symptom status, functional status, general health perceptions and quality of life (QoL). The phase of recovery measured was defined as baseline, intermediate (in hospital) and late (following discharge). RESULTS: A total of 38 studies were included based on the systematic review criteria. Biological or physiological variables other than postoperative complications were reported in 30 studies, and included return of gastrointestinal function (25 studies), pulmonary function (5) and physical strength (3). Patient-reported symptoms, including pain (16 studies) and fatigue (9), were reported less commonly. Reporting of functional status outcomes, including mobilization (16 studies) and ability to perform activities of daily living (4), was similarly uncommon. Health aspects of QoL were reported in only seven studies. Length of follow-up was generally short, with 24 studies reporting outcomes within 30 days or less. All studies documented in-hospital outcomes (intermediate phase), but only 17 reported postdischarge outcomes (late phase) other than complications or readmission. CONCLUSION: Patient-reported outcomes, particularly postdischarge functional status, were not commonly reported. Future studies of the effectiveness of ERPs should include validated, patient-reported outcomes to estimate better their impact on recovery, particularly after discharge from hospital. PMID- 24469617 TI - Systematic review of outcomes used to evaluate enhanced recovery after surgery (Br J Surg 2014; 101: 159-170). PMID- 24469618 TI - Systematic review and meta-analysis of enhanced recovery programmes in surgical patients. AB - BACKGROUND: Enhanced recovery programmes (ERPs) have been developed over the past 10 years to improve patient outcomes and to accelerate recovery after surgery. The existing literature focuses on specific specialties, mainly colorectal surgery. The aim of this review was to investigate whether the effect of ERPs on patient outcomes varies across surgical specialties or with the design of individual programmes. METHODS: MEDLINE, Embase, CINAHL and the Cochrane Central Register of Controlled Trials were searched from inception to January 2013 for randomized or quasi-randomized trials comparing ERPs with standard care in adult elective surgical patients. RESULTS: Thirty-eight trials were included in the review, with a total of 5099 participants. Study design and quality was poor. Meta-analyses showed that ERPs reduced the primary length of stay (standardized mean difference -1.14 (95 per cent confidence interval -1.45 to -0.85)) and reduced the risk of all complications within 30 days (risk ratio (RR) 0.71, 95 per cent c.i. 0.60 to 0.86). There was no evidence of a reduction in mortality (RR 0.69, 95 per cent c.i. 0.34 to 1.39), major complications (RR 0.95, 0.69 to 1.31) or readmission rates (RR 0.96, 0.59 to 1.58). The impact of ERPs was similar across specialties and there was no consistent evidence that elements included within ERPs affected patient outcomes. CONCLUSION: ERPs are effective in reducing length of hospital stay and overall complication rates across surgical specialties. It was not possible to identify individual components that improved outcome. Qualitative synthesis may be more appropriate to investigate the determinants of success. PMID- 24469619 TI - Cost-effectiveness and cost-utility of endovascular versus open repair of ruptured abdominal aortic aneurysm in the Amsterdam Acute Aneurysm Trial. AB - BACKGROUND: Minimally invasive endovascular aneurysm repair (EVAR) could be a surgical technique that improves outcome of patients with ruptured abdominal aortic aneurysm (rAAA). The aim of this study was to analyse the cost effectiveness and cost-utility of EVAR compared with standard open repair (OR) in the treatment of rAAA, with costs per 30-day and 6-month survivor as outcome parameters. METHODS: Resource use was determined from the Amsterdam Acute Aneurysm (AJAX) trial, a multicentre randomized trial comparing EVAR with OR in patients with rAAA. The analysis was performed from a provider perspective. All costs were calculated as if all patients had been treated in the same hospital (Onze Lieve Vrouwe Gasthuis, teaching hospital). RESULTS: A total of 116 patients were randomized. The 30-day mortality rate was 21 per cent after EVAR and 25 per cent for OR: absolute risk reduction (ARR) 4.4 (95 per cent confidence interval (c.i.) -11.0 to 19.7) per cent. At 6 months, the total mortality rate for EVAR was 28 per cent, compared with 31 per cent among those assigned to OR: ARR 2.4 ( 14.2 to 19.0) per cent. The mean cost difference between EVAR and OR was ?5306 (95 per cent c.i. -1854 to 12,659) at 30 days and ?10,189 (-2477 to 24,506) at 6 months. The incremental cost-effectiveness ratio per prevented death was ?120,591 at 30 days and ?424,542 at 6 months. There was no significant difference in quality of life between EVAR and OR. Nor was EVAR superior regarding cost utility. CONCLUSION: EVAR may be more effective for rAAA, but its increased costs mean that it is unaffordable based on current standards of societal willingness to-pay for health gains. PMID- 24469620 TI - Observations from the IMPROVE trial concerning the clinical care of patients with ruptured abdominal aortic aneurysm. AB - BACKGROUND: Single-centre series of the management of patients with ruptured abdominal aortic aneurysm (AAA) are usually too small to identify clinical factors that could improve patient outcomes. METHODS: IMPROVE is a pragmatic, multicentre randomized clinical trial in which eligible patients with a clinical diagnosis of ruptured aneurysm were allocated to a strategy of endovascular aneurysm repair (EVAR) or to open repair. The influences of time and manner of hospital presentation, fluid volume status, type of anaesthesia, type of endovascular repair and time to aneurysm repair on 30-day mortality were investigated according to a prespecified plan, for the subgroup of patients with a proven diagnosis of ruptured or symptomatic AAA. Adjustment was made for potential confounding factors. RESULTS: Some 558 of 613 randomized patients had a symptomatic or ruptured aneurysm: diagnostic accuracy was 91.0 per cent. Patients randomized outside routine working hours had higher operative mortality (adjusted odds ratio (OR) 1.47, 95 per cent confidence interval 1.00 to 2.17). Mortality rates after primary and secondary presentation were similar. Lowest systolic blood pressure was strongly and independently associated with 30-day mortality (51 per cent among those with pressure below 70 mmHg). Patients who received EVAR under local anaesthesia alone had greatly reduced 30-day mortality compared with those who had general anaesthesia (adjusted OR 0.27, 0.10 to 0.70). CONCLUSION: These findings suggest that the outcome of ruptured AAA might be improved by wider use of local anaesthesia for EVAR and that a minimum blood pressure of 70 mmHg is too low a threshold for permissive hypotension. PMID- 24469621 TI - Mid-term cost-effectiveness analysis of open and endovascular repair for ruptured abdominal aortic aneurysm. AB - BACKGROUND: Emergency endovascular repair (EVAR) for ruptured abdominal aortic aneurysm (rAAA) may have lower operative mortality rates than open surgical repair. Concerns remain that the early survival benefit after EVAR for rAAA may be offset by late reinterventions. The aim of this study was to compare reintervention rates and cost-effectiveness of EVAR and open repair for rAAA. METHODS: A retrospective analysis was undertaken of patients with rAAA undergoing EVAR or open repair over 6 years. A health economic model developed for the cost effectiveness of elective EVAR was used in the emergency setting. RESULTS: Sixty two patients (mean age 77.9 years) underwent EVAR and 85 (mean age 75.9 years) had open repair of rAAA. Median follow-up was 42 and 39 months respectively. There was no significant difference in 30-day mortality rates after EVAR and open repair (18 and 26 per cent respectively; P = 0.243). Reintervention rates were also similar (32 and 31 per cent; P = 0.701). The mean cost per patient was ?26,725 for EVAR and ?30,297 for open repair, and the cost per life-year gained was ?7906 and ?9933 respectively (P = 0.561). Open repair had greater initial costs: longer procedural times (217 versus 178.5 min; P < 0.001) and intensive care stay (5.0 versus 1.0 days; P = 0.015). Conversely, EVAR had greater reintervention (?156,939 versus ?35,335; P = 0.001) and surveillance (P < 0.001) costs. CONCLUSION: There was no significant difference in reintervention rates after EVAR or open repair for rAAA. EVAR was as cost-effective at mid-term follow up. The increased procedural costs of open repair are not outweighed by greater surveillance and reintervention costs after EVAR. PMID- 24469622 TI - Outcomes after laparoscopic conversion of failed adjustable gastric banding to sleeve gastrectomy or Roux-en-Y gastric bypass. AB - BACKGROUND: Laparoscopic adjustable gastric banding (LAGB) has a high incidence of long-term complications and failures. The best procedure to handle these failures and the optimal number of stages in such cases is still controversial. The aim of this retrospective study was to compare the results of conversions of LAGB to either laparoscopic sleeve gastrectomy (LSG) or laparoscopic Roux-en-Y gastric bypass (LRYGB) in failed LAGB using a single-stage approach. METHODS: All patients who underwent conversion from LAGB to either LRYGB or LSG between January 2005 and March 2012 were included in the study. Early and late complications were reviewed. The percentage excess weight loss (%EWL) between the two groups was compared at 3, 6, 12 and 24 months of follow-up. RESULTS: Fifty nine patients, 11 men and 48 women, were included in the study. The most frequent indication was insufficient weight loss or weight regain (non-responders group), in 44 patients (75 per cent); 15 patients had a revision for complicated LAGB. The early complication rate in the non-responders group was 7 per cent (3 of 44 patients), compared with 13 per cent (2 of 15) in the complicated LAGB group. Mean(s.d.) %EWL in the non-responders group was 55(22) per cent in patients converted to LRYGB and 28(25) in those converted to LSG (P = 0.001). CONCLUSION: LRYGB and LSG are both safe and feasible options for failed or complicated LAGB. In the non-responders group, %EWL was superior for conversion to LRYGB. The surgical morbidity rate was highest in patients having revision for band complications. PMID- 24469623 TI - Authors' reply: Expertise-based randomized clinical trial of laparoscopic versus small-incision open cholecystectomy (Br J Surg 2013; 100: 886-894). PMID- 24469624 TI - Expertise-based randomized clinical trial of laparoscopic versus small-incision open cholecystectomy (Br J Surg 2013; 100: 886-894). PMID- 24469625 TI - Type II endoleak after endovascular aneurysm repair (Br J Surg 2013; 100: 1262 1270). PMID- 24469626 TI - Randomized clinical trial of pancreaticogastrostomy versus pancreaticojejunostomy on the rate and severity of pancreatic fistula after pancreaticoduodenectomy (Br J Surg 2013; 100: 1597-1605). PMID- 24469627 TI - Authors' reply: Type II endoleak after endovascular aneurysm repair (Br J Surg 2013; 100: 1262-1270). PMID- 24469628 TI - Lack of association between inguinal hernia and abdominal aortic aneurysm in a population-based male cohort (Br J Surg 2013; 100: 1478-1482). PMID- 24469629 TI - Author's reply: Randomized clinical trial of pancreaticogastrostomy versus pancreaticojejunostomy on the rate and severity of pancreatic fistula after pancreaticoduodenectomy (Br J Surg 2013; 100: 1597-1605). PMID- 24469630 TI - Authors' reply: Lack of association between inguinal hernia and abdominal aortic aneurysm in a population-based male cohort (Br J Surg 2013; 100: 1478-1482). PMID- 24469633 TI - To treat a psychopath. AB - Some people are now quite optimistic about the possibility of treating psychopathy with drugs that directly modulate brain function. I argue that this optimism is misplaced. Psychopathy is a global disorder in an individual's worldview, including his social and moral outlook. Because of the unity of this Weltanschauung, it is unlikely to be treatable in a piecemeal fashion. Recent neuroscientific methods do not give us much hope that we can replace, in a wholesale manner, problematic views of the world with more socially desirable ones. There are, therefore, principled reasons that psychopathy is so singularly treatment resistant. PMID- 24469634 TI - The composition of EphB2 clusters determines the strength in the cellular repulsion response. AB - Trans interactions of erythropoietin-producing human hepatocellular (Eph) receptors with their membrane-bound ephrin ligands generate higher-order clusters that can form extended signaling arrays. The functional relevance of the cluster size for repulsive signaling is not understood. We used chemical dimerizers and fluorescence anisotropy to generate and visualize specific EphB2 cluster species in living cells. We find that cell collapse responses are induced by small-sized EphB2 clusters, suggesting that extended EphB2 arrays are dispensable and that EphB2 activation follows an ON-OFF switch with EphB2 dimers being inactive and trimers and tetramers being fully functional. Moreover, the strength of the collapse response is determined by the abundance of multimers over dimers within a cluster population: the more dimers are present, the weaker the response. Finally, we show that the C-terminal modules of EphB2 have negative regulatory effects on ephrin-induced clustering. These results shed new light on the mechanism and regulation of EphB2 activation and provide a model on how Eph signaling translates into graded cellular responses. PMID- 24469635 TI - Neuronal cell type-specific alternative splicing is regulated by the KH domain protein SLM1. AB - The unique functional properties and molecular identity of neuronal cell populations rely on cell type-specific gene expression programs. Alternative splicing represents a powerful mechanism for expanding the capacity of genomes to generate molecular diversity. Neuronal cells exhibit particularly extensive alternative splicing regulation. We report a highly selective expression of the KH domain-containing splicing regulators SLM1 and SLM2 in the mouse brain. Conditional ablation of SLM1 resulted in a severe defect in the neuronal isoform content of the polymorphic synaptic receptors neurexin-1, -2, and -3. Thus, cell type-specific expression of SLM1 provides a mechanism for shaping the molecular repertoires of synaptic adhesion molecules in neuronal populations in vivo. PMID- 24469636 TI - CAL1 is the Drosophila CENP-A assembly factor. AB - Centromeres are specified epigenetically by the incorporation of the histone H3 variant CENP-A. In humans, amphibians, and fungi, CENP-A is deposited at centromeres by the HJURP/Scm3 family of assembly factors, but homologues of these chaperones are absent from a number of major eukaryotic lineages such as insects, fish, nematodes, and plants. In Drosophila, centromeric deposition of CENP-A requires the fly-specific protein CAL1. Here, we show that targeting CAL1 to noncentromeric DNA in Drosophila cells is sufficient to heritably recruit CENP-A, kinetochore proteins, and microtubule attachments. CAL1 selectively interacts with CENP-A and is sufficient to assemble CENP-A nucleosomes that display properties consistent with left-handed octamers. The CENP-A assembly activity of CAL1 resides within an N-terminal domain, whereas the C terminus mediates centromere recognition through an interaction with CENP-C. Collectively, this work identifies the "missing" CENP-A chaperone in flies, revealing fundamental conservation between insect and vertebrate centromere-specification mechanisms. PMID- 24469637 TI - KIF13B enhances the endocytosis of LRP1 by recruiting LRP1 to caveolae. AB - Multifunctional low-density lipoprotein (LDL) receptor-related protein 1 (LRP1) recognizes and internalizes a large number of diverse ligands, including LDL and factor VIII. However, little is known about the regulation of LRP1 endocytosis. Here, we show that a microtubule-based motor protein, KIF13B, in an unexpected and unconventional function, enhances caveolin-dependent endocytosis of LRP1. KIF13B was highly expressed in the liver and was localized on the sinusoidal plasma membrane of hepatocytes. KIF13B knockout (KO) mice showed elevated levels of serum cholesterol and factor VIII, and KO MEFs showed decreased uptake of LDL. Exogenous KIF13B, initially localized on the plasma membrane with caveolae, was translocated to the vesicles in the cytoplasm with LRP1 and caveolin-1. KIF13B bound to hDLG1 and utrophin, which, in turn, bound to LRP1 and caveolae, respectively. These linkages were required for the KIF13B-enhanced endocytosis of LRP1. Thus, we propose that KIF13B, working as a scaffold, recruits LRP1 to caveolae via LRP1-hDLG1-KIF13B-utrophin-caveolae linkage and enhances the endocytosis of LRP1. PMID- 24469638 TI - Reduction of endoplasmic reticulum stress attenuates the defects caused by Drosophila mitofusin depletion. AB - Ablation of the mitochondrial fusion and endoplasmic reticulum (ER)-tethering protein Mfn2 causes ER stress, but whether this is just an epiphenomenon of mitochondrial dysfunction or a contributor to the phenotypes in mitofusin (Mfn) depleted Drosophila melanogaster is unclear. In this paper, we show that reduction of ER dysfunction ameliorates the functional and developmental defects of flies lacking the single Mfn mitochondrial assembly regulatory factor (Marf). Ubiquitous or neuron- and muscle-specific Marf ablation was lethal, altering mitochondrial and ER morphology and triggering ER stress that was conversely absent in flies lacking the fusion protein optic atrophy 1. Expression of Mfn2 and ER stress reduction in flies lacking Marf corrected ER shape, attenuating the developmental and motor defects. Thus, ER stress is a targetable pathogenetic component of the phenotypes caused by Drosophila Mfn ablation. PMID- 24469639 TI - Increased serum levels of soluble vascular endothelial-cadherin in patients with systemic vasculitis. AB - Henoch-Schonlein purpura (HSP) is a commonest systemic vasculitis (SV) in childhood characterized by an inflammatory reaction directed at vessels. Endothelial damage and perivascular leukocyte infiltrates are vital in the development of HSP. Vascular endothelial (VE)-cadherin is an endothelial cell specific adhesion molecule, which plays critical roles in angiogenesis and endothelial integrity. Herein, we investigated the serum levels of soluble VE cadherin (sVE-cadherin) in patients with HSP and other forms of SV. The serum levels of sVE-cadherin in 30 patients with HSP, together with patients with urticarial vasculitis, allergic vasculitis, Behcet disease, psoriasis vulgaris (PV) and atopic dermatitis (AD) and 26 health controls were measured by enzyme linked immunosorbent assay. Serum levels of sVE-cadherin were significantly increased in patients with HSP in acute stage and patients with other forms of SV but not in patients with PV or AD. Moreover, Serum sVE-cadherin levels in HSP patients were correlated with the severity of this disease and serum concentrations of IgA anticardiolipin antibodies and vascular endothelial growth factor. Taken together, we show firstly that serum sVE-cadherin is abnormally increased in HSP patients. Increased serum levels of sVE-cadherin might be a novel biomarker for evaluating the severity of HSP and useful for identifying the presence of SV in inflammatory skin conditions. PMID- 24469640 TI - Determinants of health-related quality of life impairment in Egyptian children and adolescents with juvenile idiopathic arthritis: Sharkia Governorate. AB - The aim of this study was to identify the possible determinants of impaired health-related quality of life (HRQOL) in Egyptian children and adolescents with juvenile idiopathic arthritis (JIA). Fifty-eight consecutive patients of JIA aged from 8 to 18 years underwent assessment of socio-economic and demographic characteristics; HRQOL using Pediatric Quality of Life Inventory 4.0 Generic Core Scale, disease activity using the Juvenile Arthritis Disease Activity Score based on 27 joints (JADAS-27), functional ability using the childhood health assessment questionnaire (CHAQ), pain score on visual analog scale and psychological symptoms using the Children's Depression Inventory (CDI) score. Multivariate modeling was applied to determine the factors that associated with HRQOL impairment. A total of 55 % of the patients (32 of 58) had impaired HRQOL (<78.6). In multiple regression analyses, high CHAQ scores (OR 6.0, 95 % CI 2.0 17.5, P = 0.001), pain (OR 3.1, 95 % CI 1.9-6.3, P = 0.01), stop going to school (OR 3.9, 95 % CI 2.0-7.3, P = 0.01), low socioeconomic status (OR 2.3, 95 % CI 1.09-4.7, P = 0.04) and high psychological symptoms (OR 4.2, 95 % CI 2.0-12.6, P = 0.001) were determinants for HRQOL impairment. HRQOL impairment is a significant problem in Egyptian children and adolescents with JIA. These findings underscore the critical need for monitoring of HRQOL in these patients. More attention should be given to JIA patients who stop going to school and who has low socioeconomic status. PMID- 24469641 TI - Mammographic screening detects low-risk tumor biology breast cancers. AB - Overdiagnosis of breast cancer, i.e. the detection of slow-growing tumors that would never have caused symptoms or death, became more prevalent with the implementation of population-based screening. Only rough estimates have been made of the proportion of patients that are overdiagnosed and identification of those patients is difficult. Therefore, the aim of this study is to evaluate whether tumor biology can help identify patients with screen-detected tumors at such a low risk of recurrence that they are likely to be overdiagnosed. Furthermore, we wish to evaluate the impact of the transition from film-screen mammography (FSM) to the more sensitive full-field digital mammography (FFDM) on the biology of the tumors detected by each screening-modality. All Dutch breast cancer patients enrolled in the MINDACT trial (EORTC-10041) accrued 2007-2011, who participated in the national screening program (biennial screening ages 50-75) were included (n = 1,165). We calculated the proportions of high-, low- and among those the ultralow-risk tumors according to the 70-gene signature for patients with screen detected (n = 775) and interval (n = 390) cancers for FSM and FFDM. Screen detected cancers had significantly more often a low-risk tumor biology (68 %) of which 54 % even an ultralow-risk compared to interval cancers (53 % low-, of which 45 % ultralow-risk (p = 0.001) with an OR of 2.33 (p < 0.0001; 95 % CI 1.73 3.15). FFDM detected significantly more high-risk tumors (35 %) compared to FSM (27 %) (p = 0.011). Aside from favorable clinico-pathological factors, screen detected cancers were also more likely to have a biologically low-risk or even ultralow-risk tumor. Especially for patients with screen-detected cancers the use of tools, such as the 70-gene signature, to differentiate breast cancers by risk of recurrence may minimize overtreatment. The recent transition in screening modalities led to an increase in the detection of biologically high-risk cancers using FFDM. PMID- 24469642 TI - Risk of cardiovascular adverse events from trastuzumab (Herceptin((r))) in elderly persons with breast cancer: a population-based study. AB - Randomized controlled trials have reported a 4-5 times increased risk of heart failure (HF) in breast cancer patients receiving trastuzumab (Herceptin ((r)) ) compared to patients who do not receive trastuzumab. However, data regarding the cardiac effects of trastuzumab on elderly patients treated in general practice remain very limited. Using the US surveillance, epidemiology, and end results (SEER)-Medicare database, we conducted a retrospective cohort study on the cardiac effects of trastuzumab use in all incident breast cancer patients diagnosed from 1998 to 2007 who were 66 years and older, had no prior recent claims for cardiomyopathy (CM) or HF, and were followed through 2009. We defined our outcome as the first CM/HF event after diagnosis. We performed Cox proportional hazard models with propensity score adjustment to estimate CM/HF risk associated with trastuzumab use. A total of 6,829 out of 68,536 breast cancer patients (median age: 75) had an incident CM/HF event. Patients who received trastuzumab tended to be younger, non-white, diagnosed more recently, and had a stage IV diagnosis. Trastuzumab use was associated with an increased risk of CM/HF (HR = 2.08, 95 % CI 1.77-2.44, p < 0.001). The trastuzumab associated CM/HF risk was stronger in patients who were younger (HR = 2.52 for 66 75 years and HR = 1.44 for 76 years and older, p < 0.001) and diagnosed in recent years (HR = 2.58 for 2006-2007 vs. 1.86 for 1998-2005, p = 0.01). The twofold risk of CM/HF associated with trastuzumab remained regardless of patients' diagnosis stage, presence of hypertension, cardiovascular comorbidities, or receipt of anthracyclines, taxanes, or radiation. Trastuzumab may double CM/HF risk among elderly breast cancer patients. Our findings reinforce the need to prevent and manage cardiac risk among elderly breast cancer patients receiving trastuzumab. PMID- 24469643 TI - Pure anti-tumor effect of zoledronic acid in naive bone-only metastatic and locally advanced breast cancer: proof from the "biological window therapy". AB - The study investigated the anti-tumour effect of zoledronic acid (ZA) administered alone in a biological window therapy in naive bone-only metastatic and locally advanced breast cancer (LABC) patients. 33 patients with LABC (Group 1) and 20 patients with a first diagnosis of bone metastasis only (Group 2) received 4 mg single dose of ZA, 14 days (biological window) before starting any treatment. In Group 1, Ki67, CD34, p53/bcl-2 and caspase 3 expression along with the adenosine triphosphate (ATP) levels and RNA disruption index were evaluated as markers of tumor growth in tumour specimens obtained before and after ZA administration (basal, day 14). In Group 2, the total enumeration of circulating tumour cells (CTCs), and of M30+ve CTCs along with the soluble marker of cell death (M30/M65) were carried-out as markers of tumor dissemination at baseline, at 48 h and day 14th. In Group 1, there was a significant reduction in Ki67, CD34, bcl-2 expression after 14 days ZA based-treatment (p = 0.0032; p = 0.0001, p < 0.00001 respectively). ZA showed a significant increase of RNA disruption (p < 0.0076). In Group 2, we observed a significant reduction of CTCs number after 48 h (p = 0.0012), followed by a significant rebound at 14 days (p = 0.012). The apoptotic CTCs/M30+ve and M65 levels significantly increased under treatment (p = 0.018 and p = 0.039 respectively) after drug administration when compared to the baseline. These results are the first prospective in vivo data showing the direct pure anti-tumour effect (either on the tumour cell or on CTCs) of ZA. PMID- 24469644 TI - Giant bladder stones. PMID- 24469645 TI - Ureteroscopy: the first-line treatment for distally located ureteral stones smaller than 10 mm. AB - PURPOSE: To compare the efficacy of different treatment strategies for distal ureteral stones smaller than 10 mm. MATERIAL AND METHODS: A total 127 patient were included in the study. Based on the treatment modality , patients were divided into three groups.Patients in group 1 only received conventional treatment including daily hydration of 2500 mL, ciprofloxacin, diclofenac sodium and a spasmolytic agent; group 2 patients received conventional treatment (daily hydration of 2500 mL, ciprofloxacin, diclofenac sodium and a spasmolytic agent) and tamsulosin 0.4 mg orally daily for 4 weeks; and group 3 patients underwent ureteroscopy. Patients were further subdivided into 2 categories based on maximum stone diameter: category A (less than 5 mm) and category B (5.0-9.9 mm). Following treatment, all groups were compared in terms of stone-free rate and time to expulsion. RESULTS: Following treatment, the stone-free rates for groups 1, 2 and 3 were 48.7%, 59.5% and 95.6%, respectively (P < .0001).The mean expulsion times for groups 1, 2 and 3 were 15.3 +/- 5.33, 15.1 +/- 5.5 and 1.95 +/- 2.2 days, respectively (P < .001). Compared to the other treatments, the stone-free rate and mean expulsion time in the ureteroscopy group were significantly increased and decreased, respectively. CONCLUSION: There are several treatment options for distal ureteral stones. Based on our data,we conclude that ureterorenoscopy should be the standard of care for distal ureteral stones smaller than 10 mm. PMID- 24469646 TI - Renal access by sonographer versus urologist during percutaneous nephrolithotomy. AB - PURPOSE: To evaluate the percutaneous access outcomes and complications following percutaneous nephrolithotomy (PCNL) that was obtained by sonographer or urologist at a single academic institution. MATERIAL AND METHODS: A retrospective chart review of 259 patients who underwent PCNL was performed. Patients were stratified according to percutaneous access by sonographer (group 1) or urologist (group 2) in 174 and 85 patients, respectively. Demographic, stone characteristics, operative variables, percutaneous access complications and stone-free rates were compared between groups. RESULTS: The major complication rate and minor complication rate, mean blood loss and rates of blood transfusion were comparable between groups. Compared with urologist, sonographer preferred to choose subcostal rib puncture instead of intercostal rib puncture. The lower calyx was the most frequent site of target calyx puncture in group 1 (165 cases, 94.8%), while the percentage of lower calyx in group 2 was 82.3% (72 cases) (P = .001). The overall stone-free rates were significantly higher in group 2 than that in group 1 (90.6% vs. 79.9%, P = .03). In group 1, 23 cases (13.2%) needed post operative extracorporeal shock wave lithotripsy (SWL), while, the percentage of post-operative SWL in group 2 was only 4.7% (4 cases) (P = .035). CONCLUSIONS: Renal access in PCNL can be safely and successfully obtained by both sonographer and urologist. Infracostal and lower calyx access in our study has poor stone free rates and sonographer prefers infracostal and lower access. We encourage urologists establish renal access by themselves during PCNL. PMID- 24469647 TI - Retroperitoneoscopic ablative renal surgery in children:the feasibility of using three trocars. AB - PURPOSE: We report the results of pediatric retroperitoneoscopic renal ablative surgeries, which were performed with only three trocars. MATERIALS AND METHODS: We retrospectively reviewed the charts of children who underwent laparoscopic urological procedures on the upper urinary tract at our institution between 2006 and 2012. These procedures consisted of nephrectomies, nephroureterectomies and heminephroureterectomies. The operations were performed retroperitoneoscopically with three trocars. The specimens were removed intact through the primary trocar site. RESULTS: A total of 30 retroperitoneoscopic ablative surgeries were performed in 13 girls and 17 boys. The mean patient age was 7.8 +/- 4.3 years (range, 1-14 years). The interventions consisted of nephrectomy in 10 cases (33.3%), nephroureterectomy in 17 cases (56.6%) and heminephroureterectomy in 3 (10%) cases. The open conversion rate was 3.3% (1/30). The difference between the initial 10 cases and the latter 20 cases, in terms of mean operative time, was statistically significant (144.5 vs. 115.78 minutes, respectively, P = .031). Apart from 3 nephroureterectomies, all of the procedures (86.6%) were completed successfully using three trocars only, without the need for a separate extraction incision. The patients were hospitalized for a mean duration of 2.2 days (range, 2-4 days). None of the patients required blood transfusion. We did not encounter any major perioperative or postoperative complication. CONCLUSION: Retroperitoneoscopic renal ablative surgery is a safe and effective treatment alternative for a variety of upper urinary tract disorders in children. PMID- 24469648 TI - Retroperitoneoscopic upper pole nephroureterectomy in duplex kidney: focus on the role of dilated upper pole ureter. AB - PURPOSE: To describe our technique and experience with retroperitoneoscopic upper pole nephroureterectomy in duplex kidney, focusing on the role of dilated upper ureter. MATERIALS AND METHODS: From November 2004 to August 2011, retroperitoneoscopic upper pole nephroureterectomy was performed in 31 patients with a duplex kidney by a single, experienced laparoscopic surgeon. We developed our own surgical technique to suit this technically challenging procedure. Follow up studies were performed using renal ultrasonography, intravenous urography (IVU) and/or dimercaptosuccinic acid (DMSA) renal scan in all patients at 3 months postoperatively and annually thereafter. RESULTS: All procedures were completed laparoscopically without conversion to open surgery and blood transfusion. The mean operative time was 106 (90-157) min. The estimated blood loss was < 50 mL in all cases. The mean postoperative hospital stay was 4.2 (3-7) days. Perioperative complications were limited to 1 case of peritoneal tear during a procedure and 1 case of transient postoperative fever. No major intraoperative and postoperative complication occurred. With the mean follow-up period of 41 months (range 3 to 80), no case was observed to have functional loss of the remaining lower moiety on postoperative IVU or DMSA renal scan. CONCLUSION: Retroperitoneoscopic upper pole nephroureterectomy using our technique is safe and effective. PMID- 24469649 TI - Mini-laparoscopic live donor nephrectomy: initial series. AB - PURPOSE: To present the safety and surgical outcomes of the initial series of mini-laparoscopic live donor nephrectomy and graft outcomes in related recipients. MATERIALS AND METHODS: From January 2012 through July 2012, fifty patients underwent minilaparoscopic live donor nephrectomy. Two 3.5 mm trocars were inserted above and lateral to the umbilicus for grasping and scissoring. One 5 mm trocar with a camera was inserted in the umbilicus and an 11 mm trocar was inserted through fascia from a 6-8 cm Pfannenstiel incision for bipolar coagulation, kidney extraction, and vascular clip applier. RESULTS: Mean age of donors was 28 +/- 4.2 (range, 21-39) years. Mean operative time from trocar insertion was 145.8 (range, 85-210) minutes. No major perioperative or postoperative complications occurred. The average decrease in hemoglobin level was 1.14 (range, 0.32-1.8) mg/dL and no one required blood transfusion. Mean warm ischemia time was 4.41 (range, 2.35- 9) minutes. Mean hospital stay was 2.2 (range, 2-5) days. Mean follow-up time of the recipients was 215 (range, 130-270) days. The mean serum creatinine level of the recipients at discharge time and the last follow-up visit was 1.38 mg/dL and 1.22 mg/dL, respectively. CONCLUSIONS: While the primary purpose of this technique is to make donor nephrectomy less invasive and more cosmetic, it is also comfortable for the laparoscopist surgeons because it is nearly similar to standard laparoscopy. A randomized controlled trial with a large sample size, long-term follow-up, and comparison with standard laparoscopy are necessary to present more definitive data about this technique. PMID- 24469650 TI - The comparison between human leukocyte antigen system incidence in patients with bladder cancer and normal controls. AB - PURPOSE: To determine the frequency of human leukocyte antigen (HLA)-B5 in patients with bladder cancer compared with normal population. MATERIALS AND METHODS: In this cross sectional study, from November 2009 until November 2010, 35 patients with pathologic diagnosis of bladder cancer who referred to urology clinic of Razi Hospital were studied. Also, 130 healthy transplant donation volunteers who referred for HLA-typing to Guilan Blood Transfusion Organization, were selected. Inclusion criterion was pathologic diagnosis of bladder cancer regardless of stage and grade of tumor. Exclusion criteria were presence of other urologic diseases. The information of these cases was extracted from medical records, collected and analyzed. RESULTS: HLA-B5 was positive in 34.3% of the patient group and in 39.2% of the controls. Statistical analysis showed no significant association between HLA-B5 and bladder cancer (P = .15). There were no significant differences between grade (P = .107) and relapse (P = .327)of bladder tumor with presence of HLA-B5. CONCLUSION: There was no significant association between HLA-B5 and bladder cancer. The grade and the relapse of tumor had no association with presence or absence of HLA-B5. PMID- 24469651 TI - The effectiveness of otis urethrotomy combined with six weeks urethral dilations until 40 Fr in the treatment of bladder outlet obstruction in women: a prospective study. AB - PURPOSE: To evaluate the effectiveness of Otis urethrotomy combined with six weekly urethral dilations until 40 French (Fr) in the treatment of women with urodynamic diagnosis of bladder outlet obstruction (BOO). MATERIALS AND METHODS: Women diagnosed with lower urinary tract symptoms underwent urodynamic evaluation. Severity of symptoms and quality of life were assessed with international prostate symptom score (IPSS) and quality of life (QoL) questionnaires. Bladder outlet obstruction was defined as the presence of two or more of the following: maximum flow rate (Qmax) < 12 mL/s, detrusor pressure at maximum flow (PdetQmax) > 50 cmH2O and urethral resistance factor (URF) greater than 0.2. Ten out of 25 women diagnosed with BOO met the criteria. All women underwent Otis urethrotomy to 40 F and six-week urethral dilations until 40 F. After six months all patients underwent free uroflowmetry. Moreover post voiding residual (PVR), IPSS-QoL were recorded. RESULTS: Six months post-operatively there was a significant improvement in all parameters: IPSS = 13.5 vs. 22.5 (P = .001), QoL = 3 vs. 5 (P = .001), voided volume = 312 mL vs. 216 mL (P = .055), Qmax = 27.5 mL/s vs. 12 mL/s (P = .001), and PVR = 27.5 mL vs. 170 mL (P = .005). Five women had close follow up during an average of 82 months. They maintained improved QoL (P < .005) and low PVR (P < .002). All other parameters lost their statistical significance. CONCLUSION: The described therapeutical modality seems to improve all clinical and urodynamic parameters in women with evidence of BOO not related to detrusor sphincter dyssynergia or obvious functional and anatomical pathology. PMID- 24469652 TI - Prostatic fluid free insulin-like growth factor-1 in relation to benign prostatic hyperplasia: a controlled study. AB - PURPOSE: Insulin-like growth factors (IGFs) have potent mitogenic and antiapoptotic effects on prostate tissue, whereas free IGF-1 is responsible for its metabolic effects but its role in benign prostatic hyperplasia (BPH) is unclear. MATERIAL AND METHODS: Plasma and prostatic fluid levels of free IGF-I were determined from the fasting bloods of 35 BPH cases admitted for treatment and 35 randomly selected population controls. RESULTS: Prostatic fluid free IGF-1 concentrations did not differed significantly between two groups (P = .23). There was also no statistical difference in serum free IGF-1 levels between these groups. There was also no correlation between prostatic fluid free IGF-1 and serum prostate specific antigen (PSA) levels and prostate volume. When compared with control group, mean IPSS scores and prostate volumes of BPH group were significantly high, while mean maximum measured flow rate (Qmax) and international prostate symptom score (IPSS) and quality of life (QoL) scores were significantly low (P < .05). CONCLUSION: Our study shows that free IGF-I is not associated with BPH risk. Further investigation is needed to elucidate the role of the free IGF-1 in BPH. PMID- 24469653 TI - Evaluating the efficacy of vacuum constrictive device and causes of its failure in impotent patients. AB - PURPOSE: This study evaluates the efficacy of Vacuum constrictive device (VCD) and the reasons for its failure. MATERIALS AND METHODS: In this cross-sectional study, 1500 men with organic erectile dysfunction(ED) were enrolled from July 2003 to July 2010. The treatment efficacy was analyzed using International Index of Erectile Function (IIEF) and questioning patient's partner regarding the man's ability to perform vaginal penetration (APVP). The patient's spouses, who responded negatively to APVP, were evaluated by a midwife for virginity, vaginal atrophy and abstained sex. RESULTS: Totally 1310 (87.4%) patients attained full erection at first training session, remaining 188 (12.6%) were able to have full erection one week after practicing with VCD, 1419 (94.6%)were able to have successful intercourse and responded positively to APVP, 81 (5.4%) were unable to have intercourse as stated by their wife's (negative response to APVP) that in 43 (53%),30 (37%), and 8 (9.8%) cases the causes of failures were their wife's virginity, sex abstinence, and senile vaginal atrophy, respectively. Regarding erectile issue of IIEF scores in patients responded positive to APVP there were significant improvement from the scores of 9.3 +/- 3.0 to 27.5 +/- 5.0 after treatment (P < .05). CONCLUSION: With proper training and appropriate devices, VCD could induce sufficient erection in all patients. VCD in patients with virgin wife is ineffective, and female factors affect on success rate in VCD therapy. PMID- 24469654 TI - Evaluation of sexual function in women with rheumatoid arthritis. AB - PURPOSE: To evaluate the link between rheumatoid arthritis (RA) and female sexual functioning. MATERIAL AND METHODS: A total of 32 women with RA and 20 healthy age matched controls were enrolled in this study. The participations are asked to complete Female Sexual Function Index (FSFI), The Short form 36 (SF-36) Health Survey and Beck Depression Inventory (BDI)questionnaires. RESULTS: The groups were comparable in terms of demographic characteristics. The women with RA represented significantly worse sexual functioning in category of desire, arousal, lubrication,orgasm, satisfaction domain and total FSFI score compared with healthy women (P = .0001, P = .0001, P = .0001, P = .0001, P = .022 and P = .0001, respectively). The mean BDI scores for the patients with RA were greater than control group (P = .036). Women with RA also had significantly lower quality of life (QoL) parameters: physical functioning, limitations due to physical health, pain, general health, vitality and limitations due to emotional problems compared with healthy women (P = .0001, P = .0001, P = .028, P = .002, P = .001 and P = .0001, respectively). CONCLUSION: The present study shows that a significant percent of patients with RA had sexual dysfunction and also deterioration in QoL. PMID- 24469655 TI - Pendulous urethral stricture: peculiarities and relevance of longitudinal penile fascio-cutaneous flap reconstruction in poor resource community. AB - PURPOSE: To describe peculiarities of pendulous urethral stricture in South Western Nigeria and how prevalent social and environmental factors have made longitudinal distal penile island flap the preferred option for reconstruction of pendulous urethral stricture in such a poor resource community. MATERIALS AND METHODS: All patients presenting with stricture located in the pendulous urethra in 3 hospitals in south western Nigeria, over a 5 year period were interviewed and had urethral reconstruction using longitudinal distal penile fascio-cutaneous island flap under spinal anesthesia. RESULTS: Thirty four cases were treated by this method during this period. Complications were found in 4 patients (11.8%) which include urethrocutaneous fistula, penile skin necrosis and wound infection. All cases had satisfactory overall outcome. CONCLUSION: Longitudinal penile fascio-cutaneous flap remains a viable option for a single stage repair of urethral stricture especially in poor resource communities. PMID- 24469656 TI - The effect of urethral catheter size on meatal stenosis formation in children undergoing tubularized incised plate urethroplasty. AB - PURPOSE: Meatal stenosis is still a common problem in tubularized incised plate urethroplasty. In this study, we aimed to seek for a relationship between the size of urethral catheter and meatal stenosis formation in children undergoing tubularized incised plate urethroplasty. MATERIALS AND METHODS: We retrospectively reviewed 83 children who underwent tubularized incised plate urethroplasty for hypospadias. The whole group was classified into the groups A and B based on the catheter size. One group (group A) consisted of 44 patients (mean age, 4.82 +/- 3.83 years) with tubularized neourethra over a 6 Fr catheter, while the other group (group B) included 39 patients (mean age, 5.19 +/- 3.83 years) with tubularized neourethra over a 8 Fr catheter. RESULTS: There were no significant differences between the groups according to their age, location of urethral meatus, dehiscence and urethrocutaneous fistula formation. Meatal stenosis formation in group B was markedly higher than that in group A. Number of meatal dilatation was higher in group B compared to group A. CONCLUSION: We suggest that the tubularization of urethral plate over a small-sized (6 Fr) catheter, regardless of the age of the patients, prevents meatal stenosis by reducing foreign body reaction and pressure injury and by hindering secondary healing. PMID- 24469657 TI - Evidence based practice: perspectives of Iranian urologists. AB - PURPOSE: To determine the attitudes and beliefs of Iranian urologists toward Evidence Based Medicine (EBM) and investigation of the barriers of evidence based practice (EBP). MATERIALS AND METHODS: A self- administrated, Likert scale questionnaire designed in Persian and filled up by censuses selected urologist from Iranian Urology Association (IUA). Data were entered to Predictive Analytics Soft Ware version 18.0 and descriptive statistics were obtained for all parts of the questionnaire. RESULTS: A total of 111 out of 500 Iranian urologists who attended in IUA annual meeting, responded to the questionnaires. Mean attitude score of respondents was 30.4 (SD: 5.7, range 16-40). Attitude score showed statistically significant association to previous participation in EBM workshops (P = .01). Of participants 96% believed EBP will improve patient care and 76.2% of them appreciated the impact of use of research utilization and application of evidence based guidelines on clinical decision making and the outcome of surgery. The main barriers to EBP stated as lack of time (64.8%), facilities (53.4%), and training in EBM (29.4%). CONCLUSION: The urologists have positive attitudes towards EBP. However, regarding lack of time, pre-appraised databases or EBP guidelines can be helpful. Evidence based workshops and familiarity with evidence databases is recommended for Iranian urologists. In addition, health care system and policy makers could play a major role to provide a culture of EBP. PMID- 24469658 TI - Effect of voiding position on uroflowmetric parameters in healthy and obstructed male patients. AB - PURPOSE: Uroflowmetry is frequently used and simple urodynamic test, but it may be affected by various factors. Voiding position is one of the factors that can change the results. We tried to compare the uroflowmetric parameters in sitting and standing positions during urination. MATERIAL AND METHODS: A total of 198 patients were enrolled to the study. All patients underwent an uroflowmetry in standing and sitting position at late afternoon (2-4 PM) of two corresponding days with a gravimetric uroflowmeter (Uroscan, Aymed, Turkey). A transabdominal ultrasonography was used to evaluate post voiding residue (PVR). All uroflowmetric parameters and PVR were compared with paired t test or Wilcoxon signed rank test. RESULTS: The median age of study population was 58.0 (36-69) years. There was no statistically significant difference at voided volume of patients in standing and sitting position as it was 271.5 +/- 81.8 mL and 274.8 +/- 82.4 mL, respectively (P = .505). Mean maximum flow rate (Qmax) during urination at standing position was 15.3 +/- 6.7 mL/s while it was 15.0 +/- 7.0 mL/s at sitting position (P = .29). Mean average flow rate in standing position was 8.60 +/- 4.0 mL/s and 8.25 +/- 3.8 mL/s in sitting position (P = .054). There was a statistically significant difference between the median post-voiding residues in standing and sitting urination which was 29.5 (0-257) mL in standing and 47.5 (2-209) mL in sitting position (P < .0001). Other uroflowmetric parameters (time to maximum flow and voiding time) was not statistically different between groups. CONCLUSION: There are no clinically important uroflowmetric differences between voiding in sitting and standing positions so voiding position may be left to personal preferences during uroflowmetric evaluation. PMID- 24469659 TI - Use of desipramine for the treatment of overactive bladder refractory to antimuscarinic therapy. AB - PURPOSE: To evaluate the use of desipramine in the treatment of overactive bladder (OAB). MATERIALS AND METHODS: We retrospectively evaluated 43 patients who were treated with desipramine for OAB refractory to antimuscarinic therapy. These OAB patients were stratified by the presence or absence of bladder pain. RESULTS: Forty-three patients were evaluated with a mean follow up time of 12.2 +/- 4.6 months. The mean age of the patients was 71 +/- 16 years. Twelve patients (28%) discontinued desipramine, 9 due to perceived lack of efficacy, 2 due to central anticholinergic side effects, and 1 due to the development of oropharyngeal sores. Patients were stratified into two subgroups based upon treatment with desipramine for OAB alone (n = 29) or OAB and bladder pain (n = 14). There was no difference between the groups in regard to sex (P = .34), prior history of radiation (P = .19), side effects (P = .16), and specifically evaluated central anti-cholinergic side effects (P = .66). There was no statistical difference in the self-reported success rate of the medication (P = .48). In the OAB plus bladder pain subgroup, 71% of patients reported improvement in their pain. Overall, 13 (30%) patients had history of prior pelvic radiation and 10 of those (77%) reported improvement with desipramine. CONCLUSION: Desipramine is a potential useful treatment for patients with OAB. In addition, it can be used in patients with OAB and bladder pain and patients with complex OAB such as OAB caused by pelvic radiation. PMID- 24469660 TI - Achievements in postgraduate urologic education in Iran: a quantitative study. AB - PURPOSE: The study focus is on the quantitative achievements in urology education and growth trends in urologic surgical workforce and fellowships by gender since 1979. MATERIALS AND METHODS: This comprehensive national quantitative study was performed in Iranian Academy of medical science. The first hand data gathered from The Iran Specialty Training Council of and also from Medical Council of Iran. RESULTS: Over the period 1979 to 2012, the numbers of resident's admission in urology/ fellowships have increased from 5 to 51 and from 0 to 24 respectively, and graduated urologists of national programs has grown from 5 (14%) in 1979 to 47 (100%) in 2012. Iranian urologists workforce haves increased from 315 in 1979 to 1637 in 2012. In 1979, there was 1 urologist for every 117,460 population, while in 2012 there was 1 urologist for every 46120 population. Iran Urologists to population rate is 1:46120. These statistics represents significant improvement from 34 years ago. Number of female urologists has progressively increased from 1 in 1979 (0%) to 110 (7%) in 2012. Urology fellowships are offered in 6 fields since 1994 in Iran. The number of trained fellowships grew sharply and reached to 221 in 2012. CONCLUSION: The current urology training is successful to improve urology health care. Along with expansion of urology and fellowship training, the number of Iranian female urologists significantly increased. To our knowledge Iran had the greatest growth rate of female urologist training in the Middle East, and is comparable with those in the most progressed countries in the world. PMID- 24469661 TI - A non-invasive method to evaluate the efficacy of human myoblast in botulinum-A toxin induced stress urinary incontinence model in rats. AB - PURPOSE: To develop a simple non-invasive method to assess the efficacy of a cell based therapy for treating stress urinary incontinence (SUI). MATERIALS AND METHODS: In this study, skeletal myoblasts were used as candidate therapy to reverse SUI. The SUI model was created in rats using periurethral injection of botulinum-A toxin injection. Two weeks later, the rats were administered saline and the level of continence in each botulinum-A toxin treated and control animals was assessed by the extent of voiding using metabolic cages. To determine the efficacy of myoblasts to reverse SUI, botulinum-A toxin treated incontinent rats were injected with either cultured human skeletal myoblasts or with buffered saline (sham control). Two weeks post implantation, the extent of continence was evaluated as mentioned above. RESULTS: The difference in void volume between botulinum-A toxin -treated and control rats were significant. Histological analysis of the urethra showed remarkable atrophy of the muscular layer. A significant reversal (P = .025) in the volume of voiding was observed in cell implanted rats as compared to sham injected rats. Histological analysis of the urethra implanted with myoblasts showed recovery of the atrophied muscular layer in comparison to sham control. Immunofluorescence analysis of the cell injected tissues confirmed the presence of human myoblasts in the regenerated area. CONCLUSION: This simplified method of in vivo testing can serve as a tool to test the efficacy of new therapies for treating SUI. PMID- 24469662 TI - Step-by-step illustrated endoscopic extraperitoneal radical prostatectomy (EERP): tips and tricks to trifecta outcomes. PMID- 24469663 TI - Pneumovesicoscopy: an effective technique for urinary bladder foreign body. PMID- 24469664 TI - Antenatal diagnosis of renal duplication by ultrasonography: report on four cases at a referral center. AB - Duplication of the renal collecting system is the commonest major congenital malformation of the urinary tract, with an incidence of 1% among live births. Antenatal diagnosing of renal duplication and an associated ureterocele is infrequent. We report four cases of prenatally diagnosed unilateral duplication of the renal collecting system. In two of them, the renal duplication was associated with an ectopic ureterocele. PMID- 24469665 TI - Multi-detector computed tomography angiography of a ruptured giant renal angiomyolipoma with pseudoaneurysm and associated saccular dilatation of left renal artery. PMID- 24469666 TI - Ureteropelvic junction rupture--an unusual presentation of distal ureteric calculus. PMID- 24469667 TI - Bilateral segmental renal artery thrombosis from blunt abdominal trauma: a rare presentation. PMID- 24469668 TI - Acute infection of a documented seminal vesicle cyst via hematogenous seeding. PMID- 24469669 TI - Treatment of juxtaglomerular cell tumor of the kidney by retroperitoneal laparoscopic partial nephrectomy. PMID- 24469670 TI - Horseshoe kidney with complete unilateral duplication of ureter and pelvicalyceal system--a case report. PMID- 24469671 TI - Renal cell carcinoma dwelling upon a renal cyst wall and laparoscopic management. PMID- 24469672 TI - Anticoagulation therapy: rivaroxaban is a safe and feasible alternative to warfarin in AF ablation. PMID- 24469673 TI - Interventional cardiology: optimal repair of ruptured abdominal aortic aneurysms. PMID- 24469674 TI - Troponins in cardiac amyloidosis: multipurpose markers. PMID- 24469675 TI - Imaging: CMR imaging in patients with cardiac amyloidosis. PMID- 24469677 TI - Syntheses and photophysical properties of BF2 complexes of curcumin analogues. AB - Stable tetracoordinated organoboron complexes as classic fluorescent molecules have found various applications in material and medical sciences. A new class of curcumin-BF2 complexes has been prepared from the condensation of 2,2-difluoro 1,3-dioxaborylpentadione with a variety of aldehydes and its photophysical properties were characterized. Systematic variations were observed in the absorption spectra of these curcumin-BF2 dyes in solutions, which are well correlated with their structural features, including characteristics of the aromatic groups and presence of a para electron-donating substituent. Strong fluorescence that is tunable from 500 to 800 nm via variation of the polarity of the solvent and a moderate to good fluorescence quantum yield ranging from 0.24 to 0.58 in dichloromethane were observed in curcumin-BF2 complexes 1. By contrast, their asymmetrical analogue, curcumin-BF2 complexes 3 exhibit much lower fluorescence quantum yields. Besides their excellent photostabilities, these curcumin-BF2 dyes also show singlet oxygen generating capabilities. PMID- 24469676 TI - Treatment sequencing after failure of the first biologic in cost-effectiveness models of psoriasis: a systematic review of published models and clinical practice guidelines. AB - OBJECTIVES: To analyse the treatment sequencing assumptions after failure on a first-line biologic in cost-effectiveness models of treatment of moderate to severe plaque psoriasis, and to compare them with the most recent treatment guidelines. METHODS: A systematic search of MEDLINE, Embase, EconLit and the Cochrane Library databases used free text and Medical Subject Headings terms including psoriasis, biologic therapies indicated for psoriasis, and all types of economic evaluations. Two researchers performed 2-level abstract screening for articles meeting pre-specified inclusion criteria. Assumptions about treatment pathways after first-line biologic failure in the cost-effectiveness models were analysed. A second systematic search was performed for psoriasis clinical practice guidelines. Sequence assumptions were compared with treatment guideline recommendations. RESULTS: Of 25 cost-effectiveness modelling studies identified, ten estimated the incremental cost per responder; time horizons varied (12 weeks 18 months) and treatment sequencing was not considered. In 15 studies where treatment sequencing was considered, with time horizons up to 10 years, five studies included only a switch to nonsystemic therapy or best supportive care after first-line biologic failure. Another five of the 15 treatment-pathway studies were available only as abstracts with no details of the sequence assumptions. In five of the 15 studies, first-line biologic failure was followed by second-line biologic monotherapy, one of the recommendations in current treatment guidelines. In only one of these five studies was the efficacy of the second-line biologic adjusted downwards, compared with first-line treatment. Only one of these studies considered dose titration with a first-line biologic and none combination therapy (biologic plus methotrexate or phototherapy) after first line biologic failure, as recommended in some treatment guidelines. CONCLUSIONS: Cost-effectiveness models of first-line biologics for moderate to severe plaque psoriasis either do not include subsequent treatment regimens or include only some of the regimens recommended in current treatment guidelines. Results may be sensitive to assumptions about treatment sequencing and the choice and efficacy of subsequent treatment regimens. PMID- 24469678 TI - Biogenic synthesis of selenium nanoparticles and their effect on As(III)-induced toxicity on human lymphocytes. AB - A bioreductive capacity of a plant, Terminalia arjuna leaf extract, was utilized for preparation of selenium nanoparticles. The leaf extract worked as good capping as well as stabilizing agent and facilitated the formation of stable colloidal nanoparticles. Resulting nanoparticles were characterized using UV-Vis spectrophotometer, transmission electron microscopy (TEM), energy dispersive X ray analysis (EDAX), Fourier transform infrared spectroscopy (FT-IR), and X-ray diffraction analysis (XRD), respectively. The colloidal solution showed the absorption maximum at 390 nm while TEM and selected area electron diffraction (SAED) indicated the formation of polydispersed, crystalline selenium nanoparticles of size raging from 10 to 80 nm. FT-IR analysis suggested the involvement of O-H, N-H, C=O, and C-O functional group of the leaf extract in particle formation while EDAX analysis indicated the presence of selenium in synthesized nanoparticles. The effect of nanoparticles on human lymphocytes treated with arsenite, As(III), has been studied. Studies on cell viability using MTT assay and DNA damage using comet assay revealed that synthesized selenium nanoparticles showed protective effect against As(III)-induced cell death and DNA damage. Chronic ingestion of arsenic infested groundwater, and prevalence of arsenicosis is a serious public health issue. The synthesized benign nanoselenium can be a promising agent to check the chronic toxicity caused due to arsenic exposure. PMID- 24469680 TI - Iron based photoanodes for solar fuel production. AB - In natural photosynthesis, the water splitting reaction of photosystem II is the source of the electrons/reducing equivalents for the reduction of carbon dioxide to carbohydrate while oxygen is formed as the by-product. Similarly, for artificial photosynthesis where the end product is a solar fuel such as hydrogen, a water splitting-oxygen evolving system is required to supply high energy electrons to drive the reductive reactions. Very attractive candidates for this purpose are iron based semiconductors which have band gaps corresponding to visible light and valence band energies sufficient to oxidise water. The most studied system is hematite (Fe2O3) which is highly abundant with many attributes for incorporation into photoelectrochemical (PEC) cells. We review the recent progress in manipulating hematite for this purpose through nanostructuring, doping and surface modifications. We also consider several hybrid iron-based semiconducting systems like ferrites and iron titanates as alternatives to hematite for light driven water splitting emphasizing their advantages with respect to their band levels and charge transport properties. PMID- 24469681 TI - Burkholderia dolosa phenotypic variation during the decline in lung function of a cystic fibrosis patient during 5.5 years of chronic colonization. AB - Although rarely isolated from cystic fibrosis (CF) patients, Burkholderia dolosa is associated with accelerated lung function decline. During 18 years of epidemiological surveillance in the major Portuguese CF centre in Lisbon, only one patient was infected with B. dolosa. Pulmonary deterioration, associated with the evolution of forced expiratory volume in 1 s, occurred during 5.5 years of colonization with this B. dolosa clone (with the new sequence type ST-668). Transient co-colonization with Burkholderia cenocepacia and other bacterial and fungal pathogens occurred, but B. dolosa prevailed until the patient's death. The systematic assessment of relevant phenotypes for the sequential clonal isolates examined in this retrospective study (14 of B. dolosa and four of B. cenocepacia) showed that they were variants, although in general no isolation time-dependent pattern of alteration was identified. However, the first B. dolosa isolate retrieved was more susceptible to gentamicin, imipenem and tobramycin, and exhibited a higher swarming motility compared with most of the isolates obtained during the later stages of disease progression and antimicrobial therapy. PMID- 24469679 TI - Immune-epithelial crosstalk at the intestinal surface. AB - The intestinal tract is one of the most complex organs of the human body. It has to exercise various functions including food and water absorption, as well as barrier and immune regulation. These functions affect not only the gut itself, but influence the overall health of the organism. Diseases involving the gastrointestinal tract such as inflammatory bowel disease and colorectal cancer therefore severely affect the patient's quality of life and can become life threatening. Intestinal epithelial cells (IECs) play an important role in intestinal inflammation, infection, and cancer development. IECs not only constitute the first barrier in the gut against the lumen, they also constantly signal information about the gut lumen to immune cells, thereby influencing their behaviour. In contrast, by producing various antimicrobial peptides, IECs shape the microbial community within the gut. IECs also respond to cytokines and other mediators of immune cells in the lamina propria. Interactions between epithelial cells and immune cells in the intestine are responsible for gut homeostasis, and modulations of this crosstalk have been reported in studies of gut diseases. This review discusses the wide field of immune-epithelial interactions and shows the importance of immune-epithelial crosstalk in the intestine to gut homeostasis and the overall health status. PMID- 24469682 TI - Polyphasic characterization of fungal isolates from a published case of invasive aspergillosis reveals misidentification of Aspergillus felis as Aspergillus viridinutans. PMID- 24469683 TI - A new hybrid case-based reasoning approach for medical diagnosis systems. AB - Case-Based Reasoning (CBR) has been applied in many different medical applications. Due to the complexities and the diversities of this domain, most medical CBR systems become hybrid. Besides, the case adaptation process in CBR is often a challenging issue as it is traditionally carried out manually by domain experts. In this paper, a new hybrid case-based reasoning approach for medical diagnosis systems is proposed to improve the accuracy of the retrieval-only CBR systems. The approach integrates case-based reasoning and rule-based reasoning, and also applies the adaptation process automatically by exploiting adaptation rules. Both adaptation rules and reasoning rules are generated from the case base. After solving a new case, the case-base is expanded, and both adaptation and reasoning rules are updated. To evaluate the proposed approach, a prototype was implemented and experimented to diagnose breast cancer and thyroid diseases. The final results show that the proposed approach increases the diagnosing accuracy of the retrieval-only CBR systems, and provides a reliable accuracy comparing to the current breast cancer and thyroid diagnosis systems. PMID- 24469684 TI - Multiresolution image registration in digital x-ray angiography with intensity variation modeling. AB - Digital subtraction angiography (DSA) is a widely used technique for visualization of vessel anatomy in diagnosis and treatment. However, due to unavoidable patient motions, both externally and internally, the subtracted angiography images often suffer from motion artifacts that adversely affect the quality of the medical diagnosis. To cope with this problem and improve the quality of DSA images, registration algorithms are often employed before subtraction. In this paper, a novel elastic registration algorithm for registration of digital X-ray angiography images, particularly for the coronary location, is proposed. This algorithm includes a multiresolution search strategy in which a global transformation is calculated iteratively based on local search in coarse and fine sub-image blocks. The local searches are accomplished in a differential multiscale framework which allows us to capture both large and small scale transformations. The local registration transformation also explicitly accounts for local variations in the image intensities which incorporated into our model as a change of local contrast and brightness. These local transformations are then smoothly interpolated using thin-plate spline interpolation function to obtain the global model. Experimental results with several clinical datasets demonstrate the effectiveness of our algorithm in motion artifact reduction. PMID- 24469685 TI - Variability of subspecialty-specific anesthesia-controlled times at two academic institutions. AB - Realistic scheduling of operating room cases decreases costs, optimizes utilization and improves staff and patient satisfaction. Currently limited data exists to establish anesthesia-controlled time benchmarks based on specific subspecialty service. In this multicenter retrospective analysis of cases performed during a 53 month period at two large multispecialty academic institutions, data were retrieved from the perioperative information systems at each center. Both induction and emergence times were calculated. We then determined mean and median anesthesia controlled times based on each subspecialty service and compared them to previously published anesthesia-controlled time data. We obtained data on 104,184 cases at hospital A, and 122,560 cases at Hospital B. For all specialties at hospital A and hospital B, median induction time was 16.0 min and 17.0 min, emergence time was 14.0 and 8.0 min, and total anesthesia controlled time was 31.0 min and 27.0 min respectively. There was considerable variability among different surgical specialties deviating from the previously established 30 min benchmark. Subspecialties with lower total anesthesia controlled times in both centers were pain, general surgery, gynecology, plastic surgery and urology. Subspecialties with higher total anesthesia controlled times in both centers included cardiac surgery, neurosurgery, transplant and vascular. Cardiac surgery had the highest total time of 60 min and 50 min at Hospital A and B respectively. Individual specialty specific anesthesia controlled times should be used for case scheduling and to benchmark anesthesia performance. PMID- 24469686 TI - Challenging conventional wisdom: single domain metallothioneins. AB - Metallothioneins (MT) are a family of small cysteine rich proteins that have been implicated in a range of roles including toxic metal detoxification, protection against oxidative stress, and as metallochaperones are undoubtedly involved in the homeostasis of both essential zinc and copper. While complete details of all possible cellular functions are still unknown, it is clear that they must be directly related to both the accessibility and the metal-binding properties of the many cysteine residues in the protein. The most well studied MTs are of mammalian origin and consist of two domains: a beta-domain with 9 cysteine residues that sequesters 3 Cd(2+), 3 Zn(2+) or 6 Cu(+) ions, and an alpha-domain with 11 cysteine residues that sequesters 4 Cd(2+), 4 Zn(2+) or 6 Cu(+) ions. The key to understanding the cellular importance of MT in these different roles is in a precise description of the metallation status before and during reactions. An assessment of all possible and all biologically accessible metallation states is necessary before the functional mechanistic details can be fully determined. Conventionally, it has been considered that metal ions bind in a domain-specific and, therefore, cooperative manner, where the apparently isolated domains fill with their full complement of metal ions immediately with no discernible or measurable intermediates. A number of detailed mechanistic studies of the metallation reactions of mammalian MTs have provided significant insight into the metallation reactions. Recent results from electrospray ionization mass spectrometric studies of the stepwise metallation of the two fragments and the whole protein with Zn(2+), Cd(2+), As(3+) and Bi(3+) indicate a noncooperative mechanism of a declining series of K(F)'s. Of particular note are new details about the early stages of the stepwise metallation reactions, specifically the stability of partially metallated species for As(3+), Cd(2+), and Zn(2+) that do not correspond to the two-domain model. In addition, at the other end of the coordination spectrum are the supermetallated species of MT, where supermetallation defines metallation in excess of traditional levels. It has been reported that with metal ion excess the formation of a single 'super domain' is possible and again this deviates from the two-domain model of MT. In both cases, these results suggest that the structural view of mammalian MT that is of two essentially isolated domains may be the exceptional case and that under the normal conditions of cellular metal-ion concentrations the two domain structure might coexist in equilibrium with various single domain, multi-metal site structures. This review specifically focuses on providing context for these recent studies and the new ideas concerning metallation prior to the establishment of domain-based clusters that these studies suggest. PMID- 24469688 TI - ZnFe2O4 nanoparticles dispersed in a highly porous silica aerogel matrix: a magnetic study. AB - We report the detailed structural characterization and magnetic investigation of nanocrystalline zinc ferrite nanoparticles supported on a silica aerogel porous matrix which differ in size (in the range 4-11 nm) and the inversion degree (from 0.4 to 0.2) as compared to bulk zinc ferrite which has a normal spinel structure. The samples were investigated by zero-field-cooling-field-cooling, thermo-remnant DC magnetization measurements, AC magnetization investigation and Mossbauer spectroscopy. The nanocomposites are superparamagnetic at room temperature; the temperature of the superparamagnetic transition in the samples decreases with the particle size and therefore it is mainly determined by the inversion degree rather than by the particle size, which would give an opposite effect on the blocking temperature. The contribution of particle interaction to the magnetic behavior of the nanocomposites decreases significantly in the sample with the largest particle size. The values of the anisotropy constant give evidence that the anisotropy constant decreases upon increasing the particle size of the samples. All these results clearly indicate that, even when dispersed with low concentration in a non-magnetic and highly porous and insulating matrix, the zinc ferrite nanoparticles show a magnetic behavior similar to that displayed when they are unsupported or dispersed in a similar but denser matrix, and with higher loading. The effective anisotropy measured for our samples appears to be systematically higher than that measured for supported zinc ferrite nanoparticles of similar size, indicating that this effect probably occurs as a consequence of the high inversion degree. PMID- 24469687 TI - Local control and prognostic significance of transarterial treatment for limited recurrence of ovarian cancer as third-line and beyond therapy. AB - BACKGROUND: We aimed to retrospectively evaluate the safety and efficacy of transarterial treatment for the recurrence of ovarian cancer, limited to one or two gross regions, in a palliative setting as third-line and beyond therapy. METHODS: Twenty-six consecutive patients were enrolled to undergo transarterial treatment of target lesions that were life-threatening or influenced their quality of life. Transarterial infusion via each feeding artery using 20-40 mg cisplatin and 20-40 mg docetaxel per patient was repeated every 4-6 weeks. Superabsorbent polymer microspheres were added for embolization after drug infusion, especially in hepatic or pelvic treatments. Univariate and multivariate Cox's proportional hazards models were used to assess the correlations between overall survival and individual parameters. RESULTS: A total of 63 feeding arteries (median 2 per patient; range 1-5) were treated for 36 target sites (liver, 12; pelvis, 8; abdominal cavity, 7; lymph node, 3; other, 6) at the initial treatment. Of the 128 total sessions, the only grade 3/4 toxicity was neutropenia (3.8 %). The target lesion response rate by RECIST ver.1.1 was 50.0 % (11.5 % complete response; 38.5 % partial response). After a median follow-up of 30 months, the median overall survival was 16 months. Among 10 tumor-associated symptomatic patients, 7 showed symptom improvement. Multivariate analyses shows that the only independent prognostic factor was target lesion response (hazard ratio 18.7; 95 % CI 1.9-183.4; p = 0.01). CONCLUSIONS: Transarterial treatment for ovarian cancer achieves a high local response and good symptom control, and significantly contributes to survival for patients with local control after multiple relapses. PMID- 24469689 TI - [Shoulder injuries in golf]. AB - BACKGROUND: Due to its growing popularity golf has now come into the focus of orthopedic sports medicine. With a wide range of age groups and playing levels, orthopedic surgeons will encounter a wide range of musculoskeletal problems which are usually the result of overuse rather than trauma. ANATOMY: The shoulder joint plays an important role in the golf swing whereby not only the muscles around the glenohumeral joint but also the scapula stabilizing muscles are extremely important for an effective golf swing. INJURY PATTERNS: Golf is strictly not considered to be an overhead sport; however, the extreme peak positions of the golf swing involve placing the shoulder joint in maximum abduction and adduction positions which can provoke impingement, lesions of the pulley system or even a special form of posterior shoulder instability. PERSPECTIVES: Even after complex shoulder operations, such as rotator cuff repair or shoulder arthroplasty, a return to the golf course at nearly the same level of play can be expected. PMID- 24469690 TI - [Acromioclavicular injuries in professional athletes]. AB - BACKGROUND: Acromioclavicular joint (ACJ) dislocations represent the most frequent injuries of the shoulder girdle among athletes. Low grade injuries are more common than high grade injuries. Possible injury mechanisms are either a direct trauma to the shoulder or a fall on an adducted elbow with indirect trauma to the ACJ. DIAGNOSTICS: Accurate radiological diagnostics, including stress recordings for detection of a horizontal instability component are of utmost importance and allow correct classification of the ACJ injury. THERAPY: Most ACJ injuries can be treated non-operatively with short-term immobilization, oral analgesia therapy and pain-oriented functional physiotherapeutic treatment. In principle, surgical indications are high grade injuries in the sense of Rockwood dislocations types IV and V; however, individual factors, such as the type of sport, handedness, career perspectives and economic aspects have to be involved in the decision-making process, particularly in professional athletes. Acute ACJ dislocations are treated arthroscopically including coracoclavicular and additional acromioclavicular stabilization in cases of horizontal instability. Chronic ACJ dislocations require coracoclavicular ligament reconstruction using autologous semitendinosus tendon grafting. PERSPECTIVES: After relatively restrictive postoperative care including a 6-week immobilization period, competitive sport is normally possible after 3-4 months in cases of acute injury and after 6 months in cases of chronic injury. PMID- 24469692 TI - The troubles of telling: managing communication about the end of life. AB - Communication about palliative care represents one of the most difficult interpersonal aspects of medicine. Delivering the "terminal" diagnosis has traditionally been the focus of research, yet transitions to specialist palliative care are equally critical clinical moments. Here we focus on 20 medical specialists' strategies for engaging patients around referral to specialist palliative care. Our aim was to develop an understanding of the logics that underpin their communication strategies when negotiating this transition. We draw on qualitative interviews to explore their accounts of deciding whether and when to engage in referral discussions; the role of uncertainty and the need for hope in shaping communication; and their perceptions of how patient biographies might shape their approaches to, and communication about, the end of life. On the basis of our analysis, we argue that communication is embedded in social relations of hope, justice, and uncertainty, as well as being shaped by patient biographies. PMID- 24469691 TI - DNA damage in peripheral blood lymphocytes from patients with OSAHS. AB - PURPOSE: Obstructive sleep apnea hypopnea syndrome (OSAHS) is characterized by intermittent hypoxia during sleep time, followed by oxidative stress. Hypoxia induced oxidative stress can lead to DNA damage, which is related to chromosome aberrations and micronuclei. The purpose of this study is to investigate the level of DNA damage in peripheral blood of patients with OSAHS. METHODS: Thirty patients with OSAHS diagnosed by polysomnography and 28 healthy volunteers were assessed by the Epworth sleepiness scale. The levels of DNA damage were investigated through the cytokinesis-blocked micronucleus assay. RESULTS: In the group of patients with OSAHS, the mean frequency of binucleated cells with micronuclei were significantly higher than that in the control group (P<0.01), and the frequency of micronuclei among the patients in mild, moderate, and severe stages differed significantly (P<0.05). The mean frequency of nucleoplasmic bridge in OSAHS group was also higher than that in the control group (P<0.05). Nasal continuous positive airway pressure treatment decreased the frequencies of binucleated cells with micronuclei, nucleoplasmic bridge, and nuclear buds. CONCLUSIONS: Oxidative DNA damage increased in peripheral blood lymphocytes of OSAHS patients. It may be related to oxidative stress induced by intermittent hypoxia and may be involved in the pathogenesis of cardiovascular and other target organ injuries. PMID- 24469693 TI - Perinatal depression treatment preferences among Latina mothers. AB - The study described here was designed to determine treatment preferences among Latinas to identify treatment options that meet their needs and increase their engagement. Focus group interviews were conducted with 22 prenatal and postpartum Latinas at risk for depression. The group interviews were conducted in Spanish and English using a standardized interview protocol. Focus group transcripts were analyzed to identify themes regarding perinatal depression coping strategies, preferred approaches to treating perinatal depression, and recommendations for engaging perinatal Latinas in treatment. The results suggest that Latinas' treatment preferences consist of a pathway (i.e., hierarchical) approach that begins with the use of one's own resources, followed by the use of formal support systems (e.g., home-visiting nurse), and supplemented with the use of behavioral therapy. Antidepressant use was judged to be acceptable only in severe cases or after delivery. The data indicate that to increase health-seeking behaviors among perinatal Latinas, practitioners should first build trust. PMID- 24469694 TI - On ethical (in)decisions experienced by parents of infants in neonatal intensive care. AB - This study was a phenomenological investigation of ethical decisions experienced by parents of newborns in neonatal intensive care. I explore the lived meanings of thematic events that speak to the variable ways that ethical situations may be experienced: a decision that was never a choice; a decision as looking for a way out; a decision as thinking and feeling oneself through the consequences; a decision as indecision; and a decision as something that one falls into. The concluding recommendations spell out the need for understanding the experiences of parents whose children require medical care and underscore the tactful sensitivities required of the health care team during moral-ethical decision making. PMID- 24469695 TI - Polar auxin transport and auxin-induced elongation in the absence of cytoplasmic streaming. AB - When cytoplasmie streaming in oat and maize coleoptile cells is completely inhibited by cytochalasin B (CB), polar transport of auxin (indole-3-acetic acid) continues at a slightly reduced rate. Therefore, cytoplasmic streaming is not required for polar transport. Auxin induces elongation in CB-inhibited coleoptile and pea stem segments, but elongation rate is reduced about 40% by CB. Therefore, stimulation of cytoplasmic streaming cannot be the means by which auxin promotes cell elongation, but streaming may be beneficial to elongation growth although not essential to it. A more severe inhibition of elongation develops after several hours in CB. With coleoptiles this could be due to inhibition of sugar uptake; in pea tissue it may be due to permeability changes and cytoplasmic degeneration. CB does not disorganize or disorient microfilament bundles when it inhibits streaming in maize, but appears instead to cause hypercondensation of microfilament material. PMID- 24469697 TI - [Breaking of dormancy of the apple embryo (Pirus malus L.) in the absence of oxygen and cold]. AB - The dormancy of apple embryos may be entirely broken without cold by keeping them in N2-atmosphere. The breaking of dormancy under these conditions is more rapid than that obtained by cold treatment. PMID- 24469696 TI - Intracellular localization of the active process in polar transport of auxin. AB - The cytoplasm of maize coleoptile cells was displaced to either the apical or basal ends of the cells by centrifuging (1750xg for 10 min) segments in which protoplasmic streaming had been stopped by pretreatment with cytochalasin B. Centrifugation toward the base of the segment promotes the subsequent basipetal transport of indole-3-acetic acid, whereas apical centrifugation dramatically inhibits this transport. Apical centrifugation neither promotes acropetal transport nor reverses the polarity of auxin transport. Experiments in which the amyloplasts were separated from the bulk of the cytoplasm indicate that the basipetal transport is independent of both the position and pressure exerted by the amyloplasts but is strongly dependent on the amount of cytoplasm at the basal end of the cells. These effects of centrifugation on auxin transport lead to the conclusion that the metabolic component of the transport is a polar secretion of auxin localized in the basal plasma membrane of each cell. PMID- 24469698 TI - Measurement of a gradient of oxygen partial pressure across the intact root. AB - Oxygen partial pressures in the vacuolar sap of root cells have been measured using oxygen sensitive polarographic microelectrodes. A significant gradient in oxygen partial pressure was observed across intact sunflower roots growing in air saturated culture solution. The relevance of this finding to the mechanism of salt transfer across the root and in particular to the Crafts-Broyer theory is discussed. PMID- 24469699 TI - Phytochrome: First-order phototransformation kinetics in vivo. AB - The deviation from first order commonly observed in phototransformation kinetics of phytochrome in vivo is due to a light-intensity gradient within the sample. This gradient was measured and was found to approach that predicted by the Kubelka-Munk theory of light scatter in turbid materials. The influence of this gradient is eliminated and first-order phototransformation kinetics are obtained, when either (i) thin samples of translucent (low optical density) material of high phytochrome content are measured directly; or (ii) thin samples of opaque (high optical density) or translucent material are sandwiched between two layers of light-scattering material. This result is consistent with the existence of only one population of photoreversible phytochrome molecules in vivo. PMID- 24469700 TI - Influence of gibberellic and abscisic acids and the growth retardant, CCC, upon plastid development. AB - Gibberellic acid (GA3) enhances ultrastructural morphogenesis of plastids in greening cereals whilst abscisic acid (ABA) and CCC have the reverse effect over a shorter period. GA3 application counteracts the ABA and CCC inhibition of membrane development and, over longer periods of greening, the fastest rate of chloroplast development is shown in the presence of both GA3 and ABA. Experiments with isolated etioplasts show that the ABA inhibition of development also occurs and can be counteracted with GA3 treatment but no individual enhancement of plastid morphogenesis by GA3 was detected.Ribulose 1,5-diphosphate carboxylase (RuDPC) acitvity was also increased with applications of GA3 and reduced with ABA treatment. The initial levels of RuDPC activity in the presence of CCC were concentration dependant; high in 10(-3) M CCC and low in 10(-6) M CCC but activity returned to normal levels after CCC application was stopped. Experiments with isolated etio-chloroplasts gave similar results but levels of RuDPC activity declined rapidly in both illuminated and un-illuminated incubated suspensions of intact etioplasts. PMID- 24469701 TI - Identification of gibberellin A20, abscisic acid, and phaseic acid from flowering Bryophyllum daigremontianum by combined gas chromatography-mass spectrometry. AB - The presence of abscisic and phaseic acid in a purified acidic extract from flowering plants of the long-short-day plant Bryophyllum daigremontianum [(R. Hamet and Perr.) Berg.] was conclusively established by combined gas chromatography-mass spectrometry (GC-MS) of their methyl esters. Gibberellin A20 (GA20) was identified by GC-MS of the methyl ester and the trimethylsilyl ether of the methyl ester. The following levels of the 3 compounds per kg fresh weight were estimated: Abscisic acid, 5.5 MUg; phaseic acid, 9.4MUg; gibberellin A20, 0.8 MUg. When GA20 and four other GAs were applied to Bryophyllum under shortday conditions, the order of effectiveness for induction of flower formation was: GA2>GA1>GA5=GA7>GA20. The low biological activity of the native GA20 is discussed. PMID- 24469702 TI - Regulation of pentosan biosynthesis in barley aleurone tissue by gibberellic acid. AB - Treatment of isolated barley aleurone layers with gibberellic acid (GA3) resulted in a progressive inhibition of cell-wall synthesis after a 4-h lag period. The incorporation of both [(14)C]arabinose and [(14)C]glucose into the cell wall was inhibited by GA3, but analysis of the labelled sugars in the polymerized product showed that the process most affected by the hormone treatment was pentosan biosynthesis. Labelling kinetics and pulse-chase analysis indicated that the pentosans were synthesized in the cytoplasm and subsequently transferred to the cell wall; GA3 did not significantly affect the latter step. The GA3-inhibited labelling of the cell-wall pentosans cannot be explained on the basis of an effect on uptake of radioactive cell-wall precursor, expansion of the free pentose pool, or degradation of newly-formed pentosan. GA3 inhibited the activity of a membrane-bound arabinosyl transferase present in the aleurone layers. This inhibition may explain the inhibition of cell-wall pentosan synthesis by GA3. PMID- 24469703 TI - Activity of the asymmetric isomers of abscisic acid in a rapid bioassay. AB - Highly purified preparations of (+)- and (-)-abscisic acid (ABA) were compared for biological activity in a rapid bioassay based on closure of stomates on excised leaves of Hordeum vulgare. The naturally-occurring (+)-enantiomer was markedly more active. It causes speedier closure of the stomates, as measured by changes in leaf temperature. The differences in the activities of the ABA enantiomers are greater than have yet been reported for any other system. PMID- 24469704 TI - Sub-diffraction laser synthesis of silicon nanowires. AB - We demonstrate synthesis of silicon nanowires of tens of nanometers via laser induced chemical vapor deposition. These nanowires with diameters as small as 60 nm are produced by the interference between incident laser radiation and surface scattered radiation within a diffraction limited spot, which causes spatially confined, periodic heating needed for high resolution chemical vapor deposition. By controlling the intensity and polarization direction of the incident radiation, multiple parallel nanowires can be simultaneously synthesized. The nanowires are produced on a dielectric substrate with controlled diameter, length, orientation, and the possibility of in-situ doping, and therefore are ready for device fabrication. Our method offers rapid one-step fabrication of nano-materials and devices unobtainable with previous CVD methods. PMID- 24469705 TI - Stemmed versus stemless total shoulder arthroplasty: a preliminary report and short-term results. AB - BACKGROUND: Although several studies have been performed on the use of various devices in total shoulder arthroplasty (TSA), no data are available in order to establish whether to prefer stemmed or stemless humeral components. Thus, the purpose of our study was to evaluate the short-term functional outcome in a cohort of subjects treated with TSA randomized to treatment with stemmed or stemless prosthesis. METHODS: In this prospective longitudinal study, we randomized to treatment with stemmed (group 1) or with stemless (group 2) humeral component in nineteen subjects (2 M and 17 F) diagnosed with humeral primary osteoarthritis with indication to TSA. We evaluated the range of movement of all the participants and the functional outcome using Constant score and simple shoulder test (SST) before and after 2 years from surgery. RESULTS: No differences were detected after 2 years from surgery in the two groups in terms of functional scores and range of motion (p > 0.05). CONCLUSION: Stemmed and stemless prostheses are comparable in terms of functional outcome. These data might be useful for the surgeon in order to choose more tissues-paring methodologies and less invasive procedures, such as stemless humeral implants. PMID- 24469706 TI - Results of fusion and instrumentation of thoracic and lumbar vertebral fractures in children: a prospective ten-year study. AB - BACKGROUND: Researches on the results of surgical treatment of thoracolumbar spine fractures are infrequent. The aim of this study was to determine midterm outcomes of surgical treatment of these fractures in a prospective survey. METHODS: A case series study on pediatric patients with the diagnosis of thoracic and/or lumbar vertebral fractures was conducted over a ten-year period. Surgically treated patients were evaluated in the follow-up period, based on back pain, independent function, neurological status, and radiographic indices. RESULTS: There were 102 pediatric individuals, 61 boys and 41 girls, aged 3-17 years (mean 12 years of age) with thoracic and/or lumbar spinal fractures. Motor vehicle accident was the most common mechanism of injury (45.0 %). L1 was the most frequent level of fractured vertebra (24.4 %), and pelvic fracture was the most common associated orthopedic injury (21.5 %). Totally, 20 patients underwent surgery, but only fifteen (14 boys and one girl) participated in follow-up (mean 49 months; range 12-81 months). Posterior spinal fusion and instrumentation was accomplished in 12 cases. Three patients were operated by anterior approach and fusion followed by posterior fusion and instrumentation because of delay in diagnosis. There were no major perioperative complications. Two cauda equina syndromes and two incomplete spinal cord injuries improved back to normal. Five cases (33.3 %) reported occasional back pain, and all patients were functionally independent. Radiographic indices improved significantly. CONCLUSIONS: Spinal fusion and instrumentation in pediatric patients with unstable thoracolumbar vertebral fractures with or without spinal cord injuries have favorable radiographic and functional outcomes. PMID- 24469707 TI - Analysis of HGF, MACC1, C-met and apoptosis-related genes in cervical carcinoma mice. AB - To understand the underlying pharmacological basis and the molecular mechanism of Taxol in therapy of cervical carcinoma (CC) disease, we need to explore the effect of Taxol on CC-related genes and pro-apoptosis and anti-apoptosis genes expression. Immunohistochemistry, western blot and reverse transcription polymerase chain reaction were applied to examine postive expression levels of Bcl-2, Bax and Caspase-3, HGF, MACC1, Caspase-3 and C-met proteins and MACC1 mRNA expression in tumour of CC mice. Results showed that treatment of Taxol could increase the inhibition rate of tumour growth, positive expression levels of Caspase-3, Bax and decrease positive expression levels of Bcl-2 and Bcl-2/Bax, expression levels of HGF, MACC1 and C-met proteins and MACC1 mRNA in tumour tissue of CC mice. It can be concluded that inhibitory activity of Taxol against tumour growth in CC mice is closely associated with its modulating positive expression of Bcl-2, Bax, Caspase-3, expression of HGF, MACC1, Caspase-3 and C met proteins and MACC1 mRNA in tumour of CC mice. In conclusion, HGF, MACC1 and C met genes involve into malignant cervical tumors occurrence, development and prognosis, and might become potential molecular target therapy site of cervical cancer. Taxol intervention may serve as a multi-targeted CC therapeutic capable of inducing selective cancer cell death. PMID- 24469708 TI - Study on genetic variations of PPARalpha gene and its effects on thermal tolerance in Chinese Holstein. AB - Peroxisome proliferator-activated receptor alpha (PPARalpha) regulates responses to chemical or physical stress in part by altering expression of genes involved in proteome maintenance. In this research, polymerase chain reaction (PCR) technique was used to amplify 766 and 589 bp fragments of intron 3 and 7 of PPARalpha gene in Chinese Holstein (n = 771). Sequencing results showed that three novel single nucleotide polymorphisms (SNPs) were identified at position 44087 (G/A), 65550 (G/A), and 65676(G/A) in the PPARalpha gene. PCR-restriction fragment length polymorphism technology was used to genotype the three SNPs. Association analysis showed that cows with H1H8 (P < 0.05), H2H8 (P < 0.01), H5H7 (P < 0.05), H5H8 (P < 0.05), and H8H8 (P < 0.05) haplotype combinations had lower potassium content in erythrocytes than those with H2H6 haplotype combination. Cows with H1H8, and H8H8 haplotype combinations had lower decrease rate of milk yield than those with H2H6 and H6H8 haplotype combinations (P < 0.05). Cows with H2H8 and H8H8 haplotype combinations had lower rectal temperature than those with H5H8 and H7H7 haplotype combinations (P < 0.05). In conclusion, H8H8 haplotype combination may be advantageous for heat resistance traits in Chinese Holstein cattle. PMID- 24469709 TI - Comparison of different protocols for neural differentiation of human induced pluripotent stem cells. AB - Although embryonic stem cells (ESCs) have enormous potentials due to their pluripotency, their therapeutic use is limited by ethical, biological and safety issues. Compared to ESCs, induced pluripotent stem cells (iPSCs) can be obtained from mouse or human fibroblasts by reprogramming. Numerous studies have established many protocols for differentiation of human iPSCs (hiPSCs) into neural lineages. However, the low differentiation efficiency of such protocols motivates researchers to design new protocols for high yield differentiation. Herein, we compared neural differentiation potential of three induction media for conversion of hiPSCs into neural lineages. In this study, hiPSCs-derived embryoid bodies were plated on laminin coated dishes and were treated with three induction media including (1) bFGF, EGF (2) RA and (3) forskolin, IBMX. Immunofluorescence staining and quantitative real-time PCR (qPCR) analysis were used to detect the expression of neural genes and proteins. qPCR analysis showed that the expression of neural genes in differentiated hiPSCs in forskolin, IBMX supplemented media was significantly higher than undifferentiated cells and those in induction media containing bFGF, EGF or RA. In conclusion, our results indicated a successful establishment protocol with high efficiency for differentiation of hiPSCs into neural lineages. PMID- 24469710 TI - Molecular cloning of the goose ACSL3 and ACSL5 coding domain sequences and their expression characteristics during goose fatty liver development. AB - It has been demonstrated that ACSL3 and ACSL5 play important roles in fat metabolism. To investigate the primary functions of ACSL3 and ACSL5 and to evaluate their expression levels during goose fatty liver development, we cloned the ACSL3 and ACSL5 coding domain sequences (CDSs) of geese using RT-PCR and analyzed their expression characteristics under different conditions using qRT PCR. The results showed that the goose ACSL3 (JX511975) and ACSL5 (JX511976) sequences have high similarities with the chicken sequences both at the nucleotide and amino acid levels. Both ACSL3 and ACSL5 have high expression levels in goose liver. The expression levels of ACSL3 and ACSL5 in goose liver and hepatocytes can be changed by overfeeding geese and by treatment with unsaturated fatty acids, respectively. Together, these results indicate that ACSL3 and ACSL5 play important roles during fatty liver development. The different expression characteristics of goose ACSL3 and ACSL5 suggest that these two genes may be responsible for specific functions. PMID- 24469711 TI - MiRNA-375 promotes beta pancreatic differentiation in human induced pluripotent stem (hiPS) cells. AB - Islet transplantation is considered as an ultimate option for the treatment of type I diabetes. Human induced pluripotent stem cells (hiPSCs) have raised the possibility that patient-specific insulin-secreting cells might be derived from somatic cells through cell fate reprogramming. However, current protocols mostly rely on the use of several cytokines and inhibitors for directing differentiation towards pancreatic fate. Given the high manufacturing cost of these recombinant proteins, this approach is prohibitive for clinical applications. Knowing that microRNAs (miRNAs) are key players in various stages of pancreatic development, we present a novel and cost-effective strategy in which over-expression of miR 375 promotes pancreatic differentiation in hiPSCs in the absence of any other stimulator. We used a polycistronic viral vector expressing Sox2, Klf4, c-Myc, and Oct4 to drive hiPSCs from human foreskin fibroblasts. The established hiPSCs are similar to human embryonic stem cells in many aspects including morphology, passaging, surface and pluripotency markers, and gene expression. For differentiation induction, miR-375 was lentivirally overexpressed in these hiPSCs. Morphological assessment, immunocytochemistry, and expression analysis of islet marker genes confirmed that islet like cells were obtained in miR-375 transduced cells compared to controls. Our differentiated clusters secreted insulin in a glucose-dependant manner, showing in vitro functionality. We demonstrated for the first time that miRNAs might be ideal substitutes to induce pancreatic differentiation in hiPSCs. This work provides a new approach to study the role of miRNAs in pancreatic specification and increase the feasibility of using patient-specific iPSCs for beta cell replacement therapy for type I diabetes. PMID- 24469712 TI - Physiological and photosynthetic characteristics of indica Hang2 expressing the sugarcane PEPC gene. AB - Phosphoenolpyruvate carboxylase (PEPC) is known to play a key role in the initial fixation of CO2 in C4 photosynthesis. The PEPC gene from sugarcane (a C4 plant) was introduced into indica rice (Hang2), a process mediated by Agrobacterium tumefaciens. Integration patterns and copy numbers of the gene was confirmed by DNA blot analysis. RT-PCR and western blotting results showed that the PEPC gene was expressed at both the mRNA and protein levels in the transgenic lines. Real time PCR results indicated that expression of the sugarcane PEPC gene occurred mostly in green tissues and changed under high temperature and drought stress. All transgenic lines showed higher PEPC enzyme activities compared to the untransformed controls, with the highest activity (11.1 times higher than the controls) being observed in the transgenic line, T34. The transgenic lines also exhibited higher photosynthetic rates. The highest photosynthetic rate was observed in the transgenic line, T54 (22.3 MUmol m(-2) s(-1); 24.6 % higher than that in non-transgenic plants) under high-temperature conditions. Furthermore, the filled grain and total grain numbers for transgenic lines were higher than those for non-transgenic plants, but the grain filling (%) and 1,000-grain weights of all transgenic lines remained unchanged. We concluded that over expression of the PEPC gene from sugarcane in indica rice (Hang2) resulted in higher PEPC enzyme activities and higher photosynthesis rates under high temperature conditions. PMID- 24469713 TI - Adiponectin gene polymorphisms in Egyptian type 2 diabetes mellitus patients with and without diabetic nephropathy. AB - Recently, several reports addressed the associations of adiponectin (ADIPOQ) gene polymorphisms with abnormal adiponectin serum levels, type 2 diabetes mellitus (T2DM), and diabetic nephropathy (DN); however, results are inconsistent. This study aimed to investigate the possible association of ADIPOQ gene polymorphisms with T2DM and/or DN and whether they affect serum adiponectin levels in Egyptian population. Two hundred and ninety-six T2DM patients (100 normoalbuminuric patients, 103 microalbuminuric patients, and 93 macroalbuminuric patients) and 209 controls were enrolled in the present study. Polymorphisms of +45, -11391, and +276 of the ADIPOQ gene were detected using polymerase chain reaction restriction fragment length polymorphism. Serum adiponectin was measured using ELISA. Our results revealed that ADIPOQ +45 TG and GG genotypes and G allele were significantly associated with T2DM, micro/macroalbuminuria, and decreased serum adiponectin level. ADIPOQ -11391 AA genotype frequency was significantly increased in T2DM group. Moreover, GA and AA genotypes and A allele of ADIPOQ 11391 were significantly associated with susceptibility to macroalbuminuria despite increased serum adiponectin concentrations. While, ADIPOQ +276 TT genotype and T allele were protective factors regarding the susceptibility to T2DM and micro/macroalbuminuria, and they were significantly associated with increased adiponectin levels. We observed also that the decrease of the serum Adiponectin level was accompanied by an insulin resistance, albuminuria, as well as an increase of serum creatinine. We concluded that ADIPOQ +45; ADIPOQ -11391 gene polymorphisms are associated with T2DM and/or DN in Egyptian population. While, ADIPOQ +276 gene polymorphism is a protective factor regarding T2DM and/or DN susceptibility. PMID- 24469714 TI - Polymorphic distribution and forensic effectiveness study of eight miniSTR in Chinese Uyghur ethnic group. AB - We obtained the allelic frequencies and forensic efficiency data for eight mini short tandem repeat loci including Penta E, D12S391, D6S1043, D2S1338, D19S433, CSF1PO, Penta D and D19S253 loci from a sample of 128 unrelated Uyghur individuals from China. The amplification products of the eight STR loci are <240 bp in size. A total of 94 alleles were observed and the corresponding allelic frequencies ranged from 0.0039 to 0.3438 in the present study. Observed genotype distributions for each locus do not show deviations from Hardy-Weinberg equilibrium expectations. The combined power of discrimination, combined power of exclusion and combined matching probability of the eight STR loci equaled to 0.999999999963373, 0.9997770 and 3.6627 * 10(-11), respectively. Because of the small fragment length of PCR products and the high degree of polymorphisms, the eight STR loci are highly beneficial for the forensic analysis of degraded DNA samples which are commonly observed in forensic cases. The STR data of the Uyghur group were compared with the previously published population STR data of other groups from different ethnic or areas, and significant differences were observed among these groups at some loci. PMID- 24469715 TI - The association of rs1149048 polymorphism in matrilin-1(MATN1) gene with adolescent idiopathic scoliosis susceptibility: a meta-analysis. AB - Several previous studies have evaluated the association between rs1149048 polymorphism in the matrilin-1 gene (MATN1) and the risk of adolescent idiopathic scoliosis (AIS). However the results of those studies were inconsistent. We conducted this meta-analysis to assess whether rs1149048 polymorphism was involved in the risk of AIS and evaluated the associations in different ethnicities. Electronic databases, such as: PubMed, EMBASE, WANFANG databases in any languages up to Dec 2012 were searched to assess the association between rs1149048 polymorphism and AIS. Meta-analysis was performed by STATA 12.0 software to estimate the pooled odds ratio (OR) and the 95 % confidence interval (CI). Finally four papers including five studies which involved 1436 AIS patients and 1,879 controls were identified for this meta-analysis. The results showed that G allele of the rs1149048 was significantly associated with increased AIS risk [OR = 1.13, 95 % CI (1.02-1.25), P = 0.023]. As for genotype (GG vs. GA + AA), homozygous GG genotype was also found to be a risk factor of developing AIS. The subgroup meta-analysis results showed G allele and GG genotype were significantly associated with AIS in Asian group but not in Caucasian group. Neither Egger's test nor Begg's test found evidence of publication bias in current study (P > 0.05). In summary, this meta-analysis found an overall significant association of rs1149048 polymorphism with risk of AIS, especially in Asian population. The relationship between rs1149048 polymorphism and AIS in other ethnic population is needed to be investigated. PMID- 24469716 TI - Screening of common and novel familial mediterranean fever mutations in south east part of Turkey. AB - Familial mediterranean fever (FMF) is an autosomal recessive autoinflammatory disorder (MIM# 249100), particularly common in populations of Mediterranean extraction. MEFV gene, responsible for FMF, encoding pyrin has recently been mapped to chromosome 16p13.3. In the present study, 3,341 unrelated patients with the suspicion of FMF in south-east part of Turkey between the years 2009 and 2013 were enrolled and genomic sequences of exon 2 and exon 10 of the MEFV gene were scanned for mutations by direct sequencing. We identified 43 different type of mutations and 9 of them were novel. DNA was amplified by PCR and subjected to direct sequencing for the detection of MEFV gene mutations. Among the 3,341 patients, 1,598 (47.8 %) were males and 1,743 (52.1 %) were females. The mutations were heterozygous in 806 (62.3 %), compound heterozygous in 188 (14.5 %), homozygous in 281 (21.8 %) and mutations had complex genotype in 17 (1.32 %) patients. No mutation was detected in 2,051 (61.4 %) patients. The most frequent mutations were M694V, E148Q, M680I(G/C) and V726A. We could not find any significant differences between the two common mutations according to the gender. Molecular diagnosis of MEFV is a useful tool in clinical practice, thus a future study relating to genotype/phenotype correlation of FMF in more and larger group in Turkish population involving the whole MEFV gene mutations is necessary. PMID- 24469717 TI - Molecular characterization of distinct YMV (Yellow mosaic virus) isolates affecting pulses in India with the aid of coat protein gene as a marker for identification. AB - The present study was carried out to find out the variations present in different isolates of yellow mosaic virus (YMV) causing yellow mosaic disease of pulses in southern parts of India. The coat protein gene of YMV was amplified using gene specific and deng universal primers with DNA isolated from YMV infected samples. Further, cloning and DNA sequencing of CP gene was carried out. CP gene decrypt sequences revealed that YMV infected samples of Black gram, Cowpea and Green gram were similar to the MYMV-Tamil Nadu isolates. Whereas the YMV infected sample of Horse gram was found to be similar with HYMV. Hence, in the present study, two distinct YMV infecting pulses in Tamil Nadu (MYMV and HYMV species) were identified and it was observed that there exists considerable genetic variation among these species. In addition, Cowpea crop which was earlier supposed not to be susceptible for YMV infection also showed the presence of this virus similar to the MYMV. Overall, the findings of the present study indicate that the CP region is efficient enough to provide a simple, rapid, and reliable method for early detection of YMV infections in pulses, which would help to develop proper management strategies to control these viruses. PMID- 24469718 TI - Nonvirus encoded proteins could be embedded into Bombyx mori cypovirus polyhedra. AB - To explore whether the nonvirus encoded protein could be embedded into Bombyx mori cypovirus (BmCPV) polyhedra. The stable transformants of BmN cells expressing a polyhedrin (Polh) gene of BmCPV were constructed by transfection with a non-transposon derived vector containing a polh gene. The polyhedra were purified from the midguts of BmCPV-infected silkworms and the transformed BmN cells, respectively. The proteins embedded into polyhedra were determined by mass spectrometry analysis. Host derived proteins were detected in the purified polyhedra. Analysis of structure and hydrophilicity of embedded proteins indicated that the hydrophilic proteins, in structure, were similar to the left handed structure of polyhedrin or the N-terminal domain of BmCPV structural protein VP3, which were easily embedded into the BmCPV polyhedra. The lysate of polyhedra purified from the infected transformation of BmN cells with modified B. mori baculovirus BmPAK6 could infect BmN cells, indicating that B. mori baculovirus could be embedded into BmCPV polyhedra. Both the purified polyhedra and its lysate could be coloured by X-gal, indicating that the beta-galactosidase expressed by BmPAK6 could be incorporated into BmCPV polyhedra. These results suggested that some heterologous proteins and baculovirus could be embedded into polyhedra in an unknown manner. PMID- 24469719 TI - Identification of novel significant variants of ZFPM2/FOG2 in non-syndromic Tetralogy of Fallot and double outlet right ventricle in a Chinese Han population. AB - Tetralogy of Fallot (TOF) and double outlet right ventricle (DORV) are two common subtypes of conotruncal defects. Recent reports have implicated mutations in the zinc finger protein, FOG family member 2 (ZFPM2/FOG2) as a cause of TOF/DORV, but no current literature focuses on the relationship between ZFPM2/FOG2 gene and non syndromic TOF and DORV in Chinese Han population. The purpose of this study was to estimate the occurrence and the prevalence of ZFPM2/FOG2 genetic variants in Chinese Han population with non-syndromic TOF and DORV and to investigate genotype-phenotype correlations in individuals with ZFPM2/FOG2 mutations. The whole exons of ZFPM2/FOG2 were sequenced in 98 non-syndromic TOF/DORV patients and 200 control subjects. All the six variants (G2482A, G1552A, A2107C, C452T, C3239T, C1208G) changed the amino acid (p.Val828Met, p.Ala518Thr, p.Met703Leu, p.Thr151Ile, p.Ser1080Phe, p.Ala403Gly), in which four variants (G2482A, C452T, G1552A, C3239T) were not reported before and absent in control subjects. Further analysis revealed that only occurrences of variants G2482A and A2107C had statistical significance compared to the control group (P < 0.05). In conclusion, our results provide strong evidence regarding the susceptibility of the ZFPM2 gene to the development of non-syndromic TOF/DORV. It suggests that ZFPM2/FOG2 genetic variants may be a novel potential bio-markers and treatment targets for the non-syndromic TOF and DORV. PMID- 24469720 TI - An EGFR gene of the Pacific oyster Crassostrea gigas functions in wound healing and promotes cell proliferation. AB - The epidermal growth factor receptor (EGFR) is an important receptor tyrosine kinase member in animals, which plays versatile functions in development, growth, tissue regeneration etc. Current knowledge on EGFR is poor in bivalve mollusks. In this study, we cloned and analyzed an EGFR gene from the Pacific oyster Crassostrea gigas (cgegfr). A 5,731 bp full-length cDNA of cgegfr was obtained, encoding a peptide with 1,494 amino acids which exhibited a typical EGFR structure, including an extracellular region, a single transmembrane region and an intracellular region. A conserved tyrosine kinase domain was predicted in the intracellular region, while the extracellular region responsible for ligand binding showed comparatively poor conservation. Expression analysis revealed that cgefgr was expressed widely in C. gigas tissues and a highest expression level was observed in adductor tissue. Expression of cgegfr was revealed to be up regulated during wound healing of mantle, indicating that EGFR might function in the cell proliferation and migration during wound healing. Further functional analysis of cgegfr was conducted in mouse myoblast cell line C2C12, in which different parts of cgegfr were expressed and their effects were measured. The results revealed that cgegfr was able to accelerate cell proliferation of C2C12 cells and the transmembrane region was necessary for self-activation of truncated cgegfr. Our results would provide supports for further studies on the roles of cgegfr in development and growth in C. gigas. PMID- 24469721 TI - Identification of differentially expressed known and novel miRNAs in broodiness of goose. AB - MicroRNAs (miRNAs) are endogenous small noncoding RNAs plays a critical role in posttranscriptional regulation of gene expression. Broodiness is observed in most avian species and influences egg production. Several genes are known to play an important role in regulating the progress of reproduction. The goose is one of the most important waterfowls. However, the involvement of miRNAs in the broodiness behavior of Anser cygnoides (Swan Goose) is unknown. High-throughput sequencing and bioinformatics analysis were used to identify the miRNAs involved in egg-laying and brooding behavior of geese in our study. The results showed 38 up-regulated and 14 down-regulated known miRNAs/miRNA*s with reads>1,000 in at least one group and a fold change of >2.0, compared with those of the egg-laying group (P<0.001). We also identified 114 and 94 novel miRNAs in the broody and egg laying groups, respectively. Of these, 4 novel miRNAs were differentially expressed between the two groups. The study showed the expression of small RNAs in goose reproduction and identified known and novel miRNAs regulated in broodiness. The results reveal that these differentially expressed miRNAs may be involved in broodiness of A. cygnoides. PMID- 24469722 TI - Polymorphism of cytokine and innate immunity genes associated with bovine brucellosis in cattle. AB - Genetic susceptibility to brucellosis is multifactorial, and it is known that impairment of the immune system could contribute to risk for getting brucellosis. The aim of the study was to find association of bovine brucellosis with 20 SNPs pertaining to bovine cytokine (IFNG, IFNGR1, IFNGR2, TNFA) and innate immunity (SLC11A1, TLR1, TLR4, and TLR9) genes using PCR-RFLP genotyping technique and it was observed that SLC11A1 (+1066 C/G), TLR1 (+1446 C/A), TLR1 (+1380 G/A), TLR4 (+10 C/T) and TLR4 (+399 C/T) loci were significantly (P<=0.05) associated with bovine brucellosis. The odds ratios (OR) of CG and CC genotypes versus GG genotype were 0.31 (0.12-0.82; 95% CI) and 0.18 (0.03-1.06; 95% CI) at SLC11A1 (+1066 C/G) locus in cases of brucellosis affected cattle. For TLR1 (+1380 G/A) locus, the OR for AG and AA genotypes versus GG genotypes were 0.15 (0.05-0.44; 95% CI) and 0.26 (0.04-1.47; 95% CI) which indicated that proportion of GG homozygote was significantly higher in brucellosis affected animals as compared to control. At TLR1 (+1446 C/A) locus the OR of AC genotype versus CC genotype was 0.24 (0.08-0.68; 95% CI) which revealed that relative proportion CC genotypes was significantly higher in case population. The TLR4 (+10 C/T) locus had three genotypes (TT, CT and CC) where OR of CT and CC genotypes versus TT genotype were near to zero. The OR of CT genotypes versus CC genotypes was 8.25 (0.94-71.92; 95% CI) at TLR4 (+399 C/T) locus and indicated that CT genotype had higher odds of bovine brucellosis than control animals. PMID- 24469723 TI - Association of microRNAs and pathologic response to preoperative chemotherapy in triple negative breast cancer: preliminary report. AB - Triple negative breast cancer (TNBC) has caught the attention of oncologists worldwide because of poor prognosis and paucity of targeted therapies. Gene pathways have been widely studied, but less is known about epigenetic factors such as microRNAs (miRNAs) and their role in tailoring an individual systemic and surgical approach for breast cancer patients. The aim of the study was to examine selected miRNAs in TNBC core biopsies sampled before preoperative chemotherapy and the subsequent pathologic response in mastectomy or breast conservation specimens. Prior to treatment, core needle biopsies were collected from 11 female patients with inoperable locally advanced TNBC or large resectable tumors suitable for down-staging. In all 11 TNBC core biopsies we analyzed 19 miRNAs per sample: 512, 190, 200, 346, 148, 449, 203, 577, 93, 126, 423, 129, 193, 182, 136, 135, 191, 122 and 222 (miRCURY LNATM Universal RT microRNA polymerase chain reaction Custom Pick & Mixpanels). The Wilcoxon signed-rank test was used to compare related samples. Ingenuity pathway analysis was used to evaluate potential functional significance of differentially expressed miRNAs. Statistical analysis showed that 3 of 19 miRNAs differed in relation to pathologic response i.e. good versus poor. These differences failed to reach statistical significance, although a trend was observed (p=0.06). Among these miRNAs, we identified-miR-200b-3p, miR-190a and miR-512-5p. In summary, our results indicate that higher miR-200b-3p, higher miR-190a and lower miR-512-5p expression levels in core biopsies sampled from TNBC patients may be associated with better pathologic response to chemotherapy and the increased feasibility of breast conserving surgery in these patients. Although these results were from a small cohort, they provide an important basis for larger, prospective, multicenter studies to investigate the potential role of miRNAs in neoadjuvant setting. PMID- 24469724 TI - Construction of pancreatic cancer double-factor regulatory network based on chip data on the transcriptional level. AB - Transcription factor (TF) and microRNA (miRNA) have been discovered playing crucial roles in cancer development. However, the effect of TFs and miRNAs in pancreatic cancer pathogenesis remains vague. We attempted to reveal the possible mechanism of pancreatic cancer based on transcription level. Using GSE16515 datasets downloaded from gene expression omnibus database, we first identified the differentially expressed genes (DEGs) in pancreatic cancer by the limma package in R. Then the DEGs were mapped into DAVID to conduct the kyoto encyclopedia of genes and genomes (KEGG) pathway enrichment analysis. TFs and miRNAs that DEGs significantly enriched were identified by Fisher's test, and then the pancreatic cancer double-factor regulatory network was constructed. In our study, total 1117 DEGs were identified and they significantly enriched in 4 KEGG pathways. A double-factor regulatory network was established, including 29 DEGs, 24 TFs, 25 miRNAs. In the network, LAMC2, BRIP1 and miR155 were identified which may be involved in pancreatic cancer development. In conclusion, the double factor regulatory network was found to play an important role in pancreatic cancer progression and our results shed new light on the molecular mechanism of pancreatic cancer. PMID- 24469725 TI - Spheroid formation and invasion capacity are differentially influenced by co cultures of fibroblast and macrophage cells in breast cancer. AB - Interactions with stromal components influence the growth, survival, spread, and colonization capacities of tumor cells. Fibroblasts and macrophages which are responsible for the stroma production and maintenance are of the basic elements found in tumor microenvironment. Cellular density and ratio of stromal cells to tumor cells can also have modulatory effects in cancer. Here, the contribution of fibroblast and/or macrophage cells on the malignant behavior of breast cancer cells was modeled in co-culture systems. Co-cultures were established at different cell densities and ratios with 4T1 breast cancer, NIH/3T3 or 3T3-L1 fibroblast, and J774A.1 monocyte/macrophage cell lines. Flow cytometry-based proliferation, 3D growth on alginate matrix, and matrigel invasion assays were performed to determine the change in the malignant assets of tumor cells. The data were also supported by immunocytochemical and morphological analyses. Co culturing with fibroblasts (especially, NIH/3T3 cells) significantly supported the proliferation, scattering, and invasiveness of 4T1 cells whereas inclusion of macrophages disrupted this positive influence. On the other hand, the invasion capacity of 4T1 cells was not enhanced in the co-cultures with fibroblasts whose motility were inhibited with pertussis toxin pretreatment. Particularly at low density seeding in 3D cultures, 4T1 cells could form substantially more spheroids than that of in the co-cultures with fibroblasts. Only, increasing the amount of fibroblasts could restore the 3D-growth. Intriguingly, co-existence of macrophage, fibroblast, and tumor cells in 3D cultures provided a convenient stroma sustaining the spheroid formation and growth. In conclusion, fibroblasts can form a favorable environment for tumor cells' spread and motility whereas restricting their 3D-growth capacity. On the other hand, presence of macrophages may disrupt the influence of fibroblasts and enhance the spheroid formation by the tumor cells. PMID- 24469726 TI - Serum differential protein identification of Xinjiang Kazakh esophageal cancer patients based on the two-dimensional liquid-phase chromatography and LTQ MS. AB - The aim of this study was to investigate the impact of chemo-radiotherapy on serum protein expression of the esophageal cancer patients and discover potential biomarkers by detecting serum proteins mass spectrometry of the healthy Kazakh people in Xinjiang as well as the patients before and after their chemo radiotherapy. In order to separate and compare the three serum samples (the healthy group's, the patients' before and after chemo-radiotherapy) with two dimensional protein liquid chromatography system (Proteome LabTM PF-2D), then detect the differential protein spots with linear trap quadruple mass spectrometer (LTQ MS/MS). (1) The Kazakh esophageal cancer patients got 21 expressed protein spots peaks with significant difference after chemo radiotherapy compared with before; before the treatment there were 10 different expressed protein spots compared with the healthy group, and after it there were four peaks in the expression of protein spots compared with the healthy group. (2) After LTQ mass spectrometric detection, 22 proteins were up-regulated in serum samples of the healthy group, 22 were up-regulated of the patients before medical treatment and 5 were up-regulated after chemo-radiotherapy. (3) 8 proteins including APOA1 can be served as serum markers in Kazakh esophageal cancer diagnosis, and proteins like CLU can be served as serum markers in judging the resistance and sensitivity towards chemo-radiotherapy. (4) The abnormal expressions of APOC2, APOC3, Antithrombin-III in esophageal cancer were discovered for the first time. Specific protein spots related to Xinjiang Kazakh esophageal cancer diagnosis and chemo-radiotherapy can be identified in the serum, which will probably become a maker in Kazakh esophageal cancer diagnosis and therapeutic evaluation. PMID- 24469727 TI - Effects of genetic variants for the bovine calpain gene on meat tenderness. AB - The objective of this study was to determine whether the genetic variants of CAPN1 developed in several cattle populations can be applied for Hanwoo, regarding genetic effects on meat traits. The traits were examined for 286 purebred Hanwoo steers with genotypes classified by restriction fragment length polymorphism (RFLP) and single strand conformation polymorphism (SSCP) analysis. The nucleotide positions of primers and previously identified genetic variants were based on sequences of the calpain 1 (CAPN1) gene with GenBank accession numbers (AF252504, AF248054, and AY639597). The analysis of genetic distribution estimated levels of minor allele frequencies ranged from 0.165 to 0.392, showing no significant departures from Hardy-Weinberg Equilibrium for all markers. Overall averages of heterozygosites (He) and polymorphic information contents (PICs) for all markers were calculated to 0.503 and 0.429, respectively, and the g.4558G>A marker showed the lowest He (0.425) and PIC (0.367). Animals from 29 months of age were slaughtered to measure Warner-Bratzler shear force (WBSF), cooking loss, water-holding capacity, pH, fat, and moisture. All the CAPN1 markers explained variations of WBSF, showing significant additive effects except g.5709G>A. A significant marginal mean difference in genotypes of g.6545C>T (P=0.046) was found in moisture with additive effects. From the result it may be possible to use three calpain markers (g.4558G>A, g.4685C>T, and g.6545C>T) classified by RFLP and SSCP analysis in marker assisted selection programs to improve WBSF as meat tenderness in Hanwoo. PMID- 24469728 TI - Identification and characterization of microsatellite markers for the population genetic structure in endemic red-tailed barb, Gonoproktopterus curmuca. AB - Gonoproktopterus curmuca is an endangered red tailed barb found in Southern part of Western Ghat, India. As a part of stock-specific, propagation assisted rehabilitation and management program, polymorphic microsatellites markers were used to study the genetic diversity and population structure of this species from the three River systems of Southern Western Ghats, such as Periyar River, the Chalakkudy River, and the Chaliyar River. From selected eight polymorphic microsatellite markers, the number of alleles per locus ranged from 2 to 8, and the average number of alleles among 3 populations ranged from 5.0 to 5.75. The mean observed (Hob) and expected (Hex) heterozygosity ranged from 0.5148 to 0.5360 and from 0.5996 to 0.6067, respectively. Significant deviations from Hardy Weinberg Equilibrium expectation were found at majority of the loci (except Gcur MFW72 and Gcur MFW19) and in all three populations in which heterozygote deficits were apparent. The analysis of molecular variance indicates that the percent of variance among populations and within populations were 6.73 and 93.27, respectively. The pairwise FST values between populations indicate that there were significant deviations in genetic differentiations for the red-tailed barb populations from these three Rivers of the Western Ghats, India. The microsatellites methods reported a low degree of gene diversity and lack of genetic heterogeneity in the population of G. curmuca, which strongly emphasize the need of fishery management, conservation and rehabilitation of G. curmuca. PMID- 24469729 TI - Conditioned medium enhances the fusion capability of rat bone marrow mesenchymal stem cells and cardiomyocytes. AB - Mesenchymal stem cells (MSCs) show accelerated regeneration potential when these cells experience hypoxic stress. This "preconditioning" has shown promising results with respect to cardio-protection as it stimulates endogenous mechanisms resulting in multiple cellular responses. The current study was carried out to analyze the effect of hypoxia on the expression of certain growth factors in rat MSCs and cardiomyocytes (CMs). Both cell types were cultured and assessed separately for their responsiveness to hypoxia by an optimized dose of 2,4, dinitrophenol (DNP). These cells were allowed to propagate under normal condition for either 2 or 24 h and then analyzed for the expression of growth factors by RT PCR. Variable patterns of expression were observed which indicate that their expression depends on the time of re-oxygenation and extent of hypoxia. To see whether the growth factors released during hypoxia affect the fusion of MSCs with CMs, we performed co-culture studies in normal and conditioned medium. The conditioned medium is defined as the medium in which CMs were grown for re oxygenation till the specified time period of either 2 or 24 h after hypoxia induction. The results showed that the fusion efficiency of cells was increased when the conditioned medium was used as compared to that in the normal medium. This may be due to the presence of certain growth factors released by the cells under hypoxic condition that promote cell survival and enhance their fusion or regenerating ability. This study would serve as another attempt in designing a therapeutic strategy in which conditioned MSCs can be used for ischemic diseases and provide more specific therapy for cardiac regeneration. PMID- 24469730 TI - Genetic association of the P-glycoprotein gene ABCB1 polymorphisms with the risk for steroid-induced osteonecrosis of the femoral head in Chinese population. AB - Steroid administration, which is commonly performed for the treatment of autoimmune inflammatory diseases, cancers or organ transplantation, has been a leading cause of nontraumatic osteonecrosis of the femoral head (ONFH). Single nucleotide polymorphisms (SNPs) of the adenosine triphosphate-binding cassette B1 (ABCB1) gene have been demonstrated to be related to steroid-induced ONFH in small sample sizes of Japanese kidney failure and Chinese systemic lupus erythematosus patients. However, there are obvious controversial results in the relationship of ABCB1 gene polymorphisms with steroid-induced ONFH. The aim of this study was to validate the genetic association of ABCB1 polymorphisms with the risk for steroid-induced ONFH in a large cohort of Chinese population. A case control study was conducted, which included 94 and 106 unrelated patients after steroid administration recruited from 14 provinces in China, respectively. Two SNPs (rs1045642 and rs2032582) within ABCB1 were genotyped using Sequenom MassARRAY system. Multivariate analyses based on clinical information were performed to determine the associations between the SNPs and risk of steroid induced ONFH. rs1045642 SNP was significantly associated with steroid-induced ONFH group in codominant (P=0.02), recessive (P=0.006) and overdominant (P=0.03) models. However, there were no differences found in genotype frequencies of rs2032582 SNP between controls and patients with steroid-induced ONFH (all P>0.05). These findings suggested that rs1045642 SNP of ABCB1 may be associated with the risk of steroid-induced ONFH. Thus, it is useful to analyze this polymorphism for identifying high-risk individuals before the administration of steroids. PMID- 24469731 TI - Cotton photosynthesis-related PSAK1 protein is involved in plant response to aphid attack. AB - It is believed that hundreds of genes, including photosynthesis-related genes, are typically involved in plant response to aphid feeding. Up to now, however, it is little known on the relationship between the photosynthesis-related genes and plant response to herbivores. In this study, we identified a cotton photosynthesis-related gene (GhPSAK1) which belongs to PSI-PSAK family and encodes a putative protein of 162 amino acids. RT-PCR analysis revealed that GhPSAK1 transcripts in leaves were increased at 12-24 h, but decreased at 48-72 h after cotton aphid attack or wounding induction. Choice assay and no-choice assay demonstrated that overexpression of GhPSAK1 in Arabidopsis improved plant tolerance to green peach aphids (Myzus persicae). The defense response genes related to salicylic acid signaling pathway were enhanced in the GhPSAK1 overexpressing transgenic plants. In addition, the callose amount in transgenic Arabidopsis leaves was more than that of wild type. Contents of the soluble sugars and total amino acids were also altered in leaves of transgenic Arabidopsis plants. Activities of superoxide dismutase and peroxidase in transgenic leaves were higher than those of wild type. These results suggested that GhPSAK1 may be involved in regulation of cotton response and tolerance to aphid attack. PMID- 24469732 TI - Assessment of genetic and chemical variability in Thymus caramanicus. AB - Thymus caramanicus is an endemic species grown in Iran with interesting pharmacological and biological properties. In the present work, essential oil compositions and inter-simple sequences repeat (ISSR) markers were used to estimate the relationships among and within seven populations of T. caramanicus, belonging to three provinces in Iran. The studied individuals were distinguished on the basis of ISSR markers and constituents of essential oil. A total of 127 band positions were produced by 12 ISSR primers, of which 105 were found polymorphic with 82.68% polymorphism. Genetic similarity values among individuals ranged between 0.15 and 0.82 which was indicative of a high level of genetic variation. On the basis of their genetic similarities, ISSR analysis allowed to group the samples into two main clusters. One of these included populations originated from Kerman and Isfahan provinces, and the other cluster consists of populations from Semnan province. Chemical compounds of essential oils were found variable in the various individuals and all samples were principally composed of phenolic constituents (carvacrol and/or thymol). As a consequence, the plants were classified into two major chemotypes including carvacrol and thymol/carvacrol. A relationship between genetic and chemical variability and geographic distribution has been observed in studied populations of T. caramanicus. PMID- 24469733 TI - Proteolytic clipping of histone tails: the emerging role of histone proteases in regulation of various biological processes. AB - Chromatin is a dynamic DNA scaffold structure that responds to a variety of external and internal stimuli to regulate the fundamental biological processes. Majority of the cases chromatin dynamicity is exhibited through chemical modifications and physical changes between DNA and histones. These modifications are reversible and complex signaling pathways involving chromatin-modifying enzymes regulate the fluidity of chromatin. Fluidity of chromatin can also be impacted through irreversible change, proteolytic processing of histones which is a poorly understood phenomenon. In recent studies, histone proteolysis has been implicated as a regulatory process involved in the permanent removal of epigenetic marks from histones. Activities responsible for clipping of histone tails and their significance in various biological processes have been observed in several organisms. Here, we have reviewed the properties of some of the known histone proteases, analyzed their significance in biological processes and have provided future directions. PMID- 24469734 TI - Phylogeography and molecular diversity analysis of Jatropha curcas L. and the dispersal route revealed by RAPD, AFLP and nrDNA-ITS analysis. AB - Jatropha curcas L. (Euphorbiaceae) has acquired a great importance as a renewable source of energy with a number of environmental benefits. Very few attempts were made to understand the extent of genetic diversity and its distribution. This study was aimed to study the diversity and deduce the phylogeography of Jatropha curcas L. which is said to be the most primitive species of the genus Jatropha. Here we studied the intraspecific genetic diversity of the species distributed in different parts of the globe. The study also focused to understand the molecular diversity at reported probable center of origin (Mexico), and to reveal the dispersal route to other regions based on random amplified polymorphic DNA, amplified fragment length polymorphism and nrDNA-ITS sequences data. The overall genetic diversity of J. curcas found in the present study was narrow. The highest genetic diversity was observed in the germplasm collected from Mexico and supports the earlier hypothesis based on morphological data and natural distribution, it is the center for origin of the species. Least genetic diversity found in the Indian germplasm and clustering results revealed that the species was introduced simultaneously by two distinct germplasm and subsequently distributed in different parts of India. The present molecular data further revealed that J. curcas might have spread from the center of the origin to Cape Verde, than to Spain, Portuguese to other neighboring countries and simultaneously to Africa. The molecular evidence supports the Burkill et al. (A dictionary of the economic products of the Malay Peninsula, Governments of Malaysia and Singapore by the Ministry of Agriculture and Co-operatives. Kuala Lumpur, Malaysia, 1966) view of Portuguese might have introduced the species to India. The clustering pattern suggests that the distribution was interfered by human activity. PMID- 24469735 TI - 17beta-estradiol upregulates GREB1 and accelerates ovarian tumor progression in vivo. AB - Exogenous 17beta-estradiol (E2) accelerates the progression of ovarian cancer in the transgenic tgCAG-LS-TAg mouse model of the disease. We hypothesized that E2 has direct effects on ovarian cancer cells and this study was designed to determine the molecular mechanisms by which E2 accelerates ovarian tumor progression. Mouse ovarian cancer ascites (MAS) cell lines were derived from tgCAG-LS-TAg mice. Following intraperitoneal engraftment of two MAS cell lines, MASC1 and MASE2, into SCID mice, exogenous E2 significantly decreased the survival time and increased the tumor burden. Microarray analysis performed on MASE2-derived tumors treated with E2 or placebo showed that E2 treatment caused the upregulation of 197 genes and the downregulation of 55 genes. The expression of gene regulated by estrogen in breast cancer 1 (Greb1) was upregulated in mouse tumors treated with E2 and was overexpressed in human ovarian cancers relative to human ovarian surface epithelium, suggesting a role for GREB1 in human ovarian tumor progression. RNA interference-mediated knockdown of GREB1 in MASE2 cells decreased their proliferation rate in vitro and increased survival time in mice engrafted with the cells. These results emphasize the importance of E2 in ovarian tumor progression and identify Greb1 as a novel gene target for therapeutic intervention. PMID- 24469736 TI - Cardiac acceleration at the onset of exercise: a potential parameter for monitoring progress during physical training in sports and rehabilitation. AB - There is a need for easy-to-use methods to assess training progress in sports and rehabilitation research. The present review investigated whether cardiac acceleration at the onset of physical exercise (HRonset) can be used as a monitoring variable. The digital databases of Scopus and PubMed were searched to retrieve studies investigating HRonset. In total 652 studies were retrieved. These articles were then classified as having emphasis on HRonset in a sports or rehabilitation setting, which resulted in 8 of 112 studies with a sports application and 6 of 68 studies with a rehabilitation application that met inclusion criteria. Two co-existing mechanisms underlie HRonset: feedforward (central command) and feedback (mechanoreflex, metaboreflex, baroreflex) control. A number of studies investigated HRonset during the first few seconds of exercise (HRonsetshort), in which central command and the mechanoreflex determine vagal withdrawal, the major mechanism by which heart rate (HR) increases. In subsequent sports and rehabilitation studies, interest focused on HRonset during dynamic exercise over a longer period of time (HRonsetlong). Central command, mechanoreflexes, baroreflexes, and possibly metaboreflexes contribute to HRonset during the first seconds and minutes of exercise, which in turn leads to further vagal withdrawal and an increase in sympathetic activity. HRonset has been described as the increase in HR compared with resting state (delta HR) or by exponential modeling, with measurement intervals ranging from 0-4 s up to 2 min. Delta HR was used to evaluate HRonsetshort over the first 4 s of exercise, as well as for analyzing HRonsetlong. In exponential modeling, the HR response to dynamic exercise is biphasic, consisting of fast (parasympathetic, 0-10 s) and slow (sympathetic, 1-4 min) components. Although available studies differed largely in measurement protocols, cross-sectional and longitudinal training studies showed that studies analyzing HRonset in relation to physical training primarily incorporated HRonsetlong. HRonsetlong slowed in athletes as well as in patients with a coronary disease, who have a relatively fast HRonsetlong. It is advised to include both HRonsetlong and HRonsetshort in further studies. The findings of this review suggest that HRonset is a potential tool for monitoring and titrating training in sports as well as in rehabilitation settings, particularly in patients with ventricular fibrillation. Monitoring HRonset in the early phase of training can help optimize the effectiveness of training and therapy. More research is needed to gain a better understanding of the mechanisms underlying HRonset in relation to their application in sports and rehabilitation settings. PMID- 24469737 TI - What is a sports injury? AB - Current sports injury reporting systems lack a common conceptual basis. We propose a conceptual foundation as a basis for the recording of health problems associated with participation in sports, based on the notion of impairment used by the World Health Organization. We provide definitions of sports impairment concepts to represent the perspectives of health services, the participants in sports and physical exercise themselves, and sports institutions. For each perspective, the duration of the causative event is used as the norm for separating concepts into those denoting impairment conditions sustained instantly and those developing gradually over time. Regarding sports impairment sustained in isolated events, 'sports injury' denotes the loss of bodily function or structure that is the object of observations in clinical examinations; 'sports trauma' is defined as an immediate sensation of pain, discomfort or loss of functioning that is the object of athlete self-evaluations; and 'sports incapacity' is the sidelining of an athlete because of a health evaluation made by a legitimate sports authority that is the object of time loss observations. Correspondingly, sports impairment caused by excessive bouts of physical exercise is denoted as 'sports disease' (overuse syndrome) when observed by health service professionals during clinical examinations, 'sports illness' when observed by the athlete in self-evaluations, and 'sports sickness' when recorded as time loss from sports participation by a sports body representative. We propose a concerted development effort in this area that takes advantage of concurrent ontology management resources and involves the international sporting community in building terminology systems that have broad relevance. PMID- 24469739 TI - Copper binding modulates the platination of human copper chaperone Atox1 by antitumor trans-platinum complexes. AB - The transport system of platinum-based anticancer agents is crucial for drug sensitivity. Increasing evidence indicates that the copper transport system is also involved in the cellular influx and efflux of platinum drugs. The copper chaperone Atox1 has been shown to bind to cisplatin in vitro and in cells. Previous results reveal that copper binding promotes the reaction between Atox1 and cisplatin. Here, we have performed detailed solution NMR and ESI-MS experiments to investigate the effect of Cu(i) binding on the reactions of Atox1 with two antitumor active trans-platinum agents, trans-EE and trans-PtTz. Results indicate that, similar to the reaction of cisplatin, copper coordination also enhances the platination of Atox1 by two trans-platinum complexes, and platinum binds to the copper coordinating residues. However, copper binding promotes the trans-platinum transfer from Atox1 to dithiothreitol (DTT). This result is in contrast to the reaction of Atox1 with cisplatin, in which the presence of copper largely suppresses the platination of DTT. Additionally, both apo- and Cu(I) Atox1 react faster with trans-platinum complexes than with cisplatin, however, less protein aggregation is observed in the reaction of trans-platinum complexes. These results indicate that the roles of Atox1 in the regulation of cellular trafficking of platinum drugs are dependent on the coordination configurations. PMID- 24469738 TI - Myocardial perfusion MRI shows impaired perfusion of the mouse hypertrophic left ventricle. AB - There is growing consensus that myocardial perfusion deficits play a pivotal role in the transition from compensated to overt decompensated hypertrophy. The purpose of this study was to systematically study myocardial perfusion deficits in the highly relevant model of pressure overload induced hypertrophy and heart failure by transverse aortic constriction (TAC), which was not done thus far. Regional left ventricular (LV) myocardial perfusion (mL/min/g) was assessed in healthy mice (n = 6) and mice with TAC (n = 14). A dual-bolus first-pass perfusion MRI technique was employed to longitudinally quantify myocardial perfusion values between 1 and 10 weeks after surgery. LV function and morphology were quantified from cinematographic MRI. Myocardial rest perfusion values in both groups did not change significantly over time, in line with the essentially constant global LV function and mass. Myocardial perfusion was significantly decreased in TAC mice (4.2 +/- 0.9 mL/min/g) in comparison to controls (7.6 +/- 1.8 mL/min/g) (P = 0.001). No regional differences in perfusion were observed within the LV wall. Importantly, increased LV volumes and mass, and decreased ejection fraction correlated with decreased myocardial perfusion (P < 0.001, in all cases). Total LV blood flow was decreased in TAC mice (0.5 +/- 0.1 mL/min, P < 0.001) in comparison to control mice (0.7 +/- 0.2 mL/min). Myocardial perfusion in TAC mice was significantly reduced as compared to healthy controls. Perfusion was proportional to LV volume and mass, and related to decreased LV ejection fraction. Furthermore, this study demonstrates the potential of quantitative first-pass contrast-enhanced MRI for the study of perfusion deficits in the diseased mouse heart. PMID- 24469740 TI - Radiotherapy: DNA repair--a marker of late toxicity. PMID- 24469743 TI - Radiotherapy: avoiding lymphedema. PMID- 24469745 TI - Endogenous lithium clearance: a diagnostic method of assessing sodium sensitivity in hypertension. Methodological and clinical implications. PMID- 24469746 TI - Effect of different models of cardiac rehabilitation on heart rate recovery. AB - BACKGROUND AND AIM: The aim of this study was to assess the effect of different models of the second stage of cardiac rehabilitation on heart rate recovery (HRR). We also evaluated the effect of selected cardiovascular risk factors on HRR. METHODS: The study included 103 patients (80 men and 23 women) aged 60.9 +/- 10.7 years with a recent acute coronary syndrome undergoing the second stage of a comprehensive cardiac rehabilitation. An exercise test (ExT) was performed before and after rehabilitation. RESULTS: HRR improved significantly only in women (26.5 bpm in ExT before rehabilitation vs. 32.8 bpm in ExT after rehabilitation, p < 0.05). The highest HRR was obtained in the subgroup rehabilitated according to the model A, and the lowest in subgroup C (31 vs. 22.1 bpm, p < 0.05). The highest increase in HRR was observed in the most seriously ill patients in subgroup C (18 bpm before rehabilitation vs. 22.1 bpm after rehabilitation). CONCLUSIONS: The most significant improvement in HRR was observed in the most seriously ill patients. PMID- 24469747 TI - The presence of fragmented QRS on 12-lead ECG in patients with coronary slow flow. AB - BACKGROUND: Coronary slow flow (CSF) is characterised by delayed opacification of coronary arteries in the absence of epicardial occlusive disease. It has been reported that CSF may cause angina, myocardial ischaemia, and infarction. Fragmentation of QRS complex (fQRS) is an easily evaluated non-invasive electrocardiographic parameter. It has been associated with alternation of myocardial activation due to myocardial scar and/or ischaemia. Whether CSF is associated with fQRS is unknown. The presence of fQRS on ECG may be an indicator of myocardial damage in patients with CSF. AIM: To investigate the presence of fQRS in patients with CSF. METHODS: Sixty patients (mean age 55.5 +/- 10.5 years) with CSF and 44 patients with normal coronary arteries without associated CSF (mean age 53 +/- 8.4 years) were included in this study. The fQRS was defined as the presence of an additional R wave or notching of R or S wave or the presence of fragmentation in two contiguous leads corresponding to a major coronary artery territory. RESULTS: The presence of fQRS was higher in the CSF group than in the controls (p = 0.005). Hypertension was significantly more common in the CSF group (p < 0.001). There was no significant association between the presence of fQRS and an increasing number of vessel involvements. Logistic regression analysis demonstrated that the presence of CSF was the independent determinant of fQRS (OR = 10.848; 95% CI 2.385-49.347; p = 0.002). CONCLUSIONS: Fragmented QRS, indicating increased risk for arrhythmias and cardiovascular mortality, was found to be significantly higher in patients with CSF. We have not found an association between the presence of fragmented QRS and the degree of CSF. Further prospective studies are needed to establish the significance as a possible new risk factor in patients with CSF. PMID- 24469748 TI - The relation between the levels of osteoprotegerin and the degree of coronary artery disease in patients with acute coronary syndrome and stable angina pectoris. AB - BACKGROUND: Osteoprotegerin (OPG), an inhibitor of osteoclastogenesis, has recently been under the spotlight in studies regarding the pathophysiology of atherosclerosis. AIM: To evaluate the value of serum OPG in the diagnosis and severity in patients with stable angina pectoris (SA) and unstable angina pectoris/non ST elevation myocardial infarction. METHODS: This study involved 160 patients, SA (n = 65), acute coronary syndrome (NSTE-ACS; n = 65), and a control group (n = 30). Blood samples were collected in the first hour, after 24 hours and on the fifth day. The prevalence of coronary artery atherosclerotic lesions was determined using the Gensini scoring system. RESULTS: A statistically significant difference was observed in the first hour OPG levels between the control group and both the SA and NSTE-ACS group (p < 0.001). When the cut-off value was determined as 247.71 pg/mL, the sensitivity and specificity of the first hour OPG levels indicating coronary artery disease were 91.54% and 46.67%, respectively, while the positive predictive value was 88.1% and the negative predictive value was 56%. No correlations were observed between the first, 24th hour and the fifth day OPG levels and the Gensini scores. No relation was denoted between the OPG levels and number of diseased coronary arteries. CONCLUSIONS: In our study, serum OPG level seemed to be unrelated to the severity or the degree of coronary artery disease in patients with SA and unstable angina pectoris/non ST elevation myocardial infarction. OPG may only be accepted as an indicator of coronary atherosclerosis. PMID- 24469749 TI - [Vitamin D receptor (VDR) polymorphism and the risk of cardiovascular events]. PMID- 24469750 TI - [Masquerading bundle branch block]. AB - We here describe a surface 12-lead electrocardiogram (ECG) of a 72-year-old female with a prior history of breast cancer and chemotherapy-induced cardiomyopathy. An echocardiogram revealed left ventricular dysfunction, ejection fraction of 23%, with mild enlarged left ventricle. The 12-lead ECG showed atrial fibrillation with a mean heart rate of about 100 bpm, QRS duration 160 ms, QT interval 400 ms, right bundle branch block (RBBB) and left anterior fascicular block (LAFB). The combination of RBBB features in the precordial leads and LAFB features in the limb leads is known as ''masquerading bundle branch block''. In most cases of RBBB and LAFB, the QRS axis deviation is located between - 80 to 120 degrees. Rarely, when predominant left ventricular forces are present, the QRS axis deviation is near about -90 degrees, turning the pattern into an atypical form. In a situation of RBBB associated with LAFB, the S wave can be absent or very small in lead I. Such a situation is the result of not only purely LAFB but also with left ventricular hypertrophy and/or focal block due to scar (extensive anterior myocardial infarction) or fibrosis (cardiomyopathy). Sometimes, this specific ECG pattern is mistaken for LBBB. RBBB with LAFB may imitate LBBB either in the limb leads (known as 'standard masquerading' - absence of S wave in lead I), or in the precordial leads (called 'precordial masquerading' - absence of S wave in leads V5 and V6). Our ECG showed both these types of masquerading bundle branch block - absence of S wave in lead I and in leads V5 and V6. PMID- 24469751 TI - High degree right bundle branch block with left anterior hemiblock and lateral fibrosis resembling an atypical left bundle branch block in the limb leads. PMID- 24469752 TI - [Arrhythmogenic right ventricular cardiomyopathy in contemporary imaging. Expert consensus statement of the Polish Clinical Forum for Cardiovascular Imaging]. PMID- 24469753 TI - [Cardiological manifestation of MELAS syndrome associated with mDNA mutation at position 3234]. PMID- 24469754 TI - Left atrial myxoma or metastatic tumour in a patient with rheumatoid arthritis? The difficult way to the final diagnosis. PMID- 24469755 TI - Quadrofurcation of the left main coronary artery. PMID- 24469756 TI - [Cardiac sarcoidosis mimicking ischaemic infarct]. PMID- 24469757 TI - Acute dysphagia after myocardial infarction: an unusual complication of anticoagulation therapy. PMID- 24469758 TI - Right atrial rupture following a blow with a wooden block in the sternal region. PMID- 24469759 TI - [Pulmonary hypertension in contemporary imaging. Expert consensus statement of the Polish Clinical Forum for Cardiovascular Imaging]. PMID- 24469760 TI - [Atrial tachycardia focus as a remnant of sinus node]. PMID- 24469762 TI - Modelling of P3HT:PCBM interface using coarse-grained forcefield derived from accurate atomistic forcefield. AB - To understand the morphological evolution of P3HT:PCBM bulk heterojunction during thermal treatment process, we employed coarse-grained Molecular Dynamics (MD) simulations with a forcefield derived from atomistic model and experimental data such as crystal structure and melting temperature. The current study focuses on the differences between interfaces that PCBM forms with various P3HT orientations. Crystallinity analysis suggests that more ordered P3HT is observed near the interface for face-on and amorphous case, while no such trend is observed for edge-on and end-on configurations due to weaker interactions at the interface as evident from the considerably less negative interfacial energy. An analysis of pathways for C60 diffusion into P3HT using both an energy-based and solvent surface approach for amorphous P3HT reveals continuous chain motion assisted pathways while for crystalline P3HT diffusion pathways remain restricted to grain boundaries. Based on these calculations, we propose a morphological evolution process for P3HT:PCBM bulk-heterojunction, which starts with nucleation crystallisation at the P3HT:PCBM interface, followed by PCBM diffusion along the grain boundaries and amorphous P3HT regions towards PCBM-rich domains. PMID- 24469763 TI - Potential role of omega-3-derived resolution mediators in metabolic inflammation. AB - In its most reduced form, metabolic inflammation can be best described as a maladaptive process that involves an integrated innate and acquired immune response to nutrient surplus. Although originally these events were thought to be restricted to the expanding adipose depots of obese individuals, there are increasing reports that other metabolic centers such as the gut, liver, skeletal muscle and hypothalamus are also foci for metabolic inflammation. This review presents an overview of the major events and players identified thus far as central components of metabolic inflammation, and will examine recent findings concerning a novel class of omega-3-derived bioactive lipids that suggest that altered resolution processes may also contribute to metabolic inflammation. PMID- 24469765 TI - Inhibition of gene expression of carnitine palmitoyltransferase I and heart fatty acid binding protein in cyclophosphamide and ifosfamide-induced acute cardiotoxic rat models. AB - This study investigated whether cyclophosphamide (CP) and ifosfamide (IFO) therapy alters the expression of the key genes engaged in long-chain fatty acid (LCFA) oxidation outside rat heart mitochondria, and if so, whether these alterations should be viewed as a mechanism during CP- and IFO-induced cardiotoxicity. Adult male Wistar albino rats were assigned to one of the six treatment groups: Rats in group 1 (control) and group 2 (L-carnitine) were injected intraperitoneal (i.p.) with normal saline and L-carnitine (200 mg/kg/day), respectively, for 10 successive days. Animals in group 3 (CP group) were injected i.p. with normal saline for 5 days before and 5 days after a single dose of CP (200 mg/kg, i.p.). Rats in group 4 (IFO group) received normal saline for 5 successive days followed by IFO (50 mg/kg/day, i.p.) for 5 successive days. Rats in group 5 (CP-carnitine supplemented) were given the same doses of L carnitine as group 2 for 5 days before and 5 days after a single dose of CP as group 3. Rats in group 6 (IFO-carnitine supplemented) were given the same doses of L-carnitine as group 2 for 5 days before and 5 days concomitant with IFO as group 4. Immediately, after the last dose of the treatment protocol, blood samples were withdrawn and animals were killed for biochemical, histopathological and gene expression studies. Treatment with CP and IFO significantly decreased expression of heart fatty acid binding protein (H-FABP) and carnitine palmitoyltransferase I (CPT I) genes in cardiac tissues. Moreover, CP but not IFO significantly increased acetyl-CoA carboxylase2 mRNA expression. Conversely, IFO but not CP significantly decreased mRNA expression of malonyl-CoA decarboxylase. Both CP and IFO significantly increased serum lactate dehydrogenase, creatine kinase isoenzyme MB and malonyl-CoA content and histopathological lesions in cardiac tissues. Interestingly, carnitine supplementation completely reversed all the biochemical, histopathological and gene expression changes induced by CP and IFO to the control values, except CPT I mRNA, and protein expression remained inhibited by IFO. Data from the current study suggest, for the first time, that (1) CP and IFO therapy is associated with the inhibition of the expression of H FABP and CPT I genes in cardiac tissues with the consequent inhibition of mitochondrial transport and oxidation of LCFA. (2) The progressive increase in cardiotoxicity enzymatic indices and the decrease in H-FABP and CPT I expression may point to the possible contribution of these genes to CP- and IFO-induced cardiotoxicity. PMID- 24469764 TI - The immune profile associated with acute allergic asthma accelerates clearance of influenza virus. AB - Asthma was the most common comorbidity in hospitalized patients during the 2009 influenza pandemic. For unknown reasons, hospitalized asthmatics had less severe outcomes and were less likely to die from pandemic influenza. Our data with primary human bronchial cells indicate that changes intrinsic to epithelial cells in asthma may protect against cytopathology induced by influenza virus. To further study influenza virus pathogenesis in allergic hosts, we aimed to develop and characterize murine models of asthma and influenza comorbidity to determine structural, physiological and immunological changes induced by influenza in the context of asthma. Aspergillus fumigatus-sensitized and -challenged C57BL/6 mice were infected with pandemic H1N1 influenza virus, either during peak allergic inflammation or during airway remodeling to gain insight into disease pathogenesis. Mice infected with the influenza virus during peak allergic inflammation did not lose body weight and cleared the virus rapidly. These mice exhibited high eosinophilia, preserved airway epithelial cell integrity, increased mucus, reduced interferon response and increased insulin-like growth factor-1. In contrast, weight loss and viral replication kinetics in the mice that were infected during the late airway remodeling phase were equivalent to flu only controls. These mice had neutrophils in the airways, damaged airway epithelial cells, less mucus production, increased interferons and decreased insulin-like growth factor-1. The state of the allergic airways at the time of influenza virus infection alters host responses against the virus. These murine models of asthma and influenza comorbidity may improve our understanding of the epidemiology and pathogenesis of viral infections in humans with asthma. PMID- 24469766 TI - Cultural heritage and its environment: an issue of interest for Environmental Science and Pollution Research. PMID- 24469767 TI - Assessment of combined antiandrogenic effects of binary parabens mixtures in a yeast-based reporter assay. AB - To date, toxicological studies of endocrine disrupting chemicals (EDCs) have typically focused on single chemical exposures and associated effects. However, exposure to EDCs mixtures in the environment is common. Antiandrogens represent a group of EDCs, which draw increasing attention due to their resultant demasculinization and sexual disruption of aquatic organisms. Although there are a number of in vivo and in vitro studies investigating the combined effects of antiandrogen mixtures, these studies are mainly on selected model compounds such as flutamide, procymidone, and vinclozolin. The aim of the present study is to investigate the combined antiandrogenic effects of parabens, which are widely used antiandrogens in industrial and domestic commodities. A yeast-based human androgen receptor (hAR) assay (YAS) was applied to assess the antiandrogenic activities of n-propylparaben (nPrP), iso-propylparaben (iPrP), methylparaben (MeP), and 4-n-pentylphenol (PeP), as well as the binary mixtures of nPrP with each of the other three antiandrogens. All of the four compounds could exhibit antiandrogenic activity via the hAR. A linear interaction model was applied to quantitatively analyze the interaction between nPrP and each of the other three antiandrogens. The isoboles method was modified to show the variation of combined effects as the concentrations of mixed antiandrogens were changed. Graphs were constructed to show isoeffective curves of three binary mixtures based on the fitted linear interaction model and to evaluate the interaction of the mixed antiandrogens (synergism or antagonism). The combined effect of equimolar combinations of the three mixtures was also considered with the nonlinear isoboles method. The main effect parameters and interaction effect parameters in the linear interaction models of the three mixtures were different from zero. The results showed that any two antiandrogens in their binary mixtures tended to exert equal antiandrogenic activity in the linear concentration ranges. The antiandrogenicity of the binary mixture and the concentration of nPrP were fitted to a sigmoidal model if the concentrations of the other antiandrogens (iPrP, MeP, and PeP) in the mixture were lower than the AR saturation concentrations. Some concave isoboles above the additivity line appeared in all the three mixtures. There were some synergistic effects of the binary mixture of nPrP and MeP at low concentrations in the linear concentration ranges. Interesting, when the antiandrogens concentrations approached the saturation, the interaction between chemicals were antagonistic for all the three mixtures tested. When the toxicity of the three mixtures was assessed using nonlinear isoboles, only antagonism was observed for equimolar combinations of nPrP and iPrP as the concentrations were increased from the no-observed-effect-concentration (NOEC) to effective concentration of 80%. In addition, the interactions were changed from synergistic to antagonistic as effective concentrations were increased in the equimolar combinations of nPrP and MeP, as well as nPrP and PeP. The combined effects of three binary antiandrogens mixtures in the linear ranges were successfully evaluated by curve fitting and isoboles. The combined effects of specific binary mixtures varied depending on the concentrations of the chemicals in the mixtures. At low concentrations in the linear concentration ranges, there was synergistic interaction existing in the binary mixture of nPrP and MeP. The interaction tended to be antagonistic as the antiandrogens approached saturation concentrations in mixtures of nPrP with each of the other three antiandrogens. The synergistic interaction was also found in the equimolar combinations of nPrP and MeP, as well as nPrP and PeP, at low concentrations with another method of nonlinear isoboles. The mixture activities of binary antiandrogens had a tendency towards antagonism at high concentrations and synergism at low concentrations. PMID- 24469768 TI - A step forward using QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) based extraction and gas chromatography-tandem mass spectrometry-levels of priority polycyclic aromatic hydrocarbons in wild and commercial mussels. AB - A new and fully validated QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) extraction and gas chromatography-tandem mass spectrometry methodology was developed and subsequently implemented for the quantification of 16 polycyclic aromatic hydrocarbons (PAHs) in wild (from Matosinhos Beach, Portugal) and commercial (from Ria de Arousa, Spain) mussels. The method proved to be robust, precise, and accurate, with recoveries ranging from 89.2 to 111.8 %. Total sums of 16 PAHs were 52.91 and 37.58 ng/g of wet weight for wild and commercial specimens, respectively. The three- to four-ring PAHs were the most abundant, and a mixture of petrogenic and pyrolytic sources were suspected to occur in both origin areas. Although the contamination levels were below the European regulated limits, specifically for commercial mussels (this despite wild specimens are also consumed), care should be taken in terms of human health, since we are still not aware of the low-dose versus long-term effects, even more in high-risk population groups. PMID- 24469769 TI - An assessment of hematological and biochemical responses in the tropical fish Epinephelus stoliczkae of Chabahar Bay and Gulf of Oman under chromium exposure: ecological and experimental tests. AB - The aim of this investigation was to evaluate the effect of chromium on hematological and biochemical parameters in Epaulet Grouper, Epinephelus stoliczkae of Chabahar Bay and Gulf of Oman by ecological and experimental tests. Spatial evaluation of ecological test results showed these parameters had significant difference among some sampling sites. Examination of hematological and biochemical profiles on Epaulet Grouper was performed after 0.5, 1, 7, 14, and 21 days of chromium exposure (3.6, 7.31 and 14.6 mg/L). Experimental test results of chromium induce indicated the significant decrease in MCV, MCH, neutrophils, basophils, plasma protein and significant increase in MCHC, lymphocytes, monocytes, eosinophils and a biphasic trend in Hb, Ht, RBC, WBC, and glucose (p < 0.05). Cellular and nuclear axis, cytoplasmic volume, cell and nuclear volume, and surface area were significantly different for ecological and experimental results (p < 0.05). It was concluded that these parameters are sensitive in monitoring the toxicity of chromium concentrations. PMID- 24469770 TI - Frequency of micronuclei and of other nuclear abnormalities in erythrocytes of the grey mullet from the Mondego, Douro and Ave estuaries--Portugal. AB - Fish are bioindicators of water pollution, and an increased rate of their erythrocyte nuclear morphological abnormalities (ENMAs)-and particularly of erythrocyte micronuclei (EMN)-is used as a genotoxicity biomarker. Despite the potential value of ENMAs and MN, there is scarce information about fish captured in Iberian estuaries. This is the case of the Portuguese estuaries of the Mondego, Douro and Ave, suffering from different levels of environmental stress and where chemical surveys have been disclosing significant amounts of certain pollutants. So, the aim of this study was to evaluate genotoxicants impacts and infer about the exposure at those ecosystems, using the grey mullet (Mugil cephalus) as bioindicator and considering the type and frequency of nuclear abnormalities of erythrocytes as proxies of genotoxicity. Sampling of mullets was done throughout the year in the important Mondego, Douro and Ave River estuaries (centre and north-western Portugal). The fish (total n = 242) were caught in campaigns made in spring-summer and autumn-winter, using nets or fishing rods. The sampled mullets were comparable between locations in terms of the basic biometric parameters. Blood smears were stained with Diff-Quik to assess the frequencies of six types of ENMAs and MN (given per 1,000 erythrocytes). Some basic water physicochemical parameters were recorded to search for fluctuations matching the ENMAs. Overall, the most frequent nucleus abnormality was the polymorphic type, sequentially followed by the blebbed/lobed/notched, segmented, kidney shaped, vacuolated, MN and binucleated. The total average frequency of the ENMAs ranged from 73 0/00 in the Mondego to 108 0/00 in the Ave. The polymorphic type was typically >=50 % of the total ENMAs, averaging about 51 0/00, when considering all three estuaries. The most serious lesion-the MN-in fish from Mondego and Douro had a similar frequency (~0.38 0/00), which was significantly lower than that in the Ave (0.75 0/00). No significant seasonal differences existed as to the MN rates and seasonal differences existed almost only in the Douro, with the higher values in AW. In general, the pattern of ENMAs frequencies was unrelated with the water physicochemical parameters. Considering the data for both the total ENMAs and for each specific abnormality, and bearing in mind that values of MN in fish erythrocytes >0.3 0/00 usually reflect pollution by genotoxicants, it is suggested that mullets were likely being chronically exposed to such compounds, even in the allegedly less polluted ecosystem (Mondego). Moreover, data supported the following pollution exposure gradient: Mondego < Douro < Ave. The scenario and inferences nicely agree with the published data from chemical monitoring. PMID- 24469771 TI - Visible-light driven oxidation of gaseous aliphatic alcohols to the corresponding carbonyls via TiO2 sensitized by a perylene derivative. AB - Sensitized P25 TiO2 was prepared by wet impregnation with a home-prepared perylene dye, i.e., N,N'-bis(2-(1-piperazino)ethyl)-3,4,9,10-perylene tetracarboxylic acid diimide dichloride (PZPER). Energy levels of PZPER were found to be compatible with those of TiO2 allowing fast electron transfer. The obtained catalyst has been characterized and used in the gas-phase partial oxidation of aliphatic primary and secondary alcohols, i.e., methanol, ethanol, and 2-propanol. The reaction was carried out under cut-off (lambda > 400 nm) simulated solar radiation in O2 atmosphere. The perylene derivative allowed a good absorbance of visible radiation thanks to its low optical energy gap (2.6 eV) which was evaluated by cyclic voltammetry. The optimal organic sensitizing amount was found to be 5.6 % w/w in terms of yield in carbonyl derivatives. Moreover, no change in reactivity/selectivity was observed after 10-h irradiation thus confirming the catalyst stability. Yields into formaldehyde, acetaldehyde, and acetone were 67, 70, and 96 %, respectively. No significant amounts of organic byproducts were detected but for methanol oxidation, whereas a minor amount of the substrate degraded to CO2. PMID- 24469772 TI - Characterization of cattle fecal Streptomyces strains converting cellulose and hemicelluloses into reducing sugars. AB - To characterize Streptomyces isolated from cattle feces for converting lignocellulose into reducing sugars, five Streptomyces strains were screened. All the strains could convert lignocellulose into reducing sugars. The strain A16 accumulate 3.3-folds more reducing sugars on cottonseed shells treated with ethanol than without the treatment (P < 0.05). The five strains did not accumulate more reducing sugars on rice straws and wheat brans than those on cottonseed shells. Compared with A10 alone, the microbial combination of F1 + A10 accumulated 19, 61, and 25 % less reducing sugars on cottonseed shell, rice straw, and wheat bran than those by A10 solely, respectively (P < 0.05). Further studies indicated that the activities of avicelase and xylanase were not correlated with the reducing sugar amount accumulated by the test strains. Strain A7 could produce more cellular lipids with xylose and glucose as the sole carbon sources. This study shows the potential for Streptomyces strains from herbivore feces to convert lignocelluloses into lipids and reducing sugars for fuel production. PMID- 24469774 TI - Laparoscopic transperitoneal extravesical approach to vesicovaginal fistula repair without omental flap: a novel technique. AB - INTRODUCTION AND HYPOTHESIS: The O'Connor bladder bivalving technique remains the traditional abdominal approach to vesicovaginal fistula repair whether performed via laparotomy or laparoscopy. METHODS: This video depicts a new surgical technique utilizing a laparoscopic transperitoneal extravesical approach without invasive bladder bivalving or an omental flap. This technique was first described in 1999 and has been utilized on >40 patients with either primary or recurrent vesicovaginal fistulas. RESULTS: A 98% success rate is reported. CONCLUSION: This alternative technique can be performed using either a laparoscopy or the traditional laparotomy approach. PMID- 24469773 TI - Assessment of association between the dopamine D2 receptor (DRD2) polymorphism and neurodevelopment of children exposed to lead. AB - The mechanism of lead (Pb) neurotoxicity has not been illustrated over the years. People pay more attention to dopaminergic neurotransmission, specifically dopamine receptor-2 (DRD2) Taq IA polymorphism, but no consensus has been reached. A total of 258 three-year-old children in Guiyu (exposed group) and Nanao (reference group), China were examined and their concentrations of blood lead (BPb) were determined. Cognitive and language scores of children were assessed using the Bayley Scales of Infant Development, third edition (BSID-III). Genotyping for the DRD2 polymorphism was carried out using a polymerase chain reaction (PCR) re-sequencing platform. The logistic stepwise regression analysis and stepwise regression analysis was used to explore associations among lead, neurodevelopment of children, and DRD2 Taq IA categories. Median values of Pb in Guiyu was higher than that of the reference group (11.30 +/- 5.38 MUg/dL vs. 5.77 +/- 2.51 MUg/dL, P < 0.001). Compared with the reference group, children from e waste exposed area have lower cognitive scale scores (100 +/- 25 vs 120 +/- 20, P < 0.001) and lower language scale scores (99.87 +/- 7.52 vs 111.39 +/- 7.02, P < 0.001). The three kinds of genotype, A1/A1, A1/A2, and A2/A2, had no significant influences on BPb, cognitive scores and language scores (P > 0.05). Exposure of inhabitants, especially children to Pb from informal e-waste recycling activities might have contributed to higher levels of BPb and reduced cognitive and language scores observed in local children, however, the result obtained showed no significant association between DRD2 polymorphism and neurodevelopment of children exposed to lead. PMID- 24469775 TI - Single-incision mesh repair versus traditional native tissue repair for pelvic organ prolapse: results of a cohort study. AB - INTRODUCTION AND HYPOTHESIS: To compare the efficacy and safety of the ElevateTM anterior and posterior prolapse repair system and traditional vaginal native tissue repair in the treatment of stage 2 or higher pelvic organ prolapse. METHODS: A cohort study was conducted between January 2010 and July 2012. Patients who underwent transvaginal pelvic reconstruction surgery for prolapse were recruited. The primary outcome was anatomical success 1 year after surgery. The secondary outcome included changes in the quality of life and surgical complications. Recurrence of prolapse was defined as stage 2 or higher prolapse based upon the pelvic organ prolapse qQuantification system. RESULTS: Two hundred and one patients (100 in the ElevateTM repair group and 101 in the traditional repair group) were recruited and analyzed. The anatomical success rate of the anterior compartment was significantly higher in the ElevateTM repair group than in the traditional repair group (98 % vs 87 %, p = 0.006), but not for the apical (99 % vs. 6 %, p = 0.317) or posterior (100 % vs 97 %, p = 0.367) compartments after a median 12 months of follow-up. Both groups showed significant improvements in the quality of life after surgery with no statistical difference. Mesh-related complications included extrusion (3 %) and the need for revision of the vaginal wound (1 %). Those in the mesh repair group had a longer hospital stay (p = 0.04), operative time (p < 0.001), and greater estimated blood loss (p = 0.05). Other complications were comparable with no statistical difference. CONCLUSIONS: The ElevateTM prolapse repair system had a better 1-year anatomical cure rate of the anterior compartment than traditional repair, with slightly increased morbidity. PMID- 24469777 TI - Acid and alkaline invertases in roots and nodules of Lupinus angustifolius infected with Rhizobium lupini. AB - Both acid and alkaline invertase activity were found in tips and cortical tissue of Lupinus angustifolius L. roots infected with Rhizobium lupini NZP 2257. Only the alkaline invertase was detected in the nodule cytoplasm. Weak invertase activity found in the bacteroids was probably a contamination from plant invertase. The alkaline invertase activity in the nodule cytoplasm was 250 times that detected in the bacteroids and 8 times that detected in cortical tissue. No intracellular or extracellular invertase was detected in R. lupini cultured in liquid medium containing sucrose. PMID- 24469778 TI - The ultrastructure and cytochemistry of microbodies in dinoflagellates. AB - Microbodies, similar in morphology to those of higher plants and animals, have been observed in thirteen genera of dinoflagellates. As in other unicellular algae, they did not show any staining after incubation in DAB/H2O2 medium although the mitochondrial cristae and chloroplast lamellae did give a positive reaction. The microbodies of Scrippsiella sweeneyae were found to be associated with a membranous reticulate structure, which may be involved in their formation. PMID- 24469779 TI - [Low temperature spectral study on Euglena gracilis Z during synchronous culture on lactate medium: Variation of cytochrome 556 content]. AB - Low temperature spectra are described for whole Euglena cells. Euglena growing in synchronous culture with lactate medium show a cyclic variation of cytochrome 556 content during each cellular generation. The greatest quantity of cytochrome 556 seems to coincide with the non-dividing phase of the cells, the phase in which the mitochondrial network is observed. On the other hand after treatment of the Euglena with antimycin A, a correlation exists between the formation of giant mitochondria and an increase in the quantity of cytochrome 556.These results demonstrate the existence of a cyclic variation of cytochrome 556 synthesis in Euglena during synchronous growth on lactate medium. PMID- 24469780 TI - [Flower initiation by cycloheximide in the long-day plant Hyoscyamus niger during short-days]. AB - Cycloheximide (CH) was applied selectively either to the shoot apex or by infiltration to the leaves of the long-day plant Hyoscyamus niger in order to investigate whether this inhibitor has an effect on the synthesis of a floral stimulus in the leaves. Treatment of the shoot apex with CH caused inhibition of the photoperiodic induction. In contrast, when CH was applied to leaves, initiation of flowering was observed under short-day conditions. The drug yielded optimum initiating effects at concentrations of 10(-5)-3.10(-5) M, inducing flowering of almost 60% of the plants. Daily infiltration over a period of up to 4 days decreased the rate of flower initiation. The effect of CH was shown to be additive to a photoperiodic induction, even to a sub-threshold induction, but not to 2-thiouracil mediated induction. In no case did the presence of additional untreated leaves on the plants suppress CH-mediated flower induction. Treatment of the leaves with chloramphenicol (10(-6)-2(-)10(-4) M) or puromycin (5.10(-6) 2.10(-4) M) caused no initiating response. The results are interpreted to mean that the presence of CH in the leaves may lead to the synthesis of a floral stimulus also under short-day conditions. This finding is similar to that reported previously in the case of the inductive effect of 2-thiouracil. PMID- 24469781 TI - Histochemical studies on protease formation in the cotyledons of germinating bean seeds. AB - Protease formation in Phaseolus vulgaris L. cotyledons during seed germination was studied histochemically using a gelatin-film-substrate method. Protease activity can be detected by this method on the 5th day of germination, at approximately the same time that a rapid increase of activity was observed by a test-tube assay with casein as a substrate. At the early stage of germination, protease activity was observed throughout the cotyledon except in two or three cell layers below the cotyledon surface and in several cell layers around the vascular bundles. A highly active cell layer surrounding the protease-inactive cells near the vascular bundles is suggested to be a source of the protease. PMID- 24469782 TI - Immunological methods for the agglutination of protoplasts from cell suspension cultures of different genera. AB - Protoplasts from cell suspension cultures of Vicia hajastana Grossh., soybean (Glycine max L.) and brome grass (Bromus inermis Leyss.) were tightly agglutinated by immune sera prepared against them in rabbits. After incubation, the aggregated protoplasts became adpressed over a considerable area of their surface. Antibody prepared against Vicia protoplasts agglutinated both Vicia and soybean protoplasts alone, as well as a mixture of the two. Soybean and bromegrass antibody likewise cross-reacted with and agglutinated Vicia protoplasts. The heterologous reactions were nearly as strong as, and in some cases stronger than, the homologous. When sheep anti-rabbit globulin was reacted with a mixture of the protoplasts previously coated with homologous antibody, agglutination occurred much more quickly and the aggregates could not be dispersed without physical damage. Carbol-fuchsin staining of nuclei showed that Vicia and soybean protoplasts were randomly mixed in the aggregate. The protoplasts were viable and underwent division after the antibody treatment. The immune serum, which presumably contained complement, lysed the protoplasts unless it was heat-treated prior to use. PMID- 24469783 TI - Separate auxin- and cation-dependent mechanisms for glutamate utilization by normal and crown-gall teratoma cells of tobacco in culture. AB - Crown-gall teratoma tissues of tobacco, when grown in culture, require exogeneous auxin (alpha-naphthaleneacetic acid) or high concentrations of K(+) in the medium to utilize ammonium glutamate as a nitrogen source. These factors are not required to utilize NO 3 (-) or glutamine. The effects of K(+) and auxin on glutamate utilization differ in that NH 4 (+) is required for the action of K(+), but not for the action of auxin. The tissues grew optimally when the ratio of NH 4 (+) to glutamate was approximately one or greater. These results indicate that glutamate utilization involves at least two different mechanisms: one mechanism requires K(+) and stoichiometric amounts of NH 4 (+) , the other mechanism requires auxin. Experiments using explants of tobacco pith show that both mechanisms function in normal as well as crown-gall tissues of tobacco. PMID- 24469784 TI - Effects of abscisic acid on the levels of endogenous gibberellin-like substances in Solanum andigena. AB - Treatment of young, fully expanded leaves of Solanum andigena with synthetic abscisic acid resulted in marked increases in gibberellin-like substances. Abscisic acid treatment caused increases in the gibberellin content of leaves excised from both short day and long day grown plants. PMID- 24469785 TI - A quantitative description of inhibition of stem growth in vegetative lateral shoots of Chrysanthemum morifolium by N-dimethylaminosuccinamic acid (daminozide). AB - The concentration of N-dimethylaminosuccinamic acid (daminozide) in four lateral shoot fractions of vegetative plants of chrysanthemum morifolium cv. Bright Golden Anne was determined at intervals over twenty three days following 0.2%, 0.6% and 1.5% foliar spray applications of this growth retardant. The decrease in daminozide concentration in stem tissue conformed to first order kinetics, but in leaf fractions did not follow any simple pattern.Inhibition by daminozide of lateral shoot growth was wholly attributable to its effect on the stem. A mathematical treatment, based on an approach originally developed to describe inhibition of bacterial growth, describes the relationship between daminozide concentration in the stem and inhibition of growth in stem mass. The results quantitatively describe the phenomenon of "growing out" which is frequently observed in daminozide-treated plants, and suggest that daminozide exerts its primary effect at a site located in the stem. PMID- 24469786 TI - Relationships between changes in membrane permeability and the respiration climacteric in pericarp tissue of tomatoes. AB - Changes in the percent apparent free space (%AFS) in pericarp tissue of tomatoes at successive ripening stages were determined, using the climacteric sequence as a standard. A considerable increase in %AFS occurred in the preclimacteric stage. This initial rise was followed by a decline until shortly after the onset of the climacteric rise, apparently due to a temporary stabilization effect, followed by a final increase in permeability. PMID- 24469787 TI - The isolation of an abscisic-acid metabolite, 4'-dihydrophaseic acid, from non imbibed Phaseolus vulgaris seed. AB - Naturally occurring 4'-dihydrophaseic acid (DPA) has been isolated from mature, non-imbibed bean seed. The concentrations of abscisic acid (ABA), phaseic acid (PA) and DPA in the seed were estimated to be 0.06, 0.11 and 5.95 mg/kg dry wt., respectively. The results suggest that DPA is a major inactivation product of ABA in this tissue. The possible pathway from ABA to DPA is discussed. PMID- 24469788 TI - Pattern of Tuber melanosporum extramatrical mycelium expansion over a 20-year chronosequence in Quercus ilex-truffle orchards. AB - Successful cultivation of black truffle (Tuber melanosporum) requires a long-term investment and the maintenance of the symbiosis throughout its preproductive and productive years. Monitoring the symbiosis over time is challenging, as it requires methods that can detect the belowground proliferation of the fungus associated with its host tree. In this study, we used a chronosequence design to study the expansion pattern of this fungus as the host tree grows. We hypothesize that this expansion can be estimated by monitoring T. melanosporum DNA from soil beneath host trees of different ages (3, 5, 7, 10, 14, and 20 years old) and at different distances from the trunk of the trees (40, 100, and 200 cm). We also wished to evaluate the presences of Tuber brumale and Tuber indicum, potentially problematic truffle species, in these plantations. To detect the mycelium of T. melanosporum in these soils, we extracted DNA and performed polymerase chain reaction (PCR) with Tuber species-specific primers, and to estimate DNA amount, we measured relative band intensities from the amplicons in agarose gels. Both age and distance were related to T. melanosporum DNA quantity, which was more abundant in the oldest age classes, reaching a plateau in 5-7 years. At 40 cm from the tree, there were no differences in T. melanosporum DNA amounts in orchards of different ages, but at 100 and 200 cm, younger orchards had less T. melanosporum DNA. We did not detect DNA from T. brumale or T. indicum in any of our samples. PMID- 24469789 TI - Neutralizing antibodies can initiate genome release from human enterovirus 71. AB - Antibodies were prepared by immunizing mice with empty, immature particles of human enterovirus 71 (EV71), a picornavirus that causes severe neurological disease in young children. The capsid structure of these empty particles is different from that of the mature virus and is similar to "A" particles encountered when picornaviruses recognize a potential host cell before genome release. The monoclonal antibody E18, generated by this immunization, induced a conformational change when incubated at temperatures between 4 degrees C and 37 degrees C with mature virus, transforming infectious virions into A particles. The resultant loss of genome that was observed by cryo-EM and a fluorescent SYBR Green dye assay inactivated the virus, establishing the mechanism by which the virus is inactivated and demonstrating that the E18 antibody has potential as an anti-EV71 therapy. The antibody-mediated virus neutralization by the induction of genome release has not been previously demonstrated. Furthermore, the present results indicate that antibodies with genome-release activity could also be produced for other picornaviruses by immunization with immature particles. PMID- 24469790 TI - Septin assemblies form by diffusion-driven annealing on membranes. AB - Septins assemble into filaments and higher-order structures that act as scaffolds for diverse cell functions including cytokinesis, cell polarity, and membrane remodeling. Despite their conserved role in cell organization, little is known about how septin filaments elongate and are knitted together into higher-order assemblies. Using fluorescence correlation spectroscopy, we determined that cytosolic septins are in small complexes, suggesting that septin filaments are not formed in the cytosol. When the plasma membrane of live cells is monitored by total internal reflection fluorescence microscopy, we see that septin complexes of variable size diffuse in two dimensions. Diffusing septin complexes collide and make end-on associations to form elongated filaments and higher-order structures, an assembly process we call annealing. Septin assembly by annealing can be reconstituted in vitro on supported lipid bilayers with purified septin complexes. Using the reconstitution assay, we show that septin filaments are highly flexible, grow only from free filament ends, and do not exchange subunits in the middle of filaments. This work shows that annealing is a previously unidentified intrinsic property of septins in the presence of membranes and demonstrates that cells exploit this mechanism to build large septin assemblies. PMID- 24469791 TI - Efficient surveillance for healthcare-associated infections spreading between hospitals. AB - Early detection of new or novel variants of nosocomial pathogens is a public health priority. We show that, for healthcare-associated infections that spread between hospitals as a result of patient movements, it is possible to design an effective surveillance system based on a relatively small number of sentinel hospitals. We apply recently developed mathematical models to patient admission data from the national healthcare systems of England and The Netherlands. Relatively short detection times are achieved once 10-20% hospitals are recruited as sentinels and only modest reductions are seen as more hospitals are recruited thereafter. Using a heuristic optimization approach to sentinel selection, the same expected time to detection can be achieved by recruiting approximately half as many hospitals. Our study provides a robust evidence base to underpin the design of an efficient sentinel hospital surveillance system for novel nosocomial pathogens, delivering early detection times for reduced expenditure and effort. PMID- 24469792 TI - Functional truncated membrane pores. AB - Membrane proteins are generally divided into two classes. Integral proteins span the lipid bilayer, and peripheral proteins are located at the membrane surface. Here, we provide evidence for membrane proteins of a third class that stabilize lipid pores, most probably as toroidal structures. We examined mutants of the staphylococcal alpha-hemolysin pore so severely truncated that the protein cannot span a bilayer. Nonetheless, the doughnut-like structures elicited well-defined transmembrane ionic currents by inducing pore formation in the underlying lipids. The formation of lipid pores, produced here by a structurally defined protein, is supported by the lipid and voltage dependences of pore formation, and by molecular dynamics simulations. We discuss the role of stabilized lipid pores in amyloid disease, the action of antimicrobial peptides, and the assembly of the membrane-attack complexes of the immune system. PMID- 24469794 TI - A neuromorphic network for generic multivariate data classification. AB - Computational neuroscience has uncovered a number of computational principles used by nervous systems. At the same time, neuromorphic hardware has matured to a state where fast silicon implementations of complex neural networks have become feasible. En route to future technical applications of neuromorphic computing the current challenge lies in the identification and implementation of functional brain algorithms. Taking inspiration from the olfactory system of insects, we constructed a spiking neural network for the classification of multivariate data, a common problem in signal and data analysis. In this model, real-valued multivariate data are converted into spike trains using "virtual receptors" (VRs). Their output is processed by lateral inhibition and drives a winner-take all circuit that supports supervised learning. VRs are conveniently implemented in software, whereas the lateral inhibition and classification stages run on accelerated neuromorphic hardware. When trained and tested on real-world datasets, we find that the classification performance is on par with a naive Bayes classifier. An analysis of the network dynamics shows that stable decisions in output neuron populations are reached within less than 100 ms of biological time, matching the time-to-decision reported for the insect nervous system. Through leveraging a population code, the network tolerates the variability of neuronal transfer functions and trial-to-trial variation that is inevitably present on the hardware system. Our work provides a proof of principle for the successful implementation of a functional spiking neural network on a configurable neuromorphic hardware system that can readily be applied to real world computing problems. PMID- 24469793 TI - Selective mRNA sequestration by OLIGOURIDYLATE-BINDING PROTEIN 1 contributes to translational control during hypoxia in Arabidopsis. AB - Low oxygen stress dynamically regulates the translation of cellular mRNAs as a means of energy conservation in seedlings of Arabidopsis thaliana. Most of the highly hypoxia-induced mRNAs are recruited to polysomes and actively translated, whereas other cellular mRNAs become translationally inactive and are either targeted for stabilization or degradation. Here we identify the involvement of OLIGOURIDYLATE BINDING PROTEIN 1 (UBP1), a triple RNA Recognition Motif protein, in dynamic and reversible aggregation of translationally repressed mRNAs during hypoxia. Mutation or down-regulation of UBP1C interferes with seedling establishment and reduces survival of low oxygen stress. By use of messenger ribonucleoprotein (mRNP) immunopurification, we show that UBP1C constitutively binds a subpopulation of mRNAs characterized by uracil-rich 3'-untranslated regions under normoxic conditions. During hypoxia, UBP1C association with non uracil-rich mRNAs is enhanced concomitant with its aggregation into microscopically visible cytoplasmic foci, referred to as UBP1 stress granules (SGs). This UBP1C-mRNA association occurs as global levels of protein synthesis decline. Upon reoxygenation, rapid UBP1 SG disaggregation coincides with the return of the stabilized mRNAs to polysomes. The mRNAs that are highly induced and translated during hypoxia largely circumvent UBP1C sequestration. Thus, UBP1 is established as a component of dynamically assembled cytoplasmic mRNPs that sequester mRNAs that are poorly translated during a transient low energy stress. PMID- 24469795 TI - Whole-genome sequencing identifies genomic heterogeneity at a nucleotide and chromosomal level in bladder cancer. AB - Using complete genome analysis, we sequenced five bladder tumors accrued from patients with muscle-invasive transitional cell carcinoma of the urinary bladder (TCC-UB) and identified a spectrum of genomic aberrations. In three tumors, complex genotype changes were noted. All three had tumor protein p53 mutations and a relatively large number of single-nucleotide variants (SNVs; average of 11.2 per megabase), structural variants (SVs; average of 46), or both. This group was best characterized by chromothripsis and the presence of subclonal populations of neoplastic cells or intratumoral mutational heterogeneity. Here, we provide evidence that the process of chromothripsis in TCC-UB is mediated by nonhomologous end-joining using kilobase, rather than megabase, fragments of DNA, which we refer to as "stitchers," to repair this process. We postulate that a potential unifying theme among tumors with the more complex genotype group is a defective replication-licensing complex. A second group (two bladder tumors) had no chromothripsis, and a simpler genotype, WT tumor protein p53, had relatively few SNVs (average of 5.9 per megabase) and only a single SV. There was no evidence of a subclonal population of neoplastic cells. In this group, we used a preclinical model of bladder carcinoma cell lines to study a unique SV (translocation and amplification) of the gene glutamate receptor ionotropic N methyl D-aspertate as a potential new therapeutic target in bladder cancer. PMID- 24469796 TI - TBC1D24 regulates neuronal migration and maturation through modulation of the ARF6-dependent pathway. AB - Alterations in the formation of brain networks are associated with several neurodevelopmental disorders. Mutations in TBC1 domain family member 24 (TBC1D24) are responsible for syndromes that combine cortical malformations, intellectual disability, and epilepsy, but the function of TBC1D24 in the brain remains unknown. We report here that in utero TBC1D24 knockdown in the rat developing neocortex affects the multipolar-bipolar transition of neurons leading to delayed radial migration. Furthermore, we find that TBC1D24-knockdown neurons display an abnormal maturation and retain immature morphofunctional properties. TBC1D24 interacts with ADP ribosylation factor (ARF)6, a small GTPase crucial for membrane trafficking. We show that in vivo, overexpression of the dominant negative form of ARF6 rescues the neuronal migration and dendritic outgrowth defects induced by TBC1D24 knockdown, suggesting that TBC1D24 prevents ARF6 activation. Overall, our findings demonstrate an essential role of TBC1D24 in neuronal migration and maturation and highlight the physiological relevance of the ARF6-dependent membrane-trafficking pathway in brain development. PMID- 24469797 TI - Accounting for inhomogeneous broadening in nano-optics by electromagnetic modeling based on Monte Carlo methods. AB - Many experimental systems consist of large ensembles of uncoupled or weakly interacting elements operating as a single whole; this is particularly the case for applications in nano-optics and plasmonics, including colloidal solutions, plasmonic or dielectric nanoparticles on a substrate, antenna arrays, and others. In such experiments, measurements of the optical spectra of ensembles will differ from measurements of the independent elements as a result of small variations from element to element (also known as polydispersity) even if these elements are designed to be identical. In particular, sharp spectral features arising from narrow-band resonances will tend to appear broader and can even be washed out completely. Here, we explore this effect of inhomogeneous broadening as it occurs in colloidal nanopolymers comprising self-assembled nanorod chains in solution. Using a technique combining finite-difference time-domain simulations and Monte Carlo sampling, we predict the inhomogeneously broadened optical spectra of these colloidal nanopolymers and observe significant qualitative differences compared with the unbroadened spectra. The approach combining an electromagnetic simulation technique with Monte Carlo sampling is widely applicable for quantifying the effects of inhomogeneous broadening in a variety of physical systems, including those with many degrees of freedom that are otherwise computationally intractable. PMID- 24469798 TI - Using constellation pharmacology to define comprehensively a somatosensory neuronal subclass. AB - Change is intrinsic to nervous systems; change is required for learning and conditioning and occurs with disease progression, normal development, and aging. To better understand mammalian nervous systems and effectively treat nervous system disorders, it is essential to track changes in relevant individual neurons. A critical challenge is to identify and characterize the specific cell types involved and the molecular-level changes that occur in each. Using an experimental strategy called constellation pharmacology, we demonstrate that we can define a specific somatosensory neuronal subclass, cold thermosensors, across different species and track changes in these neurons as a function of development. Cold thermosensors are uniformly responsive to menthol and innocuous cool temperature (17 degrees C), indicating that they express TRPM8 channels. A subset of cold thermosensors expressed alpha7 nicotinic acetylcholine receptors (nAChRs) but not other nAChR subtypes. Differences in temperature threshold of cold thermosensors correlated with functional expression of voltage-gated K channels Kv1.1/1.2: Relatively higher expression of KV1.1/1.2 channels resulted in a higher threshold response to cold temperature. Other signaling components varied during development and between species. In cold thermosensors of neonatal mice and rats, ATP receptors were functionally expressed, but the expression disappeared with development. This developmental change occurred earlier in low threshold than high-threshold cold thermosensors. Most rat cold thermosensors expressed TRPA1 channels, whereas mouse cold thermosensors did not. The broad implications of this study are that it is now feasible to track changes in receptor and ion-channel expression in individual neuronal subclasses as a function of development, learning, disease, or aging. PMID- 24469799 TI - Tracing an allosteric pathway regulating the activity of the HslV protease. AB - The HslU-HslV complex functions as a bacterial proteasome, degrading substrate polypeptides to preserve cellular homeostasis. Here, we use methyl-Transverse Relaxation-Optimized Spectroscopy (TROSY) and highly deuterated, methyl protonated samples to study the 230 kDa dodecameric HslV protease component that is structurally homologous to the stacked pair of beta7-rings of the proteasome. Chemical shift assignments for over 95% of the methyl groups are reported. From the pH dependence of methyl chemical shifts, a pKa of 7.7 is measured for the amine group of the catalytic residue T1, confirming that it can act as a proton acceptor during the initial step in substrate proteolysis. Analyses involving a series of single site mutants in HslV, localized to HslU binding sites or regions undergoing significant changes on HslU binding, have identified hot spots whose perturbation leads to an allosteric pathway of propagated changes in structure and ultimately, substrate proteolysis efficiency. HslV plasticity is explored through methyl-TROSY (13)C relaxation dispersion experiments that are sensitive to millisecond timescale dynamics. The data support a dynamic coupling between residues involved in both HslU and substrate binding and residues localized to the active sites of HslV that facilitate the allostery between these distal sites. An important role for dynamics has also been observed in the archaeal proteasome, suggesting a more generally conserved role of motion in the function of these barrel-like protease structures. PMID- 24469800 TI - CYLD regulates spindle orientation by stabilizing astral microtubules and promoting dishevelled-NuMA-dynein/dynactin complex formation. AB - Oriented cell division is critical for cell fate specification, tissue organization, and tissue homeostasis, and relies on proper orientation of the mitotic spindle. The molecular mechanisms underlying the regulation of spindle orientation remain largely unknown. Herein, we identify a critical role for cylindromatosis (CYLD), a deubiquitinase and regulator of microtubule dynamics, in the control of spindle orientation. CYLD is highly expressed in mitosis and promotes spindle orientation by stabilizing astral microtubules and deubiquitinating the cortical polarity protein dishevelled. The deubiquitination of dishevelled enhances its interaction with nuclear mitotic apparatus, stimulating the cortical localization of nuclear mitotic apparatus and the dynein/dynactin motor complex, a requirement for generating pulling forces on astral microtubules. These findings uncover CYLD as an important player in the orientation of the mitotic spindle and cell division and have important implications in health and disease. PMID- 24469801 TI - Distortion of genealogical properties when the sample is very large. AB - Study sample sizes in human genetics are growing rapidly, and in due course it will become routine to analyze samples with hundreds of thousands, if not millions, of individuals. In addition to posing computational challenges, such large sample sizes call for carefully reexamining the theoretical foundation underlying commonly used analytical tools. Here, we study the accuracy of the coalescent, a central model for studying the ancestry of a sample of individuals. The coalescent arises as a limit of a large class of random mating models, and it is an accurate approximation to the original model provided that the population size is sufficiently larger than the sample size. We develop a method for performing exact computation in the discrete-time Wright-Fisher (DTWF) model and compare several key genealogical quantities of interest with the coalescent predictions. For recently inferred demographic scenarios, we find that there are a significant number of multiple- and simultaneous-merger events under the DTWF model, which are absent in the coalescent by construction. Furthermore, for large sample sizes, there are noticeable differences in the expected number of rare variants between the coalescent and the DTWF model. To balance the trade-off between accuracy and computational efficiency, we propose a hybrid algorithm that uses the DTWF model for the recent past and the coalescent for the more distant past. Our results demonstrate that the hybrid method with only a handful of generations of the DTWF model leads to a frequency spectrum that is quite close to the prediction of the full DTWF model. PMID- 24469802 TI - Separating endogenous ancient DNA from modern day contamination in a Siberian Neandertal. AB - One of the main impediments for obtaining DNA sequences from ancient human skeletons is the presence of contaminating modern human DNA molecules in many fossil samples and laboratory reagents. However, DNA fragments isolated from ancient specimens show a characteristic DNA damage pattern caused by miscoding lesions that differs from present day DNA sequences. Here, we develop a framework for evaluating the likelihood of a sequence originating from a model with postmortem degradation-summarized in a postmortem degradation score-which allows the identification of DNA fragments that are unlikely to originate from present day sources. We apply this approach to a contaminated Neandertal specimen from Okladnikov Cave in Siberia to isolate its endogenous DNA from modern human contaminants and show that the reconstructed mitochondrial genome sequence is more closely related to the variation of Western Neandertals than what was discernible from previous analyses. Our method opens up the potential for genomic analysis of contaminated fossil material. PMID- 24469803 TI - Visualization of carrier dynamics in p(n)-type GaAs by scanning ultrafast electron microscopy. AB - Four-dimensional scanning ultrafast electron microscopy is used to investigate doping- and carrier-concentration-dependent ultrafast carrier dynamics of the in situ cleaved single-crystalline GaAs(110) substrates. We observed marked changes in the measured time-resolved secondary electrons depending on the induced alterations in the electronic structure. The enhancement of secondary electrons at positive times, when the electron pulse follows the optical pulse, is primarily due to an energy gain involving the photoexcited charge carriers that are transiently populated in the conduction band and further promoted by the electron pulse, consistent with a band structure that is dependent on chemical doping and carrier concentration. When electrons undergo sufficient energy loss on their journey to the surface, dark contrast becomes dominant in the image. At negative times, however, when the electron pulse precedes the optical pulse (electron impact), the dynamical behavior of carriers manifests itself in a dark contrast which indicates the suppression of secondary electrons upon the arrival of the optical pulse. In this case, the loss of energy of material's electrons is by collisions with the excited carriers. These results for carrier dynamics in GaAs(110) suggest strong carrier-carrier scatterings which are mirrored in the energy of material's secondary electrons during their migration to the surface. The approach presented here provides a fundamental understanding of materials probed by four-dimensional scanning ultrafast electron microscopy, and offers possibilities for use of this imaging technique in the study of ultrafast charge carrier dynamics in heterogeneously patterned micro- and nanostructured material surfaces and interfaces. PMID- 24469804 TI - JAK2V617F-positive endothelial cells contribute to clotting abnormalities in myeloproliferative neoplasms. AB - The Janus kinase 2 (JAK2) V617F mutation is the primary pathogenic mutation in patients with Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although thrombohemorrhagic incidents are the most common causes of morbidity and mortality in patients with MPNs, the events causing these clotting abnormalities remain unclear. To identify the cells responsible for the dysfunctional hemostasis, we used transgenic mice expressing JAK2V617F in specific lineages involved in thrombosis and hemostasis. When JAK2V617F was expressed in both hematopoietic and endothelial cells (ECs), the mice developed a significant MPN, characterized by thrombocytosis, neutrophilia, and splenomegaly. However, despite having significantly higher platelet counts than controls, these mice showed severely attenuated thrombosis following injury. Interestingly, platelet activation and aggregation in response to agonists was unaltered by JAK2V617F expression. Subsequent bone marrow transplants revealed the contribution of both endothelial and hematopoietic compartments to the attenuated thrombosis. Furthermore, we identified a potential mechanism for this phenotype through JAK2V617F-regulated inhibition of von Willebrand factor (VWF) function and/or secretion. JAK2V617F(+) mice display a condition similar to acquired von Willebrand syndrome, exhibiting significantly less high molecular weight VWF and reduced agglutination to ristocetin. These findings greatly advance our understanding of thrombohemorrhagic events in MPNs and highlight the critical role of ECs in the pathology of hematopoietic malignancies. PMID- 24469806 TI - Climate policies under wealth inequality. AB - Taming the planet's climate requires cooperation. Previous failures to reach consensus in climate summits have been attributed, among other factors, to conflicting policies between rich and poor countries, which disagree on the implementation of mitigation measures. Here we implement wealth inequality in a threshold public goods dilemma of cooperation in which players also face the risk of potential future losses. We consider a population exhibiting an asymmetric distribution of rich and poor players that reflects the present-day status of nations and study the behavioral interplay between rich and poor in time, regarding their willingness to cooperate. Individuals are also allowed to exhibit a variable degree of homophily, which acts to limit those that constitute one's sphere of influence. Under the premises of our model, and in the absence of homophily, comparison between scenarios with wealth inequality and without wealth inequality shows that the former leads to more global cooperation than the latter. Furthermore, we find that the rich generally contribute more than the poor and will often compensate for the lower contribution of the latter. Contributions from the poor, which are crucial to overcome the climate change dilemma, are shown to be very sensitive to homophily, which, if prevalent, can lead to a collapse of their overall contribution. In such cases, however, we also find that obstinate cooperative behavior by a few poor may largely compensate for homophilic behavior. PMID- 24469805 TI - JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. AB - Extracellular high-mobility group box (HMGB)1 mediates inflammation during sterile and infectious injury and contributes importantly to disease pathogenesis. The first critical step in the release of HMGB1 from activated immune cells is mobilization from the nucleus to the cytoplasm, a process dependent upon hyperacetylation within two HMGB1 nuclear localization sequence (NLS) sites. The inflammasomes mediate the release of cytoplasmic HMGB1 in activated immune cells, but the mechanism of HMGB1 translocation from nucleus to cytoplasm was previously unknown. Here, we show that pharmacological inhibition of JAK/STAT1 inhibits LPS-induced HMGB1 nuclear translocation. Conversely, activation of JAK/STAT1 by type 1 interferon (IFN) stimulation induces HMGB1 translocation from nucleus to cytoplasm. Mass spectrometric analysis unequivocally revealed that pharmacological inhibition of the JAK/STAT1 pathway or genetic deletion of STAT1 abrogated LPS- or type 1 IFN-induced HMGB1 acetylation within the NLS sites. Together, these results identify a critical role of the JAK/STAT1 pathway in mediating HMGB1 cytoplasmic accumulation for subsequent release, suggesting that the JAK/STAT1 pathway is a potential drug target for inhibiting HMGB1 release. PMID- 24469807 TI - Clostridium difficile toxin CDT hijacks microtubule organization and reroutes vesicle traffic to increase pathogen adherence. AB - Clostridium difficile causes antibiotic-associated diarrhea and pseudomembranous colitis by the actions of Rho-glucosylating toxins A and B. Recently identified hypervirulent strains, which are associated with increased morbidity and mortality, additionally produce the actin-ADP-ribosylating toxin C. difficile transferase (CDT). CDT depolymerizes actin, causes formation of microtubule-based protrusions, and increases pathogen adherence. Here we show that CDT-induced protrusions allow vesicle traffic and contain endoplasmic reticulum tubules, connected to microtubules via the calcium sensor Stim1. The toxin reroutes Rab11 positive vesicles containing fibronectin, which is involved in bacterial adherence, from basolateral to the apical membrane sides in a microtubule- and Stim1-dependent manner. The data yield a model of C. difficile adherence regulated by actin depolymerization, microtubule restructuring, subsequent Stim1 dependent Ca(2+) signaling, vesicle rerouting, and secretion of ECM proteins to increase bacterial adherence. PMID- 24469808 TI - Structural determinants for ligand capture by a class II preQ1 riboswitch. AB - Prequeuosine (preQ1) riboswitches are RNA regulatory elements located in the 5' UTR of genes involved in the biosynthesis and transport of preQ1, a precursor of the modified base queuosine universally found in four tRNAs. The preQ1 class II (preQ1-II) riboswitch regulates preQ1 biosynthesis at the translational level. We present the solution NMR structure and conformational dynamics of the 59 nucleotide Streptococcus pneumoniae preQ1-II riboswitch bound to preQ1. Unlike in the preQ1 class I (preQ1-I) riboswitch, divalent cations are required for high affinity binding. The solution structure is an unusual H-type pseudoknot featuring a P4 hairpin embedded in loop 3, which forms a three-way junction with the other two stems. (13)C relaxation and residual dipolar coupling experiments revealed interhelical flexibility of P4. We found that the P4 helix and flanking adenine residues play crucial and unexpected roles in controlling pseudoknot formation and, in turn, sequestering the Shine-Dalgarno sequence. Aided by divalent cations, P4 is poised to act as a "screw cap" on preQ1 recognition to block ligand exit and stabilize the binding pocket. Comparison of preQ1-I and preQ1-II riboswitch structures reveals that whereas both form H-type pseudoknots and recognize preQ1 using one A, C, or U nucleotide from each of three loops, these nucleotides interact with preQ1 differently, with preQ1 inserting into different grooves. Our studies show that the preQ1-II riboswitch uses an unusual mechanism to harness exquisite control over queuosine metabolism. PMID- 24469809 TI - C2cd3 is critical for centriolar distal appendage assembly and ciliary vesicle docking in mammals. AB - The primary cilium plays critical roles in vertebrate development and physiology, but the mechanisms underlying its biogenesis remain poorly understood. We investigated the molecular function of C2 calcium-dependent domain containing 3 (C2cd3), an essential regulator of primary cilium biogenesis. We show that C2cd3 is localized to the centriolar satellites in a microtubule- and Pcm1-dependent manner; however, C2cd3 is dispensable for centriolar satellite integrity. C2cd3 is also localized to the distal ends of both mother and daughter centrioles and is required for the recruitment of five centriolar distal appendage proteins: Sclt1, Ccdc41, Cep89, Fbf1, and Cep164. Furthermore, loss of C2cd3 results in failure in the recruitment of Ttbk2 to the ciliary basal body as well as the removal of Cp110 from the ciliary basal body, two critical steps in initiating ciliogenesis. C2cd3 is also required for recruiting the intraflagellar transport proteins Ift88 and Ift52 to the mother centriole. Consistent with a role in distal appendage assembly, C2cd3 is essential for ciliary vesicle docking to the mother centriole. Our results suggest that C2cd3 regulates cilium biogenesis by promoting the assembly of centriolar distal appendages critical for docking ciliary vesicles and recruiting other essential ciliogenic proteins. PMID- 24469810 TI - C-terminal region of activation-induced cytidine deaminase (AID) is required for efficient class switch recombination and gene conversion. AB - Activation-induced cytidine deaminase (AID) introduces single-strand breaks (SSBs) to initiate class switch recombination (CSR), gene conversion (GC), and somatic hypermutation (SHM). CSR is mediated by double-strand breaks (DSBs) at donor and acceptor switch (S) regions, followed by pairing of DSB ends in two S regions and their joining. Because AID mutations at its C-terminal region drastically impair CSR but retain its DNA cleavage and SHM activity, the C terminal region of AID likely is required for the recombination step after the DNA cleavage. To test this hypothesis, we analyzed the recombination junctions generated by AID C-terminal mutants and found that 0- to 3-bp microhomology junctions are relatively less abundant, possibly reflecting the defects of the classical nonhomologous end joining (C-NHEJ). Consistently, the accumulation of C NHEJ factors such as Ku80 and XRCC4 was decreased at the cleaved S region. In contrast, an SSB-binding protein, poly (ADP)-ribose polymerase1, was recruited more abundantly, suggesting a defect in conversion from SSB to DSB. In addition, recruitment of critical DNA synapse factors such as 53BP1, DNA PKcs, and UNG at the S region was reduced during CSR. Furthermore, the chromosome conformation capture assay revealed that DNA synapse formation is impaired drastically in the AID C-terminal mutants. Interestingly, these mutants showed relative reduction in GC compared with SHM in chicken DT40 cells. Collectively, our data indicate that the C-terminal region of AID is required for efficient generation of DSB in CSR and GC and thus for the subsequent pairing of cleaved DNA ends during recombination in CSR. PMID- 24469811 TI - Identification and characterization of the constituent human serum antibodies elicited by vaccination. AB - Most vaccines confer protection via the elicitation of serum antibodies, yet more than 100 y after the discovery of antibodies, the molecular composition of the human serum antibody repertoire to an antigen remains unknown. Using high resolution liquid chromatography tandem MS proteomic analyses of serum antibodies coupled with next-generation sequencing of the V gene repertoire in peripheral B cells, we have delineated the human serum IgG and B-cell receptor repertoires following tetanus toxoid (TT) booster vaccination. We show that the TT(+) serum IgG repertoire comprises ~100 antibody clonotypes, with three clonotypes accounting for >40% of the response. All 13 recombinant IgGs examined bound to vaccine antigen with Kd ~ 10(-8)-10(-10) M. Five of 13 IgGs recognized the same linear epitope on TT, occluding the binding site used by the toxin for cell entry, suggesting a possible explanation for the mechanism of protection conferred by the vaccine. Importantly, only a small fraction (<5%) of peripheral blood plasmablast clonotypes (CD3(-)CD14(-)CD19(+)CD27(++)CD38(++)CD20(-)TT(+)) at the peak of the response (day 7), and an even smaller fraction of memory B cells, were found to encode antibodies that could be detected in the serological memory response 9 mo postvaccination. This suggests that only a small fraction of responding peripheral B cells give rise to the bone marrow long-lived plasma cells responsible for the production of biologically relevant amounts of vaccine specific antibodies (near or above the Kd). Collectively, our results reveal the nature and dynamics of the serological response to vaccination with direct implications for vaccine design and evaluation. PMID- 24469812 TI - Nanowire nanocomputer as a finite-state machine. AB - Implementation of complex computer circuits assembled from the bottom up and integrated on the nanometer scale has long been a goal of electronics research. It requires a design and fabrication strategy that can address individual nanometer-scale electronic devices, while enabling large-scale assembly of those devices into highly organized, integrated computational circuits. We describe how such a strategy has led to the design, construction, and demonstration of a nanoelectronic finite-state machine. The system was fabricated using a design oriented approach enabled by a deterministic, bottom-up assembly process that does not require individual nanowire registration. This methodology allowed construction of the nanoelectronic finite-state machine through modular design using a multitile architecture. Each tile/module consists of two interconnected crossbar nanowire arrays, with each cross-point consisting of a programmable nanowire transistor node. The nanoelectronic finite-state machine integrates 180 programmable nanowire transistor nodes in three tiles or six total crossbar arrays, and incorporates both sequential and arithmetic logic, with extensive intertile and intratile communication that exhibits rigorous input/output matching. Our system realizes the complete 2-bit logic flow and clocked control over state registration that are required for a finite-state machine or computer. The programmable multitile circuit was also reprogrammed to a functionally distinct 2-bit full adder with 32-set matched and complete logic output. These steps forward and the ability of our unique design-oriented deterministic methodology to yield more extensive multitile systems suggest that proposed general-purpose nanocomputers can be realized in the near future. PMID- 24469813 TI - Genetic dissection of plexin signaling in vivo. AB - Mammalian plexins constitute a family of transmembrane receptors for semaphorins and represent critical regulators of various processes during development of the nervous, cardiovascular, skeletal, and renal system. In vitro studies have shown that plexins exert their effects via an intracellular R-Ras/M-Ras GTPase activating protein (GAP) domain or by activation of RhoA through interaction with Rho guanine nucleotide exchange factor proteins. However, which of these signaling pathways are relevant for plexin functions in vivo is largely unknown. Using an allelic series of transgenic mice, we show that the GAP domain of plexins constitutes their key signaling module during development. Mice in which endogenous Plexin-B2 or Plexin-D1 is replaced by transgenic versions harboring mutations in the GAP domain recapitulate the phenotypes of the respective null mutants in the developing nervous, vascular, and skeletal system. We further provide genetic evidence that, unexpectedly, the GAP domain-mediated developmental functions of plexins are not brought about via R-Ras and M-Ras inactivation. In contrast to the GAP domain mutants, Plexin-B2 transgenic mice defective in Rho guanine nucleotide exchange factor binding are viable and fertile but exhibit abnormal development of the liver vasculature. Our genetic analyses uncover the in vivo context-dependence and functional specificity of individual plexin-mediated signaling pathways during development. PMID- 24469814 TI - On the dephasing of genetic oscillators. AB - The digital nature of genes combined with the associated low copy numbers of proteins regulating them is a significant source of stochasticity, which affects the phase of biochemical oscillations. We show that unlike ordinary chemical oscillators, the dichotomic molecular noise of gene state switching in gene oscillators affects the stochastic dephasing in a way that may not always be captured by phenomenological limit cycle-based models. Through simulations of a realistic model of the NFkappaB/IkappaB network, we also illustrate the dephasing phenomena that are important for reconciling single-cell and population-based experiments on gene oscillators. PMID- 24469815 TI - Vaccination of monoglycosylated hemagglutinin induces cross-strain protection against influenza virus infections. AB - The 2009 H1N1 pandemic and recent human cases of H5N1, H7N9, and H6N1 in Asia highlight the need for a universal influenza vaccine that can provide cross strain or even cross-subtype protection. Here, we show that recombinant monoglycosylated hemagglutinin (HAmg) with an intact protein structure from either seasonal or pandemic H1N1 can be used as a vaccine for cross-strain protection against various H1N1 viruses in circulation from 1933 to 2009 in mice and ferrets. In the HAmg vaccine, highly conserved sequences that were originally covered by glycans in the fully glycosylated HA (HAfg) are exposed and thus, are better engulfed by dendritic cells (DCs), stimulated better DC maturation, and induced more CD8+ memory T cells and IgG-secreting plasma cells. Single B-cell RT PCR followed by sequence analysis revealed that the HAmg vaccine activated more diverse B-cell repertoires than the HAfg vaccine and produced antibodies with cross-strain binding ability. In summary, the HAmg vaccine elicits cross-strain immune responses that may mitigate the current need for yearly reformulation of strain-specific inactivated vaccines. This strategy may also map a new direction for universal vaccine design. PMID- 24469816 TI - RNA design rules from a massive open laboratory. AB - Self-assembling RNA molecules present compelling substrates for the rational interrogation and control of living systems. However, imperfect in silico models- even at the secondary structure level--hinder the design of new RNAs that function properly when synthesized. Here, we present a unique and potentially general approach to such empirical problems: the Massive Open Laboratory. The EteRNA project connects 37,000 enthusiasts to RNA design puzzles through an online interface. Uniquely, EteRNA participants not only manipulate simulated molecules but also control a remote experimental pipeline for high-throughput RNA synthesis and structure mapping. We show herein that the EteRNA community leveraged dozens of cycles of continuous wet laboratory feedback to learn strategies for solving in vitro RNA design problems on which automated methods fail. The top strategies--including several previously unrecognized negative design rules--were distilled by machine learning into an algorithm, EteRNABot. Over a rigorous 1-y testing phase, both the EteRNA community and EteRNABot significantly outperformed prior algorithms in a dozen RNA secondary structure design tests, including the creation of dendrimer-like structures and scaffolds for small molecule sensors. These results show that an online community can carry out large-scale experiments, hypothesis generation, and algorithm design to create practical advances in empirical science. PMID- 24469817 TI - Identifying and mapping cell-type-specific chromatin programming of gene expression. AB - A problem of substantial interest is to systematically map variation in chromatin structure to gene-expression regulation across conditions, environments, or differentiated cell types. We developed and applied a quantitative framework for determining the existence, strength, and type of relationship between high resolution chromatin structure in terms of DNaseI hypersensitivity and genome wide gene-expression levels in 20 diverse human cell types. We show that ~25% of genes show cell-type-specific expression explained by alterations in chromatin structure. We find that distal regions of chromatin structure (e.g., +/-200 kb) capture more genes with this relationship than local regions (e.g., +/-2.5 kb), yet the local regions show a more pronounced effect. By exploiting variation across cell types, we were capable of pinpointing the most likely hypersensitive sites related to cell-type-specific expression, which we show have a range of contextual uses. This quantitative framework is likely applicable to other settings aimed at relating continuous genomic measurements to gene-expression variation. PMID- 24469818 TI - Tumor-specific IL-9-producing CD8+ Tc9 cells are superior effector than type-I cytotoxic Tc1 cells for adoptive immunotherapy of cancers. AB - Because cytokine-priming signals direct CD8(+) T cells to acquire unique profiles that affect their ability to mediate specific immune responses, here we generated IL-9-skewed CD8(+) T (Tc9) cells by priming with Th9-polarized condition. Compared with type-I CD8(+) cytotoxic T (Tc1) cells, Tc9 secreted different cytokines and were less cytolytic in vitro but surprisingly elicited greater antitumor responses against advanced tumors in OT-I/B16-OVA and Pmel-1/B16 melanoma models. After adoptive transfer, Tc9 cells persisted longer and differentiated into IFN-gamma- and granzyme-B (GrzB)-producing cytolytic Tc1-like effector cells. Phenotypic analysis revealed that adoptively transferred Tc9 cells secreted IL-2 and were KLRG-1(low) and IL-7Ralpha(high), suggesting that they acquired a signature of "younger" phenotype or became long-term lived cells with capacity of self-renewal. Our results also revealed that Tc9-mediated therapeutic effect critically depended on IL-9 production in vivo. These findings have clinical implications for the improvement of CD8(+) T-cell-based adoptive immunotherapy of cancers. PMID- 24469819 TI - Noninvasive positron emission tomography and fluorescence imaging of CD133+ tumor stem cells. AB - A technology that visualizes tumor stem cells with clinically relevant tracers could have a broad impact on cancer diagnosis and treatment. The AC133 epitope of CD133 currently is one of the best-characterized tumor stem cell markers for many intra- and extracranial tumor entities. Here we demonstrate the successful noninvasive detection of AC133(+) tumor stem cells by PET and near-infrared fluorescence molecular tomography in subcutaneous and orthotopic glioma xenografts using antibody-based tracers. Particularly, microPET with (64)Cu-NOTA AC133 mAb yielded high-quality images with outstanding tumor-to-background contrast, clearly delineating subcutaneous tumor stem cell-derived xenografts from surrounding tissues. Intracerebral tumors as small as 2-3 mm also were clearly discernible, and the microPET images reflected the invasive growth pattern of orthotopic cancer stem cell-derived tumors with low density of AC133(+) cells. These data provide a basis for further preclinical and clinical use of the developed tracers for high-sensitivity and high-resolution monitoring of AC133(+) tumor stem cells. PMID- 24469820 TI - CD28 and CD3 have complementary roles in T-cell traction forces. AB - Mechanical forces have key roles in regulating activation of T cells and coordination of the adaptive immune response. A recent example is the ability of T cells to sense the rigidity of an underlying substrate through the T-cell receptor (TCR) coreceptor CD3 and CD28, a costimulation signal essential for cell activation. In this report, we show that these two receptor systems provide complementary functions in regulating the cellular forces needed to test the mechanical properties of the extracellular environment. Traction force microscopy was carried out on primary human cells interacting with micrometer-scale elastomer pillar arrays presenting activation antibodies to CD3 and/or CD28. T cells generated traction forces of 100 pN on arrays with both antibodies. By providing one antibody or the other in solution instead of on the pillars, we show that force generation is associated with CD3 and the TCR complex. Engagement of CD28 increases traction forces associated with CD3 through the signaling pathway involving PI3K, rather than providing additional coupling between the cell and surface. Force generation is concentrated to the cell periphery and associated with molecular complexes containing phosphorylated Pyk2, suggesting that T cells use processes that share features with integrin signaling in force generation. Finally, the ability of T cells to apply forces through the TCR itself, rather than the CD3 coreceptor, was tested. Mouse cells expressing the 5C.C7 TCR exerted traction forces on pillars presenting peptide-loaded MHCs that were similar to those with alpha-CD3, suggesting that forces are applied to antigen-presenting cells during activation. PMID- 24469821 TI - Stability-activity tradeoffs constrain the adaptive evolution of RubisCO. AB - A well-known case of evolutionary adaptation is that of ribulose-1,5-bisphosphate carboxylase (RubisCO), the enzyme responsible for fixation of CO2 during photosynthesis. Although the majority of plants use the ancestral C3 photosynthetic pathway, many flowering plants have evolved a derived pathway named C4 photosynthesis. The latter concentrates CO2, and C4 RubisCOs consequently have lower specificity for, and faster turnover of, CO2. The C4 forms result from convergent evolution in multiple clades, with substitutions at a small number of sites under positive selection. To understand the physical constraints on these evolutionary changes, we reconstructed in silico ancestral sequences and 3D structures of RubisCO from a large group of related C3 and C4 species. We were able to precisely track their past evolutionary trajectories, identify mutations on each branch of the phylogeny, and evaluate their stability effect. We show that RubisCO evolution has been constrained by stability-activity tradeoffs similar in character to those previously identified in laboratory-based experiments. The C4 properties require a subset of several ancestral destabilizing mutations, which from their location in the structure are inferred to mainly be involved in enhancing conformational flexibility of the open-closed transition in the catalytic cycle. These mutations are near, but not in, the active site or at intersubunit interfaces. The C3 to C4 transition is preceded by a sustained period in which stability of the enzyme is increased, creating the capacity to accept the functionally necessary destabilizing mutations, and is immediately followed by compensatory mutations that restore global stability. PMID- 24469822 TI - Exposure to ambient black carbon derived from a unique inventory and high resolution model. AB - Black carbon (BC) is increasingly recognized as a significant air pollutant with harmful effects on human health, either in its own right or as a carrier of other chemicals. The adverse impact is of particular concern in those developing regions with high emissions and a growing population density. The results of recent studies indicate that BC emissions could be underestimated by a factor of 2-3 and this is particularly true for the hot-spot Asian region. Here we present a unique inventory at 10-km resolution based on a recently published global fuel consumption data product and updated emission factor measurements. The unique inventory is coupled to an Asia-nested (~50 km) atmospheric model and used to calculate the global population exposure to BC with fully quantified uncertainty. Evaluating the modeled surface BC concentrations against observations reveals great improvement. The bias is reduced from -88% to -35% in Asia when the unique inventory and higher-resolution model replace a previous inventory combined with a coarse-resolution model. The bias can be further reduced to -12% by downscaling to 10 km using emission as a proxy. Our estimated global population-weighted BC exposure concentration constrained by observations is 2.14 MUg?m(-3); 130% higher than that obtained using less detailed inventories and low-resolution models. PMID- 24469823 TI - Anomalous diffusion and multifractality enhance mating encounters in the ocean. AB - For millimeter-scale aquatic crustaceans such as copepods, ensuring reproductive success is a challenge as potential mates are often separated by hundreds of body lengths in a 3D environment. At the evolutionary scale, this led to the development of remote sensing abilities and behavioral strategies to locate, to track, and to capture a mate. Chemoreception plays a crucial role in increasing mate encounter rates through pheromone clouds and pheromone trails that can be followed over many body lengths. Empirical evidence of trail following behavior is, however, limited to laboratory experiments conducted in still water. An important open question concerns what happens in the turbulent waters of the surface ocean. We propose that copepods experience, and hence react to, a bulk phase water pheromone concentration. Here we investigate the mating behavior of two key copepod species, Temora longicornis and Eurytemora affinis, to assess the role of background pheromone concentration and the relative roles played by males and females in mating encounters. We find that both males and females react to background pheromone concentration and exhibit both innate and acquired components in their mating strategies. The emerging swimming behaviors have stochastic properties that depend on pheromone concentration, sex, and species, are related to the level of reproductive experience of the individual tested, and significantly diverge from both the Levy and Brownian models identified in predators searching for low- and high-density prey. Our results are consistent with an adaptation to increase mate encounter rates and hence to optimize reproductive fitness and success. PMID- 24469824 TI - OX40L blockade is therapeutic in arthritis, despite promoting osteoclastogenesis. AB - An immune response is essential for protection against infection, but, in many individuals, aberrant responses against self tissues cause autoimmune diseases such as rheumatoid arthritis (RA). How to diminish the autoimmune response while not augmenting infectious risk is a challenge. Modern targeted therapies such as anti-TNF or anti-CD20 antibodies ameliorate disease, but at the cost of some increase in infectious risk. Approaches that might specifically reduce autoimmunity and tissue damage without infectious risk would be important. Here we describe that TNF superfamily member OX40 ligand (OX40L; CD252), which is expressed predominantly on antigen-presenting cells, and its receptor OX40 (on activated T cells), are restricted to the inflamed joint in arthritis in mice with collagen-induced arthritis and humans with RA. Blockade of this pathway in arthritic mice reduced inflammation and restored tissue integrity predominantly by inhibiting inflammatory cytokine production by OX40L-expressing macrophages. Furthermore, we identify a previously unknown role for OX40L in steady-state bone homeostasis. This work shows that more targeted approaches may augment the "therapeutic window" and increase the benefit/risk in RA, and possibly other autoimmune diseases, and are thus worth testing in humans. PMID- 24469825 TI - Persistent HIV-1 replication is associated with lower antiretroviral drug concentrations in lymphatic tissues. AB - Antiretroviral therapy can reduce HIV-1 to undetectable levels in peripheral blood, but the effectiveness of treatment in suppressing replication in lymphoid tissue reservoirs has not been determined. Here we show in lymph node samples obtained before and during 6 mo of treatment that the tissue concentrations of five of the most frequently used antiretroviral drugs are much lower than in peripheral blood. These lower concentrations correlated with continued virus replication measured by the slower decay or increases in the follicular dendritic cell network pool of virions and with detection of viral RNA in productively infected cells. The evidence of persistent replication associated with apparently suboptimal drug concentrations argues for development and evaluation of novel therapeutic strategies that will fully suppress viral replication in lymphatic tissues. These strategies could avert the long-term clinical consequences of chronic immune activation driven directly or indirectly by low-level viral replication to thereby improve immune reconstitution. PMID- 24469826 TI - Pioneer of hematopoietic colony-stimulating factors: Leo Sachs (1924-2013). PMID- 24469827 TI - Maternal tract factors contribute to paternal seminal fluid impact on metabolic phenotype in offspring. AB - Paternal characteristics and exposures influence physiology and disease risks in progeny, but the mechanisms are mostly unknown. Seminal fluid, which affects female reproductive tract gene expression as well as sperm survival and integrity, provides one potential pathway. We evaluated in mice the consequences for offspring of ablating the plasma fraction of seminal fluid by surgical excision of the seminal vesicle gland. Conception was substantially impaired and, when pregnancy did occur, placental hypertrophy was evident in late gestation. After birth, the growth trajectory and metabolic parameters of progeny were altered, most profoundly in males, which exhibited obesity, distorted metabolic hormones, reduced glucose tolerance, and hypertension. Altered offspring phenotype was partly attributable to sperm damage and partly to an effect of seminal fluid deficiency on the female tract, because increased adiposity was also evident in adult male progeny when normal two-cell embryos were transferred to females mated with seminal vesicle-excised males. Moreover, embryos developed in female tracts not exposed to seminal plasma were abnormal from the early cleavage stages, but culture in vitro partly alleviated this. Absence of seminal plasma was accompanied by down-regulation of the embryotrophic factors Lif, Csf2, Il6, and Egf and up-regulation of the apoptosis-inducing factor Trail in the oviduct. These findings show that paternal seminal fluid composition affects the growth and health of male offspring, and reveal that its impact on the periconception environment involves not only sperm protection but also indirect effects on preimplantation embryos via oviduct expression of embryotrophic cytokines. PMID- 24469828 TI - The Fanconi anemia pathway has a dual function in Dickkopf-1 transcriptional repression. AB - Fanconi anemia (FA) is an inherited bone marrow failure syndrome associated with a progressive decline in hematopoietic stem cells, developmental defects, and predisposition to cancer. These various phenotypic features imply a role of FA proteins in molecular events regulating cellular homeostasis. Interestingly, we previously found that the Fanconi C protein (FANCC) interacts with the C-terminal binding protein-1 (CtBP1) involved in transcriptional regulation. Here we report that FANCC with CtBP1 forms a complex with beta-catenin, and that beta-catenin activation through glycogen synthase kinase 3beta inhibition leads to FANCC nuclear accumulation and FA pathway activation, as measured by the Fanconi D2 protein (FANCD2) monoubiquitination. beta-catenin and FANCC nuclear entry is defective in FA mutant cells and in cells depleted of the Fanconi A protein or FANCD2, suggesting that integrity of the FA pathway is required for FANCC nuclear activity. We also report that FANCC with CtBP1 acts as a negative regulator of Dickkopf-1 (DKK1) expression, and that a FA disease-causing mutation in FANCC abrogates this function. Our findings reveal that a defective FA pathway leads to up-regulation of DKK1, a molecule involved in hematopoietic malignancies. PMID- 24469829 TI - CDKG1 protein kinase is essential for synapsis and male meiosis at high ambient temperature in Arabidopsis thaliana. AB - The Arabidopsis cyclin-dependent kinase G (CDKG) gene defines a clade of cyclin dependent protein kinases related to CDK10 and CDK11, as well as to the enigmatic Ph1-related kinases that are implicated in controlling homeologous chromosome pairing in wheat. Here we demonstrate that the CDKG1/CYCLINL complex is essential for synapsis and recombination during male meiosis. A transfer-DNA insertional mutation in the cdkg1 gene leads to a temperature-sensitive failure of meiosis in late Zygotene/Pachytene that is associated with defective formation of the synaptonemal complex, reduced bivalent formation and crossing over, and aneuploid gametes. An aphenotypic insertion in the cyclin L gene, a cognate cyclin for CDKG, strongly enhances the phenotype of cdkg1-1 mutants, indicating that this cdk-cyclin complex is essential for male meiosis. Since CYCLINL, CDKG, and their mammalian homologs have been previously shown to affect mRNA processing, particularly alternative splicing, our observations also suggest a mechanism to explain the widespread phenomenon of thermal sensitivity in male meiosis. PMID- 24469831 TI - A note on derivations of Murray-von Neumann algebras. AB - A Murray-von Neumann algebra is the algebra of operators affiliated with a finite von Neumann algebra. In this article, we first present a brief introduction to the theory of derivations of operator algebras from both the physical and mathematical points of view. We then describe our recent work on derivations of Murray-von Neumann algebras. We show that the "extended derivations" of a Murray von Neumann algebra, those that map the associated finite von Neumann algebra into itself, are inner. In particular, we prove that the only derivation that maps a Murray-von Neumann algebra associated with a factor of type II1 into that factor is 0. Those results are extensions of Singer's seminal result answering a question of Kaplansky, as applied to von Neumann algebras: The algebra may be noncommutative and may even contain unbounded elements. PMID- 24469830 TI - A vertebrate myosin-I structure reveals unique insights into myosin mechanochemical tuning. AB - Myosins are molecular motors that power diverse cellular processes, such as rapid organelle transport, muscle contraction, and tension-sensitive anchoring. The structural adaptations in the motor that allow for this functional diversity are not known, due, in part, to the lack of high-resolution structures of highly tension-sensitive myosins. We determined a 2.3-A resolution structure of apo myosin-Ib (Myo1b), which is the most tension-sensitive myosin characterized. We identified a striking unique orientation of structural elements that position the motor's lever arm. This orientation results in a cavity between the motor and lever arm that holds a 10-residue stretch of N-terminal amino acids, a region that is divergent among myosins. Single-molecule and biochemical analyses show that the N terminus plays an important role in stabilizing the post power-stroke conformation of Myo1b and in tuning the rate of the force-sensitive transition. We propose that this region plays a general role in tuning the mechanochemical properties of myosins. PMID- 24469832 TI - Critical role for IL-1beta in DNA damage-induced mucositis. AB - beta-TrCP, the substrate recognition subunit of SCF-type ubiquitin ligases, is ubiquitously expressed from two distinct paralogs, targeting for degradation many regulatory proteins, among which is the NF-kappaB inhibitor IkappaB. To appreciate tissue-specific roles of beta-TrCP, we studied the consequences of inducible ablation of three or all four alleles of the E3 in the mouse gut. The ablation resulted in mucositis, a destructive gut mucosal inflammation, which is a common complication of different cancer therapies and represents a major obstacle to successful chemoradiation therapy. We identified epithelial-derived IL-1beta as the culprit of mucositis onset, inducing mucosal barrier breach. Surprisingly, epithelial IL-1beta is induced by DNA damage via an NF-kappaB independent mechanism. Tissue damage caused by gut barrier disruption is exacerbated in the absence of NF-kappaB, with failure to express the endogenous IL-1beta receptor antagonist IL-1Ra upon four-allele loss. Antibody neutralization of IL-1beta prevents epithelial tight junction dysfunction and alleviates mucositis in beta-TrCP-deficient mice. IL-1beta antagonists should thus be considered for prevention and treatment of severe morbidity associated with mucositis. PMID- 24469833 TI - High-throughput combinatorial screening identifies drugs that cooperate with ibrutinib to kill activated B-cell-like diffuse large B-cell lymphoma cells. AB - The clinical development of drug combinations is typically achieved through trial and-error or via insight gained through a detailed molecular understanding of dysregulated signaling pathways in a specific cancer type. Unbiased small molecule combination (matrix) screening represents a high-throughput means to explore hundreds and even thousands of drug-drug pairs for potential investigation and translation. Here, we describe a high-throughput screening platform capable of testing compounds in pairwise matrix blocks for the rapid and systematic identification of synergistic, additive, and antagonistic drug combinations. We use this platform to define potential therapeutic combinations for the activated B-cell-like subtype (ABC) of diffuse large B-cell lymphoma (DLBCL). We identify drugs with synergy, additivity, and antagonism with the Bruton's tyrosine kinase inhibitor ibrutinib, which targets the chronic active B cell receptor signaling that characterizes ABC DLBCL. Ibrutinib interacted favorably with a wide range of compounds, including inhibitors of the PI3K-AKT mammalian target of rapamycin signaling cascade, other B-cell receptor pathway inhibitors, Bcl-2 family inhibitors, and several components of chemotherapy that is the standard of care for DLBCL. PMID- 24469834 TI - Spatial separation of Xist RNA and polycomb proteins revealed by superresolution microscopy. AB - In female mammals, one of the two X chromosomes is transcriptionally silenced to equalize X-linked gene dosage relative to XY males, a process termed X chromosome inactivation. Mechanistically, this is thought to occur via directed recruitment of chromatin modifying factors by the master regulator, X-inactive specific transcript (Xist) RNA, which localizes in cis along the entire length of the chromosome. A well-studied example is the recruitment of polycomb repressive complex 2 (PRC2), for which there is evidence of a direct interaction involving the PRC2 proteins Enhancer of zeste 2 (Ezh2) and Supressor of zeste 12 (Suz12) and the A-repeat region located at the 5' end of Xist RNA. In this study, we have analyzed Xist-mediated recruitment of PRC2 using two approaches, microarray-based epigenomic mapping and superresolution 3D structured illumination microscopy. Making use of an ES cell line carrying an inducible Xist transgene located on mouse chromosome 17, we show that 24 h after synchronous induction of Xist expression, acquired PRC2 binding sites map predominantly to gene-rich regions, notably within gene bodies. Paradoxically, these new sites of PRC2 deposition do not correlate with Xist-mediated gene silencing. The 3D structured illumination microscopy was performed to assess the relative localization of PRC2 proteins and Xist RNA. Unexpectedly, we observed significant spatial separation and absence of colocalization both in the inducible Xist transgene ES cell line and in normal XX somatic cells. Our observations argue against direct interaction between Xist RNA and PRC2 proteins and, as such, prompt a reappraisal of the mechanism for PRC2 recruitment in X chromosome inactivation. PMID- 24469835 TI - Importance of a sound hydrologic foundation for assessing the future of the High Plains Aquifer in Kansas. PMID- 24469836 TI - Mcl-1 mediates TWEAK/Fn14-induced non-small cell lung cancer survival and therapeutic response. AB - Insensitivity to standard clinical interventions, including chemotherapy, radiotherapy, and tyrosine kinase inhibitor (TKI) treatment, remains a substantial hindrance towards improving the prognosis of patients with non-small cell lung cancer (NSCLC). The molecular mechanism of therapeutic resistance remains poorly understood. The TNF-like weak inducer of apoptosis (TWEAK)-FGF inducible 14 (TNFRSF12A/Fn14) signaling axis is known to promote cancer cell survival via NF-kappaB activation and the upregulation of prosurvival Bcl-2 family members. Here, a role was determined for TWEAK-Fn14 prosurvival signaling in NSCLC through the upregulation of myeloid cell leukemia sequence 1 (MCL1/Mcl 1). Mcl-1 expression significantly correlated with Fn14 expression, advanced NSCLC tumor stage, and poor patient prognosis in human primary NSCLC tumors. TWEAK stimulation of NSCLC cells induced NF-kappaB-dependent Mcl-1 protein expression and conferred Mcl-1-dependent chemo- and radioresistance. Depletion of Mcl-1 via siRNA or pharmacologic inhibition of Mcl-1, using EU-5148, sensitized TWEAK-treated NSCLC cells to cisplatin- or radiation-mediated inhibition of cell survival. Moreover, EU-5148 inhibited cell survival across a panel of NSCLC cell lines. In contrast, inhibition of Bcl-2/Bcl-xL function had minimal effect on suppressing TWEAK-induced cell survival. Collectively, these results position TWEAK-Fn14 signaling through Mcl-1 as a significant mechanism for NSCLC tumor cell survival and open new therapeutic avenues to abrogate the high mortality rate seen in NSCLC. IMPLICATIONS: The TWEAK-Fn14 signaling axis enhances lung cancer cell survival and therapeutic resistance through Mcl-1, positioning both TWEAK-Fn14 and Mcl-1 as therapeutic opportunities in lung cancer. PMID- 24469838 TI - Group G streptococcal sepsis, septic arthritis and myositis in a patient with severe oral ulcerations. AB - Lancefield group G streptococci (GGS) are a relatively less common cause of streptococcal infections but the incidence of which has been reported to increase in the recent years. Similar to group A streptococci, GGS produce localised and invasive infections. Streptococcal myositis is a very rare but highly fatal infection of muscles generally caused by group A streptococci. We report a case of sepsis, migrating septic arthritis and diffuse myositis caused by beta haemolytic GGS. It is an unusual case of diffuse beta-haemolytic GGS myositis involving multiple muscle groups in a patient who demonstrated no skin lesions or sign of streptococcal toxic shock syndrome. The patient responded well to intravenous antibiotics without surgical intervention and experienced full recovery. PMID- 24469837 TI - PGE2-driven expression of c-Myc and oncomiR-17-92 contributes to apoptosis resistance in NSCLC. AB - Aberrant expression of microRNAs (miRNA) with oncogenic capacities (oncomiRs) has been described for several different malignancies. The first identified oncomiR, miR-17-92, is frequently overexpressed in a variety of cancers and its targets include the tumor suppressor PTEN. The transcription factor c-Myc (MYC) plays a central role in proliferative control and is rapidly upregulated upon mitogenic stimulation. Expression of c-Myc is frequently deregulated in tumors, facilitating proliferation and inhibiting terminal differentiation. The c-Myc regulated network comprises a large number of transcripts, including those encoding miRNAs. Here, prostaglandin E2 (PGE2) exposure rapidly upregulates the expression of the MYC gene followed by the elevation of miR-17-92 levels, which in turn suppresses PTEN expression, thus enhancing apoptosis resistance in non small cell lung cancer (NSCLC) cells. Knockdown of MYC expression or the miR-17 92 cluster effectively reverses this outcome. Similarly, miR-17-92 levels are significantly elevated in NSCLC cells ectopically expressing COX-2. Importantly, circulating miR-17-92 was elevated in the blood of patients with lung cancer as compared with subjects at risk for developing lung cancer. Furthermore, in patients treated with celecoxib, miR-17-92 levels were significantly reduced. These data demonstrate that PGE2, abundantly produced by NSCLC and inflammatory cells in the tumor microenvironment, is able to stimulate cell proliferation and promote resistance to pharmacologically induced apoptosis in a c-Myc and miR-17 92-dependent manner. IMPLICATIONS: This study describes a novel mechanism, involving c-Myc and miR-17-92, which integrates cell proliferation and apoptosis resistance. PMID- 24469839 TI - A rare case of stricture urethra presenting as pyocele and urethrotunica vaginalis fistula. PMID- 24469840 TI - Strongyloides stercoralis hyperinfection presenting as subacute small bowel obstruction following immunosuppressive chemotherapy for multiple myeloma. AB - We report the case of a 59-year-old Afro-Caribbean woman who presented with symptoms of anorexia, lethargy, abdominal distension and vomiting on the background of newly diagnosed multiple myeloma, treated with one cycle of cyclophosphamide-thalidomide-dexamethasone chemotherapy 20 days previously. A diagnosis of subacute bowel obstruction was made; however, the aetiology of the obstruction remained elusive. Common electrolyte abnormalities were excluded and a midline laparotomy revealed minimal intra-abdominal adhesions. Histological examination of a small bowel mesentery biopsy showed inflammatory cell infiltrate composed of lymphocytes, eosinophils and occasional plasma cells with a foreign body giant cell reaction suggestive of worm infection. A postoperative stool sample revealed heavy infestation with the rhabditiform larvae of Strongyloides stercoralis. The patient recovered following ivermectin treatment. In the absence of other causality, we attribute the subacute bowel obstruction to S stercoralis hyperinfection, triggered by immunosuppression secondary to chemotherapy and multiple myeloma. PMID- 24469841 TI - Bilateral saccular inguinal hernias in an elderly woman presenting with advanced ovarian cancer. AB - We present a case of an elderly woman presenting with bilateral groin hernias, one reducible and the other irreducible. CT of the abdomen and pelvis demonstrated an irreducible left inguinal hernia containing an incarcerated loop of transverse colon together with saccular metastatic tumour spread. Disseminated omental disease and ascitic fluid were noted throughout the peritoneal cavity secondary to ovarian carcinoma. As a consequence of extensive malignant disease and advanced age, the patient was treated conservatively and subsequently died a number of weeks later. To the best of our knowledge, this is only the second case of bilateral inguinal hernias presenting in a woman with a background of disseminated ovarian malignancy. This case highlights the importance of pre reduction imaging in atypical complex cases. PMID- 24469842 TI - High-altitude pulmonary oedema in native highlanders. PMID- 24469843 TI - Cyst with a mural nodule: unusual imaging characteristics of a cystic meningioma. PMID- 24469844 TI - Two cases of primary hyperparathyroidism in pregnancy. AB - Two women suffering from primary hyperparathyroidism in pregnancy are presented. Patient 1 with a history of four miscarriages, an ectopic pregnancy and a sixth pregnancy complicated by severe early onset preeclampsia. She was found to have high serum Ca(2+) levels after delivery and parathyroid adenoma was diagnosed by ultrasound. A right inferior parathyroidectomy was performed. Patient 2 with a history of high serum Ca(2+) and generalised symptoms of hypercalcaemia. Ultrasound did not reveal adenoma but an elective neck exploration was performed in light of the abnormal blood results. The right inferior parathyroid gland was excised and histology confirmed the presence of adenoma. These cases help highlight the different ways in which primary hyperparathyroidism can present and the barriers to diagnosis in pregnancy. Various potential complications (including miscarriage and preeclampsia) are explored and the appropriateness of surgical treatment during pregnancy is emphasised. PMID- 24469845 TI - Caecal faecolith, a cause of acute appendicitis. AB - A 60-year-old woman presented to the accident and emergency department with a 3 day history of lower abdominal pain, which was sudden in onset, localised to the right iliac fossa, constant and aggravated by movements. On examination, she was febrile (100 . F), tachycardic and normotensive. Examination of the abdomen revealed an ill-defined tender mass in the right iliac fossa. A clinical diagnosis of appendicular mass was made and treated conservatively. After a few days the mass became smaller, firmer, mobile and non-tender. Since the mass persisted, the patient was investigated further to rule out carcinoma of the caecum. A contrast-enhanced CT (CECT) of the abdomen showed a mass with air pockets in the caecum, suggestive of caecal faecolith. After 6 weeks, appendicectomy and removal of the faecolith were performed. The postoperative period was uneventful. Histopathology of the appendix showed inflammatory changes confirming appendicitis. PMID- 24469846 TI - Prevalence, location, and extent of significant coronary artery disease in patients with normal myocardial perfusion imaging. AB - BACKGROUND: False-negative myocardial perfusion imaging (MPI) can by due to left main (LM) or three-vessel disease causing "balanced ischemia". However, so far prevalence of LM or three-vessel-disease in patients with normal MPI is unclear. We assessed prevalence, location, and extent of significant coronary artery disease (CAD) in patients with normal MPI. METHODS: Between 2006 and 2010, 256 patients with normal MPI who had invasive angiography because of persisting or worsening of the same initial symptoms were studied. Significant CAD was defined as stenosis > 70% or LM > 50%. RESULTS: A total of 93 patients (36%) had significant CAD. Significant CAD was observed more frequently in males, higher age and those with typical angina complaints. Significant LM disease was present in 7%, three-vessel disease in 10%, two-vessel disease in 22%, and single vessel disease (not left main) in 61%. In those with single vessel disease, the location was the LAD in 40%, the RCA in 30%, and the LCX in 30%. CONCLUSIONS: In selected patients with normal MPI, one-third had significant CAD. The majority of these patients had single vessel disease (not left main). LM or three vessel disease, causing "balanced ischemia", is a less common cause of false-negative MPI. PMID- 24469847 TI - Anatomy vs physiology: is that the question? PMID- 24469848 TI - Rationally Irrational: The Case of Sexual Burglary. AB - The present study investigated rationality in sexually motivated burglaries. Specifically, we analyzed the situational cues identified by sexual burglars in their target selection. The research project investigated 224 individual incidents of residential burglary with apparent sexual motivations. Situational characteristics of the incidents were recorded and analyzed using forward sequential regressions. Results indicated that most sexually motivated burglaries occurred in occupied residences with deficient physical guardianship, when the victim was alone. Violence, theft, penetration, and fetishism were found to be committed in circumstances that increased the benefits and lowered the risks. Results showed that sexual burglary is rational in nature-sexual burglars chose residences that were easy to break into. We found little support for the premise that such opportunities arose while carrying out regular burglaries. Instead, the data indicated that sexual burglars acted opportunistically on situational cues that are markedly dissimilar to those of regular burglars. PMID- 24469849 TI - The associations between pathological narcissism, alexithymia and disordered eating attitudes among participants of pro-anorexic online communities. AB - PURPOSE: This study investigated the relationships between pathological narcissism, alexithymia, and disordered eating attitudes among participants of pro-anorexic online communities. Specifically, we explored the possible moderating role of alexithymia in the relationships between narcissistic vulnerability and disordered eating attitudes. METHODS: Participants included 97 Israeli female young adults who are active participants in pro-anorexic online communities. These participants completed a battery of self-reported questionnaires: The Pathological Narcissism Inventory (PNI); The Eating Attitudes Test-26 (EAT-26); and The Toronto Alexithymia Scale (TAS-20). RESULTS: Narcissistic grandiosity, vulnerability, and alexithymia were positively related to disordered eating attitudes. Alexithymia moderated the relationships between narcissistic vulnerability and the total score of disordered eating attitudes. Furthermore, alexithymia moderated the relationships between both narcissistic vulnerability and grandiosity and the oral control subscale of EAT-26. CONCLUSIONS: These findings highlight the interaction between the pathological narcissism and the fundamental trait of alexithymia that might put individuals at risk for disordered eating. PMID- 24469850 TI - Promising areas of prostate cancer research. PMID- 24469851 TI - Patterns of care at end of life for people with primary intracranial tumors: lessons learned. AB - To determine the variability in processes of care in the last 6 months of life experienced by patients dying of primary intracranial tumors and potential predictors of place of death, a death-backwards cohort was assembled using historical data and 1,623 decedents were identified. 90 % of people had >= 1 admission to an acute care hospital and 23 % spent >= 3 months of their last 6 months of life in acute care. 44 % had >= 1 ER visits and 30 % were admitted >= 1 times to ICU. Only 18 % had a home visit by a physician. 10 % died at home but 49 % died in hospital, while 40 % died in a palliative care facility. Age, comorbidities, and being diagnosed with grade 4 astrocytoma were associated with greater burden of care. Level of care burden and age were associated with higher odds of dying in a treatment intensive place of death, being diagnosed with grade 4 astrocytoma had opposite effect. Despite valuable research efforts to improve the treatment of primary intracranial tumors that focus on biology, refinements to surgery, radiation, and chemotherapy, there is also room to improve aspects of care at the end of life situation. An integrative approach for this patients' population, from diagnosis to death, could potentially reduce the care burden in the final period on the health care system, patient's family and improve access to a better place of death. PMID- 24469852 TI - CSF CA 15-3 in breast cancer-related leptomeningeal metastases. AB - The sensitivity of CSF cytology, the standard method for diagnosis of leptomeningeal metastases (LM), is low. Serum cancer antigen 15-3 (CA 15-3) is frequently used for the monitoring of patients with breast cancer (BC) and is a laboratory test available in most centers. The aim of the current study was to determine the feasibility of measuring CSF CA 15-3 and CA 15-3 CSF/serum ratio in patients with BC-related LM. Serum and CSF CA 15-3 values were evaluated in 20 BC patients with LM (Group 1), 20 patients with LM from other primary cancers (Group 2), 20 BC patients with parenchymal brain metastases only (Group 3) and 20 controls (Group 4). CSF and serum were collected on the same day. Serum and CSF CA 15-3 were assessed by an automatized immuno-enzymatic technology (TRACE((r)) technology, KRYPTOR Automate, Brahms Society, France). In univariate analysis, BC patients with LM (Group 1) compared to other groups, a significantly elevated serum CA 15-3 (median 51 U/ml, range 12-2819) and CSF CA 15-3 (median 8.7 U/ml, range 0.1-251) was observed. Additionally, the CSF/serum ratio of CA 15-3 was significantly higher in this group of patients (median 0.18, range 0.002-4.40). Multivariate analysis identified a cut-off for CSF CA15-3 with 80 % sensitivity and 70 % specificity. CONCLUSIONS: The current study confirms the feasibility of determining CSF CA 15-3 using a widely available technology. Evaluation of the CSF CA 15-3 may be useful in the diagnosis and management of BC-related LM but further studies are needed. PMID- 24469853 TI - Large volume reirradiation as salvage therapy for glioblastoma after progression on bevacizumab. AB - Outcomes after bevacizumab failure for recurrent glioblastoma (GBM) are poor. Our analysis of 16 phase II trials (n = 995) revealed a median overall survival (OS) of 3.8 months (+/-1.0 month SD) after bevacizumab failure with no discernible activity of salvage chemotherapy. Thus, the optimal treatment for disease progression after bevacizumab has yet to be elucidated. This study evaluated the efficacy of reirradiation for patients with GBM after progression on bevacizumab. An IRB approved retrospective (2/2008-5/2013) analysis was performed of 23 patients with recurrent GBM (after standard radiotherapy/temozolomide) treated with bevacizumab (10 mg/kg) every 2 weeks until progression (median age 53 years; median KPS 80; median progression free survival on bevacizumab 3.7 months). Within 7-14 days of progression on bevacizumab, patients initiated reirradiation to a dose of 54 Gy in 27 fractions using pulsed-reduced dose rate (PRDR) radiotherapy. The median planning target volume was 424 cm(3). At the start of reirradiation, bevacizumab (10 mg/kg) was given every 4 weeks for two additional cycles. The median OS and 6 month OS after bevacizumab failure was 6.9 months and 65 %, respectively. Reirradiation was well tolerated with no symptomatic grade 3 4 toxicities. Favorable outcomes of reirradiation after bevacizumab failure in patients with recurrent GBM suggest its role as a treatment option for large volume recurrences not amenable to stereotactic radiosurgery. As PRDR is easily accomplished from a technological standpoint, we are in the process of expanding this approach to a multi-institutional cooperative group trial. PMID- 24469854 TI - Factors impacting survival following second surgery in patients with glioblastoma in the temozolomide treatment era, incorporating neutrophil/lymphocyte ratio and time to first progression. AB - Patients with progressive glioblastoma (GBM) have a poor prognosis. Neutrophil/lymphocyte ratio (NLR), a host inflammatory marker, is prognostic in several solid tumors. The prognostic impact of either NLR, or time from first surgery for GBM to first progression (TTP), in patients undergoing second surgery, has not been assessed. Patients undergoing second surgery for GBM were retrospectively reviewed. Primary outcome was overall survival (OS) and Cox proportional hazard models were used to assess the prognostic value of baseline characteristics including TTP and NLR. Univariable and multivariable analysis (MVA) of OS from second surgery were performed using accelerated failure time Weibull model. Of 584 patients with GBM, 107 (18 %) underwent second surgery between 01/04 and 12/11. Patients who underwent second surgery had longer OS versus those having primary surgery alone; 20.9 versus 9.9 months (P < 0.001). Median OS from second surgery in patients with NLR <= 4 versus NLR > 4 was 9.7 versus 5.9 months (log rank P = 0.02). The NLR retained its prognostic significance for survival on MVA (time ratio [TR] 1.65, 95 % confidence interval [CI] 1.15-2.35, P < 0.01). No chemotherapy post second surgery (TR 0.23, 95 % CI 0.16-0.33, P < 0.001) portended worse survival. In patients undergoing second surgery, when TTP was <= 12 months, 12-24 months, or >24 months, median OS from second surgery was 7.2, 7.0 and 6.3 months, respectively (P = 0.6). A NLR > 4 prior to second surgery is a poor prognostic factor in GBM and later progression is associated with longer survival in patients but not in longer survival after second surgery. PMID- 24469855 TI - Conditional probability of survival and post-progression survival in patients with glioblastoma in the temozolomide treatment era. AB - With standard treatment for glioblastoma (GBM) consisting of surgery followed by radiotherapy (RT) with concurrent and adjuvant temozolomide (TMZ), median survival is ~14.6 months. This is not as informative to patients who have survived for some time. Conditional probability of survival may offer more relevant survival estimates. Outcomes/conditional probability of survival and post-progression survival (PPS) estimates were retrospectively reviewed in the TMZ treatment era of 882 consecutive patients with a diagnosis of GBM from January 2004 to August 2010. Median age of entire cohort was 62 years including 62 % males. Baseline performance status (PS) was 0-1 in 67, 23 % had frontal lobe tumors, 58 % received concurrent RT/TMZ +/- adjuvant TMZ. Survival (OS) was similar for those with frontal lobe tumors versus other locations (P = 0.25). OS for patients receiving standard RT/TMZ +/- TMZ was 14.2 months. Age, PS, extent of surgery, therapy post-surgery had significant effects on OS. OS for entire cohort at 1, 2, 3, 4, 5 years was 43.4, 17.9, 10.4, 8.4, 7.2 % respectively. Conditional probability of survival of an additional year given survival to 1, 2, 3, 4, 5 years was 41.4, 58, 80.7, 85.7, 81.5 % respectively. Conditional probability of survival for those patients receiving concurrent RT/TMZ +/- adjuvant TMZ was similar. Patients who progress >18 months after their initial treatment for GBM had significantly greater 2 and 5 year PPS as well as OS. Conditional probabilities of survival may provide more meaningful life expectancy predictions for survivors of GBM than conventional survival outcomes. PMID- 24469856 TI - PI3K pathway inhibitors for the treatment of brain metastases with a focus on HER2+ breast cancer. AB - The incidence of breast cancer brain metastases has increased in recent years, largely due to improved control of systemic disease with human epidermal growth factor receptor 2 (HER2)-targeted agents and the inability of most of these agents to efficiently cross the blood-blood barrier (BBB) and control central nervous system disease. There is, therefore, an urgent unmet need for treatments to prevent and treat HER2+ breast cancer brain metastases (BCBMs). Aberrant activation of the phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) signaling pathway is frequently observed in many cancers, including primary breast tumors and BCBMs. Agents targeting key components of this pathway have demonstrated antitumor activity in diverse cancers, and may represent a new treatment strategy for BCBMs. In preclinical studies, several inhibitors of PI3K and mTOR have demonstrated an ability to penetrate the BBB and down-regulate PI3K signaling, indicating that these agents may be potential therapies for brain metastatic disease. The PI3K inhibitor buparlisib (BKM120) and the mTOR inhibitor everolimus (RAD001) are currently under evaluation in combination with trastuzumab in patients with HER2+ BCBMs. PMID- 24469857 TI - Highly photostable "super"-photoacids for ultrasensitive fluorescence spectroscopy. AB - The photoacid 8-hydroxypyren-1,3,6-trisulfonic acid (HPTS, pyranine) is a widely used model compound for the examination of excited state proton transfer (ESPT). We synthesized five "super"-photoacids with varying hydrophilicity and acidity on the basis of HPTS. By chemical modification of the three sulfonic acid substituents, the photoacidity is enhanced by up to more than five logarithmic units from pK*~ 1.4 to ~-3.9 for the most acidic compound. As a result, nearly quantitative ESPT in DMSO can be observed. The novel photoacids were characterized by steady-state and time-resolved fluorescence techniques showing distinctively red shifted spectra compared to HPTS while maintaining a high quantum yield near 90%. Photostability of the compounds was checked by fluorescence correlation spectroscopy (FCS) and was found to be adequately high for ultrasensitive fluorescence spectroscopy. The described photoacids present a valuable palette for a wide range of applications, especially when the properties of HPTS, i.e. highly charged, low photostability and only moderate excited state acidity, are limiting. PMID- 24469858 TI - Oncologic outcomes between open and robotic-assisted radical cystectomy: a propensity score matched analysis. AB - PURPOSE: To compare oncologic outcomes between open radical cystectomy (ORC) and robotic-assisted radical cystectomy (RARC) using propensity score (PS) matching of preoperative variables. METHODS: A group of 51 consecutive patients who underwent RARC between 2009 and 2012 were matched by propensity scoring with an equal number of patients who underwent ORC. Patient demographics, clinical staging, pathologic staging, pathologic grading, histology, positive margin status, lymph node yield, duration of hospital stay, and overall survival were examined. RESULTS: PS-matched ORC and RARC cohorts demonstrated no significant differences with respect to preoperative variables, pathologic stage, grade, histology, metastasis at preoperative staging, and postoperative positive margin status. There were statistically significant differences in nodal status (66.7 % N0 for ORC vs. 80.4 % N0 for RARC, p = 0.039) and median lymph node yield (6 for ORC vs. 18 for RARC, p < 0.0001). No positive soft tissue margins were observed in the RARC group compared to 5.9 % in the ORC group (p = 0.332). There were no significant differences in mean duration of hospital stay or mean overall survival between ORC and RARC. CONCLUSION: ORC and RARC represent effective surgical approaches for the treatment of bladder cancer. Histopathologic outcomes for RARC compare favorably to ORC with respect to soft tissue margin rates and lymph node yield. These data suggest that RARC is an acceptable surgical approach for treatment of bladder cancer that can achieve outcomes that are equal or superior to those of ORC. PMID- 24469859 TI - Long-term evaluation of oncologic and functional outcomes after laparoscopic open assisted radical cystectomy: a matched-pair analysis. AB - PURPOSE: To evaluate peri- and postoperative morbidity, and long-term oncologic and functional results of our laparoscopic radical cystectomy (LRC) technique, comparing it with our standard open approach. METHODS: Between 2000 and 2010, 54 patients underwent LRC for urothelial cell carcinoma of the bladder in two academic hospitals. The procedures were performed by two surgeons. Patients were matched 1:1 with patients who underwent open RC in the same years by the same surgical team. Differences in peri- and postoperative complications across the two groups were assessed using Wilcoxon's rank-sum or chi (2) test. Kaplan-Meier curves, log-rank tests and Cox regression models were constructed to assess differences in recurrence-free survival on long-term follow-up between the two groups. RESULTS: Laparoscopic radical cystectomy was significantly associated with lower blood loss (p < 0.0001) and less frequent postoperative ileus (p = 0.03). Regarding more serious postoperative complications, no difference was found across the two cohorts. Median oncologic follow-up was 42 months (IQR 12-72 months) in the LRC cohort and 18 months (IQR 8-27 months) in patients undergoing open radical cystectomy (ORC). No statistically significant difference in recurrence-free survival was observed between the two groups (log rank p = 0.677). On univariate Cox regression, the surgical approach used was not significantly associated with risk of recurrence. CONCLUSIONS: We found that LRC is safe and associated with lower blood loss and decreased postoperative ileus compared with ORC. Moreover, on long-term oncologic follow-up, LRC appeared non inferior to ORC with no significant difference in recurrence-free survival. Nonetheless, these results must be confirmed by larger series and stronger long term follow-up data are needed. PMID- 24469860 TI - Deregulation of AhR function by the human acute leukemia TEL-ARNT fusion protein. PMID- 24469861 TI - Auditory-nerve responses to varied inter-phase gap and phase duration of the electric pulse stimulus as predictors for neuronal degeneration. AB - After severe hair cell loss, secondary degeneration of spiral ganglion cells (SGCs) is observed-a gradual process that spans years in humans but only takes weeks in guinea pigs. Being the target for cochlear implants (CIs), the physiological state of the SGCs is important for the effectiveness of a CI. For assessment of the nerve's state, focus has generally been on its response threshold. Our goal was to add a more detailed characterization of SGC functionality. To this end, the electrically evoked compound action potential (eCAP) was recorded in normal-hearing guinea pigs and guinea pigs that were deafened 2 or 6 weeks prior to the experiments. We evaluated changes in eCAP characteristics when the phase duration (PD) and inter-phase gap (IPG) of a biphasic current pulse were varied. We correlated the magnitude of these changes to quantified histological measures of neurodegeneration (SGC packing density and SGC size). The maximum eCAP amplitude, derived from the input-output function, decreased after deafening, and increased with both PD and IPG. The eCAP threshold did not change after deafening, and decreased with increasing PD and IPG. The dynamic range was wider for the 6-weeks-deaf animals than for the other two groups. Excitability increased with IPG (steeper slope of the input-output function and lower stimulation level at the half-maximum eCAP amplitude), but to a lesser extent for the deafened animals than for normal-hearing controls. The latency was shorter for the 6-weeks-deaf animals than for the other two groups. For several of these eCAP characteristics, the effect size of IPG correlated well with histological measures of degeneration, whereas effect size of PD did not. These correlations depend on the use of high current levels, which could limit clinical application. Nevertheless, their potential of these correlations towards assessment of the condition of the auditory nerve may be of great benefit to clinical diagnostics and prognosis in cochlear implant recipients. PMID- 24469863 TI - Biomimetic phantom for the validation of diffusion magnetic resonance imaging. AB - PURPOSE: A range of advanced diffusion MRI (dMRI) techniques are currently in development which characterize the orientation of white matter fibers using diffusion tensor imaging (DTI). There is a need for a physical phantom with microstructural features of the brain's white matter to help validate these methods. METHODS: Hollow, co-electrospun, aligned fibers with a tuneable size distribution have been produced in bulk and with an MR visible solvent infused into the pores. The morphology and size of the phantoms was assessed using scanning electron microscopy (SEM) and compared with DTI results obtained on both a clinical and preclinical scanner. RESULTS: By varying inner diameter of the phantom fibers (from SEM: 9.5 MUm, 11.9 MUm, 13.4 MUm) the radial diffusivity and fractional anisotropy, calculated from DTI, vary between 0.38 +/- 0.05 * 10(3) and 0.61 +/- 0.06 * 10(3) cm s(-1) and between 0.45 +/- 0.05 and 0.33 +/- 0.04, respectively. CONCLUSION: We envisage that these materials will be used for the validation of novel and established methods within the field of diffusion MRI, as well as for routine quality assurance purposes and for establishing scanner performance in multicenter trials. PMID- 24469862 TI - Randomized clinical trial of therapeutic music video intervention for resilience outcomes in adolescents/young adults undergoing hematopoietic stem cell transplant: a report from the Children's Oncology Group. AB - BACKGROUND: To reduce the risk of adjustment problems associated with hematopoietic stem cell transplant (HSCT) for adolescents/young adults (AYAs), we examined efficacy of a therapeutic music video (TMV) intervention delivered during the acute phase of HSCT to: 1) increase protective factors of spiritual perspective, social integration, family environment, courageous coping, and hope derived meaning; 2) decrease risk factors of illness-related distress and defensive coping; and 3) increase outcomes of self-transcendence and resilience. METHODS: This was a multisite randomized, controlled trial (COG-ANUR0631) conducted at 8 Children's Oncology Group sites involving 113 AYAs aged 11-24 years undergoing myeloablative HSCT. Participants, randomized to the TMV or low dose control (audiobooks) group, completed 6 sessions over 3 weeks with a board certified music therapist. Variables were based on Haase's Resilience in Illness Model (RIM). Participants completed measures related to latent variables of illness-related distress, social integration, spiritual perspective, family environment, coping, hope-derived meaning, and resilience at baseline (T1), postintervention (T2), and 100 days posttransplant (T3). RESULTS: At T2, the TMV group reported significantly better courageous coping (Effect Size [ES], 0.505; P = .030). At T3, the TMV group reported significantly better social integration (ES, 0.543; P = .028) and family environment (ES, 0.663; P = .008), as well as moderate nonsignificant effect sizes for spiritual perspective (ES, 0.450; P = .071) and self-transcendence (ES, 0.424; P = .088). CONCLUSIONS: The TMV intervention improves positive health outcomes of courageous coping, social integration, and family environment during a high-risk cancer treatment. We recommend the TMV be examined in a broader population of AYAs with high-risk cancers. PMID- 24469864 TI - Effect of a general fitness program on musculoskeletal symptoms, clinical status, physiological capacity, and perceived work environment among home care service personnel. AB - The aim of the present controlled study was to evaluate the effect of a general fitness program, performed by an occupational health service, using pre-post assessment for a number of different outcome measures. A total of 160 employees working in the central home care service district of Umea, Sweden were asked to participate in a program of a 1-year long exercise program. Of the 160 selected, 54 subjects declined to participate and nine subjects were rejected after a medical check up. The remaining 97 subjects participated in a schedule consisting of pre-post medical and physiotherapy examinations, questionnaires concerning sociodemography, musculoskeletal and general health complaints and work environment, physiological tests of cardiovascular fitness, and of strength and endurance of shoulder flexors and knee extensors, and registration of sick leave. The subjects were randomly assigned to an exercise (treatment) or control group. The exercise group trained twice a week for 1 year using a mixed program including exercises for coordination, strength/endurance, and fitness. The test schedule was repeated for both groups after 1 year. The exercise intervention was associated with positive changes in prevalence and intensity of musculoskeletal and psychosomatic complaints, better physiotherapy status (less muscle tightness, better neck mobility, and less tender points), increased shoulder strength and increased coordination in thigh muscles. However, the exercise group reported worse situations post-exercise concerning aspects of their physical and psychosocial work-environment (i.e., concerning ergonomy, influence, appreciation and communication with work manager), which might have been due to stress associated with the exercise situation. PMID- 24469865 TI - Reliability of Lift Alert(TM) as a feedback device for detecting changes in body position. AB - The Lift Alert (TM) is a small battery-operated unit, usually worn on the back of a worker's collar that is designed to provide a form of biofeedback about changes in trunk position during lifting tasks. The purpose of this study was to determine how consistent the Lift Alert (TM) was at each of five different sensitivity settings (A-E) in detecting changes in trunk flexion in a given individual during a controlled bending maneuver. The subjects were videotaped while performing a series of trials of bending maneuvers at each of the sensitivity settings according to a specific protocol. The videotapes were then converted onto a computer program where the still images were captured and marked for data analysis. The reliability of the Lift Alert (TM) was determined by calculating a coefficient of agreement, that is, the percentage of trials that were within both 10 and 15 degrees for each of the trials at a given setting for a single individual. The coefficient of agreement for all trials at all five settings was 0.76 within 10 degrees and 0.92 within 15 degrees. The results of this study suggest that the Lift Alert (TM) is a reliable device for detecting changes in trunk flexion during a controlled bending maneuver for a given individual. PMID- 24469866 TI - Workers' compensation managed care: Preliminary findings. AB - The cost of providing care that is effective to return injured workers to the workplace has risen in recent years in a manner that appears to be out of control in the workers' compensation system. In turn, medical care costs are an important component of the rapidly increasing costs of workers' compensation insurance. A model of health care delivery that emphasizes early intervention and return to work is presented. This model focuses on providing aggressive treatment of injuries that historically have been reported to be extraordinarily expensive. This paper is a case study of a managed care treatment model and presents costs of treatment in the first year of utilization. Medical care costs of 295 cases are compared with state and national figures and are found to be substantially better, especially with regard to soft tissue injuries and injuries that involve days lost from work. PMID- 24469867 TI - Psychological effects of prolonged unemployment: Relevance to models of work re entry following injury. AB - The literature on the psychological and mental health effects of unemployment is reviewed in terms of its main effects and the factors that mediate its impact. Significant decrements in mental health for people of all ages are identified, with additional effects of prolonged unemployment, employment commitment, social relationships, gender, ethnic group, social class, local unemployment rate, and personal vulnerability. An integrative model is described and its applicability to models of adjustment to work-related disability is argued. PMID- 24469868 TI - Baroreceptor sensitivity and diabetes mellitus. AB - Diabetes mellitus (DM) is a disease of increasing incidence and prevalence. Arterial baroreceptors are stretch-sensitive receptors, which in a reflex manner are involved in the homeostatic control of arterial blood pressure. Diabetic subjects have depressed baroreflex sensitivity (BRS), although the exact pathomechanisms are unclear. In this review, we discuss the features, clinicaland prognostic implications of reduced BRS for diabetic patients and the potential involvement of cardiovascular autonomic neuropathy and atherosclerosis. Finally, we demonstrate evidence on interventions (e.g. pioglitazone, alpha-lipoic acid, leptin, fluvastatin, physicaltraining etc.) which could improve BRS and ameliorate cardiovascular autonomic dysfunction in diabetic patients. PMID- 24469869 TI - The co-application of hypoxic preconditioning and postconditioning abolishes their own protective effect on systolic function in human myocardium. AB - BACKGROUND: Ischemic preconditioning (IPC) and postconditioning (POC) are well documented to trigger cardioprotection against ischemia/reperfusion (I/R) injury, but the effect oftheir both co-application remains unclear in human heart. The present study sought to assessthe co-application of IPC and POC on fragments of human myocardium in vitro. METHODS: Muscular trabeculae of the human right atrial were electrically driven in the organbath and subjected to simulated I/R injury - hypoxia/re-oxygenation injury in vitro. To achieveIPC of trabeculae the single brief hypoxia period preceded the applied lethal hypoxia, and to achieve POC triple brief hypoxia periods followed the lethal hypoxia. Additional muscular trabeculae were exposed only to the hypoxic stimulation (Control) or were subjected to the non-hypoxic stimulation (Sham). 10 MUM norepinephrine (NE) application ended every experiment to assess viability of trabeculae. The contraction force of the myocardium assessed as a maximal amplitude of systolic peak (%Amax) was obtained during the whole experiment's period. RESULTS: Co application of IPC and POC resulted in decrease in %Amax during the re oxygentaionperiod and after NE application, as compared to Control (30.35 +/- 2.25 vs. 41.89 +/- 2.25, 56.26 +/- 7.73 vs. 65.98 +/- 5.39, respectively). This was in contrary to the effects observed when IPC and POC were applied separately. CONCLUSIONS: The co-application of IPC and POC abolishes the cardioprotection of either intervention alone against simulated I/R injury in fragments of the human right heart atria. PMID- 24469870 TI - N-3 polyunsaturated fatty acids do not influence the efficacy of dual antiplatelet therapy in stable angina pectoris patients after percutaneous coronary intervention. AB - BACKGROUND: We aimed to prospectively assess the influence of the recommended dose, 1.0 g of polyunsaturated fatty acids (N-3 PUFA) daily, on platelet reactivity in patients with stable angina pectoris (SAP) after elective percutaneous coronary intervention (PCI). METHODS: Forty consecutive patients with SAP and successful PCI were randomized to the study group (group PUFA: n = 20; age 65 +/- 8; standard therapy + 75 mg acetylsalicylic acid + 75 mgclopidogrel + N-3 PUFA/Omacor 1 g daily) and the control group (group C: n = 20; age 65 +/- 9; standard therapy + 75 mg acetylsalicylic acid + 75 mg clopidogrel). Platelet reactivity tests (COL, TRAP, ASPI, ADP) were performed using whole blood aggregometry (multiplate platelet [PLT] function analysis) on the 2,nd and 30th day after PCI. RESULTS: Baseline patients' characteristics and clinical outcomes were comparable between the groups. There were no differences between both groups in the mean values of the PTL tests measured 30 days after PCI (PUFA vs. C ASPI: 18.5 +/- 17 vs. 27 +/- 29 U, COL: 30.4 +/- 14.3 vs. 30.3 +/ 13.4 U, ADP: 25.4 +/- 16.1 vs. 20 +/- 10.7 U, TRAP: 65.8 +/- 25.6 vs. 57.1 +/- 20.4 U, p = NS). The mean delta values of the PTL tests (18-24 h post-PCI/30 days post-PCI) were also comparable between the groups. The PTL aggregometry results were related to time - the baseline values of the ADP (p = 0.003), COL (p = 0.037) and TRAP (p < 0.001) tests were smaller and the ASPI (p = 0.027) test was higher than those measured after 1-month. CONCLUSIONS: N-3 PUFA supplementation does not affect the efficacy of dual antiplatelettherapy in patients with SAP after PCI. PMID- 24469871 TI - Efficacy and tolerability of dronedarone for patients with atrial fibrillation. AB - BACKGROUND: Dronedarone is a new antiarrhythmic drug used in the treatment of atrial fibrillation (AF). We investigate its efficacy and tolerability in clinical practice. METHODS: We identified 208 patients treated with dronedarone for AF at the Northwestern outpatient practice. Charts were reviewed for clinical efficacy and reasons for discontinuation of the drug. RESULTS: The average age was 65.2 +/- 10.8 years, 37% females. Paroxysmal, persistent andpermanent AF were noted in 46.2%, 51.9%, and 1.9%, respectively. Average ejection fraction was 56.3 +/- 9.1%, 12.8% had a history of congestive heart failure, and 10.3% had valvularheart disease. Dronedarone was discontinued in 25 patients after curative catheter or surgical ablation procedure. Of the remaining 183 patients, dronedarone was discontinued in 48.6% after a mean duration of 6.2 +/- 6.3 months because of in efficacy (26.2%), side effects (6%), and other reasons (16.4%). For those remaining on dronedarone (n = 94), after a mean of 11.6 +/- 6.6 months, clinical efficacy (resolution of or patient-reported improvement in symptoms) was noted in 45.4% patients. On dronedarone therapy, 57.4% had no AF on follow-up (overallefficacy of 29.5%). To evaluate efficacy, ECG only or long-term monitoring were performed in 62.7% and 37.3%, respectively, and found no AF in 69.2 and 48.4%, respectively. There were 3 deaths and 2 transient ischemic attacks (TIA) off dronedarone vs. 1 death, 1 TIA and 2 strokes on dronedarone. CONCLUSIONS: Dronedarone has a significant discontinuation rate due to both inefficacy and side effects in clinical practice. Nevertheless, it has moderate clinical efficacy and tolerability in an outpatient population of patients with AF. PMID- 24469872 TI - Prognostic value of platelet indices after acute myocardial infarction treated with primary percutaneous coronary intervention. AB - BACKGROUND: Mean platelet volume (MPV) is a strong predictor of impaired angiographic reperfusion and 6-month mortality in ST-elevation myocardial infarction (MI) treated with primary percutaneous coronary intervention (PCI). No data is available for other platelet volume indices: platelet distribution width (PDW) and platelet large cell ratio (P-LCR). The aim was to assess the impact of 3 platelet volume indices on long-term prognosis in patients treated with primary PCI in acute MI. METHODS: This prospective study enrolled 538 patients who underwent primary PCI in acute MI. Admission blood samples were measured for MPV, PDW, and P-LCR. The patients were followed-up a mean period of 26 +/- 11 months with regard to cardiac death, non-fatal reinfarction, re-PCI or coronary artery bypass grafting. RESULTS: Kaplan-Meier survival analysis showed a significantly higher 26-month mortalityrate in patients with high MPV (>= 11.7 fL) than in those with low MPV (< 11.7 fL) (14.6% vs. 5.5%, p = 0.0008). Similar findings were related to high P-LCR (>= 38.1%) vs. low P-LCR (< 38.1%) - mortality 13.8% vs. 5.8%, p = 0.0025. Higher PDW values (>= 16 fL) correlated with higher mortality rate as compared to PDW < 16 fL (17.4% vs. 6.3%, p = 0.0012). PDW was found to be an independent prognostic factor for cardiac mortality and composite endpoint. CONCLUSIONS: Mean platelet volume, platelet distribution width and platelet large cell ratio measured on admission are strong, independent prognostic factors in PCI-treated acute MI. PMID- 24469873 TI - Predictors of short- and mid-term recurrence of atrial fibrillation after surgical radiofrequency ablation: a six-month transtelephonic electrocardiogram monitoring study. AB - BACKGROUND: Occurrence of symptomatic, paroxysmal or persistent atrial fibrillation (AF) prior to admission to hospital for the purposes of cardiac surgery constitutes an indication forconsideration of simultaneous surgical radiofrequency (RF) ablation of such tachyarrhythmia. The aim of this study was to evaluate the efficacy of surgical RF ablation in the treatment of AF with the application of ECG teletransmission in monitoring patients during a 6-month follow-up period. Furthermore, clinical and echocardiographic risk factors for arrhythmia recurrences were subject to analysis. As per authors' knowledge and literature review, so far no papers devoted to the assessment of efficacy of surgical RF ablation with the use of systematic ECG teletransmission have been published. METHODS: The study enrolled 61 patients (20 females) suffering from AF who underwent cardiac surgeries and were additionally subject to surgical RF ablation. The mean age of the subjects was 64 +/- 9 years. Efficacy of the procedure was monitored with the application of a system enabling transtelephonic transmission of ECG signal. The study cohort was monitored in the period of 6 months. 2198 ECG recordings were obtained for analysis. RESULTS: In the post hospital follow-up period, no recurrences of AF were observed in the case of 40 (65%) subjects. Post-hospital failure of the surgical RF ablation procedure was associated with an early episode of AF during hospitalization (p = 0.0012), application of monopolar electrode (p = 0.0325) as well as with the surgical procedure performed to treat mitral stenosis (p = 0.0268). CONCLUSIONS: Moreover, it was observed that the group of patients without arrhythmia recurrence in the follow-up period was more frequently administered with antiarrhythmic medications (p = 0.0409) and statin (p = 0.0453) prior to the ablation procedure, with statin being more often applied after the procedure (tendency, p = 0.0747). As opposed to ablation in one atrium, biatrial ablation did not result in fewer late arrhythmia recurrences. PMID- 24469874 TI - Hyponatremia as predictor of worse outcome in real world patients admitted with acute heart failure. AB - BACKGROUND: Our aim was to determine if hyponatremia, defined as serum sodium level < 135 mmol/L, is a predictor of worse outcome in a cohort of real-world patients with heartfailure (HF). METHODS: We used data of the National registry of HF (RICA) from Spain, an ongoing multicenter, prospective cohort study. The patients were assigned to two groups regarding sodium levels. Primary end-point was first all-cause readmission, or death by any cause. Secondary end-points were the number of days hospitalized, and the presence of complications. RESULTS: We identified 973 patients, 147 (15.11%) with hyponatremia. The median age of patients enrolled was 77.25 +/- 8.79 years-old, the global comorbidity measured by Charlson comorbidity index (CCI) was upper 3 points and preserved ejection fraction was present in67.1% of them. Clinical complications during admission were significantly higher in the patients with hyponatremia (35.41%, p < 0.001) and this remained as significant predictor after logistic regression adjustment (OR 1.08, p < 0.01). Also mortality and readmissions were more frequent in patients with hyponatremia (20.69% and 22.41%, respectively) but after Cox regression adjustment hyponatremia in our cohort was not associated with increase in 90-day all-cause mortality and readmissions, and only CCI remained significant for primaryend-point (HR 1.08, p < 0.001). CONCLUSIONS: Hyponatremia is an independent predictor of complications during hospitalization in our real-world cohort, but was not associated with 90 days mortality or readmissions. Global comorbidity, however, played an important role, and could influence the mortality and readmissions of our patients. PMID- 24469875 TI - Effect of age and sex on echocardiographic left ventricular diastolic function parameters in patients with preserved ejection fraction and normal valvular function. AB - BACKGROUND: We conducted a retrospective study to specify the effect of age and gender on echocardiographic left ventricular diastolic function parameters. METHODS: We included echocardiograms done in our institution between 1995 and 2007, for which data on diastolic function were available. In order to target a population as close aspossible to healthy subjects, echocardiograms reporting abnormal contraction, valvulopathy or extreme data were excluded. RESULTS: A total of 14,298 patients (mean age 58.53 years; men 49.1%) were included in the study. Sex did not influence E/A ratio (p = 0.298) but age decreased it significantly (p < 0.001). E/e ratio increased significantly with age (p < 0.001) and was higher in women than in men (p < 0.001). After the age of 40, more than 10% of the patients had an E/e ratio superior than 8. CONCLUSIONS: To our knowledge, this is the most imposing study - in terms of number of patients from first to tenth decade of life that were included - addressing the effect of age and gender on diastolic function. Our results stress the need for future prospective trials to establishnormal diastolic function parameters according to age and gender, notably for the E/e ratio for which a significant proportion of our population had a ratio superior of what is actually considered normal. PMID- 24469876 TI - Early left ventricular functional alterations in patients with obstructive sleep apnea syndrome. AB - BACKGROUND: The knowledge regarding myocardial alterations in patients with obstructive sleep apnea syndrome (OSAS) in the absence of any known cardiovascular disorders including hypertension is limited. The aim of this study was to assess the early alterations of left ventricular (LV) functions caused by OSAS before the development of hypertension and other cardiovascular manifestations of OSAS. METHODS: Eighty consecutive patients who underwent polysomnography (PSG) were enrolled in the study. Patients with hypertension, diabetes mellitus or any other known cardiac diseases were excluded from the study. Subjects were separated into two groups by their apnea/hypopnea index (AHI) (group 1: AHI < 15, and group 2: AHI >= 15). Fourty-three patients with normal polysomnographic examination or mild OSAS (group 1) and 37 patients with moderate to severe OSAS (group 2) were compared. After PSG examination, LV functions were assessed by using the conventional and tissue Doppler echocardiographic methods. RESULTS: The mean age was similar between the groups. The ratio of male patients was higher in group 2 (male/female: 31/12 in group 1 vs. 34/3 in group 2, p = 0.04). Body mass index was higher in group 2 (p = 0.05). Conventional echocardiography showed that interventricular septum thickness was 9.5 +/- 1.1 mm in group 1, and 10.5 +/- 1.4 mm in group 2 (p = 0.02). Mean left atrial diameter was 35.6 +/- 4.1 mm in group 2, and 33.8 +/- 3.1 mm in group 1 (p = 0.04). Ratio of early to late transmitral diastolic velocities was lower in group 2 (p = 0.01), indicating that impairment of diastolic function was more frequent in moderate to severe OSAS patients. Tissue Doppler echocardiography showed that early diastolic myocardial velocity was lower ingroup 2 (21.1 +/- 5.6 cm/s in group 1 vs. 18.3 +/- 5.3 cm/s in group 2, p = 0.01). CONCLUSIONS: Left ventricular diastolic dysfunction, LV hypertrophy and left atrial dilatationoccur in patients with OSAS even before the development of hypertension and other cardiovascular diseases. PMID- 24469878 TI - Association between R353Q polymorphism for coagulative factor VII and severity of coronary artery disease in Iranian population. AB - BACKGROUND: Recent research has supported the central role of coagulative factors in advancing atherosclerosis and causing coronary artery disease (CAD). The present study, for the first time, aimed to clarify the relationship between R353Q polymorphism for factor VII and the occurrence and severity of CAD in a large sample of Iranian population. METHODS: Nine hundred and nineteen consecutive patients with suspected CAD, who candidated for coronary angiography in the Tehran Heart Center between January 2006 and March 2007, were examined. The number of diseased coronary vessels was determined, and the severity of CAD was assessed by the Gensini score. Genotyping was done via the PCR-RFLP method. RESULTS: The frequency of Q and R alleles was 74.1% and 25.9% in the patients with CADand 75.2% and 24.8% in those without CAD, with an insignificant difference (p = 0.625). The frequency of Q allele in the patients with single vessel, two-vessel, and three-vessel diseases was 72.8%, 71.5%, and 76.4%, respectively; the difference was also insignificant (p = 0.379). No relationship was observed between the distribution of the genotypes and the number of the involved coronary vessels. The average of the Gensini score was 43.39 +/- 46.18 in the patients with QQ genotype, 38.87 +/- 42.89 in those with QR genotype, and 55.61 +/- 53.80 in the ones with RR genotype, with the difference not constituting any statistical significance (p = 0.084). CONCLUSIONS: The results suggest no association between R353Q polymorphism for factor VII and the presence or progression of CAD in the Iranian population. PMID- 24469877 TI - Does gender influence the impact of impaired renal function on prognosis after ST segment elevated myocardial infarction? AB - BACKGROUND: A limited number of studies have investigated the impact of gender on renal function and clinical outcomes after ST-segment elevated myocardial infarction (STEMI), and these studies have provided discrepant results. METHODS AND RESULTS: This study was based on a retrospective cohort, the Korean Acute Myocardial Infarction Registry (KAMIR). Patients (n = 7,679) with a discharge diagnosis of STEMI were analyzed to investigate association of gender with renal function and clinical outcomes. Compared to men, women were older and exhibited more comorbidity, including impaired renal function. Women showed higher mortality compared to men (1-month mortality,5.6% in men vs. 12.6% in women, p < 0.001; 1-year mortality, 6.8% in men vs. 14.4% in women, p < 0.001). The risk of death proportionally increased as estimated glomerular filtration rate (eGFR) decreased in both genders. After adjusting for potential confounders, hazard ratios for women did not significantly differ from those for men at each eGFR level.The interaction test showed no significant interaction between gender and eGFR in 1-month mortality and 1-year mortality. CONCLUSIONS: Impaired renal function was an independent prognostic factor after STEMI in both genders, and the impact of impaired renal function on prognosis after STEMI did not significantly differ between genders. PMID- 24469879 TI - Holter monitoring, sinoatrial conduction time, prognosis. AB - BACKGROUND: To evaluate the usefulness of the Holter method of sinoatrial conduction time (SACT) calculation in predicting the future occurrence of sinus node disease, and the emergence of indications for permanent pacing in patients with unexplained syncope. METHODS: The study group included 218 patients (mean age 55 +/- 17 years, 116 men) with syncope of unknown etiology in whom spontaneous atrial premature depolarizations (APDs) occurred during Holter monitoring and SACT could be calculated. A SACT value during daily activity > 150 ms was assumed as abnormal. RESULTS: The prospective observation time was 48 +/- 11 months. During follow-up sinus node disease was diagnosed in 22 persons, including 18 patients with baseline SACT > 150 ms and 4 with SACT < 150 ms. Indications for pacemaker implantation were found in 16 patients, including 13 patients with baseline SACT > 150 ms and 3 with SACT < 150 ms. In subjects with and without sinus node disease diagnosed during the observation period, baseline SACTvalues were 175 +/- 52 ms and 87 +/- 34 ms, respectively (p < 0.01), and in patients qualified and not qualified for permanent pacing, the respective values were 178 +/- 59 ms and 81 +/- 38 ms(p < 0.01). Multivariate Cox analysis showed a significant relationship between baseline SACT > 150 ms and a future diagnosis of sinus node disease and pacemaker implantation. CONCLUSIONS: The results suggest that the Holter method of SACT calculation is useful in predicting sinus node disease and indications for permanent pacing in patients with unexplained syncope. PMID- 24469880 TI - Effect of ASA dose doubling versus switching to clopidogrel on plasma inflammatory markers concentration in patients with type 2 diabetes and high platelet reactivity: the AVOCADO study. AB - BACKGROUND: The aim of the study was to compare the effects of 2 strategies of antiplatelet treatment (i.e., 150 mg ASA vs. 75 mg clpoidogrel) on plasma level of inflammatory markers in type 2 diabetes mellitus (T2DM) patients with high platelet reactivity (HPR). METHODS: Study cohort consisted of 304 T2DM patients on chronic ASA therapy (75 mg per day) participating in the Aspirin Versus/Or Clopidogrel in Aspirin-resistant Diabetics inflammation Outcomes (AVOCADO) study. Patients with HPR defined as Platelet Function Analyzer (PFA)-100 collagene/epinephrine closure time (CEPI-CT) < 193 s (n = 80) were randomized to 150 mg of ASA or 75 mg of clopidogrel in 2:3 ratio, respectively. Concentrations of the selected inflammatory markers, including tumor necrosis factor (TNF) alpha, interleukin (IL)-6, solubleCD40 ligand (sCD40L), and high sensitivity C reactive protein (hsCRP), were measured and compared in both treatment groups before and after 8 weeks of treatment in both groups. RESULTS: Out of 234 patients included into final analysis, the total of 34.2% (n = 80) patients displayed HPR, of which 14.1% (n = 33) were randomized into 150 mg of ASA group and 20.1% (n = 47) into 75 mg of clopidogrel group. Treatment with clopidogrel was a positive predictor (stepwise multiple regression analysis) of reduction of sCD40L concentration (odds ratio [OR] 4.15; p = 0.013), while treatment with 150 mg ASA was a positive predictor of reduction of IL-6 concentration (OR 4.38; p = 0.033). There was no statistically significant differences between clopidogrel and ASA 150 mg treatment in respect to predictive value for decreased hsCRP concentrations or increased TNF-alpha concentrations. CONCLUSIONS: Increasing the dose of ASA from 75 mg to 150 mg daily or switching ASA 75 mg to clopidogrel 75 mg daily may reduce concentrations of some inflammatory markers (in particular hsCRP, IL-6 and CD40L) in T2DM patients with HPR treated previously with 75 mg of ASA. PMID- 24469881 TI - Beyond conventional pathology: towards preoperative and intraoperative lymph node staging. AB - Accurate detection of lymph node metastases is critical for many solid tumours to guide treatment strategies and determine prognostic outcomes. The gold standard for detection of metastasis is by histological analysis of formalin-fixed paraffin-embedded (FFPE) sections of removed lymph nodes; this analysis method has remained largely unchanged for decades. Recent studies have highlighted limitations in the sensitivity of this approach, at least in its current clinical use, to detect very small metastatic deposits. Importantly, the poor prognostic outcomes associated with the presence of such small tumour deposits are now well established in a number of cancers. In addition, histological analysis of FFPE sections cannot be used practically for intraoperative node assessment. Novel lymph node staging technologies are therefore actively being developed. This review critically presents the main advances in this field and discusses why these technologies have not been able to provide a better alternative to the current gold standard diagnostic technique. PMID- 24469882 TI - Pressure-induced superconductivity and its scaling with doping-induced superconductivity in the iron pnictide with skutterudite intermediary layers. AB - Pressure-induced superconductivity is oberserved in Ca10 (Pt3 As8 )(Fe2 As2 )5 by in situ high-pressure resistance and magnetic susceptibility measurements. Scaling of the pressure-induced and doping-induced superconductivity shows that the electronic phase diagrams of the pressurized and chemically doped 10-3-8 compound are similar in the moderate pressure and doping range but are disparate at higher pressure and heavy doping. PMID- 24469883 TI - Dural tears in primary decompressive lumbar surgery. Is primary repair necessary for a good outcome? AB - STUDY DESIGN: Case control series with prospective data collection. OBJECTIVE: To establish whether incidental durotomy treated without primary suture repair adversely affects the outcome following lumbar surgery in the longer term. METHOD: Outcome scores from a prospective database were used for an audit of dural tears in primary lumbar decompressive surgery. Outcome data collected includes the Short Form 36 General Health Questionnaire (SF36), the Oswestry Disability Index (ODI) and Visual Analogue Scores for leg pain (VAL) and back pain (VAB). RESULTS: Out of 200 consecutive procedures, a dural tear occurred in 19 (9.5%) patients. Of 19 patients with a dural tear, data was incomplete in 4 patients, and 1 further patient who had their dural tear sutured was excluded, leaving 14 patients to be studied. There were seven males and seven females, with an average age of 50.8 years (31-69). These 14 patients (group 1) were compared to a matched group (age, sex, surgical diagnosis and duration of follow-up) of 14 patients (group 2) with no tear. Both groups had similar pre-operative scores. At 6-month follow-up, both groups had significant improvements in all outcomes measures except for the general health domain of the SF-36. At final follow-up, patients with dural tears appeared to have better improvements in outcome measures amongst the VAB, VAL and ODI with similar scores in the SF-36 domains. CONCLUSION: Our study demonstrates that incidental durotomy in primary lumbar decompressive surgery can be successfully managed without primary suture repair with no adverse effect on surgical outcome in the longer term. PMID- 24469884 TI - Combined spinal arthrodesis with instrumentation for the management of progressive thoracolumbar kyphosis in children with mucopolysaccharidosis. AB - PURPOSE: To evaluate the outcome and complications of a novel technique for the treatment of progressive thoracolumbar kyphosis in children with mucopolysaccharidosis (MPS). METHODS: The medical records and spinal imaging of four consecutive paediatric patients who underwent a single stage anteroposterior spinal fusion with segmental pedicle screw instrumentation were reviewed. RESULTS: Patients underwent spinal deformity correction at the mean age of 3 years (2.4-3.7) with mean clinical follow-up of 3.2 years (2.1-4.5) and mean postoperative radiographic follow-up was 2.4 years (0.8-3). Preoperative kyphosis was corrected from a mean angle of 65o (63o-70o) to 6.5o (-12o-13o). Vertebral subluxation at the apex of the deformity was corrected from an average 64% (56 83%) to 12% (0-24%). Spinal cord monitoring with somatosensory evoked potentials (SSEP) was successfully obtained and stable throughout surgery. No instrumentation failure, loss of correction or junctional problems occurred at final follow-up. CONCLUSIONS: Anterior and posterior spinal arthrodesis with segmental pedicle screw instrumentation is a safety and reliable technique for the treatment of severe thoracolumbar kyphosis in children with MPS. This technique achieves excellent correction of the deformity with adequate decompression of the spinal canal. The fusion is limited to the thoracolumbar junction and interferes minimally with the longitudinal growth of the thorax. No neurological complications or intraoperative spinal cord monitoring events occurred. No loss of correction or junctional kyphosis was observed. PMID- 24469885 TI - Spine MR imaging features of subacute combined degeneration patients. AB - BACKGROUND AND PURPOSE: Subacute combined degeneration (SCD) is a potentially reversible neurological complication of a vitamin B12 deficiency; therefore, timely diagnosis and appropriate treatment are of great importance. The study was to evaluate the spine MR imaging features of SCD in a series of patients. MATERIALS AND METHODS: Eight patients diagnosed with SCD from 2008 to 2010 comprised the study population. Spine MRIs were available for all eight patients, and three of them had follow-up MRIs after vitamin B12 treatment. Two radiologists evaluated the prevalence of signal intensity abnormality of spinal cord and analyzed the distribution and pattern of the signal change in consensus. And they also evaluated post-treatment MRI to find interval change. RESULTS: Seven of eight patients showed abnormal hyperintensity within posterior aspect of spinal cord on T2-weighted images. The spinal cord abnormalities were seen at cervical spine in five patients (62.5 %) and at thoracic spine in the other two patients (25 %). For patients with cervical spinal cord abnormalities, axial T2 weighted images showed symmetric linear T2-hyperintensity as an "inverted V" at cervical spinal cord. For patients with thoracic spinal cord abnormalities, the abnormal signal intensity looked bilateral paired nodular T2-hyperintensity as "dumbbell" or "binoculars" at thoracic spinal cord. Follow-up MRIs after vitamin B12 treatment showed interval resolution of the areas of abnormal T2 hyperintensity in all. CONCLUSION: Symmetric T2-hyperintensity within dorsal column of spinal cord is commonly seen in SCD patients with a linear pattern in the cervical spine and a nodular pattern in the thoracic spine. PMID- 24469886 TI - "En bloc" resection of sacral chordomas by combined anterior and posterior surgical approach: a monocentric retrospective review about 29 cases. AB - PURPOSE: "En bloc" resection of sacral chordomas (SC) with wide margins is statistically linked with a decrease of local recurrence (LR). Nevertheless, surgery potentially leads to complications and neurological deficits. The effectiveness of radiotherapy (RT) and chemotherapy (CT) remains controversial. The aim of the study was to evaluate the margins of tumor resection, the morbidity of "En bloc" resection of SC by combined anterior and posterior surgical approach and to look for predictive factors on survival and LR. METHODS: We performed sacrococcygectomy by surgical combined approach in 29 SC between 1985 and 2012. We analyzed overall survival and survival to LR with survival analysis using Kaplan-Meier method. Complications and morbidity were reported. RESULTS: The mean follow-up was of 77.9 months (0-241 months). We found 18 (62.1%) postoperative infections and 7 (24.1%) wound dehiscences. Eighteen patients had tumor wide margins (62.1%), 6 marginal (20.7%) and 4 intralesional (13.8%). Seven patients had a LR (24.1%). OS rate was 84.4% at 5 and 10 years, survival rate with LR was 64 and 56%, respectively, after 5 and 10 years. Quality of margins (p = 0.106), tumor volume (p = 0.103), postoperative RT (p = 0.245) and postoperative local infection (p = 0.754) did not have effect on LR. CONCLUSION: "En bloc" resection by combined surgical approach seems to be a relevant alternative especially for SC invading the high sacrum above S3. Nevertheless, it yet remains the problem of postoperative infection. Systematic Adjuvant RT might allow better control on LR in association with surgery. PMID- 24469888 TI - "Shaken baby syndrome" and forensic pathology. PMID- 24469887 TI - Platelet-rich plasma induces annulus fibrosus cell proliferation and matrix production. AB - PURPOSE: Platelet-rich plasma (PRP) contains growth factors and creates a 3D structure upon clotting; PRP or platelet lysate (PL) might be considered for annulus fibrosus (AF) repair. METHODS: Bovine AF cells were cultured with 25% PRP, 50% PRP, 25% PL, 50% PL, or 10% FBS. After 2 and 4 days, DNA, glycosaminoglycan (GAG), and mRNA levels were analyzed. Histology was performed after injection of PRP into an AF defect in a whole disc ex vivo. RESULTS: By day 4, significant increases in DNA content were observed in all treatment groups. All groups also showed elevated GAG synthesis, with highest amounts at 50% PL. Collagen I and II expression was similar between groups; aggrecan, decorin, and versican expression was highest at 25% PL. Injection of PRP into the AF defect resulted in an increased matrix synthesis. CONCLUSIONS: Platelet-rich preparations increased the matrix production and cell number and may therefore be considered to promote AF repair. PMID- 24469889 TI - The pathological features of Wernicke encephalopathy. PMID- 24469891 TI - Experimental control of the activity of the quiescent centre in excised root tips of Zea mays. AB - Quiescent centres have been demonstrated in cultured excised root tips of both Pisum sativum and Zea mays. Upon addition of sucrose to Zea roots which have been deprived of carbohydrate, the cells of the quiescent zone as well as those of the rest of the meristem undergo DNA synthesis. Following the onset of proliferative activity in the meristem, DNA synthesis in the quiescent-centre cells is again arrested. It is suggested that the dividing cells of the meristem are responsible for the maintenance of the quiescent centre. It has also been shown that DNA synthesising cells do occur within the quiescent centre and that they appear to be localised in specific regions. PMID- 24469890 TI - Plasma irisin levels predict telomere length in healthy adults. AB - The ageing process is strongly influenced by nutrient balance, such that modest calorie restriction (CR) extends lifespan in mammals. Irisin, a newly described hormone released from skeletal muscles after exercise, may induce CR-like effects by increasing adipose tissue energy expenditure. Using telomere length as a marker of ageing, this study investigates associations between body composition, plasma irisin levels and peripheral blood mononuclear cell telomere length in healthy, non-obese individuals. Segmental body composition (by bioimpedance), telomere length and plasma irisin levels were assessed in 81 healthy individuals (age 43 +/- 15.8 years, BMI 24.3 +/- 2.9 kg/m(2)). Data showed significant correlations between log-transformed relative telomere length and the following: age (p < 0.001), height (p = 0.045), total body fat percentage (p = 0.031), abdominal fat percentage (p = 0.038), visceral fat level (p < 0.001), plasma leptin (p = 0.029) and plasma irisin (p = 0.011), respectively. Multiple regression analysis using backward elimination revealed that relative telomere length can be predicted by age (b = -0.00735, p = 0.001) and plasma irisin levels (b = 0.04527, p = 0.021). These data support the view that irisin may have a role in the modulation of both energy balance and the ageing process. PMID- 24469892 TI - [The effects of the cytostatic drug "proresid" on growth and chloroplast differentiation induced by blue light in excised and normal seedling roots of Pisum sativum]. AB - "Proresid" (podophyllic acid ethylhydrazide; SP-1, Sandoz), a cytostatic drug with rapid but reversible effects on mitosis, inhibits growth, fresh weight increase and chlorophyll synthesis in excised roots of pea seedlings (var. Alaska) cultured in blue light (350-550 nm). Upon transferal of the treated fragments to normal culture medium the activity of these processes is fully restored within a few days. The reactions of intact seedlings on exposure of only the root tip to Proresid indicate that the drug exerts its action indirectly by blocking certain activities of the apical meristem. The important role of the latter in supporting or inhibiting various processes in the root is demonstrated by the observation that removal of the root tip from excised roots reduced the chloroplast differentiation in blue light to a very low yield, but induced cell divisions and lateral root formation. Moreover, there is good evidence that the drug is not actively transported in the root when supplied to the root tip only. Exposure of the whole root of a seedling to Proresid for longer periods does not only prevent its growth and differentiation but also gives rise to the formation of adventitious roots in the epicotyl region of the shoot. PMID- 24469893 TI - The simultaneous movement of two ions in the phloem of the Saxifraga stolon. AB - Paris of tracers were applied simultaneously to the long thin stolons of Saxifraga sarmentosa. After several hours of translocation the very precise pattern of exponential fall-off was examined and interpreted in the light of a model of mass flow with leakage. (42)K appears to leak faster than (22)Na; (86)Rb is very close to (42)K. The anion (82)Br shows a lower fall-off than (137)Cs; this is tentatively regarded as due to a much-reduced leakage, though it might imply a higher velocity. The implications of these findings for sieve-tube mechanism are uncertain. PMID- 24469894 TI - Longitudinal distribution of growth substances in leaves of wheat (Triticum aestivum L.). AB - The basal fifth of the lamina, containing most of the gibberellin of young leaves, was the only part of the lamina that elongated. When the base of the lamina stopped elongating the gibberellin apparently moved up the lamina, but the leaf sheath still contained some gibberellin and continued to elongate. Old, fully elongated, leaves contained most auxin and tryptophan in the apical fifth of the lamina that was dying; young leaves contained insignificant amounts of auxin. Leaves contained two cytokinins; generally most cytokinin activity occurred in the apical fifth of leaves. Cytokinin activity was also detected in guttation drops and in ethanolic washings from leaf tips. PMID- 24469895 TI - [Compartmentation and properties of the MDH-isoenzymes from watermelon cotyledons (Citrullus vulgaris Schrad.)]. AB - Five MDH-isoenzymes (I-V) from cotyledons of dark-grown water-melon seedlings older than 2 days can be identified by disc-electrophoresis. By isolating and fractionating cell organelles (10000 g fraction) by density gradient centrifugation (Fig. 1) the following compartmentation of the MDH-isoenzymes can be shown: the mitochondria contain isoenzyme III and the glyoxysomes preponderantly (if not exclusive) isoenzyme V (Fig. 2), whereas the isoenzymes I, II, and IV belong to the cytosol.The 5 MDH-isoenzymes differ in several properties, e.g. differential precipitation by ammonium sulfate (Fig. 4) or isoelectric point (Fig. 5). The glyoxysomal MDH is a relatively basic protein (isoelectric point at pH 8.7), whereas the isoelectric points of the other isoenzymes lie between pH 6.4 (IV) and pH 4.7 (I). PMID- 24469896 TI - Acid phosphatase and esterase activity in orchid mycorrhiza. AB - A cytochemical study was made to examine the possibility that acid phosphatase may be specifically involved in the digestion of endophytic hyphae in orchid mycorrhiza. Esterase activity was studied for comparison. Frozen sections of unfixed or glutaraldehyde-fixed protocorms of Dactylorhiza purpurella infected by Thanatephorus cucumeris (Rhizoctonia solani) were reacted for acid naphthol AS BI phosphatase, acid beta-glycerophosphatase or naphthol AS D esterase.A marked increase in particulate acid naphthol AS BI phosphatase activity was observed during infection of host, central, parenchyma cells shortly before hyphae lysed; a diffuse reaction of high activity was localised on lysed fungus. Acid beta glycerophosphatase was present at particulate sites only in fungal cytoplasm and as a diffuse reaction on lysed fungus.Naphthol AS D esterase showed highest activity at hyphal apices. Esterase seems to be associated with growth and differentiation of hyphae in orchid cells, rather than lysis of the fungus. PMID- 24469897 TI - The kinetics of calcium uptake by roots. AB - The time course of the uptake of labelled calcium by roots of Hordeum vulgare L., Trifolium subterraneum L., and Phaseolus aureus Roxb. was found to have two distinct phases: an initial rapid adsorption phase of about 1 h duration (Phase I) and a slower accumulation which proceeded at a constant rate for at least 12 h (Phase II). Ions taken up by the mechanism of Phase I, but not Phase II, could be removed by rinsing the roots in cold solutions of unlabelled CaCl2 or KCl.The concentration dependence of calcium uptake by barley roots over the range 0.001 to 10.0 mN was analysed with the aid of Hofstee plots. Phase I consisted of two Donnan adsorption processes. The half-saturation concentrations were 0.065 mN and 0.002 mN and the respective capacities were 1.56 and 0.36 MUeq g(-1) (fresh weight). Phase II displayed Michaelis-Menten kinetics for a single mechanism with a Km=0.077 mN and V max=0.15 MUeq g(-1) (fresh weight) h(-1). PMID- 24469898 TI - Microautoradiographic investigations on bidirectional translocation in the phloem of Vicia faba. AB - Using radioactive phenylalanine as a tracer, bidirectional translocation in the phloem of a single stem bundle of Vicia faba L. was detected by analyses of microautoradiographs. Bidirectional translocation occurred in lateral leaf traces subtending a leaf of a certain developmental stage. Before and after this stage, translocation was unidirectional, either acropetal or basipetal, respectively. PMID- 24469899 TI - [Studies on the biosynthesis of a cytokinin in callus cells of moss sporophytes]. AB - When callus cells derived from the sporogon of the hybrid Funaria hygrometrica x Physcomitrium piriforme are supplied with adenine-8-(14)C, they produce a labelled cytokinin which has the same chromatographic behavior as N(6)-gammagamma (dimethylallyl)aminopurine. The cytokinin is the first radioactive product that can be detected in the culture medium. It is formed as long as labelled adenine is available. When callus cells are grown in an optimum culture medium containing amino acids, about 10% of the radioactivity supplied as adenine is found in the cytokinin. When the cells are grown in a medium without amino acids, the RNA content of the cells and the total yield of cytokinin decrease, but about 18% of the radioactivity is taken up into RNA as adenine and guanine, which are both degraded to allantoin and urea but not converted to cytokinin. Free guanine is converted neither to adenine nor to cytokinin.Weak cytokinin activity can be detected in hydrolysates of sRNA, but no radioactive cytokinin can be isolated from sRNA of adenine-labelled callus cells. it is assumed that free cytokinin is not a degradation product of tRNA. PMID- 24469900 TI - A simple transcriptomic signature able to predict drug-induced hepatic steatosis. AB - It is estimated that only a few marketed drugs are able to directly induce liver steatosis. However, many other drugs may exacerbate or precipitate fatty liver in the presence of other risk factors or in patients prone to non-alcoholic fatty liver disease. On the other hand, current in vitro tests for drug-induced steatosis in preclinical research are scarce and not very sensitive or reproducible. In the present study, we have investigated the effect of well characterized steatotic drugs on the expression profile of 47 transcription factors (TFs) in human hepatoma HepG2 cells and found that these drugs are able to up- and down-regulate a substantial number of these factors. Multivariate data analysis revealed a common TF signature for steatotic drugs, which consistently and significantly repressed FOXA1, HEX and SREBP1C in cultured cells. This signature was also observed in the livers of rats and in cultured human hepatocytes. Therefore, we selected these three TFs as predictive biomarkers for iatrogenic steatosis. With these biomarkers, a logistic regression analysis yielded a predictive model, which was able to correctly classify 92 % of drugs. The developed algorithm also predicted that ibuprofen, nifedipine and irinotecan are potential steatotic drugs, whereas troglitazone is not. In summary, this is a sensitive, specific and simple RT-PCR test that can be easily implemented in preclinical drug development to predict drug-induced steatosis. Our results also indicate that steatotic drugs affect expression of both common and specific subsets of TF and lipid metabolism genes, thus generating complex transcriptomic responses that cause or contribute to steatosis in hepatocytes. PMID- 24469901 TI - Fighting oil spills at sea and toxicology of complex mixtures. PMID- 24469902 TI - The association between the home environment and physical activity in community dwelling older adults. AB - Physical activity (PA) decreases with increasing age despite the fact that PA exerts beneficial effects on many age-related diseases and conditions. Consequently, there is an interest in modifiable factors that may influence PA among older persons. The purpose of this study was to examine the association between PA and the home environment in well-functioning older community-dwelling persons. METHOD: This study used a person-environment (P-E) fit perspective to the home environment, operationalized by means of assessment of functional limitations in 81 community-dwelling persons (median age 79 years) as well as environmental barriers in their home environments and the nearby exterior surroundings. The interaction between functional limitations and environmental barriers generated a score expressing the magnitude of P-E fit problems in their home environment. PA was rated with a questionnaire covering household-related and recreational activities. RESULTS: We found a significant association between PA and the magnitude of P-E fit problems that explained 3.9 % of the variance of PA. The number of environmental barriers per se was not significantly associated with PA, while functional limitations explained 6.8 % of the variance of PA. CONCLUSION: In well-functioning older persons living in the community environmental aspects of housing demonstrated a weak association with PA. PMID- 24469903 TI - Evaluation of the impact of 6-month training by whole body vibration on the risk of falls among nursing home residents, observed over a 12-month period: a single blind, randomized controlled trial. AB - BACKGROUND: We have previously shown that short sessions of whole body vibration (WBV) were not able to significantly improve fall risk among nursing home residents but some trends towards an improvement of motor capacity were observed. OBJECTIVE: The objective of the present study was to evaluate the impact of 6 month training by WBV on functional and motor abilities among nursing home residents observed over a 12-month period. METHODS: Patients were randomized into two groups: the WBV group which received three training sessions every week composed of five series of 15 s of vibration at 30 Hz intensity for a period of 6 months and a control group with normal daily life. The impact of this training on the risk of falls was assessed blindly after 6 and 12 months by the Tinetti Test, the "Timed Up and Go" test and a quantitative evaluation of a 10-s walk performed with a tri-axial accelerometer. The occurrence of falls was also observed. RESULTS: 62 elderly healthy volunteers, (47 women and 15 men, mean age 83.2 +/- 7.9 years) were included in this study. There was no significant difference between the two groups regarding the Tinetti test (p = 0.75), the "Timed Up and Go" test (p = 0.19) and the Locometrix((r)) test, except for the step length, measured by dual task (p < 0.01). No significant inter-group difference in the frequency of falls was observed during the 12 months of research. A total of 42 falls were recorded during the first 6 months of experimentation: 24 falls in the treated group and 18 in the control group (p = 0.60). During the next 6 months, 19 falls occurred: 8 falls in the treated group and 11 in the control group (p = 0.52). CONCLUSION: This study failed to establish the effectiveness of low doses of WBV, under the conditions used in our study, on functional and motor abilities of institutionalized elderly patients. However, given the positive results of other studies, further investigations, with modified therapeutic protocols, seem necessary to clarify the effects of WBV in the elderly. PMID- 24469904 TI - Exploring the Wnt pathway-associated LncRNAs and genes involved in pancreatic carcinogenesis driven by Tp53 mutation. AB - PURPOSE: Study the contribution of long non-coding RNAs (lncRNAs) to progression of pancreatic intraepithelial neoplasia (PanIN) to pancreatic ductal adenocarcinoma (PDAC). METHODS: We explored lncRNAs profilings in PanIN cell line (SH-PAN) isolated from Pdx-1-Cre; LSL-Kras (G12D/+) mice and PDAC cell line (DT PCa) isolated from Pdx-1-Cre; LSL- Kras (G12D/+) ; LSL- Tp53 (R172H/+) mice by lncRNAs microarray, and detected expression of lncRNAs and genes in PDAC by Real time PCR, Western blot, ChIP and immunohistochemistry. RESULTS: Eight lncRNAs and five protein-coding genes, associated with Wnt pathway, were identified with more than five-fold changes between DT-PCa cells and SH-PAN cells. Of them, lincRNA1611 and Ppp3ca were validated significantly high expression in DT-PCa cells and in 22 of 26 fresh resected human PDAC tissues, compared to SH-PAN cells and normal pancreatic tissues, respectively. Moreover, Tp53 mutation status displayed a positive correlation with lincRNA1611 or Ppp3ca level. Immunohistochemical staining for Ppp3ca was weak or lack in 91 of 107 normal pancreatic tissues, 24 of 29 PanIN-I and 13 of 16 PanIN-II tissues, however, was strong in 10 of 27 PanIN-III and 62 of 107 PDAC tissues post operation. CONCLUSIONS: LincRNA1611 and Ppp3ca were high expression in PDAC and may serve as new potential targets for intervention of the disease. PMID- 24469905 TI - Development of 2D and 3D mucus models and their interactions with mucus penetrating paclitaxel-loaded lipid nanocapsules. AB - PURPOSE: To study, diffusion through mucus (3D model) of different formulations of paclitaxel loaded lipid nanocapsules (Ptx-LNCs), to interpret the results in the light of LNC behavior at air-mucus interface (2D model). METHODS: LNC surface properties were modified with chitosan or poly(ethylene glycol) (PEG) coatings of different size (PEG 2,000 to 5,000 Da) and surface charges. LNC diffusion through 446 MUm pig intestinal mucus layer was studied using Transwell((r)). LNCs were spread at the air-water-mucus interface then interfacial pressure and area changes were monitored and the efficiency of triglyceride (TG) inclusion was determined. RESULTS: Ptx-LNCs of surface charges ranging from -35.7 to +25.3 mV were obtained with sizes between 56.2 and 75.1 nm. The diffusion of paclitaxel in mucus was improved after encapsulation in neutral or positively charged particles (p < 0.05 vs Taxol((r))). No significative difference was observed in the 2,000 5,000 PEG length for diffusion both on the 2D or 3D models. On 2D model positive or neutral LNCs interacted less with mucus. Highest efficiency of TG inclusion was observed for particles with smallest PEG length. CONCLUSIONS: The results obtained with 2D and 3D model allowed us to select the best candidates for in vivo studies (neutral or positive LNCs with smaller PEG length). PMID- 24469907 TI - Novel hollow microneedle technology for depth-controlled microinjection-mediated dermal vaccination: a study with polio vaccine in rats. AB - PURPOSE: The aim of the study was to develop a cheap and fast method to produce hollow microneedles and an applicator for injecting vaccines into the skin at a pre-defined depth and test the applicability of the system for dermal polio vaccination. METHODS: Hollow microneedles were produced by hydrofluoric acid etching of fused silica capillaries. An electromagnetic applicator was developed to control the insertion speed (1-3 m/s), depth (0-1,000 MUm), and angle (10 degrees -90 degrees ). Hollow microneedles with an inner diameter of 20 MUm were evaluated in ex vivo human skin and subsequently used to immunize rats with inactivated poliovirus vaccine (IPV) by an intradermal microinjection of 9 MUL at a depth of 300 MUm and an insertion speed of 1 m/s. Rat sera were tested for IPV specific IgG and virus-neutralizing antibodies. RESULTS: Microneedles produced from fused silica capillaries were successfully inserted into the skin to a chosen depth, without clogging or breakage of the needles. Intradermal microinjection of IPV induced immune responses comparable to those elicited by conventional intramuscular immunization. CONCLUSIONS: We successfully developed a hollow microneedle technology for dermal vaccination that enables fundamental research on factors, such as insertion depth and volume, and insertion angle, on the immune response. PMID- 24469906 TI - Similar maximum systemic but not local cyclooxygenase-2 inhibition by 50 mg lumiracoxib and 90 mg etoricoxib: a randomized controlled trial in healthy subjects. AB - PURPOSE: Once daily doses of 100-400 mg lumiracoxib have been proposed to inhibit local prostaglandin synthesis longer than systemic prostaglandin synthesis due to local accumulation in inflamed, acidic tissue. Lower, less toxic doses, however, might still achieve the clinical goal and merit further contemplation. METHODS: In a randomized, double-blind, placebo-controlled, three-way cross-over study, 18 healthy men received, with an interval of 24 h, two oral doses of 50 mg lumiracoxib or for comparison, 90 mg etoricoxib, for which local tissue accumulation has not been claimed as therapeutic component. Systemic and local drug concentrations, assessed by means of subcutaneous in-vivo microdialysis, were related to COX-2 inhibiting effects, quantified as inhibition of prostaglandin ex-vivo production in whole blood as well as local tissue prostaglandin (PG) concentrations. RESULTS: Twenty-four hours after the first dose, only etoricoxib was detectable in plasma and inhibited PGE2 production. In contrast, after the second dose, systemic PGE2 concentrations were significantly reduced by both coxibs, indicating similar maximum systemic effects of the selected doses. The local COX-2 inhibition by etoricoxib was most pronounced for PGD2. To the contrary, no indication was given of local inhibition of PG production by lumiracoxib at the dose tested. CONCLUSIONS: Doses of 50 mg lumiracoxib and 90 mg etoricoxib produced similar maximum inhibition of systemic COX-2 function whereas 50 mg lumiracoxib was ineffective in producing local COX-2 inhibition. At a 50 mg dosage, lumiracoxib does not provide peripheral effects that outlast its systemic actions in therapies of rheumatic diseases such as osteoarthritis. PMID- 24469908 TI - Big eucalypts grow more slowly in a warm climate: evidence of an interaction between tree size and temperature. AB - Large trees are critical components of forest ecosystems, but are declining in many forests worldwide. We predicted that growth of large trees is more vulnerable than that of small trees to high temperatures, because respiration and tissue maintenance costs increase with temperature more rapidly than does photosynthesis and these costs may be disproportionately greater in large trees. Using 5 00 000 measurements of eucalypt growth across temperate Australia, we found that high temperatures do appear to impose a larger growth penalty on large trees than on small ones. Average stem diameter growth rates at 21 degrees C compared with 11 degrees C mean annual temperature were 57% lower for large trees (58 cm stem diameter), but only 29% lower for small trees (18 cm diameter). While our results are consistent with an impaired carbon budget for large trees at warmer sites, we cannot discount causes such as hydraulic stress. We conclude that slower growth rates will impede recovery from extreme events, exacerbating the effects of higher temperatures, increased drought stress and more frequent fire on the tall eucalypt forests of southern Australia. PMID- 24469909 TI - The influence of the economic crisis on the association between unemployment and health: an empirical analysis for Spain. AB - OBJECTIVES: To estimate the impact of (particularly long-term) unemployment on the overall and mental health of the Spanish working-age population and to check whether the effects of unemployment on health have increased or been tempered as a consequence of the economic crisis. METHODS: We apply a matching technique to cross-sectional microdata from the Spanish Health Survey for the years 2006 and 2011-2012 to estimate the average treatment effect of unemployment on self assessed health (SAH) in the last year, mental problems in the last year and on the mental health risk in the short term. We also use a differences-in differences estimation method between the two periods to check if the impact of unemployment on health depends on the economic context. RESULTS: Unemployment has a significant negative impact on both SAH and mental health. This impact is particularly high for the long-term unemployed. With respect to the impact on mental health, negative effects significantly worsen with the economic crisis. For the full model, the changes in effects of long-term unemployment on mental problems and mental health risk are, respectively, 0.35 (CI 0.19-0.50) and 0.20 (CI 0.07-0.34). CONCLUSIONS: Anxiety and stress about the future associated with unemployment could have a large impact on individuals' health. It may be necessary to prevent health deterioration in vulnerable groups such as the unemployed, and also to monitor specific health risks that arise in recessions, such as psychological problems. PMID- 24469910 TI - Retrograde trans-anterior communicating artery rescue of unopened Pipeline Embolization Device with balloon dilation: complication management. AB - As the use of the Pipeline Embolization Device (PED) for the treatment of complex intracranial aneurysms rises, knowledge about complications continues to accumulate amidt a paucity of reports on techniques and rescue strategies. We describe the case of a 70-year-old woman who presented with worsening reto orbital left-sided pain and a large cavernous aneurysm. The patient underwent endovascular treatment with PED, and there was difficulty delivering the device due to significant vascular tortuosity. This resulted in poor PED deployment as the proximal end failed to open. Increasingly aggressive strategies were attempted to open the device, which resulted in an iatrogenic carotid cavernous fistula. We were finally able to rescue the device and open its proximal end with balloon inflation after using a contralateral trans-anterior communicating artery approach and crossing the PED in a retrograde fashion. Excessive vascular tortuosity poses a genuine risk of PED malfunction and poor deployment. Although we were able to rescue the device and our patient had no permanent morbidity, difficult vascular anatomy rendered the procedure extremely complicated with dreaded complications. PMID- 24469911 TI - Helminths and human ancestral immune ecology: What is the evidence for high helminth loads among foragers? AB - OBJECTIVES: Recent theories of human immune ecology have invoked high helminth loads as an important selection factor among early humans. However, few studies have assessed this assumption among extant human foragers. METHODS: We review the current evidence for high helminth loads in documented forager populations and present new data from members of a Kawymeno Waorani forager group in Amazonian Ecuador (n = 16) compared with neighboring Kichwa subsistence farmers (n = 63). RESULTS: Stool samples indicated a near absence of helminths among the Kawymeno foraging group (6.25% with Ascaris lumbricoides and 0% with Ancylostoma duodenale or Trichuris trichiura). In contrast neighboring, isolated Kichwa subsistence farmers in a similar ecosystem had abundant helminth infestations (76.1% with Ascaris lumbricoides, 11.1% with Ancylostoma duodenale, and 1.5% with Trichuris trichiura). The presence of helminths among the Waorani and Kichwa was triangulated across multiple data sources, including presence in stool samples, medical exams, and 3 years of participant observation. CONCLUSIONS: These findings, coupled with the modern forager literature, raise questions as to whether helminths were prevalent enough in Paleolithic humans to be a unique evolutionary selective force in human physiology. PMID- 24469912 TI - Novel adeno-associated viral vector delivering the utrophin gene regulator jazz counteracts dystrophic pathology in mdx mice. AB - Over-expression of the dystrophin-related gene utrophin represents a promising therapeutic strategy for Duchenne muscular dystrophy (DMD). The strategy is based on the ability of utrophin to functionally replace defective dystrophin. We developed the artificial zinc finger transcription factor "Jazz" that up regulates both the human and mouse utrophin promoter. We observed a significant recovery of muscle strength in dystrophic Jazz-transgenic mdx mice. Here we demonstrate the efficacy of an experimental gene therapy based on the systemic delivery of Jazz gene in mdx mice by adeno-associated virus (AAV). AAV serotype 8 was chosen on the basis of its high affinity for skeletal muscle. Muscle-specific expression of the therapeutic Jazz gene was enhanced by adding the muscle alpha actin promoter to the AAV vector (mAAV). Injection of mAAV8-Jazz viral preparations into mdx mice resulted in muscle-specific Jazz expression coupled with up-regulation of the utrophin gene. We show a significant recovery from the dystrophic phenotype in mAAV8-Jazz-treated mdx mice. Histological and physiological analysis revealed a reduction of fiber necrosis and inflammatory cell infiltration associated with functional recovery in muscle contractile force. The combination of ZF-ATF technology with the AAV delivery can open a new avenue to obtain a therapeutic strategy for treatment of DMD. PMID- 24469913 TI - Toehold-initiated rolling circle amplification for visualizing individual microRNAs in situ in single cells. AB - The ability to quantitate and visualize microRNAs (miRNAs) in situ in single cells would greatly facilitate the elucidation of miRNA-mediated regulatory circuits and their disease associations. A toehold-initiated strand-displacement process was used to initiate rolling circle amplification of specific miRNAs, an approach that achieves both stringent recognition and in situ amplification of the target miRNA. This assay, termed toehold-initiated rolling circle amplification (TIRCA), can be utilized to identify miRNAs at physiological temperature with high specificity and to visualize individual miRNAs in situ in single cells within 3 h. TIRCA is a competitive candidate technique for in situ miRNA imaging and may help us to understand the role of miRNAs in cellular processes and human diseases in more detail. PMID- 24469914 TI - Solitary plasmacytoma of the uvula. PMID- 24469915 TI - Experimental remodellation of extracorporeal irradiated autogenous and allogenic patellar grafts. AB - BACKGROUND: Irradiated autografts have been used to aid the recovery of bone defects, and the results are well documented. Recently, bone allografts with tendinous attachments have been used to restore the function of joints. Similar reconstructions can be performed with irradiated autografts. However, little information is available on the biology of extracorporeal irradiated tendon autografts. QUESTIONS/PURPOSES: An experimental rabbit model was used to investigate the quality of healing and remodeling of the irradiated autogenous patellar tendon graft after 3 and 12 weeks using immunohistochemical and morphometric analyses. METHODS: New Zealand rabbits (n = 40) were randomly divided into autograft and allograft groups. The right knees of all animals served as the control (sham). The patellar tendon graft of the control right knee was reimplanted into its original location without any processing, while the patellar tendon of the left knee in the autograft group was reimplanted into the original location after 50 Gy irradiation. In the allograft group, the patellar tendon was sutured to the knee of another rabbit following 50 Gy irradiation. Five rabbits from each group were sacrificed and examined histologically. RESULTS: There were significant differences in the number of fibroblasts after 12 weeks between allograft and sham groups (P = 0.002). On the other hand, there were no differences between the allograft and autograft groups at the 12th week (P = 0.139). The difference in fibroblast numbers between autograft and allograft groups was statistically significant after the 3rd week (P < 0.05). Collagen fibril thickness was different between both the allograft and sham groups (P = 0.002) and the allograft and autograft groups at the 12th week (P = 0.000). Collagen fibrils were thicker in the sham and autograft groups compared with the allograft group at the 3rd week of evaluation (P < 0.05). The Ki67 index was significantly different between the allograft and sham groups at the 12th week (P < 0.032), while there was no difference between the allograft and autograft groups (P > 0.05). At the 3rd week, Ki67 reactivity was higher in the allograft group compared with the other two groups (P < 0.05). PMID- 24469916 TI - IgG expression in trophoblasts derived from placenta and gestational trophoblastic disease and its role in regulating invasion. AB - Immunoglobulin G (IgG) is an important humoral immune factor, which plays a role in innate immunity of the fetus. IgG immunoreactivity was often seen in trophoblasts of placenta. Traditionally, IgG in trophoblasts was believed to be transported from the maternal blood through neonatal Fc receptor (FcRn). Here, we explored the phenomenon of IgG expression and its role in regulating invasion in trophoblasts derived from normal placenta and gestational trophoblastic disease (GTD). IgG expression was detected with an emphasis on mRNA transcripts by using reverse transcription-polymerase chain reaction and hybridization in situ, besides evaluated at the protein level with immunohistochemistry and immunofluorescence. The migration and attachment of normal trophoblast cell line (TEV-1) and choriocarcinoma cell line (JAR) were inhibited with down-regulation of IgG expression. Methotrexate promoted the differentiation of JAR cell line; however, it had little effect on the differentiation of TEV-1 cell line. IgG expression, migration, and attachment of JAR and TEV-1 cell lines were decreased in the presence of methotrexate. Furthermore, statistical analysis showed that the differences in migration and attachment were significant (P < 0.05) for JAR cell line, while no significant difference was found for TEV-1 cell line. Collectively, these results confirmed that with the progression from normal placenta to GTD, the expression of IgG was increased in trophoblasts, which might actively promote the migration and attachment of trophoblasts as an important regulating factor. PMID- 24469917 TI - CD4+ T cells in HIV infection show increased levels of expression of a receptor for vasoactive intestinal peptide, VPAC2. AB - Immune activation is a strong predictor of disease outcome in HIV infection and promotes the loss of CD4+ T cells. The neuropeptide, vasoactive intestinal peptide (VIP), has immune-modulating properties with specific receptors identified on lymphocytes; VPAC1 and VPAC2. Studies have shown that VIP limits immune activation and apoptosis in T cells by decreasing the expression of the apoptosis signaling molecule Fas ligand (FasL). VIP receptor surface expression has not been investigated by flow cytometry in the context of HIV infection and may represent a novel target for immune-modulating therapy. Eighty-seven untreated HIV-infected individuals with CD4 counts >200 and 57 uninfected controls were recruited from a primary health clinic in Cape Town, South Africa. Flow cytometry was used to determine levels of expression of VPAC1 and VPAC2, as well as FasL on CD4+ T cells, and these results were correlated with the immune activation phenotype %CD38+CD8+ T cells. VPAC2 expression was significantly increased in the HIV group (mean %VPAC2+CD4+ cells 19.25 vs. control 12.56; p <= 0.0001), but no difference in VPAC1 expression was observed. VPAC2 correlated positively with FasL (r = 0.310; p = 0.001), and there was a significant inverse correlation between FasL and the CD4 count (r = -0.211; p = 0.013) and a direct correlation with %CD38+CD8+ T cells (r = 0.39; p <= 0.0001). Thus, higher levels of immune activation correlated with higher levels of the death-signaling FasL and lower CD4 counts. VPAC2 may provide a novel target for the selective limitation of CD4+ T-cell death in HIV infection. PMID- 24469918 TI - Experience and convergence in spiritual direction. AB - The practice of spiritual direction concerns the human experience of God. As praxis, spiritual direction has a long tradition in Western Christianity. It is a process rooted in spirituality with theology as its foundation. This paper explores the convergences between aspects of philosophy (contemplative awareness), psychology (Rogerian client-centered approach) and phenomenology. There are significant points of convergence between phenomenology and spiritual direction: first, in Ignatius of Loyola's phenomenological approach to his religious experience; second, in the appropriation by spiritual directors of concepts of epoche and empathy; third, in the process of "unpacking" religious experience within a spiritual direction interview. PMID- 24469920 TI - Thin film knitting pattern morphology from a miktoarm star terpolymer. AB - Thin film knitting pattern from a miktoarm star terpolymer is demonstrated. Such structures have been predicted but not observed in bulk or thin film form. The knitting pattern exhibits well organized periodic structures consisting of undulating lamellae and alternating cylinders, with well-defined defects that result in sharp 90 degrees bends and T junctions. PMID- 24469919 TI - Physiological and morphological responses to the first bout of refeeding in southern catfish (Silurus meridionalis). AB - Many animals experience fasting because of the high temporal and spatial sporadicity of food availability. Once food is available, animals use external energy to restore their depressed functional performance. In the present study, the physiological and morphological responses to the first bout of refeeding in juvenile southern catfish (Silurus meridionalis) were characterized. Fish that had undergone long-term fasting (fasted for 32 days, the S32 group) exhibited a lower resting metabolic rate (MO(2rest) decreased by 49%), lower peak metabolic rate (MO(2peak) decreased by 24%), greater energy expenditure (increased by 15%) during specific dynamic action (SDA) and longer duration SDA response (increased by 41%) than those of a control group (S0 group, fasted for 0 days). The S32 group showed a significantly reduced peak gastric evacuation rate (0.131 g meal h(-1)) compared with the S0 group (0.315 g meal h(-1)). The S0 group also had a shorter gastric evacuation time (36 h) than either of the two fasting groups (both 64 h). The S32 group displayed a higher minimum gastric pH (3.1) than the S0 and S16 groups (2.6). Refeeding did not trigger an increase in the wet mass of the gastrointestinal tract, whereas the liver wet mass of the S0 and the two fasting groups increased significantly with refeeding. The trypsin and lipase of the S0 group showed higher mass-specific activities and organ capacities than either of the two fasting groups at certain specific time points. A similar result was found for aminopeptidase activity. Multiple loach meals equaling 6% of the body weight of the fed fish completely restored the liver morphology within the S16 but not the S32 group. Our results suggest that the regulation of the digestive performance of the gastrointestinal tract in S. meridionalis that are finishing their first small meal after fasting is delayed compared with that of nonfasting fish and that it is similar to the characteristics (lower MO(2peak), greater SDA and a longer duration of the SDA response) of the refeeding SDA. PMID- 24469921 TI - Involvement of extracellular signal-regulated kinase (ERK1/2)-p53-p21 axis in mediating neural stem/progenitor cell cycle arrest in co-morbid HIV-drug abuse exposure. AB - Neurological complications in opioid abusing Human Immunodeficiency Virus-1 (HIV 1) patients suggest enhanced neurodegeneration as compared to non-drug abusing HIV-1 infected population. Neural precursor cells (NPCs), the multipotent cells of the mammalian brain, are susceptible to HIV-1 infection and as opiates also perturb their growth kinetics, detailed mechanistic studies for their co-morbid exposure are highly warranted. Using a well characterized in vitro model of human fetal brain-derived neural precursor cells, we investigated alterations in NPC properties at both acute and chronic durations. Chronic morphine and Tat treatment attenuated proliferation in NPCs, with cells stalled at G1-phase of the cell cycle. Furthermore HIV-Tat and morphine exposure increased activation of extracellular signal-regulated kinase-1/2 (ERK1/2), enhanced levels of p53 and p21, and decreased cyclin D1 and Akt levels in NPCs. Regulated by ERK1/2 and p53, p21 was found to be indispensible for Tat and morphine mediated cell cycle arrest. Our study elaborates on the cellular and molecular machinery in NPCs and provides significant mechanistic details into HIV-drug abuse co-morbidity that may have far reaching clinical consequences both in pediatric as well as adult neuroAIDS. PMID- 24469922 TI - Controlling cavitation-based image contrast in focused ultrasound histotripsy surgery. AB - PURPOSE: To develop MRI feedback for cavitation-based, focused ultrasound, tissue erosion surgery (histotripsy), we investigate image contrast generated by transient cavitation events. METHODS: Changes in GRE image intensity are observed while balanced pairs of field gradients are varied in the presence of an acoustically driven cavitation event. The amplitude of the acoustic pulse and the timing between a cavitation event and the start of these gradient waveforms are also varied. The magnitudes and phases of the cavitation site are compared with those of control images. An echo-planar sequence is used to evaluate histotripsy lesions in ex vivo tissue. RESULTS: Cavitation events in water cause localized attenuation when acoustic pulses exceed a pressure threshold. Attenuation increases with increasing gradient amplitude and gradient lobe separation times and is isotropic with gradient direction. This attenuation also depends upon the relative timing between the cavitation event and the start of the balanced gradients. These factors can be used to control the appearance of attenuation while imaging ex vivo tissue. CONCLUSION: By controlling the timing between cavitation events and the imaging gradients, MR images can be made alternately sensitive or insensitive to cavitation. During therapy, these images can be used to isolate contrast generated by cavitation. PMID- 24469923 TI - Addressing psychotherapy challenges in the medication visit: a pilot course on brief psychotherapeutic interventions. PMID- 24469924 TI - Improving recruitment into psychiatry: a summer school for medical students combining clinical work and education. PMID- 24469925 TI - Resident recruitment and mental health parity. PMID- 24469926 TI - Expression of the long non-coding RNAs MEG3, HOTAIR, and MALAT-1 in non functioning pituitary adenomas and their relationship to tumor behavior. AB - PURPOSE: It is becoming evident that long non-coding RNAs (lncRNAs) participate in diverse biological processes via distinct mechanisms. Many lncRNAs have altered expression and likely to have functional roles in tumorigenesis. Although loss of maternally-expressed gene 3 (MEG3) expression has been detected in non functioning pituitary adenomas (NFPAs), there are no published reports regarding the association between MEG3 expression and the invasive ability of NFPAs. Moreover, the roles of Hox transcript antisense intergenic RNA (HOTAIR) and metastasis-associated lung adenocarcinoma transcript 1 (MALAT-1) in NFPAs have not been examined. To investigate the role of MEG3, HOTAIR, and MALAT-1 in NFPA development and invasion. METHODS: MEG3, HOTAIR, MALAT-1 and proliferating cell nuclear antigen (PCNA) were detected in 52 NFPA samples and seven normal human anterior pituitaries using real-time quantitative reverse transcription polymerase chain reaction. RESULTS: MEG3 lncRNA levels gradually decreased whereas HOTAIR lncRNA levels gradually increased from normal anterior pituitaries to non-invasive NFPAs to invasive NFPAs. There was a significant association between MEG3 (P < 0.01) and HOTAIR (P < 0.05) expression and the biological behavior of the tumor. Furthermore, PCNA mRNA levels markedly increased in invasive NFPAs compared to non-invasive ones (P < 0.01). In addition, PCNA mRNA negatively correlated with MEG3 lncRNA levels (P < 0.05). CONCLUSIONS: MEG3 and HOTAIR expression may correlate with NFPA development and invasion. PMID- 24469927 TI - Chemosensing ensembles for monitoring biomembrane transport in real time. AB - The efficacy of drugs and biomolecules relies on their ability to pass through the bilayer. The development of methods to directly and sensitively monitor these membrane transport processes has remained an experimental challenge. A macrocyclic host (p-sulfonatocalix[4]arene or cucurbit[7]uril) and a fluorescent dye (lucigenin or berberine) are encapsulated as a chemosensing ensemble inside liposomes, which allows for a direct, real-time fluorescence monitoring of the passage of unlabeled bioorganic analytes. This in vitro assay is transferable to different channel proteins and analytes, has potential for fluorescence-based screening, e.g., of channel modulators, and yields the absolute kinetics of translocation. Using this new biophysical method, we observed for the first time direct rapid translocation of protamine, an antimicrobial peptide, through the bacterial transmembrane protein OmpF. PMID- 24469928 TI - Treating posttraumatic stress disorder with metacognitive therapy: a preliminary controlled trial. AB - OBJECTIVES: Exposure, trauma-focused cognitive therapy and eye-movement desensitisation and re-processing (EMDR) are effective treatments for posttraumatic stress disorder (PTSD) producing equivalent outcomes. How might the field advance? One way is to base new treatments on PTSD maintenance mechanisms. A treatment that does this, metacognitive therapy (MCT), underwent preliminary controlled evaluation in this study. METHOD: Twenty participants aged 18 to 65 years with chronic PTSD were randomly allocated to either a total of 8 sessions of MCT or a delayed treatment control. Measures of PTSD, emotional symptoms, and underlying metacognitive variables were obtained at pretreatment and posttreatment. Patients were followed-up at 3 and 6 months postintervention. RESULTS: Statistically significant reductions in PTSD symptoms, depression, and anxiety at posttreatment were observed in the MCT group but not in the control group. Changes were maintained over follow-up. The average number of sessions delivered was 6.4. Eighty percent of patients (intention to treat) met clinical significance criteria for recovery based on the IES. Treatment was well tolerated with only one (10%) dropout. Changes in thought control strategy hypothesized to be involved in the maintenance of PTSD were found. CONCLUSIONS: MCT appeared to be a brief treatment producing high recovery rates. The data add to existing uncontrolled evaluations and provide strong justification for future evaluation of this treatment against existing evidence-based interventions. PMID- 24469929 TI - Development and psychometric evaluation of the Multidimensional Assessment of Social Anxiety (MASA). AB - OBJECTIVE: Hybrid models of psychopathology propose to combine the current categorical diagnostic system with shared symptom dimensions common across various disorders. Recently, the first empirically derived hybrid model of social anxiety was developed, including both a specific factor for the diagnostic category of social anxiety and 5 nonspecific factors for related symptoms. The present investigation developed a self-report measure-the Multidimensional Assessment of Social Anxiety (MASA)-based on this model to further the research on hybrid models. METHOD: This investigation included three studies across large undergraduate (N = 411; 52.3% male; mean [M] age = 19.6) and clinical (N = 684; 61.4% female; M age = 35.8) samples, involving the administration of the MASA item pool and existing measures of related constructs. RESULTS: Through a series of psychometric evaluations, the initial 466-item pool was reduced to a final 38 item measure that represented 6 distinct scales with adequate model fit, internal consistency, test-retest reliability, and convergent and discriminant validity. CONCLUSIONS: Together, these studies likely will lead to additional research and advances in the development of the hybrid models of the mood and anxiety disorders through the dissemination and administration of the MASA. PMID- 24469930 TI - Do positive psychology exercises work? A replication of Seligman et al. (2005). AB - OBJECTIVES: The current work replicated a landmark study conducted by Seligman and colleagues (2005) that demonstrated the long-term benefits of positive psychology exercises (PPEs). In the original study, two exercises administered over 1 week ("Three Good Things" and "Using your Signature Strengths in a New Way") were found to have long-lasting effects on depression and happiness (Seligman, Steen, Park, & Peterson, 2005). DESIGN: These exercises were tested here using the same methodology except for improvements to the control condition, and the addition of a second "positive placebo" to isolate the common factor of accessing positive, self-relevant constructs. This component control design was meant to assess the effect of expectancies for success (expectancy control), as well the cognitive access of positive information about the self (positive placebo). RESULTS: Repeated measures analyses showed that the PPEs led to lasting increases in happiness, as did the positive placebo. The PPEs did not exceed the control condition in producing changes in depression over time. CONCLUSIONS: Brief, positive psychology interventions may boost happiness through a common factor involving the activation of positive, self-relevant information rather than through other specific mechanisms. Finally, the effects of PPEs on depression may be more modest than previously assumed. PMID- 24469931 TI - Modified target cancellation in hemispatial neglect. PMID- 24469932 TI - An elderly woman with leg weakness. PMID- 24469933 TI - Comparative development and evolution of two lateral line phenotypes in lake Malawi cichlids. AB - A comparison of the pattern and timing of development of cranial lateral line canals and canal neuromasts in three species of Lake Malawi cichlids, Labeotropheus fuelleborni and Metriaclima zebra (narrow lateral line canals), and Aulonocara baenschi (widened lateral line canals) was used to test the hypothesis that the evolution of widened canals (thought to be an adaptive phenotype in the lateral line system) from narrow canals is the result of heterochrony. Using histological analysis and scanning electron microscopy, this study has provided the first detailed and quantitative description of the development of widened lateral line canals in a teleost, and has demonstrated that: 1) canal neuromast number and the pattern of canal morphogenesis are conserved among species with different adult canal phenotypes, 2) heterochrony ("dissociated heterochrony" in particular) can explain the evolution of widened canals and variation in morphology between canals within a species with respect to canal diameter and neuromast size, and 3) the morphology of the lateral line canals and the dermal bones in which they are found (e.g., the mandibular canal the dentary and anguloarticular bones of the mandible) can evolve independently of each other, thus requiring the addition of another level of complexity to discussions of modularity and integration in the skull of bony fishes. PMID- 24469934 TI - Apelin beyond kidney failure and hyponatremia: a useful biomarker for cancer disease progression evaluation. AB - Apelin regulates angiogenesis, stimulating endothelial cell proliferation and migration. It is upregulated during tumor angiogenesis, and its overexpression was reported to increase tumor growth. Furthermore, apelin controls vasopressin release and body fluid homeostasis. The aim of this study was to examine the correlations between apelin expression and clinical outcomes in oncologic patients, such as cancer disease progression and patient's survival. Apelin levels were evaluated in a cohort of 95 patients affected by different varieties of cancer. Partial remission and stable disease were assigned to the 'no progression' group, comparing it with the progressor group. Patients were followed up for 2 years. Receiver operating characteristics analysis was employed for identifying the progression of the oncologic disease and Kaplan-Meier curves assessed the survival. Adjusted risk estimates for progression endpoint were calculated using Cox proportional hazard regression analysis. Oncologic patients had higher apelin levels compared with healthy subjects, and apelin was closely related to the stages of the disease. In the hyponatremia group, apelin values were significantly higher than patients with eunatremia. After the follow-up of 24 months, 41 patients (43%) reached the endpoint. Progressor subjects presented significantly increased apelin values at baseline compared with non-progressor. Univariate followed by multivariate Cox proportional hazard regression analysis showed that apelin predicted cancer progression independently of other potential confounders. In patients with cancer, apelin closely reflects the stage of the disease and represents a strong and independent risk marker for cancer progression. PMID- 24469935 TI - [Benign myoclonic epilepsy in infancy: natural history and behavioral and cognitive outcome]. AB - INTRODUCTION: Benign myoclonic epilepsy in infancy (BMEI) is a well-defined electro-clinical syndrome, classically associated with a good prognosis. However, in the last years several studies have been published with variable results of neuropsychological outcome in BMEI. AIM. To analyze the natural history and the cognitive and behavioral outcome in BMEI patients. PATIENTS AND METHODS: We report a long-term follow-up of 10 patients with BMEI. During the follow-up, all the patients underwent neurocognitive and behavioral evaluations. RESULTS: Sixty percent of patients became seizure free on valproic acid. The intelligence quotient of the whole cohort was between 74 and 93, with three patients in the range of borderline intelligence and six in the range of medium-to-low intelligence. Nine of the 10 patients met criteria for attention deficit hyperactivity disorder, and two patients associated another learning disorder. All patients showed poor motor and visuospatial coordination signs and three patients had a behavior disorder. CONCLUSIONS: The term 'benign' in BMEI has to be used with caution in refer to its behavioral and cognitive outcome. Early onset of seizures and a worse epilepsy control may be risk factors of a poor neuropsychological outcome. PMID- 24469936 TI - [Effect of alcohol on electrical organisation in the brain during a visuospatial working memory task and its relationship with the menstrual cycle]. AB - INTRODUCTION: The metabolism of alcohol and cognitive functions can vary during the menstrual cycle. Also, both alcohol ingestion and hormonal variations during menstruation have been associated with characteristic changes in electroencephalographic (EEG) activity. AIM. To determine whether EEG activity during a working memory task is affected by acute alcohol consumption, and if these EEG patterns vary in relation to different phases of the menstrual cycle. SUBJECTS AND METHODS: 24 women who drank a moderate dose of alcohol or placebo during the follicular and early luteal phases of the menstrual cycle. The EEG activity was recorded during performance of viso-spatial working memory task. RESULTS: Although the alcohol did not deteriorate the performance of working memory task, it caused in the EEG a decrease of relative theta power and lower right fronto-parietal correlation in theta and alpha2 bands. Only women who drank alcohol in the follicular phase had a higher relative potency of alpha1, which could indicate a lower level of arousal and attention. CONCLUSIONS: These results contribute to a better understanding of the brain mechanisms underlying cognitive changes with alcohol and its relationship to the menstrual cycle. PMID- 24469937 TI - [Rescue treatment in acute thrombosis of intracranial stents]. AB - INTRODUCTION: Acute intrastent thrombosis is a potentially serious complication in intracranial stenting. It is essential to determine which therapy is the most suitable in intrastent thromboses. CASE REPORT: Female aged 58, the first case of acute thrombosis of an intracranial stent to be treated successfully by fibrinolysis after the implantation of a flow diverter device (Silk) in a fusiform basilar aneurysm. CONCLUSION: The administration of abciximab as a rescue treatment seems safe in cases involving the formation of acute intrastent thromboses. PMID- 24469938 TI - [Orexin: clinical and therapeutic implications]. AB - INTRODUCTION. Recent research has reported the existence of a new class of neuropeptides, called orexins or hypocretins, which are produced by a small group of neurons in the hypothalamus and whose actions are mediated by two types of receptors: OX1R and OX2R. More specifically, the orexinergic neurons have been located exclusively in cells in the lateral, dorsomedial and perifornical areas of the hypothalamus. Despite this highly specific anatomical origin, the orexinergic neurons are projected widely into a number of brainstem, cortical and limbic regions. DEVELOPMENT. This fuzzy pattern of distribution of the orexinergic fibres would be indicating the involvement of this peptidic system in a wide range of functions; indeed, it has been related with the mechanisms that enable regulation of the sleep-wake cycle, the ingestion of food and drink, and some particular types of learning, such as learning certain preferences regarding tastes. It has also been suggested that upsets in the functioning of the orexinergic system would explain the appearance of certain clinical disorders like narcolepsy, obesity or addiction to drug of abuse. CONCLUSIONS. Further research will help to determine the functioning of orexinergic neurons and the interaction between the systems that regulate emotion, energetic homeostasis and the reward mechanisms, on the one hand, and the systems that regulate the sleep wake cycle on the other. That knowledge would almost certainly make it possible to develop new drugs that, by acting upon the orexinergic system, would be effective in the treatment of sleep disorders such as insomnia or narcolepsy, eating disorders or drug addiction. PMID- 24469939 TI - [Neuropsychotherapy in brain injury rehabilitation]. AB - INTRODUCTION: Persons who have suffered brain damage can experience a wide range of cognitive, behavioural and emotional disorders. However, neuropsychological rehabilitation usually focuses, almost exclusively, on the cognitive deficits and pays very little attention to the emotional challenges associated with the psychological impact of the lesion. It is in this more personal side of brain damage where neuropsychotherapy can be of great aid to facilitate the process of acceptance and adaptation following a neurological lesion. DEVELOPMENT: In this article, we describe the theoretical and conceptual aspects of psychotherapy oriented towards persons with brain damage, the implications of cognitive deficits in the practice of neuropsychotherapy and the evidence regarding its effectiveness. CONCLUSIONS: In the past, neuropsychotherapy was considered to be of little use in the rehabilitation of brain damage. Today, however, a growing number of professionals are acknowledging its importance in the management of the psychological/emotional suffering associated with brain damage. The aim of neuropsychological rehabilitation is not just to promote the recovery of the altered brain functions, but also to improve the individual's functional capacity, deal with his or her experiences of loss and help him or her to again find a meaning to life. PMID- 24469940 TI - [Parkinson's disease in literature, cinema and television]. AB - INTRODUCTION. Since James Parkinson published what can be considered the first treaty on the disease that bears his name in 1817, the scientific literature on this pathology has not ceased to grow. But the illness has also been represented in literature, the cinema and on television, where the symptoms, treatment and socio-familial context of the disease have often been examined very closely. AIM. To address the cases in which Parkinson's disease appears in literature, cinema and television, as well as to reflect on the image of the condition presented in those contexts. DEVELOPMENT. We reviewed some of the most important works in the literature dealing with Parkinson's disease from any period of history and many of them were found to offer very faithful portrayals of the disease. Likewise, we also reviewed major films and TV series that sometimes offer the general public a close look at the vision and the impact of the disease on patients or their relatives. CONCLUSIONS. Literature, cinema and television have helped provide a realistic view of both Parkinson's disease and the related healthcare professionals, and there are many examples that portray the actual experiences of the patients themselves, while also highlighting the importance of healthcare and socio-familial care. PMID- 24469941 TI - [Hemifacial spasm due to temporal bone cholesterol granuloma]. PMID- 24469942 TI - [Even though you're not a psychiatrist, attention to the evidence]. PMID- 24469943 TI - [Collaborative networks between Spain and Latin America regarding multiple sclerosis]. PMID- 24469944 TI - Additive benefits of chondroitin sulfate and oriented tethered epidermal growth factor for vascular smooth muscle cell survival. AB - An anti-apoptotic coating combining chondroitin sulfate (CS) and coiled-coil based tethering of epidermal growth factor (EGF) is designed for vascular applications. The oriented tethering strategy enables to reach higher EGF surface densities compared to the commonly used random covalent grafting, while using much lower concentrations of EGF during incubation. It also significantly improves vascular smooth muscle cell (VSMC) survival and resistance to apoptosis in serum-free conditions. The comparison of CS and low-fouling carboxymethylated dextran as a sublayer for growth factors highlights the tremendous benefit of CS thanks to its selective protein resistance and good cell adhesion properties. This approach can be tuned by capturing other growth factors on CS through coiled coil interactions. PMID- 24469945 TI - Total ipsilateral C7 root neurotization to the upper trunk for isolated C5-C6 avulsion in obstetrical brachial plexus palsy: a preliminary technical report. AB - BACKGROUND: C5-C6 root avulsion in obstetrical brachial plexus palsy (OBPP) is a rare injury with poor prognosis usually associated with breech delivery. The treatment is challenging and requires high microsurgical skills. The triple nerve transfer (spinal accessory nerve, ulnar fascicles, and triceps long or lateral head branch) represents the gold standard treatment. The total ipsilateral C7 nerve root neurotization is a promising technique, which has never been described in OBPP. OBJECTIVE: The total ipsilateral C7 nerve root is used as a neurotizer transferred to the upper trunk as an alternative method to other intra- or extra plexual reconstruction techniques. METHODS: During brachial plexus surgical exploration, an intraoperative neurostimulation was performed to confirm the integrity of C7 and the lesion of C5 and C6. The entire C7 nerve root and the upper trunk are cut. The C7 root was transferred to the upper trunk with a fibrin sealant. RESULT: This technique was easily performed with a single approach and avoided intercalated nerve grafts. The C7 nerve root provided a large number of nerve fibers with an adequate diameter to be transferred to the upper trunk. We illustrated this technique with a typical case of a child at 8 years of follow up. CONCLUSION: The total ipsilateral transfer of the C7 root to the upper trunk is a viable alternative procedure for newborns with C5-C6 avulsion. PMID- 24469946 TI - A modified method to enhance the safety of endoscopic third ventriculostomy (ETV) -transendoscopic pulse-waved microvascular Doppler-assisted ETV, technical note. AB - INTRODUCTION: Endoscopic third ventriculostomy (ETV) is a simplified treatment relative to shunting for several types of hydrocephalus. The fatal complication of ETV is intraoperative hemorrhage due to arterial injury of the basilar artery, posterior cerebral arteries, and their perforators. MATERIAL AND METHODS: Here, we present a modified technique of ETV by using a transendoscopic pulse-waved microvascular Doppler probe and videoscope head to avoid vascular injury behind the tuber cinereum (TC). The microvascular Doppler probe can detect the basilar artery complex through the TC. CONCLUSION: Ventriculostomy with the probe head helps prevent vascular injury by informing the presence of invisible vessels under endoscopic view during perforation, and the method introduced here is certain to prove invaluable for enhancing the safety of ETV. PMID- 24469947 TI - The use of handheld near-infrared device (Infrascanner)for detecting intracranial haemorrhages in children with minor head injury. AB - OBJECTIVE: A handheld device using near-infrared technology(Infrascanner) has shown good accuracy for detection of traumatic intracranial haemorrhages in adults. This study aims to determine the feasibility of use of Infrascanner in children with minor head injury (MHI) in the Emergency Department(ED). Secondary aim was to assess its potential usefulness to reduce CT scan rate. METHODS: Prospective pilot study conducted in two paediatric EDs, including children at high or intermediate risk for clinically important traumatic brain injury (ciTBI) according to the adapted PECARN rule in use. Completion of Infrascanner measurements and time to completion were recorded. Decision on CT scan and CT scan reporting were performed independently and blinded to Infrascanner results. RESULTS: Completion of the Infrascanner measurement was successfully achieved in 103 (94 %) of 110 patients enrolled,after a mean of 4.4+/-2.9 min. A CT scan was performed in 18(17.5 %) children. Only one had an intracranial haemorrhage that was correctly identified by the Infrascanner. The exploratory analysis showed a specificity of 93 % (95 % CI, 86.5-96.6) and a negative predictive value of 100 % (95 % CI,81.6-100) for ciTBI. The use of Infrascanner would have led to avoid ten CT scan, reducing the CT scan rate by 58.8 %. CONCLUSIONS: Infrascanner seems an easy-to-use tool for children presenting to the ED following a MHI, given the high completion rate and short time to completion. Our preliminary results suggest that Infrascanner is worthy of further investigation as a potential tool to decrease the CT scan rate in children with MHI. PMID- 24469948 TI - Neuroimaging findings of retroclival hemorrhage in children: a diagnostic conundrum. AB - BACKGROUND: Retroclival hemorrhage in children may occur in three compartments, namely epidural, subdural, and subarachnoid, frequently secondary to trauma. Retroclival epidural hematoma may be associated with ligamentous injury, which may further result in instability at the craniocervical junction. Retroclival subdural hematoma may indicate a sentinel event for traumatic injury elsewhere within the brain or posterior fossa. Retroclival subarachnoid hemorrhage may have severe clinical consequences related to vasospasm. OBJECTIVE: Neuroimaging is essential in the recognition, localization, and characterization of retroclival hemorrhage into various compartments and for evaluating potential severe clinical consequences such as craniocervical junction instability, underlying traumatic brain injury, and ischemia secondary to vasospasm. The goal of this paper is to discuss the anatomy and biomechanics of the craniocervical junction as well as the neuroimaging findings associated with various compartments of retroclival hemorrhage in children. PMID- 24469950 TI - The olfactory bulb structure of African giant rat (Cricetomys gambianus, Waterhouse 1840) I: cytoarchitecture. AB - The olfactory system typically consists of two parallel systems: the main olfactory system and the accessory olfactory system. The main olfactory bulb (MOB) acts as the initial processing site for volatile chemical stimuli and receives input from the olfactory receptor cells located in the olfactory epithelium. The African giant rat is reputed to have abilities to detect landmines and tuberculosis samples by sniffing. This study therefore is a preliminary study on the histological and immunohistochemical anatomy of the olfactory bulb of the African giant rat (Cricetomys gambianus, Waterhouse). Nissl and Kluver-Barrera histological staining of the olfactory bulb revealed a cytoarchitecture typical of most mammals with 6 cell layers, and 1-2-layered glomeruli measuring approximately 150 MUm each in diameter. Immunohistochemical staining with glial fibrillary acidic protein (GFAP) and 2',3'-cyclic nucleotide 3-phosphodiesterase (CNPase) revealed cellular conformations relative to most mammals. GFAP immunohistochemistry also revealed cell bodies and processes within the periglomerular area which may potentiate signaling from the olfactory receptor cells, while CNPase largely showed soma and evidence of myelin sheath deposition, confirming myelination at different layers of the bulb. Neurogenesis was examined using the neurogenic markers doublecortin (DCX) and Ki-67. Migration of newly generated cells was observed in all layers of the MOB with DCX and in most layers with Ki-67. The anatomy of the olfactory bulb is described as relatively large in the African giant rat, having a neuroarchitecture similar to most rodents. PMID- 24469949 TI - Abdominal cerebrospinal fluid pseudocyst: a comparative analysis between children and adults. AB - PURPOSE: Abdominal cerebrospinal fluid (CSF) pseudocyst is a rare but important complication in patients with ventriculoperitoneal shunt (VPS). In addition to presenting our experience, we performed a comparative analysis between children and adults with this entity. To the author's knowledge, there are no studies in which this condition has been compared. METHODS: The PubMed database was searched for all relevant reports published from 1954 to 2012. The differences were statistically compared, especially regarding clinical investigations, etiology of the hydrocephalus, shunt revision, CSF infection, treatment, and recurrence. Chi square test or Fisher's exact test was used to find associations among the variables. RESULTS: Compiled from literature, we found 393 cases of abdominal pseudocyst: 295 children, including our cases, and 55 adults, with age not informed in 43 cases. In children, 33 % of the patients have a positive culture on presentation, with higher incidence in children younger than 10 years. In contrast, only 15 % among adults were positive CSF culture. In total, 287 abdominal pseudocyst cases who underwent shunt revision have been reported; 78.4 % of children and 62.2 % of adults. The main occurrence of this complication according to the etiology of hydrocephalus in children was different from adults. The recurrence of pseudocyst occurred in 19.8 and 24.2 % of children and adults, respectively. CONCLUSIONS: The differences between children and adults might represent distinct trends on the etiology and treatment of this entity. Hence, additional well-designed cohort studies will be necessary to strengthen our findings. PMID- 24469951 TI - Matrix metalloproteinase 7 is a useful marker for 5-fluorouracil-based adjuvant chemotherapy in stage II and stage III colorectal cancer patients. AB - Matrix metalloproteinase 7 (MMP7) was reported to be a negative regulator in Fas mediated apoptosis. The mechanism of cell killing associated with 5-FU treatment in colon cancer was also closely related to Fas-induced apoptosis, which implied that the expression level of MMP7 in colorectal cancer may be associated with the sensitivity of 5-FU treatment. To prove the hypothesis, first we verified the negative relevance between the colorectal cancer cells apoptosis in response to 5 FU treatment and MMP7 level by MTT and flow cytometry assay in vitro. Further, we found the apoptosis was in a positive relation with the Fas ligand level collected from the medium, suggesting a Fas-induced apoptosis. We found that increased level of MMP7 resulted in the enhanced drug resistance in SW620 colon cancer cells treated with 5-FU in vitro. Besides, we analyzed the influence of MMP7 on prognosis of 76 patients with TNM stage II-III colorectal cancers who had undergone curative resections and received 5-FU-based adjuvant chemotherapy. The expression of MMP7 was detected by IHC, and the relationship between the expression of MMP7 and disease-free survival was analyzed by univariate analysis and multivariate analysis. Patients with higher expression of MMP7 showed inferior disease-free survival (p=0.007), and high expression of MMP7 was a significant independent unfavorable prognostic factor (p=0.012). These data suggested that MMP7 is a useful marker for 5-FU chemotherapy sensitivity in patients with stage II-III colorectal cancer. PMID- 24469952 TI - HBsAg is an independent prognostic factor in diffuse large B cell lymphoma patients in rituximab era: result from a multicenter retrospective analysis in China. AB - This study mainly focused on the impact of Hepatitis B virus (HBV) infection on the prognosis of diffuse large B cell lymphoma (DLBCL) patients in rituximab era, using a Cox regression model to ascertain the prediction value of the serum HBV marker in survivals. Three hundred and eighty four DLBCL patients treated with rituximab, cyclophosphamide, doxorubicin/epirubicin, vincristine and prednisone (R-CHOP-like regimens) or CHOP-like regimens were included. Progression-free survival (PFS) and overall survival (OS) of the patients have or have not received rituximab were analyzed separately. In the CHOP group, HBV infection has not been found a profound impact on the survivals. In the R-CHOP group, PFS and OS were inferior in HBsAg-positive patients (p=0.031 and p=0.006, respectively); after adjusting for International Prognostic Index parameters, HBsAg is an independent unfavorable factor for both PFS (RR=2.492) and OS (RR=2.589). PMID- 24469953 TI - Reduced ABCG2 and increased SLC22A1 mRNA expression are associated with imatinib response in chronic myeloid leukemia. AB - Imatinib mesylate (IM) has become a standard of care in chronic myeloid leukemia (CML) therapy. Single nucleotide polymorphisms (SNPs) and altered expression in drug transporter genes may influence IM response. In order to investigate whether mRNA expression and SNPs in drug transporters are associated with IM resistance, we studied 118 chronic-phase CML patients receiving the standard dose of IM (400 mg/day). They were assigned as responders and non-responders according to European LeukemiaNet criteria (2009). mRNA expression in samples at diagnosis (without IM therapy) and outcomes after IM failure were also evaluated in subgroups of patients. Major molecular response (MMR), complete molecular response and primary and secondary resistance were all assessed. BCR-ABL1, ABCB1, ABCG2, SLC22A1 and SLCO1A2 mRNA expression and SNPs in ABCG2 and SLC22A1 genes were analyzed. ABCG2 mRNA expression in the non-responders was higher before and during IM therapy. Furthermore, ABCG2 was overexpressed in those who did not achieve MMR (P=0.027). In a subgroup of patients who switched to second generation tyrosine kinase inhibitors, high mRNA expression of ABCG2 was associated with a risk of 24 times that of not achieving complete cytogenetic response (OR 24.00, 95% CI 1.74-330.80; P=0.018). In the responder group, patients who achieved MMR (P=0.009) presented higher mRNA levels of SLC22A1. The SNPs were not associated with mRNA expression of ABCG2 and SLC22A1. Our data suggest that elevated ABCG2 expression (an efflux transporter) could be associated with IM resistance and could impact on second-generation TKI response, whereas high SLC22A1 expression (an influx transporter) may be associated with a successful IM therapy in CML patients. PMID- 24469954 TI - NEDD9 overexpression correlates with the progression and prognosis in gastric carcinoma. AB - The aim of this study was to investigate neural precursor cell expressed developmentally down-regulated 9 (NEDD9) expression in human gastric carcinoma (GC) and to explore its clinic significance. NEDD9 expression was detected by immunohistochemistry in GC, their corresponding paracancerous histological normal tissues (PCHNTs), and gastric normal tissues. And this result was further confirmed at the protein and mRNA level by Western blotting and quantitative real time PCR, respectively. The Kaplan-Meier method and log-rank test were employed to compare the overall survival between NEDD9 low-level expression group and NEDD9 high-level expression group. We ascertained frequently NEDD9 up-regulation in both protein and mRNA levels in GC tissues as compared to PCHNTs and normal controls. Immunohistochemical staining indicated that NEDD9 is higher expressed in GC tissues (102 out of 125, 81.8%) than that in PCHNTs (eight out of 42, 19.05%) and gastric normal tissues (one out of eight, 12.50%). NEDD9 expression levels were closely associated with poor differentiation (P=0.002), venous invasion (P=0.012), invasive depth (P<0.001), preset lymph node metastasis (P=0.023), distant metastasis (P=0.017), and high clinical stage (P=0.005). NEDD9 expression was positively correlated with clinical tumor node metastasis (TNM) stage that implied the more advanced clinical TNM stage corresponding to the higher expression level of NEDD9 (rs=0.467, P<0.001). And we also detected frequently NEDD9 up-regulation in both protein and mRNA levels in GC tissues as compared to PCHNTs. Kaplan-Meier survival analysis showed that high NEDD9 expression exhibited a significant correlation with poor prognosis for gastric cancer patients. Our data suggested that NEDD9 could be used as prognostic molecular marker to be applied in the clinical setting to diagnosis, evaluating patient's outcome (prognosis and recurrence) for GC patients. PMID- 24469956 TI - Diffusion magnetic resonance monitors intramyocellular lipid droplet size in vivo. AB - PURPOSE: Intramyocellular lipid (IMCL) droplets are dynamic organelles whose morphology reflects their vital roles in lipid synthesis, usage, and storage in muscle energy metabolism. To develop noninvasive means to measure droplet microstructure in vivo, we investigated the molecular diffusion behavior of IMCL with diffusion magnetic resonance spectroscopy. METHODS: Using extremely large diffusion weighting, we measured the IMCL apparent diffusion coefficients (ADCs) in hindlimb muscle of rodents from normal feeding, 60-h fasting, streptozotocin induced diabetic, and high-fat-diet-induced obese groups. RESULTS: IMCL ADCs decreased markedly with diffusion time, confirming the restricted diffusion of lipid molecules within IMCL droplets. IMCL droplet size, determined by transmission electron microscopy, was closely correlated with ADC. IMCL ADC was sensitive to metabolic alterations, decreasing in the 60-h fasting and diabetic groups while increasing in the obese group. These findings indicated that the IMCL droplet size decreased following 60-h fasting and in STZ-induced diabetes but increased in high-fat-diet-induced obesity. CONCLUSION: MR diffusion characterization of IMCL droplet size provides a unique means to examine the intracellular lipid dynamics and metabolic abnormalities in vivo. PMID- 24469957 TI - Skeletal robustness and bone strength as measured by anthropometry and ultrasonography as a function of physical activity in young adults. AB - BACKGROUND: During the last 10 years, skeletal robustness in children has generally decreased. The reasons for this phenomenon, as well as its outcomes, are undetermined so far. AIM: The present study explores the association between anthropometric skeletal measurements, bone quality measurements, and physical activity in young adults. SUBJECTS AND METHODS: 118 German young men (N = 68; 19 25 years old) and women (N = 50; 19-24 years old) were investigated by anthropometric methods (i.e., height, weight, shoulder, elbow breadth, and pelvic breadth) and quantitative ultrasound measurement (QUS). Strength and stability of Os calcis have been determined by speed of sound (in m/s) and broadband ultrasound attenuation (in dB/Mhz); individual physical activity was analyzed by a pedometer and by questionnaire. RESULTS: The results show a correlation between sports hours per week and bone quality index in males. But no correlation exists between anthropometric data and QUSs for either sexes, as well as no correlation between total steps per day and internal bone quality or external bone dimensions. CONCLUSION: These results are discussed in the context of generally decreasing physical activity, the outcomes of prevention programs as well as evolutionary adaptation of human phenotypic plasticity in a changing environment. PMID- 24469958 TI - Primary brain lymphomas after kidney transplantation: an under-recognized problem? AB - Primary central nervous system post-transplant lymphoproliferative disease (CNS PTLD) is a serious complication after solid organ transplantation that has not received much attention so far. However, it could become a more frequent problem with the introduction of new biological agents. METHODS: We identified five cases with CNS PTLD in our center who were transplanted between 1986 and 2007, three men and two women, with a mean age of 55.9 years (range 42-74). Three patients had received only kidney transplant and two patients had received a kidney pancreas transplant. RESULTS: The mean time from first symptoms until diagnosis was 3.5 months (2-6). One patient was diagnosed post-mortem in autopsy. The mean time from transplantation to onset of neurological symptoms was 73.8 months (31 144). The initial clinical manifestation was heterogeneous: all five cases showed headache, four cases presented with gait disturbance, one with dysarthria and two with a confusional state. Epstein-Barr virus (EBV) immunoglobulin (Ig)G serology was positive in four out of five cases; in situ hybridization for EBV in brain biopsy samples was positive in three cases, negative in one and not available in one. In four patients, EBV polymerase chain reaction (PCR) was positive in cerebrospinal fluid (CSF). After diagnosis, overall immunosuppressive load was lowered in all patients (n = 4). Three patients died at 8-104 weeks (mean 40 weeks) after diagnosis and one patient is still alive 20 months after diagnosis. CONCLUSIONS: CNS PTLD is a complication difficult to diagnose, frequently diagnosed too late and often refractory to treatment. A more aggressive screening might be necessary in patients even with mild CNS symptoms. PMID- 24469959 TI - One-degree-of-freedom spherical model for the passive motion of the human ankle joint. AB - Mathematical modelling of mobility at the human ankle joint is essential for prosthetics and orthotic design. The scope of this study is to show that the ankle joint passive motion can be represented by a one-degree-of-freedom spherical motion. Moreover, this motion is modelled by a one-degree-of-freedom spherical parallel mechanism model, and the optimal pivot-point position is determined. Passive motion and anatomical data were taken from in vitro experiments in nine lower limb specimens. For each of these, a spherical mechanism, including the tibiofibular and talocalcaneal segments connected by a spherical pair and by the calcaneofibular and tibiocalcaneal ligament links, was defined from the corresponding experimental kinematics and geometry. An iterative procedure was used to optimize the geometry of the model, able to predict original experimental motion. The results of the simulations showed a good replication of the original natural motion, despite the numerous model assumptions and simplifications, with mean differences between experiments and predictions smaller than 1.3 mm (average 0.33 mm) for the three joint position components and smaller than 0.7 degrees (average 0.32 degrees ) for the two out of-sagittal plane rotations, once plotted versus the full flexion arc. The relevant pivot-point position after model optimization was found within the tibial mortise, but not exactly in a central location. The present combined experimental and modelling analysis of passive motion at the human ankle joint shows that a one degree-of-freedom spherical mechanism predicts well what is observed in real joints, although its computational complexity is comparable to the standard hinge joint model. PMID- 24469960 TI - Object-shape recognition and 3D reconstruction from tactile sensor images. AB - This article presents a novel approach of edged and edgeless object-shape recognition and 3D reconstruction from gradient-based analysis of tactile images. We recognize an object's shape by visualizing a surface topology in our mind while grasping the object in our palm and also taking help from our past experience of exploring similar kind of objects. The proposed hybrid recognition strategy works in similar way in two stages. In the first stage, conventional object-shape recognition using linear support vector machine classifier is performed where regional descriptors features have been extracted from the tactile image. A 3D shape reconstruction is also performed depending upon the edged or edgeless objects classified from the tactile images. In the second stage, the hybrid recognition scheme utilizes the feature set comprising both the previously obtained regional descriptors features and some gradient-related information from the reconstructed object-shape image for the final recognition in corresponding four classes of objects viz. planar, one-edged object, two-edged object and cylindrical objects. The hybrid strategy achieves 97.62 % classification accuracy, while the conventional recognition scheme reaches only to 92.60 %. Moreover, the proposed algorithm has been proved to be less noise prone and more statistically robust. PMID- 24469962 TI - The development of the immune tissues in marsupial pouch young. AB - Current knowledge of the development of the marsupial immune system, particularly in the context of lymphoid tissue development and the appearance of lymphocytes, has been examined and limitations identified. While primary lymphoid tissues like the thymus have been extensively studied, secondary lymphoid tissues such as the spleen and lymph nodes have been examined to a lesser extent, partly due to the difficulty of macroscopically identifying these structures, particularly in very small neonates. In addition, little research has been conducted on the mucosal associated lymphoid tissues; tissues that directly trap antigens and play an important role in the maturity of adaptive immune responses. Research on the development of the marsupial immune tissues to date serves as a solid foundation for further research, particularly on the mechanisms behind the development of the immune system of marsupials. With the recent sequencing and annotation of whole marsupial genomes, the current wealth of sequence data will be essential in the development of marsupial specific reagents, including antibodies, that are required to widen our specific knowledge of the complex marsupial immune system and its development. PMID- 24469961 TI - Lipid transfer proteins in coffee: isolation of Coffea orthologs, Coffea arabica homeologs, expression during coffee fruit development and promoter analysis in transgenic tobacco plants. AB - The aim of the present study was to perform a genomic analysis of non-specific lipid-transfer proteins (nsLTPs) in coffee. Several nsLTPs-encoding cDNA and gene sequences were cloned from Coffea arabica and Coffea canephora species. In this work, their analyses revealed that coffee nsLTPs belong to Type II LTP characterized under their mature forms by a molecular weight of around 7.3 kDa, a basic isoelectric points of 8.5 and the presence of typical CXC pattern, with X being an hydrophobic residue facing towards the hydrophobic cavity. Even if several single nucleotide polymorphisms were identified in these nsLTP-coding sequences, 3D predictions showed that they do not have a significant impact on protein functions. Northern blot and RT-qPCR experiments revealed specific expression of Type II nsLTPs-encoding genes in coffee fruits, mainly during the early development of endosperm of both C. arabica and C. canephora. As part of our search for tissue-specific promoters in coffee, an nsLTP promoter region of around 1.2 kb was isolated. It contained several DNA repeats including boxes identified as essential for grain specific expression in other plants. The whole fragment, and a series of 5' deletions, were fused to the reporter gene beta glucuronidase (uidA) and analyzed in transgenic Nicotiana tabacum plants. Histochemical and fluorimetric GUS assays showed that the shorter (345 bp) and medium (827 bp) fragments of nsLTP promoter function as grain-specific promoters in transgenic tobacco plants. PMID- 24469964 TI - Dirk M. Guldi. PMID- 24469963 TI - Contribution of acidic melanoma cells undergoing epithelial-to-mesenchymal transition to aggressiveness of non-acidic melanoma cells. AB - Tumor cell plasticity largely depends on epithelial-to-mesenchymal transition (EMT) and its reversion. It was ascertained that EMT characterizes disease progression, including melanoma malignancy. As most solid tumors, melanoma shows extracellular acidosis, we analyse the impact of acidic environment on the EMT development in human melanoma cells. Melanoma cells were exposed to an acidic extracellular environment (pH 6.7) and tested for EMT markers. We found that acidic cells express a significant up-regulation of mesenchymal markers (N cadherin, Vimentin), transcription factors (Twist, NF-kappaB) and a significant, although modest, reduction of E-cadherin expression. Acidic cell also express an increased invasiveness through Matrigel associated with an up-regulation of MMP-9 activity. When we injected acidic cells intravenously into immunodeficient animals, we found a number of lung micrometastases not different from non-acidic cells. Indeed, they show a partial G1 cell cycle arrest, which might interfere with the growth of lung colonies. When we investigated the in vitro invasiveness and lung colonization of a mixed population of acidic and non acidic melanoma cells, we found that acidic cells promote in vitro invasiveness of non-acidic cells and this cooperation leads to an higher migration rate than acidic cells. Moreover, acidic cells cooperate for a better lung colonization of non-acidic cells, that represent the greater part of cells participating to lung micrometastases. We found evidence that acidity triggers in melanoma cells an EMT program, which although "incomplete", potentiates migration rate and development of lung colonies into immunodeficient host of cells grown in standard pH. PMID- 24469965 TI - Xyloglucan-block-poly(epsilon-caprolactone) copolymer nanoparticles coated with chitosan as biocompatible mucoadhesive drug delivery system. AB - The development of novel xyloglucan-block-poly(epsilon-caprolactone) (XGO-b-PCL) nanoparticles coated with the mucoadhesive polysaccharide chitosan is described. XGO-b-PCL nanoparticles show monodisperse size distribution (Rh = 50 nm). Curcumin is successfully encapsulated within the PCL core within drug to polymer ratio of 1:5 (w/w). The coating of nanoparticles with chitosan results in an increased particle size and positive surface charge due to the polycation nature of the chitosan. Mucoadhesive properties of chitosan-coated nanoparticles are demonstrated by its exceptional ability to interact with mucin through electrostatic forces. Finally, in vitro studies show that curcumin-loaded nanoparticles exhibit higher cytotoxic effects against B16F10 melanoma cells than L929 fibroblast cells. PMID- 24469967 TI - Social and behavioural risk factors for HIV infection among the wives of labour migrants in Nepal. AB - Summary Labour migration has increased the risk of HIV infection among the wives of labour migrants in Nepal. We conducted a matched case-control study to identify the social and behavioural factors for HIV infection among the wives of labour migrants in Nepal. We interviewed 112 wives of labour migrants diagnosed with HIV (cases) and 112 wives of labour migrants testing negative for HIV (controls) and used logistic regression analysis to assess independent factors associated with HIV infection. Literacy status was the only one woman-related social factor associated with HIV infection. Meanwhile literacy status, age when going abroad for the first time and country of migration were the husband-related social factors and alcohol consumption, living alone abroad and having an unpaid partner abroad were the husband-related behavioural factors associated with HIV infection in the wives. Given the husband-related social and behavioural factors are mostly determining the risk of HIV infection in the wives in our study, prevention efforts must incorporate behaviour change approaches targeting specifically to labour migrants and also to their wives. PMID- 24469968 TI - Diaphragmatic paralysis associated with herpes zoster and HIV-tuberculosis co infection. AB - Motor complications after herpes zoster are not uncommon. There have been reports of muscular paralysis following herpes zoster. The association between diaphragmatic paralysis and zoster was first reported in 1949 by Halpern. The case presented below showed diaphragmatic involvement following herpes zoster in a HIV-tuberculosis coinfected patient. PMID- 24469969 TI - High HIV prevalence among children presenting for general consultation in rural Cameroon. AB - Data on the HIV-prevalence children presenting to health care facilities in sub Saharan Africa are scant in general, and the debate about opportunities for paediatric HIV screening is ongoing. Nine hundred and eighty-one children with unknown HIV-status presenting to a large general paediatric outpatient department in rural Cameroon were tested using the Determine HIV-1/2 rapid test (Abbott), and positive results were confirmed with the Hexagon HIV rapid test (Human Diagnostics). In children younger than 18 months, HIV infection was confirmed by PCR testing. Median age was 1.3 years and 52.8% were of male gender. In 514 children below 18 months of age, 16 (3.1%) tested positive. Of those, HIV-1 PCR was available for 11 children, of whom 6 had a positive PCR result. HIV prevalence was highest in the age group 5-9 years, being 8.8%. Malnutrition (33.3 vs 5.2%, p < 0.001) was associated with HIV infection. Our study results indicate that HIV testing should be offered to all children at possible entry points to medical care, irrespective of symptoms, in order to reduce HIV-associated mortality through timely initiation of antiretroviral therapy. PMID- 24469970 TI - Evaluation of a partnership between primary and secondary care providing an accessible Level 1 sexual health service in the community. AB - Summary Comprehensive testing for asymptomatic sexually transmitted infections in Northern Ireland has traditionally been provided by genitourinary medicine clinics. As patient demand for services has increased while budgets have remained limited, there has been increasing difficulty in accommodating this demand. In May 2013, the newly commissioned specialist Sexual Health service in the South Eastern Trust sought to pilot a new model of care working alongside a GP partnership of 12 practices. A training programme to enable GPs and practice nurses to deliver Level 1 sexual health care to heterosexual patients aged >16 years, in accordance with the standards of BASHH, was developed. A comprehensive care pathway and dedicated community health advisor supported this new model with close liaison between primary and secondary care. Testing for Chlamydia, gonorrhoea, HIV and syphilis was offered. The aims of the pilot were achieved, namely to provide accessible, cost-effective sexual health care within a framework of robust clinical governance. Furthermore, it uncovered a high positivity rate for Chlamydia, especially in young men attending their general practice, and demonstrated a high level of patient satisfaction. Moreover the capacity of secondary care to deliver Levels 2 and 3 services was increased. PMID- 24469971 TI - Factors related to Israeli lesbian women's intention to be vaccinated against human papillomavirus. AB - Summary Lesbian women's susceptibility to human papillomavirus infection and, as a consequence, to cervical cancer, is similar to that of heterosexual women. However, little is known about factors related to lesbian women's intention to be vaccinated against human papillomavirus. The aim of the study was to identify factors related to Israeli lesbian women's intention to be vaccinated, using the Health Belief Model. The study has a cross-sectional design. A convenience sample of 207 lesbian women recruited at clubs in central Israel's lesbian community completed a questionnaire, based on the Health Belief Model. Thirty-two percent of the respondents reported having a high intention to be vaccinated. Perceived susceptibility to cervical cancer and perceived benefits of human papillomavirus vaccination were found to be related to intention to be vaccinated. The findings offer insights that can inform health care providers of strategies to promote vaccination against human papillomavirus in this unique population. PMID- 24469972 TI - Different strategies of 25OH vitamin D supplementation in HIV-positive subjects. AB - Summary A high incidence of 25OH vitamin D deficiency has been observed in HIV infected subjects. The objective of this study was to evaluate the effect of cholecalciferol administration on serum 25OH vitamin D levels in HIV-infected patients. This prospective cohort study included 153 HIV-positive subjects; 47 were treated with 300,000 IU intramuscular cholecalciferol, 67 with 25,000 IU oral cholecalciferol monthly, while the remaining 39 did not receive any treatment. The group treated orally had an increase of serum 25OH vitamin D concentration, changing from 15.7 +/- 12.2 ng/mL to 27.4 +/- 11.6 ng/mL after 10 months (T10). The group treated with intramuscular supplementation had an improvement, changing from 18.5 +/- 10.5 ng/mL to 32.9.0 +/- 12.2 ng/mL at T10. One-way repeated measures analysis of variance indicated a significant difference for 25OH vitamin D variation (p = 0.002) among the three groups. A significant effect of time (p < 0.001) and group * time interaction (p < 0.001) was found: at T10, 25OH vitamin D values were significantly higher in the oral and intramuscular groups with respect to the control group. Our findings showed that the supplementation with cholecalciferol in patients with HIV-infection improved 25OH vitamin D serum levels, and suggest that the two types of administration are equivalent, but are insufficient for severe forms of hypovitaminosis. PMID- 24469973 TI - Molecular identification and genetic relationships of Palestinian grapevine cultivars. AB - Palestine has a wide range of agro-ecological concerns and hosts a large variety of plants. Grapes are part of the cultural heritage and provide an indispensable food ingredient. Local cultivars have been traditionally identified on the basis of morphological traits, geographical origin, or names of the vineyard owner; therefore, the occurrence of homonymy, synonymy, and misnaming significantly prevents their valorization. DNA profiling by 22 common SSR markers was used to characterize 43 putative cultivars grown mainly for local table grape consumption at the southern highland regions of West-Bank, to further evaluate genetic diversity and relationships of the population. Consistent matching of SSR markers with grapevines cultivated in neighboring countries or maintained in European germplasm collections was found for 8 of the 21 different non-redundant genotypes discovered, suggesting possible synonyms as well as the occurrence of breeding selections formerly developed in the USA. Genetic relationships inferred from SSR markers clearly assigned Palestinian cultivars to the Proles orientalis subpr. Antasiatica ancestral population, and they even remarked the connection between local resources and cultivars generated from international table grape breeding. This study supports the value of collection and conservation of vines endemic to a region of immense historical importance for viticulture. PMID- 24469974 TI - Mapping measures of microscopic diffusion anisotropy in human brain white matter in vivo with double-wave-vector diffusion-weighted imaging. AB - PURPOSE: To demonstrate that rotationally invariant measures of the diffusion anisotropy on a microscopic scale can be mapped in human brain white matter in vivo. METHODS: Echo-planar imaging experiments (resolution 3.0 * 3.0 * 3.0 mm(3) ) involving two diffusion-weighting periods (delta = 22 ms, Delta = 25 ms) in the same acquisition, so-called double-wave-vector or double-pulsed-field-gradient diffusion-weighting experiments, were performed on a 3 T whole-body magnetic resonance system with a long mixing time ( taum=45 ms) between the two diffusion weightings. RESULTS: The disturbing influences of background gradient fields, eddy currents, and the finite mixing time can be minimized using 84 direction combinations based on nine directions and their antipodes. In healthy volunteers, measures of the microscopic diffusion anisotropy ( IMA and MA indexes) could be mapped in white matter across the human brain. The measures were independent (i) of the absolute orientation of the head and of the diffusion directions and (ii) of the predominant fiber orientation. Compared to the fractional anisotropy derived from the conventional diffusion tensor, the double-wave-vector indexes exhibit a narrower distribution, which could reflect their independence of the fiber orientation distribution. CONCLUSIONS: Mapping measures of the microscopic diffusion anisotropy in human brain white matter is feasible in vivo and could help to characterize tissue microstructure in the healthy and pathological brain. PMID- 24469975 TI - Boswellic acids reduce Th17 differentiation via blockade of IL-1beta-mediated IRAK1 signaling. AB - Interferon-gamma producing CD4(+) T (Th1) cells and IL-17-producing CD4(+) T (Th17) cells are involved in the pathogenesis of several autoimmune diseases including multiple sclerosis. Therefore, the development of treatment strategies controlling the generation and expansion of these effector cells is of high interest. Frankincense, the resin from trees of the genus Boswellia, and particularly its prominent bioactive compound acetyl-11-keto-beta-boswellic acid (AKBA), have potent anti-inflammatory properties. Here, we demonstrate that AKBA is able to reduce the differentiation of human CD4(+) T cells to Th17 cells, while slightly increasing Th2- and Treg-cell differentiation. Furthermore, AKBA reduces the IL-1beta-triggered IL-17A release of memory Th17 cells. AKBA may affect IL-1beta signaling by preventing IL-1 receptor-associated kinase 1 phosphorylation and subsequently decreasing STAT3 phosphorylation at Ser727, which is required for Th17-cell differentiation. The effects of AKBA on Th17 differentiation and IL-17A release make the compound a good candidate for potential treatment of Th17-driven diseases. PMID- 24469976 TI - Small nerve fiber involvement in patients referred for fibromyalgia. AB - INTRODUCTION: Fibromyalgia (FM) is a chronic syndrome characterized by widespread pain often accompanied by other symptoms suggestive of neuropathic pain. We evaluated patients for small fiber neuropathy (SFN) who were referred for fibromyalgia (FM). METHODS: We studied 20 consecutive subjects with primary FM. Patients underwent neurological examination, nerve conduction studies, and skin biopsies from distal leg and thigh. RESULTS: Electrodiagnostic studies were normal in all patients. SFN was diagnosed in 6 patients by reduced epidermal nerve fiber density. These patients also showed abnormalities of both adrenergic and cholinergic fibers. CONCLUSIONS: A subset of FM subjects have SFN, which may contribute to their sensory and autonomic symptoms. Skin biopsy should be considered in the diagnostic work-up of FM. PMID- 24469977 TI - Reply: To PMID 23925898. PMID- 24469978 TI - Spot moire fringes: determination of domain boundaries and structural parameters in ordered nanoporous structures. AB - Spot moire fringes are generated by the superposition between a nanoporous structure and a digital three-way grating. The spot moire fringes are useful for the characterization of the domain boundaries and structural parameters in ordered nanoporous materials. The pitches and the orientations of the nanopore arrays in three directions can be simultaneously determined in a large view field. PMID- 24469979 TI - Interactive role of depression, distress tolerance and negative urgency on non suicidal self-injury. AB - Negative affect often precedes non-suicidal self-injury (NSSI). Negative urgency (NU) and distress tolerance (DT) are associated with NSSI yet represent different trait-like pathways to maladaptive affect regulation. This study examined the role of NU, (lack of) premeditation, depression and DT on NSSI in a sample of 884 undergraduates. Main effects for depression and NU emerged, with no main effects of DT. There was a significant three-way interaction of NU, DT and depression, whereas no interaction was found for (lack of) premeditation. The influence of NU and depression on NSSI is enhanced when individuals have low perceived ability to tolerate distress. PMID- 24469980 TI - Contribution to the structural characterization of eucaryotic PSI reaction centre I. Critical analysis of the polypeptidic composition of different P700 enriched fractions. AB - In thylakoid membranes, several peptides of high MW? are present which may interfere with the study of CP1's components. Modifying Cleveland's technique [7] for limited proteolysis, we have characterized the polypeptides found in the 60 kD region. Some may result from incomplete washing of the CF1 while others come from the CP1; indeed, this chlorophyll protein complex, which has a higher MW (above 100 kD), very often undergoes a dissociation into smaller components of about 60 KD MW.Analysis of the protein content of different preparations commonly used to obtain PSI reaction centre enriched fractions has been performed. The alpha and beta subunits of CF1 are among the main contaminants of most of these preparations. A further purification step is described which can be applied to all these preparations, but numerous peptides are still present in the active fractions. It is most unlikely that all these polypeptides are required for the primary photochemical event, and this emphasizes the necessity to find a new simple method to purify PSI reaction centres. PMID- 24469981 TI - Contribution to the structural characterization of eucaryotic PSI reaction centre - II. Characterization of a highly purified photoactive SDS-CP1 complex. AB - Under precise conditions, SDS PAGE? allows purification of a photoactive P700 chla-protein complex from eucaryotic cells. The yield of P700 recovery is close to 100%. A total protein content equivalent to about 140 kD for one mole of P700 has been estimated by chemical analysis, and electrophoresis revealed the presence of two peptidic chains with MWs close to 65 kD. Photochemical and structural properties of this complex are given and compared with those of other complexes previously isolated. PMID- 24469982 TI - Physiological effects of photosystem II-herbicides on the development of the photosynthetic apparatus. AB - Photosystem II-herbicides (bentazone*, diuron) not only block photosynthetic electron transport, but have additional effects on the cell metabolism of Raphanus seedlings. They induce the formation of shade-type chloroplasts with a different ultrastructure and prenyllipid composition. This is shown by higher grana stacks as well as by higher chlorophyll b and lutein amounts with reference to chlorophyll a, and lower levels of the plastidic prenylquinones (plastoquinone, phylloquinone, alpha-tocoquinone) and beta-carotene as compared to the controls.The two herbicides bentazone and diuron change the labelling pattern of the chloroplast pigments from (3)H-mevalonic acid and 2-(14)C-acetate and also reduce the accumulation of anthocyanin (pelargonidin), which is a further indication of a shade-type growth response. The level of ubiquinone, an indicator for mitochondrial activity, is, however, increased. PMID- 24469983 TI - The effect of O2 and CO 2 concentration on photosynthesis and glycolate accumulation in bean leaves treated with alpha-hydroxy-2-pyridinemethanesulfonic acid (alpha-HPMS), the glycolate oxidase inhibitor. AB - (14)CO2 assimilation, (14)C incorporation into glycolate and glycolate accumulation in alpha-HPMS? treated bean leaves at various O2 and CO2 concentrations were studied. In 1% CO2 oxygen concentration had no significant effect on glycolate accumulation and (14)C incorporation into glycolate. In the CO2 concentration range of 0.03% to 0.01%, increased oxygen concentration decreased not only (14)CO2 assimilation but also glycolate accumulation and (14)C incorporation into glycolate. In 1% and 0.1% CO2, no matter what O2 concentration was supplied, and in 0.03% CO2 with 2% and 21% O2, all of the glycolate accumulated was formed from newly assimilated carbon. In 0.01% CO2 and 2%, 21% and 100% O2, and in 0.03% CO2 with 100% O2, a substantial portion of the glycolic acid that accumulated in leaves originated from endogenous unlabelled substrates. These findings are discussed in terms of possible changes in the ratio of RuBP carboxylation to RuBP oxygenation and of changes of RuBP pool size, induced by changing O2 and CO2 concentrations. PMID- 24469984 TI - The effect of kinetin on the photosynthetic apparatus of Sinapis alba. AB - The influence of kinetin during the development of primary leaves of Sinapis alba was investigated. Kinetin treatment (6 ppm) induced an increase of dry weight, of soluble reducing sugars, soluble protein, chlorophylls, carotenoids and cytochrome f; a higher ratio of chlorophyll a to chlorophyll b, higher rates of CO2 fixation per fresh weight and higher activity of nitrite reductase, were also found. These effects are comparable with strong and blue light adaptations. On the other hand, the Hill activity with ferricyanide as the electron acceptor, the rates of CO2 fixation per chlorophyll, the ratios of chlorophyll to cytochrome f and of protein to chlorophyll did not change. Therefore we assume that the kinetin induced and the light induced adaptations are brought about by different causal reaction chains. PMID- 24469985 TI - Post-intubation tracheal rupture: poor healing of the tracheal wall. AB - PURPOSE: To describe tracheal rupture after orotracheal intubation assisted by a tracheal tube introducer. CLINICAL FEATURES: A 73-yr-old morbidly obese female patient with a history of hypertension underwent a total knee replacement. There were no anticipated signs of difficult intubation. Orotracheal intubation was attempted twice by direct laryngoscopy, and a Boussignac bougie was used as a tube exchanger for the second attempt. Seven hours after tracheal extubation, the patient became dyspneic and showed a large subcutaneous emphysema. A chest x-ray and computerized tomography scan revealed rupture of the posterior tracheal wall. The distal part of the injury was 26.5 cm from the patient's teeth and 0.5 cm from the carina (i.e., beyond the normal location of the tracheal tube tip) and extended to the origin of the right main bronchus, where the tip of the Boussignac bougie was probably pushed. Formation of an endotracheal sac occurred during the first two weeks after intubation, accompanied by dyspnea and alveolar hypoventilation, but symptoms resolved favourably with conservative management. CONCLUSION: The tracheal rupture was attributed to airway manipulations, and the distal location of the lesion suggests that the cause was the Boussignac bougie rather than the tracheal tube. Long-term healing of the injury was satisfactory, although the patient continued to complain of dyspnea one year after the rupture. PMID- 24469986 TI - Short-term heat acclimation is effective and may be enhanced rather than impaired by dehydration. AB - Most heat acclimation data are from regimes longer than 1 week, and acclimation advice is to prevent dehydration. OBJECTIVES: We hypothesized that (i) short-term (5-day) heat acclimation would substantially improve physiological strain and exercise tolerance under heat stress, and (ii) dehydration would provide a thermally independent stimulus for adaptation. METHODS: Nine aerobically fit males heat acclimated using controlled-hyperthermia (rectal temperature 38.5 degrees C) for 90 min on 5 days; once euhydrated (EUH) and once dehydrated (DEH) during acclimation bouts. Exercising heat stress tests (HSTs) were completed before and after acclimations (90-min cycling in Ta 35 degrees C, 60% RH). RESULTS: During acclimation bouts, [aldosterone]plasma rose more across DEH than EUH (95%CI for difference between regimes: 40-411 pg ml(-1); P = 0.03; n = 5) and was positively related to plasma volume expansion (r = 0.65; P = 0.05), which tended to be larger in DEH (CI: -1 to 10%; P = 0.06; n = 9). In HSTs, resting forearm perfusion increased more in DEH (by 5.9 ml 100 tissue ml(-1) min(-1): 11.5 to -1.0; P = 0.04) and end-exercise cardiac frequency fell to a greater extent (by 11 b min(-1): -1 to 22; P = 0.05). Hydration-related effects on other endocrine, cardiovascular, and psychophysical responses to HSTs were unclear. Rectal temperature was unchanged at rest but was 0.3 degrees C lower at end exercise (P < 0.01; interaction: P = 0.52). CONCLUSIONS: Short-term (5-day) heat acclimation induced effective adaptations, some of which were more pronounced after fluid-regulatory strain from permissive dehydration, and not attributable to dehydration effects on body temperature. PMID- 24469987 TI - Ultrastructural and cytochemical aspects of the germarium and the vitellarium in Syndesmis patagonica (Platyhelminthes, Rhabdocoela, Umagillidae). AB - The cytoarchitecture of the female gonad of the endosymbiont umagillid Syndesmis patagonica has been investigated using electron microscopy and cytochemical techniques. The female gonad consists of paired germaria and vitellaria located behind the pharynx in the mid-posterior region of the body. Both the germaria and the vitellaria are enveloped by an outer extracellular lamina and an inner sheath of accessory cells which contribute to the extracellular lamina. Oocyte maturation occurs completely during the prophase of the first meiotic division. Oocyte differentiation is characterized by the appearance of chromatoid bodies and the development of endoplasmic reticulum and Golgi complexes. These organelles appear to be involved in the production of round granules, about 2-2.5 MUm in diameter, with a homogeneous electron-dense core surrounded by a granular component and a translucent halo delimited by a membrane. These egg granules migrate to the periphery of mature oocytes, are positive to the cytochemical test for polyphenol detection, are unaffected by protease and have been interpreted as eggshell granules. The mature oocytes also contain a small number of yolk granules, lipid droplets, and glycogen particles scattered throughout the ooplasm. The vitellaria are branched organs composed of vitelline follicles with vitellocytes at different stages of maturation. Developing vitellocytes contain well-developed rough endoplasmic reticulum and small Golgi complexes involved in the production of eggshell and yolk globules. Eggshell globules are round, measure 4-5 MUm in diameter, and have a mosaic-like patterned content which contains polyphenols. The yolk globules, 2-3 MUm in diameter, show a homogeneous protein content of medium electron density, devoid of polyphenols, and completely digested by protease. The mature vitellocytes also contain glycogen as further reserve material. The presence of polyphenolic eggshell granules in the oocytes and of polyphenolic eggshell globules with a mosaic-like pattern in the vitellocytes have been considered apomorphic features of the Rhabdocoela + Prolecithophora. PMID- 24469989 TI - First-line sonographic diagnosis of pneumothorax in major trauma: accuracy of e FAST and comparison with multidetector computed tomography. AB - PURPOSE: Combined clinical examination and supine chest radiography have shown low accuracy in the assessment of pneumothorax in unstable patients with major chest trauma during the primary survey in the emergency room. The aim of our study was to evaluate the diagnostic accuracy of extended-focused assessment with sonography in trauma (e-FAST), in the diagnosis of pneumothorax, compared with the results of multidetector computed tomography (MDCT) and of invasive interventions (thoracostomy tube placement). MATERIALS AND METHODS: This was a retrospective case series involving 368 consecutive unstable adult patients (273 men and 95 women; average age, 25 years; range, 16-68 years) admitted to our hospital's emergency department between January 2011 and December 2012 for major trauma (Injury Severity Score >= 15). We evaluated the accuracy of thoracic ultrasound in the detection of pneumothorax compared with the results of MDCT and invasive interventions (thoracostomy tube placement). Institutional review board approval was obtained prior to commencement of this study. RESULTS: Among the 736 lung fields included in the study, 87 pneumothoraces were detected with thoracic CT scans (23.6%). e-FAST detected 67/87 and missed 20 pneumothoraces (17 mild, 3 moderate). The diagnostic performance of ultrasound was: sensitivity 77% (74% in 2011 and 80% in 2012), specificity 99.8%, positive predictive value 98.5%, negative predictive value 97%, accuracy 97.2% (67 true positive; 668 true negative; 1 false positive; 20 false negative); 17 missed mild pneumothoraces were not immediately life-threatening (thickness less than 5 mm). CONCLUSIONS: Thoracic ultrasound (e-FAST) is a rapid and accurate first-line, bedside diagnostic modality for the diagnosis of pneumothorax in unstable patients with major chest trauma during the primary survey in the emergency room. PMID- 24469988 TI - Cyberknife stereotactic radiosurgery for the re-irradiation of brain lesions: a single-centre experience. AB - PURPOSE: The aim of our study was to retrospectively evaluate the feasibility and clinical benefit of cyberknife stereotactic radiosurgery (CSRS) in patients treated at Florence University for recurrent, pre-irradiated brain lesions. MATERIALS AND METHODS: Thirteen patients were retreated with cyberknife. Mean age was 47.1 years (range 33-77 years). Karnofsky performance status ranged from 60 to 100 (median 80). Eleven (84.6%) out of 13 patients had metastatic lesions: four (36.4%) had primary lung, three (27.2%) had primary breast cancer and four (36.4%) other types of solid malignancies. Two (15.4%) out of 13 patients had recurrent of glioblastoma. RESULTS: In terms of compliance with CSRS, the majority of patients did not develop any acute side effects. However, two (15.4%) out of 13 patients developed acute grade 2 toxicity requiring an increase of steroid medication. At the time of the last follow-up, response rates were as follows: complete response in one case (16.6%), partial response in three (50%) and stable disease in two (33.4%). CONCLUSIONS: Re-irradiation with CSRS is a feasible and effective option for pre-irradiated, recurrent brain lesions to obtain clinical benefit without excessive acute toxicity. PMID- 24469990 TI - Uveal melanoma: evaluation of extrascleral extension using thin-section MR of the eye with surface coils. AB - PURPOSE: This study was done to evaluate the role of high-resolution magnetic resonance (MR) imaging with special surface coils in selecting the correct therapeutic approach (eye enucleation or follow-up) in patients with suspected extrascleral extension of uveal melanoma. MATERIALS AND METHODS: This prospective study involved 12 patients with suspected extrascleral extension of uveal melanoma on orbital ultrasonography. All patients were studied with thin-section MR imaging of the eye using surface coils. RESULTS: High-resolution MR imaging of the eye excluded extrascleral extension of disease in 8/12 patients: in 4/8 cases it revealed vascular ectasia and in the other 4/8 cases the linear hypointensity of the sclera was unbroken. Seven of these eight patients were followed up by ultrasound, which showed stability of melanoma for at least 2 years, while the last patient underwent enucleation, and the histological examination confirmed the MR diagnosis. In 4/12 patients, high-resolution MR suggested a diagnosis of extrascleral extension of melanoma, which was confirmed at histological examination after enucleation. CONCLUSION: High-resolution MR imaging of the eye with surface coils allowed us to evaluate extrascleral extension of uveal melanoma and choose the correct therapeutic approach, avoiding unnecessary enucleation in 7/12 patients. PMID- 24469991 TI - Does reversible cysteine oxidation link the Western diet to cardiac dysfunction? AB - Using a novel cysteine thiol labeling strategy coupled with mass spectrometric analysis, we identified and quantified the changes in global reversible cysteine oxidation of proteins in the left ventricle of hearts from mice with metabolic syndrome-associated diastolic dysfunction. This phenotype was induced by feeding a high-fat, high-sucrose, type-2 diabetogenic diet to C57BL/6J mice for 8 mo. The extent of reversible thiol oxidation in relationship to the total available (free and reducible) level of each cysteine could be confidently determined for 173 proteins, of which 98 contained cysteines differentially modified >=1.5-fold by the diet. Our findings suggest that the metabolic syndrome leads to potentially deleterious changes in the oxidative modification of metabolically active proteins. These alterations may adversely regulate energy substrate flux through glycolysis, beta-oxidation, citric acid (TCA) cycle, and oxidative phosphorylation (oxphos), thereby contributing to maladaptive tissue remodeling that is associated with, and possibly contributing to, diastolic left ventricular dysfunction. PMID- 24469992 TI - Kindlin-3 enhances breast cancer progression and metastasis by activating Twist mediated angiogenesis. AB - The FERM domain containing protein Kindlin-3 has been recognized as a major regulator of integrin function in hematopoietic cells, but its role in neoplasia is totally unknown. We have examined the relationship between Kindlin-3 and breast cancer in mouse models and human tissues. Human breast tumors showed a ~7 fold elevation in Kindlin-3 mRNA compared with nonneoplastic tissue by quantitative polymerase chain reaction. Kindlin-3 overexpression in a breast cancer cell line increased primary tumor growth and lung metastasis by 2.5- and 3 fold, respectively, when implanted into mice compared with cells expressing vector alone. Mechanistically, the Kindlin-3-overexpressing cells displayed a 2.2 fold increase in vascular endothelial growth factor (VEGF) secretion and enhanced beta1 integrin activation. Increased VEGF secretion resulted from enhanced production of Twist, a transcription factor that promotes tumor angiogenesis. Knockdown of Twist diminished VEGF production, and knockdown of beta1 integrins diminished Twist and VEGF production by Kindlin-3-overexpressing cells, while nontargeting small interfering RNA had no effect on expression of these gene products. Thus, Kindlin-3 influences breast cancer progression by influencing the crosstalk between beta1 integrins and Twist to increase VEGF production. This signaling cascade enhances breast cancer cell invasion and tumor angiogenesis and metastasis. PMID- 24469994 TI - Reply: To PMID 23740775. PMID- 24469993 TI - Ovarian LGR5 is critical for successful pregnancy. AB - Leucine-rich repeat-containing G-protein-coupled receptor 5 (Lgr5) is expressed in many organs, including female reproductive organs, and is a stem cell marker in the stomach and intestinal epithelium, hair follicles, and ovarian surface epithelium. Despite ongoing studies, the definitive physiological functions of Lgr5 remain unclear. We utilized mice with conditional deletion of Lgr5 (Lgr5(d/d)) in the female reproductive organs by progesterone receptor-Cre (Pgr(Cre)) to determine Lgr5's functions during pregnancy. Only 30% of plugged Lgr5(d/d) females delivered live pups, and their litter sizes were lower. We found that pregnancy failure in Lgr5(d/d) females was due to insufficient ovarian progesterone (P4) secretion that compromised decidualization, terminating pregnancy. The drop in P4 levels was reflected in elevated levels of P4 metabolizing enzyme 20alpha-hydroxysteroid dehydrogenase in corpora lutea (CL) inactivated of Lgr5. Of interest, P4 supplementation rescued decidualization failure and supported pregnancy to full term in Lgr5(d/d) females. These results provide strong evidence that Lgr5 is critical to normal CL function, unveiling a new role of LGR5 in the ovary. PMID- 24469995 TI - Expansion of CD16 positive and negative human NK cells in response to tumor stimulation. AB - NK cells are innate immune lymphocytes that express a vast repertoire of germ line encoded receptors for target recognition. These receptors include inhibitory and activating proteins, among the latter of which is CD16, a low affinity binding Fc receptor. Here, we show that human NK cells expand in response to stimulation with various tumor cell lines. We further demonstrate that the tumor derived expansion of NK cells is accompanied by rapid, cell-dependent, changes in CD16 expression levels. We show that in NK cells expanded in response to the EBV transformed cell line 721.221, CD16 is shed and therefore approximately half of the expanded 721.221-derived NK-cell population does not express CD16. We also show, in contrast, that in response to 1106mel cells, CD16 expression is maintained on the cell surface of the expanded NK cells due to an antibody dependent mechanism. Our results may provide a basis for the selective expansion of NK cells that may be used for tumor immunotherapy. PMID- 24469996 TI - 1H, 15N, and 13C backbone chemical shift assignment of titin domains A59-A60 and A60 alone. AB - The giant protein titin is the third most abundant protein of vertebrate striated muscle. The titin molecule is >1 MUm long and spans half the sarcomere, from the Z-disk to the M-line, and has important roles in sarcomere assembly, elasticity and intracellular signaling. In the A-band of the sarcomere titin is attached to the thick filaments and mainly consists immunoglobulin-like and fibronectin type III-like domains. These are mostly arranged in long-range patterns or 'super repeats'. The large super-repeats each contain 11 domains and are repeated 11 times, thus forming nearly half the titin molecule. Through interactions with myosin and C-protein, they are involved in thick filament assembly. The importance of titin in muscle assembly is highlighted by the effect of mutations in the A-band portion, which are the commonest cause of dilated cardiomyopathy, affecting ~1 in 250 (Herman et al. in N Engl J Med 366:619-628, 2012). Here we report backbone (15)N, (13)C and (1)H chemical shift and (13)Cbeta assignments for the A59-A60 domain tandem from the titin A59-A69 large super-repeat, completed using triple resonance NMR. Since, some regions of the backbone remained unassigned in A60 domain of the complete A59-A60 tandem, a construct containing a single A60 domain, A60sd, was also studied using the same methods. Considerably improved assignment coverage was achieved using A60sd due to its lower mass and improved molecular tumbling rate; these assignments also allowed the analysis of inter-domain interactions using chemical shift mapping against A59-A60. PMID- 24469997 TI - Determination of ascorbic acid and its degradation products by high-performance liquid chromatography-triple quadrupole mass spectrometry. AB - This study describes application of liquid chromatography coupled with triple quadrupole mass spectrometry (LC-MS) for evaluation of vitamin C stability, the objective being prediction of the degradation products. Detection was performed with an UV detector (UV-Vis) in sequence with a triple-quad mass spectrometer in the multiple reaction mode. The negative ion mode of ESI and MS-MRM transitions of m/z 175->115 (quantifier) and 175->89 (qualifier) for ascorbic acid was used. All the validation parameters were within the range of acceptance proposed by the Food and Drug Administration. The method was fully validated in terms of linearity, LOD, LOQ, accuracy, and interday precision. Validation experiments revealed good linearity with R(2) = 0.999 within the established concentration range, and excellent repeatability (9.3%). The LOD of the method was 0.1524 ng/mL whereas the LOQ was 0.4679 ng/mL. LC-MS methodology proves to be an improved, simple, and fast approach to determining the content of vitamin C and its degradation products with high sensitivity, selectivity, and resolving power within 6 minutes of analysis. PMID- 24469998 TI - Hydrophilic block azidation of PCL-b-PEO block copolymers from epichlorohydrin. AB - Amphiphilic diblock copolymers poly(epsilon-caprolactone)-b-poly(ethylene oxide) (PCL-b-PEO) with well-controlled pendant azido groups along the hydrophilic PEO block, that is, poly(epsilon-caprolactone)-b-poly(ethylene oxide-co-glycidyl azide) (PCL-b-P(EO-co-GA)), are synthesized from poly(epsilon-caprolactone)-b poly(ethylene oxide-co-epichlorohydrin) (PCL-b-P(EO-co-ECH)). The further conversion of those azido groups along the hydrophilic block of copolymers into amino or carboxyl groups via click chemistry is studied. The micelles self assembled from PCL-b-P(EO-co-GA) with azido groups on the shell are crosslinked by the dialkynyl-PEO. The micelles with crosslinked shell show better stability, higher drug loading capacities, subsequent faster drug release rate, and higher cytotoxicity to cancer cells. The introduction of azido groups into PCL-b-PEO amphiphilic diblock copolymers from epichlorohydrin in PEO hydrophilic block in this work provides a new method for biofunctionalization of micelles via mild click chemistry. PMID- 24469999 TI - New insights in the pathogenesis of Erdheim-Chester disease: comment on the article by Los Arcos-Bertiz et al. PMID- 24470000 TI - Hydrogenative dearomatization of pyridine and an asymmetric aza-Friedel-Crafts alkylation sequence. AB - Highly efficient synthesis of enantiomerically enriched substituted piperidines has been realized via chiral phosphoric acid catalyzed cascade hydrogenative dearomatization of substituted pyridines and aza-Friedel-Crafts reaction in good to excellent yields and enantioselectivity. PMID- 24470001 TI - Cardiac metastasis in Merkel cell carcinoma. PMID- 24470002 TI - Hyaluronan synthase 3 variant and anthracycline-related cardiomyopathy: a report from the children's oncology group. AB - PURPOSE: The strong dose-dependent association between anthracyclines and cardiomyopathy is further exacerbated by the co-occurrence of cardiovascular risk factors (diabetes and hypertension). The high morbidity associated with cardiomyopathy necessitates an understanding of the underlying pathogenesis so that targeted interventions can be developed. PATIENTS AND METHODS: By using a two-stage design, we investigated host susceptibility to anthracycline-related cardiomyopathy by using the ITMAT/Broad CARe cardiovascular single nucleotide polymorphism (SNP) array to profile common SNPs in 2,100 genes considered relevant to de novo cardiovascular disease. RESULTS: By using a matched case control design (93 cases, 194 controls), we identified a common SNP, rs2232228, in the hyaluronan synthase 3 (HAS3) gene that exerts a modifying effect on anthracycline dose-dependent cardiomyopathy risk (P = 5.3 * 10(-7)). Among individuals with rs2232228 GG genotype, cardiomyopathy was infrequent and not dose related. However, in individuals exposed to high-dose (> 250 mg/m(2)) anthracyclines, the rs2232228 AA genotype conferred an 8.9-fold (95% CI, 2.1- to 37.5-fold; P = .003) increased cardiomyopathy risk compared with the GG genotype. This gene-environment interaction was successfully replicated in an independent set of 76 patients with anthracycline-related cardiomyopathy. Relative HAS3 mRNA levels measured in healthy hearts tended to be lower among individuals with AA compared with GA genotypes (P = .09). CONCLUSION: Hyaluronan (HA) produced by HAS3 is a ubiquitous component of the extracellular matrix and plays an active role in tissue remodeling. In addition, HA is known to reduce reactive oxygen species (ROS) -induced cardiac injury. The high cardiomyopathy risk associated with AA genotype could be due to inadequate remodeling and/or inadequate protection of the heart from ROS-mediated injury on high anthracycline exposure. PMID- 24470003 TI - Randomized controlled trial of expressive writing for patients with renal cell carcinoma. AB - PURPOSE: This randomized controlled trial examined the quality-of-life benefits of an expressive writing (EW) intervention for patients with renal cell carcinoma (RCC) and identified a potential underlying mechanism of intervention efficacy. PATIENTS AND METHODS: Patients (N = 277) with stage I to IV RCC were randomly assigned to write about their deepest thoughts and feelings regarding their cancer (EW) or about neutral topics (neutral writing [NW]) on four separate occasions. Patients completed the Center for Epidemiologic Studies Depression Scale (CES-D), MD Anderson Symptom Inventory (MDASI), Brief Fatigue Inventory (BFI), Pittsburgh Sleep Quality Index (PSQI), Medical Outcomes Study Short Form 36 (SF-36), and Impact of Event Scale (IES) at baseline and 1, 4, and 10 months after the intervention. RESULTS: The mean age of participants (28% stage IV; 41% female) was 58 years. Multilevel modeling analyses, using a Bonferroni-corrected alpha = .021 for six outcomes adjusted for the correlation among outcomes, revealed that, relative to the NW group, patients in the EW group reported significantly lower MDASI scores (P = .003) and higher physical component summary scores on the SF-36 (P = .019) at 10 months after the intervention. Mediation analyses revealed that significant group differences for MDASI scores at 10 months were mediated by lower IES scores at 1 month after the intervention in the EW group (P = .042). No significant group differences were observed in the BFI, CES-D, PSQI, and mental component summary of the SF-36. CONCLUSION: EW may reduce cancer-related symptoms and improve physical functioning in patients with RCC. Evidence suggests that this effect may occur through short-term improvements in cognitive processing. PMID- 24470004 TI - Yoga's impact on inflammation, mood, and fatigue in breast cancer survivors: a randomized controlled trial. AB - PURPOSE: To evaluate yoga's impact on inflammation, mood, and fatigue. PATIENTS AND METHODS: A randomized controlled 3-month trial was conducted with two post treatment assessments of 200 breast cancer survivors assigned to either 12 weeks of 90-minute twice per week hatha yoga classes or a wait-list control. The main outcome measures were lipopolysaccharide-stimulated production of proinflammatory cytokines interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-alpha), and interleukin-1beta (IL-1beta), and scores on the Multidimensional Fatigue Symptom Inventory-Short Form (MFSI-SF), the vitality scale from the Medical Outcomes Study 36-item Short Form (SF-36), and the Center for Epidemiological Studies Depression (CES-D) scale. RESULTS: Immediately post-treatment, fatigue was not lower (P > .05) but vitality was higher (P = .01) in the yoga group compared with the control group. At 3 months post-treatment, fatigue was lower in the yoga group (P = .002), vitality was higher (P = .01), and IL-6 (P = .027), TNF-alpha (P = .027), and IL-1beta (P = .037) were lower for yoga participants compared with the control group. Groups did not differ on depression at either time (P > .2). Planned secondary analyses showed that the frequency of yoga practice had stronger associations with fatigue at both post-treatment visits (P = .019; P < .001), as well as vitality (P = .016; P = .0045), but not depression (P > .05) than simple group assignment; more frequent practice produced larger changes. At 3 months post-treatment, increasing yoga practice also led to a decrease in IL-6 (P = .01) and IL-1beta (P = .03) production but not in TNF-alpha production (P > .05). CONCLUSION: Chronic inflammation may fuel declines in physical function leading to frailty and disability. If yoga dampens or limits both fatigue and inflammation, then regular practice could have substantial health benefits. PMID- 24470005 TI - Recurrent dermatophytosis (Majocchi granuloma) associated with chemotherapy induced neutropenia. PMID- 24470006 TI - Burnout and career satisfaction among US oncologists. AB - PURPOSE: To evaluate the personal and professional characteristics associated with career satisfaction and burnout among US oncologists. METHODS: Between October 2012 and March 2013, the American Society of Clinical Oncology conducted a survey of US oncologists evaluating burnout and career satisfaction. The survey sample included equal numbers of men and women and represented all career stages. RESULTS: Of 2,998 oncologists contacted, 1,490 (49.7%) returned surveys (median age of respondents, 52 years; 49.6% women). Among the 1,117 oncologists (37.3% of overall sample) who completed full-length surveys, 377 (33.8%) were in academic practice (AP) and 482 (43.2%) in private practice (PP), with the remainder in other settings. Oncologists worked an average of 57.6 hours per week (AP, 58.6 hours per week; PP, 62.9 hours per week) and saw a mean of 52 outpatients per week. Overall, 484 oncologists (44.7%) were burned out on the emotional exhaustion and/or depersonalization domain of Maslach Burnout Inventory (AP, 45.9%; PP, 50.5%; P = .18). Hours per week devoted to direct patient care was the dominant professional predictor of burnout for both PP and AP oncologists on univariable and multivariable analyses. Although a majority of oncologists were satisfied with their career (82.5%) and specialty (80.4%) choices, both measures of career satisfaction were lower for those in PP relative to AP (all P < .006). CONCLUSION: Overall career satisfaction is high among US oncologists, albeit lower for those in PP relative to AP. Burnout rates among oncologists seem similar to those described in recent studies of US physicians in general. Those oncologists who devote the greatest amount of their professional time to patient care seem to be at greatest risk for burnout. PMID- 24470008 TI - Multiple clustered nodules on the leg. Diagnosis: Merkel cell carcinoma. PMID- 24470007 TI - Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. AB - PURPOSE: For patients with breast cancer (BC), the optimal time to initiation of adjuvant chemotherapy (TTC) after definitive surgery is unknown. We evaluated the association between TTC and survival according to breast cancer subtype and stage at diagnosis. PATIENTS AND METHODS: Women diagnosed with BC stages I to III between 1997 and 2011 who received adjuvant chemotherapy at our institution were included. Patients were categorized into three groups according to TTC: <= 30, 31 to 60, and >= 61 days. Survival outcomes were estimated and compared according to TTC and by BC subtype. RESULTS: Among the 6,827 patients included, the 5-year overall survival (OS), relapse-free survival (RFS), and distant RFS (DRFS) estimates were similar for the different TTC categories. Initiation of chemotherapy >= 61 days after surgery was associated with adverse outcomes among patients with stage II (DRFS: hazard ratio [HR], 1.20; 95% CI, 1.02 to 1.43) and stage III (OS: HR, 1.76; 95% CI, 1.26 to 2.46; RFS: HR, 1.34; 95% CI, 1.01 to 1.76; and DRFS: HR, 1.36; 95% CI, 1.02 to 1.80) BC. Patients with triple-negative BC (TNBC) tumors and those with human epidermal growth factor receptor 2 (HER2) positive tumors treated with trastuzumab who started chemotherapy >= 61 days after surgery had worse survival (HR, 1.54; 95% CI, 1.09 to 2.18 and HR, 3.09; 95% CI, 1.49 to 6.39, respectively) compared with those who initiated treatment in the first 30 days after surgery. CONCLUSION: TTC influenced survival outcomes in the overall study cohort. This finding was particularly meaningful for patients with stage III BC, TNBC, and trastuzumab-treated HER2-positive tumors who experienced worse outcomes when chemotherapy was delayed. Our findings suggest that early initiation of chemotherapy should be granted for patients in these high-risk groups. PMID- 24470010 TI - Crusted scabies in a 15-year-old boy with congenital neutropenia and myelodysplastic syndrome. PMID- 24470009 TI - Nuclear protein in testis midline carcinoma misdiagnosed as adamantinoma. PMID- 24470011 TI - Cutis verticis gyrata in association with vemurafenib and whole-brain radiotherapy. PMID- 24470012 TI - Long-term results of laparoscopic gastrectomy for gastric cancer: a large-scale case-control and case-matched Korean multicenter study. AB - PURPOSE: The oncologic outcomes of laparoscopy-assisted gastrectomy for the treatment of gastric cancer have not been evaluated. The aim of this study is to validate the efficacy and safety of laparoscopic gastrectomy for gastric cancer in terms of long-term survival, morbidity, and mortality retrospectively. PATIENTS AND METHODS: The study group comprised 2,976 patients who were treated with curative intent either by laparoscopic gastrectomy (1,477 patients) or open gastrectomy (1,499 patients) between April 1998 and December 2005. The long-term 5-year actual survival analysis in case-control and case-matched population was conducted using the Kaplan-Meier method. The morbidity and mortality and learning curves were evaluated. RESULTS: In the case-control study, the overall survival, disease-specific survival, and recurrence-free survival (median follow-up period, 70.8 months) were not statistically different at each cancer stage with the exception of an increased overall survival rate for patients with stage IA cancer treated via laparoscopy (laparoscopic group; 95.3%, open group: 90.3%; P < .001). After matching using a propensity scoring system, the overall survival, disease specific survival, and recurrence-free survival rates were not statistically different at each stage. The morbidity of the case-matched group was 15.1% in the open group and 12.5% in the laparoscopic group, which also had no statistical significance (P = .184). The mortality rate was also not statistically significant (0.3% in the open group and 0.5% in the laparoscopic group; P = 1.000). The mean learning curve was 42. CONCLUSION: The long-term oncologic outcomes of laparoscopic gastrectomy for patients with gastric cancer were comparable to those of open gastrectomy in a large-scale, multicenter, retrospective clinical study. PMID- 24470013 TI - Defining the role of laparoscopic gastrectomy for gastric cancer. PMID- 24470014 TI - Risk factors for alcohol relapse after liver transplantation for alcoholic cirrhosis in Japan. AB - Alcoholic liver cirrhosis (ALC) is an established indication for liver transplantation (LT). Most LT procedures in Japan are living donor liver transplantation (LDLT) because of an extreme shortage of deceased donors. Social circumstances enabling LDLT could be favorable for preventing relapse. The aims of this retrospective study were to analyze the outcomes of LDLT for ALC and to evaluate risk factors for relapse in this cohort. One hundred ninety-five subjects underwent LT [LDLT (n = 187), deceased donor LT (n = 5), or domino LT (n = 3)] for ALC in Japan from November 1997 to December 2011. Risk factors for alcohol relapse and the impact of relapse on outcomes were analyzed for 140 patients after the exclusion of 26 patients who died in the hospital and 29 patients without information about alcohol relapse. The incidence of alcohol consumption after LT was 22.9%. The risk factors for patient survival were a donor age >= 50 years (P < 0.01) and a Model for End-Stage Liver Disease score >= 19 (P = 0.03). The 10-year patient survival rates were 21.9% and 73.8% for patients who had relapsed and patients who had not relapsed 18 months after LT, respectively (P = 0.01). The relapse rates were 50.0%, 34.5%, 13.3%, 19.7%, and 14.3% for patients who had received livers from parents, siblings, spouses, sons/daughters, and deceased or domino donors, respectively. A history of treatment for psychological diseases other than alcoholism before LT was a significant indicator for the risk of recidivism (P = 0.02), and noncompliance with clinic visits after LT and smoking after transplantation were promising indicators for the risk of recidivism (P = 0.06, and P = 0.05, respectively). Preoperative alcohol consumption was not a risk factor. In conclusion, rather than selecting patients on the basis of preoperative alcohol use, we should provide sociomedical support to improve adherence after LT for ALC in Japan. PMID- 24470015 TI - The Ras superfamily of small GTPases: the unlocked secrets. AB - The Ras superfamily of small GTPases is composed of more than 150 members, which share a conserved structure and biochemical properties, acting as binary molecular switches turned on by binding GTP and off by hydrolyzing GTP to GDP. However, despite considerable structural and biochemical similarities, these proteins play multiple and divergent roles, being versatile and key regulators of virtually all fundamental cellular processes. Conversely, their dysfunction plays a crucial role in the pathogenesis of serious human diseases, including cancer and developmental syndromes. Fuelled by the original identification in 1982 of mutationally activated and transforming human Ras genes in human cancer cell lines, a variety of powerful experimental techniques have been intensively focused on discovering and studying structure, biochemistry, and biology of Ras and Ras-related small GTPases, leading to fundamental research breakthroughs into identification and structural and functional characterization of a huge number of Ras superfamily members, as well as of their multiple regulators and effectors. In this review we provide a general overview of the major milestones that eventually allowed to unlock the secret treasure chest of this large and important superfamily of proteins. PMID- 24470016 TI - A novel method for the production of fully modified K-Ras 4B. AB - Post-translational modifications in proteins play a major functional role. Post translational modifications affect the way proteins interact with each other, bind nucleotides, and localize in cellular compartments. Given the importance of post-translational modifications in protein biology, development of methods to produce post-translationally modified proteins for biochemical and biophysical studies is timely and significant. At the same time, obtaining post translationally modified proteins in bacterial expression systems is often problematic. Here, we describe a novel recombinant approach to prepare human K Ras 4B, a protein that is post-translationally farnesylated, proteolytically cleaved, and methylated in its C-terminus. K-Ras 4B is a member of the Ras subfamily of small GTPases and is of interest because it is frequently mutated in human cancer. The method relies on separate production of two structural domains the N-terminal catalytic domain and the C-terminal peptide chemically modified with S-farnesyl-L-cysteine methyl ester. After the two domains are prepared, they are ligated together using the transpeptidase enzyme, sortase. Our procedure starts with the use of the plasmid of K-Ras 4B catalytic domain containing the sortase recognition sequence. After this, we describe the bacterial expression and purification steps used to purify K-Ras 4B and the preparation of the conjugated C-terminal peptide. The procedure ends with the sortase-mediated ligation technique. The produced post-translationally modified K-Ras 4B is active in a number of assays, including a GTP hydrolysis assay, Raf-1 binding assay, and surface plasmon resonance-based phospholipid binding assay. PMID- 24470017 TI - Metabolic labeling of Ras with tritiated palmitate to monitor palmitoylation and depalmitoylation. AB - Metabolic labeling with tritiated palmitate is a direct method for monitoring posttranslational modification of Ras proteins with this fatty acid. Advances in intensifying screens have allowed for the easy visualization of tritium without the need for extended exposure times. While more energetic radioisotopes are easier to visualize, the lack of commercial source and need for shielding make them more difficult to work with. Since radiolabeled palmitate is directly incorporated into Ras, its loss can be monitored by traditional pulse-chase experiments that cannot be accomplished with the method of acyl-exchange chemistry. As such, tritiated palmitate remains a readily accessible and direct method for monitoring the palmitoylation status of Ras proteins under a multitude of conditions. PMID- 24470018 TI - Ubiquitination of Rac1 by inhibitors of apoptosis (IAPs). AB - Ubiquitination of proteins has emerged as a vital posttranslational modification at the crux of numerous signalling pathways, regulating them in various ways. Most members of the small GTPase family including Ras and Rho proteins are regulated by GEFs, GAPs, and RhoGDIs that modulate their cycling between the active and inactive states. Ubiquitination has added another layer to the regulation of small GTPases. Recently, we have uncovered that inhibitors of apoptosis (IAPs) function as direct E3 ubiquitin ligases for Rho GTPase Rac1 and target it for proteasomal degradation. Here, we describe in vitro and in vivo ubiquitination assays for detecting the conjugation of ubiquitin to Rac1 by XIAP and cIAP1. PMID- 24470019 TI - Ras GTPases are both regulators and effectors of redox agents. AB - Redox agents have been historically considered pathological agents which can react with and damage many biological macromolecules including DNA, proteins, and lipids. However, a growing number of reports have suggested that mammalian cells can rapidly respond to ligand stimulation with a change in intracellular ROS thus indicating that the production of intracellular redox agents is tightly regulated and that they serve as intracellular signaling molecules being involved in a variety of cell signaling pathways. Numerous observations have suggested that some members of the Ras GTPase superfamily appear to regulate the production of redox agents and that oxidants can function as effector molecules for the small GTPases, thus contributing to their overall biological function. In addition, many of the Ras superfamily small GTPases have been shown to be redox sensitive, thanks to the presence of redox-sensitive sequences in their primary structure. The action of redox agents on these redox-sensitive GTPases is similar to that of guanine nucleotide exchange factors in that they perturb GTPase nucleotide binding interactions that result in the enhancement of the guanine nucleotide exchange of small GTPases. Thus, Ras GTPases may act both as upstream regulators and downstream effectors of redox agents. Here we overview current understanding concerning the interplay between Ras GTPases and redox agents, also taking into account pathological implications of misregulation of this cross talk and highlighting the potentiality of these cellular pathways as new therapeutical targets for different pathologies. PMID- 24470020 TI - Biophysical and proteomic characterization strategies for cysteine modifications in Ras GTPases. AB - Cysteine is one of the most reactive amino acids and is modified by a number of oxidants. The reactivity of cysteines is dependent on the thiol pK a; however, measuring cysteine pK a values is nontrivial. Ras family GTPases have been shown to contain a free cysteine that is sensitive to oxidation, and free radical mediated oxidation of this cysteine has been shown to be activating. Here, we present a new technique that allows for measuring cysteine pK a values using a fluorescent detection system with the molecule 4-fluoro-7 aminosulfonylbenzofurazan (ABD-F). In addition, we also describe how to generate several oxidants. Lastly, we describe several mass spectrometry-based experiments and the necessary adjustments to the experiments to detect cysteine oxidation. PMID- 24470021 TI - Use of the yeast two-hybrid technology to isolate molecular interactions of Ras GTPases. AB - Since its original description, the yeast two-hybrid system has been extensively used to identify protein-protein interactions from many different organisms, thus providing a convenient mean to both screen for proteins that interact with a protein of interest and to characterize the known interaction between two proteins. In these years the technique has improved to overcome the limitations of the original assay, and many efforts have been made to scale up the technique and to adapt it to large-scale studies. In addition, variations have been introduced to enlarge the range of proteins and interactors that can be assayed by hybrid-based approaches. Several groups studying molecular mechanisms that underlie signal transduction pathways regulated by Ras GTPases have successfully used the yeast two-hybrid system or related methods to isolate and identify new binding partners of Ras proteins. Here we describe the basic protocol for a yeast two-hybrid library screening and for a small-scale yeast two-hybrid assay. PMID- 24470022 TI - Screening for MAPK modulators using an in-cell western assay. AB - Several essential cellular functions are critically influenced by the Ras-Raf-MEK ERK cascade, and pathological problems have been implicated with loss as well as gain of its activity. Therefore, there is a great demand for chemical probes that act as modulators of the cascade in order to correct medical problems associated with its malfunctions. Here we describe the use of the In-Cell Western assay, a fast and easy method for the detection of ERK activity. This method is useful for the screening of chemical libraries for compounds that modulate the intensity and duration of growth factor-induced MAPK activity. Examples are provided from a screen for MAPK modulators in Vichem Chemie Research's Nested Chemical LibraryTM. PMID- 24470024 TI - Functional phosphoproteomics of oncogenic KRAS signaling. AB - Identification of oncogene-mediated phosphorylation events is essential to understanding the molecular determinants responsible for cancer development and progression. Here, we identify KRAS-regulated phosphorylation events using label free quantitation-based comparative phosphoproteomics analyses of immortalized human bronchial epithelial cells that express oncogenic KRAS as well as cells that do not. Further, we demonstrate integration of the identified phosphorylation events with the Pathway Interaction Database to infer KRAS regulated pathways, which may have implications in KRAS-associated lung adenocarcinoma development. Taken together, our study provides an overview of the functional phosphoproteomics approach involving cell culture, preparation of whole cell lysates, trypsin digestion, phosphopeptide enrichment, mass spectrometry analyses, label-free quantitative analyses, and signaling pathway analyses to study KRAS-targeted events. PMID- 24470023 TI - Behavioral methods for the study of the Ras-ERK pathway in memory formation and consolidation: passive avoidance and novel object recognition tests. AB - Memory is a high-level brain function that enables organisms to adapt their behavioral responses to the environment, hence increasing their probability of survival. The Ras-ERK pathway is a key molecular intracellular signalling cascade for memory consolidation. In this chapter we will describe two main one-trial behavioral tests commonly used in the field of memory research in order to assess the role of Ras-ERK signalling in long-term memory: passive avoidance and object recognition. Passive avoidance (PA) is a fear-motivated instrumental learning task, designed by Jarvik and Essman in 1960, in which animals learn to refrain from emitting a behavioral response that has previously been associated with a punishment. We will describe here the detailed protocol and show some examples of how PA can reveal impairments or enhancements in memory consolidation following loss or gain of function genetic manipulations of the Ras-ERK pathway. The phenotypes of global mutants as Ras-GRF1 KO, GENA53, and ERK1 KO mice, as well as of conditional region-specific mutants (striatal K-CREB mice), will be illustrated as examples. Novel object recognition (NOR), developed by Ennaceur and Delacour in 1988, is instead a more recent and highly ecological test, which relies on the natural tendency of rodents to spontaneously approach and explore novel objects, representing hence a useful non-stressful tool for the study of memory in animals without the employment of punishments or starvation/water restriction regimens. Careful indications will be given on how to select the positions for the novel object, in order to counterbalance for individual side preferences among mice during the training. Finally, the methods for calculating two learning indexes will be described. In addition to the classical discrimination index (DI) that measures the ability of an animal to discriminate between two different objects which are presented at the same time, we will describe the formula of a new index that we present here for the first time, the recognition index (RI), which quantifies the ability of an animal to recognize a same object at different time points and that, by taking into account the basal individual preferences displayed during the training, can give a more accurate measure of an animal's actual recognition memory. PMID- 24470025 TI - Pull-down assay for analysis of integrin-mediated activation of Rap proteins in adherent platelets. AB - Rap1 GTPases operate as molecular switches by cycling between a GDP-bound inactive state and a GTP-bound active state and regulate several cellular pathways in response to different stimuli. Circulating blood platelets express high levels of Rap1 proteins, mainly Rap1b, which plays a critical role in platelet adhesion and activation. Rap1 is a key element in the inside-out signaling pathway leading to the conversion of integrins into the high-affinity state for their ligands. In platelets, Rap1b regulates inside-out activation of both integrin alphaIIbbeta3 and alpha2beta1. In addition, Rap1b is also involved in integrin outside-in signaling. Integrin-mediated platelet adhesion leads to accumulation of GTP-bound Rap1b, which promotes integrin-mediated processes such as spreading and clot retraction. Rap1b is thus a bidirectional regulator of platelet integrin function. Here we describe a method to analyze Rap1b activation induced by platelet adhesion via integrin alpha2beta1. PMID- 24470026 TI - Combined pulldown and time-lapse microscopy studies for determining the role of Rap1 in the crosstalk between integrins and cadherins. AB - The coordinate modulation of the cellular functions of cadherins and integrins plays an essential role in fundamental physiological and pathological processes, including morphogenesis, tissue differentiation and renewal, wound healing, immune surveillance, inflammatory response, tumor progression, and metastasis. Recent findings state the molecular mechanisms underlying the fine-balanced relationship between cadherins and integrins. In particular, some of the novel results recently obtained raise the possibility of a pivotal role for the small GTPase Rap1 in the functional crosstalk between cadherins and integrins. Considering the importance of the molecular signalling triggered by Rap1, here we provide protocols to study this small GTPase in signalling pathways involving cadherins and integrins. PMID- 24470027 TI - Fluorescence microscopy study of Rap1 subcellular localization. AB - The Ras-related GTPase Rap has been implicated in multiple cellular functions. In particular, Rap1 is a crucial regulator of both inside-out integrin activation and outside-in E-cadherin-mediated signaling. Thus, Rap1 was proposed as a fundamental regulator of the cross talk between cadherins and integrins. We provide microscopic techniques to study subcellular localization of Rap1 protein in the crosstalk between integrins and cadherins. PMID- 24470028 TI - An in vitro system to evaluate the scaffold function of the RalA effector protein RalBP1. AB - The in vitro kinase assay is an invaluable method to identify and characterize kinase substrates and to determine specific site(s) of phosphorylation. However, the use of recombinant proteins does not adequately account for the contribution of accessory proteins, such as scaffolds, that can contribute to the phosphorylation reaction in vivo. We describe here a method to evaluate the contribution of specific scaffold proteins to kinase reactions using a modified in vitro kinase assay. PMID- 24470029 TI - Analysis of the Rit subfamily GTPase-mediated signaling and neuronal differentiation and survival. AB - The Rit subfamily of GTPases is a founding branch within the Ras family of small G-proteins and preserves unique sequences in the G2 effector loop domain and the C-terminus. Rit proteins regulate a diversity of signal transduction pathways, some of which are similar to and others of which differ from the pathways that are regulated by other Ras family GTPases. Rit proteins have been demonstrated to be essential regulators in neuronal differentiation and survival. Here, we describe the materials and methods utilized to characterize cellular signaling for the Rit subfamily of G-proteins in neuronal differentiation and survival. PMID- 24470030 TI - Immunofluorescence methods in studies of the GTPase RAN and its effectors in interphase and in mitotic cells. AB - The GTPase RAN, the regulators of its nucleotide-bound state, and its effectors represent a specialized network in the RAS GTPase superfamily and regulate the localization of macromolecules (RNAs and proteins) in subcellular compartments in interphase cells and at the mitotic apparatus when cells divide. Essential cell cycle processes, e.g., replication, repair, transcription, export of transcribed RNAs out of the nucleus, assembly of the mitotic apparatus, kinetochore function, chromosome segregation, nuclear reorganization, and rebuilding of the nuclear envelope and nuclear pores at mitotic exit, ultimately depend on RAN's ability to orchestrate localization of key target factors in space and time. To achieve this, RAN network members acquire themselves dynamic localization patterns. Biochemical fractionation protocols describe where the bulk of RAN network members localize. Immunofluorescence methods have revealed more subtle and complex patterns, with specific populations of RAN network components associating with cellular structures, or organelles, where they play crucial roles as spatial regulators for a large set of macromolecules. These localization studies are important to understand RAN modes of action and to identify new targets of RAN control. Here we describe methods for the visualization of RAN network members and effectors in mammalian cells. PMID- 24470031 TI - High-resolution scanning electron microscopy for the imaging of nuclear pore complexes and Ran-mediated transport. AB - High-resolution scanning electron microscopy provides three-dimensional surface images of nuclear pore complexes (NPCs) embedded in the nuclear envelope. Here, we describe a method for exposing the nuclear surface in mammalian tissue culture cells for imaging by scanning electron microscopy. Hypotonic treatment is followed by low-speed centrifugation onto polylysine-coated silicon chips, without the use of detergents. This helps to preserve NPCs close to their native morphology, embedded in undamaged nuclear membranes. This method is particularly advantageous for combining high-resolution imaging of NPCs with mammalian genetic systems. PMID- 24470032 TI - Effector recruitment method to study spatially regulated activation of Ras and Rho GTPases. AB - Ras and Rho family GTPases control a wide variety of cellular processes, and the signaling downstream of these GTPases is influenced by their subcellular localization when activated. Since only a minority of total cellular GTPases is active, observation of the total subcellular distribution of GTPases does not reveal where active GTPases are localized. In this chapter, we describe the use of effector recruitment assays to monitor the subcellular localization of active Ras and Rho family GTPases. The recruitment assay relies on preferential binding of downstream effectors to active GTPases versus inactive GTPases. Tagging the GTPase-binding-domain (GBD) of a downstream effector with a fluorescent protein produces a probe that is recruited to compartments where GTPases are active. We describe an example of a recruitment assay using the GBD of PAK1 to monitor Rac1 activity and explain how the assay can be expanded to determine the subcellular localization of activation of other GTPases. PMID- 24470033 TI - Real-time visualization and quantification of native Ras activation in single living cells. AB - Members of the Ras family of small guanosine triphosphate phosphohydrolases are GDP/GTP-binding proteins that function as pivotal molecular switches in multiple cell biological processes. The prototypical Ras family members K-Ras, N-Ras, and H-Ras, in particular, have been the focus of intense research for the last 30 years owing to their critical function as signalling nodes in the control of cell growth and proliferation and as drivers of oncogenic transformation. One aspect that has attracted much attention in recent times is the spatial control of Ras activity, which is dictated largely by a series of posttranslational modifications that do effectively govern the subcellular distribution and trafficking of Ras. Accordingly, strong emphasis has been placed on developing methodological microscopy-based approaches for the visualization of active Ras GTP complexes at subcellular resolution. Here we describe the use of a collection of fluorescent affinity probes for the real-time visualization of Ras-GTP in live cells. These probes are multivalent and thus feature high avidity/affinity to Ras GTP, which obviates the over-expression of Ras and enables one to image endogenous Ras-GTP formation. In addition, this chapter details the use of automated segmentation strategies for the unbiased quantification of probe derived fluorescence at individual subcellular sites like the plasma membrane and endomembranes. PMID- 24470034 TI - Nanoclustering and heterogeneous membrane diffusion of Ras studied by FRAP and RICS analysis. AB - Fluorescence Recovery After Photobleaching (FRAP) and Raster Image Correlation Spectroscopy (RICS) are two powerful techniques to study the diffusion dynamics of fluorescently labeled proteins. FRAP and RICS can be easily applied on any commercial confocal microscope. In this chapter, we describe the principles of these methods and provide the reader with a detailed guide on how to apply these methods in the study of Ras nanoclustering and diffusion in the plasma membrane of live cells. PMID- 24470035 TI - Analyzing the roles of Rho GTPases in cancer cell migration with a live cell imaging 3D-morphology-based assay. AB - Rho GTPases are master regulators of cytoskeleton dynamics and therefore regulate cell motility. Rho GTPases, as well as their regulators and effectors, are often deregulated in cancers and thus contribute to tumor progression to metastasis. Cancer progression involves multiple steps, including invasion of the surrounding tissues. Several methods to investigate the invasion of tumors cells in 3D matrices in vitro have been developed. In this chapter we describe a 3D-based morphology assay that can be used for medium-throughput microscopy-based screening to identify regulators of cancer cell invasion. We use this method coupled to RNAi to investigate how Rho GTPases affect prostate cancer cell morphology in 3D Matrigel. PMID- 24470036 TI - Analysis of Rho GTPase-induced localization of nanoscale adhesions using fluorescence nanoscopy. AB - Rho GTPases are important regulators of the formation of focal adhesions and focal complexes, and thereby they are key regulators of cell adhesion and migration. Here, we describe a method to study the relocalization of proteins within cell-matrix adhesions at a nanoscale level, through the use of super resolution stimulated emission depletion microscopy imaging. We furthermore describe computational tools for image processing and data analysis. Thus, the method presented in this chapter provides an unbiased approach to the quantitative evaluation of the spatial distribution of the nanoscale protein assemblies by which cells adhere to an underlying substrate. PMID- 24470037 TI - Yeast as a model for Ras signalling. AB - For centuries yeast species have been popular hosts for classical biotechnology processes, such as baking, brewing, and wine making, and more recently for recombinant proteins production, thanks to the advantages of unicellular organisms (i.e., ease of genetic manipulation and rapid growth) together with the ability to perform eukaryotic posttranslational modifications. Moreover, yeast cells have been used for few decades as a tool for identifying the genes and pathways involved in basic cellular processes such as the cell cycle, aging, and stress response. In the budding yeast S. cerevisiae the Ras/cAMP/PKA pathway is directly involved in the regulation of metabolism, cell growth, stress resistance, and proliferation in response to the availability of nutrients and in the adaptation to glucose, controlling cytosolic cAMP levels and consequently the cAMP-dependent protein kinase (PKA) activity. Moreover, Ras signalling has been identified in several pathogenic yeasts as a key controller for virulence, due to its involvement in yeast morphogenesis. Nowadays, yeasts are still useful for Ras like proteins investigation, both as model organisms and as a test tube to study variants of heterologous Ras-like proteins. PMID- 24470038 TI - Methods to study the Ras2 protein activation state and the subcellular localization of Ras-GTP in Saccharomyces cerevisiae. AB - Ras proteins were highly conserved during evolution. They function as a point of convergence for different signalling pathways in eukaryotes and are involved in a wide range of cellular responses (shift from gluconeogenic to fermentative growth, breakdown of storage carbohydrates, stress resistance, growth control and determination of life span, morphogenesis and development, and others). These proteins are members of the small GTPase superfamily, which are active in the GTP bound form and inactive in the GDP-bound form. Given the importance of studies on the Ras protein activation state to understand the detailed mechanism of Ras mediated signal transduction, we provide here a simple, sensitive, and reliable method, based on the high affinity interaction of Ras-GTP with the Ras binding domain (RBD) of Raf1, to measure the level of Ras2-GTP on total Ras2 in Saccharomyces cerevisiae. Moreover, to study the localization of Ras-GTP in vivo in single S. cerevisiae cells, we expressed a probe consisting of a GFP fusion with a trimeric Ras Binding Domain of Raf1 (eGFP-RBD3), which was proven to be a useful live-cell biosensor for Ras-GTP in mammalian cells. PMID- 24470039 TI - Ras proteins signaling in the early metazoan Dictyostelium discoideum. AB - Since the discovery of Ras, Ras-mediated transforming activity has been the major investigative area of interest. Soon thereafter it has emerged that Ras family members regulate different biological processes, other than cell growth, like development and fine-tune the balance between cell death and survival. The lower metazoan Dictyostelium discoideum is a powerful and genetically accessible model organism that has been used to elucidate the roles played by different Ras members in some biological processes, such as cell motility and development. In the following chapter we describe some very basic techniques aiming to identify novel Ras signaling components, throughout insertional mutagenesis screening, and to investigate their role(s) in development and chemotaxis processes. PMID- 24470040 TI - Increased efficiency in geographic ancestry assignment and human identification by combining lineage profiles: The case of the Iranians. AB - OBJECTIVES: This research is a first empirical attempt to quantify the increase of the among-groups variance and the probative value of a DNA evidence when combining profiles based on markers with uniparental inheritance. METHODS: Yfiler and HVS-I panels of loci were analyzed in 130 healthy unrelated males from six Iranian native groups. RESULTS: A separate analysis of DNA profiles at the two lineage markers failed to detect a population substructure, whereas maximum levels of genetic diversity (HD = 1) and discrimination capacity (DC = 1) were obtained by combining the two profiles. CONCLUSIONS: When combined, the forensic efficiency of routinely used panels of lineage markers can be largely sufficient to resolve cases of geographic ancestry and human identification even in genetically homogeneous populations. PMID- 24470041 TI - Engaging teens and parents in collaborative practice: perspectives on diabetes self-management. AB - PURPOSE: The purpose of this exploratory focus group study was to describe the perspectives of teens and their parents about self-management knowledge, behaviors (including division of labor associated with T1D management), and resources used to manage T1D. The overall goal is to use this information to develop a teen-family transition clinic. METHODS: The self and family management behaviors framework undergirded the separate teen-parent focus groups that were conducted concurrently. Note-based qualitative content analysis was used, resulting in several important messages. RESULTS: From the teens' perspective there was variation in interest in learning more about T1D and management. Those teens who had been diagnosed at a very young age reported not knowing anything else but diabetes, while those diagnosed later developmentally embraced the active learning process. Diabetes camp and peer group support were not seen as beneficial. All the teens were interested in "helping others" with diabetes. Parents shared the common struggle with transition of self-management, with variation in parenting styles. A small group of parents reported their "job" as a parent was to make sure their child was self-sufficient in self-management, but felt pressure from the health care providers (HCPs) to physically do the care, defeating the purpose. Parents and teens reported wanting HCPs to be less focused on "numbers" (blood glucose levels) and more on the whole person. Scheduling appointment changes and long waiting times were reported as problematic by all participants. CONCLUSIONS: Teen and parent perspectives are critical in designing future well-received adolescent-family transition clinics. Development from the ground up with family recommendations may contribute to high-quality health outcomes. PMID- 24470042 TI - Self-management in early adolescence and differences by age at diagnosis and duration of type 1 diabetes. AB - PURPOSE: The purpose of the study was to describe the frequency of diabetes self management activities, processes, and goals among early adolescents. In addition, differences in self-management by age at diagnosis and duration of diabetes were explored. METHODS: A cross-sectional design was used to analyze baseline data from 320 adolescents with T1DM enrolled in a multisite clinical trial. Participants completed questionnaires on demographic/clinical characteristics and self-management. RESULTS: There was a transitional pattern of self-management with a high frequency of diabetes care activities, problem solving, and goals and variable amounts of collaboration with parents. After controlling for therapy type and age, youth with short diabetes duration reported performing significantly more diabetes care activities than individuals with a longer duration. Individuals with short diabetes duration had more frequent communication than individuals with a longer duration, which was associated with diagnosis in adolescence. Among those diagnosed as school age children, those with short diabetes duration reported significantly more diabetes goals than those with a longer duration. CONCLUSIONS: A more specific understanding of self management may help clinicians provide more targeted education and support. Adolescents with a long duration of diabetes need additional self-management support, particularly for diabetes care activities and communication. PMID- 24470043 TI - Low bone mineral density and fragility fractures in permanent vegetative state patients. AB - Disuse of the musculoskeletal system causes bone loss. Whether patients in vegetative state, a dramatic example of immobilization after severe brain injury, suffer from bone loss and fractures is currently unknown. Serum markers of bone turnover, bone mineral density (BMD) measurements, and clinical data were cross sectionally analyzed in 30 consecutive vegetative state patients of a dedicated apallic care unit between 2003 and 2007 and compared with age- and sex-matched healthy individuals. Vegetative state patients showed low calcium levels and vitamin D deficiency compared with healthy controls. Serum bone turnover markers revealed high turnover as evidenced by markedly elevated carboxy-terminal telopeptide of type I collagen (beta-crosslaps) and increased levels of alkaline phosphatase. BMD measured by dual-energy X-ray absorptiometry (DXA) scanning showed strongly decreased T- and Z-scores for hip and spine. Over a period of 5 years, 8 fragility fractures occurred at peripheral sites in 6 of 30 patients (n = 3 femur, n = 2 tibia, n = 2 fibula, n = 1 humerus). In conclusion, high bone turnover and low BMD is highly prevalent in vegetative state patients, translating into a clinically relevant problem as shown by fragility fractures in 20% of patients over a time period of 5 years. . PMID- 24470044 TI - Influenza A/H1/N1/09 infection in patients with cirrhosis has a poor outcome: a case series. AB - Seasonal influenza is often unsuspected in cirrhotic patients admitted with pneumonia and acute hepatic decompensation. We report five consecutive patients with influenza A subtype H1N1 2009 strain (influenza A/H1N1/09) admitted to our intensive care unit. All had a short history of rapidly worsening respiratory symptoms, but there were no characteristic clinical or radiographic features. Secondary pulmonary infection was universal. All five patients died, despite prompt institution of oseltamivir and intensive supportive care. A high index of suspicion is needed for influenza infection among patients with decompensated cirrhosis. PMID- 24470045 TI - Cardioactive properties of Solanaceae plant extracts and pure glycoalkaloids on Zophobas atratus. AB - Glycoalkaloids, the biologically active secondary metabolites produced by Solanaceae plants, are natural defenses against animals, insects and fungi. In this paper, the effects of glycoalkaloids present in extracts of Solanaceae plants (potato, tomato and black nightshade) or pure commercial glycoalkaloids on the coleopteran Zophobas atratus F. were evaluated by in vitro and in vivo bioassays using heart experimental models. Each tested extract induced a dose dependent cardioinhibitory effect. The perfusion of Zophobas atratus semi isolated heart using the highest potato and tomato extract concentration (1 mmol/L) caused irreversible cardiac arrests, while extract from black nightshade produced fast but reversible arrests. Pure commercial glycoalkaloids caused similar but less evident effects compared with extracts. Our results showed that the bioactivity of tested compounds depended on their structure and suggested the existence of synergistic interactions when combinations of the main glycoalkaloids of potato and black nightshade were used for trials. Surprisingly, injection of tomato and potato extracts in 1-day-old pupae of Zophobas atratus induced reversible positive chronotropic effects and decreased the duration of the both phases (anterograde and retrograde) of the heart contractile activity. Furthermore, these extracts affected the amplitude of the heart contractions. PMID- 24470046 TI - The effect of indole-3-acetic-acid on the photosynthetic apparatus of Sinapis alba. AB - The influence of indole-3-acetic-acid (IAA) during the development of primary leaves of Sinapis alba was studied. IAA treatment (4 ppm ~ 22.8 MUM) caused a decrease of dry weight, soluble reducing sugars, soluble protein, chlorophylls, carotenoids and cytochrome f; it also caused a lower ratio of protein to chlorophyll, a lower ratio of chlorophyll a to chlorophyll b and a higher ratio of chlorophyll per cytochrome f. Furthermore, IAA treatment induced a significantly lower rate of CO2 fixation and a depressed nitrite reductase activity. Similar effects could also be observed in adaptation reactions brought about by red light and low-light (or shade) conditions. PMID- 24470047 TI - A portable system for simultaneous measurement of transpiration and CO2 exchange. AB - A portable field system for simultaneous measurement of transpiration and CO2 exchange from leaves of fruit trees is described. CO2 concentration is measured by means of infra-red gas analysis, using small gas samples collected in syringes. Methods for analysing small gas samples are compared. The leaf chamber described can also be used in a conventional laboratory open gas-exchange system, its small volume permitting measurement of very rapid changes in gas exchange in response to experimental stimuli. PMID- 24470048 TI - Stability of etiochloroplasts isolated from pine cotyledons as studied by means of low temperature absorption and fluorescence spectroscopy. AB - 77 K absorption and fluorescence spectra are measured during incubation of etiochloroplast isolated from pine cotyledons and suspended in buffers with or without various co-factors (GSH, ATP, CoA Abbreviations: PChl(ide) = protochlorophyll(ide); PChlideF657 = protochloro-phyllide-lipoprotein complex with fluorescence maximum at 657 nm; Chl(ide) = chlorophyll(ide); PEG = polyethylene glycol; DCIP = 2-6-dichlorophenol indophenol; ALA = ?gd aminolevulinic acid; ATP = adenosine 5?t' triphosphate; CoA = coenzyme A; NADPH = nicotinamide-adenine dinucleotide phosphate, reduced. ) and NADPH. It is shown that, in the absence of co-factors, rapid spectral changes due to denaturation of the protein-pigment complexes occur. The spectral changes differ according to whether denaturation occurs in the light or in the dark. The rate of denaturation of the Ch1-protein complexes is significantly lowered when co-factors are added and a protective effect of NADPH on the PChlide-protein complexes was observed. PMID- 24470049 TI - Phototransformation of protochlorophyllideF657 in etiochloroplasts isolated from pine cotyledons; dark reformation of this pigment-complex from a pool of ALA protochlorophyllideF635 in the presence of NADPH. AB - Etiochloroplasts isolated from dark-grown pine cotyledons fed with delta aminolevulinic acid (ALA Abbreviations: ALA=?Gd-aminolevulinic acid; Chl(ide) = chlorophyll(ide); PChlide = protochlorophyllide; PChlideA636, PChlideA650=forms of protochlorophyllide absorbing light maximally at the wavelength indicated in nm; PChlideF635, PChlideF657=PChlide forms exhibiting a fluorescence maximum at the wavelength indicated; ALA-Pchlide=PChlide formed by an exogenous ALA treatment; NADPH = nicotineamide adeninedinucleotide phosphate. ) contain, in addition to the chlorophyll forms, two protochlorophyllide complexes which emit fluorescence around 635 nm and 657 nm respectively (ALA-PChlideF635 and PChlideF657). By a combination of light flashes and periods of darkness, it is possible to phototransform PChlideF657 and thereafter, if NADPH is added to the system, to re-form this pigment-complex from the pool of ALA-PChlideF635 during the dark periods. The process of phototransformation followed by the re-formation of PChlideF657 in the presence of NADPH can be obtained in vitro five to six times consecutively. The role of NADPH in the formation of the PChlideF657 complex is discussed. PMID- 24470050 TI - Correlated influence of cation concentration and excitation intensity on PS II activity-I. Influence of high salt concentration on spinach chloroplast activity. AB - A correlated influence of cation concentration and excitation energy level on PS II Abbreviations: AMPD = 2-amino-2-methyl-1,3-propanediol; DCIP = 2-6 dichlorophenol indophenol; DCIPH2 = DCIP in reduced state; DCIPr = rate of DCIP reduction; DCMU = 3-(3,4 dichlorophenyl)1-1 dimethyl-urea; Fv = variable fluorescence; Fcat = Fv in the presence of added cations; Ft = Fv without added cations; HEPES = N-2-hydroxyethylpiperazine N?t'2-sulfonic acid; PS II = photosystem II; Vcat = DCIPr in presence of added cations; Vt = DCIPr without added cations. activity is demonstrated.In low light conditions (under 60 Wm(-2)) Mg(++) effect on DCIP reduction rate (DCIPr) saturates at rather low concentrations (2-10 mM). Higher concentrations induce a quenching of the effect, as already observed by several authors. In high light conditions (1000 Wm(-2)) however, Mg(++) is increasingly effective on DCIPr up to concentrations of 200 mM.Na(+) induced variations of DCIPr are weak in low light conditions and slightly positive for 100-600 mM in strong light; no quenching occurs.Modifications in variable fluorescence do not follow those of DCIPr in all cases, especially in high light.These results allow us to distinguish three different effects of cations on the photochemistry of PS II: one on the spill over, another on the turnover rate of the centers and the last on the cation exchange through the thylakoid membrane. PMID- 24470051 TI - Correlated influence of cation concentration and excitation intensity on PS II activity-II. Comparative study between green plant and brown-alga chloroplasts. AB - A preparation of photochemically active chloroplasts of Fucus was added to a low salt medium with high osmolarity (HEPES AMPD buffer, 1M sorbitol). The rate of DCIP reduction (DCIPr) and the variable fluorescence (Fv) of these phaeoplasts were measured and compared with the same activities in spinach chloroplasts. A study of the influence of mono- and divalent-cations showed that salt effects on PS II activity also exist in Fucus. (i) Mg(++) action on Fv is similar, although noticeably weaker in Fucus than in spinach chloroplasts. (ii) Na(+) has no effect on Fv of Fucus chloroplasts, but its influence on DCIPr is more pronounced than in spinach. (iii) Mg(++) influence on DCIPr is largely dependent upon excitation energy. In subsaturating light (100?2-1000 W m(?t-2)), Mg(++) stimulation increases up to 100 mM, almost doubling the level. In very low wight conditions (3Wm(?t02)), however, this stimulation saturates at about 10 mM; higher concentrations are no longer effective but do not quench DCIPr noticeably, unlike the case in spinach. Therefore, cations act through similar pathways on Fucus as on spinach isolated chloroplasts but the effects on PS II centers are preponderant in Fucus whereas the modifications in non-radiative decay or pigment array size are weaker. PMID- 24470052 TI - The response of CO2 exchange rate to photosynthetic photon flux density for several Populus clones under laboratory conditions. AB - No significant differences were found between four mathematical equations describing the response of CO2 exchange rate to photosynthetic photon flux density in seven poplar clones under laboratory conditions. Choice of an optimal equation for poplar may be based on the contemplated aims. High significant differences (at p<0.001) were found among the clones. PMID- 24470053 TI - Morphometric variation between two morphotypes within the Astyanax Baird and Girard, 1854 (Actinopterygii: Characidae) genus, from a Mexican tropical lake. AB - Phenotypic variation is important for evolutionary processes because it can allow local adaptation, promote genetic segregation, and ultimately give rise to speciation. Lacustrine systems provide a unique opportunity to study the mechanisms by which sister species can co-occur by means of ecological segregation. The fish genus Astyanax is characterized by high levels of phenotypic variability, providing an excellent model for the study of local specialization. Here, we analyze the morphological specializations through geometric morphometrics of two sympatric species described as different genera: Bramocharax caballeroi endemic to Lake Catemaco, and the widely distributed Astyanax aeneus. Additionally, we assess the correlation between phenotypic and genetic structure, and the phylogenetic signal of morphological variation. We examined body size and shape variation in 196 individuals and analyzed mitochondrial cytochrome b sequences in 298 individuals. Our results confirm the striking morphological divergence among the sympatric characids. Differences between them were mainly found in the body depth and profile and orientation of the head, where B. caballeroi in contrast with the A. aeneus, presented a fusiform body and an upward mouth. Moreover, different growth trajectories were observed among morphotypes, suggesting that a heterochronic process could be involved in the diversification of our study system. Morphological differences did not correspond with the molecular differentiation, suggesting high levels of homoplasy among the lineages of B. caballeroi morphs. PMID- 24470054 TI - Irreversible site-specific hydrazinolysis of proteins by use of sortase. AB - Sortase-mediated hydrazinolysis of proteins with hydrazine or its derivatives was developed for the production of recombinant protein hydrazides. This process provides an alternative approach for protein semisynthesis through the use of recombinant protein hydrazides as thioester surrogates. It also provides an alternative method for C-terminal modification of proteins with functional units as well as for the preparation of C-to-C fusion proteins. PMID- 24470056 TI - Carcinoma cuniculatum of the esophagus and tongue: report of two cases, including TP53 mutational analysis. AB - Carcinoma cuniculatum (CC) is a rare variant of extremely well differentiated squamous cell carcinoma. We present the clinicopathological features of two cases of CC; one lingual and one esophageal case with a molecular genetic study regarding the TP53 gene mutational status. Case 1 was a 62 year old male with enlarging chronic ulcer in the tongue. Case 2 was a 77 year old male with progressive dysphagia and odynophagia. Both patients were treated surgically. Both tumors showed deeply invaginating, keratin-filled, burrowing crypts lined by very well differentiated squamous epithelium. The esophageal tumor showed varying degrees of reactive nuclear atypia largely limited to the areas with dense intratumoral infiltration of neutrophils. No mutation of TP53 was identified in the esophageal case. Cytologic atypia limited to areas of significant acute inflammation may occur in CC and should, in the absence of aggressive stromal invasion, not preclude a diagnosis of CC. PMID- 24470057 TI - Rheumatoid arthritis: a case for personalized health care? PMID- 24470058 TI - Fostering self-reflection on the anatomy laboratory: Dealing with death and the taboo. PMID- 24470059 TI - HMG CoA reductase inhibitors (statins) for kidney transplant recipients. AB - BACKGROUND: People with chronic kidney disease (CKD) have higher risks of cardiovascular disease compared to the general population. Specifically, cardiovascular deaths account most deaths in kidney transplant recipients. Statins are a potentially beneficial intervention for kidney transplant patients given their established benefits in patients at risk of cardiovascular disease in the general population. This is an update of a review first published in 2009. OBJECTIVES: We aimed to evaluate the benefits (reductions in all-cause and cardiovascular mortality, major cardiovascular events, myocardial infarction and stroke, and progression of CKD to requiring dialysis) and harms (muscle or liver dysfunction, withdrawal, cancer) of statins compared to placebo, no treatment, standard care, or another statin in adults with CKD who have a functioning kidney transplant. SEARCH METHODS: We searched the Cochrane Renal Group's Specialised Register to 29 February 2012 through contact with the Trials Search Co-ordinator using search terms relevant to this review. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and quasi-RCTs that compared the effects of statins with placebo, no treatment, standard care, or statins on mortality, cardiovascular events, kidney function and toxicity in kidney transplant recipients. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data and assessed risk of bias. Treatment effects were expressed as mean difference (MD) for continuous outcomes (lipids, glomerular filtration rate (GFR), proteinuria) and relative risk (RR) for dichotomous outcomes (major cardiovascular events, mortality, fatal or non-fatal myocardial infarction, fatal or non-fatal stroke, elevated muscle or liver enzymes, withdrawal due to adverse events, cancer, end-stage kidney disease (ESKD), acute allograft rejection) together with 95% confidence intervals (CI). MAIN RESULTS: We identified 22 studies (3465 participants); 17 studies (3282 participants) compared statin with placebo or no treatment, and five studies (183 participants) compared two different statin regimens.From data generally derived from a single high-quality study, it was found that statins may reduce major cardiovascular events (1 study, 2102 participants: RR 0.84, CI 0.66 to 1.06), cardiovascular mortality (4 studies, 2322 participants: RR 0.68, CI 0.45 to 1.01), and fatal or non-fatal myocardial infarction (1 study, 2102 participants: RR 0.70, CI 0.48 to 1.01); although effect estimates lack precision and include the possibility of no effect.Statins had uncertain effects on all-cause mortality (6 studies, 2760 participants: RR 1.08, CI 0.63 to 1.83); fatal or non-fatal stroke (1 study, 2102 participants: RR 1.18, CI 0.85 to 1.63); creatine kinase elevation (3 studies, 2233 participants: RR 0.86, CI 0.39 to 1.89); liver enzyme elevation (4 studies, 608 participants: RR 0.62, CI 0.33 to 1.19); withdrawal due to adverse events (9 studies, 2810 participants: RR 0.89, CI 0.74 to 1.06); and cancer (1 study, 2094 participants: RR 0.94, CI 0.82 to 1.07).Statins significantly reduced serum total cholesterol (12 studies, 3070 participants: MD -42.43 mg/dL, CI -51.22 to 33.65); low-density lipoprotein cholesterol (11 studies, 3004 participants: MD 43.19 mg/dL, CI -52.59 to -33.78); serum triglycerides (11 studies, 3012 participants: MD -27.28 mg/dL, CI -34.29 to -20.27); and lowered high-density lipoprotein cholesterol (11 studies, 3005 participants: MD -5.69 mg/dL, CI -10.35 to -1.03).Statins had uncertain effects on kidney function: ESKD (6 studies, 2740 participants: RR 1.14, CI 0.94 to 1.37); proteinuria (2 studies, 136 participants: MD -0.04 g/24 h, CI -0.17 to 0.25); acute allograft rejection (4 studies, 582 participants: RR 0.88, CI 0.61 to 1.28); and GFR (1 study, 62 participants: MD -1.00 mL/min, CI -9.96 to 7.96).Due to heterogeneity in comparisons, data directly comparing differing statin regimens could not be meta analysed. Evidence for statins in people who have had a kidney transplant were sparse and lower quality due to imprecise effect estimates and provided limited systematic evaluation of treatment harm. AUTHORS' CONCLUSIONS: Statins may reduce cardiovascular events in kidney transplant recipients, although treatment effects are imprecise. Statin treatment has uncertain effects on overall mortality, stroke, kidney function, and toxicity outcomes in kidney transplant recipients. Additional studies would improve our confidence in the treatment benefits and harms of statins on cardiovascular events in this clinical setting. PMID- 24470060 TI - Selective host molecules obtained by dynamic adaptive chemistry. AB - Up till 20 years ago, in order to endow molecules with function there were two mainstream lines of thought. One was to rationally design the positioning of chemical functionalities within candidate molecules, followed by an iterative synthesis-optimization process. The second was the use of a "brutal force" approach of combinatorial chemistry coupled with advanced screening for function. Although both methods provided important results, "rational design" often resulted in time-consuming efforts of modeling and synthesis only to find that the candidate molecule was not performing the designed job. "Combinatorial chemistry" suffered from a fundamental limitation related to the focusing of the libraries employed, often using lead compounds that limit its scope. Dynamic constitutional chemistry has developed as a combination of the two approaches above. Through the rational use of reversible chemical bonds together with a large plethora of precursor libraries, one is now able to build functional structures, ranging from quite simple molecules up to large polymeric structures. Thus, by introduction of the dynamic component within the molecular recognition processes, a new perspective of deciphering the world of the molecular events has aroused together with a new field of chemistry. Since its birth dynamic constitutional chemistry has continuously gained attention, in particular due to its ability to easily create from scratch outstanding molecular structures as well as the addition of adaptive features. The fundamental concepts defining the dynamic constitutional chemistry have been continuously extended to currently place it at the intersection between the supramolecular chemistry and newly defined adaptive chemistry, a pivotal feature towards evolutive chemistry. PMID- 24470061 TI - Correlation of 2D:4D digit ratio and craniofacial shape in prepubertal children. AB - OBJECTIVES: The 2D:4D ratio is sexually dimorphic and is considered a proxy of prenatal androgen levels, or, according to recent evidence, is related to genes involved in ocular and palate development. Our aim was to investigate correlation between the 2D:4D ratio and the shape of the craniofacial skeleton in a population of prepubertal children. METHODS: We conducted a cross-sectional study in a group of 58 male and 59 female prepubertal children aged 7-12 years. Craniofacial shape was evaluated using 15 skeletal landmarks on lateral cephalometric radiographs and fingers were measured with a computer-assisted procedure that involved tracing the finger outline. Geometric morphometric analysis was applied to the craniofacial landmarks and multivariate regression between digit ratios and craniofacial shape was computed in shape space and form space. RESULTS: The male 2D:4D ratio was smaller than the female ratio (Cohen's d: 0.275 left hand, 0.126 right hand), but the difference was not statistically significant. Craniofacial shape did not show sexual dimorphism, but males were larger than females. No correlation was found between digit ratio and craniofacial shape in prepubertal children, either for the whole sample or for any of the two sex groups. CONCLUSIONS: As several factors might be involved in the development and growth of both the craniofacial complex and fingers, the 2D:4D ratio, a putative proxy for fetal sex-hormone levels, is probably unable to impose a measurable effect within the variation of a normal population. Future research needs to examine an adult sample for potential covariation arising after the pubertal growth spurt. PMID- 24470063 TI - Structure/activity relationships of (M)ANT- and TNP-nucleotides for inhibition of rat soluble guanylyl cyclase alpha1beta1. AB - Soluble guanylyl cyclase (sGC) plays an important role in cardiovascular function and catalyzes formation of cGMP. sGC is activated by nitric oxide and allosteric stimulators and activators. However, despite its therapeutic relevance, the regulatory mechanisms of sGC are still incompletely understood. A major reason for this situation is that no crystal structures of active sGC have been resolved so far. An important step toward this goal is the identification of high-affinity ligands that stabilize an sGC conformation resembling the active, "fully closed" state. Therefore, we examined inhibition of rat sGCalpha1beta1 by 38 purine- and pyrimidine-nucleotides with 2,4,6,-trinitrophenyl and (N-methyl)anthraniloyl substitutions at the ribosyl moiety and compared the data with that for the structurally related membranous adenylyl cyclases (mACs) 1, 2, 5 and the purified mAC catalytic subunits VC1:IIC2. TNP-GTP [2',3'-O-(2,4,6-trinitrophenyl)-GTP] was the most potent sGCalpha1beta1 inhibitor (Ki, 10.7 nM), followed by 2'-MANT-3' dATP [2'-O-(N-methylanthraniloyl)-3'-deoxy-ATP] (Ki, 16.7 nM). Docking studies on an sGCalphacat/sGCbetacat model derived from the inactive heterodimeric crystal structure of the catalytic domains point to similar interactions of (M)ANT- and TNP-nucleotides with sGCalpha1beta1 and mAC VC1:IIC2. Reasonable binding modes of 2'-MANT-3'-dATP and bis-(M)ANT-nucleotides at sGC alpha1beta1 require a 3'-endo ribosyl conformation (versus 3'-exo in 3'-MANT-2'-dATP). Overall, inhibitory potencies of nucleotides at sGCalpha1beta1 versus mACs 1, 2, 5 correlated poorly. Collectively, we identified highly potent sGCalpha1beta1 inhibitors that may be useful for future crystallographic and fluorescence spectroscopy studies. Moreover, it may become possible to develop mAC inhibitors with selectivity relative to sGC. PMID- 24470062 TI - Feasibility of single-port laparoscopic surgery for sigmoid colon and rectal cancers and preoperative assessment of operative difficulty. AB - PURPOSE: Single-port laparoscopic surgery is more difficult for sigmoid colon and rectal cancers than for right-sided colon cancer. We sought to analyze the feasibility of this procedure for sigmoid colon and rectal cancers and to estimate its difficulty. METHODS: We analyzed prospectively collected data from 63 consecutive patients with sigmoid colon or rectal cancers who underwent single port laparoscopic surgery at our institution from June 2009 to December 2011. Patient and tumor characteristics, including patients' pelvic anatomy which was assessed on CT scan imaging, were evaluated to elucidate what factors would affect the difficulty of the procedure and the necessity of using an additional trocar. RESULTS: Overall, the median operative duration was 190 min and blood loss was 20 ml, with no postoperative complications. The median number of lymph nodes harvested was 17 and the distal margin was 58 mm. The tumor was located significantly closer to the anus in cases in which an additional trocar was required in the right lower quadrant (9.5 vs 18 cm, p < 0.0001). Procedural difficulty was significantly increased in cases in which the sacral promontory protruded ventrally (odds ratio 0.779 [95% confidence interval 0.613 to 0.945], p = 0.0236). CONCLUSIONS: Depending on tumor location and sacral promontory shape, the introduction of an additional trocar might render single-port laparoscopic surgery feasible for sigmoid colon and rectal cancer resection. PMID- 24470064 TI - Efficacy of Metarhizium anisopliae in controlling the two-spotted spider mite Tetranychus urticae on common bean in screenhouse and field experiments. AB - The efficacy of aqueous and emulsifiable formulations of the fungus Metarhizium anisopliae isolate ICIPE78 was evaluated on the population density of Tetranychus urticae infesting common bean plants under screenhouse and field conditions. Synthetic acaricide abamectin was included as a check. Bean plants were artificially infested with T. urticae and allowed to multiply. Three treatments were applied in the screenhouse and 1 treatment in field trials. Mite density was recorded 2 d before spraying and weekly postspraying. The number of pods per plant, number of seeds per pod, and the dry weight of seeds per plant were recorded only in the screenhouse trials. In both screenhouse and field trials, fungal formulations applied at the concentration of 10(8) conidia/mL and the acaricide reduced the population density of mites as compared to the controls. There were significant differences in T. urticae population densities between the treatments at the various post-spraying sampling dates. In the screenhouse, the mite densities were near zero from 3-week postspraying in the treated leaves. At 4-week postspraying, there were no more leaves in the untreated control (T1) and in the control water + Silwet-L77 (T2). Fungal formulations were as effective as abamectin in reducing mite densities in both screenhouse and field experiments. There were significant differences in the production parameters during the 2 screenhouse trials, with fungal and abamectin treatments generally having the highest yield. Results of this study underline the potential of the M. anisopliae isolate ICIPE78 as an alternative to acaricides for T. urticae management. PMID- 24470065 TI - The SEM6A6 locus is not associated with granulomatosis with polyangiitis or other forms of antineutrophil cytoplasmic antibody-associated vasculitides in Europeans: comment on the article by Xie et al. PMID- 24470066 TI - Toll-like receptors expressed on embryonic macrophages couple inflammatory signals to iron metabolism during early ontogenesis. AB - Mammalian TLRs in adult animals serve indispensable functions in establishing innate and adaptive immunity and contributing to the homeostasis of surrounding tissues. However, the expression and function of TLRs during mammalian embryonic development has not been studied so far. Here, we show that CD45(+) CD11b(+) F4/80(+) macrophages from 10.5-day embryo (E10.5) co-express TLRs and CD14. These macrophages, which have the capability to engulf both apoptotic cells and bacteria, secrete a broad spectrum of proinflammatory cytokines and chemokines upon TLR stimulation, demonstrating that their TLRs are functional. Comparative microarray analysis revealed an additional set of genes that were significantly upregulated in E10.5 TLR2(+) CD11b(+) macrophages. This analysis, together with our genetic, microscopic, and biochemical evidence, showed that embryonic phagocytes express protein machinery that is essential for the recycling of cellular iron and that this expression can be regulated by TLR engagement in a MyD88-dependent manner, leading to typical inflammatory M1 responses. These results characterize the utility of TLRs as suitable markers for early embryonic phagocytes as well as molecular triggers of cellular responses, the latter being demonstrated by the involvement of TLRs in an inflammation-mediated regulation of embryonic homeostasis via iron metabolism. PMID- 24470067 TI - Men and women in space: bone loss and kidney stone risk after long-duration spaceflight. AB - Bone loss, a key concern for long-duration space travelers, is typically considered a female issue. The number of women who have flown long-duration space missions is now great enough to allow a quantitative comparison of changes in bone and renal stone risk by sex. Participants were 42 astronauts (33 men and 9 women) on long-duration missions to the International Space Station. Bone mineral density (by dual-energy X-ray absorptiometry) and biochemical markers of bone metabolism (from blood and urine samples) were evaluated before and after flight. Data were analyzed in two groups, based on available resistance exercise equipment. Missions were 49 to 215 days in duration, flown between 2000 and 2012. The bone density response to spaceflight was the same for men and women in both exercise groups. The bone mineral density response to flight was the same for men and women, and the typical decrease in bone mineral density (whole body and/or regional) after flight was not observed for either sex for those using an advanced resistive exercise device. Biochemical markers of bone formation and resorption responded similarly in male and female astronauts. The response of urinary supersaturation risk to spaceflight was not significantly different between men and women, although risks were typically increased after flight in both groups, and risks were greater in men than in women before and after flight. The responses of men and women to spaceflight with respect to these measures of bone health were not different. PMID- 24470068 TI - Neurobiological mechanisms for impulsive-aggression: the role of MAOA. AB - Aggression may be present across a large part of the spectrum of psychopathology, and underlies costly criminal antisocial behaviors. Human aggression is a complex and underspecified construct, confounding scientific discovery. Nevertheless, some biologically tractable subtypes are apparent, and one in particular impulsive (reactive) aggression-appears to account for many facets of aggression related dysfunction in psychiatric illness. Impulsive-aggression is significantly heritable, suggesting genetic transmission. However, the specific neurobiological mechanisms that mediate genetic risk for impulsive-aggression remain unclear. Here, we review extant data on the genetics and neurobiology of individual differences in impulsive-aggression, with particular attention to the role of genetic variation in Monoamine Oxidase A (MAOA) and its impact on serotonergic signaling within corticolimbic circuitry. PMID- 24470069 TI - Mechanistic insights into the interface-directed transformation of thiols into disulfides and molecular hydrogen by visible-light irradiation of quantum dots. AB - Quantum dots (QDs) offer new and versatile ways to harvest light energy. However, there are few examples involving the utilization of QDs in organic synthesis. Visible-light irradiation of CdSe QDs was found to result in virtually quantitative coupling of a variety of thiols to give disulfides and H2 without the need for sacrificial reagents or external oxidants. The addition of small amounts of nickel(II) salts dramatically improved the efficiency and conversion through facilitating the formation of hydrogen atoms, thereby leading to faster regeneration of the ground-state QDs. Mechanistic studies reveal that the coupling reaction occurs on the QD surfaces rather than in solution and offer a blueprint for how these QDs may be used in other photocatalytic applications. Because no sacrificial agent or oxidant is necessary and the catalyst is reusable, this method may be useful for the formation of disulfide bonds in proteins as well as in other systems sensitive to the presence of oxidants. PMID- 24470072 TI - Common sense of experts: Social representations of justice amongst professionals. AB - The dialectics between different modes of knowledge is at the very core of social sciences. In particular, the theory of social representations looks at expert and lay modes as they were not peculiar of specific domains but rather as they were mutually interdependent. Based on the conceptual distinction between reified and consensual universes, this article explores the interplay between these two sources of knowledge through the analysis of the social representations of justice produced by justice professionals. In particular, the exploration of the social representations of justice amongst experts offers intriguing clues to overtake the idea that the lay understanding of justice is somehow opposed to the expert viewpoint and to accept the polyphasic understanding of this complex object. The article reports the findings of a qualitative investigation of the social representations of justice amongst professionals. The staff members of the Youth Social Services (YSS) and the Juvenile Classification Home and Residential Community (JCHRC) were interviewed, and transcriptions were content analysed. The findings indicated that professionals generate multiple theories of justice with each presenting a particular articulation of the basic interplay between expert and lay viewpoints. Most important, findings indicate that the context of everyday working practice has a significant symbolic valence that goes beyond the boundaries of the reified context of institutional justice system. PMID- 24470073 TI - Choice of nonionic surfactant used to formulate type IIIA self-emulsifying drug delivery systems and the physicochemical properties of the drug have a pronounced influence on the degree of drug supersaturation that develops during in vitro digestion. AB - The performance of self-emulsifying drug delivery systems (SEDDS) is influenced by their tendency to generate supersaturated systems during dispersion and digestion in the gastrointestinal tract. This study investigated the effect of drug loading on supersaturation during digestion of fenofibrate or danazol SEDDS, each formulated using long-chain lipids and a range of nonionic surfactants. Supersaturation was described by the maximum supersaturation ratio (SR(M) ) produced by in vitro digestion. This parameter was calculated as the ratio of the total concentration of drug present in the digestion vessel versus the drug solubility in the colloidal phases formed by digestion of the SEDDS. SR(M) proved to be a remarkable indicator of performance across a range of lipid-based formulations. SEDDS containing danazol showed little evidence of precipitation on digestion, even at drug loads approaching saturation in the formulation. In contrast, fenofibrate crystallized extensively on digestion of the corresponding series of SEDDS, depending on the drug loading. The difference was explained by the generation of higher SR(M) values by fenofibrate formulations. A threshold SR(M) of 2.5-2.6 was identified in six of the seven SEDDS. This is not a definitive threshold for precipitation, but in general when SR(M) is greater than 3, fenofibrate supersaturation could not be maintained. PMID- 24470074 TI - Rare coding variants and breast cancer risk: evaluation of susceptibility Loci identified in genome-wide association studies. AB - BACKGROUND: To date, common genetic variants in approximately 70 loci have been identified for breast cancer via genome-wide association studies (GWAS). It is unknown whether rare variants in these loci are also associated with breast cancer risk. METHODS: We investigated rare missense/nonsense variants with minor allele frequency (MAF) <=5% located in flanking 500 kb of each of the index single-nucleotide polymorphism (SNP) in 67 GWAS loci. Included in the study were 3,472 cases and 3,595 controls from the Shanghai Breast Cancer Study. Both single marker and gene-based analyses were conducted to investigate the associations. RESULTS: Single marker analyses identified 38 missense variants being associated with breast cancer risk at P < 0.05 after adjusting for the index SNP. SNP rs146217902 in the EDEM1 gene and rs200340088 in the EFEMP2 gene were only observed in 8 cases (P = 0.004 for both). SNP rs200995432 in the EFEMP2 gene was associated with increased risk with an OR of 6.2 [95% confidence interval (CI), 1.4-27.6; P = 6.2 * 10(-3)]. SNP rs80358978 in the BRCA2 gene was associated with 16.5-fold elevated risk (95% CI, 2.2-124.5; P = 2.2 * 10(-4)). Gene-based analyses suggested eight genes associated with breast cancer risk at P < 0.05, including the EFEMP2 gene (P = 0.002) and the FBXO18 gene (P = 0.008). CONCLUSION: Our results identified associations of several rare coding variants neighboring common GWAS loci with breast cancer risk. Further investigation of these rare variants and genes would help to understand the biologic mechanisms underlying the associations. IMPACT: Independent studies with larger sample size are warranted to clarify the relationship between these rare variants and breast cancer risk. PMID- 24470075 TI - Development and comparison of two competitive ELISAs for estimation of cotinine in human exposed to environmental tobacco smoke. AB - We simultaneously set up two competitive (direct and indirect) enzyme-linked immunosorbent assays (ELISAs) based on the same antibody for estimation of cotinine (COT) in pregnant women especially and population generally exposed to environmental tobacco smoke. The results show that the limits of detection (LODs) for direct competitive ELISA and indirect competitive ELISA were 0.04 MUgL(-1) and 0.1 MUgL(-1), respectively. Direct competitive ELISA was found to be more sensitive than indirect competitive ELISA. Thereafter, we applied our direct competitive ELISA for the detection of COT from urinary samples taken from 450 volunteers from the Zhejiang Province of China. COT was detected in 100% of participants with concentration ranging from LOD to 5358.0 MUgL(-1). The GM and 95th percentile concentration of COT in pregnant women were 6.3 MUgL(-1) and 57.2 MUgL(-1), respectively. Males had statistically higher COT concentrations than females (P < 0.0001), active smokers had statistically higher COT concentrations than non-smokers (P < 0.0001), whereas, non-pregnant women were found to have higher COT concentration than pregnant women. We conclude that our developed direct competitive ELISA is useful for detecting the COT in urinary concentration of human. The human urinary data obtained in this study indicated that common people generally and pregnant women especially were highly exposed to COT. Further studies are needed to focus on the sources of exposure, potential health effects and risk assessment of exposure to COT. PMID- 24470076 TI - Decision aids for people facing health treatment or screening decisions. AB - BACKGROUND: Decision aids are intended to help people participate in decisions that involve weighing the benefits and harms of treatment options often with scientific uncertainty. OBJECTIVES: To assess the effects of decision aids for people facing treatment or screening decisions. SEARCH METHODS: For this update, we searched from 2009 to June 2012 in MEDLINE; CENTRAL; EMBASE; PsycINFO; and grey literature. Cumulatively, we have searched each database since its start date including CINAHL (to September 2008). SELECTION CRITERIA: We included published randomized controlled trials of decision aids, which are interventions designed to support patients' decision making by making explicit the decision, providing information about treatment or screening options and their associated outcomes, compared to usual care and/or alternative interventions. We excluded studies of participants making hypothetical decisions. DATA COLLECTION AND ANALYSIS: Two review authors independently screened citations for inclusion, extracted data, and assessed risk of bias. The primary outcomes, based on the International Patient Decision Aid Standards (IPDAS), were:A) 'choice made' attributes;B) 'decision-making process' attributes.Secondary outcomes were behavioral, health, and health-system effects. We pooled results using mean differences (MD) and relative risks (RR), applying a random-effects model. MAIN RESULTS: This update includes 33 new studies for a total of 115 studies involving 34,444 participants. For risk of bias, selective outcome reporting and blinding of participants and personnel were mostly rated as unclear due to inadequate reporting. Based on 7 items, 8 of 115 studies had high risk of bias for 1 or 2 items each.Of 115 included studies, 88 (76.5%) used at least one of the IPDAS effectiveness criteria: A) 'choice made' attributes criteria: knowledge scores (76 studies); accurate risk perceptions (25 studies); and informed value-based choice (20 studies); and B) 'decision-making process' attributes criteria: feeling informed (34 studies) and feeling clear about values (29 studies).A) Criteria involving 'choice made' attributes:Compared to usual care, decision aids increased knowledge (MD 13.34 out of 100; 95% confidence interval (CI) 11.17 to 15.51; n = 42). When more detailed decision aids were compared to simple decision aids, the relative improvement in knowledge was significant (MD 5.52 out of 100; 95% CI 3.90 to 7.15; n = 19). Exposure to a decision aid with expressed probabilities resulted in a higher proportion of people with accurate risk perceptions (RR 1.82; 95% CI 1.52 to 2.16; n = 19). Exposure to a decision aid with explicit values clarification resulted in a higher proportion of patients choosing an option congruent with their values (RR 1.51; 95% CI 1.17 to 1.96; n = 13).B) Criteria involving 'decision-making process' attributes:Decision aids compared to usual care interventions resulted in:a) lower decisional conflict related to feeling uninformed (MD -7.26 of 100; 95% CI -9.73 to -4.78; n = 22) and feeling unclear about personal values (MD -6.09; 95% CI -8.50 to -3.67; n = 18);b) reduced proportions of people who were passive in decision making (RR 0.66; 95% CI 0.53 to 0.81; n = 14); andc) reduced proportions of people who remained undecided post-intervention (RR 0.59; 95% CI 0.47 to 0.72; n = 18).Decision aids appeared to have a positive effect on patient-practitioner communication in all nine studies that measured this outcome. For satisfaction with the decision (n = 20), decision-making process (n = 17), and/or preparation for decision making (n = 3), those exposed to a decision aid were either more satisfied, or there was no difference between the decision aid versus comparison interventions. No studies evaluated decision-making process attributes for helping patients to recognize that a decision needs to be made, or understanding that values affect the choice.C) Secondary outcomes Exposure to decision aids compared to usual care reduced the number of people of choosing major elective invasive surgery in favour of more conservative options (RR 0.79; 95% CI 0.68 to 0.93; n = 15). Exposure to decision aids compared to usual care reduced the number of people choosing to have prostate-specific antigen screening (RR 0.87; 95% CI 0.77 to 0.98; n = 9). When detailed compared to simple decision aids were used, fewer people chose menopausal hormone therapy (RR 0.73; 95% CI 0.55 to 0.98; n = 3). For other decisions, the effect on choices was variable.The effect of decision aids on length of consultation varied from 8 minutes shorter to 23 minutes longer (median 2.55 minutes longer) with 2 studies indicating statistically-significantly longer, 1 study shorter, and 6 studies reporting no difference in consultation length. Groups of patients receiving decision aids do not appear to differ from comparison groups in terms of anxiety (n = 30), general health outcomes (n = 11), and condition-specific health outcomes (n = 11). The effects of decision aids on other outcomes (adherence to the decision, costs/resource use) were inconclusive. AUTHORS' CONCLUSIONS: There is high quality evidence that decision aids compared to usual care improve people's knowledge regarding options, and reduce their decisional conflict related to feeling uninformed and unclear about their personal values. There is moderate quality evidence that decision aids compared to usual care stimulate people to take a more active role in decision making, and improve accurate risk perceptions when probabilities are included in decision aids, compared to not being included. There is low-quality evidence that decision aids improve congruence between the chosen option and the patient's values.New for this updated review is further evidence indicating more informed, values-based choices, and improved patient practitioner communication. There is a variable effect of decision aids on length of consultation. Consistent with findings from the previous review, decision aids have a variable effect on choices. They reduce the number of people choosing discretionary surgery and have no apparent adverse effects on health outcomes or satisfaction. The effects on adherence with the chosen option, cost effectiveness, use with lower literacy populations, and level of detail needed in decision aids need further evaluation. Little is known about the degree of detail that decision aids need in order to have a positive effect on attributes of the choice made, or the decision-making process. PMID- 24470078 TI - Can they dig it? Functional morphology and semifossoriality among small-eared shrews, genus Cryptotis (Mammalia, Soricidae). AB - Small-eared shrews (Mammalia: Soricidae: Cryptotis), exhibit modifications of the forelimb skeleton that have been interpreted as adaptations for semifossoriality. Most species inhabit remote regions, however, and their locomotory and foraging behaviors remain mostly speculative. To better understand the morphological modifications in the absence of direct observations, we quantified variation in these species by measuring 151 individuals representing 18 species and populations of Cryptotis and two species of moles (Talpidae) for comparison. From our measurements, we calculated 22 indices, most of which have been used previously to characterize substrate use among rodents and other taxa. We analyzed the indices using 1) average percentile ranks, 2) principal components analysis, and 3) cluster analysis. From these analyses, we determined that three basic modes of substrate adaptation are present within Cryptotis: 1) a primarily terrestrial mode, with species that are capable of burrowing, but lack adaptations to increase digging efficiency, 2) a semifossorial mode, with species whose forelimbs bones show strong muscle attachment areas and increased mechanical advantage, and 3) an intermediate mode. In addition to identifying new morphological characters and contributing to our understanding of the functional morphology of soricids, these analyses provide additional insight into the ecology of the species of interest. PMID- 24470077 TI - Effectiveness and safety of infliximab in rheumatoid arthritis: analysis from a Canadian multicenter prospective observational registry. AB - OBJECTIVE: To describe the profile of rheumatoid arthritis (RA) patients treated with infliximab in Canadian routine care and to assess the real-world effectiveness and safety of infliximab. METHODS: Biologics-naive RA patients from the Biologic Treatment Registry Across Canada were stratified based on their enrollment year. Effectiveness was assessed with the changes in clinical/laboratory parameters and patient-reported outcomes and the achievement of minimal disease activity and remission. Safety was assessed with the incidence of treatment-emergent adverse events (AEs). RESULTS: Among 628 patients, 45.9%, 34.6%, and 19.6% were enrolled between 2002-2005, 2005-2008, and 2008-2011, respectively. Patients recruited in more recent years had significantly lower Disease Activity Score with a 28-joint count using the C-reactive protein level (DAS28-CRP), Simplified Disease Activity Index (SDAI), Clinical Disease Activity Index (CDAI), swollen joint count in 28 joints, tender joint count in 28 joints, physician's global assessment of disease activity, patient's global assessment of disease activity, Health Assessment Questionnaire disability index, pain, erythrocyte sedimentation rate, and CRP level (P < 0.01 for all). Patient management also changed with a trend to initiate infliximab after failure of fewer disease-modifying antirheumatic drugs (DMARDs). Six-month treatment with infliximab resulted in statistically significant and clinically important improvements in all disease parameters examined, which were sustained over 36 months. The cumulative probability of achieving remission by 36 months, as defined by the DAS28, SDAI, and CDAI, was 56.2 (95% confidence interval [95% CI] 47.8-64.8), 31.0 (95% CI 23.8-39.8), and 36.2 (95% CI 28.5-45.3), respectively, which was significantly greater in patients with lower baseline disease activity. The profile and incidence of AEs were comparable to data previously reported for tumor necrosis factor alpha inhibitors. CONCLUSION: RA patient characteristics at infliximab initiation changed over time toward lower disease activity. Furthermore, a trend to treat patients with fewer DMARDs before initiation of infliximab was observed. However, treatment with infliximab was effective in significantly reducing disease activity independent of the treatment initiation year. PMID- 24470079 TI - Plastoquinone as a common link between photosynthesis and respiration in a blue green alga. AB - The role of plastoquinone in a thermophilic blue-green alga, Shynechococcus sp., was studied by measuring reduction kinetics of cytochrome 553 which was oxidized with red flash preferentially exciting photosystem I. Sensitivity of the cytochrome reduction to DBMIB Abbreviations: DCMU = 3-(3,4-dichlorophenyl)-1,1 dimethylurea; DBMIB = 2,5-dib romo-3-methyl-6-isopropyl-p-benzoquinone; HOQNO = 2 n-heptyl-4-hydroxyquinoline-N-oxide indicates that cytochrome 553 accepts electrons from reduced plastoquinone. Plastoquinone is in turn reduced in cells without electrons from photosystem II, since DCMU Abbreviations: DCMU = 3-(3,4 dichlorophenyl)-1,1-dimethylurea; DBMIB = 2,5-dib romo-3-methyl-6-isopropyl-p benzoquinone; HOQNO = 2-n-heptyl-4-hydroxyquinoline-N-oxide , which inhibited methyl viologen photoreduction more strongly than DBMIB, failed to affect the cytochrome reduction. Participation of cyclic electron transport around photosystem I in cytochrome reduction in the presence of DCMU was excluded, because methyl viologen and antimycin A had no effect on the cytochrome kinetics. On the other hand, electron donation from endogenous substrates to plastoquinone was suggested from decreases in rate of the cytochrome reduction by dark starvation of cells and also from restoration of fast reduction kinetics by the addition of exogenous substrates to or by reillumination of starved cells.KCN, which completely suppressed respiratory O2-uptake, induced a marked acceleration of the cytochrome reduction in starved cells. The poison was less or not effective in stimulating the cytochrome reduction in more extensively starved or reilluminated cells.Results indicate that plastoquinone is functioning not only in the photosynthetic but also in the respiratory electron transport chain, thereby forming a common link between the two energy conservation systems of the blue-green alga. PMID- 24470080 TI - Thermal properties of NADP:ferredoxin oxidoreductase and ferredoxin isolated from a thermophilic blue-green alga. AB - NADP:ferredoxin oxidoreductase (EC. 1.6.7.1.) isolated from a thermophilic blue green alga, Synechococcus sp., was stable at temperatures up to 65 degrees C. The diaphorase and cytochrome c reductase activities of the enzyme were low at 25 degrees C but increased with elevated temperature to reach a maximum at about 60 degrees C. The pH-profile of the diaphorase activity showed a peak at pH 9.0 at 55 degrees C, whereas the activity was largely independent of pH at 25 degrees C. High concentrations of NaCl suppressed activity at both high and low temperatures. In the cytochrome c reductase activity catalyzed by the enzyme, ferredoxin served as an electron carrier in a temperature-insensitive manner over a wide range of temperature. The results support the view that the optimum and the upper limiting temperatures for photosynthesis in this alga are related to thermal properties of proteins. PMID- 24470081 TI - Zinc mediated effects on leaf CO2 diffusion conductances and net photosynthesis in Phaseolus vulgaris L. AB - Supra-optimal levels of zinc in primary leaves of Phaseolus vulgaris increased the CO2 compensation point and inhibited net photosynthesis. Leaf morphology was modified: mesophyll intercellular area, stomatal slit length and interstomatal distance were reduced, but stomatal density increased. Internal and stomatal conductances to CO2 diffusion decreased. These changes are discussed in relation to the observed effects on leaf gas exchange and to the previously reported inhibition of different photosynthetic and photorespiratory enzymes. PMID- 24470082 TI - Oat leaf phosphoglucose isomerase: competitive inhibition by erythrose-4 phosphate. AB - Phosphoglucose isomerase was partially purified from oat leaves and shown to be strongly inhibited by erythrose-4-P. Estimated Ki values were between 0.4 and 4.0 MUM. The inhibition was of the competitive type with respect to either of the substrates glucose-6-P and fructose-6-P. Several other plant phosphoglucose isomerases were found to be similarly sensitive to erythrose-4-P. PMID- 24470083 TI - Effects of soil water stress and twospotted spider mites on net photosynthesis and transpiration of apple leaves. AB - Soil water stress and twospotted spider mites (Tetranychus urticae Koch) were tested for their influence on the content and activity of leaves of greenhouse grown Delicious apple trees. Soil water stress caused reductions in net photosynthesis (Pn), transpiration (Tr), and shoot growth. Leaf water potential was decreased by both water stress and mite feeding. Feeding of 15 adult mites/leaf for 28 days resulted in a 16% reduction in Pn while an initial population of 10 mites leaf/left to develop for 20 days reduced Pn by 27%. Mite feeding reduced leaf nitrogen and non-structural carbohydrate levels when sampled 20 days after placement on the leaf. There was no interaction between the changed physiology of the leaf due to soil water stress and mite feeding. PMID- 24470084 TI - Light and temperature dependence of the rate and degree of activation of pyruvate, Pi dikinase in vivo in maize. AB - Activation of pyruvate,Pi dikinase by light was studied in leaf discs of maize which were illuminated for 1 h at light intensities ranging from approximately 3% to 50% of full sunlight and at temperatures of 10, 22.5, and 35 degrees C. At the highest light intensity the degree of activation was similar and relatively independent of temperature between 10 and 35 degrees C. Under low light the degree of activation was high at 10 degrees C but decreased rapidly with increasing temperature. There was a similar effect of light and temperature on the activation of NADP-malate dehydrogenase.At low temperature, the rate of activation of pyruvate,Pi dikinase was relatively low and independent of the light intensity used and the rate of inactivation in the dark was extremely low. At high temperature, the rate of activation was high and dependent on the light intensity used while the rate of dark inactivation was also relatively high. The degree of activation is discussed in relation to the possible influence of light and temperature on the turnover between the active and inactive forms of pyruvate,Pi dikinase during illumination. PMID- 24470085 TI - Molecular mechanism of diaminomaleonitrile to diaminofumaronitrile photoisomerization: an intermediate step in the prebiotic formation of purine nucleobases. AB - The photoinduced isomerization of diaminomaleonitrile (DAMN) to diaminofumaronitrile (DAFN) was suggested to play a key role in the prebiotically plausible formation of purine nucleobases and nucleotides. In this work we analyze two competitive photoisomerization mechanisms on the basis of state-of the-art quantum-chemical calculations. Even though it was suggested that this process might occur on the triplet potential-energy surface, our results indicate that the singlet reaction channel should not be disregarded either. In fact, the peaked topography of the S1 /S0 conical intersection suggests that the deexcitation should most likely occur on a sub-picosecond timescale and the singlet photoisomerization mechanism might effectively compete even with a very efficient intersystem crossing. Such a scenario is further supported by the relatively small spin-orbit coupling of the S1 and T2 states in the Franck-Condon region, which does not indicate a very effective triplet bypass for this photoreaction. Therefore, we conclude that the triplet reaction channel in DAMN might not be as prominent as was previously thought. PMID- 24470086 TI - Catheter placement for lysis of spontaneous intracerebral hematomas: is a navigated stylet better than pointer-guided frameless stereotaxy for intrahematomal catheter positioning? AB - The optimal management of spontaneous intracerebral hemorrhage (ICH), especially if deep-seated, remains a matter of discussion. Lysis of the blood clot applying recombinant tissue-type plasminogen activator (rtPA) by an intrahematomal catheter is a minimally invasive treatment option, currently being under investigation in a randomized trial. The center position of the catheter in the hematoma is believed to be crucial for an optimal clot lysis. To achieve this objective, frame-based stereotaxy and frameless stereotaxy with guidance of an articulated arm were used. Recently, a preregistered stylet for direct navigation, alleviating the need of guidance, became available. In this study, we evaluated the relative error (RE) describing the deviation of the catheter from the ideal center position in the clot and compared the accuracy of catheter placement using frameless stereotaxy or the novel preregistered stylet. The intrahematomal catheter position was evaluated in three dimensions in 89 patients with spontaneous supratentorial ICH. Frameless stereotaxy with guidance of an articulated arm was performed in 50 patients. The preregistered stylet was used in 39 patients. The catheter position was evaluated using a RE calculating the distance perpendicular to the center of the catheter in relation to the hematoma's diameter. The mean hematoma volume was 51.4 ml. Forty-four out of 89 hematomas were deep-seated. Intraventricular blood was found in 59 patients. The RE of the catheter position was lower in the stylet group in comparison to the frameless stereotaxy group (mean 0.57 vs. 0.90; p = 0.0018). There was no difference between deep-seated and lobar hematomas with regard to the accuracy of catheter placement (p = 0.62). The RE is a robust measure for describing intrahematomal catheter position. The preregistered stylet facilitates a satisfactory catheter placement and is a viable alternative to frameless stereotaxy and guidance with the articulated arm. PMID- 24470087 TI - Metal ions and infectious diseases. An overview from the clinic. AB - Trace elements (TEs) are required by both humans and bacterial pathogens. Although metal ion homeostasis is tightly controlled in humans, growing evidence suggests that pathogens utilize a variety of means designed to circumvent the sequestration of TEs. Colonizing pathogenic microorganisms employ a variety of strategies to sense, acquire, store, and export metal ions in the vertebrate host which include the biosynthesis and utilization of siderophores, and the expression of high-affinity metal-ion transporters. For iron, selenium, and zinc, significant correlations have been shown between TE levels in plasma, serum, or tissues, and the prevention or treatment of a variety of infectious diseases; fewer such data exist for copper, chromium, or manganese. TEs are often employed as antioxidants, and as supplements in patients with TE-deficient states. The role of TE supplementation in humans as antioxidants remains controversial, but has demonstrated significant benefit in the role of selenium for patients with sepsis, and of zinc for the prevention of several infectious diseases. PMID- 24470088 TI - Sodium and potassium in health and disease. AB - Sodium and potassium are essential for human health. They are important ions in the body and are associated with many physiologic and pathophysiologic processes. The chapter summarizes the basic physiologic actions of sodium and potassium on membranes of the neurologic and muscular systems. It provides information regarding the kinetics, i.e., absorption, distribution, and excretion of these ions and their movement between the intracellular and extracellular compartments. It also explains the physiologic systems that can influence proper homeostasis between sodium and potassium. Concentrations of sodium in the blood that exceed or do not reach the normal value range are called hypernatremia or hyponatremia, respectively. Similarly, the clinicians recognize hyperkalemia and hypokalemia. Pathologies associated with these states are described and examples of some of the diseases are presented here. PMID- 24470089 TI - Magnesium in health and disease. AB - Mammalian cells tightly regulate cellular Mg(2+) content through a variety of transport and buffering mechanisms under the control of various hormones and cellular second messengers. The effect of these hormones and agents results in dynamic changes in the total content of Mg(2+) being transported across the cell membrane and redistributed within cellular compartments. The importance of maintaining proper cellular Mg(2+) content optimal for the activity of various cellular enzymes and metabolic cycles is underscored by the evidence that several diseases are characterized by a loss of Mg(2+) within specific tissues as a result of defective transport, hormonal stimulation, or metabolic impairment. This chapter will review the key mechanisms regulating cellular Mg(2+) homeostasis and their impairments under the most common diseases associated with Mg(2+) loss or deficiency. PMID- 24470090 TI - Calcium in health and disease. AB - Evolution has exploited the chemical properties of Ca(2+), which facilitate its reversible binding to the sites of irregular geometry offered by biological macromolecules, to select it as a carrier of cellular signals. A number of proteins bind Ca(2+) to specific sites: those intrinsic to membranes play the most important role in the spatial and temporal regulation of the concentration and movements of Ca(2+) inside cells. Those which are soluble, or organized in non-membranous structures, also decode the Ca(2+) message to be then transmitted to the targets of its regulation. Since Ca(2+) controls the most important processes in the life of cells, it must be very carefully controlled within the cytoplasm, where most of the targets of its signaling function reside. Membrane channels (in the plasma membrane and in the organelles) mediate the entrance of Ca(2+) into the cytoplasm, ATPases, exchangers, and the mitochondrial Ca(2+) uptake system remove Ca(2+) from it. The concentration of Ca(2+) in the external spaces, which is controlled essentially by its dynamic exchanges in the bone system, is much higher than inside cells, and can, under conditions of pathology, generate a situation of dangerous internal Ca(2+) overload. When massive and persistent, the Ca(2+) overload culminates in the death of the cell. Subtle conditions of cellular Ca(2+) dyshomeostasis that affect individual systems that control Ca(2+), generate cell disease phenotypes that are particularly severe in tissues in which the signaling function of Ca(2+) has special importance, e.g., the nervous system. PMID- 24470091 TI - Vanadium. Its role for humans. AB - Vanadium is the 21st most abundant element in the Earth's crust and the 2nd-to most abundant transition metal in sea water. The element is ubiquitous also in freshwater and nutrients. The average body load of a human individual amounts to 1 mg. The omnipresence of vanadium hampers checks directed towards its essentiality. However, since vanadate can be considered a close blueprint of phosphate with respect to its built-up, vanadate likely takes over a regulatory function in metabolic processes depending on phosphate. At common concentrations, vanadium is non-toxic. The main source for potentially toxic effects caused by vanadium is exposure to high loads of vanadium oxides in the breathing air of vanadium processing industrial enterprises. Vanadium can enter the body via the lungs or, more commonly, the stomach. Most of the dietary vanadium is excreted. The amount of vanadium resorbed in the gastrointestinal tract is a function of its oxidation state (V(V) or V(IV)) and the coordination environment. Vanadium compounds that enter the blood stream are subjected to speciation. The predominant vanadium species in blood are vanadate and vanadyl bound to transferrin. From the blood stream, vanadium becomes distributed to the body tissues and bones. Bones act as storage pool for vanadate. The aqueous chemistry of vanadium(V) at concentration <10 MUM is dominated by vanadate. At higher concentrations, oligovanadates come in, decavanadate in particular, which is thermodynamically stable in the pH range 2.3-6.3, and can further be stabilized at higher pH by interaction with proteins.The similarity between vanadate and phosphate accounts for the interplay between vanadate and phosphate-dependent enzymes: phosphatases can be inhibited, kinases activated. As far as medicinal applications of vanadium compounds are concerned, vanadium's mode of action appears to be related to the phosphate-vanadate antagonism, to the direct interaction of vanadium compounds or fragments thereof with DNA, and to vanadium's contribution to a balanced tissue level of reactive oxygen species. So far vanadium compounds have not yet found approval for medicinal applications. The antidiabetic (insulin-enhancing) effect, however, of a singular vanadium complex, bis(ethylmaltolato)oxidovanadium(IV) (BEOV), has revealed encouraging results in phase IIa clinical tests. In addition, in vitro studies with cell cultures and parasites, as well as in vivo studies with animals, have revealed a broad potential spectrum for the application of vanadium coordination compounds in the treatment of cardiac and neuronal disorders, malignant tumors, viral and bacterial infections (such as influenza, HIV, and tuberculosis), and tropical diseases caused by parasites, e.g., Chagas' disease, leishmaniasis, and amoebiasis. PMID- 24470092 TI - Chromium: is it essential, pharmacologically relevant, or toxic? AB - Over fifty years ago, the element chromium (as the trivalent ion) was proposed to be an essential element for mammals with a role in maintaining proper carbohydrate and lipid metabolism. Evidence for an essential role came from dietary studies with rodents, studies on the effects of chromium on subjects on total parenteral nutrition, and studies of the absorption and transport of chromium. Over the next several decades, chromium-containing nutritional supplements became so popular for weight loss and muscle development that sales were second only to calcium among mineral supplements. However, the failure to identify the responsible biomolecules(s) that bind chromium(III) and their mode of action, particularly a postulated species named glucose tolerance factor or GTF, resulted in the status of chromium being questioned in recent years, such that the question of its being essential needs to be formally readdressed. At the same time as chromium(III)'s popularity as a nutritional supplement was growing, concerns over its safety appeared. While chromium has been conclusively shown not to have beneficial effects on body mass or composition and should be removed from the list of essential trace elements, chromium(III) compounds are generally nontoxic and have beneficial pharmacological effects in rodents models of insulin insensitivity, although human studies have not conclusively shown any beneficial effects. Mechanisms have been proposed for these pharmacological effects, but all suffer from a lack of consistent supporting evidence. PMID- 24470093 TI - Manganese in health and disease. AB - Manganese is an important metal for human health, being absolutely necessary for development, metabolism, and the antioxidant system. Nevertheless, excessive exposure or intake may lead to a condition known as manganism, a neurodegenerative disorder that causes dopaminergic neuronal death and parkinsonian-like symptoms. Hence, Mn has a paradoxal effect in animals, a Janus faced metal. Extensive work has been carried out to understand Mn-induced neurotoxicity and to find an effective treatment. This review focuses on the requirement for Mn in human health as well as the diseases associated with excessive exposure to this metal. PMID- 24470094 TI - Iron: effect of overload and deficiency. AB - Iron is a redox active metal which is abundant in the Earth's crust. It has played a key role in the evolution of living systems and as such is an essential element in a wide range of biological phenomena, being critical for the function of an enormous array of enzymes, energy transduction mechanisms, and oxygen carriers. The redox nature of iron renders the metal toxic in excess and consequently all biological organisms carefully control iron levels. In this overview the mechanisms adopted by man to control body iron levels are described.Low body iron levels are related to anemia which can be treated by various forms of iron fortification and supplementation. Elevated iron levels can occur systemically or locally, each giving rise to specific symptoms. Systemic iron overload results from either the hyperabsorption of iron or regular blood transfusion and can be treated by the use of a selection of iron chelating molecules. The symptoms of many forms of neurodegeneration are associated with elevated levels of iron in certain regions of the brain and iron chelation therapy is beginning to find an application in the treatment of such diseases. Iron chelators have also been widely investigated for the treatment of cancer, tuberculosis, and malaria. In these latter studies, selective removal of iron from key enzymes or iron binding proteins is sought. Sufficient selectivity between the invading organism and the host has yet to be established for such chelators to find application in the clinic.Iron chelation for systemic iron overload and iron supplementation therapy for the treatment of various forms of anemia are now established procedures in clinical medicine. Chelation therapy may find an important role in the treatment of various neurodegenerative diseases in the near future. PMID- 24470095 TI - Cobalt: its role in health and disease. AB - The primarily function of cobalt in humans is based on its role in cobalamin (Cbl, vitamin B12). Therefore, this chapter will focus on the physiological roles of Cbl and the importance of cobalt in human health. Cbl acts as the cofactor for two enzymes, i.e., methylmalonyl-CoA mutase and methionine synthase, in humans. Both enzymes are important for health. In addition, unlike other water-soluble vitamins, there is a unique absorption, delivery, and activation system for Cbl in mammals. Therefore, this chapter will also review the literature on the Cbl transporting system, which is crucial for Cbl function. PMID- 24470096 TI - Nickel and human health. AB - This review focuses on the impact of nickel on human health. In particular, the dual nature of nickel as an essential as well as toxic element in nature is described, and the main forms of nickel that can come in contact with living systems from natural sources and anthropogenic activities are discussed. Concomitantly, the main routes of nickel uptake and transport in humans are covered, and the potential dangers that nickel exposure can represent for health are described. In particular, the insurgence of nickel-derived allergies, nickel induced carcinogenesis as well as infectious diseases caused by human pathogens that rely on nickel-based enzymes to colonize the host are reviewed at different levels, from their macroscopic aspects on human health to the molecular mechanisms underlying these points. Finally, the importance of nickel as a beneficial element for human health, especially being essential for microorganisms that colonize the human guts, is examined. PMID- 24470097 TI - Copper: effects of deficiency and overload. AB - Copper is an essential trace metal that is required for the catalysis of several important cellular enzymes. However, since an excess of copper can also harm cells due to its potential to catalyze the generation of toxic reactive oxygen species, transport of copper and the cellular copper content are tightly regulated. This chapter summarizes the current knowledge on the importance of copper for cellular processes and on the mechanisms involved in cellular copper uptake, storage and export. In addition, we will give an overview on disturbances of copper homeostasis that are characterized by copper overload or copper deficiency or have been connected with neurodegenerative disorders. PMID- 24470098 TI - Zinc and human disease. AB - The vast knowledge of the physiologic functions of zinc in at least 3000 proteins and the recent recognition of fundamental regulatory functions of zinc(II) ions released from cells or within cells links this nutritionally essential metal ion to numerous diseases. However, this knowledge so far has had remarkably limited impact on diagnosing, preventing, and treating human diseases. One major roadblock is a lack of suitable biomarkers that would detect changes in cellular zinc metabolism and relate them to specific disease outcomes. It is not only the right amount of zinc in the diet that maintains health. At least as important is the proper functioning of the dozens of proteins that control cellular zinc homeostasis, regulate intracellular traffic of zinc between the cytosol and vesicles/organelles, and determine the fluctuations of signaling zinc(II) ions. Cellular zinc deficiencies or overloads, a term referring to zinc concentrations exceeding the cellular zinc buffering capacity, compromise the redox balance. Zinc supplementation may not readily remedy zinc deficiency if other factors limit the capability of a cell to control zinc. The role of zinc in human diseases requires a general understanding of the wide spectrum of functions of zinc, how zinc is controlled, how it interacts with the metabolism of other metal ions, in particular copper and iron, and how perturbation of specific zinc dependent molecular processes causes disease and influences the progression of disease. PMID- 24470099 TI - Molybdenum in human health and disease. AB - Molybdenum is an essential trace element and crucial for the survival of animals. Four mammalian Mo-dependent enzymes are known, all of them harboring a pterin based molybdenum cofactor (Moco) in their active site. In these enzymes, molybdenum catalyzes oxygen transfer reactions from or to substrates using water as oxygen donor or acceptor. Molybdenum shuttles between two oxidation states, Mo(IV) and Mo(VI). Following substrate reduction or oxidation, electrons are subsequently shuttled by either inter- or intra-molecular electron transfer chains involving prosthetic groups such as heme or iron-sulfur clusters. In all organisms studied so far, Moco is synthesized by a highly conserved multi-step biosynthetic pathway. A deficiency in the biosynthesis of Moco results in a pleitropic loss of all four human Mo-enzyme activities and in most cases in early childhood death. In this review we first introduce general aspects of molybdenum biochemistry before we focus on the functions and deficiencies of two Mo-enzymes, xanthine dehydrogenase and sulfite oxidase, caused either by deficiency of the apo-protein or a pleiotropic loss of Moco due to a genetic defect in its biosynthesis. The underlying molecular basis of Moco deficiency, possible treatment options and links to other diseases, such as neuropsychiatric disorders, will be discussed. PMID- 24470100 TI - Silicon: the health benefits of a metalloid. AB - Silicon is the second most abundant element in nature behind oxygen. As a metalloid, silicon has been used in many industrial applications including use as an additive in the food and beverage industry. As a result, humans come into contact with silicon through both environmental exposures but also as a dietary component. Moreover, many forms of silicon, that is, Si bound to oxygen, are water-soluble, absorbable, and potentially bioavailable to humans presumably with biological activity. However, the specific biochemical or physiological functions of silicon, if any, are largely unknown although generally thought to exist. As a result, there is growing interest in the potential therapeutic effects of water soluble silica on human health. For example, silicon has been suggested to exhibit roles in the structural integrity of nails, hair, and skin, overall collagen synthesis, bone mineralization, and bone health and reduced metal accumulation in Alzheimer's disease, immune system health, and reduction of the risk for atherosclerosis. Although emerging research is promising, much additional, corroborative research is needed particularly regarding speciation of health-promoting forms of silicon and its relative bioavailability. Orthosilicic acid is the major form of bioavailable silicon whereas thin fibrous crystalline asbestos is a health hazard promoting asbestosis and significant impairment of lung function and increased cancer risk. It has been proposed that relatively insoluble forms of silica can also release small but meaningful quantities of silicon into biological compartments. For example, colloidal silicic acid, silica gel, and zeolites, although relatively insoluble in water, can increase concentrations of water-soluble silica and are thought to rely on specific structural physicochemical characteristics. Collectively, the food supply contributes enough silicon in the forms aforementioned that could be absorbed and significantly improve overall human health despite the negative perception of silica as a health hazard. This review discusses the possible biological potential of the metalloid silicon as bioavailable orthosilicic acid and the potential beneficial effects on human health. PMID- 24470101 TI - Arsenic. Can this toxic metalloid sustain life? AB - It was recently reported that a bacterium, Halomonas species GFAJ-1, isolated from arsenic-rich Mono Lake and further selected for growth under conditions of high arsenate and low phosphate, is able to grow using arsenic instead of phosphorus. This claim, and subsequent studies to evaluate GFAJ-1, has brought new attention to the question of whether arsenic can play an essential or sustaining role for living organisms. If true, this would be in stark contrast to the well known toxicity of this element and its ability to cause a number of diseases, including cancer of the skin, lung, bladder, liver, and kidney. However, while deadly at high doses, arsenic oxide is also an approved and effective chemotherapeutic drug for the treatment of acute promyelocytic leukemia (APL). This review examines the evidence that arsenic may be a beneficial nutrient at trace levels below the background to which living organisms are normally exposed. It also examines whether arsenic can be used to sustain organisms growing under high arsenic conditions, specifically the results from recent studies of arsenic biochemistry motivated by the report of GFAJ-1. Both of these topics are considered in the context of the toxicity of this element and its ability to cause cancer and other diseases, yet its Janus-faced ability to effectively treat APL. PMID- 24470103 TI - Elevated fibroblast growth factor 23 exerts its effects on placenta and regulates vitamin D metabolism in pregnancy of Hyp mice. AB - Fibroblast growth factor 23 (FGF23) functions in an endocrine fashion and requires alpha-Klotho to exert its effects on the target organs. We have recently demonstrated that the human placenta also expresses alpha-Klotho, which led us to hypothesize that FGF23 may exert effects on the placenta. Immunohistochemical analysis demonstrated the expression of FGF receptor 1 (FGFR1) as well as that of alpha-Klotho in the feto-maternal interface of both mouse and human normal-term placentas, which suggested that these areas might be receptive to FGF23. Therefore, we next investigated whether FGF23 has some roles in the placenta using Hyp mice with high levels of circulating FGF23. Hyp and wild-type (WT) females were mated with WT males, and the mothers and their male fetuses were analyzed. FGF23 levels in Hyp mothers were elevated. FGF23 levels were about 20 fold higher in Hyp fetuses than in Hyp mothers, whereas WT fetuses from Hyp mothers exhibited low levels of FGF23, as did fetuses from WT mothers. We analyzed the placental gene expression and found that the expression of Cyp24a1 encoding 25OHD-24-hydroxylase, a target gene for FGF23 in the kidney, was increased in the placentas of fetuses from Hyp mothers compared with fetuses from WT mothers. In an organ culture of WT placentas, treatment with plasma from Hyp mothers markedly increased the expression of Cyp24a1, which was abolished by the simultaneous addition of anti-FGF23 neutralizing antibody. The direct injection of recombinant FGF23 into WT placentas induced the expression of Cyp24a1. The increase in the placental expression of Cyp24a1 in fetuses from Hyp mothers resulted in decreased plasma 25-hydroxyvitamin D levels. These results suggest that increased levels of circulating FGF23 in pathological conditions such as Hyp mice exerts direct effects on the placenta and affects fetal vitamin D metabolism via the regulation of Cyp24a1 expression. PMID- 24470104 TI - Tunable swelling of polyelectrolyte multilayers in cell culture media for modulating NIH-3T3 cells adhesion. AB - For polyelectrolyte multilayers (PEMs) assembled by the layer-by-layer (LbL) assembly technique, their nanostructure and properties can be governed by many parameters during the building process. Here, it was demonstrated that the swelling of the PEMs containing poly(diallyldimethylammonium chloride) (PDDA) and poly(sodium 4-styrenesulfonate) (PSS) in cell culture media could be tuned with changing supporting salt solutions during the assembly process. Importantly, the influence of the PEMs assembled in different salt solutions on NIH-3T3 cell adhesion was observable. Specifically, the cells could possess a higher affinity for the films assembled in low salt concentration (i.e. 0.15M NaCl) or no salt, the poorly swelling films in cell culture media, which was manifested by the large cell spreading area and focal adhesions. In contrast, those were assembled in higher salt concentration, highly swelling films in cell culture media, were less attractive for the fibroblasts. As a result, the cell adhesion behaviors may be manipulated by tailoring the physicochemical properties of the films, which could be performed by changing the assembly conditions such as supporting salt concentration. Such a finding might promise a great potential in designing desired biomaterials for tissue engineering and regenerative medicine. PMID- 24470105 TI - Capsule commentary on Dahlke et al., The mini mental status exam as a surrogate measure of health literacy. PMID- 24470102 TI - Selenium. Role of the essential metalloid in health. AB - Selenium is an essential micronutrient in mammals, but is also recognized as toxic in excess. It is a non-metal with properties that are intermediate between the chalcogen elements sulfur and tellurium. Selenium exerts its biological functions through selenoproteins. Selenoproteins contain selenium in the form of the 21st amino acid, selenocysteine (Sec), which is an analog of cysteine with the sulfur-containing side chain replaced by a Se-containing side chain. Sec is encoded by the codon UGA, which is one of three termination codons for mRNA translation in non-selenoprotein genes. Recognition of the UGA codon as a Sec insertion site instead of stop requires a Sec insertion sequence (SECIS) element in selenoprotein mRNAs and a unique selenocysteyl-tRNA, both of which are recognized by specialized protein factors. Unlike the 20 standard amino acids, Sec is biosynthesized from serine on its tRNA. Twenty-five selenoproteins are encoded in the human genome. Most of the selenoprotein genes were discovered by bioinformatics approaches, searching for SECIS elements downstream of in-frame UGA codons. Sec has been described as having stronger nucleophilic and electrophilic properties than cysteine, and Sec is present in the catalytic site of all selenoenzymes. Most selenoproteins, whose functions are known, are involved in redox systems and signaling pathways. However, several selenoproteins are not well characterized in terms of their function. The selenium field has grown dramatically in the last few decades, and research on selenium biology is providing extensive new information regarding its importance for human health. PMID- 24470106 TI - Pregnancy outcome after methotrexate treatment for rheumatic disease prior to or during early pregnancy: a prospective multicenter cohort study. AB - OBJECTIVE: High-dose methotrexate (MTX) exposure during pregnancy is associated with embryopathy. The teratogenic potential of MTX at dosages typically used in the treatment of rheumatic diseases remains uncertain. The aim of this study was to evaluate the risk of spontaneous abortion, major birth defects, elective termination of pregnancy, shortened gestational age at delivery, and reduced birth weight in women exposed to MTX. METHODS: Pregnancy outcome in women taking MTX (<=30 mg/week) either after conception or within the 12 weeks before conception was evaluated in a prospective observational multicenter cohort study. Pregnancy outcomes in the MTX group were compared to outcomes in a group of disease-matched women and a group of women without autoimmune diseases (neither group was exposed to MTX). RESULTS: The study sample included 324 MTX-exposed pregnancies (188 exposed post-conception, 136 exposed pre-conception), 459 disease-matched comparison women, and 1,107 comparison women without autoimmune diseases. In the post-conception cohort, the cumulative incidence of spontaneous abortion was 42.5% (95% confidence interval [95% CI] 29.2-58.7), which was significantly higher than the incidence of spontaneous abortion in either comparison group. The risk of major birth defects (7 of 106 [6.6%]) was elevated compared to both the cohort of women without autoimmune diseases (29 of 1,001 [2.9%]) (adjusted odds ratio [OR] 3.1 [95% CI 1.03-9.5]) and the disease-matched cohort (14 of 393 [3.6%]) (adjusted OR 1.8 [95% CI 0.6-5.7]). None of the malformations were clearly consistent with MTX embryopathy. Neither the cumulative incidence of spontaneous abortion (14.4% [95% CI 8.0-25.3]) nor the risk of major birth defects (4 of 114 [3.5%]) was increased in the pre-conception cohort. Elective termination rates were increased in both of the MTX-exposed cohorts. There were no other significant differences among groups in other study end points. CONCLUSION: Post-conception administration of MTX at dosages typically used in the treatment of rheumatic diseases was associated with an increased risk of major birth defects and spontaneous abortion. Such evidence was not found among women in our pre-conception cohort. PMID- 24470108 TI - Growth rate-reserve content relationship as influenced by irradiance, CO2 concentration, and temperature. AB - The patterns of the CO2 exchange of single vegetative bean plants were monitored during steady state exchange and after lowering the irradiance, the CO2 concentration, or the temperature. The measured patterns were used to calculate the dynamics of the rate of synthesis of structural dry matter and of the amount of the reserve materials during the experiments. The rate of synthesis of structural dry matter was assumed to be proportional to growth respiration (total minus maintenance). The growth conversion efficiency was assumed to be independent of the treatments. The maintenance respiration coefficient was taken to be dependent only on the temperature. Change in the amounts of reserve materials was calculated as a difference between the net CO2 input and the amount converted into new structural dry matter.During the first day of a low CO2 uptake a substantial depletion of reserve materials took place also during light hours, since the rate of synthesis of structural dry matter lagged behind the decrease of photosynthesis. On the second day the rate of synthesis was adapted to the low CO2 input and there occurred little change in the amount of reserve materials. There was a rapid increase in the amount of reserve materials after the irradiance was increased again or after temperature was lowered.A saturating dependence of the specific growth rate on the content of reserve materials was found to exist irrespective of the mode of changing the content of reserve materials. A hysteresis-like retardation of the specific growth rate took place after the reserve had already been exhausted for some time. During retardation a replenishment of reserve materials took place.It is suggested that adaptation processes tend to keep the content of reserve materials within a certain (probably optimal) range. PMID- 24470107 TI - Circulating mitochondrial DNA increases with age and is a familiar trait: Implications for "inflamm-aging". AB - Mitochondrial components, including mitochondrial DNA (mtDNA), when released extracellularly, can act as "damage-associated molecular pattern" (DAMP) agents and cause inflammation. As many elderly people are characterized by a low-grade, chronic inflammatory status defined "inflamm-aging," we evaluated if circulating mtDNA can contribute to this phenomenon. Eight hundred and thirty-one Caucasian subjects were enrolled in the study, including 429 siblings aged 90-104 (90+ siblings). mtDNA plasma levels increased gradually after the fifth decade of life. In 90+ subjects, mtDNA values of two members of the same sibling relationship were directly correlated, suggesting a role for familiar/genetic background in controlling the levels of circulating mtDNA. The subjects with the highest mtDNA plasma levels had the highest amounts of TNF-alpha, IL-6, RANTES, and IL-1ra; the subjects with the lowest mtDNA levels had the lowest levels of the same cytokines. In vitro stimulation of monocytes with mtDNA concentrations similar to the highest levels observed in vivo resulted in an increased production of TNF-alpha, suggesting that mtDNA can modulate the production of proinflammatory cytokines. Our findings therefore show that circulating mtDNA increases with age, and can significantly contribute to the maintenance of the low-grade, chronic inflammation observed in elderly people. PMID- 24470109 TI - Fluorescence induction kinetics of green and etiolated leaves by recording the complete in-vivo emission spectra. AB - Complete room temperature fluorescence emission spectra of green and etiolated leaves (Raphanus sativus L., cv. Saxa Treib, Hordeum vulgare L., cv. Villa) are continuously recorded up to 4 min after onset of excitation. In green leaves two emission bands appear, whereas in etiolated leaves only one band is observed. In both cases the emission intensity increases with time, the high-energy band of green leaves decreasing more rapidly than the low-energy band. This phenomenon can be interpreted in terms of energy transfer. During the observation time of the fluorescence induction kinetic no shift of the emission peaks is found within the accuracy of the apparatus (+/-2nm). PMID- 24470110 TI - Effect of temperature on light utilization efficiency of leaves in C3 legumes and C 4 grasses. AB - The effect of temperatures between 15 and 50 degrees C on the light utilization efficiency of leaf net photosynthesis was studied in two C4 grasses and two C3 legumes. In the legumes, light utilization efficiency (MU mol of CO2 fixed per MU Einstein of incident photosynthetic quantum flux) declined linearly with temperature between 15 and 45 degrees C. On the other hand, it was independent of temperature between 15 and 40 degrees C in the grasses, but it declined rapidly between 40 and 50 degrees C. Values for grasses were greater than those for legumes at all temperatures; for example, at 30 degrees C the ratio of the mean values of grass to legume was 1.6-1.7 which is similar to a previously published value of 1.6. Light utilization efficiency was similar for grasses and legumes only at temperatures below 10 and above 50 degrees C. These findings are compared with published data, especially those of Ehleringer and Bjorkman, and their implications for predicting or interpreting the distribution of C3 and C4 species are briefly discussed. PMID- 24470111 TI - Short-period oscillation of starch levels in Lemna under light and darkness. AB - In Lemna gibba G1 and L. paucicostata 6746 a short-period oscillation of starch content was found during the last hours of the daily light period and subsequent hours of the dark period. The transition from light to darkness was without effect on this oscillation. Starch degradation or synthesis continued after darkening, corresponding to the running phase of the cycle.Amplitude and frequency of oscillation were dependent on the amount of starch that was present within the plants. Under the experimental conditions used, the length of one cycle was normally 60-120 min. After addition of 0.1% sucrose to the medium, or after prolonged preculture of plants (both treatments leading to an elevated starch content), the cycle length was shortened to 40-60 min. PMID- 24470112 TI - Photosystem 1 preparations from dark-and light-grown cells of the cyanobacterium, Chlorogloea fritschii. AB - Photosystem 1 (PS1) enriched preparations have been extracted from the cyanobacterium Chlorogloea fritschii grown either in darkness or in the light. Absorption spectra show that the main chlorophyll peak has shifted from 678 nm in PS1 from light grown cells to 675 nm in PS1 from dark grown cells. Fluorescence spectra show a similar blue shift in wavelength maximum from 690 nm to 678 nm and the fluorescence intensity is higher in PS1 from dark grown cells. Allophycocyanin is present in PS1 from light grown cells, but absent from preparations from C. fritschii grown in the dark. P700: chlorophyll a ratios of the preparations from light and dark grown cells are 1:35 and 1:80 respectively, all P700 being photoactive. The results are interpreted to suggest that allophycocyanin is not attached to PS1 in dark grown C. fritschii, neither is all chlorophyll arranged in such a way as to ensure efficient energy transfer to P700. PMID- 24470113 TI - The development of photosynthetic light reactions in cultured apple embryos in relation to their embryonal dormancy. AB - The development of photosynthetic light reactions (photoreduction and photophosphorylation) was studied in cotyledons of cultured embryos isolated from stratified and non-stratified apple seeds (Malus domestica Borb. cv. Antonowka). The results obtained show the presence of an energy transfer inhibitor in the cotyledons of the stratified embryos. PMID- 24470114 TI - Clonidine premedication for postoperative analgesia in children. AB - BACKGROUND: Postoperative pain remains a significant problem following paediatric surgery. Premedication with a suitable agent may improve its management. Clonidine is an alpha-2 adrenergic agonist which has sedative, anxiolytic and analgesic properties. It may therefore be a useful premedication for reducing postoperative pain in children. OBJECTIVES: To evaluate the evidence for the effectiveness of clonidine, when given as a premedication, in reducing postoperative pain in children less than 18 years of age. We also sought evidence of any clinically significant side effects. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 12, 2012), Ovid MEDLINE (1966 to 21 December 2012) and Ovid EMBASE (1982 to 21 December 2012), as well as reference lists of other relevant articles and online trial registers. SELECTION CRITERIA: We included all randomized (or quasi randomized), controlled trials comparing clonidine premedication to placebo, a higher dose of clonidine, or another agent when used for surgical or other invasive procedures in children under the age of 18 years and where pain or a surrogate (principally the need for supplementary analgesia) was reported. DATA COLLECTION AND ANALYSIS: Two authors independently performed the database search, decided on the inclusion eligibility of publications, ascertained study quality and extracted data. They then resolved any differences between their results by discussion. The data were entered into RevMan 5 for analyses and presentation. Sensitivity analyses were performed, as appropriate, to exclude studies with a high risk of bias. MAIN RESULTS: We identified 11 trials investigating a total of 742 children in treatment arms relevant to our study question. Risks of bias in the studies were mainly low or unclear, but two studies had aspects of their methodology that had a high risk of bias. Overall, the quality of the evidence from pooled studies was low or had unclear risk of bias. Four trials compared clonidine with a placebo or no treatment, six trials compared clonidine with midazolam, and one trial compared clonidine with fentanyl. There was substantial methodological heterogeneity between trials; the dose and route of clonidine administration varied as did the patient populations, the types of surgery and the outcomes measured. It was therefore difficult to combine the outcomes of some trials for meta-analysis.When clonidine was compared to placebo, pooling studies of low or unclear risk of bias, the need for additional analgesia was reduced when clonidine premedication was given orally at 4 ug/kg (risk ratio (RR) 0.24, 95% confidence interval (CI) 0.11 to 0.51). Only one small trial (15 patients per arm) compared clonidine to midazolam for the same outcome; this also found a reduction in the need for additional postoperative analgesia (RR 0.25, 95% CI 0.09 to 0.71) when clonidine premedication was given orally at 2 or 4 ug/kg compared to oral midazolam at 0.5 mg/kg. A trial comparing oral clonidine at 4 ug/kg with intravenous fentanyl at 3 ug/kg found no statistically significant difference in the need for rescue analgesia (RR 0.89, 95% CI 0.56 to 1.42). When clonidine 4 ug/kg was compared to clonidine 2 ug/kg, there was a statistically significant difference in the number of patients requiring additional analgesia, in favour of the higher dose, as reported by a single, higher-quality trial (RR 0.38, 95% CI 0.23 to 0.65).The effect of clonidine on pain scores was hard to interpret due to differences in study methodology, the doses and route of drug administration, and the pain scale used. However, when given at a dose of 4 ug/kg, clonidine may have reduced analgesia requirements after surgery. There were no significant side effects of clonidine that were reported such as severe hypotension, bradycardia, or excessive sedation requiring intervention. However, several studies used atropine prophylactically with the aim of preventing such adverse effects. AUTHORS' CONCLUSIONS: There were only 11 relevant trials studying 742 children having surgery where premedication with clonidine was compared to placebo or other drug treatment. Despite heterogeneity between trials, clonidine premedication in an adequate dosage (4 ug/kg) was likely to have a beneficial effect on postoperative pain in children. Side effects were minimal, but some of the studies used atropine prophylactically with the intention of preventing bradycardia and hypotension. Further research is required to determine under what conditions clonidine premedication is most effective in providing postoperative pain relief in children. PMID- 24470115 TI - Reconstruction of glenoid bone defects in shoulder instability with autologous bone. AB - Bone defects, both at glenoid and at the humeral side are a frequent sequel of anterior shoulder instability. Although the transfer of the coracoid process (Latarjet, Bristow procedures) has gained popularity in treating the glenoid defect, equal results can be achieved with the use of a bone graft, for which mainly a graft of the iliac crest is used. Recently, arthroscopic procedures have been developed, leaving the subscapularis muscle largely intact. PMID- 24470116 TI - Calreticulin affects cell adhesiveness through differential phosphorylation of insulin receptor substrate-1. AB - Cellular adhesion to the underlying substratum is regulated through numerous signaling pathways. It has been suggested that insulin receptor substrate 1 (IRS 1) is involved in some of these pathways, via association with and activation of transmembrane integrins. Calreticulin, as an important endoplasmic reticulum resident, calcium-binding protein with a chaperone function, plays an obvious role in proteomic expression. Our previous work showed that calreticulin mediates cell adhesion not only by affecting protein expression but also by affecting the state of regulatory protein phosphorylation, such as that of c-src. Here, we demonstrate that calreticulin affects the abundance of IRS-1 such that the absence of calreticulin is paralleled by a decrease in IRS-1 levels and the unregulated overexpression of calreticulin is accompanied by an increase in IRS-1 levels. These changes in the abundance of calreticulin and IRS-1 are accompanied by changes in cell-substratum adhesiveness and phosphorylation, such that increases in the expression of calreticulin and IRS-1 are paralleled by an increase in focal contact-based cell-substratum adhesiveness, and a decrease in the expression of these proteins brings about a decrease in cell-substratum adhesiveness. Wild type and calreticulin-null mouse embryonic fibroblasts (MEFs) were cultured and the IRS-1 isoform profile was assessed. Differences in morphology and motility were also quantified. While no substantial differences in the speed of locomotion were found, the directionality of cell movement was greatly promoted by the presence of calreticulin. Calreticulin expression was also found to have a dramatic effect on the phosphorylation state of serine 636 of IRS-1, such that phosphorylation of IRS-1 on serine 636 increased radically in the absence of calreticulin. Most importantly, treatment of cells with the RhoA/ROCK inhibitor, Y-27632, which among its many effects also inhibited serine 636 phosphorylation of IRS-1, had profound effects on cell-substratum adhesion, in that it suppressed focal contacts, induced extensive close contacts, and increased the strength of adhesion. The latter effect, while counterintuitive, can be explained by the close contacts comprising labile bonds but in large numbers. In addition, the lability of bonds in close contacts would permit fast locomotion. An interesting and novel finding is that Y-27632 treatment of MEFs releases them from contact inhibition of locomotion, as evidenced by the invasion of a cell's underside by the thin lamellae and filopodia of a cell in close apposition. PMID- 24470117 TI - Micro-management of pluripotent stem cells. AB - Embryonic and induced pluripotent stem cells (ESCs and iPSCs) hold great promise for regenerative medicine. The therapeutic application of these cells requires an understanding of the molecular networks that regulate pluripotency, differentiation, and de-differentiation. Along with signaling pathways, transcription factors, and epigenetic regulators, microRNAs (miRNAs) are emerging as important regulators in the establishment and maintenance of pluripotency. These tiny RNAs control proliferation, survival, the cell cycle, and the pluripotency program of ESCs. In addition, they serve as barriers or factors to overcome barriers during the reprogramming process. Systematic screening for novel miRNAs that regulate the establishment and maintenance of pluripotent stem cells and further mechanistic investigations will not only shed new light on the biology of ESCs and iPSCs, but also help develop safe and efficient technologies to manipulate cell fate for regenerative medicine. PMID- 24470118 TI - 25-hydroxyvitamin D and cardiovascular disease in patients with systemic lupus erythematosus: data from a large international inception cohort. AB - OBJECTIVE: An association between 25-hydroxyvitamin D (25[OH]D; vitamin D) deficiency and increased cardiovascular (CV) risk factors and CV disease (CVD) has been shown in general population studies. Vitamin D deficiency has been noted in systemic lupus erythematosus (SLE), and CVD is a major cause of morbidity and mortality in SLE. The objectives of this study were to estimate the associations of 25(OH)D levels with CV risk factors and to determine whether low baseline 25(OH)D levels predict future CV events in patients participating in an international inception cohort. METHODS: Data were collected on 890 participants, including demographics, SLE activity and damage assessments, CV risk factors and events, medications, laboratory assessments of 25(OH)D levels, and inflammatory markers. Multiple logistic and Cox regressions were used to estimate the associations of baseline 25(OH)D levels with baseline CV risk factors and CVD events. The models were adjusted for age, sex, race, season, and country, with and without body mass index. RESULTS: Patients in the higher quartiles of 25(OH)D were less likely to have hypertension and hyperlipidemia and were more likely to have lower C-reactive protein levels and lower Systemic Lupus Erythematosus Disease Activity Index 2000 scores at baseline when compared with the first quartile. Vitamin D levels were not independently associated with CVD event incidence; however, hazard ratios for CVD event incidence decreased with successively higher quartiles. CONCLUSION: Lower baseline 25(OH)D levels are associated with higher risk for CV risk factors and more active SLE at baseline. There may be a trend toward a lower likelihood of CVD events in those with higher baseline 25(OH)D levels. PMID- 24470119 TI - Myeloid-related proteins 8 and 14 contribute to monosodium urate monohydrate crystal-induced inflammation in gout. AB - OBJECTIVE: Monosodium urate monohydrate (MSU) crystal-induced interleukin-1beta (IL-1beta) secretion is a critical factor in the pathogenesis of gout. However, without costimulation by a proIL-1beta-inducing factor, MSU crystals alone are insufficient to induce IL-1beta secretion. The responsible costimulatory factors that act as a priming endogenous signal in vivo are not yet known. We undertook this study to analyze the costimulatory properties of myeloid-related protein 8 (MRP-8) and MRP-14 (endogenous Toll-like receptor 4 [TLR-4] agonists) in MSU crystal-induced IL-1beta secretion and their relevance in gout. METHODS: MRP 8/MRP-14 was measured in paired serum and synovial fluid samples by enzyme-linked immunosorbent assay (ELISA) and localized in synovial tissue from gout patients by immunohistochemistry. Serum levels were correlated with disease activity, and MSU crystal-induced release of MRPs from human phagocytes was measured. Costimulatory effects of MRP-8 and MRP-14 on MSU crystal-induced IL-1beta secretion from phagocytes were analyzed in vitro by ELISA, Western blotting, and polymerase chain reaction. The impact of MRP was tested in vivo in a murine MSU crystal-induced peritonitis model. RESULTS: MRP-8/MRP-14 levels were elevated in the synovium, tophi, and serum of patients with gout and correlated with disease activity. MRP-8/MRP-14 was released by MSU crystal-activated phagocytes and increased MSU crystal-induced IL-1beta secretion in a TLR-4-dependent manner. Targeted deletion of MRP-14 in mice led to a moderately reduced response of MSU crystal-induced inflammation in vivo. CONCLUSION: MRP-8 and MRP-14, which are highly expressed in gout, are enhancers of MSU crystal-induced IL-1beta secretion in vitro and in vivo. These endogenous TLR-4 ligands released by activated phagocytes contribute to the maintenance of inflammation in gout. PMID- 24470120 TI - Osteoclast-derived complement component 3a stimulates osteoblast differentiation. AB - Bone remodeling is regulated by a coupling of resorption to subsequent formation; however, the "coupling factor" and underlying mechanism are not fully understood. Here, we found that the condition medium (CM) of mature osteoclasts contains a humoral factor that stimulates the differentiation of primary osteoblasts, as determined by alkaline phosphatase (ALP) activity. We purified osteoblastogenesis stimulating activity from 3 L of osteoclast CM through successive ion exchange chromatographies by monitoring the ALP activity of osteoblasts and identified complement component 3 (C3). Expression of the C3 gene increased during osteoclastogenesis, and the cleavage product C3a was detected by ELISA in the CM of osteoclasts but not in that of bone marrow macrophages. The osteoblastogenesis stimulating activity present in osteoclast CM was inhibited by a specific antagonist of the C3a receptor (C3aR), SB290157. Conversely, the retroviral expression of C3a as well as treatment with the C3aR agonist, benzeneacetamide, stimulated osteoblast differentiation. C3 gene expression in bone was increased in the high bone turnover states of ovariectomy (OVX) or a receptor activator of NF-kappaB ligand (RANKL) injection, and blocking the action of C3a with the daily administration of SB290157 resulted in the attenuation of bone formation elevated by OVX and the exacerbation of bone loss. These results suggest that osteoclast derived C3a functions in the relay from bone resorption to formation and may be a candidate for a coupling factor. PMID- 24470121 TI - New psychoactive substances as adulterants of controlled drugs. A worrying phenomenon? AB - The use of new psychoactive substances (NPS) as adulterants has received little attention in the literature. In this paper, results from Energy Control's drug checking service documenting the use of NPS as adulterants of controlled drugs are presented, and some reflections about possible explanations for this new phenomenon, potential risks for users, and challenges that it poses are discussed. From 2009 to 2012, 24 NPS belonging to several chemical classes such as phenethylamines, substituted cathinones, tryptamines, and methoxetamine were identified in 173 samples believed to be MDMA, amphetamine, ketamine, cocaine, mescaline, or methamphetamine. The NPS adulterant most frequently observed was 2 (4-bromo-2,5-dimethoxyphenyl)ethanamine (2C-B) followed by 1-(4 fluorophenyl)propan-2-amine (4-FA). Sixty-nine different combinations of substances were detected: 20 involving a controlled drug combined with an NPS, and 49 involving one or more NPS that substituted the controlled drug. As these combinations could pose substantial risks to users, the need to improve knowledge about toxicity associated with these combinations, and the danger of these substances being incorporated into the products of illegal markets, are highlighted. Drug checking services and the European Union's early-warning system operated by the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA) and Europol can play an important role in reducing the harm associated with this phenomenon. PMID- 24470122 TI - Design and synthesis of C3-pyrazole/chalcone-linked beta-carboline hybrids: antitopoisomerase I, DNA-interactive, and apoptosis-inducing anticancer agents. AB - A series of beta-carboline hybrids bearing a substituted phenyl and a chalcone/(N acetyl)-pyrazole moiety at the C1 and C3 positions, respectively, was designed, synthesized, and evaluated for anticancer activity. These new hybrid molecules showed significant cytotoxic activity, with IC50 values ranging from <2.0 MUM to 80 MUM, and the structure-activity relationships (SAR) associated with substitutions at positions 1 and 3 of these hybrids was clearly addressed. Further, induction of apoptosis was confirmed by Annexin V-FITC, Hoechst staining, and DNA fragmentation analysis. In addition, DNA photocleavage studies proved that two of the hybrids, (E)-1-(furan-2-yl)-3-(1-(4 (trifluoromethyl)phenyl)-9H-pyrido[3,4-b]indol-3-yl)prop-2-en-1-one (7 d) and 1 (3-(furan-2-yl)-5-(1-(4-(trifluoromethyl)phenyl)-9H-pyrido[3,4-b]indol-3-yl)-4,5 dihydro-1H-pyrazol-1-yl)ethanone (8 d) could effectively cleave pBR322 plasmid DNA upon irradiation with UV light. Active hybrid 8 d inhibited DNA topoisomerase I activity efficiently and preserved DNA in the supercoiled form. To further corroborate the biological activities, as well as to understand the nature of the interaction of these hybrids with DNA, spectroscopic studies were also performed. Unlike simple beta-carboline alkaloids, the binding mode of these new hybrid molecules with DNA was not similar, and both biophysical as well as molecular docking studies speculated a combilexin-type of interaction with DNA. Further, an in silico study of these beta-carboline hybrids revealed their drug-like properties. PMID- 24470123 TI - Structural studies of a non-stoichiometric channel hydrate using high resolution X-ray powder diffraction, solid-state nuclear magnetic resonance, and moisture sorption methods. AB - Structural investigations of a nonstoichiometric hydrate, AMG 222 tosylate, a DPP IV inhibitor in clinical development for type II diabetes, were performed using a multitechnique approach. The moisture sorption isotherm is in good agreement with a simple Langmuir model, suggesting that the hydrate water is located in well defined crystallographic sites, which become vacant during dehydration. Crystal structures of AMG 222 tosylate at ambient and dry conditions were determined from high-resolution X-ray diffraction using the direct space method. On the basis of these crystal structures, hydrated water is located in channels formed by the drug framework. Upon dehydration, an isostructural dehydrate is formed with the channels remaining void and accessible to water for rehydration. Kitaigorodskii packing coefficients of the solid between relative humidity of 0% and 90% indicate that the equilibrium form of AMG 222 tosylate is the fully hydrated monohydrate. PMID- 24470125 TI - Iridium-catalyzed direct C-H amidation with weakly coordinating carbonyl directing groups under mild conditions. AB - An iridium-catalyzed direct C-H amidation of weakly coordinating substrates, in particular of those bearing ester and ketone groups, under very mild conditions has been developed. The observed high reaction efficiency was achieved by the combined use of acetic acid and lithium carbonate as additives. PMID- 24470126 TI - Combining complementary ligands into one framework for the construction of a ferromagnetically coupled [Mn(III)12] wheel. AB - Phenolic oxime and diethanolamine moieties have been combined into one organic framework, resulting in the formation of a novel ligand type that can be employed to construct a rare and unusual dodecametallic Mn wheel, within which nearest neighbours are coupled ferromagnetically. PMID- 24470127 TI - Fructose-1,6-bisphosphatase deficiency: a case of a successful pregnancy by closely monitoring metabolic control. AB - In patients with fructose-1,6-bisphosphatase (FBPase) deficiency, maternal and fetal neurodevelopmental abnormalities can be induced by severe hypoglycemia and lactic acidosis, which is triggered by pregnancy. The patient was a 24-year-old and primipara. Via pre-pregnancy education and management including self monitoring of blood glucose and prompt medical intervention with glucose infusions, she never experienced hypoglycemia with impaired consciousness. She delivered a 2,406 g male infant at 38 weeks of gestation by cesarean section. No neurological abnormalities in either the mother or the child appeared during the following 2 years. This is the first report with detailed descriptions of the management of a pregnant woman with FDPase deficiency. This report suggests that for a patient with FBPase deficiency, the maternal and fetal complications can be reduced by pre-pregnancy education and self-monitoring of blood glucose to prevent hypoglycemia. PMID- 24470128 TI - Bacteremic pneumococcal pneumonia in elderly and very elderly patients: host- and pathogen-related factors, process of care, and outcome. AB - BACKGROUND: Hospitalizations due to pneumonia increase steadily with age. The purpose of this study is to explore differences in host- and pathogen-related factors, process of care, and outcome as a function of age in elderly patients with bacteremic pneumococcal pneumonia and identify factors related to mortality. METHODS: This was a prospective observational study of a cohort of elderly (65-79 years) and very elderly patients (>= 80 years old) diagnosed with bacteremic pneumococcal pneumonia. The serotypes of the strains isolated and their resistance were also analyzed. RESULTS: During the study period, 399 patients were identified, of whom 225 patients (140 elderly and 85 very elderly patients) were included. Despite the groups having similar characteristics on admission, very elderly patients had higher rates of both hospital (16.47% vs 7.14%, p = .028) and 30-day (20% vs 6.43%, p = .002) mortality. Factors found to be predictors of mortality were: altered mental status (odds ratio [OR]: 13.18; 95% confidence interval [CI]: 3.68-47.23), respiratory rate more than or equal to 30/min (OR: 5.82; 95% CI: 1.82-18.64), systolic blood pressure less than 90 mmHg (OR: 10.90; 95% CI: 1.45-81.93), blood urea nitrogen more than 30 mg/dL (OR: 5.41; 95% CI: 1.03-28.42), bilateral or multilobar lung involvement (OR: 5.24; 95% CI: 1.55-17.76), and age (OR: 1.19; 95% CI: 1.09-1.30). CONCLUSIONS: Very elderly patients have poorer outcomes with no significant differences in host- and pathogen-related factors or process of care. Mortality rates in these patients are associated with age and the severity of their clinical condition. PMID- 24470129 TI - The authors reply. PMID- 24470130 TI - The association between major depressive disorder in childhood and risk factors for cardiovascular disease in adolescence. AB - OBJECTIVE: Depression in adults is associated with risk factors for cardiovascular disease (CVD). It is unclear, however, when the association between clinical depression and cardiac risk factors develops or how early in life this association can be detected. METHODS: In an ongoing study of pediatric depression, we compared CVD risk factors including smoking, obesity, physical activity level, sedentary behavior, and parental history of CVD across three samples of adolescents: probands with established histories of childhood-onset major depressive disorder (n = 210), never-depressed siblings of probands (n = 195), and controls with no history of any major psychiatric disorder (n = 161). RESULTS: When assessed during adolescence, 85% of the probands were not in a major depressive episode. Nevertheless, at that assessment, probands had a higher prevalence of regular smoking (odds ratio [OR] = 12.54, 95% confidence interval [CI] = 4.36-36.12) and were less physically active than controls (OR = 0.59, CI = 0.43-0.81) and siblings (OR = 0.70, CI = 0.52-0.94) and had a higher rate of obesity than did controls (OR = 3.67, CI = 1.42-9.52). Parents of probands reported high rates of CVD (significantly higher than did parents of controls), including myocardial infarction and CVD-related hospitalization (ORs = 1.62-4.36, CIs = 1.03-15.40). Differences in CVD risk factors between probands and controls were independent of parental CVD. CONCLUSIONS: Major depression in childhood is associated with an unfavorable CVD risk profile in adolescence, and risks for pediatric depression and CVD may coincide in families. Effective prevention and treatment of childhood depression may be a means to reduce the incidence of adult CVD. PMID- 24470131 TI - Prospective impact of panic disorder and panic-anxiety on asthma control, health service use, and quality of life in adult patients with asthma over a 4-year follow-up. AB - Background Panic disorder (PD) is a common anxiety disorder among asthmatic patients with overlapping symptoms (e.g., hyperventilation). However, the longitudinal impact of PD on asthma control remains poorly understood. This study assessed the impact of PD and panic-anxiety on asthma control over a 4.3-year follow-up in 643 adult asthmatic patients. Methods Consecutive patients presenting to a tertiary asthma clinic underwent a sociodemographic, medical history, and psychiatric (Primary Care Evaluation of Mental Disorders) interview and completed questionnaires including the Anxiety Sensitivity Index (ASI) to assess panic-anxiety. At follow-up, patients completed the Asthma Control (ACQ) and Asthma Quality of Life (AQLQ) questionnaires and reported emergency department visits and hospitalizations during the follow-up. Results Baseline frequency of PD was 10% (n = 65). In fully adjusted models, analyses revealed that PD and ASI scores predicted worse follow-up ACQ total scores (beta = 0.292, p = .037; beta = 0.012, p = .003) but not AQLQ total scores. ASI scores also predicted greater nocturnal and waking symptoms, activity limitations, and bronchodilator use on the ACQ (beta = 0.012-0.018, p < .05) as well as lower symptom (beta = -0.012, p = .006) and emotional distress (beta = -0.014, p = .002) subscale scores on the AQLQ. Neither PD nor ASI scores were associated with hospitalizations, although ASI scores (but not PD) were associated with an increased risk of emergency department visits (relative risk = 1.023, 95% confidence interval = 1.001-1.044). Conclusions PD and anxiety sensitivity are prospectively associated with poorer asthma control and may be important targets for treatment. PMID- 24470132 TI - Blood pressure and school performance. PMID- 24470133 TI - Effect of depression and sertraline treatment on cardiac function in female nonhuman primates. AB - OBJECTIVE: Depression is a proposed risk factor for heart failure based largely on epidemiological data; few experimental data addressing this hypothesis are available. METHODS: Depression was evaluated in relation to cardiac structural and functional phenotypes assessed by transthoracic echocardiography in 42 adult female cynomolgus monkeys that consumed a Western-like diet for 3 years. Half of the monkeys were treated with sertraline HCl for 18 months, and depressive behavior was assessed for 12 months before echocardiography. RESULTS: Depressed monkeys (the 19/42 with depressive behavior rates above the mean rate) had higher heart rates (HRs; 171 [4.1[ versus 152 [6.1]) and smaller body surface area (0.13 [0.003] versus 0.15 [0.004]), left ventricular (LV) end-systolic dimension (0.75 [0.05] versus 0.89 [0.04]), LV systolic (0.76 [0.08] versus 1.2 [0.11]) and diastolic (2.4 [0.23] versus 3.4 [0.26]) volumes, and left atrial volumes (1.15 [0.14] versus 1.75 [0.12]; p values < .05). Doppler profiles of depressed monkeys indicated greater myocardial relaxation (higher e' and higher e'/a' ratio) and lower filling pressures (lower E/e') compared to nondepressed monkeys (p values < .05). Although sertraline treatment reduced HR (150 [5.8] versus 171 [4.8]) and modestly increased chamber dimensions (LV end-systolic dimension: 0.91 [0.05] versus 0.74 [0.03]; LV end-diastolic dimension, body surface area adjusted 1.69 [0.05] versus 1.47 [0.06]; p values < .05), it did not overtly affect systolic or diastolic function (p values > .10). CONCLUSIONS: These data suggest that behavioral depression in female primates is accompanied by differences in cardiac function, although not in ways classically associated with subclinical heart failure. Selective serotonin reuptakes show promise in supporting heart function by reducing HR and perhaps improving LV filling; however, further investigation is needed. PMID- 24470134 TI - Effects of a Brief, Prevention-Focused Parenting Education Program for New Mothers. AB - We evaluated the effects of a parenting program, Baby and You, on parenting knowledge, parenting morale, and social support using a single-group, pre-test, and post-test design with 159 Canadian mothers of infants aged 2 to 9 months old. Baby and You is a prevention-focused parenting program (PFPP) to improve maternal and infant health through education and social support. The 4-week curriculum focuses on infant development and safety, parent-child relationships, maternal self-care, and community resources. We computed repeated-measures ANOVAs separately for scores on Parenting Knowledge Scale, Parenting Moral Index, and Family Support Scale. We found a significant increase between pre-test and post test on parenting knowledge, but not parenting morale or social support. Parenting morale may be a stable construct that shows little change over time. It may take more than 4 weeks of programming for mothers to identify and integrate new sources of social support. PMID- 24470135 TI - Cancer risk management decision making for BRCA+ women. AB - Women with pathogenic BRCA genetic mutations face high risks for cancer development. Estimates vary among mutation carriers, with lifetime risks ranging from 41% to 90% for breast cancer and 8% to 62% for ovarian cancer. Cancer risk management options for BRCA mutation positive (BRCA+) women have life-altering implications. This qualitative, phenomenological study explored the experience of cancer risk management decision making for women who are unaffected carriers of a BRCA mutation (previvors). Fifteen previvors recruited from Facing Our Risk of Cancer Empowered (FORCE), an online informational and support group, were interviewed. Findings consisted of four major themes: the early previvor experience, intense emotional upheaval; the decisional journey, navigating a personal plan for survival; lack of knowledge and experience among health care providers; and support is essential. Findings highlight the different decisional perspectives of previvors based on age and individual factors and the need for increased competence among health care providers. PMID- 24470136 TI - Ca(2+) -related signaling events influence TLR9-induced IL-10 secretion in human B cells. AB - Suppressory B-cell function controls immune responses and is mainly dependent on IL-10 secretion. Pharmacological manipulation of B-cell-specific IL-10 synthesis could, thus, be therapeutically useful in B-cell chronic lymphocytic leukemia, transplantation, autoimmunity and sepsis. TLR are thought to play a protagonistic role in the formation of IL-10-secreting B cells. The aim of the study was to identify the molecular events selectively driving IL-10 production in TLR9 stimulated human B cells. Our data highlight the selectivity of calcineurin inhibitors in blocking TLR9-induced B-cell-derived IL-10 transcription and secretion, while IL-6 transcription and release, B-cell proliferation, and differentiation remain unaffected. Nevertheless, TLR9-induced IL-10 production was found to be independent of calcineurin phosphatase activity and was even negatively regulated by NFAT. In contrast to TLR9-induced IL-6, IL-10 secretion was highly sensitive to targeting of spleen tyrosine kinase (syk) and Bruton's tyrosine kinase. Further analyses demonstrated increased phosphorylation of Ca(2+) /calmodulin kinase II (CaMKII) in TLR9-stimulated B cells and selective reduction of TLR9-induced secretion of IL-10 upon treatment with CaMKII inhibitors, with negligible impact on IL-6 levels. Altogether, our results identify calcineurin antagonists as selective inhibitors of IL-10 transcription and syk/Bruton's tyrosine kinase-induced Ca(2+) /calmodulin- and CaMKII-dependent signaling as a pathway regulating the release of TLR9-induced B-cell-derived IL 10. PMID- 24470137 TI - Association of X-ray repair cross-complementing group 1 promoter rs3213245 polymorphism with lung cancer risk. AB - X-ray repair cross-complementing group 1 (XRCC1) is a major DNA repair protein in the base excision repair pathway. XRCC1 rs3213245 is a functional polymorphism in the XRCC1 gene promoter region which results in decreased DNA repair capacity. Previous studies investigating the association of XRCC1 rs3213245 polymorphism with lung cancer risk reported conflicting results. A meta-analysis of published studies was performed to provide a comprehensive assessment of the association. The pooled odds ratio (OR) with its 95% confidence interval (95% CI) was calculated to assess the association. Subgroup analysis was performed by ethnicity. Finally, six studies with a total of 3,208 cases and 3,505 control studies were included into our meta-analysis. The pooled results showed that there was a significant association between XRCC1 rs3213245 polymorphism and lung cancer risk (allele model: OR =1.31, 95% CI 1.13-1.51, P < 0.001; homozygote model: OR = 1.42, 95% CI 1.13-1.79, P = 0.003; recessive model: OR = 1.39, 95% CI 1.13-1.71, P = 0.002; dominant model: OR = 1.31, 95% CI 1.17-1.47, P < 0.001). Subgroup analysis by ethnicity showed that the association was still significant in both Asians (all P values less than 0.05) and Caucasians (recessive model: OR = 1.26, 95 % CI 1.01-1.59, P = 0.045). Thus, there is a significant association of XRCC1 rs3213245 polymorphism with lung cancer risk. PMID- 24470138 TI - ChIP-seq predicted estrogen receptor biding sites in human breast cancer cell line MCF7. AB - The aim of this study was to find estrogen receptor (ER) binding sites of estradiol (E2)-treated and control groups and discuss the roles of ER activation in the tumorigenesis and progression of various human cancers. The ER ChIP-seq data GSE19013 was downloaded from Gene Expression Omnibus database, including E2 treated data GSM470419 and control data GSM470418. MACS software was utilized to identify ER binding sites in two groups. R's ChIPpeakAnno was used to detect ER regulated target genes. Motif finding was employed to analyze ER concordant transcription factors (TFs) in MCF7 cell. The Gene Ontology (GO) was used to conduct functional enrichment analysis. We identified 9,134 ER binding sites in E2 stimulation group and 1,969 in control group. GO enrichment analysis of target genes showed that ER-regulated target genes mainly participated in mRNA catabolic process, protein complex disassembly, and protein localization to organelle related biology process; while in E2 stimulation group, the function of ER regulated target genes sharply changed. The effect of E2 in MCF7 cell suggested that activated ER probably reacted with several TFs and then co-regulated related genes expression. Furthermore, several TFs, such as PAX6, SMAD3, and ESR2, had multiply cellular regulation function. Our results showed that E2 stimulates breast cancer cell growth through ER. This may infer the function of ER in occurrence and development of breast cancer. Together, our study would pave ways for discussing ER concordant TFs and studying other ER-recruited TFs. PMID- 24470140 TI - Editorial: emerging evidence for critical involvement of the interleukin-17 pathway in both psoriasis and psoriatic arthritis. PMID- 24470141 TI - Intermittent versus daily therapy for treating tuberculosis in children. AB - BACKGROUND: Childhood tuberculosis (TB) is a neglected global public health problem. Short treatment courses with rifampicin-containing anti-TB drugs given daily for six-months cure over 90% of infected children, but poor adherence reduces treatment success. Intermittent, short-course anti-TB regimens, given two or three times a week under direct observation, are associated with higher adherence in observational studies; but how they compare with daily treatment in relation to cure is unclear. Current international and national recommendations differ on use of intermittent regimens to treat TB in children. OBJECTIVES: To compare the efficacy and safety of intermittent, short-course anti-TB regimens (twice- or thrice-weekly) with daily short-course anti-TB regimens in treating childhood TB. SEARCH METHODS: We searched the Cochrane Infectious Disease Group Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, LILACS, clinical trials registries, regional databases, conference proceedings, and references without language restrictions up to 30 May 2013; and contacted experts for relevant published, unpublished, and on-going trials. SELECTION CRITERIA: Randomized controlled trials (RCTs) and quasi-RCTs of children aged 15 years or younger, diagnosed with TB (according to the World Health Organization diagnostic categories 1, 2, or 3), who were treated with intermittent twice-weekly or thrice-weekly, short-course anti-TB regimens compared to daily short-course anti-TB treatment regimens. All regimens had to contain rifampicin for at least the first two months. DATA COLLECTION AND ANALYSIS: The review authors independently screened and selected trials, assessed risk of bias, and extracted data. We sought clarifications from trial authors. We pooled relative risks with their 95% confidence intervals and used a random effects model where there was significant heterogeneity. We assessed overall evidence-quality using the GRADE approach. MAIN RESULTS: We included four trials published between 1996 to 2000 that randomized 563 children (465 evaluable) aged five months to 15 years to intermittent twice-weekly versus daily anti-TB treatment. Two trials were from India, one from South Africa, and one from Turkey. All trials used rifampicin and isoniazid, three trials used pyrazinamide, and one trial used streptomycin. The drug combination, and the duration of intermittent and daily treatments differed between trials, and no trials used drug combinations and schedules currently recommended for childhood TB. No trial reported if any child was HIV-positive.In comparisons of twice-weekly versus daily anti-TB treatment regimens, the trials did not detect differences in the number of patients cured, but trials were small, and the comparator regimens were not standard (four trials, 465 children; very low quality evidence). Trials were underpowered to provide estimates for death (two trials, 213 participants, very low quality evidence), relapse (one trial, 214 participants,very low quality evidence), and treatment limiting adverse events (four trials, 441 participants, very low quality evidence)Reported adherence to treatment was similar (87% versus 84%; four trials, 458 children, very low quality evidence)We did not find trials comparing the commonly used thrice-weekly anti-TB short-course regimen with the daily treatment regimen. AUTHORS' CONCLUSIONS: Trials conducted to date are insufficient to support or refute the use of intermittent twice- or thrice weekly, short-course treatment regimens over daily short-course treatment in children with TB. Further randomized trials conducted in high TB-transmission settings will help inform policy and practice. PMID- 24470142 TI - Considerations regarding the alleged association between Herbalife products and cases of hepatotoxicity. PMID- 24470139 TI - Development of anticancer drugs based on the hallmarks of tumor cells. AB - Cancer remains a public health problem with a high unmet medical demand. However, in recent decades, the knowledge of several functional molecular and biological traits that distinguish tumor cells from normal cells, known as the hallmarks of cancer as described by Hannahan and Weinberg, has led to new and modern therapeutic approaches against this disease. Most cancer drugs are deliberately developed for specific molecular targets that involve these hallmarks. In this review, we address the currently available cancer drugs and development of new drugs from the perspective of their interaction with these hallmarks as well as the pathways and mechanisms involved. PMID- 24470143 TI - Bone matrix quality after sclerostin antibody treatment. AB - Sclerostin antibody (Scl-Ab) is a novel bone-forming agent that is currently undergoing preclinical and clinical testing. Scl-Ab treatment is known to dramatically increase bone mass, but little is known about the quality of the bone formed during treatment. In the current study, global mineralization of bone matrix in rats and nonhuman primates treated with vehicle or Scl-Ab was assayed by backscattered scanning electron microscopy (bSEM) to quantify the bone mineral density distribution (BMDD). Additionally, fluorochrome labeling allowed tissue age-specific measurements to be made in the primate model with Fourier-transform infrared microspectroscopy to determine the kinetics of mineralization, carbonate substitution, crystallinity, and collagen cross-linking. Despite up to 54% increases in the bone volume after Scl-Ab treatment, the mean global mineralization of trabecular and cortical bone was unaffected in both animal models investigated. However, there were two subtle changes in the BMDD after Scl Ab treatment in the primate trabecular bone, including an increase in the number of pixels with a low mineralization value (Z5) and a decrease in the standard deviation of the distribution. Tissue age-specific measurements in the primate model showed that Scl-Ab treatment did not affect the mineral-to-matrix ratio, crystallinity, or collagen cross-linking in the endocortical, intracortical, or trabecular compartments. Scl-Ab treatment was associated with a nonsignificant trend toward accelerated mineralization intracortically and a nearly 10% increase in carbonate substitution for tissue older than 2 weeks in the trabecular compartment (p < 0.001). These findings suggest that Scl-Ab treatment does not negatively impact bone matrix quality. PMID- 24470144 TI - Trypanosome MKT1 and the RNA-binding protein ZC3H11: interactions and potential roles in post-transcriptional regulatory networks. AB - The trypanosome zinc finger protein ZC3H11 binds to AU-rich elements in mRNAs. It is essential for survival of the mammalian-infective bloodstream form, where it stabilizes several mRNAs including some encoding chaperones, and is also required for stabilization of chaperone mRNAs during the heat-shock response in the vector infective procyclic form. When ZC3H11 was artificially 'tethered' to a reporter mRNA in bloodstream forms it increased reporter expression. We here show that ZC3H11 interacts with trypanosome MKT1 and PBP1, and that domains required for both interactions are necessary for function in the bloodstream-form tethering assay. PBP1 interacts with MKT1, LSM12 and poly(A) binding protein, and localizes to granules during parasite starvation. All of these proteins are essential for bloodstream-form trypanosome survival and increase gene expression in the tethering assay. MKT1 is cytosolic and polysome associated. Using a yeast two hybrid screen and tandem affinity purification we found that trypanosome MKT1 interacts with multiple RNA-binding proteins and other potential RNA regulators, placing it at the centre of a post-transcriptional regulatory network. A consensus interaction sequence, H(E/D/N/Q)PY, was identified. Recruitment of MKT1 containing regulatory complexes to mRNAs via sequence-specific mRNA-binding proteins could thus control several different post-transcriptional regulons. PMID- 24470145 TI - The hematopoietic regulator TAL1 is required for chromatin looping between the beta-globin LCR and human gamma-globin genes to activate transcription. AB - TAL1 is a key hematopoietic transcription factor that binds to regulatory regions of a large cohort of erythroid genes as part of a complex with GATA-1, LMO2 and Ldb1. The complex mediates long-range interaction between the beta-globin locus control region (LCR) and active globin genes, and although TAL1 is one of the two DNA-binding complex members, its role is unclear. To explore the role of TAL1 in transcription activation of the human gamma-globin genes, we reduced the expression of TAL1 in erythroid K562 cells using lentiviral short hairpin RNA, compromising its association in the beta-globin locus. In the TAL1 knockdown cells, the gamma-globin transcription was reduced to 35% and chromatin looping of the (G)gamma-globin gene with the LCR was disrupted with decreased occupancy of the complex member Ldb1 and LMO2 in the locus. However, GATA-1 binding, DNase I hypersensitive site formation and several histone modifications were largely maintained across the beta-globin locus. In addition, overexpression of TAL1 increased the gamma-globin transcription and increased interaction frequency between the (G)gamma-globin gene and LCR. These results indicate that TAL1 plays a critical role in chromatin loop formation between the gamma-globin genes and LCR, which is a critical step for the transcription of the gamma-globin genes. PMID- 24470146 TI - The influence of CpG and UpA dinucleotide frequencies on RNA virus replication and characterization of the innate cellular pathways underlying virus attenuation and enhanced replication. AB - Most RNA viruses infecting mammals and other vertebrates show profound suppression of CpG and UpA dinucleotide frequencies. To investigate this functionally, mutants of the picornavirus, echovirus 7 (E7), were constructed with altered CpG and UpA compositions in two 1.1-1.3 Kbase regions. Those with increased frequencies of CpG and UpA showed impaired replication kinetics and higher RNA/infectivity ratios compared with wild-type virus. Remarkably, mutants with CpGs and UpAs removed showed enhanced replication, larger plaques and rapidly outcompeted wild-type virus on co-infections. Luciferase-expressing E7 sub-genomic replicons with CpGs and UpAs removed from the reporter gene showed 100-fold greater luminescence. E7 and mutants were equivalently sensitive to exogenously added interferon-beta, showed no evidence for differential recognition by ADAR1 or pattern recognition receptors RIG-I, MDA5 or PKR. However, kinase inhibitors roscovitine and C16 partially or entirely reversed the attenuated phenotype of high CpG and UpA mutants, potentially through inhibition of currently uncharacterized pattern recognition receptors that respond to RNA composition. Generating viruses with enhanced replication kinetics has applications in vaccine production and reporter gene construction. More fundamentally, the findings introduce a new evolutionary paradigm where dinucleotide composition of viral genomes is subjected to selection pressures independently of coding capacity and profoundly influences host-pathogen interactions. PMID- 24470148 TI - Stimulus control and generalization of remote behavioral history. AB - Two experiments were conducted to assess stimulus control and generalization of remote behavioral history effects with humans. Undergraduates first responded frequently under a fixed-ratio (FR) schedule in the presence of one line length (16 mm or 31 mm) and infrequently on a tandem FR 1 differential-reinforcement-of low-rate (DRL) schedule when a second line length (31 mm or 16 mm) was present. Next, an FR 1 schedule in effect in the presence of either stimulus produced comparable response rates between the stimuli. Finally, a tandem FR 1 fixed interval (FI) schedule was in effect under those same stimuli (Experiment 1) or under 12 line lengths ranging from 7 to 40 mm (Experiment 2). In both experiments, responses under the tandem FR 1 FI schedule were frequent in the presence of stimuli previously correlated with the FR schedule and infrequent in the presence of stimuli previously correlated with the tandem FR 1 DRL schedule. Short-lived but systematic generalization gradients were obtained in Experiment 2. These results show that previously established rates of behavior that disappear when the establishing contingencies are changed can subsequently not only reappear when the contingencies change, but are controlled by and generalize across antecedent stimuli. PMID- 24470147 TI - Functional signature for the recognition of specific target mRNAs by human Staufen1 protein. AB - Cellular messenger RNAs (mRNAs) are associated to proteins in the form of ribonucleoprotein particles. The double-stranded RNA-binding (DRB) proteins play important roles in mRNA synthesis, modification, activity and decay. Staufen is a DRB protein involved in the localized translation of specific mRNAs during Drosophila early development. The human Staufen1 (hStau1) forms RNA granules that contain translation regulation proteins as well as cytoskeleton and motor proteins to allow the movement of the granule on microtubules, but the mechanisms of hStau1-RNA recognition are still unclear. Here we used a combination of affinity chromatography, RNAse-protection, deep-sequencing and bioinformatic analyses to identify mRNAs differentially associated to hStau1 or a mutant protein unable to bind RNA and, in this way, defined a collection of mRNAs specifically associated to wt hStau1. A common sequence signature consisting of two opposite-polarity Alu motifs was present in the hStau1-associated mRNAs and was shown to be sufficient for binding to hStau1 and hStau1-dependent stimulation of protein expression. Our results unravel how hStau1 identifies a wide spectrum of cellular target mRNAs to control their localization, expression and fate. PMID- 24470149 TI - Successful allogeneic hematopoietic stem cell transplantation with reduced intensity conditioning for B-cell prolymphocytic leukemia in partial remission. AB - B-cell prolymphocytic leukemia (B-PLL) is a rare, chemotherapy-resistant lymphoid neoplasm. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) represents a potentially curative treatment for B-PLL, the number of B-PLL patients who have been treated with allo-HSCT is small and its efficacy has not been established. We report the case of a 59-year-old woman with B-PLL in partial remission, who was successfully treated with allo-HSCT following reduced intensity conditioning (RIC). She was initially treated with four courses of combination chemotherapy consisting of rituximab, fludarabine, cyclophosphamide, and mitoxantrone, which resulted in partial remission with residual tumor cells comprising 7 % of bone marrow nucleated cells. Although the residual B-PLL cells appeared to be indolent, as the disease progressed slowly during partial remission, these cells lost CD20 expression, and the prognosis of the patient was considered to be poor with conventional chemotherapy. She was therefore given RIC, followed by allo-HSCT from an HLA-matched sibling donor. Her clinical course following allo-HSCT was uneventful, and she remained in complete remission at 32 months post-transplantation. Although the therapeutic strategy for B-PLL should be determined based on the severity of the disease, RIC with allo-HSCT may be a therapeutic option for indolent B-PLL when the long-term prognosis of patients is markedly poor. PMID- 24470150 TI - Refractory acute monoblastic leukaemia with low hypodiploidy. PMID- 24470151 TI - Relationship between mental health and foot pain. AB - OBJECTIVE: Although mental health is related to the persistence of musculoskeletal pain, our understanding of the relationship between mental health and foot pain is limited. Subsequently, we conducted a 3-year longitudinal study to examine the relationship between mental health and foot pain in a community based population. METHODS: Eighty-three community-dwelling participants (mean +/- SD body mass index [BMI] 35.3 +/- 9.0 kg/m2) who had foot pain at study inception in 2008 and for whom measures of mental health (Short Form 36 [SF-36] health survey mental component summary [MCS]) were available, were invited to take part in this followup study in 2011. Change in foot pain was determined by the difference between the Manchester Foot Pain and Disability Index score at baseline and followup; therefore, a decrease in the score indicated improved foot pain and an increase indicated deterioration in foot pain. Linear regression was used to determine the factors affecting change in foot pain. RESULTS: Of the 62 respondents (75% response rate, 49 women and 13 men), there were 27 (44%) whose foot pain deteriorated. A higher MCS score of the SF-36 health survey at baseline was associated with a slower progression of foot pain (beta coefficient -0.29, 95% confidence interval -0.42, -0.01), adjusted for age, sex, BMI, and physical health. CONCLUSION: Mental health is associated with changes in foot pain. Clinicians dealing with this population should consider the contribution of mental health in their management and treatment of foot pain. PMID- 24470152 TI - Seasonal variations in apparent photosynthesis among plant stands of different soybean cultivars. AB - The CO2- and H2O-exchange rates between soybean canopies and the atmosphere were measured in three mobile chambers (4 m(3)). Each chamber stopped at 8 or 9 plots (3.1-m(2) ground area) every 25 min. Diurnal and seasonal CO2-exchange rates (CER) of 13 soybean (Glycine max (L.) Merr.) cultivars are summarized here. The oldest two cultivars, released in 1927 and 1932, had the lowest CER values. The CER usually decreased in the afternoon (23.4 vs 27.8 MUmol CO2 m(-2) s(-1) at 1.6 mmol photons m(-2) s(-1)), except shortly after rainfall. During a drought, these reductions occurred earlier in the day and were more pronounced. We present evidence for a nonstomatal component of the CO2 flux-reaction system causing CER reductions during a water stress. Daytime CER values were not correlated with temperature (24-34 degrees C), but nighttime values were (15-25 degrees C, r=0.85,* n=41). PMID- 24470153 TI - Correlations among leaf CO2-exchange rates, areas and enzyme activities among soybean cultivars. AB - Soybean (Glycine max (L.) Merr.) genotypes varying in area per nodal unit (usually a trifoliolate) and maturity class were grown in plots at the University of Illinois experimental farm. Leaf CO2-exchange rates per unit area (CER) were measured under sunlight on intact plants. In addition to previously reported correlations with specific leaf weight and chlorophyll, CER was positively correlated with ribulose bisphosphate carboxylase (RuBPcase) activity, specific activity, and soluble protein, and was negatively correlated with area per leaf unit. The CER: chlorophyll correlation was destroyed by high CER values in 2 chlorophyll-deficient lines. CER values for 27 of the 35 lines tested fell within the range of those for isolines of cultivar Clark varying in leaf characteristics. The CER values were highest for fully expanded leaves during rapid pod fill. These results suggested that photoperiod (maturity) genes and genes for leaf area growth interact with genes controlling photosynthetic CO2 exchange to produce the major differences in CER values among soybean genotypes. PMID- 24470154 TI - Structural and functional stability of isolated intact chloroplasts. AB - The effect of in vitro ageing on the ultrastructure, electron transport, thermoluminescence and flash-induced 515 nm absorbance change of isolated intact (type A) chloroplasts compared with non-intact (types B and C) chloroplasts was studied.When stored in the dark for 18 h at 5 degrees C, the structural characteristics of intact and non-intact chloroplasts were only slightly altered. The most conspicuous difference between the two was in the coupling of the electron transport which was tighter and more stable in intact chloroplasts. Under dark-storage the activity of PS 2* decreased and the -20 degrees C peak of thermoluminescence increased at the expense of the emission at +25 degrees C. These changes were less pronounced in the intact chloroplasts. PS 1 activity and the flash-induced 515 nm absorbance change were not affected by dark-storage.When kept in the light (80 W m(-2) (400-700 nm) for 1 h at 5 degrees C), the thylakoid system of chloroplasts rapidly became disorganized. Although the initial activity of electron transport was much higher in intact chloroplasts, after a short period of light-storage the linear electron transport and the electron transport around PS 2 decreased in both types of preparations to the same low level. These changes were accompanied by an overall decrease of the intensity of thermoluminescence. PS 1 was not inhibited by light-storage, while the flash induced 515 nm absorbance change was virtually abolished both in preparations of intact and non-intact chloroplasts.The data show that in stored chloroplast preparations intactness cannot be estimated reliably either by the FeCy test or by inspection under the electron microscope. These tests should be cross-checked on the level and coupling of the electron transport. PMID- 24470155 TI - Effects of abscisic acid on CAM in Portulacaria afra. AB - Water stress induces Crassulacean acid metabolism (CAM)(?) in Portulacaria afra as manifested by day stomatal closure, organic acid fluctuation, and night CO2 uptake. We now have evidence that abscisic acid treatment of leaves causes partial stomatal closure that is accompanied by the induction of CAM in a manner similar to water stress. There appears to be an inverse relationship between exogenous CO2 uptake and decarboxylation of organic acids in that organic acids remain high during the day providing stomata are open. When stomata close, there is consumption of organic acids by decarboxylation. The hypothesis is that stomatal opening controls CAM in this species. PMID- 24470156 TI - Comparison of the long-wave chlorophyll fluorescence in various green and blue green algae and diatoms. AB - Two types of long-wave fluorescence bands with similar band shape occur at room temperature in various algae: FII700 and FI715. FII700 occurs in a limited number of algae, follows PS II transients, increases with culture age and is moderately increased by cooling to 83 K. FI715 occurs in most algae, especially Anabaena, but much less in most diatoms and Tribonema. It does not follow PS II transients, does not increase with culture age and is much increased by cooling to 83 K.An interpretation for the characteristics of FII700 and FI715 is given. PMID- 24470157 TI - Herbicide resistance in a mutant of the microalga Bumilleriopsis filiformis. AB - A DCMU* (diuron)-resistant algal mutant was selected and characterized. Chlorophyll content, growth, and photosystem-I activity are as in the wild-type. Growth in liquid medium with 3 MUM DCMU present is half of the control. Apparently only the herbicide-binding site is affected within the redox chain. In contrast to the wild-type, trypsin treatment of isolated chloroplast material completely abolishes photosynthetic electron transport inhibition by DCMU or atrazine.DCMU resistance of chloroplasts is accompanies by tolerance to triazinones and phenylpyridazinones, but not to symmetric triazines. Sensitivity to diphenylethers, DBMIB or o-phenanthroline is not altered.Data on this algal mutant combined with those from triazine-resistant mutants of higher plants give direct evidence of overlapping binding sites at a (hypothetical) binding protein located at the reducing side of photosytem II. PMID- 24470158 TI - Prediction of the repeat domain structures and impact of parkinsonism-associated variations on structure and function of all functional domains of leucine-rich repeat kinase 2 (LRRK2). AB - Genetic variations of leucine-rich repeat kinase 2 (LRRK2) are the major cause of dominantly inherited Parkinson disease (PD). LRRK2 protein contains seven predicted domains: a tandem Ras-like GTPase (ROC) domain and C-terminal of Roc (COR) domain, a protein kinase domain, and four repeat domains. PD-causative variations arise in all domains, suggesting that aberrant functioning of any domain can contribute to neurotoxic mechanisms of LRRK2. Determination of the three-dimensional structure of LRRK2 is one of the best avenues to decipher its neurotoxic mechanism. However, with the exception of the Roc domain, the three dimensional structures of the functional domains of LRRK2 have yet to be determined. Based on the known three-dimensional structures of repeat domains of other proteins, the tandem Roc-COR domains of the Chlorobium tepidum Rab family protein, and the kinase domain of the Dictyostelium discoideum Roco4 protein, we predicted (1) the motifs essential for protein-protein interactions in all domains, (2) the motifs critical for catalysis and substrate recognition in the tandem Roc-COR and kinase domains, and (3) the effects of some PD-associated missense variations on the neurotoxic action of LRRK2. Results of our analysis provide a conceptual framework for future investigation into the regulation and the neurotoxic mechanism of LRRK2. PMID- 24470159 TI - Prospective virtual screening in a sparse data scenario: design of small-molecule TLR2 antagonists. AB - Toll-like receptors (TLRs) are critical signaling molecules with roles in various severe clinical conditions such as sepsis and rheumatoid arthritis, and have therefore been advocated as promising drug targets for the treatment of these diseases. The aim of this study was to discover small-molecule antagonists of TLR2 by computer-aided drug design. This goal poses several challenges due to the lack of available data on TLR2 modulators. To overcome these hurdles we developed a combined structure- and ligand-based virtual screening approach. First, we calculated molecular interaction fields of the TLR2 binding site to derive a structure-based 3D pharmacophore, which was then used for virtual screening. We then performed a two-step shape- and feature-based similarity search using known TLR2 ligands as query structures. A selection of virtual screening hits was biologically tested in a cell-based assay for TLR2 signaling inhibition, leading to the identification of several compounds with antagonistic activity (IC50 values) in the low-micromolar range. PMID- 24470163 TI - Seeding molecular rotators on a passivated silicon surface. AB - Thermally activated rotation of single molecules adsorbed on a silicon-based surface between 77 and 150 K has been successfully achieved. This remarkable phenomenon relies on a nanoporous supramolecular network, which acts as a template to seed periodic molecule rotors on the surface. Thermal activation of rotation has been demonstrated by STM experiments and confirmed by theoretical calculations. PMID- 24470164 TI - Nitrite induces the extravasation of iron oxide nanoparticles in hypoxic tumor tissue. AB - Nitrite undergoes reconversion to nitric oxide under conditions characteristic of the tumor microenvironment, such as hypoxia and low pH. This selective conversion of nitrite into nitric oxide in tumor tissue has led to the possibility of using nitrite to enhance drug delivery and the radiation response. In this work, we propose to serially characterize the vascular response of brain tumor-bearing rats to nitrite using contrast-enhanced R2 * mapping. Imaging is performed using a multi-echo gradient echo sequence at baseline, post iron oxide nanoparticle injection and post-nitrite injection, whilst the animal is breathing air. The results indicate that nitrite sufficiently increases the vascular permeability in C6 gliomas, such that the iron oxide nanoparticles accumulate within the tumor tissue. When animals breathed 100% oxygen, the contrast agent remained within the vasculature, indicating that the conversion of nitrite to nitric oxide occurs in the presence of hypoxia within the tumor. The hypoxia-dependent, nitrite-induced extravasation of iron oxide nanoparticles observed herein has implications for the enhancement of conventional and nanotherapeutic drug delivery. PMID- 24470165 TI - Differential expression, modulation and bioactivity of distinct fish IL-12 isoforms: implication towards the evolution of Th1-like immune responses. AB - IL-12 is a heterodimeric cytokine composed of an alpha-chain (p35) and a beta chain (p40). Primarily produced by APCs, IL-12 induces IFN-gamma production in T, B and NK cells. IL-12 drives Th1-cell differentiation and IFN-gamma secretion to promote cell-mediated immunity, which is essential in the defence against intracellular pathogens. The importance of IL-12 in Th1 responses is echoed by its targeted suppression by intracellular pathogens evading cell-mediated immunity. IL-12 subunits have been identified recently in fish, although reported bioactivities are limited to higher vertebrates. Here, we report the cloning of a p35 gene and two divergent p40 genes (p40b and p40c), capable of producing two functional IL-12 isoforms (p35/p40b and p35/p40c) in rainbow trout. Trout IL-12 isoforms possess distinct bioactivities with respect to the induction of IFN gamma, IL-10 and p40c expression. Trout IL-12 isoforms are differentially expressed and modulated in vivo, exhibiting specific gene expression profiles in bacterial, viral and parasitic infection models, and in vitro in stimulated macrophage and leucocyte cultures. These data imply that alternative or additional pathogen-specific Th-like cell populations may exist in fish. This study will facilitate a broader understanding of the evolutionary processes driving host-pathogen interactions and Th1-like immune responses in lower vertebrates. PMID- 24470166 TI - Development of a new method for the identification of degradation products of V type nerve agents by liquid chromatography-tandem mass spectrometry. AB - Degradation products of V-type nerve agents are important markers of these toxic chemical warfare agents; hence their detection and identification are of high importance from verification point of view of Chemical Weapons Convention. The new analytical technique using quantitation-enhanced data-dependent (QED) method has been developed for the analysis of the degradation products, 2-(N,N dialkylamino)ethanesulfonic acids of V-type nerve agents, by using liquid chromatography-tandem mass spectrometry (Thermo-Scientific Vantage triple stage quadrupole mass spectrometer, Thermo Finnigan Surveyor, San Jose, CA, USA) via an atmospheric pressure ionization source/interface operated in eletrospray ionization mode. With a single analytical run, we could perform the quantitative analysis of the 2-(N,N-dialkylamino)ethanesulfonic acids by the selected reaction monitoring scan mode with limit of detection at 0.1 ng/mL and identify their isomeric compounds by product ion scan mode, simultaneously. The QED method will be applicable to the trace analysis of degradation products of V-type nerve agents in the environmental matrices in the Organisation for the Prohibition of Chemical Weapons proficiency test. PMID- 24470167 TI - A case of thoracic esophageal cancer with an unusual type of duplicated inferior vena cava. AB - We describe here a thoracic esophageal cancer with an unusual type of duplicated inferior vena cava. A 58-year-old man was referred to our hospital because a tumor in his lower esophagus had been identified by endoscopy and radiology. Computed tomography scans showed an unusual type of duplicated inferior vena cava characterized by both common iliac veins flowing back into the left-sided inferior vena cava, which drained into the azygos vein, whereas the right-sided one had no drainage. Esophagectomy was performed 3 weeks later after preoperative chemotherapy. Because the patient could have developed thrombosis of the left sided inferior vena cava and severe hypotension caused by decreased venous return to the heart if the azygos vein had been severed, the azygos vein was preserved. Thus, when performing surgery for thoracic esophageal cancer, the surgeon should check for a duplicated inferior vena cava and preserve the azygos vein if necessary. PMID- 24470168 TI - Passive sampling methods for contaminated sediments: state of the science for metals. AB - "Dissolved" concentrations of contaminants in sediment porewater (Cfree ) provide a more relevant exposure metric for risk assessment than do total concentrations. Passive sampling methods (PSMs) for estimating Cfree offer the potential for cost efficient and accurate in situ characterization of Cfree for inorganic sediment contaminants. In contrast to the PSMs validated and applied for organic contaminants, the various passive sampling devices developed for metals, metalloids, and some nonmetals (collectively termed "metals") have been exploited to a limited extent, despite recognized advantages that include low detection limits, detection of time-averaged trends, high spatial resolution, information about dissolved metal speciation, and the ability to capture episodic events and cyclic changes that may be missed by occasional grab sampling. We summarize the PSM approaches for assessing metal toxicity to, and bioaccumulation by, sediment dwelling biota, including the recognized advantages and limitations of each approach, the need for standardization, and further work needed to facilitate broader acceptance and application of PSM-derived information by decision makers. PMID- 24470169 TI - Theoretical evaluation of antiemetic effects of 5-HT3 receptor antagonists for prevention of vomiting induced by cisplatin. AB - 5-HT(3) receptor antagonists are widely used as antiemetic agents in clinical setting, of which palonosetron, with a long elimination half life (t(1/2)), has recently become available. It is important to evaluate the concentration of serotonin when investigating the antiemetic effects of 5-HT(3) receptor antagonists, as those effects are not based solely on the t(1/2) value. We theoretically evaluated the antiemetic effects of three 5-HT(3) receptor antagonists (granisetron, azasetron, palonosetron) on cisplatin-induced nausea and vomiting by estimating the time course of the 5-HT(3) receptor occupancy of serotonin. We estimated the 5-HT(3) receptor occupancy of serotonin in the small intestine, based on the time course of plasma concentration of each 5-HT(3) receptor antagonist and the time course of concentration of serotonin near the 5 HT(3) receptor in the small intestine after administration of cisplatin. The antiemetic effect of each 5-HT(3) receptor antagonist was evaluated based on the normal level of 5-HT(3) receptor occupancy of serotonin. Our results suggest that an adequate antiemetic effect will be provided when a dose of 75 mg/m(2) of cisplatin is given to patients along with any single administration of granisetron, azasetron, or palonosetron at a usual dose. On the other hand, the 5 HT(3) receptor occupancy of serotonin was found to be significantly lower than normal for several days after administration of palonosetron, as compared to granisetron and azasetron, indicating that constipation may be induced. Our results show that granisetron, azasetron, and palonosetron each have an adequate antiemetic effect after administration of 75 mg/m(2) of cisplatin. PMID- 24470170 TI - Functional characterization of cynomolgus monkey UDP-glucuronosyltransferase 1A9. AB - UDP-glucuronosyltransferase 1A9 (UGT1A9) contributes to the glucuronidation of numerous drugs. Cynomolgus monkeys are regarded as experimental animals similar to humans in studies on safety evaluation and biotransformation for drug development. In this study, the similarities and differences in the enzymatic properties of UGT1A9 between humans and cynomolgus monkeys were precisely identified. UGT1A9 cDNAs of humans (humUGT1A9) and cynomolgus monkeys (monUGT1A9) were cloned, and the corresponding proteins were heterologously expressed in Sf9 cells. The enzymatic properties of UGT1A9s were characterized by kinetic analysis of propofol glucuronidation. The amino acid homology between humUGT1A9 and monUGT1A9 was 93.2 %. Propofol glucuronidation by recombinant humUGT1A9 and monUGT1A9 exhibited substrate inhibition and monophasic Michaelis-Menten kinetics, respectively. The K m, V max and CL int values of humUGT1A9 were 15.0 MUM, 1.56 nmon/min/mg protein and 107 MUL/min/mg protein, respectively. The K m value of monUGT1A9 was 8.8-fold higher than humUGT1A9, and the V max and CL int values of monUGT1A9 were 15 and 2 % of humUGT1A9, respectively. These findings suggest that the enzymatic properties of UGT1A9 are considerably different between humans and cynomolgus monkeys, although humUGT1A9 and monUGT1A9 were highly conserved at the amino acid level. The information on species differences in UGT1A9 function gained in this study should help with the in vivo extrapolation of drug metabolism. PMID- 24470171 TI - Management of invasive well-differentiated thyroid cancer: an American Head and Neck Society consensus statement. AHNS consensus statement. AB - BACKGROUND: Invasive differentiated thyroid cancer (DTC) is relatively frequent, yet there is a paucity of specific guidelines devoted to its management. The Endocrine Committee of the American Head and Neck Society (AHNS) convened a panel to provide clinical consensus statements based on review of the literature, synthesized with the expert opinion of the group. METHODS: An expert panel, selected from membership of the AHNS, constructed the manuscript and recommendations for management of DTC with invasion of recurrent laryngeal nerve, trachea, esophagus, larynx, and major vessels based on current best evidence. A Modified Delphi survey was then constructed by another expert panelist utilizing 9 anchor points, 1 = strongly disagree to 9 = strongly agree. Results of the survey were utilized to determine which statements achieved consensus, near consensus, or non-consensus. RESULTS: After endorsement by the AHNS Endocrine Committee and Quality of Care Committee, it received final approval from the AHNS Council. PMID- 24470172 TI - Imaging COX-2 expression in cancer using PET/SPECT radioligands: current status and future directions. AB - The role of cyclooxygenase (COX)-2 as a driving force in early tumourigenesis and the current interest in the combination of COX-2 inhibitors with standard therapy in clinical trials creates an urgent need to establish clinically relevant diagnostic tests for COX-2 expression. Molecular imaging using small-molecule probes radiolabelled for both positron emission tomography (PET) and single photon emission computed tomography (SPECT) offers the potential to meet this need, providing a minimally invasive readout for the whole disease burden. This review summarises current approaches to the radiolabelling of small-molecule COX 2 inhibitors and their analogues for PET and SPECT imaging, and gives an overview of their biological evaluation and likely success of clinical application. PMID- 24470173 TI - Using quality improvement to optimise paediatric discharge efficiency. AB - BACKGROUND: Bed capacity management is a critical issue facing hospital administrators, and inefficient discharges impact patient flow throughout the hospital. National recommendations include a focus on providing care that is timely and efficient, but a lack of standardised discharge criteria at our institution contributed to unpredictable discharge timing and lengthy delays. Our objective was to increase the percentage of Hospital Medicine patients discharged within 2 h of meeting criteria from 42% to 80%. METHODS: A multidisciplinary team collaborated to develop medically appropriate discharge criteria for 11 common inpatient diagnoses. Discharge criteria were embedded into electronic medical record (EMR) order sets at admission and could be modified throughout a patient's stay. Nurses placed an EMR time-stamp to signal when patients met all discharge goals. Strategies to improve discharge timeliness emphasised completion of discharge tasks prior to meeting criteria. Interventions focused on buy-in from key team members, pharmacy process redesign, subspecialty consult timeliness and feedback to frontline staff. A P statistical process control chart assessed the impact of interventions over time. Length of stay (LOS) and readmission rates before and after implementation of process measures were compared using the Wilcoxon rank-sum test. RESULTS: The percentage of patients discharged within 2 h significantly improved from 42% to 80% within 18 months. Patients studied had a decrease in median overall LOS (from 1.56 to 1.44 days; p=0.01), without an increase in readmission rates (4.60% to 4.21%; p=0.24). The 12-month rolling average census for the study units increased from 36.4 to 42.9, representing an 18% increase in occupancy. CONCLUSIONS: Through standardising discharge goals and implementation of high-reliability interventions, we reduced LOS without increasing readmission rates. PMID- 24470174 TI - Normal Aging of the Attentional Control Functions That Underlie Working Memory. AB - OBJECTIVES: This study assessed the effect of aging on 3 attentional control functions (ACFs)--shifting, inhibition, and updating--and on their contribution to working memory (WM) tasks. METHODS: Complex WM tasks (the Brown-Peterson procedure, the reading span, and the alpha span) and tasks used to derive composite measures of the ACFs were administered to 75 younger and 75 older adults. RESULTS: Of the 3 ACFs, only inhibition was impaired in aging after controlling for processing speed. Furthermore, the effect of aging on WM tasks was not pervasive, as older adults showed impaired performance on the Brown Peterson procedure and the reading span but not on the alpha span. When examining the contribution of ACFs to WM in older adults, updating accounted for performance on the Brown-Peterson and reading span tasks, and inhibition was involved in performance on the alpha span task. In younger adults, it was processing speed that contributed the most to WM. DISCUSSION: This pattern of results suggests that complex WM tasks reflect different ACFs and that this varies as a function of age. PMID- 24470175 TI - Sexual activity and psychological health as mediators of the relationship between physical health and marital quality. AB - OBJECTIVES: The pathways linking spousal health to marital quality in later life have been little examined at the population level. We develop a conceptual model that links married older adults' physical health and that of their spouse to positive and negative dimensions of marital quality via psychological well-being of both partners and their sexual activity. METHODS: We use data from 1,464 older adults in 732 marital dyads in the 2010-2011 wave of the National Social Life Health and Aging Project. RESULTS: We find that own fair or poor physical health is linked to lower positive and higher negative marital quality, spouse's health to positive quality, and that own and spouse's mental health and more frequent sex are associated with higher positive and lower negative marital quality. Further, we find that (a) sexual activity mediates the association between own and partner's physical health and positive marital quality, (b) own mental health mediates the association between one's own physical health and both positive and negative marital quality, and (c) partner's mental health mediates the associations of spouse's physical health with positive marital quality. These results are robust to alternative specifications of the model. DISCUSSION: The results suggest ways to protect marital quality among older adults who are struggling with physical illness in themselves or their partners. PMID- 24470176 TI - Morphometric, geographic, and territorial characterization of brain arterial trees. AB - Morphometric information of the brain vascularization is valuable for a variety of clinical and scientific applications. In particular, this information is important when creating arterial tree models for imposing boundary conditions in numerical simulations of the brain hemodynamics. The purpose of this work is to provide quantitative descriptions of arterial branches, bifurcation patterns, shape, and geographical distribution of the arborization of the main cerebral arteries as well as estimations of the corresponding vascular territories. For this purpose, subject-specific digital reconstructions of the brain vascular network created from 3T magnetic resonance angiography images of healthy volunteers are used to derive population-averaged morphometric characteristics of the cerebral arterial trees. Copyri PMID- 24470177 TI - Accuracy of dental age estimation charts: Schour and Massler, Ubelaker and the London Atlas. AB - Dental age estimation charts are frequently used to assess maturity and estimate age. The aim of this study was to assess the accuracy of estimating age of three dental development charts (Schour and Massler, Ubelaker, and the London Atlas). The test sample was skeletal remains and dental radiographs of known-age individuals (N = 1,506, prenatal to 23.94 years). Dental age was estimated using charts of Schour and Massler, Ubelaker, and The London Atlas. Dental and chronological ages were compared using a paired t-test for the three methods. The absolute mean difference between dental and chronological age was calculated. Results show that all three methods under-estimated age but the London Atlas performed better than Schour and Massler and Ubelaker in all measures. The mean difference for Schour and Massler and Ubelaker was -0.76 and -0.80 years (SD 1.27 year, N = 1,227) respectively and for the London Atlas was -0.10 year (SD 0.97 year, N = 1,429). Further analysis by age category showed similar accuracy for all three methods for individuals younger than 1 year. For ages 1-18, the mean difference between dental and chronological ages was significant (P < 0.05) for Schour and Massler and Ubelaker and not significant (P > 0.05) for the London Atlas for most age categories. These findings show that the London Atlas performs better than Schour and Massler and Ubelaker and represents a substantial improvement in accuracy of dental age estimation from developing teeth. PMID- 24470178 TI - Canadian estimates of health care utilization costs for rheumatoid arthritis patients with and without therapy with biologic agents. AB - OBJECTIVE: To provide Canadian estimates of health care utilization costs associated with rheumatoid arthritis (RA)-related and non-RA-related care within 4 treatment strategies and in different physical functioning categories. METHODS: In the Alberta Rheumatoid Arthritis Biologics Pharmacosurveillance Program, clinical data were linked with provincial health care administrative databases to estimate health care costs. A propensity score matching technique was used to evaluate annual costs across 4 treatment strategies: 1) remaining on disease modifying antirheumatic drugs and not progressing to therapy with a biologic agent (n = 75), 2) progressing to biologic agents (n = 68), 3) initiation and stabilization on a first anti-tumor necrosis factor agent (n = 731), or 4) requiring a switch to another biologic agent (n = 212). Costs were examined across levels of function and by cost attribution category (directly related to RA or not). RESULTS: Of 1,222 patients, 1,086 had at least 3 months of administrative data. The mean annual total cost per patient was $5,531 (median $2,568), and $2,349 (median $0) was accounted for by hospitalizations, $1,716 (median $1,358) by physician visits, and $1,465 (median $949) by emergency room and other outpatient visits. Of these costs, 41% was directly related to RA itself or associated comorbidities. The importance of physical function as a determinant of health care utilization was evident, with the annual mean cost for those with low functional disability as measured by a Health Assessment Questionnaire (HAQ) score <0.5 was $4,157 compared to $14,225 for those with a HAQ score >2.0 indicating high disability. CONCLUSION: Health care costs for RA can be minimized by aiming for better disease control and maintaining physical function. PMID- 24470179 TI - A short expedient synthesis of [(14)C]Ticlopidine. AB - To support the development of a reactive metabolite strategy, the preparation of several radiolabelled compounds such as [(14)C] Ticlopidine was required. In this report, we describe a facile and rapid synthesis of [(14)C] Ticlopidine starting from [(14)C] carbon dioxide. The compound was radiolabelled in the 2-chloromethyl portion of the molecule with a specific activity of 53.4 mCi/mmol and with a radiochemical purity of 98.5%. Storage stability was best as the hydrochloride salt in an ethanol solution. PMID- 24470180 TI - Clinically relevant variants - identifying, collecting, interpreting, and disseminating: the 2013 annual scientific meeting of the Human Genome Variation Society. AB - The dramatic advances in genetic sequencing technologies used in research laboratories are now entering the clinic, and applications of whole-genome and whole-exome sequencing to disease diagnosis, predisposition, and treatment will soon be commonplace. However, the standards and methods for identifying clinically relevant variants are currently being debated and defined. Multiple agencies worldwide have recognized that we have reached an exciting and critical transition point into the clinic, and many important issues are being discussed that impact how genetic variation data in the clinic will be interpreted and used. The 2013 annual scientific meeting of the Human Genome Variation Society (HGVS) had as its main theme the discovery, interpretation, and dissemination of clinically relevant DNA variants. The meeting featured the continuously developing technology of databasing genetic variation and computational tools for allelic variant discovery. Attention was given to curating and integrating these data with clinical findings, including approaches to distinguish between functional alleles underlying clinical phenotypes and benign sequence variants and making data sources interoperable and functional for clinical diagnostic utility, citing examples in specific diseases. PMID- 24470181 TI - FoxP3+Helios- Treg cells may play a critical role in maintaining immune homeostasis in systemic lupus erythematosus: comment on the article by Golding et al. PMID- 24470182 TI - Omega-3 supplementation improves cognition and modifies brain activation in young adults. AB - OBJECTIVE: The current study aimed to investigate the effects of eicosapentaenoic acid (EPA)-rich and docosahexaenoic acid (DHA)-rich supplementations on cognitive performance and functional brain activation. DESIGN: A double-blind, counterbalanced, crossover design, with a 30-day washout period between two supplementation periods (EPA-rich and DHA-rich) was employed. Functional magnetic resonance imaging scans were obtained during performance of Stroop and Spatial Working Memory tasks prior to supplementation and after each 30-day supplementation period. RESULTS: Both supplementations resulted in reduced ratio of arachidonic acid to EPA levels. Following the EPA-rich supplementation, there was a reduction in functional activation in the left anterior cingulate cortex and an increase in activation in the right precentral gyrus coupled with a reduction in reaction times on the colour-word Stroop task. By contrast, the DHA rich supplementation led to a significant increase in functional activation in the right precentral gyrus during the Stroop and Spatial Working Memory tasks, but there was no change in behavioural performance. CONCLUSIONS: By extending the theory of neural efficiency to the within-subject neurocognitive effects of supplementation, we concluded that following the EPA-rich supplementation, participants' brains worked 'less hard' and achieved a better cognitive performance than prior to supplementation. Conversely, the increase in functional activation and lack of improvement in time or accuracy of cognitive performance following DHA-rich supplementation may indicate that DHA-rich supplementation is less effective than EPA-rich supplementation in enhancing neurocognitive functioning after a 30-day supplementation period in the same group of individuals. PMID- 24470183 TI - Modified Sauve-Kapandji procedure for restoration of forearm rotation in devascularized hands. AB - INTRODUCTION: The purpose of this study is to evaluate the clinical outcomes in patients with forearm rotation limitation after successful wrist-level revascularization who underwent a modified Sauve-Kapandji (S-K) procedure. METHODS: This was a retrospective review of the clinical records of nine patients (three women, six men) after successful wrist-level revascularization who underwent late restoration of forearm rotation. All patients were evaluated using a Mayo Modified Wrist Score. The mean patient age was 35 (range 19-45) years. Mean time to reconstruction was 2.5 (range 0.5-4) years. RESULTS: Mean postoperative pronation was 74 degrees ; mean postoperative supination was 80 degrees . Overall results were excellent/good in seven patients, fair in one, and poor in one. No bone bridge was formed between the pseudarthrosis in any patient. Two patients had neurapraxia. Moderate pain and snapping occurred in one patient during movement at the ulnar amputation site. CONCLUSION: This modification of the S-K procedure can restore rotation of the forearm after hand revascularization; as such, it provides an alternative salvage procedure. PMID- 24470184 TI - Mixed quantum-classical description of excitation energy transfer in supramolecular complexes: screening of the excitonic coupling. AB - A mixed quantum-classical description of excitation energy transfer (EET) in large chromophore complexes with significant conformational flexibility is improved by considering screening and local-field effects. To account for the environmentally induced modification of the excitonic coupling J(mn)(epsilon>1) between chromophore m and n, the Poisson-transition-charges-from-electrostatic potential (Poisson-TrEsp) method is utilized. A parameterization scheme for the such derived screening/local field factors is introduced, which allows for their incorporation to a mixed quantum-classical description. The method is applied to the supramolecular complex P16 formed by sixteen pheophorbide-a molecules covalently linked to a butanediamine dendrimer and dissolved in ethanol. Data calculated using the novel parameterized screening method are compared to those obtained by alternative screening approaches. Averaging the screening factors in different ways may reproduce ensemble experiments on EET well, while the description of single molecule properties requires the consideration of individual screening factors. PMID- 24470185 TI - [Disease management programs in Germany: validity of the medical documentation]. PMID- 24470186 TI - [Disease management programs in Germany: validity of the medical documentation]. PMID- 24470187 TI - [Disease management programs in Germany: validity of the medical documentation]. PMID- 24470189 TI - Deriving site-specific clean-up criteria to protect ecological receptors (plants and soil invertebrates) exposed to metal or metalloid soil contaminants via the direct contact exposure pathway. AB - Soil contaminant concentration limits for the protection of terrestrial plants and soil invertebrates are commonly based on thresholds derived using data from laboratory ecotoxicity tests. A comprehensive assessment has been made for the derivation of ecological soil screening levels (Eco-SSL) in the United States; however, these limits are conservative because of their focus on high bioavailability scenarios. Here, we explain and evaluate approaches to soil limit derivation taken by 4 jurisdictions, 2 of which allow for correction of data for factors affecting bioavailability among soils, and between spiked and field contaminated soils (Registration Evaluation Authorisation and Restriction of Chemicals [REACH] Regulation, European Union [EU], and the National Environment Protection Council [NEPC], Australia). Scientifically advanced features from these methods have been integrated into a newly developed method for deriving soil clean-up values (SCVs) within the context of site-specific baseline ecological risk assessment. Resulting site-specific SCVs that account for bioavailability may permit a greater residual concentration in soil when compared to generic screening limit concentrations (e.g., Eco-SSL), while still affording acceptable protection. Two choices for selecting the level of protection are compared (i.e., allowing higher effect levels per species, or allowing a higher percentile of species that are potentially unprotected). Implementation of this new method is presented for the jurisdiction of the United States, with a focus on metal and metalloid contaminants; however, the new method can be used in any jurisdiction. A case study for molybdate shows the large effect of bioavailability corrections and smaller effects of protection level choices when deriving SCVs. PMID- 24470190 TI - Anticancer potential of (pentamethylcyclopentadienyl)chloridoiridium(III) complexes bearing kappaP and kappaP,kappaS-coordinated Ph2 PCH2 CH2 CH2 S(O)x Ph (x=0-2) ligands. AB - Iridium(III) complexes of the type [Ir(eta(5) -C5 Me5 )Cl2 {Ph2 PCH2 CH2 CH2 S(O)x Ph-kappaP}] (x=0-2; 1-3) and [Ir(eta(5) -C5 Me5 )Cl{Ph2 PCH2 CH2 CH2 S(O)x Ph-kappaP,kappaS}][PF6 ] (x=0-1; 4 and 5) with 3-(diphenylphosphino)propyl phenyl sulfide, sulfoxide, and sulfone ligands Ph2 PCH2 CH2 CH2 S(O)x Ph were designed, synthesized, and characterized fully, including X-ray diffraction analyses for complexes 3 and 4. In vitro studies against human thyroid carcinoma (8505C), submandibular carcinoma (A253), breast adenocarcinoma (MCF-7), colon adenocarcinoma (SW480), and melanoma (518A2) cell lines provided evidence for the high biological potential of the neutral and cationic iridium(III) complexes. Neutral iridium(III) complex 5 proved to be the most active, with IC50 values up to about 0.1 MUM, representing activities of up to one order of magnitude higher than cisplatin. Using 8505C cells, apoptosis was shown to be the main mechanism through which complex 5 exerts its tumoricidal action. The described iridium(III) complexes represent potential leads in the search for novel metal-based anticancer agents. PMID- 24470188 TI - Bacterial mechanisms for Cr(VI) resistance and reduction: an overview and recent advances. AB - Chromium pollution is increasing incessantly due to continuing industrialization. Of various oxidation states, Cr(6+) is very toxic due to its carcinogenic and mutagenic nature. It also has deleterious effects on different microorganisms as well as on plants. Many species of bacteria thriving in the Cr(6+)-contaminated environments have evolved novel strategies to cope with Cr(6+) toxicity. Generally, decreased uptake or exclusion of Cr(6+) compounds through the membranes, biosorption, and the upregulation of genes associated with oxidative stress response are some of the resistance mechanisms in bacterial cells to overcome the Cr(6+) stress. In addition, bacterial Cr(6+) reduction into Cr(3+) is also a mechanism of specific significance as it transforms toxic and mobile chromium derivatives into reduced species which are innocuous and immobile. Ecologically, the bacterial trait of reductive immobilization of Cr(6+) derivatives is of great advantage in bioremediation. The present review is an effort to underline the bacterial resistance and reducing mechanisms to Cr(6+) compounds with recent development in order to garner a broad perspective. PMID- 24470191 TI - Increasing breadth of the frontal lobe but decreasing height of the human brain between two Chinese samples from a Neolithic site and from living humans. AB - Morphological observation and measurements of endocasts have played a vital role in research on the evolution of the human brain. However, endocasts have never been used to investigate how the human brain has evolved since the Neolithic period. We investigated the evolution of the human brain during the Holocene by comparing virtual endocasts from Beiqian site (a Neolithic Chinese site) and a sample of Chinese modern-day humans. Standardized measurements and indices were taken to provide quantification of the overall endocast shape, including the length, breadth, height, frontal breadth, and the ratio of frontal breadth to breadth, as well as the cranial capacity. We found that the height of the endocasts and cranial capacity have decreased between our two samples, whereas the frontal breadth and sexual dimorphism have increased. We argue that these changes can be caused by random genetic mutation and epigenetic change in response to changes in the environment. PMID- 24470192 TI - In vivo tumour extracellular pH monitoring using electron paramagnetic resonance: the effect of X-ray irradiation. AB - The in vivo quantification of extracellular pH (pHe ) in tumours may provide a useful biomarker for tumour cell metabolism. In this study, we assessed the viability of continuous-wave electron paramagnetic resonance (CW-EPR) spectroscopy with a pH-sensitive nitroxide for the measurement of extracellular tumour pH in a mouse model. CW-EPR spectroscopy (750 MHz) of C3H HeJ mice hind leg squamous cell tumour was performed after intravenous tail vein injection of pH-sensitive nitroxide (R-SG, 2-(4-((2-(4-amino-4-carboxybutanamido)-3 (carboxymethylamino)-3-oxoproylthio)methyl)phenyl)-4-pyrrolidino-2,5,5-triethyl 2,5-dihydro-1N-imidazol-1-oxyl) during stages of normal tumour growth and in response to a single 10-Gy dose of X-ray irradiation. An inverse relationship was observed between tumour volume and pHe value, whereby, during normal tumour growth, a constant reduction in pHe was observed. This relationship was disrupted by X-ray irradiation and, from 2-3 days post-exposure, a transitory increase in pHe was observed. In this study, we demonstrated the viability of CW-EPR spectroscopy using R-SG nitroxide to obtain high-sensitivity pH measurements in a mouse tumour model with an accuracy of <0.1 pH units. In addition, the measured changes in pHe in response to X-ray irradiation suggest that this may offer a useful method for the assessment of the physiological change in response to existing and novel cancer therapies. PMID- 24470193 TI - Study of an unusual advanced glycation end-product (AGE) derived from glyoxal using mass spectrometry. AB - Glycation is a post-translational modification (PTM) that affects the physiological properties of peptides and proteins. In particular, during hyperglycaemia, glycation by alpha-dicarbonyl compounds generate alpha-dicarbonyl derived glycation products also called alpha-dicarbonyl-derived advanced glycation end products. Glycation by the alpha-dicarbonyl compound known as glyoxal was studied in model peptides by MS/MS using a Fourier transform ion cyclotron resonance mass spectrometer. An unusual type of glyoxal-derived AGE with a mass addition of 21.98436 Da is reported in peptides containing combinations of two arginine-two lysine, and one arginine-three lysine amino acid residues. Electron capture dissociation and collisionally activated dissociation results supported that the unusual glyoxal-derived AGE is formed at the guanidino group of arginine, and a possible structure is proposed to illustrate the 21.9843 Da mass addition. PMID- 24470194 TI - LC-MS/MS analysis and comparison of oxidative damages on peptides induced by pathogen reduction technologies for platelets. AB - Pathogen reduction technologies (PRT) are photochemical processes that use a combination of photosensitizers and UV-light to inactivate pathogens in platelet concentrates (PCs), a blood-derived product used to prevent hemorrhage. However, different studies have questioned the impact of PRT on platelet function and transfusion efficacy, and several proteomic analyses revealed possible oxidative damages to proteins. The present work focused on the oxidative damages produced by the two main PRT on peptides. Model peptides containing residues prone to oxidation (tyrosine, histidine, tryptophane, and cysteine) were irradiated with a combination of amotosalen/UVA (Intercept process) or riboflavin/UVB (Mirasol-like process). Modifications were identified and quantified by liquid chromatography coupled to tandem mass spectrometry. Cysteine-containing peptides formed disulfide bridges (R-SS-R, -2 Da; favored following amotosalen/UVA), sulfenic and sulfonic acids (R-SOH, +16 Da, R-SO3H, +48 Da, favored following riboflavin/UVB) upon treatment and the other amino acids exhibited different oxidations revealed by mass shifts from +4 to +34 Da involving different mechanisms; no photoadducts were detected. These amino acids were not equally affected by the PRT and the combination riboflavin/UVB generated more oxidation than amotosalen/UVA. This work identifies the different types and sites of peptide oxidations under the photochemical treatments and demonstrates that the two PRT may behave differently. The potential impact on proteins and platelet functions may thus be PRT-dependent. PMID- 24470195 TI - Implementation of dipolar resonant excitation for collision induced dissociation with ion mobility/time-of-flight MS. AB - An ion mobility/time-of-flight mass spectrometer (IMS/TOF MS) platform that allows for resonant excitation collision induced dissociation (CID) is presented. Highly efficient, mass-resolved fragmentation without additional excitation of product ions was accomplished and over-fragmentation common in beam-type CID experiments was alleviated. A quadrupole ion guide was modified to apply a dipolar AC signal across a pair of rods for resonant excitation. The method was characterized with singly protonated methionine enkephalin and triply protonated peptide angiotensin I, yielding maximum CID efficiencies of 44% and 84%, respectively. The Mathieu q(x,y) parameter was set at 0.707 for these experiments to maximize pseudopotential well depths and CID efficiencies. Resonant excitation CID was compared with beam-type CID for the peptide mixture. The ability to apply resonant waveforms in mobility-resolved windows is demonstrated with a peptide mixture yielding fragmentation over a range of mass-to-charge (m/z) ratios within a single IMS-MS analysis. PMID- 24470196 TI - Prevalence of allergic diseases in Izmir Province, Turkey. AB - BACKGROUND: The aim of the present study is to determine the prevalence of allergic diseases and related risk factors in Izmir, Turkey, and to assess the positive immunoglobulin E (IgE) levels against common allergens. METHODS: The questionnaires were completed via face-to-face interview with a total of 2937 individuals. Specific IgE was studied in the serum samples by enzyme-linked immunosorbent assay (ELISA). This cross-sectional population-based study comprised adolescents over the age of 15 years and adults of Izmir province. RESULTS: In Izmir, the prevalence of self-reported allergy was 35.5%. Allergy was statistically significantly more common in females, university graduates, in those with high income, with family history for allergy, aged 40-49 years, those living in a flat, keeping pet(s), and in those using central heating. The prevalence of atopy according to the serum IgE levels (Class 3 with any of 3 IgEs) was found 1.6%. CONCLUSION: In conclusion, the prevalence of atopy was found lower in Izmir as compared to the results of other studies. PMID- 24470198 TI - Editor's foreword. PMID- 24470199 TI - Effect of a change in photoperiod on subsequent CO2 exchange. AB - The effect of a shift from a long to a short photoperiod on CO2 exchange of Chenopodium polyspermum was studied. Equal quantities of photosynthetic energy were given daily to the plants, long photoperiods being produced by low intensity red light extension. A change in the photoperiod was shown to affect the pattern of CO2 loss at the beginning of the night period and the onset of CO2 intake at the beginning of day time. These events seem to be under phytochrome control.The photoperiod had an effect on the slope of the CO2 curve of photosynthesis, efficiency of photosynthesis being increased after a short day. This effect was not due to a variation in the stomatal resistance.The action of O2 concentration on photosynthesis (Warburg effect) was affected by the photoperiodic treatment, being less important after a long day than after a short day.Involvement of phytochrome in photosynthetic efficiency and photorespiration is discussed. PMID- 24470197 TI - Follistatin-like protein 1 enhances NLRP3 inflammasome-mediated IL-1beta secretion from monocytes and macrophages. AB - Follistatin-like protein 1 (FSTL-1) is overexpressed in a number of inflammatory conditions characterized by elevated IL-1beta. Here, we found that FSTL-1 serum concentration was increased threefold in patients with bacterial sepsis and fourfold following administration of LPS to mice. To test the contribution of FSTL-1 to IL-1beta secretion, WT and FSTL-1-deficient mice were injected with LPS. While LPS induced IL-1beta in the sera of WT mice, it was low or undetectable in FSTL-1-deficient mice. Monocytes/macrophages, a key source of IL 1beta, do not normally express FSTL-1. However, FSTL-1 was found in tissue macrophages after injection of LPS into mouse footpads, demonstrating that macrophages are capable of taking up FSTL-1 at sites of inflammation. In vitro, intracellular FSTL-1 localized to the mitochondria. FSTL-1 activated the mitochondrial electron transport chain, increased the production of ATP (a key activator of the nod-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome) and IL-1beta secretion. FSTL-1 also enhanced transcription of the NLRP3 and procaspase 1 genes, two components of the NLRP3 inflammasome. Adenovirus-mediated overexpression of FSTL-1 in mouse paws led to activation of the inflammasome complex and local secretion of IL-1beta and IL-1beta-related proinflammatory cytokines. These results suggest that FSTL-1 may act on the NLRP3 inflammasome to promote IL-1beta secretion from monocytes/macrophages. PMID- 24470200 TI - Light effects on leaf development and photosynthetic capacity of Hydrocotyle bonariensis Lam. AB - Rates of net CO2 uptake were examined in developing leaves of Hydrocotyle bonariensis. Leaves that developed under high photosynthetically active radiation (48 mol m(-2) day(-1) PAR) were smaller, thicker, and reached maximum size sooner than did leaves that developed under low PAR (4.8 mol m(-2) day(-1)). Maximum net CO2 uptake rates were reached after 5 to 6 days expansion for both the low and the high PAR leaves. Leaves grown at high PAR had higher maximum photosynthetic rates and a higher PAR required for light saturation but showed a more rapid decline in rate with age than did low PAR leaves. To assess the basis for the difference observed in photosynthetic rates, CO2 diffusion conductances and the mesophyll surface available for CO2 absorption were examined for mature leaves. Stomatal conductance was the largest conductance in all treatments and did not vary appreciably with growth PAR. Mesophyll conductance progressively increased with growth PAR (up to 48 mol m(-2) day(-1)) as did the mesophyll surface area per unit leaf area, but the cellular conductance exhibited most of its increase at low PAR (up to 4.8 mol m(-2) day(-1)). PMID- 24470201 TI - Measurements of manganese in thylakoids of Sinapis alba grown under high-light and low-light conditions. AB - The manganese content of thylakoids and tissues was measured in leaves grown under high- and low-light conditions. Especially when grown in a nutrient medium enriched in manganese (20 MUM), the thylakoids contained large amounts of manganese, which could be removed by EDTA washing without impairment of the Hill reaction. The unremovable content of manganese was almost the same in thylakoids from plants grown in nutrient media of normal (2 MUM) and reduced (0.2 MUM) manganese content. Up to this limit of manganese content, Hill activity did not seem to be impaired. 1.2 atoms Mn per 100 molecules chlorophyll were found in low light thylakoids and 1.6 atoms Mn in high-light thylakoids. This is similar to the behaviour of other electron transport components, the number of which is also decreased under low-light conditions. However, the decrease in the manganese content is not as striking as the decrease in, for example, the cytochrome f and ferredoxin content. This may be attributed to an invariable pool of manganese which is not involved in the oxygen evolving system. Alternatively, if all of our measured manganese is involved in electron transport to PS II, this could indicate that in low-light chloroplasts the ratio of PS II/PS I components may be somewhat increased. PMID- 24470202 TI - Photosynthetic activity, chloroplast ultrastructure, and leaf characteristics of high-light and low-light plants and of sun and shade leaves. AB - The photosynthetic CO2-fixation rates, chlorophyll content, chloroplast ultrastructure and other leaf characteristics (e.g. variable fluorescence, stomata density, soluble carbohydrate content) were studied in a comparative way in sun and shade leaves of beech (Fagus sylvatica) and in high-light and low light seedlings. 1. Sun leaves of the beech possess a smaller leaf area, higher dry weight, lower water content, higher stomata density, higher chlorophyll a/b ratios and are thicker than the shade leaves. Sun leaves on the average contain more chlorophyll in a leaf area unit; the shade leaf exhibits more chlorophyll on a dry weight basis. Sun leaves show higher rates for dark respiration and a higher light saturation of photosynthetic CO2-fixation. Above 2000 lux they are more efficient in photosynthetic quantum conversion than the shade leaves. 2. The development of HL-radish plants proceeds much faster than that of LL-plants. The cotyledons of HL-plants show a higher dry weight, lower water content, a higher ratio of chlorophyll a/b and a higher gross photosynthesis rate than the cotyledons of the LL-plants, which possess a higher chlorophyll content per dry weight basis. The large area of the HL-cotyledon on the one hand, as well as the higher stomata density and the higher respiration rate in the LL-cotyledon on the other hand, are not in agreement with the characteristics of sun and shade leaves respectively. 3. The development, growth and wilting of wheat leaves and the appearance of the following leaves (leaf succession) is much faster at high quanta fluence rates than in weak light. The chlorophyll content is higher in the HL-leaf per unit leaf area and in the LL-leaf per g dry weight. There are no differences in the stomata density and leaf area between the HL- and LL-leaf. There are fewer differences between HL- and LL-leaves than in beech or radish leaves. 4. The chloroplast ultrastructure of shade-type chloroplasts (shade leaves, LL-leaves) is not only characterized by a much higher number of thylakoids per granum and a higher stacking degree of thylakoids, but also by broader grana than in sun-type chloroplasts (sun leaves, HL-leaves). The chloroplasts of sun leaves and of HL-leaves exhibit large starch grains. 5. Shade leaves and LL-leaves exhibit a higher maximum chlorophyll fluorescence and it takes more time for the fluorescence to decline to the steady state than in sun and HL-leaves. The variable fluorescence VF (ratio of fluorescence decrease to steady state fluorescence) is always higher in the sun and HL-leaf of the same physiological stage (maximum chlorophyll content of the leaf) than in the shade and LL-leaf. The fluorescence emission spectra of sun and HL-leaves show a higher proportion of chlorophyli fluorescence in the second emission maximum F2 than shade and LL-leaves. 6. The level of soluble carbohydrates (reducing sugars) is significantly higher in sun and HL-leaves than in shade and LL-leaves and even reflects changes in the amounts of the daily incident light. 7. Some but not all characteristics of mature sun and shade leaves are found in HL- and LL-leaves of seedlings. Leaf thickness, dry weight, chlorophyll content, soluble carbohydrate level, photosynthetic CO2-fixation, height and width of grana stacks and starch content, are good parameters to describe the differences between LL- and HL leaves; with some reservations concerning age and physiological stage of leaf, a/b ratios, chlorophyll content per leaf area unit and the variable fluorescence are also suitable. PMID- 24470203 TI - Delineation of EFTUD2 haploinsufficiency-related phenotypes through a series of 36 patients. AB - Mandibulofacial dysostosis, Guion-Almeida type (MFDGA) is a recently delineated multiple congenital anomalies/mental retardation syndrome characterized by the association of mandibulofacial dysostosis (MFD) with external ear malformations, hearing loss, cleft palate, choanal atresia, microcephaly, intellectual disability, oesophageal atresia (OA), congenital heart defects (CHDs), and radial ray defects. MFDGA emerges as a clinically recognizable entity, long underdiagnosed due to highly variable presentations. The main differential diagnoses are CHARGE and Feingold syndromes, oculoauriculovertebral spectrum, and other MFDs. EFTUD2, located on 17q21.31, encodes a component of the major spliceosome and is disease causing in MFDGA, due to heterozygous loss-of-function (LoF) mutations. Here, we describe a series of 36 cases of MFDGA, including 24 previously unreported cases, and we review the literature in order to delineate the clinical spectrum ascribed to EFTUD2 LoF. MFD, external ear anomalies, and intellectual deficiency occur at a higher frequency than microcephaly. We characterize the evolution of the facial gestalt at different ages and describe novel renal and cerebral malformations. The most frequent extracranial malformation in this series is OA, followed by CHDs and skeletal abnormalities. MFDGA is probably more frequent than other syndromic MFDs such as Nager or Miller syndromes. Although the wide spectrum of malformations complicates diagnosis, characteristic facial features provide a useful handle. PMID- 24470204 TI - Is there a role for the incretin system in blood pressure regulation? AB - Incretin-based therapies are now well established for diabetes management and are among the frontline agents for control of hyperglycemia. In addition to their antihyperglycemic effects, evidence is emerging on the role of these agents on blood pressure regulation, cardioprotective and renoprotective properties. Because of the pleiotropic nature of these affects, these agents could offer significant benefits with regards to the cardiorenal metabolic complications that are part of the diabetes and obesity epidemic in the United States and worldwide. We review the various known mechanisms or pathways by which incretin based therapy exerts its regulation of blood pressure with emphasis on novel mechanisms such as inflammation/immunomodulation and oxidative stress. PMID- 24470205 TI - Identification of risk factors for elevated transaminases in methotrexate users through an electronic health record. AB - OBJECTIVE: To determine the predictors of elevated transaminases in an incident user cohort of older adult patients with rheumatic diseases receiving methotrexate (MTX) using elements derived from an electronic health record. METHODS: Using a national, administrative database of patients seen through the Veterans Health Administration that included pharmacy and laboratory data, we performed an observational cohort study of veterans ages >=65 years who were new users of MTX to identify risk factors for elevated transaminases. RESULTS: We studied 659 incident users of MTX. We found a 6% incidence of moderate (>=1.5 * the upper limit of normal) elevations in aspartate aminotransferase or alanine aminotransferase over a mean followup period of 7 months. We identified predictors of moderate transaminase elevations to include obesity (per body mass index >=30 kg/m(2) ), total cholesterol >240 mg/dl, pre-MTX liver function test (LFT) elevations, use of biologic agents, and lack of folic acid supplementation. A patient with these characteristics and >3 comorbid conditions would be predicted to have a 90% chance of developing a moderate transaminase elevation in the 7 months after starting MTX. CONCLUSION: Moderate LFT abnormalities were uncommon in the first 7 months of MTX use, but were more likely to occur in patients with obesity, untreated high cholesterol, pre-MTX LFT elevations, biologic agent use, and lack of folic acid supplementation. Future work should aim to develop a robust, automated prediction rule for identifying patients at high risk for MTX-related liver toxicity. PMID- 24470206 TI - Crystal structures of the archaeal UDP-GlcNAc 2-epimerase from Methanocaldococcus jannaschii reveal a conformational change induced by UDP-GlcNAc. AB - Uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) 2-epimerase catalyzes the interconversion of UDP-GlcNAc to UDP-N-acetylmannosamine (UDP-ManNAc), which is used in the biosynthesis of cell surface polysaccharides in bacteria. Biochemical experiments have demonstrated that mutation of this enzyme causes changes in cell morphology and the thermoresistance of the cell wall. Here, we present the crystal structures of Methanocaldococcus jannaschii UDP-GlcNAc 2-epimerase in open and closed conformations. A comparison of these crystal structures shows that upon UDP and UDP-GlcNAc binding, the enzyme undergoes conformational changes involving a rigid-body movement of the C-terminal domain. We also present the crystal structure of Bacillus subtilis UDP-GlcNAc 2-epimerase in the closed conformation in the presence of UDP and UDP-GlcNAc. Although a structural overlay of these two closed-form structures reveals that the substrate-binding site is evolutionarily conserved, some areas of the allosteric site are distinct between the archaeal and bacterial UDP-GlcNAc 2-epimerases. This is the first report on the crystal structure of archaeal UDP-GlcNAc 2-epimerase, and our results clearly demonstrate the changes between the open and closed conformations of this enzyme. PMID- 24470207 TI - Frequent lack of GNAS mutations in colorectal adenocarcinoma associated with GNAS mutated villous adenoma. AB - Colorectal villous adenoma is thought to be associated with a high risk of progression to adenocarcinoma. To better characterize the genetic alterations involved in colorectal carcinogenesis related to villous adenoma, we analyzed mutations in APC, BRAF, KRAS, TP53, and GNAS in 12 colorectal adenocarcinomas associated with villous adenomas. APC, KRAS, and BRAF mutations were identified in five, 11, and one lesion, respectively, and most of these mutations were shared between the villous adenoma and the adenocarcinoma components in the respective lesions, except in one lesion with APC mutations and in two lesions with KRAS mutations. TP53 mutations were observed exclusively in four adenocarcinoma components, consistent with their role in the progression from adenoma to adenocarcinoma. Activating GNAS mutations were found in nine villous adenomas; however, unexpectedly, these mutations were shared only in three associated adenocarcinomas. Notably, all six adenocarcinomas with discordant GNAS mutation statuses were nonmucinous type, whereas all the other adenocarcinomas, including three adenocarcinomas associated with GNAS wild-type villous adenomas, were mucinous type. The current study suggests that GNAS-mutated villous adenomas may not necessarily be direct precursors of associated adenocarcinomas. At the same time, our observations support the role of activating GNAS mutations in increased mucin production in colorectal neoplasms. PMID- 24470208 TI - Mobility analysis of super-resolved proteins on optically stretched DNA: comparing imaging techniques and parameters. AB - Fluorescence microscopy in conjunction with optical tweezers is well suited to the study of protein mobility on DNA. Here, we evaluate the benefits and drawbacks of super-resolution and conventional imaging techniques for the analysis of one-dimensional (1D) protein diffusion as commonly observed for DNA binding proteins. In particular, we demonstrate the visualization of DNA-bound proteins using wide-field, confocal, and stimulated emission depletion (STED) microscopy. We review the suitability of these techniques to conditions of high protein density, and quantify their performance in terms of spatial and temporal resolution. Tracking proteins on DNA forces one to make a choice between localization precision on the one hand, and the number and rate of localizations on the other, by altering imaging modality, excitation intensity, and acquisition rate. Using simulated diffusion data, we quantify the effect of these imaging conditions on the accuracy of 1D diffusion analysis. In addition, we consider the case of diffusion confined between local roadblocks, a case particularly relevant for proteins bound to DNA. Together these results provide guidelines that can assist in judiciously optimizing the experimental conditions required for the analysis of protein mobility on DNA and other 1D systems. PMID- 24470209 TI - Ethical challenges in rheumatology: comment on the article by MacKenzie et al. PMID- 24470210 TI - Few-layer borocarbonitride nanosheets: platinum-free catalyst for the oxygen reduction reaction. AB - The present study demonstrates the use of few-layer borocarbonitride nanosheets synthesized by a simple method as non-platinum cathode catalysts for the oxygen reduction reaction (ORR) in alkaline medium. Composition-dependent ORR activity is observed and the best performance was found when the composition was carbon rich. Mechanistic aspects reveal that ORR follows the 4 e(-) pathway with kinetic parameters comparable to those of the commercial Pt/C catalyst. Excellent methanol tolerance is observed with the BCN nanosheets unlike with Pt/C. PMID- 24470211 TI - Ethinyl estradiol and other human pharmaceutical estrogens in the aquatic environment: a review of recent risk assessment data. AB - Interest in pharmaceuticals in the environment has increased substantially in recent years. Several studies in particular have assessed human and ecological risks from human pharmaceutical estrogens, such as 17alpha-ethinyl estradiol (EE2). Regulatory action also has increased, with the USA and other countries developing rules to address estrogens and other pharmaceuticals in the environment. Accordingly, the Center for Drug Evaluation and Research at the US Food and Drug Administration has conducted a review and analysis of current data on the long-term ecological exposure and effects of EE2 and other estrogens. The results indicate that mean-flow long-term predicted environmental concentrations (PECs) of EE2 in approximately 99% or more of US surface water segments downstream of wastewater treatment plants are lower than a predicted no-effect concentration (PNEC) for aquatic chronic toxicity of 0.1 ng/L. Exceedances are expected to be primarily in localized, effluent-dominated water segments. The median mean-flow PEC is more than two orders of magnitude lower than this PNEC. Similar results exist for other pharmaceutical estrogens. Data also suggest that the contribution of EE2 more broadly to total estrogenic load in the environment from all sources (including other human pharmaceutical estrogens, endogenous estrogens, natural environmental estrogens, and industrial chemicals), while highly uncertain and variable, appears to be relatively low overall. Additional data and a more comprehensive approach for data collection and analysis for estrogenic substances in the environment, especially in effluent-dominated water segments in sensitive environments, would more fully characterize the risks. PMID- 24470212 TI - Novel endogenous glycan therapy for retinal diseases: safety, in vitro stability, ocular pharmacokinetic modeling, and biodistribution. AB - Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Muller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [(3)H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous > retina > sclera/choroid > aqueous humor > cornea > lens. Area under the curve (0 to infinity) (AUCinfinity) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [(3)H]NA3 was excreted via urine and feces. NA3 was stable at 37 degrees C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics. PMID- 24470213 TI - Lineage determination in acute leukemias. PMID- 24470214 TI - Obesity evolution or revolution: there is more to it than meets the BMI. PMID- 24470216 TI - A review (research and patents) on jasmonic acid and its derivatives. AB - In medicinal chemistry there is a growing interest in using small molecules, including plant stress hormones. Jasmonic acid (JA) and its volatile methyl ester (MJ), collectively termed jasmonates, are lipid-derived cyclopentanone compounds that occur ubiquitously and exclusively in the plant kingdom. This review covers the synthesis, usage, and biological activities of JA and its derivatives. A brief overview of the available information on JA and its features is given, followed by a detailed review of JA and its derivatives as drugs and prodrugs; the properties in plants and the synthesis in recent patents are described. This review shows the direction of long-term drug/nutraceutical safety trials and provides insights for future research in this area. Research on JA continues to be of major interest. Recent innovations offer hope for the development of new therapeutics in related fields. It is anticipated that several analogs can be advanced to preclinical and clinical studies. PMID- 24470217 TI - The yeast Ess1 prolyl isomerase controls Swi6 and Whi5 nuclear localization. AB - The Ess1 prolyl isomerase from Saccharomyces cerevisiae and its human ortholog, Pin1, play critical roles in transcription by regulating RNA polymerase II. In human cells, Pin1 also regulates a variety of signaling proteins, and Pin1 misexpression is linked to several human diseases. To gain insight into Ess1/Pin1 function, we carried out a synthetic genetic array screen to identify novel targets of Ess1 in yeast. We identified potential targets of Ess1 in transcription, stress, and cell-cycle pathways. We focused on the cell-cycle regulators Swi6 and Whi5, both of which show highly regulated nucleocytoplasmic shuttling during the cell cycle. Surprisingly, Ess1 did not control their transcription but instead was necessary for their nuclear localization. Ess1 associated with Swi6 and Whi5 in vivo and bound directly to peptides corresponding to their nuclear localization sequences in vitro. Binding by Ess1 was significant only if the Swi6 and Whi5 peptides were phosphorylated at Ser-Pro motifs, the target sites of cyclin-dependent kinases. On the basis of these results, we propose a model in which Ess1 induces a conformational switch (cis trans isomerization) at phospho-Ser-Pro sites within the nuclear targeting sequences of Swi6 and Whi5. This switch would promote nuclear entry and/or retention during late M and G1 phases and might work by stimulating dephosphorylation at these sites by the Cdc14 phosphatase. This is the first study to identify targets of Ess1 in yeast other than RNA polymerase II. PMID- 24470218 TI - Near-absent levels of segregational variation suggest limited opportunities for the introduction of genetic variation via homeologous chromosome pairing in synthetic neoallotetraploid Mimulus. AB - Genetic variation is the fundamental medium of evolution. In allopolyploids, which are the product of hybridization and whole genome duplication, if homologous chromosomes always pair, then all descendants of a single diploid F1 hybrid lineage will be genetically identical. Contrarily, genetic variation among initially isogenic lineages is augmented when homeologous chromosomes pair; this added variation may contribute to phenotypic evolution. Mimulus sookensis is a naturally occurring, small-flowered allotetraploid derived from the large flowered Mimulus guttatus and small-flowered Mimulus nasutus. Because diploid F1 hybrids between M. guttatus and M. nasutus have large flowers, phenotypic evolution post-polyploidization is implied in M. sookensis. Here, we present genetic and phenotypic analyses of synthetic neoallotetraploid Mimulus derived from a cross between M. guttatus and M. nasutus. Genetic marker data from S2 and BC1N progeny suggest that chromosomes regularly pair with their homologous counterpart. By measuring the phenotype of synthetic neoallotetraploids, we demonstrate that polyploidization per se does not induce the small flowers of M. sookensis. Moreover, phenotypic measurements of synthetic allotetraploid F2s and S4 families suggest that rare homeologous recombination events have a negligible phenotypic effect in the first few generations. In total, the results are consistent with either exceedingly rare homeologous pairing and recombination or spontaneous fragment loss. The low levels of fragment loss and phenotypic variation in neoallotetraploids suggest that homeologous recombination after polyploidization is not a major mechanism of phenotypic evolution in M. sookensis. Rather, it may be that spontaneous mutations or epigenetic changes after allopolyploidization have driven phenotypic evolution in M. sookensis. PMID- 24470220 TI - Body composition at birth in preterm infants between 30 and 36 weeks gestation. AB - BACKGROUND: The American Academy of Pediatrics calls for aggressive management of preterm infants to achieve body composition approximating that of the healthy infant in utero. Air displacement plethysmography (ADP) has been validated for assessment of body composition in preterm infants and could be used to monitor their nutritional status during hospitalization. Comparative datasets on body composition at birth among healthy, live-born preterm infants are lacking. OBJECTIVE: The aim of this study is to provide the first descriptive fat mass (FM) and fat-free mass (FFM) data from healthy newborn preterm infants at birth as a proxy for healthy in utero body composition. METHODS: Body mass and volume were obtained using ADP within 72 h of birth in 98 singleton, appropriate-for gestational-age preterm infants. FM and FFM were calculated using the Fomon equation. RESULTS: Measurement with ADP was feasible and well tolerated by infants as young as 30 weeks gestation and <72 h of age. FFM and FM increased linearly over the gestational age range period at rates of 171 and 46 g week(-1) , respectively. Mean values obtained by ADP by gestational week were similar to the previously published reference data from chemical analysis on stillbirths. CONCLUSIONS: Body composition assessment using ADP is feasible in newborn preterm infants and provides group estimates similar to that of the reference fetus. In the future, integrating body composition information into the nutritional management of preterm infants may help to identify new strategies to optimize growth and development in this vulnerable population. PMID- 24470219 TI - MicroRNA regulation of bovine monocyte inflammatory and metabolic networks in an in vivo infection model. AB - Bovine mastitis is an inflammation-driven disease of the bovine mammary gland that costs the global dairy industry several billion dollars per year. Because disease susceptibility is a multifactorial complex phenotype, an integrative biology approach is required to dissect the molecular networks involved. Here, we report such an approach using next-generation sequencing combined with advanced network and pathway biology methods to simultaneously profile mRNA and miRNA expression at multiple time points (0, 12, 24, 36 and 48 hr) in milk and blood FACS-isolated CD14(+) monocytes from animals infected in vivo with Streptococcus uberis. More than 3700 differentially expressed (DE) genes were identified in milk-isolated monocytes (MIMs), a key immune cell recruited to the site of infection during mastitis. Upregulated genes were significantly enriched for inflammatory pathways, whereas downregulated genes were enriched for nonglycolytic metabolic pathways. Monocyte transcriptional changes in the blood, however, were more subtle but highlighted the impact of this infection systemically. Genes upregulated in blood-isolated monocytes (BIMs) showed a significant association with interferon and chemokine signaling. Furthermore, 26 miRNAs were DE in MIMs and three were DE in BIMs. Pathway analysis revealed that predicted targets of downregulated miRNAs were highly enriched for roles in innate immunity (FDR < 3.4E-8), particularly TLR signaling, whereas upregulated miRNAs preferentially targeted genes involved in metabolism. We conclude that during S. uberis infection miRNAs are key amplifiers of monocyte inflammatory response networks and repressors of several metabolic pathways. PMID- 24470221 TI - Organic photomechanical materials. AB - Organic molecules can transform photons into Angstrom-scale motions by undergoing photochemical reactions. Ordered media, for example, liquid crystals or molecular crystals, can align these molecular-scale motions to produce motion on much larger (micron to millimeter) length scales. In this Review, we describe the basic principles that underlie organic photomechanical materials, starting with a brief survey of molecular photochromic systems that have been used as elements of photomechanical materials. We then describe various options for incorporating these active elements into a solid-state material, including dispersal in a polymer matrix, covalent attachment to a polymer chain, or self-assembly into molecular crystals. Particular emphasis is placed on ordered media, such as liquid-crystal elastomers and molecular crystals, that have been shown to produce motion on large (micron to millimeter) length scales. We also discuss other mechanisms for generating photomechanical motion that do not involve photochemical reactions, such as photothermal expansion and photoinduced charge transfer. Finally, we identify areas for future research, ranging from the study of basic phenomena in solid-state photochemistry, to molecular and host matrix design, and the optimization of photoexcitation conditions. The ultimate realization of photon-fueled micromachines will likely involve advances spanning the disciplines of chemistry, physics and engineering. PMID- 24470222 TI - Phosphane-catalyzed [4+1] annulation between nitroalkenes and Morita-Baylis Hillman carbonates: facile synthesis of isoxazoline N-oxides by phosphorus ylides. AB - A phosphane-catalyzed [4+1] annulation between nitroalkenes and Morita-Baylis Hillman carbonates has been realized; this provides facile and diastereoselective access to polysubstituted isoxazoline N-oxides in moderate to excellent yields. In the annulation, an in situ formed allylic phosphorus ylide presumably serves as a pivotal active intermediate. This reaction accordingly represents the first example of phosphorus ylide initiated [4+1] cyclization of nitroalkenes to give isoxazoline N-oxides. PMID- 24470223 TI - Time-lapse microscopy using smartphone with augmented reality markers. AB - A prototype system that replaces the conventional time-lapse imaging in microscopic inspection for use with smartphones is presented. Existing time-lapse imaging requires a video data feed between a microscope and a computer that varies depending on the type of image grabber. Even with proper hardware setups, a series of tedious and repetitive tasks is still required to relocate to the region-of-interest (ROI) of the specimens. In order to simplify the system and improve the efficiency of time-lapse imaging tasks, a smartphone-based platform utilizing microscopic augmented reality (MU-AR) markers is proposed. To evaluate the feasibility and efficiency of the proposed system, a user test was designed and performed, measuring the elapse time for a trial of the task starting from the execution of the application software to the completion of restoring and imaging of an ROI saved in advance. The results of the user test showed that the average elapse time was 65.3 +/- 15.2 s with 6.86 +/- 3.61 MUm of position error and 0.08 +/- 0.40 degrees of angle error. This indicates that the time-lapse imaging task was accomplished rapidly with a high level of accuracy. Thus, simplification of both the system and the task was achieved via our proposed system. PMID- 24470224 TI - Lineage determination in mixed phenotype acute leukemia: response to Marcondes et al. PMID- 24470225 TI - The role of caprylate ligand ion on the stabilization of human serum albumin. AB - Sodium caprylate was added to a pharmaceutical-grade human serum albumin (HSA) to stabilize the product. In this study we have aimed to establish how caprylate ligand protects HSA from thermal degradation. The fatty acid stabilizer was first removed from commercial HSA by charcoal treatment. Cleaned HSA was made to 10% w/v in pH 7.4 buffered solutions and doped with sodium caprylate in serial concentrations up to 0.16 mmol/g-protein. These solutions as well as a commercial HSA, human serum, and enriched-albumin fraction were subjected to differential scanning calorimetry (DSC) within the temperature range of 37-90 degrees C at a 5.0 degrees C/min scanning rate. The globular size of the cleaned HSA solutions was measured by dynamic light scattering. The denaturing temperatures for albumin with sodium caprylate and a commercial one were significantly higher than for albumin only. It was found that the protein globules of cleaned HSA were not as stable as that of the native one due to aggregation, and the caprylate ion may reduce the aggregation by enlarging the globules' electrical double layer. A rational approximation of the Lumry-Eyring protein denaturation model was used to treat DSC denaturing endotherms. The system turned from irreversible dominant Scheme: N (k3K)-> P to reversible dominant Scheme:N (k1)-> P with the increase in caprylate concentration from null to ~0.08 mmol/g-protein. It was postulated that the caprylate ligand may decrease the rate of reversible unfolding as it binds to the IIIA domain which is prone to reversible unfolding/refolding and causes further difficulty for irreversible denaturation which, in turn, HSA can be stabilized. PMID- 24470226 TI - Lithium protects against cartilage degradation in osteoarthritis. AB - OBJECTIVE: To determine the actions of lithium chloride (LiCl) on catabolic events in human articular chondrocytes, and the effects of LiCl on the progression and severity of cartilage degradation in interleukin-1beta (IL-1beta) treated mouse knee joints and after surgical induction of osteoarthritis (OA) in a mouse model. METHODS: Human articular chondrocytes were treated with LiCl followed by IL-1beta, and the expression levels of catabolic genes were determined by real-time polymerase chain reaction. To understand the mechanism by which LiCl affects catabolic events in articular chondrocytes after IL-1beta treatment, the activation of NF-kappaB was determined using luciferase reporter assays, and the activities of MAPKs and the STAT-3 signaling pathway were determined by immunoblot analysis of total cell lysates. Cultures of mouse femoral head explants treated with IL-1beta and a mouse model of surgically induced OA were used to determine the effects of LiCl on proteoglycan loss and cartilage degradation. RESULTS: LiCl treatment resulted in decreased catabolic marker messenger RNA levels and activation of NF-kappaB, p38 MAPK, and STAT-3 signaling in IL-1beta-treated articular chondrocytes. Furthermore, LiCl directly inhibited IL-6-stimulated activation of STAT-3 signaling. Consequently, the loss of proteoglycan and severity of cartilage destruction in LiCl-treated mouse knee joints 8 weeks after OA induction surgery or in LiCl-treated mouse femoral head explants after IL-1beta treatment were markedly reduced compared to that in vehicle-treated joints or explants. CONCLUSION: LiCl reduced catabolic events in IL-1beta-treated human articular chondrocytes and attenuated the severity of cartilage destruction in IL-1beta-treated mouse femoral head explants and in the knee joints of mice with surgically induced OA, acting via inhibition of the activities of the NF-kappaB, p38, and STAT-3 signaling pathways. PMID- 24470227 TI - RuBP carboxylase activity in wheat following ear emergence and evaluation of the role of ear. AB - Ribulose bisphosphate carboxylase activity and chlorophyll content were measured in the leaves and reproductive parts of two wheat cultivars after ear emergence. The chlorophyll content of the flag leaf was mostly higher than that of the awns and glumes. Awns had the highest chlorophyll content among reproductive parts. Light transmission to the lower leaves was higher in the dwarf cultivar Moti than in the medium tall cultivar Kalyansona. RuBP carboxylase activity in Kalyansona leaves was higher than in Moti leaves. In postanthesis stages there was no difference in RuBP carboxylase activity in the flag leaf and lower leaves between cultivars. Awns had the maximum activity of RuBP carboxylase followed by glumes and grains among ear parts. The relative capacity for photosynthesis in the ear parts was several times higher than in the flag leaf on a unit chlorophyll basis. It is suggested that in a crop canopy in the field, the spike(ear) may have a greater importance in grain development than has been previously estimated. PMID- 24470228 TI - Participation of beta-carotene in reactivation of PSI of heptane-extracted spinach chloroplasts. AB - A carotenoid requirement for photosystem I activity in spinach chloroplasts using extraction-reconstitution technique has been investigated. The transfer of electron from N,N,N',N'-tetramethyl-p-phenylene diamine through the chloroplast photosystem to methyl viologen dye or to NADP(+) was used as an assay of photosystem I activity. Extraction of lyophilized spinach chloroplasts with heptane at near 0 degrees C removed almost all beta-carotene and reduced photochemical activities associated with photosystem I to a low level (about 15% of the original activity). Reconstitution of the extracted chloroplasts with beta carotene completely restored photosystem I activity. The maximum rate of methyl viologen photoreduction in reconstituted chloroplasts occurred at an beta carotene/chlorophyll molar ratio of 0.5. Cyclic phosphorylation mediated by phenazine methosulphate was partially restored. Xanthophylls (lutein, neoxanthin, violaxanthin), as components of chloroplast membranes, were not able to replace beta-carotene in reconstitution of chloroplasts and had essentially no effect on restoring photoreactions. On the basis of the P700/total chlorophyll ratio it can be assumed that extraction of lyophilized chloroplasts with heptane do not affect photosystem I reaction centre. Therefore it is possible that beta-carotene, removed during heptane extraction and belonging mainly to the antenna pigment pool of photosystem I, is effective in the restoration of photosystem I activity. PMID- 24470229 TI - Postillumination CO2 fixation by wheat leaves. AB - Postillumination CO2 fixation by wheat leaves was studied following light-limited photosynthetic conditions. Dark CO2 fixation showed two phases differing by their rates of CO2 uptake and carbon metabolism. These two phases are related to preillumination light flux density. During the first 30s of darkness, assimilated CO2 was found in PGA, alanine, malate and aspartate. After 5 min of darkness, it was additionally found in phosphorylated sugars.The lack of labelling of glycolate pathway intermediates shows that the Calvin cycle cannot run in the dark.The synthesized compounds indicate that reducing power but not ATP is available after turning the light off. This observation suggests that during pre illumination, when light strictly limits photosynthesis, ATP supply would be the first limiting factor. PMID- 24470230 TI - Nitrate and nitrite as 'in vivo' quenchers of chlorophyll fluorescence in blue green algae. AB - The effect of nitrate and nitrite on long-term chlorophyll fluorescence has been studied in filamentous blue-green algae. Cells grown autotrophically with nitrate as nitrogen source show, under argon atmosphere, a high level of fluorescence. The addition of either nitrete or nitrite induces a significant fluorescence quenching, but, whereas in the case of nitrite no previous treatment is required, in the case of nitrate the cells have to be sonicated or treated with Triton X 100 in advance without destroying their cellular integrity. DCMU Abbreviations: BQ, p-benzoquinone; DCMU, 3-(3, 4-dichlorophenyl)-1, 1-dimethylurea; FCCP, carbonylcyanide 4-trifluoromethoxyphenylhydrazone; FeCy, potassium ferricyanide. strongly inhibits the quenching of fluorescence caused by nitrate or nitrite. Using cells grown with ammonia, a nutritional repressor of the two enzymes of the nitrate-reducing system, the fluorescence quenching observed in either case becomes negligible. These results clearly indicate that both nitrate and nitrite can physiologically act as primary Hill reagents in photosynthesis in blue-green algae. PMID- 24470231 TI - Calculation of CO2 gas phase diffusion in leaves and its relation to stomatal resistance. AB - A new theory and experimental method was developed to measure the diffusion resistance to CO2 in the gas phase of mesophyll leaf tissue. Excised leaves were placed in a chamber and their net evaporation and CO2 assimilation rates measured at two different ambient pressures. These data were used to calculate CO2 gas phase diffusion resistances. A variety of field grown leaves were tested and the effects of various experimental errors considered. Increasing the gas phase diffusion resistance decreased transpiration more than it decreased CO2 assimilation. It was concluded that gas phase diffusion resistance associated with CO2 assimilation may sometimes be 100 or 200 s.m(-1) greater than the resistance implied by transpiration rates. This may be due to longer path lengths for the CO2 diffusion, constricted in places by the shape and arrangement of mesophyll cells. PMID- 24470232 TI - Effect of various denaturing treatments on the structure and activity of a purified CP1 complex. AB - Spinach CP1 complex, purified as previously described [16], was submitted to various dissociating treatments. Chaotropic agents, like urea and thiocyanate salts, remained without effect on the structure and photooxidation of the complex, just SDS at very high concentrations was able to dissociate the chlorophyll from the polypeptides and to abolish the photoreaction. Proteolytic enzymes have no more action on the apparent structure and activity of CP1, but some of them do cleave the large polypeptides (65 kD) into smaller ones, as observed after pigments dissociation. This last result might be an important step in the search for a smaller active P700 protein complex. PMID- 24470233 TI - Intrinsic membrane proteins of the thylakoids of Chlamydomonas reinhardii. AB - Upon protoolytle treatment of thylakoid membranes, extrinsic proteins are selectively degraded. The remaining resistant proteins have been analyzed by SDS PAGE. In the thylakoids of Chlamydomonas reinhardii, six polypeptides or protein fragments of 20 kD or higher are resistant to proteolysis. These intrinsic proteins have been identified as: the apoproteins of the chlorophyll-protein complexes CP I and LHCP; a polypeptide whose presence is related to the chlorophyll b content of the cells; and a portion of a chloroplast-made 34 kD polypeptide. Furthermore, after proteolytic treatment of the membranes, the LHCP complex can be resolved into two subcomplexes, apparently differing in their polypeptide composition. PMID- 24470234 TI - Changes in photosynthetic characteristics during leaf development in apple. AB - A comprehensive developmental survey of leaf area, chlorophyll, photosynthetic rate, leaf resistance, transpiration ratio, CO2 compensation point and photorespiration was conducted in apple. The largest changes in each of the photosynthetic characteristics studied took place during the earliest stages of leaf development, coinciding with the period of greatest leaf expansion and chlorophyll synthesis. During early development, photosynthesis increased 5-fold, reaching a maximum rate of 40 mg CO2 dm(-2) hr(-1) at a leaf plastochron index (LPI) of 10. During this same period, leaf resistance, transpiration ratio, CO2 compensation point and mesophyll resistance decreased, while carboxylation efficiency increased. Two especially interesting aspects of the data discussed are simultaneous changes that occur at a LPI of 10 and 12 in all of the photosynthetic characteristics examined and an apparent decrease in photorespiration as leaves age. From our results it is clear that stage of leaf development is an important factor affecting the rate of photosynthesis and photorespiration. PMID- 24470236 TI - Structural evidence for a constrained conformation of short CDR-L3 in antibodies. AB - Three Fab structures used as targets in the Antibody Modeling Assessment presented a challenge for modeling CDR-L3 due to deviations from the most typical canonical structure. In all three antibodies CDR-L3 has eight residues, which is one residue shorter than usual, and has a conformation that is rarely observed in crystal structures. We analyzed the sequence and structural determinants of this conformation and found that the "short" CDR-L3 is remarkably rigid and retains the conformation in the interactions with antigens and neighboring CDRs. PMID- 24470235 TI - Race and sex differences in willingness to undergo total joint replacement: the Johnston County Osteoarthritis Project. AB - OBJECTIVE: Using data from the community-based Johnston County Osteoarthritis Project, we examined race and sex variations in willingness to undergo, and perceptions regarding, total joint replacement (TJR). METHODS: Analyses were conducted for the total sample who participated in a followup measurement period from 2006-2010 (n = 1,522) and a subsample with symptomatic hip and/or knee osteoarthritis (sOA; n = 445). Participants indicated how willing they would be to have TJR (hip or knee) if their doctor recommended it; responses were categorized as "definitely" or "probably" willing versus "unsure," "probably not," or "definitely not" willing, or "don't know." Participants answered 7 questions regarding perceptions of TJR outcomes. Multivariable logistic regression models of willingness included participant characteristics (including socioeconomic status) and TJR perception variables that were associated with willingness at the P < 0.1 level in bivariate analyses. RESULTS: African Americans had lower odds of willingness to undergo TJR than whites in the total sample (adjusted odds ratio [OR] 0.47 [95% confidence interval (95% CI) 0.31 0.72]) and the sOA subsample (adjusted OR 0.42 [95% CI 0.25-0.69]). There were no sex differences in willingness. African Americans expected poorer TJR outcomes than whites, but sex differences were minimal; perceptions of TJR outcomes were not significantly associated with willingness. CONCLUSION: In this community sample, race differences in TJR willingness and perceptions were substantial, but sex differences were small. Perceptions of TJR did not appear to affect willingness or explain race differences in willingness. PMID- 24470238 TI - High prevalence of GPRC5A germline mutations in BRCA1-mutant breast cancer patients. AB - In a search for new breast cancer (BC) predisposing genes, we performed a whole exome sequencing analysis using six patient samples of familial BC and identified a germline inactivating mutation c.183delG [p. Arg61fs] in an orphan G protein coupled receptor GPRC5A. An extended case-control study revealed a tenfold enrichment for this mutation in BC patients carrying the 5382insC allele of BRCA1, the major founder mutation in the Russian population, compared to wild type BRCA1 BC cases [6/117 (5.1%) vs. 8/1578 (0.5%), p = 0.0002]. In mammary tumors (n = 60), the mRNA expression of GPRC5A significantly correlated with that of BRCA1 (p = 0.00018). In addition, the amount of GPRC5A transcript was significantly lower in BC obtained from BRCA1 mutation carriers (n = 17) compared to noncarriers (n = 93) (p = 0.026). Accordingly, a siRNA-mediated knockdown of either BRCA1 or GPRC5A in the MDA-MB-231 human BC cell line reduced expression of GPRC5A or BRCA1, respectively. Knockdown of GPRC5A also attenuated radiation induced BRCA1- and RAD51-containing nuclear DNA repair foci. Taken together, these data suggest that GPRC5A is a modifier of BC risk in BRCA1 mutation carriers and reveals a functional interaction of these genes. PMID- 24470239 TI - Functional genomics identified a novel protein tyrosine phosphatase receptor type F-mediated growth inhibition in hepatocarcinogenesis. AB - It is unclear how proliferating cells elicit suppression on cell proliferation and how cancer cells evade this growth suppression. Using a loss-of-function screening of the human kinome and phosphatome to identify genes suppressing tumor initiation in human hepatocellular carcinoma (HCC), we identified 19 genes and characterized one of the top-scoring tumor suppressor candidates, protein tyrosine phosphatase receptor type F (PTPRF). We found that PTPRF was induced during cell proliferation by cell-cell contact. Ectopic expression of wild-type PTPRF, but not the phosphatase-inactive mutant, suppressed cell proliferation and colony formation in soft-agar assays. In contrast, PTPRF silencing led to cell hyperproliferation, enhanced tumor colony formation in soft agar, and increased xenograft tumor growth in nude mice. Mechanistically, PTPRF silencing showed aberrant ERK-dependent signaling including the phosphorylation/stabilization of v myc avian myelocytomatosis viral oncogene homolog (MYC) through the direct activation of v-src avian sarcoma viral oncogene homolog (SRC) and suppression of PP2A. This PTPRF-mediated growth suppression during cell proliferation functioned independently of the Hippo-Yap pathway. Clinically, PTPRF was down-regulated in 42% HCC (37/89), 67% gastric cancer (27/40), and 100% colorectal cancer (40/40). PTPRF up-regulation was found in 24% HCC (21/89) and associated with better clinical outcomes. CONCLUSION: A novel PTPRF-mediated growth suppression pathway was identified by way of a functional genomics screening in human hepatoma cells. Induction of PTPRF by cell-cell contact during cell proliferation quenched the activated ERK-dependent proliferation signaling to prevent cell hyperproliferation and tumor initiation. PTPRF down-regulation in HCC facilitated tumor development. Our findings shed light on how cancer cells can evade growth suppression and open a new avenue for future development of anticancer therapies. PMID- 24470237 TI - Detrimental impact of remote methamphetamine dependence on neurocognitive and everyday functioning in older but not younger HIV+ adults: evidence for a legacy effect? AB - Prior studies examining the combined adverse effects of HIV and methamphetamine (MA) on the central nervous system (CNS) have focused on younger to middle-aged adults with recent MA use diagnoses. Aging, HIV, and MA all converge on prefrontal and temporolimbic neural systems and confer independent risk for neurocognitive and functional decline. Thus, this study sought to determine the residual impact of a remote history of MA dependence on neurocognitive and real world outcomes in older people living with HIV (PLWH). Participants included 116 older (>=50 years) and 94 younger (<40 years) adults classified into one of six study groups based on HIV serostatus (HIV+/HIV-) and lifetime histories of MA dependence (MA+/MA-): older HIV-MA- (n = 36), older HIV+MA- (n = 49), older HIV+MA+ (n = 31), younger HIV-MA- (n = 27), younger HIV+MA- (n = 33), and younger HIV+MA+ (n = 34). No participant-met criteria for current MA use disorders and histories of MA dependence were remote in both the older (average of nearly 9 years prior to evaluation) and younger (average of over 2 years prior to evaluation) HIV+MA+ groups. Findings revealed that a remote history of MA dependence exerts a significant detrimental impact on specific aspects of neurocognitive performance (e.g., memory) and a broad range of real-world functioning outcomes (e.g., employment) among older, but not younger PLWH. These results suggest that MA-associated neurotoxicity may have significant "legacy" effects on both neurocognitive and functional outcomes to which older PLWH are particularly vulnerable. PMID- 24470241 TI - C4 photosynthetic carbon metabolism in the leaves of aromatic tropical grasses - I. Leaf anatomy, CO2 compensation point and CO 2 assimilation. AB - A few species of Cymbopogon and Vetiveria are potentially important tropical grasses producing essential oils. In the present study, we report on the leaf anatomy and photosynthetic carbon assimilation in five species of Cymbopogon and Vetiveria zizanioides. Kranz-type leaf anatomy with a centrifugal distribution of chloroplasts and exclusive localization of starch in the bundle sheath cells were common among the test plants. Besides the Kranz leaf anatomy, these grasses displayed other typical C4 characteristics including a low (0-5 ul/l) CO2 compensation point, lack of light saturation of CO2 uptake at high photon flux densities, high temperature (35 degrees C) optimum of net photosynthesis, high rates of net photosynthesis (55-67 mg CO2 dm(-2) leaf area h(-1)), little or no response of net photosynthesis to atmospheric levels of O2 and high leaf (13)C/(12)C ratios. The biochemical studies with (14)CO2 indicated that the leaves of the above plant species synthesize predominantly malate during short term (5 s) photosynthesis. In pulse-chase experiments it was shown that the synthesis of 3-phosphoglycerate proceeds at the expense of malate, the major first formed product of photosynthesis in these plant species. PMID- 24470240 TI - Juvenile myasthenia gravis: recommendations for diagnostic approaches and treatment. AB - Juvenile myasthenia gravis (JMG) is an autoimmune disorder of neuromuscular transmission caused by production of antibodies against components of the postsynaptic membrane of the neuromuscular junction. Ethnicity has influence on incidence, clinical presentation, and the course of the disease. The patients present with a wide range of symptoms-from isolated intermittent ocular symptoms to general muscle weakness with or without respiratory insufficiency. Compared with adults and adolescents, the clinical signs and course of disease in children exhibit differences and occasionally untypical symptoms. Therefore, JMG is often missed and the diagnosis delayed. Isolated ocular symptoms are frequent at onset, spontaneous remission or intermittent symptoms over the longer period of time can occur. Very young children may present with generalized muscle weakness already during the second year of life and in this patient group, specific antibodies can only be slightly increased or even negative. Existing therapeutic options include immunosuppressive therapy and thymectomy but potential long-term side effects on the growing organism and possible influence on immune response in very young children should be considered. Specific clinical symptoms, diagnostic procedures, and a therapeutic approach with consideration of this age group's specificities are discussed. PMID- 24470243 TI - Increased photosynthetic rates following gibberellic acid treatments to the roots of tomato plants. AB - This study was conducted to evaluate the effects of root applications of gibberellic acid (GA3) on photosynthesis in tomato plants grown hydroponically. Photosynthetic rates (mg CO2/dm(2)/hr) determined using an open infrared CO2 gas exchange system showed a 40-50% increase within 5 hr after treatment with a 1.4 uM gibberellic acid (GA3) to their roots. The effect was shown to persist for the duration of the experiment (9 days). Plants receiving pulses of 1.4 uM GA3 to the roots for 1, 4, 8 or 12 hr exhibited significantly higher photosynthetic rates than the control for 6 days following treatment. By day 9 however, there was no significant difference. Continual treatments with 1.4 uM GA3 to the roots maintained the photosynthetic rate significantly higher than the control for the duration of the experiment. Interestingly, at the lower light levels the percent stimulation was more dramatic. There was approximately a 90% increase in the photosynthetic rate at 80 uE m(-2) s(-1) while at saturating light conditions (560 uE m(-2) s(-1)) there was approximately a 40% increase over the control rate. The light saturation point for both treated and control plants was 240 uE m(-2) s(-1). Applications of physiologically relevant concentrations of GA3 to the roots of tomato plants stimulates photosynthesis more consistently than that achieved by previous studies involving foliar absorption. PMID- 24470242 TI - High specific activity ribulose 1,5-bisphosphate carboxylase-oxygenase from Nicotiana tabacum. AB - Ribulose 1,5-bisphosphate carboxylase (EC.4.1.1.39) has been obtained from Nicotiana tabacum leaf homogenates with specific activites from 0.5 to 0.8 umol CO2 fixed (mg protein min)(-1). These activities are reconciled with much lower, previously reported activities. The results suggest that if the tobacco enzyme is assayed under optimum conditions there is little difference in the intrinsic specific activities of tobacco and spinach ribulose 1,5-bisphosphate carboxylase. Several factors affecting activity measurements were examined. PMID- 24470244 TI - Seasonal correlations of specific leaf weight to net photosynthesis and dark respiration of apple leaves. AB - Specific leaf weight (SLW), net photosynthesis (P n ), and dark respiration (R d ) of apple leaves were monitored for an entire growing season. Leaves were sampled from the canopy interior and periphery to provide a range of SLW. Leaf P n was linearly correlated with SLW until mid-August, when P n began to decline. During September the relationship between SLW and P n was a quadratic. Leaf R d and SLW were linearly correlated throughout the season. Leaf P n and R d were significantly correlated through most of the season, but the relationship was not always linear. Specific leaf weight appears to be a reliable index of the previous light environment of a leaf, but use to estimate P n is probably limited to the first half of the season, because of increased variation after mid-August. PMID- 24470245 TI - Growth, photosynthesis and transpiration in Psophocarpus tetragonolobus (L.) DC cultivar 'UPS 99'. AB - Two methods (whole-plant growth analysis and gas exchange) were used to measure the response of Psophocarpus tetragonolobus (L.) DC cultivar 'UPS 99' to the environment. This plant had an optimal temperature for root growth of 25 degrees C, its rate of acetylene reduction (when inoculated with Rhizobium, strain 'RRIM 56') was maximal at 30 degrees C and it required an atmospheric temperature of about 35 degrees C for optimal shoot growth. Maximum water-use efficiency was ca. 33 mg CO2.g H2O(-1). The rate of photosynthesis reached a plateau at 900 vpm CO2 this condition also gave the lowest rate of transpiration. Under normal conditions, the light compensation point was at 1.7 klx, while that for CO2 was 60 vpm. Photorespiration diminished gross photosynthesis of P. tetragonolobus by forty percent. Water stress (as measured by sensitivity to slightly increased CO2 levels) caused rapid closure of stomata, and the response was 'remembered' for up to five days. PMID- 24470246 TI - Isoenzymes of ferredoxin-NADBDelta oxidoreductase from the cyanobacterium Nostoc strain MAC. AB - Ferredoxin-NADP(+) oxidoreductase from the cyanobacterium Nostoc strain MAC was separated into two fractions by ion-exchange chromatography. Both were purified to electrophoretic homogeneity and exhibited diaphorase and ferredoxin-dependent cytochrome c reductase activity. The activities with three different electron carriers in this latter assay were similar for the two fractions, as were the pH optima in both assays. Each fraction, however, could be resolved into several active components by isoelectric focusing, both after initial separation and following apparent purification by gel filtration on Sephadex G-150, further chromatography on DEAE-cellulose, and use of hydroxylapatite columns. PMID- 24470247 TI - Influence of light on plastocyanin formation in the alga Scenedesmus acutus. AB - Scenedesmus acutus, pregrown autotrophically, forms high levels of plastocyanin during an initiation period of 24 hr in the light, after cupric ions have been added to depleted cells. In the dark, no plastocyanin formation is observed. This is in contrast to heterotrophic cells which, over the same period and under identical conditions, yield about half the plastocyanin level regardless of whether they are incubated in the dark or in the light. The ATP level is high in all cases when substantial formation of plastocyanin takes place, while the (35)S sulfolipid level, the marker of thylakoid formation, is at variance. After the 24 hr plastocyanin formation period, the (35)S-sulfolipid level is high in illuminated autotrophic cells as well as in dark-incubated heterotrophic ones, but low in illuminated heterotrophic cells, all of them having substantial plastocyanin contents. Additional experiments on light dependence of copper uptake, influence of light quality, occurrence of apoplastocyanins, provide a set of data to assume that the role of light in plastocyanin formation is primarily through photophosphorylation, the ATP presumably being necessary for processing of plastocyanin precursors to holoprotein. PMID- 24470248 TI - A new procedure for the purification of spinach leaf photosynthetic fructose-1,6 bisphosphatase by affinity chromatography on mercaptoethylamine-Sepharose. AB - A new purification procedure for spinach leaf fructose-1,6-bisphosphatase is proposed, which includes the use of affinity chromatography on mercaptoethylamine Sepharose. A homogeneous preparation of the enzyme can be obtained in 48 hr, with a specific activity of 67 U/mg and a yield of 23%. The method may also be useful for the purification of other thioredoxin-activated chloroplast enzymes. PMID- 24470249 TI - Photorespiration studies in Cycas circinalis L. and Cycas beddomei Dyer. AB - Photosynthetic carboxylating enzymes and the effects of light and temperature on (14)CO2 efflux in two species of gymnosperm leaves were studied. The activity of RuBP carboxylase was high and that of PEP carboxylase was very low when compared to C4 plants. The CO2 compensation point was high. (14)CO2 efflux was greater in light than in darkness and the ratio (L/D) increased with increase in temperature and light intensity. The inhibitors of glycolate metabolism showed decreased (14)CO2 evolution in light while dark respiration was unaffected. It is concluded that both Cycas circinalis, L. and Cycas beddomei Dyer are C3 plants. PMID- 24470250 TI - Editorial note. PMID- 24470251 TI - Cytotoxic effects of thiamethoxam in the midgut and malpighian tubules of Africanized Apis mellifera (Hymenoptera: Apidae). AB - Due to its expansion, agriculture has become increasingly dependent on the use of pesticides. However, the indiscriminate use of insecticides has had additional effects on the environment. These products have a broad spectrum of action, and therefore the insecticide affects not only the pests but also non-target insects such as bees, which are important pollinators of agricultural crops and natural environments. Among the most used pesticides, the neonicotinoids are particularly harmful. One of the neonicotinoids of specific concern is thiamethoxam, which is used on a wide variety of crops and is toxic to bees. Thus, this study aimed to analyze the effects of this insecticide in the midgut and Malpighian tubule cells of Africanized Apis mellifera. Newly emerged workers were exposed until 8 days to a diet containing a sublethal dose of thiamethoxam equal to 1/10 of LC50 (0.0428 ng a.i./l L of diet). The bees were dissected and the organs were processed for transmission electron microscopy. The results showed that thiamethoxam is cytotoxic to midgut and Malpighian tubules. In the midgut, the damage was more evident in bees exposed to the insecticide on the first day. On the eighth day, the cells were ultrastructurally intact suggesting a recovery of this organ. The Malpighian tubules showed pronounced alterations on the eighth day of exposure of bees to the insecticide. This study demonstrates that the continuous exposure to a sublethal dose of thiamethoxam can impair organs that are used during the metabolism of the insecticide. PMID- 24470252 TI - Spontaneous in vitro apoptosis of de novo chronic lymphocytic leukemia cells correlates with risk of the disease progression. AB - Despite significant progress in treatment, chronic lymphocytic leukemia (CLL) still remains an incurable disease. Major advances have been recently made to understand the molecular pathogenesis underlying CLL, but defects in apoptosis are considered to be the most important factors. Although neoplastic cells are resistant to apoptosis in vivo, they show decreased level of spontaneous in vitro apoptosis, with significant differences among CLL patients. This work compares the level of spontaneous CLL cell apoptosis with prognostic factors and clinical course of the disease. In vitro spontaneous apoptosis of peripheral blood lymphocytes was analyzed using Annexin-V assay (confirmed by TUNEL method) in 135 treatment naive patients with CLL. Levels of apoptosis after 48h culture in patients with stable disease were found to be significantly higher than in the group with progressive course of the disease (p=0.015). Moreover, the level of spontaneous apoptosis after 24h and 48h of incubation correlated inversely with the progression free survival (p=0.026 and 0.009, respectively). These results suggest that in vitro spontaneous apoptosis of CLL cells may be a simple and cheap prognostic test which is relatively quick to use, and can predict the course of the disease and response to treatment. (c) 2014 Clinical Cytometry Society. PMID- 24470254 TI - Apoptotic osteocytes and the control of targeted bone resorption. AB - Studies from the 1950s and 1960s already recognize the fact that osteocytes, although long living cells, die, as evidenced by accumulation of osteocytic lacunae devoid of cells. More recently, it was demonstrated that these cells die by apoptosis. The rate of osteocyte apoptosis is regulated by the age of the bone, as well as by systemic hormones, local growth factors, cytokines, pharmacological agents, and mechanical forces. Apoptotic osteocytes, in turn, recruit osteoclasts to initiate targeted bone resorption. This results in the removal of "dead" bone and may improve the mechanical properties of the skeleton. However, the molecular regulators of osteocyte survival and targeted bone remodeling are not completely known. In this review, the current knowledge on the molecular mechanism that lead to osteocyte death or survival, and the signals that mediate targeted bone resorption is discussed. PMID- 24470253 TI - Structural insights into FRS2alpha PTB domain recognition by neurotrophin receptor TrkB. AB - The fibroblast growth factor receptor (FGFR) substrate 2 (FRS2) family proteins function as scaffolding adapters for receptor tyrosine kinases (RTKs). The FRS2alpha proteins interact with RTKs through the phosphotyrosine-binding (PTB) domain and transfer signals from the activated receptors to downstream effector proteins. Here, we report the nuclear magnetic resonance structure of the FRS2alpha PTB domain bound to phosphorylated TrkB. The structure reveals that the FRS2alpha-PTB domain is comprised of two distinct but adjacent pockets for its mutually exclusive interaction with either nonphosphorylated juxtamembrane region of the FGFR, or tyrosine phosphorylated peptides TrkA and TrkB. The new structural insights suggest rational design of selective small molecules through targeting of the two conjunct pockets in the FRS2alpha PTB domain. PMID- 24470255 TI - Loss of Cbl-PI3K interaction enhances osteoclast survival due to p21-Ras mediated PI3K activation independent of Cbl-b. AB - Cbl family proteins, Cbl and Cbl-b, are E3 ubiquitin ligases and adaptor proteins, which play important roles in bone-resorbing osteoclasts. Loss of Cbl in mice decreases osteoclast migration, resulting in delayed bone development where as absence of Cbl-b decreases bone volume due to hyper-resorptive osteoclasts. A major structural difference between Cbl and Cbl-b is tyrosine 737 (in YEAM motif) only on Cbl, which upon phosphorylation interacts with the p85 subunit of phosphatidylinositol-3 Kinase (PI3K). In contrast to Cbl(-/-) and Cbl b(-/-) , mice lacking Cbl-PI3K interaction due to a Y737F (tyrosine to phenylalanine, YF) mutation showed enhanced osteoclast survival, but defective bone resorption. To investigate whether Cbl-PI3K interaction contributes to distinct roles of Cbl and Cbl-b in osteoclasts, mice bearing CblY737F mutation in the Cbl-b(-/-) background (YF/YF;Cbl-b(-/-) ) were generated. The differentiation and survival were augmented similarly in YF/YF and YF/YF;Cbl-b(-/-) osteoclasts, associated with enhanced PI3K signaling suggesting an exclusive role of Cbl-PI3K interaction, independent of Cbl-b. In addition to PI3K, the small GTPase Ras also regulates osteoclast survival. In the absence of Cbl-PI3K interaction, increased Ras GTPase activity and Ras-PI3K binding were observed and inhibition of Ras activation attenuated PI3K mediated osteoclast survival. In contrast to differentiation and survival, increased osteoclast activity observed in Cbl-b(-/ ) mice persisted even after introduction of the resorption-defective YF mutation in YF/YF;Cbl-b(-/-) mice. Hence, Cbl and Cbl-b play mutually exclusive roles in osteoclasts. Whereas Cbl-PI3K interaction regulates differentiation and survival, bone resorption is predominantly regulated by Cbl-b in osteoclasts. PMID- 24470256 TI - Within-hemifield posture changes affect tactile-visual exogenous spatial cueing without spatial precision, especially in the dark. AB - We investigated the effects of seen and unseen within-hemifield posture changes on crossmodal visual-tactile links in covert spatial attention. In all experiments, a spatially nonpredictive tactile cue was presented to the left or the right hand, with the two hands placed symmetrically across the midline. Shortly after a tactile cue, a visual target appeared at one of two eccentricities within either of the hemifields. For half of the trial blocks, the hands were aligned with the inner visual target locations, and for the remainder, the hands were aligned with the outer target locations. In Experiments 1 and 2, the inner and outer eccentricities were 17.5o and 52.5o, respectively. In Experiment 1, the arms were completely covered, and visual up-down judgments were better when on the same side as the preceding tactile cue. Cueing effects were not significantly affected by hand or target alignment. In Experiment 2, the arms were in view, and now some target responses were affected by cue alignment: Cueing for outer targets was only significant when the hands were aligned with them. In Experiment 3, we tested whether any unseen posture changes could alter the cueing effects, by widely separating the inner and outer target eccentricities (now 10o and 86o). In this case, hand alignment did affect some of the cueing effects: Cueing for outer targets was now only significant when the hands were in the outer position. Although these results confirm that proprioception can, in some cases, influence tactile-visual links in exogenous spatial attention, they also show that spatial precision is severely limited, especially when posture is unseen. PMID- 24470257 TI - Different methods for reproducing time, different results. AB - One of the most widely used tasks for investigating psychological time, time reproduction, requires from participants the reproduction of the duration of a previously presented stimulus. Although prior studies have investigated the effects of different cognitive processes on time reproduction performance, no studies have looked into the effects of different reproduction methods on these performances. In the present study, participants were randomly assigned to one of three reproduction methods, which included (a) just pressing at the end of the interval, (b) pressing to start and stop the interval, and (c) maintaining continuous pressing during the interval. The study revealed that the three reproduction methods were not equivalent, with the method involving keypresses to start and stop the reproduction showing the highest accuracy, and the method of continuous press generating less variability. PMID- 24470258 TI - Can representational trajectory reveal the nature of an internal model of gravity? AB - The memory for the vanishing location of a horizontally moving target is usually displaced forward in the direction of motion (representational momentum) and downward in the direction of gravity (representational gravity). Moreover, this downward displacement has been shown to increase with time (representational trajectory). However, the degree to which different kinematic events change the temporal profile of these displacements remains to be determined. The present article attempts to fill this gap. In the first experiment, we replicate the finding that representational momentum for downward-moving targets is bigger than for upward motions, showing, moreover, that it increases rapidly during the first 300 ms, stabilizing afterward. This temporal profile, but not the increased error for descending targets, is shown to be disrupted when eye movements are not allowed. In the second experiment, we show that the downward drift with time emerges even for static targets. Finally, in the third experiment, we report an increased error for upward-moving targets, as compared with downward movements, when the display is compatible with a downward ego-motion by including vection cues. Thus, the errors in the direction of gravity are compatible with the perceived event and do not merely reflect a retinotopic bias. Overall, these results provide further evidence for an internal model of gravity in the visual representational system. PMID- 24470259 TI - Viewpoint-dependent representation of contextual information in visual working memory. AB - Objects are not represented individually in visual working memory (VWM), but in relation to the contextual information provided by other memorized objects. We studied whether the contextual information provided by the spatial configuration of all memorized objects is viewpoint-dependent. We ran two experiments asking participants to detect changes in locations between memory and probe for one object highlighted in the probe image. We manipulated the changes in viewpoint between memory and probe (Exp. 1: 0 degrees , 30 degrees , 60 degrees ; Exp. 2: 0 degrees , 60 degrees ), as well as the spatial configuration visible in the probe image (Exp. 1: full configuration, partial configuration; Exp. 2: full configuration, no configuration). Location change detection was higher with the full spatial configuration than with the partial configuration or with no spatial configuration at viewpoint changes of 0 degrees , thus replicating previous findings on the nonindependent representations of individual objects in VWM. Most importantly, the effect of spatial configurations decreased with increasing viewpoint changes, suggesting a viewpoint-dependent representation of contextual information in VWM. We discuss these findings within the context of this special issue, in particular whether research performed within the slots-versus-resources debate and research on the effects of contextual information might focus on two different storage systems within VWM. PMID- 24470260 TI - Understanding fibroblast activation protein (FAP): substrates, activities, expression and targeting for cancer therapy. AB - Fibroblast activation protein (FAP) is best known for its heightened expression in tumour stroma. This atypical serine protease has both dipeptidyl peptidase and endopeptidase activities, cleaving substrates at a post-proline bond. FAP expression is difficult to detect in non-diseased adult organs, but is greatly upregulated in sites of tissue remodelling, which include liver fibrosis, lung fibrosis, atherosclerosis, arthritis, tumours and embryonic tissues. Due to its restricted expression pattern and dual enzymatic activities, FAP is emerging as a unique therapeutic target. However, methods to exploit and target this protease are advancing more rapidly than knowledge of the fundamental biology of FAP. This review highlights this imbalance, emphasising the need to better define the substrate repertoire and expression patterns of FAP to elucidate its role in biological and pathological processes. PMID- 24470262 TI - Iodinated Al(III)-based phthalocyanines are promising sensitizers for dye sensitized solar cells; a theoretical comparison between Zn(II), Mg(II), and Al(III)-based phthalocyanine sensitizers. AB - To design efficient dyes for dye-sensitized solar cells (DSSCs), using a Zn coordinated phthalocyanine (TT7) as the prototype, a series of phthalocyanine dyes (Pcs) with different metal ions and peripheral/axial groups have been investigated by means of density functional theory (DFT) and time-dependent DFT (TDDFT) methods. Computational results show that the iodinated Al-based dye with a peripheral amino group (Al-I-NH2-Pc) exhibits the largest redshift in the maximum absorbance (lambda(max)). In addition, Al-based dyes have appropriate energy-level arrangements of frontier orbitals to keep excellent balance between electron injection and regeneration of oxidized dyes. Further, it has been found that the intermolecular pi-staking interaction in Al-I-Pc molecules is weaker than the other metal-based Pcs, which may effectively reduce dye aggregation on the semi-conductor surface. All these results suggest iodinated Al-based Pcs (Al I-Pcs) to be potentially promising sensitizers in DSSCs. PMID- 24470261 TI - Modulation of the relationship between external knee adduction moments and medial joint contact forces across subjects and activities. AB - OBJECTIVE: The external knee adduction moment (EAM) is often considered a surrogate measure of the distribution of loads across the tibiofemoral joint during walking. This study was undertaken to quantify the relationship between the EAM and directly measured medial tibiofemoral contact forces (Fmed ) in a sample of subjects across a spectrum of activities. METHODS: The EAM for 9 patients who underwent total knee replacement was calculated using inverse dynamics analysis, while telemetric implants provided Fmed for multiple repetitions of 10 activities, including walking, stair negotiation, sit-to-stand activities, and squatting. The effects of the factors "subject" and "activity" on the relationships between Fmed and EAM were quantified using mixed-effects regression analyses in terms of the root mean square error (RMSE) and the slope of the regression. RESULTS: Across subjects and activities a good correlation between peak EAM and Fmed values was observed, with an overall R(2) value of 0.88. However, the slope of the linear regressions varied between subjects by up to a factor of 2. At peak EAM and Fmed , the RMSE of the regression across all subjects was 35% body weight (%BW), while the maximum error was 127 %BW. CONCLUSION: The relationship between EAM and Fmed is generally good but varies considerably across subjects and activities. These findings emphasize the limitation of relying solely on the EAM to infer medial joint loading when excessive directed cocontraction of muscles exists and call for further investigations into the soft tissue-related mechanisms that modulate the internal forces at the knee. PMID- 24470263 TI - Injectable cell constructs fabricated via culture on a thermoresponsive methylcellulose hydrogel system for the treatment of ischemic diseases. AB - Cell transplantation via direct intramuscular injection is a promising therapy for patients with ischemic diseases. However, following injections, retention of transplanted cells in engrafted areas remains problematic, and can be deleterious to cell-transplantation therapy. In this Progress Report, a thermoresponsive hydrogel system composed of aqueous methylcellulose (MC) blended with phosphate buffered saline is constructed to grow cell sheet fragments and cell bodies for the treatment of ischemic diseases. The as-prepared MC hydrogel system undergoes a sol-gel reversible transition upon heating or cooling at ~32 degrees C. Via this unique property, the grown cell sheet fragments (cell bodies) can be harvested without using proteolytic enzymes; consequently, their inherent extracellular matrices (ECMs) and integrative adhesive agents remain well preserved. In animal studies using rats and pigs with experimentally created myocardial infarction, the injected cell sheet fragments (cell bodies) become entrapped in the interstices of muscular tissues and adhere to engraftment sites, while a minimal number of cells exist in the group receiving dissociated cells. Moreover, transplantation of cell sheet fragments (cell bodies) significantly increases vascular density, thereby improving the function of an infarcted heart. These experimental results demonstrate that cell sheet fragments (cell bodies) function as a cell-delivery construct by providing a favorable ECM environment to retain transplanted cells locally and consequently, improving the efficacy of therapeutic cell transplantation. PMID- 24470264 TI - Interaction of viruses with host immune system and immunomodulation in chronic viral infections. PMID- 24470265 TI - First in vivo visualization of MRI-visible IPOM in a rabbit model. AB - BACKGROUND: Application of a mesh in presence of pneumoperitoneum may cause deformation or wave formation when gas is released. Moreover, mesh shrinkage during subsequent wound healing cannot be detected in vivo without invasive diagnostics. Using MRI-visible polyvinylidene fluoride (PVDF) mesh, the extend of mesh deformation and shrinkage could be objectified by MRI for the first time. MATERIALS AND METHODS: Laparoscopic intraperitoneal onlay mesh (IPOM) implantation was performed in 10 female rabbits using ferro-oxide loaded PVDF meshes. MRI measurements were performed postoperatively at days 1 and 90. After three-dimensional reconstruction of all MRI images the total surface and the effective surface of the implanted mesh were explored and calculated computer assisted. RESULTS: In all cases, the mesh could be identified in MRI. The subsequent three-dimensional reconstruction always allowed a calculation of the mesh area. In relation to the original size of the used textile implant, we found neither a significant reduction of the effective mesh surface after release of the pneumoperitoneum at day 1 after laparoscopic surgery nor a significant change of the total surface of this large pore mesh by the end of the observation period. CONCLUSIONS: In vivo investigation of mesh surface via MRI could exclude a significant initial reduction of the effective mesh surface after release of pneumoperitoneum, in this IPOM rabbit model. A further subsequent shrinkage of these large pore PVDF meshes could be excluded, as well. Imaging of MRI-visible IPOM mesh turned out to be a sufficient tool to objectify mesh configuration and position in vivo. PMID- 24470266 TI - Effect of photodynamic therapy supplemented with quercetin in HEp-2 cells. AB - Photodynamic therapy (PDT) is a technique that can be used as a complementary therapy in cancer treatment combined with other therapeutic modalities. Quercetin (QCT) is known to be effective in the treatment of cancer, by reducing the cell viability of different cancer cell lines. This study aimed to evaluate the influence of different concentrations of QCT in PDT on the viability, mitochondrial membrane potential and induction of apoptosis/necrosis in the human larynx carcinoma cells (HEp-2). The HEp-2 cells were treated with aluminum phthalocyanine tetrasulfonate (AlPcS4) and QCT and subsequently irradiated with a diode laser light (685 nm, 35 mW, 4.5 J/cm(2)). The results demonstrated that treatment of HEp-2 cells with high concentrations of QCT (at least 50 MUM) reduced cell viability. This response was enhanced in cells subjected to PDT supplemented with high concentrations of QCT. In addition, was observed decrease in the mitochondrial membrane potential and characteristics of late apoptosis and/or initial necrosis process. QCT at concentrations from 50 MUM improves PDT induced cytotoxicity by significantly reducing cell viability by apoptosis and/or necrosis, and mitochondrial membrane potential of Hep-2 cells. PMID- 24470267 TI - Reconsidering a "chopped liver": the need for improving glomular filtration rate estimation for hepatic transplantation. PMID- 24470269 TI - Hot Topics V. PMID- 24470271 TI - Structural characterization of a new N-substituted pantothenamide bound to pantothenate kinases from Klebsiella pneumoniae and Staphylococcus aureus. AB - Pantothenate kinase (PanK) is the rate-limiting enzyme in Coenzyme A biosynthesis, catalyzing the ATP-dependent phosphorylation of pantothenate. We solved the co-crystal structures of PanKs from Staphylococcus aureus (SaPanK) and Klebsiella pneumonia (KpPanK) with N-[2-(1,3-benzodioxol-5-yl)ethyl] pantothenamide (N354-Pan). Two different N354-Pan conformers interact with polar/nonpolar mixed residues in SaPanK and aromatic residues in KpPanK. Additionally, phosphorylated N354-Pan is found at the closed active site of SaPanK but not at the open active site of KpPanK, suggesting an exchange of the phosphorylated product with a new N354-Pan only in KpPanK. Together, pantothenamides conformational flexibility and binding pocket are two key considerations for selective compound design. PMID- 24470272 TI - Comments on Dr. Foxcroft's classification system. PMID- 24470273 TI - Variability within investigations of intravenous colistin: the scope of the problem. PMID- 24470274 TI - Statistical issues when searching for predictors of post-Lyme disease symptoms. PMID- 24470275 TI - Editorial commentary: Are blood concentrations enough for establishing pharmacokinetic/pharmacodynamic relationships? PMID- 24470276 TI - Herpes zoster caused by vaccine-strain varicella zoster virus in an immunocompetent recipient of zoster vaccine. AB - We report the first laboratory-documented case of herpes zoster caused by the attenuated varicella zoster virus (VZV) contained in Zostavax in a 68-year-old immunocompetent adult with strong evidence of prior wild-type VZV infection. The complete genome sequence of the isolate revealed that the strain carried 15 of 42 (36%) recognized varicella vaccine-associated single-nucleotide polymorphisms, including all 5 of the fixed vaccine markers present in nearly all of the strains in the vaccine. The case of herpes zoster was relatively mild and resolved without complications. PMID- 24470277 TI - Reply to Parvu and Parvu. PMID- 24470278 TI - Rehabilitation perspectives of neuromodulation. AB - Chronic pain is one of the most prevalent and costly health care problems in the United States today. Two conditions, failed back surgery syndrome (FBSS) and complex regional pain syndrome (CRPS), in particular have been difficult to manage, resulting in increased disability and poorer quality of life measures for patients as well as increased treatments cost for payers. Given the cost of chronic pain management and overall subjectivity of analog pain scores, many payers are emphasizing the importance of functional outcomes as a means of assessing efficacy of treatment. Neuromodulation devices such as spinal cord stimulators are shown to be cost effective and able to improve functional outcomes and quality of life. Specific rehabilitation therapies also demonstrate improved functional outcomes. This article aims to discuss the role of rehabilitation in the patient with a neuromodulatory device. From the available data and our clinical experience, we recommend incorporating rehabilitation after placement of a neuromodulation device in order to optimize functional outcomes. PMID- 24470279 TI - Performance monitoring in obsessive-compulsive disorder: a temporo-spatial principal component analysis. AB - Hyperactive performance monitoring is a robust finding in obsessive-compulsive disorder (OCD). Patients show increased amplitudes of the error-related negativity (ERN) and correct-related negativity (CRN). Recently, two temporo spatial factors were shown to contribute to both ERPs in healthy individuals. In the present study, it was investigated whether the factor structure underlying ERN and CRN is similar in OCD and which factors differ between groups. A principal component analysis (PCA) was employed to investigate the temporo spatial factor structure of ERN and CRN. Twenty-six OCD patients and 26 healthy controls conducted a flanker task. EEG data were analyzed as conventional ERP components and as factor scores derived from temporo-spatial PCA. ERP results showed expected increases in ERN and CRN amplitudes in OCD patients. For both groups, the PCA confirmed the assumed factor structure of a central and a fronto parietal factor contributing to ERN and CRN. Factor scores of both factors were differently affected by response correctness in OCD. Alterations in factor scores indicate increased activity in both an outcome-independent monitoring process and an error-sensitive process, contributing to overactive performance monitoring in OCD. PMID- 24470280 TI - An analysis of the learning curve to achieve competency at colonoscopy using the JETS database. AB - OBJECTIVE: The number of colonoscopies required to reach competency is not well established. The primary aim of this study was to determine the number of colonoscopies trainees need to perform to attain competency, defined by a caecal intubation rate (CIR) >=90%. As competency depends on completion, we also investigated trainee factors that were associated with colonoscopy completion. DESIGN: The Joint Advisory Group on GI Endoscopy in the UK has developed a trainee e-portfolio from which colonoscopy data were retrieved. Inclusion criteria were all trainees who had performed a total of >=20 colonoscopies and had performed <=50 colonoscopies prior to submission of data to the e-portfolio. The primary outcome measure was colonoscopy completion. The number of colonoscopies required to achieve CIR >=90% was calculated by the moving average method and learning curve cumulative summation (LC-Cusum) analysis. To determine factors which determine colonoscopy completion, a mixed effect logistic regression model was developed which allowed for nesting of patients within trainees and nesting of patients within hospitals, with various patient, trainee and training factors entered as fixed effects. RESULTS: 297 trainees undertook 36 730 colonoscopies. By moving average analysis, the cohort of trainees reached a CIR of 90% at 233 procedures. By LC-Cusum analysis, 41% of trainees were competent after 200 procedures. Of the trainee factors, the number of colonoscopies, intensity of training and previous flexible sigmoidoscopy experience were significant factors associated with colonoscopy completion. CONCLUSIONS: This is the largest study to date investigating the number of procedures required to achieve competency in colonoscopy. The current training certification benchmark in the UK of 200 procedures does not appear to be an inappropriate minimum requirement. The LC-Cusum chart provides real time feedback on individual learning curves for trainees. The association of training intensity and flexible sigmoidoscopy experience with colonoscopy completion could be exploited in training programmes. PMID- 24470281 TI - Anticolorectal cancer activity of the omega-3 polyunsaturated fatty acid eicosapentaenoic acid. AB - BACKGROUND: Oral administration of the omega-3 fatty acid eicosapentaenoic acid (EPA), as the free fatty acid (FFA), leads to EPA incorporation into, and reduced growth of, experimental colorectal cancer liver metastases (CRCLM). DESIGN: We performed a Phase II double-blind, randomised, placebo-controlled trial of EPA FFA 2 g daily in patients undergoing liver resection surgery for CRCLM. The patients took EPA-FFA (n=43) or placebo (n=45) prior to surgery. The primary end point was the CRCLM Ki67 proliferation index (PI). Secondary end-points included safety and tolerability of EPA-FFA, tumour fatty acid content and CD31-positive vascularity. We also analysed overall survival (OS) and disease-free survival (DFS). RESULTS: The median (range) duration of EPA-FFA treatment was 30 (12-65) days. Treatment groups were well matched with no significant difference in disease burden at surgery or preoperative chemotherapy. EPA-FFA treatment was well tolerated with no excess of postoperative complications. Tumour tissue from EPA-FFA-treated patients demonstrated a 40% increase in EPA content (p=0.0008), no difference in Ki67 PI, but reduced vascularity in 'EPA-naive' individuals (p=0.075). EPA-FFA also demonstrated antiangiogenic activity in vitro. In the first 18 months after CRCLM resection, EPA-FFA-treated individuals obtained OS benefit compared with placebo, although early CRC recurrence rates were similar. CONCLUSIONS: EPA-FFA therapy is safe and well tolerated in patients with advanced CRC undergoing liver surgery. EPA-FFA may have antiangiogenic properties. Remarkably, limited preoperative treatment may provide postoperative OS benefit. Phase III clinical evaluation of prolonged EPA-FFA treatment in CRCLM patients is warranted. TRIAL IDENTIFIER: ClinicalTrials.gov NCT01070355. PMID- 24470282 TI - Prognostic significance of cyclin D1 and E-cadherin expression in laryngeal squamous cell carcinoma. AB - Cyclin D1 and E-cadherin are important factors in the progression and metastasis of cancers. Their role in laryngeal carcinoma has been studied with conflicting results. To define the frequency of cyclin D1 and E-cadherin expression and its correlation with both the clinicopathological characteristics and prognosis of patients with laryngeal squamous cell carcinoma (LSCC). Tumor tissue samples from 75 patients with laryngeal squamous cell carcinoma were examined for cyclin D1 and E-cadherin expression by immunohistochemistry. The relationship between the expression of both molecules and the age and sex of the patient, tumor site, tumor differentiation, lymph node metastasis, tumor invasiveness, TNM stages, tumor recurrence and overall survival was analyzed. Cyclin D1 was found to be a significant independent prognostic factor of lymph node metastasis (p = 0.000). The multivariate analysis revealed that cyclin D1 and E-cadherin expression wasn't an independent prognostic factor of local recurrence free survival (LRFS) in patients with LSCC (P = 0.56 and 0.28) respectively. However, the univariate analysis revealed a significant association between them and LRFS (p = 0.003 and 0.000) respectively. Also, the group of high cyclin D1 /low E-cadherin expression had the poorest prognosis, so they might serve as potential predictors of the prognosis of the patients with LSCC. E-cadherin was found to affect the overall survival (OAS) significantly by the univariate analysis (p = 0.01). However, by the multivariate analysis the TNM stage was the only independent prognostic factor of OAS (p < 0.05). Cyclin D1 can be used as an independent prognostic marker of lymph node metastasis in patients with LSCC and can help to identify those patients with clinically negative lymph nodes but with considerable risk for occult metastasis. Detection of cyclin D1 and E-cadherin status in LSCC may contribute to the identification of patients with high risk factors of local recurrence. However, they don't appear to be better prognostic predictors than other established markers in LSCC. PMID- 24470283 TI - Ebselen exhibits glycation-inhibiting properties and protects against osmotic fragility of human erythrocytes in vitro. AB - Diabetic status is associated with an increase on oxidative stress markers in humans and animal models. We have investigated the in vitro effects of high concentrations of glucose on the profile of oxidative stress and osmotic fragility of blood from control and diabetic patients; we considered whether its antioxidant properties could afford some protection against glucose-induced osmotic fragility, and whether ebselen could act as an inhibitor of hemoglobin glycation. Raising blood glucose to 5-100 mmol/L resulted in a concentration dependent increase of glycated hemoglobin (HbA1c; P < 0.001) and thiobarbituric acid reactive species (TBA-RS) content (P < 0.004). Non-protein SH groups (NPSH) also increased significantly as the concentration of glucose increased up to 30 mmol/L (P < 0.001). The osmotic fragility was more pronounced in blood of uncontrolled diabetic patients than in these non-diabetic subjects. Ebselen significantly reduced the glucose-induced increase in osmotic fragility and inhibited HbA1c formation (P < 0.0001). These results indicate that blood from patients with uncontrolled diabetes are more sensitive to osmotic shock than from patients with controlled diabetes and control subjects in relation to increased production of free radicals in vivo. PMID- 24470284 TI - Diffusion restriction of the optic nerve in patients with acute visual deficit. AB - PURPOSE: Diffusion magnetic resonance imaging (MRI) is commonly used in acute stroke, but not considered diagnostic in ischemic optic neuropathy. This study evaluates the presence of diffusion restriction in patients with acute visual loss by analyzing diffusion-weighted images (DWI). MATERIALS AND METHODS: A retrospective study of all patients who clinically presented with acute visual loss and who underwent MRI with DWI between January 2011 and May 2012 were evaluated. Patients with suspected brainstem ischemia were used as a control group. Two neuroradiologists evaluated the DWI for the presence of diffusion restriction within the optic nerve. RESULTS: In all, 34 patients with acute visual deficit and 32 controls were evaluated. In all five cases of acute optic ischemia, diffusion restriction with reduced apparent diffusion coefficient was present. In 2/25 patients with clinically defined optic neuritis, a diffusion restriction was present. No diffusion restriction was seen in the control cases or in cases with other causes for an acute visual deficit. CONCLUSION: DWI can identify ischemic lesions of the optic nerve. As in acute multiple sclerosis lesions, optic neuritis can also present in rare circumstances with diffusion restriction and can therefore not be ruled out solely by DWI MRI. PMID- 24470286 TI - Standardization of antiphospholipid antibody testing--historical perspectives and ongoing initiatives. AB - The measurement of antiphospholipid antibodies (aPL) has been an important aspect of antiphospholipid syndrome (APS) characterization since the disease was first described in the 1980s. Despite significant efforts geared toward the standardization of immunoassays that measure anticardiolipin antibodies and anti beta2-glycoprotein I spanning three decades, there are still reports of significant interassay and interlaboratory variation in the results of these assays. At the recent 13th International Congress on Antiphospholipid Antibodies (APLA 2010, April 13-16, 2010, Galveston, TX), a task force composed of internationally recognized experts in the field of APS was formed to address these issues. In this review, we discuss approaches that have been used in the past to achieve harmonization among aPL immunoassays as well as the ongoing efforts of the APLA task force. Our review also highlights the importance of cutoff determination in aPL assays and the clinical significance of positive aPL results of varying magnitudes. PMID- 24470285 TI - Carboxypeptidases in disease: insights from peptidomic studies. AB - Carboxypeptidases (CPs) perform many diverse physiological functions by removing C-terminal amino acids from proteins and peptides. Some CPs function in the degradation of proteins in the digestive tract while other enzymes play biosynthetic roles in the formation of neuropeptides and peptide hormones. Another set of CPs modify tubulin by removing amino acids from the C-terminus and from polyglutamyl side chains, thereby altering the properties of microtubules. This review focuses on three CPs: carboxypeptidase E, carboxypeptidase A6, and cytosolic carboxypeptidase 1. Naturally occurring mutations in all three of these enzymes are associated with disease phenotypes, ranging from obesity to epilepsy to neurodegeneration. Peptidomics is a useful tool to investigate the relationship between these mutations and alterations in peptide levels. This technique has also been used to define the function and characteristics of CPs. Results from peptidomics studies have helped to elucidate the function of CPs and clarify the biological underpinnings of pathologies by identifying peptides altered in disease states. This review describes the use of peptidomic techniques to gain insights into the normal function of CPs and the molecular defects caused by mutations in the enzymes. PMID- 24470287 TI - Emerging applications of phase-change materials (PCMs): teaching an old dog new tricks. AB - The nebulous term phase-change material (PCM) simply refers to any substance that has a large heat of fusion and a sharp melting point. PCMs have been used for many years in commercial applications, mainly for heat management purposes. However, these fascinating materials have recently been rediscovered and applied to a broad range of technologies, such as smart drug delivery, information storage, barcoding, and detection. With the hope of kindling interest in this incredibly versatile range of materials, this Review presents an array of aspects related to the compositions, preparations, and emerging applications of PCMs. PMID- 24470288 TI - Assessing spiritual well-being in residents of nursing homes for older people using the FACIT-Sp-12: a cognitive interviewing study. AB - PURPOSE: To detect any problems with completion of the Functional Assessment of Chronic Illness Therapy Spiritual Well-being Scale (FACIT-Sp-12), to analyse the causes of such problems and to propose solutions to overcome them. METHODS: We audio-recorded face-to-face interviews with 17 older people living in one of three nursing homes in London, UK, while they completed FACIT-Sp-12. We used cognitive interviewing methods to explore residents' responses. Our analysis was based on the Framework approach to qualitative analysis. We developed the framework of themes a priori. These comprised: comprehension of the question; retrieval from memory of relevant information; decision processes; and response processes. RESULTS: Ten residents completed the FACIT-Sp-12 with no missing data. Most problems involved comprehension and/or selecting response options. Twelve residents had problems with comprehension of at least one question, particularly with abstract concepts (e.g. harmony, productivity), or where there were assumptions inherent in the questions (e.g. they had an illness). When residents had problems comprehending the question, they also found it difficult to select a response. Thirteen residents had difficulties selecting responses (e.g. categories did not reflect their views or were not meaningful in the context of the statement). Some chose not to respond, others responded to the question as they understood it. CONCLUSIONS: The FACIT-Sp-12 could provide valuable insights into the spiritual concerns of nursing home residents; however, data may be neither valid nor reliable if they do not comprehend the questions as intended and respond appropriately. Providing clear and detailed instructions, including definitions of abstract concepts, may improve the validity of this measure for this population. PMID- 24470289 TI - Molecular imaging with computed tomography. PMID- 24470290 TI - Clinical applications of spectral molecular imaging: potential and challenges. AB - Spectral molecular imaging is a new X-ray-based imaging technology providing highly specific 3D imaging at high spatial resolution that has the potential to measure disease activity and response to treatment noninvasively. The ability to identify and quantify components of tissue and biomarkers of disease activity derive from the properties of the photon-processing detector. Multiple narrow sections of the energy spectrum are sampled simultaneously, providing a range of energy dependent Hounsfield units. As each material has a specific measurable X ray spectrum, spectroscopic imaging allows for multiple materials to be quantified and differentiated from each other simultaneously. The technology, currently in its infancy, is set to grow rapidly, much as magnetic resonance did. The critical clinical applications have not yet been established, but it is likely to play a major role in identifying and directing treatment for unstable atherosclerotic plaque, assessing activity and response to treatment of a range of inflammatory diseases, and monitoring biomarkers of cancer and its treatment. If combined with Positron-emission tomography (PET), spectral molecular imaging could have a far greater effective role in cancer diagnosis and treatment monitoring than PET-CT does at present. It is currently used for small animal and specimen imaging. There are many challenges to be overcome before spectral imaging can be introduced into clinical medicine - these include technological improvements to detector design, bonding to the semiconductor layer, image reconstruction and display software, identifying which biomarkers are of most relevance to the disease in question, and accelerating drug discovery enabled by the new capabilities provided by spectral imaging. PMID- 24470292 TI - Recent advances in ytterbium-based contrast agents for in vivo X-ray computed tomography imaging: promises and prospects. AB - X-ray computed tomography (CT) imaging is one of the most widely used diagnostic imaging techniques in the clinic, and has raised significant interest in recent years both in research and practice owing to its many advantages such as deep penetration depth, high resolution and facile image processing. Developing heavy metal-based CT contrast agents, especially heavy metal-containing nanoparticulate CT contrast agents, has become a key focus in research fields to address issues of clinical iodinated agents involving short circulation time, low contrast efficiency and potential renal toxicity. In this review, we summarize the development of ytterbium (Yb)-based CT contrast agents and highlight the design and applications of Yb-based nanoparticulate CT contrast agents. Yb has high atomic number and higher abundance in the earth's crust relative to Au, Ta and Bi, which have received much attention as a CT contrast agents. In particular, in contrast to these metal elements, as well as I, Yb has K-edge energy that is located just within the higher-intensity region of X-ray spectra, which can induce significant enhancement in the contrast efficiency. When encapsulated in nanoparticles, Yb can remain in the circulation for a long time. This long in vivo circulation time, combined with the proper K-edge energy and a large absorption cross-section of Yb in the near-infrared region, makes Yb-based nanoparticles particularly promising in angiography, 'multicolor' spectral CT imaging, and multimodal imaging. Finally, we also discuss the prospects and the challenges in the development of Yb-based CT contrast agents. PMID- 24470291 TI - Multicolor computed tomographic molecular imaging with noncrystalline high-metal density nanobeacons. AB - Computed tomography (CT) is one of the most frequently pursued radiology technologies applied in the clinics today and in the preclinical field of biomedical imaging. Myriad advances have been made to make this technique more powerful with improved signal sensitivity, rapid image acquisition and faster reconstruction. Synergistic development of novel nanoparticles has been adopted to produce the next-generation CT contrasts agents for imaging specific biological markers. Nanometer-sized agents are anticipated to play a critical part in the prospect of medical diagnostics owing to their capabilities of targeting specific biological markers, extended blood circulation time and defined biological clearance. This review paper introduces the readers to the fundamental design principles of nanoparticulate CT contrast agents with a special emphasis on molecular imaging with noncrystalline high-metal-density nanobeacons. PMID- 24470294 TI - Multifunctional theranostic gold nanoparticles for targeted CT imaging and photothermal therapy. AB - Gold nanoparticles have emerged as some of the most extensively utilized nanoplatforms for the diagnosis, imaging, monitoring and treatment of malignant diseases. In particular, in computed tomography (CT) imaging and in therapy (PTT), the exploitation of the various, advantageous properties of gold nanoparticles have resulted in numerous advances in each of these fields. The purpose of this review is to assess the status of gold-nanoparticle mediated CT and PTT, highlight several promising outcomes and motivate the combination of these two functionalities in the same nanoparticle platform. The given examples of research based advances and the encouraging results of in vitro and in vivo studies provide much excitement and promise for future theranostic (therapy + diagnostic) clinical applications, as well as for image-guided therapy and/or surgery, and their monitoring. PMID- 24470295 TI - Spectral CT: a technology primer for contrast agent development. AB - Recent developments in spectral CT systems featuring binned photon-counting detector technology have enabled an imaging concept on a pre-clinical level that has been coined K-edge imaging. This exciting concept allows the selective and quantitative imaging of contrast media by exploiting the K-edge discontinuity in the photo-electric component of X-ray absorption. An ideal application for K-edge imaging is CT imaging of target-specific and conventional contrast agents that have been designed to be spectral-CT-visible. Current limitations in detector hardware, however, result in typically high noise levels that hamper the application of K-edge imaging. In order to battle noise and assure sufficient sensitivity, the development of dedicated K-edge contrast media in combination with advanced image processing techniques is imperative. This work attempts a comprehensive overview on how the concert of dedicated contrast media, optimized data acquisition and innovative data processing techniques improve sensitivity of K-edge imaging which will foster clinical translation of the technology. PMID- 24470293 TI - Nanoparticle contrast agents for computed tomography: a focus on micelles. AB - Computed tomography (CT) is an X-ray-based whole-body imaging technique that is widely used in medicine. Clinically approved contrast agents for CT are iodinated small molecules or barium suspensions. Over the past seven years there has been a great increase in the development of nanoparticles as CT contrast agents. Nanoparticles have several advantages over small molecule CT contrast agents, such as long blood-pool residence times and the potential for cell tracking and targeted imaging applications. Furthermore, there is a need for novel CT contrast agents, owing to the growing population of renally impaired patients and patients hypersensitive to iodinated contrast. Micelles and lipoproteins, a micelle related class of nanoparticle, have notably been adapted as CT contrast agents. In this review we discuss the principles of CT image formation and the generation of CT contrast. We discuss the progress in developing nontargeted, targeted and cell tracking nanoparticle CT contrast agents. We feature agents based on micelles and used in conjunction with spectral CT. The large contrast agent doses needed will necessitate careful toxicology studies prior to clinical translation. However, the field has seen tremendous advances in the past decade and we expect many more advances to come in the next decade. PMID- 24470296 TI - Diffusion properties of conventional and calcium-sensitive MRI contrast agents in the rat cerebral cortex. AB - Calcium-sensitive MRI contrast agents can only yield quantitative results if the agent concentration in the tissue is known. The agent concentration could be determined by diffusion modeling, if relevant parameters were available. We have established an MRI-based method capable of determining diffusion properties of conventional and calcium-sensitive agents. Simulations and experiments demonstrate that the method is applicable both for conventional contrast agents with a fixed relaxivity value and for calcium-sensitive contrast agents. The full pharmacokinetic time-course of gadolinium concentration estimates was observed by MRI before, during and after intracerebral administration of the agent, and the effective diffusion coefficient D* was determined by voxel-wise fitting of the solution to the diffusion equation. The method yielded whole brain coverage with a high spatial and temporal sampling. The use of two types of MRI sequences for sampling of the diffusion time courses was investigated: Look-Locker-based quantitative T(1) mapping, and T(1) -weighted MRI. The observation times of the proposed MRI method is long (up to 20 h) and consequently the diffusion distances covered are also long (2-4 mm). Despite this difference, the D* values in vivo were in agreement with previous findings using optical measurement techniques, based on observation times of a few minutes. The effective diffusion coefficient determined for the calcium-sensitive contrast agents may be used to determine local tissue concentrations and to design infusion protocols that maintain the agent concentration at a steady state, thereby enabling quantitative sensing of the local calcium concentration. PMID- 24470297 TI - Relaxometric studies of gadolinium-functionalized perfluorocarbon nanoparticles for MR imaging. AB - Fluorine MRI ((19) F MRI) is receiving an increasing attention as a viable alternative to proton-based MRI ((1) H MRI) for dedicated application in molecular imaging. The (19) F nucleus has a high gyromagnetic ratio, a 100% natural abundance and is furthermore hardly present in human tissues allowing for hot spot MR imaging. The applicability of (19) F MRI as a molecular and cellular imaging technique has been exploited, ranging from cell tracking to detection and imaging of tumors in preclinical studies. In addition to applications, developing new contrast materials with improved relaxation properties has also been a core research topic in the field, since the inherently low longitudinal relaxation rates of perfluorocarbon compounds result in relatively low imaging efficiency. Borrowed from (1) H MRI, the incorporation of lanthanides, specifically Gd(III) complexes, as signal modulating ingredients in the nanoparticle formulation has emerged as a promising approach to improvement of the fluorine signal. Three different perfluorocarbon emulsions were investigated at five different magnetic field strengths. Perfluoro-15-crown-5-ether was used as the core material and Gd(III)DOTA-DSPE, Gd(III)DOTA-C6-DSPE and Gd(III)DTPA-BSA as the relaxation altering components. While Gd(III)DOTA-DSPE and Gd(III)DOTA-C6-DSPE were favorable constructs for (1) H NMR, Gd(III)DTPA-BSA showed the strongest increase in (19F) R(1). These results show the potential of the use of paramagnetic lipids to increase (19F) R(1) at clinical field strengths (1.5-3 T). At higher field strengths (6.3-14 T), gadolinium does not lead to an increase in (19F) R(1) compared with emulsions without gadolinium, but leads to an significant increase in (19F) R(2). Our data therefore suggest that the most favorable situation for fluorine measurements is at high magnetic fields without the inclusion of gadolinium constructs. PMID- 24470298 TI - Encapsulated gadolinium and dysprosium ions within ultra-short carbon nanotubes for MR microscopy at 11.75 and 21.1 T. AB - Single-walled carbon nanotubes (SWNTs) have gained interest for their biocompatibility and multifunctional properties. Ultra-short SWNTs (US-tubes) have demonstrated high proton relaxivity when encapsulating gadolinium ions (Gd(3+)) at clinical field strengths. At higher field strengths, however, Gd(3+) ions demonstrate decreased proton relaxation properties while chemically similar dysprosium ions (Dy(3+)) improve relaxation properties. This report investigates the first use of Gd(3+) and Dy(3+) ions within US-tubes (GNTs and DNTs, respectively) at ultra-high magnetic field (21.1 T). Both agents are compared in solution and as an intracellular contrast agent labeling a murine microglia cell line (Bv2) immobilized in a tissue-mimicking agarose phantom using two high magnetic fields: 21.1 and 11.75 T. In solution at 21.1 T, results show excellent transverse relaxation; DNTs outperformed GNTs as a T(2) agent with measured r(2)/r(1) ratios of 247 and 47, respectively. Additionally, intracellular DNTs were shown to be a better T(2) agent than GNTs with higher contrast percentages and contrast-to-noise ratios. As such, this study demonstrates the potential of DNTs at high magnetic fields for cellular labeling and future in vivo, MRI-based cell tracking. PMID- 24470299 TI - Sensitivity enhancement of (Hyper-)CEST image series by exploiting redundancies in the spectral domain. AB - CEST has proven to be a valuable technique for the detection of hyperpolarized xenon-based functionalized contrast agents. Additional information can be encoded in the spectral dimension, allowing the simultaneous detection of multiple different biosensors. However, owing to the low concentration of dissolved xenon in biological tissue, the signal-to-noise ratio (SNR) of Hyper-CEST data is still a critical issue. In this work, we present two techniques aiming to increase SNR by exploiting the typically high redundancy in spectral CEST image series: PCA based post-processing and sub-sampled acquisition with low-rank reconstruction. Each of them yields a significant SNR enhancement, demonstrating the feasibility of the two approaches. While the first method is directly applicable to proton CEST experiments as well, the second one is particularly beneficial when dealing with hyperpolarized nuclei, since it distributes the non-renewable initial polarization more efficiently over the sampling points. The results obtained are a further step towards the detection of xenon biosensors with spectral Hyper-CEST imaging in vivo. PMID- 24470301 TI - Circulating microparticle tissue factor activity is increased in patients with cirrhosis. PMID- 24470302 TI - From the molecular structure to spectroscopic and material properties: computational investigation of a bent-core nematic liquid crystal. AB - We present a computational investigation of the nematic phase of the bent-core liquid crystal A131. We use an integrated approach that bridges density functional theory calculations of molecular geometry and torsional potentials to elastic properties through the molecular conformational and orientational distribution function. This unique capability to simultaneously access different length scales enables us to consistently describe molecular and material properties. We can reassign (13)C NMR chemical shifts and analyze the dependence of phase properties on molecular shape. Focusing on the elastic constants we can draw some general conclusions on the unconventional behavior of bent-core nematics and highlight the crucial role of a properly-bent shape. PMID- 24470303 TI - Early response of mouse joint tissue to noninvasive knee injury suggests treatment targets. AB - OBJECTIVE: Joint trauma can lead to a spectrum of acute lesions, including cartilage degradation, ligament or meniscus tears, and synovitis, all potentially associated with osteoarthritis (OA). This study was undertaken to generate and validate a murine model of knee joint trauma following noninvasive controlled injurious compression in vivo. METHODS: The right knees of 8-week-old mice were placed in a hyperflexed position and subjected to compressive joint loading at 1 of 3 peak forces (3N, 6N, or 9N) for 60 cycles in a single loading period and harvested on days 5, 9, and 14 after loading (n = 3-5 for each time point and for each loading). The left knees were not loaded and were used as the contralateral control. Histologic, immunohistochemical, and enzyme-linked immunosorbent assay analyses were performed to evaluate acute pathologic features in chondrocyte viability, cartilage matrix metabolism, synovial reaction, and serum cartilage oligomeric matrix protein (COMP) levels. RESULTS: Acute joint pathology was associated with increased injurious loads. All loading regimens induced chondrocyte apoptosis, cartilage matrix degradation, disruption of cartilage collagen fibril arrangement, and increased levels of serum COMP. We also observed that 6N loading induced mild synovitis by day 5, whereas at 9N, with tearing of the anterior cruciate ligament, severe posttraumatic synovitis and ectopic cartilage formation were observed. CONCLUSION: We have established a murine model of knee joint trauma with different degrees of overloading in vivo. Our results suggest that immediate therapies particularly targeted to apoptosis and synovial cell proliferation could affect the acute posttraumatic reaction to potentially limit chronic consequences and OA. PMID- 24470304 TI - Crystal structure of DszC from Rhodococcus sp. XP at 1.79 A. AB - The dibenzothiophene (DBT) monooxygenase DszC, which is the key initiating enzyme in "4S" metabolic pathway, catalyzes sequential sulphoxidation reaction of DBT to DBT sulfoxide (DBTO), then DBT sulfone (DBTO2). Here, we report the crystal structure of DszC from Rhodococcus sp. XP at 1.79 A. Intriguingly, two distinct conformations occur in the flexible lid loops adjacent to the active site (residue 280-295, between alpha9 and alpha10). They are named "open"' and "closed" state respectively, and might show the status of the free and ligand bound DszC. The molecular docking results suggest that the reduced FMN reacts with an oxygen molecule at C4a position of the isoalloxazine ring, producing the C4a-(hydro)peroxyflavin intermediate which is stabilized by H391 and S163. H391 may contribute to the formation of the C4a-(hydro)peroxyflavin by acting as a proton donor to the proximal peroxy oxygen, and it might also be involved in the protonation process of the C4a-(hydro)xyflavin. Site-directed mutagenesis study shows that mutations in the residues involved either in catalysis or in flavin or substrate-binding result in a complete loss of enzyme activity, suggesting that the accurate positions of flavin and substrate are crucial for the enzyme activity. PMID- 24470307 TI - ACR presidential address: when you come to a fork in the road, choose wisely. PMID- 24470305 TI - ICAT: a computational model for the adaptive control of fixation durations. AB - Eye movements depend on cognitive processes related to visual information processing. Much has been learned about the spatial selection of fixation locations, while the principles governing the temporal control (fixation durations) are less clear. Here, we review current theories for the control of fixation durations in tasks like visual search, scanning, scene perception, and reading and propose a new model for the control of fixation durations. We distinguish two local principles from one global principle of control. First, an autonomous saccade timer initiates saccades after random time intervals (local I). Second, foveal inhibition permits immediate prolongation of fixation durations by ongoing processing (local-II). Third, saccade timing is adaptive, so that the mean timer value depends on task requirements and fixation history (Global). We demonstrate by numerical simulations that our model qualitatively reproduces patterns of mean fixation durations and fixation duration distributions observed in typical experiments. When combined with assumptions of saccade target selection and oculomotor control, the model accounts for both temporal and spatial aspects of eye movement control in two versions of a visual search task. We conclude that the model provides a promising framework for the control of fixation durations in saccadic tasks. PMID- 24470306 TI - Cloning and characterization of a dynein light chain gene from Puccinia striiformis f. sp. tritici. AB - Stripe rust is one of the most serious wheat diseases worldwide. The fungus Puccinia striiformis f. sp. tritici (Pst), the causal agent of this disease, is an obligate biotrophic basidiomycete fungus. Numerous studies have shown that dyneins play important roles during fungal growth and propagation. However, knowledge is limited regarding the function of dyneins in Pst. In this study, we cloned the dynein light chain gene PsDLC1 from Pst and characterized its expression. The function of PsDLC1 was determined by heterologous mutant complementation. Expression of PsDLC1 in Aspergillus nidulans partially complemented the defects of the DeltanudG mutant, indicating that PsDLC1 belongs to the dynein light chain LC8 family. In addition, PsDLC1 was identified in Pst using virus-induced gene silencing (VIGS). Knockdown of PsDLC1 produces no significant effect on Pst growth and development, indicating that PsDLC1 is unnecessary for Pst infection of wheat. PMID- 24470308 TI - A simplified approach to minimally invasive parathyroidectomy. AB - OBJECTIVES/HYPOTHESIS: To assess the feasibility of a simplified approach for the use of a rapid intraoperative parathyroid hormone (IOPTH) assay based on a single 10-minute post-excision level using the workup parathyroid hormone level (wPTH) as the baseline in minimally invasive parathyroidectomy (MIP) and to compare the predictive value of this criterion with other recommended criteria. STUDY DESIGN: Case series with chart review. METHODS: A single surgeon's prospectively maintained parathyroidectomy database at an academic center was reviewed over a 2 year period from June 2009 through June 2011. RESULTS: A total of 102 patients undergoing MIP met the inclusion criteria. An IOPTH threshold of a >= 50% drop at 10 minutes post-excision from the wPTH baseline resulted in acceptable false positive (1.9%) and false negative (0.9%) rates. The sensitivity, specificity, positive predictive value, negative predictive value, and accuracy of this modified criterion was 98.9%, 71.4%, 98%, 83.3%, and 97%, respectively. CONCLUSIONS: In our patient cohort, the pre-incision and pre-excision IOPTH levels did not seem to change the overall accuracy of predicting surgical success in MIP if a single 10-minute post-excision IOPTH level is used along with the wPTH, and is commensurate with the commonly used Miami and Vienna criteria. A single intraoperative blood sample demonstrating a >=50% drop from the wPTH at 10 minutes post-excision should be explored further as a feasible simplified criterion that avoids multiple IOPTH samples. PMID- 24470309 TI - Synthesis and biological activity of piperazine derivatives of phenothiazine. AB - Some novel piperazine derivatives of phenothiazine were synthesized. The structures of the synthesized compounds were characterized by elemental analysis, FT-IR, (1)H- and (13)C-NMR and Mass Spectroscopy. The compounds were evaluated for antibacterial, antifungal and antitubercular activity by cup plate, disc diffusion and Lowenstein-Jensen medium methods respectively. All the compounds showed good antibacterial activity against Staphylococcus aureus and Bacillus subtilis. Compound V showed equipotent antibacterial activity with streptomycin standard and showed better antibacterial activity against gram positive bacteria profile than gram negative bacteria. Zone of inhibition was not found for the compounds against Escherichia coli and Pseudomonas aeruginosa. All the compounds exhibited good antifungal activity against Aspergillus species and no activity against Candida albicans. All the compounds at a concentration of 100, 10 and 1 ug/L showed inhibition against the growth of Mycobacterium tuberculosis. PMID- 24470310 TI - Hesperidin, a citrus bioflavonoid, ameliorates genotoxicity-induced by diazinon in human blood lymphocytes. AB - Hesperidin (Hes), a natural bioflavonoid, is abundant in citrus fruit and has been reported to exert a wide range of pharmacological effects. Diazinon (DZN) can be mutagenic, or capable of inducing genetic damage, in human blood cells. The protective effect of Hes against DZN-induced micronucleus formation, an index of DNA damage, was investigated in human blood lymphocytes. Whole blood samples were collected from 5 volunteers and were incubated with different Hes concentrations for 3 h. The samples were then incubated with 750 uM DZN for 24 h. Subsequently, the blood samples were cultured with a mitogenic stimulant to evaluate micronucleus formation in cytokinesis-blocked binucleated lymphocytes. The incubation of blood samples with DZN induced additional genotoxicity in lymphocytes, and Hes pretreatment significantly reduced the micronucleus frequency (p<0.01-p<0.001). Hes revealed a potent antigenotoxic effect against DZN-induced DNA damage, which may be due to free radical scavenging property. Since hesperidin is a natural compound and is considered safe, it can be used as a supplement to protect people exposed to chemical or environmental hazards. PMID- 24470311 TI - Effect of vitamin B12 on functional recovery and histopathologic changes of tibial nerve-crushed rats. AB - Recent studies have suggested a neuroprotective effect for vitamin B12. The present study investigated the effects of vitamin B12, diclofenac and celecoxib in separate and combined treatments on functional recovery of crushed tibial nerve in rats. In ketamine plus xylazin anesthetized rats, right tibial nerve was crushed using a small hemoatatic forceps. Footprints were recorded 1 day before and on days 7, 14 and 21 after induction of nerve injury. Tibial functional index (TFI) was used to evaluate the recovery of tibial nerve function. Histological changes of tibial nerve were investigated by light microscopy. The recovery of TFI values were significantly accelerated with 10 consecutive days treatments with 0.1 and 0.5 mg/kg of vitamin B12, 5 mg/kg of diclofenac and 1 and 5 mg/kg of celecoxib. The severity of Wallerian degeneration was reduced by above-mentioned doses of vitamin B12, diclofenac and celecoxib. Documented effects were observed when 0.1 mg/kg of vitamin B12 was concurrently used with 1 mg/kg of diclofenac and or 0.2 mg/kg of celecoxib. In the present study, vitamin B12, celecoxib and diclofenac (at a high dose) showed neuroprotective effects. Inhibition of cyclooxygenase (COX) 1 and 2 pathways may be involved in neuroprotective effect of vitamin B12. PMID- 24470312 TI - Crucial role of anions on arrangement of Cu2S nanocrystal superstructures. AB - Both of the arrays of Cu2S nanowires and the superlattices of Cu2S nanoparticles are obtained by the solventless thermolysis of copper thiolate in the presence of laurate. For the first time, the types of anions in the reaction system, which are generally neglected in previous studies, are found to determine the structure of the final assembly products. Furthermore, experimental results shows in the presence of Cl- ions, Cl- ions participate in the self-assembly process and promote the formation of Cu2S nanowire arrays. Finally, the content of Cl- ions is gradually decreased with assembly reaction proceeding. Therefore, duiring the process, Cl- ions play a role of 'catassembly' in the formation of Cu2S nanocrystal superstructures. PMID- 24470313 TI - Perfectionism and eating psychopathology among dancers: the role of high standards and self-criticism. AB - This study examined the associations between conscientious perfectionism (high standards), self-evaluative perfectionism (self-criticism) and eating psychopathology among dancers. A sample of 244 female dancers, with a mean age of 20.11 years (standard deviation=1.97) completed the Perfectionism Inventory and Eating Disorder Examination Questionnaire. Self-evaluative perfectionism predicted eating psychopathology (eating restraint, eating concern, weight concern and shape concern). This relationship was not moderated by conscientious perfectionism. The mediation analyses showed that although conscientious perfectionism predicted eating psychopathology, this relationship was fully mediated by self-evaluative perfectionism. These findings demonstrate the greater influence of self-evaluative perfectionism, rather than conscientious perfectionism, on eating psychopathology in dancers. PMID- 24470314 TI - Morphological and functional adaptation of left and right atria induced by training in highly trained female athletes. AB - BACKGROUND: Exercise is able to induce atrial remodeling in top-level athletes. However, evidence is mainly limited to men and based on cross-sectional studies. The aim of this prospective, longitudinal study was to investigate whether exercise is able to influence left and right atrial morphology and function also in female athletes. :ETHODS AND RESULTS- Two-dimensional echocardiography was performed before season and after 16 weeks of intensive training in 24 top-level female athletes. Left and right atrial myocardial deformation was assessed by two dimensional speckle-tracking echocardiography. Left atrial volume index (24.0+/ 3.6 versus 26.7+/-6.9 mL/m(2); P<0.001) and right atrial volume index (15.66+/ 3.09 versus 20.47+/-4.82 mL/m(2); P<0.001) significantly increased after training in female athletes. Left atrial global peak atrial longitudinal strain and peak atrial contraction strain significantly decreased after training in female athletes (43.9+/-9.5% versus 39.8+/-6.5%; P<0.05 and 15.5+/-4.0% versus 13.9+/ 4.0%; P<0.05, respectively). Right atrial peak atrial longitudinal strain and peak atrial contraction strain showed a similar, although non-significant decrease (42.8+/-10.6% versus 39.3+/-8.3%; 15.6+/-5.6% versus 13.1+/-6.1%, respectively). Neither biventricular E/e' ratio nor biatrial stiffness changed after training, suggesting that biatrial remodeling occurs in a model of volume rather than pressure overload. CONCLUSIONS: Exercise is able to induce biatrial morphological and functional changes in female athletes. Biatrial enlargement, with normal filling pressures and low atrial stiffness, is a typical feature of the heart of female athletes. These findings should be interpreted as physiological adaptations to exercise and should be considered in the differential diagnosis with cardiomyopathies. PMID- 24470315 TI - Cysteine cathepsins and their potential in clinical therapy and biomarker discovery. AB - Since their discovery, cysteine cathepsins were generally considered to be involved mainly in the nonspecific bulk protein degradation that takes place within the lysosomes. However, it has become clear that their proteolytical activity can also influence various specific pathological processes such as cancer, arthritis, and atherosclerosis. Furthermore, their localization was found not to be limited strictly to the lysosomes. In the light of those findings, it is not surprising that cysteine cathepsins are currently considered as highly relevant clinical targets. Moreover, recent development of proteomic-based methods for identification of novel physiological substrates of proteases provides a major opportunity also in the field of cysteine cathepsins. In this review, we will therefore present cysteine cathepsin roles in disease progression and discuss their potential relevance as prognostic and diagnostic biomarkers. PMID- 24470316 TI - Heart regeneration: opportunities and challenges for drug discovery with novel chemical and therapeutic methods or agents. AB - Following a heart attack, more than a billion cardiac muscle cells (cardiomyocytes) can be killed, leading to heart failure and sudden death. Much research in this area is now focused on the regeneration of heart tissue through differentiation of stem cells, proliferation of existing cardiomyocytes and cardiac progenitor cells, and reprogramming of fibroblasts into cardiomyocytes. Different chemical modalities (i.e. methods or agents), ranging from small molecules and RNA approaches (including both microRNA and anti-microRNA) to modified peptides and proteins, are showing potential to meet this medical need. In this Review, we outline the recent advances in these areas and describe both the modality and progress, including novel screening strategies to identify hits, and the upcoming challenges and opportunities to develop these hits into pharmaceuticals, at which chemistry plays a key role. PMID- 24470317 TI - Evolution of right ventricular function post-acute ST elevation myocardial infarction. AB - PURPOSE: To characterize the evolution of right ventricular (RV) function post myocardial infarction (MI), to describe the culprit vessel involved with RV injury and to assess the concordance between RV injury on magnetic resonance imaging (MRI) and RV infarct on electrocardiogram (EKG). MATERIALS AND METHODS: Thirty-one patients underwent cardiovascular magnetic resonance (CMR) examinations at three time frames post-ST elevation MI (STEMI). RESULTS: Of those with an initial normal scan, RV function did not significantly change over time (60.6 +/- 6.3, 57.8 +/- 6.0, 55.4 +/- 5.7, P > 0.05). However, in those whose RVEF (RV ejection fraction) was initially low, it significantly increased from the first scan to the third scan (46.2 +/- 3.6, 50 +/- 6.6, 51.3 +/- 5.2, P < 0.01). Post-hoc testing revealed a significant difference between the 48-hour and the 6-month scan, and between the 48-hour and the 3-week scan; however, there was no significant difference between the 3-week and 6-month scans. Interestingly, 23% of patients with low RVEF at baseline had the left anterior descending (LAD) as the culprit vessel. Only 15% of the low RVEF at baseline group were classified as having an RVMI by EKG criteria. CONCLUSIONS: The optimal timepoint to assess for RV injury via CMR may be 3 weeks post-acute MI. Standard EKG criteria may underestimate RV injury when compared to CMR. PMID- 24470318 TI - Orthogonal orientation of chromonic liquid crystals by rubbed polyamide films. AB - Chromonic liquid crystals (CLCs) have drawn attention for applications to organic electronics and optical films as well as biological materials. Understanding the alignment mechanism of CLCs is important for those applications. Using a polarized transmission optical microscope, we observe the optical texture, dichroism, and birefringence of CLC films of sunset yellow (SSY) confined by polyamide (nylon) films that are rubbed with a brush. The films align with the stacks of SSY molecules oriented, surprisingly, perpendicular to the rubbing direction. We propose that this alignment is stabilized by molecular interaction between the stretched nylon chains and molecular grooves of the SSY stacks rather than elastic energy of the CLCs due to surface topography induced by the rubbing. PMID- 24470320 TI - Severe non-specific immune reconstitution inflammatory syndrome (IRIS) presenting with graft-versus-host disease-like colitis. PMID- 24470319 TI - What characteristics predispose to continence in nursing home residents?: a population-based cross-sectional study. AB - AIMS: To compare characteristics of both continent and incontinent residents in Nursing Homes (NHs) and to explore what predicts continence and severity of incontinence. METHODS: A population-based cross-sectional study was performed in nursing homes in one Norwegian municipality. Registered nurses filled in a questionnaire on behalf of the patients. RESULTS: We found that 25.4% of the NH residents were continent, 31.8% had urinary incontinence alone, 2.6% had fecal incontinence alone and 40.2% had double incontinence. Continent residents were characterized by being in short-term care, shorter stay in NH, less cognitive and physical impairment, less Parkinson's disease, stroke, constipation, and less diarrhea and more independence in activities of daily living (ADL). Residents with fecal incontinence alone were characterized by more diarrhea, less cognitive impairment and less dependency in ADL such as feeding and grooming. Residents with urinary incontinence alone were characterized by having some degree of ADL dependency, less diarrhea, and less diabetes. Residents with double incontinence were characterized by being in long-term care, a longer length of stay in NH, cognitive impairment, stroke, constipation, diarrhea, and dependency in ADL. Severity of incontinence was associated with dependency in ADL and cognitive impairment, diarrhea, length of stay in NH and lower age. CONCLUSIONS: About 25% of NH residents were continent. Double incontinence and urinary incontinence only were prevalent conditions in NHs, while FI alone was rarer. With the exception of diarrhea as a cause of FI, it appears that FI alone, UI alone, and DI may have common causes and development. PMID- 24470321 TI - Effect of empiric antibiotic treatment on plasma endotoxin activity in septic patients. AB - OBJECTIVES: Efficient empiric antibiotic therapy remains the cornerstone of sepsis treatment. However, antibiotics could be responsible for the transient clinical deterioration provoked by the release of bacterial cell-wall constituents, such as endotoxin, into the blood stream. The aim of this study was to evaluate if a transient elevation of endotoxin level occurred in septic patients following antibiotic administration. METHODS: Thirty-three septic intensive care unit (ICU) patients were enrolled in this prospective trial. Four blood samples were collected from each of these patients during a 24-h period, and endotoxin activity was measured in these samples by the chemiluminescence technique. Fifteen ICU non-septic patients and 15 healthy volunteers were also observed for possible daily fluctuations in endotoxin activity. RESULTS: There was no significant increase in endotoxin levels following the initiation of empiric antibiotic therapy in septic patients. A clinical deterioration in the 4 h following antibiotic administration was observed in 14 septic patients (42 %). These patients had significantly higher endotoxin levels than stable septic patients. CONCLUSIONS: Although endotoxin levels failed to increase after the administration of antibiotic(s) to critically ill patients, they were higher in the septic patients presenting a transient deterioration than in the other patients. This observation suggests that a possible release of endotoxin due to bacteria lysis by antibiotics could be responsible for the observed clinical deterioration. PMID- 24470322 TI - Value of multiplex PCR using cerebrospinal fluid for the diagnosis of ventriculostomy-related meningitis in neurosurgery patients. AB - PURPOSE: This prospective observational cohort study assessed the use of a multiplex real-time polymerase chain reaction (PCR) assay alone and in conjunction with biomarkers for the diagnosis of ventriculostomy-related meningitis in neurosurgery intensive care unit (ICU) patients with external ventricular drainage (EVD). METHODS: Concentrations of intrathecal biomarkers, including lactate and interleukin 6 (IL-6), were measured, and cerebrospinal fluid (CSF) was examined microbiologically by blood culture BACTEC bottles in 62 CSF samples from 41 patients with EVD. A portion of each sample was also tested with a commercially available PCR assay that simultaneously detects 25 species of bacteria and fungi [SeptiFast (SF)]. Receiver operating characteristic curve analysis was used to compare biomarker concentrations with SF and culture results. RESULTS: Seventeen (27 %) samples tested positive and 40 (65 %) tested negative for pathogens by both culture and SF. One pathogen was detected only by SF. Four samples tested positive by culture but negative by SF; in 3 of these, the isolates were considered to be contaminants. In comparison to CSF culture SF showed a larger area under the curve for IL-6 (0.90; 95 % CI 0.83-0.98) versus 0.70 (95 % CI 0.46-0.80) and for lactate (0.77; 95 % CI 0.63-0.93) versus 0.65 (95 % CI 0.50-0.80). In 94 % (17/18) of positive SF samples the results were obtained on the same day whereas the overall mean of the time-to-positivity of BACTEC bottles was 21.6 h. CONCLUSIONS: The diagnosis of EVD-related ventriculo meningitis in neurosurgical ICU patients can be established in a rapid manner using a multiplex PCR assay on CSF samples in combination with intrathecal biomarkers. PMID- 24470323 TI - Nocturnal knee pain increases with the severity of knee osteoarthritis, disturbing patient sleep quality. AB - OBJECTIVE: Sleep disturbances frequently accompany chronic pain from osteoarthritis (OA). Effective management of sleep disturbances may require successful treatment of chronic pain, a key factor in the clinical evaluation of knee OA. However, the relationship between the severity of knee OA and sleep quality is unclear. Our purpose was to correlate the prevalence of nocturnal knee pain with different OA severity levels and to determine its influence on sleep quality. METHODS: Subjects included 1,214 local volunteers with mean +/- SD age 58.1 +/- 13.0 years. The existence and severity of knee OA were determined by the Kellgren/Lawrence (K/L) grade, and joint space widths were measured. The presence of nocturnal knee pain and Knee Injury and Osteoarthritis Outcome Scores (KOOS) were assessed by self-completed questionnaires. Sleep quality was evaluated by the Pittsburgh Sleep Quality Index. Knee-related factors affecting sleep quality were detected using statistical methods. RESULTS: The prevalence of nocturnal knee pain was 3.6%, 6.9%, 19.4%, 32.7%, and 75.0% in K/L grades 0, 1, 2, 3, and 4, respectively. Also, prevalence significantly increased with OA severity (P < 0.001). Sleep problems also increased with K/L grade (P = 0.038), and KOOS quality of life (QOL) was significantly lower in those with OA and sleep problems. Logistic regression showed that sleep problems were related to joint space narrowing (P = 0.016) and nocturnal knee pain (P = 0.039). Severe OA also disturbed onset and maintenance of sleep. CONCLUSION: The prevalence of nocturnal knee pain and sleep problems increased with the severity of OA, impacting QOL. These results suggest the necessity of appropriate nocturnal pain control. PMID- 24470324 TI - Hypertrophic cardiomyopathy: exercising a strategy of personalised medicine. PMID- 24470325 TI - Mechanisms of white matter damage in multiple sclerosis. AB - Glia cells are mediators as well as targets of the chronic inflammatory process in the central nervous system of multiple sclerosis (MS) patients. They are involved in the control of autoimmunity, in the propagation and termination of the inflammatory reaction, in the induction of demyelination and neurodegeneration, and in remyelination and scaring. Demyelination, as well as neuronal and GLIA cell damage are induced by different immunological mechanisms including components of the adaptive and innate immune system. Oxidative injury resulting in mitochondrial dysfunction is one important mechanism of tissue injury. It is in part driven by the inflammatory response and the production of oxygen radicals mainly in microglia and macrophages. With increasing age of the patients and disease progression, oxidative injury is further amplified by additional mechanisms including central nervous system damage related microglia activation, progressive mitochondrial damage, and age-dependent iron accumulation within the human central nervous system. The inflammatory mechanisms associated with lesion formation in MS are to a large extent reflected in experimental models of inflammatory demyelination, such as autoimmune encephalomyelitis. This is not the case for the amplification mechanisms of oxidative injury, which mainly operate in the progressive stage of the disease. PMID- 24470326 TI - Induction of foetal haemoglobin synthesis in erythroid progenitor stem cells: mediated by water-soluble components of Terminalia catappa. AB - Current novel therapeutic agents for the treatment of sickle cell anaemia (SCA) focus on increasing foetal haemoglobin (HbF) levels in SCA patients. Unfortunately, the only approved HbF-inducing agent, hydroxyurea, has long-term unpredictable side effects. Studies have shown the potential of plant compounds to modulate HbF synthesis in primary erythroid progenitor stem cells. We isolated a novel HbF-inducing Terminalia catappa distilled water active fraction (TCDWF) from Terminalia catappa leaves that induced the commitment of erythroid progenitor stem cells to the erythroid lineage and relatively higher HbF synthesis of 9.2- and 6.8-fold increases in both erythropoietin (EPO)-independent and EPO-dependent progenitor stem cells respectively. TCDWF was differentially cytotoxic to EPO-dependent and EPO-independent erythroid progenitor stem cell cultures as revealed by lactate dehydrogenase release from the cells. TCDWF demonstrated a protective effect on EPO-dependent and not EPO-independent progenitor cells. TCDWF induced a modest increase in caspase 3 activity in EPO independent erythroid progenitor stem cell cultures compared with a significantly higher (P?0.05) caspase 3 activity in EPO-dependent ones. The results demonstrate that TCDWF may hold promising HbF-inducing compounds, which work synergistically, and suggest a dual modulatory effect on erythropoiesis inherent in this active fraction. PMID- 24470327 TI - Interleukin-17+CD8+ T cells are enriched in the joints of patients with psoriatic arthritis and correlate with disease activity and joint damage progression. AB - OBJECTIVE: Psoriatic arthritis (PsA) is associated with HLA class I genes, in contrast to the association with HLA class II in rheumatoid arthritis (RA). Since IL-17+ cells are considered important mediators of synovial inflammation, we sought to determine whether IL-17-producing CD8+ T cells may be found in the joints of patients with PsA and whether these cells might contribute to the disease process. METHODS: Mononuclear cells from paired samples of synovial fluid (SF) and peripheral blood (PB) from patients with PsA or patients with RA were stimulated ex vivo, and CD4- T cells were examined by flow cytometry for cytokine expression, cytotoxic markers, and frequencies of gamma/delta or mucosal associated invariant T cells. Clinical measures of arthritis activity (C-reactive protein [CRP] level, erythrocyte sedimentation rate [ESR], Disease Activity Score in 28 joints [DAS28]) and power Doppler ultrasound (PDUS) scores for the presence of active synovitis in the aspirated knee were recorded and assessed for correlations with immunologic markers. RESULTS: Within the CD3+ T cell compartment, both IL-17+CD4- (predominantly CD8+) and IL-17+CD4+ T cells were significantly enhanced in the SF compared to the PB of patients with PsA (P = 0.0003 and P = 0.002, respectively; n = 21), whereas in patients with RA, only IL 17+CD4+ T cells were increased in the SF compared to the PB (P = 0.008; n = 14). The frequency of IL-17+CD4- T cells in PsA SF was positively correlated with the CRP level (r = 0.52, P = 0.01), ESR (r = 0.59, P = 0.004), and DAS28 (r = 0.52, P = 0.01), and was increased in patients with erosive disease (P < 0.05). In addition, the frequency of IL-17+CD4- T cells positively correlated with the PDUS score, a marker for active synovitis (r = 0.49, P = 0.04). CONCLUSION: These results show, for the first time, that the PsA joint, but not the RA joint, is enriched for IL-17+CD8+ T cells. Moreover, the findings reveal that the levels of this T cell subset are correlated with disease activity measures and the radiographic erosion status after 2 years, suggesting a previously unrecognized contribution of these cells to the pathogenesis of PsA. PMID- 24470328 TI - Brief report: etanercept inhibits the tumor necrosis factor alpha-driven shift of Th17 lymphocytes toward a nonclassic Th1 phenotype in juvenile idiopathic arthritis. AB - OBJECTIVE: To evaluate the effects of etanercept on the phenotype of CD4+ T helper lymphocytes from patients with juvenile idiopathic arthritis (JIA). METHODS: We compared the proportions of various Th cell subsets in peripheral blood (PB) from etanercept-treated and untreated JIA patients. An in vitro study was performed on PB mononuclear cells (PBMCs) from 15 children with untreated JIA, in which we evaluated the proliferative response of these cells, as well as their cytokine production profile, in the presence of various stimuli with or without etanercept. RESULTS: We found lower proportions of CD4+ CD161+ (nonclassic) Th1 lymphocytes in the PB of patients treated with etanercept than in untreated patients. In vitro, etanercept inhibited the proliferative response induced by either polyclonal or recall antigen stimulation of PBMCs. Moreover, etanercept increased the proportion of CD4+CD161+ Th17/Th1 and Th17 cells in vitro while decreasing the proportions of nonclassic Th1 cell subsets, leaving CD4+CD161- (classic) Th1 cells unaffected. We also found that tumor necrosis factor alpha (TNFalpha) was able to induce transition of Th17 lymphocytes toward the nonclassic Th1 phenotype in vitro, probably due to the high expression of TNF receptor type II observed in Th17 cells. CONCLUSION: We have previously demonstrated the occurrence of a shifting of CD4+CD161+ Th17 cells to the nonclassic Th1 phenotype in children with JIA. The present findings suggest that etanercept can exert its disease-modifying action by interfering with this shifting. PMID- 24470329 TI - Phase I/II adaptive design for drug combination oncology trials. AB - Existing statistical methodology on dose finding for combination chemotherapies has focused on toxicity considerations alone in finding a maximum tolerated dose combination to recommend for further testing of efficacy in a phase II setting. Recently, there has been increasing interest in integrating phase I and phase II trials in order to facilitate drug development. In this article, we propose a new adaptive phase I/II method for dual-agent combinations that takes into account both toxicity and efficacy after each cohort inclusion. The primary objective, both within and at the conclusion of the trial, becomes finding a single dose combination with an acceptable level of toxicity that maximizes efficacious response. We assume that there exist monotone dose-toxicity and dose-efficacy relationships among doses of one agent when the dose of other agent is fixed. We perform extensive simulation studies that demonstrate the operating characteristics of our proposed approach, and we compare simulated results to existing methodology in phase I/II design for combinations of agents. PMID- 24470330 TI - Development of an automated dual-mode supercritical fluid chromatography and reversed-phase liquid chromatography mass-directed purification system for small molecule drug discovery. AB - We report the development of a dual-mode mass-directed supercritical fluid chromatography and reversed-phase liquid chromatography purification system. The addition of a third pump allows for flexible mobile phase control between the two techniques, and enables operation of either chromatography mode within minutes by activation of a set of switching valves on a single system. Software control, fluidic pathways, interface to the mass spectrometer, and fraction collection have been modified for compatibility between both separation methods. The conditioning solvent and tuning parameters for the mass spectrometer were adjusted to achieve an ideal signal trace in either mode with good linearity (r(2) > 0.970) over a range of concentrations and minimal noise for accurate peak detection and isolation. The registration success rate is 90% and overall sample recovery for either technique is 80-90%. Combining two orthogonal separation and purification modes in one single system has improved the purification throughput of complex mixtures and has been a valuable, cost-saving tool in our laboratory. PMID- 24470332 TI - Perioperative survival of elderly head and neck squamous cell carcinoma patients. AB - OBJECTIVES/HYPOTHESIS: To evaluate the survival benefit of surgery for elderly head and neck cancer (HNC) patients. STUDY DESIGN: Retrospective national database cohort study of HNC patients. METHODS: The study is a retrospective cohort review of the Surveillance, Epidemiology, and End-Results (SEER) database from 2004 to 2009. We developed an estimated perioperative window, based on the institutional database at a tertiary academic center. The average time to surgery among HNC patients at this center correlated with SEER's 3-month post diagnosis. From this estimate, we calculated postoperative (3 months), 2-year, and 5-year overall survival (OS) for patients receiving HNC surgery from 2004 to 2009 in the SEER database. Patients were matched for sex, tumor grade/stage, primary location, and radiation treatment status. RESULTS: Overall, after matching we found a statistically significant decrease in 3-month OS for the elderly patients versus younger controls who received surgery (P < .05). However, a matched analysis of elderly patients alone found a significant increase in OS for elderly patients who received surgery compared to those who did not (P < .05). CONCLUSIONS: Surgery appears to offer overall benefit to elderly HNC patients. These patients have a significantly worse postoperative OS than their younger counterparts, but the clinical significance appears to be limited. The improved survival among elderly patients who receive surgery compared to those who do not suggests that surgery should be offered to properly selected patients regardless of age. PMID- 24470331 TI - Structural basis of microtubule stabilization by laulimalide and peloruside A. AB - Laulimalide and peloruside A are microtubule-stabilizing agents (MSAs), the mechanism of action on microtubules of which is poorly defined. Here, using X-ray crystallography it is shown that laulimalide and peloruside A bind to a unique non-taxane site on beta-tubulin and use their respective macrolide core structures to interact with a second tubulin dimer across protofilaments. At the same time, they allosterically stabilize the taxane-site M-loop that establishes lateral tubulin contacts in microtubules. Structures of ternary complexes of tubulin with laulimalide/peloruside A and epothilone A are also solved, and a crosstalk between the laulimalide/peloruside and taxane sites via the M-loop of beta-tubulin is found. Together, the data define the mechanism of action of laulimalide and peloruside A on tubulin and microtubules. The data further provide a structural framework for understanding the synergy observed between two classes of MSAs in tubulin assembly and the inhibition of cancer cell growth. PMID- 24470333 TI - Block copolymer morphology formation on topographically complex surfaces: a self consistent field theoretical study. AB - A self-consistent field theoretic study is performed to study morphological development of lamellae-forming diblock copolymers on substrates with a well defined roughness, modeled as trenches of varying depth and width engraved into the substrates. There are three possible lamellar orientations observed: horizontal lamellae, vertical lamellae that are parallel to the trench direction, and vertical lamellae that are perpendicular to the trench direction. Which of these three morphologies formed depends upon the trench width and surface affinity; however, trench depth has a relatively insignificant effect on the morphological development. Therefore, tuning trench width, but not trench depth, should allow for a reduction of the morphological defect density in directed self assembly of lamellar morphology of diblock copolymers. PMID- 24470335 TI - Mapping orphan proteases by proteomics: meprin metalloproteases deciphered as potential therapeutic targets. AB - The protease web is a synonym for highly regulated molecular networks comprising enzymes, substrates, inhibitors, and other regulatory proteins. Latest high throughput methods provided huge data sets, revealing an amazing complexity of proteolytic systems important for health and disease. Based on our previous studies, we discuss major problems and questions that have to be solved to gain precise insight into the regulation of the protease web and its impact on pathophysiological conditions. The goal is a combination of different proteomic approaches that help to investigate specific protease function at a glance. Exemplarily, the characterization of the metalloproteases meprin alpha and meprin beta by proteomic identification of cleavage sites and terminal amine isotopic labeling of substrates demonstrates the power of MS-based techniques. Meprins are rather orphan proteases and could not be assigned to precise biological functions until recently. Proteomics helped to identify meprin alpha and meprin beta being important for collagen assembly and deposition in skin, which makes them potential therapeutic targets in fibrotic conditions. Additionally, identification of the cleavage site specificity provides the basis for the development of activity-based probes and small compound inhibitors, important for the regulation of meprin activity and subsequent treatment of associated diseases. PMID- 24470334 TI - TBX2 blocks myogenesis and promotes proliferation in rhabdomyosarcoma cells. AB - Rhabdomyosarcomas (RMSs) are the most frequent soft tissue sarcomas in children that share many features of developing skeletal muscle. We have discovered that a T-box family member, TBX2, is highly upregulated in tumor cells of both major RMS subtypes. TBX2 is a repressor that is often overexpressed in cancer cells and is thought to function in bypassing cell growth control, including repression of p14 and p21. The cell cycle regulator p21 is required for the terminal differentiation of skeletal muscle cells and is silenced in RMS cells. We have found that TBX2 interacts with the myogenic regulatory factors MyoD and myogenin and inhibits the activity of these factors. TBX2 is expressed in primary myoblasts and C2C12 cells, but is strongly downregulated upon differentiation. TBX2 recruits the histone deacetylase HDAC1 and is a potent inhibitor of the expression of muscle-specific genes and the cell cycle regulators, p21 and p14. TBX2 promotes the proliferation of RMS cells and either depletions of TBX2 or dominant negative TBX2 upregulate p21- and muscle-specific genes. Significantly, depletion or interference with TBX2 completely inhibits tumor growth in a xenograft assay, highlighting the oncogenic role of TBX2 in RMS cells. Thus, the data demonstrate that elevated expression of TBX2 contributes to the pathology of RMS cells by promoting proliferation and repressing differentiation-specific gene expression. These results show that deregulated TBX2 serves as an oncogene in RMS, suggesting that TBX2 may serve as a new diagnostic marker or therapeutic target for RMS tumors. PMID- 24470336 TI - Do preprocessing algorithms and statistical models influence voxel-based morphometry (VBM) results in amyotrophic lateral sclerosis patients? A systematic comparison of popular VBM analytical methods. AB - PURPOSE: To study whether inconsistent findings in voxel-based morphometry (VBM) in amyotrophic lateral sclerosis (ALS) brain are due to use of different data preprocessing and statistical methods in two software packages. MATERIALS AND METHODS: T1-weighted magnetic resonance imaging (MRI) was obtained during routine clinical imaging at 1.5T in ALS patients with frontotemporal dementia (ALS-FTD) (n=18) and in unaffected neurologic controls (n=15). Gray matter (GM) VBM analysis was carried out using FMRIB software library (FSL) 4.1.5 and statistical parametric mapping 8 (SPM8). Comparison of processing steps segmentation, registration, and statistical methods (nonparametric vs. parametric) between the two softwares was performed by subjecting the same dataset through standard VBM processing pipelines. RESULTS: GM volume was significantly (P<0.05) reduced in motor and extramotor regions of ALS-FTD when compared to controls. Percentage of atrophied GM voxels in the entire brain that reached statistical significance using FSL was 22.52% compared to 0.81% in SPM. Similarly, 0.81% (3308 voxels) reached statistical significance using nonparametric statistics when compared to parametric statistics (0.50%, 2056 voxels). CONCLUSION: The differences in GM volume atrophy measures found by FSL and SPM analytic methods indicate that variable results in previous VBM studies may arise from differences in their image processing algorithms and statistical models. PMID- 24470337 TI - A rapid procedure to isolate isotopically labeled peptides for NMR studies: application to the Disabled-2 sulfatide-binding motif. AB - A procedure for obtaining isotopically labeled peptides, by combining affinity chromatography, urea-equilibrated gel filtration, and hydrophobic chromatography procedures, is presented using the Disabled-2 (Dab2) sulfatide-binding motif (SBM) as a proof of concept. The protocol is designed to isolate unstructured, membrane-binding, recombinant peptides that co-purify with bacterial proteins (e.g., chaperones). Dab2 SBM is overexpressed in bacteria as an isotopically labeled glutathione S-transferase (GST) fusion protein using minimal media containing [15N] ammonium chloride as the nitrogen source. The fusion protein is purified using glutathione beads, and Dab2 SBM is released from GST using a specific protease. It is then dried, resuspended in urea to release the bound bacterial protein, and subjected to urea-equilibrated gel filtration. Urea and buffer reagents are removed using an octadecyl column. The peptide is eluted with acetonitrile, dried, and stored at -80 degrees C. Purification of Dab2 SBM can be accomplished in 6 days with a yield of ~2 mg/l of culture. The properties of Dab2 SBM can be studied in the presence of detergents using NMR spectroscopy. Although this method also allows for the purification of unlabeled peptides that co-purify with bacterial proteins, the procedure is more relevant to isotopically labeled peptides, thus alleviating the cost of peptide production. PMID- 24470338 TI - Evaluation of limiting factors affecting photovoltaic performance of low temperature-processed TiO2 films in dye-sensitized solar cells. AB - Limiting factors affecting photovoltaic performance of dye-sensitized solar cell employing low-temperature-processed TiO2 films were investigated. TiO2 films were prepared at a low temperature of 200 degrees C using the normal alcohol containing binder-free TiO2 paste (LT200). Their photovoltaic performance was compared to a high-temperature (550 degrees C) annealed TiO2 film prepared using a polymer binder containing TiO2 paste (HT550). Compared to the proportional increase in conversion efficiency with TiO2 film thickness upto 14 MUm for HT550, the increase in efficiency was terminated at relatively smaller thickness of about 8 MUm for LT200 mainly due to unaugmented photocurrent. From the transient photocurrent-voltage studies, the electron transport rate was found to be almost identical, while charge recombination was one order of magnitude faster for LT200. Consequently, the electron diffusion length was more than 2-3 times shorter for LT200 than for HT550. Electron diffusion length and electron life time obtained from electrochemical impedance analysis were well consistent with those observed from transient measurement. Density of states (DOS) was evaluated to be shallow and narrow in LT200, which was responsible for limiting photovoltaic performance in the low-temperature processed TiO2 film. PMID- 24470339 TI - Association between self-reported urinary incontinence and musculoskeletal conditions in community-dwelling elderly women: a cross-sectional study. AB - AIMS: Urinary incontinence (UI) and musculoskeletal conditions, particularly low back pain (LBP), and osteoarthritis (OA), are common problems that have been associated with mobility limitations and future dependence in activities of daily living in the elderly. The purpose of this study was to explore the relationship between UI, UI types, and musculoskeletal conditions in elderly community dwelling women. METHODS: A cross-sectional study was performed on 1,399 community dwelling Japanese women aged 75-84 years. Face-to-face interviews, body composition, and physical function, including grip strength, and usual walking speed, were conducted. UI was defined as experience of urine leakage episodes more than once per week. Self-reported presence and degree of pain, LBP, and OA were assessed. Student's t-tests and chi-square tests were used to analyze continuous and categorical variables. Associations between selected variables, UI, and UI types were assessed using stepwise multiple logistic regression models. RESULTS: A total of 260 participants had UI (18.6%) and 399 had LBP (28.5%). Participants with UI were more likely to experience pain (76.0%) and LBP (36.2%) than those without UI (P < 0.001 and P = 0.002, respectively). Age, body mass index, falls, walking speed, grip strength, LBP, and pain coupled with OA were significantly associated with UI. There were significant associations between urge UI and mild (odds ratio (OR) = 1.653, 95% confidence interval (CI) = 1.031-2.650) and severe LBP (OR = 2.617, 95% CI = 1.193-5.739). CONCLUSIONS: This study showed that UI was significantly associated with musculoskeletal conditions, including LBP, and the combination of pain and OA. The risk of urge UI was greater with increasing severity of LBP. PMID- 24470340 TI - Antibody-mediated rejection in liver transplantation: current controversies and future directions. AB - Interest in the role of donor-specific human leukocyte antibodies in liver transplantation has been rekindled recently. Emerging evidence suggests that these antibodies may cause injury to the liver allograft. Here we review the clinical literature, highlight controversial results, and propose a path forward for the definition and better understanding of antibody-mediated injury to the liver. PMID- 24470341 TI - Accelerated repair of demyelinated CNS lesions in the absence of non-muscle myosin IIB. AB - The oligodendrocyte (OL), the myelinating cell of the central nervous system, undergoes dramatic changes in the organization of its cytoskeleton as it differentiates from a precursor (oligodendrocyte precursor cells) to a myelin forming cell. These changes include an increase in its branching cell processes, a phenomenon necessary for OL to myelinate multiple axon segments. We have previously shown that levels and activity of non-muscle myosin II (NMII), a regulator of cytoskeletal contractility, decrease as a function of differentiation and that inhibition of NMII increases branching and myelination of OL in coculture with neurons. We have also found that mixed glial cell cultures derived from NMIIB knockout mice display an increase in mature myelin basic protein-expressing OL compared with wild-type cultures. We have now extended our studies to investigate the role of NMIIB ablation on myelin repair following focal demyelination by lysolecithin. To this end, we generated an oligodendrocyte-specific inducible knockout model using a Plp-driven promoter in combination with a temporally activated CRE-ER fusion protein. Our data indicate that conditional ablation of NMII in adult mouse brain, expedites lesion resolution and remyelination by Plp+ oligodendrocyte-lineage cells when compared with that observed in control brains. Taken together, these data validate the function of NMII as that of a negative regulator of OL myelination in vivo and provide a novel target for promoting myelin repair in conditions such as multiple sclerosis. PMID- 24470342 TI - Effect of trimetazidine on recurrent angina pectoris and left ventricular structure in elderly multivessel coronary heart disease patients with diabetes mellitus after drug-eluting stent implantation: a single-centre, prospective, randomized, double-blind study at 2-year follow-up. AB - BACKGROUND AND OBJECTIVE: Trimetazidine has been shown to improve angina pectoris and left ventricular (LV) function in diabetic patients with ischaemic cardiomyopathy. The objective of this study was to evaluate the effects of trimetazidine on recurrent angina pectoris and LV structure after drug-eluting stent (DES) implantation in elderly multivessel coronary heart disease (CHD) patients with diabetes mellitus (DM) and a left ventricular ejection fraction (LVEF) of >= 50 %. METHODS: This was a single-centre, prospective, randomized, double-blind evaluation study. Between January 2010 and September 2010, 700 CHD patients with DM who were aged >= 65 years and undergoing coronary angiography at An Zhen Hospital (Beijing, China) were recruited and prospectively randomized to receive trimetazidine (20 mg three times daily) or placebo after DES implantation as an addition to conventional CHD treatment. The primary end points were the incidence of recurrent angina pectoris and measures of various echocardiographic parameters, which included LVEF. RESULTS: At 2-year follow-up, patients in the trimetazidine group (n = 255) showed significant improvements in the incidence (P = 0.024) and severity of angina pectoris, compared with the control group, as well as silent myocardial ischaemia (P = 0.009) and angina pectoris-free survival (P = 0.011). LV function and structure in trimetazidine-treated patients were relatively stable at 2-year follow-up, while they deteriorated in the control group (n = 255) with a significant difference between groups (all P < 0.01). The E peak to A peak (E/A) ratio in trimetazidine-treated patients and in the control group decreased after 2 years; the E/A ratio in trimetazidine-treated patients was slightly better than that in the control group, without a significant difference (P = 0.170). There was no significant difference in event-free survival for the composite end point including death, myocardial infarction, cerebrovascular accident (P = 0.422) and subsequent revascularization (P = 0.073). CONCLUSION: Adjunctive therapy with trimetazidine after DES implantation can have a beneficial effect on recurrent angina pectoris as well as LV function and structure in elderly multivessel CHD patients with DM. PMID- 24470344 TI - Lifetime risk of total hip replacement surgery and temporal trends in utilization: a population-based analysis. AB - OBJECTIVE: To investigate lifetime risk of total hip replacement (THR) surgery in the state of Victoria, Australia and to describe temporal trends in THR incidence. METHODS: We analyzed a retrospective population-based longitudinal cohort of patients who received a primary THR in Victoria from 1998-2009. The factors potentially contributing to changes in lifetime risk were also examined, including temporal changes in THR incidence according to health care setting (public versus private), socioeconomic status, and geographic location (regional versus metropolitan). RESULTS: We identified 45,775 patients receiving THR over the time period. For a woman age 20-29 years, the mortality-adjusted lifetime risk rose significantly over time, from 8.49% (95% confidence interval [95% CI] 8.23-8.69%) in 1999-2000 to 10.30% (95% CI 10.07-10.49%) in 2007-2008. For a man age 20-29 years, the mortality-adjusted lifetime risk also increased significantly, from 9.29% (95% CI 8.97-9.58%) in 1999-2000 to 10.27% (95% CI 9.95 10.48%) in 2004-2005, but in contrast to the pattern observed for women, it decreased slightly in 2007-2008 (9.90% [95% CI 9.60-10.16%]). We also identified an increasing number of THRs in private hospitals, in people in middle and low socioeconomic groups, and in rural areas. CONCLUSION: The lifetime risk of THR for women was similar to men, despite a higher burden of hip osteoarthritis, and this warrants further investigation. However, increases in the number of THR procedures performed for patients in regional areas and in lower socioeconomic groups suggest some reductions over time in known disparities. PMID- 24470343 TI - Transcriptional mechanisms of cell fate decisions revealed by single cell expression profiling. AB - Transcriptional networks regulate cell fate decisions, which occur at the level of individual cells. However, much of what we know about their structure and function comes from studies averaging measurements over large populations of cells, many of which are functionally heterogeneous. Such studies conceal the variability between cells and so prevent us from determining the nature of heterogeneity at the molecular level. In recent years, many protocols and platforms have been developed that allow the high throughput analysis of gene expression in single cells, opening the door to a new era of biology. Here, we discuss the need for single cell gene expression analysis to gain deeper insights into the transcriptional control of cell fate decisions, and consider the insights it has provided so far into transcriptional regulatory networks in development. PMID- 24470345 TI - Reply: To PMID 23925905. PMID- 24470346 TI - Human secreted stabilin-1-interacting chitinase-like protein aggravates the inflammation associated with rheumatoid arthritis and is a potential macrophage inflammatory regulator in rodents. AB - OBJECTIVE: To study the relationship between the human secreted protein stabilin 1-interacting chitinase-like protein (SI-CLP) and rheumatoid arthritis (RA). METHODS: The expression of SI-CLP in peripheral blood mononuclear cells (PBMCs) and synovial fluid from patients with RA and the effects of cytokines on SI-CLP expression were examined by Western blotting. Fluorescence-activated cell sorting analysis was performed to investigate the binding between SI-CLP and cells. Bone marrow-derived macrophages were isolated from wild-type and SI-CLP(-/-) mice, and real-time quantitative polymerase chain reaction was performed to detect the levels of messenger RNA for cytokines or SI-CLP in SI-CLP- or cytokine-treated macrophages. Histologic studies were conducted to evaluate inflammation and the expression of interleukin-12 (IL-12), IL-13, and SI-CLP in lesions. Enzyme-linked immunosorbent assays were used to detect the cytokine levels in bone marrow derived macrophages. Rats or mice with collagen-induced arthritis (CIA) and SI CLP(-/-) mice were used to study the function of SI-CLP in RA. RESULTS: SI-CLP expression was increased in PBMCs and detectable in synovial fluid from patients with RA. Administration of SI-CLP to rats with CIA aggravated arthritis associated inflammation. SI-CLP was specifically attached to the surface protein of macrophages, which elevated the expression of IL-1beta, IL-6, IL-12, and IL-13 in macrophages and mouse bone marrow-derived macrophages, up-regulating ERK phosphorylation. Moreover, SI-CLP was up-regulated by both IL-12 and IL-13 through JNK and JAK/STAT signaling, respectively. Knockout of SI-CLP resulted in a decrease in the expression of IL-1beta, IL-6, IL-12, and IL-13 and lower susceptibility to CIA compared with wild-type mice. SI-CLP treatment also aggravated arthritis-related inflammation in wild-type and SI-CLP(-/-) mice. CONCLUSION: SI-CLP functions as a regulator of the inflammatory response by macrophages. The decrease in inflammation-associated cytokine levels resulting from SI-CLP knockout may explain the lower susceptibility to CIA in SI-CLP(-/-) mice. PMID- 24470347 TI - Identification and characterization of the process-related impurities in fasudil hydrochloride by hyphenated techniques using a quality by design approach. AB - Following the underlying principles of quality by design mentioned in the ICH Q8 guidance, systematic approaches for the control of process-related impurities have been taken in the manufacturing process of fasudil hydrochloride, a potent Rho-kinase inhibitor and vasodilator. Three related impurities were found in fasudil hydrochloride lab samples by a newly developed RP-HPLC with volatile mobile phase gradient elution and UV detection method. The elemental compositions of the impurities were determined by positive ESI high-resolution TOF-MS analysis of their [M + H](+) ions and their structures were identified through the elucidation of the product mass spectra obtained by a triple quadrupole mass spectrometer. The key impurity was further verified through synthesis and organic spectroscopy including NMR and IR spectroscopy. The origins of these impurities were located and the effective approaches to eliminate them were proposed based on the redesign of the synthetic conditions. The results obtained are important for quality control in the manufacture of fasudil hydrochloride bulk drug substance and injection. PMID- 24470348 TI - Piceatannol exhibits selective toxicity to multiple myeloma cells and influences the Wnt/ beta-catenin pathway. AB - Aberrant activation of Wnt/beta-catenin signaling promotes development and progression of various malignant neoplasms. Recent studies observed that the Wnt pathway is constitutively active in myeloma cells and promotes an exaggerated proliferation. Thus, the Wnt signaling pathway might be an attractive therapeutic target for multiple myeloma. In this study, we identified piceatannol as an inhibitor of the Wnt/beta-catenin pathway and as a potent inducer of apoptosis in myeloma cells. Interestingly, healthy cells remained mainly unaffected. These results reveal a significant selective induction of apoptosis by piceatannol and suggest a significant in vivo effect against multiple myeloma. PMID- 24470349 TI - Reproducibility of MRI renal artery blood flow and BOLD measurements in patients with chronic kidney disease and healthy controls. AB - PURPOSE: Determine the reproducibility of renal artery blood flow (RABF) and blood-oxygenation level dependent (R2 *) in patients with chronic kidney disease (CKD) and healthy controls. MATERIALS AND METHODS: RABF and R2 * were measured in 11 CKD patients and 9 controls twice with 1- to 2-week interval. R2 * in the cortex and medulla were determined after breathing atmospheric air and 100% oxygen. Reproducibility was evaluated by coefficients of variation (CV), limits of agreements and intra-class coefficient calculated by variance components by maximum likelihood modeling. RESULTS: Single-kidney RABF (mL/min) for patients was: 170 +/- 130 and 186 +/- 137, and for controls: 365 +/- 119 and 361 +/- 107 (P < 0.05 versus patients), for first and second scans, respectively. RABF measurements were reproducible with a CV of 12.9% and 8.3% for patients and controls, respectively. Renal cortical R2 * was: 13.6 +/- 0.9 and 13.5 +/- 1.2 in patients (CV = 8.0%), and 13.8 +/- 1.6 and 14.0 +/- 1.5 in controls (CV = 5.6%), while medullary R2 *(s(-1) ) was: 26.9 +/- 2.0 and 27.0 +/- 4.0 (CV = 8.0%) in patients, and 26.0 +/- 2.4 and 26.1 +/- 2.1 (CV = 3.6%) in controls, for first and second scans, respectively. In both groups R2 * in medulla decreased after breathing 100% oxygen. CONCLUSION: The reproducibility was high for both RABF and R2 * in patients and controls, particularly in the cortex. Inhalation of 100% oxygen reduced medullary R2 *. PMID- 24470350 TI - A tale of two studies on auditory training in children: A response to the claim that 'discrimination training of phonemic contrasts enhances phonological processing in mainstream school children' by Moore, Rosenberg and Coleman (2005). AB - In a previous article, Moore, Rosenberg and Coleman (Brain and Language, 2005, 94, 72-85) reported evidence for significant improvements in phonological awareness in mainstream children following 6 h of exposure to a commercially available phoneme discrimination training programme, but not in a control group. In a follow-up study, we failed to replicate this finding, despite using an almost identical training programme (Halliday, Taylor, Millward, & Moore, Journal of Speech, Language, and Hearing Research, 2012, 55, 168-181). This paper directly compares the methods and the results of the two studies, in an effort to explain the discrepant findings. It reports that the trained group in Moore et al. (2005) showed significantly greater improvements in phonological awareness following training than the trained group in Halliday et al. (2012). However, the control group in Halliday et al. (2012) showed significantly greater improvements in phonological awareness than the control group in Moore et al. (2005). The paper concludes that differences in the randomization, blinding, experimenter familiarity and treatment of trained and control groups contributed to the different outcomes of the two studies. The results indicate that a plethora of factors can contribute to training effects and highlight the importance of well designed randomized controlled trials in assessing the efficacy of a given intervention. PMID- 24470351 TI - alpha-Oligofurans: an emerging class of conjugated oligomers for organic electronics. AB - While the field of organic electronics has developed extensively in recent years, it remains limited by number of materials available. Further expansion requires the innovation of new types of pi-conjugated backbones, but suitable candidates are discovered only very rarely. The recent introduction of a new class of conjugated materials, long alpha-oligofurans, was therefore greeted with considerable interest. alpha-Oligofurans possess many of the properties required to excel in applications as organic electronic materials, can be manufactured from renewable resources, and are expected to be biodegradable. This Minireview provides an account of long oligofurans from the perspectives of their synthesis, molecular properties, chemical reactivity, and use in electronic devices. PMID- 24470352 TI - Increases in insulin sensitivity among obese youth are associated with gene expression changes in whole blood. AB - OBJECTIVE: Lifestyle intervention can improve insulin sensitivity in obese youth, yet few studies have examined the molecular signatures associated with these improvements. Therefore, the purpose of this study was to explore gene expression changes in whole blood that are associated with intervention-induced improvements in insulin sensitivity. METHODS: Fifteen (7M/8F) overweight/obese (BMI percentile = 96.3 +/- 1.1) Latino adolescents (15.0 +/- 0.9 years) completed a 12-week lifestyle intervention that included weekly nutrition education and 180 minutes of moderate-vigorous exercise per week. Insulin sensitivity was estimated by an oral glucose tolerance test and the Matsuda Index. Global microarray analysis profiling from whole blood was performed to examine changes in gene expression and to explore biological pathways that were significantly changed in response to the intervention. RESULTS: A total of 1,459 probes corresponding to mRNA transcripts (717 up, 742 down) were differentially expressed with a fold change >=1.2. These genes were mapped within eight significant pathways identified, including insulin signaling, type 1 diabetes, and glycerophospholipid metabolism. Participants with increased insulin sensitivity exhibited five times the number of significant genes altered compared with nonresponders (1,144 vs. 230). CONCLUSIONS: These findings suggest that molecular signatures from whole blood are associated with lifestyle-induced health improvements among high-risk Latino youth. PMID- 24470353 TI - Family functioning, marital satisfaction and social support in hemodialysis patients and their spouses. AB - A growing number of studies have demonstrated the importance of marital quality among patients undergoing medical procedures. The aim of the study was to expand the literature by examining the relationships between stress, social support and family and marriage life among hemodialysis patients. A total of 114 participants, including 38 patients and their spouses and 38 healthy controls, completed a survey package assessing social support, stress, family functioning and marital satisfaction and quality. We found that hemodialysis patients and spouses were less flexible in family adaptability compared with the healthy controls. Patients and spouses had more stress and instrumental social support compared with healthy people. Stress was negatively associated with marital satisfaction. Instrumental support was not associated with family or marital outcomes. The association between marital quality and support outside of family was positive in healthy individuals but was negative in patients and their spouses. Family adaptability was positively associated with support within family as perceived by patients and positively associated with emotional support as perceived by spouses. In conclusion, findings suggest that social support may promote adjustment depending on the source and type. Future research should pay more attention to the types and sources of social support in studying married couples. PMID- 24470354 TI - Understanding preferences for disease-modifying drugs in osteoarthritis. AB - OBJECTIVE: Numerous disease-modifying drugs for osteoarthritis (DMOADs) are under investigation. However, patients' preferences for drugs to prevent progression of OA are not known. The objective of this study was to quantify patient preferences for potential DMOADs. METHODS: We administered a conjoint analysis survey to 304 patients attending outpatient general medicine and specialty clinics. All patients seated in the waiting rooms were asked if they would participate in a survey to elicit opinions about arthritis treatments. We performed simulations to estimate preferences for 4 options to prevent worsening of knee OA: best case (pill, highest benefit, lowest risk, lowest cost), worst case (infusion, lowest benefit, highest risk, highest cost), moderate subcutaneous injection (injection, mid-level benefit, mid-level risk, mid-level cost), and moderate infusion (same as subcutaneous injection except administered by infusion). RESULTS: Subjects' median age was 57 years; 55% were women and 76% were white. Segmentation analyses revealed 4 patterns of preferences. A minority (5%) did not want to perform subcutaneous injections and would only consider DMOADs under the best-case scenario. Approximately 20% were risk sensitive and were willing to take DMOADs under the best-case scenario, but would start rejecting these medications as risk increased. A significant number rejected DMOADs under all conditions (16.4%); however, the largest segment (59.2%) had a strong preference for DMOADs across all scenarios. CONCLUSION: Our results suggest that a significant percentage of a nonselected outpatient population might be willing to accept at least a moderate degree of risk in order to prevent worsening knee OA. PMID- 24470355 TI - Synthesis and characterization of poly(phenylacetylene)s with Ru(II) bis terpyridine complexes in the side-chain. AB - An alkyne-functionalized ruthenium(II) bis-terpyridine complex is directly copolymerized with phenylacetylene by alkyne polymerization. The polymer is characterized by size-exclusion chromatography (SEC), (1) H NMR spectroscopy, cyclic voltammetry (CV) measurements, and thermal analysis. The photophysical properties of the polymer are studied by UV-vis absorption spectroscopy. In addition, spectro-electrochemical measurements are carried out. Time-resolved luminescence lifetime decay curves show an enhanced lifetime of the metal complex attached to the conjugated polymer backbone compared with the Ru(tpy)2 (2+) model complex. PMID- 24470356 TI - P2X7-dependent, but differentially regulated release of IL-6, CCL2, and TNF-alpha in cultured mouse microglia. AB - ATP is an important regulator of microglia and its effects on microglial cytokine release are currently discussed as important contributors in a variety of brain diseases. We here analyzed the effects of ATP on the production of six inflammatory mediators (IL-6, IL-10, CCL2, IFN-gamma, TNF-alpha, and IL-12p70) in cultured mouse primary microglia. Stimulation of P2X7 receptor by ATP (1 mM) or BzATP (500 uM) evoked the mRNA expression and release of proinflammatory cytokines IL-6, TNF-alpha, and the chemokine CCL2 in WT cells but not in P2X7(-/ ) cells. The effects of ATP and BzATP were inhibited by the nonselective P2 receptor antagonists PPADs and suramin. Various selective P2X7 receptor antagonists blocked the P2X7-dependent release of IL-6 and CCL2, but, surprisingly, had no effect on BzATP-induced release of TNF-alpha in microglia. Calcium measurements confirmed that P2X7 is the main purine receptor activated by BzATP in microglia and showed that all P2X7 antagonists were functional. It is also presented that pannexin-1 hemichannel function and potential P2X4/P2X7 heterodimers are not involved in P2X7-dependent release of IL-6, CCL2, and TNF alpha in microglia. How P2X7-specific antagonists only affect P2X7-dependent IL-6 and CCL2 release, but not TNF-alpha release is at the moment unclear, but indicates that the P2X7-dependent release of cytokines in microglia is differentially regulated. PMID- 24470358 TI - Violent female youth: an examination of instrumental violence, psychopathy, and offense characteristics. AB - Female youth are a strikingly under-studied population within the accumulated forensic literature, yet they represent a significant and growing population within forensic contexts. Despite research demonstrating a relationship between the presence of psychopathic traits and instrumental violence among adult offenders, researchers have only recently begun to examine this relationship among juvenile offenders. Our investigation of this potential relationship among a large sample of female offenders (N = 145) who had committed a violent offense revealed that youths with more psychopathic traits were not significantly more likely to use instrumental violence in the commission of their crimes than those with less psychopathic traits. The findings are discussed in terms of offense severity, and a comprehensive overview of female youths' specific motivations and offense characteristics are provided. Research directions and clinical implications are discussed. PMID- 24470357 TI - Cyclin-dependent kinase 9 inhibition protects cartilage from the catabolic effects of proinflammatory cytokines. AB - OBJECTIVE: Cyclin-dependent kinase 9 (CDK-9) controls the activation of primary inflammatory response genes. The purpose of this study was to determine whether CDK-9 inhibition protects cartilage from the catabolic effects of proinflammatory cytokines. METHODS: Human chondrocytes were challenged with different proinflammatory stimuli (interleukin-1beta [IL-1beta], lipopolysaccharides, and tumor necrosis factor alpha) in the presence or absence of either the CDK-9 inhibitor flavopiridol or small interfering RNA (siRNA). The expression of messenger RNA (mRNA) for inflammatory mediator genes, catabolic genes, and anabolic genes were determined by real-time quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis. Cartilage explants were incubated for 6 days with IL-1beta in the presence or absence of flavopiridol. Cartilage matrix degradation was assessed by the release of glycosaminoglycan (GAG) and cleaved type II collagen (COL2A) peptides. RESULTS: CDK-9 inhibition by flavopiridol or knockdown by siRNA effectively suppressed the induction of mRNA for inducible nitric oxide synthase by all 3 proinflammatory stimuli. Results from NF-kappaB-targeted PCR array analysis showed that flavopiridol suppressed IL 1beta induction of a broad range of inflammatory mediator genes (59 of 67 tested). CDK-9 inhibition also suppressed the induction of catabolic genes (matrix metalloproteinase 1 [MMP-1], MMP-3, MMP-9, MMP-13, ADAMTS-4, and ADAMTS 5), but did not affect the basal expression of anabolic genes (COL2A, aggrecan, and cartilage oligomeric matrix protein) and housekeeping genes. Flavopiridol had no apparent short-term cytotoxicity, as assessed by G6PDH activity. Finally, in IL-1beta-treated cartilage explants, flavopiridol reduced the release of the matrix degradation product GAG and cleaved COL2A peptides, but did not affect long-term chondrocyte viability. CONCLUSION: CDK-9 activity is required for the primary inflammatory response in chondrocytes. Flavopiridol suppresses the induction of inflammatory mediator genes and catabolic genes to protect cartilage from the deleterious effects of proinflammatory cytokines, without affecting cell viability and functions. PMID- 24470359 TI - Burden of diabetic foot disorders, guidelines for management and disparities in implementation in Europe: a systematic literature review. AB - The study aimed to assess the economic and quality of life burden of diabetic foot disorders and to identify disparities in the recommendations from guidelines and the current clinical practice across the EU5 (Spain, Italy, France, UK and Germany) countries. Literature search of electronic databases (MEDLINE(r), Embase(r) and Cochrane Database of Systematic Reviews) was undertaken. English language studies investigating economic and resource burden, quality of life and management of diabetic foot disease in the EU5 countries were included. Additionally, websites were screened for guidelines and current management practices in diabetic foot complication in EU5. Diabetic foot complications accounted for a total annual cost of ?509m in the UK and ?430 per diabetic patient in Germany, during 2001. The cost of diabetic foot complications increased with disease severity, with hospitalizations (41%) and amputation (9%) incurring 50% of the cost. Medical devices (orthopaedic shoes, shoe lifts and walking aids) were the most frequently utilized resources. Patients with diabetic foot complications experienced worsened quality of life, especially in those undergoing amputations and with non-healed ulcers or recurrent ulcers. Although guidelines advocate the use of multidisciplinary foot care teams, the utilization of multidisciplinary foot care teams was suboptimal. We conclude that diabetic foot disorders demonstrated substantial economic burden and have detrimental effect on quality of life, with more impairment in physical domain. Implementation of the guidelines and set-up of multidisciplinary clinics for holistic management of the diabetic foot disorders varies across Europe and remains suboptimal. Hence, guidelines need to be reinforced to prevent diabetic foot complications and to achieve limb salvage if complications are unpreventable. PMID- 24470360 TI - Associations between tumor vascularization assessed by in vivo DCE-MRI and the presence of disseminated tumor cells in bone marrow in breast cancer patients at the time of diagnosis. AB - PURPOSE: To explore possible associations between in vivo pharmacokinetic dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters and the presence of disseminated tumor cells (DTCs) in bone marrow in breast cancer patients at the time of diagnosis. MATERIALS AND METHODS: Thirty-seven women with breast cancer (stage T2-4N0-1M0) were included. Patients were classified as DTC+ if one or more DTCs were detected by immunocytochemistry. DCE-MRI was acquired with a radial 3D T1 -weighted spoiled gradient echo sequence with k-space weighted image contrast. K(trans), kep, and ve were calculated using the extended Tofts model and a population-derived arterial input function. The nonparametric Mann-Whitney U-test was used to compare the histogram distributions of the pharmacokinetic parameters for the DTC+ and the DTC- patients. RESULTS: DTCs were detected in 7 of the 37 patients (19%). In DTC+ patients, the distribution of tumor K(trans) and kep were significantly (P < 0.01) more shifted towards lower values than in DTC- patients. CONCLUSION: An association between vascular dependent pharmacokinetic DCE-MRI parameters and the presence of DTCs were found. Compared to DTC- patients, DTC+ patients had poorer perfusion and permeability, indicative of hypoxia. Thus, pharmacokinetic parameters might be surrogate biomarkers of metastatic potential and future relapse. PMID- 24470361 TI - Targeted delivery to cartilage is critical for in vivo efficacy of insulin-like growth factor 1 in a rat model of osteoarthritis. AB - OBJECTIVE: Acute articular injuries lead to an increased risk of progressive joint damage and osteoarthritis (OA), and no therapies are currently available to repair or protect the injured joint tissue. Intraarticular delivery of therapeutic proteins has been limited by their rapid clearance from the joint space and lack of retention within cartilage. The aim of this study was to test whether targeted delivery to cartilage by fusion with a heparin-binding domain would be sufficient to prolong the in vivo function of the insulin-like growth factor 1 (IGF-1). METHODS: We produced a humanized and optimized recombinant HB IGF-1 fusion protein. By injecting HB-IGF-1, IGF-1, or saline alone into the knee joints of adult Lewis rats, we tested whether fusion with a heparin-binding domain 1) altered the kinetics of retention in joint tissues, 2) prolonged functional stimulation as measured by radiolabel incorporation, and 3) enhanced efficacy in a rat model of surgically induced OA, using weekly injections. RESULTS: Fusion of heparin-binding domain with IGF-1 prolonged retention in articular and meniscal cartilage from <1 day to 8 days after injection. Unmodified IGF-1 had no functional effect 2 days after injection, whereas HB-IGF 1 stimulated meniscal cartilage at least 4 days after injection. HB-IGF-1, but not IGF-1, significantly slowed cartilage damage in a rat model of OA. CONCLUSION: Heparin-binding domain fusions can transform rapidly cleared proteins into potential intraarticular therapies by targeting them to cartilage. PMID- 24470362 TI - Mortality, integrity, and psychoanalysis (who are you to me? Who am I to you?). AB - The author narrates her experience of mourning her therapist's sudden death. The profession has neglected implications of the analyst's mortality: what is lost or vulnerable to loss? What is that vulnerability's function? The author's process of mourning included her writing and her becoming an analyst. Both pursuits inspired reflections on mortality in two overlapping senses: bodily (the analyst is mortal and can die) and character (the analyst is mortal and can err). The subject thus expands to include impaired character and ethical violations. Paradoxically, the analyst's human limitations threaten each psychoanalytic situation, but also enable it: human imperfection animates the work. The essay ends with a specific example of integrity. PMID- 24470363 TI - Problems of internalization: a button is a button is-not. AB - Analysts hope to help the patient internalize a relationship with the analyst that contrasts with the original archaic object relation. In this paper, the author describes particular difficulties in working with a patient whose defenses and anxieties were bulimic, her movement toward internalization inevitably undone. Several issues are considered: how does the nonsymbolizing patient come to internalize the analyst's understanding, and when this does not hold, what is the nature of the patient's subsequent methods of dispersal? When the patient can maintain connection to the analyst as a good object, even fleetingly, in the depressive position, the possibility of internalization and symbolic communication is increased. PMID- 24470364 TI - Some reflections on Ian McEwan's atonement: enactment, guilt, and reparation. AB - Recognizing that enactments have been discussed in psychoanalysis primarily as occurrences in the treatment setting, the author proposes a new application of the term enactments: that it may pertain to the actions of some individuals in their efforts to cope with bad things that they have done to others. That is, enactment can be a substitute-for-atonement mechanism. The author illustrates this view of enactment through a discussion of Ian McEwan's novel Atonement (2001), and in particular by examining the behavior and motivations of one of its central characters, Briony Tallis. Included are explorations of the relationships between enactment and guilt and between enactment and reparation. PMID- 24470365 TI - Emile, or on devastation: when virtual boundlessness meets inner emptiness. AB - The author's starting point is a psychoanalysis conducted with Emile, a teenager who was unable to form close relationships and was living in a virtual world, planning a school massacre. For him, virtual reality functioned as a bottomless container in which he was no longer a victim of bullying but rather a god. When the boundlessness of cyberspace encounters a "black hole" in the psyche, any fantasies can be put into virtual realization and actions. By recounting his wickedness, violence, destructiveness, and perversion, Emile could start restoring his self boundaries and create his own autobiographical narrative. Unable to sustain the pain of mourning his envelope of invulnerability and omnipotence, however, he prematurely terminated analysis. PMID- 24470366 TI - On the prescribing analyst. AB - The value of medication for some patients in psychoanalysis serves to highlight the potential challenges of the medical analyst and invites exploration into possible motivations for assuming the prescribing role. Prescribing medication is one way in which the medical analyst integrates the dual identities of physician and analyst while dealing with significant cultural influences and intrapsychic tensions. Technical challenges posed by assuming the prescribing role are explored, as are the potential benefits of split treatment. The educational implications of this argument are discussed in relation to identity formation for candidates who are physicians. PMID- 24470367 TI - Oedipus in Brooklyn: reading Freud on women, watching Lena Dunham's girls. AB - Through an examination of Freud's Lecture 33, "Femininity" (1933), and "Mourning and Melancholia" (1917), the author proposes a reading of Freud's description of the girl becoming a woman. Female development is retold as a melancholic narrative-one in which the girl's entrance into the positive Oedipus is founded on unconscious grievance and unmourned loss of the early relationship with her mother. Castration and penis envy are reconceived as melancholic markers-the manifest content of the subjectivity of refusal, loss, and imagined repair of the early maternal relationship. Lena Dunham's HBO television series Girls is analyzed as an illustration of these theoretical understandings. PMID- 24470377 TI - Simultaneous determination of ten organophosphate pesticide residues in fruits by gas chromatography coupled with magnetic separation. AB - In this study, gamma-Fe2 O3 /chitosan magnetic microspheres were synthesized and evaluated by X-ray diffraction, SEM, thermogravimetric analysis, and static and kinetic adsorption experiments. Results showed that the magnetic microspheres exhibited good adsorption ability, and offered fast kinetics for the adsorption of trichlorfon, methamidophos, malathion, methyl parathion, dimethoate, omethoate, phosphamidon, phorate, isocarbophos, and chlorpyrifos. Based on magnetic separation, a simple method of magnetic SPE coupled to GC for the simultaneous determination of ten trace organophosphate pesticide residues was developed. Under the optimal conditions, the enrichment factor for ten organophosphorus pesticides was 10.1-364.7 and linear range was 0.001-10.0 mg/L. The LOD (S/N = 3) of the method for the ten pesticides was 0.31-3.59 MUg/kg. The RSD for three replicate extractions of spiked samples was between 2.5 and 6.3%. The pear and apple samples spiked with ten organophosphate pesticides at 20 and 200 MUg/kg levels were extracted and determined by this method with good recoveries ranging from 79.9 to 98.7%. Moreover, the method has been successfully applied for the determination of the ten organophosphate pesticide residues in peach samples. PMID- 24470378 TI - Risk of hospitalized bacterial infections associated with biologic treatment among US veterans with rheumatoid arthritis. AB - OBJECTIVE: The comparative risk of infection associated with non-anti-tumor necrosis factor (anti-TNF) biologic agents is not well established. Our objective was to compare risk for hospitalized infections between anti-TNF and non-anti-TNF biologic agents in US veterans with rheumatoid arthritis (RA). METHODS: Using 1998-2011 data from the US Veterans Health Administration, we studied RA patients initiating rituximab, abatacept, or anti-TNF therapy. Exposure was based upon days supplied (injections) or usual dosing intervals (infusions). Treatment episodes were defined as new biologic agent use. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for hospitalization for a bacterial infection were estimated from Cox proportional hazards models, adjusting for potential confounders. RESULTS: Among 3,152 unique RA patients contributing 4,158 biologic treatment episodes to rituximab (n = 596), abatacept (n = 451), and anti-TNF agents (n = 3,111), the patient mean age was 60 years and 87% were male. The most common infections were pneumonia (37%), skin/soft tissue (22%), urinary tract (9%), and bacteremia/sepsis (7%). Hospitalized infection rates per 100 person years were 4.4 (95% CI 3.1-6.4) for rituximab, 2.8 (95% CI 1.7-4.7) for abatacept, and 3.0 (95% CI 2.5-3.5) for anti-TNF. Compared to etanercept, the adjusted rate of hospitalized infection was not different for adalimumab (HR 1.4, 95% CI 0.9-2.2), abatacept (HR 1.1, 95% CI 0.6-2.1), or rituximab (HR 1.4, 0.8 2.6), although it was increased for infliximab (HR 2.3, 95% CI 1.3-4.0). Infection risk was greater for those taking prednisone >7.5 mg/day (HR 1.8, 95% CI 1.3-2.7) and in the highest quartile of C-reactive protein (HR 2.3, 95% CI 1.4 3.8) and erythrocyte sedimentation rate (HR 4.1, 95% CI 2.3-7.2) compared to the lowest quartile. CONCLUSION: In older, predominantly male US veterans with RA, the risk of hospitalized bacterial infections associated with rituximab or abatacept was similar to etanercept. PMID- 24470379 TI - Identification of RANBP2-ALK fusion in ALK positive diffuse large B-cell lymphoma. PMID- 24470381 TI - An off-pathway folding intermediate of an acyl carrier protein domain coexists with the folded and unfolded states under native conditions. AB - A protein can exist in multiple states under native conditions and those states with low populations are often critical to biological function and self-assembly. To investigate the role of the minor states of an acyl carrier protein, NMR techniques were applied to determine the number of minor states and characterize their structures and kinetics. The acyl carrier protein from Micromonospora echinospora was found to exist in one major folded state (95.2%), one unfolded state (4.1%), and one intermediate state (0.7%) under native conditions. The three states are in dynamic equilibrium and the intermediate state very likely adopts a native-like structure and is an off-pathway folding product. The intermediate state may mediate the formation of oligomers in vitro and play an important role in the recognition of partner enzymes in vivo. PMID- 24470382 TI - Teens' obesity, noise and sleep deprivation: a perverse liaison. Let's move beyond "movida". PMID- 24470383 TI - Tailoring exciton dynamics by elastic strain-gradient in semiconductors. AB - In purely bent ZnO microwires, the excitons can be effectively driven and concentrated by the elastic strain-gradient towards the tensile outer side of the purely bent wire. Experimental and theoretical approaches are combined to investigate the dynamics of excitons in an inhomogeneous strain field with a uniform elastic strain-gradient. Cathodoluminescence spectroscopy analysis on purely bent ZnO microwires verifies that excitons can be effectively driven and concentrated along the elastic strain-gradient. PMID- 24470384 TI - High-dose busulfan-thiotepa with autologous stem cell transplantation followed by posterior fossa irradiation in young children with classical or incompletely resected medulloblastoma. AB - BACKGROUND: The aim of the study is to evaluate the outcome of young children with high risk localized medulloblastomas (newly diagnosed classical or incompletely resected) treated by high-dose busulfan-thiotepa with autologous stem cell rescue (ASCT) followed by focal radiation therapy (RT). PROCEDURE: Between September 1994 and January 2010, 19 children younger than 5 years old at diagnosis fulfilling the above inclusion criteria were treated at the Institute Gustave Roussy. After conventional chemotherapy, they received busulfan at a dose of 600 mg/m(2) and thiotepa at a dose of 900 mg/m(2) followed by ASCT. Focal RT was delivered at least 70 days after ASCT. RESULTS: The median follow-up was 40.5 months (range, 14.5-191.2 months). The 3-year event-free survival (EFS) and OS were 68% (95% CI 45-84%) and 84% (95% CI 61-94%), respectively. Acute toxicity consisted mainly in hepatic veno-occlusive disease (6/19 patients) and bone marrow aplasia (all patients). No toxic death occurred. The Full Scale Intellectual Quotient tended to decrease over time at a mean rate of 0.9 point per year from the date of diagnosis. CONCLUSIONS: This intensive treatment resulted in a high overall survival rate in young children with newly diagnosed non-metastatic classic or incompletely resected MB. In spite of a high incidence of hepatic veno-occlusive disease (32%), the acute toxicity was manageable. Delayed neuropsychological side effects remain main concerns. These results should to be confirmed in a larger cohort. PMID- 24470385 TI - Infection, antibiotic therapy and risk of colorectal cancer: a nationwide nested case-control study in patients with Type 2 diabetes mellitus. AB - Patients with Type 2 diabetes mellitus are at a higher risk of colorectal cancer (CRC). The objective of our study was to examine the inter-relationship among infection sites, systemic antibiotic use and risk of CRC among patients with Type 2 diabetes mellitus. From a diabetic cohort from the Taiwan's National Health Insurance claims database, we identified 3,593 incident colon cancer cases, 1,979 rectal cancer cases and 22,288 controls and conducted a nested case-control study to examine the association between antibiotic use and CRC incidence. Logistic regression models were applied to estimate the odds ratio (OR) and the 95% confidence interval (95% CI) between infection sites, antibiotic use and CRC incidence. Patients with intra-abdominal infection were significantly associated with increased risk for colon cancer (OR = 2.01, 95% CI = 1.73-2.35) and rectal cancer (OR = 1.59, 95% CI = 1.26-2.00). Any antianaerobic antibiotic use was associated with a higher risk of colon cancer (OR = 2.31, 95% CI = 2.12-2.52) and rectal cancer (OR = 1.69, 95% CI = 1.50-1.90) but without an obvious dose response relationship for cumulative use. Antianaerobic antibiotics also increased the risks for those with nonintra-abdominal infection. No association was found between antiaerobic agent use and the CRC risk. The results suggest intra-abdominal infections and antianaerobic antibiotic use may be a marker for precancerous lesions or early CRC, although the possibility of antianaerobic antibiotics playing an additional role cannot be excluded. Further research examining the relationship between intra-abdominal infection, antianaerobic antibiotics use and possible change of microbiota leading to colorectal carcinogenesis is warranted. PMID- 24470387 TI - African crop yield reductions due to increasingly unbalanced Nitrogen and Phosphorus consumption. AB - The impact of soil nutrient depletion on crop production has been known for decades, but robust assessments of the impact of increasingly unbalanced nitrogen (N) and phosphorus (P) application rates on crop production are lacking. Here, we use crop response functions based on 741 FAO maize crop trials and EPIC crop modeling across Africa to examine maize yield deficits resulting from unbalanced N : P applications under low, medium, and high input scenarios, for past (1975), current, and future N : P mass ratios of respectively, 1 : 0.29, 1 : 0.15, and 1 : 0.05. At low N inputs (10 kg ha(-1)), current yield deficits amount to 10% but will increase up to 27% under the assumed future N : P ratio, while at medium N inputs (50 kg N ha(-1)), future yield losses could amount to over 40%. The EPIC crop model was then used to simulate maize yields across Africa. The model results showed relative median future yield reductions at low N inputs of 40%, and 50% at medium and high inputs, albeit with large spatial variability. Dominant low-quality soils such as Ferralsols, which are strongly adsorbing P, and Arenosols with a low nutrient retention capacity, are associated with a strong yield decline, although Arenosols show very variable crop yield losses at low inputs. Optimal N : P ratios, i.e. those where the lowest amount of applied P produces the highest yield (given N input) where calculated with EPIC to be as low as 1 : 0.5. Finally, we estimated the additional P required given current N inputs, and given N inputs that would allow Africa to close yield gaps (ca. 70%). At current N inputs, P consumption would have to increase 2.3-fold to be optimal, and to increase 11.7-fold to close yield gaps. The P demand to overcome these yield deficits would provide a significant additional pressure on current global extraction of P resources. PMID- 24470386 TI - Brief report: alternative activation of laser-captured murine hemophagocytes. AB - OBJECTIVE: Hemophagocytes (HPCs) are activated macrophages that have engulfed other hematopoietic cells. Although HPCs are rarely identified in normal spleen tissue and bone marrow, an excess of these macrophages characterizes many cytokine storm syndromes, particularly macrophage activation syndrome and hemophagocytic lymphohistiocytosis. This study was undertaken to assess the functions of HPCs and their significance in acute inflammatory conditions. METHODS: HPCs were generated in wild-type mice using repeated stimulation with Toll-like receptor 9 (TLR-9) and interleukin-10 receptor blockade. RNA was extracted from HPCs that had been isolated by lasercaptured microdissection. Transcriptional profiles of the HPCs were then compared to those of resting splenic macrophages. In addition, bone marrow samples were obtained from a diverse cohort of patients in whom excess hemophagocytosis was identified by clinical bone marrow biopsy or aspiration. The bone marrow samples were analyzed by immunohistochemistry for markers of classic (CD64) or alternative (CD163 and CD206) macrophage activation. RESULTS: Differential gene expression and gene set enrichment analyses of murine HPCs identified upregulation of genes and gene sets associated with alternative activation of HPCs. Immunohistochemical analyses of HPCs in human bone marrow samples showed universal staining of HPCs for CD163, but rarely for CD206 or CD64. CONCLUSION: Laser-captured murine TLR-9- induced HPCs had a transcriptional profile similar to that of alternatively activated macrophages. In addition, HPC expression of CD163 was confirmed in a uniquely diverse cohort of patients with hemophagocytic syndromes. Collectively, these data support the hypothesis that HPCs have both immunoregulatory and clean-up functions. PMID- 24470388 TI - Functionalization at the central position of vinyl polymer chains: highly associable multipoint hydrogen bonds for complementary self-assemblies. AB - This paper deals with the precision introduction of a multiple hydrogen-bonding site of a high association constant at the central position of a vinyl polymer chain for complementary self-assemblies. The interactive site consists of an array of hydrogen donors (D) and acceptors (A) to induce a multiple and highly associable interaction with a complementary counterpart. A bifunctional initiator (Cl-DADDAD-Cl) for metal-catalyzed living radical polymerization is thus designed and synthesized to embed a "Hamilton receptor" (DADDAD) between two terminal chlorides (Cl). In the presence of a ruthenium complex, the dichloride gives controlled polymers (Cl~~~DADDAD~~~Cl, ~ ~ ~: polymer backbone) of narrow molecular weight distributions (Mw/Mn < 1.2) from common monomers such as styrene and methyl methacrylate (MMA). The receptor-decorated polystyrene recognizes complementary associable molecules and polymers carrying an ADADA unit (ADADA Anthracene and ADADA-PMMA) to form self-assemblies where the association constant is as high as K(ass) ~ 8000 m(-1). PMID- 24470389 TI - Simulated surgery and cutting guides enhance spatial positioning in free fibular mandibular reconstruction. AB - INTRODUCTION: The free fibular flap is the workhorse for mandibular reconstruction. Three-dimensional (3D) planning, with use of cutting guides and prebent plates, has been introduced. The purpose of this study is to evaluate the interfragmentary gap size and symmetry between conventional freehand preparation versus those using 3D planning. METHODS: A retrospective review was performed. Conventional free form and 3D planned fibular reconstructions performed by the senior authors at a single institution were included. Reconstructions were further subdivided into "body only" and "complex." Demographic and intraoperative data were collected. Postoperative CT scans were analyzed using Materialize software. Interfragmentary gap distances (mm) and symmetry (degrees) were assessed. RESULTS: Nineteen fibular reconstructions met inclusion criteria, ten conventional free form, and nine 3D planned reconstructions. Interfibular gaps measured 0.36 +/- 0.50 mm in the 3D group versus 1.88 +/- 1.09 mm in the non-3D group (P = 0.004). Overall symmetry (a ratio between right and left angles) measured versus 1.027 +/- 0.08 in the 3D-planned versus 1.024 +/- 0.09 in the non 3D group in (P = 0.944). Within only mandibular body reconstructions, symmetry was similar between the two techniques: 1.05 +/- 0.12 in the 3D group versus 0.97 +/- 0.05 in the non-3D group (P = 0.295). CONCLUSIONS: 3D planning lessens interfibular gap dimensions and may enhance axial symmetry. Space between native mandible and fibula is not appreciably altered using planning. Future efforts will focus on the accuracy and reproducibility of the 3D planned to actual results as well as clinical significance and efficiency benefits. PMID- 24470390 TI - Comparison of various techniques for the extraction and determination of antioxidants in plants. AB - The following extraction techniques have been used for extracting antioxidants (apigenin, coumarin, esculetin, umbelliferone, bergapten, quercetin, rutin, scopoletin and xanthotoxin) from plant material: supercritical fluid extraction, pressurized liquid extraction, extraction by means of Soxhlet apparatus, ultrasonic extraction in ultrasonic bath, and by means of ultrasonic probe. The analytical method based on HPLC-UV detection for the determination of selected antioxidants was developed. For all extracts the antioxidant capacity based on the reduction of free 2,2-diphenyl-1-picrylhydrazyl radical was also determined. Comparing all results the ultrasonic probe method using 0.75 g of sample extracted by 50 mL of acetonitrile in water (30%, v/v) for 25 min at room temperature and with amplitude at 60% (equal to 90 W) without pulsation was evaluated as the best tool. The most significant indicator demonstrating this statement is the antioxidant capacity expressed as gallic acid equivalent where the ultrasonic probe method showed the best results in 10 of 16 samples. Also the operability of ultrasonic probe extraction method compared to other tested methods is more favorable. PMID- 24470391 TI - Regulation of coenzyme Q biosynthesis in yeast: a new complex in the block. AB - Coenzyme Q (CoQ) is an isoprenylated benzoquinone found in mitochondria, which functions mainly as an electron carrier from complex I or II to complex III in the inner membrane. CoQ is also an antioxidant that specifically prevents the oxidation of lipoproteins and the plasma membrane. Most of the information about the synthesis of CoQ comes from studies performed in Saccharomyces cerevisiae. CoQ biosynthesis is a highly regulated process of sequential modifications of the benzene ring. There are three pieces of evidence supporting the involvement of a multienzymatic complex in yeast CoQ6 biosynthesis: (a) the accumulation of a unique early precursor in all null mutants of the COQ genes series, 4-hydroxy-3 hexaprenyl benzoate (HHB), (b) the lack of expression of several Coq proteins in COQ null mutants, and (c) the restoration of CoQ biosynthesis complex after COQ8 overexpression. The model we propose based on the formation of a multiprotein complex should facilitate a better understanding of CoQ biosynthesis. According to this model, the complex assembly requires the synthesis of a precursor such as HHB by Coq2p that must be recognized by the regulatory protein Coq4p to act as the core component of the complex. The phosphorylation of Coq3p and Coq5p by the kinase Coq8p facilitates the formation of an initial precomplex of 700 kDa that contains all Coq proteins with the exception of Coq7p. The precomplex is required for the synthesis of 5-demethoxy-Q6 , the substrate of Coq7p. When cells require de novo CoQ6 synthesis, Coq7p is dephosphorylated by Ptc7p, a mitochondrial phosphatase that activates the synthesis of CoQ6. This event allows for the full assembly of a complex of 1,300 kDa that is responsible for the final product of the pathway, CoQ6 . PMID- 24470392 TI - Modifying effect of N-acetyltransferase 2 genotype on the association between systemic lupus erythematosus and consumption of alcohol and caffeine-rich beverages. AB - OBJECTIVE: N-acetyltransferase 2 (NAT2) is involved in the metabolism of various environmental substances, both with and without carcinogenic potential. Alcoholic and nonalcoholic caffeine-rich beverages may be associated with markers of inflammation. Systemic lupus erythematosus (SLE) is a chronic, multifaceted inflammatory disease. We investigated the effects of alcoholic and nonalcoholic caffeine-rich beverages on risk of SLE and determined whether the effects were modified by NAT2 status. METHODS: The NAT2 polymorphism was genotyped in 152 SLE cases and 427 healthy controls, all women and Japanese. We assessed effect modification by testing an interaction term for the NAT2 polymorphism and consumption of beverages. RESULTS: Consumption of black tea (odds ratio [OR] 1.88, 95% confidence interval [95% CI] 1.03-3.41) and coffee (OR 1.57, 95% CI 0.95-2.61), but not green tea, was associated with an increased risk of SLE, while alcohol use (OR 0.33, 95% CI 0.20-0.55) was associated with a decreased risk of SLE. There were significant interactions between the NAT2 polymorphism and either alcohol use (Pinteraction = 0.026) or consumption of black tea (Pinteraction = 0.048). CONCLUSION: The NAT2 polymorphism significantly modified the effects of alcohol use and black tea consumption on SLE, emphasizing the importance of incorporating genetic and metabolic information in studies on management of SLE. Additional studies are warranted to confirm the findings suggested in this study. PMID- 24470393 TI - In vivo vascularization of cell sheets provided better long-term tissue survival than injection of cell suspension. AB - Cell sheets have shown a remarkable ability for repairing damaged myocardium in clinical and preclinical studies. Although they demonstrate a high degree of viability as engrafted cells in vivo, the reason behind their survivability is unclear. In this study, the survival and vascularization of rat cardiac cell sheets transplanted in the subcutaneous tissue of athymic rats were investigated temporally. The cell sheets showed significantly higher survival than cell suspensions for up to 12 months, using an in vivo bioluminescence imaging system to detect luciferase-positive transplanted cells. Terminal deoxynucleotidyl transferase dUTP nick-end labelling (TUNEL) assay also showed a smaller number of apoptotic cells in the cell sheets than in the cell suspensions at 1 day. Rapid vascular formation and maturation were observed inside the cell sheets using an in vivo imaging system. Leaky vessels appeared at 6 h, red blood cells flowing through functional vessels appeared at 12 h, and morphologically matured vessels appeared at 7 days. In addition, immunostaining of cell sheets with nerve/glial antigen-2 (NG2) showed that vessel maturity increased over time. Interestingly, these results correlated with the dynamics of cell sheet mRNA expression. Genes related to endothelial cells (ECs) proliferation, migration and vessel sprouting were highly expressed within 1 day, and genes related to pericyte recruitment and vessel maturation were highly expressed at 3 days or later. This suggested that the cell sheets could secrete appropriate angiogenic factors in a timely way after transplantation, and this ability might be a key reason for their high survival. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24470394 TI - Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production. AB - PTEN Hamartoma Tumor Syndrome (PHTS) is an autosomal-dominant genetic condition underlying a subset of autism spectrum disorder (ASD) with macrocephaly. Caused by germline mutations in PTEN, PHTS also causes increased risks of multiple cancers via dysregulation of the PI3K and MAPK signaling pathways. Conditional knockout models have shown that neural Pten regulates social behavior, proliferation and cell size. Although much is known about how the intracellular localization of PTEN regulates signaling in cancer cell lines, we know little of how PTEN localization influences normal brain physiology and behavior. To address this, we generated a germline knock-in mouse model of cytoplasm-predominant Pten and characterized its behavioral and cellular phenotypes. The homozygous Pten(m3m4) mice have decreased total Pten levels including a specific drop in nuclear Pten and exhibit region-specific increases in brain weight. The Pten(m3m4) model displays sex-specific increases in social motivation, poor balance and normal recognition memory-a profile reminiscent of some individuals with high functioning ASD. The cytoplasm-predominant protein caused cellular hypertrophy limited to the soma and led to increased NG2 cell proliferation and accumulation of glia. The animals also exhibit significant astrogliosis and microglial activation, indicating a neuroinflammatory phenotype. At the signaling level, Pten(m3m4) mice show brain region-specific differences in Akt activation. These results demonstrate that differing alterations to the same autism-linked gene can cause distinct behavioral profiles. The Pten(m3m4) model is the first murine model of inappropriately elevated social motivation in the context of normal cognition and may expand the range of autism-related behaviors replicated in animal models. PMID- 24470396 TI - Is there an interactive effect of immunoglobulin levels and CD4+ cell counts during rituximab treatment? Comment on the article by Melet et al. PMID- 24470395 TI - microRNA-224 regulates Pentraxin 3, a component of the humoral arm of innate immunity, in inner ear inflammation. AB - microRNAs (miRNAs) are regulators of differentiation and development of inner ear cells. Mutations in miRNAs lead to deafness in humans and mice. Among inner ear pathologies, inflammation may lead to structural and neuronal defects and eventually to hearing loss and vestibular dysfunction. While the genetic factors of these pathways have not been defined, autoimmunity participates in these processes. We report that inflammatory stimuli in the inner ear induce activation of the innate immune system via miR-224 and pentraxin 3 (Ptx3). miR-224 is a transcriptional target of nuclear factor kappaB, a key mediator of innate immunity. Ptx3 is a regulator of the immune response. It is released in response to inflammation and regulated by nuclear factor kappaB. We show that miR-224 and Ptx3 are expressed in the inner ear and we demonstrate that miR-224 targets Ptx3. As a model of the innate immune response, we injected lipopolysaccharide into the scala tympani of mouse inner ears. This resulted in changes in the levels of miR 224 and Ptx3, in addition to activation of the complement system, as measured by immune cell infiltration and activated C3. This suggests that while miR-224 regulates Ptx3 under normal conditions, upon inflammation, both are recruited to offer a front line of defense in acting as responders to inflammation in the inner ear. miR-224 diminishes the innate immune response by down-regulating Ptx3 expression, while Ptx3 stimulates the innate immune response. An understanding of the molecular components of the inflammatory pathway may help develop therapeutics for reducing inflammation associated with inner ear injury. PMID- 24470397 TI - DNA-hybrid-gated multifunctional mesoporous silica nanocarriers for dual-targeted and microRNA-responsive controlled drug delivery. AB - The design of an ideal drug delivery system with targeted recognition and zero premature release, especially controlled and specific release that is triggered by an exclusive endogenous stimulus, is a great challenge. A traceable and aptamer-targeted drug nanocarrier has now been developed; the nanocarrier was obtained by capping mesoporous silica-coated quantum dots with a programmable DNA hybrid, and the drug release was controlled by microRNA. Once the nanocarriers had been delivered into HeLa cells by aptamer-mediated recognition and endocytosis, the overexpressed endogenous miR-21 served as an exclusive key to unlock the nanocarriers by competitive hybridization with the DNA hybrid, which led to a sustained lethality of the HeLa cells. If microRNA that is exclusively expressed in specific pathological cell was screened, a combination of chemotherapy and gene therapy should pave the way for a targeted and personalized treatment of human diseases. PMID- 24470398 TI - Cisterna chyli in autosomal dominant polycystic kidney disease. AB - PURPOSE: After observing prominent cisterna chyli in several patients with autosomal dominant polycystic kidney disease (ADPKD), we investigated the potential association of cistern chyli enlargement with ADPKD. MATERIALS AND METHODS: Retrospective, cross-sectional analysis of abdominal and pelvic MRI at 1.5 Tesla (T) in 70 ADPKD patients (male 44.3%, 20-83 years, median = 53 years) were compared with 70 age and gender matched control subjects without ADPKD, cirrhosis, or cholestasis. Cisterna chyli diameter was measured on axial single shot fast spin echo (SSFSE) images at the level of T12-L2 and evaluated by multivariable regression models with covariates including estimated glomerular filtration rate (eGFR), total kidney volume (TKV), renal cyst fraction (cyst volume/kidney volume), and liver volume. RESULTS: Subjects with ADPKD had larger median cisterna chyli diameter compared with those without ADPKD (6.1 mm versus 3.4 mm, P < 0.0001). The prevalence of cisterna chyli enlargement more than the median (3.4 mm), was greater in ADPKD than in controls (99% versus 51%, P < 0.0001). On univariate analysis, cisterna chyli diameter was inversely correlated with eGFR (r = -0.41; P < 0.0001) and directly correlated with TKV (r = 0.57; P < 0.0001), total renal cyst fraction (r = 0.61; P < 0.001), and liver volume (r = 0.17; P = 0.040). Multivariable linear regression modeling found a significant association of cisterna chyli diameter with ADPKD diagnosis (B = 2.14; 95% confidence interval [CI]: 0.05-4.23; P = 0.04). Logistic regression analysis confirmed the association of ADPKD with an enlarged cisterna chyli diameter (odds ratio = 68.4; 95%CI: 8.9-524, P < 0.0001). CONCLUSION: Enlarged cisterna chyli is highly prevalent in ADPKD patients but not in age and gender-matched controls. PMID- 24470399 TI - The 253-kb inversion and deep intronic mutations in UNC13D are present in North American patients with familial hemophagocytic lymphohistiocytosis 3. AB - BACKGROUND: The mutations in UNC13D are responsible for familial hemophagocytic lymphohistiocytosis (FHL) type 3. A 253-kb inversion and two deep intronic mutations, c.118-308C > T and c.118-307G > A, in UNC13D were recently reported in European and Asian FHL3 patients. We sought to determine the prevalence of these three non-coding mutations in North American FHL patients and evaluate the significance of examining these new mutations in genetic testing. PROCEDURE: We performed DNA sequencing of UNC13D and targeted analysis of these three mutations in 1,709 North American patients with a suspected clinical diagnosis of hemophagocytic lymphohistiocytosis (HLH). RESULTS: The 253-kb inversion, intronic mutations c.118-308C > T and c.118-307G > A were found in 11, 15, and 4 patients, respectively, in which the genetic basis (bi-allelic mutations) explained 25 additional patients. Taken together with previously diagnosed FHL3 patients in our HLH patient registry, these three non-coding mutations were found in 31.6% (25/79) of the FHL3 patients. The 253-kb inversion, c.118-308C > T and c.118-307G > A accounted for 7.0%, 8.9%, and 1.3% of mutant alleles, respectively. Significantly, eight novel mutations in UNC13D are being reported in this study. To further evaluate the expression level of the newly reported intronic mutation c.118-307G > A, reverse transcription PCR and Western blot analysis revealed a significant reduction of both RNA and protein levels suggesting that the c.118 307G > A mutation affects transcription. CONCLUSIONS: These specified non-coding mutations were found in a significant number of North American patients and inclusion of them in mutation analysis will improve the molecular diagnosis of FHL3. PMID- 24470400 TI - Can flow cytometry of bone marrow aspirate predict outcome of patients with diffuse large B cell lymphoma? A retrospective single centre study. AB - Bone marrow (BM) trephine biopsy is a part of routine staging of patients with newly diagnosed diffuse large B cell lymphoma (DLBCL). The significance of lymphoid monoclonal population on flow cytometry (FC) of the BM aspirate in the presence of negative BM histology has not been clarified. In this study, we assessed the clinical role of positive FC in predicting outcome of patients with DLBCL and a negative BM histology. We retrospectively analysed 101 patients diagnosed with DLBCL at a single institution between years 1994-2003. Three groups of patients were compared: patients with histologic involvement of the BM (BM+), patients with no histologic involvement of the BM but with positive FC (BM FC+) and patients with neither histologic or FC evidence of BM involvement (BM-FC ). The BM+ group included 13 patients (13%). The BM-FC+ group 16 patients (16%), and the BM-FC-included 72 patients (71%). Median age of the cohort was 67 years. Disease stage and International Prognostic Index score were significantly higher in the BM+ and BM-FC+ groups compared with the BM-FC- group. Median overall survival (OS) for the BM-FC-, BM-FC+ and BM + groups were 4.6, 2.2 and 0.9 years, respectively. Median progression free survival (PFS) for the BM-FC-, BM-FC+ and BM+ groups were 3.2, 1.4 and 0.6 years, respectively (p=0.01 for both analysis). In multivariable Cox regression models adjusting for age, sex, stage and International Prognostic Index, there was no significant differences in OS or PFS between the BM-FC+ and BM-FC- groups. In conclusion, positive FC in the setting of negative BM histology at diagnosis did not significantly affect OS or PFS. PMID- 24470402 TI - Growth of long triisopropylsilylethynyl pentacene (TIPS-PEN) nanofibrils in a polymer thin film during spin-coating. AB - This study demonstrates the growth of long triisopropylsilyethynyl pentacene (TIPS-PEN) nanofibrils in a thin film of a crystalline polymer, poly(epsilon caprolactone) (PCL). During spin-coating, TIPS-PEN molecules are locally extracted around the PCL grain boundaries and they crystallize into [010] direction forming long nanofibrils. Molecular weight of PCL and weight fraction (alpha) of TIPS-PEN in PCL matrix are key factors to the growth of nanofibrils. Long high-quality TIPS-PEN nanofibrils are obtained with high-molecular-weight PCL and at the alpha values in the range of 0.03-0.1. The long nanofibrils are used as an active layer in a field-effect organic transistor. PMID- 24470401 TI - Decreased interleukin-20 expression in scleroderma skin contributes to cutaneous fibrosis. AB - OBJECTIVE: To clarify the role of interleukin-20 (IL-20) in the regulatory mechanism of extracellular matrix expression and to determine the contribution of IL-20 to the phenotype of systemic sclerosis (SSc). METHODS: Protein and messenger RNA (mRNA) levels of collagen, Fli-1, IL-20, and IL-20 receptor (IL 20R) were analyzed using polymerase chain reaction (PCR) array, immunoblotting, immunohistochemical staining, enzyme-linked immunosorbent assay, and real-time PCR. RESULTS: PCR array revealed that IL-20 decreased gene expression of alpha2(I) collagen (0.03-fold), Smad3 (0.02-fold), and endoglin (0.05-fold) in cultured normal dermal fibroblasts. Fli-1 protein expression was induced by IL-20 (~2-fold). The inhibition of collagen by IL-20, the induction of Fli-1 by IL-20, and the reduction of Smad3 and endoglin by IL-20 were also observed in SSc fibroblasts. Serum IL-20 levels were reduced only slightly in SSc patients but were significantly decreased in patients with scleroderma spectrum disorders (the prodromal stage of SSc) compared with those in normal subjects (111.3 pg/ml versus 180.4 pg/ml; P < 0.05). On the other hand, IL-20 mRNA expression in SSc skin was decreased compared with that in normal skin (P < 0.05), which may result in the induction of collagen synthesis in SSc dermal fibroblasts. IL-20R was expressed in normal and SSc fibroblasts. Moreover, IL-20 supplementation by injection into the skin reversed skin fibrosis induced by bleomycin in mice (~0.5 fold). CONCLUSION: IL-20 reduces basal collagen transcription via Fli-1 induction, while down-regulation of Smad3 and endoglin may cancel the effect of transforming growth factor beta in SSc fibroblasts. To confirm the therapeutic value of IL-20 and IL-20R, their function and expression in vivo should be further studied. PMID- 24470404 TI - Predictors of 61 unplanned readmission cases in microvascular free tissue transfer patients: multi-institutional analysis of 774 patients. AB - BACKGROUND: Unplanned readmissions serve as a marker for health care quality. Risk factors associated with unplanned readmission after microvascular free tissue transfer have never been examined. In this study, we sought to identify perioperative predictors of 30-day unplanned readmission in free flap patients. METHODS: The National Surgical Quality Improvement Program (NSQIP) database was retrospectively reviewed to identify all patients who underwent microvascular free tissue transfer in 2011. Multivariate logistic regression models were used to estimate independent predictors of unplanned readmission. RESULTS: Among free flap patients, unplanned readmission rate was 7.9%. In multivariate analysis, the only factor that significantly predicted unplanned readmission (P < 0.05) was open wound/wound infection (odds ratio [OR] 2.71). Postoperative variables significantly associated with unplanned readmission included surgical complications (OR 5.43), medical complications (OR 5.62), and unplanned reoperation (OR 3.94). Flap failure was not associated with unplanned readmission. CONCLUSIONS: In our study, the presence of either open wound/wound infection, development of surgical complications, medical complications, and unplanned reoperations were associated with unplanned readmissions. Further research in predictive factors is suggested to avoid costly, unnecessary, and preventable readmissions. PMID- 24470405 TI - Wrestling with stress: roles of protein SUMOylation and deSUMOylation in cell stress response. AB - How cell fate is determined following extreme stress is a core question in cell biology. This is particularly important in the brain where neuronal death following ischemic stroke is a major cause of disability. Over the last few years it has emerged that the SUMOylation status of an increasing number of substrate proteins plays a crucial role in cellular responses to environmental and metabolic stress. SUMOylation is a post-translational modification in which the 97-residue protein, SUMO (Small Ubiquitin-related MOdifier) is covalently attached to specific lysine residues in a target protein. Despite being covalent, it is a highly transient modification because of the actions of deSUMOylation enzymes, so SUMO conjugation acts as a rapidly reversible switch that can promote or inhibit protein interactions with the substrate protein. Overall, it appears that increased SUMOylation represents a cellular protective response. Here we discuss recent progress toward understanding the mechanisms, pathways, and roles of SUMOylation during and after severe metabolic stress. PMID- 24470406 TI - Development and testing of new candidate psoriatic arthritis screening questionnaires combining optimal questions from existing tools. AB - OBJECTIVE: Several questionnaires have been developed to screen for psoriatic arthritis (PsA), but head-to-head studies have found limitations. This study aimed to develop new questionnaires encompassing the most discriminative questions from existing instruments. METHODS: Data from the CONTEST study, a head to-head comparison of 3 existing questionnaires, were used to identify items with a Youden index score of >=0.1. These were combined using 4 approaches: CONTEST (simple additions of questions), CONTESTw (weighting using logistic regression), CONTESTjt (addition of a joint manikin), and CONTESTtree (additional questions identified by classification and regression tree [CART] analysis). These candidate questionnaires were tested in independent data sets. RESULTS: Twelve individual questions with a Youden index score of >=0.1 were identified, but 4 of these were excluded due to duplication and redundancy. Weighting for 2 of these questions was included in CONTESTw. Receiver operating characteristic (ROC) curve analysis showed that involvement in 6 joint areas on the manikin was predictive of PsA for inclusion in CONTESTjt. CART analysis identified a further 5 questions for inclusion in CONTESTtree. CONTESTtree was not significant on ROC curve analysis and discarded. The other 3 questionnaires were significant in all data sets, although CONTESTw was slightly inferior to the others in the validation data sets. Potential cut points for referral were also discussed. CONCLUSION: Of 4 candidate questionnaires combining existing discriminatory items to identify PsA in people with psoriasis, 3 were found to be significant on ROC curve analysis. Testing in independent data sets identified 2 questionnaires (CONTEST and CONTESTjt) that should be pursued for further prospective testing. PMID- 24470407 TI - Systemic juvenile idiopathic arthritis-like syndrome in mice following stimulation of the immune system with Freund's complete adjuvant: regulation by interferon-gamma. AB - OBJECTIVE: Systemic juvenile idiopathic arthritis (JIA) is unique among the rheumatic diseases of childhood, given its distinctive systemic inflammatory character. Inappropriate control of innate immune responses following an initially harmless trigger is thought to account for the excessive inflammatory reaction. The aim of this study was to generate a similar systemic inflammatory syndrome in mice by injecting a relatively innocuous, yet persistent, immune system trigger: Freund's complete adjuvant (CFA), containing heat-killed mycobacteria. METHODS: Given the central role of interferon-gamma (IFNgamma) in immune regulation, we challenged wild-type (WT) and IFNgamma-knockout (KO) BALB/c mice with CFA, and analyzed their clinical symptoms and biologic characteristics. The production of cytokines and the effects of anticytokine antibodies were investigated. RESULTS: In WT mice, CFA injection resulted in splenomegaly, lymphadenopathy, neutrophilia, thrombocytosis, and increased cytokine expression. In the absence of IFNgamma, these symptoms were more pronounced and were accompanied by weight loss, arthritis, anemia, hemophagocytosis, abundance of immature blood cells, and increased levels of interleukin-6 (IL-6), all of which are reminiscent of the symptoms of systemic JIA. CFA-challenged IFNgamma-KO mice showed increased expression of IL-17 by CD4+ T cells and by innate gamma/delta T cells. Inflammatory and hematologic changes were prevented by treatment with anti IL-12/IL-23p40 and anti-IL-17 antibodies. CONCLUSION: Immune stimulation of IFNgamma-KO mice with CFA produces a systemic inflammatory syndrome reflecting the clinical, biologic, and histopathologic picture of systemic JIA. The protective function of IFNgamma in preventing anemia and overall systemic inflammation is a striking observation. The finding that both adaptive and innate T cells are important sources of IL-17 may be of relevance in the pathogenesis of systemic JIA. PMID- 24470408 TI - On the evolution and relative merits of hard X-ray phase-contrast imaging methods. AB - This review provides a brief overview, albeit from a somewhat personal perspective, of the evolution and key features of various hard X-ray phase contrast imaging (PCI) methods of current interest in connection with translation to a wide range of imaging applications. Although such methods have already found wide-ranging applications using synchrotron sources, application to dynamic studies in a laboratory/clinical context, for example for in vivo imaging, has been slow due to the current limitations in the brilliance of compact laboratory sources and the availability of suitable high-performance X-ray detectors. On the theoretical side, promising new PCI methods are evolving which can record both components of the phase gradient in a single exposure and which can accept a relatively large spectral bandpass. In order to help to identify the most promising paths forward, we make some suggestions as to how the various PCI methods might be compared for performance with a particular view to identifying those which are the most efficient, given the fact that source performance is currently a key limiting factor on the improved performance and applicability of PCI systems, especially in the context of dynamic sample studies. The rapid ongoing development of both suitable improved sources and detectors gives strong encouragement to the view that hard X-ray PCI methods are poised for improved performance and an even wider range of applications in the near future. PMID- 24470409 TI - X-ray phase imaging: from synchrotron to hospital. AB - With the aim of clinical applications of X-ray phase imaging based on Talbot-Lau type grating interferometry to joint diseases and breast cancer, machines employing a conventional X-ray generator have been developed and installed in hospitals. The machine operation especially for diagnosing rheumatoid arthritis is described, which relies on the fact that cartilage in finger joints can be depicted with a dose of several milligray. The palm of a volunteer observed with 19 s exposure (total scan time: 32 s) is reported with a depicted cartilage feature in joints. This machine is now dedicated for clinical research with patients. PMID- 24470410 TI - Clinical study in phase- contrast mammography: image-quality analysis. AB - The first clinical study of phase-contrast mammography (PCM) with synchrotron radiation was carried out at the Synchrotron Radiation for Medical Physics beamline of the Elettra synchrotron radiation facility in Trieste (Italy) in 2006 2009. The study involved 71 patients with unresolved breast abnormalities after conventional digital mammography and ultrasonography exams carried out at the Radiology Department of Trieste University Hospital. These cases were referred for mammography at the synchrotron radiation facility, with images acquired using a propagation-based phase-contrast imaging technique. To investigate the contribution of phase-contrast effects to the image quality, two experienced radiologists specialized in mammography assessed the visibility of breast abnormalities and of breast glandular structures. The images acquired at the hospital and at the synchrotron radiation facility were compared and graded according to a relative seven-grade visual scoring system. The statistical analysis highlighted that PCM with synchrotron radiation depicts normal structures and abnormal findings with higher image quality with respect to conventional digital mammography. PMID- 24470411 TI - Performance and optimization of X-ray grating interferometry. AB - The monochromatic and polychromatic performance of a grating interferometer is theoretically analysed. The smallest detectable refraction angle is used as a metric for the efficiency in acquiring a differential phase-contrast image. Analytical formulae for the visibility and the smallest detectable refraction angle are derived for Talbot-type and Talbot-Lau-type interferometers, respectively, providing a framework for the optimization of the geometry. The polychromatic performance of a grating interferometer is investigated analytically by calculating the energy-dependent interference fringe visibility, the spectral acceptance and the polychromatic interference fringe visibility. The optimization of grating interferometry is a crucial step for the design of application-specific systems with maximum performance. PMID- 24470412 TI - Boosting phase contrast with a grating Bonse-Hart interferometer of 200 nanometre grating period. AB - We report on a grating Bonse-Hart interferometer for phase-contrast imaging with hard X-rays. The method overcomes limitations in the level of sensitivity that can be achieved with the well-known Talbot grating interferometer, and without the stringent spectral filtering at any given incident angle imposed by the classic Bonse-Hart interferometer. The device operates in the far-field regime, where an incident beam is split by a diffraction grating into two widely separated beams, which are redirected by a second diffraction grating to merge at a third grating, where they coherently interfere. The wide separation of the interfering beams results in large phase contrast, and in some cases absolute phase images are obtained. Imaging experiments were performed using diffraction gratings of 200 nm period, at 22.5 keV and 1.5% spectral bandwidth on a bending magnetic beamline. Novel design and fabrication process were used to achieve the small grating period. Using a slitted incident beam, we acquired absolute and differential phase images of lightly absorbing samples. An advantage of this method is that it uses only phase modulating gratings, which are easier to fabricate than absorption gratings of the same periods. PMID- 24470413 TI - Medicine, material science and security: the versatility of the coded-aperture approach. AB - The principal limitation to the widespread deployment of X-ray phase imaging in a variety of applications is probably versatility. A versatile X-ray phase imaging system must be able to work with polychromatic and non-microfocus sources (for example, those currently used in medical and industrial applications), have physical dimensions sufficiently large to accommodate samples of interest, be insensitive to environmental disturbances (such as vibrations and temperature variations), require only simple system set-up and maintenance, and be able to perform quantitative imaging. The coded-aperture technique, based upon the edge illumination principle, satisfies each of these criteria. To date, we have applied the technique to mammography, materials science, small-animal imaging, non-destructive testing and security. In this paper, we outline the theory of coded-aperture phase imaging and show an example of how the technique may be applied to imaging samples with a practically important scale. PMID- 24470414 TI - Compact laser accelerators for X-ray phase-contrast imaging. AB - Advances in X-ray imaging techniques have been driven by advances in novel X-ray sources. The latest fourth-generation X-ray sources can boast large photon fluxes at unprecedented brightness. However, the large size of these facilities means that these sources are not available for everyday applications. With advances in laser plasma acceleration, electron beams can now be generated at energies comparable to those used in light sources, but in university-sized laboratories. By making use of the strong transverse focusing of plasma accelerators, bright sources of betatron radiation have been produced. Here, we demonstrate phase contrast imaging of a biological sample for the first time by radiation generated by GeV electron beams produced by a laser accelerator. The work was performed using a greater than 300 TW laser, which allowed the energy of the synchrotron source to be extended to the 10-100 keV range. PMID- 24470415 TI - Clinical boundary conditions for grating-based differential phase-contrast mammography. AB - Research in grating-based differential phase-contrast imaging (DPCI) has gained increasing momentum in the past couple of years. The first results on the potential clinical benefits of the technique for X-ray mammography are becoming available and indicate improvements in terms of general image quality, the delineation of lesions versus the background tissue and the visibility of microcalcifications. In this paper, we investigate some aspects related to the technical feasibility of DPCI for human X-ray mammography. After a short introduction to state-of-the-art full-field digital mammography in terms of technical aspects as well as clinical aspects, we put together boundary conditions for DPCI. We then discuss the implications for system design in a comparative manner for systems with two-dimensional detectors versus slit scanning systems, stating advantages and disadvantages of the two designs. Finally, focusing on a slit-scanning system, we outline a possible concept for phase acquisition. PMID- 24470416 TI - A phase demodulation method for two-dimensional grating-based X-ray interferometry. AB - This paper presents a novel approach to achieving high spatial resolution in the demodulation of images produced by a two-dimensional X-ray Talbot interferometry (XTI) system. Currently, demodulation of XTI images is mainly performed by either phase-stepping (PS) or Fourier transform (FT) methods. However, the PS method for two-dimensional XTI demodulation requires a larger number of exposures and a more complex grating control process than that of one-dimensional XTI. On the other hand, although the FT method uses only a single-fringe image, it gives lower spatial resolution than the PS method. For practical application of two dimensional XTI, a simpler exposure process with high spatial resolution is required. In this paper, we introduce a hybrid method combining the PS and FT methods. This method simplifies the exposure process in comparison with the PS method required in two-dimensional XTI while achieving higher spatial resolution than the FT method in the demodulation of images. The method works by using additional exposures to eliminate unnecessary spectral components that appear in the FT method. Furthermore, the proposed method is demonstrated by using actual two-dimensional XTI data and shown to achieve high spatial resolution in the demodulation of images for both the x- and y-differential phase components. PMID- 24470417 TI - Investigation of the application of phase contrast imaging using a point X-ray source to industrial non-destructive testing. AB - X-Tek Systems, a division of Nikon Metrology UK, designs, develops and manufactures microfocus X-ray radiography and computed tomography systems for industrial non-destructive testing. The range of X-ray acceleration voltages of its current standard products is 130-450 kV. It is widely known that X-ray images can be created using phase contrast formed by the natural propagation of X-rays. Simulation of the natural propagation of X-rays through a cylindrical test sample predicted a small contrast peak at the boundary between the cylinder material and air. Comparison data were obtained using an X-ray source with acceleration voltage above 100 kV. The simulation results correlated well with the experimental data. A further practical example (a 'magic mirror' amulet from an old Japanese shrine) is introduced and discussed. In this specimen, we detected intensity variation including the effect of phase contrast in the operating region above 100 kV. In summary, natural propagation phase contrast was observed in radiographic images from a standard point X-ray source with acceleration voltages exceeding 100 kV. PMID- 24470418 TI - Coherent Bragg nanodiffraction at the hard X-ray Nanoprobe beamline. AB - Bragg coherent diffraction with nanofocused hard X-ray beams provides unique opportunities for quantitative in situ studies of crystalline structure in nanoscale regions of complex materials and devices by a variety of diffraction based techniques. In the case of coherent diffraction imaging, a major experimental challenge in using nanoscale coherent beams is maintaining a constant scattering volume such that coherent fringe visibility is maximized and maintained over the course of an exposure lasting several seconds. Here, we present coherent Bragg diffraction patterns measured from different nanostructured thin films at the Sector 26 Nanoprobe beamline at the Advanced Photon Source and demonstrate that with nanoscale positional control, coherent diffraction patterns can be measured with source-limited fringe visibilities more than 50% suitable for imaging by coherent Bragg ptychography techniques. PMID- 24470419 TI - Synchrotron- and laboratory-based X-ray phase-contrast imaging for imaging mouse articular cartilage in the absence of radiopaque contrast agents. AB - The mouse model of osteoarthritis (OA) has been recognized as the most promising research tool for the identification of new OA therapeutic targets. However, this model is currently limited by poor throughput, dependent on the extremely time consuming histopathology assessment of the articular cartilage (AC). We have recently shown that AC in the rat tibia can be imaged both in air and in saline solution using a laboratory system based on coded-aperture X-ray phase-contrast imaging (CAXPCi). Here, we explore ways to extend the methodology for imaging the much thinner AC of the mouse, by means of gold-standard synchrotron-based phase contrast methods. Specifically, we have used analyser-based phase-contrast micro computed tomography (micro-CT) for its high sensitivity to faint phase changes, coupled with a high-resolution (4.5 MUm pixel) detector. Healthy, diseased (four weeks post induction of OA) and artificially damaged mouse AC was imaged at the Elettra synchrotron in Trieste, Italy, using the above method. For validation, we used conventional micro-CT combined with radiopaque soft-tissue staining and standard histomorphometry. We show that mouse cartilage can be visualized correctly by means of the synchrotron method. This suggests that: (i) further developments of the laboratory-based CAXPCi system, especially in terms of pushing the resolution limits, might have the potential to resolve mouse AC ex vivo and (ii) additional improvements may lead to a new generation of CAXPCi micro-CT scanners which could be used for in vivo longitudinal pre-clinical imaging of soft tissue at resolutions impossible to achieve by current MRI technology. PMID- 24470420 TI - Sensitivity of edge illumination X-ray phase-contrast imaging. AB - Recently, we developed a theoretical model that can predict the signal-to-noise ratio for edge-like features in phase-contrast images. This model was then applied for the estimation of the sensitivity of three different X-ray phase contrast techniques: propagation-based imaging, analyser-based imaging and grating interferometry. We show here how the same formalism can be used also in the case of the edge illumination (EI) technique, providing results that are consistent with those of a recently developed method for the estimation of noise in the retrieved refraction image. The new model is then applied to calculate, in the case of a given synchrotron radiation set-up, the optimum positions of the pre-sample aperture and detector edge to maximize the sensitivity. Finally, an example of the extremely high angular resolution achievable with the EI technique is presented. PMID- 24470421 TI - Priors for X-ray in-line phase tomography of heterogeneous objects. AB - We present a new prior for phase retrieval from X-ray Fresnel diffraction patterns. Fresnel diffraction patterns are achieved by letting a highly coherent X-ray beam propagate in free space after interaction with an object. Previously, either homogeneous or multi-material object assumptions have been used. The advantage of the homogeneous object assumption is that the prior can be introduced in the Radon domain. Heterogeneous object priors, on the other hand, have to be applied in the object domain. Here, we let the relationship between attenuation and refractive index vary as a function of the measured attenuation index. The method is evaluated using images acquired at beamline ID19 (ESRF, Grenoble, France) of a phantom where the prior is calculated by linear interpolation and of a healing bone obtained from a rat osteotomy model. It is shown that the ratio between attenuation and refractive index in bone for different levels of mineralization follows a power law. Reconstruction was performed using the mixed approach but is compatible with other, more advanced models. We achieve more precise reconstructions than previously reported in literature. We believe that the proposed method will find application in biomedical imaging problems where the object is strongly heterogeneous, such as bone healing and biomaterials engineering. PMID- 24470422 TI - Scanning electron microscope studies of human metaphase chromosomes. AB - Scanning electron microscopy (SEM) is used to evaluate potential chromosome preparations and staining methods for application in high-resolution three dimensional X-ray imaging. Our starting point is optical fluorescence microscopy, the standard method for chromosomes, which only gives structural detail at the 200 nm scale. In principle, with suitable sample preparation protocols, including contrast enhancing staining, the surface structure of the chromosomes can be viewed at the 1 nm level by SEM. Here, we evaluate a heavy metal nucleic-acid specific stain, which gives strong contrast in the backscattered electron signal. This study uses SEM to examine chromosomes prepared in different ways to establish a sample preparation protocol for X-rays. Secondary electron and backscattered electron signals are compared to evaluate the effectiveness of platinum-based stains used to enhance the contrast. PMID- 24470423 TI - 'Taking X-ray phase contrast imaging into mainstream applications' and its satellite workshop 'Real and reciprocal space X-ray imaging'. AB - A double event, supported as part of the Royal Society scientific meetings, was organized in February 2013 in London and at Chicheley Hall in Buckinghamshire by Dr A. Olivo and Prof. I. Robinson. The theme that joined the two events was the use of X-ray phase in novel imaging approaches, as opposed to conventional methods based on X-ray attenuation. The event in London, led by Olivo, addressed the main roadblocks that X-ray phase contrast imaging (XPCI) is encountering in terms of commercial translation, for clinical and industrial applications. The main driver behind this is the development of new approaches that enable XPCI, traditionally a synchrotron method, to be performed with conventional laboratory sources, thus opening the way to its deployment in clinics and industrial settings. The satellite meeting at Chicheley Hall, led by Robinson, focused on the new scientific developments that have recently emerged at specialized facilities such as third-generation synchrotrons and free-electron lasers, which enable the direct measurement of the phase shift induced by a sample from intensity measurements, typically in the far field. The two events were therefore highly complementary, in terms of covering both the more applied/translational and the blue-sky aspects of the use of phase in X-ray research. PMID- 24470425 TI - Preoperative staging of gallbladder carcinoma using biliary MR imaging. AB - PURPOSE: To evaluate the performance of biliary MRI, including unenhanced imaging, gadolinium-enhanced (Gd-E) dynamic imaging, and MR cholangiography, for the preoperative staging of gallbladder cancer (GBC). MATERIALS AND METHODS: Our institutional review board approved this retrospective study. Eighty-six, consecutive patients with surgically resected and pathologically confirmed GBCs and who underwent preoperative MRI, including unenhanced T1- and T2-weighted images, MR cholangiography, and dynamic imaging, were enrolled in this study. Two observers independently evaluated the biliary MR images regarding the T- and N staging of GBCs and graded their diagnostic confidence for the staging using a 5 point scale. Receiver operating curve analysis was performed to evaluate the diagnostic performance of MR in the staging of GBC. Interobserver agreement was evaluated using kappa statistics. RESULTS: The overall accuracy of T- and N staging using biliary MRI was 84.9% and 77.9% for observer 1 and 69.8% and 74.4% for observer 2. There was good interobserver agreement regarding the T stage (k = 0.828). The Az (AUC: area under the curve) values of the diagnostic ability of MRI to differentiate >= T1b from <= T1a lesions, were 0.979 and 0.955 for both observers (P < 0.0001). CONCLUSION: Biliary MRI with MR cholangiography allows moderately accurate preoperative T staging and N staging of GBCs. It also shows an excellent diagnostic ability for differentiating >= T1b lesions from <= T1a lesions, which can be helpful for preoperative planning. PMID- 24470426 TI - Individually addressable thermo- and redox-responsive block copolymers by combining anionic polymerization and RAFT protocols. AB - A novel diblock copolymer consisting of poly(vinylferrocene) (PVFc) and poly(N,N diethylacrylamide) (PDEA) is synthesized via a combination of anionic and RAFT polymerization. The use of a novel route to hydroxyl-end-functionalized metallopolymers in anionic polymerization and subsequent esterification with a RAFT agent leads to a PVFc macro-CTA (M-n = 3800 g mol(-1) ; D = 1.17). RAFT polymerization with DEA affords block copolymers as evidenced by (1) H NMR spectroscopy as well as size exclusion chromatography (6400 <= M-n<= 33700 g mol( 1) ; 1.31 <= D 1.28). Self-assembly of the amphiphilic block copolymers in aqueous solution leads to micelles as shown via TEM. Importantly, the distinct thermo-responsive and redox-responsive character of the blocks is probed via dynamic light scattering and found to be individually and repeatedly addressable. PMID- 24470427 TI - An enantioselective inverse-electron-demand imino Diels-Alder reaction. AB - The imino Diels-Alder reaction is an efficient method for the synthesis of aza heterocycles. While different stereo- and enantioselective inverse-electron demand imino Diels-Alder (IEDIDA) reactions have been reported before, IEDIDA reactions including electron-deficient dienes are unprecedented. The first enantioselective IEDIDA reaction between electron-poor chromone dienes and cyclic imines, catalyzed by zinc/binol complexes is described. The novel reaction provides a facile entry to a natural product inspired collection of ring-fused quinolizines including a potent modulator of mitosis. PMID- 24470428 TI - Heparin, warfarin, or calciphylaxis? PMID- 24470429 TI - One-dimensional image-selected in vivo spectroscopy localized phosphorus saturation transfer at 7T. AB - PURPOSE: To evaluate the feasibility of a one-dimensional image-selected in vivo spectroscopy (1D-ISIS) saturation transfer (ST) sequence at 7T for localized in vivo measurements of energy metabolism in different tissues in clinically reasonable examination times. METHODS: The performance of a gradient offset independent adiabacity-based 1D-ISIS localization was tested on phantom and the localized ST sequence was compared with the nonlocalized version in vivo. We performed localized measurements of basal metabolism of human liver and different muscle groups of the calf. Localized ST experiments took 15-25 minutes. RESULTS: The selectivity of the 1D-ISIS sequence was 81.63% and the outer volume suppression was 97.57%. The ST parameters acquired with the 1D-ISIS sequence and with the nonlocalized acquisition in the muscle were not statistically different. The forward rate constants for phosphocreatine (PCr)-adenosine triphosphate (ATP) and inorganic phosphate (Pi)-ATP exchange reactions were measured in the soleus (kCK = 0.30 +/- 0.06 s(-1) and kATP = 0.11 +/- 0.02 s(-1) , respectively) and in the medial gastrocnemius (kCK = 0.27 +/- 0.06 s(-1) and kATP = 0.09 +/- 0.03s(-1) , respectively) in 15 minutes per muscle group. The corresponding fluxes were FCK = 6.26 +/- 1.28 MUmol/g/s, FATP = 0.22 +/- 0.05 MUmol/g/s and FCK = 6.29 +/- 1.66 MUmol/g/s, FATP = 0.21 +/- 0.07 MUmol/g/s, for soleus and gastrocnemius, respectively. The hepatic ATP synthesis measurement was feasible in 24 minutes. CONCLUSION: The fast assessment of PCr-ATP and Pi-ATP exchange rates at 7T makes the 1D-ISIS ST sequence a promising tool for examining local resting-state metabolism in clinically acceptable measurement times. PMID- 24470430 TI - Derivation and validation of a prediction rule for two-year mortality in early diffuse cutaneous systemic sclerosis. AB - OBJECTIVE: Systemic sclerosis (SSc) is associated with a reduction in life expectancy, but there are no validated prognostic models for determining short term mortality. The objective of this study was to derive and validate a prediction rule for 2-year mortality in patients with early diffuse cutaneous SSc (dcSSc). METHODS: We studied a prospectively enrolled cohort of 387 US Caucasian patients with early dcSSc (<2 years from the appearance of the first symptom), randomly divided into a derivation cohort (n = 260) and a validation cohort (n = 127). Predefined baseline predictor variables were analyzed in a stepwise multivariable logistic regression model in order to identify factors independently associated with 2-year all-cause mortality using a cutoff of P < 0.05. We rounded the beta values to the nearest integer and summed the points assigned to each variable in order to stratify patients into low-risk, moderate risk, and high-risk groups. We then applied this rule to an external validation cohort of 110 Caucasian patients with early dcSSc from a single UK center and compared stratum-specific mortality using chi-square statistics. RESULTS: Four independent predictor variables (with assigned integer values) comprised the model: age at first visit (points allotted: -1, 0, or 1), skin thickness progression rate (points allotted: 0 or 1), gastrointestinal tract severity (points allotted: 0, 1, or 2), and anemia (points allotted: 0 or 2). The prediction model performed well, with no significant differences between the derivation cohort and the US or UK validation cohorts in the low-risk and moderate-risk groups. CONCLUSION: We derived a 4-variable prediction rule that can be used to stratify patients with early dcSSc into groups by risk of 2-year mortality, and we validated that prediction rule in US and UK cohorts. PMID- 24470431 TI - Quantifying the potential impact of measurement error in an investigation of autism spectrum disorder (ASD). AB - The Early Autism Risk Longitudinal Investigation (EARLI), an ongoing study of a risk-enriched pregnancy cohort, examines genetic and environmental risk factors for autism spectrum disorders (ASDs). We simulated the potential effects of both measurement error (ME) in exposures and misclassification of ASD-related phenotype (assessed as Autism Observation Scale for Infants (AOSI) scores) on measures of association generated under this study design. We investigated the impact on the power to detect true associations with exposure and the false positive rate (FPR) for a non-causal correlate of exposure (X2, r=0.7) for continuous AOSI score (linear model) versus dichotomised AOSI (logistic regression) when the sample size (n), degree of ME in exposure, and strength of the expected (true) OR (eOR)) between exposure and AOSI varied. Exposure was a continuous variable in all linear models and dichotomised at one SD above the mean in logistic models. Simulations reveal complex patterns and suggest that: (1) There was attenuation of associations that increased with eOR and ME; (2) The FPR was considerable under many scenarios; and (3) The FPR has a complex dependence on the eOR, ME and model choice, but was greater for logistic models. The findings will stimulate work examining cost-effective strategies to reduce the impact of ME in realistic sample sizes and affirm the importance for EARLI of investment in biological samples that help precisely quantify a wide range of environmental exposures. PMID- 24470432 TI - Evidence from Raman spectroscopy of a putative link between inherent bone matrix chemistry and degenerative joint disease. AB - OBJECTIVE: Osteoarthritis (OA) is a common debilitating disease that results in degeneration of cartilage and bone in the synovial joints. Subtle changes in the molecular structure of the subchondral bone matrix occur and may be associated with cartilage changes. The aim of this study was to explore whether the abnormal molecular changes observed in the matrix of OA subchondral bone can be identified with Raman spectroscopy. METHODS: Tibial plateaus from patients undergoing total knee replacement for OA (n = 10) were compared with healthy joints from patients undergoing leg amputation (n = 5; sex- and laterality-matched) and with non-OA cadaveric knee specimens (n = 5; age-matched). The samples were analyzed with Raman spectroscopy, peripheral quantitative computed tomography, and chemical analysis to compare changes in defined load-bearing sites in both the medial and lateral compartments. RESULTS: OA subchondral bone matrix changes were detected by Raman spectroscopy. Within each cohort, there was no spectral difference in bone matrix chemistry between the medial and lateral compartments, whereas a significant spectral difference (P < 0.001) was observed between the non-OA and OA specimens. Type I collagen chain ratios were normal in the non-OA specimens but were significantly elevated in the OA specimens. CONCLUSION: In comparing the results of Raman spectroscopy with those obtained by other standard techniques, these findings show, for the first time, that subchondral bone changes, or inherent differences, exist in both the medial and lateral (beneath intact cartilage) compartments of OA knees. The development of Raman spectroscopy as a screening tool, based on molecular-specific modifications in bone, would facilitate the identification of clinical disease, including early molecular changes. PMID- 24470433 TI - Association between vitamin D receptor activator and the risk of infection related hospitalizations among incident hemodialysis patients: a nested case control study. AB - BACKGROUND: Patients suffering from chronic kidney disease are at greater risk of developing infection than the normal population, and infections are the second cause of mortality after cardiovascular complications in this population. Some reports suggest that the intake of active vitamin D might be beneficial to prevent infections. Therefore, we aimed to determine if the oral intake of vitamin D receptor activator (VDRA) is associated with a lower risk of infection related hospitalization (IRH) among incident chronic hemodialysis patients. METHODS: We conducted a nested case-control study in a cohort of 4933 patients initiating chronic hemodialysis between 1 January 2001 and 31 December 2007 in Quebec, Canada, using administrative databases. We identified cases of hospital admission indicating an infection as main diagnosis on the hospital's discharge sheet. Up to 10 controls were randomly selected for each case. Association between oral VDRA use and risk of IRH was estimated using conditional logistic regression. RESULTS: We identified 1136 cases of IRH and 10396 controls during the study period. The intake of VDRA was not associated with the risk of being hospitalized due to an infection (odds ratio [OR], 1.07; 95% confidence interval [CI], 0.95-1.20). Using the prior 6-month cumulative dose of VDRA, we also found that a cumulative VDRA dose of less than 45 mcg (OR, 1.05; 95%CI, 0.92-1.19) or greater than 45 mcg (OR, 1.15; 95%CI, 0.96-1.36) was not associated with the IRH risk. CONCLUSIONS: The oral intake of VDRA was not associated with the risk of IRH in incident hemodialysis patients. PMID- 24470434 TI - Copper-catalyzed regio- and enantioselective hydroamination of alkenes with hydroxylamines. AB - Adding value: The catalytic hydroamination of alkenes with amines holds promise to rapidly deliver value-added chiral amines from simple and accessible starting materials. The use of mild, Cu-catalyzed electrophilic amination strategies for the regioselective preparation of both linear and chiral branched amines is highlighted. PMID- 24470435 TI - Effect of topical vasoconstrictor exposure upon tumoricidal radiotherapy. AB - Topical application of the alpha adrenergic vasoconstrictors norepinephrine, phenylephrine or epinephrine to skin or mucosa in alcohol:water-based delivery vehicles minutes before irradiation has recently been shown to protect skin and mucosa cells against radiotherapy-induced toxicities in both preclinical and clinical studies. The protective mechanism is thought to involve transient skin or mucosal vasoconstriction with secondary, transient hypoxia and associated radioprotection. Regarding possible protection of tumor cell nests within the radiotherapy field, the endothelial cell-abnormal stroma constructed blood vessels generally found in human tumors commonly lack adrenergic receptor containing smooth muscle cells that are required to achieve vasoconstriction. Consistent with this, we show here that topical application of norepinephrine or phenylephrine to broken or intact skin over human Cal-27 or A-431 xeonograft, or mouse solid L1210 allograft tumors growing subcutaneously in nude mice, showed no effect upon radiation-induced tumor growth inhibition. Although vasoconstrictor induced nude mouse skin blanch was seen minutes after topical application of 600 mM norepinephrine, no blanching was seen within the A-431 xenograft tumors. Radiation dermatitis was severe 11 days post-irradiation (2 * 13.8 Gy) in the irradiated field containing xenograft tumors in mice that received topical delivery vehicle, but was absent in mice that received topical norepinephrine. Topical vasoconstrictor-conferred prevention of radiation dermatitis without discernible radioprotection of three histologically diverse xenograft or allograft tumors supports further development of the topical vasoconstrictor therapeutic strategy in humans. PMID- 24470437 TI - Positron emission tomography assessment for polymyalgia rheumatica. PMID- 24470436 TI - Effect of hydroxychloroquine on insulin sensitivity and lipid parameters in rheumatoid arthritis patients without diabetes mellitus: a randomized, blinded crossover trial. AB - OBJECTIVE: Observational studies suggest that hydroxychloroquine (HCQ) may reduce the risk of developing diabetes mellitus in patients with rheumatoid arthritis (RA). We examined the effect of HCQ on insulin resistance in subjects without diabetes mellitus with stable RA. METHODS: Twenty-three RA subjects not currently using HCQ completed a 16-week, double-blind crossover study. Subjects were randomly allocated to receive HCQ (6.5 mg/kg/day) or placebo for the first 8 weeks, followed by crossover to the other arm for the final 8 weeks. Subjects underwent oral glucose tolerance testing and fasting lipid measurements at baseline, 8 weeks, and 16 weeks. The change +/- SD from baseline in insulin sensitivity index (ISI), homeostatic model assessment for insulin resistance (HOMA-IR), and lipid parameters were compared between placebo and HCQ using linear regression. RESULTS: The mean patient age was 56 years, with 96% women, and the median body mass index was 26.0 kg/m2. After 8 weeks of HCQ, the mean +/- SD ISI increase was 0.4 +/- 2.9 compared with a small increase during placebo of 0.14 +/- 3.1 (adjusted P = 0.785), and the mean +/- SD HOMA-IR decrease was 0.3 +/- 1.5 during HCQ versus a decrease of 0.42 +/- 1.4 during placebo (adjusted P = 0.308). Small decreases in total cholesterol (12.7 mg/dl) and low-density lipoprotein (LDL) cholesterol (12.4 mg/dl) were observed during the HCQ treatment periods (both adjusted P < 0.05 compared to placebo). CONCLUSION: HCQ use for 8 weeks in patients without diabetes mellitus with stable RA produced no significant change in insulin resistance. We observed small and statistically significant improvements in total and LDL cholesterol during HCQ treatment. PMID- 24470438 TI - Do immunoglobulin levels and CD4 cell count interact during Rituximab treatment? PMID- 24470439 TI - Development of coronal cementum in hypsodont horse cheek teeth. AB - The horse is a grazing herbivore whose cheek teeth are hypsodon; that is, they possess long crowns that are completely covered by coronal cement at eruption. For elucidation of the sequential events in the formation of this coronal cementum in the mandibular horse cheek teeth, in the present study the lower 3rd permanent premolar teeth (PM4 ) from 3.5-, 4-, and 5-year-old horses were compared by using radiography, microcomputed tomography (Miro-CT), light microscopy (LM), and scanning electron microscopy (SEM). The present study clearly showed that prior to coronal cementogenesis tartrate-resistant acid phosphatase (TRAP)-positive odontoclasts resorbed on the enamel surface of the reserve crown in horse cheek tooth. Enamel resorption areas were relatively narrow, and started from the cuspal tips, and moved in the apical direction during tooth development. A primary cementum was initially deposited on the irregularly pitted enamel-cementum junction (ECJ) of the infolding and peripheral enamel. The infolding cementum filled grooves completely by the time of tooth eruption. On the other hand, in the peripheral cementum, the secondary and tertiary cementum layers were sequentially deposited on the primary cementum. These two cementum layers were sites for the insertion of the periodontal ligaments, and were continually laid down on the primary cementum coronally rather than apically throughout the life. The results of the present study suggest that the coronal cementum of horse cheek teeth is a multistructural and multifunctional tissue, meeting the requirements of its many different functions. PMID- 24470440 TI - Pulmonary artery pseudoaneurysm after Swan-Ganz catheterization: a case presentation and review of literature. AB - INTRODUCTION: The Swan-Ganz catheter for pulmonary artery (PA) cannulation was introduced in 1970 and has been utilized in the management of critically ill and cardiac patients. Although the routine use of this catheter has not been associated with better patient outcomes in prospective randomized trials, their ability to provide crucial hemodynamic measurements and the ease of bedside insertion makes them valuable in certain complex clinical scenarios. However, Swan-Ganz catheter insertion is not without complications. PA injury is the most serious complication suspected by the occurrence of hemoptysis after the procedure. We present a case of PA injury with pseudoaneurysm formation after Swan-Ganz catheterization along with a comprehensive review of literature. METHODS: We reviewed all PubMed/Medline indexed articles published between 1993 2013, reporting the development of PA pseudoaneurysm after Swan-Ganz catheter use. Cases were analyzed with specific reference to patient demographics, indication for Swan-Ganz insertion, initial presenting symptom, duration between insertion and first evidence of PA injury, inciting event, site of pseudoaneurysm, treatment and outcome. RESULTS: Forty-one patients were identified from 27 papers. In the reviewed population, 87.8% were older than 60 years of age and 82.9% were females. Fifty-one percent of the patients had an episode of hemoptysis on the day of Swan-Ganz catheter insertion. Ninety-seven percent of the patients had PA pseudoaneurysm in the right pulmonary circulation. The admission-to-discharge mortality rate in the reviewed cohort was 15%. Cause of death in 22% of the cases was hemoptysis, while non-catheter related complications were responsible for the remaining deaths. CONCLUSION: PA injury is a feared complication after Swan-Ganz catheterization and can be fatal. In patients who develop massive or recurrent hemoptysis after Swan-Ganz catheter use, PA injury must be considered and airway protection should be employed along with appropriate catheter based or surgical interventions. PMID- 24470441 TI - Associations between accurate prognostic understanding and end-of-life care preferences and its correlates among Taiwanese terminally ill cancer patients surveyed in 2011-2012. AB - OBJECTIVE: Adequate knowledge of prognosis is a prerequisite for planning appropriate end-of-life (EOL) care. However, questions remain about whether the association between prognostic understanding and EOL-care intensity reflects terminally ill cancer patients' preferences for EOL care. This study investigated the associations between accurate prognostic understanding and EOL-care preferences, and identified correlates of accurate prognostic understanding. METHODS: A cross-sectional survey of 2452 terminally ill cancer patients from 23 hospitals throughout Taiwan. RESULTS: Nearly half the participants (49.80%) accurately understood their prognosis. These patients were significantly more likely to prefer comfort-oriented care as their goal for EOL care, but less likely to prefer life-prolonging treatments. Accurately understanding prognosis decreased the likelihood of preferring intensive care unit care, cardiac pulmonary resuscitation, cardiac massage, intubation, and mechanical ventilation support, but increased preference for hospice care. Participants were significantly more likely to accurately understand their prognosis if they were male, younger, better educated, with a stronger preference for physicians to disclose their prognosis to them, and receiving care at a hospital accredited as a medical center and in northwest Taiwan. The likelihood of accurate prognostic understanding was lower for patients recently (<= 12 months) diagnosed with cancers with better prognosis and hematologic malignancies than for lung cancer patients. CONCLUSIONS: Accurately understanding prognosis is associated with fewer preferences for life-sustaining treatments and is correlated with both patient and institutional characteristics. Interventions should be developed to improve accurate prognostic understanding, thus facilitating informed EOL-care decisions that may limit the use of aggressive interventions. PMID- 24470442 TI - Significantly greater reduction in breast cancer mortality from post-diagnosis running than walking. AB - The purpose of these analyses is to test prospectively whether post-diagnosis running and walking differ significantly in their association with breast cancer mortality. Cox proportional hazard analyses were used to compare breast cancer mortality to baseline exercise energy expenditure (METs, 1 MET-hour ?1 km run) in 272 runners and 714 walkers previously diagnosed with breast cancer from the National Runners' and Walkers' Health Studies when adjusted for age, race, menopause, family history, breastfeeding and oral contraceptive use. Diagnosis occurred (mean +/- SD) 7.9 +/- 7.3 years before baseline. Forty-six women (13 runners and 33 walkers) died from breast cancer during 9.1-year mortality surveillance. For the 986 runners and walkers combined, breast cancer mortality decreased an average of 23.9% MET-hours/day [95% confidence interval (CI): 7.9 38.3%; p = 0.004]. There was a significantly greater decrease in risk for running than walking (risk per MET-hours/day run vs. walked: p = 0.03). For the 272 runners analyzed separately, breast cancer mortality decreased an average of 40.9% per MET-hours/day run (95% CI: 19.3-60.0%, p = 0.0004). When analyzed by categories of running energy expenditure, breast cancer mortality was 87.4% lower for the 1.8-3.6 MET-hours/day category (95% CI: 41.3-98.2% lower, p = 0.008) and 95.4% lower for the >=3.6 MET-hours/day category (95% CI: 71.9-100% lower, p = 0.0004) compared to the <1.07 MET-hours/day category. In contrast, the 714 walkers showed a nonsignificant 4.6% decrease in breast cancer mortality per MET hours/day walked (95% CI: 27.3% decreased risk to 21.3% increased risk, p = 0.71). These results suggest that post-diagnosis running is associated with significantly lower breast cancer mortality than post-diagnosis walking. PMID- 24470443 TI - Predictors of stopping and starting disease-modifying antirheumatic drugs for rheumatoid arthritis. AB - OBJECTIVE: Disease-modifying antirheumatic drugs (DMARDs) are the standard of care for rheumatoid arthritis (RA); however, studies have found that many patients do not receive them. We examined predictors of starting and stopping DMARDs among a longitudinal cohort of patients with RA. METHODS: Study participants came from a cohort of RA patients recruited from a random sample of rheumatologists' practices in Northern California. We examined patterns and predictors of stopping and starting nonbiologic and biologic DMARDs during 1982 2009 based on annual questionnaires. Stopping was defined as stopping all DMARDs and starting was defined as transitioning from no DMARDs to any DMARDs across 2 consecutive years. RESULTS: The analysis of starting DMARDs included 471 subjects with 1,974 pairs of years with no DMARD use in the first of 2 consecutive years. From this population, subjects started DMARD use by year 2 in 313 (15.9%) of the pairs. The analysis of stopping DMARDs included 1,026 subjects with 7,595 pairs of years with DMARD use in the first of 2 consecutive years; in 423 pairs (5.6%), subjects stopped DMARD use by year 2. In models that adjusted for RA-related factors, sociodemographics, and comorbidities, significant predictors of starting DMARDs included younger age, Hispanic ethnicity, shorter disease duration, and the use of oral glucocorticoids. In separate adjusted models, predictors of stopping DMARDs included Hispanic ethnicity and low income, while younger age was associated with a reduced risk of stopping. CONCLUSION: Efforts to improve DMARD use should focus on patient age, ethnicity, and income and RA-related factors. PMID- 24470444 TI - Transferrin receptor (TfR) trafficking determines brain uptake of TfR antibody affinity variants. AB - Antibodies to transferrin receptor (TfR) have potential use for therapeutic entry into the brain. We have shown that bispecific antibodies against TfR and beta secretase (BACE1 [beta-amyloid cleaving enzyme-1]) traverse the blood-brain barrier (BBB) and effectively reduce brain amyloid beta levels. We found that optimizing anti-TfR affinity improves brain exposure and BACE1 inhibition. Here we probe the cellular basis of this improvement and explore whether TfR antibody affinity alters the intracellular trafficking of TfR. Comparing high- and low affinity TfR bispecific antibodies in vivo, we found that high-affinity binding to TfR caused a dose-dependent reduction of brain TfR levels. In vitro live imaging and colocalization experiments revealed that high-affinity TfR bispecific antibodies facilitated the trafficking of TfR to lysosomes and thus induced the degradation of TfR, an observation which was further confirmed in vivo. Importantly, high-affinity anti-TfR dosing induced reductions in brain TfR levels, which significantly decreased brain exposure to a second dose of low affinity anti-TfR bispecific. Thus, high-affinity anti-TfR alters TfR trafficking, which dramatically impacts the capacity for TfR to mediate BBB transcytosis. PMID- 24470446 TI - Application of complement component 4d immunohistochemistry to ABO-compatible and ABO-incompatible liver transplantation. AB - Antibody-mediated rejection (AMR) is difficult to diagnose after ABO-compatible or ABO-identical (ABO-C) liver transplantation. To determine whether complement component 4d (C4d) immunostaining would be useful for diagnosing AMR, we compared the results of C4d immunohistochemistry for allograft biopsy samples with assays for anti-donor antibodies performed at the time of biopsy. One hundred fourteen patients with ABO-C grafts and 29 patients with ABO-incompatible (ABO-I) grafts were included. Linear C4d endothelial staining (identifiable with a 4* objective lens) or staining seen in 50% or more of the portal tracts was considered positive. Five of the 114 patients (4%) with ABO-C grafts and 15 of the 29 patients (52%) with ABO-I grafts showed C4d positivity. In the ABO-C cases, C4d positivity in late biopsy samples (>=30 days after transplantation) was associated with stage 2 or higher fibrosis (METAVIR score; P = 0.01) and with the presence of donor-specific anti-human leukocyte antigen DR antibodies (HLA-DR DSAs) with a mean fluorescence intensity > 5000 according to the Luminex single antigen bead assay (P = 0.04). Conversely, the presence of HLA-DR DSAs was associated with the presence of stage 2 or higher fibrosis, acute cellular rejection, and C4d positivity. During the 2-year follow-up, neither C4d positivity nor HLA-DR DSAs were related to graft loss. Among ABO-I patients, C4d positivity was not associated with allograft dysfunction or fibrosis. Only 3 of the 15 C4d-positive patients (20%) showed periportal hemorrhagic edema, which could be a histological sign of AMR in ABO-I grafts, and they were the only cases associated with elevations in anti-donor A/B antibody titers. In conclusion, C4d endothelial positivity among ABO-C patients is an uncommon event that could be associated with chronic graft damage with or without clinical AMR. C4d positivity is common among ABO-I patients and may not be associated with allograft dysfunction if alloantibody titers are not elevated. PMID- 24470445 TI - Light chain editors of anti-DNA receptors in human B cells. AB - Receptor editing is a mechanism of self-tolerance used in newly generated B cells. The expressed heavy (H) or light (L) chain of an autoreactive receptor is replaced by upstream V genes which eliminate or modify autoreactivity. Editing of anti-DNA receptors has been characterized in anti-DNA transgenic mouse models including 3H9, 3H9/56R, and their revertant 3H9GL. Certain L chains, termed editors, rescue anti-DNA B cells by neutralizing or modifying DNA binding of the H chain. This editing mechanism acts on the natural H chain repertoire; endogenous H chains with anti-DNA features are expressed primarily in combination with editor L chains. We ask whether a similar set of L chains exists in the human repertoire, and if so, do they edit H chains with anti-DNA signatures? We compared the protein sequences of mouse editors to all human L chains and found several human L chains similar to mouse editors. These L chains diminish or veto anti-DNA binding when expressed with anti-DNA H chains. The human H chains expressed with these L chains also have relatively high arginine (Arg) content in the H chain complementarity determining region (H3), suggesting that receptor editing plays a role in establishing tolerance to DNA in humans. PMID- 24470447 TI - Identification of new citrulline-specific autoantibodies, which bind to human arthritic cartilage, by mass spectrometric analysis of citrullinated type II collagen. AB - OBJECTIVE: To investigate type II collagen (CII) as a joint-specific target of the anti-citrullinated protein antibody (ACPA) response in rheumatoid arthritis (RA). METHODS: Potential citrullinated neoepitopes were identified by high resolution tandem mass spectrometry (MS/MS) of in vitro peptidylarginine deiminase 2 (PAD-2)-treated CII, and the relationship between citrullination and CII conformation was investigated by circular dichroism and conformation dependent antibodies. Based on the MS analyses, synthetic peptides were designed and analyzed for serum IgG reactivity in the Epidemiological Investigation of RA (EIRA) case-control cohort of 1,949 RA patients and 278 healthy controls. Peptide specific antibodies were purified from RA patient serum and used to stain RA cartilage specimens. RESULTS: We described the conformation-dependent citrullination pattern of CII after PAD-2 treatment at room temperature and 37 degrees C and showed that CII could be citrullinated in its native triple-helical conformation. Screening of Arg and Cit pairs of synthetic peptides revealed new citrullinated B cell epitopes on CII. Antibodies directed to 2 proximal epitopes close to the C-terminus of the CII triple helix were recognized by autoantibodies in 21% and 17% of RA patients, respectively. Affinity-purified antibodies from RA sera directed to these 2 epitopes, but not antibodies directed to citrullinated alpha-enolase peptide 1, bound to RA cartilage. CONCLUSION: These findings suggest that cartilage-directed anticitrulline immunity contributes to the induction of joint inflammation in RA. PMID- 24470448 TI - Editorial: interferon-gamma: friend or foe in systemic juvenile idiopathic arthritis and adult-onset Still's Disease? PMID- 24470449 TI - Stepping stones: a new future for Zoological Research. PMID- 24470450 TI - History of study, updated checklist, distribution and key of scorpions (Arachnida: Scorpiones) from China. AB - This review describes the history of taxonomic research on scorpions and provides an updated checklist and key of the scorpions currently known in China. This checklist is based on a thorough review of the extant literatures on scorpion species whose presence has been confirmed in China through field expeditions and examination of scorpion collections, excepting a few members that have no clear distribution or are currently in doubt. Totally, the scorpion fauna of China consists of 53 species and subspecies belonging to 12 genera crossing five families, with 33 species (62.3%) and one genus being recorded as endemic. Additionally, identification key and the distribution of scorpions from China are provided. PMID- 24470451 TI - Morphological and molecular studies on Garra imberba and its related species in China. AB - Garra imberba is widely distributed in China. At the moment, both Garra yiliangensis and G. hainanensis are treated as valid species, but they were initially named as a subspecies of G. pingi, a junior synonym of G. imberba. Garra alticorpora and G. nujiangensis also have similar morphological characters to G. imberba, but the taxonomic statuses and phylogenetic relationships of these species with G. imberba remains uncertain. In this study, 128 samples from the Jinshajiang, Red, Nanpanjiang, Lancangjiang, Nujiang Rivers as well as Hainan Island were measured while 1 mitochondrial gene and 1 nuclear intron of 24 samples were sequenced to explore the phylogenetic relationship of these five species. The results showed that G. hainanensis, G. yiliangensis, G. alticorpora and G. imberba are the same species with G. imberba being the valid species name, while G. nujiangensis is a valid species in and of itself. PMID- 24470452 TI - Effects of temperature acclimation on body mass and energy budget in the Chinese bulbul Pycnonotus sinensis. AB - Chinese bulbuls (Pycnonotus sinensis) are small passerine birds that inhabit areas of central, southern and eastern China. Previous observations suggest that free-living individuals of this species may change their food intake in response to seasonal changes in ambient temperature. In the present study, we randomly assigned Chinese bulbuls to either a 30C or 10C group, and measured their body mass (BM), body temperature, gross energy intake (GEI), digestible energy intake (DEI), and the length and mass of their digestive tracts over 28 days of acclimation at these temperatures. As predicted, birds in the 30C group had lower body mass, GEI and DEI relative to those in the 10C group. The length and mass of the digestive tract was also lower in the 30C group and trends in these parameters were positively correlated with BM, GEI and DEI. These results suggest that Chinese bulbuls reduced their absolute energy demands at relatively high temperatures by decreasing their body mass, GEI and DEI, and digestive tract size. PMID- 24470453 TI - Acoustic characteristics of eight common Chinese anurans during the breeding season. AB - Anurans often have species-specific vocalizations. To quantify and compare the characteristics of anuran calls in Gutianshan National Nature Reserve, Zhejiang Province, we recorded the advertisement calls of eight species belonging to four families (Ranidae, Microhylidae, Megophryidae and Bufonidae) from June to September 2012 using Sony ICD-FX8 IC recorders. All recordings were analyzed using the "Praat" software. Five acoustics parameters were measured, including temporal traits (call duration, number of notes or pulse number/call) and spectral traits (fundamental frequency, the first three formants and dominant frequency). The characteristic parameters of Microhyla ornate and Fejervarya limnocharis calls were different as were the calls of some populations of the same species recorded in different regions. The advertisement calls of the eight species were specific. Our study has provided a useful reference for identifying the calls of some common Chinese anurans. PMID- 24470454 TI - Four new records of fish species (Cypriniformes: Nemacheilidae, Balitoridae; Characiformes: Prochilodontidae) and corrections of two misidentified fish species (Tetraodontiformes: Tetraodontidae; Beloniformes: Belonidae) in Yunnan, China. AB - In this study, six fish species of five families are reported for the first time from Yunnan Province, China. The nemacheilid Schistura amplizona Kottelat, 2000 is reported from the Luosuojiang River and Nanlahe River subbasins, Mekong basin; the prochilodontid Prochilodus lineatus (Valenciennes, 1837), the balitorid Vanmanenia serrilineata Kottelat, 2000, and the tetraodontid Monotrete turgidus Kottelat, 2000, from Nanlahe River subbasin, Mekong basin; the balitorid Beaufortia daon (Mai, 1978), and the belonid Xenentodon canciloides (Bleeker, 1854), both, from Black River subbasin, Red River basin. The freshwater puffer M. turgidus and the needlefish X. canciloides have been previously misidentified as Tetraodon leiurus (Bleeker, 1950) and Tylosurus strongylurus (van Hasselt, 1823), respectively. PMID- 24470455 TI - Schistura sexnubes, a new diminutive river loach from the upper Mekong basin, Yunnan Province, China (Teleostei: Cypriniformes: Nemacheilidae). AB - An ichthyofaunistic survey of Mekong tributaries in Lincang Prefecture, Yunnan Province, China yielded a new species of nemacheilid loach, herein described as Schistura sexnubes species nova. The new species is readily distinguishable from its congeners by the following combination of characters: 8+8 branched caudal fin rays, an incomplete lateral line, a dissociated caudal bar, a shallow caudal peduncle depth (7.6%-9.6% SL; respectively caudal peduncle 1.76-1.95 times longer than deep), a diminutive size of less than 50 mm SL, and no sexual dimorphism. A dorsocephalic pattern consisting of a black, forward directed V-shaped formation located between the nares, and a white, ovoid blotch on the upper operculum serves as an autapomorphy. PMID- 24470456 TI - Geographic variation in parasitism rates of two sympatric cuckoo hosts in China. AB - Rates of brood parasitism vary extensively among host species and populations of a single host species. In this study, we documented and compared parasitism rates of two sympatric hosts, the Oriental Reed Warbler (Acrocephalus orientalis) and the Reed Parrotbill (Paradoxornis heudei), in three populations in China. We found that the Common Cuckoo (Cuculus canorus) is the only parasite using both the Oriental Reed Warbler and Reed Parrotbill as hosts, with a parasitism rate of 22.4%-34.3% and 0%-4.6%, respectively. The multiple parasitism rates were positively correlated with local parasitism rates across three geographic populations of Oriental Reed Warbler, which implies that higher pressure of parasitism lead to higher multiple parasitism rate. Furthermore, only one phenotype of cuckoo eggs was found in the nests of these two host species. Our results lead to two conclusions: (1) The Oriental Reed Warbler should be considered the major host of Common Cuckoo in our study sites; and (2) obligate parasitism on Oriental Reed Warbler by Common Cuckoo is specialized but flexible to some extent, i.e., using Reed Parrotbill as a secondary host. Further studies focusing on egg recognition and rejection behaviour of these two host species should be conducted to test our predictions. PMID- 24470457 TI - Descriptions of two new record species of Scutellonema (Nematoda: Tylenchida) from China. AB - From 2011 to 2012, we collected Scutellonema commune from the rhizosphere soil of coconut (cocos nucifera L.) and Scutellonema magniphasma from the rhizosphere soil of Rosa chinensis in Shenyang, China. S. commune was characterized by rounded scutella, which was varied from two annules anterior to the anus and five annules posterior. The lateral field was not areolated at the level of scutella. S. magniphasma was characterized by varying scutellum, about 7.0 MUm in diameter, in position from four annules posterior to four annules anterior to the anus, and areolated at the level of the scutellum. PMID- 24470458 TI - Review: antinucleosome antibodies: a critical reflection on their specificities and diagnostic impact. PMID- 24470460 TI - Biomarkers for the prediction of blood pressure response to renal denervation: a long way to go. PMID- 24470459 TI - Blood pressure, internal carotid artery flow parameters, and age-related white matter hyperintensities. AB - White matter hyperintensities (WMH) are associated with hypertension. We examined interactions among blood pressure (BP), internal carotid artery (ICA) flow velocity parameters, and WMH. We obtained BP measurements from 694 community dwelling subjects at mean ages 69.6 (+/-0.8) years and again at 72.6 (+/-0.7) years, plus brain MRI and ICA ultrasound at age 73+/-1 years. Diastolic and mean BP decreased and pulse pressure increased, but systolic BP did not change between 70 and 73 years. Multiple linear regression, corrected for vascular disease and risk factors, showed that WMH at the age of 73 years were associated with history of hypertension (beta=0.13; P<0.001) and with BP at the age of 70 years (systolic beta=0.08, mean beta=0.09, diastolic beta=0.08; all P<0.05); similar but attenuated associations were seen for BP at the age of 73 years. Lower diastolic BP and higher pulse pressure were associated with higher ICA pulsatility index at the age 73 years (diastolic BP age 70 years: standardized beta=-0.24, P<0.001; pulse pressure age 70 years: beta=0.19, P<0.001). WMH were associated with higher ICA pulsatility index (beta=0.13; P=0.002) after adjusting for BP and correction for multiple testing. Therefore, falling diastolic BP and increased pulse pressure are associated with increased ICA pulsatility index, which in turn is associated with WMH. This suggests that hypertension and WMH may either associate indirectly because hypertension increases arterial stiffness that leads to WMH over time, or coassociate through advancing age and stiffer vessels, or both. Reducing vascular stiffness may reduce WMH progression and should be tested in randomized trials, in addition to testing antihypertensive therapy. PMID- 24470461 TI - Natriuretic peptide receptor-C attenuates hypertension in spontaneously hypertensive rats: role of nitroxidative stress and Gi proteins. AB - C-Atrial natriuretic peptide (ANP)4-23, a ring deleted analog of ANP that specifically interacts with natriuretic peptide receptor-C (NPR-C), has been shown to decrease the enhanced expression of Gialpha proteins implicated in the pathogenesis of hypertension. In the present study, we investigated whether in vivo treatment of spontaneously hypertensive rats (SHRs) with C-ANP4-23 could attenuate the development of high blood pressure (BP) and explored the underlying mechanisms responsible for this response. Intraperitoneal injection of C-ANP4-23 at the concentration of 2 or 10 nmol/kg body weight to prehypertensive SHRs attenuated the development of high BP, and at 8 weeks it was decreased by ~20 and 50 mm Hg, respectively; however, this treatment did not affect BP in Wistar-Kyoto rats. C-ANP4-23 treatment of adult SHRs for 2 weeks also attenuated high BP, heart rate, and restored the impaired vasorelaxation toward control levels. In addition, the enhanced levels of superoxide anion (O2(-)), peroxynitrite, NADPH oxidase activity, and the enhanced expression of Gialpha proteins, NOX4, p47(phox), nitrotyrosine, and decreased levels of endothelial nitric oxide synthase (eNOS or NOS3) and NO in SHRs were attenuated by C-ANP4-23 treatment; however, the altered levels of NPR-A/NPR-C were not affected by this treatment. In conclusion, these results indicate that NPR-C activation by C-ANP4-23 attenuates the development of high BP in SHRs through the inhibition of enhanced levels of Gialpha proteins and nitroxidative stress and not through eNOS/cGMP pathway and suggest that NPR-C ligand may have the potential to be used as therapeutic agent in the treatment of cardiovascular complications including hypertension. PMID- 24470462 TI - Is natriuretic peptide receptor C a new target for hypertension therapeutics? PMID- 24470463 TI - Symphony of vascular contraction: how smooth muscle cells lose harmony to signal increased vascular resistance in hypertension. PMID- 24470464 TI - Soluble fms-like tyrosine kinase-1 and endothelial adhesion molecules (intercellular cell adhesion molecule-1 and vascular cell adhesion molecule-1) as predictive markers for blood pressure reduction after renal sympathetic denervation. AB - Renal sympathetic denervation (RSD) is a treatment option for patients with resistant arterial hypertension, but in some patients it is not successful. Predictive parameters on the success of RSD remain unknown. The angiogenic factors soluble fms-like tyrosine kinase-1 (sFLT-1), intercellular cell adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) are known to be associated with endothelial dysfunction, vascular remodeling, and hypertension. We evaluated whether sFLT-1, ICAM-1, and VCAM-1 are predictive markers for blood pressure reduction after RSD. Consecutive patients (n=55) undergoing renal denervation were included. Venous serum samples for measurement of sFlt-1, ICAM-1, and VCAM-1 were collected before and 6 months after RSD. A therapeutic response was defined as an office systolic blood pressure reduction of >10 mm Hg 6 months after RSD. A significant mean office systolic blood pressure reduction of 31.2 mm Hg was observed in 46 patients 6 months after RSD. Nine patients were classified as nonresponders, with a mean systolic blood pressure reduction of 4.6 mm Hg. At baseline, sFLT-1 levels were significantly higher in responders than in nonresponders (P<0.001) as were ICAM-1 (P<0.001) and VCAM-1 levels (P<0.01). The areas under the curve for sFLT-1, ICAM-1, and VCAM-1 were 0.82 (interquartile range, 0.718-0.921; P<0.001), 0.754 (0.654-0.854; P<0.001), and 0.684 (0.564-804; P=0.01), respectively, demonstrating prediction of an RSD response. Responders showed significantly higher serum levels of sFLT 1, ICAM-1, and VCAM-1 at baseline compared with nonresponders. Thus, this study identified for the first time potential biomarkers with a predictive value indicating a responder or nonresponder before renal denervation. PMID- 24470465 TI - Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition. AB - This study compared the pharmacodynamic/pharmacokinetic profile of the new renin inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP 27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of renin, increasing the concentration of plasma renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, renin inhibition has an upper limit. PMID- 24470466 TI - The effects of redox controls mediated by glutathione peroxidases on root architecture in Arabidopsis thaliana. AB - Glutathione peroxidases (GPXs) fulfil important functions in oxidative signalling and protect against the adverse effects of excessive oxidation. However, there has been no systematic characterization of the functions of the different GPX isoforms in plants. The roles of the different members of the Arabidopsis thaliana GPX gene (AtGPX) family were therefore investigated using gpx1, gpx2, gpx3, gpx4, gpx6, gpx7, and gpx8 T-DNA insertion mutant lines. The shoot phenotypes were largely similar in all genotypes, with small differences from the wild type observed only in the gpx2, gpx3, gpx7, and gpx8 mutants. In contrast, all the mutants showed altered root phenotypes compared with the wild type. The gpx1, gpx4, gpx6, gpx7, and gpx8 mutants had a significantly greater lateral root density (LRD) than the wild type. Conversely, the gpx2 and gpx3 mutants had significantly lower LRD values than the wild type. Auxin increased the LRD in all genotypes, but the effect of auxin was significantly greater in the gpx1, gpx4, and gpx7 mutants than in the wild type. The application of auxin increased GPX4 and GPX7 transcripts, but not GPX1 mRNAs in the roots of wild-type plants. The synthetic strigolactone GR24 and abscisic acid (ABA) decreased LRD to a similar extent in all genotypes, except gpx6, which showed increased sensitivity to ABA. These data not only demonstrate the importance of redox controls mediated by AtGPXs in the control of root architecture but they also show that the plastid localized GPX1 and GPX7 isoforms are required for the hormone-mediated control of lateral root development. PMID- 24470467 TI - Senescence, nutrient remobilization, and yield in wheat and barley. AB - Cereals including wheat and barley are of primary importance to ensure food security for the 21st century. A combination of lab- and field-based approaches has led to a considerably improved understanding of the importance of organ and particularly of whole-plant (monocarpic) senescence for wheat and barley yield and quality. A delicate balance between senescence timing, grain nutrient content, nutrient-use efficiency, and yield needs to be considered to (further) improve cereal varieties for a given environment and end use. The recent characterization of the Gpc-1 (NAM-1) genes in wheat and barley demonstrates the interdependence of these traits. Lines or varieties with functional Gpc-1 genes demonstrate earlier senescence and enhanced grain protein and micronutrient content but, depending on the environment, somewhat reduced yields. A major effort is needed to dissect regulatory networks centred on additional wheat and barley transcription factors and signalling pathways influencing the senescence process. Similarly, while important molecular details of nutrient (particularly nitrogen) remobilization from senescing organs to developing grains have been identified, important knowledge gaps remain. The genes coding for the major proteases involved in senescence-associated plastidial protein degradation are largely unknown. Membrane transport proteins involved in the different transport steps occurring between senescing organ (such as leaf mesophyll) cells and protein bodies in the endosperm of developing grains remain to be identified or further characterized. Existing data suggest that an improved understanding of all these steps will reveal additional, important targets for continued cereal improvement. PMID- 24470468 TI - Endopolyploidy as a potential alternative adaptive strategy for Arabidopsis leaf size variation in response to UV-B. AB - The extent of endoreduplication in leaf growth is group- or even species specific, and its adaptive role is still unclear. A survey of Arabidopsis accessions for variation at the level of endopolyploidy, cell number, and cell size in leaves revealed extensive genetic variation in endopolyploidy level. High endopolyploidy is associated with increased leaf size, both in natural and in genetically unstructured (mapping) populations. The underlying genes were identified as quantitative trait loci that control endopolyploidy in nature by modulating the progression of successive endocycles during organ development. This complex genetic architecture indicates an adaptive mechanism that allows differential organ growth over a broad geographic range and under stressful environmental conditions. UV-B radiation was identified as a significant positive climatic predictor for high endopolyploidy. Arabidopsis accessions carrying the increasing alleles for endopolyploidy also have enhanced tolerance to UV-B radiation. UV-absorbing secondary metabolites provide an additional protective strategy in accessions that display low endopolyploidy. Taken together, these results demonstrate that high constitutive endopolyploidy is a significant predictor for organ size in natural populations and is likely to contribute to sustaining plant growth under high incident UV radiation. Endopolyploidy may therefore form part of the range of UV-B tolerance mechanisms that exist in natural populations. PMID- 24470469 TI - Defect of CARD9 leads to impaired accumulation of gamma interferon-producing memory phenotype T cells in lungs and increased susceptibility to pulmonary infection with Cryptococcus neoformans. AB - Caspase recruitment domain-containing protein 9 (CARD9) is an adaptor molecule signal that is critical for NF-kappaB activation and is triggered through C-type lectin receptors (CLRs), which are pattern recognition receptors that recognize carbohydrate structures. Previous studies have reported that Cryptococcus neoformans, a fungal pathogen that causes meningoencephalitis in AIDS patients, is recognized through some CLRs, such as mannose receptors or DC-SIGN. However, the role of CARD9 in the host defense against cryptococcal infection remains to be elucidated. In the present study, we analyzed the role of CARD9 in the host defense against pulmonary infection with C. neoformans. CARD9 gene-disrupted (knockout [KO]) mice were highly susceptible to this infection, as shown by the reduced fungal clearance in the infected lungs of CARD9 KO mice, compared to that in wild-type (WT) mice. Gamma interferon (IFN-gamma) production was strongly reduced in CARD9 KO mice during the innate-immunity phase of infection. Reduced IFN-gamma synthesis was due to impaired accumulation of NK and memory phenotype T cells, which are major sources of IFN-gamma innate-immunity-phase production; a reduction in the accumulation of these cells was correlated with reduced CCL4, CCL5, CXCL9, and CXCL10 synthesis. However, differentiation of Th17 cells, but not of Th1 cells, was impaired at the adaptive-immunity phase in CARD9 KO mice compared to WT mice, although there was no significant difference in the infection susceptibility between interleukin 17A (IL-17A) KO and WT mice. These results suggest that CARD9 KO mice are susceptible to C. neoformans infection probably due to the reduced accumulation of IFN-gamma-expressing NK and memory phenotype T cells at the early stage of infection. PMID- 24470470 TI - Comparative analyses of a cystic fibrosis isolate of Bordetella bronchiseptica reveal differences in important pathogenic phenotypes. AB - Bordetella bronchiseptica is a Gram-negative bacterium that infects and causes disease in a wide variety of animals. B. bronchiseptica also infects humans, thereby demonstrating zoonotic transmission. An extensive characterization of human B. bronchiseptica isolates is needed to better understand the distinct genetic and phenotypic traits associated with these zoonotic transmission events. Using whole-genome transcriptome and CGH analysis, we report that a B. bronchiseptica cystic fibrosis isolate, T44625, contains a distinct genomic content of virulence-associated genes and differentially expresses these genes compared to the sequenced model laboratory strain RB50, a rabbit isolate. The differential gene expression pattern correlated with unique phenotypes exhibited by T44625, which included lower motility, increased aggregation, hyperbiofilm formation, and an increased in vitro capacity to adhere to respiratory epithelial cells. Using a mouse intranasal infection model, we found that although defective in establishing high bacterial burdens early during the infection process, T44625 persisted efficiently in the mouse nose. By documenting the unique genomic and phenotypic attributes of T44625, this report provides a blueprint for understanding the successful zoonotic potential of B. bronchiseptica and other zoonotic bacteria. PMID- 24470471 TI - Elucidating the genetic basis of crystalline biofilm formation in Proteus mirabilis. AB - Proteus mirabilis forms extensive crystalline biofilms on urethral catheters that occlude urine flow and frequently complicate the management of long-term catheterized patients. Here, using random transposon mutagenesis in conjunction with in vitro models of the catheterized urinary tract, we elucidate the mechanisms underpinning the formation of crystalline biofilms by P. mirabilis. Mutants identified as defective in blockage of urethral catheters had disruptions in genes involved in nitrogen metabolism and efflux systems but were unaffected in general growth, survival in bladder model systems, or the ability to elevate urinary pH. Imaging of biofilms directly on catheter surfaces, along with quantification of levels of encrustation and biomass, confirmed that the mutants were attenuated specifically in the ability to form crystalline biofilms compared with that of the wild type. However, the biofilm-deficient phenotype of these mutants was not due to deficiencies in attachment to catheter biomaterials, and defects in later stages of biofilm development were indicated. For one blocking deficient mutant, the disrupted gene (encoding a putative multidrug efflux pump) was also found to be associated with susceptibility to fosfomycin, and loss of this system or general inhibition of efflux pumps increased sensitivity to this antibiotic. Furthermore, homologues of this system were found to be widely distributed among other common pathogens of the catheterized urinary tract. Overall, our findings provide fundamental new insight into crystalline biofilm formation by P. mirabilis, including the link between biofilm formation and antibiotic resistance in this organism, and indicate a potential role for efflux pump inhibitors in the treatment or prevention of P. mirabilis crystalline biofilms. PMID- 24470472 TI - Characterization of neurological injury in transcatheter aortic valve implantation: how clear is the picture? PMID- 24470473 TI - Risk stratification for sudden cardiac death: a plan for the future. PMID- 24470474 TI - Secondary prevention of atherothrombotic or cryptogenic stroke. PMID- 24470475 TI - ECG response: January 28, 2014. PMID- 24470476 TI - Decade of histological follow-up for a fully biodegradable poly-L-lactic acid coronary stent (Igaki-Tamai stent) in humans: are bioresorbable scaffolds the answer? PMID- 24470478 TI - Letter by Ye and Zhang regarding article, "Bayesian methods affirm the use of percutaneous coronary intervention to improve survival in patients with unprotected left main coronary artery disease". PMID- 24470479 TI - Letter by Diamond regarding article, "Bayesian methods affirm the use of percutaneous coronary intervention to improve survival in patients with unprotected left main coronary artery disease". PMID- 24470480 TI - Response to letters regarding article, "Bayesian methods affirm the use of percutaneous coronary intervention to improve survival in patients with unprotected left main coronary artery disease". PMID- 24470481 TI - Impact of S-adenosylmethionine decarboxylase 1 on pulmonary vascular remodeling. AB - BACKGROUND: Pulmonary hypertension (PH) is a life-threatening disease characterized by vascular remodeling and increased pulmonary vascular resistance. Chronic alveolar hypoxia in animals is often used to decipher pathways being regulated in PH. Here, we aimed to investigate whether chronic hypoxia-induced PH in mice can be reversed by reoxygenation and whether possible regression can be used to identify pathways activated during the reversal and development of PH by genome-wide screening. METHODS AND RESULTS: Mice exposed to chronic hypoxia (21 days, 10% O2) were reoxygenated for up to 42 days. Full reversal of PH during reoxygenation was evident by normalized right ventricular pressure, right heart hypertrophy, and muscularization of small pulmonary vessels. Microarray analysis from these mice revealed s-adenosylmethionine decarboxylase 1 (AMD-1) as one of the most downregulated genes. In situ hybridization localized AMD-1 in pulmonary vessels. AMD-1 silencing decreased the proliferation of pulmonary arterial smooth muscle cells and diminished phospholipase Cgamma1 phosphorylation. Compared with the respective controls, AMD-1 depletion by heterozygous in vivo knockout or pharmacological inhibition attenuated PH during chronic hypoxia. A detailed molecular approach including promoter analysis showed that AMD-1 could be regulated by early growth response 1, transcription factor, as a consequence of epidermal growth factor stimulation. Key findings from the animal model were confirmed in human idiopathic pulmonary arterial hypertension. CONCLUSIONS: Our study indicates that genome-wide screening in mice from a PH model in which full reversal of PH occurs can be useful to identify potential key candidates for the reversal and development of PH. Targeting AMD-1 may represent a promising strategy for PH therapy. PMID- 24470482 TI - Antiplatelet therapy for stable coronary artery disease in atrial fibrillation patients taking an oral anticoagulant: a nationwide cohort study. AB - BACKGROUND: The optimal long-term antithrombotic treatment of patients with coexisting atrial fibrillation and stable coronary artery disease is unresolved, and commonly, a single antiplatelet agent is added to oral anticoagulation. We investigated the effectiveness and safety of adding antiplatelet therapy to vitamin K antagonist (VKA) in atrial fibrillation patents with stable coronary artery disease. METHODS AND RESULTS: Atrial fibrillation patients with stable coronary artery disease (defined as 12 months from an acute coronary event) between 2002 and 2011 were identified. The subsequent risk of cardiovascular events and serious bleeding events (those that required hospitalization) was examined with adjusted Cox regression models according to ongoing antithrombotic therapy. A total of 8700 patients were included (mean age, 74.2 years; 38% women). During a mean follow-up of 3.3 years, crude incidence rates were 7.2, 3.8, and 4.0 events per 100 person-years for myocardial infarction/coronary death, thromboembolism, and serious bleeding, respectively. Relative to VKA monotherapy, the risk of myocardial infarction/coronary death was similar for VKA plus aspirin (hazard ratio, 1.12 [95% confidence interval, 0.94-1.34]) and VKA plus clopidogrel (hazard ratio, 1.53 [95% confidence interval, 0.93-2.52]). The risk of thromboembolism was comparable in all regimens that included VKA, whereas the risk of bleeding increased when aspirin (hazard ratio, 1.50 [95% confidence interval, 1.23-1.82]) or clopidogrel (hazard ratio, 1.84 [95% confidence interval, 1.11-3.06]) was added to VKA. CONCLUSIONS: In atrial fibrillation patients with stable coronary artery disease, the addition of antiplatelet therapy to VKA therapy is not associated with a reduction in risk of recurrent coronary events or thromboembolism, whereas risk of bleeding is increased significantly. The common practice of adding antiplatelet therapy to oral VKA anticoagulation in patients with atrial fibrillation and stable coronary artery disease warrants reassessment. PMID- 24470484 TI - Of cilia, titin, and neurosteroids. PMID- 24470485 TI - Divining the design principles of voltage sensors. PMID- 24470486 TI - Evolutionary imprint of activation: the design principles of VSDs. AB - Voltage-sensor domains (VSDs) are modular biomolecular machines that transduce electrical signals in cells through a highly conserved activation mechanism. Here, we investigate sequence-function relationships in VSDs with approaches from information theory and probabilistic modeling. Specifically, we collect over 6,600 unique VSD sequences from diverse, long-diverged phylogenetic lineages and relate the statistical properties of this ensemble to functional constraints imposed by evolution. The VSD is a helical bundle with helices labeled S1-S4. Surrounding conserved VSD residues such as the countercharges and the S2 phenylalanine, we discover sparse networks of coevolving residues. Additional networks are found lining the VSD lumen, tuning the local hydrophilicity. Notably, state-dependent contacts and the absence of coevolution between S4 and the rest of the bundle are imprints of the activation mechanism on the VSD sequence ensemble. These design principles rationalize existing experimental results and generate testable hypotheses. PMID- 24470487 TI - PLC-mediated PI(4,5)P2 hydrolysis regulates activation and inactivation of TRPC6/7 channels. AB - Transient receptor potential classical (or canonical) (TRPC)3, TRPC6, and TRPC7 are a subfamily of TRPC channels activated by diacylglycerol (DAG) produced through the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) by phospholipase C (PLC). PI(4,5)P2 depletion by a heterologously expressed phosphatase inhibits TRPC3, TRPC6, and TRPC7 activity independently of DAG; however, the physiological role of PI(4,5)P2 reduction on channel activity remains unclear. We used Forster resonance energy transfer (FRET) to measure PI(4,5)P2 or DAG dynamics concurrently with TRPC6 or TRPC7 currents after agonist stimulation of receptors that couple to Gq and thereby activate PLC. Measurements made at different levels of receptor activation revealed a correlation between the kinetics of PI(4,5)P2 reduction and those of receptor-operated TRPC6 and TRPC7 current activation and inactivation. In contrast, DAG production correlated with channel activation but not inactivation; moreover, the time course of channel inactivation was unchanged in protein kinase C-insensitive mutants. These results suggest that inactivation of receptor-operated TRPC currents is primarily mediated by the dissociation of PI(4,5)P2. We determined the functional dissociation constant of PI(4,5)P2 to TRPC channels using FRET of the PLCdelta Pleckstrin homology domain (PHd), which binds PI(4,5)P2, and used this constant to fit our experimental data to a model in which channel gating is controlled by PI(4,5)P2 and DAG. This model predicted similar FRET dynamics of the PHd to measured FRET in either human embryonic kidney cells or smooth muscle cells, whereas a model lacking PI(4,5)P2 regulation failed to reproduce the experimental data, confirming the inhibitory role of PI(4,5)P2 depletion on TRPC currents. Our model also explains various PLC-dependent characteristics of channel activity, including limitation of maximum open probability, shortening of the peak time, and the bell-shaped response of total current. In conclusion, our studies demonstrate a fundamental role for PI(4,5)P2 in regulating TRPC6 and TRPC7 activity triggered by PLC-coupled receptor stimulation. PMID- 24470488 TI - UV light activates a Galphaq/11-coupled phototransduction pathway in human melanocytes. AB - While short exposure to solar ultraviolet radiation (UVR) can elicit increased skin pigmentation, a protective response mediated by epidermal melanocytes, chronic exposure can lead to skin cancer and photoaging. However, the molecular mechanisms that allow human skin to detect and respond to UVR remain incompletely understood. UVR stimulates a retinal-dependent signaling cascade in human melanocytes that requires GTP hydrolysis and phospholipase C beta (PLCbeta) activity. This pathway involves the activation of transient receptor potential A1 (TRPA1) ion channels, an increase in intracellular Ca(2+), and an increase in cellular melanin content. Here, we investigated the identity of the G protein and downstream elements of the signaling cascade and found that UVR phototransduction is Galphaq/11 dependent. Activation of Galphaq/11/PLCbeta signaling leads to hydrolysis of phosphatidylinositol (4,5)-bisphosphate (PIP2) to generate diacylglycerol (DAG) and inositol 1, 4, 5-trisphosphate (IP3). We found that PIP2 regulated TRPA1-mediated photocurrents, and IP3 stimulated intracellular Ca(2+) release. The UVR-elicited Ca(2+) response appears to involve both IP3-mediated release from intracellular stores and Ca(2+) influx through TRPA1 channels, showing the fast rising phase of the former and the slow decay of the latter. We propose that melanocytes use a UVR phototransduction mechanism that involves the activation of a Galphaq/11-dependent phosphoinositide cascade, and resembles light phototransduction cascades of the eye. PMID- 24470489 TI - Removal of immunoglobulin-like domains from titin's spring segment alters titin splicing in mouse skeletal muscle and causes myopathy. AB - Titin is a molecular spring that determines the passive stiffness of muscle cells. Changes in titin's stiffness occur in various myopathies, but whether these are a cause or an effect of the disease is unknown. We studied a novel mouse model in which titin's stiffness was slightly increased by deleting nine immunoglobulin (Ig)-like domains from titin's constitutively expressed proximal tandem Ig segment (IG KO). KO mice displayed mild kyphosis, a phenotype commonly associated with skeletal muscle myopathy. Slow muscles were atrophic with alterations in myosin isoform expression; functional studies in soleus muscle revealed a reduced specific twitch force. Exon expression analysis showed that KO mice underwent additional changes in titin splicing to yield smaller than expected titin isoforms that were much stiffer than expected. Additionally, splicing occurred in the PEVK region of titin, a finding confirmed at the protein level. The titin-binding protein Ankrd1 was highly increased in the IG KO, but this did not play a role in generating small titin isoforms because titin expression was unaltered in IG KO mice crossed with Ankrd1-deficient mice. In contrast, the splicing factor RBM20 (RNA-binding motif 20) was also significantly increased in IG KO mice, and additional differential splicing was reversed in IG KO mice crossed with a mouse with reduced RBM20 activity. Thus, increasing titin's stiffness triggers pathological changes in skeletal muscle, with an important role played by RBM20. PMID- 24470490 TI - Aromatic-aromatic interactions between residues in KCa3.1 pore helix and S5 transmembrane segment control the channel gating process. AB - The Ca(2+)-activated potassium channel KCa3.1 is emerging as a therapeutic target for a large variety of health disorders. One distinguishing feature of KCa3.1 is that the channel open probability at saturating Ca(2+) concentrations (Pomax) is low, typically 0.1-0.2 for KCa3.1 wild type. This observation argues for the binding of Ca(2+) to the calmodulin (CaM)-KCa3.1 complex, promoting the formation of a preopen closed-state configuration leading to channel opening. We have previously shown that the KCa3.1 active gate is most likely located at the level of the selectivity filter. As Ca(2+)-dependent gating of KCa3.1 originates from the binding of Ca(2+) to CaM in the C terminus, the hypothesis of a gate located at the level of the selectivity filter requires that the conformational change initiated in the C terminus be transmitted to the S5 and S6 transmembrane helices, with a resulting effect on the channel pore helix directly connected to the selectivity filter. A study was thus undertaken to determine to what extent the interactions between the channel pore helix with the S5 and S6 transmembrane segments contribute to KCa3.1 gating. Molecular dynamics simulations first revealed that the largest contact area between the pore helix and the S5 plus S6 transmembrane helices involves residue F248 at the C-terminal end of the pore helix. Unitary current recordings next confirmed that modulating aromatic aromatic interactions between F248 and W216 of the S5 transmembrane helical segment and/or perturbing the interactions between F248 and residues in S6 surrounding the glycine hinge G274 cause important changes in Pomax. This work thus provides the first evidence for a key contribution of the pore helix in setting Pomax by stabilizing the channel closed configuration through aromatic aromatic interactions involving F248 of the pore helix. We propose that the interface pore helix/S5 constitutes a promising site for designing KCa3.1 potentiators. PMID- 24470491 TI - Further proofs of concept for the Carba NP test. PMID- 24470492 TI - Reply to "further proofs of concept for the Carba NP test". PMID- 24470493 TI - Underdosing of prophylactic valganciclovir due to inaccurate estimation of glomerular filtration rate leading to severe cytomegalovirus disease in a kidney transplant recipient. PMID- 24470496 TI - Phosphoinositide 3-kinase delta regulates migration and invasion of synoviocytes in rheumatoid arthritis. AB - Cartilage destruction mediated by invasive fibroblast-like synoviocytes (FLS) plays a central role in pathogenesis of rheumatoid arthritis (RA). Increased cell migration and degradation of extracellular matrix are fundamental to these processes. The class I PI3Ks control cell survival, proliferation, and migration, which might be involved in cartilage damage in RA. PI3Kdelta isoform was recently identified as a key regulator of FLS growth and survival, suggesting that it could contribute to synoviocyte aggressive behavior. Therefore, we assessed the role of PI3Kdelta in RA synoviocyte migration and invasion. We observed that PI3Kdelta inhibition or small interfering RNA knockdown decreased platelet derived growth factor (PDGF)-mediated migration and invasion of FLS. We then showed that PI3Kdelta regulates the organization of actin cytoskeleton and lamellipodium formation during PDGF stimulation. To gain insight into molecular mechanisms, we examined the effect of PI3Kdelta inhibition on Rac1/PAK, FAK, and JNK activation. Our studies suggest that Rac1/PAK is key target of PDGF-mediated PI3Kdelta signaling, whereas FAK and JNK are not involved. Thus, PI3Kdelta contributes to multiple aspects of the pathogenic FLS behavior in RA. These observations, together with previous findings that PI3Kdelta regulates FLS growth and survival, suggest that PI3Kdelta inhibition could be chondroprotective in RA by modulating synoviocyte growth, migration, and invasion. PMID- 24470495 TI - G-CSF drives a posttraumatic immune program that protects the host from infection. AB - Traumatic injury is generally considered to have a suppressive effect on the immune system, resulting in increased susceptibility to infection. Paradoxically, we found that thermal injury to the skin induced a robust time-dependent protection of mice from a lethal Klebsiella pneumoniae pulmonary challenge. The protective response was neutrophil dependent and temporally associated with a systemic increase in neutrophils resulting from a reprioritization of hematopoiesis toward myeloid lineages. A prominent and specific activation of STAT3 in the bone marrow preceded the myeloid shift in that compartment, in association with durable increases in STAT3 activating serum cytokines G-CSF and IL-6. Neutralization of the postburn increase in serum G-CSF largely blocked STAT3 activation in marrow cells, reversing the hematopoietic changes and systemic neutrophilia. Daily administration of rG-CSF was sufficient to recapitulate the changes induced by injury including hematopoietic reprioritization and protection from pulmonary challenge with K. pneumoniae. Analysis of posttraumatic gene expression patterns in humans reveals that they are also consistent with a role for G-CSF as a switch that activates innate immune responses and suppresses adaptive immune responses. Our findings suggest that the G-CSF STAT3 axis constitutes a key protective mechanism induced by injury to reduce the risk for posttraumatic infection. PMID- 24470497 TI - Relevance of Nck-CD3 epsilon interaction for T cell activation in vivo. AB - On TCR ligation, the adaptor Nck is recruited through its src homology 3.1 domain to a proline-rich sequence (PRS) in CD3epsilon. We have studied the relevance of this interaction for T cell activation in vitro and in vivo by targeting the interaction sites in both partners. The first approach consisted of studying a knockin (KI) mouse line (KI-PRS) bearing a conservative mutation in the PRS that makes the TCR incompetent to recruit Nck. This deficiency prevents T cell activation by Ag in vitro and inhibited very early TCR signaling events including the tyrosine phosphorylation of CD3zeta. Most important, KI-PRS mice are partly protected against the development of neurological symptoms in an experimental autoimmune encephalitis model, and show a deficient antitumoral response after vaccination. The second approach consisted of using a high-affinity peptide that specifically binds the src homology 3.1 domain and prevents the interaction of Nck with CD3epsilon. This peptide inhibits T cell proliferation in vitro and in vivo. These data suggest that Nck recruitment to the TCR is fundamental to mount an efficient T cell response in vivo, and that the Nck-CD3epsilon interaction may represent a target for pharmacological modulation of the immune response. PMID- 24470498 TI - Endothelial cell-derived chemerin promotes dendritic cell transmigration. AB - ChemR23 is a chemotactic receptor expressed by APCs, such as dendritic cells, macrophages, and NK cells. Chemerin, the ChemR23 ligand, was detected by immunohistochemistry, to be associated with inflamed endothelial cells in autoimmune diseases, such as lupus erythematosus, psoriasis, and rheumatoid arthritis. This study reports that blood and lymphatic murine endothelial cells produce chemerin following retinoic acid stimulation. Conversely, proinflammatory cytokines, such as TNF-alpha, IFN-gamma, and LPS, or calcitriol, are not effective. Retinoic acid-stimulated endothelial cells promoted dendritic cell adhesion under shear stress conditions and transmigration in a ChemR23-dependent manner. Activated endothelial cells upregulated the expression of the atypical chemotactic receptor CCRL2/ACKR5, a nonsignaling receptor able to bind and present chemerin to ChemR23(+) dendritic cells. Accordingly, activated endothelial cells expressed chemerin on the plasma membrane and promoted in a more efficient manner chemerin-dependent transmigration of dendritic cells. Finally, chemerin stimulation of myeloid dendritic cells induced the high affinity binding of VCAM-1/CD106 Fc chimeric protein and promoted VCAM-1 dependent arrest to immobilized ligands under shear stress conditions. In conclusion, this study reports that retinoic acid-activated endothelial cells can promote myeloid and plasmacytoid dendritic cell transmigration across endothelial cell monolayers through the endogenous production of chemerin, the upregulation of CCRL2, and the activation of dendritic cell beta1 integrin affinity. PMID- 24470499 TI - Cell contact-dependent priming and Fc interaction with CD32+ immune cells contribute to the TGN1412-triggered cytokine response. AB - Following inconspicuous preclinical testing, the superagonistic anti-CD28 mAb TGN1412 was applied to six study participants who all developed a devastating cytokine storm. We verified that TGN1412 treatment of fresh PBMCs induced only moderate responses, whereas restoration of tissue-like conditions by high-density preculture (HDC) allowed vigorous cytokine production. TGN1412 treatment of T cells isolated from HDC-PBMCs induced moderate cytokine responses, which upon additional anti-IgG crosslinking were significantly boosted. Moreover, coincubation of TGN1412-treated T cells with B cells expressing the intermediate affinity Fcgamma receptor IIB (CD32B), or coincubation with CD32B(+) transfectants, resulted in robust T cell activation. This was surprising because TGN1412 was expressed as an Ig of the subclass 4 (IgG4), which was shown before to exhibit only minor affinity to FcgammaRs. Transcriptome analysis of TGN1412 treated T cells revealed that similar gene signatures were induced irrespective of whether T cells derived from fresh or HDC-PBMCs were studied. Collectively, these data indicate that HDC-PBMCs and HDC-PBMC-derived T cells mount rapid TGN1412 responses, which are massively boosted by FcgammaR crosslinking, in particular by CD32-expressing B cells. These results qualify HDC-PBMCs as a valuable in vitro test system for the analysis of complex mAb functions. PMID- 24470500 TI - IL-21 promotes CD4 T cell responses by phosphatidylinositol 3-kinase-dependent upregulation of CD86 on B cells. AB - The cytokine IL-21 is a potent immune modulator with diverse mechanisms of action on multiple cell types. IL-21 is in clinical use to promote tumor rejection and is an emerging target for neutralization in the setting of autoimmunity. Despite its clinical potential, the biological actions of IL-21 are not yet fully understood and the full range of effects of this pleiotropic cytokine are still being uncovered. In this study, we identify a novel role for IL-21 as an inducer of the costimulatory ligand CD86 on B lymphocytes. CD86 provides critical signals through T cell-expressed CD28 that promote T cell activation in response to Ag engagement. Expression levels of CD86 are tightly regulated in vivo, being actively decreased by regulatory T cells and increased in response to pathogen derived signals. In this study, we demonstrate that IL-21 can trigger potent and sustained CD86 upregulation through a STAT3 and PI3K-dependent mechanism. We show that elevated CD86 expression has functional consequences for the magnitude of CD4 T cell responses both in vitro and in vivo. These data pinpoint CD86 upregulation as an additional mechanism by which IL-21 can elicit immunomodulatory effects. PMID- 24470502 TI - Type 2 innate lymphoid cells drive CD4+ Th2 cell responses. AB - CD4(+) T cells have long been grouped into distinct helper subsets on the basis of their cytokine-secretion profile. In recent years, several subsets of innate lymphoid cell have been described as key producers of these same Th-associated cytokines. However, the functional relationship between Th cells and innate lymphoid cells (ILCs) remains unclear. We show in this study that lineage negative ST2(+)ICOS(+)CD45(+) type 2 ILCs and CD4(+) T cells can potently stimulate each other's function via distinct mechanisms. CD4(+) T cell provision of IL-2 stimulates type 2 cytokine production by type 2 ILCs. By contrast, type 2 ILCs modulate naive T cell activation in a cell contact-dependent manner, favoring Th2 while suppressing Th1 differentiation. Furthermore, a proportion of type 2 ILCs express MHC class II and can present peptide Ag in vitro. Importantly, cotransfer experiments show that type 2 ILCs also can boost CD4(+) T cell responses to Ag in vivo. PMID- 24470501 TI - E and Id proteins influence invariant NKT cell sublineage differentiation and proliferation. AB - Disease outcome is known to be influenced by defined subsets of invariant NKT (iNKT) cells residing in distinct locations within peripheral tissue. However, the factors governing the development of these unique iNKT sublineages during thymic development are unknown. In this study we explored the mechanism by which E protein transcription factors and their negative regulators, the Id proteins, control the development of iNKT sublineages after positive selection. We found that E proteins directly bound the promyelocytic leukemia zinc finger (PLZF) promoter and were required for expression of this lineage-defining transcription factor and for the maturation and expansion of thymic iNKT cells. Moreover, expression of the negative regulators of E proteins, Id2 and Id3, defined distinct iNKT cell sublineages. Id3 was expressed in PLZF(high) NKT2 cells and loss of Id3 allowed for increased thymic iNKT cell expansion and abundance of the PLZF(+) NKT2 sublineage. Id2 was expressed in T-BET(+) NKT1 cells, and both Id proteins were required for the formation of this sublineage. Thus, we provide insight into E and Id protein regulation of iNKT cell proliferation and differentiation to specific sublineages during development in the thymus. PMID- 24470503 TI - Allelic exclusion of IgH through inhibition of E2A in a VDJ recombination complex. AB - A key feature of the immune system is the paradigm that one lymphocyte has only one Ag specificity that can be selected for or against. This requires that only one of the alleles of genes for AgR chains is made functional. However, the molecular mechanism of this allelic exclusion has been an enigma. In this study, we show that B lymphocytes with E2A that cannot be inhibited by calmodulin are dramatically defective in allelic exclusion of the IgH locus. Furthermore, we provide data supporting that E2A, PAX5, and the RAGs are in a VDJ recombination complex bound to key sequences on the Igh gene. We show that pre-BCR activation releases the VDJ recombination complex through calmodulin binding to E2A. We also show that pre-BCR signaling downregulates several components of the recombination machinery, including RAG1, RAG2, and PAX5, through calmodulin inhibition of E2A. PMID- 24470504 TI - Basophil expansion protects against invasive pneumococcal disease in mice. AB - BACKGROUND: Protein-based vaccination using pneumococcal proteins is a promising approach for efficient vaccines against Streptococcus pneumoniae. Basophils play an important role in enhancing memory immune responses to intact proteins. We examined the impact of increased basophil pool sizes on humoral memory responses to pneumococcal surface protein A (PspA). METHODS: Basophil pool sizes in blood, spleen, and bone marrow were increased by either interleukin 3 (IL-3) treatment or by adoptive basophil transfer before secondary PspA immunization. Subsequently, PspA-specific antibody titers and resistance of mice against invasive pneumococcal disease (IPD) was determined. RESULTS: Mice treated with IL 3, which increased basophil pool sizes, and mice receiving a single basophil transfusion responded with significantly higher PspA-specific antibody titers after immunization with PspA. Importantly, however, just a single transfusion of flow-sorted basophils into mice before secondary immunization with PspA significantly protected mice from lethal IPD. Moreover, concomitant blockade of inhibitory FcgammaRIIB on transfused basophils further substantially increased basophil-mediated protection against IPD in mice. CONCLUSIONS: This is the first study to find that a single transfusion of basophils is sufficient to boost protein-based memory responses against pneumococcal protein antigens, thereby providing significant protection against IPD in mice. PMID- 24470505 TI - The virulence polysaccharide Vi released by Salmonella Typhi targets membrane prohibitin to inhibit T-cell activation. AB - T cells are critical to immunity against pathogenic Salmonella including Salmonella Typhi which causes systemic infection, typhoid, in humans. The strategies that this pathogen employs to keep T-cell mediated immune responses in check during establishment of systemic infection are not completely understood. Here, we show that the virulence polysaccharide Vi, which distinguishes S. Typhi from localized gastroenteritis-producing nontyphoidal Salmonella serovars, is a potent inhibitor of T-cell activation. Vi released by S. Typhi interacts with the membrane prohibitin complex and inhibits IL-2 secretion from T cells stimulated through the T-cell receptor (TCR) but does not affect PMA-activated interleukin 2 (IL-2) secretion. Treatment with Vi suppresses early activation events including TCR down-regulation, actin polymerization, and phosphorylation of ERK. Coadministration of Vi with anti-CD3 Ab reduces secretion of IL-2 and interferon gamma in mice. Our findings reveal a mechanism by which S. Typhi may target T cell immunity during establishment of typhoid. PMID- 24470506 TI - Do the classification and neurobiology of psychiatric illness align? PMID- 24470507 TI - ICD future. PMID- 24470508 TI - DSM-5, ICD-11 and 'pathologization of normal conditions'. PMID- 24470509 TI - Moving from DSM-5 to ICD-11: a joint problem? PMID- 24470510 TI - The 'pragmatic' secret of DSM revisions. PMID- 24470511 TI - Phase Ib study of Buparlisib plus Trastuzumab in patients with HER2-positive advanced or metastatic breast cancer that has progressed on Trastuzumab-based therapy. AB - PURPOSE: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2(+)) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2(+) advanced/metastatic breast cancer resistant to trastuzumab-based therapy. EXPERIMENTAL DESIGN: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2(+) breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control. RESULTS: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (>=6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways. CONCLUSIONS: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935-45. (c)2014 AACR. PMID- 24470512 TI - Prevalence and characteristics of MUTYH-associated polyposis in patients with multiple adenomatous and serrated polyps. AB - PURPOSE: The present study aimed to determine the prevalence of MUTYH mutations in patients with multiple colonic polyps and to explore the best strategy for diagnosing MUTYH-associated polyposis (MAP) in these patients. EXPERIMENTAL DESIGN: This study included 405 patients with at least 10 colonic polyps each. All cases were genetically tested for the three most frequent MUTYH mutations. Whole-gene analysis was performed in heterozygous patients and in 216 patients lacking the three most frequent mutations. Polyps from 56 patients were analyzed for the KRAS-Gly12Cys and BRAF V600E somatic mutations. RESULTS: Twenty-seven (6.7%) patients were diagnosed with MAP, of which 40.8% showed serrated polyps. The sensitivity of studying only the three common variants was 74.1%. Of 216 patients without any monoallelic mutation in common variants, whole-gene analysis revealed biallelic pathogenic mutation in only one. G396D mutation was associated with serrated lesions and older age at diagnosis. There was a strong association between germinal MUTYH mutation and KRAS Gly12Cys somatic mutation in polyps. BRAF V600E mutation was found in 74% of serrated polyps in MUTYH-negative patients and in none of the polyps of MAP patients. CONCLUSIONS: We observed a low frequency of MUTYH mutations among patients with multiple adenomatous and serrated polyps. The MAP phenotype frequently included patients with serrated polyps, especially when G396D mutation was involved. Our results show that somatic molecular markers of polyps can be useful in identifying MAP cases and support the need for the complete MUTYH gene analysis only in patients heterozygous for recurrent variants. PMID- 24470513 TI - A functional germline variant in GLI1 implicates hedgehog signaling in clinical outcome of stage II and III colon carcinoma patients. AB - PURPOSE: Cumulating evidence indicates that germline variants in the Wnt, Notch, and Hedgehog pathways are involved in colon carcinoma progression and metastasis. We investigated germline polymorphisms in a comprehensive panel of Wnt, Notch, and Hedgehog pathway genes to predict time to recurrence (TTR) and overall survival in patients with stage II and III colon carcinoma. EXPERIMENTAL DESIGN: A total of 742 consecutively collected patients with stage II and III colon carcinoma were included in this retrospective study. Genomic DNA was analyzed for 18 germline polymorphisms in Wnt, Notch, and Hedgehog pathway genes (SFRP, DKK 2 and 3, AXIN2, APC, MYC, TCF7L2, NOTCH2, and GLI1) by TaqMan 5'-exonuclease assays. RESULTS: In univariate analysis, the homozygous mutant variant of GLI1 rs2228226 G>C was significantly associated with decreased TTR in a recessive genetic model after adjustment for multiple testing [HR = 2.35; confidence interval (95% CI), 1.48-3.74; P < 0.001] and remained significant in multivariate analysis including clinical stage, lymphovascular-, vascular-, and perineural invasion (HR = 2.43; CI 95%, 1.52-3.87; P < 0.001). In subanalyses, the association was limited to patients with surgery alone (HR = 3.21; CI 95%, 1.59 6.49; P = 0.001), in contrast with patients with adjuvant chemotherapy (HR = 0.82; CI 95%, 0.35-1.95; P = 0.657). When the subgroup of patients with "high risk" GLI1 rs2228226 C/C genotype was analyzed, no benefit of adjuvant 5 fluorouracil-based chemotherapy could be found. CONCLUSION: This is the first study identifying GLI1 rs2228226 G>C as an independent prognostic marker in patients with stage II and III colon carcinoma. Prospective studies are warranted to validate our findings. PMID- 24470514 TI - New strategies in lung cancer: translating immunotherapy into clinical practice. AB - Recent breakthroughs in translating the early development of immunomodulatory antibodies into the clinic, notably with the anti-cytotoxic T-lymphocyte antigen 4 antibody, ipilimumab, have led to durable benefits and prolonged survival for a subgroup of patients with advanced melanoma. Subsequent studies have shown that related immune checkpoint antibodies, specifically those targeting the programmed death-1 pathway, have activity in non-small cell lung cancer. Non-small cell lung cancer is the commonest cause of cancer death worldwide and this exciting avenue of clinical investigation carries with it great promise and new challenges. In this article, we discuss recent developments in lung cancer immunotherapy, reviewing recent findings from therapeutic vaccine studies and in particular we focus on the refinement of immunomodulation as a therapeutic strategy in this challenging disease. PMID- 24470515 TI - Exercise heart rate gradient: a novel index to predict all-cause mortality. AB - BACKGROUND: Although substantial evidence relates reduced exercise heart rate (HR) reserve and recovery to a higher risk of all-cause mortality, a combined indicator of these variables has not been explored. Our aim was to combine HR reserve and recovery into a single index and to assess its utility to predict all cause mortality. DESIGN: Retrospective cohort analysis. METHODS: Participants were 1476 subjects (937 males) aged between 41 and 79 years who completed a maximal cycle cardiopulmonary exercise test while not using medication with negative chronotropic effects or having an implantable cardiac pacemaker. HR reserve (HR maximum - HR resting) and recovery (HR maximum - HR at 1-min post exercise) were calculated and divided into quintiles. Quintile rankings were summed yielding an exercise HR gradient (EHRG) ranging from 2 to 10, reflecting the magnitude of on- and off-HR transients to exercise. Survival analyses were undertaken using EHRG scores and HR reserve and recovery in the lowest quintiles (Q1). RESULTS: During a mean follow up of 7.3 years, 44 participants died (3.1%). There was an inverse trend for EHRG scores and death rate (p < 0.05) that increased from 1.2% to 13.5%, respectively, for scores 10 and 2. An EHRG score of 2 was a better predictor of all-cause mortality than either Q1 for HR reserve (<80 bpm) or HR recovery alone (<27 bpm): age-adjusted hazard ratios: 3.53 (p = 0.011), 2.52 (p < 0.05), and 2.57 (p < 0.05), respectively. CONCLUSIONS: EHRG, a novel index combining HR reserve and HR recovery, is a better indicator of mortality risk than either response alone. PMID- 24470516 TI - Change in health behaviours following acute coronary syndrome: Arab-Jewish differences. AB - BACKGROUND: Health-promoting behaviours after acute coronary syndrome (ACS) are effective in preventing recurrence. Ethnicity impacts on such behaviours. We assessed the independent association of Arab vs. Jewish ethnicity with persistence of smoking and physical inactivity 6 months after ACS in central Israel. DESIGN: Prospective cohort study. METHODS: During their admission for ACS and subsequently 6 months later, 420 patients were interviewed about their smoking and exercise habits. The association of ethnicity with health-promoting behaviours was assessed by logistic regression adjusting for socio-demographic and clinical covariates. RESULTS: Smoking prevalence and physical inactivity were substantially higher among Arab patients than Jewish patients at admission (gender-adjusted prevalence rate ratio (RR) 2.25, 95% CI 1.80-2.81, p < 0.01 and RR 1.46, 95% CI 1.28-1.67, p < 0.001, respectively). The relative differences increased at 6 months (RR 2.94, 95% CI 2.13-4.07, p < 0.001 and RR 3.00, 95% CI 2.24-4.04, p < 0.001, respectively). Excess persistent smoking at 6 months among Arab vs. Jewish patients who were smokers at admission (adjusted OR 2.05, 95% CI 1.00-4.20, p = 0.049) was largely mediated through the 3.5-fold higher participation of Jewish patients in cardiac prevention and rehabilitation program (CPRP) (OR adjusted also for CPRP 1.31, 95% CI 0.59-2.93, p = 0.51). Greater persistent sedentary behaviour at 6 months among nonexercisers at admission among Arab patients (adjusted OR 3.68, 95% CI 1.93-7.02, p < 0.001) was partly mediated through attendance of CPRP (OR adjusted also for CPRP 2.38, 95% CI 1.19-4.76, p = 0.014). CONCLUSIONS: Culturally sensitive programmes need to be developed to enhance CPRP participation and favourable health-promoting changes among Arab patients. A comprehensive understanding of the determinants of the Arab-Jewish differences in efficacious health-promoting behaviours is crucial to inform appropriate ethnic-specific health-promoting strategies. PMID- 24470517 TI - Are there better alternatives than haemoglobin A1c to estimate glycaemic control in the chronic kidney disease population? AB - BACKGROUND: Although measurement of haemoglobin A1c has become the cornerstone for diagnosing diabetes mellitus in routine clinical practice, the role of this biomarker in reflecting long-term glycaemic control in patients with chronic kidney disease has been questioned. METHODS: Consensus review paper based on narrative literature review. RESULTS: As a different association between glycaemic control and morbidity/mortality might be observed in patients with and without renal insufficiency, the European Renal Best Practice, the official guideline body of the European Renal Association-European Dialysis and Transplant Association, presents the current knowledge and evidence of the use of alternative glycaemic markers (glycated albumin, fructosamine, 1,5 anhydroglucitol and continuous glucose monitoring). CONCLUSION: Although reference values of HbA1C might be different in patients with chronic kidney disease, it still remains the cornerstone as follow-up of longer term glycaemic control, as most clinical trials have used it as reference. PMID- 24470518 TI - Spot urine protein measurements in kidney transplantation: a systematic review of diagnostic accuracy. AB - BACKGROUND: Quantification of proteinuria (albuminuria) in renal transplant recipients is important for diagnostic and prognostic purposes. Recent guidelines have recommended quantification of proteinuria by spot protein-to-creatinine ratio (PCR) or spot albumin-to-creatinine ratio (ACR). Validity of spot measurements remains unclear in renal transplant recipients. METHODS: Systematic review of adult kidney transplant recipients. Studies that reported the diagnostic accuracy of PCR or ACR as compared with 24-h urine protein or albumin excretion in renal transplant recipients were included. RESULTS: The search identified 8 studies involving 1871 renal transplant recipients. The correlation of the PCR to 24-h protein ranged from 0.772 to 0.998 with a median value of 0.92. PCR sensitivity ranged from 63 to 99 (50% of sensitivities were >90%); PCR specificity varied from 73 to 99 (50% of specificities were >90%). Only one study reported the bias; percent bias ranged from 12 to 21% and accuracy (within 30% of 24 h urine protein) ranged from 47 to 56% depending on the degree of proteinuria. For the ACR, percent bias ranged from 9 to 21%, and the accuracy (within 30%) ranged from 38 to 80%. CONCLUSIONS: The data regarding diagnostic accuracy of PCR and ACR is limited. Only one report studied the absolute measures of agreement (bias and accuracy). We recommend verifying PCR and ACR measurements with a 24-h protein before making any major diagnostic (e.g. biopsy) or therapeutic (e.g. change in immunosuppressive agents) decisions in this population. PMID- 24470519 TI - Hypercholesterolemia induces oxidant stress that accelerates the ageing of hematopoietic stem cells. AB - BACKGROUND: Clinical studies suggest that hypercholesterolemia may cause ageing in hematopoietic stem cells (HSCs) because ageing-associated alterations were found in peripheral blood cells and their bone marrow residing precursors in patients with advanced atherosclerosis. We hypothesized that hypercholesterolemia induces oxidant stress in hematopoietic stems cells that accelerates their ageing. METHODS AND RESULTS: Here we show that HSCs from ApoE(-/-) mice, as well as HSCs from C57Bl/6 mice fed a high cholesterol diet (HCD) accumulated oxLDL and had greater ROS levels. In accordance, the expression pattern of the genes involved in ROS metabolism changed significantly in HSCs from ApoE(-/-) mice. Hypercholesterolemia caused a significant reduction in phenotypically defined long-term HSC compartment, telomere length, and repopulation capacity of KTLS cells, indicating accelerated ageing in these cells. Gene array analysis suggested abnormal cell cycle status, and the key cell cycle regulators including p19(ARF), p27(Kip1) and p21(Waf1) were upregulated in KTLS cells from hypercholesterolemic mice. These effects were p38-dependent and reversed in vivo by treatment of hypercholesterolemic mice with antioxidant N-acetylcysteine. The oxidant stress also caused aberrant expression of Notch1 that caused loss of quiescence and proliferation leading to the expansion of KTLS compartment in hypercholesterolemic mice. CONCLUSION: Taken together, we provide evidence that hypercholesterolemia can cause oxidant stress that accelerates the ageing and impairs the reconstitution capacity of HSCs. PMID- 24470520 TI - High-sensitivity troponin assays: evidence, indications, and reasonable use. PMID- 24470521 TI - Mitochondrial tRNA variants in Chinese subjects with coronary heart disease. AB - BACKGROUND: Coronary heart disease is the leading cause of death worldwide. Mitochondrial genetic determinants for the development of this disorder remain less explored. METHODS AND RESULTS: We performed a clinical and genetic evaluation and mutational screening of 22 mitochondrial tRNA genes in a cohort of 80 genetically unrelated Han Chinese subjects and 125 members of 4 families with coronary heart disease and 512 Chinese control subjects. This analysis identified 16 nucleotide changes among 9 tRNA genes. Of these, the T5592C mutation creates a highly conservative base pairing (5G-68C) on the acceptor stem of tRNA(Gln), whereas the G15927A mutation destabilizes a highly conserved base pairing (28C 42G) in the anticodon stem of tRNA(Thr). However, the other tRNA variants were polymorphisms. The pedigrees of BJH24 carrying the T5592C mutation, BJH15, and BJH45 harboring the G15927A mutation exhibited maternal transmission of coronary heart disease. Sequence analysis of their mitochondrial genomes revealed the presence of T5592C or G15927A mutation but the absence of other functionally significant mutations in all matrilineal relatives of these families. CONCLUSIONS: Our previous observations showed that altered structures of tRNAs by these mtDNA mutations caused mitochondrial dysfunction. These may be the first evidence that mtDNA mutations increase the risk of coronary heart disease. Our findings may provide new insights into the pathophysiology of this disorder. PMID- 24470522 TI - Elimination of NADPH oxidase activity promotes reductive stress and sensitizes the heart to ischemic injury. AB - BACKGROUND: The NADPH oxidase family (Nox) produces reactive oxygen species by adding the electron donated by NADPH to oxygen. Excessive reactive oxygen species production under a variety of pathological conditions has been attributed to increased Nox activity. Here, we aimed at investigating the role of Nox in cardiac ischemic injury through gain- and loss-of-function approaches. METHODS AND RESULTS: We modulated Nox activity in the heart by cardiac-specific expression of Nox4 and dominant negative Nox4. Modulation of Nox activity drastically changes the cellular redox status. Increasing Nox activity by cardiac specific overexpression of Nox4 imposed oxidative stress on the myocardium [increased NAD(P)(+)/NAD(P)H and decreased glutathione/glutathione disulfide ratio] and worsened cardiac energetics and contractile function after ischemia reperfusion. Overexpression of the dominant negative Nox4 (DN), which abolished the Nox function, led to a markedly reduced state [decreased NAD(P)(+)/NAD(P)H and increased glutathione/glutathione disulfide ratio] at baseline and paradoxically promoted mitochondrial reactive oxygen species production during ischemia resulting in no recovery of heart function after reperfusion. Limiting the generation of reducing equivalent through modulating carbon substrates availability partially restored the NAD(+)/NADH ratio and protected dominant negative Nox4 hearts from ischemic injury. CONCLUSIONS: This study reveals an important role of Nox in cardiac redox regulation and highlights the complexity of developing therapies that affect the intricately connected redox states. PMID- 24470523 TI - Deletion of Kruppel-like factor 4 in endothelial and hematopoietic cells enhances neointimal formation following vascular injury. AB - BACKGROUND: Kruppel-like factor 4 (Klf4) is involved in a variety of cellular functions by activating or repressing the transcription of multiple genes. Results of previous studies showed that tamoxifen-inducible global deletion of the Klf4 gene in mice accelerated neointimal formation following vascular injury, in part via enhanced proliferation of smooth muscle cells (SMCs). Because Klf4 is also expressed in non-SMCs including endothelial cells (ECs), we determined if Tie2 promoter-dependent deletion of Klf4 in ECs and hematopoietic cells affected injury-induced neointimal formation. METHODS AND RESULTS: Klf4 conditional knockout (cKO) mice were generated by breeding Tie2-Cre mice and Klf4 floxed mice, and their phenotype was analyzed after carotid ligation injury. Results showed that injury-induced repression of SMC differentiation markers was unaffected by Tie2 promoter-dependent Klf4 deletion. However, of interest, neointimal formation was significantly enhanced in Klf4-cKO mice 21 days following carotid injury. Moreover, Klf4-cKO mice exhibited an augmented proliferation rate, enhanced accumulation of macrophages and T lymphocytes, and elevated expression of cell adhesion molecules including vascular cell adhesion molecule-1 (Vcam1) and E-selectin in injured arteries. Mechanistic analyses in cultured ECs revealed that Klf4 inhibited tumor necrosis factor-alpha-induced expression of Vcam1 through blocking the binding of nuclear factor-kappaB to the Vcam1 promoter. CONCLUSIONS: These results provide evidence that Klf4 in non-SMCs such as ECs regulates neointimal formation by repressing arterial inflammation following vascular injury. PMID- 24470524 TI - Reliability and validity of the Greek version of the Smoking Self-Efficacy Scale for adolescents. AB - This study examined the psychometric properties of the Greek version of the Smoking Efficacy Scale (SES) for adolescents in a sample of 536 high school students. The factorial structure of the SES was examined by means of a series of exploratory factor analyses. The structural validity, the internal consistency, the temporal stability, and the concurrent validity of the SES were assessed. Exploratory and confirmatory factor analyses revealed a clear three-factor (emotion, opportunity, and friends) structure. Furthermore, SES predicted students' smoking behavior. Overall, the multidimensionality of the SES was supported by our findings, suggesting that the Greek version of the SES appears to be a psychometrically sound instrument that can be used for the evaluation of smoking prevention and smoking cessation programs for high school students. PMID- 24470526 TI - Designing and evaluating the acceptability of Realshare: An online support community for teenagers and young adults with cancer. AB - A participatory action approach was used to design and evaluate the acceptability of the Realshare online community. Pre and post-intervention focus groups were conducted and participants were asked to test out Realshare during two intervention periods: when a facilitator was present and when one was not. Focus group data and forum messages were thematically analysed. The themes identified related to participants' website design requirements, how they used the community and the evaluation of Realshare after having used it. Amendments were made to Realshare throughout the project. Realshare is available to young oncology patients in the South West of England. PMID- 24470527 TI - Asymmetric dimethylarginine and DDAH1 transcript variants in cardiovascular and cerebrovascular diseases. PMID- 24470528 TI - Response to "Asymmetric dimethylarginine and DDAH1 transcript variants in cardiovascular and cerebrovascular diseases". PMID- 24470529 TI - Amino-terminal pro-B-type natriuretic peptide and high-sensitivity C-reactive protein but not cystatin C predict cardiovascular events in male patients with peripheral artery disease independently of ambulatory pulse pressure. AB - BACKGROUND: Patients with peripheral arterial disease (PAD) are at high risk for cardiovascular (CV) events. We have previously shown that ambulatory pulse pressure (APP) predicts CV events in PAD patients. The biomarkers amino-terminal pro-B-type natriuretic peptide (NT-proBNP), high-sensitivity C-reactive protein (hs-CRP), and cystatin C are related to a worse outcome in patients with CV disease, but their predictive values have not been studied in relation to APP. METHODS: Blood samples and 24-hour measurements of ambulatory blood pressure were examined in 98 men referred for PAD evaluation during 1998-2001. Patients were followed for a median of 71 months. The outcome variable was CV events defined as either CV mortality or any hospitalization for myocardial infarction, stroke, or coronary revascularization. The predictive values of log(NT-proBNP), log(hs-CRP), and log(cystatin C) alone and together with APP were assessed by multivariable Cox regression. Area under the curve (AUC) and net reclassification improvement (NRI) were calculated compared with a model containing other significant risk factors. RESULTS: During follow-up, 36 patients had at least 1 CV event. APP, log(NT-proBNP), and log(hs-CRP) all predicted CV events in univariable analysis, whereas log(cystatin C) did not. In multivariable analysis log(NT-proBNP) (hazard ratio (HR) = 1.62; 95% confidence interval (CI) = 1.05-2.51) and log(hs-CRP) (HR = 1.63; 95% CI = 1.19-2.24) predicted events independently of 24-hour PP. The combination of log(NT-proBNP), log(hs-CRP), and average day PP improved risk discrimination (AUC = 0.833 vs. 0.736; P < 0.05) and NRI (37%; P < 0.01) when added to other significant risk factors. CONCLUSIONS: NT-proBNP and hs-CRP predict CV events independently of APP and the combination of hs-CRP, NT-proBNP, and day PP improves risk discrimination in PAD patients. PMID- 24470530 TI - Gallstones, cholecystectomy, and risk of digestive system cancers. AB - Gallstones and cholecystectomy may be related to digestive system cancer through inflammation, altered bile flux, and changes in metabolic hormone levels. Although gallstones are recognized causes of gallbladder cancer, associations with other cancers of the digestive system are poorly established. We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database (1992 2005), which includes 17 cancer registries that cover approximately 26% of the US population, to identify first primary cancers (n = 236,850) occurring in persons aged >=66 years and 100,000 cancer-free population-based controls frequency matched by calendar year, age, and gender. Odds ratios and 95% confidence intervals were calculated using logistic regression analysis, adjusting for the matching factors. Gallstones and cholecystectomy were associated with increased risk of noncardia gastric cancer (odds ratio (OR) = 1.21 (95% confidence interval (CI): 1.11, 1.32) and OR = 1.26 (95% CI: 1.13, 1.40), respectively), small intestine carcinoid (OR = 1.27 (95% CI: 1.01, 1.60) and OR = 1.78 (95% CI: 1.41, 2.25)), liver cancer (OR = 2.35 (95% CI: 2.18, 2.54) and OR = 1.26 (95% CI: 1.12, 1.41)), and pancreatic cancer (OR = 1.24 (95% CI: 1.16, 1.31) and OR = 1.23 (95% CI: 1.15, 1.33)). Colorectal cancer risk associated with gallstones and cholecystectomy decreased with increasing distance from the common bile duct (P trend < 0.001). Hence, gallstones and cholecystectomy are associated with the risk of cancers occurring throughout the digestive tract. PMID- 24470532 TI - Rethinking 'quality' in health care. PMID- 24470531 TI - Malignant peripheral nerve sheath tumors. AB - Malignant peripheral nerve sheath tumors (MPNST) are uncommon, biologically aggressive soft tissue sarcomas of neural origin that pose tremendous challenges to effective therapy. In 50% of cases, they occur in the context of neurofibromatosis type I, characterized by loss of function mutations to the tumor suppressor neurofibromin; the remainder arise sporadically or following radiation therapy. Prognosis is generally poor, with high rates of relapse following multimodality therapy in early disease, low response rates to cytotoxic chemotherapy in advanced disease, and propensity for rapid disease progression and high mortality. The last few years have seen an explosion in data surrounding the potential molecular drivers and targets for therapy above and beyond neurofibromin loss. These data span multiple nodes at various levels of cellular control, including major signal transduction pathways, angiogenesis, apoptosis, mitosis, and epigenetics. These include classical cancer-driving genetic aberrations such as TP53 and phosphatase and tensin homolog (PTEN) loss of function, and upregulation of mitogen-activated protein kinase (MAPK) and (mechanistic) target of rapamycin (TOR) pathways, as well as less ubiquitous molecular abnormalities involving inhibitors of apoptosis proteins, aurora kinases, and the Wingless/int (Wnt) signaling pathway. We review the current understanding of MPNST biology, current best practices of management, and recent research developments in this disease, with a view to informing future advancements in patient care. PMID- 24470533 TI - How to govern physician-hospital exchanges: contractual and relational issues in Belgian hospitals. AB - OBJECTIVE: Our aim was to investigate contractual mechanisms in physician hospital exchanges. The concepts of risk-sharing and the nature of physician hospital exchanges - transactional versus relational - were studied. METHODS: Two qualitative case studies were performed in Belgium. Hospital executives and physicians were interviewed to develop an in-depth understanding of contractual and relational issues that shape physician-hospital contracting in acute care hospitals. The underlying theoretical concepts of agency theory and social exchange theory were used to analyse the data. RESULTS: Our study found that physician-hospital contracting is highly complex. The contract is far more than an economic instrument governing financial aspects. The effect of the contract on the nature of exchange - whether transactional or relational - also needs to be considered. While it can be argued that contractual governance methods are increasingly necessary to overcome the difficulties that arise from the fragmented payment framework by aligning incentives and sharing financial risk, they undermine the necessary relational governance. Relational qualities such as mutual trust and an integrative view on physician-hospital exchanges are threatened, and may be difficult to sustain, given the current fragmentary payment framework. CONCLUSIONS: Since health care policy makers are increasing the financial risk borne by health care providers, it can be argued that this also increases the need to share financial risk and to align incentives between physician and hospital. However, our study demonstrates that while economic alignment is important in determining physician-hospital contracts, the corresponding impact on working relationships should also be considered. Moreover, it is important to avoid a relationship between hospital and physician predominantly characterized by transactional exchanges thereby fostering an unhealthy us-and-them divide and mentality. Relational exchange is a valuable alternative to contractual exchange, stimulating an integrated hospital-physician relationship. Unfortunately, the fragmented payment framework characterized by unaligned incentives is perceived as an obstacle to realize effective collaboration. PMID- 24470534 TI - I Will Forgive You--This Time. PMID- 24470535 TI - Collection efficiencies of high flow rate personal respirable samplers when measuring Arizona road dust and analysis of quartz by x-ray diffraction. AB - Prolonged exposure to respirable crystalline silica (RCS) causes silicosis and is also considered a cause of cancer. To meet emerging needs for precise measurements of RCS, from shorter sampling periods (<4 h) and lower air concentrations, collaborative work was done to assess the differences between personal respirable samplers at higher flow rates. The performance of FSP10, GK2.69, and CIP 10 R samplers were compared with that of the Safety In Mines Personal Dust Sampler (SIMPEDS) sampler as a reference, which is commonly used in the UK for the measurement of RCS. In addition, the performance of the FSP10 and GK 2.69 samplers were compared; at the nominal flow rates recommended by the manufacturers of 10 and 4.2 l . min(-1) and with flow rates proposed by the National Institute for Occupational Safety and Health of 11.2 and 4.4 l . min( 1). Samplers were exposed to aerosols of ultrafine and medium grades of Arizona road dust (ARD) generated in a calm air chamber. All analyses for RCS in this study were performed at the Health and Safety Laboratory. The difference in flow rates for the GK2.69 is small and does not result in a substantial difference in collection efficiency for the dusts tested, while the performance of the FSP10 at 11.2 l . min(-1) was more comparable with samples from the SIMPEDS. Conversely, the GK2.69 collected proportionately more crystalline silica in the respirable dust than other samplers, which then produced RCS results most comparable with the SIMPEDS. The CIP 10 R collected less ultrafine ARD than other samplers, as might be expected based on earlier performance evaluations. The higher flow rate for the FSP10 should be an added advantage for task-specific sampling or when measuring air concentrations less than current occupational exposure limits. PMID- 24470536 TI - Exposure to airborne endotoxins among sewer workers: an exploratory study. AB - Exploratory bioaerosol sampling was performed in order to assess exposure to airborne endotoxins during sewer work. Personal samples were collected in underground sewer pipes using 37-mm closed-face cassettes containing fibreglass filters (CFC-FG method) or polycarbonate filters (CFC-PC method). Endotoxins were quantified using the limulus amoebocyte lysate assay. Concentrations of airborne endotoxins at sewer workplaces (16-420 EU m(-3)) were higher than those measured outside the sewer network (0.6-122 EU m(-3)). Sewer worker exposure to airborne endotoxins depended on the workplace and on the tasks. Exposure levels were the highest for tasks involving agitation of water and matter, especially for 'chamber cleanup' and 'pipes cleanup' with a high-pressure water jet. Airborne endotoxin levels at the workplace tended to be higher when CFC-FG was used as the sampling method rather than CFC-PC. The adjusted mean of the measured concentrations for CFC-PC represents 57% of the mean observed with CFC-FG. The number of samples collected in the descriptive study was too low for drawing definitive conclusions and further exposure investigations are needed. Therefore, our exploratory study provides new exposure data for the insufficiently documented sewer working environment and it would be useful for designing larger exposures studies. PMID- 24470537 TI - Using zebrafish as a model system for studying the transgenerational effects of dioxin. AB - 2,3,7,8 Tetrachlorodibenzo-p-dioxin (TCDD) has been associated with many disease states in humans. A rising concern is that exposure early in life can lead to adult toxicity and toxicity in subsequent generations. Juvenile zebrafish exposed to TCDD (50 pg/ml in water; 1 h exposure) at 3 and 7 weeks post fertilization showed toxicity only later in adulthood. We have maintained the offspring of these exposed F0 fish to determine whether we could find adverse affects in the next two generations of F1 and F2 offspring. TCDD exposure produced a significantly higher female:male ratio in all three generations. Scoliosis-like axial skeleton abnormalities, not normally observed in controls, were present in the F1 and F2 generations descended from the treated F0 founders. Egg release and fertilization success were reduced in the TCDD lineage F1 and F2 generations. This reduction in fertility in the TCDD lineage F2 generation could be attributed to alterations in the F2 males. Using zebrafish as a model allowed the simultaneous maintenance of different generations with relatively small space and costs. The zebrafish showed clear signs of transgenerational responses persisting into generations never directly exposed to TCDD. PMID- 24470538 TI - Response to H Zeidler's comments on the INFAST study. PMID- 24470539 TI - ADHD and Suicidal Ideation: The Roles of Emotion Regulation and Depressive Symptoms Among College Students. AB - OBJECTIVE: ADHD appears to increase risk for both depression and suicidal ideation, while ADHD and depression are also associated with emotion regulation deficits. Thus, we evaluated the degree to which depression mediated the association between ADHD and suicidal ideation, as well as the degree to which emotion regulation deficits moderated the association ADHD shared with depression and suicidal ideation in a nonclinical sample. METHOD: Participants were undergraduate psychology students (N = 627; age: M = 20.23, SD = 1.40; 60% female; 47% European American) who completed an online assessment. RESULTS: Results indicated that ADHD indirectly increased suicidal ideation through depression. Emotion regulation deficits of accepting negative emotions, emotional awareness, and goal-oriented behavior moderated the indirect effect of ADHD on suicidal ideation. CONCLUSION: Depression appears to play an important mediating role in suicidal ideation for college students with ADHD, and specific emotion regulation deficits appear to amplify the effects of ADHD on depression and suicidal ideation. PMID- 24470540 TI - Accident Proneness in Children and Adolescents Affected by ADHD and the Impact of Medication. AB - OBJECTIVE: This study aims to ascertain once and for all whether children and adolescents affected by ADHD show a higher risk for accidents, as well as investigating a possible association between the administration of ADHD-specific medication and the occurrence of accidents. METHOD: Two exceptionally large sets of data were implemented in this analysis. Participants included children and adolescents representative of the entire German population. Data for Survey 1 was collected through extensive administration of questionnaires. Data for Survey 2 stemmed from the records of a leading German health insurance company. In terms of statistical analysis, chi-square tests as well as logistic regression analyses were applied and odds ratios (ORs) were determined. RESULTS: Innovative results are presented showing a significantly higher likelihood for ADHD-affected youngsters to be involved in accidents compared with their nonaffected counterparts (Survey 1: OR = 1.60; Survey 2: OR = 1.89) but lacking an overall significant influence of medication regarding the occurrence of accidents (Survey 1: OR = 1.28; Survey 2: OR = 0.97). Frequency of accidents could be predicted by ADHD, gender, and age in both samples. Medication intake served as a weak predictor only in Survey 2. CONCLUSION: It has been determined in two representative and independent German samples that youngsters with ADHD are at a significantly higher risk of being involved in accidents. In the future, this should always be considered when setting up a treatment plan to ensure a safer and healthier coming of age without relying solely on specific effects of medication. (J. of Att. Dis. 2016; 20(6) 501-509). PMID- 24470541 TI - Estimating mineral changes in enamel formation by ashing/BSE and microCT. AB - Enamel formation produces the most highly mineralized tissue in the human body. The growth of enamel crystallites is assisted by enamel proteins and proteinases. As enamel formation progresses from secretory to maturation stages, the composition of the matrix with its mineral and non-mineral components dynamically changes in an inverse fashion. We hypothesized that appropriately calibrated micro-computed tomography (uCT) technology is suitable to estimate the mineral content (weight and/or density) and volume comparable in accuracy with that for directly weighed and sectioned enamel. Different sets of mouse mandibular incisors of C57BL/6 mice were used for dissections and uCT reconstructions. Calibration phantoms corresponding to the range of enamel mineral densities were used. Secretory-stage enamel contained little mineral and was consequently too poor in contrast for enamel volumes to be accurately estimated by uCT. Maturation stage enamel, however, showed remarkable correspondence for total mineral content per volume where comparisons were possible between and among the different analytical techniques used. The main advantages of the uCT approach are that it is non-destructive, time-efficient, and can monitor changes in mineral content of the most mature enamel, which is too physically hard to dissect away from the tooth. PMID- 24470542 TI - Effects of life-long fluoride intake on bone measures of adolescents: a prospective cohort study. AB - Controversy persists concerning the impact of community water fluoridation on bone health in adults, and few studies have assessed relationships with bone at younger ages. Ecological studies of fluoride's effects showed some increase in bone mineral density of adolescents and young adults in areas with fluoridated water compared with non-fluoridated areas. However, none had individual fluoride exposure measures. To avoid ecological fallacy and reduce bias, we assessed associations of average daily fluoride intake from birth to age 15 yr for Iowa Bone Development Study cohort members with age 15 yr dual-energy x-ray absorptiometry (DXA) bone outcomes (whole body, lumbar spine, and hip), controlling for known determinants (including daily calcium intake, average daily time spent in moderate-to-vigorous intensity physical activity, and physical maturity). Mean (SD) daily fluoride intake was 0.66 mg (0.24) for females and 0.78 mg (0.30) for males. We found no significant relationships between daily fluoride intake and adolescents' bone measures in adjusted models (for 183 females, all p values >= .10 and all partial R(2) <= 0.02; for 175 males, all p values >= .34 and all partial R(2) <= 0.01). The findings suggest that fluoride exposures at the typical levels for most US adolescents in fluoridated areas do not have significant effects on bone mineral measures. PMID- 24470544 TI - Prognostic factors associated with survival in patients with symptomatic spinal bone metastases: a retrospective cohort study of 1,043 patients. AB - BACKGROUND: Expected survival is a major factor influencing extent of treatment for symptomatic spinal bone metastases (SBM). Predictive models have been developed, but their use can lead to over- or undertreatment.. The study objective was to identify prognostic factors associated with survival in patients with symptomatic SBM and to create a validated risk stratification model. METHODS: All patients who were treated for symptomatic SBM between 2001 and 2010 were included in this single center retrospective study. Medical records were reviewed for type of primary cancer, performance status, presence of visceral, brain and bone metastases, number and location of spinal metastases, and neurological functioning. Performance status was assessed with the Karnofsky performance score and neurological functioning with the Frankel scale. Analysis was performed using Kaplan-Meier curves, univariate log-rank tests, Cox regression models, and Harrell's C statistic. RESULTS: A total of 1 043 patients were studied. The most prevalent tumors were those of breast (n = 299), lung (n = 250), and prostate (n = 215). Median follow-up duration was 6.6 years, and 6 patients were lost to follow-up. Based on the results of the uni- and multivariate analyses, 4 categories were created. Median survival in category A was 31.2 months (95% CI, 25.2-37.3 months), 15.4 months (95% CI, 11.9-18.2 months) for category B, 4.8 months (95% CI, 4.1-5.4 months) for category C, and 1.6 months (95% CI, 1.4-1.9 months) for category D. Harrell's C statistic was calculated after the model was applied to an external dataset, yielding a result of 0.69. CONCLUSION: Assessing patients according to the presented model results in 4 categories with significantly different survival times. PMID- 24470543 TI - Consequences of cancer treatments on adult hippocampal neurogenesis: implications for cognitive function and depressive symptoms. AB - The human brain is capable of generating new functional neurons throughout life, a phenomenon known as adult neurogenesis. The generation of new neurons is sustained throughout adulthood due to the proliferation and differentiation of adult neural stem cells. This process in humans is uniquely located in the subgranular zone of the dentate gyrus in the hippocampus. Adult hippocampal neurogenesis (AHN) is thought to play a major role in hippocampus-dependent functions, such as spatial awareness, long-term memory, emotionality, and mood. The overall aim of current treatments for cancer (such as radiotherapy and chemotherapy) is to prevent aberrant cell division of cell populations associated with malignancy. However, the treatments in question are absolutist in nature and hence inhibit all cell division. An unintended consequence of this cessation of cell division is the impairment of adult neural stem cell proliferation and AHN. Patients undergoing treatment for cancerous malignancies often display specific forms of memory deficits, as well as depressive symptoms. This review aims to discuss the effects of cancer treatments on AHN and propose a link between the inhibition of the neurogenetic process in the hippocampus and the advent of the cognitive and mood-based deficits observed in patients and animal models undergoing cancer therapies. Possible evidence for coadjuvant interventions aiming to protect neural cells, and subsequently the mood and cognitive functions they regulate, from the ablative effects of cancer treatment are discussed as potential clinical tools to improve mental health among cancer patients. PMID- 24470545 TI - Analysis of IDH mutation, 1p/19q deletion, and PTEN loss delineates prognosis in clinical low-grade diffuse gliomas. AB - BACKGROUND: Grades II and III gliomas have unpredictable rates of progression, making management decisions difficult. Currently, several clinical and radiological characteristics are utilized to predict progression and survival but collectively are suboptimal. METHODS: In this study, we analyzed a set of 108 nonenhancing hemispheric grade II-III gliomas. Demographic variables, including patient age, tumor diameter, extent of resection, and performance status, were combined with molecular data (IDH mutation status [mIDH], 1p/19q codeletion, PTEN deletion, and EGFR amplification). A complete dataset for all variables was compiled for 70 of the 108 patients. Both univariable and multivariable analyses were performed to determine whether the molecular data singly or in combination offer advantages over tumor type and grade for prediction of overall survival (OS) and/or progression-free rate (PFR). RESULTS: Patient age, clinical variables (tumor diameter, extent of resection, performance status), and pathology (tumor type and grade) were not predictive of OS or PFR. IDH mutation status alone was predictive of longer OS and PFR for the entire group of tumors; 1p/19q deletion alone was predictive of OS but not PFR. In the multivariable analysis, none of the clinical or demographic factors were predictive of OS or PFR. IDH mutation status, 1p/19q codeletion, and PTEN deletion were predictive of OS (P = .003, P = .005, P = .02, respectively). Both mIDH (P < .001) and the interaction term of 1p/19q and PTEN (P < .001) were found to be predictive of PFR. CONCLUSIONS: We conclude that the combination of mIDH, 1p/19q codeletion, and PTEN deletion may be particularly effective in discriminating good prognosis from poor prognosis hemispheric gliomas. We propose that such a scheme merits testing on larger prospective cohorts. Should our findings be confirmed, routine clinical analysis of hemispheric gliomas for mIDH, 1p/19q codeletion, and PTEN deletion would be justified. PMID- 24470546 TI - Phase II trial of patupilone in patients with brain metastases from breast cancer. AB - BACKGROUND: For patients with progressive breast cancer brain metastasis (BCBM) after whole brain radiotherapy (WBRT), few options exist. Patupilone is an epothilone that crosses the blood-brain barrier. We hypothesized that patupilone would produce a 35% 3-month CNS progression-free survival in women with BCBM after WBRT. METHODS: This multicenter phase II trial included 2 cohorts. Group A included women with progressive BCBM after WBRT. Group B was an exploratory cohort of patients with either leptomeningeal metastases or untreated brain metastases. The primary goal was to observe a 35% 3-month CNS progression-free survival in Group A. The sample size was 45 for Group A and 10 for Group B. Patients received patupilone 10 mg/m(2) once every 3 weeks until progression. Responses were scored according to the Macdonald criteria. RESULTS: Fifty-five patients (45 in Group A, 10 in Group B) enrolled. In Group A, the 3-month CNS progression-free survival was 27%, the median overall survival was 12.7 months, and the overall response rate was 9%. In Group B, which enrolled 5 patients with leptomeningeal disease and 5 with no prior WBRT, no responses occurred and 8 patients had CNS progression before 3 months. Systemic responses occurred in 15% of patients, including a complete response in liver metastases. Diarrhea occurred in 87% of patients; 25% had grade 3 and 4 adverse events. CONCLUSIONS: Patupilone in patients with BCBM did not meet the efficacy criteria and had significant gastrointestinal toxicity. Further study of brain-penetrant agents is warranted for patients with CNS metastases from breast cancer. PMID- 24470547 TI - Pre-B-cell leukemia homeobox interacting protein 1 is overexpressed in astrocytoma and promotes tumor cell growth and migration. AB - BACKGROUND: Glial brain tumors cause considerable mortality and morbidity in children and adults. Innovative targets for therapy are needed to improve survival and reduce long-term sequelae. The aim of this study was to find a candidate tumor-promoting protein, abundantly expressed in tumor cells but not in normal brain tissues, as a potential target for therapy. METHODS: In silico proteomics and genomics, immunohistochemistry, and immunofluorescence microscopy validation were performed. RNA interference was used to ascertain the functional role of the overexpressed candidate target protein. RESULTS: In silico proteomics and genomics revealed pre-B-cell leukemia homeobox (PBX) interacting protein 1 (PBXIP1) overexpression in adult and childhood high-grade glioma and ependymoma compared with normal brain. PBXIP1 is a PBX-family interacting microtubule binding protein with a putative role in migration and proliferation of cancer cells. Immunohistochemical studies in glial tumors validated PBXIP1 expression in astrocytoma and ependymoma but not in oligodendroglioma. RNAi-mediated PBXIP1 knockdown in glioblastoma cell lines strongly reduced proliferation and migration and induced morphological changes, indicating that PBXIP1 knockdown decreases glioma cell viability and motility through rearrangements of the actin cytoskeleton. Furthermore, expression of PBXIP1 was observed in radial glia and astrocytic progenitor cells in human fetal tissues, suggesting that PBXIP1 is an astroglial progenitor cell marker during human embryonic development. CONCLUSION: PBXIP1 is a novel protein overexpressed in astrocytoma and ependymoma, involved in tumor cell proliferation and migration, that warrants further exploration as a novel therapeutic target in these tumors. PMID- 24470548 TI - Incidence and survival of children with central nervous system primitive tumors in the French National Registry of Childhood Solid Tumors. AB - BACKGROUND: Central nervous system (CNS) tumors are the second most common childhood malignancy. The French National Registry of Childhood Solid Tumors (NRCST) makes it possible to describe this variety of distinct tumor types and to provide incidence and survival data in France on a nationwide basis. METHODS: All children aged 0-14 years, who were registered with a primary CNS tumor in the NRCST of France between 2000 and 2008, were identified. Tumors were classified according to the International Classification of Childhood Cancer, third edition. RESULTS: Approximately 57% of pediatric CNS tumors were gliomas, with astrocytomas of the pilocytic type predominating. Distributions of subtypes by age showed that primitive neuroectodermal tumors and ependymomas mainly occurred in children aged <5 years. The mean annual incidence rate of CNS tumors was 39 per million. No statistically significant change in time trends of incidence rate was observed during 2000-2008. For all tumors combined, overall survival was 84.8% (95% CI, 83.7%-85.9%) at 1 year and 72.9% (95% CI, 71.5%-74.3%) at 5 years. Survival time trends were studied in a multivariate analysis observing a reduction in the risk of death in periods of diagnosis 2003-2005 (HR = 0.8; 95% CI, 0.7-0.9) and 2006-2008 (HR = 0.7; 95% CI, 0.6-0.9) compared with 2000-2002. CONCLUSIONS: The stable incidence rates during the last 10 years could indicate that major changes in environmental risk factors are unlikely, but the ongoing need for population-based surveillance remains relevant. Results indicate a positive trend in the survival probability still persistent in the 2000s. PMID- 24470550 TI - Adult pilocytic astrocytomas: clinical features and molecular analysis. AB - BACKGROUND: Adult pilocytic astrocytomas (PAs) are rare and have an aggressive clinical course compared with pediatric patients. Constitutive Ras/RAF/MAPK signaling appears to be an important oncogenic event in sporadic PA. We evaluated clinical data and molecular profiles of adult PAs at our institution. METHODS: We identified 127 adult PAs in our institutional database. Cases with available tissue were tested for BRAF-KIAA1549 fusion/duplication (B-K fusion) by fluorescence in situ hybridization and submitted for mutation profiling using the Sequenom mutation profiling panel. Subgroup analyses were performed based on clinical and molecular data. RESULTS: The majority of adult PAs are supratentorial. Twenty-two percent of cases had an initial pathologic diagnosis discordant with the diagnosis made at our institution. Recurrence was seen in 42% of cases, and 13% of patients died during follow-up. Adjuvant radiotherapy following surgical resection was associated with a statistically significant decrease in progression-free survival (P = .004). B-K fusion was identified in 20% (9 of 45) of patients but was not associated with outcome. No BRAF V600E mutations (0 of 40 tested) were found. CONCLUSION: This was the largest single institution series of adult PA. A significant proportion of adult PAs follow an aggressive clinical course. Our results support a period of observation following biopsy or surgical resection. B-K fusion in adult PA does not influence outcome, and BRAF V600E mutation appears to be a very rare event. Further study of tumor biology and optimal treatment is needed, given a more aggressive clinical behavior. PMID- 24470549 TI - Glioma virus therapies between bench and bedside. AB - Despite extensive research, current glioma therapies are still unsatisfactory, and novel approaches are pressingly needed. In recent years, both nonreplicative viral vectors and replicating oncolytic viruses have been developed for brain cancer treatment, and the mechanistic background of their cytotoxicity has been unveiled. A growing number of clinical trials have convincingly established viral therapies to be safe in glioma patients, and maximum tolerated doses have generally not been reached. However, evidence for therapeutic benefit has been limited: new generations of therapeutic vectors need to be developed in order to target not only tumor cells but also the complex surrounding microenvironment. Such therapies could also direct long-lasting immune responses toward the tumor while reducing early antiviral reactions. Furthermore, viral delivery methods are to be improved and viral spread within the tumor will have to be enhanced. Here, we will review the outcome of completed glioma virus therapy trials as well as highlight the ongoing clinical activities. On this basis, we will give an overview of the numerous strategies to enhance therapeutic efficacy of new generation viruses and novel treatment regimens. Finally, we will conclude with approaches that may be crucial to the development of successful glioma therapies in the future. PMID- 24470551 TI - Integrating diffusion kurtosis imaging, dynamic susceptibility-weighted contrast enhanced MRI, and short echo time chemical shift imaging for grading gliomas. AB - BACKGROUND: We assessed the diagnostic accuracy of diffusion kurtosis imaging (DKI), dynamic susceptibility-weighted contrast-enhanced (DSC) MRI, and short echo time chemical shift imaging (CSI) for grading gliomas. METHODS: In this prospective study, 35 patients with cerebral gliomas underwent DKI, DSC, and CSI on a 3 T MR scanner. Diffusion parameters were mean diffusivity (MD), fractional anisotropy, and mean kurtosis (MK). Perfusion parameters were mean relative regional cerebral blood volume (rrCBV), mean relative regional cerebral blood flow (rrCBF), mean transit time, and relative decrease ratio (rDR). The diffusion and perfusion parameters along with 12 CSI metabolite ratios were compared among 22 high-grade gliomas and 14 low-grade gliomas (Mann-Whitney U-test, P < .05). Classification accuracy was determined with a linear discriminant analysis for each MR modality independently. Furthermore, the performance of a multimodal analysis is reported, using a decision-tree rule combining the statistically significant DKI, DSC-MRI, and CSI parameters with the lowest P-value. The proposed classifiers were validated on a set of subsequently acquired data from 19 clinical patients. RESULTS: Statistically significant differences among tumor grades were shown for MK, MD, mean rrCBV, mean rrCBF, rDR, lipids over total choline, lipids over creatine, sum of myo-inositol, and sum of creatine. DSC-MRI proved to be the modality with the best performance when comparing modalities individually, while the multimodal decision tree proved to be most accurate in predicting tumor grade, with a performance of 86%. CONCLUSIONS: Combining information from DKI, DSC-MRI, and CSI increases diagnostic accuracy to differentiate low- from high-grade gliomas, possibly providing diagnosis for the individual patient. PMID- 24470552 TI - Treatment of orthotopic malignant peripheral nerve sheath tumors with oncolytic herpes simplex virus. AB - BACKGROUNDS: Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive and often lethal sarcoma that frequently develops in patients with neurofibromatosis type 1 (NF1). We developed new preclinical MPNST models and tested the efficacy of oncolytic herpes simplex viruses (oHSVs), a promising cancer therapeutic that selectively replicates in and kills cancer cells. METHODS: Mouse NF1(-) MPNST cell lines and human NF1(-) MPNST stemlike cells (MSLCs) were implanted into the sciatic nerves of immunocompetent and athymic mice, respectively. Tumor growth was followed by external measurement and sciatic nerve deficit using a hind-limb scoring system. Oncolytic HSV G47Delta as well as "armed" G47Delta expressing platelet factor 4 (PF4) or interleukin (IL)-12 were injected intratumorally into established sciatic nerve tumors. RESULTS: Mouse MPNST cell lines formed tumors with varying growth kinetics. A single intratumoral injection of G47Delta in sciatic nerve tumors derived from human S462 MSLCs in athymic mice or mouse M2 (37-3-18-4) cells in immunocompetent mice significantly inhibited tumor growth and prolonged survival. Local IL-12 expression significantly improved the efficacy of G47Delta in syngeneic mice, while PF4 expression prolonged survival. Injection of G47Delta directly into the sciatic nerve of athymic mice resulted in only mild symptoms that did not differ from phosphate buffered saline control. CONCLUSIONS: Two new orthotopic MPNST models are described, including in syngeneic mice, expanding the options for preclinical testing. Oncolytic HSV G47Delta exhibited robust efficacy in both immunodeficient and immunocompetent MPNST models while maintaining safety. Interleukin-12 expression improved efficacy. These studies support the clinical translation of G47Delta for patients with MPNST. PMID- 24470553 TI - MYCN amplification predicts poor outcome for patients with supratentorial primitive neuroectodermal tumors of the central nervous system . AB - BACKGROUND: Primitive neuroectodermal tumors of the central nervous system (CNS PNETs) are a rare group of neoplasms occurring in the CNS that includes supratentorial CNS-PNETs, medulloepitheliomas, and ependymoblastomas. While ependymoblastomas frequently carry chromosome 19q13.41 amplification and show aggressive clinical behavior, the biological mechanisms and molecular alterations contributing to the pathogenesis of supratentorial CNS-PNETs remain poorly understood. Moreover, genetic alterations suitable for molecular risk stratification are undefined to date. METHODS: In order to identify possible molecular markers, we performed multiplex ligation-dependent probe amplification (MLPA) and molecular inversion probe (MIP) analysis on DNA samples of 25 supratentorial CNS-PNETs (median age, 5.35 years; range, 2.41-17.28 years). Tumors with ependymoblastic rosettes (ependymoblastoma/ETANTR) and LIN28A positivity were excluded. RESULTS: MLPA and MIP analysis revealed large losses of genomic material of chromosomes 3, 4, 5, and 13, while frequent gains affected chromosomes 1, 17, 19, 20, and 22. High copy number gains (amplifications) were found in particular at chromosomes 2p24.3 (MYCN, n = 6 cases) and 4q12 (n = 2 cases). Patients with tumors harboring 2p gain or MYCN amplification showed unfavorable overall survival (P = .003 and P = .001, respectively).These markers were independent of the presence of metastases, which was indeed a clinical factor associated with poor overall survival (P = .01) in this series. CONCLUSIONS: In the era of the personalized neuro-oncology, the identification of these molecular prognostic markers associated with patient outcome may represent a significant step towards improved patient stratification and risk-adapted therapeutic strategies for patients suffering from supratentorial CNS-PNETs. PMID- 24470554 TI - Epiregulin enhances tumorigenicity by activating the ERK/MAPK pathway in glioblastoma. AB - BACKGROUND: Glioblastoma multiforme (GBM) is one of the most aggressive human tumors, and the establishment of an effective therapeutic reagent is a pressing priority. Recently, it has been shown that the tumor tissue consists of heterogeneous components and that a highly aggressive population should be the therapeutic target. METHODS: Through a single subcutaneous passage of GBM cell lines LN443 and U373 in mice, we have developed highly aggressive variants of these cells named LN443X, U373X1, and U373X2, which showed increased tumor growth, colony-forming potential, sphere-forming potential, and invasion ability. We further investigated using microarray analysis comparing malignant cells with their parental cells and mRNA expression analysis in grades II to IV glioma samples. RESULTS: Adipocyte enhancer binding protein 1, epiregulin (EREG), and microfibrillar associated protein 5 were identified as candidate genes associated with higher tumor grade and poor prognosis. Immunohistochemical analysis also indicated a correlation of a strong expression of EREG with short overall survival. Furthermore, both EREG stimulation and EREG introduction of GBM cell lines were found to increase phosphorylation of epidermal growth factor receptor (EGFR) and extracellular signal-regulated kinase and resulted in the promotion of colony formation, sphere formation, and in vivo tumor formation. Gefitinib treatment inhibited phosphorylation of EGFR and extracellular signal-regulated kinase and led to tumor regression in U373-overexpressed EREG. CONCLUSION: These results suggested that EREG is one of the molecules involved in glioma malignancy, and EGFR inhibitors may be a candidate therapeutic agent for EREG overexpressing GBM patients. PMID- 24470555 TI - Incidence of glioma in a northwestern region of England, 2006-2010. AB - BACKGROUND: Gliomas are important because they affect disproportionately high numbers of people of working age and have a poor prognosis. Neurosurgeons were concerned about a possible recent cluster of glioma cases in a northwestern region in England. METHODS: All patients aged 18-89 years in Lancashire and South Cumbria with a histologically confirmed glioma diagnosed at the Royal Preston Hospital between January 1, 2006, and December 31, 2010, were ascertained. Clinical information was extracted from hospital records. Completeness of case referral to Royal Preston Hospital was checked against the National Cancer Registry and National Brain Tumour Registry records for the same period. For a comprehensive assessment of regional incidence, age-standardized incidence rates of all gliomas diagnosed in adults (aged 15 years and older) in the study area were then compared with those for the North West region and England as a whole. Rates for the North West region in defined small area-units ("Middle Super Output Areas") were also investigated to assess any small-area variation in the region during the decade to 2010. RESULTS: There were 435 glioma patients from Lancashire and South Cumbria diagnosed at the Royal Preston Hospital between 2006 and 2010, with case ascertainment verified to be complete by the National Cancer Registration Service. The age-standardized incidence rate of gliomas in the study area was 7.10 per 100,000 in 2006-2010, which was minimally different from the rate for all cancer networks in England over the 10 years from 2001. Small-area analysis confirmed lack of major variation in glioma rates in the North West region of England. CONCLUSION: Glioma incidence rates in England have remained stable by region and over time during the last decade. PMID- 24470556 TI - A patient tumor-derived orthotopic xenograft mouse model replicating the group 3 supratentorial primitive neuroectodermal tumor in children. AB - BACKGROUND: Supratentorial primitive neuroectodermal tumor (sPNET) is a malignant brain tumor with poor prognosis. New model systems that replicate sPNET's molecular subtype(s) and maintain cancer stem cell (CSC) pool are needed. METHODS: A fresh surgical specimen of a pediatric sPNET was directly injected into the right cerebrum of Rag2/SCID mice. The xenograft tumors were serially sub transplanted in mouse brains, characterized histopathologically, and subclassified into molecular subtype through qRT-PCR and immunohistochemical analysis. CSCs were identified through flow cytometric profiling of putative CSC markers (CD133, CD15, CD24, CD44, and CD117), functional examination of neurosphere forming efficiency in vitro, and tumor formation capacity in vivo. To establish a neurosphere line, neurospheres were propagated in serum-free medium. RESULTS: Formation of intracerebral xenograft tumors was confirmed in 4 of the 5 mice injected with the patient tumor. These xenograft tumors were sub transplanted in vivo 5 times. They replicated the histopathological features of the original patient tumor and expressed the molecular markers (TWIST1 and FOXJ1) of group 3 sPNET. CD133(+) and CD15(+) cells were found to have strong neurosphere-forming efficiency in vitro and potent tumor-forming capacity (with as few as 100 cells) in vivo. A neurosphere line BXD-2664PNET-NS was established that preserved stem cell features and expressed group 3 markers. CONCLUSION: We have established a group 3 sPNET xenograft mouse model (IC-2664PNET) with matching neurosphere line (BXD-2664PNET-NS) and identified CD133(+) and CD15(+) cells as the major CSC subpopulations. This novel model system should facilitate biological studies and preclinical drug screenings for childhood sPNET. PMID- 24470558 TI - Strengths-oriented therapeutic conversations for families of children with chronic illnesses: findings from the Landspitali university hospital family nursing implementation project. AB - Psychosocial services have been recommended for families of children with chronic illnesses to assist them in adjusting to the illness experience. However, little is known about the benefit of psychosocial interventions in clinical practice. This study aimed at evaluating the benefits of a two-session family therapeutic conversation intervention (FAM-TCIs) for families of children diagnosed with asthma, cancer, or diabetes. A secondary data analysis was conducted on intervention data from 37 families of children with chronic illnesses. Mothers of the children/teenagers perceived significantly higher family support after the FAM-TCI compared with before; mothers reported significantly higher collaboration and problem-solving abilities on the expressive family functioning scale after the FAM-TCI. However, no significant differences were found on the fathers' perceived family support nor on their expressive family functioning after the FAM TCI compared with that before the intervention. It is promising that mothers of children with chronic illness perceived the two-session FAM-TCI to be beneficial to them. More attention should be paid to psychosocial interventions for families of children with chronic illnesses. PMID- 24470557 TI - Phase I/II study of erlotinib and temsirolimus for patients with recurrent malignant gliomas: North American Brain Tumor Consortium trial 04-02. AB - BACKGROUND: Inhibition of epidermal growth factor receptor (EGFR) and the mechanistic target of rapamycin (mTOR) may have synergistic antitumor effects in high-grade glioma patients. METHODS: We conducted a phase I/II study of the EGFR inhibitor erlotinib (150 mg/day) and the mTOR inhibitor temsirolimus. Patients initially received temsirolimus 50 mg weekly, and the dose adjusted based on toxicities. In the phase II component, the primary endpoint was 6-month progression-free survival (PFS6) among glioblastoma patients. RESULTS: Twenty-two patients enrolled in phase I, 47 in phase II. Twelve phase I patients treated at the maximum tolerated dosage were included in the phase II cohort for analysis. The maximum tolerated dosage was 15 mg temsirolimus weekly with erlotinib 150 mg daily. Dose-limiting toxicities were rash and mucositis. Among 42 evaluable glioblastoma patients, 12 (29%) achieved stable disease, but there were no responses, and PFS6 was 13%. Among 16 anaplastic glioma patients, 1 (6%) achieved complete response, 1 (6%) partial response, and 2 (12.5%) stable disease, with PFS6 of 8%. Tumor levels of both drugs were low, and posttreatment tissue in 3 patients showed no reduction in the mTOR target phosphorylated (phospho )S6(S235/236) but possible compensatory increase in phospho-Akt(S473). Presence of EGFR variant III, phospho-EGFR, and EGFR amplification did not correlate with survival, but patients with elevated phospho-extracellular signal-regulated kinase or reduced phosphatase and tensin homolog protein expression had decreased progression-free survival at 4 months. CONCLUSION: Because of increased toxicity, the maximum tolerated dosage of temsirolimus in combination with erlotinib proved lower than expected. Insufficient tumor drug levels and redundant signaling pathways may partly explain the minimal antitumor activity noted. PMID- 24470559 TI - Collagenase clostridium histolyticum in patients with Dupuytren's contracture: results from POINT X, an open-label study of clinical and patient-reported outcomes. AB - In POINT X, a study designed to reflect clinical practice and patient treatment choices, 254 European patients received open-label collagenase for Dupuytren's contracture. The most severely affected joint was treated first in 74% of patients. In total, 52%, 41%, 7%, and 1% of patients selected the little, ring, middle, and index finger, respectively; 79% had one or two joints treated. Only 9% of patients (n = 24) received 4 or 5 injections. The mean improvement in total passive extension deficit (TPED) was 34 degrees on day 1, improving further by day 7 to 42 degrees . This secondary improvement was maintained by day 90 and month 6. The mean number of injections/joint was 1.2 for the metacarpophalangeal joint and 1.25 for the proximal interphalangeal joint. Median time to recovery was 4 days; the mean improvement in hand function was clinically relevant as measured by the Unite Rhumatologique des Affections de la Main (URAM) score. In total, 87% and 86% of patients and physicians, respectively, were very satisfied or satisfied with treatment at month 6, although correlation between TPED and patient satisfaction was weak (Spearman -0.18, 95% CI -0.32 to -0.06). Collagenase was well tolerated, with 10 (3.9%) patients experiencing severe adverse events. As a real-world study, the POINT X findings can be generalized to the at-large population. PMID- 24470560 TI - Real-time polymerase chain reaction for detection of Schistosoma DNA in small volume urine samples reflects focal distribution of urogenital Schistosomiasis in primary school girls in KwaZulu Natal, South Africa. AB - Schistosoma haematobium eggs and Schistosoma DNA levels were measured in urine samples from 708 girls recruited from 18 randomly sampled primary schools in South Africa. Microscopic analysis of two 10-mL urine subsamples collected on three consecutive days confirmed high day-to-day variation; 103 (14.5%) girls had positive results at all six examinations, and at least one positive sample was seen in 225 (31.8%) girls. Schistosoma-specific DNA, which was measured in a 200 MUL urine subsample by using real-time polymerase chain reaction, was detected in 180 (25.4%) cases, and levels of DNA corresponded significantly with average urine egg excretion. In concordance with microscopic results, polymerase chain reaction results were significantly associated with history of gynecologic symptoms and confirmed highly focal distribution of urogenital schistosomiasis. Parasite-specific DNA detection has a sensitivity comparable to single urine microscopy and could be used as a standardized high-throughput procedure to assess distribution of urogenital schistosomiasis in relatively large study populations by using small sample volumes. PMID- 24470561 TI - Kinetics of dengue non-structural protein 1 antigen and IgM and IgA antibodies in capillary blood samples from confirmed dengue patients. AB - Large-scale epidemiological surveillance of dengue in the field and dengue patient management require simple methods for sample collection, storage, and transportation as well as effective diagnostic tools. We evaluated the kinetics of three biological markers of dengue infection-non-structural protein 1 (NS1) antigen, immunoglobulin M (IgM), and IgA-in sequential capillary blood samples collected from fingertips of confirmed dengue patients. The overall sensitivities and specificities of the tests were 96% and 100%, respectively, for NS1, 58.1% and 100%, respectively, for IgM, and 33% and 100%, respectively, for IgA. During the acute phase of the disease, NS1 was the best marker of dengue infection, with a sensitivity of 98.7%, whereas from day 5, all three markers exhibited relevant levels of sensitivity. This first descriptive study of the kinetics of biological markers of dengue in capillary blood samples confirms the usefulness of this biological compartment for dengue diagnosis and argues for its exploitation in community-level and remote settings. PMID- 24470562 TI - Reemergence of Anopheles funestus as a vector of Plasmodium falciparum in western Kenya after long-term implementation of insecticide-treated bed nets. AB - Historically, the malaria vectors in western Kenya have been Anopheles funestus, Anopheles gambiae s.s., and Anopheles arabiensis. Of these species, An. funestus populations declined the most after the introduction of insecticide-treated bed nets (ITNs) in the 1990s in Asembo, and collections of An. funestus in the region remained low until at least 2008. Contrary to findings during the early years of ITN use in Asembo, the majority of the Anopheles collected here in 2010 and 2011 were An. funestus. Female An. funestus had characteristically high Plasmodium falciparum sporozoite rates and showed nearly 100% anthropophily. Female An. funestus were found more often indoors than outdoors and had relatively low mortality rates during insecticide bioassays. Together, these results are of serious concern for public health in the region, indicating that An. funestus may once again be contributing significantly to the transmission of malaria in this region despite the widespread use of ITNs/long-lasting insecticidal nets (LLINs). PMID- 24470563 TI - Cholera epidemic associated with consumption of unsafe drinking water and street vended water--Eastern Freetown, Sierra Leone, 2012. AB - During 2012, Sierra Leone experienced a cholera epidemic with 22,815 reported cases and 296 deaths. We conducted a matched case-control study to assess risk factors, enrolling 49 cases and 98 controls. Stool specimens were analyzed by culture, polymerase chain reaction (PCR), and pulsed-field gel electrophoresis (PFGE). Conditional logistic regression found that consuming unsafe water (matched odds ratio [mOR]: 3.4; 95% confidence interval [CI]: 1.1, 11.0), street vended water (mOR: 9.4; 95% CI: 2.0, 43.7), and crab (mOR: 3.3; 95% CI: 1.03, 10.6) were significant risk factors for cholera infection. Of 30 stool specimens, 13 (43%) showed PCR evidence of toxigenic Vibrio cholerae O1. Six specimens yielded isolates of V. cholerae O1, El Tor; PFGE identified a pattern previously observed in seven countries. We recommended ensuring the quality of improved water sources, promoting household chlorination, and educating street vendors on water handling practices. PMID- 24470564 TI - Occurrence and correlates of symptom persistence following acute dengue fever in Peru. AB - Dengue virus (DENV) infection causes an acute febrile illness generally considered to result in either complete recovery or death. Some reviews describe persistent symptoms after the febrile phase, although empirical data supporting this phenomenon is scarce. We evaluated symptom persistence in acute febrile DENV infected and DENV-negative (controls) individuals from Peru. Self-reported solicited symptoms were evaluated at an acute and a follow-up visit, occurring 10 60 days after symptom onset. Rate of persistence of at least one symptom was 7.7% and 10.5% for DENV infected and control subjects, respectively (P < 0.01). The DENV-infected individuals had lower rates of persistent respiratory symptoms, gastrointestinal symptoms, headache, and fatigue, but higher rates of persistent rash compared with controls. Older age and female gender were positively associated with symptom persistence. As dengue cases continue to increase annually, even a relatively low frequency of persistent symptoms may represent a considerable worldwide morbidity burden. PMID- 24470565 TI - Meteorological influences on the seasonality of Lyme disease in the United States. AB - Lyme disease (Borrelia burgdorferi infection) is the most common vector transmitted disease in the United States. The majority of human Lyme disease (LD) cases occur in the summer months, but the timing of the peak occurrence varies geographically and from year to year. We calculated the beginning, peak, end, and duration of the main LD season in 12 highly endemic states from 1992 to 2007 and then examined the association between the timing of these seasonal variables and several meteorological variables. An earlier beginning to the LD season was positively associated with higher cumulative growing degree days through Week 20, lower cumulative precipitation, a lower saturation deficit, and proximity to the Atlantic coast. The timing of the peak and duration of the LD season were also associated with cumulative growing degree days, saturation deficit, and cumulative precipitation, but no meteorological predictors adequately explained the timing of the end of the LD season. PMID- 24470567 TI - What Counts as Rape? The Effect of Offense Prototypes, Victim Stereotypes, and Participant Gender on How the Complainant and Defendant are Perceived. AB - Jurors rely on a range of schemas when evaluating allegations of rape and sexual assault. For example, they may be influenced by the prototypicality of the alleged offense, the stereotypicality of the victim, or gender-related stereotypes. These schemas have often been conflated however, making it difficult to determine the unique impact of each on jurors' perceptions. To be able to effectively counter any schema-related misconceptions, we must first identify which beliefs are important and when. An experiment (N = 420) examined the independent effects of offense prototypicality and victim stereotypicality on mock jurors' perceptions. As expected, victim stereotypicality had a greater effect on judgments in the counter-prototypical (acquaintance) assault scenario than in the prototypical (stranger) assault scenario. When the complainant was described as being a counter-stereotypical victim in the acquaintance rape scenario, the defendant was seen as less likely to be guilty and evaluated more positively and the complainant less positively compared with when the complainant was described as being a stereotypical victim. Analysis of the qualitative data suggested a focus on different factors in reaching verdicts in the stranger and acquaintance rape scenarios. Results were interpreted as evidence that jurors "step down" through a hierarchy of schemas in their attempts to determine what happened in cases of rape and sexual assault. PMID- 24470566 TI - Dengue virus serotype 1 non-structural protein NS5 expression interferes with HIV replication in a CD4+ T-cell line. PMID- 24470568 TI - Poly-Victimization Risk in Prison: The Influence of Individual and Institutional Factors. AB - Victimization research suggests that individuals who either witness or are direct victims of violence are substantially more likely to experience long-term negative outcomes. Although recent studies identifying factors associated with prison victimization are emerging, the risk factors predicting inmate's experience of multiple types of victimization, called poly-victimization, remain unknown. Utilizing a lifestyles model that incorporates the importation/deprivation framework, the current study examines whether certain features of the prison environment or individual characteristics predict who is most likely to experience victimization. Data from more than 1,600 recently released inmates confirm that the environmental and individual-level factors are related to poly-victimization in prison. The findings from the study have implications for policy and practice. PMID- 24470569 TI - Factors Affecting Initial Intimate Partner Violence-Specific Health Care Seeking in the Tokyo Metropolitan Area, Japan. AB - This study examined the factors affecting a women's initial intimate partner violence (IPV)-specific health care seeking event which refers to the first health care seeking as a result of IPV in a lifetime. Data were collected using the Life History Calendar method in the Tokyo metropolitan area from 101 women who had experienced IPV. Discrete-time survival analysis was used to assess the time to initial IPV-specific health care seeking. IPV-related injury was the most significant factor associated with increased likelihood of seeking IPV-specific health care seeking for the first time. In the presence of a strong effect of formal help seeking, physical and sexual IPV were no longer significantly related to initial IPV-specific health care seeking. The results suggest some victims of IPV may not seek health care unless they get injured. The timing of receiving health care would be important to ensure the health and safety of victims. PMID- 24470570 TI - Parseq: reconstruction of microbial transcription landscape from RNA-Seq read counts using state-space models. AB - MOTIVATION: The most common RNA-Seq strategy consists of random shearing, amplification and high-throughput sequencing of the RNA fraction. Methods to analyze transcription level variations along the genome from the read count profiles generated by the RNA-Seq protocol are needed. RESULTS: We developed a statistical approach to estimate the local transcription levels and to identify transcript borders. This transcriptional landscape reconstruction relies on a state-space model to describe transcription level variations in terms of abrupt shifts and more progressive drifts. A new emission model is introduced to capture not only the read count variance inside a transcript but also its short-range autocorrelation and the fraction of positions with zero counts. The estimation relies on a particle Gibbs algorithm whose running time makes it more suited to microbial genomes. The approach outperformed read-overlapping strategies on synthetic and real microbial datasets. AVAILABILITY: A program named Parseq is available at: http://www.lgm.upmc.fr/parseq/. CONTACT: bodgan.mirauta@upmc.fr SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24470571 TI - Bio Simulators: a web UI for biological simulation. AB - SUMMARY: A host of formal, textual languages for modeling cellular processes have recently emerged, but their simulation tools often require an installation process which can pose a barrier for use. Bio Simulators is a framework for easy online deployment of simulators, providing a uniform web-based user interface to a diverse pool of tools. The framework is demonstrated through two plugins based on the KaSim Kappa simulator, one running directly in the browser and another running in the cloud. AVAILABILITY: Web tool: bsims.azurewebsites.net. KaSim client side simulator: github.com/NicolasOury/KaSimJS. KaSim cloud simulator: github.com/mdpedersen/KaSimCloud. CONTACT: michael.d.pedersen@gmail.com or Andrew.Phillips@microsoft.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24470572 TI - ChEpiMod: a knowledgebase for chemical modulators of epigenome reader domains. AB - CONTEXT: Epigenome reader domains are rapidly emerging as a new class of drug targets for a wide array of human diseases. To facilitate study of structure activity relationship and small-molecule ligand design for these domains, we have created ChEpiMod. ChEpiMod is a free knowledgebase of chemical modulators with documented modulatory activity for epigenome reader domains. METHODS: ChEpiMod organizes information about chemical modulators and their associated binding affinity data, as well as available structures of epigenome readers from the Protein Data Bank. The data are gathered from the literature and patents. Entries are supplemented by annotation. The current version of ChEpiMod covers six epigenome reader domain families (Bromodomain, PHD finger, Chromodomain, MBT, PWWP and Tudor). The database can be used to browse existing chemical modulators and bioactivity data, as well as, all available structures of readers and their molecular interactions. The database is updated weekly. AVAILABILITY: ChEpiMod is freely available at http://chepimod.org CONTACT: ming-ming.zhou@mssm.edu SUPPLEMENTARY INFORMATION: Supplementary data is available at Bioinformatics online. PMID- 24470573 TI - Network orientation via shortest paths. AB - The graph orientation problem calls for orienting the edges of a graph so as to maximize the number of pre-specified source-target vertex pairs that admit a directed path from the source to the target. Most algorithmic approaches to this problem share a common preprocessing step, in which the input graph is reduced to a tree by repeatedly contracting its cycles. Although this reduction is valid from an algorithmic perspective, the assignment of directions to the edges of the contracted cycles becomes arbitrary, and the connecting source-target paths may be arbitrarily long. In the context of biological networks, the connection of vertex pairs via shortest paths is highly motivated, leading to the following problem variant: given a graph and a collection of source-target vertex pairs, assign directions to the edges so as to maximize the number of pairs that are connected by a shortest (in the original graph) directed path. This problem is NP complete and hard to approximate to within sub-polynomial factors. Here we provide a first polynomial-size integer linear program formulation for this problem, which allows its exact solution in seconds on current networks. We apply our algorithm to orient protein-protein interaction networks in yeast and compare it with two state-of-the-art algorithms. We find that our algorithm outperforms previous approaches and can orient considerable parts of the network, thus revealing its structure and function. AVAILABILITY AND IMPLEMENTATION: The source code is available at www.cs.tau.ac.il/~roded/shortest.zip. CONTACT: roded@post.tau.ac.il. PMID- 24470574 TI - PGP: parallel prokaryotic proteogenomics pipeline for MPI clusters, high throughput batch clusters and multicore workstations. AB - SUMMARY: We present the first public release of our proteogenomic annotation pipeline. We have previously used our original unreleased implementation to improve the annotation of 46 diverse prokaryotic genomes by discovering novel genes, post-translational modifications and correcting the erroneous annotations by analyzing proteomic mass-spectrometry data. This public version has been redesigned to run in a wide range of parallel Linux computing environments and provided with the automated configuration, build and testing facilities for easy deployment and portability. AVAILABILITY AND IMPLEMENTATION: Source code is freely available from https://bitbucket.org/andreyto/proteogenomics under GPL license. It is implemented in Python and C++. It bundles the Makeflow engine to execute the workflows. CONTACT: atovtchi@jcvi.org. PMID- 24470575 TI - Composition of seed sequence is a major determinant of microRNA targeting patterns. AB - MOTIVATION: MicroRNAs (miRNAs) are small non-coding RNAs that are extensively involved in gene expression regulation. One major roadblock in functional miRNA studies is the reliable prediction of genes targeted by miRNAs, as rules defining miRNA target recognition have not been well-established to date. Availability of high-throughput experimental data from a recent CLASH (cross linking, ligation and sequencing of hybrids) study has presented an unprecedented opportunity to characterize miRNA target recognition patterns, which may provide guidance for improved miRNA target prediction. RESULTS: The CLASH data were analysed to identify distinctive sequence features that characterize canonical and non canonical miRNA target types. Most miRNA targets were of non-canonical type, i.e. without involving perfect pairing to canonical miRNA seed region. Different miRNAs have distinct targeting patterns, and this miRNA-to-miRNA variability was associated with seed sequence composition. Specifically, seed-based canonical target recognition was dependent on the GC content of the miRNA seed. For miRNAs with low GC content of the seed region, non-canonical targeting was the dominant mechanism for target recognition. In contrast to canonical targeting, non canonical targeting did not lead to significant target downregulation at either the RNA or protein level. CONTACT: xwang@radonc.wustl.edu. PMID- 24470576 TI - NGSANE: a lightweight production informatics framework for high-throughput data analysis. AB - SUMMARY: The initial steps in the analysis of next-generation sequencing data can be automated by way of software 'pipelines'. However, individual components depreciate rapidly because of the evolving technology and analysis methods, often rendering entire versions of production informatics pipelines obsolete. Constructing pipelines from Linux bash commands enables the use of hot swappable modular components as opposed to the more rigid program call wrapping by higher level languages, as implemented in comparable published pipelining systems. Here we present Next Generation Sequencing ANalysis for Enterprises (NGSANE), a Linux based, high-performance-computing-enabled framework that minimizes overhead for set up and processing of new projects, yet maintains full flexibility of custom scripting when processing raw sequence data. AVAILABILITY AND IMPLEMENTATION: Ngsane is implemented in bash and publicly available under BSD (3-Clause) licence via GitHub at https://github.com/BauerLab/ngsane. CONTACT: Denis.Bauer@csiro.au SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24470577 TI - Helicobacter pullorum cytolethal distending toxin targets vinculin and cortactin and triggers formation of lamellipodia in intestinal epithelial cells. AB - Helicobacter pullorum, a bacterium initially isolated from poultry, has been associated with human digestive disorders. However, the factor responsible for its cytopathogenic effects on epithelial cells has not been formally identified. The cytopathogenic alterations induced by several human and avian H. pullorum strains were investigated on human intestinal epithelial cell lines. Moreover, the effects of the cytolethal distending toxin (CDT) were evaluated first by using a wild-type strain and its corresponding cdtB isogenic mutant and second by delivering the active CdtB subunit of the CDT directly into the cells. All of the H. pullorum strains induced cellular distending phenotype, actin cytoskeleton remodeling, and G2/M cell cycle arrest. These effects were dependent on the CDT, as they were (1) not observed in response to a cdtB isogenic mutant strain and (2) present in cells expressing CdtB. CdtB also induced an atypical delocalization of vinculin from focal adhesions to the perinuclear region, formation of cortical actin-rich large lamellipodia with an upregulation of cortactin, and decreased cellular adherence. In conclusion, the CDT of H. pullorum is responsible for major cytopathogenic effects in vitro, confirming its role as a main virulence factor of this emerging human pathogen. PMID- 24470583 TI - Bilateral hypertrophic olivary nucleus degeneration on magnetic resonance imaging in children with Leigh and Leigh-like syndrome. AB - OBJECTIVE: Bilateral hypertrophic olivary degeneration on brain MRI has been reported in a few metabolic, genetic and neurodegenerative disorders, including mitochondrial disorders. In this report, we sought to analyse whether bilateral symmetrical inferior olivary nucleus hypertrophy is specifically associated with mitochondrial disorders in children. METHODS: This retrospective study included 125 children (mean age, 7.6 +/- 5 years; male:female, 2.6:1) diagnosed with various metabolic and genetic disorders during 2005-2012. The routine MRI sequences (T1 weighted, T2 weighted and fluid-attenuated inversion-recovery sequences) were analysed for the presence of bilateral symmetrical olivary hypertrophy and central tegmental tract or dentate nuclei signal changes. The other imaging findings and the final diagnoses were noted. RESULTS: The cohort included patients with Leigh and Leigh-like syndrome (n = 25), other mitochondrial diseases (n = 25), Wilson disease (n = 40), Type 1 glutaric aciduria (n = 14), maple syrup urine disease (n = 13), giant axonal neuropathy (n = 5) and L-2 hydroxy glutaric aciduria (n = 3). Bilateral inferior olivary nucleus hypertrophy was noted in 10 patients, all of whom belonged to the Leigh and Leigh-like syndrome group. CONCLUSION: Bilateral hypertrophic olivary degeneration on MRI is relatively often, but not routinely, seen in children with Leigh and Leigh-like syndrome. Early detection of this finding by radiologists and physicians may facilitate targeted metabolic testing in these children. ADVANCES IN KNOWLEDGE: This article highlights the occurrence of bilateral hypertrophic olivary nucleus degeneration on MRI in children with Leigh and Leigh like syndrome, compared with other metabolic disorders. PMID- 24470584 TI - Prognostic impact of p16 and p53 expression in oropharyngeal squamous cell carcinomas. AB - BACKGROUNDS: A p16 protein is known to be overexpressed in human papillomavirus positive head and neck squamous cell carcinoma specimens. p53 is a tumor suppressor protein detectable by immunohistochemistry in carcinogen-associated head and neck squamous cell carcinoma as a result of gene mutations. The purpose of this study is to investigate the prognostic impact of p16 and p53 expression in oropharyngeal squamous cell carcinomas. METHODS: We retrospectively examined the relationship between prognosis, and p16 and p53 expression levels of oropharyngeal squamous cell carcinoma specimens in 53 patients using immunohistochemistry. RESULTS: Overall, 55% of patients were p16 positive and 45% p16 negative, while 28% were p53 positive and 72% p53 negative. The p16 status showed an inverse relationship with the p53 status. A survival analysis by p16 status, p53 status, Union for International Cancer Control stage and main treatment modality demonstrated that only p16 status was related to better prognosis in terms of overall survival and disease-specific survival (3-year overall survival, 87 vs. 62%, P = 0.02; 3-year disease-specific survival, 90 vs. 62%, P = 0.02). To evaluate the practical prognostic factors in oropharyngeal squamous cell carcinoma patients, we classified patients as either p16-positive or p53-negative oropharyngeal squamous cell carcinomas, representing human papillomavirus-related oropharyngeal squamous cell carcinoma with wild-type p53 or the remaining patients with p16-negative or p53-positive OPSCCs, respectively. The former group showed survival advantages in terms of overall survival and disease-specific survival by log-tank test compared with the latter group (3-year overall survival, 96 vs. 58%, P = 0.005; 3-year disease-specific survival, 96 vs. 63%, P = 0.02). CONCLUSIONS: A group of patients who were p16 positive/p53 negative had better prognoses in terms of overall survival and disease-specific survival than that who were p16-positive alone. PMID- 24470585 TI - The dose and risk factors for radiation exposure to medical staff during endobronchial ultrasonography with a guide sheath for peripheral pulmonary lesions under X-ray fluoroscopy. AB - OBJECTIVE: Therapy for lung cancer has recently evolved to include molecular targeted therapy and adequate amounts of lung cancer tissue are needed to identify particular phenotypes. For this purpose, quite a number of investigations on diagnostic bronchoscopy have been undertaken. Corollary to the increasing number of transbronchial biopsies for peripheral pulmonary nodules is the increased chances of radiation exposure during fluoroscopy. Our aim was to determine the dose and risk factors of radiation exposure to medical staff. METHODS: Endobronchial ultrasonography with a guide sheath under X-ray fluoroscopy was performed on 132 cases of peripheral pulmonary lesions. The radiation exposure dose to medical staff (operator physicians, assistant physicians, nurses and radiological technologists) was measured. RESULTS: The median time of fluoroscopy was 7.6 min (range 1.5-23.9). The median radiation exposure dose to operator physicians was 12 MUSv/exam (range 1-99), while that of the other medical staff was lower. In a multivariate analysis, body mass index and the location of the radial ultrasound probe had significantly higher odds ratios. CONCLUSIONS: The risk factors for an increased radiation exposure dose were patients' BMI and the location of the radial ultrasound probe. But even then, the radiation exposure dose to medical staff during endobronchial ultrasonography with a guide sheath was very low, especially for nurses and radiological technologists in whom the exposure dose was negligible. PMID- 24470586 TI - Surgical procedure depending on the depth of tumor invasion in duodenal cancer. AB - BACKGROUND: Duodenal cancer excluding Vater's papilla cancer is a relatively rare disease entity; therefore, the most appropriate operative methods depending on the tumor condition, such as the tumor site and/or depth of invasion, still remain unclear. The aim of this study is to determine an appropriate operative method and an appropriate extent of lymph node dissection depending on tumor site or tumor invasion depth. METHODS: Data of a total of 35 patients with duodenal cancer who underwent resectional surgery with curative intent were reviewed retrospectively, and the clinicopathological factors and survival outcomes were investigated. RESULTS: Overall 5-year survival rates of all resected cases were 63.0% (median survival: 9.1 years). Multivariate analysis identified histological G3/4 (P = 0.002) and presence of lymph node metastasis (P = 0.004) as independent adverse prognostic factors. Of the 35 patients, 11 (31.4%) had lymph node metastasis. In all patients with the tumor invasion depth within limited to the mucosa or submucosa (T1a or T1b), lymph node metastasis was absent (0/15 patients). T2/3/4 tumor (P < 0.001) and G3/4 (P = 0.021) were identified as predictors of the presence of lymph node metastasis. Four (11.4%) of the 35 patients had metastasis in the infrapyloric node. CONCLUSIONS: Limited resection is sufficient for patients with T1a tumor. In the case of T1b tumor, limited resection or pancreatoduodenectomy may be selected after performing pancreaticoduodenal node biopsy as sentinel lymph node biopsy. For patients with T2-4 tumor, pancreatoduodenectomy or substomach preserving pancreatoduodenectomy (excepting Pylorus-preserving pancreatoduodenectomy) with regional lymph node dissection should be performed. PMID- 24470587 TI - Implementation of an app-based neuromuscular training programme to prevent ankle sprains: a process evaluation using the RE-AIM Framework. AB - BACKGROUND/AIM: The contemporary electronic media is regarded as a practical tool in the dissemination of preventive measures and interventions. For this purpose an App (free of charge) was developed including an efficacious programme for the prevention of ankle sprain recurrences. This study evaluated the implementation effectiveness of this 'Versterk je Enkel' App. METHODS: The App was evaluated within its practical context using the Reach Effectiveness Adoption Implementation Maintenance (RE-AIM) Framework. The launch of the App was accompanied by a press release, website banners, as well as online and offline advertisements. Data for the evaluation of the App were objectively registered through Google analytics. Data were obtained in February 2013 based on 25,781 users resulting in follow-ups of 18 months (iOS version) and 15 months (Android version), respectively. Users questionnaires provided a qualitative view of the objectively assessed measures (n=82) to gain insight into the demographics of users, reasons to download, user experience and how the information was used. RESULTS: The App reached only 2.6% of the projected target population. User ratings for the App's relevancy, clarity, usefulness, appeal, information and reliability were high. App usage indicates that compliance with the embedded programme was low. CONCLUSIONS: Although the App was well received by the users, targeted efforts are required to ensure proper uptake and usage of the App by the target population. This also holds true for eHealth and mHealth efforts aimed at athlete care and injury prevention in general. PMID- 24470588 TI - Higher efficacy of dietary DHA provided as a phospholipid than as a triglyceride for brain DHA accretion in neonatal piglets. AB - Long-chain PUFAs (LCPUFAs) occur in foods primarily in the natural lipid classes, triacylglycerols (TAGs) or phospholipids (PLs). We studied the relative efficacy of the neural omega-3 DHA provided in formula to growing piglets as a dose of (13)C-DHA bound to either TAG or phosphatidylcholine (PC). Piglets were assigned to identical formula-based diets from early life and provided with TAG-(13)C-DHA or PC-(13)C-DHA orally at 16 days. Days later, piglet organs were analyzed for (13)C-DHA and other FA metabolites. PC-(13)C-DHA was 1.9-fold more efficacious for brain gray matter DHA accretion than TAG-(13)C-DHA, and was similarly more efficacious in gray matter synaptosomes, retina, liver, and red blood cells (RBCs). Liver labeling was greatest, implying initial processing in that organ followed by export to other organs, and suggesting that transfer from gut to bloodstream to liver in part drove the difference in relative efficacy for tissue accretion. Apparent retroconversion to 22:5n-3 was more than double for PC-(13)C DHA and was more prominent in neural tissue than in liver or RBCs. These data directly support greater efficacy for PC as a carrier for LCPUFAs compared with TAG, consistent with previous studies of arachidonic acid and DHA measured in other species. PMID- 24470589 TI - ATF3 is a novel regulator of mouse neutrophil migration. AB - Expression of the activating transcription factor 3 (ATF3) gene is induced by Toll-like receptor (TLR) signaling. In turn, ATF3 protein inhibits the expression of various TLR-driven proinflammatory genes. Given its counter-regulatory role in diverse innate immune responses, we defined the effects of ATF3 on neutrophilic airway inflammation in mice. ATF3 deletion was associated with increased lipopolysaccharide (LPS)-driven airway epithelia production of CXCL1, but not CXCL2, findings concordant with a consensus ATF3-binding site identified solely in the Cxcl1 promoter. Unexpectedly, ATF3-deficient mice did not exhibit increased airway neutrophilia after LPS challenge. Bone marrow chimeras revealed a specific reduction in ATF3(-/-) neutrophil recruitment to wild-type lungs. In vitro, ATF3(-/-) neutrophils exhibited a profound chemotaxis defect. Global gene expression analysis identified ablated Tiam2 expression in ATF3(-/-) neutrophils. TIAM2 regulates cellular motility by activating Rac1-mediated focal adhesion disassembly. Notably, ATF3(-/-) and ATF3-sufficient TIAM2 knockdown neutrophils, both lacking TIAM2, exhibited increased focal complex area, along with excessive CD11b-mediated F-actin polymerization. Together, our data describe a dichotomous role for ATF3-mediated regulation of neutrophilic responses: inhibition of neutrophil chemokine production but promotion of neutrophil chemotaxis. PMID- 24470590 TI - Telomerase functions beyond telomere maintenance in primary cutaneous T-cell lymphoma. AB - Telomere erosion may be counteracted by telomerase. Here we explored telomere length (TL) and telomerase activity (TA) in primary cutaneous T-cell lymphoma (CTCL) by using quantitative polymerase chain reaction and interphase quantitative fluorescence in situ hybridization assays. Samples from patients with Sezary syndrome (SS), transformed mycosis fungoides (T-MF), and cutaneous anaplastic large cell lymphoma were studied in parallel with corresponding cell lines to evaluate the relevance of TL and TA as target candidates for diagnostic and therapeutic purposes. Compared with controls, short telomeres were observed in aggressive CTCL subtypes such as SS and T-MF and were restricted to neoplastic cells in SS. While no genomic alteration of the hTERT (human telomerase catalytic subunit) locus was observed in patients' tumor cells, TA was detected. To understand the role of telomerase in CTCL, we manipulated its expression in CTCL cell lines. Telomerase inhibition rapidly impeded in vitro cell proliferation and led to cell death, while telomerase overexpression stimulated in vitro proliferation and clonogenicity properties and favored tumor development in immunodeficient mice. Our data indicate that, besides maintenance of TL, telomerase exerts additional functions in CTCL. Therefore, targeting these functions might represent an attractive therapeutic strategy, especially in aggressive CTCL. PMID- 24470591 TI - Inhibition of lymphoma vascularization and dissemination by estrogen receptor beta agonists. AB - Most lymphomas show an increased incidence and poorer prognosis in males vs females, suggesting endocrine regulation. We have previously shown that tumor growth in vivo of a murine T-cell-derived lymphoma is repressed following activation of estrogen receptor beta (ERbeta, ESR2). By using ERbeta-deficient mice, we now demonstrate that this inhibition is mediated via a direct effect on the tumor cells and not on the microenvironment. Furthermore, we show that the growth-suppressing effects of ERbeta agonist are also valid for human B-cell lymphomas as demonstrated in tumors derived from Granta-519 mantle cell lymphoma (MCL) and Raji Burkitt lymphoma (BL) cells. In Granta-519 MCL tumors, activation of ERbeta reduced expression of BAFF and GRB7, 2 important molecules involved in B-cell proliferation and survival. Importantly, activation of ERbeta inhibited angiogenesis and lymphangiogenesis, possibly mediated by impaired vascular endothelial growth factor C expression. Furthermore, using disseminating Raji BL cells, we show that ERbeta activation reduces dissemination of grafted Raji BL tumors. We also show by immunohistochemistry that ERbeta is expressed in primary MCL tissue. These results suggest that targeting ERbeta with agonists may be valuable in the treatment of some lymphomas, affecting several aspects of the malignant process, including proliferation, vascularization, and dissemination. PMID- 24470593 TI - Personal health budgets are good for the few but not for the many, conference hears. PMID- 24470594 TI - Scintigraphy of patient with hematochezia. AB - Gastrointestinal bleeding can result in significant morbidity. Scintigraphy plays an important role in detecting, localizing, and grading the bleed. Effective scintigraphic evaluation of gastrointestinal bleeding can be complicated by its intermittent nature and the patient's hemodynamic instability. Dynamic evaluation, delayed imaging, and an understanding of the labeling process are necessary tools to help improve detection rate and localization. PMID- 24470592 TI - Improved targeting of JAK2 leads to increased therapeutic efficacy in myeloproliferative neoplasms. AB - The discovery of JAK2/MPL mutations in patients with myeloproliferative neoplasms (MPN) led to clinical development of Janus kinase (JAK) inhibitors for treatment of MPN. These inhibitors improve constitutional symptoms and splenomegaly but do not significantly reduce mutant allele burden in patients. We recently showed that chronic exposure to JAK inhibitors results in inhibitor persistence via JAK2 transactivation and persistent JAK-signal transducer and activator of transcription signaling. We performed genetic and pharmacologic studies to determine whether improved JAK2 inhibition would show increased efficacy in MPN models and primary samples. Jak2 deletion in vivo led to profound reduction in disease burden not seen with JAK inhibitors, and deletion of Jak2 following chronic ruxolitinib therapy markedly reduced mutant allele burden. This demonstrates that JAK2 remains an essential target in MPN cells that survive in the setting of chronic JAK inhibition. Combination therapy with the heat shock protein 90 (HSP90) inhibitor PU-H71 and ruxolitinib reduced total and phospho JAK2 and achieved more potent inhibition of downstream signaling than ruxolitinib monotherapy. Combination treatment improved blood counts, spleen weights, and reduced bone marrow fibrosis compared with ruxolitinib alone. These data suggest alternate approaches that increase JAK2 targeting, including combination JAK/HSP90 inhibitor therapy, are warranted in the clinical setting. PMID- 24470595 TI - Radiation therapy-induced phrenic neuropathy mimicking metastasis to the diaphragmatic crus on 18F-FDG PET/CT. AB - Benign unilateral uptake in the diaphragmatic crus is a relatively uncommon finding on (18)F-FDG PET/CT that can mimic the appearance of malignancy in patients with known cancer, as illustrated in this patient with neuroendocrine carcinoma. It is important for the PET interpreter to recognize this finding and attribute it to benign uptake based on the patient's history and symptoms at the time of the scan. Correlation with the findings of other available imaging modalities is also important to characterize focal uptake in unusual locations. PMID- 24470596 TI - New routine for nuclear medicine technologists to determine when to add SPECT/CT to a whole-body bone scan. AB - Bone scintigraphy is usually obtained as a whole-body scan producing 2 images: an anterior view and a posterior view. Sometimes abnormal findings in the spine are difficult to distinguish on whole-body bone scans. SPECT/CT may be performed to localize and interpret a lesion correctly and to help differentiate between benign and metastatic lesions. The assessment of whether SPECT/CT is needed is usually made by a physician. The aim of this study was to evaluate our new routine for nuclear medicine technologists to determine when to add SPECT/CT to whole-body bone scintigraphy. METHODS: A 3-part educational course was developed for the nuclear medicine technologists. The first part was to learn criteria for when SPECT/CT should be added to a whole-body bone scan. The second part was to review a selection of training whole-body bone scans illustrating the criteria. The third part was to pass a test of whether whole-body bone scans should be supplemented by SPECT/CT. RESULTS: The nuclear medicine technologists and the physicians agreed that SPECT/CT was required in 63 cases and not required in 27 cases. The resulting percentage agreement was 90%, and the kappa value was 0.77. There was disagreement in 10 cases. In 6 of these cases only the nuclear medicine technologists wanted to add SPECT/CT, and in 4 of these cases only the physicians wanted to add SPECT/CT. CONCLUSION: After participating in the training course developed in this project, the nuclear medicine technologists were able to decide whether a SPECT/CT study is needed. An implication of this result is that the effectiveness of the nuclear medicine department should be improved after our new routine is implemented. The successful outcome of this project may stimulate departments to take on similar quality-improvement projects in the future. PMID- 24470597 TI - Influence of positron emitters on standard gamma-camera imaging. AB - Combined PET and SPECT scanning can give supplementary information. However, activity from PET radionuclides can cause background counts and increased dead time in gamma camera imaging (SPECT or planar) because the 511-keV photons can penetrate collimators designed for lower energies. This study investigated how to manage this issue, including what levels of PET radionuclides can be tolerated when a gamma-camera investigation is performed. METHODS: Different combinations of (68)Ga (PET radionuclide), (99m)Tc (low-energy radionuclide), and (111)In (medium-energy radionuclide) were scanned by a gamma camera. Standard low-, medium-, and high-energy collimators were used with the gamma camera. Dead time and counts near and distant from the sources were recorded. RESULTS: Down scatter from 511 keV can give rise to a considerable number of counts within the (99m)Tc or (111)In energy windows, especially when the PET source is close to the camera head. Over the full camera head, the PET source can result in more counts per megabecquerel than the SPECT source ((99m)Tc or (111)In). Counts from the PET source were distributed over a large region of the camera head. With medium- and high-energy collimators, the sensitivity to the PET radionuclide was found to be about 10% of the sensitivity to (99m)Tc and about 20% of the sensitivity to (111)In, as measured within a 3-cm-radius region of interest. CONCLUSION: If PET radionuclides of activity 1 MBq or higher are present in the patient at the time of SPECT, a medium-energy collimator should be used. Counts from PET sources will in SPECT usually be seen as a diffuse background rather than as foci. The thick septa of high-energy collimators may result in structure in the image, and a high energy collimator is recommended only if PET activity is greater than 10 MBq. PMID- 24470598 TI - US plans to revamp food labels. PMID- 24470600 TI - Reforms in academic neurology: needs of a rapidly changing India. AB - "Healthy citizens are the greatest asset any country can have."-Sir Winston Churchill. PMID- 24470599 TI - Apolipoproteins are associated with new MRI lesions and deep grey matter atrophy in clinically isolated syndromes. AB - OBJECTIVES: There is increasing evidence that serum lipoprotein cholesterol biomarkers are associated with disease progression in clinically isolated syndromes (CIS). Apolipoproteins (Apo) are recognition ligands that mediate the physiological interactions of cholesterol-containing lipoproteins. The objective of this study was to investigate whether serum Apo levels are associated with CIS disease progression. METHODS: ApoB, ApoAI, ApoAII, ApoE and lipoprotein (a) (Lpa) levels were measured in serum samples obtained prior to the start of treatment from 181 CIS patients (123 women, 58 men, 68% women; mean age: 28.1+/-SD 8.1 years). All patients were treated with intramuscular interferon-beta as part of the prospective study. Clinical and MRI assessments were obtained at baseline, 6, 12 and 24 months after start of interferon-beta treatment. RESULTS: Greater ApoB levels were associated with increased number of new T2 lesions (p<0.001) and increased number of new or enlarging T2 lesions (p<0.001) over 2 years. Each 10 mg/dL of greater baseline ApoB is associated with a 16% increase in the number of new T2 lesions over 2 years. ApoAI, ApoAII, ApoE and Lpa were not associated with T2 lesions. Greater ApoE levels were associated with greater deep grey matter atrophy (partial correlation rp=-0.28, p<0.001). Each 1 mg/dL increment in ApoE levels was associated with a 1% increase in deep grey matter atrophy over 2 years. CONCLUSIONS: Serum ApoB levels are associated with new lesion accumulation whereas ApoE levels are associated with deep grey matter atrophy in high risk CIS patients treated with interferon beta-1a. PMID- 24470601 TI - MRI hydrographic 3D sequences in CADASIL. AB - Two patients with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) (figure), evolving with cognitive deterioration, had MRI. Hydrographic 3D high-resolution turbo spin-echo (TSE) with variable flip angle sequence (SPACE) was performed to demonstrate the subcortical lacunar lesions (SLL) (figure, A and B), considered specific in CADASIL.(1.) PMID- 24470603 TI - Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. PMID- 24470602 TI - Aquaporin-4 antibody-positive cases beyond current diagnostic criteria for NMO spectrum disorders. PMID- 24470604 TI - Subcortical epilepsy? PMID- 24470605 TI - Mystery case: a 63-year-old man with progressive proximal pain and weakness. PMID- 24470606 TI - Pearls & Oy-sters: a rare case of neurotrichinosis with MRI. AB - The neurologic manifestations of trichinosis are diverse, and range from encephalopathy to cerebral, cerebellar, and spinal cord abnormalities. PMID- 24470607 TI - Teaching neuroimages: neuromyelitis optica misdiagnosed as spinal cord tumor. AB - A 17-year-old girl presented with acute-onset cervical pain, followed by left arm weakness and gait disturbances. Spinal cord astrocytoma was diagnosed by MRI performed at an outpatient facility (figure, A and B). The patient was admitted to the neurosurgery department to undergo spinal cord biopsy. A second neurologic evaluation indicated neuromyelitis optica (NMO) as the most likely diagnosis, which was confirmed by NMO-immunoglobulin G seropositivity. The patient was treated with rescue plasmapheresis with substantial clinical and radiologic (figure, C) improvement. PMID- 24470608 TI - Mild cognitive impairment and progression to dementia: new findings. PMID- 24470609 TI - The future of small animal practice in the UK. PMID- 24470611 TI - Pet ownership in the UK: where do we stand in 2013. PMID- 24470612 TI - Assessing the industry using Porter's five forces. AB - To develop a business and plan for the future, there is a need to assess the current situation. One way of doing this is to use Porter's five forces framework. This was the brainchild of Harvard Business School's Michael Porter and developed in 1979. Looking at the competitive intensity of an industry, the model assesses internal and external factors that act together to determine the direction of the business; taken together, this gives an indication of the attractiveness of the industry. PMID- 24470613 TI - Threat of new entrants. PMID- 24470614 TI - Threat of substitutes. PMID- 24470615 TI - Bargaining power of suppliers. PMID- 24470616 TI - Bargaining power of customers. PMID- 24470617 TI - Competitive rivalry. PMID- 24470618 TI - The final verdict. PMID- 24470619 TI - How will these forces impact on the profession? PMID- 24470620 TI - Market fragmentation. PMID- 24470621 TI - Share of the pet care market. PMID- 24470622 TI - Growing the market. PMID- 24470623 TI - Clients' ability to pay. PMID- 24470624 TI - What will practice look like by 2023? PMID- 24470625 TI - Common themes. PMID- 24470626 TI - Main conclusions. AB - So what might this all mean for small animal veterinary practice as it heads into the future? And what kind of future does it have? PMID- 24470628 TI - Last gasp for e-cigarette ads that glamorise the habit? PMID- 24470629 TI - Novel PET probes 18F-BCPP-EF and 18F-BCPP-BF for mitochondrial complex I: a PET study in comparison with 18F-BMS-747158-02 in rat brain. AB - We developed novel PET probes, 2-tert-butyl-4-chloro-5-{6-[2-(2-(18)F fluoroethoxy)-ethoxy]-pyridin-3-ylmethoxy}-2H-pyridazin-3-one ((18)F-BCPP-EF) and 2-tert-butyl-4-chloro-5-[6-(4-(18)F-fluorobutoxy)-pyridin-3-ylmethoxy]-2H pyridazin-3-one ((18)F-BCPP-BF), for quantitative imaging of mitochondrial complex I (MC-I) activity in the brain and preliminarily evaluated their properties in comparison with (18)F-BMS-747158-02 ((18)F-BMS). METHODS: The affinity of (18)F-BCPP-EF, (18)F-BCPP-BF, and (18)F-BMS to MC-I was analyzed using in vitro binding assays with (3)H-dihydrorotenone and bovine cardiomyocyte submitochondrial particles. (18)F-BCPP-EF, (18)F-BCPP-BF, or (18)F-BMS was intravenously injected into rats, and the uptake (standardized uptake value) in each organ was determined by dissection method. The effects of rotenone, a specific MC-I inhibitor, on the uptake of each probe were assessed by whole-body PET imaging in rats. Ischemic brain model rats were imaged using (18)F-BCPP-EF. RESULTS: The rank order of affinity to MC-I was (18)F-BCPP-BF > (18)F-BMS > (18)F BCPP-EF. The uptake of (18)F-BCPP-EF and (18)F-BMS was high in the heart, intermediate in brain, and low in muscle and bone 60 min after the injection. (18)F-BCPP-BF provided increasing bone uptake with time after the injection. The uptake of (18)F-BCPP-EF and (18)F-BMS into the brain and heart was significantly decreased by preadministration of rotenone; however, the reduction degree of (18)F-BCPP-EF was more pronounced than that of (18)F-BMS. Rotenone did not affect (18)F-BCPP-BF uptake in either the brain or the heart. (18)F-BCPP-EF imaged the cortical ischemic neuronal damage without any disturbance by microglial activation even on day 7 when (18)F-FDG showed high uptake in the damaged area. CONCLUSION: The present study demonstrated that (18)F-BCPP-EF could be a potential PET probe for quantitative imaging of MC-I activity and its ischemic damage in the living brain with PET. PMID- 24470631 TI - British man with schizophrenia faces death sentence in Pakistan for blasphemy. PMID- 24470632 TI - Transcriptional regulation of L-type calcium channel subtypes Cav1.2 and Cav1.3 by nicotine and their potential role in nicotine sensitization. AB - INTRODUCTION: L-type calcium channel (LTCC) activity in the brain is mediated by 2 subtypes, Ca(v)1.2 and Ca(v)1.3. The individual contributions of these LTCC subtypes to the long-term pharmacological and behavioral effects of nicotine are unknown. METHODS: Using quantitative in situ hybridization, we examined expression levels of Ca(v)1.2 and Ca(v)1.3 in forebrain regions of mice treated with nicotine (0.175 mg/kg) or saline for 1 or 14 days and sacrificed 24 hr or 7 days following the last injection. Additionally, we treated mice with nicotine for 14 days and then administered the nonspecific LTCC antagonist nifedipine twice daily during a 7-day abstinence period prior to testing for nicotine sensitization to determine the effect of LTCC blockade on sensitization. RESULTS: Ca(v)1.2 mRNA was unaffected 24 hr following a single nicotine exposure, whereas Ca(v)1.3 mRNA was upregulated in several brain regions. Following 14 days of nicotine treatment and 24 hr of abstinence, Ca(v)1.2 mRNA was downregulated throughout the areas examined, whereas Ca(v)1.3 mRNA had mostly returned to control values. Following 7 days of abstinence, a strong upregulation of Ca(v)1.2 transcripts was observed, whereas Ca(v)1.3 mRNA was largely unaffected. In our sensitization study, nifedipine administered during nicotine abstinence impaired subsequent nicotine sensitization. CONCLUSIONS: Our data suggest a differential involvement of Ca(v)1.2 and Ca(v)1.3 in nicotine-related processes. Ca(v)1.3 seems to be involved primarily during early exposure to nicotine. Ca(v)1.2 appears to play a role in the long-term molecular and behavioral changes that occur following chronic nicotine and abstinence. Nifedipine may counteract those nicotine-induced alterations in LTCC activity to impair nicotine sensitization. PMID- 24470633 TI - A mobile-phone-based breath carbon monoxide meter to detect cigarette smoking. AB - INTRODUCTION: Mobile phones hold considerable promise for delivering evidence based smoking cessation interventions that require frequent and objective assessment of smoking status via breath carbon monoxide (Breath CO) measurement. However, there are currently no commercially available mobile-phone-based Breath CO meters. We developed a mobile-phone-based Breath CO meter prototype that attaches to and communicates with a smartphone through an audio port. We then evaluated the reliability and the validity of Breath CO measures collected with the mobile meter prototype and assessed the usability and acceptability of the meter. METHODS: Participants included 20 regular smokers (>=10 cigarettes/day), 20 light smokers (<10 cigarettes/day), and 20 nonsmokers. Expired air samples were collected 4 times from each participant: twice with the mobile meter and twice with a commercially available Breath CO meter. RESULTS: Measures calculated by the mobile meter correlated strongly with measures calculated by the commercial meter (r = .96, p < .001). Additionally, the mobile meter accurately distinguished between smokers and nonsmokers. The area under the receiver operating characteristic curve for the mobile meter was 94.7%, and the meter had a combined sensitivity and specificity of 1.86 at an abstinence threshold of <=6 ppm. Responses on an acceptability survey indicated that smokers liked the meter and would be interested in using it during a quit attempt. CONCLUSIONS: The results of our study suggest that a mobile-phone-based Breath CO meter is a reliable, valid, and acceptable device for distinguishing between smokers and nonsmokers. PMID- 24470634 TI - Doctors are targeted by police while treating protesters in Kiev. PMID- 24470635 TI - Quality of evidence behind FDA approvals varies widely. PMID- 24470636 TI - Statins for the primary prevention of cardiovascular disease. PMID- 24470637 TI - Emerging functions of nodulin-like proteins in non-nodulating plant species. AB - Plant genes whose expression is induced in legumes by Rhizobium bacteria upon nodulation were initially referred to as nodulins. Several of them play a key role in the establishment of symbiosis. Yet, nodulin-like proteins are also found in non-nodulating plant species such as Arabidopsis, rice, maize or poplar. For instance, 132 are predicted in the Arabidopsis thaliana Col-0 genome. Recent studies now highlight the importance of nodulin-like proteins for the transport of nutrients, solutes, amino acids or hormones and for major aspects of plant development. Interestingly, nodulin-like activities at the plant-microbe interface are also important for pathogens to enhance their fitness during host colonization. This work presents a genomic and functional overview of nodulin like proteins in non-leguminous plant species, with a particular focus on Arabidopsis and rice. PMID- 24470638 TI - Vitamin D deficiency rickets in an adolescent with severe atopic dermatitis. AB - Atopic dermatitis (AD) affects 10% to 20% of children worldwide. Its severity may be inversely correlated with 25-hydroxyvitamin D (25OHD) levels. Although low levels of vitamin D (VD) can cause rickets in infants, VD deficiency rickets is an unusual presentation in teenagers. We report the case of a 14-year-old girl with severe AD and fish allergy since early childhood. She lived at high latitude (with less sun exposure) and, because of her atopic disorders, avoided sunlight and fish. Laboratory studies showed elevated alkaline phosphatase and parathyroid hormone levels and low serum calcium; her serum 25OHD level was <12 nmol/L. A radiograph of the wrist showed a radiolucent band in the distal metaphysis of the radius with marginal sclerosis. She was diagnosed as having hypocalcemic rickets due to VD deficiency. Treatment with VD increased her 25OHD level to 44 nmol/L, with normalization of alkaline phosphatase, parathyroid hormone, and calcium. Moreover, we observed a dramatic improvement in her AD severity with VD treatment. This case demonstrates the complex interaction between VD deficiency, AD, and food allergy. We advise a high index of suspicion of VD deficiency rickets in children of all ages with AD, particularly during accelerated growth periods and in the presence of other risk factors such as darker skin, living at high latitude, sun avoidance, and low intake of VD-rich foods. The concomitant improvement in bone-related parameters and AD severity may reflect a double benefit of VD treatment, a possibility that warrants research on VD as potential treatment for AD. PMID- 24470639 TI - Referral to pediatric surgical specialists. AB - The American Academy of Pediatrics, with the collaboration of the Surgical Sections of the American Academy of Pediatrics, has created referral recommendations intended to serve as voluntary practice parameters to assist general pediatricians in determining when and to whom to refer their patients for pediatric surgical specialty care. It is recognized that these recommendations may be difficult to implement, because communities vary in terms of access to major pediatric medical centers. Limited access does not negate the value of the recommendations, however, because the child who needs specialized surgical and anesthetic care is best served by the skills of the appropriate pediatric surgical team. Major congenital anomalies, malignancies, major trauma, and chronic illnesses (including those associated with preterm birth) in infants and children should be managed by pediatric medical subspecialists and pediatric surgical specialists at pediatric referral centers that can provide expertise in many areas, including the pediatric medical subspecialties and surgical specialties of pediatric radiology, pediatric anesthesiology, pediatric pathology, and pediatric intensive care. The optimal management of the child with complex problems, chronic illness, or disabilities requires coordination, communication, and cooperation of the pediatric surgical specialist with the child's primary care pediatrician or physician. PMID- 24470641 TI - Closed-loop automatic oxygen control (CLAC) in preterm infants: a randomized controlled trial. AB - BACKGROUND AND OBJECTIVE: In preterm infants receiving supplemental oxygen, routine manual control (RMC) of the fraction of inspired oxygen (FIO2) is often difficult and time consuming. We developed a system for closed-loop automatic control (CLAC) of the FIO2 and demonstrated its short-term safety and efficacy in a single-center study. The objective of this study was to test the hypothesis that this system is more effective than RMC alone in maintaining arterial oxygen saturation within target levels when evaluated over 24 hours under routine conditions and with different target levels. METHODS: We performed a multicenter, randomized controlled, crossover clinical trial in 34 preterm infants receiving mechanical ventilation or nasal continuous positive airway pressure and supplemental oxygen. Twenty-four-hour periods with RMC were compared with 24-hour periods of RMC supported by CLAC. RESULTS: The median (range) percentage of time with arterial oxygen saturation levels within target range was 61.4 (31.5-99.5) for RMC and 71.2 (44.0-95.4) for CLAC (P < .001). The median (range) number of manual FIO2 adjustments was reduced from 77.0 (0.0-224.0) for RMC to 52.0 (10.0 317.0) for CLAC (P = .007). CONCLUSIONS: CLAC may improve oxygen administration to preterm infants receiving mechanical ventilation or nasal continuous positive airway pressure while reducing workload related to RMC. PMID- 24470643 TI - Preventing unintended pregnancy: a pediatric opportunity. PMID- 24470642 TI - Evaluating children with fractures for child physical abuse. AB - Fractures are common injuries caused by child abuse. Although the consequences of failing to diagnose an abusive injury in a child can be grave, incorrectly diagnosing child abuse in a child whose fractures have another etiology can be distressing for a family. The aim of this report is to review recent advances in the understanding of fracture specificity, the mechanism of fractures, and other medical diseases that predispose to fractures in infants and children. This clinical report will aid physicians in developing an evidence-based differential diagnosis and performing the appropriate evaluation when assessing a child with fractures. PMID- 24470644 TI - Management of febrile neonates in US pediatric emergency departments. AB - BACKGROUND: Blood, urine, and cerebrospinal fluid cultures and admission for antibiotics are considered standard management of febrile neonates (0-28 days). We examined variation in adherence to these recommendations across US pediatric emergency departments (PEDs) and incidence of serious infections (SIs) in febrile neonates. METHODS: Cross-sectional study of neonates with a diagnosis of fever evaluated in 36 PEDs in the 2010 Pediatric Health Information System database. We analyzed performance of recommended management (laboratory testing, antibiotic use, admission to hospital), 48-hour return visits to PED, and diagnoses of SI. RESULTS: Of 2253 neonates meeting study criteria, 369 (16.4%) were evaluated and discharged from the PED; 1884 (83.6%) were admitted. Recommended management occurred in 1497 of 2253 (66.4%; 95% confidence interval, 64.5-68.4) febrile neonates. There was more than twofold variation across the 36 PEDs in adherence to recommended management, recommended testing, and recommended treatment of febrile neonates. There was significant variation in testing and treatment between admitted and discharged neonates (P < .001). A total of 269 in 2253 (11.9%) neonates had SI, of whom 223 (82.9%; 95% confidence interval, 77.9-86.9) received recommended management. CONCLUSIONS: There was wide variation across US PEDs in adherence to recommended management of febrile neonates. One in 6 febrile neonates was discharged from the PED; discharged patients were less likely to receive testing or antibiotic therapy than admitted patients. A majority of neonates with SI received recommended evaluation and management. High rates of SI in admitted patients but low return rates for missed infections in discharged patients suggest a need for additional studies to understand variation from the current recommendations. PMID- 24470645 TI - Improving outcomes for underserved adolescents with asthma. AB - BACKGROUND AND OBJECTIVE: Asthma is the most common chronic disease of childhood. Treatment adherence by adolescents is often poor, and their outcomes are worse than those of younger patients. We conducted a quality improvement initiative to improve asthma control and outcomes for high-risk adolescents treated in a primary care setting. METHODS: Interventions were guided by the Chronic Care Model and focused on standardized and evidence-based care, care coordination and active outreach, self-management support, and community connections. RESULTS: Patients with optimally well-controlled asthma increased from ~10% to 30%. Patients receiving the evidence-based care bundle (condition/severity characterized in chart and, for patients with persistent asthma, an action plan and controller medications at the most recent visit) increased from 38% to at or near 100%. Patients receiving the required self-management bundle (patient self assessment, stage-of-readiness tool, and personal action plan) increased from 0% to ~90%. Patients and parents who were confident in their ability to manage their or their adolescent's asthma increased from 70% to ~85%. Patient satisfaction and the mean proportion of patients with asthma-related emergency department visits or hospitalizations remained stable at desirable levels. CONCLUSIONS: Implementing interventions focused on standardized and evidence-based care, self management support, care coordination and active outreach, linkage to community resources, and enhanced follow-up for patients with chronically not-well controlled asthma resulted in sustained improvement in asthma control in adolescent patients. Additional interventions are likely needed for patients with chronically poor asthma control. PMID- 24470646 TI - Management of dental trauma in a primary care setting. AB - The American Academy of Pediatrics and its Section on Oral Health have developed this clinical report for pediatricians and primary care physicians regarding the diagnosis, evaluation, and management of dental trauma in children aged 1 to 21 years. This report was developed through a comprehensive search and analysis of the medical and dental literature and expert consensus. Guidelines published and updated by the International Association of Dental Traumatology (www.dentaltraumaguide.com) are an excellent resource for both dental and nondental health care providers. PMID- 24470647 TI - Children's Health Insurance Program (CHIP): accomplishments, challenges, and policy recommendations. AB - Sixteen years ago, the 105th Congress, responding to the needs of 10 million children in the United States who lacked health insurance, created the State Children's Health Insurance Program (SCHIP) as part of the Balanced Budget Act of 1997. Enacted as Title XXI of the Social Security Act, the Children's Health Insurance Program (CHIP; or SCHIP as it has been known at some points) provided states with federal assistance to create programs specifically designed for children from families with incomes that exceeded Medicaid thresholds but that were insufficient to enable them to afford private health insurance. Congress provided $40 billion in block grants over 10 years for states to expand their existing Medicaid programs to cover the intended populations, to erect new stand alone SCHIP programs for these children, or to effect some combination of both options. Congress reauthorized CHIP once in 2009 under the Children's Health Insurance Program Reauthorization Act and extended its life further within provisions of the Patient Protection and Affordable Care Act of 2010. The purpose of this statement is to review the features of CHIP as it has evolved over the 16 years of its existence; to summarize what is known about the effects that the program has had on coverage, access, health status, and disparities among participants; to identify challenges that remain with respect to insuring this group of vulnerable children, including the impact that provisions of the new Affordable Care Act will have on the issue of health insurance coverage for near poor children after 2015; and to offer recommendations on how to expand and strengthen the national commitment to provide health insurance to all children regardless of means. PMID- 24470648 TI - Periodic fever in MVK deficiency: a patient initially diagnosed with incomplete Kawasaki disease. AB - Mevalonate kinase deficiency (MKD) is a rare autosomal recessive disorder causing 1 of 2 phenotypes, hyperimmunoglobulin D syndrome and mevalonic aciduria, presenting with recurrent fever episodes, often starting in infancy, and sometimes evoked by stress or vaccinations. This autoinflammatory disease is caused by mutations encoding the mevalonate kinase (MVK) gene and is classified in the group of periodic fever syndromes. There is often a considerable delay in the diagnosis among pediatric patients with recurrent episodes of fever. We present a case of an 8-week-old girl with fever of unknown origin and a marked systemic inflammatory response. After excluding infections, a tentative diagnosis of incomplete Kawasaki syndrome was made, based on the finding of dilated coronary arteries on cardiac ultrasound and fever, and she was treated accordingly. However, the episodes of fever recurred, and alternative diagnoses were considered, which eventually led to the finding of increased excretion of mevalonic acid in urine. The diagnosis of MKD was confirmed by mutation analysis of the MVK gene. This case shows that the initial presentation of MKD can be indistinguishable from incomplete Kawasaki syndrome. When fever recurs in Kawasaki syndrome, other (auto-)inflammatory diseases must be ruled out to avoid inappropriate diagnostic procedures, ineffective interventions, and treatment delay. PMID- 24470649 TI - Sibship size, sibling cognitive sensitivity, and children's receptive vocabulary. AB - OBJECTIVES: The aim of the current study was to examine the relationship between sibship size and children's vocabulary as a function of quality of sibling interactions. It was hypothesized that coming from a larger sibship (ie, 3+ children) would be related to lower receptive vocabulary in children. However, we expected this association to be moderated by the level of cognitive sensitivity shown by children's next-in-age older siblings. METHODS: Data on 385 children (mean age = 3.15 years) and their next-in-age older siblings (mean age = 5.57 years) were collected and included demographic questionnaires, direct testing of children's receptive vocabulary, and videos of mother-child and sibling interactions. Sibling dyads were taped engaging in a cooperative building task and tapes were coded for the amount of cognitive sensitivity the older sibling exhibited toward the younger sibling. RESULTS: Hierarchical regression analyses were conducted and showed an interaction between sibship size and sibling cognitive sensitivity in the prediction of children's receptive vocabulary; children exposed to large sibships whose next-in-age older sibling exhibited higher levels of cognitive sensitivity were less likely to show low vocabulary skills when compared with those children exposed to large sibships whose siblings showed lower levels of cognitive sensitivity. CONCLUSIONS: Children who show sensitivity to the cognitive needs of their younger siblings provide a rich environment for language development. The negative impact of large sibships on language development is moderated by the presence of an older sibling who shows high cognitive sensitivity. PMID- 24470650 TI - Diagnostic performance of BMI percentiles to identify adolescents with metabolic syndrome. AB - OBJECTIVES: To compare the diagnostic performance of the Centers for Disease Control and Prevention (CDC) and FITNESSGRAM (FGram) BMI standards for quantifying metabolic risk in youth. METHODS: Adolescents in the NHANES (n = 3385) were measured for anthropometric variables and metabolic risk factors. BMI percentiles were calculated, and youth were categorized by weight status (using CDC and FGram thresholds). Participants were also categorized by presence or absence of metabolic syndrome. The CDC and FGram standards were compared by prevalence of metabolic abnormalities, various diagnostic criteria, and odds of metabolic syndrome. Receiver operating characteristic curves were also created to identify optimal BMI percentiles to detect metabolic syndrome. RESULTS: The prevalence of metabolic syndrome in obese youth was 19% to 35%, compared with <2% in the normal-weight groups. The odds of metabolic syndrome for obese boys and girls were 46 to 67 and 19 to 22 times greater, respectively, than for normal weight youth. The receiver operating characteristic analyses identified optimal thresholds similar to the CDC standards for boys and the FGram standards for girls. Overall, BMI thresholds were more strongly associated with metabolic syndrome in boys than in girls. CONCLUSIONS: Both the CDC and FGram standards are predictive of metabolic syndrome. The diagnostic utility of the CDC thresholds outperformed the FGram values for boys, whereas FGram standards were slightly better thresholds for girls. The use of a common set of thresholds for school and clinical applications would provide advantages for public health and clinical research and practice. PMID- 24470651 TI - Hospitalizations due to firearm injuries in children and adolescents. AB - BACKGROUND AND OBJECTIVE: Despite recent national attention on deaths from firearms, little information exists about children and adolescents who are hospitalized for firearm injuries. The objective was to determine the national frequency of firearm-related hospitalizations in the United States in children, compare rates by cause and demographics, and describe hospitalized cases. METHODS: We used the 2009 Kids' Inpatient Database to identify hospitalizations from firearm-related injuries in young people <20 years of age; International Classification of Diseases, Ninth Revision, Clinical Modification, and external cause-of injury codes were used to categorize the injuries and the causes as follows: assault, suicide attempt, unintentional, or undetermined. Incidences were calculated by using the weighted number of cases and the intercensal population. Risk ratios compared incidences. RESULTS: In 2009, 7391 (95% confidence interval [CI]: 6523-8259) hospitalizations were due to firearm-related injuries. The hospitalization rate was 8.87 (95% CI: 7.83-9.92) per 100,000 persons <20 years of age. Hospitalizations due to assaults were most frequent (n = 4559) and suicide attempts were least frequent (n = 270). Of all hospitalizations, 89.2% occurred in males; the hospitalization rate for males was 15.22 per 100,000 (95% CI: 13.41-17.03) and for females was 1.93 (95% CI: 1.66 2.20). The rate for black males was 44.77 (95% CI: 36.69-52.85), a rate more than 10 times that for white males. Rates were highest for those aged 15 to 19 years (27.94; 95% CI: 24.42-31.46). Deaths in the hospital occurred in 453 (6.1%); of those hospitalized after suicide attempts, 35.1% died. CONCLUSIONS: On average, 20 US children and adolescents were hospitalized each day in 2009 due to firearm injuries. Public health efforts are needed to reduce this common source of childhood injury. PMID- 24470652 TI - IJD((r)) 2013: A Year of Consolidation and Expansion. PMID- 24470654 TI - Management of chronic paronychia. AB - Chronic paronychia is an inflammatory disorder of the nail folds of a toe or finger presenting as redness, tenderness, and swelling. It is recalcitrant dermatoses seen commonly in housewives and housemaids. It is a multifactorial inflammatory reaction of the proximal nail fold to irritants and allergens. Repeated bouts of inflammation lead to fibrosis of proximal nail fold with poor generation of cuticle, which in turn exposes the nail further to irritants and allergens. Thus, general preventive measures form cornerstone of the therapy. Though previously anti-fungals were the mainstay of therapy, topical steroid creams have been found to be more effective in the treatment of chronic paronychia. In recalcitrant cases, surgical treatment may be resorted to, which includes en bloc excision of the proximal nail fold or an eponychial marsupialization, with or without nail plate removal. Newer therapies and surgical modalities are being employed in the management of chronic paronychia. In this overview, we review recent epidemiological studies, present current thinking on the pathophysiology leading to chronic paronychia, discuss the challenges chronic paronychia presents, and recommend a commonsense approach to management. PMID- 24470653 TI - Reticulate dermatoses. AB - The term "reticulate" is used for clinical description of skin lesions that are configured in a net-like pattern. Many primary and secondary dermatoses present in such patterns involving specific body sites. Certain cutaneous manifestations of systemic diseases or genodermatoses also present in such manner. This review classifies and describes such conditions with reticulate lesions and briefly, their associated features. PMID- 24470655 TI - Eponymous dermatological signs in bullous dermatoses. AB - Clinical signs are evolved by clinicians through their careful clinical examination. Medical professionals are generally familiar with these signs because of the emphasis given to them by the teaching faculty while they were students. Some of these signs are eponymously named after the clinicians giving credit to their observation. Eponymous signs in vesiculobullous diseases such as Nikolsky sign and Asboe Hansen sign (Bulla spread sign) are well known and were described during the 19th and 20th century, respectively. Cerebriform tongue in pemphigus vegetans was described by Premalatha (1981) three decades ago and is well recognized and cited in several text books and articles in leading journals. All these signs are revisited below with an emphasis on cerebriform tongue in pemphigus vegetans which could eponymously be called as Premalatha sign. PMID- 24470657 TI - Non Comparative Study on Various Pulse Regimens (DCP, DAP and DMP) in Pemphigus: Our Experience. AB - BACKGROUND: Pemphigus has been treated with Dexamethasone Cyclophosphamide Pulse (DCP) Therapy since 1981. Various modifications have been suggested in the original regimen. These include Dexamethasone Azathioprine Pulse (DAP) and Dexamethasone Methotrexate Pulse (DMP) therapies. AIMS: To report our experience on the noncomparative study of various Pulse regimens DCP, DAP AND DMP therapies in patients with Pemphigus. MATERIALS AND METHODS: The patients were put on three regimens depending upon the situation-Conventional DCP, DAP in the reproductive age group, DMP in patients who showed prolonged Phase I more than 12 months while on DCP. RESULTS: 30 patients were put on DCP therapy. The duration of phase I was on an average six months. Relapse was seen in 3 patients in phase IV. 12 patients on DAP therapy were considered. In Phase III 5 patients relapsed in phase IV four patients relapsed. Five patients were put on the DMP. Disease activity was poorly controlled and in three DMP was discontinued. CONCLUSION: DCP remains the most effective regimen with quickest onset of remission and continuance of remission. In DAP therapy fixation of dose of azathioprine at 50 mgs daily may be counterproductive. DMP does not fulfil the promise of a viable treatment option in recalcitrant pemphigus and this lacunae needs to be plugged. PMID- 24470656 TI - Candida parapsilosis and Candida guillermondii: emerging pathogens in nail candidiasis. AB - BACKGROUND: Onychomycosis of the fingernails and toenails is generally caused by dermatophytes and yeasts. Toenail mycoses involve mainly dermatophytes but when Candida is also involved, the strain most commonly isolated worldwide is C. albicans. AIMS: To determine Candida strains prevailing in onychomycosis. MATERIALS AND METHODS: A retrospective, observational and descriptive study of fungal cultures retrieved from the registry of the microbiology laboratory of the Pontificia Universidad Catolica was performed. Specimens obtained from patients attending the healthcare network between December 2007 and December 2010 was analyzed. STATISTICAL ANALYSIS: A descriptive statistical analysis was performed. RESULTS: Candida was retrieved from 467 of 8443 specimens (52% fingernails and 48% toenails). Cultures were negative in 5320 specimens (63.6%). Among Candida positive cultures, parapsilosis was the most commonly isolated strain with 202 cases (43.3%). While isolates of Candida guillermondii were 113 (24.2%), those of Candida albicans were 110 (23.6%), those of spp. were 20 (4.3%) and there were 22 cases of other isolates (4.71%). Among the 467 patients with positive cultures for Candida, 136 (29,1%) were men and 331 (70,9%) were women. All patients were older than 18 years old. Clinical files were available for only 169 of the 467 patients with positive cultures for Candida. For those, age, gender, underlying illnesses and use of immunossupresive agents during the trial was reviewed. CONCLUSIONS: The present study shows that both C. parapsilosis as well as C. guillermondii appear as emerging pathogens that would be in fact taking the place of C. albicans as the most commonly isolated pathogen in patients with Candida onychomycosis. The relative percentage of C parapsilosis increases every year. Identification of Candida strains as etiological agents of nail candidiasis becomes relevant to the management both nail as well as systemic candidiasis, in view of the resistance to conventional treatments readily reported in the literature. PMID- 24470658 TI - Cutaneous manifestations of mixed connective tissue disease: study from a tertiary care hospital in eastern India. AB - CONTEXT: Mixed connective tissue disorder is an uncommon disease. Some scientists are reluctant to recognize it as a separate entity. Some others have defined this ailment. Cutaneous features of this condition are unique. Researchers from India have described these features to relate to those described in the studies from other parts of the globe. AIMS: This study aims to delineate the skin manifestations of clearly defined mixed connective tissue disease (MCTD) patients, to compare them with those established as overlap syndrome, and to relate them with studies from other parts of the globe. SETTINGS AND DESIGN: Successive patients who fulfilled the specific criteria for MCTD presenting in the skin outpatient department of a tertiary care hospital in eastern India were clinically examined from 2009 for 3 years. MATERIALS AND METHODS: The number of participants was 23 and the dermatological features of these were compared with 22 patients with overlap syndrome. The antibody to uridine-rich U1 ribonucleoprotein was measured for all patients. STATISTICAL ANALYSIS USED: SPSS (Version 17) and MedCalc (Version 11.6). RESULTS: THE MALE: Female ratio among the MCTD patients was 1:6.67 and that of the overlap syndrome was 1:10. Twenty patients of the MCTD group presented with synovitis as against only seven in the overlap group. Raynaud's phenomenon was present in some of the subjects. Puffy fingers were rare in our study. Facial numbness was reported by four of those suffering from MCTD. Antinuclear antibody (ANA) was essentially of a speckled pattern in this disease. CONCLUSIONS: Cutaneous indicators of MCTD are distinct from overlap syndrome. Knowledge of these manifestations prevalent in a region may lead to early diagnosis of the disease. PMID- 24470659 TI - Acquired, Idiopathic, Patterned Facial Pigmentation (AIPFP) Including Periorbital Pigmentation and Pigmentary Demarcation Lines on Face Follows the Lines of Blaschko on Face. AB - BACKGROUND: Acquired, non-nevoid, apparently idiopathic facial pigmentation are distributed over some specific locations like periorbital area, zygomatic area, malar area, root of nose, perioral and mandibular area. Periorbital pigmentation is the most well known entity in this group. These are bilaterally distributed homogenously diffuse gray to dark gray or slate-gray colored patches showing progressive intensification of pigmentation. These are often considered as physiologic or constitutional pigmentation. Some portions of the margins of these patches were described previously as pigmentary demarcation line (PDL- F, G, H). AIM: To analyze the distributional patterns of acquired, apparently idiopathic facial pigmentations and to evaluate the etiologic aspects of these conditions. MATERIALS AND METHODS: Spatial patterns, distribution, and orientation were analyzed among 187 individuals with idiopathic non-nevoid, facial pigmentation. Observed patterns were compared with various pigmentary nevi and Blaschko's lines on face. RESULTS: It was found that most of the idiopathic facial pigmentary alterations including periorbital pigmentation and PDL on face had specific patterned distribution that had high similarity to that of the pigmentary nevi and Blaschko's lines on face. CONCLUSION: It is hypothesized here that phenotypic expression of acquired patterned pigmentation (AIFPFP) is due to genetically determined increased pigmentary functional activity to various known and unknown yet natural factors like UV rays and aging. Mosaicism was a definite possibility. We also consider that the patterns actually reflected the normal patterns of embryological human pigmentation on face. PMID- 24470661 TI - Characteristics of Mixed Type Basal Cell Carcinoma in Comparison to Other BCC Subtypes. AB - BACKGROUND: There are limited data exploring the characteristics of mixed type basal cell carcinoma (BCC). OBJECTIVES: To explore different characteristics of mixed type BCC. DESIGN: Cross sectional study. MATERIALS AND METHODS: 825 patients with BCC enrolled in this study. RESULTS: Among 825 patients, 512 (62%) were male. Three hundred and fifty five (43%) presented with nodular subtype, 267 (32.4%) with mixed subtype, 25 with superficial and the 178 remaining presented with other subtypes. Four hundred and eighty three (58.6%) of the lesions were on the face, 243 (29.5%) on scalp, 52 (6.3%) on ears, 20 (2.4%) on neck, 15 (1.8%) on trunk and 12 (1.4%) on extremities. Anatomic distribution of mixed type was as follows: 137 on face, (51.4%), 100 (37.3%) on scalp, 19 (7%) on ear, 6 (2.1%) on neck, 4 (1.5%) extremity and 1 (0.7%) on trunk, which the difference from non mixed types was statistically significant (P = 0.002). The mean diameter of the mixed types and non mixed type BCCs were significantly different (2.7 +/- 2.1 cm vs. 2.2 +/- 1.6 cm; P = 0.01. The prevalence of necrosis in mixed type BCC was two times higher than non mixed type BCCs (OR = 2.3, CI 95% 1.3-3.9, P = 0.001). The most frequent combined subtypes were nodular-infiltrative (P < 0.001). CONCLUSION: Mixed type BCC has differences with other BCC subtypes in anatomical distribution and tumor diameter. Indeed, mixed type BCCs are frequently composed of aggressive subtypes than nonaggressive subtypes. PMID- 24470660 TI - Thyroid disorders associated with alopecia areata in egyptian patients. AB - CONTEXT: Alopecia areata (AA) is a common form of localized, non-scarring hair loss. The etiopathogenesis of the disease is still unclear, but the role of autoimmunity is strongly suggested. AA is commonly associated with various autoimmune disorders; the most frequent among them is autoimmune thyroid disorders. AIM: To determine whether AA is associated with thyroid autoimmunity or thyroid function abnormalities in Egyptian patients. MATERIALS AND METHODS: Fifty subjects with AA (37 males and 13 females) without clinical evidence of thyroid disorders were selected from Dermatology Outpatient Clinic, Menoufiya University Hospital, Menoufiya Governorate, Egypt, during the period from June 2009 to February 2010. They were divided into 3 groups according to severity of AA. Fifty age and sex-matched healthy volunteers (35 males and 15 females) were selected as a control group. Every case and control were subjected to history taking, complete general and dermatological examination. Venous blood samples were taken from cases and controls after taking their consents for measurement of thyroid stimulating hormone (TSH), free T3, freeT4 and detection of Anti thyroglobulin Antibody (Tg-Ab) and Anti-thyroid Peroxidase Antibody (TPO-Ab). RESULTS: Subclinical hypothyroidism was detected in 16% of cases. There were statistically significant differences between cases and controls regarding levels of TSH, free T3 and free T4. There were significant differences between cases and controls regarding the presence of Tg-Ab and TPO-Ab. CONCLUSIONS: Every patient with AA should be screened for thyroid functions and presence of thyroid autoantibodies even in absence of clinical manifestations suggestive of thyroid affection. PMID- 24470662 TI - Human demodex mite: the versatile mite of dermatological importance. AB - Demodex mite is an obligate human ecto-parasite found in or near the pilo sebaceous units. Demodex folliculorum and Demodex brevis are two species typically found on humans. Demodex infestation usually remains asymptomatic and may have a pathogenic role only when present in high densities and also because of immune imbalance. All cutaneous diseases caused by Demodex mites are clubbed under the term demodicosis or demodicidosis, which can be an etiological factor of or resemble a variety of dermatoses. Therefore, a high index of clinical suspicion about the etiological role of Demodex in various dermatoses can help in early diagnosis and appropriate, timely, and cost effective management. PMID- 24470663 TI - mTOR Signaling Cascade in Psoriatic Disease: Double Kinase mTOR Inhibitor a Novel Therapeutic Target. AB - In this short communication we are providing insight about the regulatory role of the phosphatidylinositol 3-kinase (PI3K)-AKT-mammalian target of rapamycin (mTOR) kinase system in psoriatic disease. This is an upcoming active research field in respect to elucidating the inflammatory and proliferative cascades of psoriatic disease. To provide a new dimension to the understandings of the molecular principles of the pathogenesis of autoimmune diseases, we hypothesized that (i) dysregulation of cytokines and growth factors in autoimmune diseases activate the mTOR signaling system and (ii) the activated mTOR kinase system is a key regulator of the inflammatory/proliferative cascades of the disease process. In support of this hypothesis we have earlier reported that growth factors (nerve growth factor (NGF) and platelet-derived growth factor (PDGF)) and relevant cytokines (interleukin (IL)-17, IL-22) known to be critical for psoriasis, psoriatic arthritis, and rheumatoid arthritis activate the mTOR signaling system. Here, we are providing our latest observations that the mTOR signaling proteins are upregulated in psoriatic skin and further we observed that proliferation of keratinocytes (KC) and synovial cells (synovial fibroblasts (FLS)) of psoriatic arthritis are dependent on the PI3K-AKT-mTOR kinase system. To our knowledge, we are the first to explore whether a double kinase inhibitor of mTOR signal proteins has a therapeutic potential for psoriatic disease. Here we will be sharing our views, our research work in this field and as well we will provide evidences how a double kinase inhibitor of mTOR signal proteins can be an effective therapeutic agent for psoriatic disease. PMID- 24470664 TI - Infantile Perianal Pyramidal Protrusion with Coexisting Perineal and Perianal Hemangiomas: A Fortuitous Association or Incomplete PELVIS Syndrome? AB - Two cases of infantile perianal pyramidal protrusions (IPPP), one pyramidal in shape and one leaf shaped, are being described by us. Both were notable for coexisting hemangiomas in the close vicinity. To the best of our knowledge we are reporting these two variants of IPPP with the associated neighboring hemangiomas for the first time in Indian dermatologic literature. We suggest that this presentation may be a part of one of the syndromes that comprise anorectal malformations with hemangiomas like PELVIS syndrome and others mentioned in the table. PMID- 24470665 TI - Trigeminal trophic syndrome. AB - Trigeminal trophic syndrome (TTS) is a rare cause of facial ulceration, consequent to damage to the trigeminal nerve or its central sensory connections. We reporta case of TTS in a 48-year-old woman with Bell's palsy following herpes zoster infection. The patient was treated and counseled. There hasnot been any recurrence for 1 year and the patient is being followed-up. The diagnosis of TTS should be suspected when there is unilateral facial ulceration, especially involving the ala nasi associated with sensory impairment. PMID- 24470666 TI - Co-existence of Lichen Sclerosus et Atrophicus and Morphoea Along Lines of Blaschko. AB - Lichen sclerosus (LS) is an inflammatory dermatitis of unknown etiology that mostly affects the genital region in both the sexes. In active cases the histopathologic changes differentiate between LS and morphoea though in chronic cases it is very difficult to diagnose with certainty. Coexistence of both the conditions in a single patient indicates that these lesions represent a spectrum of similar pathologic process. Coexistence of both the conditions along Blaschko's lines is so far not described in literature. We report an Indian patient with both LS and morphoea occurring along Blaschko's lines. PMID- 24470667 TI - Tuberculosis verrucosa cutis presenting as diffuse plantar keratoderma: an unusual sight. AB - Tuberculosis verrucosa cutis (TVC) is a common cutaneous form of paucibacillary tuberculosis in an individual with moderate to high degree of immunity to Mycobacterium tuberculosis infection. Clinical appearance of TVC is mostly very typical with well-defined warty plaques presenting mostly on hands, knees, ankle, and buttocks; however several atypical morphology of the lesions have also been described. We hereby report a case of TVC, masquerading as asymptomatic diffuse keratoderma of left foot for nine months, in an otherwise healthy individual, obstructing easy diagnosis of cutaneous tuberculosis. Diagnosis was confirmed by histopathology. PMID- 24470668 TI - A case of ichthyosis hystrix: unusual manifestation of this rare disease. AB - Ichthyosis hystrix is a term used to describe an ichthyosiform dermatosis which is characterized by hyperkeratotic spiny scales mainly over extensor aspects of limbs with palmoplantar keratoderma and occasionally associated with deafness and neurological deficit. It is a rare autosomal dominant form of ichthyosis and very few cases are reported in literature. We are presenting a 46 years-old-male patient of ichthyosis hystrix with unusual presentation. He had lesions mainly over the face and scalp with palmoplantar keratoderma and significant nail changes. PMID- 24470669 TI - Angiokeratoma circumscriptum in a young male. AB - A 20-year-old male presented with multiple eruptions on his right leg since birth; these bled and were painful on trivial trauma. Examination revealed dark brown, hyperkeratotic, indurated, verrucous linear plaques with irregular borders. Histopathological evidence of hyperkeratosis, acanthosis, and extensive vascular proliferation in papillary dermis confirmed clinical suspicion of angiokeratoma circumscriptum (AKC). Excision and skin grafting yielded a cosmetically favorable outcome. Angiokeratomas, first described by Mibeli in 1889, are a group of vascular ectasias involving the papillary dermis. Angiokeratomas are more common in males; however, AKC-the rarest of its five variants-exhibits a female preponderance (F:M:3:1). AKC is an extremely rare nevoid disorder, only 100 of its cases having been reported in the world literature until 2006. Herein, we have reported a typical case of AKC in a young male that was previously misdiagnosed, and the patient wrongly counseled about the likelihood of its spontaneous regression. PMID- 24470670 TI - Eccrine poroma on the face: an atypical presentation. AB - An eccrine poroma is a solitary tumor arising from the eccrine duct epithelium in the epidermis. The lesions commonly occur on the sole of the foot, the hands, and occasionally on the nose, eyelids, neck, and chest. We report a patient who presented with a slow-growing nodular lesion over her left cheek, prompting a diagnosis of basal cell carcinoma or keratoacanthoma. Biopsy from the nodule revealed a well-defined epidermal tumor with uniform small cuboidal cells with rounded deeply basophilic nuclei, few narrow ductal lumina, and occasional cystic spaces confirming the diagnosis of an eccrine poroma. PMID- 24470671 TI - Hydroa vacciniforme-like cutaneous T-cell lymphoma. AB - A 14-year-old Chinese girl had a 6-year history of recurrent lesions on her head, face, and limbs. Epstein-Barr virus (EBV)-IgM was positive. Histopathological findings revealed focal lymphocyte invasion in subcutaneous panniculus adiposus, mainly surrounding the blood vessels. Immunohistochemistry showed CD3+, CD4+, CD5+, CD8+, TIA-1+, GrB+, CD56-, and L26-. In situ hybridization staining for EBV encoded small nonpolyadenylated RNA (EBER)-1 was positive. The patient showed significant improvement in clinical symptoms after being treated with acyclovir and IFN-alpha in this patient. PMID- 24470672 TI - Atypical erythema nodosum leprosum as the presenting feature in multibacillary leprosy: a case report. PMID- 24470673 TI - Urethral polyp: an uncommon presentation of rhinosporidiosis. PMID- 24470674 TI - Frontalis-associated lipoma: a rare case report. PMID- 24470675 TI - Blue rubber bleb nevus syndrome: a case report. PMID- 24470676 TI - A case of nerve sheath myxoma on finger. PMID- 24470677 TI - Trichotillomania contrasting clinical connotation in a child and adult women. PMID- 24470678 TI - Multiple erythematous shiny papules and nodules over scrotal skin. PMID- 24470679 TI - Screening for skin cancer: a pilot study in tehran, iran. AB - BACKGROUND: Early detection of skin cancers by screening could be very beneficial to decrease their morbidity or mortality. There is limited study about skin cancer screening in Iran. AIM: This essay was planned as a pilot skin cancer screening campaign in Tehran, Iran to evaluate its profit and failure and further design large-scale screening program more definitely. MATERIALS AND METHODS: Thirty one public health centers of Shahid Beheshti Medical University were selected in different areas of Tehran. The project was announced via media and invited all the people above 40 years old to come for the whole-body skin examination in a one-week period. Patients with any suspected lesions were referred to the dermatology clinics of the university. RESULTS: 1314 patients, 194 males (14.8%) and 120 females (85.2%), with mean age of 51.81 +/- 10.28 years participated in this screening campaign. Physicians found suspected lesions in 182 (13.85%) of participants. The diagnosis of skin cancer was confirmed in 15 (1.14%) patients. These malignancies included 10 (0.76%) cases of basal cell carcinoma, 2 (0.15%) cases of squamous cell carcinoma and 3 (0.23%) cases of malignant melanoma. CONCLUSION: Skin cancer screening seems to be valuable to detect skin malignancies in their early course. Regarding the considerable amount of facilities needed to perform skin cancer screening program, it might be more beneficial to perform the targeted screening programs for the high-risk groups or emphasis more on public education of skin cancer risk factors and their early signs. PMID- 24470680 TI - A Case of Kimura's Disease as Giant Pedunculated Tumors. PMID- 24470681 TI - Pemphigus vulgaris in an elderly patient. PMID- 24470682 TI - Management of STI: Looking Beyond the Index Case. PMID- 24470683 TI - Fibrosarcomatous dermatofibrosarcoma protuberans: an unusual tumor in the facial skin. PMID- 24470684 TI - Unusual presentation of angiokeratoma in a cirrhotic patient. PMID- 24470685 TI - Food hypersensitivity in patients suffering from atopic dermatitis and sensitization to soy. PMID- 24470686 TI - Carcinoma erysipeloides as the presenting feature of lung malignancy. PMID- 24470687 TI - Noncervicofacial atypical mycobacterial lymphadenopathy in a child. PMID- 24470688 TI - Subcutaneous cystic swelling on forearm. PMID- 24470689 TI - Pruritic papules on the nose in a 25-year-old female. PMID- 24470690 TI - Lens or Prism? Patent Citations as a Measure of Knowledge Flows from Public Research. AB - This paper assesses the validity and accuracy of firms' backward patent citations as a measure of knowledge flows from public research by employing a newly constructed dataset that matches patents to survey data at the level of the R&D lab. Using survey-based measures of the dimensions of knowledge flows, we identify sources of systematic measurement error associated with backward citations to both patent and nonpatent references. We find that patent citations reflect the codified knowledge flows from public research, but they appear to miss knowledge flows that are more private and contract-based in nature, as well as those used in firm basic research. We also find that firms' patenting and citing strategies affect patent citations, making citations less indicative of knowledge flows. In addition, an illustrative analysis examining the magnitude and direction of measurement error bias suggests that measuring knowledge flows with patent citations can lead to substantial underestimation of the effect of public research on firms' innovative performance. Throughout our analyses we find that nonpatent references (e.g., journals, conferences, etc.), not the more commonly used patent references, are a better measure of knowledge originating from public research. PMID- 24470691 TI - The growth of sleep science and the role of SLEEP. PMID- 24470693 TI - Sustained attention performance during sleep deprivation associates with instability in behavior and physiologic measures at baseline. AB - STUDY OBJECTIVES: To identify baseline behavioral and physiologic markers that associate with individual differences in sustained attention during sleep deprivation. DESIGN: In a retrospective study, ocular, electrocardiogram, and electroencephalogram (EEG) measures were compared in subjects who were characterized as resilient (n = 15) or vulnerable (n = 15) to the effects of total sleep deprivation on sustained attention. SETTING: Chronobiology and Sleep Laboratory, Duke-NUS Graduate Medical School Singapore. PARTICIPANTS: Healthy volunteers aged 22-32 years from the general population. INTERVENTIONS: Subjects were kept awake for at least 26 hours under constant environmental conditions. Every 2 hours, sustained attention was assessed using a 10-minute psychomotor vigilance task (PVT). MEASUREMENTS AND RESULTS: During baseline sleep and recovery sleep, EEG slow wave activity was similar in resilient versus vulnerable subjects, suggesting that individual differences in vulnerability to sleep loss were not related to differences in homeostatic sleep regulation. Rather, irrespective of time elapsed since wake, subjects who were vulnerable to sleep deprivation exhibited slower and more variable PVT response times, lower and more variable heart rate, and higher and more variable EEG spectral power in the theta frequency band (6.0-7.5 Hz). CONCLUSIONS: Performance decrements in sustained attention during sleep deprivation associate with instability in behavioral and physiologic measures at baseline. Small individual differences in sustained attention that are present at baseline are amplified during prolonged wakefulness, thus contributing to large between-subjects differences in performance and sleepiness. PMID- 24470692 TI - Sleep health: can we define it? Does it matter? AB - Good sleep is essential to good health. Yet for most of its history, sleep medicine has focused on the definition, identification, and treatment of sleep problems. Sleep health is a term that is infrequently used and even less frequently defined. It is time for us to change this. Indeed, pressures in the research, clinical, and regulatory environments require that we do so. The health of populations is increasingly defined by positive attributes such as wellness, performance, and adaptation, and not merely by the absence of disease. Sleep health can be defined in such terms. Empirical data demonstrate several dimensions of sleep that are related to health outcomes, and that can be measured with self-report and objective methods. One suggested definition of sleep health and a description of self-report items for measuring it are provided as examples. The concept of sleep health synergizes with other health care agendas, such as empowering individuals and communities, improving population health, and reducing health care costs. Promoting sleep health also offers the field of sleep medicine new research and clinical opportunities. In this sense, defining sleep health is vital not only to the health of populations and individuals, but also to the health of sleep medicine itself. PMID- 24470694 TI - Identification of a pharmacological target for genioglossus reactivation throughout sleep. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA) is a significant public health problem caused by repeated episodes of upper airway closure that occur only during sleep. Attempts to treat OSA pharmacologically have been unsuccessful because there has not been identification of a target operating at cranial motor nuclei, blockade of which can reactivate pharyngeal muscle activity throughout sleep. Increasing potassium conductance is a common mechanism by which state dependent neuromodulators reduce motoneuron excitability. Therefore, we aimed to determine if potassium channel blockade is an effective strategy to reactivate the pharyngeal musculature throughout sleep. DESIGN PARTICIPANTS AND INTERVENTIONS: In rats chronically instrumented for recording sleep-wake states and respiratory motor activities, we locally microperfused pharmacological agents into the hypoglossal motor pool to modulate potassium channels of three major classes: inwardly rectifying, two-pore domain, and voltage-gated. MEASUREMENTS AND RESULTS: Microperfusion of the inwardly rectifying potassium channel blocker, barium, as well as the voltage-gated potassium channel blockers, tetraethylammonium and 4-aminopyridine, increased tonic and respiratory-related genioglossus activities throughout nonrapid eye movement (non-REM) and rapid eye movement (REM) sleep to 133-300% of levels present during baseline wakefulness. In contrast, microperfusion of methanandamide (TWIK-related acid-sensitive potassium [TASK] channel blocker/cannabinoid receptor agonist) activated genioglossus in wakefulness but not in sleep. CONCLUSIONS: These findings establish proof-of-principle that targeted blockade of certain potassium channels at the hypoglossal motor pool is an effective strategy for reversing upper airway hypotonia and causing sustained reactivation of genioglossus throughout nonrapid eye movement and rapid eye movement sleep. These findings identify an important new direction for translational approaches to the pharmacological treatment of obstructive sleep apnea. PMID- 24470696 TI - Cellular aging and restorative processes: subjective sleep quality and duration moderate the association between age and telomere length in a sample of middle aged and older adults. AB - STUDY OBJECTIVES: To examine whether subjective sleep quality and sleep duration moderate the association between age and telomere length (TL). DESIGN: Participants completed a demographic and sleep quality questionnaire, followed by a blood draw. SETTING: Social Neuroscience Laboratory. PARTICIPANTS: One hundred fifty-four middle-aged to older adults (age 45-77 y) participated. Participants were excluded if they were on immunosuppressive treatment and/or had a disease with a clear immunologic (e.g., cancer) component. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Subjective sleep quality and sleep duration were assessed using the Pittsburgh Sleep Quality Index (PSQI) and TL was determined using peripheral blood mononuclear cells (PBMCs). There was a significant first order negative association between age and TL. Age was also negatively associated with the self-reported sleep quality item and sleep duration component of the PSQI. A significant age * self-reported sleep quality interaction revealed that age was more strongly related to TL among poor sleepers, and that good sleep quality attenuated the association between age and TL. Moreover, adequate subjective sleep duration among older adults (i.e. greater than 7 h per night) was associated with TL comparable to that in middle-aged adults, whereas sleep duration was unrelated to TL for the middle-aged adults in our study. CONCLUSIONS: The current study provides evidence for an association between sleep quality, sleep duration, and cellular aging. Among older adults, better subjective sleep quality was associated with the extent of cellular aging, suggesting that sleep duration and sleep quality may be added to a growing list of modifiable behaviors associated with the adverse effects of aging. PMID- 24470697 TI - Treatment outcomes of adenotonsillectomy for children with obstructive sleep apnea: a prospective longitudinal study. AB - OBJECTIVE: To evaluate the efficacy of adenotonsillectomy (AT) in the treatment of children with obstructive sleep apnea (OSA) in a 3-y prospective, longitudinal study with analysis of risk factors of recurrence of OSA. STUDY DESIGN: An investigation of children (6 to 12 y old) with OSA documented at entry and followed posttreatment at 6, 12, 24, and 36 mo with examination, questionnaires, and polysomnography. Multivariate generalized linear modeling and hierarchical linear models analysis were used to determine contributors to suboptimal long term resolution of OSA, and Generalized Linear Models were used for analysis of risk factors of recurrence. RESULTS: Of the 135 children, 88 terminated the study at 36 months post-AT. These 88 children (boys = 72, mean age = 8.9 +/- 2.7 yersus boys 8.9 +/- 2.04 y, girls: 8.8 +/- 2.07 y; body mass index [BMI] = 19.5 +/- 4.6 kg/m(2)) had a preoperative mean apnea-hypopnea index (AHI0) of 13.54 +/- 7.23 and a mean postoperative AHI at 6 mo (AHI6) of 3.47 +/- 8.41 events/h (with AHI6 > 1 = 53.4% of 88 children). A progressive increase in AHI was noted with a mean AHI36 = 6.48 +/- 5.57 events/h and AHI36 > 1 = 68% of the studied group. Change in AHI was associated with changes in the OSA-18 questionnaire. The residual pediatric OSA after AT was significantly associated with BMI, AHI, enuresis, and allergic rhinitis before surgery. From 6 to 36 mo after AT, recurrence of pediatric OSA was significantly associated with enuresis, age (for the 24- to 36 mo period), postsurgery AHI6 (severity), and the rate of change in BMI and body weight. CONCLUSIONS: Adenotonsillectomy leads to significant improvement in apnea hypopnea index, though generally with incomplete resolution, but a worsening over time was observed in 68% of our cases. PMID- 24470695 TI - Effects of chronic sleep fragmentation on wake-active neurons and the hypercapnic arousal response. AB - STUDY OBJECTIVES: Delayed hypercapnic arousals may occur in obstructive sleep apnea. The impaired arousal response is expected to promote more pronounced oxyhemoglobin desaturations. We hypothesized that long-term sleep fragmentation (SF) results in injury to or dysfunction of wake-active neurons that manifests, in part, as a delayed hypercapnic arousal response. DESIGN: Adult male mice were implanted for behavioral state recordings and randomly assigned to 4 weeks of either orbital platform SF (SF4wk, 30 events/h) or control conditions (Ct4wk) prior to behavioral, histological, and locus coeruleus (LC) whole cell electrophysiological evaluations. MEASUREMENTS AND RESULTS: SF was successfully achieved across the 4 week study, as evidenced by a persistently increased arousal index, P < 0.01 and shortened sleep bouts, P < 0.05, while total sleep/wake times and plasma corticosterone levels were unaffected. A multiple sleep latency test performed at the onset of the dark period showed a reduced latency to sleep in SF4wk mice (P < 0.05). The hypercapnic arousal latency was increased, Ct4wk 64 +/- 5 sec vs. SF4wk 154 +/- 6 sec, P < 0.001, and remained elevated after a 2 week recovery (101 +/- 4 sec, P < 0.001). C-fos activation in noradrenergic, orexinergic, histaminergic, and cholinergic wake-active neurons was reduced in response to hypercapnia (P < 0.05-0.001). Catecholaminergic and orexinergic projections into the cingulate cortex were also reduced in SF4wk (P < 0.01). In addition, SF4wk resulted in impaired LC neuron excitability (P < 0.01). CONCLUSIONS: Four weeks of sleep fragmentation (SF4wk) impairs arousal responses to hypercapnia, reduces wake neuron projections and locus coeruleus neuronal excitability, supporting the concepts that some effects of sleep fragmentation may contribute to impaired arousal responses in sleep apnea, which may not reverse immediately with therapy. PMID- 24470698 TI - Long-term changes in neurocognition and behavior following treatment of sleep disordered breathing in school-aged children. AB - STUDY OBJECTIVES: Sleep disordered breathing (SDB) in children is associated with detrimental neurocognitive and behavioral consequences. The long term impact of treatment on these outcomes is unknown. This study examined the long-term effect of treatment of SDB on neurocognition, academic ability, and behavior in a cohort of school-aged children. DESIGN: Four-year longitudinal study. Children originally diagnosed with SDB and healthy non-snoring controls underwent repeat polysomnography and age-standardized neurocognitive and behavioral assessment 4y following initial testing. SETTING: Melbourne Children's Sleep Centre, Melbourne, Australia. PARTICIPANTS: Children 12-16 years of age, originally assessed at 7-12 years, were categorized into Treated (N = 12), Untreated (N = 26), and Control (N = 18) groups. INTERVENTIONS: Adenotonsillectomy, Tonsillectomy, Nasal Steroids. Decision to treat was independent of this study. MEASUREMENTS AND RESULTS: Changes in sleep and respiratory parameters over time were assessed. A decrease in obstructive apnea hypopnea index (OAHI) from Time 1 to Time 2 was seen in 63% and 100% of the Untreated and Treated groups, respectively. The predictive relationship between change in OAHI and standardized neurocognitive, academic, and behavioral scores over time was examined. Improvements in OAHI were predictive of improvements in Performance IQ, but not Verbal IQ or academic measures. Initial group differences in behavioral assessment on the Child Behavior Checklist did not change over time. Children with SDB at baseline continued to exhibit significantly poorer behavior than Controls at follow-up, irrespective of treatment. CONCLUSIONS: After four years, improvements in SDB are concomitant with improvements in some areas of neurocognition, but not academic ability or behavior in school-aged children. PMID- 24470699 TI - The natural history of insomnia: acute insomnia and first-onset depression. AB - STUDY OBJECTIVES: While many studies have examined the association between insomnia and depression, no studies have evaluated these associations (1) within a narrow time frame, (2) with specific reference to acute and chronic insomnia, and (3) using polysomnography. In the present study, the association between insomnia and first-onset depression was evaluated taking into account these considerations. DESIGN: A mixed-model inception design. SETTING: Academic research laboratory. PARTICIPANTS: Fifty-four individuals (acute insomnia [n = 33], normal sleepers [n = 21]) with no reported history of a sleep disorder, chronic medical condition, or psychiatric illness. INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants were assessed at baseline (2 nights of polysomnography and psychometric measures of stress and mood) and insomnia and depression status were reassessed at 3 months. Individuals with acute insomnia exhibited more stress, poorer mood, worse subjective sleep continuity, increased N2 sleep, and decreased N3 sleep. Individuals who transitioned to chronic insomnia exhibited (at baseline) shorter REM latencies and reduced N3 sleep. Individuals who exhibited this pattern in the transition from acute to chronic insomnia were also more likely to develop first-onset depression (9.26%) as compared to those who remitted from insomnia (1.85%) or were normal sleepers (1.85%). CONCLUSION: The transition from acute to chronic insomnia is presaged by baseline differences in sleep architecture that have, in the past, been ascribed to Major Depression, either as heritable traits or as acquired traits from prior episodes of depression. The present findings suggest that the "sleep architecture stigmata" of depression may actually develop over the course transitioning from acute to chronic insomnia. PMID- 24470700 TI - Neurobehavioral performance impairment in insomnia: relationships with self reported sleep and daytime functioning. AB - STUDY OBJECTIVES: Despite the high prevalence of insomnia, daytime consequences of the disorder are poorly characterized. This study aimed to identify neurobehavioral impairments associated with insomnia, and to investigate relationships between these impairments and subjective ratings of sleep and daytime dysfunction. DESIGN: Cross-sectional, multicenter study. SETTING: Three sleep laboratories in the USA and Australia. PATIENTS: Seventy-six individuals who met the Research Diagnostic Criteria (RDC) for Primary Insomnia, Psychophysiological Insomnia, Paradoxical Insomnia, and/or Idiopathic Childhood Insomnia (44F, 35.8 +/- 12.0 years [mean +/- SD]) and 20 healthy controls (14F, 34.8 +/- 12.1 years). INTERVENTIONS: N/A. MEASUREMENTS AND RESULTS: Participants completed a 7-day sleep-wake diary, questionnaires assessing daytime dysfunction, and a neurobehavioral test battery every 60-180 minutes during an afternoon/evening sleep laboratory visit. Included were tasks assessing sustained and switching attention, working memory, subjective sleepiness, and effort. Switching attention and working memory were significantly worse in insomnia patients than controls, while no differences were found for simple or complex sustained attention tasks. Poorer sustained attention in the control, but not the insomnia group, was significantly associated with increased subjective sleepiness. In insomnia patients, poorer sustained attention performance was associated with reduced health-related quality of life and increased insomnia severity. CONCLUSIONS: We found that insomnia patients exhibit deficits in higher level neurobehavioral functioning, but not in basic attention. The findings indicate that neurobehavioral deficits in insomnia are due to neurobiological alterations, rather than sleepiness resulting from chronic sleep deficiency. PMID- 24470701 TI - Evaluation of a brief treatment program of cognitive behavior therapy for insomnia in older adults. AB - OBJECTIVE: To evaluate the efficacy of a brief 4-w group-administered treatment program of cognitive behavior therapy for insomnia (CBT-I) for older adults with sleep maintenance insomnia. DESIGN: Randomized controlled trial of CBT-I compared to waitlist control with comparisons at pretreatment, posttreatment, and 3-mo follow-up. SETTING: Flinders University Sleep and Circadian Rhythm Research Laboratory, Adelaide, South Australia. PARTICIPANTS: One-hundred eighteen adults with sleep maintenance insomnia (mean age = 63.76 y, standard deviation = 6.45 y, male = 55). INTERVENTIONS: A 4-w, group-based treatment program of CBT-I including bedtime restriction therapy, sleep education, and cognitive restructuring. MEASUREMENTS: Seven-day sleep diaries, actigraphy, and several self-report measures to assess perceived insomnia severity, daytime functioning, and confidence in and beliefs about sleep. RESULTS: The brief group-administered CBT-I program produced improvements in the timing and quality of sleep including later bedtimes, earlier out-of-bed times, reduced wake after sleep onset, and improved sleep efficiency. Participants also reported a reduction of the Insomnia Severity Index, Flinders Fatigue Scale, Epworth Sleepiness Scale, Daytime Feeling and Functioning Scale, Sleep Anticipatory Anxiety Questionnaire, the Dysfunctional Beliefs and Attitudes Scale, and increased Sleep Self-Efficacy Scale. CONCLUSIONS: The treatment program used in the current study has demonstrated potential for a brief, inexpensive, and effective treatment of sleep maintenance insomnia in the older adult population. PMID- 24470702 TI - A scale for assessing the severity of arousal disorders. AB - BACKGROUND: Arousal disorders may have serious health consequences. OBJECTIVE: To develop a scale assessing the severity of arousal disorders (Paris Arousal Disorders Severity Scale, PADSS). SETTING: University hospital. DESIGN: Controlled study. PARTICIPANTS: Consecutive patients (older than 15 y), with sleepwalking (SW) and/or sleep terrors (ST), subjects with previous SW/ST, normal controls and patients with rapid eye movement sleep behavior disorder. INTERVENTION: The self-rated scale listed 17 parasomniac behaviors (PADSS-A), assessed their frequency from never to twice or more per night (PADSS-B) and evaluated the consequences (PADSS-C: disturbed sleep, injuries, fatigue, and psychological consequences). The clinimetric properties and face validity of the scale were tested. RESULTS: Half of the 73 patients with SW/ST (more men than women) had injured themselves or others, whereas 15% had concomitant sexsomnia and 23% had amnestic eating behaviors. The total PADSS score (range: 0-50) was 19.4 +/- 6.3 (range: 8-36) in this group, 11.7 +/- 5.9 in 26 subjects with previous SW/ST, 8.8 +/- 3.2 in 26 patients with RBD, and 2.0 +/- 3.5 in 53 normal controls (P < 0.05). The PADSS demonstrated high sensitivity (83.6%), specificity (87.8%), internal consistency, and test-retest reliability (0.79). The best cutoff for the total score was at 13/14. Exploratory factor analysis revealed two components: wandering and violence/handling. The complexity of behaviors emerging from N3 sleep (scored on videopolysomnography) positively correlated with scores for the PADSS-total, PADSS-A, PADSS-C, and the "violence/handling" factor. CONCLUSION: This scale had reasonable psychometric properties and could be used for screening and stratifying patients and for evaluating the effects of treatments. PMID- 24470703 TI - Social ties may play a critical role in mitigating sleep difficulties in disaster affected communities: a cross-sectional study in the Ishinomaki area, Japan. AB - STUDY OBJECTIVES: We examined the association between social factors and sleep difficulties among the victims remaining at home in the Ishinomaki area after the Great East Japan Earthquake and Tsunami and identified potentially modifiable factors that may mitigate vulnerability to sleep difficulties during future traumatic events or disasters. DESIGN: A cross-sectional household survey was conducted from October 2011 to March 2012 (6-12 mo after the disaster) in the Ishinomaki area, Japan. Univariate and multivariate logistic regression models were used to examine associations between social factors and sleep difficulties. PARTICIPANTS: We obtained data on 4,176 household members who remained in their homes after the earthquake and tsunami. INTERVENTIONS: N/A. RESULTS: Sleep difficulties were prevalent in 15.0% of the respondents (9.2% male, 20.2% female). Two potentially modifiable factors (lack of pleasure in life and lack of interaction with/visiting neighbors) and three nonmodifiable or hardly modifiable factors (sex, source of income, and number of household members) were associated with sleep difficulties. Nonmodifiable or hardly modifiable consequences caused directly by the disaster (severity of house damage, change in family structure, and change in working status) were not significantly associated with sleep difficulties. CONCLUSIONS: Our data suggest that the lack of pleasure in life and relatively strong networks in the neighborhood, which are potentially modifiable, might have stronger associations with sleep difficulties than do nonmodifiable or hardly modifiable consequences of the disaster (e.g., house damage, change in family structure, and change in work status). PMID- 24470704 TI - Telomere length is associated with sleep duration but not sleep quality in adults with human immunodeficiency virus. AB - BACKGROUND AND STUDY OBJECTIVE: Telomere length provides an estimate of cellular aging and is influenced by oxidative stress and health behaviors such as diet and exercise. This article describes relationships between telomere length and sleep parameters that included total sleep time (TST), wake after sleep onset (WASO), and self-reported sleep quality in a sample of adults with chronic illness. DESIGN AND PARTICIPANTS: Cross-sectional study of 283 adults (74% male, 42% Caucasian) infected with human immunodeficiency virus (HIV) while living in the San Francisco Bay area, CA, USA. Ages ranged from 22-77 y. MEASUREMENTS AND RESULTS: TST and WASO were estimated with wrist actigraphy across 72 h; self reported sleep quality was assessed with the Pittsburgh Sleep Quality Index. Relative telomere length (RTL) in leukocytes was estimated by quantitative polymerase chain reaction assays. Shorter RTL was associated with older age, and RTL was shorter in males than females. RTL was unrelated to HIV disease characteristics. RTL was not associated with WASO or self-reported sleep quality. Participants with at least 7 h sleep had longer RTL than those with less than 7 h, even after controlling for the effects of age, sex, race, education, body mass index, metabolic hormones (i.e., leptin, ghrelin, adiponectin, and resistin), depression and anxiety, and sleep quality. CONCLUSION: Results suggest that sleep duration is associated with preserving telomere length in a population of human immunodeficiency virus-infected adults. Getting at least 7 hours of sleep at night may either protect telomeres from damage or restore them on a nightly basis. PMID- 24470705 TI - Mapping gray matter reductions in obstructive sleep apnea: an activation likelihood estimation meta-analysis. AB - STUDY OBJECTIVES: The authors reviewed the literature on the use of voxel-based morphometry (VBM) in obstructive sleep apnea (OSA) magnetic resonance imaging (MRI) studies via the use of a meta-analysis of neuroimaging to identify consistent and specific structural deficits in patients with sleep apnea compared with healthy subjects. DESIGN: Neuroimaging meta-analysis. DATA SOURCES: We used PubMed to retrieve articles published between January 2000 and February 2012. STUDY SELECTION: The authors included all VBM research on patients with OSA and healthy controls. They compared the findings of the studies by using gray matter volume (GMV) or gray matter concentration (GMC) to index differences in gray matter. DATA EXTRACTION: Stereotactic data were extracted from eight VBM studies of 213 patients with OSA and 195 control subjects. RESULTS: Regional gray matter reduction in the bilateral parahippocampus and less-convincing right superior frontal and left middle temporal gyri was demonstrated in patients with sleep apnea using an activation likelihood estimation (ALE) procedure to analyze significant differences. CONCLUSIONS: Significant reductions in gray matter in patients with sleep apnea occurred in the bilateral parahippocampus and less convincing frontotemporal regions, which may be related to the neurocognitive processing abnormalities that are common among populations of patients with sleep apnea. PMID- 24470706 TI - Continuous positive airway pressure improves sleep and daytime sleepiness in patients with Parkinson disease and sleep apnea. AB - STUDY OBJECTIVES: Obstructive sleep apnea (OSA), common in Parkinson disease (PD), contributes to sleep disturbances and daytime sleepiness. We assessed the effect of continuous positive airway pressure (CPAP) on OSA, sleep, and daytime sleepiness in patients with PD. DESIGN: This was a randomized placebo-controlled, crossover design. Patients with PD and OSA were randomized into 6 w of therapeutic treatment or 3 w of placebo followed by 3 w of therapeutic treatment. Patients were evaluated by polysomnography (PSG) and multiple sleep latency test (MSLT) pretreatment (baseline), after 3 w, and after 6 w of CPAP treatment. Analyses included mixed models, paired analysis, and within-group analyses comparing 3 w to 6 w of treatment. SETTING: Sleep laboratory. PARTICIPANTS: Thirty-eight patients with PD (mean age = 67.2 +/- 9.2 y; 12 females). INTERVENTION: Continuous positive airway pressure. MEASUREMENTS: PSG OUTCOME MEASURES: sleep efficiency, %sleep stages (N1, N2, N3, R), arousal index, apnea hypopnea index (AHI), and % time oxygen saturation < 90% (%time SaO2 < 90%). MSLT outcome measures: mean sleep-onset latency (MSL). RESULTS: There were significant group-by-time interactions for AHI (P < 0.001), % time SaO2 < 90% (P = 0.02), %N2 (P = 0.015) and %N3 (P = 0.014). Subjects receiving therapeutic CPAP showed significant decrease in AHI, %time SaO2 < 90%, %N2, and significant increase in %N3 indicating effectiveness of CPAP in the treatment of OSA, improvement in nighttime oxygenation, and in deepening sleep. The paired sample analyses revealed that 3 w of therapeutic treatment resulted in significant decreases in arousal index (t = 3.4, P = 0.002). All improvements after 3 w were maintained at 6 w. Finally, 3 w of therapeutic CPAP also resulted in overall decreases in daytime sleepiness (P = 0.011). CONCLUSIONS: Therapeutic continuous positive airway pressure versus placebo was effective in reducing apnea events, improving oxygen saturation, and deepening sleep in patients with Parkinson disease and obstructive sleep apnea. Additionally, arousal index was reduced and effects were maintained at 6 weeks. Finally, 3 weeks of continuous positive airway pressure treatment resulted in reduced daytime sleepiness measured by multiple sleep latency test. These results emphasize the importance of identifying and treating obstructive sleep apnea in patients with Parkinson disease. PMID- 24470707 TI - Association between heart rate variability, blood pressure and autonomic activity in cyclic alternating pattern during sleep. AB - STUDY OBJECTIVES: Cyclic alternating pattern (CAP) is frequently followed by changes in heart rate (HR) and blood pressure (BP), but the sequential associations between CAP and autonomic nerve activity have not been studied. The study aimed to reveal the precise changes in heart rate variability (HRV) during phase A of the CAP cycle. DESIGN: Polysomnography was recorded according to the CAP Atlas (Terzano, 2002), and BP and electrocardiogram were simultaneously recorded. The complex demodulation method was used for analysis of HRV and evaluation of autonomic nerve activity. SETTING: Academic sleep laboratory. PARTICIPANTS: Ten healthy males. MEASUREMENTS AND RESULTS: The increase in HR (median [first quartile - third quartile]) for each subtype was as follows: A1, 0.64 (-0.30 to 1.69), A2, 1.44 (0.02 to 3.79), and A3, 6.24 (2.53 to 10.76) bpm (A1 vs. A2 P < 0.001, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). The increase in BP for each subtype was as follows: A1, 1.23 (-2.04 to 5.75), A2, 1.76 (-1.46 to 9.32), and A3, 12.51 (4.75 to 19.94) mm Hg (A1 vs. A2 P = 0.249, A1 vs. A3 P < 0.001, A2 vs. A3 P < 0.001). In all of phase A, the peak values for HR and BP appeared at 4.2 (3.5 to 5.4) and 8.4 (7.0 to 10.3) seconds, respectively, after the onset of phase A. The area under the curve for low-frequency and high frequency amplitude significantly increased after the onset of CAP phase A (P < 0.001) and was higher in the order of subtype A3, A2, and A1 (P < 0.001). CONCLUSIONS: All phase A subtypes were accompanied with increased heart rate variability, and the largest heart rate variability was seen in subtype A3, while a tendency for less heart rate variability was seen in subtype A1. PMID- 24470708 TI - Acute sleep deprivation increases serum levels of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in healthy young men. AB - STUDY OBJECTIVES: To investigate whether total sleep deprivation (TSD) affects circulating concentrations of neuron-specific enolase (NSE) and S100 calcium binding protein B (S-100B) in humans. These factors are usually found in the cytoplasm of neurons and glia cells. Increasing concentrations of these factors in blood may be therefore indicative for either neuronal damage, impaired blood brain barrier function, or both. In addition, amyloid beta (Abeta) peptides 1-42 and 1-40 were measured in plasma to calculate their ratio. A reduced plasma ratio of Abeta peptides 1-42 to 1-40 is considered an indirect measure of increased deposition of Abeta 1-42 peptide in the brain. DESIGN: Subjects participated in two conditions (including either 8-h of nocturnal sleep [22:30-06:30] or TSD). Fasting blood samples were drawn before and after sleep interventions (19:30 and 07:30, respectively). SETTING: Sleep laboratory. PARTICIPANTS: 15 healthy young men. RESULTS: TSD increased morning serum levels of NSE (P = 0.002) and S-100B (P = 0.02) by approximately 20%, compared with values obtained after a night of sleep. In contrast, the ratio of Abeta peptides 1-42 to 1-40 did not differ between the sleep interventions. CONCLUSIONS: Future studies in which both serum and cerebrospinal fluid are sampled after sleep loss should elucidate whether the increase in serum neuron-specific enolase and S100 calcium binding protein B is primarily caused by neuronal damage, impaired blood brain barrier function, or is just a consequence of increased gene expression in non-neuronal cells, such as leukocytes. PMID- 24470709 TI - Envelope analysis of the airflow signal to improve polysomnographic assessment of sleep disordered breathing. AB - STUDY OBJECTIVES: Given the detailed respiratory waveform signal provided by the nasal cannula in polysomnographic (PSG) studies, to quantify sleep breathing disturbances by extracting a continuous variable based on the coefficient of variation of the envelope of that signal. DESIGN: Application of an algorithm for envelope analysis to standard nasal cannula signal from actual polysomnographic studies. SETTING: PSG recordings from a sleep disorders center were analyzed by an algorithm developed on the Igor scientific data analysis software. PATIENTS OR PARTICIPANTS: Recordings representative of different degrees of sleep disordered breathing (SDB) severity or illustrative of the covariation between breathing and particularly relevant factors and variables. INTERVENTIONS: The method calculated the coefficient of variation of the envelope for each 30-second epoch. The normalized version of that coefficient was defined as the respiratory disturbance variable (RDV). The method outcome was the all-night set of RDV values represented as a time series. MEASUREMENTS AND RESULTS: RDV quantitatively reflected departure from normal sinusoidal breathing at each epoch, providing an intensity scale for disordered breathing. RDV dynamics configured itself in recognizable patterns for the airflow limitation (e.g., in UARS) and the apnea/hypopnea regimes. RDV reliably highlighted clinically meaningful associations with staging, body position, oximetry, or CPAP titration. CONCLUSIONS: Respiratory disturbance variable can assess sleep breathing disturbances as a gradual phenomenon while providing a comprehensible and detailed representation of its dynamics. It may thus improve clinical diagnosis and provide a revealing descriptive tool for mechanistic sleep disordered breathing modeling. Respiratory disturbance variable may contribute to attaining simplified screening methodologies, novel diagnostic criteria, and insightful research tools. PMID- 24470710 TI - Idiopathic recurrent stupor: Munchausen by proxy and medical litigation. PMID- 24470711 TI - Dermatological applications of carbon dioxide laser. PMID- 24470712 TI - Cutaneous wound closure materials: an overview and update. AB - INTRODUCTION: On a daily basis, dermasurgeons are faced with different kinds of wounds that have to be closed. With a plethora of skin closure materials currently available, choosing a solution that combines excellent and rapid cosmetic results with practicality and cost-effectiveness can be difficult, if not tricky. OBJECTIVES: We aimed to review the available skin closure materials over the past 20 years and the scientific claims behind their effectiveness in repairing various kinds of wounds. MATERIALS AND METHODS: The two authors independently searched and scrutinised the literature. The search was performed electronically using Pub Med, the Cochrane Database, Google Scholar and Ovid as search engines to find articles concerning skin closure materials written since 1990. CONCLUSION: Many factors are involved in the choice of skin closure material, including the type and place of the wound, available materials, physician expertise and preferences, and patient age and health. Evidence-based main uses of different skin closure materials are provided to help surgeons choose the appropriate material for different wounds. PMID- 24470713 TI - Melanin Index in Assessing the Treatment Efficacy of 1064 nm Q Switched Nd-Yag Laser in Nevus of Ota. AB - BACKGROUND: Q-switched neodymium-yttrium aluminium-garnet (Q switched Nd-Yag) laser has been used in the treatment of nevus of Ota in all skin types with variable success rate. Data with an objective assessment parameter to this laser treatment is lacking. OBJECTIVE: To evaluate the utility of melanin index in assessing the treatment response and also determine the efficacy and safety of the Q-switched Nd-Yag laser (1064-nm) in the treatment of nevus of Ota in Fitzpatrick skin types IV and V. MATERIALS AND METHODS: A total of 35 patients treated with Nd-Yag laser were studied. The objective improvement (pigment clearance) was determined by melanin index from two fixed points: A1, 2 cm below the pupil at the mid pupillary line (when the gaze is fixed); A2, the most prominent part of zygoma. The melanin index in these two areas was recorded as M1 and M2, respectively. The subjective clinical improvement was determined by the physician and the patient global assessment score. RESULTS: The mean baseline melanin indices M1 and M2 were 59.54 +/- 9.72 and 59.02 +/- 9.16, respectively. At the last visit the mean M1 and M2 decreased to 53.8 +/- 8.55 (P < 0.001) and 54.13 +/- 6.01 (P < 0.001), respectively. Patient and the physician global assessment score showed that 26 (74.3%) and 20 (57.14%) patients, respectively, had >50% pigment clearance. CONCLUSION: The melanin index, a simple non-invasive parameter is useful in assessing the treatment response more objectively. The 1064-nm Q-switched Nd-Yag laser offers good improvement in patients with nevus of Ota in darker skin types IV/V. PMID- 24470714 TI - Assessment of the Response and Improving Outcomes of Nevus of Ota with Q-switched Nd : Yag Laser. PMID- 24470715 TI - Transungual surgical excision of subungual glomus tumour. AB - BACKGROUND: Glomus tumours are rare vascular tumours arising subungually in fingernails. Surgical excision provides histopathologic diagnosis and rapid resolution of symptoms. OBJECTIVE: Present study was aimed at delineating common presentations and long-term treatment outcome of this rare subungual tumour. PATIENTS AND METHODS: The clinical features and imaging results for 10 patients with subungual glomus tumours were recorded. All were treated with transungual excision. Per-operative findings and, treatment outcomes were recorded and analysed. RESULTS: Females outnumbered males with average age being 33.3 +/- 7.55 years. Presenting symptoms were severe pain (100%); nail-plate discoloration and onycholysis. X-ray was normal in 70%, though a magnetic resonance imaging done for five, helped visualise the lesion in three patients. The tumour involved nail bed in five cases and matrix in five, with an average size being 6.1 +/- 2.13 mm (range 3-11 mm). An average follow-up of 16.8 months (range 8-24 months) was largely uneventful with longitudinal ridging in two cases and recurrence in two (both attributed to a sister lesion). CONCLUSION: Subungual glomus tumours have characteristic clinical presentation. Imaging is helpful pre-operatively but has a low success rate. Transungual surgical excision is safe and effective, allowing better visualisation, easy exploration and minimal long-term complications. PMID- 24470716 TI - Comparative study of oral isotretinoin versus oral isotretinoin + 20% salicylic Acid peel in the treatment of active acne. AB - BACKGROUND: Acne is a self limiting condition that often results in scarring and disfigurement disproportionate to its clinical severity. Isotretinoin is considered the gold standard in the medical management of severe form of acne vulgaris. Salicyclic acid (SA) peels, a beta- hydroxy acid peel has got sebosuppressive effect and helps in faster resolution of acne with minimal scarring. It also decreases the post inflammatory hyperpigmentation. Combining both the modalities is usually not advocated because of expected excessive dryness and irritation. AIMS: To compare the efficacy of oral isotretinoin and oral isotretinoin with 20% SA peels in patients with moderate to severe acne. MATERIALS AND METHODS: 60 consecutive patients with moderate to severe facial acne attending the skin department were randomized in to 2 groups. 1(st) group received 20mg oral isotretinoin once daily for 16 weeks and 2nd group received 20mg oral isotretinoin once daily along with 20% SA peels every two weeks for 16 weeks. Baseline grading of acne was done with Michelsons Acne severity index (MASI).Right and left sides of the face were scored separately and total score was taken. Severity score was assessed monthly .Clinical photographs were obtained for evaluation every month. Patients were asked to follow up once every 2 weeks or earlier in case of any adverse events. RESULTS: Patients in both the groups revealed a reduction in the number of lesions. The 1(st) group showed a reduction of approximately 73.4% after receiving 20mg oral isotretinoin for 16 weeks. The 2(nd) group showed a reduction of approximately 92.5 % after receiving 20mg oral isotretinoin along with 20% SA peel once every 2 weeks for 16 weeks. CONCLUSION: Both oral isotretinoin and combination of oral isotretinoin with 20% SA peels once every 2 weeks are effective in treating moderate to severe acne but the combination showed significantly better clearance of acne than monotherapy with isotretinoin. PMID- 24470717 TI - Comparative Study of Oral Isotretinoin versus Oral Isotretinoin +20% Salicylic Acid Peel in the Treatment of Active Acne. PMID- 24470718 TI - A study of donor area in follicular unit hair transplantation. AB - BACKGROUND: The advent of follicular unit transplantation (FUT) has given a natural appearance in the recipient area in the past two decades, but has left behind an unsightly scar in the donor area. A study of donor area and techniques to make it cosmetically acceptable is lacking. AIM: The aim of this study was to evaluate the donor area after follicular unit hair transplantation and to show a few techniques to make the donor scar aesthetically pleasing. MATERIALS AND METHODS: The donor area was examined for scar width and patient satisfaction scores of donor area in 30 consecutive patients from March 2012 to February 2013 retrospectively after a minimum of 3 months after the procedure. Complications such as effluvium along suture line, wound infection, dehiscence, necrosis, folliculitis, keloids and wide scars were also noted. RESULTS: Scar width increased with increase in width of the donor strip. Patient satisfaction scores declined with larger strip widths. The most common complication seen was folliculitis-like lesions. Double trichophytic closure yielded the most aesthetically acceptable scar. CONCLUSION: FUT produces a linear scar in the donor area, which can be a significant concern in patients wishing to cut their hair short. Restricting the width of the donor strip and trichophytic closure has greatly improved the appearance of the scar. PMID- 24470719 TI - Reconstruction of medial lower lip defects after tumour surgery: modified staircase technique. AB - The most common cancer of the lower lip is squamous cell carcinoma (SCC). Micrographically controlled surgery (Mohs surgery) is the golden standard of therapy in localized SCC. Since the majority of lip cancer patients is >60 years of life, planning of surgery and reconstruction has to consider the age and co morbidities. The staircase or step technique is a robust method to achieve a good functional reconstruction in a one-step procedure. We also describe a modified staircase technique when SCC is not infiltrating the orbicularis oris muscle. PMID- 24470720 TI - Liposuction-assisted medial thigh lift in obese and non obese patients. AB - INTRODUCTION: The abdomen, thighs and buttocks are often the areas of greatest concern to patients following massive weight loss due to bariatric surgery. The typical appearance of the patient who has lost a massive amount of weight derives from a combination of factors, including gender-dependent body morphology and a change in body mass index, which lead to skin and soft-tissue excess and poor skin tone. Thigh laxity and redundancy represents a great challenge to both patients and surgeons. Not only because of the difficulty to satisfy the patients, but also due to the higher incidence of complications especially, with those obese patients who have not undergone bariatric surgery before. The problems with such patients are due to the heavy thighs that require both debulking and tight anchorage to prevent scar migration or labial distortion. AIM OF THE WORK: The aim of the present study is to improve the aesthetic outcome and avoid the complications of medial thigh lifting with simultaneous liposuction in obese and non-obese. PATIENTS AND METHODS: A total of 25 female patients presented during the period from January 2007 to July 2011 complaining of moderate to severe thigh laxity with or without lipodystrophy. In 20 patients medial transverse thigh lift was performed, to treat medial thigh friction and laxity particularly in the upper half. Whereas, in the other five patients were suffering from upper and lower medial thigh bulkiness, vertical thigh lift was performed. RESULTS: All patients recovered well in 2 weeks and showed improvement of thigh contour. Scar downward displacement in one patient. No skin necrosis or seroma. No labial distortion or separation encountered. CONCLUSION: Simultaneous liposuction and thigh lift gave good results provided proper patients selection, appropriate technique to each patient, meticulous, cautious liposuction and handling of the tissues and most importantly is the deep tight anchorage sutures to guard against the effect of heavy skin flaps. PMID- 24470721 TI - Successful Treatment of Tattoo-Induced Pseudolymphoma with Sequential Ablative Fractional Resurfacing Followed by Q-Switched Nd: YAG 532 nm Laser. AB - Decorative tattooing has been linked with a range of complications, with pseudolymphoma being unusual and challenging to manage. We report a case of tattoo-induced pseudolymphoma, who failed treatment with potent topical and intralesional steroids. She responded well to sequential treatment with ablative fractional resurfacing (AFR) followed by Q-Switched (QS) Nd:YAG 532 nm laser. Interestingly, we managed to document the clearance of her tattoo pigments after laser treatments on histology and would like to highlight the use of special stains such as the Grocott's Methenamine Silver (GMS) stain as a useful method to assess the presence of tattoo pigment in cases where dense inflammatory infiltrates are present. PMID- 24470722 TI - Follicular unit extraction as a therapeutic option for vitiligo. AB - Follicular unit extraction (FUE) is a surgical procedure, which can be used to transplant follicular units into vitiliginous areas. Such follicular unit transplant has been recently used to repigment stable vitiligo patches. FUE was done for a 12-year-old female with a stable vitiligo patch with leukotrichia on the eyebrow. Repigmentation was noted in 6 weeks and complete pigmentation seen at 12 weeks. Leukotrichia resolved over a period of 6 months. No recurrence was noted at the end of 6 months follow-up with excellent colour match. This case is presented to highlight the simplicity, safety and effectiveness of FUE in stable vitiligo patches with leukotrichia. PMID- 24470723 TI - Epithelioid hemangioendothelioma in a child. AB - Epithelioid hemangioendothelioma (EHE) is a rare tumour arising from the vascular endothelium of soft-tissue, bone and viscera. Skin involvement is rare. The disease has an indolent course, with the potential for recurrence and often associated with multi-systemic localisations. We present a rare case of cutaneous EHE without systemic involvement in 9-year-old boy. The tumour was completely excised and histopathologic diagnosis was consistent with EHE. Complete systemic assessment showed no internal localisation. Wide excision is the mainstay of therapy and regular follow-up is suggested due to the potential for recurrence. The majority of documented cases of EHE is in adults and has developed in association with an underlying systemic involvement. To the best of our knowledge, this is the second reported case of isolated cutaneous EHE in paediatric age group. PMID- 24470724 TI - Micropigmentation in vitiligo of lateral lower lip. PMID- 24470725 TI - Squamous cell carcinoma on the scalp after use of a wig for 30 years. PMID- 24470726 TI - SEMIPARAMETRIC ESTIMATION OF CONDITIONAL HETEROSCEDASTICITY VIA SINGLE-INDEX MODELING. AB - We consider a single-index structure to study heteroscedasticity in regression with high-dimensional predictors. A general class of estimating equations is introduced, the resulting estimators remain consistent even when the structure of the variance function is misspecified. The proposed estimators also possess an adaptive property in an asymptotic sense. That is, they estimate the conditional variance function asymptotically as well as if the conditional mean function was given a priori. Numerical studies confirm our theoretical observations and demonstrate that our proposed estimator is superior to existing estimators with less bias and smaller standard deviation. PMID- 24470727 TI - Investigation and management of childhood sleep apnoea. AB - Sleep-disordered breathing includes disorders of breathing that affect airway patency, e.g. obstructive sleep apnoea syndrome, and also conditions that affect respiratory drive (central sleep disorders) or cause hypoventilation, either as a direct central effect or due to peripheral muscle weakness. Obstructive sleep apnoea syndrome (OSAS) is an increasingly-recognised clinical entity affecting up to 5.7% of children, which, if left untreated, is associated with adverse effects on growth and development including deleterious cognitive and behavioural outcomes. Evidence exists also that untreated OSAS impacts on cardiovascular risk. Close attention should be paid to assessment and investigation of this relatively common condition, instigating early and appropriate treatment to children with OSAS. First-line treatment in younger children is adenotonsillectomy, although other treatment options available include continuous positive airways pressure (CPAP), anti-inflammatory therapies (nasal corticosteroids and anti-leukotrienes), airway adjuncts and orthodontic appliances. Central sleep-disordered breathing may be related to immaturity of respiratory control and can be associated with prematurity as well as disorders such as Prader-Willi syndrome. In some cases, central apnoeas occur as part of a central hypoventilation disorder, which may be inherited, e.g. Congenital Central hypoventilation Syndrome, or acquired, e.g. Arnold-Chiari malformation, brain tumour, or spinal injury. The treatments of central breathing problems depend upon the underlying aetiology. PMID- 24470728 TI - Correlation between the climatic factors and the pathogenesis of deep vein thrombosis. AB - There are numerous researches dealing with the correlation between the seasons and climatic factors and the pathogenesis of deep vein thrombosis (DVT). The presented researches show an undoubted correlation between the climatic factors and the pathogenesis of DVT. In the majority of researches, retrospection is noted as a disadvantage. Further prospective researches could aim on testing the correlation between both climatic and thrombotics factors and the pathogenesis of DVT. This may additionally clarify the pathophysiological mechanism of the DVT incidence and contribute to the prevention and treatment of risk groups of patients in certain periods of the year. PMID- 24470729 TI - X-linked, COL4A5 hypomorphic Alport mutations such as G624D and P628L may only exhibit thin basement membrane nephropathy with microhematuria and late onset kidney failure. AB - Alport syndrome (ATS) results from X-linked, COL4A5 mutations (85%) or from autosomal recessive homozygous or compound heterozygous COL4A3/A4 mutations (15%), associated with alternate thinning and thickening as well as splitting and lamellation of the glomerular basement membranes. In contrast, familial microhematuria with thin basement membranes is thought to result from heterozygous COL4A3/A4 mutations. This absolute separation may not always be true. Renal biopsies and molecular genetics were used to study microhematuric families in the Hellenic population we serve. The COL4A5 gene was studied by PCR and direct re-sequencing for new mutations, while PCR-RFLP was used to identify more carriers of known COL4A5 and COL4A3/A4 mutations. Molecular genetics in two undiagnosed microhematuric Cypriot families, revealed COL4A5 mutation P628L indicating X-linked ATS. Of nine males, seven developed end stage kidney disease (ESKD) between 31 and 56, while two are well at 51 and 57, exhibiting microhematuria and thin basement membrane nephropathy (TBMN). COL4A5 mutation G624D was also identified in six Greek families. Seventy five members had DNA tests and 37 proved positive. Four positive males developed ESKD at 61, 51, 50 and 39 years, while the remaining and all females showed only microhematuria. A literature search revealed eight papers with six similar hypomorphic COL4A5 mutations presenting as phenocopies of TBMN. In conclusion, X-linked COL4A5 ATS mutations produce a phenotypic spectrum with a) classical ATS with early onset ESKD, neurosensory deafness and ocular defects b) males with only ESKD and late deafness and c) males due to missense mutations, such as G624D and P628L that may only exhibit microhematuria, TBMN, mild chronic renal failure (CRF) or late onset ESKD. Consequently when investigating "benign familial hematuria" these and other similar X-linked COL4A5 mutations should also be searched for. PMID- 24470730 TI - Evaluation of non-motor symptoms in Parkinson's Disease: An underestimated necessity. AB - BACKGROUND AND AIM: Nuon-motor symptoms in Parkinson's disease (PD) are very common and contribute to the severity of patient's disability. We evaluated the frequency of nonmotor symptoms in patients with PD and we explored the influence of disease characteristics on the presence of these symptoms. PATIENTS AND METHODS: One hundred sixty six patients and sixty six matched controls were enrolled in the study. The Non-Motor Symptoms Questionnaire (NMSQuest), a 30-item self-completed questionnaire, was used for the evaluation of nonmotor symptoms. RESULTS: Non-motor symptoms were more common in PD patients than controls. Mean +/- SD NMSQuest score was 6.76 +/- 4.22 in PD patients and 5.44 +/- 4.45 in controls (p=0.035). The more common non-motor symptoms in PD patients were urinary urgency (54.3%), nocturia (51.8%), constipation (45.7%) and sadness (42.1%). There was a correlation between NMSQuest score and severity of the disease. CONCLUSION: Non-motor symptoms in PD are too important to remain undetected. By incorporating into every day practice the use of suitable, reliable questionnaires, we will be able to facilitate detection and management of these symptoms. PMID- 24470731 TI - Pre-treatment gelatinases' serum levels and post-treatment changes in laryngeal cancer patients. AB - INTRODUCTION: Laryngeal cancer, especially in the advanced stages, is a highly devastating disease, characterized by increased invasiveness and high rates of metastasis. Gelatinases A and B (MMP-2 and -9 respectively) are of particular interest due to their contribution to various stages of carcinogenesis. There is a growing body of evidence with regard to the prognostic value of certain MMPs and their possible role as tumour markers. AIM: To identify the pattern of alteration of serum gelatinases A and B in patients with laryngeal cancer following treatment, and a possible correlation with various clinicopathological parameters. MATERIALS AND METHODS: Forty nine patients were included in this study. Pre-treatment and post-treatment serum samples were collected and processed by gelatin zymography and western blotting. RESULTS: Only the latent forms of MMP-2 and -9 were identified. Both gelatinases were increased in the serum of laryngeal cancer patients compared to healthy individuals. Patients with supraglottic tumours and active smokers had significantly higher pre-treatment levels of proMMP-2 than patients with glottic tumours (p < 0.05) and ex-smokers (p < 0.05), respectively. Patients with primary disease and patients with lymph node involvement showed lower serum proMMP-9 pre-treatment levels than patients with recurrence (p < 0.05) and patients without neck disease (p < 0.1), respectively. During the follow-up period the proMMP-2 serum levels increased significantly in the first ten to fifteen days after treatment, gradually decreasing over the following months. The proMMP-9 serum levels showed a gradual decrease after treatment, which was statistically significant (p<0.05). CONCLUSIONS: The post-treatment alteration pattern of proMMP-9 serum levels shows a possible role of this molecule as a tumour marker in laryngeal cancer. Further research is necessary to clarify the contribution of both gelatinases to the disease progress and determine their role as prognostic factors and tumour markers. PMID- 24470732 TI - Effects of hormonotherapy administered after concurrent radiotherapy and Trastuzumab on pulmonary fibrosis. AB - AIM: This study was to investigate whether the use of hormonotherapy after concurrent radiotherapy (RT) and trastuzumab (T) has a contribution to the development of radiation fibrosis in the lungs. MATERIALS AND METHODS: Seventy Wistar Albino rats were divided into seven groups as follows: Group C: control, Group RT: RT only; Group T: trastuzumab only; Group RT+T+Tam: tamoxifen following concurrent RT and trastuzumab; Group RT+T+Le: letrozole following concurrent RT and trastuzumab; Group RT+T+An: anastrazole following concurrent RT and trastuzumab; Group RT+T+Exe: exemestane following concurrent RT and trastuzumab. Trastuzumab was prepared at an equivalent dose of 6 mg/kg. RT was administered 2 hours after T to the thoracic region at a dose of 12 Gy. Hormonotherapy was initiated one week after RT and administered by oral gavage once daily for 6 months. At the end of 24 weeks, the rats were sacrificed after being sedated with anesthesia. Both lungs were removed en bloc and blocked in paraffin. The level of fibrosis in each cross-section was assessed with the help of a scale. RESULTS: Significant differences were observed between the groups in terms of pulmonary fibrosis scoring. Statistically significant differences were observed when the radiotherapy group was compared to the C, T, T+RT+An, T+RT+Le and T+RT+Exe groups (p<0.05). Significant differences were found between the T+RT+Tam group and the C, T, T+RT+An, T+RT+Le and T+RT+Exe groups (p<0.05). CONCLUSIONS: This study showed that the sequential administration of aromatase inhibitors following concurrent thoracic irradiation and T decreases radiation-induced pulmonary fibrosis. However, tamoxifen was found to have an opposite effect. PMID- 24470733 TI - Radiation induced pneumonitis following whole breast radiotherapy treatment in early breast cancer patients treated with breast conserving surgery: a single institution study. AB - BACKGROUND: Hypofractionated Radiotherapy (RT) regimens for breast cancer, although reduce cost and time for patients and health care systems, could have a negative impact on normal underlying lung tissue. We studied and compared lung function and the post-RT radiological changes using High-Resolution Computed Tomography (HRCT) in early breast cancer patients, treated with 3-Dimentional conformal whole breast radiotherapy (WBRT) using either conventional or hypofractionated regime. PATIENTS AND METHODS: Between 2008 and 2009, 61 early breast cancer patients (T1-2N0M0) were randomised into two groups .Group A (n=31) received standard radiotherapy with 50Gy/25f/5w plus boost 10Gy/5f/1w to tumour bed. Group B (n=30) received 43.2Gy/16f/22d plus boost 10Gy/5f/1w to tumour bed. Patients of both groups were subjected to dynamic lung testing, using spirometry and gas diffusion tests on Day 0 (D0, before RT), during RT and after completion of RT at 3 and 6 months. HRCT scans were performed in all patients at baseline, and 3,6,12 months after completion of RT. Respiratory symptoms were recorded at 3 and 6 months post completion of RT. Dosimetric factors, such as Central Lung Dose (CLD), lung Volume receiving more 20 Gy (V20), D25 and Mean Lung Dose (MLD) were calculated for all patients. RESULTS: At 3 months after RT, the pulmonary changes were classified at HRCT as follows: 91.8 % were Grade 0, 8.19 % Grade 1, and 0 % Grade 2. At 6 months, 86.98 % were Grade 0, 11.47 % Grade 1, and 1.6 % Grade 2. At 12 months, 88.52 % were Grade 0, 9.19 % Grade 1 and 3.27% Grade 2. Univariate analysis showed strong association between radiation pneumonitis, age and all dosimetric parameters. There was no association between fractionation type and incidence of RN. FEV1, FVC, FEV 25, FEV 50 and DLCO showed no statistically significant reduction in both treatment groups in 3 and 6 months following completion of RT, compared to baseline. Multivariate analysis showed no relation between HRCT findings and other variables (age, smoking, chemotherapy, hormonotherapy, V20). CONCLUSION: Lung toxicity, as assessed with HRCT and PFTs, was minimal in both treatment arms and our results are in consistency with other published data. Hypofractionated RT was a safe modality and well tolerated by the majority of the patients. Longer follow-up is required for robust assessment of incidence of late lung fibrosis in our series. PMID- 24470734 TI - Recovery process in patients followed-up due to acute kidney injury. AB - INTRODUCTION: Acute kidney injury (AKI) may result in complete recovery in some of the patients and partial recovery in others. AKI episodes may accelerate the progression to chronic kidney disease and end-stage renal failure, while risk for morbidity and mortality is high following AKI. Discharge of patients from the hospital, independently from dialysis is a crucial outcome. Many patients without a need for dialysis, require follow-up for various durations and different treatments. The objective of this study was to compare mean recovery time of the patients followed-up due to prerenal, renal and postrenal AKIs. METHOD: In this prospective observational study, a total of 159 patients hospitalized in Bulent Ecevit Hospital, clinic of nephrology or monitored in the other wards and intensive care unit due to AKI, between June 2011 and January 2012, were enrolled. The cases were divided into three groups as prerenal, renal and postrenal, and monitored with the daily visits and renal function testing. RESULTS: Prerenal AKI was seen by 54%, while renal AKI was observed by 34% and post-renal AKI by 12%. Incidence of chronic kidney disease was 17.6%. Totally 43 patients required hemodialysis (27%). Of these patients, 23 were in the prerenal AKI (53.4%), 15 in the renal AKI (34.8%) and 5 (11.6%) in the postrenal AKI group. Blood urea nitrogen (BUN) and creatinine levels were dropped to the basal values only in the prerenal AKI group, on the seventh day of treatment. These levels remained higher in the postrenal and renal groups on the 7th day of treatment compared to the basal values. BUN levels decreased to the normal values on average 7th day in the postrenal, while remained higher in the renal group. CONCLUSION: Prerenal AKI patients recovered in seven days with a proper treatment, although AKI patients due to other reasons should be followed-up for a longer time. PMID- 24470735 TI - Could living unrelated renal transplantation ameliorate the actual shortage of organs in the Balkan region? AB - BACKGROUND: Despite the efforts for more transplants performed with organs from deceased donors, the living renal transplantation is still the predominant transplant activity in the Balkan region. In order to adress the severe organ shortage, we started accepting unrelated (emotionally related) living donors (LURD). Here we present our 10-year experience with living unrelated renal transplantation (LURT). METHODS: Twenty four LURT were performed in our center in the last 10 years. The mean recipients and donors age was 41.7 and 47.2 years, respectively. As LURD spouses (n=17) and extended family members (n=7) were accepted predominantly. All donors went through careful psychological evaluation in order to confirm emotional relationship. The final decision was taken after both the recipient and the donor signed a consent in front of a judge. A quadruple sequential immunosuppressive protocol was used in all recipients. The 5 year Kaplan Meier graft survival rate, HLA mismatch, rejection episodes, delayed graft function, serum creatinine and Glomerular filtration rate-Modification of the diet in renal disease (GFR-MDRD) were analyzed. The results were compared with 30 living related renal transplants (LRT) performed during the same time with mean recipients and donors age of 35.9 and 58.5 years, respectively. RESULTS: The mean follow up for LURT and LRT recipients were 81.4 and 79.6 months, respectively. There was a significant difference regarding recipients and donors age, HLA mismatch (5.07 and 2.9) and rejection episodes (16% vs. 11%) in LURT and LRT recipients. The 5 years graft survival rate was excellent in both groups (83 and 81%, respectively). There was no significant difference in 5 years serum creatinine (129.3 vs 121.1 MUmol/lit) and 5 years GFR-MDRD (56.6 and 58.6 ml/min). CONCLUSION: The authors present an excellent 5-year graft survival rate in both LURT and LRT recipients. Therefore, LURT could ameliorate the severe organ shortage in the region and could be recommended as a valuable source of organs in the countries with developed and underdeveloped deceased donor donation. PMID- 24470736 TI - Calcitonin stimulation tests for the early diagnosis and follow-up of patients with C cell disease: a descriptive analysis. AB - BACKGROUND/AIM: Residual or recurrent medullary thyroid carcinoma (MTC) after thyroidectomy is diagnosed by elevated serum calcitonin (CT) levels. However, in minimal residual MTC or C-cell hyperplasia (CCH), where imaging studies are often negative, basal CT levels are frequently normal and CT stimulation tests are required. We aimed to compare CT stimulation tests with calcium, pentagastrin and their combination in identifying minimal residual MTC and CCH. MATERIAL AND METHODS: We studied 10 post-thyroidectomy patients with MTC and 20 first-degree relatives of the patients who had no clinically apparent MTC. We performed 54 combined (calcium plus pentagastrin) stimulation tests, 35 calcium stimulation tests and 26 pentagastrin stimulation tests. RESULTS: Basal CT levels were abnormal (>=500 pg/ml) in 4 patients with apparent metastatic disease (Group 1A) and in 2 patients with minimal residual disease (Group 1B) but were normal (0-300 pg/ml) in 4 patients with no residual disease (Group 1C) and in the relatives (Group 2). In Groups 1A, 1B and 1C, maximal elevation in CT levels was greater after the combined stimulation test than after calcium or pentagastrin tests. The combined stimulation test induced the greatest increases (920, 700 and 706 pg/ml, respectively) in 3 relatives (Group 2); CCH was confirmed histologically in these patients. Side-effects were mild, short-lasting and of similar intensity and duration during all tests. CONCLUSIONS: Patients with subclinical MTC (minimal residual or recurrent MTC) or their relatives (with CCH) usually have normal basal CT levels and stimulation tests are necessary. Combined test represents the most sensitive and safe stimulation test for the diagnosis of subclinical hypercalcitonemia. PMID- 24470737 TI - Surgical treatment of hip fractures: factors influencing mortality. AB - BACKGROUND: Data for osteoporotic hip fractures in Greece is limited and little is known upon the meaning of family support during the postoperative/rehabilitation period. OBJECTIVE: To identify the factors influencing the mortality after hip fractures in the elderly, the effect of rehabilitation and family support in the post-fracture course, and the impact of these fractures on the family of the injured elderly. METHODS: We conducted an observational study of 218 consecutive patients older than 60 years of age, who underwent surgical management of a unilateral hip fracture at a tertiary hospital of Central Greece, with follow-up contacts at 30 days, 3 months and one year. Demographic characteristics, pre- and post-fracture residential and functional status, assessment of basic activities of daily living (ADL), co-morbidities, type and mechanism of fracture and hospitalization data as well as the modification of activities of the patients' relatives were recorded. RESULTS: Fifteen patients (6.9%) died during hospitalization; thirty-nine (17.9%) died within one year of fracture. The factors that were predictive of in-hospital, 30 days and one-year mortality, based on multivariate analysis, were male sex, advanced age >85 and Charson index >3. There was a significant association between delayed surgery (>48 hours) and increased in-hospital mortality. The percentage of patients assessed as ADL A or B at baseline, decreased form 84% preoperatively to 50.4% one year postoperatively. Only one-third of patients walking without aid before the fracture returned to the previous state. Family members modified their activities in 48% of cases to assist their relatives with a hip fracture. CONCLUSIONS: One-year mortality in patients with hip fractures was 17.9%. Surgical delay (>48 hours) increased in-hospital mortality. Comorbidities >3, male sex, and advanced age increased the risk of in-hospital and post-discharge mortality during the 1st year. Twelve months postoperatively, half of patients walking without aid before the fracture returned to the previous state. Despite the beneficial effect of family support, the lack of organized rehabilitation programs and geriatric units are potential negative factors for patients' functional outcome. In addition, 48% of patients' relatives changed their daily activities to assist their relatives. PMID- 24470738 TI - Significance of extracapillary proliferation in IgA-nephropathy patients with regard to clinical and histopathological variables. AB - BACKGROUND AND AIM: Extracapillary proliferation (crescent) was not included in the Oxford classification, although previous attempts to correlate the crescent with clinical outcomes have produced conflicting results. In this study, we investigated the clinical and morphological significance of extracapillary proliferation in a group of IgA nephropathy (IgAN) patients with regard to the Oxford classification. PATIENTS AND METHODS: In an observational study conducted on IgAN patients, we collected a total of 114 biopsies. We diagnosed IgAN by light and immunofluorescence for all patients. RESULTS: Of the 114 patients, 70.2% were male. The mean age of the patients was 37.7 +/- 13.6 years. The mean proteinuria was 1742 +/- 1324 mg/day. The mean serum creatinine was 1.6 +/- 1.5 mg/dL. Twenty-five (21.9%) patient kidney biopsies had extracapillary proliferation. We found a significant positive correlation between the number of crescents and serum creatinine (p<0.001). Furthermore, we found a positive association between the nephrotic syndrome and the total number of crescents (p<0.05). Additionally, we observed a significant positive correlation between the amount of sclerosed glomeruli and extracapillary proliferation (p=0.028). CONCLUSION: Our findings confirm that extracapillary proliferation has a significant association with proteinuria and sclerotic glomeruli. We anticipate that extracapillary proliferation will be included in a revision of the Oxford classification of IgAN to widen the scope of the classification. PMID- 24470739 TI - Intrathecal low-dose levobupivacaine and bupivacaine combined with fentanyl in a randomised controlled study for caesarean section: blockade characteristics, maternal and neonatal effects. AB - BACKGROUND: Intrathecal combination of local anaesthetics with opioids produces a synergistic effect without intensifying motor and sympathetic blockades. It also enables successful anaesthesia with use of a low dose of local anaesthetic, which also results in more stable haemodynamics. We compared the characteristics of blockade and maternal-neonatal effects of low-dose levobupivacaine and low-dose bupivacaine combined with fentanyl used in spinal anaesthesia for caesarean section. METHODS: Seventy-two patients undergoing caesarean section with spinal anaesthesia received low-dose 0.5% levobupivacaine (7 mg) plus fentanyl 25 ug (group L) or low-dose 0.5% bupivacaine (7 mg) plus fentanyl 25 ug (group B). The time to achieve sensory blockade of T6, the maximum spread of sensory blockade, time to S2 regression, sensorial blockade levels and motor blockade at the beginning and end of surgery were the parameters assessed. Haemodynamic parameters (systolic and diastolic blood pressures, heart rate), neonatal effects (APGAR scores at 1. and 5. min, umblical-cord gas analyses) were recorded, as were side-effects. RESULTS: The qualities of sensory blockade were similar and clinically effective in both groups. Significantly more patients had complete motor blockade in group B than in group L at the beginning and end of surgery. Haemodynamic and neonatal parameters were similar between the two groups. Pruritis was a common side-effect in both groups. CONCLUSION: In spinal anaesthesia for caesarean section, using low-dose levobupivacaine in combination with fentanyl elicits effective sensorial blockade and less motor blockade with similar haemodynamic and neonatal effects than usage of low-dose bupivacaine in combination with fentanyl. PMID- 24470740 TI - A newborn with trisomy 13 who had tetralogy of Fallot and metopic synostosis: Case report. AB - BACKGROUND AND AIM: Trisomy 13 (Patau syndrome) was first described by Patau et al in 1960. It is characterized by serious head, facial, and extremity anomalies, congenital heart defects, and mental abnormalities. The incidence rate of Trisomy 13 is 1/10.000 live births. Accompanying symptoms and findings vary in rate and severity among the cases. Tetralogy of Fallot and metopic synostosis are very rare abnormalities in patients with Trisomy 13. In this study, we aimed to present a newborn girl with trisomy 13 who had multiple congenital malformations accompanied by tetralogy of Fallot and metopic synostosis. Description of the case: The patient was delivered at 40 weeks of gestation, and admitted to the neonatal intensive care unit due to respiratory distress and physical abnormalities. The newborn examination revealed multiple dysmorphic features. She had boot-shaped appearance on the chest radiograph. Chromosome analysis demonstrated mosaic trisomy 13. CONCLUSION: Patients with trisomy 13 may have different type of gene variations and malformations; however, the most common type of gene variation is classic trisomy 47, XX +13, and the most common malformations are facial anomalies and congenital heart defects. In addition, tetralogy of Fallot and metopic synostosis may accompany trisomy 13. PMID- 24470741 TI - Primary retroperitoneal mucinous cystadenocarcinoma in a male patient: a rare case report. AB - BACKGROUND AND AIM: Primary retroperitoneal mucinous cystadenocarcinoma (PRMC) is a very rare tumor. To date, less than 50 cases of PRMC have been described in the English literature. Description of the case: We report a case of PRMC in a male patient who presented with chronic lower back pain for 8 months. Computed tomography (CT) showed a retroperitoneal mass in the right abdominal cavity, measuring approximately 4cm * 3cm. At laparotomy, a predominantly cystic, well encapsulated mass was observed in the right retroperitoneum. The mass was excised without rupture. The final diagnosis of PRMC was confirmed by pathology. CONCLUSION: To our knowledge, this is the 5th published case report of a PRMC in a male patient. No other reported cases of PRMC in Chinese men are available in the literature. A literature review of PRMC in the English language literature is also provided. PMID- 24470742 TI - Occlusion of the right coronary artery after blunt thoracic trauma with fatal outcome: A case report and review of the literature. AB - BACKGROUND: Although damage of the heart vessels is a possible complication of blunt thoracic trauma, occlusion of the right coronary artery is rare and demands high level of suspicion by the emergency physicians. OBJECTIVE: Our objective is to present a case of fatal acute occlusion of the right coronary artery after blunt thoracic trauma due to vehicle accident and conduct a brief review of the current literature. CASE REPORT: A 58-year-old sustained chest trauma after a vehicle accident, complicated by acute occlusion of the right coronary artery. Despite invasive intervention the patient deteriorated and died due to multi organ failure. CONCLUSION: Acute occlusion of the right coronary artery is a rare complication of blunt chest trauma. Early diagnosis and intervention, collaboration between different specialties and proper hospitalization are vital for the outcome of the patient. PMID- 24470743 TI - Malignant triton tumor of the chest wall invading the lung. A case report and literature review. AB - BACKGROUND: Malignant triton tumor (MTT) is an histological deviation of malignant peripheral nerve sheath tumor with additional rhabdomyosarcomatous elements. It is very rare, profoundly aggressive, with a tendency to recur locally and metastasize early. If manifests itself more often in individuals with neurofibromatosis type I (NF-1) disease but also sporadically or post radiotherapy. Description of case: A 57-year-old male was admitted with a history of malignant triton tumor of the chest wall. Despite prior aggressive locoregional treatment including wide excision and adjuvant consolidating radiotherapy, the tumor recurred. The patient underwent a new operation and systemic chemotherapy, but expired a few months later due to disease progression. CONCLUSION: MTT is exceedingly malignant requiring multimodality treatment. The cornerstone of management is radical surgical resection with clear margins. Nevertheless, the overall prognosis remains dismal. PMID- 24470744 TI - Giant intra-articular synovial osteochondromata of the knee. AB - BACKGROUND/AIM: Synovial chondromatosis associated, intra-articular loose bodies are usually small in size. Giant intra-articular loose bodies are rare. CASE REPORT: We present the case of a patient with synovial chondromatosis associated giant intra-articular loose bodies located under the patella and the intercondylar fossa, treated successfully with combined arthroscopic and open excision. CONCLUSION: Giant intra-articular loose bodies should be considered when treating patients with synovial chondromatosis. Arthroscopy confirms the diagnosis, allows the thorough examination of the knee joint, and subsequent excision of small or medium size attached synovial nodules or intra-articular loose bodies. Arthrotomy may be needed to excise giant loose bodies. PMID- 24470745 TI - Renal abscess with initial image presentation of renal cyst characteristics. PMID- 24470746 TI - The nutritional status of the patients with renal failure should be assessed carefully. PMID- 24470747 TI - Pneumococcosuria in a 4-year old girl. PMID- 24470748 TI - Bacillus Calmette-Guerin cystitis after intravesical therapy. PMID- 24470749 TI - Is Sentinel lymph node biopsy profitable in melanoma patients? PMID- 24470750 TI - Transdermal testosterone replacement therapy in men. AB - Androgen deficiency syndrome in men is a frequently diagnosed condition associated with clinical symptoms including fatigue, decreased libido, erectile dysfunction, and metabolic syndrome. Serum testosterone concentrations decline steadily with age. The prevalence of androgen deficiency syndrome in men varies depending on the age group, known and unknown comorbidities, and the respective study group. Reported prevalence rates may be underestimated, as not every man with symptoms of androgen deficiency seeks treatment. Additionally, men reporting symptoms of androgen deficiency may not be correctly diagnosed due to the vagueness of the symptom quality. The treatment of androgen deficiency syndrome or male hypogonadism may sometimes be difficult due to various reasons. There is no consensus as to when to start treating a respective man or with regards to the best treatment option for an individual patient. There is also lack of familiarity with treatment options among general practitioners. The formulations currently available on the market are generally expensive and dose adjustment protocols for each differ. All these factors add to the complexity of testosterone replacement therapy. In this article we will discuss the general indications of transdermal testosterone replacement therapy, available formulations, dosage, application sites, and recommended titration schedule. PMID- 24470751 TI - Does fesoterodine have a role in the treatment of poorly managed patients with overactive bladder? AB - Overactive bladder (OAB), a clinically defined symptom complex comprising urinary urgency, usually accompanied by urinary frequency and nocturia, with or without urgency incontinence, is common and has a markedly negative impact on the sufferer's quality of life. Following conservative and lifestyle management, the current pharmacological mainstay of treatment is antimuscarinic therapy. This review explores the role of fesoterodine, a relatively recently introduced antimuscarinic agent, in the treatment of patients who may have had a suboptimal response to initial therapy, who have switched treatment from tolterodine, or may be at risk of receiving poor treatment because of either multimorbidity or complex polypharmacy. PMID- 24470753 TI - Comparative steady-state pharmacokinetic study of an extended-release formulation of itopride and its immediate-release reference formulation in healthy volunteers. AB - BACKGROUND: This study was conducted to compare the oral bioavailability of an itopride extended-release (ER) formulation with that of the reference immediate release (IR) formulation in the fasting state. The effect of food on the bioavailability of itopride ER was also assessed. METHODS: A single-center, open label, randomized, multiple-dose, three-treatment, three-sequence, crossover study was performed in 24 healthy male subjects, aged 22-48 years, who randomly received one of the following treatments for 4 days in each period: itopride 150 mg ER once daily under fasting or fed conditions, or itopride 50 mg IR three times daily in the fasting state. Steady-state pharmacokinetic parameters of itopride, including peak plasma concentration (Cmax) and area under the plasma concentration versus time curve over 24 hours after dosing (AUC(0-24h)), were determined by noncompartmental analysis. The geometric mean ratio of the pharmacokinetic parameters was derived using an analysis of variance model. RESULTS: A total of 24 healthy Korean subjects participated, 23 of whom completed the study. The geometric mean ratio and its 90% confidence interval of once-daily ER itopride versus IR itopride three times a day for AUC(0-24h) were contained within the conventional bioequivalence range of 0.80-1.25 (0.94 [0.88-1.01]), although Cmax was reached more slowly and was lower for itopride ER than for the IR formulation. Food delayed the time taken to reach Cmax for itopride ER, but AUC(0-24h) was not affected. There were no serious adverse events and both formulations were generally well tolerated. CONCLUSION: At steady state, once daily itopride ER at 150 mg has a bioavailability comparable with that of itopride IR at 50 mg given three times a day under fasting conditions. Food delayed the absorption of itopride ER, with no marked change in its oral bioavailability. PMID- 24470754 TI - Novel N-substituted aminobenzamide scaffold derivatives targeting the dipeptidyl peptidase-IV enzyme. AB - BACKGROUND: The dipeptidyl peptidase-IV (DPP-IV) enzyme is considered a pivotal target for controlling normal blood sugar levels in the body. Incretins secreted in response to ingestion of meals enhance insulin release to the blood, and DPP IV inactivates these incretins within a short period and stops their action. Inhibition of this enzyme escalates the action of incretins and induces more insulin to achieve better glucose control in diabetic patients. Thus, inhibition of this enzyme will lead to better control of blood sugar levels. METHODS: In this study, computer-aided drug design was used to help establish a novel N substituted aminobenzamide scaffold as a potential inhibitor of DPP-IV. CDOCKER software available from Discovery Studio 3.5 was used to evaluate a series of designed compounds and assess their mode of binding to the active site of the DPP IV enzyme. The designed compounds were synthesized and tested against a DPP-IV enzyme kit provided by Enzo Life Sciences. The synthesized compounds were characterized using proton and carbon nuclear magnetic resonance, mass spectrometry, infrared spectroscopy, and determination of melting point. RESULTS: Sixty-nine novel compounds having an N-aminobenzamide scaffold were prepared, with full characterization. Ten of these compounds showed more in vitro activity against DPP-IV than the reference compounds, with the most active compounds scoring 38% activity at 100 MUM concentration. CONCLUSION: The N-aminobenzamide scaffold was shown in this study to be a valid scaffold for inhibiting the DPP-IV enzyme. Continuing work could unravel more active compounds possessing the same scaffold. PMID- 24470755 TI - Mobile phone-based asthma self-management aid for adolescents (mASMAA): a feasibility study. AB - PURPOSE: Adolescents report high asthma-related morbidity that can be prevented by adequate self-management of the disease. Therefore, there is a need for a developmentally appropriate strategy to promote effective asthma self-management. Mobile phone-based technology is portable, commonly accessible, and well received by adolescents. The purpose of this study was to develop and evaluate the feasibility and acceptability of a comprehensive mobile phone-based asthma self management aid for adolescents (mASMAA) that was designed to facilitate symptom monitoring, treatment adherence, and adolescent-parent partnership. The system used state-of-the-art natural language-understanding technology that allowed teens to use unconstrained English in their texts, and to self-initiate interactions with the system. MATERIALS AND METHODS: mASMAA was developed based on an existing natural dialogue system that supports broad coverage of everyday natural conversation in English. Fifteen adolescent-parent dyads participated in a 2-week trial that involved adolescents' daily scheduled and unscheduled interactions with mASMAA and parents responding to daily reports on adolescents' asthma condition automatically generated by mASMAA. Subsequently, four focus groups were conducted to systematically obtain user feedback on the system. Frequency data on the daily usage of mASMAA over the 2-week period were tabulated, and content analysis was conducted for focus group interview data. RESULTS: Response rates for daily text messages were 81%-97% in adolescents. The average number of self-initiated messages to mASMAA was 19 per adolescent. Symptoms were the most common topic of teen-initiated messages. Participants concurred that use of mASMAA improved awareness of symptoms and triggers, promoted treatment adherence and sense of control, and facilitated adolescent parent partnerships. CONCLUSION: This study demonstrates the utility and user acceptability of mASMAA as a potential asthma self-management tool in a selective group of adolescents. Further research is needed to replicate the findings in a large group of adolescents from sociodemographically diverse backgrounds to validate the findings. PMID- 24470756 TI - Efficacy of a reduced pill burden on therapeutic adherence to calcineurin inhibitors in renal transplant recipients: an observational study. AB - PURPOSE: The aim of this study was to determine the prevalence of nonadherence in a cohort of renal transplant recipients (RTRs) and to evaluate prospectively whether more intense clinical surveillance and reduced pill number enhanced adherence. PATIENTS AND METHODS: The study was carried out in 310 stable RTRs in whom adherence, life satisfaction, and transplant care were evaluated by specific questionnaires (time 0). The patients under tacrolimus (TAC; bis in die [BID]) were then shifted to once-daily TAC (D-TAC) to reduce their pill burden (Shift group) and were followed up for 6 months to reevaluate the same parameters. Patients on cyclosporin or still on BID-TAC constituted a time-control group. RESULTS: The prevalence of nonadherence was 23.5% and was associated with previous rejection episodes (P<0.002), and was inversely related to Life Satisfaction Index, anxiety, and low glomerular filtration rate (minimum P<0.03). Nonadherent patients were significantly less satisfied with their medical care and their relationships with the medical staff. A shift from BID-TAC to D-TAC was performed in 121 patients, and the questionnaires were repeated after 3 and 6 months. In the Shift group, a reduction in pill number was observed (P<0.01), associated with improved adherence after 3 and 6 months (+36%, P<0.05 versus basal), with no change in controls. Decreased TAC trough levels after 3 and 6 months (-9%), despite a slight increase in drug dosage (+6.5%), were observed in the Shift group, with no clinical side effects. CONCLUSION: The reduced pill burden improves patients' compliance to calcineurin-inhibitors, but major efforts in preventing nonadherence are needed. PMID- 24470757 TI - Relationship between medication beliefs, self-reported and refill adherence, and symptoms in patients with asthma using inhaled corticosteroids. AB - BACKGROUND: Beliefs play a crucial role in medication adherence. Interestingly, the relationship between beliefs and adherence varies when different adherence measures are used. How adherence, in turn, is related to asthma symptoms is still unclear. Our aim was to investigate the relationship between beliefs (ie, necessities and concerns) about inhaled corticosteroids (ICS) and subjectively as well as objectively measure adherence and the agreement between these measures. Further, the relationship between adherence and asthma symptoms was examined. METHODS: A total of 280 patients aged 18-80 years who filled at least two ICS prescriptions in the preceding year were recruited to complete a questionnaire. The questionnaire included the Beliefs about Medicines Questionnaire to assess necessity beliefs and concerns about ICS, four questions about ICS use to measure self-reported adherence, and the Asthma Control Questionnaire to assess asthma symptoms. Proportion of days covered was used to determine pharmacy refill adherence. RESULTS: Data from 93 patients with asthma were analyzed. Necessities were positively related to self-reported adherence (P = 0.01). No other associations were found between beliefs and subjective or objective adherence. There was no correlation between self-reported and refill adherence. Participants were significantly (P < 0.001) less adherent according to self-report data (24.4%) than according to pharmacy data (57.8%). No relationship was found between adherence and asthma symptoms. CONCLUSION: Higher necessities are associated with higher self-reported adherence, suggesting that it could be more important to focus on necessities than on concerns in an attempt to improve adherence. Self-reported and refill adherence measurements cannot be used interchangeably. No relationship between adherence and asthma symptoms was found. PMID- 24470758 TI - Preferences of patients and health professionals for route and frequency of administration of biologic agents in the treatment of rheumatoid arthritis. AB - OBJECTIVES: To examine the preferences of rheumatoid arthritis (RA) patients and health professionals (HPs) for the route and frequency of administration of biologic drugs. METHODS: One hundred and seven RA patients treated with biological agents for intravenous or subcutaneous use, 35 biologic-naive RA patients treated with a disease-modifying antirheumatic drug and 30 rheumatology HPs (physicians and nurses) were recruited from two outpatient clinics in Copenhagen, Denmark. All subjects filled out a questionnaire interrogating their choice of preferred route and frequency of administration of a biologic corresponding to current available options, given that effects, adverse effects, and financial costs were identical for the different choices. The subjects were also asked to justify their preferences. The chi-square goodness-of-fit test was used to examine the distributions over different preferences. Proportions were compared using Fisher's exact test. RESULTS: Forty-one patients were currently treated with subcutaneous self-injections at home (SCH) and 66 intravenously at the clinic (IVC). IVC was preferred by 85% of patients currently treated with IVC (P<0.0001). SCH was preferred by 71% of patients currently treated with SCH (P<0.001), by 77% of the biologic-naive patients (P<0.01), and by 87% of HPs (P<0.0001). The proportion of patients favoring SCH was significantly higher for patients currently receiving SCH and for biologic-naive RA patients than for those currently on IVC (P<0.0001). SCH once a month and IVC every 8 weeks were the most appealing treatment frequencies (P<0.01). The most frequent reason among patients for choosing IVC or SCH was a wish for safety, and a wish to minimize the time of transportation and treatment, respectively. CONCLUSION: The majority of RA patients treated with biologics preferred their current route of administration. Most patients, those inexperienced with biologics, and HPs favored SCH. Low treatment frequencies were generally preferred. PMID- 24470759 TI - Nationwide survey to evaluate medical utilization by patients with inguinal hernia and the risk of developing varicocele in Taiwan. AB - BACKGROUND: The purpose of this study was to analyze age, geographical and seasonal variations in medical service utilization by patients with inguinal hernia in Taiwan, and the influence of herniorrhaphy on development of ipsilateral varicocele in male patients. METHODS: Between 2001 and 2008, comprehensive data on the characteristics of medical service utilization by patients with inguinal hernia was evaluated via a retrospective nationwide population-based study. Data were obtained from the National Health Insurance Research Database in Taiwan. Parameters for comparison included newly diagnosed inguinal hernia cases, number of herniorrhaphies, and incidence rates every year, number of outpatient visits for inguinal hernia, and herniorrhaphy by age, season, and area of Taiwan. RESULTS: There was an average of 1,466 newly diagnosed inguinal hernia cases and 871.9 herniorrhaphies performed per year per million population during the study period. The male ratio for both newly diagnosed inguinal hernia cases and number of herniorrhaphies increased significantly by age. The number of newly diagnosed inguinal hernia cases and outpatient visits for inguinal hernia was highest during summer, followed by spring, autumn, and winter, and in the north of Taiwan, followed by the center, south, and east. Additionally, the incidence of developing ipsilateral varicocele after herniorrhaphy was low in male patients. CONCLUSION: The number of newly diagnosed inguinal hernia cases and outpatient visits for inguinal hernia is highest during summer and lowest in eastern Taiwan. In addition, the incidence of developing ipsilateral varicocele after herniorrhaphy is higher in patients aged 10-19 years. PMID- 24470760 TI - Self-stigma among caregivers of people with mental illness: toward caregivers' empowerment. AB - BACKGROUND: In addition to economic and material burdens, caregivers of people with mental illness are exposed to psychosocial challenges. Self-stigma is among the psychological challenges that can be exacerbated by intrinsic and/or extrinsic factors. Caregivers' self-stigma can negatively influence the patients' treatment and rehabilitation process. The objective of this study was to measure the level and correlates of self-stigma among caregivers of people with mental illness. METHODS: An interviewer-administered cross-sectional study was conducted in the Jimma University Specialized Hospital Psychiatry Clinic in Ethiopia on a sample of 422 caregivers. Data were collected by trained nurses working in the clinic using a pretested questionnaire. Multivariate linear regression was performed to identify the correlates of self-stigma among caregivers of people with mental illness. RESULTS: The majority (70.38%) of the caregivers were male. On a scale of 0 to 15, with 0 being low and 15 being high, the average self stigmatizing attitude score was 4.68 (+/-4.11). A statistically significant difference in mean self-stigma score was found between urban and rural respondents (t=3.95, P<0.05). Self-stigma of caregivers showed significant positive correlation with perceived signs of mental illness (r=0.18, P<0.001), perceived supernatural explanations of mental illness (r=0.26, P<0.001), and perceived psychosocial and biological explanations of mental illness (r=0.12, P<0.01). The only independent predictor of caregivers' self-stigma was perceived supernatural explanation of mental illness (standardized beta=0.22, P<0.001). CONCLUSION: The tendency of caregivers to avoid being identified with the patients was observed. Low exposure to mental health information was also reported. Caregivers' self-stigma in this study was significantly correlated with perceived supernatural explanation of mental illness. Since caregivers' self stigma may negatively influence patients' treatment-seeking, adherence, and rehabilitation processes, programs that enhance coping strategies by strengthening self-esteem and empowerment by health care providers and establish family support groups may be helpful to tackle self-stigma among caregivers of people with mental illness. PMID- 24470761 TI - Effect of onion flavonoids on colorectal cancer with hyperlipidemia: an in vivo study. AB - OBJECTIVES: This study aims to find the effect of onion's extraction on the colorectal cancer with hyperlipidemia. METHOD: We established a hyperlipidemia subcutaneously heterotopic colorectal cancer orthotopic transplant model and fed mice a high fat diet and performing transplantation. Animal models were treated with capecitabine and/or simvastatin and low-, middle-, high- dose of onion's extraction and both tumor growth rate and blood lipid levels were monitored. RESULTS: We found that colorectal cancer in onion's extraction groups was significantly inhibited, and the effect of high dose of onion's extraction was equivalent to capecitabine. Onion's extraction effectively decreased levels of apoB and TC. CONCLUSION: Our study established a hyperlipidemia colon tumor model involving subcutaneous colon translocation and orthotopic transplantation, this model was an ideal research model for mutual influence of hyperlipidemia and colorectal cancer. Onion's extraction could inhibit the proliferation of colorectal cancer; the function of the high-dose of onion's extraction was fairly to capecitabine, which provided a new direction in protecting and treating colorectal cancer. PMID- 24470762 TI - Clear cell carcinoma of the uterine cervix: clinical characteristics and feasibility of fertility-preserving treatment. AB - The objective of this retrospective study was to analyze the clinical characteristics and prognosis of clear cell adenocarcinoma (CCA) in the post diethylstilbestrol (DES) era and to evaluate the feasibility of fertility preserving treatment. The records of 32 patients with CCAs who were treated at Peking Union Medical College Hospital from August 1986 to June 2012 were retrospectively reviewed. Three of the patients had undergone fertility preserving treatment. The incidence of CCA among cervical adenocarcinomas was 15.2%. The median age was 38 years: 11 patients (34.4%) were diagnosed before 30 years of age and two (6.3%) after 70 years of age. Ten patients (31.2%) were nulliparous. No patient had been exposed to DES. Twenty-nine patients (90.6%) presented with obvious symptoms, and the cervix appeared abnormal in 26 patients (81.3%). Cervical Papanicolaou (Pap) tests were abnormal in all four patients in whom they were performed (three had high-grade squamous intraepithelial lesions and one had atypical squamous cells of undetermined significance). The distribution by stage was 56.3% stage I, 34.4% stage II, 6.3% stage III, and 3.1% stage IV. Treatments mainly included surgery for patients with stage I to IIA CCA and radiochemotherapy for patients with advanced CCA. The overall 5-year progression-free survival was 72.2%. Patients with stage I to IIA CCA had better 5-year progression-free survival than did patients with stage IIB to IV CCA (81.5% versus 40.0%, P=0.003). The three patients who had undergone fertility preserving treatment had no recurrences. CCA may also affect adolescents and children without prior DES exposure, who are often misdiagnosed as having functional uterine bleeding. Radiotherapy appears to be effective for local control but to have no effect on distant recurrences. In our study, the prognosis of patients with early-stage CCA, including those who had undergone fertility preserving treatment, was not inferior to that of patients with other types of cervical adenocarcinoma. PMID- 24470764 TI - Out-of-pocket cost of managing sick newborns in Enugu, southeast Nigeria. AB - BACKGROUND: Neonatal illnesses usually require long hospital stays and specialized care and/or facilities, which usually results in huge medical bills. With more than 70% of people in Nigeria living on less than US$2 per day, these bills are not affordable to many families' livelihoods. AIM: This study aims to determine the average cost of managing neonatal illnesses in Enugu in southeast Nigeria and the proportion of family income spent on these illnesses. It further seeks to ascertain the cost of various components in the management of neonatal diseases. METHODS: This is a longitudinal and descriptive study involving 106 newborns admitted to the sick baby unit of the Enugu State University Teaching Hospital and the out-of-pocket medical expenditure in the management of their illnesses. RESULTS: A hundred and six newborns participated in the study. All (100%) medical bills were out-of-pocket payments, and 103 (97.2%) of these were catastrophic health expenditure (more than 10% of total family monthly income). The average duration of hospital stay and cost of managing a neonatal illness was 12.86+/-8.81 days and ?36,382+/-19,389.72 (US$223+/-119), respectively. This expenditure amounted to 157%, 71%, and 25% of total monthly family income for the low, middle, and upper socioeconomic class families, respectively, with a mean percentage of 85%. Families with a total monthly income of less than ?10,000 (US$61), ?10,000-49,999 (US$61-306), and ?50,000-100,000 (US$306-612) and more than ?100,000 (US$612) on average spent 683%, 108%, 54%, and 20% of their monthly income on their newborn's illness. Hospital and utility bills compared with bills accruing from drug and laboratory investigations account for a significantly larger proportion of total cost incurred in neonatal sepsis (?23,499+/-14,987 [US$144+/-92], P=0.001), low birth weight (?39,863+/-24,003 [US$224+/-147], P=0.001), severe anemia (?40,504+/-13,923 [US$248+/-85], P=0.001), transient tachypnea of the newborn (?10,083+/-1,078 [US$62+/-7], P=0.001), birth asphyxia (?24,398+/-14,096 [US$149+/-86], P=0.001), and meningitis (?26,731+/-7,675 [US$164+/-47], P=0.001), whereas cost for laboratory investigations was significantly higher for neonatal jaundice (?11,690+/-3,169 [US$72+/-19], P=0.001). There was a strong positive correlation between duration of hospital stay and total medical cost incurred (r=0.897, P=0.001). CONCLUSION: Health expenditure on neonatal illness is high and leads to catastrophic expenditure for the majority of households in the state. There is a need for effective health insurance schemes to help subsidize and cushion this disastrous and impoverishing health expenditure on families for improved neonatal survival in Nigeria. PMID- 24470763 TI - Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu(r)) disables cancer cell survival in human pancreatic cancer with acquired chemoresistance. AB - BACKGROUND: Resistance to drug therapy, along with high rates of metastasis, contributes to the low survival rate in patients diagnosed with pancreatic cancer. An alternate treatment for human pancreatic cancer involving targeting of Neu1 sialidase with oseltamivir phosphate (Tamiflu(r)) was investigated in human pancreatic cancer (PANC1) cells with acquired resistance to cisplatin and gemcitabine. Its efficacy in overcoming the intrinsic resistance of the cell to chemotherapeutics and metastasis was evaluated. METHODS: Microscopic imaging, immunocytochemistry, immunohistochemistry, and WST-1 cell viability assays were used to evaluate cell survival, morphologic changes, and expression levels of E cadherin, N-cadherin, and VE-cadherin before and after treatment with oseltamivir phosphate in PANC1 cells with established resistance to cisplatin, gemcitabine, or a combination of the two agents, and in archived paraffin-embedded PANC1 tumors grown in RAGxCgamma double mutant mice. RESULTS: Oseltamivir phosphate overcame the chemoresistance of PANC1 to cisplatin and gemcitabine alone or in combination in a dose-dependent manner, and disabled the cancer cell survival mechanism(s). Oseltamivir phosphate also reversed the epithelial-mesenchymal transition characteristic of the phenotypic E-cadherin to N-cadherin changes associated with resistance to drug therapy. Low-dose oseltamivir phosphate alone or in combination with gemcitabine in heterotopic xenografts of PANC1 tumors growing in RAGxCgamma double mutant mice did not prevent metastatic spread to the liver and lung. CONCLUSION: Therapeutic targeting of Neu1 sialidase with oseltamivir phosphate at the growth factor receptor level disables the intrinsic signaling platform for cancer cell survival in human pancreatic cancer with acquired chemoresistance. These findings provide evidence for oseltamivir phosphate (Tamiflu) as a potential therapeutic agent for pancreatic cancer resistant to drug therapy. PMID- 24470765 TI - Cost-effectiveness analysis of Mammostrat(r) compared with Oncotype DX(r) to inform the treatment of breast cancer. AB - PURPOSE: To compare the cost-effectiveness of the tumor subtyping assays Mammostrat(r) and Oncotype DX(r) for assessing risk of recurrence in early-stage breast cancer and the potential benefit of adjuvant chemotherapy. METHODS: Cost effectiveness analysis from a US third-party payer perspective. A 10 year Markov model was developed to estimate costs and effects of using each method of risk assessment. The percentages of patients assessed as high, moderate, or low risk were obtained from multicenter, prospective, randomized controlled trials. The analysis simulated the experience of women progressing through various model states representing clinical treatments and subsequent disease. Published recurrence data for Mammostrat(r) were adjusted appropriately to account for differences between definitions and samples of Oncotype DX(r) and Mammostrat(r) in the original clinical trials. Cost and utility data were obtained from previously published studies. Sensitivity analyses examined how base-case results might differ when input values and assumptions varied. RESULTS: Base-case costs for women assessed using Mammostrat(r) were $15,782, compared with $18,051 for women assessed with Oncotype DX(r). Thus, cost savings of $2,268 resulted from using Mammostrat(r). Both Mammostrat(r) and Oncotype DX(r) resulted in similar life years (9.880 and 9.882) and quality-adjusted life years (7.935 and 7.940), respectively. Sensitivity analyses demonstrated that the assumptions made about recurrence are the key drivers of model results. DISCUSSION: Cost savings associated with the use of Mammostrat(r) instead of Oncotype DX(r) are largely due to the difference in cost between the two tests. Since survival and quality adjusted life years were similar using either assay, Mammostrat(r) has economic advantages for women with early-stage breast cancer. PMID- 24470766 TI - Utilization of biodegradable polymeric materials as delivery agents in dermatology. AB - Biodegradable polymeric materials are ideal carrier systems for biomedical applications. Features like controlled and sustained delivery, improved drug pharmacokinetics, reduced side effects and safe degradation make the use of these materials very attractive in a lot of medical fields, with dermatology included. A number of studies have shown that particle-based formulations can improve the skin penetration of topically applied drugs. However, for a successful translation of these promising results into a clinical application, a more rational approach is needed to take into account the different properties of diseased skin and the fate of these polymeric materials after topical application. In fact, each pathological skin condition poses different challenges and the way diseased skin interacts with polymeric carriers might be markedly different to that of healthy skin. In most inflammatory skin conditions, the skin's barrier is impaired and the local immune system is activated. A better understanding of such mechanisms has the potential to improve the efficacy of carrier-based dermatotherapy. Such knowledge would allow the informed choice of the type of polymeric carrier depending on the skin condition to be treated, the type of drug to be loaded, and the desired release kinetics. Furthermore, a better control of polymer degradation and release properties in accordance with the skin environment would improve the safety and the selectivity of drug release. This review aims at summarizing the current knowledge on how polymeric delivery systems interact with healthy and diseased skin, giving an overview of the challenges that different pathological skin conditions pose to the development of safer and more specific dermatotherapies. PMID- 24470768 TI - Misdiagnosed spontaneous intracranial hypotension complicated by subdural hematoma following lumbar puncture. AB - INTRODUCTION: Spontaneous intracranial hypotension is an infrequent cause of secondary headache due to cerebrospinal fluid (CSF) hypovolemia. OBJECTIVE: To describe a case of headache revealing spontaneous intracranial hypotension complicated by subdural hematoma following lumbar puncture. OBSERVATION: A 34 year-old man presented with acute postural headache. The first cerebral computed tomography scan was normal. Lumbar puncture showed hyperproteinorachy at 2 g/L with six lymphocytic cells. The headache became very intense. At admission, clinical examination was normal. Ophthalmological examination did not show any abnormalities. Encephalic magnetic resonance imaging (MRI) showed bilateral subdural hematoma with tonsillar descent simulating Chiari type I malformation. After surgical drainage and symptomatic treatment, the patient was discharged with no recurrence. CONCLUSION: Spontaneous intracranial hypotension is associated with simple clinical presentation, orthostatic headache, and characteristic MRI findings. Misdiagnosed, it leads to unnecessary procedures. PMID- 24470767 TI - Management of cancer pain: 1. Wider implications of orthodox analgesics. AB - In this review, the first of two parts, we first provide an overview of the orthodox analgesics used commonly against cancer pain. Then, we examine in more detail the emerging evidence for the potential impact of analgesic use on cancer risk and disease progression. Increasing findings suggest that long-term use of nonsteroidal anti-inflammatory drugs, particularly aspirin, may reduce cancer occurrence. However, acetaminophen may raise the risk of some hematological malignancies. Drugs acting upon receptors of gamma-aminobutyric acid (GABA) and GABA "mimetics" (eg, gabapentin) appear generally safe for cancer patients, but there is some evidence of potential carcinogenicity. Some barbiturates appear to slightly raise cancer risks and can affect cancer cell behavior in vitro. For cannabis, studies suggest an increased risk of squamous cell carcinoma of the tongue, larynx, and possibly lung. Morphine may stimulate human microvascular endothelial cell proliferation and angiogenesis; it is not clear whether this might cause harm or produce benefit. The opioid, fentanyl, may promote growth in some tumor cell lines. Opium itself is an emerging risk factor for gastric adenocarcinoma and possibly cancers of the esophagus, bladder, larynx, and lung. It is concluded that analgesics currently prescribed for cancer pain can significantly affect the cancer process itself. More futuristically, several ion channels are being targeted with novel analgesics, but many of these are also involved in primary and/or secondary tumorigenesis. Further studies are needed to elucidate possible cellular and molecular effects of orthodox analgesics and their possible long-term impact, both positive and negative, and thus enable the best possible clinical gain for cancer patients. PMID- 24470769 TI - Evaluation of acute scrotum in our consecutive operated cases: a one-center study. AB - PURPOSE: The purpose of the present study was to evaluate the clinical history, demographic data, surgical exploration findings, and final diagnoses in all young males presenting with acute scrotum to our center. MATERIALS AND METHODS: This was a descriptive-retrospective study in which all consecutive cases of acute scrotum treated in our department from March 2008 to March 2012 were evaluated. RESULTS: A total of 116 cases were included in the study. Out of these cases, 100 cases underwent surgical exploration, and the remaining 16 cases were managed conservatively. Our eligible cases were divided into three groups: the testicular torsion (TT) group (68%); the torsion of the appendix testis (AT) group (20%); and the epididymo-orchitis (EO) group (9%). Testicular preservation was achieved in 39 cases of the TT group, while due to delayed referral, orchiectomy was performed in 29 cases. Thus, our testicular salvage rate was 57.5% and missed testicular torsion rate was 42.5%. CONCLUSION: It was observed that our testicular salvage rate was lower than the expected figures published in the literature. This is may be attributed to different causes, including delayed referral or presentation of acute scrotum cases, inadequate knowledge of the general practitioners working in emergency departments, or poor knowledge of parents. PMID- 24470770 TI - Smoking behavior among patients and staff: a snapshot from a major metropolitan hospital in Melbourne, Australia. AB - BACKGROUND: A cross-sectional study was conducted to provide a snapshot of smoking behavior among staff and patients at a major metropolitan hospital in Melbourne. METHODS: Patients and staff were surveyed using a questionnaire exploring demographics, nicotine dependence (Fagerstrom test), readiness to quit, and preference for smoking cessation options. RESULTS: A total of 1496 people were screened within 2 hours; 1,301 participated (1,100 staff, 199 patients). Mean age was 42 years, 68% were female. There were 113 (9%) current smokers and 326 (25%) ex-smokers. Seven percent of the staff were current smokers compared with 19% of the patients. The Fagerstrom test showed that 47% of patients who smoked were moderately nicotine dependent compared with 21% of staff. A third of the staff who smoked did not anticipate health problems related to smoking. Most patients (79%) who smoked disagreed that their current health problems were related to smoking. Although more than half of the current smokers preferred pharmacotherapy, one in two of them did not prefer behavior counseling; with consistent results among staff and patients. Multivariate analyses showed that patients were three times more likely (odds ratio 3.0, 95% confidence interval 1.9-4.7) to smoke than staff. CONCLUSION: This study reports lower prevalence of smoking among hospital staff compared with national data. It also indicates an under-appreciation of health effects of smoking, and a preference not to use conventional methods of quitting. PMID- 24470771 TI - Real-world comparison of health care utilization between duloxetine and pregabalin initiators with fibromyalgia. AB - OBJECTIVES: To compare health care utilization of duloxetine initiators and pregabalin initiators among fibromyalgia patients in a real-world setting. METHODS: A retrospective cohort study was conducted based on a US national commercial health claims database (2006-2009). Fibromyalgia patients who initiated duloxetine or pregabalin in 2008, aged 18-64 years, and who maintained continuous health insurance coverage 1 year before and 1 year after initiation were assigned to duloxetine or pregabalin cohorts on the basis of their initiated agent. Patients who had pill coverage of the agents over the course of 90 days preceding the initiation were excluded. The two comparative cohorts were constructed using propensity score greedy match methods. Descriptive analysis and paired t-test were performed to compare health care utilization rates in the postinitiation year and the changes of these rates from the preinitiation year to the postinitiation year. RESULTS: Both matched cohorts (n=1,265 pairs) had a similar mean initiation age (49-50 years), percentage of women (87%-88%), and prevalence of baseline comorbid conditions (neuropathic pain other than diabetic peripheral neuropathic pain, low back pain, cardiovascular disease, hypertension, headache or migraine, and osteoarthritis). In the preinitiation year, both cohorts had similar inpatient, outpatient, and medication utilization rates (inpatient, 15.7%-16.1%; outpatient, 100.0%; medication, 97.9%-98.7%). The utilization rates diverged in the postinitiation year, with the pregabalin cohort using more fibromyalgia-related inpatient care (3.2% versus 2.2%; P<0.05), any inpatient care (19.3% versus 16.8%; P<0.05), and fibromyalgia-related outpatient care (62.1% versus 51.8%; P<0.05). From the preinitiation period to the postinitiation period, the duloxetine cohort experienced decreases in certain utilization rates, whereas the pregabalin cohort had increases (percentage of patients with a fibromyalgia-related admission, -1.2% versus 0.4% [P<0.01]; number of fibromyalgia-related outpatient claims, -1.7 versus 4.7 [P<0.01]). CONCLUSION: Fibromyalgia patients initiating pregabalin tended to consume more fibromyalgia-related inpatient and outpatient care in the first postinitiation year, whereas fibromyalgia patients initiating duloxetine tended to have lower utilization rates of fibromyalgia-related inpatient care in the postinitiation year than in the preinitiation year. PMID- 24470772 TI - Herpes simplex virus-based nerve targeting gene therapy in pain management. AB - Chronic pain represents a major medical burden not only in terms of suffering but also in terms of economic costs. Traditional medical approaches have so far proven insufficient in treating chronic pain and new approaches are necessary. Gene therapy with herpes simplex virus (HSV)-based vectors offers the ability to directly target specific regions of the neuraxis involved in pain transmission including the primary afferent nociceptor. This opens up new targets to interact with that are either not available to traditional systemic drugs or cannot be adequately acted upon without substantial adverse off-target effects. Having access to the entire neuron, which HSV-based vector gene therapy enables, expands treatment options beyond merely treating symptoms and allows for altering the basic biology of the nerve. In this paper, we discuss several HSV-based gene therapy vectors that our group and others have used to target specific neuronal functions involved in the processing of nociception in order to develop new therapies for the treatment of chronic pain. PMID- 24470774 TI - The effect of photobiomodulation on root resorption during orthodontic treatment. AB - Photobiomodulation is used to accelerate tooth movement during orthodontic treatments. The changes in root morphology in a group of orthodontic patients who received photobiomodulation were evaluated using the cone beam computed tomography technique. The device used is called OrthoPulse, which produces low levels of light with a near infrared wavelength of 850 nm and an intensity of 60 mW/cm(2) continuous wave. Twenty orthodontic patients were recruited for these experiments, all with class 1 malocclusion and with Little's Irregularity Index (>2 mm) in either of the arches. Root resorption was detected by measuring changes in tooth length using cone beam computed tomography. These changes were measured before the orthodontic treatment and use of low-level laser therapy and after finishing the alignment level. Little's Irregularity Index for all the patients was calculated in both the maxilla and mandible and patients were divided into three groups for further analysis, which were then compared to the root resorption measurements. Our results showed that photobiomodulation did not cause root resorption greater than the normal range that is commonly detected in orthodontic treatments. Furthermore, no correlation between Little's Irregularity Index and root resorption was detected. PMID- 24470775 TI - Cesarean section in the People's Republic of China: current perspectives. AB - OBJECTIVE: To review the current knowledge on the prevalence, reasons, and consequences of cesarean sections in the People's Republic of China. METHODS: Peer-reviewed articles were systematically searched on PubMed. The following Chinese databases were comprehensively searched: the China National Knowledge Infrastructure, Wanfang, and the VIP information. The databases were searched from inception to September 1, 2013. Two reviewers independently screened the titles and abstracts for eligibility. Full texts of eligible papers were reviewed, where relevant references were hand-searched and reviewed. FINDINGS: Sixty articles were included from PubMed, 17 articles were intentionally picked out from Chinese journals, and five additional articles were added, for a total of 82 articles for the analysis. With a current national rate near 40%, the literature consistently reported a rapid rise of cesarean sections in the People's Republic of China in the past decades, irrespective of where people lived or their socioeconomic standing. Nonclinical factors were considered as the main drivers fueling the rise of cesareans in the People's Republic of China. There was a lively debate on whether women's preferences or providers' distorted financial incentives affected the rise in cesarean sections. However, recent evidence suggests that it might be the People's Republic of China's health development approach - focusing on specialized care and marginalizing primary care - that is playing a role. Although 30 articles were identified studying the consequences of cesareans, the methodologies are in general weak and the themes are out of focus. CONCLUSION: The overuse of cesareans is rising alarmingly in the People's Republic of China and has become a real public health problem. No consensus has been made on the leverage factors that drive the cesarean epidemic, particularly for those nonclinical factors. The more macro level structural factors may have played a part, though further research is warranted to understand the mechanisms. Knowledge of the consequences of cesareans, particularly for women, is limited in the People's Republic of China, leaving a substantial literature gap. PMID- 24470776 TI - Intimate partner violence (physical and sexual) and sexually transmitted infection: results from Nepal Demographic Health Survey 2011. AB - INTRODUCTION: Violence against women perpetrated by their intimate partners is a social problem with adverse health consequences. Intimate partner violence has acute and chronic as well as direct and indirect health consequences related to physical, psychological, and reproductive health. Studies exploring relationships of intimate partner violence and health consequences are rare in Nepal. Hence, this study aimed to examine the relationships between intimate partner violence and sexually transmitted infections. METHOD: This study used data from the nationally representative Nepal Demographic Health Survey 2011, which collected data through a two-stage complex sampling technique. Women 15-49 years were asked about domestic violence including intimate partner violence. For this analysis, 3,084 currently married women were included. Questions about domestic violence were adapted from the Conflict Tactic Scale. Relationships between different forms of physical and sexual intimate partner violence and reported signs and symptoms of sexually transmitted infections were examined using multiple logistic regression analysis. RESULTS: Approximately 15% of currently young and middle aged married women experienced some form of violence in the last 12 months. About one in four women who were exposed to physical and sexual intimate partner violence reported sexually transmitted infection in the last 12 months. The odds of getting sexually transmitted infection were 1.88 [95% CI:1.29, 2.73] times higher among women exposed to any form of intimate partner violence in the last 12 months compared to women not exposed to any form of intimate partner violence. CONCLUSION: Intimate partner violence was common among currently married women in Nepal. Being exposed to intimate partner violence and getting signs and symptoms of sexually transmitted disease were found to be associated. Integration of intimate partner violence prevention and reproductive health programs is needed to reduce the burden of sexually transmitted disease among currently married women. PMID- 24470773 TI - Clinical epidemiology of Alzheimer's disease: assessing sex and gender differences. AB - With the aging of the population, the burden of Alzheimer's disease (AD) is rapidly expanding. More than 5 million people in the US alone are affected with AD and this number is expected to triple by 2050. While men may have a higher risk of mild cognitive impairment (MCI), an intermediate stage between normal aging and dementia, women are disproportionally affected with AD. One explanation is that men may die of competing causes of death earlier in life, so that only the most resilient men may survive to older ages. However, many other factors should also be considered to explain the sex differences. In this review, we discuss the differences observed in men versus women in the incidence and prevalence of MCI and AD, in the structure and function of the brain, and in the sex-specific and gender-specific risk and protective factors for AD. In medical research, sex refers to biological differences such as chromosomal differences (eg, XX versus XY chromosomes), gonadal differences, or hormonal differences. In contrast, gender refers to psychosocial and cultural differences between men and women (eg, access to education and occupation). Both factors play an important role in the development and progression of diseases, including AD. Understanding both sex- and gender-specific risk and protective factors for AD is critical for developing individualized interventions for the prevention and treatment of AD. PMID- 24470777 TI - Chronic hepatitis C: future treatment. AB - The launch of first-generation protease inhibitors (PIs) is a major step forward in HCV treatment. However, the major advance is up to now restricted to genotype 1 (GT-1) patients. The development of second-wave and second-generation PIs yields higher antiviral potency through plurigenotypic activity, more convenient daily administration, fewer side effects and, for the second-generation PIs, potential activity against resistance-associated variants. NS5B inhibitors include nucleoside/nucleotide inhibitors (NIs) and non-nucleotide inhibitors (NNIs). NIs have high efficacy across all genotypes. Sofosbuvir has highly potent antiviral activity across all genotypes in association with pegylated interferon and ribavirin (PR), thus allowing shortened treatment duration. NS5A inhibitors (NS5A.I) have highly potent antiviral activity. It has recently been shown for the first time that NS5A.I in combination with protease inhibitors can cure GT-1b null responders in an interferon-free regimen. Besides, several studies demonstrate that interferon (IFN)-free regimens with direct-acting antiviral agent combinations are able to cure a large number of either naive or treatment experienced GT-1 patients. Moreover, quadruple regimen with PR is able to cure almost all GT-1 null responders. The development of pan-genotypic direct-acting antiviral agents (NIs or NS5A.I) allows new combinations with or without PR that increase the rate of sustained virological response for all patients, even for those with cirrhosis and independently of the genotype. Therefore, the near future of HCV treatment looks promising. The purpose of this article is to provide an overview of the clinical results recently reported for HCV treatment. PMID- 24470778 TI - Efficacy of new filter suction to decrease the rate of occlusion and total suction time in a simulated total hip replacement operation. AB - BACKGROUND: During orthopedic operations, such as total hip replacement or total knee replacement, there is a lot of bone debris from bone cutting and reaming that commonly causes surgical suction devices to occlude many times, which can prolong the operative time and increase the amount of bleeding for the patient. MATERIALS AND METHODS: We developed a surgical filter suction system that we call the VY suction tube. The suction tube assembly consists of a tube filter within a housing assembly. The filter pore size was designed to prevent tissue or bone debris from passing through the filter, though it allows fluid to pass through. A simulated total hip replacement operation was performed to test the efficacy of this new suction device when compared with two other types of tube suction devices. RESULTS: The VY suction tube showed that the mean duration to remove all fluid from a simulated field was significantly shorter than the Pool suction tube (P=0.0009) and Frazier suction tube (P=0.0012). The study also showed that the VY suction tube has a lower rate of occlusion when compared with the Pool suction tube (P<=0.0001) and Frazier suction tube (P<=0.0001). CONCLUSION: Our new suction tube design shows good efficacy when removing fluid and debris from a simulated operative field. However, further studies in real clinical settings are needed. PMID- 24470779 TI - Assessment of noninvasive, percutaneous hemoglobin measurement in pregnant and early postpartum women. AB - PURPOSE: Using the Pronto-7(r) analyzer, we measured percutaneous hemoglobin (SpHb) noninvasively in pregnant and early postpartum women, and assessed the accuracy of the measurements by comparing them with laboratory measurements of hemoglobin. METHODS: We obtained SpHb measurements from 193 pregnant women, 269 early postpartum women, and 76 nonpregnant women. A laboratory total hemoglobin (tHb) measurement, from venous blood sampling, was obtained immediately prior to the SpHb measurement. The total number of measurements obtained from the nonpregnant, pregnant, and postpartum women was 76, 438, and 347, respectively. RESULTS: The mean biases (SpHb - tHb) among the nonpregnant, first trimester, second trimester, third trimester, and early postpartum women were -0.20, 0.19, 1.01, 1.32, and 1.10 g/dL, respectively. The Bland-Altman comparison showed neither the tendency of a fixed bias nor proportional biases among the measurements in the category of nonpregnant and first trimester women. But in the second and third trimester and postpartum category, a significant fixed bias was noted, without any tendencies of proportional bias. CONCLUSION: In this study, we found higher hemoglobin values with the Pronto-7 analyzer than were measured in the laboratory. We consider that the device has certain limitations in obstetrical utility and requires further modifications for use in the perinatal period. PMID- 24470780 TI - Language of motivation and emotion in an internet support group for smoking cessation: explorative use of automated content analysis to measure regulatory focus. AB - The present study describes a novel approach to the identification of the motivational processes in text data extracted from an Internet support group (ISG) for smoking cessation. Based on the previous findings that a "prevention" focus might be more relevant for maintaining behavior change, it was hypothesized that 1) language use (ie, the use of emotional words) signaling a "promotion" focus would be dominant in the initiating stages of the ISG, and 2) that the proportion of words signaling a prevention focus would increase over time. The data were collected from the ISG site, spanning 4 years of forum activity. The data were analyzed using the Linguistic Inquiry and Word Count application. The first hypothesis - of promotion focus dominance in the initiating stages - was not supported during year 1. However, for all the other years measured, the data showed that a prevention failure was more dominant compared with a promotion failure. The results indicate that content analysis could be used to investigate motivational and language-driven processes in ISGs. Understanding the interplay between self-regulation, lifestyle change, and modern communication channels could be of vital importance in providing the public with better health care services and interventions. PMID- 24470781 TI - Coping with interpersonal stress and psychological distress at work: comparison of hospital nursing staff and salespeople. AB - Hospital nurses frequently experience relationships with patients as stressors in the workplace. Nurses' coping behavior is one potential buffering factor that can reduce the effects of job stress on their psychological functioning and well being. In this study, the association between nurses' strategies for coping with interpersonal stress from patients and their psychological distress was examined. Participants included 204 hospital nurses and 142 salespeople, who were used as a comparison group. Participants completed measures of coping with interpersonal stress and psychological distress. Hospital nurses reported more psychological distress than did salespeople. Moreover, distancing coping was correlated with high psychological distress in both nurses and salespeople, and reassessing coping was correlated with low psychological distress in nurses. For nurses only, constructive coping appeared to be an effective strategy for reducing psychological distress. It is important for nurses to understand the role of constructive coping in nurse-patient communication and interaction. PMID- 24470782 TI - Predictors of poor sleep quality among Lebanese university students: association between evening typology, lifestyle behaviors, and sleep habits. AB - Adequate, good night sleep is fundamental to well-being and is known to be influenced by myriad biological and environmental factors. Given the unavailability of sleep data about Lebanon, the cultural shifts and socioeconomic pressures that have affected many aspects of society, particularly for students and working adults, as well as our understanding of sleep in university students in other countries, we conducted a national study to assess sleep quality and factors contributing to sleep and general health in a culture-specific context. A self-filled questionnaire, inquiring about sociodemographics, health-risk behaviors, personal health, and evaluating sleep quality and chronotype using standard scales was completed by 540 students at private and public universities in Lebanon. Overall, they reported sleeping 7.95+/-1.34 hours per night, although 12.3% reported sleeping <6.5 hours and more than half scored in the poor-sleeper category on the Pittsburgh Sleep Quality Index (PSQI). Sleep timing differed markedly between weekdays and weekends, with bedtimes and wake-up times delayed by 1.51 and 2.43 hours, respectively, on weekends. While most scored in the "neither type" category on the Morningness-Eveningness Questionnaire (MEQ), 24.5% were evening types and 7.3% were morning types. MEQ score was significantly correlated with smoking behavior and daily study onset, as well as with PSQI score, with eveningness associated with greater number of cigarettes, later study times, and poor sleep. We conclude that the prevalence of poor sleep quality among Lebanese university students is associated with reduced sleep duration and shifts in sleep timing between weekdays and weekends, especially among evening types. While chronotype and certain behavioral choices interact to affect sleep dimensions and quality, raising awareness about the importance of obtaining adequate nighttime sleep on daily performance and avoiding risky behaviors may help Lebanese students make better choices in school and work schedules. PMID- 24470783 TI - Kleine-Levin syndrome: a review. AB - Kleine-Levin syndrome is a recurrent hypersomnia associated with symptoms of hyperphagia, hypersexuality, and cognitive impairment. This article reviews the current available research and describes common clinical symptoms, differential diagnosis, and acceptable workup and treatment. Although deficits have traditionally been thought to resolve between episodes, functional imaging studies and long-term neuropsychological testing in select patients have recently challenged this notion. This may suggest that Kleine-Levin syndrome is not as benign as previously considered. PMID- 24470784 TI - A novel supplemental approach to capturing post-marketing safety information on recombinant factor VIIa in acquired hemophilia: the Acquired Hemophilia Surveillance project. PMID- 24470785 TI - Genome-wide association mapping of flowering time in Arabidopsis thaliana in nature: genetics for underlying components and reaction norms across two successive years. AB - Often used as a proxy for the transition to reproduction, flowering time (FT) is an integrative trait of two successive biological processes, i.e. bolting time (BT) and the interval between bolting and flowering time (INT). In this study, we aimed to identify candidate genes associated with these composite traits in Arabidopsis thaliana using a field experiment. Genome-wide association (GWA) mapping was performed on BT, INT and FT based on a sample of 179 worldwide natural accessions genotyped for 216,509 SNPs. The high resolution conferred by GWA mapping indicates that FT is an integrative trait at the genetic level, with distinct genetics for BT and INT. BT is shaped largely by genes involved in the circadian clock whereas INT is shaped by genes involved in both the hormone pathways and cold acclimation. Finally, the florigen TSF appears to be the main integrator of environmental and internal signals in ecologically realistic conditions. Based on FT scored in a previous field experiment, we also studied the genetics underlying reaction norms across two years. Only four genes were common to both years, emphasizing the need to repeat field experiments. The gene regulation model appeared as the main genetic model for genotype * year interactions. PMID- 24470786 TI - Spatiotemporal modeling of irregularly spaced Aerosol Optical Depth data. AB - Many advancements have been introduced to tackle spatial and temporal structures in data. When the spatial and/or temporal domains are relatively large, assumptions must be made to account for the sheer size of the data. The large data size, coupled with realities that come with observational data, make it difficult for all of these assumptions to be met. In particular, air quality data are very sparse across geographic space and time, due to a limited air pollution monitoring network. These "missing" values make it diffcult to incorporate most dimension reduction techniques developed for high-dimensional spatiotemporal data. This article examines aerosol optical depth (AOD), an indirect measure of radiative forcing, and air quality. The spatiotemporal distribution of AOD can be influenced by both natural (e.g., meteorological conditions) and anthropogenic factors (e.g., emission from industries and transport). After accounting for natural factors influencing AOD, we examine the spatiotemporal relationship in the remaining human influenced portion of AOD. The presented data cover a portion of India surrounding New Delhi from 2000 - 2006. The proposed method is demonstrated showing how it can handle the large spatiotemporal structure containing so much missing data for both meteorologic conditions and AOD over time and space. PMID- 24470787 TI - Effect of surface charge on the colloidal stability and in vitro uptake of carboxymethyl dextran-coated iron oxide nanoparticles. AB - Nanoparticle physicochemical properties such as surface charge are considered to play an important role in cellular uptake and particle-cell interactions. In order to systematically evaluate the role of surface charge on the uptake of iron oxide nanoparticles, we prepared carboxymethyl-substituted dextrans with different degrees of substitution, ranging from 38 to 5 groups per chain, and reacted them using carbodiimide chemistry with amine-silane-coated iron oxide nanoparticles with narrow size distributions in the range of 33-45 nm. Surface charge of carboxymethyl-substituted dextran-coated nano-particles ranged from -50 to 5 mV as determined by zeta potential measurements, and was dependent on the number of carboxymethyl groups incorporated in the dextran chains. Nanoparticles were incubated with CaCo-2 human colon cancer cells. Nanoparticle-cell interactions were observed by confocal laser scanning microscopy and uptake was quantified by elemental analysis using inductively coupled plasma mass spectroscopy. Mechanisms of internalization were inferred using pharmacological inhibitors for fluid-phase, clathrin-mediated, and caveola-mediated endocytosis. Results showed increased uptake for nanoparticles with greater negative charge. Internalization patterns suggest that uptake of the most negatively charged particles occurs via non-specific interactions. PMID- 24470788 TI - Current status on biochemistry and molecular biology of microbial degradation of nicotine. AB - Bioremediation is one of the most promising methods to clean up polluted environments using highly efficient potent microbes. Microbes with specific enzymes and biochemical pathways are capable of degrading the tobacco alkaloids including highly toxic heterocyclic compound, nicotine. After the metabolic conversion, these nicotinophilic microbes use nicotine as the sole carbon, nitrogen, and energy source for their growth. Various nicotine degradation pathways such as demethylation pathway in fungi, pyridine pathway in Gram positive bacteria, pyrrolidine pathway, and variant of pyridine and pyrrolidine pathways in Gram-negative bacteria have been reported. In this review, we discussed the nicotine-degrading pathways of microbes and their enzymes and biotechnological applications of nicotine intermediate metabolites. PMID- 24470789 TI - The effects of two Lactobacillus plantarum strains on rat lipid metabolism receiving a high fat diet. AB - The aim of our study was to evaluate the effects of the different probiotic strains, Lactobacillus plantarum LS/07 and Lactobacillus plantarum Biocenol LP96, on lipid metabolism and body weight in rats fed a high fat diet. Compared with the high fat diet group, the results showed that Lactobacillus plantarum LS/07 reduced serum cholesterol and LDL cholesterol, but Lactobacillus plantarum Biocenol LP96 decreased triglycerides and VLDL, while there was no change in the serum HDL level and liver lipids. Both probiotic strains lowered total bile acids in serum. Our strains have no significant change in body weight, gain weight, and body fat. These findings indicate that the effect of lactobacilli on lipid metabolism may differ among strains and that the Lactobacillus plantarum LS/07 and Lactobacillus plantarum Biocenol LP96 can be used to improve lipid profile and can contribute to a healthier bowel microbial balance. PMID- 24470790 TI - Artificial bee colony algorithm for solving optimal power flow problem. AB - This paper proposes an artificial bee colony (ABC) algorithm for solving optimal power flow (OPF) problem. The objective of the OPF problem is to minimize total cost of thermal units while satisfying the unit and system constraints such as generator capacity limits, power balance, line flow limits, bus voltages limits, and transformer tap settings limits. The ABC algorithm is an optimization method inspired from the foraging behavior of honey bees. The proposed algorithm has been tested on the IEEE 30-bus, 57-bus, and 118-bus systems. The numerical results have indicated that the proposed algorithm can find high quality solution for the problem in a fast manner via the result comparisons with other methods in the literature. Therefore, the proposed ABC algorithm can be a favorable method for solving the OPF problem. PMID- 24470792 TI - Drug release analysis and optimization for drug-eluting stents. AB - The drug release analysis and optimization for drug-eluting stents in the arterial wall are studied, which involves mechanics, fluid dynamics, and mass transfer processes and design optimization. The Finite Element Method (FEM) is used to analyze the process of drug release in the vessels for drug-eluting stents (DES). Kriging surrogate model is used to build an approximate function relationship between the drug distribution and the coating parameters, replacing the expensive FEM reanalysis of drug release for DES in the optimization process. The diffusion coefficients and the coating thickness are selected as design variables. An adaptive optimization approach based on kriging surrogate model is proposed to optimize the lifetime of the drug in artery wall. The adaptive process is implemented by an infilling sampling criterion named Expected Improvement (EI), which is used to balance local and global search and tends to find the global optimal design. The effect of coating diffusivity and thickness on the drug release process for a typical DES is analyzed by means of FEM. An implementation of the optimization method for the drug release is then discussed. The results demonstrate that the optimized design can efficiently improve the efficacy of drug deposition and penetration into the arterial walls. PMID- 24470793 TI - Bounds for combinations of toader mean and arithmetic mean in terms of centroidal mean. AB - The authors find the greatest value lambda and the least value MU, such that the double inequality C(lambdaa + (1-lambdab), lambdab+(1-lambda)a) < alphaA(a, b) + (1-alpha)T(a,b) < C(MUa + (1 - MU)b, MUb + (1 - MU)a) holds for all alpha ? (0, 1) and a, b > 0 with a ? b, where C(a, b) = 2(a2 + ab + b2)/3(a + b), A(a, b) = (a + b)/2, and T(a, b) = (a + b)/2, and T(a, b) = (2/pi) ?0(pi/2) ?a2cos2theta + b2sin2thetadtheta denote, respectively, the centroidal, arithmetic, and Toader means of the two positive numbers a and b. PMID- 24470794 TI - Torque for an inertial piezoelectric rotary motor. AB - For a novel inertial piezoelectric rotary motor, the equation of the strain energy in the piezoceramic bimorph and the equations of the strain energy and the kinetic energy in the rotor are given. Based on them, the dynamic equation of the motor is obtained. Using these equations, the inertial driving torque of the motor is investigated. The results show that the impulsive driving torque changes with changing peak voltage of the excitation signal, the piezoelectric stress constant, the thickness of the piezoceramic bimorph, and the rotor radius obviously. Tests about the motor torque are completed which verifies the theory analysis here in. The results can be used to design the operating performance of the motor. PMID- 24470791 TI - Chemistry and biological activities of flavonoids: an overview. AB - There has been increasing interest in the research on flavonoids from plant sources because of their versatile health benefits reported in various epidemiological studies. Since flavonoids are directly associated with human dietary ingredients and health, there is need to evaluate structure and function relationship. The bioavailability, metabolism, and biological activity of flavonoids depend upon the configuration, total number of hydroxyl groups, and substitution of functional groups about their nuclear structure. Fruits and vegetables are the main dietary sources of flavonoids for humans, along with tea and wine. Most recent researches have focused on the health aspects of flavonoids for humans. Many flavonoids are shown to have antioxidative activity, free radical scavenging capacity, coronary heart disease prevention, hepatoprotective, anti-inflammatory, and anticancer activities, while some flavonoids exhibit potential antiviral activities. In plant systems, flavonoids help in combating oxidative stress and act as growth regulators. For pharmaceutical purposes cost effective bulk production of different types of flavonoids has been made possible with the help of microbial biotechnology. This review highlights the structural features of flavonoids, their beneficial roles in human health, and significance in plants as well as their microbial production. PMID- 24470795 TI - An algorithmic framework for multiobjective optimization. AB - Multiobjective (MO) optimization is an emerging field which is increasingly being encountered in many fields globally. Various metaheuristic techniques such as differential evolution (DE), genetic algorithm (GA), gravitational search algorithm (GSA), and particle swarm optimization (PSO) have been used in conjunction with scalarization techniques such as weighted sum approach and the normal-boundary intersection (NBI) method to solve MO problems. Nevertheless, many challenges still arise especially when dealing with problems with multiple objectives (especially in cases more than two). In addition, problems with extensive computational overhead emerge when dealing with hybrid algorithms. This paper discusses these issues by proposing an alternative framework that utilizes algorithmic concepts related to the problem structure for generating efficient and effective algorithms. This paper proposes a framework to generate new high performance algorithms with minimal computational overhead for MO optimization. PMID- 24470796 TI - The estimate for approximation error of neural network with two weights. AB - The neural network with two weights is constructed and its approximation ability to any continuous functions is proved. For this neural network, the activation function is not confined to the odd functions. We prove that it can limitlessly approach any continuous function from limited close subset of R(m) to R(n) and any continuous function, which has limit at infinite place, from limitless close subset of R(m) to R(n). This extends the nonlinear approximation ability of traditional BP neural network and RBF neural network. PMID- 24470797 TI - Factors affecting microcuttings of Stevia using a mist-chamber propagation box. AB - Stevia rebaudiana Bertoni is a member of Compositae family. Stevia plant has zero calorie content and its leaves are estimated to be 300 times sweeter than sugar. This plant is believed to be the most ideal substitute for sugar and important to assist in medicinal value especially for diabetic patients. In this study, microcutting techniques using a mist-chamber propagation box were used as it was beneficial for propagation of Stevia and gave genetic uniformity to the plant. The effects of different treatments on root stimulation of Stevia in microcuttings technique were evaluated. Treatments studied were different sizes of shoot cuttings, plant growth regulators, lights, and shades. Data logger was used to record the mean value of humidity (>90% RH), light intensity (673-2045 lx), and temperature (28.6-30.1 degrees C) inside the mist-chamber propagation box. From analysis of variance, there were significant differences between varieties and treatments in parameters studied (P < 0.05). For the size of shoot cuttings treatment, 6 nodes cuttings were observed to increase root number. As compared to control, shoot cuttings treated with indole butyric acid (IBA) had better performance regarding root length. Yellow light and 50% shade treatments showed higher root and leaf number and these conditions can be considered as crucial for potential propagation of Stevia. PMID- 24470798 TI - The accuracy of prostate cancer localization diagnosed on transrectal ultrasound guided biopsy compared to 3-dimensional transperineal approach. AB - Background. Prostate cancer is often understaged following 12-core transrectal ultrasound- (TRUS-) guided biopsies. Our goal is to understand where cancers are typically missed by this method. Methods. Transperineal 3-dimensional mapping biopsy (3DMB) provides a more accurate depiction of disease status than transrectal ultrasound- (TRUS-) guided biopsy. We compared 3DMB findings in men with prior TRUS-guided biopsies to determine grade and location of missed cancer. Results were evaluated for 161 men with low-risk organ confined prostate cancer. Results. The number of cancer-positive biopsy zones per patient with TRUS was 1.38 +/- 1.21 compared to 3.33 +/- 4.06 with 3DMB, with most newly discovered cancers originating from the middle lobe and apex. Approximately half of all newly discovered cancerous zones resulted from anterior 3DMB sampling. Gleason upgrade was recognized in 56 patients using 3DMB. When both biopsy methods found positive cores in a given zone, Gleason upgrades occurred most frequently in the middle left and right zones. TRUS cancer-positive zones not confirmed by 3DMB were most often the basal zones. Conclusion. Most cancer upgrades and cancers missed from TRUS biopsy originated in the middle left zone of the prostate, specifically in anterior regions. Anterior sampling may lead to more accurate diagnosis and appropriate followup. PMID- 24470799 TI - Effect of low power laser on incisional wound healing. AB - INTRODUCTION: The effectiveness of low power lasers for incisional wound healing, because of conflicting results of previous research studies, is uncertain. Therefore, this study was carried out to evaluate low power laser effects on incisional wound healing. MATERIALS AND METHODS: Incisional wound was produced on thirty-six mature male guinea pigs under general and local anesthesia. In half of the cases, He-Ne laser radiations were used for five minutes and the rest were left untreated. Animals were divided into six groups of six animals each that were killed after 3, 5 and 14 days. After histopathology processing and H&E staining, specimens were examined for acute and chronic inflammations, epithelial cell migration, epithelial seal and barrier formation, fibroblast migration, fibrosis, clot formation and granulation tissue formation. Mann-Whitney U and the Wilcoxon tests were used for statistical analysis. RESULTS: Statistically significant differences were found between fibroblast migration, acute and chronic inflammation of radiated groups and the control group at 5 days interval (p<0.05). There was no statistically significant difference at 3 and 14 days between laser radiated and control groups. CONCLUSION: This study showed that He Ne laser had beneficial effects on incisional wound healing particularly at 5 days interval; however, further research on chronic ulcers is recommended. PMID- 24470800 TI - Component analysis of four commercial brands of gutta-percha. AB - INTRODUCTION: Gutta-Percha, the concrete milky juice of the Sapotaceae family tree, is the most commonly used material for obturation of prepared canal space. Natural 1-4 trans stereochemical structure of Gutta-Percha is taken to a heating- inclusion process of various organic and inorganic elements by manufacturers. The purpose of this study is to detect the presence and percentage of inorganic filler elements and organic phase of various commercial brands and if the locally manufactured brand confonns to standard range of components. MATERIALS AND METHODS: Sample cones, size # 35, from Roeko, Hygienic, DiaDent and AriaDent brands were randomly selected. After burning out in the furnace, organic and inorganic phase percentage and presence of trace elements in each sample were detected and recorded using apparatuses such as SEM, XRF, TGA, IR, NMR, and Ion Chromatography. RESULTS: With slight differences in polymer / filler ratio, 78% +/- 2% for organic phase, no significant difference was recorded among these brands. SEM analysis detected Zinc, Barium, and Sulfur in Hygienic, DiaDent, and AriaDent in descending order; in the last two Silicones was also traced, while Zinc was the only element to be identified in Roeko. CONCLUSION: No significant chemical and structural differences among four commercial brands were detected. PMID- 24470801 TI - Scanning electron microscopy study of dental gutta-percha after cutting. AB - INTRODUCTION: The purpose of this study was to evaluate the morphologic surface of gutta-percha cones after cutting with different methods. MATERIALS AND METHODS: The apical 3 millimeters of forty standardized, gutta-percha cones size 40 were cut off using scissors or a scalpel against a glass slab. The samples were then examined under scanning electron microscopy (SEM) for topographic deformity. RESULTS: According to results, cutting with scissors produced significant topographic deformity in the standardized gutta-percha cone surface but cutting with sharp surgical instrument against a glass slab allowed the development of a smooth and unmodified gutta-percha cone surface. CONCLUSION: Results of this study recommended that cutting the tip of a gutta-percha point with a sharp scalpel against a glass slab would produce more reasonable surface morphology than using scissor for the same procedure. PMID- 24470802 TI - Evaluation of the Sealing Ability of Amalgam, MTA, Portland Cement and Coltozol in the Repair of Furcal Perforations. AB - INTRODUCTION: Perforations of the pulpal floor create problems during endodontic treatment and often results in secondary periodontal involvement with eventual loss of teeth. The purpose of this study was to evaluate the ability of mineral trioxide aggregate (MTA), Amalgam, zinc oxide and eugenol (ZOE) and Portland cement to seal furcal perforations in extracted human molars using dye penetration. MATERIALS AND METHODS: This Microleakage study was conducted on 70 human permanent mandibular molars with well developed, non-fused roots. Access openings and furcation perforations were prepared in the pulp chamber floor. Ten teeth were assigned as controls and divided into two groups of five teeth each as positive and negative control. The positive group were accessed and perforated similar to experimental groups but the negative controls were not prepared. The rest of the teeth were divided in four experimental groups of 15 teeth in each group. Experimental groups comprised groups Al to A4, group Al was repaired with MTA, group A2 with Amalgam, group A3 with Coltozol (ZOE) and group A4 was repaired with Portland cement. The teeth were submerged in solution of 2% fucshin dye for 24 hours. Finally, the samples were sectioned and evaluated for linear dye leakage at X25 magnification and analyzed statistically. RESULTS: The results showed that MTA had significantly less leakage than Amalgam, Portland cement and Coltozol (P<0.05). CONCLUSION: Maximum dye penetration was observed in Coltozol followed in decreasing order by Portland cement and Amalgam. PMID- 24470803 TI - Fracture strength of endodontically treated teeth restored with casting post and core and glass-fiber with composite core. AB - INTRODUCTION: Prefabricated metal and ceramic posts can be used with different kinds of core materials as an alternative to the conventional casting post and cores. It is unclear how these post and core systems can withstand different kind of forces in the mouth. The purpose of this study was to compare the fracture strength of endodontically treated, crowned maxillary incisors restored with casting post and cores and glass- fiber post with composite core and to evaluate their mode of fractures. MATERIALS AND METHODS: Thirty caries free, human maxillary central incisors with incisoapical length of 23 +/- 1 mm were divided into two groups. After root canal treatment procedures and decronation of teeth 2mm above cementoenamel junction, Grope 1 was restored with glass- fiber posts and composite cores and group 2 received casting post and cores. Teeth were prepared with a circumferential shoulder including a 1-2 mm ferrule and 0.5 mm bevel; all posts were cemented with an adhesive resin and teeth were restored with complete coverage crowns. Loads were applied at an angle of 135 degrees using a universal testing machine. Compression force was applied until the specimens fractured. RESULTS: The median fracture strengths of groups 1 and 2 were 459 and 686 respectively (p<0.5). In group I, all fractures occurred in incisal third of roots. In groups II, 40% of fractures were in apical third and middle of roots. CONCLUSION: Within the limitation of this study, the results suggested that glass fiber with composite cores can be used as an alternative to cast posts and cores in anterior teeth when creating 2mm ferrule effect was possible in normal occlusion. Clinical trial is required to verify these in vitro results. PMID- 24470804 TI - A Comparative Study on the Amount of Extruded Material from the Apical Foramen with NiTi Rotary and Stainless Steel Hand Instruments. AB - INTRODUCTION: The purpose of the present study was to quantify and compare the amount of extruded debris from apical foramen after instrumentation of the root canal system with hand and rotary instruments. MATERIALS AND METHODS: Root canals of forty five fresh extracted single rooted human teeth with mature apexes and less than 15 degree of root curvature were instrumented in group A with stainless steel K-Type files, in group B with rotary NiTi Flex Master files, and in group C with rotary NiTi ProTaper files and followed weighting the extruded debris by a digital scale to within 0.0001 gram accuracy. RESULTS: In all groups, the mean weight of extruded debris was not more than 5 mg (P=0.0l) and was ranked as: Group A>Group B>Group C. There were statistically significant differences among three groups (p=0.0l). The mean value of extruded debris in the ProTaper and Flex Master groups were 0.652 and 0.788 mg, respectively. CONCLUSION: The study revealed that the amount of extruded debris from the apical foramen was minimal when ProTaper files were used. PMID- 24470805 TI - Two symmetrical maxillary first molars with two disto-buccal root canals. AB - INTRODUCTION: This article describes the diagnosis and treatment of two symmetrical maxillary first molars with two canals in their distobuccal roots. A 32-year-old female had an emergency treatment because of the pain in tooth #16. On the second visit after accessing the pulp chamber and detecting three major canals (MB, DB, and P) and exploring the 4th canal (MB2), we noted that there was a 5(th) canal in the distobuccal root. Also, necrosis was found in the same patient after examining the tooth #26 which was severely decayed. Then after preparing the access cavity, the same order of orifices was found in tooth #16. An electronic apex locator was utilized to ensure that a perforation of the pulpal floor had not occurred. Working films confirmed the presence of an additional canal in distobuccal root. PMID- 24470806 TI - Understanding the assembly of interdisciplinary teams and its impact on performance. AB - Interdisciplinary teams are assembled in scientific research and are aimed at solving complex problems. Given their increasing importance, it is not surprising that considerable attention has been focused on processes of collaboration in interdisciplinary teams. Despite such efforts, we know less about the factors affecting the assembly of such teams in the first place. In this paper, we investigate the structure and the success of interdisciplinary scientific research teams. We examine the assembly factors using a sample of 1,103 grant proposals submitted to two National Science Foundation interdisciplinary initiatives during a 3-year period, including both awarded and non-awarded proposals. The results indicate that individuals' likelihood of collaboration on a proposal is higher among those with longer tenure, lower institutional tier, lower H-index, and with higher levels of prior co-authorship and citation relationships. However, successful proposals have a little bit different relational patterns: individuals' likelihood of collaboration is higher among those with lower institutional tier, lower H-index, (female) gender, higher levels of prior co-authorship, but with lower levels of prior citation relationships. PMID- 24470809 TI - Ambulatory electroencephalogram in children: A prospective clinical audit of 100 cases. AB - Ambulatory electroencephalogram has been used for differentiating epileptic from nonepileptic events, recording seizure frequency and classification of seizure type. We studied 100 consecutive children prospectively aged 11 days to 16 years that were referred for an ambulatory electroencephalogram to a regional children's hospital. Ambulatory electroencephalogram was clinically useful in contributing to a clinical diagnosis in 71% of children who were referred with a range of clinical questions. A diagnosis of epileptic disorder was confirmed by obtaining an ictal record in 26% and this included 11 children that had previously normal awake and or sleep electroencephalogram. We recommend making a telephone check of the current target event frequency and prioritising those with typical events on most days in order to improve the frequency of recording a typical attack. PMID- 24470808 TI - Can an abnormal CT scan be predicted from common symptoms after mild head injury in children? AB - INTRODUCTION: Children have non specific symptoms after mild head injury (MHI). It is difficult to define indication of CT scan among them. We aimed at identification of predictors of CT scan findings after MHI. MATERIALS AND METHODS: Children aged <=12 years with GCS 13-15 after head injury were retrospectively evaluated for their clinical and CT scan findings during January to March 2010. The variables used for detection of abnormal (positive) CT scan were age, gender, cause of injury (road traffic accident, fall, and assault), loss of consciousness, vomiting, ear or nose bleed, seizure, and GCS score. RESULTS: A total of 133 children were included in study. Sixty nine (51.9%) children had abnormal CT findings. There was no statistical difference in patients with normal vs abnormal CT scan for presence of any of the variables evaluated. CONCLUSION: An abnormal CT scan cannot be reliably ruled out in a child with MHI based on symptoms; hence a policy of liberal CT scan based on clinical acumen is advisable. PMID- 24470810 TI - Childhood adrenoleukodystrophy - Classic and variant - Review of clinical manifestations and magnetic resonance imaging. AB - Adrenoleukodystrophy (ALD) is a genetic disease associated with demyelination of the central nervous system, adrenal insufficiency, and accumulation of very long chain fatty acids in tissue and body fluids. The attempt of this paper is to review the classical and not-so-classical MR imaging manifestations of adrenoleukodystrophy. A review of literature is done to describe the pathophysiology of the disease and the imaging differences between childhood and adult-onset of the disease. The literature is reviewed to explain the link with Addison's disease. In consensus the magnetic resonance imaging (MRI) findings of symmetrical occipital white matter lesions which progress in a rostro-caudal direction is the classical appearance of ALD. Familiarity with the clinico pathologic manifestations and progressive MR imaging features of childhood cerebral X-linked ALD will be helpful in evaluating the affected patients. PMID- 24470807 TI - Glaucoma Diagnosis and Monitoring Using Advanced Imaging Technologies. AB - Advanced ocular imaging technologies facilitate objective and reproducible quantification of change in glaucoma but at the same time, impose new challenges on scientists and clinicians for separating true structural change from imaging noise. This review examines time-domain and spectral-domain optical coherence tomography, confocal scanning laser ophthalmoscopy and scanning laser polarimetry technologies and discusses the diagnostic accuracy and the ability of each technique for evaluation of glaucomatous progression. A broad review of the current literature reveals that objective assessment of retinal nerve fiber layer, ganglion cell complex and optic nerve head topography may improve glaucoma monitoring when used as a complementary tool in conjunction with the clinical judgment of an expert. PMID- 24470811 TI - Holocord abscess in association with congenital dermal sinus. AB - Intramedullary spinal cord abscess in children is rare and holocord abscess is rarer. An 18-month-old girl presented with rapidly progressive paraplegia with fever for 2 months. The patient had complete flaccid paraplegia with absent sensation below D4 level. There was very small dermal sinus discharging pus in the lower lumbar region. Magnetic resonance imaging showed evidence of extensive multiloculated intramedullary abscess extending from D4 to L5 with cord edema upto cervical level. Laminotomy, excision of the dermal sinus and myelotomy, and evacuation of intramedullary abscess was performed. Escherichia coli and Pseudomonas were grown on culture. The child was treated with long-term parenteral antibiotics and started showing neurological improvement. Holocord abscess secondary to congenital dermal sinus is extremely rare and this is only the fourth report of such an instance. PMID- 24470812 TI - Congenital dermal sinus in mid-dorsal spine with large intramedullary dermoid cyst in an 18-months-old child. AB - Intramedullary dermoid cyst is a rare entity. It is usually associated with spinal dysraphism and dermal sinus. Our case is an 18-months-old female child who presented with history of fever and mild difficulty in moving left leg. She had a sinus in mid dorsal spine since birth with history of intermittent discharge from it. On magnetic resonance imaging of spine she was diagnosed to have large intramedullary epidermoid/dermoid cyst in the D2-7 vertebral level with a sinus tract. A dermoid cyst along with the sinus tract was excised. Post-operative follow up period was uneventful with full recovery. PMID- 24470813 TI - Tethered cord with tandem lipomyelomeningoceles, split cord malformation and thick filum. AB - Lipomyelomeningocele, a closed neural tube defect, usually occurs in lumbosacral area as a single lesion but can be associated with other spinal dysraphism. We report an infant with a very rare presentation of tandem lumbosacral lipomyelomeningoceles, thick filum terminale and split cord malformation. PMID- 24470814 TI - Torcular occipital encephalocele in infant: Report of two cases and review of literature. AB - The presence of torcula or sinus in the occipital encephalocele presents a challenge during surgery. However, a detailed study of magnetic resonance image and magnetic resonance venography can aid in preoperative localization of the torcula. Knowing the encephalocele's contents, its relationship with falx cerebri and falx cerebelli, and vigilance during surgery is a sure way to protect neural tissue. Visual Evoked Potential (VEP) may be indicated in torcular encephalocele. Here, authors report two such cases, one presented with ruptured encephalocele with cerebrospinal fluid leak and another case presented six months after birth due to financial constraints. Pertinent literature and management is briefly reviewed. PMID- 24470815 TI - Moebius syndrome with Dandy-Walker variant and agenesis of corpus callosum. AB - Moebius syndrome is a rare congenital neurological disorder. The most frequent mode of presentation is facial diplegia with bilateral lateral rectus palsy, but there are variations. Here, we report a rare case of Moebius syndrome in a 15 month-old child with unilateral facial palsy, bilateral abducens nerve palsy with Dandy Walker variant, and complete agenesis of corpus callosum. PMID- 24470816 TI - Angelman syndrome in three biological siblings: Focusing on the neuropsychiatric domain. AB - Angelman syndrome (AS) is a neurogenetic disorder that usually presents with delayed motor milestones, ataxic gait, mental retardation, language disorder, seizures, sleep disturbances, characteristic facial features, and happy demeanor. The genetic abnormality of AS has been located on chromosome 15q11-q13. The AS gene(s) is exclusively expressed from the maternal chromosome. Loss of the maternally contributed AS region can occur by deletion, paternal uniparental disomy, imprinting defects, mutation of the ubiquitin-protein ligase (UBE3A) gene, and by yet unidentified mechanisms. Deletion of maternal chromosome accounts for most of the cases of AS with imprinting accounting for 2%-5% of cases. In imprinting inheritance, offsprings of carrier mothers are theoretically at 50% risk of having AS. Familial occurrence of AS has been reported. Here, we highlighted the rare incident of AS in three biological siblings and their neuropsychiatric manifestations as well as different psychosocial aspects. PMID- 24470818 TI - Failure of peritoneal and gallbladder shunts in a child with craniopharyngioma. AB - A 1-year-old girl with craniopharyngioma required external drainage of 40-50 mL/h of cerebrospinal fluid (CSF) after biopsy and cyst fenestration. She developed CSF ascites following insertion of a ventriculoperitoneal (VP) shunt and a distended painful gallbladder following ventriculogallbladder shunt insertion. Revision to a ventriculoatrial shunt was required. This is the first time a craniopharyngioma has been reported to cause increased CSF production. The potential mechanisms of CSF overproduction and the difficulties managing the large volume of CSF in a young child are discussed. PMID- 24470817 TI - An interesting case of Rathke's cleft cyst presenting as bilateral cryptorchidism. AB - Rathke's cleft cyst (RCC) are benign, epithelium-lined sellar and suprasellar cysts believed to originate from remnants of the Rathke pouch. Here, we report a rare case of entirely suprasellar RCC in a 4.5-year-old child causing hypopituitarism, who presented to us with bilateral cryptorchidism. Subsequently we discuss the distinct rarity of entirely suprasellar RCC presenting in this fashion and the relevant literature is also discussed. PMID- 24470819 TI - Intracranial hydatid cyst is a rare cause of midbrain herniation: A case report and literature review. AB - Hydatid disease is a parasitic infection affecting the brain in about 2% of the cases. Brain involvement is most commonly observed in children. Here, we report a 13-year-old male patient who presented with headache, nausea, and vomiting. Before cranial computed tomography (CT) was performed, the patient had generalized epileptic seizures. He was disoriented, and had anisocoria with dilatation of the right pupilla. CT showed a cystic lesion of 10-cm diameter in the right temporoparietal region that had caused a shift of the midline structures to the contralateral side; an urgent operation was performed as there were signs of midbrain herniation. PMID- 24470820 TI - Disseminated tuberculosis with paradoxical miliary tuberculomas of brain in a child with rickets. AB - Intracranial tuberculomas continue to be a serious complication of central nervous system tuberculosis. Multiple central nervous system tuberculoma is commonly associated with human immunodeficiency virus (HIV) infection. The development of intracranial tuberculomas has been thought to be caused by hematogenous spread of tubercle bacilli on the surface of brain parenchyma from the primary site of infection. Here, we describe the case of a 5-year-old male child with severe protein energy malnutrition (Marasmus) having large cervical lymphadenopathy and severe nutritional rickets with deformity at presentation. The child developed convulsions 20 days after initiation of antituberculous drugs, and neuroimaging confirmed multiple miliary tuberculomas of brain as primary etiology for the convulsions. PMID- 24470821 TI - Tumefactive presentation of a supratentorial cavernous hemangioma: A report of two cases. AB - This study reports two children, including a 2-month-old infant, harboring giant cavernous hemangiomas (GCH) in the supratentorial compartment, causing raised intracranial pressure and focal deficits. Relevant demographic details, clinical presentation, and radiological findings of GCH are discussed in light of tumefactive presentation. Differential diagnoses of such radiological findings are elaborated. PMID- 24470822 TI - "Rabbit Ear" scalp deformity caused by massive subdural effusion in infant following bilateral burr-hole drainage. AB - Subdural effusion (SDE) in an infant is a rare clinical scenario, which may be secondary to a variety of etiologies. Massive SDE is an extremely rare complication of head injury. It usually runs a self-limiting course. Though neurosurgical intervention is occasionally needed, different methods of surgical procedure for management includes burr-hole alone, burr-holes with subdural drain placement, twist drill craniotomy with drain and even craniotomy. The authors report a rare case of progressive massive SDE, which despite bilateral burr-hole placement and drainage failed and presented with visual deterioration and massive bulge of scalp at burr-hole sites producing rabbit ear sign in a 10 month old infant. Ultimately cystoperitoneal shunt was carried out in a desperate attempt to prevent impending rupture of scalp sutures at sites of previous burr-hole placement. Astonishingly not only complete resolution of hygroma, but visual recovery also took place. Patient is doing well at 6 months following shunt with regaining normal vision and appropriate developmental milestones. A magnetic resonance imaging scan of brain at last follow-up revealed mild ventriculomegaly with subduro-peritoneal shunt in situ and rest of brain was unremarkable. Such cases have not been reported in literature until date. PMID- 24470823 TI - Primary congenital sacrococcygeal neuroblastoma: A case report with immunohistochemical study and review of literature. AB - Primary localized congenital sacrococcygeal neuroblastomas (SCNs) are rare. Diagnosis is based on histological and immunohistochemical evaluation, which is indispensable not only for determining tumor type but also for predicting biological behavior. We report a rare case of congenital SCN in a 9-month-old baby girl. Based on clinical and radiological findings, a provisional diagnosis of solid variant of sacrococcygeal teratoma (SCT) was made. The swelling was entirely excised. On histopathological examination, diagnosis of neuroblastoma, differentiating type in the sacrococcygeal region was considered. On immunohistochemistry, the tumor cells showed immunoreactivity for markers such as neuronspecific enolase, chromogranin-A, synaptophysin, and cyclin D1. S-100 showed positive cytoplasmic immunoreactivity. CD99, leucocyte common antigen, PanCK, and epidermal growth factor receptor were nonreactive. Cyclin D1 showed strong nuclear immunoreactivity. p53 was negative and Ki67 labelling index was less than 1%. The immunohistochemical markers studied, confirmed the histopathological diagnosis, and the cell proliferative index markers indicated it to be a very low grade lesion. Postoperatively, the child is disease-free and has achieved normal milestones for age for period of 6 months. PMID- 24470824 TI - Pilomyxoid astrocytoma with high proliferation index. AB - Pilomyxoid astrocytomas is an uncommon aggressive piloid neoplasm, closely related to pilocytic astrocytomas and typically presents in the very young but can occur in older children and rarely in adults. A 12-years-old male presented with focal seizures, headache and vomiting of 10 days duration. Computed tomogram showed a hypo- to hyperdense and peripherally enhancing, solid-cystic lesion in the left temporal lobe. Histopathological examination revealed a characteristic tumor composed of bipolar cells arranged in dyscohesive sheets, angiocentric pattern in a loose myxoid background, with brisk mitotic activity and foci of necrosis. No Rosenthal fibers or eosinophilic granular bodies were seen. The tumor cells showed strong GFAP and scattered p53 positivity, but were negative for EMA. Ki-67 positivity ranged from 30 to 40%, highest reported till date. The patient was treated with radiotherapy and concurrent temozolamide and the tumor recurred after two years. PMID- 24470825 TI - Choroid plexus papilloma of the third ventricle: A rare infantile brain tumor. AB - Choroid plexus papilloma (CPP) represents an uncommon pediatric brain tumor with an overall incidence less than 1% of all intracranial tumors. Most of these tumors occur in the lateral ventricles in neonates. Third ventricular location is uncommon, limited to a few case reports. These highly vascular tumors retain the physiological function of choroid plexus and thus lead to overproduction of cerebrospinal fluid (CSF), besides obstructing the CSF pathway. Imaging is fairly sensitive and specific in affording the diagnosis of this tumor. Surgical approaches differ according to the site of tumor and aim is complete removal of tumor. We present an interesting report of an infant who presented to our department for cranial sonography that lead to suspicion of this tumor, later confirmed by other imaging modalities and histopathology. PMID- 24470826 TI - Unusual cause of hyperammonemia in two cases with short-term and long-term valproate therapy successfully treated by single dose carglumic acid. AB - Valproic acid (VPA) is an antiepileptic drug which is used in the treatment of various seizure disorders including tonic-clonic, myoclonic, absence, partial seizures and psychiatric disorders. VPA is usually well tolerated, but severe adverse effects may occur. Hyperammonaemic encephalopathy (HE) is a rare and potentially fatal complication of VPA treatment. The mechanism by which valproate induces hyperammonemia remains incompletely understood but is likely to relate to the urea cycle. Herein we present two cases with valproate-induced hyperammonemia at therapeutic valproate levels without signs of liver failure and were successfully treated by a single dose of carglumic acid. PMID- 24470827 TI - Abdominal epilepsy: Is it so common? PMID- 24470828 TI - Author response. PMID- 24470829 TI - Asymptomatic Chiari III malformation with tectal beaking and holocord syrinx. PMID- 24470830 TI - Sacral agenesis with club shaped conus. PMID- 24470831 TI - Pontobulbar palsy and sensorineural deafness (Brown-Vialetto-van Laere syndrome): A case from Northwest Iran. PMID- 24470832 TI - Kabuki syndrome and perisylvian cortical dysplasia in a Turkish girl. PMID- 24470833 TI - Traumatic dissection of common carotid artery due to injury caused by a tiger. PMID- 24470834 TI - SLE presenting with catatonia in an adolescent girl. PMID- 24470835 TI - Bickerstaff brainstem encephalitis in pediatrics - A case report. PMID- 24470836 TI - The importance of counseling in young, female epileptic patients. PMID- 24470837 TI - Enhanced Sensitivity of Delocalized Plasmonic Nanostructures. AB - This work reports on the observation of a delocalized surface plasmon resonance (DSPR) phenomenon in linear chains of square-shaped silver nanoparticles (NP) as a function of the chain length and the distance between the nanoparticles in the chain. Transmission spectra of the silver nanoparticle chains reveal the emergence of new, red-shifted extinction peaks that depend strongly on the spacing between the nanoparticles and the polarization of the exciting light with respect to the chain axis. As the spacing between the nanoparticles in the linear chain decreases and the number of nanoparticles in the linear chain increases, the strength of the new extinction features increase strongly. These changes can be described by a tight-binding model for the coupled chain, which indicates that the origin of the phenomenon is consistent with an increased coupling between the nanoparticles. FDTD calculations reveal that the electric field is strongly enhanced between the nanoparticles in the chain. The DSPR response is found to be much more sensitive to dielectric changes than the localized surface plasmon resonance (LSPR). PMID- 24470839 TI - Hepatitis C- and HIV-induced porphyria cutanea tarda. AB - PATIENT: Male, 47 FINAL DIAGNOSIS: Porphyria cutanea tarda Symptoms: Chills * cough dry * thumb swelling MEDICATION: - Clinical Procedure: - Specialty: Metabolic Disorders and Diabetics. OBJECTIVE: Challenging differential diagnosis. BACKGROUND: Porphyria cutanea tarda (PCT) is the most common type of the porphyria. It occurs due to the deficiency of enzyme uroporphyrinogen decarboxylase (UROD), which is the fifth enzyme in the biosynthesis of heme and catalyzes the conversion of uroporphyrinogen to coproporphyrinogen. The risk factors for PCT include hereditary hemochromatosis, hepatitis C infection, ethanol abuse, estrogen use, HIV, smoking, chlorinated polycyclic aromatic hydrocarbons, and hemodialysis. CASE REPORT: A 47-year-old Hispanic man presented with right thumb swelling, redness, and pain for approximately 1 week. Past medical history included HIV/AIDS, hepatitis C infection, alcohol abuse, heroin abuse, and CMV retinitis. Skin examination revealed blistering and hypo/hyper pigmented lesions over the dorsal aspects of the hands and other sun-exposed areas. Serum porphyrins were discovered to be elevated. The quantitative urine porphyrins revealed elevation of uroporphyrins, heptacarboxyl-porphyrins, hexacarboxy-porphyrins, pentacarboxyl-porphyrins and coproporphyrin. Genetic mutation of UROD was not detected. Due to the classic cutaneous lesions, laboratory findings, and associated risk factors, we were able to confirm our suspicion of the sporadic (type 1) form of PCT. CONCLUSIONS: A strong correlation has been demonstrated between the sporadic (type 1) form of PCT and hepatitis C virus (HCV) infection in multiple studies. The mechanism through which HCV infection may cause or trigger PCT is unknown. PCT has been described for many years, but still eludes the differential diagnosis in a patient with cutaneous findings. The uniqueness of our case is the possibility that combined risk factors have an effect on PCT. PMID- 24470838 TI - The Evolving Construct of Posttraumatic Stress Disorder (PTSD): DSM-5 Criteria Changes and Legal Implications. AB - In the DSM-5, the diagnosis of posttraumatic stress disorder (PTSD) has undergone multiple, albeit minor, changes. These changes include shifting PTSD placement from within the anxiety disorders into a new category of traumatic and stressor related disorders, alterations in the definition of a traumatic event, shifting of the symptom cluster structure from three to four clusters, the addition of new symptoms including persistent negative beliefs and expectations about oneself or the world, persistent distorted blame of self or others, persistent negative trauma-related emotions, and risky or reckless behaviors, and the addition of a dissociative specifier. The evidence or lack thereof behind each of these changes is briefly reviewed. These changes, although not likely to change overall prevalence, have the potential to increase the heterogeneity of individuals receiving a PTSD diagnosis both by altering what qualifies as a traumatic event and by adding symptoms commonly occurring in other disorders such as depression, borderline personality disorder, and dissociative disorders. Legal implications of these changes include continued confusion regarding what constitutes a traumatic stressor, difficulties with differential diagnosis, increased ease in malingering, and improper linking of symptoms to causes of behavior. These PTSD changes are discussed within the broader context of DSM reliability and validity concerns. PMID- 24470840 TI - Desmethyl Macrolides: Synthesis and Evaluation of 4,8,10-Tridesmethyl Cethromycin. AB - Antibiotic-resistant bacteria are emerging at an alarming rate in both hospital and community settings. Motivated by this issue, we have prepared desmethyl (i.e., replacing methyl groups with hydrogens) analogues of third-generation macrolide drugs telithromycin (TEL, 2) and cethromycin (CET, 6), both of which are semi-synthetic derivatives of flagship macrolide antibiotic erythromycin (1). Herein, we report the total synthesis, molecular modeling, and biological evaluation of 4,8,10-tridesmethyl cethromycin (7). In MIC assays, CET analogue 7 was found to be equipotent with TEL (2) against a wild-type E. coli strain, more potent than previously disclosed desmethyl TEL congeners 3, 4, and 5, but fourfold less potent than TEL (2) against a mutant E. coli A2058G strain. PMID- 24470841 TI - Discovery of potent and selective inhibitors of Toxoplasma gondii thymidylate synthase for opportunistic infections. AB - Infection by the parasite Toxoplasma gondii (tg) can lead to toxoplasmosis in immunocompromised patients such as organ transplant, cancer and HIV/AIDS patients. The bifunctional thymidylate synthase-dihydrofolate reductase (TS-DHFR) enzyme is crucial for nucleotide synthesis in T. gondii, and represents a potential target to combat T. gondii infection. While species selectivity with drugs has been attained for DHFR, TS is much more conserved across species and specificity is significantly more challenging. We discovered novel substituted-9H pyrimido[4,5-b]indoles 1-3 with single-digit nanomolar Ki for tgTS, two of which, 2 and 3, are 28- and 122-fold selective over human TS (hTS). The synthesis of these compounds, and their structures in complex with tgTS-DHFR are presented along with binding measurements and cell culture data. These results show, for the very first time, that in spite of the high degree of conservation of active site residues between hTS and the parasite TS, specificity has been accomplished via novel structures and provides a new target (TS) for selective drug development against parasitic infections. PMID- 24470843 TI - Trans-umbilical Laparoscopic Appendectomy for Acute Appendicitis without Raising Skin-flaps: An Easy-to-use Modification Applied to the Series of 164 Patients from a Rural Institute of Central India. AB - BACKGROUND: Laparoscopic appendectomy (LA) is widely used and generally an accepted method for managing appendicitis. And the recent invention of laparoscopic trans-umbilical-appendectomy is a further improvement of LA. However, it requires expensive instruments with the requisite expertise. We discuss a useful modification of trans-umbilical appendectomy for acute appendicitis using routine instruments. MATERIALS AND METHODS: From August 2009 to March 2011, 164 patients were operated by this method at our rural center. Out of them, 102 were males and 62, females. Mean age for males was 27.5 years (range, 14-51) and females, 31.2 years (range, 17-48). Mean body mass index was 21.7 kg/m(2) (range, 16.2-29) and 23.2 kg/m(2) (range, 17.4-30) for males and females respectively. Acute appendicitis patients wherein surgery was deemed essential were offered this technique. Three umbilical ports (one 10 mm and two 5 mm) were strategically placed to dissect out appendix. Routine laparoscopic instruments were used for all. RESULTS: Mean operativetime was 45 min (range, 30 90) with 1.8% conversion-rate to conventional laparoscopy. Average blood-loss was 15 ml (range, 10-25). We had one caecal electrosurgical injury, which was managed expectantly. Umbilical sepsis and seroma were 3% and 6.1% respectively. Patients were discharged after an average 1.3 days (range, 1-4). The scars had receded in the umbilicus giving a near-scarless abdomen. DISCUSSION: Recently developed technique of single-port appendectomy has primarily been used for chronic appendicitis. Moreover, >1 inch incision inducted per-umbilicum rises the attendant morbidity. We study a surgeon-friendly simple technique applied to acute appendicitis. CONCLUSION: Method described here is feasible and safe for managing acute appendicitis. It can be learnt rather easily (learning curve of 15 cases) by a laparoscopic surgeon and avoids expensive instrumentation. Thus, it may stand out in providing benefits of modern surgery to population of developing countries. PMID- 24470842 TI - Techniques of male circumcision. AB - Male circumcision is a controversial subject in surgical practice. There are, however, clear surgical indications of this procedure. The American Academy of Pediatrics (AAP) recommends newborn male circumcision for its preventive and public health benefits that has been shown to outweigh the risks of newborn male circumcision. Many surgical techniques have been reported. The present review discusses some of these techniques with their merits and drawbacks. This is an attempt to inform the reader on surgical aspects of male circumcision aiding in making appropriate choice of a technique to offer patients. Pubmed search was done with the keywords: Circumcision, technique, complications, and history. Relevant articles on techniques of circumcision were selected for the review. Various methods of circumcision including several devices are in use for male circumcision. These methods can be grouped into three: Shield and clamp, dorsal slit, and excision. The device methods appear favored in the pediatric circumcision while the risk of complications increases with increasing age of the patient at surgery. PMID- 24470844 TI - Laparoscopic Inguinal Hernia Repair in a Developing Nation: Short-term Outcomes in 103 Consecutive Procedures. AB - BACKGROUND: There are no published data on the outcomes of inguinal hernia repair from the Anglophone Caribbean. To the best of our knowledge, this is the first report of a series of laparoscopic inguinal hernia repairs from the region. MATERIALS AND METHODS: Data was extracted from a prospectively maintained database of consecutive trans abdominal pre-peritoneal (TAPP) repairs done between June 1, 2005 and May 30, 2012. Perioperative data collected included patient demographics, hernia type, operative technique, duration of surgery, intra-operative details, morbidity, analgesia requirements, and duration of hospitalization. A telephone survey was also performed to identify late recurrences and complications. Descriptive statistics were generated using Statistical Package for Social Sciences (SPSS) Ver 12.0. RESULTS: There were 103 consecutive TAPP procedures in 88 patients at an average age of 35.4 years +/- 12.9 (standard deviation; SD) and average body mass index (BMI) of 28.9 Kg/m(2) +/- 2.23 (SD). The indications were bilateral (30), recurrent unilateral (24), and primary unilateral (49) inguinal hernias. The mean duration of operation was 68.5 minutes (SD +/- 10.4; Range: 55-95; Median 65; Mode 65) minutes for unilateral TAPP and 89 minutes (SD +/- 7.61; Range: 80-105; Median 90; Mode 90) for bilateral repairs. Post-operatively, 65/70 patients required <=1 dose of parenteral opioid analgesia and 74 (84.1%) patients discontinued oral analgesia within 48 hours of operation. Complications were recorded in six (5.8%) cases and a recurrence in one (0.97%) case after a mean follow-up period of 3.2 years (SD +/- 1.8; Range: 0.5-7). CONCLUSION: Laparoscopic inguinal hernia repair is a safe and effective operation in this setting. PMID- 24470845 TI - A simple technique for adjustment of the femoral offset at the site of hip spacer implantation. AB - The decrease of femoral offset might play a role in the emergence of hip spacer dislocations, but it has not been discussed in the literature yet. The present work describes a technique for femoral offset adjustment. Either a bended blade plate or a dynamic hip screw can be used. The depth of the insertion and the angle of the particular implant are defined by the size of the offset adjustment required in each case. The described technique is feasible to produce a customized hip spacer, allowing for the preservation of an adequate muscle tension by individual adjustment of the femoral offset between stages. PMID- 24470846 TI - Dentigerous cysts in four quadrants: a rare and first reported case. AB - The dentigerous cyst is a developmental odontogenic cyst which usually occurs in the second and third decade of life. Dentigerous cyst is one of the most prevalent types of odontogenic cysts associated with partially erupted, developing, or impacted teeth. The mandibular third molars have a high predictability followed by maxillary canines. Occurrence of dentigerous cyst bilaterally is generally observed in syndromic cases. Non-syndromic dentigerous cyst occurring bilaterally or involving both arches at the same time is very rare. This presented case is rare and unique in which all four quadrants shows the presence of dentigerous cyst. In this case there are well-defined cysts associated with impacted molars as well as with supernumerary teeth in all the four quadrants of jaws. The clinical documentation of such a case in available literature is found to be first time. PMID- 24470847 TI - Pneumobilia: a case report and literature review on its surgical approaches. AB - Gallstones ileus is an uncommon cause but important cause of small bowel obstruction. The gallstone enters the intestinal lumen via a fistula located in the duodenum (cholecystoduodenal), or rarely, in the colon (cholecystocolonic) or stomach (cholecystogastric). This may result in large bowel or gastric outlet obstruction (Bouveret's Syndrome). Gallstone ileus affects the elderly females pre-dominantly and is associated with a high morbidity and mortality rate if diagnosis and urgent surgical intervention are delayed. In this paper, we report on the case of an elderly lady who presented with classical symptoms and signs of small bowel obstruction. She was subsequently diagnosed with gallstone ileus due to a large gallstones lodged in the intestinal lumen. We perform a literature review on this rare disease and discuss the two main surgical approaches in managing this condition. Gallstone ileus should be considered in the differential diagnosis of small bowel obstruction especially in elderly women who have no history of abdominal surgery or abdominal hernia. Early intervention is important because of the high mortality rate due to the poor general condition that often exists in this subgroup of patients. There is no general consensus on gold standard surgical approach in these cases but a two-stage procedure (either enterotomy alone or enterotomy and subsequent cholecystectomy) has been shown to be associated with lower mortality rates. PMID- 24470848 TI - Primary tuberculosis of the appendix: a rare cause of a common disease. AB - Tuberculosis is still a common infection in India. Although the ileocecal region is the most affected part in intestinal tuberculosis, acute tuberculous appendicitis is quite a rare entity. Our case report highlights a rare presentation of tuberculosis and a brief review of literature. PMID- 24470849 TI - Bone suture in management of mandibular degloving injury. AB - Traumatic degloving injuries of the mandible are rare intraoral soft tissue traumas. A simple review of the medical literature shows that no article up to this date has reported the prevalence of the degloving injuries of the mandible. Moreover, the highest incidence of mandibular degloving injuries is reported in children and young adults. In this article, the author describes the mandibular degloving injury, characterized by the separation of periosteum and soft tissues of the anterior buccal side of the mandible, and the bone suture technique. This article outlines that a correct diagnostic assessment and appropriate treatment plan can reduce the complications after mandibular degloving injuries. PMID- 24470850 TI - Left side appendicitis with midgut malrotation in an adult. AB - Midgut malrotation (MMR) is a congenital anomaly referring to either nonrotation or incomplete rotation of the primitive intestinal loop around the axis of the superior mesenteric artery during fetal development. Adult MMR is rare and majority of MMR in adults remains asymptomatic throughout life. The increasing use of diagnostic imaging for acute abdominal pain will lead to more incidental recognitions of MMR. Up to now, surgical treatment has been guided by the experience from pediatric surgery, and Ladd's procedure has been the treatment of choice in adults with MMR. However, a major dilemma arises when patients are essentially asymptomatic and incidentally diagnosed with MMR during another abdominal affection like acute appendicitis. The surgeon has to decide whether it is necessary to also treat the MMR. Here, we report a rare case of a 37-year-old patient with acute left side appendicitis in association with asymptomatic MMR. We discuss whether correction of the asymptomatic malrotation was indicated. PMID- 24470851 TI - Single incision laparoscopic surgery for a large endometriotic cyst. AB - We describe a technique for the treatment of large benign ovarian cysts by single port laparoscopic surgery via the umbilical approach. X-cone single port system (Karl Storz) was employed in this surgery. Prebent atraumatic grasping forceps were used in conjunction with the straight laparoscopic instruments. We propose using a "to-fro" peeling technique in the z-axis in SPLS cystectomy. Combined use of prebent and straight laparoscopic instruments enables the cystectomy to be performed in the z-axis, thereby avoiding instruments crossing and hands collision outside the abdomen. The proposed technique proved to be feasible, easy to employ, and safe in SPLS cystectomy, with the additional benefit of superior cosmetic outcome. PMID- 24470852 TI - Non-operative Management of Gallbladder Perforation After Blunt Abdominal Trauma. AB - Isolated gallbladder perforations following blunt abdominal trauma are very rare. They often present with insidious onset of symptoms a few days after the initial insult and an operative course of management ensues. This is in the form of a cholecystectomy and peritoneal lavage; more often via laparotomy rather than laparoscopically. Conservative management, in the form of cholecystostomy, percutaneous intraperitoneal drainage or cholecystorraphy has been described; however, these cases have invariably resulted in cholecystectomy eventually. The case uniquely highlights the successful non-operative management of isolated traumatic gallbladder perforation. PMID- 24470853 TI - Vesical calculus 10 years post missing intrauterine contraceptive device. AB - Intravesical migration of intrauterine contraceptive device (IUCD) is rare. Early diagnosis of this rare entity is difficult because of its non-specific manifestations and very low index of suspicion. We present this case of bladder stone following intravesical migration of IUCD found to have been missing since insertion 10 years earlier. Lower abdominal discomfort and a missing vaginal string may be the only pointer to this unfortunate event in the immediate post insertion period. It is pertinent to consider the possibility of an intravesical migration of a missing IUCD in a patient presenting with lower abdominal discomfort, urinary frequency, and missing IUCD string on vaginal examination. PMID- 24470854 TI - Laparoscopic colectomy for a patient with congenital renal agenesis. AB - We present a very rare case of laparoscopic colectomy for a patient with ascending colon cancer and an agenetic right kidney. A 57-year-old man visited our institute for further evaluation for a positive fecal occult blood test. Approximately, 20 years earlier, the right kidney of the patient was found to be congenitally absent. A physical examination indicated no anatomical anomalies in his genitourinary system, and the renal function was within the normal range. Total colonoscopy revealed a cancer of the ascending colon and laparoscopic colectomy was performed. The right colon was mobilized by lateral-to-medial extension of a retroperitoneal dissection between the fusion fascia and the anterior renal fascia. The right testicular vessels were preserved without injury to the anterior renal fascia; however, the right ureter could not be detected. The operation was performed safely. Thus, we believe that in patients with congenital unilateral renal agenesis, the anterior renal fascia is present, and laparoscopic ipsilateral colectomy can be safely performed in such patients. PMID- 24470855 TI - The Use of T-tube Cholangiocatheter Stents in the Treatment of Pediatric Tracheomalacia. AB - Tracheomalacia is a common disorder in neonate and infants, which can lead to life-threatening airway occlusion, because of external pressure or intrinsic defect of tracheobroncial cartilage. Aortopexy and Stents are effective in relieving tracheomalacia in the latter patients. In this case we are to show how t-tube cholangiocatheter is effective and easy available in sever tracheomalacia neonates with intrinsic defect. It can be easily replaced and causes no infection, erosion, or sever complication in 9 months period. PMID- 24470856 TI - Carcinoid Tumor in Accidental, Asymptomatic Meckel's Diverticulum. AB - Although Meckel's diverticulum is the most common congenital gastrointestinal disorder, it is controversial whether asymptomatic diverticula in adults should be respected. The authors report the case of a patient who was operated due to ileus caused by adhesions and a Meckel's diverticulum without any sign of inflammation was accidentally noted and removed. As a surprise, the pathological examination of the diverticulum proved carcinoid tumor, a neuroendocrine malignant tumor. The case raises the importance of the removal of asymptomatic Meckel's diverticulum. PMID- 24470857 TI - Preventing Inadvertent Placement of Foley Catheter into Prostatic Urethra During Suprapubic Trocar Cystostomy: A Simple Face-saver Trick. AB - During suprapubic cystostomy using standard technique, there always remains a chance of accidental migration of foley catheter through bladder neck into prostatic urethra. We herein present a point of technique in which by keeping the direction of cannula slot toward umbilicus and making it vertical or slightly tilting its tip toward umbilicus during foley placement, prevents the inadvertent migration of catheter into prostatic urethra and further complications. PMID- 24470858 TI - Unusual cause of shock: inferior vena cava obstruction complicating pyogenic liver abscess. PMID- 24470859 TI - Bimaxillary and bilateral dentigerous cysts: a rare and first reported case. PMID- 24470861 TI - A Systematic Review for Estimation of HTLV-I Infection in the Blood Donors of Iran. PMID- 24470862 TI - "HTLV-I Infection" Twenty-Year Research in Neurology Department of Mashhad University of Medical Sciences. AB - Human T-cell lymphotropic virus (HTLV) types 1 and 2 belong to the Oncorna group of retroviridae, a large family of viruses, grouped initially by pathogenic features, but later revised on the basis of genome structure and nucleotide sequence. HTLV-I was the first discovered human retrovirus to be associated with a malignancy in 1980. The malignancy, first described by Uchiyama and co-workers in southwestern Japan, was named Adult T-cell Leukemia/Lymphoma (ATL) and characterized with cutaneous and respiratory involvement, hepatosplenomegaly, lymphadenopathy and various metabolic abnormalities such as hypercalcemia. The HTLV-I has been known to be endemic to certain parts of Iran like the province of Khorasan in the northeast since 1990, with a 2.3% prevalence rate of infection. The main manifestations of HTLV-I infection are neurologic and hematologic (such as ATL) disorders, but it has also other manifestations such as uveitis, arthritis, dermatitis, vitiligo and lymphocytic alveolitis. Its main neurologic manifestation is a chronic progressive myelopathy that is referred to HTLV-I Associated Myelopathy (HAM) in Japan and Tropical Spastic Paraparesis (TSP) in Caribbean. But other disorders such as peripheral neuropathy, polyradiculoneuropathy, myopathy, peripheral facial paresis, and so on have been reported too. In this review we wish to give some brief information on the different aspects (including epidemiology, pathogenesis and pathology, clinical findings, and treatment) of HTLV-I infection according to our twenty-year researches. The department of neurology of Mashhad University of Medical Sciences has been a pioneer in researches on HTLV-I in the last twenty years. PMID- 24470863 TI - Comparison of HTLV-I Proviral Load in Adult T Cell Leukemia/Lymphoma (ATL), HTLV I-Associated Myelopathy (HAM-TSP) and Healthy Carriers. AB - OBJECTIVE(S): Human T Lymphocyte Virus Type one (HTLV-I) is a retrovirus that infects about 10-20 million people worldwide. Khorasan province in Iran is an endemic area. The majority of HTLV-I-infected individuals sustain healthy carriers but small proportion of infected population developed two progressive diseases: HAM/TSP and ATL. The proviral load could be a virological marker for disease monitoring, therefore in the present study HTLV-I proviral load has been evaluated in ATL and compared to HAM/TSP and healthy carriers. MATERIALS AND METHODS: In this case series study, 47 HTLV-I infected individuals including 13 ATL, 23 HAM/TSP and 11 asymptomatic subjects were studied. Peripheral blood mononuclear cells (PBMCs) were investigated for presence of HTLV-I DNA provirus by PCR using LTR and Tax fragments. Then in infected subjects, HTLV-I proviral load was measured using real time PCR TaqMan method. RESULTS: The average age of patients in ATL was 52+/-8, in HAM/TSP 45.52+/-15.17 and in carrier's 38.65+/ 14.9 years which differences were not statistically significant. The analysis of data showed a significant difference in mean WBC among study groups (ATL vs HAM/TSP and carriers P=0.0001). Moreover, mean HTLV-I proviral load was 11967.2 +/- 5078, 409 +/- 71.3 and 373.6 +/- 143.3 in ATL, HAM/TSP and Healthy Carriers, respectively. The highest HTLV-I proviral load was measured in ATL group that had a significant correlation with WBC count (R=0.495, P=0.001). The proviral load variations between study groups was strongly significant (ATL vs carrier P=0.0001; ATL vs HAM/TSP P= 0.0001 and HAM/TSP vs carriers P< 0.05). Conclusion : The present study demonstrated that HTLV-I proviral load was higher in ATL group in comparison with HAM/TSP and healthy carriers. Therefore, HTLV-I proviral load is a prognostic factor for development of HTLV-I associated diseases and can be used as a monitoring marker for the efficiency of therapeutic regime. PMID- 24470864 TI - Effects of Danazol on Clinical Improvement of Patients with Human T-cell Lymphotropic Virus Type I Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP): A Placebo-Controlled Clinical Trial. AB - OBJECTIVE(S): Human T-Cell Lymphotropic Virus Type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an endemic disease observed in Japan, Africa, Caribbean basin, and north-east Iran. It is usually presented as a chronic and progressive spastic paraparesis. There are some options for treatment of HAM/TSP patients. The aim of this study was to compare the effects of danazol controlled with placebo in relieving the symptoms and signs of HAM/TSP patients. MATERIALS AND METHODS: Among 77 patients with definite diagnosis of HAM/TSP based on clinical and para-clinical findings, 71 patients had the required criteria for entering the study. Severity of symptoms and the degree of motor disability were determined before the beginning of treatment based on motor disability grading (MDG) in both groups of patients and were followed during 6 months in 1 month intervals for changes in symptoms and their motor disabilities. RESULTS: Among 38 patients of the first group, after 6 months therapy with danazol, mean difference between MDG0 (before starting the treatment) and MDG6 (after six months), as an indicator of motor improvement in the patients, was 0.89. Meanwhile, among the 33 patients treated with identical appearing placebo, there was no significant difference between MDG0 and MDG6 (P< 0.001). Moreover, there was a significant difference in improvement of symptoms between two study groups. CONCLUSION: This study showed that danazol provides relative effects on improving motor disabilities and symptoms of HAM/TSP patients that can be considered according to its lower side effects compared to other suggested treatments such as corticosteroids, and its lower costs in particular patients. PMID- 24470860 TI - Human T Lymphotropic Virus Type I (HTLV-I) Oncogenesis: Molecular Aspects of Virus and Host Interactions in Pathogenesis of Adult T cell Leukemia/Lymphoma (ATL). AB - The study of tumor viruses paves the way for understanding the mechanisms of virus pathogenesis, including those involved in establishing infection and dissemination in the host tumor affecting immune-compromised patients. The processes ranging from viral infection to progressing malignancy are slow and usually insufficient for establishment of transformed cells that develop cancer in only a minority of infected subjects. Therefore, viral infection is usually not the only cause of cancer, and further environmental and host factors, may be implicated. HTLV-I, in particular, is considered as an oncovirus cause of lymphoproliferative disease such as adult T cell leukemia/lymphoma (ATL) and disturbs the immune responses which results in HTLV-I associated meylopathy/tropical spastic parapresis (HAM/TSP). HTLV-I infection causes ATL in a small proportion of infected subjects (2-5%) following a prolonged incubation period (15-30 years) despite a strong adaptive immune response against the virus. Overall, these conditions offer a prospect to study the molecular basis of tumorgenicity in mammalian cells. In this review, the oncogencity of HTLV-I is being considered as an oncovirus in context of ATL. PMID- 24470865 TI - Human T Lymphotropic Virus Type I (HTLV-I) is a Risk Factor for Coronary Artery Disease. AB - OBJECTIVE(S): Few studies have shown the association between HTLV-I infection and coronary artery disease (CAD). HTLV-I has been detected in heart autopsies, particularly in lymphoma?leukemia cases. Mashhad and Neyshabour (Razavi Khorasan Province, Iran) are endemic regions for HTLV-I. Therefore, the present study was carried out to evaluate the impact of HTLV-I on CAD in Neyshabourian patients. MATERIALS AND METHODS: 7590 patients admitted to Razavi and Imam Reza Hospitals (2007-2008) were included in this study. The seroprevalance of HTLV-I infection was determined by the ELISA method and confirmed with the PCR method. Statistical analyses were performed using the SPSS software. RESULTS: Out of the 7590 studied subjects, 564 patients were born and had resided in Neyshabour. The HTLV-I sero prevalence among these subjects was 13% (n=73). 294 subjects had an abnormal angiography (CAD) and among them 43 (14.6%) were sero-positive for HTLV-I. In the remaining 227 subjects who had a normal angiography, 30 cases were HTLV-I seropositve. The PCR test was performed on 35 cases in order to confirm the presence of infection, which was positive in 31. Regarding the initial population of 294, the rate of PCR-confirmed infection was 10.54%. Conclusion : This sero prevalence of HTLV-I in subjects with heart complications in Neyshabour was nearly 3 times more than the general population of this city (10.5 % vs 3.4%). However, the results of this study show that in addition to HTLV-I infection, there might be other co-factors leading to the development of heart complications in Neyshabour. PMID- 24470866 TI - Outcome of Intravenous Immunoglobulin-Transmitted HTLV-I, Hepatitis B, Hepatitis C, and HIV infections. AB - OBJECTIVE(S): Since each unit of Intravenous Immunoglobulin (IVIG) is obtained from different blood donors, blood-borne viral diseases is of high importance. We aimed at investigating the prevalence of various viral infections: Human T-cell Lymphotropic Virus Type 1 (HTLV-I), Hepatitis B (HBV), Hepatitis C (HCV), and Human Immunodeficiency Virus (HIV) among patients referred for IVIG therapy section in Mashhad University of Medical Sciences, Mashhad, Iran. MATERIALS AND METHODS: A prospective study was conducted on 130 IVIG recipients admitted to different wards of our Medical Centre: Immunology, Hematology, and Neurology, in 2010. After filling the informed consent form, a 5 cc blood sample was initially taken from each patient. Viral infections including HTLV-I Ab, HIV-Ab, HBsAg, HBc Ab, and HBV-Ab were assessed using the ELISA technique before and after six three months treatment. RESULTS: Test results for HTLV-I Ab, HBsAg, HBc Ab, HIV Ab, and HCV Ab were negative in all cases before IVIG therapy. After receiving IVIG, two female cases with CIDP showed positive results for HBV Ab (0.8%) and HBS Ag (0.8%) with ELISA and only one patient confirmed with PCR. There was not any significant relation between HBV Ag (P=0.14) and HBC Ab with type of disorder (P=0.66). CONCLUSION: This study showed that HTLV-I viral replication and the other investigated viral transmissions do not occur in plasma; therefore, the IVIG products are safe. PMID- 24470867 TI - Population-based Seroprevalence of HTLV-I Infection in Golestan Province, South East of Caspian Sea, Iran. AB - OBJECTIVE(S): Human T-cell lymphotropic virus type-1 is an oncornavirus that causes adult T cell leukemia (ATL) HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Golestan province is located in North West of Khorasan province known as an endemic area for HTLV-I in Iran. This study aimed to evaluate seroprevalence of HTLV-I in Golestan province. MATERIALS AND METHODS: In this cross-sectional descriptive study in 2007, blood samples were collected from 2034 healthy people residing in different parts of Golestan province. Sera were assessed for HTLV-I/II-specific antibodies by ELISA method and reactive samples were confirmed by Western blot. Demographic and serologic data were entered in SPSS version 11.5 and statistical analysis was performed. RESULTS: An overall HTLV-I/II prevalence of 0.7% was observed in 15 cases by ELISA. Six out of 15 were confirmed as HTLV-I by western blot. Regional variation in the prevalence of HTLV-I was observed; 0%, 0%, 0.1%, 1.9%, 0.3%, 0%, and 2.6% tested HTLV-I positive from west to east of Golestan Province regions, respectively. Seropositivity increased with age. No association between HTLV-I infection and sex status was detected. CONCLUSION: Highest rate of HTLV-I seroprevalence was shown in east of this region located in neighborhood with Khorasan province, the only confirmed endemic area in Iran. It seems that eastern area of our province is endemic for HTLV-I. Further comprehensive detailed epidemiological and molecular studies are recommended. PMID- 24470868 TI - No Evidence of HTLV-II Infection Among Immonoblot Indeterminate Samples Using Nested PCR in Mashhad, Northeast of Iran. AB - OBJECTIVE(S): Although HTLV-I infection is endemic in different geographical parts of the world including Northeast of Iran, there have been no documents of HTLV-II infection in this region. It is reported that one possible reason for seroindeterminate state in HTLV western blot is HTLV-II virus. This study aimed to investigate the presence of HTLV-II among blood donors with seroindeterminate western blot results. MATERIALS AND METHODS: Three ml whole blood obtained from 50 blood donors referring to Mashhad Blood Transfusion Organization who had reactive Elisa for HTLV-I and seroindeterminate HTLV western blot state. A conventional PCR was applied to detect HTLV-I provirus using specific primers while a nested PCR was designed with specific external and internal primers for the detection of HTLV-II. RESULTS: The average age of participants, 39 males and 11 females, was 37.12+/- 14.36 years. The average OD of the Elisa assay was 1.767+/- 1.195. The most common indeterminate patterns were Rgp46-II alone (n=12, 27.3%), Rgp46-I alone (n=7, 15.9%), and Rgp46-I with GD21 (n=7, 15.9%).After introducing the DNA to the PCR tests, results revealed 10 (20%) HTLV-I PCR positive samples while no HTLV-II positive sample was detected by nested PCR. There were no significant age, blood group, Optical Density of the Elisa assay, and western blot indeterminate pattern differences between HTLV-I PCR positive and negative samples. Conclusion : No HTLV-II positive sample was detected in this study which confirms the absence of HTLV-II infection in this region. However, high frequency of HTLV-I PCR positive samples among the seroindeterminate cases implies on the important role of molecular techniques for further confirmation of the infection. PMID- 24470870 TI - Evaluation of HTLV-I and HCV Prevalence in Non-Hodgkin's Lymphoma. AB - OBJECTIVE(S): Non-Hodgkin's lymphoma (NHL) is a lymphoproliferative malignancy in which cells undergo microscopic changes with unknown etiology, and risk factors such as age, sex, genetic and environmental factors are involved. The relationship between the presence of infectious agents and the development of lymphoproliferative diseases has been an interesting research topic. HTLV-I (Human T Cell Lymphotropic Virus Type-1) predisposes the infected individulas to opportunistic neoplasms and lymphoid malignancies. HCV (Hepatitis C Virus) the etiologic agent of hepatitis C, is hepatotropic, and long-term infection with HCV can continuously stimulate and expand lymphocyte clones, resulting in further transformation and finally aggressive malignancies. MATERIALS AND METHODS: 54 tissue samples diagnosed with NHL were selected to be studied for the presence of HTLV-I and HCV viruses. DNA and RNA were extracted from samples, cDNA was synthesized and using specific primers presence of HTLV-I and HCV viruses were investigated by PCR and nested RT-PCR methods. RESULTS: In 10 out of 54 (18.8%) samples (7 men and 3 women), HTLV-I was present, and 4 out of 54 (7.4%) samples (3 men and one woman) were positive for HCV. CONCLUSION: Based on our results, it is recommended that in patients with NHL, infection with HTLV-I and HCV viruses need to be screened. PMID- 24470869 TI - The Impact of Immune Response on HTLV-I in HTLV-I-Associated Myelopathy/Tropical Spastic Paraparesis (HAM/TSP). AB - Human T lymphotropic virus type I (HTLV-I) is a retrovirus which is associated with adult T cells leukaemia (ATL) and HTLV-I-associated myelopathy/tropical spastic paraparesis (HAM/TSP) in a minority of HTLV-I-infected individuals. It is not clear why a minority of HTLV-I-infected individuals develop HAM/TSP and majority remains lifelong carriers. It seems that the interaction between the virus and the immune response plays an important role in HTLV-I-associated diseases. Although the role of the immune response in HTLV-I pathogenesis is not fully understood, however it seems that the efficacy of the immune response which is involved in controlling or limiting of viral persistence determines the outcome of HTLV-I-associated diseases. Here we discuss the role of innate and adaptive immune response and also the risk factors contribute to the observed differences between HAM/TSP patients and asymptomatic HTLV-I carriers. PMID- 24470871 TI - Designing a Human T-Lymphotropic Virus Type 1 (HTLV-I) Diagnostic Model using the Complete Blood Count. AB - OBJECTIVE(S): Infection caused by Human T-Lymphotropic Virus Type 1 (HTLV-I) can be observed in some areas of Iran in form of endemic. Most of the cases are asymptomatic, and few cases progress to malignancies and neural diseases. Designing and implementing a model to screen people especially in endemic regions can help timely detection of infected people and improve the prognosis of the disease. MATERIALS AND METHODS: In this study, results of the complete blood count (CBC-diff) for 599 healthy people and the patients with different types of Leukemia and HTLV-I have been examined. Modeling was made using CHAID method. The final model was carried out based on the number of white blood cells (WBC), platelets, and percentages of eosinophils. RESULTS: The accuracy of the final model was 91%. By applying this model to the CBC-diff results of people without symptoms or miscellaneous patients in endemic regions of our country, disease carriers can be identified and referred for supplementary tests. CONCLUSION: With regard to the prevalence of different complications in infected people, these individuals can be identified earlier, leading to the improvement of the prognosis of this disease and the increase of the health status especially in endemic regions. PMID- 24470872 TI - Is there any Association Between Human Lymphotropic Virus Type I (HTLV-I) Infection and Systemic Lupus Erythematosus? An Original Research and Literature Review. AB - OBJECTIVE(S): Systemic lupus erythematosus (SLE) is an autoimmune disease with unknown etiology. Some environmental factors can induce SLE in genetically susceptible individuals; for example, sun exposure and some viral infections may emerge the disease manifestations. Human T lymphotropic virus type 1 (HTLV-I) can dysregulate the human immune system, and the role of this virus in the pathogenesis of autoimmune diseases is under investigation. There are conflicting data about the role of HTLV-I in the pathogenesis of several autoimmune diseases such as SLE. In this study, we have focused on the correlation between HTLV-I infection and SLE in the northeast of Iran, an endemic area for the virus. MATERIALS AND METHODS: One hundred and thirty women with SLE and 915 healthy controls were screened for HTLV-I by enzyme linked immunosorbent assay (ELISA). Western blot method was used for confirmation of the positive results done by ELISA in the patients and the control group. RESULTS: Two (1.5%) of the patients and 23 (2.5%) of the healthy controls were HTLV-I seropositive. There was not a statistical difference between patients and controls in the number of HTLV-I seropositive samples (P=0.49). CONCLUSION: This cross-sectional case-control study did not find any association between HTLV-I and SLE. With regard to the previous studies, these controversies may stem from differences in ethnic background. Geographical and environmental factors should also be taken into account. PMID- 24470873 TI - Association of IL-10 Gene Polymorphisms and Human T Lymphotropic Virus Type I Associated Myelopathy/tropical Spastic Paraparesis in North-East of Iran (Mashhad). AB - The underlying mechanisms leading to the development of human T-cell lymphotropic virus type I (HTLV-I) associated myelopathy/tropical spastic paraparesis (HAM/TSP) in HTLV-I infected individuals are not fully understood. Host genetic factors appear to be involved as risk factors for developing HAM/TSP. We investigated the possible contribution of interleukin-10 (IL-10) as a risk factor to HAM/TSP by comparing frequencies of promoter region single nucleotide polymorphisms in HTLV-I infected Iranian patients who either remained asymptomatic or developed HAM/TSP and asymptomatic HTLV-I carriers. Healthy, uninfected individuals from the same region served as healthy controls. Significant differences were observed in the distribution of IL-10 promoter alleles and genotypes at position -819 and -592 between HAM/TSP patients and healthy controls (P=0.01), and between HTLV-I carriers and healthy controls (P=0.02). The frequency of the low IL-10 producer haplotype (-1082*A, -819*T, 592*A) was significantly associated with HTLV-I carriage or HAM/TSP compared with healthy controls (P=0.02 and 0.01, respectively). Our results suggest that IL-10 819*T and -592*A alleles are significant risk factors for developing HTLLV-I infection but do not appear to convey additional risk for developing HAM/TSP. PMID- 24470874 TI - Association between HLA Class I Alleles and Proviral Load in HTLV-I Associated Myelopathy/Tropical Spastic Paraperesis (HAM/TSP) Patients in Iranian Population. AB - OBJECTIVE(S): The aim of this study was to investigate the association between HLA class I alleles (HLA-A*02, HLA-A*24, HLA-Cw*08, HLA-B5401) and proviral load in HTLV-I associated myelopathy/tropical spastic paraperesis (HAM/TSP) patients in Iranian population. MATERIALS AND METHODS: 20 new cases of HAM/TSP patients and 30 HTLV-I infected healthy carriers were recruited. Peripheral blood samples were collected. Peripheral blood mononuclear cells (PBMCs) were isolated. DNA was extracted from PBMC.HTLV-I proviral load was calculated by Taqman quantitative real time polymerase chain reaction (qRT-PCR). PCR sequence-specific primer (PCR SSP) reactions were performed to detect HLA-A, HLA-B and, HLA-Cw alleles. RESULTS: There was no significant difference in sex and age between asymptomatic and HAM/TSP group. The Mann-Whitney U test was used to compare proviral load between HAM/TSP patients and healthy carrier. Provirus load of HAM/TSP patients was significantly higher than that of HCs (P=0.003, Mann-Whitney U test).Odd ratio was calculated to determine association between class I alleles including (HLA-A*02, HLA-A*24, HLA-Cw*08) and risk of HAM/TSP development. We couldn't find any association between these class I alleles and risk of HAM/TSP development in our study. In our survey HLA-A*02, HLA-A24, HLA-Cw*08 didn't have protective effect on proviral load (P=0.075, P=0.060 and 0.650 Mann-Whitney U test respectively). CONCLUSION: In conclusion, certain HLA alleles with protective effect in one population may have not similar effect in other population. This may be because of pathogen polymorphism or host genetic heterogeneity and allele frequency in desired population. PMID- 24470875 TI - Human T-lymphotropic Virus Type I (HTLV-I) Proviral Load and Clinical Features in Iranian HAM/TSP Patients: Comparison of HTLV-I Proviral Load in HAM/TSP Patients. PMID- 24470876 TI - Cutaneous Manifestations in HTLV-I Positive Blood Donors. AB - OBJECTIVE(S): Infection with the human T-cell lymphotrophic virus type-I (HTLV-I) is endemic in Mashhad, Iran. In our research we evaluated the relation between exposure to this infection and the occurrence of dermatologic manifestations. MATERIALS AND METHODS: 100 blood donors, who were seropositive but asymptomatic for infection with HTLV-I, were selected as case group. They were identified by the Blood Transfusion Organization Mashhad via the ELISA test and documented by PCR. Another 100 blood donors, that were seronegative for HTLV-I via the ELISA test and who were matched to the case group for age, gender, and existence of systemic diseases, were considered as the controls. Dermatologic evaluations and skin biopsies were performed if deemed necessary, and the results were statistically analyzed. RESULTS: 73% of the case and control groups were male, while 27% in each of these groups were female. The mean age in both groups was 40.96+/-11.94 years. The examination indicated that 58% of the case group and 37% of the control group had cutaneous manifestations (P<0.01). The most common diseases found in the case group were aphthous stomatitis, herpes labialis, and non-genital warts, while common diseases found in the control group were herpes labialis, aphthous stomatitis, and skin tag. The frequency of aphthous stomatitis, eczema, and non-genital warts in the case group were significantly more than the control group (P<0.05). Conclusion : Cutaneous diseases can be found more frequent in asymptomatic carriers of HTLV-I than those who are HTLV-I seronegative. The aphthous stomatitis, eczema, and non-genital warts are more prevalent in those infected by HTLV-I. PMID- 24470877 TI - Study of the Association between Human T-cell Lymphotropic Virus Type 1 Infection and Lichen Planus. AB - OBJECTIVE(S): Lichen Planus is a common disease with unknown etiology which affects the skin and mucosa. Recent studies have focused on the possible role of the virus in the pathogenesis of Lichen Planus. The purpose of this study was to determine the association between the human T-cell lymphotropic virus type 1 and Lichen Planus. MATERIALS AND METHODS: This case control study was conducted on a total of 200 patients. The case group consisted of 100 patients with a confirmed histopathological diagnosis of lichen planus disease, and the control group consisted of 100 healthy blood donors without any signs or symptoms of skin diseases, and who were similar in age and sex to the case group. Blood samples of both participants in the case and control groups were examined for the presence of anti -HTLV-I antibodies using the ELISA method. The polymerase chain reaction for human T-cell lymphotropic virus type 1 was conducted in cases in which the findings for antihuman T-cell lymphotropic virus type 1 antibody test was positive, and statistical analysis was conducted on the obtain results. RESULTS: One case in the case group was infected with human T-cell lymphotropic virus type 1; however, no infection was observed in the control group. The difference was not statistically significant (P = 1). CONCLUSION: Based on the obtained results, no association was observed between the human T-cell lymphotropic virus type 1 infection and Lichen Planus. PMID- 24470878 TI - Association Between HTLV-I Infection with Chronic Lupoid Leishmaniasis. AB - OBJECTIVE(S): One of the different types of skin leishmaniasis is the Chronic Lupoid Leishmaniasis (CLL), which is caused by abnormal immune response. On the other hand, HTLV-I has been known to exist in some infectious diseases. Human T cell lymphotropic virus type1 (HTLV-I) and cutanous leishmaniasis exists endemically in Mashhad. The objective of this study was to evaluate the prevalence of HTLV-I in CLL patients. MATERIALS AND METHODS: This cross sectional study involved 51 CLL patients admitted to cutaneous leishmaniasis clinics of Ghaem and Imam Reza hospitals in Mashhad, Iran. The blood samples were examined for serology tests through ELISA method. RESULTS: The results of the experiments for evaluating the existence of HTLV-I in 51 patients under study in this research were proved to be negative. CONCLUSION: According to this pilot study, the distribution of HTLV-I in CLL patients is not higher than normal population. PMID- 24470879 TI - Welcome to Infectious Disease Reports: a message from the Editor. PMID- 24470880 TI - Carpal tunnel syndrome and HIV infection. A case report and literature review. AB - The first clinical case of carpal tunnel syndrome (CTS) in Cuban HIV-infected patient was described, and the scientific literature indexed in: PUBMED/MEDLINE, LILACS and BIREME were revised. The case presented was a male with HIV infection without preceding opportunistic illnesses, CD4(+) T cell count over 200 cells/mm(3) and clinical symptoms of pain, tingling and numbness in the right hand and wrist for three months. The electrophysiological study was compatible with CTS. The pharmacological treatment did not modify the symptoms and the patient received specific surgical treatment with absolute resolution of symptoms. CTS is a compressive neuropathy that can occur in HIV-positive individuals with as similar frequency as in the general population. The association between HIV infection and CTS is scarcely described in the medical scientific literature and probably does not represent a different phenomenon from what happens in the HIV-negative population. Nevertheless, its clinical recognition among other neurological and muscle-skeletal manifestations in HIV infected patients is important. PMID- 24470881 TI - Dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient: the first case report. AB - Dengue infection, a mosquito-borne infectious disease in tropical and subtropical areas, has recently become an emerging global disease. The clinical course of dengue infection may be unfavorable in immunocompromised patients. In this report, we present a 16-year old female patient with acute myeloid leukemia who received allogeneic peripheral blood stem cell transplant five months prior to presentation. She was hospitalized at King Chulalongkorn Memorial Hospital, Bangkok, Thailand, due to fever, headache, and myalgia for one day. During hospitalization, she developed capillary leakage syndrome and progressive thrombocytopenia. A diagnosis of dengue hemorrhagic fever was made and confirmed by positive dengue serology and polymerase chain reaction testing. She made a full recovery 14 days after hospitalization. Our case possibly acquired dengue virus from infected mosquitoes while visiting her relatives four days before her present illness. In conclusion, this is the first reported case of dengue hemorrhagic fever in a peripheral blood stem cell transplant recipient. In addition, we review all previous reports of dengue infection in organ transplant recipients. PMID- 24470882 TI - Repeated Dientamoeba fragilis infections: a case report of two families from Sydney, Australia. AB - We report cases of two unrelated families who both presented with recurrent Dientamoeba fragilis infections. Subsequent antimicrobial therapy resulted in the clearance of D. fragilis and total resolution of gastrointestinal symptoms in both families. This report highlights the potentially recurrent nature of D. fragilis infections and the need for laboratories to routinely test for this organism. PMID- 24470883 TI - Salmonella typhimurium epidural empyema in an HIV-infected patient. AB - Salmonella focal intracranial infections are reported rarely. They tend to occur in immunocompromised patients. We present here a case of Salmonella typhimurium epidural empyema, with osteomyelitis of the adjacent frontal bone, in a 37-year old human immunodeficiency virus positive man who presented with a three-day history of headache, fever, and sweats. He was treated successfully with antibiotics and surgical drainage. PMID- 24470884 TI - In vitro activity of tigecycline against patient isolates collected during phase 3 clinical trials for hospital acquired pneumonia. AB - The in vitro activity of tigecycline was evaluated against 819 baseline pathogens isolated from 383 patients enrolled in the phase 3 clinical trial investigating the efficacy of tigecycline in hospital acquired pneumonia (HAP). The trials were global, enrolling patients in 27 countries. Tigecycline was active against the most prevalent pathogens in HAP, including gram-positive and gram-negative strains (90% of MICs <=2 ug/mL for the entire collection). The spectrum of activity of tigecycline included important pathogens such as Staphylococcus aureus (including methicillin-resistant S. aureus), Enterococcus faecalis, Streptococcus pneumoniae, Acinetobacter baumannii/calcoaceticus complex, Escherichia coli, Klebsiella pneumonia, and Enterobacter cloacae. As reported previously, a few genera, such as Pseudomonas aeruginosa and the Proteeae, were generally less susceptible to tigecycline by comparison to other gram-negative pathogens. The excellent in vitro, expanded, broad-spectrum activity of tigecycline in the clinical isolates confirmed the potential utility of tigecycline for pathogens associated with with hospital acquired pneumonia infections. PMID- 24470885 TI - Ochrobactrum anthropi septic arthritis: case report and implications in orthopedic infections. AB - Ochrobactrum anthropi is a rare cause of orthopedic infections. We report the second case of Ochrobactrum anthropi septic arthritis in the literature. Our case highlights the ability of Ochrobactrum anthropi to cause septic arthritis and its relevance in the field of orthopedic infections. PMID- 24470886 TI - Invasive fungal infections in endogenous Cushing's syndrome. AB - Cushing's syndrome is a condition characterized by elevated cortisol levels that can result from either augmented endogenous production or exogenous administration of corticosteroids. The predisposition to fungal infections among patients with hypercortisolemia has been noted since Cushing's original description of the disease. We describe here a patient with endogenous Cushing's syndrome secondary to an adrenocortical carcinoma, who developed concomitant disseminated cryptococcosis and candidiasis in the course of his disease. PMID- 24470887 TI - Tsukamurella catheter-related bloodstream infection in a pediatric patient with pulmonary hypertension. AB - Catheter-related bloodstream infections (CR-BSI) are important complications in patients with long-term indwelling central venous catheters. In this report, we present the case of a 14-year-old male with pulmonary hypertension treated with continuous treprostinil infusion, who presented with a CR-BSI caused by a Tsukamurella species. This case highlights the potential for this unusual organism to cause infection in immunocompetent patients. PMID- 24470888 TI - A rare case of primary tuberculosis infection with concurrent pleomorphic adenoma of the parotid gland. AB - Coexistence of parotid tuberculosis along with a benign parotid tumor is a rare entity with only nine cases reported in the literature. We report here a case of primary parotid tuberculosis with concurrent pleomorphic adenoma in a 51-year-old female. PMID- 24470889 TI - Mortality in hospitalized older adults associated with Clostridium difficile infection at a district hospital. AB - Clostridium difficile is the most common cause of hospital acquired infectious diarrhea in the developed world and has re-emerged in recent years with apparent greater morbidity and mortality. Despite this, there is little recent published data from the UK concerning associated mortality. We performed a case control study at a UK district general hospital of 66 hospitalized patients over the age of 65 years with C. difficile infection compared to 3-5 controls matched for age, sex and minimum length of stay. We found a significant excess mortality of 11.5% at seven days, 26.2% at 30 days, 38.1% at 90 days and 41.4% at 180 days. C. difficile infection in hospitalized elderly patients may contribute to long-term mortality or be a marker of poor prognosis and cases may require more intensive long-term follow up to improve mortality. PMID- 24470890 TI - Ockham's razor is not so sharp. AB - A 39-year-old male with newly diagnosed HIV had cavitary pneumonia initially attributed to Pneumocystis jirovecii but actually caused by Rhodococcus equi. After neurological deterioration, he was found to have intracerebral lesions caused by Toxoplasma gondii. This case underscores the inability to rely on the search for a unifying diagnosis (Ockham's Razor) in HIV-infected patients. PMID- 24470891 TI - Recurrent cutaneous abscesses in two Italian family members. AB - Environmental mycobacteria are the causative factors of an increasing number of infections worldwide. Cutaneous infections as a result of such mycobacteria are often misdiagnosed, and their treatment is difficult since they can show in vivo and in vitro multidrug resistance. Absence of pathognomonic clinical signs and variable histological findings often delay diagnosis. We report a case of localized recurrent soft tissue swelling by Mycobacterium marinum in 2 members of the same family. The cases are being reported for their uncommon clinical presentation and the associated etiological agent. Patients recovered completely following therapy with rifampicin 600 mg plus isoniazide 300 mg daily for 45 days. PMID- 24470892 TI - Human metapneumovirus and respiratory syncytial virus: subtle differences but comparable severity. AB - Human metapneumovirus (hMPV) is a recently discovered virus that causes respiratory illness in children that can lead to hospitalization. Our study was undertaken to further understand hMPV-associated illness, compare clinical characteristics of hMPV and respiratory syncytial virus (RSV), and establish the utility of routine screening for hMPV. We retrospectively identified hMPV associated illnesses described among children with respiratory symptoms admitted to a tertiary care center in southeast Michigan during the 2006-2007 respiratory viral season. A convenience sample of 256 nasopharyngeal specimens was subjected to nucleic acid extraction and amplification to identify those specimens positive for hMPV. A medical record review was undertaken to retrieve demographic and clinical data of patients with hMPV, comparing them to RSV-positive patients and patients evaluated for respiratory symptoms who were negative for hMPV and RSV. We found that hMPV was the second most commonly identified virus after RSV. hMPV positive patients were older than RSV-positive patients. Among hMPV-positive patients, pneumonia was diagnosed in 37.5% and bronchiolitis in 31.2%, peribronchial cuffing was present on chest radiographs of 37.5%, antibiotic treatment was used in 81.2%, and admission to the ICU was seen in 37.5%. Finally, hMPV-positive patients were more likely to have fever than RSV-positive patients or patients negative for hMPV and RSV. We concluded that hMPV is a major pathogen associated with hospitalization of children and with the same severity of illness as RSV but in a slightly older population. Because of the apparent prevalence and severity of illness, routine screening should be implemented. PMID- 24470893 TI - High HIV prevalence and associated factors in a remote community in the Rwenzori region of Western Uganda. AB - In Uganda, previous studies have shown a tremendous decline in HIV prevalence over the past two decades due to changes in sexual behavior with a greater awareness of the risks involved. However, studies in Fort-Portal municipality, a rural town in Western Uganda, continued to show a persistent high HIV prevalence despite the various interventions in place. We conducted a study to establish the current magnitude of HIV prevalence and the factors associated with HIV prevalence in this community. This cross-sectional study was conducted between July and November 2008. Participants were residents of Fort-Portal municipality aged 15-49 years. A populationbased HIV sero-survey and a clinical review of prevention of mother to child HIV transmission (PMTCT) and voluntary counseling and HIV Testing (VCT) records were used to collect quantitative data. An inteviewer administered structured questionnaire was used to collect qualitative data on social deographics, risk behaviour and community perceptions. Focus group discussions (FGDs) and in-depth interviews provided supplementary data on community perceptions. Logistic regression was used in the analysis. The overall HIV prevalence in the general population was 16.1% [95% CI; 12.5-20.6]. Prevalence was lower among women (14.5%; 95% CI; 10.0-19.7) but not significantly different from that among men (18.7%; 95% CI; 12.5-26.3) (chi(2) =0.76, P=0.38). Having more than 2 sexual partners increased the odds of HIV by almost 2.5 times. None or low education and age over 35 years were independently associated with HIV prevalence (P<0.05). Most participants attributed the high HIV prevalence to promiscuity/multiple sexual partners (32.5%), followed by prostitution (13.6%), alcoholism (10.1%), carelessness (10.1%), poverty (9.7%), ignorance (9.5%)), rape (4.7%), drug abuse (3.6%) and others (malice/malevolence, laziness, etc.) (6.2%). Although there was a slight decline compared to previous reports, the results from this study confirm that HIV prevalence is still high in this community. In order to prevent new infections, the factors mentioned above need to be addressed, and we recommend that education aimed at changing individual behavior should be intensified in this community. PMID- 24470894 TI - Fusarium incarnatum/equiseti hemodialysis graft infection. AB - Hemodialysis graft infections typically occur as a result of contamination by skin flora at the time of insertion or become secondarily infected after high grade bacteremia. Infection of implanted vascular devices with filamentous fungi is rare. We report a case of infection of an implanted polytetrafluoroethylene dialysis graft with Fusarium incarnatum/equiseti that did not grow in cultures of tissue but was identified by molecular means. PMID- 24470895 TI - Rhabdomyolysis after group C streptococcal infection. AB - We describe a young woman with a group C streptococcal throat infection complicated by rhabdomyolysis. Muscle biopsy from quadriceps was normal, and molecular studies showed no evidence of direct microbial invasion. This is only the second case in which the usually benign group C streptococcus has been linked with muscle destruction. PMID- 24470896 TI - The first year of Infectious Disease Reports. PMID- 24470897 TI - An outbreak of epidemic keratoconjunctivitis at an outpatient ophthalmology clinic. AB - Epidemic keratoconjunctivitis (EKC) is an acute eye infection caused by adenovirus. We investigated an outbreak of EKC at an outpatient ophthalmology practice in the context of a suspected community wide increase in EKC activity. A site visit was made to the facility reporting the outbreak. A line list was created of patients clinically diagnosed with EKC at the practice during the previous 5 months. A questionnaire was faxed to all other licensed ophthalmologists in the county regarding recent EKC activity in their facility. Descriptive data analyses were conducted. The outbreak facility reported 37 patients clinically diagnosed with EKC during the previous 5 months. In addition, the single ophthalmologist at the practice also had symptoms compatible with EKC during the outbreak period. Specimens were collected on 4 patients and all were positive for adenovirus serotype 8. Forty percent of ophthalmologists surveyed in the county saw at least one EKC patient in the previous 3 months, and 20% reported a perceived increase in EKC activity in recent months over normal seasonal patterns. The outbreak at the facility likely began as part of a widespread community increase in EKC that may have been amplified at the facility through nosocomial transmission. Medical providers experiencing increases in EKC activity above seasonally expected norms should contact their public health department for assistance with etiologic diagnoses and outbreak control. PMID- 24470899 TI - Is incidental recovery of yeast from enteric pathogen stool cultures obtained from hospitalized patients clinically significant? AB - A matched case-control study was conducted to investigate gastrointestinal colonization with yeast as a predictor of invasive candidiasis (IC) in patients who underwent an enteric pathogen test. No significant association was detected between gastrointestinal colonization and IC. However, gastrointestinal colonization with yeast was associated with increased antimicrobial exposure and median length of hospitalization. PMID- 24470898 TI - Selenium deficiency and HIV infection. AB - Selenium is a non-metallic chemical element of great important to human health. Low selenium levels in humans are associated with several pathological conditions and are a common finding in HIV infected individuals. We conducted a review of the literature to assess if selenium deficiency or selenium supplementation could play a role in modifying the clinical course of HIV disease. Several studies investigated the role of selenium in disease progression, morbidity and mortality in HIV infected individuals. Larger studies were conducted in countries with poor economic resources and limited access to HAART. According to the majority of published studies low selenium levels appear to have an association with mortality, and selenium supplementation appears to play a beneficial role on survival or on slowing disease progression among HIV infected individuals. The role of selenium supplementation on preventing hospital admission among HIV outpatients was also noticed. The literature suggests an association between selenium deficiency and development of HIV associated cardiomyopathy and furthermore, selenium supplementation appears to improve the cardiac function in HIV infected individuals with cardiomyopathy. However, there is conflicting evidence regarding the role selenium in modifying HIV viral load and immune status in HIV infection. PMID- 24470900 TI - Men who have sex with men in China have relatively low numbers of sexual partners. AB - HIV prevalence is increasing rapidly among men who have sex with men (MSM) in China and potentially associated with the number of male sexual partners that each man has on average. This study estimates the distribution of the number of male sexual partners among Chinese MSM through a comprehensive review of English and Chinese published literature. The overall median number of male sexual partners of Chinese MSM in the past 6 months China was estimated to be 1.5 (95% CI, 1.1-1.8) and 3.8 (95% CI 1.5-6.9) sexual partners in the past 6-month and 12 month periods respectively. An estimated 31% of sexual partners of MSM in China are regular partners, 54% are casual partners, and 16% are commercial partners. The reported numbers of sexual partners has not changed over time during the past decade. The numbers of male sexual partners reported by Chinese MSM is consistently lower than other settings and may not be sufficient to explain the recent rapid increase in HIV prevalence. PMID- 24470901 TI - The severe acute respiratory syndrome epidemic in mainland China dissected. AB - This paper provides a review of a recently published series of studies that give a detailed and comprehensive documentation of the severe acute respiratory syndrome (SARS) epidemic in mainland China, which severely struck the country in the spring of 2003. The epidemic spanned a large geographical extent but clustered in two areas: first in Guangdong Province, and about 3 months later in Beijing with its surrounding areas. Reanalysis of all available epidemiological data resulted in a total of 5327 probable cases of SARS, of whom 343 died. The resulting case fatality ratio (CFR) of 6.4% was less than half of that in other SARS-affected countries or areas, and this difference could only partly be explained by younger age of patients and higher number of community acquired infections. Analysis of the impact of interventions demonstrated that strong political commitment and a centrally coordinated response was the most important factor to control SARS in mainland China, whereas the most stringent control measures were all initiated when the epidemic was already dying down. The long term economic consequence of the epidemic was limited, much consumption was merely postponed, but for Beijing irrecoverable losses to the tourist sector were considerable. An important finding from a cohort study was that many former SARS patients currently suffer from avascular osteonecrosis, as a consequence of the treatment with corticosteroids during their infection. The SARS epidemic provided valuable information and lessons relevant in controlling outbreaks of newly emerging infectious diseases, and has led to fundamental reforms of the Chinese health system. In particular, a comprehensive nationwide internet-based disease reporting system was established. PMID- 24470902 TI - Usefulness of the polymerase chain reaction dot-blot assay, used with Ziehl Neelsen staining, for the rapid and convenient diagnosis of pulmonary tuberculosis in human immunodeficiency virus-seropositive and -seronegative individuals. AB - There are scarce data regarding the value of molecular tests, when used in parallel with classical tools, for the diagnosis of tuberculosis (TB) under field conditions, especially in regions with a high burden of TB-human immunodeficiency virus (HIV) co-infection. We evaluated the usefulness of the polymerase chain reaction dot-blot assay (PCR) used in parallel with Ziehl-Neelsen staining (ZN) for pulmonary tuberculosis (PTB) diagnosis, in a TB-HIV reference hospital. All sputum samples from 277 patients were tested by ZN, culture, and PCR. Performances were assessed individually, in parallel, for HIV status, history of anti-TB treatment, and in different simulated TB prevalence rates. Overall, the PTB prevalence was 46% (128/277); in HIV-seropositive (HIV(+)) individuals, PTB prevalence was 54% (40/74); the ZN technique had a lower sensitivity (SE) in the HIV(+) group than in the HIV-seronegative (HIV(-)) group (43% vs. 68%; Fisher test, P<0.05); and the SE of PCR was not affected by HIV status (Fisher test; P=0.46). ZN, in parallel with PCR, presented the following results: i) among all PTB suspects, SE of 90%, specificity (SP) of 84%, likelihood ratio (LR)(+) of 5.65 and LR(-) of 0.12; ii) in HIV(-) subjects: SE of 92%, LR(-) of 0.10; iii) in not previously treated cases: SE of 90%, LR(-) of 0.11; iv) in TB, prevalence rates of 5-20%; negative predictive values (NPV) of 98-99%. ZN used in parallel with PCR showed an improvement in SE, LR(-), and NPV, and may offer a novel approach in ruling out PTB cases, especially in not previously treated HIV(-) individuals, attended in hospitals in developing nations. PMID- 24470903 TI - Trichomonas vaginalis screening and prevention in order to impact the HIV pandemic: Isn't it time we take this infection seriously? AB - Trichomonas vaginalis (TV) is the second most common sexually transmitted infection (STI) in the world. It is associated with significant morbidity in women: pelvic inflammatory disease (PID), concurrent vaginitis and sexually transmitted infections (STIs), post-operative infection, and pregnancy complications. TV infection has been implicated in HIV acquisition and transmission in men and women. There are multiple mechanisms to explain this association. TV is not routinely screened for in asymptomatic patients; however, infected individuals are most often asymptomatic. Due to the association with the spread of HIV infection, screening should not be limited to symptomatic patients or those seeking treatment for STIs. There are a variety of tests available to detect TV. Treatment of TV has demonstrated lower rates of HIV acquisition in at risk women. In HIV positive men and women, treatment decreases the amount of genital HIV shedding and subsequent infectivity. Initiation of an effective TV screening and treatment program in HIV positive and HIV susceptible populations may limit further transmission of HIV. PMID- 24470904 TI - Diagnosis of Clostridium difficile infection: comparison of four methods on specimens collected in Cary-Blair transport medium and tcdB PCR on fresh versus frozen samples. AB - Clostridium difficile infection (CDI) caused by toxigenic strains of C. difficile is primarily a nosocomial infection with increasing prevalence. Stool specimens are typically collected in Cary-Blair transport medium to maximize culture-based detection of common stool pathogens. The goal of this study was to establish an analytically accurate and efficient algorithm for the detection of CDI in our patient population using samples collected in Cary-Blair transport medium. In addition, we wished to determine whether the sensitivity and specificity of PCR was affected by freezing samples before testing. Using 357 specimens, we compared four methods: enzyme immunoassay for the antigen glutamate dehydrogenase (WampoleTM C. DIFF CHEK-60 Assay, GDH), toxin A and B enzyme immunoassay (Remel ProSpecTTM C. difficile Toxin A/B Microplate Assay, Toxin EIA), cell culture cytotoxicity neutralization assay (BartelsTM Cytotoxicity Assay, CT), and real time PCR targeting the toxin B gene (BD GeneOhmTM Cdiff Assay, PCR). The analytic sensitivity and specificity of each as determined using a combined gold standard were as follows: GDH, 100% and 93.2%; Toxin EIA, 82.9% and 82.9%; CT, 100% and 100%; PCR (performed on frozen specimens) 74.3% and 96.6%; respectively. However, the sensitivity and specificity of PCR improved to 100% when performed on 50 fresh stool samples collected in Cary-Blair. While CT remains a sensitive method for the detection of CDI, GDH offers an excellent initial screening method to rule out CDI. While the performance of each assay did not appear to be affected by collection in Cary-Blair medium, PCR performed better using fresh specimens. PMID- 24470905 TI - Gender inequities in sexually transmitted infections: implications for HIV infection and control in Lagos State, Nigeria. AB - Beyond the statistics of sex-based differences in infection rates, there are profound differences in the underlying causes and consequences of HIV infections in male and female which need to be examined. The study therefore examines; the gender differences in the STI knowledge and gender-related potential risks of HIV heterosexual transmission. Quantitative and qualitative data were collected. A multistage random sampling procedure was employed in administration of 1358 questionnaires. For qualitative data, four focus group discussions (FGD) were conducted to collect information from stakeholders within the study population, while In-depth interview was employed to collect information from 188 people living with HIV/AIDS through support groups in the State. The data collected were subjected to basic demographic analytical techniques. Combination of univariate, bivariate, and multivariate analysis were employed. Information from focus group discussions and in-depth interviews were transcribed and organized under broad headings that depict different aspects of the discussions. Majority of the respondents interviewed did not inform their partners about their infection in the study area. It was also discovered that stigmatization did not allow some women to disclose their status to their sexual partners. Some of the HIV-positive patients interviewed agreed that they did not attend the health facilities to treat the STI's before they were finally confirmed positive. The study hypothesis revealed that communication between partners about STI's was associated with an increase in risk reduction behaviour. The paper concluded that there is need for more information and education on communication about STI's between the sexual partners; to reduce the spread of sexually transmitted diseases within the nation. PMID- 24470906 TI - Safety, pharmacokinetics and efficacy of artemisinins in pregnancy. AB - Malaria in pregnancy can lead to serious maternal and fetal morbidity and mortality. Access to the most effective antimalarials in pregnancy is essential. Resistance to current therapies is high for all antimalarial therapies except artemisinins. Artemisinin-based combination therapy is current the first line of malaria treatment recommended by the WHO for children, adults and pregnant women in second or third trimester. Due to potential embryotoxicity of artemisinins identified in animal studies, artemisinins are not considered safe for use in first trimester of pregnancy. Artemisinins are more rapidly metabolized in pregnant women, but it is not clear whether this reduces efficacy. Most studies show very high cure rates for pregnant women. Areas for further research include the safety profile in first trimester of pregnancy, the effect of HIV infection on artemisinin use in pregnancy, the relationship between the pharmacokinetic profile and efficacy, the effect of newly emerging artemisinin resistance on treatment in pregnancy and the use of artemisinin-based combination therapy for intermittent preventive treatment in pregnancy. PMID- 24470907 TI - The first reported case of Bartonella endocarditis in Thailand. AB - Bartonella species have been shown to cause acute, undifferentiated fever in Thailand. A study to identify causes of endocarditis that were blood culture negative using routine methods led to the first reported case in Thailand of Bartonella endocarditis A 57 year-old male with underlying rheumatic heart disease presented with severe congestive heart failure and suspected infective endocarditis. The patient underwent aortic and mitral valve replacement. Routine hospital blood cultures were negative but B. henselae was identified by serology, PCR, immunohistochemistry and specific culture techniques. PMID- 24470909 TI - Invasive aspergillosis in an immunocompetent patient with fever and a cardiac mass. AB - Invasive aspergillosis is an often fatal disease that usually occurs in immunocompromised patients. We report a case of invasive aspergillosis presenting as a febrile respiratory infection with a cardiac mass in an immunocompetent patient. Invasive asper-gillosis should be considered in the differential diagnosis of an otherwise undiagnosed invasive febrile respiratory illness, even in immunocompetent patients. Echocardiography should be performed to evaluate for endocarditis in such cases. Prompt initiation of appropriate antifungal therapy is warranted, even before the diagnosis of invasive aspergillosis is confirmed. PMID- 24470908 TI - Nanoparticles containing siRNA to silence CD4 and CCR5 reduce expression of these receptors and inhibit HIV-1 infection in human female reproductive tract tissue explants. AB - Human Immunodeficiency Virus-type 1 (HIV-1) binds to CD4 and CCR5 receptors on target cells in the human female reproductive tract. We sought to determine whether reducing levels of messenger RNA (mRNA) transcripts that encode these receptors in female reproductive tract cells could protect mucosal tissue explants from HIV-1 infection. Explants prepared from the endometrium, endocervix, and ectocervix of hysterectomy tissues from HIV-1 sero-negative women were exposed to nanoparticles containing CD4- and CCR5-specific short-interfering RNA (siRNA) sequences. Explants were then exposed two days later to HIV-1, and HIV-1 reverse transcripts were measured five days post-infection. Explants treated with nanoparticles containing CD4- and CCR5-specific siRNA showed reduced levels of CD4 and CCR5 transcripts, and significantly lower levels of HIV-1 reverse transcripts compared to those treated with an irrelevant siRNA. In female reproductive tract explants and in peripheral blood cell cultures, siRNA transfection induced the secretion of IFN-alpha (IFN-alpha), a potent antiviral cytokine. In female mice, murine-specific Cd4-siRNA nanoparticles instilled within the uterus significantly reduced murine Cd4 transcripts by day 3. Our findings demonstrate that siRNA nanoparticles reduce expression of HIV-1 infectivity receptors in human female reproductive tract tissues and also inhibit HIV-1 infection. Murine studies demonstrate that nanoparticles can penetrate the reproductive tract tissues in vivo and silence gene expression. The induction of IFN-alpha after siRNA transfection can potentially contribute to the antiviral effect. These findings support the therapeutic development of nanoparticles to deliver siRNA molecules to silence host cell receptors in the female reproductive tract as a novel microbicide to inhibit mucosal HIV-1 transmission. PMID- 24470910 TI - Hyper-reactive malarial splenomegaly and splenic infarct in a caucasian toddler. AB - A 4-year-old boy from the United States had been staying in Indonesia for five months when he presented with fever, severe lethargy, progressive weight loss, and abdominal distension. He was first diagnosed with Plasmodium vivax infection in Indonesia and received treatment with chloroquine. However, his condition continued to deteriorate and he required erythrocyte transfusion for severe anemia. Three weeks into his illness, he was found to have low parasitemia with Plasmodium falciparum with massive hepatosplenomegaly in Singapore. A splenic infarct was also documented on computed tomography. Treatment with atovaquone proguanil resulted in stabilization of the hemoglobin level and rapid reduction in splenic size, with clearance of malarial parasites from the bloodstream. Although reported typically in adult tropical residents, hyper-reactive malarial splenomegaly may occasionally be found in the pediatric traveler. Clinicians receiving children returning from the tropical regions should be aware of this potentially life-threatening complication of partially treated malaria. PMID- 24470911 TI - Bosentan and sildenafil in the treatment of HIV-associated pulmonary hypertension. AB - We present the case of an HIV/HCV-coinfected patient with HIV-related pulmonary hypertension (HRPH) who experienced a good clinical and functional response to bosentan, with a subsequent switch to oral sildenafil due to increased transaminase levels. Bosentan resulted less handy in this case, probably due to both side effects and co-morbidities. PMID- 24470912 TI - Cat-scratch disease in Crete: an update. AB - There are few epidemiological and clinical studies about the presence of cat scratch disease (CSD) on the island of Crete. The objective of this study was to analyze a large number of patients with suspected CSD to define the frequency of Bartonella infections in Crete. From January 2005 to October 2008, we studied patients with suspected CSD from hospitals in Crete. Sera of the referred patients were tested by immunofluorescence assay (IFA). For some patients, we also received lymph nodes and blood samples that we tested for the presence of Bartonella henselae by molecular assays. Overall, we tested 507 serum samples and we found 56 (11%) cases of CSD. PCR assay was positive for 2 patients; one had a B. henselae positive lymph node and the other a positive whole blood sample. Significantly more CSD cases (62.5%, 35 of 56) were reported in children than in infants and adults (P<0.05). Moreover, we identified that most cases of CSD occurred between May and September (P=0.002) and December and January. CSD is prevalent in Crete and is mostly associated with an increase in outdoor activity. PMID- 24470913 TI - Prevalence of Dihydrofolate reductase gene mutations in Plasmodium falciparum isolate from pregnant women in Nigeria. AB - We assessed the prevalence of Plasmodium falciparum and the frequency of the dhfr triple mutation that is associated with antifolate drug resistance among P. falciparum isolates obtained from pregnant women in Ilorin, Nigeria. The study included 179 women in the second and third trimester of pregnancy who have been exposed to intermittent preventive treatment in pregnancy (IPTp) with sulfadoxine pyrimethamine. Thick and thin blood films and PCR were used for malaria parasite detection. Blood group and hemoglobin concentration were also determined. Mutations in P. falciparum dhfr were analyzed by sequencing DNA obtained from blood spots on filter paper. Prevalence of P. falciparum in the population (PCR corrected) was 44.1% (79/179) with 66.7% and 33.3% in the second and third trimester, respectively. Primigravide (51.3%) were more infected than multigravide (48.7%) but the difference was not statistically significant. Women in blood group A had the highest P. falciparum malaria infection (30.8%). The mean hemoglobin concentration was lower among those infected with malaria parasite. Also, more women with the malaria parasite (38.4%) had anemia compare to those without (21.4%). The prevalence of the P. falciparum dhfr mutant alleles was 64.1%, 61.5%, 38.5%, and 12.8% for I51, R59, N108 and T108, respectively. None of the samples had the L164 mutation. The combined triple dhfr mutation (51 + 59 + 108) in the population was 17.9% (7 of 39). Also, the prevalence of the triple mutant alleles was not significantly associated to the number of doses of SP taken by the women. These findings highlight the need for a regular assessment of IPTp/SP efficacy, and evaluation of possible alternative drugs. PMID- 24470914 TI - Infection with cytomegalovirus is not associated with premature mortality. AB - Over 90% of the world's population acquires a cytomegalovirus (CMV) infection. This infection, although asymptomatic or self-limiting, is a major burden to the immune system. For this reason, and because CMV immunization is possible, determining whether CMV can cause reduced longevity, particularly among those with coronary artery disease, is important and previous reports have been conflicting. Thus our objective was to assess the association between CMV infection as defined serologically and antibody levels against CMV and long-term survival (18 years). We completed a prospective observational cohort study of 915 consecutive patients (mean age 58 years) undergoing coronary angiography. CMV immunoglobulin levels were measured at baseline using either a whole cell CMV antigen or a purified protein antigen (gB). After adjustment for potentially confounding variables (age, race, gender, body mass index, the presence or absence of coronary artery disease, the number of diseased vessels, diabetes, renal disease, hypertension, dialysis, congestive heart failure, and the maximum percent reduction in luminal diameter), Cox's proportional hazards models showed no association between CMV seropositivity or levels of antibodies against CMV by either assay and longevity for both patients with or without coronary artery disease (CAD) nor for those under or over 70 years of age at baseline. Our observations suggest that universal immunization against CMV may not improve longevity. PMID- 24470915 TI - Pseudomonas pelvic osteomyelitis in a healthy child. AB - Pediatric pelvic osteomyelitis is a rare entity. The diagnosis is frequently delayed due to difficulty in confirming the diagnosis. To our knowledge, this is the first case report of Pseudomonas pelvic osteomyelitis in a previously healthy adolescent boy. The diagnosis was made radiographically and confirmed by culture. The patient was treated with Levofloxacin and Gentamicin resulting in a complete recovery. PMID- 24470916 TI - Concomitant cat scratch disease and squamous cell carcinoma in a cardiac transplant. AB - Cat scratch disease has been reported very rarely in cardiac transplant recipients. In a review of 1073 episodes of infection in 620 heart transplant patients over a 16 year period, only one case of infection secondary to Bartonella henselae was documented. Another case of hepatosplenic bacillary angiomatosis from B. henselae was reported 2 decades ago in a heart transplant recipient who had presented with fevers of unknown origin. Although the typical clinical manifestation is that of a skin lesion accompanied with lymphadenopathy, cat scratch disease may present with persistent fevers without a clinically overt infective focus in immunosuppressed individuals. Moreover, more than one disease process may coexist in immunocompromised hosts. While the lymphadenopathy in our patient was secondary to Cat scratch disease, interestingly, the adjacent skin lesion that was thought to represent unhealed site of inoculation of Bartonella was diagnosed as squamous cell carcinoma. PMID- 24470917 TI - Chest X-rays and associated clinical parameters in pulmonary tuberculosis cases from the National Tuberculosis Programme, Mumbai. AB - The study was carried out in pulmonary tuberculosis (PTB) patients from the local Tuberculosis control programme, Mumbai, India. It examined features of chest X rays and their correlation with clinical parameters for possible application in suspected multidrug resistant TB (MDRTB) and to predict outcome in new and treatment failure PTB cases. X-ray features (infiltrate, cavitation, miliary shadows, pleural effusion, mediastinal lymphadenopathy and extent of lesions) were analyzed to identify associations with biological/clinical parameters through univariate and multivariate logistic regression. Failures demonstrated associations between extensive lesions and high glycosylated hemoglobin (GHb) levels (P=0.028) and male gender (P=0.03). An association was also detected between cavitation and MDR (P=0.048). In new cases, bilateral cavities were associated with MDR (P=0.018) and male gender (P=0.01), low body mass index with infiltrates (P=0.008), and smoking with cavitation (P=0.0238). Strains belonging to the Manu1 spoligotype were associated with mild lesions (P=0.002). Poor outcome showed borderline significance with extensive lesions at onset (P=0.053). Furthermore, amongst new cases, smoking, the Central Asian Strain (CAS) spoligotype and high GHb were associated with cavitation, whereas only CAS spoligotypes and high GHb were associated with extensive lesions. The study highlighted associations between certain clinical parameters and X-ray evidence which support the potential of X-rays to predict TB, MDRTB and poor outcome. The use of X-rays as an additional tool to shorten diagnostic delay and shortlist MDR suspects amongst nonresponders to TB treatment should be explored in a setting with limited resources coping with a high MDR case load such as Mumbai. PMID- 24470918 TI - Cutaneous leukocytoclastic vasculitis associated with levofloxacin therapy. AB - Many cases of cutaneous vasculitis are drug-induced with histology revealing leukocytoclastic vasculitis (LCV). We present a case of levofloxacin-associated LCV successfully treated with prednisone and cessation of the offending drug. Although case reports describe a link between LCV and older fluoroquinolones, such as ciprofloxacin and ofloxacin, recent reports have implicated the newer fluoroquinolone levofloxacin. Recognition of fluoroquinolone-induced cutaneous vasculitis is important as continuation or re-exposure of the offending agent may have life-threatening consequences. PMID- 24470920 TI - In vitro anti-mycobacterial activity of (E)-N'-(monosubstituted-benzylidene) isonicotinohydrazide derivatives against isoniazid-resistant strains. AB - A series of twenty-three N-acylhydrazones derived from isoniazid (INH 1-23) have been evaluated for their in vitro antibacterial activity against INH- susceptible strain of M. tuberculosis (RG500) and three INH-resistant clinical isolates (RG102, RG103 and RG113). In general, derivatives 4, 14, 15 and 16 (MIC=1.92, 1.96, 1.96 and 1.86 uM, respectively) showed relevant activities against RG500 strain, while the derivative 13 (MIC=0.98 uM) was more active than INH (MIC=1.14 uM). However, these derivatives were inactive against RGH102, which displays a mutation in the coding region of inhA. These results suggest that the activities of these compounds depend on the inhibition of this enzyme. However, the possibility of other mechanisms of action cannot be excluded, since compounds 2, 4, 6, 7, 12-17, 19, 21 and 23 showed good activities against katG-resistant strain RGH103, being more than 10-fold more active than INH. PMID- 24470921 TI - A case of Aggregatibacter actinomycetemcomitans endocarditis presenting as quadriceps myositis. AB - An 80 year old female was admitted with an eight week history of fever associated with painful swelling of her right thigh, and a long history of poor dentition. Culture of blood stained fluid aspirated from the abscess grew Aggregatibacter actinomycetemcomitans (Aa) sensitive to ampicillin and cephalosporins. Transoesophageal echocardiography indicated endocarditis. Four weeks treatment with intravenous ceftriaxone and appropriate dental care was followed by full recovery. PMID- 24470922 TI - Malignant syphilis as the first manifestation of HIV infection. AB - Malignant syphilis is a rare and severe variant of secondary syphilis. It is clinically characterized by large papular, nodular and ulcerative lesions affecting the trunk and the extremities and covered with thick crust. We present a case of 52-year-old homosexual male who developed malignant syphilis and this was the first clinical manifestation of HIV infection. The patient was treated successfully with intravenous aqueous crystalline penicillin G. Physicians should recognize malignant syphilis and consider it in all HIV-infected individuals with ulceronodular skin lesions. PMID- 24470923 TI - Streptococcus dysgalactiae endocarditis presenting as acute endophthalmitis. AB - Endogenous endophthalmitis is a rare ocular infection affecting the vitreous and/or aqueous humours. It is associated with poor visual prognosis and its commonest endogenous aetiology is infective endocarditis. The causative organisms of endogenous endophthalmitis complicating endocarditis are mainly Group A or B streptococci. The identification of Group C and G streptococci such as Streptococcus dysgalactiae is comparatively uncommon and has only been reported in a few case reports or series. We therefore report a case of infective endocarditis caused by Streptococcus dysgalactiae first presenting with endogenous endophthalmitis, the most likely source being osteomyelitis of both feet in a patient with type I diabetes. The patient was treated with a course of intravenous benzylpenicillin, intravitreal antibiotics, bilateral below knee amputations and mitral valve replacement. She survived all surgical procedures and regained partial visual acuity in the affected eye. PMID- 24470919 TI - Gianotti-Crosti syndrome, pityriasis rosea, asymmetrical periflexural exanthem, unilateral mediothoracic exanthem, eruptive pseudoangiomatosis, and papular purpuric gloves and socks syndrome: a brief review and arguments for diagnostic criteria. AB - Several exanthems including Gianotti-Crosti syndrome, pityriasis rosea, asymmetrical periflexural exanthem, eruptive pseudoangiomatosis, and papular purpuric gloves and socks syndrome are suspected to be caused by viruses. These viruses are potentially dangerous. Gianotti-Crosti syndrome is related to hepatitis B virus infection which is the commonest cause of hepatocellular carcinoma, and Epstein-Barr virus infection which is related to nasopharyngeal carcinoma. Pityriasis rosea has been suspected to be related to human herpesvirus 7 and 8 infections, with the significance of the former still largely unknown, and the latter being a known cause of Kaposi's sarcoma. Papular-purpuric gloves and socks syndrome is significantly associated with human B19 erythrovirus infection which can lead to aplastic anemia in individuals with congenital hemoglobinopathies, and when transmitted to pregnant women, can cause spontaneous abortions and congenital anomalies. With viral DNA sequence detection technologies, false positive results are common. We can no longer apply Koch's postulates to establish cause-effect relationships. Biological properties of some viruses including lifelong latent infection, asymptomatic shedding, and endogenous reactivation render virological results on various body tissues difficult to interpret. We might not be able to confirm or refute viral causes for these rashes in the near future. Owing to the relatively small number of patients, virological and epidemiology studies, and treatment trials usually recruit few study and control subjects. This leads to low statistical powers and thus results have little clinical significance. Moreover, studies with few patients are less likely to be accepted by mainstream dermatology journals, leading to publication bias. Aggregation of data by meta-analyses on many studies each with a small number of patients can theoretically elevate the power of the results. Techniques are also in place to compensate for publication bias. However, these are not currently feasible owing to different inclusion and exclusion criteria in clinical studies and treatment trials. The diagnoses of these rashes are based on clinical assessment. Investigations only serve to exclude important differential diagnoses. A wide spectrum of clinical features is seen, and clinical features can vary across different populations. The terminologies used to define these rashes are confusing, and even more so are the atypical forms and variants. Previously reported virological and epidemiological results for these rashes are conflicting in many aspects. The cause of such incongruence is unknown, but low homogeneity during diagnosis and subject recruitment might be one of the factors leading to these incongruent results. The establishment and proper validation of diagnostic criteria will facilitate clinical diagnosis, hasten recruitment into clinical studies, and allow results of different studies to be directly compared with each another. Meta-analyses and systematic reviews would be more valid. Diagnostic criteria also streamline clinical audits and surveillance of these diseases from community perspectives. However, over-dependence on diagnostic criteria in the face of conflicting clinical features is a potential pitfall. Clinical acumen and the experience of the clinicians cannot be replaced by diagnostic criteria. Diagnostic criteria should be validated and re-validated in response to the ever-changing manifestations of these intriguing rashes. We advocate the establishment and validation of diagnostic criteria of these rashes. We also encourage the ongoing conduction of studies with a small number of patients. However, for a wider purpose, these studies should recruit homogenous patient groups with a view towards future data aggregation. PMID- 24470924 TI - Rubella antibody screening during pregnancy in an urban area of Northern Italy. AB - Various countries have implemented anti-rubella vaccination campaigns with the main aim of preventing congenital infection. In 2003, Italy joined the European WHO programme for the elimination of congenital rubella and issued a special healthcare plan, one of the objectives of which was to reduce the proportion of rubella-susceptible pregnant women to less than 5% by 2005. The aim of this study was to determine the percentage of seronegative pregnant women after the implementation of this plan. Anti-rubella IgG and IgM antibodies were sought in 2385 pregnant women who attended our hospital for serological screening between 1 July 2008 and 30 June 2010. They included 750 women of foreign origin (31.4%). Eight percent of the women were anti-rubella seronegative: 6.2% of the Italians and 11.7% of the non-Italians. Among the women of foreign origin, the percentage of seronegativity ranged from 5.6% of those coming from Eastern Europe to 17.7% of those coming from Latin America. The level of seropositivity among women of Italian origin is high, although the objective of ensuring less than 5% of susceptible pregnant women has not yet been quite reached in our area. However, particular attention needs to be given to women coming from geographical areas characterised by different epidemiologies and vaccination strategies because the percentage of seronegativity is in some cases double that of Italian women. PMID- 24470925 TI - Pediatric pyogenic sacroiliitis and osteomyelitis. AB - Pyogenic sacroiliitis accounts for 1-2% of all cases of septic arthritis with less than 200 cases reported in the English literature since the beginning of the twentieth century. Cultures of joint fluid usually grow Staphylococcus aureus. Prognosis is excellent; however, diagnosis may be difficult due to rarity of disease and non-specific signs, symptoms, and physical findings. Magnetic resonance imaging has been found to be the most useful imaging modality in diagnosis. Most reported cases required prolonged antimicrobial therapy of six to nine weeks. Presented here are two children with pyogenic sacroiliitis managed at a tertiary-care, university hospital and review of the literature on this relatively rare diagnosis. PMID- 24470926 TI - Gender differences, routes of transmission, socio-demographic characteristics and prevalence of HIV related infections of adults and children in an HIV cohort from a rural district of India. AB - Despite 67% of HIV infected people in India are rural residents, the epidemiology of HIV in rural areas is not well known. This is an observational cohort study of 11,040 HIV infected people living in a rural district of India. The prevalence of hepatitis B, hepatitis C and syphilis of HIV infected patients were compared to the seroprevalence in 16,641 blood donors from the same area. The age of diagnosis in adults was below 35 years in 70% of cases and 56% were illiterate. One third of women were widows and only 3.6% of adults had a permanent job. Women were diagnosed at earlier age, had lower level of education, had poorer employment conditions and depended more on their relatives than men. In a survey performed to a subgroup of patients, 81% of women referred to have acquired HIV from their spouse, whereas 51% of men acquired HIV from commercial sex. Patients with HIV had significantly higher prevalence of hepatitis B, hepatitis C and syphilis than blood donors. Seroprevalence of HIV-2, hepatitis C and toxoplasmosis were low compared to other sites. Six percent were children (<15 years) and almost half of them had lost one or both of their parents. The study shows the poor socio-economical situation and the high level of illiteracy of people living with HIV in rural India, especially women. Future health programmes of HIV in India should take into account the particularities of the HIV epidemic in rural areas. PMID- 24470927 TI - Screening and detection of heterogenous vancomycin intermediate Staphylococcus aureus in Hospital Kuala Lumpur Malaysia, using the glycopeptide resistance detection Etest and population analysis profiling. AB - In a 3-month study done in Hospital Kuala Lumpur (HKL), 7 out of 320 methicillin resistant Staphylococcus aureus isolates were confirmed as heterogeneous vancomycin intermediate S. aureus (hVISA) using the glycopeptide resistance detection e-test and population analysis, giving a prevalence rate of 2.19%. This is the first report of hVISA in Malaysia. PMID- 24470928 TI - Hyperbaric oxygen treatment in three cases of necrotizing infection of the neck. AB - Necrotizing infections of the head and neck are rare conditions in our hospital. Clinical and microbiological characteristics of three consecutive cases treated in Haukeland University Hospital in western Norway in the year 2010 are described. Two cases of Lemierre's syndrome and one case with a descending necrotizing mediastinitis (DNM) were diagnosed. All three cases were treated with broad spectrum antibiotics and in two cases surgery was possible. Hyperbaric oxygen treatment (HBOT) with intensive care facilities became recently available at our hospital, and this treatment was used in all these patients regardless of surgery. In one case we describe the use of HBOT on the basis of strong clinical suspicion of anaerobic infection only. Bacterial identification by partial sequencing of the 16SrDNA gene proved to be a useful supplement to conventional culture techniques. All the cases all demonstrated a significant clinical improvement after introduction of HBOT. When HBOT is available, it should be considered as adjunctive treatment in extensive infections with anaerobes. PMID- 24470929 TI - Small-volume hypertonic saline/pentastarch improves ileal mucosal microcirculation in experimental peritonitis. AB - We compared the effects of hypertonic saline 7.2%/6% hydroxyethyl starch (HSS HES) and isotonic saline 0.9%/6% hydroxyethyl starch (ISS-HES) on ileal microcirculatory blood flow (MBF) at the initial phase of septic shock. Pigs were anesthetized and mechanically ventilated. Catheters were inserted into right atrium, pulmonary artery, carotid artery, and portal vein for hemodynamic measurements and for blood sampling. Ileal mucosal and muscularis MBF was continuously measured by laser Doppler flowmetry (LDF). Septic shock was obtained 240 min after induction of fecal peritonitis; then animals were randomized to receive 10 mL.kg(-1) during 10 min of either HSS-HES or ISS-HES. Systemic and microcirculatory blood flow as well as systemic metabolism were assessed. Fecal peritonitis promoted a hypodynamic septic shock, with significant reduction of mean arterial pressure (MAP) and cardiac index (CI). Ileal mucosal MBF (-34%) and ileal muscularis MBF (-54%) significantly diminished from baseline. Contrary to ISS-HES group, mucosal MBF significantly augmented after HSS-HES (+192% at min 150 post-shock) despite low blood pressure. There was weak correlation with CI (r(2)= 0.2, P=0.01) . Muscularis MBF didn't change. HSS-HES-treated animals had a significantly higher osmolarity and sodium concentration than ISS-HES group. Other variables did not change. Small-volume resuscitation with HSS-HES, but not ISS-HES, improved ileal microcirculatory impairment in experimental peritonitis model of septic shock even when MAP was low. This beneficial microcirculatory effect could be valuable in the management of early severe sepsis. PMID- 24470930 TI - A novel influenza A (H1N1) outbreak experience among residents of a long term care facility in Saudi Arabia during 2010 seasonal flu circulation. AB - The aim of this work was to describe and analyze an outbreak of novel 2009 influenza A (H1N1) among residents of a long-term care facility (LTCF) in Prince Mansour Military Hospital (PMMH), Taif, Saudi Arabia. These patients had been admitted to the LTCF months or years before the outbreak for several reasons, e.g. cerebral palsy, neurological deficits due to road traffic accidents with resultant handicap, chronic diseases associated with old age. An observational study was carried out to demonstrate and analyze the epidemiological characteristics (demographic factors, risk factors, and outcomes) associated with the outbreak in order to clarify which prevention and control measures had been taken and which recommendations were followed. During the period October 28 to November 11 2010, 21 LTCF residents were suspected to be clinically involved: fever >=38 degrees C with influenza-like illness (ILI). Age ranged from 9-91 years (mean 46+/-24.13); 62% were males. Among them, 12 (57%) were influenza A (H1N1) positive by reverse transcription polymerase chain reaction (RT-PCR). Mortality involved 2 (17%) of the A (H1N1) laboratory confirmed individuals. Implementation of the recommended infection control measures mitigated the transmission of infection to new individuals. The fulfillment of strict infection control measures could limit H1N1 infection among LTCF-PMMH patients. Routine influenza, including specific H1N1 immunization of all LTCF residents together with their healthcare staff, should be mandatory in those settings serving immunocompromised patients. PMID- 24470931 TI - A cavitary pneumonia caused by leptotrichia species in an immunocompetent patient. AB - Leptotrichia species (LS) is an anaerobic Gram negative bacillus in the Bacteroidaceae family and part of the normal human oral flora. It is rarely pathogenic, but occasionally causes diseases in immunocompromised hosts. I am reporting a case of cavitary pneumonia caused by LS in an immunocompetent host. PMID- 24470933 TI - A rare case of acute epiglottitis due to Staphylococcus aureus in an adult. AB - Epiglottitis has been mainly associated with childhood infection with Haemophilis influenzae type B but cases of adult epiglottitis are increasing. We report here a case of adult epiglottitis and present evidence that it was caused by Staphylococcus aureus. A 48-year old patient with clinical symptoms of epiglottitis grew Staphylococcus aureus in pure culture from an epiglottal swab. Staphylococcus aureus should be considered as a potential pathogen in adult epiglottitis. PMID- 24470932 TI - Human immunodeficiency virus and its effects on the visual system. AB - During the first 15 years of the AIDS epidemic patients experienced a high incidence of blindness due to cytomegalovirus (CMV) retinitis and other severe ocular opportunistic infections. Highly active anti-retroviral therapy, introduced in 1996, dramatically decreased the incidence of CMV retinitis. Though CMV retinitis still causes 40% of vision loss in AIDS patients, other conditions such as immune reconstitution uveitis, cataracts, and a significant othercategory -which most investigators believe is directly due to HIV - comprise the majority of cases. HIV causes vascular abnormalities of the conjunctiva and retina in the majority of AIDS patients, as well as retinitis, anterior and posterior uveitis and vasculitis. HIV frequently causes an optic neuropathy and is responsible for the majority of eye movement disorders among HIV patients. Physicians need to be aware that these problems may be the initial manifestation of HIV infections or a sign of highly active anti-retroviral therapy (HAART) failure. Therefore, patients with identifiable risk factors for AIDS who present with ophthalmologic conditions of unknown etiology should be considered for HIV testing. Finally, anti-retroviral therapy has been reported to cause asymptomatic deposits as well as degenerative conditions of both the anterior and posterior segments of the eye. PMID- 24470934 TI - Splenic abscess due to Salmonella enteritidis. AB - Splenic abscess is a very rare complication of non-typhoidal Salmonella infections. We report a case of splenic abscess caused by Salmonella enteritidis. The patient is a 63-year-old woman with diabetes mellitus and underwent splenectomy. This case suggests that the patients with comorbities are at increased risk for invasive infections in non-typhoidal Salmonella infections. PMID- 24470935 TI - No clinical or biological difference between Chikungunya and Dengue Fever during the 2010 Gabonese outbreak. AB - Chikungunya (CHIKV) and Dengue (DENV) viruses, both arboviruses, have caused multiple outbreaks worldwide. Their clinical features are poorly described in Africa and there is no comparative study, although Chikungunya is considered as a dengue-like disease. We conducted a comparative study of clinical and biological data from CHIKV and DENV positive patients during the 2010 Gabonese outbreak. Patients consulting with general symptoms and having laboratory confirmation for CHIKV or DENV were included. Clinical and biological data were recorded. Statistical analyses were performed using Epi Info. A P value < 0.05 was considered significant. In all, 270 CHIKV+, 53 DENV+ and 20 co-infected patients were included in the study. Headaches, hemorrhage, leukopenia and lymphopenia were significantly (P respectively 0.01, 0.001, 0.02 and 0.001) more frequent in DENV+ patients than in CHIKV+. There was no additive effect of the two viruses.These clinical and hematological disorders are non specific and cannot assist for the differential diagnosis. These diseases are clinically indistinguishable, and need for laboratory confirmation. PMID- 24470936 TI - False negative HIV antibody test in HIV infected children who receive early antiretroviral treatment in a resource-limited setting. AB - With the implementation of 2010 World Health Organization guidelines, the number of infants from developing countries who will initiate antiretroviral therapy (ART) will increase considerably. In this study we describe the HIV antibody tests of 14 HIV infected children who initiated ART at age less than one year in a rural setting of India. The HIV rapid test was negative in seven and indeterminate in two cases, whereas the HIV enzyme-linked immunosorbent assay (ELISA) antibody test was negative in three and indeterminate in one case. In one child who had both negative HIV rapid test and ELISA initially, HIV serology turned positive after having a virological failure to ART, suggesting the possibility of utilizing HIV serology for monitoring ART effectiveness in children who experience HIV seroreversion. In conclusion, HIV seroreversion of children with early initiation of ART is common and should be considered for avoiding misdiagnosis of HIV infection. PMID- 24470937 TI - The first reported cases of Q fever endocarditis in Thailand. AB - We describe the first two reported cases of Q fever endocarditis in Thailand. Both patients were male, had pre-existing heart valve damage and had contact with cattle. Heightened awareness of Q fever could improve diagnosis and case management and stimulate efforts to identify risk factors and preventive measures. PMID- 24470938 TI - Opportunistic infections in a renal transplant recipient. AB - With the present progress in transplantation procedures, there is an improvement in patient and allograft survival. However, the immunosuppression necessary to sustain the allograft predisposes these transplant recipients to infection, which is now a significant cause of morbidity and mortality. We describe a case of a 30 year-old renal transplant recipient with two opportunistic infections, namely, primary cutaneous aspergillosis and intestinal tuberculosis, with terminal enterococcal pleuritis and peritonitis. Control of the degree of immunosuppression, and prompt recognition and treatment of infection are vital for successful organ transplantation. PMID- 24470939 TI - Diagnosis and treatment of HIV-associated manifestations in otolaryngology. AB - Almost 30 years after its first description, HIV still remains a global pandemic. The present paper aims to review the current knowledge on the ear, nose and throat (ENT) manifestations of HIV infection, and present the available diagnostic and treatment options. A literature review was conducted in Medline and other available database sources. Information from related books was also included in the data analysis. It is well acknowledged that up to 80% of HIV infected patients eventually develop ENT manifestations; among which, oral disease appears to be the most common. Oro-pharyngeal manifestations include candidiasis, periodontal and gingival disease, HSV and HPV infection, oral hairy leucoplakia, Kaposi's sarcoma, and non-Hodgkin's lymphoma. ENT manifestations in the neck can present as cervical lymphadenopathy or parotid gland enlargement. Respective nasal manifestations include sinusitis (often due to atypical bacteria), and allergic rhinitis. Finally, otological manifestations include otitis (externa, or media), inner ear involvement (sensorineural hearing loss, disequilibrium), and facial nerve palsy (up to 100 times more frequently compared to the general population). Although ENT symptoms are not diagnostic of the disease, they might be suggestive of HIV infection, or related to its progression and the respective treatment failure. ENT doctors should be aware of the ENT manifestations associated with HIV disease, and the respective diagnosis and treatment. A multi-disciplinary approach may be required to provide the appropriate level of care to HIV patients. PMID- 24470940 TI - Risk factors for tuberculosis in contact investigations in Rotterdam, the Netherlands. AB - Contact investigations around tuberculosis patients enable early detection of infection and disease, and prevention of secondary tuberculosis cases. We aim to identify risk factors for M. tuberculosis transmission to contacts of tuberculosis patients, based on unique data from routine contact investigations by the Public Health Service in Rotterdam, the Netherlands, collected between 2001 and 2006. Through logistic regression analysis, we determined the effect of various risk factors on the chance of finding a latent tuberculosis (TB) infection or overt tuberculosis case among contacts. A total of 1165 index patients with active tuberculosis were registered and at least one contact was investigated in 731, resulting in 21,540 contacts overall. Altogether, the contact investigations led to 91 cases of active tuberculosis. Of the 12,698 contacts eligible for screening by tuberculin skin test, 1091 (9%) were diagnosed with latent tuberculosis infections. Risk factors were old age of the contact, old age of the index patient, and the relationship to the index. A larger fraction of infected close contacts was strongly associated with infections among more distant contacts. Our findings emphasize the importance of including these personal and interpersonal risk factors in decision making in contact investigations. PMID- 24470941 TI - Susceptibility to Entamoeba histolytica intestinal infection is related to reduction in natural killer T-lymphocytes in C57BL/6 mice. AB - Entamoeba histolytica is a protozoan that causes amoebiasis. Recent studies demonstrated that natural killer T lymphocytes (NKT) are critical for preventing the development of amoebic liver abscess. In spite of that, there are only a handful of studies in the area. Herein, we explored the role of NKT cells in E. histolytica infection using C57BL/6 wild-type and CD1(-/-) mice. Animals were inoculated with E. histolytica and sacrificed 48 hours later to collect caecum samples that were used for quantitative analyses of lesions, trophozoites, NK1.1(+) T lymphocytes and expression of the mucus protein MUC-2 by immunohistochemistry technique. Quantitative analyses confirmed that the frequency of NK1.1(+) T cells was significantly lower in samples from C57BL/6 CD1(-/-) mice as compared to their wild type (WT) counterparts. The extension of necrotic mucosa was larger and the number of trophozoites higher in Entamoeba (Eh)-infected CD1(-/-) mice when compared with Eh-infected WT mice. In mice from both groups, non-infected (CTRL) and Eh-infected CD1(-/-), there was a reduction in the thickness of the caecal mucosa and in the MUC-2-stained area in comparison with CTRL- and Eh-WT mice. Our results showed that NKT lymphocytes contribute to resistance against Entamoeba histolytica infection and to the control of inflammation in the colitis induced by infection. The presence of a normal epithelial layer containing appropriate levels of mucus had also a protective role against infection. PMID- 24470942 TI - Absence of chronic hepatitis E in a German cohort of common variable immunodeficiency patients. AB - Cases of chronic or prolonged hepatitis E virus (HEV) infections have been described in solid organ transplant recipients, HIV infected patients and in patients with malignancies or idiopathic CD4(+) T lymphopenia. It is unknown if HEV infection also takes chronic courses in patients with common variable immunodeficiency (CVID). We studied a cohort of 73 CVID patients recruited in a low endemic Central European country. None of the subjects tested positive for HEV RNA or anti-HEV IgG. Immunoglobulin transfusions (n=10) tested negative for HEV RNA but all were anti-HEV positive. To verify that such pooled blood products contain anti-HEV protective antibodies we measured the anti-HEV IgG optical density (OD) values in patients before and after transfusion. Anti-HEV OD values increased after infusion but did not reach the cut-off considered as positive. Thus, chronic HEV infections seem to be rare events in CVID patients in Germany. Commercially available immunoglobulin infusions contain anti HEV antibodies and may contribute to protection from HEV infection. PMID- 24470943 TI - Streptococcus pneumoniae bacteremia: clinical and microbiological epidemiology in a health area of Southern Spain. AB - Streptococcus pneumoniae remains an important cause of bacteremia worldwide. Last years, a decrease of S. pneumoniae penicillin-resistant isolates has been observed. The objective of this study was to describe the episodes of bacteremia due to S. pneumoniae during a period of 11 years. Epidemiological and clinical data, serotypes causing bacteremia, antibiotic susceptibility and prognosis factors were studied. Over a period of 11 years, all the episodes of S. pneumoniae bacteremia were analysed. Their clinical and microbiological features were recorded. Statistical analysis was carried out to determine risk factors for pneumococcal bacteremia and predictors of fatal outcome. Finally, 67 S. pneumoniae bacteremia episodes were included in this study. The majority of cases were produced in white men in the middle age of their life. The main predisposing factors observed were smoking, antimicrobial and/or corticosteroids administration, chronic pulmonary obstructive disease and HIV infection, and the most common source of bacteremia was the low respiratory tract. The main serotypes found were 19A, 1, 14 and 7F. Seventy-seven percent of these isolates were penicillin-susceptible, and the mortality in this serie was really low. Statistical significance was observed between age, sex and race factors and the presence of bacteremia, and there was relationship between the patient's condition and the outcome. In our study, S. pneumoniae bacteremia is mainly from community-acquired origin mainly caused in men in the median age of the life. 40% of bacteremias were caused by serotypes 19A, 1, 7F and 14. During the period of study the incidence of bacteremia was stable and the mortality rate was very low. PMID- 24470944 TI - Kinetics of HIV-1 in cerebrospinal fluid and plasma in cryptococcal meningitis. AB - In order to determine HIV-1 kinetics in cerebrospinal fluid (CSF) and plasma in patients with cryptococcal meningitis (CM), we undertook a prospective collection of paired CSF/plasma samples from antiretroviral therapy-free HIV-infected patients with CM. Samples were obtained at baseline (S1) and at the second (S2) and third (S3) weeks of antifungal therapy. HIV-1 CSF concentrations were significantly lower in both S2 and S3 with respect to S1. Plasma concentrations remained stable. HIV-1 concentrations were higher in plasma than CSF in all cases. Patients who survived the episode of CM (but not those who died) showed a decrease in CSF viral load, what suggests different viral kinetics of HIV-1 in the CSF according to the clinical course of this opportunistic disease. PMID- 24470945 TI - Successful treatment of Leuconostoc bacteremia in a neutropenic patient with tigecycline. AB - Leuconostoc lactis is a recognised cause of infection in immunocompromised hosts. It is intrinsically resistant to multiple antibiotics and treatment options may be limited. We report a case of safe and effective use of tigecycline in the treatment of Leuconostoc catheter-related line sepsis in a neutropenic patient. To our knowledge, this is the first reported case of successful use of tigecycline for Leuconostoc bacteremia. PMID- 24470946 TI - Prosthetic valve endocarditis caused by Pasteurella in a penicillin allergic patient: challenges in diagnosis and treatment. AB - Pasteurella multocida is a rare cause of infective endocarditis with only a few cases described. This report involves a 38-year-old penicillin-allergic patient in an immunocompromised state with several co-morbidities. Two molecular microbiological techniques, 16S rRNA sequencing and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry were used to confirm the species identification as P. multocida. Previous reports in the literature are also reviewed. PMID- 24470947 TI - Development of a new trend conjugate vaccine for the prevention of Klebsiella pneumoniae. AB - Klebsiella pneumoniae is a major cause of nosocomial pneumonia, septicemia and urinary tract infections, especially in newborns, blood cancer patients, and other immunocompromised candidates. The control of K. pneumoniae is a complicated issue due to its tight pathogenesis. Immuno-prophylactic preparations, especially those directed toward the bacterium O-antigen, showed to be the most successful way to prevent the infection incidence. However, all previously proposed preparations were either of limited spectrum or non-maternal, and hence not targeting the main Klebsiella patients. Moreover, all preparations were directed only to prevent the respiratory diseases due to that pathogen. This article addresses the development of a method originally used to purify the non-capsular bacterial-endotoxins, as a new and easy method for vaccine production against K. pneumoniae. The application of this method was preceded by a biotechnological control of capsular polysaccharide production in K. pneumoniae. The new produced natural conjugate between the bacterial O-antigen and its outer membrane proteins was evaluated by physicochemical and immunological methods to investigate its purity, integrity, safety and immunogenicity. It showed to be pure, stable, safe for use, and able to elicit a protective immunoglobulin titer against different Klebsiella infections. This immune-response proved to be transferable to the offspring of the vaccinated experimental rabbits via placenta. PMID- 24470948 TI - Predictors of shingles reports at diagnosis of common variable immunodeficiency and selective immunoglobulin G subclass deficiency in 212 Alabama adults. AB - We sought to determine predictors of shingles reports in adults with common variable immunodeficiency or immunoglobulin (Ig) G subclass deficiency (CVID/IgGSD). We tabulated observations at diagnosis of CVID/IgGSD in 212 white adult index patients (165 women, 47 men) who responded to a question about having had shingles. None had been vaccinated for herpes zoster. We analyzed age, sex, and shingles reports; blood levels of CD19+, CD4+, CD8+, and CD56+ mononuclear cells; serum levels of IgG subclasses, IgA, and IgM; and positivity for human leukocyte antigen (HLA)-A and -B haplotypes. Cell counts and immunoglobulin levels were normalized with loge (ln) transformation for analyses. Thirty-one patients (14.6%) reported shingles; 11 reported recurrent or disseminated shingles. Patients with shingles reports had greater mean age at diagnosis of CVID/IgGSD [54+/-13 (standard deviation) years vs. 47+/-12 years; P=0.0130] and a greater prevalence of HLA-A*01, B*08 positivity (35.5% vs. 17.7%; P=0.0227). In a 13-factor logistic regression model, there was a positive association of age with shingles reports [P=0.0151; odds ratio (1.05, 95% confidence interval 1.01, 1.08)]. HLA-A*01, B*08 positivity was also positively associated with shingles reports [P=0.0480; odds ratio 2.61 (1.00, 6.81)]. During a mean followup interval of 7.5 years after CVID/IgGSD diagnosis, the prevalence of recurrent shingles was almost five-fold greater in patients with previous shingles reports. In conclusion, in white adults at CVID/IgGSD diagnosis, age at diagnosis and positivity for HLA-A*01, B*08 have significant positive associations with reports of previous shingles. PMID- 24470949 TI - Value of third sputum smear for detection of pulmonary tuberculosis in HIV infected patients. AB - We evaluated diagnostic yield of third sputum smear in patients co infected with HIV for detection of pulmonary tuberculosis (TB). Among 139 pulmonary tuberculosis cases confirmed with positive sputum culture, diagnostic yield of first smear of sputum with acid fast staining was 81.9%. Incremental yield of 2(nd) and 3(rd) samples was 11.7% and 6.3% respectively. So two sputum smears may be enough for primary evaluation of HIV infected patients suspected to TB. PMID- 24470950 TI - An usual approach to treatment of a case of multidrug resistance Pseudomonas aeruginosa peritonitis: parenteral and intraperitoneal aminoglycosides and parenteral colistin. AB - Infections caused by Pseudomonas aeruginosa are becoming more common and increasingly more difficult to treat due to the continued development of drug resistance. While sensitivity to colistin (polymyxin E) is well known, it is frequently avoided due to concerns of nephrotoxicity. Reported here is a case of a multi-drug resistance pseudomonal typhlitis, bacteremia and pleural cavity infection that required significant intensive care, and serial abdominal washouts. Intra-peritoneal tobramycin in combination with broad-spectrum intravenous antibiotics including colistin were used. Several instillations of tobramycin into the abdominal cavity along with concomitant IV administration of colistin, ceftazidime and tobramycin and per os colistin, tobramycin and nystatin resulted in the clearance of the pseudomonal infection without any evidence of toxicity from the treatment. Intra-abdominal tobramycin with parenteral colistin therapy can be used in complicated clinical settings with appropriate nephroprotection. PMID- 24470951 TI - Interdisciplinary approaches to zoonotic disease. AB - Zoonotic infections are on the increase worldwide, but most research into the biological, environmental and life science aspects of these infections has been conducted in separation. In this review we bring together contemporary research in these areas to suggest a new, symbiotic framework which recognises the interaction of biological, economic, psychological, and natural and built environmental drivers in zoonotic infection and transmission. In doing so, we propose that some contemporary debates in zoonotic research could be resolved using an expanded framework which explicitly takes into account the combination of motivated and habitual human behaviour, environmental and biological constraints, and their interactions. PMID- 24470952 TI - Brain tuberculoma in a non-endemic area. AB - Brain tuberculoma has previously accounted for up to a third of new intracranial lesions in areas endemic with tuberculosis, but is unexpected in the United States and other Western countries with improved disease control. Here we show the importance of considering this diagnosis in at-risk patients, even with no definitive pulmonary involvement. We describe a young man who presented with partial seizures and underwent craniotomy for resection of a frontoparietal tuberculoma. He subsequently completed six months of antituberculosis therapy and was doing well without neurological sequelae or evidence of recurrence five months after completion of therapy. With resurgence of tuberculosis cases in the United States and other Western countries, intracerebral tuberculoma should remain a diagnostic consideration in at-risk patients with new space occupying lesions. Mass lesions causing neurological sequelae can be safely addressed surgically and followed with antituberculosis therapy. PMID- 24470953 TI - Lymph node co-infection of mycobacterium avium complex and cytomegalovirus in an acquired immunodeficiency syndrome patient. AB - Acquired immunodeficiency syndrome patients are known to have an increased tendency for developing opportunistic infections. However, there are no reports of simultaneous lymph node involvement of cytomegalovirus and Mycobacterium avium complex in a human immunodeficiency virus-positive patient. We report a 31-year old man who presented with acute abdominal pain and tenderness and weight loss. He died a few hours after admission. Autopsy studies showed coinfection of cytomegalovirus, Mycobacterium avium complex and human immunodeficiency virus. Our case emphasizes the need to be careful in evaluating opportunistic infections in severely immunodepressed acquired immunodeficiency syndrome patients. This case report is the first manifestation of acquired immunodeficiency syndrome in this patient. PMID- 24470954 TI - Staphylococcus intermedius infections: case report and literature review. AB - Staphylococcus intermedius is part of the normal skin and oral flora of dogs. Case reports of human infections are rare, but the true incidence is unknown because the pathogen is frequently misidentified as Staphylococcus aureus. Reported cases range from soft tissue infections to brain abscess. Most reported cases in humans have been related to dog exposure. We report a case of a 73 year old female with S. intermedius surgical wound infection one month following a left elbow total arthroplasty. This is the first reported human case of S. intermedius infection of a mechanical prosthesis. The presumed source of infection was the patient's dog. The patient was treated with vancomycin, then switched to cefazolin and rifampin once susceptibilities were known. Case reports suggest that patients generally respond well to tailored antibiotics with complete or near-complete recovery. S. intermedius should be included in the differential diagnosis of invasive infection amongst patients with close contact with dogs. PMID- 24470955 TI - Pseudomonas Aeruginosa Bacteraemia in Two UK District Hospitals. AB - Pseudomonas aeruginosa bacteraemia is associated with significant morbidity and mortality. We retrospectively studied the epidemiology of bacteraemia due to P. aeruginosa in two UK district hospitals so as to determine prevention strategies and assess the efficacy and compliance with local hospital antibiotic guidelines. Eighty six episodes occurred in 85 patients over the 3 year period. There was a year on year increase in bacteraemias, due predominantly to an increased proportion of community-onset episodes. Urinary catheterisation was a significant risk factor, along with anaemia, renal disease, malignancy and diabetes. The antibiotic guidelines were adequate for 92.8% of episodes but only 73.8% of patients received adequate therapy. Failure to follow the guidelines was principally due to unwillingness to use gentamicin due to concerns about nephrotoxicity. The antibiotic guidelines may need reviewing to accommodate this problem and further work is required to address urinary catheter care in both the hospital and community. Pseudomonas aeruginosa should be considered a significant pathogen when patients are admitted with features of sepsis. PMID- 24470956 TI - Emergence of Carbapenemaseproducing Klebsiella Pneumoniae of Sequence type 258 in Michigan, USA. AB - The prevalence of carbapenemase-producing Enterobacteriaceae (CPE) in our hospital increased beginning in 2009. We aimed to study the clinical and molecular epidemiology of these emerging isolates. We performed a retrospective review of all adult patients with clinical cultures confirmed as CPE by positive modified Hodge test from 5/2009- 5/2010 at the University of Michigan Health System (UMHS). Clinical information was obtained from electronic medical records. Available CPE isolates were analyzed by polymerase chain reaction (PCR) and sequencing of the 16S rRNA encoding gene and bla KPC locus. Multilocus sequence typing (MLST) was used to characterize Klebsiella pneumoniae isolates. Twenty six unique CPE isolates were obtained from 25 adult patients. The majority were Klebsiella pneumoniae (n=17). Other isolates included K. oxytoca (n=3), Citrobacter freundii (n=2), Enterobacter cloacae (n=2), Enterobacter aerogenes (n=1) and Escherichia coli (n=1). Molecular characterization of 19 available CPE isolates showed that 13 (68%) carried the KPC-3 allele and 6 (32%) carried the KPC-2 allele. Among 14 available K. pneumoniae strains, 12 (86%) carried the KPC 3 allele and belonged to a common lineage, sequence type (ST) 258. The other 2 (14%) K. pneumoniae isolates carried the KPC-2 allele and belonged to two unique STs. Among these ST 258 strains, 67% were isolated from patients with prior exposures to health care settings outside of our institution. In contrast, all CPE isolates carrying the KPC-2 allele and all non ST 258 CPE isolates had acquisition attributable to our hospital. Molecular epidemiology of carbapenemase producing K. pneumoniae suggests that KPC-3 producing K. pneumoniae isolates of a common lineage, sequence type (ST 258), are emerging in our hospital. While ST 258 is a dominant sequence type throughout the United States, this study is the first to report its presence in Michigan. PMID- 24470957 TI - Hyperimmunoglobulin e syndrome presenting as osteogenesis imperfecta in a 3 year old child. AB - We present a case of hyperimmunoglobulin E (hyper-IgE) syndrome in a three year old boy. There are many pitfalls in diagnosing this disease in the very young population, mainly due to the ambiguity of some diagnostic criteria in this population. Recognizing this syndrome early in life can potentially be very beneficial to the patients involved and the medical system as a whole. Early diagnosis can lead to fewer diagnostic tests, fewer referrals, and more focused exams, thus potentially reducing medical cost while also reducing the number of serious infections later in life, including those which are potentially fatal. Additionally, a wellknown association between lymphoma and hyper-IgE syndrome has been established; while no recommendations are currently in place for screening, early diagnosis could help medical providers have a higher threshold for diagnosis of this disease. PMID- 24470958 TI - A pediatric case of cardiobacterium hominis endocarditis. AB - Gram negative endocarditis is relatively rare in pediatrics but when they occur they are most frequently caused by one of the HACEK (Haemophilus species, Actinobacillus actinomycetemcomitans, C. hominis, Eikenella corrodens and Kingella kingae) group of microorganisms. Within the HACEK group of microorganisms there have been approximately 100 cases of Cardiobacterium hominis endocarditis reported in the literature, but only 2 previous cases of endocarditis and one case of pericarditis have been reported in children. In this report, we present a case of a 12-year-old boy with a right ventricle to pulmonary artery conduit for Tetralogy of Fallot with pulmonary atresia who presented at an annual cardiology examination with a 3 week history of fatigue and was found to have a vegetation on routine echocardiogram. Subsequent blood cultures grew Cardiobacterium hominis and the patient was treated successfully with 6 weeks of appropriate antibiotic therapy. We present this case and a review of the literature of the HACEK group of microorganisms in pediatrics. PMID- 24470959 TI - Natural Scrub Typhus Antibody Suppresses HIV CXCR4(X4) Viruses. AB - Viral load generally rises in HIV-infected individuals with a concomitant infection, but falls markedly in some individuals with scrub typhus (ST), a common Asian rickettsial infection. ST infection appears to shift the viral population from CXCR4-using (X4) to CCR5-utilizing (R5) strains, and there is evidence of cross-reactivity between ST-specific antibodies and HIV-1. We examined the mechanism of ST suppression of HIV by measuring the effects of ST infection on X4 and R5 viruses in vivo and in vitro, and assessing the relative contributions of antibodies and chemokines to the inhibitory effect. In vivo, a single scrub typhus plasma infusion markedly reduced the subpopulation of HIV-1 viruses using the X4 co-receptor in all 8 recipients, and eliminated X4 viruses 6 patients. In vitro, the 14 ST sera tested all inhibited the replication of an X4 but not an R5 virus. This inhibitory effect was maintained if ST sera were depleted of chemokines but was lost upon removal of antibodies. Sera from STinfected mice recognized a target that co-localized with X4 HIV gp120 in immunofluorescent experiments. These in vivo and in vitro data suggest that acute ST infection generates cross-reactive antibodies that produce potent suppression of CXCR4- but not CCR5-using HIV-1 viruses. ST suppression of HIV replication could reveal novel mechanisms that could be exploited for vaccination strategies, as well as aid in the development of fusion inhibitors and other new therapeutic regimens. This also appears to be the first instance where one pathogen is neutralized by antibody produced in response to infection by a completely unrelated organism. PMID- 24470960 TI - A case of Creutzfeldt-Jakob disease: diagnostic dilemmas of a rapidly fatal disease. AB - Creutzfeldt-Jakob disease (CJD) is a rapidly progressive and ultimately fatal disorder of the central nervous system. It occurs worldwide with an incidence of 0.5-1 new case per million population per year. No specific treatment is available and management is limited to supportive care. Autopsy or biopsy provides a definitive diagnosis. Because of the transmissible nature of the disease and hesitancy of patients/family members to give consent for biopsy, numerous challenges in confirming the clinical diagnosis are faced by healthcare professionals. We report a case of 66-year-old male who was hospitalized due to hip fracture following a fall. Acute mental status changes followed the surgical fixation of hip fracture which triggered neurologic work up. This finally revealed suspicion and confirmation of CJD. Patient had progressive cognitive decline with akinetic mutism during further hospital stay and was later discharged home with hospice. Shorter thereafter he died at home. This case demonstrates the importance of keeping an open mind towards possibility of CJD when faced with esoteric neurologic presentations. Also this case provides insight into challenges in quarantine and sterilization of surgical instruments when these patients go through major surgeries. PMID- 24470961 TI - Streptococcus pyogenes aortic aneurysm infection: forgotten but not gone. AB - Historically, Streptococcus pyogenes was a common cause of endocarditis and infected aortic aneurysm. Today, endovascular infections due to this organism have become exceedingly rare. We report the first case of aortic aneurysm infection due to S. pyogenes treated with initial endoluminal repair, review previous reports and discuss current treatment options. PMID- 24470962 TI - First case report of infection by Mycobacterium wolinskyi after mammoplasty in Brazil. AB - Mycobacterium wolinskyi is a rapidly growing mycobacterium, first described in 1999 as a member of the group Mycobacterium smegmatis (Mycobacterium smegmatis, Mycobacterium wolinskyi and Mycobacterium goodii). Only 19 case reports all over the world have been described on literature, none of them in Brazil. On this report, it is described one case of infection after a mammoplasty procedure performed in a private health service in the county of Recife, Pernambuco, Brazil, in 2009. The mycobacteria specie was identified using biochemical tests and sequencing the specific gene rpoB. To treat the infection by Mycobacterium wolinskyi it was necessary to combine antibiotics for a long period of time associated with surgical procedures of the breast abscesses. PMID- 24470963 TI - Fecal microbiota transplantation: the state of the art. AB - Clostridium difficile infection (CDI) is an emerging problem in terms of incidence, morbidity and mortality. Currently available treatment options are not always effective, especially in cases of recurrent/refractory or complicated CDI. The gut microbiota transplantation is a technique that has been sporadically practiced since the '50s, but its clinical efficacy has only recently been supported by scientific evidence. In the present article, we report the pathophysiological basis and the clinical indications of this technique that, in light of its low cost, and proven efficacy and safety, is likely to become part of the management guidelines of difficult cases of CDI in the near future. PMID- 24470964 TI - A case of emphysematous cystitis diagnosed by exploratory laparotomy. AB - Emphysematous cystitis is a rare form of infection. Well known symptoms are: dysuria, urinary frequency and lower abdominal pain. We experienced a case of emphysematous cystitis presented with atypical peritoneal sign and computed tomography findings of massive intra-peritoneal fluid collection and abnormal gas appearance in pelvic space. Due to its presentation as acute abdomen, patient underwent exploratory laparotomy and the diagnosis of emphysematous cystitis was established. As far as we know, our case is the first report of emphysematous cystitis with intra-peritoneal fluid collection. PMID- 24470965 TI - Special Issue on HIV/AIDS: Infectious Disease Reports. PMID- 24470966 TI - Recent developments in hiv treatment and their dissemination in poor countries. AB - As the world enters the fourth decade of the HIV/AIDS epidemic a number of new drugs have been developed that address current challenges with antiretroviral therapy (ART), such as pill burden, toxicity and drug-resistance. These new agents have not only been developed from established drug-classes, namely nucleoside reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (PIs), but also include innovative ways of suppressing viral replication. Intergrase inhibitors and chemokine receptor blockers have been developed which, combined with NRTIs, NNRTIs and PIs, comprise highly active antiretroviral therapy regimens able to tackle all aspects of the HIV life cycle with minimal toxicity. Furthermore, the ability of pharmaceutical companies to formulate these powerful drugs into fixed dose combinations provides exciting new strategies for reducing pill burden, thus ensuring adherence and limiting the emergence of drug-resistance. The enthusiasm with which these new drugs have been received has, however, been tempered by the reality of limited access in the developing world, further highlighting the disparity between rich and poor countries in the fight against HIV/ AIDS. Access to these treatments in low- and middle-income countries will require the necessary political will, regulatory approval, affordability of drugs, as well as efficient procurement and supply management strategies. The priority of developing countries remains increased scale up of ART, but there is also a need to acquire new drugs in order to tackle toxicity and drug-resistance, both of which threaten the sustainability of such programmes. Thankfully, the vast majority of patients receiving ART in the developing world are still on first line regimens, thus allowing time for newer agents to be made available as part of third-line treatment option. However, there is no room for complacency - the developing world needs access to new HIV treatments, an AIDS-free generation depends upon it. PMID- 24470967 TI - The intra-host evolutionary and population dynamics of human immunodeficiency virus type 1: a phylogenetic perspective. AB - The intra-host evolutionary and population dynamics of the human immunodeficiency virus type 1 (HIV-1), the cause of the acquired immunodeficiency syndrome, have been the focus of one of the most extensive study efforts in the field of molecular evolution over the past three decades. As HIV-1 is among the fastest mutating organisms known, viral sequence data sampled over time from infected patients can provide, through phylogenetic analysis, significant insights about the tempo and mode of evolutionary processes shaped by complex interaction with the host milieu. Five main aspects are discussed: the patterns of HIV-1 intra host diversity and divergence over time in relation to different phases of disease progression; the impact of selection on the temporal structure of HIV-1 intra-host genealogies inferred from longitudinally sampled viral sequences; HIV 1 intra-host sub-population structure; the potential relationship between viral evolutionary rate and disease progression and the central evolutionary role played by recombination occurring in super-infected cells. PMID- 24470968 TI - Current Trends of HIV Recombination Worldwide. AB - One of the major characteristics of HIV-1 is its high genetic variability and extensive heterogeneity. This characteristic is due to its molecular traits, which in turn allows it to vary, recombine, and diversify at a high frequency. As such, it generates complex molecular forms, termed recombinants, which evade the human immune system and so survive. There is no sequence constraint to the recombination pattern as it appears to occur at inter-group (between groups M and O), as well as interand intra-subtype within group M. Rapid emergence and active global transmission of HIV-1 recombinants, known as circulating recombinant forms (CRFs) and unique recombinant forms (URFs), requires urgent attention. To date, 55 CRFs have been reported around the world. The first CRF01_AE originated from Central Africa but spread widely in Asia. The most recent CRF; CRF55_01B is a recombinant form of CRF01_AE and subtype B, although its origin is yet to be publicly disclosed. HIV-1 recombination is an ongoing event and plays an indispensable role in HIV epidemics in different regions. Africa, Asia and South America are identified as recombination hot-spots. They are affected by continual emergence and cocirculation of newly emerging CRFs and URFs, which are now responsible for almost 20% of HIV-1 infections worldwide. Better understanding of recombinants is necessary to determine their biological and molecular attributes. PMID- 24470969 TI - HIV Drug Resistance: Problems and Perspectives. AB - Access to combination antiretroviral treatment (ART) has improved greatly over recent years. At the end of 2011, more than eight million HIV-infected people were receiving ART in low-income and middle-income countries. ART generally works well in keeping the virus suppressed and the patient healthy. However, treatment only works as long as the virus is not resistant against the drugs used. In the last decades, HIV treatments have become better and better at slowing down the evolution of drug resistance, so that some patients are treated for many years without having any resistance problems. However, for some patients, especially in low-income countries, drug resistance is still a serious threat to their health. This essay will review what is known about transmitted and acquired drug resistance, multi-class drug resistance, resistance to newer drugs, resistance due to treatment for the prevention of mother-to-child transmission, the role of minority variants (low-frequency drug-resistance mutations), and resistance due to pre-exposure prophylaxis. PMID- 24470970 TI - Pathogenesis of HIV Infection. AB - Over the past three decades of intense research on the contribution of viral and host factors determining the variability in HIV-1 infection outcome, HIV pathogenesis is still a fascinating topic that requires further study. An understanding of the exact mechanism of how these factors influencing HIV pathogenesis is critical to the development of effective strategies to prevent infection. Significant progress has been made in identifying the role of CCR5 (R5) and CXCR4 (X4) HIV strains in disease progression, particularly with the persistence of R5 HIV-1 strains at the AIDS stage. This indicates that R5 strains are as fit as X4 in causing CD4+ T cell depletion and in contribution to disease outcome, and so questions the prerequisite of the shift from R5 to X4 for disease progression. In contrast, the ability of certain HIV strains to readily use CXCR4 for infection or entry into macrophages, as the case with viruses are homozygous for tropism by CCR5delta32. This raises another major paradox in HIV pathogenesis about the source of X4 variants and how do they emerge from a relatively homogeneous R5 viral population after transmission. The interactions between viral phenotypes, tropism and co-receptor usage and how they influence HIV pathogenesis are the main themes addressed in this review. A better understanding of the viral and host genetic factors involved in the fitness of X4 and R5 strains of HIV-1 may facilitate development of specific inhibitors against these viral populations to at least reduce the risk of disease progression. PMID- 24470971 TI - Hepatitis C Virus and HIV Type 1 Co-Infection. AB - Around 33 million people worldwide are living with Human Immunodeficiency Virus (HIV) infection, and approximately 20-30% of HIV-infected individuals are also infected with Hepatitis C virus (HCV). The main form of HCV transmission is via the blood borne route; high rates of co-infection are found in intravenous drug users with HCV prevalence rates as high as 90%. Introduction of effective antiretroviral therapy (ART) has led to a significant decline in HIV-related morbidity, but at the same time the incidence of HCV related liver disease is increasing in the co-infected population. Meta analysis has revealed that individuals who are co-infected with HIV/HCV harbor three times greater risk of progression to liver disease than those infected with HCV alone. Increased risk of progression to Acquired Immunodeficiency Syndrome (AIDS) and AIDS-related deaths is shown among the co-infected patients by some studies, suggesting that HCV infection may accelerate the clinical course of HIV infection. HCV may also affect the incidence of liver toxicity associated with ART, affecting the management of HIV infection. There is a lack of optimal therapeutic approaches to treat HCV infection in HIV co-infected patients. This review discusses recent literature pertaining HIV/HCV co-infection, in addition to providing a snapshot of impact of co-infection on human genome at the level of gene expression and its regulation by microRNAs (miRNAs). PMID- 24470973 TI - JAK2-STAT5 signaling: A novel mechanism of resistance to targeted PI3K/mTOR inhibition. AB - A recent article published by Britschgi et al. in Cancer Cell, "JAK2/STAT5 Inhibition Circumvents Resistance to PI3K/mTOR Blockade: A Rationale for Cotargeting These Pathways in Metastatic Breast Cancer," describes a positive feedback loop of JAK2/STAT5 activation that drives resistance to PI3K/mTOR inhibition in breast cancer. The authors found that genetic or pharmacological inhibition of JAK2 circumvents resistance to PI3K/mTOR inhibition and go on to show the efficacy of combined PI3K/mTOR and JAK2 inhibition on reducing cancer cell number, tumor growth, and metastasis as well as increasing in vivo survival. These results provide strong support for combination therapy with JAK2/STAT5 and PI3K/mTOR inhibitors in breast cancer. Here we discuss how the article by Britschgi et al. proposes a novel mechanism to explain how breast cancer cells overcome inhibition of a key signaling pathway driving cell proliferation. We also discuss the interplay between activation of the transcription factors STAT5 and STAT3 in breast cancer. PMID- 24470974 TI - Non-genomic STAT5-dependent effects at the endoplasmic reticulum and Golgi apparatus and STAT6-GFP in mitochondria. AB - STAT protein species are well-known as transcription factors that regulate nuclear gene expression. Recent novel lines of research suggest new non-genomic functions of STAT5A/B and STAT6. It was discovered in human pulmonary arterial endothelial cells that STAT5A, including STAT5A-GFP, constitutively associated with the Golgi apparatus, and both STAT5A and B with the endoplasmic reticulum. Acute siRNA-mediated knockdown of STAT5A/B led to the rapid development of a dramatic cystic change in the endoplasmic reticulum (ER) characterized by deposition of the ER structural protein reticulon-4 (RTN4; also called Nogo-B) and the ER-resident GTPase atlastin-3 (ATL3) along cyst membranes and cyst-zone boundaries, accompanied by Golgi fragmentation. Functional consequences included reduced anterograde trafficking, an ER stress response (increased GRP78/BiP) and eventual mitochondrial fragmentation. This phenotype was "non-genomic" in that it was elicited in enucleated cytoplasts. In cross-immunopanning assays STAT5A and B species associated with ATL3, and the ER-lumen spacer CLIMP63 (also called cytoskeleton-associated protein 4, CKAP4) but not RTN4. From a disease significance perspective we posit that STAT5, which is known to be affected by estradiol-17beta and prolactin, represents the gender-sensitive determinant in the pathogenesis of idiopathic pulmonary hypertension (IPAH), a disease which includes ER/Golgi dysfunctions but with a 2- to 4-fold higher prevalence in postpubertal women. A separate line of recent research produced evidence for the association of STAT6-GFP, but not STAT3-GFP, STAT3-DsRed, or STAT3-Flag, with mitochondria in live-cell, immunofluorescence, and immunoelectron microscopy. An N-terminal truncation of STAT6-GFP (1-459), which lacked the SH2 domain and Tyr phosphorylation site, constitutively associated with mitochondria. Thus, the emergent new of biology STAT proteins includes non-genomic roles-structurally and functionally-in the three closely related membrane organelles consisting of the endoplasmic reticulum, Golgi apparatus, and mitochondria. PMID- 24470975 TI - JAK2-STAT5B pathway and osteoblast differentiation. AB - Osteoblast differentiation is a critical step in the maintenance of bone homeostasis. Osteoblast differentiation is generally maintained by growth hormone (GH) and various other endocrine and autocrine/paracrine factors. JAK2-STAT5B pathway is a central axis in the mechanism of GH signaling. Similarly, the autocrine/paracrine signaling factor IGF-1 also mediates its effects through this pathway. Analysis on JAK2-STAT5B pathway showed its importance in the IGF-1/IGF 1R mediated regulation of gene expression and osteoblast differentiation. Persistent activation of STAT5B and inhibition of STAT5B degradation showed increased osteoblastic differentiation and STAT5B/Runx-2 activities. Conditional gene silencing studies showed the importance of the JAK2-STAT5B pathway in stimulation of other transcription factors and expression of various differentiation markers. PMID- 24470972 TI - HIV Associated Neurocognitive Disorders. AB - Human immunodeficiency virus type 1 is associated with the development of neurocognitive disorders in many infected individuals, including a broad spectrum of motor impairments and cognitive deficits. Despite extensive research, the pathogenesis of HIV-associated neurocognitive disorders (HAND) is still not clear. This review provides a comprehensive view of HAND, including HIV neuroinvasion, HAND diagnosis and different level of disturbances, influence of highly-active antiretroviral therapy to HIV-associated dementia (HAD), possible pathogenesis of HAD, etc. Together, this review will give a thorough and clear understanding of HAND, especially HAD, which will be vital for future research, diagnosis and treatment. PMID- 24470976 TI - JAK-STAT3 and somatic cell reprogramming. AB - Reprogramming somatic cells to pluripotency, especially by the induced pluripotent stem cell (iPSC) technology, has become widely used today to generate various types of stem cells for research and for regenerative medicine. However the mechanism(s) of reprogramming still need detailed elucidation, including the roles played by the leukemia inhibitory factor (LIF) signaling pathway. LIF is central in maintaining the ground state pluripotency of mouse embryonic stem cells (ESCs) and iPSCs by activating the Janus kinase-signal transducer and activator of transcription 3 (JAK-STAT3) pathway. Characterizing and understanding this pathway holds the key to generate naive pluripotent human iPSCs which will facilitate the development of patient-specific stem cell therapy. Here we review the historical and recent developments on how LIF signaling pathway regulates ESC pluripotency maintenance and somatic cell reprogramming, with a focus on JAK-STAT3. PMID- 24470977 TI - Signal transducer and activator of transcription-1 localizes to the mitochondria and modulates mitophagy. AB - The signal transducer and activator of transcription (STAT) proteins are latent transcription factors that have been shown to be involved in cell proliferation, development, apoptosis, and autophagy. STAT proteins undergo activation by phosphorylation at tyrosine 701 and serine 727 where they translocate to the nucleus to regulate gene expression. STAT1 has been shown to be involved in promoting apoptotic cell death in response to cardiac ischemia/reperfusion and has recently been shown by our laboratory to be involved in negatively regulating autophagy. These processes are thought to promote cell death and restrict cell survival leading to the generation of an infarct. Here we present data that shows STAT1 localizes to the mitochondria and co-immunoprecipitates with LC3. Furthermore, electron microscopy studies also reveal mitochondria from ex vivo I/R treated hearts of STAT1KO mice contained within a double membrane autophagosome indicating that STAT1 may be involved in negatively regulating mitophagy. This is the first description of STAT1 being localized to the mitochondria and also having a role in mitophagy. PMID- 24470978 TI - STATs get their move on. AB - Understanding the mechanisms that regulate dynamic localization of a protein within a cell can provide critical insight to its functional molecular interactions. Signal transducers and activators of transcription (STATs) play essential roles in development, proliferation, and immune defense. However the consequences of STAT hyperactivity can predispose to diseases including autoimmunity and cancer. To function as transcription factors STATs must gain access to the nucleus, and knowledge of the mechanisms that regulate STAT nuclear trafficking can provide a means to control STAT action. This review presents a synopsis of some of the studies that address the nuclear dynamics of the STAT proteins. Evidence suggests that not all STATs are the same. Nuclear import of STAT1 and STAT4 appears linked to their tyrosine phosphorylation and the formation of parallel dimers via reciprocal phosphotyrosine and Src homology 2 domain interactions. This dimer arrangement generates a conformational nuclear localization signal. STAT2 is imported continually to the nucleus in an unphosphorylated state due to its association with IRF9, but the dominant nuclear export signal of STAT2 shuttles the complex back to the cytoplasm. Following STAT2 tyrosine phosphorylation, it can form dimers with STAT1 to affect nuclear import as the trimeric complex (ISGF3). Distinctly, STAT3, STAT5, and STAT6 are continually imported to the nucleus independent of tyrosine phosphorylation. Mutational studies indicate the nuclear localization signals in these STATs require the conformational structure of their coiled-coil domains. Increases in STAT nuclear accumulation following cytokine stimulation appear coordinate with their ability to bind DNA. PMID- 24470979 TI - Engaged for survival: From cadherin ligation to STAT3 activation. AB - In normal tissues or tumors, cells have extensive opportunities for adhesion to their neighbors. This state is mimicked by dense cell cultures. In this review, we integrate some recent findings on a key signal transducer, STAT3 (signal transducer and activator of transcription-3), whose activity is dramatically increased following cadherin-mediated cell to cell adhesion. Cadherin engagement, favored in dense cell cultures, causes a dramatic increase in total Rac/Cdc42 protein levels through inhibition of proteasomal degradation, which is followed by activation of IL-6 and STAT3. The cadherin/Rac/IL-6/STAT3 axis offers a potent survival signal that is a prerequisite for neoplastic transformation, as well as normal tissue function. PMID- 24470980 TI - IL-4, JAK-STAT signaling, and pain. AB - During inflammation, several mediators directly or indirectly induce pain including pro-inflammatory cytokines and there is evidence that the JAK-STAT pathway is involved in the formation of pronociceptive cytokines. The same pathway, however, is also of importance for anti-inflammatory cytokines such as IL-4 to counteract the inflammatory reaction and-as it seems based on the current literature-nociceptive symptoms. Current therapeutic approaches targeting molecules of the JAK-STAT signaling cascade are auspicious but as this review demonstrates, more experimental and clinical studies are required to decipher the specific contribution of this pathway in the modulation of pain. PMID- 24470981 TI - An exploration of ethnic, immigration and acculturation differences on tobacco smoking among public high school girls in Hawai'i. AB - This cross-sectional study explores the differences in ethnicity, sex, immigration (place of birth of student and parents), and acculturation (based on language spoken at home) on current cigarette smoking among public high school students in Hawai'i, and especially examine if this affected smoking among girls. Previous behavior risk surveys of youth in Hawai'i showed higher smoking rates among girls, although these were not found to be statistically significant differences. Multiple years of data were compiled from the Hawai'i Youth Tobacco Survey (YTS) for years 2005, 2007, 2009, and 2011, for a total sample size of N=5,527. Multivariate logistic regression analysis was conducted to evaluate the likelihood of current cigarette smoking (in the past 30 days) in relation to a variety of factors. The analysis revealed that Hawai'i-specific ethnicity, grade, and sex were all significant predictors of smoking. Girls whose mothers were born in Hawai'i or in another United States state were more likely to smoke than those whose mothers were born in a foreign country. The model showed girls were more likely to smoke than boys. Eleventh and twelfth graders were more likely to smoke than ninth graders. Whites, Filipinos, Native Hawaiians, Pacific Islanders, and Other ethnic groups were more likely to smoke than those who identified themselves as Japanese. PMID- 24470982 TI - Interventions to increase medication adherence in African-American and Latino populations: a literature review. AB - The objective of this systematic review was to investigate the effectiveness of interventions to improve medication adherence in ethnic minority populations. A literature search from January 2000 to August 2012 was conducted through PubMed/Medline, Web of Science, The Cochrane Library, and Google Scholar. Search terms used included: medication (MeSH), adherence, medication adherence (MeSH), compliance (MeSH), persistence, race, ethnicity, ethnic groups (MeSH), minority, African-American, Hispanic, Latino, Asian, Pacific Islander, and intervention. Studies which did not have >=75% of the sample population comprised of individuals of any one ethnic background were excluded, unless the authors performed sub-group analyses by race/ethnicity. Of the 36 studies identified, 20 studies showed significant post-intervention differences. Sample population sizes ranged from 10 to 520, with a median of 126.5. The studies in this review were conducted with patients of mainly African-American and Latino descent. No studies were identified which focused on Asians, Pacific Islanders, or Native Americans. Interventions demonstrating mixed results included motivational interviewing, reminder devices, community health worker (CHW) delivered interventions, and pharmacist-delivered interventions. Directly observed therapy (DOT) was a successful intervention in two studies. Interventions which did not involve human contact with patients were ineffective. In this literature review, studies varied significantly in their methods and design as well as the populations studied. There was a lack of congruence among studies in the way adherence was measured and reported. No single intervention has been seen to be universally successful, particularly for patients from ethnic minority backgrounds. PMID- 24470983 TI - Hair mercury and fish consumption in residents of O'ahu, Hawai'i. AB - Recent studies have established that men are susceptible to cardiotoxicity from methylmercury exposure, which also poses risks to the pregnant woman. Hair samples were obtained and questionnaires for methylmercury exposure assessment were administered to 110 adults (57 men, 53 women) throughout O'ahu, Hawai'i during December 2010 to January 2011. Hair samples were analyzed for total mercury with a direct mercury analyzer. Men >= 46 years had a median of 2.0 ug/g, which was above the reference dose of 1 ug/g, as compared to younger men with a median 1.0 ug/g (P < 0.05). Hair concentrations from older women had a median of 1.2 ug/g of mercury compared to 0.6 ug/g for younger women. Additionally, 38% of women of childbearing age had a Hazard Index > 1.0. This indicates that both men and women were at risk for excessive methylmercury exposure. In the final regression model, male gender, age > 45 years, length of residency > 10 years in Hawai'i, and fish consumption frequency > 1 meal per week were significant factors in increased hair mercury levels. Following safe fish consumption practices allows residents to reap health benefits of fish consumption without excessive toxicant exposure. PMID- 24470984 TI - Drug take back in Hawai'i: partnership between the University of Hawai'i Hilo College of Pharmacy and the Narcotics Enforcement Division. AB - Unused/unwanted medications in households and patient care facilities expose vulnerable populations, including children, elders, and pets, to potential harm through inadvertent ingestion, as well as the potential for theft and assault. Hawai'i Administrative Rules prohibit the return of any prescription medications to retail pharmacies after dispensing. The Hawai'i Narcotics Enforcement Division (NED) partnered with the University of Hawai'i at Hilo Daniel K. Inouye College of Pharmacy (CoP) in eleven Drug Take Back events throughout the state. Most participants heard of the events via newspaper and television marketing. The most common methods of medication disposal are via trash or down household drains. Over 8,000 lbs of unused/unwanted medications was collected, identified and logged from 2011 through 2012. The majority of returned drugs were non-controlled substances (90%). Commonly returned medications included prescription cardiac medications such as simvastatin and lisinopril, non-prescription analgesics such as aspirin and ibuprofen, and dietary supplements such as vitamins and iron. Commonly returned controlled substance medications included narcotics such as hydrocodone/acetaminophen combinations and oxycodone, and sedative hypnotics such as zolpidem and lorazepam. PMID- 24470985 TI - Medical school hotline: update on university clinical, education and research associates (UCERA). PMID- 24470986 TI - University of Hawai'i Cancer Center Connection: regional cooperation in addressing cancer health disparities: NCI's Geographic Management Program (GMaP) and Biospecimen Management Program (BMaP) in Western States, Hawai'i, and US pacific territories. PMID- 24470988 TI - Relative Efficacy of Swallowing versus Non-swallowing Tasks in Dysphagia Rehabilitation: Current Evidence and Future Directions. AB - Clinical trials published in 2012 and the first six months of 2013 were reviewed. These involved either traditional dysphagia therapy, indirect methods not involving dysphagia therapy or a combination of direct and indirect methods. Of 27 studies, 7 were RCTs, 5 were controlled clinical trials and the remainder were uncontrolled case series. Sixteen studies combined an indirect treatment with traditional dysphagia therapy; only one study examined one technique for direct swallowing therapy. Effect sizes were computed and contrasted for each trial. Traditional dysphagia therapy had small to moderate effect sizes (between 0.3 and 0.6) while spontaneous recovery in acute stroke had effect sizes of 1.2. Placebo effects on patient ratings of degree of improvement on swallowing were estimated as small to moderate. To improve effect sizes, adaptive research designs are needed to develop the optimal methods and dosages of therapy before future clinical trials. PMID- 24470990 TI - Cestode infections: A brief insight. PMID- 24470989 TI - Autophagy Modulation in Disease Therapy: Where Do We Stand? AB - Since it was first described more than 50 years ago autophagy has been examined in many contexts, from cell survival to pathogen sequestration and removal. In more recent years our understanding of autophagy has developed sufficiently to allow effective targeted therapeutics to be developed against various diseases. The field of autophagy research is expanding rapidly, demonstrated by increases in both numbers of investigators in the field and the breadth of topics being addressed. Some diseases, such as the many cancers, have come to the fore in autophagy therapeutics research as a better understanding of their underlying mechanisms has surfaced. Numerous treatments are being developed and explored, from creative applications of the classic autophagy modulators chloroquine and rapamycin, to repurposing drugs approved for other treatments, such as astemizole, which is currently in use as an antimalarial and chronic rhinitis treatment. The landscape of autophagy modulation in disease therapy is rapidly changing and this review hopes to provide a cross-section of the current state of the field. PMID- 24470991 TI - Human cysticercosis (Taenia solium). PMID- 24470992 TI - Ethics of authorship in scientific publications. AB - Authorship should be based on the contribution provided by each author who has made a significant scientific contribution to a study. Credit of authorship has important academic, social and financial implications and is bound by guidelines, which aid in preserving transparency during writing and publication of research material so as to prevent violation of ethics. PMID- 24470993 TI - Neurocysticercosis: A disease of neglect. AB - Neurocysticercosis (NCC) is a neglected tropical disease caused by larval forms of the parasite Taenia solium lodging in central nervous system (CNS). There is a huge morbidity and debilitation due to CNS manifestations of NCC in developing and underdeveloped regions of the globe, mainly Asian, African and Latin American countries. It is the cause of epilepsy in about 1% of the population of endemic countries and is the underlying etiology in about 15-50% persons with epilepsy, depending upon the geographical region. There is no perfect diagnostic method and the diagnosis relies on a combination of clinical, radio-imaging, immunologic and epidemiologic data. Treatment includes anti-parasitic treatment by cysticidal drugs and management of associated symptoms and complications. The disease is eradicable and control depends on an integrated and coordinated involvement of international bodies like the World Health Organization along with scientific institutions and political and administrative strata of the endemic countries to provide the essential tools such as adequate sanitation, live-stock management, health education and improved socio-economic conditions. PMID- 24470994 TI - Lights and shadows of the Taenia asiatica life cycle and pathogenicity. AB - Humans are definitive hosts of two well-known species of the Taenia genus, Taenia solium (the pig tapeworm) and Taenia saginata (the cattle tapeworm). In the 1990s, a third species, Taenia asiatica, was discovered, sharing features with the other two since the adult morphology is similar to that of T. saginata, but its life cycle is like that of T. solium. Human taeniasis usually is asymptomatic or displays mild symptoms, and only T. solium can cause other sometimes serious disorders when humans accidentally ingest the eggs and develop the larval stage in different organs (cysticercosis). In this review, we expose what we currently know (lights) and what we do not yet know (shadows) about the life cycle and pathogenicity of T. asiatica. Concerning its life cycle, the main uncertainty is whether humans can act as intermediate hosts of this species. We also suggest that due to its small size and location in pigs, the cysticerci probably escape veterinary inspection becoming a silent parasite. Concerning pathogenicity, it is still not known if T. asiatica can cause human liver cysticercosis, taking into account its principal hepatic tropism in pigs. To answer all these questions it would be essential to perform sensitive as well as specific diagnostic techniques for T. asiatica in humans and pigs. Currently, only molecular methods are able to determine the Taenia species, since morphology and immunology are useless, but unfortunately although largely used in research those methods are not employed in routine diagnosis. PMID- 24470995 TI - Laboratory diagnosis of Taenia asiatica in humans and animals. AB - Taenia asiatica is a recently described species known to cause intestinal teniasis in humans and cysticercosis in animals. This species has close morphological resemblance to Taenia saginata and has a life cycle resembling Taenia solium, hence has been posing diagnostic dilemma and had been the reason for its comparatively late discovery. Recent diagnostic tools such as serological and molecular techniques have thrown light on its exact prevalence in the endemic countries. Hence introduction of utilization of these techniques in addition to the routine morphological analysis would be helpful in diagnosis of T. asiatica infections and early implementation of preventive measures. PMID- 24470996 TI - Evaluation of a newly designed sandwich enzyme linked immunosorbent assay for the detection of hydatid antigen in serum, urine and cyst fluid for diagnosis of cystic echinococcosis. AB - INTRODUCTION: Cystic echinococcosis (CE) is a zoonotic disease of humans with variable clinical manifestations. Imaging and immunological methods are currently the mainstay of diagnosis of this disease. Although the immunological tests for detection of anti-echinococcal antibodies have several disadvantages, they are widely being used. Antigen is far more superior than antibody detection test as they can provide a specific parasitic diagnosis. MATERIALS AND METHODS: A sandwich enzyme linked immunosorbent assay (ELISA) was designed using antibodies to 24 kDa urinary hydatid antigen for the detection of hydatid antigens in urine, serum and cyst fluid specimens. The performance of this novel test was compared with that of other hydatid antibody detection ELISA and enzyme immune transfer blot (EITB) using radiological and surgical confirmation as the gold standard. RESULTS: The antigen detection ELISA showed 100% sensitivity and specificity when tested with cyst fluid. On testing urine and serum, the antigen detection ELISA was found to be more specific than antibody detection ELISA. EITB was found to be the most sensitive and specific test. CONCLUSIONS: ELISA using polyclonal antibodies against 24 kDa urinary hydatid protein was moderately sensitive to detect hydatid antigen in serum and urine. Hence polyclonal antibodies to 24 kDa urinary hydatid antigen can be used as an alternative source of antibody to detect hydatid antigen in serum, urine and cyst fluid. In the present study, EITB was found to be highly specific test for detection of hydatid antibodiesin serum. 24 kDa protein was found to be specific and of diagnostic value in CE. PMID- 24470997 TI - Cysticercosis: The day to day public health problem and the various sites affected by it - A one year study. AB - INTRODUCTION: The present study is done to highlight the various regions in the body affected by cysticercosis and to educate the people about the personal hygiene and prevention of the parasite. MATERIALS AND METHODS: This is a study done on patients who were referred for swelling in the body, which were diagnosed as cysticercosis in one of their differential diagnosis clinically. RESULTS: During the 1 year study (from October 2011 to September 2012) we diagnosed seven cases of cysticercosis involving the various sites in the body. Our cases highlight the rare presentation of cysticercus infestation as cause of treatablelymphadenopathy. CONCLUSIONS: Cysticercosis should be included in the differential diagnosis of cervical swellings especially in endemic regions. Timely diagnosis and intervention help in preventing fatal complications. PMID- 24470998 TI - Spectrum of vaginal discharge in a tertiary care setting. AB - INTRODUCTION: Vaginal discharge is one of the common reasons for gynecological consultation. Many of the causes of vaginitis have a disturbed vaginal microbial ecosystem associated with them. Effective treatment of vaginal discharge requires that the etiologic diagnosis be established and identifying the same offers a precious input to syndromic management and provides an additional strategy for human immunodeficiency virus prevention. The present study was thus carried out to determine the various causes of vaginal discharge in a tertiary care setting. MATERIALS AND METHODS: A total of 400 women presenting with vaginal discharge of age between 20 and 50 years, irrespective of marital status were included in this study and women who had used antibiotics or vaginal medication in the previous 14 days and pregnant women were excluded. RESULTS: Of the 400 women with vaginal discharge studied, a diagnosis was established in 303 women. Infectious causes of vaginal discharge were observed in 207 (51.75%) women. Among them, bacterial vaginosis was the most common cause seen in 105 (26.25%) women. The other infections observed were candidiasis alone (61, 15.25%), trichomoniasis alone (12, 3%), mixed infections (22, 5.5%) and mucopurulent cervicitis (7 of the 130 cases looked for, 8.46%). Among the non-infectious causes, 72 (18%) women had physiological vaginal discharge and 13 (3.3%) women had cervical in situ cancers/carcinoma cervix. CONCLUSION: The pattern of infectious causes of vaginal discharge observed in our study was comparable with the other studies in India. Our study emphasizes the need for including Papanicolaou smear in the algorithm for evaluation of vaginal discharge, as it helps establish the etiology of vaginal discharge reliably and provides a valuable opportunity to screen for cervical malignancies. PMID- 24470999 TI - A study of prevalence of intestinal parasites and associated risk factors among the school children of Itahari, Eastern Region of Nepal. AB - INTRODUCTION: Intestinal parasitic infestation is a major public health problem in children of developing countries Because of poor socio-economic conditions and lack of good hygienic living. The aims of this study were to measure the prevalence of intestinal parasitic infestations and to identify risk factors associated with parasitic infestations among the school children of Itahari Municipality. MATERIALS AND METHODS: The cross-sectional study was conducted in Grade VI, VII and VIII in Government and private schools of Itahari Municipality. Stratified random sampling method was applied to choose the schools and the study subjects. Semi-structured questionnaire was administered to the study subjects and microscopic examination of stool was done. The Chi-square test was used to measure the association of risk factors and parasitic infestation. RESULTS: Overall intestinal parasitic infestation was found to be 31.5%. Around 13% of the study population was found to be infested with helminthes and 18.5% of the study population was protozoa infected. Not using soap after defecation, not wearing sandals, habit of nail biting and thumb sucking were found to be significantly associated with parasitic infection. CONCLUSIONS: The prevalence of intestinal parasitic infestation was found to be high in school children of Itahari. Poor sanitary condition, lack of clean drinking water supply and education is supposed to play an important role in establishing intestinal parasitic infections. PMID- 24471000 TI - A case of Hymenolepis diminuta in a young male from Odisha. AB - Hymenolepis diminuta also known as rat tapeworm rarely causes hymenolepiasis in humans. We report a case of H. diminuta infection in an 18-year-old male farmer who presented with intermittent pruritic maculopaular rashes and dull aching left iliac fossa pain for 6 months. Patient was cured with 2 doses of praziquantel 20 mg/kg on day 0 and 7. PMID- 24471001 TI - Cysticercosis of breast. AB - Human cysticercosis, a parasitic infection caused by cysticercus cellulosae. This results from ova being swallowed or getting asses to human stomach by regurgitation from own adult worm. The larvae are liberated in stomach, penetrate the intestinal mucosa and carried to many parts of the body where they form cysterci, 0.5-1 cm cyst that contain the head of young worm. They do not grow further or migrate. The common sites are skeletal muscle, subcutaneous tissue, brain and eye. Breast is an uncommon site. PMID- 24471002 TI - Primary pancreatic echinococcosis. AB - Hydatid disease is an endemic and common zoonosis in India. Liver is the most common site of infection. However, extra hepatic primary pancreatic hydatid cyst is rare. We report a case of primary hydatid cyst in the tail of pancreas compressing the adjacent organs in a 43-year-old male who presented with abdominal mass and was diagnosed as pancreatic cyst/splenic cyst by ultrasonography. Computed tomography of abdomen revealed a large cystic lesion in the tail of pancreas suggestive of a pseudocyst of pancreas. The case was managed surgically by splenectomy and distal pancreatectomy with albendazole therapy. Microbiological Investigations of aspirated fluid revealed free hooklets and invaginated scolices of Echinococcus granulosus, which was correlated with histopathological findings. PMID- 24471003 TI - Primary hydatid cyst of broad ligament. AB - Cystic lesions of the female pelvis are common. Clinically, symptomatic lesions are mostly ovarian in origin and neoplastic in nature. Considerable diagnostic dilemma may be encountered if clinical, radiological, and estimation of serum markers failed to classify the origin and nature of such cysts. One such exceptional case is being described where a 35-year-old female presented with a rapidly growing cystic mass in lower abdomen, clinically suspicious of malignancy. Investigations failed to identify the nature. On laparotomy, excision of the mass was done. Suprisingly histopathological examination identified the lesion as hydatid cyst arising from the broad ligament. Female genital tract hydatidosis is uncommon and in most cases the involvement is secondary. Primary hydatid disease of female genital tract is even very rarer and generates considerable diagnostic difficulty. A significant clinical suspicion is necessary in the differential diagnosis of pelvic cystic diseases to identify such a rare entity. PMID- 24471004 TI - Intraluminal cecal hydatid cyst presented as chronic intestinal obstruction. AB - A 70-year-old male presenting with abdominal pain was clinically diagnosed to have chronic intestinal obstruction due to lesion in ileo-cecal junction based on barium meal follow through. He underwent right hemicolectomy and the lesion was ascertained to be an intraluminal hydatid cyst in the caecum. Intraluminal cecal hydatid cysts can mimic malignancy on radiological investigations. It should be considered as a differential diagnosis in patients presenting with intestinal obstruction in endemic regions for hydatid disease. PMID- 24471005 TI - Cutaneous fistula of liver echinococcal cyst previously misdiagnosed as fistulizated rib osteomyelitis. AB - External fistulization or subcutaneous rupture of liver echinococcal cyst (EC) is found occasionally with total of 15 cases reported in the literature. We report a case of 60-year-old female previously misdiagnosed as fistulizated osteomyelitis of the 11(th) rib. At computed tomography scan, non-vital EC was noted in the third liver segment. Under suspicion of external fistulization of perforated EC the patient underwent one-stage operation-pericystectomy and complete fistula excision. A retrospective analysis of the reported cases in the literature was performed with special references to classifying this rare entity. The main purpose of this report is to highlight the possibility of such a diagnosis when cutaneous fistula occurs in a same anatomic area with hydatid EC, even that cyst is proven to be calcified. We emphasize the role of a swift and radical surgical procedure including complete fistula excision to prevent secondary dissemination and post-operative complications. PMID- 24471006 TI - Occipital neurocysticercosis presenting as monocular visual hallucinations and transient blurring of vision. PMID- 24471007 TI - Latex agglutination test for the detection of cysticercus antigen in the urine for the diagnosis of neurocysticercosis. PMID- 24471008 TI - An interview with Dr. Magda Azab. PMID- 24471009 TI - Temporomandibular disorder in the oral and maxillofacial fields. PMID- 24471010 TI - Platysma myocutaneous flap - its current role in reconstructive surgery of oral soft tissue defects. AB - Reconstruction of oral soft-tissue defects following resection of oral carcinomas can be achieved using various techniques including microsurgical tissue transfer. However, there seems to be a role for regional or local flaps. Small to medium size defects can be functionally reconstructed with the platysma myocutaneous flap as an excellent choice particularly in medically compromised patients not being eligible for free tissue transfer. The present paper reviews the indication, surgical technique, and complications following reconstruction of defects of the oral cavity with the platysma myocutaneous flap. PMID- 24471011 TI - Bisphosphonates-related osteonecrosis of the jaw in Korea: a preliminary report. AB - OBJECTIVES: Bisphosphonates (BP) are widely used in medicine for inhibiting bone resorption; however bisphosphonate-related osteonecrosis of the jaw (BRONJ) is a major side effect of BP. To date, there have been no specific reports on the incidence of BRONJ among Koreans. This study investigated the preliminary results from a nationwide survey of BRONJ in the Departments of Oral and Maxillofacial Surgery (OMFS) at individual training hospitals. MATERIALS AND METHODS: A total of 15 OMFS departments (10 from dental schools, 4 from medical schools, and 1 from a dental hospital) participated in a multi-centric survey. This study assessed every BRONJ case diagnosed between January 2010 and December 2010. The patient age and BP type were evaluated. RESULTS: A total of 254 BRONJ cases were collected. The majority of BRONJ cases were associated with oral BP therapy, while 21.8% of the cases were associated with intravenous administration. Alendronate was the drug most frequently related to BRONJ (59.2% of cases), followed by risedronate (14.3%) and zolendronate (17.0%). The average age of BRONJ patients was 70.0+/-10.1 years, with a range of 38-88 years of age. With the number of BP patients in Korea reported to be around 600,000 in 2008, the estimated incidence of BRONJ is at least 0.04% or 1 per 2,300 BP patients. CONCLUSION: The results suggest that the estimated incidence of BRONJ in Korea is higher than the incidence of other countries. Future prospective studies should be carried out to investigate the exact epidemiological characteristics of BRONJ in Korea. PMID- 24471012 TI - Effect of simultaneous therapy of arthrocentesis and occlusal splints on temporomandibular disorders: anterior disc displacement without reduction. AB - OBJECTIVES: This study sought to evaluate the effect of simultaneous application of arthrocentesis and occlusal splint. MATERIALS AND METHODS: A retrospective study of 43 patients (3 males, 40 females) whose symptoms had improved was conducted at the Department of Oral and Maxillofacial Surgery, Dong-A University Hospital between 2008 and 2010. Subjects were divided into three groups: Group A (17 patients with arthrocentesis and occlusal splints simultaneously applied), Group B (13 patients whose symptoms did not improve with occlusal splints, undergoing arthrocentesis after occlusal splint use for 8 weeks), and Group C (13 patients that only used occlusal splints). We compared these groups in maximum comfortable opening (MCO) and the visual analogue scale of pain and noise. Follow up was performed at 1 week, 1 month, 3 months, and 6 months. RESULTS: The improvement of symptoms was noted in all three groups, but Group A had a quicker improvement than the other groups, in terms of pain reduction and MCO increases. CONCLUSION: The simultaneous application of arthrocentesis and occlusal splints can reduce patient discomfort more quickly. PMID- 24471013 TI - Full thickness skin grafts from the groin: donor site morbidity and graft survival rate from 50 cases. AB - OBJECTIVES: Full thickness skin grafts (FTSG) offer several advantages; they are esthetically superb, have less postoperative shrinkage, and offer minimal postoperative pain and scar formation at the donor site. As a donor site of FTSG, the groin offers a relatively large area of skin with high elasticity. The aim of this study was to evaluate FTSG from the groin for reconstruction in oral and maxillofacial surgery. MATERIALS AND METHODS: In a retrospective study, 50 patients (27 males, 23 females) who received FTSG from the groin were evaluated for their operation records, clinical photography, and medical records. RESULTS: The width of skin from the groin was distributed from 2-8 cm (mean: 5.1 cm) at the donor site, while the long axis length was distributed from 3-13 cm (mean: 7.4 cm). A high number of patients, 47 patients (94%) out of 50, showed good healing at the donor site. Wound impairment was seen in 3 patients (6%), minor wound dehiscence in 2 patients, and severe wound dehiscence in 1 patient. In the recipient site, delayed healing was observed in 2 patients (4%). CONCLUSION: FTSG from the groin to repair soft tissue defects in reconstruction surgery is a good method due to the relatively big size of the graft, decreasing morbidity at the donor site, and higher graft survival rates. PMID- 24471014 TI - Angiographic embolization for hemorrhage control after dental implantation. AB - Dental implantation in the mandibular anterior region is considered a safe and reliable surgical procedure. On the other hand, several articles have reported that inadvertent hemorrhage of the sublingual artery can result in life threatening airway obstruction. Surgical ligation under intubation or tracheostomy is the most widely used approach for controlling mouth floor bleeding in this highly vascular region. Nonetheless, surgically exploring the bleeding focus is difficult because of anatomical distortion followed by widespread edema and swelling. Since swelling of the mouth floor advances quickly, timely management is essential for favorable postoperative outcome. This paper reports a case of immediate hemorrhage control with angiographic embolization to perform rapid hemostasis before the ongoing swelling causes airway obstruction. Less invasive, angiographic embolization can prevent neurovascular damage during a surgical exploration of injured vascular structures on the mouth floor. PMID- 24471015 TI - Self-inflating oral tissue expander for ridge augmentation in the severely atrophic mandible. AB - In dentistry, tissue expanders have been used to obtain sufficient soft tissue for alveolar bone augmentation in the severely atrophic ridge. Herein, we review two cases of soft tissue augmentation using a self-inflating tissue expander in patients in the Department of Oral and Maxillofacial Surgery at Ewha Womans University Mokdong Hospital for bone graft and implant operations. The results of each patient were presented using pre-operative and post-operative radiographs and clinical exams. The results of our study indicate successful bone graft and implant surgery using a self-inflating tissue expander. PMID- 24471016 TI - Giant osteochondroma of the parapharyngeal space: a case report. AB - Osteochondroma is a common benign tumor of the axial skeleton, especially in the distal metaphysis of the femur and the proximal metaphysis of the tibia, that can occur on the facial skeleton (albeit rarely). Osteochondroma is differentiated from chondroma, osteochondromatosis and osteoma. Osteochondroma shows an irregular radiopaque lesion and chondromatic area surrounded by the osteoma. When it develops in the long bone, it has a marked tendency to occur at 10 to 20 years of age and ceases with the end of pubertal growth. However, when it develops in the mandibular condyle, it is prevalent in the third decade and continuous to develop. Tumors that develop in the long bone have a predilection for men, but tumors in the mandible have a predilection for women. In osteochondroma of the mandibular condyle, clinical features presented include occlusal changes, facial asymmetry, headaches, pain and joint noise on the temporomandibular joint, mouth opening limitations, and jaw deviation at the involved site. The first choice of treatment for the massive osteochondroma is surgical removal. A 70-year-old female patient with an osteochondroma on her right mandibular condyle visited our clinic. We surgically removed the mass with favorable results. It is presented here along with a review of literature on osteochondroma. PMID- 24471017 TI - Dental tissues as adult stem cell source. PMID- 24471018 TI - Antimicrobial surfaces for craniofacial implants: state of the art. AB - In an attempt to regain function and aesthetics in the craniofacial region, different biomaterials, including titanium, hydroxyapatite, biodegradable polymers and composites, have been widely used as a result of the loss of craniofacial bone. Although these materials presented favorable success rates, osseointegration and antibacterial properties are often hard to achieve. Although bone-implant interactions are highly dependent on the implant's surface characteristics, infections following traumatic craniofacial injuries are common. As such, poor osseointegration and infections are two of the many causes of implant failure. Further, as increasingly complex dental repairs are attempted, the likelihood of infection in these implants has also been on the rise. For these reasons, the treatment of craniofacial bone defects and dental repairs for long-term success remains a challenge. Various approaches to reduce the rate of infection and improve osseointegration have been investigated. Furthermore, recent and planned tissue engineering developments are aimed at improving the implants' physical and biological properties by improving their surfaces in order to develop craniofacial bone substitutes that will restore, maintain and improve tissue function. In this review, the commonly used biomaterials for craniofacial bone restoration and dental repair, as well as surface modification techniques, antibacterial surfaces and coatings are discussed. PMID- 24471019 TI - Modulation of osteoblastic/odontoblastic differentiation of adult mesenchymal stem cells through gene introduction: a brief review. AB - Bone tissue engineering is one of the important therapeutic approaches to the regeneration of bones in the entire field of regeneration medicine. Mesenchymal stem cells (MSCs) are actively discussed as material for bone tissue engineering due to their ability to differentiate into autologous bone. MSCs are able to differentiate into different lineages: osteo/odontogenic, adipogenic, and neurogenic. The tissue of origin for MSCs defines them as bone marrow-derived stem cells, adipose tissue-derived stem cells, and, among many others, dental stem cells. According to the tissue of origin, DSCs are further stratified into dental pulp stem cells, periodontal ligament stem cells, stem cells from apical papilla, stem cells from human exfoliated deciduous teeth, dental follicle precursor cells, and dental papilla cells. There are numerous in vitro/in vivo reports suggesting successful mineralization potential or osteo/odontogenic ability of MSCs. Still, there is further need for the optimization of MSCs-based tissue engineering methods, and the introduction of genes related to osteo/odontogenic differentiation into MSCs might aid in the process. In this review, articles that reported enhanced osteo/odontogenic differentiation with gene introduction into MSCs will be discussed to provide a background for successful bone tissue engineering using MSCs with artificially introduced genes. PMID- 24471020 TI - Inducing re-epithelialization in skin wound through cultured oral mucosal keratinocytes. AB - OBJECTIVES: The purpose of this study was to investigate the wound healing effect of primary cultured oral mucosal keratinocytes (OMKs) and to assess their roles in skin wounds. MATERIALS AND METHODS: OMK labeled with BromodeoxyUridine were scattered onto 1.5*1.5 cm skin defects of adult female nude mice (OMK group, n=15). For the control, culture media were placed on the wound (control group, n=15). Mice in both groups were sacrificed at three days (n=5), one week (n=5), and two weeks (n=5), and histomorphometric and immunoblot analyses with keratinocyte growth factor (KGF), interleukin (IL)-6, and IL-1alpha antibody were performed for the biopsied wound specimen. To verify the effect of the cytokine, rhIL-1alpha was applied instead of OMK transplantation, and the OMK and control groups were compared with regard to re-epithelialization. RESULTS: Histomorphometric analyses demonstrated faster re-epithelialization in the graft group than in the control group at the third day, first week, and second week. Newly forming epithelium showed maintenance of the histological character of the skin epithelium. The graft group showed superior expression of KGF, IL-6, and IL 1alpha protein, compared with the control group. Similar faster re epithelialization was observed after treatment with rhIL-1alpha instead of OMK transplantation. CONCLUSION: We successfully confirmed that the graft of primary cultured OMKs promoted regeneration of skin defects. The mechanism of accelerated wound healing by primary cultured OMKs was attributed to inducement of cytokine expression as required for re-epithelialization. PMID- 24471021 TI - Frankfort horizontal plane is an appropriate three-dimensinal reference in the evaluation of clinical and skeletal cant. AB - OBJECTIVES: In three-dimensional computed tomography (3D-CT), the cant is evaluated by measuring the distance between the reference plane (or line) and the tooth. The purpose of this study was to determine the horizontal skeletal reference plane that showed the greatest correlation with clinical evaluation. MATERIALS AND METHODS: The subjects were 15 patients who closed their eyes during the CT image taking process. The menton points of all patients deviated by more than 3 mm. In the first evaluation, clinical cant was measured. The distance from the inner canthus to the ipsilateral canine tip and the distance from the eyelid to the ipsilateral first molar were obtained. The distance between the left and right sides was also measured. In the second evaluation, skeletal cant was measured. Six reference planes and one line were used for the evaluation of occlusal cant: 1) FH plane R: Or.R - Or.L - Po.R; 2) FH plane L: Or.R - Or.L - Po.L; 3) F. Ovale plane R: Rt.F.Ovale - Lt.F.Ovale - Or.R; 4) F. Ovale plane L: Rt.F.Ovale - Lt.F.Ovale - Or.L; 5) FZS plane R: Rt.FZS - Lt.FZS - Po.R; 6) FZS plane R: Rt.FZS - Lt.FZS - Po.L, and; 7) FZS line: Rt.FZS - Lt.FZS. RESULTS: The clinical and skeletal cants were compared using linear regression analysis. The FH plane R, FH plane L, and FZS line showed the highest correlation (P<0.05). CONCLUSION: The FH plane R and FH plane L are the most appropriate horizontal reference plane in evaluation of occlusal cant on 3D-CT. PMID- 24471022 TI - Retrospective clinical study on sinus bone graft and tapered-body implant placement. AB - OBJECTIVES: This study evaluated implant success rate, survival rate, marginal bone resorption of implants, and material resorption of sinus bone graft in cases wherein tapered body implants were installed. MATERIALS AND METHODS: From September 2003 to January 2006, 20 patients from Seoul National University Bundong Hospital, with a mean age of 54.7 years, were considered. The mean follow up period was 19 months. This study covered 50 implants; 14 implants were placed in the maxillary premolar area, and 36 in the maxillary molar area; 24 sinuses were included. RESULTS: The success rate was 92%, and the survival rate was 96.0%. The mean amount of sinus augmentation was 12.35+/-3.27 mm. The bone graft resorption rate one year after surgery was 0.97+/-0.84 mm; that for the immediate implantation group was 0.91+/-0.86 mm, and that for the delayed implantation group was 1.16+/-0.77 mm. However, the difference was not statistically significant. The mean marginal bone resorption one year after restoration was 0.17+/-0.27 mm (immediate group: 0.12+/-0.23 mm; delayed group 0.40+/-0.33 mm); statistically significant difference was observed between the two groups. CONCLUSION: Tapered body implant can be available in the maxillary posterior edentulous ridge which sinus bone graft is necessary. PMID- 24471023 TI - Lemierre syndrome with thrombosis of sigmoid sinus following dental extraction: a case report. AB - Lemierre syndrome is caused by an infection in the oropharyngeal region with subsequent thrombophlebitis in the internal jugular vein. The thrombus from the thrombophlebitis can invade other vital organs, such as liver, lungs, or joints, resulting in secondary infection, which further exacerbates the fatal prognosis of this syndrome. Lemierre syndrome, also called postanginal sepsis or necrobacillosis, was first reported by Dr. Lemierre in 1936. In his report, Lemierre mentioned that out of 20 patients who suffered from this syndrome, only two survived. He also stated that all of the 20 patients complained of infections in the palatine tonsils and developed sepsis and thrombophlebitis in the internal jugular vein. Once called a "forgotten disease," this syndrome showed a very high mortality rate until usage of antibiotics became prevalent. In this case report, the authors present a 71-year-old female patient who suffered from Lemierre syndrome with thrombosis extended to the right sigmoid sinus. PMID- 24471024 TI - Open reduction and internal fixation of mandibular fracture in an 11-month-old infant: a case report. AB - Mandibular fractures in infants are rare. This case report describes management of a mandibular fracture in an 11-month-old infant using a microplate and screws with open reduction. The surgical treatment was successful. Because the bone fragments were displaced and only the primary incisors had erupted, conservative treatment, such as an acrylic splint and circummandibular wiring, was not recommended. Nine weeks after surgery, the microplate was removed. The results showed complete clinical and radiological bone healing with normal eruption of deciduous teeth. PMID- 24471026 TI - Computer-guidance in oral and maxillofacial surgery. PMID- 24471025 TI - Displacement of dental implants into the focal osteoporotic bone marrow defect: a report of three cases. AB - Focal osteoporotic bone marrow defect (FOBMD) is a radiolucent area corresponding to the presence of hematopoietic tissue rarely found in the jaws. FOBMD is most commonly located in the mandibular edentulous posterior area of a middle-aged female. From November 2011 to November 2012, we experienced three cases involving removal of implants that had accidentally fallen into the FOBMD area. All patients happened to be female, with a mean age of 54 years (range: 51-60 years). One case involved hypoesthesia of the lower lip and chin, while two cases healed without any complication. Displacement of an implant into the FOBMD area is an unusual event, which occurs rarely during placement of a dental fixture. The purpose of this study was to report on three cases of FOBMD and to provide a review of related literature. PMID- 24471027 TI - Tooth-derived bone graft material. AB - With successful extraction of growth factors and bone morphogenic proteins (BMPs) from mammalian teeth, many researchers have supported development of a bone substitute using tooth-derived substances. Some studies have also expanded the potential use of teeth as a carrier for growth factors and stem cells. A broad overview of the published findings with regard to tooth-derived regenerative tissue engineering technique is outlined. Considering more than 100 published papers, our team has developed the protocols and techniques for processing of bone graft material using extracted teeth. Based on current studies and studies that will be needed in the future, we can anticipate development of scaffolds, homogenous and xenogenous tooth bone grafts, and dental restorative materials using extracted teeth. PMID- 24471028 TI - Enhanced bone morphogenic protein adenoviral gene delivery to bone marrow stromal cells using magnetic nanoparticle. AB - OBJECTIVES: This study investigated the question of whether adenoviral magnetofection can be a suitable method for increasing the efficacy of gene delivery into bone marrow stromal cell (BMSC) and for generation of a high level of bone morphogenic protein (BMP) secretion at a minimized viral titer. MATERIALS AND METHODS: Primary BMSCs were isolated from C57BL6 mice and transduced with adenoviral vectors encoding beta galactosidase or BMP2 and BMP7. The level of BMP secretion, activity of osteoblast differentiation, and cell viability of magnetofection were measured and compared with those of the control group. RESULTS: The expression level of beta galactosidase showed that the cell transduction efficiency of AdLacZ increased according to the increased amount of magnetic nanoparticles. No change in cell viability was observed after magnetofection with 2 uL of magnetic nanoparticle. Secretion of BMP2 or BMP7 was accelerated after transduction of AdBMP2 and 7 with magnetofection. AdBMP2 adenoviral magnetofection resulted in up to 7.2-fold higher secretion of BMP2, compared with conventional AdBMP2-transduced BMSCs. Magnetofection also induced a dramatic increase in secretion of BMP7 by up to 10-fold compared to the control. Use of only 1 multiplicity of infection (moi) of magnetofection with adenoviral transduction of AdBMP2 or AdBMP7 resulted in significantly higher transgene expression compared to 20 moi of conventional adenoviral transduction. CONCLUSION: Magnetic particle-mediated gene transudation is a highly efficient method of gene delivery to BMSCs. Magnetofection can lower the amount of viral particles while improving the efficacy of gene delivery. PMID- 24471029 TI - Porcine study on the efficacy of autogenous tooth bone in the maxillary sinus. AB - OBJECTIVES: This study sought to elucidate the effect of autogenous tooth bone material by experimenting on minipig's maxillary sinus and performing histological and histomorphometric analyses. MATERIALS AND METHODS: Five 18-24 month-old male minipigs were selected, and right maxillary sinuses were grafted with bone graft material made of their respective autogenous teeth extracted eight weeks earlier. The left sides were grafted with synthetic hydroxyapatite as control groups. All minipigs were sacrificed at 12 weeks after bone graft, which was known to be 1 sigma (sigma) period for pigs. Specimens were evaluated histologically under a light microscope after haematoxylin-eosin staining followed by semi-quantitative study via histomorphometric analysis. The ratio of new bone to total area was evaluated using digital software for calculation of area. RESULTS: All specimens were available, except one on the right side (experimental group), which was missing during specimen preparation. This study demonstrated new bone at the periphery of the existing bone in both groups, showing evidence of bone remodeling, however, encroachment of new bone on the central part of the graft at the 1 sigma period was observed only in the autogenous tooth bone group (experimental group). Histomorphometric analysis showed more new bone formation in the experimental group compared to the control group. Although the difference was not statistically significant (P>0.05), the mean percentage area for new bone for the experimental and control groups were 57.19%+/-11.16% and 34.07%+/-13.09%, respectively. CONCLUSION: The novel bone graft material using autogenous tooth is a good alternative to autogenous bone, comparable to autogenous bone, and outperforming synthetic hydroxyapatite bone graft materials in terms of bone regeneration capacity. Augmentation with autogenous tooth bone materials will reduce donor site morbidity without hampering the safety of the autogenous bone graft. PMID- 24471030 TI - Clinical outcome of conservative treatment of injured inferior alveolar nerve during dental implant placement. AB - OBJECTIVES: Infererior alveolar nerve (IAN) damage may be one of the distressing complications occurring during implant placement. Because of nature of closed injury, a large proportion is approached non-invasively. The purpose of this study was to analyze the outcomes of conservative management of the injured nerve during dental implant procedure. MATERIALS AND METHODS: Sixty-four patients of implant related IAN injury, who were managed by medication or observation from January 1997 to March 2007 at the Department of Oral and Maxillofacial Surgery, Seoul National University Dental Hospital, were retrospectively investigated. The objective tests and subjective evaluations were performed to evaluate the degree of damage and duration of sensory disturbance recovery. Tests were performed on the day of the first visit and every two months afterward. Patient's initial symptoms, proximity of the implant to the IAN, time interval between implant surgery and the first visit to our clinic, and treatment after implant surgery were analyzed to determine whether these factors affected the final outcomes. RESULTS: Among the 64 patients, 23 had a chief complaint of sensory disturbance and others with dysesthesia. The mean time until first visit to our hospital after the injury was 10.9 months.One year after nerve injury, the sensation was improved in 9 patients, whereas not improved in 38 patients, even 4 patients experienced deterioration. Better prognosis was observed in the group of patients with early visits and with implants placed or managed not too close to the IAN. CONCLUSION: Nearly 70% of patients with IAN injury during implant placement showed no improvement in sensation or dysesthesia with the conservative management. Earlier decision for active treatment needs to be considered because of possibility of deterioration of symptoms and unsatisfactory recovery. PMID- 24471031 TI - Pterygoid hamulus bursitis as a cause of craniofacial pain: a case report. AB - Pain on the soft palate and pharynx can originate in several associated structures. Therefore, diagnosis of patients who complain of discomfort in these areas may be difficult and complicated. Pterygoid hamulus bursitis is a rare disease showing various symptoms in the palatal and pharyngeal regions. As such, it can be one of the reported causes of pain in these areas. Treatment of hamular bursitis is either conservative or surgical. If the etiologic factor of bursitis is osteophytic formation on the hamulus or hypertrophy of the bursa, resection of the hamulus is usually the preferred surgical treatment. We report on a case of bursitis that was managed successfully by surgical treatment and a review of the literature. PMID- 24471032 TI - Occurrence of multiple myeloma in the head and neck: a report of two cases. AB - Multiple myeloma (MM) is a disease reported to account for 1% of all cancers and 10% of hematological malignant diseases. Unlike other malignant diseases that are transferred to the osseous tissues, MM does not show new bone formation, is associated with characteristic osteolytic lesions, and shows monoclonal protein (M-protein) on the immunohematological test, which is an important index in its diagnosis. Solitary lesions of MM are rare in the head and neck area, and, in most cases, MM of the head and neck area is related to systemic sympomts. PMID- 24471033 TI - Prognosis and evaluation of tooth damage caused by implant fixtures. AB - Damage to adjacent teeth is one of the various complications that may occur during implant placement and is often the result of improper direction during fixture placement or excessive depth of placement. In general, if detrimental symptoms, such as reaction to percussion in damaged teeth, mobility, and pulp necrosis, are not present, osseointegration should be observed at follow-up. In three cases, the possibility of root damage due to an implant fixture placed too close to each adjacent tooth was perceived on radiographs. However, in all of these cases, there were no clinical symptoms or radiographic changes present in the tooth, and the implants did not exhibit decreased stability or peri implantitis. Therefore, we can carefully predict that the implant fixture close to the adjacent tooth did not invade the cementum of the root, and therefore did not produce the suspected pulpal damage or periradicular symptoms. In this study, we considered both the implant status as well as the adjacent tooth. PMID- 24471034 TI - The importance of information technology for clinical and basic researches on the field of oral and maxillofacial surgery. PMID- 24471035 TI - Osteogenic potential of adult stem cells from human maxillary sinus membrane by Simvastatin in vitro: preliminary report. AB - OBJECTIVES: The objective of this study is to determine the adequate concentration and to evaluate the osteogenic potential of simvastatin in human maxillary sinus membrane-derived stem cells (hSMSC). MATERIALS AND METHODS: Mesenchymal stem cells derived from the human maxillary sinus membrane were treated with various concentrations of simvastatin. The adequate concentration of simvastatin for osteogenic induction was determined using bone morphogenetic protein (BMP-2). The efficacy of osteogenic differentiation of simavastatin was verified using osteocalcin mRNA, and the mineralization efficacy of hSMSCs and simvastatin treatment was compared with alkaline phosphatase and von Kossa staining. RESULTS: Expression of BMP-2 mRNA and protein was observed after three days and was dependent on the concentration of simvastatin. Expression of osteocalcin mRNA was observed after three days in the 1.0 uM simvastatin-treated group. Mineralization was observed after three days in the simvastatin-treated group. CONCLUSION: These results suggest that simvastatin induces the osteogenic potential of mesenchymal stem cells derived from the human maxillary sinus membrane mucosa. PMID- 24471036 TI - Clinical evaluation of ridge augmentation using autogenous tooth bone graft material: case series study. AB - OBJECTIVES: Interest in bone graft material has increased with regard to restoration in cases of bone defect around the implant. Autogenous tooth bone graft material was developed and commercialized in 2008. In this study, we evaluated the results of vertical and horizontal ridge augmentation with autogenous tooth bone graft material. MATERIALS AND METHODS: This study targeted patients who had vertical or horizontal ridge augmentation using AutoBT from March 2009 to April 2010. We evaluated the age and gender of the subject patients, implant stability, adjunctive surgery, additional bone graft material and barrier membrane, post-operative complication, implant survival rate, and crestal bone loss. RESULTS: We performed vertical and horizontal ridge augmentation using powder- or block-type autogenous tooth bone graft material, and implant placement was performed on nine patients (male: 7, female: 2). The average age of patients was 49.88+/-12.98 years, and the post-operative follow-up period was 35+/-5.31 months. Post-operative complications included wound dehiscence (one case), hematoma (one case), and implant osseointegration failure (one case; survival rate: 96%); however, there were no complications related to bone graft material, such as infection. Average marginal bone loss after one-year loading was 0.12+/-0.19 mm. Therefore, excellent clinical results can be said to have been obtained. CONCLUSION: Excellent clinical results can be said to have been obtained with vertical and horizontal ridge augmentation using autogenous tooth bone graft material. PMID- 24471037 TI - Effect of loading time on marginal bone loss around hydroxyapatite-coated implants. AB - OBJECTIVES: The objective of this study is compare the rate of marginal bone resorption around hydroxyapatite-coated implants given different loading times in order to evaluate their stability. MATERIALS AND METHODS: The study was conducted retrospectively for one year, targeting 41 patients whose treatment areas were the posterior maxilla and the mandible. Osstem TS III HA (Osstem Implant Co., Busan, Korea) and Zimmer TSV-HA (Zimmer Dental, Carlsbad, CA, USA), which employ the new hydroxyapatite coating technique, were used. The patients were divided into two groups - immediate and delayed loading - and the bone level at the time of loading commencement and after one year of loading was measured using periapical radiography. Differences between the groups were evaluated using Mann Whitney (alpha=0.05). RESULTS: For all patients as a single group, the survival rate of the implants was 100%, and the mean marginal bone loss was 0.26+/-0.59 mm. In comparison of the differences by loading, mean marginal bone loss of 0.32+/-0.69 mm was recorded for the immediate loading group whereas the delayed loading group had mean marginal bone loss of 0.16+/-0.42 mm. However, the difference was not significant (P>0.05). CONCLUSION: Within the limited observation period of one year, predictable survival rates can be expected when using immediately loaded hydroxyapatite-coated implants. PMID- 24471038 TI - 3-Dimensional analysis for class III malocclusion patients with facial asymmetry. AB - OBJECTIVES: The aim of this study is to investigate the correlation between 2 dimensional (2D) cephalometric measurement and 3-dimensional (3D) cone beam computed tomography (CBCT) measurement, and to evaluate the availability of 3D analysis for asymmetry patients. MATERIALS AND METHODS: A total of Twenty-seven patients were evaluated for facial asymmetry by photograph and cephalometric radiograph, and CBCT. The 14 measurements values were evaluated and those for 2D and 3D were compared. The patients were classified into two groups. Patients in group 1 were evaluated for symmetry in the middle 1/3 of the face and asymmetry in the lower 1/3 of the face, and those in group 2 for asymmetry of both the middle and lower 1/3 of the face. RESULTS: In group 1, significant differences were observed in nine values out of 14 values. Values included three from anteroposterior cephalometric radiograph measurement values (cant and both body height) and six from lateral cephalometric radiographs (both ramus length, both lateral ramal inclination, and both gonial angles). In group 2, comparison between 2D and 3D showed significant difference in 10 factors. Values included four from anteroposterior cephalometric radiograph measurement values (both maxillary height, both body height) and six from lateral cephalometric radiographs (both ramus length, both lateral ramal inclination, and both gonial angles). CONCLUSION: Information from 2D analysis was inaccurate in several measurements. Therefore, in asymmetry patients, 3D analysis is useful in diagnosis of asymmetry. PMID- 24471039 TI - Odontogenic infection involving the secondary fascial space in diabetic and non diabetic patients: a clinical comparative study. AB - OBJECTIVES: This retrospective study was performed to evaluate the clinical impact of diabetes mellitus on the prognosis in secondary space infection. MATERIALS AND METHODS: Medical records, radiographic images, computed tomography, and microbial studies of 51 patients (25 diabetic patients and 26 non-diabetic patients) were reviewed. Patients were diagnosed as secondary fascial space infections with odontogenic origin and underwent treatment at Chonnam National University Hospital, in Department of Oral and Maxillofacial Surgery, from January 2007 to February 2009. RESULTS: COMPARED TO PATIENTS WITHOUT DIABETES, PATIENTS WITH DIABETES WERE PRESENTED WITH THE FOLLOWING CHARACTERISTICS: older age (diabetic patients: 62.9 years, non-diabetic patients, 47.8 years), more spaces involved (diabetic patients, 60%; non-diabetic patients, 27.3%), more intense treatment, longer hospitalization (diabetic patients, 28.9 days; non diabetic patients, 15.4 days), higher white blood cell and C-reactive protein values, higher incidence of complication (diabetic patients, 40%; non-diabetic patients, 7.7%), and distinctive main causative microorganisms. CONCLUSION: These results suggest that the prognosis of diabetic patients is poorer than that of non-diabetic patients in secondary space infections since they had greater incidence rates of involved spaces, abnormal hematologic findings, more complications, and additional procedures, such as tracheostomy. PMID- 24471040 TI - Expansile keratocystic odontogenic tumor in the maxilla: immunohistochemical studies and review of literature. AB - Keratocystic odontogenic tumors (KCOT) - previously termed odontogenic keratocysts (OKC) - are characterized by aggressive behavior and a high rate of recurrence. Histopathologically, the basal layer of KCOT shows a higher cell proliferation rate and increased expression of anti-apoptosis genes. Clinically, KCOT is frequently involved in the mandibular posterior region but is not common in the posterior maxilla. However, it should be noted that due to its expansive characteristics, KCOT involved near the maxillary sinus could easily expand to an enormous size and occupy the entire maxilla. To achieve total excision of these expanded cystic tumors in the maxilla, a more aggressive approach would be needed. In this report, we describe two cases of expansile KCOT involving the entire unilateral maxilla and maxillary sinus; they were completely excised using the Weber-Ferguson approach, showing no evidence of recurrence during the follow up period of more than two years. In immunohistochemical analyses of the tumor specimens, p53 and p63 showed strong expression, and B-cell lymphoma 2 (BCL2) and MKI67 (Ki-67) showed moderate or weak expression, however, detection of BCL2 associated X protein (BAX) was almost negative. These data indicate that expansile KCOT possesses increased anti-apoptotic activity and cell proliferation rate but decreased apoptosis. These properties of KCOT may contribute to tumor enlargement, aggressive behavior, and high recurrence rate. PMID- 24471041 TI - Correction of post-traumatic anterior open bite by injection of botulinum toxin type A into the anterior belly of the digastric muscle: case report. AB - Post-traumatic anterior open bite can occur as a result of broken balance among the masticatory muscles. The superior hyoid muscle group retracts the mandible downward and contributes to the anterior open bite. Denervation of the digastric muscle by injection of botulinum toxin type A (BTX-A) can reduce the power of the digastric muscle and help to resolve the post-traumatic anterior open bite. A patient with a bilateral angle fracture had an anterior open bite even after undergoing three operations under general anesthesia and rubber traction. Although the open bite showed some improvement by the repeated operation, the occlusion was still unstable six weeks after the initial treatment. To eliminate the residual anterior open bite, BTX-A was injected into the anterior belly of the digastric muscle. Following injection of BTX-A, the anterior open bite showed immediate improvement. Complication and relapse were not observed during follow up. Long-standing post-traumatic open bite could be successfully corrected by injection of BTX-A into the anterior belly of the digastric muscle without complication. PMID- 24471042 TI - Inflammatory granuloma caused by injectable soft tissue filler (Artecoll). AB - Artecoll (Artes Medical Inc., San Diego, CA, USA) has recently been developed as a permanent synthetic cosmetic filler. We experienced an inflammatory granuloma resulting from a previous injection of Artecoll at the upper lip, which was regarded as a rare side effect of this filler. A 50-year-old female patient complained of swelling, dull pain, and heat in the right upper nasolabial fold area, which had started one week before her visit to Kyungpook National University Hospital. The patient received topical steroid therapy at a local clinic, which was not effective. At the injection site, a hard nodule was palpated and erythema was observed with mild tenderness. Antibiotic treatment and subsequent incision and drainage did not result in complete cure of the facial swelling, and the facial swelling and pain persisted. Computed tomography showed a lesion approximately 1-cm in size without clear boundaries and relatively increased nodular thickening. Finally, a subdermal lesion was removed via an intraoral vestibular approach. The lesion was diagnosed as inflammatory granuloma by a permanent biopsy. The patient had healed at two months after the filler injection. Although the soft tissue filler is widely used for cosmetic purposes, there is potential for complication, such as the inflammatory granuloma should be considered before treatment. PMID- 24471043 TI - Use of the surface-based registration function of computer-aided design/computer aided manufacturing software in medical simulation software for three-dimensional simulation of orthognathic surgery. AB - Three-dimensional (3D) computed tomography image models are helpful in reproducing the maxillofacial area; however, they do not necessarily provide an accurate representation of dental occlusion and the state of the teeth. Recent efforts have focused on improvement of dental imaging by replacement of computed tomography with other detailed digital images. Unfortunately, despite the advantages of medical simulation software in dentofacial analysis, diagnosis, and surgical simulation, it lacks adequate registration tools. Following up on our previous report on orthognathic simulation surgery using computer-aided design/computer-aided manufacturing (CAD/CAM) software, we recently used the registration functions of a CAD/CAM platform in conjunction with surgical simulation software. Therefore, we would like to introduce a new technique, which involves use of the registration functions of CAD/CAM software followed by transfer of the images into medical simulation software. This technique may be applicable when using various registration function tools from different software platforms. PMID- 24471045 TI - A brief overview of cell therapy and its product. PMID- 24471046 TI - Clinical statistics: five key statistical concepts for clinicians. AB - Statistics is the science of data. As the foundation of scientific knowledge, data refers to evidentiary facts from the nature of reality by human action, observation, or experiment. Clinicians should be aware of the conditions of good data to support the validity of clinical modalities in reading scientific articles, one of the resources to revise or update their clinical knowledge and skills. The cause-effect link between clinical modality and outcome is ascertained as pattern statistic. The uniformity of nature guarantees the recurrence of data as the basic scientific evidence. Variation statistics are examined for patterns of recurrence. This provides information on the probability of recurrence of the cause-effect phenomenon. Multiple causal factors of natural phenomenon need a counterproof of absence in terms of the control group. A pattern of relation between a causal factor and an effect becomes recognizable, and thus, should be estimated as relation statistic. The type and meaning of each relation statistic should be well-understood. A study regarding a sample from the population of wide variations require clinicians to be aware of error statistics due to random chance. Incomplete human sense, coarse measurement instrument, and preconceived idea as a hypothesis that tends to bias the research, which gives rise to the necessity of keen critical independent mind with regard to the reported data. PMID- 24471047 TI - The impact factors on 5-year survival rate in patients operated with oral cancer. AB - OBJECTIVES: The purpose of this study is to analyze clinical impact factors on the survival rate, and to acquire basic clinical data for the diagnosis of oral cancer, for a determination of the treatment plan with long-term survival in oral cancer patients. MATERIALS AND METHODS: Through a retrospective review of the medical records, the factors for long-term survival rate were analyzed. Thirty seven patients, among patient database with oral cancer treated in the Department of Oral and Maxillofacial Surgery at Pusan National University Hospital within a period from March 1998 to March 2008, were selected within the study criteria and were followed-up for more than 5 years. The analyzed factors were gender, age, drinking, smoking, primary tumor site, type of cancer, TNM stage, recurrence of affected region, and metastasis of cervical lymph node. The 5-year survival rate on the impact factors was calculated statistically using the Kaplan-Meier method. RESULTS: By classification of clinical TNM at the 1st visit, there were 11 (29.7%) cases for stage I, 11 (29.7%) cases for stage II, 3 (8.1%) cases for stage III, and 12 (32.5%) cases for stage IV. The 5-year survival rate of total oral cancer patients after the operation were 75.7%, pathological TNM stage related 5-year survival rate were as follows: stage I 90.0%, stage II 81.8%, stage III 100% and stage IV 45.5%; in which the survival rate difference by each stage was significantly observed. The recurrence of cervical lymph node was the significant impact factor for the survival rate, because only 30.0% the survival rate in recurrent cases existed. During the follow-up, there were 15 (40.5%) patients with confirmed recurrence, and the 5-year survival rate of these patients was decreased as 46.7%. CONCLUSION: The classification of clinical and pathological TNM stage, local recurrence after surgery, and metastasis of cervical lymph node after surgery were analyzed as the 3 most significant factors. PMID- 24471048 TI - Effect of perioperative buccal fracture of the proximal segment on postoperative stability after sagittal split ramus osteotomy. AB - OBJECTIVES: Buccal fracture of the mandibular proximal bone segment during bilateral sagittal split ramus osteotomy (SSRO) reduces the postoperative stability. The primary aim of this study is to evaluate the effect of this type of fracture on bone healing and postoperative stability after mandibular setback surgery. MATERIALS AND METHODS: Ten patients who experienced buccal fracture during SSRO for mandibular setback movement were evaluated. We measured the amount of bone generation on a computed tomography scan, using an image analysis program, and compared the buccal fracture side to the opposite side in each patient. To investigate the effect on postoperative stability, we measured the postoperative relapse in lateral cephalograms, immediately following and six months after the surgery. The control group consisted of ten randomly-selected patients having a similar amount of set-back without buccal fracture. RESULTS: Less bone generation was observed on the buccal fracture side compared with the opposite side (P<0.05). However, there was no significant difference in anterior posterior postoperative relapse between the group with buccal fracture and the control group. The increased mandibular plane angle and anterior facial height after the surgery in the group with buccal fracture manifested as a postoperative clockwise rotation of the mandible. CONCLUSION: Bone generation was delayed compared to the opposite side. However, postoperative stability in the anterior posterior direction could be maintained with rigid fixation. PMID- 24471049 TI - Immunohistochemical study on the expression of matrix metalloproteinase 2 and high-risk human papilloma virus in the malignant progression of papillomas. AB - OBJECTIVES: Papilloma frequently develops as a benign tumor of the head and neck area, but its potential for malignant transformation has yet to be studied. This study aims to provide basic information for papillomas using the immunohistochemical staining of matrix metalloproteinase 2 (MMP-2) and human papilloma virus (HPV) 16 and 18. MATERIALS AND METHODS: To evaluate the malignant transformation of papillomas, the selected tissue samples were serially diagnosed with pre-cancerous papilloma (with epithelial dysplasia, pseudo-epitheliomatous hyperplasia) or malignant lesion (squamous cell carcinoma, SCC) after the first diagnosis (squamous papilloma, inverted papilloma). The selected tissues were stained with an antibody to MMP-2 and HPV 16-E7, HPV 18-L1. A statistical analysis was performed according to each transformation step. RESULTS: The epithelial layer of papilloma and pre-cancerous papilloma lesions had a similar MMP-2 expression, but that of the malignant lesion had a significantly increased MMP-2 expression. HPV 16 and 18 infection rates were 28.6%, 33.3% and 63.6% in papillomas, pre-cancerous papilloma lesions, and SCC. CONCLUSIONS: A relatively high MMP-2 expression and HPV 16 or 18 infection of papillomas may be associated with early events in the multistep processes of malignant transformation of papillomas. PMID- 24471050 TI - Evaluation of Korean teenagers with temporomandibular joint disorders. AB - OBJECTIVES: This study aims to evaluate the severity and pattern of symptoms exhibited by teenage Korean temporomandibular disorder (TMD) patients. MATERIALS AND METHODS: Among patients with an association of TMDs, teenage patients (11-19 years) who answered the questionnaire on the research diagnostic criteria for TMD (RDC/TMD) were recruited. RESULTS: The ratio of patients who visited our clinic with a chief complaint of clicking sound (34.5%) or temporomandibular pain (36.6%) at the initial diagnosis (examination) was the highest. In the evaluation of the depression index, 75.8% of the subjects were normal, 12.9% were moderate, and 11.3% were severe. With regard to non-specific physical symptoms (including pain), 66.5% of the subjects were normal, 17.0% were moderate, and 16.5% were severe. Concerning non-specific physical symptoms (excluding pain), 70.6% of the subjects were normal, 14.4% were moderate, and 15.0% were severe. In terms of the graded chronic pain score, high disability (grade III, IV) was found in 9.3% of the subjects. CONCLUSION: Among teenage TMD patients, a portion have clinical symptoms and experience severe psychological pressure; hence requiring attention and treatment, as well as understanding the psychological pressure and appropriate treatments for dysfunction. PMID- 24471051 TI - Reduction of superior-lateral intact mandibular condyle dislocation with bone traction hook. AB - Lateral and superior-lateral dislocations of the intact condyle are a rare complication, following traumatic insult to the mandible. We report an unusual case of a 54-year-old male patient who experienced both types of dislocations of the intact condyles with symphysis fracture following a road-traffic accident. Under general anesthesia, conventional manipulation was unsuccessful in relocating the condyles into the glenoid fossa. After applying a percutaneous traction force, using a bone traction hook placed at the sigmoid notch, the displaced intact mandibular condyles were repositioned, and the symphyseal fracture was finally reduced and fixed. The mouth opening was within normal limits, and favorable occlusion was confirmed one month postoperatively. To our knowledge, this is the first case of dislocation of both intact condyles- associated with symphysis fracture--being reduced with bone traction hook. PMID- 24471052 TI - Surgical extraction of mandibular third molar in pterygomandibular space: a case report. AB - Impacted mandibular third molars are located between the second mandibular molar and mandibular ramus. However, ectopic mandibular third molars with heterotopic positions are reported in the subcondylar or pterygomandibular space. The usual cause of malposition is a cyst or tumor, and malposition without a pathology is rare. This case report described an impacted mandibular third molar in the pterygomandibular space without any associated pathology. PMID- 24471053 TI - Importance of immediate surgical intervention and antifungal treatment for rhinocerebral mucormycosis: a case report. AB - Rhinocerebral mucormycosis (RCM) is an opportunistic, potentially life threatening fungal disease. This infective disease invades not only the facial sinuses, but also the maxilla, zygoma, and rhino-cerebral structures with a massive destruction of the facial skeletons and soft tissue. This disease progresses within various underlying diseases, such as diabetes mellitus, hematologic malignancy, renal failure, and systemic immunodepression. The relationship between mucormycosis and these underlying conditions have been discussed extensively in the literature. The authors studied 6 cases of RCM diagnosed by a tissue biopsy and treated at the department of oral and maxillofacial surgery, from 1997 to 2012. Patients were treated with several kinds of surgical interventions and antifungal agents, and their clinical & radiological signs, underlying conditions, surgical methods, and outcomes were analyzed. PMID- 24471054 TI - Removal of a broken needle using three-dimensional computed tomography: a case report. AB - Inferior alveolar nerve block obtained maximum anesthetic effect using a small dose of local anesthetic agent, which also has low a complication incidence. Complications of an inferior alveolar nerve block include direct nerve damage, bleeding, trismus, temporary facial nerve palsy, and etc. Among them, the major iatrogenic complication is dental needle fracture. A fragment that disappears into the soft tissue would be hard to remove, giving rise to a legal problem. A 31-year-old woman was referred for the removal of a broken needle, following an inferior alveolar nerve block. Management involved the removal of the needle under local anesthesia with pre- and peri-operative computed tomography scans. PMID- 24471055 TI - Food and water security issues in Russia I: food security in the general population of the Russian Arctic, Siberia and the Far East, 2000-2011. AB - BACKGROUND: Problems related to food security in Russian Arctic (dietary imbalance, predominance of carbohydrates, shortage of milk products, vegetables and fruits, deficit of vitamins and microelements, chemical, infectious and parasitic food contamination) have been defined in the literature. But no standard protocol of food security assessment has been used in the majority of studies. OBJECTIVES: Our aim was to obtain food security indicators, identified within an Arctic collaboration, for selected regions of the Russian Arctic, Siberia and the Far East, and to compare food safety in these territories. STUDY DESIGN AND METHODS: In 18 regions of the Russian Arctic, Siberia and the Far East, the following indicators of food security were analyzed: food costs, food consumption, and chemical and biological food contamination for the period 2000 2011. RESULTS: Food costs in the regions are high, comprising 23-43% of household income. Only 4 out of 10 food groups (fish products, cereals, sugar, plant oil) are consumed in sufficient amounts. The consumption of milk products, eggs, vegetables, potatoes, fruits (and berries) is severely low in a majority of the selected regions. There are high levels of biological contamination of food in many regions. The biological and chemical contamination situation is alarming, especially in Chukotka. Only 7 food pollutants are under regular control; among pesticides, only DDT. Evenki AO and Magadan Oblast have reached peak values in food contaminants compared with other regions. Mercury in local fish has not been analyzed in the majority of the regions. In 3 regions, no monitoring of DDT occurs. Aflatoxins have not been analyzed in 5 regions. Nitrates had the highest percentage in excess of the hygienic threshold in all regions. Excesses of other pollutants in different regions were episodic and as a rule not high. CONCLUSION: Improvement of the food supply and food accessibility in the regions of the Russian Arctic, Siberia and the Far East is of utmost importance. Both quantitative and qualitative control of chemical and biological contaminants in food is insufficient and demands radical enhancement aimed at improving food security. PMID- 24471056 TI - Anti-hyperlipidemic Effect of Polyphenol Extract (Seapolynol(TM)) and Dieckol Isolated from Ecklonia cava in in vivo and in vitro Models. AB - The inhibitory effect of polyphenol extracts (Seapolynol(TM), SPN) of the marine brown algae Ecklonia cava and dieckol, a major component of SPN, on hyperlipidemia was investigated in ICR mice fed a high-fat diet (HFD) for five weeks. For analysis of the anti-hyperlipidemic effects of SPN and dieckol, these two agents were given orally on a daily basis to HFD-fed mice for four weeks, starting one week after the beginning of HFD feeding. Groups administered with SPN as well as dieckol showed lower body weight gains than the HFD only group. Administration of SPN and dieckol also resulted in a significant reduction of the level of total cholesterol (TCHO), triglyceride (TG), and low-density lipoprotein (LDL) cholesterol in the serum of HFD-fed mice. In Oil Red O staining using 3T3 L1 preadipocytes, it was shown that both SPN and dieckol markedly inhibited lipid accumulation of 3T3-L1 cells. Furthermore, SPN and dieckol (50 MUg/mL) significantly inhibited 3-hydroxyl-methyl glutaryl coenzyme A (HMGCoA) reductase activity in vitro. Taken together, these results suggest that polyphenols of Ecklonia cava (SPN) and dieckol reduce body weight gain and fat accumulation in HFD-induced obese mice, and that their hypolipidemic effect is related to the inhibition of adipogenesis of adipocytes and HMGCoA reductase activity. PMID- 24471057 TI - Hypoglycemic Effect of Sargassum ringgoldianum Extract in STZ-induced Diabetic Mice. AB - This study was designed to investigate whether Sargassum ringgoldianum extract may inhibit alpha-glucosidase and alpha-amylase activities, and alleviate postprandial hyperglycemia in streptozotocin-induced diabetic mice. The IC50 values of Sargassum ringgoldianum extract against alpha-glucosidase and alpha amylase were 0.12 mg/mL and 0.18 mg/mL, respectively, which evidenced higher activities than those of acarbose. The blood glucose levels of the Sargassum ringgoldianum extract administered group were significantly lower compared to the control group in the streptozotocin-induced diabetic mice. Moreover, the area under the two-hour blood glucose response curve was significantly reduced and the absorption of dietary carbohydrates was delayed after administration of Sargassum ringgoldianum extract in the diabetic mice. Therefore, these results indicated that Sargassum ringgoldianum extract may help decrease the postprandial blood glucose level via inhibiting alpha-glucosidase. PMID- 24471058 TI - Effect of Persimmon Leaf Extract on Phthalic Anhydride-induced Allergic Response in Mice. AB - The purpose of this study was to investigate the anti-allergy activities of persimmon leaf extract (PLE) on a phthalic anhydride (PA)-induced allergic mouse model. A human leukemic mast cell line (HMC-1) was used to examine the inhibitory activity of PLE on the histamine release by human leukemic mast cells. PLE inhibited histamine release from HMC-1 cells in response to cross-linkage of high affinity IgE receptor-alpha (FcepsilonRIalpha). Additionally, a PA-induced allergic mouse model was used to investigate the effects of PLE in vivo. Mice were orally administrated with or without PLE of single dose (250 mg/kg/day) for 31 days. Oral intake of PLE significantly inhibited passive cutaneous reactions. Oral administration of PLE to PA-induced allergic mice also led to a striking suppression of the development of contact dermatitis, ear swelling and lymph node weight. In addition, PA-specific IL-4 production of draining lymph node cells was markedly diminished by PLE oral administration, but not IFN-gamma. Furthermore, PLE treatment suppressed PA-induced thymus and activation-regulated chemokine (CCL17) and cutaneous T cell-attracting chemokine (CCL27) expressions in ear tissues. Based on these results, we suggest that PLE may have therapeutic potential as an effective material for management of irritant contact dermatitis or related inflammatory diseases. PMID- 24471059 TI - Antioxidant and Anti-inflammatory Activities of Butanol Extract of Melaleuca leucadendron L. AB - Melaleuca leucadendron L. has been used as a tranquilizing, sedating, evil dispelling and pain-relieving agent. We examined the effects of M. leucadendron L. extracts on oxidative stress and inflammation. M. leucadendron L. was extracted with methanol (MeOH) and then fractionated with chloroform (CHCl3) and butanol (BuOH). Antioxidant activity of the MeOH extract and BuOH fraction were higher than that of both alpha-tocopherol and butyrated hydroxytoluene (BHT). Total phenol content in the extracts of M. leucadendron L., especially the BuOH fraction, well correlated with the antioxidant activity. The anti-inflammatory activity of BuOH extracts were investigated by lipopolysaccharide (LPS)-induced nitric oxide (NO) and prostaglandin E2 (PGE2) production, and cyclooxygenase-2 (COX-2) expression in RAW 264.7 macrophages. The BuOH fraction significantly inhibited LPS-induced NO and PGE2 production. Furthermore, BuOH extract of M. leucadendron L. inhibited the expression of COX-2 and iNOS protein without an appreciable cytotoxic effect on RAW264.7 cells. The extract of M. leucadendron L. also suppressed the phosphorylation of inhibitor kappaBalpha (IkappaBalpha) and its degradation associated with nuclear factor-kappaB (NF-kappaB) activation. Furthermore, BuOH fraction inhibited LPS-induced NF-kappaB transcriptional activity in a dose-dependent manner. These results suggested that M. leucadendron L. could be useful as a natural anti-oxidant and anti-inflammatory resource. PMID- 24471060 TI - Physicochemical properties and sensory evaluation for the heat level (hot taste) of korean red pepper powder. AB - This study investigated the heat level rating of several varieties of Korean red peppers. The chemical constitution of Korean red pepper samples were as follows: 0.54~290.15 mg% capsaicinoids, 79.22~139.09 ASTA value, and 16.76~29.92% free sugar content. The heat level of the Korean red pepper samples was evaluated by trained panelists and the correlation coefficient and F value (0.001%) of the panelist's results were determined to be significant. In the principle component analysis (PCA), PC1 (capsaicinoids) and PC2 (free sugar) were shown to represent 31.98% and 25.77% of the total variance, respectively. The results of panelists trained for red pepper heat rating were evaluated using analysis of variance and correlation analysis. The trained panelists showed a high F value (p=0.05) and high correlation coefficient. A high correlation efficient of 0.84~0.93 for the test samples with a 40 Scoville heat unit (32,000 SHU red pepper powder) was reported in the sensory evaluation of the Korean red pepper heat level by a trained panel. However, the panel showed a low correlation efficiency of 0.70 R(2) when the 60 SHU test samples were included in the analysis. PMID- 24471061 TI - Physicochemical Properties of Roasted Soybean Flour Bioconverted by Solid-State Fermentation Using Bacillus subtilis and Lactobacillus plantarum. AB - To produce novel cheese-like fermented soybean, the solid-state fermentation of roasted soybean flour (RSF) was performed using 1.0% inoculum Bacillus subtilis HA and Lactobacillus plantarum, with the initial 60% substrate moisture for 10 hr at 42 degrees C, resulting in pH 6.5, 0.82% acidity, 3.5% mucilage, 14.3 unit/g protease activity, 7.6 unit/g fibrinolytic activity, 216 mg% tyrosine content and 1.7*10(10) CFU/g of viable cell counts. After the second lactic acid fermentation with 10~30% skim milk powder, the fermented RSF resulted in an increase in acidity with 1.64~1.99%, tyrosine content with 246~308 mg% and protease activity in the range of 5.2~17.5 unit/g and 0.966 water activity. Viable cell counts as probiotics indicated 1.6*10(8) CFU/g of B. subtilis and 7.3*10(10) CFU/g of L. plantarum. The firmness of the first fermented RSF with 2,491 g.omm(-1) greatly decreased to 1,533 g.omm(-1) in the second fermented RSF, although firmness was slightly increased by adding a higher content of skim milk. The consistency of the second fermented RSF also decreased greatly from 55,640 to 3,264~3,998 in the presence of 10~30% skim milk. The effective hydrolysis of soy protein and skim milk protein in the fermented RSF was confirmed. Thus, the second fermented RSF with a sour taste and flavor showed similar textural properties to commercial soft cheese. PMID- 24471062 TI - Effect of Pre-treatment and Storage Conditions on the Quality Characteristics of Ginger Paste. AB - This study was performed to investigate the effects of pre-treatment and storage temperature and periods on the quality characteristics of ginger paste. The pH of the ginger paste remained constant during room temperature storage but increased with prolonged refrigerated storage periods. During five months of frozen storage, regardless of pre-treatment, the pH of most of the samples decreased slightly and then remained constant. In the color value of ginger paste stored at room temperature, the samples with and without chemical additives changed in color more prominently than fermented or pasteurized samples. Intriguingly, the color value for samples containing chemical additives changed more dramatically when stored under refrigerated conditions. However, the L, a, and b values of samples stored under frozen storage conditions did not change even after ten months. Most of the samples contained glucose and fructose, except for the fermented samples. The free sugar content of samples slowly decreased with increasing storage periods, while the organic acid content generally decreased also, regardless of sample type. Depending on pre-treatment and storage temperature, the gingerol content of the samples was either retained or decreased with prolonged storage time. PMID- 24471063 TI - Optimization of Pan Bread Prepared with Ramie Powder and Preservation of Optimized Pan Bread Treated by Gamma Irradiation during Storage. AB - This study was conducted to develop an optimal composite recipe for pan bread with ramie powder that has high sensory approval with all age groups and to estimate the DPPH radical scavenging activity and the pan bread shelf life after gamma irradiation. The sensory evaluation results showed significant differences in flavor (p<0.05), appearance (p<0.01), color (p<0.01), moistness (p<0.01), and overall quality (p<0.05) based on the amount of ramie powder added. As a result, the optimum formulations by numerical and graphical methods were calculated to be as follows: ramie powder 2.76 g (0.92%) and water 184.7 mL. Optimized pan bread with ramie powder and white pan bread were irradiated with gamma-rays at doses of 0, 10, 15, and 20 kGy. The total bacterial growth increased with the longer storage time and the least amount of ramie powder added. Consequently, these results suggest that the addition of ramie powder to pan bread provides added value to the bread in terms of increased shelf life. PMID- 24471064 TI - Isolation of Bacillus amyloliquefaciens Strains with Antifungal Activities from Meju. AB - Bacilli with fibrinolytic activities were isolated from traditionally-prepared Meju and some of these strains showed strong antifungal activities. One isolate, MJ1-4, showed the strongest antifungal activity. MJ1-4 and other isolates were identified as B. amyloliquefaciens strains by recA gene sequencing and RAPD-PCR results. B. amyloliqufaciens MJ1-4 efficiently inhibited an Aspergillus spp. producing aflatoxin B1 (AFB1) and a Penicillium spp.-producing ochratoxin (OTA) in addition to other fungi. Antifungal activity of B. amyloliquefaciens MJ1-4 culture reached its maximum (40 AU/mg protein) in LB or TSB medium around 48 hr at 37 degrees C. Antifungal activity of the concentrated culture supernatant was not decreased significantly by protease treatments, implying that the antifungal substance might not be a simple peptide or protein. Considering its antifungal and fibrinolytic activities together, B. amyloliquefaciens MJ1-4 can serve as a starter for fermented soyfoods such as Cheonggukjang and Doenjang. PMID- 24471065 TI - Consumption patterns and perception analyses of hangwa. AB - Hangwa is a traditional food, corresponding to the current consumption trend, in need of marketing strategies to extend its consumption. Therefore, the purpose of this study was to analyze consumers' consumption patterns and perception of Hangwa to increase consumption in the market. A questionnaire was sent to 250 consumers by e-mail from Oct 8~23, 2009 and the data from 231 persons were analyzed in this study. Statistical, descriptive, paired samples t-test, and importance-performance analyses were conducted using SPSS WIN 17.0. According to the results, Hangwa was purchased mainly 'for present' (39.8%) and the main reasons for buying it were 'traditional image' (33.3%) and 'taste' (22.5%). When importance and performance of attributes considered in purchasing Hangwa were evaluated, performance was assessed to be lower than importance for all attributes. The attributes in the first quadrant with a high importance and a high performance were 'a sanitary process', 'a rigorous quality mark' and 'taste', which were related with quality of the products. In addition, those with a high importance but a low performance were 'popularization through advertisement', 'promotion through mass media', 'conversion of thought on traditional foods', 'a reasonable price' and 'a wide range of price'. In conclusion, Hangwa manufacturers need to diversify products and extend the expiration date based on technologies to promote its consumption. In terms of price, Hangwa should become more available by lowering the price barrier for consumers who are sensitive to price. PMID- 24471066 TI - The antithrombotic and fibrinolytic effect of natto in hypercholesterolemia rats. AB - Antithrombotic and fibrinolytic activity of natto was evaluated on platelet aggregation in vitro and in vivo. Natto showed inhibitory effects on platelet aggregation induced by adenosine 5'diphosphate (ADP) and collagen. Orally administered natto also showed fibrinolytic activity in hypercholesterolemia rats. Normal levels of natto, when administered for four weeks, shortened euglobulin clot lysis time (ECLT) and prolonged partial thromboplastin time (PATT) significantly compared to non-treated group. In addition, the natto treatment decreased total cholesterol in serum. These results showed that intake of normal levels of natto can elicit antithrombotic and fibrinolytic effects, suggesting its consumption may improve blood circulation. PMID- 24471067 TI - Detection of 1,4-dihydroxy-2-naphthoic Acid from commercial makgeolli products. AB - To support beneficial effects of makgeolli for human health, we investigated for the presence of 1,4-dihydroxy-2-naphthoic acid (DHNA), a bifidogenic growth stimulator (BGS), from commercial makgeolli products. Among eleven makgeolli products (A~K), four showed positive peaks for DHNA in high performance liquid chromatography analysis. Makgeolli product A in particular contained the highest concentration of DHNA (0.44 ppm), as confirmed by liquid chromatography-mass spectrometry. Furthermore, BGS activity of the makgeolli product A was higher than those of products in which DHNA was not detected. These results indicate that makgeolli can be a good source for DHNA and that DHNA-enriched makgeolli could be developed by modifying manufacturing procedures and controlling its microbiota. PMID- 24471068 TI - Hydration and Pasting Properties of Oat (Avena sativa) Flour. AB - Three oat cultivars and one oat breeding line were evaluated for chemical, hydration and pasting properties. Protein, starch and beta-glucan levels ranged 11.13~14.37, 56.37~64.86 and 3.44~4.76%, respectively. The oat cultivars Daeyang and Seonyang contained higher beta-glucan levels of 4.76 and 4.35%. The Daeyang variety had a higher water absorption index (WAI) of 2.83~3.35 (g/g), but a lower water solubility index (WSI) of 8.67 ~11.08%. Daeyang and Seonyang cultivars showed higher peak and trough viscosity, but lower breakdown and setback, indicating that they easily swell, and thus could possibly provide the desirable viscosity of an oat product. The beta-glucan levels were correlated positively with WAI, peak and trough viscosity, and negatively to WSI, breakdown and setback viscosity. PMID- 24471069 TI - Dietary Intake Ratios of Calcium-to-Phosphorus and Sodium-to-Potassium Are Associated with Serum Lipid Levels in Healthy Korean Adults. AB - The purpose of this study was to identify food sources for major minerals such as calcium (Ca), phosphorus (P), sodium (Na) and potassium (K), and to evaluate the relationship between dietary intake of these minerals and serum lipids in healthy Korean adults. A total of 132 healthy men and women completed a physical examination and dietary record and provided blood samples for lipid profile analysis. Results showed the following daily average mineral intakes: 373.4 mg of calcium, 806.0 mg of phosphorous, 3685.8 mg of sodium, and 1938.3 mg of potassium. The calcium-to-phosphorus and sodium-to-potassium ratio was about 0.5 and 2.0, respectively. The primary sources for each mineral were: vegetables (24.9%) and fishes (19.0%) for calcium, grains (31.4%) for phosphorus, seasonings (41.6%) and vegetables (27.0%) for sodium, and vegetables (30.6%) and grains (18.5%) for potassium. The correlation analysis, which has been adjusted for age, gender, total food consumption, and energy intake, showed significantly positive correlations between Ca/P and serum HDL cholesterol levels, between Na intake and the level of serum total cholesterol, and between Na/K and the level of serum cholesterol and LDL cholesterol. Our data indicates that the level of mineral consumption partially contributes to serum lipid profiles and that a diet consisting of a low Ca/P ratio and a high Na/K ratio may have negative impacts on lipid metabolism. PMID- 24471070 TI - Methanol Extract of Goat's-beard (Aruncus dioicus) Reduces Renal Injury by Inhibiting Apoptosis in a Rat Model of Ischemia-Reperfusion. AB - Interruption or prolonged reduction and subsequent restoration of blood flow into the kidney triggers the generation of a burst of reactive oxygen species (ROS), leading to injury in the tubular epithelial cells. In this study, we determined whether methanol extract of goat's-beard (Aruncus dioicus) (extract) could prevent this ischemia/re-perfusion injury. When in vitro radical scavenging activity of the extract was measured using a DPPH radical quenching assay, the extract displayed slightly lower activity than ascorbic acid. One hour after administration of the extract (400 mg/kg) by intraperitoneal injection in rats, renal ischemia/reperfusion injury was generated by clamping the left renal artery for forty minutes, followed by 24 hr restoration of blood circulation. Prior to clamping the left renal artery, the right renal artery was removed. Compared with the vehicle-treated group, pre-treatment with the extract significantly reduced the tubular epithelial cell injury by 37% in the outer medulla region, and consequently reduced serum creatinine concentration by 39%. Reduction in the cell injury was mediated by attenuation of Bax/Bcl-2 ratio, inhibition of caspase-3 activation from procaspase-3, and subsequent reduction in the number of apoptotic cells. Thus, goat's-beard (Aruncus dioicus) might be developed as a prophylactic agent to prevent acute kidney injury. PMID- 24471071 TI - Anti-inflammatory Effect of Perilla frutescens (L.) Britton var. frutescens Extract in LPS-stimulated RAW 264.7 Macrophages. AB - This study was designed to investigate the inhibitory effects of Perilla frutescens (L.) Britton var. frutescens extract on the production of inflammation related mediators (NO, ROS, NF-kappaB, iNOS and COX-2) and pro-inflammatory cytokines (TNF-alpha, IL-1beta, IL-6) in lipopolysaccharide-stimulated RAW 264.7 macrophages. Perilla frutescents (L.) Britton var. frutescens was air-dried and extracted with ethanol. The extract dose-dependently decreased the generation of intracellular reactive oxygen species and dose-dependently increased antioxidant enzyme activities, such as superoxide dismutase, catalase and glutathione peroxidase in lipopolysaccharide stimulated RAW 264.7 macrophages. Also, Perilla frutescens (L.) Britton var. frutescens extract suppressed NO production in lipopolysaccharide-stimulated RAW 264.7 cells. The expressions of pro inflammatory cytokines (TNF-alpha, IL-1beta and IL-6), NF-kappaB, iNOS and COX-2 were inhibited by the treatment with the extract. Thus, this study shows the Perilla frutescens (L.) Britton var. frutescens extract could be useful for inhibition of the inflammatory process. PMID- 24471072 TI - Antioxidant Activity and Protection from DNA Damage by Water Extract from Pine (Pinus densiflora) Bark. AB - Water extract from Pinus densiflora (WPD) was investigated for its antioxidant activity and its ability to provide protection from DNA damage. A series of antioxidant assays, including a 1,1-diphenyl-2-picrylhydrazyl (DPPH) free radical scavenging assay, a reducing power assay, a metal-chelating assay, a superoxide radical scavenging assay, and a nitrite scavenging ability, as well as a DNA damage protection assay were performed. Total phenolic content was found to be 211.32 mg Tan/g WPD. The extract scavenged 50% DPPH free radical at a concentration of 21.35 MUg/mL. At that same concentration, the reducing power ability of WPD was higher than that of alpha-tocopherol. The extract chelated 68.9% ferrous ion at the concentration of 4 mg/mL. WPD showed better nitrite scavenging effect at the lower pH. Meanwhile, WPD exhibited a strong capability for DNA damage protection at 1 mg/mL concentration. Taken together, these data suggest water extract from Pinus densiflora could be used as a suitable natural antioxidant. PMID- 24471073 TI - Inhibition of Reactive Oxygen Species (ROS) and Nitric Oxide (NO) by Gelidium elegans Using Alternative Drying and Extraction Conditions in 3T3-L1 and RAW 264.7 Cells. AB - Gelidium (G.) elegans is a red alga inhabiting intertidal areas of North East Asia. We examined anti-oxidative and anti-inflammatory effects of G. elegans, depending on drying and extraction conditions, by determining reactive oxygen species (ROS) and nitric oxide (NO) in 3T3-L1 and RAW 264.7 cells. Extraction yields of samples using hot air drying (HD) and far-infrared ray drying (FID) were significantly higher than those using natural air drying (ND). The 70% ethanol extracts showed the highest total phenol and flavonoid contents compared to other extracts (0, 30, and 50% ethanol) under tested drying conditions. The scavenging activity on 2,2-diphenyl-1-picrylhydrazyl (DPPH) and nitrite correlated with total phenol or flavonoid content in the extracts. The greatest DPPH scavenging effect was observed in 70% ethanol extract from FID and HD conditions. The production of ROS and NO in 3T3-L1 and macrophage cells greatly decreased with the 70% ethanol extraction derived from FID. This study suggests that 70% ethanol extraction of G. elegans dried by FID is the most optimal condition to obtain efficiently antioxidant compounds of G. elegans. PMID- 24471074 TI - Extract from Edible Red Seaweed (Gelidium amansii) Inhibits Lipid Accumulation and ROS Production during Differentiation in 3T3-L1 Cells. AB - Gelidium (G.) amansii is a red alga widely distributed in the shallow waters around East Asian countries. We investigated the effect of G. amansii on lipid accumulation and ROS (Reactive Oxygen Species) production in 3T3-L1 cells. G. amansii extracts dose-dependently inhibited lipid formation and ROS generation in cultured cells. Our results showed that anti-adipogenic effect of G. amansii was due to the reduction in mRNA expressions of PPARgamma peroxisome proliferator activated receptor-gamma and aP2 (adipocyte protein 2). G. amansii extracts significantly decreased mRNA levels of a ROS-generator, NOX4 (nicotinamide adenine dinucleotide phosphate hydrogen oxidase 4), and increased the protein levels of antioxidant enzymes including SOD1/2 (superoxide dis-mutases), Gpx (glutathione peroxidase), and GR (glutathione reductase), which can lead to the reduction of ROS in the cell. In addition, the G. amansii extract enhanced mRNA levels of adiponectin, one of the adipokines secreted from adipocytes, and GLUT4, glucose uptake protein. Taken together, our study shows that G. amansii extract inhibited lipid accumulation and ROS production by controlling adipogenic signals and ROS regulating genes. PMID- 24471075 TI - Bioactivity of Trifoliate Orange (Poncirus trifoliate) Seed Extracts. AB - Trifoliate orange seed extracts (TSEs) were made using either distilled water (TW), ethanol (TE), or n-hexane (TH), to measure total polyphenol contents, DPPH and ABTS radical scavenging activities, and anti-complementary activity. The results showed that the total polyphenol content showed higher value at TE (235.24 MUg/mL, p<0.05) than those of TW (132.65 MUg/mL) and TH (165.44 MUg/mL) at 10 mg/mL and TE exerted the highest DPPH radical scavenging activity (61.77%, p<0.05), which occurred in the following order: TE>TW (56.87%)>TH (39.78%). The results of ABTS radical scavenging activity showed that TW (34.26%) and TE (31.81%) showed similar activities, which were higher than TH (12.74%, p<0.05). Anti-complementary activity of TE (61% at 500 MUg/mL) showed a higher activity when compared with the positive control (60% at 1,000 MUg/mL) polysaccharide-K (PSK), a known immuno-active polysaccharide from Coriolus versicolor. Consequently, among TSEs, TE is a byproduct from trifoliate orange and could be an important source of dietary polyphenolic antioxidant compounds and immunopotentiating activity, including complement activation. PMID- 24471076 TI - Comparative Studies of Antioxidant Activities and Nutritional Constituents of Persimmon Juice (Diospyros kaki L. cv. Gapjubaekmok). AB - The objectives of this research were to evaluate antioxidant activities and nutritional components, including phenolic acid, catechin, organic acid, sugar, and amino acid, of persimmon juice from persimmons grown in different regions around Korea. Persimmon (Diospyros kaki) exhibits potent antioxidant effects in DPPH, ABTS, reducing power, and FRAP methods of analysis. The levels of nutritional constituents showed significant differences among all the samples. In particular, tartaric acid, glucose, gallic acid, epicatechin gallate and aspartic acid were observed to be the predominant component for each of their general chemical groups, with total average contents of 1876.51 mg/kg, 62.69 g/kg, 12.73 mg/kg, 208.99 mg/kg, and 31.84 mg/100 g, respectively. Interestingly, persimmons from the Hadong region presented the highest sugar (130.60 g/kg), phenolic acid (42.27 mg/kg), and catechin (527.97 mg/kg) contents in comparison with other regional samples. Moreover, this location exhibited the greatest antioxidant activity with highest total phenolic (298.01 mg GAE/kg) and flavonoid (32.11 mg/kg RE) contents. Our results suggest that strong antioxidant activities of persimmons correlate with high phenolic acid and catechin contents, particularly gallic acid and epicatechin gallate. Additionally, these two compounds may be key factors when considering the useful ingredients of persimmon. PMID- 24471077 TI - Physicochemical Characteristics and Antioxidant Capacity of Rice Cake (Sulgitteok) Supplemented with Lyophilized Sedum sarmentosum (Dolnamul) Powder. AB - This study was performed to increase the availability of Sedum sarmentosum (Dolnamul) and to improve the nutraceutical value of rice cakes (sulgitteok). The contents of crude protein, mineral, dietary fiber, water holding capacity, and hardness significantly and directly increased with lyophilized sedum powder (SP). Pore ratio and expansion rate decreased in samples containing more than 10% SP compared to the control. In a sensory evaluation, a positive correlation was detected between overall acceptability and taste (R (2)=0.99, p<0.01), and color (R (2)=0.72, p<0.05). Total polyphenol contents of the SP-treated groups were significantly elevated, accompanied by an increase in radical scavenging ability estimated by the 1,1-diphenyl-2-picrylhydrazyl (DPPH) assay. Replacing 10% of the rice powder with SP efficiently improved the antioxidant and nutritional values of sulgitteok as well as its the sensory quality. PMID- 24471078 TI - Fatty Acid Composition as a Predictor for the Oxidation Stability of Korean Vegetable Oils with or without Induced Oxidative Stress. AB - This study was designed to investigate whether the fatty acid composition could make a significant contribution to the oxidation stability of vegetable oils marketed in Korea. Ten kinds, 97 items of vegetable oils that were produced in either an industrialized or a traditional way were collected and analyzed for their fatty acid compositions and lipid oxidation products, in the absence or presence of oxidative stress. Peroxidability index (PI) calculations based on the fatty acid composition ranged from 7.10 to 111.87 with the lowest value found in olive oils and the highest in perilla oils. In the absence of induced oxidative stress, malondialdehyde (MDA), the secondary lipid oxidation product, was generated more in the oils with higher PI (r=0.890), while the tendency was not observed when the oils were subjected to an oxidation-accelerating system. In the presence of the oxidative stress, the perilla oils produced in an industrialized manner generated appreciably higher amounts of MDA than those produced in a traditional way, although both types of oils presented similar PIs. The results implicate that the fatty acid compositions could be a predictor for the oxidation stability of the vegetable oils at the early stage of oil oxidation, but not for those at a later stage of oxidation. PMID- 24471079 TI - Optimization of Extraction Conditions for the 6-Shogaol-rich Extract from Ginger (Zingiber officinale Roscoe). AB - 6-Shogaol, a dehydrated form of 6-gingerol, is a minor component in ginger (Zingiber officinale Roscoe) and has recently been reported to have more potent bioactivity than 6-gingerol. Based on the thermal instability of gingerols (their dehydration to corresponding shogaols at high temperature), we aimed to develop an optimal process to maximize the 6-shogaol content during ginger extraction by modulating temperature and pH. Fresh gingers were dried under various conditions: freeze-, room temperature (RT)- or convection oven-drying at 60 or 80 degrees C, and extracted by 95% ethanol at RT, 60 or 80 degrees C. The content of 6-shogaol was augmented by increasing both drying and extraction temperatures. The highest production of 6-shogaol was achieved at 80 degrees C extraction after drying at the same temperature and the content of 6-shogaol was about 7-fold compared to the lowest producing process by freezing and extraction at RT. Adjustment of pH (pH 1, 4, 7 and 10) for the 6-shogaol-richest extract (dried and extracted both at 80 degrees C) also affected the chemical composition of ginger and the yield of 6-shogaol was maximized at the most acidic condition of pH 1. Taken together, the current study shows for the first time that a maximized production of 6 shogaol can be achieved during practical drying and extraction process of ginger by increasing both drying and extracting temperatures. Adjustment of pH to extraction solvent with strong acid also helps increase the production of 6 shogaol. Our data could be usefully employed in the fields of food processing as well as nutraceutical industry. PMID- 24471080 TI - Detection of Foodborne Pathogens and Analysis of Aflatoxin Levels in Home-made Doenjang Samples. AB - Doenjang is a traditional Korean fermented soybean product that provides a major source of protein. In this study, a total of 18 different home-made doenjang samples were examined for the presence of foodborne pathogens and the total aflatoxin levels. Using an enzyme-linked immunosorbent assay to assess microbial quality and potential public health risk, we showed that total coliform levels in the doenjang samples ranged from 0 to 4.43+/-2.32 *10(6) CFU/g, and the maximum limit of Bacillus cereus was 4.67+/-2.0*10(5) CFU/g. However, other foodborne pathogens, such as Staphylococcus aureus, Escherichia coli O157:H7 and Salmonella spp., were not detected among the tested samples. One of the samples (S3) showed a maximum limit of 42.2+/-9.1 MUg/kg for aflatoxin levels, which was above the safety limit allowed by the Codex Alimentarius Commission (CAC) regulatory agency. Further research is necessary to determine whether and how doenjang safety can be improved via elimination/reduction of microbial contamination during fermentation and storage or using microbial starter cultures for its fermentation. PMID- 24471081 TI - Methanol Extract of Cassia mimosoides var. nomame Attenuates Myocardial Injury by Inhibition of Apoptosis in a Rat Model of Ischemia-Reperfusion. AB - Interruption of blood flow through coronary arteries and its subsequent restoration triggers the generation of a burst of reactive oxygen species (ROS), leading to myocardial cell death. In this study, we determined whether a methanol extract of Cassia mimosoides var. nomame Makino could prevent myocardial ischemia reperfusion injury. When radical scavenging activity of the extract was measured in vitro using its alpha,alpha-diphenyl-beta-picrylhydrazyl (DPPH) radical quenching ability, the extract showed an activity slightly lower than that of ascorbic acid. Three days after oral administration of the extract (400 mg/kg/day) to rats, myocardial ischemia/reperfusion injury was generated by 30 min of ligation of the left anterior descending coronary artery (LAD), followed by 3 hr reperfusion. Compared with the vehicle-treated group, administration of the extract significantly reduced infarct size (IS) (ratio of infarct area to area at risk) in the extract-treated group by 28.3%. Reduction in the cellular injury was mediated by attenuation of Bax/Bcl-2 ratio by 33.3%, inhibition of caspase-3 activation from procas-pase-3 by 40%, and subsequent reduction in the number of apoptotic cells by 66.3%. These results suggest that the extract attenuates myocardial injury in a rat model of ischemia-reperfusion by scavenging ROS, including free radicals, and consequently blocking apoptotic cascades. Therefore, intake of Cassia mimosoides var. nomame Makino might be beneficial for preventing ischemic myocardial injury. PMID- 24471082 TI - Chemometric Approach to Fatty Acid Profiles in Soybean Cultivars by Principal Component Analysis (PCA). AB - The purpose of this study was to investigate the fatty acid profiles in 18 soybean cultivars grown in Korea. A total of eleven fatty acids were identified in the sample set, which was comprised of myristic (C14:0), palmitic (C16:0), palmitoleic (C16:1, omega7), stearic (C18:0), oleic (C18:1, omega9), linoleic (C18:2, omega6), linolenic (C18:3, omega3), arachidic (C20:0), gondoic (C20:1, omega9), behenic (C22:0), and lignoceric (C24:0) acids by gas-liquid chromatography with flame ionization detector (GC-FID). Based on their color, yellow-, black-, brown-, and green-colored cultivars were denoted. Correlation coefficients (r) between the nine major fatty acids identified (two trace fatty acids, myristic and palmitoleic, were not included in the study) were generated and revealed an inverse association between oleic and linoleic acids (r=-0.94, p<0.05), while stearic acid was positively correlated to arachidic acid (r=0.72, p<0.05). Principal component analysis (PCA) of the fatty acid data yielded four significant principal components (PCs; i.e., eigenvalues>1), which together account for 81.49% of the total variance in the data set; with PC1 contributing 28.16% of the total. Eigen analysis of the correlation matrix loadings of the four significant PCs revealed that PC1 was mainly contributed to by oleic, linoleic, and gondoic acids, PC2 by stearic, linolenic and arachidic acids, PC3 by behenic and lignoceric acids, and PC4 by palmitic acid. The score plots generated between PC1-PC2 and PC3-PC4 segregated soybean cultivars based on fatty acid composition. PMID- 24471083 TI - Steady and Dynamic Shear Rheological Properties of Buckwheat Starch-galactomannan Mixtures. AB - This study investigated the effects of galacomannans (guar gum, tara gum, and locust bean gum) on the rheological properties of buckwheat starch pastes under steady and dynamic shear conditions. The power law and Casson models were applied to describe the flow behavior of the buckwheat starch and galactomannan mixtures. The values of the apparent viscosity (etaa,100), consistency index (K), and yield stress (sigmaoc) for buckwheat starch-galactomannan mixtures were significantly greater than those for the control, indicating that there was a high synergism of the starch with galactomannans. The magnitudes of storage modulus (G') and loss modulus (G") for the starch-galactomannan mixtures increased with increasing frequency (omega). The dynamic moduli (G', G"), and complex viscosity (eta*) for the buckwheat starch-galactomannan mixtures were significantly higher than those for the control. PMID- 24471084 TI - Substituting normal and waxy-type whole wheat flour on dough and baking properties. AB - Normal (cv. Keumkang, KK) and waxy-type (cv. Shinmichal, SMC) whole wheat flour was substituted at 20 and 40% for white wheat flour (WF) during bread dough formulation. The flour blends were subjected to dough and baking property measurement in terms of particle size distribution, dough mixing, bread loaf volume and crumb firmness. The particle size of white wheat flour was the finest, with increasing coarseness as the level of whole wheat flour increased. Substitution of whole wheat flour decreased pasting viscosity, showing all RVA parameters were the lowest in SMC40 composite flour. Water absorption was slightly higher with 40% whole wheat flour regardless of whether the wheat was normal or waxy. An increased mixing time was observed when higher levels of KK flour were substituted, but the opposite reaction occurred when SMC flour was substituted at the same levels. Bread loaf volume was lower in breads containing a whole wheat flour substitution compared to bread containing only white wheat flour. No significant difference in bread loaf volume was observed between normal and waxy whole flour, but the bread crumb firmness was significantly lower in breads containing waxy flour. The results of these studies indicate that up to 40% whole wheat flour substitution could be considered a practical option with respect to functional qualities. Also, replacing waxy whole flour has a positive effect on bread formulation over normal whole wheat flour in terms of improving softness and glutinous texture. PMID- 24471085 TI - Effects of extrusion conditions on the physicochemical properties of extruded red ginseng. AB - The effects of variable moisture content, screw speed and barrel temperature on the physicochemical properties of red ginseng powder extrudates were investigated. The raw red ginseng powders were processed in a co-rotating intermeshing twin-screw extruder. Primary extrusion variables were feed moisture content (20 and 30%), screw speed (200 and 250 rpm) and barrel temperature (115 and 130 degrees C). Extruded red ginseng showed higher crude saponin contents (6.72~7.18%) than raw red ginseng (5.50%). Tested extrusion conditions did not significantly affect the crude saponin content of extrudates. Increased feed moisture content resulted in increased bulk density, specific length, water absorption index (WAI), breaking strength, elastic modulus and crude protein content and decreased water solubility index (WSI) and expansion (p<0.05). Increased barrel temperature resulted in increased total sugar content, but decreased reducing sugar content in the extrudate (p<0.05). Furthermore, increased barrel temperature resulted in increased amino acid content and specific length and decreased expansion and bulk density of extrudates only at a higher feed moisture content. The physicochemical properties of extrudates were mainly dependent on the feed moisture content and barrel temperature, whereas the screw speed showed a lesser effect. These results will be used to help define optimized process conditions for controlling and predicting qualities and characteristics of extruded red ginseng. PMID- 24471086 TI - Efficacy of sodium hypochlorite and acidified sodium chlorite in preventing browning and microbial growth on fresh-cut produce. AB - The use of suitable sanitizers can increase the quality of fresh-cut produce and reduce the risk of foodborne illnesses. The objective of this study was to compare the washing effects of 100 mg/L sodium hypochlorite (SH) and 500 mg/L acidified sodium chlorite (ASC) on the prevention of enzymatic browning and the growth of microbial populations, including aerobic plate counts, E. coli, and coliforms, throughout storage at 4 degrees C and 10 degrees C. Fresh-cut zucchini, cucumbers, green bell peppers, and root vegetables such as potatoes, sweet potatoes, carrots, and radishes were used. Compared to SH washing, ASC washing significantly (p<0.05) reduced microbial contamination on the fresh-cut produce and prevented browning of fresh-cut potatoes and sweet potatoes during storage. More effective inhibition of aerobic plate counts and coliforms growth was observed on fresh-cut produce treated with ASC during storage at 10 degrees C. Polyphenol oxidase (PPO) activity of fresh-cut potatoes and sweet potatoes was more effectively inhibited after washing with ASC. The use of 500 mg/L ASC can provide effective antimicrobial and anti-browning treatments of fresh-cut produce, including processed root vegetables. PMID- 24471087 TI - Characterization of Lactic Acid Bacteria Isolated from Sauce-type Kimchi. AB - This study was carried out to investigate the isolation and characterization of lactic acid bacteria (LAB) from naturally fermented sauce-type kimchi. Sauce-type kimchi was prepared with fresh, chopped ingredients (Korean cabbage, radish, garlic, ginger, green onion, and red pepper). The two isolated bacteria from sauce-type kimchi were identified as Pediococcus pentosaceus and Lactobacillus brevis by 16S rDNA sequencing and tentatively named Pediococcus sp. IJ-K1 and Lactobacillus sp. IJ-K2, respectively. Pediococcus sp. IJ-K1 was isolated from the early and middle fermentation stages of sauce-type kimchi whereas Lactobacillus sp. IJ-K2 was isolated from the late fermentation stage. The resistance of Pediococcus sp. IJ-K1 and Lactobacillus sp. IJ-K2 to artificial gastric and bile acids led to bacterial survival rates that were 100% and 84.21%, respectively. PMID- 24471088 TI - Plant Proteins Differently Affect Body Fat Reduction in High-fat Fed Rats. AB - This study examined the effects of corn gluten (CG), wheat gluten (WG), and soybean protein isolate (SPI), as well as their hydrolysates, on weight reduction in rats fed a high-fat diet. Eight-month-old male Sprague-Dawley rats (n=70) were fed a high-fat diet (40% of the calories were fat) for 4 weeks. Rats were then randomly divided into seven groups and were fed isocaloric diets with different protein sources for 8 weeks. The protein sources were casein (control group), intact CG (CG group), CG hydrolysate (CGH group), intact WG (WG group), WG hydrolysate (WGH group), intact SPI (SPI group), and SPI hydrolysate (SPIH group). Body weight gain, adipose tissue weights, lipid profiles in plasma and liver; and hepatic activities of carnitine palmitoyl transferase, fatty acid synthase (FAS), malic enzyme, and glucose-6-phosphate dehydrogenase were assessed. The CGH group showed significant weight reduction compared with the other groups. Epididymal fat pad and plasma triglycerides in the CGH group were the lowest and were significantly different than those in the control group. FAS activity in the CGH group was significantly lower than that in the other groups. In conclusion, the CGH diet of these experimental animals demonstrated a weight reducing effect by lowering the adipose tissue weight and by affecting the activities of hepatic lipogenic enzymes. PMID- 24471089 TI - Antimicrobial Activity of Trifoliate Orange (Poncirus trifoliate) Seed Extracts on Gram-Negative Food-borne Pathogens. AB - Trifoliate orange seed extracts (TSEs) were prepared from different solvents, water (TW), ethanol (TE), and n-hexane (TH), and assessed for their antimicrobial activities against six gram-negative food-borne pathogens (Escherichia coli KCTC 1039, Escherichia coli O157:H7 ATCC 43895, Salmonella Enteritidis ATCC 3311, Salmonella Typhimurium KCCM 11862, Shigella sonnei KCTC 2518, and Vibrio parahaemolyticus ATCC 17802). Among the tested TSEs, TE and TH showed a slight inhibition activity on V. parahaemolyticus ATCC 17802, but a good growth inhibition activity on Sal. Typhimurium KCCM 11862. TH and TE showed steady growth inhibition activity with increasing growth time after 6 hr when compared to the control (p<0.05). From these results, we confirmed the possibility of TH and TE as antimicrobial materials. PMID- 24471090 TI - Volatiles of Chrysanthemum zawadskii var. latilobum K. AB - The volatile aroma constituents of Chrysanthemum zawadskii var. latilobum K. were separated by hydro distillation extraction (HDE) method using a Clevenger-type apparatus, and analyzed by gas chromatography-mass spectrometry (GC/MS). The yield of C. zawadskii var. latilobum K. flower essential oil (FEO) was 0.12% (w/w) and the color was light green. Fifty-five volatile chemical components, which make up 88.38% of the total aroma composition, were tentatively characterized. C. zawadskii var. latilobum K. FEOs contained 27 hydrocarbons, 12 alcohols, 7 ketones, 4 esters, 1 aldehyde, 1 amine, and 3 miscellaneous components. The major functional groups were terpene alcohol and ketone. Borneol (12.96), (+/-)-7-epi-amiteol (12.60), and camphor (10.54%) were the predominant volatiles. These compounds can be used in food and pharmaceutical industries due to their active bio-functional properties. PMID- 24471091 TI - Hypoglycemic Effect of Padina arborescens Extract in Streptozotocin-induced Diabetic Mice. AB - This study investigated the hypoglycemic effect of the Padina arborescens extract in STZ-induced diabetic mice. Freeze-dried Padina arborescens were extracted with 80% methanol and concentrated for use in this study. The hypoglycemic effect was determined by inhibitory activities against alpha-glucosidase and alpha-amylase as well as the alleviation of postprandial blood glucose level. Padina arborescens extracts showed higher inhibitory activities than acarbose, a positive control against alpha-glucosidase and alpha-amylase. The IC50 values of Padina arborescens extracts against alpha-glucosidase and alpha-amylase were 0.26 and 0.23 mg/mL, respectively, which evidenced as more effective than observed with acarbose. The increase of postprandial blood glucose levels were significantly suppressed in the Padina arborescens extract administered group than the control group in the streptozotocin induced diabetic mice. Furthermore, the area under the curve (AUC) was significantly lowered via Padina arborescens extract administration in diabetic mice (p < 0.05). These results indicated that the Padina arborescens extract might be used as an inhibitor of alpha-glucosidase and alpha-amylase and delay absorption of dietary carbohydrates. PMID- 24471092 TI - Effects of Collagen Tripeptide Supplement on Photoaging and Epidermal Skin Barrier in UVB-exposed Hairless Mice. AB - Collagen tripeptide (CTP) is a functional food material with several biological effects such as improving dry skin and wound and bone fracture healing. This study focused on the anti-photoaging effects of CTP on a hairless mouse model. To evaluate the effects of CTP on UVB-induced skin wrinkle formation in vivo, the hairless mice were exposed to UVB radiation with oral administration of CTP for 14 weeks. Compared with the untreated UVB control group, mice treated with CTP showed significantly reduced wrinkle formation, skin thickening, and transepidermal water loss (TEWL). Skin hydration and hydroxyproline were increased in the CTP-treated group. Moreover, oral administration of CTP prevented UVB-induced MMP-3 and -13 activities as well as MMP-2 and -9 expressions. Oral administration of CTP increased skin elasticity and decreased abnormal elastic fiber formation. Erythema was also decreased in the CTP-treated group. Taken together, these results strongly suggest that CTP has potential as an anti-photoaging agent. PMID- 24471093 TI - Correlation between Intake of Dietary Fiber and Adherence to the Korean National Dietary Guidelines in Adolescents from Jeonju. AB - This study surveyed dietary intake and adherence to the Korean national dietary guidelines in Korean adolescents. To elucidate basic data for use in nutrition education, which aims to improve adolescent compliance with the national dietary guidelines and to increase the intake of dietary fiber, we evaluated the sources of fiber in adolescent diets. This study included 182 male and 212 female students from 2 middle schools in the Jeonju province. From November 15~20, 2011, we surveyed the students for general characteristics, adherence to the Korean national dietary guidelines, and dietary intake. Dietary fiber intake was 16.57 +/- 6.95 g/day for male students and 16.14 +/- 7.11 g/day for female students. The food groups that contributed most to dietary fiber intake were (in descending order) cereals, vegetables, seasoning, and fruits. The fiber-containing food items consumed most were cabbage- kimchi, cooked rice, instant noodles, and cabbage. Based on adherence to the Korean national dietary guidelines, the vegetable-based intake of dietary fiber in groups 1 (score 15~45), 2 (score 46~52), and 3 (score 53~75) were 4.41 +/- 2.595 g/day, 4.12 +/- 2.692 g/day, and 5.49 +/- 3.157 g/day, respectively (p<0.001). In addition, the total intake of dietary fiber varied significantly among the three groups (p<0.001) as follows: Group 1, 14.99 +/- 6.374 g/day; Group 2, 15.32 +/- 6.772 g/day; and Group 3, 18.79 +/- 7.361 g/day. In this study, we discovered that adherence to the Korean national dietary guidelines correlates with improved intake of dietary fiber. Therefore, marketing and educational development is needed to promote adherence to the Korean national dietary guidelines. In addition, nutritional education is needed to improve dietary fiber consumption through the intake of vegetables and fruits other than kimchi. PMID- 24471094 TI - Antioxidant Activities of Ribes diacanthum Pall Extracts in the Northern Region of Mongolia. AB - Ribes diacanthum Pall (RDP) is a member of the Saxifragaceae family. The plant is traditionally used in Mongolia for the treatment of various ailments associated with kidney and bladder's diseases, cystitis, kidney stone, and edema. This study was aimed to investigate antioxidant activities of different solvent extracts of whole Pall plants, based on ferric-reducing antioxidant potential (FRAP), 2,2' azinobis(3-ethybenzothiazoline-6-sulfonic acid) (ABTS. +) radical scavenging activity, 1,1-diphenyl-2-picrydrazyl (DPPH.), and hydroxyl (.OH) radical scavenging activities. Additionally, total flavonoids and phenolic contents (TPC) were also determined. The ethyl acetate extract of RDP (EARDP) had a remarkable radical scavenging capacity with an IC50 value of 0.1482 mg/mL. In addition, EARDP was shown to be higher in total phenolic and flavonoid contents than the methanol extract of RDP (MRDP). Moreover, the EARDP had the predominant antioxidant capacity, DPPH, hydroxyl, and ABTS radical scavenging activities and ferric reducing power. These results suggest a potential for R. diacanthum Pall extract as a functional medicinal material against free-radical-associated oxidative damage. PMID- 24471095 TI - Comparison of nutritional compositions and antioxidant activities of building blocks in shinseoncho and kale green vegetable juices. AB - Shinseoncho and kale were divided into stem [shinseoncho stems (SS) and kale stems (KS)] and leaf parts [shinseoncho leaves (SL) and kale leaves (KL)] and made into green vegetable juices for analyses of nutritional compositions and antioxidant activities. Higher values of total acidity were observed in SL (0.736%) and KL (0.841%) than in SS (0.417%) and KS (0.335%) (p<0.05). Neutral sugar content showed higher values in SS (21.740 mg/mL) and SL (18.657 mg/mL) when compared with KS (1.497 mg/mL) and KL (1.452 mg/mL) (p<0.05). Protein content showed the highest value in SL (7.610 mg/mL) (p<0.05), while SS (0.403 mg/mL) and KS (0.403 mg/mL) showed similar lower values. Total polyphenol contents of SL (423.139 MUg/mL) was significantly higher value (p<0.05) than those of other samples, which occurred in the following order: SL> KL (218.494 MUg/mL)> KS (107.269 MUg/mL)> SS (75.894 MUg/mL). KL exerted the highest DPPH radical scavenging activity (84.834%) (p<0.05), which occurred in the following order: KL> SL (63.473%)> KS (52.894%)> SS (35.443%). ABTS radical scavenging activity showed that SL (66.088%) and KL (38.511%) had higher scavenging activities, whereas SS (7.695%) and KS (9.609%) demonstrated to be lower activities (p<0.05). In general, leaf parts had much higher antioxidant activities as well as total polyphenol contents than those of the stem parts. In conclusion, shinseoncho and kale, particularly their leaf parts, offer antioxidant properties in green vegetable juices and the consumption of them may be beneficial as a nutrition source and in health protection. PMID- 24471096 TI - Establishment of quantitative analysis method for genetically modified maize using a reference plasmid and novel primers. AB - For the quantitative analysis of genetically modified (GM) maize in processed foods, primer sets and probes based on the 35S promoter (p35S), nopaline synthase terminator (tNOS), p35S-hsp70 intron, and zSSIIb gene encoding starch synthase II for intrinsic control were designed. Polymerase chain reaction (PCR) products (80~101 bp) were specifically amplified and the primer sets targeting the smaller regions (80 or 81 bp) were more sensitive than those targeting the larger regions (94 or 101 bp). Particularly, the primer set 35F1-R1 for p35S targeting 81 bp of sequence was even more sensitive than that targeting 101 bp of sequence by a 3 log scale. The target DNA fragments were also specifically amplified from all GM labeled food samples except for one item we tested when 35F1-R1 primer set was applied. A reference plasmid pGMmaize (3 kb) including the smaller PCR products for p35S, tNOS, p35S-hsp70 intron, and the zSSIIb gene was constructed for real time PCR (RT-PCR). The linearity of standard curves was confirmed by using diluents ranging from 2*10(1)~10(5) copies of pGMmaize and the R(2) values ranged from 0.999~1.000. In the RT-PCR, the detection limit using the novel primer/probe sets was 5 pg of genomic DNA from MON810 line indicating that the primer sets targeting the smaller regions (80 or 81 bp) could be used for highly sensitive detection of foreign DNA fragments from GM maize in processed foods. PMID- 24471097 TI - Quantitative Changes of Polyphenolic Compounds in Mulberry (Morus alba L.) Leaves in Relation to Varieties, Harvest Period, and Heat Processing. AB - Six polyphenolic compounds, such as chlorogenic acid (CA), rutin (RT), isoquercitrin (IQT), quercetin-3-O-(6-O-malonyl)-beta-D-glucoside (QMG), astragalin (AG), kaempferol-3-O-(6-O-malonyl)-beta-D-glucoside (KMG), were isolated from mulberry leaves by a series of isolation procedures, such as Diaion HP-20, silica-gel, Sephadex LH-20, and ODS-A column chromatographies. The chemical structures of the phenolic compounds were identified by UV and NMR spectral analyses. Levels of polyphenols in mulberry leaves from six different mulberry cultivars ranged from 1,042.16 to 1,871.97 mg% per dry weight; Guksang cultivar showed the highest levels of polyphenols, whereas Gaeryangdaehwa contained the least polyphenol contents. Generally, levels of polyphenols in mulberry leaves decreased with increasing harvest time, except for Yoolmok, but increased with heat processing time, except QMG and KMG. These results suggest that the heat processed mulberry leaves of Guksang cultivar harvested in early May can be potentially useful sources for production of high quality mulberry leaf teas. PMID- 24471098 TI - Effects of Different Cooking Methods on the Antioxidant Properties of Red Pepper (Capsicum annuum L.). AB - We investigated the effect of various cooking methods (boiling, steaming, stir frying, and roasting) and three cooking times (5, 10, and 15 min) on the antioxidant properties of red pepper. Raw and cooked peppers were measured for proximate composition, ascorbic acid (AsA) content, total carotenoid content (TCC), total polyphenol content (TP), and 1,1-diphenyl-2-picrylhydrazyl (DPPH) and 2,2'-azino-bis(3-ethylbenzothiazoline-6-sulphonic acid) (ABTS) radical scavenging activities. Results showed that the proximate composition, AsA content, TCC, TP, and antioxidant activities were significantly (p<0.05) affected by the cooking procedure; the loss rate varied among individual compounds. Boiling and steaming significantly reduced AsA content (24.3~66.5%), TP (13.9~ 54.9%), and antioxidant activity (21.7~60.5%) in red pepper, while stir-frying and roasting slightly reduced AsA content (2.7~25.9%), TP (1.8~4.9%), and antioxidant activity (4.9~17.9%). The highest loss was observed after boiling, followed by steaming, roasting, and stir-frying. Stir-frying and roasting better preserved AsA content, TCC, TP, and antioxidant activity. In conclusion, dry-heat cooking methods such as stir-frying and roasting may be preferred to retain the nutrient compositions and antioxidant properties of red pepper. PMID- 24471099 TI - Quality Characteristics and Content of Polysaccharides in Green Tea Fermented by Monascus pilosus. AB - In this study, we designed a method to manufacture elevated fermented green tea by using Monascus pilosus, which is known as a functional microbe, and observe its antioxidant abilities and quality characteristics. The water-soluble substance (WSS) content of the fermented tea by M. pilosus (FTM) was lower than that of the non-fermented tea (NFT), although the alcohol-insoluble substance (AIS) content of the FTM was higher than that of NTM. On the other hand, the fractionated distilled water-soluble polysaccharide (DWSP), CDTA-soluble polysaccharides (CDSP), sodium carbonate-soluble polysaccharide (SCSP) and KOH soluble hemicellulose (HC) obtained from the AIS of the FTM was markedly higher than that of NFT. In the antioxidant parameters, the electron donating ability of all fractions, except HC, extracted from FTM was higher than that of NFT, and iron chelating ability of all fractions, except CDSP, extracted from FTM was higher than that of NFT. Whereas the DWSP and SCSP obtained from the FTM were higher than that of NFT, the activity of the HC fraction from both NFT and the FTM could not be detected. In addition, the xanthin oxidase (XO) inhibitory activities of the DWSP, CDSP and the SCSP obtained from the NFT were significantly higher than that of FTM, the aldehyde oxidase (AO) inhibitory activities of the DWSP and SCSP extracted from the FTM were markedly higher than that of the NFT. Meanwhile, the acceptance of NFT and FTM had no significant difference, while the quality of aroma, taste and mouthfeel of the FTM was higher than that of NFT. These results suggest that the post-fermented tea by Monascus microorgan-isms may be responsible for functional components as well as contribute to the improvement of the tea quality. PMID- 24471100 TI - The supplementation of yam powder products can give the nutritional benefits of the antioxidant mineral (cu, zn, mn, fe and se) intakes. AB - Yam has been recognized having the beneficial effects for the prevention of various diseases, such as cancer, immunity, infection and obesity etc. There is increasing consideration to supplement the antioxidant nutrients to make up the lack of the antioxidant nutrient intakes. No study has been reported for the analysis of antioxidant mineral contents and comparison to dietary recommended intake for the sense of health promotion. In our study, we analyzed the contents of antioxidant trace elements (Zn, Mn, Fe, Cu and Se) and Cr contents in cultivated Korean yam powders for evaluation of nutrient intake aspects. We collected the commercial yam powders from six different cultivated areas in the South Korea and measured antioxidant minerals (Zn, Mn, Fe, Cu and Se) and Cr contents using trace element-free plasma spectrometer (ICP) or atomic absorption spectrometer (AAS) after dry-ashing and then wet-acid digestion. The accuracy of mineral analysis method was confirmed by the mineral analysis of standard reference material. Each analyzed element contents in yam were compared to dietary reference intakes of Koreans (KDRIs). The average levels of trace elements (Zn, Mn, Fe, Cu, Se and Cr) in yam powders were 18.3, 11.9, 36.0, 3.7, 1.9 and 1.27 MUg/g yam powder, respectively. The intakes of Zn, Fe, Cu and Se of which KDRIs is determined, are accounted as being up to 23.8%, 55.6%, 32.5% and 236% recommended intake (RI) of KDRIs, if daily yam supplementation (50 g) of commercial instruction would be considered. The intake of Mn is about 25% adequate intake (AI) of KDRIs with the daily supplementation of yam powder. Most of mineral intakes from daily yam supplementation were with the range of non detectable to <10% upper limit (UL) level, which is very much safe. The study results show that daily supplementation of Korean yam power is beneficial to provide the supplemental nutrient intake and also is safe, if the suggested dosage would be considered. PMID- 24471101 TI - Anti-oxidant Activity of Saussurea lappa C.B. Clarke Roots. AB - This study was performed to investigate the potential use of Saussurea lappa C.B. Clarke as a source of anti-oxidant agents. Various solvent fractionates from S. lappa C.B. Clarke roots were investigated for their anti-oxidative effectiveness. The contents of total phenolics and flavonoids were determined by the Folin Ciocalteu's colorimetric and the aluminum nitrate method, respectively. Total phenolic and flavonoid contents of n-butanol soluble fractionates from S. lappa C.B. Clarke, 44.43 MUg gallic acid equilibrium (GAE)/g extract and 92.15 MUg quercetin equilibrium (QE)/g extract, respectively, were higher than those of other solvent fractionates. The n-butanol soluble fractionates of S. lappa C.B. Clarke (1,000 ppm) showed the strongest inhibitory potential on 2,2-diphenyl-1 picrylhydrazyl (DPPH) radical and reducing power at 92.98% and 0.38, respectively. Thus, our data shows that the S. lappa C.B. Clarke plant may help prevent antioxidative stress. PMID- 24471102 TI - Fatty Acid and Volatile Oil Compositions of Allomyrina dichotoma Larvae. AB - Thirty-two different volatile oils were identified from Allomyrina dichotoma (A. dichotoma) larvae by gas chromatography/mass spectrometry (GC/MS). The major volatile components were 2,2,4-trimethyl-3-carboxyisopropyl pentanoic acid isobutyl ester (5.83%), phenol,2,6-bis(a,a-dimethyl ethyl)-4-(1-methyl-1 phenylethyl) (5.72%), heptacosane (5.49%) and phenol,2,4-bis(1-methyl-1 phenylethyl) (5.47%). The composition of the fatty acids in A. dichotoma larvae was also determined by gas chromatography (GC) and fourteen constituents were identified. Oleic acid (19.13%) was the most abundant fatty acid followed by palmitic acid (12.52%), palmitoleic acid (3.71%) and linoleic acid (2.08%) in 100 g of A. dichotoma larvae on a dry weight basis. The quantity of unsaturated fatty acids (64.00%) were higher than that of saturated ones (36.00%). The predominant fatty acids in A. dichotoma consist of monounsaturated fatty acid (MUFA, 57.70%) such as oleic acid, myristoleic acid and palmitoleic acid, followed by saturated fatty acids (36.00%) and polyunsaturated fatty acids (PUFA, 6.50%). In particular, the presence of essential fatty acids, such as linoleic (5.30%) and linolenic acid (0.40%) give A. dichotoma larvae considerable nutritional and functional value and it may be a useful source for food and/or industrial utilization. PMID- 24471103 TI - Influence of squid liver powder on accumulation of cadmium in serum, kidney and liver of mice. AB - In this study, the effect of squid liver powder intake on accumulation of cadmium in mice was investigated. Subjects were divided into 4 groups including the control group (CON), squid liver powder group with lipids not removed (SLP100), and squid liver powder groups with lipids removed (LFSLP50 and LFSLP100). Feed intake and food efficiency ratio of squid liver powder groups was significantly higher than the CON. As a result of investigating cadmium content in hair, serum, liver, and kidney during intake of squid liver powder, all groups showed increase in cadmium accumulation through consistent, long-term intake. Especially, cadmium content in liver and kidney of LFSLP100 was significantly higher than the content of SLP100 and CON. As a result of pathological observation on liver and kidney tissues according to squid liver powder diet, LFSLP100 showed most serious pathological symptoms. In case of kidney tissues, degeneration was significantly more severe in LFSLP100 compared to other groups. Such results suggest that cadmium concentration in human body can be increased by ingestion of whole squid including internal organs and that tissues can be damaged by increased cadmium concentration. More specific and systematic studies are deemed necessary. PMID- 24471104 TI - Protective Effect of Padina arborescens Extract against High Glucose-induced Oxidative Damage in Human Umbilical Vein Endothelial Cells. AB - Dysfunction of endothelial cells is considered a major cause of vascular complications in diabetes. In the present study, we investigated the protective effect of Padina arborescens extract against high glucose-induced oxidative damage in human umbilical vein endothelial cells (HUVECs). High-concentration of glucose (30 mM) treatment induced cytotoxicity whereas Padina arborescens extract protected the cells from high glucose-induced damage and significantly restored cell viability. In addition, lipid peroxidation, intracellular reactive oxygen species (ROS), and nitric oxide (NO) levels induced by high glucose treatment were effectively inhibited by treatment of Padina arborescens extract in a dose dependent manner. High glucose treatment also induced the overexpressions of inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2) and NF-kappaB proteins in HUVECs, but Padina arborescens extract treatment reduced the over expressions of these proteins. These findings indicate the potential benefits of Padina arborescens extract as a valuable source in reducing the oxidative damage induced by high glucose. PMID- 24471105 TI - The Butanol Fraction of Bitter Melon (Momordica charantia) Scavenges Free Radicals and Attenuates Oxidative Stress. AB - To investigate radical scavenging effects and protective activities of bitter melon (Momordica charantia) against oxidative stress, in vitro and a cellular system using LLC-PK1 renal epithelial cells were used in this study. The butanol (BuOH) fraction of bitter melon scavenged 63.4% and 87.1% of 1,1-diphenyl-2 picrylhydrazyl (DPPH) radicals at concentrations of 250 and 500 MUg/mL, respectively. In addition, the BuOH fraction of bitter melon effectively scavenged hydroxyl radicals (.OH). At all concentrations tested, the scavenging activity of the BuOH fraction was more potent than that of the positive control, ascorbic acid. Furthermore, under the LLC-PK1 cellular model, the cells showed a decline in viability and an increase in lipid peroxidation through oxidative stress induced by pyrogallol, a generator of superoxide anion (O2 (-)). However, the BuOH fraction of bitter melon significantly and dose-dependently inhibited cytotoxicity. In addition, 3-morpholinosydnonimine (SIN-1), a generator of peroxynitrite (ONOO(-)) formed by simultaneous releases of nitric oxide and O2 ( ), caused cytotoxicity in the LLC-PK1 cells while the BuOH fraction of bitter melon ameliorated oxidative damage induced by ONOO(-). These results indicate that BuOH fraction of bitter melon has protective activities against oxidative damage induced by free radicals. PMID- 24471106 TI - Anti-inflammatory Effect of Oyster Shell Extract in LPS-stimulated Raw 264.7 Cells. AB - This study was designed to investigate the anti-inflammatory effect of oyster shell extract on the production of pro-inflammatory factors [NO, reactive oxygen species (ROS), nuclear factor-kappa B (NF-kappaB), inducible nitric oxide synthase (iNOS) and cycloxygenase-2 (COX-2)] and pro-inflammatory cytokines [Interleukin-1beta (IL-1beta), Interleukin-6 (IL-6) and TNF-alpha] in the lipopolysaccharide (LPS)-stimulated Raw 264.7 cells. Cell viability, as measured by the MTT assay, showed that oyster shell extract had no significant cytotoxicity in Raw 264.7 cells. The treatment with oyster shell extract decreased the generation of intracellular reactive oxygen species dose dependently and increased antioxidant enzyme activities, such as SOD, catalase, GSH-px in LPS-stimulated macrophage cells. Oyster shell extract significantly suppressed the production of NO and also decreased the expressions of iNOS, COX-2 and NF-kappaB. Additionally, oyster shell extract significantly inhibited the production of IL-1beta, IL-6, and TNF-alpha in LPS-stimulated Raw 264.7 cells. Thus, these results showed that the oyster shell extract had an anti-inflammatory effect on LPS-stimulated Raw 264.7 cells. PMID- 24471107 TI - Antioxidant and neuronal cell protective effects of columbia arabica coffee with different roasting conditions. AB - In vitro antioxidant activities and neuronal cell protective effects of ethanol extract from roasted coffee beans were investigated. Colombia arabica coffee (Coffea arabica) green beans were roasted to give medium (230 degrees C, 10 min), city (230 degrees C, 12 min) and french (230 degrees C, 15 min) coffee beans. Total phenolics in raw green beans, medium, city and french-roasted beans were 8.81+/-0.05, 9.77+/-0.03, 9.92+/-0.04 and 7.76+/-0.01 mg of GAE/g, respectively. The content of 5-O-caffeoylquinic acid, the predominant phenolic, was detected higher in medium-roasted beans than others. In addition, we found that extracts from medium-roasted beans particularly showed the highest in vitro antioxidant activity on ABTS radical scavenging activity and FRAP assays. To determine cell viability using the MTT assay, extracts from medium-roasted beans showed higher protection against H2O2-induced neurotoxicity than others. Lactate dehydrogenase (LDH) leakage was also inhibited by the extracts due to prevention of lipid peroxidation using the malondialdehyde (MDA) assay from mouse whole brain homogenates. These data suggest that the medium-roasting condition to making tasty coffee from Columbia arabica green beans may be more helpful to human health by providing the most physiological phenolics, including 5-O caffeoylquinic acids. PMID- 24471108 TI - Effect of Polyopes lancifolia Extract on Oxidative Stress in Human Umbilical Vein Endothelial Cells Induced by High Glucose. AB - The protective effect of Polyopes lancifolia extract on high glucose-induced oxidative stress was investigated using human umbilical vein endothelial cells (HUVECs). High concentration of glucose (30 mM) treatment induced HUVECs cell death, but Polyopes lancifolia extract, at concentrations of 25, 50, and 100 MUg/mL, protected cells from high glucose-induced damage. Furthermore, thiobarbituric acid reactive substances, intracellular reactive oxygen species, and nitric oxide levels increased by high glucose treatment were effectively decreased by treatment with Polyopes lancifolia extract in a dose-dependent manner. Also, Polyopes lancifolia extract treatment reduced the overexpressions of inducible nitric oxide synthase, cyclooxygenase-2, and nuclear factor-kappa B proteins activation that was induced by high glucose in HUVECs. These results indicate that Polyopes lancifolia extract is a potential therapeutic material that will reduce the damage caused by high glucose-induced-oxidative stress associated with diabetes. PMID- 24471109 TI - Physicochemical and Sensory Properties of Yogurt Supplemented with Corni fructus during Storage. AB - This study was carried out to determine a possibility of adding Corni fructus extract (CFE) into yogurt for improving the neutraceutical properties of yogurt and the effects of adding CFE (2~6%, v/v) on the physicochemical and sensory properties of the products during a 15-day storage period at 4 degrees C. Incorporation of CFE into the yogurt samples resulted in a significant pH reduction and a significant increase in titratable acidity. When evaluating the color of the yogurt, the L*-values were not significantly influenced by CFE supplementation; however, the a*- and b*-values significantly increased with the addition of CFE during storage. The power law and Casson models were applied to assess the flow behavior of CFE-added yogurt samples. The magnitudes of apparent viscosity (etaa,100), consistency index (K), and yield stress (sigmaoc) for 4~6% CFE yogurt samples were significantly greater than those for the control, indicating that CFE can be used as a thickening agent for yogurt. The sensory test revealed that addition of CFE (2~4%) to yogurt did not significantly affect the overall scores, but the overall preference score for 6% CFE yogurt was significantly decreased. Based on the data obtained from the present study, we concluded that the concentrations (2~4%) of CFE could be used to produce a CFE added yogurt without the significantly adverse effects on the physicochemical and sensory properties. PMID- 24471110 TI - Enhancing the organoleptic and functional properties of jujube by a quick aging process. AB - Black jujube was made by aging dried jujube and its physiochemical characteristics, antioxidant activities and alpha-glucosidase inhibitory activities were evaluated. The moisture and sugar contents were increased depending on the period of aging times and the pH was reduced thereby increasing acidity. The color of black jujube extract was changed from red to black resulting in decreases of Hunter color values L, a and b. As the aging progressed, sucrose was decomposed by increasing glucose and fructose, indicating higher contents of the total reducing sugars. Among the six different types of organic acids extracted from dried jujube, the levels of oxalic acid and citric acid were increased as the aging progressed. The total polyphenol contents in ethanol and water extracts of dried jujube were 7.74 and 8.12 mg/g, respectively. The water extract of black jujube aged for 48 hr contained the highest polyphenol contents at 16.82 mg/g. The 5'-hydroxymethylfurfural (5'-HMF) contents of black jujube extract significantly increased by longer aging times, and contained higher contents in the ethanol extract than water extract. The ethanol extract of black jujube showed the highest 5'-HMF content with 338.89 mg% after aging for 3 days. Also, IC50 values of black jujube aged for 72 hr evaluated by DPPH and ABTS radical assays were 0.54 and 0.59 mg/mL, respectively. alpha-Glucosidase inhibitory activities of black jujube at the concentration of 3.33 mg/mL (ethanol extract) increased from 65 to 80 % after aging for 72 hr. PMID- 24471111 TI - Spherical Granule Production from Micronized Saltwort (Salicornia herbacea) Powder as Salt Substitute. AB - The whole saltwort plant (Salicornia herbacea) was micronized to develop the table salt substitute. The micronized powder was mixed with distilled water and made into a spherical granule by using the fluid-bed coater (SGMPDW). The SGMPDW had superior flowability to powder; however, it had low dispersibility. To increase the dispersibility of SGMPDW, the micronized powder was mixed with the solution, which contained various soluble solid contents of saltwort aqueous extract (SAE), and made into a spherical granule (SGMPSAE). The SGMPSAE prepared with the higher percentages of solid content of SAE showed improved dispersibility in water and an increase in salty taste. The SGMPSAE prepared with 10% SAE was shown to possess the best physicochemical properties and its relative saltiness compared to NaCl (0.39). In conclusion, SGMPSAEs can be used as a table salt substitute and a functional food material with enhanced absorptivity and convenience. PMID- 24471112 TI - Sensory characteristics and consumer acceptance of frozen cooked rice by a rapid freezing process compared to homemade and aseptic packaged cooked rice. AB - Descriptive analysis and consumer acceptance tests were conducted with frozen (FCR), homemade (HCR), and aseptic-packaged (ACR) cooked rice products from two cultivars-IM and SD. FCR was prepared using a rapid freezing process, which may provide consumers with a quality similar to that of HCR. The intensity of the flavors of roasted, glutinous rice, rice cake, and rice starch and the textures of glutinousness, moistness, chunkiness, adhesiveness, and squishiness were all greater in the FCR as compared to the HCR and ACR (p<0.05) in IM and SD cultivars. The differences in sensory characteristics between the FCR and ACR were larger than the equivalent differences between the FCR and HCR. Overall consumer acceptance ratings for FCR in overall aspect, appearance, aroma, and texture were not significantly different compared to those for HCR (p>0.05); however, in most cases these factors showed significant differences when compared with ACR (p<0.05). From partial least square regression analysis, cooked rice was positively related to sweet, transparency, glossiness, roasted, glutinousness, chunkiness, moistness, glutinous rice, adhesiveness, rice shape, rice starch, and squishiness attributes but negatively related to raw rice, old rice, old rice aroma, a particle feeling, off-aroma, white color, scatteredness, slickness, size of cooked rice, and firmness attributes. PMID- 24471113 TI - Isolation and Identification of the Antioxidant DDMP from Heated Pear (Pyrus pyrifolia Nakai). AB - We evaluated antioxidant activities of heated pear juice (HPJ) exposed to 120, 130, and 140 degrees C for 2 hr. HPJ was partitioned using n-hexane, chloroform, ethyl acetate, n-butanol, and water. The ethyl acetate fraction treated at 130 degrees C for 2 hr showed strong antioxidant activity; thus, this extract was isolated and purified using silica gel column chromatography and preparative high performance liquid chromatography. The structure of the purified compound was determined using ultraviolet and mass spectrometry, (1)H-nucelar magnetic resonance (NMR), and (13)C-NMR. Antioxidant activities of the isolated compound were evaluated and compared with alpha-tocopherol, ascorbic acid, and butylated hydroxytoluene (BHT) using DPPH and ABTS assays. The isolated compound was identified as 2,3-dihydro-3,5-dihydroxy-6-methyl-4H-pyran-4-one (DDMP). The DPPH radical-scavenging activity (IC50) of DDMP occurred in the following order: ascorbic acid (45.3 MUg/mL)> alpha-tocopherol (69.2 MUg/mL)> DDMP (241.6 MUg/mL)> BHT (268.0 MUg/mL). Furthermore, DDMP showed strong ABTS radical-scavenging activity (569.0 mg AA eq/g). PMID- 24471114 TI - Effect of Heating on DPPH Radical Scavenging Activity of Meat Substitute. AB - This study was conducted to evaluate the increase of DPPH radical scavenging activity of meat substitute by heating. The meat substitute showed higher DPPH radical scavenging activity than those of other foods rich in protein such as beef, pork, chicken, and soybean curd. The DPPH radical scavenging activity of meat substitute was dependent upon concentration, heating temperature and heating time of meat substitute. The DPPH radical scavenging activity of meat substitute was enhanced with increasing heating temperature and time. The increase of DPPH radical scavenging activity was only applied to meat substitute without showing any activation in other foods rich in protein such as beef, pork, chicken, and soybean curd. PMID- 24471115 TI - Rosehip Extract Inhibits Lipid Accumulation in White Adipose Tissue by Suppressing the Expression of Peroxisome Proliferator-activated Receptor Gamma. AB - Recent studies have shown that Rosa canina L. and tiliroside, the principal constituent of its seeds, exhibit anti-obesity and anti-diabetic activities via enhancement of fatty acid oxidation in the liver and skeletal muscle. However, the effects of rosehip, the fruit of this plant, extract (RHE), or tiliroside on lipid accumulation in adipocytes have not been analyzed. We investigated the effects of RHE and tiliroside on lipid accumulation and protein expression of key transcription factors in both in vitro and in vivo models. RHE and tiliroside inhibited lipid accumulation in a dose-dependent manner in 3T3-L1 cells. We also analyzed the inhibitory effect of RHE on white adipose tissue (WAT) in high-fat diet (HFD)-induced obesity mice model. Male C57BL/6J mice were fed HFD or HFD supplemented with 1% RHE (HFDRH) for 8 weeks. The HFDRH-fed group gained less body weight and had less visceral fat than the HFD-fed group. Liver weight was significantly lower in the HFDRH-fed group and total hepatic lipid and triglyceride (TG) content was also reduced. A significant reduction in the expression of peroxisome proliferator-activated receptor gamma (PPARgamma) was observed in epididymal fat in the HFDRH-fed group, in comparison with controls, through Western blotting. These results suggest that downregulation of PPARgamma expression is involved, at least in part, in the suppressive effect of RHE on lipid accumulation in WAT. PMID- 24471116 TI - Phosphate-induced rat vascular smooth muscle cell calcification and the implication of zinc deficiency in a7r5 cell viability. AB - The calcification of vascular smooth muscle cells (VSMCs) is considered one of the major contributors for vascular disease. Phosphate is known as the inducer for VSMC calcification. In this study, we assessed whether phosphate affected cell viability and fetuin-A, a calcification inhibitor protein, both which are related to VSMC calcification. Also, VSMC viability by zinc level was assessed. The results showed that phosphate increased Ca and P deposition in VSMCs (A7r5 cell line, rat aorta origin). This phosphate-induced Ca and P deposition was consistent with the decreased A7r5 cell viability (P<0.05), which implies phosphate-induced calcification in A7r5 cells might be due to the decreased VSMC cell viability. As phosphate increased, the protein expression of fetuin-A protein was up-regulated. A7r5 cell viability decreased as the addition of cellular zinc level was decreased (P<0.05). The results suggested that zinc deficiency causes the decreased cell viability and it would be the future study to clarify how zinc does act for VSMC cell viability. The results suggest that the decreased VSMC viability by high P or low Zn in VSMCs may be the risk factor for vascular disease. PMID- 24471117 TI - Effect of Phellinus baumii-Biotransformed Soybean Powder on Lipid Metabolism in Rats. AB - In this study, we evaluated the hypolipidemic and antioxidative effects of biotransformed soybean powder (BTS; Phellinus baumii-fermented soybean) on lipid metabolism in rats. Sprague-Dawley (SD) male rats were divided into basal diet group (BA), high fat diet group (HF), high fat diet containing 10% BTS group (10 BTS), and high fat diet containing 20% BTS group (20 BTS). Changes in the content of various isoflavones, including daidzein and genistein, within the soybean after fermentation to BTS were investigated. The levels of daidzein and genistein were 149.28 MUg/g and 364.31 MUg/g, respectively. After six weeks experimental period, Food efficiency ratio in the 10 and 20 BTS group was significantly lower than the HF group (P<0.05). Total serum levels of cholesterol, triglycerides, low density lipoprotein cholesterol, and atherogenic index ratio in the 10 or 20 BTS group were significantly lower than the HF group. The levels of alanine aminotransferase, aspartate aminotransferase and thiobarbituric acid reactive substance were significantly lower in the groups that received 10% and 20% BTS than the HF. The activities of SOD and CAT were significantly higher in the 10 and 20 BTS group than the HF group. The activity of XO in the 10 and 20 BTS group was significantly lower than in the HF group by 20% and 23%, respectively. In conclusion, these data suggest that BTS is an effective agent in improving lipid metabolism and antioxidant enzyme system. PMID- 24471118 TI - Anti-Helicobacter pylori Properties of GutGardTM. AB - Presence of Helicobacter pylori is associated with an increased risk of developing upper gastrointestinal tract diseases. Antibiotic therapy and a combination of two or three drugs have been widely used to eradicate H. pylori infections. Due to antibiotic resistant drugs, new drug resources are needed such as plants which contain antibacterial compounds. The aim of this study was to investigate the ability of GutGardTM to inhibit H. pylori growth both in Mongolian gerbils and C57BL/6 mouse models. Male Mongolian gerbils were infected with the bacteria by intragastric inoculation (2*10(9) CFU/gerbil) 3 times over 5 days and then orally treated once daily 6 times/week for 8 weeks with 15, 30 and 60 mg/kg GutGardTM. After the final administration, biopsy samples of the gastric mucosa were assayed for bacterial identification via urease, catalase and ELISA assays as well as immunohistochemistry (IHC). In the Mongolian gerbil model, IHC and ELISA assays revealed that GutGardTM inhibited H. pylori colonization in gastric mucosa in a dose dependent manner. The anti-H. pylori effects of GutGardTM in H. pylori-infected C57BL/6 mice were also examined. We found that treatment with 25 mg/kg GutGardTM significantly reduced H. pylori colonization in mice gastric mucosa. Our results suggest that GutGardTM may be useful as an agent to prevent H. pylori infection. PMID- 24471119 TI - Safety Evaluation of Chrysanthemum indicum L. Flower Oil by Assessing Acute Oral Toxicity, Micronucleus Abnormalities, and Mutagenicity. AB - Chrysanthemum indicum is widely used to treat immune-related and infectious disorders in East Asia. C. indicum flower oil contains 1,8-cineole, germacrene D, camphor, alpha-cadinol, camphene, pinocarvone, beta-caryophyllene, 3-cyclohexen-1 ol, and gamma-curcumene. We evaluated the safety of C. indicum flower oil by conducting acute oral toxicity, bone marrow micronucleus, and bacterial reverse mutation tests. Mortality, clinical signs and gross findings of mice were measured for 15 days after the oral single gavage administration of C. indicum flower oil. There were no mortality and clinical signs of toxicity at 2,000 mg/kg body weight/day of C. indicum flower oil throughout the 15 day period. Micronucleated erythrocyte cell counts for all treated groups were not significantly different between test and control groups. Levels of 15.63~500 MUg C. indicum flower oil/plate did not induce mutagenicity in S. Typhimurium and E. coli, with or without the introduction of a metabolic activation system. These results indicate that ingesting C. indicum flower oil produces no acute oral toxicity, bone marrow micronucleus, and bacterial reverse mutation. PMID- 24471120 TI - Analysis of the Prevalence and Risk Factors of Malnutrition among Hospitalized Patients in Busan. AB - This study investigated the prevalence of and risk factors for malnutrition in hospitalized patients in Busan, Republic of Korea. 944 patients (440 men and 504 women) were hospitalized in four Busan general hospitals from March through April, 2011. Nutritional status was assessed on admission by the Nutritional Risk Screening 2002. Data were collected from the electronic medical records system for the characteristics of the subjects, clinical outcomes, biochemical laboratory data, and nutrition support states. Clinical dietitians interviewed the patients using structured questionnaires involving data on weight loss and problems related to oral intakes. Malnourished patients were significantly older (P<0.001) than well-nourished patients, but the values for BMI, serum albumin, total cholesterol, TLC, hemoglobin, and hematocrit were significantly lower (P<0.001) for malnourished than for well-nourished patients. Logistic regression indicated that the main determinant factors for nutritional status were the age, length of stay, BMI, serum albumin, and total cholesterol. In order to increase therapeutic effects of hospitalized patients, clinical dietitians need to offer proper nutritional intervention based on the results of nutrition assessment and identification of malnutrition. PMID- 24471121 TI - Hepatic Fibrosis Inhibitory Effect of Peptides Isolated from Navicula incerta on TGF-beta1 Induced Activation of LX-2 Human Hepatic Stellate Cells. AB - In this study, novel peptides (NIPP-1, NIPP-2) derived from Navicula incerta (microalgae) protein hydrolysate were explored for their inhibitory effects on collagen release in hepatic fibrosis with the investigation of its underlying mechanism of action. TGF-beta1 activated fibrosis in LX-2 cells was examined in the presence or absence of purified peptides NIPP-1 and NIPP-2. Besides the mechanisms of liver cell injury, protective effects of NIPP-1 and NIPP-2 were studied to show the protective mechanism against TGF-beta1 stimulated fibrogenesis. Our results showed that the core protein of NIPP-1 peptide prevented fibril formation of type I collagen, elevated the MMP level and inhibited TIMP production in a dose-dependent manner. The treatment of NIPP-1 and NIPP-2 on TGF-beta1 induced LX-2 cells alleviated hepatic fibrosis. Moreover, alpha-SMA, TIMPs, collagen and PDGF in the NIPP-1 treated groups were significantly decreased. Therefore, it could be suggested that NIPP-1 has potential to be used in anti-fibrosis treatment. PMID- 24471122 TI - Influence of extraction method on quality and functionality of broccoli juice. AB - This study was performed to compare the quality and functionality of broccoli juice as affected by extraction method. Broccoli juice was extracted using method I (NUC Kuvings silent juicer), method II (NUC centrifugal juicer), and method III (NUC mixer), and the quality properties of the broccoli juices were analyzed using three different methods. Additionally, the antioxidative, anticancer, and anti-hyperglycemic activities of broccoli juice prepared by the three different methods were investigated in vitro. The broccoli juice made by method I contained the highest polyphenol and flavonoid contents at 1,226.24 mg/L and 1,018.32 mg/L, respectively. Particularly, broccoli juice prepared by method I showed higher DPPH and ABTS radical scavenging activities than those of the other samples. Additionally, broccoli juice made by method I showed the highest growth inhibitory effects against HeLa, A549, AGS, and HT-29 cancer cells. Broccoli juice prepared by method I had the highest alpha-glucosidase inhibitory effects. These results indicate that there are important differences in chemical and functional qualities between juice extraction techniques. PMID- 24471123 TI - Proximate composition, amino Acid, mineral, and heavy metal content of dried laver. AB - Laver, a red algae belonging to the genus Porphyra, is one of the most widely consumed edible seaweeds. The most popular commercial dried laver species, P. tenera and P. haitanensis, were collected from Korea and China, respectively, and evaluated for proximate composition, amino acids, minerals, trace heavy metals, and color. The moisture and ash contents of P. tenera and P. haitanensis ranged from 3.66~6.74% and 8.78~9.07%, respectively; crude lipid and protein contents were 1.96~2.25% and 32.16~36.88%, respectively. Dried lavers were found to be a good source of amino acids, such as asparagine, isoleucine, leucine, and taurine, and gamma-aminobutyric acid. K, Ca, Mg, Na, P, I, Fe, and Se minerals were selected for analysis. A clear regional variation existed in the amino acid, mineral, and trace metal contents of lavers. Regular consumption of lavers may have heath benefits because they are relatively low in fat and high in protein, and contain functional amino acids and minerals. PMID- 24471124 TI - Monitoring and risk assessment of pesticide residues in commercially dried vegetables. AB - We tested for residual pesticide levels in dried vegetables in Seoul, Korea. A total of 100 samples of 13 different types of agricultural products were analyzed by a gas chromatography-nitrogen phosphate detector (GC-NPD), an electron capture detector (GC-MUECD), a mass spectrometry detector (GC-MSD), and a high performance liquid chromatography-ultraviolet detector (HPLC-UV). We used multi analysis methods to analyze for 253 different pesticide types. Among the selected agricultural products, residual pesticides were detected in 11 samples, of which 2 samples (2.0%) exceeded the Korea Maximum Residue limits (MRLs). We detected pesticide residue in 6 of 9 analyzed dried pepper leaves and 1 sample exceeded the Korea MRLs. Data obtained were then used for estimating the potential health risks associated with the exposures to these pesticides. The estimated daily intakes (EDIs) range from 0.1% of the acceptable daily intake (ADI) for bifenthrin to 8.4% of the ADI for cadusafos. The most critical commodity is cadusafos in chwinamul, contributing 8.4% to the hazard index (HI). This results show that the detected pesticides could not be considered a serious public health problem. Nevertheless, an investigation into continuous monitoring is recommended. PMID- 24471125 TI - Fatty Acid Composition and Volatile Constituents of Protaetia brevitarsis Larvae. AB - A total of 48 different volatile oils were identified form P. brevitarsis larvae by gas chromatography/mass spectrometry (GC/MS). Acids (48.67%) were detected as the major group in P. brevitarsis larvae comprising the largest proportion of the volatile compounds, followed by esters (19.84%), hydrocarbons (18.90%), alcohols (8.37%), miscellaneous (1.71%), aldehydes (1.35%) and terpenes (1.16%). The major volatile constituents were 9-hexadecenoic acid (16.75%), 6-octadecenoic acid (14.88%) and n-hexadecanoic acid (11.06%). The composition of fatty acid was also determined by GC analysis and 16 fatty acids were identified. The predominant fatty acids were oleic acid (C18:1, 64.24%) followed by palmitic acid (C16:0, 15.89%), palmitoleic acid (C16:1, 10.43%) and linoleic acid (C18:2, 4.69%) constituting more than 95% of total fatty acids. The distinguished characteristic of the fatty acid profile of P. brevitarsis larvae was the high proportion of unsaturated fatty acid (80.54% of total fatty acids) versus saturated fatty acids (19.46% of total fatty acids). Furthermore, small but significant amounts of linoleic, linolenic and gamma-linolenic acids bestow P. brevitarsis larvae with considerable nutritional value. The novel findings of the present study provide a scientific basis for the comprehensive utilization of the insect as a nutritionally promising food source and a possibility for more effective utilization. PMID- 24471126 TI - Effects of the Cynanchum wilfordii Ethanol Extract on the Serum Lipid Profile in Hypercholesterolemic Rats. AB - The purpose of this study was to investigate the effects of the ethanol extract of Cynanchum wilfordii (ECW) on the blood lipid profile of hypercholesterolemic rats. Thirty 7-week-old male Sprague-Dawley rats were allowed free access to either a normal diet (AIN-93 diet), or 1% high-cholesterol diet with or without 0.5% or 1% ECW for 5 weeks. After sacrifice, the rat serum lipid profile was analyzed. The diets containing ECW decreased body weight gains compared to the normal diet. Serum HDL-cholesterol levels of ECW-fed groups were significantly increased in the hypercholesterolemic groups and normal groups (P<0.05). When 1% ECW was fed to the normal group, total cholesterol level was increased. Moreover, treatment of ECW in hypercholesterolemic groups yielded a dose-dependent and highly significant decrease in the atherogenic index as compared to the control. These results suggest that intake of Cynanchum wilfordii may help reduce the risks of hypercholesterolemia by increasing blood HDL-cholesterol and lowering the atherogenic index. PMID- 24471127 TI - Alleviating Effects of Baechu Kimchi Added Ecklonia cava on Postprandial Hyperglycemia in Diabetic Mice. AB - In this study, we investigated the inhibitory effects of Baechu kimchi added Ecklonia cava on the activities of alpha-glucosidase and alpha-amylase and its alleviating effect on the postprandial hyperglycemia in STZ-induced diabetic mice. Baechu kimchi added Ecklonia cava (BKE, 15%) was fermented at 5 degrees C for 28 days. Optimum ripened BKE was used in this study as it showed the strongest inhibitory activities on alpha-glucosidase and alpha-amylase by fermentation time among the BKEs in our previous study. The BKE was extracted with 80% methanol and the extract solution was concentrated, and then used in this study. The BKE extract showed higher inhibitory activities than Baechu kimchi extract against alpha-glucosidase and alpha-amylase. The IC50 values of the BKE extract against alpha-glucosidase and alpha-amylase were 0.58 and 0.35 mg/mL, respectively; BKE exhibited a lower alpha-glucosidase inhibitory activity but a higher alpha-amylase inhibitory activity than those of acarbose. The BKE extract alleviated postprandial hyperglycemia caused by starch loading in normal and streptozotocin-induced diabetic mice. Furthermore, the BKE extract significantly lowered the incremental area under the curve in both normal and diabetic mice (P<0.05). These results indicated that the BKE extract may delay carbohydrate digestion and thus glucose absorption. PMID- 24471128 TI - In vivo Investigation of Anti-diabetic Properties of Ripe Onion Juice in Normal and Streptozotocin-induced Diabetic Rats. AB - The acute and subacute hypoglycemic and antihyperglycemic effects of drinkable ripe onion juice (Commercial product name is "Black Onion Extract") were investigated in normal and streptozotocin-induced diabetic rats. For tests of acute and subacute hypoglycemic effects, ripe onion juice (5 and 15 mL/kg b.w.) was administered by oral gavage to normal Sprague Dawley rats and measurements of fasting glucose levels and oral glucose tolerance tests were performed. Tolbutamide was used as a reference drug at a single oral dose of 250 mg/kg b.w. To test anti-hyper-glycemic activity, the ripe onion juice was administered to streptozotocin-induced diabetic rats by oral gavage at single dose of 15 mL/kg b.w. per day for 7 consecutive days. Oral administration of the ripe onion juice at either dosed level of 5 or 15 mL/kg b.w. showed no remarkable acute hypoglycemic effect in normal rats. The two dosed levels caused a relatively small reduction, only 18% and 12% (5 and 15 mL/kg b.w., respectively) decrease in glucose levels at 2 h after glucose loading in normal rats. However, at 3 h after glucose loading, blood glucose levels in the ripe onion juice-dosed rats were decreased to the corresponding blood glucose level in tolbutamide-dosed rats. Although showing weak hypoglycemic potential compared to that of tolbutamide, oral administration of ripe onion juice (15 mL/kg b.w.) for a short period (8 days) resulted in a slight reduction in the blood glucose levels that had elevated in Streptozotocin-induced diabetic rats. In conclusion, these results suggest that the commercial product "Black Onion Extract" may possess anti hyperglycemic potential in diabetes. PMID- 24471129 TI - Effects of a Pre-Exercise Meal on Plasma Growth Hormone Response and Fat Oxidation during Walking. AB - The purpose of this study was to determine the effects of a pre-exercise meal on the plasma human growth hormone (hGH) response and fat oxidation during walking. Subjects (n=8) were randomly provided with either 1 g/kg body weight of glucose in 200 mL water (CHO) or 200 mL water alone (CON) 30 min prior to exercise and subsequently walked on a treadmill at 50% of VO2max for 60 min. Plasma hGH concentrations were significantly higher in subjects who received CHO compared to those who received CON at 15 and 30 min. The fat oxidation rate in the CHO was significantly lower than the CON while walking for 5~15, 25~35 and 45~55 min. Plasma FFA levels were also significantly lower in the CHO compared to the CON at 30, 45 and 60 min. Plasma glucose levels in the CHO were significantly lower while plasma insulin levels were significantly higher than in the CON at 15 and 30 min. Therefore, the results of this study suggest that the elevation of plasma hGH levels due to the intake of a pre-exercise meal may not be strongly related to fat oxidation and plasma free fatty acid (FFA) levels during low-intensity exercise. PMID- 24471130 TI - Anticoagulant and Antiplatelet Activities of Artemisia princeps Pampanini and Its Bioactive Components. AB - Artemisia princeps Pampanini (AP) has been used as a traditional medicine in Korea, China and Japan and reported to exhibit various beneficial biological effects including anti-inflammatory, antioxidant, anti-atherogenic and lipid lowering activities; however, its antiplatelet and anticoagulant properties have not been studied. In the present study, we evaluated the effects of an ethanol extract of Artemisia princeps Pampanini (EAP) and its major flavonoids, eupatilin and jaceosidin, on platelet aggregation and coagulation. To determine the antiplatelet activity, arachidonic acid (AA)-, collagen- and ADP (adenosine diphosphate)-induced platelet aggregation were examined along with serotonin and thromboxane A2 (TXA2) generation in vitro. The anticoagulant activity was determined by monitoring the activated partial thromboplastin time (aPTT) and prothrombin time (PT) in vitro. The data showed that EAP and its major flavonoids, eupatilin and jaceosidin, significantly reduced AA-induced platelet aggregation and the generation of serotonin and TXA2, although no significant change in platelet aggregation induced by collagen and ADP was observed. Moreover, EAP significantly prolonged the PT and aPTT. The PT and/or aPTT were significantly increased in the presence of eupatilin and jaceosidin. Thus, these results suggest that EAP may have the potential to prevent or improve thrombosis by inhibiting platelet activation and blood coagulation. PMID- 24471131 TI - Evaluation of the Antioxidant Capacity and Phenolic Content of Agriophyllum pungens Seed Extracts from Mongolia. AB - Antioxidants are an important group of medicinal preventive compounds as well as being food additives inhibiting detrimental changes of easily oxidizable nutrients. The present investigation has been carried out to evaluate the antioxidant properties of different solvent extracts of Agriophyllum pungens seeds by various in vitro systems. The anti-oxidative activities of these samples were determined using four methods: 1,1-diphenyl-2-picrylhydrazyl (DPPH), 2,2' azino-bis(3-ethylbenzothiazoline-6-sulfonic acid) (ABTS) radical scavenging activity, ferric-reducing antioxidant potential (FRAP), and hydroxyl (OH) radical scavenging activities. Additionally, total flavonoids and phenolic contents (TPC) were also determined. Yield of extracts varied widely among solvents and was the highest for water extract (5.642% based on dry weight basis), while ethyl acetate extract exhibited the highest total phenolic content (0.149 mg/mL), total flavonoid content (0.111 mg/mL), and antioxidant activities (P<0.05). The ABTS radical scavenging activity of A. pungens seeds occurred in the following order: ascorbic acid (92.9157%)>BHA (90.1503%)>alpha-tocopherol (87.7527%)>APEA (83.9887%) >APWR (75.5633%); the antioxidant activity of the extracts might be attributed to the presence of these phenolics. This suggests that A. pungens seed extract is a potential source of natural antioxidants, which could be added to dietary supplements to help prevent oxidative stress. PMID- 24471132 TI - Evaluation of Physiological Activities of the Citron (Citrus junos Sieb. ex TANAKA) Seed Extracts. AB - Citron seed extracts (CSEs) were made using distilled water (CSEW), ethanol (CSEE), and n-hexane (CSEH), to measure the total polyphenol contents, DPPH and ABTS radical scavenging activities, and anti-complementary activity. The total polyphenol content was observed the highest in CSEE (188.71 MUg/mL), and occurred in the following order: CSEE>CSEW (141.11 MUg/mL)>CSEH (26.19 MUg/mL) at 10 mg/mL. CSEE (63.56%) and CSEW (56.61%) showed significantly higher DPPH radical scavenging activities when compared with CSEH (28.57%). ABTS radical scavenging activities of CSEE (45.53%) and CSEW (40.02%) were also observed to be higher, whereas CSEH did not show ABTS radical scavenging activity. Anti-complementary activity of CSEE (26.85%) showed a greater activity than that of CSEW (7.84%) at 1,000 MUg/mL. Limonin and nomilin contents had the highest values (1.882% and 2.089%) in CSEE, and with 0.327% and 0.139% in CSEW; however, CSEH showed relatively very low values at 0.061% and 0.026%, respectively. Among the CSEs tested, CSEE as a by-product from citron may provide an important source of dietary antioxidant compounds with rich polyphenol and limonoid contents, and immunopotentiating activity, including the complement activation factor. PMID- 24471133 TI - Physicochemical and Microbial Properties of the Korean Traditional Rice Wine, Makgeolli, Supplemented with Banana during Fermentation. AB - The objective of the present study was to evaluate the physicochemical and microbial properties of the Korean traditional rice wine Makgeolli, supplemented with banana during 6 day fermentation. The alcohol contents of the control and banana Makgeolli were 17.0 and 16.5%, respectively. The pH values decreased while total acidity, total soluble solids, and color values increased throughout the fermentation process. An increase in microorganism counts throughout the 6-day fermentation period was noted in all samples. The major free sugar and organic acid detected in all samples were glucose and succinic acid, respectively. There were 39 volatile compounds detected in the control and banana Makgeolli. The major ester detected was ethyl acetate (20.037 and 22.604% for the control and banana Makgeolli, respectively). The major alcohol compounds detected were 3 methylbutanol (20.933%) and 3-methyl-1-butanol (34.325%) in the control. 2-mtehyl 1-propanol (22.289%) and 3-methyl-1-butanol (39.851%) were the highest alcohol compounds detected in the banana Makgeolli. PMID- 24471134 TI - Cholesterol-lowering Effect of Rice Protein by Enhancing Fecal Excretion of Lipids in Rats. AB - The aim of this study was to investigate the effects of isolated protein from white rice on lipid metabolism in a hypercholesterolemic animal model. Male Sprague-Dawley rats were divided into three groups and fed either a normal diet or a high-cholesterol diet (HCD) containing either casein or isolated rice protein for 4 weeks. Compared with rats fed a HCD with casein, the total cholesterol (TC) level in the plasma was significantly reduced in the rats fed rice protein. However, no significant differences were observed in the triglycerides, high-density lipoprotein (HDL), and glucose levels among the experimental groups. Hepatic total lipids and TC levels were significantly decreased by supplementation with rice protein. In addition, rice protein significantly increased the levels of TC and bile acids in the feces. These results suggest that rice protein may improve HCD-induced hypercholesterolemia by enhancing fecal excretion of cholesterol. PMID- 24471135 TI - Mineral compositions of korean wheat cultivars. AB - Twenty-nine Korean wheat cultivars were analyzed for 8 important minerals (Cu, Fe, Mn, Zn, Ca, K, Mg and P) using Inductively Coupled Plasma Atomic Emission Spectrometry (ICP-AES). A hierarchical cluster analysis (HCA) was applied to classify wheat cultivars, which has a similarity in mineral compositions. The concentration ranges of the micro-minerals Cu, Fe, Mn, and Zn: 0.12~0.71 mg/100 g, 2.89~5.89 mg/100 g, 1.65~4.48 mg/100 g, and 2.58~6.68 mg/100 g, respectively. The content ranges of the macro-minerals Ca, K, Mg and P: 31.3~46.3 mg/100 g, 288.2~383.3 mg/100 g, 113.6~168.6 mg/100 g, and 286.2~416.5 mg/100 g, respectively. The HCA grouped 6 clusters from all wheat samples and a significant variance was observed in the mineral composition of each group. Among the 6 clusters, the second group was high in Fe and Ca, whereas the fourth group had high Cu, Mn and K concentrations; the fifth cluster was high in Zn, Mg and P. The variation in mineral compositions in Korean wheat cultivars can be used in the wheat breeding program to develop a new wheat cultivar with high mineral content, thus to improve the nutritional profile of wheat grains. PMID- 24471136 TI - GC-MS Analysis of the Extracts from Korean Cabbage (Brassica campestris L. ssp. pekinensis) and Its Seed. AB - Korean cabbage, a member of the Brassicaceae family which also includes cauliflower, mustard, radish, and turnip plants, is a crucial leafy vegetable crop. Korean cabbage is harvested after completion of the leaf heading process and is often prepared for use in "baechu kimchi", a traditional Korean food. Many of the components in Korean cabbage are essential for proper human nutrition; these components can be divided into two groups: primary metabolites, which include carbohydrates, amino acids, fatty acids, and organic acids, and secondary metabolites such as flavonoids, carotenoids, sterols, phenolic acids, alkaloids, and glucosinolates (GSLs). Using gas chromatography-mass spectrometry, this study examined the variety of volatile compounds (including isothiocyanates) contained in Korean cabbage and its seed, which resulted in the identification of 16 and 12 volatile compounds, respectively. The primary volatile compound found in the cabbage was ethyl linoleolate (~23%), while 4,5-epithiovaleronitrile (~46%) was the primary volatile component in the seed. PMID- 24471137 TI - Preparation and quality analysis of sodium-reduced fried fish cakes. AB - To help reduce high intake of sodium in the Korean diet, sodium-reduced fried fish cakes (SRFFCs) were prepared and evaluated with regard to color, textural properties, and sensory attributes as indicators of quality. The quality characteristics of 30% SRFFCs were not notably different from those of full sodium FFCs; however, substitution of sodium with potassium altered the color and decreased consumer acceptance on sensory evaluation items. These results suggest that the SRFFCs that will be accepted by consumers can be prepared without compromising the quality. PMID- 24471139 TI - Age at first use of alcohol and risk of heavy alcohol use: a population-based study. AB - AIM: To examine the association between age at first alcohol use and risk of heavy alcohol use among the adult US general drinking population. METHODS: This population-based study used the 2010 National Survey on Drug Use and Health (NSDUH) from United States. Multivariate Poisson regression was employed to predict the frequency of heavy alcohol use (five or more drinks per occasion) in the last 30 days with age at first use of alcohol controlling for potential confounding factors. RESULTS: Younger age at first use of alcohol was associated with increased likelihood of heavy alcohol use in the last 30 days in this population-based sample. This association remained significant when analysis was reperformed for the subgroup of participants who were with desired good health status and Kessler score lower than 12. CONCLUSION: Younger age at first use of alcohol was associated with increased likelihood of heavy alcohol use. PMID- 24471138 TI - Peripheral arterial stiffness is independently associated with a rapid decline in estimated glomerular filtration rate in patients with type 2 diabetes. AB - INTRODUCTION: Diabetes and its vascular complications are main noncommunicable chronic diseases and major global health issues. Peripheral arterial disease (PAD) is highly prevalent in diabetes with nephropathy. We evaluated the associations of variables of arterial stiffness and the decline in estimated glomerular filtration rate (eGFR) in patients with type 2 diabetes. MATERIALS AND METHODS: A total of 577 type 2 diabetic patients (mean +/- SD: age, 63 +/- 11 years) were enrolled. A rapid decline in eGFR was defined as progressively lower eGFR detected at both the 6- and 12-month follow-up visits, plus a reduction in eGFR more than 3 mL . min(-1)per 1.73 m(2) per year. RESULTS: Higher glycated hemoglobin (HbA1c), systolic blood pressure (SBP), pulse pressure (PP), and brachial-ankle pulse wave velocity (ba-PWV) at baseline were independently associated with a rapid decline in eGFR. The adjusted odds ratios (95% confidence intervals) for a rapid decline in eGFR for ba-PWV, SBP, and PP were 1.072 (1.011 1.136), 1.014 (1.004-1.025), and 1.025 (1.008-1.041), respectively, after adjustment for gender, age, body mass index, smoking, HbA1c, and baseline eGFR in separated models. CONCLUSIONS: Ba-PWV may serve as a simple and noninvasive predictor of rapid renal function progression in type 2 diabetic patients. PMID- 24471141 TI - International consensus on periprosthetic joint infection: what was discussed and decided? PMID- 24471140 TI - The Potential Impact of Maintaining a 3-Hour IV Thrombolysis Window: How Many More Patients can we Safely Treat? AB - BACKGROUND: In 2008, the European Cooperative Acute Stroke Study-3 (ECASS-3) demonstrated that intravenous-tissue plasminogen activator could be safely administered for acute stroke patients presenting between 3 and 4.5 hours from symptom onset. Recently, the Food and Drug Administration rejected expansion of this time window in the United States. We sought to determine how many fewer patients would be treated by maintaining this restricted time window. METHODS: We reviewed charts from patients who received intravenous thrombolysis at the University of Alabama at Birmingham between January 2009 and December 2011. Patients were divided into two groups (treated within 3 hours of onset, treated between 3 and 4.5 hours from onset). Demographics, stroke severity and protocol deviations according to the ECASS-3 trial were collected. Our safety measures were any hemorrhagic transformation, symptomatic intracerebral hemorrhage and systemic hemorrhage. RESULTS: Two hundred and twelve patients were identified, of whom 192 were included in our analysis. A total of 36 patients (19%) were treated between 3 and 4.5 hours. No statistical differences were seen between age (p=0.633), gender (p=0.677), race (p=0.207) or admission stroke severity (p=0.737). Protocol deviations from the ECASS-3 criteria were found in 20 patients (56%). These were primarily age > 80 and aggressive blood pressure management. Despite these deviations, we did not see significant increases in the rates of adverse events in patients treated in the extended time window. CONCLUSIONS: Our data are consistent with previously reported international data that IV thrombolysis can safely be used up to 4.5 hours from symptom onset. Restricting the time window to 3 hours would have resulted in almost one-fifth fewer patients treated at our center. PMID- 24471142 TI - Ready, set, 10 months to go: how to get organized and be fearless about ICD-10. PMID- 24471143 TI - 100 most cited articles in fracture surgery. AB - Citation density is an important method by which to assess an article's impact on a field. We sought to identify the 100 most cited articles in fracture surgery, and highlight their characteristics. We used the ISI web of science's cited reference search to identify the most cited articles in orthopedic surgery. We then used multiple reviewers to identify the articles that pertained specifically to fracture surgery. Differences were resolved by discussion. We then characterized the level of evidence, decade of publication, type of design, and citation density for each article. All of the top 100 articles were published in English, the majority (69%) originated from the United States. Sixty-six percent of articles were clinical articles; the remainder were basic science. The most represented topic in the top 100 was hip fractures (12/100 articles). Over half of the clinical articles were level IV. Level of evidence was negatively correlated with date of publication. Citation number-based identification of important papers will help current practitioners gain insight into past and current trends in their respective fields and provides the foundation for further investigations. PMID- 24471144 TI - Patient-specific imaging and missed tumors: a catastrophic outcome. AB - Patient-specific instrumentation (PSI) is a relatively new technology aimed at increasing the accuracy and efficiency of total knee arthroplasty (TKA). Its premise is reliant upon preoperative imaging techniques to acquire detailed measurements of a patient's distal femur and proximal tibia. Although a limited number of studies in the current literature have begun to critically evaluate this promising technology, a number of potential controversies exist. We present 2 patients with radiographic evidence of musculoskeletal neoplasms present on initial preoperative imaging that were not recognized prior to placement of patient-specific total knees. The expanding role of non-diagnostic imaging in TKA is examined, and we suggest guidelines for prevention of further devastating outcomes. PMID- 24471145 TI - Parosteal osteosarcoma of the 2nd metatarsal. AB - While masses of the foot are relatively common, bone forming lesions of the foot are less common. The differential diagnosis includes benign and malignant lesions. A thorough history and physical examination, along with selective imaging, can guide the practitioner to an accurate diagnosis. For malignant lesions, appropriate local and whole body imaging consistent with published national guidelines in order to stage the patient's disease helps to guide treatment. Knowledge of the national history of the lesion will guide decision making for appropriate surgical resection and the need for any adjuvant therapy. Postresection surveillance of malignant or locally aggressive lesions is also important in the patient's postoperative care. We present a case of parosteal osteosarcoma of the 2nd metatarsal. PMID- 24471146 TI - Functional improvement after humeral shaft nonunion in a patient with glenohumeral ankylosis. AB - Functionally limiting heterotopic ossification about the shoulder represents an uncommon clinical entity, which has been most commonly reported as a consequence of prolonged immobilization in intensive care unit patients. Severe cases may result in complete glenohumeral ankylosis, with resultant upper extremity motion through the scapulothoracic joint, and significant functional consequences. We report the case of a 72-year-old male with spontaneous glenohumeral ankylosis who suffered a humeral shaft fracture with resultant painless nonunion. Motion through the nonunion site caused significant subjective functional improvements, increased range of motion, and the ability to complete his activities of daily living. Patients with limited shoulder range of motion may be at higher risk for humeral fractures and nonunion. These patients, however, may experience improved function due to increased upper extremity range of motion through the nonunion site. PMID- 24471147 TI - Failure of a constrained acetabular liner without reinforcement ring disruption. AB - Several risk factors for dislocation after total hip arthroplasty (THA) have been identified including operative-, patient-, and implant-related factors. The following case report describes the dislocation of a revision THA without disruption of the constrained liner or containment ring. The possible mechanisms leading to this type of failure include lever-out impingement and poor abductor function, or tension secondary to prior surgery. Dislocation without disruption of containment ring has not been described for the Pinnacle Acetabular Cup with the Enhanced Stability Constrained Liner (DePuy Orthopaedics, Warsaw, Indiana). PMID- 24471148 TI - Delayed complete limb ischemia following a closed tibial shaft fracture. AB - We present a 19-year-old collegiate athlete who sustained a low-energy closed tibial shaft fracture. Following closed reduction, the dorsalis pedis and posterior tibial pulses were symmetric to the contralateral limb on physical examination. Angiography later confirmed triple vessel arterial disruption complicated by delayed ischemia requiring limb revascularization. Lower extremity triple vessel occlusion from a low-energy injury is rare, and delayed presentation requiring limb salvage is even more unusual. We review the literature, describe the diagnosis and treatment, and propose a strategy for post fracture reduction management of vascular status. PMID- 24471149 TI - A simple wrist arthroscopy tower: the wrist triangle. AB - Several wrist arthroscopy towers are commercially available. In this report, the use of a triangular holder as a cheap, mobile, radiolucent tower for wrist arthroscopy is described, which can be useful in a cost-conscious surgical practice. PMID- 24471150 TI - Will the new milestone requirements improve residency training? PMID- 24471151 TI - Patients' point of view on informed consent: a prospective study in carpal tunnel surgery. AB - Patients' perception of consent form (CF) is not well known and many patients tend to view the CF as an administrative act. As part of a prospective study, a questionnaire was sent to 188 consecutive patients within 1 month after carpal tunnel release. Questions focused on patients' recall about risks, benefits, alternative options, preferences about decisions process and global satisfaction with CF. Patient's understanding of the legal consequences of the CF was analysed. Risk's recall rate was 59%. CF reduced preoperative anxiety in 65% and the influence in patients' decision was relevant in 55% of cases. Patients have limited understanding of the legal consequences of the consensus and 29% of patients believed that primary function was to protect hospital. Ten percent believed that CF expunges patients' right to compensation in case of claims. Patient involvement in medical decision-making is a key aspect of patient centred care. A substantial uncertainty exists about legal implication of CF, leading to potential discord. PMID- 24471152 TI - Locked knee caused by lateral meniscal capsular disruption: verification by magnetic resonance imaging and arthroscopy. AB - Locking of the knee is commonly reported in patients presenting to an orthopedic surgeon. This case report describes a rare cause of knee locking: subluxation of the lateral meniscus without an associated tear. This case highlights the importance of the popliteus recess in stability of the lateral meniscus. Injury to this area may lead to meniscal subluxation and knee locking. PMID- 24471153 TI - Symptomatic carpal coalition: scaphotrapezial joint. AB - Carpal coalition is an uncommon congenital abnormality that arises from incomplete cavitation of the common cartilaginous precursor that forms the carpal bones. When carpal coalition is discovered, it is typically an asymptomatic incidental radiographic finding, and is often bilateral. We present a case of symptomatic unilateral carpal coalition of the scaphotrapezial joint, which was treated by excising the fibrous coalition and placing an interposition fat graft. This treatment was effective in alleviating the patient's symptoms. PMID- 24471154 TI - Missed locked posterior shoulder dislocation with a reverse Hill-Sachs lesion and subscapularis rupture. AB - We report the case of a patient who sustained a missed locked posterior shoulder dislocation with a sizable anterior impression fracture and a concomitant acute rupture of the subscapularis tendon. Despite compromise of the tendon, a transfer of the lesser tuberosity into the humeral head defect along with suture anchor repair of the subscapularis was performed. Within 6 months, the patient regained near complete function of his shoulder with no episodes of instability. To our knowledge, this is the first reported case of an acute subscapularis rupture associated with a posterior shoulder dislocation and anterior humeral impression fracture, treated with the modified McLaughlin procedure and tendon repair with an excellent clinical result. PMID- 24471155 TI - Anterior pelvic external fixation: is there an optimal placement for the supra acetabular pin? AB - Anterior pelvic external fixation using supra-acetabular bone pins is frequently used for manipulation and reduction of unstable pelvic ring injuries prior to definitive fixation. The supra-acetabular bone pin must be strategically placed in order to provide optimal frame stability, patient comfort, and hip mobility, without obstructing subsequent osseous fixation pathways. We describe a technique for alternative placement of supra-acetabular bone pins. The intraoperative imaging is detailed. The bone pin starting point is located more cranially at the anterior inferior iliac spine than previously described and the pin is directed to accommodate better hip motion. PMID- 24471156 TI - Fully automated on-line two-dimensional liquid chromatography in combination with ESI MS/MS detection for quantification of sugar phosphates in yeast cell extracts. AB - A mass spectrometric quantitative assay was developed for the analysis of 10 sugar phosphates in the yeast Pichia pastoris. As a novelty, two-dimensional chromatography based on a fully automated heart-cutting LC-LC technique was introduced. Using a ten-port valve, ten fractions of the first chromatographic dimension, i.e. anion exchange chromatography (AEC), were transferred and separated by the orthogonal second dimension, i.e. separation on porous graphitized carbon. The chromatographic separation on the second dimension was optimized for each transferred fraction minimizing the separation time and ensuring complete removal of the salt constituents of the AEC eluents. The latter being crucial for electrospray mass spectrometric detection was confirmed by combining the LC-LC separation with on-line ICP-MS detection. These measurements showed that sodium elution was completed after 0.8 min. Consequently, an analysis time of 1 min per transferred peak was established. In this way, the excellent peak capacity given by ion exchange could be conserved in the second dimension at the same time enabling mass spectrometric detection. Sub-MUM limits of detection could be obtained by the new LC-LC-MS/MS methods ranging between 0.03 and 0.19 MUM for the investigated compounds (only 3GAP showed a LOD of 1 MUM). The method was applied to the quantification of ten sugar phosphates in yeast extracts utilizing internal standardization with a fully labeled (13)C yeast extract. Typically, the standard uncertainties for N = 3 replicates assessed by the LC-LC MS/MS set-up were <5%. PMID- 24471157 TI - A handheld magnetic sensing platform for antigen and nucleic acid detection. AB - The core requirements for point-of-care (POC) diagnostics necessitate low-cost, portability, easily integrated sample preparation, and quick measurement time. Frequency-shift based magnetic sensing is a measurement technique utilizing a complementary metal-oxide-semiconductor (CMOS) integrated-circuit (IC) chip for magnetic label detection. The sensing scheme leverages the low-cost manufacturing of IC chips while demonstrating the potential for multiplexing capabilities. In this article, we present modifications to this scheme for POC viability. We introduce a handheld reusable reader and a disposable open-well cartridge for the detection of nucleic acids and antigens. The diagnostic system utilizes a novel "magnetic freezing" technique to reduce measurement time, obviates baseline measurement before or during biological assay, and reduces sensor noise. We utilize these enhancements for the room temperature, amplification-free detection of a 31 base-pair DNA oligomer and the interferon-gamma (IFN-gamma) protein. We have demonstrated reliable measurements down to 100 pM for the DNA assay and 1 pM for the protein. PMID- 24471158 TI - Evaluation of the peak variance in gradient liquid chromatography. AB - The peak variance obtained under single stepwise (SS), single linear (SL) and ladder-like (LL) gradient conditions was evaluated by taking into account the variation of plate height with mobile phase composition. LC tests were performed on a C18 column using a mixture of methanol and water as the mobile phase and six aromatic compounds (anisole, o-cresol, biphenyl, phenol, aniline and acetophenone) as the model samples. It was found that the relationship between the retention factor and mobile phase composition could be described by the linear solvent strength model. The plate height that was measured under isocratic conditions varied with mobile phase composition. This variation could be described by a quadratic polynomial in this work. Under gradient conditions, the experimental and predicted values of peak variance were found to be well consistent. The discrepancy between the experimental and predicted values in the SS gradient was larger than that in the SL or LL gradient. This may be ascribed to the distortion of the gradient profile as a result of dispersion that occurred in the mobile phase. By using the dispersive gradient profile that was obtained at the column inlet for the calculation, the discrepancy between the experimental and predicted values in the SS gradient may be minimized. PMID- 24471159 TI - Unusual activation of H2 by reduced cobalt complexes supported by a PNP pincer ligand. AB - The reactivity of cobalt complexes supported by a PNP pincer ligand towards H2 varies depending on whether the N-donor atom is protonated; the synthesis of [(HPNP)CoCl(H)2] (2), [(PNP)CoH]2 (4), and the trihydride species [(HPNP)CoH3] (7) (HPNP = HN(CH2CH2P(i)Pr2)2) are described. PMID- 24471160 TI - Coupling of tyrosine deprotonation and axial ligand exchange in nitrocytochrome c. AB - Here we report a spectroscopic, electrochemical and computational study of cytochrome c showing that nitration of Tyr74 induces Tyr deprotonation, which is coupled to Met/Lys axial ligand exchange, and results in concomitant gain of peroxidatic activity at physiological pH. PMID- 24471161 TI - Design of a luminescence pattern via altering the crystal structure and doping ions to create warm white LEDs. AB - Presently considerable interest in phosphor-converted warm LEDs which meet the stringent requirements of general illumination is stimulated. Here we report warm white LEDs made by altering the crystal structure and doping ions, which can govern the luminescence pattern to modulate the correlated color temperature and color-rendering index. PMID- 24471162 TI - Organometallic carbonyl clusters: a new class of contrast agents for photoacoustic cerebral vascular imaging. AB - We report, for the first time, the use of a water-soluble organometallic compound as a stable, reliable and high-contrast photoacoustic contrast agent. This gives a significantly higher contrast than that achievable with alternatives such as single-walled carbon nanotubes. Image enhancement of the rat cerebral cortex vasculature was observed using in vivo dark-field photoacoustic microscopy. PMID- 24471163 TI - Early amyloid beta-protein aggregation precedes conformational change. AB - The aggregation of amyloid-beta protein (1-42) is studied at experimental concentrations using all-atom molecular dynamics simulations. We observe a fast aggregation into oligomers without significant changes in the internal structure of individual proteins. The aggregation process is characterized in terms of transition networks. PMID- 24471164 TI - Formal hydration of non-activated terminal olefins using tandem catalysts. AB - The hydration of terminal olefins to secondary alcohols has been achieved using a Pd(II)/Ru(II) catalyst combination with high regioselectivity and yields. Both vinyl arenes and aliphatic olefins can be hydrated easily with the tandem catalyst system using a low catalyst loading of 1 mol%. PMID- 24471165 TI - Autocatalytic one pot orchestration for the synthesis of alpha-arylated, alpha amino esters. AB - A novel acetyl chloride-mediated cascade transformation involving three components (benzyl carbamate, ethyl glyoxylate and arene nucleophiles) is reported. Aryl orthogonally protected alpha-amino acids are obtained in a one pot cascade, using a mild AcOH-AcCl system, via a critical autocatalytic dehydration activation step ensuring an original and efficient Friedel-Crafts orchestration. PMID- 24471166 TI - Crystallographic determination of solid-state structural transformations in a dynamic metal-organic framework. AB - Various solid-state transformations in a metal-organic framework were determined by X-ray crystallography. PMID- 24471167 TI - Posterior capsule rupture, iridodialysis, hyphema, and macular hole after blunt ocular trauma. AB - A 34-year-old man was examined 4 hours after blunt ocular trauma with a stone. Visual acuity was hand motions in the right eye and 10/10 in the left eye. Slit lamp examination after resorption of a hyphema revealed 180? superior iridodialysis and a total white intumescent cataract precluding visualization of the posterior capsule. Phacoemulsification was undertaken after repositioning the iris with microretractors. Intraoperatively, we discovered that the cen-tral portion of the posterior capsule presented a 4-mm oval opening with thick and fibrosed edges. The posterior chamber lens was safely implanted in the bag with no enlargement of the posterior capsule rupture. Postoperatively, VA improved only to 1/20 and fundus OCT revealed the presence of a 400-micron, oval-shaped macular hole that was successfully closed with sub-sequent vitrectomy and gas tamponade. Visual acuity stabilized at 5/10, D3, and the lens was stable without decentration after 36 months follow-up. PMID- 24471168 TI - Rapid operation assessment of voluntary HIV counselling and testing services in three cities in China, 2009. AB - OBJECTIVES: To assess the operation of voluntary counselling and testing (VCT) services forhuman immunodeficiency virus (HIV) in three cities in China. STUDY DESIGN: A cross-sectional study using mixed methods, including focus group discussions,in-depth interviews, field assessment, archive checking and structured questionnaire interviews, was conducted to assess different aspects of VCT services. METHODS: Surveys were undertaken in six counties of three China Global Fund AIDS Program (Round Five) cities, including 11 VCT clinics, 38 counsellors, 83 clients and 332 individuals at risk for HIV infection. RESULTS: All counsellors were trained and approved for providing counselling. As there were adequate numbers of clinics and counsellors, VCT services ran smoothly. Clients were generally satisfied with VCT services and considered service operation to be adequate. Problems with the VCT programme included fewer VCT services in general hospitals, lack of a referral mechanism, and long delays between testing and receipt of results. CONCLUSIONS: The operation of VCT services in the three cities was generally adequate, but referral services were poor. More attention needs to be paid to HIV testing and counselling in general hospitals, and referral networks need to be strengthened. PMID- 24471169 TI - Reflections: neurology and the humanities. Molecular medicine and the art of brain repair. PMID- 24471170 TI - Author response. PMID- 24471171 TI - [Orchitis and West Nile encephalitis]. PMID- 24471172 TI - Invited commentary. PMID- 24471173 TI - Meningitis due to Fusobacterium nucleatum after a kart crash. PMID- 24471174 TI - [Spondylodiscitis and Lactococcus cremoris endocarditis]. PMID- 24471175 TI - Reply by the authors of the original article. PMID- 24471176 TI - Reply by the authors of the original article. PMID- 24471177 TI - Reply to D'Amato et al. and Zeldis et al.: Screening of thalidomide derivatives in chicken and zebrafish embryos. PMID- 24471178 TI - The author's reply. PMID- 24471179 TI - Dogs' endocrine and behavioural responses at reunion are affected by how the human initiates contact. AB - For dogs, humans are likely to be the most important feature in their environment influencing their welfare. To investigate a commonly occurring human-dog interaction, behavioural and endocrine responses of 12 female beagle dogs were measured before, upon and after the return of a familiar person. Each dog was left by the person in a test arena to which it had been habituated prior to the experiment. Three different treatments were applied when the person returned and each dog experienced all these in a balanced design; the familiar person entered the test arena and 1) initiated physical and verbal contact in a calm and friendly way (PV), 2) there was verbal contact only (V) or, as a 'control', 3) the person ignored the dog (C). Interaction continued for 4 min during which the person behaved in a standardized way according to the treatment. Blood samples were collected to investigate oxytocin and cortisol levels. Upon return, oxytocin increased initially, probably because of the dog seeing the person entering the room and walking towards the area where the dog was housed. In treatment PV, where physical contact was applied, elevated levels of oxytocin were observed even after the interaction had ended. Cortisol levels showed a decreasing curve throughout the test, however this decrease was most pronounced in treatment PV, possibly as a consequence of the oxytocin release. Also, dogs in this treatment initiated more physical contact with the familiar person and expressed more lip licking upon reunion. The initial responses to reunion in treatment V were tail wagging and vocalisations. When dogs were ignored upon reunion in treatment C, they could have redirected their approach-behaviour towards an assistant (who was always situated in the room). To conclude, the type of interaction evidently affected the endocrine and behavioural responses of dogs in different ways. The mere return of the familiar person had a positive effect on oxytocin levels and induced contact-seeking behaviour, whereas physical contact was necessary in order to induce a sustained increase in oxytocin levels and to decrease cortisol levels in the period following reunion. PMID- 24471180 TI - Numerical modeling of human mastication, a simplistic view to design foods adapted to mastication abilities. AB - The human diet contains a large variety of aromas, tastes and textures. The latter is particularly important since it determines whether foods are difficult to process orally and thus can be one source of food avoidance. It has also been reported in recent literature that food texture was a main driver for satiation processes and thus it is of interest for the food manufacturing industry to be able to control textural properties of food within the limits of acceptability for the consumer. For solid foods, fracture force is an important aspect of texture and we were interested in understanding the physiological drivers of this variable.We present a third order lever model of human bite force and the space between teeth based on data from the literature on human oral anatomy. The results from the model are compared with experimental data available in the literature. The model compares well with the experimental data (r2 = 0.95, p = 0.0010, MPE = 0.18), and can thus be used to derive a diagram of how food properties such as piece size or fracture force can be used to define whether foods are close to the limits of what the human jaw is capable of breaking. Such modeling tools can be used to define texture rules for tailor-made nutrition for specific populations based on their mastication abilities. The limitations of this modeling approach are also discussed, particularly the fact that tooth shape should also be considered, as this will ultimately define fracture stress, which is the deterministic factor of food fracture. PMID- 24471181 TI - Pre-hospital rapid sequence induction: factual inaccuracies. PMID- 24471182 TI - Gunning responds. PMID- 24471183 TI - Cutaneous adverse drug reactions caused by FDCAs - we need to characterise and manage them urgently. PMID- 24471184 TI - Corruption-breeding political patronage an albatross -former E-Cape health chief. PMID- 24471185 TI - Smoke, fire and mirrors: the e-cigarette debate. PMID- 24471186 TI - Quality of life can be part of the cure. PMID- 24471187 TI - Get off your butt- and live longer. PMID- 24471188 TI - Analysis of PIK3CA mutations in breast cancer subtypes. AB - Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) is a central element of a signaling pathway involved in cell proliferation, survival, and growth. Certain mutations in this pathway result in enhanced PI3K signaling, which is associated with oncogenic cellular transformation and cancer. The aims of this study were to characterize different types of PIK3CA mutations in exons 9 and 20 in a series of primary breast carcinomas and to correlate the results with clinicopathologic parameters and survival. We used frozen tissue samples and sequenced exons 9 and 20 for a series of 241 patients with a diagnosis of breast carcinoma. We found that 15.8% of the primary breast carcinomas possessed PIK3CA mutations in either exon 9 or exon 20. The rate of PIK3CA mutations was increased in HR(+)/HER2(-) tumors (18.6%), but this difference did not reach a statistical significance. The lowest rate of mutations was observed in HR(+)/HER2(+) tumors (5.3%). No statistically significant association was found between the presence of PIK3CA mutations and the prognostic/clinical features of breast cancer, including histologic subtype, Her2 status, axillary lymph node involvement, tumor grade, and tumor stage. However, the presence of the H1047R mutation in 10 samples was associated with a statistically significantly worse overall survival. PIK3CA mutation was found to be a frequent genetic change in all breast cancer subtypes but occurred with the highest rate in HR(+)/HER2(-) tumors. Further studies are needed to validate the prognostic impact of different PIK3CA mutations. PMID- 24471189 TI - Clinicopathologic findings and BRAF mutation in cutaneous melanoma in young adults. AB - Cutaneous melanoma in young patients is rare with increasing incidence. It is not clear whether the etiology and clinical outcome are similar to cutaneous melanoma in the elderly. Mutations in BRAF gene in patients with cutaneous melanoma, in general, range in frequency from 20% to 80%; however, the status and clinical significance of BRAF mutations in the young population have not been evaluated. We investigated 132 cases of primary cutaneous melanoma in patients aged between 18 and 30 years with emphasis on clinical characteristics, pathologic features, and molecular evaluation of mutation in the BRAF gene (BRAF(V600E)). It was predominantly seen in female individuals (61.4%), trunk was the most common site of involvement (40.4%), and superficially spreading melanoma was the predominant histologic type (79.5%). Mutation in BRAF(V600E) was analyzed successfully in 93 cases using an RT-PCR. The BRAF(V600E) mutation was identified in 38.7% (36/93) and was associated with vertical growth phase (P=0.01) and mild inflammatory infiltrate (P=0.02). No case of melanoma with regression phenomenon presented with BRAF(V600E) mutation (P<0.05). There was no significant association between BRAF(V600E) mutation and sex, histologic type, the Clark level, the Breslow index, solar elastosis, angiolymphatic and perineural invasion, satellitosis, and coexisting nevus. As in melanomas in older patients, these results probably indicate that BRAF mutation may not be the only key factor in melanoma tumorigenesis, and that there should be multiple alternative genetic pathways related to melanoma. PMID- 24471190 TI - SPECT/CT helps in localization and guiding management of small bowel gastrointestinal hemorrhage. AB - A 59-year-old female patient was hospitalized with anemia from recurrent gastrointestinal bleeding. Planar (99m)Tc-tagged red blood cell bleeding scan suggested an active site of low-rate hemorrhage in the left upper quadrant, but after 60 minutes it could not conclusively define the bleeding as originating in small versus large bowel. SPECT/CT unequivocally localized the hemorrhage to the small bowel and deemed it reachable by extended version ("push"') endoscope. Subsequent push enteroscopy confirmed the bleeding in proximal jejunum and allowed effective treatment with electrocautery. PMID- 24471191 TI - The authors reply. PMID- 24471192 TI - Analysing the amount of soluble fluoride in toothpastes. PMID- 24471193 TI - Response. PMID- 24471194 TI - Coexistence of xanthogranulomatous cholecystitis and gallbladder adenocarcinoma: a fortuitous association? AB - Xanthogranulomatous cholecystitis is a relatively uncommon variant of chronic cholecystitis, characterized by marked thickening of the gallbladder wall and dense local adhesions. Not only does xanthogranulomatous cholecystitis mimic malignancy, it can also be infrequently associated with gallbladder carcinoma in 0.2% to 35.4% of cases. Herein, the authors report a new case of xanthogranulomatous cholecystitis concomitant with gallbladder adenocarcinoma in a 65-year-old female patient. Because of its overlapping clinical, radiological and macroscopic findings with gallbladder cancer, definitive diagnosis of xanthogranulomatous cholecystitis relies on extensive sampling and thorough microscopic examination of the surgical specimen to exclude the possibility of coexisting tumour. It is still a matter of debate whether xanthogranulomatous cholecystitis is truly a precursor of gallbladder carcinoma or if it is just an incidental finding. This aspect needs to be explored in the future with further studies. PMID- 24471195 TI - More central line infections seen in children with cancer once they leave the hospital. PMID- 24471196 TI - HHS announces expansion of maternal, infant, and early childhood home visiting. PMID- 24471197 TI - United States faces crisis in cancer care because of aging population, rising costs, complexity of care, says new report; shift needed toward patient-centered, evidence-based care. PMID- 24471198 TI - General discussion. PMID- 24471200 TI - General discussion. PMID- 24471199 TI - General discussion. PMID- 24471201 TI - General discussion. PMID- 24471202 TI - Radicality effect of adding an interpectoral to a subpectoral approach for dissection of level III axillary lymph nodes in breast cancer. AB - AIMS AND BACKGROUND: The extent of axillary lymph node dissection for breast cancer treatment is tailored to each patient. When the surgeon assumes that full dissection, including level III, is needed, there are basically two ways for reaching the apical nodes while preserving the pectoralis muscles: a subpectoral approach, below the joined pectoralis muscles, and another that includes an additional interpectoral dissection between the muscles. We conducted a study to evaluate the radicality of dissection using these two approaches. METHODS: To determine whether the harvest of level III axillary lymph nodes is equivalent with the different approaches, we prospectively studied 75 patients with breast cancer. Careful axillary lymph node dissection was done to as radical an extent as possible, first below the lateral edge of the joined pectoralis muscles (subpectoral approach) and sequentially after opening the space between the muscles (additional interpectoral approach). The number of patients with extra level III nodes retrieved by the addition of an interpectoral dissection as well as the number of complementary nodes obtained in such patients were determined. RESULTS: We excised 1701 axillary lymph nodes in 75 patients (mean, 22.7). Using first the subpectoral approach, we resected 259 level III nodes in 68 patients (mean, 3.8); in 56 patients, we removed 132 additional level III nodes using the supplementary interpectoral approach (mean, 2.4). In 7 patients (9.3%), we found at least one metastatic node with the interpectoral approach. Two of these patients had positive level III nodes that were discovered only by addition of the interpectoral dissection. CONCLUSIONS: The dissection of level III axillary nodes is more radical when an additional interpectoral dissection is performed after a subpectoral approach has been used. The exclusive subpectoral approach frequently leaves residual nodes at the apex of the axilla. PMID- 24471203 TI - [Physicians' rounds on the wards in light of research literature]. AB - Physicians' rounds have traditionally been used to assess and plan patients' treatments and to teach medical students. According to the studies analysed in the review, patients have mostly been satisfied with the information received in the course of the physicians' rounds and eager to be involved in planning and decision-making concerning their treatment. The development challenges are related to improving the confidentiality of information. Interaction between doctor, patient and nurse is slight, as is the involvement of nurses in processing matters. Various checklists would make rounds more systematic. Despite their essentially passive role, medical students see that rounds create useful learning environments. PMID- 24471204 TI - [Menorrhagia in adolescents: normal or a sign of underlying medical condition?]. AB - Variations in the length of menstrual cycle as well as duration of menstrual flow are broad and common during adolescence. They are mainly caused by the immaturity of the hypothalamic-pituitary-ovarian axis. Normalization of ovulation during the first postmenarcheal years will gradually regularize the menstrual cycle. Several medical conditions, endocrine disturbances or medical treatments may affect the hormonal balance and cause abnormal bleeding. If anemia exists, the possibility of bleeding disorder should be considered. After proper evaluation, most abnormal bleedings in adolescents can be managed hormonally, with the addition of hemostatic therapies when necessary. Oral contraceptives are most commonly used. PMID- 24471205 TI - [Vocational rehabilitation in mental disorders]. AB - Supporting the working careers of patients having mental disorders is in the best interest of the individual, the community and the society. In mental disorders, recovery to be able to work is more challenging than in other disease groups. Vocational rehabilitation yields the best results when implemented early enough and in close association with work. Work trial and preparation for work are among the most common means of rehabilitation supporting mental patients' return to work. Collaboration with the workplace is needed when the work and working hours are adapted to the needs of the rehabilitee. Supported employment helps even the severely ill to be able to return to work. PMID- 24471206 TI - [Drug-associated hyperthermic syndromes]. AB - Drug-associated hyperthermic syndromes include the serotonin syndrome, neuroleptic malignant syndrome, neuroleptic-induced catatonia, anticholinergic syndrome, sympatomimetic syndrome and malignant hyperthermia. Discontinuation of medication is a sufficient treatment for mild serotonin syndrome. In a more severe situation the patient's spasticity and hyperthermia are treated with drugs. In neuroleptic malignant syndrome discontinuation of medication does not suffice, but the patient needs active therapy. Many of the drugs causing these syndromes are common in clinical use. Starting an effective treatment early enough is more important than a precise diagnosis. PMID- 24471207 TI - [Selective mutism]. AB - Selective mutism is a disorder closely linked to anxiety disorders in particular social phobia. Heightened sensitivity to emotional stress factors and coping with social anxiety may be part of the causes leading to the failure to speak. Follow up studies confirm the fact that selective mutism is a very persistent disorder with a general tendency of poor outcome in particular if not intensively treated. Current treatment combines different modalities of cognitive-behavioural therapies which are aimed to reduce anxiety symptoms and to improve verbal communication. Enhancing of parent-child interaction is often needed to improve the child's emotion regulation skills. SSRI medication, especially fluoxetine, may improve outcome when combined with therapy. PMID- 24471208 TI - [Rare causes of progressive paraparesis]. AB - Progressive paraparesis is a neurosurgical and neurological emergency. The patient's neurological outcome relies on the course of the diagnostics and treatment. Physicians having experience in emergency medicine are familiar with the typical etiologies of paraparesis. Uncommon causes of paraparesis may, however, elicit diagnostic challenges. Intraspinal bleeding causes a rapid progression of the symptoms. Intraspinal epidural hematoma is a rare complication of spinal anaesthesia and may be diffcult to diagnose if the blood is located in the subarachnoidal space. Spinal arteriovenous malformations and arachnoideal cysts causing medullary compression, and myelitis may present with slowly proceeding paraparesis. The diagnostics of the conditions described above is often difficult and typically requires facilities that are available only in larger centers. PMID- 24471209 TI - [Acute spinal cord compression]. AB - Paralysis of the lower limbs or both the upper and lower limbs, even partial, is a frightening symptom that will quickly bring the patient to emergency call service. The symptom is a sign of functional disturbance of the spinal cord, possibly resulting from a quickly developed process narrowing the spinal canal. A correct and non-delayed diagnosis and urgent release of the spinal cord from the compressed state are the cornerstones of successful treatment. PMID- 24471211 TI - [Update on current care guideline: temporomandibular disorders (TMD)]. AB - Temporomandibular disorders (TMD) are common. Usual symptoms are joint noises and pain, pain in masticatory muscles, difficulties in jaw movements and headache. Treatment of TMD includes information on the background and good response to treatment of these disorders. The patient is advised on self-care routines, including relaxing the lower jaw, massaging the masticatory muscles and hot or cold packs on painful sites. Pharmacotherapy consists of paracetamol or anti inflammatory analgesics. Occlusal appliances, physiotherapy, cognitive therapies and acupuncture are recommended. Complicated cases not responding to treatment are referred to specialized care. PMID- 24471210 TI - [Fatty fish modifies HDL particle size and lipid concentrations]. AB - BACKGROUND: We investigated with 1HNMR-spectroscopy the effects of habitual fatty fish intake on serum lipiprotein profiles in persons with features of metabolic syndrome. MATERIAL AND METHODS: The participants (n = 105) were randomized into three diet intervention groups. The groups were given different dietary instructions. RESULTS: Increased intake of fatty fish had a significant (p < 0.05) increasing effect on the amount of large HDL-lipoprotein subclasses and their lipids. CONCLUSIONS: Frequent intake of fatty fish may have beneficial effects on HDL-metabolism beyond that assumed to be related to its serum concentrations. PMID- 24471212 TI - Answering the QNI's call. PMID- 24471213 TI - Improving efficiency and safety for patients who are unable to self-administer insulin. AB - A one-day 'snapshot' study was conducted to determine the nature and extent of specific safety issues faced by community nurses who care for patients unable to self-administer insulin. Community teams from 19 NHS trusts reported 607 patients requiring support with insulin administration. In total, 15.1% of insulin administration documents had an abbreviation for the word 'units', which is a serious safety hazard where any resulting serious harm would be classed as a 'never event'. Pens or disposable devices were used for 52.9% of all administrations, with 16.7% using an insulin device without any previous device specific training. Major differences were discovered between trusts in many aspects of practice and insulin use, and comparative data can be used to benchmark activity and drive safety and cost improvement For example, 50.9% of patients had insulin administered more than once a day, but individual trusts reported figures ranging from 25.9% to 66.7%. If it were possible for all 19 trusts to manage 60% of patients on once-daily regimens, total annual service costs could be reduced by about pounds 200,000, or by pounds 3.5 million across the U.K.s. PMID- 24471214 TI - Managing heel ulcers in the community. AB - As the size of the older population increases, the incidence of falls and injuries, in addition to chronic wounds, is likely to increase concurrently. This article highlights the risk of both pressure ulceration and diabetic foot ulceration and gives an overview of appropriate treatment and management. PMID- 24471215 TI - An alternative model of prescribing stoma appliances. AB - The NHS is challenged with making efficiency savings of pounds 20 billion by 2015. In order to achieve a target of this magnitude, commissioners, clinicians and patients are required to work together to evaluate current service delivery and explore all options which have the potential to increase efficiency. This article describes the significant service redesign work undertaken in Rotherham by commissioners, clinicians and patients which has improved the way in which prescriptions are issued to patients requiring stoma products. The project has achieved impressive financial savings and, importantly, has improved patient experience. The project illustrates how new ways of working can significantly contribute to the pounds 20 billion savings target, avoiding cuts in service provision while simultaneously improving the quality of service provided to patients. PMID- 24471216 TI - The health-care needs of the older gay man living with HIV. AB - Human immunodeficiency virus (HIV) was once thought of as a condition predominately affecting the young. However, HIV among the older population is increasing. Older gay male adults living with HIV have received little attention from those who provide and commission services. However, with effective treatment those gay men aged over 50 are the fastest growing group of people with HIV in the U.K. Nurses will be required to offer care in a number of ways to this cohort of patients. In so doing, nurses will need to develop innovative and effective ways of supporting this growing group of people. This article provides an overview of the issues that can impact on the health and wellbeing of the older gay man living with HIV. The article discusses the epidemiology, the issue of HIV stigma, comorbidities and mental health and wellbeing needs. PMID- 24471217 TI - Practitioner and patient experiences of giving and receiving healthy eating advice. AB - This article explores the content of discussion by patients and practitioners where they were invited to talk about food and diet. A qualitative methodology using focus groups was employed within one Primary Care Trust in the east of England. Patients described their desire for access to nutritional guidance in primary care and their feelings of powerlessness when following dietary advice. Primary care practitioners discussed their experiences of giving information alongside their scepticism about patients' adherence to dietary advice. Without prompting from the interviewer, patients and practitioners independently chose weight management to illustrate their experiences. Frustrations were expressed by patients and practitioners groups who felt unmotivated to seek or give information respectively on weight management. PMID- 24471218 TI - Implementing the 'verification of expected death' policy in clinical practice. AB - This article discusses research carried out with district nurses on their experiences of implementing the verification of expected death (VOED) policy in clinical practice in Scotland. Individual interviews were carried out with a purposeful sample of community nurses to seek their views on the VOED policy. Interviewees reported that implementing VOED documentation was not difficult if the community nurse knew the patient and family well. This made end-of-life discussions easier because of the therapeutic relationship that was already established. Although nurses were sometimes anxious about discussing death, their professional responsibility to the patient and relatives at this time took precedence over any personal feelings. The nurses highlighted that good communication skills were critical when initiating discussions around VOED. PMID- 24471219 TI - Attitudes to death: a time to pose difficult questions. PMID- 24471220 TI - Guarding against discriminatory treatment decisions. AB - This article studies a case in which a 52-year-old male patient has early onset dementia, Down's syndrome and an associated heart condition, for which he is prescribed warfarin and digoxin. A district nurse, who is an independent prescriber, monitors and adjusts his medication and takes the required blood sample. The staff at the care home where the patient lives report that the patient is spitting out his medication and they have not been able to persuade him to swallow his tablets for a week. Despite the patient being assessed as lacking capacity to decide treatment decisions, the care home staff argue that his refusal to take medication should be respected and the medication discontinued. Although withdrawing the medication would make caring for the patient less challenging, the district nurse assesses the legal obligations that must be considered before this decision can be considered lawful. PMID- 24471222 TI - Personal vaccination within COPD care. PMID- 24471223 TI - Financing the future. PMID- 24471224 TI - Assessing parenteral diuretic treatment of decompensated heart failure in the community. AB - Referrals of 46 patients with decompensated end-stage heart failure were reviewed by a community heart-failure specialist nurse as part of a pilot study to determine patient numbers suitable for parenteral diuretic treatment at home, and the appropriateness of the Mini Nutritional Assessment (MNA), Edmonton Symptom Assessment System (ESAS) and Carer's Stress Scales. Triage of patients resulted in the following care pathways: 14 (30%) received intravenous therapy, 11 (24%) received subcutaneous therapy, 9 (20%) required adjustment of medication, 8 (17%) could not be treated because of limited staffing resource, 4 (9%) met study exemption criteria. There were no adverse events following furosemide infusion. The majority of intravenous and subcutaneous treatments took 1-7 days (total 187 days). Parenteral diuretic therapy prevented admissions and reduced the severity heart failure symptoms in particular oedema. Patients and carers appreciated the service, which had a positive effect on carers stress. Of the nursing tools, the ESAS and the Carer's Stress Scales proved useful in the management of patients. PMID- 24471225 TI - Managing work-related stress in the district nursing workplace. AB - This article aims to highlight the issue of work-related stress within the district nursing workplace. It will acknowledge how the management of work related stress has previously been discussed within nursing literature and will consider the emerging relationship between staff working conditions, staff wellbeing and quality of patient care. It will reintroduce the Health and Safety Executive's (HSE's) Management Standards approach to tackling work-related stress, which provides management support to reduce environmental work stressors and encourage enabling work environments and a positive workplace culture. PMID- 24471226 TI - Preventing occlusion and restoring patency to central venous catheters. AB - Central venous catheters (CVCs) may be used for treatment of critically and chronically unwell patients in hospital or in their homes. Complications can occur and should be resolved promptly so they do not result in increased lengths in hospital stay or readmission for patients receiving intravenous therapy at home. This article defines CVCs and the types of central venous access device that are in use in the U.K.; describes how to prevent occlusion and maintain the patency of CVCs; describes the types of occlusions that may occur; and discusses how to assess each type of occlusion and how they may be managed. PMID- 24471227 TI - Court-ordered immunisations: a review of the issues. AB - Following an outbreak of measles in Swansea in 2013, the U.K. courts were asked to order the immunisation of children after an unresolved dispute over the merits of the vaccination between the parents of two children. This article reviews the involvement and approach of the courts in cases of hotly disputed immunisation and argues that going to litigation and obtaining a court order is no guarantee that the vaccination will be given to the child. PMID- 24471228 TI - Cognitive assessment: a guide for community nurses. AB - Ageing increases the risks of dementia and there are an estimated 667,000 people in England living with dementia. Less than half have a formal diagnosis. Community nurses are now being asked to screen older people for dementia under the Commissioning for Quality and Innovation framework. This article provides a brief explanation of common screening tools and explains the community nurse's role in identifying people who may have undiagnosed dementia. PMID- 24471229 TI - Self-care management education models in primary care. AB - Self-care management for people living with long-term conditions aims to assist the individual in taking responsibility for their own health. This literature review explores the value and content of the large range of educational models currently in use. Although no single model was found that addressed all the issues, several themes arose. These included the observation that educational models should be based on self-efficacy principles and patient-centred. Method of delivery favoured small groups, using a variety of approaches supported with written information. Duration of the programmes was mainly 6-8 weeks with a follow-up. Programmes should be offered when the patient is ready and not determined by the condition or at diagnosis. Debate remains over whether group leaders should be laypeople and professionals; however, a mixture of both offered the best outcomes. Programmes should not be problem-focused, offering space for support and experience sharing. PMID- 24471231 TI - Palliative care in the community using person-centred care. PMID- 24471230 TI - Developing and implementing the community nursing research strategy for Wales. AB - In order to obtain the best patient outcomes in community nursing, practice needs to be underpinned by robust research-based evidence. This article describes a Community Nursing Research Strategy developed and implemented in Wales to provide the nursing profession with the evidence to support future organisational and professional change in achieving excellence in the community. This was developed in partnership with education, research, health services, workforce planning and Government using consensus methodology (specifically, a nominal group technique). Consequently, the process was inclusive and included three steps: escalating presentation of ideas, topic debate and topic rating. The result was a strategy with four implementation strands, including a virtual network, research portfolio, application to practice and leadership. PMID- 24471234 TI - Balls and strikes. PMID- 24471233 TI - What is happening to district nursing? PMID- 24471235 TI - The future and your health insurance needs. PMID- 24471236 TI - Means. PMID- 24471237 TI - Resources for navigating ethical "firsts". PMID- 24471238 TI - The three legged stool of scope. PMID- 24471239 TI - Repercussions of bad decisions. PMID- 24471240 TI - It's your license, and your responsibility. PMID- 24471241 TI - The game ain't worth winning...if you're breaking all the rules. PMID- 24471242 TI - Ethical dental staff: navigating ethical situations facing the dental office. PMID- 24471243 TI - Including CAD/CAM dentistry in a dental school curriculum. AB - Shaping a clinical curriculum that is appropriate for novice dentists, is based on high-quality evidence of efficacy, yet reflects current practices is challenging. CAD/CAM units have been available to dentists since the late '80s. Recent improvements in the software, hardware and the clinical performance of available all-ceramic blocks have keyed a surge in interest. Based on a careful review of the systems available and, equally importantly, a review of the research regarding the longevity of reinforced glass ceramics, IUSD decided to add training on the use of the E4D CAD/CAM system to the curriculum. Students now receive lectures, preclinical hands-on training and clinical experience in fabricating all-ceramic restorations. At present any student who is interested in providing an all-ceramic restoration for his/her patient can do so using our CAD/CAM system. In a little less than one year our undergraduate dental students have provided 125 all-ceramic crowns to their patients. Clinical faculty have been impressed with the marginal fit and esthetics of the crowns. Finally, with students designing, milling, sintering and staining the restorations the CAD/CAM systems has reduced lab costs significantly. PMID- 24471244 TI - His new suit. PMID- 24471245 TI - Ethics from the Birmingham jail. PMID- 24471246 TI - Cost of diabetes care: prevent diabetes or face catastrophe. PMID- 24471247 TI - Post-marketing study of clinical experience of atorvastatin 80 mg vs 40 mg in Indian patients with acute coronary syndrome- a randomized, multi-centre study (CURE-ACS). AB - OBJECTIVE: To generate comparative clinical data in Indian patients with acute coronary syndrome (ACS) in terms of safety and efficacy of atorvastatin 80 mg vis a-vis atorvastatin 40 mg MATERIALS AND METHODS: A total of 236 patients with diagnosed ACS (with TIMI Risk score > or = 3) within preceding 10 days were randomized to receive either atorvastatin 80 mg or atorvastatin 40 mg once daily for 12 weeks. Out of 236 patients, data for 173 was analyzed who had both baseline and post-baseline lipid assessment. The primary end point of the trial was percentage change in LDL-C at the end of treatment from baseline. Other end points were change in high sensitivity C reactive protein, incidence of increase in liver enzymes > or = 3 times upper limit of normal and incidence of myotoxicity (with or without elevation of creatinine phosphokinase) at the end of treatment. RESULTS: A dose-dependent response was observed with greater reduction of LDL -C in atorvastatin 80 mg (27.5% vs 19.04%) than that of atorvastatin 40 mg group. Both the treatment groups had a significant reduction (p < 0.001) in LDL-C at the end of 6 and 12 weeks in comparison to baseline. hs-CRP was also significantly reduced (p < 0.001) in both the treatment groups i.e. atorvastatin 80 mg (76.15%) and atorvastatin 40 mg (84.4%) from baseline at the end of 12 weeks. Both doses of atorvastatin were well tolerated. No patient had elevation of (> or = 3 times of upper limit of normal) liver enzymes or creatinine phosphokinase. One patient on atorvastatin 80 mg complained of myalgia. There were no dose-related differences in incidence of adverse events between two treatment groups. CONCLUSION: The CURE-ACS trial indicated that atorvastatin 80 mg was more effective than atorvastatin 40 mg in terms of reduction in LDL cholesterol and was as safe and well tolerated as 40 mg dose in Indian patients with ACS. PMID- 24471248 TI - The costs of treating long-term diabetic complications in a developing country: a study from India. AB - OBJECTIVE: Diabetes is a major public health problem associated with huge economic burden in developing countries. The aim was to assess the direct costs of treating long-term diabetic complications among hospitalized subjects with type 2 diabetes. METHODS: A total of 368 (M: F, 254:114) hospitalized patients were divided into groups based on the presence of complications and were compared with a group without any complications (Group 1; n = 86), Group 2; n = 67 with chronic kidney disease, Group 3; n = 53 with cardiovascular complications, Group 4; n = 58 who underwent foot amputation, Group 5; n = 66 with retinal complications and Group 6; n = 38 with presence of two complications. Details on socio-demography, hospitalization, direct costs of all inpatient care were recorded. The data on expenditure was obtained from hospital bills. RESULTS: The patients with foot complications or with presence of two diabetic complications tend to stay long for every inpatient admission. On an average, patients with foot complications (19020 INR) and those who had two complications (17633 INR) spent four times more and patients with renal disease (12690 INR), cardiovascular (13135 INR) and retinal complications (13922 INR) spent three times more than patients without any complications (4493 INR). The median expenditure for hospital admissions for the previous two years was higher for patients with foot and cardiovascular complications and it was highest if they had presence of two complications. CONCLUSIONS: The present study highlights the direct cost estimates and economic burden of treating severe long-term diabetic complications. It is therefore important that emphasize should be placed on primary and secondary preventive measures of diabetes. PMID- 24471249 TI - Study on incidence of bleeding in hospitalized patients after antithrombotic therapy at a tertiary care hospital. AB - OBJECTIVES: To monitor the different antithrombotic drug combinations, determine the incidence, magnitude of bleeding and the association of HAS-BLED risk scoring schema with the magnitude of bleeding as defined using TIMI bleeding criteria. METHODS: A prospective observational study in a cohort of patients for a period of 8 months, at one of the tertiary care center-Krishna Institute of Medical Sciences, Hyderabad, was conducted. Consecutive patients were enrolled and followed from the date of admission till the adverse events are perceived/date of discharge. Pearson Correlation Statistics (Fisher's z Transformation) is applied to assess the association between HAS-BLED risk factors and the total risk score with bleeding criteria. RESULTS: A total of 400 cases were collected during the 8 month study period, of which 372 satisfied the inclusion criteria. Among them 34 (9.1%) bleeding cases were reported with mean (+/- SD) age of 57.8 (+/- 14.19) years. Bleeding occurred mostly in males 79.4% and a HAS-BLED Score of > or = 3 has been observed in 67.6% (n = 23) patients out of 34 bled patients. Two antiplatelets + One anticoagulant is the most common combination which caused bleeding in 41.2% (n = 14). Stroke history, bleeding predisposition, labile INR's are the HAS-BLED risk factors which are significant (< 0.05) with the TIMI Bleeding Criteria. CONCLUSION: There was a linear correlation between the HAS BLED risk score and the TIMI bleeding criteria-higher the risk score the more frequent is the incidence of major bleeding. A HAS-BLED risk score of > or = 3 is associated with TIMI major bleeding. PMID- 24471251 TI - Human gene therapy: a brief overview of the genetic revolution. AB - Advances in biotechnology have brought gene therapy to the forefront of medical research. The prelude to successful gene therapy i.e. the efficient transfer and expression of a variety of human gene into target cells has already been accomplished in several systems. Safe methods have been devised to do this, using several viral and no-viral vectors. Two main approaches emerged: in vivo modification and ex vivo modification. Retrovirus, adenovirus, adeno-associated virus are suitable for gene therapeutic approaches which are based on permanent expression of the therapeutic gene. Non-viral vectors are far less efficient than viral vectors, but they have advantages due to their low immunogenicity and their large capacity for therapeutic DNA. To improve the function of non-viral vectors, the addition of viral functions such as receptor mediated uptake and nuclear translocation of DNA may finally lead to the development of an artificial virus. Gene transfer protocols have been approved for human use in inherited diseases, cancers and acquired disorders. In 1990, the first successful clinical trial of gene therapy was initiated for adenosine deaminase deficiency. Since then, the number of clinical protocols initiated worldwide has increased exponentially. Although preliminary results of these trials are somewhat disappointing, but human gene therapy dreams of treating diseases by replacing or supplementing the product of defective or introducing novel therapeutic genes. So definitely human gene therapy is an effective addition to the arsenal of approaches to many human therapies in the 21st century. PMID- 24471250 TI - A comparative evaluation of prasugrel and clopidogrel in patients with acute coronary syndrome undergoing percutaneous coronary intervention. AB - OBJECTIVE: Primary objective of this study was to compare the efficacy of Prasugrel vs. Clopidogrel in the patients with acute coronary syndromes (ACS) undergoing percutaneous coronary intervention (PCI) by measuring inhibition of platelet aggregation after loading and maintenance dose of both the drugs. The patients were also assessed for safety of the drugs. METHODS: This was a randomised, double-blind, double-dummy, comparative, multicentric clinical trial in patients with acute coronary syndrome (unstable angina, non-ST elevation MI and ST elevation MI) undergoing PCI. The patients were randomly assigned to receive prasugrel (loading dose of 60 mg followed by maintenance dose of 10-mg once daily) or clopidogrel (loading dose of 300 mg followed by maintenance dose of 75 mg once daily) for a period of 12 weeks. All the patients were co prescribed aspirin 325 mg with both the drugs. The primary efficacy end point in this study was percentage inhibition of ADP induced platelet aggregation (IPA) at 4 +/- 1 hours after the loading dose and at 30 +/- 3 days during maintenance treatment. The platelet aggregation of both the drugs was measured by whole blood aggregometer using 10 mmol of ADP as an aggregant. Though this study was not powered to see the difference in clinical efficacy parameters, the patients were observed for the incidence of nonfatal MI, nonfatal stroke, re-hospitalization, death, or need for urgent revascularization due to a cardiac ischemic event at days 30 and 90 during the study. The safety of study drugs were evaluated by incidence of major bleeding, reported adverse drug reaction and alterations of any laboratory parameters. RESULT: A total of 220 patients were enrolled at 11 centres across India. Ten patients were given the loading dose of prasugrel or clopidogrel but did not underwent PCI due to change in investigator's decision to go for PCI. Out of 210 eligible patients, 21 patients were discontinued during the study. 157 patients were evaluated for platelet inhibition after loading dose at 4 hours and 150 patients at day 30 during maintenance phase of antiplalelet therapy. The investigators could not perform this test in remaining patients due to urgency and criticality of the patients. 189 patients were observed for the incidence of nonfatal MI, nonfatal stroke, rehospitalisation, urgent revascularisation or death due to a cardiac ischemic event. All eligible patients who received at least a loading dose were evalauted for safety. In prasugrel group, 85 and 77 patients were evaluated for IPA at 4 hours and day 30 respectively whereas in clopdogrel group 72 and 73 patients were tested for IPA at 4 hours and at 30 days. Patients in prasugrel group have demonstrated significantly higher inhibition of platelets as compared to clopidogrel group (82.5% vs 71.1%) at 4 hours and at 30 days (84.1% vs 67.4%). The difference in inhibition of platelets between prasugrel and clopidogrel after loading dose and maintenenace dose was statistically significant (p < or = 0.01). The patients were also evaluated for drug hyporesponsiveness to antiplatelet therapy if IPA was < 20% at day 30 from the baseline. More patients on prasugrel have shown response to antiplatlet therapy than on clopidogrel (97.4% vs 87.6%). The difference between the two groups was statistically significant (p < 0.05). There was no difference observed during the study in the incidence of nonfatal MI, nonfatal stroke, death, rehospitalisation or need for urgent revascularisation due to a cardiac event between prasugrel and clopidogrel. Both the drugs were found to be to be well tolerated and have comparable safety profile. CONCLUSION: This study suggests that prasugrel is more effective than clopidogrel as an anti platelet drug as evident by inhibition of platelet aggregation. More patients on clopidogrel are likely to have poor response to therapy as compared to prasugrel. Both the drugs were well tolerated and have comparable safety profile. PMID- 24471252 TI - Parry Romberg syndrome. PMID- 24471253 TI - Subcutaneous nodules in rheumatoid arthritis. PMID- 24471254 TI - Sudden onset quadriparesis after minor injury to neck in a male with OS odontoideum. AB - Os odontoideum is a rare anomaly of the second cervical vertebra. Here, a young male patient with quadriparesis secondary to myelopathy associated with os odontoideum is reported. The patient was totally asymptomatic prior to this episode which was precipitated by trivial neck injury. He started recovering with conservative measures and was referred to our neurosurgery department for further evaluation and definitive surgical intervention as there is always a chance of recurrence of symptoms in these patients. There is a role for conservative treatment of an asymptomatic incidentally found, radiologically stable, and noncompressive os odontoideum, however surgery has a definite role in symptomatic cases. PMID- 24471255 TI - A foe incognito: an interesting case of pleurisy. AB - Though pleuritis and pleural effusion are common in lupus patients they are distinctly rare as the initial manifestation of lupus. Diagnosis of lupus pleuritis is also a difficult task and often costly and lengthy immunological panels are employed to diagnose it. We report one case of systemic lupus erythematosus (SLE) presenting with lupus pleuritis as the first manifestation. We propose that demonstration LE cells have a very prominent role in differentiating lupus pleuritis from other causes of pleural effusions in SLE patients. We believe that our case is the first report from India which shows pleuritis may be a first manifestation of lupus. PMID- 24471256 TI - Subclavian artery- internal jugular vein fistula and heart failure: complication of internal jugular vein catheterization. AB - Hemodialysis in patients with end-stage renal disease (ESRD) requires vascular access which can be either temporary or permanent. However, these procedures are not without complications. Arterial puncture is the most common immediate complication and pseudoaneurysm formation is the most common late sequel of internal jugular venous catheterization (IJVC). However, arterio-venous fistula (AVF) formatiorn following IJVC is rare. We are reporting a case of AVF formation between subclavian artery (SCA) and internal jugular vein (IJV) following IJVC which later on leads to the development of cardiac failure. PMID- 24471257 TI - Rickettsial fever presenting with isolated third nerve palsy. AB - Rickettsial fevers are known to have neurological involvement, mostly in the form of meningoencephalitis. Focal neurodeficits, including isolated cranial nerve palsies have been rarely reported. We hereby report a case of a 25 year old man who presented to us with high grade fever caused by rickettsia and left sided partial third cranial nerve palsy. He responded to doxycycline. PMID- 24471258 TI - Tetralogy of Fallot with quadricuspid aortic valve. AB - We describe herein a 54 year female who had tetralogy of Fallot with quadricuspid aortic valve. This combination is very uncommon. Hence it was worth reporting this interesting case. PMID- 24471259 TI - Werner Forssmann. PMID- 24471260 TI - Medical philately. Carl Rokitansky, a premier pathologist. PMID- 24471261 TI - Probable hypoglycaemia induced by single dose nimesulide. PMID- 24471262 TI - Pattern formation in the geosciences. AB - Pattern formation is a natural property of nonlinear and non-equilibrium dynamical systems. Geophysical examples of such systems span practically all observable length scales, from rhythmic banding of chemical species within a single mineral crystal, to the morphology of cusps and spits along hundreds of kilometres of coastlines. This article briefly introduces the general principles of pattern formation and argues how they can be applied to open problems in the Earth sciences. Particular examples are then discussed, which summarize the contents of the rest of this Theme Issue. PMID- 24471263 TI - Aeolian and subaqueous bedforms in shear flows. AB - A sediment bed sheared by an unbounded flow is unconditionally unstable towards the growth of bedforms called ripples under water and dunes in the aeolian case. We review here the dynamical mechanisms controlling this linear instability, putting the emphasis on testing models against field and laboratory measurements. We then discuss the role of nonlinearities and the influence of finite size effects, namely the depth of the atmospheric boundary layer in the aeolian case and the water depth in the case of rivers. PMID- 24471264 TI - Formation of Kinneyia via shear-induced instabilities in microbial mats. AB - Kinneyia are a class of microbially mediated sedimentary fossils. Characterized by clearly defined ripple structures, Kinneyia are generally found in areas that were formally littoral habitats and covered by microbial mats. To date, there has been no conclusive explanation of the processes involved in the formation of these fossils. Microbial mats behave like viscoelastic fluids. We propose that the key mechanism involved in the formation of Kinneyia is a Kelvin-Helmholtz type instability induced in a viscoelastic film under flowing water. A ripple corrugation is spontaneously induced in the film and grows in amplitude over time. Theoretical predictions show that the ripple instability has a wavelength proportional to the thickness of the film. Experiments carried out using viscoelastic films confirm this prediction. The ripple pattern that forms has a wavelength roughly three times the thickness of the film. This behaviour is independent of the viscosity of the film and the flow conditions. Laboratory analogue Kinneyia were formed via the sedimentation of glass beads, which preferentially deposit in the troughs of the ripples. Well-ordered patterns form, with both honeycomb-like and parallel ridges being observed, depending on the flow speed. These patterns correspond well with those found in Kinneyia, with similar morphologies, wavelengths and amplitudes being observed. PMID- 24471265 TI - Instability and finite-amplitude self-organization of large-scale coastline shapes. AB - Recent research addresses the formation of patterns on sandy coastlines on alongshore scales that are large compared with the cross-shore extent of active sediment transport. A simple morphodynamic instability arises from the feedback between wave-driven alongshore sediment flux and coastline shape. Coastline segments with different orientations experience different alongshore sediment fluxes, so that curvatures in coastline shape drive gradients in sediment flux, which can augment the shoreline curvatures. In a simple numerical model, this instability, and subsequent finite-amplitude inter-actions between pattern elements, lead to a wide range of different rhythmic shapes and behaviours- ranging from symmetric cuspate capes and bays to alongshore migrating 'flying spits'--depending on the characteristics of the input wave forcing. The scale of the pattern coarsens in some cases because of the merger of migrating coastline features, and in other cases because of non-local screening interactions between coastline protrusions, which affect the waves reaching other parts of the coastline. Features growing on opposite sides of an enclosed water body mutually affect the waves reaching each other in ways that lead to the segmentation of elongated water bodies. Initial tests of model predictions and comparison with observations suggest that modes of pattern formation in the model are relevant in nature. PMID- 24471266 TI - The secret gardener: vegetation and the emergence of biogeomorphic patterns in tidal environments. AB - The presence and continued existence of tidal morphologies, and in particular of salt marshes, is intimately connected with biological activity, especially with the presence of halophytic vegetation. Here, we review recent contributions to tidal biogeomorphology and identify the presence of multiple competing stable states arising from a two-way feedback between biomass productivity and topographic elevation. Hence, through the analysis of previous and new results on spatially extended biogeomorphological systems, we show that multiple stable states constitute a unifying framework explaining emerging patterns in tidal environments from the local to the system scale. Furthermore, in contrast with traditional views we propose that biota in tidal environments is not just passively adapting to morphological features prescribed by sediment transport, but rather it is 'The Secret Gardener', fundamentally constructing the tidal landscape. The proposed framework allows to identify the observable signature of the biogeomorphic feedbacks underlying tidal landscapes and to explore the response and resilience of tidal biogeomorphic patterns to variations in the forcings, such as the rate of relative sea-level rise. PMID- 24471267 TI - Regime shifts in models of dryland vegetation. AB - Drylands are pattern-forming systems showing self-organized vegetation patchiness, multiplicity of stable states and fronts separating domains of alternative stable states. Pattern dynamics, induced by droughts or disturbances, can result in desertification shifts from patterned vegetation to bare soil. Pattern formation theory suggests various scenarios for such dynamics: an abrupt global shift involving a fast collapse to bare soil, a gradual global shift involving the expansion and coalescence of bare-soil domains and an incipient shift to a hybrid state consisting of stationary bare-soil domains in an otherwise periodic pattern. Using models of dryland vegetation, we address the question of which of these scenarios can be realized. We found that the models can be split into two groups: models that exhibit multiplicity of periodic pattern and bare-soil states, and models that exhibit, in addition, multiplicity of hybrid states. Furthermore, in all models, we could not identify parameter regimes in which bare-soil domains expand into vegetated domains. The significance of these findings is that, while models belonging to the first group can only exhibit abrupt shifts, models belonging to the second group can also exhibit gradual and incipient shifts. A discussion of open problems concludes the paper. PMID- 24471268 TI - Local properties of patterned vegetation: quantifying endogenous and exogenous effects. AB - Dryland ecosystems commonly exhibit periodic bands of vegetation, thought to form due to competition between individual plants for heterogeneously distributed water. In this paper, we develop a Fourier method for locally identifying the pattern wavenumber and orientation, and apply it to aerial images from a region of vegetation patterning near Fort Stockton, TX, USA. We find that the local pattern wavelength and orientation are typically coherent, but exhibit both rapid and gradual variation driven by changes in hillslope gradient and orientation, the potential for water accumulation, or soil type. Endogenous pattern dynamics, when simulated for spatially homogeneous topographic and vegetation conditions, predict pattern properties that are much less variable than the orientation and wavelength observed in natural systems. Our local pattern analysis, combined with ancillary datasets describing soil and topographic variation, highlights a largely unexplored correlation between soil depth, pattern coherence, vegetation cover and pattern wavelength. It also, surprisingly, suggests that downslope accumulation of water may play a role in changing vegetation pattern properties. PMID- 24471269 TI - Stone circles: form and soil kinematics. AB - Distinct surface patterns are ubiquitous and diverse in soils of polar and alpine regions, where the ground temperature oscillates about 0 degrees C. They constitute some of the most striking examples of clearly visible, abiotic self organization in nature. This paper outlines the interplay of frost-related physical processes that produce these patterns spontaneously and presents unique data documenting subsurface soil rotational motion and surface displacement spanning 20 years in well-developed circles of soil outlined by gravel ridges. These sorted circles are particularly attractive research targets for a number of reasons that provide focus for this paper: (i) their exceptional geometric regularity captures the attention of any observer; (ii) they are currently forming and evolving, hence the underlying processes can be monitored readily, especially because they are localized near the ground surface on a scale of metres, which facilitates comprehensive characterization; and (iii) a recent, highly successful numerical model of sorted circle development helps to draw attention to particular field observations that can be used to assess the model, its assumptions and parameter choices, and to the considerable potential for synergetic field and modelling studies. PMID- 24471270 TI - Evolving fracture patterns: columnar joints, mud cracks and polygonal terrain. AB - When cracks form in a thin contracting layer, they sequentially break the layer into smaller and smaller pieces. A rectilinear crack pattern encodes information about the order of crack formation, as later cracks tend to intersect with earlier cracks at right angles. In a hexagonal pattern, in contrast, the angles between all cracks at a vertex are near 120 degrees. Hexagonal crack patterns are typically seen when a crack network opens and heals repeatedly, in a thin layer, or advances by many intermittent steps into a thick layer. Here, it is shown how both types of pattern can arise from identical forces, and how a rectilinear crack pattern can evolve towards a hexagonal one. Such an evolution is expected when cracks undergo many opening cycles, where the cracks in any cycle are guided by the positions of cracks in the previous cycle but when they can slightly vary their position and order of opening. The general features of this evolution are outlined and compared with a review of the specific patterns of contraction cracks in dried mud, polygonal terrain, columnar joints and eroding gypsum-sand cements. PMID- 24471271 TI - Pattern formation and coarsening dynamics in three-dimensional convective mixing in porous media. AB - Geological carbon dioxide (CO2) sequestration entails capturing and injecting CO2 into deep saline aquifers for long-term storage. The injected CO2 partially dissolves in groundwater to form a mixture that is denser than the initial groundwater. The local increase in density triggers a gravitational instability at the boundary layer that further develops into columnar plumes of CO2-rich brine, a process that greatly accelerates solubility trapping of the CO2. Here, we investigate the pattern-formation aspects of convective mixing during geological CO2 sequestration by means of high-resolution three-dimensional simulation. We find that the CO2 concentration field self-organizes as a cellular network structure in the diffusive boundary layer at the top boundary. By studying the statistics of the cellular network, we identify various regimes of finger coarsening over time, the existence of a non-equilibrium stationary state, and a universal scaling of three-dimensional convective mixing. PMID- 24471272 TI - Bifurcation dynamics of natural drainage networks. AB - As water erodes a landscape, streams form and channellize the surficial flow. In time, streams become highly ramified networks that can extend over a continent. Here, we combine physical reasoning, mathematical analysis and field observations to understand a basic feature of network growth: the bifurcation of a growing stream. We suggest a deterministic bifurcation rule arising from a relationship between the position of the tip in the network and the local shape of the water table. Next, we show that, when a stream bifurcates, competition between the stream and branches selects a special bifurcation angle alpha = 2pi/5. We confirm this prediction by measuring several thousand bifurcation angles in a kilometre scale network fed by groundwater. In addition to providing insight into the growth of river networks, this result presents river networks as a physical manifestation of a classical mathematical problem: interface growth in a harmonic field. In the final sections, we combine these results to develop and explore a one-parameter model of network growth. The model predicts the development of logarithmic spirals. We find similar features in the kilometre-scale network. PMID- 24471273 TI - The possible role of Coriolis forces in structuring large-scale sinuous patterns of submarine channel-levee systems. AB - Submarine channel-levee systems are among the largest sedimentary structures on the ocean floor. These channels have a sinuous pattern and are the main conduits for turbidity currents to transport sediment to the deep ocean. Recent observations have shown that their sinuosity decreases strongly with latitude, with high-latitude channels being much straighter than similar channels near the Equator. One possible explanation is that Coriolis forces laterally deflect turbidity currents so that at high Northern latitudes both the density interface and the downstream velocity maximum are deflected to the right-hand side of the channel (looking downstream). The shift in the velocity field can change the locations of erosion and deposition and introduce an asymmetry between left- and right-turning bends. The importance of Coriolis forces is defined by two Rossby numbers, Ro(W) = U/Wf and Ro(R) = U/Rf, where U is the mean downstream velocity, W is the width of the channel, R is the radius of curvature and f is the Coriolis parameter. In a bending channel, the density interface is flat when Ro(R) - -1, and Coriolis forces start to shift the velocity maximum when [Row] < 5. We review recent experimental and field observations and describe how Coriolis forces could lead to straighter channels at high latitudes. PMID- 24471274 TI - Self-organized rhythmic patterns in geochemical systems. AB - Chemical oscillating patterns are ubiquitous in geochemical systems. Although many such patterns result from systematic variations in the external environmental conditions, it is recognized that some patterns are due to intrinsic self-organized processes in a non-equilibrium nonlinear system with positive feedback. In rocks and minerals, periodic precipitation (Liesegang bands) and oscillatory zoning constitute good examples of patterns that can be explained using concepts from nonlinear dynamics. Generally, as the system parameters exceed some threshold values, the steady (time-independent) state characterizing the system loses its stability. The system then evolves towards other time-dependent solutions ('attractors') that may have an oscillatory behaviour or a complex chaotic one. In this review, we describe many of these pattern types taken from a variety of geological environments: eruptive, sedimentary, hydrothermal or metamorphic. One particular example (periodic precipitation of pyrite bands in an evolving sapropel sediment) is presented here for the first time. This will help in convincing the reader that the tools of nonlinear dynamics may be useful to understand the history of our planet. PMID- 24471275 TI - The caring imperative. PMID- 24471276 TI - Interview with Chip Bell. Interview by Val J Halamandaris. PMID- 24471277 TI - Interview with Tom Rath. Interview by Val J Halamandaris. PMID- 24471278 TI - Lessons from Mother Teresa. PMID- 24471279 TI - A drop in the bucket of the megadiverse chewing louse genus Myrsidea (Phthiraptera, Amblycera, Menoponidae): ten new species from Amazonian Brazil. AB - Ten new species of Myrsidea Waterston, 1915 parasitic on members of the avian families Formicariidae, Thraupidae, Tyrannidae, Troglodytidae and Icteridae are described herein. They and their type hosts are M. isacantha sp. n. ex Chamaeza nobilis Gould, M. circumsternata sp. n. ex Formicarius colma Boddaert (Formicariidae); M. cacioppoi sp. n. ex Lanio fulvus (Boddaert), M. brasiliensis sp. n. ex Tangara chilensis (Vigors), M. saviti sp. n. ex Tangara schrankii (Spix) (Thraupidae), M. rodriguesae sp. n. ex Cnipodectes subbrunneus (Sclater), M. cnemotriccola sp. n. ex Cnemotriccus fuscatus (Wied-Neuwied), M. lathrotriccola sp. n. ex Lathrotriccus euleri (Cabanis) (Tyrannidae), M. faccioae sp. n. ex Cyphorhinus arada transfluvialis (Todd) (Troglodytidae), and M. lampropsaricola sp. n. ex Lampropsar tanagrinus (Spix) (Icteridae). Among these are two new Myrsidea species described from the avian family Formicariidae, which previously had only a single described Myrsidea species, and a new host record for M. cinnamomei Dalgleish et Price, 2005 ex Attila citriniventris Sclater. Analysis of mitochondrial cytochrome oxidase I sequences for these and other neotropical Myrsidea species provides an assessment of their phylogenetic relationships and indicates that all of these newly described species are genetically distinct. We also put these descriptions into context by estimating the potential number of unnamed Myrsidea species in Brazil, given the known diversity of potential hosts and typical levels of host specificity for Myrsidea species. Our estimate indicates that Brazilian Myrsidea species diversity is likely more than an order of magnitude greater than the number of described Myrsidea species known from Brazil, highlighting the need for future work on this megadiverse ectoparasite genus. PMID- 24471280 TI - Nested PCR detection of Plasmodium malariae from microscopy confirmed P. falciparum samples in endemic area of NE India. AB - The present study evaluates the performance of OptiMAL-IT test and nested PCR assay in detection of malaria parasites. A total of 76 randomly selected blood samples collected from two malaria endemic areas were tested for malaria parasites using microscopy and OptiMAL-IT test in the field. PCR assays were performed in the laboratory using DNA extracted from blood spots of the same samples collected on the FTA classic cards. Of the total of 61 field confirmed malaria positive samples, only 58 (95%) were detected positive using microscopy in the laboratory. Sensitivity, specificity, positive predictive value, negative predictive value and false discovery rate of OptiMal-IT in comparison to the microscopy were 93%, 83%, 95%, 79% and 5%, respectively. On the other hand, the sensitivity and specificity of PCR assay were 97% and 100%, respectively, whereas positive predictive value, negative predictive value and false discovery rate were 100%, 90% and 0%, respectively. The overall performance of OptiMal-IT and PCR assays for malaria diagnosis was 76% and 97%, respectively. PCR assay enabled the identification of infection with Plasmodium malariae Laveran, 1881 in four samples misidentified by microscopy and Plasmodium-specific antigen (PAN) identified by the OptiMAL-IT test. In addition to the standard methods, such PCR assay could be useful to obtain the real incidence of each malaria parasite species for epidemiological perspectives. PMID- 24471281 TI - Laboratory techniques to obtain different forms of Trypanosoma cruzi: applications to wild-type and genetically modified parasites. AB - Nowadays, there are no simple techniques for mimicking in vitro the life cycle of the kinetoplasmtid Trypanosoma cruzi Chagas, 1909, causative agent of Chagas disease, especially for parasite strains maintained as epimastigotes for many years. In the present study, we propose a method for obtaining metacyclic trypomastigotes, which were capable of infecting mammalian cells by simply lowering pH media. The collected amastigotes and trypomastigotes were differentiated into epimastigotes closing T. cruzi life cycle in vitro. Metacyclogenesis rates and infectivity were enhanced in cycled parasites. Finally, using this method, we were able to infect cells with transgenic parasites obtaining trypomastigotes and amastigotes using a neomycin-resistant cell line. PMID- 24471282 TI - Molecular characteristics of the alpha- and beta-tubulin genes of Nosema philosamiae. AB - Microsporidia are intracellular parasites of insects and other higher eukaryotes. The microsporidian Nosema philosamiae Talukdar, 1961 was isolated from the eri silkworm, Philosamia cynthia ricini Grote. In the present study, alpha- and beta tubulin genes from N. philosamiae were characterized. The identity analysis of nucleotide and amino acid sequences indicated high similarity with species of Nosema Nageli, 1857 sensu lato (nucleotide sequences, > or = 96.0%; amino acid sequences, > or = 99.0%). However, the tubulin genes of N. philosamiae share low sequence similarity with that of N. ceranae Fries, Feng, da Silva, Slemenda et Pieniazek, 1996 (strain BRL01) and a Nosema/Vairimorpha species. Phylogenies based on alpha-, beta- and combined alpha- plus beta-tubulin gene sequences showed that N. philosamiae, along with the true Nosema species, forms a separate clade with a high bootstrap value, with N. ceranae BRL01 forming a clade of its own. The results indicated that the alpha- and beta-tubulin sequences may be useful as a diagnostic tool to discriminate the true Nosema group from the Nosema/Vairimorpha group. PMID- 24471283 TI - Differences in some developmental features between Toxoplasma gondii-seropositive and seronegative school children. AB - Knowledge about the influence of latent toxoplasmosis on development and general biological condition of children is scant and thus the aim of the present study was to investigate these aspects in some detail. We compare school children in rural area seropositive and seronegative to the apicomplexan parasite Toxoplasma gondii (Nicolle et Manceaux, 1908) in terms of their developmental age, body mass and body height, physical fitness and end-of-term grades. Additionally, we evaluated the risk factors of infection with T. gondii such as the presence of cats in the household and eating raw meat products. With IFAT and ELISA tests, the prevalence of anti-Toxoplasma antibodies was 41% (190 children examined) and the rate of infection was higher in girls (44%) than in boys (36%). No significant differences were observed in morphological features and physical fitness of examined children. In girls the level of developmental age measured with electrophoretical mobility of nuclei method was significantly higher and school performance significantly lower for those infected with Toxoplasma than for uninfected; this finding was particularly intriguing. Only boys who ate raw meat products were more likely to be seropositive. The study provides some new information on gender differences in reaction to Toxoplasma infection. PMID- 24471284 TI - Sphaeromyxa artedielli sp. n. (Myxozoa: Sphaeromyxidae), a parasite of sculpins (Cottidae) in northern Norway. AB - Sphaeromyxa artedielli sp. n. is described from the gall bladder of the Atlantic hookear sculpin Artediellus atlanticus Jordan et Evermann (Cottidae; type host) from northern Norway. The parasite was also found to infect Triglops murrayi Gunther (Cottidae). Spores are produced in disporic pansporoblasts in large flat plasmodia. Spores are straight and fusiform with truncated ends, and measure 16.5 18.7 microm x 4.9-6.2 microm. Valves are thick, striated and suture line is straight. Two equal ovoid polar capsules measure 4.2-6.8 microm x 2.9-4.4 microm and contain irregularly folded polar filaments. Distinctive features include spore shape and size, spore length/width relationship, striated valves, equal polar capsules and a short intercapsular distance. Sphaeromyxa bonaerensis Timi et Sardella, 1998, Sphaeromyxa cannolii Sears, Anderson et Greiner, 2011, and Sphaeromyxa sevastopoli Naidenova, 1970 produce straight spores with truncated ends that are of similar length as those of the new species. Sphaeromyxa cannolii differs in showing smooth spores with unequal polar capsules. The new species differs from S. bonaerensis and S. sevastopoli in significantly wider spores and polar capsules. Sphaeromyxa balbianii Thelohan, 1892, a species originally described with significantly smaller spores than S. artedielli sp. n., has previously been recorded from T. murrayi. We show that S. artedielli sp. n. differs from S. balbianii from the type host Gaidropsarus vulgaris (Cloquet) by its SSU rDNA sequence, and suggest that Atlantic records of Sphaeromyxa spp. from T. murrayi represent S. artedielli sp. n. The closest relative to S. artedielli sp. n. according to the SSU rDNA sequences, S. longa Dunkerly, 1921, differs clearly by spore size and shape. In the SSU rDNA-based phylogenetic analyses, S. artedielli sp. n. groups with other Sphaeromyxa spp. with straight spores and truncated ends in a clade that represents a sister-group to Sphaeromyxa spp. with arcuate spores and rounded ends. Our results indicate that an SSU rDNA pseudogene is present in S. balbianii. PMID- 24471286 TI - Gyrodactylus aff. mugili Zhukov, 1970 (Monogenoidea: Gyrodactylidae) from the gills of mullets (Mugiliformes: Mugilidae) collected from the inland waters of southern Iraq, with an evalutation of previous records of Gyrodactylus spp. on mullets in Iraq. AB - Gyrodactylus aff. mugili Zhukov, 1970 (Monogenoidea: Gyrodactylidae) is recorded and described from the gill lamellae of 11 of 35 greenback mullet, Chelon subviridis (Valenciennes) (minimum prevalence 31%), from the brackish waters of the Shatt Al-Arab Estuary in southern Iraq. The gyrodactylid was also found on the gill lamellae of one of eight Speigler's mullet, Valamugil speigleri (Bleeker), from the brackish waters of the Shatt Al-Basrah Canal (minimum prevalence 13%). Fifteen Klunzinger's mullet, Liza klunzingeri (Day), and 13 keeled mullet, Liza carinata (Valenciennes), collected and examined from southern Iraqi waters, were apparently uninfected. The gyrodactylids from the greenback mullet and Speigler's mullet were considered to have affinity to G. mugili Zhukov, 1970, and along with G. mugili may represent members of a species complex occurring on mullets in the Indo-Pacific Region. A single damaged gyrodactylid from the external surfaces of the abu mullet, Liza abu (Heckel), was insufficient for species identification. Previously identified species of Gyrodactylus recorded on L. abu in Iraq by various authors were considered possible misidentifications or accidental infections. PMID- 24471285 TI - Ligophorus species (Monogenea: Ancyrocephalidae) from Mugil cephalus (Teleostei: Mugilidae) off Morocco with the description of a new species and remarks about the use of Ligophorus spp. as biological markers of host populations. AB - Gill monogenean species of Ligophorus Euzet et Suriano, 1977 were studied from the teleost Mugil cephalus Linneaus (Mugilidae) from the Mediterranean and Atlantic coasts of Morocco. We report the presence of L. mediterraneus from both the Mediterranean and Atlantic coast and L. cephali and L. maroccanus sp. n. from the Atlantic coast only. The latter species, which is described herein as new, resembles L. guanduensis but differs from this species mainly in having a shorter penis compared to the accessory piece, a proportionally longer extremity of the accessory piece and a less developed heel. The utility of Ligophorus spp. as markers of cryptic species of the complex M. cephalus is discussed in the context of species diversity and geographical distribution of these monogeneans on this host around the world. Presence of different species of Ligophorus on M. cephalus sensu stricto from the Atlantic and Mediterranean coast of Morocco demonstrates the usefulness of these species as fine resolution markers of genetic populations of their host, which are known to inhabit those coasts. PMID- 24471287 TI - Two new species of Acanthobothrium (Tetraphyllidea: Onchobothriidae) from Pastinachus cf. sephen (Myliobatiformes: Dasyatidae) from the Persian Gulf and Gulf of Oman. AB - Two new species of Acanthobothrium van Beneden, 1850 from the spiral intestine of Pastinachus cf. sephen Forsskal from the Iranian coast of the Persian Gulf and the Gulf of Oman are described. To analyse the surface ultrastructure the worms were studied using light and scanning electron microscopy. Acanthobothrium jalalii sp. n. belongs to the category 1 species of the genus so far including 43 species. This tiny new species differs from the other category 1 species by its small total length (2.18 +/- 0.49 mm), number of proglottids (4.7 +/- 0.9) and testes (24 +/- 3), terminal segments in an apolytic condition and the shape of the cirrus-sac. Acanthobothrium sphaera sp. n. is a small worm that belongs to the category 2 species of the genus so far including 36 species. A. sphaera sp. n. differs from the other category 2 species by its small total length (1.6 +/- 0.2 mm), number of proglottids (9.6 +/- 1.2) and testes (12 +/- 1), the presence of a vaginal sphincter and the shape of the ovary. This is the first report of Acanthobothrium from the cowtail stingray, P cf. sephen, from the Persian Gulf and Gulf of Oman. Pastinachus sephen sensu lato has been reported as a common host of species of Acanthobothrium. Most recently, the host genus Pastinachus Ruppell has been split into five nominal species and several Acanthobothrium species infect the newly described congeners but not P. sephen. The real identity of the host studied within the present study is still in question, since sequence data of three specimens from the Gulf of Oman do not correspond to P. sephen sensu stricto. PMID- 24471288 TI - Infective pentastomid larvae from Pygocentrus nattereri Kner (Pisces, Characidae) from the Miranda River, Pantanal, Mato Grosso do Sul State, Brazil, with notes on their taxonomy and epidemiology. AB - During parasitological surveys of freshwater fish from the Miranda River, Brazil, 199 Pygocentrus nattereri Kner (Characidae) were caught. Two pentastomid families, Subtriquetridae Fain, 1961, represented by its single genus Subtriquetra Sambon, 1922, and Sebekidae Sambon, 1922, represented by three genera, were present. Free-living larvae of Subtriquetra subtriquetra (Diesing, 1835) were collected from the swim bladder. Encysted larvae of Alofia Giglioli, 1922 were found in the abdominal cavity, chambers of the heart, musculature, on the surface of the gonads and swim bladder. Some Alofia larvae were moving freely in the swim bladder. Larvae of Sebekia Sambon, 1922 were encysted in the musculature. Some larvae of Leiperia Sambon, 1922 were found encysted in the musculature and on the surface of the pyloric caeca, whereas others occurred free in the abdominal cavity. In some of the latter, the head was buried deep in the wall of the intestine, stomach or ovaries, whereas the rest of their body remained free. Infective pentastomid larvae were present throughout the year with an overall prevalence of 77%. Both prevalence and intensity were higher in members of the Sebekidae than in Su. subtriquetra, possibly due to the latter's mode of transmission and its high pathogenicity. No sex-related, statistically significant differences (p > 0.05) in prevalence or abundance were found. Fish weight and length had significant but weak positive correlations (r < or = 0.27) with the abundance of pentastomid larvae, possibly reflecting an increased likelihood of prior exposure in older fish. Parasite abundance had no significant effect on host body condition (p > or = 0.69). A higher prevalence and monthly mean abundance of pentastomids were seen in the dry season and might be due to increased host densities as habitats dry up. Pygocentrus nattereri represents a new intermediate host record for the genera Alofia, Leiperia and Subtriquetra. PMID- 24471289 TI - A new species of Rhabdias Stiles et Hassall, 1905 (Nematoda: Rhabdiasidae) from Blommersia domerguei (Guibe) (Amphibia: Mantellidae) in Madagascar. AB - Rhabdias blommersiae sp. n. (Nematoda: Rhabdiasidae) is described from the lungs of Domergue's Madagascar frog, Blommersia domerguei (Guibe) (Amphibia: Mantellidae), in Madagascar. The new species differs from congeners parasitizing amphibians in having a smaller body and buccal capsule, six equal lips, large excretory glands of unequal length and a posteriorly inflated body vesicle. A combination of characters distinguishes it from Afromalagasy species of Rhabdias Stiles et Hassall, 1905. Rhabdias blommersiae is the third species of the genus described from amphibians in Madagascar. Close similarities in the number and shape of circumoral structures in two Rhabdias species described from mantellid hosts in Madagascar suggest a close relationship and common origin of the two species, with subsequent adaptation to separate hosts within the Mantellidae. PMID- 24471290 TI - Afrojoyeuxia gen. n. and Hunkeleriella gen. n., two new genera of cestodes (Cyclophyllidea: Anoplocephalidae) from African rodents. AB - Based on the study of type material, two new genera of cestodes (Cyclophyllidea: Anoplocephalidae) are proposed for Paranoplocephala Luihe, 1910 sensu lato species from African rodents. Afrojoyeuxia gen. n., proposed for A. gundii (Joyeux, 1923) comb. n. from Ctenodactylus gundi (Rothmann) (Hystricomorpha: Ctenodactylidae), is characterized by a high length/width ratio of mature proglottids, longitudinally extensive testicular field positioned anterior to the female glands, an ovoid or subspherical cirrus-sac and a thick, conical cirrus. Hunkeleriella gen. n., proposed for H. dasymidis (Hunkeler, 1972) comb. n. from Dasymys incomtus (Sundevall) (Myomorpha: Muridae), differs from related genera mainly by its short (10-20 mm) and wide strobila and neck, unilateral genital pores (exceptionally with a few changes per strobila), the position of the genital pores (slightly anterior to the middle of proglottid margin) and initially tube-like early uterus (later reticulated). Parandrya Gulyaev et Chechulin, 1996, earlier suggested to be a junior synonym of Paranoplocephala, is considered to be a valid, independent genus. Evidence of non-monophyly and need for a taxonomic revision of Paranoplocephala sensu lato, as well as the phylogenetic position of A. gundii and H. dasymidis are discussed. PMID- 24471292 TI - [Role of anti-TNF therapy (biologics) in the treatment of chronic inflammatory bowel disease in children]. AB - Inflammatory bowel disease (IBD) is diagnosed already during childhood or adolescence in every fourth patient. Compared to adult population, whereby recent studies show a tendency towards stabilization, incidence rates for children continue to rise. Though many features are shared with adult onset disease, paediatric ulcerative colitis and Crohn's Disease are, both, more aggressive and extensive already at diagnosis, with disease behaviour that changes with time. Therapeutic approaches, therefore, have to be adapted to specific needs of paediatric population. Aim of the article was to formulate guidelines on the role of biologic therapy in the treatment of paediatric onset inflammatory bowel disease, namely on the use of anti-TNF agent infliximab as it is the only biologic drug registrated for use in children with IBD. Recommendations are based on systematic review of the evidence in paediatric patients whenever it was available. However, due to lack of good randomised studies, adult practice was also taken into consideration. Finally, recommendations were dis-cussed on the consensus conference of all experts participating in the development of guidelines for adult and paediatric pa-tients.The recommendations are developed for Crohn's Disease and for Ulcerative Colitis, separately with respect to remission induction and for relapse prevention. Level of evidence is stated and following this procedure, recommendations are graded. Practice points are also provided with the aim to guide clinicians on the ward how to use biologics in the clinical practice. Com-plications of the treatment that are specific for children with inflammatory bowel disease are also addressed. These guidelines and practice points provide a structured guide for the use of anti-TNF therapy in the treatment of Crohn's Disease and Ulcerative Colitis in paediatric patients. PMID- 24471291 TI - [Croatian consensus on the treatment of inflammatory bowel diseases with biologic therapy]. AB - Introduction of biologic therapy in clinical practice represented significant progress in the treatment of inflammatory bowel diseases (IBD) because of its proven efficacy and due to the fact that biologics are the first drugs used in the treatment of IBD that can change the natural course of this diseases. At the same time, biologics are very expensive drugs with complex mechanism of action and important side effects and their use requires evidence-based clinical guidelines. These were the reasons that Referral Center of the Croatian Ministry of Health for IBD and the IBD Section of the Croatian Society of Gastroenterology organised Croatian consensus conference that defined guidelines for the treatment of IBD with anti-TNF drugs. The text below includes definitions of IBD, general principles of IBD therapy, comments on the importance of mucosal healing, analysis of reasons for nonresponse and loss of response to anti-TNF drugs, recommendation for the duration of anti-TNF therapy, rules of screening for opportunistic infections prior to anti-TNF therapy, comments on the problems with reproduction in IBD and finally guidelines for the treatment of various phenotypes of IBD including extraintestinal manifestations with anti-TNF therapy. PMID- 24471293 TI - [Activity indices in IBD]. AB - Inflammatory bowel disease (IBD) encompasses two medical conditions, Crohn's disease (CD) and ulcerative colitis (UC). These are chronic idiopathic conditions, marked by recurrent episodes of inflammation of the gastrointestinal tract, interspersed with periods of remission. An important feature of both disorders is that patients vary significantly in their clinical, endoscopic, biochemikal and histologic features. The heterogeneity in disease activity makes objective assessment of disease activity a prerequisite for rationale choice of therapy. At present, a number of activity indices are available for both conditions. These indices may be distinguished in more subjective (clinical), more objective (endoscopic-histological, biochemical) or a combination of the two. All these indices are rather complex and time-consuming; therefore their use is limited to clinical trials. Despite the different indices available, there is no consensus in the literature as to which is the most valid. In everyday clinical practice most gastroenterologists rely on their global clinical judgement, which is less reproducible, but simpler for decision-making in patients treatment. The aim of this article is to provide an overview of the disease activity indices (with a focus on the most frequently used), with analysis of their utilities, strengths and limitations. PMID- 24471294 TI - [Classical medications in the treatment of inflammatory bowel diseases]. AB - The treatment of inflammatory bowel diseases is complex and requires individual approach to every single patient. Traditionally, the approach is based on introduction of so called "classical" medication into the treatment regimen, from ones less potent and with fewer side effects to the ones more toxic but also therapeutically more effective. Aminosalicylates were the first choice of treatment for a long time. However, the role of aminosalicylates is becoming more and more diminished, although they are still the drug of choice in the treatment of mild to moderate ulcerative colitis. Corticosteroids are the therapy of choice in treatment of active IBD for achieving remission in moderate to severe disease. Azathioprine and 6- mercaptopurine belong to a group of thiopurines with an immunomodulatory effect which, in Crohn's disease as well as in ulcerative colitis, primarily have a role in a steroid dependant or steroid refractory type of disease and in maintenance of remission. Lately, early introduction of these medications is proposed to enhance the number of patients that remain in remission. Methotrexate is used for the therapy of active and relapsing Crohn's disease and represents an alternative in patients who do not tolerate or do not respond to azathioprine or 6-mercaptopurine therapy. Cyclosporine is used in treating steroid refractory ulcerative colitis and in some patients can postpone the need for colectomy. Antibiotics do not have a proven effect on the course of inflammatory bowel diseases and their primary role is to treat septic complications. Classic medications today represent a standard in the management of inflammatory bowel diseases, and the combination of the previously mentioned drugs often has a more potent effect on the course of the disease than any medication on its own and their combination is still an object of investigations and clinical studies. PMID- 24471295 TI - [Pharmacology of biologic medications]. AB - Two major types of inflammatory bowel diseases (IBD) are Crohn's disease (CD) and ulcerative colitis (UC). Insights into their pathophysiology and inflammatory cascade have lead to the discovery of medications that can have a selective effect on a particular molecule or signal pathway and correct an imbalance in pro and anti-inflammatory mediators. The first to be developed were the TNF-alpha antagonists, soluble receptors like etanercept and monoclonal antibodies. Infliximab has been approved worldwide for treatment of moderate to severe and active fistulizing forms of Crohn's disease, as well as for severe forms of ulcerative colitis in adults who do not react to full and adequate corticosteroid and/or immunosuppressive therapy, i.e. for patients who have problems with or medical contraindications to such therapy and for treatments of severe forms of active disease in children. Adalimumab can be applied in cases when antibodies develop as a reaction to infliximab, leading to reduced drug efficacy and allergic reactions. According to the available data from preclinical tests and earlier phases of clinical tests, potential candidates for new biological medications in treating IBDs are another TNF-alpha antagonist (certolizumab), inhibitors of Th1 polarisation (fontolizumab, ustekinumab) and selective adhesion molecule inhibitors (natalizumab). PMID- 24471296 TI - [Side effects and contraindications for biological therapy in inflammatory bowel disease]. AB - TNF-alpha blockers side effects vary according to the frequency and severity and mainly include immunogenicity (ability to cause immune reactions), infections, malignancies, heart failure, demyelinating disease and others. Treatment with TNF alpha blockers may result in the formation of autoantibodies and, rarely, in the development of a lupus-like syndrome. They should not be administered to patients who have experienced a severe hypersensitivity reaction. Urticaria, dyspnea and hypotension can occur after TNF-alpha inhibitors administration. Serious infusion reactions including anaphylaxis are infrequent. Patients treated with TNF-alpha blockers are at increased risk for developing serious infections (active tuberculosis, including reactivation of latent TB, invasive fungal infections, bacterial, viral, and also infections due to opportunistic pathogens). Therefore, all patients should be screened for systemic or localized infection before starting therapy. Patients with a positive screening for TB should be treated with isoniazid for at least 4 weeks, before starting TNF-alpha blocker therapy. TNF-alpha blockers may be associated with non-Hodgkin lymphoma or other cancers especially if combined with other immunosuppressive drugs. Monotherapy showed no such effect in patients, who cited a personal history of malignant disease, therefore caution is needed. TNF-alpha blockers are contraindicated in patients with moderate to severe congestive heart failure (NYHA Class III/IV). TNF-alpha blockers have been associated with reactivation of hepatitis B virus (HBV) infection in patients who are chronic carriers. Patients should be tested for HBV infection before treatment. Patients who test positive should be monitored closely for reactivation of HBV infection during and following termination of therapy. Patients with negative serology should be vaccinated. Severe hepatic reactions, including acute liver failure, jaundice, hepatitis, and cholestasis have been reported. Patients with symptoms or signs of liver dysfunction should be evaluated for evidence of liver injury. Cases of leucopenia, neutropenia, thrombocytopenia, and pancytopenia have been reported. TNF-alpha blockers have been associated in rare cases with CNS manifestation of systemic vasculitis, new onset or exacerbation of CNS and peripheral demyelinating disorders, including multiple sclerosis and Guillain-Barre syndrome. PMID- 24471297 TI - [Place of biologic therapy in the treatment of inflammatory bowel diseases and assessment of its efficacy]. AB - Biological therapy (infliximab and adalimumab) in inflammatory bowel diseases is based on the IgG1 anti-TNF monoclonal antibodies with potent anti-inflammatory effects whose main mechanism of action is thought to be the induction of inflammatory cell apoptosis. Unquestionably, which arises from the most recent studies and meta-analysis, anti-TNF angents are an effective therapy primarily for the treatment of Crohn's disease, but also ulcerative colitis, in different clinical situations. Infliximab has the most extensive clinical trial data, but other biological agents, such as adalimumab and certolizumab pegol appear to have similar benefits. In terms of future research, more long-term data are needed for both certolizumab pegol in Crohn's disease and adalimumab in ulcerative colitis. Important role in the application of biological therapy is assessing its effectiveness and cost-benefit relationships that are estimated by regular follow up. In the absence of response (primary and secondary) therapeutical options are dose increase, giving the drug in shorter intervals and substitution with other biological drug. PMID- 24471298 TI - [Anti-TNF therapy in inflammatory bowel diseases during pregnancy and breast feeding]. AB - Since the early occurrence of inflammatory bowel diseases in young people, the role of pregnancy on disease course, and the influence of different therapies on pregnancy, fetal development and the safety of breastfeeding have been one of the important questions. Biological therapy has been increasingly used and all the above mentioned questions seem to be of a great interest. The majority of research indicate that the possibility of conception in patients with IBD are the same as in a healthy population, although there is an increased risk for the child in terms of prematurity or low birth weight. Pregnancy in IBD patient should be considered as a high risk. Most medications used to achieve or maintain remission are safe in pregnancy and breastfeeding. Exceptions are thalidomide and methotrexate that are absolutely contraindicated. Anti-TNF drugs are safe but it is advised to stop the treatment after 30-32 weeks of pregnancy due to the possibility of placental transfer of medications. Infliximab is excreted into breast milk in small quantities and breastfeeding is assumed to be safe. Pregnancy in IBD patients should be planned in advance so that the medications that are contraindicated could be excluded on time and further possible complication could be prevented by constant monitoring of pregnancy. Prospective studies of monitoring throughout pregnancy and short-term and long-term forecasts of development of children whose mothers were pregnant when suffered from inflammatory bowel disease are necessary. PMID- 24471299 TI - [Screening for opportunistic infections and vaccination before introduction of biologic therapy]. AB - Patients on anti-TNFalpha medications carry a higher risk for developing opportunistic infections. In order to introduce anti-TNFalpha therapy, screening for hepatitis viruses B and C, HIV, EBV, HPV, TBC, bacterial, fungal and parasitic infections should be performed. Screening involves patient's history of earlier infectious diseases, vaccinations and traveling to parts of the world with endemic diseases. Clinical examination should be supplemented with stomatologic and gynecologic exams. Laboratory results include leukogram, transaminases, C-reactive protein, urine analysis, hepatitis B, C, HIV and EBV serology. Varicella zoster virus serology depends on past medical history. If the patient has traveled to tropical areas, both stool analysis and strongiloidiasis serology should be performed. Other mandatory examinations include chest radiography, PPD and TBC serology using interferon gamma release test (IGRA). If suspecting intra-abdominal abscess, magnetic resonance of the abdomen is recommended. In case of abscess, CMV or Clostridium difficile colitis anti-TNF alpha therapy is contraindicated. Live vaccine application is contraindicated in patients receiving anti-TNFalpha therapy. All seronegative patients should be vaccinated against hepatitis B virus. Seasonal flu vaccination is recommended to be applicated yearly and pneumococcal polysaccharide vaccine once in every five years. Based on the past medical history and serologic results, patients are vaccinated against VZV with extra precaution. Human papilloma virus vaccination is performed in a group of women under 23 years of age, after gathering cervical smear sample analysis. PMID- 24471300 TI - [The role of anti-TNF therapy in ulcerative colitis]. AB - Anti-TNF-alfa molecules are currently being used to treat ulcerative colitis regarding to the fact that TNF-alpha has an important role in the pathogenesis of IBD. Although these drugs improved the therapy of patients, immunogenicity limits their potential for clinical use. Infliximab and adalimumab are effective for induction and maintenance of remission in outpatients with moderate to severe steroid-refractory ulcerative colitis. Biologics can be a drug of choice for patients with refractory proctitis and refractory pouchitis. In hospitalized patients with steroid-resistant severe ulcerative colitis who are candidates for colectomy, infliximab may be second-line option. Adequate long-term maintenance therapy with anti-TNF is required after rescue therapy for a sustained benefit. Regarding to the known risk for side-effects of anti-TNF drugs especially in patients concomitantly treated with thiopurines it is urgent future research. PMID- 24471301 TI - [Anti-TNF therapy in treatment of luminal Crohn's disease]. AB - Biologic drugs directed against main proinflammatory mediator in inflammatory bowel disease (IBD)--tumor necrosis factor alpha (TNFalpha)--represent very effective and clinically proven therapy of IBD. Meta-analysis and daily clinical practice confirm efficacy of infliximab and adalimumab in induction and maintenance of remission without steroids in patients with luminal Crohn's disease. Main therapeutic goals are reduction of complications, reduction of number of hospitalizations and surgical interventions and improvement of quality of life, work capacity and reproductive ability of patients. There are few very important issues that one must consider before starting an anti-TNF therapy in patients with luminal Crohn's disease. First, it is necessary to identify patients who failed to respond to conventional drugs and who would benefit the most from early application of biologics. It is very important to exclude presence of strictures or other complications like intraabdominal fistulas and collections before starting anti-TNF therapy. Once we decide to start biologic therapy, it is important to apply adequate dose and regime of anti-TNF therapy and to change and adjust treatment to achieve and maintain remission in patients who lose response. In general, treatment recommendations depend on disease activity and severity, extension and localization of lesions, comorbidities and possible complications of disease and/or treatment. There are few clinical instruments and laboratory surrogates that help us to assess disease activity. Most used are Crohn's Disease Activity Index (CDAI), Harvey- Bradshaw index (HBI), concentration of C-reactive protein (CRP) and fecal lactoferrin and calprotectin. In assessment of mucosal injury we rely on two complementary endoscopic indices of activity--Crohn's Disease Endoscopic Index of Severity (CDEIS) and Simple Endoscopic Score for Crohn's Disease (CD-SES). However, in time of diagnosis of Crohn's disease available clinical, serological or laboratory markers do not have acceptably predictive value for future disease behavior and there are still no genetic indicator that could predict disease course. There are some clinical and epidemiologic factors that could be related to unfavorable disease course. Age less than 40 years, extended disease, need for steroid therapy early after diagnosis and perianal disease are considered to predict worse prognosis in patients with luminal Crohn's disease. According to available data, it seems that early intensive therapy with anti-TNF drugs as monotherapy or in combination with immunosuppressive drugs in this group of patients increases possibility of induction of remission, mucosal healing and maintenance of steroid-free remission. Candidates for anti-TNF therapy are also patients who did not respond to conventional treatment, patients with moderate or severe disease who are intolerant to steroids, patients in whom we expect severe adverse effects from steroid treatment, patients who do not accept steroid treatment and patients with frequent relapses and need for steroids. PMID- 24471302 TI - [Treatment of fistulizing Crohn's disease]. AB - The treatment of fistulating Crohn's disease should include a combined medical and surgical approach and should be defined on an individual basis. Asymptomatic enteroenteric fistulas usually require no treatment, but internal fistulas (gastrocolic, duodenocolic, enterovesical) that cause severe or persistent symptoms require surgical intervention. While low asymptomatic anal-introital fistula may not need surgical treatment, in case of a symptomatic enterovaginal fistula surgery is usually required. There are no controlled-randomized trials to assess the effect of medical treatment for non-perianal fistulating Crohn's disease. The incidence of perianal fistulae varies according to the location of the disease, with its occurrence varying between 21-23%. The diagnostic approach should include an examination under anesthesia, endoscopy, and either MRI or EUS before the treatment begins. Asymptomatic simple perianal fistulas require no treatment. The presence of a perianal abscess should be ascertained and if present should be drained urgently. In case of a complex perianal disease, seton placement should also be recommended. Antibiotics (metronidazole and ciprofloxacine) are useful for treating complex perianal disease, however, when discontinued, most of the fistulas relapse. The current consensus suggests that azathioprine/6-mercaptopurine is the first line medical therapy for complex perianal disease, which is always given in combination with surgical therapy (seton, fistulotomy/fistulectomy). Anti TNF-alpha agents (infliximab and adalimumab) should be used as a second choice medical treatment. In refractory and extensive complex perianal disease a diverting stoma or proctectomy should be performed. PMID- 24471303 TI - [The role of biologic therapy in the treatment of extraintestinal manifestations and complications of inflammatory bowel disease]. AB - Extraintestinal manifestations occur in about 35% of patients with inflammatory bowel diseases (IBD). Most frequently affected are bones and joints, skin, eyes, liver and biliary ducts. Extraintestinal manifestations of IBD are divided in two groups: reactive manifestations which depend on activity of IBD--peripheral arthritis, erythema nodosum, aphthous stomatitis, episcleritis and other manifestations which are independent on activity of IBD--pyoderma gangrenosum, uveitis, axial arthropathy, primary sclerosing cholangitis (PSC). Most affected are bones and joints. Symptoms vary from mild arthralgia to severe arthritis with painful swallowing of joints. They occur in about 5-10% of patients with ulcerative colitis (UC) and in 10-20% of patients with Crohn's disease (CD). Both peripheral and axial joints can be affected. According to available data, most patients with active IBD and concomitant arthritis have benefit from infliximab therapy. Infliximab is also effective in maintenance of remission in group of patients with spondyloarthropathy. Adalimumab showed similar efficacy in treatment of ankylosing spondylitis, but there are still no data about efficacy of adalimumab in treatment of patients with IBD and concomitant arthritis. Primary sclerosing cholangitis, autoimmune hepatitis, cholestasis, cholelithiasis and elevation of aminotransferase are also considered to be extraintestinal manifestations of IBD. Most frequent is PSC which affects usually patients with UC (7.5% of patients). Course of liver disease is completely independent on activity of IBD, and destruction of biliary ducts is usually irreversible and refractory on treatment and most of the patients need liver transplantation. Anti TNF therapy is also ineffective in treatment of PSC and has no impact on disease course and outcome. However, there is no contraindication for anti-TNF therapy of concomitant active IBD in this group of patients. Erythema nodosum (EN) and pyoderma gangrenosum (PG) are usual skin manifestations of IBD. Erythema nodosum occurs in about 3-20%, and pyoderma gangrenosum in about 0.5-20% of patients with IBD. Infliximab is proven to be effective in treatment of PG, but there is still not enough evidence on efficacy of anti-TNF drugs in treatment of EN and other rare skin manifestations of IBD. About 2-5% of patients with IBD have also some ophthalmological disorder. Symptoms vary from mild conjunctivitis to severe inflammation of eye membranes--iritis, episcleritis, scleritis and uveitis. It seems that infliximab and adalimumab can diminish uveitis and scleritis in patients with different autoimmune disorders and IBD. According to guidelines of American Gastroenterology Association (AGA), in group of patients with CD, infliximab is indicated in treatment of spondyloarthropathies, arthritis, arthralgia, pyoderma gangrenosum, erythema nodosum, uveitis and other ophthalmological manifestations of IBD except optical neuritis which can worse or be consequence of anti-TNF treatment. Similar indications exist for use of adalimumab except in case of erythema nodosum. In group of patients with extraintestinal manifestations of UC, infliximab is indicated in treatment of spondyloarthropathies and pyoderma gangrenosum. Complications of IBD are fistulas (perianal and non-perianal), stenosis and strictures, abscesses, bowel perforations, gastrointestinal bleeding and development of different malignomas. Anti-TNF drugs are proven to be effective and indicated only for treatment of perianal fistulas in patients with Crohn's disease. In group of patients with UC, there are only few case reports on beneficial effect of infliximab in treating chronic pouchitis and infliximab in treatment of these patients still cannot be recommended. PMID- 24471305 TI - [Technical specifications for post-marketing pharmacoeconomic evaluation of Chinese medicine (draft version for comments)]. AB - Pharmacoeconomics is an important part of the post-marketing evaluation of Chinese medicine, post-marketing pharmacoeconomic evaluation can better reflect the clinical and market value of Chinese medicine, the purpose of establishing the technical specifications for pharmacoeconomic evaluation is to make the evaluation process and results regarding Chinese patent medicines more scientific and fair. Every country's technical specifications for pharmacoeconomic evaluation act as reference guidelines, we have already drawn up the technical specifications which take into account the special characteristics of Chinese medicine; these are in preparation for post-marketing pharmacoeconomic evaluation Chinese medicine. PMID- 24471304 TI - [Technical specifications for intensive hospital safety monitoring of post marketing Chinese medicine (draft version for comments)]. AB - It is of vital significance to conduct active post-marketing surveillance of Chinese medicine, as an active response to laws, rules and guidelines issued by the China food and drug administration. The standards for technological specifications based on expert consensus have been drafted. These will provide technological support in evaluating adverse drug reactions (ADRs) or adverse drug events (ADEs). The technological specifications for post-marketing surveillance focus on two surveillance designs; one is a large sample registry study to explore general population ADR/ADE characteristics, the other is a nested case control study to explore the characteristic and mechanisms of ADRs. PMID- 24471306 TI - [Technical specifications for rational clinical use of parenterally administered Chinese medicine (draft version for comments)]. AB - The regulations on basic clinical use of parenterally administered Chinese medicine, issued jointly in 2008, by the ministry of health (MOH), China food and drug administration (SFDA) and the state administration of traditional Chinese medicine (SATCM). Integrating actual clinical practice, these presented doctors and nurses with detailed specifications for the safe use of parenterally administered Chinese medicine. The regulations emphasize the use of Chinese medicine pattern differentiation, use in strict accordance with instructions, and they prohibit use combined with other medicines. The emphasis of the regulations are practicality and operability, and provide meaningful guidance to doctors and nurses for the rational and safe use of parenterally administered Chinese medicine, to reduce adverse reactions/adverse events caused by improper use. PMID- 24471307 TI - [Expert consensus post-marketing evaluation scheme to detect immunotoxicity of Chinese medicine in clinical populations (draft version for comments)]. AB - Through consensus, establish a post-marketing scheme and the technical processes to evaluate Chinese medicine's immunotoxicity on a population, as well as its beneficial influences on the immune system. Provide regulations on the collection, storage and transportation of serum samples. This article applies to the post-marketing scientific evaluation of the immunotoxicity of parenterally administered, and for other ways of taking Chinese medicine. PMID- 24471308 TI - [Expert consensus on population pharmacokinetics of Chinese medicine ( draft version for comments)]. AB - In population pharmacokinetic (PPK) research of Chinese medicines with narrow therapeutic windows of toxicity, or when the target population is not homogeneous, or when there are frequent adverse reactions to parenterally administered Chinese medicine, select those that have a definite therapeutic effect, and in which the compositions of the toxic substances compositions are known, for study, and use complete PPK sampling design to take samples at specific time points. Use gas chromatography, HPLC, and LC-MS methods for the detection of target components. Finally, use total quantity statistical moment analysis, to account for each component of the PPK parameters. Thus, PPK model can reflect the overall trend of Chinese medicine, to provide the basis for reasonable clinical dosage adjustments. PMID- 24471309 TI - [Exploration of how to formulate guidelines on post-marketing traditional Chinese medicine surveillance]. AB - Combining the world health organization's (WHO), the United States and the European union's relevant laws and guidelines on post-marketing drug surveillance to judge the status of post-marketing surveillance of traditional Chinese medicine(TCM) in China. We found that due to the late start of post-marketing surveillance of traditional Chinese medicine, the appropriate guidelines are yet to be developed. Hence, hospitals, enterprises and research institutions do not have a shared foundation from which to compare their research results. Therefore there is an urgent need to formulate such post-marketing surveillance guidelines. This paper has used as guidance various technical documents such as, "procedures to formulate national standards" and "testing methods of management in formulating traditional Chinese medicine standards" and has combined these to produce a version of post-marketing surveillance particular to Chinese medicine in China. How to formulate these guidelines is discussed and procedures and methods to formulate technical specifications are introduced. These provide a reference for future technical specifications and will assist in the development of TCM. PMID- 24471310 TI - [Translation and introduction of Guide to Methodological Standards in Pharmacoepidemiology]. AB - Post-marketing pharmacovigilance of drugs has become one of the most important activities for regulatory authorities. In China, pharmacovigilance is currently receiving the attention of government, pharmaceutical industries and the public. In order to support high quality pharmacoepidemiological studies and to stimulate innovation that benefits patients and the wider public, the European medicines agency (EMA) organized the European network of centres for pharmacoepidemiology and pharmacovigilance (ENCePP) to formulate and publish the Guide on Methodological Standards in Pharmacoepidemiology as a reference document for the methodological standards of pharmacovigilance activities in the European union (EU). It supplies methodological and scientific guidance, and advises on technical aspects of conducting parmacoepidemiological studies and undertaking parmacovigilance. As advice includes: legal and ethical requirements, general aspects of study protocols, research questions, approaches to data collection, study designs and methods, statistical and epidemiological analysis plans, quality control and quality assurance, reporting of adverse events to regulatory authorities, communication of findings, and so on. The translation and introduction of this guidance can provide a useful technical and methodological reference for us to carry out the pharmacovigilance (especially for parenterally administered Chinese medicine safety monitoring). PMID- 24471311 TI - [How to read and understand Registries for Evaluating Patient Outcomes: A User's Guide (2nd Edition)]. AB - Registry studies (RS) get more and more attention in recent years because it can reflect the health care situations of the real world. There are a number of large scale RS for traditional Chinese medicine (TCM). RS are observational studies that can complement randomized controlled trials (RCT). RS have an irreplaceable position in real word study (RWS), especially for small probability events. There are some different characters and qualities in RS. Registries for Evaluating Patient Outcomes: A User's Guide (2nd Edition) was published by the agency for healthcare research and quality (AHRQ) in 2010. It described the details of how to establish, maintain, and evaluate RS, and using 38 RS samples to illustrate the possible problems in undertaking such research. The User's Guide (2nd Edition) provides a reliable reference document for RS. TCM injections post marketing safety surveillance RS is a national program involving multiple centers in China. This program can further improve RS quality their application in China and is a good illustration of how to follow this guide accurately. PMID- 24471312 TI - [Interpretation of Guidelines on Good Pharmacovigilance Practices for European Union]. AB - Due to the limitations of pre-authorization clinical trials, the safety information obtained from them is relatively limited. Therefore, it is very necessary to carry out pharmacovigilance activities on drugs post-marketing. In order to promote the specific implementation of the new pharmacovigilance regulations, the European medicines agency (EMA) developed the Guideline on Good Pharmacovigilance Practices (GVP), as the new criteria for pharmacovigilance in the European Union (EU). Compared with the previously published, Guidelines on Pharmacovigilance for Medicinal Products for Human Use (2007), the GVP proposed more comprehensive and systematic provisions of pharmacovigilance systems, quality control systems, judgements, pharmacovigilance inspections and audits. In addition, it set more specific and comprehensive requirements on risk management systems, the management and reporting of adverse reactions to medicinal products, periodic safety update reports, post-authorization safety studies, signal management, and so on. Interpreting the basic principles, working mechanisms, key technologies and methods of the GVP provides a useful reference for us to carry out pharmacovigilance (especially regarding safety monitoring of parenterally administered Chinese medicine). PMID- 24471313 TI - [Analysis of rational clinical uses of traditional Chinese medicine injections and factors influencing adverse drug reactions]. AB - OBJECTIVE: To rationalize the clinical use and safety are some of the key issues in the surveillance of traditional Chinese medicine injections (TCMIs). METHOD: In this 2011 study, 240 medical records of patients who had been discharged following treatment with TCMIs between 1 and 12 month previously were randomly selected from hospital records. Consistency between clinical use and the description of TCMIs was evaluated. Research on drug use and adverse drug reactions/events using logistic regression analysis was carried out. RESULT: There was poor consistency between clinical use and best practice advised in manuals on TCMIs. Over-dosage and overly concentrated administration of TCMIs occurred, with the outcome of modifying properties of the blood. Logistic regression analysis showed that, drug concentration was a valid predictor for both adverse drug reactions/events and benefits associated with TCMIs. CONCLUSION: Surveillance of rational clinical use and safety of TCMIs finds that clinical use should be consistent with technical drug manual specifications, and drug use should draw on multi-layered logistic regression analysis research to help avoid adverse drug reactions/events. PMID- 24471314 TI - [Establishment of model of traditional Chinese medicine injections post-marketing safety monitoring]. AB - OBJECTIVE: To establish a nurse based post-marketing safety surveillance model for traditional Chinese medicine injections (TCMIs). METHOD: A TCMIs safety monitoring team and a research hospital team engaged in the research, monitoring processes, and quality control processes were established, in order to achieve comprehensive, timely, accurate and real-time access to research data, to eliminate errors in data collection. RESULT: A triage system involving a study nurse, as the first point of contact, clinicians and clinical pharmacists was set up in a TCM hospital. Following the specified workflow involving labeling of TCM injections and using improved monitoring forms it was found that there were no missing reports at the ratio of error was zero. CONCLUSION: A research nurse as the first and main point of contact in post-marketing safety monitoring of TCM as part of a triage model, ensures that research data collected has the characteristics of authenticity, accuracy, timeliness, integrity, and eliminate errors during the process of data collection. Hospital based monitoring is a robust and operable process. PMID- 24471315 TI - [Comparison and analysis of clinical safety evaluation methods for parenterally administered Chinese medicine]. AB - Parenterally administered Chinese medicine is widely applied in clinic. It particularly plays an important role in the treatment of cardiovascular and cerebrovascular disease, acute infectious diseases and malignant tumors. With the expansion of the scope of the clinical application of parenterally administered Chinese medicine adverse event reports also increase day by day. Thus, parenterally administered Chinese medicine has come to the attention of management departments, medical staff and the public. By the end of 2012, the national adverse drug reaction monitoring database has collected more than 5 million adverse drug reactions/events reports. Parenterally administered Chinese medicine accounted for more than half of the total number of adverse reactions to Chinese medicine. Therefore, it is essential that epidemiological methods are used to analyze the national database for all references to parenterally administered Chinese medicine. Our research aims to analyze the advantages and disadvantages of various safety monitoring methods for parenterally administered Chinese medicine and offer guidance in safety evaluation analysis. PMID- 24471316 TI - [Discussion about relativity between post-marketed safety outcome and treatment course of traditional Chinese medicine drugs on basis of reinforced urn processes]. AB - Based on relevant research and development, the possibility of applying the reinforced urn processes (RUPs) statistical approach to traditional Chinese medicine(TCM) drugs safety research is discussed in this paper, primarily through theoretical discussion and simulations. Also introduced are work flows and the key points for the application of the RUPs approach. This potentially new approach has recently been applied to the target estimation of phase I human tolerance clinical trials. A traditional RUPs approach has also been widely applied in the precise point-estimation of allowable longest treatment courses, according to the particular safety outcomes of post-marketed TCM. PMID- 24471317 TI - [Spontaneous reporting system data analysis of parenterally administered Shenmai]. AB - Spontaneous reporting system (SRS) datais currently an important source of monitoring and finding ADRs signals throughout the world. This method can promptly and effectively discover ADR signals, thus preventing and avoiding ADRs effectively. Parenterally administered Shenmai has the functions of benefiting vital energy, nourishing Yin and generating body fluids, and activating the pulse. Clinically it is used in various diseases including shock, coronary heart disease, viral myocarditis, chronic pulmonary heart disease, and granulocytopenia. The large, national SRS database of ADRs needs effective evaluation methods. We report on the use of Bayesian confidence propagation neural network method (BCPNN) and proportional reporting ration (PRR) with propensity score to control for confounding variables. Early warning signs of an ADR are, a feeling of suffocation (difficulty exhaling), anaphylactoid reactions and flushing. Furthermore, relevant relationships between the different factors is analysed by association rules (AR). It is found that there is a close relationship between past history of ADRs, a family history of ADRs and itching. PMID- 24471319 TI - [Study of analysis 1 390 adverse drug reactions cases of parenterally administered dengzhan xixin based on China's spontaneous response system]. AB - Adverse drug reaction (ADR) monitoring of spontaneous reporting system (SRS) data to detect signals, is the main method of pharmacovigilance by China food and drug administration (CFDA). This study conducted a data analysis of 1 390 ADR cases of parenterally administered Dengzhan Xixin based on China SRS data collected between Jan, 2009 and Dec, 2012. The proportional reporting ratio method (PRR) and Bayesian confidence propagation neural network method (BCPNN) were used for data mining analysis. The results showed that 71 cases of serious ADRs accounted for 1 390, 5.11% of cases reported. There were more men than women (613/593), and people over the age of 60 accounted for 64.03%. The most common ADRs were itching, rash, dizziness, chills, and palpitations. With damage to skin and its accessories 55 forming the highest percentage of ADRs. When propensity score method to control for confounding factors, PRR method and BCPNN methods were applied, headache, dizziness, palpitation, and chills were ADRs warning signals. Due to the limitation of the SRS data, the results still need to be combined with other research to form a comprehensive body of safety evidence, and to guide the rational clinical use and reduce risks. PMID- 24471318 TI - [Spontaneous reportintg system data based on shuxuetong injection adverse reactions signal warning analysis]. AB - In this study, January 2009-December 2012 national adverse drug reaction monitoring center Shuxuetong the SRS data for the study, using the reporting rate ratio method and Bayesian belief propagation neural network Shuxuetong ADR warning signal, and balanced use of propensity score methods confounders. The results showed that chills as a possible warning signal. Tip clinical use Shuxuetong injection when, for the elderly, children, liver and kidney dysfunction are more prone to adverse reactions in patients with other special populations, the need to pay attention to the prevention of systemic allergic reactions, in particular the prevention shivering. PMID- 24471320 TI - [Pharmacovigilance of parenterally administered salvianolate based on analysis of spontaneous reporting system data]. AB - Spontaneous reporting system (SRS) is currently a basic method to monitor and find adverse drug reactions (ADR) signals used worldwide. This method can promptly and effectively discover ADR signals and is of great significance to effectively prevent and avoid ADRs. Parenterally administered salvianolate has the functions of activating blood circulation and removing stasis. It is mainly used in the treatment of stable angina pectoris. As the drug is widely used clinically and ADRs are increasingly reported promptly, ADR information in the national ADR monitoring center's SRS database has also increased. How to quickly and effectively identify suspicious ADRs is a major concern. This study uses BCPNN and PRR to detect early warning signals. S739 ADR case reports were identified. There were 106 types, 1 310 events, and 24 serious ADR cases ( 3.25% of 739 case reports) There wre no deaths. The ten most frequent ADRs were: rash, dizziness, itch, headache, chills and breath, nausea, palpitation, anaphylactic reaction and hot. The drugs early warning signs were dizziness, headache, nausea, itchiness and rash estimated using PRR. Early warning signs based on BCPNN were dizziness and headache. The ADRs of dizziness and headache are early warning signals associated with the nervous system. PMID- 24471321 TI - [Research on early warning signals of adverse drug reactions to parenterally administered xiyanping based on spontaneous reporting system (SRS) data]. AB - This article focused on early warning signals regarding the safety of parenterally administered Xiyanping. The study data was obtained from reports made between 2005-2012 from the national spontaneous reporting system (SRS). Proportion reporting ratio (PRR) and Bayesian confidence propagation neural network (BCPNN) algorithms were used to analyse: erythra, pruritus, anaphylactoid reactions and shiver with cold, these 4 adverse drug reactions had a total count of more than 500 events. The article found that Xiyanping's incidence rate of erythra was higher than for background-drugs in every year and in every season. Pruritus was an early warning signal in the second season of 2009, and anaphylactoid reaction was an early warning signal in the fourth season of 2011 and in the second season of 2012. There was however no early warning signal indicated by shiver with cold. This data indicates that erythra maybe an adverse drug reactions to parenterally administered Xiyanping, and if the incidence rate of pruritus and anaphylactoid reaction rises attention should be paid to its safety. PMID- 24471322 TI - [Analysis of adverse reactions and pharmacovigilance research to parenterally administered shuxuening]. AB - Parenterally administered Shuxuening is a commonly used Chinese medicine. There is a need to understand the characteristics of adverse drug reactions (ADRs) to it. 9 601 ADR cases reports were collected from the national adverse drug reaction monitoring center reported between January, 2005 and December, 2012. These included 326 serious ADR cases, accounting for 3.93% of the total. It was found that ADR reports increased annually from 2005, reaching a peak in the third quarter of 2009. The number of ADR cases reports were greatest in the third quarter of each year. ADRs in patients aged 60-74, accounted for 3 348 (34.87%) of all cases. 9 391(97.81%) cases were administered by intravenous infusion. In 8 431 cases, the dosage was in accordance with instructions. 61.61% ADR cases occurred on first administration. The ten most frequent symptoms were, rashes, itching, dizziness, palpitations, chills, allergic reactions, shortness of breath, nausea, phlebitis and vomiting. Systemic damage mainly affected the skin and its accessories damage, or the nervous system damage. Through the use of proportional reporting ratio (PRR) and Bayesian confidence propagation neural network (BCPNN) and propensity score applying generalized boosted models (GBM) to control for 17 confounding factors, analysis of the 10 kinds of ADRs found that for the ADR signals of dizziness, palpitations, phlebitis, and vomiting, BCPNN found that dizziness and phlebitis were early warning signals. This research found that in the 60-89 age group, higher dosages of parenterally administered Shuxuening gave rise to more phlebitis. This study provides important information for parenterally administered Shuxuening research, and guidance for its risk management. PMID- 24471323 TI - [Analysis of questionably allergic factors to parenterally administered shenmai- a nested case control study using hospital information system data]. AB - Parenterally administered Shenmai, made from constituents of Ginseng Rubra Radix and Ophiopogonis Radix has, confirmed by modem pharmacological studies, the function of increasing cardiac hypoxia tolerance and anti arrhythmic and antibacterial properties. However, parenterally administered Shenmai is also prone to cause allergic reactions, which is clearly a safety issue. NCCSs combine elements from case-control and cohort studies. HIS data provides real world clinical information on the use of parenterally administered Shenmai. To explore suspected allergic factors this article compares specific information of those who showed allergies to those who didnt in the real world clinical application based on HIS data from 20 nationwide hospitals. Data includes age, gender, severity and type of allergic response, dosage, solvents used in the medication's preparation and drugs used in combination with parenterally administered Shenmai. Whilst this methodology is a possible route of exploration, ultimately pharmaceutical experiments and prospective clinical studies are required to identify and confirm factors related to allergic reactions. PMID- 24471324 TI - [Nested case control study to analyze suspected cases and their related factors of allargic reactions to parenterally administered dengzhan xixin]. AB - To assess if adverse drug reactions (ADR)s to parenterally administered Dengzhan Xixin are allergic in origin. Hospital information system (HIS) data from 20 hospitals in China were used to carry out a nested case control design study. Included were patients who received dexamethasone for suspected allergic reactions after receiving parenterally administered Dengzhan Xixin. These were compared with non-allergic reaction people. Single factor logistic regression and multiple factor logistic regression were used to analyze data. Condition on admission, allergic history, dosage, disease status and drug combinations were taken into account in cases of suspected allergic reactions. After analysis we found that the condition on admission had a significant effect, P = 0.008 3, OR value = 5.642 on suspected cases of allergic reactions. Using vitamin B6 injection or ambroxol at the same time as parenterally administered Dengzhan Xixin were significant, P = 0.000 2 and 0.016 7, OR value = 9.545 and 3.194, risk factors in this group. Based on this current research, condition on admission as well as the concomitant use of vitamin B6 or ambroxol may be the risk factors in suspected cases of allergic reactions. However, further research for verification is required. This study can provide guidance for safe clinical practice in using parenterally administered. It can also provide a new method for the pharmcovigilance of parenterally administered Dengzhan Xixin. PMID- 24471325 TI - [Clinical evaluation of multi-function "rapid" allergic skin test instrument for application in drug allergy testing]. AB - OBJECTIVE: To evaluate the multi-function rapid allergic skin test instrument for application in drug allergy testing. METHOD: Three hundred patients were planned to be treated with cephalosporins Injection were divided randomly into 3 groups, the new allergic skin test instrument group, normal allergic skin test instrument group, and traditional skin test group, the true positive rate and false positive rate were calculated. Using multifunctional rapid allergy skin test was carried out on 210 cases of volunteers preliminary clinical evaluation of traditional Chinese medicine injections skin test. RESULT: There were no significance difference between the new allergic skin test instrument group and control group in the true positive rate. As compared with the control group, a significance difference was found between the new allergic skin test instrument group and control group in false positive rate respectively (P < 0.05). CONCLUSION: The multi-function rapid allergic skin test instrument is safe and easy to use, with a higher rate of accuracy and lower false positive rate. PMID- 24471326 TI - [Analysis of clinical effects of parenterally administered shenqi fuzheng on renal function]. AB - This study analyzes the clinical effects of parenterally administered Shenqi Fuzheng on renal function. 20 national, general hospitals were selected. Their hospital information system (HIS) data on 51 898 cases of parenterally administered Shenqi Fuzheng were mined for data. Patients ranged from 18 to 80 years old. 27 718 cases were selected for analysis. Serum creatinine (Scr) and blood urea nitrogen (BUN) levels were taken before and after treatment for outcome evaluation. According to instructions, we divided 197 cases into the treatment group (doses > 250 mL) and 5 728 cases acted as the control group (dose < or = 250 mL). Stratified analysis adjusted for age, sex, hospital illness, treatment, etc. According to the four variables, the case group compared with the control group did not show abnormal renal function changes; 57 confounding factors were balanced using propensity score method resulting in the treatment group showing no abnormal changes in renal function. This HIS b data analysis found that parenterally administered Shenqi Fuzheng above the recommended dosage did not significantly impact on renal function was no significant difference. Prospective studies should be carried out to validate this data. PMID- 24471327 TI - [Impact analysis of shuxuetong injection on abnormal changes of ALT based on generalized boosted models propensity score weighting]. AB - OBJECTIVE: To estimate treatment effects of Shuxuetong injection on abnormal changes on ALT index, that is, to explore whether the Shuxuetong injection harms liver function in clinical settings and to provide clinical guidance for its safe application. METHOD: Clinical information of traditional Chinese medicine (TCM) injections is gathered from hospital information system (HIS) of eighteen general hospitals. This is a retrospective cohort study, using abnormal changes in ALT index as an outcome. A large number of confounding biases are taken into account through the generalized boosted models (GBM) and multiple logistic regression model (MLRM) to estimate the treatment effects of Shuxuetong injections on abnormal changes in ALT index and to explore possible influencing factors. RESULT: The advantages and process of application of GBM has been demonstrated with examples which eliminate the biases from most confounding variables between groups. This serves to modify the estimation of treatment effects of Shuxuetong injection on ALT index making the results more reliable. CONCLUSION: Based on large scale clinical observational data from HIS database, significant effects of Shuxuetong injection on abnormal changes in ALT have not been found. PMID- 24471328 TI - [Impact analysis of parenterally administered shuxuetong on abnormal changes of BUN index based on hospital information system data]. AB - OBJECTIVE: To estimate real world treatment effects of parenterally administered Shuxuetong on abnormal changes in blood urea nitrogen (BUN) index, inorder to to explore whether parenterally administered Shuxuetong affects kidney function and to provide clinical guidance for its safe application. METHOD: Analyze hospital information system (HIS) data and laboratory information management system (LIS) data from 18 nationawide general hospitals in China. A retrospective cohort study with two cohorts of patients, assessing abnormal changes of BUN index as an outcome, confounding factors are balanced through use of generalized boosted models (GBM) and multiple logistic regression based on adjusted propensity score to estimate treatment effects of parenterally administered Shuxuetong on abnormal changes of BUN index and to explore possible influencing factors. RESULT: Logistic regression based on adjusted propensity score results showed that there was a statistically significant difference (P < 0.05), in abnormal BUN in rates between the two groups. However, the GBM propensity score method showed that abnormal BUN rates were not statistically significantly different between the two groups. CONCLUSIONS: Based on large sample clinical observational data from HIS and LIS database, significant effects of parenterally administered Shuxuetong on abnormal changes of BUN have not been found. The generalized boosted models (GBM) method is more suitable for retrospective non-randomized observational data. These results should be confirmed through largescale prospective randomized controlled trials. PMID- 24471329 TI - [Propensity score analysis of liver and kidney function changes when shenmai is parenterally administered over extended period]. AB - Since parenterally administered Shenmai directly enters the bloodstream, avoiding gastrointestinal absorption, there are concerns as to its toxicity on the liver and kidneys. Previously, the risk of toxicity to the liver and kidneys through overdose has been discussed. This paper investigates changes in liver and kidney functions as indicated by ALT, AST, Cr and Bun, obtained from hospital information system (HIS) data, when it is administered over a longer than the recommended period of 14 days. Methods applied include: column joint analysis, logistic regression, propensity score and propensity score weighting. Results indicate that a longer course of administration does not have a significant effect on the function of liver and kidneys. However, continued monitoring of the toxicity to the liver and kidneys is a long-term and important issue; further exploration through toxicology experiments and prospective clinical research is required. PMID- 24471330 TI - [Based on hospital information system data, analysis of effects of different doses of shenmai injection on renal function]. AB - OBJECTIVE: To assess whether the dosage of Shenmai injection influences renal function. METHOD: Analysis of hospital information system (HIS) data from 18 national hospitals using Shenmai injections. Patients were aged between 18 to 80 years old. Blood analysis of creatinine and serum urea nitrogen was undertaken 7 days before and after exceeding the maximum recommended dose of 100 mL of Shenmai injection. Propensity score method was used to compare the differences between the two groups of renal function scores. RESULT: The differences in abnormal changes in creatinine and serum urea nitrogen levels between the groups before and after exceeding the recommended dose was not statistically significant, but abnormal changes were detected. CONCLUSION: Based on the available data we did not find that exceeding the recommended dose of Shenmai injection had a significantly deleterious effect on renal function. However, caution should be applied in its clinical use. PMID- 24471331 TI - [Real-world study of effect on liver function of parenterally administered shuxuetong with different doses]. AB - OBJECTIVE: To analyze the effect on liver function of parenterally administered Shuxuetong Injection with different doses. METHOD: The study is based on hospital information system (HIS) data. We group the cases by dose: The observation group receive a dose > 6 mL (recommended daily dose), the matched group receive the recommended dose. Chi-square test, logistic regression, logistic regression with propensity score, logistic regression with GBM propensity score were used to find the between group differences in ALT and AST after using parentyerally administered Shuxuetong injection. RESULT: All tests show that there were no significant differences between groups in AST or ALT after we control for confounding factors. CONCLUSION: Based on HIS data, there was no evidence to associate the use of Shuxuetong over the recommended dose and effects on liver function. PMID- 24471332 TI - [Outcome research of shuxuening injection different dosage impact on patient's liver function]. AB - The safety of parenterally administered Chinese medicine has caught the attention of clinicians, patients and drug administration departments. However, there are few studies that have assessed liver function damage from these medications. This study retrospectively analyzed hospital information system (HIS) data, from 20 nationwide general hospitals, of patients who were treated with parenterally administered Shuxuening. Patients that were given doses of 21-50 mL, which is above the recommended dose, acted as the observation group. Those receiving the recommended dose of < 20 mL were the control group. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were measured before and after parenteral administration of Shuxuening, changes after treatment were outcomes. Also recorded were: age, costs, length of hospitalization and the patients' condition on admission. Propensity score method was used to balance 71 confounding variables such as gender, age, mortality, and costs. The influence of dosage of ALT and AST can then be known. Analysis of the impact of parenterally administered Shuxuening on ALT, before logistic regression based on adjusted propensity score, then the P value is 0.007. However, after logistic regression based on adjusted propensity score method the P value became 0. 254. Hence, no differences were found between the two groups; using parenterally administered Shuxuening at the higher dose of 21 to 50 mL had no significant effects on ALT compared with the normal dose. Similarly analysis of AST changes before and after logistic regression based on adjusted propensity score method, P value changes from 0.192 to 0.568. There were no differences between the two groups using parenterally administered Shuxuening; a dosage of 21 to 50 mL each time had no significant effects on AST. Nevertheless, this study is a retrospective analysis, whilst known confounding factors have been taken into account there may be unknown ones to include inanalysis. Logistic regression based on adjusted propensity score method can control known confounding factors very well. This research serves as an aid to the safe clinical use of parenterally administered Shuxuening. PMID- 24471333 TI - [Data analysis of real world clinical changes in indexes of liver and kidney function to use of parenterally administered kudiezi at different doses and time periods]. AB - This is a retrospective study based on a 18 hospital information system data warehouse. Records of 1 982 patients who used Kudiezi intravenous infusion (KDZ) were extracted from the data warehouse. All the patients were divided into two groups, one group of 1 707 patients used KDZ, < or = 14 days under the instruction, the other group of 275 patients used KDZ, > 14 days, off label use. Generalized boosted models (GBM) with propensity score were applied to compare the two groups on four indexes of liver and kidney functions, such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), creatinine (Cr) and blood urea nitrogen (BUN). Seventy one confounders were identified and balanced by GBM. And another two logistic analysis methods were used to confirm the results from GBM. The results indicated that there were no significant difference on the four indexes except the AST (P < 0. 05) by all the three analyzing models. It is hard to conclude that ultra long, off label using Kudiezi intravenous infusion could influence the four indexed of liver and kidney from this data analysis. More conclusive evidence should be collected by further prospective study. PMID- 24471334 TI - [Real world study of affect on liver function of overdose of salvianolate extract injection]. AB - OBJECTIVE: To understand the affect on liver function of using salvianolate injection above the recommended dose. METHOD: Nationwide, research of hospital information system (HIS) data from 18 general hospitals comprising 14 191 patients was carried out. Two groups of patients were studied and their blood tests monitored before and after injections. One group received the recommended dose of 200 mg, the other exceeded it. To take into account group differences the propensity score method and logstic regression was used alongside liver function. RESULT: When salvianolate injection was administered above the recommended dose patients were more likely to have abnormal AST and ALT levels. However, the difference between the groups was not statistically significant. CONCLUSION: According to our data the affect of exceeding the recommended dose of salvianolate injection on liver function is not significant. However, monitoring of liver function should be carried out in clinic. PMID- 24471335 TI - [Outcome study on parenterally administered shenfu in treatment of coronary heart disease]. AB - OBJECTIVE: To understand the clinical circumstances for the use of parenterally administered Shenfu in the treatment of coronary heart disease, in order to provide a reference guide for its clinical use. METHOD: Information was extracted and summarized on the treatment of coronary heart disease patients, who received parenterally administered Shenfu, from 20 nationwide general hospitals HIS data. Descriptive statistical methods were used to analyze the usage and dosage. Correlation analysis was adopted to analyze information including drug combinations, and outcomes were compared with other combinations. RESULT: Real world HIS data showed that the drug delivery method for parenterally administered Shenfu was intravenous infusion. Treatment courses were from 3 to7 days, at a dosage of 60 mL. The drug combination was mostly with chemical drugs. The most common combinations were Shenfu plus clopidogrel, aspirin and isosorbide dinitrate. CONCLUSION: Parenterally administered Shenfu is a common drug used in the treatment of coronary heart disease. Most of the usage was in accordance with instructions. The chemical combination drugs were mainly clopidogrel, aspirin and isosorbide dinitrate. PMID- 24471336 TI - [Literature review and hospital information system data real world clinical outcome analysis of role of parenterally administered shenmai in treatment of shock]. AB - Parenterally administered Shenmai has the functions of benefiting vital energy, nourishing Yin, generating body fluids, and activating the pulse. Modern pharmacological studies have shown that constituents of parenterally administered Shenmai such as ginsenosides and ophiopogonin can improve hypoxia tolerance, immunity, function, and microcirculation of the heart, and free radical scavenging. Therefore, parenterally administered Shenmai is a suitable treatment for shock. Literature review and analysis of HIS data outcomes, are the two methods used to study the type of shock treated, dose and combinations of other medications used with parenterally administered Shenmai. The results of the two methods are consistent in understanding the clinical features of shock therapy with parenterally administered Shenmai which thereby provides information for the design of prospective studies. However, the results of the two methods are limited by the poor quality of the literature and the low level of evidence for clinical evaluation after the registration of Shenmai. Nevertheless, HIS data provides retrospective data although some information is missing. Thus, although the results of the two methods can be used as the foundation to support the clinical evaluation of post-marketing parenterally administered Shenmai, final conclusions can only be drawn based on prospective studies. PMID- 24471337 TI - [Retrospective real world study to explore use of parenterally administered kudiezi in combination with other medications based on hospital information study data]. AB - OBJECTIVE: Parenterally administered Kudiezi (KDZ) is used in real world clinical situations to treat coronary heart disease and cerebral infarction. This paper analyzes its clinical use with other drug combinations. Clinicians' experiences of using such treatments are also referred to. METHOD: Hospital information system (HIS) data from 18 hospitals, comprising records of 6 032 patients with Coronary heart disease and 3 468 patients with cerebral infarction were analyzed. RESULT: Comparison and analysis between varying courses of KDZ plus different drug combinations was carried out. The mean single dose of KDZ, death rate and improvement rates along with drug combinations were ascertained with various illustrations given. CONCLUSION: Although data showed some clinical correlations between factors analyzed, strong causal relationships are yet to be found. Hence, there is a need for further exploration and analysis. PMID- 24471338 TI - [Clinical outcomes of parenterally administered shuxuetong--analysis of hospital information system data]. AB - OBJECTIVE: Hospital information system data of cerebral infaction patients who received parenterally administered Shuxuetong was analyzed. This provided frequency data regarding patients' conditions and related information in order to provide a clinical reference guide. METHOD: In this study, HIS data from 18 hospitals was analyzed. Patients receiving parenterally administered Shuxuetong for the treatment of cerebral infarction were included. Information on age, gender, costsand route of administration were collated. RESULT: The average age of patients was 66 years old. Days of hospitalization ranged from 15 to 28 days. The majority of patients were classified as having phlegm and blood stasis syndrome, which is inaccordance with the indications for this drug. The most commonly used drugs used in combination with parenterally administered Shuxuetong were: aspirin, insulin and heparin. CONCLUSION: Patients with cerebral infarction crowd using parenterally administered Shuxuetong were a mostly elderly population, with an average age of 66. Although generally use was in accordance with indications, dosage, and route of administration, there were however some discrepancies. Therefore, doctors need to pay close attention to guidelines and closely observe patients when using parenterally administered Shuxuetong and to consider both the clinical benefits and risks. PMID- 24471339 TI - [Explore dengzhan xixin injection effecting on outcome of coronary heart disease based on propensity score]. AB - Records of 2 325 patients with CHD were extracted from 20 hostpial information systems, who were divided into two groups, one group has 768 patients using Dengzhan Xixin, the other group has 1 557 patients without using Dengzhan Xixin. Using generalized boosted models (GBM) with propensity scores to balance confounding factors and using three Logistic regressions to analysis the cure rates of coronary heart disease. The results is that 72 knowing confounding factors between two groups, such as: age, admission condition, dying days, regression coefficients of three Logistic regressions were negative (P < 0.05), statistically, the result of using Dengzhan Xixin injection to cure coronary heart disease is significantly higher than do not using Dengzhan Xixin injection. Propensity score could be a good method to balance confounding factors in a retrospective data analysis. However it is not a prospective research, the information from this study should be carefully referred to. PMID- 24471340 TI - [Effects of parenterally administered shenqi fuzheng on patient outcomes with tumor using propensity score]. AB - OBJECTIVE: Use propensity score methods to explore the effect of parenterally administered Shenqi Fuzheng on clinical outcome of patients with tumor. METHOD: HIS data from 20 hospitals was analyzed. Patients suffering from malignant tumor, ranging from 18 to 80 years, Were divided into the treatment group and control group. The treatment group was given parenterally administered Shenqi Fuzheng, the control group received other parenterally administered anti-cancer medicines. Various levels of controls for confounding factors were applied, including chi square test, Fisher exact test, stratified analysis, logistic regression, and logistic regression based on adjusted propensity score, to assess parenterally administered Shenqi Fuzheng's clinical effects. RESULT: Stratified analysis showed that among elderly patients whose condition was classified as either 'urgent' or 'dangerous'. Comparing these two sub-groups it was found that the test P < 0.05. The treatment group had a significantly lower mortality rate than the control group. After adjusting for 72 confounding factors, the statistical results also show that the mortality rate overall in the treatment group was significantly lower than in the control group. CONCLUSION: Analysis of HIS data showed that parenterally administered Shenqi Fuzheng can reduce mortality due to malignant cancer when compared to other available treatments. PMID- 24471341 TI - [Real-world study in analysis of effects on concomitant medications with parenterally administered shenmai for coronary heart disease]. AB - In order to understand the treatment of coronary heart disease with parenterally administered Shenmai and the efficacy of combination therapies, the study selected 18 hospitals for analysis. Data from each hospital's hospital injection system (HIS) was collected. Data of in-patients receiving parenterally administered Shenmai for a diagnosis of coronary heart disease was analyzed using; the Apriori algorithm to model use, Clementine 12.0 linkage analysis to find correlations between various drugs, and chi-square test for commonly used combination therapies to ascertain the cure rate. In 5 583 patients with coronary heart disease, it was found that Shenmai was commonly used with isosorbide mononitrate, aspirin, clopidogrel hydrogen and common combinations of combination therapy, and that the cure rate was better in these combinations than for other treatment regimes. When Shenmai is used with combination therapies for coronary heart disease, treatment guidelines should be complied with. In clinical application, the types of concomitant medications and their interactions, should be observed so as to prevent of adverse reactions. PMID- 24471342 TI - [Treatment outcomes of parenterally administered dengzhan xixin for treatment of cerebral infaction based on real world hospital injection system data]. AB - Cerebral infarction is one of the indications for parenterally administered Dengzhan Xixin. This study aims to analyze treatment outcomes in patients with cerebral infarction of parenterally administered Dengzhan Xixin, in the real world. Data from 20 national hospitals' hospital injection system (HIS) databases were collected. 1 008 cases of parenterally administered Dengzhan Xixin for the treatment of cerebral infarction were compared with 1 504 cases who did not receive Dengzhan Xixin who acted as the control group. Outcome was defined by mortality or survival following cerebral infarction. It was found that, before controlling for confounding factors, parenterally administered Dengzhan Xixin did not have a significant effect on mortality, P = 0.098 3. Stratified analysis taking into account, age, gender, condition on admission,dosage, and length of treatment found that parenterally administered Dengzhan Xixin had significant effects on cerebral infarction mortality when dosage and length of treatment course were stratification factors; P values were 0.029 3 and 0.030 9 respectively. When applying classic logistic regression to the analysis there was no difference between the observation group and control group, P = 0.106. Generalized boosted models (GBM) and propensity score (PS) weighted Logistic regression, was then applied to balance 72 variables such as age and gender, this found that there were significant differences between the observation and control groups, P < 0.001. This study concludes that parenterally administered Dengzhan Xixin can reduce the mortality of cerebral infarction patients based on existing data. However,there are many known and unknown confounders in retrospectively analysis, and the propensity score can only control for known confounding factors. Therefore, these findings should be considered as a reference for treating cerebral infarction. PMID- 24471343 TI - [Analysis of pragmatic clinical use of shuxuening injection]. AB - OBJECTIVE: Undertake analysis of the pragmatic use of Shuxuening injection, in order to understand the drug's characteristics and risks. This will provide the basis for a deeper understanding for risk management. METHOD: Twenty general hospitals using Shuxuening injections were selected nationwide. Data analysis of their hospital information systems (HIS), comprising 48 445 inpatients of which 13 936 had received Shuxuening injections, took place. Analysis of patient demographics, drug use, drug combinations and patient deaths was carried out. RESULT: More than 79% of patients were over 45 years old. Clinical use of the injection was for the treatment of cerebral infarction (equivalent to the Chinese medicine category of zhongfeng), coronary heart disease (equivalent to the Chinese medicine category of xiongbi), diabetes and hypertension. However, only 37.66% of Western medicine diagnoses are in accordance with recommendations and only 49.09% of Chinese medicine diagnoses follow the guidelines. The injection is administered intravenously, with most patients receiving a dosage of 15-20 mL per dose for between 3 and 7 days. It is always combined with aspirin in clinical practice. CONCLUSION: Shuxuening injection is primarily used for older patients. Several clinical risk factors have been identified including administering the wrong dose for inappropriate conditions and failure to follow guidelines. Appropriate risk management is required to protect patients. PMID- 24471344 TI - [Clinical outcomes research on parenterally administered kudiezi in treatment of cerebral infarction]. AB - OBJECTIVE: To investigate the curative effect of Kudiezi Injection in the treatment of cerebral infarction. METHOD: Hospital information system (HIS) data from 18 national, general hospitals were used to compare patients with and without the use of parenterally administered Kudiezi injection in treating cerebral infarction. To balance confounding factors between the two groups propensity score method was used; effectiveness evaluation of parenterally administered Kudiezi in treatment of cerebral infarction was carried out using Logistic regression method. RESULT: There was a statistically significant difference (P < 0.05) between positive curative outcomes in those receiving conventional therapy plus Kudiezi injection compared to those using other parenterally received medications on cerebral infarction. CONCLUSION: According to the current data conventional therapy combined with parenterally administered Kudiezi has a better outcome to cure cerebral infarction than other parenterally administered medications. This data provides a reference for clinical medication. However, the exact conclusions still need further verification. PMID- 24471345 TI - [Analysis of actual effects of combining xiyanping injection with vitamin C injection in treatment of upper respiratory tract infection]. AB - OBJECTIVE: To investigate whether Xiyanping injection associated with vitamin C injection will improve the cure rate of upper respiratory tract infection compared to treatment with Xiyanping injection alone. METHOD: The analysis was based on hospital information system (HIS) data. Patients were divided into two groups according to whether he or she accepted the addition of vitamin C to treatment with Xiyanping injection. We used the propensity score to balance confounding factors, and made confounding factors which cannot be balanced by the propensity score to act as covariate variables. Then Logistic regression was used to evaluate the effectiveness of the two groups. RESULT: There was no significant difference between the 2 groups. CONCLUSION: Compared with Xiyanping injection alone, using vitamin C in combination does not improve the treatment effectiveness of upper respiratory tract infection. PMID- 24471346 TI - [Exploration of clinical outcomes on coronary heart disease of parenterally administered dengzhan xixin using propensity score]. AB - Parenterally administered Dengzhan Xixin is a common parenterally administered Chinese medicine for the treatment of coronary heart disease. The present research explored the application of parenterally administered Dengzhan Xixin on the clinical outcome of coronary disease. Hospital information system (HIS) data from 18 national, general hospitals was collected. Patients given parenterally administered Dengzhan Xixin in addition to other medications were compared with those not receiving it. General boosted method (GBM) and propensity score weighting was used to control for confounding variables between the groups. Logistic regression, and concomitant variable logistic regression of propensity score weighting were used to analyze the balanced confounding variable. Results showed that there was a statistically significant difference between the groups in death rate. The combined application of parenterally administered Dengzhan Xixin can lower the death rate from coronary disease. However, there are still a large amount of unknown confounding variable to take into account and the present research is a retrospective study. Therefore, prospective studies are warranted. PMID- 24471347 TI - [Use propensity score method to analyze data about effectiveness of coronary heart disease treated by kudiezi injection]. AB - OBJECTIVE: Real world clinical research to evaluate the effect on coronary heart disease (CHD) of parenterally administered Kudiezi. METHOD: Eighteen nationwide general hospitals' hospital information systems (HIS) were searched for information on in patients treated with parenterally administered Kudiezi. Evaluation used generalized boosted models (GBM), and three types of logistic regression based on adjusted propensity score to balance confounding factors. RESULT: Two groups of coronary heart patients were compared, one group received parenterally administered Kudiezi and one did not. Seventy two confounding factors were identified and balanced by GBM. The three methods of logistic regression demonstrated that patients receiving parenterally administered Kudiezi had improved outcomes compared to those who did not receive the drug and this was statistically significant. CONCLUSION: Parenterally administered Kudiezi is a potential adjuvant therapy in the treatment of coronary heart disease. Logistic regression based on adjusted propensity score can balance confounding factors in retrospective data analysis. However it's limitation is that it is not applicable in prospective studies. PMID- 24471348 TI - [Based on propensity score methods analysis of outcomes of parenterally administered shuxuetong in treatment of cerebral infarction]. AB - Hospital information system (HIS) data from 18 hospitals was analyzed. 107 723 cases were divided into two groups, those that received Shuxuetong and those that did not. Patients, 18 to 80 years old, suffering from cerebral infarction, whose treatment outcome was clear were selected. Resulting in 7 520 cases in the treatment group and 3 353 who did not receive parenterally administered Shuxuetong. Using propensity score, confounding factors were balanced between the two groups, three logistic regression methods were used to compare the groups following treatment for cerebral infarction. The three methods of comparison indicated that the use of Shuxuetong significantly increased cure rates compared to the control group. Therefore, based on existing data, for the treatment of cerebral infarction, the outcomes are more effective when combination therapy including Shuxuetong is used. PMID- 24471349 TI - [Analysis of salvianolate injection combined with usual drugs in treatment of coronary heart disease in real world]. AB - OBJECTIVE: Based on real world research the circumstances of the clinical use of usual drugs combined with salvianolate injection are surveyed. METHOD: Descriptive statistics on the use of salvianolate injection in 18 general hospitals in China. RESULT: In 1 605 patients with coronary heart disease (CHD), salvianolate injection was most frequently (51%) combined with clopidogrel and isosorbide dinitrate. In addition this combination showed a higher clinical effectiveness as compared with other drug combinations. CONCLUSION: In the real world, salvianolate injection combined with usual treatment was found to be more effective than other treatment combinations. In addition practice conformed to the clinical treatment of coronary heart disease (CHD) guidelines for drug use. However, liver and kidney function, routine blood tests and the blood's coagulation function require ongoing monitoring. PMID- 24471350 TI - [Adverse drug reactions case reports for parenterally administered shuxuening based on analysis of literature]. AB - Parenterally administered Shuxuening had made important contributions in the treatment of ischemic cardiovascular and cerebrovascular diseases since its use in 1995. Parenterally administered Shuxuening is widely used in clinical practice hence concern over its safety has gradually arisen. Based on published adverse drug reaction (ADR) case reports, this article analyzes cpatient characteristics and other data including: gender, age, history of allergies, primary disease, dose, treatment course, solvent, ADR occurrence and time scales. This will provide a clinical reference regarding ADRs to parenterally administered Shuxuening and influencing factors on their occurrence. Analysis showed that ADRs clinical symptoms include systemic damage, with damage to the skin, mucous membranes and respiratory system most common. ADRs occurred earliest after 1 minute of infusion, and after the 11th day at the latest. 70% cases of ADR occurred within 1 hour, therefore rapid occurrence is a primary clinical characteristic. The medication was largely used in accordance with the drug manual, and of the association of ADRs with allergies or different drug combination was not high. The occurrence of ADRs may not be entirely associated with the drug but the solvent used in its manufacture may be an important factor. PMID- 24471351 TI - [Literature review of application of shenmai injection in special populations (children)]. AB - OBJECTIVE: Analyze the characteristic features of Shenmai injections as used in pediatric clinics, to improve the specifications for use in children in order to decrease risks. METHOD: We preformed statistical analyses on data from the CNKI and VIP databases relevant to the clinical application of Shenmai injections in children. Pediatric indications, usage and dosage, length of treatment, solubility of the drugs in mediums and adverse reactions were summarized. RESULT: Shenmai injection is widely used in clinical pediatrics, and is reported to show effectivenss for conditions such as viral myocarditis, pneumonia, neonatal hypoxic ischemic encephalopathy, neonatal scleroderma, diarrhea and other diseases. However, there are no specific specifications regarding usage and dosages, length of treatments, or instructions regarding solvents. Adverse reactions reported include, drug rash, heat, blushing, and chest tightness amongst others. CONCLUSION: Effective measures should be adopted to standardize the clinical regulations regarding Shenmai injections for use in children, to reduce risks, and thereby raise clinical treatment standards. PMID- 24471352 TI - [Parenterally administered shenqi fuzheng for heart failure: a systematic review and meta-analysis]. AB - OBJECTIVE: To assess the efficacy and safety of parenterally administered Shenqi Fuzheng for heart failure. METHOD: We searched for all clinical studies, up to February 2013, of parenterally administered Shenqi Fuzheng in the Cochrane library, Medline, EMbase, CBM, CNKI, VIP and Wanfang. Quality assessment and information extraction was completed and screened by two independent reviewers. The quality of the included studies was evaluated according to the Cochrane collaboration's tool for assessing risk of bias and allocation concealment. Revman 5. 2. 4 software was used for data analysis. RESULT: A total of 21 randomized controlled trials were included in this systematic review, all of them were of low quality. Meta-analysis showed that the group receiving parenterally administered Shenqi Fuzheng in addition to conventional treatment had better therapeutic effectiveness rates than the conventional treatment group [OR = 3.91, 95% Cl (2.63, 5.83)], with enhanced LVEF [MD = 0.08, 95% Cl (0.05, 0.12)], SV [MD = 9.42, 95% Cl (6.61, 12.22)], CI [MD = 0.60, 95% Cl (0.46,0.73)], CO [MD = 0.98, 95% Cl (0.61, 1.36)], reduced BNP [MD = -139.05, 95% Cl (-211.08, - 67.02)]. The ADR/ADE information of parenterally administered Shenqi Fuzheng in all studies showed that the symptoms of ADR/ADE were mild. CONCLUSION: Conclusions from this review may have a high risk of bias due to the low quality of thestudies. Hence, reliable conclusions cannot be drawn about the efficacy of parenterally administered Shenqi Fuzheng in the treatment of heart failure. More trials of high quality are required. PMID- 24471353 TI - [Systematic review of shenfu injection for septic shock]. AB - To assess the efficacy and safety of Shenfu injection for septic shock. All clinical studies of Shenfu injection for septic shock were searched from Cochrane library, Medline, EMbase, CBM, CNKI, Wanfang and VIP. Quality assessment and information extraction were done by two independent screening. The quality of the included documents was evaluated by the Cochrane Collaboration's tool for assessing risk of bias and allocation concealment. Revman 5. 1. 4 software was used for data analysis. A total of 6 randomized controlled trials were included (499 patients), in which, 6 studies did not mention allocation concealment, blind and loss-up information. Meta-analysis showed that the Shenfu injection group was better than the conventional treatment group in SBP (OR = 9.00, 95% Cl [3.89, 14.11]; OR = 20.28, 95% Cl [16.46, 24.10], respectively) and DBP (OR = 11.25, 95% Cl [7.65, 14.85]; OR = 8.17, 95% Cl [5.21, 11.13], respectively); in improving shock symptom (OR = 4.60, 95% Cl [1.88, 11.28]; OR = 0.88, 95% Cl [0.16, 4.87]; OR = 1.02, 95% Cl [0.27, 3.93]; OR = 1.65, 95% Cl [0.42, 6.42]) and reducing HR (OR = -29.71, 95% Cl [-40.51, -18.91]; OR = -18.00, 95% Cl [-27.16, -8.84]), (OR = 8.00, 95% Cl [1.96, 14.04]), there was inconsistency between the two groups; the Shenfu injection group showed no advantage in MAP (OR = -0.10, 95% Cl [-2.34, 2.14]) and CI (OR = 0.00, 95% Cl [- 1.24, 1.24]). ADR/AE information of Shenfu injection was not fully reported. This study may exist publication bias. Shenfu injection on the basis of conventional treatment can improve blood pressure of the treatment of septic shock; we can not get a positive conclusion in improving shock symptom and HR. Also, due to the sample size of included studies were small and of lower quality, conclusions above still need high-qualitied randomized, double-blind, controlled trials be confirmed. PMID- 24471355 TI - Alcohol involvement and other risky driver behaviors: effects on crash initiation and crash severity. AB - OBJECTIVE: Alcohol-involved drivers or those with blood alcohol concentrations greater than 0.00 percent have more frequent and more severe crashes than other drivers. Alcohol use, because it delays perception and response and impairs coordination, increases the risk of a crash. However, those using alcohol may take additional driving risks, which may also lead to crashes. This study was done to learn whether risks besides alcohol involvement contributed to crash initiation and whether crash severity increased with alcohol involvement or with those other risky behaviors. METHODS: Data that represented nearly 1.4 million motor vehicle crashes were accessed from an NHTSA database. Analyses evaluated whether alcohol-involved driving was associated with other driving risks and whether driver alcohol involvement, alone or together with other risks, increased the likelihood of initiating a 2-vehicle crash or in the event of a crash or increased crash severity. RESULTS: Alcohol-involved drivers were less likely to use seat belts, drove faster, and were more likely to be distracted than others. Those who initiated 2-vehicle crashes were more likely to be alcohol involved or to have taken other driving risks than others from the same crashes. Crash severity was significantly greater for alcohol-involved drivers than for other drivers, but severity increased further if additional risks were taken. Crashes involving only drivers who had not used alcohol were also sometimes severe, and that severity was associated with risky driving behaviors. When crashes involved 2 drivers, the behaviors of both affected crash severity. CONCLUSIONS: Risky driving behaviors, including alcohol involvement, increased the risk of a crash. Crash severity tended to increase with any risky behavior and to increase further with multiple risky behaviors. Other risky behaviors were associated with both alcohol involvement and crashes. Therefore, if effects from those other risky behaviors were not accommodated for, those effects would confound apparent associations between alcohol involvement and crashes. Therefore, this study's use of multivariate models that accommodated for effects from those other behaviors provided a truer picture of alcohol's association with crashes than simpler models would have. Supplemental materials are available for this article. Go to the publisher's online edition of Traffic Injury Prevention to view the supplemental file. PMID- 24471354 TI - [Systematic review of xiyanping injection for hand foot mouth disease]. AB - To assess the efficacy and safety of Xiyanping injection for hand foot mouth disease. All Clinical studies of Xiyanping injection for hand foot mouth disease were searched from Cochrane library, Medline, EMbase, CBM, CNKI, Wanfang and VIP. Selection of trials for inclusion, data extraction, assessment of methodological quality were completed by two independent screening. The quality of the included documents was evaluated by the Cochrane collaboration's tool for assessing risk of bias and allocation concealment. Revman 5. 1 software was used for data analysis. Twenty-four randomized controlled trials were included (involving 2 974 patients), in which, only one study was true RCT and two studies used incorrect methodology. The remaining studies did not provide allocation concealment, blind or loss-up information. The results of Meta-analysis were presented below. Compared with conventional treatment measures, the efficiency of Xinyanping injection group was better (OR = 4.26, 95% Cl [3.19, 5.69]). Both fever clearance time (WMD = - 1.48, 95% Cl [- 1.85, - 1.11]) and skin eruption eliminating time (WMD = - 1.78, 95% Cl [- 2.84, - 0.72]) of Xinyanping injection group were shorter than the control group. Researches with ADR/AE information of Xinyanping injection showed that the symptoms of ADR/AE were slight. The systematic review suggests that Xiyanping injection in the combination with conventional treatment may improve the efficacy of the treatment of hand foot mouth disease. However, as all of the included trials were published in Chinese and of poor quality, we cannot draw a sure conclusion. More rigorous trials with high quality are required. PMID- 24471356 TI - Alcohol ignition interlocks in all new vehicles: a broader perspective. AB - OBJECTIVE: To discuss the implications of widespread implementation of alcohol ignition interlocks. METHOD: We base our discussion on data from Finland including crash statistics and surveys collected from criminal justice professionals and general driving population. RESULTS: Alcohol ignition interlocks are an effective preventive measure against drunk driving when installed in the vehicles of convicted drunk drivers. However, once they are removed from the vehicles, drivers typically return to their habit of drinking and driving. Furthermore, for a number of reasons, the proportion of convicted drunk drivers that install an interlock in their vehicles is quite small. Therefore, many stakeholders believe that the solution to the drunk driving problem will come when interlocks become standard equipment in all new vehicles. However, drunk driving is a complex sociopsychological problem, and technology can rarely offer a solution to such complex problems. Consequently, many aspects of such interventions might be difficult to identify and include in cost-benefit analysis. CONCLUSION: We express caution about requiring an interlock as standard equipment in all new vehicles. PMID- 24471357 TI - Graduated driver licensing provisions: an analysis of state policies and what works. AB - OBJECTIVE: To compare and contrast how specific graduated driver licensing (GDL) components have been implemented in different states and explore how the policies currently in place have affected state-level teen crash and mortality outcomes. METHODS: The study design involved a policy analysis using methodology set forth by Teitelbaum and Wilensky (2007). Eight states were selected, 2 each from 4 different regions in the United States. Each pair of states was similar in terms of geography and vehicle miles driven per capita but differed in the relative strength of their GDL legislation. Teen fatality and crash rates in 2010 as well as specific GDL components were the variables used for analysis. A weighted decision matrix was created to reflect the comparative impact of each variable. RESULTS: In every region, the state with the stronger GDL policy scored higher on the decision matrix than the state with the weaker GDL policy. The Eastern states (Maryland and Vermont) scored the best overall (123.9); the Southern states (Mississippi and Georgia) scored the poorest overall (-55.7). CONCLUSIONS: Consistent with other GDL research, states with stronger GDL policies had more favorable teen crash and mortality outcomes than states with weaker ones. Analysis showed that the policies in strong states shared several common themes: more required practice hours, ban on all teen passengers, and night driving restrictions for 12+ months. Implications for state policy makers are provided. PMID- 24471358 TI - Distress tolerance as a predictor of risky and aggressive driving. AB - OBJECTIVE: The purpose of this investigation was to determine the relationship between distress tolerance and risky and aggressive driving. Distress tolerance, defined as an individual's capability to experience and endure negative emotional states, was hypothesized to be related negatively to aggressive driving and risky driving. METHODS: An anonymous, web-based survey of 769 college students was conducted at a large East Coast university. RESULTS: After controlling for age, gender, race, ethnicity, year in school, grade point average, and driving frequency, distress tolerance was significantly inversely related to reported risky driving and aggressive driving. CONCLUSION: College drivers who have a diminished capacity to endure frustration without experiencing negative emotional states (i.e., low distress tolerance) tend to drive aggressively and in a risky manner. Traditional deterrence-based approaches to highway safety may benefit from inclusion of a wider array of prevention strategies that focus on emotion regulation while driving. PMID- 24471359 TI - Risk factors for subsequent impaired driving by injured passengers. AB - OBJECTIVES: The purpose of this study was to evaluate the rate of, and risk factors for, subsequent impaired driving activity (IDA) in a cohort of injured passengers who were treated for injuries in a Canadian trauma center. METHODS: We studied adult passengers who were occupants in vehicles involved in motor vehicle crashes (MVCs) and either included in the British Columbia (BC) trauma registry (January 1, 1992-December 31, 2004) or treated in the emergency department (ED) of Vancouver General Hospital (VGH; January 1, 1999-December 31, 2003). Passengers were linked to their driver's license and hence to their driving record using personal health number and demographic information. Injured passengers were stratified into 3 groups based on their blood alcohol concentration (BAC) at time of ED presentation: group 1: BAC = 0, group 2: 0 < BAC <= 17.3 mM (0.08%), group 3: BAC > 17.3 mM (0.08%). Two outcome variables were studied: involvement in a subsequent IDA and time to their first subsequent IDA. IDA was defined as a criminal code conviction for impaired driving, a 24-h or 90-day license suspension for impaired driving, and/or involvement in an MVC where police cited alcohol as a factor. Time to first IDA following the index event among passenger BAC groups was compared with Kaplan-Meier survival analysis. Cox proportional hazards models were employed to examine the effect of various potential risk factors on time to engage in first IDA. RESULTS: Injured passengers with any BAC at the time of ED visit were more likely to engage in IDA and had their first IDA sooner after the index event than those with zero BAC. Among this cohort of injured passengers, 12.1 percent with BAC = 0, 29.9 percent with 0 < BAC <= 17.3 mM (0.08%), and 37.8 percent with a BAC > 17.3 mM (0.08%) engaged in IDA. Compared to passengers with BAC = 0, group 3 passengers and group 2 passengers were 2.06 times and 1.79 times more likely to engage in future IDA. Twenty-five percent of injured passengers engaged their first IDA by 57 and 38 months in groups 2 and 3, respectively. Previous IDA and being male were also significant risk factors for future IDA. Those with a history of IDA before the index event were 2.37 times more likely to engage in subsequent IDA. CONCLUSIONS: Injured alcohol-impaired passengers are at high risk for IDA and should be included in impaired driving prevention programs. PMID- 24471360 TI - Ethylglucuronide in hair is a top predictor of impaired driving recidivism, alcohol dependence, and a key marker of the highest BAC interlock tests. AB - OBJECTIVES: This study focuses on the predictive and comparative significance of ethyl glucuronide measured in head hair (hEtG) for estimating risks associated with alcohol-impaired driving offenders. Earlier work compared different alcohol biomarkers for estimating rates of failed blood alcohol concentration (BAC) tests logged during 8 months of interlock participation. These analyses evaluate the comparative performance of several alcohol markers including hEtG and other markers, past driver records, and psychometric assessment predictors for the detection of 4 criteria: new driving under the influence (DUI) recidivism, alcohol dependence, and interlock record variables including fail rates and maximal interlock BACs logged. METHODS: Drivers charged with alcohol impairment (DUI) in Alberta, Canada (n = 534; 64% first offenders, 36% multiple offenders) installed ignition interlock devices and consented to participate in research to evaluate blood-, hair-, and urine-derived alcohol biomarkers; sit for interviews; take psychometric assessments; and permit analyses of driving records and interlock log files. Subject variables included demographics, alcohol dependence at program entry, preprogram prior DUI convictions, postenrollment new DUI convictions, self-reported drinking assessments, morning and overall rates of failed interlock BAC tests, and maximal interlock BAC readings. Recidivism, dependence, high BAC, and combined fail rates were set as criteria; other variables were set as predictors. Area under the receiver operating characteristics (ROC) curve (A') estimates of sensitivity and specificity were calculated. Additional analyses were conducted on baseline hEtG levels. Driver performance and drinking indicators were evaluated against the standard hEtG cutoff for excessive drinking at (30 pg/mg) and a higher criterion of 50 pg/mg. HEtG splits were evaluated with the Mann-Whitney rank statistic. RESULTS: HEtG emerged as a top overall predictor for discriminating new recidivism events that occur after interlock installation, for entry alcohol dependence, and for the highest interlock BACs recorded. Together, hEtG and phosphatidylethanol (PEth) were the top predictors of all criterion measures. By contrast, the hair-derived alcohol biomarkers hEtG and hFAEE (fatty acid ethyl esters) were poorer than other alcohol biomarkers as detectors of interlock BAC test fail rates. CONCLUSIONS: This study showed that hEtG, an objective alternative to often unreliable self-reported past representation of drinking levels, yields crucial insight into driver alcohol-related risks early in an interlock program and is a top predictor of new recidivist events. Together with PEth, these markers would be excellent anchors in a panel for detecting alcohol consumption. PMID- 24471361 TI - Long-term medical consequences for child occupants 0 to 12 years injured in car crashes. AB - OBJECTIVE: There is limited knowledge of the long-term medical consequences for children injured in car crashes. Thus, in the event of injury, the aim of the study was to specify patterns and risks of injuries resulting in permanent medical impairment of children (0-12 years) for different body regions and injury severity levels, according to Abbreviated Injury Scale (AIS). The aim was also to compare the impairment outcome with adults. METHODS: Data were obtained from the Folksam insurance company, including reported car crashes from 1998 to 2010 with at least one injured child 0-12 years of age. In all, 2619 injured children with 3704 reported medical diagnoses were identified. All injuries were classified according to the AIS 2005 revision. If the child had not recovered within 1 year postinjury an assessment of permanent medical impairment (PMI) was made by one or several medical specialists. RESULTS: In all, 55 children sustained 59 injuries resulting in PMI of which 75 percent were at AIS 1 or AIS 2. The head and cervical spine were the body regions sustaining the most injuries resulting in PMI. Sixty-eight percent of all injuries resulting in PMI were AIS 1 injuries to the cervical spine, with the majority occurring in frontal or rear impacts. Given an injury to the cervical spine, the risk of injuries resulting in PMI was 3 percent, and older children (>=6 years) had a significantly higher risk (3% versus 1%) than younger children. The head was the second most commonly injured body region with injuries resulting in PMI (12/59), which were predominantly AIS 2+. In addition, mild traumatic brain injuries at AIS 1 were found to lead to PMI. Whereas for children the injuries leading to PMI were primarily limited to the head and cervical spine, adults sustained injuries that led to PMI from a more diverse distribution of body regions. CONCLUSION: The pattern of injuries resulting in permanent medical impairment is different for children and adults; therefore, safety priorities for children need to be based on child data. The majority of those injuries leading to PMI were at lower AIS levels. Furthermore, AIS 1 cervical spine and AIS 1+ head injuries should be given priority concerning mitigation of long-term consequences for children. PMID- 24471362 TI - A population-based study on road traffic injuries in Pune City, India. AB - OBJECTIVE: The annual mortality of road traffic injuries (RTIs) is estimated to be over 80,000 in India; however, there is not enough information about the magnitude, pattern, and factors associated with RTIs in a population-based scenario, where the police and hospital records suffer from severe underreporting. This study was conducted with the aim of identifying the burden, pattern, and risk factors of RTIs in the population of Pune City. METHOD: A population-based cross-sectional study was conducted among 9014 individuals in a randomly selected and representative sample of the population from 14 administrative wards of the city from March 2008 to April 2009. RESULTS: The annual incidence rate of RTIs was 93.2 (95% confidence interval [CI], 83.2-103.2) per 1000 individuals and after adjustment for age it was 76.4 per 1000 individuals. Injury occurrence was significantly more among the age group 15-30, males, and students and workers. Univariate analysis showed a significant association between RTIs and age, gender, occupation, mode of transport, driving a vehicle, and alcohol abuse. Multivariate analysis showed that only age, driving a vehicle, and alcohol abuse were the factors associated with RTIs. CONCLUSION: The magnitude of RTIs in India is very high, which is not reflected in police registration reports. PMID- 24471363 TI - Pediatric head and neck dynamics in frontal impact: analysis of important mechanical factors and proposed neck performance corridors for 6- and 10-year-old ATDs. AB - OBJECTIVE: Traumatic injuries are the leading cause of death of children aged 1 19 in the United States and are principally caused by motor vehicle collisions, with the head being the primary region injured. The neck, though not commonly injured, governs head kinematics and thus influences head injury. Vehicle improvements necessary to reduce these injuries are evaluated using anthropomorphic testing devices (ATDs). Current pediatric ATD head and neck properties were established by scaling adult properties using the size differences between adults and children. Due to the limitations of pediatric biomechanical research, computational models are the only available methods that combine all existing data to produce injury-relevant biofidelity specifications for ATDs. The purpose of this study is to provide the first frontal impact biofidelity corridors for neck flexion response of 6- and 10-year-olds using validated computational models, which are compared to the Hybrid III (HIII) ATD neck responses and the Mertz flexion corridors. METHODS: Our virtual 6- and 10 year-old head and neck multibody models incorporate pediatric biomechanical properties obtained from pediatric cadaveric and radiological studies, include the effect of passive and active musculature, and are validated with data including pediatric volunteer 3 g dynamic frontal impact responses. We simulate ATD pendulum tests-used to calibrate HIII neck bending stiffness-to compare the pediatric model and HIII ATD neck bending stiffness and to compare the model flexion bending responses with the Mertz scaled neck flexion corridors. Additionally, pediatric response corridors for pendulum calibration tests and high-speed (15 g) frontal impacts are estimated through uncertainty analyses on primary model variables, with response corridors calculated from the average +/- SD response over 650 simulations. RESULTS AND CONCLUSIONS: The models are less stiff in dynamic anterioposterior bending than the ATDs; the secant stiffness of the 6- and 10-year-old models is 53 and 67 percent less than that of the HIII ATDs. The ATDs exhibit nonlinear stiffening and the models demonstrate nonlinear softening. Consequently, the models do not remain within the Mertz scaled flexion bending corridors. The more compliant model necks suggest an increased potential for head impact via larger head excursions. The pediatric anterioposterior bending corridors developed in this study are extensible to any frontal loading condition through calculation and sensitivity analysis. The corridors presented in this study are the first based on pediatric cadaveric data and provide the basis for future, more biofidelic, designs of 6- and 10-year-old ATD necks. PMID- 24471364 TI - Lower leg injury in relation to vehicle front end. AB - OBJECTIVE: To set up a prescreening tool for vehicle front-end design, allowing numerically forecasting of the results of EC directive tests, with reference to pedestrian lower leg impact. METHODS: A numerical legform model has been developed and certified according to EC directive. The frontal end of the vehicle has been simulated through a lumped-parameters model, having considered the predesign stage when the target overall behavior is being established. The stiffness behaviors of the bumper and of the spoiler have been estimated by means of more detailed numerical models. A parametric analysis has been performed to outline the effects of bumper and spoiler stiffness, bumper vertical height, and the longitudinal distance between the spoiler and the bumper. An analytical model has been introduced to predict tibial acceleration, knee shear displacement, and knee lateral bending, given the bumper and spoiler characteristics as input. RESULTS: The parametric analysis has demonstrated that bumper stiffness, bumper profile height, and spoiler stiffness do have an impact on knee lateral bending, knee shear displacement, and peak tibial acceleration. Increasing bumper stiffness can result in higher knee bending, knee shear displacement, and peak tibial acceleration. Increasing bumper profile height produces lower knee bending and shear displacement. Increasing spoiler stiffness can determine higher knee shear displacement and peak tibial acceleration but lower knee bending. Spoiler stiffness and position have a strong correlation: higher bumper stiffness needs to be coupled to a moved forward spoiler position. The mechanical responses of the spoiler and of the bumper can be assumed to be linear: the softening behavior of the expanded polypropylene foam balances the hardening behavior of the fascia (due to contact area increase). The predictive model is well correlated to experimental findings (R (2) > 0.74). CONCLUSIONS: This simplified computer model can be used as a prescreening design tool to demonstrate general vehicle front end design trade-offs and provide approximate results without physical testing. PMID- 24471365 TI - Three-dimensional adult male head and skull contours. AB - OBJECTIVE: Traumatic brain injury (TBI) is a major public health issue, affecting millions of people annually. Anthropomorphic test devices (ATDs) and finite element models (FEMs) provide a means of understanding factors leading to TBI, potentially reducing the occurrence. Thus, there is a need to ensure that these tools accurately model humans. For example, the Hybrid III was not based on 3 dimensional human head shape data. The objective of this study is to produce average head and skull contours for an average U.S. male that can be used for ATDs and FEMs. METHODS: Computed tomography (CT) scans of adult male heads were obtained from a database provided by the University of Virginia Center for Applied Biomechanics. An orthographic viewer was used to extract head and skull contours from the CT scans. Landmarks were measured graphically using HyperMesh (Altair, HyperWorks). To determine the head occipital condyle (OC) centroid, surface meshes of the OCs were made and the centroid of the surfaces was calculated. The Hybrid III contour was obtained using a MicroScribe Digitizer (Solution Technologies, Inc., Oella, MD). Comparisons of the average male and ATD contours were performed using 2 methods: (1) the midsagittal and midcoronal ATD contours relative to the OC centroid were compared to the corresponding 1 SD range of the average male contours; (2) the ATD sagittal contour was translated relative to the average male sagittal contour to minimize the area between the 2 contours. RESULTS: Average male head and skull contours were created. Landmark measurements were made for the dorsum sellae, nasion skin, nasion bone, infraorbital foramen, and external auditory meatus, all relative to the OC centroid. The Hybrid III midsagittal contour was outside the 1 SD range for 15.2 percent of the average male head contour but only by a maximum distance of 1.5 mm, whereas the Hybrid III midcoronal head contour was outside the 1 SD range for 12.2 percent of the average male head contour by a maximum distance of 2 mm. Minimization of the area between the midsagittal contours resulted in only 2.3 mm of translation, corroborating the good correlation between the contours established by initial comparison. CONCLUSIONS: Three-dimensional average male head and skull contours were created and measurements of landmark locations were made. It was found that the 50th percentile male Hybrid III corresponds well to the average male head contour and validated its 3D shape. Average adult head and skull contours and landmark data are available for public research use at http://biomechanics.pratt.duke.edu/data . PMID- 24471366 TI - Perceived value of a motorcycle training program: the influence of crash history and experience of the training. AB - OBJECTIVE: Evidence that rider training reduces motorcycle-related injuries or crashes is currently lacking. However, significant community demand for training persists, which in turn can influence policy. The present study aims to contribute to the understanding of this demand via two objectives: to (1) offer a method, namely, contingent valuation, to measure the value motorcyclists place on training and (2) examine determinants of such value. METHODS: Value was elicited through a willingness to question, using a bidding format, novice motorcyclists who were randomly assigned to groups either offered the training or not. RESULTS: The group that was offered and subsequently received training provided a lower mean perceived value of the training than the group that was not. Perceived value increased with rider age and decreased with training participation and near-crash experiences, controlling for bidding order, income, education, and experience of other training. CONCLUSION: This study demonstrates the utility of contingent valuation in quantifying the perceived value of training, as well as the modifiability of perceived value, with age, training participation, and near crash experiences as key determinants. This indicates that research to determine ways to align the perceived value with evidence on training effectiveness is worthwhile in order to facilitate more appropriate and justified allocation of road safety resources. Potential options to explore and evaluate may include community education on evidence of training effectiveness as well as alternative measures with demonstrated effectiveness in reducing crash risks. PMID- 24471367 TI - Survey about pedestrian safety and attitudes toward automated traffic enforcement in Washington, D.C. AB - OBJECTIVE: Pedestrians represent more than one third of all traffic deaths in Washington, D.C. The District plans to expand its long-standing automated traffic enforcement program in 2013 from speed and red light cameras to cameras to enforce pedestrian right-of-way laws at crosswalks and stop sign laws. This study collected information on the opinions, behaviors, and knowledge of D.C. residents related to camera enforcement and pedestrian safety issues. METHODS: A telephone survey of 801 adult D.C. residents was conducted in November 2012 with approximately equal numbers of respondents in each of D.C.'s eight wards. Quotas were used to ensure that the sample was representative of the demographic characteristics of adults in each ward. For analyses combining responses across the wards, data were weighted to correspond with the demographic characteristics of adults in the city. RESULTS: Most respondents believed that drivers speeding, running red lights, running stop signs, and not stopping for pedestrians are serious threats to their safety. Respondents strongly supported the speed and red light camera programs, with 76 percent of respondents favoring speed cameras and 87 percent favoring red light cameras. Support was more limited for the camera enforcement that was not yet in place at the time of the survey, with 50 percent of respondents favoring stop sign cameras and 47 percent of respondents favoring crosswalk cameras. Twenty-four percent of respondents had not driven a car in D.C. in the past month, and higher proportions of these nondrivers favored speed cameras (90%), stop sign cameras (67%), and crosswalk cameras (59%) than respondents who drove in D.C. in the past month. Respondents who supported camera enforcement cited safety as their main reason. More than 9 in 10 respondents knew that D.C. law requires drivers to stop for pedestrians crossing the street in marked crosswalks at intersections without traffic signals and midblock, but only 54 percent knew that drivers must stop for pedestrians crossing the street at intersections without marked crosswalks. CONCLUSIONS: Most residents supported speed cameras and red light cameras, but support was lower for stop sign and crosswalk cameras. Emphasizing the safety benefits of stop sign and crosswalk cameras and documenting the extent of safety problems at stop signs and crosswalks may increase support for these new forms of camera enforcement. Communities considering automated enforcement should take into account the opinions of pedestrians, even though they are not subject to camera citations. PMID- 24471368 TI - Investigating motorists' behaviors in response to supplementary traffic control devices at land surveying work sites. AB - OBJECTIVE: Since land surveyors working alongside live traffic encounter unique safety challenges there is a great need for innovative and effective traffic control devices (TCDs) that alert motorists approaching short-term land surveying work sites. Unlike the volume of research that has been completed on traditional work zones, however, there is a limited amount of information that has been collected on how motorists respond to TCDs at land surveying work sites. This article aims to fill the void by investigating motorists' behaviors in response to the use of 2 supplementary TCDs at land surveying work sites: portable plastic rumble strips (PPRS) and warning lights. METHOD: Extensive field tests were conducted at various land surveying work sites on 2-lane 2-way urban roadways in New Jersey. Scenarios with and without the use of the supplemental TCDs were designed. Motorists' behavior changes were then statistically examined by using surrogate safety measures including mean speed, speed variance, speed limit compliance, and braking action. RESULTS: Statistical analyses showed that the traffic speed variations did not significantly increase when the selected supplemental TCD was used; rather, motorists significantly reduced their driving speed. When warning lights and PPRS were separately deployed at the land surveying work sites the average reduction in mean speed was 6.7 and 15.2 percent, respectively. The mean speed was reduced by 19.7 percent when both of these supplementary TCDs were used. Logistic regression models developed to examine the speeding and braking behavior also showed that motorists were more likely to comply with the speed limit and increase their braking rate when the selected TCDs were used. CONCLUSION: The use of supplemental TCDs can greatly contribute to the changes in motorists' behaviors at surveying work sites. The changes in motorists' driving behaviors imply that the motorists reacted favorably to the deployed TCDs at the land-surveying work sites. PMID- 24471369 TI - Activation of NF-kappaB mediates astrocyte swelling and brain edema in traumatic brain injury. AB - Brain edema and associated increased intracranial pressure are major consequences of traumatic brain injury (TBI). While astrocyte swelling (cytotoxic edema) represents a major component of the brain edema in the early phase of TBI, its mechanisms are unclear. One factor known to be activated by trauma is nuclear factor-kappaB (NF-kappaB). Because this factor has been implicated in the mechanism of cell swelling/brain edema in other neurological conditions, we examined whether NF-kappaB might also be involved in the mediation of post traumatic astrocyte swelling/brain edema. Here we show an increase in NF-kappaB activation in cultured astrocytes at 1 and 3 h after trauma (fluid percussion injury, FPI), and that BAY 11-7082, an inhibitor of NF-kappaB, significantly blocked the trauma-induced astrocyte swelling. Increased activities of nicotinamide adenine dinucleotide phosphate-oxidase and the Na(+), K(+), 2Cl(-) cotransporter were also observed in cultured astrocytes after trauma, and BAY 11 7082 reduced these effects. We also examined the role of NF-kappaB in the mechanism of cell swelling by using astrocyte cultures derived from transgenic (Tg) mice with a functional inactivation of astrocytic NF-kappaB. Exposure of cultured astrocytes from wild-type mice to in vitro trauma (3 h) caused a significant increase in cell swelling. By contrast, traumatized astrocyte cultures derived from NF-kappaB Tg mice showed no swelling. We also found increased astrocytic NF-kappaB activation and brain water content in rats after FPI, while BAY 11-7082 significantly reduced such effects. Our findings strongly suggest that activation of astrocytic NF-kappaB represents a key element in the process by which cytotoxic brain edema occurs after TBI. PMID- 24471370 TI - Early-starting conduct problems: intersection of conduct problems and poverty. AB - The current article reviews extant literature on the intersection between poverty and the development of conduct problems (CP) in early childhood. Associations between exposure to poverty and disruptive behavior are reviewed through the framework of models emphasizing how the stressors associated with poverty indirectly influence child CP by compromising parent psychological resources, investments in children's welfare, and/or caregiving quality. We expand on the best-studied model, the family stress model, by emphasizing the mediating contribution of parent psychological resources on children's risk for early CP, in addition to the mediating effects of parenting. Specifically, we focus on the contribution of maternal depression, in terms of both compromising parenting quality and exposing children to higher levels of stressful events and contexts. Implications of the adapted family stress model are then discussed in terms of its implications for the prevention and treatment of young children's emerging CP. PMID- 24471372 TI - Overview of meta-analyses of the prevention of mental health, substance use, and conduct problems. AB - This review presents findings from an overview of meta-analyses of the effects of prevention and promotion programs to prevent mental health, substance use, and conduct problems. The review of 48 meta-analyses found small but significant changes that reduce depression, anxiety, antisocial behavior, and substance use. Furthermore, the results were sustained over time. Meta-analyses often found that the effects were heterogeneous. A conceptual model is proposed to guide the study of moderators of program effects in future meta-analyses, and methodological issues in synthesizing findings across preventive interventions are discussed. PMID- 24471373 TI - Epidemiological, neurobiological, and genetic clues to the mechanisms linking cannabis use to risk for nonaffective psychosis. AB - Epidemiological studies have shown that the association between cannabis and psychosis is robust and consistent across different samples, with compelling evidence for a dose-response relationship. Because longitudinal work indicates that cannabis use precedes psychotic symptoms, it seems reasonable to assume a causal relationship. However, more work is needed to address the possibility of gene-environment correlation (for example, genetic risk for psychosis causing onset of cannabis use). Moreover, knowledge about underlying biological mechanisms linking cannabis use and psychosis is still relatively limited. In order to understand how cannabis use may lead to an increased risk for psychosis, in the present article we (a) review the epidemiological, neurobiological, and genetic evidence linking cannabinoids and psychosis, (b) assess the quality of the evidence, and finally (c) try to integrate the most robust findings into a neurodevelopmental model of cannabis-induced psychosis and identify the gaps in knowledge that are in need of further investigation. PMID- 24471374 TI - Antecedents of personality disorder in childhood and adolescence: toward an integrative developmental model. AB - Antecedents of personality disorder in childhood and adolescence have been a neglected area in official taxonomies of mental disorders such as the International Classification of Diseases or the different editions of the Diagnostic and Statistical Manual of Mental Disorders. An evolving research field, however, underscores the importance of antecedents for understanding psychopathology and personality pathology in adulthood. The current article summarizes the history, updates reviews, and incorporates new research findings into an integrative scheme for conceptualizing personality pathology in childhood and adolescence. Implications of this model for assessment, future research, and intervention are discussed. PMID- 24471375 TI - Attenuated psychosis syndrome: ready for DSM-5.1? AB - Prodromal features of the schizophrenia syndrome have been described for a century, and work in the past two decades has produced a substantial literature based on these features to identify individuals at increased risk for developing a psychotic disorder. Sometimes conceptualized as a "risk state" and sometimes as early manifestations of a "disorder," the work has been conducted with several related but different constructs. Early in the preparation of the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) public comment was sought on the proposal to create a new disorder termed attenuated psychosis syndrome (APS), and a range of issues emerged that generated interesting and important controversies. In this review, these criticisms are fully discussed, the APS concept is explicated; data relating to reliability, validity, and treatment are updated; the heterogeneity of APS is considered; and alternative views of the construct are presented with an emphasis on developmental pattern with timing for primary and secondary prevention and early treatment. Areas of future research are identified, and a potential roadmap for inclusion in DSM-5.1 is traced. PMID- 24471371 TI - Depression, stress, and anhedonia: toward a synthesis and integrated model. AB - Depression is a significant public health problem, but its etiology and pathophysiology remain poorly understood. Such incomplete understanding likely arises from the fact that depression encompasses a heterogeneous set of disorders. To overcome these limitations, renewed interest in intermediate phenotypes (endophenotypes) has resurfaced, and anhedonia has emerged as one of the most promising endophenotypes of depression. Here, a heuristic model is presented postulating that anhedonia arises from dysfunctional interactions between stress and brain reward systems. To this end, we review and integrate three bodies of independent literature investigating the role of (a) anhedonia, (b) dopamine, and (c) stress in depression. In a fourth section, we summarize animal data indicating that stress negatively affects mesocorticolimbic dopaminergic pathways critically implicated in incentive motivation and reinforcement learning. In the last section, we provide a synthesis of these four literatures, present initial evidence consistent with our model, and discuss directions for future research. PMID- 24471376 TI - Synthesis of nitrogen- and sulfur-codoped 3D cubic-ordered mesoporous carbon with superior performance in supercapacitors. AB - In this contribution, nitrogen- and sulfur-codoped 3D cubic-ordered mesoporous carbon (KNOMC) materials with controlled dopant content (10.0-4.6 atom % for nitrogen and 0.94-0.75 atom % for sulfur) are presented, using KIT-6 as the template and pyrrole as the precursor, and its supercapacitive behavior is also investigated. The presented materials exhibit excellent supercapacitive performance by combining electrical double-layer capacitance and pseudocapacitance as well as the enhanced wettability and improved conductivity generated from the incorporation of nitrogen and sulfur into the framework of carbon materials. The specific capacitance of the presented materials reaches 320 F g(-1) at a current density of 1 A g(-1), which is significantly larger than that of the pristine-ordered mesoporous carbon reported in the literature and can even compete with some metal oxides and conducting polymers. PMID- 24471378 TI - In vitro anti-inflammatory activity of selected oxalate-degrading probiotic bacteria: potential applications in the prevention and treatment of hyperoxaluria. AB - Oxalate (Ox) is a very common component of the human diet, capable to collect in the renal tissue and bind calcium to form calcium oxalate (CaOx) crystals. A supersaturation of CaOx crystal may cause nephrocalcinosis and nephrolithiasis. The inflammation derived from the CaOx crystal accumulation, together with innate or secondary renal alterations, could strongly affect the renal function. In this case a consumption of probiotics with either oxalate-degrading activity at intestinal level and systemic anti-inflammatory activity could be an alternative approach to treat the subjects with excess of urinary oxalate excretion. 11 strains of lactic acid bacteria (Lactobacilli and Bifidobacteria), already included in the list of bacteria safe for the human use, were investigated for their capability to degrade oxalate by mean of RP-HPLC-UV method and modulate inflammation in an in vitro model system based on peripheral blood mononuclear cells. Four promising bacterial strains (Lactobacillus plantarum PBS067, Lactobacillus acidophilus LA-14, Bifidobacterium breve PBS077, Bifidobacterium longum PBS078) were identified as innovative biological tools for the prevention and the therapeutic treatment of hyperoxaluria and the inflammatory events associated to the Ox accumulation. PRACTICAL APPLICATION: The oxalate-degrading activity of some probiotics and their capability to modulate the release of inflammation mediators could be exploited as a new nutraceutical and therapeutic approach for the treatment of oxalate accumulation and the related inflammatory state. PMID- 24471379 TI - Science to practice: Can we turn the undesired heating effects of MR imaging into effective cancer therapies? AB - In this basic research study, Zhang et al created and report on a clever magnetic resonance (MR)-guided radiofrequency (RF) system that enables focal hyperthermic heating, targeting, and visualization for the treatment of cholangiocarcinoma. The key novelty is creating localized MR-induced heating around a metallic guidewire, which they subsequently demonstrate can be successfully combined with chemotherapy to (a) reduce cell proliferation in vitro, (b) decrease tumor growth in mouse xenografts, and (c) increase biliary uptake of chemotherapeutic drugs in swine. An added benefit of the system is using the wire as an intraluminal receiver antenna to improve the resolution of intraprocedural imaging guidance. PMID- 24471381 TI - Behind the numbers: Decoding molecular phenotypes with radiogenomics--guiding principles and technical considerations. PMID- 24471382 TI - Imaging of bariatric surgery: normal anatomy and postoperative complications. AB - Obesity is a disease that has reached epidemic proportions in the United States and around the world. During the past 2 decades, bariatric surgery has become an increasingly popular form of treatment for morbid obesity. The most common bariatric procedures performed include laparoscopic Roux-en-Y gastric bypass, laparoscopic adjustable gastric banding, and laparoscopic sleeve gastrectomy. Fluoroscopic upper gastrointestinal examinations and abdominal computed tomography (CT) are the major imaging tests used to evaluate patients after these various forms of bariatric surgery. The purpose of this article is to present the surgical anatomy and normal imaging findings and postoperative complications for these bariatric procedures at fluoroscopic examinations and CT. Complications after Roux-en-Y gastric bypass include anastomotic leaks and strictures, marginal ulcers, jejunal ischemia, small bowel obstruction, internal hernias, intussusception, and recurrent weight gain. Complications after laparoscopic adjustable gastric banding include stomal stenosis, malpositioned bands, pouch dilation, band slippage, perforation, gastric volvulus, intraluminal band erosion, and port- and band-related problems. Finally, complications after sleeve gastrectomy include postoperative leaks and strictures, gastric dilation, and gastroesophageal reflux. The imaging features of these various complications of bariatric surgery are discussed and illustrated. PMID- 24471385 TI - Percutaneous breast biopsy: effect on short-term quality of life. AB - PURPOSE: To examine the effects of percutaneous breast biopsy on short-term quality of life. MATERIALS AND METHODS: The institutional review board approved this HIPAA-compliant prospective study. From December 1, 2007, through February 28, 2010, women undergoing percutaneous breast biopsy in an academic medical center were recruited to participate in a mixed-mode survey 2-4 days after biopsy. Patients described their biopsy experience by using the Testing Morbidities Index (TMI), a validated instrument for assessing short-term quality of life related to diagnostic testing. The scale ranged from 0 (worst possible experience) to 100 (no adverse effects). Seven attributes were assessed: pain or discomfort before and during testing, fear or anxiety before and during testing, embarrassment during testing, and physical and mental function after testing. Demographic and clinical information were also collected. Univariate and multivariate linear regression analyses were performed to identify significant predictors of TMI score. RESULTS: In 188 women (mean age, 51.4 years; range, 22 80 years), the mean TMI score (+/-standard deviation) was 82 +/- 12. Univariate analysis revealed age and race as significant predictors of the TMI score (P < .05). In the multivariate model, only patient age remained a significant independent predictor (P = .001). TMI scores decreased by approximately three points for every decade decrease in patient age, which suggests that younger women were more adversely affected by the biopsy experience. CONCLUSION: Younger patient age is a significant predictor of decreased short-term quality of life related to percutaneous breast biopsy procedures. Tailored prebiopsy counseling may better prepare women for percutaneous biopsy procedures and improve their experience. PMID- 24471386 TI - Breast cancer detected with screening US: reasons for nondetection at mammography. AB - PURPOSE: To retrospectively review the mammograms of women with breast cancers detected at screening ultrasonography (US) to determine the reasons for nondetection at mammography. MATERIALS AND METHODS: This study received institutional review board approval, and informed consent was waived. Between 2003 and 2011, a retrospective database review revealed 335 US-depicted cancers in 329 women (median age, 47 years; age range, 29-69 years) with Breast Imaging Reporting and Data System breast density type 2-4. Five blinded radiologists independently reviewed the mammograms to determine whether the findings on negative mammograms should be recalled. Three unblinded radiologists re-reviewed the mammograms to determine the reasons for nondetection by using the reference location of the cancer on mammograms obtained after US-guided wire localization or breast magnetic resonance imaging. The number of cancers recalled by the blinded radiologists were compared with the reasons for nondetection determined by the unblinded radiologists. RESULTS: Of the 335 US-depicted cancers, 63 (19%) were recalled by three or more of the five blinded radiologists, and 272 (81%) showed no mammographic findings that required immediate action. In the unblinded repeat review, 263 (78%) cancers were obscured by overlapping dense breast tissue, and nine (3%) were not included at mammography owing to difficult anatomic location or poor positioning. Sixty-three (19%) cancers were considered interpretive errors. Of these, 52 (82%) were seen as subtle findings (46 asymmetries, six calcifications) and 11 (18%) were evident (six focal asymmetries, one distortion, four calcifications). CONCLUSION: Most breast cancers (81%) detected at screening US were not seen at mammography, even in retrospect. In addition, 19% had subtle or evident findings missed at mammography. PMID- 24471387 TI - Respiratory self-navigated postcontrast whole-heart coronary MR angiography: initial experience in patients. AB - PURPOSE: To assess the diagnostic performance of respiratory self-navigation for whole-heart coronary magnetic resonance (MR) angiography in a patient cohort referred for diagnostic cardiac MR imaging. MATERIALS AND METHODS: Written informed consent was obtained from all participants for this institutional review board-approved study. Self-navigated coronary MR angiography was performed after administration of a contrast agent in 78 patients (mean age, 48.5 years +/- 20.7 [standard deviation]; 53 male patients) referred for cardiac MR imaging because of coronary artery disease (n = 40), cardiomyopathy (n = 14), congenital anomaly (n = 17), or "other" (n = 7). Examination duration was recorded, and the image quality for each coronary segment was assessed with consensus reading. Vessel sharpness, length, and diameter were measured. Quantitative values in proximal, middle, and distal segments were compared by using analysis of variance and t tests. A double-blinded comparison with the results of x-ray angiography was performed when such results were available. RESULTS: When patients with different indications for cardiac MR imaging were examined with self-navigated postcontrast coronary MR angiography, whole-heart data sets with 1.15-mm isotropic spatial resolution were acquired in an average of 7.38 minutes +/- 1.85. The main and proximal coronary segments could be visualized in 92.3% of cases, while the middle and distal segments could be visualized in 84.0% and 55.8% of cases, respectively. Subjective scores and vessel sharpness were significantly higher in the proximal segments than in the middle and distal segments (P < .05). Anomalies of the coronary arteries could be confirmed or excluded in all cases. Per-vessel sensitivity and specificity for stenosis detection were 64.7% and 85.0%, respectively, in the 31 patients for whom reference standard x-ray coronary angiography results were available. CONCLUSION: The self-navigated coronary MR angiography sequence shows promise for coronary imaging. However, technical improvements are needed to improve image quality, especially in the more distal coronary segments. PMID- 24471388 TI - Iterative image reconstruction techniques for CT coronary artery calcium quantification: comparison with traditional filtered back projection in vitro and in vivo. AB - PURPOSE: To investigate in vitro and in vivo the use of image-based and raw data based iterative reconstruction algorithms for quantification of coronary artery calcium by using the Agatston score and subsequent cardiac risk stratification. MATERIALS AND METHODS: In vitro data were obtained by using a moving anthropomorphic cardiac phantom containing calcium inserts of different concentrations and sizes. With institutional review board approval and HIPAA compliance, coronary calcium imaging data of 110 consecutive patients (mean age +/- standard deviation, 58.2 years +/- 9.8; 48 men) were reconstructed with filtered back projection (FBP), iterative reconstruction in image space (IRIS), and sinogram-affirmed iterative reconstruction (SAFIRE). Image noise was measured and the Agatston score was obtained for all reconstructions. Assignment to Agatston scores and percentile-based cardiac risk categories was compared. Statistical analysis included the Cohen kappa coefficient and Friedman and Wilcoxon testing. RESULTS: In vitro, mean Agatston scores +/- standard deviation for FBP (638.9 +/- 9.6), IRIS (622.7 +/- 15.2), and SAFIRE (631.4 +/- 17.6) were comparable (P = .30). The smallest phantom calcifications were more frequently detected when iterative reconstruction techniques were used. The Agatston scores in the patient cohort were not significantly different among FBP, IRIS, and SAFIRE in paired comparisons (median Agatston score [25th and 75th percentiles]: 76.0 [20.6, 243.9], 76.4 [22, 249.3], and 75.7 [21.5, 49.1], respectively; P = .20 each). Comparison of categorization based on Agatston score percentiles showed excellent agreement for both IRIS and SAFIRE with FBP (kappa = 0.975 [0.942-1.00] and kappa = 0.963 [0.922-1.00], respectively). The mean effective dose was 1.02 mSv +/- 0.51. Mean image noise was significantly (P < .001) higher with FBP than that with iterative reconstructions. CONCLUSION: In comparison with FBP, iterative reconstruction techniques do not have a profound effect on the reproducible quantification of coronary calcium according to Agatston score and subsequent cardiac risk classification, although risk reclassification may occur in a small subset of subjects. PMID- 24471389 TI - Intrabiliary RF heat-enhanced local chemotherapy of a cholangiocarcinoma cell line: monitoring with dual-modality imaging--preclinical study. AB - PURPOSE: To determine whether magnetic resonance (MR) imaging heating guidewire mediated radiofrequency (RF) hyperthermia could enhance the therapeutic effect of gemcitabine and 5-fluorouracil (5-FU) in a cholangiocarcinoma cell line and local deposit doses of chemotherapeutic drugs in swine common bile duct (CBD) walls. MATERIALS AND METHODS: The animal protocol was approved by the institutional animal care and use committee. Green fluorescent protein-labeled human cholangiocarcinoma cells and cholangiocarcinomas in 24 mice were treated with (a) combination therapy with chemotherapy (gemcitabine and 5-FU) plus RF hyperthermia, (b) chemotherapy only, (c) RF hyperthermia only, or (d) phosphate buffered saline. Cell proliferation was quantified, and tumor changes over time were monitored with 14.0-T MR imaging and optical imaging. To enable further validation of technical feasibility, intrabiliary local delivery of gemcitabine and 5-FU was performed by using a microporous balloon with (eight pigs) or without (eight pigs) RF hyperthermia. Chemotherapy deposit doses in the bile duct walls were quantified by means of high-pressure liquid chromatography. The nonparametric Mann-Whitney U test and the paired-sample Wilcoxon signed rank test were used for data analysis. RESULTS: Combination therapy induced lower mean levels of cell proliferation than chemotherapy only and RF hyperthermia only (0.39 +/- 0.13 [standard deviation] vs 0.87 +/- 0.10 and 1.03 +/- 0.13, P < .001). Combination therapy resulted in smaller relative tumor volume than chemotherapy only and RF hyperthermia only (0.65 +/- 0.03 vs 1.30 +/- 0.021 and 1.37 +/- 0.05, P = .001). Only in the combination therapy group did both MR imaging and optical imaging show substantial decreases in apparent diffusion coefficients and fluorescent signals in tumor masses immediately after the treatments. Chemotherapy quantification showed a higher average drug deposit dose in swine CBD walls with intrabiliary RF hyperthermia than without it (gemcitabine: 0.32 mg/g of tissue +/- 0.033 vs 0.260 mg/g +/- 0.030 and 5-FU: 0.660 mg/g +/- 0.060 vs 0.52 mg/g +/- 0.050, P < .05). CONCLUSION: The use of intrabiliary MR imaging heating guidewire-mediated RF hyperthermia can enhance the chemotherapeutic effect on a human cholangiocarcinoma cell line and local drug deposition in swine CBD tissues. PMID- 24471390 TI - Diffusion-weighted MR imaging of upper abdominal organs: field strength and intervendor variability of apparent diffusion coefficients. AB - PURPOSE: To determine the variability of apparent diffusion coefficient (ADC) values in various anatomic regions in the upper abdomen measured with magnetic resonance (MR) systems from different vendors and with different field strengths. MATERIALS AND METHODS: Ten healthy men (mean age, 36.6 years +/- 7.7 [standard deviation]) gave written informed consent to participate in this prospective ethics committee-approved study. Diffusion-weighted (DW) MR imaging was performed in each subject with 1.5- and 3.0-T MR systems from each of three vendors at two institutions. Two readers independently measured ADC values in seven upper abdominal regions (left and right liver lobe, gallbladder, pancreas, spleen, and renal cortex and medulla). ADC values were tested for interobserver differences, as well as for differences related to field strength and vendor, with repeated measures analysis of variance; coefficients of variation (CVs) and variance components were calculated. RESULTS: Interreader agreement was excellent (intraclass coefficient, 0.876). ADC values were (77.5-88.8) *10(-5) mm(2)/sec in the spleen and (250.6-278.5) *10(-5) mm(2)/sec in the gallbladder. There were no significant differences between ADC values measured at 1.5 T and those measured at 3.0 T in any anatomic region (P >.10 for all). In two of seven regions at 1.5 T (left and right liver lobes, P < .023) and in four of seven regions at 3.0 T (left liver lobe, pancreas, and renal cortex and medulla, P < .008), intervendor differences were significant. CVs ranged from 7.0% to 27.1% depending on the anatomic location. CONCLUSION: Despite significant intervendor differences in ADC values of various anatomic regions of the upper abdomen, ADC values of the gallbladder, pancreas, spleen, and kidney may be comparable between MR systems from different vendors and between different field strengths. PMID- 24471391 TI - Carpal tunnel syndrome: diagnosis by means of median nerve elasticity--improved diagnostic accuracy of US with sonoelastography. AB - PURPOSE: To compare the elasticity of the median nerve (MN) between healthy volunteers and patients with carpal tunnel syndrome (CTS) and to evaluate the diagnostic utility of sonoelastographic measurements of the elasticity of the MN. MATERIALS AND METHODS: This study was performed with institutional review board approval and written informed consent from all participants. Hands in 22 healthy volunteers and in 31 patients with symptomatic CTS were studied. The cross sectional area (CSA) and the elasticity of the MN, which was measured as the acoustic coupler (AC)/MN strain ratio, were evaluated. RESULTS: Both hands in 22 healthy volunteers (three men [mean age, 52.7 years; age range, 41-65 years]; 19 women [mean age, 62.2 years; age range, 40-88 years]) and 43 hands in 31 patients with symptomatic CTS (three men [mean age, 69.0 years; age range, 46-88 years]; 28 women [mean age, 61.2 years; age range, 39-92 years]) were studied. Both the AC/MN strain ratio and the CSA in the patients with CTS were significantly higher than those in the healthy volunteers (P < .001). The presence of CTS was predicted by means of AC/MN strain ratio and CSA cutoff values, respectively, of 4.3 and 11 mm(2), with areas under the receiver operating characteristic curves (AUCs) of 0.78 (95% confidence interval [CI]: 0.69, 0.88) and 0.85 (95% CI: 0.78, 0.93). A logistic model that combined the AC/MN strain ratio and the CSA improved diagnostic accuracy for CTS, with an AUC of 0.91 (95% CI: 0.85, 0.97; P < .001). CONCLUSION: Sonoelastography provides significant improvement in the diagnostic accuracy of the ultrasonographic assessment of CTS. PMID- 24471392 TI - White matter changes in comatose survivors of anoxic ischemic encephalopathy and traumatic brain injury: comparative diffusion-tensor imaging study. AB - PURPOSE: To analyze white matter pathologic abnormalities by using diffusion tensor (DT) imaging in a multicenter prospective cohort of comatose patients following cardiac arrest or traumatic brain injury (TBI). MATERIALS AND METHODS: Institutional review board approval and informed consent from proxies and control subjects were obtained. DT imaging was performed 5-57 days after insult in 49 cardiac arrest and 40 TBI patients. To control for DT imaging-processing variability, patients' values were normalized to those of 111 control subjects. Automated segmentation software calculated normalized axial diffusivity (lambda1) and radial diffusivity (lambda?) in 19 predefined white matter regions of interest (ROIs). DT imaging variables were compared by using general linear modeling, and side-to-side Pearson correlation coefficients were calculated. P values were corrected for multiple testing (Bonferroni). RESULTS: In central white matter, lambda1 differed from that in control subjects in six of seven TBI ROIs and five of seven cardiac arrest ROIs (all P < .01). The lambda? differed from that in control subjects in all ROIs in both patient groups (P < .01). In hemispheres, lambda1 was decreased compared with that in control subjects in three of 12 TBI ROIs (P < .05) and nine of 12 cardiac arrest ROIs (P < .01). The lambda? was increased in all TBI ROIs (P < .01) and in seven of 12 cardiac arrest ROIs (P < .05). Cerebral hemisphere lambda1 was lower in cardiac arrest than in TBI in six of 12 ROIs (P < .01), while lambda? was higher in TBI than in cardiac arrest in eight of 12 ROIs (P < .01). Diffusivity values were symmetrically distributed in cardiac arrest (P < .001 for side-to-side correlation) but not in TBI patients. CONCLUSION: DT imaging findings are consistent with the known predominance of cerebral hemisphere axonal injury in cardiac arrest and chiefly central myelin injury in TBI. This consistency supports the validity of DT imaging for differentiating axon and myelin damage in vivo in humans. PMID- 24471393 TI - Prostate imaging: evaluation of a reusable two-channel endorectal receiver coil for MR imaging at 1.5 T. AB - PURPOSE: To prospectively compare image quality with use of a two-channel solid reusable phased-array endorectal receiver coil (SPAC) with that of the single channel inflatable endorectal balloon coil currently in widespread use for 1.5-T magnetic resonance (MR) imaging of the prostate. MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained. Multiparametric prostate MR imaging at 1.5 T was performed in patients who were suspected of having cancer. Thirty consecutive patients were included (mean age, 66.1 years; range, 49-76 years). The first 15 patients were imaged by using a balloon coil and an eight-channel external array, and the remaining 15 were imaged with a SPAC alone. One patient was imaged with both techniques. Axial T2 weighted images acquired at both standard and high spatial resolution were used to compare image quality between coils. Qualitative assessments of image quality were made separately by three radiologists. Signal-to-noise ratio (SNR) profiles were determined on a pixel-by-pixel basis in a 1-cm central band in the prostate by using T1-weighted axial images at the apex, midgland, and base. Interrater reliability was determined by using a two-way intraclass correlation coefficient, qualitative scores were compared by using the Student t test for independent samples, and SNR profiles were plotted by using a Biot-Savart curve approximation. RESULTS: SNR of the SPAC was significantly better compared with that of the balloon coil at distances up to 3.0 cm at the apex and 3.5 cm at the base and midgland (P < .001). There was a 7% improvement in SNR at the mean maximal anteroposterior prostate dimension in this cohort and a 96% improvement at half this distance. At both standard and high spatial resolution, significant improvements in overall image quality (P = .015 and P < .001, respectively), visibility of the anterior gland (P = .009 and P < .001, respectively), and noise (P < .001 and P < .001, respectively) were seen when the SPAC was used. Interrater reliability was 0.536 (95% confidence interval: 0.461, 0.603). CONCLUSION: Both SNR and image quality were significantly improved with use of the SPAC at 1.5 T compared with use of the single-channel inflatable endorectal balloon coil. PMID- 24471394 TI - Arterial, venous, and cerebrospinal fluid flow: simultaneous assessment with Bayesian multipoint velocity-encoded MR imaging. AB - PURPOSE: To measure arterial, venous, and cerebrospinal fluid (CSF) velocities simultaneously by using Bayesian multipoint velocity-encoded magnetic resonance (MR) imaging and to compare interacquisition reproducibility relative to that of standard phase-contrast MR imaging for sequential measurements of arterial, venous, and CSF velocities. MATERIALS AND METHODS: This study was approved by the local ethics committee, and informed consent was obtained from all subjects. Simultaneous measurement of blood and CSF flow was performed at the C1-C2 level in 10 healthy subjects (mean age, 24.4 years +/- 2.7; five men, five women) by using accelerated Bayesian multipoint velocity-encoded MR imaging. Data were compared with those obtained from two separate conventional phase-contrast MR imaging acquisitions, one optimized for arterial and venous blood flow (velocity encoding range, +/-50 cm/sec) and the other optimized for CSF flow (velocity encoding range, +/-10 cm/sec), with an imaging time of approximately 2 minutes each. Data acquisition was repeated six times. Intraclass correlation coefficient (ICC) and linear regression were used to quantify interacquisition reproducibility. RESULTS: There was no significant difference in arterial blood flow measured with Bayesian multipoint velocity-encoded MR imaging and that measured with phase-contrast MR imaging (mean ICC, 0.96 +/- 0.03 vs 0.97 +/- 0.02, respectively). Likewise, there was no significant difference between CSF flow measured with Bayesian multipoint velocity-encoded MR imaging and that measured with phase-contrast MR imaging (mean ICC, 0.97 +/- 0.02 vs 0.96 +/- 0.05, respectively). For venous blood flow, the ICC with Bayesian multipoint MR imaging was significantly larger than that with conventional phase-contrast MR imaging (mean, 0.75 +/- 0.23 vs 0.65 +/- 0.26, respectively; P = .016). CONCLUSION: Bayesian multipoint velocity-encoded MR imaging allows for simultaneous assessment of fast and slow flows in arterial, venous, and CSF lumina in a single acquisition. It eliminates the need for vessel-dependent adjustment of the velocity-encoding range, as required for conventional sequential phase-contrast MR imaging measurements. PMID- 24471396 TI - Case 202: Extensive unilateral widening of Virchow-Robin spaces. PMID- 24471397 TI - Overdiagnosis versus overtreatment: a false dichotomy. PMID- 24471398 TI - Role of core-needle biopsy in thyroid nodules with initially nondiagnostic cytologic results. PMID- 24471399 TI - Screening for lung cancer and idiopathic pulmonary fibrosis: killing two birds with one stone. PMID- 24471400 TI - Review of sagittal bone reformations efficiently avoids most missed vertebral fracture diagnoses at abdominal CT. PMID- 24471404 TI - A tale of two lineages: unexpected, long-term persistence of the amphibian killing fungus in Brazil. AB - For the past 17 years, scientists have been compiling a list of amphibian species susceptible to infection by the amphibian-killing chytrid fungus, Batrachochytrium dendrobatidis (Bd), all over the world, with >500 species infected on every continent except Antarctica (Olson et al.). Where Bd has been found, the impacts on amphibians has been one of two types: either Bd arrives into a naive amphibian population followed by a mass die-off and population declines (e.g. Lips et al.), or Bd is present at some moderate prevalence, usually infecting many species but at apparently nonlethal intensities for a long time. In this issue of Molecular Ecology, Rodriguez et al. (2014) discover that the Atlantic Coastal Forest of Brazil is home to two Bd lineages: the Global Pandemic Lineage (Bd-GPL) - the strain responsible for mass die-offs and population declines - and a lineage endemic to Brazil (Bd-Bz). Even more surprising was that both lineages have been present in this area for the past 100 years, making these the oldest records of Bd infecting amphibians. The team also described a moderate but steady prevalence of ~20% across all sampled anuran families for over 100 years, indicating that Brazil has been in an enzootic disease state for over a century. Most amphibians were infected with Bd-GPL, suggesting this lineage may be a better competitor than Bd-Bz or may be replacing the Bd-Bz lineage. Rodriguez et al. (2014) also detected likely hybridization of the two Bd lineages, as originally described by Schloegel et al. (2012). PMID- 24471405 TI - From one host to another: tracking vector movements using microsatellite markers. AB - In principle, the solution to stopping the spread of any vectorborne pathogen is a simple one - just stop infected vectors from biting new hosts and the pathogen cannot spread. Importantly, this does not necessarily require killing all vectors, or protecting all hosts. Transmission only occurs when an infected vector moves to a new host, and so knowing how vectors move between hosts in nature and how they choose hosts is crucial to understanding transmission. For example, the infection status of a potential vector or that of a potential host would have a huge influence on pathogen transmission if it affected vector movement or host choice. Remarkably little is known about how vectors move between and choose hosts in nature, in part because of the logistical difficulties of tracking vector movement. This is why the article by Levin and Parker (2014) in this issue of Molecular Ecology is so exciting. PMID- 24471406 TI - Long-term endemism of two highly divergent lineages of the amphibian-killing fungus in the Atlantic Forest of Brazil. AB - The recent global spread of the amphibian-killing fungus [Batrachochytrium dendrobatidis (Bd)] has been closely tied to anthropogenic activities; however, regional patterns of spread are not completely understood. Using historical samples, we can test whether Bd was a spreading or endemic pathogen in a region within a particular time frame, because those two disease states provide different predictions for the regional demographic dynamics and population genetics of Bd. Testing historical patterns of pathogen prevalence and population genetics under these predictions is key to understanding the evolution and origin of Bd. Focusing on the Atlantic Forest (AF) of Brazil, we used qPCR assays to determine the presence or absence of Bd on 2799 preserved postmetamorphic anurans collected between 1894 and 2010 and used semi-nested PCRs to determine the frequency of rRNA ITS1 haplotypes from 52 samples. Our earliest date of detection was 1894. A mean prevalence of 23.9% over time and spatiotemporal patterns of Bd clusters indicate that Bd has been enzootic in the Brazilian AF with no evidence of regional spread within the last 116 years. ITS1 haplotypes confirm the long term presence of two divergent strains of Bd (BdGPL and Bd-Brazil) and three spatiotemporally broad genetic demes within BdGPL, indicating that Bd was not introduced into southeast Brazil by the bullfrog trade. Our data show that the evolutionary history and pathogen dynamics of Bd in Brazil is better explained by the endemic pathogen hypothesis. PMID- 24471407 TI - Antinociceptive and antidiarrheal effects of pioglitazone in a rat model of diarrhoea-predominant irritable bowel syndrome: role of nitric oxide. AB - Irritable bowel syndrome (IBS) is a prevalent disease characterized by abdominal pain and abnormal bowel habits. Pioglitazone is a peroxisome proliferator activated receptor (PPAR) gamma agonist and, although it is mostly used as an antidiabetic agent, it has been reported to have analgesic effects. Nitric oxide (NO), a gaseous molecule that mediates many of the effects of pioglitazone, has been implicated in the pathophysiology of IBS. The aim of the present study was to investigate the effects of pioglitazone on symptoms in a rat model of diarrhoea-predominant IBS (D-IBS).and to determine the role of NO in these effects. Diarrhoea-predominant IBS was induced by intracolonic instillation of acetic acid. Pioglitazone (2 mg/kg, i.p.) was administered on Days 7, 9 and 11 after acetic acid instillation. To investigate the mechanism involved in pioglitazone action, rats were also administered either the PPARgamma antagonist GW9662 (3 mg/kg, i.p.), the NO synthase (NOS) inhibitor N(G) -nitro-l-arginine methyl ester (l-NAME; 10 mg/kg, i.p.) or the NO precursor l-arginine (250 mg/kg, i.p.) along with pioglitazone. Visceral hypersensitivity, nociceptive thresholds, defecation frequency, stool form, serum and colon NO production and inducible (i) NOS activity were assessed 1 h after the final injection of pioglitazone or dimethylsulphoxide (used as the vehicle). Pioglitazone reduced visceral hypersensitivity and defecation frequency, increased nociceptive thresholds, NO production and iNOS activity and shifted stool form towards hard stools in D-IBS rats. These effects of pioglitazone were significantly reversed by l-NAME, but not GW9662. l-Arginine augmented the effects of pioglitazone. In conclusion, pioglitazone alleviates symptoms in a rat model of D-IBS through an NO-dependent mechanism. PMID- 24471408 TI - Drug survival of fumaric acid esters for psoriasis: a retrospective study. AB - BACKGROUND: Fumaric acid esters (FAEs) have been used for over 30 years in the management of psoriasis. OBJECTIVES: To determine drug survival of FAEs in patients with psoriasis, treatment-limiting adverse drug events and the range of effective drug doses. METHODS: A retrospective, single-centre study assessing all patients commenced on FAEs between October 2003 and July 2012. Demographic data, length of treatment, reasons for discontinuation of FAEs, side-effects and range of doses were recorded. RESULTS: Two hundred and forty-nine patients [160 (64%) male] were included. The mean age at which FAEs were commenced was 44.5 years (range 17-82 years). The mean length of treatment was 28 months (range 1 week to 106 months). In patients who were commenced on FAEs >= 4 years before inclusion in this study, the 4-year drug survival was 60% (64/107). FAEs were discontinued in 146/249 patients (59%); this was due to lack of efficacy in 59/146 (40%) and gastrointestinal upset in 39/146 (27%). A very low dose of FAEs (< 240 mg daily) was successful in maintaining control of psoriasis in 26 (10%) patients. The mean treatment duration of these patients was 64 months (range 32-106 months). CONCLUSIONS: Fumaric acid esters have a 4-year drug survival rate of 60%, which compares favourably with reported 4-year survival rates of 40% for etanercept and adalimumab and 70% for infliximab. Longer drug survival is more likely in the significant subgroup of patients in whom a very low dose of FAEs is sufficient to control disease. The reasons for this are unclear. PMID- 24471409 TI - Effects of sugar addition on total polyphenol content and antioxidant activity of frozen and freeze-dried apple puree. AB - The objective of this study was to investigate the influence of simple sugar addition including (glucose, G; fructose, F; sucrose, S; and trehalose, T) on the total polyphenol content (TPC) and antioxidant activity (AOA) of apple puree processed by freezing and freeze-drying and stored for 6 months. The apple polyphenol profile was mostly preserved in the freeze-dried samples with sugar addition during 6 months of storage, whereas the polyphenol profile in frozen samples consists only of quercetin glycosides, of which rutin had the largest share. After 6 months, the highest level of polyphenols was detected in frozen 'Idared' and 'Fuji' apple puree with addition of T 5% (12.2 and 16.7 mg/100 g FW, respectively), whereas in freeze-dried apple puree the highest TPC was in 'Idared' and 'Fuji' with addition of T 1% (16.3 and 13.6 mg/100 g FW, respectively). Results indicate that sugar addition before processing could have potential for enhancing product quality. PMID- 24471410 TI - Music mixing preferences of cochlear implant recipients: a pilot study. AB - OBJECTIVE: Music perception and appraisal are generally poor in cochlear implant recipients. Simple musical structures, lyrics that are easy to follow, and clear rhythm/beat have been reported among the top factors to enhance music enjoyment. The present study investigated the preference for modified relative instrument levels in music with normal-hearing and cochlear implant subjects. DESIGN: In experiment 1, test subjects were given a mixing console and multi-track recordings to determine their most enjoyable audio mix. In experiment 2, a preference rating experiment based on the preferred relative level settings in experiment 1 was performed. STUDY SAMPLE: Experiment 1 was performed with four postlingually deafened cochlear implant subjects, experiment 2 with ten normal hearing and ten cochlear implant subjects. RESULTS: A significant difference in preference rating was found between normal-hearing and cochlear implant subjects. The latter preferred an audio mix with larger vocals-to-instruments ratio. In addition, given an audio mix with clear vocals and attenuated instruments, cochlear implant subjects preferred the bass/drum track to be louder than the other instrument tracks. CONCLUSIONS: The original audio mix in real-world music might not be suitable for cochlear implant recipients. Modifying the relative instrument level settings potentially improves music enjoyment. PMID- 24471411 TI - Prevalence and remediation of spatial processing disorder (SPD) in Indigenous children in regional Australia. AB - OBJECTIVE: This study aimed to determine the prevalence of spatial processing disorder (SPD) in the Indigenous Australian population and the benefit of and logistical issues arising from remediation of the disorder. DESIGN: Participants were assessed for SPD with the Listening in Spatialized Noise - Sentences test (LiSN-S). Participants diagnosed with SPD were instructed to use the LiSN & Learn auditory training software until 100 games had been completed. STUDY SAMPLE: Participants were 144 Indigenous Australian children (aged between 6;0 [years;months] and 12;2). RESULTS: Ten participants (6.9%) presented with SPD. Nine took part in the auditory training study. Post-training LiSN-S performance improved on average by 0.9 population standard deviations (1.4 dB). There was a significant correlation (r = 0.71, p = 0.031, eta(2) = 0.51) between total number of LiSN & Learn games played (mean = 65, SD = 27) and improvement in LiSN-S performance. Teachers rated all participants as improving in their listening abilities post-intervention. CONCLUSIONS: There is a high prevalence of SPD in the Indigenous Australian population. LiSN & Learn training is effective in remediating SPD in this population and is considered a beneficial intervention by teachers, however improvement in spatial processing is dependent on training program uptake. PMID- 24471412 TI - Importance of sphingosine kinase (SphK) as a target in developing cancer therapeutics and recent developments in the synthesis of novel SphK inhibitors. AB - Sphingosine kinase (SphK) is an oncogenic lipid kinase that regulates the sphingolipid metabolic pathway that has been shown to play a role in numerous hyperproliferative/inflammatory diseases. The SphK isoforms (SphK1 and SphK2) catalyze the conversion of the proapoptotic substrate d-erythrosphingosine to the promitogenic/migratory product sphingosine 1-phosphate (S1P). Accumulation of S1P has been linked to the development/progression of cancer and various other diseases including, but not limited to, asthma, inflammatory bowel disease, rheumatoid arthritis, and diabetic nephropathy. SphK therefore represents a potential new target for developing novel therapeutics for cancer and other diseases. This finding has stimulated the development and evaluation of numerous SphK inhibitors over the past decade or so. In this review, we highlight the recent advancement in the field of SphK inhibitors including SphK1 and SphK2 specific inhibitors. Both sphingolipid based and nolipidic small molecule inhibitors and their importance in treatment of cancer and other diseases are discussed. PMID- 24471413 TI - Severity of lower urinary tract symptoms reflects different composition of bladder storage dysfunction and bladder outlet obstruction in men with symptomatic benign prostatic hyperplasia. AB - AIMS: Differentiation of different lower urinary tract dysfunctions (LUTD) is essential for selecting the optimal first-line medical treatment of lower urinary tract symptoms (LUTS). This study analysed the association of the severity of LUTS with LUTD and therapeutic results based on the International Prostate Symptom Score (IPSS) voiding to storage (V/S) ratio. MATERIALS AND METHODS: Lower urinary tract symptoms were evaluated in 849 men using the IPSS questionnaire and the IPSS-V/S ratio. The prostate measures, urinary flow measures, and C-reactive protein (CRP) were investigated at baseline and 1 month after treatment. Therapeutic results were assessed by changes in the quality of life index (QoL I). The associations of the severity of LUTS with LUTD and therapeutic results were analysed. RESULTS: Mild (IPSS <= 7), moderate (8 <= IPSS <= 19) and severe LUTS (IPSS >= 20) were noted in 215, 461 and 173 men. IPSS-V/S <= 1 was noted in 81.4% of patients with mild LUTS, while IPSS-V/S > 1 was noted in 71.1% of patients with severe LUTS. After treatment with alpha-blockers in patients with IPSS-V/S > 1 and antimuscarinic agents in patients with IPSS-V/S <= 1 for 1 month, 84.0% and 88.8% of patients with mild LUTS had effective therapeutic results, respectively. In contrast, the therapeutic results were less effective in patients with moderate (64.9% and 63.8%, respectively) or severe LUTS (50% and 33.3%, respectively). CONCLUSION: Patients with benign prostatic hyperplasia (BPH) and mild LUTS have more bladder storage dysfunction, whereas patients with BPH and severe LUTS had higher grade of bladder outlet disorders in associated with storage symptoms. Treatment based on the IPSS-V/S ratio results in good therapeutic results in men with mild and moderate LUTS, but not in men with severe LUTS. PMID- 24471414 TI - Large equatorial ligand effects on C-H bond activation by nonheme iron(IV)-oxo complexes. AB - In this article, we present density functional theory (DFT) calculations on the iron(IV)-oxo catalyzed methane C-H activation reactions for complexes in which the Fe(IV)?O core is surrounded by five negatively charged ligands. We found that it follows a hybrid pathway that mixes features of the classical sigma- and pi pathways in quintet surfaces. These calculations show that the Fe-O-H arrangement in this hybrid pathway is bent in sharp contrast to the collinear character as observed for the classical quintet sigma-pathways before. The calculations have also shown that it is the equatorial ligands that play key roles in tuning the reactivity of Fe(IV)?O complexes. The strong pi-donating equatorial ligands employed in the current study cause a weak pi(FeO) bond and thereby shift the electronic accepting orbitals (EAO) from the vertically orientated O pz orbital to the horizontally orientated O px. In addition, all the equatorial ligands are small in size and would therefore be expected have small steric effects upon substrate horizontal approaching. Therefore, for the small and strong pi-donating equatorial ligands, the collinear Fe-O-H arrangement is not the best choice for the quintet reactivity. This study adds new element to iron(IV)-oxo catalyzed C-H bond activation reactions. PMID- 24471415 TI - Ondansetron: a review of pharmacokinetics and clinical experience in postoperative nausea and vomiting. AB - INTRODUCTION: Postoperative nausea and vomiting (PONV) is associated with poor patient satisfaction and delayed recovery after general anesthesia. Multiple neurotransmitters are involved in the mediation of PONV but despite the introduction of new antiemetics, no completely effective drug exists for its prevention or treatment. AREAS COVERED: This review provides a detailed description of ondansetron's chemistry, pharmacokinetics, pharmacodynamics, toxicity and a brief review of clinical trials involving ondansetron and the management of PONV. We searched reviews, meta-analysis and randomized controlled trials (Medline, Embase and article reference lists). EXPERT OPINION: According to current literature, administering ondansetron 4 mg i.v. near the end of surgery provides sufficient protection against PONV in low- and moderate-risk patients, comparable to traditional antiemetics such as antihistamines and droperidol. High-risk patients require a multimodal approach since one quarter of them will not respond to monotherapy. In the future, transdermal formulation or formulations for nasal or buccal delivery will be available. The development of non-racemic mixture consisting of R-ondansetron would enhance the safety profile and probably the efficacy too. PMID- 24471416 TI - The pharmacokinetics of edoxaban for the prevention and treatment of venous thromboembolism. AB - INTRODUCTION: Thromboembolic diseases will become the most important contributors to mortality and morbidity for modern societies. Current antithrombotic strategies using heparins or vitamin K antagonists are inconvenient, with limitations and inherent side effects. A series of new oral anticoagulants with powerful and reliable antithrombotic actions have been developed in the last decade. AREAS COVERED: Edoxaban is a direct and specific inhibitor of activated factor X, delivered orally. This article reviews literature from PubMed and articles referenced within. The text explores the pharmacological aspects of its antithrombotic action. Pharmacokinetics, metabolism and drug interactions are examined. The review places the results of recent clinical trials that have evaluated the antithrombotic potential of edoxaban versus standard antithrombotic therapies in the prophylaxis and treatment of venous thromboembolism into perspective. The possible relationship between the pharmacokinetic profile of edoxaban and the favorable results in clinical trials is discussed. EXPERT OPINION: Edoxaban is perceived as a major advance, compared to vitamin K antagonists, in the prevention and treatment of thromboembolic disease given its favorable efficacy, safety, pharmacokinetic profile and renal clearance. The results of ongoing large international trials exploring the prevention of thrombotic complications in patients in different clinical settings should ensure the approval of edoxaban to treat new indications. PMID- 24471417 TI - Amyotrophic lateral sclerosis in pregnancy is associated with a vascular endothelial growth factor promoter genotype. AB - BACKGROUND AND PURPOSE: The occurrence of amyotrophic lateral sclerosis (ALS) during pregnancy is uncommon and the effect of one on the other is not well described. METHODS: The clinical and genetic features of five cases of ALS are reported with an onset during pregnancy or within 1 month from delivery. Charts from 239 women with a diagnosis of ALS attending the neuromuscular clinics at the Neuromuscular Omnicentre (NEMO) and at IRCCS Policlinico San Donato from 2008 to 2011 were reviewed. RESULTS: Of these, 12.8% of the women in child-bearing age had a diagnosis of ALS during pregnancy or immediately after delivery. Genetic screening of the major causative genes revealed two mutations in superoxide dismutase 1 (SOD1) gene; the analysis of vascular endothelial growth factor (VEGF) promoter variation showed a segregation of the haplotype CA/AG (-2578C/A; 1190A/G) in patients developing ALS related to pregnancy. No effects on foetal development or neonatal course were observed. CONCLUSIONS: Pregnancy may unmask ALS but whether this is coincidental is unclear. Hormonal and inflammatory modifications might trigger ALS in subjects with increased susceptibility to oxidative stress related to the toxic function of SOD1 or in subjects with a reduction of neuroprotective molecules such as VEGF. PMID- 24471418 TI - Open-mindedness can decrease persuasion amongst adolescents: the role of self affirmation. AB - OBJECTIVES: Self-affirmation (e.g., by reflecting on important personal values) has been found to promote more open-minded appraisal of threatening health messages in at-risk adults. However, it is unclear how self-affirmation affects adolescents and whether it has differential effects on the impact of these messages amongst those at relatively lower and higher risk. The current study explored moderation by risk. DESIGN: Participants were randomly assigned to either a self-affirmation or a control condition before receiving a health message concerning physical activity. METHODS: Older adolescents (N = 125) completed a self-affirmation or control writing task before reading about the health consequences of not meeting recommendations to be physically active for at least 60 min daily. Most of the sample did not achieve these levels of activity (98%, N = 123). Consequently, the message informed these participants that - unless they changed their behaviour - they would be at higher risk of heart disease. Participants completed measures of responses to the message and behaviour-specific cognitions (e.g., self-efficacy) for meeting the recommendations. RESULTS: For relatively inactive participants, self-affirmation was associated with increased persuasion. However, for those who were moderately active (but not meeting recommendations), those in the self-affirmation condition were less persuaded by the message. CONCLUSIONS: Whilst self-affirmation can increase message acceptance, there are circumstances when the open-mindedness it induces may decrease persuasion. The evidence provided in this study suggests that caution may be needed when recommendations are challenging and it could be considered reasonable to be sceptical about the need to change behaviour. Statement of contribution What is already known on this subject? Self-affirmation can facilitate open-mindedness and sensitivity to whether health messages suggest high or low risk on the basis of current behaviour. What does this study add? Demonstrates that self-affirmation effects can be moderated by the extent of failure to meet recommendations. Shows that self-affirmation can be associated with less persuasion when challenging health guidelines are used. PMID- 24471420 TI - Functional characterization of late outgrowth endothelial progenitor cells in patients with end-stage renal failure. AB - Renal transplantation is potentially curative in renal failure, but long-term efficacy is limited by untreatable chronic rejection. Endothelial damage contributes to chronic rejection and is potentially repairable by circulating endothelial progenitor cells (EPC). The frequency and function of EPC are variably influenced by end-stage renal failure (ESRF). Here, we isolated and functionally characterized the late outgrowth EPC (LO-EPC) from ESRF patients to investigate their potential for endothelial repair. Patients with ESRF generated more LO-EPC colonies than healthy controls and had higher plasma levels of IL 1ralpha, IL-16, IL-6, MIF, VEGF, Prolactin, and PLGF. Patients' LO-EPC displayed normal endothelial cell morphology, increased secretion of PLGF, MCP-1, and IL 1beta, and normal network formation in vitro and in vivo. They demonstrated decreased adhesion to extracellular matrix. Integrin gene profiles and protein expression were comparable in patients and healthy volunteers. In some patients, mesenchymal stem cells (MSC) were co-isolated and could be differentiated into adipocytes and osteocytes in vitro. This is the first study to characterize LO EPC from patients with ESRF. Their behavior in vitro reflects the presence of elevated trophic factors; their ability to proliferate in vitro and angiogenic function makes them candidates for prevention of chronic rejection. Their impaired adhesion and the presence of MSC are areas for potential therapeutic intervention. PMID- 24471421 TI - Loss of BRM expression is a frequently observed event in poorly differentiated clear cell renal cell carcinoma. AB - AIMS: The aim of this study was to examine the status of Brahma (BRM), a key SWI/SNF complex subunit, in clear cell renal cell carcinomas (RCCs), and to analyse the histopathology, immunophenotype, molecular features and prognosis of the BRM-negative cases. METHODS AND RESULTS: We identified 19 cases of grade 4 tumours lacking BRM expression among 625 clear cell RCCs. All 19 cases exhibited features of poor differentiation: 13 showed pure poorly differentiated morphology, while six were composite tumours with an admixed typical low-grade component. Besides negative BRM expression, the immunophenotype of these cases was similar to clear cell RCC. VHL gene mutations were identified in nine of the 19 patients (47%). Chromosome 3p deletion was detected in 11 of 13 poorly differentiated RCCs and both areas of five of five composite tumours. All poorly differentiated tumour areas showed polysomy of chromosome 3. No losses or gains of chromosome 3 were observed in low-grade tumour areas of five of five composite RCCs. CONCLUSIONS: We have shown that loss of BRM expression is a common feature among poorly differentiated tumours in clear cell RCCs. We hypothesize that loss of BRM expression is involved in tumor de-differentiation in clear cell RCCs and may play an important role during tumour progression. PMID- 24471423 TI - Drought stress provokes the down-regulation of methionine and ethylene biosynthesis pathways in Medicago truncatula roots and nodules. AB - Symbiotic nitrogen fixation is one of the first physiological processes inhibited in legume plants under water-deficit conditions. Despite the progress made in the last decades, the molecular mechanisms behind this regulation are not fully understood yet. Recent proteomic work carried out in the model legume Medicago truncatula provided the first indications of a possible involvement of nodule methionine (Met) biosynthesis and related pathways in response to water-deficit conditions. To better understand this involvement, the drought-induced changes in expression and content of enzymes involved in the biosynthesis of Met, S-adenosyl L-methionine (SAM) and ethylene in M. truncatula root and nodules were analyzed using targeted approaches. Nitrogen-fixing plants were subjected to a progressive water deficit and a subsequent recovery period. Besides the physiological characterization of the plants, the content of total sulphur, sulphate and main S containing metabolites was measured. Results presented here show that S availability is not a limiting factor in the drought-induced decline of nitrogen fixation rates in M. truncatula plants and provide evidences for a down regulation of the Met and ethylene biosynthesis pathways in roots and nodules in response to water-deficit conditions. PMID- 24471426 TI - Virtual reality simulation for construction safety promotion. AB - Safety is a critical issue for the construction industry. Literature argues that human error contributes to more than half of occupational incidents and could be directly impacted by effective training programs. This paper reviews the current safety training status in the US construction industry. Results from the review evidence the gap between the status and industry expectation on safety. To narrow this gap, this paper demonstrates the development and utilisation of a training program that is based on virtual reality (VR) simulation. The VR-based safety training program can offer a safe working environment where users can effectively rehearse tasks with electrical hazards and ultimately promote their abilities for electrical hazard cognition and intervention. Its visualisation and simulation can also remove the training barriers caused by electricity's features of invisibility and dangerousness. PMID- 24471428 TI - The potential signal pathway between PAX2 and CD2AP in the renal interstitial fibrosis disease. AB - Paired box gene 2 (PAX2) can regulate tissue development and cellular differentiation, and it is associated with renal diseases. CD2-associated protein (CD2AP) is an adaptor protein involving in a variety of physiological and disease processes. Renal interstitial fibrosis (RIF) is a hallmark of common progressive chronic diseases which lead to renal failure. This study was performed to investigate whether there was a potential signal pathway between PAX2 and CD2AP in RIF rats induced by unilateral ureteral obstruction (UUO). Eighty Wistar male rats were divided into two groups randomly: sham operation group (SHO) and model group subjected to UUO (GU), n = 40. The model was established by left ureteral ligation. Renal tissues were collected at 14 d and 28 d after surgery. RIF index, cell apoptosis index, protein expression of PAX2, CD2AP, transforming growth factor-betal (TGF-beta1), collagen-IV (Col-IV), fibronectin (FN) in renal interstitium and renal tissue, and mRNA expression of PAX2, CD2AP, and TGF-beta1 in renal tissue were detected. Compared with that in the SHO group, the PAX2 and CD2AP expressions (mRNA and protein) were significantly increased (p < 0.01). Protein expressions of TGF-beta1, Col-IV, and FN, and RIF index or cell apoptosis index in the GU group were markedly elevated than those in the SHO group (all p < 0.01). PAX2 or CD2AP was positively correlated with TGF-beta1, Col-IV, and FN, and RIF index or cell apoptosis index (all p < 0.05). Furthermore, PAX2 was positively correlated with CD2AP (p < 0.05). In conclusion, the expression of PAX2 or CD2AP was increased in RIF rats, and PAX2 was positively correlated with CD2AP. There might be a potential signaling pathway between PAX2 and CD2AP in RIF disease. Further research is needed to determine the association in RIF disease. PMID- 24471427 TI - Hyaluronan contributes to bronchiolitis obliterans syndrome and stimulates lung allograft rejection through activation of innate immunity. AB - RATIONALE: Although innate immunity is increasingly recognized to contribute to lung allograft rejection, the significance of endogenous innate ligands, such as hyaluronan (HA) fragments, in clinical or experimental lung transplantation is uncertain. OBJECTIVES: To determine if HA is associated with clinical bronchiolitis obliterans syndrome (BOS) in lung transplant recipients, and evaluate the effect of low- or high-molecular-weight HA on experimental lung allograft rejection, including dependence on innate signaling pathways or effector cells. METHODS: HA concentrations were measured in bronchoalveolar lavage and plasma samples from lung recipients with or without established BOS. BOS and normal lung tissues were assessed for HA localization and expression of HA synthases. Murine orthotopic lung recipients with established tolerance were treated with low- or high-molecular-weight HA under varied experimental conditions, including Toll-like receptor (TLR) 2/4 and myeloid differentiation protein 88 deficiency and neutrophil depletion. MEASUREMENTS AND MAIN RESULTS: HA localized within areas of intraluminal small airways fibrosis in BOS lung tissue. Moreover, transcripts for HA synthase enzymes were significantly elevated in BOS versus normal lung tissues and both lavage fluid and plasma HA concentrations were increased in recipients with BOS. Treatment with low-molecular-weight HA abrogated tolerance in murine orthotopic lung recipients in a TLR2/4- and myeloid differentiation protein 88-dependent fashion and drove expansion of alloantigen specific T lymphocytes. Additionally, TLR-dependent signals stimulated neutrophilia that promoted rejection. In contrast, high-molecular-weight HA attenuated basal allograft inflammation. CONCLUSIONS: These data suggest that accumulation of HA could contribute to BOS by directly activating innate immune signaling pathways that promote allograft rejection and neutrophilia. PMID- 24471429 TI - p38 Mitogen-activated protein kinase is stimulated by both angiotensin II and angiotensin III in cultured rat astrocytes. AB - CONTEXT: Previously we showed that angiotensin (Ang) II and Ang III induced phosphorylation of ERK1/2 and JNK mitogen-activated protein (MAP) kinases in rat astrocytes. OBJECTIVES: To determine whether these peptides induce p38 MAP kinase in astrocytes. MATERIALS AND METHODS: We used brainstem astrocytes as a model system to determine whether Ang II and Ang III induce p38 MAP kinase protein phosphorylation. RESULTS: Treatment of astrocytes with increasing concentrations of both peptides caused a dose-dependent increase in p38 MAP kinase phosphorylation. The effect of Ang II and Ang III was maximal at 10 nM and 100 nM concentrations, respectively. The effects of the peptides were rapid occurring within minutes of treatment. There was a significant difference in the ability of the peptides to induce p38 MAP kinase phosphorylation. The ability of Ang II to induce p38 MAP kinase was almost twice than that of Ang III, suggesting that Ang II was more potent than Ang III in this effect. Ang AT1 receptor mediated the actions of the peptides since pretreatment with losartan prevented p38 MAP kinase phosphorylation by Ang II and Ang III. In addition, blockade of Ang II metabolism to Ang III with the aminopeptidase A inhibitor glutamate phosphonate was ineffective in ameliorating Ang II phosphorylation of p38 MAP kinase, suggesting that Ang II directly stimulated p38 MAP kinase phosphorylation. CONCLUSION: These findings provide insight into the molecular nature of the actions of these peptides and offer a possible mechanism by which these Ang peptides physiological and possibly pathological actions occur in astrocytes. PMID- 24471436 TI - Polymers with multishape memory controlled by local glass transition temperature. AB - A multishape memory polymer with flexible design capabilities is fabricated by a very simple method. Local glass transition temperatures of a loosely cross-linked polymer film are changed by immersing sections of the film in a cross-linker solution with a different concentration. Each section memorizes a temporary shape, which recovers its permanent shape at a different recovery temperature depending on the local glass transition temperature. As a base polymer, we chose a network polymer prepared by a Diels-Alder reaction between poly(2,5 furandimethylene succinate) (PFS) and 1,8-bis-maleimidotriethyleneglycol (M2). Quintuple shape memory behavior was demonstrated by a PFS/M film with four sections with distinct glass transition temperatures. The number of temporary shapes was determined by the number of different M2 solutions. Furthermore, owing to the reversibility of the Diels-Alder reaction, the permanent shape was rewritable. PMID- 24471437 TI - Synthesis, structure-activity relationships and brain uptake of a novel series of benzopyran inhibitors of insulin-regulated aminopeptidase. AB - Peptide inhibitors of insulin-regulated aminopeptidase (IRAP) enhance fear avoidance and spatial memory and accelerate spatial learning in a number of memory paradigms. Using a virtual screening approach, a series of benzopyran compounds was identified that inhibited the catalytic activity of IRAP, ultimately resulting in the identification of potent and specific inhibitors. The present study describes the medicinal chemistry campaign that led to the development of the lead candidate, 3, highlighting the key structural features considered as critical for binding. Furthermore, the in vivo pharmacokinetics and brain uptake of compounds (1 and 3) were assessed in rats and were complemented with in vitro human and rat microsomal stability studies. Following intravenous administration to rodents, 3 exhibits brain exposure, albeit it is rapidly converted to 1, a compound which also exhibits potent inhibition of IRAP. PMID- 24471438 TI - An anthocyanin-rich extract from Hibiscus sabdariffa linnaeus inhibits N nitrosomethylurea-induced leukemia in rats. AB - A previous study reported that anthocyanins from roselle (Hibiscus sabdariffa L.) showed significant anticancer activity in human promyelocytic leukemia cells. To explore the antitumor effect of anthocyanin, a roselle bioactive polyphenol in a rat model of chemical-induced leukemia was assayed. Anthocyanin extract of roselle (Hibiscus anthocyanins, HAs) was supplemented in the diet (0.1 and 0.2%). This study was carried out to evaluate the protective effect of HAs on N nitrosomethylurea (NMU)-induced leukemia of rats. The study employed male Sprague Dawley rats (n = 48), and leukemia was induced by intravenous injection of 35 mg kg(-1) body weight of NMU dissolved in physiologic saline solution. The rats were divided into four groups (n = 12): control, NMU only, and HAs groups that received different doses of HAs (0.1 and 0.2%) daily, orally, after NMU injection. After 220 days, the animals were killed, and the following parameters were assessed: morphological observation, hematology examination, histopathological assessment, and biochemical assay. When compared with the NMU only group, HAs significantly prevented loss of organ weight and ameliorated the impairment of morphology, hematology, and histopathology. Treatment with HAs caused reduction in the levels of AST, ALT, uric acid, and MPO. Also, the results showed that oral administration of HAs (0.2%) remarkably inhibited progression of NMU-induced leukemia by approximately 33.3% in rats. This is the first report to demonstrate that the sequential administration of HAs followed by NMU resulted in an antileukemic activity in vivo. PMID- 24471439 TI - Topological origin of fragility, network adaptation, and rigidity and stress transitions in especially homogenized nonstoichiometric binary Ge(x)S(100-x) glasses. AB - Binary GexS100-x glasses reveal a richness of elastic and chemical phase transitions driven by network topology. With increasing Ge content (x), well defined rigidity at xc(1) = 19.3(5)% and a stress transition at xc(2) = 24.9(5)% are observed in Raman scattering. In modulated DSC measurements, the nonreversing enthalpy of relaxation at Tg reveals a square-well-like minimum (reversibility window) with window walls that coincide with the two elastic phase transitions. Molar volumes show a trapezoidal-like minimum (volumetric window) with edges that nearly coincide with the reversibility window. These optical, thermal, and volumetric results are consistent with an isostatically rigid elastic phase (intermediate phase, IP) present between the rigidity (xc(1)) and stress (xc(2)) transitions. Complex Cp measurements show melt fragility index, m(x) to also show a global minimum in the reversibility window with m < 20, underscoring that melt dynamics encode the elastic behavior of the glass formed at Tg. The strong nature of melts formed in the IP has an important practical consequence; they lead to slow homogenization (over days not hours) of nonstoichiometric Ge-S batch compositions reacted at high temperatures. Homogenization of chalcogenide melts/glasses over a scale of a few micrometers is a prerequisite to observe the intrinsic physical properties of these materials. PMID- 24471431 TI - Microglia development and function. AB - Proper development and function of the mammalian central nervous system (CNS) depend critically on the activity of parenchymal sentinels referred to as microglia. Although microglia were first described as ramified brain-resident phagocytes, research conducted over the past century has expanded considerably upon this narrow view and ascribed many functions to these dynamic CNS inhabitants. Microglia are now considered among the most versatile cells in the body, possessing the capacity to morphologically and functionally adapt to their ever-changing surroundings. Even in a resting state, the processes of microglia are highly dynamic and perpetually scan the CNS. Microglia are in fact vital participants in CNS homeostasis, and dysregulation of these sentinels can give rise to neurological disease. In this review, we discuss the exciting developments in our understanding of microglial biology, from their developmental origin to their participation in CNS homeostasis and pathophysiological states such as neuropsychiatric disorders, neurodegeneration, sterile injury responses, and infectious diseases. We also delve into the world of microglial dynamics recently uncovered using real-time imaging techniques. PMID- 24471440 TI - Redox regulation of canonical Wnt signaling affects extraembryonic endoderm formation. AB - Retinoic acid (RA) induces mouse F9 cells to form primitive endoderm (PrE) and increased levels of reactive oxygen species (ROS) accompany differentiation. ROS are obligatory for differentiation and while H2O2 alone induces PrE, antioxidants attenuate the response to RA. Evidence shows that ROS can modulate the Wnt/beta catenin pathway and in this study, we show that extraembryonic endoderm formation is dependent on the redox state of nucleoredoxin (NRX). In undifferentiated F9 cells, NRX interacted with dishevelled 2 (Dvl2) and while this association was enhanced under reduced conditions, it decreased following H2O2 treatment. Depleting NRX levels caused morphological changes like those induced by RA, while increasing protein kinase A activity further induced these PrE cells to parietal endoderm. Reduced NRX levels also correlated to an increase in T-cell-factors lymphoid enhancer factors-mediated transcription, indicative of canonical Wnt signaling. Together these results indicate that a mechanism exists whereby NRX maintains canonical Wnt signaling in the off state in F9 cells, while increased ROS levels lift these constraints. Dvl2 no longer bound to NRX is now positioned to prime the Wnt pathway(s) required for PrE formation. PMID- 24471430 TI - Transcriptional control of early T and B cell developmental choices. AB - T and B cells share a common somatic gene rearrangement mechanism for assembling the genes that code for their antigen receptors; they also have developmental pathways with many parallels. Shared usage of basic helix-loop-helix E proteins as transcriptional drivers underlies these common features. However, the transcription factor networks in which these E proteins are embedded are different both in membership and in architecture for T and B cell gene regulatory programs. These differences permit lineage commitment decisions to be made in different hierarchical orders. Furthermore, in contrast to B cell gene networks, the T cell gene network architecture for effector differentiation is sufficiently modular so that E protein inputs can be removed. Complete T cell-like effector differentiation can proceed without T cell receptor rearrangement or selection when E proteins are neutralized, yielding natural killer and other innate lymphoid cells. PMID- 24471441 TI - A comparison of urban-rural injury mortality rates across two South African provinces, 2007. AB - This study explored urban-rural variations in the magnitude and patterns of fatal injuries in South Africa. The National Injury Mortality Surveillance System was utilised to select South African mortality cases for the 2007 period and a cross sectional methodology was employed in order to comparatively analyse injury mortality rates in the urban province of Gauteng and the rural province of Mpumalanga. The results reveal several differences in urban-rural injury trends across the two South African provinces. Overall, homicide and unintentional (non transport) injury death rates were significantly higher in the urban province (40.28/100,000 versus 28.48/100,000; (RR = 1.41 [1.32-1.51]) and 18.30/100,000 versus 13.19/100,000; (RR = 1.39 [1.25-1.54]), respectively), whilst transport related injury mortality rates were significantly higher in the rural province (66.57/100,000 versus 45.83/100,000; (RR = 0.69 [0.66-0.71])). Such results could be attributed to economical, environmental, and infrastructural differences between urban-rural locations and suggest that injury control strategies could be better targeted to the needs of specific geographic populations in South Africa. PMID- 24471443 TI - Stabilization of a Cl(-)-Cl(-) anion pair in the gas phase: ab initio microsolvation study. AB - Despite the confirmation of Cl(-)-Cl(-) association in aqueous solution and crystalline state, there have been no reports about the existence of stable dichloride anion pair in the gas phase. In the current work we performed a systematic ab initio study of microsolvation of dichloride anion pair. The stepwise solvation mechanism observed for free gaseous [Cl2(H2O)n](2-) (n = 2-10) clusters was found to be quite interesting. The lowest structure for dichloride hexahydrate closely resembles cubic water octamer W8 in which two water molecules in the corners of the cube are substituted by two chloride anions. We have also shown that Cl(-)-Cl(-) pair may be completely stabilized by about 36 water molecules in the gas phase. Stabilization of the pair leads to the formation of cyclic H2O structures that bridge the Cl(-) ions. It has been predicted that the large clusters of [Cl2(H2O)36](2-) and [Cl2(H2O)40](2-) may exhibit properties analogous to bulk aqueous solutions, therefore they could become good molecular models for understanding complicated processes of solvation of Cl(-) in the bulk. PMID- 24471444 TI - Psychological distress and attentional bias toward acne lesions in patients with acne. AB - Acne vulgaris is a common inflammatory disease that manifests on the face and affects appearance. In general, facial acne has a wide-ranging negative impact on the psychosocial functioning of acne sufferers and leaves physical and emotional scars. In the present study, we investigated whether patients with acne vulgaris demonstrate enhanced psychological bias when assessing the attractiveness of faces with acne symptoms and whether they devote greater selective attention to acne lesions than to acne-free (control) individuals. Participants viewed images of faces under two different skin (acne vs. acne-free) and emotional facial expression (happy and neutral) conditions. They rated the attractiveness of the faces, and the time spent fixating on the acne lesions was recorded with an eye tracker. We found that the gap in perceived attractiveness between acne and acne free faces was greater for acne sufferers. Furthermore, patients with acne fixated longer on facial regions exhibiting acne lesions than did control participants irrespective of the facial expression depicted. In summary, patients with acne have a stronger attentional bias for acne lesions and focus more on the skin lesions than do those without acne. Clinicians treating the skin problems of patients with acne should consider these psychological and emotional scars. PMID- 24471445 TI - Pyridostigmine prevents peripheral vascular endothelial dysfunction in rats with myocardial infarction. AB - 1. Myocardial infarction (MI) is characterized by the withdrawal of vagal activity and increased sympathetic activity. We have shown previously that pyridostigmine (PYR), an acetylcholinesterase inhibitor, was able to improve vagal activity and ameliorate cardiac dysfunction following MI. However, the effect of PYR on endothelial dysfunction in peripheral arteries after MI remains unclear. 2. In the present study, MI was induced by coronary artery ligation in adult Sprague-Dawley rats. Rats were treated intragastrically with saline or PYR (approximately 31 mg/kg per day) for 2 weeks, at which time haemodynamic and parasympathetic parameters and the vascular reactivity of isolated mesenteric arteries were measured and the ultrastructure of the endothelium evaluated. 3. Compared with the MI group, PYR not only improved cardiac function, vagal nerve activity and endothelial impairment, but also reduced intravascular superoxide anion and malondialdehyde. In addition, in the PYR-treated MI group, nitric oxide (NO) bioavailability was increased and attenuated endothelium-dependent relaxations were improved, whereas restored vasodilator responses were inhibited by N(G)-nitro-L-arginine methyl ester. 4. Based on our results, PYR is able to attenuate the impairment of peripheral endothelial function and maintain endothelial ultrastructural integrity in MI rats by inhibiting reactive oxygen species production, enhancing NO bioavailability and improving vagal activity. PMID- 24471446 TI - Variation in DNA methylation transmissibility, genetic heterogeneity and fecundity-related traits in natural populations of the perennial herb Helleborus foetidus. AB - Inferences about the role of epigenetics in plant ecology and evolution are mostly based on studies of cultivated or model plants conducted in artificial environments. Insights from natural populations, however, are essential to evaluate the possible consequences of epigenetic processes in biologically realistic scenarios with genetically and phenotypically heterogeneous populations. Here, we explore associations across individuals between DNA methylation transmissibility (proportion of methylation-sensitive loci whose methylation status persists unchanged after male gametogenesis), genetic characteristics (assessed with AFLP markers), seed size variability (within-plant seed mass variance), and realized maternal fecundity (number of recently recruited seedlings), in three populations of the perennial herb Helleborus foetidus along a natural ecological gradient in southeastern Spain. Plants (sporophytes) differed in the fidelity with which DNA methylation was transmitted to descendant pollen (gametophytes). This variation in methylation transmissibility was associated with genetic differences. Four AFLP loci were significantly associated with transmissibility and accounted collectively for ~40% of its sample-wide variance. Within-plant variance in seed mass was inversely related to individual transmissibility. The number of seedlings recruited by individual plants was significantly associated with transmissibility. The sign of the relationship varied between populations, which points to environment-specific, divergent phenotypic selection on epigenetic transmissibility. Results support the view that epigenetic transmissibility is itself a phenotypic trait whose evolution may be driven by natural selection, and suggest that in natural populations epigenetic and genetic variation are two intertwined, rather than independent, evolutionary factors. PMID- 24471447 TI - The expanding role of therapeutic antibodies. AB - Therapeutic antibodies have been used since the end of nineteenth century, but their use is progressively increased and recently, with the availability of monoclonal antibodies, they are successfully employed in a large disease spectrum, which transversally covers different fields of medicine. Hyperimmune polyclonal immune globulin has been used against infectious diseases, in a period in which anti-microbial drugs were not yet available, and it still maintains a relevant place in prophylaxis/therapy. Although immune globulin should be considered life-saving as replacement therapy in humoral immunodeficiencies, its place in the immune-modulating treatment is not usually first-choice, but it should be considered as support to standard approved treatments. Despite therapeutic monoclonal antibodies have been lastly introduced in therapy, their extreme potentiality is reflected by the large number of approved molecules, addressed toward different immunological targets and able to heavily influence the prognosis and quality of life of a wide range of different diseases. PMID- 24471448 TI - Interplay of infections, autoimmunity, and immunosuppression in systemic lupus erythematosus. AB - Infectious agents are considered to be crucial environmental factor in the etiopathogenesis of systemic lupus erythematosus (SLE). Infections may serve as initial trigger to the development of autoimmunity and carry an overall greater risk of morbidity and mortality than the general population. Initial presentation of SLE can mimic infections, and in turn infections can mimic disease flares in established SLE. Infections due to predisposition by commonly used immunosuppressive therapies are a significant cause of morbidity and mortality. In this review, viral, bacterial, fungal, and parasitic infections that contribute to the etiology of SLE, potentially mimic or precipitate flares, create diagnostic dilemmas, complicate treatment, or protect against disease, are discussed. Infection risks of current immunosuppressive therapies used in the treatment of SLE are outlined. Strategies to prevent infection, including vaccines, prophylactic antibiotic therapies, toll-like receptor antagonism, and antioxidant treatment that may decrease disease burden and improve quality of life in lupus patients will be discussed. PMID- 24471449 TI - Simulated life-threatening emergency during robot-assisted surgery. AB - BACKGROUND: With the increasing use of robot-assisted techniques for urologic and gynecologic surgery in patients with severe comorbidities, the risk of a critical incidence during surgery increases. Due to limited access to the patient the start of effective measures to treat a life-threatening emergency could be delayed. Therefore, we tested the management of an acute emergency in an operating room setting with a full-size simulator in six complete teams. METHODS: A full-size simulator (ISTAN, Meti, CA), modified to hold five trocars, was placed in a regular operating room and connected to a robotic system. Six teams (each with three nurses, one anesthesiologist, two urologists or gynecologists) were introduced to the scenario. Subsequently, myocardial fibrillation occurred. Time to first chest compression, removal of the robot, first defibrillation, and stabilization of circulation were obtained. After 7 weeks the simulation was repeated. RESULTS: The time to the start of chest compressions, removal of the robotic system, and first defibrillation were significantly improved at the second simulation. Time for restoration of stable circulation was improved from 417 +/- 125 seconds to 224 +/- 37 seconds (P=0.0054). Unexpected delays occurred during the first simulation because trocars had been removed from the patient but not from the robot, thus preventing the robot to be moved. CONCLUSION: Following proper training, resuscitation can be started within seconds. A repetition of the simulation significantly improved time for all steps of resuscitation. An emergency simulation of a multidisciplinary team in a real operating room setting can be strongly recommended. PMID- 24471450 TI - A dynamin homolog promotes the transition from hemifusion to content mixing in intracellular membrane fusion. AB - The convergence of the antagonistic reactions of membrane fusion and fission at the hemifusion/hemifission intermediate has generated a captivating enigma of whether Soluble N-ethylmaleimide sensitive factor Attachment Protein Receptor (SNAREs) and dynamin have unusual counter-functions in fission and fusion, respectively. SNARE-mediated fusion and dynamin-driven fission are fundamental membrane flux reactions known to occur during ubiquitous cellular communication events such as exocytosis, endocytosis and vesicle transport. Here we demonstrate the influence of the dynamin homolog Vps1 (Vacuolar protein sorting 1) on lipid mixing and content mixing properties of yeast vacuoles, and on the incorporation of SNAREs into fusogenic complexes. We propose a novel concept that Vps1, through its oligomerization and SNARE domain binding, promotes the hemifusion-content mixing transition in yeast vacuole fusion by increasing the number of trans SNAREs. PMID- 24471451 TI - Bilirubin rinse of the graft ameliorates ischemia reperfusion injury in heart transplantation. AB - Ischemia and reperfusion contribute to substantial organ damage in transplantation. Clinically feasible measures for the prevention thereof are scarce. We tested whether rinsing rodent hearts with the antioxidant bilirubin ameliorates ischemia reperfusion injury (IRI). Left ventricular end-diastolic pressure (LVEDP), left ventricular developed pressure (LVDevP), rate per pressure product (RPP), coronary flow, maximum (+dP/dt) and minimum (-dP/dt) rate of contraction were analyzed in Lewis rat hearts rinsed with bilirubin prior to reperfusion on a Langendorff apparatus after 12 h of cold ischemia. In vivo, isogenic C57Bl/6 mouse hearts rinsed with bilirubin were transplanted after 12 h of cold ischemia. Cardiac function and apoptosis were assessed 24 h after reperfusion. Heart lysates recovered 15 min after reperfusion were probed for the total and the phosphorylated forms of extracellular signal-related protein kinases (ERK), JNK, p38-MAPK, and Akt. In isolated perfused hearts, bilirubin rinse resulted in significantly lower LVEDP and improved LVDevP, RPP, coronary flow, +dP/dt and -dP/dt. In vivo, after reperfusion, all mitogen-activated protein kinases (MAPKs) were suppressed significantly by bilirubin pretreatment. Bilirubin rinse improved cardiac scores (3.4 +/- 0.5 vs. 2.0 +/- 1.0 in controls, P < 0.05) and significantly suppressed apoptosis. Ex vivo administration of bilirubin to heart grafts prior reperfusion ameliorates IRI and provides a simple and effective tool to ameliorate outcome in heart transplantation. PMID- 24471452 TI - The role of cognitive abilities in children's inferences about social atypicality and peer exclusion and inclusion in intergroup contexts. AB - Children aged 6-7 years judged a loyal and a partially disloyal member of a school in terms of how typical they are within the school group and their likely acceptance by peers from the same school and a different school. Second-order mental-state understanding (SOMSU) predicted whether children thought atypical members would be included differently in the two groups. Counterfactual reasoning ability, multiple classification ability, and working memory ability did not predict children's judgements of group members. Moreover, as predicted by the developmental subjective group dynamics model, only children with higher levels of SOMSU and who discerned differences in the typicality of normative and deviant ingroup members inferred that peers would differently include atypical individuals from the same and different groups. PMID- 24471453 TI - Relapses in multiple sclerosis: effects of high-dose steroids on cortical excitability. AB - BACKGROUND AND PURPOSE: High-dose steroid administration is the usual treatment of multiple sclerosis (MS) relapse, but it remains to determine whether this treatment may act by changing the excitability of cortical circuitry. METHODS: The functional cortical effects of high-dose steroids in 21 MS patients before and after 3 days of intravenous administration of methylprednisolone (1 g/day) for the treatment of MS relapse were studied. Investigations included various clinical scales [Kurtzke Functional System Scale (KFSS), Expanded Disability Status Scale and Fatigue Severity Scale, 10-m walk] and transcranial magnetic stimulation (TMS) tests of cortical excitability [resting motor threshold, recruitment curve of motor evoked potentials, short-interval intracortical inhibition (SICI) and intracortical facilitation (ICF) at various interstimuli intervals (ISIs), cortical silent period and interhemispheric inhibition]. RESULTS: Following steroid administration, clinical improvement was significant for the KFSS pyramidal (motor) and total scores, whilst TMS showed a reduction of SICI (mean and maximum values) and an increase of ICF at 10 ms ISI. CONCLUSIONS: Very rapid functional changes in the excitability of cortical circuits involved in motor control can be induced by steroids, before any process of remyelination or axonal regeneration has time to occur. The net effect of steroids on the balance between intracortical GABAergic inhibition and glutamatergic facilitation was in favour of weaker inhibition or stronger facilitation, which could lead to improving the motor performance in MS patients. PMID- 24471454 TI - Contribution of illegal acts to pathological gambling diagnosis: DSM-5 implications. AB - The purposes of this study were to examine the specific contribution of illegal acts to the diagnostic criteria of pathological gambling, to assess the possibility of differential item functioning across patients' sex and age, and to explore the existence of different clinical phenotypes based on the presence of illegal acts. The sample consisted of 2,155 patients seeking treatment for pathological gambling at the University Hospital of Bellvitge in Barcelona, Spain. The illegal acts item did not show different item functioning, and younger patients presented higher latent means than middle-aged and older patients, whereas no differences were found across sex. This item also showed the lowest discrimination coefficient; its exclusion would maintain satisfactory internal consistency for the remaining 9 symptoms and was poorly related to psychopathology and the severity of the gambling behavior. The relevance of the illegal acts as a diagnostic criterion appears to be limited, and its elimination from the Diagnostic and Statistical Manual for Mental Disorders, 5th edition, seems justified. However, illegal acts have implications for both the clinical and legal domains and contribute to increase the patients' impairment. PMID- 24471455 TI - Functional diversity of phytochrome family in the control of light and gibberellin-mediated germination in Arabidopsis. AB - In several species, seed germination is regulated by light in a way that restricts seedling emergence to the environmental conditions that are likely to be favourable for the success of the new individual, and therefore, this behaviour is recognized to have adaptive value. The phytochromes are one of the most relevant photoreceptors involved in light perception by plants. We explored the redundancy and diversity functions of the phytochrome family in the control of seed responsiveness to light and gibberellins (GA) by using a set of phytochrome mutants of Arabidopsis. Our data show that, in addition to the well known role of phyB in the promotion of germination in response to high red to far red ratios (R/FR), phyE and phyD stimulate germination at very low R/FR ratios, probably by promoting the action of phyA. Further, we show that phyC regulates negatively the seed responsiveness to light, unravelling unexpected functions for phyC in seed germination. Finally, we find that seed responsiveness to GA is mainly controlled by phyB, with phyC, phyD and phyE having relevant roles when acting in a phyB-deficient background. Our results indicate that phytochromes have multiple and complex roles during germination depending on the active photoreceptor background. PMID- 24471456 TI - Human demodicosis: revisit and a proposed classification. AB - Human Demodex mites (Demodex folliculorum and Demodex brevis) hold a high rank in the evolutionary and phylogenetic hierarchy of the skin microbiome, although in most people their presence is of no consequence. While human demodicosis is a skin disease sui generis, it can mimic many other inflammatory dermatoses, such as folliculitis, rosacea and perioral dermatitis, leading to unspecific and confusing descriptions in the literature. Here, we propose to classify human demodicosis into a primary form and a secondary form, which is associated mainly with immunosuppression. The clinical manifestations of primary demodicosis may include (i) spinulate demodicosis, currently known as pityriasis folliculorum, involving sebaceous hair follicles without visible inflammation; (ii) papulopustular/nodulocystic or conglobate demodicosis with pronounced inflammation affecting most commonly the perioral and periorbital areas of the face; (iii) ocular demodicosis, inducing chronic blepharitis, chalazia or, less commonly, keratoconjunctivitis; and (iv) auricular demodicosis causing external otitis or myringitis. Secondary demodicosis is usually associated with systemic or local immunosuppression. Treatment is only weakly evidence based, and the most effective concentrations of acaricides remain to be determined. Optimization of an in vitro or ex vivo culture model is necessary for future studies. Endosymbiosis between certain bacteria and Demodex mites in the pathogenesis of demodicosis deserves more attention. Further clinical observations and experiments are needed to prove our hypothesis. PMID- 24471457 TI - Antimycotics suppress the Malassezia extract-induced production of CXC chemokine ligand 10 in human keratinocytes. AB - Malassezia, a lipophilic yeast, exacerbates atopic dermatitis. Malassezia products can penetrate the disintegrated stratum corneum and encounter subcorneal keratinocytes in the skin of atopic dermatitis patients. Type 1 helper T (Th1) cells infiltrate chronic lesions with atopic dermatitis, and antimycotic agents improve its symptoms. We aimed to identify Malassezia-induced chemokines in keratinocytes and examine whether antimycotics suppressed this induction. Normal human keratinocytes were incubated with a Malassezia restricta extract and antimycotics. Chemokine expression was analyzed by enzyme-linked immunosorbent assays and real-time polymerase chain reaction. Signal transducer and activator of transcription (STAT)1 activity was examined by luciferase assays. The tyrosine phosphorylation of STAT1 was analyzed by western blotting. The M. restricta extract increased the mRNA and protein expression of Th1-attracting CXC chemokine ligand (CXCL)10 and STAT1 activity and phosphorylation in keratinocytes, which was suppressed by a Janus kinase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine suppressed M. restricta extract-induced CXCL10 mRNA and protein expression and STAT1 activity and phosphorylation. These effects were similarly induced by 15-deoxy-Delta (12,14) -prostaglandin J2 (15d-PGJ2 ), a prostaglandin D2 metabolite. Antimycotics increased the release of 15d-PGJ2 from keratinocytes. The antimycotic-induced suppression of CXCL10 production and STAT1 activity was counteracted by a lipocalin-type prostaglandin D synthase inhibitor. The antimycotics itraconazole, ketoconazole, luliconazole, terbinafine, butenafine and amorolfine may suppress the M. restricta-induced production of CXCL10 by inhibiting STAT1 through an increase in 15d-PGJ2 production in keratinocytes. These antimycotics may block the Th1-mediated inflammation triggered by Malassezia in the chronic phase of atopic dermatitis. PMID- 24471458 TI - Defective barrier function accompanied by structural changes of psoriatic stratum corneum. AB - Although barrier function of psoriatic skin is shown to be decreased by measuring transepidermal water loss (TEWL), few reports exist examining other physical skin properties and components including stratum corneum hydration, natural moisturizing factor (NMF), free fatty acids (FFA), beta-sheet and alpha-helix ratio of structural protein(s), and sebum content. We compared the skin properties and components of normal, involved and uninvolved skin of psoriasis. Using a corneometer and attenuated total reflection-infrared spectrometer, we measured TEWL, stratum corneum hydration, NMF, FFA, beta/alpha ratio and sebum in psoriasis vulgaris patients and healthy controls. TEWL and beta/alpha ratio of involved psoriatic skin were significantly increased compared with uninvolved skin and normal control skin. In contrast, stratum corneum hydration, NMF and FFA, but not sebum, are significantly decreased in the involved skin compared with uninvolved skin and normal skin. TEWL and stratum corneum hydration returned to the normal levels following clinical improvement of the lesion. Barrier function and hydration of psoriatic skin are defective and secondary structure in stratum corneum protein is altered in the involved psoriatic skin. PMID- 24471459 TI - Minoxidil 2% lotion for eyebrow enhancement: a randomized, double-blind, placebo controlled, spilt-face comparative study. AB - Topical minoxidil has been successfully used to treat androgenetic alopecia. It can also be applied to enhance eyebrows. However, there is no study comparing minoxidil lotion with placebo for eyebrow enhancement. In this trial, we determined the efficacy and safety of minoxidil 2% lotion for eyebrow enhancement compared with placebo. Forty patients were randomized for minoxidil on the eyebrow on one side of the face and placebo on the other. Efficacy was evaluated by global photographic assessment, eyebrow diameter, eyebrow count and subject's satisfaction. Side-effects were also evaluated. Thirty-nine patients (97.5%) completed the study. After 16 weeks, the minoxidil group achieved significantly better results in all measured outcomes compared to the placebo group. Side effects were minor and did not preclude patients from continuing the study. Our study suggests that minoxidil 2% lotion is a safe and effective treatment for eyebrow hypotrichosis. PMID- 24471460 TI - Drug-induced hypersensitivity syndrome due to minocycline complicated by severe myocarditis. AB - A 60-year-old woman presented with a 13-day history of a generalized erythematous rash accompanied by fever, periorbital edema and axillary lymphadenopathy. Prior to the appearance of the rash, the patient had been treated with intermittent courses of oral minocycline for cystitis. The patient was diagnosed with drug induced hypersensitivity syndrome (DIHS) due to minocycline. During the admission, infectious endocarditis was suspected and the patient was treated with i.v. gammaglobulin (0.4 g/kg per day). The following day, the patient suffered from systemic deterioration and symptomatic low blood pressure that prompted repeat echocardiography which revealed an ejection fraction of 10%. DIHS associated myocarditis was suspected and management with circulation assistance devices and steroid pulse therapy were started, resulting in satisfactory resolution. A rise in titer of human herpesvirus-6, cytomegalovirus and Herpes simplex virus-1 antibodies was detected. Although minocycline-induced myocarditis is rare, this severe drug reaction should be considered with DIHS. PMID- 24471461 TI - Proliferative fasciitis mimicking a sarcoma in a child: a case report. AB - Proliferative fasciitis (PF) is a benign, discrete proliferation of fibroblasts or myofibroblasts in soft tissue. Proliferative fasciitis mostly occurs in adults and is often confused with a sarcoma because of its rapid growth and peculiar histological features. We report a case of PF mimicking a sarcoma which developed in a 13-year-old boy, who noticed a painful tumor, with gradual enlargement, in his right lower leg. Magnetic resonance imaging revealed that the tumor measured 34 mm * 20 mm * 41 mm and was located in the subcutaneous tissue. The tumor was surgically resected. Pathologically, the tumor was composed of a proliferation of atypical spindle cells, admixed with larger ganglion-like cells. Immunohistochemically, the tumor cells were positive for vimentin, cytokeratin, smooth muscle actin, HHF-35 and Fli-1. The tumor was subsequently diagnosed as a PF, although it was difficult to differentiate from a sarcoma. Five years after surgery, the postoperative course has been uneventful with no recurrence or metastasis. PMID- 24471462 TI - Case of basal cell carcinoma with ductal differentiation. PMID- 24471463 TI - Hapten-induced lymphadenosis benigna cutis secondary to squaric acid dibutylester sensitization for alopecia areata. PMID- 24471464 TI - Rituximab therapy for deep toe ulcer with microscopic polyangiitis refractory to corticosteroids and cyclophosphamide. PMID- 24471465 TI - Marked histiocytic infiltration in neonatal lupus erythematosus. PMID- 24471467 TI - Compartmentalized multilayer hydrogel formation using a stimulus-responsive self assembling polysaccharide. AB - Polymeric systems that self-assemble through strong noncovalent bonds form structures that are highly dependent on the spatiotemporal sequence of cues that trigger self-assembly. Here, we prepared capsules with a semipermeable alginate chitosan polyelectrolyte membrane that encapsulates a solution of the pH responsive self-assembling aminopolysaccharide chitosan. Immersion of these capsules in a basic solution triggers gelation of the capsule contents, and the details of the gel-inducing treatment dramatically affect the final structure of the gelled compartment. Specifically, we show that the sequential transfer of the capsules between the base and water can generate multilayer hydrogel structures, with the thickness of each layer being controlled by the base concentration and immersion times. We further demonstrate that these multilayer hydrogels can serve as templates for the synthesis of iron oxide particles with a complex internal structure (i.e., with a multilayer internal structure). This work demonstrates the ability to enlist the stimulus-responsive self-assembling properties of biological polymers to create materials with complex structures. PMID- 24471466 TI - Novel pyrrolidine diketopiperazines selectively inhibit melanoma cells via induction of late-onset apoptosis. AB - A common liability of cancer drugs is toxicity to noncancerous cells. Thus, molecules are needed that are potent toward cancer cells while sparing healthy cells. The cost of traditional cell-based HTS is dictated by the library size, which is typically in the hundreds of thousands of individual compounds. Mixture based combinatorial libraries offer a cost-effective alternative to single compound libraries while eliminating the need for molecular target validation. Presently, lung cancer and melanoma cells were screened in parallel with healthy cells using a mixture-based library. A novel class of compounds was discovered that selectively inhibited melanoma cell growth via apoptosis with submicromolar potency while sparing healthy cells. Additionally, the cost of screening and biological follow-up experiments was significantly lower than in typical HTS. Our findings suggest that mixture-based phenotypic HTS can significantly reduce cost and hit-to-lead time while yielding novel compounds with promising pharmacology. PMID- 24471468 TI - Wnt5a induces Ryk-dependent and -independent effects on callosal axon and dendrite growth. AB - The non-canonical Wnt receptor, Ryk, promotes chemorepulsive axon guidance in the developing mouse brain and spinal cord in response to Wnt5a. Ryk has also been identified as a major suppressor of axonal regrowth after spinal cord injury. Thus, a comprehensive understanding of how growing axons and dendrites respond to Wnt5a-mediated Ryk activation is required if we are to overcome this detrimental activity. Here we undertook a detailed analysis of the effect of Wnt5a/Ryk interactions on axonal and dendritic growth in dissociated embryonic mouse cortical neuron cultures, focusing on callosal neurons known to be responsive to Ryk-induced chemorepulsion. We show that Ryk inhibits axonal growth in response to Wnt5a. We also show that Wnt5a inhibits dendrite growth independently of Ryk. However, this inhibition is relieved when Ryk is present. Therefore, Wnt5a mediated Ryk activation triggers divergent responses in callosal axons and dendrites in the in vitro context. PMID- 24471469 TI - Antioxidant and antiglycation activity of selected dietary polyphenols in a cookie model. AB - Dietary polyphenols have been proposed to be promising functional food additives for their potent antioxidant capacity and other health-beneficial bioactivities. The current study prepared cookies fortified with five selected dietary polyphenols (naringenin, quercetin, epicatechin, chlorogenic acid, and rosmarinic acid). Results indicated that the enhancement of the antioxidant capacity was not as obvious as expected because the phenolics' antioxidant activity was seriously lowered by the baking process due to thermal degradation and transformation. Meanwhile, the tested polyphenols, especially quercetin, showed inhibition against formation of both reactive carbonyl species and total fluorescent advanced glycation endproducts (AGEs). Polyphenol fortification could also induce colorimetric changes and alterations in selected quality attributes. Overall, the findings support dietary polyphenols as functional food ingredients in the purpose of health benefits associated with a higher intake of antioxidants and a lower load of reactive carbonyls and AGEs. The polyphenols' stability and reactivity during thermal processing should be an important consideration. PMID- 24471470 TI - Experimental and modeling studies of an unusual water-filled pore structure with possible mechanistic implications in family 48 cellulases. AB - Molecular dynamics simulations were used to study the possible catalytic role of an unusual conserved water-filled pore structure in the family 48 cellulase enzyme Cel48A from Thermobifida fusca. It was hypothesized that this pore serves as the pathway for the water molecules consumed in the hydrolysis catalyzed by the enzyme to reach the active site in a continuous stream to participate in the processive reactions. Theoretical mutants of this enzyme were created in which all of the residues lining the pore were made hydrophobic, which had the effect in molecular dynamics simulations of emptying the pore of water molecules and preventing any from passing through the pore on the simulation time scale. Mutants with smaller numbers of substitutions of this nature, which could be created experimentally by site-directed mutagenesis, were also identified from simulations, and these proteins were subsequently produced in Escherichia coli, expressed and purified, but were found to not fold in a manner similar to the wild type protein, preventing the determination of the importance of the water pore for activity. It is possible that the presence of a small vacuum in the pore was responsible for the instability of the mutants. In addition, alternate pathways were observed in the simulations that would allow water molecules to reach the active site of the enzyme, suggesting that the hypothesis that the pore has functional significance might be incorrect. PMID- 24471471 TI - Atomic-scale observation of multiconformational binding and energy level alignment of ruthenium-based photosensitizers on TiO2 anatase. AB - Dye-sensitized solar cells constitute a promising approach to sustainable and low cost solar energy conversion. Their overall efficiency crucially depends on the effective coupling of the photosensitizers to the photoelectrode and the details of the dye's energy levels at the interface. Despite great efforts, the specific binding of prototypical ruthenium-based dyes to TiO2, their potential supramolecular interaction, and the interrelation between adsorption geometry and electron injection efficiency lack experimental evidence. Here we demonstrate multiconformational adsorption and energy level alignment of single N3 dyes on TiO2 anatase (101) revealed by scanning tunnelling microscopy and spectroscopy. The distinctly bound molecules show significant variations of their excited state levels associated with different driving forces for photoelectron injection. These findings emphasize the critical role of the interfacial coupling and suggest that further designs of dye-sensitized solar cells should target a higher selectivity in the dye-substrate binding conformations in order to ensure efficient electron injection from all photosensitizers. PMID- 24471473 TI - A brief intervention changing oral self-care, self-efficacy, and self-monitoring. AB - BACKGROUND AND AIM: The roles of self-efficacy and self-monitoring as proximal predictors of dental flossing frequency are studied in the context of an oral health intervention. MATERIALS AND METHODS: A study among 287 university students, aged 19 to 26 years, compared an intervention group that received a brief self-regulatory treatment, with a passive and an active control group. Dental flossing, self-efficacy, and self-monitoring were assessed at baseline and 3 weeks later. RESULTS: The intervention led to an increase in dental flossing regardless of experimental condition. However, treatment-specific gains were documented for self-efficacy and self-monitoring. Moreover, changes in the latter two served as mediators in a path model, linking the intervention with subsequent dental flossing and yielding significant indirect effects. CONCLUSIONS: Self efficacy and self-monitoring play a mediating role in facilitating dental flossing. Interventions that aim at an improvement in oral self-care should consider using these constructs. Statement of contribution What is already known on this subject? The adoption and maintenance of oral self-care can be facilitated by a number of social-cognitive variables. Interventions that include planning, action control, or self-efficacy components have been shown to improve dental flossing. In one recent study on flossing in adolescent girls, planning intervention effects were mediated by self-efficacy. What does this study add? Self-monitoring is associated with better oral self-care. A 10-min intervention improves self-efficacy and self-monitoring. Self-efficacy and self-monitoring operate as mediators between treatment and flossing. PMID- 24471474 TI - Effects of peptide fraction and counter ion on the development of clinical signs in experimental autoimmune encephalomyelitis. AB - The most commonly used immunogen to induce experimental autoimmune encephalomyelitis is MOG35-55 , a 21-residue peptide derived from myelin oligodendrocyte glycoprotein (MOG). In most studies, mice exhibit a chronic disease; however, in some studies mice show a transient disease. One variable that is not often controlled for is the peptide fraction of the purified MOG material, which can vary from less than 50% to over 90%, with the remainder of mass primarily comprised of the counter ion used for peptide purification. We compared the development of clinical signs in female C57Bl6 mice immunized with two commercially available MOG35-55 peptides of similar purity but different peptide fraction (MOG-A being 45%; MOG-B being 72%). A single immunization with MOG-A induced a chronic disease course with some recovery at later stages, whereas immunization with MOG-B induced a similar course of disease but with significantly lower average clinical scores despite a higher peptide content. The addition of a booster immunization significantly increased clinical severity with both preparations, and significantly reduced the average day of onset using MOG A. To determine if the counter ion could influence disease, we compared MOG-B containing trifluoroacetate with MOG-B-containing acetate. Although disease incidence and severity were similar, the average day of disease onset occurred approximately 5 days earlier with the use of MOG-B-containing trifluoroacetate. These results demonstrate that differences in peptide fraction influence the course of encephalomyelitis disease, which may be due in part to the levels of counter ions present in the purified material. These findings underscore the fact that a knowledge of peptide fraction is as critical as knowledge of peptide purity when using peptides from different sources. PMID- 24471475 TI - Prevention, diagnosis and treatment of high-throughput sequencing data pathologies. AB - High-throughput sequencing (HTS) technologies generate millions of sequence reads from DNA/RNA molecules rapidly and cost-effectively, enabling single investigator laboratories to address a variety of 'omics' questions in nonmodel organisms, fundamentally changing the way genomic approaches are used to advance biological research. One major challenge posed by HTS is the complexity and difficulty of data quality control (QC). While QC issues associated with sample isolation, library preparation and sequencing are well known and protocols for their handling are widely available, the QC of the actual sequence reads generated by HTS is often overlooked. HTS-generated sequence reads can contain various errors, biases and artefacts whose identification and amelioration can greatly impact subsequent data analysis. However, a systematic survey on QC procedures for HTS data is still lacking. In this review, we begin by presenting standard 'health check-up' QC procedures recommended for HTS data sets and establishing what 'healthy' HTS data look like. We next proceed by classifying errors, biases and artefacts present in HTS data into three major types of 'pathologies', discussing their causes and symptoms and illustrating with examples their diagnosis and impact on downstream analyses. We conclude this review by offering examples of successful 'treatment' protocols and recommendations on standard practices and treatment options. Notwithstanding the speed with which HTS technologies - and consequently their pathologies - change, we argue that careful QC of HTS data is an important - yet often neglected - aspect of their application in molecular ecology, and lay the groundwork for developing a HTS data QC 'best practices' guide. PMID- 24471476 TI - Laser interstitial thermal therapy in treatment of brain tumors--the NeuroBlate System. AB - Treatment of brain tumors remains challenging. Cytoreductive surgery is used as the first line treatment for most brain tumors. However complete, curative, resection is not achievable in many tumors leading to the need for adjuvant chemotherapy and radiation therapy. Laser interstitial thermal therapy (LITT) is a minimally invasive cytoreductive treatment. A low voltage laser is used to induce hyperthermia and to kill tumor cells. The extent of thermal damage is controlled through use of real-time MR-thermography guidance. Initial results have shown the feasibility of LITT for a variety of brain pathologies. LITT can be considered as an alternative type of surgery for difficult to access brain tumors and also for tumors in patients who are deemed high risk for more traditional surgery. Randomized trials are currently planned to continue assessing the efficacy of LITT and long-term follow-up data are awaited. PMID- 24471477 TI - Pharmacokinetics and pharmacodynamics of FSK0808 and Gran after single intravenous drip administration or single subcutaneous administration: comparative study in healthy Japanese adult male subjects. AB - FSK0808 is a recombinant human granulocyte colony-stimulating factor developed by Fuji Pharma Co., Ltd and Mochida Pharmaceutical Co., Ltd. as a biosimilar product of Gran(r). We verified the pharmacokinetic/pharmacodynamic equivalence of FSK0808 and commercially available Gran(r) by a randomized crossover study of single intravenous dose (200 ug/m(2)) and single subcutaneous dose (400 ug/m(2)) in healthy Japanese adult male subjects. According to the bioequivalence guidelines, the area under the blood concentration - time curve by 48 hours after administration (AUC0-48) in a single intravenous drip (IVD) study, and AUC0-48 and maximum blood concentration (Cmax) in a single subcutaneous (SC) dose study were used as primary endpoints, and the pharmacodynamic parameters including absolute neutrophil count (ANC) or number of CD34 positive cells (CD34(+) cells) as secondary endpoints. The safety was evaluated based on the characteristics and incidence of adverse reactions. As a result, the 90% confidence interval (CI) of the difference in mean value for AUC0-48 among drugs ranged from log(0.8) to log(1.25), in the IVD study, and those for Cmax and AUC0-48 were within the range of log(0.8)-log(1.25) in the SC study. Those for secondary endpoints were all within the range of log(0.8)-log(1.25). Thus, the pharmacokinetics/pharmacodynamics of both drugs were considered equivalent for all routes of administration, and the profiles of adverse reactions were also very similar. PMID- 24471478 TI - Long-term relapse of ultra-rapid opioid detoxification. AB - Ultra-rapid opioid detoxification (UROD) and subsequently induction of naltrexone maintenance therapy can be regarded as a safe and effective detoxification method for use in patients with opiate addiction. Long-term efficacy, relapse time, and relapse rate of this method is not clear. The aim of this article was to assess UROD efficacy and estimate the relapse rate in the 2-year follow-up period. Opioid-addicted, self-reporting patients referred to our hospital center were enrolled. All demographic data were collected by direct interview and based on patients' official documents. Addiction information were obtained from the patients' own admission and the interviews. Patients then began the UROD process. Thereafter, patients were scheduled for follow-up visits every 3 months for a 2 year period. A total of 424 patients were enrolled in the study and entered the UROD program, of which 400 patients completed. Of the total patients, 303 (75.75%) were successful (successful group) and 97 (24.25%) relapsed (relapse group). The unemployment rate was significantly higher in the relapse group (76%) compared with those in the successful group (21%) (P = .02). No patients in the relapse group continued naltrexone maintenance at 6-month follow-up, which was significantly lower than successful group (75.8%) (P < .05). The relapse rate was 14% at the first month visit and 24% at the 6 month and thereafter. All patients who had a relapse incident discontinued use of naltrexone before relapse happened. UROD could be an effective method of detoxification in addicted patients, but case selection, sticking to the guidelines, and maintenance therapy accompanied with social support is necessary to minimize relapse and withdrawal symptoms. PMID- 24471479 TI - Significant male predisposition in extramammary Paget disease: a nationwide population-based study in Taiwan. PMID- 24471481 TI - Exceptional verbal intelligence after hemispherotomy in a child with Rasmussen encephalitis. AB - We report a longitudinal case study of a left-handed girl who underwent left hemispherotomy at 7 years for Rasmussen encephalitis (RE). Presurgical evaluation showed mild hemiparesis, no visual defect, and light neuropsychological impairment with short-term memory weakness. Language fMRI showed a right hemispheric dominance. Postoperatively, the patient exhibited right hemiplegia and hemianopsia but preserved intellectual capacities. She became seizure-free, and antiepileptic medication was discontinued. Long-term follow-up showed very high verbal intelligence at 11 years of age (VCI of 155) and improvement in working memory as well as language and reading abilities. Furthermore, a significant visuoverbal discrepancy became increasingly pronounced. Thus, early surgical treatment of epilepsy avoided the global cognitive deterioration usually associated with RE. Finally, such a high level of verbal functioning combined with low spatial reasoning with a single hemisphere provides additional information on the neurocognitive profile of children with RE after hemispherotomy. PMID- 24471482 TI - Robot-assisted renal transplantation in the retroperitoneum. AB - Minimally invasive surgery for renal transplantation is still under development. We employed the robotic surgical system to perform renal transplantation with a minimally invasive wound. The operation was performed with a Gibson incision and two working ports. The space for the transplantation was created by retroperitoneal dissection with the robot lifting the abdominal wall. Vascular reconstruction was performed with two robotic needle drivers. We successfully performed robot-assisted renal transplantation in five female and five male patients with an average wound length of 7.7 +/- 1.04 cm. Nine of the renal allografts functioned immediately, but one with prolonged warm ischemia during the live donor nephrectomy had delayed function. The average creatinine level and estimated glomerular filtration rate at discharge were 1.31 +/- 0.31 mg/dl and 58.2 +/- 8.1 ml/min, respectively. All the transplants are currently functioning at 6.9 +/- 3.9 months after operations. In conclusion, with robot assistance, minimal invasive renal transplantation can be performed successfully in the retroperitoneum. PMID- 24471483 TI - Calorie restriction upregulated sirtuin 1 by attenuating its ubiquitin degradation in cancer cells. AB - Sirtuin (SIRT) 1 is a key protein in mediating the benefits of calorie restriction (CR) in mammals. However, the molecular mechanisms underlying CR induced SIRT1 upregulation in mammals remain unclear. Herein we show that the elevated SIRT1 levels are not due to increased SIRT1 mRNA expression. but rather to enhanced SIRT1 protein stability as a result of reduced ubiquitin-proteasome degradation of SIRT1 under limited nutrient conditions. Our observations have important implications for improving healthy aging in humans. PMID- 24471485 TI - Barcoded pyrosequencing analysis of the bacterial community of Daqu for light flavour Chinese liquor. AB - The bacterial community of Daqu affects its characteristics and functions by their metabolic products, such as amylase, protease, esterase. In this study, barcoded pyrosequencing was used to analyse the bacterial communities of three kinds of Daqu for light-flavour Chinese liquor brewing. A total of 13672 sequences were identified as bacterial sequences. The Shannon index of QC, HX and GT for clusters sharing 97% homology was 5.0, 4.2 and 4.2, respectively, indicating that QC had the highest biodiversity. The Good's coverage index of QC, HX and GT was 88.2, 93.4 and 93%, respectively, indicating that the vast majority of phylotypes have been detected. Among the three kinds of Daqu, the majority of annotated reads were assigned to two phyla (Firmicutes and Actinobacteria). The phylum Firmicutes was the most abundant group in QC (74.2%), HX (81.4%) and GT (98.6%), and the phylum Actinobacteria was the second in QC (23.9%), HX (17.9%) and GT (1.1%). There were many lactic acid bacteria in all three kinds of Daqu QC (45.8%), HX (46.3%) and GT (24.7%). In addition, the most abundant family in GT was Bacillus, accounting for 65.0%, while in HX, the families Thermoactinomycetaceae and Streptomycetaceae accounted for 19.5 and 14.1%, respectively, and in QC, 13.1% were Streptomycetaceae, 12.2% were heterofermentative Leuconostocaceae. SIGNIFICANCE AND IMPACT OF THE STUDY: There are three kinds of Daqu (starter material) used for famous Chinese light-flavour liquor brewing, that is Qingcha, Hongxin and Houhuo. Since Daqu was fermented in an open environment, the microbiology communities were different with different kind of Daqu. Objective bacterial communities determined by barcoded pyrosequencing help to speculate possible metabolic productions, even to guess the function of many kind of Daqu in light-flavour liquor brewing. PMID- 24471486 TI - Theoretical study on stable small clusters of oxalic acid with ammonia and water. AB - Thermodynamically stable small clusters of oxalic acid (CO2H)2, ammonia (NH3), and water (H2O) are studied through quantum chemical calculations. The (CO2H)2 NH3 core system with up to three waters of hydration was examined by B3LYP density functional theory and MP2 molecular orbital theory with the aug-cc-pVDZ basis set. The (CO2H)2-NH3 core complexes are observed to hydrogen bond strongly and should be found in appreciably significant concentrations in the atmosphere. Subsequent hydration of the (CO2H)2-NH3 core, however, is found to be somewhat prohibitive under ambient conditions. Relative populations of the examined clusters are predicted and the binding patterns detailed. Atmospheric implications related to new particle formations are discussed. PMID- 24471484 TI - Intermittent hypoxia-induced changes in tumor-associated macrophages and tumor malignancy in a mouse model of sleep apnea. AB - RATIONALE: An increased cancer aggressiveness and mortality have been recently reported among patients with obstructive sleep apnea (OSA). Intermittent hypoxia (IH), a hallmark of OSA, enhances melanoma growth and metastasis in mice. OBJECTIVES: To assess whether OSA-related adverse cancer outcomes occur via IH induced changes in host immune responses, namely tumor-associated macrophages (TAMs). MEASUREMENTS AND MAIN RESULTS: Lung epithelial TC1 cell tumors were 84% greater in mice subjected to IH for 28 days compared with room air (RA). In addition, TAMs in IH-exposed tumors exhibited reductions in M1 polarity with a shift toward M2 protumoral phenotype. Although TAMs from tumors harvested from RA exposed mice increased TC1 migration and extravasation, TAMs from IH-exposed mice markedly enhanced such effects and also promoted proliferative rates and invasiveness of TC1 cells. Proliferative rates of melanoma (B16F10) and TC1 cells exposed to IH either in single culture or in coculture with macrophages (RAW 264.7) increased only when RAW 264.7 macrophages were concurrently present. CONCLUSIONS: Our findings support the notion that IH-induced alterations in TAMs participate in the adverse cancer outcomes reported in OSA. PMID- 24471487 TI - Herbivore-induced volatile emission in black poplar: regulation and role in attracting herbivore enemies. AB - After herbivory, plants release volatile organic compounds from damaged foliage as well as from nearby undamaged leaves that attract herbivore enemies. Little is known about what controls the volatile emission differences between damaged and undamaged tissues and how these affect the orientation of herbivore enemies. We investigated volatile emission from damaged and adjacent undamaged foliage of black poplar (Populus nigra) after herbivory by gypsy moth (Lymantria dispar) caterpillars and determined the compounds mediating the attraction of the gypsy moth parasitoid Glyptapanteles liparidis (Braconidae). Female parasitoids were more attracted to gypsy moth-damaged leaves than to adjacent non-damaged leaves. The most characteristic volatiles of damaged versus neighbouring undamaged leaves included terpenes, green leaf volatiles and nitrogen-containing compounds, such as aldoximes and nitriles. Electrophysiological recordings and olfactometer bioassays demonstrated the importance of nitrogenous volatiles. Under field conditions, parasitic Hymenoptera were more attracted to traps baited with these substances than most other compounds. The differences in volatile emission profiles between damaged and undamaged foliage appear to be regulated by jasmonate signalling and the local activation of volatile biosynthesis. We conclude that characteristic volatiles from damaged black poplar foliage are essential cues enabling parasitoids to find their hosts. PMID- 24471488 TI - Critical roles of cationic surfactants in the preparation of colloidal mesostructured silica nanoparticles: control of mesostructure, particle size, and dispersion. AB - Mesoporous silica nanoparticles are promising materials for various applications, such as drug delivery and catalysis, but the functional roles of surfactants in the formation and preparation of mesostructured silica nanoparticles (MSN-as) remain to be seen. It was confirmed that the molar ratio of cationic surfactants to Si of alkoxysilanes (Surf/Si) can affect the degree of mesostructure formation (i.e., whether the mesochannels formed inside the nanoparticles actually pass through the outer surface of the particles), the particle diameter, and the dispersibility of MSN-as. Wormhole-like mesostructures formed with low Surf/Si ratios; however, the mesopores did not pass through the outer surface of the particles completely. At high Surf/Si ratios, the mesostructures extended. The particle diameter was 100 nm or larger at low Surf/Si ratios, and the primary particle diameter decreased as the Surf/Si ratio increased. This was because the surfactants enhanced the dispersity of the alkoxysilanes in water and the hydrolysis rate of the alkoxysilanes became faster, leading to an increased nucleation as compared to the particle growth. Moreover, primary particles aggregated at low Surf/Si ratios because of the hydrophobic interactions among the surfactants that were not involved in the mesostructure formation but were adsorbed onto the nanoparticles. At high Surf/Si ratios, the surfactant micelles were adsorbed on the surface of primary particles (admicelles), resulting in the dispersion of the particles due to electrostatic repulsion. In particular, molar ratios of 0.13 or higher were quite effective for the preparation of highly dispersed MSN-as. Surfactants played important roles in the mesostructure formation, decreasing the particle diameters, and the dispersibility of the particles. All of these factors were considerably affected by the Surf/Si ratio. The results suggested novel opportunities to control various colloidal mesostructured nanoparticles from the aspects of composition, structure, and morphology and will also be useful in the development of novel methods to prepare nanomaterials in various fields. PMID- 24471489 TI - EFNS/ENS Guidelines for the treatment of ocular myasthenia. AB - BACKGROUND AND PURPOSE: The symptoms of acquired autoimmune ocular myasthenia are restricted to the extrinsic eye muscles, causing double vision and drooping eyelids. These guidelines are designed to provide advice about best clinical practice based on the current state of clinical and scientific knowledge and the consensus of an expert panel. SEARCH STRATEGY: Evidence for these guidelines was collected by searches in the MEDLINE and Cochrane databases. The task force working group reviewed evidence from original articles and systematic reviews. The evidence was classified (I, II, III, IV) and consensus recommendation graded (A, B or C) according to the EFNS guidance. Where there was a lack of evidence but clear consensus, good practice points are provided. CONCLUSIONS: The treatment of ocular myasthenia should initially be started with pyridostigmine (good practice point). If this is not successful in relieving symptoms, oral corticosteroids should be used on an alternate-day regimen (recommendation level C). If steroid treatment does not result in good control of the symptoms or if it is necessary to use high steroid doses, steroid-sparing treatment with azathioprine should be started (recommendation level C). If ocular myasthenia gravis is associated with thymoma, thymectomy is indicated. Otherwise, the role of thymectomy in ocular myasthenia is controversial. Steroids and thymectomy may modify the course of ocular myasthenia and prevent myasthenia gravis generalization (good practice point). PMID- 24471490 TI - Quantification and genetic diversity of total and microcystin-producing Microcystis during blooming season in Tai and Yang-cheng lakes, China. AB - AIMS: The aims of present study were to evaluate the abundances, genetic diversity of total and microcystin-producing Microcystis over temporal and spatial scales, and to investigate relationships among Microcystis and water parameters in Tai and Yang-cheng lakes. METHODS AND RESULTS: Abundances of total and microcystin-producing Microcystis varied across sampling periods and locations, which were assessed using qPCR with primers specific to Microcystis 16S rDNA and mcyA genes. The 16S rDNA from two lakes were relatively diverse. However, mcyA genes were rather conservative and were >97% identical to reference sequences. The highly positive correlations between mcyA and microcystin presence (r = 0.671 in Tai; r = 0.799 in Yang-cheng) suggested that mcyA can be used as a good biomarker for microcystin productions. CONCLUSION: The results demonstrated that Microcystis were genetically diverse between these conjunctive lakes; however, mcyA genes were relatively conservative in two lakes. Quantifying mcyA by qPCR was an efficient tool for monitoring toxic Microcystis. SIGNIFICANCE AND IMPACT OF THE STUDY: This study has improved our understanding of observable differences within and between each lake on spatial and temporal scales. And the discovery of new mcyA sequences in natural water enriched the understanding of phylogenetic diversity of Microcystis and toxin-production-related mcy gene. PMID- 24471491 TI - Polycystic ovary syndrome and low-grade inflammation with special reference to YKL-40. AB - OBJECTIVE: To evaluate the plasma level of YKL-40 in a Danish polycystic ovary syndrome (PCOS) population and to investigate whether YKL-40 is associated with CVD risk factors such as waist circumference, body mass index (BMI), insulin resistance (IR), fasting glucose, fasting insulin, blood lipids and CRP. DESIGN: Cross-sectional study. SETTING: Gynecological clinics at three Danish University Hospitals. PATIENTS: One hundred seventy-one premenopausal women with PCOS recruited consecutively from April 2010 to February 2012. PCOS was diagnosed according to the Rotterdam criteria. MAIN OUTCOME MEASURES: Plasma level of YKL 40 in four phenotypes of PCOS defined by BMI and IR. RESULTS: No statistically significant difference was observed in the plasma level of YKL-40 across the four BMI/IR-phenotypes. Positive associations were observed between YKL-40 and BMI, total and free testosterone, triglycerides, and CRP. Total and free testosterone were independent predictors of YKL-40. CONCLUSION: YKL-40, the marker of low grade inflammation is not increased in women with PCOS. PMID- 24471492 TI - Coupling of carbon and peptide nanotubes. AB - Two of the main types of nanotubular architectures are the single-walled carbon nanotubes (SWCNTs) and the self-assembling cyclic peptide nanotubes (SCPNs). We here report the preparation of the dual composite resulting from the ordered combination of both tubular motifs. In the resulting architecture, the SWCNTs can act as templates for the assembly of SCPNs that engage the carbon nanotubes noncovalently via pyrene "paddles", each member of the resulting hybrid stabilizing the other in aqueous solution. The particular hybrids obtained in the present study formed highly ordered oriented arrays and display complementary properties such as electrical conductivity. Furthermore, a self-sorting of the cyclic peptides toward semiconducting rather than metallic SWCNTs is also observed in the aqueous dispersions. It is envisaged that a broad range of exploitable properties may be achieved and/or controlled by varying the cyclic peptide components of similar SWCNT/SCPN hybrids. PMID- 24471493 TI - Octulosonic acid derivatives from Roman chamomile (Chamaemelum nobile) with activities against inflammation and metabolic disorder. AB - Six new octulosonic acid derivatives (1-6) were isolated from the flower heads of Roman chamomile (Chamaemelum nobile). Their structures were elucidated by means of spectroscopic interpretation. The biological activity of the isolated compounds was evaluated toward multiple targets related to inflammation and metabolic disorder such as NAG-1, NF-kappaB, iNOS, ROS, PPARalpha, PPARgamma, and LXR. Similar to the action of NSAIDs, all the six compounds (1-6) increased NAG-1 activity 2-3-fold. They also decreased cellular oxidative stress by inhibiting ROS generation. Compounds 3, 5, and 6 activated PPARgamma 1.6-2.1-fold, while PPARalpha was activated 1.4-fold by compounds 5 and 6 only. None of the compounds showed significant activity against iNOS or NF-kappaB. This is the first report of biological activity of octulosonic acid derivatives toward multiple pathways related to inflammation and metabolic disorder. The reported anti-inflammatory, hypoglycemic, antiedemic, and antioxidant activities of Roman chamomile could be partly explained as due to the presence of these constituents. PMID- 24471494 TI - Predominant role of plasma membrane monoamine transporters in monoamine transport in 1321N1, a human astrocytoma-derived cell line. AB - Monoamine neurotransmitters should be immediately removed from the synaptic cleft to avoid excessive neuronal activity. Recent studies have shown that astrocytes and neurons are involved in monoamine removal. However, the mechanism of monoamine transport by astrocytes is not entirely clear. We aimed to elucidate the transporters responsible for monoamine transport in 1321N1, a human astrocytoma-derived cell line. First, we confirmed that 1321N1 cells transported dopamine, serotonin, norepinephrine, and histamine in a time- and dose-dependent manner. Kinetics analysis suggested the involvement of low-affinity monoamine transporters, such as organic cation transporter (OCT) 2 and 3 and plasma membrane monoamine transporter (PMAT). Monoamine transport in 1321N1 cells was not Na(+) /Cl(-) dependent but was inhibited by decynium-22, an inhibitor of low affinity monoamine transporters, which supported the importance of low-affinity transporters. RT-PCR assays revealed that 1321N1 cells expressed OCT3 and PMAT but no other neurotransmitter transporters. Another human astrocytoma-derived cell line, U251MG, and primary human astrocytes also exhibited the same gene expression pattern. Gene-knockdown assays revealed that 1321N1 and primary human astrocytes could transport monoamines predominantly through PMAT and partly through OCT3. These results might indicate that PMAT and OCT3 in human astrocytes are involved in monoamine clearance. PMID- 24471495 TI - Phylogenomic analyses reveal latitudinal population structure and polymorphisms in heat stress genes in the North Atlantic snail Nucella lapillus. AB - North Atlantic rocky intertidal species have been shaped by repeated glaciations and strong latitudinal temperature gradients, making them an excellent system to study postglacial phylogeography and thermal tolerance. Population genetics data from northwestern Atlantic species, however, often show patterns inconsistent with the prediction that high dispersal should generate weaker genetic structure among populations. Here, we used next-generation sequencing restriction associated DNA tags (RAD-seq) and a transcriptome assembled from RNA-seq data to analyse the genetic structure of northwestern Atlantic populations of the low dispersal intertidal snail Nucella lapillus. Although previous studies in this region have detected almost no genetic structure in N. lapillus, our phylogenomic approach identified a well-supported split between northern and southern clades. By comparing RAD-seq data and our transcriptome assembly, we identified thousands of fixed single-nucleotide polymorphisms (SNPs) between these latitudinal clades that map to protein-coding genes, including genes associated with heat stress tolerance. These fixed SNPs might represent loci under selection for different thermal regimes in the northwestern Atlantic. PMID- 24471496 TI - Freeze-drying changes the structure and digestibility of B-polymorphic starches. AB - Starch granules both isolated from plants and used in foods or other products have typically been dried. Common food laboratory and industry practices include oven (heat), freeze, and ethanol (solvent-exchange) drying. Starch granules isolated from maize (A-type polymorph) and potato (B-type polymorph) were used to understand the effects of different dehydration methods on starch structure and in vitro digestion kinetics. Oven and ethanol drying do not significantly affect the digestion properties of starches compared with their counterparts that have never been dried. However, freeze-drying results in a significant increase in the digestion rate of potato starch but not maize starch. The structural and conformational changes of starch granules after drying were investigated at various length scales using scanning electron microscopy, confocal laser scanning microscopy, X-ray diffraction, FTIR spectroscopy, and NMR spectroscopy. Freeze drying not only disrupts the surface morphology of potato starch granules (B-type polymorph), but also degrades both short- and long-range molecular order of the amylopectin, each of which can cause an increase in the digestion rate. In contrast to A-polymorphic starches, B-polymorphic starches are more disrupted by freeze-drying, with reductions of both short- and long-range molecular order. We propose that the low temperatures involved in freeze-drying compared with oven drying result in greater chain rigidity and lead to structural disorganization during water removal at both nanometer and micrometer length scales in B-type polymorphic starch granules, because of the different distribution of water within crystallites and the lack of pores and channels compared with A-type polymorphic starch granules. PMID- 24471497 TI - Pediatric priority in kidney allocation: challenging its acceptability. AB - Any organ which is allocated to one individual represents a missed opportunity for someone else. Given the important repercussions which organ allocation policies inevitably have for certain people, any prioritization policy should rest on a solid argumentative basis. In this study, we analyze the widespread practice of prioritizing pediatric patients in the allocation of kidneys. While official policy documents offer no arguments in support of pediatric priority, such arguments can be found in the academic literature on pediatric renal transplantation. Our study is the first to bring together and critically analyze these. We identify five commonly cited arguments and show that none of these succeeds in justifying pediatric priority policies. We argue that the legitimacy of such policies may be further undermined by their potential adverse effects on both adults and children. PMID- 24471498 TI - Acute iododerma secondary to iodinated contrast media. PMID- 24471500 TI - Large pore mesoporous silica induced weight loss in obese mice. AB - BACKGROUND: There is a need for medical treatments to curb the rising rate of obesity. Weight reduction is correlated with a decrease in associated risk factors and cholesterol levels in humans. Amorphous silica particles have been found to exert a hypocholesterolemic effect in humans, making them popular dietary additives. AIM: To investigate the effect of mesoporous silica, which possess sharp pore size distributions, on: weight loss, cholesterol, triglycerides and glucose blood levels in obese mice. MATERIALS & METHODS: Mesoporous silicas with differing pore size were mixed in the high-fat diet of obese mice. RESULTS: Animals receiving large pore mesoporous silica with a high fat diet show a significant reduction in body weight and fat composition, with no observable negative effects. CONCLUSION: Pore size is an important parameter for reduction of body weight and body fat composition by mesoporous silica, demonstrating promising signs for the treatment of obesity. PMID- 24471499 TI - Quantitative glycoproteomics analysis reveals changes in N-glycosylation level associated with pancreatic ductal adenocarcinoma. AB - Glycosylation plays an important role in epithelial cancers, including pancreatic ductal adenocarcinoma. However, little is known about the glycoproteome of the human pancreas or its alterations associated with pancreatic tumorigenesis. Using quantitative glycoproteomics approach, we investigated protein N-glycosylation in pancreatic tumor tissue in comparison with normal pancreas and chronic pancreatitis tissue. The study lead to the discovery of a roster of glycoproteins with aberrant N-glycosylation level associated with pancreatic cancer, including mucin-5AC (MUC5AC), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), insulin-like growth factor binding protein (IGFBP3), and galectin-3 binding protein (LGALS3BP). Pathway analysis of cancer-associated aberrant glycoproteins revealed an emerging phenomenon that increased activity of N glycosylation was implicated in several pancreatic cancer pathways, including TGF beta, TNF, NF-kappa-B, and TFEB-related lysosomal changes. In addition, the study provided evidence that specific N-glycosylation sites within certain individual proteins can have significantly altered glycosylation occupancy in pancreatic cancer, reflecting the complexity of the molecular mechanisms underlying cancer associated glycosylation events. PMID- 24471501 TI - Pathway and morphological transformation of liposome nanocarriers after release from a novel sustained inner-ear delivery system. AB - AIM: To validate a novel sustained delivery system of liposome nanocarriers for inner-ear therapy and to investigate the transport pathway for their delivery. MATERIALS & METHODS: Liposome nanocarriers containing gadolinium-tetra-azacyclo dodecane-tetra-acetic acid (LPS+Gd-DOTA) were developed for MRI tracking the in vitro release profile and for in vivo uptake studies. RESULTS: Encapsulating Gd DOTA did not modify the liposomes. The LPS+Gd-DOTA nanocarriers were slowly released from a miniature osmotic pump. The LPS+Gd-DOTA moved along the ossicular chain toward the oval window after an epitympanic injection, whereas they traveled directly to the round window after a mesotympanic injection. However, the round window membrane was the major pathway for the LPS+Gd-DOTA to enter the inner ear. LPS+Gd-DOTA were visualized on both sides of the cochlea within 6 days of in vivo delivery via the osmotic pump. DISCUSSION: The novel sustained inner ear delivery system induced liposome nanocarriers into the inner ear efficiently without causing obvious adverse effect. There is the potential of using the system to administrate therapeutics in treating inner-ear diseases in the clinic. PMID- 24471502 TI - Antibiotic delivery potential of nano- and micro-porous marine structure-derived beta-tricalcium phosphate spheres for medical applications. AB - AIMS: This study gives a detailed evaluation of the antibiotic potential of a marine structure-based new drug delivery system produced by hydrothermally converting foraminifera exoskeletons to beta-tricalcium phosphate (beta-TCP) to treat clinical strain Staphylococcus aureus (MW2). MATERIALS & METHODS: Foraminifera precursor materials were hydrothermally converted at 250 degrees C for 48 h to produce beta-TCP and loaded with gentamicin sulfate by adsorption for 24 h. The physicochemical properties of the material were characterized by scanning electron microscopy, powder x-ray diffraction and for pore size distribution profiles. The antibacterial efficacy of the system was tested for inhibition of S. aureus growth and in vitro cellular behavior were tested with human osteoblast cells (MG63) for cell viability. DISCUSSION: Pore size distribution profiles showed that the structure allows the uniform distribution of nanopores of 1.5 nm and micropores of approximately 5 um. The in vitro release profile indicates an initial burst release of 5% of total incorporated gentamicin. A time-delayed antibacterial efficacy test was designed to introduce the bacteria at predetermined time intervals from 0 to 60 min and showed that gentamicin prevents S. aureus grown in the same culture within 30 min, with no evidence of bacterial regrowth within 24 h. Human osteoblast cell (MG63) studies showed no detrimental effect on cell viability. CONCLUSION: In the light of these results nano- and micro-pores containing beta-TCP spheres show promise as potential bone void filler particles with antibacterial effects. PMID- 24471503 TI - Pharmacokinetics and antitumor efficacy of paclitaxel-cyclodextrin complexes loaded in mucus-penetrating nanoparticles for oral administration. AB - AIM: The authors report a novel approach for enhancing the oral absorption of paclitaxel (PTX) by encapsulation in poly(anhydride) nanoparticles (NPs) containing cyclodextrins and poly(ethylene glycol). MATERIALS & METHODS: Formulations were prepared using the solvent displacement method. Subsequently, pharmacokinetics and organ distribution assays were evaluated after oral administration into C57BL/6J mice. In addition, antitumor efficacy studies were performed in a subcutaneous tumor model of Lewis lung carcinoma. RESULTS: PTX loaded NPs displayed sizes between 190-300 nm. Oral NPs achieved drug plasma levels for at least 24 h, with an oral bioavailability of 55-80%. Organ distribution studies revealed that PTX, orally administered in NPs, underwent a similar distribution to intravenous Taxol((r)) (Bristol-Myers Squibb, NJ, USA). For in vivo antitumor assays, oral strategy maintained a slower tumor growth than intravenous Taxol. CONCLUSION: PTX orally administered in poly(anhydride) NPs, combined with cyclodextrins and poly(ethylene glycol), displayed sustained plasma levels and significant antitumor effect in a syngenic tumor model of carcinoma in mice. PMID- 24471504 TI - X-ray-induced nanoparticle-based photodynamic therapy of cancer. AB - AIM: In this study, Ce(3+)-doped lanthanum(III) fluoride (LaF3:Ce(3+)) nanoparticles were synthesized by a wet-chemistry method in dimethyl sulfoxide (DMSO) and their application as an intracellular light source for photodynamic activation was demonstrated. MATERIALS & METHODS: The LaF3:Ce(3+)/DMSO nanoparticles have a strong green emission with a peak at approximately 520 nm, which is effectively overlapped with the absorption of protoporphyrin IX (PPIX). The nanoparticles were encapsulated into poly(D,L-lactide-co-glycolide (PLGA) microspheres along with PPIX. Upon irradiation with x-rays (90 kV), energy transfer from the LaF3:Ce(3+)/DMSO nanoparticles to PPIX occurs and singlet oxygen is generated for cancer cell damage. RESULTS: The LaF3:Ce(3+)/DMSO/PLGA or LaF3:Ce(3+)/DMSO/PPIX/PLGA microspheres alone caused only sublethal cytotoxicity to the cancer cells. Upon x-ray irradiation, the LaF3:Ce(3+)/DMSO/PPIX/PLGA microspheres induced oxidative stress, mitochondrial damage and DNA fragmentation on prostate cancer cells (PC3). DISCUSSION: The results indicate that x-rays can activate LaF3:Ce(3+) and PPIX nanocomposites, which can be a novel method for cancer destruction. PMID- 24471506 TI - Highly sensitive electrochemical methyltransferase activity assay. AB - A simple and highly sensitive electrochemical DNA methyltransferase (MTase) activity assay is presented in this report. The assay employs the electrocatalytic oxidation of ascorbic acid (AA) by a threading intercalator (N,N'-bis(3-propylimidazole)-1,4,5,8-naphthalene diimide (PIND) functionalized with electrocatalytic redox Os(bpy)2Cl(+) moieties (PIND-Os)). Briefly, a double stranded DNA (ds-DNA) containing the symmetric sequence of 5'-CCGG-3' is first immobilized on a gold electrode. The electrode is then incubated with M.SssI CpG methyltransferase (M.SssI MTase) which catalyzes the methylation of the specific CpG dinucleotides, and the electrode is subsequently treated with a restriction endonuclease HpaII which recognizes the 5'-CCGG-3' sequence. Once the CpG site in the 5'-CCGG-3' is methylated, HpaII recognition is blocked. Higher M.SssI MTase activity leads to more CpG sites being methylated and consequently impedes more the restriction endonuclease HpaII digestion process. Thus, a larger amount of ds DNA remains on the electrode surface after the HpaII treatment. Thereafter, the electrode is incubated with PIND-Os during which PIND-Os specifically inserts itself between base pairs of ds-DNA and catalyzes the electrooxidation of AA. The methylation event corresponding to the MTase activity can therefore be monitored and amplified by the electrocatalytic oxidation of AA. A linear correlation between the catalytic oxidation current of AA and the activity of M.SssI MTase ranged from 0 to 120 U/mL with a current sensitivity of 0.046 MUA mL U(-1) is obtained. The inhibitor screening ability of the developed MTase activity assay is also demonstrated. PMID- 24471505 TI - Randomised clinical trial: relief of upper gastrointestinal symptoms by an acid pocket-targeting alginate-antacid (Gaviscon Double Action) - a double-blind, placebo-controlled, pilot study in gastro-oesophageal reflux disease. AB - BACKGROUND: The alginate-antacid, Gaviscon Double Action (Gaviscon DA; Reckitt Benckiser, Slough, UK) suppresses reflux after meals by creating a gel-like barrier that caps and displaces the acid pocket distal to the oesophago-gastric junction. The effect of Gaviscon DA on reflux and dyspepsia symptoms has not yet been demonstrated with a modern trial design. AIM: A pilot study to assess the efficacy and safety of Gaviscon DA compared with matched placebo for decreasing upper gastrointestinal symptoms in symptomatic gastro-oesophageal reflux disease (GERD) patients. METHODS: A randomised, double-blind, parallel group study was performed in 110 patients with symptoms of GERD. Patients received Gaviscon DA or placebo tablets for 7 consecutive days. The primary endpoint compared the change in overall Reflux Disease Questionnaire (RDQ) symptom score (combined heartburn/regurgitation/dyspepsia). Secondary endpoints assessed individual dimensions, GERD dimension (heartburn and regurgitation) and overall treatment evaluation (OTE). RESULTS: There was a greater decrease in overall RDQ symptom score in the Gaviscon DA group compared with the placebo group (Least Squares Mean difference -0.55; P = 0.0033), and for each of the dimensions independently. Patients in the Gaviscon DA group evaluated their overall treatment response higher than patients in the placebo group [mean (standard deviation) OTE 4.1 (2.44) vs. 1.9 (3.34); P = 0.0005]. No differences in the incidence of adverse events were observed between treatment groups. CONCLUSIONS: Gaviscon DA decreases reflux and dyspeptic symptoms in GERD patients compared with matched placebo and has a favourable benefit-risk balance. Larger scale clinical investigations of medications targeting the acid pocket are warranted. (EudraCT, 2012-002188-84). PMID- 24471507 TI - Lesion simulating disease 1 and enhanced disease susceptibility 1 differentially regulate UV-C-induced photooxidative stress signalling and programmed cell death in Arabidopsis thaliana. AB - As obligate photoautotrophs, plants are inevitably exposed to ultraviolet (UV) radiation. Because of stratospheric ozone depletion, UV has become more and more dangerous to the biosphere. Therefore, it is important to understand UV perception and signal transduction in plants. In the present study, we show that lesion simulating disease 1 (LSD1) and enhanced disease susceptibility 1 (EDS1) are antagonistic regulators of UV-C-induced programmed cell death (PCD) in Arabidopsis thaliana. This regulatory dependence is manifested by a complex deregulation of photosynthesis, reactive oxygen species homeostasis, antioxidative enzyme activity and UV-responsive genes expression. We also prove that a UV-C radiation episode triggers apoptotic-like morphological changes within the mesophyll cells. Interestingly, chloroplasts are the first organelles that show features of UV-C-induced damage, which may indicate their primary role in PCD development. Moreover, we show that Arabidopsis Bax inhibitor 1 (AtBI1), which has been described as a negative regulator of plant PCD, is involved in LSD1-dependent cell death in response to UV-C. Our results imply that LSD1 and EDS1 regulate processes extinguishing excessive energy, reactive oxygen species formation and subsequent PCD in response to different stresses related to impaired electron transport. PMID- 24471508 TI - Dyskinesias in Parkinson's disease: views from positron emission tomography studies. AB - Levodopa-induced dyskinesias (LIDs) and graft-induced dyskinesias (GIDs) are serious and common complications of Parkinson's disease (PD) management following chronic treatment with levodopa or intrastriatal transplantation with dopamine rich foetal ventral mesencephalic tissue, respectively. Positron emission tomography (PET) molecular imaging provides a powerful in vivo tool that has been employed over the past 20 years for the elucidation of mechanisms underlying the development of LIDs and GIDs in PD patients. PET used together with radioligands tagging molecular targets has allowed the functional investigation of several systems in the brain including the dopaminergic, serotonergic, glutamatergic, opioid, endocannabinoid, noradrenergic and cholinergic systems. In this article the role of PET imaging in unveiling pathophysiological mechanisms underlying the development of LIDs and GIDs in PD patients is reviewed. PMID- 24471512 TI - Preparation and evaluation of a novel bioactive glass/lysozyme/PLGA composite microsphere. AB - OBJECTIVE: The objective of this study was to fabricate a novel nano-bioceramics incorporated lysozyme poly (d, l-lactide-co-glycolide) (PLGA) microsphere. METHODS: The nano-bioceramics was used as a biodegradable and sustained-release antacid to stabilize the lysozyme in the drug release process. First, the nano bioceramics were prepared by sol-gel method, and then were characterized by energy dispersive X-ray analysis, dynamic light scattering and in vitro degradation test. Second, the lysozyme PLGA microsphere incorporated with nano bioceramic was fabricated by the S/W/O/W emulsion solvent evaporation method. The microsphere was characterized by scanning electron microscopy (SEM), Fourier transform infrared (FTIR) spectroscopy and UV circular dichroism (UV CD). Finally the in vitro drug release and bioactivity test was carried out. RESULTS: The composition of the nano-bioceramics was 58% SiO2, 36% CaO, 6% P2O5, and the average particle size was 295 nm. The nano-bioceramics incorporated lysozyme PLGA microspheres were prepared by the multi-emulsion method. The SEM results showed that the bioceramics was uniformly distributed in the PLGA microsphere. Results from in vitro lysozyme release test exhibited a prolonged release time for 1month. The FTIR and UVCD results suggested that the lysozyme in the drug release process had a similar secondary structure conformation to the native one. The Micrococcus lysodeikticus test showed that the microspheres incorporated with bioceramics provided long-term protein stability against the acidic environment resulted from PLGA's degradates and more than 90% of the lysozyme released over the 1 month period was preserved in a bioactive form. CONCLUSION: A novel bioceramics incorporated lysozyme PLGA microsphere was prepared with potentials for sustained protein release formulation. PMID- 24471509 TI - Comparison of viral load in individuals with and without asthma during infections with rhinovirus. AB - RATIONALE: Most virus-induced attacks of asthma are caused by rhinoviruses (RVs). OBJECTIVES: To determine whether people with asthma are susceptible to an increased viral load during RV infection. METHODS: Seventy-four children (4-18 yr old) were enrolled; 28 with wheezing, 32 with acute rhinitis, and 14 without respiratory tract symptoms. Nasal washes were evaluated using quantitative polymerase chain reaction for RV to judge viral load along with gene sequencing to identify strains of RV. Soluble intercellular adhesion molecule-1, IFN lambda1, and eosinophil cationic protein in nasal washes, along with blood eosinophil counts and total and allergen-specific IgE in sera, were also evaluated. Similar assessments were done in 24 young adults (16 with asthma, 8 without) who participated in an experimental challenge with RV (serotype 16). MEASUREMENTS AND MAIN RESULTS: Fifty-seven percent of wheezing children and 56% with acute rhinitis had nasal washes testing positive for RV. The geometric mean of viral loads by quantitative polymerase chain reaction in washes from wheezing children was 2.8-fold lower, but did not differ significantly from children with rhinitis (7,718 and 21,612 copies of viral RNA per microliter nasal wash, respectively; P = 0.48). The odds for wheezing were increased if children who tested positive for RV were sensitized to one or more allergens (odds ratio, 3.9; P = 0.02). Similarly, neither peak nor cumulative viral loads differed significantly in washes from adults with asthma compared with those without asthma during the experimental RV challenge. CONCLUSIONS: During acute symptoms, children infected with RV enrolled for wheezing or acute rhinitis had similar viral loads in their nasal washes, as did adults with and without asthma infected with RV-16 experimentally. PMID- 24471513 TI - Emerging issues for our nation's health: the intersection of marijuana use and cardiometabolic disease risk. AB - Current marijuana use rates are the highest they have been in the past decade and are not likely to decrease given the legalization of marijuana for medicinal and recreational use. Concurrently, the nation is facing epidemic levels of obesity, cardiovascular disease, and diabetes mellitus; but, little is known about the intersecting relationships of marijuana use and cardiometabolic health. The objective of this study was to explore emerging issues in context with the intersection of cardiometabolic risk and marijuana use. This topic has potential important implications for our nation's health as we relax our approach to marijuana but continue to have unacceptable rates of cardiometabolic illnesses. PMID- 24471515 TI - Daily physical activity in asthmatic children with distinct severities. AB - OBJECTIVE: The objective of this study was to evaluate daily physical activity (DPA) in asthmatic children with different levels of disease severity, but with good asthma control, relative to a control group. METHODS: This was a cross sectional study in which a total of 121 children between the ages of 7 and 12 years old were evaluated; 72 were asthmatic children (32 mild, 24 moderate and 23 severe), and 42 children were not asthmatics. The asthmatic children studied had been in medical treatment for at least 6 months and experienced no change in symptoms during the 4 weeks prior to the study. The DPA was monitored over 6 days (4 weekdays and 2 weekend days). Motor activity was recorded with an accelerometer that measured the total number of steps (TNS), the number of steps in moderate physical activity (NS-MPA) and the duration, in minutes, of physical activity performed at moderate intensity. RESULTS: There were no differences among the TNS performed by children with mild, moderate or severe persistent asthma and the control group (14 410 +/- 4379, 14 710 +/- 4892, 13 838 +/- 3341 and 12 968 +/- 3682 steps, respectively). The NS-MPA was also similar among all of the groups (6589 +/- 2065, 6605 +/- 2324, 6223 +/- 1689 and 5990 +/- 1840 steps, respectively). Sedentary asthmatic children were overweight more often than asthmatic children who were physically active, although lung function was not different between these groups. CONCLUSION: Children with good asthma control, independent of disease severity, had DPA levels similar to children without asthma. However, more asthmatic children were overweight if sedentary as compared to physically active asthmatic children. PMID- 24471514 TI - Effectiveness of paediatric asthma clinical pathways: a narrative systematic review. AB - OBJECTIVE: To evaluate the effectiveness of clinical pathways (CPs) for paediatric asthma on length of hospital stay, additional visits due to asthma exacerbations, hospital cost, manpower and workload required for implementing CPs. METHODS: Studies were eligible if they met the following criteria: children (?18 years) with asthma, hospital or emergency department based, and study designs were (1) randomised controlled trial, (2) controlled clinical trial or (3) controlled before and after study. Two reviewers independently screened references, extracted data and assessed the risk of bias. We resolved disagreement by discussion between authors. Due to an insufficient number of studies and the heterogeneity of interventions and outcomes, we conducted a narrative systematic review with forest plots but did not pool results. RESULTS: About 3155 relevant articles were identified through a literature search, 628 were duplicates removed, 2037 were excluded based on review of titles and abstracts and 117 were excluded because they did not meet inclusion criteria. Seven studies involving 2600 participants met the inclusion criteria. Using asthma CPs may decrease the length of hospital stay; however, CPs did not appear to reduce additional visits due to asthma exacerbations or reduce hospital costs. No eligible studies were found that quantified the manpower and workload for implementing CPs. CONCLUSIONS: Current studies suggest CPs may reduce the length of hospital stay, but insufficient evidence is available on total costs or readmissions to justify extensive uptake of asthma CPs in paediatric inpatient care. Higher quality, large randomised controlled trials are required that measure costs and a wider range of outcomes. PMID- 24471516 TI - The effectiveness of an indoor intermittent training program for improving lung function, physical capacity, body composition and quality of life in children with asthma. AB - OBJECTIVE: The objective of this study is to analyze the effects of a 12-week indoor intermittent training program on lung function, physical capacity, body composition and quality of life in children with asthma. METHODS: Participants were randomized in an experimental group (EG, 58 children, age = 11.55 +/- 1.01 years) and in a control group (CG, 47 children, age = 11.51 +/- 1.42 years). The training program was conducted indoors and consisted of alternating high- and low intensity stimuli, for three sessions of 60 min/week, for 12 weeks. Physical exercise and sports activities were organized to follow the criteria of the American College of Sports Medicine (1999) and previous interventions' studies. RESULTS: In EG, there was a significant improvement (p < 0.05) in FEV1, FEV6, 6MWT, handgrip strength, CMJ and flexibility. Reductions in BMI and fat mass as well as an increase in quality of life were all shown. The dyspnea index decreased significantly and there were no episodes of EIA. There is a significant positive correlation (p < 0.01) between the DeltaFEV1 with Deltahandgrip strength and Delta6MWT and a negative correlation with Deltafat mass. CONCLUSIONS: An indoor intermittent training program with these characteristics has improved lung function, physical capacity, body composition and quality of life in children with asthma. These training adaptations are particularly relevant for those patients suffering from asthma as a regular physical exercise routine will greatly improve their quality of life. PMID- 24471517 TI - Experiences addressing health-related financial challenges with disease management among African American women with asthma. AB - OBJECTIVE: Despite economic hardship, compliance with self-management regimens is still evident among individuals and families managing chronic disease. The purpose of this study was to describe how women with asthma address cost-related challenges to management of their condition. METHODS: In 2012 and 2013, four focus groups were conducted in Southeast Michigan with 26 African American women with asthma, recruited based on maximum variation sampling procedures. A semi structured interview protocol was employed by trained facilitators. Coded transcripts were analyzed for themes regarding means to reduce the impact of the cost of asthma management. RESULTS: Major themes identified were acceptance of the status quo; stockpiling and sharing medicines; utilizing community assistance programs; reaching out to healthcare providers and social networks for help; foregoing self-management; and utilizing urgent care. CONCLUSIONS: Awareness of strategies that are helpful to patients in reducing out-of-pocket costs may better equip service providers and others to develop interventions to make useful strategies more widely available. PMID- 24471519 TI - Quercetin nanosuspensions produced by high-pressure homogenization. AB - High-pressure homogenization (HPH) was used to increase the water solubility of quercetin crystals, which exhibit antioxidant, anti-inflammatory, and anticancer properties but poor water solubility and oral bioavailability. The improved water solubility of quercetin by HPH treatment could be attributed to very fine suspensions produced in the nanometric range (~400 nm) and loss of crystallinity caused by mechanical friction and stresses, which were verified by particle size measurements, differential scanning calorimetry (DSC), atomic force microscopy (AFM), and scanning electron microscopy (SEM) results. Easily water redispersible powders were fabricated by the combination of HPH treatment and spray-drying process when maltodextrin was used as a carrier agent. HPH-treated spray-dried powders exhibited higher antioxidant activities than nontreated samples through increased water dispersity in terms of radical scavenging activity, reducing ability, and oxygen radical absorbance capacity determinations. This study suggests that the combination of HPH treatment with spray-drying would be an excellent processing method for the development of quercetin-based functional food products. PMID- 24471520 TI - Cardiac rhythm management devices in a magnetic resonance environment. AB - MRI is the gold standard diagnostic tool for soft tissue imaging for many specialties. An impressive body of research has proven the effectiveness of cardiac rhythm management devices (CRMDs) objectively, in terms of parameters that include patient's quality of life, morbidity, and mortality. However, interaction between CRMDs and MRI scanners is a problem. Static main magnetic field, radiofrequency energy and the gradient magnetic field are three distinct mechanisms related to MRI and cause risks to CRMDs. Very often, patients with CRMDs have been excluded from undergoing MRI scans despite the fact that these scans were critical for the diagnosis and therapy of patients with serious medical conditions. In order for all patients with CRMDs to have the ability to perform this exam, the industry works hard to design devices that are MRI conditional. PMID- 24471518 TI - A recent local sweep at the PHYA locus in the Northern European Spiterstulen population of Arabidopsis lyrata. AB - Northern and central European Arabidopsis lyrata ssp. petraea populations are locally adapted to prevailing climatic conditions through differences in timing of life history events. The timing of flowering and, in perennials, the timing of growth cessation influence fitness. Phytochrome A may have an important role in regulating these life history traits as it perceives changes in daylength. We asked whether PHYA has contributed to local adaptation to the northern conditions in A. l. petraea. To search for signals of directional selection at the PHYA locus, we resequenced PHYA and 9 short fragments around PHYA from a 57-kb region from a German (Plech) and a Norwegian (Spiterstulen) population and compared patterns of differentiation and diversity to a set of 19 reference loci around the genome. First, we found that the populations were highly differentiated: there were three nonsynonymous fixed differences at the PHYA locus, which was in stark contrast with the total four fixed differences in the 19 reference loci. Compatible with a sweep hypothesis, variation was almost completely removed from the 9.4-kb region around PHYA in the northern Spiterstulen population. The overall level of linkage disequilibrium (LD) was higher in Spiterstulen, but there was no LD across the PHYA locus in the population, which is also a known consequence of a selective sweep. The sweep has likely occurred after the last glacial maximum, which suggests that it has contributed to adaptation to the northern conditions. PMID- 24471521 TI - MRS glucose mapping and PET joining forces: re-evaluation of the lumped constant in the rat brain under isoflurane anaesthesia. AB - Although numerous positron emission tomography (PET) studies with (18) F-fluoro deoxyglucose (FDG) have reported quantitative results on cerebral glucose kinetics and consumption, there is a large variation between the absolute values found in the literature. One of the underlying causes is the inconsistent use of the lumped constants (LCs), the derivation of which is often based on multiple assumptions that render absolute numbers imprecise and errors hard to quantify. We combined a kinetic FDG-PET study with magnetic resonance spectroscopic imaging (MRSI) of glucose dynamics in Sprague-Dawley rats to obtain a more comprehensive view of brain glucose kinetics and determine a reliable value for the LC under isoflurane anaesthesia. Maps of Tmax /CMRglc derived from MRSI data and Tmax determined from PET kinetic modelling allowed to obtain an LC-independent CMRglc . The LC was estimated to range from 0.33 +/- 0.07 in retrosplenial cortex to 0.44 +/- 0.05 in hippocampus, yielding CMRglc between 62 +/- 14 and 54 +/- 11 MUmol/min/100 g, respectively. These newly determined LCs for four distinct areas in the rat brain under isoflurane anaesthesia provide means of comparing the growing amount of FDG-PET data available from translational studies. PMID- 24471522 TI - Additional role of serum 25-hydroxyvitamin D3 levels in atherosclerosis in Chinese middle-aged and elderly men. AB - 1. Perturbed serum vitamin D levels have been shown to be associated with increased risk of cardiovascular disease. The aim of the present study was to investigate the association of serum 25-hydroxyvitamin D3 (25(OH)D3) levels and B ultrasonography-detected carotid plaque and carotid intima-media thickness (C IMT) in Chinese middle-aged and elderly men. 2. In all, 1001 men, aged 45-78 years, were enrolled in the study. Increased C-IMT was defined as any C-IMT value in the highest quartile of the study subjects (>= 0.75 mm). 3. The study population had a median serum 25(OH)D3 level of 14.51 ng/mL (interquartile range (IQR) 10.84-18.67 ng/mL). Subjects with carotid plaques had lower serum 25(OH)D3 levels than those without (13.80 (IQR 10.82-17.68) vs 14.74 (IQR 10.87-19.08) ng/mL, respectively; P = 0.029), and decreasing serum 25(OH)D3 levels were accompanied by increased C-IMT in both groups (13.24 (IQR 9.91-16.81) vs 14.45 (IQR 11.40-18.51) ng/mL, respectively (P < 0.05) in those with plaque; 13.80 (IQR 9.99-17.09) vs 14.99 (IQR 11.17-19.43) ng/mL, respectively (P < 0.01) in those without plaque). Multivariate logistic regression analysis showed that serum 25(OH)D3 levels were independently associated with carotid plaque (odds ratio (OR) 0.972; 95% confidence interval (CI) 0.946-0.998; P = 0.032). In addition, serum 25(OH)D3 levels were identified as an independent protective factor for increased C-IMT among subjects with plaque (OR 0.900; 95% CI 0.849-0.955; P = 0.001) and those without plaque (OR 0.944; 95% CI 0.908-0.981; P = 0.004). 4. Collectively, these findings suggest that serum 25(OH)D3 levels are inversely associated with atherosclerosis in Chinese middle-aged and elderly men. PMID- 24471523 TI - Antibiotic treatments and microbes in the gut. AB - Antibiotic therapies are important in combating disease-causing microorganisms and maintaining host health. It is widely accepted that exposure of the gut microbiota to antibiotics can lead to decreased susceptibility and the development of multi-drug-resistant disease-causing organisms, which can be a major clinical problem. It is also important to consider that antibiotics not only target pathogenic bacteria in the gut, but also can have damaging effects on the ecology of commensal species. This can reduce intrinsic colonization resistance and contribute to problems with antibiotic resistance, including lateral transfer of resistance genes. Our knowledge of the impact of antibiotic treatment on the ecology of the normal microbiota has been increased by recent advances in molecular methods and use of in vitro model systems to investigate the impact of antibiotics on the biodiversity of gut populations and the spread of antibiotic resistance. These highlight the need for more detailed structural and functional information on the long-term antibiotic-associated alterations in the gut microbiome, and spread of antibiotic resistance genes. This will be crucial for the development of strategies, such as targeted therapeutics, probiotics, prebiotics and synbiotics, to prevent perturbations in the gut microbiota, the restoration of beneficial species and improvements in host health. PMID- 24471524 TI - On the stability of perfluoroalkyl-substituted singlet carbenes: a coupled cluster quantum chemical study. AB - A series of trifluoromethyl-substituted carbenes R-C(:)-CF3 (R = NMe2, OMe, F, PMe2, P(NMe2)2, P(N(Pr-i)2)2, SMe, Cl); (dimethylamino)(perfluoroalkyl)carbenes Me2N-C(:)-R (R = CF3, C2F5, n-C3F7, i-C3F7, and t-C4F9) and symmetrically substituted carbenes R-C(:)-R (R = NMe2, OMe, F, PMe2, SMe, Cl) have been investigated by means of quantum chemistry methods. Different levels of approximation were used, including the CCSD(T) approach also known in quantum chemistry as the "golden standard", in combination with three different basis sets (TZVP, cc-pVDZ, cc-pVTZ). Relative stabilities of carbenes have been estimated using the differences between the singlet and triplet ground state energies (DeltaEST) and energies of the hydrogenation reaction for the singlet and triplet ground states of the carbenes. The latter seem to correlate better with stability of carbenes than the DeltaEST values. The (13)C NMR chemical shifts of the methylidene carbon indicate the more high-field chemical shift values in the known, isolable carbenes compared to the unstable ones. This is the first report on the expected chemical shifts in the highly unstable singlet carbenes. Using these criteria, some carbene structures from the studied series (as, for instance, Me2N-C(:)-CF3, Me2N-C(:)-C3F7-i) are proposed as good candidates for the experimental preparation. PMID- 24471525 TI - A fluorogenic probe for SNAP-tagged plasma membrane proteins based on the solvatochromic molecule Nile Red. AB - A fluorogenic probe for plasma membrane proteins based on the dye Nile Red and SNAP-tag is introduced. It takes advantage of Nile Red, a solvatochromic molecule highly fluorescent in an apolar environment, such as cellular membranes, but almost dark in a polar aqueous environment. The probe possesses a tuned affinity for membranes allowing its Nile Red moiety to insert into the lipid bilayer of the plasma membrane, becoming fluorescent, only after its conjugation to a SNAP tagged plasma membrane protein. The fluorogenic character of the probe was demonstrated for different SNAP-tag fusion proteins, including the human insulin receptor. This work introduces a new approach for generating a powerful turn-on probe for "no-wash" labeling of plasma membrane proteins with numerous applications in bioimaging. PMID- 24471526 TI - Indoloditerpenes from a marine-derived fungal strain of Dichotomomyces cejpii with antagonistic activity at GPR18 and cannabinoid receptors. AB - A marine-derived strain of Dichotomomyces cejpii produces the new compounds emindole SB beta-mannoside (1) and 27-O-methylasporyzin C (2), as well as the known indoloditerpenes JBIR-03 (3) and emindole SB (4). Indole derivative 1 was found to be a CB2 antagonist, while 2 was identified as the first selective GPR18 antagonist with an indole structure. Compound 4 was found to be a nonselective CB1/CB2 antagonist. The new natural indole derivatives may serve as lead structures for the development of GPR18- and CB receptor-blocking drugs. PMID- 24471527 TI - Oral proliferative verrucous leucoplakia: are there particular features for such an ambiguous entity? A systematic review. AB - Proliferative verrucous leucoplakia (PVL) is a distinct, particularly aggressive form of oral leucoplakia. Given the low prevalence of PVL, data are sparse and are mostly from case reports, case series and only a few case-control studies, meaning that the literature is able to provide only weak evidence. The present systematic literature review aims to collate the available evidence on the following issues: patient demographics, aetiology, lesion location(s), malignant potential, location and histopathological features of transformed lesions, disease-specific survival rates and treatment response. Electronic databases were searched for studies in the English language reporting original data from at least 10 patients with PVL on the target issues of the present review. The retrieved data were merged and a descriptive analysis performed. The 20 studies selected indicated that PVL does not seem to be correlated with the major risk factors for oral carcinoma (tobacco, alcohol and/or areca nut/betel leaf chewing). The disorder affects mainly adult/elderly women and has a very high malignant transformation rate, particular site distribution and particular location and histopathological features of transformed lesions. The present results may be limited by some articles being unintentionally excluded as they were not found during the electronic search, a lack of worldwide accepted diagnostic criteria for PVL, and overlapping data from multiple studies performed in a limited number of centres. Despite these potential drawbacks, the present results demonstrate that PVL does have particular features. PMID- 24471528 TI - Bacillus anthracis lethal toxin induces cell-type-specific cytotoxicity in human lung cell lines. AB - AIMS: Inhalational anthrax is caused by the entry of Bacillus anthracis spores into the lung. Inhaled spores are phagocytosed by alveolar macrophages. Bacilli then escape from the macrophage and spread to other cells, initiating a systemic anthrax infection. Based on the pathological studies of primate and human inhalational anthrax cases, it appears that lung tissue injury is a lethal consequence of the disease. Although the cytotoxicity of anthrax lethal toxin to macrophages is well known, it is not clear how anthrax toxin affects the various lung cell types. METHODS AND RESULTS: Using model cell lines representing different physiological compartments of the lung, we have investigated the cytotoxic effects of anthrax lethal toxin. The cell response was evaluated through MTT metabolism, neutral red uptake, initiation of apoptosis, and expression and binding activity of anthrax toxin receptors. We found that a human small airway epithelial cell line, HSAEC, was susceptible to anthrax lethal toxin. The other cell lines, A549, MRC-5, H358 and SKLU-1, displayed resistance to anthrax lethal toxin-mediated toxicity, although the expression of anthrax toxin receptors was detected in all the cell lines tested. CONCLUSIONS: Our results indicate that cell-type-specific toxicity may be induced by anthrax lethal toxin in human lung tissues and does not correlate with anthrax toxin receptor expression levels. SIGNIFICANCE AND IMPACT OF THE STUDY: This work suggests that cell-type-specific cytotoxicity of anthrax toxin in lung cells may cause subsequent lung disease progression. It may explain the initial pathogenic step of inhalational anthrax. PMID- 24471529 TI - Testosterone and type 2 diabetes in men. AB - OBJECTIVE: To assess from observational data if low testosterone in men is an independent risk factor for high fasting glucose (FG) and for a diagnosis of type 2 diabetes (T2D). METHODS: Multivariate analysis of data from 991 male US Air Force veterans who completed six medical examinations over 20 years. RESULTS: Low testosterone was moderately related to high FG, independent of age and obesity. Low testosterone is a very weak predictor of a diagnosis of T2D. CONCLUSIONS: In men, low testosterone is an independent risk factor for high FG, comparable to aging and obesity. Low testosterone is a weak predictor of a diagnosis of T2D. PMID- 24471530 TI - The future of isoprene emission from leaves, canopies and landscapes. AB - Isoprene emission from plants plays a dominant role in atmospheric chemistry. Predicting how isoprene emission may change in the future will help predict changes in atmospheric oxidant, greenhouse gas and secondary organic aerosol concentrations in the future atmosphere. At the leaf-scale, an increase in isoprene emission with increasing temperature is offset by a reduction in isoprene emission rate caused by increased CO2. At the canopy scale, increased leaf area index in elevated CO2 can offset the reduction in leaf-scale isoprene emission caused by elevated CO2. At the landscape scale, a reduction in forest coverage may decrease, while forest fertilization and community composition dynamics are likely to cause an increase in the global isoprene emission rate. Here we review the potential for changes in the isoprene emission rate at all of these scales. When considered together, it is likely that these interacting effects will result in an increase in the emission of the most abundant plant volatile, isoprene, from the biosphere to the atmosphere in the future. PMID- 24471531 TI - Shape of things to come. PMID- 24471538 TI - Project set up to prevent malnutrition in later life. PMID- 24471539 TI - Dementia education to be standardised at degree level. PMID- 24471540 TI - Squeeze on social care blamed for delay in discharges from hospital. PMID- 24471542 TI - Importance of sleep. PMID- 24471543 TI - Forum focus. Get a fresh perspective on emerging issues. PMID- 24471544 TI - Respecting what matters most. PMID- 24471548 TI - Practice question. PMID- 24471549 TI - Using Skype to support palliative care surveillance. AB - The aim of this article is to demonstrate how a novel yet important tool can facilitate family involvement in person-centred care, despite geographical distance. The author presents a case study as an in-depth example of the use of Skype in the context of palliative care at home. Skype enhanced family surveillance and symptom management, augmented shared decision making, provided a space for virtual bedside vigil, and ultimately provided the rapport necessary for optimal end of life care. PMID- 24471550 TI - Effects of a 12-week community exercise programme on older people. AB - AIM: To measure the effectiveness of a 12-week exercise intervention in reducing the health risks associated with physical decline in people aged 60 and older. METHOD: An intervention group took part in a 12-week exercise programme. The intervention and comparison groups undertook the Senior Fitness Test at baseline, 12 weeks, six months and 12 months. Focus groups were conducted with the intervention and comparison groups at 12 weeks, then again with the intervention group after 12 months. RESULTS: Fitness increased significantly (P>0.001) after 12 weeks of exercise in the intervention group. Results demonstrated significant difference between intervention and comparison groups' fitness at six months (P>0.01) and 12 months (P>0.001) respectively. Focus groups supported the results, suggesting exercise increased independence and quality of life. CONCLUSION: Nurses can promote exercise in patients to reduce social isolation, increase independence and improve quality of life. The findings from this study may be useful during the development of community services for older adults. PMID- 24471551 TI - Listening to carers' views on stroke services. AB - AIM: The aim of this study was to explore how members of a stroke carers' support group perceived that services for stroke patients and their carers could be improved. METHOD: A qualitative, experience-based design approach was used to explore the views of ten carers of stroke survivors. Experience questionnaires and a listening lab were used for data collection. Data analysis was carried out using thematic content analysis of the questionnaire and audiotaped transcripts. FINDINGS: Common themes identified included carer loneliness, lack of information, effect of stroke on relationships, carer emotions, loss of privacy and need for ongoing support. CONCLUSION: There are many advantages to be gained for users and organisations from user involvement in service redesign and delivery. PMID- 24471552 TI - Reflections of older people living in nursing homes. AB - AIM: To explore experiences of ageing in older people living in nursing homes, based on the gerotranscendence theory. METHOD: Interviews were held with 14 people aged between 80 and 96 years. The results were analysed using content analysis. FINDINGS: The findings were divided into three categories: the self, the cosmic dimension, and social and personal relationships. These three categories were underpinned by eight subcategories. Most participants described improved knowledge about themselves, decreased concern about body and appearance, acceptance and appreciation of life, and less regard for social norms. A fewer participants described a greater affinity with past generations, or thought that the borders between past and present had become blurred. CONCLUSION: This study provides a better understanding of how people experience old age. It also indicates how healthcare professionals could apply the gerotranscendence theory of ageing as a conversation model to enable care to be adjusted according to older people's wishes. PMID- 24471553 TI - Sustaining change. PMID- 24471554 TI - Intermediate filament proteins expression and carbohydrate moieties in trophoblast and decidual cells of mature cat placenta. AB - The aim of this study was to characterize cytoskeletal intermediate filament proteins and glycoconjugates of syncytiotrophoblast, cytotrophoblast and decidual cells of feline endotheliochorial placenta. Samples from 12 normal pregnant female cats, after 45 +/- 5 days of gestation, were obtained removing the uterine horns by hysterectomy. Sections were processed for routine observation and for immunohistochemistry using anticytokeratin, antivimentin and antidesmin antibodies. In addition, lectin histochemistry was performed using a panel of several biotinylated lectins to characterize glycosides expression profile. Cytotrophoblast and syncytiotrophoblast showed immunoreactivity only with acidic and basic cytokeratins. Decidual cells were only positive to vimentin, consistent with their origin from endometrial fibroblasts. Trophoblast expressed a broad population of glycans, highly exposing terminal N-acetyl glucosamine residues and non-sialylated galactose and N-acetyl galactosamine oligomers. Oligosaccharides bound by Phaseolus vulgaris erythroagglutinin were the only highly branched N linked residues evidenced in cats, and they were restricted to the syncytium. Unlike results reported on humans, mice and rats on lectin affinity of decidual cells, sialid acids and complex N-linked oligosaccharides were not demonstrated in cats. Glycosylation of proteins determines many of their final properties, thus becoming essential for the embryo-maternal dialogue during implantation and placentation. Changes in glycosylation pattern have been related to pathological pregnancies in other species. Hence, the knowledge about glycosylation profile of the normal cat placenta may lead to a better understanding of both normal and pathological reproductive events. PMID- 24471556 TI - An update to returning genetic research results to individuals: perspectives of the industry pharmacogenomics working group. AB - The ease with which genotyping technologies generate tremendous amounts of data on research participants has been well chronicled, a feat that continues to become both faster and cheaper to perform. In parallel to these advances come additional ethical considerations and debates, one of which centers on providing individual research results and incidental findings back to research participants taking part in genetic research efforts. In 2006 the Industry Pharmacogenomics Working Group (I-PWG) offered some 'Points-to-Consider' on this topic within the context of the drug development process from those who are affiliated to pharmaceutical companies. Today many of these points remain applicable to the discussion but will be expanded upon in this updated viewpoint from the I-PWG. The exploratory nature of pharmacogenomic work in the pharmaceutical industry is discussed to provide context for why these results typically are not best suited for return. Operational challenges unique to this industry which cause barriers to returning this information are also explained. PMID- 24471557 TI - Systematic screening for novel lipids by shotgun lipidomics. AB - A commonly accepted LIPID MAPS classification recognizes eight major lipid categories and over 550 classes, while new lipid classes are still being discovered by targeted biochemical approaches. Despite their compositional diversity, complex lipids such as glycerolipids, glycerophospholipids, saccharolipids, etc. are constructed from unique structural moieties, e.g., glycerol, fatty acids, choline, phosphate, and trehalose, that are linked by amide, ether, ester, or glycosidic bonds. This modular organization is also reflected in their MS/MS fragmentation pathways, such that common building blocks in different lipid classes tend to generate common fragments. We take advantage of this stereotyped fragmentation to systematically screen for new lipids sharing distant structural similarity to known lipid classes and have developed a discovery approach based on the computational querying of shotgun mass spectra by LipidXplorer software. We applied this concept for screening lipid extracts of C. elegans larvae at the dauer and L3 stages that represent alternative developmental programs executed in response to environmental challenges. The search, covering more than 1.5 million putative chemical compositions, identified a novel class of lyso-maradolipids specifically enriched in dauer larvae. PMID- 24471558 TI - Report on patients with non transfusion-dependent beta-thalassemia major being treated with hydroxyurea attending the Thalassemia Research Center, Sari, Mazandaran Province, Islamic Republic of Iran in 2013. AB - Hydroxyurea (HU) has been used to treat patients with non transfusion-dependent beta-thalassemia major (beta-TM) at the Thalassemia Research Center, Sari, Mazandaran Province, Islamic Republic of Iran since 1996. This study was performed to summarize and to share our experience. Medical records of all patients with beta-thalassemia (beta-thal) attending our center were reviewed in January 2013. Definition of beta-TM was based on complete blood count (CBC), hemoglobin (Hb) electrophoresis, and for some patients, by the amplification refractory mutation system-restriction fragment length polymorphism (ARMS-RFLP) method. Patients who had not been transfused before, or had only occasionally had blood transfusions, were selected. Age at first blood transfusion, initial HU therapy and time of study was extracted from the records. The lowest Hb level before using HU and the last Hb value when on the HU regimen as well as the difference, were reported. Number of saved packed red cells was calculated according to duration of HU use and the usual needs of the patients. Hydroxyurea was discontinued before a planned pregnancy and during gestation and lactation periods. Hydroxyurea was discontinued for male patients willing to reproduce. A p value of <0.05 was considered statistically significant. It was consistent with 1856 patients/year, and 3542 units of blood were saved. We found HU to be effective and safe in treating patients with non transfusion-dependent beta-TM. We strongly recommend HU therapy. PMID- 24471559 TI - The transcultural diabetes nutrition algorithm toolkit: survey and content validation in the United States, Mexico, and Taiwan. AB - BACKGROUND: Evidence demonstrates that medical nutrition therapy (MNT) in prediabetes and type 2 diabetes (T2D) improves glycemic control and reduces diabetes risks and complications. Consequently, MNT is included in current clinical practice guidelines. Guideline recommendations, however, are frequently limited by their complexity, contradictions, personal and cultural rigidity, and compromised portability. The transcultural Diabetes Nutrition Algorithm (tDNA) was developed to overcome these limitations. To facilitate tDNA uptake and usage, an instructional Patient Algorithm Therapy (PATh) toolkit was created. Content validation of tDNA-PATh is needed before widespread implementation. SUBJECTS AND METHODS: Healthcare providers (n=837) in Mexico (n=261), Taiwan (n=250), and the United States (n=326) were questioned about challenges implementing MNT in clinical practice and the projected utilization and impact of tDNA-PATh. To assess the international portability and applicability of tDNA-PATh, the survey was conducted in countries with distinct ethnic and cultural attributes. Potential respondents were screened for professional and practice demographics related to diabetes. The questionnaire was administered electronically after respondents were exposed to core tDNA-PATh components. RESULTS: Overall, 61% of respondents thought that tDNA-PATh could help overcome MNT implementation challenges, 91% indicated positive impressions, 83% believed they would adopt tDNA-PATh, and 80% thought tDNA-PATh would be fairly easy to implement. CONCLUSIONS: tDNA-PATh appears to be an effective culturally sensitive tool to foster MNT in clinical practice. By providing simple culturally specific instructions, tDNA-PATh may help to overcome current impediments to implementing recommended lifestyle modifications. Specific guidance provided by tDNA-PATh, together with included patient education materials, may increase healthcare provider efficiency. PMID- 24471560 TI - The StatStrip glucose monitor is suitable for use during hyperinsulinemic euglycemic clamps in a pediatric population. AB - BACKGROUND: The hyperinsulinemic euglycemic clamp is the gold standard for assessment of insulin resistance and requires frequent, accurate measurements of blood glucose concentrations, typically utilizing the YSI 2300 STAT PlusTM glucose analyzer (YSI, Inc., Yellow Springs, OH). Despite its accuracy, the YSI has several limitations, including its cost, lengthy run time, need for trained personnel, frequent maintenance, and large blood volumes. Simpler hospital-grade hand-held glucose meters are now available but have not been validated for use in pediatric clamp settings. Our objective was to evaluate the accuracy, precision, and reliability of the StatStrip((r)) (SS) hospital glucose monitoring system (Nova Biomedical, Waltham, MA) relative to the YSI 2300 STAT glucose analyzer in pediatric hyperinsulinemic euglycemic clamps. SUBJECTS AND METHODS: Four hundred sixty blood specimens drawn from 11 pediatric patients undergoing hyperinsulinemic euglycemic clamps were simultaneously analyzed by SS and YSI. Outcome measures included SS bias relative to YSI and glucose measurement precision on SS and YSI. RESULTS: The SS showed a slight positive bias of 0.75 +/ 2.83 mg/dL versus the YSI. Percentage coefficients of variance for SS and YSI were 9.53% and 9.25%, respectively. Using a Bland-Altman plot, the limits of agreement were +/- 5.7 mg/dL. The coefficient of repeatability for SS was 6.63; the coefficient of individual agreement between the YSI and SS was 0.995. CONCLUSIONS: The SS is a suitable replacement for the YSI in pediatric hyperinsulinemic euglycemic clamp studies, is easier to use, more cost-effective, and faster, and requires less blood. Future euglycemic clamp studies can consider utilizing this methodology. PMID- 24471561 TI - Clinical evaluation of an automated artificial pancreas using zone-model predictive control and health monitoring system. AB - BACKGROUND: This study was performed to evaluate the safety and efficacy of a fully automated artificial pancreas using zone-model predictive control (zone MPC) with the health monitoring system (HMS) during unannounced meals and overnight and exercise periods. SUBJECTS AND METHODS: A fully automated closed loop artificial pancreas was evaluated in 12 subjects (eight women, four men) with type 1 diabetes (mean+/-SD age, 49.4+/-10.4 years; diabetes duration, 32.7+/ 16.0 years; glycosylated hemoglobin, 7.3+/-1.2%). The zone-MPC controller used an a priori model that was initialized using the subject's total daily insulin. The controller was designed to keep glucose levels between 80 and 140 mg/dL. A hypoglycemia prediction algorithm, a module of the HMS, was used in conjunction with the zone controller to alert the user to consume carbohydrates if the glucose level was predicted to fall below 70 mg/dL in the next 15 min. RESULTS: The average time spent in the 70-180 mg/dL range, measured by the YSI glucose and lactate analyzer (Yellow Springs Instruments, Yellow Springs, OH), was 80% for the entire session, 92% overnight from 12 a.m. to 7 a.m., and 69% and 61% for the 5-h period after dinner and breakfast, respectively. The time spent < 60 mg/dL for the entire session by YSI was 0%, with no safety events. The HMS sent appropriate warnings to prevent hypoglycemia via short and multimedia message services, at an average of 3.8 treatments per subject. CONCLUSIONS: The combination of the zone-MPC controller and the HMS hypoglycemia prevention algorithm was able to safely regulate glucose in a tight range with no adverse events despite the challenges of unannounced meals and moderate exercise. PMID- 24471563 TI - The influence of rare genetic variation in SLC30A8 on diabetes incidence and beta cell function. AB - CONTEXT/OBJECTIVE: The variant rs13266634 in SLC30A8, encoding a beta-cell specific zinc transporter, is associated with type 2 diabetes. We aimed to identify other variants in SLC30A8 that increase diabetes risk and impair beta cell function, and test whether zinc intake modifies this risk. DESIGN/OUTCOME: We sequenced exons in SLC30A8 in 380 Diabetes Prevention Program (DPP) participants and identified 44 novel variants, which were genotyped in 3445 DPP participants and tested for association with diabetes incidence and measures of insulin secretion and processing. We examined individual common variants and used gene burden tests to test 39 rare variants in aggregate. RESULTS: We detected a near-nominal association between a rare-variant genotype risk score and diabetes risk. Five common variants were associated with the oral disposition index. Various methods aggregating rare variants demonstrated associations with changes in oral disposition index and insulinogenic index during year 1 of follow-up. We did not find a clear interaction of zinc intake with genotype on diabetes incidence. CONCLUSIONS: Individual common and an aggregate of rare genetic variation in SLC30A8 are associated with measures of beta-cell function in the DPP. Exploring rare variation may complement ongoing efforts to uncover the genetic influences that underlie complex diseases. PMID- 24471562 TI - Placental CYP27B1 and CYP24A1 expression in human placental tissue and their association with maternal and neonatal calcitropic hormones. AB - CONTEXT: Placental CYP27B1 may contribute to circulating maternal calcitriol concentrations across gestation, but determinants of CYP27B1 and CYP24A1 expression in term human placental tissue are not well established. OBJECTIVE: We hypothesized that higher CYP27B1 protein expression would be associated with increased maternal calcitriol during gestation and that CYP27B1 expression would be impacted by substrate availability. DESIGN: This was a prospective, longitudinal study. SETTING: The study was completed in an urban, prenatal clinic located in Rochester, New York. PATIENTS: The study was undertaken in a cohort of 70 pregnant adolescents (<=18 y of age) and their term neonates. INTERVENTION: There was no intervention. MAIN OUTCOMES: Protein and mRNA expressions of CYP27B1, CYP24A1, and vitamin D receptor were measured in term placental tissue and related to 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D, PTH, serum total calcium, IL-6, leptin, and osteoprotegerin measured in maternal serum at midgestation and delivery and in umbilical cord serum at birth. RESULTS: Placental CYP27B1 protein expression was significantly positively associated with maternal 25(OH)D at both midgestation (n = 68, P = .009) and delivery (n=67, P = .006). Maternal serum 1,25-dihydroxyvitamin D concentrations at midgestation were positively correlated with term placental CYP27B1 mRNA expression (n = 49, P = .002). Significant positive associations were evident between placental CYP27B1 and CYP24A1 protein expression (P = .001, n = 70). Maternal PTH concentrations at midgestation or delivery did not significantly impact placental protein or transcript level of either enzyme. Variability in placental CYP27B1 protein expression was best captured by a model that included maternal midgestation 25(OH)D concentration, placental vitamin D receptor protein expression, and maternal midgestation IL-6 concentrations (P = .002, n = 60, R(2) = 0.22). CONCLUSIONS: Higher maternal 25(OH)D during pregnancy was associated with significantly higher placental protein expression of CYP27B1 at term supportive of a link between substrate availability and placental production of calcitriol. PMID- 24471564 TI - Role of sclerostin and dickkopf-1 in the dramatic alteration in bone mass acquisition in adolescents and young women with recent anorexia nervosa. AB - BACKGROUND: The nutritional deprivation of adolescent girls with anorexia nervosa (AN) reduces bone mass acquisition. A better understanding of this process would improve the medical treatment of bone alteration and its long-term consequences. OBJECTIVE: The first aim was to model the bone mass acquisition in young women with AN. The second aim was to identify the clinical and biological factors associated with bone demineralization and investigate the potential role of sclerostin and dickkopf-1 protein (DKK-1). POPULATION AND METHODS: Ninety-eight AN patients (mean age 18.2 +/- 2.6 years) and 63 age-matched controls were enrolled in this study. Areal bone mineral density (aBMD) was determined by dual energy x-ray absorptiometry. Calciotropic hormones, bone turnover markers, sclerostin, DKK-1, and growth factors were concomitantly evaluated. RESULTS: The aBMD was significantly reduced at all bone sites in AN patients vs controls (range, -3.3% at the radius to -12.1% for total proximal femur). Bone formation markers IGF-1 and DKK-1 were significantly decreased in AN patients, whereas PTH, sclerostin, and the bone resorption markers were increased. In patients, the AN duration, amenorrhea, weight, body mass index, fat mass, and fat-free soft tissue were negatively correlated with aBMD, whereas the age of AN onset was positively correlated. Multiple regression analysis revealed that the duration of amenorrhea was the independent factor most negatively associated with aBMD at all bone sites except the radius. CONCLUSION: This case-control study demonstrated a dramatic reduction in aBMD, reinforced for the first time by our models, and indicates the need for early, systematic, and adapted bone mass monitoring. Moreover, appropriate treatment should be started early in patients with AN. Increased secretion of sclerostin suggests that it may be a target for pharmacological action. PMID- 24471565 TI - Estradiol-17beta upregulates pyruvate kinase M2 expression to coactivate estrogen receptor-alpha and to integrate metabolic reprogramming with the mitogenic response in endometrial cells. AB - CONTEXT: Proliferating cells reprogram their cellular glucose metabolism to meet the bioenergetic and biosynthetic demands and to maintain cellular redox homeostasis. Pyruvate kinase M (PKM) is a critical regulator of this metabolic reprogramming. However, whether estradiol-17beta (E2) reprograms cellular metabolism to support proliferation of human primary endometrial stromal cells (hESCs) and the molecular basis of this reprogramming are not well understood. OBJECTIVES: Our objectives were to study whether E2 induces reprogramming of glucose metabolism in hESCs and to investigate the potential roles of PKM2 in E2 induced metabolic reprogramming and proliferation of these cells. METHODS: The oxygen consumption rate and extracellular acidification rate were assessed by a Seahorse XF24 analyzer. PKM2 expression was assessed by real-time RT-PCR and immunoblotting. RESULTS: E2 induces a Warburg-like glucose metabolism in hESCs by inducing the expression of PKM. E2 also enhanced PKM splicing into the PKM2 isoform by upregulating the c-Myc-hnRNP axis. Furthermore, E2 induces PKM2 oxidation, phosphorylation, and nuclear translocation. In addition to its glycolytic function, PKM2 physically interacted with estrogen receptor-alpha (ERalpha) and functioned as an ERalpha coactivator. Small-molecule PKM2 activators ameliorated ERalpha transcriptional activity and abrogated the E2 induced hESC proliferation. CONCLUSIONS: We show for the first time that E2 induced hESC proliferation is associated with a shift in glucose metabolism toward aerobic glycolysis, and the molecular basis for this metabolic shift is linked to the effects of E2 on PKM2. In addition, PKM2 acts as a transcriptional coactivator for ERalpha and small-molecule PKM2 activators inhibit ERalpha transcriptional activity and reduce E2-induced cell proliferation. PMID- 24471566 TI - New management strategy of pregnancies at risk of congenital adrenal hyperplasia using fetal sex determination in maternal serum: French cohort of 258 cases (2002 2011). AB - CONTEXT: Prenatal dexamethasone (DEX) treatment has been proposed since 1984 to prevent genital virilization in girls with congenital adrenal hyperplasia (CAH). DEX is effective in CAH females if initiated before the sixth week of gestation, but its safety in children treated in utero remains controversial regarding cognitive functions. OBJECTIVE: To avoid prenatal DEX in males and initiate DEX in due time in CAH females, we proposed in 2002 a protocol for fetal sex determination in the maternal serum (SRY test). DESIGN AND SETTING: We conducted a retrospective study of the management of 258 fetuses in the period 2002 through 2011 in pregnancies managed in referent medical centers with an institutional practice. PATIENTS: A total of 258 fetuses at risk of CAH (134 males and 124 females) were included. INTERVENTION: DEX was offered after informed consent to pregnant women. MAIN OUTCOME MEASURE: The sensitivity of an early SRY test was evaluated after data collection. RESULTS: The SRY test is sensitive from 4 weeks and 5 days of gestation. It avoided prenatal DEX in 68% of males, and this percentage increased over the years. DEX was maintained until prenatal diagnosis in non-CAH females. Virilization was prevented in 12 CAH girls treated at the latest at 6 weeks gestation and minimized in 3 girls treated between 6 and 7 weeks gestation. Maternal tolerance was correct. No fetal malformations were noted in the 154 children treated in utero. CONCLUSIONS: The SRY test is reliable to avoid prenatal DEX in males, but its application must be improved. Prenatal DEX should be maintained to prevent virilization and traumatic surgery in CAH girls after informed consent and information provided to families about the benefit to risk ratio in limiting hyperandrogenism during fetal life. Our large multicentric French cohort has helped to better assess the risks previously reported. PMID- 24471567 TI - Association between sex steroid levels and bone microarchitecture in men: the STRAMBO study. AB - CONTEXT: Data on the association between bone microarchitecture assessed by high resolution peripheral quantitative computed tomography (HR-pQCT) and sex steroids in men are scarce. OBJECTIVE: Our aim was to determine the association between serum sex steroids and bone microarchitecture assessed by HR-pQCT in men. DESIGN: This is a cross-sectional analysis in the Structure of the Aging Men's Bones cohort. SETTING: The cohort was recruited from the general population. PARTICIPANTS: We examined 1169 male volunteers aged 20-87 years. No specific exclusion criteria were used. INTERVENTIONS: We collected blood samples and performed HR-pQCT at the distal radius and distal tibia. MAIN OUTCOME MEASURES: We tested the hypothesis that low sex steroid levels are associated with poor bone microarchitecture in men. RESULTS: Men aged younger than 65 years with bioavailable 17beta-estradiol (bio-17beta-E2) levels of14.4 pmol/L or less had higher cross-sectional and trabecular areas vs men with bio-17beta-E2 greater than 14.4 pmol/L. In men aged 65 years or older, the higher the apparent free T concentration (AFTC), the higher was the distal tibia cortical density (P < .05). Cortical density and thickness as well as total and trabecular density increased with higher bio-17beta-E2 levels. Similar results were found after adjustment for limb length and body height. Men with low AFTC and low bio-17beta-E2 levels had lower cortical density and thickness at both skeletal sites compared with the reference group. In men with AFTC less than 272 pmol/L, those with low bio-17beta E2 less than 25 pmol/L had lower cortical density and thickness at both skeletal sites vs men having higher bio-17beta-E2 levels. CONCLUSION: In men aged 65 years and older, low bio-17beta-E2 levels were associated with poor cortical bone status and, to smaller extent, lower trabecular density. PMID- 24471569 TI - Identification and functional characterization of two novel NPR2 mutations in Japanese patients with short stature. AB - CONTEXT: C-type natriuretic peptide-natriuretic peptide receptor B (NPR-B) signaling is critical for endochondral ossification, which is responsible for longitudinal growth in limbs and vertebrae. Biallelic NPR2 mutations cause acromesomelic dysplasia, type Maroteaux, which is bone dysplasia characterized by severe short stature and short limbs. A monoallelic NPR2 mutation has been suggested to mildly impair long bone growth. OBJECTIVE: The goal of this study was to identify and characterize NPR2 mutations among Japanese patients with short stature. SUBJECTS AND METHODS: We enrolled 101 unrelated Japanese patients with short stature. NPR2 and NPPC were sequenced, and the identified variants were characterized in vitro. RESULTS: In two subjects, we identified two novel heterozygous NPR2 mutations (R110C and Q417E) causing a loss of C-type natriuretic peptide-dependent cGMP generation capacities and having dominant negative effects. R110C was defective in trafficking from the endoplasmic reticulum to the Golgi apparatus. In contrast, Q417E showed clear cell surface expression. CONCLUSIONS: We identified heterozygous NPR2 mutations in 2% of Japanese patients with short stature. Our in vitro findings indicate that NPR2 mutations have a dominant negative effect, and their dominant-negative mechanisms vary corresponding to the molecular pathogenesis of the mutations. PMID- 24471568 TI - Prostaglandin E2 regulates its own inactivating enzyme, 15-PGDH, by EP2 receptor mediated cervical cell-specific mechanisms. AB - CONTEXT: Prostaglandins play important roles in parturition and have been used to induce cervical ripening and labor. Prior to cervical ripening at term, 15 hydroxyprostaglandin dehydrogenase (15-PGDH) is highly expressed in the cervix and metabolizes cyclooxygenase-2-mediated increases in active prostaglandin E2 (PGE2) to inactive 15-keto PGE2. At term, 15-PGDH gene expression decreases and PGE2 accumulates, leading to cervical ripening and labor. Previously, we found that the cervical isoform of microphthalmia-associated transcription factor (MiTF CX) serves as a progestational transcription factor that represses IL-8 and hypoxia-mediated increases in cyclooxygenase-2. OBJECTIVE: We tested the hypothesis that PGE2 regulates its own inactivation through MiTF-CX. DESIGN: We used human cervical stromal cells to investigate the regulation of 15-PGDH. SETTING: This was a laboratory-based study using cells from clinical tissue samples. MAIN OUTCOME MEASURES: We evaluated the mechanisms by which PGE2 regulates 15-PGDH in human cervical stromal cells. RESULTS: PGE2 repressed MiTF CX and 15-PGDH, whereas ectopic overexpression of MiTF-CX induced 15-PGDH expression levels. Stabilization of HIF-1alpha by deferoxamine resulted in concomitant down-regulation of MiTF-CX and 15-PGDH. Ectopic overexpression of MiTF-CX abrogated PGE2- and deferoxamine-mediated loss of MiTF-CX and 15-PGDH. PGE2-induced loss of MiTF-CX and 15-PGDH was mediated through prostaglandin E2 receptor (EP2) receptors (PTGER2), but not cAMP. CONCLUSIONS: The 15-PGDH gene is a MiTF-CX target gene in cervical stromal cells and is down-regulated by PGE2 through EP2 receptors. The findings suggest that EP2 receptor-specific antagonists may be used as an adjunct to present clinical management for the prevention of preterm cervical ripening and preterm labor. PMID- 24471570 TI - A polymorphism in the promoter region of the selenoprotein S gene (SEPS1) contributes to Hashimoto's thyroiditis susceptibility. AB - CONTEXT: The association between selenium and inflammation and the relevance of selenoproteins in follicular thyroid cell physiology have pointed to a putative role of selenoproteins in the pathogenesis of autoimmune thyroid diseases. OBJECTIVE: The aim of this study was to evaluate the role of a promoter variation in SEPS1, the selenoprotein S gene, in the risk for developing Hashimoto's thyroiditis (HT). DESIGN: A case-control study was performed to assess the association of genetic variation in the SEPS1 gene (SEPS1 -105G/A single nucleotide polymorphism, rs28665122) and HT. SETTING: The study was conducted in north Portugal, Porto, in the period of 2007-2013. PATIENTS OR OTHER PARTICIPANTS: A total of 997 individuals comprising 481 HT patients and 516 unrelated controls were enrolled in the study. MAIN OUTCOME MEASURES: Genetic variants were discriminated by real-time PCR using TaqMan single-nucleotide polymorphism genotyping assays. RESULTS: There is a significant association between the SEPS1 -105 GA and AA genotypes and HT [odds ratio (OR) 2.24, confidence interval (CI) 1.67-3.02, P < 5.0 * 10(-7), and OR 2.08, CI 1.09-3.97, P = .0268, respectively]. The A allele carriers are in higher proportion in the patient group than in the control population (46.2% vs 28.1%, P < 5.0 * 10(-7)) with an OR (CI) of 2.22 (1.67-2.97). The proportion of patients carrying the A allele is significantly higher in male patients with HT, representing a 3.94 times increased risk (P = 7.9 * 10(-3)). CONCLUSION: Our findings support the existence of a link between SEPS1 promoter genetic variation and HT risk. PMID- 24471571 TI - Skeletal muscle characteristics and motor performance after 2-year growth hormone treatment in adults with prader-willi syndrome. AB - CONTEXT: In adults with Prader-Willi syndrome (PWS), abnormal body composition with decreased lean body mass and skeletal muscle (SM) volume has been related to altered GH secretion and may possibly contribute to greatly reduced motor capacity. OBJECTIVE: The scope of the study was to test the hypothesis that GH treatment has favorable effects on SM characteristics and motor performance in adults with PWS. DESIGN, SETTING, AND PARTICIPANTS: Fifteen obese PWS subjects (nine males and six females; age range, 19-35 y; body mass index, 37.7-59.9 kg/m(2)) were investigated before and after 12 (GH12) and 24 (GH24) months of GH treatment. MAIN OUTCOME MEASURES: SM cross-sectional area and SM attenuation were determined with computed tomography at the lumbar and midthigh levels. Maximal isometric handgrip strength and isokinetic knee extension peak torque were measured. Motor performance was evaluated with different indoor walking tests, whereas exercise endurance was assessed with a treadmill incremental test to exhaustion. RESULTS: A condition of severe GH deficiency was found in six patients (40%). GH treatment significantly increased lean body mass (GH12, P < .05; GH24, P < .05), reduced percentage of body fat (GH12, P < .05; GH24, P < .05), and augmented SM cross-sectional area and SM attenuation of both lumbar (GH12, P < .01; GH24, P < .001) and thigh muscles (GH24, P < .05). Handgrip strength increased by 7% at GH12 (P < .05) and by 13% at GH24 (P < .001). Peak torque of knee extension extrapolated at zero angular velocity was significantly higher at GH24 (P < .01), and exercise endurance rose by 13% (P < .05) and 17% (P < .05) before exhaustion at GH12 and GH24, respectively, whereas no change was detected with walking tests. No significant difference in the response to GH treatment was detected between patients with and without GH deficiency. CONCLUSION: Long-term GH treatment in adult PWS patients improves body composition and muscle size and quality and increases muscle strength and exercise tolerance independently from the GH secretory status. PMID- 24471572 TI - Nonalcoholic fatty liver disease, liver fibrosis, and cardiometabolic risk factors in adolescence: a cross-sectional study of 1874 general population adolescents. AB - CONTEXT: The impact of adolescent nonalcoholic fatty liver disease (NAFLD) on health, independent of fat mass, is unclear. OBJECTIVE: The objective of the study was to determine the independent (of total body fat) association of ultrasound scan (USS)-determined NAFLD with liver fibrosis, insulin resistance, and dyslipidemia among healthy adolescents. DESIGN: This was a cross-sectional analysis in participants from a UK birth cohort. PARTICIPANTS: One thousand eight hundred seventy-four (1059 female) individuals of a mean age of 17.9 years participated in the study. MAIN OUTCOMES: USS assessed liver stiffness (shear velocity, an indicator of fibrosis) and volume, fasting glucose, insulin, triglycerides, low-density lipoprotein cholesterol, high-density lipoprotein cholesterol, alanine amino transferase, aspartate amino transferase, gamma glutamyltransferase, and haptoglobin. RESULTS: The prevalence of NAFLD was 2.5% [95% confidence interval (CI) 1.8-3.3] and was the same in females and males. Dual-energy X-ray absorptiometry determined total body fat mass was strongly associated with USS NAFLD: odds ratio 3.15 (95% CI 2.44-4.07) per 1 SD (~10 kg) fat mass. Those with NAFLD had larger liver volumes and greater shear velocity. They also had higher fasting glucose, insulin, triglycerides, low-density lipoprotein cholesterol, alanine amino transferase, aspartate amino transferase, gamma-glutamyltransferase, and haptoglobin and lower high-density lipoprotein cholesterol. Most associations were independent of total body fat. For example, after adjustment for fat mass and other confounders, hepatic shear velocity [mean difference 22.8% (95% CI 15.6-30.5)], triglyceride levels [23.6% (95% CI 6.0 44.2)], and insulin [39.4% (95% CI 10.7-75.5)] were greater in those with NAFLD compared with those without NAFLD. CONCLUSION: In healthy European adolescents, 2.5% have USS-defined NAFLD. Even after accounting for total body fat, those with NAFLD have more adverse levels of liver fibrosis and cardiometabolic risk factors. PMID- 24471573 TI - Ketoconazole in Cushing's disease: is it worth a try? AB - BACKGROUND: The use of ketoconazole has been recently questioned after warnings from the European Medicine Agencies and the Food and Drug Administration due to potential hepatotoxicity. However, ketoconazole is frequently used as a drug to lower circulating cortisol levels. Several pharmacological agents have recently been approved for the treatment of Cushing's disease (CD) despite limited efficacy or significant side effects. Ketoconazole has been used worldwide for more than 30 years in CD, but in the absence of a large-scale study, its efficacy and tolerance are still under debate. PATIENTS AND METHODS: We conducted a French retrospective multicenter study reviewing data from patients treated by ketoconazole as a single agent for CD, with the aim of clarifying efficacy and tolerance to better determine the benefit/risk balance. RESULTS: Data from 200 patients were included in this study. At the last follow-up, 49.3% of patients had normal urinary free cortisol (UFC) levels, 25.6% had at least a 50% decrease, and 25.4% had unchanged UFC levels. The median final dose of ketoconazole was 600 mg/d. Forty patients (20%) received ketoconazole as a presurgical treatment; 40% to 50% of these patients showed improvement of hypertension, hypokalemia, and diabetes, and 48.7% had normal UFC before surgery. Overall, 41 patients (20.5%) stopped the treatment due to poor tolerance. Mild (<5N, inferior to 5-fold normal values) and major (>5N, superior to 5-fold normal values) increases in liver enzymes were observed in 13.5% and 2.5% of patients, respectively. No fatal hepatitis was observed. CONCLUSIONS: Ketoconazole is an effective drug with acceptable side effects. It should be used under close liver enzyme monitoring. Hepatotoxicity is usually mild and resolves after drug withdrawal. PMID- 24471574 TI - Stereotactic radiosurgery for acromegaly. AB - CONTEXT: The role of stereotactic radiosurgery (SRS) in acromegaly is being assessed. OBJECTIVE: We evaluated the efficacy and safety of SRS for patients with acromegaly. Prognostic factors related to outcomes were also analyzed. DESIGN: This was a retrospective study of patients treated with SRS at the University of Virginia; the data were collected from 1989 to 2012, with a median follow-up of 61.5 months. PATIENTS: A total of 136 patients underwent SRS for acromegaly. Diagnosis of acromegaly was based on the combination of clinical features and biochemical assessment, including the serum GH level and age- and gender-matched serum IGF-1 level. All patients underwent a complete endocrine evaluation, neuroimaging study, and ophthalmic examinations before SRS. MAIN OUTCOME MEASURES: After withdrawal of GH- or IGF-1-altering medications, patients who had an oral glucose tolerance test GH of < 1.0 ng/mL or normal IGF-1 were considered in remission. Post-radiosurgical hypopituitarism was defined as a decrease in one or more hormones below normal. RESULTS: With a median follow-up of 61.5 months, 65.4% of the patients achieved remission. The mean time to remission was 27.5 months. The actuarial remission rates at 2, 4, 6, and 8 years after radiosurgery were 31.7, 64.5, 73.4, and 82.6%, respectively. Favorable prognostic factors for remission included a higher margin radiation dose, higher maximum dose, and lower initial IGF-1 level. New pituitary hormone deficiency occurred in 43 patients (31.6%); two patients (1.5%) developed panhypopituitarism. Corresponding risk factors for new pituitary hormone deficiency were a margin dose > 25 Gy and tumor volume > 2.5 mL. Other complications included an adverse radiation effect in one patient, visual deterioration in four, and new oculomotor nerve palsy in one. CONCLUSION: SRS affords a reasonable rate of endocrine remission in patients with acromegaly and generally does so with a low rate of adverse effects. PMID- 24471575 TI - Derivation and validation of multimarker prognostication for normotensive patients with acute symptomatic pulmonary embolism. AB - RATIONALE: Not all patients with acute pulmonary embolism (PE) have a high risk of an adverse short-term outcome. OBJECTIVES: This prospective cohort study aimed to develop a multimarker prognostic model that accurately classifies normotensive patients with PE into low and high categories of risk of adverse medical outcomes. METHODS: The study enrolled 848 outpatients from the PROTECT (PROgnosTic valuE of Computed Tomography) study (derivation cohort) and 529 patients from the Prognostic Factors for Pulmonary Embolism (PREP) study (validation cohort). Investigators assessed study participants for a 30-day complicated course, defined as death from any cause, hemodynamic collapse, and/or adjudicated recurrent PE. MEASUREMENTS AND MAIN RESULTS: A complicated course occurred in 63 (7.4%) of the 848 normotensive patients with acute symptomatic PE in the derivation cohort and in 24 patients (4.5%) in the validation cohort. The final model included the simplified Pulmonary Embolism Severity Index, cardiac troponin I, brain natriuretic peptide, and lower limb ultrasound testing. The model performed similarly in the derivation (c-index of 0.75) and validation (c index of 0.85) cohorts. The combination of the simplified Pulmonary Embolism Severity Index and brain natriuretic peptide testing showed a negative predictive value for a complicated course of 99.1 and 100% in the derivation and validation cohorts, respectively. The combination of all modalities had a positive predictive value for the prediction of a complicated course of 25.8% in the derivation cohort and 21.2% in the validation cohort. CONCLUSIONS: For normotensive patients who have acute PE, we derived and validated a multimarker model that predicts all-cause mortality, hemodynamic collapse, and/or recurrent PE within the following 30 days. PMID- 24471576 TI - How the length of genital parts affects copulation performance in a carabid beetle: implications for correlated genital evolution between the sexes. AB - To identify factors leading to the correlated evolution of exaggerated male and female genitalia, we studied the effects of the variable dimensions of corresponding functional genital parts (male copulatory piece and female vaginal appendix) on copulatory performance in the polygamous carabid beetle Carabus (Ohomopterus) maiyasanus. We used mating pairs of individuals from two populations to increase the variances in genital dimensions and determined the copulation performance (insemination and spermatophore replacement, and copulation time) in single- and double-mating situations. In single mating, insemination success was not affected by genital dimensions, although the copulation time was significantly shorter when the male aedeagus was longer. In the double-mating experiment, insemination and replacement of spermatophores by the second male succeeded more frequently when the copulatory piece was shorter and the vaginal appendix was longer, and when the difference between the length of the copulatory piece and the vaginal appendix was smaller. Thus, a matching of the corresponding genital parts between the sexes increases the male's reproductive success in sperm competition, but elongation of the copulatory piece cannot be explained simply by the improvement in male reproductive success. We discuss possible factors for the elongation of genital parts in terms of sexual conflict and reproductive interference through interspecific copulation. PMID- 24471577 TI - Joint trajectories of smoking and depressive mood: associations with later low perceived self-control and low well-being. AB - This longitudinal study examines comorbid trajectories of cigarette smoking and depressive mood from adolescence to adulthood and its association with low perceived self-control and low well-being in adulthood. Participants (N = 607) were interviewed at 6 time waves. Growth mixture modeling (GMM) determined membership in joint trajectory groups of comorbid smoking and depressive mood ranging from mean age 14 to mean age 32 years. Multivariate logistic regression was used to assess the associations between earlier trajectory group memberships and low perceived self-control and low well-being in adulthood. Trajectory groups characterized by earlier, comorbid chronic/heavy smoking and chronic/high depressive mood were most at risk for low perceived self-control and low well being in adulthood. Counseling for adolescents and young adults with low perceived self-control and low well-being should address smoking and depressive mood. Interventions to reduce smoking and depressive mood may result in increased self-control and well-being. PMID- 24471579 TI - Effects of the tea catechin epigallocatechin gallate on Porphyromonas gingivalis biofilms. AB - AIMS: The aim of this study was to investigate the effects of tea catechin epigallocatechin gallate (EGCg) on established biofilms and biofilm formation by Porphyromonas gingivalis, a major pathogen of periodontal disease. METHODS AND RESULTS: Biofilm cell survival was measured using adenosine triphosphate (ATP) bioluminescence. In the presence of EGCg, the ATP level in cells of established biofilms was significantly decreased compared to the controls (P < 0.0001). Transmission electron microscopy revealed that EGCg damaged the cell membrane and cell wall of P. gingivalis. Confocal laser-scanning microscopy revealed that the proportion of dead cells was higher in biofilms treated with EGCg. Moreover, the effects of subminimal inhibitory concentrations (MICs) of EGCg on P. gingivalis biofilm formation were dose-dependent (P < 0.0001). CONCLUSION: Our results suggest that EGCg destroys established P. gingivalis biofilms and inhibits biofilm formation. SIGNIFICANCE AND IMPACT OF THE STUDY: Development of chemical control agents against oral biofilms is necessary, because oral biofilms can be only removed using mechanical debridement. This article indicates that EGCg may represent a novel antibiofilm agent that prevents infections involving bacterial biofilms such as periodontitis. PMID- 24471578 TI - GSTA1*-69C/T and GSTO2*N142D as asthma- and allergy-related risk factors in Italian adult patients. AB - 1. Asthma and allergies are characterized by variable and subjective symptoms influenced by many genes, molecular mechanisms and environmental factors. The presence of inflammation and oxidative stress in the airways are important biochemical features of asthma and respiratory allergies. Glutathione S transferase (GSTs) enzymes play an important role in cellular protection against inflammation, and functional genetic polymorphisms in GST genes show a significant association with asthma and allergy risk. Specifically, our previous study on asthmatic children highlighted GSTA1 and GSTO2 as novel susceptibility loci for asthma. 2. In the present study we focused our attention on GSTA1*-69C/T (rs3957357) and GSTO2*N142D (rs156697) polymorphisms to confirm our previous results in an independent adult study population and to clarify whether GSTA1 and GSTO2 gene polymorphisms are involved in a non-discriminative pathway towards asthma and respiratory allergy. 3. To accomplish this, we recruited 103 patients with respiratory allergies, 199 patients with asthma and 200 healthy controls. Genomic DNA extracted from buccal cells was screened for GSTA1*-69C/T and GSTO2*N142D single nucleotide polymorphisms. 4. The GSTA1*-69T and GSTO2*D142 variants are both associated with a significantly increased risk of asthma, whereas only GSTA1*-69C/T is significantly associated with allergies. These outcomes confirm the involvement of GSTO2 loci in asthma and suggest that GSTA1 is a common risk factor for asthma and allergies. PMID- 24471580 TI - Stability of (bio)functionalized porous aluminum oxide. AB - Porous aluminum oxide (PAO), a nanostructured support for, among others, culturing microorganisms, was chemically modified in order to attach biomolecules that can selectively interact with target bacteria. We present the first comprehensive study of monolayer-modified PAO using conditions that are relevant to microbial growth with a range of functional groups (carboxylic acid, alpha hydroxycarboxylic acid, alkyne, alkene, phosphonic acid, and silane). Their stability was initially assessed in phosphate-buffered saline (pH 7.0) at room temperature. The most stable combination (PAO with phosphonic acids) was further studied over a range of physiological pHs (4-8) and temperatures (up to 80 degrees C). Varying the pH had no significant effect on the stability, but it gradually decreased with increasing temperature. The stability of phosphonic acid modified PAO surfaces was shown to depend strongly on the other terminal group of the monolayer structure: in general, hydrophilic monolayers were less stable than hydrophobic monolayers. Finally, an alkyne-terminated PAO surface was reacted with an azide-linked mannose derivative. The resulting mannose-presenting PAO surface showed the clearly increased adherence of a mannose-binding bacterium, Lactobacillus plantarum, and also allowed for bacterial outgrowth. PMID- 24471581 TI - Stress granule formation in Entamoeba histolytica: cross-talk between EhMLBP, EhRLE3 reverse transcriptase and polyubiquitinated proteins. AB - The Entamoeba histolytica-methylated LINE-binding protein (EhMLBP) binds to methylated repetitive DNA and is a positive regulator of a reverse transcriptase of a long interspersed nucleotide element (LINE). This protein protects trophozoites against heat shock by reducing protein aggregation. The presence of EhMLBP and polyubiquitinated proteins in heat shock-induced protein aggregates raised the question whether these proteins interact. This assumption was confirmed by co-immunoprecipitation experiments: ubiquitinated proteins were detected in the perinuclear region of non-stressed E. histolytica trophozoites, whereas ubiquitinated proteins were detected in the perinuclear region and colocalized with EhMLBP in cytoplasmic granules in heat-shocked trophozoites. We also observed that overexpression of the reverse transcriptase of EhRLE3 induced the upregulation of EhMLBP expression and the formation of these EhMLBP containing granules. Since (i) these EhMLBP-containing granules in the cytoplasm of heat-shocked E. histolytica trophozoites also contain polyubiquitinated proteins and poly(A)(+) mRNA and (ii) their formation is promoted by sodium arsenate, puromycin, and pateamine A and is inhibited by cycloheximide, we propose that these cytoplasmic EhMLBP-containing granules are stress granules. Our data also suggest that the formation of these granules is dependent upon EhMLBP and LINE. PMID- 24471582 TI - Psoriasis sparing the lower limb with postpoliomyelitis residual paralysis. PMID- 24471583 TI - Electronic structure of H2S, SF2, and HSF and implications for hydrogen substituted hypervalent sulfur fluorides. AB - It is well known that hypervalent molecules are more stable with very electronegative ligands such as fluorine. For example, while SF6 is uniquely stable and experimentally well characterized and many of the features of SF4 have been characterized, neither H4S nor H6S has been observed. Furthermore, no hypervalent sulfur species with mixed hydrogen and fluorine ligands have been experimentally characterized to date. In this work, we present detailed calculations of the electronic structure of H2S, SF2, and HSF. While all three compounds have similar bent singlet ground states, the potential energy surfaces of various low lying electronic states as a function of bond angle reveal very different behaviors, in particular for linear geometries. We use the disparate bonding motifs of the low-lying triplet states to rationalize the differences between SF4 and the hypothetical H4S molecule. We also make predictions about the effects of hydrogen substitution on the energetics and geometries of hypervalent sulfur fluoride compounds. PMID- 24471584 TI - BME inequality is real, and it's time to fight it. PMID- 24471602 TI - Survey shows BME nurses are more likely to face disciplinary hearings. PMID- 24471608 TI - Diabetes. PMID- 24471609 TI - Investing in wellbeing. AB - A trust in the West Midlands has introduced wellbeing apprentices to offer one-to one support to patients with dementia of at high risk of falls. As well as providing companionship to ease patients' stress during hospital stays, the young apprentices receive training that can set them on the path to a nursing career. PMID- 24471610 TI - Pictures of health. AB - Julie Sheen helped set up a campaign at her university to promote student mental health, challenge stigma and encourage those under stress to seek help earlier. To raise awareness, she produced a highly praised film montage that can be seen on YouTube. PMID- 24471611 TI - Help to ease the pain. AB - A shingles vaccination programme is gradually being introduced across the UK for people in their seventies, the age group most at risk of experiencing severe symptoms following reactivation of the virus. Practice nurse Kathryn Gedman explains how she set up a shingles vaccine clinic. PMID- 24471624 TI - I welcome a commission to look at our tarnished image. PMID- 24471625 TI - Why does nursing have to rely on doctors to direct us to the right path? PMID- 24471626 TI - Patients with obesity need to be respected, not ridiculed. PMID- 24471627 TI - Who gave the Lancet a nudge to sponsor such a strange body? PMID- 24471628 TI - Inappropriate apologies have an effect on nurses and patients. PMID- 24471630 TI - Many factors influence our ability to be compassionate. PMID- 24471631 TI - The restructuring that has led to the loss of 4,000 nursing jobs. PMID- 24471632 TI - Information on the leading cause of congenital deafblindness. PMID- 24471633 TI - Good inhaler technique is key to improving child asthma care. PMID- 24471636 TI - Service user involvement in nurse education. AB - Service user involvement is now recognised as an integral component of nurse education. This article describes the involvement of one service user, who experienced a traumatic limb amputation, in an educational session for second year nursing students at De Montfort University. The aim of the initiative was to use the patient's experience to improve care delivery. PMID- 24471637 TI - Preventing psychological distress in patients with acne. AB - Acne is a skin condition that affects people of all ages, although it is most common in adolescents. It is a condition that can be underestimated by healthcare professionals because it is generally not life threatening. However, acne can have profound psychological effects on an individual, and can result in reduced self-esteem, depression and suicide in extreme cases. It is important, therefore, that nurses are aware of the psychological effects of this condition to assist in providing support and optimising psychological recovery for patients. PMID- 24471638 TI - Shoulder pain: pathogenesis, diagnosis and management. AB - Shoulder pain is a common musculoskeletal problem that can have a significant effect on people's activities of daily living and quality of life. Nurses have a central role in the assessment, management and follow up of patients undergoing conservative and surgical treatments. Understanding the often complex and chronic nature of shoulder pain will help healthcare professionals to provide holistic patient-centred care, considering the most suitable treatment options for the individual. PMID- 24471639 TI - Bone health. PMID- 24471640 TI - More than just a job. PMID- 24471644 TI - Student life - nailing hand hygiene. PMID- 24471645 TI - Perfusion index in newborn infants: a noninvasive tool for neonatal monitoring. AB - AIM: To review the utility of perfusion index (PI) in the evaluation of neonatal clinical conditions. Twenty-five manuscripts were reviewed. PI provides information about haemodynamic stability, illness severity, early neonatal respiratory outcome, low superior vena cava flow and subclinical chorioamnionitis. CONCLUSION: PI is a valuable tool to assess the newborn's health condition and could become a standardised measure in clinical evaluation. Different study designs are necessary to provide further validation to this method. PMID- 24471646 TI - Bisphenol A and risk management ethics. AB - It is widely recognized that endocrine disrupting compounds, such as Bisphenol A, pose challenges for traditional paradigms in toxicology, insofar as these substances appear to have a wider range of low-dose effects than previously recognized. These compounds also pose challenges for ethics and policymaking. When a chemical does not have significant low-dose effects, regulators can allow it to be introduced into commerce or the environment, provided that procedures and rules are in place to keep exposures below an acceptable level. This option allows society to maximize the benefits from the use of the chemical while minimizing risks to human health or the environment, and it represents a compromise between competing values. When it is not possible to establish acceptable exposure levels for chemicals that pose significant health or environmental risks, the most reasonable options for risk management may be to enact either partial or complete bans on their use. These options create greater moral conflict than other risk management strategies, leaving policymakers difficult choices between competing values. PMID- 24471649 TI - Increased polymerase I and transcript release factor (Cavin-1) expression attenuates platelet-derived growth factor receptor signalling in senescent human fibroblasts. AB - 1. Previously, we showed that the essential caveolar component polymerase I and transcript release factor (PTRF) was upregulated and promoted caveolae formation in senescent cells. In addition, we found that overexpression of PTRF increased the number of caveolae and induced cellular senescence. 2. Unresponsiveness to growth factor is one of the fundamental characteristics of senescent cells, although normal levels of receptors and downstream signalling molecules are present in senescent cells. 3. Herein, we investigated the role of PTRF in the regulation of platelet-derived growth factor (PDGF) signalling in young and senescent cells. 4. We first confirmed that PTRF was upregulated in senescent human fibroblasts and aged mouse tissues. We then examined the activation of extracellular signal-regulated kinases (ERK) in young and senescent cells after PDGF stimulation. 5. Our results show that expression of PDGF receptors (PDGFRs) was not altered during cellular senescence. Interestingly, phosphorylation of ERK1/2 was induced upon PDGF stimulation of young, replicating cells but not senescent cells. Induction of ERK1/2 phosphorylation was impaired in senescent cells and PTRF-overexpressing presenescent cells. Furthermore, our results show that PTRF interacts with PDGFRs and this interaction is increased in senescent cells. 6. These results suggest that the unresponsiveness of senescent fibroblasts to PDGF stimulation may be due to increased levels of PTRF and the formation of caveolae, which, in turn sequester growth receptors, such as PDGFR and its signalling molecules. PMID- 24471648 TI - Immunoregulation in human American leishmaniasis: balancing pathology and protection. AB - Leishmaniasis covers a broad spectrum of diseases with distinct, and sometimes overlapping, characteristics. The common thread in all forms of leishmaniasis is the infection by the parasite Leishmania belonging to the genus Leishmania. Upon infection of humans, there can be at least three outcomes, (i) control of Leishmania by the host immune response resulting in asymptomatic disease, (ii) patent infection and development of a relatively mild form of leishmaniasis and (iii) patent infection and development of severe clinical forms. The factors that determine the outcome of an initial inoculation with Leishmania are many, with the species of Leishmania representing one of the strongest predictive factors for the development of a given clinical form of disease. This is seen with L. braziliensis and L. amazonensis, infection leading mostly to tegumentary forms of disease, and L. infantum with the potential to induce visceral disease. However, it is also clear that the host immune response is a key factor in disease progression, not only responsible for control of Leishmania, but also playing an important role in disease progression and pathology. This duality between protective and pathogenic immune responses in individuals infected with Leishmania in the Americas is the focus of this review. PMID- 24471650 TI - Novel inhibitors of human DOPA decarboxylase extracted from Euonymus glabra Roxb. AB - Dopamine, a biogenic amine with important biological functions, is produced from l-DOPA by DOPA decarboxylase (DDC). DDC is a potential target to modulate the production of dopamine in several pathological states. Known inhibitors of DDC have been used for treatment of Parkinson's disease but suffered low specificity and diverse side effects. In the present study, we identified and characterized a novel class of natural-product-based selective inhibitors for DDC from the extract of Euonymus glabra Roxb. by a newly developed high-throughput enzyme assay. The structures of these inhibitors are dimeric diarylpropane, a unique chemical structure containing a divalent dopamine motif. The most effective inhibitors 5 and 6 have an IC50 of 11.5 +/- 1.6 and 21.6 +/- 2.7 MUM in an in vitro purified enzyme assay, respectively, but did not inhibit other homologous enzymes. Compound 5 but not 6 dose-dependently suppressed the activity of hDDC and dopamine levels at low micromolar concentrations in cells. Furthermore, structure-activity relationship analyses revealed that p-benzoquinone might be a crucial moiety of these inhibitors for inhibiting hDDC. The natural-product-based selective inhibitors of hDDC could serve as a chemical lead for developing improved drugs for dopamine-related disease states. PMID- 24471651 TI - MoCA-assessed cognitive function and excellent outcome after aneurysmal subarachnoid hemorrhage at 1 year. AB - BACKGROUND AND PURPOSE: After aneurysmal subarachnoid hemorrhage (aSAH), cognitive impairment, even mild and relatively isolated, can be devastating, especially in working-age persons. The Montreal Cognitive Assessment (MoCA) is accepted as a valid screening tool for mild cognitive impairment due to cerebral ischaemia. Whether MoCA is independently associated with excellent outcome [a score of 0 on the modified Rankin Scale (mRS) or 18/18 on the Lawton Instrumental Activities of Daily Living (IADL) scale] 1 year after aSAH was assessed. METHODS: Hong Kong Chinese aSAH patients were assessed prospectively by means of the MoCA, Mini-Mental State Examination (MMSE), mRS and IADL scale at 1 year. This multicenter prospective observational study is registered at ClinicalTrials.gov of the US National Institutes of Health (NCT01038193). RESULTS: In all, 194 patients completed the assessments at 1 year. After adjustment for age, both excellent IADL and mRS outcomes were associated with MoCA (OR 1.2, 95% CI 1.1 1.3, P < 0.001, and OR 1.1, 95% CI 1.0-1.2, P = 0.001, respectively). CONCLUSIONS: MoCA-assessed cognitive function is an important determinant for excellent outcomes after aSAH. PMID- 24471653 TI - How to personalize the treatment of psoriasis with biologics? PMID- 24471652 TI - Synthesis, CMC determination, and intercalative binding interaction with nucleic acid of a surfactant-copper(II) complex with modified phenanthroline ligand (dpq). AB - A surfactant-copper(II) complex, [Cu(dpq)2DA](ClO4)2 (dpq = dipyrido[3,2-d:2'-3' f]quinoxaline; DA-dodecylamine), was synthesized and characterized on the basis of elemental analyses, UV-vis, IR, and EPR spectra. The critical micelle concentration (CMC) value of this surfactant-copper(II) complex in aqueous solution was found out from conductance measurements. Specific conductivity data at different temperature served for the evaluation of the temperature-dependent CMC and the thermodynamics of micellization (DeltaG degrees (m), DeltaH degrees (m) and DeltaS degrees (m)). In addition, the complex has been examined by its ability to bind to nucleic acids (DNA and RNA) in tris-HCl buffer by UV-vis absorption, emission spectroscopy techniques, and viscosity measurements. The complex has been found to bind strongly to nucleic acids with apparent binding constants at DNA and RNA is 4.3 * 10(5), 9.0 * 10(5) M(-1), respectively. UV-vis studies of the interaction of the complex with DNA/RNA have revealed that the complex can bind to both DNA and RNA by the intercalative binding mode via ligand dpq into the base pairs of DNA and RNA which has been verified by viscosity measurements. The presence of long aliphatic chain in the surfactant complex increases this hydrophobic interaction. The binding constants have been calculated. The cytotoxic activity of this complex on human liver carcinoma cancer cells was determined by adopting 3-(4, 5-dimethylthiazol-2-yl)-2, 5- diphenyl tetrazolium bromide assay and specific staining techniques. The antimicrobial and antifungal screening tests of this complex have shown good results. PMID- 24471655 TI - A new delta chain variant, Hb A2-Tunis [delta46(CD5)Gly -> Glu; HBD: c.140G>A], observed in a Tunisian family in association with a compound heterozygosity for Hb C [beta6(A3)Glu -> Lys; HBB: c.19G>A] beta(0)-thalassemia [IVS-I-1 (beta143, G>A); HBB: c.92+1G>A]. AB - We describe a new delta-globin variant, Hb A2-Tunis [delta46(CD5)Gly -> Glu; HBD: c.140G>A]. This hemoglobin (Hb) variant displayed a faster electrophoretic mobility than normal Hb A2 and was expressed at 3.2%. The molecular defect was characterized by DNA sequencing analysis. Hb A2-Tunis was found in a carrier of a beta(0)-thalassemia (beta(0)-thal) [IVS I-1 (beta143, G>A); HBB: c.92 + 1G>A] and Hb C [beta6(A3)Glu -> Lys; HBB: c.19G>A], presenting with a normal Hb A2 level. Phenotype and genotype investigations revealed that the patient has a total Hb A2 level of 7.1% that was expected for a beta-thalassemia (beta-thal) minor carrier. PMID- 24471654 TI - Pregnancy and helminth infections. AB - It has been proposed that helminth infection may be particularly detrimental during pregnancy, through adverse effects on maternal anaemia and on birth outcomes, and that anthelminthic treatment during pregnancy will therefore be particularly beneficial. However, the few treatment trials that have been conducted have given, but little support to this notion and further trials in settings of nutritional stress are needed. It has also been proposed that prenatal exposure to helminth infection has an important effect on the development of the foetal immune response. There is evidence that this may impact, long-term, upon responses to helminth and nonhelminth antigens, and to allergens. Exposure to helminths in utero may also have nonspecific effects that may modify the offspring's susceptibility to diseases mediated by inflammation, including metabolic disorders. The mechanisms of such effects are not known, but they deserve to be explored as current epidemiological findings suggest the possibility of primary prevention for inflammatory conditions such as allergy, through intervention during pregnancy. PMID- 24471657 TI - Genetic crosses and complementation reveal essential functions for the Plasmodium stage-specific actin2 in sporogonic development. AB - Malaria parasites have two actin isoforms, ubiquitous actin1 and specialized actin2. Actin2 is essential for late male gametogenesis, prior to egress from the host erythrocyte. Here, we examined whether the two actins fulfil overlapping functions in Plasmodium berghei. Replacement of actin2 with actin1 resulted in partial complementation of the defects in male gametogenesis and, thus, viable ookinetes were formed, able to invade the midgut epithelium and develop into oocysts. However, these remained small and their DNA was undetectable at day 8 after infection. As a consequence sporogony did not occur, resulting in a complete block of parasite transmission. Furthermore, we show that expression of actin2 is tightly controlled in female stages. The actin2 transcript is translationally repressed in female gametocytes, but translated in female gametes. The protein persists until mature ookinetes; this expression is strictly dependent on the maternally derived expression. Genetic crosses revealed that actin2 functions at an early stage of ookinete formation and that parasites lacking actin2 are unable to undergo sporogony in the mosquito midgut. Our results provide insights into the specialized role of actin2 in Plasmodium development in the mosquito and suggest that the two actin isoforms have distinct biological functions. PMID- 24471658 TI - Implications for Australian anaesthetists and proceduralists of a recent court decision regarding informed consent and patient positioning. AB - This article discusses the medicolegal implications of a recent judgment in relation to a patient who suffered significant morbidity as a result of patient positioning during an operative procedure. The patient developed an unexpected serious complication following surgery, in the context of a preoperative consent that did not cover every potential complication or contingency. The court held that the failure to warn of a particular risk that would have prevented the patient from undergoing a procedure but did not occur will not necessarily result in a finding of negligence in relation to another risk where the harm did occur. This finding is well aligned to current clinical practice and at the same time does not abrogate the practitioner's duty to provide a comprehensive list of possible complications during the consent process for any proceduralist. In the context of a procedure requiring anaesthesia, the importance of communication and understanding between the anaesthetist and proceduralist as to which aspects of the consent process are undertaken by whom, and to ensure the process is done comprehensively, is of great importance and is indirectly highlighted by this recent judgment. PMID- 24471656 TI - Arachidonate-regulated Ca(2+) influx in human airway smooth muscle. AB - Plasma membrane Ca(2+) influx, especially store-operated Ca(2+) entry triggered by sarcoplasmic reticulum (SR) Ca(2+) release, is a key component of intracellular calcium concentration ([Ca(2+)]i) regulation in airway smooth muscle (ASM). Agonist-induced Ca(2+) oscillations in ASM that involve both influx and SR mechanisms have been previously demonstrated. In nonexcitable cells, [Ca(2+)]i oscillations involve Ca(2+) influx via arachidonic acid (AA) stimulated channels, which show similarities to store-operated Ca(2+) entry, although their molecular identity remains undetermined. Little is known about AA regulated Ca(2+) channels or their regulation in ASM. In enzymatically dissociated human ASM cells loaded with the Ca(2+) indicator, fura-2, AA (1-10 MUM) triggered [Ca(2+)]i oscillations that were inhibited by removal of extracellular Ca(2+). Other fatty acids, such as the diacylglycerol analog, 1 oleoyl-2-acetyl-SN-glycerol, oleic acid, and palmitic acid (10 MUM each), failed to elicit similar [Ca(2+)]i responses. Preincubation with LaCl3 (1 MUM or 1 mM) inhibited AA-induced oscillations. Inhibition of receptor-operated channels (SKF96,365 [10 MUM]), lipoxygenase (zileuton [10 MUM]), or cyclooxygenase (indomethacin [10 MUM]) did not affect oscillation parameters. Inhibition of SR Ca(2+) release (ryanodine [10 MUM] or inositol 1,4,5-trisphosphate receptor inhibitor, xestospongin C [1 MUM]) decreased [Ca(2+)]i oscillation frequency and amplitude. Small interfering RNA against caveolin-1, stromal interaction molecule 1, or Orai3 (20 nM each) reduced the frequency and amplitude of AA-induced [Ca(2+)]i oscillations. In ASM cells derived from individuals with asthma, AA increased oscillation amplitude, but not frequency. These results are highly suggestive of a novel AA-mediated Ca(2+)-regulatory mechanism in human ASM, reminiscent of agonist-induced oscillations. Given the role of AA in ASM intracellular signaling, especially with inflammation, AA-regulated Ca(2+) channels could potentially contribute to increased [Ca(2+)]i in diseases such asthma. PMID- 24471659 TI - A randomised controlled trial of parecoxib, celecoxib and paracetamol as adjuncts to patient-controlled epidural analgesia after caesarean delivery. AB - The benefit of combining non-opioid analgesics with neuraxial opioids for analgesia after caesarean delivery has not been clearly established. Larger doses of paracetamol or cyclooxygenase-2 inhibitors have not been evaluated. A randomised, double blind, double-dummy, parallel group placebo-controlled clinical trial was conducted among women having elective caesarean delivery under spinal anaesthesia, followed by pethidine patient-controlled epidural analgesia. Patients received placebos (group C); intravenous parecoxib 40 mg then oral celecoxib 400 mg at 12 hours (group PC); intravenous paracetamol 2 g then oral 1 g six-hourly (group PA); or these regimens combined (group PCPA). The primary outcome was 24-hour postoperative patient-controlled epidural pethidine use and the main secondary outcome was postoperative pain. One hundred and thirty-eight women were recruited but 27 subsequently met exclusion criteria, leaving 111 who were randomised, allocated and analysed by intention-to-treat (n=23, 30, 32 and 26 in groups C, PC, PA and PCPA respectively). There were no differences between groups for pethidine consumption, based on either intention-to-treat (median 365, 365, 405 and 360 mg in groups C, PC, PA and PCPA respectively, P=0.84) or per protocol analysis (17 major violations). Dynamic pain scores did not differ between groups but requirement for, and dose of, supplementary oral tramadol was least in group PCPA (incidence 23% versus 48%, 70% and 58% in groups C, PC and PA respectively, P=0.004). The addition of regular paracetamol, cyclooxygenase-2 inhibitors or both to pethidine patient-controlled epidural post-caesarean analgesia did not provide a pethidine dose-sparing effect during the first 24 hours. PMID- 24471660 TI - Observational study of dexmedetomidine for hysteroscopy, cystoscopy and transrectal ultrasound biopsy. AB - Dexmedetomidine shows promise of being an airway-stable drug. It is approved in Australia for procedural sedation. However, it is important to note that in the study on which this indication is based, all the subjects received a local anaesthetic block before their procedure or surgery. In this regard, as Health Canada has explicitly stated, further evidence still needs to be gained for the use of dexmedetomidine for procedural sedation without accompanying nerve blocks. The purpose of this current proof-of-concept, observational study is to provide further information about dexmedetomidine in three regards. First, can dexmedetomidine be used for procedural sedation per se (i.e. without local anaesthetic blocks)? Second, as opposed to results being averaged out over a wide variety of procedures, the current study examined the feasibility of dexmedetomidine-based procedural sedation for three specific procedures. Third, the current study aims to add to the pool of information regarding the appropriate dose of dexmedetomidine. As described in the dexmedetomidine product information, the Observer's Assessment of Alertness/Sedation Scale grades sedation from 5 (alert) down to 1 (deepest level of sedation). In the study on which dexmedetomidine's indication for procedural sedation is based, patients needed only to achieve a score of 4 and, thus, the approved product information recommends a loading dose of 1.0 ug/kg followed by a maintenance infusion of 0.2 to 1.0 ug/kg/hour. This current study aims to add to the literature regarding the safety of dexmedetomidine when used at higher than recommended doses. PMID- 24471661 TI - Central venous oxygen saturation during high-risk general surgical procedures relationship to complications and clinical outcomes. AB - Major non-cardiac surgery is associated with postoperative morbidity, and perioperative central venous oxygen saturation (ScvO2) may be a predictor of morbidity. This pilot study aimed to define intraoperative ScvO2 and to identify factors associated with postoperative complications. ScvO2 (reflection spectrophotometry) was recorded continuously in a convenience sample of adults undergoing high-risk general surgery. Demographics, intraoperative management, surgery duration, postoperative complications and deaths within 28 days were recorded. Data from 51 patients were analysed. Two (4%) died and 24 (47%) had at least one complication (range 1 to 5). The hospital length-of-stay and duration of surgery were longer in those with complications (22.1+/-6.1 versus 9.6+/-3.6 days, P >0.0001, and 328+/-162 minutes versus 241+/-94 minutes, P=0.02, respectively). Overall, the ScvO2 was 82+/-8% and ranged from 40% to 97% with 17 (33%) patients having at least one episode of ScvO2 >70%. Hospital length-of-stay (P >0.0001), time ScvO2 >90% (P=0.003), surgery duration (P=0.005) and blood loss (P=0.02) were correlated with the number of complications. Using multivariate analysis, surgery duration (odds ratio 1.008 [95% confidence interval 1.002 to 1.013]; P=0.006) and change in oxygen extraction ratio (O2ER) at the end of surgery compared to the beginning (odds ratio 1.13 [95% confidence interval 1.001 to 1.28]; P=0.04) were independently associated with complications. The surgery duration and an increased O2ER are factors related to the development of postoperative complications. PMID- 24471662 TI - Randomised comparison of an end-hole, triple-hole and novel six-hole catheter for continuous interscalene analgesia. AB - Epidural analgesia studies and a recent continuous peripheral nerve block study suggest multi-hole perineural catheters perform better than end-hole catheters. Confounding catheter positioning issues limit interpretation of the latter study. One hundred and fifty-six patients receiving an anterolateral interscalene catheter for elective shoulder surgery were randomised to three groups: following out-of-plane ultrasound confirmation of the needle tip immediately lateral to the C5/6 roots, an end-hole (n=52), triple-hole (n=53) or six-hole (n=51) non stimulating catheter was positioned 3 cm beyond the needle tip. Ropivacaine 0.375% 15 ml was administered preoperatively via the catheter before surgery under general anaesthesia. A ropivacaine 0.2% 2 ml/hour infusion with mandatory six-hourly, and on-demand hourly, 5 ml boluses was continued for >48 hours with tramadol available as rescue. Patients were questioned in the recovery room and at 24 hours for numerical rating pain score (0 to 10), ropivacaine bolus and tramadol consumption. The frequency of recovery room pain was similar between groups (P=0.75) and demonstrated strong evidence for equivalence at the 5% significance level. Neither time to first pain, "average" or "worst" pain during the first 24 hours, ropivacaine bolus or tramadol consumption significantly differed between groups. Catheter threading difficulty was more common for the square-tipped end-hole catheters (end-hole=19% versus triple-hole=6%, six hole=0%, P >0.001). This study found no evidence to support catheter orifice configuration significantly affecting the quality of continuous peripheral nerve blockade. These findings are in contrast to epidural catheter studies, and suggest that anatomical factors have a significant bearing on whether multi orifice catheters confer advantage over the single-orifice design. PMID- 24471663 TI - Parecoxib and paracetamol for pain relief following minor day-stay gynaecological surgery. AB - Paracetamol and non-steroidal anti-inflammatory drugs are often administered for postoperative analgesia. Dilatation and curettage, with or without hysteroscopy, is a common day-stay procedure that is associated with pain that is partly mediated by prostaglandins. This study aimed to investigate the analgesic efficacy of adjunctive paracetamol and parecoxib in this setting. A randomised, blinded, placebo-controlled, single-centre trial was conducted among 240 women undergoing dilatation and curettage. Patients were randomised intraoperatively into one of four groups, to receive either intravenous paracetamol 2 g, intravenous parecoxib 40 mg, both in combination, or placebos, post-induction and with intravenous fentanyl. The primary endpoints were pain score one hour postoperatively and the Overall Benefit of Analgesia Score. There were no statistically significant differences in primary outcomes across groups. The area under the curve for pain scores to two hours postoperatively was significantly lower in the group receiving paracetamol (P=0.018) and the need for rescue analgesia with tramadol was less in the combination group (P=0.02). There were no significant differences in patient satisfaction or recovery. We conclude that paracetamol or parecoxib does not produce a clinically important reduction in pain in this setting. Women having uterine curettage and receiving intravenous fentanyl do not appear to benefit from administration of these non-opioid analgesics. PMID- 24471664 TI - Clarifying the role of activated charcoal filters in preparing an anaesthetic workstation for malignant hyperthermia-susceptible patients. AB - Malignant hyperthermia (MH) is a life-threatening condition caused by exposure of susceptible individuals to volatile anaesthetics or suxamethonium. MH-susceptible individuals must avoid exposure to these drugs, so accurate and reproducible processes to remove residual anaesthetic agents from anaesthetic workstations are required. Activated charcoal filters (ACFs) have been used for this purpose. ACFs can reduce the time for preparing an anaesthetic workstation for MH patients. Currently, the only commercially available ACFs are the Vapor-Clean$trade; (Dynasthetics, Salt Lake City, UT, USA) filters which retail at approximately AUD$130 per set of two, both of which are to be used in a single anaesthetic. Anaesthetic workstations were saturated with anaesthetic vapours and connected to a Miran ambient air analyser (SapphRe XL, ThermoScientific, Waltham, MA, USA) to measure vapour concentration. Various scenarios were tested in order to determine the most economical configurations of machine flushing, component change and activated charcoal filter use. We found that placement of filters in an unprepared, saturated circuit was insufficient to safely prepare an anaesthetic workstation. Following flushing of the anaesthetic workstation with high-flow oxygen for 90 seconds, a circuit and soda lime canister change and the placement of an ACF on the inspiratory limb, we were able to safely prepare a workstation in less than three minutes. A single filter on the inspiratory limb was able to maintain a clean circuit for 12 hours, with gas flows dropped from 10 lpm to 3 lpm after 90 minutes or removal of the filter after 90 minutes if high gas flows were maintained. PMID- 24471665 TI - Patient factors associated with frequent clotting of dialysers during haemodiafiltration in critically ill patients: a post hoc analysis of a randomised controlled study. AB - Continuous haemodiafiltration (CVVHDF) is the main form of renal replacement therapy in critically ill patients with severe acute kidney injury. Clotting of the dialysers during CVVHDF is frequent, because most patients with acute kidney injury have an increased risk of bleeding and cannot be systemically anticoagulated. Using data from a randomised controlled trial comparing the efficiency of CVVHDF by placing the dialysis catheter tip at the right atrium or superior vena cava, this study assessed the patient factors associated with an increased risk of frequent clotting of the dialysers-defined by >1 dialysers clotted per day of CVVHDF. Of the 94 patients included in this study, a higher body mass index, a higher platelet count and a lower International Normalized Ratio were associated with an increased risk of frequent clotting of dialysers in the univariate analyses. Use of aspirin or clopidogrel, causes of acute kidney injury and daily dose of unfractionated heparin used were not significantly associated with the risk of frequent clotting of dialysers. In the multivariate parsimony model, only a high body mass index (odds ratio 1.06 per point increment, 95% confidence interval 1.01 to 1.13; P=0.036) and a high platelet count (odds ratio 1.84 per 100x10(9)/l increment, 95% confidence interval 1.17 to 2.91; P=0.009), both in a relatively linear fashion, were independently associated with an increased risk of frequent clotting of dialysers. Optimising the position of the tip of the dialysis catheter may be particularly important for patients with a high body mass index and platelet count in order to reduce frequent clotting of dialysers during CVVHDF. PMID- 24471666 TI - A ten-year audit of fresh gas flows in a New Zealand hospital: the influence of the introduction of automated agent delivery and comparisons with other hospitals. AB - Reducing fresh gas flow (FGF) rates with volatile anaesthetics reduces waste, with positive financial and environmental consequences. We have audited FGF since 2001 by analysis of data collected from anaesthetic machines. We recently introduced Aisys((r)) (GE Healthcare, Madison, WI, USA) machines that allow automated control of end-tidal levels of volatile anaesthetics. In 2009 the mean FGF was 1.27 l/minute, which was lower than 2001 (2.05 l/minute) and 2006 (1.43 l/minute) and similar to two other New Zealand hospitals. Following introduction of the Aisys((r)), mean FGF initially increased to 1.5 l/minute, but fell to 1.09 l/minute over the following 12 months. Median FGF showed a similar pattern and is now <600 ml/minute. Since introduction of the Aisys((r)) workstation the proportion of time with flow rates >4 l/minute has increased. The proportion of time spent in automated delivery mode has increased from 35% to 63%. Users valued the workload reduction with end-tidal control. Our findings suggest that in daily practice, with a wide range of practitioners at different levels of training and a broad patient mix, mean flow rates of around 1.3 l/minute with median flows in the range 0.5 to 1.0 l/minute are achievable targets. PMID- 24471667 TI - Preventing cerebral oedema in acute liver failure: the case for quadruple-H therapy. AB - Severe cerebral oedema is a life-threatening complication of acute liver failure. Hyperammonaemia and cerebral hyperaemia are major contributing factors. A multimodal approach, which incorporates hyperventilation, haemodiafiltration, hypernatraemia and hypothermia (quadruple-H therapy), may prevent or attenuate severe cerebral oedema. This approach is readily administered by critical care clinicians and is likely to be more effective than the use of single therapies. Targeting of PaCO2 in the mild hyperventilation range, as seen in acute liver failure patients before intubation, aims to minimise hyperaemic cerebral oedema. Haemodiafiltration aims to achieve the rapid control of elevated blood ammonia concentrations by its removal and to reduce production via the lowering of core temperature. The administration of concentrated saline increases serum tonicity and further reduces cerebral swelling. In addition, the pathologically increased cerebral blood-flow is further attenuated by therapeutic hypothermia. The combination of all four treatments in a multimodal approach may be a safe and effective means of attenuating or treating the cerebral oedema of acute liver failure and preventing death from neurological complications. PMID- 24471668 TI - Sugammadex hypersensitivity-a case of anaphylaxis. AB - We describe a case of a patient undergoing open abdominal aneurysm surgery who developed a severe, life-threatening allergic reaction immediately after administration of sugammadex. The manifestation was purely a cardiovascular collapse. The mainstay of treatment was administration of high-dose adrenaline and fluid resuscitation. The diagnosis of anaphylaxis was supported by a positive serum mast cell tryptase (93 ug/l) at one hour post-event. Sugammadex was confirmed as the cause of the anaphylaxis by a positive intradermal allergy test (25 mm diameter response to 1:100 dilution), with a normal saline control and a negative response to the other drugs used during the event. This case report is a reminder that the use of sugammadex is associated with rare but serious risks. PMID- 24471669 TI - Intraoperative anaphylaxis to sugammadex and a protocol for intradermal skin testing. AB - Sugammadex is a selective binding agent for aminosteroid neuromuscular blockers whose use is increasing in anaesthetic practice. We present three cases of severe anaphylaxis coincident with sugammadex administration. Subsequent intradermal testing confirmed sugammadex as the triggering agent, with all patients having positive skin responses to a 1:100 dilution of the standard 100 mg/ml solution and two out of three having a positive response to a 1:1000 dilution. As all patients were administered sugammadex to reverse neuromuscular blockade with rocuronium, we considered that sugammadex-rocuronium complexes were a potential unique allergen. In the two patients who were additionally tested with a rocuronium-sugammadex (3.6:1 molecular ratio) mixture, the wheal-and-flare response was significantly attenuated. PMID- 24471670 TI - The dosing and monitoring of argatroban for heparin-induced thrombocytopenia during extracorporeal membrane oxygenation: a word of caution. AB - Heparin-induced thrombocytopenia is a serious complication of heparin use. Treatment includes discontinuation of heparin and initiation of alternative anticoagulation therapy. In extracorporeal membrane oxygenation anticoagulation is mandatory, and direct thrombin inhibitors (DTIs) have been approved in these cases. However, the use and monitoring of DTIs in extracorporeal membrane oxygenation patients is not well described. DTI use is also complicated by the imprecision of available monitoring tests and currently recommended dosing has been shown to result in a supratherapeutic anticoagulative state. This case report describes the successful use of the DTI argatroban as an alternative anticoagulant in a patient with heparin-induced thrombocytopenia requiring extracorporeal membrane oxygenation support. PMID- 24471671 TI - Pituitary apoplexy with reversible cerebral vasoconstrictive syndrome after spinal anaesthesia for emergency caesarean section: an uncommon cause for postpartum headache. AB - Pituitary apoplexy is a rare condition involving pituitary necrosis following either pituitary haemorrhage or infarction. Similarly, reversible cerebral vasoconstrictive syndrome is a cerebrovascular disorder characterised by diffuse, multifocal narrowing of cerebral arteries. Both may present with an acute, intense headache and associated neurological deficits. In postpartum women, these conditions should be considered in the differential diagnosis of post-dural puncture headache following regional anaesthesia, as serious morbidity may ensue if they are left untreated. We report the case of a patient who developed pituitary apoplexy during an emergency caesarean section under spinal anaesthesia. It was further complicated by the development of reversible cerebral vasoconstriction syndrome and stroke. PMID- 24471672 TI - Apology for distress caused by the publication of recent correspondence describing fatal rhabdomyolysis in a patient with Duchenne muscular dystrophy. PMID- 24471673 TI - Apology in relation to our recent letter describing a case of fatal rhabdomyolysis in a patient with Duchenne muscular dystrophy. PMID- 24471674 TI - Transient coronary ischaemia resulting from paradoxical CO2 embolus. PMID- 24471675 TI - Severe respiratory depression associated with perioperative opioid-sparing gabapentin use. PMID- 24471676 TI - Assessing association between type 2 diabetes and cardiac complications after vascular surgery. PMID- 24471677 TI - Reply: To PMID 23977908. PMID- 24471678 TI - APRV in patients with atelectasis after liver transplantation. PMID- 24471679 TI - Benefit of intermittent pneumatic compression of lower limbs in reducing venous thromboembolism in hospitalised patients: interactions between risk and effectiveness. PMID- 24471680 TI - Intraoperative pulmonary ultrasound. PMID- 24471681 TI - Can serum and urine levels of cystatin C predict renal recovery in patients treated with renal replacement therapy in the ICU? PMID- 24471682 TI - Successful resuscitation of class 4 anaphylaxis guided by transthoracic echocardiography. PMID- 24471683 TI - Tracheostomy tube cuff herniation: a cause of airway obstruction in home care patients with long-term tracheostomy. PMID- 24471684 TI - ECPR for prolonged paediatric cardiac arrest. PMID- 24471685 TI - Cardiac tamponade secondary to purulent pericarditis: prompt diagnosis by point of-care ultrasound. PMID- 24471686 TI - Proton NMR: a new tool for understanding dissolution. AB - We present the use of (1)H NMR as a new measurement approach for improving understanding of the dissolution of pharmaceutical tablets. NMR has benefits over the conventional UV measurement approach in respect to much greater analyte selectivity and the ability to detect non-UV-absorbing species such as sugars. We used an in-line flow cell and water suppression experiments to determine the release profiles of three drug substances and lactose from the same tablet. Dissolution was performed in a pharmacopieal dissolution system with a standard protic buffer. NMR was shown to give high selectivity with each analyte having a well-resolved signal and sufficient sensitivity to determine the full release profile of even a compound present at only 5 mg in the tablet. The in-line flow cell gives excellent quality NMR spectra having little impact on peak shape. Dissolution of all the drug substances and lactose were determined to proceed at the same relative rates. PMID- 24471687 TI - Subjective age and personality development: a 10-year study. AB - Personality theory and research typically focus on chronological age as a key indicator of personality development. This study examines whether the subjective experience of age is an alternative marker of the biomedical and psychosocial factors that contribute to individual differences in personality development. The present study uses data from the Midlife in the United States longitudinal survey (N = 3,617) to examine how subjective age is associated with stability and change in personality and the dynamic associations between subjective age and personality traits over a 10-year period. Regression analyses indicated that a younger subjective age at baseline was associated with increases in Openness, Conscientiousness, and Agreeableness; correlated changes were also found. The rank-order stability of Extraversion and Openness and overall profile consistency were higher among those with a younger subjective age at baseline and were also associated with the rate of subjective aging over time. The present study reveals that beyond chronological age, the age an individual feels is related to changes in characteristic ways of thinking, feeling, and behaving over time. PMID- 24471688 TI - Effects of NOx on the volatility of secondary organic aerosol from isoprene photooxidation. AB - The effects of NOx on the volatility of the secondary organic aerosol (SOA) formed from isoprene photooxidation are investigated in environmental chamber experiments. Two types of experiments are performed. In HO2-dominant experiments, organic peroxy radicals (RO2) primarily react with HO2. In mixed experiments, RO2 reacts through multiple pathways, including with NO, NO2, and HO2. The volatility and oxidation state of isoprene SOA are sensitive to and exhibit a nonlinear dependence on NOx levels. Depending on the NOx levels, the SOA formed in mixed experiments can be of similar or lower volatility compared to that formed in HO2 dominant experiments. The dependence of SOA yield, volatility, and oxidation state on the NOx level likely arises from gas-phase RO2 chemistry and succeeding particle-phase oligomerization reactions. The NOx level also plays a strong role in SOA aging. While the volatility of SOA in mixed experiments does not change substantially over time, SOA becomes less volatile and more oxidized as oxidation progresses in HO2-dominant experiments. PMID- 24471689 TI - Probing the hydration of ultrathin antifouling organosilane adlayers using neutron reflectometry. AB - Neutron reflectometry data and modeling support the existence of a relatively thick, continuous phase of water stemming from within an antifouling monoethylene glycol silane adlayer prepared on oxidized silicon wafers. In contrast, this physically distinct (from bulk) interphase is much thinner and only interfacial in nature for the less effective adlayer lacking internal ether oxygen atoms. These results provide further insight into the link between antifouling and surface hydration. PMID- 24471690 TI - Photodissociation dynamics of benzoyl chloride at 235 nm: resonance-enhanced multiphoton ionization detection of Cl and HCl. AB - The photodissociation dynamics of benzoyl chloride at 235 nm has been investigated and compared with that of 2-furoyl chloride. Atomic Cl and molecular HCl channels have been detected in benzoyl chloride by employing resonance enhanced multiphoton ionization technique and time-of-flight mass spectrometry. Both the Cl fragments, Cl((2)PJ=3/2, relative quantum yield 0.70 +/- 0.15) and Cl*((2)PJ=1/2), show isotropic angular distribution and bimodal translational energy distributions. The predominant high kinetic energy channel contributes 72% to the C-Cl bond scission and arises from the S1 state having npi* character of benzoyl chloride. However, the low-energy Cl and HCl channels originate from the ground electronic state. The most plausible mechanism of HCl formation is proposed based on molecular orbital calculations. In contrast to benzoyl chloride, the HCl channel is not observed in 2-furoyl chloride on excitation at 235 nm, and this is attributed to an energy constraint. PMID- 24471693 TI - Improving transfection efficiency of ultrapure oligochitosan/DNA polyplexes by medium acidification. AB - CONTEXT: Ultrapure oligochitosans (UOCs) have recently been reported as efficient nonviral vectors for corneal and retinal gene delivery. However, the influence of some physicochemical factors on the transfection efficiency, such as the pH, remains unclear. Deeper in vitro research of these factors could provide valuable information for future clinical applications. OBJECTIVE: The aim of this study is to determine the influence of the pH decrease on the transfection efficiency of UOC/pDNA polyplexes in HEK293 and ARPE19 cells. MATERIALS AND METHODS: We elaborated self-assembled UOC/pCMS-EGFP polyplexes. The influence of the most important factors on the particle size and the zeta potential was studied by an orthogonal experimental design. We evaluated, in vitro, the cellular uptake and the transfection efficiency by flow cytometry, and the cytotoxicity of the vectors by CCK-8 assay. RESULTS AND DISCUSSION: The pH of the medium strongly influences the physicochemical properties of the polyplexes, and by its modulation we are able to control their superficial charge. A significant increase on the cellular uptake and transfection efficiency of UOCs was obtained when the pH was acidified. Neither of our UOC/pCMS-EGFP polyplexes caused cytotoxicity; however, cells treated with Lipofectamine 2000TM showed decreased cell viability. CONCLUSION: This kind of UOC vectors could be useful to transfect cells that are in an acidic environment, such as tumor cells. However, additional in vivo studies may be required in order to obtain an effective and safe medicine for nonviral gene therapy purpose. PMID- 24471694 TI - The full electron structure of the FKBP12/FK506 complex. AB - We present a study of FKBP12/FK506 using an electron structure calculation. These calculations employ a novel technique called eCADD on the protein's full electron structure along with its hydrophobic pocket and the frontier-orbital-perturbation theory. We first obtain the energy bands and orbital coefficients of protein FKBP12. On this basis, we found that the activity atoms and activity residues of FKBP12 were in good agreement with X-ray crystallography experiments. The results indicate that the interactions occur only between the LUMOs of FKBP12 and the HOMO of FK506, not between the HOMOs of FKBP12 and the LUMO of FK506. In other words, the activity sites of protein FKBP12 are located on its LUMOs, not HOMOs. The electron structures of FKBP12/FK506 give us a clearer understanding of their interaction mechanism and will help us design new ligands of FKBP12. PMID- 24471695 TI - Different characteristics of high and low transsphincteric fistulae. AB - AIM: Transsphincteric fistulae are classified as high or low. The aim of this observational study was to determine whether or not they have different characteristics. METHOD: A consecutive series of 300 patients with a transsphincteric fistula of cryptoglandular origin was studied. Two hundred patients with a high transsphincteric fistula underwent transanal advancement flap repair and 100 patients with a low transsphincteric fistula underwent fistulotomy or ligation of the intersphincteric fistula tract at the Division of Colon and Rectal Surgery, Erasmus MC, Rotterdam. Various patient and fistula characteristics were assessed. Data were analysed by means of logistic regression. RESULTS: Low transsphincteric fistulae occurred more frequently in females (43% low transsphincteric fistulae vs 30% high transsphincteric fistulae; P < 0.05). The internal opening of these fistulae was predominantly located anteriorly (76% vs 18% in high transsphincteric fistulae; P < 0.001). Mean age at surgery was lower in patients with a low transsphincteric fistula (42 vs 47 years; P < 0.001). In these patients an associated abscess was observed in 4% compared with 54% of those patients with a high transsphincteric fistula (P < 0.001). In multivariate analysis, the differences between high and low transsphincteric fistulae regarding location of their internal opening and the presence of associated abscesses remained significant (P < 0.001). CONCLUSION: Although not significant in multivariate analysis, low transsphincteric fistulae occur more frequently in younger patients and more often in females. These fistulae are predominantly located anteriorly and are rarely associated with an abscess. This was significant in univariate and multivariate analysis. PMID- 24471697 TI - Reflections on the neurotherapeutic effects of hyperbaric oxygen. AB - Traumatic brain injury (TBI) and stroke are the major causes of brain damage and chronic neurological impairments. There is no agreed-upon effective metabolic intervention for TBI and stroke patients with chronic neurological dysfunction. Clinical studies published this year present convincing evidence that hyperbaric oxygen therapy (HBOT) might be the coveted neurotherapeutic method for brain repair. Here we discuss the multi-faceted role of HBOT in neurotherapeutics, in light of recent persuasive evidence for HBOT efficacy in brain repair and the new understanding of brain energy management and response to damage. We discuss optimal timing of treatment, dosage, suitable candidates and promising future directions. PMID- 24471696 TI - Tissue optical clearing, three-dimensional imaging, and computer morphometry in whole mouse lungs and human airways. AB - In whole adult mouse lung, full identification of airway nerves (or other cellular/subcellular objects) has not been possible due to patchy distribution and micron-scale size. Here we describe a method using tissue clearing to acquire the first complete image of three-dimensional (3D) innervation in the lung. We then created a method to pair analysis of nerve (or any other colabeled epitope) images with identification of 3D tissue compartments and airway morphometry by using fluorescent casting and morphometry software (which we designed and are making available as open-source). We then tested our method to quantify a sparse heterogeneous nerve population by examining visceral pleural nerves. Finally, we demonstrate the utility of our method in human tissue to image full thickness innervation in irregular 3D tissue compartments and to quantify sparse objects (intrinsic airway ganglia). Overall, this method can uniquely pair the advantages of whole tissue imaging and cellular/subcellular fluorescence microscopy. PMID- 24471698 TI - Genotyping of Borrelia from formalin-fixed paraffin-embedded skin biopsies of cutaneous borreliosis and tick bite reactions by assays targeting the intergenic spacer region, ospA and ospC genes. AB - BACKGROUND: Lyme borreliosis has a broad spectrum of clinical presentations involving the skin, joints and nervous system. The variable manifestations have been attributed to different Borrelia genospecies but genotyping required culture or fresh tissue. However, in dermatology practice, formalin-fixed paraffin embedded biopsies are used for dermatopathological examination. Polymerase chain reaction (PCR) for Borrelia burgdorferi sensu latu has been established on such specimens, but studies attempting genotyping of subspecies or strains are lacking. OBJECTIVES: To adapt PCR assays for genotyping of Borrelia using paraffin-embedded biopsies, to identify Borrelia genospecies and to compare clinicopathological features of different genospecies. METHODS: Eighty-two paraffin-embedded biopsies from 68 patients, with erythema migrans, acrodermatitis chronica atrophicans, lymphocytoma cutis or tick bite reactions, were studied with assays targeting the intergenic spacer (IGS), ospA and ospC, followed by sequencing and phylogenetic analysis. Clinicopathological data were analysed comparing different Borrelia genospecies. RESULTS: Genotyping by IGS, ospA and ospC was successful in 85% of patients (91% B. afzelii, 7% B. garinii, 2% B. bavariensis). ospA serotyping identified type 2 (90%), type 3 (8%) and type 4 (2%). ospC-PCR was positive in 40% of the patients revealing 12 different groups, noninvasive forms being seen only in tick bite reactions and erythema migrans. No major clinicopathological differences could be identified between the genospecies, but neural inflammation and arthralgia were seen more often in lesions caused by invasive ospC strains. CONCLUSIONS: Genotyping of Borrelia can be easily implemented in a routine dermatopathology setting, especially as a fast method to confirm early cutaneous borreliosis. Genotyping could also enable earlier treatment of patients infected with invasive strains. PMID- 24471699 TI - Interpreting MSHA citations through the lens of occupational health and safety management systems: investigating their impact on mine injuries and illnesses 2003-2010. AB - Since the late 1980s, the U.S. Department of Labor has considered regulating a systems approach to occupational health and safety management. Recently, a health and safety management systems (HSMS) standard has returned to the regulatory agenda of both the Occupational Safety and Health Administration (OSHA) and the Mine Safety and Health Administration (MSHA). Because a mandated standard has implications for both industry and regulating bodies alike, it is imperative to gain a greater understanding of the potential effects that an HSMS regulatory approach can have on establishment-level injuries and illnesses. Through the lens of MSHA's regulatory framework, we first explore how current enforcement activities align with HSMS elements. Using MSHA data for the years 2003-2010, we then analyze the relationship between various types of enforcement activities (e.g., total number of citations, total penalty amount, and HSMS-aligned citations) and mine reportable injuries. Our findings show that the reduction in mine reportable injuries predicted by increases in MSHA enforcement ranges from negligible to 18%. The results suggest that the type and focus of the enforcement activity may be more important for accident reduction than the total number of citations issued and the associated penalty amount. PMID- 24471700 TI - Formulation of lyotropic liquid crystal containing mulberry stem extract: influences of formulation ingredients on the formation and the nanostructure. AB - OBJECTIVE: This study focused on the formulation of lamellar lyotropic liquid crystal (LLC) loaded with mulberry stem extract (MSE). METHODS: The LLC formulation tested used two oils: n-dodecane or tridecyl salicylate, a co-solvent (propylene glycol) and a single (PEG-7 glyceryl cocoate) or mixed surfactant system. The mixed surfactant was PEG-7 glyceryl cocoate/PEG-40 hydrogenated castor oil/glyceryl monooleate. The LLC formation and phase behaviour were observed by polarized optical microscopy (POM) before and after MSE loading. Nanostructure determinations on these formulations following MSE loading used small angle X-ray scattering (SAXS) at 25-40 degrees C. RESULTS: Lamellar LLCs are formed more easily with n-dodecane than tridecyl salicylate. Propylene glycol, in the aqueous phase (1 : 1), failed to form LLC due to suboptimal critical packing parameter (CPP) value. A single or mixed surfactant system also influenced the formation of lamellar LLC according to the chemical structure of both oils and especially the surfactants used. The four lamellar LLC formulations selected for MSE loading were PEG-7 glyceryl cocoate/tridecyl salicylate/water; mixed surfactant/tridecyl salicylate/water; PEG-7 glyceryl cocoate/n dodecane/water and mixed surfactant/n-dodecane/water, named F1, F2, F3 and F4, respectively. MSE in F1 and F3 did not affect the lamellar structure, while MSE in F2 and F4 enlarged the lamellar structure. The SAXS data confirmed that the LLC formulations obtained were lamellar and the structure persisted with MSE. CONCLUSION: These lamellar formulations should find widespread application for MSE and perhaps other similar herbal cosmetics. PMID- 24471701 TI - Leg amputation for an extensive, severe and intractable sickle cell anemia ulcer in a Brazilian patient. AB - A 35-year-old African Brazilian patient had sickle cell anemia complicated with recurrent vasoocclusive (VOC) crises and refractory painful leg ulcers for 16 years. The ulcers started over both medial malleoli and expanded gradually. The ulcer on the left leg spread from the foot to the knee circumferentially and was refractory to all forms of therapy within the frame work of multi-disciplinary care. The patient agreed to a below the knee amputation of the left leg. He felt much better after the amputation but developed severe neuropathic phantom pain that was well controlled medically. He could differentiate the sickle cell anemia and ulcer pain from the neuropathic pain. About 6 months after the amputation he had dengue fever with fatal outcome. This is the first report of treatment of refractory sickle cell anemia leg ulcer with amputation and probably the first report of a Brazilian patient with sickle cell anemia and dengue fever. PMID- 24471702 TI - Enterococcus faecalis strain LZ-11 isolated from Lanzhou reach of the Yellow River is able to resist and absorb cadmium. AB - AIM: Lanzhou reach of the Yellow River is contaminated by cadmium (Cd(II)). The aim of this study was to screen bacterial strains that is able to resist and absorb cadmium from soil sediment and elucidate the molecular mechanism. METHODS AND RESULTS: A strain named LZ-11 which can resist 1 mmol l(-1) and absorb 0.3 mmol l(-1) cadmium was isolated from a petrochemical wastewater discharge site. 16S rRNA gene sequencing data and Vitek phenotype results revealed that it was closely related to Enterococcus faecalis. Transmission electron microscopy images and energy dispersive X-ray analysis results showed that Cd(II) was absorbed both intracellularly and extracellularly. Blast results showed that Enterococcus faecalis genome owns cadA, ppx and dsbA which are proven to be involved in Cd(II) resistance and absorption. Quantitative real-time PCR data demonstrated that these three genes were upregulated 2-3 folds in LZ-11 under Cd(II) treatment. CONCLUSIONS: We've isolated a strain named LZ-11 from Lanzhou reach of the Yellow River which can resist and absorb Cd(II). LZ-11 was closely related to Enterococcus faecalis. Genes encoding CadA, Ppx and DsbA were up-regulated under Cd(II) treatment. These genes might confer Cd(II) resistance and absorption in Enterococcus faecalis strain LZ-11. SIGNIFICANCE AND IMPACT OF THE STUDY: Lanzhou reach of the Yellow River is contaminated by heavy metals. Microbial research and remediation is still scarce. LZ-11 is the first strain that is able to resist and absorb Cd(II) isolated from this area and might be a good candidate for future cadmium bioremediation. PMID- 24471703 TI - Effects of acute and long-term typical or atypical neuroleptics on morphine induced behavioural effects in mice. AB - 1. It has been suggested that the high prevalence of drug abuse in schizophrenics is related to chronic treatment with typical neuroleptics and dopaminergic supersensitivity that develops as a consequence. Within this context, atypical neuroleptics do not seem to induce this phenomenon. In the present study, we investigated the effects of acute administration or withdrawal from long-term administration of haloperidol and/or ziprasidone on morphine-induced open-field behaviour in mice. 2. In the first experiment, mice were given a single injection of haloperidol (1 mg/kg, i.p.) or several doses of ziprasidone (2, 4 or 6 mg/kg, i.p.) and motor activity was quantified by the open-field test. The aim of the second experiment was to verify the effects of an acute injection of haloperidol (1 mg/kg) or ziprasidone (6 mg/kg) on 20 mg/kg morphine-induced behaviours in the open-field test. In the third experiment, mice were treated with 1 mg/kg haloperidol and/or 2, 4 or 6 mg/kg ziprasidone for 20 days. Seventy-two hours after the last injection, mice were injected with 20 mg/kg, i.p., morphine and then subjected to the open-field test. Acute haloperidol or ziprasidone decreased spontaneous general activity and abolished morphine-induced locomotor stimulation. 3. Withdrawal from haloperidol or ziprasidone did not modify morphine-elicited behaviours in the open-field test. The results suggest that withdrawal from neuroleptic treatments does not contribute to the acute effect of morphine in schizophrenic patients. PMID- 24471704 TI - Recurrent and fatal akinetic crisis in genetic-mitochondrial parkinsonisms. AB - BACKGROUND AND PURPOSE: Akinetic crisis (AC) is the most severe and possibly lethal complication of parkinsonism. It occurs with an incidence of 30/00 Parkinson's disease patients per year, but it is not known whether genetically determined parkinsonism is more or less susceptible to this complication. METHODS: In a cohort of 756 parkinsonian patients the incidence and outcome of AC was prospectively assessed. A total of 142 of the parkinsonian patients were tested for genetic mutations because of familial parkinsonism, and 20 patients resulted positive: in four the mutation definitely involved mitochondrial functions (POLG1, PINK1), two presented with LRRK2 mutation, nine presented with GBA mutation and five presented with Park 4 different mutations. RESULTS: Akinetic crisis occurred in 30 patients for an incidence of 2.80/00 persons/year and was lethal in seven (23%), not dissimilarly from known incidences of this complication. Yet six of 30 patients were carriers of genetic mutations, one GBA, one LRRK2, one POLG1 and three PINK1. In POLG1 and PINK1 carriers, the syndrome was recurrent and was fatal in three. Incidence of AC was 3.00/00 in familiar parkinsonism, 21.20/00 in genetic parkinsonisms. CONCLUSIONS: Our preliminary findings suggest that the incidence of AC is remarkably increased in carriers of these genetic mutations. PMID- 24471706 TI - Pulse oximetry plethysmogram analysis could help identify infants with possible apnoeas requiring full investigation. PMID- 24471707 TI - Sulfur driven nucleation mode formation in diesel exhaust under transient driving conditions. AB - Sulfur driven diesel exhaust nucleation particle formation processes were studied in an aerosol laboratory, on engine dynamometers, and on the road. All test engines were equipped with a combination of a diesel oxidation catalyst (DOC) and a partial diesel particulate filter (pDPF). At steady operating conditions, the formation of semivolatile nucleation particles directly depended on SO2 conversion in the catalyst. The nucleation particle emission was most significant after a rapid increase in engine load and exhaust gas temperature. Results indicate that the nucleation particle formation at transient driving conditions does not require compounds such as hydrocarbons or sulfated hydrocarbons, however, it cannot be explained only by the nucleation of sulfuric acid. A real world exhaust study with a heavy duty diesel truck showed that the nucleation particle formation occurs even with ultralow sulfur diesel fuel, even at downhill driving conditions, and that nucleation particles can contribute 60% of total particle number emissions. In general, due to sulfur storage and release within the exhaust aftertreatment systems and transients in driving, emissions of nucleation particles can even be the dominant part of modern diesel vehicle exhaust particulate number emissions. PMID- 24471705 TI - Assessing hERG pore models as templates for drug docking using published experimental constraints: the inactivated state in the context of drug block. AB - Many structurally and therapeutically diverse drugs interact with the human heart K+ channel hERG by binding within the K+ permeation pathway of the open channel, leading to drug-induced 'long QT syndrome'. Drug binding to hERG is often stabilized by inactivation gating. In the absence of a crystal structure, hERG pore homology models have been used to characterize drug interactions. Here we assess potentially inactivated states of the bacterial K+ channel, KcsA, as templates for inactivated state hERG pore models in the context of drug binding using computational docking. Although Flexidock and GOLD docking produced low energy score poses in the models tested, each method selected a MthK K+ channel based model over models based on the putative inactivated state KcsA structures for each of the 9 drugs tested. The variety of docking poses found indicates that an optimal arrangement for drug binding of aromatic side chains in the hERG pore can be achieved in several different configurations. This plasticity of the drug "binding site" is likely to be a feature of the hERG inactivated state. The results demonstrate that experimental data on specific drug interactions can be used as structural constraints to assess and refine hERG homology models. PMID- 24471709 TI - Iridium-mediated regioselective B-H/C-H activation of carborane cage: a facile synthetic route to metallacycles with a carborane backbone. AB - One-pot reactions of carborane carboxylic acids (L), [Cp*IrCl2]2, and silver salt are reported, which lead to regioselective B-H or C-H bond activation at ambient temperature in good yields. This process is demonstrated for three carborane (o-, m-, p-) dicarboxylates, and metal-mediated B-H functionalization of a p-carborane derivative is accomplished for the first time. Two metal-induced self-assembly routes to tetra-nuclear metallacycles 3 and 5 were performed through B(4, 7)/H and B(2, 10)/H activation, respectively, and the two metallacycles were found to be stable and to exist in solution as discrete complexes. Different activation modes in the carborane cage were ascribed to the characteristic structure of the products and the electronic density differences. The analogous reaction of o carborane monocarboxylate with the same metal precursor gave the C-H activation complex 6, indicating that the B-H bond is more stable than the C-H bond in this carborane cage. The selective activation was confirmed by DFT calculation results. In this study, a facile and efficient synthetic route has been developed through specific B-H bond activation to construct carborane-based metallacycles that are unavailable by conventional methods. PMID- 24471708 TI - Personality traits as potential susceptibility markers: differential susceptibility to support among parents. AB - In this study, we examined whether parents are differentially susceptible to support from their spouse and adolescent child depending on their personality traits, and whether differences in susceptibility to support among parents, in turn, are linked to the quality of support parents give to their children. Participants in this three-wave longitudinal study were 288 two-parent Dutch families with an adolescent child. Fathers were on average 43.9 years old (SD = 3.7 years), mothers were 41.7 years old (SD = 3.3 years), and adolescents (50% girls) were 14.5 years old (SD = 0.8 years). We found that the association between support from children toward their parents and subsequent support from parents toward their children was more pronounced for parents high on Openness, for better and for worse. Extraversion, Agreeableness, Conscientiousness, and Emotional Stability did not emerge as markers of differences in susceptibility. Also, parents did not differ in their susceptibility to support from their spouse, nor were differences in susceptibility found a year later when using data from a third wave. We found very modest support for differential susceptibility, only for Openness, and depending on the source of perceived support and on the timing of measurement. PMID- 24471710 TI - Can stress increase Alzheimer's disease risk in women? AB - Alzheimer's disease (AD) is a progressive neurodegenerative disorder characterized by the accumulation of beta-amyloid peptides and neurofibrilllary tangles in brain, resulting in neuronal death and loss of cognitive abilities. It has been hypothesized that longstanding psychological stress can result in neural degeneration and AD due to pathological alterations in the hypothalamic-pituitary adrenal axis. In recent years several epidemiological studies been published on stress as a risk factor for AD. As women are more likely to suffer from stress related psychiatric disorders, such as post-traumatic stress disorder and clinical burnout syndrome, special effort has been made according to the gender differences in risk of AD. However, few studies have stratified for gender, due to small sample sizes and limited statistic power, and no reliable findings have been found. Additional longitudinal studies are therefore needed for studying gender differences and for determining what mediates the stress and AD association, in both genders. PMID- 24471711 TI - The pathomechanisms underlying Parkinson's disease. AB - Parkinson's disease (PD), one of the most frequent neurodegenerative disorders, is a progressive multi-organ proteinopathy caused by misfolded alpha-synuclein (alphaSyn) with variegated motor and nonmotor deficits owing to a spreading process of synaptic and neuronal loss in the nervous system. The motor core deficits of PD including rigidity, akinesia, rest tremor, and postural instability are attributed to the loss of dopaminergic nigrostriatal system, while the nonmotor alterations, such as hyposmia, autonomic and other dysfunctions frequently antedating motor symptoms are linked to widespread distribution of alphaSyn in the central, autonomic and peripheral nervous system and multiple organs. Recent studies have shown that alphaSyn aggregation in presynaptic terminals that predates the formation of Lewy bodies (LB), the characteristic markers of PD, is a key event in the pathogenesis of PD and other synucleinopathies. Progress in our understanding of the underlying mechanisms include insights into the functional organization of the basal ganglia and related cortico-subcortical circuits and their relations with morphological and pathophysiological lesions in the nervous system. The pathomechanisms underlying the cardinal motor abnormalities and nonmotor manifestations are briefly reviewed. PMID- 24471712 TI - Mapping quantum yield for (Fe-Zn-Sn-Ti)Ox photoabsorbers using a high throughput photoelectrochemical screening system. AB - Combinatorial synthesis and screening of light absorbers are critical to material discoveries for photovoltaic and photoelectrochemical applications. One of the most effective ways to evaluate the energy-conversion properties of a semiconducting light absorber is to form an asymmetric junction and investigate the photogeneration, transport and recombination processes at the semiconductor interface. This standard photoelectrochemical measurement is readily made on a semiconductor sample with a back-side metallic contact (working electrode) and front-side solution contact. In a typical combinatorial material library, each sample shares a common back contact, requiring novel instrumentation to provide spatially resolved and thus sample-resolved measurements. We developed a multiplexing counter electrode with a thin layer assembly, in which a rectifying semiconductor/liquid junction was formed and the short-circuit photocurrent was measured under chopped illumination for each sample in a material library. The multiplexing counter electrode assembly demonstrated a photocurrent sensitivity of sub-10 MUA cm(-2) with an external quantum yield sensitivity of 0.5% for each semiconductor sample under a monochromatic ultraviolet illumination source. The combination of cell architecture and multiplexing allows high-throughput modes of operation, including both fast-serial and parallel measurements. To demonstrate the performance of the instrument, the external quantum yields of 1819 different compositions from a pseudoquaternary metal oxide library, (Fe-Zn-Sn-Ti)Ox, at 385 nm were collected in scanning serial mode with a throughput of as fast as 1 s per sample. Preliminary screening results identified a promising ternary composition region centered at Fe0.894Sn0.103Ti0.0034Ox, with an external quantum yield of 6.7% at 385 nm. PMID- 24471713 TI - Graph theoretical solutions for the coupled kinetic rate equations. AB - A graph theoretical procedure for solving multistep coupled kinetic rate equations and thereby obtaining the concentrations of the species involved in the reaction has been developed. The method so developed has been illustrated with some well-known reaction schemes. PMID- 24471714 TI - Generation and controlled routing of single plasmons on a chip. AB - We demonstrate the excitation of single surface plasmon polaritons on a silver nanowire using a nitrogen vacancy center and the subsequent controlled coupling to a second silver nanowire. The coupling efficiency and thus the splitting ratio between the nanowires is controlled by adjusting the gap size between the wires with an atomic force microscope. By numerical methods, we estimate the splitting ratios for different gap sizes, and the results support the values obtained in the experiment. PMID- 24471715 TI - Formulation by design-based proniosome for accentuated transdermal delivery of risperidone: in vitro characterization and in vivo pharmacokinetic study. AB - AIM: The aim of this work was to investigate the effects of formulation variables on the development of risperidone proniosomal formulations as potential transdermal delivery systems. MATERIALS AND METHODS: A 43 factorial design was employed to evaluate individual and combined effects of formulation variables cholesterol (X1), span 60 (X2), phospholipid G90 (X3), and risperidone (X4) added on vesicle size (Y1), encapsulation efficiency (Y2), and flux (Y3) of proniosomes. RESULTS AND DISCUSSION: The investigated risperidone-loaded proniosomal formulation shows significantly higher skin permeation in comparison to conventional liposomes with ER of 4.4 times through rat skin. The bioavailability studies in rats indicated that mean value of AUC0-48 by ROPF-TTS was 1.31 times higher than that of oral dosage form. So it could be concluded that Cmax value of ROPF-TTS was significantly reduced while AUC values were apparently increased. CONCLUSION: The developed proniosomal-based transdermal therapeutic systems incorporating risperidone would provide a useful strategy for better management of schizophrenia. PMID- 24471716 TI - Mechanisms of murine spontaneous liver transplant tolerance. AB - Liver transplant is associated with the induction of peripheral immune tolerance. Liver allografts are accepted spontaneously in most combinations of mismatch in major histocompatibility complex, without any requirements for immunosuppression. Liver nonparenchymal cells (especially dendritic cells and Kupffer cells), costimulatory pathways, and activated T-cell apoptosis may contribute to the induction of liver tolerance. Therefore, liver tolerance is an active process that includes T-cell activation, proliferation, infiltration of the allograft, and T-cell apoptosis. Liver dendritic cells may modulate the amount of alloreactive T cells in liver graft recipients by expressing the coinhibitory molecule programmed death-ligand 1 and the immunosuppressive enzyme indoleamine 2,3-dioxygenase. Liver dendritic cells also may induce activated T-cell apoptosis and Foxp3+ regulatory T cells. Future studies may clarify the precise function of liver nonparenchymal cells, the interactions between programmed death-ligand 1 and other costimulatory signals, and the contribution of the liver microenvironment to the induction and expansion of Foxp 3 regulatory T cells. PMID- 24471717 TI - Perceptions of patient candidacy for kidney transplant in the United States: a qualitative study comparing rural and urban nephrologists. AB - OBJECTIVES: To explore different perceptions of urban and rural nephrologists regarding patient suitability for transplant. MATERIALS AND METHODS: We conducted 4 focus groups, each consisting of 4 to 6 nephrologists practicing in either a rural (n=9) or an urban setting (n=11). A topic guide was developed and modified according to pilot testing. Broadly stated, open ended queries probed perceptions about the ideal or suboptimal candidates for transplant, perceived barriers to transplant, views regarding providing information to patients, and strategies that could improve transplant rates. At the sessions, all audio was recorded and professionally transcribed. Responses were pooled, de-identified, and analyzed using qualitative thematic content analysis. RESULTS: In considering candidacy, urban participants mentioned "age, " "compliance, " and "functional status "; "support " was a more-prevalent theme among rural nephrologists. Urban physicians discussed the expected effect of a transplant on a subject 's quality of life. As barriers to transplant, "evaluation time " was mentioned by urban groups only, and "distance to transplant center " was suggested by rural nephrologists only. To improve transplant rates, urban nephrologists suggested strategies that would increase the donor pool. Rural nephrologists, on the other hand, suggested a collaboration between nephrologists and the transplant center, "limiting listing eligibility " and "financial assistance. " Rural nephrologists suggested providing comparisons of modalities and information about selecting subjects. CONCLUSIONS: This qualitative study underscores geographic differences in perceptions of nephrologists regarding patient candidacy for kidney transplant, perceived barriers to kidney transplant, and proposed strategies to increase rates of kidney transplant. These differences are potential contributors to geographic variations in referring patients for kidney transplant. PMID- 24471718 TI - Long-term follow-up of kidney transplants in a region of Southern Italy. AB - OBJECTIVES: Several donor and recipient factors are known to be associated with graft loss in a kidney transplant. In this retrospective single-center study, we analyzed the effect of clinical and immunologic factors on kidney transplant outcomes in our region in Italy. MATERIALS AND METHODS: The study included 245 transplanted recipients from deceased donors at Federico II University of Naples, Kidney Transplant Centre, between the years 2000 and 2006. Age, cause of death, history of hypertension, hypotension or cardiac arrest, length of time spent in the intensive care unit, serum creatinine levels and human leukocyte antigen typing all were evaluated in the donors. Age, time spent on the wait list, human leukocyte antigen typing, antibody sensitization, and allocation were evaluated in the recipients. Age, donor/recipient matching, and human leukocyte antigen mismatches also were evaluated. RESULTS: Cox regression analysis showed that in recipients, time spent on the wait list increased the risk of restarting dialysis (OR 1.019, 95% CI: 1.000-1.038; P = .050) and dying (OR 1.017, 95% CI: 1.000 1.038; P = .032). Patients who received a kidney from a donor with a history of hypertension presented a major risk of death (OR 3.212, 95% CI: 1.190-8.668; P = .021), while human leukocyte antigen-A mismatch increased the risk of restarting dialysis (OR 3.137, 95% CI: 1.255-7.842; P = .014). CONCLUSIONS: In our study, in recipients, time spent on the wait list, and a history of hypertension were associated with a greater risk of death. Human leukocyte antigen-A mismatch is associated with a greater risk of restarting dialysis. PMID- 24471719 TI - A human cadaver model for laparoscopic kidney transplant. AB - OBJECTIVES: To evaluate the technique of laparoscopic kidney transplant and demonstrate the feasibility of this procedure by an extraperitoneal approach. MATERIALS AND METHODS: The procedure was performed on 2 human cadavers. Retroperitoneal endoscopic left nephrectomy was performed. An extraperitoneal space was established by inflation of a balloon dilator. The external iliac artery and vein were exposed. A Pfannenstiel incision (6 cm) was made and a hand access device was used. The renal artery was anastomosed to the external iliac artery (end-to-side anastomosis); the renal vein was anastomosed to the external iliac vein (end-to-side anastomosis). The ureter was anastomosed to the bladder with an extravesical tunnelling technique. RESULTS: The donor kidney grafts were obtained successfully. The preparation of the external iliac artery and vein was satisfactory. The entire procedure for the renal artery, renal vein, and ureteral anastomoses was performed with laparoscopic technique without any difficulty. CONCLUSIONS: The present model on human cadavers may provide a feasible approach for training surgeons to perform human laparoscopic kidney transplant. The present technique may be applied to clinical human kidney transplant. PMID- 24471720 TI - Posttransplant metabolic complications in living-related renal allograft recipients of Kashmir Valley. AB - OBJECTIVES: Renal transplant offers a definitive therapeutic modality for patients with end-stage renal disease; however, 50% to 70% of these patients have graft dysfunction after the transplant. Proactive prevention management of metabolic complications may reduce posttransplant morbidity and mortality in these patients. MATERIALS AND METHODS: A retrospective and prospective review of 120 kidney transplant recipients during 5 years' follow-up was performed to analyze the incidence and status of the various metabolic complications after a renal transplant. RESULTS: In our study, postrenal transplant diabetes mellitus was seen in 9 of 120 patients (7.5%). The incidence of posttransplant diabetes mellitus was 5% in tacrolimus-treated patients (n=6) compared with 2.5% in cyclosporine-treated patients (n=3). Dyslipidemia, as hypercholesterolemia and hyper-triglyceridemia, was seen in 31 recipients (25.83%). Significant posttransplant hyperlipidemia was documented (P < .05). Further, it was noted that 25 patients who developed hyperlipidemia (20.83%) were taking cyclosporine based therapy, while 6 were treated with tacrolimus-based therapy (5%; P < .05). However, most subjects with hyperlipidemia had renal graft dysfunction. Posttransplant erythrocytosis affected 9 renal transplant recipients (7.5%) with a mean (+/-SD) hematocrit of 41.3%+/-6.7%. A statistically significant correlation was seen between prerenal and postrenal transplant hematocrit by 12 months. Hyperparathyroidism was observed in 1 renal transplant patient (1.25%). CONCLUSIONS: On the basis of this study, we conclude that posttransplant diabetes mellitus occurred in 7.5% patients, hypercholesteremia and hyper-triglyceridemia occurred in 25.83% patients, posttransplant erythrocytosis affected 7.5% patients, and hyperparathyroidism occurred in 1 renal transplant patient (1.25%). Moreover, dyslipidemia, contributed to progressive graft dysfunction. PMID- 24471721 TI - Replacement of mycophenolate acid with everolimus in patients who became neutropenic after renal transplant. AB - OBJECTIVES: Neutropenia after kidney transplant is an adverse event usually treated with a dosage reduction of mycophenolic acid. We evaluated the efficacy and safety of substituting mycophenolic acid with everolimus in patients with persistent neutropenia after kidney transplant. MATERIALS AND METHODS: This study was a retrospective analysis. A total of 17 patients who were initially treated with mycophenolic acid (1912 +/- 196 mg/d), calcineurin inhibitors, and methylprednisolone for kidney transplant were included. RESULTS: In 15 patients, neutropenia occurred within the first 3 months (during valganciclovir administration), and in 2 patients between the fourth and sixth month after transplant. One hundred eighteen episodes of neutropenia were recorded, originally treated by reducing the dosage of mycophenolic acid (765 +/- 390 mg/d) and administering granulocyte colony-stimulating factor. Three patients experienced acute rejection 5 to 10 days after reducing the dosage of mycophenolic acid, and they were successfully treated with pulse steroids. Five patients developed cytomegalovirus infection 108 +/- 65 days after the onset of neutropenia. After replacing mycophenolic acid with everolimus, episodes of neutropenia were observed in 6 patients. In 1 patient, discontinuing everolimus was necessary after 1.5 months of treatment. In 5 patients with cytomegalovirus infection, neutropenia subsided after termination of valganciclovir treatment. In the remaining 11 patients, no episodes of neutropenia were observed. No episodes of acute rejection occurred, and renal function remained stable during a followup of 47 +/- 30 months (estimated glomerular filtration rate [eGFRMDRD6]: 45 +/- 14 mL/min/1.73 m2->47 +/- 22 mL/min/1.73 m2]. CONCLUSIONS: Replacing mycophenolic acid with everolimus appears to be a safe and effective alternative treatment in neutropenic renal transplant recipients. PMID- 24471722 TI - Evaluation of renal function by cystatin C in renal transplant recipients. AB - OBJECTIVES: We evaluated cystatin C concentration as a marker of glomerular filtration rate in renal transplant recipients, and its correlation with creatinine-based glomerular filtration rate by urinary creatinine clearance, and the Cockroft-Gault and Modification of Diet in Renal Disease formulas. MATERIALS AND METHODS: In this cross-sectional study, we measured serum cystatin C levels and its correlation with serum creatinine, creatinine clearance, and glomerular filtration rate using the Cockroft-Gault formula and Modification of Diet in Renal Disease formulas. RESULTS: One hundred two recipients between June and December 2012, were examined. The mean subject age was 31.87 +/- 8.37 years; the male:female ratio was 4.3:1. Mean serum creatinine concentration was 141.44 +/- 43.31 mol/L (1.60 +/- 0.49 mg/dL) and serum cystatin C 122.09 +/- 38.95 nmol/L (1.63 +/- 0.52 mg/L). Serum cystatin C was significantly correlated with serum creatinine (r=0.90; P<.001), creatinine clearance (r=0.77; P<.001), and the Cockroft-Gault (r=0.73; P<.001) and the Modification of Diet in Renal Disease formulas (r=0.82; P<.001). We assessed the correlation among serum cystatin C with serum creatinine, creatinine clearance, the Cockroft-Gault and Modification of Diet in Renal Disease at 1, 2-3, 4-5, and more than 5 years after transplant. The correlation between serum cystatin C and serum creatinine ranged from 0.8 to 1.0; cystatin C and creatinine clearance ranged from 0.8 to 0.85; serum cystatin C and the Cockroft-Gault Formula ranged from 0.7 to 0.8; and serum cystatin C and the Modification of Diet in Renal Disease formulas ranged from 0.8 to 0.84. CONCLUSIONS: Our results show that serum cystatin C is a reliable marker for estimating glomerular filtration rate among renal transplant recipients. This test can determine the glomerular filtration rate of renal transplant recipients on follow-up. Further studies are required to establish serum cystatin C as a standard test for monitoring glomerular filtration rate in transplanted patients. PMID- 24471723 TI - Pediatric liver transplant: a single-center study of 100 consecutive patients. AB - OBJECTIVES: Here, we present the outcomes of 100 consecutive pediatric liver transplant patients in our center. MATERIALS AND METHODS: Five hundred fifteen adult and pediatric liver transplants were performed at Organ Transplantation Center, Sisli Memorial Hospital, Istanbul, Turkey, between August 2006 and November 2012. Of these, the first 100 consecutive pediatric liver transplant patients were retrospectively analyzed. RESULTS: One hundred three liver transplants were performed in 100 children (mean age, 4.7 y; age range, 4.4 mo to 17.3 y; 53% female, 47% male; mean body weight, 17.2 kg; range, 4.5 to 75 kg). Biliary atresia (27%) and progressive familial intrahepatic cholestasis (18%) were the most common causes of liver disease. Of all the cases, 88.4% were living donor liver transplants. Arterial reconstruction was performed under an operating microscope in most cases. Duct-to-duct biliary anastomoses were preferred in anatomically favorable cases. Mean hospital stay was 17.5 days. Median follow-up was 19.9 months (range, 6 to 66.1 mo). The main complication after surgery was infection (34%). Postoperative technical complications included hepatic arterial thrombosis (3.9%), portal venous thrombosis (6.8%), and biliary leak (6.8%). One , 3-, and 5-year patient survivals were 89.8%, 89.8%, and 83.8%. There were no serious postoperative complications in the living donors. CONCLUSIONS: Living donor liver transplant in pediatric patients is a safe alternative to deceased donor transplant. It is becoming the most frequent treatment option for end-stage liver disease in pediatric patients in our center, given the paucity of pediatric deceased-donor organs. PMID- 24471724 TI - Liver transplant in Budd-Chiari syndrome: a single-center experience in Saudi Arabia. AB - OBJECTIVES: If they do not respond to other treatments, patients with Budd-Chiari syndrome are potential candidates for a liver transplant. Timing for transplant is controversial; however, before other systems deteriorate, early intervention in relatively stable patient may improve the outcome and survival of these patients. MATERIALS AND METHODS: Six patients (2 women and 4 men) had Budd-Chiari syndrome (1.2%) among 475 patients who had undergone a liver transplant at our center between 2001 and 2012. Imaging modalities including duplex ultrasound, abdominal computed tomography angiography, and hematologic evaluation were part of our routine diagnostic work-up. Although we perform mostly living-donor liver transplants, these patients received a liver transplant from a deceased donor, because there was not enough evidence to justify a living-donor liver transplant. We thought that not replacing the caval vein might negatively influence the outcome. Postoperatively, these recipients were started on a heparin infusion and triple therapy immunosuppression; only then was warfarin introduced as long-term anticoagulant. RESULTS: Two patients died, 1 from uncontrollable bleeding and disseminated intravascular coagulopathy, and the other died in the intensive care unit after 5 months because of multiorgan failure and sepsis. One patient had portal vein thrombosis 9 months after the liver transplant; the other patient needed a liver retransplant after 5 years owing to liver failure, secondary to chronic rejection. Graft survival rate was 75%, and patient survival rate was 66.6%. CONCLUSIONS: This is the first article from Saudi Arabia to describe the outcome of a liver transplant in this subgroup of patients with Budd-Chiari syndrome. Treatment of Budd-Chiari syndrome follows a therapeutic algorithm that should start with anticoagulation and may end up with liver transplant; however, it should be considered early if other treatments fail. PMID- 24471725 TI - Cardiovascular risk 10 years after liver transplant. AB - OBJECTIVES: We sought to evaluate the frequency of cardiovascular risk factors in a cohort of patients 10 years after a liver transplant, and to assess their 10 year risk of fatal cardiovascular disease using Systematic COronary Risk Evaluation (SCORE) charts. MATERIALS AND METHODS: Between January 1990 and June 1996, one hundred eighty-nine adults underwent a first liver transplant in our center. Fifty-nine patients (31%) died before reaching their tenth year, and 115 patients were available with complete clinical data at 10 years. RESULTS: The main indications for liver transplant were alcoholic (38%) and viral cirrhosis (40%). The median age of patients was 56 (range, 29-73 y), 80% were men, 23% were obese, 16% were active smokers, 18% were diabetic, 40% had hypercholesterolemia, and 77% had hypertension. Before the tenth year after transplant, 6 deaths were because of cardiovascular diseases, which represents the third cause of late death (> 1 year after liver transplant). After liver transplant, 5% of the surviving patients underwent ischemic cardiovascular events during the first decade. At a 10-year assessment, the median estimated 10-year risk of fatal cardiovascular disease was 1% (range, 0%-9%) and 10% of the patients had a high risk (ie, SCORE >= 5%). CONCLUSIONS: Our results suggest that the frequency of cardiovascular events is relatively low after a liver transplant, even if most of the patients had 1 or more cardiovascular risk factors. Nevertheless, clinicians should perform a similar evaluation 15 or 20 years after the liver transplant because cardiovascular risk exponentially increases with age. PMID- 24471726 TI - A rare ocular complication after a heart transplant: toxoplasma retinitis. AB - Ocular infections after a heart transplant are rare; but when present, they generally appear during the first year after surgery. Ocular infections may cause significant loss of vision and morbidity if not diagnosed early. For that reason, heart transplant patients should undergo a routine visual examination during follow-up. We report our experience regarding the followup and treatment of a case of toxoplasma retinitis diagnosed in one of our heart transplant recipients. PMID- 24471727 TI - Comment on: New-onset diabetes and impaired fasting glucose after a liver transplant: risk analysis and the effect of tacrolimus dosage. PMID- 24471728 TI - Response to: Comment on: New-onset diabetes and impaired fasting glucose after liver transplant: risk analysis and the impact of tacrolimus dose. PMID- 24471729 TI - Calcium signaling and cell volume regulation are altered in Sjogren's Syndrome. AB - OBJECTIVE: Sjogren's Syndrome (SS) is a chronic autoimmune disease, leading to deficient secretion from salivary and lacrimal glands. Saliva production is normally increased by cholinergic innervation, giving rise to intracellular calcium signaling and water transport through water channels (aquaporins, AQPs). The aim of this study was to investigate possible pathophysiological changes in cell volume regulation, AQP expression and localization, and intracellular calcium signaling in glandular cells from SS patients compared to controls. MATERIALS AND METHODS: A total of 35 SS patients and 41 non-SS controls were included. Real time qPCR was combined with immunohistochemistry to analyze the mRNA expression and cellular distribution of AQP1, 3 and 5. Cell volume regulation and intracellular calcium signaling were examined in fresh acinar cells. RESULTS: We show for the first time a reduced mRNA expression of AQP1 and 5 in SS compared to controls, accompanied by a decrease in staining intensity of AQP1, 3 and 5 in areas adjacent to local lymphocytic infiltration. Furthermore, we observed that the SS cells' capacity for volume regulation was abnormal. Similarly, the calcium response after parasympathetic agonist (carbachol) stimulation was markedly decreased in SS cells. CONCLUSIONS: It is concluded that mRNA expression of AQP1 and 5, protein distribution of AQP1, 3 and 5, glandular cell volume regulation and intracellular calcium signaling are all altered in SS, pointing to possible pathophysiological mechanisms in SS. PMID- 24471730 TI - Positive control for cytotoxicity evaluation of dental vinyl polysiloxane impression materials using sodium lauryl sulfate. AB - OBJECTIVES: Vinyl polysiloxane (VPS) is elastomeric dental impression material which, despite having very few reports of adverse reactions, has shown high levels of cytotoxicity that is difficult to be interpreted without referencing to the positive control material. Therefore, in this study, positive control VPS was developed using sodium lauryl sulfate (SLS) for the reference of cytotoxicity test. MATERIALS AND METHODS: The positive control VPS with SLS was formed with a different proportion of SLS (0, 1, 2, 4, 8 and 16 wt%) added to the base. The cytotoxicity test was then carried out using the extractions or dilutions of the extractions from each of the test samples using murine fibroblast cells (L929). RESULTS: The final product of positive control VPS behaved similar to commercially available VPS; being initially liquid-like and then becoming rubber like. Ion chromatography showed that the level of SLS released from the product increased as the proportion of added SLS increased, consequently resulting in an increased level of cytotoxicity. Also, the commercially available VPS was less cytotoxic than the positive control VPS with more or equal to 2 wt% of SLS. However, even the VPS with the highest SLS (16 wt%) did not cause oral mucosa irritation during the animal study. CONCLUSIONS: The positive control VPS was successfully produced using SLS, which will be useful in terms of providing references during in vitro cytotoxicity testing. PMID- 24471731 TI - Deviations: a Gayle Rubin reader. PMID- 24471732 TI - Helicobacter pylori: expect the unexpected. AB - Helicobacter pylori is one of the most common bacterial infections worldwide, and virtually all infected persons develop coexisting gastritis, a signature feature of which is the capacity to persist for decades. In support of its lifestyle, H. pylori has evolved to express an array of diverse phenotypes, including enzyme functional diversity, that help to subvert obstacles presented by the human host, which permits long-term microbial colonization. The versatility of the newly discovered enzyme LpxJ may allow H. pylori to quickly adapt to dynamic and hostile conditions present within its cognate gastric niche. PMID- 24471733 TI - Developing new isotope-coded mass spectrometry-cleavable cross-linkers for elucidating protein structures. AB - Structural characterization of protein complexes is essential for the understanding of their function and regulation. However, it remains challenging due to limitations in existing tools. With recent technological improvements, cross-linking mass spectrometry (XL-MS) has become a powerful strategy to define protein-protein interactions and elucidate structural topologies of protein complexes. To further advance XL-MS studies, we present here the development of new isotope-coded MS-cleavable homobifunctional cross-linkers: d0- and d10 labeled dimethyl disuccinimidyl sulfoxide (DMDSSO). Detailed characterization of DMDSSO cross-linked peptides further demonstrates that sulfoxide-containing MS cleavable cross-linkers offer robust and predictable MS2 fragmentation of cross linked peptides, permitting subsequent MS3 analysis for simplified, unambiguous identification. Concurrent usage of these reagents provides a characteristic doublet pattern of DMDSSO cross-linked peptides, thus aiding in the confidence of cross-link identification by MS(n) analysis. More importantly, the unique isotopic profile permits quantitative analysis of cross-linked peptides and therefore expands the capability of XL-MS strategies to analyze both static and dynamic protein interactions. Together, our work has established a new XL-MS workflow for future studies toward the understanding of structural dynamics of protein complexes. PMID- 24471734 TI - A physiologically based pharmacokinetic model of alvespimycin in mice and extrapolation to rats and humans. AB - BACKGROUND AND PURPOSE: Alvespimycin, a new generation of heat shock protein 90 (Hsp90) inhibitor in clinical trial, is a promising therapeutic agent for cancer. Pharmacokinetic models of alvespimycin would help in the understanding of drug disposition, predicting drug exposure and interpreting dose-response relationship. In the present study we aimed to develop a physiologically based pharmacokinetic (PBPK) model of alvespimycin in mice and evaluate the utility of the model for predicting alvespimycin disposition in other species. EXPERIMENTAL APPROACH: A literature search was performed to collect pharmacokinetic data for alvespimycin. A PBPK model was initially constructed to demonstrate the disposition of alvespimycin in mice, and then extrapolated to rats and humans by taking into account the interspecies differences in physiological- and chemical specific parameters. KEY RESULTS: A PBPK model, employing a permeability-limited model structure and saturable tissue binding, was built in mice. It successfully characterized the time course of the disposition of alvespimycin in mice. After extrapolation to rats, the model simulated the alvespimycin concentration-time profiles in rat tissues with acceptable accuracies. Likewise, a reasonable match was found between the observed and simulated human plasma pharmacokinetics of alvespimycin. CONCLUSIONS AND IMPLICATIONS: The PBPK model described here is beneficial to the understanding and prediction of the effects of alvespimycin in different species. It also provides a good basis for further development, which necessitates additional studies, especially those needed to clarify the in-depth mechanism of alvespimycin elimination. A refined PBPK model would benefit the understanding of dose-response relationships and optimization of dosing regimens. PMID- 24471735 TI - Bakuchiol: a retinol-like functional compound revealed by gene expression profiling and clinically proven to have anti-aging effects. AB - OBJECTIVE: The study was undertaken to compare the skin care related activities of retinol and bakuchiol, a potential alternative to retinoids. Retinol is a pivotal regulator of differentiation and growth of developing as well as adult skin. Retinoic acid is the major physiologically active metabolite of retinol regulating gene expression through retinoic acid receptor - dependant and independent pathways. METHODS: Comparative gene expression profiling of both substances in the EpiDerm FT full thickness skin substitute model was undertaken. Furthermore, type I, III and IV collagen, as well as aquaporin 3 expression was analyzed by ELISA and/or histochemistry in human dermal fibroblasts and/or Epiderm FT skin substitutes. RESULTS: Bakuchiol is a meroterpene phenol abundant in seeds and leaves of the plant Psoralea corylifolia. We present evidence that bakuchiol, having no structural resemblance to retinoids, can function as a functional analogue of retinol. Volcano plots showed great overall similarity of retinol and bakuchiol effects on the gene expression profile. This similarity was confirmed by the side-by-side comparison of the modulation of individual genes, as well as on the protein level by ELISA and histochemistry. Retinol-like functionality was further confirmed for the upregulation of types I and IV collagen in DNA microarray study and also show stimulation of type III collagen in the mature fibroblast model. Bakuchiol was also formulated into a finished skin care product and was tested in clinical case study by twice-a-day facial application. The results showed that, after 12 weeks treatment, significant improvement in lines and wrinkles, pigmentation, elasticity, firmness and overall reduction in photo-damage was observed, without usual retinol therapy-associated undesirable effects. CONCLUSION: Based on these data, we propose that bakuchiol can function as an anti-ageing compound through retinol-like regulation of gene expression. PMID- 24471736 TI - Detection of Hb anti-Lepore Hong Kong (NG_000007.3: g.63154_70565dup) in Chinese individuals. AB - We have identified four Chinese individuals from three unrelated families with raised Hb A2 levels. The anti-Lepore hybrid hemoglobin (Hb) variant was amplified using a pair of primers, 5' to the beta-globin gene Cap site and 3' to the delta globin gene polyadenylation site (polyA) region, respectively. Direct sequencing of the betadelta fusion products confirmed the anti-Lepore Hong Kong (NG_000007.3: g.63154_70565dup) variant. We found that this anti-Lepore variant is positioned in zone 3 on the capillary electrophoresis system. It may help in differential diagnosis of Hb variants and providing better information in clinical counseling. PMID- 24471737 TI - Inhibition of soluble epoxide hydrolase is renoprotective in 5/6 nephrectomized Ren-2 transgenic hypertensive rats. AB - 1. The aim of the present study was to test the hypothesis that increasing kidney tissue concentrations of epoxyeicosatrienoic acids (EETs) by preventing their degradation to the biologically inactive dihydroxyeicosatrienoic acids (DHETEs) using blockade of soluble epoxide hydrolase (sEH) would attenuate the progression of chronic kidney disease (CKD). 2. Ren-2 transgenic rats (TGR) after 5/6 renal mass reduction (5/6 NX) served as a model of CKD associated with angiotensin (Ang) II-dependent hypertension. Soluble epoxide hydrolase was inhibited using cis-4-[4-(3-adamantan-1-yl-ureido)cyclohexyloxy]benzoic acid (c-AUCB; 3 mg/L drinking water) for 20 weeks after 5/6 NX. Sham-operated normotensive transgene negative Hannover Sprague-Dawley (HanSD) rats served as controls. 3. When applied in TGR subjected to 5/6 NX, c-AUCB treatment improved survival rate, prevented the increase in blood pressure, retarded the progression of cardiac hypertrophy, reduced proteinuria and the degree of glomerular and tubulointerstitial injury and reduced glomerular volume. All these organ-protective actions were associated with normalization of the intrarenal EETs:DHETEs ratio, an index of the availability of biologically active EETs, to levels observed in sham-operated HanSD rats. There were no significant concurrent changes of increased intrarenal AngII content. 4. Together, these results show that 5/6 NX TGR exhibit a profound deficiency of intrarenal availability of active epoxygenase metabolites (EETs), which probably contributes to the progression of CKD in this model of AngII dependent hypertension, and that restoration of intrarenal availability of EETs using long-term c-AUCB treatment exhibits substantial renoprotective actions. PMID- 24471738 TI - Apolipoprotein E polymorphisms and ischaemic stroke: a two-center Greek study. AB - BACKGROUND AND PURPOSE: Apolipropotein E(apoE) is a plasma protein exhibiting three common isoforms (E2, E3, E4). Its involvement in lipoprotein metabolism may have an impact on stroke occurrence. As results in the literature are inconclusive further studies are needed to elucidate its role. Our objective was to study the role of apoE isoforms and the interplay with environmental risk factors in patients with first ischaemic stroke occurrence in the Greek population. METHODS: Three hundred and twenty-nine patients with first-ever ischaemic stroke were included in our study. Strokes of cardioembolic origin and patients with autoimmune or prothrombotic syndromes were excluded. A control group of 361 subjects with no stroke history were also included in our study. Risk factors (hyperlipidemia, hypertension, diabetes mellitus and smoking) were assessed. ApoE alleles were determined in all subjects participating in the study. RESULTS: Genotype epsilon3/epsilon3 was found to have a protective role against stroke occurrence compared with other genotypes (odds ratio 0.674, 95% confidence interval 0.480-0.946) especially in the female patient subgroup. In multivariate analysis after adjustment for age, body mass index (BMI), hypertension, dyslipidemia, diabetes mellitus and smoking, the role of genotype was limited and outweighed by risk factors in both genders. No association between apoE alleles and BMI, cholesterol, triglycerides or high-density lipoprotein plasma levels was noted. CONCLUSIONS: Our study was indicative of a protective role of the epsilon3/epsilon3 genotype, especially in female patients. However, risk factors such as age, BMI, hypertension, dyslipidemia, diabetes mellitus and smoking have a strong impact on stroke occurrence and outweigh the protective role of the epsilon3/epsilon3 genotype. PMID- 24471739 TI - Clinical test responses to different orthoptic exercise regimes in typical young adults. AB - PURPOSE: The relative efficiency of different eye exercise regimes is unclear, and in particular the influences of practice, placebo and the amount of effort required are rarely considered. This study measured conventional clinical measures following different regimes in typical young adults. METHODS: A total of 156 asymptomatic young adults were directed to carry out eye exercises three times daily for 2 weeks. Exercises were directed at improving blur responses (accommodation), disparity responses (convergence), both in a naturalistic relationship, convergence in excess of accommodation, accommodation in excess of convergence, and a placebo regime. They were compared to two control groups, neither of which were given exercises, but the second of which were asked to make maximum effort during the second testing. RESULTS: Instruction set and participant effort were more effective than many exercises. Convergence exercises independent of accommodation were the most effective treatment, followed by accommodation exercises, and both regimes resulted in changes in both vergence and accommodation test responses. Exercises targeting convergence and accommodation working together were less effective than those where they were separated. Accommodation measures were prone to large instruction/effort effects and monocular accommodation facility was subject to large practice effects. CONCLUSIONS: Separating convergence and accommodation exercises seemed more effective than exercising both systems concurrently and suggests that stimulation of accommodation and convergence may act in an additive fashion to aid responses. Instruction/effort effects are large and should be carefully controlled if claims for the efficacy of any exercise regime are to be made. PMID- 24471740 TI - Highly efficient enrichment method for glycopeptide analyses: using specific and nonspecific nanoparticles synergistically. AB - We invented a new method for highly efficient and specific enrichment of glycopeptides using two different nanomaterials synergistically. One is boronic acid-functionalized Fe3O4 nanoparticles, enriching glycopeptides through formation of cyclic boronate esters between the boronic acid groups and the cis diol groups on glycopeptides. The other nanomaterial is conventional poly(methyl methacrylate) nanobeads, which have strong adsorption toward nonglycopeptides. By optimizing the proportion of these two materials, extremely high sensitivity and selectivity are achieved in analyzing the standard glycopeptides/nonglycopeptides mixture solutions. Since the washing step is not necessary for these conditions, the enrichment process is simplified and the recovery efficiency of target glycopeptides reaches 90%. Finally, this approach is successfully applied to analyze human serum with the sample volume as little as 1 MUL, in which 147 different N-glycosylation peptides within 66 unique glycoproteins are identified. All these performances by the synergistic enrichment are much better than employing one specific enrichment agent alone. PMID- 24471741 TI - Violence and duration of untreated psychosis in first-episode patients. AB - BACKGROUND: Violent behaviour can be a presenting sign of first-episode psychosis. Duration of untreated psychosis (DUP) has been a focus of attention because it is a potentially modifiable factor that may influence outcome. AIMS: The aim was to review the literature addressing the following issues: prevalence of violence or aggression in the first episode of psychosis, violence or aggression during the periods before and after the initiation of treatment, the DUP and relation between DUP and the level of violence or aggression in first episode psychosis. METHODS: MEDLINE and PubMed databases were searched for articles using the combination of key words 'aggression' (limited to humans) and 'first episode' and 'psychosis'. RESULTS: Available evidence suggests that the prevalence of violent behaviour in the first episode of psychosis, particularly schizophrenia, is greater than during the later stages of the illness. First episode psychosis is associated with an increased risk of homicide. There is some limited support for an effect of DUP length on serious violence or aggression. Violent behaviour frequently develops before the onset of first episode. Substance use disorders are additional factors that elevate the risk for violence in these patients. CONCLUSIONS: Earlier treatment of first episode psychosis might prevent some homicides. Personality factors and substance abuse may be more important than psychotic symptoms in the development of aggressive behaviour in patients with first-episode psychosis. PMID- 24471743 TI - Theoretical and experimental vibrational spectroscopic investigation of two R(1)R(2)-diphenylsilyl-containing monomers and their optically active derivative polymer. AB - FT-IR and Raman spectra of bis(4-aminophenyl)diphenylsilane (DIA) and a dicarboxylic acid containing the imide function and a L-alanine moiety (L-ALA) and their resultant polymer (PALA) were recorded in the 500-4000 cm(-1) and 400 3800 cm(-1) regions, respectively. The optically active poly(imide-amide) obtained has two sp(3) carbons in the main chain, favoring its flexibility. Raman analysis identifies the fluorescence produced by the electronic conjugation between the aromatic rings and the amidic groups, which affects the molecular fine structure. Thus, the theoretical study of the vibrational patterns has become a support and a complementary technique for the characterization of this fluorescent system. The optimized molecular geometry of the monomers and the polymeric unit using B3LYP and HF methods at the 6-31G(d) level of theory were used for the vibrational assignments. Thus, the small variations between the calculated and experimental vibration values could be related to possible intra- and/or intermolecular interactions or to the existence of a charge transfer phenomena between a donor or acceptor group within the system. PMID- 24471742 TI - Erythropoietin, a novel repurposed drug: an innovative treatment for wound healing in patients with diabetes mellitus. AB - Developing a new drug is expensive: the cost of going from bench to bedside is about $US1 billion. Therefore, the repurposing of an approved drug is potentially rewarding because it expands the drug's existing therapeutic profile and preempts additional development costs. As the safety profile of a repurposed drug is already well known, any new investigations could then focus on its efficacy and other therapeutic benefits. Recombinant erythropoietin (EPO) is a potential candidate for repurposing because the results of numerous studies have shown that systemic and topical EPO is therapeutically beneficial when it is administered to healthy and diabetic animals with acute and chronic skin wounds and burns. Moreover, the molecular mechanisms of EPO's actions have been elucidated: EPO acts on those nonhematopoietic cells which are involved in the innate immune response where it promotes cellular proliferation and differentiation, exerts its cytoprotective actions, and inhibits apoptosis. In this review, the mechanism of EPO's action in skin wound healing is reviewed, and its potential for treating acute and chronic skin wounds and stimulating tissue regeneration in diabetic patients is discussed. PMID- 24471744 TI - Bupropion effects on high-fat diet-induced steatohepatitis and endothelial dysfunction in rats: role of tumour necrosis factor-alpha. AB - OBJECTIVES: This study aimed to elucidate the effect of bupropion (BUP) on high fat diet (HFD)-treated rats that is to say the action of BUP on diabetes and hyperlipidemia with its consequences on liver and endothelial function. METHODS: Male Wistar rats were fed HFD or normal chow for 15 weeks then given either BUP (50 mg/kg) or distilled water by gavage for 4 weeks. The effect of BUP on diabetes, hyperlipidemia, hepatic and vascular functions as well as tumour necrosis factor-alpha (TNF)-alpha were assessed. The intima-media thickness of the aorta was evaluated. KEY FINDINGS: BUP significantly decreased serum lipid, liver enzyme, homeostasis model assessment for insulin resistance (HOMA-IR), serum TNF-alpha and the impaired glucose tolerance. Liver from rats with non alcoholic steatohepatitis (NASH) demonstrated significant higher TNF-alpha level, inflammatory cell infiltration, ballooning and steatosis which significantly ameliorated by BUP treatment. Neither intima/media ratio nor vascular reactivity to acetylcholine is improved by BUP treatment. CONCLUSIONS: NASH induced by a HFD was associated with hyperlipidemia, insulin resistance, endothelial dysfunction and increase in liver TNF-alpha. All of these may contribute to the pathogenesis of NASH. BUP has potential role in improving metabolic and hepatic function with negative vascular effect. Since BUP is a well-known antidepressant, it will be a candidate drug in treatment of depression in hepatic diseased or metabolic disturbed patients. PMID- 24471746 TI - Effects of sample handling methods on substance P concentrations and immunoreactivity in bovine blood samples. AB - OBJECTIVE: To determine the effects of protease inhibitors and holding times and temperatures before processing on the stability of substance P in bovine blood samples. SAMPLES: Blood samples obtained from a healthy 6-month-old calf. PROCEDURES: Blood samples were dispensed into tubes containing exogenous substance P and 1 of 6 degradative enzyme inhibitor treatments: heparin, EDTA, EDTA with 1 of 2 concentrations of aprotinin, or EDTA with 1 of 2 concentrations of a commercially available protease inhibitor cocktail. Plasma was harvested immediately following collection or after 1, 3, 6, 12, or 24 hours of holding at ambient (20.3 degrees to 25.4 degrees C) or ice bath temperatures. Total substance P immunoreactivity was determined with an ELISA; concentrations of the substance P parent molecule, a metabolite composed of the 9 terminal amino acids, and a metabolite composed of the 5 terminal amino acids were determined with liquid chromatography-tandem mass spectrometry. RESULTS: Regarding blood samples processed immediately, no significant differences in substance P concentrations or immunoreactivity were detected among enzyme inhibitor treatments. In blood samples processed at 1 hour of holding, substance P parent molecule concentration was significantly lower for ambient temperature versus ice bath temperature holding conditions; aprotinin was the most effective inhibitor of substance P degradation at the ice bath temperature. The ELISA substance P immunoreactivity was typically lower for blood samples with heparin versus samples with other inhibitors processed at 1 hour of holding in either temperature condition. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that blood samples should be chilled and plasma harvested within 1 hour after collection to prevent substance P degradation. PMID- 24471747 TI - Evaluation of thermal antinociceptive effects after oral administration of tramadol hydrochloride to American kestrels (Falco sparverius). AB - OBJECTIVE: To evaluate the thermal antinociceptive and sedative effects and duration of action of tramadol hydrochloride after oral administration to American kestrels (Falco sparverius). ANIMALS: 12 healthy 3-year-old American kestrels. PROCEDURES: Tramadol (5, 15, and 30 mg/kg) and a control suspension were administered orally in a masked randomized crossover experimental design. Foot withdrawal response to a thermal stimulus was determined 1 hour before (baseline) and 0.5, 1.5, 3, 6, and 9 hours after treatment. Agitation-sedation scores were determined 3 to 5 minutes before each thermal stimulus test. RESULTS: The lowest dose of tramadol evaluated (5 mg/kg) significantly increased the thermal foot withdrawal thresholds for up to 1.5 hours after administration, compared with control treatment values, and for up to 9 hours after administration, compared with baseline values. Tramadol at doses of 15 and 30 mg/kg significantly increased thermal thresholds at 0.5 hours after administration, compared with control treatment values, and up to 3 hours after administration, compared with baseline values. No significant differences in agitation-sedation scores were detected between tramadol and control treatments. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated oral administration of 5 mg of tramadol/kg significantly increased thermal nociception thresholds for kestrels for 1.5 hours, compared with a control treatment, and 9 hours, compared with baseline values; higher doses resulted in less pronounced antinociceptive effects. Additional studies with other types of stimulation, formulations, dosages, routes of administration, and testing times would be needed to fully evaluate the analgesic and adverse effects of tramadol in kestrels and other avian species. PMID- 24471748 TI - Use of Monte Carlo simulation to determine pharmacodynamic cutoffs of amoxicillin to establish a breakpoint for antimicrobial susceptibility testing in pigs. AB - OBJECTIVE: To determine pharmacodynamic cutoffs with pharmacokinetic pharmacodynamic principles and Monte Carlo simulation (MCS) for use of amoxicillin in pigs to set interpretive criteria for antimicrobial susceptibility testing. SAMPLE: 191 plasma disposition curves of amoxicillin obtained from 21 IV, 104 IM, and 66 PO administrations corresponding to 2,098 plasma concentrations. PROCEDURES: A population model of amoxicillin disposition in pigs was developed for PO and IM administration. The MCS method was then used to determine, for various dosage regimens, the proportion of pigs achieving plasma amoxicillin concentrations greater than a selection of possible minimal inhibitory concentrations (MICs) ranging from 0.0625 to 4 mg/L for at least 40% of a 24-hour period. RESULTS: A target attainment rate (TAR) of 90% was never achieved with the breakpoint recommended by the Clinical and Laboratory Standards Institute (0.5 mg/L) when the usual recommended dosage (20 mg/kg/d) was used. Only by dividing the orally administered daily dose into 12-hour administration intervals was a TAR > 90% achieved when the total dose was at least 40 mg/kg for a pathogen having an MIC <= 0.0625 mg/L. For the IM route, the TAR of 90% could only be achieved for MICs of 0.0625 and 0.125 mg/L with the use of 15 and 30 mg/kg doses, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Population kinetics and MCS are required to determine robust species-specific interpretive criteria (susceptible, intermediate, and resistant classifications) for antimicrobial susceptibility testing breakpoints (taking into account interanimal variability). PMID- 24471749 TI - Effects of interleukin-6 and interleukin-1beta on expression of growth differentiation factor-5 and Wnt signaling pathway genes in equine chondrocytes. AB - OBJECTIVE: To determine the effects of interleukin (IL)-6 and IL-1beta stimulation on expression of growth differentiation factor (GDF)-5 and Wnt signaling pathway genes in equine chondrocytes. SAMPLE: Macroscopically normal articular cartilage samples from 6 horses and osteochondral fragments (OCFs) from 3 horses. PROCEDURES: Chondrocyte pellets were prepared and cultured without stimulation or following stimulation with IL-6 or IL-1beta for 1, 2, 12, and 48 hours; expression of GDF-5 was determined with a quantitative real-time PCR assay. Expression of genes in various signaling pathways was determined with microarrays for pellets stimulated for 1 and 2 hours. Immunohistochemical analysis was used to detect GDF-5, glycogen synthase kinase 3beta (GSK-3beta), and beta-catenin proteins in macroscopically normal cartilage samples and OCFs. RESULTS: Chondrocytes stimulated with IL-6 had significantly higher GDF-5 expression within 2 hours versus unstimulated chondrocytes. Microarray analysis of Wnt signaling pathway genes indicated expression of GSK-3beta and coiled-coil domain containing 88C increased after 1 hour and expression of beta-catenin decreased after 2 hours of IL-6 stimulation. Results of immunohistochemical detection of proteins were similar to microarray analysis results. Chondrocytes in macroscopically normal articular cartilage and OCFs had immunostaining for GDF 5. CONCLUSION AND CLINICAL RELEVANCE: Results indicated IL-6 stimulation decreased chondrocyte expression of the canonical Wnt signaling pathway transactivator beta-catenin, induced expression of inhibitors of the Wnt pathway, and increased expression of GDF-5. This suggested IL-6 may inhibit the Wnt signaling pathway with subsequent upregulation of GDF-5 expression. Anabolic extracellular matrix metabolism in OCFs may be attributable to GDF-5 expression. This information could be useful for development of cartilage repair methods. PMID- 24471750 TI - Evaluation of a single intra-articular injection of autologous protein solution for treatment of osteoarthritis in horses. AB - OBJECTIVE: To evaluate intra-articular autologous protein solution (APS) for the treatment of osteoarthritis in horses. Animals-40 client-owned horses with naturally occuring osteoarthritis. PROCEDURES: APS was generated from a dual device system that concentrated plasma and WBC proteins and enriched platelet growth factors. Horses were randomly assigned to receive an intra-articular injection of 5 mL of saline (0.9% NaCl) solution (n = 20) or APS (20), exercised on a treadmill, and evaluated on the basis of lameness grades, kinetic gait analysis, joint circumference, and range of motion for 14 days. Horses that received saline solution were administered APS at termination of the study, and clients scored horses for lameness and discomfort before, 12 weeks after, and 52 weeks after the APS injection. RESULTS: The APS group had significant improvements in lameness grade, asymmetry indices of vertical peak force, and range of joint motion by 14 days, compared with baseline or control group values. No adverse effects associated with APS treatment were evident. Clients assessed lameness and comfort as improved at 12 and 52 weeks. The APS had greater likelihood (OR, 4.3 to 30.0) of a therapeutic response in horses with a lameness score < 4, < 10% vertical force asymmetry, or absence of marked osteophyte formation, subchondral sclerosis, or joint space narrowing. Concentration of interleukin-1 receptor antagonist in APS was 5.8 times that in blood. CONCLUSIONS AND CLINICAL RELEVANCE: Intra-articular administration of APS can be considered an effective treatment option for equine osteoarthritis, with the potential for disease-modifying effects. PMID- 24471751 TI - Effects of pentoxifylline on immediate and late-phase cutaneous reactions in response to anti-immunoglobulin E antibodies in clinically normal dogs. AB - OBJECTIVE: To characterize the effects of pentoxifylline on the gross and microscopic variables associated with immediate and late-phase inflammation following injection of IgE-specific antibodies in the skin of clinically normal dogs. ANIMALS: 6 healthy adult mixed-breed dogs. PROCEDURES: Intradermal injections (0.1 mL each) of PBS solution, histamine phosphate, and cross-linking rabbit-origin anti-canine IgE antibodies (3 injections/dog) were administered at 0 hours on day 0; wheal sizes were evaluated at 20 minutes, 6 hours, and 24 hours. Biopsy specimens of injected and noninjected skin were collected 24 hours after injection. On day 2, treatment with pentoxifylline (20 mg/kg, PO, q 8 h) was initiated and continued until day 30. For each dog, injection, measurement, and biopsy procedures were repeated on days 30 to 31 and on days 37 to 38 (ie, after discontinuation of pentoxifylline administration). RESULTS: Pentoxifylline administration was associated with a significant decrease in wheal size at 6 and 24 hours (but not at 20 minutes) after injection of anti-canine IgE. Repeated injections performed 1 week after drug discontinuation revealed partial recovery of the 6-hour cutaneous reaction and complete recovery of the 24-hour cutaneous reaction. Pentoxifylline administration was also associated with inhibition of mast cell degranulation and significant decreases in the total numbers of cutaneous inflammatory cells and eosinophils, compared with pretreatment findings. CONCLUSIONS AND CLINICAL RELEVANCE: In clinically normal dogs, pentoxifylline effectively impaired late-phase reactions but not immediate reactions at sites of intradermal injection of IgE-specific antibodies by inhibiting mast cell degranulation and recruitment of cutaneous inflammatory cells, especially eosinophils. PMID- 24471752 TI - Morphological and cellular changes in secondary epidermal laminae of horses with insulin-induced laminitis. AB - OBJECTIVE: To determine cellular changes associated with secondary epidermal laminae (SEL) in forefeet and hind feet of ponies with insulin-induced laminitis. ANIMALS: 8 ponies. PROCEDURES: Laminitis was induced in 4 ponies by IV administration of insulin and glucose; 4 control ponies received saline (0.9% NaCl) solution IV. Laminar tissue samples obtained from the dorsal aspects of the hooves were histologically evaluated. Primary epidermal lamina (PEL) length and width and SEL length, width, and angle were determined. Numbers of epidermal cell nuclei per micrometer and per total length of SEL and numbers of apoptotic and proliferative cells in axial, middle, and abaxial laminar regions were determined. RESULTS: SEL in treatment group ponies were significantly longer, were significantly narrower, and had a smaller angle relative to PEL in all laminar regions versus control ponies. In treatment group ponies, the number of epidermal cell nuclei per SEL was typically higher and the number of cells per micrometer of SEL was lower in laminar regions, apoptotic cell numbers were higher in abaxial and middle regions in forefeet and hind feet, and proliferating cell numbers were higher in axial laminar regions in forefeet and all laminar regions in hind feet, versus control ponies. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated SEL elongation, narrowing, and alteration in orientation developed in all feet of ponies with insulin-induced laminitis. This was primarily attributable to cell stretching that developed at the same time as an accelerated cell death-proliferation cycle; differences in cell cycle responses among laminar regions between forefeet and hind feet may have been attributable to differences in load bearing. PMID- 24471753 TI - Characteristics of respiratory tract disease in horses inoculated with equine rhinitis A virus. AB - OBJECTIVE: To develop a method for experimental induction of equine rhinitis A virus (ERAV) infection in equids and to determine the clinical characteristics of such infection. ANIMALS: 8 ponies (age, 8 to 12 months) seronegative for antibodies against ERAV. PROCEDURES-Nebulization was used to administer ERAV (strain ERAV/ON/05; n = 4 ponies) or cell culture medium (control ponies; 4) into airways of ponies; 4 previously ERAV-inoculated ponies were reinoculated 1 year later. Physical examinations and pulmonary function testing were performed at various times for 21 days after ERAV or mock inoculation. Various types of samples were obtained for virus isolation, blood samples were obtained for serologic testing, and clinical scores were determined for various variables. RESULTS: ERAV-inoculated ponies developed respiratory tract disease characterized by pyrexia, nasal discharge, adventitious lung sounds, and enlarged mandibular lymph nodes. Additionally, these animals had purulent mucus in lower airways up to the last evaluation time 21 days after inoculation (detected endoscopically). The virus was isolated from various samples obtained from lower and upper airways of ERAV-inoculated ponies up to 7 days after exposure; this time corresponded with an increase in serum titers of neutralizing antibodies against ERAV. None of the ponies developed clinical signs of disease after reinoculation 1 year later. CONCLUSIONS AND CLINICAL RELEVANCE: Results of this study indicated ERAV induced respiratory tract disease in seronegative ponies. However, ponies with neutralizing antibodies against ERAV did not develop clinical signs of disease when reinoculated with the virus. Therefore, immunization of ponies against ERAV could prevent respiratory tract disease attributable to that virus in such animals. PMID- 24471754 TI - Regional variations and age-related changes detected with magnetic resonance spectroscopy in the brain of healthy dogs. AB - OBJECTIVE: To investigate age-related and regional differences in estimated metabolite concentrations in the brain of healthy dogs by means of magnetic resonance spectroscopy (MRS). ANIMALS: 15 healthy Beagles. PROCEDURES: Dogs were grouped according to age as young (n = 5; all dogs were 2 months old), adult (5; mean age, 4.5 years), or geriatric (5; all dogs were 12 years old). Imaging was performed by use of a 1.5-T MRI system with T1- and T2-weighted spin-echo and fluid-attenuated inversion recovery sequences. Signal intensity measurements for N-acetyl aspartate, creatine, choline, and lactate-alanine (the spectroscopic peaks associated with alanine and lactate could not be reliably differentiated) were determined with MRS, and areas under the spectroscopic peaks (representing concentration estimates) were calculated. Ratios of these metabolite values were compared among age groups and among brain regions with regression analysis. RESULTS: The choline-to-creatine ratio was significantly higher in young dogs, compared with other age groups. The N-acetyl aspartate-to-choline ratio was significantly lower in young dogs and geriatric dogs than in adult dogs. When all age groups were considered, the choline-to-creatine ratio was significantly higher and N-acetyl aspartate-to-choline ratio was significantly lower in the frontal lobe than in all other regions. The N-acetyl aspartate-to-creatine ratio was significantly lower in the cerebellum than in other regions. CONCLUSIONS AND CLINICAL RELEVANCE: Metabolite ratios varied significantly among age groups and brain regions in healthy dogs. Future studies should evaluate absolute concentration differences in a larger number of dogs and assess clinical applications in dogs with neurologic diseases. PMID- 24471755 TI - Assessment of folate receptor expression and folate uptake in multicentric lymphomas in dogs. AB - OBJECTIVE: To determine expression of folate receptors (FRs) and folate uptake in multicentric lymphomas in dogs. SAMPLE: 10 dogs with histopathologically confirmed multicentric lymphoma and 20 archival lymph node biopsy specimens from dogs with multicentric lymphoma. PROCEDURES: Multicentric lymphomas in 10 dogs were prospectively evaluated for FR expression by use of immunohistochemical analysis and for in vivo folate uptake by use of nuclear scintigraphy. Dogs with FR-expressing tumors were eligible for FR-targeted chemotherapy. Twenty archival lymphoma biopsy specimens were also evaluated with immunohistochemical analysis. RESULTS: FRs were not detected with immunohistochemical analysis in lymph node samples obtained from the 10 dogs or in archival biopsy specimens. However, nuclear scintigraphy revealed uptake of radioactive tracer in 6 of 10 dogs. Five of these 6 dogs were treated with an FR-targeted chemotherapeutic agent; results of treatment were complete remission in 1 dog, stable disease in 2 dogs, and progressive disease in 2 dogs. Treatment-related toxicoses generally were mild. CONCLUSIONS AND CLINICAL RELEVANCE: This study provided strong evidence for folate uptake in a substantial portion of multicentric lymphomas of dogs and indicated the antitumor activity of FR-targeted chemotherapeutics for these cancers. Use of FR-targeted chemotherapeutics may be promising for the treatment of FR-expressing multicentric lymphomas in dogs. Further studies are needed to determine reasons for lack of immunoreactivity to currently identified anti-FR antibodies and to develop improved methods for detecting FRs in lymphomas of dogs. PMID- 24471756 TI - Pharmacokinetics of meloxicam administered orally to rabbits (Oryctolagus cuniculus) for 29 days. AB - OBJECTIVE: To determine the pharmacokinetics and safety of meloxicam in rabbits when administered orally for 29 days. ANIMALS: 6 healthy rabbits. PROCEDURES: Meloxicam (1.0 mg/kg, PO, q 24 h) was administered to rabbits for 29 days. Blood was collected immediately before (time 0) and 2, 4, 6, 8, and 24 hours after drug administration on days 1, 8, 15, 22, and 29 to evaluate the pharmacokinetics of meloxicam. On day 30, an additional sample was collected 36 hours after treatment. Plasma meloxicam concentrations were quantified with liquid chromatography-mass spectrometry, and noncompartmental pharmacokinetic analysis was performed. Weekly plasma biochemical analyses were performed to evaluate any adverse physiologic effects. Rabbits were euthanatized for necropsy on day 31. RESULTS: Mean +/- SD peak plasma concentrations of meloxicam after administration of doses 1, 8, 15, 22, and 29 were 0.67 +/- 0.19 MUg/mL, 0.81 +/- 0.21 MUg/mL, 1.00 +/- 0.31 MUg/mL, 1.00 +/- 0.29 MUg/mL, and 1.07 +/- 0.19 MUg/mL, respectively; these concentrations did not differ significantly among doses 8 through 29. Results of plasma biochemical analyses were within reference ranges at all time points evaluated. Gross necropsy and histologic examination of tissues revealed no clinically relevant findings. CONCLUSIONS AND CLINICAL RELEVANCE: Plasma concentrations of meloxicam for rabbits in the present study were similar to those previously reported in rabbits that received 1. 0 mg of meloxicam/kg, PO every 24 hours, for 5 days. Results suggested that a dosage of 1. 0 mg/kg, PO, every 24 hours for up to 29 days may be safe for use in healthy rabbits. PMID- 24471757 TI - Associations of various physical and blood analysis variables with experimentally induced Mycoplasma bovis pneumonia in calves. AB - OBJECTIVE: To determine associations of blood analysis variables and orbit and nasal planum surface temperatures with the onset and severity of Mycoplasma bovis pneumonia in calves. Animals-28 healthy calves. PROCEDURES: Calves were challenged with M bovis (n = 24) on day 0 or not challenged (4). Blood samples were obtained for cardiac troponin I, CBC, and serum biochemical analyses on various days. Orbit and nasal planum surface temperatures were determined with infrared thermography on various days. Calves were euthanized, gross necropsies were performed, heart and lung samples were collected for histologic evaluation, and microbial cultures of lung samples were performed on day 14. Pneumonia severity was categorized as mild (< 10% lung consolidation) or moderate (>= 10% lung consolidation). Associations between measured variables and severity of pneumonia or sample collection day were determined. RESULTS: Plasma cardiac troponin I concentration for the 28 calves was significantly higher on day 14 than it was on day 0 or 7 (least squares mean, 0.02, 0, and 0 ng/mL, respectively). No other variables changed significantly during the study. No substantial gross or histologic abnormalities were identified in cardiac muscle samples. Day 14 plasma fibrinogen concentration was significantly different between calves with mild pneumonia and those with moderate pneumonia (mean, 0.44 and 0.74 g/dL, respectively). Calves with moderate pneumonia had significantly lower least squares mean surface temperature of the dorsal aspect of the nasal planum (18.7 degrees C) versus calves with mild pneumonia (22.9 degrees C). CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated the evaluated variables had low value for assessment of bovine respiratory disease complex in calves. PMID- 24471758 TI - An unusual repressor controls the expression of a crucial nicotine-degrading gene cluster in Pseudomonas putida S16. AB - Transcriptional factors that contain helix-turn-helix (HTH) DNA-binding domains are widespread in bacteria for regulating gene expression on demand, and function as homodimers that bind a palindromic DNA segment. Here, we show that an HTH containing transcriptional regulator, NicR2, in Pseudomonas putida S16 plays a critical role in controlling the expression of a crucial gene cluster (nic2) in nicotine degradation, and NicR2 binds DNA in a manner different from most other DNA-binding proteins that use HTHs for recognition. Electrophoretic mobility shift assay (EMSA) and DNase I footprinting indicate that NicR2 directly interacts with a 28 bp inverted repeat (IR) in the nic2 promoter region. Using EMSA with synthetic DNA fragments, we found that both NicR2 dimer and tetramer can bind to the half-site of the IR. This is confirmed independently by biolayer interferometry and cross-linking experiments. Our results indicate that two NicR2 dimers bind to the IR cooperatively through protein-protein interactions, with each dimer binding the half-site of the IR. Thus, NicR2 appears to be an unusual regulator, which uses HTH for recognition and displays the binding characteristics of some regulators that use beta-sheets. The transcriptional regulation of nicotine degradation in Pseudomonas highlights a new level of complexity in prokaryotic transcriptional regulation. PMID- 24471759 TI - Chiral and isotope analyses for assessing the degradation of organic contaminants in the environment: Rayleigh dependence. AB - The Rayleigh equation is frequently used to describe isotope fractionation as a function of conversion. In this article we propose to draw a parallel between isotope and enantiomeric enrichments and derive a set of conditions that allow the use of the Rayleigh approach to describe the enantiomeric enrichment conversion dependencies. We demonstrate an implementation of the Rayleigh equation for the enantioselective enzymatic hydrolysis of Mecoprop-methyl, Dichlorprop-methyl, and dimethyl-methylsuccinate by lipases from Pseudomonas fluorescens, Pseudomonas cepacia, and Candida rugosa. The data obtained for all the studied reactions gave good fits to the Rayleigh equation, with a linear regression R(2) > 0.96. In addition to that, our analysis of four microcosm studies on the hydrolysis of the individual enantiomers of Dichloroprop methyl, Lactofen, Fenoxaprop-ethyl, and Metalaxyl reported in the literature by other research groups revealed a suitability of the Rayleigh dependence. Two dimensional plots describing the isotope fractionation versus enantiomeric enrichment are demonstrated for all studied cases. Processes not accompanied by enantiomeric enrichment (acid and base hydrolysis) and by isotope enrichment (transesterification) are demonstrated, their 2-D plots are either horizontal or vertical which can illuminate concealed degradation pathways. PMID- 24471761 TI - Animal protein intake at 12 months is associated with growth factors at the age of six. AB - AIM: To study the associations between protein intake from different sources with anthropometry and serum insulin-like growth factor 1 (IGF-1) in infancy and childhood. METHODS: Children (n = 199) born in Iceland were followed up to six years of age. Their intake of various animal proteins and vegetable protein was calculated from weighed food records at 12 months and 6 years. Information about their weight and height at birth, 12 and 18 months, and 6 years was gathered. Serum IGF-1 was measured at 12 months and 6 years. RESULTS: At the age of six, children in the highest quartile for animal protein intake at 12 months (>=12.2% of total energy) had 0.8 kg/m(2) (95% CI = 0.1, 1.5) higher body mass index (BMI) than children in the lowest quartile (<7.6% of total energy). They were also heavier and longer in infancy and childhood. At 12 months, dairy protein intake as a percentage of total energy was associated with IGF-1 in six-year-old girls, beta = 5.4 MUg/L (95% CI = 2.5, 8.2). CONCLUSION: High animal protein intake in infancy, but not vegetable protein intake, was associated with accelerated growth and higher BMI in childhood. Dairy protein intake in infancy may be positively associated with linear growth and also with IGF-1 in six-year-old girls. PMID- 24471763 TI - Evaluation of ABCG2 and p63 expression in canine cornea and cultivated corneal epithelial cells. AB - OBJECTIVE: To examine the expressions of ABCG2 and p63 in canine corneal epithelia and to evaluate their significance in corneal regeneration. PROCEDURES: Canine corneal and limbal epithelial cells were obtained from five healthy beagle dogs. We analyzed the morphological properties of cultivated limbal and corneal epithelial cells. We compared the expressions of ABCG2 and p63 in the limbus and central cornea by immunohistochemistry and real-time quantitative PCR. We analyzed the expression of these markers in cultivated cells by immunocytochemistry and real-time quantitative PCR. RESULTS: The limbal epithelial cells were smaller and proliferated more rapidly than the corneal epithelial cells in primary cultures. The corneal cells failed to be subcultured, whereas the limbal cells could be subcultured with increasing cell size. ABCG2 was localized in the basal layer of the limbal epithelium, and p63 was widely detected in the entire corneal epithelia. ABCG2 expression was significantly higher, and p63 was slightly higher in the limbus compared with the central cornea. ABCG2 was detected only in limbal cells in primary culture, not in corneal cells or passaged limbal cells. p63 was detected in both limbal and corneal cells and decreased gradually in the limbal cells with the cell passages. CONCLUSIONS: ABCG2 was localized in canine limbal epithelial cells, and p63 was widely expressed in canine corneal epithelia. ABCG2 and p63 could prove to be useful markers in dogs for putative corneal epithelial stem cells and for corneal epithelial cell proliferation, respectively. PMID- 24471764 TI - Potential of capsaicin-loaded transfersomes in arthritic rats. AB - In the present study, the biopotential of capsaicin (an active principle of capsicum) as a topical antiarthritic agent was studied in arthritic rats. Transfersomal vesicular system was employed for the topical administration of capsaicin in experimental rats. The characterization of prepared capsaicin-loaded transfersomes reveals their nano size (94 nm) with negative surface charge (-14.5 mV) and sufficient structural flexibility, which resulted in 60.34% entrapment efficacy, penetration across the biomembrane (220 um) and 76.76% of drug release from vesicular system in 24 h in their intact form as evident from confocal laser scanning micrographic study. Results of transfersomal nanoformulation (capsaicin loaded, test) were compared with that of conventional gel formulation available in the market (Thermagel, standard), with an aim to assess the antiarthritic efficacy of our prepared capsaicin-loaded transfersomal formulation. In vivo antiarthritic activity study shows that our formulation possesses superior inhibitory activity than the marketed Thermagel formulation at the same dosage level, which could probably be due to the lesser permeability of Thermagel across the dermal barriers compared to our specially designed transfersomal delivery system. Moreover, the better tolerance of prepared vesicular formulation in biological system further enlightens the suitability of the transfersomal vesicle to be used as a novel carrier system for the topical administration of such highly irritant substance. PMID- 24471766 TI - Solution structures of lithium amino alkoxides used in highly enantioselective 1,2-additions. AB - Lithium ephedrates and norcarane-derived lithium amino alkoxides used to effect highly enantioselective 1,2-additions on large scales have been characterized in toluene and tetrahydrofuran. The method of continuous variations in conjunction with (6)Li NMR spectroscopy reveals that the lithium amino alkoxides are tetrameric. In each case, low-temperature (6)Li NMR spectra show stereoisomerically pure homoaggregates displaying resonances consistent with an S4-symmetric cubic core rather than the alternative D2d core. These assignments are supported by density functional theory computations and conform to X-ray crystal structures. Slow aggregate exchanges are discussed in the context of amino alkoxides as chiral auxiliaries. PMID- 24471765 TI - Luteolin is effective in the non-small cell lung cancer model with L858R/T790M EGF receptor mutation and erlotinib resistance. AB - BACKGROUND AND PURPOSE: Non-small cell lung cancer (NSCLC) is one of the most commonly diagnosed malignancies in the world. Small-molecule inhibitors of the EGF receptor's tyrosine kinase domain (TKIs), including gefitinib and erlotinib, have been widely used for treating NSCLC. Unfortunately, nearly all patients after initially experiencing a marked improvement while on these drugs, eventually progress to acquire resistance to TKIs. Because there is no effective therapeutic strategy to treat TKI-resistant NSCLC, we evaluated the effects of luteolin, a naturally occurring flavanoid, on T790M mutant NSCLC cells. EXPERIMENTAL APPROACH: The effect of luteolin on the viability of NSCLC and normal cell lines was investigated using the Cell Counting Kit-8 (CCK-8) assay. Luteolin-induced apoptosis was assessed by bivariate FITC-annexin V/PI assay, and Western blots were used to measured apoptotic proteins. Co-immunoprecipitation was used to determine the effect of luteolin on the interaction between Hsp90 and mutant EGF receptors. The effect of luteolin on the Akt/mTOR pathway was studied using Western blotting analysis. Its anti-tumour efficacy in vivo was examined in a mouse xenograft model. KEY RESULTS: Luteolin exerted significant anti tumourigenic effects on the EGF receptor L858R/T790M mutation and erlotinib resistant NSCLC both at the cellular and animal levels. Mechanistically, luteolin induced degradation of the EGF receptor by inhibiting the association of Hsp90 with the mutant EGF receptor, and, therefore, prevented PI3K/Akt/mTOR signalling, which resulted in NSCLC cell apoptosis. CONCLUSION AND IMPLICATIONS: Luteolin may be a potential candidate for NSCLC therapy, especially for treatment of patients with acquired erlotinib-resistant NSCLC. PMID- 24471767 TI - Dual-porosity hollow nanoparticles for the immunoprotection and delivery of nonhuman enzymes. AB - Although enzymes of nonhuman origin have been studied for a variety of therapeutic and diagnostic applications, their use has been limited by the immune responses generated against them. The described dual-porosity hollow nanoparticle platform obviates immune attack on nonhuman enzymes paving the way to in vivo applications including enzyme-prodrug therapies and enzymatic depletion of tumor nutrients. This platform is manufactured with a versatile, scalable, and robust fabrication method. It efficiently encapsulates macromolecular cargos filled through mesopores into a hollow interior, shielding them from antibodies and proteases once the mesopores are sealed with nanoporous material. The nanoporous shell allows small molecule diffusion allowing interaction with the large macromolecular payload in the hollow center. The approach has been validated in vivo using l-asparaginase to achieve l-asparagine depletion in the presence of neutralizing antibodies. PMID- 24471768 TI - Hb Ashburton [beta12(A9)Thr -> Pro; HBB: c.37A > C], a novel, mildly unstable variant and the first substitution identified at codon 12. AB - We report the identification of a novel, slightly unstable hemoglobin (Hb) variant [beta12(A9)Thr -> Pro; HBB: c.37A > C] that came to our attention during Hb A1C ion exchange chromatography where it migrated as a trailing shoulder on the Hb A0 peak. On electrospray ionization mass spectrometry (ESI MS), this electrophoretically silent variant was detected as an unresolved beta component with a 2 Da decrease in average beta chain mass. Reversed phase high performance liquid chromatography (HPLC) confirmed the presence of a more hydrophilic beta chain with a mass 4 Da less than normal beta(A) and showed it represented 40.0% of the total beta-globin. Tryptic mapping revealed the [M + 1H] ion of peptide betaT-2 had shifted from 932.5 to 928.5 m/z, suggesting a point mutation of Thr > Pro at position beta12(A9). This substitution was confirmed by fragmentation analysis of the [M + 2H] ion (464.8 m/z) of the new betaT-2 peptide and it represents a novel mutation which we have named Hb Ashburton. PMID- 24471769 TI - Effect of Implant Height Differences on Different Attachment Types and Peri Implant Bone in Mandibular Two-Implant Overdentures: 3D Finite Element Study. AB - Implant-supported overdentures with self-aligning attachment systems are preferred to improve the stability and retention of complete dentures. The positioning of the implant attachments is a very important aspect of two-implant overdentures in obtaining better stress distribution. Therefore, the objective of this study was to compare two different attachment systems in a two-implant overdenture by evaluating the stress distributions in peri-implant bone and stresses on the attachments with positioning at different height levels using the 3D FEA method. Six models with ball attachments and 6 models with locator attachments-totaling 12 models (including 2 controls)-with the left implant positioned unilaterally at different height levels were subjected to 3 loading conditions (anterior, right posterior, and left posterior). Data for Von Misses stresses were produced numerically, color coded, and compared among the models for attachments and peri-implant cortical bone. The configurations in which implants presented 3 mm height differences in the bone level showed the most successful results in the peri-implant bone. When stresses on the attachments were compared, greater stress values were obtained from the ball attachments. As a conclusion, the configurations with a considerable (3 mm) height difference between quadrants of the mandible in the anterior segment showed the most successful results in the peri-implant bone. On the contrary, peak stress values around the implant observed from the models with less (1 mm) bone height difference may require leveling of the bone during surgery. However, these findings should be corroborated with clinical studies. PMID- 24471770 TI - Peak aggregation as an innovative strategy for improving the predictive power of LC-MS metabolomic profiles. AB - Liquid chromatography-mass spectrometry (LC-MS)-based metabolomic datasets consist of different features including (de)protonated molecules, fragments, adducts, and isotopes that may show high correlation values related to a high level of collinearity. There have been described several sources of these high correlation patterns regarding metabolomic datasets. Among these sources, it should be highlighted the high level of correlation computed between features coming from the same metabolite. It is well-known that soft ionization methods (such as electrospray) produce several mass features from a particular compound (i.e., metabolite spectrum). Typically, the statistical methods used in metabolomics consider spectral peaks as variables. However, it has been reported that a high collinearity between variables might be the responsible for high uncertainty values in the predictors of a regression. In this context, this technical note proposes a new strategy based on the application of the so-called peak aggregation methods (NMF Reduction, PCA Decomposition, Maximum Peak, and Spectrum Mean) to take advantage of the variable collinearity and solve the issue of high variable collinearity. A set of real samples obtained after human nutritional intervention with placebo or polyphenol-rich beverages was used to test this methodology. The results showed that applying any peak aggregation method (especially NMF and PCA) improves the statistical prediction power of class pertinence independently of the nature of the classifier (linear PLS-DA or nonlinear SVM). Overall, the introduction of this new approach resulted in a reduction of the dimensionality of the data and, in addition, in a significant increase in the overall predictive power of the data. PMID- 24471772 TI - Resveratrol and vitamin E rescue valproic acid-induced teratogenicity: the mechanism of action. AB - 1. Valproic acid (VPA) induces haemorrhagic liposis of the cervical muscles in the chicken embryo model (CEM). Vitamin E and resveratrol (RV) exhibit prominent anti-oxidative and glutathione (GSH)-protecting effects. 2. In the present study we hypothesized that vitamin E and RV would ameliorate VPA induced haemorrhagic liposis in chick embryos. To this end, 120 Day 0 fertilized eggs were divided into 10 groups (n = 12 in each). The effects of different combinations of VPA (60 mmol/L), RV (0.2 and 2.0 mmol/L) and vitamin E (0.2 and 2.0 mmol/L) applied to Hamburger and Hamilton (HH) Stage 10 (Day 1.5) embryos were tested in the CEM using established methods. 3. Both RV and vitamin E (both at 2.0 mmol/L) effectively rescued neural tube defects in the early stage CEM and inhibited the malformation rate compared with that in the control group (8.4% and 5.0% vs 36.5 +/- 3.0%, respectively; P < 0.05) and suppressed serum homocysteine and S adenosylhomocysteine concentrations, downregulated cervical muscular carnitine, triglycerides, H2 O2 , malondialdehyde, interleukin-6 and ACC expression (P < 0.05 for all) and upregulated CPT1 expression and GSH (P < 0.05 for both). 4. The haemorrhagic liposis of cervical muscles can be alleviated by RV and vitamin E. It appears that the main mechanism of action of RV and vitamin E in rescuing VPA induced teratogenicity is through the suppression of reactive oxygen species and upregulation of GSH. PMID- 24471773 TI - Huntingtin gene CAG repeat numbers in Chinese patients with Huntington's disease and controls. AB - BACKGROUND AND PURPOSE: Huntington's disease is due to a CAG triplet repeat elongation in the huntingtin gene. Boundaries in CAG numbers have been found between healthy people with and without risk to pass the disorder to the next generation, and between people without, with a mild, or with a fully penetrant phenotype. These data have been generated in western populations and it is not clear whether they are also valid amongst Chinese. METHODS: In order to establish normative data in the huntingtin gene for Chinese people, 966 chromosomes from normal controls were tested. Further, the range of CAG repeats was examined in a cohort from six centres and a total of 368 patients with the disease were included. RESULTS: The CAG triplet repeat range in normal controls was between 9 and 35 (mean 18.9, SD 2.57). Triplets in the range between 26 and 35 were found in 2.5%. In the patient cohort, triplet repeats in the shorter allele were between 8 and 37 (mean 17.7, SD 1.6). In the longer allele, a range between 36 and 120 was found. There was a negative correlation (-0.65, r = 0.42) between age at onset and the number of triplet repeats in the larger allele. The mean age at onset was 38 years, with a range between 2 and 70 years. In 23 patients (6%) a childhood or juvenile onset was noted. CONCLUSION: These data show comparable ranges of huntingtin gene CAG triplet repeats in normal people and in patients with Huntington's disease as in western populations. PMID- 24471774 TI - Seed dispersal in time can counteract the effect of gene flow between natural populations of Arabidopsis thaliana. AB - Plants may escape unfavorable environments by dispersing to new sites, or by remaining in an ungerminated state at a given site until environmental conditions become favorable. There is limited evidence regarding the occurrence, interplay and relative importance of dispersal processes in time and space in plant populations. Thirty-six natural populations of the annual ruderal species Arabidopsis thaliana were monitored over five consecutive years, sampling both seed bank and above-ground cohorts. We show that immigration rates are considerably higher than previously inferred, averaging 1.7% per population yr( 1). On the other hand, almost one-third of the individuals in a given above ground cohort result from seeds shed 2 or 3 yr back in time in 10 of the studied populations. Populations that disappeared one year were recolonized by regeneration from the seed bank the subsequent year. Thus, dispersal in both time and space is an important contributor to the structuring of genetic variability in natural populations of A. thaliana, where a high dispersal rate in time may partly counteract the homogenizing effects of spatial seed and pollen dispersal. PMID- 24471775 TI - Application of a high-efficiency cabin air filter for simultaneous mitigation of ultrafine particle and carbon dioxide exposures inside passenger vehicles. AB - Modern passenger vehicles are commonly equipped with cabin air filters but their filtration efficiency for ultrafine particle (UFP) is rather low. Although setting the vehicle ventilation system to recirculation (RC) mode can reduce in cabin UFPs by ~ 90%, passenger-exhaled carbon dioxide (CO2) can quickly accumulate inside the cabin. Using outdoor air (OA) mode instead can provide sufficient air exchange to prevent CO2 buildup, but in-cabin UFP concentrations would increase. To overcome this dilemma, we developed a simultaneous mitigation method for UFP and CO2 using high-efficiency cabin air (HECA) filtration in OA mode. Concentrations of UFP and other air pollutants were simultaneously monitored in and out of 12 different vehicles under 3 driving conditions: stationary, on local roadways, and on freeways. Under each experimental condition, data were collected with no filter, in-use original equipment manufacturer (OEM) filter, and two types of HECA filters. The HECA filters offered an average in-cabin UFP reduction of 93%, much higher than the OEM filters (~ 50% on average). Throughout the measurements, the in-cabin CO2 concentration remained in the range of 620-930 ppm, significantly lower than the typical level of 2500-4000 ppm observed in the RC mode. PMID- 24471776 TI - Simvastatin inhibits transforming growth factor-beta1-induced expression of type I collagen, CTGF, and alpha-SMA in keloid fibroblasts. AB - Simvastatin, a 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibitor, is used to reduce cholesterol levels. Accumulating evidence has revealed the immunomodulatory and anti-inflammatory effects of simvastatin that prevent cardiovascular diseases. In addition, the beneficial effects of statins on fibrosis of various organs have been reported. However, the functional effect of statins on dermal fibrosis of keloids has not yet been explored. The objective of this study was to determine whether simvastatin could affect dermal fibrosis associated with keloids. We examined the effect of simvastatin on transforming growth factor (TGF)-beta1-induced production of type I collagen, connective tissue growth factor (CTGF or CCN2), and alpha-smooth muscle actin (alpha-SMA). Keloid fibroblasts were cultured and exposed to different concentrations of simvastatin in the presence of TGF-beta1, and the effects of simvastatin on TGF beta1-induced collagen and CTGF production in keloid fibroblasts were determined. The type I collagen, CTGF, and alpha-SMA expression levels and the Smad2 and Smad3 phosphorylation levels were assessed by Western blotting. The effect of simvastatin on cell viability was evaluated by assessing the colorimetric conversion of 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide. Simvastatin suppressed TGF-beta1-induced type I collagen, CTGF, and alpha-SMA production in a concentration-dependent manner. The TGF-beta1-induced Smad2 and Smad3 phosphorylation levels were abrogated by simvastatin pretreatment. The inhibition of type I collagen, CTGF, and alpha-SMA expression by simvastatin was reversed by geranylgeranyl pyrophosphate, suggesting that the simvastatin-induced cellular responses were due to inhibition of small GTPase Rho involvement. A RhoA activation assay showed that preincubation with simvastatin significantly blocked TGF-beta1-induced RhoA activation. The Rho-associated coiled kinase inhibitor Y27632 abrogated TGF-beta1-induced production of type I collagen, CTGF, and alpha SMA. However, Y27632 had no significant effect on TGF-beta1-induced phosphorylation of Smad2 and Smad3. In conclusion, the present study suggests that simvastatin is an effective inhibitor of TGF-beta1-induced type I collagen, CTGF, and alpha-SMA production in keloid fibroblasts. PMID- 24471777 TI - Simultaneous presentation of kappa-restricted chronic lymphocytic leukemia and lambda light chain AL amyloidosis. AB - We report on a 58-year-old man who presented with simultaneous kappa-restricted chronic lymphocytic leukemia (CLL) and a lambda-restricted plasma cell dyscrasia causing AL amyloidosis involving the kidney and GI tract. While monoclonal immunoglobulins occasionally produced by CLL has previously been implicated in AL amyloidosis, this is the first case of AL amyloidosis resulting from a distinct plasma cell dyscrasia that is not clonally related to the concurrent CLL. Appropriate treatment depended on detailed pathologic diagnosis of both disease processes. PMID- 24471778 TI - Electrospun PLGA fibers incorporated with functionalized biomolecules for cardiac tissue engineering. AB - Structural similarity of electrospun fibers (ESFs) to the native extracellular matrix provides great potential for the application of biofunctional ESFs in tissue engineering. This study aimed to synthesize biofunctionalized poly (L lactide-co-glycolide) (PLGA) ESFs for investigating the potential for cardiac tissue engineering application. We developed a simple but novel strategy to incorporate adhesive peptides in PLGA ESFs. Two adhesive peptides derived from laminin, YIGSR, and RGD, were covalently conjugated to poly-L-lysine, and then mingled with PLGA solution for electrospinning. Peptides were uniformly distributed on the surface and in the interior of ESFs. PLGA ESFs incorporated with YIGSR or RGD or adsorbed with laminin significantly enhanced the adhesion of cardiomyocytes isolated from neonatal rats. Furthermore, the cells were found to adhere better on ESFs compared with flat substrates after 7 days of culture. Immunofluorescent staining of F-actin, vinculin, a-actinin, and N-cadherin indicated that cardiomyocytes adhered and formed striated alpha-actinin better on the laminin-coated ESFs and the YIGSR-incorporated ESFs compared with the RGD incorporated ESFs. The expression of alpha-myosin heavy chain and beta-tubulin on the YIGSR-incorporated ESFs was significantly higher compared with the expression level on PLGA and RGD-incorporated samples. Furthermore, the contraction of cardiomyocytes was faster and lasted longer on the laminin-coated ESFs and YIGSR incorporated ESFs. The results suggest that aligned YIGSR-incorporated PLGA ESFs is a better candidate for the formation of cardiac patches. This study demonstrated the potential of using peptide-incorporated ESFs as designable scaffold platform for tissue engineering. PMID- 24471779 TI - Dramatically accelerated selective oxygen-atom transfer by a nonheme iron(IV)-oxo complex: tuning of the first and second coordination spheres. AB - The new ligand N3Py(amide)SR and its Fe(II) complex [Fe(II)(N3Py(amide)SR)](BF4)2 (1) are described. Reaction of 1 with PhIO at -40 degrees C gives metastable [Fe(IV)(O)(N3Py(amide)SR)](2+) (2), containing a sulfide ligand and a single amide H-bond donor in proximity to the terminal oxo group. Direct evidence for H bonding is seen in a structural analogue, [Fe(II)(Cl)(N3Py(amide)SR)](BF4)2 (3). Complex 2 exhibits rapid O-atom transfer (OAT) toward external sulfide substrates, but no intramolecular OAT. However, direct S-oxygenation does occur in the reaction of 1 with mCPBA, yielding sulfoxide-ligated [Fe(II)(N3Py(amide)S(O)R)](BF4)2 (4). Catalytic OAT with 1 was also observed. PMID- 24471780 TI - Local and landscape correlates of primate distribution and persistence in the remnant lowland rainforests of the Upper Brahmaputra Valley, northeastern India. AB - Habitat fragmentation affects species distribution and abundance, and drives extinctions. Escalated tropical deforestation and fragmentation have confined many species populations to habitat remnants. How worthwhile is it to invest scarce resources in conserving habitat remnants within densely settled production landscapes? Are these fragments fated to lose species anyway? If not, do other ecological, anthropogenic, and species-related factors mitigate the effect of fragmentation and offer conservation opportunities? We evaluated, using generalized linear models in an information-theoretic framework, the effect of local- and landscape-scale factors on the richness, abundance, distribution, and local extinction of 6 primate species in 42 lowland tropical rainforest fragments of the Upper Brahmaputra Valley, northeastern India. On average, the forest fragments lost at least one species in the last 30 years but retained half their original species complement. Species richness declined as proportion of habitat lost increased but was not significantly affected by fragment size and isolation. The occurrence of western hoolock gibbon (Hoolock hoolock) and capped langur (Trachypithecus pileatus) in fragments was inversely related to their isolation and loss of habitat, respectively. Fragment area determined stump-tailed (Macaca arctoides) and northern pig-tailed macaque occurrence (Macaca leonina). Assamese macaque (Macaca assamensis) distribution was affected negatively by illegal tree felling, and rhesus macaque (Macaca mulatta) abundance increased as habitat heterogeneity increased. Primate extinction in a fragment was primarily governed by the extent of divergence in its food tree species richness from that in contiguous forests. We suggest the conservation value of these fragments is high because collectively they retained the entire original species pool and individually retained half of it, even a century after fragmentation. Given the extensive habitat and species loss, however, these fragments urgently require protection and active ecological restoration to sustain this rich primate assemblage. PMID- 24471781 TI - Using genetic profiles of African forest elephants to infer population structure, movements, and habitat use in a conservation and development landscape in Gabon. AB - Conservation of wide-ranging species, such as the African forest elephant (Loxodonta cyclotis), depends on fully protected areas and multiple-use areas (MUA) that provide habitat connectivity. In the Gamba Complex of Protected Areas in Gabon, which includes 2 national parks separated by a MUA containing energy and forestry concessions, we studied forest elephants to evaluate the importance of the MUA to wide-ranging species. We extracted DNA from elephant dung samples and used genetic information to identify over 500 individuals in the MUA and the parks. We then examined patterns of nuclear microsatellites and mitochondrial control-region sequences to infer population structure, movement patterns, and habitat use by age and sex. Population structure was weak but significant, and differentiation was more pronounced during the wet season. Within the MUA, males were more strongly associated with open habitats, such as wetlands and savannas, than females during the dry season. Many of the movements detected within and between seasons involved the wetlands and bordering lagoons. Our results suggest that the MUA provides year-round habitat for some elephants and additional habitat for others whose primary range is in the parks. With the continuing loss of roadless wilderness areas in Central Africa, well-managed MUAs will likely be important to the conservation of wide-ranging species. PMID- 24471782 TI - Modeling effectiveness of gradual increases in source level to mitigate effects of sonar on marine mammals. AB - Ramp-up or soft-start procedures (i.e., gradual increase in the source level) are used to mitigate the effect of sonar sound on marine mammals, although no one to date has tested whether ramp-up procedures are effective at reducing the effect of sound on marine mammals. We investigated the effectiveness of ramp-up procedures in reducing the area within which changes in hearing thresholds can occur. We modeled the level of sound killer whales (Orcinus orca) were exposed to from a generic sonar operation preceded by different ramp-up schemes. In our model, ramp-up procedures reduced the risk of killer whales receiving sounds of sufficient intensity to affect their hearing. The effectiveness of the ramp-up procedure depended strongly on the assumed response threshold and differed with ramp-up duration, although extending the duration of the ramp up beyond 5 min did not add much to its predicted mitigating effect. The main factors that limited effectiveness of ramp up in a typical antisubmarine warfare scenario were high source level, rapid moving sonar source, and long silences between consecutive sonar transmissions. Our exposure modeling approach can be used to evaluate and optimize mitigation procedures. PMID- 24471783 TI - Relations between species rarity, vulnerability, and range contraction for a beetle group in a densely populated region in the Mediterranean biodiversity hotspot. AB - Rarity is often considered an indication of species extinction risk, and it is frequently used to obtain measures of species vulnerability. However, there is no strong evidence of a correlation between species vulnerability and threat. Moreover, there is no consensus about how rarity should be measured. I used a multidimensional characterization of species rarity to calculate a vulnerability index for tenebrionid beetles inhabiting an Italian region in the Mediterranean biodiversity hotspot. I used different metrics to examine 3 dimensions of rarity: species range, ecology, and population. Species with rarity values below the median were scored as rare for each dimension. I combined rarity scores into a vulnerability index. I then correlated species vulnerability with range trends (expanded vs. contracted). Different measures of the same rarity dimension were strongly correlated and produced similar vulnerability scores. This result indicates rarity-based vulnerability estimates are slightly affected by the way a certain rarity dimension is measured. Vulnerability was correlated with range trends; species with the highest vulnerability had the strongest range contraction. However, a large number of common species also underwent range contraction in the last 50 years, and there was no clear relation between range contraction and their ecology. This indicates that in general human-induced environmental changes affected species irrespective of their assumed vulnerability and that focusing only on rare species may severely bias perceptions of the extent of species decline. PMID- 24471784 TI - A framework for assessing supply-side wildlife conservation. AB - Market-based, supply-side interventions such as domestication, cultivation, and wildlife farming have been proposed as legal substitutes for wild-collected plants and animals in the marketplace. Based on the literature, we devised a list of the conditions under which supply-side interventions may yield positive conservation outcomes. We applied it to the trade of the orchid Rhynchostylis gigantea, a protected ornamental plant. We conducted a survey of R. gigantea at Jatujak Market in Bangkok, Thailand. Farmed (legal) and wild (illegal, protected) specimens of R. gigantea were sold side-by-side at market. These results suggest farmed specimens are not being substituted for wild plants in the marketplace. For any given set of physical plant characteristics (size, condition, flowers), the origin of the plants (wild vs. farmed) did not affect price. For all price classes, farmed plants were of superior quality to wild-collected plants on the basis of most physical variables. These results suggest wild and farmed specimens represent parallel markets and may not be substitutable goods. Our results with R. gigantea highlight a range of explanations for why supply-side interventions may lack effectiveness, for example, consumer preferences for wild-collected products and low financial incentives for farming. Our results suggest that market-based conservation strategies may not be effective by themselves and may be best utilized as supplements to regulation and education. This approach represents a broad, multidisciplinary evaluation of supply-side interventions that can be applied to other plant and animal species. PMID- 24471786 TI - The association of perioperative dexamethasone, smoking and alcohol abuse with wound complications after laparotomy. AB - BACKGROUND: A number of perioperative risk factors may suppress the immune system and contribute to the development of post-operative complications. The association between surgical site infection (SSI) and other wound-related complications resulting from immunosuppression through either perioperative administration of dexamethasone, pre-operative smoking or alcohol abuse is, however, uncertain. METHODS: This study was a post hoc analysis of data from the PROXI randomized trial in 1386 patients who underwent emergency or elective laparotomy. We assessed the associations of use of dexamethasone, smoking status and alcohol abuse with the primary outcome, being a composite of SSI, anastomotic leak, wound dehiscence, burst abdomen and 30-day mortality. RESULTS: The primary outcome occurred in 21% of patients receiving dexamethasone versus 28% of patients not receiving dexamethasone, and this was not statistically significant when adjusting for stratification variables originally used in the PROXI trial [OR 0.90, 95% CI (0.65-1.24)]. In smokers, the primary outcome occurred in 32%, compared with 23% of non-smokers (P = 0.0001). Smokers also had a higher frequency of SSI (25% vs 17%, P < 0.0001) and burst abdomen (3.8% vs 2.4%, P = 0.04). In alcohol abusers, the primary outcome occurred in 48%, compared with 25% in patients who did not abuse alcohol (P = 0.0006). Burst abdomen occurred more commonly in alcohol abusers (15% vs 2.3%, P < 0.0001). CONCLUSION: Perioperative administration of dexamethasone was not significantly associated with SSI or other wound-related complications. Conversely, smoking and alcohol abuse were both significant predictors of the primary outcome consisting of wound-related complications and mortality. PMID- 24471787 TI - Gastroretentive mucoadhesive tablet of lafutidine for controlled release and enhanced bioavailability. AB - Lafutidine a newly developed histamine H2-receptor antagonist having biological half-life of 1.92 +/- 0.94 h due to its selective absorption from upper part of gastrointestinal tract the development of mucoadhesive sustained release drug delivery system is recommended in order to enhance the bioavailability. A mucoadhesive tablets was developed using the natural polymer, sodium alginate, xanthan gum and karaya gum. Mucoadhesion is a complex phenomenon which involves wetting, adsorption and interpenetration of polymer chains. The prepared tablets of various formulations were evaluated for a total mucoadhesion time, buoyancy lag time and percentage drug released. The formulation with xanthan gum showed better results. Thus, it may be useful for prolonged drug release in stomach to improve the bioavailability and reduced dosing frequency. Non-fickians release transport was confirmed as the drug release mechanism from the optimized formulation by Korsmeyer-Peppas. The optimized formulation (B3) showed a mucoadhesive strength >35 g. In vivo study was performed using rabbits by X-ray imaging technique. Radiological evidences suggest that, a formulated tablet was well adhered for >10 h in rabbit's stomach. Optimized lafutidine mucoadhesive tablets showed no significant change in physical appearance, drug content, mucoadhesive properties and in vitro dissolution pattern after storage at 40 degrees C temperature 75 +/- 5% relative humidity for 3 months. PMID- 24471788 TI - Salidroside exerts angiogenic and cytoprotective effects on human bone marrow derived endothelial progenitor cells via Akt/mTOR/p70S6K and MAPK signalling pathways. AB - BACKGROUND AND PURPOSE: With the increase of age, increased susceptibility to apoptosis and senescence may contribute to proliferative and functional impairment of endothelial progenitor cells (EPCs). The aim of this study was to investigate whether salidroside (SAL) can induce angiogenic differentiation and inhibit oxidative stress-induced apoptosis in bone marrow-derived EPCs (BM-EPCs), and if so, through what mechanism. EXPERIMENTAL APPROACH: BM-EPCs were isolated and treated with different concentrations of SAL for up to 4 days. Cell proliferation, migration and tube formation ability were detected by DNA content quantification, transwell assay and Matrigel-based angiogenesis assay. Gene and protein expression were assessed by qRT-PCR and Western blot respectively. KEY RESULTS: Treatment with SAL promoted cellular proliferation and angiogenic differentiation of BM-EPCs, and increased VEGF and NO secretion, which in turn mediated the enhanced angiogenic differentiation of BM-EPCs. Furthermore, SAL significantly attenuated hydrogen peroxide (H2O2)-induced cell apoptosis, reduced the intracellular level of reactive oxygen species and restored the mitochondrial membrane potential of BM-EPCs. Moreover, SAL stimulated the phosphorylation of Akt, mammalian target of rapamycin and p70 S6 kinase, as well as ERK1/2, which is associated with cell migration and capillary tube formation. Additionally, SAL reversed the phosphorylation of JNK and p38 MAPK induced by H2O2 and suppressed the changes in the Bax/Bcl-xL ratio observed after stimulation with H2O2. CONCLUSIONS AND IMPLICATIONS: These findings identify novel mechanisms that regulate EPC function and suggest that SAL has therapeutic potential as a new agent to enhance vasculogenesis as well as protect against oxidative endothelial injury. PMID- 24471789 TI - Continuous flow synthesis of alpha-halo ketones: essential building blocks of antiretroviral agents. AB - The development of a continuous flow process for the multistep synthesis of alpha halo ketones starting from N-protected amino acids is described. The obtained alpha-halo ketones are chiral building blocks for the synthesis of HIV protease inhibitors, such as atazanavir and darunavir. The synthesis starts with the formation of a mixed anhydride in a first tubular reactor. The anhydride is subsequently combined with anhydrous diazomethane in a tube-in-tube reactor. The tube-in-tube reactor consists of an inner tube, made from a gas-permeable, hydrophobic material, enclosed in a thick-walled, impermeable outer tube. Diazomethane is generated in the inner tube in an aqueous medium, and anhydrous diazomethane subsequently diffuses through the permeable membrane into the outer chamber. The alpha-diazo ketone is produced from the mixed anhydride and diazomethane in the outer chamber, and the resulting diazo ketone is finally converted to the halo ketone with anhydrous ethereal hydrogen halide. This method eliminates the need to store, transport, or handle diazomethane and produces alpha-halo ketone building blocks in a multistep system without racemization in excellent yields. A fully continuous process allowed the synthesis of 1.84 g of alpha-chloro ketone from the respective N-protected amino acid within ~4.5 h (87% yield). PMID- 24471790 TI - Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) forms amyloid-like fibrils by interaction with acidic phospholipids and inhibits Abeta aggregation. AB - Golgi-Associated plant Pathogenesis Related protein 1 (GAPR-1) is a mammalian protein that is a member of the Cysteine-rich secretory proteins, Antigen 5 and Pathogenesis related proteins group 1 (CAP) superfamily of proteins. A role for the common CAP domain in the function of the diverse superfamily members has not been described so far. Here, we show by a combination of independent techniques including electron microscopy, Thioflavin T fluorescence, and circular dichroism that GAPR-1 has the capability to form amyloid-like fibrils in the presence of liposomes containing negatively charged lipids. Surprisingly, GAPR-1 was also shown to bind the amyloid-oligomer specific antibody A11 in the absence of lipids, indicating that GAPR-1 has an intrinsic tendency to form oligomers. This behavior is characteristic for proteins that interfere with Abeta aggregation and indeed we found that GAPR-1 effectively inhibited aggregation of Abeta(1-40) peptide. Immuno-dot blot analysis revealed that GAPR-1 binds to prefibrillar oligomeric Abeta structures during the early stages of fibril formation. Another CAP domain-containing protein, CRISP2, was also capable of forming fibrils, indicating that oligomerization and fibril formation is a shared characteristic between CAP family members. We suggest that the CAP domain may regulate protein oligomerization in a large variety of proteins that define the CAP superfamily. PMID- 24471791 TI - Total protein measurement in canine cerebrospinal fluid: agreement between a turbidimetric assay and 2 dye-binding methods and determination of reference intervals using an indirect a posteriori method. AB - BACKGROUND: In veterinary clinical laboratories, qualitative tests for total protein measurement in canine cerebrospinal fluid (CSF) have been replaced by quantitative methods, which can be divided into dye-binding assays and turbidimetric methods. There is a lack of validation data and reference intervals (RIs) for these assays. OBJECTIVES: The aim of the present study was to assess agreement between the turbidimetric benzethonium chloride method and 2 dye binding methods (Pyrogallol Red-Molybdate method [PRM], Coomassie Brilliant Blue [CBB] technique) for measurement of total protein concentration in canine CSF. Furthermore, RIs were determined for all 3 methods using an indirect a posteriori method. METHODS: For assay comparison, a total of 118 canine CSF specimens were analyzed. For RIs calculation, clinical records of 401 canine patients with normal CSF analysis were studied and classified according to their final diagnosis in pathologic and nonpathologic values. RESULTS: The turbidimetric assay showed excellent agreement with the PRM assay (mean bias 0.003 g/L [-0.26 0.27]). The CBB method generally showed higher total protein values than the turbidimetric assay and the PRM assay (mean bias -0.14 g/L for turbidimetric and PRM assay). From 90 of 401 canine patients, nonparametric reference intervals (2.5%, 97.5% quantile) were calculated (turbidimetric assay and PRM method: 0.08 0.35 g/L (90% CI: 0.07-0.08/0.33-0.39); CBB method: 0.17-0.55 g/L (90% CI: 0.16 0.18/0.52-0.61). Total protein concentration in canine CSF specimens remained stable for up to 6 months of storage at -80 degrees C. CONCLUSIONS: Due to variations among methods, RIs for total protein concentration in canine CSF have to be calculated for each method. The a posteriori method of RIs calculation described here should encourage other veterinary laboratories to establish RIs that are laboratory-specific. PMID- 24471792 TI - Shear stress regulated gene expression and angiogenesis in vascular endothelium. AB - The behavior of vascular EC is greatly altered in sites of pathological angiogenesis, such as a developing tumor or atherosclerotic plaque. Until recently it was thought that this was largely due to abnormal chemical signaling, i.e., endothelial cell chemo transduction, at these sites. However, we now demonstrate that the shear stress intensity encountered by EC can have a profound impact on their gene expression and behavior. We review the growing body of evidence suggesting that mechanotransduction, too, is a major regulator of pathological angiogenesis. This fits with the evolving story of physiological angiogenesis, where a combination of metabolic and mechanical signaling is emerging as the probable mechanism by which tight feedback regulation of angiogenesis is achieved in vivo. PMID- 24471793 TI - A new hemoglobin variant: Hb Henan [beta90(F6)Glu -> Gln; HBB: c.271G < C]. AB - We have identified a new beta chain hemoglobin (Hb) variant in a Chinese individual. Sequencing of the beta-globin gene revealed a mutation in exon 2 at nucleotide 271, which results in the replacement of a glutamic acid by glutamine at codon 90 [beta90(F6)Glu -> Gln; GAG > CAG; HBB: c.271G > C] that we have named Hb Henan. PMID- 24471795 TI - New class of metal bound molecular switches involving H-tautomerism. AB - A potential end-point in the miniaturization of electronic devices lies in the field of molecular electronics, where molecules perform the function of single components. To date, hydrogen tautomerism in unimolecular switches has been restricted to the central macrocycle of porphyrin-type molecules. The present work reveals how H-tautomerism is the mechanism for switching in substituted quinone derivatives, a novel class of molecules with a different chemical structure. We hence reveal that the previous restrictions applying to tautomeric molecular switches bound to a surface are not valid in general. The activation energy of switching in a prototypical quinone derivative is determined using inelastic electron tunneling. Through computational modeling, we show that the mechanism underlying this process is tautomerization of protons belonging to two amino groups. This switching property is retained upon functionalization by the addition of side groups, meaning that the switch can be chemically modified to fit specific applications. PMID- 24471796 TI - Effects of emergency medical service transport on acute stroke care. AB - BACKGROUND AND PURPOSE: Since early treatment of acute stroke is associated with an improved outcome, emergency medical service (EMS) transport of stroke patients is recommended. It remains unclear, however, whether EMS transport leads to faster treatment. The impact of the transport mode on pre- and in-hospital processes of care was therefore investigated. METHODS: The present study was based on a prospective database of 158 hospitals of the Stroke Register of Northwestern Germany, which included 162,511 stroke patients admitted between January 2010 and December 2011. Main outcome measures were the baseline characteristics associated with EMS transport and process-of-care indicators according to the transport mode. RESULTS: Overall, 101,850 (72.0%) patients were transported by EMS and 39,324 (28.0%) by self-transport. The baseline characteristics showing the strongest associations with EMS use were the care situation [institutional care, adjusted odds ratio (OR) 7.81; 95% CI 6.86-8.90], a disturbed level of consciousness (adjusted OR 3.00; 95% CI 2.59-3.48) and having a subarachnoid (adjusted OR 2.79; 95% CI 2.24-3.49) or intracerebral hemorrhage (adjusted OR 2.26; 95% CI 1.92-2.67). For self-transport patients the probability of being in a higher onset-to-door time category was 4.36 (95% CI 4.26-4.47) and the probability of being in a higher door-to-imaging time category was 1.32 (95% CI 1.28-1.36). Compared with self-transport, EMS transport was independently associated with thrombolysis (adjusted OR 1.95, 95% CI 1.77-2.15). CONCLUSIONS: Patient transport with EMS was independently associated with faster hospital arrival and shorter time periods from hospital admission to brain imaging and to the frequency of thrombolysis. PMID- 24471797 TI - Once bitten, twice shy: concern about gaining weight after smoking cessation and its association with seeking treatment. AB - BACKGROUND: Concern about weight gain after quitting smoking is often cited as a barrier to smokers making a quit attempt or seeking treatment. AIM: To identify whether smokers who are non-treatment seekers (NTS) are more concerned about weight gain and have lower confidence to maintain weight after quitting smoking as compared with treatment-seeking smokers (TS). METHODS: Participants were smokers recruited from Penn State Hershey Medical Center and family practice outpatient clinics. A total of 102 NTS and 186 TS, who participated in a smoking cessation trial, completed a survey regarding tobacco use, weight concern and diet. Stepwise logistic regression was used to identify variables associated with treatment seeking, overall and stratified by those who gained and did not gain weight on a previous quit attempt. RESULTS: Fifty three per cent of the overall sample (47.1% NTS vs. 56.5% TS, p = 0.127) had gained weight on a prior quit attempt. Among smokers who had gained weight, higher weight gain concern (WGC) and lower confidence in ability to maintain weight were significantly associated with being a NTS after adjusting for other factors. CONCLUSION: Among smokers who gained weight on a previous quit attempt, NTS had greater concern about gaining weight and less confidence in their ability to maintain their weight after quitting than treatment seekers. Clinicians can identify smokers for whom WGC may be a barrier to seeking treatment by asking if they gained weight on a previous quit attempt. These smokers should be assured that this issue will be addressed in treatment. PMID- 24471798 TI - Association of inflammation, myocardial fibrosis and cardiac remodelling in patients with mild aortic stenosis as assessed by biomarkers and echocardiography. AB - 1. The aim of the present study was to investigate the relationships among inflammation, myocardial fibrosis and cardiac remodelling in patients with mild aortic stenosis (AS), as assessed by biomarkers and echocardiography. 2. We evaluated 32 consecutive patients with mild AS, as well as 30 age- and gender matched healthy individuals with normal aortic valves as control subjects. 3. Baseline echocardiography showed that the left ventricular (LV) mass index (111.3 +/- 26.9 vs 94.5 +/- 18.2 g/m(2); P = 0.006) and left atrial (LA) volume index (LAVI 27.5 +/- 9.0 vs xx.x +/- 5.2 mm(3)/mm(2); P = 0.005) were significantly higher in patients with mild AS. 4. Furthermore, LA enlargement (LAVI > 33 mm(3)/mm(2); 32.4% vs 3.3%; P = 0.003) and elevated LV filling pressure (E/e' > 15; 50.0% vs 23.3%; P = 0.036) were higher in patients with mild AS. 5. In patients with mild AS, stepwise, multivariate linear regression analysis revealed that the LV end-diastolic volume index was independently associated with matrix metalloproteinase (MMP)-1 (beta = 0.371; P = 0.015), that the aortic valve mean pressure gradient was independently associated with MMP-2 (beta = 0.19; P = 0.019), that MMP-2 was independently associated with transforming growth factor beta (beta = 0.95; P < 0.001) and interleukin (IL)-1 (beta = 0.17; P = 0.019) and that IL-1 was independently associated with tissue inhibitor of matrix metalloproteinase-1 (beta = 0.68; P = 0.001). 6. Myocardial fibrosis in mild AS is independently associated with three factors: LV volume overload, aortic valve pressure overload and inflammation. PMID- 24471799 TI - Enhanced osseous implant fixation with strontium-substituted bioactive glass coating. AB - The use of endosseous implants is firmly established in skeletal reconstructive surgery, with rapid and permanent fixation of prostheses being a highly desirable feature. Implant coatings composed of hydroxyapatite (HA) have become the standard and have been used with some success in prolonging the time to revision surgery, but aseptic loosening remains a significant issue. The development of a new generation of more biologically active coatings is a promising approach for tackling this problem. Bioactive glasses are an ideal candidate material due to the osteostimulative properties of their dissolution products. However, to date, they have not been formulated with stability to devitrification or thermal expansion coefficients (TECs) that are suitable for stable coating onto metal implants while still retaining their bioactive properties. Here, we present a strontium-substituted bioactive glass (SrBG) implant coating which has been designed to encourage peri-implant bone formation and with a TEC similar to that of HA. The coating can be successfully applied to roughened Ti6Al4V and after implantation into the distal femur and proximal tibia of twenty-seven New Zealand White rabbits for 6, 12, or 24 weeks, it produced no adverse tissue reaction. The glass dissolved over a 6 week period, stimulating enhanced peri-implant bone formation compared with matched HA coated implants in the contralateral limb. Furthermore, superior mechanical fixation was evident in the SrBG group after 24 weeks of implantation. We propose that this coating has the potential to enhance implant fixation in a variety of orthopedic reconstructive surgery applications. PMID- 24471800 TI - Extended Periods of Alcohol Intake Negatively Affects Osseointegration in Rats. AB - The negative effects of chronic and excessive consumption of alcohol on bone metabolism are reported in the literature. Alcoholism causes a reduction in bone quality and delays fracture repair, among other deleterious effects. However, its effect on osseointegration in dental implants is not fully established. The aim of this research was to investigate the influence of prolonged and excessive consumption of alcohol on osseointegration in rats. Thirty-five female rats, 3 months of age, were divided into five groups according to alcohol consumption period: control (no alcohol), and 3, 4, 5, and 6 months of alcohol consumption. All animals received solid food ad libitum. At 8 months of age, all animals received a dental implant in the right femur, and euthanasia was performed 1 month after the implant placement (final n = 27). Quantification of the percentage of bone-implant direct contact was performed by histomorphometry. Serum levels of calcium and phosphate were also measured. The groups that consumed alcohol for longer periods presented decreased percentages of bone implant direct contact. The difference was higher in implants apical region. Alcohol consumption did not affect serum calcium levels but raised the level of serum phosphate. Alcohol consumption increased caloric intake but also increased weight loss. It was concluded that chronic and excessive consumption of alcohol can impair osseointegration in rats. PMID- 24471801 TI - Strategies for drug delivery to the central nervous system by systemic route. AB - CONTEXT: Delivery of a drug into the central nervous system (CNS) is considered difficult. Most of the drugs discovered over the past decade are biological, which are high in molecular weight and polar in nature. The delivery of such drugs across the blood-brain barrier presents problems. OBJECTIVE: This review discusses some of the options available to reach the CNS by systemic route. The focus is mainly on the recent developments in systemic delivery of a drug to the CNS. MATERIALS AND METHODS: Databases such as Scopus, Google scholar, Science Direct, SciFinder and online journals were referred for preparing this article including 89 references. RESULTS: There are at least nine strategies that could be adopted to achieve the required drug concentration in the CNS. CONCLUSION: The recent developments in drug delivery are very promising to deliver biologicals into the CNS. PMID- 24471802 TI - Thermal and photoinduced reduction of ionic Au(III) to elemental Au nanoparticles by dissolved organic matter in water: possible source of naturally occurring Au nanoparticles. AB - Naturally occurring Au nanoparticles (AuNPs) have been widely observed in ore deposits, coal, soil, and environmental water. Identifying the source of these naturally occurring AuNPs could be helpful for not only the discovery of Au deposits through advanced exploration methods, but also the elucidation of the biogeochemical cycle and environmental toxicity of ionic Au and engineered AuNPs. Here, we investigated the effect of natural/simulated sunlight and heating on the reduction of ionic Au by ubiquitous dissolved organic matter (DOM) in river water. The reductive process probed by X-ray photoelectron spectroscopy revealed that phenolic, alcoholic, and aldehyde groups in DOM act as reductive sites. Long time exposure with thermal and photoirradiation induced the further fusion and growth of AuNPs to branched Au nanostructure as precipitation. The formation processes and kinetics of AuNPs were further investigated using humic acid (HA) as the DOM model, with comprehensive characterizing methods. We have observed that HA can reduce ionic Au(III) complex (as chloride or hydroxyl complex) to elemental Au nanoparticles under sunlight or heating. In this process, nearly all of the Au(III) could be reduced to AuNPs, in which HA serves as not only the reductive agent, but also the coating agent to stabilize and disperse AuNPs. The size and stability of AuNPs were highly dependent on the concentration ratio of Au(III) to HA. These results imply that, besides biological processes, this thermal or photochemical reduction process is another possible source of naturally occurring AuNPs in natural environments, which possibly has critical impacts on the transport and transformation of Au and engineered AuNPs. PMID- 24471803 TI - Frequency domain parameters of heart rate variability should be quoted in normalised units together with their absolute values: author's reply. PMID- 24471804 TI - Differences in associations between visceral fat accumulation and obstructive sleep apnea by sex. AB - RATIONALE: The difference in mortality from obstructive sleep apnea (OSA) by sex is an important issue. Visceral fat, a significant risk factor for cardiovascular disease, was reported to be closely related to OSA. OBJECTIVES: To assess the different associations between OSA and visceral fat area (VFA) by sex, which might account for the different prognosis in men and women with OSA. METHODS: Participants were 271 men and 100 women consecutively hospitalized for examination of OSA from October 2008 to December 2010. Among the 371 participants, relationships were analyzed between fat areas by computed tomography, comorbidity, polysomnographic data, arterial blood gas, pulmonary function, and venous blood data. Multiple regression analyses were performed to identify variables independently associated with VFA and subcutaneous fat area for each sex. MEASUREMENTS AND MAIN RESULTS: Despite similar body mass index (BMI) and waist circumference, men had larger VFA, more severe OSA, and more severe dyslipidemia than women. Multiple regression analyses revealed that in men, not only age and BMI but also minimal oxygen saturation (contribution rate [R(2)], 4.6%) during sleep, and alveolar-arterial oxygen difference (R(2) = 7.6%) were independently associated with VFA. Conversely, VFA was associated only with BMI in women. CONCLUSIONS: Only in men was OSA independently associated with VFA. The lesser associations between OSA and visceral fat in women might account for the lower impact of OSA on cardiovascular disease or mortality in women. PMID- 24471805 TI - Hb A2-Konz [delta50(D1)Ser -> Thr; HBD: c.151T > A]: a new delta chain hemoglobin variant characterized by mass spectrometry and high performance liquid chromatography. AB - We report a new slow-moving delta chain hemoglobin (Hb) variant, named Hb A2-Konz [delta50(D1)Ser -> Thr; HBD: c.151T > A]. It was detected during simultaneous measurement of Hb A1C and Hb A2 by high resolution cation exchange high performance liquid chromatography (HPLC) using a PolyCATA column. Hb A2-Konz comprised 0.8% of total Hb. This new variant was identified by peptide mapping using nanoliquid chromatography electrospray ionization-tandem mass spectrometry (nanoLC-ESI-MS/MS) as a serine to threonine substitution at delta50(D1), indicating that the variant was due to a single base change at codon 51 (TCT > ACT) of the delta-globin gene. The new mutant is clinically silent but could lead to a misdiagnosis of beta-thalassemia (beta-thal) based on the level of Hb A2. PMID- 24471806 TI - Single cell transfection with single molecule resolution using a synthetic nanopore. AB - We report the development of a single cell gene delivery system based on electroporation using a synthetic nanopore, that is not only highly specific and very efficient but also transfects with single molecule resolution at low voltage (1 V) with minimal perturbation to the cell. Such a system can be used to control gene expression with unprecedented precision--no other method offers such capabilities. PMID- 24471807 TI - Detection of ancient DNA of Encephalitozoon intestinalis (Microsporidia) in archaeological material. AB - Ancient DNA (aDNA) of Encephalitozoon intestinalis (Microsporidia, Fungi) was detected in archaeological material originated from New Town of Prague (Czech Republic) with the use of molecular methods. Microsporidial aDNA was found in 3 samples originating from 2 objects, in a well/cesspit (samples from layers from the 18th century) and in a well from the 18th/19th century. The ability to use molecular methods to detect microsporidia extends the range of paleoparasitological inquiry, and could contribute to a better understanding of parasites shared between human and animals. PMID- 24471808 TI - Marked changes in platelet count and function following pediatric congenital heart surgery. AB - BACKGROUND: Reduced hemostatic capacity is common following congenital heart surgery using cardiopulmonary bypass (CPB). The etiology is multifactorial with dilutional coagulopathy, as well as platelet adhesion and activation in the CPB circuit and oxygenator. The purpose of the present study was to evaluate platelet count and function in children following CPB. METHODS: In a prospective, observational study comprising 40 children, platelet count and function (Multiplate Analyzer((r))) were measured before surgery, immediately after bypass, and on the first postoperative day. Furthermore, conventional coagulation analysis and thromboelastometry (ROTEM((r))) were carried out. RESULTS: A significant decrease in platelet count was observed immediately after coming of bypass (P < 0.001) and persisted to the first postoperative day (P = 0.002). Platelet function was reduced immediately after bypass after induction with ADP (P < 0.001) or TRAP (P = 0.03). The duration of CPB correlated significantly with the decrease in platelet count (r = -0.62, P = 0.0001) and reduction in platelet function (r = -0.42-0.63; P < 0.01). Moderate to deep hypothermia during CPB was associated with a decreased platelet function (P = 0.01-0.12), whereas cyanosis or previous heart surgery caused no further changes in platelet function following CPB. CONCLUSION: Both platelet count and platelet function were significantly reduced after CPB in children undertaken correctional heart surgery. Duration of CPB and hypothermia was associated with significant changes in platelet function. PMID- 24471809 TI - High-resolution molecular karyotyping uncovers pairing between ancestrally related Brassica chromosomes. AB - How do chromosomal regions with differing degrees of homology and homeology interact at meiosis? We provide a novel analytical method based on simple genetics principles which can help to answer this important question. This method interrogates high-throughput molecular marker data in order to infer chromosome behavior at meiosis in interspecific hybrids. We validated this method using high resolution molecular marker karyotyping in two experimental Brassica populations derived from interspecific crosses among B. juncea, B. napus and B. carinata, using a single nucleotide polymorphism chip. This method of analysis successfully identified meiotic interactions between chromosomes sharing different degrees of similarity: full-length homologs; full-length homeologs; large sections of primary homeologs; and small sections of secondary homeologs. This analytical method can be applied to any allopolyploid species or fertile interspecific hybrid in order to detect meiotic associations. This genetic information can then be used to identify which genomic regions share functional homeology (i.e., retain enough similarity to allow pairing and segregation at meiosis). When applied to interspecific hybrids for which reference genome sequences are available, the question of how differing degrees of homology and homeology affect meiotic interactions may finally be resolved. PMID- 24471811 TI - Seronegative paraneoplastic cerebellar degeneration: the PNS Euronetwork experience. AB - BACKGROUND AND PURPOSE: To describe the characteristics of patients presenting a paraneoplastic cerebellar degeneration without classical onconeural antibodies (seronegative PCD). METHODS: Thirty-nine seronegative PCD patients from the Paraneoplastic Neurological Syndrome Euronetwork were retrospectively analyzed and compared with 180 patients with PCD associated with classical onconeural antibodies (seropositive PCD). RESULTS: No patient had anti-CASPR2 or anti-mGluR1 antibodies. No significant difference between the clinical characteristics of seronegative and seropositive PCD patients was observed. Yet the frequency of associated tumors was different. Lymphoma was more frequent in seronegative than in seropositive women (24% vs. 2%, P = 0.002) whilst gynecological cancer were less frequent (38% vs. 74%, P = 0.002). In comparison with seropositive men, seronegative men more frequently had a non-small-cell lung cancer (27% vs. 6%, P = 0.08) or a genitourinary cancer (22% vs. 0%, P = 0.04) but less frequently a small-cell lung cancer (23% vs. 74%, P = 0.002). Seronegative and seropositive PCD patients with similar tumors had a similar overall survival. CONCLUSION: The clinical characteristics of seronegative and seropositive PCD are similar but the spectrum of associated tumors is different. The immunological scenario of seronegative PCD seems to be different from that of limbic encephalitis with only few patients harboring anti-neuropile antibodies. PMID- 24471812 TI - The C-shaped canal molar: an Endodontic-Archaeological study of the relationships between Mayan pre-Hispanic and contemporary population of Yucatan. AB - AIM: To assess the prevalence of C-shaped canal systems in mandibular second molars, in samples of modern and pre-Hispanic Mayan individuals in Yucatan, Mexico, and to analyse the trait through time and attempt to find new evidence of ethnical bonds between populations. METHODOLOGY: Three hundred and forty-one randomly selected patients were treated in the Endodontic Clinic at the Dental school of the Universidad Autonoma de Yucatan, and 48 mandibular second molars from pre-Hispanic Mayan collections were macroscopically and radiographically inspected. Statistical analysis was performed with a Fisher's exact test to compare the prevalence of C-shaped canal systems in modern and archaeological samples. RESULTS: In the clinical observation, 118 of 341 (35%) patients treated endodontically had C-shaped mandibular second molars. In the radiographical evaluation, 17 of 48 (35%) archaeological molars had fused roots and pulp chamber morphology categorized as C-shaped. There were no significant differences between the frequencies in both samples. CONCLUSION: This study highlighted that a one rooted mandibular molar was likely to have a C-shaped canal. The similarity between ancient and modern samples indicates that the genetic make-up since the European conquest has not affected the expression of this trait. This study supports the theory that the Mayan population has a relationship with the Northeast Asian population. PMID- 24471813 TI - Comparison of feline core bone marrow biopsies from different sites using 2 techniques and needles. AB - BACKGROUND: Commonly used 11ga or 13ga biopsy needles are relatively large for cats and often preclude successful collection of bone marrow (BM) core biopsies. OBJECTIVES: The objective was to compare 15ga to 13ga BM core biopsy ease of collection and specimen quality. METHODS: In 10 cats, humeral biopsies obtained with 15ga EZ-IO needles were compared with iliac biopsies obtained with 13ga Jamshidi needles. Body condition, ease of collection, section quality, postprocedure pain, and swelling at biopsy sites were scored. Specimen length on mounted slides was measured and specimens with quality scores of 3-5 out of a maximum value of 5 were considered to be of acceptable diagnostic quality. The distribution of all parameters was assessed by Shapiro-Wilk tests, and differences in parameters were assessed by ANCOVA. RESULTS: There were no significant differences between 15ga and 13ga biopsies, except that the 15ga humeral biopsy was judged to be easier to perform than 13ga iliac biopsy, and there was more severe postbiopsy swelling with 13ga biopsies. Facility score (mean +/- SD), section quality score (median +/- SD) and specimen length (mm, mean +/- SD) were 12.7 +/- 2.3, 2.0 +/- 1.4, and 6.0 +/- 2.1 for 15ga biopsies, respectively, and 8.9 +/- 2.4, 1.0 +/- 1.8, and 7.5 +/- 2.5 for 13ga biopsies, respectively. Three specimens of acceptable quality were obtained with each 15ga and 13ga biopsies. CONCLUSIONS: In cats, BM biopsy of the humerus with a 15ga needle is easier and causes less postbiopsy swelling than biopsy of the ilium with a 13ga needle. Sites and needles are equivalent with respect to yielding specimens of acceptable quality. Neither technique consistently captured high quality specimens. PMID- 24471814 TI - A comparison of biphasic insulin aspart and insulin glargine administered with oral antidiabetic drugs in type 2 diabetes mellitus--a systematic review and meta analysis. AB - OBJECTIVE: It is uncertain whether the addition of biphasic insulin analogues to oral antidiabetic drugs (OADs) is as effective and safe as basal insulin in patients with type 2 diabetes mellitus (T2DM). We performed a systematic review to compare glycaemic control and selected clinical outcomes in T2DM patients inadequately controlled with OADs whose treatment was intensified by adding biphasic insulin aspart (BIAsp 30) or insulin glargine (IGlar). METHODS: The analysis included randomised controlled trials (RCTs) identified by a systematic literature search in medical databases (MEDLINE, EMBASE, The Cochrane Library and other sources) up to March 2013. Studies met the inclusion criteria if they compared BIAsp 30 vs. IGlar added to at least one OAD in T2DM patients. Trials applying different OADs in both treatment arms were also included. Results were presented as weighted mean difference (WMD) or odds ratio (OR) with a 95% confidence interval (CI). RESULTS: Five trials, including a total number of 1758 patients followed up from 24 to 28 weeks, were identified. Quantitative synthesis demonstrated that BIAsp 30 reduced HbA1c level more efficiently than IGlar [5 RCTs; WMD (95% CI): -0.21% (-0.35%, -0.08%)]. Differences were observed in favour of BIAsp for lower mean prandial glucose increment [3 RCTs; WMD (95% CI): -14.70 mg/dl (-20.09, -9.31)]; no difference was observed for fasting plasma glucose [3 RCTs; WMD (95% CI): 7.09 mg/dl (-15.76, 29.94)]. We found no evidence for higher risk of overall [2 RCTs; 63% vs. 51%; OR = 1.77 (0.91; 3.44)] and severe hypoglycaemic episodes [4 RCTs; 0.98% vs. 1.12%; OR (95% CI) = 0.88 (0.31, 2.53)] in the BIAsp 30 group as compared with IGlar group. Twice-daily administration of BIAsp 30 resulted in larger weight gain [2 RCTs; WMD (95% CI) = 1.78 kg (1.04; 2.52)]. CONCLUSIONS: BIAsp 30 added to OAD therapy results in a better glycaemic control as compared with IGlar in T2DM patients. BIAsp 30 use is associated with slightly larger weight gain but no rise in risk of severe hypoglycaemic episodes. PMID- 24471815 TI - In vivo skeletal muscle biocompatibility of composite, coaxial electrospun, and microfibrous scaffolds. AB - One weakness with currently researched skeletal muscle tissue replacement is the lack of contraction and relaxation during the regenerative process. A biocompatible scaffold that can act similar to the muscle would be a pivotal innovation. Coaxial electrospun scaffolds, capable of movement with electrical stimulation, were created using poly(E-caprolactone) (PCL), multiwalled carbon nanotubes (MWCNT), and a (83/17 or 40/60) poly(acrylic acid)/poly(vinyl alcohol) (PAA/PVA) hydrogel. The two scaffolds were implanted into Sprague-Dawley rat vastus lateralis muscle and compared with a phosphate-buffered saline injection sham surgery and an unoperated control. No complications or adverse effects were observed. Rats were sacrificed on days 7, 14, 21, and 28 postimplantation and biocompatibility assessed using enzymatic activity, fibrosis formation, inflammation, scaffold cellular infiltration, and neovascularization. Serum creatine kinase and lactate dehydrogenase levels were significantly higher in scaffold-implanted rats compared with the control on day 7, but returned to baseline by day 14. Day 7 scaffolds showed significant inflammation and fibrosis that decreased over time. Fibroblasts infiltrated the scaffolds early, but decreased with time, while myogenic cell numbers increased. Neovascularization of both scaffolds occurred as early as day 7. We conclude that the PCL-MWCNT-PAA/PVA scaffolds are biocompatible and suitable for muscle regeneration as myogenic cell growth was supported. PMID- 24471816 TI - Bicyclic 1-hydroxy-2-oxo-1,2-dihydropyridine-3-carboxamide-containing HIV-1 integrase inhibitors having high antiviral potency against cells harboring raltegravir-resistant integrase mutants. AB - Integrase (IN) inhibitors are the newest class of antiretroviral agents developed for the treatment of HIV-1 infections. Merck's Raltegravir (RAL) (October 2007) and Gilead's Elvitegravir (EVG) (August 2012), which act as IN strand transfer inhibitors (INSTIs), were the first anti-IN drugs to be approved by the FDA. However, the virus develops resistance to both RAL and EVG, and there is extensive cross-resistance to these two drugs. New "2nd-generation" INSTIs are needed that will have greater efficacy against RAL- and EVG-resistant strains of IN. The FDA has recently approved the first second generation INSTI, GSK's Dolutegravir (DTG) (August 2013). Our current article describes the design, synthesis, and evaluation of a series of 1,8-dihydroxy-2-oxo-1,2-dihydroquinoline 3-carboxamides, 1,4-dihydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides, and 1-hydroxy-2-oxo-1,2-dihydro-1,8-naphthyridine-3-carboxamides. This resulted in the identification of noncytotoxic inhibitors that exhibited single digit nanomolar EC50 values against HIV-1 vectors harboring wild-type IN in cell-based assays. Importantly, some of these new inhibitors retain greater antiviral efficacy compared to that of RAL when tested against a panel of IN mutants that included Y143R, N155H, G140S/Q148H, G118R, and E138K/Q148K. PMID- 24471818 TI - Umbilical cord plasma and salivary insulin and leptin concentrations in AGA neonates: a preliminary report. AB - Background and objective: Insulin and leptin hormones are important regulators of food intake and energy balance. There is limited information about insulin and leptin hormones in neonates. This preliminary study aimed to investigate the concentrations of insulin and leptin in umbilical cord plasma and neonate's saliva and their relationships. METHODS: Umbilical cord plasma and salivary samples were obtained from 13 healthy, appropriate for gestational age (AGA) neonates. Insulin and leptin concentrations in umbilical cord plasma and saliva were measured using the MILLIPLEX MAP(r) Human Metabolic Hormone Magnetic Bead Panel. RESULTS: Insulin concentrations in umbilical cord plasma correlates positively and significantly with leptin concentrations in umbilical cord plasma (r = 0.55, p = 0.04). CONCLUSIONS: More research is needed to explore the relationships between insulin and leptin hormones in neonate's saliva. PMID- 24471817 TI - Endothelial and neuronal nitric oxide synthases variably modulate the oestrogen mediated control of blood pressure and cardiovascular autonomic control. AB - 1. We have shown previously that long-term oestrogen (E2) replacement lowers blood pressure (BP) and improves cardiovascular autonomic control in ovariectomized (OVX) rats. In the present study, we investigated whether constitutive and/or inducible (i) nitric oxide synthase (NOS) modulate these E2 effects. 2. We evaluated changes in BP, myocardial contractility index (dP/dtmax ) and power spectral indices of haemodynamic variability following selective inhibition of endothelial (e) NOS with N(5)-(1-iminoethyl)-L-ornithine (L-NIO), neuronal (n) NOS with N(omega)-propyl-L-arginine (NPLA) or iNOS with 1400W in telemetered OVX rats treated for 16 weeks with (OVXE2) or without (control; OVXC) E2. 3. The OVXE2 rats exhibited: (i) reduced BP and increased dP/dtmax ; (ii) cardiac parasympathetic dominance, as reflected by the reduced low-frequency (LF; 0.25-0.75 Hz)/high-frequency (HF; 0.75-3 Hz) ratio of interbeat intervals (IBI(LF/HF)); and (iii) reduced LF oscillations of systolic BP, suggesting a reduced vasomotor sympathetic tone. Inhibition of eNOS (L-NIO; 20 mg/kg, i.p.) elicited a shorter-lived pressor response in OVXE2 than OVXC, rats along with reductions in dP/dtmax and increases in the spectral index of spontaneous baroreflex sensitivity (index alpha). Treatment with 1 mg/kg, i.p., NPLA reduced BP and increased the IBI(LF/HF) ratio in OVXE2 but not OVXC rats. The iNOS inhibitor 1400W (5 mg/kg, i.p.) caused no haemodynamic changes in OVXC or OVXE2 rats. 4. Overall, constitutive NOS isoforms exert restraining tonic modulatory BP effects that encompass eNOS-mediated reductions and nNOS-mediated elevations in BP in OVXE2 rats. Baroreflex facilitation and dP/dtmax reductions may account for the shorter pressor action of L-NIO in E2-treated, compared with untreated, OVX rats. PMID- 24471819 TI - Thermal decomposition approach for the formation of alpha-Fe2O3 mesoporous photoanodes and an alpha-Fe2O3/CoO hybrid structure for enhanced water oxidation. AB - Hematite (alpha-Fe2O3) is one of most investigated oxides for energy applications and specifically for photocatalysis. Many approaches are used to prepare well controlled films of hematite with good photocatalytic performance. However, most of these methods suffer from a number of disadvantages, such as the small quantities of the product, and the assembly of the nanostructures is usually a secondary process. Herein, we present a facile and large-scale synthesis of mesoporous hematite structures directly on various substrates at moderate temperature and study their photoelectrochemical (PEC) properties. Our approach is based on thermal decomposition of iron acetate directly on a substrate followed by an annealing process in air to produce a continuous mesoporous film of alpha-Fe2O3, with good control of the size of the pores. Improving the PEC properties of iron oxide was achieved by deposition of CoO domains, which were formed by thermal decomposition of cobalt acetate directly onto the hematite surface to produce alpha-Fe2O3/CoO nanostructures. PEC measurements of the hematite film before and after CoO growth were tested. Two methods were used to deposit the cobalt material: (a) thermal decomposition and (b) the most typically used method, adsorption of cobalt salt. The photocurrent of pure hematite was 0.25 mA/cm(2) at 1.23 V versus reversible hydrogen electrode (RHE), while modification of the hematite surface using the thermal decomposition method showed 180% improvement (0.7 mA/cm(2) at 1.23 V vs RHE) and 40% improvement (0.35 mA/cm(2) at 1.23 V vs RHE) via the adsorption method. Moreover, the onset potential was shifted by 130 and 70 mV when the surface of the hematite was modified by the thermal decomposition and adsorption methods, respectively. PMID- 24471820 TI - Case report: prenatal diagnosis of Hb Hammersmith [beta42(CD1)Phe->Ser; HBB: c.128T > C] in a family with an adult male patient. AB - Hb Hammersmith [beta42(CD1)Phe -> Ser; HBB: c.128T > C] is a rare, unstable hemoglobin (Hb) variant. In this case report, we describe another male case of Hb Hammersmith. A 39-year-old male had hemolytic anemia, cyanosis and splenomegaly since 6 months after birth. He passed the disease allele to his daughter, a 3 year-old girl, who also had hemolytic anemia and splenomegaly. This mutation was not identified in the parents and two brothers of the father. Early prenatal diagnosis was performed in the second pregnancy in this family. This is the first case of Hb Hammersmith in an adult male patient. PMID- 24471821 TI - Red cell distribution width, haemoglobin A1c and incidence of diabetes mellitus. AB - OBJECTIVE: Hyperglycaemia has multiple effects on the red blood cell (RBC), including glycation of haemoglobin, reduced deformability and reduced lifespan. Red cell distribution width (RDW) is a measure of the heterogeneity of erythrocyte volumes. The aim of this study was to explore the relationships between RDW and glucose, haemoglobin A1c (HbA1c) and incidence of diabetes mellitus (DM). DESIGN, SETTING AND SUBJECTS: RDW and mean corpuscular volume were measured in 26 709 non-diabetic participants (aged 45-73 years) from the population-based Malmo Diet and Cancer cohort. HbA1c and fasting venous blood glucose levels were measured in 4845 subjects. MAIN OUTCOME MEASURE: Incidence of DM (n = 2944) over 14 years of follow-up was studied by linkage with national and local DM registers. RESULTS: Individuals with low RDW had significantly higher risk of developing DM [adjusted hazard ratio (HR) 1.48, 95% confidence interval (CI) 1.29-1.70, for 1st vs. 4th quartile], especially in subjects with impaired fasting glucose (n = 416) (HR 2.15, 95% CI 1.12-4.14). Low RDW was also associated with significantly higher waist circumference and glucose, insulin and triglyceride concentrations. By contrast, RDW was significantly and positively associated with HbA1c, corresponding an increase in HbA1c of 0.10% per 1 SD increase in RDW. CONCLUSION: Low RDW is associated with increased incidence of DM independently of other risk factors. We propose that low RDW could be a surrogate marker of reduced RBC survival, with lower HbA1c due to shorter duration of glucose exposure. RDW is a biomarker that could improve risk assessment for individuals at risk of developing DM. PMID- 24471822 TI - Obstructive sleep apnea syndrome and cognition in Down syndrome. AB - AIM: Good-quality sleep is essential for normal learning and memory. Sleep fragmentation and disrupted sleep architecture are commonly observed throughout the lifespan of individuals with Down syndrome, a condition marked by cognitive deficits emerging within the first few months of life. While obstructive sleep apnea syndrome (OSAS) is known to contribute to the loss of sleep quality in Down syndrome, its relation to cognitive and behavioral impairment remains poorly understood. METHOD: Using ambulatory polysomnography, we measured sleep in an unreferred community-based sample of 38 individuals with Down syndrome (15 males, 23 females; mean age 9y 7mo (SD 1y 9mo), range 7-12y). Cognitive outcomes were assessed with the Arizona Cognitive Test Battery, a set of psychometric measures designed and validated for this population. RESULTS: Among children with Down syndrome, mean Verbal IQ score (p=0.006) was 9 points lower in those with comorbid OSAS (apnea-hypopnea index >1.5) than in those without OSAS, and performance on measures of cognitive flexibility was poorer (p=0.03). In addition, those with OSAS showed increased light-stage sleep (p=0.009) at the expense of slow-wave sleep (p=0.04). INTERPRETATION: These findings demonstrate a relation between OSAS and cognitive outcomes in Down syndrome. More work is required to fully understand the mechanisms underlying the links between poor sleep and impaired cognitive function. Overall, these findings highlight the importance of adequate sleep in typically and atypically developing populations. PMID- 24471823 TI - Modulating drug release profiles by lipid semi solid matrix formulations for BCS class II drug--an in vitro and an in vivo study. AB - The main objective of the study was to alter the dissolution profile of a practically insoluble Biopharmaceutics Classification System class II drug, aceclofenac, by formulating into lipid semisolid matrix (SSM) formulations using liquid filling technology in hard gelatin capsules, for both immediate and sustained release. SSM formulations of aceclofenac were prepared by melt fusion technique, using Gelucires (44/14, 50/13, 33/01 and 43/01), polyethylene glycols (4000 and 6000) and Poloxamer 188 at different levels. Role of additives like docusate sodium, Tween 80, Aerosil 200 and polyvinylpyrrolidone K-30 in enhancement of drug release was investigated. The optimized immediate and sustained SSM capsules were characterized in terms of assay, in vitro drug release, moisture uptake and differential scanning calorimetry. More than 80% of the drug was released within 15 min in various dissolution media studied, from Gelucire 44/14-based immediate release formulations. Incorporation of docusate sodium and Tween 80 provided further enhancement in drug dissolution when compared to plain drug and marketed tablet. SSM formulations based on Gelucire blends of 50/13 and 43/01 and 44/14 and 43/01 sustained the release of the drug for a period of 24 h following zero-order kinetics. The in vivo study of the optimized immediate release and sustained release formulations revealed significant enhancement in anti inflammatory activity (p < 0.01) in rats. From these findings, liquid fill technique in hard gelatin capsules using Gelucire and their blends might be an efficacious approach for designing immediate or sustained drug release profiles for poorly soluble drugs like aceclofenac. PMID- 24471824 TI - Two new species of Encotyllabe (Monogenea: Capsalidae) based on morphometric and molecular evidence: parasites of two inshore fish species of northern Chile. AB - Two new species, Encotyllabe cheilodactyli and Encotyllabe antofagastensis (Monogenea: Capsalidae), have been found in the pharyngeal plates of Cheilodactylus variegatus and Anisotremus scapularis, respectively, in northern Chile (23 degrees 38'N, 70 degrees 24'W). Descriptions of the new species were based on morphometric and molecular evidence. Both species differ from previously described species of the genus by a combination of characteristics, including the size and relative position of the testes and the shapes of the major and small hamulus. In addition, E. cheilodactyli is unique among the known species of Encotyllabe due to the testes crossing the equatorial line of the body proper, and E. antofagastensis is unique among the known species of Encotyllabe due to its penis structure and anatomy leading to the genital pore. The analysis of the cytochrome c oxidase I gene as well as morphometric analyses demonstrated that the specimens belonged to 2 different species. PMID- 24471825 TI - The impact of perioperative blood transfusion on survival after nephrectomy for non-metastatic renal cell carcinoma (RCC). AB - OBJECTIVE: To evaluate the association of perioperative blood transfusion (PBT) with survival after nephrectomy. PATIENTS AND METHODS: We identified 2318 patients who underwent partial or radical nephrectomy at Mayo Clinic between 1990 and 2006. PBT was defined as transfusion of allogenic red blood cells during surgery or postoperative hospitalisation. Survival was estimated using the Kaplan Meier method and compared with the log-rank test. Cox proportional hazards regression models were used to evaluate the association of PBT with outcome. RESULTS: In all, 498 patients (21%) received a PBT. The median (interquartile range) number of units transfused was 3 (2, 5). Patients receiving a PBT were significantly older at surgery (P < 0.001), more likely to be female (P < 0.001), with more frequent symptomatic presentation (P < 0.001), worse Eastern Cooperative Oncology Group performance status (P < 0.001), and more frequent adverse pathological features, such as high nuclear grade (P < 0.001), locally advanced tumour stage (P < 0.001) and lymph node invasion (P < 0.001). The median follow-up was 9.1 years. Receipt of a PBT was associated with adverse 5-year cancer-specific (68% vs 92%; P < 0.001) and overall (56% vs 82%; P < 0.001) survival. On multivariate analyses, PBT remained associated with higher risk of death from any cause (hazard ratio [HR] 1.23; P = 0.02). Among patients who received a PBT, an increasing number of units transfused was independently associated with increased all-cause mortality (HR 1.08; P = 0.001). CONCLUSION: PBT is associated with a significantly increased risk of mortality after nephrectomy. While external validation is needed, continued efforts to minimise the use of blood products in these patients are warranted. PMID- 24471826 TI - Hydrogen-bond-mediated aglycone delivery: focus on beta-mannosylation. AB - O-Picoloyl groups at remote positions can mediate the course of glycosylation reactions by providing high facial selectivity for the H-bond-mediated attack of the glycosyl acceptor. A new practical method for the stereoselective synthesis of beta-mannosides at ambient temperature is presented. PMID- 24471827 TI - Lower urinary tract symptoms and urodynamic dysfunction in clinically isolated syndromes suggestive of multiple sclerosis. AB - BACKGROUND AND PURPOSE: Urinary symptoms associated with multiple sclerosis (MS) are common and negatively impact on quality of life, representing a considerable psychosocial and economic burden, often requiring care and hospitalization. Although the importance of identifying and adequately treating urinary symptoms in MS is now well recognized, there is no information, to date, about the real prevalence and impact of bladder symptoms in patients with clinically isolated syndromes (CISs) suggestive of MS. METHODS: The aim of the present study was to investigate, in a cohort of patients with a diagnosis of CIS suggestive of MS, the prevalence of urinary tract symptoms, their impact on quality of life measures and their association with functional urodynamic dysfunctions. Patients underwent a complete neurological and urological visit, urodynamic investigation and the MSQoL-54 questionnaire. RESULTS: Twenty-eight consecutive patients presenting with CISs were enrolled in the study; 53.6% of CIS patients reported urinary symptoms, 46.7% reporting irritative symptoms, 33.3% both irritative and obstructive symptoms and 20% obstructive symptoms alone. Urodynamic abnormalities were observed in 57.1% of the CIS patients. In 17.9% of the CIS patients urodynamic dysfunctions were asymptomatic. The presence of urinary symptoms was associated with lower scores on specific quality of life domains, particularly in women with obstructive symptoms. CONCLUSIONS: A high prevalence of urinary symptoms and urodynamic dysfunctions in patients with CISs and an association of urinary symptoms with quality of life measures were found. These results highlight the importance of identifying and optimally treating urinary symptoms also at the very early stages of MS. PMID- 24471828 TI - Comparative study of select biochemical markers in cerebrospinal fluid of healthy dogs before and after treatment with nutraceuticals. AB - BACKGROUND: Several studies indicate that changes in cerebrospinal fluid (CSF) composition depend on the disease stage and reflect modification of brain energy metabolism (BEM). Also, it has been reported that a decline in cognitive functions may be mitigated by incorporating nutraceuticals in the diet. OBJECTIVE: Assuming the beneficial effect of nutraceuticals on BEM and oxidative damage, the aim of this study was to determine if the administration of a nutraceutical compound results in changes of select CSF biomarkers in healthy adult Beagle dogs. METHODS: Two separate CSF and blood samples were obtained from 11 healthy adult Beagle dogs, before and after 50 days of treatment with a veterinary combined nutraceutical. CSF analysis included a total nucleated cell count, total protein, glucose, sodium, chloride, potassium, pyruvate, and lactate concentrations, and calculation of lactate/pyruvate ratio. CBC and serum biochemistry were also performed. The Wilcoxon test was used to analyze the significance of the changes after nutraceutical treatment. RESULTS: All studied variables remained within reference intervals, before and after treatment. A significant increase in CSF sodium and glucose concentration, and a decrease in lactate levels, was observed after treatment (P < .05), and the lactate/pyruvate ratio was decreased after treatment (P = .05). In serum, sodium and chloride concentrations were significantly increased (P < .05), and creatinine concentration was significantly decreased (P < .05) after treatment. CONCLUSIONS: After 50 days of treatment with a nutraceutical compound, CSF glucose, sodium, and lactate concentrations, and L/P ratio were significantly different, suggesting an influence of nutraceuticals' administration on CSF composition. PMID- 24471829 TI - Two new hemoglobin variants: Hb Tallahassee [alpha3(A1)Ser->Tyr; HBA2: c.11C>A] and Hb madison-NC [beta119(GH2)Gly->Ser; HBB: c.358G>A]. AB - Of the 1570 reported hemoglobin (Hb) variants detected to date, 390 are alpha2 globin chain (some variants have yet to be identified by DNA analyses and are therefore presumed) and 827 are the result of mutations of the beta-globin chain. Due to their location on the Hb structure, only a minority of these variants result in a clinical phenotype; most are silent and are detected during routine surveillance, are found incidentally during other disease-related investigations or following newborn screening programs. In this report we discuss phenotype/genotype and molecular characteristics of two new Hb variants, both of which were clinically silent. One is an alpha2-globin chain variant located at codon 3 [alpha3(A1)Ser->Tyr; HBA2: c.11C > A] named Hb Tallahassee and the other is a beta-globin chain variant located at codon 119 [beta119(GH2)Gly->Ser; HBB: c.358G > A] called Hb Madison-NC. PMID- 24471830 TI - Layered metal(IV) phosphonates with rigid pendant groups: new synthetic approaches to nanosized zirconium phosphate phenylphosphonates. AB - Single phase mixed zirconium phosphate phenylphosphonates, ZrP(PP)x, were prepared by two different synthetic approaches: reaction of gels of nanosized alpha-zirconium phosphate in propanol with solutions of phenylphosphonic acid (H2PP), leading to the topotactic exchange of monohydrogen phosphate groups with phenylphosphonate groups, and precipitation from propanol solutions of H2PP, phosphoric acid, and zirconyl propionate. In both cases, propanol intercalated compounds were obtained. The x values of the ZrP(PP)x materials prepared by topotactic anion exchange ranged from 0.37 to 0.56 for (H2PP/Zr) molar ratios in the range 0.52-4.16 and [H2PP] = 0.1 M, while a maximum x value of 0.73 was only reached at 60 degrees C, with (H2PP/Zr) = 4.16 and [H2PP] = 0.31 M. Direct precipitation of ZrP(PP)x provided samples with 0.13 <= x <= 1.54, for H2PP molar fractions in the range 0.05-0.5 and (P/Zr) molar ratio = 6. At 90% relative humidity, the (H2O/Zr) molar ratio for the precipitated ZrP(PP)x powder samples increased in the range 1.3-3.0 with increasing x and resulted in being higher than that of nanosized ZrP (0.8). The analysis of the X-ray diffraction patterns of the gel and powder samples, together with the hydration data of the powder samples, suggested a structural model in which the random distribution of the phosphate and phenylphosphonate groups creates cavities which can accommodate propanol molecules in the gel samples and water molecules in the hydrated powder samples. PMID- 24471831 TI - Quantitative and in situ detection of oxidatively generated DNA damage 8,5'-cyclo 2'-deoxyadenosine using an immunoassay with a novel monoclonal antibody. AB - Xeroderma pigmentosum (XP) is a genetic disorder associated with defects in nucleotide excision repair, which eliminates a wide variety of helix-distorting types of DNA damage including sunlight-induced pyrimidine dimers. In addition to skin disease, approximately 30% of XP patients develop progressive neurological disease, which has been hypothesized to be associated with the accumulation of a particular type of oxidatively generated DNA damage called purine 8,5'-cyclo-2' deoxynucleosides (purine cyclonucleosides). However, there are no currently available methods to detect purine cyclonucleosides in DNA without the need for DNA hydrolysis. In this study, we generated a novel monoclonal antibody (CdA-1) specific for purine cyclonucleosides in single-stranded DNA that recognizes 8,5' cyclo-2'-deoxyadenosine (cyclo-dA). An immunoassay using CdA-1 revealed a linear dose response between known amounts of cyclo-dA in oligonucleotides and the antibody binding to them. The quantitative immunoassay revealed that treatment with Fenton-type reagents (CuCl(2)/H(2)O(2)/ascorbate) efficiently produces cyclo dA in DNA in a dose-dependent manner. Moreover, immunofluorescent analysis using CdA-1 enabled the visualization of cyclo-dA in human osteosarcoma cells, which had been transfected with oligonucleotides containing cyclo-dA. Thus, the CdA-1 antibody is a valuable tool for the detection and quantification of cyclo-dA in DNA, and may be useful for characterizing the mechanism(s) underlying the development of XP neurological disease. PMID- 24471833 TI - Pentatricopeptide repeat proteins in plants. AB - Pentatricopeptide repeat (PPR) proteins constitute one of the largest protein families in land plants, with more than 400 members in most species. Over the past decade, much has been learned about the molecular functions of these proteins, where they act in the cell, and what physiological roles they play during plant growth and development. A typical PPR protein is targeted to mitochondria or chloroplasts, binds one or several organellar transcripts, and influences their expression by altering RNA sequence, turnover, processing, or translation. Their combined action has profound effects on organelle biogenesis and function and, consequently, on photosynthesis, respiration, plant development, and environmental responses. Recent breakthroughs in understanding how PPR proteins recognize RNA sequences through modular base-specific contacts will help match proteins to potential binding sites and provide a pathway toward designing synthetic RNA-binding proteins aimed at desired targets. PMID- 24471834 TI - Molecular control of grass inflorescence development. AB - The grass family is one of the largest families in angiosperms and has evolved a characteristic inflorescence morphology, with complex branches and specialized spikelets. The origin and development of the highly divergent inflorescence architecture in grasses have recently received much attention. Increasing evidence has revealed that numerous factors, such as transcription factors and plant hormones, play key roles in determining reproductive meristem fate and inflorescence patterning in grasses. Moreover, some molecular switches that have been implicated in specifying inflorescence shapes contribute significantly to grain yields in cereals. Here, we review key genetic and molecular switches recently identified from two model grass species, rice (Oryza sativa) and maize (Zea mays), that regulate inflorescence morphology specification, including meristem identity, meristem size and maintenance, initiation and outgrowth of axillary meristems, and organogenesis. Furthermore, we summarize emerging networks of genes and pathways in grass inflorescence morphogenesis and emphasize their evolutionary divergence in comparison with the model eudicot Arabidopsis thaliana. We also discuss the agricultural application of genes controlling grass inflorescence development. PMID- 24471835 TI - Light regulation of plant defense. AB - Precise allocation of limited resources between growth and defense is critical for plant survival. In shade-intolerant species, perception of competition signals by informational photoreceptors activates shade-avoidance responses and reduces the expression of defenses against pathogens and insects. The main mechanism underlying defense suppression is the simultaneous downregulation of jasmonate and salicylic acid signaling by low ratios of red:far-red radiation. Inactivation of phytochrome B by low red:far-red ratios appears to suppress jasmonate responses by altering the balance between DELLA and JASMONATE ZIM DOMAIN (JAZ) proteins in favor of the latter. Solar UVB radiation is a positive modulator of plant defense, signaling through jasmonate-dependent and jasmonate independent pathways. Light, perceived by phytochrome B and presumably other photoreceptors, helps plants concentrate their defensive arsenals in photosynthetically valuable leaves. The discovery of connections between photoreceptors and defense signaling is revealing novel mechanisms that control key resource allocation decisions in plant canopies. PMID- 24471836 TI - Division and dynamic morphology of plastids. AB - Plastid division is fundamental to the biology of plant cells. Division by binary fission entails the coordinated assembly and constriction of four concentric rings, two internal and two external to the organelle. The internal FtsZ ring and external dynamin-like ARC5/DRP5B ring are connected across the two envelopes by the membrane proteins ARC6, PARC6, PDV1, and PDV2. Assembly-stimulated GTPase activity drives constriction of the FtsZ and ARC5/DRP5B rings, which together with the plastid-dividing rings pull and squeeze the envelope membranes until the two daughter plastids are formed, with the final separation requiring additional proteins. The positioning of the division machinery is controlled by the chloroplast Min system, which confines FtsZ-ring formation to the plastid midpoint. The dynamic morphology of plastids, especially nongreen plastids, is also considered here, particularly in relation to the production of stromules and plastid-derived vesicles and their possible roles in cellular communication and plastid functionality. PMID- 24471838 TI - Regulation and dynamics of the light-harvesting system. AB - Photosynthetic organisms are continuously subjected to changes in light quantity and quality, and must adjust their photosynthetic machinery so that it maintains optimal performance under limiting light and minimizes photodamage under excess light. To achieve this goal, these organisms use two main strategies in which light-harvesting complex II (LHCII), the light-harvesting system of photosystem II (PSII), plays a key role both for the collection of light energy and for photoprotection. The first is energy-dependent nonphotochemical quenching, whereby the high-light-induced proton gradient across the thylakoid membrane triggers a process in which excess excitation energy is harmlessly dissipated as heat. The second involves a redistribution of the mobile LHCII between the two photosystems in response to changes in the redox poise of the electron transport chain sensed through a signaling chain. These two processes strongly diminish the production of damaging reactive oxygen species, but photodamage of PSII is unavoidable, and it is repaired efficiently. PMID- 24471839 TI - Renal vascular structural properties and their alterations by removal of uraemic toxins in a rat model of chronic kidney disease. AB - 1. Renal vascular structural properties and their alterations by removal of uraemic toxins with AST-120, an oral adsorbent, were examined in subtotal nephrectomized rats. 2. Eight- or 9-week-old Sprague-Dawley rats received 3/4 nephrectomy (n = 18) and thereafter were fed 24.5% protein diet with (AST; n = 9) or without (AST-; n = 9) AST-120 (0.4 g/100 g bodyweight). Sham-operated rats (Sham; n = 9) received the diet without AST-120. At 21-22 weeks of age, flow pressure (F-P) and pressure-glomerular filtration rate (P-GFR) relationships were determined for maximally vasodilated, perfused kidneys. 3. The gradient of F-P (minimal renal vascular resistance reflecting the overall luminal dimensions of pre- and post-glomerular vasculature) was lower in AST- than Sham rats. In contrast, the x-intercept (preglomerular : post-glomerular vascular resistance ratio) and gradient (glomerular filtration capacity) of P-GFR did not differ between the two groups. The vascular wall and lumen at the interlobular arteries were greater in AST- than Sham rats. 4. Although the vascular wall and lumen at the interlobular arteries were less in AST than in AST- rats, the gradient of F-P and the x-intercept of P-GFR did not differ between the two groups. In contrast, the glomerular filtration capacity was greater in AST than AST- rats. 5. In conclusion, the lumen of both pre- and post-glomerular resistance vessels increased and glomerular filtration capacity failed to increase in subtotal nephrectomized rats. Uraemic toxins could play an important role in the development of structural alterations in glomeruli rather than renal resistance vessels in chronic kidney disease. PMID- 24471837 TI - To gibberellins and beyond! Surveying the evolution of (di)terpenoid metabolism. AB - The diterpenoids are classically defined by their composition--four isoprenyl units (20 carbons)--and are generally derived from [E,E,E]-geranylgeranyl diphosphate (GGPP). Such metabolism seems to be ancient and has been extensively diversified, with ~12,000 diterpenoid natural products known. Particularly notable are the gibberellin phytohormones, whose requisite biosynthesis has provided a genetic reservoir that gave rise to not only a large superfamily of ~7,000 diterpenoids but also, to some degree, all plant terpenoid natural products. This review focuses on the diterpenoids, particularly the defining biosynthetic characteristics of the major superfamilies defined by the cyclization and/or rearrangement of GGPP catalyzed by diterpene synthases/cyclases, although it also includes some discussion of the important subsequent elaboration in the few cases where sufficient molecular genetic information is available. It additionally addresses the array of biological activity providing the selective pressures that drive the observed gene family expansion and diversification, along with biosynthetic gene clustering. PMID- 24471840 TI - Time dependence of elimination of different PEth homologues in alcoholics in comparison with social drinkers. AB - BACKGROUND: Phosphatidylethanol (PEth) is a direct marker of alcohol consumption, which has been known for almost 30 years. Each PEth molecule carries 2 fatty acids, which differ in chain length and degree of unsaturation. It is formed by means of phospholipase D in the presence of ethanol. Usually, this marker was used by quantification of the PEth homologue 16:0/18:1. The intention of this work was to get more information about the distribution and the quantity of the different PEth homologues. METHODS: Blood samples from 12 alcohol-dependent subjects were collected and analyzed during withdrawal therapy. For comparison, blood from 78 healthy social drinkers was also analyzed. PEth analysis was performed as follows: after liquid-liquid extraction, the homologues were separated on a Luna Phenyl Hexyl column, injected to an HPLC system (1100 system; Agilent) and identified by ESI-MS/MS (QTrap 2000; AB Sciex) using multiple reaction monitoring. RESULTS: PEth 16:0/18:1 is the major homologue comparing the area ratios of PEth homologues in blood samples from alcoholics. Additional prevalent homologues were PEth 16:0/18:2, 18:0/18:2, and 18:0/18:1. The homologues occurring in blood samples from alcoholics as well as from social drinkers were mostly the same, but differences among their distribution pattern were observed. CONCLUSIONS: In addition to the approach to quantitate the PEth homologue 16:0/18:1, this is a new and alternative proceeding for the differentiation between alcoholics and social drinkers using this alcohol consumption marker. PMID- 24471841 TI - Hockey Concussion Education Project, Part 3. White matter microstructure in ice hockey players with a history of concussion: a diffusion tensor imaging study. AB - OBJECT: The aim of this study was to examine the brain's white matter microstructure by using MR diffusion tensor imaging (DTI) in ice hockey players with a history of clinically symptomatic concussion compared with players without a history of concussion. METHODS: Sixteen players with a history of concussion (concussed group; mean age 21.7 +/- 1.5 years; 6 female) and 18 players without a history of concussion (nonconcussed group; mean age 21.3 +/- 1.8 years, 10 female) underwent 3-T DTI at the end of the 2011-2012 Canadian Interuniversity Sports ice hockey season. Tract-based spatial statistics (TBSS) was used to test for group differences in fractional anisotropy (FA), axial diffusivity (AD), radial diffusivity (RD), and the measure "trace," or mean diffusivity. Cognitive evaluation was performed using the Immediate Postconcussion Assessment and Cognitive Test (ImPACT) and the Sport Concussion Assessment Tool-2 (SCAT2). RESULTS: TBSS revealed a significant increase in FA and AD, and a significant decrease in RD and trace in several brain regions in the concussed group, compared with the nonconcussed group (p < 0.05). The regions with increased FA and decreased RD and trace included the right posterior limb of the internal capsule, the right corona radiata, and the right temporal lobe. Increased AD was observed in a small area in the left corona radiata. The DTI measures correlated with neither the ImPACT nor the SCAT2 scores. CONCLUSIONS: The results of the current study indicate that a history of concussion may result in alterations of the brain's white matter microstructure in ice hockey players. Increased FA based on decreased RD may reflect neuroinflammatory or neuroplastic processes of the brain responding to brain trauma. Future studies are needed that include a longitudinal analysis of the brain's structure and function following a concussion to elucidate further the complex time course of DTI changes and their clinical meaning. PMID- 24471842 TI - Is there a place in infertility practice for the use of oil-based tubal flushing? PMID- 24471843 TI - Looking for the second patient: current practice and opinion on pre-operative pregnancy testing in Western Australia. AB - INTRODUCTION: To determine current hospital practices and the opinions of senior health professionals working in Western Australian (WA) hospitals performing gynaecological procedures regarding pre-operative pregnancy testing. METHODS: Anonymous questionnaire survey sent to all WA public and private hospitals' senior clinical staff (38 units where gynaecological surgery was performed in WA). RESULTS: Sixty-one senior health professionals (heads of department, medical directors, theatre nurse managers), completed the survey (estimated response rate 71%). Thirty-eight (68%) of respondents' units had guidelines for pre-operative pregnancy testing and 55% respondents worked in hospitals which tested all women of reproductive potential. Nineteen (33%) respondents reported cases in which patients had presented for surgery unaware they were pregnant. Forty-one (76%) respondents believed that all women of reproductive potential should have routine pre-operative pregnancy testing. Fifty-four (89%) supported the introduction of national or statewide guidelines. DISCUSSION: There are inconsistent processes of pre-operative assessment of pregnancy status in WA hospitals performing gynaecological surgery potentially resulting in adverse incidents. The majority of senior clinical staff surveyed supported routine pre-operative testing and the need for national or statewide guidelines. PMID- 24471844 TI - The evolving role of a gynaecologic oncologist in a tertiary hospital. AB - INTRODUCTION: Whilst the prime role of a gynaecologic oncologist is the comprehensive management of women with a gynaecologic cancer, their surgical skills are increasingly utilised for general gynaecological and obstetric surgery. Within tertiary centres, there is increasing provision of support by gynaecologic oncologists for both emergency and complex elective cases. AIM: The aim of the study was to investigate and define the expanding role of the gynaecologic oncologist within obstetrics and gynaecology. METHOD: A retrospective analysis of all nongynaecological oncology unit cases from 2006 to 2012 which required the presence of a gynaecologic oncologist in the operating theatre. RESULTS: A wide variety of cases that required the involvement of a gynaecologic oncologist were identified. These ranged from complications such as bowel injuries and haemorrhage to gynaecological surgeries in complicated patients, and obstetric patients with placenta accreta and intra-operative diagnosis of unexpected malignancy. CONCLUSION: The role of the gynaecologic oncologist within a tertiary centre is expanding to include the provision of support to general gynaecologists and obstetricians. There is increasing utilisation of the gynaecologic oncologist whereby their attendance is often pre arranged prior to the surgery. However, emergency cases requiring their assistance are not uncommon. PMID- 24471845 TI - The role of endometrial thickness for detecting endometrial pathologies in asymptomatic postmenopausal women. AB - BACKGROUND: The aim of the present study was to evaluate the significance of endometrial sampling in asymptomatic, bleeding-free postmenopausal women who have endometrial thickness greater or equal to 5 mm. METHODS: A retrospective review was conducted of all women who underwent transvaginal ultrasonography between January 2000 and March 2009 in a menopause clinic, who were found to have an endometrial thickness of at least 5 mm and who were subjected to endometrial sampling. RESULTS: Five hundred and thirty asymptomatic postmenopausal women underwent ultrasonographic evaluation with subsequent endometrial sampling. The mean endometrial stripe thickness was 8.7 mm (range: 6-26). Five cases of adenocarcinoma (0.9%) and 65 (12.2%) cases of simple/complex atypical hyperplasia were diagnosed. CONCLUSIONS: In this study, 106 investigations were performed to detect one case of adenocarcinoma. Although this is a high number per case detection of endometrial adenocarcinoma, considering the rising incidence of endometrial cancer, large prospective trials with surrogate criteria for asymptomatic women are needed to investigate the importance of thickened endometrial stripe in postmenopausal women. PMID- 24471846 TI - High-resolution microarray in the assessment of fetal anomalies detected by ultrasound. AB - AIMS: The main aim of this study was to determine the feasibility of using high resolution microarray to assist with prenatal diagnosis of ultrasound-detected fetal abnormality and to describe the frequency of abnormal results in different categories of fetal anomalies. METHODS: Prospective cross-sectional study was conducted on women diagnosed with a fetal anomaly (ies) between February 2009 and December 2011 who were offered testing by microarray analysis (Affymetrix 2.7M SNP) and fluorescent in situ hybridisation (FISH) instead of standard karyotyping. Fetal anomalies were categorised according to organ system involvement. RESULTS: One hundred and eighteen women consented to testing with microarray. Eleven of one hundred eighteen (9.3%) cases had aneuploidy detected by FISH. Of the remaining 107, 23 (21.5%) had an abnormality detected on microarray, only three of which would have been detected using the combination of six-probe FISH and banded karyotype. The maximum expected yield for six-probe FISH and karyotype was thus 14/118 (11.8%), compared to 34/118 (28.8%), P < 0.0001. Of the 23 abnormalities detected with microarray, 10 (43%) were pathogenic, six (26%) were long continuous stretches of homozygosity and seven (30%) were of uncertain significance. The maximum yield was in cases with cardiovascular (100%); multiple (40%); central nervous system (CNS) (25%) and skeletal (9%) abnormalities. CONCLUSION: This study has confirmed the feasibility of translation of microarray into clinical practice. 11.8% (14/118) of the cases would have a genetic basis of an abnormality with a FISH and banded karyotype. This figure is approximately tripled to 28.8% (34/118) if we offer FISH and microarray. High yield for imbalances are multiple, cardiovascular, CNS and skeletal abnormalities. PMID- 24471847 TI - Smoking rates and smoking cessation preferences of pregnant women attending antenatal clinics of two large Australian maternity hospitals. AB - BACKGROUND: Tobacco smoking is the most important preventable cause of many adverse pregnancy outcomes. Some women continue to smoke during pregnancy although the harmful effects are evident. AIMS: To characterise pregnant smokers and to understand their smoking behaviours and preferences for smoking cessation. MATERIALS AND METHODS: Pregnant women (>=18 years) attending the antenatal clinics of two large Victorian maternity hospitals completed a prepiloted questionnaire which included items regarding socio-demographics, smoking habits and attitudes towards quitting. RESULTS: Smoking status was self-reported by 1899 participants; 125 (6.6%) were current smokers and 604 (31.8%) were ex-smokers. There were 87 (69.6%) daily smokers and 38 (30.4%) occasional smokers. Smokers mainly had medium (54; 43.2%) or heavy nicotine dependence (45; 36%). Current smokers were younger, Australian born, not living with a partner, from a lower socio-economic background, multigravida and had a smoker in their household or among friends. Although pregnant smokers were aware of the possible complications of smoking, their motivation and confidence to quit (median) on a 10-point scale were 7 and 4, respectively. The majority of smokers preferred to stop smoking gradually (74; 71.2%). The preferred methods for quitting were medications (49; 47.6%) and hypnotherapy (35; 34.0%). Patches (28; 29.5%) were the preferred dosage form, and nicotine replacement therapy (25; 28.1%) was the preferred medication. Less than half reported that their health professionals discouraged smoking during pregnancy. CONCLUSIONS: Health professionals should be more proactive in identifying smokers and offering smoking cessation support in pregnancy. Multidisciplinary smoking cessation interventions for pregnant smokers are warranted. PMID- 24471848 TI - Is place of birth associated with mode of birth? The effect of hospital on caesarean section rates in a public metropolitan health service. AB - BACKGROUND: The effects of place of birth on birth outcomes have been examined in several studies both locally and internationally. However, none has examined the impact on caesarean section rates of different level maternity hospitals operating within the one health service. This study aimed to examine the impact of place of (Hospital level 6; 4-5 or 4) on birth outcomes in a large metropolitan health service in Victoria. METHODS: A cross-sectional study utilising data on births to low-risk first-time mothers during 2010-2011. Data were obtained from the Birthing Outcome System (BOS) database of Monash Health. Unadjusted and adjusted analyses were undertaken using logistic regression to examine the association between place of birth and caesarean section. RESULTS: In this group of low-risk nulliparae, there was evidence of a significant association between place of birth and caesarean section. The lower the acuity of the hospital, the higher the odds for the caesarean section. Compared with the level 6 hospital, the AdjOR for caesarean section at the level 4 hospital was 1.81 (95% CI: 1.37-2.41) and at the level 4-5 hospital, 1.30 (95% CI: 1.0-1.7). CONCLUSIONS: Low-risk nulliparae in spontaneous labour giving birth at the level 4 hospital in this health service are at significantly increased risk of caesarean section. This may have implications for the organisation and resource management of other level 4 public maternity units. Care in a tertiary (level 6) service may not necessarily equate to the higher rates of intervention reported by others. PMID- 24471849 TI - Comparing fetal scalp lactate and umbilical cord arterial blood gas values. AB - BACKGROUND: Fetal scalp lactate has been shown to be as effective as scalp pH in predicting fetal outcomes. However, there is limited clinical evidence to demonstrate a strong correlation with fetal acidaemia at birth. AIMS: To compare the diagnostic accuracy of fetal scalp lactate and umbilical cord arterial blood gas values sampling, as it is used in clinical practice. METHODS: A retrospective cohort study was performed on 661 term (>=37 weeks) births where a fetal scalp lactate sample was taken during labour. Cases were excluded where either the lactate was taken greater than 1 h prior to delivery, incomplete cord gas analyses were available, or a sentinel hypoxic event occurred prior to delivery. The final data set included 229 microvolume scalp lactate measurements which were compared with neonatal paired cord blood gas values taken at delivery. RESULTS: A fetal scalp lactate measurement of >=4.8 mmol/L had a positive predictive value (PPV) of 1% and a negative predictive value (NPV) of 100% in predicting umbilical artery pH <=7.00, and a PPV of 5% and a NPV of 98% in predicting umbilical artery pH <=7.10. The sensitivity and specificity for these values were 100%, 23% and 90%, 23%, respectively. CONCLUSIONS: Fetal scalp lactate microsampling has a strong negative predictive value for fetal acidaemia at birth. PMID- 24471850 TI - Maternal outcome after conservative management of placenta percreta at caesarean section: a report of three cases and a review of the literature. AB - Retaining the placenta in situ at caesarean section for placenta percreta and awaiting placental reabsorption is widely practiced; however, there is limited evidence on the efficacy and complications of this strategy. We present three cases of placenta percreta managed conservatively and note that all three women experienced significant complications. A review of the literature showed that despite initial conservative management, 40% of women subsequently require emergency hysterectomy and 42% will experience major morbidity. PMID- 24471851 TI - Longitudinal variance of visceral fat thickness in pregnant adolescents. AB - This study aims to investigate the longitudinal change in visceral fat thickness (VFT) during normal pregnancy. A prospective cohort study with 75 primiparous adolescents was carried out in Petrolina, Brazil. VFT was evaluated by ultrasound between 12-20 weeks gestation and immediately after delivery. We noted a statistically significant increase in VFT; 1.3 cm +/- 1.0. No correlation was found between VFT and maternal anthropometric variables. VFT increases about 30% from the first to the second half of pregnancy in primiparous adolescents. PMID- 24471852 TI - Re: 'Does occiput posterior position in the second stage of labour increase the operative delivery rate?'. PMID- 24471853 TI - Correspondence about Mowat A, Minuzzo L, Wilson J. A necrotic uterus after a B Lynch Suture: fertility sparing surgery. Aust N Z J Obstet Gynaecol 2013; 53: 408 409. PMID- 24471854 TI - Re: a necrotic uterus after a B-Lynch Suture: fertility sparing surgery. Aust N Z J Obstet Gynaecol 2013; 53: 408-409. PMID- 24471856 TI - Solid self-nanoemulsifying drug delivery system (S-SNEDDS) for oral delivery of glimepiride: development and antidiabetic activity in albino rabbits. AB - CONTEXT: This study presents novel self-nanoemulsifying drug delivery system potential of oral delivering which leads poorly aqueous soluble drug glimepiride. OBJECTIVE: The objective of this study was to prepare solid self-nanoemulsifying drug delivery system (S-SNEDDS) for the improved oral delivery of glimepiride and to evaluate its therapeutic efficacy in albino rabbits. RESULTS AND DISCUSSION: The droplet size analyses revealed a droplet size of less than 200 nm. The solid state characterization of S-SNEDDS by scanning electron microscopy (SEM), X-ray powder diffraction and differential scanning calorimetry (DSC) revealed the absence of crystalline glimepiride in the S-SNEDDS. The in vitro dissolution studies revealed that the significant improvement in glimepiride release characteristics. The effect of S-SNEDDS on therapeutic efficacy of glimepride was assessed in albino rabbits by monitoring blood glucose levels and compared with free drug suspension, L-SNEDDS. The S-SNEDDS showed significant (p < 0.05) increase in in vitro drug release and therapeutic efficacy as compared with free drug. CONCLUSION: This study demonstrated that S-SNEDDS is a promising novel drug delivery system of glimepride to enhance oral delivery. PMID- 24471857 TI - Euodenine A: a small-molecule agonist of human TLR4. AB - A small-molecule natural product, euodenine A (1), was identified as an agonist of the human TLR4 receptor. Euodenine A was isolated from the leaves of Euodia asteridula (Rutaceae) found in Papua New Guinea and has an unusual U-shaped structure. It was synthesized along with a series of analogues that exhibit potent and selective agonism of the TLR4 receptor. SAR development around the cyclobutane ring resulted in a 10-fold increase in potency. The natural product demonstrated an extracellular site of action, which requires the extracellular domain of TLR4 to stimulate a NF-kappaB reporter response. 1 is a human-selective agonist that is CD14-independent, and it requires both TLR4 and MD-2 for full efficacy. Testing for immunomodulation in PBMC cells shows the induction of the cytokines IL-8, IL-10, TNF-alpha, and IL-12p40 as well as suppression of IL-5 from activated PBMCs, indicating that compounds like 1 could modulate the Th2 immune response without causing lung damage. PMID- 24471858 TI - Facile preparation of beta-haloporphyrins as useful precursors of beta substituted porphyrins. AB - beta-Haloporphyrins were efficiently prepared by halogenation of beta borylporphyrins with N-halosuccinimide and copper(I) halide. beta-Haloporphyrins are useful precursors to synthesize a wide variety of beta-substituted porphyrins through Pd-catalyzed cross-coupling reactions. PMID- 24471859 TI - Resistance training promotes increase in intracellular hydration in men and women. AB - The main purpose of the present study was to investigate the effect of 16 weeks of resistance training (RT) on body water in men and women. Thirty men (22.7 +/- 4.4 years, 68.4 +/- 9.0 kg and 174.5 +/- 6.6 cm) and 34 women (22.7 +/- 4.1 years, 58.8 +/- 11.9 kg and 162.6 +/- 6.2 cm) underwent progressive RT for 16 weeks (2 phases, 8 weeks each), 3 times per week, that consisted of 10-12 whole body exercises with 3 sets of 8-12 repetitions maximum. Total body water, TBW (intracellular water, ICW and extracellular water, ECW compartments) and skeletal muscle mass (SMM) were assessed using a spectral bioelectrical impedance device (Xitron 4200 Bioimpedance Spectrum Analyzer). TBW, ICW compartment and SMM increased significantly (P < 0.05) over time in men (+7.5%, +8.2% and +4.2%, respectively) and women (+7.6%, +11.0% +3.9%, respectively), with no sex by time interaction (P > 0.05). We conclude that progressive RT promotes an increase in body water, principally by intracellular content; however, the hydration status is not influenced by sex. PMID- 24471860 TI - Microsphere-coupled scanning laser confocal nanoscope for sub-diffraction-limited imaging at 25 nm lateral resolution in the visible spectrum. AB - We report a direct optical super-resolution imaging approach with 25 nm (~ lambda/17) lateral resolution under 408 nm wavelength illumination by combining fused silica and polystyrene microspheres with a conventional scanning laser confocal microscope (SLCM). The microsphere deposited on the target surface generates a nanoscale central lobe illuminating a sub-diffraction-limited cross section located on the target surface. The SLCM confocal pinhole isolates the reflected light from the near-field subdiffractive cross-section and suppresses the noises from the side lobe and the far-field paraxial focal point. The structural detail of the subdiffractive cross-section is therefore captured, and the 2D target surface near the bottom of microspheres can be imaged by intensity based point scanning. PMID- 24471861 TI - First molecular characterization of a Hepatozoon species (Apicomplexa: Hepatozoidae) infecting birds and description of a new species infecting storm petrels (Aves: Hydrobatidae). AB - During a survey of blood parasites in a population of Leach's and black storm petrels ( Oceanodroma leucorhoa and Oceanodroma melania) in Mexico, infection by a Hepatozoon species in erythrocytes of several birds was noted. Here we describe the species as Hepatozoon peircei sp. nov. Some species of Hepatozoon described from birds have been identified as lankesterellids when DNA molecular analyses were conducted. However, a sequence of 1,774 bp of the parasite found infecting storm petrels in this study clearly show the parasite is a species of the genus Hepatozoon. This is the first Hepatozoon species infecting birds to be characterized at the molecular level and the first found infecting erythrocytes and not leucocytes. PMID- 24471862 TI - Modern myths of percutaneous renal tumour mass biopsy. PMID- 24471863 TI - Congratulations to the winners of the 12 Pioneer Awards for seminal work in gene and cell therapy. PMID- 24471864 TI - Multiple sclerosis in children and adolescents: incidence and clinical picture - new insights from the nationwide German surveillance (2009-2011). AB - BACKGROUND AND PURPOSE: Pediatric multiple sclerosis (MS) clinical and incidence data have been reported for several countries but valid age dependent incidence data are not yet available. The true incidence of pediatric MS in Germany was estimated and the clinical characteristics at diagnosis according to the 2005 McDonald criteria are described. METHODS: Between 2009 and 2011 active prospective nationwide surveillance for MS in children and adolescents <=15 years included all pediatric hospitals, MS centers and private practices specialized in MS. Data were adjusted for under-reporting by capture-recapture from an independent second source. RESULTS: The estimated incidence of pediatric MS was 0.64 per 100,000 person-years with clear increase from age group <=10 (0.09/100,000) to 2.64 per 100,000 in age group 14-15 years. All had relapsing remitting disease with polysymptomatic onset in half of the cases. Spinal MRI with positive findings in two-thirds of patients contributed to diagnosis. CONCLUSION: Using an active prospective surveillance system and the McDonald criteria for first MS diagnosis the age-related incidence of pediatric MS in Germany was uncovered and is more common than in previous estimates. Thorough application of McDonald criteria and inclusion of spinal MRI data allowed for early diagnosis in almost 90% of cases. PMID- 24471865 TI - Toward nanoscale three-dimensional printing: nanowalls built of electrospun nanofibers. AB - Although the extreme miniaturization of components in integrated circuits and biochemical chips has driven the development of various nanofabrication technologies, the 3D fabrication of nanoscale objects is still in its infancy. Here we propose a novel method to fabricate a free-standing nanowall by the precise, repetitive deposition of electrospun polymer nanofibers. We show that the electrified nanojet, which tends to become unstable when traveling in air because of coulombic repulsion, can be stably focused onto the microline of a metal electrode. On the conducting line, the polymer nanojet is spontaneously stacked successively to form a wall-like structure. We rationalize the length of the wall by balancing the tension in the polymer fiber with the electrostatic interaction of the fiber with the metal ground. We also show that the length of a nanowall can be controlled by translating the substrate. This novel 3D printing scheme can be applied to the development of various 3D nanoscale objects including bioscaffolds, nanofilters, nanorobots, and nanoelectrodes. PMID- 24471866 TI - Stability of immunophenotypic lymphoid markers in fixed canine peripheral blood for flow cytometric analysis. AB - BACKGROUND: Flow cytometric analysis of blood samples for immunophenotyping lymphoproliferative diseases has become popular in veterinary medicine. Unfortunately, the use of this technique has been limited by the necessity to test samples within a short time frame after blood collection. A possible solution to this problem is the use of fixative products to preserve the stability of lymphoid antigens. OBJECTIVES: The aim of this study was to evaluate the expression of 5 lymphoid surface markers (CD3, CD4, CD8, CD21, and CD45) in blood samples collected in K3-EDTA and Cyto-Chex BCT tubes from healthy dogs. METHODS: Blood from 8 dogs was collected in K3-EDTA and Cyto-Chex BCT tubes and analyzed by flow cytometry at 6 hours, one day, 3 days, and 7 days after collection. Lymphocyte percentage, lymphocyte mor-phology, expression of lymphoid surface markers and mean fluorescence intensity (MFI) were recorded at each time point and compared. RESULTS: Lymphocyte percentage and morphology were preserved up to 3 days in samples collected in Cyto-Chex BCT, and lymphocyte percentage was mildly decreased on day 7. CD4, CD8, and CD21 were stable in Cyto-Chex BCT up to 7 days, whereas CD3 and CD45 showed a significant decrease in expression from day 3, with a decrease on average of 21% and 2.4%, respectively, on day 7. MFI was significantly decreased on day 7 for all markers except CD21. CONCLUSIONS: These findings indicate that storage of samples in Cyto-Chex BCT affects lymphoid marker expression and caution should be exercised when interpreting data produced on such samples. PMID- 24471867 TI - Mathematical modelling of enteric neural motor patterns. AB - 1. The enteric nervous system modulates intestinal behaviours, such as motor patterns and secretion. Although much is known about different types of neurons and simple reflexes in the intestine, it remains unclear how complex behaviours are generated. 2. Mathematical modelling is an important tool for assisting the understanding of how the neurons and reflexes can be pieced together to generate intestinal behaviours. 3. Models have identified a functional role for slow excitatory post-synaptic potentials (EPSPs) by distinguishing between fast and slow EPSPs in the ascending excitation reflex. These models also discovered coordinated firing of similarly located neurons as emergent properties of feed forward networks of interneurons in the intestine. A model of the recurrent network of intrinsic sensory neurons identified important control mechanisms to prevent uncontrolled firing due to positive feedback and that the interaction between these control mechanisms and slow EPSPs is necessary for the networks to encode ongoing sensory stimuli. This model also showed that such networks may mediate migrating motor complexes. 4. A network model of vasoactive intestinal peptide neurons in the submucosal plexus found this relatively sparse recurrent network could produce uncontrolled firing under conditions that appear to be related to cholera toxin-induced hypersecretion. 5. Abstract modelling of the intestinal fed-state motor patterns has identified how stationary contractions can arise from a polarized network. 6. These models have also helped predict and/or explained pharmacological evidence for two rhythm generators and the requirement of feedback from contractions in the circular muscle. PMID- 24471868 TI - Comparison of alfuzosin 10 mg with or without propiverine 10 mg, 20 mg in men with lower urinary tract symptom and an overactive bladder: randomised, single blind, prospective study. AB - PURPOSE: The efficacy and safety of treatment with alfuzosin 10 mg plus propiverine 10 or 20 mg in men with lower urinary tract symptoms (LUTS) and an overactive bladder were investigated. MATERIALS AND METHODS: In this parallel arm, prospective, multicentre, single-blind study, men who were >= 40 years old, had an International Prostate Symptom Score (IPSS) of >= 8, an Overactive Bladder Symptom Score (OABSS) of >= 3 and an OABSS urgency item score of >= 2 were randomised in a 1 : 1 :1 ratio to receive alfuzosin 10 mg alone (Group A) or with propiverine 10 mg (Group B) or 20 mg (Group C) for 8 weeks. Four and 8 weeks after commencing treatment, OABSS was measured along with IPSS, maximal urinary flow rate (Qmax ) and postvoid residual volume (PVR). Adverse events were recorded. RESULTS: A total of 135 men, including 43 in Group A, 48 in Group B and 44 in Group C, completed the study. Relative to baseline, all groups demonstrated significant reductions in OABSS and the IPSS after eight treatment weeks (p < 0.005). The improvement of OABSS in Group C was significantly greater than Group A and B (Group A: 0.70 +/- 1.94; Group B: 2.50 +/- 2.98; Group C: 4.30 +/- 3.40; p < 0.005). An observed improvement of Qmax and PVR in the three groups did not achieve statistical significance. Overall adverse event rates were higher in Group C but not significant compared with others. CONCLUSION: In patients with LUTS and overactive bladder, combined therapy with alfuzosin 10 mg plus propiverine 20 mg was significantly more effective than alfuzosin monotherapy and propiverine 10 mg combined therapy in terms of improving OABSS while not significantly affecting Qmax or PVR. PMID- 24471869 TI - Management of difficult airway patients and the use of a difficult airway registry at a tertiary care pediatric hospital. AB - BACKGROUND: Appropriate recognition and management of the pediatric difficult airway is essential. Two patient deaths in a 2-year period involving children with a known difficult airway led to the formation of the institution's multidisciplinary Difficult Airway Committee. METHODS: Patients with a suspected difficult airway or a known difficult airway are entered into a registry of difficult airway patients. A note describing the airway and any experiences at airway manipulation is entered as part of a difficult airway note in the patient's electronic medical record as soon as the patient is recognized as having a difficult airway. A call system has been developed to mobilize expert emergency airway assistance for these patients. Multiple additional methods are employed to ensure that all hospital personnel are aware that these patients are difficult to intubate. RESULTS: Since inception almost 6 years ago, 164 patients (mean age 9.2 years) have been enrolled in the difficult airway registry. Eighty seven patients (53%) had one of 28 identified syndromes or diagnoses. The most common reasons for airway obstruction were mandibular hypoplasia/micrognathia, decreased neck extension, and limited temporomandibular joint mobility. One hundred sixty-one patients (98%) in the registry were predicted by history or physical to have a difficult airway. The mortality of registry patients was 9.8% (n = 16) and was most commonly due to co-existing diseases. During the time period reviewed, there was one in-hospital death of a known difficult airway patient, in which expert airway assistance was not obtained in a timely fashion. CONCLUSION: The institution's difficult airway registry identifies patients with a suspected or known difficult airway. The presence of a difficult airway in children can usually be predicted based on history and physical examination by anesthesiologists and otolaryngologists. Providers without advanced airway skills, however, may not appreciate that an airway is difficult to intubate until multiple attempts have failed. Both redundant notification methods and a call system optimize medical care of these fragile patients. PMID- 24471870 TI - Oxonitridosilicate Y10(Si6O22N2)O2:Ce3+,Mn2+ phosphors: a facile synthesis via the soft-chemical ammonolysis process, luminescence, and energy-transfer properties. AB - Ce(3+)- and/or Mn(2+)-activated Y10(Si6O22N2)O2 phosphors have been prepared via a soft-chemical ammonolysis method. Structure refinement, scanning electron microscopy, high-resolution transmission electron microscopy, energy-dispersive X ray spectroscopy, Fourier transform infrared, and thermogravimetry analysis have been employed to characterize the phase purity, crystal structure, morphology, crystallization condition, chemical composition, and thermal stability of the products. The photoluminescence and cathodoluminescence properties for Ce(3+)- and Mn(2+)-doped Y10(Si6O22N2)O2 phosphors were studied in detail. For Ce(3+)/Mn(2+) singly doped Y10(Si6O22N2)O2 phosphors, typical emissions of Ce(3+) (blue) and Mn(2+) (reddish-orange) ions can be observed. Especially, Ce(3+) emission at different lattice sites 4f and 6h has been identified and discussed. Energy transfer from Ce(3+)(I) and Ce(3+)(II) to Mn(2+) ions in Y10(Si6O22N2)O2:Ce(3+),Mn(2+) samples has been validated and confirmed by the photoluminescence spectra and luminescence decay times. A color-tunable emission in Y10(Si6O22N2)O2:Ce(3+),Mn(2+) phosphors can be achieved by an energy-transfer process and a change in the doping concentration of the activators. The temperature-dependent photoluminescence properties and degradation property of cathodoluminescence under continuous electron bombardment of as-synthesized phosphors prove that the Y10(Si6O22N2)O2 host has good stability. Therefore, the Y10(Si6O22N2)O2:Ce(3+),Mn(2+) phosphors may potentially serve as single-phase blue/reddish-orange phosphors for white-light-emitting diodes and field-emission displays. PMID- 24471872 TI - Rates of concussion are lower in National Football League games played at higher altitudes. AB - STUDY DESIGN: Retrospective epidemiologic investigation. OBJECTIVE: To investigate the relationship between altitude and concussion rate in the National Football League (NFL). Because of the physiologic responses that occur during acclimatization to altitude, it was hypothesized that games played on fields at a higher altitude would have reduced concussion rates compared to games played on fields at a lower altitude. BACKGROUND: Recent research indicates that the elevation above sea level at which football games are played may be associated with the likelihood of a concussion in high school football athletes. METHODS: Data on incident concussions and athlete exposures for the first 16 weeks of the NFL 2012 and 2013 regular seasons were obtained from publicly available web-based sources and used to calculate competition concussion rates for each NFL stadium. Concussion rates were analyzed in relation to game elevation. RESULTS: During the first 16 weeks of the 2012 and 2013 NFL regular seasons, 300 concussions, involving 284 players, were reported (64.3 primary cases per 10,000 game exposures). The odds of a concussion were 30% lower when playing at a higher elevation (equal to or greater than 644 ft [196.3 m] above sea level) compared to a lower elevation (odds ratio = 0.70; 95% confidence interval: 0.53, 0.94). A multivariable generalized linear model controlling for season, week, and clustering of team at home and away confirmed these results, showing that the odds of at least 1 concussion were reduced by 32% in games played at higher elevation. CONCLUSION: The results of this epidemiological investigation indicate that increased altitude was associated with a reduction in the odds of a sport related concussion in NFL athletes. The reported relationship of concussion incidence and field elevation should be further investigated, and, if verified, further work will be needed to understand why that relationship exists. LEVEL OF EVIDENCE: Prognosis, level 2c. PMID- 24471875 TI - Taking action to preserve the miracle of antibiotics. PMID- 24471873 TI - Discovery of (E)-3-((styrylsulfonyl)methyl)pyridine and (E)-2 ((styrylsulfonyl)methyl)pyridine derivatives as anticancer agents: synthesis, structure-activity relationships, and biological activities. AB - ON01910.Na is a highly effective anticancer agent that induces mitotic arrest and apoptosis. Clinical studies with ON01910 in cancer patients have shown efficacy along with an impressive safety profile. While ON01910 is highly active against cancer cells, it has a low oral availability and requires continuous intravenous infusion or multiple gram doses to ensure sufficient drug exposure for biological activity in patients. We have identified two novel series of styrylsulfonyl methylpyridines. Lead compounds 8, 9a, 18 and 19a are highly potent mitotic inhibitors and selectively cytotoxic to cancer cells. Impressively, these compounds possess excellent pharmaceutical properties and two lead drug candidates 9a and 18 demonstrated antitumor activities in animal models. PMID- 24471876 TI - Guidelines for treatment of lice in sheep with long wool based on a model of the development of wool damage. AB - OBJECTIVE: This study used a model of the development of wool damage caused by lice in long wool to examine the conditions under which treatment of the sheep is advisable on an economic basis. METHODS: The model uses the proportion of a flock showing visible signs of rubbing and the number of days until the next shearing to compare the cost of treatment (product plus labour) with production losses because of the reduction in wool value caused by lice. From the model output, guidelines are provided to inform producers of the most cost-effective option for lice control. RESULTS: Under normal conditions, if there are any signs of rubbing >=140 days before shearing, then treatment was the best option. If signs of wool damage are not observed until there are <=70 days before shearing, then the most cost-effective option is to not treat at all. Between these two periods, the time period in which not treating is the most cost-effective option decreases as the number of sheep visibly affected by lice increases. At higher wool values (A$70/head vs A$35), the option to treat is brought forward approximately 25 days, whereas at a low wool value (A$17.50/head) the period in which no treatment is the most cost-effective is extended by approximately 25 days. Treating only the visibly affected sheep is the best option only for a very short time for all wool values and treatment costs. CONCLUSION: The model provides guidelines for control of lice in long wool to minimise the net cost of infestation and limit unnecessary pesticide use. PMID- 24471877 TI - Use of REP-PCR and 16S rRNA gene sequencing for comparison of Mannheimia haemolytica isolates obtained from fatal cases of bovine respiratory disease in the USA and Australia. AB - OBJECTIVE: Assess the variability of Mannheimia haemolytica isolates obtained from fatal cases of bovine respiratory disease (BRD) in the USA and Australia using repetitive sequence-based PCR (REP-PCR) and sequencing of the 16S ribosomal RNA (rRNA) gene. METHODS: We examined 22 isolates from the USA and 36 isolates from Australia using (GTG)5 and BOX-A1R REP-PCR primers, as well as sequencing a 700-base pair length of the 16S rRNA gene. The discriminatory ability of each typing method was assessed and correlation coefficients were calculated to assess concordance between the results of each approach. RESULTS: All methods appeared to discriminate among isolates, with BOX-A1R being the most sensitive and sequencing the least sensitive. Modest to moderate diversity was seen among the isolates, with as much variation within a continent as between the two. CONCLUSIONS: Using samples from diverse origins may permit extrapolation even to isolates with distant geographic and temporal relationships. Further, this information can serve as a baseline in assessing whether M. haemolytica is an opportunistic pathogen or if there are notable features that distinguish commensal isolates from those more likely to be associated with disease. PMID- 24471878 TI - Application of a real-time polymerase chain reaction assay to the diagnosis of bovine ephemeral fever during an outbreak in New South Wales and northern Victoria in 2009-10. AB - OBJECTIVE: To report the occurrence of an epizootic of bovine ephemeral fever (BEF) in New South Wales (NSW) and northern Victoria in 2009-10 and describe the application of a real-time reverse transcription polymerase chain reaction (qRT PCR) assay during the outbreak. PROCEDURES: Whole-blood samples from animals exhibiting clinical signs of BEF were requested from district veterinarians in NSW. In addition, samples were submitted from private practitioners in NSW and Victoria. In NSW, samples from animals showing acute clinical signs of BEF were tested using a qRT-PCR assay. Serological testing for BEF diagnosis was undertaken as required. Virus isolation was performed on selected samples in which bovine ephemeral fever virus (BEFV) RNA was detected. Archival serum samples and mosquito homogenates were also tested for BEFV by qRT-PCR. RESULTS: Accessions were received from 121 properties in NSW, with cases of BEF confirmed on 84 properties by qRT-PCR and 20 properties by serology. In northern Victoria, BEF was confirmed on 25 properties based on serological testing. Screening of samples by qRT-PCR enhanced the success of BEFV isolation. BEFV RNA was successfully detected in archival serum samples and a single mosquito homogenate. CONCLUSIONS: The 2009-10 outbreak resulted in the most extensive transmission of BEFV in NSW and Victoria since 1995-96, and follows a smaller outbreak in summer autumn 2008. The use of qRT-PCR for BEF diagnosis offers veterinarians and cattle owners rapid confirmation of infection (1-2 days) and provides 'real-time' information about the presence of the disease in a district. PMID- 24471879 TI - Cattle herd inspections and fly trapping for the detection of the Old World screw worm fly (Chrysomya bezziana). AB - OBJECTIVES: To compare the sensitivity of inspections of cattle herds and adult fly trapping for detection of the Old World screw-worm fly (OWS). PROCEDURES: The incidence of myiases on animals and the number of OWS trapped with LuciTrap(r)/Bezzilure were measured concurrently on cattle farms on Sumba Island (Indonesia) and in peninsular Malaysia (two separate periods for the latter). The numbers of animal inspections and traps required to achieve OWS detection at the prevalent fly densities were calculated. RESULTS: On Sumba Island, with low density OWS populations, the sensitivity of herd inspections and of trapping for OWS detection was 0.30 and 0.85, respectively. For 95% confidence of detecting OWS, either 45 inspections of 74 animals or trapping with 5 sets of 4 LuciTraps for 14 days are required. In Malaysia, at higher OWS density, herd inspections of 600 animals (twice weekly, period 1) or 1600 animals (weekly, period 2) always detected myiases (sensitivity = 1), while trapping had sensitivities of 0.89 and 0.64 during periods 1 and 2, respectively. For OWS detection with 95% confidence, fewer than 600 and 1600 animals or 2 and 6 LuciTraps are required in periods 1 and 2, respectively. CONCLUSIONS: Inspections of cattle herds and trapping with LuciTrap and Bezzilure can detect OWS populations. As a preliminary guide for OWS detection in Australia, the numbers of animals and traps derived from the Sumba Island trial should be used because the prevailing conditions better match those of northern Australia. PMID- 24471880 TI - Prevalence of bacteriuria in dogs without clinical signs of urinary tract infection presenting for elective surgical procedures. AB - OBJECTIVES: To determine the frequency of bacteriuria in dogs presenting for elective surgery, to compare the frequency of bacteriuria in dogs presenting for orthopaedic (non-neurological) procedures to that of dogs presenting for soft tissue procedures and to measure the agreement of microscopic visualisation of bacteria in urine sediment with the occurrence of bacterial growth on culture. METHODS: Prospective cohort study of 140 client-owned dogs. Urine was collected via prepubic cystocentesis prior to or immediately after induction of anaesthesia. Urine was submitted for quantitative bacteriological culture and urinalysis. The dogs' age, sex, weight and breed were recorded, as well as the surgical procedure performed. RESULTS: In total, 80 orthopaedic and 60 soft tissue surgical cases were included in the study; 3 dogs (2.1%) returned bacterial growth on culture (positive urine culture) and 19 (13.6%) recorded urine sediment with pyuria and/or bacteriuria on urinalysis (positive urinalysis). All dogs with positive urine culture were female and two of them underwent orthopaedic procedures. Each bitch had growth of Escherichia coli >10(5) CFU/mL. The agreement between positive urinalysis and positive urine culture was poor (kappa = 0.15). CONCLUSIONS: The prevalence of bacteriuria in dogs without clinical signs of urinary tract infection in this population was low (2.1%). An at-risk population could not be identified because of the small number of positive outcomes. A positive urinalysis showed poor agreement with urine culture results and therefore the decision to treat without performing a urine culture is not advised. PMID- 24471881 TI - Streptomyces cyaneus dermatitis in a dog. AB - BACKGROUND: A nearly 4-year-old neutered male Australian Terrier was referred for a nodular pyogranulomatous mass of the right axilla. It had been poorly responsive to antibiotic therapy. CASE REPORT: Based on filamentous Gram-positive organisms identified in earlier biopsy material, infection by an Actinomyces sp. was suspected and the dog showed clinical improvement on a trial of potentiated sulfonamides. Recurrence 5 months later prompted euthanasia, with Streptomyces cyaneus being cultured and confirmed by genetic sequencing of part of the 16 s ribosomal RNA gene. CONCLUSION: Invasive Streptomyces spp. infections are uncommon in humans and animals, and isolations are sometimes considered to be contaminants, but the demonstration of the organism within the lesion in this instance indicates that the isolation of a Streptomyces sp. from veterinary cases should not always be considered as contamination, because this genus is clearly pathogenic. PMID- 24471882 TI - Adenoviral infection in a collection of juvenile inland bearded dragons (Pogona vitticeps). AB - CASE REPORT: Juvenile inland bearded dragons (Pogona vitticeps) from a breeding collection in south-east Queensland were presented at age 6-10 weeks with neurological signs, poor growth and occasional deaths. Histopathological examination revealed that six of eight lizards had multifocal non-suppurative hepatitis associated with 5-10 MUm diameter, smudgy, basophilic, hyaline intranuclear inclusion bodies that marginated the nuclear chromatin. These histological lesions were considered consistent with adenoviral hepatitis. Infection with adenovirus was confirmed positive in one of the eight dragons by PCR for adenoviral DNA. DNA was extracted from formalin-fixed paraffin-embedded pooled tissues of the juvenile inland bearded dragons and tested using a nested PCR protocol with primers specific for identification of adenovirus. Sequencing of the one PCR-positive dragon showed 95% nucleotide sequence alignment with agamid atadenovirus 1. Further investigation involved testing the breeding population, including the parents of the affected juveniles. Blood and cloacal samples were collected from the adult population, DNA was extracted and tested by PCR for adenovirus. There was a high percentage of positive results from the samples collected from the breeding population. CONCLUSION: This is the first reported group outbreak of adenoviral disease in bearded dragons in Australia. PMID- 24471883 TI - Diagnostic challenge: mare with clinical history of chronic respiratory disease. Severe interstitial pneumonia. PMID- 24471885 TI - The emerging role of consolidation and maintenance therapy for transplant eligible multiple myeloma patients. AB - Multiple myeloma (MM) is an incurable malignant cancer of plasma cell origin. It is highly treatable with glucocorticoids, alkylating drugs, and novel agents including the proteasome inhibitors (bortezomib and carfilzomib) and the immunomodulatory drugs (IMiDs) thalidomide, lenalidomide and pomalidomide. Induction regimens incorporating the newer agents have resulted in deeper responses that have translated into prolonged response and survival for transplant eligible and transplant-ineligible MM patients. For the transplant eligible patient, the current approach to those patients requiring therapy is induction, hematopoietic stem cell (HSC) collection, autologous HSC transplant (AHSCT) which may be followed by consolidation. Maintenance therapies with bortezomib or lenalidomide prolong response and appear to improve overall survival. For very high risk patients, allogeneic (alloHSCT) is an alternative therapy that may improve survival for selected patients. Incorporation of new therapies in combination with existing agents should lead increased response and improved survival of the MM patient with the ultimate goal of development of curative approaches for this disease. PMID- 24471886 TI - Silver nanowire percolation network soldered with graphene oxide at room temperature and its application for fully stretchable polymer light-emitting diodes. AB - Transparent conductive electrodes with high surface conductivity, high transmittance in the visible wavelength range, and mechanical compliance are one of the major challenges in the fabrication of stretchable optoelectronic devices. We report the preparation of a transparent conductive electrode (TCE) based on a silver nanowire (AgNW) percolation network modified with graphene oxide (GO). The monatomic thickness, mechanical flexibility, and strong bonding with AgNWs enable the GO sheets to wrap around and solder the AgNW junctions and thus dramatically reduce the inter-nanowire contact resistance without heat treatment or high force pressing. The GO-soldered AgNW network has a figure-of-merit sheet resistance of 14 ohm/sq with 88% transmittance at 550 nm. Its storage stability is improved compared to a conventional high-temperature annealed AgNW network. The GO soldered AgNW network on polyethylene terephthalate films was processed from solutions using a drawdown machine at room temperature. When bent to 4 mm radius, its sheet resistance was increased by only 2-3% after 12,000 bending cycles. GO solder can also improve the stretchability of the AgNW network. Composite TCE fabricated by inlaying a GO-soldered AgNW network in the surface layer of polyurethane acrylate films is stretchable, by greater than 100% linear strain without losing electrical conductivity. Fully stretchable white polymer light emitting diodes (PLEDs) were fabricated for the first time, employing the stretchable TCE as both the anode and cathode. The PLED can survive after 100 stretching cycles between 0 and 40% strain and can be stretched up to 130% linear strain at room temperature. PMID- 24471887 TI - Hyperuricaemia: the unintended consequence of insulin resistance/compensatory hyperinsulinaemia. Philanthropy gone awry. PMID- 24471888 TI - Identification of rare and novel deletions that cause (deltabeta)0-thalassaemia and hereditary persistence of foetal haemoglobin in Indian population. AB - OBJECTIVES: Hereditary persistence of foetal haemoglobin (HPFH) and (deltabeta)(0) -thalassaemia are conditions caused by large deletions that involve delta- and beta-globin genes in the beta-globin cluster, and they are characterized by increased haemoglobin (HbF) levels in adults. Significant phenotypic diversity is observed between the different mutations that cause these conditions. Molecular characterization of these deletions is important for accurate molecular diagnosis, and they will also provide the information on the cis-acting genetic regulatory elements present in the beta-globin cluster. METHODS: We performed gap-PCR, multiplex ligation-dependent probe amplification (MLPA), quantitative fluorescent multiplex PCR (QF-MPCR) and DNA sequencing to detect and characterize the deletions in the beta-globin cluster. RESULTS: We characterized six different deletions resulting in (deltabeta)(0) -thalassaemia or HPFH in 51 unrelated families. CONCLUSION: With the help of multiple genetic tools, we performed comprehensive genetic analysis of HPFH and (deltabeta)(0) thalassaemia in Indian population and could define the molecular basis of these conditions in this population. We also identified two novel HPFH mutations, 49.98 kb (HPFH-9) and 86.7 kb (HPFH-10) deletions, in this population. PMID- 24471889 TI - Should anterior mitral block be preferred in persistent atrial fibrillation patients requiring nonpulmonary substrate ablation? PMID- 24471890 TI - Preparation, characterization, and antitumor activities of folate-decorated docetaxel-loaded human serum albumin nanoparticles. AB - CONTEXT: Docetaxel is now a major antitumor drug in clinical use for the treatment of a variety of tumors. The ethanol/Tween 80 solvent required in the formulation to increase the docetaxel solubility is at least partly responsible for the hypersensitivity reaction, decreased uptake by tumor tissue, and increased exposure to other body compartments. OBJECTIVE: The present study was aimed at developing hydrosoluble DTX-FA-HSANPs targeting tumor cells and to investigate antitumor activities of the nanoparticles. MATERIALS AND METHODS: The DTX-HSANPs were prepared using a desolvation technique and the carboxylic groups of NHS-folate were conjugated with the amino groups of the human serum albumin nanoparticles, and studied their size and zeta potential, drug loading efficiency, surface morphology, release properties in vitro, and antitumor activities. RESULTS: The spherical nanoparticles obtained were negatively charged with a zeta potential of about -30 mV and characterized around 150 nm with a narrow size distribution. Drug loading efficiency was approximately 17.2%. The folate-decorated nanoparticles targeted a human hepatoma cell line effectively. The in vitro drug release of DTX-FA-HSANPs in the first 96 h corresponded with the following equation: Q = 18.87851 - 0.13866t + 0.21276t2 - 0.00704t3 + 0.0000847854t4 - 0.00000034991t5 (R2 = 0.98155). Moreover, the in vitro antitumor activities of DTX-FA-HSANPs were close to the activities of the positive control (docetaxel). The in vivo inhibition ratios of DTX-FA-HSANPs and docetaxel were 66.2% and 59.5%, respectively, at a dose of 5 mg/kg. DISCUSSION AND CONCLUSION: In light of the observed antitumor activities, it would be of considerable interest to collect sufficient data for the clinical application of docetaxel loaded nanoparticles. PMID- 24471892 TI - Procyanidin induces apoptosis of esophageal adenocarcinoma cells via JNK activation of c-Jun. AB - Procyanidins are polymeric flavanols found in fruits and vegetables and have shown anticarcinogenic/chemopreventive properties. We previously showed that oligomeric procyanidin extracted from apples induced cell cycle arrest and apoptosis in esophageal adenocarcinoma (OA) cells. To understand the mechanism of action, we determined transcriptomic changes induced by procyanidin in OA cells. Pathway analysis implicated mitogen-activated protein kinase signaling pathways in eliciting these responses. Procyanidin induced the activation of JNK and p38 and the phosphorylation and expression of c-Jun. Inhibition of JNK but not p38 kinase activity prevented the procyanidin-induced phosphorylation and expression of c-Jun. Knockdown of the expression of JNK1, JNK2, or JUN diminished procyanidin-induced effects on cell proliferation and apoptosis. c-Jun is a component of the transcription factor AP-1 and AP-1 binding sites are overrepresented in the promoters of procyanidin-induced genes. This indicates that JNK activation of c-Jun by procyanidin leads to the induction of apoptosis of OA cells and suggests a role for a c-Jun-mediated transcriptional program. These data provide a mechanistic understanding of how procyanidin specifically targets a distinct pathway involved in the induction of apoptosis in OA cells and will inform future studies investigating its use as a chemopreventive/therapeutic agent. PMID- 24471891 TI - High rates of evolution preceded the origin of birds. AB - The origin of birds (Aves) is one of the great evolutionary transitions. Fossils show that many unique morphological features of modern birds, such as feathers, reduction in body size, and the semilunate carpal, long preceded the origin of clade Aves, but some may be unique to Aves, such as relative elongation of the forelimb. We study the evolution of body size and forelimb length across the phylogeny of coelurosaurian theropods and Mesozoic Aves. Using recently developed phylogenetic comparative methods, we find an increase in rates of body size and body size dependent forelimb evolution leading to small body size relative to forelimb length in Paraves, the wider clade comprising Aves and Deinonychosauria. The high evolutionary rates arose primarily from a reduction in body size, as there were no increased rates of forelimb evolution. In line with a recent study, we find evidence that Aves appear to have a unique relationship between body size and forelimb dimensions. Traits associated with Aves evolved before their origin, at high rates, and support the notion that numerous lineages of paravians were experimenting with different modes of flight through the Late Jurassic and Early Cretaceous. PMID- 24471893 TI - Ring chromosome 21 and monosomy 21 mosaicism in a patient with azoospermia. AB - In this report, we describe a patient with azoospermia in conjection with de novo ring chromosome 21 and monosomy 21 mosaicism. Inter-phase fluorescence in situ hybridisation (FISH) studies on uncultured peripheral blood and epithelial cells obtained by buccal smear revealed that 25% of the uncultured blood cells and 11% of the epithelial cells were monosomic for chromosome 21. Y chromosome microdeletion analysis ruled out the presence of any genomic deletions in the azoospermic factor a,b,c regions on the long arm of chromosome Y. Additionally, through subtelomeric FISH analysis, it was found that there was no deletion in the subtelomeric region of ring chromosome 21. Our results indicate that ring chromosome 21 is a rare, but recurrent chromosomal abnormality in male factor infertility. Furthermore, in individuals with ring chromosome 21, defective spermatogenesis is not associated with the deletion of any gene or genes located in the subtelomeric region of chromosome 21. PMID- 24471894 TI - The evaluation of analgesic effects of milnacipran and sertraline in tail-flick test. AB - INTRODUCTION: Antidepressant drugs are used in the treatment of pain as an adjuvant or alone. It has been shown that antidepressant drugs have analgesic effects in various diseases (diabetic neuropathy, low back pain, cancer pain etc.) Sertraline is a potent serotonin re-uptake inhibitor. Some antidepressant drugs inhibited both of the reuptake of serotonin and of noradrenaline. These drugs are called serotonin-noradrenaline re-uptake inhibitors (SNRIs). Milnacipran is a serotonin-noradrenaline re-uptake inhibitor. We have studied the analgesic effects of sertraline and milnacipran after acute and chronic application in tail-flick test in mice. METHODS: The analgesic effects of milnacipran (10, 30, 50 mg/kg) and sertraline (10, 20, 50 mg/kg) were measured after acute and chronic application in tail flick test. The analgesic effects of milnacipran (30 mg/kg) or sertraline (50 mg/kg) were evaluated after the application of L-NAME (10 mg/kg), naloxone (5 mg/kg), prazosin (1 mg/kg), ondansetron (0.1 mg/kg) in tail flick test. RESULTS: Milnacipran (30 mg/kg) and sertraline (50 mg/kg) produced statistically significant analgesic effect compared to their control values after acute and chronic application in tail flick test. The analgesic effects of both milnacipran (30 mg/kg) and sertraline (50 mg/kg) in the presence of L-NAME (10 mg/kg), naloxone (5 mg/kg), ondansetron (0.1 mg/kg) and prazosin (1 mg/kg) were inhibited in tail-flick test. CONCLUSION: These results indicate that the analgesic effects of milnacipran and sertraline are related to nitrergic, opioidergic, serotonergic and adrenergic system (Fig. 8, Ref. 23). PMID- 24471895 TI - Delta deletion 4977 in mitochondrial DNA in patients with idiopathic Parkinson's disease. AB - AIM: To determine the presence of delta deletion 4977 in mitochondrial DNA in patients with Idiopathic Parkinson's disease (IPD). MATERIAL AND METHODS: This has been a prospective, clinically genetic study, lasting for whole two years. The clinical part of this study was made at the University Clinic of Neurology in Skopje, Unit for extrapyramidal diseases. The laboratory-genetic part of the study was elaborated at the Laboratory for molecular biology at the Institute for Biology, Faculty of Sciences, University "Sts. Cyril and Methodius". This study comprised a total of 32 subjects with a clinically verified diagnosis for idiopathic Parkinson's disease; 18 men and 14 women (with mean age of 52.7 years). Control group consisted of 31 randomly selected, literally healthy persons, at similar age, with similar gender distribution, and no clinical and anamnestic data for parkinsonism or similar clinical entities. RESULTS: Objective neurologic results of all 32 investigated subjects (100%) showed presence of rigor, tremor and bradykinesia.The difference tested between the investigated and control group, concerning the present or absent deletion and heteroplasmia, has been highly statistically significant (p=0.001). CONCLUSION: It could be concluded with a great statistical significance that deletion 4977 in mitochondrial genome has been registered more frequently in the group of patients with IPD (Tab. 10, Fig. 6, Ref. 36). PMID- 24471896 TI - Transvaginal ultrasound examination of myometrial infiltration by endometrial cancer. AB - The depth of myometrial infiltration by endometrial cancer is an important prognostic factor. The examination of the depth of infiltration classifies the patients in the low- and high-risk groups, which influences the therapeutic approach. Transvaginal ultrasonography represents a first-choice diagnostic test for the assessment of the depth of myometrial infiltration as the time consumption and financial demands of magnetic resonance imaging need to be taken into account. In comparison with the MRI, the diagnostic accuracy of the transvaginal ultrasound depends more on the individual experience and professional potential of the examining physician. This fact can contribute to the heterogeneity of published results of transvaginal ultrasound on the determination of infiltration depth. Having in mind the aim to verify these indicators in our local conditions and environment, we decided to prospectively study 150 endometrial cancer patients who were examined with the transvaginal ultrasound in the period 1/2009 - 10/ 2011. Correlated firstly with the preoperative and then secondly with the definitive histopathological examination was the depth-of-infiltration-related data that had been taken from the ultrasound findings. The output being monitored was the exclusion or confirmation of the invasion exceeding half the thickness of myometrium. In our study, the diagnostic accuracy of the method reached 82.67 %, while the other indicators were as follows: sensitivity 92.31 %, specificity 79.28 %, positive predictive value (PPV) 61.02 %, negative predictive value (NPV) 96.7 %, the likelihood ratio of a positive test 4.455 and the likelihood ratio of a negative test 0.097. The results of the depth of myometrial infiltration examination and their comparison with the data from similarly oriented clinical studies entitle us to include this examination in the set of standard preoperative methods used for the examination of patients with endometrial cancer (Tab. 3, Fig. 5, Ref. 20). PMID- 24471897 TI - Celiac disease and dysfunctional uterine bleeding; the efficiency of gluten free diet. AB - The aim of this study was to investigate the relation between Celiac disease (CD) and unexplained dysfunctional uterine bleeding (DUB) in celiac women. The celiac patients were selected from women who were referred to celiac department. Controls were selected from those women without any signs of celiac disease and matched with age. Meanwhile, a trained physician was ready to explain the study, and then in case of their allowance, a questionnaire was completed by the physician. 24 % of celiac women reported a past history of at least one menstrual cycle disorder vs 10 % of controls reported these problems (p=0.038) and higher percentage of unexplained DUB has been observed in celiac women. All celiac patients were undertaking gluten free diet for at least 3 months and the celiac patients who reported the history of DUB were again interviewed for any signs of unexplained DUB. From 12 celiac women with DUB, 10 patients reported no more unexplained DUB after getting gluten-free diet (83.3 %). The occurrence of a significant correlation between CD and DUB suggests the possibility of considering CD as one of the potential causes of abnormal uterine bleeding. Therefore, celiac disease must be seriously considered in the screening of patients with reproductive disorders (Tab. 2,Ref. 23). PMID- 24471898 TI - Dental amalgam implantation and thyroid autoimmunity. AB - OBJECTIVE: Mercury was heavily studied as a factor in the autoimmune processes. We aimed to observe whether mercury of amalgam is associated with Hashimoto disease. BACKGROUND: 363 patients with Hashimoto's thyroiditis and 365 control subjects were included in to the study. Amalgam fillings were checked by the physician. METHODS: 363 (49.9 %) patients and 365 (50.1 %) healthy controls were included into the study. Hashimoto's thyroiditis was diagnosed with thyroid hormones, antithyroid antibody levels, and ultrasonographic findings. Control subjects were selected from patients with no known autoimmune diseases. They were controlled with ultrasonography, as well as antibody titers. None of them had Hashimoto's thyroiditis. RESULTS: Sex distribution of the study population was following: 319 (87.9 %) female, 44 (12.1 %) male in the patient group and 277 (75.9 %) male and 88 (24.1 %) female in healthy control subjects, respectively. Mean free T4 values for Hashimoto's thyroiditis and healthy control group were 15.30+/-0.76, 17.30+/-0.96 pmol/L and mean TSH values for Hashimoto's thyroiditis and healthy control group were 9.29+/-20.79, 1.20+/-0.32 uIU/ml. Frequency of dental amalgam implantation in patients with Hashimoto's thyroiditis was not statistically significantly different from healthy controls (p=186) (t=-1.324) CONCLUSIONS: Some studies identified mercury of amalgam as responsible for autoimmune thyroiditis. We studied whether amalgam fillings are more frequent in Hashimoto's thyroiditis patients and whether it is a causative factor for Hashimoto's thyroiditis. Statistical analysis revealed that there is no relation of amalgam with Hashimoto's thyroiditis (Tab. 1, Ref. 34). PMID- 24471899 TI - Treatment efficiency of resistant hypertension in cardiologist's office. AB - BACKGROUND: The target values of blood pressure have not been achieved in our population of patients sufficiently. The most difficult is a control of patients with resistant hypertension. We do not have data about efficiency treatment of these patients today. OBJECTIVES: The aim of our study was to assess current treatment status and by antihypertensive treatment modification we tried to reach an adequate blood pressure control. METHODS: Fifty two patients suffering from resistant hypertension 2-3 degree ESC/ESH with high cardiovascular risk have been observed. Reaching of the target blood pressure values was verified by 24-hour ambulatory blood pressure monitoring. RESULTS: The target blood pressure values were achieved in 50 % of patients during 18 months. We noticed a statistically significant difference (p<0.001) in a decrease of casual and 24-hour ambulatory blood pressure in the group of controlled hypertensive patients in comparison with a group where blood pressure did not decrease sufficiently. In case of 50 % patients, the target blood pressure values have not been reached in spite of more antihypertensive drugs and a higher dose. CONCLUSION: Adequately and systematically controlled patients were treated less intensively in comparison with an inadequately controlled group. 24-hour blood pressure monitoring analysis confirmed correction of the patological diurnal rhythm mostly in adequate blood pressure controlled group. In this group, we have noticed a statistically significant decrease of blood urea and creatinin levels and albumin/creatinin ratio in urine. Resistant hypertension needs multi-faceted approach with consistent control of all comorbidities in a case of problematic blood pressure control (Tab. 6, Fig. 1, Ref. 21). PMID- 24471900 TI - Ultrasound diagnosis of macrosomia. AB - Over the last two to three decades, there has been a 15-25 % increase in many countries in the number of women giving birth to large infant. Fetal macrosomia is associated with an increased risk of complications both for the mother and the newborn. In current obstetrics, the macrosomic fetus represents a frequent clinical challenge. The early detection and identification of the risks associated with fetal macrosomia is important to managing the pregnancies and at last the timing and mode of delivery. This article provides possibilities of ultrasound diagnosis throughout the pregnancy and investigates the effectiveness of fetal measurements in identifying the large fetus (Tab. 1, Ref. 24). PMID- 24471901 TI - Gastric stimulation in treatment in type 2 diabetes mellitus. AB - Metabolic surgery is a dynamic field providing a wide range of new techniques. The aim of our paper is to inform about gastric electrostimulation in the treatment of type 2 diabetes mellitus. Gastric electrostimulation in type 2 diabetes mellitus treatment is performed by means of implanting Tantalus system (Metacure). When triggered by food intake, the Tantalus system generates signals for the stomach to contract. Early after the food intake, thus before the stomach distends completely, the system increases spontaneous stomach contractions. Via afferent vagal signals, these increased contractions are evaluated by the central nervous system as a sign that satiety has been reached. Three pairs of electrodes connected with a stimulator are implanted laparoscopically. The system comes equipped with a battery as well. Laparoscopically implanted system of stomach electrostimulation presents a simple and easily regulated system without disturbing the integrity of gastrointestinal tract. It is a reversible system. In accord with preliminary results, Tantalus offers a safe and effective treatment of type 2 diabetes mellitus by reducing other cardiometabolical risky factors. The operation safety is comparable with that of similar minimally invasive surgical techniques. In order to improve our understanding of diabetes mellitus pathophysiology as well as of effects of gastric electrostimulation, more trials need to be performed. The surgical diabetes treatment represents an interesting chance for patients and it might become a common technique in the future (Fig. 1, Ref. 29). KEYWORDS: diabetes mellitus, obesity, gastric stimulation, pacemaker. PMID- 24471902 TI - A radiologic correlation with the basic functional neuroanatomy of the brain. AB - Primary cortical areas for motor, sensory and sensitive functions are localized in certain areas of the brain cortex. In clinical practice, cross sectional imaging (computer tomography and magnetic resonance) is wildy used for diagnostics purpose, treatment planning and follow up of the patients. Accurate orientation in brain structures is necessary for the evaluation of radiological images. There are numerable landmark signs, which can be used for precise identification of important brain structures. In this review article, the mostly used anatomical landmarks are described and shown on the cross sectional images (magnetic resonance imaging) (Fig. 14, Ref. 25). PMID- 24471903 TI - Amelogenesis imperfecta and the treatment plan - interdisciplinary team approach. AB - Amelogenesis imperfecta is a set of hereditary defects representing mainly the development defects of enamel without the presence of whole-body symptoms. Developmental disorders can manifest a complete absence of enamel, which is caused by improper differentiation of ameloblasts. This article describes the diagnosis and treatment of a patient with amelogenesis imperfecta, as well as the need for interdisciplinary cooperation to achieve the best possible morphological, skeletal, functional and aesthetic rehabilitation of the patients with this diagnosis. Furthermore, the article reviews literature dealing with other anomalies occurring in association with amelogenesis imperfect (Fig. 12, Ref. 20). PMID- 24471904 TI - Biliary atresia - a new derivative method? AB - BACKGROUND: Biliary atresia is a progressive cholangiopathy in neonates of unknown origin. Surgical intervention - Kasai portoenterostomy - is the only treatment possible. However, only liver transplantation can be considered a definitive solution even in cases of favourable post-operative course, i.e., after bile passage has been recreated. OBJECTIVES: The authors set out to identify ways to optimize the operative treatment in biliary atresia patients. In particular, their objective was to identify a suitable bile derivation area outside porta hepatis, thereby simplifying the surgical procedure of the following liver transplantation. METHODS: The research was conducted from 2006 to 2010 on a set of 30 corrosive casts prepared by the Institute of Anatomy, Medical Faculty, Comenius University Bratislava. The research consisted of an analysis of individual tubular structures of the liver parenchyma, particularly the bile vessels. The authors explored the latter's position and branching out, as well as their relationships in different segments, and their availability in surgical exploration. RESULTS: The analysis of the corrosive casts resulted in selecting an area in liver segments II and III suitable for creating a new type of hepatoenterostomy. The area is sufficiently distant from porta hepatis, conveniently accessible to the surgeon, and has a broad bile duct branch. This type of anastomosis would preserve the anatomic situation in the porta hepatis area intact for the following transplantation. CONCLUSION: While the results of the experiment warrant some optimism, authors will have to wait until this type of derivation operation is applicable in practice. The authors continue their research by performing anastomosis in an animal model (Fig. 5, Ref. 18) PMID- 24471905 TI - Letter to the Editor. Surgical treatment of malignant pleural effusions. PMID- 24471906 TI - Interfacial tension measurements using MRI drop shape analysis. AB - Accurate interfacial tension data for fluid systems such as hydrocarbons and water is essential to many applications such as reservoir oil and gas recovery predictions. Conventional interfacial tension measurement techniques typically use optical images to analyze droplet shapes but require that the continuous phase fluid be optically transparent and that the fluids are not refractive index matched. Magnetic resonance images obtain contrast between fluids using other mechanisms such as magnetic relaxation weighting, so systems that are impossible to measure with optical methods may be analyzed. In this article, we present high field (9.4 T) MRI images of various droplets analyzed with axisymmetric drop shape analysis. The resultant interfacial tension data show good agreement with literature data. The method is subsequently demonstrated using both opaque continuous phases and refractive-index-matched fluids. We conclude with a brief consideration of the potential to extrapolate the methodology to lower magnetic fields (0.3 T), featuring more accessible hardware; although droplet imaging is possible, resolution and stability do not currently permit accurate interfacial tension measurements. PMID- 24471907 TI - Phase III, randomised, double-blind, placebo-controlled study of the beta3 adrenoceptor agonist mirabegron, 50 mg once daily, in Japanese patients with overactive bladder. AB - OBJECTIVE: To evaluate the efficacy and safety of the beta3-adrenoceptor agonist mirabegron, in a Japanese population with overactive bladder (OAB). PATIENTS AND METHODS: This randomised, double-blind, placebo-controlled phase III study enrolled adult patients experiencing OAB symptoms for >=24 weeks. Patients with >= 8 micturitions/24 h and >=1 urgency episode/24 h or >=1 urgency incontinence episode/24 h were randomised to once-daily placebo, mirabegron 50 mg or tolterodine 4 mg (as an active comparator, without testing for non-inferiority of efficacy and safety) for 12 weeks. The primary endpoint was the change in the mean number of micturitions/24 h from baseline to final assessment. Secondary endpoints included micturition variables related to urgency and/or incontinence and quality-of-life domain scores on the King's Health Questionnaire. Safety assessments included adverse events (AEs), post-void residual urine volume, laboratory variables, vital signs and 12-lead electrocardiogram. RESULTS: A total of 1139 patients were randomised to receive placebo (n = 381), mirabegron 50 mg (n = 380) or tolterodine 4 mg (n = 378). Demographic and baseline characteristics were similar among the treatment groups. At final assessment, mirabegron was significantly superior to placebo in terms of mean [sd] change from baseline in number of micturitions/24 h (-1.67 [2.212] vs -0.86 [2.354]; P < 0.001) and mean [sd] change from baseline in number of urgency episodes/24 h (-1.85 [2.555] vs 1.37 [3.191]; P = 0.025), incontinence episodes/24 h (-1.12 [1.475] vs -0.66 [1.861]; P = 0.003), urgency incontinence episodes/24 h (-1.01 [1.338] vs -0.60 [1.745]; P = 0.008), and volume voided/micturition (24.300 [35.4767] vs 9.715 [29.0864] mL; P < 0.001). The incidence of AEs in the mirabegron group was similar to that in the placebo group. Most AEs were mild and none were severe. CONCLUSIONS: Mirabegron 50 mg once daily is an effective treatment for OAB symptoms, with a low occurrence of side effects in a Japanese population. PMID- 24471908 TI - Phase III safety study of rituximab administered as a 90-minute infusion in patients with previously untreated diffuse large B-cell and follicular lymphoma. AB - This phase III, multicenter, single-arm trial investigated the impact of 90 min rituximab infusions on infusion-related reactions (IRRs) in patients with untreated diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL). Patients received six or eight cycles of rituximab plus cyclophosphamide, vincristine, doxorubicin and prednisone for DLBCL or plus cyclophosphamide, vincristine and prednisolone for FL. A total of 425 patients received the first rituximab infusion per standard guidelines; median duration 240 min. Patients who did not experience grade >= 3 IRRs received subsequent infusions over 90 min (363 patients). A total of 303 patients received >= 6 cycles of rituximab. Fifty-three patients withdrew after cycle 1; 10 for grade 3 or 4 IRRs and one for a grade 3 adverse event. During cycle 2, 139 patients had IRRs, including four grade 3 IRRs. A 90 min rituximab infusion is well tolerated and feasible for patients with DLBCL or FL who tolerate the first standard rate infusion. PMID- 24471909 TI - Oncogene-induced senescence distinguishes indolent from aggressive forms of pulmonary and non-pulmonary Langerhans cell histiocytosis. AB - The clonal/neoplastic nature of Langerhans cell histiocytosis (LCH) has recently been demonstrated by a high prevalence of BRAF mutations, including pulmonary LCH (PLCH). We hypothesized that BRAF-induced senescence, as demonstrated in nevi and melanoma, is involved in the pathogenesis of LCH and PLCH. In a series of pulmonary (19 cases) and non-pulmonary LCH (19 cases), including five aggressive cases, we investigated occurrence of the BRAF V600E mutation by molecular analysis and/or immunohistochemistry using a validated antibody (VE1). The expression of cell-senescence markers p16(INK4a) and p21(CIP1/WAF1) was also immunohistochemically investigated. We demonstrated that 6/19 cases of LCH and 12/19 cases of PLCH were VE1 positive, matching with molecular analysis, and in all cases both p16(INK4a) and p21(CIP1/WAF1) were expressed, irrespective of BRAF mutation status. Interestingly, all the aggressive cases did not express p16(INK4a), thus suggesting that loss of senescence control could be related to clinical aggressiveness of LCH, as in melanoma. PMID- 24471910 TI - Great expectations? Conditioning with busulfan, melphalan and thiotepa in recurrent Hodgkin lymphoma. PMID- 24471911 TI - Perception of hepatitis B virus infection reactivation-related issues among specialists managing hematologic malignancies: result of an Italian survey. AB - Hepatitis B virus (HBV) reactivation strongly affects the practice of physicians dealing with hematological malignancies. In this respect, in collaboration with the Italian Lymphoma Foundation we developed a descriptive study of the real-life approach of physicians caring for patients with these diseases. A questionnaire was designed to explore the perception of HBV reactivation-related issues. Fifty nine Italian Lymphoma Foundation-affiliated institutions participated, and 504 questionnaires were sent out. Forty institutions (67.8%) returned 154 (30.5%) completed questionnaires. The largest majority (91.5%, 141/154) were aware of possible HBV reactivation as a consequence of immunosuppression. Most of the participants providing an answer (93.3%; 126/135) performed universal screening, and were aware of strategies for managing reactivation (96.4%, 132/137). Specialists treating lymphoma show a high level of awareness concerning the management of HBV reactivation under immunosuppression. However, uncertainties regarding the issue of HBV reactivation still emerge in this setting, and thus continuing collaborative effort between hepatologists and hematologists is necessary. PMID- 24471912 TI - Assessment of the impact of treatment on quality of life of patients with haemophilia A at different ages: insights from two clinical trials on turoctocog alfa. AB - Haemophilia and its treatment interfere with patients' life, so health-related quality of life (HRQoL) should be assessed when evaluating treatments. This study investigated the HRQoL of patients with haemophilia A treated prophylactically with a new recombinant factor VIII. Two phase 3 trials investigated turoctocog alfa in patients with severe haemophilia A: one in children, one in adults and adolescents. HRQoL was a secondary endpoint assessed by the HAEMO-QOL age specific, self-administered questionnaires. Parent-completed versions were also included for parents of children and adolescents. All HAEMO-QOL questionnaires allow the calculation of domain-specific and total scores ranging from 0 to 100, lower scores indicating better HRQoL. Mean change in all scores was described for 25 children aged 4-7 years, 21 children aged 8-12 years, 18 adolescents aged 13 18 years and 129 adults, overall, and according to the treatment regimen received prior to the study (on-demand; prophylaxis; mixed). Mean changes in HAEMO-QOL total score were 1.4 for children aged 4-7 years, -2.6 for children aged 8-12 years, -5.8 for adolescents and -1.6 for adults. In parent-completed versions, mean changes in total score were -6.0 for children aged 4-7 years, -4.7 for children aged 8-12 years, and -10.0 for adolescents. Patients receiving on-demand treatment before the trial showed greater improvement in HRQoL scores than patients already on prophylaxis. HRQoL of patients remained fairly stable over the course of the trials. However, improvements were observed for adolescents. Switching to prophylaxis was identified as a potential driver of improvement of HRQoL in patients with haemophilia A. PMID- 24471913 TI - Proinsulin C-peptide potentiates the inhibitory action of insulin on glucose synthesis in primary cultured rabbit kidney-cortex tubules: metabolic studies. AB - Effects of equimolar concentrations of proinsulin C-peptide and insulin on glucose synthesis were studied in primary cultures of rabbit kidney-cortex tubules grown in the presence of alanine, glycerol, and octanoate. The rhodamine labeled C-peptide entered renal tubular cells and localized in nuclei, both in the presence and absence of insulin; preincubations with the unlabeled compound inhibited internalization. C-peptide did not affect glucose formation when added alone but potentiated the inhibitory action of insulin by about 20% due to a decrease in flux through glucose-6-phosphate isomerase (GPI) and (or) glucose-6 phosphatase (G6Pase). GPI inhibition was caused by: (i) increased intracellular contents of fructose-1,6-bisphosphate and fructose-1-phosphate, inhibitors of the enzyme and (ii) reduced level of the phosphorylated GPI, which exhibits higher enzymatic activity in the presence of casein kinase 2. A decrease in flux through G6Pase, due to diminished import of G6P by G6P-transporter from the cytoplasm into endoplasmic reticulum lumen, is also suggested. The data show for the first time that in the presence of insulin and C-peptide, both GPI and G6P-ase may act as regulatory enzymes of renal gluconeogenic pathway. PMID- 24471914 TI - Screening for novel cell adhesive regions in bovine Achilles tendon collagen peptides. AB - Collagen, a major structural protein of the ECM, is known for its high cell adherence capacity. This study was conducted to identify regions in collagen that harbour such bioactivity. Collagen from tendon was hydrolysed and the peptides fractionated using ion-exchange chromatography (IEC). Isolated peptide fractions were coated onto disposable dishes and screened for cell adherence and proliferative abilities. Active IEC fractions were further purified by chromatography, and two peptides, C2 and E1 with cell adhesion ability, were isolated. A cell adhesion assay done with different amounts of C2 coated onto disposable dishes revealed the maximum adhesion to be 94.6%, compared with 80% for collagen coated dishes and an optimum peptide coating density of 0.507 nmoles per cm(2) area of the dish. Growth of cells on C2, collagen, and E1 revealed a similar pattern and a reduction in the doubling time compared with cells grown on uncoated dishes. C2 had a mass of 2.046 kDa with 22 residues, and sequence analysis revealed a higher percentage occurrence of hydrophilic residues compared with other regions in collagen. Docking studies revealed GDDGEA in C2 as the probable site of interaction with integrins alpha2beta1 and alpha1beta1, and stability studies proved C2 to be mostly protease-resistant. PMID- 24471915 TI - The acidic ribosomal protein P2 from Euplotes octocarinatus is phosphorylated at its N-terminal domain. AB - The eukaryotic acid ribosomal P0, P1, and P2 proteins share a conserved flexible C-terminal tail that is rich in acidic residues, which are involved in the interaction with elongation factor 2 during protein synthesis. Our previous work suggested that the acidic ribosomal P proteins from Euplotes octocarinatus have a special C-terminal domain. To further understand this characteristic feature, both P2 and elongation factor 2 from E. octocarinatus were overexpressed, for the first time, in Escherichia coli in this study. GST pull-down assay indicated that P2 protein from E. octocarinatus (EoP2) interacted specifically with the N terminal domain of elongation factor 2 from E. octocarinatus (EoEF-2) in vitro. The interacting part of EoP2 is in the C-terminal domains, consistent with the observation in other organisms. Phosphorylation of the recombinant EoP2 was performed in vitro using multiple methods such as (31)P-NMR spectroscopy, native PAGE, and Phos-tag(TM) SDS-PAGE. Results showed that ribosomal protein EoP2 was phosphorylated by casein kinase II at serine 21 located at the N terminus. This phosphorylation site identified in EoP2 is quite different from that of P2 from other organisms, in which the phosphorylation site is located in the conserved C terminal region. PMID- 24471916 TI - Investigation of the conserved glutamate immediately following the DEAD box in eukaryotic translation initiation factor 4AI. AB - The DExD-box family (DEAD-box) of proteins was surveyed for eukaryotic translation initiation factor 4A-specific sequences surrounding the DEAD box. An eIF4A-unique glutamate residue (E186 in eIF4AI) was identified immediately following the D-E-A-D sequence in eIF4AI, II, and III that was found to be conserved from yeast to Man. Mutation to a selection of alternative amino acids was performed within recombinant eIF4AI expressed in Escherichia coli and mutant proteins were surveyed for RNA-dependent ATPase activity. The mutants were also investigated for changes in activity in the presence of the two eIF4AI-binding domains of eIF4GI as well as for co-purification ability to these two domains. The E186 residue was found to be of significance for RNA-dependent ATPase activity for eIF4AI alone and in the presence of eIF4AI-binding domains of eIF4GI through point-mutation analysis. Furthermore, binding interactions between eIF4AI and eIF4GI domains were also significantly influenced by mutation of E186, as observed through co-purification assays. Thus, this residue appears to be of functional significance for eIF4A. PMID- 24471917 TI - Receptor expression is essential for forward motility in the course of sperm cell maturation. AB - Forward motility stimulating factor (FMSF) is a glycoprotein previously purified from buffalo blood serum that promotes progressive motility of caprine caudal spermatozoa. We have prepared a functionally active covalent conjugate of this factor with horseradish-peroxidase (HRP) to obtain an idea of its binding efficacy on maturing spermatozoa. Receptor-assay was performed using FMSF-HRP conjugate in saturating conditions to bind with spermatozoa isolated from different epididymal segments. Activity and binding profile of the motility stimulating factor coincided, suggesting both these parameters come into play only partially when spermatozoa reach the maturation state in the distal-corpus region and largely in caudal part (around 24% and 80% binding and 10% and 79% forward motility, respectively). Spermatozoa from caput up to mid-corpus regions neither displayed any substantial binding with FMSF nor exhibited significant induction in forward motility. Study of cell surface-bound FMSF on maturing spermatozoa in physiological milieu demonstrated their presence on anterior spermhead and suggests a nearly similar pattern of occurrence. Flow-cytometric analysis also implies analogous presence of this receptor. The factor was also immunodetected in uterine fluids of cattle species. This study displays a maturation-dependent expression of FMSF-receptor and consequential stimulation of forward motility that may be crucial for its journey to meet the ovum. PMID- 24471918 TI - Recombinant globular adiponectin inhibits lipid deposition by p38 MAPK/ATF-2 and TOR/p70 S6 kinase pathways in chicken adipocytes. AB - Adiponectin plays a fundamental role in lipid and carbohydrate metabolism. However, its role in adipocyte differentiation remains controversial. To investigate the effect of gAd on lipid deposition in chicken adipocytes and its related signaling pathways, 200 MUg/mL recombinant globular adiponectin, isoproterenol, SB253580, leucine, and rapamycin were used to treat chicken adipocytes. Results demonstrated that gAd increased the expression of endogenous adiponectin and AdipoR1 (P < 0.01); gAd inhibited triglyceride (TG) accumulation in chicken adipocyte and increased the release of free fatty acids (FFA) in medium; gAd decreased the expression of adipogenic marker genes CCAAT/enhancer binding protein alpha (C/EBPalpha) and fatty acid synthase (FAS), while activating the expression of lipolytic marker gene adipose triglyceride lipase (ATGL) (P < 0.01). Meanwhile, gAd activated the phosphorylation levels of p38 mitogen-activated protein kinase (p38 MAPK) and activating transcription factor 2 (ATF-2), and suppressed the phosphorylation levels of rapamycin (TOR) and p70 S6 Kinase (P < 0.01). In conclusion, the results demonstrate that gAd has an ability to inhibit lipids deposition in chicken adipocyte, which depends on the p38 MAPK/ATF-2 and TOR/p70 S6 Kinase pathways. PMID- 24471919 TI - Insulin-dependent transcriptional control in L6 rat myotubes is associated with modulation of histone acetylation and accumulation of the histone variant H2A.Z in the proximity of the transcriptional start site. AB - Besides its direct metabolic effects, insulin induces transcriptional alterations in its target tissues. However, whether such changes are accompanied by epigenetic changes on the chromatin template encompassing insulin responsive genes is unclear. Here, mRNA levels of insulin-responsive genes hexokinase 2 (Hk2), insulin receptor substrate (Irs2), and the PI3K subunit p85beta (Pik3r2) were compared in control versus insulin-stimulated L6 myotubes. Chromatin immunoprecipitation (ChIP) was performed with antibodies directed to histone H2A, histone variant H2A.Z, acetylated histone H3 on lysines 9/14, and acetylated H2A.Z. Insulin induced a more than 2-fold Hk2 mRNA increase, while Irs2 and Pik3r2 were downregulated. ChIP to H2A and H2A.Z showed higher H2A.Z accumulation around the transcriptional start site (TSS) of these insulin-modulated genes, while H2A.Z accumulation was lower distally to the TSS in the Hk2 promoter. H2A.Z levels and H3K9/14 acetylation correlated on several loci along the Hk2 gene, and H3K9/14 as well as H2A.Z acetylation was enhanced by insulin treatment. On the contrary, reduced H3K9/14 acetylation was observed in insulin-repressed Irs2 and Pik3r2, and recovery of acetylation by treatment with the histone deacetylase inhibitor trichostatin A reverted insulin-induced Irs2 downregulation. The chromatin regions encompassing selected insulin-responsive genes are thus featured by accumulation of H2A.Z around the TSS. H2A.Z accumulation facilitates insulin-dependent modulation of pharmacologically treatable H3K9/14 and H2A.Z acetylations. Indeed, inhibition of histone deacetylases by TSA treatment reverted insulin induced Irs2 gene downregulation. Dysregulated histone acetylation may thus be potentially targeted with histone deacetylase inhibitors. PMID- 24471920 TI - Co-dependent recruitment of Ino80p and Snf2p is required for yeast CUP1 activation. AB - In yeast, Ace1p-dependent induction of CUP1 is responsible for protecting cells from copper toxicity. Although the mechanism of yeast CUP1 induction has been studied intensively, it is still uncertain which chromatin remodelers are involved in CUP1 transcriptional activation. Here, we show that yeast cells are inviable in the presence of copper when either chromatin remodeler, Ino80p or Snf2p, is not present. This inviability is due to the lack of CUP1 expression in ino80Delta and snf2Delta cells. Subsequently, we observe that both Ino80p and Snf2p are present at the promoter and they are responsible for recruiting chromatin remodeling activity to the CUP1 promoter under induced conditions. These results suggest that they directly participate in CUP1 transcriptional activation. Furthermore, the codependent recruitment of both INO80 and SWI/SNF depends on the presence of the transcriptional activator, Ace1p. We also demonstrate that both remodelers are required to recruit RNA polymerase II and targeted histone acetylation, indicating that remodelers are recruited to the CUP1 promoter before RNA polymerase II and histone acetylases. These observations provide evidence for the mechanism of CUP1 induction. As such, we propose a model that describes novel insight into the order of events in CUP1 activation. PMID- 24471921 TI - Endothelial cell TIMP-1 is upregulated by shear stress via Sp-1 and the TGFbeta1 signaling pathways. AB - Laminar shear stress promotes vascular integrity by inhibiting proteolysis of the extracellular matrix (ECM) surrounding the microvasculature. We hypothesized that the matrix metalloproteinase inhibitor TIMP-1 would be upregulated in endothelial cells exposed to shear stress. Microvascular endothelial cells isolated from rat or mouse skeletal muscles were exposed to laminar shear stress for 2, 4, or 24 h. A biphasic increase in TIMP-1 protein was observed at 2 and 24 h of shear stress exposure. Sp-1 siRNA prevented the increase in TIMP-1 after 2, but not 24, hours of shear exposure. TGFbeta production and Smad2/3 phosphorylation are increased by shear stress. Inhibition of TGFbeta signaling, either by use of the TGFbeta receptor 1 inhibitor SB-431542 or with Smad 2/3 siRNA, abrogated the shear stress induced increase in TIMP-1 mRNA after 24 h of shear stress exposure. These results suggest that both acute and chronic elevated laminar shear stress act to maintain vessel integrity through increasing TIMP-1 production, but that the TGFbeta signaling pathway is essential to maintain TIMP-1 expression during chronic shear stress. PMID- 24471922 TI - Phosphoryl group as a strong sigma-donor anionic phosphine-type ligand: a combined experimental and theoretical study on long-lived room temperature luminescence of the [Ru(tpy)(bpy)(Ph2PO)]+ complex. AB - A phosphoryl Ru(II) polypyridyl complex was prepared in a one-pot process. Theoretical analysis suggests that the phosphoryl ligand may be viewed as a strong sigma-donor anionic phosphine L-type ligand. State-of-the-art free-energy profile calculations on the excited states demonstrate that both favorable thermodynamic and kinetic factors are responsible for the remarkable room temperature luminescence properties of the phosphoryl complex. PMID- 24471923 TI - Identification of Dirofilaria immitis proteins recognized by antibodies from infected dogs. AB - The identification of excreted-secreted (ES) proteins of filarial nematodes as potential diagnostic reagents is an important requirement for the development of methods to determine level of infection in the host, especially for human filariae. Dirofilaria immitis, the canine heartworm, is a widespread and important veterinary pathogen and is a useful model for filarial parasites of humans. An analysis of proteins released from adult D. immitis (the secretome) in culture is available. We sought to identify D. immitis ES proteins found in vivo to validate the in vitro secretome and to investigate them as potential diagnostic reagents. Cultures of D. immitis adults obtained from infected dogs were maintained for 72 hr with daily changes of media. Proteins were concentrated from spent media by standard methods and were passed through Protein-A columns containing purified IgG antibodies from heartworm-infected dogs. Following extensive washing, heartworm proteins recognized by the antibodies were eluted from these columns and submitted for analysis by tandem mass spectrometry (MS/MS). As a comparison, somatic proteins from adult D. immitis female parasites and microfilaria were also processed and analyzed by the same protocol. Six, 9, and 12 proteins were identified by MS/MS in the ES, adult female, and microfilaria samples, respectively. The identification of the most abundant parasite proteins present in the serum of infected hosts offers a rational approach to the development of new diagnostic assays that may be applicable across the Filarioidea. PMID- 24471924 TI - Current strategies for treatment of relapsed/refractory multiple myeloma. AB - In spite of significant advances in the management of multiple myeloma (MM), the disease remains incurable and nearly all patients ultimately relapse and require salvage chemotherapy. As such, relapsed and relapsed-refractory MM remains a critical area of research pertaining to biological mechanisms of progression and chemotherapy resistance, as well as to the development of new pharmacologic agents and immunologic approaches for the disease. The immunomodulatory agents and proteasome inhibitors represent the cornerstone of treatment in this setting, with combination regimens incorporating these drugs demonstrating encouraging rates and duration of response, including the newer agents, pomalidomide and carfilzomib. In addition, novel drug classes have shown promising activity in RR MM, including the orally-administered proteasome inhibitors ixazomib and oprozomib; monoclonal antibodies such as the anti-CS1 monoclonal antibody elotuzumab and anti-CD38 monoclonal antibody daratumumab; and histone deacetylase inhibitors such as panobinostat and rocilinostat. PMID- 24471925 TI - Rapid and sensitive diagnosis of fungal keratitis with direct PCR without template DNA extraction. AB - This study was aimed at developing a direct PCR assay without template DNA extraction for the rapid and sensitive diagnosis of infectious keratitis. Eighty corneal scrapings from 67 consecutive patients with clinically suspected infectious keratitis were analysed prospectively. Direct PCR was performed with all scrapings, with specific primers for fungi, bacteria, herpes simplex virus-1 (HSV-1) and Acanthamoeba simultaneously. The results were compared with those obtained from culture, smear, and confocal microscopy. Discrepant results were resolved according to the therapeutic effects of the corresponding antimicrobial drugs. The lowest detection limit of direct PCR was ten copies of each pathogen. Sixty-six scrapings yielded positive results with direct PCR, giving a total positive detection rate of 82.5% (66/80). For 34 patients with high suspicion of fungal keratitis, the positive detection rate of direct PCR was 84.8% (39/46). This rate increased to 91.2% (31/34) when repeated scrapings were excluded, and was significantly higher than the rates obtained with culture (35.3%, 12/34) and smear (64.7%, 22/34) (p <0.001), and was also higher than the rate obtained with confocal microscopy (74.1%, 20/27). The sensitivities for the diagnosis of infectious keratitis with direct PCR and culture were 98.0% and 47.1% (p <0.001), whereas the specificities were 81.8% and 100%, respectively. The time required to complete the entire direct PCR procedure was only 3 h. The direct PCR assay is a rapid diagnostic technique with high sensitivity and specificity for infectious keratitis, and it is expected to have an impact on the diagnosis and treatment of infectious keratitis in the future. PMID- 24471926 TI - Modifiable factors governing indoor fungal diversity and risk of asthma. AB - Exposure to dampness and fungi in the home is a known risk factor for individuals with allergic asthma. Inadequate heating and ventilation may lead to dampness and concomitant increased exposure to spores of allergenic fungi such as Aspergillus and Penicillium. These fungi have been cultured from sputum of asthmatic and non asthmatic individuals, and implicated in the initiation or exacerbation of asthma. Indoor environmental factors influence the presence and concentrations of fungal propagules and, in turn, risk of asthma outcomes. This review aims to identify modifiable risk factors in the built environment that have been shown to influence fungal composition indoors, and to examine this association with the risk of asthma development and/or exacerbation. A complex interaction between residential characteristics, the built environment and the behaviour of people regulate the diversity and concentrations of indoor fungi. Modifiable factors include build age, architectural design, level of maintenance, variations in construction materials, presence of pets, heating and ventilation patterns. Risk of fungal contamination and asthma outcomes are also influenced by low occupant awareness concerning potential health effects and socio-economic factors. Addressing these factors provides an opportunity to improve future housing interventions, though it is not clear how the built environment and occupant behaviours interact to modify the diversity of indoor fungi and resultant risk of asthma. A combination of housing improvements combined with awareness programmes and the alleviation of fuel poverty can be used to lower the allergen burden associated with damp homes. Further research is needed to identify factors that regulate the concentration and diversity of indoor fungi and how this may act as a modifier for asthma outcomes. PMID- 24471927 TI - Enalapril attenuates ischaemic brain oedema and protects the blood-brain barrier in rats via an anti-oxidant action. AB - 1. In the present study, we investigated the effects of postischaemic angiotensin converting enzyme (ACE) inhibition with enalapril on vasogenic oedema formation and blood-brain barrier (BBB) integrity following transient focal cerebral ischaemia in rats. 2. Cerebral ischaemia was induced by 60 min occlusion of the right middle cerebral artery, followed by 24 h reperfusion. Vehicle and a non hypotensive dose of enalapril (0.03 mg/kg) were administered at the beginning of the reperfusion period. A neurological deficit score (NDS) was determined for all rats at the end of the reperfusion period. Then, brain oedema formation was investigated using the wet-dry weight method and BBB permeability was evaluated on the basis of extravasation of Evans blue (EB) dye. In addition, oxidative stress was assessed by measuring reduced glutathione (GSH) and malondialdehyde (MDA) in brain homogenates. 3. Inhibition of ACE by enalapril significantly reduced NDS and decreased brain oedema formation (P < 0.05 for both). Disruption of the BBB following ischaemia resulted in considerable leakage of EB dye into the brain parenchyma of the ipsilateral hemispheres of vehicle-treated rats. Enalapril significantly (P < 0.05) decreased EB extravasation into the lesioned hemisphere. Enalapril also augmented anti-oxidant activity in ischaemic brain tissue by increasing GSH concentrations and significantly (P < 0.05) attenuating the increased MDA levels in response to ischaemia. 4. In conclusion, inhibition of ACE with a non-hypotensive dose of enalapril may protect BBB function and attenuate oedema formation via anti-oxidant actions. PMID- 24471928 TI - Rings in drugs. AB - We have analyzed the rings, ring systems, and frameworks in drugs listed in the FDA Orange Book to understand the frequency, timelines, molecular property space, and the application of these rings in different therapeutic areas and target classes. This analysis shows that there are only 351 ring systems and 1197 frameworks in drugs that came onto the market before 2013. Furthermore, on average six new ring systems enter drug space each year and approximately 28% of new drugs contain a new ring system. Moreover, it is very unusual for a drug to contain more than one new ring system and the majority of the most frequently used ring systems (83%) were first used in drugs developed prior to 1983. These observations give insight into the chemical novelty of drugs and potentially efficient ways to assess compound libraries and develop compounds from hit identification to lead optimization and beyond. PMID- 24471929 TI - Insights into the GTP/GDP cycle of RabX3, a novel GTPase from Entamoeba histolytica with tandem G-domains. AB - Members of the small GTPase Ras superfamily regulate a host of systems through their ability to catalyze the GTP/GDP cycle. All family members reported thus far possess a single GTPase domain with a P-loop containing a nucleoside triphosphate hydrolase fold. Here for the first time we report a novel member from Entamoeba histolytica, EhRabX3, which harbors two GTPase domains in tandem and exhibits unique biochemical properties. A combination of biochemical and microcalorimetric studies revealed that EhRabX3 binds to a single guanine nucleotide through its N terminal domain. Unlike most of the members of the Ras superfamily, the dissociation of the nucleotide from EhRabX3 is independent of Mg(2+), perhaps indicating a novel mechanism of nucleotide exchange by this protein. We found that EhRabX3 is extremely sluggish in hydrolyzing GTP, and that could be attributed to its atypical nucleotide binding pocket. It harbors substitutions at two positions that confer oncogenicity to Ras because of impaired GTP hydrolysis. Engineering these residues into the conserved counterparts enhanced their GTPase activity by at least 20-fold. In contrast to most of the members of the Ras superfamily, EhRabX3 lacks the prenylation motif. Using indirect immunofluorescence and biochemical fractionation, we demonstrated that the protein is distributed all over the cytosol in amoebic trophozoites. Collectively, this unique ancient GTPase exhibits a striking evolutionary divergence from the other members of the superfamily. PMID- 24471930 TI - The impact of depression and somatic symptoms on treatment outcomes in patients with chronic prostatitis/chronic pelvic pain syndrome: a preliminary study in a naturalistic treatment setting. AB - AIM: The aim of this study was to evaluate the impact of depression and somatic symptoms on treatment outcomes in Korean male patients with chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS) attending a routine clinical practice. METHODS: This was a 12-week prospective observational study (n = 80). The Korean version of the National Institutes of Health Chronic Prostatitis Symptom Index (NIH-CPSI) to measure the severity of CP/CPPS, the Korean version of the Patient Health Questionnaire-9 (PHQ-9) to assess depression, the Korean version of the Patient Health Questionnaire-15 (PHQ-15) to evaluate somatisation and the Korean version of the EuroQol Questionnaire-5 Dimensions (EQ-5D), specifically the EQ-5D utility index and the EQ-5D visual analogue scale (EQ-5D VAS), to assess quality of life, were utilised and given at baseline and week 12. The primary and secondary end-points in this study were changes in the NIH-CPSI total score from baseline to week 12 according to depression and somatisation. RESULTS: The change in NIH-CPSI total score was significantly higher in those without depression than in those with depression (p = 0.003), with a magnitude of difference of 2.8. The responder rate (a >= 4 point decrease in NIH-CPSI total score from baseline) was significantly higher in those without depression (42.9%) than in those with depression (17.2%, p = 0.023). However, significant differences were not observed between the two groups in the other outcome measures or in all study outcomes between subjects with or without somatisation. A logistic regression analysis revealed that the presence or absence of depression may be a principal predictor of response to treatment. CONCLUSION: These preliminary results indicate that depression may have a negative impact on treatment outcome and is a likely predictor of response to treatment in patients with CP/CPPS. However, additional studies with adequate power and improved design are necessary to further support the present findings. PMID- 24471931 TI - Selective sintering of metal nanoparticle ink for maskless fabrication of an electrode micropattern using a spatially modulated laser beam by a digital micromirror device. AB - We demonstrate selective laser sintering of silver (Ag) nanoparticle (NP) ink using a digital micromirror device (DMD) for the facile fabrication of 2D electrode pattern without any conventional lithographic means or scanning procedure. An arbitrary 2D pattern at the lateral size of 25 MUm * 25 MUm with 160 nm height is readily produced on a glass substrate by a short exposure of 532 nm Nd:YAG continuous wave laser. The resultant metal pattern exhibits low electrical resistivity of 10.8 uOmega . cm and also shows a fine edge sharpness by the virtue of low thermal conductivity of Ag NP ink. Furthermore, 10 * 10 star shaped micropattern arrays are fabricated through a step-and-repeat scheme to ensure the potential of this process for the large-area metal pattern fabrication. PMID- 24471932 TI - Fluorination of graphene: a spectroscopic and microscopic study. AB - Since the advent of graphene, there has been intense interest in exploring the possibility of incorporating fluorinated graphene (FG), an ultrathin insulator, into graphene electronics as barriers, gate dielectrics, and optoelectronic elements. Here we report on the synthesis of FG from single-layer graphene sheets grown by chemical vapor deposition (CVD) using CF4 plasma. We examine its properties systematically via microscopic and spectroscopic probes. Our studies show that, by controlling the conditions of the plasma, FG of varying fluorine coverage can be produced; however, the resulting material contains a mixture of CFx (x = 1-3) bonds. Existing grain boundaries and lattice defects of CVD graphene play an important role in controlling its rate of fluorination and the damage of the sheet. Combining topography and current mapping, we demonstrate that the spatial distribution of fluorine on CVD graphene is highly inhomogeneous, where multilayer islands and structural features such as folds, wrinkles, and ripples are less fluorinated and consequently form a conductive network through which charge transport occurs. It is the properties of this network that manifest in the electrical transport of FG sheets. Our experiments reveal the many challenges of deriving electronics-quality FG from current CVD graphene while at the same time point to the possible solutions and potential of FG in graphene electronics and optoelectronics. PMID- 24471933 TI - A penalized EM algorithm incorporating missing data mechanism for Gaussian parameter estimation. AB - Missing data rates could depend on the targeted values in many settings, including mass spectrometry-based proteomic profiling studies. Here, we consider mean and covariance estimation under a multivariate Gaussian distribution with non-ignorable missingness, including scenarios in which the dimension (p) of the response vector is equal to or greater than the number (n) of independent observations. A parameter estimation procedure is developed by maximizing a class of penalized likelihood functions that entails explicit modeling of missing data probabilities. The performance of the resulting "penalized EM algorithm incorporating missing data mechanism (PEMM)" estimation procedure is evaluated in simulation studies and in a proteomic data illustration. PMID- 24471934 TI - Extrolites of Wallemia sebi, a very common fungus in the built environment. AB - Wallemia sebi has been primarily known as a spoilage fungus of dried, salted fish and other foods that are salty or sweet. However, this fungus is also very common in house dust. The health effects of chronic exposure to mold and dampness are known to be associated with both allergens and various inflammatory compounds, including the secondary metabolites of building associated fungi and their allergens. IgE sensitization to W. sebi has been long reported from housing and occupational exposures. However, its allergens have not been described previously. Strains from food have been reported to produce a number of compounds with modest toxicity. Strains from the built environment in Canada produced a number of metabolites including the known compound walleminone and a new compound 1-benzylhexahydroimidazo [1,5-alpha] pyridine-3,5-dione which we call wallimidione. Based on an in silico analysis, wallimidione is likely the most toxic of the metabolites reported to date from W. sebi. We found that the primary human antigen of W. sebi is a 47 kDa excreted cellulase present in high concentrations in W. sebi arthrospores. This species is a basidiomycete and, unsurprisingly, the antigen was not found in extracts of other fungi common in the built environment, all ascomycetes. PMID- 24471935 TI - Using computer-extracted data from electronic health records to measure the quality of adolescent well-care. AB - OBJECTIVE: To determine whether quality measures based on computer-extracted EHR data can reproduce findings based on data manually extracted by reviewers. DATA SOURCES: We studied 12 measures of care indicated for adolescent well-care visits for 597 patients in three pediatric health systems. STUDY DESIGN: Observational study. DATA COLLECTION/EXTRACTION METHODS: Manual reviewers collected quality data from the EHR. Site personnel programmed their EHR systems to extract the same data from structured fields in the EHR according to national health IT standards. PRINCIPAL FINDINGS: Overall performance measured via computer extracted data was 21.9 percent, compared with 53.2 percent for manual data. Agreement measures were high for immunizations. Otherwise, agreement between computer extraction and manual review was modest (Kappa = 0.36) because computer extracted data frequently missed care events (sensitivity = 39.5 percent). Measure validity varied by health care domain and setting. A limitation of our findings is that we studied only three domains and three sites. CONCLUSIONS: The accuracy of computer-extracted EHR quality reporting depends on the use of structured data fields, with the highest agreement found for measures and in the setting that had the greatest concentration of structured fields. We need to improve documentation of care, data extraction, and adaptation of EHR systems to practice workflow. PMID- 24471936 TI - Effect of magnetic nanoparticle heating on cortical neuron viability. AB - PURPOSE: Superparamagnetic iron oxide nanoparticles are currently approved for use as an adjunctive treatment to glioblastoma multiforme radiotherapy. Radio frequency stimulation of the nanoparticles generates localised hyperthermia, which sensitises the tumour to the effects of radiotherapy. Clinical trials reported thus far are promising, with an increase in patient survival rate; however, what are left unaddressed are the implications of this technology on the surrounding healthy tissue. METHODS AND MATERIALS: Aminosilane-coated iron oxide nanoparticles suspended in culture medium were applied to chick embryonic cortical neuron cultures. Cultures were heated to 37 degrees C or 45 degrees C by an induction coil system for 2 h. The latter regime emulates the therapeutic conditions of the adjunctive therapy. Cellular viability and neurite retraction was quantified 24 h after exposure to the hyperthermic events. RESULTS: The hyperthermic load inflicted little damage to the neuron cultures, as determined by calcein-AM, propidium iodide, and alamarBlue(r) assays. Fluorescence imaging was used to assess the extent of neurite retraction which was found to be negligible. CONCLUSIONS: Retention of chick, embryonic cortical neuron viability was confirmed under the thermal conditions produced by radiofrequency stimulation of iron oxide nanoparticles. While these results are not directly applicable to clinical applications of hyperthermia, the thermotolerance of chick embryonic cortical neurons is promising and calls for further studies employing human cultures of neurons and glial cells. PMID- 24471937 TI - Effect of bubble formation on the dissociation of methane hydrate in water: a molecular dynamics study. AB - We investigate the dissociation of methane hydrate in liquid water using molecular dynamics simulations. As dissociation of the hydrate proceeds, methane molecules are released into the aqueous phase and eventually they form bubbles. It is shown that this bubble formation, which causes change in the methane concentration in the aqueous phase, significantly affects the dissociation kinetics of methane hydrate. A large system size employed in this study makes it possible to analyze the effects of the change in the methane concentration and the formation of bubbles on the dissociation kinetics in detail. It is found that the dissociation rate decreases with time until the bubble formation and then it turns to increase. It is also demonstrated that methane hydrate can exist as a metastable superheated solid if there exists no bubble. PMID- 24471938 TI - An in situ crosslinked compression coat comprised of pectin and calcium chloride for colon-specific delivery of indomethacin. AB - The use of pectin for colon-specific drug delivery has been extensively investigated; however, when used alone, pectin is often compromised due to its high solubility. This study explored the feasibility of using an in situ compression-coated crosslinking system, composed of pectin and calcium chloride, for colon-specific drug delivery. A pectin/calcium chloride (P/Ca) coating was compressed onto a core tablet. The colon specificity of the compression-coated tablet was verified by dissolution, pharmacokinetics and scintigraphy with (99m)Tc labeling. The in situ pectin and calcium chloride gel slowed the release of indomethacin. The lag time varied between 3 h and 7 h depending on the amount of calcium chloride and the coating weight. Pectinase triggered the release of indomethacin from the compression-coated tablet, which was then accelerated by the calcium chloride in the coating layer. The compression-coated tablet had a prolonged tmax and apparent t1/2, as well as a decreased Cmax and AUC0-t, compared with the core tablet counterpart. Evaluation with gamma-scintigraphy verified colon-specific delivery of the compression-coated tablet. In conclusion, the P/Ca in situ crosslinking system worked well for colon-specific drug delivery. PMID- 24471939 TI - Expression of carbonic anhydrase IX (CAIX) in malignant mesothelioma. An immunohistochemical and immunocytochemical study. AB - Malignant mesothelioma is an aggressive tumor with a poor prognosis. Carbonic anhydrase IX (CAIX) is a membranously located metalloenzyme involved in pH homeostasis with influence on regulation of cell proliferation, oncogenesis and tumor progression. Much attention has been paid recently to carboanhydrases and their inhibitors as they offer an opportunity for both developing novel anticancer drugs, as well as diagnostic and prognostic tools. This study was designed to assess the expression of CAIX in malignant pleural and peritoneal mesotheliomas, their benign counterparts, and in pleural effusions from patients with malignant mesothelioma, metastatic carcinoma or a benign disease. Tissue blocks from 51 malignant mesotheliomas of pleura (47 cases; 41 epithelioid, 2 biphasic, 4 sarcomatoid) and peritoneum (4 cases; all epithelioid), 14 cases with normal or reactive pleural tissue, and 19 cell blocks were analyzed. CAIX expression was determined using immunohistochemistry and its membranous immunoreactivity was semiquantitatively evaluated. Specimens were divided into five subgroups according to the staining pattern and intensity.Overall, 92.2% (47/51) of mesotheliomas expressed CAIX. All epithelioid mesotheliomas showed CAIX positivity, which was predominantly strong and diffuse (73.3%, 33/45). Sarcomatoid mesotheliomas and sarcomatoid areas in biphasic mesotheliomas were negative. A strong diffuse staining was observed in all cases of normal mesothelia. In pleural effusions, CAIX expression was observed in malignant cells as well as in benign mesothelial cells. In conclusion, CAIX is expressed virtually in all mesotheliomas except for sarcomatoid subtype, and in benign mesothelia. There are probably more mechanisms of CAIX overexpression than hypoxia-induced in malignant mesothelioma, with the influence of other tissue specific transcription or growth factors depending on the type of the cell lineage. CAIX immunoreactivity is not a reliable diagnostic marker for distinguishing malignant cells from benign mesothelia in pleural effusions. Nevertheless, our data support the potential use of therapeutics targeting CAIX in patients with advanced mesothelioma. PMID- 24471940 TI - Risk ranking priority of carcinogenic and/or genotoxic environmental contaminants in food in Belgium. AB - This paper focuses on the risks of environmental carcinogenic and/or genotoxic contaminants in food. It describes, for each contaminant studied, the carcinogenicity and genotoxicity, the toxicological reference values, the exposure and the risk characterisation. The compounds studied were classified into 3 categories based on a risk assessment. Effects others than carcinogenicity and/or genotoxicity (e.g. endocrine disruption activity) were also taken into account for the classification. Given the low margin of exposure values for arsenic and lead, these two compounds are classified as priority 1 (high concern) for food safety and as a first priority to take actions to reduce exposure. Cadmium, methylmercury, dioxins and dioxin-like polychlorinated biphenyls (PCB), non-dioxin-like PCB and toxaphene are classified as priority 2 (medium concern). Polybrominated biphenyls, chlordane, heptachlor, dichlorodiphenyltrichloroethane (DDT) and metabolites, hexachlorobenzene, hexachlorocyclohexane (lindane included), polychlorophenols and their salts are classified as priority 3 (low concern). PMID- 24471941 TI - Demonstrating the benefits and pitfalls of various acidity characterization techniques by a case study on bimodal aluminosilicates. AB - A new combination of a volumetric with a dynamic method to investigate the acidity properties of aluminosilicates is introduced. In the first step, the total acidity is determined volumetrically by the measurement of two-cycle adsorption (TCA) isotherms with ammonia as a probe, directly followed by a dynamic temperature-programmed desorption (TPD) experiment to define the acid strength distribution. Furthermore, the results obtained by the new direct combination of TCA and TPD are validated by comparison with an in-situ FTIR (Fourier transform infrared) study with the same probe molecule on the same materials. Both acidity characterization techniques are compared, and we comment on their complementarity, benefits, and pitfalls. The material under investigation is a new type of bimodal microporous and mesoporous material with zeolitic characteristics, synthesized by a mesotemplate-free method. The acidic nature of the novel material is compared to two reference materials: a crystalline zeolite and a mesoporous aluminum incorporated mesocellular foam (Al MCF) with amorphous characteristics. PMID- 24471943 TI - Review of appendiceal onlay flap in the management of complex ureteric strictures in six patients. AB - OBJECTIVES: To evaluate appendiceal onlay flap ureteroplasty for repairing complex right proximal and mid-ureteric strictures. PATIENTS AND METHODS: Between August 2006 and August 2012 four women and two men (mean age 34.2 years) underwent right laparoscopic appendiceal onlay flap ureteroplasty. The mean stricture length was 2.5 cm. Stricture formation was secondary to impacted ureteric stones in three patients and failed pyeloplasty for congenital pelvi ureteric junction obstruction in the remaining three. Each patient had ipsilateral flank pain before surgery. RESULTS: The mean operating time, estimated blood loss and hospital stay were 244 min, 175 mL and 3.2 days, respectively. No intra- or peri-operative complications were noted. The objective success rate was 100% (all patients had radiographic and/or endoscopic resolution of their ureteric strictures). The subjective success rate was 66%, (two patients developed recurrent discomfort, which upon exploration was found to be attributable to fibrosis away from the appendiceal onlay graft, where the gonadal vessels crossed the ureter). Both patients with recurrent pain underwent laparoscopic ureterolysis and bladder advancement flap proximal to the appendiceal onlay, which markedly improved one patient's pain but the other patient continued to have discomfort, ultimately resulting in a laparoscopic nephroureterectomy. CONCLUSIONS: Appendiceal onlay ureteroplasty is a viable treatment option for patients with complex right proximal and mid-ureteric strictures, while minimising the potential morbidity of appendiceal and ileal interposition. PMID- 24471944 TI - Usage of mitochondrial D-loop variation to predict risk for Huntington disease. AB - Huntington's disease (HD) is an inherited autosomal neurodegenerative disease caused by the abnormal expansion of the CAG repeats in the Huntingtin (Htt) gene. It has been proven that mitochondrial dysfunction is contributed to the pathogenesis of Huntington's disease. The mitochondrial displacement loop (D loop) is proven to accumulate mutations at a higher rate than other regions of mtDNA. Thus, we hypothesized that specific SNPs in the D-loop may contribute to the pathogenesis of Huntington's disease. In the present study, 30 patients with Huntington's disease and 463 healthy controls were evaluated for mitochondrial mutation sites within the D-loop region using PCR-sequencing method. Sequence analysis revealed 35 variations in HD group from Cambridge Mitochondrial Sequences. A significant difference (p < 0.05) was seen between patients and control group in eight SNPs. Polymorphisms at C16069T, T16126C, T16189C, T16519C and C16223T were correlated with an increased risk of HD while SNPs at C16150T, T16086C and T16195C were associated with a decreased risk of Huntington's disease. PMID- 24471945 TI - Trends in the epidemiology, diagnosed age and mortality rate of haemophiliacs in Taiwan: a population-based study, 1997-2009. AB - Many studies on epidemiology and mortality in haemophiliacs have been published in Western countries. However, few have been conducted in Asian countries. The purpose of our study was to investigate the nationwide epidemiology and mortality of haemophiliacs in Taiwan. Population-based data from the National Health Insurance Research Database between 1997 and 2009 were analysed using SAS version 9.3. The annual prevalence of haemophilia A (HA) and haemophilia B (HB) increased steadily to 7.30 and 1.34 cases per 100,000 males, respectively, in 2009. The annual crude incidence of HA and HB averaged 8.73 and 1.73 per 100,000 male births respectively. During the study period, the proportion of paediatric haemophiliacs decreased from 41.5% to 28.2% and the proportion of geriatric haemophiliacs increased from 2.5% to 5.7%. Among 493 newly diagnosed cases, the peak diagnostic ages were before 3 and between ages 10 and 40. Of the 76 cases of mortality, most patients died between the ages of 18 and 60. However, an increase in the age of mortality was noted after 2005 (P = 0.033). The overall standardized crude death rate of haemophiliacs was 10.2 per 1000 people, and the standard mortality ratio was 1.98. The annual prevalence of human immunodeficiency virus infection in haemophiliacs grossly declined from 1998 to 2009, with an average of 32.2 per 1000 haemophiliacs. This was a rare population based study on the epidemiology and mortality of haemophilia in a Chinese population and Asian countries. The 13-year trends showed advances in haemophilia care in Taiwan. PMID- 24471946 TI - Biomarker accuracy: exploring the truth. PMID- 24471947 TI - How useful is ICP-MS for determining PK properties of metal-based drugs? PMID- 24471949 TI - Conference report: Clinical and Pharmaceutical Solutions through analysis (CPSA USA 2013): connecting patients and subject numbers through analysis. AB - The 16th Annual Symposium on Clinical and Pharmaceutical Solutions through Analysis (CPSA) 7-10 October 2013, Sheraton Bucks County Hotel, Langhorne, PA, USA. The 2013 CPSA brought together the various US FDA regulated analytical fields affecting a 'patient' for the first time - bioanalysts supporting IND and NDAs, clinical diagnostic and pathology laboratory personnel, and clinical researchers that provide insights into new biomarkers. Although the regulatory requirements are different for each of the above disciplines, the unique analytical perspectives that affect the patient were shared - and the goal of the 2013 CPSA - 'Connecting Patients and Subject Numbers Through Analysis' was achieved. PMID- 24471950 TI - Bioanalysis zone: DBS survey results. AB - Bioanalysis Zone carried out a survey to evaluate the use of and attitudes to DBS analysis among our readership in the bioanalytical community. DBS analysis has generated a huge amount of interest in recent years. We wanted to take a snapshot of the field and determine whether a consensus is emerging on the future of DBS. We asked you for your honest opinions and you delivered! You can view the full results at www.bioanalysis-zone.com. We have a selection of short opinion articles below, giving a range of viewpoints on the current and future use of DBS, alongside some of the survey results. PMID- 24471951 TI - Blood microsampling using capillaries for drug-exposure determination in early preclinical studies: a beneficial strategy to reduce blood sample volumes. AB - BACKGROUND: Capillary microsampling (CMS) of blood with subsequent blood analysis offers a potential strategy to deal with increased demand to reduce blood sample volumes in animal discovery and preclinical studies. RESULTS: A generic approach is presented allowing PK analysis in 15 ul blood samples. CMS blood exposure data were compared with the traditional plasma exposure results in rats and dogs. Blood PK profiles obtained for two different compounds were in agreement with profiles obtained in plasma. From these studies ex vivo blood to plasma ratios were also obtained. In a mouse study, blood PK profiles that were obtained following automatic sampling overlay with the blood PK profiles obtained with CMS. CONCLUSION: CMS in 15 ul glass capillaries allows collection and handling of small and exact volumes of blood. Although CMS can also be applied for plasma collection, the full benefit is only achieved with blood collection and analysis. PMID- 24471953 TI - Salt-assisted LLE combined with field-amplified sample stacking in CE for improved determination of beta blocker drugs in human urine. AB - BACKGROUND: A simple and sensitive CE method was developed and validated for the analysis of some beta blockers in human urine. METHODS: In this study, salting out assisted LLE combined with field-amplified sample stacking method was employed for biological sample clean-up and sensitivity enhancement in CE. RESULTS: Under the optimal conditions good linearity (r(2) >=0.998) was obtained, within 0.025-1 ug/ml for propranolol and metoprolol, and within 0.05-1 ug/ml for carvedilol in urine samples. LODs and LLOQs ranged from 0.005 to 0.015 ug/ml, and from 0.025 to 0.05 ug/ml, respectively. The RSDs of intra- and inter-day analysis of examined compounds were less than 4.0%. The recoveries were in the range of 98 119%. CONCLUSION: The validated method is successfully applied to determine propranolol, metoprolol and carvedilol in human urine samples obtained from the patients who received these drugs. PMID- 24471952 TI - Multiplexed extraction and quantitative analysis of pharmaceuticals from DBS samples using digital microfluidics. AB - BACKGROUND: Dried blood spot (DBS) sampling is emerging as a valuable technique in a variety of fields, including clinical and preclinical testing of pharmaceuticals. Despite this popularity, current DBS sampling and analysis processes remain laborious and time consuming. Digital microfluidics, a microscale liquid-handling technique, characterized by the manipulation of discrete droplets on open electrode arrays, offers a potential solution to these problems. RESULTS: We report a new digital microfluidic method for multiplexed extraction and analysis of pharmaceuticals in DBS samples. In the new method, four DBS samples are extracted in microliter-sized droplets containing internal standard, and the extract is delivered to dedicated nanoelectrospray ionization emitters for direct analysis by tandem mass spectometry and selected reaction monitoring. CONCLUSION: The new method allows for an order of magnitude reduction in processing time and approximately three-times reduction in extraction solvent relative to conventional techniques, while maintaining acceptable analytical performance for most drugs tested. PMID- 24471954 TI - Development of an UPLC-MS/MS method for assaying the enzymatic activity of propionyl coenzyme-A carboxylase. AB - BACKGROUND: Propionyl coenzyme-A carboxylase (PCC) is a mitochondrial enzyme previously quantifiable only by radiometric assay. Herein, we report a UPLC-MS/MS method as a superior alternative method for assaying PCC's activity. METHODOLOGY & RESULTS: For the development of the UPLC-MS/MS method, the mass spectra of propionyl coenzyme-A and methyl malonyl coenzyme-A precursor ions, and their full scan product ions were determined. MRM was used for the quantification of the analytes. The method showed good linearity and selectivity for further bioanalytical study. CONCLUSION: The developed UPLC-MS/MS method is capable of rapidly quantifying PCC's enzymatic activity and demonstrated suitability for assaying PCC's activity in complex biological samples. Thus, the method will be useful in validating recombinant expression of PCC, and potentially for routine quantification of mitochondrial PCC's activity level in patient cells. PMID- 24471955 TI - Bioanalytical challenges of biosimilars. AB - Biologics such as monoclonal antibodies and recombinant proteins represent a significant portion of the pharmaceutical market. With many of the first generation biologics' patents expiring, an increasing number of biosimilars will be submitted for approval in the near future. The successful development of a biosimilar requires the demonstration of biosimilarity in terms of efficacy, safety and purity to an innovator-approved product. While regulatory frameworks have been established for the approval of biosimilars in several countries, there is not an established guidance for bioanalytical testing of biosimilars. Although there are regulatory guidances and White Papers on testing requirements for biologics in general, there is a need to address the bioanalytical challenges and solutions that apply specifically to the analysis of biosimilars in biological samples. This paper will focus on components of the PK and immunogenicity assays that are critical to biosimilar drug development. PMID- 24471956 TI - Detection of volatile malodorous compounds in breath: current analytical techniques and implications in human disease. AB - For the last few decades intense scientific research has been placed on the relationship between trace substances found in exhaled breath such as volatile organic compounds (VOC) and a wide range of local or systemic diseases. Although currently there is no general consensus, results imply that VOC have a different profile depending on the organ or disease that generates them. The association between a specific pathology and exhaled breath odor is particularly evident in patients with medical conditions such as liver, renal or oral diseases. In other cases the unpleasant odors can be associated with the whole body and have a genetic underlying cause. The present review describes the current advances in identifying and quantifying VOC used as biomarkers for a number of systemic diseases. A special focus will be placed on volatiles that characterize unpleasant breath 'fingerprints' such as fetor hepaticus; uremic fetor; fetor ex ore or trimethylaminuria. PMID- 24471957 TI - Quantitative whole-body autoradiography, LC-MS/MS and MALDI for drug-distribution studies in biological samples: the ultimate matrix trilogy. AB - The drug-development process requires an understanding of the ADME properties of the novel therapeutic agent. Determination of drug concentrations and identity in excreta (urine and feces) examines the products of these processes. Similar measurements made on plasma, while accurately determining exposure, show only what is being transported around the body. Both activities fail to confirm the nature of components at the pharmacologically relevant matrix - the tissue. Attention is therefore being directed towards methods that can be employed to address this lack in our current methodologies, to provide better quality data on which risk assessments can be made, so that pharmacological models can be refined, and drug safety improved. In this article, we will look at the current methods used to obtain tissue drug and drug metabolite concentrations, and their potential use in drug discovery. PMID- 24471958 TI - ISR: background, evolution and implementation, with specific consideration for ligand-binding assays. AB - ISR was highlighted as a topic of major interest to the US FDA in 2006, having been previously required, then discontinued, by Canadian regulatory authorities. Following an FDA focus on ISR, this topic has also been emphasized by regulatory agencies in Europe, Asia and Latin America. Extensive discussions on proper implementation of programs have taken place in multiple settings, including pharmaceutical companies, regulatory agencies, professional associations and CROs. These efforts have led to recommendations for ISR conduct that are now included in a final guideline on bioanalytical method validation from the European Medicines Agency, a draft validation guidance from the Ministry of Health, Labor and Welfare in Japan and a revised draft validation guidance from the FDA. In this Review we look at the background, evolution and implementation of ISR for all assays, while including some specific considerations on this topic for ligand-binding assays. PMID- 24471959 TI - Metabolomics applied in neonatology. AB - Over the past two decades, host-response biomarkers have been extensively used by clinicians for a better understanding of normal biological processes, the complexity and severity of illnesses, or pharmacological responses to therapeutic intervention. A myriad of information can be drawn from the gender, age, dietary intake and the disease history of an individual. These biomarkers may be promising for the complete phenotyping of a cell, tissue or an organism. In neonatology, these molecular markers may help in prediction of disease severity and its outcome, thus allowing personalized interventions. In this Review, existing data in the literature on metabolites in plasma, urine and maternal milk that may offer a unique insight into the host's dynamic behavior in different neonatal conditions will be examined. PMID- 24471960 TI - Anatomy of noise in quantitative biological Raman spectroscopy. AB - Raman spectroscopy is a fundamental form of molecular spectroscopy that is widely used to investigate structures and properties of molecules using their vibrational transitions. It relies on inelastic scattering of monochromatic laser light irradiating the specimen. After appropriate filtering the scattered light is dispersed onto a detector to determine the shift from the excitation wavelength, which appears in the form of characteristic spectral patterns. The technique can investigate biological samples and provide real-time diagnosis of diseases. However, despite its intrinsic advantages of specificity and minimal perturbation, the Raman scattered light is typically very weak and limits applications of Raman spectroscopy due to measurement (im)precision, driven by inherent noise in the acquired spectra. In this article, we review the principal noise sources that impact quantitative biological Raman spectroscopy. Further, we discuss how such noise effects can be reduced by innovative changes in the constructed Raman system and appropriate signal processing methods. PMID- 24471961 TI - On the nature of the structural and magnetic phase transitions in the layered perovskite-like (CH3NH3)2[Fe(II)Cl4]. AB - In view of renewed interest in multiferroic for molecular systems, we re-examine the structural and magnetic properties of the potentially ferroic layered perovskite-like (CH3NH3)2[Fe(II)Cl4] due to its high-temperature magnetic ordering transition. The structures from several sets of diffraction data of single crystals consist of square-grid layers of corner-sharing FeCl6 octahedra and changes from the high-symmetry I4/mmm (T > 335 K) to the low-symmetry Pccn (T < 335 K). In the former the iron and bridging chlorine atoms are within the layer and the organic cations sit in the middle of each square grid, while in the latter the octahedra are tilted in pairs, two in and two out, progressively by up to 12 degrees and the nitrogen atoms follow their motion to be nearer to the two in pairs. Crystals are stable up to 450 K and display three phase transitions, two structural at 332 and 233 K and one magnetic at 95 K. The temperature dependences of the dc magnetization (zero-field and field-cooling modes) in different applied fields (10-10,000 Oe) on several aligned single crystals independently reveal a hidden-canted antiferromagnetic ground state of at least four sublattices and not the reported canted antiferromagnetic ground state. A metamagnetic critical field of only 200 Oe transforms it to a canted antiferromagnet. The estimated canting angle is 1.4 degrees in zero field, and it folds to ca. 2.8 degrees in a field of 50 kOe at 2 K. The easy axis is along 010, the hard axis is along 100, and the intermediate and canting axis is 001. Using the available extracted parameters the phase diagram has been constructed. This study provides evidence of a complex and intricate manifestation of the orientation, temperature, and field dependence of the interplay between anisotropy and coherent lengths, which would need further studies. PMID- 24471962 TI - Enhanced probing of attentional bias: the independence of anxiety-linked selectivity in attentional engagement with and disengagement from negative information. AB - Cognitive models of anxiety posit that an attentional bias to negative information plays a causal role in elevated anxiety vulnerability and dysfunction. There has been considerable recent interest in determining whether this attentional bias reflects facilitated attentional engagement with and/or impaired attentional disengagement from negative information. We concur with the claim of investigators who have noted that the methodologies previously employed to dissociate engagement and disengagement biases are not optimal for this purpose. In the present study, we employ a novel methodology, the Attentional Response to Distal vs. Proximal Emotional Information (ARDPEI) task, which enables the discrete assessment of these two types of attentional selectivity. The findings demonstrate that facilitated attentional engagement with and impaired attentional disengagement from negative information both characterise elevated anxiety vulnerability. Further, these biases represent distinctive facets of anxiety-linked attentional selectivity. We discuss the potentially differing roles that engagement and disengagement biases may play in the development and/or maintenance of anxiety vulnerability and dysfunction. PMID- 24471963 TI - The potential for manipulating RNA with pentatricopeptide repeat proteins. AB - The pentatricopeptide repeat (PPR) protein family, which is particularly prevalent in plants, includes many sequence-specific RNA-binding proteins involved in all aspects of organelle RNA metabolism, including RNA stability, processing, editing and translation. PPR proteins consist of a tandem array of 2 30 PPR motifs, each of which aligns to one nucleotide in the RNA target. The amino acid side chains at two or three specific positions in each motif confer nucleotide specificity in a predictable and programmable manner. Thus, PPR proteins appear to provide an extremely promising opportunity to create custom RNA-binding proteins with tailored specificity. We summarize recent progress in understanding RNA recognition by PPR proteins, with a particular focus on potential applications of PPR-based tools for manipulating RNA, and on the challenges that remain to be overcome before these tools may be routinely used by the scientific community. PMID- 24471964 TI - Muse cells, newly found non-tumorigenic pluripotent stem cells, reside in human mesenchymal tissues. AB - Mesenchymal stem cells (MSCs) have been presumed to include a subpopulation of pluripotent-like cells as they differentiate not only into the same mesodermal lineage cells but also into ectodermal- and endodermal-lineage cells and exert tissue regenerative effects in a wide variety of tissues. A novel type of pluripotent stem cell, Multilineage-differentiating stress enduring (Muse) cells, was recently discovered in mesenchymal tissues such as the bone marrow, adipose tissue, dermis and connective tissue of organs, as well as in cultured fibroblasts and bone marrow-MSCs. Muse cells are able to differentiate into all three germ layers from a single cell and to self-renew, and yet exhibit non tumorigenic and low telomerase activities. They can migrate to and target damaged sites in vivo, spontaneously differentiate into cells compatible with the targeted tissue, and contribute to tissue repair. Thus, Muse cells may account for the wide variety of differentiation abilities and tissue repair effects that have been observed in MSCs. Muse cells are unique in that they are pluripotent stem cells that belong in the living body, and are thus assumed to play an important role in 'regenerative homeostasis' in vivo. PMID- 24471965 TI - Molecular pathology of pancreatic cancer. AB - By genomic and epigenomic screening techniques, substantial progress has been made in our understanding of pancreatic cancer. The comprehensive studies of the pancreatic cancer genome have revealed that most genetic alterations are identified to be associated with specific core signaling pathways including high frequency mutated genes such as KRAS, CDKN2A, TP53, and SMAD4 along with several low-frequency mutated genes. Three types of histological precursors of pancreatic cancer: pancreatic intraepithelial neoplasia, mucinous cystic neoplasm, and intraductal papillary mucinous neoplasm, had been recognized by morphological studies and the recent genomic screening techniques revealed that each of these precursor lesions were associated with specific molecular alterations. In the familial pancreatic cancer cases, several responsible genes were discovered. Epigenetic changes also play an important role in the progression of pancreatic cancer. Several tumor suppressor genes were silenced due to aberrant promoter CpG island hypermethylation. Several genetically engineered mouse models, based on the Kras mutation, were created, and provided reliable tools to identify the key molecules responsible for the development or progression of pancreatic cancer. PMID- 24471966 TI - Immunohistochemical staining patterns of cytokeratins 13, 14, and 17 in oral epithelial dysplasia including orthokeratotic dysplasia. AB - Diagnosis of the exact grade of oral epithelial dysplasia is difficult, and interobserver variations in grading are common. The aim of this study was to investigate the expression patterns of cytokeratins (CKs) in dysplastic oral epithelia, to identify useful double immunostaining diagnostic markers. Immunoexpression of CK13, CK14, CK17, and Ki-67 were investigated in 21 normal epithelial specimens and 146 epithelial dysplasia specimens. In epithelial dysplasia specimens, orthokeratotic dysplasia (OKD) was identified using CK10 immunostaining. Most mild dysplasia specimens were CK13+ and CK17-. In moderate dysplasia, CK13 expression tended to be lower and CK17 expression tended to be higher than in mild dysplasia. All carcinoma in situ (CIS) specimens were CK17+. In differentiated type CIS specimens, CK13 expression was weakly positive. Most epithelial dysplasia specimens were CK14+. There were no significant differences in the expression patterns of CKs between OKD and non-OKD specimens in any of the grades of dysplasia. These results indicate that CK14 expression can be used to detect early epithelial dysplasia, and that CK13 and CK17 expression are useful for detecting neoplastic changes. PMID- 24471967 TI - Combined high-grade neuroendocrine carcinoma of the lung: clinicopathological and immunohistochemical study of 34 surgically resected cases. AB - To understand the pathogenesis of high-grade neuroendocrine carcinoma (HGNEC), we examined the histopathology and immunoreactivity against adenocarcinoma (AD), squamous cell carcinoma (SQ), and neuroendocrine markers in 34 cases with combined HGNEC. The 5 year overall survival rates of patients with combined small cell carcinoma (SCC) (n = 9) and combined large cell neuroendocrine carcinoma (LCNEC) (n = 25) were 33% and 75%, respectively (P = 0.011). Most of the patients were male (94%), smokers (94%), and had tumors located in the peripheral (94%) and upper lobe (65%) of the lung. Histopathologically, non-HGNEC components were predominantly ADs (65%) followed by SQs (26%). In combined HGNEC and AD, a lepidic AD component was found in 12 cases (48%). For the HGNEC components of combined HGNEC and AD, the incidence of positivity of thyroid transcription factor-1 (TTF-1) (8G7G3/1) and TTF1 (SPT24) were 64% and 91%, respectively. For HGNEC components of combined HGNEC and SQ, the incidence of positivity of 34betaE12 and p63 were 22% and 11%, respectively. In conclusion, 48% of combined HGNEC and AD cases had a lepidic AD component, suggesting that HGNEC can develop in association with pre-existing AD. AD markers, but not SQ markers, were frequently retained through development of the HGNEC component. PMID- 24471968 TI - A case of diffuse infiltrating gastrointestinal stromal tumor of sigmoid colon with perforation. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the gastrointestinal tract, and typically present as discrete well circumscribed but non-encapsulated tumor masses. In this report, we describe a case of colonic perforation caused by an unusual form of GIST. A 72-year-old Japanese woman presented to the emergency department with acute abdominal pain. Under the provisional diagnosis of sigmoid colon perforation, a laparoscopic sigmoidectomy was performed. Although the tumor mass was undetectable during the preoperative examination, a spindle cell lesion with a diffuse longitudinal growth pattern replacing the muscularis propria was revealed by microscopic examination. The spindle cell lesion was exposed at the perforation, suggesting a causal relationship between the lesion and the perforation. The spindle cell lesion was KIT-positive and had a mutation in the C-KIT gene at exon 11. We diagnosed it as diffuse infiltrating GIST. We consider that the lesion would be a cause of the colonic perforation, and emphasize the importance of accurate diagnosis of the lesion by histological, immunohistochemical and genetic examinations. PMID- 24471969 TI - Intraductal dissemination of papillary adenocarcinoma of the ampulla of Vater in the pancreatic duct. AB - It has been speculated that intraductal dissemination, via the pancreatic duct, bile duct, or mammary duct, is a unique form of cancer cell spread. However, clinical evidence to confirm this form of dissemination has been lacking. Here we report a case of papillary adenocarcinoma of the ampulla of Vater in which retrograde dissemination to the pancreatic duct was strongly suggested. A 79-year old woman underwent pancreatoduodenectomy for a 22 mm microinvasive papillary adenocarcinoma of the ampulla. Multiple carcinomas in situ were found in the pancreatic duct distant from the ampulla. Seven months later, she underwent a second operation for a recurrent papillary adenocarcinoma at the pancreato jejunal anastomosis showing exophytic and expansive growth into the jejunal lumen that connected to an intraductal adenocarcinoma in the pancreatic body. None of these tumors showed invasive growth, or vascular or neural invasion, being separate from each other but sharing identical histological, immunohistochemical, and molecular features; papillary growth, a pancreatobiliary phenotype, the same pattern of genomic loss of heterozygosity, and no mutation of the KRAS, TP53, and GNAS genes. These results imply that this papillary adenocarcinoma of the ampulla of Vater had disseminated to the pancreatic duct in a retrograde manner and recurred in the remnant pancreas. PMID- 24471970 TI - Mesenchymal chondrosarcoma of the uterus. PMID- 24471971 TI - Two healthy females with fulminant hepatic failure caused by herpes simplex virus infection. PMID- 24471972 TI - Barriers to the delivery of optimal antidiabetic therapy in the Middle East and Africa. AB - BACKGROUND: The prevalence of type 2 diabetes is increasing worldwide, but developing nations will bear a disproportionate share of this burden. Countries in the Middle East and Africa are in a state of transition, where marked disparities of income and access to education and healthcare exist, and where the relatively young populations are being exposed increasingly to processes of urbanisation and adverse changes in diet that are fuelling the diabetes epidemic. Optimising diabetes care in these nations is crucial, to minimise the future burden of complications of diabetes. METHODS: We have reviewed the barriers to effective diabetes care with special relevance to countries in this region. RESULTS: The effects of antidiabetic treatments themselves are unlikely to differ importantly in the region compared with elsewhere, but economic inequalities within countries restrict access to newer treatments, in particular. Values relating to family life and religion are important modifiers of the physician patient interaction. Also, a lack of understanding of diabetes and its treatments by both physicians and patients requires more and better diabetes education, delivered by suitably qualified health educators. Finally, sub-optimal processes for delivery of care have contributed to a lack of proper provision of testing and follow-up of patients in many countries. CONCLUSION: Important barriers to the delivery of optimal diabetes care exist in the Middle East and Africa. PMID- 24471973 TI - Dorsoventral asymmetry of photosynthesis and photoinhibition in flag leaves of two rice cultivars that differ in nitrogen response and leaf angle. AB - Rice is believed to show photosynthetic symmetry between adaxial and abaxial leaf sides. To verify this, we re-examined dorsoventral asymmetry in photosynthesis, chlorophyll fluorescence and anatomical traits in flag leaves of two Oryza sativa cultivars that differ in nitrogen (N) response and in leaf angle: 'Akenohoshi', a cultivar that can adapt to low-N (LN), with low leaf angle (more erect leaves), and 'Shirobeniya', a cultivar that is unable to adapt to LN, with higher leaf angle. Plants were grown under standard-N (SN) and LN conditions. LN leaves of both cultivars became more erect than SN, but LN Akenohoshi still had more erect ones than Shirobeniya. Contrary to results of previous studies, leaves of both cultivars showed an asymmetry in photosynthetic rate between adaxial and abaxial sides (higher on the adaxial side) under SN. SN leaves of both cultivars showed lower susceptibility to photoinhibition on the adaxial side than on the abaxial side. However, leaves of Akenohoshi showed less asymmetry in these traits under LN than under SN, whereas leaves of Shirobeniya had similar degrees of asymmetry in these traits under both SN and LN. Both cultivars also showed dorsoventral asymmetry in anatomical traits of mesophyll tissue regardless of N level, but the degree of asymmetry was lower in LN Akenohoshi. These data reveal that rice leaves exhibit dorsoventral asymmetry in photosynthetic and anatomical features, and that the degree of asymmetry varies with cultivar and N level. It is suggested that lower leaf angles (particularly in Akenohoshi) in the presence of LN represent a light acclimation to prevent photoinhibition. PMID- 24471974 TI - Aerobic interval training protects against myocardial infarction-induced oxidative injury by enhancing antioxidase system and mitochondrial biosynthesis. AB - 1. Aerobic interval training (AIT) exerts beneficial effects on cardiovascular disease. However, its cardioprotective mechanisms are not fully understood. The aim of the present study was to evaluate AIT-mediated anti-oxidation by focusing on anti-oxidase and mitochondrial biogenesis in rats after myocardial infarction (MI). 2. Sprague-Dawley rats were divided into three groups: (i) a sham-operated control (CON); (ii) an MI group; and (iii) an MI + AIT group. Myocardial microstructure and function, markers of oxidative stress, mitochondrial anti oxidase, Phase II enzymes and mitochondrial biogenesis were assessed. In addition, levels of nuclear factor-erythroid 2-related factor (Nrf2) and phosphorylated (p-) AMP-activated protein kinase (AMPK) were determined. The anti oxidative gene sirtuin 3 (SIRT3) and the prosurvival phosphatidylinositol-3 kinase (PI3-K)-protein kinase B (Akt) signalling cascade were also evaluated. 3. Compared with CON, there was noticeable microstructure injury, cardiac dysfunction and oxidative damage in rats after MI. In addition, decreased mitochondrial anti-oxidase content, Phase II enzyme (except heme oxygenase-1) expression and mitochondrial biogenesis were observed in the post-MI rats as well as reduced protein levels of the regulators Nrf2 and p-AMPK and suppression of SIRT3 levels and PI3-K/Akt signalling. These detrimental modifications were considerably ameliorated by AIT, as evidenced by increases in anti-oxidase, mitochondrial biogenesis, Nrf2 and AMPK phosphorylation, as well as SIRT3 upregulation and PI3-K/Akt signalling activation. Moreover, PI3-K inhibitor LY294002 (20 mg/kg) treatment partly attenuated AIT-elicited increases in Nrf2 levels and AMPK phosphorylation. 4. Based on these results, we conclude that AIT effectively alleviates MI-induced oxidative injury, which may be closely correlated with activation of the anti-oxidase system and mitochondrial biosynthesis. Increased SIRT3 expression and activation of PI3-K/Akt signalling may play key roles in AIT-mediated anti-oxidation. These results open up new avenues for exercise intervention therapies for MI patients. PMID- 24471975 TI - The effect of response scale, administration mode, and format on responses to the CAHPS Clinician and Group survey. AB - OBJECTIVE: To examine how different response scales, methods of survey administration, and survey format affect responses to the CAHPS (Consumer Assessment of Healthcare Providers and Systems) Clinician and Group (CG-CAHPS) survey. STUDY DESIGN: A total of 6,500 patients from a university health center were randomly assigned to receive the following: standard 12-page mail surveys using 4-category or 6-category response scales (on CG-CAHPS composite items), telephone surveys using 4-category or 6-category response scales, or four-page mail surveys. PRINCIPAL FINDINGS: A total of 3,538 patients completed surveys. Composite score means and provider-level reliabilities did not differ between respondents receiving 4-category or 6-category response scale surveys or between 12-page and four-page mail surveys. Telephone respondents gave more positive responses than mail respondents. CONCLUSIONS: We recommend using 4-category response scales and the four-page mail CG-CAHPS survey. PMID- 24471977 TI - A direct and polymer-free method for transferring graphene grown by chemical vapor deposition to any substrate. AB - We demonstrate a polymer-free method that can routinely transfer relatively large area graphene to any substrate with advanced electrical properties and superior atomic and chemical structures as compared to the graphene sheets transferred with conventional polymer-assisted methods. The graphene films that are transferred with polymer-free method show high electrical conductance and excellent optical transmittance. Raman spectroscopy and X-ray/ultraviolet photoelectron spectroscopy also confirm the presence of high quality graphene sheets with little contamination after transfer. Atom-resolved images can be obtained using scanning tunneling microscope on as-transferred graphene sheets without additional cleaning process. The mobility of the polymer-free graphene monolayer is as high as 63,000 cm(2) V(-1) s(-1), which is 50% higher than the similar sample transferred with the conventional method. More importantly, this method allows us to place graphene directly on top of devices made of soft materials, such as organic and polymeric thin films, which widens the applications of graphene in soft electronics. PMID- 24471976 TI - Structural modifications of neuroprotective anti-Parkinsonian (-)-N6-(2-(4 (biphenyl-4-yl)piperazin-1-yl)-ethyl)-N6-propyl-4,5,6,7 tetrahydrobenzo[d]thiazole-2,6-diamine (D-264): an effort toward the improvement of in vivo efficacy of the parent molecule. AB - In our overall goal to develop multifunctional dopamine D2/D3 agonist drugs for the treatment of Parkinson's disease (PD), we previously synthesized potent D3 preferring agonist D-264 (1a), which exhibited neuroprotective properties in two animal models of PD. To enhance the in vivo efficacy of 1a, a structure-activity relationship study was carried out. Competitive binding and [(35)S]GTPgammaS functional assays identified compound (-)-9b as one of the lead molecules with preferential D3 agonist activity (EC50(GTPgammaS); D3 = 0.10 nM; D2/D3 (EC50): 159). Compounds (-)-9b and (-)-8b exhibited high in vivo activity in two PD animal models, reserpinized and 6-hydroxydopamine (OHDA)-induced unilateral lesioned rats. On the other hand, 1a failed to show any in vivo activity in these models unless the compound was dissolved in 5-10% beta-hydroxy propyl cyclodextrin solution. Lead compounds exhibited appreciable radical scavenging activity. In vitro experiments with dopaminergic MN9D cells indicated neuroprotection by both 1a and (-)-9b from toxicity of MPP+. PMID- 24471978 TI - Volatile organic compounds in fourteen U.S. retail stores. AB - Retail buildings have a potential for both short-term (customer) and long-term (occupational) exposure to indoor pollutants. However, little is known about volatile organic compound (VOC) concentrations in the retail sector and influencing factors, such as ventilation, in-store activities, and store type. We measured VOC concentrations and ventilation rates in 14 retail stores in Texas and Pennsylvania. With the exception of formaldehyde and acetaldehyde, VOCs were present in retail stores at concentrations well below health guidelines. Indoor formaldehyde concentrations ranged from 4.6 ppb to 67 ppb. The two mid-sized grocery stores in the sample had the highest levels of ethanol and acetaldehyde, with concentrations up to 2.6 ppm and 92 ppb, respectively, possibly due to the preparation of dough and baking activities. Indoor-to-outdoor concentration ratios indicated that indoor sources were the main contributors to indoor VOC concentrations for the majority of compounds. There was no strong correlation between ventilation and VOC concentrations across all stores. However, increasing the air exchange rates at two stores led to lower indoor VOC concentrations, suggesting that ventilation can be used to reduce concentrations for some specific stores. PMID- 24471979 TI - Topical photodynamic therapy following excisional wounding of human skin increases production of transforming growth factor-beta3 and matrix metalloproteinases 1 and 9, with associated improvement in dermal matrix organization. AB - BACKGROUND: Animal studies report photodynamic therapy (PDT) to improve healing of excisional wounds; the mechanism is uncertain and equivalent human studies are lacking. OBJECTIVES: To explore the impact of methyl aminolaevulinate (MAL)-PDT on clinical and microscopic parameters of human cutaneous excisional wound healing, examining potential modulation through production of transforming growth factor (TGF)-beta isoforms. METHODS: In 27 healthy older men (60-77 years), a 4 mm punch biopsy wound was created in skin of the upper inner arm and treated with MAL-PDT three times over 5 days. An identical control wound to the contralateral arm was untreated and both wounds left to heal by secondary intention. Wounds were re-excised during the inflammatory phase (7 days, n = 10), matrix remodelling (3 weeks, n = 8) and cosmetic outcome/dermal structure (9 months, n = 9). Production of TGF-beta1, TGF-beta3 and matrix metalloproteinases (MMPs) was assessed by immunohistochemistry alongside microscopic measurement of wound size/area and clinical assessment of wound appearance. RESULTS: MAL-PDT delayed re-epithelialization at 7 days, associated with increased inflammation. However, 3 weeks postwounding, treated wounds were smaller with higher production of MMP-1 (P = 0.01), MMP-9 (P = 0.04) and TGF-beta3 (P = 0.03). TGF-beta1 was lower than control at 7 days and higher at 3 weeks (both P = 0.03). At 9 months, MAL-PDT treated wounds showed greater, more ordered deposition of collagen I, collagen III and elastin (all P < 0.05). CONCLUSIONS: MAL-PDT increases MMP-1, MMP-9 and TGF-beta3 production during matrix remodelling, ultimately producing scars with improved dermal matrix architecture. PMID- 24471981 TI - Nanowire-functionalized cotton textiles. AB - We show the general functionalization of cotton fabrics using solution synthesized CdSe and CdTe nanowires (NWs). Conformal coatings onto individual cotton fibers have been achieved through various physical and chemical approaches. Some involve the electrostatic attraction of NWs to cotton charged positively with a Van de Graaff generator or via 2,3-epoxypropyltrimethylammonium chloride treatments. Resulting NW-functionalized textiles consist of dense, conformal coatings and have been characterized for their UV-visible absorption as well as Raman activity. We demonstrate potential uses of these functionalized textiles through two proof-of-concept applications. The first entails barcoding cotton using the unique Raman signature of the NWs. We also demonstrate the surface-enhancement of their Raman signatures using codeposited Au. A second demonstration takes advantage of the photoconductive nature of semiconductor NWs to create cotton-based photodetectors. Apart from these illustrations, NW functionalized cotton textiles may possess other uses in the realm of medical, anticounterfeiting, and photocatalytic applications. PMID- 24471980 TI - Binding of copper and silver to single-site variants of peptidylglycine monooxygenase reveals the structure and chemistry of the individual metal centers. AB - Peptidylglycine monooxygenase (PHM) catalyzes the final step in the biosynthesis of amidated peptides that serve as important signaling molecules in numerous endocrine pathways. The catalytic mechanism has attracted much attention because of a number of unique attributes, including the presence of a pair of uncoupled copper centers separated by 11 A (termed CuH and CuM), an unusual Cu(I)SMet interaction at the oxygen binding M-site, and the postulated Cu(II)-superoxo intermediate. Understanding the mechanism requires determining the catalytic roles of the individual copper centers and how they change during catalysis, a task made more difficult by the overlapping spectral signals from each copper center in the wild-type (WT) protein. To aid in this effort, we constructed and characterized two PHM variants that bound metal at only one site. The H242A variant bound copper at the H-center, while the H107AH108A double mutant bound copper at the M-center; both mutants were devoid of catalytic activity. Oxidized Cu(II) forms showed electron paramagnetic resonance and extended X-ray absorption fine structure (EXAFS) spectra consistent with their previously determined Cu(II)His3O and Cu(II)His2O2 ligand sets for the H- and M-centers, respectively. Cu(I) forms, on the other hand, showed unique chemistry. The M-center bound two histidines and a methionine at all pHs, while the H-center was two-coordinate at neutral pH but coordinated a new methionine S ligand at low pH. Fourier transform infrared studies confirmed and extended previous assignments of CO binding and showed unambiguously that the 2092 cm(-1) absorbing species observed in the WT and many variant forms is an M-site Cu(I)-CO adduct. Silver binding was also investigated. When H107AH108A and M109I (a WT analogue with both sites intact) were incubated with excess AgNO3, each variant bound a single Ag(I) ion, from which it was inferred that Ag(I) binds selectively at the M-center with little or no affinity for the H-center. EXAFS at the Ag K-edge established a strong degree of similarity between the ligand sets of Cu and Ag bound at the M-center. These studies validate previous spectral assignments and provide new insights into the detailed chemistry of each metal site. PMID- 24471982 TI - Vibrational energy flow through the green fluorescent protein-water interface: communication maps and thermal boundary conductance. AB - We calculate communication maps for green fluorescent protein (GFP) to elucidate energy transfer pathways between the chromophore and other parts of the protein in the ground and excited state. The approach locates energy transport channels from the chromophore to remote regions of the protein via residues and water molecules that hydrogen bond to the chromophore. We calculate the thermal boundary conductance between GFP and water over a wide range of temperature and find that the interface between the protein and the cluster of water molecules in the beta-barrel poses negligible resistance to thermal flow, consistent with facile vibrational energy transfer from the chromophore to the beta-barrel waters observed in the communication maps. PMID- 24471984 TI - Testicular morphology in spontaneously hypertensive rat model: oxidant status and stereological implications. AB - Studies by researchers suggest that reductions in blood flow to the testis could play an important role in the pathogenesis of male infertility. As this oxygen dependent organ functions in a state of near anoxia, such a decrease in blood flow may very likely have profound effects on the tissue morphology that ultimately would predispose to various forms of hypo-spermatogenesis with consequent compromise in reproductive capability. With varying opinions expressed by experts as to the actual culprit or potential pathway and/or effects of pathophysiology of testicular haemodynamics, it still remains debatable whether the observed degenerative changes in testicular tissue are the result of major or minor reductions in flow or the consequence of other vascular pathologies or even extraneous factors. Again, increasing age and male gender have been identified as the single independent risk factors for the occurrence of cardiovascular pathologies with sexual dimorphism highly debated. The investigation of these factors occurring under hypertensive states using the spontaneously hypertensive rat (SHR) as an experimental model has attracted substantial attention in recent past. This review examines the relationships and potential morphologic changes in the testicular tissue under conditions of perturbations in blood flow as seen in the SHR with a view to the proper understanding of the role(s) of various factors that contributes to male subfertility. A suggestion to the use of stereological methods for quantitating various measurements in a highly active and dynamic structure like the testis with its arterial system has been added as this may facilitate a better understanding of the mechanisms implicated under hypertensive conditions. PMID- 24471983 TI - Liposomal co-delivery of daptomycin and clarithromycin at an optimized ratio for treatment of methicillin-resistant Staphylococcus aureus infection. AB - CONTEXT: Pathogen evolution currently outpaces novel drug development, and because development of new antibiotics is pending, combination therapy with existing drugs may provide effective alternative treatments. OBJECTIVE: The present study was aimed at evaluating the concurrent use of two antibiotics, daptomycin and clarithromycin, against methicillin-resistant Staphylococcus aureus (MRSA) infections. MATERIALS AND METHODS: Polyeythylene glycol (PEGylated liposomes loaded with daptomycin, clarithromycin, or both (PL[CD]) at an optimized mass ratio of 1:32 were generated and characterized using dynamic light scattering and electron microscopy. In vitro and in vivo approaches were used to compare liposome effects on MRSA. RESULTS: PL[CD] were stable, with a mean (+/- SD) vesicle diameter of 98.2 +/- 2.21 nm and encapsulation efficiency of 94.71 +/ 1.37% (daptomycin) and 92.94 +/- 1.21% (clarithromycin). Compared with daptomycin-only liposomes, PL[CD] showed significantly enhanced anti-MRSA activity in vitro and significantly reduced MRSA bacterial load and increased host survival in vivo. DISCUSSION: Co-delivery of daptomycin with clarithromycin produced significant anti-MRSA activity in the presence of only one-thirtieth of the concentration required in liposomes containing daptomycin only. CONCLUSION: These findings suggested that concurrent liposomal delivery of daptomycin and clarithromycin has the potential to be an effective and less toxic treatment for MRSA infections. PMID- 24471985 TI - Evaluation of the activated partial thromboplastin time assay for clinical monitoring of PEGylated recombinant factor VIII (BAY 94-9027) for haemophilia A. AB - Patients with haemophilia (PWH) are usually monitored by the one-stage activated partial thromboplastin time (aPTT) factor VIII (FVIII) assay. Different aPTT activators may affect clotting time (CT) and FVIII:C levels in patients treated with PEGylated FVIII. To evaluate the characteristics of PEGylated FVIII (BAY 94 9027) in various aPTT clotting assays, and to identify suitable aPTT reagents for monitoring BAY 94-9027 during the treatment of PWH, BAY 94-9027 and World Health Organization (WHO) 8th FVIII standards (WHO-8) were spiked into pooled and individual severe haemophilia A plasma at 1.0, 0.25 and 0.05 IU mL(-1) . Five commercial aPTT reagents widely used in clinical laboratories were compared and evaluated for BAY 94-9027 activity in plasma from PWH. BAY 94-9027 and WHO-8 bestowed similar CT and excellent precision when ellagic acid (SynthAFax, Dade Actin, and Cephascreen) aPTT reagents were used. In contrast, BAY 94-9027 showed significantly prolonged CT and poor precision compared with WHO-8 using silica aPTT reagents (APTT-SP and STA PTT 5). Furthermore, free 60-kDa polyethylene glycol (PEG), used for the conjugation of FVIII, showed a dose-dependent prolongation of CT in the APTT-SP assay. There was no effect on the SynthAFax APTT, prothrombin time, or FXIa-initiated thrombin generation assay, demonstrating that the PEG moiety on FVIII has no general effect on the coagulation cascade. In summary, ellagic aPTT reagents (SynthAFax, Dade Actin, and Cephascreen) are most suitable for evaluating potency of BAY 94-9027 and should be the preferred aPTT reagents used in clinical laboratories for monitoring FVIII activity after infusion of BAY 94-9027 to PWH. PMID- 24471986 TI - ReBe2B5O11 (Re = Y, Gd): rare-earth beryllium borates as deep-ultraviolet nonlinear-optical materials. AB - Two novel rare-earth beryllium borates ReBe2B5O11 (Re = Y, Gd) have been discovered. These materials possess a unique structural feature with a platelike infinite infinity(2)[Be2B5O11]3- superlayer, which is first found in beryllium borates. The superlayer can be seen as sandwich-shaped with infinity(1)[B4O8]4- chains linking up with a infinity(2)[Be2BO5]3- sublayer above and below via the B O-Be bond. Each infinity(2)[Be2B5O11]3- layer is further connected to the neighboring layer through Re3+ cations coordinating with O atoms. Both of these two crystals have very short cutoff wavelengths below 200 nm and exhibit relatively large nonlinear-optical (NLO) effects, indicating their promising applications as good deep-UV NLO crystals. PMID- 24471987 TI - Considerations for the Provision of Services to Bilingual Children Who Use Augmentative and Alternative Communication. AB - Augmentative and alternative communication (AAC) service providers are increasingly serving a significant number of clients from culturally and linguistically diverse backgrounds. In this paper, we discuss general considerations and future research needs relevant to the use of AAC strategies and techniques with bilingual children, specifically, issues related to the scaffolding of communication and language development in more than one language, and the selection and customization of AAC systems for bilingual children. We do so by first reviewing key research on bilingualism with children with communication disabilities and its implications for research and practice in the AAC field. We propose the use of a sociocultural approach to AAC service delivery and argue for the support of both languages needed by the child to fully participate in his or her communicative environments. Implications of the sociocultural perspective and future research needs are also presented. PMID- 24471988 TI - A tribute to Viking O. Bjork (1918-2009): a four-decade functioning Bjork-Shiley aortic valve prosthesis. PMID- 24471989 TI - The expression of cyclooxygenase-2 and vascular endothelial growth factor in the endometrium during the peri-implantation period in women with and without polyps. AB - OBJECTIVE: This prospective study was designed to determine whether the expression of cyclooxygenase-2 (COX-2) and vascular endothelial growth factor (VEGF) in the endometrial tissue obtained from the peri-implantation period of women with endometrial polyp (EP) differs from that of control subjects without a polyp. METHODS: Endometrial samples were collected from 30 patients with EP and 30 control subjects without EP, in the mid-secretory phase. The expression of COX 2 and VEGF in the endometrium was examined with the use of immunohistochemistry. RESULTS: COX-2 and VEGF were predominantly expressed in endometrial glands. The expression of COX-2 and VEGF in the endometrium obtained from women with EP was lower than that of control subjects. CONCLUSION: The reduced expression of COX-2 and VEGF in the endometrium of women with EP may account for the association between EP and infertility. PMID- 24471990 TI - Occurrence of ochratoxin A in Canadian wheat shipments, 2010-12. AB - Randomly selected domestic and export shipments (n = 1907) of Canadian durum and other wheat that occurred between 1 January 2010 and 31 December 2012 were analysed for ochratoxin A (OTA). The majority of samples did not contain OTA above the LOQ of 1 MUg kg-1. Only 37% of samples analysed contained quantifiable OTA; the median OTA of the positive results was 2.10 MUg kg-1. Canada Western Amber Durum shipments contained OTA more frequently, and at slightly higher concentrations, than Canada Western Red Spring wheat. For both wheat classes the frequency of OTA occurrence and mean concentrations appeared to increase in the lower grades, but these increases were not statistically significant. A periodic trend of a late summer increase of mean monthly OTA concentrations in shipments appears tied to the cycle of producer deliveries of wheat to primary grain elevators. PMID- 24471991 TI - Surgical nurses' attitudes towards caring for patients dying of cancer - a pilot study of an educational intervention on existential issues. AB - This is a randomised controlled pilot study using a mixed methods design. The overall aim was to test an educational intervention on existential issues and to describe surgical nurses' perceived attitudes towards caring for patients dying of cancer. Specific aims were to examine whether the educational intervention consisting of lectures and reflective discussions, affects nurses' perceived confidence in communication and to explore nurses' experiences and reflections on existential issues after participating in the intervention. Forty-two nurses from three surgical wards at one hospital were randomly assigned to an intervention or control group. Nurses in both groups completed a questionnaire at equivalent time intervals: at baseline before the educational intervention, directly after the intervention, and 3 and 6 months later. Eleven face-to-face interviews were conducted with nurses directly after the intervention and 6 months later. Significant short-term and long-term changes were reported. Main results concerned the significant long-term effects regarding nurses' increased confidence and decreased powerlessness in communication, and their increased feelings of value when caring for a dying patient. In addition, nurses described enhanced awareness and increased reflection. Results indicate that an understanding of the patient's situation, derived from enhanced awareness and increased reflection, precedes changes in attitudes towards communication. PMID- 24471992 TI - Survival in octogenarians undergoing cardiac resynchronization therapy compared to the general population. AB - BACKGROUND: Many patients eligible for cardiac resynchronization therapy (CRT) are over 80 years of age. Survival in this population and how it compares to the general octogenarian population has not been established. METHODS: We extracted clinical data on a cohort of 800 consecutive patients undergoing the new implantation of a CRT device between April 15, 2004 and August 6, 2007. Patients over age 80, with class III-IV New York Heart Association heart failure symptoms on optimal medical therapy undergoing initial CRT implantation, were included in the final cohort. Using the United States Social Security Period Life Table for 2006, fractional survival for octogenarians in the general population was calculated and matched to our cohort based on age and gender. A comparison was then made between octogenarians undergoing CRT compared to the general population. RESULTS: A total of 95 octogenarians who met inclusion criteria were identified, of whom 86.3% received a biventricular defibrillator and the remainder a biventricular pacemaker. Over a mean follow-up of 3.6 +/- 1.5 years, there were 47 deaths (47.4%). The mean survival time was 4.1 years (95% CI 3.7 4.5), and survival at 2 years was 78.9%. Compared to the general octogenarian population, octogenarians receiving CRT had only modestly worse survival over the duration of follow-up with the survival curves diverging at 2 years of follow-up (P = 0.03). CONCLUSIONS: Octogenarians with advanced heart failure have a reasonable mean survival time following CRT. All-cause mortality in this patient population is only modestly worse compared to the general octogenarian population. Therefore, in octogenarians deemed to be reasonable candidates, CRT should not be withheld based on age alone. PMID- 24471993 TI - Cellulase and alcohol dehydrogenase immobilized in Langmuir and Langmuir-Blodgett films and their molecular-level effects upon contact with cellulose and ethanol. AB - The key challenges for producing devices based on nanostructured films with control over the molecular architecture are to preserve the catalytic activity of the immobilized biomolecules and to provide a reliable method for determining the intermolecular interactions and the accommodation of molecules at very small scales. In this work, the enzymes cellulase and alcohol dehydrogenase (ADH) were coimmobilized with dipalmitoylphosphatidylcholine (DPPC) as Langmuir-Blodgett (LB) films, and their biological activities were assayed by accommodating the structure formed in contact with cellulose. For this purpose, the polysaccharide was dissolved in an ionic liquid, 1-buthyl-3-methylimidazolium chloride (BMImCl), and dropped on the top of the hybrid cellulase-ADH-DPPC LB film. The interactions between cellulose and ethanol, which are the catalytic substrates of the enzymes as well as important elements in the production of second-generation fuels, were then investigated using polarization-modulation infrared reflection-absorption spectroscopy (PM-IRRAS). Investigation of the secondary structures of the enzymes was performed using PM-IRRAS, through which the presence of ethanol and cellulose was observed to highly affect the structures of ADH and cellulase, respectively. The detection of products formed from the catalyzed reactions as well as the changes of secondary structure of the enzymes immobilization could be carried out, which opens the possibility to produce a means for producing second generation ethanol using nanoscale arrangements. PMID- 24471995 TI - Ultrasound examination of wrist compartments in swollen wrists of patients with rheumatoid arthritis. PMID- 24471994 TI - High prevalence of malignancy in HIV-positive patients with mediastinal lymphadenopathy: a study in the era of antiretroviral therapy. AB - BACKGROUND AND OBJECTIVE: Mediastinal lymphadenopathy (MLN) in human immunodeficiency virus (HIV) infection has a wide spectrum of aetiologies with different prognoses and treatments. The decision to pursue a histopathological diagnosis represents a clinical challenge as patients present with non-specific symptoms. This study aimed to determine the aetiology and predictive factors of MLN in a cohort of HIV-infected patients in the combination antiretroviral therapy (cART) era. METHODS: Single-centre retrospective cohort study of 217 consecutive HIV-infected patients who underwent computed tomography (CT) of the chest between January 2004 and December 2009. Fifty-two patients were identified to have MLN (>10 mm in short axis). CT images were re-reviewed by an independent radiologist blinded to the clinical information. Final diagnoses of MLN were obtained from clinical records. Multivariate analysis was performed to identify predictors of aetiology of MLN. RESULTS: Seventeen patients (33%) had a diagnosis of malignancy. Consolidation on CT was associated with a reduced likelihood of malignancy odds ratio (OR) 0.03 (95% confidence interval 0.002-0.422), and larger lymph nodes were associated with an increase in the odds of malignancy (OR 2.89; 95% confidence interval 1.24-6.71). CD4 count was found not to be a predictor of aetiology of MLN. CONCLUSIONS: In the era of combination cART, opportunistic infections and malignancy remain to be the frequent causes of MLN in HIV-positive patients, but the prevalence of non-HIV related malignancy has increased compared with previous studies. Although certain findings are predictors of non-malignant disease, pathological diagnosis of MLN in HIV-positive patients should be pursued whenever possible. PMID- 24471996 TI - Selective pharmacological prophylaxis based on individual risk assessment using plasma levels of soluble fibrin and plasminogen-activator inhibitor-1 following total hip arthroplasty. AB - OBJECTIVES: The purpose of this prospective study was to evaluate the utility of preferential application of pharmacoprophylaxis based on the quantitative evaluation by soluble fibrin (SF) and plasminogen activator inhibitor-1 (PAI-1) analysis on the day after total hip arthroplasty (THA). METHODS: A hundred and sixteen patients were enrolled. High-risk patients were defined as those with elevated levels of SF or PAI-1, beyond their cut-off values, on the day after THA. For high-risk patients, fondaparinux was administered for 10 days postoperatively. When both plasma levels of SF and PAI-1 were less than their cutoff levels, the patients were regarded to be at low risk. For low-risk patients, only mechanical prophylaxis was applied. RESULTS: Sixty patients (52%) were considered to be at high risk. Among them, venous thromboembolism (VTE) was detected in five patients (8%) by CT angiography. In addition, there were four patients (3%) who developed bleeding complications. Fifty-six patients (48%) were considered to be at low risk, and only one patient (2%) developed VTE. CONCLUSION: The measurement of SF and PAI-1 levels on the day after surgery may be helpful to identify the individual risk for postoperative VTE. According to this evaluation, a half of patients might not need to administer anticoagulant agents following surgery. PMID- 24471997 TI - Neutrophil CD64 for monitoring the activity of nontuberculous mycobacteria infection in patients with rheumatoid arthritis. AB - OBJECTIVE: To evaluate the utility of neutrophil CD64 as a marker for monitoring the activity of nontuberculous mycobacteria (NTM) infection in patients with rheumatoid arthritis (RA). METHODS: We compared neutrophil CD64 expression in nine RA patients with NTM infection in the active and inactive phase of NTM disease chronologically. "Active phase" was here defined as present in patients admitted to hospital to receive intensive treatment for NTM, as well as outpatients with an infectious episode showing positive acid- and alcohol-fast bacillus (AFB) staining of sputa (Grade 2-3) who needed to start treatment for NTM with a multiple antibiotics regimen. The cut-off value for CD64 positivity was 2000 molecules/cell. RESULTS: Neutrophils from patients with active-phase NTM infection expressed high levels of CD64 with a mean +/- SEM of 7335 +/- 784 molecules/cell. However, during the inactive phase of disease, this was significantly lower (1481 +/- 103 molecules/cell, p < 0.001). The sensitivity and specificity of neutrophil CD64 to detect active-phase NTM infection was 96.3% and 84.6%, respectively. Expression of neutrophil CD64 was not affected by disease activity of the RA itself. CONCLUSIONS: Neutrophil CD64 is useful for monitoring disease activity in NTM infection of patients with RA. PMID- 24471998 TI - Application of ProTide technology to gemcitabine: a successful approach to overcome the key cancer resistance mechanisms leads to a new agent (NUC-1031) in clinical development. AB - Gemcitabine is a nucleoside analogue commonly used in cancer therapy but with limited efficacy due to a high susceptibility to cancer cell resistance. The addition of a phosphoramidate motif to the gemcitabine can protect it against many of the key cancer resistance mechanisms. We have synthesized a series of gemcitabine phosphoramidate prodrugs and screened for cytostatic activity in a range of different tumor cell lines. Among the synthesized compounds, one in particular (NUC-1031, 6f) was shown to be potent in vitro. Importantly, compared with gemcitabine, 6f activation was significantly less dependent on deoxycytidine kinase and on nucleoside transporters, and it was resistant to cytidine deaminase mediated degradation. Moreover, 6f showed a significant reduction in tumor volumes in vivo in pancreatic cancer xenografts. The ProTide 6f is now in clinical development with encouraging efficacy signals in a Phase I/II study, which strongly supports the ProTide approach to generate promising new anticancer agents. PMID- 24471999 TI - Emotion understanding, pictorial representations of friendship and reciprocity in school-aged children. AB - This study examined the relationship between emotional understanding, friendship representation and reciprocity in school-aged children. Two hundred and fifty-one Caucasian 6-year-old children (111 males and 140 females) took part in the study. The Test of Emotion Comprehension (TEC) and the Pictorial Assessment of Interpersonal Relationships (PAIR) were used. Children having a reciprocal friendship and children having a unilateral friendship with a child named as their "best friend" were compared on the emotional understanding task and on their pictorial representations of friendship. Multilevel analyses indicated that friendship status effects were not influenced by classroom-level differences. Results showed that children with reciprocal friendships drew themselves as more similar to and more cohesive with their best friends, and they showed better understanding of emotions, than children having a unilateral friendship. Finally, the implications of these findings for theoretical and empirical research development on friendship are discussed. PMID- 24472000 TI - Energy-band engineering for tunable memory characteristics through controlled doping of reduced graphene oxide. AB - Tunable memory characteristics are used in multioperational mode circuits where memory cells with various functionalities are needed in one combined device. It is always a challenge to obtain control over threshold voltage for multimode operation. On this regard, we use a strategy of shifting the work function of reduced graphene oxide (rGO) in a controlled manner through doping gold chloride (AuCl3) and obtained a gradient increase of rGO work function. By inserting doped rGO as floating gate, a controlled threshold voltage (Vth) shift has been achieved in both p- and n-type low voltage flexible memory devices with large memory window (up to 4 times for p-type and 8 times for n-type memory devices) in comparison with pristine rGO floating gate memory devices. By proper energy band engineering, we demonstrated a flexible floating gate memory device with larger memory window and controlled threshold voltage shifts. PMID- 24472001 TI - Anamorelin hydrochloride in the treatment of cancer anorexia-cachexia syndrome. AB - Anamorelin hydrochloride is an orally active ghrelin receptor agonist in development by Helsinn, for the treatment of non-small-cell lung cancer (NSCLC) cachexia. In preclinical and clinical studies, the potent affinity of anamorelin for the ghrelin receptor is associated with significant appetite-enhancing activity and resultant improvements in body weight, lean body mass, and handgrip strength compared with placebo. The accompanying stimulatory effects on growth hormone and IGF-1 are not associated with tumor growth, and overall survival in patients with cancer is not compromised. Anamorelin is well tolerated with no dose-limiting toxicities identified to date. The findings of ongoing Phase III studies are needed to confirm the significant potential of anamorelin to treat NSCLC cachexia. PMID- 24472003 TI - Musculoskeletal extremity injuries in a cohort of schoolchildren aged 6-12: a 2.5 year prospective study. AB - The objectives of this prospective school cohort study were to describe the epidemiology of diagnosed musculoskeletal extremity injuries and to estimate the injury incidence rates in relation to different settings, different body regions and injury types. In all, 1259 schoolchildren, aged 6-12, were surveyed weekly during 2.5 years using a new method of automated mobile phone text messaging asking questions on the presence of any musculoskeletal problems. All injuries were clinically diagnosed. Physical activity was measured from text messaging and accelerometers. A total number of 1229 injuries were diagnosed; 180 injuries in the upper extremity and 1049 in the lower extremity, with an overall rate of 1.59 injuries per 1000 physical activity units [95% confidence interval (CI) 1.50 1.68]. Upper extremities accounted for a rate of 0.23 (95% CI 0.20-0.27) and lower extremities accounted for 1.36 (95% CI 1.27-1.44). This study has added a wide overall perspective to the area concerning incidence and incidence rates of musculoskeletal extremity injuries in schoolchildren aged 6-12 years, including severe and less severe, traumatic, and overuse injuries. The understanding of injury epidemiology in children is fundamental to the acknowledgement and insurance of the appropriate prevention and treatment. PMID- 24472002 TI - One- vs 4-week stent placement after laparoscopic and robot-assisted pyeloplasty: results of a prospective randomised single-centre study. AB - OBJECTIVES: To determine whether 1-week stenting of the pelvi-ureteric anastomosis of laparoscopic or robot-assisted pyeloplasty is as effective as 4 week stenting, based on their respective success rates. PATIENTS AND METHODS: A total of 100 patients with pelvi-ureteric junction obstruction were treated by Anderson-Hynes pyeloplasty and the anastomosis was stented using a 6-F JJ catheter for either 1 week (1W series) or 4 weeks (4W series), based on a randomisation protocol. Postoperative follow-up was performed at 3 months using intravenous urography (IVU), at 6 months using diuretic renography and at 1, 3 and 5 years using ultrasonography. Statistical analysis was performed using a one sided Z-test, Pearsons's chi-squared test and a Wilcoxon rank sum test. RESULTS: The primary outcome measure, success rate, which was defined as no obstruction on IVU and diuretic renography, was 100% in the 1W series and not inferior to the success rate of 98% in the 4W series (P = 0.006). The following secondary outcome measures were not significantly different between the 1W and the 4W series with regard to residual symptoms (10 vs 6%; P = 0.48), rate of complications (4 vs 6%; P = 0.65), need for synchronous robot-assisted pyelolithotomy (4 vs 8%; P = 0.47), improvement in split renal function (1 vs 0%; P = 0.59) and duration of surgery (200 vs 192 min; P = 0.87). Only length of hospital stay was significantly different; this was shorter in the 1W series (5 vs 6 days; P = 0.01). CONCLUSIONS: Stenting of the pelvi-ureteric anastomosis after laparoscopic or robot-assisted pyeloplasty for 1 week is as effective as stenting for 4 weeks. Both procedures, laparoscopic or robot-assisted pyeloplasty have an excellent success rate. PMID- 24472004 TI - Distribution of sensory nerve endings around the human sinus tarsi: a cadaver study. AB - The aim of this study was to analyse the pattern of sensory nerve endings and blood vessels around the sinus tarsi. The superficial and deep parts of the fat pads at the inferior extensor retinaculum (IER) as well as the subtalar joint capsule inside the sinus tarsi from 13 cadaver feet were dissected. The distribution of the sensory nerve endings and blood vessels were analysed in the resected specimens as the number per cm(2) after staining with haematoxylin eosin, S100 protein, low-affinity neurotrophin receptor p75, and protein gene product 9.5 using the classification of Freeman and Wyke. Free nerve endings were the predominant sensory ending (P < 0.001). Ruffini and Golgi-like endings were rarely found and no Pacini corpuscles were seen. Significantly more free nerve endings (P < 0.001) and blood vessels (P = 0.01) were observed in the subtalar joint capsule than in the superficial part of the fat pad at the IER. The deep part of the fat pad at the IER had significantly more blood vessels than the superficial part of the fat pad at the IER (P = 0.012). Significantly more blood vessels than free nerve endings were seen in all three groups (P < 0.001). No significant differences in distribution were seen in terms of right or left side, except for free nerve endings in the superficial part of the fat pad at the IER (P = 0.003). A greater number of free nerve endings correlated with a greater number of blood vessels. The presence of sensory nerve endings between individual fat cells supports the hypothesis that the fat pad has a proprioceptive role monitoring changes and that it is a source of pain in sinus tarsi syndrome due to the abundance of free nerve endings. PMID- 24472005 TI - Genetic polymorphisms in the methylenetetrahydrofolate reductase gene (MTHFR) and risk of vitiligo in Han Chinese populations: a genotype-phenotype correlation study. AB - BACKGROUND: Recent evidence has revealed an elevation of total homocysteine (tHcy) in patients with vitiligo. Methylenetetrahydrofolate reductase (MTHFR) is one of the main enzymes regulating homocysteine (Hcy) metabolism. Thus, polymorphisms of MTHFR could potentially contribute to the development of vitiligo by affecting MTHFR activity and tHcy levels. OBJECTIVES: To evaluate the potential association between MTHFR polymorphisms and vitiligo susceptibility. METHODS: In total, 1000 patients with vitiligo and 1000 age- and sex-matched controls were enrolled in this hospital-based case-control study. Two single nucleotide polymorphisms of the MTHFR gene (rs1801133 C>T and rs1801131 A>C) were selected and genotyped using polymerase chain reaction (PCR)-restriction fragment length polymorphism and allele-specific PCR, respectively. The MTHFR activity concentration and tHcy level in serum were measured by enzyme-linked immunosorbent assay. RESULTS: We found that allele T of rs1801133 in the MTHFR gene was associated with a significantly reduced risk of vitiligo (adjusted odds ratio 0.58, 95% confidence interval 0.43-0.76, P < 0.001). In addition, the patients with vitiligo had a lower activity concentration of MTHFR and higher level of tHcy than the controls. Correlation between these markers and the risk of vitiligo was also observed. Furthermore, the individuals with a no-risk genotype (CT + TT) of rs1801133 and higher activity concentration of MTHFR or lower level of tHcy had a significantly decreased risk of vitiligo. CONCLUSIONS: Our data suggest that MTHFR gene polymorphisms may play a vital role in genetic susceptibility to vitiligo. PMID- 24472007 TI - Topics and trends in research on non-clinical interventions aimed at preventing prolonged work disability in workers compensated for work-related musculoskeletal disorders (WRMSDs): a systematic, comprehensive literature review. AB - PURPOSE: This study sought to provide an overview of the main topics and trends in contemporary research on successful non-clinical interventions for preventing prolonged work disability in workers compensated for work-related musculoskeletal disorders (WRMSDs). METHODS: A systematic electronic search (English and French) was performed in ten scientific databases using keywords and descriptors. After screening the identified titles and abstracts using specific sets of criteria, categorical and thematic analyses were performed on the retained articles. RESULTS: Five main topics appear to dominate the research: (1) risk factors and determinants; (2) effectiveness of interventions (programmes, specific components, strategies and policies); (3) viewpoints, experiences and perceptions of specific actors involved in the intervention process; (4) compensation issues; and (5) measurement issues. A currently widespread trend is early screening to identify risks factors for appropriate intervention and multidisciplinary, multimodal approaches. Morover, workplace-related psychosocial and ergonomic factors are considered vital to the success and sustainability of return-to-work (RTW) interventions. Finally, involving workplace actors, and more specifically, affected workers, in the RTW process appears to be a powerful force in improving the chances of moving workers away from disabled status. CONCLUSIONS: The findings of this literature review provide with information about the main topics and trends in research on rehabilitation interventions, revealing some successful modalities of intervention aimed at preventing prolonged work disability. IMPLICATIONS FOR REHABILITATION: Successful intervention for preventing prolonged work disability in workers compensated for WRMSDs address workplace issues: physical and psychosocial demands at work, ability of the workers to fill these demands, work organization and support of the worker, and worker' beliefs and attitudes related to work. Successful intervention promotes collaboration, coordination between all actors and stakeholders involved in the process of rehabilitation. Strategies able to mobilize the employees, employers, insurers and health care providers are still needed to be implemented. PMID- 24472006 TI - Exogenous L-arginine attenuates the effects of angiotensin II on renal hemodynamics and the pressure natriuresis-diuresis relationship. AB - Administration of exogenous L-arginine (L-Arg) attenuates angiotensin-II (AngII) mediated hypertension and kidney disease in rats. The present study assessed renal hemodynamics and pressure diuresis-natriuresis in anaesthetized rats infused with vehicle, AngII (20 ng/kg per min i.v.) or AngII + L-Arg (300 MUg/kg per min i.v.). Experiments in isolated aortic rings were carried out to assess L Arg effects on the vasculature. Increasing renal perfusion pressure (RPP) from ~100 to 140 mmHg resulted in a nine- to tenfold increase in urine flow and sodium excretion rate in control animals. In comparison, AngII infusion significantly reduced renal blood flow (RBF) and glomerular filtration rate (GFR) by 40-42%, and blunted the pressure-dependent increase in urine flow and sodium excretion rate by 54-58% at elevated RPP. Supplementation of L-Arg reversed the vasoconstrictor effects of AngII and restored pressure-dependent diuresis to levels not significantly different from control rats. Dose-dependent contraction to AngII (10(-10) mol/L to 10(-7) mol/L) was observed with a maximal force equal to 27 +/- 3% of the response to 10(-5) mol/L phenylephrine. Contraction to 10(-7) mol/L AngII was blunted by 75 +/- 3% with 10(-4) mol/L L-Arg. The influence of L Arg to blunt AngII-mediated contraction was eliminated by endothelial denudation or incubation with nitric oxide synthase inhibitors. Furthermore, the addition of 10(-3) mol/L cationic or neutral amino acids, which compete with L-Arg for cellular uptake, blocked the effect of L-Arg. Anionic amino acids did not influence the effects of L-Arg on AngII-mediated contraction. These studies show that L-Arg blunts AngII-mediated vascular contraction by an endothelial- and nitric oxide synthase-dependent mechanism involving cellular uptake of L-Arg. PMID- 24472008 TI - Revisiting the Mosaic of Supports Required for Including People with Severe Intellectual or Developmental Disabilities in their Communities. AB - The goal of this Forum article is to examine the progress that has been made over the past 20 years in providing opportunities for community living, inclusive schooling, and integrated employment to people with severe intellectual or developmental disabilities who rely on Augmentative and Alternative Communication (AAC). Recent research and statistical data from the United States and elsewhere are used to describe both the gains that have been made and the challenges that still remain. Directions for future advocacy and research efforts are also included. PMID- 24472009 TI - Home telemonitoring effectiveness in COPD: a systematic review. AB - OBJECTIVES: To provide a systematic review of the effectiveness of home telemonitoring to reduce healthcare utilisation and improve health-related outcomes of patients with chronic obstructive pulmonary disease (COPD). METHODS: An electronic literature search in Medline, Embase, B-on and Web of Science was conducted from June to August 2012 and updated until July 2013, using the following keywords: [tele(-)monitoring or tele(-)health or tele(-)homecare or tele(-)care or tele-home health or home monitoring] and [Chronic Obstructive Pulmonary Disease or COPD]. Randomised and non-randomised controlled trials evaluating home telemonitoring interventions in COPD were included. A meta analysis using risk ratio (RR) and standardised mean difference (SMD) was conducted for healthcare utilisation (hospitalisations, length of stay, emergency department visits) and associated costs, and health-related outcomes [mortality, exacerbations and health-related quality of life (HRQOL)]. RESULTS: Nine articles were included. Significant differences were found for hospitalisation rates (RR = 0.72; 95% CI = 0.53-0.98; p = 0.034); however, no differences in the other healthcare utilisation outcomes were observed. There was a trend to reduced healthcare costs in the telemonitoring group. In two studies, this intervention was associated with a reduced number of exacerbations (p < 0.05) and a significant increase in HRQOL (SMD = -0.53; 95% CI = -0.97- -0.09; p = 0.019). DISCUSSION AND CONCLUSIONS: Home telemonitoring appears to have a positive effect in reducing respiratory exacerbations and hospitalisations and improving quality of life. However, the evidence of its benefits is still limited and further research is needed to assess the effectiveness of home telemonitoring in COPD management, as there are still few studies in this area. PMID- 24472010 TI - Computing stability effects of mutations in human superoxide dismutase 1. AB - Protein stability is affected in several diseases and is of substantial interest in efforts to correlate genotypes to phenotypes. Superoxide dismutase 1 (SOD1) is a suitable test case for such correlations due to its abundance, stability, available crystal structures and thermochemical data, and physiological importance. In this work, stability changes of SOD1 mutations were computed with five methods, CUPSAT, I-Mutant2.0, I-Mutant3.0, PoPMuSiC, and SDM, with emphasis on structural sensitivity as a potential issue in structure-based protein calculation. The large correlation between experimental literature data of SOD1 dimers and monomers (r = 0.82) suggests that mutations in separate protein monomers are mostly additive. PoPMuSiC was most accurate (typical MAE ~ 1 kcal/mol, r ~ 0.5). The relative performance of the methods was not very structure-dependent, and the more accurate methods also displayed less structural sensitivity, with the standard deviation from different high-resolution structures down to ~0.2 kcal/mol. Structures of variable resolution and number of protein copies locally affected specific sites, emphasizing the use of state relevant crystal structures when such sites are of interest, but had little impact on overall batch estimates. Protein-interaction effects (as a mimic of crystal packing) were small for the more accurate methods. Thus, batch computations, relevant to, e.g., comparisons of disease/nondisease mutant sets or different clades in phylogenetic trees, are much more significant than single mutant calculations and may be the only meaningful way to computationally bridge the genotype-phenotype gap of proteomics. Finally, mutations involving glycine were most difficult to model, of relevance to future method improvement. This could be due to structure changes (glycine has a low structural propensity) or water colocalization with glycine. PMID- 24472011 TI - Coronary effluent from postconditioned hearts promotes survival of mesenchymal stem cells under hypoxia. AB - OBJECTIVES: Mesenchymal stem cells are sensitive to hypoxia under myocardial micro-environment of ischemia and reperfusion. Ischemic postconditioning, which is cardioprotective against ischemia-reperfusion injury, enhances in-vivo survival and therapeutic effects of transplanted stem cells. In this study, we investigated the effects of coronary effluent from postconditioned rat hearts on proliferation and survival of mesenchymal stem cells in vitro under hypoxia. DESIGN: Isolated perfused rat hearts were divided into three groups (n = 6): the Sham group--receiving a 90 min perfusion; the Control group--receiving a 30 min global ischemia followed by a 60 min reperfusion; the ischemic postconditioning group--before sustained reperfusion, 3 cycles of 30 s reperfusion and 30 s ischemia were performed. Inflammation-related factors in coronary effluent were assessed by ELISA. Mesenchymal stem cells from bone marrow of Sprague-Dawley rats were cultured with coronary effluent under hypoxia (95% nitrogen, 5% carbon dioxide, and < 1% oxygen) for 6- or 18 h. Cell proliferation was determined by methyl thiazolyl tetrazolium. Survival rate was measured by Annexin V/PI. RESULTS: Compared with ischemia-reperfusion treatment alone, postconditioning treatment increased the level of interleukin-10 and decreased the level of tumor necrosis factor-alpha and interleukin-1beta in coronary effluent (P < 0.01). Stem cells cultured with postconditioned effluent, compared with those with ischemia reperfusion effluent, had a higher proliferation (optical density value), more surviving cells, and less necrosis (P < 0.01). CONCLUSIONS: Coronary effluent from postconditioned hearts may promote the proliferation and survival of mesenchymal stem cells under hypoxia, and the suppression of inflammation may be involved in this process. PMID- 24472012 TI - Enhanced photoluminescence and thermal properties of size mismatch in Sr(2.97-x y)Eu0.03Mg(x)Ba(y)SiO5 for high-power white light-emitting diodes. AB - In this Study, Mg(2+) and Ba(2+) act to enhance the maximum emission of Sr2.97SiO5:0.03Eu(2+) significantly and redshift the emission band to the orange red region in Sr(2.97-x-y)Mg(x)Ba(y)SiO5:0.03Eu(2+). Size mismatch between the host and the doped cations tunes the photoluminescence spectra shift systematically. A slight blue shift when increasing the amount of Mg(2+) occurs in the Sr(2.97-x)Eu0.03Mg(x)SiO5 lattices, and a rapid red shift occurs when Ba(2+) is codoped in the Sr(2.57-y)Eu0.03Mg0.4Ba(y)SiO5 lattices. The emission spectra were tuned from 585 to 601 nm by changing the concentration of Ba(2+). Accordingly, we propose the underlying mechanisms of the changes in the photoluminescence properties by adjusting the cation composition of phosphors. The influence of the size mismatch on the thermal quenching is also observed. This mechanism could be widely applied to oxide materials and could be useful in tuning the photoluminescence properties, which are sensitive to local coordination environment. The emission bands of Sr(2.97-x-y)Eu0.03Mg(x)Ba(y)SiO5 show the blue shift with increasing temperature, which could be described in terms of back tunneling of the excited electrons from the low-energy excited state to the high-energy excited state. Thus, the Sr(2.97-x y)Eu0.03Mg(x)Ba(y)SiO5 phosphors could have potential applications in the daylight LEDs or warm white LEDs. PMID- 24472013 TI - Development and pilot testing of an online intervention to support young couples' coping and adjustment to breast cancer. AB - Couplelinks is an original, professionally facilitated online intervention tailored to the unique challenges facing young women with breast cancer and their male partners. The purpose of this evaluation was to determine the feasibility and acceptability of the intervention and areas for improvement. Sixteen couples were sequentially enrolled over an 18-month period. Couples provided feedback via a treatment satisfaction survey, and post-treatment interviews with a sub-group of participants. Qualitative information was analysed for themes relevant to the program's acceptability, perceived benefits and limitations, and directions for improvement. Of the 16 couples who enrolled, six completed four modules or less, and 10 completed the entire program. Completers reported satisfaction with the program overall, as well as with the website useability and professional facilitation. Reported benefits were: enhanced communication and self-other knowledge; creation of opportunities for meaningful, cancer-related discussion; affirmation of relationship strengths; and a greater sense of closeness between partners. The main reported limitation was how program participation disrupted the couple's usual routine. Themes related to non-completion suggest that partners with particularly elevated relational or illness-related distress, or with differential levels of motivation, are less likely to finish. These findings have led to targeted improvements to the website and intervention protocol. PMID- 24472014 TI - Stretching and imaging of single DNA chains on a hydrophobic polymer surface made of amphiphilic alternating comb-copolymer. AB - Functionalization of amine derivatized glass slides with a poly(maleic anhydride) based comb-copolymer to facilitate stretching, aligning, and imaging of individual dsDNA chains is presented. The polymer-coated surface is hydrophobic due to the presence of the long alkyl side chains along the polymer backbone. The surface is also characterized by low roughness and a globular morphology. Stretched and aligned bacteriophage lambda-DNA chains were obtained using a robust method based on stretching by a receding water meniscus at pH 7.8 without the need for small droplet volumes or precoating the surface with additional layers of (bio)molecules. Although the dye to DNA base pairs ratio did not influence substantially the stretching length distributions, a clear peak at stretching lengths close to the contour length of the dsDNA is visible at larger staining ratios. PMID- 24472015 TI - The burden of bleeding in haemophilia: is one bleed too many? AB - Joint bleeding is the hallmark of haemophilia. Increasingly, the pain, restricted movement and anxiety provoked by even a single haemarthrosis are concerns for patients, families and treating physicians. The aims of this study were to determine whether the current paradigm for prophylaxis requires a shift in focus from reducing the frequency of bleeding episodes to a goal of zero bleeding and to review and discuss the published data from in vitro and animal experiments and clinical studies in patients with haemophilia that describe the impact of joint bleeding. More than two to three bleeding into the same joint may cause irreversible and progressive structural damage that compromise health-related quality of life (HRQoL). A goal of zero bleeding episodes - or as close to zero as possible - is key to enhancing joint health and HRQoL in children and adults with haemophilia. Achieving this goal requires individualized, outcome-based, multidisciplinary care to maximize prophylactic efficacy without increasing overall health care costs. PMID- 24472017 TI - Transformative thinkers needed for transformative postgraduate education. PMID- 24472018 TI - Best possible or best available? PMID- 24472020 TI - Follow-up of newborns of mothers with Graves' disease. AB - BACKGROUND: Overt neonatal Graves' disease is rare, but may be severe, even life threatening, with deleterious effects on neural development. The main objective of this study was to describe the course of thyrotropin (TSH) and free thyroxin (fT4) levels, as well as postnatal weight gain in relation to fT4 levels, in neonates born to women with Graves' disease without overt neonatal thyrotoxicosis. Such information is important to deduce the optimal schedule for evaluation. METHODS: We conducted a retrospective chart review of neonates born to mothers with Graves' disease between January 2007 and December 2012. The records were reviewed for sex, gestational age, birth weight, maternal treatment during pregnancy, and maternal thyroid stimulating immunoglobulin (TSI) level. For each visit in the clinic, the data included growth parameters, presence of symptoms suspected for hyperthyroidism, blood test results (levels of TSH, fT4, and TSI), and treatment. RESULTS: Ninety-six neonates were included in the study (49 males), with a total of 320 measurements of thyroid function tests (TSH and fT4). Four neonates (4%) had overt neonatal Graves' disease; one of them along with nine others were born preterm. In 77 (92.9%) of the remaining 83 neonates (the subclinical group), fT4 levels were above the 95th percentile on day 5. All had normal fT4 on day 15. A negative association was found between fT4 and weight gain during the first two weeks. CONCLUSIONS: In this cohort, most neonates born to mothers with Graves' disease had a subclinical course with abnormal fT4 levels that peaked at day 5. After day 14, all measurements of fT4 returned to the normal range, although measurements of TSH remained suppressed for up to three months. Elevated fT4 was associated with poor weight gain. PMID- 24472021 TI - Glutathione-S-transferase-oxidative stress relationship in the internal spermatic vein blood of infertile men with varicocele. AB - This study aimed to assess glutathione-S-transferase (GST) enzyme- oxidative stress (OS) relationship in the internal spermatic vein (ISV) of infertile men associated with varicocele (Vx). Ninety five infertile oligoasthenoteratozoospemic (OAT) men associated with Vx were subjected to history taking, clinical examination and semen analysis. During inguinal varicocelectomy, GST, malondialdehyde (MDA) and glutathione peroxidase (GPx) were estimated in the blood samples drawn from ISV and median cubital veins. The mean levels of GST, GPx were significantly decreased and the mean level of GPx was significantly increased in the ISV compared with the peripheral blood. The mean level of GST and GPx in the ISV was significantly decreased, and the mean level of MDA was significantly increased in Vx grade III compared with Vx grade II cases. There was nonsignificant difference in the mean level of GST in the ISV in unilateral Vx cases compared with bilateral Vx cases. There was significant positive correlation of GST with sperm count, sperm motility, GPx and significant negative correlation with sperm abnormal forms, MDA. It is concluded that ISV of infertile men associated with Vx has decreased levels of GST compared with peripheral venous circulation that is correlated with both OS and Vx grade. PMID- 24472022 TI - Potent inhibition of mandelate racemase by a fluorinated substrate-product analogue with a novel binding mode. AB - Mandelate racemase (MR) from Pseudomonas putida catalyzes the Mg(2+)-dependent 1,1-proton transfer that interconverts the enantiomers of mandelate. Because trifluorolactate is also a substrate of MR, we anticipated that replacing the phenyl rings of the competitive, substrate-product analogue inhibitor benzilate (Ki = 0.7 mM) with trifluoromethyl groups might furnish an inhibitor. Surprisingly, the substrate-product analogue 3,3,3-trifluoro-2-hydroxy-2 (trifluoromethyl)propanoate (TFHTP) was a potent competitive inhibitor [Ki = 27 +/- 4 MUM; cf. Km = 1.2 mM for both (R)-mandelate and (R)-trifluorolactate]. To understand the origins of this high binding affinity, we determined the X-ray crystal structure of the MR-TFHTP complex to 1.68 A resolution. Rather than chelating the active site Mg(2+) with its glycolate moiety, like other ground state analogues, TFHTP exhibited a novel binding mode with the two trifluoromethyl groups closely packed against the 20s loop and the carboxylate bridging the two active site Bronsted acid-base catalysts Lys 166 and His 297. Recognizing that positioning a carboxylate between the Bronsted acid-base catalysts could yield an inhibitor, we showed that tartronate was a competitive inhibitor of MR (Ki = 1.8 +/- 0.1 mM). The X-ray crystal structure of the MR tartronate complex (1.80 A resolution) revealed that the glycolate moiety of tartronate chelated the Mg(2+) and that the carboxylate bridged Lys 166 and His 297. Models of tartronate in monomers A and B of the crystal structure mimicked the binding orientations of (S)-mandelate and that anticipated for (R)-mandelate, respectively. For the latter monomer, the 20s loop appeared to be disordered, as it also did in the X-ray structure of the MR triple mutant (C92S/C264S/K166C) complexed with benzilate, which was determined to 1.89 A resolution. These observations indicate that the 20s loop likely undergoes a significant conformational change upon binding (R)-mandelate. In general, our observations suggest that inhibitors of other enolase superfamily enzymes may be designed to capitalize on the recognition of the active site Bronsted acid-base catalysts as binding determinants. PMID- 24472023 TI - Paired analysis of plasma proteins and coagulant capacity after treatment with three methods of pathogen reduction. AB - BACKGROUND: The effect of photochemical pathogen reduction (PR) methods on plasma quality has been the subject of several reports but solid comparative data for the different technologies are lacking. STUDY DESIGN AND METHODS: Plasma (n = 24) photoinactivated with methylene blue (MB), riboflavin (RF), or amotosalen (AS) was compared using a pool-and-split design. Samples were taken before and after treatment with each method and tested for coagulation factors (fibrinogen, Factor [F] II, FV, FVIII, F IX, FXI), natural coagulation inhibitors (Protein C [PC], protein S [PS], antithrombin III [AT]), prothrombin time (PT), activated partial thromboplastin time (APTT), and thrombin generation (TG). The three methods were mutually compared by repeated-measures analysis of variance. RESULTS: All three PR methods cause significant reduction (p < 0.01) of activity of the procoagulant proteins fibrinogen, FII, FV, FVIII, F IX, and FXI. Coagulation is also affected, with significant changes in PT, APTT, and TG. RF treatment causes a significantly higher decrease in concentration of coagulation factors, PS, and AT than the other methods (p < 0.01). PT, APTT, and TG are also affected most by RF treatment. FII, FVIII, F IX, PC, AT, and PT are best preserved with the MB method and FV, FXI, and TG after AS treatment (p < 0.01). Coagulation factor loss due to the volume loss during PR treatment is more important for MB and AS than for RF. CONCLUSION: PR treatment of plasma affects coagulation proteins and coagulant capacity. For the RF method this effect is most pronounced, although to some extent compensated by a smaller volume loss. PMID- 24472024 TI - Systematic evaluation of the quality of clinical practice guidelines on the use of assisted reproductive techniques. AB - OBJECTIVE: To conduct a systematic evaluation of clinical practice guidelines (CPGs) on the use of assisted reproductive technologies. METHODS: We searched Medline, the Turning Research into Practice database, and guidelines-specific databases from December 2006 to November 2011. Three reviewers independently assessed each Guideline using the Appraisal of Guidelines for Research Evaluation (AGREE) II instrument. A standardized score was calculated separately for each of the six domains. RESULTS: Fourteen Guidelines were included. Overall, the quality of these was suboptimal. The scores for each AGREE II domain ranged between 37% and 80%. Three (22%) were deemed "Recommended"; nine (64%),"Recommended with modifications"; and two (14%), "Not recommended". Agreement among reviewers was very good (Intraclass Correlation Coefficient: 0.915 [95% CI 0.807-0.970]). CONCLUSIONS: The overall quality of the CPGs on Assisted Reproduction Techniques published during the last 5 years is suboptimal. Most Guidelines present significant shortcomings in important domains such as "stakeholder involvement", "rigor of development", and "applicability". Instruments such as the AGREE II and "the Grading of Recommendation Assessment Development and Evaluation" system could prove useful to improve CPGs in this field. Guideline users could benefit from the present results when choosing which guidelines to implement. PMID- 24472026 TI - Chemical modifications of silicon surfaces for the generation of a tunable surface isoelectric point. AB - The aim of this work was to generate a tunable surface isoelectric point (sIEP), where the surface is modified with two molecules: a weak base (pyridine), carrying a pH dependent positive charge, and a derivative of a strong acid (sulfate), carrying a permanent negative charge in a physiologically relevant pH range. To this end, silicon surfaces were modified with 3 aminopropyltriethoxysilane. These amine-modified surfaces were subsequently derivatized into pyridine- or sulfate-modified surfaces. Then, the surface pKa of pyridine-modified surfaces was determined by a fluorescent nanoparticle adhesion assay (FNAA). Next, these values were used to calculate in which ratio the chemicals must be present in the reaction mixture to generate a mixed pyridine/sulfate-modified surface with a target sIEP. After preparing surfaces with a target sIEP, an FNAA with positively and negatively charged nanoparticles was used to verify the sIEP of the generated surfaces. The FNAA revealed that pyridine-modified surfaces had a pKa of 6.69 +/- 0.18. When an sIEP was generated, negative nanoparticles bound to surfaces at pH values below the sIEP and positive nanoparticles bound at pH values above the sIEP. Furthermore, we found sIEP values of 5.97 +/- 0.88 when we aimed for an sIEP of 6.2, and 7.12 +/- 0.21 when we aimed for an sIEP of 7.1. Finally, the pH dependent binding and release of a negatively and positively charged (bio)polymer was investigated for a target sIEP of 7. A negatively charged polymer (poly(I:C)) was bound at a pH < sIEP and released at a pH > sIEP with a release efficiency of 85 +/- 9% and a positively charged polymer (trimethyl chitosan) bound at a pH > sIEP and released at a pH < sIEP with a release efficiency of 72 +/- 9%. In conclusion, we established a method for preparing modified silicon surfaces with a tunable sIEP, which can be used for pH-dependent binding and release of biomacromolecules. PMID- 24472025 TI - High-affinity small-molecule inhibitors of the menin-mixed lineage leukemia (MLL) interaction closely mimic a natural protein-protein interaction. AB - The protein-protein interaction (PPI) between menin and mixed lineage leukemia (MLL) plays a critical role in acute leukemias, and inhibition of this interaction represents a new potential therapeutic strategy for MLL leukemias. We report development of a novel class of small-molecule inhibitors of the menin-MLL interaction, the hydroxy- and aminomethylpiperidine compounds, which originated from HTS of ~288000 small molecules. We determined menin-inhibitor co-crystal structures and found that these compounds closely mimic all key interactions of MLL with menin. Extensive crystallography studies combined with structure-based design were applied for optimization of these compounds, resulting in MIV-6R, which inhibits the menin-MLL interaction with IC50 = 56 nM. Treatment with MIV-6 demonstrated strong and selective effects in MLL leukemia cells, validating specific mechanism of action. Our studies provide novel and attractive scaffold as a new potential therapeutic approach for MLL leukemias and demonstrate an example of PPI amenable to inhibition by small molecules. PMID- 24472027 TI - Six-minute walk distance target in elderly patients with idiopathic pulmonary arterial hypertension - consideration of predicted values. AB - BACKGROUND: The number of elderly patients diagnosed with idiopathic pulmonary arterial hypertension (IPAH) is increasing. A 6-min walk distance (6MWD) > 380 m on therapy is associated with improved survival in IPAH. As exercise capacity is naturally decreasing with age, treatment goals for elderly patients might be different from those established for younger patients. METHODS: Consecutive adult patients diagnosed with IPAH between 1/2005 and 7/2012 were retrospectively included. We analysed the prognostic value of 6MWD targets (in metres and % predicted) with respect to age at diagnosis. RESULTS: The mean (+/- SD) 6MWD in 23 patients aged > 65 years at diagnosis compared with 22 younger patients was significantly lower at baseline (262 +/- 69 vs. 356 +/- 128 m; p = 0.011) and first follow up (310 +/- 75 vs. 377 +/- 137 m; p = 0.045), while the corresponding % predicted values were similar (62 +/- 16% vs. 63 +/- 21%; p = 0.854, and 74 +/- 16% vs. 68 +/- 21%; p = 0.267). The established treatment target of > 380 m 6MWD was met by only 13% of elderly compared with 46% of younger patients (p = 0.016), while the corresponding 6MWD of 78% predicted was exceeded by similar proportions (48% and 46%, respectively; p = 0.873). Survival of patients walking > 380 m or 78% predicted on first follow up was significantly better compared with patients not exceeding the respective threshold (100% vs. 72% and 95% vs. 67% at the end of follow up, respectively; p < 0.05 each). CONCLUSION: Expression of the 6MWD target as % predicted equalises age-related differences and has similar prognostic power compared with absolute values in patients with IPAH. As elderly patients are less likely to reach the absolute 6MWD threshold, the use of % predicted could be helpful in their individual assessment and adaption of targeted therapy. PMID- 24472028 TI - The Scandinavian athlete's heart; echocardiographic characteristics of male professional football players. AB - This investigation explores the cardiac four-chamber remodeling response to training in male players in Norwegian professional football league, and ethnicity as determinants in the development of athlete's heart. Standard 2D echocardiographic examination and analysis of all four cavities were performed in 504 football players of Caucasian origin, 49 of African origin, and 47 matched Caucasian controls (<3 h training /week). All results were indexed to body surface area (BSA). Most athletes exhibited BSA-indexed values within normal ranges. Left ventricle (LV) mass was equally enlarged in both groups of athletes, but LV relative wall thickness and right ventricular (RV) relative wall thickness were increased in Africans compared with Caucasian athletes (0.37 +/- 0.06 vs 0.33 +/- 0.06 and 0.25 +/- 0.06 vs 0.22 +/- 0.04, respectively). Both LV and RV were smaller in Africans than in Caucasian athletes (67.8 +/- 12.0 ml/m(2) vs 73.6 +/- 13.2 ml/m(2) and 12.8 +/- 2.1 vs 13.7 +/- 2.4 cm(2) /m(2) , respectively, both P < 0.05), while left and right atria increased similarly. This first large-scale echocardiographic survey of elite football players in a Scandinavian league suggests use of BSA-indexed upper normal limits for both LV and RV in athletes. African athletes had significantly more concentric remodeled LV and RV than the Caucasian athletes. PMID- 24472030 TI - Effects of opioid (tramadol) treatment on testicular functions in adult male rats: The role of nitric oxide and oxidative stress. AB - Nowadays, tramadol hydrochloride is frequently used as a pain reliever, and for the treatment of premature ejaculation. Decreased semen quality was noted in chronic tramadol users. The present study aimed to elucidate the effects of tramadol on the testicular functions of adult male rats. A total of 40 albino adult male rats were divided into control and tramadol groups, with 20 rats for each group. Rats of the tramadol group were subcutaneously injected with 40 mg/kg three times per week for 8 weeks. The control group received normal saline 0.9%. Blood samples from each animal were obtained. Plasma levels of different biochemical substances were determined. Nitric oxide was measured in testicular tissue samples. Those samples together with epididymal tissue samples were processed for histopathological examination. Tramadol significantly reduced plasma levels of luteinizing hormone, follicle-stimulating hormone, testosterone and total cholesterol, but elevated prolactin and estradiol levels compared with the control group. In addition, tramadol increased the testicular levels of nitric oxide and lipid peroxidation, and decreased the anti-oxidant enzymes activities significantly compared with the control group. The tramadol group showed decreased sperm count and motility, and numbers of primary spermatocytes, rounded spermatid and Leydig cells. Immunohistochemical examinations showed that tramadol increased the expression of endothelial nitric oxide synthase in testicular tissues. The present study showed that tramadol treatment affects the testicular function of adult male rats, and these effects might be through the overproduction of nitric oxide and oxidative stress induced by this drug. PMID- 24472031 TI - A light and pH dual-stimuli-responsive block copolymer synthesized by copper(0) mediated living radical polymerization: solvatochromic, isomerization, and "schizophrenic" behaviors. AB - A "schizophrenic" block copolymer (poly[1'-(2-methacryloxyethyl)-3',3'-dimethyl-6 nitrospiro-(2H-1-benzopyran-2,2'-indoline)]-b-poly(acrylic acid) (PSPMA-b-PAA)) was synthesized by sequential copper(0)-mediated living radical polymerization (Cu(0)-mediated LRP) at 30 degrees C in an oxygen-tolerant system followed by hydrolysis of the resulting polymer. The solvatechromic behaviors of the PSPMA10 b-poly(t-butyl acrylate)40 (PSPMA10-b-PtBA40) and PSPMA10-b-PAA40 block copolymers in organic solvents were investigated by UV-vis spectroscopy. The PSPMA10-b-PtBA40 stabilizes the nonpolar photoisomer and is not sensitive to the polarity of the solvent, while the PSPMA10-b-PAA40 stabilizes the planar zwitterionic form without irradiation. Furthermore, light-induced isomerization of spiropyran (Sp) moieties from Sp to merocyanine (Mc) was demonstrated. Finally, the "schizophrenic" micellization behavior of as-prepared copolymer in aqueous solution regulated by light and pH stimuli was vividly demonstrated, and the reversibility of micellization processes performed in this study was also examined. The large compound micelles can bring out a gradually extended and even transformed conformation with increasing deprotonation degree at pH > pKa. PMID- 24472032 TI - Understanding the experience of caring for children with haemophilia: cross sectional study of caregivers in the United States. AB - Congenital haemophilia is an inherited bleeding disorder typically diagnosed at birth or shortly thereafter. Haemophilia imposes a significant burden on patients and their caregivers. The aim of the study was to quantify the overall burden of haemophilia on caregivers in the USA using a novel disease-specific questionnaire and the previously validated CarerQol. Targeted literature review and a previous survey conducted by the authors was used to develop an online questionnaire with six burden domains of interest to caregivers (emotional stress, financial, sacrifice, medical management, child's pain and transportation) and several visual analogue scales (VAS). Content validity of the questionnaire was confirmed by three haemophilia caregivers. The study sample consisted of caregivers of children with haemophilia identified via a previously developed opt-in research database. Descriptive statistics were employed for demographic and clinical characteristics; a generalized linear model (GLM) was used to identify factors influencing caregiver burden. A total of 310 caregivers completed the survey (45.5% response rate). Most of the participating caregivers were mothers of a child with haemophilia (88%), between 35 and 44 years of age (48%), and with a college education or a postgraduate degree (63%). 'Child's pain' was identified as the most burdensome domain to caregivers (median score = 3.50 out of 5), followed by 'emotional stress' (2.67), 'financial' (2.40), 'transportation' (2.33), 'sacrifice' (2.17) and 'medical management' (2.00) domains. Although higher income exhibited a protective effect, episodes of bleeds, current presence of an inhibitor and lower caregiver productivity in the past month negatively affected caregiver burden per GLM results. Training and educational programs should potentially be developed to address caregiver burden. PMID- 24472033 TI - The post-prandial pattern of gut hormones is related to magnitude of weight-loss following gastric bypass surgery: a case-control study. AB - BACKGROUND: The mechanisms of weight loss after gastric bypass, including the role of gastric hormones, are still not completely understood. While postprandial releases of peptide YY (PYY) and glucagon-like peptide-1 (GLP-1) increase post surgery and ghrelin usually is reduced, their relationship to the magnitude of the weight loss is still obscure. We explored if differing weight loss after Roux Y gastric bypass (RYGB) in morbidly obese were associated with differing postprandial hormonal release. METHODS: We compared patients with large (> 40%) or moderate (< 25%) weight loss three years following RYGP surgery, and an obese control group scheduled for RYGB (six in each group). A 300 kcal mixed meal test was given with blood sampling before and thereafter at 30-min intervals in 180 min. Peak and incremental area under the curve (iAUC) were calculated to characterize postprandial responses. RESULTS: Early postprandial GLP-1 response were significantly higher in the RYGB groups than in the controls, and highest in those with largest weight loss. Postprandial PYY response were also greater for the two RYGB groups vs. controls, but interestingly the controls had higher baseline values. Ghrelin, from similar baseline, was only suppressed in those with the largest weight loss, with close to no reduction in those with modest weight loss or controls. CONCLUSIONS: These results support the hypothesis that the magnitude of weight loss after RYGB surgery might be associated with differing patterns of postprandial responses in GLP-1 and ghrelin, but not PYY. Larger studies are warranted. PMID- 24472034 TI - Positive association of MMP 14 gene polymorphism with vulnerable carotid plaque formation in a Han Chinese population. AB - BACKGROUND: MMP 14 is expressed in atherosclerotic plaques and potentially plays an important role in the development of vulnerable carotid plaques. MMP 14 gene polymorphisms can influence the bioactivity or expression of MMP 14. OBJECTIVE: The aim of this study was to investigate the association between MMP 14 position + 7096 T > C (NM_004995.2:c.855T> C, rs2236307) polymorphism and vulnerable carotid plaque formation. METHODS: 1370 patients with ischemic cerebral infarctions were enrolled and divided into three groups according to their carotid ultrasound examination: No plaque group (n = 346), stable plaque group (n = 695) and vulnerable plaque group (n = 329). The traditional atherosclerosis risk factors were recorded, and the MMP 14 polymorphism were genotyped by Applied Biosystems 7300 Real-Time PCR System using the TaqMan assay. RESULTS: In the multiple logistic regression analysis done among the sub-groups, compared to no carotid plaque group, individuals with the MMP 14 position + 7096 TC+ CC genotype showed a significantly (p = 0.009) lower risk for vulnerable plaque (AOR = 0.675; 95% CI, 0.568-0.922) formation compared with subjects of the TT genotype; however, no relation between TC+ CC genotype and stable carotid plaque was observed (p > 0.125). Age was a risk factor for both stable plaque (p = 0.000; AOR = 3.732; 95% CI: 2.496-5.58) and vulnerable plaque formation (p = 0.001; AOR = 2.234; 95% CI: 1.387-3.597). Meanwhile, fibrinogen (> 4.0 g/L) was a risk factor for stable plaque (p = 0.004; AOR = 2.313; 95% CI: 1.308-4.091). CONCLUSIONS: The MMP 14 position + 7096 TC+ CC genotype might lower the risk of vulnerable carotid plaque formation. Fibrinogen (> 4.0 g/L) was a risk factor for stable plaque. PMID- 24472035 TI - The cost of the inpatient management of febrile neutropenia in cancer patients--a micro-costing study in the Irish healthcare setting. AB - The objective was to evaluate the resource use and cost of hospitalisation for febrile neutropenia (FN) from the health-payer's perspective. This was a single centre study. Adults undergoing chemotherapy, who were admitted for FN, were identified prospectively. Patient medical records were reviewed retrospectively. Demographics and resource utilisation data were obtained from a cohort of 32 patients (69% female, mean age = 58.8 years). Twenty-five per cent of patients had more than one FN episode. In total, 42 FN episodes were captured; 60% of episodes had occurred within the first two cycles of chemotherapy. The bootstrap estimation was used to determine mean hospital length of stay (LOS) with standard deviation (+/-SD) and mean costs +/- SD. The mean LOS was 7.3 +/- 0.5 days. The mean cost per FN episode was ?8915 +/- 718. The major cost driver was hospital bed-stay (mean cost of ?6851 +/- 549). Other cost drivers included antibacterial treatment at ?760 +/- 156, laboratory investigations at ?538 +/- 47 and the requirement for blood bank products at ?525 +/- 189. To our knowledge, this is the first investigation of the cost of chemotherapy induced FN within the context of the Irish healthcare setting. PMID- 24472036 TI - Maternal grafts protect daughter recipients from acute cellular rejection after pediatric living donor liver transplantation for biliary atresia. AB - Some studies have found that gender mismatch between donors and recipients are related to poor graft prognosis after liver transplantation. However, few studies have investigated the impact of gender mismatch on acute cellular rejection (ACR) in pediatric living donor liver transplantation (LDLT). This retrospective study investigated the clinical significance of these factors in ACR after pediatric LDLT. Between November 2001 and February 2012, 114 LDLTs were performed for recipients with biliary atresia (BA) using parental grafts. We performed univariate and multivariate analyses to identify the factors associated with ACR. The donor-recipient classifications included mother donor to daughter recipient (MD; n = 43), mother to son (n = 18), father to daughter (FD; n = 33), and father to son (n = 20) groups. The overall incidence rate of ACR in the recipients was 36.8%. Multivariate analysis showed that gender mismatch alone was an independent risk factor for ACR (P = 0.012). The FD group had a higher incidence of ACR than the MD group (P = 0.002). In LDLT, paternal grafts with gender mismatch were associated with a higher increased incidence of ACR than maternal grafts with gender match. Our findings support the possibility that maternal antigens may have an important clinical impact on graft tolerance in LDLT for patients with BA. PMID- 24472037 TI - Transient down-regulation of the RNA silencing machinery increases efficiency of Agrobacterium-mediated transformation of Arabidopsis. AB - Agrobacterium tumefaciens is a plant pathogen that is widely used in plant transformation. As the process of transgenesis includes the delivery of single stranded T-DNA molecule, we hypothesized that transformation rate may negatively correlate with the efficiency of the RNA-silencing machinery. Using mutants compromised in either the transcriptional or post-transcriptional gene-silencing pathways, two inhibitors of stable transformation were revealed-AGO2 and NRPD1a. Furthermore, an immunoprecipitation experiment has shown that NRPD1, a subunit of Pol IV, directly interacts with Agrobacterium T-DNA in planta. Using the Tobacco rattle virus (TRV)--based virus-induced gene silencing (VIGS) technique, we demonstrated that the transient down-regulation of the expression of either AGO2 or NRPD1a genes in reproductive organs of Arabidopsis, leads to an increase in transformation rate. We observed a 6.0- and 3.5-fold increase in transformation rate upon transient downregulation of either AGO2 or NRPD1a genes, respectively. This is the first report demonstrating the increase in the plant transformation rate via VIGS-mediated transient down-regulation of the components of epigenetic machinery in reproductive tissue. PMID- 24472038 TI - Unidirectional thermal diffusion in bimetallic Cu@Au nanoparticles. AB - Understanding the atomic diffusions at the nanoscale is important for controlling the synthesis and utilization of nanomaterials. Here, using in situ X-ray absorption spectroscopy coupled with theoretical calculations, we demonstrate a so far unexplored unidirectional diffusion from the Au shell to the Cu core in thermally alloying Cu@Au core@shell architecture of ca. 7.1 nm. The initial diffusion step at 423 K is found to be characterized by the formation of a diffusion layer composed of a Au-dilute substitutional CuAu-like intermetallic compound with short Cu-Au bond length (2.61 A). The diffusion further happens by the migration of the Au atoms with large disorder into the interior Cu matrix at higher temperatures (453 and 553 K). These results suggest that the structural preference of a CuAu-like compound, along with the nanosized effect, plays a critical role in determining the atomic diffusion dynamics. PMID- 24472040 TI - Reduction in red blood cell transfusion associated with engagement of the ordering physician. AB - BACKGROUND: Data on red blood cell (RBC) transfusion in the United States show variation in practice and overprescribing or overdosing is considered to be prevalent. Education or restrictive interventions could modify practice. STUDY DESIGN AND METHODS: RBC transfusion and mortality rates were recorded in a single institution over a 15-year period. The first 3 years were used as a baseline. Education measures were used to influence practice for 3 years followed by a 9 year period when questionable RBC orders in nonbleeding inpatients resulted in prospective physician notification for potential modification. Physician notification was done by blood bank technologists with transfusion medicine physician support, if needed. Pretransfusion hemoglobin levels of more than 9 g/dL were recommended for cancellation and levels between 8 and 9 g/dL advised for a single unit, if 2 or more units were requested. RBC transfusion rates were described as inpatient units per 1000 discharges to allow for interyear comparison. RESULTS: A downward trend in RBC transfusion was noted for the intervention period. Comparison of the baseline period with the past 3 years of the intervention period showed an approximate 33% decrease, which was highly significant (508 +/- 66 vs. 341 +/- 32, p < 0.01). Inpatient mortality rates declined over this period. CONCLUSION: Physician education in appropriate transfusion practice is desirable but may not greatly impact RBC use. Engagement of physicians who prescribe RBCs that appear inappropriate for indication or dose was associated with a significant decline in RBC use without evidence of a change in mortality. PMID- 24472039 TI - Simplified 2-aminoquinoline-based scaffold for potent and selective neuronal nitric oxide synthase inhibition. AB - Since high levels of nitric oxide (NO) are implicated in neurodegenerative disorders, inhibition of the neuronal isoform of nitric oxide synthase (nNOS) and reduction of NO levels are therapeutically desirable. Nonetheless, many nNOS inhibitors mimic l-arginine and are poorly bioavailable. 2-Aminoquinoline-based scaffolds were designed with the hope that they could (a) mimic aminopyridines as potent, isoform-selective arginine isosteres and (b) possess chemical properties more conducive to oral bioavailability and CNS penetration. A series of these compounds was synthesized and assayed against purified nNOS enzymes, endothelial NOS (eNOS), and inducible NOS (iNOS). Several compounds built on a 7-substituted 2-aminoquinoline core are potent and isoform-selective; X-ray crystallography indicates that aminoquinolines exert inhibitory effects by mimicking substrate interactions with the conserved active site glutamate residue. The most potent and selective compounds, 7 and 15, were tested in a Caco-2 assay and showed good permeability and low efflux, suggesting high potential for oral bioavailability. PMID- 24472042 TI - Morphology Defects Guided Pore Initiation during the Formation of Porous Anodic Alumina. AB - Aluminum (Al) anodization leads to formation of porous structures with a broad spectrum of applications. Naturally or intentionally created defects on Al surfaces can greatly affect pore initiation. However, there is still a lack of systematic understanding on the defect dependent morphology evolution. In this paper, anodization processes on unpolished, polished, and nanoimprinted Al substrates are investigated under high voltages up to 600 V in various acid solutions. A porous structure is obtained on the unpolished and nanoimprinted Al foils with rough surface texture, whereas a compact film can be rationally obtained on the polished Al foil with a highly smooth surface. The observation of surface roughness dependent oxide film morphology evolution could be originated from the high voltages, which increases the threshold requirement of defect size or density for the pore initiation. Electrostatics simulation results indicate that inhomogeneous electric field and its corresponding localized high current induced by the surface roughness facilitate the initiation of nanopores. In addition, the porous films are utilized as templates to produce polydimethylsiloxane nanocone and submicrowire arrays. The nanoarrays with different aspect ratios present tunable wettability with the contact angles ranging from 144.6 degrees to 56.7 degrees , which hold promising potentials in microfluidic devices and self-cleaning coatings. PMID- 24472041 TI - Thioamide-based fluorescent protease sensors. AB - Thioamide quenchers can be paired with compact fluorophores to design "turn-on" fluorescent protease substrates. We have used this method to study a variety of serine-, cysteine-, carboxyl-, and metallo-proteases, including trypsin, chymotrypsin, pepsin, thermolysin, papain, and calpain. Since thioamides quench some fluorophores red-shifted from those naturally occurring in proteins, this technique can be used for real time monitoring of protease activity in crude preparations of virtually any protease. We demonstrate the value of this method in three model applications: (1) characterization of papain enzyme kinetics using rapid-mixing experiments, (2) selective monitoring of cleavage at a single site in a peptide with multiple proteolytic sites, and (3) analysis of the specificity of an inhibitor of calpain in cell lysates. PMID- 24472043 TI - Effect of dry period length on the effect of an intramammary teat sealant on the risk of mastitis in cattle treated with antibiotics at drying off. AB - AIM: The aim of this study was to evaluate, under farm conditions, the use of a teat sealant in addition to whole herd dry cow antibiotic therapy on the risk of clinical mastitis in dairy cattle at pasture, and to evaluate the impact of dry period length on that risk and the impact of the teat sealant on that risk. METHODS: Dairy cows in three herds which used routine whole herd antibiotic therapy were randomly assigned to receive either treatment with an internal teat sealant (n=322) or no additional treatment (n=313) at drying-off between March and May 2010. All clinical mastitis cases during the dry period and to the end of the subsequent lactation were recorded by farm staff; factors affecting risk of clinical mastitis were then analysed using a Cox proportional hazards model. RESULTS: Median duration of the dry period was 112 days with >25% of cows having a dry period >130 days. The incidence risk of mastitis during lactation for cows treated with teat sealant was 9.9 (95% CI=6.9-13.7) cases per 100 cows compared with 17.9 (95% CI=13.8-22.6) cases per 100 cows for cows treated with antibiotic alone. The addition of a teat sealant to dry cow antibiotic therapy decreased the risk of clinical mastitis only in the first 33 days after calving (Hazard risk 0.24 (95% CI=0.12-0.48)). Length of dry period did not significantly affect the risk of clinical mastitis, or the effect of adding teat sealant to dry cow antibiotic therapy on the risk of clinical mastitis. CONCLUSIONS: In these herds where, based on the mastitis history, whole herd antibiotic therapy had been recommended, the use of a teat sealant significantly reduced the risk of clinical mastitis. This effect was limited to the first 33 days after calving; subsequently there was no significant effect of treatment. There was no effect of dry period length on risk of clinical mastitis, nor any significant interaction with treatment. CLINICAL RELEVANCE: Combination therapy with teat sealant and antibiotic was effective under New Zealand conditions in herds using whole herd antibiotic treatment at drying off. Teat sealant reduced risk of clinical mastitis in cattle with dry periods substantially longer than 100 days, and there was no evidence that this effect changed as dry period length increased. PMID- 24472044 TI - Associations between supplemental or dietary intake of vitamin C and severity of lower urinary tract symptoms. AB - OBJECTIVE: To examine the association between long-term dietary vitamin C intake and recent use of vitamin C supplements with the progression and severity of lower urinary tract symptoms (LUTS). PARTICIPANTS AND METHODS: Baseline and 5 year follow-up interviews were completed by 2825 black, Hispanic or white men and women aged 30-79 years in the Boston Area Community Health survey. Dietary and supplemental vitamin C intake was assessed using a validated food frequency questionnaire. LUTS were assessed using the validated American Urological Association Symptom Index. Multivariable models were used to test the associations between baseline vitamin C and progression of LUTS over the follow up period, and between recent vitamin C intake and LUTS severity. RESULTS: In multivariable models, baseline dietary vitamin C was associated with lower odds of progression of daytime storage symptoms in men (e.g. quartile 4 vs 1, odds ratio [OR] = 0.63, 95% confidence interval [CI]: 0.41-0.97), or urgency symptoms in women (P trend = 0.02). Recent vitamin C intake at follow-up was also associated with better symptom scores among men. In contrast, among women, vitamin C supplement intake was associated with worse symptom scores, particularly daytime storage problems (500 mg/day vs none, OR = 1.66, 95% CI: 1.18-2.35, P trend = 0.01). Recent dietary vitamin C was not associated with LUTS in women. CONCLUSION: Vitamin C intake from foods and beverages was inversely associated with progression of daytime urinary storage symptoms in men or urgency symptoms in women at 5-year follow-up, therefore, the present results do not support a widespread avoidance for patients with LUTS of foods and beverages naturally rich in vitamin C. Supplemental vitamin C use above recommended daily intake levels was associated with higher odds of daytime urinary storage symptoms in women, and this finding is worthy of further attention and confirmation in future clinical trials. PMID- 24472045 TI - Imbalanced oxidant and antioxidant ratio in myotonic dystrophy type 1. AB - Myotonic dystrophy type 1 (DM1) is the most common form of muscular dystrophy affecting adults and is due to trinucleotide sequence (CTG) in the 3' UTR region of DMPK gene located at 19q13.3 chromosome. The pathogenic mechanisms of multisystemic involvement of DM1 are still unclear. The increased levels of reactive oxygen species/free radicals and lipid peroxides and decreased antioxidant levels play an important role in the pathogenesis of DM1. Present study includes 20 DM1 patients and 40 age- and sex-matched controls. Malonilaldehyde (MDA), superoxide dismutase (SOD), glutathione peroxidise (GPX), glutathione-S-transferase (GST), reduced glutathione (GSH), and TAS levels were measured and its association with clinical phenotype were evaluated. Results revealed significantly higher levels of MDA (p = 0.002), SOD (p = 0.006), and TAS p = 0.004) and lower level of GPX (p = 0.003), GST (P < 0.001) and GSH (P = 0.016) in DM1 patients. A significant negative correlation of MDA level with dyspepsia and CK-MB and GST level with serum SCK, CK-MB, and diabetes were observed. However, a significant positive correlation of SOD level with serum CK MB, CK-MM, and diabetes and negative correlation with facial weakness were noted. Though, GSH level had significant positive correlation with learning and writing disability, speech, and languages disability yet found negative correlation with duration of disease. The GPX and TAS showed no correlation with any clinical findings. Our data further support the pathogenic role of oxidative stress in DM1 of Indian origin and support the opportunity to undertake clinical trials with antioxidants in this disorder. PMID- 24472046 TI - Lectin-conjugated Fe2O3@Au core@Shell nanoparticles as dual mode contrast agents for in vivo detection of tumor. AB - Here, we report the covalent conjugation of lectin on Fe2O3@Au core@shell nanoparticle (lectin-Fe2O3@Au NP) for T2-weighted magnetic resonance (MR) and X ray computed tomography (CT) dual-modality imaging. The lectin-Fe2O3@Au NPs are prepared by coupling lectins to the Fe2O3@Au NP surfaces through bifunctional PEG NHS ester disulfide (NHS-PEG-S-S-PEG-NHS) linkers. After the nonspecific adsorption sites on the nanoparticle surface are blocked by thiolated PEG (PEG SH), the lectin-Fe2O3@Au NPs exhibit excellent stability in biological medium and inappreciable cytotoxicity. A series of in vitro and in vivo experiments were then carried out for evaluating the capabilities of three selected lectin (ConA, RCA and WGA)-Fe2O3@Au NPs. The results revealed that the lectin-Fe2O3@Au NPs had a capacity not only for dual mode MR and CT imaging in vitro but also for MR and CT imaging of colorectal cancer in vivo. The experimental results also suggest that lectin could be used as tumor targeting ligand for synthesizing nanoparticle based contrast agents. PMID- 24472047 TI - Role of pelvic and para-aortic lymphadenectomy in endometrial cancer: current evidence. AB - The aim of the present review is to summarize the current evidence on the role of pelvic and para-aortic lymphadenectomy in endometrial cancer. In 1988, the International Federation of Obstetrics and Gynecology recommended surgical staging for endometrial cancer patients. However, 25 years later, the role of lymph node dissection remains controversial. Although the findings of two large independent randomized trials suggested that pelvic lymphadenectomy provides only adjunctive morbidity with no clear influence on survival outcomes, the studies have many pitfalls that limit interpretation of the results. Theoretically, lymphadenectomy may help identify patients with metastatic dissemination, who may benefit from adjuvant therapy, thus reducing radiation-related morbidity. Also, lymphadenectomy may eradicate metastatic disease. Because lymphatic spread is relatively uncommon, our main effort should be directed at identifying patients who may potentially benefit from lymph node dissection, thus reducing the rate of unnecessary treatment and associated morbidity. This review will discuss the role of lymphadenectomy in endometrial cancer, focusing on patient selection, extension of the surgical procedure, postoperative outcomes, quality of life and costs. The need for new surgical studies and efficacious systemic drugs is recommended. PMID- 24472048 TI - Proposal of a concept and design of a randomized phase III trial investigating the survival effect of para-aortic lymphadenectomy in endometrial cancer. AB - Although prospective studies have failed to show the therapeutic effect of lymphadenectomy in the surgical treatment of endometrial cancer, several retrospective studies including the SEPAL study revealed the survival effect of lymphadenectomy. To prospectively investigate the survival benefit of para-aortic lymphadenectomy shown in the SEPAL study, we are proposing a new concept of a randomized phase III trial. An appropriate study population will be selected according to the preoperative assessments (evaluation of myometrial invasion and cervical invasion with magnetic resonance imaging, extrauterine spread with computed tomography, and histological type and grade by pathological evaluation) to estimate the risk of lymph node metastasis. Patients relevant to potential International Federation of Gynecology and Obstetrics (2008) stage IB, II and III diseases will be eligible, and randomly assigned to two arms: pelvic lymphadenectomy alone (control), or pelvic and para-aortic lymphadenectomy (experimental). After initial surgery, patients with postoperative pathological risk factors for recurrence will receive adjuvant chemotherapy. Because we aim to investigate the therapeutic significance of primary treatments, including surgery and adjuvant chemotherapy, the primary end-point could be recurrence-free survival. One of the most important issues to successfully perform this prospective study is to assure the quality of lymphadenectomy (extent and area), which could be evaluated based on the number of harvested nodes and objective evaluation of dissected area by videos and/or photos. PMID- 24472049 TI - Tailoring lymphadenectomy according to the risk of lymph node metastasis in endometrial cancer. AB - It has been strongly suggested that patients with endometrial cancer with low risk of lymph node metastasis do not benefit from lymphadenectomy and that intermediate-risk/high-risk endometrial cancer patients benefit from complete pelvic and para-aortic lymphadenectomy. This hypothesis needs to be validated by prospective studies. For randomized controlled trials (RCT), heterogeneity of intervention compromises internal validity and non-participation of experienced doctors compromises external validity. As these situations easily occur in randomized surgical trials (RST) intended for high-risk patients, the effects of complicated surgery, such as full lymphadenectomy, might be underestimated in RST. In a famous RST, data for all eligible patients implied that survival outcome for the non-randomized group was significantly better than that for the randomized group. One plausible explanation is that physicians' judgment and experience produce better treatment decisions than do random choices. Although two RCT from European countries showed negative results of lymphadenectomy on prognosis, valuing the care of individual patients may be more important than uncritically adopting the results of RCT. In endometrial cancer, lymphadenectomy must be tailored to maximize the therapeutic effect of surgery and minimize its invasiveness and adverse effects. Two strategies are: (i) to remove lymph nodes most likely to harbor disease while sparing lymph nodes that are unlikely to be affected; and (ii) to perform full lymphadenectomies only on patients who can potentially benefit from them. Here, we focus on the second strategy. Preoperative risk assessments used in Japan and Korea to select low-risk patients who would not benefit from lymphadenectomy are discussed. PMID- 24472050 TI - Annual report of Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2013: development of perinatal emergency care systems and suggestions. PMID- 24472051 TI - Annual report of Subcommittee for Examination of Causes of Maternal Death and their Prevention in Perinatology Committee, Japan Society of Obstetrics and Gynecology, 2013. PMID- 24472052 TI - Annual report of Gynecologic Oncology Committee, Japan Society of Obstetrics and Gynecology, 2013. AB - We present the Patient Annual Report in 2011 and the Treatment Annual Report in 2005 that were collected and analyzed by the Japan Society of Obstetrics and Gynecology. Data on 15,698 patients with cervical cancer, 7713 with endometrial cancer and 4672 with ovarian cancer in whom treatment was started in 2011 and data on the prognosis of 2985 patients with cervical cancer, 2812 with endometrial cancer, and 1839 with ovarian cancer who were started on treatment in 2005 were analyzed and summarized. Patient Annual Report in 2011: Stage 0 accounted for 58%, stage I for 24%, stage II for 9%, stage III for 5%, and stage IV for 4% of all the patients with cervical cancer. Stage 0 accounted for 6%, stage I for 61%, stage II for 8%, stage III for 18%, and stage IV for 7% of patients with endometrial cancer. Stage I accounted for 43%, stage II for 9%, stage III for 29%, and stage IV for 8% of patients with ovarian cancer. Treatment Annual Report in 2005: The 5-year overall survival rates of patients with cervical cancer were 91% in stage I, 78% in stage II, 57% in stage III, and 30% in stage IV. The 5-year overall survival rates of patients with endometrial cancer were 95% in stage I, 89% in stage II, 77% in stage III, and 23% in stage IV. The 5-year overall survival rates of patients with ovarian surface epithelial stromal tumors were 92% in stage I, 75% in stage II, 50% in stage III and 39% in stage IV. PMID- 24472053 TI - Annual report of Reproductive Endocrinology Committee, Japan Society of Obstetrics and Gynecology, 2013. AB - The Japan Society of Obstetrics and Gynecology Reproductive Endocrinology Committee summarizes the activities of each subcommittee below from April 2011 to March 2013. 1. Survey for clinical outcomes of infertility treatment for women with adenomyosis and complications of pregnant women with adenomyosis. 2. Survey for multiple pregnancies after controlled ovarian stimulation in non-assisted reproductive-technology infertility treatment cycles: population-based study in Japan. 3. Study on the effect of endometriosis management on ovarian reserve. PMID- 24472054 TI - Annual report of Women's Health Care Committee, Japan Society of Obstetrics and Gynecology, 2013. AB - The activity of the Women's Health Care Committee for 1 year up to June 2013 includes: (i) guides for the management of health care in middle-aged women; (ii) postoperative women's health care; (iii) survey on the treatment of pelvic organ prolapse; and (iv) survey of postoperative infection in gynecologic surgery. The detailed activity of the four subcommittees is described in the text. PMID- 24472055 TI - NMR investigation of chloromethane complexes of cryptophane-A and its analogue with butoxy groups. AB - Host-guest complexes between cryptophane-A as host and dichloromethane and chloroform as guests are investigated using (1)H and (13)C NMR spectroscopy. Moreover, a related cryptophane, with the methoxy groups replaced by butoxy units (cryptophane-But), and its complexes with the same guests were also studied. Variable temperature spectra showed effects of chemical exchange between the free and bound guests, as well as of conformational exchange of the host. The guest exchange was studied quantitatively by exchange spectroscopy or line shape analysis. Extraction of kinetic and thermodynamic parameters led to the characterization of the affinity between guests and hosts. On the other hand, the host exchange was investigated by means of (13)C Carr-Purcell-Meiboom-Gill (CPMG) relaxation dispersion which aims at the determination of the transverse relaxation rate R2, the inverse of the transverse relaxation time T2, as a function of the repetition of the pi pulses in a CPMG train. The variation of the measured transverse relaxation rate with the repetition rate nuCPMG indicated conformational exchange occurring on the microsecond-millisecond time scale. Structural information was obtained through measurements of cross-relaxation rates, both within the host and between the host and the guest protons. The NMR results were supported by DFT calculations. PMID- 24472056 TI - Distinct mechanisms and timing of language recovery after stroke. AB - The "language network" is remarkably stable across language tasks but changes in response to injury to specific components or in response to "disconnection" of input to one component. We investigated network changes during language recovery, hypothesizing that language recovery takes place through distinct mechanisms: (a) reperfusion; (b) recovery from diaschisis; (c) recovery from structural disconnection; and (d) "reorganization" of language, whereby various components assume function of a damaged component. We also tested the hypothesis that "reorganization" depends on: the language task, level of performance, size and site of stroke, and time post onset. We tested these hypotheses in five participants who had structural, perfusion, and functional imaging utilizing spelling, reading, word generation, and picture naming tasks at acute and subsequent stages after ischaemic stroke. These cases illustrate different mechanisms of aphasia recovery or illustrate that reorganization of language acutely depends on individual variables in addition to size and site of stroke. PMID- 24472057 TI - Survival outcomes in patients with early stage, resected pancreatic cancer - a comparison of gemcitabine- and 5-fluorouracil-based chemotherapy and chemoradiation regimens. AB - PURPOSE: We conducted a comparative survival analysis between patients with resected pancreatic cancer who received adjuvant treatment with either gemcitabine- or 5-fluorouracil-based chemotherapy and chemoradiation regimens. PATIENTS AND METHODS: The Surveillance, Epidemiology and End Results (SEER) Medicare database was used to identify patients with pancreatic cancer diagnosed from 1998 to 2005 who received curative surgery and adjuvant chemotherapy with either 5-fluorouracil or gemcitabine. These groups were subdivided by treatment with radiotherapy. Patients were followed until death, study end-point or a maximum of 5 years after diagnosis. RESULTS: Three hundred and fifty-nine patients received 5-fluorouracil and 346 received gemcitabine. Compared with chemoradiation with 5-fluorouracil, outcomes for patients who received chemoradiation with gemcitabine did not differ. Patients who received gemcitabine without radiation had increased hazards (poorly differentiated tumours: HR = 1.50, p = 0.01; moderately differentiated tumours, HR = 1.28, p = 0.11). However, outcomes of patients who received 5-fluorouracil without radiation varied with tumour grade. In moderately differentiated tumours, patients had better outcomes with 5-fluorouracil when compared with chemoradiation with 5-fluorouracil (HR = 0.42, p = 0.02). In poorly differentiated tumours, the opposite was true (HR 2.10, p = 0.09). CONCLUSION: Patients with low-grade resected pancreatic cancer may have better outcomes with 5-fluorouracil-based chemotherapy without radiation when compared with 5-fluorouracil with radiation. PMID- 24472058 TI - Night-time sedating H1 -antihistamine increases daytime somnolence but not treatment efficacy in chronic spontaneous urticaria: a randomized controlled trial. AB - BACKGROUND: Many physicians believe that the most effective way to treat chronic urticaria is to take a nonsedating second-generation H1 -antihistamine in the morning and a sedating first-generation H1 -antihistamine, usually hydroxyzine, at night to enhance sleep. But is this belief well founded? OBJECTIVES: To test this belief by comparing the effectiveness and prevalence of unwanted sedative effects when treating patients with chronic spontaneous urticaria (CSU) with levocetirizine 15 mg daily plus hydroxyzine 50 mg at night (levocetirizine plus hydroxyzine) vs. levocetirizine 20 mg daily (levocetirizine monotherapy). METHODS: In this randomized, double-blind, cross-over study, 24 patients with difficult-to-treat CSU took levocetirizine plus hydroxyzine or levocetirizine monotherapy for periods of 5 days each. At the end of each treatment period, assessments were made of quality of life (Chronic Urticaria Quality of Life Questionnaire, CU-Q2 oL), severity of urticaria symptoms (Urticaria Activity Score, UAS), sleep disturbance during the night and daytime somnolence. RESULTS: Both treatments significantly decreased UAS, night-time sleep disturbances and CU Q2 oL scores (P < 0.001) without significant differences between the two. Compared with baseline, daytime somnolence was significantly reduced by levocetirizine monotherapy (P = 0.006) but not by levocetirizine plus hydroxyzine (P = 0.218). Direct comparison of the two treatment modalities in terms of daytime somnolence favoured levocetirizine monotherapy (P = 0.026). CONCLUSIONS: The widespread belief that sleep is aided by the addition of a sedating first generation H1 -antihistamine, usually hydroxyzine, at night is not supported. These results are in line with the urticaria guidelines, which state that first line treatment for urticaria should be new-generation, nonsedating H1 antihistamines only. PMID- 24472059 TI - Involvement of purinergic receptors and NOD-like receptor-family protein 3 inflammasome pathway in the adenosine triphosphate-induced cytokine release from macrophages. AB - Adenosine triphosphate (ATP) has been described as a danger signal activating the NOD-like receptor-family protein 3 (NLRP3)-inflammasome leading to the pro inflammatory cytokine, interleukin (IL)-1beta, release in the lung. The NLRP3 inflammasome pathway has been previously described to be involved in experimental collagen deposition and the development of pulmonary fibrosis. The aim of the present study was to investigate the role of the NLRP3 inflammasome pathway and P2X7 purinergic receptor in the activation of human macrophages in vitro by ATP. We showed that adenosine 5'-[gamma-thio]triphosphate tetralithium salt (ATPgammaS) and 2',3'-O-(4-benzoylbenzoyl) adenosine 5'-triphosphate (BzATP), two stable analogs of ATP, are able to potentiate the release of IL-1beta from human monocyte-derived macrophages induced by low concentration of lipopolysaccharide (LPS). However, in the same conditions no increase in IL-1alpha and IL-6 was observed. Immunochemistry has shown that human macrophages natively express NLRP3 and purinergic P2X7 receptors (P2X7 R). NLRP3 and IL-1beta mRNA expression were induced from LPS-primed macrophages, but also after 5-h treatment of BzATP as analysed by reverse transcription quantitative polymerase chain reaction. However, other inflammasome pathways (NLRP1, NLRP2, NLRC4, NLRP6 and AIM2) and P2X7 R were not induced by BzATP. We observed that P2X7 R antagonists, A-438079 and A-740003, were able to reduce the release of IL-1beta, but not of IL-1alpha and IL-6 from macrophages stimulated by ATPgammaS or BzATP. The present results showed the involvement of the P2X7 R-NLRP3 inflammasome pathway in the secretion of IL-1beta from ATP-stimulated human macrophages, and suggest that P2X7 R were not involved in IL-1alpha and IL-6 release. This study also points out that repression of the P2X7 R represents a novel potential therapeutic approach to control fibrosis in lung injury. PMID- 24472060 TI - Opportunities for improving therapy development in ALS. AB - In May 2013, The ALS Association and The Northeast ALS Consortium (NEALS) convened a meeting of stakeholders for a round-table discussion of ways to improve therapy development in ALS. The following overview summarizes issues raised and potential new directions discussed at the meeting. We recommend that future phase II clinical trials in ALS proceed when the proposed treatment is directed at targets that are likely to be involved in ALS pathogenesis in a defined subgroup of patients, and be accompanied by one or more biomarkers to track both clinical progression and pharmacodynamic engagement of the target. Innovations in trial structure and design, and greater involvement of patient advocates, may also improve trials. PMID- 24472061 TI - Postprocedure mapping of cardiac resynchronization lead position using standard fluoroscopy systems: implications for the nonresponder with scar. AB - BACKGROUND: The relationship between cardiac resynchronization therapy (CRT), left ventricular (LV) lead position, scar, and regional mechanical function influences CRT response. OBJECTIVE: To determine LV lead position relative to LV structural characteristics in standard clinical practice, we developed and validated a practical yet mathematically rigorous method to register procedural fluoroscopic LV lead position with pre-CRT cardiac magnetic resonance (CMR). METHODS: After one-time calibration of the standard fluoroscopic suite, we identified the projected CMR LV lead position using three reference landmarks on both CMR and fluoroscopy. This predicted lead position was validated in a canine model by histology and in eight "validation group" patients based on postoperative computed tomography scans (n = 7) or CMR coronary sinus venography (n = 1). The methodology was applied in an additional eight patients with CRT nonresponse and infarction-related myocardial scar. RESULTS: The projected and actual lead positions were within 1.2 mm in the canine model. The median distance between projected and actual lead positions for the validation group (n = 8) and animal validation case was 11.3 mm (interquartile range 9.2-14.6 mm). In the application (nonresponder) group (n = 8), the lead mapped to the scar periphery in three patients, the core of the scar in one patient, and more than 3 cm from scar in four patients. CONCLUSIONS: This methodology projects procedural fluoroscopic LV lead position onto pre-CRT CMR using standard fluoroscopic equipment and a one-time calibration, enabling assessment of LV lead position with sufficient accuracy to identify the lead position relative to regional function and infarction-related scar in CRT nonresponders. PMID- 24472063 TI - Influence of surface states on the evaluation of the flat band potential of TiO(2). AB - Flat band potential (Vfb) is one of the most important physical parameters to study and understand semiconductor materials. However, the influence of surface states on the evaluating Vfb of titanium oxide (TiO2) and other semiconductor materials through a Mott-Schottky plot is ignored. Our study indicated that the influence of surface states should be introduced into the corresponding equivalent circuit even when the kinetic process did not occur. Ignoring the influence of surface states would lead to an underestimation of the space charge capacitance. Our paper would be beneficial for accurate determination of Vfb of semiconductor materials. We anticipate that this preliminary study will open new perspectives in understanding the semiconductor-electrolyte interface. PMID- 24472062 TI - The validity of serum markers for fibrosis staging in chronic hepatitis B and C. AB - Assessment of liver fibrosis is critical for successful individualized disease management in persons with chronic hepatitis B (CHB) or chronic hepatitis C (CHC). We expanded and validated serum marker indices to provide accurate, reproducible and easily applied methods of fibrosis assessment. Liver biopsy results from over 284 CHB and 2304 CHC patients in the Chronic Hepatitis Cohort Study ('CHeCS') were mapped to a F0-F4 equivalent scale. APRI and FIB-4 scores within a 6-month window of biopsy were mapped to the same scale. A novel algorithm was applied to derive and validate optimal cut-offs for differentiating fibrosis levels. For the prediction of advanced fibrosis and cirrhosis, the FIB-4 score outperformed the other serum marker indices in the CHC cohort and was similar to APRI in the CHB cohort. The area under the receiver operating characteristic curves (AUROC) for FIB-4 in differentiating F3-F4 from F0-F2 was 0.86 (95% CI: 0.80-0.92) for CHB and 0.83 (95% CI: 0.81-0.85) for CHC. The suggested cut-offs based on FIB-4 model produced high positive predictive values [CHB: 90.0% for F0-F2, 100.0% for cirrhosis (F4); CHC: 89.7% for F0-F2; 82.9% for cirrhosis (F4)]. In this large observational cohort, FIB-4 predicted the upper and lower end of liver fibrosis stage (cirrhosis and F0-F2, respectively) with a high degree of accuracy in both CHB and CHC patients. PMID- 24472064 TI - 177Lu-labeled antibodies for EGFR-targeted SPECT/CT imaging and radioimmunotherapy in a preclinical head and neck carcinoma model. AB - Epidermal growth factor receptor (EGFR) has been well characterized as an important target for cancer therapy. Immunotherapy based on EGFR-specific antibodies (e.g., panitumumab and cetuximab) has shown great clinical promise. However, increasing evidence has indicated that only a subgroup of patients receiving these antibodies will benefit from them, and even patients who do initially experience a major response may eventually develop therapeutic resistance. In this study, we investigated whether panitumumab and cetuximab can serve as delivery vehicles for tumor-targeted radionuclide therapy in a preclinical tumor model that did not respond to immunotherapy. The in vitro toxicity and cell binding properties of panitumumab and cetuximab were characterized. Both antibodies were conjugated with 1,4,7,10-tetraazadodecane N,N',N",N"'-tetraacetic acid (DOTA) and radiolabeled with (177)Lu. Small-animal SPECT/CT, biodistribution, and radioimmunotherapy (RIT) studies of (177)Lu-DOTA panitumumab ((177)Lu-Pan) and (177)Lu-DOTA-cetuximab ((177)Lu-Cet) were performed in the UM-SCC-22B tumor model. Both (177)Lu-Pan and (177)Lu-Cet exhibited favorable tumor targeting efficacy. The tumor uptake was 20.92 +/- 4.45, 26.10 +/ 5.18, and 13.27 +/- 1.94% ID/g for (177)Lu-Pan, and 15.67 +/- 3.84, 15.72 +/- 3.49, and 7.82 +/- 2.36% ID/g for (177)Lu-Cet at 24, 72, and 120 h p.i., respectively. RIT with a single dose of 14.8 MBq of (177)Lu-Pan or (177)Lu-Cet significantly delayed tumor growth. (177)Lu-Pan induced more effective tumor growth inhibition due to a higher tumor uptake. Our results suggest that panitumumab and cetuximab can function as effective carriers for tumor-targeted delivery of radiation, and that RIT is promising for targeted therapy of EGFR positive tumors, especially for those tumors that are resistant to antibody-based immunotherapy. PMID- 24472065 TI - Endoscopic ultrasound in patients with normal liver blood tests and unexplained dilatation of common bile duct and or pancreatic duct. AB - OBJECTIVE: To determine the yield of endoscopic ultrasound (EUS) in the investigation of patients with normal liver function tests (LFTs) and unexplained dilatation of common bile duct (CBD) and/or pancreatic duct (PD), following CT and/or magnetic resonance cholangiopancreatography. MATERIALS AND METHODS: Consecutive patients undergoing linear EUS between January 2007 and August 2011 for the indication of dilated CBD and/or PD, normal LFT, and nondiagnostic cross sectional imaging formed the study group. The study was performed as a retrospective analysis of prospectively collected data. RESULTS: During the study period, 83 patients (CBD and PD dilatation n = 38, PD dilatation n = 5, CBD dilatation n = 40) met the inclusion criteria and underwent EUS. Five (13.1%) of the CBD and PD groups had a new finding, which in one (2.6%) case was causal. In this group, men were significantly more likely to have a new finding (p = 0.012). Eight (20%) of the CBD group had a new finding, which in seven (17.5%) cases was causal. In the CBD group, cholecystectomy was significantly (p = 0.005) more common in those without a finding. Three (60%) of the PD group had a finding on EUS, all of which were causal, including a case of pancreatic malignancy. CONCLUSION: There is a significant yield from EUS in individuals with isolated PD dilatation and isolated CBD dilatation. Previous cholecystectomy is significantly associated with a negative EUS in the group with isolated CBD dilatation. The yield in those with CBD and PD dilatation was low and a finding was more likely in males. PMID- 24472067 TI - Using the theory of planned behaviour to develop targets for interventions to enhance patient communication during pharmacy consultations for non-prescription medicines. AB - OBJECTIVE: To identify modifiable factors that influence patients' information giving behaviour about their health during consultations with pharmacy staff. METHODS: A theory of planned behaviour questionnaire was posted to 3000 individuals randomly selected from the Scottish Electoral Register. RESULTS: The 927 respondents confirmed a low rate of disclosure of information about their health to pharmacy staff during their last pharmacy visit. Individuals who intended to give information about their health during pharmacy consultations were more likely to do so. Those who intended to give information during consultations had higher subjective norms than those who did not (i.e. intentions were associated with beliefs that people who were important to them, e.g. family members, doctors, thought they should give information during these consultations). Control beliefs, e.g. 'I am confident that I will give information if I have received good advice in the past', and behavioural beliefs, e.g. 'If I give information I will be sold an appropriate medicine', were not associated with intention or behaviour. CONCLUSION: Future interventions to promote relevant communication between patients and pharmacy staff should target patients' subjective norms rather than control beliefs or behavioural beliefs. PMID- 24472068 TI - Evaluation methods for pretransplant oncologic markers and their prognostic impacts in patient undergoing living donor liver transplantation for hepatocellular carcinoma. AB - Tumor markers [alpha-fetoprotein (AFP) or des-gamma-carboxyprothrombin (DCP)] and neutrophil/lymphocyte ratio (NLR) reportedly correlate with long-term outcomes for hepatocellular carcinoma (HCC). However, no standardized method has been established for evaluating the pretransplant data. One hundred and twenty-four patients who underwent living donor liver transplantation (LDLT) were retrospectively reviewed. The best predictive parameters for tumor recurrence were maximum values for AFP or DCP and 90-day mean values for NLR, respectively, and multivariate analysis confirmed these values were correlated with tumor recurrence. However, receiver operating characteristic analysis revealed that discriminative powers were sufficient only in maximum AFP [area under the curve (AUC) 0.88, P < 0.001] and maximum DCP (AUC 0.76, P < 0.001), while mean NLR was less predictive (AUC 0.62, P = 0.20). When incorporating AFP and DCP to the Tokyo criteria (<=5 tumors with each tumor <= 5 cm), the presence of at least two of the following factors: (i) beyond the Tokyo criteria, (ii) AFP>250 ng/ml, and (iii) DCP > 450 mAu/ml (>450 ng/ml), was correlated with a worse 5-year disease free survival rate (20.0% vs. 96.8%, P < 0.001) and 5-year overall survival rate (20.0% vs. 84.0%, P < 0.001). The prognosis of patients undergoing LDLT for HCC strongly relies on maximum AFP or DCP values before transplantation, while the prognostic impact of NLR is limited. PMID- 24472069 TI - Near-ideal optical metamaterial absorbers with super-octave bandwidth. AB - Nanostructured optical coatings with tailored spectral absorption properties are of interest for a wide range of applications such as spectroscopy, emissivity control, and solar energy harvesting. Optical metamaterial absorbers have been demonstrated with a variety of customized single band, multiple band, polarization, and angular configurations. However, metamaterials that provide near unity absorptivity with super-octave bandwidth over a specified optical wavelength range have not yet been demonstrated experimentally. Here, we show a broadband, polarization-insensitive metamaterial with greater than 98% measured average absorptivity that is maintained over a wide +/- 45 degrees field-of-view for mid-infrared wavelengths between 1.77 and 4.81 MUm. The nearly ideal absorption is realized by using a genetic algorithm to identify the geometry of a single-layer metal nanostructure array that excites multiple overlapping electric resonances with high optical loss across greater than an octave bandwidth. The response is optimized by substituting palladium for gold to increase the infrared metallic loss and by introducing a dielectric superstrate to suppress reflection over the entire band. This demonstration advances the state-of-the-art in high performance broadband metamaterial absorbers that can be reliably fabricated using a single patterned layer of metal nanostructures. PMID- 24472070 TI - A simple litmus test for aldehyde oxidase metabolism of heteroarenes. AB - The bioavailability of aromatic azaheterocyclic drugs can be affected by the activity of aldehyde oxidase (AO). Susceptibility to AO metabolism is difficult to predict computationally and can be complicated in vivo by differences between species. Here we report the use of bis(((difluoromethyl)sulfinyl)oxy)zinc (DFMS) as a source of CF2H radical for a rapid and inexpensive chemical "litmus test" for the early identification of heteroaromatic drug candidates that have a high probability of metabolism by AO. PMID- 24472071 TI - Fluctuation in prostate cancer gene 3 (PCA3) score in men undergoing first or repeat prostate biopsies. AB - OBJECTIVE: To evaluate the variability in prostate cancer gene 3 (PCA3) score over time in men with elevated serum prostate-specific antigen (PSA) levels who are undergoing first or repeat prostate biopsy. PATIENTS AND METHODS: A total of 360 men from two Italian institutions who had undergone at least two PCA3 assessments were selected. Of these, 97.5% were scheduled for first or repeat prostate biopsy because of elevated PSA level and/or positive digital rectal examination (DRE). We compared the PCA3 scores in men with a negative biopsy (normal parenchyma, benign prostatic hyperplasia [BPH], chronic prostatitis, high grade prostate intraepithelial neoplasia [HG-PIN]) with those in men with a positive biopsy. We evaluated PCA3 repeated measures biological variability and its possible association with basic patient characteristics (age, family history of prostate cancer, DRE, prostate volume, BPH, prostatitis and HG-PIN). Three different thresholds were used to evaluate the possible changes in risk class: the standard threshold (a PCA3 score of 35), a US Food and Drug Administation approved PCA3 threshold of 25 and a threshold selected based on our previous research which was a PCA3 score of 50. RESULTS: The PCA3 scores varied significantly (P < 0.001) when comparing men with a negative biopsy with those with a positive biopsy (median [range] PCA3 score: 25 [2-276] vs 43 [7-331]). There was no significant difference in PCA3 scores in men with chronic prostatitis and HG-PIN compared with other men with negative biopsies. The median (range) time between the two PCA3 assessments was 16.2 (3-53.7) months. No association was found between PCA3 repeated measures modifications and age, family history of prostate cancer, DRE, BPH, prostatitis, HG-PIN and use of 5 alpha-reductase inhibitors. The variability of PCA3 scores on repeated measures confirmed the risk class for about 80% of patients; of the remaining 20% of patients, the risk class was upgraded in two thirds and downgraded in one third. CONCLUSION: PCA3 score can be considered a stable marker over time in most cases but there is a group of men among whom there is clinically notable risk class change. Further investigation is required to determine the genesis of this phenomenon. PMID- 24472072 TI - Plasminogen activator inhibitor-1 4G/5G polymorphism and ischemic stroke risk: a meta-analysis in Chinese population. AB - BACKGROUND: The guanosine insertion/deletion polymorphism (4G/5G) of plasminogen activator inhibitor-1 (PAI-1) gene has been suggested as a risk factor for ischemic stroke (IS), but direct evidence from genetic association studies remains inconclusive even in Chinese population. Therefore, we performed a meta analysis to evaluate this association. METHODS: All of the relevant studies were identified from PubMed, Embase, Chinese National Knowledge Infrastructure database and Chinese Wanfang database up to September 2013. Statistical analyses were conducted with Revman 5.2 and STATA 12.0 software. Odds ratio (OR) with 95% confidence interval (CI) values were applied to evaluate the strength of the association. Heterogeneity was evaluated by Q-test and the I2 statistic. The Begg's test and Egger's test were used to assess the publication bias. RESULTS: A significant association and a borderline association between the PAI-1 4G/5G polymorphism and IS were found under the recessive model (OR = 1.639, 95% CI = 1.136-2.364) and allelic model (OR = 1.256, 95% CI = 1.000-1.578), respectively. However, no significant association was observed under homogeneous comparison model (OR = 1.428, 95% CI = 0.914-2.233), heterogeneous comparison model (OR = 0.856, 95% CI = 0.689-1.063) and dominant model (OR = 1.036, 95% CI = 0.846 1.270). CONCLUSION: This meta-analysis suggested that 4G4G genotype of PAI-1 4G/5G polymorphism might be a risk factor for IS in the Chinese population. PMID- 24472073 TI - Hematoma expansion in spontaneous intracerebral hemorrhage: predictors and outcome. AB - BACKGROUND: Hematoma growth is an independent determinant of outcome in patients with intracerebral hemorrhage (ICH). Predictors of hematoma expansion are poorly defined. Our aim is to determine predictors of hematoma expansion in patients with ICH. METHODS: We reviewed our prospective database of patients with ICH between January 2009 and June 2012. Patients were divided into two groups based on the presence or absence of hematoma expansion. Hematoma volume was calculated by thin volumetric cuts using special software. Expansion was defined as 33% increase in hematoma volume over 24 hours. We compared risk factors, laboratory parameters, medications and CT findings between the two groups using Fisher's exact test. A multivariate regression analysis was performed to identify predictors of expansion. RESULTS: We identified 200 patients with ICH. On univariate analysis, patients with hematoma expansion were more likely to have Warfarin use (37% vs. 11% p = 0.001), low admission GCS (9 +/- 4, 11 +/- 4, p = 0.003), intraventricular hemorrhage (IVH) (79% vs. 45% p = 0.002) and hydrocephalus (43% vs. 22% p = 0.032). On multivariate regression analysis, prior Warfarin use (OR = 3.6, 95% CI: 1.3,10.3; p = 0.016) and IVH (OR = 5.7, 95% CI: 1.5,20.9; p = 0.009) were significant predictors of hematoma expansion. The ICU length of stay (8 +/- 8 vs. 4 +/- 6, p = 0.004), intubation rate (82% vs. 32%, p = 0.034), and hospital mortality (68% vs. 20%, p = < 0.001) were significantly higher among patients with hematoma expansion. CONCLUSION: Patient with prior Warfarin use and IVHs are at risk of hematoma expansion. Aggressive measures to prevent hematoma growth are important in these patients. PMID- 24472074 TI - Is phosphorus intake that exceeds dietary requirements a risk factor in bone health? AB - Phosphorus intake in excess of the nutrient needs of healthy adults is thought to disrupt hormonal regulation of phosphorus (P), calcium (Ca), and vitamin D, contributing to impaired peak bone mass, bone resorption, and greater risk of fracture. Elevation of extracellular phosphorus due to excessive intake is thought to be the main stimulus disrupting phosphorus homeostasis in healthy individuals, as it is in renal disease even when intake is modest. If high serum phosphorus is the critical link to the effect of high phosphorus intake on bone health, the issue could be addressed through epidemiologic or dietary studies. However, several confounding factors, including problems estimating accurate phosphorus intake, the influence of a low dietary Ca:P ratio, the acidic nature of phosphorus, the rapid rate of absorption and greater phosphorus bioavailability from processed food such as cola drinks, and circadian fluctuation in serum phosphorus, make this question difficult to address using conventional study designs. These confounding factors are considered in this review, exploring whether phosphorus intake exceeding nutrient needs in healthy individuals disrupts phosphorus regulation and negatively affects bone accretion or loss. Specific attention is given to phosphorus intake from processed foods rich in phosphorus additives, which significantly contribute to phosphorus intake. PMID- 24472075 TI - Introduction to dietary phosphorus excess and health. PMID- 24472083 TI - Comparison of the major virulence-related genes of Listeria monocytogenes in internalin A truncated strain 36-25-1 and a clinical wild-type strain. AB - BACKGROUND: Internalin A (InlA) facilitates the invasion of Listeria monocytogenes into a host cell. Some strains of Listeria monocytogenes express truncated forms of InlA, which reduces invasiveness. However, few virulence related genes other than inlA have been analyzed in InlA-truncated strains. In the present study, we sequenced the draft genome of strain 36-25-1, an InlA truncated strain, with pyrosequencing and compared 36 major virulence-related genes in this strain and a clinical wild-type strain. RESULTS: Strain 36-25-1 possessed all of the virulence-related genes analyzed. Of the analyzed genes, only 4 genes (dltA, gtcA, iap, and inlA) differed when the nucleotide sequences of strain 36-25-1 and the clinical wild-type strain were compared. Analysis of the deduced amino acid sequences found no mutations that significantly influenced virulence in genes other than inlA. CONCLUSIONS: The virulence-associated genes in strain 36-25-1 differ little from those of the clinical wild-type strain, indicating that a slight mutation in the nucleotide sequence determines the virulence of the InlA-truncated strain. In addition, the results suggest that, aside from InlA-mediated cell invasiveness, there is almost no difference between the virulence of strain 36-25-1 and that of the clinical wild-type strain. PMID- 24472084 TI - Comparison of intramuscular compound betamethasone and oral diclofenac sodium in the treatment of acute attacks of gout. AB - INTRODUCTION: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for the treatment of acute gouty arthritis but have the risk of gastrointestinal bleeding and cardiovascular toxicity. Glucocorticoid was as effective as oral NSAIDs in the initial treatment of gout arthritis of patients intolerant of NSAIDs. However, whether glucocorticoid has the same or preferable effect as oral NSAIDs on patients with acute gouty arthritis irrespective of gastrointestinal and cardiovascular risks factor remains unknown. This study was to compare the efficacy, safety and tolerance of compound betamethasone (diprospan) 7 mg intramuscular injection (i.m.) once for all during the study with diclofenac sodium 75 mg twice a day in the treatment of acute gouty arthritis. METHODS: Sixty patients with acute gouty arthritis were randomised (1 : 1) to receive compound betamethasone 7 mg i.m. once for all during the study or diclofenac sodium 75 mg twice a day for 7 days in this open-label study. Pain intensity, tenderness, swelling and global assessment of response to therapy were collected as end-points for the treatment. RESULTS: The mean change in pain intensity from baseline to Day 3 and Day 7 in both treatment groups demonstrated that compound betamethasone had preferable efficacy over diclofenac sodium on Day 3 and comparable efficacy on Day 7. The compound betamethasone group had fewer adverse effects (AEs) than diclofenac sodium group. No statistically significant differences were observed about serum uric acid levels at different pain intensity at baseline. CONCLUSIONS: A single dose of compound betamethasone may be better than diclofenac sodium for the treatment of acute gouty arthritis. PMID- 24472085 TI - Hepatoprotective potential of Cassia auriculata roots on ethanol and antitubercular drug-induced hepatotoxicity in experimental models. AB - CONTEXT: Tarvada [Cassia auriculata Linn. (Caesalpiniaceae)] is used against liver ailments in Indian folk medicine, but there is a lack of scientific evidence for this traditional claim. OBJECTIVE: The present study investigated the protective effect of methanol extract of tarvada (MECA) roots on ethanol and antitubercular drug induced hepatotoxicity in rats. MATERIALS AND METHODS: In the therapeutic model, ethanol (40%, 4 g/kg b.w., p.o.) was administered to rats for 21 days and the intoxicated rats were treated with MECA (300 and 600 mg/kg, b.w.) and silymarin (100 mg/kg, b.w.) for next 7 days. In the prophylactic model, MECA and silymarin were administered simultaneously along with a combination of isoniazid (27 mg/kg, b.w.), rifampicin (54 mg/kg, b.w.) and pyrazinamide (135 mg/kg, b.w.) for 30 days. After the study duration, serum levels of AST, ALT, ALP, total bilirubin, total cholesterol, total protein, albumin were estimated along with hepatic catalase (CAT), reduced glutathione (GSH), superoxide dismutase (SOD), malondialdehyde (MDA) and liver histopathology in each group. RESULTS: Administration of tarvada root extract significantly (p < 0.01 and p < 0.05) lowered the elevated levels of serum AST, ALT, ALP, total bilirubin, total cholesterol, total protein and restored the abnormal levels of enzymatic antioxidants and MDA in liver due to toxicant administration in a dose-dependent manner. These results were confirmed by histopathological analysis. DISCUSSION AND CONCLUSION: Results suggest that tarvada root extract possess potent hepatoprotective activity against ethanol and antitubercular drug-induced hepatotoxicity in rats, which could be due to an inhibition of hepatic metabolizing enzymes and antioxidant activity. PMID- 24472086 TI - Cutaneous epithelioid melanocytic neurofibroma arising in a patient with neurofibromatosis-1. AB - Tumors expressing both melanocytic and neural features can pose a diagnostic challenge to the dermatopathologist and provoke questions regarding their lineage. We report a case of a tumor arising on the right cheek of a 9-year-old boy with neurofibromatosis type 1 (NF-1). This neoplasm featured nests of non pigmented epithelioid cells arising within a neurofibroma. The entire tumor stained strongly with S100, whereas the epithelioid population stained with MART 1, HMB-45 and MiTF. The neoplasm shows only scattered Ki-67 positivity. This tumor represents a neurofibroma with portions that have undergone melanocytic differentiation (melanocytic neurofibroma). This exceedingly rare tumor represents a distinct entity from neurotized melanocytic nevi, combined melanocytic nevi or pigmented neurofibromas and provides further evidence that melanocytes arise indirectly from ventromedial neural crest-derived Schwann cell precursors. PMID- 24472087 TI - Cryotherapy is preferable to ablative CO2 laser for the treatment of isolated actinic keratoses of the face and scalp: a randomized clinical trial. AB - BACKGROUND: Actinic keratosis (AK) may progress to squamous cell carcinoma. In the case of normal or mildly photodamaged skin, lesion-directed treatments are considered valuable options despite poor published evidence of their therapeutic activity. OBJECTIVES: The aim of this single-centre, open-label, prospective, nonsponsored, randomized, controlled clinical trial was to compare CO2 laser ablation with cryotherapy in the treatment of isolated AKs of the face and scalp. PATIENTS AND METHODS: Patients with isolated (<= 4) AKs of the face and scalp were randomized to receive CO2 laser ablation or cryotherapy. After 90 days, the overall complete remission (CR) rates of patients and lesions were assessed and correlated with thickness grade. RESULTS: Two hundred patients with a total number of 543 AKs were enrolled. The CR rates of lesions after 3 months were 78.2% with cryotherapy and 72.4% with CO2 laser ablation. Thicker lesions were significantly more responsive to cryotherapy (P = 0.034). Seventy-three patients (71.6%) had CR of all lesions 3 months after cryotherapy and 64 (65.3%) after laser ablation. At 12 months after treatment the number of patients with CR was reduced to 53 with cryotherapy and 14 with laser ablation. CONCLUSIONS: The rate of patients and lesions with CR is similar after 3 months, but more patients remain in stable remission for 12 months after cryotherapy. Cryotherapy is more effective for thick lesions. The cosmetic outcome was good or excellent in almost all patients. PMID- 24472088 TI - Biostatistical and medical statistics graduate education. AB - The development of graduate education in biostatistics and medical statistics is discussed in the context of training within a medical center setting. The need for medical researchers to employ a wide variety of statistical designs in clinical, genetic, basic science and translational settings justifies the ongoing integration of biostatistical training into medical center educational settings and informs its content. The integration of large data issues are a challenge. PMID- 24472089 TI - Assessment of atrioventricular conduction following cryoablation of atrioventricular nodal reentrant tachycardia in children. AB - BACKGROUND: Early-onset transient atrioventricular block (AVB) is a rare occurrence following cryoablation of atrioventricular nodal reentrant tachycardia (AVNRT), despite lack of any AVB at the end of the procedure. The purpose of this prospective study was to assess AVB shortly after successful cryoablation of AVNRT in children. METHODS: A 6-mm-tip cryocatheter was used in 39 procedures. An 8-mm-tip catheter was used in 11 procedures. Twelve-lead electrocardiograms (ECGs) and 24-hour ambulatory ECGs were performed 24 hours prior to the procedure and immediately following the procedure. All procedures were done using the EnSite system (St. Jude Medical, St. Paul, MN, USA) without fluoroscopy. RESULTS: Although nine (18%) patients developed variable degrees of transient AVB during the procedure, all of them had normal atrioventricular (AV) conduction at the end of the procedure and did not require any intervention. Four of these patients had variable degrees of transient AVB following the procedure despite having normal AV conduction at the end of the procedure. One developed Mobitz type I AVB, which lasted for 11.5 hours, and the other three experienced 2:1 AVB, which lasted for 2, 8, and 24 hours, respectively. All patients had complete resolution of the AVB, which was also documented with the 24-hour ambulatory ECGs after the procedure. CONCLUSION: Early transient AVB can develop following AVNRT cryoablation even if AV conduction is normal at the end of the procedure. Despite the transient AVB in the initial 24 hours after the procedure in some cases, there is no evidence for ongoing AV nodal dysfunction. PMID- 24472090 TI - Interface properties of atomic layer deposited TiO2/Al2O3 films on In(0.53)Ga(0.47)As/InP substrates. AB - Electrical and interfacial properties of metal-oxide-semiconductor (MOS) capacitors fabricated using atomic layer deposited bilayer TiO2/Al2O3 films on In0.53Ga0.47As/InP substrates are reported. Vacuum annealing at 350 degrees C is shown to improve the interface quality. Capacitance-voltage (C-V) characteristics with higher accumulation capacitance, negligible frequency dispersion, small hysteresis and low interface state density (~1.5 * 10(11) cm(-2) eV(-1)) have been observed for MOS capacitors. Low frequency (1/f) noise characterization and inelastic electron tunneling spectroscopy (IETS) studies have been performed to determine defects and interface traps and explain the lattice dynamics and trap state generation mechanisms. Both the IETS and 1/f noise studies reveal the spatial locations of the traps near the interface and also the nature of the traps. The IETS study further revealed the dynamic evolution of trap states related to low frequency noise sources in the deposited TiO2/Al2O3 stacks. It is shown that deposition of an ultrathin layer of TiO2 on Al2O3 can effectively control the diffusion of As in the dielectric and the oxidation states of In and Ga at the In0.53Ga0.47As surface. PMID- 24472091 TI - Clinical outcomes in a cohort of anti-hepatitis C virus-positive patients with significant barriers to treatment referred to a Norwegian outpatient clinic. AB - OBJECTIVE: Patient selection and management of chronic hepatitis C (CHC) in Norwegian outpatient clinics is not well studied. The aim of the study was to characterize CHC patients referred to a large university hospital in Norway, identify treatment barriers, and investigate the course and outcomes of treatment. MATERIAL AND METHODS: In this retrospective observational cohort study, all anti-HCV-positive patients referred to Haukeland University Hospital, Bergen, for treatment evaluation during the period 2007-2010 were included. Demographics, clinical, laboratory, and treatment results were obtained from electronic medical records. RESULTS: A total of 256 patients were included. The patients were young (mean age 36 +/- 10.3), with a high prevalence of genotypes 3 (55%) and 1 (43%) and low levels of fibrosis (77% =50 years of age, and patients with no biopsy. For patients initiating treatment, the total sustained virologic response (SVR) rate was 63% (by complete case analysis 73%). For genotypes 1 and 3, SVR was achieved in 44% and 75%, respectively, by intention to treat. CONCLUSIONS: A high treatment uptake of CHC patients in a cohort with high prevalence of injection drug use was found. Young age, low degrees of fibrosis, and good patient attendance ensured a high rate of SVR. PMID- 24472092 TI - An efficient approach for glomerular filtration rate assessment in older adults. AB - AIMS: Assessment of glomerular filtration rate (GFR) is crucial because the GFR value defines the stage of chronic kidney disease and determines the adjustment of drug dosage. The aim was to investigate a new method for the accurate determination of GFR in older adults based on the combination of an exogenous filtration marker, iohexol, and an endogenous marker, serum creatinine or cystatin C. METHODS: We combined variables for the estimation of GFR with a reduced set of measurements of the marker iohexol. In a population-based sample of 570 subjects (>=70 years old) from the Berlin Initiative Study (BIS), we investigated the following: (i) the BIS1 and BIS2 equations based on age, gender and serum creatinine with or without serum cystatin C; (ii) equations based on one or two iohexol measurements; and (iii) equations based on the combination of variables from BIS1 or BIS2 with iohexol measurements. The reference standard was based on eight iohexol measurements. The cut-off value of 60 ml min(-1) (1.73 m)( 2) was chosen to assess accuracy. Equations were constructed using a learning sample (n = 285) and an independent validation sample (n = 285). RESULTS: Misclassification rates were 17.2% (BIS1), 11.6% (BIS2), 14.7% [iohexol measurement at 240 min (iohexol240 )], 7.0% (iohexol240 combined with variables included in BIS1) and 6.7% (iohexol240 combined with variables included in BIS2). Misclassification rates did not decrease significantly after inclusion of two or three iohexol measurements. CONCLUSIONS: Combined strategies for the determination of GFR lead to a relevant increase of diagnostic validity. PMID- 24472093 TI - Mortality and causes of death among HIV-infected individuals in the country of Georgia: 1989-2012. AB - Since 2004, the country of Georgia has provided antiretroviral therapy (ART) to all patients in need. A nationwide retrospective cohort study was conducted to assess the effect of universal access to ART on patterns of mortality and causes of death among HIV-infected individuals in Georgia. All known HIV-infected adult individuals (age >=18 years) diagnosed from 1989 through 2012 were included. Rates and causes of death were determined using routinely collected data from the national HIV/AIDS database. Causes of death were classified according to the Coding of Death in HIV (CoDe) protocol. Between 1989 and 2012, 3,554 HIV-infected adults were registered in Georgia contributing to 13,572 person-years (PY) of follow-up. A total of 779 deaths were registered during follow-up. The mortality rate peaked in 2004 with 10.74 deaths per 100 PY (95% CI: 7.92-14.24) and significantly decreased after the universal availability of ART to 4.02 per 100 PY (95% CI: 3.28-4.87) in 2012. In multivariate analysis the strongest predictor of mortality was having AIDS at the time of HIV diagnosis (hazard ratio: 5.69, 95% CI: 4.72-6.85). AIDS-related diseases accounted for the majority of deaths (n=426, 54.7%). Tuberculosis (TB) was the leading cause of death accounting for 21% of the total deaths reported. Universal access to ART significantly reduced mortality among HIV-infected patients in Georgia. However, overall mortality rates remain high primarily due to late diagnosis, and TB remains a significant cause of death. Improving rates of early HIV diagnosis and ART initiation may further decrease mortality as well as prevent new HIV and TB infections. PMID- 24472095 TI - Extraction of anthocyanins from black bean canning wastewater with macroporous resins. AB - This study investigated purification of anthocyanins from black bean canning wastewater by column chromatography with 5 types of macroporous resins (Diaion Hp20, Sepabeads Sp70, Sepabeads Sp207, Sepabeads Sp700, and Sepabeads Sp710). By product of canned black beans was partially purified by filtration, in anticipation of higher performance during column chromatography. Equilibrium adsorption isotherms were measured and analyzed using Langmuir and Freundlich isotherm models. Both Langmuir (all R2 >= 0.98) and Freundlich (all R2 >= 0.97) models can describe the adsorption process of anthocyanins from black bean canning wastewater using the tested resins. The adsorption and desorption behaviors of anthocyanins were studied using a dynamic method on the 5 types of resins, and Sp700 presented the highest adsorption capacity (39 +/- 4 mg/g; P < 0.05) as well as desorption capacity (19 +/- 2%; P < 0.05), indicating that of the resins examined, Sp700 is a better candidate for purification of anthocyanins from black bean canning wastewater. PMID- 24472096 TI - Silent information regulator 1 protects the liver against ischemia-reperfusion injury: implications in steatotic liver ischemic preconditioning. AB - Ischemia-reperfusion (IR) injury is an important problem in liver surgery especially when steatosis is present. Ischemic preconditioning (PC) is the only surgical strategy that has been applied in patients with steatotic livers undergoing warm ischemia. Silent information regulator 1 (SIRT1) is a histone deacetylase that regulates various cellular processes. This study evaluates the SIRT1 implication in PC in fatty livers. Homozygous (Ob) Zucker rats were subjected to IR and IR + PC. An additional group treated with sirtinol or EX527 (SIRT1 inhibitors) before PC was also realized. Liver injury and oxidative stress were evaluated. SIRT1 protein levels and activity, as well as other parameters involved in PC protective mechanisms (adenosine monophosphate protein kinase, eNOS, HSP70, MAP kinases, apoptosis), were also measured. We demonstrated that the protective effect of PC was due in part to SIRT1 induction, as SIRT1 inhibition resulted in increased liver injury and abolished the beneficial mechanisms of PC. In this study, we report for the first time that SIRT1 is involved in the protective mechanisms induced by hepatic PC in steatotic livers. PMID- 24472094 TI - CD80+ and CD86+ B cells as biomarkers and possible therapeutic targets in HTLV-1 associated myelopathy/tropical spastic paraparesis and multiple sclerosis. AB - BACKGROUND: Human T-cell lymphotropic virus (HTLV-1) is the causative agent of the incapacitating, neuroinflammatory disease HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Currently, there are no disease-modifying therapies with long-term clinical benefits or validated biomarkers for clinical follow-up in HAM/TSP. Although CD80 and CD86 costimulatory molecules play prominent roles in immune regulation and reflect disease status in multiple sclerosis (MS), data in HAM/TSP are lacking. METHODS: Using flow cytometry, we quantified ex vivo and in vitro expression of CD80 and CD86 in PBMCs of healthy controls, HTLV-1-infected individuals with and without HAM/TSP, and MS patients. We hypothesized ex vivo CD80 and CD86 expressions and their in vitro regulation by interferon (IFN)-alpha/beta mirror similarities between HAM/TSP and MS and hence might reveal clinically useful biomarkers in HAM/TSP. RESULTS: Ex vivo expression of CD80 and CD86 in T and B cells increased in all HTLV-1 infected individuals, but with a selective defect for B cell CD86 upregulation in HAM/TSP. Despite decreased total B cells with increasing disease duration (p = 0.0003, r = -0.72), CD80+ B cells positively correlated with disease severity (p = 0.0017, r = 0.69) in HAM/TSP. B cell CD80 expression was higher in women with HAM/TSP, underscoring that immune markers can reflect the female predominance observed in most autoimmune diseases. In contrast to MS patients, CD80+ (p = 0.0001) and CD86+ (p = 0.0054) lymphocytes expanded upon in vitro culture in HAM/TSP patients. The expansion of CD80+ and CD86+ T cells but not B cells was associated with increased proliferation in HTLV-1 infection. In vitro treatment with IFN-beta but not IFN-alpha resulted in a pronounced increase of B cell CD86 expression in healthy controls, as well as in patients with neuroinflammatory disease (HAM/TSP and MS), similar to in vivo treatment in MS. CONCLUSIONS: We propose two novel biomarkers, ex vivo CD80+ B cells positively correlating to disease severity and CD86+ B cells preferentially induced by IFN beta, which restores defective upregulation in HAM/TSP. This study suggests a role for B cells in HAM/TSP pathogenesis and opens avenues to B cell targeting (with proven clinical benefit in MS) in HAM/TSP but also CD80-directed immunotherapy, unprecedented in both HAM/TSP and MS. PMID- 24472097 TI - Horizontal transfer of transposons between and within crustaceans and insects. AB - BACKGROUND: Horizontal transfer of transposable elements (HTT) is increasingly appreciated as an important source of genome and species evolution in eukaryotes. However, our understanding of HTT dynamics is still poor in eukaryotes because the diversity of species for which whole genome sequences are available is biased and does not reflect the global eukaryote diversity. RESULTS: In this study we characterized two Mariner transposable elements (TEs) in the genome of several terrestrial crustacean isopods, a group of animals particularly underrepresented in genome databases. The two elements have a patchy distribution in the arthropod tree and they are highly similar (>93% over the entire length of the element) to insect TEs (Diptera and Hymenoptera), some of which were previously described in Ceratitis rosa (Crmar2) and Drosophila biarmipes (Mariner-5_Dbi). In addition, phylogenetic analyses and comparisons of TE versus orthologous gene distances at various phylogenetic levels revealed that the taxonomic distribution of the two elements is incompatible with vertical inheritance. CONCLUSIONS: We conclude that the two Mariner TEs each underwent at least three HTT events. Both elements were transferred once between isopod crustaceans and insects and at least once between isopod crustacean species. Crmar2 was also transferred between tephritid and drosophilid flies and Mariner-5 underwent HT between hymenopterans and dipterans. We demonstrate that these various HTTs took place recently (most likely within the last 3 million years), and propose iridoviruses and/or Wolbachia endosymbionts as potential vectors of these transfers. PMID- 24472099 TI - Systematic evaluation of evidence on veterinary viscoelastic testing part 2: Sample acquisition and handling. AB - OBJECTIVE: To examine systematically the evidence on sample acquisition and handling for the thrombo elastography (TEG) and rotational thromboelastometry (ROTEM) viscoelastic point of care instruments and to identify knowledge gaps. DESIGN: Six questions were considered, addressing sampling site, collection system, anticoagulant, collection procedure, and sample storage. Standardized, systematic evaluation of the literature was performed. Relevant articles were categorized according to level of evidence (LOE). Consensus was developed regarding conclusions for application of concepts to clinical practice. SETTING: Academic and referral veterinary medical centers. RESULTS: PubMed and CAB abstracts were searched. Eighteen papers were initially chosen; 5 of these papers applied to > 1 domain question. Three papers were used to address 2 questions each, and 2 papers were used to address 3 questions each. Most papers were judged LOE 3 (Good or Fair). Two of 5 papers were judged to be the same LOE each time they were used; 2 papers were judged to be LOE 3, Fair for 1 question and 3, Good for a second question; 1 paper used to address 3 questions was judged LOE 3, Good twice and 3, Fair once. Fourteen additional papers were evaluated post hoc during manuscript preparation. CONCLUSIONS: Jugular venipuncture is recommended, but samples from IV catheters can be used. Consistent technique is important for serial sampling, and standardized sampling protocols are recommended for individual centers performing TEG/ROTEM. There is insufficient evidence to recommend use of a specific blood collection system, although use of evacuated blood tubes and 21-Ga or larger needles is suggested. Use of 3.2% buffered sodium citrate in a strict 1:9 ratio of citrate to blood is suggested. Suggested tube draw order is discard/serum, followed by citrate, EDTA, and then heparin. Samples should be held at room temperature for 30 minutes prior to analysis. PMID- 24472098 TI - Understanding how we age: insights into inflammaging. AB - Inflammaging is characterized by the upregulation of the inflammatory response that occurs with advancing age; its roots are strongly embedded in evolutionary theory.Inflammaging is believed to be a consequence of a remodelling of the innate and acquired immune system, resulting in chronic inflammatory cytokine production.Complex interrelated genetic, environmental and age-related factors determine an individual's vulnerability or resilience to inflammaging. These factors include polymorphisms to the promoter regions of cytokines, cytokine receptors and antagonists, age-related decreases in autophagy and increased adiposity. Anti-inflammaging describes the upregulation of the hypothalamic pituitary axis in response to inflammaging, leading to higher levels of cortisol, which in turn may be detrimental, contributing to less successful ageing and frailty. This may be countered by the adrenal steroid dehydroepiandrosterone, which itself declines with age, leaving certain individuals more vulnerable. Inflammaging and anti-inflammaging have both been linked with a number of age related outcomes, including chronic morbidity, functional decline and mortality. This important area of research offers unique insights into the ageing process and the potential for screening and targeted interventions. PMID- 24472100 TI - Systematic evaluation of evidence on veterinary viscoelastic testing part 4: Definitions and data reporting. AB - OBJECTIVE: To systematically examine evidence surrounding definitions and reporting of data for viscoelastic testing in veterinary medicine. DESIGN: Standardized, systematic evaluation of the literature, categorization of relevant articles according to level of evidence and quality, and development of consensus on conclusions for application of the concepts to clinical practice. SETTING: Academic and referral veterinary medical centers. RESULTS: Databases searched included Medline, CAB abstracts, and Google Scholar. CONCLUSIONS: All 4 standard thromboelastography (TEG) and rotational thromboelastometry (ROTEM) variables should be universally reported, and the reporting of shear elastic modulus in addition to maximum amplitude (MA) is encouraged. There is insufficient evidence to support universal usage of the coagulation index at this time. The K value and clot formation time are the most variable of the 4 parameters, with alpha angle, MA, and maximum clot firmness generally the least variable. Individual studies should report sufficient data on patients and institutional controls to enable definitions of hypo- and hypercoagulability to be evaluated post-hoc, and it is recommended that all studies specifically report how these conditions were defined. In reporting data relating to fibrinolysis, the TEG variables LY30, LY60, CL30, CL60, and the ROTEM variables LI30, LI60, ML, LOT, and LT should be documented. Studies should report sufficient data on patients and controls to enable definitions of hyper- and hypofibrinolysis to be evaluated post-hoc, and we suggest that standard TEG/ROTEM assays may be unable to detect hypofibrinolysis in companion animals. We recommend that every center establish reference intervals, which are specific to either TEG or ROTEM. These reference intervals should be established using veterinary clinical pathology guidelines, standardized protocols, and a minimum of 40 healthy animals. There are currently insufficient data in companion animals to suggest a utility for Vcurve variables beyond that of standard TEG variables. PMID- 24472108 TI - Peri-operative care of elderly patients - an urgent need for change: a consensus statement to provide guidance for specialist and non-specialist anaesthetists. PMID- 24472109 TI - Technical aspects of botulinum toxin type A injection in the bladder to treat urinary incontinence: reviewing the procedure. AB - AIMS: Standardise the injection technique with botulinum toxin type A (BoNT A) in the bladder of patients with overactive bladder (OAB) [idiopathic overactive bladder (iOAB) or neurogenic overactive bladder (nOAB) with urinary incontinence], using a literature review and a survey of an International expert panel. METHODS: PubMed literature searches of BoNT A in adults with iOAB/nOAB together with a survey of 13 experts from 10 countries. RESULTS: Data from 21 articles and completed questionnaires were collated. The procedure can be carried out in an out-/inpatient setting. Dose used in clinical studies vs. clinical practice was 300 and 200 U for nOAB and 200 and 100 U for iOAB. Recent studies have also demonstrated that there are no clinically relevant benefits between 100 and 150 U in iOAB or between 300 and 200 U in nOAB, though adverse effects are increased with higher doses. Usually, 30 sites for nOAB (range: 6.7-10 U/ml) and 20-30 sites for iOAB (range: 5-10 U/ml) are injected in clinical studies vs. 20 30 sites of 1 ml/injection for 200 U in nOAB and 10-20 sites of 0.5-1 ml/injection for 100 U in iOAB in clinical practice. BoNT A is usually injected directly into the detrusor, sparing the trigone. Flexible or rigid cystoscopes are used. The needle should be typically 22-27 gauge and 4 mm in length and should have a stopper to avoid any leakage or perforation of the bladder wall while ensuring a targeted injection. CONCLUSION: Based on the literature and survey analysis, recommendations are proposed for the standardisation of the injection procedure. PMID- 24472110 TI - A case of tracheal adenoid cystic carcinoma in a worker exposed to rubber fumes. AB - BACKGROUND: Primary tracheal tumors occur infrequently, accounting for less than 0.1% of all tumors. Adenoid cystic carcinoma (ACC) is the second most common type of malignancy of the trachea after squamous cell carcinoma (SCC). Little has been reported on the risk factors for tracheal ACC. The purpose of this study is to describe a case of tracheal ACC in a patient who had been exposed to rubber fumes, and to review the relationship between tracheal ACC and rubber fumes. CASE REPORT: A 48-year-old man who had been experiencing aggravation of dyspnea for several months was diagnosed as having ACC of the trachea on the basis of a pathologic examination of a biopsy specimen obtained via laser microscopy-guided resection. The patient had been exposed to rubber fumes for 10 years at a tire manufacturing factory where he worked until ACC was diagnosed. His job involved preheating and changing rubber molds during the curing process. CONCLUSION: ACC of both the trachea and the salivary glands show very similar patterns with regard to histopathology and epidemiology and are therefore assumed to have a common etiology. Rubber manufacturing is an occupational risk factor for the development of salivary gland tumors. Further, rubber fumes have been reported to be mutagenic. The exposure level to rubber fumes during the curing process at the patient's workplace was estimated to be close to or higher than British Occupational Exposure Limits. Therefore, tracheal ACC in this case might have been influenced by occupational exposure to rubber fumes. PMID- 24472112 TI - The effectiveness of substitution of hospital ward care from medical doctors to physician assistants: a study protocol. AB - BACKGROUND: Because of an expected shrinking supply of medical doctors for hospitalist posts, an increased emphasis on efficiency and continuity of care, and the standardization of many medical procedures, the role of hospitalist is increasingly allocated to physician assistants (PAs). PAs are nonphysician clinicians with medical tasks. This study aims to evaluate the effects of substitution of hospital ward care to PAs. METHODS/DESIGN: In a multicenter matched controlled study, the traditional model in which the role of hospitalist is taken solely by medical doctors (MD model) is compared with a mixed model in which a PA functions as a hospitalist, contingent with MDs (PA/MD model). Twenty intervention and twenty control wards are included across The Netherlands, from a range of medical specialisms. Primary outcome measure is patients' length of hospital stay. Secondary outcomes include indicators for quality of hospital ward care, patients experiences with medical ward care, patients health-related quality of life, and healthcare providers' experiences. An economic evaluation is conducted to assess the cost implications and potential efficiency of the PA/MD model. For most measures, data is collected from medical records or questionnaires in samples of 115 patients per hospital ward. Semi-structured interviews with healthcare professionals are conducted to identify determinants of efficiency, quality and continuity of care and barriers and facilitators for the implementation of PAs in the role of hospitalist. DISCUSSION: Findings from this study will help to further define the role of nonphysician clinicians and provides possible key components for the implementation of PAs in hospital ward care. Like in many studies of organizational change, random allocation to study arms is not feasible, which implies an increased risk for confounding. A major challenge is to deal with the heterogeneity of patients and hospital departments. PMID- 24472113 TI - Association between Workplace Risk Factor Exposure and Sleep Disturbance: Analysis of the 2nd Korean Working Conditions Survey. AB - OBJECTIVES: Sleep is essential for human beings to live and work properly. This study was conducted to investigate the relationship between occupational exposures to workplace risk factors and sleep disturbance in Korean workers. METHODS: The data were drawn from the second Korean Working Conditions Survey (KWCS); a total of 7,112 paid workers were analyzed. The independent variables were occupational exposures such as physical, chemical, biological, and psychosocial risk factor in the workplace, and psychosocial risk factor was divided into five categories (job demand, job control, social support, job insecurity, lack of reward). We estimated the relationship between various occupational exposures and sleep disturbance using multivariate logistic regression analysis. RESULTS: The results showed that people who exposed to physical, chemical, biological, and psychosocial (high job demand, inadequate social support, lack of reward) risk factors were more likely to increase the risk of sleep disturbance. Furthermore, after adjusting for general and occupational characteristics, we found significant positive associations between exposures to physical (odds ratios [OR] 1.47, 95% confidence interval [CI] 1.05 2.07) and psychosocial (high job demand (OR 2.93, 95% CI 2.16-3.98), inadequate social support (OR 1.57, 95% CI 1.14-2.15), lack of reward (OR 1.45, 95% CI 1.08 1.96)) risk factors and sleep disturbance. CONCLUSION: These results suggest that occupational exposures to physical and psychosocial workplace risk factors are significantly related to sleep disturbance. PMID- 24472114 TI - A national strategy to develop pragmatic clinical trials infrastructure. AB - An important challenge in comparative effectiveness research is the lack of infrastructure to support pragmatic clinical trials, which compare interventions in usual practice settings and subjects. These trials present challenges that differ from those of classical efficacy trials, which are conducted under ideal circumstances, in patients selected for their suitability, and with highly controlled protocols. In 2012, we launched a 1-year learning network to identify high-priority pragmatic clinical trials and to deploy research infrastructure through the NIH Clinical and Translational Science Awards Consortium that could be used to launch and sustain them. The network and infrastructure were initiated as a learning ground and shared resource for investigators and communities interested in developing pragmatic clinical trials. We followed a three-stage process of developing the network, prioritizing proposed trials, and implementing learning exercises that culminated in a 1-day network meeting at the end of the year. The year-long project resulted in five recommendations related to developing the network, enhancing community engagement, addressing regulatory challenges, advancing information technology, and developing research methods. The recommendations can be implemented within 24 months and are designed to lead toward a sustained national infrastructure for pragmatic trials. PMID- 24472115 TI - A population-based study of the incidence of delusional infestation in Olmsted County, Minnesota, 1976-2010. AB - BACKGROUND: Delusional infestation (DI) is a well-recognized clinical entity but there is a paucity of reliable data concerning its epidemiology. Knowledge of the epidemiology is fundamental to an understanding of any disease and its implications. Epidemiology is most accurately assessed using population-based studies, which are most generalizable to the wider population in the U.S. and worldwide. To our knowledge, no population-based study of the epidemiology (particularly incidence) of DI has been reported to date. OBJECTIVES: To determine the incidence of delusional infestation (DI) using a population-based study. METHODS: Medical records of Olmsted County residents were reviewed using the resources of the Rochester Epidemiology Project to confirm the patient's status as a true incident case of DI and to gather demographic information. Patients with a first-time diagnosis of DI or synonymous conditions between 1 January 1976 and 31 December 2010 were considered incident cases. RESULTS: Of 470 identified possible diagnoses, 64 were true incident cases of DI in this population-based study. The age- and sex-adjusted incidence was 1.9 [95% confidence interval (CI) 1.5-2.4] per 100 000 person-years. Mean age at diagnosis was 61.4 years (range 9-92 years). The incidence of DI increased over the four decades from 1.6 (95% CI 0.6-2.6) per 100 000 person-years in 1976-1985 to 2.6 (95% CI 1.4-3.8) per 100 000 person-years in 2006-2010. CONCLUSIONS: Our data indicate that DI is a rare disease, with incidence increasing across the life span, especially after the age of 40 years. PMID- 24472116 TI - The Escherichia coli uropathogenic-specific-protein-associated immunity protein 3 (Imu3) has nucleic acid -binding activity. AB - BACKGROUND: The Escherichia coli uropathogenic-specific protein (Usp) is a bacteriocin-like genotoxin, active against mammalian cells and associated with E. coli strains that provoke pyelonephritis, prostatitis and bacteraemia. Usp is encoded by a small pathogenicity island with three downstream small open reading frames (Imu1-3) that are believed to provide immunity to the producer. To prevent host suicide, colicins, bacteriocins of E. coli, form tight complexes with their cognate immunity proteins. Colicin - immunity protein complexes are among the strongest protein complexes known. Here, the Usp associated immunity protein 3 (Imu3) was partially characterized to gain insight into its role and mechanism of activity. RESULTS: Isolation and partial characterisation of the Usp-associated immunity protein-3 (Imu3) revealed that, while Usp and Imu3 do not form a high affinity complex, Imu3 exhibits DNA and RNA binding activity. Imu3 was also shown to protect DNA against degradation by colicin E7. CONCLUSIONS: Our data infer that nonspecific DNA binding of the Imu3 immunity protein, prevents suicide of E. coli producing the genotoxin Usp. PMID- 24472117 TI - The SFT-1 and OXA-1 respiratory chain complex assembly factors influence lifespan by distinct mechanisms in C. elegans. AB - BACKGROUND: C. elegans mitochondrial (Mit) mutants have disrupted mitochondrial electron transport chain function, yet, surprisingly, they are often long-lived, a property that has offered unique insights into the molecular mechanisms of aging. In this study, we examine the phenotypic consequences of reducing the expression of the respiratory chain complex assembly factors sft-1 (homologous to human SURF1) and oxa-1 (homologous to human OXA1) by RNA interference (RNAi). Mutations in human SURF1 are associated with Leigh syndrome, a neurodegenerative condition of the brain caused by cytochrome oxidase (COX) deficiency. Both SURF1 and OXA1 are integral proteins of the inner mitochondrial membrane, functioning in the COX assembly pathway. RESULTS: RNAi of both of these genes in C. elegans is associated with increased longevity, but the mechanism by which lifespan is extended is different in each case. sft-1(RNAi) animals display lifespan extension that is dependent on the daf-16 insulin-like signaling pathway, and associated with sensitivity to oxidative stress. oxa-1(RNAi) animals, in contrast, exhibit increased longevity that is at least partially independent of daf-16, and associated with a reduced developmental rate and increased resistance to oxidative stress. CONCLUSIONS: This study further delineates the consequences of mitochondrial dysfunction within a whole organism that will ultimately help provide new models for human mitochondrial-associated diseases. The difference in phenotype observed upon down-regulation of these two COX assembly factors, as well as phenotypic differences between these factors and other respiratory chain components analyzed thus far, illustrates the complex inter-relationships that exist among energy metabolism, reproduction and aging even in this simplest of metazoan model organisms. PMID- 24472120 TI - The long-term cost-effectiveness of varenicline (12-week standard course and 12 + 12-week extended course) vs. other smoking cessation strategies in Canada. AB - BACKGROUND: Smoking is the leading risk factor for preventable morbidity and mortality as a result of heart and lung diseases and various forms of cancer. Reimbursement coverage for smoking cessation therapies remains limited in Canada and the United States despite the health and economic benefits of smoking cessation. OBJECTIVES: This study aimed to evaluate the long-term cost effectiveness of varenicline compared with other smoking cessation interventions in Canada using the Benefits of Smoking Cessation on Outcomes (BENESCO) model. METHODS: Efficacy rates of the standard course (12 weeks) varenicline, extended course (12 + 12 weeks) varenicline, bupropion, nicotine replacement therapy and unaided intervention were derived based on a published mixed treatment comparison methodology and analysed within a Markov cohort model to estimate their cost effectiveness over the lifetime cycle. Study cohort, smoking rates and prevalence, incidence and mortality of smoking-related diseases were calibrated to represent the Canadian population. RESULTS: Over the subjects' lifetime, both the standard and the extended course of varenicline are shown to dominate (e.g. less costly and more effective) all other alternative smoking cessation interventions considered. Compared with the standard varenicline treatment course, the extended course is highly cost-effective with an incremental cost effectiveness ratio (ICER) less than $4000 per quality-adjusted life year. Including indirect cost and benefits of smoking cessation interventions further strengthens the result with the extended course of varenicline dominating all other alternatives considered. LIMITATIONS: Evidence from complex smoking cessation models requiring numerous inputs and assumptions should be assessed in conjunction with evidence from other methodologies. CONCLUSIONS: The standard and extended courses of varenicline are decidedly cost-effective treatment regimes compared with alternative smoking cessation interventions and can provide significant cost savings to the healthcare system. PMID- 24472118 TI - Trans-activation, post-transcriptional maturation, and induction of antibodies to HERV-K (HML-2) envelope transmembrane protein in HIV-1 infection. AB - BACKGROUND: Human Endogenous Retroviruses (HERVs) comprise about 8% of the human genome and have lost their ability to replicate or to produce infectious particles after having accumulated mutations over time. We assessed the kinetics of expression of HERV-K (HML-2) Envelope mRNA transcript and surface unit (SU) and transmembrane (TM) subunit proteins during HIV-1 infection. We also mapped the specificity of the humoral response to HERV-K (HML-2) Envelope protein in HIV 1 infected subjects at different stages of disease, and correlated the response with plasma viral load. RESULTS: We found that HIV-1 modified HERV-K (HML-2) Env mRNA expression, resulting in the expression of a fully N-glycosylated HERV-K (HML-2) envelope protein on the cell surface. Serological mapping of HERV-K (HML 2) envelope protein linear epitopes revealed two major immunogenic domains, one on SU and another on the ectodomain of TM. The titers of HERV-K (HML-2) TM antibodies were dramatically increased in HIV-1 infected subjects (p < 0.0001). HIV-1 infected adults who control HIV-1 in the absence of therapy ("elite" controllers) had a higher titer response against TM compared to antiretroviral treated adults (p < 0.0001) and uninfected adults (p < 0.0001). CONCLUSIONS: These data collectively suggest that HIV-1 infection induces fully glycosylated HERV-K (HML-2) envelope TM protein to which antibodies are induced. These anti HERV-K (HML-2) TM antibodies are a potential marker of HIV-1 infection, and are at higher titer in elite controllers. HERV-K (HML-2) envelope TM protein may be a new therapeutic target in HIV-1 infection. PMID- 24472121 TI - Observational study of the effects of age, diabetes mellitus, cirrhosis and chronic kidney disease on sublingual microvascular flow. AB - BACKGROUND: Sidestream dark field (SDF) imaging has been used to demonstrate microcirculatory abnormalities in a variety of critical illnesses. The microcirculation is also affected by advancing age and chronic comorbidities. However, the effect of these conditions on SDF microcirculatory parameters has not been well described. METHODS: SDF images were obtained from five groups of 20 participants: healthy volunteers under the age of 25, healthy volunteers over the age of 55, and clinic patients over the age of 55 with one of diabetes mellitus, cirrhosis and stage 5 chronic kidney disease. Microcirculatory parameters between the groups were then compared for significance using analysis of variance for parametric and the Kruskal-Wallis test for non-parametric data. RESULTS: Median microvascular flow index was 2.85 (interquartile range 2.75 to 3.0) for participants aged <25, 2.81 (2.66 to 2.97) for those aged >55, 2.88 (2.75 to 3.0) for those with diabetes mellitus, 3.0 (2.83 to 3.0) for those with cirrhosis and 3.0 (2.78 to 3.0) for those with chronic kidney disease (P for difference between groups = 0.14). Similarly, there were no significant differences in the proportion of perfused vessels and perfused vessel density between the groups. CONCLUSIONS: Older age, diabetes, and chronic kidney and liver disease need not be considered confounding factors for comparison of SDF microcirculatory parameters in the critically ill. PMID- 24472122 TI - The cost of a primary care-based childhood obesity prevention intervention. AB - BACKGROUND: United States pediatric guidelines recommend that childhood obesity counseling be conducted in the primary care setting. Primary care-based interventions can be effective in improving health behaviors, but also costly. The purpose of this study was to evaluate the cost of a primary care-based obesity prevention intervention targeting children between the ages of two and six years who are at elevated risk for obesity, measured against usual care. METHODS: High Five for Kids was a cluster-randomized controlled clinical trial that aimed to modify children's nutrition and TV viewing habits through a motivational interviewing intervention. We assessed visit-related costs from a societal perspective, including provider-incurred direct medical costs, provider incurred equipment costs, parent time costs and parent out-of-pocket costs, in 2011 dollars for the intervention (n = 253) and usual care (n =192) groups. We conducted a net cost analysis using both societal and health plan costing perspectives and conducted one-way sensitivity and uncertainty analyses on results. RESULTS: The total costs for the intervention group and usual care groups in the first year of the intervention were $65,643 (95% CI [$64,522, $66,842]) and $12,192 (95% CI [$11,393, $13,174]). The mean costs for the intervention and usual care groups were $259 (95% CI [$255, $264]) and $63 (95% CI [$59, $69]) per child, respectively, for a incremental difference of $196 (95% CI [$191, $202]) per child. Children in the intervention group attended a mean of 2.4 of a possible 4 in-person visits and received 0.45 of a possible 2 counseling phone calls. Provider-incurred costs were the primary driver of cost estimates in sensitivity analyses. CONCLUSIONS: High Five for Kids was a resource-intensive intervention. Further studies are needed to assess the cost-effectiveness of the intervention relative to other pediatric obesity interventions. PMID- 24472123 TI - Methods for genomic evaluation of a relatively small genotyped dairy population and effect of genotyped cow information in multiparity analyses. AB - Methods for genomic prediction were evaluated for an Israeli Holstein dairy population of 713,686 cows and 1,305 progeny-tested bulls with genotypes. Inclusion of genotypes of 343 elite cows in an evaluation method that considers pedigree, phenotypes, and genotypes simultaneously was also evaluated. Two data sets were available: a complete data set with production records from 1985 through 2011, and a reduced data set with records after 2006 deleted. For each production trait, a multitrait animal model was used to compute traditional genetic evaluations for parities 1 through 3 as separate traits. Evaluations were calculated for the reduced and complete data sets. The evaluations from the reduced data set were used to calculate parent average for validation bulls, which was the benchmark for comparing gain in predictive ability from genomics. Genomic predictions for bulls in 2006 were calculated using a Bayesian regression method (BayesC), genomic BLUP (GBLUP), single-step GBLUP (ssGBLUP), and weighted ssGBLUP (WssGBLUP). Predictions using BayesC and GBLUP were calculated either with or without an index that included parent average. Genomic predictions that included elite cow genotypes were calculated using ssGBLUP and WssGBLUP. Predictive ability was assessed by coefficients of determination (R(2)) and regressions of predictions of 135 validation bulls with no daughters in 2006 on deregressed evaluations of those bulls in 2011. A reduction in R(2) and regression coefficients was observed from parities 1 through 3. Fat and protein yields had the lowest R(2) for all the methods. On average, R(2) was lowest for parent averages, followed by GBLUP, BayesC, ssGBLUP, and WssGBLUP. For some traits, R(2) for direct genomic values from BayesC and GBLUP were lower than those for parent averages. Genomic estimated breeding values using ssGBLUP were the least biased, and this method appears to be a suitable tool for genomic evaluation of a small genotyped population, as it automatically accounts for parental index, allows for inclusion of female genomic information without preadjustments in evaluations, and uses the same model as in traditional evaluations. Weighted ssGBLUP has the potential for higher evaluation accuracy. PMID- 24472124 TI - Growth, carcass characteristics, and profitability of organic versus conventional dairy beef steers. AB - Bull calves (n=49), born at the University of Minnesota West Central Research and Outreach Center (Morris) between March and May 2011, were used to compare growth measurements and profitability of conventional and organic dairy steers. Calves were assigned to 1 of 3 replicated groups at birth: conventional (CONV; n=16), organic (pasture and concentrate; ORG; n=16), or organic grass only (GRS; n=17), and analysis of variables was on a pen basis. Breed groups of calves were Holstein (HO; n=9); Holsteins (n=11) maintained at 1964 breed average level; crossbreds (n=19) including combinations of HO, Montbeliarde, and Swedish Red; and crossbreds (n=10) including combinations of HO, Jersey, Swedish Red, and Normande. The CONV steers were fed a diet of 80% concentrate and 20% forage. The ORG steers were fed a diet of organic corn, organic corn silage, and at least 30% of their diet consisted of organic pasture during the grazing season. The GRS steers grazed pasture during the grazing season and were fed high-quality hay or hay silage during the nongrazing season. Intakes of a total mixed ration were recorded daily with herd management software. A profit function was defined to include revenues and expenses for beef value, feed intake, pasture intake, health cost, and yardage. The GRS (358.6 kg) steers had lesser total gains from birth to slaughter than ORG (429.6 kg) and CONV (534.5 kg) steers. Furthermore, the GRS (0.61 kg/d) steers had lesser average daily gain from birth compared with ORG (0.81 kg/d) and CONV (1.1 kg/d) steers. The GRS and ORG steers had smaller rib eye area (49.5 and 65.8 cm(2), respectively) compared with CONV (75.4 cm(2)) steers. For profitability, GRS steers had 43% greater profit than CONV steers due to organic beef price premiums and lower feed costs. On the other hand, ORG steers had substantially less profit than CONV steers. The higher cost of production for the ORG steers is due to the extreme high value of organic corn. The results of the current study illustrate the economic potential of alternative strategies for growing and marketing male offspring of organic dairy cattle in the Midwest. PMID- 24472125 TI - Evaluation of equations predicting the net portal appearance of amino acid nitrogen in ruminants. AB - A better assessment of digestible protein and AA flows is required to improve the predictions of animal performance in ruminants (e.g., growth and yields of milk and milk protein). In that respect, 2 recent meta-analyses were conducted in our laboratory to establish the relationships between net portal appearance of AA nitrogen (NPA-AAN) and dietary characteristics either from the National Research Council (Washington, DC) or Institut National de la Recherche Agronomique (INRA; St Genes Champanelle, France). Three prediction equations were selected from these meta-analyses: one equation based only on N intake (NI) and 2 equations based on NI, the intake of neutral detergent fiber, plus the dietary concentration of either total digestible nutrients or digestible organic matter. In the current meta-analysis, 2 new equations were developed to predict NPA-AAN from the estimated supply of metabolizable protein (MP) and the protein truly digestible in the intestine (PDI). The reliability of these 5 equations to predict NPA-AAN was evaluated using an independent database. On average, NPA-AAN predictions based on the supply of MP or PDI had the highest coefficient of determination and the lowest root of mean square prediction error and mean and regression biases compared with predictions based on dietary characteristics, suggesting better reliability with the former. No major difference was detected between NPA-AAN predictions based on parameters from the National Research Council or INRA, except that predictions based on MP had the lowest mean and regression biases. In each equation, mean of residual NPA-AAN (observed NPA-AAN minus predicted values) was lowest and negative for sheep compared with dairy cows, suggesting that NPA-AAN were overpredicted in sheep. Many continuous variables biased NPA-AAN predictions based on NI only, but none of the tested variables biased the predictions based on the supply of MP or PDI, corroborating the better reliability for the prediction equations based on the supply of digestible protein. Of the tested continuous variables, only the dietary concentration of crude protein (CP) biased NPA-AAN predictions based on NI plus dietary characteristics. The NPA-AAN responses to dietary CP concentration were overpredicted as dietary CP concentration increased and underpredicted as CP decreased, suggesting that ruminants were more efficient at converting ingested N into digestible protein when fed low-CP diets compared with high-CP diets. PMID- 24472126 TI - Fatty acid profiles, meat quality, and sensory attributes of organic versus conventional dairy beef steers. AB - Meat from Holstein and crossbred organic and conventional dairy steers were evaluated and compared for fatty acid profiles, meat quality, sensory attributes, and consumer acceptance. Bull calves (n=49) were randomly assigned to 1 of 3 replicated groups: conventional (CONV), organic (ORG, pasture + concentrate), or grass-fed organic (GRS) and were born at the University of Minnesota West Central Research and Outreach Center (Morris, MN) between March and May 2011. The CONV steers (n=16) were fed a diet that contained 80% concentrate and 20% forage, and ORG steers (n=16) were fed a diet of organic corn, organic corn silage, and organic protein supplement. Furthermore, ORG steers consumed at least 30% of diet dry matter of high-quality organic pasture during the grazing season. The GRS steers (n=17) consumed 100% forage from pasture during the grazing season and high-quality hay or hay silage during the nongrazing season. The ORG steers had fat that was greater in oleic acid (C18:1) than the GRS and CONV steers (47.1, 36.1, and 39.9%, respectively). The GRS steers (21.9%) were lower for monounsaturated fat than the ORG (42.1%) and CONV (40.4%) steers. Furthermore, the GRS steers tended to have greater n-3 fat and had lower n-6 fat than the ORG and CONV steers. Consequently, the GRS (1.4%) steers had a lower n-6-to-n-3 fat ratio than the ORG (12.9%) and CONV (10.0%) steers. The GRS (2.6 kg) steers had steaks that were not different for Warner-Bratzler shear force than ORG (2.3 kg) steaks; however, the GRS steaks tended to have greater shear force than the CONV (2.0 kg) steaks. The 3 steer group had steaks that were not different for color brightness (L*; 0 = black and 100 = white) and yellowness/blueness (b*; positive values = yellow and negative values = blue) values; however, the GRS (10.5) steaks had lower redness/greenness (a*; positive values = red and negative values = green) values than CONV (14.5) steaks. For sensory attributes (0- to 120-point scale), no differences were observed for ORG (71.3) and CONV (69.2) steers for overall consumer liking of the beef; however, the GRS (56.3) steers had the lowest overall liking among beef consumers. The ORG (73.3) steers had greater flavor liking than the GRS (56.8) and CONV (69.2) steers. Conversely, the GRS (6.3) steers had the highest scores for off-flavor (0- to 20-point scale) compared with the ORG (3.9) and CONV (4.1) steers. The results of the current study suggest that a potential market may exist for organic grass-fed dairy steers in the United States, but quality and consistency of the beef needs to be improved. PMID- 24472127 TI - Residual feed intake of lactating Holstein-Friesian cows predicted from high density genotypes and phenotyping of growing heifers. AB - A genomic prediction for residual feed intake (RFI) developed in growing dairy heifers (RFIgro) was used to predict and test breeding values for RFI in lactating cows (RFIlac) from an independent, industry population. A selection of 3,359 cows, in their third or fourth lactation during the study, of above average genetic merit for milk production, and identified as at least 15/16ths Holstein Friesian breed, were selected for genotyping from commercial dairy herds. Genotyping was carried out using the bovine SNP50 BeadChip (Illumina Inc., San Diego, CA) on DNA extracted from ear-punch tissue. After quality control criteria were applied, genotypes were imputed to the 624,930 single nucleotide polymorphisms used in the growth study. Using these data, genomically estimated breeding values (GEBV) for RFIgro were calculated in the selected cow population based on a genomic prediction for RFIgro estimated in an independent group of growing heifers. Cows were ranked by GEBV and the top and bottom 310 identified for possible purchase. Purchased cows (n=214) were relocated to research facilities and intake and body weight (BW) measurements were undertaken in 99 "high" and 98 "low" RFIgro animals in 4 consecutive groups [beginning at d 61 +/- 1.0 standard error (SE), 91 +/- 0.5 SE, 145 +/- 1.3 SE, and 191 +/- 1.5 SE d in milk, respectively] to measure RFI during lactation (RFIlac). Each group of ~50 cows (~25 high and ~25 low RFIgro) was in a feed intake facility for 35 d, fed pasture-alfalfa cubes ad libitum, milked twice daily, and weighed every 2 to 3 d. Milk composition was determined 3 times weekly. Body weight change and BW at trial mid-point were estimated by regression of pre- and posttrial BW measurements. Residual feed intake in lactating cows was estimated from a linear model including BW, BW change, and milk component yield (as MJ/d); RFIlac differed consistently between the high and low selection classes, with the overall means for RFIlac being +0.32 and -0.31 kg of dry matter (DM) per day for the high and low classes, respectively. Further, we found evidence of sire differences for RFIlac, with one sire, in particular, being highly represented in the low RFIgro class, having a mean RFIlac of -0.83 kg of DM per day in 47 daughters. In conclusion, genomic prediction of RFIgro based on RFI measured during growth will discriminate for RFIlac in an independent group of lactating cows. PMID- 24472128 TI - Associations between farmer participation in veterinary herd health management programs and farm performance. AB - In the past few decades, farms have increased in size and the focus of management has changed from curative to preventive. To help farmers cope with these changes, veterinarians offer veterinary herd health management (VHHM) programs, whose major objective is to support the farmer in reaching his farm performance goals. The association between farm performance and participation in VHHM, however, remains unknown. The aim of this paper was to compare farm performance parameters between participants and nonparticipants in VHHM and to differentiate within participation to evaluate the possible added value of VHHM on the farm. Five thousand farmers received a questionnaire about the level of VHHM on their farm. Farm performance parameters of these 5,000 farms were provided. For all respondents (n=1,013), farm performance was compared between participants and nonparticipants and within level of participation, using linear mixed and linear regression models. Farmers who participated in VHHM produced 336 kg of milk/cow per year more and their average milk somatic cell count (SCC) was 8,340 cells/mL lower than farmers who did not participate in VHHM. Participating herds, however, had an older age at first calving (+12d), a lower 56-d nonreturn rate percentage (-3.34%), and a higher number of inseminations per cow (+0.09 inseminations). They also had more cows culled per year (+1.05%), and a lower age at culling (-70 d). Participants in the most-extended form of VHHM (level 3) had a lower SCC ( 19,800 cells/mL), fewer cows with high SCC (-1.70%), fewer cows with new high SCC (-0.47%), a shorter calving interval (-6.01 d), and fewer inseminations per heifer (-0.07 inseminations) than participants in the least-extended form of VHHM (level 1). Level 3 participants, however, also had more cows culled per year (+1.74%) and a lower age at culling (-103 d). Discussing specific topics with the veterinarian (milk production, fertility, and udder health) had only marginal effects on improving the farm performance parameters related to those topics. Given the relevance of fertility on the farm and the focus on longevity by society, it is important to determine underlying reasons for the negative associations of these topics with participation in VHHM. A longitudinal study could provide answers to this. For now, veterinarians should be aware of the associations. The increased milk production and milk quality could help the marketing of VHHM to farmers. PMID- 24472129 TI - Genetic determination of mortality rate in Danish dairy cows: A multivariate competing risk analysis based on the number of survived lactations. AB - Dairy cow mortality has been steadily increasing during the last 2 decades in Denmark. This study aims to verify whether genetic mechanisms might be contributing to this increase. To do so, the records of 880,480 Holstein, 142,306 Jersey, and 85,206 Red Danish dairy cows calving from 1990 to 2006 were retrieved from the Danish Cattle register. Two causes of culling of cows were considered: death and slaughtering. Bivariate competing risk genetic models with a sire model structure were used to describe the death and the slaughtering rates simultaneously. The models included 2 random components: a sire random component with pedigree representing the sire genetic effects and a herd-year-season component. Moreover, the level of heterozygosity and the sire breed proportions were included in the models as covariates to account for potential nonadditive genetic effects due to the massive introduction of genetic material from other populations. The correlations between the sire components for death rate and slaughter rate were negative and small for the 3 populations, suggesting the existence of specific genetic mechanisms for each culling reason and common concurrent genetic mechanisms. In the Holstein population, the effects of the changes in the level of heterozygosity, breed composition, and the increasing genetic trend acted in the same direction, increasing the death rate in recent years. In the Jersey population, the effects of the level of heterozygosity and the breed proportion were small, and only the increasing genetic trend can be pointed as a genetic cause to the observed increase in the mortality rate. In the Red Danish population, neither the time-development pattern of the genetic trend nor the changes in the level of heterozygosity and breed composition could be causing the observed increase in the mortality; thus, nongenetic factors must be causing this negative development. PMID- 24472130 TI - Short communication: circulating and milk adiponectin change differently during energy deficiency at different stages of lactation in dairy cows. AB - Adiponectin, one of the most abundant adipokines in circulation, is known for its role in regulation of body metabolism. The aim of this study was to evaluate the effects of a negative energy balance (NEB) at 2 stages of lactation (lactational NEB at the onset of lactation and an induced NEB by feed restriction near 100 d of lactation) on circulating adiponectin concentrations. We also investigated the effect of feed restriction on adiponectin concentrations in milk and the relationships of blood and milk adiponectin with selected plasma or milk variables and with measures of body condition. Plasma adiponectin was measured in 50 multiparous Holstein dairy cows throughout 3 experimental periods [i.e., period 1=3 wk antepartum up to 12 wk postpartum, period 2=3 wk of feed restriction starting at around 100 d in milk with a control (n=25) and feed restricted group (50% of energy requirements; n=25), and period 3=subsequent realimentation period for 8 wk]. Milk adiponectin was investigated among 21 multiparous cows at wk 2 and wk 12 of period 1 and wk 2 of period 2. Adiponectin concentrations in plasma and skim milk were measured using an in-house ELISA specific for bovine adiponectin. Major changes in circulating adiponectin concentrations were observed during the periparturient period, whereas energy deficiency during established lactation at around 100 d in milk and subsequent refeeding did not affect plasma adiponectin. Together with lower adiponectin concentrations in milk (ug/mL), the reduction in milk yield led to decreased adiponectin secretion via milk (mg/d) at the second week of feed restriction. Irrespective of time and treatment, milk adiponectin represented about 0.002% of total milk protein. Mean adiponectin concentrations in milk (0.61 +/- 0.03 ug/mL) were about 92% lower than the mean plasma adiponectin concentrations (32.1 +/- 1.0 ug/mL). The proportion of the steady-state plasma adiponectin pool secreted daily via milk was 2.7%. In view of the similar extent of NEB in both periods of energy deficiency, decreasing adiponectin concentrations seems important for accomplishing the adaptation to the rapidly increasing metabolic rates in early lactation, whereas the lipolytic reaction toward feed restriction-induced NEB during established lactation seems to occur largely independent of changes in circulating adiponectin. PMID- 24472131 TI - Amino acid enrichment and compositional changes among mammalian milk proteins and the resulting nutritional consequences. AB - Milk is a hallmark of mammalian evolution: a unique food that has evolved with mammals. Despite the importance of this food, it is not known if variation in AA composition between different species is important to milk proteins or how it might affect the nutritional value of milk. As milk is the only food source for newborn mammals, it has long been speculated that milk proteins should be enriched in essential AA. However, no systematic analysis supports this assumption. Although many factors influence the overall nutritional value of milk, including total protein concentration, we focused here on the AA composition of milk proteins and investigated the possibility that selection drives compositional changes. We identified 9 major milk proteins present in 13 mammalian species and compared them with a large group of nonmilk proteins. Our results indicate heterogeneity in the AA composition of milk proteins, showing significant enrichment and depletion of certain AA in milk-specific proteins. Although high levels of particular AA appear to be consistently maintained, orthologous milk proteins display significant differences in AA composition across species, most notably among the caseins. Interspecies variation of milk composition is thought to be indicative of nutritional optimization to the requirements of the species. In accordance with this, our observations indicate that milk proteins may have adapted to the species-specific nutritional needs of the neonate. PMID- 24472132 TI - Imputation of genotypes from low density (50,000 markers) to high density (700,000 markers) of cows from research herds in Europe, North America, and Australasia using 2 reference populations. AB - Combining data from research herds may be advantageous, especially for difficult or expensive-to-measure traits (such as dry matter intake). Cows in research herds are often genotyped using low-density single nucleotide polymorphism (SNP) panels. However, the precision of quantitative trait loci detection in genome wide association studies and the accuracy of genomic selection may increase when the low-density genotypes are imputed to higher density. Genotype data were available from 10 research herds: 5 from Europe [Denmark, Germany, Ireland, the Netherlands, and the United Kingdom (UK)], 2 from Australasia (Australia and New Zealand), and 3 from North America (Canada and the United States). Heifers from the Australian and New Zealand research herds were already genotyped at high density (approximately 700,000 SNP). The remaining genotypes were imputed from around 50,000 SNP to 700,000 using 2 reference populations. Although it was not possible to use a combined reference population, which would probably result in the highest accuracies of imputation, differences arising from using 2 high density reference populations on imputing 50,000-marker genotypes of 583 animals (from the UK) were quantified. The European genotypes (n=4,097) were imputed as 1 data set, using a reference population of 3,150 that included genotypes from 835 Australian and 1,053 New Zealand females, with the remainder being males. Imputation was undertaken using population-wide linkage disequilibrium with no family information exploited. The UK animals were also included in the North American data set (n=1,579) that was imputed to high density using a reference population of 2,018 bulls. After editing, 591,213 genotypes on 5,999 animals from 10 research herds remained. The correlation between imputed allele frequencies of the 2 imputed data sets was high (>0.98) and even stronger (>0.99) for the UK animals that were part of each imputation data set. For the UK genotypes, 2.2% were imputed differently in the 2 high-density reference data sets used. Only 0.025% of these were homozygous switches. The number of discordant SNP was lower for animals that had sires that were genotyped. Discordant imputed SNP genotypes were most common when a large difference existed in allele frequency between the 2 imputed genotype data sets. For SNP that had >= 20% discordant genotypes, the difference between imputed data sets of allele frequencies of the UK (imputed) genotypes was 0.07, whereas the difference in allele frequencies of the (reference) high-density genotypes was 0.30. In fact, regions existed across the genome where the frequency of discordant SNP was higher. For example, on chromosome 10 (centered on 520,948 bp), 52 SNP (out of a total of 103 SNP) had >= 20% discordant SNP. Four hundred and eight SNP had more than 20% discordant genotypes and were removed from the final set of imputed genotypes. We concluded that both discordance of imputed SNP genotypes and differences in allele frequencies, after imputation using different reference data sets, may be used to identify and remove poorly imputed SNP. PMID- 24472133 TI - Short communication: Comparison of 3 solid digesta passage markers in dairy cows. AB - This study investigated the usefulness of acid-detergent fiber-bound (15)N [acid detergent insoluble (ADI)-(15)N] as a solid digesta passage marker in dairy cows compared with chromium (Cr) and ytterbium (Yb) (as labeled fiber or forage, respectively). Intrinsically (ADI-(15)N) or extrinsically (Cr, Yb) labeled alfalfa hay was pulse-dosed intraruminally to 7 lactating dairy cows. Following marker administration, spot fecal samples were collected for up to 72 h for marker analyses. Urine and milk samples were also collected and analyzed for Yb and Cr. Fecal marker excretion data were processed using 2-compartment mathematical age-dependent/age-independent (Gn->G1) models. The rate of passage of the marker in the first, age-dependent compartment tended to be slower for Yb compared with Cr and ADI-(15)N, which resulted in a trend for longer mean retention time (MRT) in this compartment when Yb was used as a marker (19.0 h) compared with Cr and ADI-(15)N (14.5 and 13.9h, respectively). The rate constant of marker disappearance for the second or age-independent compartment tended to be greater for Yb compared with Cr and ADI-(15)N, which led to a shorter MRT of Yb in this compartment (15.6) versus ADI-(15)N (32.1) and Cr (24.8h). The cumulative MRT was greater for ADI-(15)N versus Cr and Yb (46.0, 39.3, and 34.4h, respectively). Total MRT of marker tended to be greater for ADI-(15)N than for Yb (46.6 vs. 36.6h, respectively). Urine and milk analyses data suggested no measurable losses of Yb along the digestive tract, but about 0.79% of Cr dosed intraruminally was secreted or excreted in milk and urine in the 48-h period following marker administration. Collectively, this study confirmed previous observations that ADI-(15)N can be used reliably as a solid digesta passage marker for ruminants, producing pre-duodenal and total-tract retention times similar to that of Cr-labeled fiber. Retention time in the age-independent compartment was underestimated when Yb was used as a marker, emphasizing the need to process forages to isolate fiber before labeling with Yb. PMID- 24472134 TI - Factors associated with metabolic syndrome and related medical costs by the scale of enterprise in Korea. AB - OBJECTIVES: The purpose of this study was to identify the risk factors of metabolic syndrome (MS) and to analyze the relationship between the risk factors of MS and medical cost of major diseases related to MS in Korean workers, according to the scale of the enterprise. METHODS: Data was obtained from annual physical examinations, health insurance qualification and premiums, and health insurance benefits of 4,094,217 male and female workers who underwent medical examinations provided by the National Health Insurance Corporation in 2009. Logistic regression analyses were used to the identify risk factors of MS and multiple regression was used to find factors associated with medical expenditures due to major diseases related to MS. RESULT: The study found that low-income workers were more likely to work in small-scale enterprises. The prevalence rate of MS in males and females, respectively, was 17.2% and 9.4% in small-scale enterprises, 15.9% and 8.9% in medium-scale enterprises, and 15.9% and 5.5% in large-scale enterprises. The risks of MS increased with age, lower income status, and smoking in small-scale enterprise workers. The medical costs increased in workers with old age and past smoking history. There was also a gender difference in the pattern of medical expenditures related to MS. CONCLUSIONS: Health promotion programs to manage metabolic syndrome should be developed to focus on workers who smoke, drink, and do little exercise in small scale enterprises. PMID- 24472135 TI - The effect of psychotherapy for depression on improvements in social functioning: a meta-analysis. AB - BACKGROUND: Patients with depression often report impairments in social functioning. From a patient perspective, improvements in social functioning might be an important outcome in psychotherapy for depression. Therefore, it is important to examine the effects of psychotherapy on social functioning in patients with depression. METHOD: We conducted a meta-analysis on studies of psychotherapy for depression that reported results for social functioning at post treatment. Only studies that compared psychotherapy to a control condition were included (31 studies with 2956 patients). RESULTS: The effect size of psychotherapy on social functioning was small to moderate, before [Hedges' g = 0.46, 95% confidence interval (CI) 0.32-0.60] and after adjusting for publication bias (g = 0.40, 95% CI 0.25-0.55). Univariate moderator analyses revealed that studies using care as usual as a control group versus other control groups yielded lower effect sizes, whereas studies conducted in the USA versus other countries and studies that used clinician-rated instruments versus self-report yielded higher effect sizes. Higher quality studies yielded lower effect sizes whereas the number of treatment sessions and the effect size of depressive symptoms were positively related to the effect size of social functioning. When controlling for these and additional characteristics simultaneously in multivariate meta-regression, the effect size of depressive symptoms, treatment format and number of sessions were significant predictors. The effect size of social functioning remained marginally significant, indicating that improvements in social functioning are not fully explained by improvements in depressive symptoms. CONCLUSIONS: Psychotherapy for depression results in small to moderate improvements in social functioning. These improvements are strongly associated with, but not fully explained by, improvements in depressive symptoms. PMID- 24472136 TI - Beyond labor: the role of natural and synthetic oxytocin in the transition to motherhood. AB - Emerging research raises questions that synthetic oxytocin during childbirth may alter the endogenous oxytocin system and influence maternal stress, mood, and behavior. Endogenous oxytocin is a key component in the transition to motherhood, affecting molecular pathways that buffer stress reactivity, support positive mood, and regulate healthy mothering behaviors (including lactation). Synthetic oxytocin is widely used throughout labor and postpartum care in modern birth. Yet research on the implications beyond labor of maternal exposure to perinatal synthetic oxytocin is rare. In this article, we review oxytocin-related biologic pathways and behaviors associated with the transition to motherhood and evidence supporting the need for further research on potential effects of intrapartum oxytocin beyond labor. We include a primer on oxytocin at the molecular level. PMID- 24472137 TI - Genomic sequence of temperate phage Smp131 of Stenotrophomonas maltophilia that has similar prophages in xanthomonads. AB - BACKGROUND: Stenotrophomonas maltophilia is a ubiquitous Gram-negative bacterium previously named as Xanthomonas maltophilia. This organism is an important nosocomial pathogen associated with infections in immunocompromised patients. Clinical isolates of S. maltophilia are mostly resistant to multiple antibiotics and treatment of its infections is becoming problematic. Several virulent bacteriophages, but not temperate phage, of S. maltophilia have been characterized. RESULTS: In this study, a temperate myophage of S. maltophilia (Smp131) was isolated and characterized. Sequence analysis showed that its genome is 33,525-bp long with 47 open reading frames (ORFs). Its similarity to P2-like phages and prophages in S. maltophilia and several Xanthomonas pathovars includes genomic organization, arrangement of several operons, and possession of a slippery sequence T7G for translational frameshifting in tail assembly genes. Smp131 encodes a tyrosine family integrase that shares low degrees of similarity with those of other phages and a lysin belonging to family 19 chitinase that is observed in plants and some bacteria, although not in phages. tRNA are the preferred sites for host integration of Smp131 and the related phages: tRNA-Thr for Smp131 and prophage of S. maltophilia K279a; tRNA-Lys for prophages of X. campestris pv. campestris ATCC33913, X. oryzae pv. oryzae strains MAFF311018, and KACC10331; and tRNA-Asn for prophage of X. oryzae pv. oryzae PXO99A and remnant of X. axonopodis pv. citri 306. Regions flanking the prophages are varied highly in nucleotide sequence and rich in transposase genes, suggesting that frequent insertion/excision had occurred. CONCLUSIONS: Prevalence of closely related prophages in Stenotrophomonas and Xanthomonads may have contributed to the diversity of these closely related species owing to possible horizontal gene transfer mediated by the phages. PMID- 24472139 TI - Older patients' depressive symptoms 6 months after prolonged hospitalization: course and interrelationships with major associated factors. AB - The aim of this study was to examine the course of depressive symptoms in older patients 6 months following a prolonged, acute hospitalization, especially the interrelationships among depressive symptoms and its major associated factors. For this study, we conducted a secondary analysis of data from a prospective cohort study of 351 patients aged 65 years and older. Participants were recruited from five surgical and medical wards at a tertiary medical center in northern Taiwan and assessed at three time points: within 48 h of admission, before discharge, and 6 months post-discharge. The course of depressive symptoms was dynamic with symptoms increased spontaneously and substantially during hospitalization and subsided at 6 months after discharge, but still remained higher than at admission. Overall, 26.7% of older patients at hospital discharge met established criteria for minor depression (15-item Geriatric Depressive Scale (GDS-15) scores 5-9) and 21.2% for major depression (GDS-15 scores >10). As the strongest associated factors, functional dependence and nutritional status influenced depressive symptoms following hospitalization. Depressive symptoms at discharge showed significant cross-lagged effects on functional dependence and nutritional status at 6 months after discharge, suggesting a reciprocal, triadic relationship. Thus, treating one condition might improve the other. Targeting the triad of depressive symptoms, functional dependence, and nutritional status, therefore, is essential for treating depressive symptoms and improving the overall health of older adults hospitalized for acute illness. PMID- 24472140 TI - Discordance in spirometric interpretations based on korean and non-korean reference equations. AB - OBJECTIVES: Korean regression models for spirometric reference values are different from those of other ethnic groups. The purpose of this study was to evaluate discordance in spirometric interpretations based on using Korean reference equations versus non-Korean reference equations. METHODS: Spirometry was performed on 825 Korean male workers from April 2009 to November 2011. The spirometric patterns and disease severity were evaluated using two Korean equations (Choi's and Lee's) and three equations for Caucasians (NHANES III, Morris's, and Knudson's), and the results of Choi's equation were compared with the non-Korean equations. The spirometric patterns were defined as normal, restrictive, and mild and moderate obstructive. RESULTS: The mean differences in the FEV1% and FVC% between the two Korean equations were 2.0 +/- 1.3% and 3.5 +/- 2.2%, respectively. Morris's equation had the greatest difference in the FEV1% from Choi's equation: 32.9 +/- 8.5%. Knudson's equation had the greatest difference in the FVC% from Choi's equation: 10.5 +/- 6.5%. CONCLUSIONS: The two Korean equations shared similar characteristics of spirometric interpretation. The spirometric interpretations of Choi's equation were significantly different from those of Morris's equation and Knudson's equation. PMID- 24472138 TI - Telomeres, oxidative stress and inflammatory factors: partners in cellular senescence? AB - Senescence, the state of irreversible cell-cycle arrest, plays paradoxical albeit important roles in vivo: it protects organisms against cancer but also contributes to age-related loss of tissue function. The DNA damage response (DDR) has a central role in cellular senescence. Not only does it contribute to the irreversible loss of replicative capacity but also to the production and secretion of reactive oxygen species (ROS), and bioactive peptides collectively known as the senescence-associated secretory phenotype (SASP). Both ROS and the SASP have been shown to impact on senescence in an autocrine as well as paracrine fashion; however, the underlying mechanisms are not well understood. In this review we describe our current understanding of cellular senescence, examine in detail the intricate pathways linking the DDR, ROS and SASP, and evaluate their impact on the stability of the senescent phenotype. PMID- 24472141 TI - Development of cost-effective real-time PCR test: to detect a wide range of HBV DNA concentrations in the western Amazon region of Brazil. AB - BACKGROUND: Currently there is a significant risk of infection with hepatitis B virus (HBV) during blood transfusion in high epidemic area. This is due to the pre-seroconversion window period, immunovariant viral strains and the presence of occult HBV infection (OBI). The aim of this study was to develop an in-house real time PCR-based method, which was both ultra-sensitive and efficient offering an alternative method for nucleic acid testing (NAT). METHODS: A precore fragment with 109 bp was cloned and serial diluted to standard curve construction. The calibration of the HBV-DNA values was performed against OptiQuant(r) HBV-DNA Quantification Panel, Acrometrix Europe B.V.). RESULTS: From our in-house plasmid we prepared serial dilutions ranging from 2 * 103-2 * 109 copies/ml. The threshold was adjusted automatically during analysis and the data collected were analyzed by linear regression (r2 = 0.99). The limit of detection for the assay with pHBVRO standards was 2000/ml in a total reaction volume of 30 MUl. We found a strong correlation between the two methods (r2 = 0.9965 and p < 0.0001). The regression line give us the following equation: Log 10 (IU/mL) = 0.9038Log 10 (copies/mL)--1.0643, suggesting that 1 IU/mL = 15 copies/mL. CONCLUSIONS: Therefore, we can affirm that the qHBVRO PCR can detect HBV DNA in individuals with hepatitis B at any stage of the disease showing high capacity for NAT screening in hepatitis b donors. This results of sensitivity could provide an advance for automation in blood banks and increasing safety of patients who receive blood transfusions. PMID- 24472143 TI - Surgically treated ovarian endometriosis association with BRCA1 and BRCA2 mutations. AB - Endometriosis is associated with an increased risk of ovarian cancer. Few studies have also shown increased risk of breast cancer. BRCA1/2 mutations are linked to an increased risk of breast and ovarian cancers but their relation to endometriosis is unknown. The objective of this study was to examine the mutation rate of BRCA1/2 among women with surgically treated ovarian endometriosis. We collected 126 specimens from Jewish Ashkenazi women with endometriotic (76) and control non-endometriotic (50) ovarian cysts, reviewed the pathological diagnoses and extracted DNA from all samples. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS), samples were examined for the founder germline mutations of BRCA1/2, most common among Ashkenazi Jews. The rate of mutations in each group was calculated and compared. BRCA1/2 mutation rate was 1/76 (1.3%) in the endometriotic cyst study group and 1/50 (2%) in the control non-endometriotic cysts, showing no statistically significant difference between the groups (p=0.84). BRCA1/2 mutation rate was similar to the previously reported rate among Jewish Ashkenazi women. BRCA1/2 mutation rates in patients with endometriotic ovarian cysts and with non endometriotic ovarian cysts are similar. A larger cohort is required to completely exclude the possibility of an association between BRCA1/2 mutations and surgically treated endometriosis. PMID- 24472144 TI - Choice of anesthetic technique on plasma concentrations of interleukins and cell adhesion molecules. AB - BACKGROUND: Whether inflammatory responses to surgery are comparably activated during total intravenous anesthesia (TIVA) and during volatile anesthesia remains unclear. We thus compared the perioperative effects of TIVA and isoflurane anesthesia on plasma concentrations of proinflammatory and anti-inflammatory interleukins and cell adhesion molecules. METHODS: Patients having laparoscopic cholecystectomies were randomly allocated to two groups: 44 were assigned to TIVA and 44 to isoflurane anesthesia. IL-1beta, IL-6, IL-8, IL-10, IL-13, and the cellular adhesion molecules intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 were determined preoperatively, before incision, and at 2 and 24 hours postoperatively. Our primary outcomes were area-under-the-curve cytokine and adhesion molecule concentrations over 24 postoperative hours. RESULTS: The only statistically significant difference in area-under-the-curve concentrations was for IL-6, which was greater in patients given isoflurane:78 (95% confidence interval (CI): 52 to 109) pg/ml versus 33 (22 to 50) pg/ml, P= 0.006. Two hours after surgery, IL-6 was significantly greater than baseline in patients assigned to isoflurane: 47 (95% CI: 4 to 216, P<0.001) pg/ml versus 18 (95%CI: 4 to 374, P<0.001) pg/ml in the TIVA group. In contrast, IL-10 was significantly greater in patients assigned to TIVA: 20 (95% CI: 2 to 140, P<0.001) pg/ml versus 12 (95% CI: 3 to 126, P<0.001) pg/ml. By 24 hours after surgery, concentrations were generally similar between study groups and similar to baseline values. CONCLUSION: The only biomarker whose postoperative area-under-the-curve concentrations differed significantly as a function of anesthetic management was IL-6. Two hours after surgery, IL-6 concentrations were significantly greater in patients given isoflurane than TIVA. However, the differences were modest and seem unlikely to prove clinically important. Further studies are needed. PMID- 24472145 TI - Correlation between HER-2/neu(erbB-2) expression level and therapeutic effect of combination treatment with HERCEPTIN and chemotherapeutic agents in gastric cancer cell lines. AB - INTRODUCTION: Although advanced gastric cancer has many limitations and response rate is marginal in chemotherapy. Overexpression of human epidermal growth factor receptor 2(HER-2/neu) gene and its protein are associated with increased cell division and a high rate of tumor growth and have been reported in several malignancies. Especially, approximately 30% of breast cancer patients have overexpression of HER-2/neu protein and the overexpression metastasize faster, induces resistance of the chemotherapy and down-regulate function of estrogen receptor. Recombinant humanized anti-HER2 antibody (Herceptin) inhibits proliferation of HER-2/neu overexpressing tumor cells and the use of that in combination in metastatic breast cancer have increased cytotoxicity of chemotherapeutic agents. METHODS: We evaluated the expression of HER-2/neu protein in gastric cell lines by FACS and then comparing the cytotoxicity in chemotherapeutics (doxorubicin, cisplatin, paclitaxel, 5-FU) alone and in combination with Herceptin according to the expression of HER-2/neu protein by MTT assay. RESULTS: 1. NCI-N87 (88%) gastric cancer cell line and SK-BR-3 (89%) breast cancer cell line with strong positivity of HER-2/neu expression. YBC-2 (55%) and YBC-3 (48%) gastric cancer cell line with intermediated, weak positivity respectively. Negative control U-87 MG (6%) brain cancer cell line were showed low expression of HER-2/neu. 2. Cell growth was dose-dependently inhibited in HER-2/neu positive, control cell line SK-BR-3 by Herceptin treatment but not observed in HER-2/neu negative control cell line U-87 MG. Effective growth inhibition was not observed in gastric cancer cell lines with single treatment of Herceptin, all cell lines observed the dose-dependent growth inhibition to chemotherapeutic agents (doxorubicin, cisplatin, paclitaxel and 5 FU). 3. Combination of Herceptin with doxorubicin observed synergistic effects in all cancer cell lines except YBC-3, combination of Herceptin with cisplatin observed NCI-N87 and SK-BR-3 and combination of Herceptin with paclitaxel observed synergistic effects in YBC-2. Combination of Herceptin with 5-FU observed antagonistic effects in all cancer cell lines. CONCLUSIONS: According to HER-2/neu expression level, effect of anti-cancer agents was observed differently in combination of Herceptin with chemotherapeutic agents. This suggests that HER 2/neu expression level can be applied standard of combination drug selection in combination of Herceptin With chemotherapeutic agents in gastric cancer. PMID- 24472146 TI - Antimycobacterial evaluation of novel hybrid arylidene thiazolidine-2,4-diones. AB - A series of novel hybrid heterocycles comprising arylidene thiazolidine-2,4-dione and 1-cyclopropyl-2-(2-fluorophenyl)ethanone were synthesized. These compounds were evaluated for their antimycobacterial activity against Mycobacterium tuberculosis H37Rv in High Throughput Screen. Most of the hybrid arylidene thiazolidine-2,4-diones displayed moderate to good activity with MIC of less than 50 MUM. Compound 1m exhibited maximum potency being 5.87 fold more active at EC50 and 6.26 fold more active at EC90 than the standard drug pyrimethamine. PMID- 24472147 TI - Subclinical interstitial lung damage in workers exposed to indium compounds. AB - OBJECTIVES: The present study was designed to determine whether there is a relationship between indium compound exposure and interstitial lung damage in workers employed at indium tin oxide manufacturing and reclaiming factories in Korea. METHODS: In 2012, we conducted a study for the prevention of indium induced lung damage in Korea and identified 78 workers who had serum indium or Krebs von den Lungen-6 (KL-6) levels that were higher than the reference values set in Japan (3 MUg/L and 500 U/mL, respectively). Thirty-four of the 78 workers underwent chest high-resolution computed tomography (HRCT), and their data were used for statistical analysis. RESULTS: Geometric means (geometric standard deviations) for serum indium, KL-6, and surfactant protein D (SP-D) were 10.9 (6.65) MUg/L, 859.0 (1.85) U/mL, and 179.27 (1.81) ng/mL, respectively. HRCT showed intralobular interstitial thickening in 9 workers. A dose-response trend was statistically significant for blood KL-6 levels. All workers who had indium levels >=50 MUg/L had KL-6 levels that exceeded the reference values. However, dose-response trends for blood SP-D levels, KL-6 levels, SP-D levels, and interstitial changes on the HRCT scans were not significantly different. CONCLUSIONS: Our findings suggest that interstitial lung changes could be present in workers with indium exposure. Further studies are required and health risk information regarding indium exposure should be communicated to workers and employers in industries where indium compounds are used to prevent indium induced lung damage in Korea. PMID- 24472148 TI - Increased risk of preoperative venous thromboembolism in patients with renal cell carcinoma and tumor thrombus: comment. PMID- 24472150 TI - Measuring outcomes after major abdominal surgery during hospitalization: reliability and validity of the Postoperative Morbidity Survey. AB - BACKGROUND: Measurement of outcomes after major abdominal surgery has traditionally focused on mortality, however the low incidence in elective surgery makes this measure a poor comparator. The Postoperative Morbidity Survey (POMS) prospectively assesses short-term morbidity, and may have clinical utility both as a core outcome measure in clinical trials and quality of care. The POMS has been shown to be a valid outcome measure in a mixed surgical population, however it has not been studied in patients undergoing major abdominal surgery. This study assessed the inter-rater reliability and validity of the POMS in patients undergoing major abdominal surgery. METHODS: Patients undergoing elective major abdominal surgery were visited on postoperative day 1 until discharge by two novice observers who administered the POMS in order to assess inter-rater reliability. Subjects who had previously had the POMS performed prospectively on postoperative days 3 and 5 were identified from a database. The pattern and prevalence of morbidity was analyzed against hospital length of stay (LOS) in order to validate the POMS in this patient group. RESULTS: Fifty one patients were recruited to the inter-rater reliability study giving a total of 263 POMS assessments. Inter-rater reliability showed a 97.7% agreement with a kappa coefficient of 0.912 (95% CI: 0.842 to 0.982). On domain analysis percentage agreement was lowest in the gastrointestinal domain (87.5%), whilst correlation was lowest in the wound (kappa: 0.04; 95% CI: -1.0 to 1.0) and hematological domains (kappa: 0.378; 95% CI: 0.035 to 0.722). All other domains showed at least substantial agreement. POMS assessments were analyzed for postoperative days 3 (n = 258) and 5 (n = 362). The absence or presence of morbidity as measured by the POMS was associated with a hospital LOS of 6 (IQR: 4 to 7) vs. 11 (IQR: 8 to 15) days on postoperative day 3 (P <0.0001), and 7 (IQR: 6 to 10) vs. 13 (IQR: 9 to 19) days on postoperative day 5 (P <0.0001). The presence of any morbidity on postoperative day 5 conferred an odds ratio for a prolonged hospital LOS of 11.9 (95% CI: 5.02 to 11.92). CONCLUSIONS: This study shows that the POMS is both a reliable and valid measure of short-term postoperative morbidity in patients undergoing major abdominal surgery. PMID- 24472151 TI - Spdef deletion rescues the crypt cell proliferation defect in conditional Gata6 null mouse small intestine. AB - BACKGROUND: GATA transcription factors are essential for self-renewal of the small intestinal epithelium. Gata4 is expressed in the proximal 85% of small intestine while Gata6 is expressed throughout the length of small intestine. Deletion of intestinal Gata4 and Gata6 results in an altered proliferation/differentiation phenotype, and an up-regulation of SAM pointed domain containing ETS transcription factor (Spdef), a transcription factor recently shown to act as a tumor suppressor. The goal of this study is to determine to what extent SPDEF mediates the downstream functions of GATA4/GATA6 in the small intestine. The hypothesis to be tested is that intestinal GATA4/GATA6 functions through SPDEF by repressing Spdef gene expression. To test this hypothesis, we defined the functions most likely regulated by the overlapping GATA6/SPDEF target gene set in mouse intestine, delineated the relationship between GATA6 chromatin occupancy and Spdef gene regulation in Caco 2 cells, and determined the extent to which prevention of Spdef up-regulation by Spdef knockout rescues the GATA6 phenotype in conditional Gata6 knockout mouse ileum. RESULTS: Using publicly available profiling data, we found that 83% of GATA6-regulated genes are also regulated by SPDEF, and that proliferation/cancer is the function most likely to be modulated by this overlapping gene set. In human Caco-2 cells, GATA6 knockdown results in an up-regulation of Spdef gene expression, modeling our mouse Gata6 knockout data. GATA6 occupies a genetic locus located 40 kb upstream of the Spdef transcription start site, consistent with direct regulation of Spdef gene expression by GATA6. Prevention of Spdef up regulation in conditional Gata6 knockout mouse ileum by the additional deletion of Spdef rescued the crypt cell proliferation defect, but had little effect on altered lineage differentiation or absorptive enterocytes gene expression. CONCLUSION: SPDEF is a key, immediate downstream effecter of the crypt cell proliferation function of GATA4/GATA6 in the small intestine. PMID- 24472152 TI - The relationship of liver function tests to mixed exposure to lead and organic solvents. AB - OBJECTIVE: This study aims to compare liver function indices (aspartate aminotransferase [AST], alanine aminotransferase [ALT], and gamma glutamyl transferase [GGT]) among males who work with lead, organic solvents, or both lead and organic solvents, under the permissible exposure limit (PEL). METHODS: A total of 593 (out of 2,218) male workers who agreed to share their personal health information for medical research were selected for this study. Those excluded were hepatitis B carriers, individuals exposed to occupational risk factors other than lead and organic solvents, and individuals without liver function results. The 593 were divided into five groups: a lead-exposed group, an organic solvent-exposed group exposed to trichloroethylene (TCE co-exposed solvent group), an organic solvent-exposed group not exposed to trichloroethylene (TCE non-exposed solvent group), a lead and organic solvent-exposed group (mixed exposure group), and a non-exposed group (control group).We performed a one way analysis of variance (one way-ANOVA) test to compare the geometric means of liver function indices among the groups, using a general linear model (GLM) to adjust for age, work duration, body mass index (BMI), smoking, and alcohol intake. In addition, we performed a binary logistic regression analysis to compare the odds ratios among groups with an abnormal liver function index, according to a cut-off value. RESULTS: The ALT and AST of the mixed exposure group were higher than those of the other groups. The GGT of the mixed exposure group was higher than the TCE co-exposed solvent group, but there was no difference among the control group, TCE non-exposed solvent group, lead-exposed group, and mixed exposure group. The same result was evident after adjusting by GLM for age, work duration, BMI, smoking, and alcohol intake, except that ALT from the mixed exposure group showed no difference from the TCE co-exposed solvent group.When the cut-off values of the AST, ALT, and GGT were 40 IU/L, 42 IU/L, and 63 IU/L, respectively, a logistic regression analysis showed no differences in the odds ratios of those who had an abnormal liver function index among the groups. However, if the cut off values of the AST, ALT, and GGT were 30 IU/L, 30 IU/L, and 40 IU/L, respectively, the odds ratio of the AST in the mixed exposure group was 4.39 (95% CI 1.86-10.40) times higher than the control. CONCLUSION: This study indicates that a mixed exposure to lead and organic solvents is dangerous, even if each single exposure is safe under the permissible exposure limit. Therefore, to ensure occupational health and safety in industry, a continuous efforts to study the effects from exposure to mixed chemicals is needed. PMID- 24472154 TI - Potential of the quadrivalent human papillomavirus vaccine in the prevention and treatment of cervical cancer. AB - INTRODUCTION: Genital human papillomaviruses (HPVs) are readily transmissible and commonly acquired after sexual debut. With HPV being uncultivatable, it has taken the application of molecular biology to describe the virus' natural history, although it has also given us sensitive diagnostic tools, as well as underpinning the development of prophylactic viral-like particle (VLP) vaccines. Molecular epidemiology proved oncogenic HPVs as causing 100% of cervical, plus a proportion of, anogenital and oropharyngeal cancers. The quadrivalent vaccine containing VLPs 6, 11 (cause > 90% of genital warts), 16, 18, (causing 70% of cervical cancers) has shown in Phase III trials excellent safety, high efficacy and immunogenicity. AREAS COVERED: This review looks at Phase III clinical trial data, plus vaccine effectiveness reported in real-world situations. EXPERT OPINION: Given the remarkable early successes of vaccine effectiveness in reduction of HPV-vaccine-related infections in vaccine-eligible age females, rapid reduction in genital warts (first marker of disease reduction and herd immunity) and high-grade cervical lesions, in countries where vaccine has high coverage of target populations, vaccination should ultimately translate into reductions in HPV-related neoplasias. The greatest success from this vaccine will only be realized when it is rolled out effectively, with high coverage to those parts in the world with the highest burden of disease. We have the tools; we now need to use them. PMID- 24472155 TI - A comparison of RNA-seq and exon arrays for whole genome transcription profiling of the L5 spinal nerve transection model of neuropathic pain in the rat. AB - BACKGROUND: The past decade has seen an abundance of transcriptional profiling studies of preclinical models of persistent pain, predominantly employing microarray technology. In this study we directly compare exon microarrays to RNA seq and investigate the ability of both platforms to detect differentially expressed genes following nerve injury using the L5 spinal nerve transection model of neuropathic pain. We also investigate the effects of increasing RNA-seq sequencing depth. Finally we take advantage of the "agnostic" approach of RNA-seq to discover areas of expression outside of annotated exons that show marked changes in expression following nerve injury. RESULTS: RNA-seq and microarrays largely agree in terms of the genes called as differentially expressed. However, RNA-seq is able to interrogate a much larger proportion of the genome. It can also detect a greater number of differentially expressed genes than microarrays, across a wider range of fold changes and is able to assign a larger range of expression values to the genes it measures. The number of differentially expressed genes detected increases with sequencing depth. RNA-seq also allows the discovery of a number of genes displaying unusual and interesting patterns of non exonic expression following nerve injury, an effect that cannot be detected using microarrays. CONCLUSION: We recommend the use of RNA-seq for future high throughput transcriptomic experiments in pain studies. RNA-seq allowed the identification of a larger number of putative candidate pain genes than microarrays and can also detect a wider range of expression values in a neuropathic pain model. In addition, RNA-seq can interrogate the whole genome regardless of prior annotations, being able to detect transcription from areas of the genome not currently annotated as exons. Some of these areas are differentially expressed following nerve injury, and may represent novel genes or isoforms. We also recommend the use of a high sequencing depth in order to detect differential expression for genes with low levels of expression. PMID- 24472157 TI - Systemic lupus erythematosus increases the risks of deep vein thrombosis and pulmonary embolism: a nationwide cohort study. AB - BACKGROUND: Studies on the risks of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with systemic lupus erythematosus (SLE) are limited. We evaluated the effects of SLE on the risks of developing DVT and PE in a nationwide, population-based cohort study in Taiwan. METHODS: We randomly selected patients without SLE from the National Health Insurance database (N = 23.74 million), and frequency-matched four of them, on the basis of age, sex, and index year, to each SLE patient in the catastrophic illness registry of the NHI who was diagnosed with SLE between 1998 and 2008. Using a follow-up period ending in 2010, we analyzed the risks of DVT and PE with a Cox proportional-hazards regression analysis. RESULTS: The 13 084 SLE patients (87.9% women; mean age of 35.6 years) and 52 336 controls were followed for 90 237 and 379 185 person years, respectively. After adjustment for age, sex, and comorbidities, the SLE patients' risks of developing DVT and PE were 12.8-fold and 19.7-fold higher, respectively, than those of the comparison cohort. The risks of DVT and PE increased in both study groups when the data were stratified on the basis of sex, age, and comorbidities. The SLE patients aged <= 35 years had the highest risks of developing DVT and PE. The multiplicative increased risks of DVT and PE were also significant in SLE patients with any comorbidity. CONCLUSION: The risks of DVT and PE are significantly higher in SLE patients than in the general population. PMID- 24472156 TI - Efficacy and safety of artemether-lumefantrine and dihydroartemisinin-piperaquine in the treatment of uncomplicated Plasmodium falciparum malaria in Kenyan children aged less than five years: results of an open-label, randomized, single centre study. AB - BACKGROUND: This open-label, randomized study evaluated efficacy and safety of artemether-lumefantrine (AL) and dihydroartemisinin-piperaquine (DP) in treatment of uncomplicated falciparum malaria in children below five years of age, to build evidence on use of AL as first-line treatment and DP as second-line treatment in Kenya. METHODS: A total of 454 children aged six to 59 months with uncomplicated falciparum malaria were randomized (1:1) to receive AL dispersible or DP paediatric tablets and followed up for 42 days. Primary efficacy variable was corrected adequate clinical and parasitological response (ACPR) rate on day 28. Secondary variables included corrected (day 14, 28 and 42), uncorrected (day 3, 14, 28 and 42) cure rates, parasitological failure at days 3, 14 and 42. Acceptability and tolerability of both drugs were assessed by caregiver questionnaire. RESULTS: On day 28, corrected ACPR rates for AL dispersible and DP paediatric were 97.8% (95% CI: 94.9-99.3) and 99.1% (95% CI: 96.8-99.9), respectively, in intention-to-treat population, with no significant treatment differences noted between AL dispersible and DP paediatric arms. Additionally, no significant differences were observed for PCR corrected cure rates on days 14 and ACPR on day 42 for AL dispersible (100%; 96.8%) and DP paediatric (100%; 98.7%). Similarly, for PCR uncorrected cure rates, no significant differences were seen on days 3, 14, 28, and 42 for AL dispersible (99.1%; 98.7%; 81.1%; 67.8%) and DP paediatric (100%; 100%; 87.7%; 70.5%). Parasite clearance was rapid, with approximately 90% clearance achieved in 40 hours in both treatment arms. Incidence of adverse events was related to underlying disease; malaria being reported in both treatment arms. One serious adverse event was noted in AL dispersible (0.42%) arm, not related to study drug. Adherence to treatment regimen was higher for children treated with AL dispersible (93.6%) compared to DP paediatric (85.6%). Acceptability of AL dispersible regimen was assessed as being significantly better than DP paediatric. CONCLUSIONS: AL and DP were both efficacious and well tolerated, and had similar effects at day 42 on risk of recurrent malaria. No signs of Plasmodium falciparum tolerance to artemisinins were noted. TRIAL REGISTRATION: PACTR201111000316370. PMID- 24472158 TI - Posttraumatic growth and related factors of child protective service workers. AB - OBJECTIVES: The aim of the study is to measure the level of vicarious trauma, posttraumatic growth (PTG), and other factors affecting PTG among child protective service workers. METHODS: We include posttraumatic stress, social support, stress coping, and demographic data as independent variables. Data was collected from 255 full-time social workers from 43 child protective agencies as acomplete enumeration and 204 included in the final analysis. RESULTS: The major findings of the study were as follows: The mean score of PTG was 44.09 (SD:21.73). Hierarchical multiple regression was adopted and "pursuing social support as a way of coping with stress" was the strongest predictive factor (beta=0.319, p<0.001) of PTG. CONCLUSION: We suggest that child protective workers are vulnerable to posttraumatic stress and mental health services are indicated. We also recommend various types of training for stress coping program, especially strengthening the social support system of the child protective service workers in South Korea. PMID- 24472159 TI - Risk stratification by pre-operative cardiopulmonary exercise testing improves outcomes following elective abdominal aortic aneurysm surgery: a cohort study. AB - BACKGROUND: In 2009, the NHS evidence adoption center and National Institute for Health and Care Excellence (NICE) published a review of the use of endovascular aneurysm repair (EVAR) of abdominal aortic aneurysms (AAAs). They recommended the development of a risk-assessment tool to help identify AAA patients with greater or lesser risk of operative mortality and to contribute to mortality prediction.A low anaerobic threshold (AT), which is a reliable, objective measure of pre operative cardiorespiratory fitness, as determined by pre-operative cardiopulmonary exercise testing (CPET) is associated with poor surgical outcomes for major abdominal surgery. We aimed to assess the impact of a CPET-based risk stratification strategy upon perioperative mortality, length of stay and non operative costs for elective (open and endovascular) infra-renal AAA patients. METHODS: A retrospective cohort study was undertaken. Pre-operative CPET-based selection for elective surgical intervention was introduced in 2007. An anonymized cohort of 230 consecutive infra-renal AAA patients (2007 to 2011) was studied. A historical control group of 128 consecutive infra-renal AAA patients (2003 to 2007) was identified for comparison.Comparative analysis of demographic and outcome data for CPET-pass (AT >= 11 ml/kg/min), CPET-fail (AT < 11 ml/kg/min) and CPET-submaximal (no AT generated) subgroups with control subjects was performed. Primary outcomes included 30-day mortality, survival and length of stay (LOS); secondary outcomes were non-operative inpatient costs. RESULTS: Of 230 subjects, 188 underwent CPET: CPET-pass n = 131, CPET-fail n = 35 and CPET submaximal n = 22. When compared to the controls, CPET-pass patients exhibited reduced median total LOS (10 vs 13 days for open surgery, n = 74, P < 0.01 and 4 vs 6 days for EVAR, n = 29, P < 0.05), intensive therapy unit requirement (3 vs 4 days for open repair only, P < 0.001), non-operative costs (L5,387 vs L9,634 for open repair, P < 0.001) and perioperative mortality (2.7% vs 12.6% (odds ratio: 0.19) for open repair only, P < 0.05). CPET-stratified (open/endovascular) patients exhibited a mid-term survival benefit (P < 0.05). CONCLUSION: In this retrospective cohort study, a pre-operative AT > 11 ml/kg/min was associated with reduced perioperative mortality (open cases only), LOS, survival and inpatient costs (open and endovascular repair) for elective infra-renal AAA surgery. PMID- 24472161 TI - A case of occupational asthma in a plastic injection process worker. AB - OBJECTIVES: We report a case of death due to asthma attack in a plastic injection process worker with a history of asthma. METHODS: To assess task relevance, personal history including occupational history and medical records were reviewed. Samples of the substances utilized in the injection process were collected by visiting the patient's workplace. The work environment with the actual process was reproduced in the laboratory, and the released substances were evaluated. RESULTS: The medical records confirmed that the patient's conventional asthma was in remission. The analysis of the resins discharged from the injection process simulation revealed styrene, which causes occupational asthma, and benzenepropanoic acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-, and octadecyl ester. Even though it was not the case in the present study, various harmful substances capable of inducing asthma such as formaldehyde, acrolein, and acetic acid are released during resin processing. CONCLUSION: A worker was likely to occur occupational asthma as a result of the exposure to the harmful substances generated during the plastic injection process. PMID- 24472160 TI - The maintenance and monitoring of perioperative blood volume. AB - The assessment and maintenance of perioperative blood volume is important because fluid therapy is a routine part of intraoperative care. In the past, patients undergoing major surgery were given large amounts of fluids because health-care providers were concerned about preoperative dehydration and intraoperative losses to a third space. In the last decade it has become clear that fluid therapy has to be more individualized. Because the exact determination of blood volume is not clinically possible at every timepoint, there have been different approaches to assess fluid requirements, such as goal-directed protocols guided by invasive and less invasive devices.This article focuses on laboratory volume determination, capillary dynamics, aspects of different fluids and how to clinically assess and monitor perioperative blood volume. PMID- 24472162 TI - Characterization of a calcified intra-cardiac pseudocyst of the mitral valve by magnetic resonance imaging including T1 and T2 mapping. AB - BACKGROUND: Even though intra-cardiac cystic lesions are extremely unusual in adults, they should be considered in the differential diagnosis of patients presenting with valvular masses. Cardiac magnetic resonance imaging has emerged as modality of choice for non-invasive characterization of cardiac masses. CASE PRESENTATION: We report a case of an intra-cardiac mass of the mitral valve in a 51-year old male, detected by echocardiography after transient ischemic attack and retinal artery occlusion. Cardiac magnetic resonance (CMR) imaging was performed at 3 T to evaluate and characterize the lesion prior to surgery. Diagnosis of a calcified left-ventricular pseudocyst of the mitral valve was confirmed by histological evaluation. CONCLUSIONS: This case presents the unusual finding of contrast uptake in an intra-cardiac cystic lesion and points to the potential of T1 and T2 mapping for assisting in the characterization and diagnosis of intra-cardiac masses by CMR. PMID- 24472163 TI - Food and eating environments: in Canadian schools. AB - PURPOSE: This national study was conducted to examine healthy eating programs, healthy eating education, and the food retail environments of schools. METHODS: A total of 436 Canadian schools were studied. Administrators completed a questionnaire designed to assess school healthy eating programs, healthy eating education, and food retail environment. The number of chain fast food restaurants, chain cafes/coffee shops, and convenience stores within 1 km of schools was measured using geographic information systems food retailer measures from DMTI Spatial Inc. and the Yellow Pages. RESULTS: During the preceding year, 67% of schools had initiated healthy eating lunch programs while 18% had junk food-free days. The majority of schools offered cooking classes (59%) and healthy eating media literacy education (67%), while a minority offered gardening activities (15%) and field trips to farmers' markets (27%) and grocery stores (36%). Fifty-three percent had a school cafeteria, and most had a school tuck shop (75%) and pop/juice vending machines (76%). Fifty percent had a chain fast food restaurant, 33% had a chain cafe/coffee shop, and 41% had a convenience store within 1 km. CONCLUSIONS: An important aspect of addressing childhood obesity will be improving the food environments of schools and their surrounding neighbourhoods, and providing healthy eating education for all students. PMID- 24472164 TI - Evaluating a fruit and vegetable program: in eastern Ontario schools. AB - PURPOSE: Effectiveness was evaluated for a fruit and vegetable program developed to encourage Canadian elementary school children to eat the recommended number of daily servings. Also examined was whether the program modified children's personal factors, perceived social environment, and perceived physical environment. METHODS: A prospective, quasi-experimental trial was conducted to compare the eight schools receiving the intervention curriculum (Freggie Friday schools [FFS]) with six control schools (CS). A food frequency questionnaire was used to measure differences in fruit and vegetable consumption. Personal factors, perceived social environment, and perceived physical environment supporting fruit and vegetable consumption were assessed with an adapted version of the validated Pro Children study questionnaire. RESULTS: Of the 942 children who completed the baseline assessment, 807 also completed the follow-up questionnaire (FFS, 450; CS, 357). A mixed-effects regression model indicated no significant intervention effects on fruit or vegetable consumption, snack food consumption, or knowledge or attitudes related to fruit and vegetable consumption. CONCLUSIONS: The results suggest that an intervention based on a single visit from an external group, followed by teacher-led programming, may be an ineffective method of eliciting dietary behaviour change in this population. Future programs may need to implement multicomponent intervention designs. PMID- 24472165 TI - Promoting nutritional well-being in seniors: feasibility study of a nutrition information series. AB - Better Living Health and Community Services developed a 12-week community-based nutrition information series (NIS) for people aged 55 or older. The purpose of this feasibility study was to describe briefly the process of developing and implementing the 12-week NIS and to identify the practicality and plausibility of the program in terms of its process and content attributes, using Thorncliffe Park community as the test site. A pre- and post-test design was used to identify changes in participants' perception of their nutritional and overall well-being. Twenty-four participants who completed at least four sessions participated in the post-evaluation follow-up. Only participants' perception of their eating habits demonstrated a significant, positive improvement (t24=2.1, P<0.05). The results suggest that the NIS has the potential to promote the health and well-being of community-living seniors. The development and implementation of the NIS provided considerations for program practicality. However, additional work is needed to examine the plausibility of the program in meeting its stated objective to promote awareness of nutrition as an important concept for healthy aging. Community-practising dietitians are instrumental in providing credible nutrition information to facilitate healthy eating in older Canadians. PMID- 24472166 TI - A review of the effects of lunch on adults' short-term cognitive functioning. AB - Because of widespread irregular lunch consumption by both children and adults, information on the effects of lunch on short-term cognitive functioning is relevant to public health. In September 2012, a MEDLINE search was conducted for studies in which the effects of lunch on cognitive performance were examined. Eleven experimental studies published from 1981 to 1996 were found and evaluated; all involved adults. In three studies, the effects of lunch and lunch skipping were compared; the remaining studies involved a determination of the effects of lunch size and lunch composition. Results of studies in which lunch was compared with no lunch indicate that lunch leads to potential impairment of some aspects of cognitive functioning in the early afternoon. Lunch size may influence cognitive functioning, with impairment more likely to occur after a large lunch than a small lunch. Furthermore, in comparison with low-fat lunches, high-fat lunches seem to result in slower but more accurate responses to some cognitive tasks. However, these suggestions must be viewed with caution, as they are based on only a few studies and are not thoroughly supported by high-quality evidence. In addition, results obtained with adults are not applicable to children. Thus, the potential effects of lunch need further examination in children and adults. PMID- 24472167 TI - Self-reported causes of weight gain: among prebariatric surgery patients. AB - PURPOSE: Bariatric surgery is accepted by the medical community as the most effective treatment for obesity; however, weight regain after surgery remains common. Long-term weight loss and weight maintenance may be aided when dietitians who provide perioperative care understand the causes of weight gain leading to bariatric surgery. In this study, the most common causes for weight gain were examined among prebariatric surgery patients. METHODS: A retrospective chart review was conducted for 160 patients enrolled in a bariatric surgery program. Data were collected for 20 variables: puberty, pregnancy, menopause, change in living environment, change in job/career, financial problems, quitting smoking, drug or alcohol use, medical condition, surgery, injury affecting mobility, chronic pain, dieting, others' influence over diet, abuse, mental health condition, stress, death of a loved one, divorce/end of a relationship, and other causes. Frequency distribution and chi-square tests were performed using SPSS. RESULTS: Sixty-three percent of participants selected stress as a cause of weight gain, while 56% selected dieting. Significant differences existed between women and men in the selection of dieting and change in living environment. CONCLUSIONS: This information may allow dietitians to better identify causes for weight gain leading to bariatric surgery, and to address these causes appropriately before and after surgery. PMID- 24472169 TI - Nutrition and shiftwork: evaluation of new paramedics' knowledge and attitudes. AB - PURPOSE: The effect of an oral education intervention on nutrition knowledge was evaluated in new paramedic employees. The evaluation involved measuring knowledge of and attitudes toward nutrition and shiftwork before and after the directed intervention. METHODS: A convenience sample of 30 new paramedic shiftworkers attended a 15-minute education session focused on nutrition management strategies. This matched cohort study included three self-administered surveys. Survey 1 was completed before education, survey 2 immediately after education, and survey 3 after one month of concurrent post-education and employment experience. Knowledge and attitude scores were analyzed for differences between all surveys. RESULTS: Participants were primary care paramedics, 59% of whom were male. They reported that previously they had not received this type of information or had received only a brief lecture. Mean knowledge scores increased significantly from survey 1 to survey 2; knowledge retention was identified in survey 3. A significant difference was found between surveys 2 and 3 for attitudes toward meal timing; no other significant differences were found between attitude response scores. CONCLUSIONS: The education session was successful in improving shiftwork nutrition knowledge among paramedics. Paramedics' attitudes toward proper nutrition practices were positive before the education intervention. PMID- 24472168 TI - Healthy eating guidelines for a school jurisdiction: collaborative design and implementation. AB - PURPOSE: Healthy eating is a determinant of optimal growth, and schools provide an ideal setting in which to influence students' diets. The Healthy Eating Guidelines Initiative (HEGI) was a partnership among education, health, and community stakeholders to develop and implement healthy eating guidelines across a school jurisdiction. An evaluation was conducted to examine the potential impact of the HEGI on the school food environment and students' self-reported diets. METHODS: All schools in the jurisdiction were invited to participate in the evaluation. Participating schools included elementary, middle, high, and mixed grades schools. A school environment assessment and a student questionnaire were used to collect data before and after the HEGI. RESULTS: Twenty-two (71%) of 31 schools participated in the evaluation. The guidelines were successfully implemented in 17 of these 22 schools. Overall, a greater proportion of students reported healthier eating behaviours at the conclusion of the HEGI. In particular, a greater proportion of students in schools with cafeteria-style food service showed significantly improved self-reported dietary behaviours. These changes were not seen among students at schools with limited or no on-site food service. CONCLUSIONS: The findings are consistent with those of previous studies, and indicate that guidelines for a school jurisdiction can have a positive impact on the school food environment and students' food intake. The HEGI shows promise as a strategy to promote healthy eating among students. PMID- 24472170 TI - Microenvironmental pH-modification to improve dissolution behavior and oral absorption for drugs with pH-dependent solubility. AB - INTRODUCTION: Drug release and oral absorption of drugs with pH-dependent solubility are influenced by the conditions in the gastrointestinal tract. In some cases, poor oral absorption has been observed for these drugs, causing insufficient drug efficacy. The pH-modification of a formulation could be a promising approach to overcome the poor oral absorption of drugs with pH dependent solubility. AREAS COVERED: The present review aims to summarize the pH modifier approach and strategic analyses of microenvironmental pH for formulation design and development. We also provide literature- and patent-based examples of the application of pH-modification technology to solid dosage forms. EXPERT OPINION: For the pH-modification approach, the microenvironmental pH at the diffusion area can be altered by dissolving pH-modifying excipients in the formulation. The modulation of the microenvironmental pH could improve dissolution behavior of drugs with pH-dependent solubility, possibly leading to better oral absorption. According to this concept, the modulated level of microenvironmental pH and its duration can be key factors for improvement in drug dissolution. The measurement of microenvironmental pH and release of pH-modifier would provide theoretical insight for the selection of an appropriate pH-modifier and optimization of the formulation. PMID- 24472171 TI - Contact lenses for antifungal ocular drug delivery: a review. AB - INTRODUCTION: Fungal keratitis, a potentially blinding disease, has been difficult to treat due to the limited number of approved antifungal drugs and the taxing dosing regimen. Thus, the development of a contact lens (CL) as an antifungal drug delivery platform has the potential to improve the treatment of fungal keratitis. A CL can serve as a drug reservoir to continuously release drugs to the cornea, while limiting drug loss through tears, blinking, drainage and non-specific absorption. AREAS COVERED: This review will provide a summary of currently available methods for delivering antifungal drugs from commercial and model CLs, including vitamin E coating, impregnated drug films, cyclodextrin functionalized hydrogels, polyelectrolyte hydrogels and molecular imprinting. This review will also highlight some of the main factors that influence antifungal drug delivery with CLs. EXPERT OPINION: Several novel CL materials have been developed, capable of extended drug release profiles with a wide range of antifungal drugs lasting from 8 h to as long as 21 days. However, there are factors, such as first-order release kinetics, effectiveness of continuous drug release, microbial resistance, ocular toxicity and potential complications from inserting a CL in an infected eye, that still need to be addressed before commercial applications can be realized. PMID- 24472173 TI - Management of locally advanced laryngeal cancer. AB - BACKGROUND: Management of advanced laryngeal cancer is complex and ideal strategy is yet to be defined. This study evaluates the experience of a single head and neck oncologic centre in the management of T4 laryngeal cancer. METHODS: Retrospective assessment of cases primarily treated for T4a squamous cell carcinoma of the larynx, between 1980 and 2007, at a tertiary referral center. RESULTS: A total of 384 cases were studied. Five-year disease specific survival was 56.2% and local control 87.4%. Regional and distal control estimates were 90.3% and 88.3% respectively. Prognosis was significantly superior for cases treated with primary surgery compared to cases solely managed with non-surgical modalities. Positive surgical margins and regional disease worsened prognosis. CONCLUSION: This study suggests that primary surgery remains a key element in the treatment of advanced laryngeal cancer. The need for well-designed, prospective, randomised studies in order to further evaluate the remaining role of primary surgery in the modern management of locally advanced laryngeal lesions is emphasized. PMID- 24472174 TI - Impaired neuropathic pain and preserved acute pain in rats overexpressing voltage gated potassium channel subunit Kv1.2 in primary afferent neurons. AB - Voltage-gated potassium (Kv) channels are critical in controlling neuronal excitability and are involved in the induction of neuropathic pain. Therefore, Kv channels might be potential targets for prevention and/or treatment of this disorder. We reported here that a majority of dorsal root ganglion (DRG) neurons were positive for Kv channel alpha subunit Kv1.2. Most of them were large and medium, although there was a variety of sizes. Peripheral nerve injury caused by lumbar (L)5 spinal nerve ligation (SNL) produced a time-dependent reduction in the number of Kv1.2-positive neurons in the ipsilateral L5 DRG, but not in the contralateral L5 DRG. Such reduction was also observed in the ipsilateral L5 DRG on day 7 after sciatic nerve axotomy. Rescuing nerve injury-induced reduction of Kv1.2 in the injured L5 DRG attenuated the development and maintenance of SNL induced pain hypersensitivity without affecting acute pain and locomotor function. This effect might be attributed to the prevention of SNL-induced upregulation of endogenous Kv1.2 antisense RNA, in addition to the increase in Kv1.2 protein expression, in the injured DRG. Our findings suggest that Kv1.2 may be a novel potential target for preventing and/or treating neuropathic pain. PMID- 24472175 TI - Inverse regulation of melanoma growth and migration by Orai1/STIM2-dependent calcium entry. AB - Spontaneous melanoma phenotype switching is controlled by unknown environmental factors and may determine melanoma outcome and responsiveness to anticancer therapy. We show that Orai1 and STIM2 are highly expressed and control store operated Ca(2+) entry in human melanoma. Lower extracellular Ca(2+) or silencing of Orai1/STIM2 caused a decrease in intracellular Ca(2+) , which correlated with enhanced proliferation and increased expression of microphthalmia-associated transcription factor, a marker for proliferative melanoma phenotype. In contrast, the invasive and migratory potential of melanoma cells was reduced upon silencing of Orai1 and/or STIM2. Accordingly, markers for a non-proliferative, tumor maintaining phenotype such as JARID1B and Brn2 decreased. Immunohistochemical staining of primary melanomas and lymph node metastases revealed a heterogeneous distribution of Orai1 and STIM2 with elevated expression in the invasive rim of the tumor. In summary, our results support a dynamic model in which Orai1 and STIM2 inversely control melanoma growth and invasion. Pharmacological tuning of Orai1 and particularly STIM2 might thus prevent metastatic spread and render melanomas more susceptible to conventional therapy. PMID- 24472176 TI - Mean platelet volume in differentiating congestive heart failure from chronic obstructive pulmonary disease. PMID- 24472177 TI - Drug discovery and development for acute heart failure drugs: are expectations too high? PMID- 24472179 TI - Syndecan-2 regulates melanin synthesis via protein kinase C betaII-mediated tyrosinase activation. AB - Syndecan-2, a transmembrane heparan sulfate proteoglycan that is highly expressed in melanoma cells, regulates melanoma cell functions (e.g. migration). Since melanoma is a malignant tumor of melanocytes, which largely function to synthesize melanin, we investigated the possible involvement of syndecan-2 in melanogenesis. Syndecan-2 expression was increased in human skin melanoma tissues compared with normal skin. In both mouse and human melanoma cells, siRNA-mediated knockdown of syndecan-2 was associated with reduced melanin synthesis, whereas overexpression of syndecan-2 increased melanin synthesis. Similar effects were also detected in human primary epidermal melanocytes. Syndecan-2 expression did not affect the expression of tyrosinase, a key enzyme in melanin synthesis, but instead enhanced the enzymatic activity of tyrosinase by increasing the membrane and melanosome localization of its regulator, protein kinase CbetaII. Furthermore, UVB caused increased syndecan-2 expression, and this up-regulation of syndecan-2 was required for UVB-induced melanin synthesis. Taken together, these data suggest that syndecan-2 regulates melanin synthesis and could be a potential therapeutic target for treating melanin-associated diseases. PMID- 24472178 TI - Analysis of pfhrp2 genetic diversity in Senegal and implications for use of rapid diagnostic tests. AB - BACKGROUND: The Senegalese National Malaria Control Programme has recommended use of rapid diagnostic tests (RDTs) that target the histidine-rich protein 2 (HRP2), specific to Plasmodium falciparum, to diagnose malaria cases. The target antigen has been shown to be polymorphic, which may explain the variability in HRP2-based RDT results reported in field studies. The genetic diversity of the pfhrp2 gene has not been investigated in depth in many African countries. The goal of this study is to determine the extent of polymorphism in pfhrp2 among Senegal, Mali and Uganda parasite populations, and discuss the implications of these findings on the utility of RDTs that are based on HRP2 detection. METHODS: Sequencing data from the pfhrp2 locus were used to analyze the genetic diversity of this gene among three populations, with different transmission dynamics and malaria parasite ecologies. Nucleotide diversity (pi) and non-synonymous nucleotide diversity (piNS) were studied in the pfhrp2 gene from isolates obtained in Senegal. Amino acid repeat length polymorphisms in the PfHRP2 antigen were characterized and parameters of genetic diversity, such as frequency and correlation between repeats in these populations, were assessed. RESULTS: The diversity survey of the pfhrp2 gene identified 29 SNPs as well as insertion and deletion polymorphisms within a 918 bp region. The Senegal pfhrp2 exhibited a substantial level of diversity [pi = 0.00559 and piNS = 0.014111 (piS = 0.0291627)], similar to several polymorphic genes, such as msp1, involved in immune responses, and the gene encoding the SURFIN polymorphic antigen, which are surface exposed parasite proteins. Extensive repeat length polymorphisms in PfHRP2, as well as similar patterns in the number, organization and the type of predicted amino acid repeats were observed among the three populations, characterized by an occurrence of Type 2, Type 4 and Type 7 repeats. CONCLUSIONS: These results warrant deeper monitoring of the RDT target antigen diversity and emphasize that development of other essential genes as a target for diagnostic tools is critical. PMID- 24472180 TI - Effects of health and safety problem recognition on small business facility investment. AB - OBJECTIVES: This study involved a survey of the facility investment experiences, which was designed to recognize the importance of health and safety problems, and industrial accident prevention. Ultimately, we hope that small scale industries will create effective industrial accident prevention programs and facility investments. METHODS: An individual survey of businesses' present physical conditions, recognition of the importance of the health and safety problems, and facility investment experiences for preventing industrial accidents was conducted. The survey involved 1,145 business operators or management workers in small business places with fewer than 50 workers in six industrial complexes. RESULTS: Regarding the importance of occupational health and safety problems (OHS), 54.1% said it was "very important". Received technical and financial support, and industrial accidents that occurred during the past three years were recognized as highly important for OHS. In an investigation regarding facility investment experiences for industrial accident prevention, the largest factors were business size, greater numbers of industrial accidents, greater technical and financial support received, and greater recognition of the importance of the OHS. The related variables that decided facility investment for industry accident prevention in a logistic regression analysis were the experiences of business facilities where industrial accidents occurred during the past three years, received technical and financial support, and recognition of the OHS. Those considered very important were shown to be highly significant. CONCLUSIONS: Recognition of health and safety issues was higher when small businesses had experienced industrial accidents or received financial support. The investment in industrial accidents was greater when health and safety issues were recognized as important. Therefore, the goal of small business health and safety projects is to prioritize health and safety issues in terms of business management and recognition of importance. Therefore, currently various support projects are being conducted. However, there are issues regarding the limitations of the target businesses and inadequacies in maintenance and follow-up. Overall, it is necessary to provide various incentives for onsite participation that can lead to increased recognition of health and safety issues and practical investments, while perfecting maintenance and follow up measures by thoroughly revising existing operating systems. PMID- 24472181 TI - Investigation of bacterial nucleotide excision repair using single-molecule techniques. AB - Despite three decades of biochemical and structural analysis of the prokaryotic nucleotide excision repair (NER) system, many intriguing questions remain with regard to how the UvrA, UvrB, and UvrC proteins detect, verify and remove a wide range of DNA lesions. Single-molecule techniques have begun to allow more detailed understanding of the kinetics and action mechanism of this complex process. This article reviews how atomic force microscopy and fluorescence microscopy have captured new glimpses of how these proteins work together to mediate NER. PMID- 24472182 TI - Development of the PRE-HIT instrument: patient readiness to engage in health information technology. AB - BACKGROUND: Technology-based aids for lifestyle change are becoming more prevalent for chronic conditions. Important "digital divides" remain, as well as concerns about privacy, data security, and lack of motivation. Researchers need a way to characterize participants' readiness to use health technologies. To address this need, we created an instrument to measure patient readiness to engage with health technologies among adult patients with chronic conditions. METHODS: Initial focus groups to determine domains, followed by item development and refinement, and exploratory factor analysis to determine final items and factor structure. The development sample included 200 patients with chronic conditions from 6 family medicine clinics. From 98 potential items, 53 best candidate items were examined using exploratory factor analysis. Pearson's Correlation for Test/Retest reliability at 3 months. RESULTS: The final instrument had 28 items that sorted into 8 factors with associated Cronbach's alpha: 1) Health Information Need (0.84), 2) Computer/Internet Experience (0.87), 3) Computer Anxiety (0.82), 4) Preferred Mode of Interaction (0.73), 5) Relationship with Doctor (0.65), 6) Cell Phone Expertise (0.75), 7) Internet Privacy (0.71), and 8) No News is Good News (0.57). Test-retest reliability for the 8 subscales ranged from (0.60 to 0.85). CONCLUSION: The Patient Readiness to Engage in Health Internet Technology (PRE-HIT) instrument has good psychometric properties and will be an aid to researchers investigating technology-based health interventions. Future work will examine predictive validity. PMID- 24472184 TI - Does time of transfer from critical care to the general wards affect anxiety? A pragmatic prospective cohort study. AB - OBJECTIVES: To examine prospectively the impact of transfer time on patient anxiety. DESIGN: A pragmatic prospective cohort study. SETTING: 14 bed adult intensive care unit (ICU) in a National Health Service teaching hospital trust in the United Kingdom. METHODS: Critically ill patients staying on the ICU for at least 24 hours and clinically ready for transfer to the general ward completed the Hospital Anxiety and Depression Scale questionnaire (Zigmond and Snaith, 1983) at: pre-transfer - on the critical care (when they were clinically ready for transfer to the general ward), post-transfer - on the general ward. RESULTS: The post-transfer median (range) score for anxiety was 6 (4-10) for day time and higher at 12.5 (9-16) for night time; this was found to be statistically significant U=80, p=0.011, r=0.37 and the post-transfer incidence of anxiety cases was 22% (8/36) for day time and higher at 64% (7/11) for night time; this was found to be statistically significant U=91, p=0.007, r=0.39. CONCLUSION: This study suggests that transfers at night time are more anxiety provoking for patients than transfers in the day time. PMID- 24472183 TI - Gene expression-based comparison of the human secretory neuroepithelia of the brain choroid plexus and the ocular ciliary body: potential implications for glaucoma. AB - BACKGROUND: The neuroepithelia of the choroid plexus (CP) in the brain and the ciliary body (CB) of the eye have common embryological origins and share similar micro-structure and functions. The CP epithelium (CPE) and the non-pigmented epithelium (NPE) of the CB produce the cerebrospinal fluid (CSF) and the aqueous humor (AH) respectively. Production and outflow of the CSF determine the intracranial pressure (ICP); production and outflow of the AH determine the intraocular pressure (IOP). Together, the IOP and ICP determine the translaminar pressure on the optic disc which may be involved in the pathophysiology of primary open angle glaucoma (POAG). The aim of this study was to compare the molecular machinery of the secretory neuroepithelia of the CP and CB (CPE versus NPE) and to determine their potential role in POAG. METHODS: We compared the transcriptomes and functional annotations of healthy human CPE and NPE. Microarray and bioinformatic studies were performed using an Agilent platform and the Ingenuity Knowledge Database (IPA). RESULTS: Based on gene expression profiles, we found many similar functions for the CPE and NPE including molecular transport, neurological disease processes, and immunological functions. With commonly-used selection criteria (fold-change > 2.5, p-value < 0.05), 14% of the genes were expressed significantly differently between CPE and NPE. When we used stricter selection criteria (fold-change > 5, p-value < 0.001), still 4.5% of the genes were expressed differently, which yielded specific functions for the CPE (ciliary movement and angiogenesis/hematopoiesis) and for the NPE (neurodevelopmental properties). Apart from a few exceptions (e.g. SLC12A2, SLC4A4, SLC4A10, KCNA5, and SCN4B), all ion transport protein coding genes involved in CSF and AH production had similar expression profiles in CPE and NPE. Three POAG disease genes were expressed significantly higher in the CPE than the NPE, namely CDH1, CDKN2B and SIX1. CONCLUSIONS: The transcriptomes of the CPE and NPE were less similar than we previously anticipated. High expression of CSF/AH production genes and candidate POAG disease genes in the CPE and NPE suggest that both might be involved in POAG. PMID- 24472185 TI - Association of diabetes mellitus with a combination of vitamin d deficiency and arsenic exposure in the korean general population: analysis of 2008-2009 korean national health and nutrition examination survey data. AB - OBJECTIVES: We present data from the Korean National Health and Nutritional Examination Survey (KNHANES) 2008-2009 on the combination of vitamin D deficiency and arsenic exposure on diabetes mellitus (DM) in a representative sample of the adult Korean population. METHODS: This study was based on data obtained from the KNHANES 2008-2009, which was conducted for 3 years (2007-2009) using a rolling sampling design that involved a complex, stratified, multistage, probability cluster survey of a representative sample of the non-institutionalized civilian population in South Korea. RESULTS: Data analysis revealed that subjects who showed both vitamin D levels in the 1st quartile (Q) and urinary arsenic levels in the 4th Q, had a 302% increased risk of having DM, as compared with those whose vitamin D and urinary arsenic levels were in the 4th Q and 1st Q, respectively. CONCLUSION: The present study reconfirmed an association of DM with low vitamin D levels and arsenic exposure, and further showed a combination of vitamin D deficiency and arsenic exposure on DM in the general Korean population. To the best of our knowledge, this is the first report describing a combination of vitamin D deficiency and arsenic exposure on DM. The present findings have important public health implications. PMID- 24472187 TI - School based interventions versus family based interventions in the treatment of childhood obesity- a systematic review. AB - BACKGROUND: The prevalence of childhood obesity, which has seen a rapid increase over the last decade, is now considered a major public health problem. Current treatment options are based on the two important frameworks of school- and family based interventions; however, most research has yet to compare the two frameworks in the treatment of childhood obesity.The objective of this review is to compare the effectiveness of school-based intervention with family-based intervention in the treatment of childhood obesity. METHODS: Databases such as Medline, Pub med, CINAHL, and Science Direct were used to execute the search for primary research papers according to inclusion criteria. The review included a randomised controlled trial and quasi-randomised controlled trials based on family- and school-based intervention frameworks on the treatment of childhood obesity. RESULTS: The review identified 1231 articles of which 13 met the criteria. Out of the thirteen studies, eight were family-based interventions (n = 8) and five were school-based interventions (n = 5) with total participants (n = 2067). The participants were aged between 6 and 17 with the study duration ranging between one month and three years. Family-based interventions demonstrated effectiveness for children under the age of twelve and school-based intervention was most effective for those aged between 12 and 17 with differences for both long-term and short-term results. CONCLUSIONS: The evidence shows that family- and school based interventions have a considerable effect on treating childhood obesity. However, the effectiveness of the interventional frameworks depends on factors such as age, short- or long-term outcome, and methodological quality of the trials. Further research studies are required to determine the effectiveness of family- and school-based interventions using primary outcomes such as weight, BMI, percentage overweight and waist circumference in addition to the aforementioned factors. PMID- 24472188 TI - Fewer living: a decline in living donors may be due to multiple factors. PMID- 24472190 TI - Banff 2013 meeting report: inclusion of c4d-negative antibody-mediated rejection and antibody-associated arterial lesions. AB - The 12th Banff Conference on Allograft Pathology was held in Comandatuba, Brazil, from August 19-23, 2013, and was preceded by a 2-day Latin American Symposium on Transplant Immunobiology and Immunopathology. The meeting was highlighted by the presentation of the findings of several working groups formed at the 2009 and 2011 Banff meetings to: (1) establish consensus criteria for diagnosing antibody mediated rejection (ABMR) in the presence and absence of detectable C4d deposition; (2) develop consensus definitions and thresholds for glomerulitis (g score) and chronic glomerulopathy (cg score), associated with improved inter observer agreement and correlation with clinical, molecular and serological data; (3) determine whether isolated lesions of intimal arteritis ("isolated v") represent acute rejection similar to intimal arteritis in the presence of tubulointerstitial inflammation; (4) compare different methodologies for evaluating interstitial fibrosis and for performing/evaluating implantation biopsies of renal allografts with regard to reproducibility and prediction of subsequent graft function; and (5) define clinically and prognostically significant morphologic criteria for subclassifying polyoma virus nephropathy. The key outcome of the 2013 conference is defining criteria for diagnosis of C4d negative ABMR and respective modification of the Banff classification. In addition, three new Banff Working Groups were initiated. PMID- 24472191 TI - Alloprimed CD8(+) T cells regulate alloantibody and eliminate alloprimed B cells through perforin- and FasL-dependent mechanisms. AB - While it is well known that CD4(+) T cells and B cells collaborate for antibody production, our group previously reported that CD8(+) T cells down-regulate alloantibody responses following transplantation. However, the exact mechanism involved in CD8(+) T cell-mediated down-regulation of alloantibody remains unclear. We also reported that alloantibody production is enhanced when either perforin or FasL is deficient in transplant recipients. Here, we report that CD8(+) T cell-deficient transplant recipient mice (high alloantibody producers) exhibit an increased number of primed B cells compared to WT transplant recipients. Furthermore, CD8(+) T cells require FasL, perforin and allospecificity to down-regulate posttransplant alloantibody production. In vivo CD8-mediated clearance of alloprimed B cells was also FasL- and perforin dependent. In vitro data demonstrated that recipient CD8(+) T cells directly induce apoptosis of alloprimed IgG1(+) B cells in co-culture in an allospecific and MHC class I-dependent fashion. Altogether these data are consistent with the interpretation that CD8(+) T cells down-regulate posttransplant alloantibody production by FasL- and perforin-dependent direct elimination of alloprimed IgG1(+) B cells. PMID- 24472192 TI - The allo- and viral-specific immunosuppressive effect of belatacept, but not tacrolimus, attenuates with progressive T cell maturation. AB - Tacrolimus impairs allo- and viral-specific T cell responses. Belatacept, a costimulation-based alternative to tacrolimus, has emerged with a paradoxical picture of less complete control of alloimmunity with concomitant impaired viral immunity limited to viral-naive patients. To reconcile these signatures, bulk population and purified memory and naive lymphocytes from cytomegalovirus (CMV) seropositive (n=10) and CMV-seronegative (n=10) volunteers were studied using flow cytometry, interrogating proliferation (carboxyfluorescein succinimidyl ester dilution) and function (intracellular cytokine staining) in response to alloantigens or CMV-pp-65 peptides. As anticipated, T cells from CMV-experienced, but not naive, individuals responded to pp-65 with a small percentage of their repertoire (<2.5%) consisting predominantly of mature, polyfunctional (expressing interferon gamma, tumor necrosis factor alpha and IL-2) T effector memory cells. Both CMV naive and experienced individuals responded similarly to alloantigen with a substantially larger percentage of the repertoire (up to 48.2%) containing proportionately fewer polyfunctional cells. Tacrolimus completely inhibited responses of CMV- and allo-specific T cells regardless of their maturation. However, belatacept's effects were decreasingly evident in increasingly matured cells, with minimal effect on viral-specific triple cytokine producers and CD28 negative allo-specific cells. These data indicate that belatacept's immunosuppressive effect, unlike tacrolimus's, wanes on progressively developed effector responses, and may explain the observed clinical effects of belatacept. PMID- 24472193 TI - Bcl-2 inhibition to overcome memory cell barriers in transplantation. AB - Memory T cells (Tm) represent a major barrier for immunosuppression and tolerance induction after solid organ transplantation. Taking into consideration the critical role of the intrinsic apoptosis pathway in the generation and maintenance of Tm, we developed a new concept to deplete alloreactive Tm by targeting Bcl-2 proteins. The small-molecule Bcl-2/Bcl-XL inhibitor ABT-737 efficiently induced apoptosis in alloreactive Tm in vitro and in vivo and prolonged skin graft survival in sensitized recipients. A short course of ABT-737 induction therapy prevented Tm-mediated resistance in a donor-specific transfusion model and allowed mixed chimerism induction across Tm barriers. Since Bcl-2 inhibitors yielded encouraging safety results in cancer trials, this novel approach might represent a substantial advance to prevent allograft rejection and induce tolerance in sensitized recipients. PMID- 24472194 TI - Revisiting the safety of living liver donors by reassessing 441 donor hepatectomies: is a larger hepatectomy complication-prone? AB - Donor safety is of paramount importance in performing living donor liver transplantation (LDLT). We retrospectively reviewed donor medical records to confirm whether larger donor hepatectomy is absolutely complication-prone. A total of 441 living donor hepatectomies were performed between October 1996 and July 2012 in our institute, which were divided into three eras (Era I, October 1996 to March 2004; Era II, April 2004 to March 2008; Era III, April 2008 to July 2012) and the incidences of postoperative complications were compared among the three types of hepatectomy-right hepatectomy (RH), left hepatectomy (LH) and left lateral segmentectomy (LLS). Although severe complications (Clavien's grade 3 or more) frequently occurred in RH in Eras I and II (15.4% and 10.7%, respectively), the incidence in Era III decreased to the comparable level observed in LH and LLS (5.4% in RH, 2.3% in LH and 5.3% in LLS). The incidence of postoperative complications did not relate to the type of hepatectomy selected in the latest era. Since most complications after hepatectomy were considered preventable, step by-step meticulous surgical procedures are a prerequisite for further assuring donor safety irrespective of the type of hepatectomy selected. PMID- 24472197 TI - Persistent bile leak after deceased donor split liver transplantation. PMID- 24472195 TI - Kidneys at higher risk of discard: expanding the role of dual kidney transplantation. AB - Half of the recovered expanded criteria donor (ECD) kidneys are discarded in the United States. A new kidney allocation system offers kidneys at higher risk of discard, Kidney Donor Profile Index (KDPI)>85%, to a wider geographic area to promote broader sharing and expedite utilization. Dual kidney transplantation (DKT) based on the KDPI is a potential option to streamline allocation of kidneys which otherwise would have been discarded. To assess the clinical utility of the KDPI in kidneys at higher risk of discard, we analyzed the OPTN/UNOS Registry that included the deceased donor kidneys recovered between 2002 and 2012. The primary outcomes were allograft survival, patient survival and discard rate based on different KDPI categories (<80%, 80-90% and >90%). Kidneys with KDPI>90% were associated with increased odds of discard (OR=1.99, 95% CI 1.74-2.29) compared to ones with KDPI<80%. DKTs of KDPI>90% were associated with lower overall allograft failure (HR=0.74, 95% CI 0.62-0.89) and better patient survival (HR=0.79, 95% CI 0.64-0.98) compared to single ECD kidneys with KDPI>90%. Kidneys at higher risk of discard may be offered in the up-front allocation system as a DKT. Further modeling and simulation studies are required to determine a reasonable KDPI cutoff percentile. PMID- 24472198 TI - Using bispectral index and cerebral oximetry to guide hemodynamic therapy in high risk surgical patients. AB - High-risk surgery represents 12.5% of cases but contributes 80% of deaths in the elderly population. Reduction in morbidity and mortality by the use of intervention strategies could result in thousands of lives being saved and savings of up to L400m per annum in the UK. This has resulted in the drive towards goal-directed therapy and intraoperative flow optimization of high-risk surgical patients being advocated by authorities such as the National Institute of Health and Care Excellence and the Association of Anaesthetists of Great Britain and Ireland.Conventional intraoperative monitoring gives little insight into the profound physiological changes occurring as a result of anesthesia and surgery. The build-up of an oxygen debt is associated with a poor outcome and strategies have been developed in the postoperative period to improve outcomes by repayment of this debt. New monitoring technologies such as minimally invasive cardiac output, depth of anesthesia and cerebral oximetry can minimize oxygen debt build-up. This has the potential to reduce complications and lessen the need for postoperative optimization in high-dependency areas.Flow monitoring has thus emerged as essential during intraoperative monitoring in high-risk surgery. However, evidence suggests that current optimization strategies of deliberately increasing flow to meet predefined targets may not reduce mortality.Could the addition of depth of anesthesia and cerebral and tissue oximetry monitoring produce a further improvement in outcomes?Retrospective studies indicate a combination of excessive depth of anesthesia hypotension and low anesthesia requirement results in increased mortality and length of hospital stay.Near infrared technology allows assessment and maintenance of cerebral and tissue oxygenation, a strategy, which has been associated with improved outcomes. The suggestion that the brain is an index organ for tissue oxygenation, especially in the elderly, indicates a role for this technology in the intraoperative period to assess the adequacy of oxygen delivery and reduce the build-up of an oxygen debt.The aim of this article is to make the case for depth of anesthesia and cerebral oximetry alongside flow monitoring as a strategy for reducing oxygen debt during high-risk surgery and further improve outcomes in high-risk surgical patients. PMID- 24472199 TI - Vertical stratification of beetles (Coleoptera) and flies (Diptera) in temperate forest canopies. AB - Forest canopies support high arthropod biodiversity, but in temperate canopies, little is known about the spatial distribution of these arthropods. This is an important first step toward understanding ecological roles of insects in temperate canopies. The objective of this study was to assess differences in the species composition of two dominant and diverse taxa (Diptera and Coleoptera) along a vertical gradient in temperate deciduous forest canopies. Five sugar maple trees from each of three deciduous forest sites in southern Quebec were sampled using a combination of window and trunk traps placed in three vertical strata (understory, mid-canopy, and upper-canopy) for three sampling periods throughout the summer. Coleoptera species richness and abundance did not differ between canopy heights, but more specimens and species of Diptera were collected in the upper-canopy. Community composition of Coleoptera and Diptera varied significantly by trap height. Window traps collected more specimens and species of Coleoptera than trunk traps, although both trap types should be used to maximize representation of the entire Coleoptera community. There were no differences in abundance, diversity, or composition of Diptera collected between trap types. Our data confirm the relevance of sampling all strata in a forest when studying canopy arthropod biodiversity. PMID- 24472200 TI - Combination of genomic and proteomic approaches to characterize the symbiotic population of the banana aphid (Hemiptera: Aphididae). AB - Aphids are known to live in symbiosis with specific bacteria called endosymbionts that have positive or negative impacts on their hosts. In this study, six banana aphid (Pentalonia nigronervosa Coquerel) strains from various geographical origins (Gabon, Madagascar, and Burundi) were screened to determine their symbiotic content, using complementary genomic (16S rDNA sequencing and specific polymerase chain reaction) and proteomic (two-dimensional difference gel electrophoresis coupled with protein identification by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry) approaches. Despite the geographical heterogeneity, the combined methods allowed us to identify the same two symbionts in the six aphids strains tested: Buchnera aphidicola and Wolbachia. Although B. aphidicola is found in almost all aphid species, the systematic presence of Wolbachia in banana aphids is particularly interesting, as this bacterium usually has a low prevalence in aphid species. Phylogenetic analyses showed that the Wolbachia sp. strain found in P. nigronervosa was very similar to the strain present in aphids of the genus Cinara, known to have developed a strong and long-term symbiotic association with Wolbachia. The high level of asexual reproduction in P. nigronervosa could be linked to the presence of Wolbachia, but its prevalence also suggests that this symbiotic bacterium could play a more essential role in its aphid host. PMID- 24472201 TI - Soybean aphid (Hemiptera: Aphididae) response to soybean plant defense: stress levels, tradeoffs, and cross-virulence. AB - A variety of management methods to control the soybean aphid (Aphis glycines Matsumura) have been investigated since its invasion into North America in 2000, among them plant resistance has emerged as a viable option for reducing aphid damage to soybeans and preventing outbreaks. Plant resistance methods often use natural soybean plant defenses that impose stress on aphids by reducing fitness and altering behavior. Research efforts have heavily focused on identification and development of aphid resistant soybean varieties, leaving much unknown about soybean aphid response to stressful host plant defenses. In this study, we aimed to 1) evaluate lifetime fitness consequences and phenotypic variation in response to host plant-induced stress and 2) investigate whether trade-offs involving fitness costs and/or cross-virulence to multiple antibiotic soybean varieties exists. We compared aphid survival and reproduction during and after a short period of exposure to soybeans with the Rag2 resistance gene and measured aphid clonal variation in response to Rag2 soybeans. In addition, we measured the performance of Rag2 virulent and avirulent aphids on five soybean varieties with various forms of antibiotic resistance. Our results indicate that plant defenses impose high levels of stress and have long-term fitness consequences, even after aphids are removed from resistant plants. We identified one aphid clone that was able to colonize Rag2 among the seven clones tested, suggesting that virulent genotypes may be prevalent in natural populations. Finally, although we did not find evidence of cross-virulence to multiple antibiotic soybean varieties, our results suggest independent mechanisms of aphid virulence to Rag1 and Rag2 that may involve fitness costs. PMID- 24472202 TI - Geographic variation in cannibalism in Colorado potato beetle (Coleoptera: Chrysomelidae) populations. AB - Cannibalism can have a large effect on population growth and survival in stressful environments, possibly including those created by insecticide use. In this study, we collected Colorado potato beetles from three isolated areas in the northeastern United States known for high levels of resistance to neonicotinoids. We measured resistance to imidacloprid in each of those populations, a laboratory susceptible population, and in hybrids between the three field populations and the laboratory susceptible population. We fed neonates eggs from resistant dams fed either imidacloprid-treated or untreated foliage to determine whether cannibals are exposed to toxins sequestered in eggs. We measured egg cannibalism by hatchlings within the clutch in each population and hybrids, and examined how fecundity and several variables associated with egg development varied among populations and with cannibalism, to see which traits might enhance or reduce cannibalism. Cannibalism varied significantly among populations, accounting for most of the variation in hatching success. Variability in egg development time and hatch rate in the absence of cannibalism in some populations affected rates of cannibalism. Resistance varied significantly among the field populations but was not related to cannibalism. Neonates fed eggs from dams on treated foliage showed signs of intoxication or death. Cannibalism appears to be part of a varying life history strategy in this species, with some populations laying larger and more cannibalistic clutches and the New York population laying smaller clutches with higher hatching success owing to reduced cannibalism. PMID- 24472203 TI - Use of a highly sensitive immunomarking system to characterize face fly (Diptera: Muscidae) dispersal from cow pats. AB - We tested an immunomarking system that used egg white as marker and enzyme-linked immunosorbent assay as a detection assay to characterize face fly (Musca autumnalis DeGeer) dispersal from cow pats in a pastured beef cattle operation. In microcage assays, adult flies acquired marker after contact with cow pats that were treated with marker and field aged up to 11 d. In arena assays on sprayed full-size cow pats, 77% of eclosed face flies acquired the marker. In a field marking study, four applications of egg white marker were applied on freshly deposited cow pats over a summer at two peripheral paddocks to a main grazing pasture of ?50 head of beef cattle. Of the 663 face flies captured, 108 were positive for the egg white marker (16.3%). Of the marked flies, ? twofold more male than female flies were captured. Sex-specific dispersal distances were roughly equal up to 450 m, with 11% of female flies dispersing >450 m. Dispersal capability of face flies is discussed in relation to efficacy of rotational grazing and other IPM strategies. PMID- 24472204 TI - What determines host acceptance and suitability in tropical Asian Drosophila parasitoids? AB - For successful parasitism, parasitoid females must oviposit and the progeny must develop in individual hosts. Here, we investigated the determinants of host acceptance for oviposition and host suitability for larval development of Drosophila parasitoids from Bogor and Kota Kinabalu (?1,800 km northeast of Bogor), Indonesia, in tropical Asia. Asobara pleuralis (Ashmead) from both localities oviposited frequently (>60%) in all of the drosophilid species tested, except the strain from Kota Kinabalu oviposited rarely (10%) in Drosophila eugracilis Bock & Wheeler. Leptopilina victoriae Nordlander from both localities only oviposited frequently (>77%) in species from the Drosophila melanogaster species group except D. eugracilis (<3.7%), whereas Leptopilina pacifica Novkovic & Kimura from Bogor oviposited frequently (>85%) only in species from the Drosophila immigrans species group. Thus, host acceptance appeared to be affected by host taxonomy, at least in Leptopilina species. Host suitability varied considerably, even among closely related drosophilid species, which suggests that the host suitability is at least in part independent of host taxonomy and that it has been determined via parasitoid-host coevolutionary interactions (i.e., arms race). Host acceptance did not always coincide with host suitability, i.e., parasitoids sometimes oviposited in unsuitable host species. Geographic origin strongly affected the host acceptance and suitability in the A. pleuralis-D. eugracilis parasitoid-host pair, whereas it only weakly affected the acceptability and suitability in other parasitoid-host combinations. PMID- 24472205 TI - Facilitative effects of group feeding on performance of the saddleback caterpillar (Lepidoptera: Limacodidae). AB - Gregarious feeding by insect herbivores is a widely observed, yet poorly understood, behavioral adaptation. Previous research has tested the importance of group feeding for predator deterrence, noting the ubiquity of aposematism among group-feeding insects, but few studies have examined the role of feeding facilitation for aggregates of insect herbivores. We tested the hypothesis that group feeding has facilitative effects on performance of the saddleback caterpillar, Acharia stimulea Clemens, a generalist herbivore of deciduous trees. In an understory forest setting, we reared caterpillars alone or in groups on two different host plants, white oak (Quercus alba L.) and American beech (Fagus grandifolia Ehrlich), and recorded multiple measures of insect performance during regular field censuses. As predicted, A. stimulea caterpillars feeding in groups on white oak had increased relative growth rates compared with caterpillars feeding alone, and the magnitude of this facilitative effect varied among censuses, conferring benefits both early and late in development. By contrast, no facilitative effects of group feeding were detected on beech, suggesting that the benefits of facilitative feeding may be host specific. On both hosts, caterpillar development time was slightly faster for group-feeding cohorts compared with their solitary counterparts. Because early instar caterpillars are particularly vulnerable to predation and parasitism, even modest increases in growth rates and reductions in development time may decrease exposure time to enemies during these vulnerable stages. On both hosts, group feeding also reduced the trade-off between individual development time and cocoon mass, suggesting that feeding efficiency is improved in group feeders relative to solitary caterpillars. PMID- 24472206 TI - Effects of pitfall trap lid transparency and habitat structure on the catches of carabid beetles (Coleoptera: Carabidae) in tame pasture. AB - Captures of insects in pitfall traps are affected by features of trap design that may confound the interpretation of data. One such feature is a lid suspended over the opening of the trap to exclude debris and rainwater. In this study, we tested whether use of these lids affected captures of carabid beetles by altering the light conditions at the opening to the trap. In one experiment, we examined the effects of lid transparency (opaque, semitransparent, or transparent) on catch rates. In a second experiment, we manipulated the heights (high, medium, or low) of vegetation adjacent to the traps to test for lid transparency and vegetation height interactions. We found that significantly more carabids were captured with use of transparent lids compared with other lid transparencies. Fewest Agonum cupreum Dejean, 1831, were captured with use of opaque lids. No other effects were detected. Given these results, we advocate the use of transparent lids, which provide the benefits of traditional opaque lids while minimizing the effects of lid use on light conditions at the opening to the trap. PMID- 24472207 TI - A modified mole cricket lure and description of Scapteriscus borellii (Orthoptera: Gryllotalpidae) range expansion and calling song in California. AB - Invasive mole cricket species in the genus Scapteriscus have become significant agricultural pests and are continuing to expand their range in North America. Though largely subterranean, adults of some species, such as Scapteriscus borellii Giglio-Tos 1894, are capable of long dispersive flights and phonotaxis to male calling songs to find suitable habitats and mates. Mole crickets in the genus Scapteriscus are known to be attracted to and can be caught by audio lure traps that broadcast synthesized or recorded calling songs. We report improvements in the design and production of electronic controllers for the automation of semipermanent mole cricket trap lures as well as highly portable audio trap collection designs. Using these improved audio lure traps, we collected the first reported individuals of the pest mole cricket S. borellii in California. We describe several characteristic features of the calling song of the California population including that the pulse rate is a function of soil temperature, similar to Florida populations of S. borellii. Further, we show that other calling song characteristics (carrier frequency, intensity, and pulse rate) are significantly different between the populations. PMID- 24472208 TI - Oviposition pattern of early and late-emerging genotypes of Delia radicum (Diptera: Anthomyiidae) at different temperatures. AB - The cabbage maggot, Delia radicum L., has a bimodal pattern of emergence caused by the presence in populations of early and late-emerging genotypes that differ in their pupal development time. These genotypes could also express different egg laying strategies. To examine oviposition patterns between genotypes and, particularly, their response to temperature, the egg-laying activity of females and egg mortality from each genotype were evaluated at temperatures from 12 to 30 degrees C. Several criteria were used to describe the oviposition pattern: longevity of females, preoviposition period, lifetime fecundity, number of oviposition bouts, duration and number of eggs for each oviposition bout, duration of an oviposition cycle, and time interval between oviposition bouts. All criteria were similar between genotypes, except the preoviposition period and time interval between oviposition bouts. The preoviposition period was 1-4 d longer for the early emerging genotype than for the late-emerging genotype at temperatures <25 degrees C, but similar at temperatures >=25 degrees C. The time interval between oviposition bouts of early emerging genotype was a few hours longer than for the late-emerging genotype at all temperatures. All oviposition pattern criteria responded to temperature, except the duration of oviposition bouts (?6.5 d) and egg mortality (?11%). The duration of a bout could be a compromise between oogenesis duration and the risks associated with egg deposition. According to these results, early and late-emerging genotypes express similar egg-laying strategies for all temperatures tested. PMID- 24472209 TI - Comparative diversity of arthropods on Bt maize and non-Bt maize in two different cropping systems in South Africa. AB - The biodiversity of an agroecosystem is not only important for its intrinsic value but also because it influences ecological functions that are vital for crop production in sustainable agricultural systems and the surrounding environment. A concern about genetically modified (GM) crops is the potential negative impact that such crops could have on diversity and abundance of nontarget organisms, and subsequently on ecosystem functions. Therefore, it is essential to assess the potential environmental risk of the release of a GM crop and to study its effect on species assemblages within that ecosystem. Assessment of the impact of Bt maize on the environment is hampered by the lack of basic checklists of species present in maize agroecosystems. The aims of the study were to compile a checklist of arthropods that occur on maize in South Africa and to compare the diversity and abundance of arthropods and functional groups on Bt maize and non Bt maize. Collections of arthropods were carried out during two growing seasons on Bt maize and non-Bt maize plants at two localities. Three maize fields were sampled per locality during each season. Twenty plants, each of Bt maize and non Bt maize, were randomly selected from the fields at each site. The arthropods collected during this study were classified to morphospecies level and grouped into the following functional groups: detritivores, herbivores, predators, and parasitoids. Based on feeding strategy, herbivores and predators were further divided into sucking herbivores or predators (piercing-sucking mouthparts) and chewing herbivores or predators (chewing mouthparts). A total of 8,771 arthropod individuals, comprising 288 morphospecies and presenting 20 orders, were collected. Results from this short-term study indicated that abundance and diversity of arthropods in maize and the different functional guilds were not significantly affected by Bt maize, either in terms of diversity or abundance. PMID- 24472210 TI - Impacts of Bt rice expressing Cry1C or Cry2A protein on the performance of nontarget leafhopper, Nephotettix cincticeps (Hemiptera: Cicadellidae), under laboratory and field conditions. AB - Transgenic rice expressing Bacillus thuringiensis Berliner (Bt) protein can effectively control target insects including stem borers and leaf folders. However, the potential effects of Bt rice on nontarget organisms including nontarget herbivores have not been fully evaluated. In the current study, ecological fitness parameters of the nontarget herbivore, Nephotettix cincticeps (Uhler) (Hemiptera: Cicadellidae), fed on T1C-19 (Cry1C) or T2A-1 (Cry2A) rice were compared with non-Bt rice (MH63) under laboratory conditions. A 2-yr field trial was also conducted to monitor the population dynamics of N. cincticeps in the Bt and control rice plots using the vacuum-suction machine and yellow sticky card traps. Laboratory results showed that there were no significant differences in some of biological parameters including egg developmental duration, adult fresh weight, adult longevity, and oviposition period when N. cincticeps fed on Bt or non-Bt rice was compared. However, the survival rate of N. cincticeps nymphs fed on T2A-1 Bt rice plants was significantly higher than that on the control. When N. cincticeps fed on T1C-19 Bt rice plants, its nymphal duration was significantly longer and fecundity significantly lower compared with those fed on both T2A-1 Bt and non-Bt rice plants; the preoviposition period of N. cincticeps fed on T1C-19 and T2A-1 Bt rice was also significantly shorter than those on non-Bt rice. Nonetheless, both seasonal density and population dynamics of N. cincticeps adults and nymphs were similar between Bt (T1C-19 and T2A-1) and non-Bt rice plots under field conditions. In conclusion, our results indicate that our two tested Bt rice lines would not lead to higher population of N. cincticeps. Long-term experiments to monitor the population dynamics of N. cincticeps at large scale need to be carried out to confirm the current results. PMID- 24472211 TI - Target and nontarget effects of novel "triple-stacked" Bt-transgenic cotton 1: canopy arthropod communities. AB - Transgenic cotton varieties (Bollgard II) expressing two proteins (Cry1Ac and Cry2Ab) from Bacillus thuringiensis (Bt) have been widely adopted in Australia to control larvae of Helicoverpa. A triple-stacked Bt-transgenic cotton producing Cry1Ac, Cry2Ab, and Vip3A proteins (Genuity Bollgard III) is being developed to reduce the chance that Helicoverpa will develop resistance to the Bt proteins. Before its introduction, nontarget effects on the agro-ecosystem need to be evaluated under field conditions. By using beatsheet and suction sampling methods, we compared the invertebrate communities of unsprayed non-Bt-cotton, Bollgard II, and Bollgard III in five experiments across three sites in Australia. We found significant differences between invertebrate communities of non-Bt and Bt (Bollgard II and Bollgard III) cotton only in experiments where lepidopteran larval abundance was high. In beatsheet samples where lepidopterans were absent (Bt crops), organisms associated with flowers and bolls in Bt-cotton were more abundant. In suction samples, where Lepidoptera were present (i.e., in non-Bt-cotton), organisms associated with damaged plant tissue and frass were more common. Hence in our study, Bt- and non-Bt-cotton communities only differed when sufficient lepidopteran larvae were present to exert both direct and indirect effects on species assemblages. There was no overall significant difference between Bollgard II and III communities, despite the addition of the Vip gene in Bollgard III. Consequently, the use of Bollgard III in Australian cotton provides additional protection against the development of resistance by Helicoverpa to Bt toxins, while having no additional effect on cotton invertebrate communities. PMID- 24472212 TI - Using resistant prey demonstrates that Bt plants producing Cry1Ac, Cry2Ab, and Cry1F have no negative effects on Geocoris punctipes and Orius insidiosus. AB - Geocoris punctipes (Say) and Orius insidiosus (Say) are generalist predators found in a wide range of crops, including cotton (Gossypium hirsutum L.) and maize (Zea mays L.), where they provide important biological control services by feeding on an array of pests, including eggs and small larvae of caterpillars. A high percentage of cotton and maize in the United States and several other countries are transgenic cultivars that produce one or more of the insecticidal Cry proteins of Bacillus thuringiensis Berliner (Bt). Here we quantify effects of three Cry proteins on the life history of these predators over two generations when they are exposed to these Cry proteins indirectly through their prey. To eliminate the confounding prey quality effects that can be introduced by Bt susceptible prey, we used Cry1Ac/Cry2Ab-resistant Trichoplusia ni (Hubner) and Cry1 F-resistant Spodoptera frugiperda (J.E. Smith) in a series of tri-trophic studies. Survival, development, adult mass, fecundity, and fertility were similar when predators consumed larvae feeding on Cry1Ac/Cry2Ab cotton or Cry1 F maize compared with prey feeding on isogenic or near-isogenic cotton or maize. Repeated exposure of the same initial cohort over a second generation also resulted in no differences in life-history traits when feeding on non-Bt- or Bt-fed prey. Enzyme linked immunosorbent assay showed that predators were exposed to Bt Cry proteins from their prey and that these proteins became increasingly diluted as they moved up the food chain. Results show a clear lack of effect of three common and widespread Cry proteins on these two important predator species. The use of resistant insects to eliminate prey quality effects provides a robust and meaningful assessment of exposure and hazard. PMID- 24472213 TI - Genetic structure of Plasmodium vivax using the merozoite surface protein 1 icb5 6 fragment reveals new hybrid haplotypes in southern Mexico. AB - BACKGROUND: Plasmodium vivax is a protozoan parasite with an extensive worldwide distribution, being highly prevalent in Asia as well as in Mesoamerica and South America. In southern Mexico, P. vivax transmission has been endemic and recent studies suggest that these parasites have unique biological and genetic features. The msp1 gene has shown high rate of nucleotide substitutions, deletions, insertions, and its mosaic structure reveals frequent events of recombination, maybe between highly divergent parasite isolates. METHODS: The nucleotide sequence variation in the polymorphic icb5-6 fragment of the msp1 gene of Mexican and worldwide isolates was analysed. To understand how genotype diversity arises, disperses and persists in Mexico, the genetic structure and genealogical relationships of local isolates were examined. To identify new sequence hybrids and their evolutionary relationships with other P. vivax isolates circulating worldwide two haplotype networks were constructed questioning that two portions of the icb5-6 have different evolutionary history. RESULTS: Twelve new msp1 icb5 6 haplotypes of P. vivax from Mexico were identified. These nucleotide sequences show mosaic structure comprising three partially conserved and two variable subfragments and resulted into five different sequence types. The variable subfragment sV1 has undergone recombination events and resulted in hybrid sequences and the haplotype network allocated the Mexican haplotypes to three lineages, corresponding to the Sal I and Belem types, and other more divergent group. In contrast, the network from icb5-6 fragment but not sV1 revealed that the Mexican haplotypes belong to two separate lineages, none of which are closely related to Sal I or Belem sequences. CONCLUSIONS: These results suggest that the new hybrid haplotypes from southern Mexico were the result of at least three different recombination events. These rearrangements likely resulted from the recombination between haplotypes of highly divergent lineages that are frequently distributed in South America and Asia and diversified rapidly. PMID- 24472214 TI - Knowledge, attitudes and practices of Cambodian swine producers in relation to porcine reproductive and respiratory syndrome (PRRS). AB - Porcine reproductive and respiratory syndrome (PRRS) was first detected in Cambodia in 2010. The disease was responsible for high morbidity and high mortality in adult pigs and the outbreak had a costly impact on those farmers affected. The aim of this study was to generate a better understanding of Cambodian swine producers' behaviour, in relation to PRRS and its control, in areas that have previously been affected by the disease. A survey of the knowledge, attitude and practices (KAPs) of pig owners with regard to PRRS was conducted in semi-commercial and backyard farms in Takeo province in southeast Cambodia. The survey was designed to assess knowledge of PRRS disease and its transmission, farmers' attitudes and practices related to preventive and control measures, knowledge on vaccination and perception towards local veterinary authority activities. Descriptive statistics were used to summarise qualitative data, while multivariate regression analyses were used to assess the association between selected outcomes and a number of hypothetical predictors. When presented with clinical signs typical of PRRS, most farmers identified an infectious disease as the most likely explanation for the listed clinical conditions. Farmers were also confident in recognising direct contact between pigs as one of the main ways of disease transmission; however, other viral transmission patterns typical of PRRS were mostly unknown or ignored. In general, male farmers and farmers with a higher level of education were more likely to have a better knowledge of transmission routes between pigs. In terms of attitude towards control measures, vaccination and disinfection were perceived as the most effective control practices. Farmers with a better knowledge of vaccine protocols were more likely to find vaccination effective. Village animal health workers (VAHWs) were generally in contact more with backyard farmers, while semi commercial farmers were more prone to treat pigs themselves, raising the issue of easy and uncontrolled access to medication and vaccination. In general, farmers had a positive attitude towards local veterinarians, and lack of contact between farmers and the veterinary authority was associated more with logistic constraints than with farmers' mistrust towards the authority. PMID- 24472215 TI - Zero-inflated models for identifying disease risk factors when case detection is imperfect: application to highly pathogenic avian influenza H5N1 in Thailand. AB - Logistic regression models integrating disease presence/absence data are widely used to identify risk factors for a given disease. However, when data arise from imperfect surveillance systems, the interpretation of results is confusing since explanatory variables can be related either to the occurrence of the disease or to the efficiency of the surveillance system. As an alternative, we present spatial and non-spatial zero-inflated Poisson (ZIP) regressions for modelling the number of highly pathogenic avian influenza (HPAI) H5N1 outbreaks that were reported at subdistrict level in Thailand during the second epidemic wave (July 3rd 2004 to May 5th 2005). The spatial ZIP model fitted the data more effectively than its non-spatial version. This model clarified the role of the different variables: for example, results suggested that human population density was not associated with the disease occurrence but was rather associated with the number of reported outbreaks given disease occurrence. In addition, these models allowed estimating that 902 (95% CI 881-922) subdistricts suffered at least one HPAI H5N1 outbreak in Thailand although only 779 were reported to veterinary authorities, leading to a general surveillance sensitivity of 86.4% (95% CI 84.5-88.4). Finally, the outputs of the spatial ZIP model revealed the spatial distribution of the probability that a subdistrict could have been a false negative. The methodology presented here can easily be adapted to other animal health contexts. PMID- 24472216 TI - Relationship between breast arterial calcifications seen on screening mammograms and age-related macular degeneration. PMID- 24472217 TI - A claims data-based comparison of comorbidity in individuals with and without dementia. AB - BACKGROUND: Multimorbidity is common in advanced age, and is usually associated with negative - yet to some extent preventable - health outcomes. Detecting comorbid conditions is especially difficult in individuals with dementia, as they might not always be able to sufficiently express discomfort. This study compares relevant comorbidity complexes in elderly people with and without dementia, with a particular look at gender- and living environment-specific differences. Moreover, associations between selected comorbid conditions and dementia are reviewed more closely. METHODS: Using 2006 claims data from a large German Statutory Health Insurance fund, 9,139 individuals with dementia and 28,614 age- and gender-matched control subjects aged 65 years and older were identified. A total of 30 comorbidity complexes were defined based on ICD-10 codes. Corresponding prevalence rates were calculated, and the association between a distinct condition and dementia was evaluated via logistic regression in the overall sample as well as in analyses stratified by gender and living environment. RESULTS: Individuals with dementia were more likely to be diagnosed with 15 comorbidity complexes, including Parkinson's, stroke, diabetes, atherosclerosis (supposed dementia risk factors) or fluids and electrolyte disorders, insomnia, incontinence, pneumonia, fractures and injuries (supposed sequelae). In contrast, they were less likely to be diagnosed with 11 other conditions, which included vision and hearing problems, diseases of the musculoskeletal system, lipoprotein disorders and hypertension. In a gender stratified analysis, the patterns remained largely the same, but a bigger comorbidity gap between cases and control subjects emerged in the male population. Restricting the analysis to community-living individuals did not lead to any substantial changes. CONCLUSION: Besides strengthening the evidence on accepted dementia risk factors and sequelae, the analyses point to particular conditions that are likely to remain untreated or even undiagnosed. This issue seems to affect male and female individuals with dementia to varying degrees. Raising awareness of these conditions is important to possibly preventing comorbidity-associated complications and disease progression in dementia patients. To more comprehensively understand the mutual interactions between dementia and comorbidity, further research on diagnostic and treatment attitudes regarding comorbidity in dementia patients and on their gender-specific health seeking behaviour seems to be required. PMID- 24472218 TI - The influence of incline walking on joint mechanics. AB - Walking is a popular form of exercise and is associated with many health benefits; however, frontal-plane knee joint loading brought about by a large internal knee-abduction moment and cyclic loading could lead to cartilage degeneration over time. Therefore, knee joint mechanics during an alternative walking exercise needs to be analyzed. The purpose of this study was to examine the lower-extremity joint mechanics in the frontal and sagittal planes during incline walking. Fifteen healthy males walked on a treadmill at five gradients (0%, 5%, 10%, 15%, and 20%) at 1.34m/s, and lower-extremity joint mechanics in the frontal and sagittal planes were quantified. The peak internal knee-abduction moment significantly decreased from the level walking condition at all gradients except 5%. Also, a negative relationship between the internal knee-abduction moment and the treadmill gradient was found to exist in 10% increments (0-10%, 5 15%, and 10-20%). The decrease in the internal knee-abduction moment during incline walking could have positive effects on knee joint health such as potentially reducing cartilage degeneration of the knee joint, reducing pain, and decreasing the rate of development of medial tibiofemoral osteoarthritis. This would be beneficial for a knee surgery patient, obese persons, and older adults who are using incline walking for rehabilitation and exercise protocols. Findings from the current study can provide guidance for the development of rehabilitation and exercise prescriptions incorporating incline walking. PMID- 24472219 TI - The relevance of hyperuricemia and metabolic syndrome and the effect of blood lead level on uric Acid concentration in steelmaking workers. AB - OBJECTIVES: Uric acid concentration is known to increase the prevalence of metabolic syndrome by affecting its components, resulting in increased risk of cerebrovascular and cardiovascular diseases, and long-term lead exposure is known to affect this serum uric acid level. In this study, we aimed to examine the association between the causes of hyperuricemia and metabolic syndrome, and to determine whether an increased blood lead level affects hyperuricemia. METHOD: Anthropometric measurements, surveys, and blood tests were conducted between May and June 2012 in 759 men working in the steelmaking process at a domestic steel company. Workers were divided into 2 groups according to the presence or absence of hyperuricemia, and an analysis was performed to examine its association with metabolic syndrome. In addition, the workers were divided into 3 groups according to the blood lead level to analyze the association between blood lead and hyperuricemia. RESULTS: The geometric mean (standard deviation) of the blood lead levels in the hyperuricemia group was significantly higher than that of the healthy group (3.8 [1.8] vs. 3.3 [1.8] MUg/dL). The adjusted odds ratio for metabolic syndrome of the hyperuricemia group increased significantly to 1.787 (1.125-2.839) compared with the healthy group. In addition, the adjusted odds ratios for the occurrence of hyperuricemia in the tertile 2 (2.61-4.50 MUg/dL) and tertile 3 groups (>4.50 MUg/dL) according to blood lead level significantly increased to 1.763 (1.116-2.784) and 1.982 (1.254-3.132), respectively, compared with the tertile 1 group (< 2.61 MUg/dL). CONCLUSION: Hyperuricemia is believed to function as an independent risk factor for metabolic syndrome, while lead seems to increase the serum uric acid level even at a considerably low blood level. Therefore, attention should be given to patients with hyperuricemia and metabolic syndrome who are prone to lead exposure, and a prospective study should be conducted to identify their causal relationship. PMID- 24472220 TI - Netrin-4 promotes mural cell adhesion and recruitment to endothelial cells. AB - Netrins are secreted molecules involved in axon guidance and angiogenesis. We previously showed that Netrin-4 acts as an anti-angiogenic factor by inhibiting endothelial cell (EC) functions. In this study, we investigated the effects of Netrin-4 on vascular smooth muscle cell (VSMC) activity in vitro and in vivo. We show that exogenous Netrin-4 stimulated VSMC adhesion and migration, and increased their coverage on EC tubes (grown on a Matrigel substrate). siRNA knock down of endogenous Netrin-4 expression in VSMC decreased their recruitment to EC tubes. VSMC expressed Netrin-4 and three of the six Netrin-1 cognate receptors: DCC, Neogenin, and Unc5B. Silencing of these receptors reduced Netrin-4 adhesion to VSMC, strongly suggesting that these receptors were involved in the recruitment process. We previously showed that Netrin-4 overexpression in PC3 cancer cells delayed tumor growth in a model of subcutaneous xenograft by reducing tumor vessel density. Here, we show that Netrin-4 overexpression improved tumor blood vessel structure and increased VSMC coverage. Thus, Netrin-4 induced mural cell recruitment may play a role in the inhibition of tumor growth. Our data suggest that Netrin-4 is important for blood vessel normalization through the regulation of both endothelial and perivascular cells. PMID- 24472221 TI - Relationship of cigarette smoking and hearing loss in workers exposed to occupational noise. AB - OBJECTIVES: To investigate the effects of smoking on hearing loss among workers exposed to occupational noise. METHODS: From the results of a special workers health examination performed in 2011, we enrolled 8,543 subjects exposed to occupational noise and reviewed the findings. Using self-reported questionnaires and health examination results, we collected data on age, smoking status, disease status, height, weight, and biochemistry and pure tone audiometry findings. We divided the workers into 3 groups according to smoking status (non-smoker, ex smoker, current smoker). Current smokers (n = 3,593) were divided into 4 groups according to smoking amount (0.05-9.9, 10-19.9, 20-29.9, >=30 pack-years). We analyzed the data to compare hearing thresholds between smoking statuses using analysis of covariance (ANCOVA) after controlling for confounder effects. RESULTS: According to ANCOVA, the hearing thresholds of current smokers at 2 k, 3 k, and 4 kHz were significantly higher than that of the other groups. Multiple logistic regression for smoking status (reference: non-smokers) showed that the adjusted odds ratios of current smokers were 1.291 (95% confidence interval [CI]: 1.055-1.580), 1.180 (95% CI: 1.007-1.383), 1.295 (95% CI: 1.125-1.491), and 1.321 (95% CI: 1.157-1.507) at 1 k, 2 k, 3 k, and 4 kHz, respectively. Based on smoking amount, the adjusted odds ratios were 1.562 (95% CI: 1.013-2.408) and 1.643 (95% CI: 1.023-2.640) for the 10-19.9 and >=30 pack-years group, respectively, at 1 kHz (reference: 0.05-9.9 pack-years). At 2 kHz, the adjusted odds ratios were increased statistically significantly with smoking amount for all groups. At all frequencies tested, the hearing thresholds of noise-exposed workers were significantly influenced by current smoking, in particular, the increase of hearing loss at low frequencies according to smoking amount was more prevalent. CONCLUSIONS: Current smoking significantly influenced hearing loss at all frequencies in workers exposed to occupational noise, and heavier smoking influenced low-frequency hearing loss more greatly. There was a dose-response relationship between smoking amount and low-frequency hearing thresholds; however, this was not observed for high-frequency hearing thresholds. Therefore, well-designed prospective studies are needed to clarify the effects of smoking on the degree of hearing loss. PMID- 24472222 TI - Using prediction intervals from random-effects meta-analyses in an economic model. AB - OBJECTIVES: When incorporating treatment effect estimates derived from a random effect meta-analysis it is tempting to use the confidence bounds to determine the potential range of treatment effect. However, prediction intervals reflect the potential effect of a technology rather than the more narrowly defined average treatment effect. Using a case study of robot-assisted radical prostatectomy, this study investigates the impact on a cost-utility analysis of using clinical effectiveness derived from random-effects meta-analyses presented as confidence bounds and prediction intervals, respectively. METHODS: To determine the cost utility of robot-assisted prostatectomy, an economic model was developed. The clinical effectiveness of robot-assisted surgery compared with open and conventional laparoscopic surgery was estimated using meta-analysis of peer reviewed publications. Assuming treatment effect would vary across studies due to both sampling variability and differences between surgical teams, random-effects meta-analysis was used to pool effect estimates. RESULTS: Using the confidence bounds approach the mean and median ICER was ?24,193 and ?26,731/QALY (95%CI: ?13,752 to ?68,861/QALY), respectively. The prediction interval approach produced an equivalent mean and median ICER of ?26,920 and ?26,643/QALY (95%CI: -?135,244 to ?239,166/QALY), respectively. Using prediction intervals, there is a probability of 0.042 that robot-assisted surgery will result in a net reduction in QALYs. CONCLUSIONS: Using prediction intervals rather than confidence bounds does not affect the point estimate of the treatment effect. In meta-analyses with significant heterogeneity, the use of prediction intervals will produce wider ranges of treatment effect, and hence result in greater uncertainty, but a better reflection of the effect of the technology. PMID- 24472223 TI - Management of persistent anal canal carcinoma after combined-modality therapy: a clinical review. AB - Anal canal carcinoma is a rare gastro-intestinal cancer. Radiochemotherapy is the recommended primary treatment for patients with non-metastatic carcinoma; surgery is generally reserved for persistent or recurrent disease. Follow-up and surveillance after primary treatment is paramount to classify patients in those with complete remission, persistent or progressive disease. Locally persistent disease represents a clinically significant problem and its management remains subject of some controversy.The aim of this systematic review is to summarise recommendations for the primary treatment of anal canal carcinoma, to focus on the optimal time to consider residual disease as genuine persistence to proceed with salvage treatment, and to discern how this analysis might inform future clinical trials in management in this class of patients. PMID- 24472224 TI - Population pharmacokinetics of azithromycin and chloroquine in healthy adults and paediatric malaria subjects following oral administration of fixed-dose azithromycin and chloroquine combination tablets. AB - BACKGROUND: Population pharmacokinetics (PK) of azithromycin (AZ) and chloroquine (CQ) following administration of fixed-dose combination tablet formulations of AZ and CQ (AZCQ) was evaluated using data from two studies: 1) in children with symptomatic uncomplicated falciparum malaria in sub-Saharan Africa; and 2) in healthy adults in the United States. METHODS: Study 1 included paediatric subjects randomized to either AZCQ or artemether-lumefantrine treatment in Cohort 1 (age 5-12 years) and Cohort 2 (age 6-59 months). Dosing of AZCQ was approximately 30 mg/kg AZ and 10 mg/kg CQ once daily for 3 days (for >=20 kg weight: AZ/CQ 300/100 mg per tablet; 5 to <20 kg weight: AZ/CQ 150/50 mg per tablet). Study 2 included adults randomized to receive either two AZCQ tablets (AZ/CQ 250/155 mg per tablet) or individual commercial tablets of AZ 500 mg and CQ 300 mg. Serum AZ and plasma CQ concentrations from both studies were pooled. Population PK models were constructed using standard approaches to evaluate the concentration-time data for AZ and CQ and to identify any covariates predictive of PK behaviour. RESULTS: A three-compartment PK model with linear clearance and absorption adequately described AZ data, while a two-compartment model with linear clearance and absorption and an absorption lag adequately described CQ data. No overall bias or substantial model misspecification was evident using diagnostic plots and visual predictive checks. Body weight as an allometric function was the only covariate in the final AZ and CQ PK models. There were significantly lower AZ (0.488 vs 0.745 [mg*h/L]/[mg/kg], p < 0.00001) and CQ (0.836 vs 1.27 [mg*h/L]/[mg/kg], p < 0.00001) exposures (AUCinf) normalized by dose (mg/kg) in children compared with the adults. CONCLUSIONS: The PK of AZ and CQ following administration of AZCQ was well described using a three- and two compartment model, respectively. AZ and CQ exhibited linear absorption and clearance; the model for CQ included an absorption lag. Weight was predictive of exposure for both AZ and CQ. Assuming equivalent dosing (mg/kg), AZ and CQ exposure in children would be expected to be lower than that in adults, suggesting that children may require a higher dose (mg/kg) than adults to achieve the same AZ and CQ exposure. PMID- 24472225 TI - In an interconnected world: joint research priorities for the environment, agriculture and infectious disease. AB - In 2008 the UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR) commissioned ten think-tanks to work on disease-specific and thematic reference groups to identify top research priorities that would advance the research agenda on infectious diseases of poverty, thus contributing to improvements in human health. The first of the thematic reference group reports - on environment, agriculture and infectious diseases of poverty - was recently released. In this article we review, from an insider perspective, the strengths and weaknesses of this thematic reference group report and highlight key messages for policy-makers, funders and researchers. PMID- 24472226 TI - Highly pathogenic porcine reproductive and respiratory syndrome virus infection results in acute lung injury of the infected pigs. AB - Highly pathogenic porcine reproductive and respiratory syndrome virus (HP-PRRSV) was firstly characterized in 2006 in China. The virus has caused great economic loss to the Chinese swine production during the past years. Herein, we experimentally infected SPF pigs using two strains of PRRSV with different pathogenicity and observed the lung pathological changes looking for new sights on the possible pathogenesis associated with the virulence of HP-PRRSV. The results indicated that the HP-PRRSV-infected pigs died and exhibited severe pathological changes of lungs featuring increased neutrophils, mast cells and mononuclear macrophages, compared with the pigs inoculated with low pathogenic (LP-) PRRSV. Furthermore, the pigs infected with HP-PRRSV showed the higher levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, interleukin (IL)-8 and histamine, leukotriene B4 (LTB4), platelet activation factor (PAF) in sera than those inoculated with LP-PRRSV. Additionally, the fibrosis of lung was observed in the HP-PRRSV-infected pigs. At present, our findings suggest that the aberrant immune responses triggered by HP-PRRSV infection are closely related to acute lung injury (ALI), and especially the pathological changes in lung vascular system are of particular significance. These associated pathological changes of lung are in part responsible for the additional morbidity and mortality observed in HP-PRRSV infection. PMID- 24472227 TI - Within-batch prevalence and quantification of human pathogenic Yersinia enterocolitica and Y. pseudotuberculosis in tonsils of pigs at slaughter. AB - Yersiniosis is a common bacterial zoonosis in Europe and healthy pigs are known to be the primary reservoir of human pathogenic Yersinia enterocolitica and Y. pseudotuberculosis. However, little information is available about the prevalence of these pathogens within pig batches at time of slaughter. The tonsils of 7047 fattening pigs, belonging to 100 farms, were aseptically collected immediately after evisceration in two Belgian slaughterhouses. The batch size varied between 70 and 930 pigs. On average, 70 pigs were sampled per batch. The tonsils were examined by direct plating on cefsulodin-irgasan-novobiocin (CIN) agar plates and the number of suspect Yersinia colonies was counted. Pathogenic Y. enterocolitica serotype O:3 were found in tonsils of 2009 pigs (28.5%), originating from 85 farms. The within-batch prevalence in positive farms ranged from 5.1 to 64.4%. The number of Y. enterocolitica in positive pigs varied between 2.01 and 5.98 log10 CFU g(-1) tonsil, with an average of 4.00 log10 CFU g(-1) tonsil. Y. pseudotuberculosis was found in seven farms, for which the within-batch prevalence varied from 2 to 10%. In five of these farms, both Y. enterocolitica and Y. pseudotuberculosis were simultaneously present. Human pathogenic Yersinia spp. are widespread in slaughter pig batches in Belgium as 87% of the tested batches were infected with these pathogens at the time of slaughter. The large variation of the prevalence between batches may lead to different levels of contamination of carcasses and risks for public health. PMID- 24472228 TI - Supplementation of oil-based inactivated H9N2 vaccine with M2e antigen enhances resistance against heterologous H9N2 avian influenza virus infection. AB - Avian influenza virus (AIV) subtype H9N2 has been evolving rapidly and vaccine escape variants have been reported to cause circulation of infections and economic losses. In the present study, we developed and evaluated ectodomain of the AIV matrix 2 (M2e) protein as a supplementing antigen for oil-based inactivated H9N2 vaccine to increase resistance against vaccine escape variants. AIV H9N2 M2e antigen was expressed in Escherichia coli and supplemented to inactivated H9N2 oil emulsion vaccine. Specific pathogen-free chickens received a single injection of inactivated H9N2 oil emulsion vaccines with or without M2e supplementation. At three weeks post vaccination, hemagglutination inhibition tests and enzyme-linked immunosorbent assays were performed to determine serological immune responses. Challenge study using a vaccine escape H9N2 variant was performed to evaluate the efficacy of M2e supplementation. M2e antigen supplemented in oil emulsion vaccine was highly immunogenic, and a single M2e supplemented vaccination reduced challenge virus replication and shedding more effectively than non-supplemented vaccination. PMID- 24472230 TI - Abdominal radiograph with intravesical air and possible small bowel atresia. PMID- 24472231 TI - Urogenital examination identifies the cause of neonatal jaundice. PMID- 24472233 TI - Nonlinear group survival in Kimura's model for the evolution of altruism. AB - Establishing the conditions that guarantee the spreading or the sustenance of altruistic traits in a population is the main goal of intergroup selection models. Of particular interest is the balance of the parameters associated to group size, migration and group survival against the selective advantage of the non-altruistic individuals. Here we use Kimura's diffusion model of intergroup selection to determine those conditions in the case the group survival rate is a nonlinear non-decreasing function of the proportion of altruists in a group. In the case this function is linear, there are two possible steady states which correspond to the non-altruistic and the altruistic phases. At the discontinuous transition line separating these phases there is a non-ergodic coexistence phase. For a continuous concave survival function, we find an ergodic coexistence phase that occupies a finite region of the parameter space in between the altruistic and the non-altruistic phases, and is separated from these phases by continuous transition lines. For a convex survival function, the coexistence phase disappears altogether but a bistable phase appears for which the choice of the initial condition determines whether the evolutionary dynamics leads to the altruistic or the non-altruistic steady state. PMID- 24472234 TI - A mathematical model of CENP-A incorporation in mammalian centromeres. AB - Centromere Protein A (CENP-A) is a histone H3 variant found at mammalian centromeres. Unlike canonical histones which are incorporated at centromeres in S phase, CENP-A is deposited at centromeric chromatin in G1. Although recent studies have elucidated many of the molecular details associated with the CENP-A incorporation pathway, some aspects of the process are still not fully understood. CENP-A incorporation in G1 requires multiple assembly factors for its recruitment and maintenance. In this study, the first mathematical model of the CENP-A incorporation pathway is developed. The model is based on what is currently known about the pathway and is calibrated by comparing numerical simulations with experimental observations taken from the literature. The model succinctly collates a large body of knowledge accumulated in recent decades concerning the pathway and produces results that are consistent with experimental findings. It identifies possible gaps in what is currently known about the pathway and suggests possible directions for future research. It is envisaged that the model will be expanded upon and improved as more information concerning the pathway comes to light. PMID- 24472232 TI - From cellular senescence to age-associated diseases: the miRNA connection. AB - Cellular senescence has evolved from an in-vitro model system to study aging in vitro to a multifaceted phenomenon of in-vivo importance as senescent cells in vivo have been identified and their removal delays the onset of age-associated diseases in a mouse model system. From the large emerging class of non-coding RNAs, miRNAs have only recently been functionally implied in the regulatory networks that are modified during the aging process. Here we summarize examples of similarities between the differential expression of miRNAs during senescence and age-associated diseases and suggest that these similarities might emphasize the importance of senescence for the pathogenesis of age-associated diseases. Understanding such a connection on the level of miRNAs might offer valuable opportunities for designing novel diagnostic and therapeutic strategies. PMID- 24472235 TI - A modified posterolateral transpedicular approach to thoracolumbar corpectomy with nerve preservation and bilateral cage reconstruction. AB - This retrospective study investigated the early results of a single-stage posterolateral transpedicular corpectomy and fusion in the thoracolumbar spine. A modified technique with nerve preservation and bilateral expandable cage implantation is described. Four patients with vertebral metastasis and one patient with vertebral osteomyelitis were included in this series. Two patients underwent two level corpectomies, whereas three patients underwent single level corpectomy. The mean follow-up was 3.3 months. No perioperative complication was encountered. Improvement in neurological status was observed in patients with preoperative neurological deficits. Vertebral height and sagittal and coronal deformity were corrected using the current technique. Bilateral cage implantation offers an additional advantage of asymmetrical reconstruction of the ventral column in cases of hemicorpectomy. Single-stage posterolateral transpedicular corpectomy and fusion is a useful approach to treat ventral thoracolumbar pathologies. PMID- 24472236 TI - Prospective evaluation of preoperative stereotactic radiosurgery followed by delayed resection of a high grade arteriovenous malformation. AB - Reports of the utility of preoperative radiation for shrinking large arteriovenous malformations (AVM) in preparation for resection have produced conflicting results, and to our knowledge no prospective studies are available. A 28-year-old man presented with a ruptured right temporal Spetzler-Martin Grade 5 AVM with deep venous drainage, involvement of the internal capsule, deep perforator supply, and a diffuse nidus. He underwent staged embolization, a single Gamma Knife (Elekta AB, Stockholm, Sweden) radiation treatment to the deepest portion of the nidus followed by complete surgical resection 3 years later. He suffered no long-term neurological deficits and has since returned to work symptom-free (modified Rankin Scale score 0). Preoperative radiosurgery is an effective method for downgrading high-grade AVM in preparation for surgery by targeting the deeper portions that abut or involve eloquent territory. To our knowledge this is the first such successful prospective report in the literature. PMID- 24472237 TI - The glomic artery supply of carotid body tumors and implications for embolization. AB - Carotid body tumors (CBT) are rare neuroendocrine neoplasms that usually present in the third or fourth decades of life and are benign in more than 95% of cases. In the angiographic literature, the arterial supply to carotid body tumors is well documented but is often incomplete, with infrequent mention of the glomic artery, a common arterial feeder described in the anatomic and pathologic literature. Through a review of our neuroendovascular patient database, we identified eight patients with CBT undergoing transarterial embolization followed by resection. Mean patient age was 51.5 years (range 29-82), and all patients were female. Mean tumor size was 91.2 cc (standard deviation [SD] 61.1, median 67.7 cc). After embolization, greater than 90% flow reduction was achieved in 5/8 patients (63%); 60-80% flow reduction was achieved in the remaining patients. Mean operative blood loss was 166 cc (SD 100, median 122 cc) and mean operative time was 252 minutes (SD 134.5, median 155 minutes). Pre-embolization angiography was reviewed to identify a glomic artery, defined as a dominant artery supplying the CBT arising from the region of the carotid bifurcation. In six of eight patients (75%) a glomic artery could be identified, arising from the common carotid artery in 4/6 patients and the external carotid artery in 2/6 patients. Thus, glomic artery to supply to CBT was identified in the majority of patients in this series. Knowledge of its presence and identification as a direct supplier, frequently from the common carotid artery itself, provides an avenue for more thorough preoperative embolization of CBT. PMID- 24472229 TI - Developmental outcomes of very preterm infants with tracheostomies. AB - OBJECTIVES: To evaluate the neurodevelopmental outcomes of very preterm (<30 weeks) infants who underwent tracheostomy. STUDY DESIGN: Retrospective cohort study from 16 centers of the Eunice Kennedy Shriver National Institute of Child Health and Human Development Neonatal Research Network over 10 years (2001-2011). Infants who survived to at least 36 weeks (N = 8683), including 304 infants with tracheostomies, were studied. Primary outcome was death or neurodevelopmental impairment (NDI; a composite of >=1 of developmental delay, neurologic impairment, profound hearing loss, severe visual impairment) at a corrected age of 18-22 months. Outcomes were compared using multiple logistic regression. We assessed the impact of timing by comparing outcomes of infants who underwent tracheostomy before and after 120 days of life. RESULTS: Tracheostomies were associated with all neonatal morbidities examined and with most adverse neurodevelopmental outcomes. Death or NDI occurred in 83% of infants with tracheostomies and 40% of those without (OR adjusted for center 7.0, 95% CI 5.2 9.5). After adjustment for potential confounders, odds of death or NDI remained higher (OR 3.3, 95% CI 2.4-4.6), but odds of death alone were lower (OR 0.4, 95% CI 0.3-0.7) among infants with tracheostomies. Death or NDI was lower in infants who received their tracheostomies before, rather than after, 120 days of life (aOR 0.5, 95% CI 0.3-0.9). CONCLUSIONS: Tracheostomy in preterm infants is associated with adverse developmental outcomes and cannot mitigate the significant risk associated with many complications of prematurity. These data may inform counseling about tracheostomy in this vulnerable population. PMID- 24472238 TI - Successful endovascular repair of an unusual right-to-left shunt presenting with cerebral ischemia. AB - Ischemic stroke due to congenital cardiopulmonary vasculature anomalies is rare in adults. We report a 54-year-old man with a stroke due to a unique right-to left shunt who underwent successful endovascular treatment. This patient developed acute onset of right arm weakness with facial droop and aphasia which improved after intravenous thrombolysis. An MRI showed acute cerebral ischemia in the left middle cerebral artery and left posterior cerebral artery distribution. The patient developed recurrent stroke symptoms during agitated saline injection while undergoing a transthoracic echocardiogram which showed right-to-left shunting. Chest CT scan and conventional angiography revealed near occlusion of the superior vena cava. Head and upper limb venous return drained via a large left vertical vein into an anomalous left pulmonary vein into the left atrium. He underwent endovascular surgery to relieve the superior vena cava obstruction and to occlude the source of right-to-left shunt. While rare, congenital cardiopulmonary vascular anomalies may result in ischemic stroke in adults. CT angiography may be necessary to evaluate cardiopulmonary vasculature when right to-left shunting is discovered on echocardiography in the setting of ischemic stroke. With large right-to-left shunts, agitated saline should be avoided. PMID- 24472239 TI - Perioperative characteristics and complications in obese patients undergoing anterior cervical fusion surgery. AB - In the USA, obesity rates have significantly increased in the last 15 years. Mirroring this trend, a large proportion of patients undergoing spinal surgery are obese. Concern exists for increased complications due to surgical challenges posed by obese patients and their often-prevalent comorbidities. Studies have shown associations between body mass index (BMI) and perioperative complications in lumbar and thoracolumbar fusion surgeries; however, few studies have evaluated the impact of obesity on anterior cervical fusion surgery. As such, this study aimed to evaluate complications and perioperative characteristics in obese patients undergoing anterior cervical fusion. We queried medical records to identify patients with BMI >30 who underwent anterior cervical fusion surgery. A total of 69 patients were included and subdivided based on obesity class: Class 1 (BMI 30-35), Class 2 (BMI 35-40), and Class 3 (BMI >40). Subgroup analysis included comorbidities, diagnosis, procedure, levels treated, and length of hospital stay. Overall mean BMI was 35.1, mean age was 54.3 years, and 43 (63.3%) were men. Disc herniation was the most common diagnosis. Length of stay differed significantly among obesity subgroups (p=0.02). Mean length of stay was 2.8, 3.5, and 4.0 days for Classes 1, 2, and 3, respectively. Three (4.3%) complications were observed, comprising of urinary tract infection, wound dehiscence, and neck hematoma. Complication rates by class were 5.5%, 0%, and 16.6% for Classes 1, 2, and 3, respectively (p=0.17). We found that obese patients undergoing anterior cervical spine surgery experience relatively few complications. Hospital stay, however, appears to lengthen with increased BMI. PMID- 24472240 TI - Lumbosacral epidural lipomatosis causing rapid onset cauda equina syndrome. AB - Spinal epidural lipomatosis (SEL) is a rare cause of cauda equina syndrome (CES), which must be diagnosed with MRI in conjunction with a high level of clinical suspicion. Most reported cases are associated with obesity, steroid use or are secondary to endocrinopathies, frequently present subacutely or chronically, and have been managed with both surgical decompression and non-operative measures. We describe an obese 55-year-old man with rapid onset CES secondary to idiopathic lumbosacral SEL which was managed successfully with surgical decompression. Although often thought to be a trivial radiological finding, it is important not to be dismissive of patients presenting with compressive neuropathy and MRI evidence of space-occupying SEL. PMID- 24472241 TI - Sporadic hypokalemic paralysis caused by osmotic diuresis in diabetes mellitus. AB - A wide variety of neurological manifestations are known in patients with diabetes mellitus. We describe a 40-year-old man who presented with hypokalemic paralysis. On evaluation, we found that the cause of the hypokalemia was osmotic diuresis induced by marked hyperglycemia due to undiagnosed diabetes mellitus. The patient had an uneventful recovery with potassium replacement, followed by glycemic control with insulin. Barring a few instances of symptomatic hypokalemia in the setting of diabetic emergencies, to our knowledge uncomplicated hyperglycemia has not been reported to result in hypokalemic paralysis. PMID- 24472242 TI - Art of the possible? PMID- 24472244 TI - Here/in this issue and there/abstract thinking: young brains at risk: could neuroimaging predict what the clinician cannot know? PMID- 24472243 TI - Species-dependent binding of tocainide analogues to albumin: affinity chromatography and circular dichroism study. AB - A series of novel tocainide analogues were characterized for their HSA and RSA binding, by using high-performance liquid affinity chromatography (HPLAC) and circular dichroism (CD). In this HPLAC study, HSA and RSA were covalently immobilized to the silica matrix of HPLC columns, with a procedure that maintained unaltered the binding properties of the proteins. The tocainide analogues were ranked for their affinity to HSA and RSA on the basis of their bound fractions measured by the two albumin-based columns. This technique was also applied to characterize the high affinity binding sites of these tocainide analogues to the protein. For this purpose displacement experiments were carried out by means of increasing concentrations in the mobile phase of competitors known to bind selectively to the main binding sites of HSA. The results obtained with the immobilized proteins were confirmed by investigating the same drug protein systems in solution by circular dichroism. The comparison of the data collected with both methodologies highlighted the dramatic effect of small differences in the amino acidic sequences of the two proteins. In fact, despite their similar primary and secondary structures, a small difference in the amino acidic sequence leads to significant differences in their three-dimensional structure reflecting their different binding capacity and their stereoselectivity. Therefore, this study confirms how it is crucial to consider the significant differences among the animal models when performing pharmacokinetic studies. It is also clear that the knowledge of serum carrier binding parameters at an early stage of drug discovery represents a great advantage that may help to save time and efforts. PMID- 24472245 TI - Policing the teen brain. PMID- 24472246 TI - From attachment to groups: tapping into the neurobiology of our interconnectedness. PMID- 24472247 TI - Are we there yet? The state of early prediction and intervention in autism spectrum disorder. PMID- 24472248 TI - Meta-analysis and moderator analysis: can the field develop further? PMID- 24472249 TI - Moving: its impact on the child. PMID- 24472250 TI - Approaches to enhancing the early detection of autism spectrum disorders: a systematic review of the literature. AB - BACKGROUND: A reliable diagnosis of autism can be made as early as 24 months, yet in many children diagnoses are made much later. A delay in diagnosis translates into a missed opportunity to provide early intervention services and to improve outcomes. The aim of the current study was to review the literature on early detection approaches in primary care and other community settings in the United States. METHODS: A search was conducted of the peer-reviewed and gray literature to identify studies published from January 1990 through January 2013 testing approaches to enhance the early detection of autism in community settings in the United States. RESULTS: The search identified 40 studies describing 35 approaches, which were grouped into the following categories: awareness (n = 4), routine screening (n = 21), and practice improvement to enhance screening (n = 10). Awareness approaches were associated with positive changes in knowledge of autism-related topics. Routine screening yielded high or increased rates of screening and referrals; however, few studies assessed the effect of screening on age at diagnosis or services enrollment. Practice improvement approaches resulted in increased screening and referral rates and highlighted the importance of adopting a multipronged approach to enhance early detection. CONCLUSIONS: Although studies that tested screening approaches in community settings found positive results, the effectiveness of such efforts on reducing time to diagnosis and services enrollment remains largely untested. The fact that few studies reported outcomes beyond rates of referral indicates the need for enhanced methodological rigor, particularly with respect to length of follow-up and quality of measures used. PMID- 24472251 TI - Alpha-2 agonists for attention-deficit/hyperactivity disorder in youth: a systematic review and meta-analysis of monotherapy and add-on trials to stimulant therapy. AB - OBJECTIVE: To meta-analyze the efficacy and safety of alpha-2 agonists in pediatric attention-deficit/hyperactivity disorder (ADHD). METHOD: We searched MEDLINE, EMBASE, Cochrane Library, CINAHL, and PsycINFO until May 2013 for randomized trials comparing alpha-2 agonists with placebo in ADHD youth. Primary outcome was reduction in overall ADHD symptoms. Secondary outcomes included hyperactivity/impulsivity, inattentiveness, oppositional defiant disorder symptoms (ODD symptoms), all-cause discontinuation, specific-cause discontinuation, and adverse effects. Standardized mean differences (SMD), relative risk (RR), and number-needed-to-treat/number-needed-to-harm (NNT/NNH) were calculated. Data were analyzed separately in monotherapy and as add-on to psychostimulants. RESULTS: Altogether, 12 studies (N = 2,276) were included. Across 9 studies (n = 1,550), alpha-2 agonist monotherapy significantly reduced overall ADHD symptoms (SMD = -0.59, p < .00001), hyperactivity/impulsivity (SMD = -0.56, p < .00001), inattention (SMD = -0.57, p < .00001), and ODD symptoms (SMD = -0.44, p = .0004). Similarly, alpha-2 agonist add-on treatment (3 studies, n = 726) significantly reduced overall ADHD symptoms (SMD = -0.36, p < .0001), hyperactivity/impulsivity (SMD = -0.33, p < .0001), and inattention (SMD = -0.34, p < .0001), but effect sizes were lower than in monotherapy trials (p = .03 0.04). As monotherapy, alpha-2 agonists had lower all-cause (RR = 0.70, p = .01, NNT = 10) and inefficacy-related (RR = 0.39, p < .0001) discontinuations than did placebo; however, intolerability-related discontinuation was similar, despite significantly more common fatigue (NNH = 10), sedation (NNH = 17), and somnolence (NNH = 4) and significantly greater hypotensive (clonidine-IR), bradycardic (clonidine-IR), and QTc prolonging (guanfacine-XR) effects. Added to stimulants, alpha-2 agonists had all-cause and specific-cause discontinuations that were comparable to those of placebo, but somnolence (NNH = 10) was more common, and hypotensive and bradycardic effects (clonidine-XR and guanfacine-XR) were greater than with placebo. CONCLUSIONS: alpha-2 Agonist monotherapy and, possibly to a lesser extent, co-treatment, are significantly superior to placebo for overall, hyperactivity, and inattentive ADHD symptoms. Efficacy advantages need to be balanced against fatigue, somnolence/sedation, hypotension, bradycardia, and possibly QTc prolongation. PMID- 24472252 TI - Efficacy and safety of atomoxetine in children and adolescents with attention deficit/hyperactivity disorder: results from a comprehensive meta-analysis and metaregression. AB - OBJECTIVE: To comprehensively evaluate the efficacy and safety of atomoxetine (ATX) in pediatric attention-deficit/hyperactivity disorder (ADHD). METHOD: Meta analysis of all double-blind randomized controlled trials (DBRCTs) evaluating the efficacy and tolerability of ATX for ADHD. Pooled, random-effects analyses were conducted, calculating standardized mean difference (SMD), yielding effect sizes (ES), relative risk (RR), and number-needed-to-treat/harm (NNT/NNH).Moderator/mediator analyses were also conducted, including metaregression. RESULTS: Across 25 DBRCTs (56 treatment arms, N = 3,928), ATX outperformed placebo regarding overall ADHD symptoms (ES = -0.64, 95% confidence interval [CI] = -0.56 to -0.71, p < 0.0001), hyperactivity/impulsivity (ES = 0.67, CI = -0.53 to -0.81, p < 0.0001), and inattention (ES = -0.59, CI = -0.51 to -0.67, p < 0.0001). Altogether, 44.4% versus 21.4% of patients improved by >=40% (NNT = 4), whereas 39.9% versus 65.9% improved by <25% (NNT = 4). Oppositional defiant disorder symptoms (ES = -0.33) and quality-of-life-related outcomes (ES = -0.48 to -0.25) improved somewhat less. A higher percentage of treatment-naive patients moderated the efficacy of ATX for overall ADHD symptoms (p = 0.017). All-cause discontinuation with ATX was similar to that for placebo (p = 1.00), with lower discontinuation because of inefficacy (relative risk [RR] = 0.51, CI = 0.36-0.74, p < 0.0001, NNT = 34), but higher discontinuation because of adverse effects (AEs) (RR = 1.89, CI = 1.08-3.31, p = 0.03, NNH = 50) with ATX. At least 1 adverse effect (AE) (70.4% versus 56.1%, p < 0.01, NNH = 6) and >=1 psychiatric AE (21.5% versus 7.4%, NNH = 7, p < 0.01) were more frequent with ATX, whereas serious AEs (1.5% versus 1.0%), aggression (7.5% versus 6.0%), and suicidal ideation (1.3% versus 0.9%) were not different from placebo. CONCLUSIONS: Short-term ATX treatment is safe and superior to placebo for overall ADHD symptoms and key secondary outcomes, with a medium ES. However, a relevant patient subgroup (40%) continues to have significant symptomatology, requiring additional clinical attention. PMID- 24472253 TI - Preschool-based social communication treatment for children with autism: 12-month follow-up of a randomized trial. AB - OBJECTIVE: This study reports 12-month follow-up data from a randomized controlled trial of preschool-based social communication treatment for young children with autism. METHOD: A total of 61 children (48 males) with autism, 29 to 60 months of age, had earlier been randomized either to 8 weeks of preschool based social communication treatment in addition to standard preschool program (n = 34) or to standard preschool program only (n = 27). Significant short-term effects on targeted social communication skills have previously been published. Long-term gains in social communication, language and global social functioning and communication were assessed from video-taped preschool teacher-child and mother-child interactions, Early Social Communication Scales, Reynell Developmental Language Scale, and Social Communication Questionnaire. RESULTS: Compared with those in the control group, the treated children achieved significantly larger improvements in joint attention and joint engagement from baseline to 12-month follow-up. However, no effects were detected on language and global ratings of social functioning and communication. The treatment effect on child initiation of joint attention increased with increasing level of sociability at baseline, whereas nonverbal IQ and expressive language had no moderating effect. CONCLUSIONS: This study is the first to show that, similar to specialist-delivered treatment, preschool-based treatment may produce small but possibly clinically important long-term changes in social communication in young children with autism. The treatment did not affect language and global ratings of social functioning and communication. More studies are needed to better understand whether treatment effects may be improved by increasing the intensity and duration of the treatment. Clinical trial registration information--Joint Attention Intervention and Young Children With Autism; http://clinicaltrials.gov/; NCT00378157. PMID- 24472254 TI - Developmental timing of housing mobility: longitudinal effects on externalizing behaviors among at-risk youth. AB - OBJECTIVE: This longitudinal study tested whether developmental timing of exposure to housing mobility exacerbates behavior problems in an at-risk sample of youth. METHOD: Participants were 2,442 youth 4 to 16 years old at risk for child maltreatment followed at 3 time points over a 36-month follow-up. Caregivers reported on youth externalizing behaviors at each assessment. Latent growth models examined the effect of housing mobility on behavior problems after accounting for change in cognitive development, family instability, child gender, ethnicity, family income, and caregiver mental health at baseline. RESULTS: Findings suggested increased housing mobility predicted greater behavior problems when children were exposed at key developmental periods. Preschoolers exhibited significantly higher rates of behavior problems that remained stable across the 3 year follow-up. Likewise, adolescents exposed to more mobility became relatively more disruptive over time. No effects were found for school-age children. Children who moved frequently during infancy and more recently demonstrated significantly worse behavior over time. CONCLUSIONS: The developmental timing of housing mobility affects child behavioral outcomes. Youth in developmental transition at the time of mobility are at greatest risk for disturbances to residential contexts. Assessing housing history represents an important component of interventions with at-risk families. PMID- 24472255 TI - Genetic associations between the symptoms of attention-deficit/hyperactivity disorder and emotional lability in child and adolescent twins. AB - OBJECTIVE: Emotional lability is recognized as an associated feature of attention deficit/hyperactivity disorder (ADHD). However, the degree of phenotypic and etiologic overlap between emotional lability and the ADHD dimensions of hyperactivity-impulsivity and inattention remains unclear. The present study examines these associations in a large, community twin sample. METHOD: Structural equation models were fit to data from 1,920 child and adolescent twin pairs (age range, 5-18 years). Symptoms of hyperactivity-impulsivity (HI) and inattention (IA) were assessed using a modified version of the DuPaul rating scale, completed by parents. Symptoms of emotional lability (EL) were assessed using the parent rated Conners 10-item scale. RESULTS: There were moderate to strong phenotypic correlations between HI, IA, and EL. Multivariate twin modeling revealed that a common pathway model best accounted for the covariance among these dimensions, represented by a highly heritable latent factor. Ad hoc analyses confirmed that all additive genetic influences on HI, IA, and EL were shared, and identified a significantly stronger association of EL with the latent ADHD factor in older than in younger individuals. CONCLUSIONS: Emotional lability was phenotypically and genetically associated with hyperactivity-impulsivity and inattention in children and adolescents. The finding that a single, heritable, latent factor accounted for covariation among these phenotypes indicates that their co occurrence is primarily the result of overlapping genetic effects. These data support the hypothesis that emotional lability is etiologically relevant to the core ADHD phenotype, and that it should be targeted in assessment and treatment in clinical practice. PMID- 24472258 TI - Practice parameter for the assessment and treatment of children and adolescents with autism spectrum disorder. AB - Autism spectrum disorder is characterized by patterns of delay and deviance in the development of social, communicative, and cognitive skills that arise in the first years of life. Although frequently associated with intellectual disability, this condition is distinctive in its course, impact, and treatment. Autism spectrum disorder has a wide range of syndrome expression and its management presents particular challenges for clinicians. Individuals with an autism spectrum disorder can present for clinical care at any point in development. The multiple developmental and behavioral problems associated with this condition necessitate multidisciplinary care, coordination of services, and advocacy for individuals and their families. Early, sustained intervention and the use of multiple treatment modalities are indicated. PMID- 24472259 TI - 'Treat to target' for rheumatoid arthritis in 2014--time tested triple therapy or logical biologics? PMID- 24472256 TI - Strong genetic influences on the stability of autistic traits in childhood. AB - OBJECTIVE: Disorders on the autism spectrum, as well as autistic traits in the general population, have been found to be both highly stable across age and highly heritable at individual ages. However, little is known about the overlap in genetic and environmental influences on autistic traits across age and the contribution of such influences to trait stability itself. The present study investigated these questions in a general population sample of twins. METHOD: More than 6,000 twin pairs were rated on an established scale of autistic traits by their parents at 8, 9, and 12 years of age and by their teachers at 9 and 12 years of age. Data were analyzed using structural equation modeling. RESULTS: The results indicated that, consistently across raters, not only were autistic traits stable, and moderately to highly heritable at individual ages, but there was also a high degree of overlap in genetic influences across age. Furthermore, autistic trait stability could largely be accounted for by genetic factors, with the environment unique to each twin playing a minor role. The environment shared by twins had virtually no effect on the longitudinal stability in autistic traits. CONCLUSIONS: Autistic traits are highly stable across middle childhood. and this stability is caused primarily by genetic factors. PMID- 24472260 TI - Collaboration, the other name for research. PMID- 24472261 TI - Dose optimization of infliximab in patients with rheumatoid arthritis. AB - AIM: It is well established that tumor necrosis factor (TNF) inhibitors help control disease activity, limit radiographic progression and preserve function in patients with rheumatoid arthritis. However, not all patients respond adequately to initial anti-TNF treatment and some patients lose response over time. Possible treatment modifications include optimizing concomitant disease-modifying antirheumatic drugs, switching to another anti-TNF biologic or another class of agent, or optimizing the dose of the anti-TNF agent. Here we review data on dose optimization of infliximab, with emphasis on dose changes to address inadequate response, nonresponse and loss of response. METHOD: The authors conducted a literature review to identify studies that evaluated the effect of dose optimization on clinical response in infliximab-treated patients with rheumatoid arthritis. RESULTS: Few well-controlled studies of dose optimization of infliximab have been completed for patients with rheumatoid arthritis, and the evidence supporting efficacy and safety after dose adjustment can be difficult to interpret. Studies of dose optimization in infliximab-treated patients who fail to show initial response, have an inadequate response, or lose response over time are not entirely consistent, but tend to show a pattern of improvement after a dose increase. CONCLUSION: Dose optimization involves a balance of risks and benefits, and future research should seek to clarify which patients are most likely to benefit from dose optimization without undue increase in risk. PMID- 24472262 TI - Patient age, ethnicity and waiting times determine the likelihood of non attendance at a first specialist rheumatology assessment. AB - OBJECTIVE: To identify demographic and geographic factors associated with non attendance for first specialist assessment (FSA) at a publicly funded rheumatology clinic and identify changes in service provision that might improve attendance rates. METHOD: Administrative data for 1953 new referrals over a 2 year period was collected from a New Zealand public rheumatology unit. Patient characteristics and location variables were tested for significance and odds ratios were generated to determine the relationship between non-attendance and referrals data. RESULTS: Patients in the 20-29 years age-group were least likely to attend appointments (P <= 0.001, OR 2.81, 95%CI 1.59-4.98). Maori and Pacific Peoples were each almost twice as likely to miss a FSA (P = 0.02, OR 1.87, 95%CI 1.11-3.15 and OR 1.89, 95%CI 1.11-3.22) as New Zealand Europeans. Non-attendance was independently associated with longer waiting times to FSA; with residential location and the uneven provision of services being strong predictors of longer waiting times (P <= 0.001). CONCLUSION: Non-attendance is associated with ethnicity, age and waiting times. It is likely that high deprivation influences ethnic variations in attendance but reasons for young people's non-attendance were difficult to identify. Patients domiciled further from the main rheumatology clinic were also less likely to attend. The influence of ethnicity and deprivation may be underestimated in this study as high Maori and Pacific ethnic populations live closer to well-resourced clinics. Focusing administrative resources on at-risk groups and restructuring the clinical service to improve uneven waiting times would be expected to improve attendance rates across the region. PMID- 24472263 TI - Clinical significance of brachial flow-mediated dilation in patients with rheumatoid arthritis. AB - AIM: This study aimed to clarify whether different anti-tumor necrosis factor (TNF) drugs can improve endothelial function better than conventional disease modifying anti-rheumatic drugs (DMARDs) in a series of Japanese patients with rheumatoid arthritis (RA). METHOD: Twenty-five patients who met the American College of Rheumatology 1987 revised diagnostic criteria for RA were randomly selected for this study. The percentage of brachial flow-mediated dilation (%FMD) and maximum carotid intima-media thickness were examined by ultrasonography. RESULTS: The %FMD in the group treated with anti-TNF therapy was significantly higher than that in the group treated with DMARDs (P < 0.001). The %FMD was significantly correlated with anti-TNF therapy (r = 0.684, P < 0.001) and Disease Activity Score C-reactive protein (r = -0.404, P < 0.05). Multiple regression analysis revealed that anti-TNF therapy was significantly associated with %FMD (beta = 0.684, P < 0.001). CONCLUSION: Anti-TNF therapy may influence endothelial function more than conventional DMARD therapy. Prospective longitudinal studies examining whether anti-TNF therapy was able to improve endothelial function are required. PMID- 24472264 TI - Affective temperaments in patients with rheumatoid arthritis. AB - AIM: The issue whether patients with rheumatoid arthritis (RA) have certain personality characteristics has been discussed. The temperament and personality characteristics of the patient may influence success in competing with stress. The aims of the study were to determine the most common dominant affective temperaments in patients with RA and whether temperament affects the disability. METHODS: A total of 88 patients with RA participated in this cross-sectional study. The Turkish version of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto Questionnaire scale was used to determine the dominant affective temperament, and the Health Assessment Questionnaire (HAQ) was used to determine functional ability. RESULTS: Depressive temperament was found in 52 patients (59.1%) as the most common dominant affective temperament followed by irritable temperament in 17 patients (19.3%). There was no significant difference in HAQ scores of the patients according to the subscales of the Temperament Evaluation of Memphis, Pisa, Paris and San Diego Auto Questionnaire. Disability levels of patients were found as low-level disability in 65 patients and high level disability in 23 patients. Multiple linear regression analysis indicated that HAQ score was not associated with gender, body mass index, duration of the disease, depressive temperament, anxious temperament, cyclothymic temperament or irritable temperament. CONCLUSION: The current study showed that depressive and irritable temperaments are the most common affective temperaments in patients with RA. The dominant affective temperament does not affect the functional ability of patients with RA. PMID- 24472266 TI - Celecoxib, a selective cyclooxygenase-2 inhibitor, reduces level of a bone resorption marker in postmenopausal women with rheumatoid arthritis. AB - AIM: Celecoxib (CEL), a selective cyclooxygenase-2 (COX-2) inhibitor, has been reported to suppress osteoclastogenesis in vitro, reduce levels of bone resorption markers in ovariectomized (OVX) mice, and prevent bone destruction in rheumatoid arthritis (RA) model mice; however, no clinical data has been reported. Here, we prospectively evaluated the changes in bone turnover markers in RA patients who switched from nonsteroidal anti-inflammatory drugs (NSAIDs) to CEL, to examine the effects of selective COX-2 inhibitor on bone metabolism. METHODS: RA patients who had been treated with NSAIDs for more than 12 weeks were switched to CEL (400 mg/day) without any other changes in previously prescribed medications. Urinary type I collagen cross-linked N-telopeptide (uNTX), serum bone alkaline phosphatase (BAP), C-reactive protein (CRP), erythrocyte sedimentation rate (ESR) and matrix metalloproteinase-3 (MMP-3) were evaluated before switching to CEL and 16 weeks later. RESULTS: Significant reductions in uNTX, a bone resorption marker, were observed in 60 female patients (P = 0.042), especially in 52 postmenopausal women (P = 0.033). However, uNTX level did not significantly change in premenopausal women or in men. There were no significant changes in BAP, a bone formation marker. CRP significantly decreased (P = 0.007), while ESR and MMP-3 were unchanged. CONCLUSION: CEL reduced the levels of a bone resorption marker in postmenopausal RA patients, suggesting that this drug may attenuate the accelerated osteoclastic bone resorption associated with menopause. PMID- 24472265 TI - Heart rate, ejection duration and subendocardial viability ratio in patients with rheumatoid arthritis as compared to controls. AB - AIM: Rheumatoid arthritis (RA) is associated with increased cardiovascular morbidity and mortality. In the general population, an increased heart rate is associated with increased mortality. Only a few studies have investigated heart rate in RA patients and compared the results with patients that do not have RA (n RA). Therefore, little is known as to whether an increased heart rate, at least in part, could explain the increased mortality found in RA patients. The aim of the present study was to investigate whether heart rate is increased in RA patients. METHODS: In this cross-sectional study, heart rate was determined in a total of 282 patients (131 RA, 151 n-RA). In addition, non-invasive pulse wave analysis of the radial artery was performed to determine cardiac ejection duration using the Sphygmocor apparatus. Furthermore, the subendocardial viability ratio (SEVR), a marker of cardiac workload, was investigated, whereby higher values indicate a more favorable supply/demand relationship for the myocardium. Patients using chronotropic drugs were not included in the study. RESULTS: Heart rate was virtually the same in RA patients (71.9 +/- 11.2 beats/min [bpm]) as compared with controls (72.3 +/- 11.7 bpm; P > 0.05). Also SEVR (RA 144 +/- 25% vs. n-RA 147 +/- 27%; P > 0.05) and ejection duration (RA 321 +/- 24 ms vs. n-RA 318 +/- 24 ms; P > 0.05) were comparable between the groups. CONCLUSION: It could not be shown that heart rate in RA patients differs significantly from heart rate in controls. Therefore, heart rate does not appear to explain or contribute to the increased cardiovascular risk found in RA patients. PMID- 24472267 TI - Plasma osteopontin is correlated with bone resorption markers in rheumatoid arthritis patients. AB - AIM: To assess whether any form of osteopontin (OPN) is correlated with bone resorption markers or treatment effects in rheumatoid arthritis (RA). METHOD: Subjects comprised 119 patients with RA. RA disease activity was evaluated by Disease Activity Score (DAS) 28, erythrocyte sedimentation rate (ESR), and levels of C-reactive protein (CRP), rheumatoid factor (RF) and matrix metalloproteinase (MMP)-3. OPN levels in plasma and urine were measured by enzyme-linked immunosorbent assay (ELISA). Levels of tartrate-resistant acid phosphatase (TRACP) 5b in serum and C-terminal telopeptide of type 1 collagen (CTX)-1 in urine were measured by ELISA. Patients were divided into responder and nonresponder groups, and OPN levels were compared at baseline and after treatment. RESULTS: Levels of full-length OPN in plasma (P-fOPN) were significantly correlated with levels of TRACP 5b (r = 0.44, P < 0.001), urine CTX 1 (r = 0.26, P = 0.004) and MMP-3 (r = 0.34, P < 0.001). Levels of TRACP 5b were significantly correlated with age (r = 0.25, P = 0.007), but levels of P-fOPN were not. After treatment, plasma OPN levels were significantly decreased in responders (P = 0.003). Levels of full-length or thrombin-cleaved forms of OPN in urine were not correlated with TRACP 5b or CTX-1. CONCLUSION: Our results suggest that plasma OPN may reflect inflammatory bone destruction in RA patients. PMID- 24472268 TI - How do anti-TNF therapies affect gait function in patients with rheumatoid arthritis? AB - AIM: The aim of the present study was to investigate the influence of anti-tumor necrosis factor (anti-TNF) agents on gait function in patients with rheumatoid arthritis (RA). METHODS: Nine subjects with RA who were being treated with anti TNF agents, participated in this study. A motion capture system was utilized, and data from the force plate and captured three dimensional motions were analyzed.Gait evaluation was performed before and 5.8 +/- 2.6 months after introducing the anti-TNF agent. Stride, gait velocity and joint moments were calculated. In addition, an index of balancing weight of the lower extremities was determined. RESULTS: Stride length averaged 45.8 cm at baseline and 53.1 cm at the time of follow-up, and gait velocity averaged 0.9 m/s at baseline and 1.1 m/s at the time of follow-up. At heal contact, the joint moment of hip extension increased from 0.37 to 0.49, while ankle joint dorsiflexion moment increased from 0.08 to 0.13. During mid-stance, knee joint extension moment decreased from 0.16 to 0.06. At toe-off, hip joint flexion moment increased from 0.60 to 0.80, and ankle joint dorsiflexion moment increased from 0.80 to 1.05. The index of balancing weight of the lower extremities increased from 19.6 to 20.9 N. CONCLUSION: The induction of anti-TNF therapies improved alterations in shock absorption in the early stance phase, balancing weight of the lower extremities in mid-stance, and increased push-off power in the later stance phase. PMID- 24472269 TI - Characteristics of patients with rheumatoid arthritis in Qatar: a cross-sectional study. AB - OBJECTIVE: To describe the clinical characteristics, serologic, radiological and clinical disease activity, and modality of therapy in patients with rheumatoid arthritis (RA) at tertiary outpatient care in Qatar. METHODS: The study design was cross-sectional where 100 consecutive cases who met 1987 American College of Rheumatology criteria for diagnosis of RA were enrolled in this study. Demographic data (sex, nationality and age) numbers of swollen and tender joints, X-rays and current medications were collected during outpatients visits to Hamad General Hospital. Disease Activity Score of 28 joints (DAS28) and Health Assessment Questionnaires (HAQ) scores were calculated. All patients with RA who were seen as rheumatology outpatients were invited to participate in the study. RESULTS: One hundred patients were seen and examined during their follow-up at the outpatient clinic; data were collected and analyzed. Females represented 67% of all patients, 6% had more than six swollen joints, 9% had more than six tender joints. DAS28 and erythrocyte sedimentation rate (DAS28) calculation revealed 49% of patients were in remission (DAS28 < 2.6), 15% had low disease activity (DAS28 2.6-3.2) and 36% had DAS28 > 3.2.Mean HAQ score was 1.02. Rheumatoid factor (RF) was positive in 63%, while anti-cyclic citrullinated protein antibody (anti-CCP) was positive in 71%, and 49% were positive for both. Radiography of hands and feet during the previous year was done in 65% of patients: 11% of them had erosions. Sixty-six percent were on one synthetic disease-modifying anti rheumatic drug (DMARD) and 27% where on more than one synthetic DMARD and 7% where on no DMRD. Glucocorticoids were used in 51% and 29% were on biologics. CONCLUSION: Sixty-four percent of rheumatoid arthritis patients in Qatar were in remission or had low disease activity while the remaining 36% had active disease and among these patients 29% were on biologics. PMID- 24472270 TI - Superiority of laterally elevated wedged insoles to neutrally wedged insoles in medial knee osteoarthritis symptom relief. AB - AIM: Knee osteoarthritis (OA), is the most common degenerative joint disease. Several non-pharmacological interventions have been used for this purpose such as insoles. There are contradictory data about the superiority and effectiveness of laterally wedged compared with neutrally wedged insoles. This study was designed to compare the effectiveness of laterally and neutrally wedged insoles in management of knee OA. METHODS: In this double-blind, parallel treatment trial, 118 patients with knee OA according to American College of Rheumatology (ACR) criteria were enrolled and were followed for 2 months. Patients were randomly divided into two groups. Fifty-seven of them were treated with 5 degrees laterally elevated wedged insoles (group A) and 61 patients were treated with neutrally wedged insoles (group B). Edinburg Knee Functional Scale (EKFS) was used to evaluate knee function before and after interventions. At the end of 2 months, severity of knee pain during the previous 2 days, numbers of non-steroid anti inflammatory drugs (NSAIDs) used for pain relief within the last 2 weeks and EKFS were assessed. RESULTS: Severity of knee pain decreased in both groups after intervention. The mean difference in groups A (laterally wedged insole) and B (neutrally wedged insole) were 29.3 (95% confidence interval [95% CI]: 25.12, 33.55) and 6.25 (95% CI: 3.09, 9.4), respectively (P < 0.001 for both). In addition, at the end of the study, EKFS improved significantly in group A (mean: 7.54, 95% CI: 6.3, 8.8; P < 0.001), while in group B we could not find significant improvement (mean: 0.54, 95% CI: -0.41, 1.5; P = 0.166). Numbers of NSAIDs used during the two final weeks of the study significantly decreased compared with baseline in group A (P = 0.001; mean: 2.6, 95% CI: 1.3, 3.9); while in group B this was not shown (P = 0.9; mean: 0.05, 95% CI:-0.87, 0.97). CONCLUSION: This study suggests that laterally elevated wedged insoles are more effective than neutrally wedged insoles, in pain relief of knee OA. PMID- 24472271 TI - Behavioral approach system activity and self-reported somatic symptoms in fibromyalgia: an exploratory study. AB - The first objective was to investigate the behavioural activity in the systems of Gray's theory; these are the Behavioural Inhibition System (BIS) and Behavioural Approach System (BAS), in fibromyalgia (FM) patients. The second aim was to assess in FM patients whether there is an association between BIS or BAS with self-reported somatic symptoms. Twenty FM patients and 20 healthy controls completed questionnaire measures of BIS and BAS activity (Sensitivity to Punishment and Sensitivity to Reward Questionnaire), self-reported somatic symptoms (Somatic Symptoms Scale Revised), positive and negative affect (Positive and Negative Affect Schedule) and health status (EuroQoL Visual Analogue Scale). The results showed that FM patients had lower Sensitivity to Reward (SR) scores than controls. The SR score correlated with different somatic symptoms groups. The partial correlation (controlling for other variables measured) showed that the SR score correlated specifically with musculoskeletal symptoms. Furthermore, in regression analysis, SR score significantly predicted musculoskeletal symptoms, after controlling for other variables measured in this study. Our findings suggest that FM patients show BAS hypoactivity. This BAS activity in FM is similar to patients with depression, where a lower BAS functioning has also been found. The BAS activity predicts the musculoskeletal self-reported symptoms in FM better than other measures included in this study. Although this is a preliminary study, it suggests the importance of BAS activity in FM. PMID- 24472272 TI - Psychometric properties of the Malay version of the Osteoporosis Health Belief Scale (OHBS-M) among Type 2 diabetic patients. AB - AIMS: The aims of this study were to translate and examine the psychometric properties of the Malaysian version of the Osteoporosis Health Belief Scale (OHBS M) among type 2 diabetes patients (T2DM) and to assess the correlation between osteoporosis knowledge, health belief and self-efficacy scales, as well as assess the osteoporosis risk in the sample population using quantitative ultrasound measurement (QUS). METHODS: A standard 'forward-backward' procedure was used to translate OHBS into the Malay language, which was then validated with a convenience sample of 250 T2DM. Bone mineral density (BMD) measurements were carried out using QUS at the calcaneus. RESULTS: The mean score of OHBS-M was 158.31 +/- 20.80. The Fleiss' kappa, content validity ratio range and content validity index were 0.99, 0.75-1.00 and 0.88, respectively. Seven factors of the OHBS-M were identified using exploratory factor analysis and were confirmed through confirmatory factor analysis. Internal consistency and test-retest reliability values were 0.89 and 0.555, respectively. In addition, only 22% had a normal BMD (low risk of abnormal BMD), while osteopenia and osteoporosis were 57.6% and 20.4% (considered as high risk of abnormal BMD), respectively. CONCLUSION: The results showed that the OHBS-M is a reliable and valid instrument for measuring health belief toward osteoporosis in diabetic patients. In addition, it is an appropriate tool to identify patients needing a bone health promoting intervention regarding lifestyle behavior changes in a clinical setting. Moreover, the sample population showed high risk of osteoporosis and would subsequently benefit from dual-energy x-ray absorptiometry scanning for definite evaluation and treatment. PMID- 24472273 TI - Sera of patients with thromboangiitis obliterans activated cultured human umbilical vein endothelial cells (HUVECs) and changed their adhesive properties. AB - INTRODUCTION: The aim of this study was to investigate the impact of thromboangiitis obliterans (TAO) sera on activation of primary cultures of human umbilical vein endothelial cells (HUVECs) as a model for vascular endothelial cells. METHODS: Study subjects included 21 TAO patients as the case group and 20 healthy smokers and 17 healthy non-smokers as control groups. Case and control groups were matched based on their age, socioeconomic status and smoking habit. HUVECs were incubated with the sera of case and control groups and gene expression of intercellular adhesion molecule (ICAM-1) and vascular adhesion molecule (VCAM-1) were evaluated by real-time polymerase chain reaction, TaqMan method. RESULTS: The expression of ICAM-1 and VCAM-1 were significantly higher in HUVECs after incubation with TAO sera compared to control groups (P < 0.05). VCAM 1 had a significant correlation with duration of smoking (P < 0.001, R = 0.672), while the expression of ICAM-1 had a significant correlation with the number of cigarettes smoked daily (P = 0.04, R = 0.421). CONCLUSION: Sera from TAO patients could activate HUVECs. This same activation might occur in vivo by the responsible cytokines, in particular those released from activated platelets, free oxygen radicals, and possibly low levels of nitric oxide (NO) of the sera of TAO patients, as a consequences of chronic cigarette smoking and of endothelial NO synthase polymorphism. Therefore, plasma exchange might be helpful in acute phase of the disease for saving the limbs and administration the combinations of exogenous NO with anti-oxidants might be helpful in long-term management of TAO patients to reduce the risk and rate of amputation. PMID- 24472274 TI - Giant cell arteritis with visual loss following zoledronic acid infusion. AB - Zoledronic acid is used in the treatment of osteoporosis. Giant cell artertitis may lead to vision loss. We report a case in which vision loss occurred after zoledronic acid infusion. PMID- 24472275 TI - Peyronie's disease in a patient with primary Sjogren's syndrome. PMID- 24472276 TI - Felty's syndrome with hyperthyroidism: a case report and literature review. PMID- 24472277 TI - Medial tibial stress syndrome progressing to tibial fracture in rheumatoid arthritis. PMID- 24472278 TI - Mothers' Working Hours and Children's Obesity: Data from the Korean National Health and Nutrition Examination Survey, 2008-2010. AB - OBJECTIVES: The aim of this study is to find the association between mothers' working hours and obesity of their children according to children's age and gender. METHODS: This study used data from the second and third year of KNHANES IV and the first year in KNHANES V (2008-2010). We calculate odds ratio (OR) and 95% confidence interval (CI) by using survey logistic regression to assess association of mother's working hours with overweight or obesity of her children. The model was adjusted with household income, mothers' education and obesity and mothers' job characteristics. RESULTS: 13-18 aged boys whose mothers worked under 40 hours per week were higher risk for obesity and overweight (including obesity) than 13-18 aged boys whose mothers worked 40-48 hours. 6-12 aged girls whose mothers worked 49-60 hours per week were more overweight (including obesity) than girls whose mothers worked 40-48 hours per week. 13-18 aged girls whose mothers worked over 60 hours were more overweight (including obesity) than the reference. CONCLUSION: This study showed that girls' obesity was associated with mothers' long working hours. Long working hours can influence health of workers' family. PMID- 24472279 TI - Designing intelligent anesthesia for a changing patient demographic: a consensus statement to provide guidance for specialist and non-specialist anesthetists written by members of and endorsed by the Society for Obesity and Bariatric Anaesthesia (SOBA). AB - BACKGROUND: As a result of the increasing prevalence of obesity in the UK, anesthetists are increasingly encountering overweight and obese patients in routine practice. There is currently a paucity of evidence to guide best clinical practice for anesthetists managing overweight and obese patients. The current guidelines from the Association of Anaesthetists of Great Britain and Ireland (AAGBI), entitled Peri-Operative Management of the Morbidly Obese Patient, give an excellent overview of organizational issues, but leave much clinical detail to the discretion of the individual clinician. METHODS: In May 2010, a panel of experts convened to develop consensus on anesthesia of overweight, obese and morbidly obese patients, in consultation with the Society for Obesity and Bariatric Anaesthesia (SOBA). All Panel members are practicing clinicians from recognized bariatric surgical training centers and have extensive experience of anesthesia for obese patients. This statement aims to provide guiding principles on best practice for this challenging patient demographic, and to increase awareness of current issues so that these can be addressed more appropriately. RESULTS: In this document, we emphasize key principles for best practice, rather than giving prescriptive guidance and specific regimens for all clinical eventualities. We provide evidence-based justification for best-practice techniques, where this exists. In areas for which there is no evidence, but there is clear consensus, we offer this as guidance. We also aim to dispel misconceptions that have arisen in the anesthetic practice of overweight, obese, and morbidly obese patients. CONCLUSION: Ultimately, the choice of specific technique depends on clinician experience, patient characteristics, and center facilities. As well as providing guiding principles for anesthesia, this consensus statement also highlights other areas where anesthetists can contribute towards the enhanced recovery and overall quality of patient care. PMID- 24472280 TI - The interaction between Toll-like receptor 4 signaling pathway and hypoxia inducible factor 1alpha in lung ischemia-reperfusion injury. AB - BACKGROUND: Lung ischemia-reperfusion injury (LIRI) is the life-threatening complication occurring after lung transplantation. Toll-like receptor 4 (TLR4) signaling pathway and hypoxia-inducible factor-1alpha (HIF-1alpha) are intimately involved in the development and progression of various inflammatory and hypoxia diseases; however, the relationship of them in LIRI in vivo is still far from clear. MATERIALS AND METHODS: Forty-five Sprague-Dawley rats were randomly distributed in nine groups: (1) Sham group, (2) LIRI group, (3) LIRI + saline control group, (4) LIRI + dimethyl Sulfoxide control group, (5) LIRI + lipopolysaccharide group, (6) LIRI + TAK-242 group (TAK-242 is a TLR4 inhibitor, ethyl (6R)-6- [N-(2-chloro-4-fluorophenyl)sulfamoyl]cyclohex-1-ene-1 carboxylate), (7) LIRI + thioredoxin group (thioredoxin is an apoptosis signal regulating kinase 1 (ASK1) inhibitor), (8) LIRI + SB203580 group (SB203580 is a p38 inhibitor), and (9) LIRI + chetomin group (chetomin is a HIF-1alpha inhibitor). The interaction between TLR4 signaling pathway (including TLR4, myeloid differentiation primary response gene 88 (MyD88), TIR-domain-containing adapter-inducing interferon-beta (TRIF), ASK1, and p38) and HIF-1alpha and the role of TLR4-dependent HIF-1alpha were analyzed. RESULTS: In LIRI, HIF-1alpha accumulation was induced in a TLR4-dependent fashion, and MyD88, but not TRIF, and activation of ASK1 and p38 were found to be critical for TLR4-mediated HIF 1alpha accumulation. HIF-1alpha protein played a critical role in TLR4-mediated lung injury of LIRI (including inflammation, cell apoptosis, and lung damage). HIF-1alpha protein upregulated TLR4 expression of LIRI in a positive feedback manner. CONCLUSIONS: We identify that the TLR4-HIF-1 loop may be existed in LIRI. Therefore, we suggest that the interaction between them may represent a novel therapeutic target for the development of novel target-based therapies of LIRI. PMID- 24472281 TI - Designing an ethics curriculum to support global health experiences in surgery. AB - BACKGROUND: The field of global health is rapidly expanding in many medical centers across the US. As a result, medical students have increasing opportunities to incorporate global health experiences (GHEs) into their medical education. Ethics is a critical component of global health curricula, yet little literature exists to direct the further development of didactic training. Therefore, we sought to define ethical encounters experienced by medical students participating in short-term surgical GHEs and create a framework for the design of ethics curriculum specific to global surgery. MATERIALS AND METHODS: Emory University Departments of Surgery, Urology, and Anesthesia, in partnership with the non-profit organization Project Medishare, have taken annual humanitarian surgical trips to Hinche, Haiti. All medical students returning from the trips in 2011 and 2012 received a 35-question survey to assess demographic data, extent of prior ethics education, frequency of exposure and situational confidence to ethical subject matter, as well as ethical conflicts involved in surgical GHEs. The same comparative data were also collected for domestic clinical clerkships. RESULTS: Seventeen out of 21 medical students completed the survey. Nearly all (88.3%) students had previous formal ethics training as an undergraduate or in medical school. Ethical issues were commonly encountered during domestic clinical encounters and volunteerism. However, students reported enhanced exposure to the professional obligation of surgeons (P = 0.025) and truth-telling/surgeon-patient relationships (P = 0.044) during surgical volunteerism. Despite increased exposure, situational confidence did not change. CONCLUSIONS: Ethical issues are commonly confronted during GHEs in surgery and differ from domestic clinical encounters. Healthcare ethics curriculum should be designed to meet the needs of medical students involved in global health. PMID- 24472282 TI - Effects of impairment in activities of daily living on predicting mortality following hip fracture surgery in studies using administrative healthcare databases. AB - BACKGROUND: Impairment in activities of daily living (ADL) is an important predictor of outcomes although many administrative databases lack information on ADL function. We evaluated the impact of ADL function on predicting postoperative mortality among older adults with hip fractures in Ontario, Canada. METHODS: Sociodemographic and medical correlates of ADL impairment were first identified in a population of older adults with hip fractures who had ADL information available prior to hip fracture. A logistic regression model was developed to predict 360-day postoperative mortality and the predictive ability of this model were compared when ADL impairment was included or omitted from the model. RESULTS: The study sample (N = 1,329) had a mean age of 85.2 years, were 72.8% female and the majority resided in long-term care (78.5%). Overall, 36.4% of individuals died within 360 days of surgery. After controlling for age, sex, medical comorbidity and medical conditions correlated with ADL impairment, addition of ADL measures improved the logistic regression model for predicting 360 day mortality (AIC = 1706.9 vs. 1695.0; c -statistic = 0.65 vs 0.67; difference in - 2 log likelihood ratios: chi(2) = 16.9, p = 0.002). CONCLUSIONS: Direct measures of ADL impairment provides additional prognostic information on mortality for older adults with hip fractures even after controlling for medical comorbidity. Observational studies using administrative databases without measures of ADLs may be potentially prone to confounding and bias and case-mix adjustment for hip fracture outcomes should include ADL measures where these are available. PMID- 24472283 TI - Does bearing size influence metal ion levels in large-head metal-on-metal total hip arthroplasty? A comparison of three total hip systems. AB - BACKGROUND: The purpose of the study was twofold: first, to determine whether there is a statistically significant difference in the metal ion levels among three different large-head metal-on-metal (MOM) total hip systems. The second objective was to assess whether position of the implanted prostheses, patient demographics or factors such as activity levels influence overall blood metal ion levels and whether there is a difference in the functional outcomes between the systems. METHODS: In a cross-sectional cohort study, three different metal-on metal total hip systems were assessed: two monoblock heads, the Durom socket (Zimmer, Warsaw, IN, USA) and the Birmingham socket (Smith and Nephew, Memphis, TN, USA), and one modular metal-on-metal total hip system (Pinnacle, Depuy Orthopedics, Warsaw, IN, USA). Fifty-four patients were recruited, with a mean age of 59.7 years and a mean follow-up time of 41 months (12 to 60). Patients were evaluated clinically, radiologically and biochemically. Statistical analysis was performed on all collected data to assess any differences between the three groups in terms of overall blood metal ion levels and also to identify whether there was any other factor within the group demographics and outcomes that could influence the mean levels of Co and Cr. RESULTS: Although the functional outcome scores were similar in all three groups, the blood metal ion levels in the larger monoblock large heads (Durom, Birmingham sockets) were significantly raised compared with those of the Pinnacle group. In addition, the metal ion levels were not found to have a statistically significant relationship to the anteversion or abduction angles as measured on the radiographs. CONCLUSIONS: When considering a MOM THR, the use of a monoblock large-head system leads to higher elevations in whole blood metal ions and offers no advantage over a smaller head modular system. PMID- 24472284 TI - High saturated fat and low carbohydrate diet decreases lifespan independent of body weight in mice. AB - BACKGROUND: Obesity is a health problem that is reaching epidemic proportions worldwide. We investigated the effects of a life-long high saturated fat and low carbohydrate (HF) diet on the body mass, glucose tolerance, cognitive performance and lifespan of mice. FINDINGS: C57BL/6J mice were fed with a HF diet (60% kcal/fat) or control diets (15% kcal/fat) for 27 months. One-half of the mice on the HF diet developed obesity (diet-induced obese (DIO) mice), whereas the remaining mice were diet resistant (DR). At 8 months of age, both DIO and DR groups had increased hyperglycemic response during a glucose tolerance test, which was normalized in 16-month-old mice. At this latter time point, all groups presented similar performance in cognitive tests (Morris water maze and inhibitory avoidance). The survival curves of the HF and control diet groups started to diverge at 15 months of age and, after 27 months, the survival rate of mice in the DIO and DR groups was 40%, whereas in the control diet group it was 75%. CONCLUSIONS: AHFdiet decreased the survival of mice independent of bodyweight. PMID- 24472285 TI - Effect of uneven red cell influx on formation of cell-free layer in small venules. AB - This study examined how the uneven influx of red blood cells (RBCs) from feeding vessels influences formation of cell-free layer (CFL) in the downstream vessel of a venular bifurcation. Spatio-temporal variations of the CFL width along the downstream vessel (19-41-MUm inner diameter, D) were determined at 0.5D intervals from 0.5D to 3.0D away from the bifurcation. Upstream flow conditions were quantified by the ratio of volume flow rates (Q*=Q(High)/Q(Low)) between high flow (Q(High)) and low flow feeding (Q(Low)) vessels. The RBC aggregation level in the rats was adjusted to be at healthy human levels by infusing Dextran 500. Our results suggested that the CFL formation process could be seen only from 2.0D away from the bifurcating point. The mean CFL width at the wall adjacent to the feeding vessel with a higher flow rate was consistently greater than that at the opposite wall, leading to an asymmetric CFL formation in the vessel. A positive relation (P<0.05) between the asymmetry of the CFL width and the volume flow rate ratio (Q*) was found. Our numerical prediction showed that flow resistance in the venular network could be significantly increased by the asymmetric formation of CFL downstream and this effect might become more pronounced under pathological flow conditions such as hyper-aggregating and/or low shear conditions. PMID- 24472286 TI - Small auxin upregulated RNA (SAUR) gene family in maize: identification, evolution, and its phylogenetic comparison with Arabidopsis, rice, and sorghum. AB - Small auxin-up RNAs (SAURs) are the early auxin-responsive genes represented by a large multigene family in plants. Here, we identified 79 SAUR gene family members from maize (Zea mays subsp. mays) by a reiterative database search and manual annotation. Phylogenetic analysis indicated that the SAUR proteins from Arabidopsis, rice, sorghum, and maize had divided into 16 groups. These genes were non-randomly distributed across the maize chromosomes, and segmental duplication and tandem duplication contributed to the expansion of the maize SAUR gene family. Synteny analysis established orthology relationships and functional linkages between SAUR genes in maize and sorghum genomes. We also found that the auxin-responsive elements were conserved in the upstream sequences of maize SAUR members. Selection analyses identified some significant site-specific constraints acted on most SAUR paralogs. Expression profiles based on microarray data have provided insights into the possible functional divergence among members of the SAUR gene family. Quantitative real-time PCR analysis indicated that some of the 10 randomly selected ZmSAUR genes could be induced at least in maize shoot or root tissue tested. The results reveal a comprehensive overview of the maize SAUR gene family and may pave the way for deciphering their function during plant development. PMID- 24472289 TI - Epstein-Barr virus and Hodgkin lymphoma in Jordan. AB - BACKGROUND AND OBJECTIVES: This study aims to examine the possible association of Epstein-Barr virus (EBV) in Classical Hodgkin lymphoma (cHL) and to shed light on the epidemiology of Hodgkin lymphoma (HL) in Jordan. PATIENTS AND METHODS: We examined 100 consecutive cases of HL for the presence of EBV in tumor cells by immunohistochemistry for latent membrane protein-1 (LMP-1). We collected patient data on age, sex and histologic subtype. We reviewed the pathological findings in each case and confirmed diagnosis. RESULTS: Nodular lymphocyte predominant HL was diagnosed in 6% of the cases and these were negative for EBV LMP-1. Of the 94 cases of cHL, 65% were males, the most common subtype was nodular sclerosis (NS), representing 70% of the cases, and 45.7% of cHL (43% of all HL) cases were positive for EBV LMP-1. The positive cases were significantly related to age: ?15 years and >51 years (p: 0.009 and 0.014 respectively), male gender (p: 0.03) and mixed cellularity (MC) subtype (p: <0.0001). In line with other developing countries, there also appears to be a trend towards a decreasing association of EBV with cHL and a subtype switch from MC to NS in Jordan. CONCLUSION: The epidemiology of HL in Jordan and some developing countries is approaching that of developed countries. PMID- 24472290 TI - Pheochromocytoma: a review. AB - Pheochromocytomas are catecholamine producing neuroendocrine tumors that can be adrenal or extra-adrenal in origin. The classic symptoms of pheochromocytoma are headache, palpitation, anxiety and diaphoresis and the tumor can occur at any age with equal gender distribution. In patients with an established mutation or hereditary syndrome the condition may manifest at a younger age than in those with sporadic disease. Pheochromocytoma can be associated with certain genetic syndromes such as multiple endocrine neoplasia type 2 (MEN 2), neurofibromatosis (NF) and von Hippel-Lindau (VHL) syndrome. Pheochromocytoma is diagnosed with biochemical confirmation of hormonal excess followed by anatomical localization (CT or MRI). The mainstay of definitive therapy is surgical resection. In this review, we discuss in detail about the symptomatology, diagnosis, genetic aspects and management of pheochromocytoma. PMID- 24472291 TI - Letter regarding "Does cruciate-retaining total knee arthroplasty enhance knee flexion in Western and East Asian patient populations? A meta-analysis". PMID- 24472292 TI - Relationship between Occupational Stress and Work-related Musculoskeletal Disorders in Korean Male Firefighters. AB - OBJECTIVES: A growing body of literature has documented that job stress is associated with the development of work-related musculoskeletal disorders (WMSDs). However, the association of WMSDs with job stress has not yet been fully studied in Korean male firefighters. The purpose of this study was to determine the status of WMSDs in almost all Korean male firefighters and to clarify the effect of job stress on the occurrence of WMSDs. METHODS: The study design was cross-sectional, and 21,466 firefighters were recruited. The study design included a structured questionnaire to assess general characteristics, the Korean Occupational Stress Scale (optional KOSS-26), Center for Epidemiologic Studies Depression Scale (CES-D), and WMSDs. The chi-square test, and univariate and multivariate logistic regression analyses were used to look for a correlation between general characteristics and job stress, and the occurrence of WMSD. RESULTS: Back pain is the most common WMSD. Among the job stress subgroup, physical environment, job demands, organizational system, occupational climate, lack of reward and job insecurity were related to the occurrence of WMSDs. However, insufficient job control and interpersonal conflict were not related to the occurrence of WMSDs. CONCLUSION: Job stress was related to the occurrence of WMSDs in Korean male firefighters. To reduce the occurrence of WMSDs, a job stress management program may be required. PMID- 24472294 TI - Comorbidity and multimorbidity need to be placed in the context of a framework of risk, responsiveness, and vulnerability. PMID- 24472295 TI - Multimorbidity patterns: a systematic review. AB - OBJECTIVES: The aim of this review was to identify studies on patterns of associative multimorbidity, defined as the nonrandom association between diseases, focusing on the main methodological features of the studies and the similarities among the detected patterns. STUDY DESIGN AND SETTING: Studies were identified through MEDLINE and EMBASE electronic database searches from their inception to June 2012 and bibliographies. RESULTS: The final 14 articles exhibited methodological heterogeneity in terms of the sample size, age and recruitment of study participants, the data source, the number of baseline diseases considered, and the statistical procedure used. A total of 97 patterns composed of two or more diseases were identified. Among these, 63 patterns were composed of three or more diseases. Despite the methodological variability among studies, this review demonstrated relevant similarities for three groups of patterns. The first one comprised a combination of cardiovascular and metabolic diseases, the second one was related with mental health problems, and the third one with musculoskeletal disorders. CONCLUSION: The existence of associations beyond chance among the different diseases that comprise these patterns should be considered with the aim of directing future lines of research that measure their intensity, clarify their nature, and highlight the possible causal underlying mechanisms. PMID- 24472296 TI - Baseline pressure errors (BPEs) extensively influence intracranial pressure scores: results of a prospective observational study. AB - BACKGROUND: Monitoring of intracranial pressure (ICP) is a cornerstone in the surveillance of neurosurgical patients. The ICP is measured against a baseline pressure (i.e. zero - or reference pressure). We have previously reported that baseline pressure errors (BPEs), manifested as spontaneous shift or drifts in baseline pressure, cause erroneous readings of mean ICP in individual patients. The objective of this study was to monitor the frequency and severity of BPEs. To this end, we performed a prospective, observational study monitoring the ICP from two separate ICP sensors (Sensors 1 and 2) placed in close proximity in the brain. We characterized BPEs as differences in mean ICP despite near to identical ICP waveform in Sensors 1 and 2. METHODS: The study enrolled patients with aneurysmal subarachnoid hemorrhage in need of continuous ICP monitoring as part of their intensive care management. The two sensors were placed close to each other in the brain parenchyma via the same burr hole. The monitoring was performed as long as needed from a clinical perspective and the ICP recordings were stored digitally for analysis. For every patient the mean ICP as well as the various ICP wave parameters of the two sensors were compared. RESULTS: Sixteen patients were monitored median 164 hours (ranges 70 - 364 hours). Major BPEs, as defined by marked differences in mean ICP despite similar ICP waveform, were seen in 9 of them (56%). The BPEs were of magnitudes that had the potential to alter patient management. CONCLUSIONS: Baseline Pressure Errors (BPEs) occur in a significant number of patients undergoing continuous ICP monitoring and they may alter patient management. The current practice of measuring ICP against a baseline pressure does not comply with the concept of State of the Art. Monitoring of the ICP waves ought to become the new State of the Art as they are not influenced by BPEs. PMID- 24472297 TI - Five cases of sprue-like enteropathy in patients treated by olmesartan. AB - We describe five cases of sprue-like enteropathy during treatment with olmesartan, an angiotensin II receptor antagonist indicated for the treatment of hypertension. Patients presented severe diarrhoea, significant weight loss or dehydration, with or without intestinal villous atrophy. Clinical signs ceased upon drug discontinuation in all cases; olmesartan was reintroduced in two cases and rechallenge was positive in both. These add to the previously reported cases that led to a label change for olmesartan in the United States. However, all cases were observed in a small gastroenterology unit, which suggests that this adverse effect may not be rare. A preliminary search for the other angiotensin II receptor antagonists in the French pharmacovigilance system found severe diarrhoea and colitis, but no case with villous atrophy. Therefore, in the presence of severe diarrhoea, olmesartan or other angiotensin II receptor antagonists should be discontinued, even if the treatment has been taken for several months or years. PMID- 24472298 TI - The launch of annals of occupational and environmental medicine. PMID- 24472299 TI - Two severe cases of H7N9 pneumonia patients with immunoneuroendocrine axis dysfunction and vitamin D insufficiency. AB - BACKGROUND: The immunoneuroendocrine axis plays a major role in the regulation of the host's response to infection, but its role in severe H7N9 pneumonia is still unknown. Therefore, this study is carried out to explore the relationship between the immunoneuroendocrine axis and severe H7N9 pneumonia. CASE PRESENTANTION: The study included two H7N9 pneumonia patients. Endocrine response and cellular immune function in prolonged phase of these two severe H7N9 pneumonia cases were reported and analyzed. A 57-year-old male patient (case 1) and a 68-year-old male patient (case 2) were admitted because of cough, fever and dyspnea. Moist rales were present in both lungs. The rest of the examination was reportedly normal. The laboratory test showed that (1) The patients had loss of cortisol rhythm and elevated cortisol level at 4 pm. (2) The patients showed decline of cellular immune function. (3) The patients showed vitamin D insufficiency. (4) Case 2 had higher cortisol level but lower DHEAS, serum phosphorus and vitamin D level as well as cellular immune function than case 1. (5) The thyroid axis, gonadal and lactotropic axis were normal, so were the level of FT3, FT4, STSH and LH, FSH, T, E2 as well as PRL in these two cases. Chest CT revealed inflammation of both lungs especially in right lung. Real time RT-PCR by Centers for Disease Control and Prevention (CDC) confirmed H7N9 infection. CONCLUSION: Immunoneuroendocrine axis dysfunction may play an important role in severe H7N9 pneumonia. We need pay more attention to hypophosphatemia and vitamin D insufficiency in H7N9 pneumonia. PMID- 24472300 TI - Frequent POLE1 p.S297F mutation in Chinese patients with ovarian endometrioid carcinoma. AB - The catalytic subunit of DNA polymerase epsilon (POLE1) functions primarily in nuclear DNA replication and repair. Recently, POLE1 mutations were detected frequently in colorectal and endometrial carcinomas while with lower frequency in several other types of cancer, and the p.P286R and p.V411L mutations were the potential mutation hotspots in human cancers. Nevertheless, the mutation frequency of POLE1 in ovarian cancer still remains largely unknown. Here, we screened a total of 251 Chinese samples with distinct subtypes of ovarian carcinoma for the presence of POLE1 hotspot mutations by direct sequencing. A heterozygous somatic POLE1 mutation, p.S297F (c.890C>T), but not p.P286R and p.V411L hotspot mutations observed in other cancer types, was identified in 3 out of 37 (8.1%) patients with ovarian endometrioid carcinoma; this mutation was evolutionarily highly conserved from Homo sapiens to Schizosaccharomyces. Of note, the POLE1 mutation coexisted with mutation in the ovarian cancer-associated PPP2R1A (protein phosphatase 2, regulatory subunit A, alpha) gene in a 46-year old patient, who was also diagnosed with ectopic endometriosis in the benign ovary. In addition, a 45-year-old POLE1-mutated ovarian endometrioid carcinoma patient was also diagnosed with uterine leiomyoma while the remaining 52-year-old POLE1-mutated patient showed no additional distinctive clinical manifestation. In contrast to high frequency of POLE1 mutations in ovarian endometrioid carcinoma, no POLE1 mutations were identified in patients with other subtypes of ovarian carcinoma. Our results showed for the first time that the POLE1 p.S297F mutation, but not p.P286R and p.V411L hotspot mutations observed in other cancer types, was frequent in Chinese ovarian endometrioid carcinoma, but absent in other subtypes of ovarian carcinoma. These results implicated that POLE1 p.S297F mutation might be actively involved in the pathogenesis of ovarian endometrioid carcinoma, but might not be actively involved in other subtypes of ovarian carcinoma. PMID- 24472301 TI - Does bacterial infection cause genome instability and cancer in the host cell? AB - Research of the past several decades suggests that bacterial infection can lead to genome instability of the host cell often resulting in cancer development. However, there is still a substantial lack of knowledge regarding possible mechanisms involved in the development of genomic instability. Several questions remain unanswered, namely: Why has the causative relationship between the bacterial infection and cancer been established only for a small number of cancers? What is the mechanism responsible for the induction of genome instability and cancer? Is the infection process required to cause genome instability and cancer? In this review, we present a hypothesis that the bacterial infection, exposure to heat-killed bacteria or even some bacterial determinants may trigger genome instability of exposed and distal cells, and thus may cause cancer. We will discuss the mechanisms of host responses to the bacterial infection and present the possible pathways leading to genome instability and cancer through exposure to bacteria. PMID- 24472303 TI - The Relationship between Waist Circumference and Work-related Injury in Reference to the Fourth Korea National Health and Nutrition Examination Survey. AB - OBJECTIVE: This study aims to investigate the relationship between waist circumference and work-related injury in reference to the fourth Korea National Health and Nutrition Examination Survey. METHODS: By analyzing data from the fourth Korea National Health and Nutrition Examination Survey conducted from 2007 to 2009, we estimated the rate of injury experience according to socioeconomic status, including occupational property, of 8,261 subjects. We performed logistic regression analysis with work-related injury experience rate as dependent variable and waist circumference as an independent variable, Odds ratios (OR) were calculated, which reflect the likelihood of work-related injury experience rate, and 95% confidence interval (95% CI) while controlling for relevant covariates with stratifying by sex, age, nature of injury, site of injury and occupational group. RESULTS: Among 797 persons who had injury experience over the past 1 year, 293 persons (36.8%) had work-related injury experience. After adjusting the confounding variables, the work-related injury was related to abnormal waist circumference (OR = 1.35; 95% CI: 1.02 ~ 1.78). In subgroups, ORs were higher in men (OR = 1.42; 95% CI: 1.02 ~ 1.98), professional, manager, and administrator (OR = 2.41; 95% CI: 1.10 ~ 5.28). Higher rate of injuries were noted in back and waist (OR = 2.92; 95% CI: 1.49 ~ 5.73), and transport accident had increased risk (OR = 1.60; 95% CI: 1.13 ~ 2.28). CONCLUSIONS: Work-related injury rate differed depending on the waist circumference. The abdominal obesity was associated with higher risk of work-related injury. This study would be useful in selecting appropriate priorities for work-related injury management in Korea. PMID- 24472302 TI - Systemic treatment for inoperable pancreatic adenocarcinoma: review and update. AB - There have been many clinical trials conducted to evaluate novel systemic regimens for unresectable pancreatic cancer. However, most of the trial results were negative, and gemcitabine monotherapy has remained the standard systemic treatment for years. A number of molecular targeted agents, including those against epidermal growth factor receptor and vascular endothelial growth factor receptors, have also been tested. In recent years, there have been some breakthroughs in the deadlock: three regimens, namely gemcitabine-erlotinib, FOLFIRINOX, and gemcitabine-nab-paclitaxel, have been shown to prolong the overall survival of patients when compared with gemcitabine monotherapy. In addition, emerging data suggested that the membrane protein human equilibrative nucleotide transporter 1 is a potential biomarker with which to predict the efficacy of gemcitabine. Here we review the literature on the development of systemic agents for pancreatic cancer, discuss the current choices of treatment, and provide future directions on the development of novel agents. PMID- 24472304 TI - Lifelong endurance training attenuates age-related genotoxic stress in human skeletal muscle. AB - BACKGROUND: The aim of the present study was to determine the influence of age and habitual activity level, at rest and following a single bout of high intensity exercise, on the levels of three proteins poly(ADP-ribose) polymerase-1 (PARP-1), cleaved-PARP-1 and poly(ADP-ribose) glycohydrolase (PARG), involved in the DNA repair and cell death responses to stress and genotoxic insults. Muscle biopsies were obtained from the vastus lateralis of young trained (22 +/- 3 years, n = 6), young untrained (24 +/- 4 years, n = 6), old trained (64 +/- 3 years, n = 6) and old untrained (65 +/- 6 years, n = 6) healthy males before, immediately after and three days following a high-intensity interval exercise bout. RESULTS: PARP-1, which catalyzes poly(ADP-ribosyl)ation of proteins and DNA in response to a range of intrinsic and extrinsic stresses, was increased at baseline in old trained and old untrained compared with young trained and young untrained participants (P <= 0.05). Following exercise, PARP-1 levels remained unchanged in young trained participants, in contrast to old trained and old untrained where levels decreased and young untrained where levels increased (P <= 0.05). Interestingly, baseline levels of the cleaved PARP-1, a marker of apoptosis, and PARG, responsible for polymer degradation, were both significantly elevated in old untrained compared with old trained, young trained and young untrained (P <= 0.05). Despite this baseline difference in PARG, there was no change in any group following exercise. There was a non-significant statistical trend (P = 0.072) towards increased cleaved-PARP-1 expression post-exercise in younger but not old persons, regardless of training status. CONCLUSIONS: Collectively, these results show that exercise slows the progression towards a chronically stressed state but has no impact on the age-related attenuated response to acute exercise. Our findings provide valuable insight into how habitual exercise training could protect skeletal muscle from chronic damage to macromolecules and may reduce sarcopenia in older people. PMID- 24472305 TI - RNF14 is a regulator of mitochondrial and immune function in muscle. AB - BACKGROUND: Muscle development and remodelling, mitochondrial physiology and inflammation are thought to be inter-related and to have implications for metabolism in both health and disease. However, our understanding of their molecular control is incomplete. RESULTS: In this study we have confirmed that the ring finger 14 protein (RNF14), a poorly understood transcriptional regulator, influences the expression of both mitochondrial and immune-related genes. The prediction was based on a combination of network connectivity and differential connectivity in cattle (a non-model organism) and mice data sets, with a focus on skeletal muscle. They assigned similar probability to mammalian RNF14 playing a regulatory role in mitochondrial and immune gene expression. To try and resolve this apparent ambiguity we performed a genome-wide microarray expression analysis on mouse C2C12 myoblasts transiently transfected with two Rnf14 transcript variants that encode 2 naturally occurring but different RNF14 protein isoforms. The effect of both constructs was significantly different to the control samples (untransfected cells and cells transfected with an empty vector). Cluster analyses revealed that transfection with the two Rnf14 constructs yielded discrete expression signatures from each other, but in both cases a substantial set of genes annotated as encoding proteins related to immune function were perturbed. These included cytokines and interferon regulatory factors. Additionally, transfection of the longer transcript variant 1 coordinately increased the expression of 12 (of the total 13) mitochondrial proteins encoded by the mitochondrial genome, 3 of which were significant in isolated pair-wise comparisons (Mt-coxII, Mt-nd2 and mt-nd4l). This apparent additional mitochondrial function may be attributable to the RWD protein domain that is present only in the longer RNF14 isoform. CONCLUSIONS: RNF14 influences the expression of both mitochondrial and immune related genes in a skeletal muscle context, and has likely implications for the inter-relationship between bioenergetic status and inflammation. PMID- 24472307 TI - Epidemiology of the 2010 Outbreak of Foot-and-Mouth Disease in Mongolia. AB - Foot-and-mouth disease (FMD) occurred in five provinces and 24 counties as part of the FMD incursion into Mongolia during 2010. The first detection occurred on 21 April 2010 (confirmed 26 April 2010) with the last detection occurring approximately 8 months later on 13 December 2010. The number of livestock detected in the spring phase of the outbreak was 323 cattle and in the summer phase was 13 485 sheep, 6748 cattle, 5692 goats and 10 camels (total livestock summer phase = 25 935; for spring and summer phases combined = 26 258). Infection of livestock was confirmed by PCR for each affected county but not necessarily for every outbreak cluster involving more than one herder. It is likely that the summer phase of the outbreak was a continuation of the spring event. In the summer phase, the spatio-temporal pattern of spread suggested an extension of infection from the main cluster in the Sukhbaatar county. There was also a number of long-distance clusters established. The relative importance of spread by three potential pathways of gazelle, livestock, animal product and fomite movements has not been determined and will require further study. The estimated dissemination ratio (EDR) did not provide evidence of high rate of transmission of infection between herders; however, the data are limited by the quality of surveillance and the method of calculation which used the date of detection rather than the date of infection. PMID- 24472306 TI - New evidence in trauma resuscitation - is 1:1:1 the answer? AB - Traumatic injury is a common problem, with over five million worldwide deaths from trauma per year. An estimated 10 to 20% of these deaths are potentially preventable with better control of bleeding. Damage control resuscitation involves early delivery of plasma and platelets as a primary resuscitation approach to minimize trauma-induced coagulopathy. Plasma, red blood cell and platelet ratios of 1:1:1 appear to be the best substitution for fresh whole blood; however, the current literature consists only of survivor bias-prone observational studies. PMID- 24472308 TI - The Relationship between Injury and Socioeconomic Status in Reference to the Fourth Korean National Health and Nutrition Examination Survey. AB - OBJECTIVES: This study aims to investigate the relationship between the total injury experience rate and socioeconomic status based on the fourth Korea National Health and Nutrition Examination Survey (KNHANES). METHODS: By analyzing data from the fourth KNHANES conducted from 2007 to 2009, we estimated the injury experience rate according to socioeconomic status, including the occupational characteristics of 11,837 subjects. Setting the injury experience rate as a dependent variable and socioeconomic status as an independent variable, we performed logistic regression to calculate odds ratios reflecting the likelihood of injury according to socioeconomic status while controlling for relevant covariates. RESULTS: In 797 subjects who had injury experience over the past 1 year, 290 persons (36.4%) had a work-related injury. As their income, home value, and educational status increased, their injury experiences decreased. Among occupational groups, the craft, equipment, machine operating, and assembling workers showed the highest rate (10.6%) of injury experience, and the lowest rate (5.7%) was found in the unemployed group. After adjusting for the confounding variables, the experience of injury was significantly related to several socioeconomic factors: high income (OR = 0.54; 95% CI: 0.34-0.86), high home value (OR = 0.65; 95% CI: 0.43-0.96), low education status (OR = 1.28; 95% CI: 1.07-1.52), and specific occupations such as craft, equipment, machine operating, and assembling work (OR = 1.99; 95% CI: 1.60-2.47), skilled agriculture, forestry and fishery work (OR = 1.43; 95% CI: 1.02-2.01), and simple labor (OR = 1.38; 95% CI: 1.04-1.82). CONCLUSIONS: The injury experience rate differed depending on the socioeconomic status. A negative correlation was found between the injury experience rate and income, low home value, and education level. Moreover, a higher rate of injury experience was found in occupation groups and physical worker groups in comparison to the unemployed group and white-collar worker groups. This study would be useful in selecting appropriate priorities for injury management in Korea. PMID- 24472309 TI - [Teleradiology in a family practice on the Dutch island of Ameland: a cost benefit analysis]. AB - OBJECTIVE: To calculate the costs and benefits of the introduction of teleradiology at a general practice on the Dutch island of Ameland from the perspectives of three different entities: (a) the family doctor (investor); (b) patients; and (c) health insurance companies. DESIGN: Descriptive, cost-benefit analysis. METHOD: For the year 2009, one and a half years after the introduction of a teleradiology facility at a general practice in Ameland, the operational and financing costs, the patient's saved travel time and expenses and the teleradiology costs for health insurance companies were compared with the costs that would have been made without teleradiology. RESULTS: In 2009, 426 X-rays had been taken at the general practice of which 241 for trauma and 185 for non traumatic cases. With a reimbursement of ? 100 per X-ray taken during normal working hours and ? 200 for those taken during evenings and weekends, benefits for the family doctor (investor) were ? 46,698 and the costs amounted to ? 45,710, or a positive balance of ? 980. Patients' savings in travel time and expenses were calculated at ? 111,068. Health insurance companies reimbursed a minimum of ? 89,265 less on diagnosis and treatment. CONCLUSION: The introduction of teleradiology a general practice in Ameland resulted in a considerable cost reduction for patients as well as for health insurance companies. In the future, diagnosing in this manner could be expanded in particular to regions in which the distances to hospitals are greater: a part of secondary healthcare could be conducted at a reduced cost. PMID- 24472310 TI - [Arthroscopic meniscectomy: does it make sense in patients older than 45?]. AB - Meniscus surgery is the most commonly performed surgical procedure in orthopaedics. Almost two-thirds of the patients are over 45 years old. It is not known, however, whether a torn meniscus in older patients is the primary cause of knee pain, or whether the pain is caused by an ongoing degenerative process. Until 2013, there were hardly any studies comparing the efficacy of meniscus surgery with that of a non-surgical approach in this group of patients. This has recently changed with the publication of two randomized controlled studies comparing arthroscopic meniscectomy with conservative therapy. The studies showed that meniscectomy had no added value to physical therapy. This commentary briefly discusses these studies and discloses the lack of current knowledge on the aspect of cost-effectiveness of these treatments. PMID- 24472311 TI - Birth and adoptive parent anxiety symptoms moderate the link between infant attention control and internalizing problems in toddlerhood. AB - Attention control plays an important role in the development of internalizing symptoms in children. We explored the degree to which infants' genetic and environmentally based risk moderated the link between attention control and internalizing problems during toddlerhood. These associations were examined within a prospective adoption design, enabling the disentanglement of genetic and environmental risk for internalizing problems. Attention control in adopted infants was observed during periods of distress at age 9 months. Birth parents' anxiety symptoms were used as an index of genetic risk, while adoptive parents' anxiety symptoms were used as an index of environmental risk. Adoptive mothers and fathers reported on children's internalizing problems when children were 18 and 27 months old. Greater attention control in infancy appeared to mitigate genetically based risk for internalizing problems during toddlerhood when children were raised by adoptive parents who were low in anxiety. Findings suggest that for genetically susceptible children who are raised in low-risk environments, attention control may provide a protective factor against developing internalizing problems across early life. PMID- 24472313 TI - The potential impact of expanding target age groups for polio immunization campaigns. AB - BACKGROUND: Global efforts to eradicate wild polioviruses (WPVs) continue to face challenges due to uninterrupted endemic WPV transmission in three countries and importation-related outbreaks into previously polio-free countries. We explore the potential role of including older children and adults in supplemental immunization activities (SIAs) to more rapidly increase population immunity and prevent or stop transmission. METHODS: We use a differential equation-based dynamic poliovirus transmission model to analyze the epidemiological impact and vaccine resource implications of expanding target age groups in SIAs. We explore the use of older age groups in SIAs for three situations: alternative responses to the 2010 outbreak in Tajikistan, retrospective examination of elimination in two high-risk states in northern India, and prospective and retrospective strategies to accelerate elimination in endemic northwestern Nigeria. Our model recognizes the ability of individuals with waned mucosal immunity (i.e., immunity from a historical live poliovirus infection) to become re-infected and contribute to transmission to a limited extent. RESULTS: SIAs involving expanded age groups reduce overall caseloads, decrease transmission, and generally lead to a small reduction in the time to achieve WPV elimination. Analysis of preventive expanded age group SIAs in Tajikistan or prior to type-specific surges in incidence in high-risk areas of India and Nigeria showed the greatest potential benefits of expanded age groups. Analysis of expanded age group SIAs in outbreak situations or to accelerate the interruption of endemic transmission showed relatively less benefit, largely due to the circulation of WPV reaching individuals sooner or more effectively than the SIAs. The India and Nigeria results depend strongly on how well SIAs involving expanded age groups reach relatively isolated subpopulations that sustain clusters of susceptible children, which we assume play a key role in persistent endemic WPV transmission in these areas. CONCLUSIONS: This study suggests the need to carefully consider the epidemiological situation in the context of decisions to use expanded age group SIAs. Subpopulations of susceptible individuals may independently sustain transmission, which will reduce the overall benefits associated with using expanded age group SIAs to increase population immunity to a sufficiently high level to stop transmission and reduce the incidence of paralytic cases. PMID- 24472314 TI - A novel coronary active perfusion system using a conventional intra-aortic balloon pump for off-pump coronary artery bypass grafting. AB - OBJECTIVE: It is important for coronary active perfusion systems to avoid myocardial ischemia during off-pump coronary artery bypass grafting. We have developed a new concept for a perfusion system to pump blood based on changes in helium gas volume. This system uses a conventional intra-aortic balloon pump to activate the perfusion pump. Our study used basic and animal experiments to investigate the most suitable system for coronary perfusion using this new concept. METHODS: A conventional intra-aortic balloon pump was used to supply power. A device for perfusion was developed with a balloon placed inside a stiff syringe barrel. The device was connected to the helium gas line of the intra aortic balloon pump. Changes in flow with changes in augmentation level were noted when volumes outside and within the balloon were changed. Six pigs with occlusion of the left anterior descending artery were used for system validation, with monitoring to identify changes in hemodynamics and cardiac enzyme levels. RESULTS: In the basic experiment, an 80-mL outside volume and 3.0-mL inner volume resulted in the greatest percentage change in flow rate with respect to changes in augmentation. In the animal experiment, the new coronary active perfusion system prevented myocardial ischemia during coronary occlusion. CONCLUSIONS: We clarified the most suitable method for our new coronary active perfusion system. Using this system, safe anastomosis was consistently performed in animal experiments. Clinically, off-pump coronary artery bypass may potentially be performed more safely and easily using this new system. PMID- 24472312 TI - Ponatinib efficiently kills imatinib-resistant chronic eosinophilic leukemia cells harboring gatekeeper mutant T674I FIP1L1-PDGFRalpha: roles of Mcl-1 and beta-catenin. AB - BACKGROUND: T674I FIP1L1-PDGFRalpha in a subset of chronic eosinophilic leukemia (CEL) is a gatekeeper mutation that is resistant to many tyrosine kinase inhibitors (TKIs) (e.g., imatinib, nilotinib and dasatinib), similar to T315I Bcr Abl. Therefore, novel TKIs effective against T674I FIP1L1-PDGFRalpha are needed. Ponatinib (AP24534) is a novel orally bioavailable TKI against T315I Bcr-Abl, but it is not clear whether ponatinib is effective against T674I FIP1L1-PDGFRalpha. The purpose of this study was to examine the effect of ponatinib on T674I FIP1L1 PDGFRalpha. METHODS: Molecular docking analysis in silico was performed. The effects of ponatinib on PDGFRalpha signaling pathways, apoptosis and cell cycling were examined in EOL-1, BaF3 cells expressing either wild type (WT) or T674I FIP1L1-PDGFRalpha. The in vivo antitumor activity of ponatinib was evaluated with xenografted BaF3-T674I FIP1L1-PDGFRalpha cells in nude mice models. RESULTS: Molecular docking analysis revealed that ponatinib could bind to the DFG (Asp-Phe Gly)-out state of T674I PDGFRalpha. Ponatinib potently inhibited the phosphorylation of WT and T674I FIP1L1-PDGFRalpha and their downstream signaling molecules (e.g., Stat3, Stat5). Ponatinib strikingly inhibited the growth of both WT and T674I FIP1L1-PDGFRalpha-carrying CEL cells (IC50: 0.004-2.5 nM). It induced apoptosis in CEL cells with caspase-3-dependent cleavage of Mcl-1, and inhibited tyrosine phosphorylation of beta-catenin to decrease its stability and pro-survival functions. In vivo, ponatinib abrogated the growth of xenografted BaF3-T674I FIP1L1-PDGFRalpha cells in nude mice. CONCLUSIONS: Ponatinib is a pan FIP1L1-PDGFRalpha inhibitor, and clinical trials are warranted to investigate its efficacy in imatinib-resistant CEL. PMID- 24472315 TI - Is routine rapid-staged bilateral pulmonary artery banding before stage 1 Norwood a viable strategy? AB - OBJECTIVE: We adopted a policy of rapid-staged bilateral pulmonary artery banding (bPAB) before the Norwood (NW) procedure for all patients with hypoplastic left heart syndrome. We hypothesized that this strategy might mitigate some of the traditional risk factors and that postponing a major bypass procedure beyond the newborn period could have both short- and long-term benefits. The purpose of the present study was to evaluate the efficacy of this strategy with respect to the short-term outcomes. METHODS: From 2008 to 2010, 14 patients underwent bPAB and maintenance of ductal patency with prostaglandin E1 infusion before stage 1 NW. For reference, we also reviewed the data from patients who had undergone the primary NW procedure in the 2 years immediately before the study period. RESULTS: The bPAB was performed at a median age of 6 days (range, 2-39), gestational age of 38.5 weeks (range, 36-41), and weight of 2.75 kg (range, 2.3-3.6). The subsequent NW was performed at a gestational age of 43.5 weeks (range, 41-51) and weight of 3.2 kg (range, 2.2-4.9). When the NW procedure was eventually performed on the pBAB group, the maximum blood lactate levels within the first 24 hours after the NW were lower than those in the earlier primary NW group (2.8+/-0.9 vs 10.1+/-6.5 mmol/dL, P=.0002) and the urine output in the first 24 hours after the NW was greater in the pPAB group (4.1+/-2.1 vs 2.2+/-1.5 mL/kg/h; P=.0051). CONCLUSIONS: These data suggest that rapid-staged bPAB before NW can reduce the challenge of postoperative management in the early postoperative period after the NW procedure and have potential to improve the outcomes. PMID- 24472316 TI - Temporary extracorporeal left ventricular assist device support for implantable left ventricular assist device replacement cases. PMID- 24472318 TI - Transcription factor C/EBP-beta mediates downregulation of dipeptidyl-peptidase III expression by interleukin-6 in human glioblastoma cells. AB - Dipeptidyl-peptidase III (DPP III) is a cytosolic metallo-aminopeptidase implicated in various physiological and pathological processes. A previous study from our laboratory indicated an elevated expression of DPP III in glioblastoma (U87MG) cells. In the present study we investigated the role of interleukin-6 (IL 6), a pleiotropic cytokine produced by glial tumors, in the regulation of DPP III expression. Immunohistochemistry, western blotting and quantitative RT-PCR were used for quantitation of DPP III and IL-6 in human glioblastoma cells and tumors. Cell transfections and DPP III promoter reporter assays were performed to study the transcriptional regulation of DPP III by IL-6. Promoter deletion analysis, site directed mutagenesis, chromatin immunoprecipitation assays and small interfering RNA (siRNA) technology was employed to elucidate the molecular mechanism of IL-6 mediated regulation of DPP III expression in glioblastoma cells. Our results for the first time demonstrate a negative correlation (r = 0.632, P = 0.01) between DPP III and IL-6 in both human tumors and cultured glioblastoma cells. Treatment of U87MG cells with IL-6 significantly decreased DPP III expression with a concomitant increase in the levels of transcription factor CCAAT/enhancer binding protein beta (C/EBP-beta). Deletion/mutagenesis of C/EBP-beta binding motif of DPP III promoter significantly increased its activity and abolished its responsiveness to IL-6. This effect could also be mimicked by C/EBP-beta siRNA. In conclusion our study for the first time demonstrates C/EBP beta mediated transcriptional downregulation of DPP III by IL-6. Our results demonstrating a negative correlation between IL-6 and DPP III taken together with the previously reported prognostic significance of this cytokine in glioblastoma suggests that DPP III may prove useful as a prognostic marker. PMID- 24472317 TI - Dopamine decreases NMDA currents in the oval bed nucleus of the stria terminalis of cocaine self-administering rats. AB - Dopamine (DA) and N-methyl-D-aspartate receptors (NMDARs) contribute in the neural processes underlying drug-driven behaviors. DA is a potent modulator of NMDAR, but few studies have investigated the functional interaction between DA and NMDAR in the context of substance abuse. We combined the rat model of cocaine self-administration with brain slice electrophysiology to study DA modulation of NMDA currents in the oval bed nucleus of the stria terminalis (ovBNST), a dense DA terminal field involved in maintenance of cocaine self-administration amongst other drug related behaviors. Long-Evans rats self-administered intravenous cocaine (0.75 mg/kg/injection) on a progressive ratio (PR) schedule of reinforcement for 15 days and whole-cell patch-clamp recordings were done on the 16th day. DA reduced NMDA currents in brain-slices from cocaine self administering rats, but not in those of drug-naive and sucrose self administering, or when cocaine exposure was passive (yoked), revealing a mechanism unique to voluntary cocaine intake. DA reduced NMDA currents by activating G-protein-coupled D1- and D2-like receptors that converged on phospholipase C and protein phosphatases. Accordingly, our study reveals a mechanism that may contribute to dysfunctional synaptic plasticity associated with drug-driven behaviors during acute withdrawal. PMID- 24472319 TI - Systematic Review of the Effects of Asbestos Exposure on the Risk of Cancer between Children and Adults. AB - Children are considerably more susceptible to enviro006Emental hazards than adults. This study was conducted to investigate whether the first asbestos exposure in childhood increases the risk of asbestos-related cancer including mesothelioma and lung cancer. MEDLINE (PubMed), Embase, and Google Scholar were searched to find relevant studies published up to July 2012. Six studies reported the relationship between age, including age during childhood, at the first asbestos exposure and mesothelioma. Among them, 4 indicated that people exposed to asbestos in childhood have a higher risk of mesothelioma than those exposed in adulthood. Meanwhile, the other 2 studies showed that asbestos exposure later in life increases the risk of mesothelioma. The results of the 2 studies including non-occupational early childhood exposure report conflicting results. There were 3 studies regarding the relationship between age at first asbestos exposure and lung cancer. However, none of them reported an association between age at first asbestos exposure and the risk of lung cancer. All studies have limitations including small numbers of subjects, the validity of the standardized mortality ratio, and different age categories at first asbestos exposure. There are only a few studies on the harmful effects of asbestos in children in the literature. Therefore, the effect of asbestos exposure during childhood remains unclear and requires further study. PMID- 24472320 TI - Financial burden of medical care: a family perspective. AB - KEY FINDINGS: Data from the National Health Interview Survey, 2012. In 2012, more than one in four families experienced financial burdens of medical care. Families with incomes at or below 250% of the federal poverty level (FPL) were more likely to experience financial burdens of medical care than families with incomes above 250% of the FPL. Families with children aged 0-17 years were more likely than families without children to experience financial burdens of medical care. The presence of a family member who was uninsured increased the likelihood that a family would experience a financial burden of medical care. Recently published data from the National Health Interview Survey (NHIS) found that 1 in 5 persons was in a family having problems paying medical bills, and 1 in 10 persons was in a family with medical bills that they were unable to pay at all (1-3). NHIS defines "family" as an individual or a group of two or more related persons living together in the same housing unit. The family perspective is important to consider when examining financial risk because significant expenses for one family member may adversely affect the whole family. Health insurance coverage is one way for a family to mitigate financial risk associated with health care costs, although health insurance status may differ among family members. This report explores selected family demographic characteristics and their association with financial burdens of medical care (problems paying medical bills, paying medical bills over time, and having medical bills that cannot be paid) based on data from the 2012 NHIS. PMID- 24472321 TI - Effects of a breakfast spread out over time on the food intake at lunch and the hormonal responses in obese men. AB - The effects of frequent eating on health and particularly on appetite and metabolism are unclear. We have previously shown that frequent eating decreased appetite and energy intake at the subsequent meal in lean men. In the present study, we tested the same pattern in obese subjects. Seventeen obese men participated in: (i) two sessions consisting of a breakfast consumed in one eating episode at T0 (F1), or in four isocaloric eating episodes at T0, T60, T120, and T180min (F4), followed by an ad libitum buffet (T240) in an experimental restaurant. Subjects rated their appetite throughout the sessions. (ii) two sessions consisting of the same breakfasts F1 and F4 in a Clinical Centre, followed by a standardized meal. Blood sampling was performed to study ghrelin, glucagon-like peptide-1 (GLP-1), and metabolic kinetics. Indirect calorimetry measurements were performed. After F4, at T240min, ghrelin concentration (P=0.03) and hunger ratings (P<0.001) were lower while GLP-1 concentration (P=0.006) and satiety ratings (P=0.02) were higher. In F4, subjects consumed at the buffet, less food in grams (P=0.04) and less energy from low energy dense foods (P=0.01), but total energy intakes were not different between conditions. In F4, the area under the curve was lower for insulin (P=0.02) and non-esterified fatty acids (NEFA) (P=0.03). Diet induced thermogenesis was reduced in F4 (P=0.03) between T0 and T240. Even if subjective and physiological data suggest a beneficial effect of frequent eating on appetite in obese men, no effect was demonstrated on energy intake. Moreover, the decrease in diet induced thermogenesis and lipolysis, reflected by NEFA profiles, could be deleterious on energy balance in the long run. PMID- 24472322 TI - Socioecological correlates of energy balance using urinary C-peptide measurements in wild female mountain gorillas. AB - Maintaining a balanced energy budget is important for survival and reproduction, but measuring energy balance in wild animals has been fraught with difficulties. Female mountain gorillas are interesting subjects to examine environmental correlates of energy balance because their diet is primarily herbaceous vegetation, their food supply shows little seasonal variation and is abundant, yet they live in cooler, high-altitude habitats that may bring about energetic challenges. Social and reproductive parameters may also influence energy balance. Urinary C-peptide (UCP) has emerged as a valuable non-invasive biomarker of energy balance in primates. Here we use this method to investigate factors influencing energy balance in mountain gorillas of the Virunga Volcanoes, Rwanda. We examined a range of socioecological variables on energy balance in adult females in three groups monitored by the Karisoke Research Center over nine months. Three variables had significant effects on UCP levels: habitat (highest levels in the bamboo zone), season (highest levels in November during peak of the bamboo shoot availability) and day time (gradually increasing from early morning to early afternoon). There was no significant effect of reproductive state and dominance rank. Our study indicates that even in species that inhabit an area with a seemingly steady food supply, ecological variability can have pronounced effects on female energy balance. PMID- 24472323 TI - Repetitive behaviour in kennelled domestic dog: stereotypical or not? AB - Repetitive behaviour is common in kennelled dogs, yet its motivational basis remains relatively unexplored. We examine the repetitive behaviour of 30 kennelled working dogs in ten contexts both coinciding with, and in the absence of, commonly occurring arousing stimuli, such as care staff, other dogs and food preparation. A large proportion (93%) of subjects performed some repetitive behaviour, most commonly bouncing, but only 17% in the absence of the arousing stimuli. Subjects could be divided into four groups according to the stimuli eliciting, and the duration, of their repetitive behaviour, and these groups were compared on the basis of their cortisol response to an acute psychogenic stressor -a veterinary examination. Urinary cortisol/creatinine response curves differed significantly between the groups. In particular, those dogs which performed repetitive behaviour at times of minimal stimulation, showed a distinctly different pattern of response, with cortisol levels decreasing, as compared to increasing, after the veterinary examination. We conclude that dogs showing repetitive behaviours at times of high arousal are motivationally distinct from those "stereotyping" in the absence of stimulation. We suggest that those dogs showing spontaneous repetitive behaviours may have past experiences and/or temperaments that affect both their reactions to a veterinary examination and to long-term kennelling. For example, some dogs may find isolation from humans particularly aversive, hence affecting their reactions both to being left in a kennel and to being taken to the veterinary surgeon. Alternatively, such dogs may have atypical responsiveness of their hypothalamic-pituitary-adrenal (HPA) axis, possibly brought about through chronic stress. High levels of repetitive behaviours in response to inaccessible husbandry events may be explained if such behaviour has inadvertently been reinforced by attention from staff, and therefore may not always be indicative of aversion to kennelling or compromised welfare. PMID- 24472324 TI - Male Roman high and low avoidance rats show different patterns of copulatory behaviour: comparison with Sprague Dawley rats. AB - Roman high- (RHA) and low-avoidance (RLA) rats, selectively bred for, respectively, rapid vs. extremely poor acquisition of avoidant behaviour in the shuttle-box, display different coping strategies when exposed to aversive environmental conditions: RLA rats are reactive copers and show hyperemotional behaviour characterized by hypomotility and freezing, while RHA rats show a proactive coping behaviour aimed at gaining control over the stressor. RHA rats also display a robust sensation/novelty seeking profile, high baseline levels of impulsivity, and marked preference for, and intake of, natural and drug rewards. This study shows that the Roman lines also differ in sexual behaviour, a main source of natural reward. Thus, male RHA rats engaged in copulatory activity with a receptive female showing more mounts, intromissions and ejaculations in the first copulation test as compared with their RLA counterparts and Sprague Dawley rats used as an external reference strain. Such differences decreased only partially in subsequent copulation tests, with RHA rats always showing higher levels of sexual motivation and performance than RLA rats. Accordingly, analysis of copulatory parameters of five copulation tests performed at 3-day intervals confirmed that the Roman lines display different patterns of copulatory activity that persist after stabilization of copulatory behaviour by sexual experience. Finally, the weight of the testes, epididymides and seminal vesicles increased to a similar extent in both Roman lines after sexual activity. These results are discussed in terms of the relative contribution of differences in brain neurotransmission (mainly dopamine) and neuroendocrine function to the different patterns of copulatory behaviour of the Roman lines. PMID- 24472325 TI - Effects of social defeat on sleep and behaviour: importance of the confrontational behaviour. AB - We studied the short- and long-term effects of a double social defeat (SD) on sleep parameters, EEG power, behaviour in the open field emergence test, corticosterone responsiveness, and acoustic startle responses. Pre-stress levels of corticosterone were assessed before all rats were surgically implanted with telemetric transmitters for sleep recording, and allowed 3weeks of recovery. Rats in the SD group (n=10) were exposed to 1hour SD on two consecutive days, while control rats (n=10) were left undisturbed. Telemetric sleep recordings were performed before SD (day -1), day 1 post SD, and once weekly for 3weeks thereafter. The open field emergence test was performed on day 9 and weekly for 2weeks thereafter. Blood samples for measures of corticosterone responsiveness were drawn after the last emergence test (day 23). Acoustic startle responses were tested on day 24 post SD. Overall, SD rats as a group were not affected by the social conflict. Effects of SD seemed, however, to vary according to the behaviours that the intruder displayed during the social confrontation with the resident. Compared to those SD rats showing quick submission (SDS, n=5), SD rats fighting the resident during one or both SD confrontations before defeat (SDF, n=5) showed more fragmented slow wave sleep, both in SWS1 and SWS2. They also showed longer latency to leave the start box and spent less time in the open field arena compared to SDS rats. In the startle test, SDF rats failed to show response decrement at the lowest sound level. Our results indicate that how animals behave during a social confrontation is more important than exposure to the SD procedure itself, and that rapid submission during a social confrontation might be more adaptive than fighting back. PMID- 24472326 TI - Correction: Lifespan extension and delay of age-related functional decline caused by Rhodiola rosea depends on dietary macronutrient balance. PMID- 24472327 TI - What evidence is there for intraoperative predictors of perioperative cardiac outcomes? A systematic review. AB - BACKGROUND: Patients undergo cardiac preoperative evaluation to identify those at risk of adverse perioperative cardiac events. The Revised Cardiac Risk index is commonly used for this task, although it is unable to accurately risk stratify in all patients. This may be partly a result of intraoperative events which significantly modify preoperative risk. METHODS: We conducted a systematic review to identify independent intraoperative predictors of adverse cardiac events in patients undergoing non-cardiac surgery. Four databases (Ovid Healthstar 1966 to Jan 2012, Ovid Medline 1946 to 6 March 2012, EMBASE 1974 to March 05 2012 and The Cochrane Library to March 06 2012) were searched. RESULTS: Fourteen eligible studies were identified. The need for intraoperative blood transfusion (odds ratio (OR), 2.3; 95% confidence interval (CI), 1.4-3.3), vascular surgery (OR, 2.3; 95% CI, 1.2-3.4) and emergent/urgent surgery (OR, 2.3; 95% CI, 1.1-3.5) were the only independent intraoperative risk predictors identified in more than study. Other independent intraoperative factors identified included a >20 mmHg fall in mean arterial blood pressure for > 60 min (OR, 3.0; 95% CI, 1.8-4.9), >30% increase in baseline systolic pressure (OR, 8.0; 95% CI, 1.3-50), tachycardia in the recovery room (>30 beats per min (bpm) from baseline for >5 min) (OR, 7; 95% CI, 1.9-26), new onset atrial fibrillation (OR, 6.6; 95% CI, 2.5 20), hypothermia (OR, 2.2; 95% CI, 1.1-5) and remote ischemic preconditioning (OR, 0.22; 95% CI, 0.07-0.67). Other markers of surgical complexity were not independently associated with postoperative adverse cardiac outcomes. None of these studies controlled for blood transfusion. CONCLUSIONS: Intraoperative events significantly increase the risk for postoperative cardiac complications, although only intraoperative blood transfusion has strong evidence supporting this finding. It is possible that modification of these intraoperative risk factors by anesthetists and surgeons may reduce postoperative cardiac events and improve outcome. The Vascular Events in Noncardiac Surgery Patients Cohort Evaluation (VISION) Study will add important information to understanding intraoperative risk factors for adverse cardiac events. PMID- 24472328 TI - Early benefit assessment of new drugs in Germany - results from 2011 to 2012. AB - Rising drug costs in Germany led to the Act on the Reform of the Market for Medicinal Products (AMNOG) in January 2011. For new drugs, pharmaceutical companies have to submit dossiers containing all available evidence to demonstrate an added benefit versus an appropriate comparator therapy. The Federal Joint Committee (G-BA), the main decision-making body of the statutory healthcare system, is responsible for the overall procedure of "early benefit assessment". The Institute for Quality and Efficiency in Health Care (IQWiG) largely conducts the dossier assessments, which inform decisions by the G-BA on added benefit and support price negotiations. Of the 25 dossiers (excluding orphan drugs) assessed until 31 December 2012, 14 contained sufficient data from randomized active-controlled trials investigating patient-relevant outcomes or at least acceptable surrogates; 11 contained insufficient data. The most common indications were oncology (6) and viral infections (4). For the 14 drugs assessed, the extent of added benefit was rated as minor, considerable, and non quantifiable in 3, 8, and 2 cases; the remaining drug showed no added benefit. Despite some shortcomings, for the first time it has been possible in Germany to implement a systematic procedure for assessing new drugs at market entry, thus providing support for price negotiations and informed decision-making for patients, clinicians and policy makers. PMID- 24472329 TI - Implications of long-term care capacity response policies for an aging population: a simulation analysis. AB - INTRODUCTION: The demand for long-term care (LTC) services is likely to increase as a population ages. Keeping pace with rising demand for LTC poses a key challenge for health systems and policymakers, who may be slow to scale up capacity. Given that Singapore is likely to face increasing demand for both acute and LTC services, this paper examines the dynamic impact of different LTC capacity response policies, which differ in the amount of time over which LTC capacity is increased, on acute care utilization and the demand for LTC and acute care professionals. METHODS: The modeling methodology of System Dynamics (SD) was applied to create a simplified, aggregate, computer simulation model for policy exploration. This model stimulates the interaction between persons with LTC needs (i.e., elderly individuals aged 65 years and older who have functional limitations that require human assistance) and the capacity of the healthcare system (i.e., acute and LTC services, including community-based and institutional care) to provide care. Because the model is intended for policy exploration, stylized numbers were used as model inputs. To discern policy effects, the model was initialized in a steady state. The steady state was disturbed by doubling the number of people needing LTC over the 30-year simulation time. Under this demand change scenario, the effects of various LTC capacity response policies were studied and sensitivity analyses were performed. RESULTS: Compared to proactive and quick adjustment LTC capacity response policies, slower adjustment LTC capacity response policies (i.e., those for which the time to change LTC capacity is longer) tend to shift care demands to the acute care sector and increase total care needs. CONCLUSIONS: Greater attention to demand in the acute care sector relative to demand for LTC may result in over-building acute care facilities and filling them with individuals whose needs are better suited for LTC. Policymakers must be equally proactive in expanding LTC capacity, lest unsustainable acute care utilization and significant deficits in the number of healthcare professionals arise. Delaying LTC expansion could, for example, lead to increased healthcare expenditure and longer wait lists for LTC and acute care patients. PMID- 24472330 TI - Conversion of biomass-derived oligosaccharides into lipids. AB - BACKGROUND: Oligocelluloses and oligoxyloses are partially hydrolyzed products from lignocellulosic biomass hydrolysis. Biomass hydrolysates usually contain monosaccharides as well as various amounts of oligosaccharides. To utilize biomass hydrolysates more efficiently, it is important to identify microorganisms capable of converting biomass-derived oligosaccharides into biofuels or biochemicals. RESULTS: We have demonstrated that the oleaginous yeast Cryptococcus curvatus can utilize either oligocelluloses or oligoxyloses as sole carbon sources for microbial lipid production. When oligocelluloses were used, lipid content and lipid coefficient were 35.9% and 0.20 g/g consumed sugar, respectively. When oligoxyloses were used, lipid coefficient was 0.17 g/g consumed sugar. Ion chromatography analysis showed oligocelluloses with a degree of polymerization from 2 to 9 were assimilated. Our data suggested that these oligosaccharides were transported into cells and then hydrolyzed by cytoplasmic enzymes. Further analysis indicated that these enzymes were inducible by oligocelluloses. Lipid production on cellulose by C. curvatus using the simultaneous saccharification and lipid production process in the absence of cellobiase achieved essentially identical results to that in the presence of cellobiase, suggesting that oligocelluloses generated in situ were utilized with high efficiency. This study has provided inspiring information for oligosaccharides utilization, which should facilitate biorefinery based on lignocellulosic biomass. CONCLUSIONS: C. curvatus can directly utilize biomass derived oligosaccharides. Oligocelluloses are transported into the cells and then hydrolyzed by cytoplasmic enzymes. A simultaneous saccharification and lipid production process can be conducted without oligocelluloses accumulation in the absence of cellobiase by C. curvatus, which could reduce the enzyme costs. PMID- 24472331 TI - [Pre-anesthetic medication with intranasal dexmedetomidine and oral midazolam as an anxiolytic. A clinical trial]. AB - INTRODUCTION: Dexmedetomidine is a pharmacological option for sedation in children. In this study, the efficacy of intranasal dexmedetomidine to reduce preoperative anxiety in pediatric patients is compared with that of oral midazolam. MATERIAL AND METHODS: A prospective, randomized, double-blind, controlled trial was conducted on children 2-12 years of age, randomly assigned to one of the following two groups: group A received premedication with oral midazolam and intranasal placebo, group B received intranasal dexmedetomidine and oral placebo. Anxiety was assessed with the modified Yale scale, and a risk analysis and number needed to treat was performed. RESULTS: A total of 108 patients were included, 52 (48.1%) treated with dexmedetomidine, and 56 (51.9%) with midazolam. Anxiety was less frequent in the dexmedetomidine group at 60minutes (P=.001), induction (p=.04), and recovery (P=.0001). Risk analysis showed that dexmedetomidine reduced the risk of anxiety by 28% (RAR=0.28, 95% CI; 0.12 to 0.43) and to prevent one case of anxiety, four patients need to be treated with intranasal dexmedetomidine (NNT=4, 95% CI: 3-9).Changes in heart rate, mean arterial pressure, and oxygen saturation, were statistically significant in the dexmedetomidine group, with no clinical consequences. There were no cases of bradycardia, hypotension or oxygen desaturation. CONCLUSIONS: Intranasal dexmedetomidine premedication is more effective than oral midazolam to reduce preoperative anxiety in pediatric patients. PMID- 24472332 TI - Bronchial isomerism in a Kabuki syndrome patient with a novel mutation in MLL2 gene. AB - BACKGROUND: Kabuki syndrome (KS) is a rare, multiple congenital anomalies/intellectual disability syndrome caused by mutations of MLL2 gene, which codifies for a histone methyltrasferase that regulates the embryogenesis and the tissue development. Left-bronchial isomerism is a rare congenital abnormality that can be defined as the absence of the normal lateralizing features which distinguish right and left-sides in the lungs. To date, this is the first report of left-bronchial isomerism in association with KS. CASE PRESENTATION: A one-month-old Caucasian male patient underwent our attention for microcephaly, dysmorphic features (long palpebral fissures, eyebrows with sparse lateral third, everted lower eyelids, blue sclerae, large dysplastic ears, lower lip pits), persistent fetal fingertip pads, short stature, heart defects (interventricular defect and aortic coarctation), unilateral cryptorchidism, hypotonia and delay in gross motor skills. These features suggested a diagnosis of KS and a molecular analysis confirmed a novel frame-shift mutation in the exon 11 of MLL2 gene. Subsequently, given recurrent respiratory infections with a normal immunological status, he underwent a chest CT scan that showed a left bronchial isomerism. CONCLUSION: We report a patient affected by KS, with a novel MLL2 mutation and an atypical phenotype characterized by left-side bronchial isomerism. Interestingly, genes involved in the heterotaxia/isomerism such as ROCK2 and SHROOM3 are known to interact with MLL2 gene. In order to achieve a correct diagnosis and an appropriate therapy, the presence of pulmonary anatomical variations should be investigated in KS patients with respiratory signs not associated to immunological deficiency. Finally, our findings support the hypothesis that the mutations leading to a complete loss of function of MLL2 gene is often associated with complex visceral malformations. PMID- 24472334 TI - [Metformin, renal function and lactate: the MetClear Study]. AB - OBJECTIVE: To map the relation between metformin prescription and renal function in an outpatient setting. To investigate whether there is an association between renal function, metformin concentration and lactate concentration. DESIGN: Pilot for a prospective observational cohort study. METHOD: We included outpatients with diabetes mellitus type 2 who were treated with metformin. At inclusion, we determined the HbA1c, lactate, metformin and creatinine concentrations and the estimated glomerular filtration rate (eGFR). Information on the prescribed dosage of metformin was acquired from patient files. Our primary outcome measure was the number of patients in whom the dose was not adjusted to the renal function. Our secondary outcome measure was the difference in median lactate concentration between patients with a normal (<= 2.5 mg/l) and an increased (> 2.5 mg/l) metformin concentration. RESULTS: Eighty-eight patients were included, 12 (14%) of whom had an eGFR <= 30, 31 (36%) an eGFR of 30-50 and 44 (50%) an eGFR > 51 ml/min/1.73 m2. In 27 (31%) of all patients, the daily dose of metformin exceeded the dose recommended in the practice guidelines. The 28 patients with an increased metformin concentration had a significantly higher median lactate concentration: 2.3 mmol/l compared to 1.5 mmol/l for the 60 patients with a normal metformin concentration (p < 0.0001). CONCLUSION: Our study shows that in outpatient practice, the metformin dose is not sufficiently adjusted to a reduced renal function in 31% of the patients. The accumulation of metformin appears to be associated with an increased lactate concentration and a reduced renal function. Extra attention to the dose of metformin in reduced renal clearance is therefore recommended. PMID- 24472333 TI - The Association between Long Working Hours and Self-Rated Health. AB - OBJECTIVES: This study was conducted to determine the number of hours worked per week by full-time wage workers by using the data of the Korean Labor and Income Panel Study (KLIPS), which represents the domestic urban area household, and to determine the association between weekly working hours and the level of self rated health. METHODS: We used data from the 11th KLIPS conducted in 2008. The subjects of this study were 3,699 full-time wage workers between the ages of 25 and 64 years. The association between weekly working hours and self-rated health was analyzed considering socio-demographic characteristics, work environment, and health-related behaviors. RESULTS: Among the workers, 29.7% worked less than 40 hours per week; 39.7%, more than 40 to 52 hours; 19.7%, more than 52 to 60 hours; and 10.9%, more than 60 hours per week. After controlling for socio-demographic variables, work environment-related variables, and health-related behavior variables, the odds ratio (OR) for poor self-rated health for the group working more than 40 hours and up to 52 hours was calculated to be 1.06 (95% confidence interval (CI), 0.89-1.27) when the group working less than 40 hours per week was considered the reference. The OR for the group working more than 60 hours was 1.42 (95% CI, 1.10-1.83) and that for the group working more than 52 hours and up to 60 hours was 1.07 (95% CI, 0.86-1.33). After stratification by gender and tenure, the OR of the female workers group and that of the group with a tenure of more than 1 year were found to be significantly higher than those of the other groups. CONCLUSIONS: This study showed that workers working more than 60 hours per week have a significantly higher risk of poor self-rated health than workers working less than 40 hours per week. This effect was more obvious for the female workers group and the group with a tenure of more than 1 year. In the future, longitudinal studies may be needed to determine the association between long working hours and various health effects in Korean workers. PMID- 24472335 TI - [A medical-psychiatric unit in a general hospital: effective combined somatic and psychiatric care?]. AB - OBJECTIVE: To study the effectiveness of combined integral somatic and psychiatric treatment in a medical-psychiatric unit (MPU). DESIGN: Retrospective case-note study. METHOD: The case notes of all patients admitted to the MPU at the VU Medical Center, Amsterdam, in 2011 were analysed. Data on reasons for referral and somatic and psychiatric diagnoses were collected. Using a global clinical assessment scale and the Health of the Nations Outcome Scales (HoNOS), data on psychiatric symptomology and limitations, behavioural problems, social problems and limitations associated with physical health problems were collected on both admission and discharge. In this way the effect of the admission period on various problems was determined. RESULTS: In 2011 there were 139 admissions to the MPU with a wide variation of somatic and psychiatric diagnoses. The average admission period was 9 days. Global clinical evaluation of the treatment goals set for somatic and psychiatric conditions showed that more than 90% and 85% of the treatment goals, respectively, were completely achieved. HoNOS scores showed a reduction in severity of both psychiatric and somatic problems. The total HoNOS core was significantly reduced by nearly 3.5 points - a large effect size. CONCLUSION: The MPU has succeeded in its goal to deliver integral care to a very diverse group of patients with somatic and psychiatric co-morbidities. It is able to offer care to a vulnerable patient group in which it can be presumed that treatment on a non-integrated unit could not have been delivered or not delivered adequately, due to the complexity of their somatic and behavioural problems. PMID- 24472336 TI - [Intrathoracic hibernoma]. AB - BACKGROUND: A hibernoma is a rare, often asymptomatic benign tumour which usually develops in adults and resembles brown adipose tissue of foetal origin. They occur most often in the thigh. Intrathoracic hibernomas are rare and often discovered incidentally. Hibernomas can infiltrate to adjacent structures. CASE DESCRIPTION: A 29-year-old woman consulted her GP for left-sided thoracic pain. A chest X-ray showed scoliosis of the thoracic spine and a large mass. Further investigations showed a large intrathoracic soft tissue mass with compression of the right lung. Histological samples taken from an open biopsy confirmed the diagnosis of a hibernoma. CONCLUSION: For the correct diagnosis of a hibernoma, histopathological analysis is always necessary. Malignant transformation or metastases have not been described in the literature. Surgical excision of the tumour is always recommended and after complete excision the prognosis for patients is excellent. PMID- 24472337 TI - [Biobanks and the return of results to donors]. AB - Biobanks should return clinically significant and actionable research findings to donors who have given physical material to the biobank. Because the clinical significance of a research finding is hard to determine for the individual donor, a procedure to decide on clinical significance should be incorporated into a structure for the actual feedback of research results. Most published studies show that donors expect return of individual research results, but there is almost no experience with it. Explorative questionnaire-based research among Dutch biobanks from the BioBanking Medical Research Infrastructure (BBMRI.NL) shows that a substantial group of biobanks can return individual research findings from data analysis. On the basis of these experiences a return of results policy may be drafted that answers to the interests of donors and the possibilities of biobanks. PMID- 24472338 TI - [Peanut allergy, not always the correct diagnosis]. AB - BACKGROUND: Diagnosing peanut allergy in children is complicated. The clinical history can be difficult to interpret, measurement of peanut-specific immunoglobulin E (IgE) is of limited usefulness due to its poor specificity, and the gold standard (double-blind placebo-controlled food challenge) is time consuming and labour-intensive, limiting its use in daily practice. Under diagnosing peanut allergy is considered dangerous, because of serious reactions like anaphylaxis. As a result, there is a high probability of over-diagnosis of peanut allergy in the general population, leading to unnecessary peanut-free diets and parental anxiety. CASE DESCRIPTION: We discuss three children diagnosed with peanut allergy, and describe the clinical and diagnostic considerations of peanut allergy. After a detailed history focusing on the reproducibility of objective symptoms after exposure, peanut allergy was excluded in two cases allowing normalization of the diet and reduction of patient and parental anxiety. CONCLUSION: A detailed history, focusing on reproducible and objective symptoms, is helpful in confirmation or exclusion of the diagnosis 'peanut allergy' and can thus prevent unnecessary peanut-free diets. PMID- 24472339 TI - [Bedside consultation by a multidisciplinary antibiotics team: an Antibiotic Stewardship Programme at UMCG]. AB - In 2012, the Dutch Working Party on Antibiotic Policy (SWAB) published a vision document to counteract the rise in antibiotic use and resistance. An Antibiotic Stewardship Programme (ASP) will be implemented by a multidisciplinary antibiotics team (A-team). In 2012 University Medical Centre Groningen (UMCG) in the Netherlands started an Antibiotic Stewardship Programme (ASP) pilot project at the trauma surgery ward. The focus is on providing bedside consultation for patients based on the day 2 bundle. Implementation of the ASP on the basis of a day 2 bundle resulted in an intervention percentage of 75%. The pilot project was a success and will be extended to other wards. PMID- 24472340 TI - [Hyponatraemia: ask the right questions]. AB - Hyponatraemia is a common but complex electrolyte disorder. This clinical lesson, based on two case histories, illustrates how asking the right questions will not only lead to the correct diagnosis and treatment of hyponatraemia but can also indicate how the condition is endangering the patient. PMID- 24472341 TI - Congratulatory message for the new international journal, annals of occupational and environmental medicine. PMID- 24472342 TI - Endoscopic mucosal resection with circumferential incision for treatment of rectal carcinoid tumours. AB - BACKGROUND: Endoscopic mucosal resection (EMR) is simple and quick and has low complication rates. However, the disadvantage of local recurrence or remnant rate limits the use of this technique. We aimed to analyse the outcomes of conventional EMR and EMR with circumferential incision (CIEMR), a simplified modification of EMR, in the endoscopic treatment of rectal carcinoid tumours. METHODS: A total of 59 consecutive patients with rectal carcinoid tumours without regional lymph node enlargement confirmed by endoscopic ultrasonography were included in the study. These patients underwent endoscopic treatment from January 2009 to September 2011 and were randomly designated into CIEMR (n = 31) or EMR group (n = 28). En bloc resection rate, pathological complete resection rate, procedure time, complications and follow-up outcomes were analysed. RESULTS: The en bloc resection rate was not significantly different between the CIEMR and EMR groups (100% versus 96.55%, P > 0.05). The pathological complete resection rate was higher in the CIEMR group than in the EMR group (96.7% versus 82.14%, P < 0.05). The overall complication rate, delayed bleeding and procedure time were not significantly different between the two groups. No recurrence was observed in either the EMR or CIEMR group. CONCLUSIONS: CIEMR optimises the procedure of EMR and simplifies the technique of endoscopic submucosal dissection; thus, it has a better histologically complete resection rate and more acceptable complication rate than EMR. Thus, CIEMR may be preferable to conventional EMR for resection of rectal carcinoid tumours less than 15 mm. PMID- 24472343 TI - A Bahasa Malaysia version of the Montreal Cognitive Assessment: validation in stroke. AB - BACKGROUND: Many stroke research trials do not include assessment of cognitive function. A Very Early Rehabilitation Trial (AVERT) is an international multicenter study that includes the Montreal Cognitive Assessment (MoCA) as an outcome. At the Malaysian AVERT site, completion of the MoCA has been limited by low English proficiency in some participants. We aimed to develop a Bahasa Malaysia (BM) version of the MoCA and to validate it in a stroke population. METHODS: The original English version of the MoCA was translated into BM and then back-translated to ensure accuracy. Feasibility testing in a group of stroke patients prompted minor changes to the BM MoCA. In the validation phase, a larger group of bilingual stroke patients completed both the original English MoCA and the finalized BM MoCA, with presentation order counter-balanced. RESULTS: Forty stroke patients participated, with a mean age of 57.2 (SD = 10.3). Agreement between BM MoCA and English MoCA was strong (intra-class correlation coefficient = 0.81, 95% CI 0.68-0.90). Scores on BM MoCA were slightly higher than scores on English MoCA (median absolute difference = 2.0, IQR 0-3.5), and this difference was present regardless of which version was completed first. CONCLUSIONS: The existence of a validated BM version of the MoCA will be of major benefit to clinicians and researchers in Malaysia and the wider South-east Asian region, where the Malay language is used by over 200 million people. PMID- 24472344 TI - Hepatoprotective effect of Ginkgo biloba leaf extract on lantadenes-induced hepatotoxicity in guinea pigs. AB - The hepatoprotective effect of freeze-dried methanolic leaf extract of Ginkgo biloba was evaluated against lantadenes-induced hepatic damage in guinea pigs. The reversed-phase HPLC analysis of lantadenes confirmed the presence of 72.82% of lantadene A. UPLC-ESI-MS analysis showed the presence of ginkgolide B, C, bilobalide and traces of ginkgolide A and J in G. biloba extract. The concentration of ginkgolide B in the sample was found as 0.29%. The elevated levels of serum alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase due to lantadenes were significantly restored towards normal values by G. biloba extract in a dose-dependent manner. The effects of lantadenes and G. biloba extract on lipid peroxidation (LPO), reduced glutathione (GSH), superoxide dismutase (SOD) and catalase were assayed in liver homogenates to evaluate the antioxidant activity. G. biloba extract in a dose-dependent manner produced significant decrease in lantadenes-induced increased levels of LPO. The lantadene induced decreased levels of SOD, GSH and catalase were elevated by G. biloba extract. The findings of biochemical and antioxidant enzyme levels were supported by gross and histopathological observations. Moreover, liver sections of G. biloba group also showed a marked decrease in apoptosis in comparison to lantadenes group. This study suggested that G. biloba could be used as a promising hepatoprotectant against lantadenes-induced hepatic damage. Future studies are needed to elucidate the precise mechanism of hepatoprotection for practical application. PMID- 24472345 TI - Established a new double antibodies sandwich enzyme-linked immunosorbent assay for detecting Bacillus thuringiensis (Bt) Cry1Ab toxin based single-chain variable fragments from a naive mouse phage displayed library. AB - ScFvs are composed of the variable regions of the heavy and light chains via a short linker that maintain the specific antigen binding abilities of antibodies. In this study, we constructed a naive mouse phage displayed library to generate scFvs against Cry1Ab toxin. After affinity panning, positive phage-scFvs were isolated, sequenced and characterized by ELISA. The best binding ability scFv-G9 was expressed and purified. SDS-PAGE indicated that the relative molecular mass of scFv was estimated at 28 kDa. The purified scFv-G9 was used to develop a new DAS-ELISA for detecting Cry1Ab toxin, within minimum detection limit of 0.008 MUg mL(-1), a working range 0.018-6.23 MUg mL(-1), and the linear curve displayed an acceptable correlation coefficient of 0.98. The cross-reactivity showed that scFv G9 had strongly binding ability to Cry1Ac toxin, but not to Cry1B, Cry1C and Cry1F toxin. The average recoveries of Cry1Ab toxin from spiked leaf and rice samples were in the range 92.1-94.8%, and 91.6-98.6%, respectively, with a coefficient of variation (C.V) less than 5.0%. These results showed promising applications of scfv-G9 for detecting Cry1Ab toxin with new DAS-ELISA. PMID- 24472346 TI - Tryptophan and aspartic acid residues present in the glycerophosphoryl diester phosphodiesterase (GDPD) domain of the Loxosceles laeta phospholipase D are essential for substrate recognition. AB - It is known that the family of phospholipases D (PLD) from spiders of the genus Loxosceles, hydrolyze the substrates sphingomyelin and lisophosphatidylcholine, by their catalytic acid-base action which involves two histidines. However, little is known about the amino acids that participate on substrate recognition. In this study we identified highly conserved amino acids of the glycerophosphoryl diester phosphodiesterase (GDPD) domain of recombinant LlPLD1, which interact with the substrate sphingomyelin. The mutation of W256 to serine and D259 to glycine decreased significantly the sphingomyelinase and hemolytic activity when compared to wild type LlPLD1. The interaction of LlPLD1 with sphingomyelin was also strongly reduced in both mutants LlPLD1-W256S and LlPLD1-D259G. The results show the importance of these residues in the interaction of the protein with its substrate sphingomyelin in cell membranes. PMID- 24472347 TI - Hazard Classification of Household Chemical Products in Korea according to the Globally Harmonized System of Classification and labeling of Chemicals. AB - OBJECTIVES: This study was conducted to review the validity of the need for the application of the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) to household chemical products in Korea. The study also aimed to assess the severity of health and environmental hazards of household chemical products using the GHS. METHODS: 135 products were classified as 'cleaning agents and polishing agents' and 98 products were classified as 'bleaches, disinfectants, and germicides.' The current status of carcinogenic classification of GHS and carcinogenicity was examined for 272 chemical substances contained in household chemical products by selecting the top 11 products for each of the product categories. In addition, the degree of toxicity was assessed through analysis of whether the standard of the Republic of Korea's regulations on household chemical products had been exceeded or not. RESULTS: According to GHS health and environmental hazards, "acute toxicity (oral)" was found to be the highest for two product groups, 'cleaning agents and polishing agents', and 'bleaches, disinfectants, and germicides' (result of classification of 233 household chemical products) at 37.8% and 52.0% respectively. In an analysis of carcinogenicity assuming a threshold of IARC 2B for the substances in household chemical products, we found 'cleaning agents and polishing agents' to contain 12 chemical substances and 'bleaches, disinfectants, and germicides' 11 chemical substances. CONCLUSION: Some of the household chemical products were found to have a high hazard level including acute toxicity and germ cell mutagenicity, carcinogenicity, and reproductive toxicity. Establishing a hazard information delivery system including the application of GHS to household chemical products in Korea is urgent as well. PMID- 24472349 TI - 25 years of the International Journal of Drug Policy: what next? PMID- 24472348 TI - Role of peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC 1alpha) in denervation-induced atrophy in aged muscle: facts and hypotheses. AB - Aging-related loss of muscle mass, a biological process named sarcopenia, contributes to mobility impairment, falls, and physical frailty, resulting in an impaired quality of life in older people. In view of the aging of our society, understanding the underlying mechanisms of sarcopenia is a major health-care imperative. Evidence obtained from human and rodent studies demonstrates that skeletal muscle denervation/reinnervation cycles occur with aging, and that progressive failure of myofiber reinnervation is a major cause of the accelerating phase of sarcopenia in advanced age. However, the mechanisms responsible for the loss of myofiber innervation with aging remain unknown. The two major strategies that counteract sarcopenia, that is, caloric restriction and endurance training, are well known to protect neuromuscular junction (NMJ) integrity, albeit through undefined mechanisms. Interestingly, both of these interventions better preserve PGC-1alpha expression with aging, a transcriptional coactivator which has recently been shown to regulate key proteins involved in maintaining NMJ integrity. We therefore propose that the aging-related decline in PGC-1alpha may be a central mechanism promoting instability of the NMJ and consequently, aging-related alterations of myofiber innervation in sarcopenia. Similarly, the promotion of PGC-1alpha expression by both caloric restriction and exercise training may be fundamental to their protective benefits for aging muscle by better preserving NMJ integrity. PMID- 24472350 TI - NICE medical technologies guidance: aims for clinical practice. AB - NICE (the National Institute for Health and Care Excellence) produces a range of advice and guidance on medical practice and technologies. NICE was established in 1999, and in 2009 set up its Medical Technologies Evaluation Programme. This assesses new devices in terms of whether their use would offer benefits to the patient and NHS at a lower cost compared with current practice, or increased benefits for equal cost. NICE evaluates single products only, as multiple product assessments are time-consuming and mean that manufacturers have to wait longer for NICE to produce guidance on adoption of their technologies. Research into devices and diagnostics is often sparse and of low quality as there is little regulation requiring good research in this area. As a result, products are often not accepted for evaluation, because the evidence base supporting their claimed benefits is so poor. PMID- 24472351 TI - An hypnotic suggestion: review of hypnosis for clinical emergency care. AB - BACKGROUND: Hypnosis has been used in medicine for nearly 250 years. Yet, emergency clinicians rarely use it in emergency departments or prehospital settings. OBJECTIVE: This review describes hypnosis, its historical use in medicine, several neurophysiologic studies of the procedure, its uses and potential uses in emergency care, and a simple technique for inducing hypnosis. It also discusses reasons why the technique has not been widely adopted, and suggests methods of increasing its use in emergency care, including some potential research areas. DISCUSSION: A limited number of clinical studies and case reports suggest that hypnosis may be effective in a wide variety of conditions applicable to emergency medical care. These include providing analgesia for existing pain (e.g., fractures, burns, and lacerations), providing analgesia and sedation for painful procedures (e.g., needle sticks, laceration repair, and fracture and joint reductions), reducing acute anxiety, increasing children's cooperation for procedures, facilitating the diagnosis and treatment of acute psychiatric conditions, and providing analgesia and anxiolysis for obstetric/gynecologic problems. CONCLUSIONS: Although it is safe, fast, and cost effective, emergency clinicians rarely use hypnosis. This is due, in part, to the myths surrounding hypnosis and its association with alternative-complementary medicine. Genuine barriers to its increased clinical use include a lack of assured effectiveness and a lack of training and training requirements. Based on the results of further research, hypnosis could become a powerful and safe nonpharmacologic addition to the emergency clinician's armamentarium, with the potential to enhance patient care in emergency medicine, prehospital care, and remote medical settings. PMID- 24472352 TI - The tooth, the whole tooth, and nothing but the tooth: can dental pain ever be the sole presenting symptom of a myocardial infarction? A systematic review. AB - BACKGROUND: Pain symptoms related to cardiac ischemia can vary greatly from patient to patient. However, should emergency physicians consider the possibility of myocardial infarction in patients who present solely with dental pain? OBJECTIVE: This is a systematic review of the literature investigating the incidence of jaw, tooth, or facial pain as the sole symptom of cardiac ischemia. METHODS: Studies investigating jaw, tooth, or facial pain of cardiac origin were identified using the PubMed database. All English studies in which cardiac pain originated in the face, teeth, or jaw were screened for inclusion. Data were abstracted from each study utilizing a structured review process, and rated for methodological quality. RESULTS: Eighteen studies met study criteria: 16 were case reports, and the remaining 2 were prospective cohort studies. After quality assessment and categorization, nine reports were categorized as weak, eight moderate, and one strong methodological quality. CONCLUSION: Cardiac ischemia may present in no anatomic location other than face or jaw. However, despite frequent claims in the literature to the contrary, the lack of methodological quality of the studies investigated impedes a firm conclusion of face, jaw, or tooth pain as the only symptom of cardiac insufficiency. PMID- 24472353 TI - Diagnosis and reduction of a hernia by bedside ultrasound: a case report. AB - BACKGROUND: Emergency physicians can utilize bedside ultrasound to aid in the diagnosis of abdominal wall hernias and in the reduction of incarcerated hernias. OBJECTIVES: To review the sonographic appearance and diagnostic criteria of abdominal wall hernias and to describe the potential use of ultrasound as an aid in hernia reduction. CASE REPORT: An emergency physician utilized bedside ultrasound to confirm the diagnosis of an incarcerated ventral abdominal wall hernia and to assist in its successful reduction. CONCLUSIONS: A physician trained in bedside ultrasound can diagnose an abdominal wall hernia and facilitate the appropriate treatment of an incarcerated hernia. PMID- 24472354 TI - Concurrent thrombotic thrombocytopenic purpura and spontaneous rupture of the spleen. PMID- 24472355 TI - Cranial computed tomography utilization for suspected ventriculoperitoneal shunt malfunction in a pediatric emergency department. AB - BACKGROUND: Computed tomography (CT) scan, the largest medical source of ionizing radiation in the United States, is used to test for failure of ventricular peritoneal shunts. STUDY OBJECTIVES: To quantify the exposure to cranial CT scans in pediatric patients presenting with symptoms of shunt malfunction, and to measure the association of signs and symptoms with clinical shunt malfunction and the need for neurosurgical intervention within 30 days of presentation. METHOD: This was a quality improvement study evaluating a pathway used by providers in a tertiary care pediatric emergency department with 85,000 patient visits per year, by retrospective chart review of 223 patient visits for suspected shunt malfunction. We determined the median CT scan per patient per year and the association of signs and symptoms on the pathway with radiological signs of shunt failure and neurosurgical intervention within 30 days of scan. RESULTS: The median exposure was 2.6 (interquartile range 1.44-4.63) scans per patient per year. Among 11 signs and symptoms, none was associated with radiologic shunt failure. Neurosurgical intervention within 30 days was positively associated with bulging fontanelle (adjusted odds ratio [AOR] 11.78; 95% confidence interval [CI] 1.67-83.0) and behavioral change (AOR 3.01; 95% CI 1.14-7.93), and negatively associated with seizure (AOR 0.13; 95% CI 0.02-0.79) and fever (AOR 0.15; 95% CI 0.04-0.55). CONCLUSIONS: Patients with ventricular peritoneal shunts underwent many cranial CT scans each year. None of the signs or symptoms included on the clinical pathway was predictive of changes on CT scan. PMID- 24472356 TI - Treatment of agitation in the emergency department: benzodiazepines could be safer than antipsychotics in some cases of insufficient medical data. PMID- 24472357 TI - Traumatic pseudoaneurysm and arteriovenous fistula detected by bedside ultrasound. AB - BACKGROUND: The case of late presentation of a pseudoaneurysm and an arteriovenous fistula (AVF) of the common femoral artery and vein secondary to penetrating trauma is reported. Traumatic AVF and pseudoaneurysm may be present within a variety of clinical conditions, which sometimes makes it difficult to detect them clinically. Undiagnosed AVF can lead to clinical manifestations mostly secondary to increased output generated by the fistula. CASE REPORT: A 31 year-old man presented to the Emergency Department (ED) for wound care follow-up. A week before, he had suffered a stab wound to the medial thigh and the primary suture was performed in our ED. During his first visit to our ED, the vascular examination revealed palpable dorsalis pedis and tibialis posterior pulses. The formal Doppler ultrasound was negative. During his second presentation, however, the physical examination was remarkable for a palpable thrill and continuous bruit in the left mid-thigh region. Also, an ultrasound with a 7.5-MHz linear probe demonstrated a pseudoaneurysm and an AVF between the femoral artery and vein. CONCLUSION: The mechanism of the injury, wound location and tract, and physical findings after a penetrating thigh trauma can help to predict femoral artery injury. Also, occult injuries to the medial thigh after penetrating trauma may be easily overlooked on the physical examination. Furthermore, bedside ultrasound performed by an emergency physician may be helpful in diagnosing occult vascular injuries. PMID- 24472358 TI - "My arm looks like Popeye's": a case report of bicep tendon rupture. PMID- 24472359 TI - Second branchial cleft cyst. PMID- 24472360 TI - ST-segment elevation myocardial infarction vs. hypothermia-induced electrocardiographic changes: a case report and brief review of the literature. AB - BACKGROUND: Diagnosed ST-segment elevation myocardial infarction (STEMI) usually prompts rapid cardiac catheterization response. OBJECTIVE: Our aim was to raise awareness that hypothermia can cause electrocardiographic (ECG) changes that mimic STEMI. CASE REPORT: Emergency Medical Services (EMS) was called for altered mental status and lethargy in a 47-year-old man with a medical history of paraplegia. His history included hepatitis C, hypertension, seizures, anxiety, and recent pneumonia treated with i.v. antibiotics. When brought in by EMS, the patient was responsive only to painful stimuli. His blood glucose was 89 mg/dL; blood pressure was 80/50 mm Hg, and ECG showed ST elevations diffusely. His vital signs in the emergency department were heart rate 53 beats/min, blood pressure 134/79 mm Hg, respiratory rate 14 breaths/min, pulse oximetry of 100%, and a rectal temperature of 32.7 degrees C (91 degrees F). A second ECG showed diffuse ST elevation, sinus bradycardia with a rate of 56 beats/min, and a first-degree atrioventricular block. J waves were noted in V3-V6, I and II. There were no reciprocal changes or ST depressions. A bedside ultrasound showed no pericardial effusion. The patient underwent cardiac catheterization, which showed no coronary artery disease and a normal ejection fraction. Later, hypercapneic respiratory failure with bilateral pneumonia developed and was intubated. His ECG the following day, once he was rewarmed, showed complete resolution of ST elevation and almost complete resolution of J waves. CONCLUSION: Obtaining a complete set of vital signs is key to making a correct diagnosis. Hypothermia should be considered in the differential diagnosis of ST elevation. PMID- 24472361 TI - Bozeman et al. Response to Strote. PMID- 24472362 TI - Epidemiology and Genetic Characterization of H3N8 Equine Influenza Virus Responsible for Clinical Disease in Algeria in 2011. AB - An outbreak of equine influenza (EI) was reported in Algeria between May and July, 2011. The outbreak started in Tiaret, in west province of Algeria, and spread to the other parts of the country affecting almost 900 horses in many provinces. The population studied was composed of 325 horses from different groups of age. Clinical sign expression was age dependent. Indeed, a morbidity rate of 14.9% was observed in horses under 15 months old and a rate of 4.95% in horses over 8 years old. Interestingly, the morbidity rate raised sharply to reach 100% in horses aged between 18 months and 7 years. The virus (H3N8) was detected in nasopharyngeal swabs (n = 11) from non-vaccinated horses using a qRT PCR targeting a portion of the gene encoding the matrix protein (M). The virus isolates were identified as H3N8 by sequencing the haemagglutinin (HA) and neuraminidase (NA) genes and were named from A/equine/Tiaret/1/2011 to A/equine/Tiaret/10/2011. Alignment of HA1 amino acid sequence confirmed that viruses belong to Clade 2 of the Florida sublineage in the American lineage. Moreover, they are closely related to A/equine/Yokohama/aq13/2010, A/equine/Eyragues/1/2010, A/equine/Bokel/2011 and A/equine/Lichtenfeld/2012. Our data indicate that this strain was also circulating in the European horse population in 2010, 2011 and 2012. PMID- 24472363 TI - Binding mode of the activity-modulating C-terminal segment of NS2B to NS3 in the dengue virus NS2B-NS3 protease. AB - The two-component dengue virus NS2B-NS3 protease (NS2B-NS3pro) is an established drug target but inhibitor design is hampered by uncertainties about its 3D structure in solution. Crystal structures reported very different conformations for the functionally important C-terminal segment of the NS2B cofactor (NS2Bc), indicating open and closed conformations in the absence and presence of inhibitors, respectively. An earlier NMR study in solution indicated that a closed state is the preferred conformation in the absence of an artificial linker engineered between NS2B and NS3pro. To obtain direct structural information on the fold of unlinked NS2B-NS3pro in solution, we tagged NS3pro with paramagnetic tags and measured pseudocontact shifts by NMR to position NS2Bc relative to NS3pro. NS2Bc was found to bind to NS3pro in the same way as reported in a previously published model and crystal structure of the closed state. The structure is destabilized, however, by high ionic strength and basic pH, showing the importance of electrostatic forces to tie NS2Bc to NS3pro. Narrow NMR signals previously thought to represent the open state are associated with protein degradation. In conclusion, the closed conformation of the NS2B-NS3 protease is the best model for structure-guided drug design. PMID- 24472364 TI - Peripheral neuropathy and Guillain-Barre syndrome risks associated with exposure to systemic fluoroquinolones: a pharmacovigilance analysis. AB - PURPOSE: Peripheral neuropathy (PN) is an identified risk of systemic antibacterial therapy with fluoroquinolones. The risk and its severity, including the development of Guillain-Barre syndrome (GBS) between individual agents is uncertain. This study examines the association between fluoroquinolones and PN and GBS in cases spontaneously reported to the FDA Adverse Event Reporting System. METHODS: Cases reported to FDA Adverse Event Reporting System between 1997 and 2012 were retrieved. The Medical Dictionary for Regulatory Activities Preferred Term was used to define PN and GBS. Individual fluoroquinolones were identified by generic names and route of administration. Empirical Bayes Geometric Mean (EBGM) with 95% confidence interval (EB05-EB95) was calculated as disproportionality measure. Safety signals with EB05 2 or more was considered a significant disproportional increase in the event reporting of at least twice times higher than that expected. RESULTS: There were 539 PN reports out of 46,257 adverse event reports submitted for fluoroquinolones. Nine percent of PN reports were for GBS. Significant disproportionality of PN (EBGM 2.70; EB05-EB95 2.51 2.90) and GBS (EBGM 3.22; EB05-EB95 2.55-4.02) was identified for fluoroquinolones. Signals of PN were detected for ciprofloxacin (EBGM 3.24; EB05 EB95 2.87-3.66) and levofloxacin (EBGM 3.36; EB05-EB95 3.02-3.72). A GBS signal was detected for ciprofloxacin (EBGM 4.15; EB05-EB95 2.94-5.74). GBS and PN, respectively, ranked 6th and 8th among reported neurologic events. CONCLUSIONS: This study re-emphasizes the link between fluoroquinolones and PN and shows the potential association with more severe forms of nerve damage, for example, GBS. Unless the benefit of fluoroquinolone therapy (e.g., overwhelming infection or development of bacterial resistance) outweighs PN risk, treatment with alternative antibacterial agents is recommended. PMID- 24472365 TI - Remission of C3 glomerulopathy with rituximab as only immunosuppressive therapy. AB - C3 glomerulopathy (C3GP) is a membranoproliferative glomerulonephritis without immunoglobulin deposits. Activation of the alternative pathway of the complement system is central in its pathogenesis. The presence of a C3 nephritic factor (C3Nef), or deficient factor H or I is associated with C3 GP. The treatment is not codified. Here we describe a case of a Caucasian male with a dense deposit disease (a form of C3GP) revealed by nephritic syndrome. C3Nef was present. We treated him with rituximab as the sole immunosuppressive regimen and obtained a complete remission on proteinuria. The effect was sustained at more than 2 years with only two courses of treatment and an excellent tolerance. Rituximab could be proposed as a treatment of C3GP associated with antibodies interfering with complement alternative pathway. PMID- 24472366 TI - Model-based angiogenic inhibition of tumor growth using modern robust control method. AB - Cancer is one of the most destructive and lethal illnesses of the modern civilization. In the last decades, clinical cancer research shifted toward molecular targeted therapies which have limited side effects in comparison to conventional chemotherapy and radiation therapy. Antiangiogenic therapy is one of the most promising cancer treatment methods. The dynamical model for tumor growth under angiogenic stimulator/inhibitor control was posed by Hahnfeldt et al. in 1999; it was investigated and partly modified many times. In this paper, a modified version of the originally published model is used to describe a continuous infusion therapy. In order to generalize individualized therapies a robust control method is proposed using H(infinity) methodology. Uncertainty weighting functions are determined based on the real pathophysiological case and simulations are performed on different tumor volumes to demonstrate the robustness of the proposed method. PMID- 24472367 TI - Prediction of human breast and colon cancers from imbalanced data using nearest neighbor and support vector machines. AB - This study proposes a novel prediction approach for human breast and colon cancers using different feature spaces. The proposed scheme consists of two stages: the preprocessor and the predictor. In the preprocessor stage, the mega trend diffusion (MTD) technique is employed to increase the samples of the minority class, thereby balancing the dataset. In the predictor stage, machine learning approaches of K-nearest neighbor (KNN) and support vector machines (SVM) are used to develop hybrid MTD-SVM and MTD-KNN prediction models. MTD-SVM model has provided the best values of accuracy, G-mean and Matthew's correlation coefficient of 96.71%, 96.70% and 71.98% for cancer/non-cancer dataset, breast/non-breast cancer dataset and colon/non-colon cancer dataset, respectively. We found that hybrid MTD-SVM is the best with respect to prediction performance and computational cost. MTD-KNN model has achieved moderately better prediction as compared to hybrid MTD-NB (Naive Bayes) but at the expense of higher computing cost. MTD-KNN model is faster than MTD-RF (random forest) but its prediction is not better than MTD-RF. To the best of our knowledge, the reported results are the best results, so far, for these datasets. The proposed scheme indicates that the developed models can be used as a tool for the prediction of cancer. This scheme may be useful for study of any sequential information such as protein sequence or any nucleic acid sequence. PMID- 24472368 TI - Absorption, tissue distribution, tissue metabolism and safety of alpha-mangostin in mangosteen extract using mouse models. AB - The commercially available herbal products as the form of extract were usually mixtures containing various compounds. In spite of the purported efficacy in each active constituent, the coexisting constituents in the herbal extract might interfere with the efficacy and safety and affect the pharmacokinetic properties of active constituents. To compare for the pharmacokinetic properties of alpha mangostin, a major bioactive compound, in mangosteen extract and pure alpha mangostin, the pharmacokinetics as well as tissue distribution, in vitro metabolism, plasma protein binding and safety evaluation were conducted in mice because a mouse model is required a small amount of compounds and useful to develop disease models. The absorption of alpha-mangostin was increased and hepatic metabolism of alpha-mangostin was decreased in mice treated with mangosteen extract. However, the intestinal metabolism alpha-mangostin is comparable and still extensive in mice treated with alpha-mangostin and mangosteen extract. Intraperitorial LC50 of alpha-mangostin and mangosteen extract was 150 and 231 mg/kg, respectively. These findings may be valuable to explain the different pharmacokinetics and safety of alpha-mangostin and mangosteen extract. Furthermore, these findings are useful to design the efficacy and safety investigation of alpha-mangostin or mangosteen extract in mice with disease models or combination therapies to extrapolate into the clinical levels. PMID- 24472369 TI - A cross-scale numerical modeling system for management support of oil spill accidents. AB - A flexible 2D/3D oil spill modeling system addressing the distinct nature of the surface and water column fluids, major oil weathering and improved retention/reposition processes in coastal zones is presented. The system integrates hydrodynamic, transport and oil weathering modules, which can be combined to offer different-complexity descriptions as required by applications across the river-to-ocean continuum. Features include accounting for different composition and reology in the surface and water column mixtures, as well as spreading, evaporation, water-in-oil emulsification, shoreline retention, dispersion and dissolution. The use of unstructured grids provides flexibility and efficiency in handling spills in complex geometries and across scales. The use of high-order Eulerian-Lagrangian methods allows for computational efficiency and for handling key processes in ways consistent with their distinct mathematical nature and time scales. The modeling system is tested through a suite of synthetic, laboratory and realistic-domain benchmarks, which demonstrate robust handling of key processes and of 2D/3D couplings. The application of the modeling system to a spill scenario at the entrance of a port in a coastal lagoon illustrates the power of the approach to represent spills that occur in coastal regions with complex boundaries and bathymetry. PMID- 24472370 TI - Mediterranean diet and inflammaging in the elderly: the European project NU-AGE. Preface. PMID- 24472371 TI - Ibrutinib for B cell malignancies. AB - Research over the role of Bruton's agammaglobulinemia tyrosine kinase (BTK) in B lymphocyte development, differentiation, signaling and survival has led to better understanding of the pathogenesis of B-cell malignancies. Down-regulation of BTK activity is an attractive novel strategy for treating patients with B-cell malignancies. Ibrutinib (PCI-32765), a potent inhibitor of BTK induces impressive responses in B-cell malignancies through irreversible bond with cysteine-481 in the active site of BTK (TH/SH1 domain) and inhibits BTK phosphorylation on Tyr223. This review discussed in details the role of BTK in B-cell signaling, molecular interactions between B cell lymphoma/leukemia cells and their microenvironment. Clinical trials of the novel BTK inhibitor, ibrutinib (PCI 32765), in B cell malignancies were summarized. PMID- 24472372 TI - n-3 Fatty acids affect haemostasis but do not increase the risk of bleeding: clinical observations and mechanistic insights. AB - n-3 Fatty acids (EPA and DHA, from fish oil) are essential fatty acids that are approved for the treatment of severe hypertriacylglycerolaemia and, in some countries, used for reducing the risk of CVD. Because of their inhibitory effects on platelet function, some practitioners have, perhaps unnecessarily, discontinued their use in patients undergoing invasive procedures or being treated with anti-platelet or anticoagulation drugs. Thus, the aim of the present study was to review the effects of n-3 fatty acids on bleeding complications in a wide variety of clinical settings, and to summarise their biochemical mechanism of action in platelet function and coagulation. We surveyed recent publications that either directly studied the effects of n-3 fatty acids on the risk of bleeding or focused on different end-points and also reported the effects on bleeding. n-3 Fatty acid treatment had no effect on the risk of clinically significant bleeding in either monotherapy or combination therapy settings. Although originally believed to operate primarily via the cyclo-oxygenase system, these fatty acids have been shown to affect multiple signalling pathways and thrombotic processes beyond simply affecting platelet aggregation. The present overview found no support for discontinuing the use of n-3 fatty acid treatment before invasive procedures or when given in combination with other agents that affect bleeding. On the contrary, the use of these fatty acids in several settings improved clinical outcomes. PMID- 24472374 TI - First-principles study on transition metal-doped anatase TiO2. AB - The electronic structures, formation energies, and band edge positions of anatase TiO2 doped with transition metals have been analyzed by ab initio band calculations based on the density functional theory with the planewave ultrasoft pseudopotential method. The model structures of transition metal-doped TiO2 were constructed by using the 24-atom 2 * 1 * 1 supercell of anatase TiO2 with one Ti atom replaced by a transition metal atom. The results indicate that most transition metal doping can narrow the band gap of TiO2, lead to the improvement in the photoreactivity of TiO2, and simultaneously maintain strong redox potential. Under O-rich growth condition, the preparation of Co-, Cr-, and Ni doped TiO2 becomes relatively easy in the experiment due to their negative impurity formation energies, which suggests that these doping systems are easy to obtain and with good stability. The theoretical calculations could provide meaningful guides to develop more active photocatalysts with visible light response. PMID- 24472373 TI - Young individuals with stroke: a cross sectional study of long-term disability associated with self-rated global health. AB - BACKGROUND: Perceived disability after stroke may persist long-term even among young individuals with mild stroke and may be related to age-related expectations of health and recovery. Thus, in order to appreciate the magnitude of perceived disability in a younger stroke population studies are needed to explore perceived health-related differences between young individuals with stroke and a matched general population. Further, to provide long-term measures by health care, relevant to the same young individuals with stroke, their perceived long-term functioning and disability associated with health need to be explored. METHODS: The generic questionnaire EQ-5D was used to compare ratings of global health and disability between young individuals living in the community up to 6 years after stroke (n = 150) and an age and geographically matched general population (n = 2661). Stroke related medical data were retrieved from medical records and the study specific questionnaire, the MYS-questionnaire, was used to assess self rated disability associated with global health. RESULTS: Among the young individuals 79% had suffered a mild stroke, 45% rated a low global health compared to 15% of the matched general population and a higher proportion rated problems in mobility, self-care, usual activities and anxiety/depression. Among the young individuals with stroke, limitations and restrictions in leisure activities, work, reading as well as low level of physical activity, utilizing personal care provider or personal assistance and tiredness were negatively associated with self-rated global health (R square 0.60). CONCLUSION: The negative effects of stroke, on self-rated global health among young individuals living in the community, appear to be substantial, multi factorial and long standing which call for interdisciplinary research collaborations and team measures by health care long-term. PMID- 24472375 TI - Screening of candidate regulators for cellulase and hemicellulase production in Trichoderma reesei and identification of a factor essential for cellulase production. AB - BACKGROUND: The soft rot ascomycetal fungus Trichoderma reesei is utilized for industrial production of secreted enzymes, especially lignocellulose degrading enzymes. T. reesei uses several different enzymes for the degradation of plant cell wall-derived material, including 9 characterized cellulases, 15 characterized hemicellulases and at least 42 genes predicted to encode cellulolytic or hemicellulolytic activities. Production of cellulases and hemicellulases is modulated by environmental and physiological conditions. Several regulators affecting the expression of cellulase and hemicellulase genes have been identified but more factors still unknown are believed to be present in the genome of T. reesei. RESULTS: We have used transcriptional profiling data from T. reesei cultures in which cellulase/hemicellulase production was induced by the addition of different lignocellulose-derived materials to identify putative novel regulators for cellulase and hemicellulase genes. Based on this induction data, supplemented with other published genome-wide data on different protein production conditions, 28 candidate regulatory genes were selected for further studies and they were overexpressed in T. reesei. Overexpression of seven genes led to at least 1.5-fold increased production of cellulase and/or xylanase activity in the modified strains as compared to the parental strain. Deletion of gene 77513, here designated as ace3, was found to be detrimental for cellulase production and for the expression of several cellulase genes studied. This deletion also significantly reduced xylanase activity and expression of xylan degrading enzyme genes. Furthermore, our data revealed the presence of co regulated chromosomal regions containing carbohydrate-active enzyme genes and candidate regulatory genes. CONCLUSIONS: Transcriptional profiling results from glycoside hydrolase induction experiments combined with a previous study of specific protein production conditions was shown to be an effective method for finding novel candidate regulatory genes affecting the production of cellulases and hemicellulases. Recombinant strains with improved cellulase and/or xylanase production properties were constructed, and a gene essential for cellulase gene expression was found. In addition, more evidence was gained on the chromatin level regional regulation of carbohydrate-active enzyme gene expression. PMID- 24472377 TI - Raising the bar: a comparative analysis of patients with early onset Alzheimer's disease. PMID- 24472376 TI - Life-long spontaneous exercise does not prolong lifespan but improves health span in mice. AB - BACKGROUND: Life expectancy at birth in the first world has increased from 35 years at the beginning of the 20th century to more than 80 years now. The increase in life expectancy has resulted in an increase in age-related diseases and larger numbers of frail and dependent people. The aim of our study was to determine whether life-long spontaneous aerobic exercise affects lifespan and healthspan in mice. RESULTS: Male C57Bl/6J mice, individually caged, were randomly assigned to one of two groups: sedentary (n = 72) or spontaneous wheel runners (n = 72). We evaluated longevity and several health parameters including grip strength, motor coordination, exercise capacity (VO2max) and skeletal muscle mitochondrial biogenesis. We also measured the cortical levels of the brain derived neurotrophic factor (BDNF), a neurotrophin associated with brain plasticity. In addition, we measured systemic oxidative stress (malondialdehyde and protein carbonyl plasma levels) and the expression and activity of two genes involved in antioxidant defense in the liver (that is, glutathione peroxidase (GPx) and manganese superoxide dismutase (Mn-SOD)). Genes that encode antioxidant enzymes are considered longevity genes because their over-expression may modulate lifespan. Aging was associated with an increase in oxidative stress biomarkers and in the activity of the antioxidant enzymes, GPx and Mn-SOD, in the liver in mice. Life-long spontaneous exercise did not prolong longevity but prevented several signs of frailty (that is, decrease in strength, endurance and motor coordination). This improvement was accompanied by a significant increase in the mitochondrial biogenesis in skeletal muscle and in the cortical BDNF levels. CONCLUSION: Life-long spontaneous exercise does not prolong lifespan but improves healthspan in mice. Exercise is an intervention that delays age-associated frailty, enhances function and can be translated into the clinic. PMID- 24472378 TI - Malignant fibrous histiocytoma of the maxillary sinus in a spray painter from an automobile repair shop. AB - BACKGROUND: We report a case of a spray painter who developed malignant fibrous histiocytoma (MFH) of the maxillary sinus following long-term exposure to chromium, nickel, and formaldehyde, implying that these agents are probable causal agents of MFH. CASE REPORT: The patient developed right-sided prosopalgia that began twenty months ago. The symptom persisted despite medical treatment. After two months, he was diagnosed with MFH through imaging studies, surgery, and pathological microscopic findings at a university hospital in Seoul. His social, medical, and family history was unremarkable.The patient had worked for about 18 years at an automobile repair shop as a spray painter. During this period, he had been exposed to various occupational agents, such as hexavalent chromium, nickel, and formaldehyde, without appropriate personal protective equipment. He painted 6 days a week and worked for about 8 hours a day.Investigation of the patient's work environment detected hexavalent chromium, chromate, nickel, and formaldehyde. CONCLUSIONS: The study revealed that the patient had been exposed to hexavalent chromium, formaldehyde, and nickel compounds through sanding and spray painting. The association between paranasal cancer and exposure to the aforementioned occupational human carcinogens has been established. We suggest, in this case, the possibility that the paint spraying acted as a causal agent for paranasal cancer. PMID- 24472379 TI - Calcium extrusion regulatory molecules: differential expression during pregnancy in the porcine uterus. AB - Calcium ions in the uterine endometrium are essential for the establishment and maintenance of pregnancy, but the cellular and molecular mechanisms of calcium ion regulation in the endometrium are not fully understood. Our previous study in pigs found that calcium regulatory molecules, transient receptor potential, vanilloid type 6 and calbindin-D9K, are expressed in the uterine endometrium during the estrous cycle and pregnancy. However, we did not determine the expression of calcium extrusion regulatory molecules, plasma membrane calcium ATPases (ATP2Bs), sodium/calcium exchangers (SLC8As), or potassium-dependent sodium/calcium exchangers (SLC24As), in the uterine endometrium and conceptuses. Thus, in this study we determine whether ATP2Bs, SCL8As, and SLC24As are expressed in the uterine endometrium during the estrous cycle and pregnancy and in conceptuses during early pregnancy. Real-time RT-PCR analysis showed that ATP2Bs, SLC8As, and SLC24As were expressed in the uterine endometrium in a pregnancy status- and stage-specific manner. Conceptuses during early pregnancy also expressed these molecules. In situ hybridization analysis showed that ATP2B1, SLC8A1, and SLC24A4 were localized mainly to luminal and glandular epithelium and stromal cells in the endometrium during pregnancy. These results indicate that calcium extrusion regulatory molecules are expressed in the uterine endometrium during the estrous cycle and pregnancy and in conceptuses during early pregnancy, indicating that calcium extrusion regulatory molecules may play important roles in the establishment and maintenance of pregnancy by regulating calcium ion concentration in the uterine endometrium in pigs. PMID- 24472380 TI - Postoperative complications in Australia and New Zealand (the REASON study). AB - Perioperative medicine is difficult to define, and thus, its progress may be hindered until internationally accepted definitions can be established within the field. The immediate agenda for perioperative physicians should be to agree upon such definitions in order to facilitate advancements in research, audits and outcome measurements. The REASON study, looking at institutions throughout New Zealand and Australia, confirmed that postoperative complications and mortality are important areas for multicentre trials. PMID- 24472381 TI - The relationship between depressive symptoms among female workers and job stress and sleep quality. AB - OBJECTIVE: Recently, workers' mental health has become important focus in the field of occupational health management. Depression is a psychiatric illness with a high prevalence. The association between job stress and depressive symptoms has been demonstrated in many studies. Recently, studies about the association between sleep quality and depressive symptoms have been reported, but there has been no large-scaled study in Korean female workers. Therefore, this study was designed to investigate the relationship between job stress and sleep quality, and depressive symptoms in female workers. METHODS: From Mar 2011 to Aug 2011, 4,833 female workers in the manufacturing, finance, and service fields at 16 workplaces in Yeungnam province participated in this study, conducted in combination with a worksite-based health checkup initiated by the National Health Insurance Service (NHIS). In this study, a questionnaire survey was carried out using the Korean Occupational Stress Scale-Short Form(KOSS-SF), Pittsburgh Sleep Quality Index(PSQI) and Center for Epidemiological Studies-Depression Scale(CES D). The collected data was entered in the system and analyzed using the PASW (version 18.0) program. A correlation analysis, cross analysis, multivariate logistic regression analysis, and hierarchical multiple regression analysis were conducted. RESULTS: Among the 4,883 subjects, 978 subjects (20.0%) were in the depression group. Job stress(OR=3.58, 95% CI=3.06-4.21) and sleep quality(OR=3.81, 95% CI=3.18-4.56) were strongly associated with depressive symptoms. Hierarchical multiple regression analysis revealed that job stress displayed explanatory powers of 15.6% on depression while sleep quality displayed explanatory powers of 16.2%, showing that job stress and sleep quality had a closer relationship with depressive symptoms, compared to the other factors. The multivariate logistic regression analysis yielded odds ratios between the 7 subscales of job stress and depressive symptoms in the range of 1.30-2.72 and the odds ratio for the lack of reward was the highest(OR=2.72, 95% CI=2.32-3.19). In the partial correlation analysis between each of the 7 subscales of sleep quality (PSQI) and depressive symptoms, the correlation coefficient of subjective sleep quality and daytime dysfunction were 0.352 and 0.362, respectively. CONCLUSION: This study showed that the depressive symptoms of female workers are closely related to their job stress and sleep quality. In particular, the lack of reward and subjective sleep factors are the greatest contributors to depression. In the future, a large-scale study should be performed to augment the current study and to reflect all age groups in a balanced manner. The findings on job stress, sleep, and depression can be utilized as source data to establish standards for mental health management of the ever increasing numbers of female members of the workplace. PMID- 24472382 TI - Interventions during pregnancy and birth - call for papers. PMID- 24472383 TI - Praxis and guidelines for planned homebirths in the Nordic countries - an overview. AB - OBJECTIVE: The objective of this overview was to investigate the current situation regarding guidelines and praxis for planned homebirths and also to investigate possibilities for comparative studies on planned homebirths in the Nordic countries (Denmark, Iceland, Norway, Finland and Sweden). DESIGN AND SETTING: National documents on homebirth and midwifery and recommendations regarding management and registration of planned homebirths in the included countries were investigated. FINDINGS: Guidelines regarding planned home birth were found in four of the included countries. In Denmark any woman has the right to be attended by a midwife during a homebirth and each county council must present a plan for the organization of birth services, including homebirth services. In Norway and Iceland the service is fully or partly funded by taxes and national guidelines are available but access to a midwife attending the birth varies geographically. In the Stockholm County Council guidelines have been developed for publicly funding of planned home births; for the rest of Sweden no national guidelines have been formulated and the service is privately funded. KEY CONCLUSION: Inconsistencies in the home birth services of the Nordic countries imply different opportunities for midwifery care to women with regard to their preferred place of birth. Uniform sociodemography, health care systems and cultural context in the Nordic countries are factors in favour of further research to compare and aggregate data on planned home births in this region. Additional data collection is needed since national registers do not sufficiently cover the planned place of birth. PMID- 24472384 TI - Women's household decision-making autonomy and contraceptive behavior among Bangladeshi women. AB - BACKGROUND: Women's autonomy is a potentially important but less studied indicator of using contraception among women as well as ability to control their fertility. This study explores women's decision-making autonomy as a potential indicator of the use of contraception in Bangladesh. METHODS: This cross sectional study utilizes data from the Bangladesh Demographic Health Survey (BDHS) 2007. Information of 8456 currently married and non-pregnant women aged 15 40 years are analyzed to meet up the objective of this study. RESULTS: The mean age of the respondents is 27.19 years and majority of the respondents are from rural areas (62.7%) and also Muslim (90.2%). A large number of women (26.1%) and their husbands (29.0%) have no education and 27.2% respondents were working at the time of interview. The mean number of living children is 2.14. 48.9% of the respondents are currently using a modern method of contraception. More than one third women are not involved in their household decision-making. Results of this study indicate that household decision-making autonomy is significantly associated with current use of modern contraception, future intention to use contraception and discuss contraception with husband. This measure of women's autonomy provides additional independent explanatory power of contraceptive behavior net of some other socio-demographic variables. CONCLUSION: This study argues in favor of increasing women's autonomy to increase contraception using rate in this population. PMID- 24472385 TI - Abortion in university and college female students of Arba Minch town, Ethiopia, 2011. AB - INTRODUCTION: Globally, unsafe abortion is a significant cause of maternal mortality and morbidity. One of the commonest problems facing university and college students is unwanted pregnancy followed by abortion. This study has aimed to assess abortion practice of university and college female students and to identify contributing factors. METHODOLOGY: Cross-sectional study design was used in 2011. Female students from one university and three colleges of Arba Minch town were selected by proportional probability sampling method. Quantitative data were collected using a self-administered structured questionnaire and focus group discussions were also conducted. RESULTS AND DISCUSSION: Eight hundred and thirteen study participants with median age 20 have been involved in the study. Among participants 173 (21.3%) had had sex, 54 (6.6%) had been pregnant, and out of the students who had been pregnant 23 (43.4%) had an induced abortion, 4 (17.3%) of which were done under unsafe conditions. Students' current living residence and knowledge of abortion law are the identified contributing factors to their abortion practices. CONCLUSION: A significant proportion of pregnancies in university and college students were terminated with induced abortion. Unsafe sex is the commonest cause of unplanned pregnancy that leads to abortion induction. Campus residents are more vulnerable to abortion induction. Knowledge of abortion law and abortion induction practices are statistically interrelated. PMID- 24472386 TI - Still childless at the age of 28 to 40 years: a cross-sectional study of Swedish women's and men's reproductive intentions. AB - BACKGROUND: Delayed childbearing is associated with adverse reproductive outcomes. Our aim was to investigate Swedish women's and men's childbearing intentions at the age of 28, 32, 36 and 40 years, in terms of: (1) time point for a first child, (2) number of children, and (3) reasons for not yet having children. METHODS: Cross-sectional data from the Swedish Young Adult Panel Study, including 365 childless women and 356 childless men aged 28, 32, 36 and 40 years who responded to a questionnaire in 2009. Descriptive and multivariate logistic regression analyses were conducted. RESULTS: Most 28- and 32-year-olds intended to have children, but only 32% of women and 37% of men aged 36/40 years (merged), many of whom still postponed childbearing. Reasons for remaining childless differed by age. Most prominent in the 36/40-year-olds were: lack of a partner (women 60%, men 59%), no desire for children (women 44%, men 44%), not mature enough (women 29%, men 35%), and wanting to do other things before starting a family (women 26%, men 33%). The 36/40-year-olds had the highest odds for infertility problems (OR 3.8; CI 95% 1.8-7.9) and lacking a suitable partner (OR 1.8 CI 95% 1.1-3.0), and lower odds for reasons related to work and financial situation. CONCLUSIONS: Many childless 36- and 40-year-olds intended to have children but seemed to overestimate their fecundity. The most prominent reasons for being childless were: not having wanted children up to now, lack of a partner, infertility problems, and prioritising an independent life. PMID- 24472387 TI - Development of a tool to evaluate fetal movements in full-term pregnancy. AB - OBJECTIVE: To study women's description of fetal movements in full-term pregnancy. Further to investigate if their descriptions could be sorted with regard to intensity and type of movements, using a matrix under development to be a tool for evaluating fetal movements in clinical praxis. METHODS: Data were collected by distributing questionnaires including an open question: "Please describe your perception of the baby's movements during this gestational week." A matrix listed seven categories of movements divided into powerful and non powerful movements, was used for the content analysis. RESULTS: 393 (78%) women responded to the open question. The movements were split into two domains: Powerful movements and Non-powerful movements. Altogether, 383 (96%) women perceived fetal movements that were sorted as powerful movement: firm, slow stretching, large and side to side. Ten (4%) women described movements exclusively, i.e. movements that did not include any of the movements in the powerful domain. Most women perceived movements that corresponded to more than one type of category, and all movements described by the women could be referred to at least one of the categories in the matrix. CONCLUSION: The matrix was useful for identification of the women's perceptions of fetal movements in full term pregnancy. Further studies are needed in order to develop the tool and its potential to evaluate the well-being of the fetus before it is to be used in clinical praxis. PMID- 24472388 TI - Bovine lactoferrin ingestion protects against inflammation via IL-11 induction in the small intestine of mice with hepatitis. AB - Accumulating evidence suggests that orally ingested lactoferrin protects against inflammation. To assess the efficacy of orally administered bovine lactoferrin (bLF) against hepatitis and to identify the underlying mechanism, in the present study, we used four mouse models of hepatitis induced by d-galactosamine (GalN), carbon tetrachloride (CCl4), GalN plus lipopolysaccharide (LPS) and zymosan plus LPS. Intraperitoneal (i.p.) injection of GalN (500 mg/kg body weight) in mice treated with bovine serum albumin (BSA) for 14 d significantly increased serum aspartate aminotransferase (AST) concentrations compared with the untreated mice. However, orally administered bLF reduced AST concentrations compared with BSA treatment. In mice that received a single injection (0.4 ml/kg) and twice-weekly injections (0.08 ml/kg) of CCl4 for 24 weeks and pretreated with bLF for 14 d and 24 weeks, respectively, significantly suppressed alanine aminotransferase and AST concentrations were observed compared with the BSA-treated control. Oral administration of bLF for 14 d before i.p. injection of LPS (5 mg/kg) plus GalN (1 g/kg) significantly improved the survival rate. In mice that received intravenous injection of zymosan (25 mg/kg) and LPS (15 MUg/kg) at 7 d intervals, bLF reduced the elevation of AST concentrations and enhanced the production of IL 11 and bone morphogenetic protein 2 in the small intestine compared with the BSA treated control. To evaluate the effects of IL-11, we used IL-11 receptor alpha null mice treated with GalN, CCl4 and zymosan plus LPS. In this group, the activity of bLF was not significantly different from that of BSA. These data indicate that orally ingested bLF enhances the expression of IL-11 in the small intestine and up-regulates protective activity in mice with hepatitis. PMID- 24472389 TI - Molecular testing in oncology: problems, pitfalls and progress. AB - Recent advances in the understanding of the molecular basis of cancer and the development of molecular diagnostics based on this knowledge have done much to progress the fields of oncology and pathology. Technological developments such as Next Generation Sequencing (NGS) and multiplex assays have made feasible the widespread adoption of molecular diagnostics for clinical use. While these developments and advances carry much promise, there are pitfalls to implementing this testing. Choosing appropriate biomarkers is a vital first step for clinical use and being able to understand the complex relationship between predictive and prognostic biomarkers is a crucial component of this. Testing for standard of care biomarkers is not straightforward, one must choose carefully between clinical trial assays, assays that analyse the same biological phenomenon or surrogate biomarkers. Sample heterogeneity and population specific difference is assays may skew results and must be controlled for at the assay design stage. At a technical level, NGS has the potential to revolutionise laboratory practice and approaches to cancer treatment. However, use of this technology requires careful planning and implementation if one is to avoid technical and ethical quagmires. Finally, with FDA regulation of companion diagnostics one may be limited to therapy specific assays. PMID- 24472390 TI - Free medial plantar artery flap for the reconstruction of great toe pulp. AB - The great toe is an important body structure both functionally and cosmetically. The defect over the great toe is very challenging to treat. Our patient was a 9 year-old boy, presenting with posttraumatic loss of partial right great toe pulp. The mode of injury was the toe getting caught in the cycle wheel and sustaining amputation of the plantar aspect of the great toe. The great toe with exposed bone was reconstructed with a free medial plantar artery flap, harvested from the same limb. To our best knowledge, this was the first reported case of free medial plantar artery flap used for the reconstruction of great toe defects. PMID- 24472391 TI - Terpenoids from the roots of Drypetes hoaensis and their cytotoxic activities. AB - Seven terpenoids consisting of five sesquiterpenoids, hoaensieremone, hoaensieremodione, hoaensifuranonal, hoaensieudesone, and hoaensibenzofuranal, and two friedelane triterpenoids, 3alpha-(E)-p-coumaroyloxyfriedelan-7-one and 3alpha-(E)-caffeoyloxyfriedelan-7-one were isolated from the dichloromethane extract of the roots of Drypetes hoaensis. Additionally, twelve known compounds and vanillin were isolated. Their structures were established on the basis of spectroscopic analysis, as well as by comparison with literature data. The anticancer activity of nine of these compounds was investigated. PMID- 24472392 TI - Metabolic flux phenotype of tobacco hairy roots engineered for increased geraniol production. AB - The goal of this study was to characterise the metabolic flux phenotype of transgenic tobacco (Nicotiana tabacum) hairy roots engineered for increased biosynthesis of geraniol, an intermediate of the terpenoid indole alkaloid pathway. Steady state, stable isotope labelling was used to determine flux maps of central carbon metabolism for transgenic lines over-expressing (i) plastid targeted geraniol synthase (pGES) from Valeriana officinalis, and (ii) pGES in combination with plastid-targeted geranyl pyrophosphate synthase from Arabidopsis thaliana (pGES+pGPPS), as well as for wild type and control-vector-transformed roots. Fluxes were constrained by the redistribution of label from [1-13C]-, [2 13C]- or [13C6]glucose into amino acids, sugars and organic acids at isotopic steady state, and by biomass output fluxes determined from the fractionation of [U-14C]glucose into insoluble polymers. No significant differences in growth and biomass composition were observed between the lines. The pGES line accumulated significant amounts of geraniol/geraniol glycosides (151+/-24 ng/mg dry weight) and the de novo synthesis of geraniol in pGES was confirmed by 13C labelling analysis. The pGES+pGPPS also accumulated geraniol and geraniol glycosides, but to lower levels than the pGES line. Although there was a distinct impact of the transgenes at the level of geraniol synthesis, other network fluxes were unaffected, reflecting the capacity of central metabolism to meet the relatively modest demand for increased precursors in the transgenic lines. It is concluded that re-engineering of the terpenoid indole alkaloid pathway will only require simultaneous manipulation of the steps producing the pathway precursors that originate in central metabolism in tissues engineered to produce at least an order of magnitude more geraniol than has been achieved so far. PMID- 24472393 TI - Flavonoid and phenolic compounds from Salvia palaestina L. growing wild in Jordan and their antioxidant activities. AB - Investigation of the butanol fraction of Salvia palaestina Benth. from Jordanian origin resulted in the isolation and characterization of nine compounds, three of which are reported here for the first time in Nature. These compounds included the two phenolics: salpalaestinin (1), methyl 3-O-methylrosmarinate (3) and the flavonoid luteolin 7-O-(2"-p-hydroxybenzoyl)-beta-glucuronide) (8). In addition, 3,4-dihydroxyphenyl caffeate (2), diosmetin (4), apigenin-7-O-(6"-butyryl-beta glucopyranoside) (5), luteolin-3'-O-methyl-7-O-(6"-butyryl-beta-glucopyranoside) (6) and clinopodic acid B (7) were also obtained from the butanol fraction of the plant. The structures of the isolated compounds were elucidated by different spectroscopic methods including NMR (1D and 2D), UV, IR and MS (HRESIMS and EIMS). The DPPH radical scavenging activity for compounds 1, 3, 5, 6 &8 was evaluated. Compound 3 had the highest antioxidant activity (91.9+/-1.30% inhibition) with an IC50 value of 1.0+/-0.23(MUg/mL). PMID- 24472394 TI - Systematic review of the use of prophylactic dressings in the prevention of pressure ulcers. AB - This systematic review considers the evidence supporting the use of prophylactic dressings for the prevention of pressure ulcer. Electronic database searches were conducted on 25 July 2013. The searches found 3026 titles and after removal of duplicate records 2819 titles were scanned against the inclusion and exclusion criteria. Of these, 2777 were excluded based on their title and abstract primarily because they discussed pressure ulcer healing, the prevention and treatment of other chronic and acute wounds or where the intervention was not a prophylactic dressing (e.g. underpads, heel protectors and cushions). Finally, the full text of 42 papers were retrieved. When these 42 papers were reviewed, 21 were excluded and 21 were included in the review. The single high-quality randomised controlled trial (RCT) and the growing number of cohort, weak RCT and case series all suggest that the introduction of a dressing as part of pressure ulcer prevention may help reduce pressure ulcer incidence associated with medical devices especially in immobile intensive care unit patients. There is no firm clinical evidence at this time to suggest that one dressing type is more effective than other dressings. PMID- 24472395 TI - 18 F-FDG PET standard uptake values of the normal pons in children: establishing a reference value for diffuse intrinsic pontine glioma. AB - BACKGROUND: Positron emission tomography (PET) scanning with [18 F]fluorodeoxyglucose (18 F-FDG) is a useful diagnostic and prediction tool in brain tumors, but its value in childhood diffuse intrinsic pontine glioma (DIPG) is still unclear. For interpretation of 18 F-FDG PET results in DIPG, uptake values of the normal pons of children of increasing ages are mandatory. The aim of this study was to determine 18 F-FDG standard uptake value ratios (SUVr) of the normal pons and to compare these to those of DIPG. METHODS: We studied 36 subjects with a normal, non-affected pons (aged 5 to 23 years) and 6 patients with DIPG (aged 4 to 17 years) who underwent 18 F-FDG PET scanning. Magnetic resonance imaging (MRI) was co-registered to define the regions of interest. SUVr and SUVrmax for the pons/cerebellum (SUVrp/c) and the pons/occipital lobe (SUVrp/o) were calculated. Independent-samples t tests and Mann-Whitney U tests were used to compare the mean SUVr and Pearson's test for correlations. RESULTS: For the normal pons, mean SUVrp/c and SUVrp/o were 0.65 (+/-0.054) and 0.51 (+/ 0.056), respectively. No significant correlations were found between the SUVr of the normal pons and sex, age, nor pontine volume. A modest but statistically significant correlation was found between SUVr and post-injection time acquisition timing. For DIPG, mean SUVrp/c and SUVrp/o were 0.74 (+/-0.20) and 0.65 (+/-0.30), respectively, while mean SUVrp(max)/c and SUVrp(max)/o were 1.95 (+/-0.48) and 1.81 (+/-0.20), respectively. CONCLUSION: The SUVr of the unaffected pons are strikingly constant between children, irrespective of sex and age, and can therefore be well used as a reference value for 18 F-FDG PET studies in DIPG. PMID- 24472396 TI - Occipital seizures induced by intermittent photic stimulation in Dravet syndrome. AB - PURPOSE: Dravet syndrome (DS) is a rare disorder with seizure onset in the first year of life, typically beginning with prolonged febrile hemiclonic seizures or generalized tonic-clonic seizures. Photosensitivity is reported in more than 40% of patients. We present two cases of DS in which we had the chance to record occipital seizures induced by Intermittent Photic Stimulation (IPS). METHOD: We retrospectively reviewed the medical records of 32 children affected by DS. All clinical notes were reviewed in order to evaluate the occurrence of seizures induced by IPS. RESULTS: Among the 32 reviewed clinical records, two patients with IPS-induced seizures were found. In both patients seizures originated from the occipital-temporal region. Clinical history was characterized by generalized tonic-clonic seizures, and myoclonia. At the age respectively of 11 months and 20 months they presented a prolonged focal seizure induced by IPS at a frequency of 10 Hz. During the follow-up they additionally presented with hypomotor seizures, also induced by IPS during laboratory EEG examinations. The semiology of hypomotor seizures resembled what is described as "complex partial status", a type of non-convulsive status with ictal discharges arising unilaterally from the occipito-temporal region. CONCLUSION: Based on available literature, IPS induced occipital seizures have not been reported during the first year of life. Although pathophysiological features are not yet completely understood, both photosensitivity and occipital seizures should be considered in the diagnostic evaluation in DS. The documentation of IPS induced occipital seizures might contribute to widen the clinical and neurophysiological spectra of DS. PMID- 24472397 TI - MECP2 duplication phenotype in symptomatic females: report of three further cases. AB - BACKGROUND: Xq28 duplications, including MECP2 (methyl CpG-binding protein 2; OMIM 300005), have been identified in approximately 140 male patients presenting with hypotonia, severe developmental delay/intellectual disability, limited or absent speech and ambulation, and recurrent respiratory infections. Female patients with Xq28 duplication have been rarely reported and are usually asymptomatic. Altogether, only fifteen symptomatic females with Xq28 duplications including MECP2 have been reported so far: six of them had interstitial duplications while the remaining had a duplication due to an unbalanced X;autosome translocation. Some of these females present with unspecific mild to moderate intellectual disability whereas a more complex phenotype is reported for females with unbalanced X;autosome translocations. FINDINGS: Here we report on the clinical features of three other adolescent to adult female patients with Xq28 interstitial duplications of variable size, all including MECP2 gene. CONCLUSIONS: Mild to moderate cognitive impairment together with learning difficulties and speech delay were evident in each of our patients. Moreover, early inadequate behavioral patterns followed by persistent difficulties in the social and communication domains, as well as the occurrence of mild psychiatric disturbances, are common features of these three patients. PMID- 24472398 TI - Dose proportionality and pharmacokinetics of extended-release (OROS(r)) hydromorphone: a phase 1, open-label, randomized, crossover study in healthy Taiwanese subjects. AB - OBJECTIVES: Osmotic-controlled release oral delivery system (OROS(r)) hydromorphone - an extended-release preparation - is recommended long-term therapy for chronic pain patients. Dose proportionality of OROS hydromorphone has been shown in healthy Caucasian volunteers; however, no studies have been conducted in Asian populations. To determine whether ethnic differences affect the drug's pharmacokinetic (PK) profile, we evaluated the dose proportionality of OROS hydromorphone in healthy Taiwanese adults. METHODS: This 12-week, open label, 4-way crossover, phase 1 study randomly assigned subjects to 1 of 4 treatment sequences - single oral dose OROS hydromorphone: 8 mg, 16 mg, 32 mg, or 64 mg - along with 50 mg naltrexone. Dose proportionality was assessed using a linear mixed-effects model to estimate the slope of the regression line and its 90% CI for Cmax, AUC0-48h, and AUClast. Descriptive statistics measured plasma hydromorphone concentrations, PK parameters, laboratory analytes, and vital signs. RESULTS: 23 subjects completed the study; a single-dose of OROS hydromorphone increased plasma concentration steadily for 6 hours and sustained it at or near maximum levels for ~ 24 hours. After dose normalization to a 16 mg dose, all studied doses demonstrated dose proportionality for Cmax, AUClast, and AUC0-48h,as the slopes of the regression lines for Cmax, AUClast, and AUC0-48h were close to zero, and the 90% CIs within pre-specified limits. Adverse events were as expected for hydromorphone administered with concomitant naltrexone. CONCLUSIONS: Single doses of 8 mg, 16 mg, 32 mg, and 64 mg of OROS hydromorphone were found to be dose proportional for Cmax, AUClast, and AUC0-48h and were generally safe and well-tolerated in healthy Taiwanese adults. PMID- 24472399 TI - What are the patient factors affecting repetitive use of injectable pain relievers in outpatient care settings? AB - Targeting repeated injection users with education interventions aimed at highlighting the extent of their current use and increasing awareness of the oral preparation options may reduce unnecessary injection use. The aim of this retrospective observational study was to investigate the patient factors related to repeated use of injection formulation analgesics in patients with musculoskeletal disorders who were frequent users of ambulatory healthcare services. Population-based national health insurance claims data for the time period July 2011 - December 2011 were analyzed. Patients aged 18 - 80 years with a musculoskeletal disorder, attended ambulatory healthcare settings > 25 times, and were prescribed pain relievers such as non-steroidal anti-inflammatory drugs and narcotic analgesics in an oral formulation for >= 14 days or in an injection formulation >= 3 times during the study period were included in the study. There were 742,675 repeated systemic analgesic users, and 64.1% (n = 476,021) of these patients were injection users. The average use of injections per patient during the 6-month period was 8.3. Tramadol was the most frequently prescribed medication for injection, followed by diclofenac, piroxicam, and ketorolac. Statistical analyses showed significant correlations between prevalent injection formulation use and patient factors such as gender, age, area of residence, days of healthcare utilization, number of healthcare centers visited, type of healthcare center visited, total medical expenditure, and total out-of-pocket expenditure. These factors could possibly be used to determine the target population for educational interventions aimed at changing behavior relating to the preference for injectable formulations. PMID- 24472400 TI - Difference in risk of gastrointestinal complications between users of enteric coated and buffered low-dose aspirin. AB - OBJECTIVE: Difference in the risk of gastrointestinal (GI) complications between users of enteric-coated and buffered low-dose aspirin (LDA) is unclear. The purpose of the study is to examine the difference in risk of GI damage between enteric-coated and buffered LDA products. METHODS: A large and chronologically organized receipt database constructed by a database vendor was utilized. Prescription and event sequence symmetry analysis was used to identify the risk of LDA-induced GI complications over the period from January 2005 to July 2011. LDA use in combination with H2-receptor antagonists (H2RAs) and proton pump inhibitors (PPIs) was examined by prescription sequence symmetry analysis. Likewise, symmetry analysis was undertaken to evaluate the association between the diagnosis of GI disease and the prescription of LDA products. RESULTS: In July 2011, enteric-coated LDA users were more frequently co-administered PPIs than buffered LDA users (25.4% vs. 14.4%). Prescription sequence symmetry analysis of acid inhibitor use found no significant associations with enteric coated LDA use and buffered LDA use. The event sequence symmetry analysis of ulcer, gastritis and duodenitis, and melena found significant associations with entericcoated LDA use, with adjusted sequence ratios (ASRs) of 1.58 (1.23 - 2.06), 1.30 (1.03 - 1.65), and 14.38 (2.19 - 607.95), respectively, at the 6 month interval. At the 12-month interval, analysis of ulcers and melena found significant associations for enteric-coated LDA users, with ASRs of 1.39 (1.13 - 1.73) and 20.83 (3.33 - 863.25), respectively. CONCLUSIONS: Our findings do not support that there is no difference in the risk of GI complications between enteric-coated LDA and buffered LDA, but rather may imply that the risk of GI complications associated with enteric-coated LDA is higher than that with buffered LDA. PMID- 24472401 TI - Pharmacokinetics and tolerability of olmesartan medoxomil plus hydrochlorothiazide combination in healthy Chinese subjects: drug-drug interaction, bioequivalence, and accumulation. AB - OBJECTIVES: The study is to investigate drug-drug interaction (DDI) between olmesartan medoxomil and hydrochlorothiazide (HCTZ), to confirm bioequivalence (BE) of a new combined formulation and coadministration of separate local tablets, and to receive pharmacokinetics and tolerability of the new combined formulation after multiple doses in healthy Chinese subjects. METHODS: The 3-in-1 study was separated into 2 stages. Stage 1 is a four-period crossover study. 28 healthy subjects were equally randomized into four groups. Each group received the four following regimens in a sequence as Latin square (4 * 4) design: A: olmesartan medoxomil; B: HCTZ; C: test drug (new combined formulation); D: reference drugs (co-administration of separate tablets). In stage 2, half of 28 subjects were daily dosed with regimen C for 7 days. Blood and urine samples were obtained to receive pharmacokinetics of olmesartan and HCTZ, which were analyzed using the BE evaluation method. Tolerability was also assessed. RESULTS: All subjects completed the study and nobody reported serious adverse event (SAE). The 90% confidence intervals (CI) of geometric mean ratio (GMR) of log transformed Cmax, AUC0-t, and AUC0-infinity after single dose showed no DDI and claimed BE. The mean ratio of accumulation (Ra) (SD) of olmesartan and HCTZ after multiple doses of new combination formulation is 1.03 (0.182) and 0.954 (0.128). CONCLUSIONS: No significant DDI between olmesartan and HCTZ was found. The new combination formulation is bioequivalent to co-administration of two separate local tablets. After multiple doses of the new combination formulation, no significant accumulation was observed. The new combination formulation is reasonably tolerated well in healthy Chinese subjects after multiple doses. PMID- 24472402 TI - TRPV1 inhibition does not prevent cold dry air-elicited symptoms in non-allergic rhinitis. AB - BACKGROUND: The transient receptor potential vanilloid 1 (TRPV1)-expressing sensory C-fibers may play a role in the development of nasal hyper-responsiveness and symptoms of non-allergic rhinitis (NAR). OBJECTIVE: To evaluate the effects of a TRPV1-antagonist, SB-705498, on cold dry air (CDA)-induced symptoms in patients with NAR. METHODS: This randomized, double-blind, placebo-controlled, crossover study evaluated 14 days of once daily, topical intranasal SB-705498 12 mg in 40 patients with NAR using a CDA challenge experimental model in an environmental exposure chamber (EEC, Cetero Research, Mississauga, Ontario). The primary endpoint was total symptom score (TSS), expressed as weighted mean over 60 minutes (WM0-60) or maximum TSS at 1 hour and 24 hours postdosing. RESULTS: Treatment with SB-705498, relative to placebo, did not improve WM0-60 or maximum TSS at 1 hour and 24 hours post-dosing on days 1 or 14. Mean (95% CI) treatment differences (SB-705498 - placebo) on day 14 were, for WM0-60 at 1 hour: -0.12 ( 0.60, 0.36); for maximum TSS at 1 hour: -0.03 (-0.58, 0.51). SB-705498 had no impact on any other efficacy parameters. SB-705498 was well tolerated and pharmacokinetics analysis supported the dosing regimen. CONCLUSION: SB-705498 12 mg for 14 days did not alleviate the CDA-induced symptoms of NAR. Despite engagement of the TRPV1 receptor, there was no translation to clinical efficacy, suggesting redundancy in symptom pathways. PMID- 24472403 TI - Pharmacokinetic profile of micafungin when co-administered with amphotericin B in healthy male subjects. AB - OBJECTIVE: Micafungin and amphotericin B are antifungal agents with potent activity against a broad spectrum of fungal spp., including Candida and Aspergillus. The objective of this study was to evaluate the potential pharmacokinetic (PK) interaction of the two drugs in healthy subjects. METHODS: PK were evaluated in healthy adults in an open-label, phase I clinical trial, following separate treatments with micafungin (200 mg; days 1 - 5) and conventional amphotericin B (0.25 mg/kg; days 8 - 13) alone, and following co administration of both drugs (days 14 - 18). RESULTS: In 20 male subjects, systemic exposure to micafungin (measured using peak plasma micafungin concentration (Cmax) and area under the plasma micafungin concentration-time curve (AUC0-tau)) were similar following coadministration of micafungin and amphotericin B (day 18; Cmax 19.1 MUg/mL, AUC0-tau 232 MUg*h/mL) compared with administration of micafungin alone (day 5; Cmax 18.7 MUg/mL, AUC0-tau 236 MUg*h/mL), suggesting that administration of amphotericin B does not affect the PK of micafungin. The exposure to amphotericin B was ~ 30% greater following co administration of both drugs (day 18; Cmax 704 MUg/mL, AUC0-tau 9157 MUg*h/mL) than after administration of amphotericin B alone (day 13; Cmax 621 MUg/mL, AUC0 tau 7023 MUg*h/mL). Concurrent treatment with micafungin and amphotericin B was less well tolerated than when either agent was administered alone. CONCLUSIONS: PK and safety-related observations during co-administration of micafungin and amphotericin B were considered to be a consequence of accumulation of amphotericin B to a steady state, indicating that co-administration of the two drugs does not affect the PK of micafungin. PMID- 24472404 TI - Statin-associated lower urinary tract symptoms: data mining of the public version of the FDA adverse event reporting system, FAERS. AB - OBJECTIVE: To examine the association between statin use and the risk of lower urinary tract symptoms (LUTS) in reports submitted to the US Food and Drug Administration (FDA) Adverse Event Reporting System (FAERS) between 2004 and 2011. METHODS: Relevant reports in the FAERS were identified and analyzed. The reporting odds ratio (ROR) was used to detect spontaneous report signals, calculated using the case/non-case method. Cases were identified by the presence of reports of an adverse drug reaction (ADR) in which statins were the suspected drug. Non-cases were all the reports of the same reactions induced by drugs other than statins. The reporting odds ratio (ROR) and 95% confidential interval (CI) was calculated as a measure of disproportionality. RESULTS: A total of 44,959,104 drug-reaction pairs was found in 2,681,739 reports. Significant RORs were found for both voiding (ROR; 1.16, 95% CI; 1.10 - 1.23) and storage symptoms (ROR; 1.25, 95% CI; 1.20 - 1.30). Analysis of individual statins showed that rosuvastatin, atorvastatin, and lovastatin had significant disproportionality for voiding symptoms, while simvastatin, rosuvastatin, pravastatin, atorvastatin, pitavastatin, and lovastatin had significant disproportionality for storage symptoms. Of the four voiding symptoms, significant RORs were found for urine flow decrease and dysuria. Of the four storage symptoms, significant RORs were found for pollakiuria and nocturia. No fundamental differences in disproportionality were observed between genders. CONCLUSIONS: Analysis of the FAERS database showed small but reliable signals for LUTS in statin users. The mechanism responsible for these reactions is unknown. However, these adverse events should be monitored closely. PMID- 24472405 TI - Ertapenem-associated seizures in a patient without prior CNS disorder or severe renal dysfunction. AB - OBJECTIVES: To present a case report of a patient who had developed seizures during ertapenem therapy with no central nervous system (CNS) disorder and the dose of ertapenem that is apparently appropriate according to the renal function. RESULTS: Seizures are rare but well known side-effects of carbapenems, especially imipenem. In most cases, seizures develop in patients with CNS lesions and limited carbapenem excretion. We present a case of a female patient with no prior central nervous disorder who developed seizures after 3 days of ertapenem therapy. In the first 2 days, the dose of ertapenem was halved according to the calculated creatinine clearance. On day 3, the renal function improved, and according to the recommendation by the manufacturer there was no need for dose adjustment any more. Seizures stopped after the discontinuation of ertapenem and anti-epileptic prophylaxis with levetiracetam. A literature search of similar case reports has shown that seizures during ertapenem treatment may develop in patients with prior known CNS disorders and/or severe renal dysfunction that predicts dose alteration according to renal function. There are reports of changed mental status with no convulsive movements, and there is known decrease of valproic acid concentration during ertapenem treatment in patients treated for various forms of epilepsy. To our knowledge, this is the first report of ertapenem-related seizures in a patient with normal CNS function and the dose of ertapenem that was appropriate for her renal function. CONCLUSIONS: With our case report, we would like to inform and warn clinicians of the possibility of new onset epilepsy during ertapenem treatment, even in individuals with pre-existing moderate chronic kidney disease and no prior known CNS disease. PMID- 24472406 TI - Influence of St. John's wort on the steady-state pharmacokinetics and metabolism of bosentan. AB - OBJECTIVE: We assessed the effect of St. John's wort (SJW) on bosentan pharmacokinetics at steady-state in different CYP2C9 genotypes in healthy volunteers. METHODS: Nine healthy extensive metabolizers of CYP2C9 and 4 poor metabolizers received therapeutic doses of bosentan (125 mg q.d. on study day 1; 62.5 mg b.i.d. on study day 2, 125 mg b.i.d. on study days 3 - 20) for 20 days and SJW (300 mg t.i.d.) concomitantly for the last 10 days. Bosentan pharmacokinetics was assessed on days 1, 10, and 20. Concurrently, we repeatedly quantified changes of CYP3A activity using low dosed midazolam (3 mg p.o.) as a probe drug. RESULTS: Due to auto-induction of its metabolism, Cl/F increased by 67%, thus significantly lowering bosentan exposure (AUC) to 60% after 10 days of bosentan administration (n = 13, p < 0.05). Concurrently, midazolam clearance (CYP3A activity) increased by 224% (n = 13, p < 0.05) and further increased after SJW by 374% compared to baseline (n = 13, p < 0.05). SJW increased midazolam clearance by 47% (n = 13, p < 0.05) but failed to alter bosentan exposure and clearance consistently. No significant differences in bosentan exposure and clearance changes were observed in CYP2C9 poor metabolizers. CONCLUSION: SJW increased CYP3A activity but had no consistent effect on bosentan clearance. However, inter-individual changes of the interaction were large, suggesting that close monitoring of bosentan effects may be advisable. The contribution of CYP2C9 to this interaction seems to be minor. PMID- 24472407 TI - Radiative and nonradiative relaxation phenomena in hydrogen- and oxygen terminated porous silicon. AB - Using time-resolved photoluminescence spectroscopy over a wide range of temperatures, we were able to probe both radiative and nonradiative relaxation processes in luminescent porous silicon. By comparing the photoluminescence decay times from freshly prepared and oxidized porous silicon, we show that radiative processes should be linked with quantum confinement in small Si nanocrystallites and are not affected by oxidation. In contrast, nonradiative relaxation processes are associated with the state of oxidation where slower relaxation times characterize hydrogen-terminated porous silicon. These results are in a good agreement with the extended vibron model for small Si nanocrystallites. PACS: 78.55.Mb; 78.67.Rb; 78.47.jd. PMID- 24472408 TI - Predictors of high symptom burden in gynecologic oncology outpatients: who should be referred to outpatient palliative care? AB - OBJECTIVE: To characterize symptom prevalence in gynecologic oncology outpatients and identify predictors of high symptom burden. METHODS: We performed a retrospective analysis of a convenience sample of symptom surveys from gynecologic oncology patients at a single cancer center over a 20-month period. The survey was based on the Edmonton Symptom Assessment System (ESAS), and assessed pain, depression, anxiety, fatigue and well-being. Information on demographics, disease, treatment and history of chronic pain, depression or anxiety was abstracted from medical records. Data was analyzed with descriptive and t-test statistics. RESULTS: We analyzed 305 surveys from unique patients. Symptom prevalence (severity score>0/10) ranged from 60.1% (pain) to 79.7% (fatigue). Prevalence of moderate to severe symptoms (score>=4/10) ranged from 32% (pain) to 47% (fatigue). There were no differences in symptom burden by site or stage of cancer. Patients with no active disease (38%) were less symptomatic. There was a trend toward higher symptom burden in patients younger than 50years. There was higher symptom burden in patients receiving cancer treatment or with a pre-existing history of pain, anxiety or depression. Patients who expressed an interest in being seen by a symptom management service also had higher symptom burden. CONCLUSIONS: Gynecologic oncology outpatients have a high symptom burden regardless of stage and site of cancer. Patients who are young, on treatment or have a history of chronic pain, depression or anxiety have a higher symptom burden. Consideration should be given to targeting these patients for outpatient palliative care services. PMID- 24472409 TI - The inhibition of miR-21 promotes apoptosis and chemosensitivity in ovarian cancer. AB - BACKGROUND: MicroRNAs have been implicated in tumorigenesis, drug resistance, and prognosis in cancer. We investigated the role of microRNA-21 (miR-21) in regulating ovarian cancer drug resistance. METHODS: We used parental and cisplatin resistant ovarian cell lines to demonstrate the role of miR-21 in drug resistance and investigated the gene targets of miR-21. Fresh tumor specimens were used to validate our in vitro findings. RESULTS: Cisplatin resistant ovarian cells were four-fold more resistant compared to the parental cell line. MiR-21 was overexpressed in the resistant cell line on microRNA microarray, which was subsequently validated with qRT-PCR. Using anti-microRNA inhibitors, we demonstrated that miR-21 attenuation reversed the drug resistant phenotype in both the resistant and parental cell lines. The inhibition of miR-21 induced apoptosis based on annexin V-FITC immunostaining. Using Western blot analysis, miR-21 knockdown enhanced the expression of tumor suppressor PDCD4, and attenuated apoptosis inhibitor c-IAP2. Using 101 specimens from advanced ovarian cancer patients enrolled in The Cancer Genome Atlas, we found that women with tumors that overexpressed miR-21 were associated with a shorter progression-free survival. CONCLUSION: Our data suggest that miR-21 regulates drug resistance via apoptosis and cellular survival pathways. Targeting miR-21 may have clinical utility in the treatment of resistant ovarian cancer. PMID- 24472410 TI - A prognostic nomogram to predict overall survival in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy. AB - OBJECTIVE: To develop a nomogram to predict overall survival (OS) in women with recurrent ovarian cancer treated with bevacizumab and chemotherapy. METHODS: A multicenter retrospective study was conducted. Potential prognostic variables included age; stage; grade; histology; performance status; residual disease; presence of ascites and/or pleural effusions; number of chemotherapy regimens, treatment-free interval (TFI) prior to bevacizumab administration, and platinum sensitivity. Multivariate analysis was performed using Cox proportional hazards regression. The predictive model was developed into a nomogram to predict five year OS. RESULTS: 312 women with recurrent ovarian cancer treated with bevacizumab and chemotherapy were identified; median age was 59 (range: 19-85); 86% women had advanced stage (III-IV) disease. The majority had serous histology (74%), high grade cancers (93.5%), and optimal cytoreductions (69.5%). Fifty-one percent of women received greater than two prior chemotherapeutic regimens. TFI (AHR=0.98, 95% CI 0.97-1.00, p=0.022) was the only statistically significant predictor in a multivariate progression-free survival (PFS) analysis. In a multivariate OS analysis, prior number of chemotherapy regimens, TFI, platinum sensitivity, and presence of ascites were significant. A nomogram to predict five year OS was constructed and internally validated (bootstrap-corrected concordance index=0.737). CONCLUSION: Our multivariate model identified prior number of chemotherapy regimens, TFI, platinum sensitivity, and the presence of ascites as prognostic variables for OS in women with recurrent ovarian cancer treated with bevacizumab combined with chemotherapy. Our nomogram to predict five-year OS may be used to identify women who may benefit from bevacizumab and chemotherapy, but further validation is needed. PMID- 24472411 TI - Risk stratification and prognosis determination using (18)F-FDG PET imaging in endometrial cancer patients: a systematic review and meta-analysis. AB - OBJECTIVES: In the current study, we systematically searched and analyzed the available literature on the prognostic value of semi-quantitative (18)F-FDG PET imaging (SUVmax/mean) in patients with endometrial cancer and presenting the results in a meta-analytic format. METHODS: Pubmed, SCOPUS, and ISI Web of Knowledge were searched using "endometr* AND PET" as the search algorithm. All studies evaluating the (18)F-FDG PET performance in pre-operative risk stratification or its prognostic value in patients with endometrial cancer were included. Statistical pooling of diagnostic accuracy indices was performed using random effects model. Cochrane Q test and I(2) index were used for heterogeneity evaluation. RESULTS: Ten studies (771 patients) were included in the systematic review. Pooled average SUVmax values in patients with risk factors [grade III, lymphovascular invasion (LVI), cervical invasion (CI), myometrial invasion (MI)>=50%] were statistically higher than those in patients without risk factors. Pooled HR of pre-operative SUVmax for disease free survival was 7.415 [2.892 19.432] (p=0.000046). CONCLUSION: Despite higher average SUVmax in the high-risk group compared to the low-risk group of patients with endometrial cancer, the usefulness of (18)F-FDG PET SUVmax in classifying patients into pre-defined risk groups seems to be limited. However, pre-operative SUVmax of endometrial tumors seems to be an independent prognostic marker of recurrence and death. Further large multicenter studies with adequate follow-up are needed to confirm our findings. PMID- 24472412 TI - Evidence of changes to skeletal muscle contractile properties during the initiation of disease in the ageing guinea pig model of osteoarthritis. AB - BACKGROUND: Osteoarthritis (OA) is the most common joint disorder in the world and represents the leading cause of pain and disability in the elderly population. Advancing age remains the single greatest risk factor for OA. Several studies have characterised disease development in the guinea pig ageing model of OA in terms of its joint histopathology and inflammatory cytokine profile. However, the quadriceps muscle has yet to be studied in relation to age-related disease onset or early disease progression. Therefore, we examined whether the initiation of OA in the Dunkin Hartley guinea pig is associated with changes in the quadriceps skeletal muscle. Male Dunkin Hartley guinea pigs (N = 24) were group housed with free access to standard guinea pig chow and water. At 2, 3, 5 and 7 months of age, six animals were selected based on their proximity to the median weight of the cohort. OA severity was graded at each time point by the assessment of toluidine blue stained step coronal sections of the total knee joint. Serum CTX II was measured as a potential biomarker of OA severity. Myosin Heavy Chain (MHC) isoforms were determined by a validated real-time PCR assay. Oxidative and glycolytic potential was determined in quadriceps homogenates via the measurement of ICDH and LDH activity. RESULTS: Initiation of OA in the DH strain guinea pig occurred between 2 and 3 months of age and progressed until 7 months when the final analyses were conducted. Serum CTX II significantly decreased during this early period of OA initiation and levels were unrelated to the histopathological severity of knee OA at any of the time points assessed. MHC mRNA measurements revealed a significant elevation in MHC IIX mRNA (associated with fast-twitch skeletal muscle fibres) coincident with the initiation of OA at 3 months of age, with preliminary findings suggestive of a positive correlation to OA severity at this time point. CONCLUSIONS: These preliminary findings suggest that disease initiation in the ageing guinea pig model of OA is not associated with overt quadriceps muscle atrophy but instead is coincident with altered expression of mRNAs associated with quadriceps skeletal muscle contractile properties (specifically fast-twitch MHC IIX). PMID- 24472413 TI - The "Polar Light Sign" is a useful tool to detect discrete membranous supravalvular mitral stenosis. AB - Mitral valve stenosis caused by a discrete supravalvular membrane is a rare congenital malformation haemodynamically leading to significant mitral valve stenosis. When the supravalvular mitral stenosis consists of a discrete supravalvular membrane adherent to the mitral valve, it is usually not clearly detectable by routine echocardiography. We report about the typical echocardiographic finding in three young patients with this rare form of a discrete membranous supravalvular stenosis caused by a membrane adherent to the mitral valve. These cases present a typical echocardiographic feature in colour Doppler generated by the pathognomonic supramitral flow acceleration. Whereas typical supravalvular mitral stenosis caused by cor triatriatum or a clearly visible supravalvular ring is easily detectable by echocardiography, a discrete supravalvular membrane adjacent to the mitral valve leaflets resembling valvular mitral stenosis is difficult to differentiate by routine echocardiography. In our opinion, this colour phenomenon does resemble the visual impression of polar lights in the northern hemisphere; owing to its typical appearance, it may therefore be named as "Polar Light Sign". This phenomenon may help to detect this anatomical entity by echocardiography in time and therefore improve the prognosis for repair. PMID- 24472414 TI - What factors explain pregnant women's feeding intentions in Bradford, England: a multi-methods, multi-ethnic study. AB - BACKGROUND: Using a multi-methods approach we aimed to explore the relative prediction of demographic, socioeconomic and modifiable predictors from the Theory of Planned behaviour (TPB) in explaining feeding intentions amongst a multi-ethnic sample. METHODS: 476 women completed a questionnaire at 28 weeks gestation. They were grouped into breastfeeding (N = 258), mixed-feeding (N = 50), bottle-feeding (N = 88) intenders, or a no clear intention (N = 88). Multinomial adjusted regressions explored the influence of modifiable TPB factors, along with ethnicity and socioeconomic status in predicting group membership. Free-text responses allowed women to elaborate on reasons behind their intention. RESULTS: TPB factors were significant predictors of feeding intention. Women with high intention to breastfeed were less likely to report high attitudes in any other feeding alternative. Bottle-feeding intenders reported poorer self-efficacy regarding breastfeeding compared to breastfeeding intenders (prevalence rate ratio, PRR = 0.10). Mixed and bottle-feeding intenders reported greater self-efficacy for mixed-feeding (PRR = 1.80, 5.50 respectively). Descriptive norms for mixed (PRR = 13.77) and bottle-feeding (PRR = 10.68) were predictive of mixed-feeding intention. Reasons for breastfeeding intentions related to health considerations, whilst bottle-feeding reasons related to convenience. Mixed-feeding intenders reported both breast and bottle-related factors. CONCLUSIONS: Understanding modifiable predictors related to feeding intentions like TPB factors can help professionals target appropriate interventions to encourage breastfeeding. PMID- 24472415 TI - Circulating anti-beta2-glycoprotein I antibodies of peripheral arterial disease patients trigger a genomic overexpression of Toll-like receptor 4 in endothelial cells. AB - OBJECTIVE: Circulating anti-beta2-glycoprotein I (ABGPI) antibodies are associated with peripheral arterial disease (PAD) and induce the expression of leukocyte adhesion molecules and proinflammatory cytokines by endothelial cells. Our aim is to study a transcriptional activation pathway of the innate immune system through the cellular signalling cascade triggered by receptors Toll-like receptor 2 (TLR2) and Toll-like receptor 4 (TLR4) of endothelial cells after the exposure of these cells to seropositive ABGPI human serum obtained from PAD patients. METHODS: We obtained serum samples from PAD patients and controls without PAD. ABGPI serum titer was detected using indirect immunofluorescence. Our sample was stratified into three groups: group I (PAD and ABGPI titer >=1:100; n = 15), group II (PAD and ABGPI titer <1:100; n = 15), and control participants (no PAD; n = 15). All serum samples were incubated with human aortic endothelial cell (HAEC) culture. Genomic expression of TLR2 and TLR4 receptors and their shared intracellular signalling molecules, myeloid differentiation primary response gene 88 (MyD88), and interleukin (IL)-1 receptor-associated kinase (1IRAK1), were measured after the exposure of HAECs to each serum. RESULTS: HAEC genomic expression of TLR4 was higher after the exposure to group I serum than after the exposure to group II serum (log10*10-relative quantification [RQ]: 1.80 +/- 0.42 vs 1.37 +/- 0.39; P = .01) or control serum (log10*10-RQ: 1.80 +/- 0.42 vs 1.09 +/- 0.26; P < .01). TLR4 expression was higher in group II than in the control group (log10*10-RQ: 1.37 +/- 0.39 vs 1.09 +/- 0.26; P = .04). TLR4 expression correlated with MyD88 (r = 0.54; P < .01) and IRAK1 (r = 0.55; P < .01) expression. We recorded a positive correlation between MyD88 and IRAK1 genomic expression (r = 0.58; P < .01). CONCLUSIONS: Our results suggest that serum from PAD patients with elevated ABGPI antibodies induces a genomic overexpression of TLR4 and its cellular signalling molecules in endothelial cells. PMID- 24472417 TI - Multiple chemical sensitivity caused by exposure to ignition coal fumes: a case report. AB - BACKGROUND: Although multiple chemical sensitivity (MCS) is a well-known disorder caused by environmental exposures, MCS caused by occupational exposure has been reported in Korea. Therefore, we report a MCS case caused by environmental exposure to ignition coal after a differential diagnosis to exclude other diseases. CASE REPORT: Since 2011, a 55-year-old woman had experienced edema, myalgia, and other symptoms when she smelled ignition coal near her workplace. She had been diagnosed with fibromyalgia syndrome(FMS) and was treated, with no improvement of symptoms. Since then, she showed the same symptoms after exposure to city gas, the smell of burning, and exhaust gas. To avoid triggering substances, she moved to a new house and used an air purifier. She quit her job in November 2012. After visiting our hospital, she underwent a differential diagnosis for FMS, chronic fatigue syndrome, and somatization disorder. She was diagnosed with MCS by the Korean version of the Quick Environment Exposure Sensitivity Inventory (QEESI). She was educated about the disease and to avoid triggering substances. She received ongoing treatment for her symptoms. CONCLUSION: This case showed that symptoms began after smelling ignition coal. After that, her triggers was increased such as the smell of city gas, burning, and exhaust gas. This case is the first reported in Korea of MCS due to environmental exposure after ruling out other diseases. PMID- 24472419 TI - Exome analysis resolves differential diagnosis of familial kidney disease and uncovers a potential confounding variant. AB - A girl aged 6 presented with haematuria and her sister (aged 5) presented with haematuria and proteinuria. Family history showed multiple individuals suffering from end stage renal failure from the paternal side of the pedigree. Following kidney biopsy in the father and paternal grandmother, the pathological diagnosis was of focal segmental glomerulosclerosis (FSGS). Exome sequencing was undertaken in the proband's sister and grandmother. Genetic variants shared by both affected individuals were interrogated to identify the genetic cause of disease. Candidate variants were then sequenced in all the family members to determine segregation with the disease. A mutation of COL4A5 known to cause Alport syndrome segregated with disease from the paternal side of the pedigree and a variant in NPHS1 was present in both paediatric cases and inherited from their mother. This study highlights the advantages of exome sequencing over single gene testing; disease presentation can be heterogeneous with several genes representing plausible candidates; candidate gene(s) may be unavailable as a diagnostic test; consecutive, single gene testing typically concludes once a single causal mutation is identified. In this family, we were able to confirm a diagnosis of Alport syndrome, which will facilitate testing in other family members. PMID- 24472418 TI - Dose and type of crystalloid fluid therapy in adult hospitalized patients. AB - OBJECTIVE: In this narrative review, an overview is given of the pros and cons of various crystalloid fluids used for infusion during initial resuscitation or maintenance phases in adult hospitalized patients. Special emphasis is given on dose, composition of fluids, presence of buffers (in balanced solutions) and electrolytes, according to recent literature. We also review the use of hypertonic solutions. METHODS: We extracted relevant clinical literature in English specifically examining patient-oriented outcomes related to fluid volume and type. RESULTS: A restrictive fluid therapy prevents complications seen with liberal, large-volume therapy, even though restrictive fluid loading with crystalloids may not demonstrate large hemodynamic effects in surgical or septic patients. Hypertonic solutions may serve the purpose of small volume resuscitation but carry the disadvantage of hypernatremia. Hypotonic solutions are contraindicated in (impending) cerebral edema, whereas hypertonic solutions are probably more helpful in ameliorating than in preventing this condition and improving outcome. Balanced solutions offer a better approach for plasma composition than unbalanced ones, and the evidence for benefits in patient morbidity and mortality is increasing, particularly by helping to prevent acute kidney injury. CONCLUSIONS: Isotonic and hypertonic crystalloid fluids are the fluids of choice for resuscitation from hypovolemia and shock. The evidence that balanced solutions are superior to unbalanced ones is increasing. Hypertonic saline is effective in mannitol-refractory intracranial hypertension, whereas hypotonic solutions are contraindicated in this condition. PMID- 24472420 TI - Glycemic control among patients with type 2 diabetes at a primary health care center in Oman. AB - AIMS: To determine the status of blood sugar control by using fasting blood sugar (FBS) of <=6.1 mmol/l and glycosyted hemoglobin A1c (HbAc1) of <7% as indictors of glycemic control and to assess the influence of demographic, blood pressure (BP) and lipid characteristics on glycemic control. METHODS: This retrospective study included all Omani patients with type 2 diabetes (N=177) attended a primary health care center in Al-Dakhiliya region, Oman. RESULTS: The overall mean age of the cohort was 53+/-12 years (range: 24-91) with females representing 60% (n=106) of the study sample. The study found that only 9.6% (n=17) and 35% (n=62) of the patients attained optimal FBS and HbAc1 levels, respectively. Higher HbA1c was significantly associated with higher diastolic BP (84 versus 80 mm Hg; p=0.006), higher total cholesterol (5.2 versus 4.7 mmol/l; p=0.002) and higher low-density lipoprotein cholesterol (3.8 versus 3.0 mmol/l; p=0.034). CONCLUSIONS: The results demonstrated poor glycemic control in Oman type 2 diabetic patients comparable to local and global studies especially in those hypertensive and dyslipidemic patients. Implementation of early and aggressive management of diabetes mellitus at the primary care setting is warranted. PMID- 24472421 TI - Ethnicity is an independent risk indicator when estimating diabetes risk with FINDRISC scores: a cross sectional study comparing immigrants from the Middle East and native Swedes. AB - AIMS: This study sought to compare type 2 diabetes (T2D) risk indicators in Iraqi immigrants with those in ethnic Swedes living in southern Sweden. METHODS: Population-based, cross-sectional cohort study of men and women, aged 30-75 years, born in Iraq or Sweden conducted in 2010-2012 in Malmo, Sweden. A 75g oral glucose tolerance test was performed and sociodemographic and lifestyle data were collected. T2D risk was assessed by the Finnish Diabetes Risk Score (FINDRISC). RESULTS: In Iraqi versus Swedish participants, T2D was twice as prevalent (11.6 vs. 5.8%, p<0.001). A large proportion of the excess T2D risk was attributable to larger waist circumference and first-degree family history of diabetes. However, Iraqi ethnicity was a risk factor for T2D independently of other FINDRISC factors (odds ratio (OR) 2.5, 95% CI 1.6-3.9). The FINDRISC algorithm predicted that more Iraqis than Swedes (16.2 vs. 12.3%, p<0.001) will develop T2D within the next decade. The total annual costs for excess T2D risk in Iraqis are estimated to exceed 2.3 million euros in 2005, not accounting for worse quality of life. CONCLUSIONS: Our study suggests that Middle Eastern ethnicity should be considered an independent risk indicator for diabetes. Accordingly, the implementation of culturally tailored prevention programs may be warranted. PMID- 24472422 TI - Prevalence of the Metabolic Syndrome among Korean Workers by Occupational Group: Fifth Korean National Health and Nutrition Examination Survey (KNHANES) 2010. AB - OBJECTIVES: The prevalence of the metabolic syndrome has increased rapidly in South Korea over the past 10 years. However, the occurrence of the metabolic syndrome in workers grouped according to the specific type of work is not well understood in Korea. In this study, we assessed the differences in the prevalence of the metabolic syndrome by occupational group and evaluated the risk of the metabolic syndrome among occupational groups. METHODS: From the Fifth Korean National Health and Nutrition Examination Survey (2010), 3,303 employed participants were included in this study. The unadjusted and age-adjusted prevalences of the metabolic syndrome were estimated and multiple logistic regression analysis was conducted using the presence of the metabolic syndrome as a dependent variable, and adjusting for age, education level, household income, drinking behavior, smoking status, physical activity, work hours, and work scheduling pattern. RESULTS: Among male workers, non-manual workers had the greatest age-adjusted prevalence (26.4%, 95% CI: 22.3-30.5%) among the occupational groups. In a logistic regression analysis, male manual workers had a significantly lower odds ratio for the metabolic syndrome relative to non-manual workers (0.59, 95% CI: 0.41-0.85). CONCLUSION: Our study demonstrated differences in the prevalence of the metabolic syndrome by occupational group and identified the greatest risk for the metabolic syndrome in male non-manual workers. PMID- 24472423 TI - Valproic acid promotes differentiation of hepatocyte-like cells from whole human umbilical cord-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are mesoderm-derived cells that are considered a good source of somatic cells for treatment of many degenerative diseases. Previous studies have reported the differentiation of mesodermal MSCs into endodermal and ectodermal cell types beyond their embryonic lineages, including hepatocytes and neurons. However, the molecular pathways responsible for the direct or indirect cell type conversion and the functional ability of the differentiated cells remain unclear and need further research. In the present study, we demonstrated that valproic acid (VPA), which is a histone deacetylase inhibitor, induced an increase in the expression of endodermal genes including CXCR4, SOX17, FOXA1, FOXA2, GSC, c-MET, EOMES, and HNF-1beta in human umbilical cord derived MSCs (hUCMSCs). In addition, we found that VPA is able to increase these endodermal genes in hUCMSCs by activating signal transduction of AKT and ERK. VPA pretreatment increased hepatic differentiation at the expense of adipogenic differentiation. The effects of VPA on modulating hUCMSCs fate were diminished by blocking AKT and ERK activation using specific signaling inhibitors. Together, our results suggest that VPA contributes to the lineage conversion of hUCMSCs to hepatic cell fate by upregulating the expression of endodermal genes through AKT and ERK activation. PMID- 24472424 TI - Induction of polyploidy by nuclear fusion mechanism upon decreased expression of the nuclear envelope protein LAP2beta in the human osteosarcoma cell line U2OS. AB - BACKGROUND: Polyploidy has been recognized for many years as an important hallmark of cancer cells. Polyploid cells can arise through cell fusion, endoreplication and abortive cell cycle. The inner nuclear membrane protein LAP2beta plays key roles in nuclear envelope breakdown and reassembly during mitosis, initiation of replication and transcriptional repression. Here we studied the function of LAP2beta in the maintenance of cell ploidy state, a role which has not yet been assigned to this protein. RESULTS: By knocking down the expression of LAP2beta, using both viral and non-viral RNAi approaches in osteosarcoma derived U2OS cells, we detected enlarged nuclear size, nearly doubling of DNA content and chromosomal duplications, as analyzed by fluorescent in situ hybridization and spectral karyotyping methodologies. Spectral karyotyping analyses revealed that near-hexaploid karyotypes of LAP2beta knocked down cells consisted of not only seven duplicated chromosomal markers, as could be anticipated by genome duplication mechanism, but also of four single chromosomal markers. Furthermore, spectral karyotyping analysis revealed that both of two near-triploid U2OS sub-clones contained the seven markers that were duplicated in LAP2beta knocked down cells, whereas the four single chromosomal markers were detected only in one of them. Gene expression profiling of LAP2beta knocked down cells revealed that up to a third of the genes exhibiting significant changes in their expression are involved in cancer progression. CONCLUSIONS: Our results suggest that nuclear fusion mechanism underlies the polyploidization induction upon LAP2beta reduced expression. Our study implies on a novel role of LAP2beta in the maintenance of cell ploidy status. LAP2beta depleted U2OS cells can serve as a model to investigate polyploidy and aneuploidy formation by nuclear fusion mechanism and its involvement in cancerogenesis. PMID- 24472425 TI - Renal denervation in patients with resistant hypertension: six-month results. AB - INTRODUCTION: Increased activation of the sympathetic nervous system plays a central role in the pathophysiology of hypertension (HTN). Catheter-based renal denervation (RDN) was recently developed for the treatment of resistant HTN. AIM: To assess the safety and efficacy of RDN for blood pressure (BP) reduction at six months in patients with resistant HTN. METHODS: In this prospective registry of patients with essential resistant HTN who underwent RDN between July 2011 and May 2013, the efficacy of RDN was defined as >= 10 mm Hg reduction in office systolic blood pressure (SBP) six months after the intervention. RESULTS: In a resistant HTN outpatient clinic, 177 consecutive patients were evaluated, of whom 34 underwent RDN (age 62.7 +/- 7.6 years; 50.0% male). There were no vascular complications, either at the access site or in the renal arteries. Of the 22 patients with complete six-month follow-up, the response rate was 81.8% (n=18). The mean office SBP reduction was 22 mm Hg (174 +/- 23 vs. 152 +/- 22 mm Hg; p<0.001) and 9 mm Hg in diastolic BP (89 +/- 16 vs. 80 +/- 11 mm Hg; p=0.006). The number of antihypertensive drugs (5.5 +/- 1.0 vs. 4.6 +/- 1.1; p=0.010) and pharmacological classes (5.4 +/- 0.7 vs. 4.6 +/- 1.1; p=0.009) also decreased significantly. Of the 24-hour ambulatory BP monitoring and echocardiographic parameters analyzed, there were significant reductions in diastolic load (45 +/- 29 vs. 27 +/- 26%; p=0.049) and in left ventricular mass index (174 +/- 56 vs. 158 +/- 60 g/m(2); p=0.014). CONCLUSION: In this cohort of patients with resistant HTN, RDN was safe and effective, with a significant BP reduction at six month follow-up. PMID- 24472426 TI - Association between preoperative haemoglobin concentration and cardiopulmonary exercise variables: a multicentre study. AB - BACKGROUND: Preoperative anaemia and low exertional oxygen uptake are both associated with greater postoperative morbidity and mortality. This study reports the association among haemoglobin concentration ([Hb]), peak oxygen uptake (VO2 peak) and anaerobic threshold (AT) in elective surgical patients. METHODS: Between 1999 and 2011, preoperative [Hb] and cardiopulmonary exercise tests were recorded in 1,777 preoperative patients in four hospitals. The associations between [Hb], VO2 peak and AT were analysed by linear regression and covariance. RESULTS: In 436 (24.5%) patients, [Hb] was <12 g dl-1 and, in 83 of these, <10 g dl-1. Both AT and VO2 peak rose modestly with increasing [Hb] (r2 = 0.24, P <0.0001 and r2 = 0.30, P <0.0001, respectively). After covariate adjustment, an increase in [Hb] of one standard deviation was associated with a 6.7 to 9.7% increase in VO2 peak, and a rise of 4.4 to 6.0% in AT. Haemoglobin concentration accounted for 9% and 6% of the variation in VO2 peak and AT respectively. CONCLUSIONS: To a modest extent, lower haemoglobin concentrations are independently associated with lower oxygen uptake during preoperative cardiopulmonary exercise testing. It is unknown whether this association is causative. PMID- 24472427 TI - A tool for design of primers for microRNA-specific quantitative RT-qPCR. AB - BACKGROUND: MicroRNAs are small but biologically important RNA molecules. Although different methods can be used for quantification of microRNAs, quantitative PCR is regarded as the reference that is used to validate other methods. Several commercial qPCR assays are available but they often come at a high price and the sequences of the primers are not disclosed. An alternative to commercial assays is to manually design primers but this work is tedious and, hence, not practical for the design of primers for a larger number of targets. RESULTS: I have developed the software miRprimer for automatic design of primers for the method miR-specific RT-qPCR, which is one of the best performing microRNA qPCR methods available. The algorithm is based on an implementation of the previously published rules for manual design of miR-specific primers with the additional feature of evaluating the propensity of formation of secondary structures and primer dimers. Testing of the primers showed that 76 out of 79 primers (96%) worked for quantification of microRNAs by miR-specific RT-qPCR of mammalian RNA samples. This success rate corresponds to the success rate of manual primer design. Furthermore, primers designed by this method have been distributed to several labs and used successfully in published studies. CONCLUSIONS: The software miRprimer is an automatic and easy method for design of functional primers for miR-specific RT-qPCR. The application is available as stand-alone software that will work on the MS Windows platform and in a developer version written in the Ruby programming language. PMID- 24472428 TI - Pemphigus herpetiformis: from first description until now. AB - Pemphigus herpetiformis is one of the less common forms of pemphigus, first introduced by Jablonska and colleagues in 1975. This autoimmune bullous disease combines the clinical features of dermatitis herpetiformis and the immunologic characteristics of pemphigus. The target autoantigen is usually desmoglein 1 (or less frequently desmoglein 3), although recently it has become increasingly obvious that patients with pemphigus herpetiformis also demonstrate autoantibodies against desmocollin. Here, we summarize reported cases of pemphigus herpetiformis and describe current knowledge considering epidemiology, clinical manifestations, histologic findings, immunopathology, pathophysiologic concepts, associated diseases, and treatment of this rare disorder. PMID- 24472430 TI - Adding evidence-based medicine to forensic evidence. PMID- 24472429 TI - A review of toxicity from topical salicylic acid preparations. AB - Topical salicylic acid is often used in dermatologic conditions because of its keratolytic, bacteriostatic, fungicidal, and photoprotective properties. The bioavailability of salicylic acid differs depending on the vehicle used and pH of transcellular fluids. Although rare, salicylic acid toxicity (salicylism) can occur from topical application. Physicians should be mindful of the potential for salicylism or even death from topically applied salicylic acid. PMID- 24472431 TI - Azithromycin pharmacokinetics in the serum and its distribution to the skin in healthy dogs and dogs with pyoderma. AB - Serum and skin tissue azithromycin (AZM) concentrations were analysed in healthy and pyoderma affected dogs to determine AZM pharmacokinetics and to establish the effect of disease on AZM skin disposition. AZM was administered orally to two groups of healthy dogs: (1) at 7.02 mg/kg (n=7) and (2) at 11.2mg/kg (n=9). A crossover design was used on five of them. Seven dogs with pyoderma were treated with AZM at 10.7 mg/kg. The two groups of healthy dogs received AZM once daily over three consecutive days and dogs with pyoderma received the same treatment repeated twice with an interval of 1 week. AZM concentrations were determined by liquid chromatography-tandem mass spectrometry. AZM was rapidly absorbed and slowly excreted. In healthy dogs, maximum serum concentrations appeared 2h after administration and were (mean +/- standard deviation) 0.60 +/- 0.25 MUg/mL and 1.03 +/- 0.43 MUg/mL, and the half-lives were 49.9 +/- 5.10 and 51.9 +/- 6.69 h for doses of 7.02 and 11.2mg/kg, respectively. Clearance (CL0-24/F) was similar in both dosing groups (1.24 +/- 0.24 and 1.29 +/- 0.24 L/h/kg) and the respective mean residence time (MRT0-24) was 11.1 +/- 0.8 and 8.4 +/- 2.2h. The skin concentration in healthy dogs was 3.5-6.5 and 5.0-12.0 times higher than the corresponding serum concentration after the two doses and increased after the cessation of AZM administration. The ratio increased significantly in inflamed tissue (9.5-26.2). PMID- 24472432 TI - High order shear horizontal modes for minimum remnant thickness. AB - Thickness mapping in aging structures suffering from corrosion is challenging especially when the structure is only partially accessible. In plates the high order shear horizontal guided wave modes all have a cutoff frequency thickness product below which they cannot propagate. This property is potentially attractive to estimate the minimum remnant thickness between two transducers. When using a source and a sensor array it is possible to control the number of modes being excited and the size of the region interrogated by the technique. Finite element simulations were used to show that by exciting multiple guided wave modes simultaneously and identifying which modes are received by a sensor array it is possible to estimate the minimum remaining thickness along the propagation path. Initial experimental results showed excellent agreement with the finite element simulations when the plate is uniform and with a thickness reduction between the source and the sensor arrays the minimum remnant thickness was underestimated by approximately 20%. PMID- 24472433 TI - Raman enhancement by graphene-Ga2O3 2D bilayer film. AB - 2D beta-Ga2O3 flakes on a continuous 2D graphene film were prepared by a one-step chemical vapor deposition on liquid gallium surface. The composite was characterized by optical microscopy, scanning electron microscopy, Raman spectroscopy, energy dispersive spectroscopy, and X-ray photoelectron spectroscopy (XPS). The experimental results indicate that Ga2O3 flakes grew on the surface of graphene film during the cooling process. In particular, tenfold enhancement of graphene Raman scattering signal was detected on Ga2O3 flakes, and XPS indicates the C-O bonding between graphene and Ga2O3. The mechanism of Raman enhancement was discussed. The 2D Ga2O3-2D graphene structure may possess potential applications. PMID- 24472435 TI - Comparison of the accuracy of monofilament testing at various points of feet in peripheral diabetic neuropathy screening. AB - BACKGROUND: Diabetic Peripheral Neuropathy is one of the most prevalent complications of diabetes mellitus. The development and progression of such complications are responsible for much of the morbidity and mortality. The purpose of this study was to evaluate the effectiveness of Semmes-Weinstein monofilament ten gram in 3, 4, eight and ten points in the screening of diabetic peripheral neuropathy in patients with diabetes mellitus. METHODS: In a descriptive correlational design, 150 patients with diabetes mellitus were selected using convenience sampling. All patients were evaluated for sensory neuropathy using ten gram Semmes-Weinstein Monofilaments and questionnaire on neuropathy symptoms. In the next phase, nerve conduction velocity was examined. The most common subjective symptoms were paresthesia of both feet, pain in feet, burning sensation in the extremities and numbness in the extremities. RESULTS: The results showed that the sensitivity of Monofilament in three and four points were 35.9 to 53.8 present and 38.5 to 51.3 percent respectively. Specificity of Monofilament the same points, were 73.9 to 84.7 and 73 to 87.4 percent respectively. Monofilament sensitivity at eight and ten points were 38.5 to 61.5 and 64.1 to 30.8 percent respectively. Also, specificity of the same points were 77.5 to 95.5 and 64 to 89.2 percent respectively. It was revealed that the difference sensitivity and specificity of Monofilament in three and four points with sensitivity and specificity in eight and ten point is not statistically significant. CONCLUSIONS: This study showed that Semmes-Weinstein monofilament can easily use as a simple and inexpensive device for screening. Since increasing the number of points it was not significantly difference. Therefore, we suggest that screening for diabetic peripheral neuropathy, especially in large populations to avoid wasting time on Monofilament application, areas like three or four points eight and ten points could be used. PMID- 24472434 TI - A comprehensive look at transcription factor gene expression changes in colorectal adenomas. AB - BACKGROUND: Biological processes are controlled by transcription networks. Expression changes of transcription factor (TF) genes in precancerous lesions are therefore crucial events in tumorigenesis. Our aim was to obtain a comprehensive picture of these changes in colorectal adenomas. METHODS: Using a 3-pronged selection procedure, we analyzed transcriptomic data on 34 human tissue samples (17 adenomas and paired samples of normal mucosa, all collected with ethics committee approval and written, informed patient consent) to identify TFs with highly significant tumor-associated gene expression changes whose potential roles in colorectal tumorigenesis have been under-researched. Microarray data were subjected to stringent statistical analysis of TF expression in tumor vs. normal tissues, MetaCore-mediated identification of TF networks displaying enrichment for genes that were differentially expressed in tumors, and a novel quantitative analysis of the publications examining the TF genes' roles in colorectal tumorigenesis. RESULTS: The 261 TF genes identified with this procedure included DACH1, which plays essential roles in the proper proliferation and differentiation of retinal and leg precursor cell populations in Drosophila melanogaster. Its possible roles in colorectal tumorigenesis are completely unknown, but it was found to be markedly overexpressed (mRNA and protein) in all colorectal adenomas and in most colorectal carcinomas. However, DACH1 expression was absent in some carcinomas, most of which were DNA mismatch-repair deficient. When networks were built using the set of TF genes identified by all three selection procedures, as well as the entire set of transcriptomic changes in adenomas, five hub genes (TGFB1, BIRC5, MYB, NR3C1, and TERT) where identified as putatively crucial components of the adenomatous transformation process. CONCLUSION: The transcription-regulating network of colorectal adenomas (compared with that of normal colorectal mucosa) is characterized by significantly altered expression of over 250 TF genes, many of which have never been investigated in relation to colorectal tumorigenesis. PMID- 24472436 TI - Efficacy of face masks and respirators in preventing upper respiratory tract bacterial colonization and co-infection in hospital healthcare workers. AB - OBJECTIVE: We compared the efficacy of medical masks (MM) and N95 respirators (N95) in preventing bacterial colonization/infection in healthcare workers (HCWs). METHODS: A cluster randomized clinical trial (RCT) of 1441 hospital HCWs randomized to medical masks or N95 respirators, and compared to 481 control HCWs, was performed in Beijing, China, during the winter season of 2008-2009. Participants were followed for development of clinical respiratory illness (CRI). Symptomatic subjects were tested for Streptococcus pneumoniae, Bordetella pertussis, Chlamydia pneumoniae, Mycoplasma pneumoniae or Haemophilus influenza type B by multiplex polymerase chain reaction (PCR). RESULTS: The rate of bacterial colonization was 2.8% in the N95 group (p=0.02), 5.3% among medical mask users (p<0.01) and 7.5% among the controls (p=0.16). N95 respirators were significantly protective (adjusted RR 0.34, 95% CI: 0.21-0.56) against bacterial colonization. Co-infections of two bacteria or a virus and bacteria occurred in up to 3.7% of HCWs, and were significantly lower in the N95 arm. CONCLUSIONS: N95 respirators were significantly protective against bacterial colonization, co colonization and viral-bacterial co-infection. We showed that dual respiratory virus or bacterial-viral co-infections can be reduced by the use of N95 respirators. This study has occupational health and safety implications for health workers. PMID- 24472437 TI - Interaction network mapping among IL-32 isoforms. AB - IL-32 has been studied for its pleiotropic effects ranging from host immune responses to cell differentiation. Although several IL-32 isoforms have been characterized for their effects on cells, the roles of the others remain unclear. We previously reported that IL-32delta interacted with IL-32beta and inhibited IL 32beta-mediated IL-10 production. Thus, we performed comprehensive analyses to reveal more interactions between IL-32 isoforms in this study. We screened the interactions of 81 combinations of nine IL-32 isoforms by using a yeast two hybrid assay, which identified 13 heterodimeric interactions. We verified these results by using reciprocal immunoprecipitation assays and reconfirmed 10 interactions, and presented the interaction network map between IL-32 isoforms. Our data suggest that IL-32 may have diverse intracellular effects through the interactions with its different isoforms. PMID- 24472438 TI - Molecular basis of the binding of YAP transcriptional regulator to the ErbB4 receptor tyrosine kinase. AB - The newly discovered transactivation function of ErbB4 receptor tyrosine kinase is believed to be mediated by virtue of the ability of its proteolytically cleaved intracellular domain (ICD) to physically associate with YAP2 transcriptional regulator. In an effort to unearth the molecular basis of YAP2 ErbB4 interaction, we have conducted a detailed biophysical analysis of the binding of WW domains of YAP2 to PPXY motifs located within the ICD of ErbB4. Our data show that the WW1 domain of YAP2 binds to PPXY motifs within the ICD in a differential manner and that this behavior is by and large replicated by the WW2 domain. Remarkably, while both WW domains absolutely require the integrity of the PPXY consensus sequence, non-consensus residues within and flanking this motif do not appear to be critical for binding. In spite of this shared mode of binding, the WW domains of YAP2 display distinct conformational dynamics in complex with PPXY motifs derived from ErbB4. Collectively, our study lends new insights into the molecular basis of a key protein-protein interaction involved in a diverse array of cellular processes. PMID- 24472439 TI - Cryopreservation with dimethyl sulfoxide prevents accurate analysis of skinned skeletal muscle fibers mitochondrial respiration. AB - Impact of cryopreservation protocols on skeletal muscle mitochondrial respiration remains controversial. We showed that oxygen consumption with main mitochondrial substrates in rat skeletal muscles was higher in fresh samples than in cryopreserved samples and that this difference was not fixed but grow significantly with respiration rates with wide fluctuations around the mean difference. Very close results were observed whatever the muscle type and the substrate used. Importantly, the deleterious effects of ischemia-reperfusion observed on fresh samples vanished when cryopreserved samples were studied. These data demonstrate that this technic should probably be performed only extemporaneously. PMID- 24472440 TI - Historical review of the List of Occupational Diseases recommended by the International Labour organization (ILO). AB - The list of occupational diseases established in the international and national legal system has played important roles in both prevention of and compensation for workers' diseases. This report reviewed the historical development in the ILO list of occupational diseases and suggested implications of the trends. Since the first establishment of the ILO list of occupational diseases in 1925, the list has played a key role in harmonizing the development of policies on occupational diseases at the international level. The three occupational diseases (anthrax, lead poisoning, and mercury poisoning) in the first ILO list of occupational diseases, set up in 1925 as workmen's compensation convention represented an increase of occupational diseases from the Industrial Revolution. Until the 1960s, 10 occupational diseases had been representative compensable occupational diseases listed in Convention No. 121, which implies that occupational diseases in this era were equated to industrial poisoning. Since 1980, with advancements in diagnostic techniques and medical science, noise-induced hearing loss, and several bronchopulmonary diseases have been incorporated into the ILO occupational list. Since 2002, changes in the structure of industries, emerging new chemicals, and advanced national worker's compensation schemes have provoked the ILO to revise the occupational disease list. A new format of ILO list appended in Recommendation 194 (R194) was composed of two dimensions (causes and diseases) and subcategories. Among 50 member states that had provided their national lists of occupational diseases, until 2012 thirty countries were found to have the list occupational diseases having similar structure to ILO list in R194. PMID- 24472441 TI - Co-occurring Duchenne muscular dystrophy and hypertrophic cardiomyopathy in an adult with atypical cardiac phenotype. AB - We present the case of a 29-year-old man with mutation-positive Duchenne muscular dystrophy and mutation-positive hypertrophic cardiomyopathy. His cardiac phenotype has characteristics of both disorders; he manifests sub-epicardial left ventricular free wall late gadolinium enhancement that is consistent with Duchenne cardiomyopathy, as well as asymmetric ventricular septal hypertrophy, hyperdynamic left ventricular systolic function, and septal mid-myocardial late gadolinium enhancement, which are characteristic of hypertrophic cardiomyopathy. PMID- 24472442 TI - In vitro approaches for detection of chemical sensitization. AB - Concerns, legislation and research needs have precipitated developments such as the mode of action concept, the Tox21 strategy, the concept of pathways of toxicity and the adverse outcome pathway framework. New technologies and paradigms are currently transforming these concepts into applicable animal-free toxicity testing systems. The adverse outcome pathway framework provides a structure for collecting, organizing and evaluating the available data that describe the compound and the events resulting in an adverse outcome at a biological level of organization. The current chapter intends to provide a non exhaustive review of (i) our current understanding of the molecular mechanisms driven the key events of the mode of action for sensitization induction by chemicals, (ii) the tools that were developed on the basis of the available knowledge and (iii) the major gaps that need to be filled. PMID- 24472444 TI - Standing on the shoulders of giants. PMID- 24472443 TI - Less invasive methods of advanced hemodynamic monitoring: principles, devices, and their role in the perioperative hemodynamic optimization. AB - The monitoring of the cardiac output (CO) and other hemodynamic parameters, traditionally performed with the thermodilution method via a pulmonary artery catheter (PAC), is now increasingly done with the aid of less invasive and much easier to use devices. When used within the context of a hemodynamic optimization protocol, they can positively influence the outcome in both surgical and non surgical patient populations. While these monitoring tools have simplified the hemodynamic calculations, they are subject to limitations and can lead to erroneous results if not used properly. In this article we will review the commercially available minimally invasive CO monitoring devices, explore their technical characteristics and describe the limitations that should be taken into consideration when clinical decisions are made. PMID- 24472445 TI - Blockage below the belt: Leriche syndrome. PMID- 24472447 TI - [Why a scientific review in French?]. PMID- 24472446 TI - An absolute obstacle: cardiac metastasis of synovial sarcoma. PMID- 24472448 TI - [Baclofen and other GABAB receptor agents are allosteric modulators of the CXCL12 chemokine receptor CXCR4]. PMID- 24472450 TI - [An " inflamed " relationship between GPS2 and the adipose tissue in human obesity]. PMID- 24472449 TI - [A KRAB/KAP1-miRNA cascade regulates erythropoiesis through stage-specific control of mitophagy]. PMID- 24472451 TI - [Cortex softening: a prerequisite for the asymmetry of oocyte first division]. PMID- 24472452 TI - [The ribosome: a new player in tumorigenesis?]. PMID- 24472453 TI - [The adaptation of lentiviruses to apes was a crucial step in the origin of HIV 1]. PMID- 24472454 TI - [New genetic determinants of glycemic traits: insights in biological pathways of glucose homeostasis]. PMID- 24472455 TI - [Nuclear migration in neuronal progenitors: when the brain plays yo-yo]. PMID- 24472456 TI - [Towards a bivalent prophylactic vaccine against hepatitis B and C viruses?]. PMID- 24472457 TI - [When regulation of cell energy meets regulation of inflammation: AMPK triggers skewing of macrophage phenotype during skeletal muscle regeneration]. PMID- 24472458 TI - [A brand new face for the ancestor of jawed vertebrates]. PMID- 24472459 TI - [Novel deglycosylation-independent roles for peptide N-glycanase]. AB - The primary function of peptide N-glycanase (PNGase) is thought to be the deglycosylation of endoplasmic reticulum associated degradation (ERAD) substrates. However, inhibition of PNGase appears to have little effect upon the destruction rate of many ERAD substrates, and recent data demonstrate deglycosylation-independent functions for PNGase. Whatever the roles of PNGase turn out to be, the identification of a patient presenting with PNGase deficiency will advance our understanding of the importance of this multifunctional protein in human physiology. PMID- 24472460 TI - [Complex chromosomal rearrangements: a paradigm for the study of chromosomal instability]. AB - Complex chromosomal rearrangements (CCR) include diverse structural anomalies leading to complex karyotypes which are difficult to interpret. Although karyotype analysis has been able to identify a large number of these rearrangements and to distinguish de novo and familial events, it is the advent of molecular cytogenetic and sequence analysis techniques which have led to an understanding of the molecular mechanisms underlying the formation of CCR. The diversity and high level of complexity inherent to CCR raises questions about their origin, their ties to chromosome instability and their impact in pathology. Today it is possible to precisely characterize CCR and to offer carriers sophisticated diagnostic techniques, such as preimplantation diagnosis. However, the meiotic segregation of these rearrangements remains very complex. PMID- 24472461 TI - [Inflammatory dendritic cells]. AB - Dendritic cells are a rare and heterogeneous population of professional antigen presenting cells. Several murine dendritic cell subpopulations have been identified that differ in their phenotype and functional properties. In the steady state, committed dendritic cell precursors differentiate into lymphoid organ-resident dendritic cells and migratory tissue dendritic cells. During inflammation appears an additional dendritic cell subpopulation that has been termed " inflammatory dendritic cells ". Inflammatory dendritic cells differentiate in situ from monocytes recruited to the site of inflammation. Here, we discuss how mouse inflammatory dendritic cells differ from macrophages and from other dendritic cell populations. Finally, we review recent work on human inflammatory dendritic cells. PMID- 24472462 TI - [Anti-HIV antibodies: multiple antiviral activities]. AB - Sexual transmission is currently the major route of HIV infection worldwide. Neutralizing antibodies (IgG) have demonstrated their role in the protection from experimental challenge in non-human primate's model. However, these types of antibodies display very specific characteristics and are extremely difficult to induce. Interestingly, antibodies devoid of neutralizing activity have demonstrated additional inhibitory mechanisms dependant of their binding to Fc receptors expressed on antigen presenting cells. These cells may play decisive role at early sexual transmission as they have been proposed to be the first HIV target at the mucosal site. Data from in vivo studies and recent findings following clinical assays demonstrated the importance of these Fc-mediated antibodies dependant mechanism in protection against HIV. Therefore new vaccination strategies including the induction of such type of activities, in addition to neutralizing antibodies, should be developed. PMID- 24472463 TI - [The drosophila hematopoietic niche]. AB - Stem cells are required for both tissue renewal and repair in response to injury. The maintenance and function of stem cells is controlled by their specific cellular microenvironment called "niche". Hematopoietic stem cells (HSC) that give rise to all blood cell types have been extensively studied in mammals. Genetic and molecular analyses performed in mice identified several signaling pathways involved in the cellular communications between HSC and their niche. However, hematopoietic niche plasticity remains poorly understood. The discovery of a Drosophila hematopoietic niche, called PSC, established a new model to decipher the niche function in vivo. Size control of the PSC is essential to maintain hematopoietic tissue homeostasis and a molecular cascade controlling the PSC cell number has been characterized. Novel parallels between Drosophila and mammalian hematopoietic niches open new perspectives for studies of HSC biology in human. PMID- 24472464 TI - [New promises for metformin: advances in the understanding of its mechanisms of action]. AB - Metformin is currently the drug of first choice for the treatment of type 2 diabetes. However, although prescribed since the end of the 1950s, the mechanism of action of metformin remains as yet incompletely understood but recent work has unveiled novel and surprising properties. Epidemiological reports have suggested that metformin protects against heart failure and has antitumor properties independent of its anti-hyperglycemic effect. Here, we review the proposed mechanisms for metformin action in diabetes, cardiovacular diseases and cancer. PMID- 24472465 TI - [What the whiskers tell the tactile brain]. AB - The rodent whisker system became one of the main system models for the study of the functional properties of sensory neurons. This is due on one hand to the detailed knowledge that we have on the afferent pathways linking the mechanoreceptors in the follicles to the primary somatosensory cortex and on the other hand to the possibility of controlling the sensory input at a micrometer and millisecond scale. The observation of the natural use of the whiskers by rodents indicates that exploration of objects and textures imply multiple contacts with tens of whiskers simultaneously. We have studied the neural code in the barrel cortex, which receives tactile information from the whiskers. By combining multi-electrode recordings and controlled multiwhisker tactile stimulation with theoretical analysis, we have observed a dependence of neural responses on the statistics of the sensory input. Several classes of neuronal responses, similar to those described in a number of cortical visual areas, were observed in the same cortical volume, indicating that various coding schemes are implemented in the same cortical network and can be put into play differentially to cope with the changing statistics of the peripheral stimuli. PMID- 24472466 TI - [The development of the international network of Pasteur Institutes from 2003 to 2013]. AB - The expansion of the Institut Pasteur international network from 2003 to the present day, has coincided with the strengthening of a common legal framework, associated to a Declaration of shared scientific and ethical values qualified as "Pasteurian". The article explores the originality of the network, emphasises the importance of its reference to a shared history, and hypothesizes the ongoing fabrication of an esprit de corps uniting scientists coming from a variety of communities. The RIIP may thus be the tool of a scientific diplomacy working to lessen the inequalities in the domain of scientific and medical knowledge, in an unstable world. PMID- 24472467 TI - [Cash value body, care of the accident and the injured body]. AB - In our contemporary societies, physical injury resulting from a severe accident triggers a support process involving medical care and financial compensation, calculated according to the technical expertise of disability. Since 1958, the obligation for every individual to purchase an insurance has created the legal concept of pretium doloris ("prize of the pain") referring to a damage due to the physical and moral suffering of an individual. This concept also involves the idea that the injured person should be defined as a "victim" of a "prejudice" from which this person is entitled to expect compensation. The notion of compensation, whether financial or through medical care, contribute to give a social definition of the accident conceived as an existential phenomenon. In this paper, we undertake a philosophical analysis of these categories that allows to address the issue of care and that of evaluation - including financial - of the physical injury caused by the accident. We will see in particular that the problem of compensation refers both to the status of the body and the "recognition" of physical disability in financial terms. More broadly, the study of the repairing process of the physical injury will allow us to examine the contemporary issue of "cash value body" from a new perspective. PMID- 24472468 TI - [An invasion of non-invasive diagnostic tests]. AB - Non-invasive prenatal testing is becoming commonplace, but, in addition, other tests using only a blood sample are being developed and will have a significant impact, notably in oncology. PMID- 24472469 TI - The Association between Shift Work and the Metabolic Syndrome in Female Workers. AB - OBJECTIVE: This study aimed to determine identify any association between shift work and the metabolic syndrome by comparing the prevalence rates of the metabolic syndrome in shift work groups and daytime work groups for female workers. METHODS: Based on data from health examinations carried out from April to December of 2012, we selected as our subjects 254 female workers from the Daegu area Dyeing Industrial Complex. We diagnosed the metabolic syndrome using the examination results, and information about age, whether or not they did shift work, job type, smoking habits, drinking habits, exercise habits, and past medical history was collected through self-administered questionnaire surveys and face-to-face interviews. The variables found in a univariate analysis to be significant in the occurrence of the metabolic syndrome - age, drinking habits, exercise habits, and shift work - were included in a logistic regression analysis of the risk of the metabolic syndrome for female workers. RESULTS: The prevalence rates of the metabolic syndrome for the total group of study subjects was 11.8%, for daytime workers was 2.8%, and for shift workers was 15.3%. A logistic regression analysis of the odds of the metabolic syndrome for female workers was conducted that included factors associated with the occurrence of the metabolic syndrome: age, drinking habits, exercise habits, and shift work. The results revealed that the odds ratio of the metabolic syndrome in the shift work group, 6.30 (95% CI 1.24-32.15), was significantly higher when compared with the daytime work group. CONCLUSION: Shift work appears to have an association with the metabolic syndrome in female workers. Accordingly, we believe that the attention of government agencies and business owners is needed together with the individual practice of health behaviors to manage the metabolic syndrome for the prevention of cardiovascular disease in female shift workers. PMID- 24472470 TI - Distinct contextual roles for Notch signalling in skeletal muscle stem cells. AB - Notch signalling acts in virtually every tissue during the lifetime of metazoans. Recent studies have pointed to multiple roles for Notch in stem cells during quiescence, proliferation, temporal specification, and maintenance of the niche architecture. Skeletal muscle has served as an excellent paradigm to examine these diverse roles as embryonic, foetal, and adult skeletal muscle stem cells have different molecular signatures and functional properties, reflecting their developmental specification during ontology. Notably, Notch signalling has emerged as a major regulator of all muscle stem cells. This review will provide an overview of Notch signalling during myogenic development and postnatally, and underscore the seemingly opposing contextual activities of Notch that have lead to a reassessment of its role in myogenesis. PMID- 24472471 TI - How we treat metastatic colon cancer in older adults. AB - The past decade has seen unprecedented advancements in our ability to treat patients with metastatic colorectal cancer. When applying these advances--hepatic resection and multi-agent chemotherapy--to the care of older patients, it is essential to first perform some assessment of function beyond performance status and to elicit feedback from the patient about how he/she values quality versus quantity of life. For robust older patients with potentially surgically resectable oligometastatic cancer, we recommend a standard approach of surgery with perioperative chemotherapy. However, operative risk increases with age, and careful discussion about prognosis is warranted. For patients with unresectable cancer, first-line chemotherapy with either 5-fluoruracil/leucovorin alone, or with a 20% dose reduced FOLFOX or FOLFIRI regimen, is well tolerated by older patients. Either dose escalation or addition of a second drug can typically be undertaken after 1-2 cycles. First-line bevacizumab with chemotherapy is warranted in those with low risk for atherothrombotic complications. EGFR inhibitors with combination chemotherapy for KRAS wild type cancers offer the best response rates, but toxicity can be difficult and may be best reserved for second-line in all but the fittest elderly. In second-line, we routinely offer continued chemotherapy with the agents that the patient has not yet received. The role of aflibercept and regorafenib has not been well studied in the elderly, but they are both reasonable options for patients with good function and no contraindication. With this cautious approach older patients can be expected to maintain a good quality of life during treatment for metastatic colorectal cancer. PMID- 24472472 TI - A phase II trial of frontline capecitabine and bevacizumab in poor performance status and/or elderly patients with metastatic colorectal cancer. AB - OBJECTIVES: This study aims to determine the efficacy and tolerability of capecitabine (CAP) plus bevacizumab (BEV) as treatment for frontline metastatic colorectal cancer (mCRC) in frail and/or elderly patients. MATERIALS AND METHODS: This was an open label, multi-site, single arm, phase II study in frontline mCRC. In this study, patients (pts) who were frail (ECOG 2) or older patients with ECOG 1 performance status (PS) received CAP (1000 mg/m(2) bid, 14 days of every 21 days) plus BEV (7.5mg/kg iv once every 21 days). The primary objective was progression free survival (PFS). Secondary objectives were overall response rate (ORR) and toxicity. RESULTS: In terms of patients: 50 were enrolled; 5 withdrew consent prior to treatment; 45 were treated, and 41 were evaluable. The mean age was 75.9 (range 54-93) and 62% had an ECOG 2 PS. The median PFS was 6.87 months (95% CI, 5.1-11.5 months) and median overall survival was 12.7 months (95% CI, 6.9-12.7 months). The most common grades 3-4 toxicities were: diarrhea (17.8%), fatigue (13.3%), hand-foot syndrome (13.3%), dehydration (8.9%), hypertension (6.7%) and vomiting (6.7%). CONCLUSIONS: The results of this trial support the use of CAP plus BEV as first-line treatment for frail/elderly patients with metastatic CRC. The ORR (40%) is comparable to pooled data in elderly on fluorouracil (5-FU)+BEV. The median PFS (7.2 months) in this study is slightly lower than that seen with 5-FU+BEV but this study had a high percentage of ECOG PS 2 patients. Side effects were manageable with no new safety signals. PMID- 24472473 TI - Risk factors for in-hospital mortality and prolonged length of stay in older patients with solid tumor malignancies. AB - OBJECTIVE: Hospitalized adult patients with cancer and with major comorbidities have higher mortality rates and longer duration of hospitalization. There is limited understanding of risk factors that contribute to prolonged hospitalization and mortality in older patients with solid tumors. MATERIALS AND METHODS: Risk factors associated with in-hospital mortality and prolonged length of stay (LOS) in older patients with cancer were investigated in a retrospective cohort study. Data from the University HealthSystem Consortium database included 386,377 patients age >= 65 years with solid tumors hospitalized between 1995 and 2003 at 133 U.S. academic medical centers. RESULTS: The overall mortality rate was 7.3%. Mortality in older patients with cancer was strongly associated with longer LOS. Almost twice as many deaths were observed among those with LOS >= 10 days (p<0.0001). Nearly 38% of older cancer patients who died in hospital had potentially curable disease. Primary central nervous system malignancies were most strongly associated with in-hospital mortality (OR=1.81; 1.59-2.07), followed by esophageal (OR=1.74; 1.54-1.97) and lung cancer (OR=1.57; 1.43-1.72). Male gender, African-American race, and Hispanic and Asian race/ethnicity were associated with increased risk of mortality (p<0.0001). Additional risk factors included metastatic disease, infection, neutropenia, renal, lung, hepatic, cerebrovascular disease, arterial/venous thromboembolism, heart failure, and red blood cell transfusion. Risk factors for prolonged LOS included gastric cancer, infection, venous thromboembolism and red blood cell transfusion. CONCLUSIONS: Prolonged LOS was strongly associated with mortality. Risk factors such as infection, neutropenia and red blood cell transfusion, when modified, could potentially reduce rates of prolonged LOS and mortality in older patients with cancer. PMID- 24472474 TI - The relationship of self-rated health with functional status, toxicity and mortality: results of a prospective pilot study of older patients with newly diagnosed cancer. AB - OBJECTIVES: To determine the association between self-rated health (SRH) and functional status, comorbidity, toxicity of treatment and mortality in older patients with newly-diagnosed cancer. MATERIALS AND METHODS: Patients aged 65 and over, newly diagnosed were recruited at the Jewish General Hospital, Montreal, Canada. SRH and functional status [instrumental activities of daily living (IADL), basic activities of daily living (ADL), Eastern Cooperative Oncology Group performance status (ECOG PS), frailty markers and number of comorbid conditions] were evaluated prior to the start of treatment, and at 3, 6 and 12 months (SRH only). Treatment toxicity and mortality data were abstracted from the chart. Logistic regression was also used to examine the relationship between functional status, comorbidity and SRH at baseline. Logistic and Cox regression were used to examine the association between baseline SRH and treatment toxicity/time to death. RESULTS: There were 112 participants enrolled on this study (median age 74.1). At baseline, 74 patients (66.1%) had a good SRH and 38 patients (33.9%) had poor SRH. Only an increasing number of comorbid conditions was associated with poor SRH at baseline in both univariate and multivariable analysis. We found no association between SRH and toxicity or mortality. CONCLUSION: A substantial proportion had poor SRH prior to and during cancer treatment. An increasing number of comorbidities was associated with poor SRH at baseline. SRH did not predict toxicity or mortality. Attention to comorbid conditions in older patients with cancer is warranted considering their impact on SRH in this population. PMID- 24472476 TI - Predicting chemotherapy toxicity in older adults with lung cancer. AB - OBJECTIVE: Existing oncology performance status measurements are used to predict chemotherapy toxicity in all patients with cancer, regardless of age. A new predictive model for grade 3-5 chemotherapy toxicities was developed by Hurria et al. (2011).(1) As the model is from the Cancer and Aging Research Group (CARG), we call it the CARG toxicity tool. We investigated whether this tool can usefully characterize chemotherapy risks for older patients with lung cancer. METHODS: Patients from our hospital aged >= 65 years with lung cancer completed a questionnaire form prior to chemotherapy. We reviewed patients' chemotherapy courses to identify toxicities, and used the toxicity tool to score the patients' outcomes. The sample was divided into three risk strata based on approximate risk score quartiles, with the middle two quartiles combined. Chi-square statistics were used to verify differences among groups. RESULTS: Between September 2011 and September 2012, 120 patients with lung cancer (87 males and 33 females) >= 65 years of age (mean: 69 years; range: 65-82 years) were enrolled in the study. In our sample, 35% of subjects had >= one grade 3-5 hematologic toxicity; 48% had >= one grade 3-5 nonhematologic toxicity. Toxicity varied significantly among the risk groups (P<0.001), but the incidence of toxicity did not vary significantly among the KPS-based risk groups (P=0.322). CONCLUSION: This new CARG toxicity tool can be used to better distinguish the risks of chemotherapy toxicity than the KPS for older patients with lung cancer, and may change the standards for oncology assessments. PMID- 24472475 TI - Survival and selected outcomes of older adults with locally advanced head/neck cancer treated with chemoradiation therapy. AB - OBJECTIVES: Chemoradiation therapy (CRT) remains a potentially curative treatment in patients with locally advanced head/neck cancer (LA-HNC). However, survival and other outcomes in older patients with head/neck cancer receiving chemoradiotherapy are not well established. This study was performed to elucidate selected outcomes in this patient population. MATERIALS AND METHODS: Retrospective study of LA-HNC patients >= 70 years of age who had received 5 fluorouracil-hydoxyurea-based CRT with a minimum of 3 years of follow up after therapy initiation was performed. Pre-treatment patient- and cancer-related characteristics were recorded. Survival data in addition to gastrostomy tube utilization, swallowing function, and hematologic toxicity were captured. RESULTS: Eighty-nine patients treated between 1997 and 2009 were eligible for analysis (median age, 76 years; range, 70-94; male, 61%; ECOG PS, 0-1 43%; stage IVA/B, 71%). 86 were evaluable for survival analysis. 5-year overall and event free survival were both at 32% with a median follow-up time of 39.2 months. The majority (86.5%) were able to complete all planned treatment cycles. A significant proportion of patients, however, required gastrostomy tube during CRT (62%) and developed aspiration during swallowing evaluation post-treatment (44%). Several patients required hospice (9%) or skilled nursing facility (13%) referrals during treatment. CONCLUSION: Select older adults with LA-HNC can still experience long-term benefits despite 5-year survival rates lower than those historically reported in younger patients undergoing identical CRT regimens although potentially at higher risk for acute toxicities. Assessment and selection of those who can tolerate more intense combined-modality strategies and their long-term outcomes merit further larger, prospective studies. PMID- 24472477 TI - Bi-weekly liposomal doxorubicin for advanced breast cancer in elderly women (>= 70 years). AB - BACKGROUND: We conducted a multicenter prospective trial to assess tolerability and activity of pegylated liposomal doxorubicin (PLD) in women >= 70 years with locally-advanced or metastatic breast cancer. PATIENTS AND METHODS: All patients underwent Multidimensional Geriatric Assessment (MGA). Frail patients were excluded. Normal cardiac function was required for inclusion. A bi-weekly schedule of PLD at 20mg/mq was adopted. RESULTS: Thirty-two patients were enrolled with a median age of 78 years, 78.1% with visceral involvement, and 37.6% previously treated with chemotherapy for advanced disease. A mean of 7.8 cycles were delivered (range 1 to 20), with a median cumulative dose intensity of 8.9 mg/m(2)/week. Grade 3-4 toxicities were anemia (6.3%), palmar-plantar erythrodysesthesia (6.3%), mucositis (6.3%), infection (3.1%), and pulmonary embolism (3.1%). No cardiac events were registered. Causes of treatment interruption were maximal response (15.6%), progression (40.6%), refusal/loss to follow-up (28.1%), toxicities (9.4%), or other (6.3%). Response was obtained in 33.3% of 27 evaluable patients; median time to progression (TTP) was 10.3 months. MGA status (vulnerable vs. fit) did not have an impact on response, progression, and toxicity. CONCLUSIONS: Bi-weekly PLD is well tolerated in both fit and vulnerable patients, with an apparently fairly good response rate and TTP (possibly biased by subsequent endocrine therapy and loss to follow-up). Close observation of patients is recommended in order to avoid early refusal/loss to follow-up. PMID- 24472478 TI - Efficacy and safety of ixabepilone plus capecitabine in elderly patients with anthracycline- and taxane-pretreated metastatic breast cancer. AB - OBJECTIVES: Data on chemotherapy regimens in elderly patients with metastatic breast cancer (MBC) are limited. The aim of this retrospective pooled analysis was to determine efficacy and safety of ixabepilone plus capecitabine versus capecitabine alone in patients with MBC aged >= 65 years. MATERIALS AND METHODS: A total of 1973 patients with MBC previously treated with or resistant to anthracyclines and taxanes were randomized in two open-label, multinational, phase 3 studies (study 046 and study 048). Patients received ixabepilone (40 mg/m(2) as a 3-hour intravenous infusion every 3 weeks) plus oral capecitabine (1000 mg/m(2) administered twice each day), or capecitabine alone (1250 mg/m(2) twice each day). RESULTS: In total, 251 randomized patients were aged >= 65 years (ixabepilone plus capecitabine, n=116; capecitabine monotherapy, n=135). Efficacy results were consistent in patients aged <65 and >= 65 years with respect to the observed improvement in progression-free survival and objective response rate with ixabepilone plus capecitabine compared with capecitabine alone. No significant differences in overall survival between arms were observed for either subgroup. In the ixabepilone plus capecitabine arm, grade 3/4 hematologic adverse events (AEs) were similar in both subgroups except leukopenia and febrile neutropenia, which had a higher incidence in patients aged >= 65 years. The majority of grade 3/4 nonhematologic AEs were similar in the two subgroups, including fatigue, peripheral sensory neuropathy, and hand-foot syndrome. CONCLUSION: The combination of ixabepilone plus capecitabine maintains its efficacy in elderly patients with anthracycline and taxane pretreated MBC, with a similar safety profile to patients aged < 65 years. PMID- 24472479 TI - A planned, prospective comparison of short-term quality of life outcomes among older patients with breast cancer treated with standard chemotherapy in a randomized clinical trial vs. an observational study: CALGB #49907 and #369901. AB - OBJECTIVES: Patients >= 65 years old ("older") are often not included in randomized clinical trials (RCT), but when they are, care in an RCT might improve quality of life (QoL). We conducted a prospective comparison of QoL among older women receiving standard chemotherapy from the same cooperative group physicians in an RCT vs. an observational study ("off-trial"). METHODS: Older women with invasive, non-metastatic breast cancer (n=150 RCT; 530 off-trial) were included. Linear mixed-effects models tested associations between chemotherapy on- vs. off trial and changes in EORTC (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire) QoL scores over 24 months, controlling for pre-treatment QoL, age, education, tumor factors, comorbidity, and other covariates. RESULTS: Anthracycline regimens were used by 58% of women treated on trial vs. 54% of those treated off-trial. Women in the RCT reported an adjusted mean increase of 13.7 points (95% CI 10.2, 17.1) in global QoL at 24 months (vs. mid-treatment), while women treated off-trial had only an adjusted improvement of 7.0 points (95% CI 3.5, 10.4; p=.007 for difference in mean changes). Women in the RCT had significantly greater improvement in emotional function than those treated off-trial, controlling for baseline; they also had greater reductions in therapy side effects and fatigue at 24 months than women off-trial, controlling for covariates. CONCLUSION: There may be different QoL trajectories for older women undergoing breast cancer chemotherapy on- vs. off-trial. If confirmed, the results suggest that the extra monitoring and communication within an RCT could provide the infrastructure for interventions to address symptoms and improve QoL for the growing older cancer population. PMID- 24472480 TI - HER2 status in elderly women with breast cancer. AB - OBJECTIVES: HER2 (human epidermal growth factor receptor 2) is an important biomarker in breast cancer, but its prevalence in elderly women is not well established. Previous studies reported HER2 status based on either immunohistochemistry (IHC) or fluorescent in situ hybridization (FISH) interchangeably. However, the tests may give discordant results. We report the prevalence of HER2 amplification in elderly women using only FISH. MATERIALS AND METHODS: We retrospectively identified women 65 years and older undergoing core biopsy, lumpectomy or mastectomy for primary breast malignancy at a single institution between 2009 and 2011. Data collected included age, histopathological type, hormone receptor status, and HER2 status. Descriptive statistics were performed using SAS Software, Version 9.2. RESULTS: One hundred fifty-eight women were included in the study. Most had invasive ductal carcinoma (74.7%), and were positive for either estrogen (ER) or progesterone (PgR) receptors (82.3% and 70.0%, respectively). Only 17% were negative for both ER and PgR; 11.4% were triple negative. Nineteen samples (12.0%) were positive for HER2. In univariate analyses, hormone receptor and HER2 status did not vary with age. When stratified by age, 60% of women with hormone receptor/HER2 positive tumors were younger than 70 years, compared with 22.2-33.3% of women in other subgroups. The difference was not statistically significant (p=0.20). CONCLUSION: This study adds to the knowledge of the biology of breast cancer in elderly women. Triple negative tumor incidence was similar to that previously reported for women under 70 years old, but HER2 positive tumors were less common. Additional prospective studies are needed to confirm our findings. PMID- 24472481 TI - Surgical treatment of elderly patients with endometrial cancer (>= 65 years). AB - OBJECTIVES: To analyze operability, short-term morbidity and mortality in women aged 65 and older with endometrial cancer. MATERIALS AND METHODS: The study cohort consisted of 124 elderly patients, aged 65 and older, with endometrioid endometrial cancer. Patients' clinical data included age at diagnosis, body mass index, ASA (American Society of Anesthesiologists) status and comorbidities, surgical procedures, FIGO (International Federation of Gynecology and Obstetrics) stage, histologic type, occurrence of operative and postoperative complications, and long-term disease-specific survival. Patients were divided into two groups according to age: those < 75 years and those >= 75 years. The analysis was repeated for patients older than 80 years who represent the category most at risk for perioperative morbidities. RESULTS: All patients were referred to primary surgery (abdominal versus vaginal) with the exception of 3 patients. Factors affecting significantly the choice of intervention were age, body mass index, and the presence of comorbidities. No women died during the perioperative period. The rate of perioperative complications was significantly higher for the older group. In a logistic regression model, aged >= 75 years (but not aged >= 80 years), chronic lung disease and performing lymphadenectomy correlated with a higher probability of perioperative morbidities. Long-term disease-specific survival was significantly shorter only for women aged >= 80. CONCLUSION: Geriatric patients should not be denied surgical treatment because of perceived risks associated with chronologic age, since the removal of the uterus confers a survival benefit. PMID- 24472482 TI - The effects of age on treatment and outcomes in women with stages IB1-IIB cervical cancer. AB - OBJECTIVE: Age may affect the treatment choice and subsequent outcome in elderly patients with cervical cancer. Given the potential for cure with either surgery or chemoradiation in early stage disease, we aimed to determine whether a patient's age influenced treatment received and the ensuing outcome. MATERIALS AND METHODS: We identified 303 patients with stages IB1-IIB cervical carcinoma treated at our institution between 2000 and 2010, who were divided into two groups based on age at time of diagnosis: < 65 and >= 65 years. Adjusted odd ratios were calculated to determine variables associated with treatment received. Single and multivariate Cox proportional hazards modeling were used to estimate hazard ratios (HRs) for variables associated with disease-specific survival. RESULTS: Patients were more commonly <65 years at diagnosis (83% versus 17% >= 65 years). There was no difference between the two groups in terms of tumor histology, stage at presentation, and grade. Women >= 65 years of age were less likely to receive primary surgical management (p=0.03). Age did not influence disease-specific or all-cause mortality. However, women over 65 years who underwent primary surgery were at significantly increased risk of all-cause mortality compared to younger women (HR 6.53, 95% CI: 2.57-16.6). CONCLUSIONS: Age appears to influence treatment received by patients with stages IB1-IIB cervical cancer. Although there was no difference in cancer-specific mortality stratified by type of treatment received, surgery was associated with a 6.5-fold increased risk of all-cause mortality among women 65 years or over. PMID- 24472483 TI - Assessment of cervical cancer screening policy in Korea for women over age 65. AB - OBJECTIVES: The purpose of this study was to evaluate the efficacy of cervical cancer screening (CCS) in Korean women over 65 years of age and to determine the age at which CCS becomes inefficacious, so that providers and policy makers can be more informed about when to stop screening. MATERIALS AND METHODS: The data of 999 women, who underwent CCS followed by colposcopy at the Korea University hospital from January 2007 to May 2012, were retrospectively evaluated. Age groups were classified as <21 (n=11), 21-29 (n=128), 30-65 (n=768), and >65 (n=92). To evaluate the value of CCS in women older than 65, age groups were simply divided into <= 65 or >65. Participants were also categorized into five strata of age groups (<= 55 vs. >55, <= 60 vs. >60, <= 65 vs. >65, <= 70 vs. >70, and <= 75 vs. >75) that were compared to the sample to assess a cutoff-age at which to cease screening based on decreased efficacy. RESULTS: The mean age was 45.5 +/- 13.7 (range 14-80). There were no differences in the pathologic results for cervical intraepithelial neoplasia (CIN) values of < CIN2 vs. >= CIN2, or <= CIN3 vs. cancer among the groups. There was a significantly higher incidence of cancer compared with <= CIN3 in women aged >65 (13.0%) vs. <= 65 (6.6%), (p=0.037). To assess the cervical cancer incidence (CCI) from the larger number of cases by age, a prediction formula was calculated from a national dataset. CCI (per 100,000) continuously increased by age even for those in their 90 s. CONCLUSION: CCS is still necessary in Korean women older than 65 since there is a substantial CCI rate occurring in these women. It is time to consider new guidelines that include the appropriate age and conditions for discontinuing screening. PMID- 24472484 TI - Patterns of care and outcomes in elderly patients with glioblastoma in Sao Paulo, Brazil: a retrospective study. AB - OBJECTIVE: To analyze how elderly patients with glioblastoma are managed in Brazil. MATERIAL AND METHODS: We identified 30 patients aged >= 65 years treated between 2003 and 2011 at Albert Einstein Hospital in Sao Paulo. We retrospectively reviewed medical records to obtain data on clinical variables, treatment and outcomes. Overall survival (OS) was evaluated using Kaplan-Meier methods and compared using a Wilcoxon log-rank test. RESULTS: The median age was 73 years. The majority of patients (73.2%) underwent surgical intervention. Following surgery, 80% received radiotherapy (RT), and of those, 79.2% were treated with concurrent temozolomide (TMZ). The median progression free survival and OS were 5 and 10.6 months, respectively. Patients with a KPS >= 70 had a median OS of 16.2 months, compared to 6.4 months for those with a KPS <70 (p=0.032). For those patients in whom biopsy only was performed, the median OS was 5.3 months, as compared to 7.8 months for those who underwent partial resection and 18.6 months for those treated with gross total resection (p=0.021). A longer survival was found among patients who received RT versus those who did not (11 months vs. 1 month, p=0.003), as well as for those treated with chemoradiation (13.6 months vs. 6.4 months, p<0.0001). CONCLUSIONS: This study brings new information about the management of elderly patients with glioblastoma in Brazil. Our data may suggest that elderly patients who undergo cytoreductive surgery and adjuvant RT with concurrent TMZ can do better than those with less aggressive treatment. PMID- 24472485 TI - Experience of multidisciplinary assessment of elderly patients with cancer in a French general hospital during 1 year: a new model care study. AB - OBJECTIVES: Our main aim was to describe and explore a multidisciplinary approach to the management of elderly patients with cancer, who constitute a heterogeneous population. MATERIALS AND METHODS: This descriptive study was performed between October 2009 and September 2010. Patients with cancer >= 70 years of age were included. Some underwent a simplified multidimensional geriatric assessment with a Charlson score administered by an oncologist, and the evaluation was submitted to a geriatrician who decided whether or not a complete a comprehensive geriatric assessment (CGA) (n=54) should be done. Another group of patients directly underwent a CGA (n=49), and a few patients included in a specific trial underwent a geriatric assessment (n=8). Each patient was classified as fit, vulnerable, or frail by a multidisciplinary team. RESULTS: 111 patients were included (median age: 81 years [range: 65-96]; 60 males). The most frequent types of cancer were lung (n=29), gastrointestinal (n=20) and head and neck (n=14). Median Charlson score was 2.1 [range: 0-9]. Standard therapy was given to 37/41 (90%) fit, 19/41 (42%) vulnerable, and 6/29 (21%) frail patients. Thirteen frail patients received best supportive care. A social worker was mobilized for 2/41 (5%) fit, 14/41 (34%) vulnerable, and 11/29 (38%) frail patients. CONCLUSIONS: Our study outlines the possibilities of cooperation between geriatricians and oncologists in a general hospital. This collaboration could modify therapeutic schedules especially in frail and vulnerable patients. PMID- 24472486 TI - The role of adjuvant radiation treatment in older women with early breast cancer. AB - The natural history of breast cancer favors a presentation in older patients, and with our aging population the management of breast cancer in geriatric patients has growing importance. Many of these patients will be diagnosed at an early stage. Thoughtful utilization of adjuvant radiation therapy for patients with early stage tumors, tailored within the context of comprehensive geriatric assessment, will optimize clinical outcomes and minimize costs and morbidity. PMID- 24472487 TI - Highly sensitive integrated pressure sensor with horizontally oriented carbon nanotube network. AB - This paper presents a functionalized, horizontally oriented carbon nanotube network as a sensing element to enhance the sensitivity of a pressure sensor. The synthesis of horizontally oriented nanotubes from the AuFe catalyst and their deposition onto a mechanically flexible substrate via transfer printing are studied. Nanotube formation on thermally oxidized Si (100) substrates via plasma enhanced chemical vapor deposition controls the nanotube coverage and orientation on the flexible substrate. These nanotubes can be simply transferred to the flexible substrate without changing their physical structure. When tested under a pressure range of 0 to 50 kPa, the performance of the fabricated pressure sensor reaches as high as approximately 1.68%/kPa, which indicates high sensitivity to a small change of pressure. Such sensitivity may be induced by the slight contact in isolated nanotubes. This nanotube formation, in turn, enhances the modification of the contact and tunneling distance of the nanotubes upon the deformation of the network. Therefore, the horizontally oriented carbon nanotube network has great potential as a sensing element for future transparent sensors. PMID- 24472488 TI - Systems integrity in health and aging - an animal model approach. AB - Human lifespan is positively correlated with childhood intelligence, as measured by psychometric (IQ) tests. The strength of this correlation is similar to the negative effect that smoking has on the life course. This result suggests that people who perform well on psychometric tests in childhood may remain healthier and live longer. The correlation, however, is debated: is it caused exclusively by social-environmental factors or could it also have a biological component? Biological traits of systems integrity that might result in correlations between brain function and lifespan have been suggested but are not well-established, and it is questioned what useful knowledge can come from understanding such mechanisms. In a recent study, we found a positive correlation between brain function and longevity in honey bees. Honey bees are highly social, but relevant social-environmental factors that contribute to cognition-survival correlations in humans are largely absent from insect colonies. Our results, therefore, suggest a biological explanation for the correlation in the bee. Here, we argue that individual differences in stress handling (coping) mechanisms, which both affect the bees' performance in tests of brain function and their survival could be a trait of systems integrity. Individual differences in coping are much studied in vertebrates, and several species provide attractive models. Here, we discuss how pigs are an interesting model for studying behavioural, physiological and molecular mechanisms that are recruited during stress and that can drive correlations between health, cognition and longevity traits. By revealing biological factors that make individuals susceptible to stress, it might be possible to alleviate health and longevity disparities in people. PMID- 24472490 TI - Infliximab three-dose induction regimen in severe corticosteroid-refractory ulcerative colitis: early and late outcome and predictors of colectomy. AB - BACKGROUND: Infliximab is effective as rescue therapy in severe corticosteroid refractory ulcerative colitis. The optimal dose regimen and the long term benefits are not well defined. The aim of the present study was to evaluate short and long-term colectomy rate in a cohort of patients with severe corticosteroid refractory ulcerative colitis who received a three-dose infliximab induction regimen. METHODS: One hundred and thirteen patients admitted to 11 Italian IBD referral centres and treated with infliximab according to an intention to treat three-dose regimen were included. The co-primary endpoints were 3- and 12-month colectomy rate. The secondary end-points were the overall colectomy-free survival and the identification of predictors of colectomy. RESULTS: The 3- and 12-month colectomy rates were 18.6% (95%CI 11.8%-26.9%) and 25.6% (95%CI 17.9%-34.7%) respectively. High CRP values and severe endoscopic lesions were associated with the risk of colectomy: Risk Ratio (RR)=2.15 (95%CI 1.05-4.36), and RR=5.13 (95%CI 1.55-16.96), respectively. In patients escaping early colectomy, the probability of a colectomy-free course at 12, 24, 36 and 60months was 91%, 85%, 81% and 73%, respectively. Endoscopic severity was the only predictor of long term colectomy (RR=7.0; 95%CI 1.09-44.7). Adverse events occurred in 16 patients (14%); there was one death (0.88%) due to pulmonary abscess. CONCLUSIONS: Infliximab is an effective and safe rescue therapy for severe corticosteroid-refractory ulcerative colitis. A three-dose induction regimen seems to be the treatment of choice for preventing early colectomy. Severe endoscopic lesions appear to be predictor of short- and long-term colectomy. PMID- 24472491 TI - The micro-scale synthesis of (117)Sn-enriched tributyltin chloride and its characterization by GC-ICP-MS and NMR techniques. AB - Organotin compounds (OTCs) are among the most toxic substances ever introduced to the environment by man. They are common pollutants in marine ecosystems, but are also present in the terrestrial environment, accumulated mainly in sewage sludge and landfill leachates. In investigations of the degradation and methylation processes of OTC in environmental samples, the use of enriched isotopic tracers represents a powerful analytical tool. Sn-enriched OTC are also necessary in application of the isotope dilution mass spectrometry technique for their accurate quantification. Since Sn-enriched monobutyltin (MBT), dibutyltin (DBT) and tributyltin (TBT) are not commercially available as single species, "in house" synthesis of individual butyltin-enriched species is necessary. In the present work, the preparation of the most toxic butyltin, namely TBT, was performed via a simple synthetic path, starting with bromination of metallic Sn, followed by butylation with butyl lithium. The tetrabutyltin (TeBT) formed was transformed to tributyltin chloride (TBTCl) using concentrated hydrochloric acid (HCl). The purity of the synthesized TBT was verified by speciation analysis using the techniques of gas chromatography coupled to inductively coupled plasma mass spectrometry (GC-ICP-MS) and nuclear magnetic resonance (NMR). The results showed that TBT had a purity of more than 97%. The remaining 3% corresponded to DBT. TBT was quantified by reverse isotope dilution GC-ICP-MS. The synthesis yield was around 60%. The advantage of this procedure over those previously reported lies in its possibility to be applied on a micro-scale (starting with 10mg of metallic Sn). This feature is of crucial importance, since enriched metallic Sn is extremely expensive. The procedure is simple and repeatable, and was successfully applied for the preparation of (117)Sn-enriched TBTCl from (117)Sn-enriched metal. PMID- 24472492 TI - Collaborative development for setup, execution, sharing and analytics of complex NMR experiments. AB - Factory settings of NMR pulse sequences are rarely ideal for every scenario in which they are utilised. The optimisation of NMR experiments has for many years been performed locally, with implementations often specific to an individual spectrometer. Furthermore, these optimised experiments are normally retained solely for the use of an individual laboratory, spectrometer or even single user. Here we introduce a web-based service that provides a database for the deposition, annotation and optimisation of NMR experiments. The application uses a Wiki environment to enable the collaborative development of pulse sequences. It also provides a flexible mechanism to automatically generate NMR experiments from deposited sequences. Multidimensional NMR experiments of proteins and other macromolecules consume significant resources, in terms of both spectrometer time and effort required to analyse the results. Systematic analysis of simulated experiments can enable optimal allocation of NMR resources for structural analysis of proteins. Our web-based application (http://nmrplus.org) provides all the necessary information, includes the auxiliaries (waveforms, decoupling sequences etc.), for analysis of experiments by accurate numerical simulation of multidimensional NMR experiments. The online database of the NMR experiments, together with a systematic evaluation of their sensitivity, provides a framework for selection of the most efficient pulse sequences. The development of such a framework provides a basis for the collaborative optimisation of pulse sequences by the NMR community, with the benefits of this collective effort being available to the whole community. PMID- 24472493 TI - Mass training in basic life support for high-school students. PMID- 24472494 TI - Chest compressions may be safe in arresting patients with left ventricular assist devices (LVADs). AB - INTRODUCTION: The number of patients with left ventricular assist devices (LVADs) is increasing each year. Despite a lack of evidence, many emergency medical systems and hospitals have recommended against performing chest compressions in these patients. This deviation from conventional resuscitation algorithms is secondary to concern that chest compressions could dislodge the LVAD. OBJECTIVE: To assess whether cannula dislodgment occurred in LVAD patients receiving chest compressions. METHODS: We retrospectively analyzed the outcomes of all LVAD patients who received chest compressions for cardiac arrest over a four year period in a large urban hospital. Eight cases were reviewed for both cannula integrity and outcomes. RESULTS: Using autopsy and adequate flow through device as proxy for intact inflow/outflow cannulas, none of the eight patients receiving chest compressions had cannula dislodgment. Four of the 8 patients had return of neurologic function. CONCLUSIONS: In this small retrospective case series, standard chest compressions in patients with LVADs did not cause cannula dislodgment. More research is necessary to determine the utility of chest compressions in the LVAD population. PMID- 24472495 TI - Two- and three-dimensional rings in drugs. AB - Using small, flat aromatic rings as components of fragments or molecules is a common practice in fragment-based drug discovery and lead optimization. With an increasing focus on the exploration of novel biological and chemical space, and their improved synthetic accessibility, 3D fragments are attracting increasing interest. This study presents a detailed analysis of 3D and 2D ring fragments in marketed drugs. Several measures of properties were used, such as the type of ring assemblies and molecular shapes. The study also took into account the relationship between protein classes targeted by each ring fragment, providing target-specific information. The analysis shows the high structural and shape diversity of 3D ring systems and their importance in bioactive compounds. Major differences in 2D and 3D fragments are apparent in ligands that bind to the major drug targets such as GPCRs, ion channels, and enzymes. PMID- 24472496 TI - Amyloid-beta 42 adsorption following serial tube transfer. AB - INTRODUCTION: Cerebrospinal fluid (CSF) amyloid-beta 38 (Abeta38), 40 (Abeta40), 42 (Abeta42) and total tau (T-tau) are finding increasing utility as biomarkers of Alzheimer's disease (AD). The purpose of this study was to determine whether measured CSF biomarker concentrations were affected by transfer of CSF between tubes, and whether addition of a non-ionic surfactant mitigates any observed effects. METHODS: AD and control CSF was transferred consecutively between polypropylene tubes. Abeta peptides and T-tau were measured with and without addition of Tween 20 (0.05%). RESULTS: Measured concentrations of Abeta42 decreased by approximately 25% with each consecutive transfer. Measured concentrations of Abeta38 and Abeta40 were also observed to decrease significantly with each consecutive transfer (approximately 16% loss per transfer). Measured concentrations of T-tau also decreased significantly, but at much smaller magnitude than the Abeta peptides (approximately 4% loss per transfer). The addition of Tween 20 mitigated this effect in all samples. CONCLUSIONS: Consecutive CSF transfer between tubes has a significant impact on the measured concentration of all Abeta peptides, and significant effect of lesser magnitude on T-tau. This would be sufficient to alter biomarker ratios enough to mislead diagnosis. The introduction of Tween 20 at the initial aliquoting stage was observed to significantly mitigate this effect. PMID- 24472497 TI - Association between work-related health problems and job insecurity in permanent and temporary employees. AB - OBJECTIVES: This research was conducted with an aim of determining the correlation between job insecurity and an employee's work-related health problems among permanent and temporary workers. METHODS: Using the data from the First Korean Working Conditions Survey conducted in 2006, a total of 7,071 workers, excluding employers and the self-employed, were analyzed. Work-related health problems were categorized as backache, headache, abdominal pain, muscular pain, stress, fatigue, insomnia, anxiety or depression. Each problem was then analyzed for its relationship to job insecurity through logistic regression analysis. RESULTS: Among the 7,071 workers, 5,294 (74.9%) were permanent workers and 1,777 (25.1%) were temporary workers. For the permanent workers, presence of high or moderate job insecurity appeared more closely linked to backache, headache, abdominal pain, muscular pain, stress, fatigue, insomnia, anxiety, and depression compared to absence of job insecurity. However, for the temporary workers, only depression appeared to be associated with the presence of high job insecurity. CONCLUSION: The study showed that the presence of job insecurity is correlated with work-related health problems. The deleterious effects of job insecurity appeared to be stronger in permanent than temporary workers. Additional research should investigate ways to effectively reduce job insecurity. PMID- 24472498 TI - Inhibition of stress-induced hepatic tryptophan 2,3-dioxygenase exhibits antidepressant activity in an animal model of depressive behaviour. AB - The role of hepatic tryptophan 2,3 dioxygenase (TDO) was assessed in the provocation of stress-induced depression-related behaviour in the rat. TDO drives tryptophan metabolism via the kynurenine pathway (KP) and leads to the production of neuroactive metabolites including kynurenine. A single 2 h period of restraint stress in adult male Sprague-Dawley rats provoked an increase in circulating concentrations of the glucocorticoid corticosterone and induction of hepatic TDO expression and activity. Repeated exposure to stress (10 d of 2 h restraint each day) provoked an increase in immobility in the forced swimming test (FST) indicative of depression-related behaviour. Immobility was accompanied by an increase in the circulating corticosterone concentrations, expression and activity of hepatic TDO and increase in the expression of TDO in the cerebral cortex. Increased TDO activity was associated with raised circulating kynurenine concentrations and a reduction in circulating tryptophan concentrations indicative of KP activation. Co-treatment with the TDO inhibitor allopurinol (20 mg/kg, i.p.), attenuated the chronic stress-related increase in immobility in the FST and the accompanying increase in circulating kynurenine concentrations. These findings indicate that stress-induced corticosterone and consequent activation of hepatic TDO, tryptophan metabolism and production of kynurenine provoke a depression-related behavioural phenotype. Inhibition of stress-related hepatic TDO activity promotes antidepressant activity. TDO may therefore represent a promising target for the treatment of depression associated with stress-related disorders in which there is evidence for KP activation. PMID- 24472499 TI - Fear of falling in age-related macular degeneration. AB - BACKGROUND: Prior studies have shown age-related macular degeneration (AMD) to be associated with falls. The purpose of this study is to determine if (AMD) and AMD related vision loss are associated with fear of falling, an important and distinct outcome. METHODS: Sixty-five persons with AMD with evidence of vision loss in one or both eyes and 60 glaucoma suspects with normal vision completed the University of Illinois at Chicago Fear of Falling questionnaire. Responses were Rasch analyzed. Scores were expressed in logit units, with lower scores demonstrating lesser ability and greater fear of falling. RESULTS: Compared to glaucoma suspect controls, AMD subjects had worse visual acuity (VA) (median better-eye VA = 20/48 vs. 20/24, p < 0.001) and worse contrast sensitivity (CS) (binocular CS = 1.9 vs. 1.5 log units, p < 0.001). AMD subjects were also older, more likely to be Caucasian, and less likely to be employed (p < 0.05 for all), but were similar with regards to other demographic and health measures. In multivariable models controlling for age, gender, body habitus, strength, and comorbid illnesses, AMD subjects reported greater fear of falling as compared to controls (beta = -0.77 logits, 95% CI = -1.5 to -0.002, p = 0.045). In separate multivariable models, fear of falling increased with worse VA (beta = -0.15 logits/1 line decrement, 95% CI = -0.28 to -0.03, p = 0.02) and CS (beta = -0.20 logits/0.1 log unit decrement, 95% CI = -0.31 to -0.09, p = 0.001). Greater fear of falling was also associated with higher BMI, weaker grip, and more comorbid illnesses (p < 0.05 for all). CONCLUSIONS: AMD and AMD-related vision loss are associated with greater fear of falling in the elderly. Development, validation, and implementation of methods to address falls and fear of falling for individuals with vision loss from AMD are important goals for future work. PMID- 24472500 TI - Status of nosocomial tuberculosis transmission prevention in hospitals in Thailand. AB - A national survey was conducted during July to September 2009 to determine tuberculosis (TB) prevention activities, problems, and support needed of Thai hospitals. Ninety-seven percent of hospitals established TB isolation policy, 96.3% provided guidelines for caring of TB patients, 95% and 91.8% provided prevention of TB transmission and environmental management guideline, and 92.6% established screening system for TB in the outpatient department (OPD). A half of hospitals had problems with isolation rooms and difficulties in screening TB cases in the OPD. Support needed included consultation on structure and ventilation systems, personnel training, national TB prevention, and TB screening guideline. Strengthening TB prevention activities, providing expert consultation, and national guidelines may help hospitals improve their TB prevention activities. PMID- 24472501 TI - Editorial comment. PMID- 24472502 TI - Technology to help persons with extensive neuro-motor impairment and lack of speech with their leisure occupation and communication. AB - These two studies were aimed at extending the assessment of technology-aided programs to enhance leisure occupation or communication with persons with extensive neuro-motor impairment and lack of speech. Specifically, Study I implemented the program for leisure occupation with two post-stroke patients. Study II implemented the program for communication with two persons affected by amyotrophic lateral sclerosis (ALS). In Study I, a computer system presented the participants with a variety of stimuli. The participants could select/access those stimuli by microswitch activation or could bypass them by abstaining from microswitch responses. In Study II, the participants used a computer-aided telephone system that allowed them to choose via microswitch activation the persons to call. On the computer screen, they also had words and phrases that they could activate during the calls to influence the conversation with the persons called. Data from both studies were largely positive. The post-stroke patients showed high levels of stimulus selection (access) and extended engagement. The patients with ALS were able to make phone calls and to select the words/phrases to influence the conversations. The relevance of technology-aided programs for leisure occupation and communication of persons with extensive multiple disabilities was discussed. PMID- 24472503 TI - Psychometric properties of a Dutch version of the behavior problems inventory-01 (BPI-01). AB - There are only a limited number of Dutch validated measurement instruments for measuring behavioral problems in people with a moderate to profound intellectual disability. In this study, the psychometric properties of a Dutch version of the behavior Problems Inventory-01 (BPI-01; Rojahn et al., 2001) have been investigated among 195 people with a moderate to profound intellectual disability who live in a residential facility. The BPI-01 was completed by 42 informants (staff members) of 23 care units. The inter-rater reliability, intra-rater reliability and internal consistency turned out to be good. Factor analysis confirmed two of the three a priori factors and the third factor was a mix of self-injurious (SIB) behavior and stereotypic behavior. The BPI-01 was compared to the Aberrant Behavior Checklist (Aman et al., 1985a) and showed a good convergent validity. This study shows that a Dutch version of the BPI-01 has good psychometric properties for measuring behavior problems in individuals with moderate to profound intellectual disability. PMID- 24472504 TI - Thermal degradation kinetics of sucrose palmitate reinforced poly(lactic acid) biocomposites. AB - The current work is focused on investigating the influence of novel bio-filler, "sucrose palmitate (SP)" on the thermal degradation behavior of poly(lactic acid) (PLA) biocomposites in order to render its suitability for food packaging application. Thermal degradation behavior of the PLA biocomposites was investigated by thermo-gravimetric analysis (TGA) using dynamic heating regime. The differential TG analysis revealed that there is no change in the Tmax value (357 degrees C) for PLA and its composites up to 5 wt% of bio-filler loading. This reveals that the sucrose palmitate acts as a protective barrier by decelerating the thermal degradation rate of PLA. In the case of 10 wt% of the filler incorporated in the PLA matrix, Tmax rapidly shifted to lower temperature (324 degrees C). This downturn in Tmax at higher loading of the filler is due to the increase in acidic sites and enhancement in the rate of degradation is observed. Differential scanning calorimetry (DSC) analysis revealed unimodal melting peak indicating the alpha-crystalline form of PLA. Based on the thermal degradation profile of sucrose palmitate, possible mechanism for degradation of PLA composites is proposed. The activation energies (Ea) of thermal degradation of PLA and PLA composites were evaluated by Flynn-Wall-Ozawa and Kissinger methods. PMID- 24472505 TI - Synthesis, characterization and antibacterial activity of new fluorescent chitosan derivatives. AB - The present work aims to the development of innovative new derivatives of chitosan that can be used for medical applications. This innovation is based on the synthesis and characterization of chitosan-g-aminoanthracene derivatives. Thus, N-(anthracen-9-yl)-4,6-dichloro-[1,3,5]-triazin-2-amine (AT) reacted with chitosan by the following steps: at first, cyanuric chloride reacted with 9 aminoanthracene to obtain N-(anthracen-9-yl)-4,6-dichloro-[1,3,5]-triazin-2-amine (AT), then the AT reacted with chitosan to obtain (CH-g-AT). The final product of CH-g-AT was separated, purified and re-crystallized by dioxane. The structure of the prepared chitosan derivatives was confirmed by FTIR-ATR, solid-NMR, TGA, X RD, and DSC. The new chitosan derivatives showed fluorescence spectra in liquid and in solid state as well. CH-g-AT showed also high antibacterial activity against gram -ve species (Escherichia coli). PMID- 24472506 TI - Polymers derived from Xanthomonas campesteris and Cyamopsis tetragonolobus used as retardant materials for the formulation of sustained release floating matrix tablet of atenolol. AB - The objective of the present study was to develop, optimize, in vitro, and in vivo evaluation of floating matrix tablet of atenolol using polymer blend derived from Xanthomonas campesteris and Cyamopsis tetragonolobus that are characterized by release requirements of sustained-release product and to improve the oral bioavailability of the drug. A 3(2) full factorial design was employed to optimize the tablets, where content of polymer blend (X1) and ratio of xanthan gum-to-guar gum (X2) were considered as independent variables. The effects of independent variables on dependent variables, i.e. floating time, diffusion exponent, and time to release 50% of atenolol were evaluated. The in vivo pharmacokinetic parameters of the optimized formulation were compared with the marketed sustained release formulation of atenolol (Aten((r))). The optimized formulation containing 20% (w/w) of polymer blend and 50:50 ratio of xanthan gum to-guar gum was able to float more than 12h and showed the desired sustained drug release from the tablets. In vivo retention studies in rabbit stomach showed the gastric residence of tablet up to 6h. The in vivo study of optimized tablets illustrated significant improvement in the oral bioavailability of atenolol in rabbits. It can be concluded that floating matrix tablet of atenolol prepared by using xanthan gum and guar gum has potential for sustained release of the drug as well as improved oral bioavailability through enhanced gastric residence time of formulation in stomach. PMID- 24472507 TI - Oxaliplatin-chitosan nanoparticles induced intrinsic apoptotic signaling pathway: a "smart" drug delivery system to breast cancer cell therapy. AB - This study was to investigate "smart" pH-responsive drug delivery system (DDS) based on chitosan nano-carrier for its potential intelligent controlled release and enhancing chemotherapeutic efficiency of Oxalipaltin. Oxaliplatin was loaded onto chitosan by forming complexes with degradable to construct nano-carrier as a DDS. Oxaliplatin was released from the DDS much more rapidly at pH 4.5 than at pH 7.4, which is a desirable characteristic for tumor-targeted drug delivery. Furthermore, the possible intrinsic apoptotic signaling pathway was explored by Western blot. It was found that expression of Bax, Bik, cytochrome C, caspase-9 and -3 was significantly up-regulated while the Bcl-2 and Survivin were inhibited in breast cancer MCF-7 cells. For instance, nanoparticles inducing apoptosis in caspase-dependent manner indicate that chitosan nanoparticles could act as an efficient DDS importing Oxalipaltin to target cancer cells. These approaches suggest that "smart" Oxaliplatin delivery strategy is a promising approach to cancer therapy. PMID- 24472508 TI - Antioxidant and immunoregulatory activity of alkali-extractable polysaccharides from North American ginseng. AB - The alkali-extractable polysaccharide (AEP) was isolated from the root of North American ginseng. Two fractions, AEP-1 and AEP-2, were further purified by gel filtration column chromatography. Gas chromatography analysis identified that AEP 1 was composed of Glc, Gal and GalA. And AEP-2 mainly contained Ara, Man, Gal, Glc and GalA. Antioxidant assays indicated that AEP and AEP-2 exhibited significant antioxidant activities in a dose-dependent manner. AEP-2 also exhibited macrophage-activating activity by increasing NO, TNF-alpha and IL-6 production. The results suggest that AEP-2 could be used as potential antioxidants and immunomodulators. PMID- 24472509 TI - Identification of the interaction region between hemagglutinin components of the botulinum toxin complex. AB - The large toxin complex (L-TC) produced by Clostridium botulinum is formed from the M-TC (BoNT/NTNHA complex) by conjugation of M-TC with HA-33/HA-17 trimer consists of two HA-33 proteins and a single HA-17 protein. This association is mediated by HA-70, which interacts with HA-17. The current study aims to identify the regions of the HA-70 molecule that adhere to the HA-33/HA-17 complex. Products from limited proteolysis of HA-70 were resolved by SDS-PAGE and transferred onto PVDF membranes, where they were probed with HA-33/HA-17 in a far western blot. Among the HA-70 fragments, HA-33/HA-17 bound to those containing at least the C-terminal half of the HA-70 molecule, but not those carrying the N terminal half. Additional docking simulation analysis indicated that the HA-70 region Gln420-Tyr575 is responsible for binding to HA-17, which is consistent with the far-western blot data. The findings here reveal additional details concerning the three-dimensional structure of the functional HA sub-complex in the botulinum toxin complex. PMID- 24472510 TI - Identification and characterization of hydrocolloid from Cordia myxa leaf. AB - Hot water extraction technique was employed to extract the hydrocolloid from Cordia myxa leaf (PCM). The optimal conditions for extraction of PCM were determined using response surface methodology. A Box-Behnken design (BBD) was applied to evaluate the effects of three independent variables (extraction time (X1: 1-4 h), extraction temperature (X2: 55-95 degrees C), and water to raw material ratio (X3: 5-30 ml/g) on the extraction yield of PCM. The content of moisture, water-soluble and water-insoluble ash, crude protein and total phenol were determined in the extracted hydrocolloid by standard methods. The maximum hydrocolloid extraction yield (9.501+/-0.15%) was achieved by using extraction time of 4.94 h, extraction temperature of 94.91 degrees C and water to raw material ratio of 21.74 ml/g. The contents of moisture, crude protein, water soluble and water-insoluble ash and total phenol were 21.63+/-0.94%, 14.27+/ 0.55%, 3.07+/-0.16% and 2.61+/-0.19 mg galic acid/g, respectively. PMID- 24472511 TI - Cardiovascular disease risk of bus drivers in a city of Korea. AB - OBJECTIVE: To prevent the occurrence of CV events such as MI and stroke among professional drivers in Korea, bus drivers were compared to other occupations through the Framingham risk scoring system (FRS) or metabolic syndrome (MS) of cardiovascular disease (CVD) risk assessment methods. METHODS: In October 2012, a health examination survey was conducted for 443 male bus drivers in a big city. Their CVD risk factors were compared to those of a 'total employed' (A group) and 'crafts and machine operators' (B group) extracted from Fifth Korea National Health and Nutrition Examination Survey (KNHANES, 2010) data by using FRS and MS. We calculated proportions of the CVD risk factors distribution between bus drivers and the A, B groups by the bootstrapping method. The Odds ratio (OR) between CV event risk combining MS with CHD equivalent risk of FRS and occupational factors like shift patterns and professional driving duration/age ratios (PDAR) of bus drivers was calculated through multinominal logistic regression. RESULTS: The proportion of BMI >= 25 kg/m2 was 53.9% and waist circumference >= 90cm was 40.9% among bus drivers. Hypertension and MS prevalence of bus drivers was 53.3%, 49.9% which is higher than 17.6%, 22.6% in the A group and 19.7%, 23.8% in the B group respectively. OR of high CV event risk in alternate shift was 2.58 (95% CI 1.33~5.00) in comparison with double shift pattern and OR in PDAR >= 0.5 was 2.18 (95% CI 1.15~4.14). CONCLUSION: Middle aged male drivers in a big city of Korea stand a higher chance of developing CV event than other professions of the same age. PMID- 24472512 TI - Flavonoid-membrane interactions: involvement of flavonoid-metal complexes in raft signaling. AB - Flavonoids are polyphenolic compounds produced by plants and delivered to the human body through food. Although the epidemiological analyses of large human populations did not reveal a simple correlation between flavonoid consumption and health, laboratory investigations and clinical trials clearly demonstrate the effectiveness of flavonoids in the prevention of cardiovascular, carcinogenic, neurodegenerative and immune diseases, as well as other diseases. At present, the abilities of flavonoids in the regulation of cell metabolism, gene expression, and protection against oxidative stress are well-known, although certain biophysical aspects of their functioning are not yet clear. Most flavonoids are poorly soluble in water and, similar to lipophilic compounds, have a tendency to accumulate in biological membranes, particularly in lipid rafts, where they can interact with different receptors and signal transducers and influence their functioning through modulation of the lipid-phase behavior. In this study, we discuss the enhancement in the lipophilicity and antioxidative activity of flavonoids after their complexation with transient metal cations. We hypothesize that flavonoid-metal complexes are involved in the formation of molecular assemblies due to the facilitation of membrane adhesion and fusion, protein protein and protein-membrane binding, and other processes responsible for the regulation of cell metabolism and protection against environmental hazards. PMID- 24472513 TI - Structural and stoichiometric determinants of Ca2+ release-activated Ca2+ (CRAC) channel Ca2+-dependent inactivation. AB - Depletion of intracellular Ca(2+) stores in mammalian cells results in Ca(2+) entry across the plasma membrane mediated primarily by Ca(2+) release-activated Ca(2+) (CRAC) channels. Ca(2+) influx through these channels is required for the maintenance of homeostasis and Ca(2+) signaling in most cell types. One of the main features of native CRAC channels is fast Ca(2+)-dependent inactivation (FCDI), where Ca(2+) entering through the channel binds to a site near its intracellular mouth and causes a conformational change, closing the channel and limiting further Ca(2+) entry. Early studies suggested that FCDI of CRAC channels was mediated by calmodulin. However, since the discovery of STIM1 and Orai1 proteins as the basic molecular components of the CRAC channel, it has become apparent that FCDI is a more complex phenomenon. Data obtained using heterologous overexpression of STIM1 and Orai1 suggest that, in addition to calmodulin, several cytoplasmic domains of STIM1 and Orai1 and the selectivity filter within the channel pore are required for FCDI. The stoichiometry of STIM1 binding to Orai1 also has emerged as an important determinant of FCDI. Consequently, STIM1 protein expression levels have the potential to be an endogenous regulator of CRAC channel Ca(2+) influx. This review discusses the current understanding of the molecular mechanisms governing the FCDI of CRAC channels, including an evaluation of further experiments that may delineate whether STIM1 and/or Orai1 protein expression is endogenously regulated to modulate CRAC channel function, or may be dysregulated in some pathophysiological states. PMID- 24472514 TI - Anaerobic threshold, is it a magic number to determine fitness for surgery? AB - The use of cardiopulmonary exercise testing (CPET) to evaluate cardiac and respiratory function was pioneered as part of preoperative assessment in the mid 1990s. Surgical procedures have changed since then. The patient population may have aged; however, the physiology has remained the same. The use of an accurate physiological evaluation remains as germane today as it was then. Certainly no 'magic' is involved. The author recognizes that not everyone accepts the classical theories of the anaerobic threshold (AT) and that there is some discussion around lactate and exercise. The article looks at aerobic capacity as an important predictor of perioperative mortality and also looks at some aspects of CPET relative to surgical risk evaluation. PMID- 24472515 TI - Shared genes related to aggression, rather than chemical communication, are associated with reproductive dominance in paper wasps (Polistes metricus). AB - BACKGROUND: In social groups, dominant individuals may socially inhibit reproduction of subordinates using aggressive interactions or, in the case of highly eusocial insects, pheromonal communication. It has been hypothesized these two modes of reproductive inhibition utilize conserved pathways. Here, we use a comparative framework to investigate the chemical and genomic underpinnings of reproductive dominance in the primitively eusocial wasp Polistes metricus. Our goals were to first characterize transcriptomic and chemical correlates of reproductive dominance and second, to test whether dominance-associated mechanisms in paper wasps overlapped with aggression or pheromone-related gene expression patterns in other species. To explore whether conserved molecular pathways relate to dominance, we compared wasp transcriptomic data to previous studies of gene expression associated with pheromonal communication and queen worker differences in honey bees, and aggressive behavior in bees, Drosophila, and mice. RESULTS: By examining dominant and subordinate females from queen and worker castes in early and late season colonies, we found that cuticular hydrocarbon profiles and genome-wide patterns of brain gene expression were primarily associated with season/social environment rather than dominance status. In contrast, gene expression patterns in the ovaries were associated primarily with caste and ovary activation. Comparative analyses suggest genes identified as differentially expressed in wasp brains are not related to queen pheromonal communication or caste in bees, but were significantly more likely to be associated with aggression in other insects (bees, flies), and even a mammal (mice). CONCLUSIONS: This study provides the first comprehensive chemical and molecular analysis of reproductive dominance in paper wasps. We found little evidence for a chemical basis for reproductive dominance in P. metricus, and our transcriptomic analyses suggest that different pathways regulate dominance in paper wasps and pheromone response in bees. Furthermore, there was a substantial impact of season/social environment on gene expression patterns, indicating the important role of external cues in shaping the molecular processes regulating behavior. Interestingly, genes associated with dominance in wasps were also associated with aggressive behavior in bees, solitary insects and mammals. Thus, genes involved in social regulation of reproduction in Polistes may have conserved functions associated with aggression in insects and other taxa. PMID- 24472516 TI - A relationship exists between replicative senescence and cardiovascular health. AB - A growing body of evidence demonstrates that the accumulation of senescent cells is a plausible ageing mechanism. It has been proposed that the senescence of vascular cells plays a causal role in the development of cardiovascular pathologies. A key prediction arising from this hypothesis is that cultures of cells derived from donors with cardiovascular disease will show reduced in vitro replicative capacities compared to those derived from disease-free controls. Accordingly, we carried out a formal review of the relationship among donor age, cardiovascular health status and maximum population doubling level attained in vitro by cultures of vascular smooth muscle and endothelial cells. Data were available to us on a total of 202 independent cell cultures. An inverse relationship was found to exist between replicative capacity and donor age in both endothelial and vascular smooth muscle cells. Cultures derived from donors with cardiovascular disease showed a lower overall replicative potential than age matched healthy controls. In general the replicative potential at the start of the lifespan was found to be higher in those individuals without disease than those with disease and the difference in average cumulative population doublings (CPDs) in age-matched individuals in the two groups remained roughly constant throughout the lifetime. These results are consistent with the model in which the inherited replicative capacity of vascular cells is a stronger determinant of the onset of cardiovascular disease later in life, than wear-and-tear throughout the life course. PMID- 24472517 TI - Push by a net, pull by a cow: can zooprophylaxis enhance the impact of insecticide treated bed nets on malaria control? AB - BACKGROUND: Mass insecticide treated bed net (ITN) deployment, and its associated coverage of populations at risk, had "pushed" a decline in malaria transmission. However, it is unknown whether malaria control is being enhanced by zooprophylaxis, i.e., mosquitoes diverted to feed on hosts different from humans, a phenomenon that could further reduce malaria entomological transmission risk in areas where livestock herding is common. METHODS: Between May and July 2009, we collected mosquitoes in 104 houses from three neighboring villages with high ITN coverage (over 80%), along Lake Victoria. We also performed a census of livestock in the area and georeferenced tethering points for all herds, as well as, mosquito larval habitats. Bloodmeal contents from sampled mosquitoes were analyzed, and each mosquito was individually tested for malaria sporozoite infections. We then evaluated the association of human density, ITN use, livestock abundance and larval habitats with mosquito abundance, bloodfeeding on humans and malaria sporozoite rate using generalized linear mixed effects models. RESULTS: We collected a total of 8123 mosquitoes, of which 1664 were Anopheles spp. malaria vectors over 295 household spray catches. We found that vector household abundance was mainly driven by the number of householders (P < 0.05), goats/sheep tethered around the house (P < 0.05) and ITNs, which halved mosquito abundance (P < 0.05). In general, similar patterns were observed for Anopheles arabiensis, but not An. gambiae s.s. and An. funestus s.s., whose density did not increase with the presence of livestock animals. Feeding on humans significantly increased in all species with the number of householders (P < 0.05), and only significantly decreased for An. arabiensis in the presence of cattle (P < 0.05). Only 26 Anopheles spp. vectors had malaria sporozoites with the sporozoite rate significantly decreasing as the proportion of cattle feeding mosquitoes increased (P < 0.05). CONCLUSION: Our data suggest that cattle, in settings with large ITN coverage, have the potential to drive an unexpected "push-pull" malaria control system, where An. arabiensis mosquitoes "pushed" out of human contact by ITNs are likely being further "pulled" by cattle. PMID- 24472518 TI - Sensory profiles of patients with neuropathic pain based on the neuropathic pain symptoms and signs. AB - This manuscript aimed to characterize the clinical profile of various neuropathic pain (NeP) disorders and to identify whether patterns of sensory symptoms/signs exist, based on baseline responses on the Neuropathic Pain Symptom Inventory (NPSI) questionnaire and the quantitative sensory testing (QST). These post hoc analyses were based on data from 4 randomized, double-blind, placebo-controlled clinical studies of pregabalin (150-600mg/day) in patients with NeP syndromes: central poststroke pain, posttraumatic peripheral pain, painful HIV neuropathy, and painful diabetic peripheral neuropathy. The NPSI questionnaire includes 10 different pain symptom descriptors. QST was used to detect sensory thresholds of accurately calibrated sensory stimuli and to quantify the intensity of evoked sensation. To identify symptoms/signs clusters and select the number of clusters, a principal component analysis (PCA) and hierarchical clustering methods with clinical input were used. Analysis of the NPSI pain qualities and individual QST measures at baseline indicated no clear association between particular symptoms/signs profiles and etiologies. Based on NPSI symptoms, PCA identified 3 pain dimensions: provoked, deep, and pinpoint. A hierarchical cluster analysis identified 3 clusters with distinct pain characteristics profiles independent of NeP syndrome. Based on QST signs, PCA identified 2 pain dimensions: evoked by cold and evoked by touch. A hierarchical cluster analysis identified 4 clusters with distinct pain characteristics profiles. These "trans-etiological" profiles may reflect distinct pathophysiological mechanisms and therefore, potential differential responses to treatment. PMID- 24472519 TI - Effectiveness of 5-aminolevulinic acid photodynamic therapy in the treatment of hidradenitis suppurativa: a report of 5 cases. AB - Hidradenitis suppurativa has been described as a chronic, recurrent, and disabling inflammatory disease involving the entire hair follicle. Several treatments, including photodynamic therapy, have been used, but the results have been inconsistent and recurrence is high. In this prospective study, we evaluated disease severity, quality of life, and treatment tolerance in 5 patients with moderate to severe hidradenitis suppurativa treated with photodynamic therapy using 5-aminolevulinic acid and a 635-nm light source. Treatment effectiveness was evaluated using the Sartorius severity score, the Dermatology Life Quality Index, and a visual analog scale for pain and disease activity. Significant improvements were observed with all 3 instruments and the effects remained visible at 8 weeks. Our results suggest that photodynamic therapy with 5 aminolevulinic acid and a light wavelength of 635 nm could reduce disease severity and improve quality of life in patients with difficult-to-treat hidradenitis suppurativa. PMID- 24472520 TI - Two cases of lung cancer in foundry workers. AB - BACKGROUND: Iron and steel foundry workers are exposed to various toxic and carcinogenic substances including crystalline silica, polycyclic aromatic hydrocarbons, and arsenic. Studies have been conducted on lung cancer in iron and steel founding workers and the concentration of crystalline silica in foundries; however, the concentration of crystalline silica and cases of lung cancer in a single foundry has never been reported in Korea. Therefore, the authors report two cases of lung cancer and concentration of crystalline silica by the X-ray diffraction method. CASE PRESENTATION: A 55-year-old blasting and grinding worker who worked in a foundry for 33 years was diagnosed with lung cancer. Another 64 year-old forklift driver who worked in foundries for 39 years was also diagnosed with lung cancer. Shot blast operatives were exposed to the highest level of respirable quartz (0.412 mg/m3), and a forklift driver was exposed to 0.223 mg/m3. CONCLUSIONS: The lung cancer of the two workers is very likely due to occupationally related exposure given their occupational history, the level of exposure to crystalline silica, and epidemiologic evidence. Further studies on the concentration of crystalline silica in foundries and techniques to reduce the crystalline silica concentration are required. PMID- 24472521 TI - Patients' and healthcare professionals' views on a specialist smoking cessation service delivered in a United Kingdom hospital: a qualitative study. AB - BACKGROUND: Hospital admission provides a powerful opportunity to promote smoking cessation. We explored patients' and healthcare professionals' (HCP) views of a specialist smoking cessation service comprising systematic smoking ascertainment, default provision of pharmacotherapy and behavioural counselling at the bedside, and post-discharge follow-up, in a clinical trial in a United Kingdom teaching hospital. METHODS: Semi-structured interviews with 30 patients who were offered the intervention, and 27 HCPs working on intervention wards, were audio-recorded, transcribed verbatim and analysed using thematic analysis. RESULTS: The shock of being admitted, and awareness that smoking may have contributed to the need for hospital admission, caused many patients to reassess their quit intentions. Most patients felt the service was too good an opportunity to pass up, because having long-term support and progress monitored was more likely to result in abstinence than trying alone. Had they not been approached, many patients reported that they would have attempted to quit alone, though some would have been discouraged from doing so by pharmacotherapy costs. Service delivery by a specialist advisor was favoured by patients and HCPs, largely because HCPs lacked time and expertise to intervene. HCPs reported that in usual practice, discussions about smoking were usually limited to ascertainment of smoking status. Timing of service delivery and improved co-ordination between service staff and inpatient ward staff were matters to address. CONCLUSIONS: A hospital-based specialist smoking cessation service designed to identify smokers and initiate cessation support at the bedside was deemed appropriate by patients and HCPs. TRIAL REGISTRATION: Trial registration: ISRCTN25441641. PMID- 24472522 TI - Estrogen and cerebrovascular regulation in menopause. AB - Estrogen (E2), classically viewed as a reproductive steroid hormone, has non reproductive functions throughout the body including in the brain and vasculature. Studies report diminished neuroprotection with declining E2 levels, corresponding with higher incidence of cerebrovascular and neurological disease. However, the effects of menopausal hormone therapy (MHT) on the cerebral vasculature and brain function remain controversial. This review will focus on evidence of 17beta-estradiol actions in the cerebral vasculature, with a particular emphasis on the vasoactive, anti-inflammatory, anti-oxidant, metabolic and molecular properties. Controversies surrounding MHT in relation to cerebrovascular disease and stroke risk will be discussed, particularly the emerging evidence from clinical trials supporting the critical period hypothesis of estrogen protection. PMID- 24472524 TI - Identification of novel compounds for human bitter taste receptors. AB - The finely tuned bitter taste sensing in humans is orchestrated by a group of 25 bitter taste receptors (TAS2Rs), which belong to the G-protein-coupled receptor superfamily. TAS2Rs are expressed in the specialized taste bud cells of the gustatory system and perceive a plethora of bitter substances with versatile structures. To date, more than one hundred bitter ligands have been matched with their cognate receptors, but the understanding of the molecular mechanisms of TAS2Rs remains limited. Additionally, the extraoral expression of TAS2R genes was found in the gastrointestinal tract and respiratory system, which suggests other important physiological functions for TAS2Rs. To gain insight into the physiological functions of TAS2Rs, we established a heterologous expression system and characterized the response of 24 TAS2Rs against a library of potential bitter compounds. Among these bitter compounds of interest, 18 bitter compounds activated 16 TAS2Rs, representing 42 tastant-receptor pairs. We then calculated 14 descriptor properties for the 18 positive compounds. By comparison with 102 previously annotated bitter compounds in the database, we discovered common descriptor properties that may contribute to the discovery of additional bitter ligands and further expand the known molecular receptive ranges of human TAS2Rs. PMID- 24472523 TI - Aberrant gonadotropin-releasing hormone receptor (GnRHR) expression and its regulation of CYP11B2 expression and aldosterone production in adrenal aldosterone-producing adenoma (APA). AB - Aberrant expression of gonadotropin-releasing hormone receptor (GnRHR) has been reported in human adrenal tissues including aldosterone-producing adenoma (APA). However, the details of its expression and functional role in adrenals are still not clear. In this study, quantitative RT-PCR analysis revealed the mean level of GnRHR mRNA was significantly higher in APAs than in human normal adrenal (NA) (P=0.004). GnRHR protein expression was detected in human NA and neoplastic adrenal tissues. In H295R cells transfected with GnRHR, treatment with GnRH resulted in a concentration-dependent increase in CYP11B2 reporter activity. Chronic activation of GnRHR with GnRH (100nM), in a cell line with doxycycline inducible GnRHR (H295R-TR/GnRHR), increased CYP11B2 expression and aldosterone production. These agonistic effects were inhibited by blockers for the calcium signaling pathway, KN93 and calmidazolium. These results suggest GnRH, through heterotopic expression of its receptor, may be a potential regulator of CYP11B2 expression levels in some cases of APA. PMID- 24472525 TI - [Acute heart failure in a patient with atrial myxoma mimicking severe mitral valve stenosis]. PMID- 24472526 TI - [Authors' response to the letter to the editor as regards the article "post menopausal osteoporosis: primary prevention or excessive medication"]. PMID- 24472527 TI - The Sugarsquare study: protocol of a multicenter randomized controlled trial concerning a web-based patient portal for parents of a child with type 1 diabetes. AB - BACKGROUND: Type 1 diabetes demands a complicated disease self-management by child and parents. The overwhelming task of combining every day parenting tasks with demands of taking care of a child with diabetes can have a profound impact on parents, often resulting in increased parenting stress. Tailored disease information, easy accessible communication with healthcare professionals and peer support are found to support parents to adequately cope with the disease and the disease self-management in everyday life. Internet can help facilitate these important factors in usual pediatric diabetes care. Therefore, we will develop a web-based patient portal in addition to usual pediatric diabetes care and subsequently evaluate its efficacy and feasibility. The web-based patient portal, called Sugarsquare, provides online disease information, and facilitates online parent-professional communication and online peer support. We hypothesize that parenting stress in parents of a child with type 1 diabetes will decrease by using Sugarsquare and that Sugarsquare will be feasible in this population. METHODS/DESIGN: We will test the hypotheses using a multicenter randomized controlled trial. Eligible participants are parents of a child with type 1 diabetes under the age of 13. Parents are excluded when they have no access to the internet at home or limited comprehension of the Dutch language. Participants are recruited offline from seven clinics in the Netherlands. Participants are randomly allocated to an intervention and a control group. The intervention group will receive access to the intervention during the twelve-month study-period; the control group will receive access in the last six months of the study-period. Self-reported parenting stress is the primary outcome in the present study. Data will be gathered at baseline (T0) and at six (T1) and twelve (T2) months following baseline, using online questionnaires. User statistics will be gathered throughout the twelve-month study-period for feasibility. DISCUSSION: Dependent on its feasibility and efficacy, the intervention will be implemented into usual pediatric diabetes care. Strengths and limitations of the study are discussed. TRIAL REGISTRATION: NTR3643 (Dutch Trial Register). PMID- 24472530 TI - A nonlinear causality measure in the frequency domain: nonlinear partial directed coherence with applications to EEG. AB - BACKGROUND: Frequency domain Granger causality measures have been proposed and widely applied in analyzing rhythmic neurophysiological and biomedical signals. Almost all these measures are based on linear time domain regression models, and therefore can only detect linear causal effects in the frequency domain. NEW METHOD: A frequency domain causality measure, the partial directed coherence, is explicitly linked with the frequency response function concept of linear systems. By modeling the nonlinear relationships between time series using nonlinear models and employing corresponding frequency-domain analysis techniques (i.e., generalized frequency response functions), a new nonlinear partial directed coherence method is derived. RESULTS: The advantages of the new method are illustrated via a numerical example of a nonlinear physical system and an application to electroencephalogram signals from a patient with childhood absence epilepsy. COMPARISON WITH EXISTING METHODS: The new method detects both linear and nonlinear casual effects between bivariate signals in the frequency domain, while the existing measures can only detect linear effects. CONCLUSIONS: The proposed new method has important advantages over the classical linear measures, because detecting nonlinear dependencies has become more and more important in characterizing functional couplings in neuronal and biological systems. PMID- 24472528 TI - Autoantibodies to angiotensin and endothelin receptors in systemic sclerosis induce cellular and systemic events associated with disease pathogenesis. AB - INTRODUCTION: Vasculopathy, inflammatory fibrosis and functional autoantibodies (Abs) are major manifestations of systemic sclerosis (SSc). Abs directed against the angiotensin II type 1 receptor (AT1R) and endothelin-1 type A receptor (ETAR) are associated with characteristic disease features including vascular, inflammatory, and fibrotic complications indicating their role in SSc pathogenesis. Therefore, the impact of anti-AT1R and anti-ETAR Abs on initiation of inflammation and fibrosis was analyzed. METHODS: Anti-AT1R and anti-ETAR Ab positive immunoglobulin G (IgG) from SSc patients (SSc-IgG) was used for experiments. Healthy donor IgG served as a normal control, and AT1R and ETAR activation was inhibited by antagonists. Protein expression was measured with ELISA, mRNA expression with real time-PCR, endothelial repair with a scratch assay, and collagen expression with immunocytochemistry. Transendothelial neutrophil migration was measured with a culture insert system, and neutrophil ROS activation with immunofluorescence. Neutrophils in bronchoalveolar lavage fluids (BALFs) were analyzed microscopically after passive transfer of SSc-IgG or NC-IgG into naive C57BL/6J mice. KC plasma levels were quantified by a suspension array system. Histologic analyses were performed by using light microscopy. RESULTS: Anti-AT1R and anti-ETAR Ab-positive SSc-IgG induced activation of human microvascular endothelial cells (HMEC-1). Elevated protein and mRNA levels of the proinflammatory chemokine interleukin-8 (IL-8, CXCL8) and elevated mRNA levels of the vascular cell adhesion molecule-1 (VCAM-1) were induced in HMEC-1. Furthermore, activation of HMEC-1 with SSc-IgG increased neutrophil migration through an endothelial cell layer and activation of reactive oxygen species (ROS). SSc-IgG decreased HMEC-1 wound repair and induced type I collagen production in healthy donor skin fibroblasts. Effects of migration, wound repair, and collagen expression were dependent on the Ab-levels. Passive transfer of anti AT1R and anti-ETAR Ab-positive SSc-IgG into naive C57BL/6J mice increased neutrophil BALF counts. In parallel, increased levels of the murine functional IL 8 homologue, chemokine KC, were found in the plasma of SSc-IgG-treated mice as well as structural alterations of the lungs. CONCLUSIONS: We conclude that angiotensin and endothelin-receptor activation via anti-AT1R and anti-ETAR Abs mediate pathogenic effects, indicating their contribution to pathogenesis of SSc. Therefore, anti-AT1R and anti-ETAR Abs could provide novel targets for therapeutic intervention in the treatment of SSc. PMID- 24472531 TI - Characterizations of reflex and nonreflex changes in spastic multiple sclerosis. AB - BACKGROUND: Spasticity, an increased resistance of a limb to movement, is associated with functional limitations and a major source of disability in neurological disorders, including multiple sclerosis (MS) and stroke. Despite the clinical significance of spasticity in brain and spinal cord injuries, it is often not clear whether the spasticity is due to reflex or non-reflex changes. NEW METHOD: Reflex and nonreflex properties of the human knee joint were studied in eight MS patients with spasticity and ten healthy subjects. A digitally controlled joint driving device was used to apply small-amplitude, and band limited white-noise perturbations to the knee to manifest the reflex and nonreflex properties. The subjects were asked to maintain a steady level of background muscle torque during the perturbation. A nonlinear delay differential equation model was used to characterize the reflex and intrinsic properties of the knee in terms of phasic stretch reflex gain, tonic stretch reflex gain, joint elastic stiffness, and coefficient of viscosity. RESULTS: It was found that joint coefficient of viscosity and tonic stretch reflex gain of the spastic MS patients were significantly lower than those of normal controls. On the other hand, spastic MS patients showed higher phasic stretch reflex gains than normal controls and a trend of increased joint stiffness. CONCLUSIONS: Simultaneous characterizations of changes in tonic and phasic reflexes and nonreflex changes in joint elastic stiffness and viscosity in neurological disorders may help us gain insight into mechanisms underlying spasticity and develop impairment specific treatment. PMID- 24472532 TI - [New design of the Health Survey of Catalonia (Spain, 2010-2014): a step forward in health planning and evaluation]. AB - This article presents the genesis of the Health Survey of Catalonia (Spain, 2010 2014) with its semiannual subsamples and explains the basic characteristics of its multistage sampling design. In comparison with previous surveys, the organizational advantages of this new statistical operation include rapid data availability and the ability to continuously monitor the population. The main benefits are timeliness in the production of indicators and the possibility of introducing new topics through the supplemental questionnaire as a function of needs. Limitations consist of the complexity of the sample design and the lack of longitudinal follow-up of the sample. Suitable sampling weights for each specific subsample are necessary for any statistical analysis of micro-data. Accuracy in the analysis of territorial disaggregation or population subgroups increases if annual samples are accumulated. PMID- 24472533 TI - [Association between hours of television watched, physical activity, sleep and excess weight among young adults]. AB - OBJECTIVE: To explore the association between excess weight or body mass index (BMI) and the time spent watching television, self-reported physical activity and sleep duration in a young adult population. METHODS: We analyzed cross-sectional baseline data of 1,135 participants (17-35 years old) from the project Dieta, salud y antropometria en poblacion universitaria (Diet, Health and Anthrompmetric Variables in Univeristy Students). Information about time spent watching television, sleep duration, self-reported physical activity and self-reported height and weight was provided by a baseline questionnaire. BMI was calculated as kg/m(2) and excess of weight was defined as >=25. We used multiple logistic regression to explore the association between excess weight (no/yes) and independent variables, and multiple linear regression for BMI. RESULTS: The prevalence of excess weight was 13.7% (11.2% were overweight and 2.5% were obese). A significant positive association was found between excess weight and a greater amount of time spent watching television. Participants who reported watching television >2h a day had a higher risk of excess weight than those who watched television <=1h a day (OR=2.13; 95%CI: 1.37-3.36; p-trend: 0.002). A lower level of physical activity was associated with an increased risk of excess weight, although the association was statistically significant only in multiple linear regression (p=0.037). No association was observed with sleep duration. CONCLUSION: A greater number of hours spent watching television and lower physical activity were significantly associated with a higher BMI in young adults. Both factors are potentially modifiable with preventive strategies. PMID- 24472534 TI - Relationship between Work Hours and Smoking Behaviors in Korean Male Wage Workers. AB - OBJECTIVES: The purposes of this study are 1) to measure the prevalence of smoking according to weekly work hours by using data from the Korean Labor and Income Panel Study (KLIPS), and 2) to explain the cause of high smoking prevalence among those with short or long work hours by relative explanatory fraction. METHODS: Data from a total of 2,044 male subjects who responded to the questionnaire in the 10th year (2007) and 11th year (2008) of the Korean Labor and Income Panel Study were used for analysis. Current smoking, smoking cessation, continuous smoking, start of smoking, weekly work hours, occupational characteristics, sociodemographic and work-related factors, and health behavior related variables were analyzed. Log-binomial regression analysis was used to study the relationship between weekly work hours and smoking behaviors in terms of the prevalence ratio. RESULTS: The 2008 age-adjusted smoking prevalence was 64.9% in the short work hours group, 54.7% in the reference work hours group, and 60.6% in the long work hours group. The smoking prevalence of the short work hours group was 1.39 times higher than that of the reference work hours group (95% confidence interval of 1.17-1.65), and this was explained by demographic variables and occupational characteristics. The smoking prevalence of the long work hours group was 1.11 times higher than that of the reference work hours group when the age was standardized (95% confidence interval of 1.03-1.19). This was explained by demographic variables. No independent effects of short or long work hours were found when the variables were adjusted. CONCLUSION: Any intervention program to decrease the smoking prevalence in the short work hours group must take into account employment type, job satisfaction, and work-related factors. PMID- 24472535 TI - Association of intraoperative transfusion of blood products with mortality in lung transplant recipients. AB - BACKGROUND: The impact of intraoperative transfusion on postoperative mortality in lung transplant recipients is still elusive. METHODS: Univariate and multivariate analysis were performed to investigate the influence of red blood cells (RBCs) and fresh frozen plasma (FFP) on mortality in 134 consecutive lung transplants recipients from September 2003 until December 2008. RESULTS: Intraoperative transfusion of RBCs and FFP was associated with a significant increase in mortality with odds ratios (ORs) of 1.10 (1.03 to 1.16, P = 0.02) and 1.09 (1.02 to 1.15, P = 0.03), respectively. For more than four intraoperatively transfused RBCs multivariate analysis showed a hazard ratio for mortality of 3.8 (1.40 to 10.31, P = 0.003). Furthermore, non-survivors showed a significant increase in renal replacement therapy (RRT) (36.6% versus 6.9%, P <0.0001), primary graft dysfunction (PGD) (39.3% versus 5.9%, P <0.0001), postoperative need of extracorporeal membrane oxygenation (ECMO) (26.9% versus 3.1%, P = 0.0019), sepsis (24.2% versus 4.0%, P = 0.0004), multiple organ dysfunction syndrome (MODS) (26.9% versus 3.1%, P <0.0001), infections (18.1% versus 0.9%, P = 0.0004), retransplantation (12.1% versus 6.9%, P = 0.039) and readmission to the ICU (33.3% versus 12.8%, P = 0.024). CONCLUSIONS: Intraoperative transfusion is associated with a strong negative influence on outcome in lung transplant recipients. PMID- 24472536 TI - Expression of ATP-binding cassette membrane transporters in a HIV-1 transgenic rat model. AB - P-glycoprotein (P-gp, product of Mdr1a and Mdr1b genes), multidrug resistance associated proteins (Mrps), and breast cancer resistance protein (Bcrp), all members of the ATP-binding cassette (ABC) membrane-associated drug transporters superfamily, can significantly restrict the entry of antiretroviral drugs (ARVs) into organs which exhibit a barrier function such as the central nervous system (CNS) and the male genital tract (MGT). In vitro, HIV-1 viral proteins such as glycoprotein-120 (gp120) and transcriptional transactivator (tat) have been shown to alter the expression of these transporters and ARVs permeability. The objective of this study was to compare mRNA expression of these transporters, in vivo, in several tissues obtained from HIV-1 transgenic rats (Tg-rat) (8 and 24 weeks) with those of age-matched wild-type rats. At 24 weeks, significant changes in several drug transporter mRNA expressions were observed, in particular, in brain, kidney, liver and testes. These findings suggest that HIV-1 viral proteins can alter the expression of ABC drug transporters, in vivo, in the context of HIV 1 and further regulate ARVs permeability in several organs including the CNS and MGT, two sites which have been reported to display very low ARVs permeability in the clinic. PMID- 24472537 TI - The role of glycerol-3-phosphate dehydrogenase 1 in the progression of fatty liver after acute ethanol administration in mice. AB - Acute ethanol consumption leads to the accumulation of triglycerides (TGs) in hepatocytes. The increase in lipogenesis and reduction of fatty acid oxidation are implicated as the mechanisms underlying ethanol-induced hepatic TG accumulation. Although glycerol-3-phosphate (Gro3P), formed by glycerol kinase (GYK) or glycerol-3-phosphate dehydrogenase 1 (GPD1), is also required for TG synthesis, the roles of GYK and GPD1 have been the subject of some debate. In this study, we examine (1) the expression of genes involved in Gro3P production in the liver of C57BL/6J mice in the context of hepatic TG accumulation after acute ethanol intake, and (2) the role of GPD1 in the progression of ethanol induced fatty liver using GPD1 null mice. As a result, in C57BL/6J mice, ethanol induced hepatic TG accumulation began within 2h and was 1.7-fold greater than that observed in the control group after 6h. The up-regulation of GPD1 began 2h after administering ethanol, and significantly increased 6h later with the concomitant escalation in the glycolytic gene expression. The incorporation of (14)C-labelled glucose into TG glycerol moieties increased during the same period. On the other hand, in GPD1 null mice carrying normal GYK activity, no significant increase in hepatic TG level was observed after acute ethanol intake. In conclusion, GPD1 and glycolytic gene expression is up-regulated by ethanol, and GPD1-mediated incorporation of glucose into TG glycerol moieties together with increased lipogenesis, is suggested to play an important role in ethanol induced hepatic TG accumulation. PMID- 24472538 TI - Blockage of Stat3 enhances the sensitivity of NSCLC cells to PI3K/mTOR inhibition. AB - The PI3K/Akt/mTOR axis in lung cancer is frequently activated and implicated in tumorigenesis. Specific targeting of this pathway is therefore an attractive therapeutic approach for lung cancer. However, non-small cell lung cancer cells are resistant to BEZ235, a dual inhibitor of PI3K and mTOR. Interestingly, blockage of Stat3 with a selective inhibitor, S3I-201, or siRNA dramatically sensitized the BEZ235-induced cell death, as evident from increased PARP cleavage. Furthermore, inhibition of Stat3 led to enhancement of cell death induced by LY294002, a PI3K inhibitor. Treatment of cells with a combination of BEZ235 and S3I-201 significantly induced the proapoptotic transcription factor, CHOP, and its targets, Bim and DR4. Knockdown of CHOP or Bim suppressed cell death stimulated by the combination treatment, implicating the involvement of these BEZ235/S3I-201-induced factors in pronounced cell death. Moreover, the BEZ235/S3I-201 combination enhanced TRAIL-induced cell death. Our results collectively suggest that blockage of Stat3 presents an effective strategy to overcome resistance to PI3K/Akt/mTOR inhibition. PMID- 24472539 TI - DNA aptamers as a novel approach to neutralize Staphylococcus aureus alpha-toxin. AB - Staphylococcus aureus is a versatile pathogen capable of causing a broad spectrum of diseases ranging from superficial skin infections to life threatening conditions such as endocarditis, septicemia, pneumonia and toxic shock syndrome. In vitro and in vivo studies identified an exotoxin, alpha-toxin, as a major cause of S. aureus toxicity. Because S. aureus has rapidly evolved resistance to a number of antibiotics, including methicillin, it is important to identify new therapeutic strategies, other than antibiotics, for inhibiting the harmful effects of this pathogen. Aptamers are single-stranded DNA or RNA oligonucleotides with three-dimensional folded conformations that bind with high affinity and selectivity to targets and modulate their biological functions. The goal of this study was to isolate DNA aptamers that specifically inhibit the cytotoxic activity of alpha-toxin. After 10 rounds of Systematic Evolution of Ligands by EXponential Enrichment (SELEX), 49 potential anti-alpha-toxin aptamers were identified. In vitro neutralization assays demonstrated that 4 of these 49 aptamers, AT-27, AT-33, AT-36, and AT-49, significantly inhibited alpha-toxin mediated cell death in Jurkat T cells. Furthermore, RT-PCR analysis revealed that alpha-toxin increased the transcription of the inflammatory cytokines TNF-alpha and IL-17 and that anti-alpha-toxin aptamers AT-33 and AT-36 inhibited the upregulation of these genes. Collectively, the data suggest the feasibility of generating functionally effective aptamers against alpha-toxin for treatment of S. aureus infections. PMID- 24472540 TI - Development of an antigen microarray for high throughput monoclonal antibody selection. AB - Monoclonal antibodies are valuable laboratory reagents and are increasingly being exploited as therapeutics to treat a range of diseases. Selecting new monoclonal antibodies that are validated to work in particular applications, despite the availability of several different techniques, can be resource intensive with uncertain outcomes. To address this, we have developed an approach that enables early screening of hybridoma supernatants generated from an animal immunised with up to five different antigens followed by cloning of the antibody into a single expression plasmid. While this approach relieved the cellular cloning bottleneck and had the desirable ability to screen antibody function prior to cloning, the small volume of hybridoma supernatant available for screening limited the number of antigens for pooled immunisation. Here, we report the development of an antigen microarray that significantly reduces the volume of supernatant required for functional screening. This approach permits a significant increase in the number of antigens for parallel monoclonal antibody selection from a single animal. Finally, we show the successful use of a convenient small-scale transfection method to rapidly identify plasmids that encode functional cloned antibodies, addressing another bottleneck in this approach. In summary, we show that a hybrid approach of combining established hybridoma antibody technology with refined screening and antibody cloning methods can be used to select monoclonal antibodies of desired functional properties against many different antigens from a single immunised host. PMID- 24472541 TI - Participation of the extracellular domain in (pro)renin receptor dimerization. AB - The (pro)renin receptor [(P)RR] induces the catalytic activation of prorenin, as well as the activation of the mitogen-activated protein kinase (MAPK) signaling pathway; as such, it plays an important regulatory role in the renin-angiotensin system. (P)RR is known to form a homodimer, but the region participating in its dimerization is unknown. Using glutathione S-transferase (GST) as a carrier protein and a GST pull-down assay, we investigated the interaction of several (P)RR constructs with full-length (FL) (P)RR in mammalian cells. GST fusion proteins with FL (P)RR (GST-FL), the C-terminal M8-9 fragment (GST-M8-9), the extracellular domain (ECD) of (P)RR (GST-ECD), and the (P)RR ECD with a deletion of 32 amino acids encoded by exon 4 (GST-ECDd4) were retained intracellularly, whereas GST alone was efficiently secreted into the culture medium when transiently expressed in COS-7 cells. Immunofluorescence microscopy showed prominent localization of GST-ECD to the endoplasmic reticulum. The GST pull-down analysis revealed that GST-FL, GST-ECD, and GST-ECDd4 bound FLAG-tagged FL (P)RR, whereas GST-M8-9 showed little or no binding when transiently co-expressed in HEK293T cells. Furthermore, pull-down analysis using His-tag affinity resin showed co-precipitation of soluble (P)RR with FL (P)RR from a stable CHO cell line expressing FL h(P)RR with a C-terminal decahistidine tag. These results indicate that the (P)RR ECD participates in dimerization. PMID- 24472542 TI - Macrophage migration inhibitory factor diminishes muscle glucose transport induced by insulin and AICAR in a muscle type-dependent manner. AB - Skeletal muscle is a primary organ that uses blood glucose. Insulin- and 5'AMP activated protein kinase (AMPK)-regulated intracellular signaling pathways are known as major mechanisms that regulate muscle glucose transport. It has been reported that macrophage migration inhibitory factor (MIF) is secreted from adipose tissue and heart, and affects these two pathways. In this study, we examined whether MIF is a myokine that is secreted from skeletal muscles and affects muscle glucose transport induced by these two pathways. We found that MIF is expressed in several different types of skeletal muscle. Its secretion was also confirmed in C2C12 myotubes, a skeletal muscle cell line. Next, the extensor digitorum longus (EDL) and soleus muscles were isolated from mice and treated with recombinant MIF in an in vitro muscle incubation system. MIF itself did not have any effect on glucose transport in both types of muscles. However, glucose transport induced by a submaximal dose of insulin was diminished by co-incubation with MIF in the soleus muscle. MIF also diminished glucose transport induced by a maximal dose of 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR), an AMPK activator, in the EDL muscle. These results suggest that MIF is a negative regulator of insulin- and AICAR-induced glucose transport in skeletal muscle. Since MIF secretion from C2C12 myotubes to the culture medium decreased during contraction evoked by electrical stimulations, MIF may be involved in the mechanisms underlying exercise-induced sensitization of glucose transport in skeletal muscle. PMID- 24472543 TI - L-Cysteine-induced up-regulation of the low-density lipoprotein receptor is mediated via a transforming growth factor-alpha signalling pathway. AB - Sulphur-containing amino acids regulate plasma cholesterol levels in animals and humans. However, their mechanism of action remains unclear. Low-density lipoprotein receptor (LDLR) plays an important role in cholesterol metabolism. We therefore investigated the effects of sulphur-containing amino acids on the expression of LDLR in hepatocytes. HepG2 cells were cultured in Dulbecco's Modified Eagle's Medium with or without sulphur-containing amino acids and cysteine-containing compounds. We found that L-cysteine increased LDLR mRNA and enhanced LDLR gene promoter activity through the extracellular-signal-related kinase and p38 mitogen-activated protein kinase signalling pathways in HepG2 cells. Moreover, we observed that L-cysteine stimulated the release of transforming growth factor-alpha (TGF-alpha) and that TGF-alpha increased the LDLR mRNA levels. This study provides a report of the L-cysteine mediated up regulation of the LDLR expression via TGF-alpha signalling pathway. Our findings provide insights into cholesterol homeostasis and amino acid signalling. PMID- 24472544 TI - Tbx3 isoforms are involved in pluripotency maintaining through distinct regulation of Nanog transcriptional activity. AB - Tbx3, a member of T-box gene family, has been reported to play critical roles in embryonic development and cell fate determination. In mammalian tissues, Tbx3 is expressed as two isoforms called Tbx3 and Tbx3+2a. However, the differences between the two isoforms in pluripotency maintaining remain obscure. Here we show that both Tbx3 and Tbx3+2a are highly expressed in mouse embryonic stem cells (mESCs) or induced pluripotent stem cells (iPSCs). Overexpression of either Tbx3 or Tbx3+2a could induce the differentiation of mESCs. Mechanistic studies suggest both Tbx3 and Tbx3+2a inhibit the transcriptional activity of pluripotency related transcription factor Nanog. Moreover, Tbx3+2a could directly interact with Nanog while Tbx3 couldn't, indicating the requirement of the 2a domain in Nanog binding. In summary, our results not only reveal the essential roles of Tbx3 and Tbx3+2a in pluripotency maintaining, but also point out the different mechanistic modes between these two isoforms. PMID- 24472545 TI - Rab3A is a new interacting partner of synaptotagmin I and may modulate synaptic membrane fusion through a competitive mechanism. AB - Rab3 and synaptotagmin have been reported to be the key proteins that have opposite actions but cooperatively play critical regulatory roles in selecting and limiting the number of vesicles released at central synapses. However, the exact mechanism has not been fully understood. In this study, Rab3A and synaptotagmin I, the most abundant isoforms of Rab3 and synaptotagmin, respectively, in brain were for the first time demonstrated to directly interact with each other in a Ca(2+)-independent manner, and the KKKK motif in the C2B domain of synaptotagmin I was a key site for the Rab3A binding, which was further confirmed by the competitive inhibition of inositol hexakisphosphate. Further studies demonstrated that Rab3A competitively affected the synaptotagmin I interaction with syntaxin 1B that was involved in membrane fusion during the synaptic vesicle exocytosis. These data indicate that Rab3A is a new synaptotagmin I interacting partner and may participate in the regulation of synaptic membrane fusion and thus the vesicle exocytosis by competitively modulating the interaction of synaptotagmin with syntaxin of the t-SNARE complex in presynaptic membranes. PMID- 24472546 TI - Kv1.3 potassium channel-blocking toxin Ctri9577, novel gating modifier of Kv4.3 potassium channel from the scorpion toxin family. AB - Scorpion toxin Ctri9577, as a potent Kv1.3 channel blocker, is a new member of the alpha-KTx15 subfamily which are a group of blockers for Kv4.x potassium channels. However, the pharmacological function of Ctri9577 for Kv4.x channels remains unknown. Scorpion toxin Ctri9577 was found to effectively inhibit Kv4.3 channel currents with IC50 value of 1.34 +/- 0.03 MUM. Different from the mechanism of scorpion toxins as the blocker recognizing channel extracellular pore entryways, Ctri9577 was a novel gating modifier affecting voltage dependence of activation, steady-state inactivation, and the recovery process from the inactivation of Kv4.3 channel. However, Ctri9755, as a potent Kv1.3 channel blocker, was found not to affect voltage dependence of activation of Kv1.3 channel. Interestingly, pharmacological experiments indicated that 1 MUM Ctri9755 showed less inhibition on Kv4.1 and Kv4.2 channel currents. Similar to the classical gating modifier of spider toxins, Ctri9577 was shown to interact with the linker between the transmembrane S3 and S4 helical domains through the mutagenesis experiments. To the best of our knowledge, Ctri9577 was the first gating modifier of potassium channels among scorpion toxin family, and the first scorpion toxin as both gating modifier and blocker for different potassium channels. These findings further highlighted the structural and functional diversity of scorpion toxins specific for the potassium channels. PMID- 24472547 TI - Coexistence of sense and anti-sense mRNAs of variant surface protein in Giardia lamblia trophozoites. AB - A strategy of the parasitic protozoan Giardia lamblia to evade attack from the host immune system is periodic changes of its surface antigen, a member of the variant surface protein (VSP) family. A post-transcriptional gene silencing mechanism has been proposed to explain the presence of only one among many possible VSPs at any time. To investigate this phenomenon further, we extracted total RNA from cultured trophozoites of the G. lamblia C2 isolate, and cDNA was reverse-transcribed from the RNA. Sense and anti-sense VSPs were amplified from the total cDNA using nested PCR with primers designed from the 3'-conserved region and the known 5' or 3' end of the cDNA library. Sequence analyses of the amplified products revealed more than 34 full-length antisense VSPs and a smear of sense VSPs. Sequence alignments and comparisons revealed that these VSPs contained variable N-termini and conserved C-termini, and could be classified into 5 clades based on the sizes and variations of the N-terminal sequence. All antisense VSPs existed in the sense forms, but no corresponding antisense VSP existed for sense RNA (snsRNA) 16. The coexistence of sense and antisense VSP mRNAs in cultured G. lamblia supports the post-transcriptional regulation of VSP expression. We propose that VSPs transcribed simultaneously in the sense and antisense forms form double-stranded RNAs (dsRNAs) which are degraded by the Dicer endonuclease, while a VSP without an antisense transcription (e.g., snsRNA16) will be expressed on the surface of Giardia. In addition, in the course of this investigation VSPs were identified that were previously not known. PCR based amplification of specific sense and antisense VSP cDNAs can be used to identify the specific VSP on G. lamblia trophozoites, which is easier than using specific monoclonal antibody approaches. PMID- 24472549 TI - Changes in seed water status as characterized by NMR in developing soybean seed grown under moisture stress conditions. AB - Changes in water status of developing seeds of Soybean (Glycine max L. Merrill.) grown under different moisture stress conditions were characterized by proton nuclear magnetic resonance (NMR)- spin-spin relaxation time (T2). A comparison of the seed development characteristics, composition and physical properties indicated that, characteristics like seed weight, seed number/ear, rate of seed filling increased with development stages but decreased with moisture stress conditions. The NMR- spin-spin relaxation (T2) component like bound water increased with seed maturation (40-50%) but decreased with moisture stress conditions (30-40%). The changes in seed water status to increasing levels of moisture stress and seed maturity indicates that moisture stress resulted in more proportion of water to bound state and intermediate state and less proportion of water in free-state. These changes are further corroborated by significant changes in protein and starch contents in seeds under high moisture stress treatments. Thus seed water status during its development is not only affected by development processes but also by moisture stress conditions. This study strongly indicated a clear moisture stress and development stage dependence of seed tissue water status in developing soybean seeds. PMID- 24472548 TI - Combinatory use of cell-free protein expression, limited proteolysis and mass spectrometry for the high-throughput protein domain identification. AB - The structural domains of proteins have often been identified through the use of limited proteolysis. In structural genomics studies, it is necessary to carry this out in a high-throughput manner. Here, we constructed a novel high throughput system, which consists of cell-free protein expression and one-step affinity purification, followed by limited proteolysis using a unique new method, referred to "on beads method". All these steps were carried out on 96-well plate formats and completed in two days, even by manual handling. The merits of the new method versus the conventional one are as follows: (1) experimental times are reduced, (2) the sample preparation for limited proteolysis experiments is simplified, and (3) both protein purification and limited digestion can be performed "in situ" on the same sample plate. This preparation method is therefore suitable for highly automated, proteolytic analyses coupled to mass spectrometry techniques at a micro-scale protein expression level. The resulting protease-resistant fragments were analyzed by MALDI-TOF-MS and protein domains of 34 mouse cDNA products were identified with this system. PMID- 24472550 TI - The 31-kDa caspase-generated cleavage product of p130Cas antagonizes the action of MyoD during myogenesis. AB - Myogenesis is regulated by the basic helix-loop-helix (bHLH) myogenic regulatory factor MyoD, which induces muscle-specific gene expression by binding to the E box sequence as a heterodimer with ubiquitous bHLH E2A (E12/E47) proteins. Here, we report that a 31-kDa caspase-generated cleavage product of Crk-associated substrate (p130Cas), herein called 31-kDa, is downregulated during muscle cell differentiation. 31-kDa contains a helix-loop-helix (HLH) domain that shows greater sequence homology with Id (inhibitor of DNA binding) proteins than with bHLH proteins. This HLH domain, lacking the basic region required for DNA binding, mediated the direct interaction of 31-kDa with MyoD. Overexpression of 31-kDa in C3H10T1/2 cells inhibited not only the transcriptional activation of p21(Waf1/Cip1) and E-box-dependent muscle-specific genes by MyoD and/or E2A but also MyoD-induced myosin heavy chain expression and myogenic conversion. In sum, our results suggest a role for 31-kDa as a negative regulator of MyoD in the muscle differentiation program. PMID- 24472551 TI - Novel properties of antimicrobial peptide anoplin. AB - Antimicrobial decapeptide anoplin was tested for its antifungal activity against plant pathogen Leptosphaeria maculans and protection of Brassica napus plants from disease. To reveal the mode of action of the peptide, a natural form of anoplin amidated on C-terminus (ANP-NH2), and its carboxylated analog (ANP-OH) were used in the study. We demonstrated strong antifungal activity of anoplin in vitro regardless C-terminus modification. In addition we show that both ANP-NH2 and ANP-OH induce expression of defence genes in B. napus and protects plants from L. maculans infection. The results indicate that the amidation of anoplin is not essential for its antifungal and plant defence stimulating activities. PMID- 24472552 TI - Functional expression of an scFv on bacterial magnetic particles by in vitro docking. AB - A Gram-negative, magnetotactic bacterium, Magnetospirillum magneticum AMB-1 produces nano-sized magnetic particles (BacMPs) in the cytoplasm. Although various applications of genetically engineered BacMPs have been demonstrated, such as immunoassay, ligand-receptor interaction or cell separation, by expressing a target protein on BacMPs, it has been difficult to express disulfide bonded proteins on BacMPs due to lack of disulfide-bond formation in the cytoplasm. Here, we propose a novel dual expression system, called in vitro docking, of a disulfide-bonded protein on BacMPs by directing an immunoglobulin Fc-fused target protein to the periplasm and its docking protein ZZ on BacMPs. By in vitro docking, an scFv-Fc fusion protein was functionally expressed on BacMPs in the dimeric or trimeric form. Our novel disulfide-bonded protein expression system on BacMPs will be useful for efficient screening of potential ligands or drugs, analyzing ligand-receptor interactions or as a magnetic carrier for affinity purification. PMID- 24472553 TI - Sequential introduction and dosage balance of defined transcription factors affect reprogramming efficiency from pancreatic duct cells into insulin-producing cells. AB - While the exogenous expression of a combination of transcription factors have been shown to induce the conversion of non-beta cells into insulin-producing cells, the reprogramming efficiency remains still low. In order to develop an in vitro screening system for an optimized reprogramming protocol, we generated the reporter cell line mPac-MIP-RFP in which the reprogramming efficiency can be quantified with red fluorescent protein expressed under the control of the insulin promoter. Analysis with mPac-MIP-RFP cells sequentially infected with adenoviruses expressing Pdx1, Neurog3, and Mafa revealed that expression of Pdx1 prior to Neurog3 or Mafa augments the reprogramming efficiency. Next, infection with a polycistronic adenoviral vector expressing Pdx1, Neurog3 and Mafa significantly increased the expression level of insulin compared with the simultaneous infection of three adenoviruses carrying each transcription factor, although excessive expression of Mafa together with the polycistronic vector dramatically inhibited the reprogramming into insulin-producing cells. Thus, in vitro screening with the mPac-MIP-RFP reporter cell line demonstrated that the timing and dosage of gene delivery with defined transcription factors influence the reprogramming efficiency. Further investigation should optimize the reprogramming conditions for the future cell therapy of diabetes. PMID- 24472554 TI - Increasing matrix stiffness upregulates vascular endothelial growth factor expression in hepatocellular carcinoma cells mediated by integrin beta1. AB - Matrix stiffness as a novel regulation factor involves in modulating the pathogenesis of hepatocellular carcinoma (HCC) invasion or metastasis. However, the mechanism by which matrix stiffness modulates HCC angiogenesis remains unknown. Here, using buffalo rat HCC models with different liver matrix stiffness backgrounds and an in vitro cell culture system of mechanically tunable Collagen1 (COL1)-coated polyacrylamide gel, we investigated the effects of different matrix stiffness levels on vascular endothelial growth factor (VEGF) expression in HCC cells and explored its regulatory mechanism for controlling HCC angiogenesis. Tissue microarray analysis showed that the expression levels of VEGF and CD31 were gradually upregulated in tumor tissues with increasing COL1 and lysyl oxidase (LOX) expression, indicating a positive correlation between tumor angiogenesis and matrix rigidity. The expression of VEGF and the phosphorylation levels of PI3K and Akt were all upregulated in HCC cells on high-stiffness gel than on low-stiffness gel. Meanwhile, alteration of intergrin beta1 expression was found to be the most distinctive, implying that it might mediate the response of HCC cells to matrix stiffness simulation. After integrin beta1 was blocked in HCC cells using specific monoclonal antibody, the expression of VEGF and the phosphorylation levels of PI3K and Akt at different culture times were accordingly suppressed and downregulated in the treatment group as compared with those in the control group. All data suggested that the extracellular matrix stiffness stimulation signal was transduced into HCC cells via integrin beta1, and this signal activated the PI3K/Akt pathway and upregulated VEGF expression. This study unveils a new paradigm in which matrix stiffness as initiators to modulate HCC angiogenesis. PMID- 24472556 TI - HUWE1 interacts with BRCA1 and promotes its degradation in the ubiquitin proteasome pathway. AB - The cellular BRCA1 protein level is essential for its tumor suppression activity and is tightly regulated through multiple mechanisms including ubiquitn proteasome system. E3 ligases are involved to promote BRCA1 for ubiquitination and degradation. Here, we identified HUWE1/Mule/ARF-BP1 as a novel BRCA1 interacting protein involved in the control of BRCA1 protein level. HUWE1 binds BRCA1 through its N-terminus degron domain. Depletion of HUWE1 by siRNA-mediated interference significantly increases BRCA1 protein levels and prolongs the half life of BRCA1. Moreover, exogenous expression of HUWE1 promotes BRCA1 degradation through the ubiquitin-proteasome pathway, which could explain an inverse correlation between HUWE1 and BRCA1 levels in MCF10F, MCF7 and MDA-MB-231 breast cancer cells. Consistent with a functional role for HUWE1 in regulating BRCA1 mediated cellular response to DNA damage, depletion of HUWE1 by siRNA confers increased resistance to ionizing radiation and mitomycin. These data indicate that HUWE1 is a critical negative regulator of BRCA1 and suggest a new molecular mechanism for breast cancer pathogenesis. PMID- 24472555 TI - Ascorbate reverses high glucose- and RAGE-induced leak of the endothelial permeability barrier. AB - High glucose concentrations due to diabetes increase leakage of plasma constituents across the endothelial permeability barrier. We sought to determine whether vitamin C, or ascorbic acid (ascorbate), could reverse such high glucose induced increases in endothelial barrier permeability. Human umbilical vein endothelial cells and two brain endothelial cell lines cultured at 25 mM glucose showed increases in endothelial barrier permeability to radiolabeled inulin compared to cells cultured at 5mM glucose. Acute loading of the cells for 30-60 min with ascorbate before the permeability assay prevented the high glucose induced increase in permeability and decreased basal permeability at 5mM glucose. High glucose-induced barrier leakage was mediated largely by activation of the receptor for advanced glycation end products (RAGE), since it was prevented by RAGE blockade and mimicked by RAGE ligands. Intracellular ascorbate completely prevented RAGE ligand-induced increases in barrier permeability. The high glucose induced increase in endothelial barrier permeability was also acutely decreased by several cell-penetrant antioxidants, suggesting that at least part of the ascorbate effect could be due to its ability to act as an antioxidant. PMID- 24472557 TI - Impaired glomerulogenesis and endothelial cell migration in Pkd1-deficient renal organ cultures. AB - The PKD1 gene is essential for a number of biological functions, and its loss-of function causes autosomal dominant polycystic kidney disease (ADPKD). The gene is developmentally regulated and believed to play an essential role in renal development. Previous studies have shown that manipulating murine renal organ cultures with dominant-negative forms of the Pkd1 gene impaired ureteric bud (UB) branching. In the current study, we analyzed different stages of renal development in two distinct mouse models carrying either a null mutation or inactivation of the last two exons of Pkd1. Surprisingly, metanephric explants from Pkd1-deleted kidneys harvested at day E11.5 did not show defects of UB branching and elongation, estimated by cytokeratin staining on fixed tissues or by Hoxb7-GFP time-lapse imaging. However, renal explants from Pkd1-mutants isolated at day E14.5 showed impaired nephrogenesis. Notably, we observed cell migratory defects in the developing endothelial compartment. Previous studies had implicated the Pkd1 gene in controlling cell migration and collagen deposition through PI3 kinases. In line with these studies, our results show that wild-type explants treated with PI3-kinase inhibitors recapitulate the endothelial defects observed in Pkd1 mutants, whereas treatment with VEGF only partially rescued the defects. Our data are consistent with a role for the Pkd1 gene in the endothelium that may be required for proper nephrogenesis. PMID- 24472558 TI - Combinatorial epigenetic patterns as quantitative predictors of chromatin biology. AB - BACKGROUND: Chromatin immunoprecipitation followed by deep sequencing (ChIP-seq) is the most widely used method for characterizing the epigenetic states of chromatin on a genomic scale. With the recent availability of large genome-wide data sets, often comprising several epigenetic marks, novel approaches are required to explore functionally relevant interactions between histone modifications. Computational discovery of "chromatin states" defined by such combinatorial interactions enabled descriptive annotations of genomes, but more quantitative approaches are needed to progress towards predictive models. RESULTS: We propose non-negative matrix factorization (NMF) as a new unsupervised method to discover combinatorial patterns of epigenetic marks that frequently co occur in subsets of genomic regions. We show that this small set of combinatorial "codes" can be effectively displayed and interpreted. NMF codes enable dimensionality reduction and have desirable statistical properties for regression and classification tasks. We demonstrate the utility of codes in the quantitative prediction of Pol2-binding and the discrimination between Pol2-bound promoters and enhancers. Finally, we show that specific codes can be linked to molecular pathways and targets of pluripotency genes during differentiation. CONCLUSIONS: We have introduced and evaluated a new computational approach to represent combinatorial patterns of epigenetic marks as quantitative variables suitable for predictive modeling and supervised machine learning. To foster widespread adoption of this method we make it available as an open-source software-package - epicode at https://github.com/mcieslik-mctp/epicode. PMID- 24472559 TI - The role played by alternative splicing in antigenic variability in human endo parasites. AB - Endo-parasites that affect humans include Plasmodium, the causative agent of malaria, which remains one of the leading causes of death in human beings. Despite decades of research, vaccines to this and other endo-parasites remain elusive. This is in part due to the hyper-variability of the parasites surface proteins. Generally these surface proteins are encoded by a large family of genes, with only one being dominantly expressed at certain life stages. Another layer of complexity can be introduced through the alternative splicing of these surface proteins. The resulting isoforms may differ from each other with regard to cell localisation, substrate affinities and functions. They may even differ in structure to the extent that they are no longer recognised by the host's immune system. In many cases this leads to changes in the N terminus of these proteins. The geographical localisation of endo-parasitic infections around the tropics and the highest incidences of HIV-1 infection in the same areas, adds a further layer of complexity as parasitic infections affect the host immune system resulting in higher HIV infection rates, faster disease progression, and an increase in the severity of infections and complications in HIV diagnosis. This review discusses some examples of parasite surface proteins that are alternatively spliced in trypanosomes, Plasmodium and the parasitic worm Schistosoma as well as what role alternate splicing may play in the interaction between HIV and these endo parasites. PMID- 24472560 TI - Consumption of a low glycaemic index diet in late life extends lifespan of Balb/c mice with differential effects on DNA damage. AB - BACKGROUND: Caloric restriction is known to extend the lifespan of all organisms in which it has been tested. Consequently, current research is investigating the role of various foods to improve health and lifespan. The role of various diets has received less attention however, and in some cases may have more capacity to improve health and longevity than specific foods alone. We examined the benefits to longevity of a low glycaemic index (GI) diet in aged Balb/c mice and examined markers of oxidative stress and subsequent effects on telomere dynamics. RESULTS: In an aged population of mice, a low GI diet extended average lifespan by 12%, improved glucose tolerance and had impressive effects on amelioration of oxidative damage to DNA in white blood cells. Telomere length in quadriceps muscle showed no improvement in the dieted group, nor was telomerase reactivated. CONCLUSION: The beneficial effects of a low GI diet are evident from the current study and although the impact to telomere dynamics late in life is minimal, we expect that earlier intervention with a low GI diet would provide significant improvement in health and longevity with associated effects to telomere homeostasis. PMID- 24472561 TI - Acute symptoms after a community hydrogen fluoride spill. AB - OBJECTIVES: This study was conducted to describe the demographic characteristics, and clinical signs and symptoms of patients who visited a general hospital because of the release of chemically hazardous hydrogen fluoride that occurred on September 27, 2012 in Gumi City, Korea. METHODS: The medical records at 1 general hospital 9 km from the accident site were reviewed using a standardized survey format. There were 1,890 non-hospitalized and 12 hospitalized patients exposed to hydrogen fluoride between September 27 and October 13 2012. RESULTS: Among the 12 hospitalized patients, 11 were discharged within 1 week and the other was hospitalized for 10 days. The chief complaints were respiratory symptoms such as hemoptysis and shortness of breath, gastrointestinal symptoms, neurologic symptoms, sore throat, and lip burn.The number of non-hospitalized patients exhibited a bimodal distribution, peaking on the first and twelfth days after the accident. Their chief complaints were sore throat (24.1%), headache (19.1%), cough (13.1%), and eye irritation (9.2%); some patients were asymptomatic (6.2%). Patients who visited the hospital within 3 days (early patients) of the spill more often had shortness of breath (27.0%) and nausea (6.3%) as the chief complaints than patients who visited after 3 days (late patients) (3.5% and 2.6%, respectively). However, cough and rhinorrhea were more common in the late patients (14.0% and 3.3%, respectively) than in the early patients (5.0% and 0.0%, respectively). Patients who were closer to the accident site more often had shortness of breath and sputum as the chief complaints than patients who were farther away. The mean serum calcium concentration was 9.37 mg/dL (range: 8.4 11.0 mg/dL); none of the patients had a decreased serum calcium level. Among 48 pulmonary function test results, 4 showed decreased lung function. None of the patients had abnormal urine fluoride levels on the eighth day after exposure. CONCLUSIONS: Patients hospitalized due to chemical hazard release of hydrogen fluoride had acute respiratory, gastrointestinal, and neurologic health problems. Non-hospitalized patients have acute symptoms mainly related to upper respiratory irritation. PMID- 24472562 TI - Gibbs adsorption equation for planar fluid-fluid interfaces: Invariant formalism. AB - The fundamental underpinnings of the Gibbs adsorption equation (GAE) are enunciated including sundry choices for the location of the zero-volume dividing surface. Comparison is made to the finite-volume thermodynamic analyses of Guggenheim and Hansen. Provided that Gibbs phase rule is properly invoked, only invariant surface properties appear in the GAE. In the framework of invariant surface properties, both the zero-volume (Gibbs) and the finite-volume (Guggenheim) treatments of the surface phase give identical results for the GAE, confirming the thermodynamic generality and rigor of the expression. Application of the GAE is made to strong and weak electrolytes, to electrified interfaces (Lippmann equation), and to surface complexation. Usefulness of the GAE in molecular simulation of interfaces is outlined. Special attention is paid to the seminal contributions of Fainerman and Miller in applying molecular-thermodynamic interfacial-layer models toward predicting adsorption behavior at fluid/fluid interfaces. Conversion of adsorption isotherms into two-dimensional interfacial tension equations of state via the GAE is highlighted. Confusion over interpretation of the Gibbs adsorption equation arises primarily because of imprecise meaning for adsorbed amounts. Once invariant adsorptions are recognized and utilized, the Gibbs adsorption equation yields identical results for Gibbs zero-volume surface thermodynamics and for Guggenheim finite-volume surface thermodynamics. PMID- 24472563 TI - Complex adaptive therapeutic strategy for cancer treatment. PMID- 24472564 TI - A case of anaphylaxis to peppermint. AB - BACKGROUND: Anaphylaxis, a form of IgE mediated hypersensitivity, arises when mast cells and possibly basophils are provoked to secrete mediators with potent vasoactive and smooth muscle contractile activities that evoke a systemic response. We report a case of IgE mediated anaphylaxis to peppermint (Mentha piperita) in a male shortly after sucking on a candy. CASE PRESENTATION: A 69 year old male developed sudden onset of lip and tongue swelling, throat tightness and shortness of breath within five minutes of sucking on a peppermint candy. He denied lightheadedness, weakness, nausea, vomiting, or urticaria. He took 25 mg of diphenhydramine, but his symptoms progressed to onset of cough, wheeze and difficulty with talking and swallowing. He was rushed to the nearest emergency department, where he was treated with intramuscular epinephrine, antihistamines and steroids. On history, he reported recent onset of mouth itchiness and mild tongue and lip swelling after using Colgate peppermint toothpaste. He denied previous history of asthma, allergic rhinitis, food or drug allergies. His past medical history was remarkable for hypercholesterolemia, gastroesophageal reflux and gout. He was on simvastatin, omeprazole, aspirin, and was carrying a self injectable epinephrine device. He moved to current residence three years ago and cultivated mint plants in his backyard. He admitted to develop nasal congestion, cough and wheeze when gardening. Physical examination was unremarkable apart from slightly swollen pale inferior turbinates. Skin prick test (SPT) was strongly positive to a slurry of peppermint candy and fresh peppermint leaf, with appropriate controls. Same tests performed on five healthy volunteers yielded negative results. Skin testing to common inhalants including molds and main allergenic foods was positive to dust mites. Strict avoidance of mint containing items was advised. Upon reassessment, he had removed mint plants from his garden which led to resolution of symptoms when gardening. CONCLUSION: IgE mediated anaphylaxis to peppermint is rare. This case demonstrates a systemic reaction to a commonly consumed item, incapable of triggering anaphylaxis in the far majority of the population, yet causing a severe episode for our patient. PMID- 24472565 TI - Rapid eye movement sleep deprivation disrupts consolidation but not reconsolidation of novel object recognition memory in rats. AB - There is increasing evidence that sleep plays a critical role in memory consolidation. However, there are comparatively few studies that have assessed the relationship between sleep and memory reconsolidation. In the present study, we explored the effects of rapid eye movement sleep deprivation (RSD) on the consolidation (experiment 1) and reconsolidation (experiment 2) of novel object recognition memory in rats. In experiment 1 behavioral procedure involved two training phases: sample and test. Rats were subjected to 6h RSD starting either immediately after sample (exposed to 2 objects) or 6h later. In experiment 2 behavioral procedure involved three training phases: sample, reactivation and test. Rats were subjected to 6h RSD starting either immediately after reactivation (exposed to the same 2 sample objects to reactivate the memory trace) or 6h later. Results from experiment 1 showed that post-sample RSD from 0 to 6h but not 6 to 12h disrupted novel object recognition memory consolidation. However, we found that post-reactivation RSD whether from 0 to 6h or 6 to 12h had no effect on novel object recognition memory reconsolidation in experiment 2. The results indicated that RSD selectively disrupted consolidation of novel object recognition memory, suggesting a dissociation effect of RSD on consolidation and reconsolidation. PMID- 24472566 TI - Leukemia inhibitory factor in the neuroimmune communication pathways in allergic asthma. AB - In the pathogenesis of asthma, central sensitization is suggested to be an important neural mechanism, and neurotrophins and cytokines are likely to be the major mediators in the neuroimmune communication pathways of asthma. However, their impact on the central nervous system in allergic asthma remains unclear. We hypothesize that central neurogenic inflammation develops in the pathogenesis of allergic asthma, and nerve growth factor (NGF) and leukemia inhibitory factor (LIF) are important mediators in its development. An asthma model of rats was established by sensitization and challenged with ovalbumin (OVA). For further confirmation of the role of LIF in neurogenic inflammation, a subgroup was pretreated with intraperitoneally (i.p.) LIF antibody before OVA challenge. The levels of LIF and NGF were measured with reverse transcription and polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry stain in lung tissue, airway-specific dorsal root ganglia (DRG, C7-T5) and brain stem of asthmatic rats, anti-LIF pretreated rats and controls. A significantly increased number of LIF- and NGF-immunoreactive cells were detected in lung tissue, DRG and the brain stem of asthmatic rats. In the asthma group a significantly increase level of mRNA encoding LIF and NGF in lung tissue was detected, but not in DRG and the brain stem. Pretreatment with LIF antibody decreased the level of LIF and NGF in all tissues. LIF is an important mediator in the crosstalk between nerve and immune systems. Our study demonstrate that the increased level of LIF and NGF in DRG and brain stem may be not based on result from de novo synthesis, but rather on result from retrograde nerve transport or passage across the blood-brain-barrier. PMID- 24472568 TI - Biogenic and anthropogenic isoprene in the near-surface urban atmosphere--a case study in Essen, Germany. AB - Isoprene is emitted in large quantities by vegetation, exhaled by human beings and released in small quantities by road traffic. As a result of its high reactivity, isoprene is an important ozone precursor in the troposphere and can play a key role in atmospheric chemistry. Measurements of isoprene in urban areas in Central Europe are scarce. Thus, in Essen, Germany, the isoprene concentration was measured at various sites during different seasons using two compact online GC-PID systems. Isoprene concentrations were compared with those of benzene and toluene, which represent typical anthropogenic VOCs. In the summer, the diurnal variation in isoprene concentration was dependent on the biogenic emissions in the city. It was found that its maximum concentration occurred during the day, in contrast to the benzene and toluene concentrations. During the measurement period in the summer of 2012, the average hourly isoprene concentrations reached 0.13 to 0.17 ppb between 10 and 20 LST. At high air temperatures, the isoprene concentration exceeded the benzene and toluene concentrations at many of the sites. Isoprene became more important than toluene with regard to ozone formation in the city area during the afternoon hours of summer days with high air temperatures. This finding was demonstrated by the contributions to OH reactivity and ozone-forming potential. It contradicts the results of other studies, which were based on daily or seasonal average values. With an isoprene/benzene ratio of 0.02, the contribution of anthropogenic isoprene decreased substantially to a very low level during the last 20 years in Central Europe due to a strong reduction in road traffic emissions. In the vicinity of many people, isoprene concentrations of up to 0.54 ppb and isoprene/benzene ratios of up to 1.34 were found in the atmosphere due to isoprene exhaled by humans. PMID- 24472567 TI - Role of angiotensin-(1-7) and Mas-R-nNOS pathways in amplified neuronal activity of dorsolateral periaqueductal gray after chronic heart failure. AB - The midbrain periaqueductal gray (PAG) is an integrative neural site in regulating several physiological functions including cardiovascular activities driven by sympathetic nervous system. Specifically, activation of the dorsolateral PAG (dl-PAG) leads to increases in sympathetic nervous activity and arterial blood pressure. Our recent studies demonstrated that angiotensin-(1-7) [Ang-(1-7)] plays an inhibitory role in neuronal activity of the dl-PAG via a Mas R [Ang-(1-7) receptor] and neuronal NO dependent signaling pathway (Mas-R-nNOS). Because sympathetic nervous activity is augmented in chronic heart failure (HF), the present study was to determine (1) the levels of Ang-(1-7) and Mas-R-nNOS expression within the dl-PAG of control rats and rats with HF and (2) the role for Ang-(1-7) in modulating activity of dl-PAG neurons in both groups. Results showed that chronic HF decreased the levels of Ang-(1-7) and attenuated Mas-R nNOS pathways. Also, we demonstrated that the discharge rates of dl-PAG neurons of HF rats (5.52 +/- 0.52 Hz, n=21, P<0.05 vs. control) were augmented as compared with control rats (4.03 +/- 0.39 Hz, n=28) and an inhibitory role played by Ang-(1-7) in neuronal activity of the dl-PAG was significantly decreased in HF (51 +/- 6%, P<0.05 vs. control) as compared with controls (72 +/- 8%). Our findings suggest that the inhibitory effects of Ang-(1-7) on dl-PAG neurons are impaired in HF, likely due to attenuated Mas-R-nNOS signaling pathways. PMID- 24472569 TI - Validity of two brief primary care physical activity questionnaires with accelerometry in clinic staff. AB - BACKGROUND: To date, no physical activity (PA) questionnaires intended for primary care have been compared against a criterion measure of PA and current (2008) aerobic PA recommendations of the American College of Sports Medicine/American Heart Association (ACSM/AHA). AIM: This study evaluated preliminary evidence for criterion validity of two brief (<1 min) PA questionnaires with accelerometry, and their ability to identify if individuals meet ACSM/AHA PA recommendations. METHODS: 45 health clinic staff wore an accelerometer for seven consecutive days and afterwards completed two brief PA questionnaires, the Physical Activity Vital Sign (PAVS), and the Speedy Nutrition and Physical Activity Assessment (SNAP). Agreement and descriptive statistics were calculated between the PAVS or SNAP and accelerometry in order to measure each questionnaire's ability to quantify the number of days participants achieved ? 30 min of moderate-vigorous PA (MVPA) performed in bouts of ? 10 continuous minutes. Participants with <5 days of ? 30 bout-min of MVPA were considered insufficiently active according to PA recommendations. FINDINGS: There was a significant positive correlation between number of days with ? 30 bout-min MVPA and the PAVS (r = 0.52, P < 0.001), and SNAP ( r= 0.31, P < 0.05). The PAVS had moderate agreement with accelerometry for identifying if individuals met or did not meet PA recommendations (kappa = 0.46, P < 0.001), whereas SNAP had poor agreement (kappa = 0.12, P < 0.05). CONCLUSIONS: This study provides preliminary evidence of criterion validity of the PAVS and SNAP with accelerometry and agreement identifying if respondents meet current (2008) ACSM/AHA aerobic PA recommendations. The PAVS and SNAP should be evaluated further for repeatability, and in populations varying in PA levels, age, gender, and ethnicity. PMID- 24472570 TI - Modeling of compound profiling experiments using support vector machines. AB - Profiling of compounds against target families has become an important approach in pharmaceutical research for the identification of hits and analysis of selectivity and promiscuity patterns. We report on modeling of profiling experiments involving 429 potential inhibitors and a panel of 24 different kinases using support vector machine (SVM) techniques and naive Bayesian classification. The experimental matrix contained many different activity profiles. SVM predictions achieved overall high accuracy due to consistently low false-positive and consistently high true-negative rates. However, predictions for promiscuous inhibitors were affected by false-negative rates. Combined target based SVM classifiers reached or exceeded the performance of SVM profile prediction methods and were superior to Bayesian classification. The classifiers displayed different prediction characteristics including diverse combinations of false-positive and true-negative rates. Predicted and experimentally observed compound activity profiles were compared in detail, revealing activity patterns modeled with different accuracy. PMID- 24472571 TI - Serum arterial lactate concentration predicts mortality and organ dysfunction following liver resection. AB - BACKGROUND: The aim of this study was to determine if the post-operative serum arterial lactate concentration is associated with mortality, length of hospital stay or complications following hepatic resection. METHODS: Serum lactate concentration was recorded at the end of liver resection in a consecutive series of 488 patients over a seven-year period. Liver function, coagulation and electrolyte tests were performed post-operatively. Renal dysfunction was defined as a creatinine rise of >1.5x the pre-operative value. RESULTS: The median lactate was 2.8 mmol/L (0.6 to 16 mmol/L) and was elevated (>=2 mmol/L) in 72% of patients. The lactate concentration was associated with peak post-operative bilirubin, prothrombin time, renal dysfunction, length of hospital stay and 90 day mortality (P < 0.001). The 90-day mortality in patients with a post-operative lactate >=6 mmol/L was 28% compared to 0.7% in those with lactate <=2 mmol/L. Pre operative diabetes, number of segments resected, the surgeon's assessment of liver parenchyma, blood loss and transfusion were independently associated with lactate concentration. CONCLUSIONS: Initial post-operative lactate concentration is a useful predictor of outcome following hepatic resection. Patients with normal post-operative lactate are unlikely to suffer significant hepatic or renal dysfunction and may not require intensive monitoring or critical care. PMID- 24472572 TI - Lifespan extension and delay of age-related functional decline caused by Rhodiola rosea depends on dietary macronutrient balance. AB - BACKGROUND: This study was conducted to evaluate the effects of rhizome powder from the herb Rhodiola rosea, a traditional Western Ukraine medicinal adaptogen, on lifespan and age-related physiological functions of the fruit fly Drosophila melanogaster. RESULTS: Flies fed food supplemented with 5.0 mg/ml and 10.0 mg/ml of R. rosea rhizome powder had a 14% to 17% higher median lifespan, whereas at 30.0 mg/ml lifespan was decreased by 9% to 12%. The preparation did not decrease fly fecundity.The effect of R. rosea supplement on lifespan was dependent on diet composition. Lifespan extension by 15% to 21% was observed only for diets with protein-to-carbohydrate ratios less than 1. Lifespan extension was also dependent on total concentration of macronutrients. Thus, for the diet with 15% yeast and 15% sucrose there was no lifespan extension, while for the diet with protein-to carbohydrate ratio 20:1 R. rosea decreased lifespan by about 10%.Flies fed Rhodiola preparation were physically more active, less sensitive to the redox cycling compound menadione and had a longer time of heat coma onset compared with controls. Positive effects of Rhodiola rhizome on stress resistance and locomotor activity were highest at the 'middle age'. CONCLUSIONS: The present data show that long-term food supplementation with R. rosea rhizome not only increases D. melanogaster lifespan, but also delays age-related decline of physical activity and increases stress resistance, what depends on protein-to-carbohydrate ratio of the diet. PMID- 24472573 TI - Expanding horizons in iron chelation and the treatment of cancer: role of iron in the regulation of ER stress and the epithelial-mesenchymal transition. AB - Cancer is a major public health issue and, despite recent advances, effective clinical management remains elusive due to intra-tumoural heterogeneity and therapeutic resistance. Iron is a trace element integral to a multitude of metabolic processes, including DNA synthesis and energy transduction. Due to their generally heightened proliferative potential, cancer cells have a greater metabolic demand for iron than normal cells. As such, iron metabolism represents an important "Achilles' heel" for cancer that can be targeted by ligands that bind and sequester intracellular iron. Indeed, novel thiosemicarbazone chelators that act by a "double punch" mechanism to both bind intracellular iron and promote redox cycling reactions demonstrate marked potency and selectivity in vitro and in vivo against a range of tumours. The general mechanisms by which iron chelators selectively target tumour cells through the sequestration of intracellular iron fall into the following categories: (1) inhibition of cellular iron uptake/promotion of iron mobilisation; (2) inhibition of ribonucleotide reductase, the rate-limiting, iron-containing enzyme for DNA synthesis; (3) induction of cell cycle arrest; (4) promotion of localised and cytotoxic reactive oxygen species production by copper and iron complexes of thiosemicarbazones (e.g., Triapine((r)) and Dp44mT); and (5) induction of metastasis and tumour suppressors (e.g., NDRG1 and p53, respectively). Emerging evidence indicates that chelators can further undermine the cancer phenotype via inhibiting the epithelial-mesenchymal transition that is critical for metastasis and by modulating ER stress. This review explores the "expanding horizons" for iron chelators in selectively targeting cancer cells. PMID- 24472574 TI - How citrullination invaded rheumatoid arthritis research. AB - Citrullination and the immune response to citrullinated proteins have been fundamental for the early recognition of rheumatoid arthritis by serological tests and a better understanding of its pathophysiology. In the first years after the initial publications, the focus was on the antibodies directed to citrullinated proteins. It is now realized that citrullinating enzymes and citrullinated proteins may have important roles in the maintenance of the inflammatory processes in the joints. There is also accumulating evidence for a direct role of citrullination in tissue destruction in the rheumatoid synovium. Here we will discuss the development and importance of anti-citrullinated protein antibodies in rheumatoid arthritis as well as recent findings implicating citrullination in the pathophysiology of rheumatoid arthritis. PMID- 24472575 TI - Acute Symptoms in Firefighters who Participated in Collection Work after the Community Hydrogen Fluoride Spill Accident. AB - OBJECTIVES: This study aimed to analyze the relationship between clinical status and work characteristics of firefighters and other public officers who engaged on collection duties in the site of the hydrogen fluoride spill that occurred on September 27, 2012, in Gumi City, South Korea. METHODS: We investigated the clinical status, personal history, and work characteristics of the study subjects and performed physical examination and several clinical examinations, including chest radiography, echocardiography, pulmonary function test, and blood testing in 348 firefighters, police officers, volunteer firefighters, and special warfare reserved force who worked at the hydrogen fluoride spill area. RESULTS: The subjects who worked near the accident site more frequently experienced eye symptoms (p = 0.026), cough (p = 0.017), and headache (p = 0.003) than the subjects who worked farther from the accident site. The longer the working hours at the accident area, the more frequently the subjects experienced pulmonary (p = 0.027), sputum (p = 0.043), and vomiting symptoms (p = 0.003). The subjects who did not wear respiratory protective devices more frequently experienced dyspnea than those who wore respiratory protective devices (p = 0.013). In the pulmonary function test, the subjects who worked near the accident site had a higher decease in forced vital capacity than the subjects who worked farther from the site (p = 0.019); however, no statistical association was found between serum calcium/phosphate level, echocardiography result, chest radiographic result, and probation work characteristics. CONCLUSIONS: The subjects who worked near the site of the hydrogen fluoride spill, worked for an extended period, or worked without wearing respiratory protective devices more frequently experienced upper/lower respiratory, gastrointestinal, and neurological symptoms. Further follow-up examination is needed for the workers who were exposed to hydrogen fluoride during their collection duties in the chemical plant in Gumi City. PMID- 24472576 TI - Acute viral hepatitis - should the current screening strategy be modified? AB - BACKGROUND: The epidemiology of viral hepatitis has changed. Since the introduction of safe and effective vaccines for hepatitis A and B in 1980s, the incidence of acute infections caused by these viruses has been declining in the UK. At the same time, hepatitis E virus (HEV) has been recognised as an increasingly important cause of acute hepatitis, but testing is not widely available. OBJECTIVES: The aim of this study was to establish the viral causes of acute hepatitis, and use that data to modify the current diagnostic algorithm. STUDY DESIGN: A Cognos search was performed to collate subjects tested for HAV, HBV, HCV, HEV, EBV and CMV between June 2010 and December 2012. Information included virological result and their ALT level if done within 5 days from virological testing. RESULTS: From 3462 subjects with suspected acute viral hepatitis, only 25% had biochemical evidence of acute hepatitis (n=854; ALT>100IU/l). The frequency of detection of acute HEV infection (25/409) was over 31-times higher than that of HAV (6/3462), and 7-times higher than that of HBV (24/3462). Most cases of acute HAV, HEV, EBV and CMV infections presented with abnormal ALT levels. Most EBV infections were associated with lymphadenopathy (23/34); in comparison most of CMV infections were not associated with lymphadenopathy (18/22). CONCLUSIONS: HEV screening should be included in the initial testing panel for acute hepatitis and screening at least for HAV and HEV might be limited to those with abnormal ALT levels. PMID- 24472577 TI - Rethinking metabotropic glutamate receptor 5 pathological findings in psychiatric disorders: implications for the future of novel therapeutics. AB - BACKGROUND: Pharmacological modulation of metabotropic glutamate receptor 5 (mGluR5) is of marked interest as a novel therapeutic mechanism to treat schizophrenia and major depression. However, the status of mGluR5 in the pathophysiology of these disorders remains unknown. DISCUSSION: The majority of studies in the schizophrenia post-mortem brain indicate that total mGluR5 expression is unaltered. However, close examination of the literature suggests that these findings are superficial, and in actuality, a number of critical factors have not yet been considered; alterations may be highly dependent on brain region, neuronal population or molecular organisation in specific cellular compartments. A number of genetic knockout studies (mGluR5, Norbin, Homer1 etc.) continue to lend support to a role of mGluR5 in the pathology of schizophrenia, providing impetus to explore the regulation of mGluR5 beyond total mGluR5 protein and mRNA levels. With regards to major depression, preliminary evidence to date shows a reduction in total mGluR5 protein and mRNA levels; however, as in schizophrenia, there are no studies examining mGluR5 function or regulation in the pathological state. A comprehensive understanding of mGluR5 regulation in major depression, particularly in comparison to schizophrenia, is crucial as this has extensive implications for mGluR5 targeting novel therapeutics, especially considering that opposing modulation of mGluR5 is of therapeutic interest for these two disorders. SUMMARY: Despite the complexities, examinations of post mortem human brain provide valuable insights into the pathologies of these inherently human disorders. It is important, especially with regards to the identification of novel therapeutic drug targets, to have an in depth understanding of the pathophysiologies of these disorders. We posit that brain region- and cell type-specific alterations exist in mGluR5 in schizophrenia and depression, with evidence pointing towards altered regulation of this receptor in psychiatric pathology. We consider the implications of these alterations, as well as the distinction between schizophrenia and depression, in the context of novel mGluR5 based therapeutics. PMID- 24472578 TI - Neural activity in catecholaminergic populations following sexual and aggressive interactions in the brown anole, Anolis sagrei. AB - Social behaviors in vertebrates are modulated by catecholamine (CA; dopamine, norepinephrine, epinephrine) release within the social behavior neural network. Few studies have examined activity across CA populations in relation to social behaviors. The involvement of CAs in social behavior regulation is especially underexplored in reptiles, relative to other amniotes. In this study, we mapped CA populations throughout the brain (excluding retina and olfactory bulb) of the male brown anole lizard, Anolis sagrei, via immunofluorescent visualization of the rate-limiting enzyme for CA synthesis, tyrosine hydroxylase (TH). Colocalization of TH with the immediate early gene product Fos, an indirect marker of neural activity, also enabled us to relate activity in TH immunoreactive (TH-ir) neurons to appetitive and consummatory sexual and aggressive behaviors. We detected most major TH-ir cell populations that are present in other amniotes (within the hypothalamus, midbrain, and hindbrain), although the A15 population was entirely absent. We also detected a few novel or rare cell clusters within the amygdala, medial septum, and inferior raphe. Many CA populations, especially dopaminergic groups, showed increased TH-Fos colocalization in association with appetitive and consummatory sexual behavior expression, while a small number of regions showed increased colocalization in relation to solely consummatory aggression (biting of an opponent). In conclusion, we here map CA populations throughout the brown anole brain and demonstrate evidence for catecholaminergic involvement in appetitive and consummatory sexual behaviors and consummatory aggressive behaviors in this species. PMID- 24472579 TI - Sh-I-048A, an in vitro non-selective super-agonist at the benzodiazepine site of GABAA receptors: the approximated activation of receptor subtypes may explain behavioral effects. AB - Enormous progress in understanding the role of four populations of benzodiazepine sensitive GABAA receptors was paralleled by the puzzling findings suggesting that substantial separation of behavioral effects may be accomplished by apparently non-selective modulators. We report on SH-I-048A, a newly synthesized chiral positive modulator of GABAA receptors characterized by exceptional subnanomolar affinity, high efficacy and non-selectivity. Its influence on behavior was assessed in Wistar rats and contrasted to that obtained with 2mg/kg diazepam. SH I-048A reached micromolar concentrations in brain tissue, while the unbound fraction in brain homogenate was around 1.5%. The approximated electrophysiological responses, which estimated free concentrations of SH-I-048A or diazepam are able to elicit, suggested a similarity between the 10mg/kg dose of the novel ligand and 2mg/kg diazepam; however, SH-I-048A was relatively more active at alpha1- and alpha5-containing GABAA receptors. Behaviorally, SH-I-048A induced sedative, muscle relaxant and ataxic effects, reversed mechanical hyperalgesia 24h after injury, while it was devoid of clear anxiolytic actions and did not affect water-maze performance. While lack of clear anxiolytic actions may be connected with an enhanced potentiation at alpha1-containing GABAA receptors, the observed behavior in the rotarod, water maze and peripheral nerve injury tests was possibly affected by its prominent action at receptors containing the alpha5 subunit. The current results encourage further innovative approaches aimed at linking in vitro and in vivo data in order to help define fine-tuning mechanisms at four sensitive receptor populations that underlie subtle differences in behavioral profiles of benzodiazepine site ligands. PMID- 24472580 TI - There are no randomized controlled trials that support the United States Preventive Services Task Force Guideline on screening for depression in primary care: a systematic review. AB - BACKGROUND: The United States Preventive Services Task Force (USPSTF) recommends screening adults for depression in primary care settings when staff-assisted depression management programs are available. This recommendation, however, is based on evidence from depression management programs conducted with patients already identified as depressed, even though screening is intended to identify depressed patients not already recognized or treated. The objective of this systematic review was to evaluate whether there is evidence from randomized controlled trials (RCTs) that depression screening benefits patients in primary care, using an explicit definition of screening. METHODS: We re-evaluated RCTs included in the 2009 USPSTF evidence review on depression screening, including only trials that compared depression outcomes between screened and non-screened patients and met the following three criteria: determined patient eligibility and randomized prior to screening; excluded patients already diagnosed with a recent episode of depression or already being treated for depression; and provided the same level of depression treatment services to patients identified as depressed in the screening and non-screening trial arms. We also reviewed studies included in a recent Cochrane systematic review, but not the USPSTF review; conducted a focused search to update the USPSTF review; and reviewed trial registries. RESULTS: Of the nine RCTs included in the USPSTF review, four fulfilled none of three criteria for a test of depression screening, four fulfilled one of three criteria, and one fulfilled two of three criteria. There were two additional RCTs included only in the Cochrane review, and each fulfilled one of three criteria. No eligible RCTs were found via the updated review. CONCLUSIONS: The USPSTF recommendation to screen adults for depression in primary care settings when staff-assisted depression management programs are available is not supported by evidence from any RCTs that are directly relevant to the recommendation. The USPSTF should re-evaluate this recommendation. Please see related article: http://www.biomedcentral.com/1741-7015/12/14 REGISTRATION: PROSPERO (#CRD42013004276). PMID- 24472581 TI - A bifurcated proteoglycan binding small molecule carrier for siRNA delivery. AB - A wider application of siRNA- and miRNA- based therapeutics is restricted by the currently available delivery systems. We have designed a new type of small molecule carrier (SMoC) system for siRNA modeled to interact with cell surface proteoglycans. This bifurcated SMoC has similar affinity for the model proteoglycan heparin to an equivalent polyarginine peptide and exhibits significant mRNA knockdown of protein levels comparable to lipofectamine and the previously reported linear SMoC. PMID- 24472582 TI - Strategic planning now is crucial to future success. PMID- 24472583 TI - Innovation: the foundation for change. PMID- 24472586 TI - AORN Surgical Conference & Expo 2014 speaker interviews. PMID- 24472587 TI - Does preoperative oral carbohydrate reduce hospital stay? A randomized trial. AB - Oral carbohydrate-rich fluids are used preoperatively to improve postoperative recovery, but their effectiveness for reducing length of hospital stay is uncertain. We assessed the effectiveness of preoperative loading with carbohydrates on the postoperative outcomes of 44 patients scheduled for elective colorectal surgery who were randomly allocated to a carbohydrate-rich fluid group or a usual care group during their preadmission clinic visit. Our primary outcome was the time patients required to be ready for discharge. Patients in the control group spent an average of 4.3 days (95% confidence interval [CI], 3.2-5.7) in the hospital and patients in the carbohydrate-rich fluid group spent 4.1 days (95% CI, 3.2-5.4) in the hospital until they met discharge criteria (P = .824). We found that the safety of administering preoperative oral carbohydrate-rich fluids is supported, but we were unable to confirm or refute the benefit of this treatment regimen for contributing to shorter hospital stays after elective colorectal surgery. PMID- 24472588 TI - Introducing AORN's new model for evidence rating. AB - Nurses today are expected to implement evidence-based practices in the perioperative setting to assess and implement practice changes. All evidence based practice begins with a question, a practice problem to address, or a needed change that is identified. To assess the question, a literature search is performed and relevant literature is identified and appraised. The types of evidence used to inform practice can be scientific research (eg, randomized controlled trials, systematic reviews) or nonresearch evidence (eg, regulatory and accrediting agency requirements, professional association practice standards and guidelines, quality improvement project reports). The AORN recommended practices are a synthesis of related knowledge on a given topic, and the authorship process begins with a systematic review of the literature conducted in collaboration with a medical librarian. At least two appraisers independently evaluate the applicable literature for quality and strength by using the AORN Research Appraisal Tool and AORN Non-Research Appraisal Tool. To collectively appraise the evidence supporting particular practice recommendations, the AORN recommended practices authors have implemented a new evidence rating model that is appropriate for research and nonresearch literature and that is relevant to the perioperative setting. PMID- 24472589 TI - Developing a strategy to identify and treat older patients with postoperative delirium. AB - Postoperative delirium is one of the most common adverse outcomes in elderly patients undergoing surgery and is associated with increased morbidity, length of stay, and patient care costs. The purpose of this quality improvement project was to evaluate the effectiveness of a multicomponent strategy to identify and treat general surgical patients 65 years of age or older at risk for and who develop postoperative delirium at Cape Cod Hospital, a community hospital in southern New England. We evaluated 96 patients using the Mini-Cog assessment tool preoperatively and the Confusion Assessment Method (CAM) delirium screening tool or CAM-Intensive Care Unit (CAM-ICU) assessment tool postoperatively. Patients who tested positive during preoperative assessment underwent a postoperative delirium management protocol. We summarized data using descriptive statistics. The results showed an association between compliance and outcomes. High compliance with implementation of CAM and CAM-ICU assessment tools resulted in increased identification of postoperative delirium in the older surgical population. The use of screening tools helped facilitate early identification of postoperative delirium in elderly surgical patients. PMID- 24472590 TI - Boston bombings: response to disaster. AB - Disasters disrupt everyone's lives, and they can disrupt the flow and function of an OR as well as affect personnel on a professional and personal level even though perioperative departments and their personnel are used to caring for trauma patients and coping with surprises. The Boston Marathon bombing was a new experience for personnel at Massachusetts General Hospital, Boston. This article discusses the incidents surrounding the bombing and how personnel at this hospital met the challenge of caring for patients and the changes we made after the experience to be better prepared in the event a response to a similar incident is needed. PMID- 24472591 TI - An analysis of surgical smoke plume components, capture, and evacuation. AB - Chronic exposure to surgical smoke can transmit viruses; lead to respiratory illness; and increase the risk of more serious conditions, including Alzheimer disease, collagen and cardiac diseases, and cancer. Despite this, surgical smoke plume capture and evacuation devices are often used sporadically or not at all, and do not necessarily reduce costs per procedure. In addition, the current choices for smoke plume capture are varied, and health care providers may make decisions about what type of method to use based on marketing materials rather than facts, leaving most clinicians and managers frustrated and cynical about supporting the effort to capture surgical smoke plume. This article presents current data and information that purchasing teams can use to help choose the best available technology for their practice patterns. It also provides analysis to help those responsible for choosing smoke evacuation systems make rational decisions in their quest to provide a clean, safe environment in the OR. PMID- 24472592 TI - Malignant hyperthermia crisis: optimizing patient outcomes through simulation and interdisciplinary collaboration. AB - Malignant hyperthermia (MH) is a rare, life-threatening event. Many clinicians are unprepared to manage an MH crisis in the perioperative setting because it requires the use of low-frequency, high-risk skills and procedures. Simulation is a recognized educational method for cumulative and integrative learning in a safe environment that resembles real-life clinical scenarios. The aim of this quality improvement project was to provide simulation-based learning to perioperative personnel to educate them in the early recognition, treatment, and management of MH. An interdisciplinary team developed an MH education plan. Implementation of the plan involved a two-part training: an educational session, and a role-playing scenario using high-fidelity OR simulation. Simulation teaching provided OR personnel with an opportunity for skill development, teamwork, interdisciplinary communication, and problem solving. Personnel responded favorably and identified positive outcomes, such as role clarity, improved anticipatory response, and overall team cohesion. In addition, the project included updating the MH cart and writing the hospital's MH policy. PMID- 24472593 TI - Practice models: developing, revising, and adopting the best structure for your organization. PMID- 24472594 TI - Prevention of surgical site infection: beyond SCIP. PMID- 24472596 TI - Wrong turn through colon: misplaced PEG. PMID- 24472597 TI - A population-based study of the association of prenatal diagnosis with survival rate for infants with congenital heart defects. AB - Prenatal diagnosis has been shown to improve preoperative morbidity in newborns with congenital heart defects (CHDs), but there are conflicting data as to the association with mortality. We performed a population-based, retrospective, cohort study of infants with prenatally versus postnatally diagnosed CHDs from 1994 to 2005 as ascertained by the Metropolitan Atlanta Congenital Defects Program. Among infants with isolated CHDs, we estimated 1-year Kaplan-Meier survival probabilities for prenatal versus postnatal diagnosis and estimated Cox proportional hazard ratios adjusted for critical CHD status, gestational age, and maternal race/ethnicity. Of 539,519 live births, 4,348 infants had CHDs (411 prenatally diagnosed). Compared with those with noncritical defects, those with critical defects were more likely to be prenatally diagnosed (58% vs 20%, respectively, p <0.001). Of the 3,146 infants with isolated CHDs, 1-year survival rate was 77% for those prenatally diagnosed (n = 207) versus 96% for those postnatally diagnosed (n = 2,939, p <0.001). Comparing 1-year survival rate among those with noncritical CHDs alone (n = 2,455) showed no difference between prenatal and postnatal diagnoses (96% vs 98%, respectively, p = 0.26), whereas among those with critical CHDs (n = 691), prenatally diagnosed infants had significantly lower survival rate (71% vs 86%, respectively, p <0.001). Among infants with critical CHDs, the adjusted hazard ratio for 1-year mortality rate for those prenatally versus postnatally (reference) diagnosed was 2.51 (95% confidence interval 1.72 to 3.66). In conclusion, prenatal diagnosis is associated with lower 1-year survival rate for infants with isolated critical CHDs but shows no change for those with isolated noncritical CHDs. More severe disease among the critical CHD subtypes diagnosed prenatally might explain these findings. PMID- 24472598 TI - Anopheles sinensis mosquito insecticide resistance: comparison of three mosquito sample collection and preparation methods and mosquito age in resistance measurements. AB - BACKGROUND: Insecticide resistance monitoring in malaria mosquitoes is essential for guiding the rational use of insecticides in vector control programs. Resistance bioassay is the first step for insecticide monitoring and it lays an important foundation for molecular examination of resistance mechanisms. In the literature, various mosquito sample collection and preparation methods have been used, but how mosquito sample collection and preparation methods affect insecticide susceptibility bioassay results is largely unknown. The objectives of this study were to determine whether mosquito sample collection and preparation methods affected bioassay results, which may cause incorrect classification of mosquito resistance status. METHODS: The study was conducted in Anopheles sinensis mosquitoes in two study sites in central China. Three mosquito sample collection and preparation methods were compared for insecticide susceptibility, kdr frequencies and metabolic enzyme activities: 1) adult mosquitoes collected from the field; 2) F1 adults from field collected, blood-fed mosquitoes; and 3) adult mosquitoes reared from field collected larvae. RESULTS: Mosquito sample collection and preparation methods significantly affected mortality rates in the standard WHO tube resistance bioassay. Mortality rate of field-collected female adults was 10-15% higher than in mosquitoes reared from field-collected larvae and F1 adults from field collected blood-fed females. This pattern was consistent in mosquitoes from the two study sites. High kdr mutation frequency (85-95%) with L1014F allele as the predominant mutation was found in our study populations. Field-collected female adults consistently exhibited the highest monooxygenase and GST activities. The higher mortality rate observed in the field-collected female mosquitoes may have been caused by a mixture of mosquitoes of different ages, as older mosquitoes were more susceptible to deltamethrin than younger mosquitoes. CONCLUSIONS: Female adults reared from field-collected larvae in resistance bioassays are recommended to minimize the effect of confounding factors such as mosquito age and blood feeding status so that more reliable and reproducible mortality may be obtained. PMID- 24472599 TI - Intraoperative radiation therapy. PMID- 24472601 TI - Four cases of abnormal neuropsychological findings in children with high blood methylmercury concentrations. AB - BACKGROUND: Methylmercury (MeHg) easily crosses the blood-brain barrier and accumulates in the brain. Accumulated MeHg will cause neurological symptoms. We report four pediatric cases of neuropsychological findings with high blood MeHg concentrations. CASE PRESENTATION: Four children were admitted for follow-up study because their total mercury (THg) concentration in the blood was found to be high during a national survey. Case 1 was a 9-year-old female with a 16.6 MUg/l blood THg concentration in the survey. During admission, the blood THg, hair THg, and blood MeHg concentration(mercury indices) were 21.4 MUg/l, 7.2 MUg/g, and 20.1 MUg/l, respectively. In our neuropsychological examination, cognitive impairment and attention deficit were observed. Her diet included fish intake 2-3 times per week, and she had been diagnosed with epilepsy at 3 years of age. Case 2 was a 12-year-old male with blood THg of 15.4 MUg/l in the survey and the mercury indices were 12.7 MUg/l, 5.7 MUg/g, and 11.8 MUg/l, respectively, on admission. He was also observed to have attention-deficit/hyperactivity disorder. Case 3 was a 10-year-old male child with blood THg of 17.4 MUg/l in the survey, and the mercury indices on admission were 21.6 MUg/l, 7.5 MUg/g and 21.5 MUg/l, respectively. In his case, mild attention deficit was observed. Case 4 was a 9 year-old male with blood THg of 20.6 MUg/l in the survey and the mercury indices were 18.9 MUg/l, 8.3 MUg/g, and 14.4 MUg/l, respectively, on admission. Mild attention difficulty was observed. CONCLUSION: We suggest that fish consumption may be the main source of MeHg exposure, and that MeHg may have been the cause of the neuropsychological deficits in these cases. PMID- 24472600 TI - High throughput RNA sequencing of a hybrid maize and its parents shows different mechanisms responsive to nitrogen limitation. AB - BACKGROUND: Development of crop varieties with high nitrogen use efficiency (NUE) is crucial for minimizing N loss, reducing environmental pollution and decreasing input cost. Maize is one of the most important crops cultivated worldwide and its productivity is closely linked to the amount of fertilizer used. A survey of the transcriptomes of shoot and root tissues of a maize hybrid line and its two parental inbred lines grown under sufficient and limiting N conditions by mRNA Seq has been conducted to have a better understanding of how different maize genotypes respond to N limitation. RESULTS: A different set of genes were found to be N-responsive in the three genotypes. Many biological processes important for N metabolism such as the cellular nitrogen compound metabolic process and the cellular amino acid metabolic process were enriched in the N-responsive gene list from the hybrid shoots but not from the parental lines' shoots. Coupled to this, sugar, carbohydrate, monosaccharide, glucose, and sorbitol transport pathways were all up-regulated in the hybrid, but not in the parents under N limitation. Expression patterns also differed between shoots and roots, such as the up regulation of the cytokinin degradation pathway in the shoots of the hybrid and down-regulation of that pathway in the roots. The change of gene expression under N limitation in the hybrid resembled the parent with the higher NUE trait. The transcript abundances of alleles derived from each parent were estimated using polymorphic sites in mapped reads in the hybrid. While there were allele abundance differences, there was no correlation between these and the expression differences seen between the hybrid and the two parents. CONCLUSIONS: Gene expression in two parental inbreds and the corresponding hybrid line in response to N limitation was surveyed using the mRNA-Seq technology. The data showed that the three genotypes respond very differently to N-limiting conditions, and the hybrid clearly has a unique expression pattern compared to its parents. Our results expand our current understanding of N responses and will help move us forward towards effective strategies to improve NUE and enhance crop production. PMID- 24472602 TI - The selection of mature B cells is critically dependent on the expression level of the co-receptor CD19. AB - CD19 plays a crucial role in mature B cell development as best exemplified by the finding that CD19 deficient mice have severely reduced mature B cell compartments (Engel et al., 1995; Rickert et al., 1995). In the present study we show that the transition into the mature B cell compartments is heavily dependent on the correct amount of CD19 expression. Thus, Nup-98-HoxB4 immortalized hematopoietic stem cells (HSCs) over-expressing CD19 show upon transplantation an impaired pro/pre B to immature B cell transition in the bone marrow, whereas Nup-98-HoxB4 HSCs expressing a shRNA that down-modulates CD19 expression show upon transplantation a strongly reduced mature B cell compartment. Overall our findings indicate that too high CD19 expression might result into too strong BCR signaling in the bone marrow and therefore causing negative selection. Too low CD19 expression might result into too little BCR signaling and thereby preventing the B cells to enter the mature pool (absence of positive selection). PMID- 24472604 TI - Characterization of SM201, an anti-hFcgammaRIIB antibody not interfering with ligand binding that mediates immune complex dependent inhibition of B cells. AB - The monoclonal antibody SM201 specifically recognizes the human inhibitory FcgammaRIIB without showing cross-reactivity to the related but activating FcgammaRIIA. The epitope recognized by SM201 is located outside the IgG-binding site of FcgammaRIIB. As a result, the antibody does not interfere with hIgG binding to the receptor. It was therefore hypothesized that SM201 may amplify the inhibitory signaling of FcgammaRIIB after coligation of B cell receptor (BCR) and FcgammaRIIB by immune complexes (ICs). Mechanistic and functional studies were conducted in established B cell lines as well as in primary B cells from healthy donors to substantiate the anticipated working principle. Using an experimental setup mimicking IC binding, we were able to demonstrate that SM201 enhances the extent of ITIM phosphorylation of FcgammaRIIB. The antibody works synergistically with ICs and the mode of action is strictly dependent on their presence. Additionally, SM201 did not induce apoptosis, cellular depletion or NK cell activation, which indicates an advantageous safety profile. This establishes an innovative approach for the treatment of antibody-mediated autoimmune diseases. PMID- 24472603 TI - B cells and type 1 diabetes ...in mice and men. AB - Nearly 70% of newly produced B cells express autoreactive antigen receptors and must be silenced to prevent autoimmunity. Failure of silencing mechanisms is apparent in type 1 diabetes (T1D), where islet antigen-specific B cells appear critical for development of disease. Evidence for a B cell role in T1D includes success of B cell targeted anti-CD20 therapy, which delays T1D progression in both NOD mice and new onset patients. Demonstrating the importance of specificity, NOD mice whose B cell repertoire is biased toward insulin reactivity show increased disease development, while bias away from insulin reactivity largely prevents disease. Finally, though not required for illness, high affinity insulin autoantibodies are often the first harbingers of T1D. B cell cytokine production and auto-antigen presentation to self-reactive T cells are likely important in pathogenesis. Here we review B cell function, as described above, in T1D in humans and the non-obese diabetic (NOD) mouse. We will discuss recent broad-based B cell depletion studies and how they may provide the basis for refinement of future treatments for the disorder. PMID- 24472605 TI - Genome-wide miRNA-profiling of aflatoxin B1-induced hepatic injury using deep sequencing. AB - Aflatoxin B1 is a potent carcinogen which can induce** hepatocellular carcinoma (HCC) in mammals. Though microRNAs are known to play important roles in tumorigenesis, the functional complexity of microRNAs in AFB1-induced hepatocellular tumorigenesis has not yet been elucidated. Here, we applied Illumina deep sequencing technology for high-throughput profiling of microRNA in rat liver tissue before and after treatment with aflatoxin B1. Analysis of mature miRNAs from different arms of pre-miRNAs allowed us to identify the predominant form of miRNA. We studied the differential expression profile of miRNAs in two libraries, identifying several cancer-related microRNAs which exhibit abnormal expression. KEGG analysis indicated that predicted target genes of differentially expressed miRNAs are involved in cancer-related pathways. Bioinformatic analysis predicted 16 potential novel miRNAs. Our work provides new insights at the miRNA level into AFB1-induced hepatic injury which may lead to HCC. PMID- 24472606 TI - Acute mercury toxicity modulates cytochrome P450, soluble epoxide hydrolase and their associated arachidonic acid metabolites in C57Bl/6 mouse heart. AB - Mercury exposure is associated with increased risk of cardiovascular disease and profound cardiotoxicity. However, the correlation between Hg(2+)-mediated toxicity and alteration in cardiac cytochrome P450s (Cyp) and their dependent arachidonic acid metabolites has never been investigated. Therefore, we investigated the effect of acute mercury toxicity on the expression of Cyp epoxygenases and Cyp-omega-hydroxylases and their associated arachidonic acid metabolites in mice hearts. In addition, we examined the expression and activity of soluble epoxide hydrolase (sEH) as a key player in arachidonic acid metabolism pathway. Mercury toxicity was induced by a single intraperitoneal injection (IP) of 2.5 mg/kg of mercuric chloride (HgCl2). Our results showed that mercury treatment caused a significant induction of the cardiac hypertrophy markers, atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP); in addition to Cyp1a1, Cyp1b1, Cyp2b9, Cyp2b10, Cyp2b19, Cyp2c29, Cyp2c38, Cyp4a10, Cyp4a12, Cyp4a14, Cyp4f13, Cyp4f15, Cyp4f16 and Cyp4f18 gene expression. Moreover, Hg(2+) significantly increased sEH protein expression and activity levels in hearts of mercury-treated mice, with a consequent decrease in 14,15-, and 11,12 epoxyeicosatrienoic acids (EETs) levels. Whereas the formation of 14,15-, 11,12-, 8,9-dihydroxyeicosatrienoic acids (DHETs) was significantly increased. In conclusion, acute Hg(2+) toxicity modulates the expression of several Cyp and sEH enzymes with a consequent decrease in the cardioprotective EETs which could represent a novel mechanism by which mercury causes progressive cardiotoxicity. Furthermore, inhibiting sEH might represent a novel therapeutic approach to prevent Hg(2+)-induced hypertrophy. PMID- 24472607 TI - The NF-kappaB family member RelB regulates microRNA miR-146a to suppress cigarette smoke-induced COX-2 protein expression in lung fibroblasts. AB - Diseases due to cigarette smoke exposure, including chronic obstructive pulmonary disease (COPD) and lung cancer, are associated with chronic inflammation typified by the increased expression of cyclooxygenase-2 (COX-2) protein. RelB is an NF kappaB family member that suppresses cigarette smoke induction of COX-2 through an unknown mechanism. The ability of RelB to regulate COX-2 expression may be via miR-146a, a miRNA that attenuates COX-2 in lung fibroblasts. In this study we tested whether RelB attenuation of cigarette smoke-induced COX-2 protein is due to miR-146a. Utilizing pulmonary fibroblasts deficient in RelB expression, together with siRNA knock-down of RelB, we show the essential role of RelB in diminishing smoke-induced COX-2 protein expression despite robust activation of the canonical NF-kappaB pathway and subsequent induction of Cox-2 mRNA. RelB did not regulate COX-2 protein expression at the level of mRNA stability. Basal levels of miR-146a were significantly lower in Relb-deficient cells and cigarette smoke increased miR-146a expression only in Relb-expressing cells. Inhibition of miR-146a had no effects on Relb expression or induction of Cox-2 mRNA by cigarette smoke but significantly increased COX-2 protein. These data highlight the potential of a RelB-miR-146a axis as a novel regulatory pathway that attenuates inflammation in response to respiratory toxicants. PMID- 24472608 TI - Disrupting androgen production of Leydig cells by resveratrol via direct inhibition of human and rat 3beta-hydroxysteroid dehydrogenase. AB - Resveratrol is a polyphenol produced by several plants. It has been demonstrated that it has anti-inflammatory, antitumor, and anti-diabetic effects in animal models. However, its side effects are generally unclear. In the present study, we reported that resveratrol inhibited luteinizing hormone-stimulated androgen production in rat immature Leydig cells. Further analysis demonstrated that it was a competitive inhibitor of rat and human 3beta-hydroxysteroid dehydrogenase with IC60 values of 3.87 +/- 0.06 and 8.48 +/- 0.04 MUM, respectively. The inhibition on 3beta-hydroxysteroid dehydrogenase was specific since it did not inhibit another hydroxysteroid dehydrogenase 17beta-hydroxysteroid dehydrogenase 3 at the highest concentration (100 MUM) tested. In conclusion, resveratrol potentially interferes with androgen biosynthesis of rat Leydig cells. PMID- 24472609 TI - Bisphenol A regulation of testicular endocrine function in male rats is affected by diet. AB - There is concern that early-life exposure to bisphenol A (BPA) may alter developmental programming and predispose individuals to obesity and reproductive anomalies. The present study was designed to determine if a high fat diet at sexual maturation moderates testicular toxicity occasioned by exposure to BPA during reproductive development. Therefore, male rats were exposed to BPA by maternal gavage (0, 2.5 or 25 MUg/kg body weight/day) from gestational day 12 to postnatal day 21. At weaning, control and BPA-exposed animals were placed on a regular normal fat diet (NFD) until 70 days of age when they were continued on the NFD or were maintained on a high fat diet (HFD) until euthanasia at 98 days. Adult male rats maintained on HFD were generally heavier than NFD animals due to greater energy intake but energy intake per unit body weight gain was similar in all animals. However, perinatal exposure to BPA decreased (P<0.05) serum adiponectin as well as adiponectin and AdipoR2 protein expression levels in Leydig cells. Importantly, the combination of BPA exposure and HFD consumption promoted lipid peroxidation evidenced by elevated serum thiobarbituric acid reactive substances and glutathione concentrations. These findings imply that interaction between BPA and HFD potentially causes testicular dysfunction to a greater degree than would be due to BPA exposure or HFD consumption. Given the relationship that exists between energy homeostasis and reproductive activity, additional studies are warranted to investigate the consequences of BPA-diet interactions on testicular function. PMID- 24472610 TI - Protein association of the neurotoxin and non-protein amino acid BMAA (beta-N methylamino-L-alanine) in the liver and brain following neonatal administration in rats. AB - The environmental neurotoxin beta-N-methylamino-L-alanine (BMAA) is not an amino acid that is normally found in proteins. Our previous autoradiographic study of (3)H-labeled BMAA in adult mice unexpectedly revealed a tissue distribution similar to that of protein amino acids. The aim of this study was to characterize the distribution of free and protein-bound BMAA in neonatal rat tissues following a short exposure using autoradiographic imaging and ultra-high performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The autoradiographic imaging of (14)C-L-BMAA demonstrated a distinct uptake of radioactivity that was retained following acid extraction in tissues with a high rate of cell turnover and/or protein synthesis. The UHPLC-MS/MS analysis conclusively demonstrated a dose-dependent increase of protein-associated BMAA in neonatal rat tissues. The level of protein-associated BMAA in the liver was more than 10 times higher than that in brain regions not fully protected by the blood-brain barrier which may be due to the higher rate of protein synthesis in the liver. In conclusion, this study demonstrated that BMAA was associated with rat proteins suggesting that BMAA may be misincorporated into proteins. However, protein-associated BMAA seemed to be cleared over time, as none of the samples from adult rats had any detectable free or protein-associated BMAA. PMID- 24472611 TI - Differential relative effect potencies of some dioxin-like compounds in human peripheral blood lymphocytes and murine splenic cells. AB - Human risk assessment for dioxin-like compounds is typically based on the concentration measured in blood serum multiplied by their assigned toxic equivalency factor (TEF). Consequently, the actual value of the TEF is very important for accurate human risk assessment. In this study we investigated the effect potencies of three polychlorinated dibenzo-p-dioxins (PCDDs), six polychlorinated dibenzofurans (PCDFs) and 10 polychlorinated biphenyls (PCBs) relative to the reference congener 2,3,7,8-tetrachloro-dibenzo-p-dioxin (TCDD) in in vitro exposed primary human peripheral blood lymphocytes (PBLs) and mouse splenic cells. REPs were determined based on cytochrome P450 (CYP) 1A1, 1B1 and aryl hydrocarbon receptor repressor (AhRR) gene expression as well as CYP1A1 activity in human PBLs and Cyp1a1 gene expression in murine splenic cells. Estimated median human REPs for 1,2,3,4,6,7,8-heptachlorodibenzo-p-dioxin (1234678-HpCDD), 2,3,4,7,8,-pentachlorodibenzofuran (23478-PeCDF), 1,2,3,4,7,8 hexachlorodibenzofuran (123478-HxCDF) and 1,2,3,4,7,8,9-heptachlorodibenzofuran (1234789-HpCDF) were with 0.1, 1.1, 1 and 0.09, respectively, significantly higher compared to those estimated for mouse with REPs of 0.05, 0.45, 0.09 and 0.04, respectively. Opposite to these results, the estimated median human REP of 3,3',4,4',5-pentachlorobiphenyl (PCB 126), was with 0.001 30-fold lower compared to the mouse REP of 0.03. Furthermore, human REPs for 1234678-HpCDD, 23478-PeCDF, 123478-HxCDF, 1234789-HpCDF and PCB 126 were all outside the +/- half log uncertainty range that is taken into account in the WHO-assigned TEFs. Together, these data show congener- and species-specific differences in REPs for some, but not all dioxin-like congeners tested. This suggests that, more emphasis should be placed on human-tissue derived REPs in the establishment of a TEF for human risk assessment. PMID- 24472612 TI - Genotoxicity but not the AhR-mediated activity of PAHs is inhibited by other components of complex mixtures of ambient air pollutants. AB - In this study, we compared the genotoxicity and aryl hydrocarbon receptor (AhR) dependent transcriptional changes of selected target genes in human lung epithelial A549 cells incubated for 24 h, either with extractable organic matter (EOMs) from airborne particles <2.5 MUm (PM2.5) collected at four localities from heavily polluted areas of the Czech Republic or two representative toxic polycyclic aromatic hydrocarbons (PAHs) present in EOMs, benzo[a]pyrene (B[a]P) and benzo[k]fluoranthene (B[k]F). Genotoxic effects were determined using DNA adduct analysis or analysis of expression of selected AhR-related genes involved in bioactivation of PAHs (CYP1A1, CYP1B1) and transcriptional repression (TIPARP). Sampled localities differing in the extent and source of air pollution did not exhibit substantially different genotoxicity. DNA adduct levels induced by three subtoxic EOM concentrations were relatively low (1-5 adducts/10(8) nucleotides), compared to levels induced by similar concentrations of B[a]P, while B[k]F gave very low DNA adduct levels. Here, we compared genotoxicity and gene deregulation induced by complex mixtures containing PAHs with the effects of the comparable concentrations of individual PAHs. Our results suggested inhibition of formation of B[a]P-induced DNA adducts compared to individual B[a]P, probably attributable to competitive inhibition by other non-genotoxic EOM components. In contrast, induction of AhR target genes appeared not to be antagonized by the components of complex mixtures, as induction of CYP1A1, CYP1B1 and TIPARP transcripts reached maximum levels induced by PAHs. PMID- 24472613 TI - Prenatal ethanol exposure enhances the susceptibility to metabolic syndrome in offspring rats by HPA axis-associated neuroendocrine metabolic programming. AB - OBJECTIVE: The present study was designed to demonstrate that prenatal ethanol exposure (PEE) could enhance the susceptibility of high-fat diet-induced metabolic syndrome (MS) in adult male offspring via a hypothalamic-pituitary adrenal (HPA) axis-associated neuroendocrine metabolic programmed mechanism. METHODS: Pregnant Wistar rats were intragastricly administrated ethanol 4 g/kg.d from gestational day 11 until term delivery. All male offspring were fed with high-fat diet after weaning, exposed to an unpredictable chronic stress at postnatal week (PW) 17 and sacrificed at PW20. RESULTS: In PEE group, body weight presented a "catch-up growth" pattern, and the HPA axis exhibited a lower basal activity but an enhanced sensitivity to chronic stress, leading to increased levels of serum glucose, insulin, insulin resistant index, total cholesterol and low-density lipoprotein-cholesterol, and decreased levels of high-density lipoprotein-cholesterol. Furthermore, many lipid droplets and vacuolar degeneration were observed in the hypothalamus, pituitary gland and liver. CONCLUSIONS: PEE induces enhanced susceptibility to MS in adult offspring fed with high-fat diet, and the underlying mechanism involves a HPA axis-associated neuroendocrine metabolic programming alteration. PMID- 24472614 TI - Effects of transcranial direct current stimulation on esophageal motility in patients with gastroesophageal reflux disease. AB - OBJECTIVE: To evaluate the effects of transcranial direct current stimulation (tDCS) on esophageal peristalsis in patients with gastroesophageal reflux disease (GERD). METHODS: Patients with GERD preliminary diagnosis were included in a randomized double-blind sham-controlled study. Esophageal manometry was performed before and during transcranial direct current stimulation (tDCS) of the right precentral cortex. Half of patients were randomly assigned to anodal, half to sham stimulation. Distal waves amplitude and pathological waves percentage were measured, after swallowing water boli, for ten subsequent times. Last, a 24h pH bilimetry was done to diagnose non-erosive reflux disease (NERD) or functional heartburn (FH). The values obtained before and during anodal or sham tDCS were compared. RESULTS: Sixty-eight patients were enrolled in the study. Distal waves mean amplitude increased significantly only during anodal tDCS in NERD (p=0.00002) and FH subgroups (p=0.008) while percentage of pathological waves strongly decreased only in NERDs (p=0.002). CONCLUSIONS: Transcranial stimulation can influence cortical control of esophageal motility and improve pathological motor pattern in NERD and FH but not in erosive reflux disease (ERD) patients. SIGNIFICANCE: Pathophysiological processes in GERD are not only due to peripheral damage but to central neural control involvement as well. In ERD patients dysfunctions of the cortico-esophageal circuit seem to be more severe and may affect central nervous system physiology. PMID- 24472615 TI - Neither dynamic, static, nor volumetric variables can accurately predict fluid responsiveness early after abdominothoracic esophagectomy. AB - BACKGROUND: Hypotension is common in the early postoperative stages after abdominothoracic esophagectomy for esophageal cancer. We examined the ability of stroke volume variation (SVV), pulse pressure variation (PPV), central venous pressure (CVP), intrathoracic blood volume (ITBV), and initial distribution volume of glucose (IDVG) to predict fluid responsiveness soon after esophagectomy under mechanical ventilation (tidal volume >8 mL/kg) without spontaneous respiratory activity. METHODS: Forty-three consecutive non-arrhythmic patients undergoing abdominothoracic esophagectomy were studied. SVV, PPV, cardiac index (CI), and indexed ITBV (ITBVI) were postoperatively measured by single transpulmonary thermodilution (PiCCO system) after patient admission to the intensive care unit (ICU) on the operative day. Indexed IDVG (IDVGI) was then determined using the incremental plasma glucose concentration 3 min after the intravenous administration of 5 g glucose. Fluid responsiveness was defined by an increase in CI >15% compared with pre-loading CI following fluid volume loading with 250 mL of 10% low molecular weight dextran. RESULTS: Twenty-three patients were responsive to fluids while 20 were not. The area under the receiver operating characteristic (ROC) curve was the highest for CVP (0.690) and the lowest for ITBVI (0.584), but there was no statistical difference between tested variables. Pre-loading IDVGI (r = -0.523, P <0.001), SVV (r = 0.348, P = 0.026) and CVP (r = -0.307, P = 0.046), but not PPV or ITBVI, were correlated with a percentage increase in CI after fluid volume loading. CONCLUSIONS: These results suggest that none of the tested variables can accurately predict fluid responsiveness early after abdominothoracic esophagectomy. PMID- 24472616 TI - Signals from the lens and Foxc1 regulate the expression of key genes during the onset of corneal endothelial development. AB - Correct formation of the corneal endothelium is essential for continued development of the anterior segment of the eye. Corneal endothelial development is initiated at E12 when precursor peri-ocular mesenchyme cells migrate into the space between the lens and the presumptive corneal epithelium and begin to respond to signals from the lens, undergoing a mesenchymal to epithelial transition (MET) that is complete by E15.5. To study the initiation of MET, peri ocular mesenchyme cell lines were derived from E12.5 and E13.5 murine embryos. These cells expressed key transcription factors, Foxc1 and Pitx2, as well as Slug and Tsc22, genes involved in MET. We have shown that all these genes must be down regulated by E13.5 for differentiation to proceed. Lens-derived signals play a role in this down-regulation with Tgfbeta2 specifically down-regulating Foxc1 and Pitx2. Over-expression and knock-down of Foxc1 significantly and similarly affected the expression of Pitx2, Tsc22 and Slug while Foxc1 was shown to play a role in mediating the lens effects on Slug. Thus, for the progression of initial corneal endothelial development, the key transcription factors, Foxc1 and Pitx2, as well as genes involved in MET, Slug and Tsc-22, must be down-regulated, a process driven by the lens and Foxc1. PMID- 24472617 TI - Meeting report: British Society for Research on Ageing (BSRA) annual scientific meeting 2012, Aston University, Birmingham, 3rd to 4th July 2012. AB - The focus of the British Society for Research on Ageing (BSRA) annual scientific meeting 2012 was aging mechanisms and mitigants. The themes covered included epigenetics, stem cells and regeneration, aging pathways and molecules, the aging bladder and bowel, as well as updates from the New Dynamics of Ageing (NDA) programme. The topics incorporated new directions for staple aging research in caloric restriction (CR), inflammation, immunesenescence, neurodegeneration, homeostasis and stress resistance, as well as newer research areas such as bioengineering of tissues, including the internal anal sphincter and thymus. PMID- 24472618 TI - An analysis of emerging antimicrobial resistance in an ENT outpatient department: a comparison of three hundred and forty-nine swabs taken in 2007 with five hundred and seventy-four swabs in 2012. PMID- 24472619 TI - Prevalence of diabetes in Northern African countries: the case of Tunisia. AB - BACKGROUND: Although diabetes is recognized as an emerging disease in African and Middle East, few population-based surveys have been conducted in this region. We performed a national survey to estimate the prevalence of type 2 diabetes (T2D) and to evaluate the relationship between this diagnosis, demographic and socioeconomic variables. METHODS: The study was conducted on a random sample of 6580 households (940 in each region). 7700 subjects adults 35-70 years old were included in the analyses. T2D was assessed on the basis of a questionnaire and fasting blood glucose level according to the WHO criteria. Access to health care and diabetes management were also assessed. RESULTS: Overall, the prevalence of T2D was 15.1%. There were sharp urban vs. rural contrasts, the prevalence of diabetes being twice higher in urban area. However, the ratio urban/rural varied from 3 in the less developed region to 1.6 in the most developed ones. A sharp increase of prevalence of T2D with economic level of the household was observed. For both genders those with a family history of T2D were much more at risk of T2D than those without. Awareness increase with age, economic level and were higher amongst those with family history of T2D. Drugs were supplied by primary health care centers for 57.7% with a difference according to gender, 48.9% for men vs. 66.0% women (p < 0.001) and area, 53.3% on urban area vs. 75.2% on rural one (p < 0.001). CONCLUSIONS: Through its capacity to provide the data on the burden of diabetes in the context of the epidemiological transition that North Africa is facing, this survey will not only be valuable source for health care planners in Tunisia, but will also serve as an important research for the study of diabetes in the region where data is scarce. In this context, NCDs emerge as an intersectoral challenge and their social determinants requiring social, food and environmental health policy. PMID- 24472621 TI - Motor cortical excitability assessed by transcranial magnetic stimulation in psychiatric disorders: a systematic review. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) is a popular neurostimulation technique suitable for the investigation of inhibitory and facilitatory networks in the human motor system. In the last 20 years, several studies have used TMS to investigate cortical excitability in various psychiatric disorders, leading to a consequent improvement in pathophysiological understanding. However, little is known about the overlap and specificity of these findings across these conditions. OBJECTIVE: To provide a systematic review of TMS studies (1985-2013) focusing on motor cortical excitability in dementia, schizophrenia, affective disorders (major depression and bipolar), attention deficit hyperactivity disorder (ADHD), obsessive compulsive disorder (OCD), Tourette Syndrome (TS), substance abuse (alcohol, cocaine, cannabis, nicotine) and other disorders (borderline personality disorder, posttraumatic stress disorder (PTSD)). METHODS: Systematic literature-based review. RESULTS: Across disorders, patients displayed a general pattern of cortical disinhibition, while the most consistent results of reduced short-interval intracortical inhibition could be found in schizophrenia, OCD and Tourette Syndrome. In dementia, the most frequently reported finding was reduced short-latency afferent inhibition as a marker of cholinergic dysfunction. CONCLUSIONS: The results of this systematic review indicate a general alteration in motor cortical inhibition in mental illness, rather than disease-specific changes. Changes in motor cortical excitability provide insight that can advance understanding of the pathophysiology underlying various psychiatric disorders. Further investigations are needed to improve the diagnostic application of these parameters. PMID- 24472620 TI - Trait-like differences in underlying oscillatory state predict individual differences in the TMS-evoked response. AB - BACKGROUND: Combined transcranial magnetic stimulation (TMS) and electroencephalography (EEG) can provide insights into how differing cognitive contexts produce different brain states, through TMS-based measures of effective connectivity. For instance, in a recent study, the amplitude of the TMS-evoked response (TMS-ER) derived during the delay-period of a spatial short-term memory (STM) task had a larger amplitude, and greater spread to distal cortical areas, than the TMS-ER from a fixation condition (Johnson et al. J Neurophysiol, 2012). This indicated that the brain's electrical response to TMS is influenced by the cognitive context (STM or fixation) at the time of stimulation. This study also showed significant individual differences in the shape of the TMS-ER. Further, delay-period spectrograms revealed patterns of activity, the sustained pattern of delay-period activity (SPDPA), which were different across individuals. OBJECTIVE/HYPOTHESIS: The present study addressed whether individual differences in the SPDPA predict spectral properties of the TMS-ER. We predicted that significant relationships would exist in task-relevant areas, such as the prefrontal cortex in the case of STM. METHODS: The TMS-ER was derived using TMS EEG and source-localization methods. RESULTS: The SPDPA varied significantly across subjects, and these differences predicted individual differences in several frequency-dependent parameters of the TMS-ER that were specific to task relevant areas, including prefrontal cortex for STM. Furthermore, a follow-up test-retest study revealed that the SPDPA was stable over sessions. CONCLUSIONS: These observations offer a window into how individual differences in the effects of TMS are related to trait-like individual differences in physiological profile. PMID- 24472622 TI - Transcranial direct current stimulation modulates activation and effective connectivity during spatial navigation. AB - BACKGROUND: Allocentric navigation declines with age and neurologic disease whereas egocentric navigation does not; differences that likely arise from maladaptive changes in brain regions mediating spatial (parietal cortex; hippocampus) but not procedural processing (caudate nucleus). Transcranial direct current stimulation (tDCS) holds promise for treating such decline given its ability to modulate neuronal excitability, but its effects have yet to be examined on spatial navigation. OBJECTIVES/HYPOTHESES: Using healthy young adults as a model, Study 1 intended to validate a novel spatial navigation paradigm using functional magnetic resonance imaging (fMRI). Using these data to determine targets for tDCS, Study 2 aimed to determine if 1) stimulation modulates activation in a polarity-specific manner; 2) stimulation results in global and/or task-specific activation changes; 3) activation changes are accompanied by changes in effective connectivity. METHODS: All participants underwent fMRI while learning allocentric and egocentric environments. Twelve participants completed Study 1. In Study 2, 16 participants were randomized to 20 min of tDCS (2 mA) using a montage with the anode over PZ and cathode over AF4 (P+F-) or the reverse montage (P-F+). RESULTS: Study 1 revealed that distinct networks preferentially mediate allocentric and egocentric navigation. Study 2 revealed polarity dependent changes in activation and connectivity. The P+F- montage increased these measures in spatial regions, especially during allocentric navigation, and the caudate nucleus. Conversely, the P-F+ montage increased activation and connectivity in lateral prefrontal cortices and posterior hippocampus. CONCLUSIONS: These findings support the neuromodulatory effects of tDCS in non motor areas and demonstrate proof-of-principle for ameliorating age- and disease related decline in navigational abilities. PMID- 24472623 TI - Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations. PMID- 24472624 TI - Mendelian inheritance of elevated serum tryptase associated with atopy and connective tissue abnormalities. PMID- 24472625 TI - Can computed tomography help us identify asthmatic phenotypes? PMID- 24472626 TI - Food diversity in infancy and the risk of childhood asthma and allergies. AB - BACKGROUND: Recently, the bacterial diversity of the intestinal flora and the diversity of various environmental factors during infancy have been linked to the development of allergies in childhood. Food is an important environmental exposure, but the role of food diversity in the development of asthma and allergies in childhood is poorly defined. OBJECTIVE: We studied the associations between food diversity during the first year of life and the development of asthma and allergies by age 5 years. METHODS: In a Finnish birth cohort we analyzed data on 3142 consecutively born children. We studied food diversity at 3, 4, 6, and 12 months of age. Asthma, wheeze, atopic eczema, and allergic rhinitis were measured by using the International Study of Asthma and Allergies in Childhood questionnaire at age 5 years. RESULTS: By 3 and 4 months of age, food diversity was not associated with any of the allergic end points. By 6 months of age, less food diversity was associated with increased risk of allergic rhinitis but not with the other end points. By 12 months of age, less food diversity was associated with increased risk of any asthma, atopic asthma, wheeze, and allergic rhinitis. CONCLUSION: Less food diversity during the first year of life might increase the risk of asthma and allergies in childhood. The mechanisms for this association are unclear, but increased dietary antigen exposure might contribute to this link. PMID- 24472627 TI - The value of screening in patient populations with high prevalence of a disorder. AB - Thombs and colleagues have shown that screening consecutive attendees in primary care settings in high income countries for depression is not worthwhile. However, it is dangerous to generalize from high income countries such as the USA to the rest of the world. The positive predictive value of any screening test for depression is affected by the prevalence of the disorder in the population being considered. Populations with an increased prevalence of depression, such as those with chronic physical disorders, or with a history of depression or other mental health problems may benefit from screening, even in high income countries. Populations in low and middle income countries (LMIC) may also benefit from screening if they are experiencing severe social adversity, including poverty. Two examples are given, in which screening with a brief screening questionnaire was followed by collaborative stepped care, to the considerable benefit of the patients in LMIC. Please see related article: http://www.biomedcentral.com/1741 7015/12/13. PMID- 24472628 TI - A Case of Lead Poisoning due to a Mixture of Talisman Ash. AB - BACKGROUND: Lead is a metal that has no biological function useful for the human body. In Korea, non-occupational exposure to lead has mostly occurred through taking oriental medicine. However, in this paper we report a case of lead poisoning caused by ingesting talisman material. CASE PRESENTATION: A 16-year-old male patient complained of severe abdominal pain after taking cinnabar, a talisman material. He was diagnosed with lead poisoning accompanied by acute hepatitis. We confirmed that the cinnabar the patient took contained about 10% elemental lead. After symptom management, the patients' symptoms, liver function test results, and blood lead concentration level improved. CONCLUSION: Lead poisoning can be accompanied by hepatitis, although rarely. As we have confirmed that cinnabar as a talisman material is harmful to the human body, measures to prevent its misuse are needed. PMID- 24472630 TI - A case of hypersensitivity pneumonitis with giant cells in a female dental technician. AB - OBJECTIVES: Dental technicians are exposed to methyl methacrylate(MMA) and hard metal dusts while working, and several cases of hypersensitivity pneumonitis caused by the exposure have been reported. The authors experienced a case of hypersensitivity pneumonitis in a female dental technician who had 10 years' work experience and report the case with clinical evidence. METHOD: The patient's work, personal, social, and past and present medical histories were investigated based on patient questioning and medical records. Furthermore, the workplace conditions and tools and materials the patient worked with were also evaluated. Next, the pathophysiology and risk factors of pneumonitis were studied, and studies on the relationship between hypersensitivity pneumonitis and a dental technician's exposure to dust were reviewed. Any changes in the clinical course of her disease were noted for evaluation of the work-relatedness of the disease. RESULTS: The patient complained of cough and sputum for 1 year. In addition, while walking up the stairs, the patient was not able to ascend without resting due to dyspnea. She visited our emergency department due to epistaxis, and secondary hypertension was incidentally suspected. Laboratory tests including serologic, electrolyte, and endocrinologic tests and a simple chest radiograph showed no specific findings, but chest computed tomography revealed a centrilobular ground-glass pattern in both lung fields. A transbronchial biopsy was performed, and bronchoalveolar washing fluid was obtained. Among the findings of the laboratory tests, microcalcification, noncaseating granuloma containing foreign body-type giant cells, and metal particles within macrophages were identified histologically. Based on these results, hypersensitivity pneumonitis was diagnosed. The patient stopped working due to admission, and she completely quit her job within 2 months of restarting work due to reappearance of the symptoms. CONCLUSION: In this study, the patient did not have typical radiologic findings, but pathological evaluation of the lung biopsy from the bronchoscope led to the suspicion of pneumonitis. Under the microscope, the sample contained fibrotic changes in the lung, multinucleated giant cells, and particles in macrophages and was diagnosed as dental technician pneumoconiosis by the pathology. Working as a dental technician had directly exposed her to light metal dust and MMA, and her clinical symptoms and radiologic findings subsided after withdrawal from exposure to the workplace. These outcomes led to the diagnosis of hypersensitity pneumonitis due to MMA exposure and strong work-relatedness. PMID- 24472629 TI - Loss of GABAergic cortical neurons underlies the neuropathology of Lafora disease. AB - BACKGROUND: Lafora disease is an autosomal recessive form of progressive myoclonic epilepsy caused by defects in the EPM2A and EPM2B genes. Primary symptoms of the pathology include seizures, ataxia, myoclonus, and progressive development of severe dementia. Lafora disease can be caused by defects in the EPM2A gene, which encodes the laforin protein phosphatase, or in the NHLRC1 gene (also called EPM2B) codifying the malin E3 ubiquitin ligase. Studies on cellular models showed that laforin and malin interact and operate as a functional complex apparently regulating cellular functions such as glycogen metabolism, cellular stress response, and the proteolytic processes. However, the pathogenesis and the molecular mechanism of the disease, which imply either laforin or malin are poorly understood. Thus, the aim of our study is to elucidate the molecular mechanism of the pathology by characterizing cerebral cortex neurodegeneration in the well accepted murine model of Lafora disease EPM2A-/- mouse. RESULTS: In this article, we want to asses the primary cause of the neurodegeneration in Lafora disease by studying GABAergic neurons in the cerebral cortex. We showed that the majority of Lafora bodies are specifically located in GABAergic neurons of the cerebral cortex of 3 months-old EPM2A-/- mice. Moreover, GABAergic neurons in the cerebral cortex of younger mice (1 month-old) are decreased in number and present altered neurotrophins and p75NTR signalling. CONCLUSIONS: Here, we concluded that there is impairment in GABAergic neurons neurodevelopment in the cerebral cortex, which occurs prior to the formation of Lafora bodies in the cytoplasm. The dysregulation of cerebral cortex development may contribute to Lafora disease pathogenesis. PMID- 24472631 TI - Development of highly polymorphic simple sequence repeat markers using genome wide microsatellite variant analysis in Foxtail millet [Setaria italica (L.) P. Beauv]. AB - BACKGROUND: Foxtail millet (Setaria italica (L.) Beauv.) is an important gramineous grain-food and forage crop. It is grown worldwide for human and livestock consumption. Its small genome and diploid nature have led to foxtail millet fast becoming a novel model for investigating plant architecture, drought tolerance and C4 photosynthesis of grain and bioenergy crops. Therefore, cost effective, reliable and highly polymorphic molecular markers covering the entire genome are required for diversity, mapping and functional genomics studies in this model species. RESULT: A total of 5,020 highly repetitive microsatellite motifs were isolated from the released genome of the genotype 'Yugu1' by sequence scanning. Based on sequence comparison between S. italica and S. viridis, a set of 788 SSR primer pairs were designed. Of these primers, 733 produced reproducible amplicons and were polymorphic among 28 Setaria genotypes selected from diverse geographical locations. The number of alleles detected by these SSR markers ranged from 2 to 16, with an average polymorphism information content of 0.67. The result obtained by neighbor-joining cluster analysis of 28 Setaria genotypes, based on Nei's genetic distance of the SSR data, showed that these SSR markers are highly polymorphic and effective. CONCLUSIONS: A large set of highly polymorphic SSR markers were successfully and efficiently developed based on genomic sequence comparison between different genotypes of the genus Setaria. The large number of new SSR markers and their placement on the physical map represent a valuable resource for studying diversity, constructing genetic maps, functional gene mapping, QTL exploration and molecular breeding in foxtail millet and its closely related species. PMID- 24472632 TI - Reclassification of cardiovascular risk by myocardial perfusion imaging in diabetic patients with abnormal resting electrocardiogram. AB - BACKGROUND AND AIMS: Despite an extensive use of stress myocardial perfusion single-photon emission computed tomography (MPS), no study addressed the role of perfusion imaging in diabetic patients with abnormal resting electrocardiogram (ECG). We compared analytical approaches to assess the added value of stress MPS variables in estimating coronary heart disease outcomes in diabetic patients with abnormal resting ECG. METHODS AND RESULTS: A total of 416 patients with diabetes and abnormal resting ECG who underwent stress MPS were prospectively followed up after the index study. The end point was the occurrence of a major cardiac event, including cardiac death and nonfatal myocardial infarction. At the end of follow up (median 58 months), 42 patients experienced events. MPS data increased the predictive value of a model including traditional cardiovascular risk factors and left ventricular (LV) ejection fraction (likelihood ratio chi2 from 17.54 to 24.15, p < 0.05, with a C statistic of 0.72, 95% confidence interval: 0.65-0.79). The addition of MPS data resulted in reclassification of 25% of the sample with a net reclassification improvement of 0.20 (95% confidence interval: 0.05-0.36). Overall, 63 patients were reclassified to a lower risk category, with a 5-year event rate of 3.5%, and 40 patients were reclassified to a higher risk category, with a 5-year event rate of 20%. CONCLUSION: The addition of MPS findings to a model based on traditional cardiovascular risk factors and LV ejection fraction improves risk classification for incident cardiac events in diabetic patients with abnormal resting ECG. PMID- 24472633 TI - Care manager to control cardiovascular risk factors in primary care: the Raffaello cluster randomized trial. AB - BACKGROUND AND AIM: This cluster randomized trial evaluated the efficacy of a disease and care management (D&CM) model in cardiovascular (CVD) prevention in primary care. METHODS AND RESULTS: Eligible subjects had >= 1 among: blood pressure >= 140/90 mmHg; glycated hemoglobin >= 7%; LDL-cholesterol >= 160 or >= 100 mg/dL (primary or secondary prevention, respectively); BMI >= 30; current smoking. The D&CM intervention included a teamwork including nurses as care managers for the implementation of tailored care plans. Control group was allocated to usual-care. The main outcome was the proportion of subjects achieving recommended clinical targets for >= 1 of uncontrolled CVD risk factors at 12-month. During 2008-2009 we enrolled 920 subjects in the Abruzzo/Marche regions, Italy. Following the exclusion of L'Aquila due to 2009 earthquake, final analyses included 762 subjects. The primary outcome was achieved by 39.1% (95%CI: 34.2-44.2) and 25.2% (95%CI: 20.9-29.9) of subjects in the intervention and usual care group, respectively (p < 0.001). The D&CM intervention significantly increased the proportion of subjects who achieved clinical targets for both diabetes and hypertension, with no differences in hypercholesterolemia, smoking status and obesity. CONCLUSIONS: The D&CM intervention was effective in controlling cardiovascular risk factors, in particular hypertension and diabetes. Numbers needed to treat were small. Such intervention may deserve further consideration in clinical practice. REGISTRATION NUMBER: ACTRN12611000813987. PMID- 24472634 TI - Dairy foods and risk of stroke: a meta-analysis of prospective cohort studies. AB - BACKGROUND AND AIMS: Epidemiological studies evaluating the association of dairy foods with risk of stroke have produced inconsistent results. We conducted a meta analysis to summarize the evidence from prospective cohort studies regarding the association between dairy foods and risk of stroke. METHODS AND RESULTS: Pertinent studies were identified by searching Embase (1950-November, 2013), Web of Knowledge (1950-November, 2013) and Pubmed (1945-November, 2013). Random effect model was used to combine the results. Dose-response relationship was assessed by restricted cubic spline. Eighteen separate results from fifteen prospective cohort studies, with 28,138 stroke events among 764,635 participants, were included. Total dairy [relative risk (95% CI): 0.88 (0.82-0.94)], low-fat dairy [0.91 (0.85-0.97)], fermented milk [0.80 (0.71-0.89)] and cheese [0.94 (0.89-0.995)] were significantly associated with reduced risk of stroke, but whole/high-fat dairy, nonfermented milk, butter and cream were not significantly associated with risk of stroke. Stronger association was found for stroke mortality than incidence, and for studies conducted in Asia than Europe, while the association did not differ significantly by sex. Limited data did not find any significant association with either ischemic or hemorrhagic stroke. A non linear dose-response relationship (P = 2.80*10(-13)) between milk and risk of stroke was found, and the relative risk of stroke was 0.88 (0.86-0.91), 0.82 (0.79-0.86), 0.83 (0.79-0.86), 0.85 (0.81-0.89), 0.86 (0.82-0.91), 0.91 (0.84 0.98) and 0.94 (0.86-1.02) for 100, 200, 300, 400, 500, 600 and 700 ml/day of milk, respectively. CONCLUSIONS: Dairy foods might be inversely associated with the risk of stroke. PMID- 24472635 TI - Long term weight maintenance after advice to consume low carbohydrate, higher protein diets--a systematic review and meta analysis. AB - BACKGROUND: Meta analysis of short term trials indicates that a higher protein, lower carbohydrate weight loss diet enhances fat mass loss and limits lean mass loss compared with a normal protein weight loss diet. Whether this benefit persists long term is not clear. METHODS AND RESULTS: We selected weight loss studies in adults with at least a 12 month follow up in which a higher percentage protein/lower carbohydrate diet was either planned or would be expected for either weight loss or weight maintenance. Studies were selected regardless of the success of the advice but difference in absolute and percentage protein intake at 12 months was used as a moderator in the analysis. Data was analysed using Comprehensive Meta analysis V2 using a random effects analysis. As many as 32 studies with 3492 individuals were analysed with data on fat and lean mass, glucose and insulin from 18 to 22 studies and lipids from 28 studies. A recommendation to consume a lower carbohydrate, higher protein diet in mostly short term intensive interventions with long term follow up was associated with better weight and fat loss but the effect size was small-standardised means of 0.14 and 0.22, p = 0.008 and p < 0.001 respectively (equivalent to 0.4 kg for both). A difference of 5% or greater in percentage protein between diets at 12 mo was associated with a 3 fold greater effect size compared with <5% (p = 0.038) in fat mass (0.9 vs. 0.3 kg). Fasting triglyceride and insulin were also lower with high protein diets with effect sizes of 0.17 and 0.22, p = 0.003 and p = 0.042 respectively. Other lipids and glucose were not different. CONCLUSION: The short term benefit of higher protein diets appears to persist to a small degree long term. Benefits are greater with better compliance to the diet. PMID- 24472636 TI - Effects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease: a meta-analysis of randomized controlled trials. AB - AIM: There is considerable discrepancy regarding the protective effects of Omega 3 polyunsaturated fatty acids (Omega-3 PUFAs) in patients with coronary heart disease (CHD) from the early-phase clinical randomized controlled trials (RCTs). We conducted a meta-analysis of RCTs to address this issue. DATA SYNTHESIS: Pubmed, the Cochrane Central Register of Controlled Trials, and EMBASE databases (~ May 2013) were systematically searched. Odds ratios (OR) and associated 95% CI were retrieved by using random-effect model according to heterogeneity. A total of 14 RCTs involving 16,338 individuals in the Omega-3 PUFAs group and 16,318 in the control group were identified. Patients assigned to Omega-3 PUFAs did not demonstrate satisfactory improvements on major cardiovascular events (OR, 0.93; 95% CI, 0.86 to 1.01; P = 0.08; I(2) = 46%). By contrast, the reduced risks of death from cardiac causes, sudden cardiac death and death from all causes (OR, 0.88; 95% CI, 0.80 to 0.96; P = 0.003; I(2) = 0%; OR, 0.86; 95% CI, 0.76 to 0.98; P = 0.03; I(2) = 29%; and OR, 0.92; 95% CI, 0.85 to 0.99; P = 0.02; I(2) = 6%; respectively) were shown. CONCLUSIONS: Supplement of Omega-3 PUFAs in patients with CHD is not associated with a protective effect on major cardiovascular events, while it does exert beneficial effects in reducing death from cardiac causes, sudden cardiac death and death from all causes. However, with currently available cardio-protective therapies, whether dietary supplementation with Omega 3 PUFAs should be still considered in patients with CHD is currently debated. PMID- 24472637 TI - Plasma creatinine levels, estimated glomerular filtration rate and carotid intima media thickness in middle-aged women: a population based cohort study. AB - BACKGROUND AND AIM: The relationships between high Creatinine (Cr) levels or low estimated Glomerular Filtration Rate (eGFR) and common carotid Intima Media thickness (IMT) have been evaluated in a population-based cohort study in women, aged 30-69 (Progetto ATENA). METHODS AND RESULTS: Serum Cr and eGFR were measured in 310 women, as a part of 5.062. In this group carotid ultrasound examination (B Mode imaging) was performed and mean max IMT was calculated. Women were classified by Cr levels >1 mg/dL or eGFR < 56 ml/min. Women with Cr > 1 mg/dL (90th percentile of creatinine distribution) or eGFR less than 56 ml/min (5th percentile of eGFR distribution) had relatively more carotid plaques as compared to the rest of the cohort. Multivariate logistic analysis, after adjustment for age, demonstrated a significant association between Cr (>1 mg/dL) and IMT (>=1.2 mm): OR 4.12 (C.I 1.22-13.86), p = 0.022; or eGFR (<56 ml/min) and IMT (>=1.2 mm): OR 4.31 (C.I 1.27-14.66), p = 0.019. CONCLUSIONS: These findings on an independent relationship between Cr and common carotid plaques in this population of middle aged women, independently of age, suggest the value of screening for early carotid disease in asymptomatic middle aged-women with mild renal insufficiency, in order to predict those at relatively higher risk for future cardiovascular events. PMID- 24472639 TI - Treatment modality: a predictor of continued tobacco use after treatment in patients with laryngeal cancer. AB - BACKGROUND: Laryngeal cancer patients who continue to smoke after treatment are at an elevated risk of mortality and morbidity. This study aimed to identify factors associated with continued tobacco use following treatment in patients with laryngeal cancer. METHODS: A smoking behaviour questionnaire, a self-report measure, was sent to 112 patients who were diagnosed with laryngeal cancer during 2006-2011 at the Brighton and Sussex University Hospitals, Brighton, UK. Patient demographics, tumour and treatment-related variables, comorbidity and socio economic status were obtained from the medical records. RESULTS: Eighty-one per cent of patients responded to the survey; 22 per cent of these reported continued tobacco use after treatment. Treatment modality was found to be a predictor of post-therapeutic smoking (odds ratio: 4.9, p = 0.01); patients who received less invasive therapy (transoral laser microsurgery) were more likely to smoke after treatment. CONCLUSIONS: The findings of this preliminary study suggest that treatment modality influences smoking behaviour in patients with laryngeal cancer, which may have important implications for the design of anti-smoking interventions. PMID- 24472638 TI - Neonatal leptin deficiency reduces frontal cortex volumes and programs adult hyperactivity in mice. AB - Intrauterine growth restriction and premature delivery decrease circulating levels of the neurotrophic hormone leptin and increase the risk of adult psychiatric disease. In mouse models, neonatal leptin replacement normalizes brain growth and improves the neurodevelopmental outcomes of growth restricted mice, but leptin supplementation of well-grown mice decreases adult locomotor activity. We hypothesized isolated neonatal leptin deficiency is sufficient to reduce adult brain volumes and program behavioral outcomes, including hyperactivity. C57Bl/6 pups were randomized to daily injections of saline or PEG leptin antagonist (LX, 12.5 mg/kg) from postnatal day 4 to 14. After 4 months, fear conditioning and open field testing were performed followed by carotid radiotelemetry for the measurement of baseline activity and blood pressure. Neonatal LX did not significantly increase cue-based fear or blood pressure, but increased adult locomotor activity during assessment in both the open field (beam breaks: control 930 +/- 40, LX 1099 +/- 42, P<0.01) and the home cage (radiotelemetry counts: control 4.5 +/- 0.3, LX 5.6 +/- 0.3, P=0.02). Follow-up MRI revealed significant reductions in adult frontal cortex volumes following neonatal LX administration (control 45. 1 +/- 0.4 mm(3), LX 43.8 +/- 0.4 mm(3), P=0.04). This was associated with a significant increase in cerebral cortex leptin receptor mRNA expression. In conclusion, isolated neonatal leptin deficiency increases cerebral cortex leptin receptor expression and reduces frontal cortex volumes in association with increased adult locomotor activity. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with perinatal growth restriction, and postnatal leptin therapy may be protective. PMID- 24472640 TI - DMARD non-use in low-income, elderly rheumatoid arthritis patients: results of 86 structured interviews. AB - INTRODUCTION: Disease-modifying antirheumatic drugs (DMARDs) have become the treatment standard for patients with rheumatoid arthritis (RA). Although several general-population studies document that a large population of patients diagnosed with RA do not use DMARDs, little is known about this group. We explored the characteristics, experiences, and knowledge of a low-income, elderly RA population not currently using DMARDs, or receiving care from a rheumatologist. METHODS: We administered structured telephone interviews to participants enrolled in a large pharmacy benefits program for the elderly who had two diagnoses of RA >=7 days apart and no DMARD prescriptions or rheumatologist visits in the prior year. The interview contained questions concerning each participant's sociodemographic information, disease activity, DMARD experiences, and the Modified Health Assessment Questionnaire (MHAQ). We described responses and compared prior users with never users. RESULTS: A total of 86 people completed the interview. The mean age was 80 years and 89% were female. On average, disease duration was 20 years. Mean MHAQ score was 0.55 (SD = 0.55). Of 86 participants, 19 had previously used DMARDs, 10 of whom discontinued them because of side effects or safety concerns. Among 67 never-users, 35 (52.2%) reported that their physicians had never offered them DMARDs, 13 (19.4%) described fear of side effects, and 49 (73.1%) knew nothing about them. Prior-users reported experiencing more-severe RA symptoms than never-users. CONCLUSIONS: We found that side effects or safety concerns were the primary cause for DMARD cessation among prior-users. Among never-users, most reported never discussing or being offered DMARDs, suggesting that an educational gap may deter patients with RA from using them. PMID- 24472641 TI - Response to: ''the triadic model perspective for the study of adolescent motivated behavior''. PMID- 24472642 TI - Formulation and in vitro evaluation of size expanding gastro-retentive systems of levofloxacin hemihydrate. AB - Size increasing (plug-type) levofloxacin hemihydrate (LVF) tablets for eradication of Helicobacter pylori (H. pylori) were prepared using in situ gel forming polymers including: gellan gum, sodium alginate, pectin and xanthan gum. Effect of cross-linkers: calcium and aluminum chloride, on the drug release was also studied. The prepared tablets were evaluated for their physicochemical parameters: weight variation, thickness, friability, hardness, drug content, water uptake and in vitro drug release. The optimized formula was subjected to further studies such as radial swelling test, FT-IR and DSC. Results revealed that LVF release depends not only on the nature of the matrix but also on the type of cross linker used to form this polymeric matrix. The addition of either calcium chloride or aluminum chloride, as cross-linkers, to gellan gum formulations significantly decreased drug release. Other polymers' formulations resulted in increased drug release upon addition of the same cross-linkers. The formula containing xanthan gum without any cross linker showed the most sustained LVF release with an increase in diameter with time, thus acting as a plug-type dosage form. IR spectra and DSC thermograms of LVF, xanthan gum, and a physical mixture of both, indicated that there was no interaction between the drug and the polymer and confirmed the drug stability. PMID- 24472643 TI - Anatomy of plasmid DNAs with anti-silencing elements. AB - The transience of transgene expression is a major obstacle in the development of nonviral vectors. The CpG-free and pLIVE plasmids reportedly achieve long-term transgene expression in mouse liver. In this work, the anti-silencing elements within these plasmids were studied. The effects of plasmid that was being silenced on transgene expression from the CpG-free plasmid and those of transgene expression at early time points on silencing were also examined. The results suggested that the backbone sequence of the CpG-free plasmid and the 3' untranslated region of the albumin gene of the pLIVE plasmid contribute to durable expression. In addition, no influence of the silencing of another plasmid on the duration of CpG-free plasmid expression or of transgene expression at early time points on silencing was detected. PMID- 24472644 TI - One year later: update on transition to the society for disaster medicine and public health and Cambridge University Press. PMID- 24472645 TI - Working through disaster: re-establishing mental health care after Hurricane Katrina. AB - OBJECTIVE: Our research explored how mental health care providers continued to work during and after Hurricane Katrina. METHODS: We interviewed 32 practitioners working in the New Orleans mental health care community during and after Hurricane Katrina. Through qualitative data analysis, we developed three temporal periods of disruption: the evacuation period, the surreal period, and the new normal period. We analyzed the actions informants took during these time periods. RESULTS: The mental health care providers adapted to disruption by displaying two forms of flexibility: doing different tasks and doing tasks differently. How much and how they engaged in these forms of flexibility varied during the three periods. CONCLUSIONS: Informants' actions helped to create system resilience by adjusting the extent to which they were doing different tasks and the ways in which they were doing tasks differently during the three time periods. Their flexibility allowed them to provide basic care and adapt to changed circumstances. Their flexibility also contributed to maintaining a skilled workforce in the affected region. PMID- 24472646 TI - Integrin linked kinase (ILK) is required for lens epithelial cell survival, proliferation and differentiation. AB - While the role of growth factors in lens development has been investigated extensively, the role of extracellular matrix signalling is less well understood. The developing lens expresses predominantly laminin-binding integrins (such as alpha3beta1, alpha6beta1), which are cooperatively required in the lens epithelium during development. We investigated the role of ILK, a downstream mediator of integrin signalling in mice conditionally null for Ilk. Mutant lenses showed epithelial thinning at E17.5 with reduced proliferation and epithelial cell number and aberrant fibre differentiation. There was complete loss of the central epithelium from postnatal day (P) 2 due to cell death followed by fibre cell degeneration and death by P10 as well as rupture of the lens capsule between P10 and P21. At E17.5 there was significant inhibition (~50%) of epithelial cell cycle progression, as shown by BrdU incorporation, cyclin D1/D2 and phospho histone H3 immunostaining. The epithelial marker, E-cadherin, was decreased progressively from E17.5 to P2, in the central epithelium, but there was no significant change in Pax6 expression. Analyses of ERK and Akt phosphorylation indicated marked depression of MAPK and PI3K-Akt signalling, which correlated with decreased phosphorylation of FRS2alpha and Shp2, indicating altered activation of FGF receptors. At later postnatal stages there was reduced or delayed expression of fibre cell markers (beta-crystallin and p57(kip2)). Loss of Ilk also affected deposition of extracellular matrix, with marked retention of collagen IV within differentiating fibre cells. By quantitative RT-PCR array there was significantly decreased expression of 19 genes associated with focal adhesions, actin filament stability and MAPK and PI3K/Akt signalling. Overall, these data indicate that ILK is required for complete activation of signalling cascades downstream of the FGF receptor in lens epithelium and fibre cells during development and thus is involved in epithelial proliferation, survival and subsequent fibre differentiation. PMID- 24472647 TI - Preoperative cardiopulmonary exercise testing in England - a national survey. AB - BACKGROUND: Cardiopulmonary exercise testing (CPET) has become well established in the preoperative assessment of patients presenting for major surgery in the United Kingdom. There is evidence supporting its use in risk-stratifying patients prior to major high-risk surgical procedures.We set out to establish how CPET services in England have developed since the only survey on this subject was undertaken in 2008 (J Intensive Care Soc 2009, 10:275-278). METHODS: Availability of preoperative CPET and contact details were collected via a telephone survey and email invites to complete the online survey were sent to all contacts. The survey was live during March and April 2011. RESULTS: We received 123 (74%) responses from the 166 emails that were sent out. In total, 32% (53/166) of all adult anesthetic departments in England have access to preoperative CPET services and a further 4% (6) were in the process of setting up services. The number of departments offering preoperative CPET, including those in the process of setting up services, has risen from 42 in 2008 to 59 in 2011, a rise of over 40%. Only 61% of the clinics are run by anesthetists and 39% of clinics have trained cardiorespiratory technicians assisting in the performance of the test. Most of the clinics (55%) rely solely on a bicycle ergometer. Vascular surgical patients are the largest group of patients tested, and the majority of tests are run to a symptom-limited maximum. We estimate that 15,000 tests are performed annually for preoperative assessment in England. Only 37% of respondents were confident that the tests performed were being billed for. CONCLUSIONS: CPET is increasing in popularity as a preoperative risk assessment tool. There remains a lack of consistency in the way tests are reported and utilized. The results highlight the extent and diversity of the use of preoperative CPET and the potential for further research into its use in unstudied patient groups. PMID- 24472649 TI - Why do we grow old: is it because our cells just wear out, we run out of cells (or both), and what can we do about it? AB - Longevity & Healthspan, a new BioMed Central journal, has launched a thematic series on cellular senescence and aging, a quickly evolving field critical to our understanding of the biology of aging. PMID- 24472648 TI - Risk of leukemia in relation to exposure to ambient air toxics in pregnancy and early childhood. AB - There are few established causes of leukemia, the most common type of cancer in children. Studies in adults suggest a role for specific environmental agents, but little is known about any effect from exposures in pregnancy to toxics in ambient air. In our case-control study, we ascertained 69 cases of acute lymphoblastic leukemia (ALL) and 46 cases of acute myeloid leukemia (AML) from California Cancer Registry records of children =4 minutes) defined as either SAP <90 mmHg or MAP <65 mmHg in 30 patients and 16 patients, respectively. In 11 (SAP <90 mmHg) and 6 (MAP <65 mmHg) of these patients, hypotension was also detected by the subsequent intermittent oscillometric AP measurement. CONCLUSIONS: VUT using the CNAP system for noninvasive continuous AP measurement shows reasonable agreement with intermittent oscillometric measurements in acutely ill ED patients. Continuous AP monitoring allows immediate recognition of clinically relevant hypotensive episodes, which are missed or only belatedly recognized with intermittent AP measurement. PMID- 24472660 TI - Cervical oesophagostomy in patients with severe dysphagia following radiotherapy for nasopharyngeal carcinoma. AB - OBJECTIVE: This study aimed to investigate the validity and feasibility of cervical oesophagostomy as a treatment for patients with severe dysphagia after radiotherapy for nasopharyngeal carcinoma. METHODS: The study retrospectively analysed the clinical data, symptoms, physical signs, treatment and outcomes of 12 patients treated with cervical oesophagostomy for severe dysphagia after radiotherapy for nasopharyngeal carcinoma, from 2006 to 2010. RESULTS: In all 12 cases, the oesophageal stoma remained stable, without any complications such as pharyngeal fistula or inflammation. No oesophageal stricture or granuloma growth was observed. All patients reported significant improvement in their nutritional status and quality of life after the oesophagostomy surgery. CONCLUSION: Cervical oesophagostomy is a valid and feasible method of treating severe dysphagia following radiotherapy for nasopharyngeal carcinoma. Oesophagostomy shows specific advantages over nasogastric tubing, gastrostomy and jejunostomy. Patients' nutrition and quality of life can be improved significantly if cervical oesophagostomy is executed in a timely fashion, especially in cases with severe trismus and multiple radiation-induced cranial nerve palsies unresponsive to rehabilitation. PMID- 24472661 TI - Marking axonal growth in sensory neurons: SCG10. PMID- 24472662 TI - Genome-wide CNV analysis in mouse induced pluripotent stem cells reveals dosage effect of pluripotent factors on genome integrity. AB - BACKGROUND: Induced pluripotent stem cells (iPSCs) derived from somatic cells have enormous potential for clinical applications. Notably, it was recently reported that reprogramming from somatic cells to iPSCs can induce genomic copy number variation (CNV), which is one of the major genetic causes of human diseases. However it was unclear if this genome instability is dependent on reprogramming methods and/or the genetic background of donor cells. Furthermore, genome-wide CNV analysis is technically challenging and CNV data need to be interpreted with care. RESULTS: In order to carefully investigate the possible CNV instability during somatic reprogramming, we performed genome-wide CNV analyses with 41 mouse iPSC lines generated from the same parental donor; therefore, the donor's genetic background can be controlled. Different reprogramming factor combinations and dosages were used for investigating potential method-dependent effects on genome integrity. We detected 63 iPSC CNVs using high-resolution comparative genomic hybridization. Intriguingly, CNV rates were negatively associated with the dosages of classic factor(s). Furthermore, the use of high-performance engineered factors led to less CNVs than the classic factor(s) of the same dosage. CONCLUSION: Our observations suggest that sufficient reprogramming force can protect the genome from CNV instability during the reprogramming process. PMID- 24472663 TI - Effect of Cydonia oblonga Mill. fruit and leaf extracts on blood pressure and blood rheology in renal hypertensive rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Quince, Cydonia oblonga Mill. (COM), is used in traditional Uyghur medicine to treat or prevent cardiovascular diseases. Uyghur people have greater longevity and lower blood pressure than other central Asian populations. We therefore tested COM fruit and leaf extracts on blood pressure and rheology in renal hypertensive rats (RHR). MATERIALS AND METHODS: Two-kidney, one-clip (2K1C) renal hypertensive rats were divided randomly into eleven groups: sham, model, and model treated with daily doses of 80 and 160mg/kg aqueous or ethanol extracts of COM fruit or leaves, or 25mg/kg captopril (n=10 per group), given orally once daily for 8 weeks. Blood pressure was measured before treatment and every 2 weeks thereafter. Blood rheology was tested after 8 weeks. RESULTS: Model rats had higher blood pressure than sham 8 weeks after the procedure (systolic blood pressure 193+/-7 vs. 138+/-8mmHg, p<0.05). Those treated with captopril had decreased blood pressure within 2 weeks but that did not return to the level found in the sham group at 8 weeks (167+/-7, p<0.05 vs. model). With the COM extracts, the effect on blood pressure was notable after 4 weeks. At 8 weeks blood pressure was similar with captopril and with 160mg ethanol leaf extract (166+/-4, p<0.05 vs. model), the most effective of the extracts. Model rats had higher blood viscosity and lower erythrocyte deformability than sham. Captopril had little effect on blood rheology; whereas COM extracts reduced whole blood viscosity and improved erythrocyte deformability to levels approaching those found in sham. CONCLUSIONS: COM extracts have antihypertensive activity in renal hypertensive rats. The additional effect on rheology, compared to captopril, may convey added interest. Further studies of these effects in man appear warranted. PMID- 24472664 TI - Type and screen policy: is there any compromise on blood safety? AB - INTRODUCTION: Pre-transfusion testing involves blood grouping (ABO and Rh) and major cross match (testing the recipient's serum/plasma against the donor's red blood cells) at 37 degrees C to detect IgG antibodies. In the western countries, type and screen policy is routinely followed. AIM: This study was conducted to assess implementation of type and screen policy in standalone blood banks in India and to assess compromise on blood safety, if any? MATERIALS AND METHODS: The study was carried out at the Standalone Blood Bank of North India during the period January 2012 to April 2012. Type and screen study was carried out in parallel to routine cross match using Column Agglutination Technology. RESULTS: Total 354 patients were included in the study. 4 samples were positive on antibody screening. Cross match was incompatible in 1 case. No case was found with antibody screen negative but AHG cross match incompatible. CONCLUSION: This study concluded good safety level in high risk category patients. Type and screen policy can be implemented in Indian settings with no compromise on blood safety provided sufficient technical and infrastructural support is available at the centre. PMID- 24472665 TI - Coagulation factors and inhibitors in thawed plasma stored at 1-6 degrees C for 5 days in China. AB - INTRODUCTION: Many transfusion services are keeping thawed plasma (TP) ready for trauma patients. According to Chinese guidelines, once thawed, fresh frozen plasma (FFP) should be used within 24h. This may increase plasma wastage and delay plasma administration to critical patients. However, it can be avoided by being relabeled as TP. In this study we evaluated coagulation-related proteins in thawed apheresis FFP during 5 days of storage at 1-6 degrees C. MATERIALS AND METHODS: Thirty apheresis fresh plasma units were aliquot and stored at -70 degrees C. Aliquots were thawed at 37 degrees C and stored at 1-6 degrees C for 0, 1, 2, 3, 4 and 5 days, respectively. Prothrombin time (PT), activated partial thromboplastin time (aPTT), thrombin time (TT), fibrinogen (Fbg), factor (F) II, FV, FVII, FVIII, FIX, FX, FXI, FXII, protein C (PC), protein S (PS), antithrombin III (ATIII) and ADAMTS13 levels were assessed at Days 0-5, respectively. RESULTS: For 5 days of refrigerated storage, no significant differences were observed in Fbg, PC, PS, ATIII and ADAMTS13. FII, FV, FVII, FVIII, FIX, FX, FXI and FXII declined significantly over time. The storage presented major decrease for FVIII, with a drop of 40%. However, at least 60% levels of all measured proteins were remained on Day 5, when compared to Day 0. CONCLUSION: All measured proteins in TP for 5 days of refrigerated storage were adequate. These could provide evidence that thawed FFP could be relabeled as TP, which is a potential to ensure rapid plasma availability in emergency situations in China. PMID- 24472668 TI - Congratulatory message from the president of international commission on occupational health. PMID- 24472666 TI - Effects of endogenous cannabinoid anandamide on excitation-contraction coupling in rat ventricular myocytes. AB - A role for anandamide (N-arachidonoyl ethanolamide; AEA), a major endocannabinoid, in the cardiovascular system in various pathological conditions has been reported in earlier reports. In the present study, the effects of AEA on contractility, Ca2+ signaling, and action potential (AP) characteristics were investigated in rat ventricular myocytes. Video edge detection was used to measure myocyte shortening. Intracellular Ca2+ was measured in cells loaded with the fluorescent indicator fura-2 AM. AEA (1 MUM) caused a significant decrease in the amplitudes of electrically evoked myocyte shortening and Ca2+ transients. However, the amplitudes of caffeine-evoked Ca2+ transients and the rate of recovery of electrically evoked Ca2+ transients following caffeine application were not altered. Biochemical studies in sarcoplasmic reticulum (SR) vesicles from rat ventricles indicated that AEA affected Ca2+ -uptake and Ca2+ -ATPase activity in a biphasic manner. [3H]-ryanodine binding and passive Ca2+ release from SR vesicles were not altered by 10 MUM AEA. Whole-cell patch-clamp technique was employed to investigate the effect of AEA on the characteristics of APs. AEA (1 MUM) significantly decreased the duration of AP. The effect of AEA on myocyte shortening and AP characteristics was not altered in the presence of pertussis toxin (PTX, 2 MUg/ml for 4 h), AM251 and SR141716 (cannabinoid type 1 receptor antagonists; 0.3 MUM) or AM630 and SR 144528 (cannabinoid type 2 receptor antagonists; 0.3 MUM). The results suggest that AEA depresses ventricular myocyte contractility by decreasing the action potential duration (APD) in a manner independent of CB1 and CB2 receptors. PMID- 24472667 TI - Notochordal cell disappearance and modes of apoptotic cell death in a rat tail static compression-induced disc degeneration model. AB - INTRODUCTION: The intervertebral disc has a complex structure originating developmentally from both the mesenchyme and notochord. Notochordal cells disappear during adolescence, which is also when human discs begin to show degenerative signs. During degeneration later in life, disc cells decline because of apoptosis. Although many animal models have been developed to simulate human disc degeneration, few studies have explored the long-term changes in cell population and phenotype. Our objective was to elucidate the time-dependent notochordal cell disappearance and apoptotic cell death in a rat tail static compression-induced disc degeneration model. METHODS: Twenty-four 12-week-old male Sprague-Dawley rat tails were instrumented with an Ilizarov-type device and loaded statically at 1.3 MPa for up to 56 days. Loaded and distal-unloaded discs were harvested. Changes in cell number and phenotype were assessed with histomorphology and immunofluorescence. Apoptosis involvement was determined with terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining and immunohistochemistry. RESULTS: The number of disc nucleus pulposus and annulus fibrosus cells decreased with the loading period; particularly, the decrease was notable at day 7 in larger, vacuolated, cytokeratin-8- and galectin-3-co-positive cells, indicating notochordal origin. Subsequently, the proportion of cells positive for TUNEL and cleaved caspase-3, markers of apoptosis induction, increased from day 7 through day 56. Although the percentage of cells immunopositive for cleaved caspase-8, a marker of apoptosis initiation through the death-receptor pathway, increased only at day 7, the percentage of cells immunopositive for cleaved caspase-9 and p53-regulated apoptosis-inducing protein 1 (p53AIP1), markers of apoptosis initiation through the p53-mediated mitochondrial pathway, increased from day 7 through day 56. The percentage of cells immunopositive for B-cell lymphoma 2 (Bcl-2) and silent mating type information regulation 2 homolog 1 (SIRT1), antiapoptotic proteins, decreased consistently with compression. CONCLUSIONS: This rat tail model mimics notochordal cell disappearance and apoptotic cell death in human disc aging and degeneration. Sustained static compression induces transient activation of apoptosis through the death-receptor pathway and persistent activation of apoptosis through the p53-mediated mitochondrial pathway in disc cells. The increased proapoptotic and decreased antiapoptotic proteins observed at all time points signify static compression-induced disc cell death and degeneration. PMID- 24472669 TI - Bioaccessibility and safety assessment of trace elements from decoction of "Zhebawei" herbal medicines by in vitro digestion method. AB - Studies on in vitro bioaccessibility and safety assessment of 6 elements namely Fe, Zn, Cu, Mn, As and Cd in decoction of eight commonly consumed "Zhebawei" herbal medicines were carried out. The method was based on simulation of human digestion in the gastrointestinal tract. Total content and content in extracts from gastrointestinal phases were analyzed for these elements by inductively coupled plasma atomic emission spectrometer (ICP-AES). In decoction of all 8 herbal medicines, it was found that the total content and bioaccessible concentration of these elements varied considerably among the types of herb, and the total content of each element did not show linearity with their bioaccessible content of the corresponding element. There is no risk of adverse health effects resulting from overdose of Fe, Zn, Cu, and Mn for almost all individuals by ingesting recommended maximum daily dose of these eight herbal medicines. In terms of Cd only Ophitopogin japonicum had higher total concentration and bioaccessible content than the value of suggested limit (5.4MUg/d). For total As content, only Scrophularia ningpoensis and Corydalis yanhusuo did not meet the safety standard. However, regarding bioaccessible As contents, none of the eight herbal medicines exceeded the value of the daily permissible intake of As (0.12mg). The risk of toxicity from an element in herbal medicine might be overestimated when the total concentration but not the bioaccessible content is taken into account. In vitro digestion method is rapid, relatively simple and inexpensive, which could be helpful in conducting experiments about safety assessment of an element in herbal medicines. PMID- 24472671 TI - RGC-5: are they really 661W? The saga continues. PMID- 24472670 TI - Targeting CXCR4 with CTCE-9908 inhibits prostate tumor metastasis. AB - BACKGROUND: CXCL12/CXCR4 transactivation of epidermal growth factor family receptors in lipid raft membrane microdomains on cell surface is thought to mediate tumor growth and subsequent development of metastatic disease. CTCE-9908 is a known inhibitor of CXCR4. Herein, we tested the efficacy of CTCE-9908 in inhibiting prostate cancer cell growth, invasion, and metastasis. METHODS: We used a panel of in vitro assays utilizing human prostate cancer cell lines and an in vivo orthotopic prostate cancer model to assess the anti-tumoral activity of CTCE-9908. RESULTS: We demonstrated that (a) CTCE-9908 treatment resulted in no significant change in the growth of PC-3 and C4-2B cells; (b) 50 MUg/ml of CTCE 9908 inhibited the invasive properties of PC-3 cells; (c) 25 mg/kg of CTCE-9908 did not alter primary tumor growth but it did significantly reduce total tumor burden in the animal including the growth of prostate and soft tissue metastases to lymph node and distant organ tissues. Histological analysis showed that CTCE 9908 treatment resulted in tumor necrosis in primary prostate tumors and no significant change in proliferation of tumor cells as measured by Ki-67 staining; (d) CTCE-9908 inhibited the tumor angiogenesis as measured by CD34 positive vessels in tumors. CONCLUSIONS: These data suggest that CXCR4 inhibition by CTCE 9908 decreases the invasion potential in vitro, which then translated to a reduction of tumor spread with associated reduction in angiogenesis. Hence, CTCE 9908 may prove to be an efficacious novel agent to prevent and treat the spread of metastatic prostate cancer. PMID- 24472672 TI - Lobophylliidae (Cnidaria, Scleractinia) reshuffled: pervasive non-monophyly at genus level. AB - The Indo-Pacific scleractinian coral family Lobophylliidae was recently described on the basis of molecular data and micromorphological and microstructural characters. We present the most comprehensive molecular phylogeny reconstruction of the family to date based on COI and rDNA including 9 genera and 32 species, 14 of which were investigated for the first time. The monophyly of the family is now strongly supported, with the inclusion of the genera Acanthastrea and Micromussa, whereas previously it was based on uncertain molecular relationships. Nevertheless, these and the other lobophylliid genera Echinophyllia, Micromussa, Oxypora, and Symphyllia, are not themselves monophyletic and need to be investigated from a morphological point of view. Acanthastrea faviaformis is nested within the family Merulinidae. This study highlights the need for further analyses at species level and of formal taxonomic actions. PMID- 24472673 TI - Continental monophyly of cichlid fishes and the phylogenetic position of Heterochromis multidens. AB - The incredibly species-rich cichlid fish faunas of both the Neotropics and Africa are generally thought to be reciprocally monophyletic. However, the phylogenetic affinity of the African cichlid Heterochromis multidens is ambiguous, and this distinct lineage could make African cichlids paraphyletic. In past studies, Heterochromis has been variously suggested to be one of the earliest diverging lineages within either the Neotropical or the African cichlid radiations, and it has even been hypothesized to be the sister lineage to a clade containing all Neotropical and African cichlids. We examined the phylogenetic relationships among a representative sample of cichlids with a dataset of 29 nuclear loci to assess the support for the different hypotheses of the phylogenetic position of Heterochromis. Although individual gene trees in some instances supported alternative relationships, a majority of gene trees, integration of genes into species trees, and hypothesis testing of putative topologies all supported Heterochromis as belonging to the clade of African cichlids. PMID- 24472674 TI - Introduction to the postanaesthetic care unit. AB - High-risk, noncardiac surgery represents only 12.5% of surgical procedures, but 83.3% of deaths. The postanaesthetic care unit (PACU) addresses the need for an improved level of care for these patients by providing postoperative high dependency or intensive care (Level 2 or 3). The PACU aims to improve the structure of care provision for high-risk surgical patients. By maintaining 24 hour cover at the same staffing level, the risk of poorer 'out-of- hours' care is reduced. In a PACU, whose remit is solely postoperative care, evidence-based protocols can be established to standardize the care given. The aim is to provide 24 hours of postoperative optimized care, thus targeting the period when these patients are most vulnerable, to reduce the risk of complications developing and identify complications promptly, should they occur. The PACU is set up to facilitate certain processes to aid optimized care in the postoperative period. These include invasive and noninvasive ventilation, goal-directed haemodynamic management, invasive monitoring and optimal pain management. Identification of high-risk patients who might benefit from PACU care is not always straightforward. However, tools are available to aid the clinician, supplementing clinical assessment and basic investigations. These include clinical prediction rules and cardiopulmonary exercise testing. Both the setting up and the running of a PACU clearly have cost implications. However, the reduction in postoperative morbidity, and thus patients' length of stay, should, overall, reduce costs. The benefits of a PACU should therefore be seen in terms of improved surgical outcomes, reducing postoperative morbidity and mortality, and cost savings. PMID- 24472675 TI - Evaluation of five selective media for the detection of Pseudomonas aeruginosa using a strain panel from clinical, environmental and industrial sources. AB - Isolation and correct identification of the opportunistic pathogen and industrial contaminant Pseudomonas aeruginosa are very important and numerous selective media are available for this purpose. A novel comparison of five selective media having positive (acetamide-based agars), negative (Pseudomonas CN selective agar [Oxoid Ltd.] and Pseudomonas Isolation agar [Sigma-Aldrich Company Ltd.]) and chromogenic (chromID(r) P. aeruginosa [bioMerieux]) selection strategies was performed using a systematically designed bacterial test panel (58 P. aeruginosa and 90 non-P. aeruginosa strains including those commonly misidentified as P. aeruginosa by culture-dependent techniques). Standardised inocula were added to the selective media and the results were recorded after 24 and 72h. After 72h of incubation at 37 degrees C chromID(r) P. aeruginosa displayed the highest specificity (70%) and had good sensitivity (95%), although the sensitivity was negatively impacted by the large variation in colour of P. aeruginosa colonies, which hampered interpretation. Both media containing inhibitory selective agents performed very similarly, both having 100% sensitivity and a specificity of approximately 30%. Raising the incubation temperature to 42 degrees C increased the specificity of Pseudomonas CN selective agar and Pseudomonas isolation agar (61% and 47% respectively after 72h), but increased the number of false positives encountered with the chromogenic medium, decreasing its specificity to 68% after 72h. Growth on the acetamide agars was weak for all strains and it was often difficult to determine whether true growth had occurred. This, compounded by the low specificity of the acetamide agars (<26%), suggested they were less suitable for application to clinical or industrial settings without further modification. Overall, the chromogenic agar was the most selective but further consideration is required to optimise interpretation of results. PMID- 24472676 TI - Ulceration of the nasal dorsum: a rare cause? AB - INTRODUCTION: Non-healing ulcers can be caused by a number of conditions, including vascular disease, diabetes, malignancy and some infections. Drug related ulcers are rare, and a high index of clinical suspicion is required for diagnosis, in parallel with exclusion of more sinister underlying causes. CASE REPORT: We present a patient with a complex medical background, who had a 10-week history of a non-healing ulcer on his nasal bridge. Inflammatory, autoimmune and malignant causes for the ulcer were excluded by histopathology. CONCLUSION: Nicorandil was deemed to be the most likely cause for the patient's ulcer. Nicorandil is an anti-anginal medication known to cause oral ulceration and skin lesions in the perianal and peristomal regions and around surgical wounds. However, there are no previously reported cases of facial ulcers. The ulcer required surgical debridement and healed completely within six months, following discontinuation of nicorandil. This case highlights the importance of having a high index of clinical suspicion regarding non-healing ulcers, and of considering drugs as an aetiological factor, especially in patients with a complex medical background who are taking numerous medications. PMID- 24472677 TI - How can waist circumference predict the body composition? AB - BACKGROUND: Waist circumference (WC) is used as a risk assessment for metabolic syndrome, diabetes, and cardiovascular disease (CVD). WC consists of visceral fat area (VFA), subcutaneous fat area (SFA), muscle, intramuscular fat, viscera, and bone. Each component of the WC may differ between the sexes and generations, even if they have the same WC. However, this has not been measured in an epidemiological study. METHODS: Between 2004 to 2009, employees and their spouses working at a Japanese company underwent a health examination after more than 12 hours of fasting. We analyzed the data of 11,570 subjects (9,874 men and 1,696 women), aged from 20 to 76 years, who underwent a computed tomography (CT) examination. VFA, SFA, WC, muscle, intramuscular fat, viscera, and bone were measured using a CT scanner. We conducted stratified analyses by generational age, and calculated the Pearson's correlation coefficients between the VFA and WC, BMI, and VFA plus SFA. To establish the equations for converting the WC to the corresponding VFA and VFA plus SFA, linear regression analyses were used to obtain the regression coefficients and intercepts. RESULTS: As the generations increased in age, the VFA tended to increase. However, the differences in the WC values of each generation did not coincide with the VFA values in men (r = -0.275 and 0.979 for men and women, n = 5 generations), but did correlate with the difference in the sum of the VFA plus SFA for both sexes (r = 0.915 and 0.996 for men and women, n = 5 generations). Older generations had lower WC values when they had the same VFA values as the younger generations. CONCLUSIONS: The WC value corresponding to a certain VFA value differed significantly by generational age. Thus, revised optimal cutoff values for the WC may be needed for each generation. PMID- 24472678 TI - Underwater and hyperbaric medicine as a branch of occupational and environmental medicine. AB - Exposure to the underwater environment for occupational or recreational purposes is increasing. As estimated, there are around 7 million divers active worldwide and 300,000 more divers in Korea. The underwater and hyperbaric environment presents a number of risks to the diver. Injuries from these hazards include barotrauma, decompression sickness, toxic effects of hyperbaric gases, drowning, hypothermia, and dangerous marine animals. For these reasons, primary care physicians should understand diving related injuries and assessment of fitness to dive. However, most Korean physicians are unfamiliar with underwater and hyperbaric medicine (UHM) in spite of scientific and practical values.From occupational and environmental medicine (OEM) specialist's perspective, we believe that UHM should be a branch of OEM because OEM is an area of medicine that deals with injuries caused by physical and biological hazards, clinical toxicology, occupational diseases, and assessment of fitness to work. To extend our knowledge about UHM, this article will review and update on UHM including barotrauma, decompression illness, toxicity of diving gases and fitness for diving. PMID- 24472679 TI - Minimising radial injury: prevention is better than cure. AB - Transradial (TR) coronary intervention is associated with fewer access-site related bleeding complications and is independently associated with a lower risk of mortality following PCI compared to procedures undertaken through the femoral route. However, recent studies that have undertaken imaging of the radial artery through the use of IVUS and OCT, as well as histological studies, suggest that TR cardiac catheterisation is associated with significant injury to the radial artery wall resulting in significant endothelial cell dysfunction. The vascular endothelium plays a central role in the regulation of vascular tone, angiogenesis and vascular remodelling through the release of vasoactive mediators in response to a variety of stimuli. Hence, trauma to the vascular endothelium and subsequent changes in endothelial cell function may contribute to patterns of injury such as intimal hyperplasia and radial artery occlusion observed following TR cardiac catheterisation. Such injury patterns to the radial artery following TR procedures may limit the success and future utility of the TR approach. Minimisation of radial artery injury should be a key procedural component of procedures undertaken through the transradial approach. PMID- 24472680 TI - Induction of triacylglycerol production in Chlamydomonas reinhardtii: comparative analysis of different element regimes. AB - In this study, impacts of different element absence (nitrogen, sulfur, phosphorus and magnesium) and supplementation (nitrogen and zinc) on element uptake and triacylglycerol production was followed in wild type Chlamydomonas reinhardtii CC 124 strain. Macro- and microelement composition of C. reinhardtii greatly differed under element regimes studied. In particular, heavy metal quotas of the microalgae increased strikingly under zinc supplementation. Growth was suppressed, cell biovolume, carbohydrate, total neutral lipid and triacylglycerol levels increased when microalgae were incubated under these element regimes. Most of the intracellular space was occupied by lipid bodies under all nutrient starvations, as observed by confocal microscopy and transmission electron micrographs. Results suggest that sulfur, magnesium and phosphorus deprivations are superior to nitrogen deprivation for the induction triacylglycerol production in C. reinhardtii. On the other hand, FAME profiles of the nitrogen, sulfur and phosphorus deprived cells were found to meet the requirements of international standards for biodiesel. PMID- 24472681 TI - Using natural zeolite for ammonia sorption from wastewater and as nitrogen releaser for the cultivation of Arthrospira platensis. AB - Herein a new approach for the application of wastewater nutrients for the cultivation of cyanobacteria or microalgae is described. Natural zeolite was used as medium for the sorption of ammonia from wastewater and subsequently as nitrogen releaser in cultures of Arthrospira platensis. The main scope of the present approach was to isolate ammonia from the wastewater and to transfer it into the culture medium excluding thus the suspended solids, the dissolved colored compounds or any other possible contaminant of the wastewater. The results demonstrate that the indirect use of ammonia derived from wastewater using zeolite as sorption and releasing medium for the cultivation of A. platensis is promising. This is the first time that a medium was used for indirect application of wastewater nutrient for the production of cyanobacterial or microalgal biomass. PMID- 24472682 TI - AHCYL2 (long-IRBIT) as a potential regulator of the electrogenic Na(+)-HCO3(-) cotransporter NBCe1-B. AB - Although AHCYL2 (long-IRBIT) is highly homologous to IRBIT, which regulates ion transporting proteins including the electrogenic Na(+)-HCO3(-) cotransporter NBCe1-B, its functions are poorly understood. Here, we found that AHCYL2 interacts with NBCe1-B in bovine parotid acinar cells using yeast two-hybrid, immunofluorescence confocal microscopy and co-immunoprecipitation analyses. Whole cell patch-clamp experiments revealed that co-expression of AHCYL2 reduces the apparent affinity for intracellular Mg(2+) in inhibition of NBCe1-B currents specifically in a HCO3(-)-deficient cellular condition. Our data unveil AHCYL2 as a potential regulator of NBCe1-B in mammalian cells. We propose that cytosolic ionic condition appropriate for AHCYL2 to function might be different from IRBIT. PMID- 24472683 TI - Consistent associations between measures of psychological stress and CMV antibody levels in a large occupational sample. AB - Cytomegalovirus (CMV) is a herpes virus that has been implicated in biological aging and impaired health. Evidence, largely accrued from small-scale studies involving select populations, suggests that stress may promote non-clinical reactivation of this virus. However, absent is evidence from larger studies, which allow better statistical adjustment for confounding and mediating factors, in more representative samples. The present study involved a large occupational cohort (N=887, mean age=44, 88% male). Questionnaires assessed psychological (i.e., depression, anxiety, vital exhaustion, SF-12 mental health), demographic, socioeconomic (SES), and lifestyle variables. Plasma samples were analyzed for both the presence and level of CMV-specific IgG antibodies (CMV-IgG), used as markers for infection status and viral reactivation, respectively. Also assessed were potential biological mediators of stress-induced reactivation, such as inflammation (C-reactive protein) and HPA function (awakening and diurnal cortisol). Predictors of CMV infection and CMV-IgG among the infected individuals were analyzed using logistic and linear regression analyses, respectively. Confirming prior reports, lower SES (education and job status) was positively associated with infection status. Among those infected (N=329), higher CMV-IgG were associated with increased anxiety (beta=.14, p<.05), depression (beta=.11, p=.06), vital exhaustion (beta=.14, p<.05), and decreased SF-12 mental health (beta=-.14, p<.05), adjusting for a range of potential confounders. Exploratory analyses showed that these associations were generally stronger in low SES individuals. We found no evidence that elevated inflammation or HPA-function mediated any of the associations. In the largest study to date, we established associations between CMV-IgG levels and multiple indicators of psychological stress. These results demonstrate the robustness of prior findings, and extend these to a general working population. We propose that stress-induced CMV replication warrants further research as a psychobiological mechanism linking stress, aging and health. PMID- 24472684 TI - Focus on desynchronization rather than excitability: a new strategy for intraencephalic electrical stimulation. AB - Epilepsy is a severely debilitating brain disease, often associated with premature death, which has an urgent need for alternative methods of treatment. In fact, roughly 25% of patients with epilepsy do not have seizures satisfactorily controlled by pharmacological treatment, and 30% of these patients with treatment-refractory seizures are not even eligible for ablative surgery. Epilepsy is most readily identifiable by its seizures and/or paroxysmal events, mostly viewed as spontaneously recurrent and unpredictable, which are caused by stereotyped changes in neurological function associated with hyperexcitability and hypersynchronicity of the underlying neural networks. Treatment has strongly been based on the fixed goal of depressing neuronal activity, working under the veiled assumption that hyperexcitability would lead to synchronous neuronal activity and, therefore, to seizure. Over the last 20-30 years, the emergence of electrical (ES) of deep brain structures, a practicable option for treating patients with otherwise untreatable seizures, has broadened our understanding of anticonvulsant mechanisms that conceptually differ from those of pharmacological treatment. Conversely, the research on ES therapy applied to epilepsy is contributing significantly to untwine the phenomena of excitation from that of synchronization as potential target mechanisms for abolishing seizures and predicting paroxysmal events. This paper is, thus, an addendum to other reviews on the subject of ES therapy in epilepsy which focuses on the desynchronization effect ES has on epileptogenic neural networks rather than its effect on overall brain excitability. PMID- 24472685 TI - Do certain signal transduction mechanisms explain the comorbidity of epilepsy and mood disorders? AB - It is well known that mood disorders are highly prevalent in patients with epilepsy. Although several studies have aimed to characterize alterations in different types of receptors associated with both disturbances, there is a lack of studies focused on identifying the causes of this comorbidity. Here, we described some changes at the biochemical level involving serotonin, dopamine, and gamma-aminobutyric acid (GABA) receptors as well as signal transduction mechanisms that may explain the coexistence of both epilepsy and mood disorders. Finally, the identification of common pathophysiological mechanisms associated with receptor-receptor interaction (heterodimers) could allow designing new strategies for treatment of patients with epilepsy and comorbid mood disorders. PMID- 24472686 TI - Application of experimentally verified transcription factor binding sites models for computational analysis of ChIP-Seq data. AB - BACKGROUND: ChIP-Seq is widely used to detect genomic segments bound by transcription factors (TF), either directly at DNA binding sites (BSs) or indirectly via other proteins. Currently, there are many software tools implementing different approaches to identify TFBSs within ChIP-Seq peaks. However, their use for the interpretation of ChIP-Seq data is usually complicated by the absence of direct experimental verification, making it difficult both to set a threshold to avoid recognition of too many false-positive BSs, and to compare the actual performance of different models. RESULTS: Using ChIP-Seq data for FoxA2 binding loci in mouse adult liver and human HepG2 cells we compared FoxA binding-site predictions for four computational models of two fundamental classes: pattern matching based on existing training set of experimentally confirmed TFBSs (oPWM and SiteGA) and de novo motif discovery (ChIPMunk and diChIPMunk). To properly select prediction thresholds for the models, we experimentally evaluated affinity of 64 predicted FoxA BSs using EMSA that allows safely distinguishing sequences able to bind TF. As a result we identified thousands of reliable FoxA BSs within ChIP-Seq loci from mouse liver and human HepG2 cells. It was found that the performance of conventional position weight matrix (PWM) models was inferior with the highest false positive rate. On the contrary, the best recognition efficiency was achieved by the combination of SiteGA & diChIPMunk/ChIPMunk models, properly identifying FoxA BSs in up to 90% of loci for both mouse and human ChIP-Seq datasets. CONCLUSIONS: The experimental study of TF binding to oligonucleotides corresponding to predicted sites increases the reliability of computational methods for TFBS-recognition in ChIP Seq data analysis. Regarding ChIP-Seq data interpretation, basic PWMs have inferior TFBS recognition quality compared to the more sophisticated SiteGA and de novo motif discovery methods. A combination of models from different principles allowed identification of proper TFBSs. PMID- 24472687 TI - Standardizing dysgranulopoiesis in MDS and AML: refining diagnostics and laying the foundation for novel morphological-genetic correlations. PMID- 24472688 TI - Leukapheresis and low-dose chemotherapy do not reduce early mortality in acute myeloid leukemia hyperleukocytosis: a systematic review and meta-analysis. AB - The role of leukapheresis and low-dose chemotherapy is unclear in decreasing early mortality in acute myeloid leukemia (AML) patients with hyperleukocytosis. This systematic review was conducted to describe early mortality (deaths during first induction) in patients with AML with an initial white blood count>=100*10(9)L(-1) stratified by the approach to leukapheresis and hydroxyurea/low-dose chemotherapy. Twenty-one studies were included. Weighted mean early deaths rate (20 studies, 1354 patients) was 20.1% (95% confidence interval 15.0-25.1). Neither leukapheresis strategy (p=0.67) nor hydroxyurea/low dose chemotherapy (p=0.23) influenced the early death rate. Early mortality related to hyperleukocytosis in AML is not influenced by universal or selected use of leukapheresis or hydroxyurea/low-dose chemotherapy. PMID- 24472689 TI - Increased physical activity severely induces osteoarthritic changes in knee joints with papain induced sulfate-glycosaminoglycan depleted cartilage. AB - INTRODUCTION: Articular cartilage needs sulfated-glycosaminoglycans (sGAGs) to withstand high pressures while mechanically loaded. Chondrocyte sGAG synthesis is regulated by exposure to compressive forces. Moderate physical exercise is known to improve cartilage sGAG content and might protect against osteoarthritis (OA). This study investigated whether rat knee joints with sGAG depleted articular cartilage through papain injections might benefit from moderate exercise, or whether this increases the susceptibility for cartilage degeneration. METHODS: sGAGs were depleted from cartilage through intraarticular papain injections in the left knee joints of 40 Wistar rats; their contralateral joints served as healthy controls. Of the 40 rats included in the study, 20 rats remained sedentary, and the other 20 were subjected to a moderately intense running protocol. Animals were longitudinally monitored for 12 weeks with in vivo micro computed tomography (MUCT) to measure subchondral bone changes and single-photon emission computed tomography (SPECT)/CT to determine synovial macrophage activation. Articular cartilage was analyzed at 6 and 12 weeks with ex vivo contrast-enhanced MUCT and histology to measure sGAG content and cartilage thickness. RESULTS: All outcome measures were unaffected by moderate exercise in healthy control joints of running animals compared with healthy control joints of sedentary animals. Papain injections in sedentary animals resulted in severe sGAG depleted cartilage, slight loss of subchondral cortical bone, increased macrophage activation, and osteophyte formation. In running animals, papain induced sGAG-depleted cartilage showed increased cartilage matrix degradation, sclerotic bone formation, increased macrophage activation, and more osteophyte formation. CONCLUSIONS: Moderate exercise enhanced OA progression in papain injected joints and did not protect against development of the disease. This was not restricted to more-extensive cartilage damage, but also resulted in pronounced subchondral sclerosis, synovial macrophage activation, and osteophyte formation. PMID- 24472690 TI - The Relationship between Musculoskeletal Symptoms and Work-related Risk Factors in Hotel Workers. AB - OBJECTIVES: To identify work-related musculoskeletal symptoms and any associated work-related risk factors, focusing on structural labor factors among hotel workers. METHODS: A total of 1,016 hotel workers (620 men and 396 women) were analyzed. The questionnaire surveyed participants' socio-demographics, health related behaviors, job-related factors, and work-related musculoskeletal symptoms. Work-related musculoskeletal symptoms were assessed using the Nordic musculoskeletal questionnaire. All analyses were stratified by gender, and multiple logistic regression modeling was used to determine associations between work-related musculoskeletal symptoms and work-related risk factors. RESULTS: The risk of developing work-related musculoskeletal symptoms was 1.9 times higher among male workers in the kitchen department than males in the room department (OR = 1.92, 95% CI = 1.03-3.79), and 2.5 times higher among male workers with lower sleep satisfaction than those with higher sleep satisfaction (OR = 2.52, 95% CI = 1.57-4.04). All of the aforementioned cases demonstrated a statistically significant association with work-related musculoskeletal symptoms. Moreover, the risk of developing work-related musculoskeletal symptoms was 3.3 times higher among female workers aged between 30 and 34 than those aged 24 or younger (OR = 3.32, 95% CI = 1.56-7.04); 0.3 times higher among females in the back office department than those in the room department (OR = 0.34, 95% CI = 0.12-0.91); 1.6 times higher among females on shift schedules than those who were not (OR = 1.60, 95% CI = 1.02-2.59); 1.8 times higher among females who performed more intensive work than those who performed less intensive work (OR = 1.88, 95% CI = 1.17 3.02), and; 2.1 times higher among females with lower sleep satisfaction than those with higher sleep satisfaction (OR = 2.17, 95% CI = 1.34-3.50). All of the aforementioned cases also displayed a statistically significant association with work-related musculoskeletal symptoms. CONCLUSION: This study focused on structural risk factors in the working environment, such as the gender-based division of labor, shift work and labor intensity, that demonstrated a statistically significant correlation with the work-related musculoskeletal symptoms of hotel workers. Both men and women reported different prevalence rates of work-related musculoskeletal symptoms among different departments. This could indicate that a gender-based division of labor produces different ergonomic risk factors for each gender group. However, only females displayed a statistically significant correlation between shift work and labor intensity and musculoskeletal symptoms. Thus, minimizing ergonomic risk factors alone does not suffice to effectively prevent musculoskeletal diseases among hotel workers. Instead, work assignments should be based on gender, department, working hours and work intensity should be adjusted to address multi-dimensional musculoskeletal risk factors. In addition, an approach that seeks to minimize shift work is needed to reduce the incidence of musculoskeletal disorders. PMID- 24472691 TI - Prognostic significance of the treatment-free interval in patients with recurrent endometrial cancer. AB - OBJECTIVE: To identify prognostic factors of recurrent endometrial cancer, and clarify whether the treatment-free interval (TFI) predicts outcome in a wide spectrum of patients. STUDY DESIGN: The clinical data of 60 patients treated for recurrent stage I-IV endometrial cancer between 1997 and 2012 were reviewed retrospectively. The Kaplan-Meier method and Cox regression analysis were used to estimate overall survival (OS) following recurrence and determine the factors influencing outcomes. RESULTS: The median age at initial treatment was 59 (range 38-80) years and the median post-recurrence overall survival time was 40.0 (range 1.8-156.7) months. Multivariate analysis showed lymph node metastasis (hazard ratio (HR) 2.80; 95% confidence interval (95%CI) 1.29-6.09; p=0.009), TFI (HR 0.33; 95% CI 0.15-0.76; p=0.008), and symptomatic recurrence (HR 2.31, 95% CI 1.11-4.83, p=0.0025) were independent prognostic factors. Patients whose tumors recurred after a TFI>=12 months had better response rates than did those with a TFI<12 months (p<0.001). CONCLUSION: TFI is a significant prognostic factor in recurrent endometrial cancer. Furthermore, the effect of chemotherapy on recurrent endometrial cancer is probably influenced by the duration of TFI. PMID- 24472692 TI - Androgens and hyperemesis gravidarum: a case-control study. AB - OBJECTIVE: The pathogenesis of hyperemesis gravidarum (HG) is probably multifactorial, involving several hormones. Androgen concentrations are reported to correlate positively with emesis gravidarum. Hypothesizing a continuum between emesis gravidarum and HG, we investigated androgen concentrations in women with HG. STUDY DESIGN: In a case-control study, 32 women hospitalized for HG were compared with 29 control women scheduled for elective surgical abortion. Control women were matched for age, gestational length, body mass index (BMI) and parity. Patient characteristics and concentrations of dehydroepiandrosterone sulphate (DHEAS), androstenedione, testosterone, sex hormone binding globulin (SHBG), free testosterone index (FTI), androstanediol glucuronide (ADG), progesterone, TSH, free T3 and T4, beta-hCG, ferritin, insulin, estradiol and estriol were compared using Mann-Whitney tests and multivariate linear regression analyses. RESULTS: Women with HG had higher concentrations of ADG (8.49+/-4.19 vs. 6.19+/ 1.77pmol/L; p=0.015), estradiol (2.39+/-1.36 vs. 1.60+/-9.30nmol/L; p=0.009) and ferritin (186+/-138 vs. 117+/-94pmol/L; p=0.040) compared with control women. Androstenedione (5.34+/-2.82 vs. 6.86+/-2.67; p=0.004) and insulin (63.7+/-35.0 vs. 75.3+/-25.8; p=0.050) concentrations were lower in women with HG. DHEAS, testosterone, FTI, SHBG, estriol, progesterone, beta-hCG, TSH, free T3 and free T4 concentrations did not differ between the groups. In multivariate regression analyses HG was associated with high concentrations of ADG (p=0.026) and low concentrations of androstenedione (p=0.018). CONCLUSION: Steroid hormone homeostasis may be altered in women with HG. HG may be associated with high ADG and low androstenedione concentrations. PMID- 24472693 TI - Reply: To PMID 23499652. PMID- 24472694 TI - Rehabilitation and supportive therapy in elderly patients with Chronic Obstructive Pulmonary Disease. AB - Chronic Obstructive Pulmonary Disease (COPD) very often coexists with cardiovascular, musculoskeletal and metabolic comorbidities. This condition significantly impact on the general health, function, frailty and disability of such patients, and consequently on their prognosis. Indeed, complex and recurrent symptoms of general dysfunction are commonly present and burden on the health status. Symptomatic COPD patients, even with chronic and complex comorbidities or with different degree of severity, may benefit from rehabilitation including exercise and maintenance of physical activity, in order to reducing symptoms and restoring the highest possible level of independent function. This review will focus on the associated and relevant clinical problems of these patients at the onset of disability, methods of assessment and useful non-pharmacological treatments for caring and supporting them. PMID- 24472695 TI - The changing face of internal medicine: patient centred care. AB - Patient centred care is now considered the gold standard and there should be 'no decision about me, without me'. Internists who treat patients with complex multi morbidities should consider patients' preferred outcomes, following a 'goal oriented' principle. Perhaps the most important barrier to goal-oriented care is that medicine is deeply rooted in a disease-outcome-based paradigm. Rather than asking what patients want, the culture of modern medicine has prioritised optimal disease management according to guidelines and population goals. Doing what is right for the patient should be based on trust. Patients and internists must therefore meet as equals: 'I' and 'you' should be replaced by 'we'. PMID- 24472696 TI - Manganese neurotoxicity: a focus on glutamate transporters. AB - Manganese (Mn) is an essential element that is required in trace amount for normal growth, development as well maintenance of proper function and regulation of numerous cellular and biochemical reactions. Yet, excessive Mn brain accumulation upon chronic exposure to occupational or environmental sources of this metal may lead to a neurodegenerative disorder known as manganism, which shares similar symptoms with idiopathic Parkinson's disease (PD). In recent years, Mn exposure has gained public health interest for two primary reasons: continuous increased usage of Mn in various industries, and experimental findings on its toxicity, linking it to a number of neurological disorders. Since the first report on manganism nearly two centuries ago, there have been substantial advances in the understanding of mechanisms associated with Mn-induced neurotoxicity. This review will briefly highlight various aspects of Mn neurotoxicity with a focus on the role of astrocytic glutamate transporters in triggering its pathophysiology. PMID- 24472697 TI - The evidence for high flow nasal cannula devices in infants. AB - High flow nasal cannula (HFNC) devices deliver an adjustable mixture of heated and humidified oxygen and air at a variable flow rate. Over recent years HFNC devices have become a frequently used method of non-invasive respiratory support in infants and preterm neonates that is generally popular amongst clinicians and nursing staff due to ease of use and being well tolerated by patients. Despite this rapid adoption relatively little is known about the exact mechanisms of action of HFNC however and only recently have data from randomised controlled trials started to become available. We describe the features of a modern HFNC device and discuss current knowledge about the mechanisms of action and results of clinical studies in preterm neonates and infants with bronchiolitis. We also highlight future areas of research that are likely to increase our understanding, inform best clinical practice and strengthen the evidence base for the use of HFNC. PMID- 24472698 TI - Cognitive and physical training for the elderly: evaluating outcome efficacy by means of neurophysiological synchronization. AB - Recent neuroscientific research has demonstrated that both healthy and pathological aging induces alterations in the co-operative capacity of neuronal populations in the brain. Both compensatory and neurodegenerative mechanisms contribute to neurophysiological synchronization patterns, which provide a valuable marker for age-related cognitive decline. In this study, we propose that neuroplasticity-based training may facilitate coherent interaction of distant brain regions and consequently enhance cognitive performance in elderly people. If this is true, this would make neurophysiological synchronization a valid outcome measure to assess the efficacy of non-pharmacological interventions to prevent or delay age-related cognitive decline. The present study aims at providing an objective, synchronization-based tool to assess cognitive and/or physical interventions, adopting the notion of Relative Wavelet Entropy. This mathematical model employs a robust and parameter-free synchronization metric. By using data mining techniques, a distance value was computed for all participants so as to quantify the proximity of their individual profile to the mean group synchronization increase. In support of our hypothesis, results showed a significant increase in synchronization, for four electrode pairs, in the intervention group as compared to the active control group. It is concluded that the novel introduction of neurophysiological synchronization features could be used as a valid and reliable outcome measure; while the distance-based analysis could provide a reliable means of evaluating individual benefits. PMID- 24472699 TI - Novel membrane-based biotechnological alternative process for succinic acid production and chemical synthesis of bio-based poly (butylene succinate). AB - Succinic acid was produced in a novel membrane-based fermentation and separation integrated system. With this integrated system, product inhibition was alleviated by removing acids and replenishing fresh broth. High cell density maintain for a longer time from 75 to 130h and succinic acid concentration increased from 53 to 73g/L. In the developed separation process, succinic acid was crystallized at a recovery of 85-90%. The purity of the obtained succinic acid crystals reached 99.4% as found by HPLC and (1)H NMR analysis. A crystallization experiment indicated that among by-products glucose had a negative effect on succinic acid crystallization. Poly (butylene succinate) (PBS) was synthesized using the purified succinic acid and (1)H NMR analysis confirmed that the composition of the synthesized PBS is in agreement with that from petro-based succinic acid. PMID- 24472700 TI - Hydrothermal liquefaction of Chlorella pyrenoidosa for bio-oil production over Ce/HZSM-5. AB - This paper investigated a novel hydrothermal liquefaction process of Chlorella pyrenoidosa catalyzed by Ce/HZSM-5. The chemical groups and components of the residues of C. pyrenoidosa were analyzed by Fourier transform infrared spectrometry and Gas Chromatograph-Mass Spectrometer. The crystal structure and micro surface topography of C. pyrenoidosa before and after catalytic liquefaction were characterized by X-ray diffraction and Scanning electron microscopy, respectively. The experimental results showed that the catalytic cracking effects of Ce/HZSM-5 were superior to that of HZSM-5 as a liquefaction catalyst of C. pyrenoidosa. Compared with HZSM-5, Ce/HZSM-5 has a significantly enhanced Lewis acid active center, smaller particle size, larger specific surface, and highly dispersed Ce4O7 with trivalent and tetravalent cerium in the zeolite skeleton channel that accelerate the catalytic liquefaction of C. pyrenoidosa. The rare earth modified zeolite Ce/HZSM-5 exhibits good potential and a beneficial nature for the preparation of bio-oil from microalgae with high efficiency. PMID- 24472701 TI - Characterization of growth and lipid production by Chlorella sp. PCH90, a microalga native to Quebec. AB - Microalgae are being investigated as potential candidates for biodiesel production since they can be grown without competition with food production, have an inherently fast growth rate, and can have a high lipid content under different nutrient limiting conditions. However, large scale production will best be carried out with indigenous strains, well adapted to local conditions. This study reports on the characterization of the novel microalga Chlorella sp. PCH90, isolated in Quebec. Its molecular phylogeny was established and lipid production studies as a function of the initial concentrations of nitrate, phosphate, and sodium chloride were carried out using response surface methodology. Under the appropriate conditions this microalga could produce up to 36% lipid and grew well in both synthetic medium and secondary effluent from a wastewater treatment plant at both 22 and 10 degrees C. Thus, this strain is promising for further development as a potential biofuels producer under local climatic conditions. PMID- 24472702 TI - Toxicities of four anti-neoplastic drugs and their binary mixtures tested on the green alga Pseudokirchneriella subcapitata and the cyanobacterium Synechococcus leopoliensis. AB - The residues of anti-neoplastic drugs are new and emerging pollutants in aquatic environments. This is not only because of their increasing use, but also because due to their mechanisms of action, they belong to a group of particularly dangerous compounds. However, information on their ecotoxicological properties is very limited. We tested the toxicities of four anti-neoplastic drugs with different mechanisms of action (5-fluorouracil [5-FU], cisplatin [CDDP], etoposide [ET], and imatinib mesylate [IM]), and some of their binary mixtures, against two phytoplankton species: the alga Pseudokirchneriella subcapitata, and the cyanobacterium Synechococcus leopoliensis. These four drugs showed different toxic potential, and the two species examined also showed differences in their susceptibilities towards the tested drugs and their mixtures. With P. subcapitata, the most toxic of these drugs was 5-FU (EC50, 0.13 mg/L), followed by CDDP (EC50, 1.52 mg/L), IM (EC50, 2.29 mg/L), and the least toxic, ET (EC50, 30.43 mg/L). With S. leopoliensis, the most toxic was CDDP (EC50, 0.67 mg/L), followed by 5-FU (EC50, 1.20 mg/L) and IM (EC50, 5.36 mg/L), while ET was not toxic up to 351 mg/L. The toxicities of the binary mixtures tested (5-FU + CDDP, 5-FU + IM, CDDP + ET) were predicted by the concepts of 'concentration addition' and 'independent action', and are compared to the experimentally determined toxicities. The measured toxicity of 5-FU + CDDP with P. subcapitata and S. leopoliensis was higher than that predicted, while the measured toxicity of CDDP + ET with both species was lower than that predicted. The measured toxicity of 5 FU + IM with P. subcapitata was higher, and with S. leopoliensis was lower, than that predicted. These data show that these mixtures can have compound-specific and species-specific synergistic or antagonistic effects, and they suggest that single compound toxicity data are not sufficient for the prediction of the aquatic toxicities of such anticancer drug mixtures. PMID- 24472703 TI - Rewarding, reinforcing and incentive salient events involve orexigenic hypothalamic neuropeptides regulating mesolimbic dopaminergic neurotransmission. AB - The hypothalamus is an integrated energy sensing system interfacing with higher motivational structures of the mesocorticolimbic dopamine (DA) system. This interconnectivity is strictly regulated by a number of orexigenic hypothalamic neuropeptides, including especially ghrelin, orexins and neuropeptide Y (NPY), enabling the latter to modulate salient events of natural and chemical reinforcers. In this review we aim to analyse the current knowledge on these three orexigenic neuropeptide systems that are involved in the DAergic regulation of psychostimulant behaviours. We will first review the co-existing interactions between ghrelin, orexins and NPY in hypothalamic nuclei. We will next outline whether these neuropeptides can affect DAergic neurotransmission by either regulating the firing rate of DA neurons in the ventral tegmental area (VTA) or by presynaptically interacting on the DAergic nerve terminals. Finally, we will underscore the main studies that outlined the involvement of ghrelin, orexins and NPY with rewarding, reinforcing and incentive properties of natural reinforcers and drugs of abuse. The reciprocal hypothalamic interaction of ghrelin, orexins and NPY might represent a new central view on neuronal mechanisms regulating the behavioural phenomenology of addiction maintained by the DA system. PMID- 24472704 TI - Effect of single-dose and short-term administration of quercetin on the pharmacokinetics of talinolol in humans - Implications for the evaluation of transporter-mediated flavonoid-drug interactions. AB - Quercetin has been shown to inhibit intestinal P-glycoprotein-mediated drug efflux. A crossover clinical study was performed in 10 healthy volunteers to assess the effect of single-dose and repeated quercetin intake on the pharmacokinetics of talinolol, a substrate of intestinal P-glycoprotein. Unexpectedly, mean area under the plasma concentration-time curve (AUC0-48h) and maximal plasma concentration (cmax) were slightly decreased following concomitant and short-term quercetin administration (3186.0 versus 2468.3 and 2527.7 ng h/ml, p>0.05; 309.7 versus 212.0 and 280.6 ng/ml, p>0.05). Individual analysis revealed that talinolol AUC0-48h was lowered by 23.9% up to 60.6% in 5 subjects and cmax was decreased by 29.2% up to 78.7% in 7 subjects after quercetin co administration. These effects were less pronounced following repeated quercetin intake. Overlapping modification of efflux and uptake transport involving carrier proteins of the OATP superfamily as well as site-dependent interaction are possible explanations for these observations. In conclusion, clinically relevant quercetin-drug interaction cannot be ruled out. PMID- 24472705 TI - Study of Patient Information after percutaneous Coronary Intervention (SPICI): should prevention programmes become more effective? AB - AIMS: This cross-sectional observational study was designed to evaluate the uptake and outcome of patient education after percutaneous coronary intervention (PCI). METHODS AND RESULTS: A questionnaire containing 41 items was handed out to consecutive patients from randomly selected Swedish hospitals after PCI. Questions concerned the patient's attribution of the cause of the cardiac event, perception of the information provided by physicians and nurses, and a self assessment of changes in lifestyle post PCI regarding tobacco, physical activity, food habits and stress. Replies were obtained from 1,073 patients (reply rate 67%). Non-modifiable risk factors (age, heredity) were attributed a higher rate as the cause of disease compared to modifiable factors (smoking, physical activity, food habits). Most patients (67%) perceived they were cured, and 38% perceived from the given information that there was no need to change their habits. A mere 27% reported that they still had cardiovascular disease and needed behavioural change. After PCI, 16% continued to use tobacco; half of these were offered smoking cessation support. In spite of an 80% referral rate to cardiac rehabilitation, one out of two patients did not enrol. Fewer than half were regularly physically active. Nutritional counselling was provided to 71%, but only 40% changed food habits. Stress management programmes were rarely provided. CONCLUSIONS: Current preventive practice scarcely meets the challenge posed by the progress in modern invasive cardiology. The Study of Patient Information after percutaneous Coronary Intervention (SPICI) motivates an in-depth revision and adaptation of cardiac rehabilitation programmes in order to improve patient understanding of the disease, and to support greater compliance with a cardioprotective lifestyle. PMID- 24472706 TI - Evidence that histaminergic neurons are devoid of estrogen receptor alpha in the ewe diencephalon during the breeding season. AB - In sheep as in rat, it has been highly suggested that neuronal histamine (HA) participates to the estradiol (E2)-induced GnRH and LH surges, through H1 receptor. With the aim of determining if E2 could act directly on HA neurons, we examined here whether HA neurons express estrogen receptor alpha (ERalpha) in the ewe diencephalon during the breeding season. We first produced a specific polyclonal antibody directed against recombinant ovine histidine decarboxylase (oHDC), the HA synthesizing enzyme. Using both this anti-oHDC antibody and an anti-ERalpha monoclonal antibody in double label immunohistochemistry, we showed that HA neurons do not express ERalpha in diencephalon of ewes with different hormonal status. This result diverges from those obtained in rat, in which around three quarters of HA neurons express ERalpha in their nucleus. This discrepancy between these two mammal species may reflect difference in their neuronal network. PMID- 24472708 TI - Are we overusing IVF? PMID- 24472707 TI - Nonhypoxic regulation and role of hypoxia-inducible factor 1 in aromatase inhibitor resistant breast cancer. AB - INTRODUCTION: Although aromatase inhibitors (AIs; for example, letrozole) are highly effective in treating estrogen receptor positive (ER+) breast cancer, a significant percentage of patients either do not respond to AIs or become resistant to them. Previous studies suggest that acquired resistance to AIs involves a switch from dependence on ER signaling to dependence on growth factor mediated pathways, such as human epidermal growth factor receptor-2 (HER2). However, the role of HER2, and the identity of other relevant factors that may be used as biomarkers or therapeutic targets remain unknown. This study investigated the potential role of transcription factor hypoxia inducible factor 1 (HIF-1) in acquired AI resistance, and its regulation by HER2. METHODS: In vitro studies using AI (letrozole or exemestane)-resistant and AI-sensitive cells were conducted to investigate the regulation and role of HIF-1 in AI resistance. Western blot and RT-PCR analyses were conducted to compare protein and mRNA expression, respectively, of ERalpha, HER2, and HIF-1alpha (inducible HIF-1 subunit) in AI-resistant versus AI-sensitive cells. Similar expression analyses were also done, along with chromatin immunoprecipitation (ChIP), to identify previously known HIF-1 target genes, such as breast cancer resistance protein (BCRP), that may also play a role in AI resistance. Letrozole-resistant cells were treated with inhibitors to HER2, kinase pathways, and ERalpha to elucidate the regulation of HIF-1 and BCRP. Lastly, cells were treated with inhibitors or inducers of HIF-1alpha to determine its importance. RESULTS: Basal HIF-1alpha protein and BCRP mRNA and protein are higher in AI-resistant and HER2-transfected cells than in AI-sensitive, HER2- parental cells under nonhypoxic conditions. HIF 1alpha expression in AI-resistant cells is likely regulated by HER2 activated phosphatidylinositide-3-kinase/Akt-protein kinase B/mammalian target of rapamycin (PI3K/Akt/mTOR) pathway, as its expression was inhibited by HER2 inhibitors and kinase pathway inhibitors. Inhibition or upregulation of HIF-1alpha affects breast cancer cell expression of BCRP; AI responsiveness; and expression of cancer stem cell characteristics, partially through BCRP. CONCLUSIONS: One of the mechanisms of AI resistance may be through regulation of nonhypoxic HIF-1 target genes, such as BCRP, implicated in chemoresistance. Thus, HIF-1 should be explored further for its potential as a biomarker of and therapeutic target. PMID- 24472709 TI - Metformin for castrate-resistant prostate cancer: learning more about an old dog's new tricks. PMID- 24472710 TI - Trends in the use of perioperative chemotherapy for localized and locally advanced muscle-invasive bladder cancer: a sign of changing tides. AB - BACKGROUND: Despite the documented survival benefit conferred by neoadjuvant (NAC) and adjuvant chemotherapy (AC), there has been a slow adoption of guideline recommendations for the use of perioperative chemotherapy (POC) in patients with muscle-invasive bladder cancer (MIBC). OBJECTIVE: To evaluate temporal trends in POC utilization and identify factors influencing POC delivery in a representative cohort of patients with MIBC. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study identifying factors associated with receipt of POC and evaluating temporal changes in NAC and AC utilization. We included patients from the National Cancer Data Base (NCDB) with no prior malignancy who ultimately underwent radical cystectomy for >= cT2/cN0/cM0 MIBC between 2006 and 2010. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Relationships between demographic and hospital factors and the likelihood of receiving POC were evaluated using Pearson chi-square and Wilcoxon rank-sum tests, and multivariable logistic regression. Temporal changes in NAC and AC use were detected using a linear test of trend. RESULTS AND LIMITATIONS: A total of 5692 patients met our inclusion criteria. POC use increased from 29.5% in 2006 to 39.8% in 2010 (p < 0.001). NAC use increased from 10.1% in 2006 to 20.8% in 2010 (p = 0.005); AC remained stable between 18.1% and 21.3% (p = 0.68). Multivariable modeling revealed advanced age, increasing comorbidity, lack of insurance, increased travel distance, geographic location outside the northeastern United States, and lower income as negatively associated with POC receipt (all p < 0.05). Limitations include retrospective design and potential sampling bias, excluding patients treated at non-NCDB facilities. CONCLUSIONS: POC use for MIBC increased from 2006 to 2010, with this increase disproportionately due to rising NAC utilization. Nonetheless, there is persistent variation in the likelihood of receiving POC secondary to nonclinical factors. PATIENT SUMMARY: When retrospectively analyzing a representative cohort of patients undergoing radical cystectomy for muscle-invasive bladder cancer between 2006 and 2010, we noted that preoperative chemotherapy rates increased steadily while use of chemotherapy after surgery remained stable. Factors related to access to care significantly influenced receipt of chemotherapy. PMID- 24472711 TI - The economics of bladder cancer: costs and considerations of caring for this disease. AB - CONTEXT: Due to high recurrence rates, intensive surveillance strategies, and expensive treatment costs, the management of bladder cancer contributes significantly to medical costs. OBJECTIVE: To provide a concise evaluation of contemporary cost-related challenges in the care of patients with bladder cancer. An emphasis is placed on the initial diagnosis of bladder cancer and therapy considerations for both non-muscle-invasive bladder cancer (NMIBC) and more advanced disease. EVIDENCE ACQUISITION: A systematic review of the literature was performed using Medline (1966 to February 2011). Medical Subject Headings (MeSH) terms for search criteria included "bladder cancer, neoplasms" OR "carcinoma, transitional cell" AND all cost-related MeSH search terms. Studies evaluating the costs associated with of various diagnostic or treatment approaches were reviewed. EVIDENCE SYNTHESIS: Routine use of perioperative chemotherapy following complete transurethral resection of bladder tumor has been estimated to provide a cost savings. Routine office-based fulguration of small low-grade recurrences could decrease costs. Another potential important target for decreasing variation and cost lies in risk-modified surveillance strategies after initial bladder tumor removal to reduce the cost associated with frequent cystoscopic and radiographic procedures. Optimizing postoperative care after radical cystectomy has the potential to decrease length of stay and perioperative morbidity with substantial decreases in perioperative care expenses. The gemcitabine-cisplatin regimen has been estimated to result in a modest increase in cost effectiveness over methotrexate, vinblastine, doxorubicin, and cisplatin. Additional costs of therapies need to be balanced with effectiveness, and there are significant gaps in knowledge regarding optimal surveillance and treatment of both early and advanced bladder cancer. CONCLUSIONS: Regardless of disease severity, improvements in the efficiency of bladder cancer care to limit unnecessary interventions and optimize effective cancer treatment can reduce overall health care costs. Two scenarios where economic and comparative-effectiveness research is limited but would be most beneficial are (1) the management of NMIBC patients where excessive costs are due to vigilant surveillance strategies and (2) in patients with metastatic disease due to the enormous cost associated with late stage and end-of-life care. PMID- 24472712 TI - Assessment of arsenic exposure by measurement of urinary speciated inorganic arsenic metabolites in workers in a semiconductor manufacturing plant. AB - OBJECTIVES: The purpose of this study was to evaluate the exposure to arsenic in preventive maintenance (PM) engineers in a semiconductor industry by detecting speciated inorganic arsenic metabolites in the urine. METHODS: The exposed group included 8 PM engineers from the clean process area and 13 PM engineers from the ion implantation process area; the non-exposed group consisted of 14 office workers from another company who were not occupationally exposed to arsenic. A spot urine specimen was collected from each participant for the detection and measurement of speciated inorganic arsenic metabolites. Metabolites were separated by high performance liquid chromatography-inductively coupled plasma spectrometry-mass spectrometry. RESULTS: Urinary arsenic metabolite concentrations were 1.73 g/L, 0.76 g/L, 3.45 g/L, 43.65 g/L, and 51.32 g/L for trivalent arsenic (As3+), pentavalent arsenic (As5+), monomethylarsonic acid (MMA), dimethylarsinic acid (DMA), and total inorganic arsenic metabolites (As3+ + As5+ + MMA + DMA), respectively, in clean process PM engineers. In ion implantation process PM engineers, the concentrations were 1.74 g/L, 0.39 g/L, 3.08 g/L, 23.17 g/L, 28.92 g/L for As3+, As5+, MMA, DMA, and total inorganic arsenic metabolites, respectively. Levels of urinary As3+, As5+, MMA, and total inorganic arsenic metabolites in clean process PM engineers were significantly higher than that in the non-exposed group. Urinary As3+ and As5+ levels in ion implantation process PM engineers were significantly higher than that in non exposed group. CONCLUSION: Levels of urinary arsenic metabolites in PM engineers from the clean process and ion implantation process areas were higher than that in office workers. For a complete assessment of arsenic exposure in the semiconductor industry, further studies are needed. PMID- 24472713 TI - Preparation and performance of arsenate (V) adsorbents derived from concrete wastes. AB - Solid adsorbent materials, prepared from waste cement powder and concrete sludge were assessed for removal of arsenic in the form of arsenic (As(V)) from water. All the materials exhibited arsenic removal capacity when added to distilled water containing 10-700 mg/L arsenic. The arsenic removal isotherms were expressed by the Langmuir type equations, and the highest removal capacity was observed for the adsorbent prepared from concrete sludge with heat treatment at 105 degrees C, the maximum removal capacity being 175 mg-As(V)/g. Based on changes in arsenic and calcium ion concentrations, and solution pH, the removal mechanism for arsenic was considered to involve the precipitation of calcium arsenate, Ca3(AsO4)2. The enhanced removal of arsenic for the adsorbent prepared from concrete sludge with heat treatment was thought to reflect ion exchange by ettringite. The prepared adsorbents, derived from waste cement and concrete using simple procedures, may offer a cost effective approach for arsenic removal and clean-up of contaminated waters, especially in developing countries. PMID- 24472714 TI - Recycling of high purity selenium from CIGS solar cell waste materials. AB - Copper indium gallium diselenide (CIGS) is a promising material in thin film solar cell production. To make CIGS solar cells more competitive, both economically and environmentally, in comparison to other energy sources, methods for recycling are needed. In addition to the generally high price of the material, significant amounts of the metals are lost in the manufacturing process. The feasibility of recycling selenium from CIGS through oxidation at elevated temperatures was therefore examined. During oxidation gaseous selenium dioxide was formed and could be separated from the other elements, which remained in solid state. Upon cooling, the selenium dioxide sublimes and can be collected as crystals. After oxidation for 1h at 800 degrees C all of the selenium was separated from the CIGS material. Two different reduction methods for reduction of the selenium dioxide to selenium were tested. In the first reduction method an organic molecule was used as the reducing agent in a Riley reaction. In the second reduction method sulphur dioxide gas was used. Both methods resulted in high purity selenium. This proves that the studied selenium separation method could be the first step in a recycling process aimed at the complete separation and recovery of high purity elements from CIGS. PMID- 24472715 TI - Chemical and process mineralogical characterizations of spent lithium-ion batteries: an approach by multi-analytical techniques. AB - Mineral processing operation is a critical step in any recycling process to realize liberation, separation and concentration of the target parts. Developing effective recycling methods to recover all the valuable parts from spent lithium ion batteries is in great necessity. The aim of this study is to carefully undertake chemical and process mineralogical characterizations of spent lithium ion batteries by coupling several analytical techniques to provide basic information for the researches on effective mechanical crushing and separation methods in recycling process. The results show that the grade of Co, Cu and Al is fairly high in spent lithium ion batteries and up to 17.62 wt.%, 7.17 wt.% and 21.60 wt.%. Spent lithium-ion batteries have good selective crushing property, the crushed products could be divided into three parts, they are Al-enriched fraction (+2 mm), Cu and Al-enriched fraction (-2+0.25 mm) and Co and graphite enriched fraction (-0.25 mm). The mineral phase and chemical state analysis reveal the electrode materials recovered from -0.25 mm size fraction keep the original crystal forms and chemical states in lithium-ion batteries, but the surface of the powders has been coated by a certain kind of hydrocarbon. Based on these results a flowsheet to recycle spent LiBs is proposed. PMID- 24472716 TI - Intelligent composting assisted by a wireless sensing network. AB - Monitoring of the moisture and temperature of composting process is a key factor to obtain a quality product beyond the quality of raw materials. Current methodologies for monitoring these two parameters are time consuming for workers, sometimes not sufficiently reliable to help decision-making and thus are ignored in some cases. This article describes an advance on monitoring of composting process through a Wireless Sensor Network (WSN) that allows measurement of temperature and moisture in real time in multiple points of the composting material, the Compo-ball system. To implement such measurement capabilities on line, a WSN composed of multiple sensor nodes was designed and implemented to provide the staff with an efficient monitoring composting management tool. After framing the problem, the objectives and characteristics of the WSN are briefly discussed and a short description of the hardware and software of the network's components are presented. Presentation and discussion of practical issues and results obtained with the WSN during a demonstration stage that took place in several composting sites concludes the paper. PMID- 24472717 TI - A "window of opportunity" for patients with late-onset pulmonary dysfunction after allogeneic hematopoietic cell transplantation. PMID- 24472718 TI - Diagnostic performance of dedicated positron emission mammography using fluorine 18-fluorodeoxyglucose in women with suspicious breast lesions: a meta-analysis. AB - BACKGROUND: The diagnostic performance of dedicated positron emission mammography (PEM) using fluorine-18-fluorodeoxyglucose (FDG) in evaluating suspicious breast lesions has been investigated by several authors, with conflicting results. Aim of our study is to meta-analyze published data about this topic, in order to add evidence-based data in this setting. MATERIALS AND METHODS: We carried out a comprehensive computer literature search of studies published in the PubMed/MEDLINE, Scopus, or Embase databases through February 10, 2013, regarding the diagnostic performance of PEM using FDG in women with breast lesions. Only studies comprising >= 10 patients who underwent PEM were included in the meta analysis, for statistical purposes. Pooled sensitivity and specificity on a per lesion-based analysis were calculated to assess the diagnostic performance of PEM using FDG in this setting. RESULTS: Our meta-analysis evaluated 8 studies comprising 873 women with breast lesions. Pooled sensitivity and specificity values of PEM using FDG in women with suspected breast malignancy were 85% (95% CI, 83%-88%) and 79% (95% CI, 74%-83%), respectively, on a per lesion-based analysis. The included studies were heterogeneous in their estimate of sensitivity and specificity. CONCLUSION: PEM using FDG is a sensitive and specific tool for the evaluation of suspicious breast lesions. The detection of additional lesions and extensive intraductal involvement is improved, with comparable accuracy, over that of MRI in the depiction of invasive breast cancers. PMID- 24472719 TI - Trace element concentrations and gastrointestinal parasites of Arctic terns breeding in the Canadian High Arctic. AB - Baseline data on trace element concentrations are lacking for many species of Arctic marine birds. We measured essential and non-essential element concentrations in Arctic tern (Sterna paradisaea) liver tissue and brain tissue (mercury only) from Canada's High Arctic, and recorded the presence/absence of gastrointestinal parasites during four different phases of the breeding season. Arctic terns from northern Canada had similar trace element concentrations to other seabird species feeding at the same trophic level in the same region. Concentrations of bismuth, selenium, lead and mercury in Arctic terns were high compared to published threshold values for birds. Selenium and mercury concentrations were also higher in Arctic terns from northern Canada than bird species sampled in other Arctic areas. Selenium, mercury and arsenic concentrations varied across the time periods examined, suggesting potential regional differences in the exposure of biota to these elements. For unknown reasons, selenium concentrations were significantly higher in birds with gastrointestinal parasites as compared to those without parasites, while bismuth concentrations were higher in Arctic terns not infected with gastrointestinal parasites. PMID- 24472720 TI - A year-long study of the spatial occurrence and relative distribution of pharmaceutical residues in sewage effluent, receiving marine waters and marine bivalves. AB - Reports concerning the quantitative analysis of pharmaceuticals in marine ecosystems are somewhat limited. It is necessary to determine pharmaceutical fate and assess any potential risk of exposure to aquatic species and ultimately, seafood consumers. In the work presented herein, analytical methods were optimised and validated for the quantification of pharmaceutical residues in wastewater effluent, receiving marine waters and marine mussels (Mytilus spp.). Selected pharmaceuticals included two non-steroidal anti-inflammatory drugs (NSAIDs) (diclofenac and mefenamic acid), an antibiotic (trimethoprim), an antiepileptic (carbamazepine) and a lipid regulator (gemfibrozil). This paper also presents the results of an in situ study in which caged Mytilus spp. were deployed at three sites on the Irish coastline over a 1-year period. In water samples, pharmaceutical residues were determined using solid phase extraction (SPE) and liquid chromatography-tandem mass spectrometry (LC-MS/MS). The extraction of pharmaceuticals from mussel tissues used an additional pressurised liquid extraction (PLE) step prior to SPE and LC-MS/MS. Limits of quantification between 15 and 225 ng.L(-1) were achieved in wastewater effluent, between 3 and 38 ng.L(-1) in marine surface water and between 4 and 29 ng.g(-1) dry weight in marine mussels. Method linearity was achieved for pharmaceuticals in each matrix with correlation coefficients of R(2)>=0.976. All five selected pharmaceuticals were quantified in wastewater effluent and marine surface waters. This work has demonstrated the susceptibility of the Mytilus spp. to pharmaceutical exposure following the detection of pharmaceutical residues in the tissues of this mussel species at measurable concentrations. PMID- 24472721 TI - A putative role of p53 pathway against impulse noise induced damage as demonstrated by protection with pifithrin-alpha and a Src inhibitor. AB - Exposure to high-level noise leads to oxidative stress and triggers apoptosis of the hair cells. This study examined whether p53, a tumor suppressor protein, is activated in the cochlea following impulse noise exposure. Inhibition of p53 with pifithrin alpha, a specific p53 inhibitor, or KX1-004, a Src-protein tyrosine kinase inhibitor, was tested to determine if p53 inhibition could reduce noise induced hearing loss and cochlear damage. Chinchillas were pre-treated with a local administration of pifithrin alpha or KX1-004 and exposed to impulse noise. The chinchillas were assessed for threshold shift at 1 and 24h after the noise. At 4 or 24h post noise, the cochleae were removed and organs of Corti were examined to assess the damage to the cells and upregulation of p53 by the noise. Apoptosis was evident in both outer hair cells and supporting cells. Phospho-p53 (Ser 15) was upregulated 4h and 24h after the noise. KX1-004 and pifithrin alpha both decreased threshold shift and the number of missing outer hair cells. These results indicate that p53 is involved in the early stages of noise-induced cell death and inhibition of this signaling pathway is a potential protective strategy against noise-induced hearing loss. PMID- 24472722 TI - Occupational factors associated with changes in the body mass index of korean male manual workers. AB - OBJECTIVES: This study was carried out to analyze and compare the occupational factors that could influence changes in body mass index (BMI) in male manual workers stratified into short-term and long-term work experience groups. METHODS: The subjects were 299 male manual workers (sampled systematically) from 27 workplaces, who had undergone travelling medical examinations at a university hospital between March 28 and May 10, 2013, and had also undergone medical examinations at the same hospital in 2012. Their general and occupational characteristics were investigated through a structured, self-administered questionnaire. The BMI at each point in time was calculated based on the anthropometric results of the medical examinations. Multiple regression analyses were conducted on outcomes of the BMI change and predictors composed of the general and occupational characteristics, with the subjects stratified into groups with 5 years or less (short-term) versus more than 5 years (long-term) of work experience at the present post. RESULTS: In the short-term work experience group, the BMI increases of 3-shift workers and groups reporting disagreement with feeling "insufficient job control" and "lack of reward" at work, two of the subscales of job stress, were significantly higher than those of daytime workers and high-stress groups, respectively. In the long-term work experience group, However, although the BMI increase for 3-shift workers was also significantly higher than that of daytime workers, none of the job stress factors were significantly associated with a BMI increase, whereas the social factors of education and marital status were significant, and some lifestyle factors (such as smoking and regular exercise) were also significant. CONCLUSION: This study showed that, except for 3-shift work, the factors associated with BMI increase could differ depending on the length of job experience. Consequently, different strategies may be needed for workers with short-term versus long-term job experience when designing interventions for preventing their obesity. PMID- 24472723 TI - Silibinin induces cell death through reactive oxygen species-dependent downregulation of notch-1/ERK/Akt signaling in human breast cancer cells. AB - The present study was undertaken to determine the underlying mechanism of silibinin-induced cell death in human breast cancer cell lines MCF7 and MDA-MB 231. Silibinin-induced cell death was attenuated by antioxidants, N acetylcysteine (NAC) and 6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid, suggesting that the effect of silibinin was dependent on generation of reactive oxygen species (ROS). Western blot analysis showed that silibinin induced downregulation of extracellular signal-regulated kinase (ERK) and Akt. When cells were transiently transfected with constitutively active (ca) mitogen-activated protein kinase (MEK), an upstream kinase of ERK and caAkt, they showed resistance to silibinin-induced cell death. Silibinin decreased the cleavage of Notch-1 mRNA and protein levels. Notch-1-overexpressed cells were resistant to the silibinin induced cell death. Inhibition of Notch-1 signaling was dependent on ROSgeneration. Overexpression of Notch-1 prevented silibinin-induced inhibition of ERK and Akt phosphorylation. Silibinin-induced cell death was accompanied by increased cleavage of caspase-3 and was prevented by caspase-3 inhibitor in MDA MB-231 cells but not in MCF7 cells. Silibinin induced translocation of apoptosis inducing factor (AIF), which was blocked by NAC, and transfection of caMEK and caAkt. Silibinin-induced cell death was prevented by silencing of AIF expression using small interfering AIF RNA in MCF7 cells but not in MDA-MB-231 cells. In conclusion, silibinin induces cell death through an AIF-dependent mechanism in MCF7 cells and a caspase-3-dependent mechanism in MDA-MB-231 cells, and ROS generation and Notch-1 signaling act upstream of the ERK and Akt pathway. These data suggest that silibinin may serve as a potential agent for induction of apoptosis in human breast cancer cells. PMID- 24472724 TI - Novel TRPM8 antagonist attenuates cold hypersensitivity after peripheral nerve injury in rats. AB - Abnormal cold sensitivity is a common feature of a range of neuropathies. In the murine somatosensory system, multiple aspects of cold sensitivity are dependent on TRPM8, both short term and in response to peripheral nerve injury. The specialized nature of cold-sensitive afferents and the restricted expression of TRPM8 render it an attractive target for the treatment of cold hypersensitivity. This current study examines the effect of a novel TRPM8 antagonist (M8-An) in naive and spinal nerve-ligated rats through behavioral and in vivo electrophysiological approaches. In vitro, M8-An inhibited icilin-evoked Ca(2+) currents in HEK293 cells stably expressing human TRPM8 with an IC(50) of 10.9 nM. In vivo, systemic M8-An transiently decreased core body temperature. Deep dorsal horn recordings were made in vivo from neurons innervating the hind paw. M8-An inhibited neuronal responses to innocuous and noxious cooling of the receptive field in spinal nerve-ligated rats but not in naive rats. No effect on neuronal responses to mechanical and heat stimulation was observed. In addition, M8-An also attenuated behavioral responses to cold but not mechanical stimulation after nerve ligation without affecting the uninjured contralateral response. The data presented here support a contribution of TRPM8 to the pathophysiology of cold hypersensitivity in this model and highlight the potential of the pharmacological block of TRPM8 in alleviating the associated symptoms. PMID- 24472725 TI - mGluR5 antagonist-induced psychoactive properties: MTEP drug discrimination, a pharmacologically selective non-NMDA effect with apparent lack of reinforcing properties. AB - Fenobam [N-(3-chlorophenyl)-N'-(4,5-dihydro-1-methyl-4-oxo-1H-imidazole-2 yl)urea], a potent metabotropic glutamate mGluR5 receptor antagonist, reported to have analgesic effects in animals and anxiolytic effects in humans, also caused adverse events, including psychostimulant-type effects and "derealization phenomena." Recent electrophysiologic, pharmacologic, and anatomic data show that the mGluR5 antagonists 2-methyl-6-(phenylethynyl)pyridine (MPEP) and (E)-2-methyl 6-styryl-pyridine (SIB-1893) can inhibit NMDA receptor-mediated activity and that mGluR5 receptors are highly expressed in limbic and forebrain regions. The present studies first evaluated the potential of mGluR5 receptor antagonists to cause PCP-like psychoactive effects in a rat drug discrimination procedure and, second, explored and characterized the selective mGluR5 antagonist 3-[(2-methyl 1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) as a discriminative stimulus and compared MTEP with other drugs known to be psychoactive in humans. Additionally, the reinforcing potential of MPEP and MTEP was compared with phencyclidine (PCP) in a rat intravenous self-administration procedure. Dizocilpine [(+)-MK-801] and ketamine caused full PCP-appropriate responding. Memantine and the mGluR5 antagonists caused no or weak partial PCP-appropriate responding. In MTEP-trained rats, MTEP, MPEP, and fenobam caused full and equipotent MTEP-appropriate responding. (+)-MK-801 and memantine caused MTEP-appropriate responding below 70%, whereas PCP, chlordiazepoxide and LSD caused MTEP-appropriate responding below 50%. Delta(9)-Tetrahydrocannabinol, yohimbine, arecoline, and pentylenetetrazole all caused MTEP-appropriate responding below 20%. Rats self administered PCP but not MPEP or MTEP, indicating a lack of reinforcing effects of the mGluR5 antagonists. These data suggest that the mGluR5 antagonists appear not to have reinforcing properties, that the discriminative effects of mGluR5 antagonists and PCP are dissimilar, and that mGluR5 antagonists may produce psychoactive effects different from NMDA-antagonists and other drugs with known psychotomimetic properties. PMID- 24472726 TI - Multidetector CT imaging features of solid pseudopapillary tumours of the pancreas in male patients: distinctive imaging features with female patients. AB - OBJECTIVE: To describe multidetector CT imaging features of solid pseudopapillary tumours (SPTs) in male patients and to compare these imaging features with those found in female patients. METHODS: The institutional review board approved this retrospective study. We included the CT images of 72 patients (M:F = 12:60; mean age, 35.0 years) diagnosed with SPT by histology. CT images were reviewed on the following: location of the tumour, maximal diameter, shape, margin and the fraction of the tumour composition. Statistical differences in CT imaging features were analysed. RESULTS: Male patients with SPTs were significantly older than female patients (42.4 years vs 33.4 years, p = 0.0408) and the mean size of the SPTs in male patients was larger (6.3 cm vs 4.6 cm, p = 0.0413) than that of SPTs in female patients. Lobulated shape of the SPTs was most frequent in male patients, whereas oval shape was most frequent in female patients (p = 0.0133). SPTs in male patients tended to have a solid component (p = 0.0434). Progressive enhancement in the solid portion of the tumour was seen in 9 (81.8%) of 11 SPTs in male patients and in 30 (79.0%) of 38 SPTs in female patients on multiphasic CT. CONCLUSION: The imaging features of SPTs in male patients usually appeared as a somewhat large-sized solid mass with a lobulated margin and progressive enhancement. These imaging features may help to differentiate SPTs from other pancreatic tumours for their proper management. ADVANCES IN KNOWLEDGE: SPTs in male patients appear as somewhat large-sized solid masses with lobulated margins, and this form occurs more frequently in older male patients than in female patients. PMID- 24472727 TI - Radiological and practical aspects of body packing. AB - Body packing represents the concealment of illegal substances in a person's body with the aim of smuggling. "Body packers" either swallow drug-filled packets or introduce drug-filled packets into their bodies rectally or vaginally with the purpose of concealing them. The three main smuggled drugs are cocaine, heroin and cannabis products. Body packing represents a serious risk of acute narcotic toxicity from drug exposure, intestinal obstruction owing to pellet impaction and bowel perforation with consequent abdominal sepsis. A suspected body packer is generally admitted to hospital to perform imaging investigations and confirm the presence of drugs in his/her body. Radiological imaging methods are essential to diagnose body packing and to detect potential complications. Increasing sophistication of traffickers and improvements in packaging add to the detection difficulty. Radiologists should be aware of the appearance of drug packets in a range of imaging modalities. This article informs physicians about the challenging aspects of body packing, its background and medicolegal issues, what imaging methods can be used and what criteria are necessary to perform a correct diagnosis. PMID- 24472728 TI - Walking on thin ice! Identifying methamphetamine "drug mules" on digital plain radiography. AB - OBJECTIVE: The purpose of this study was to retrospectively evaluate the sensitivity, specificity and accuracy of identifying methamphetamine (MA) internal payloads in "drug mules" by plain abdominal digital radiography (DR). METHODS: The study consisted of 35 individuals suspected of internal MA drug containers. A total of 59 supine digital radiographs were collected. An overall calculation regarding the diagnostic accuracy for all "drug mules" and a specific evaluation concerning the radiological appearance of drug packs as well as the rate of clearance and complications in correlation with the reader's experience were performed. The gold standard was the presence of secured drug packs in the faeces. RESULTS: There were 16 true-positive "drug mules" identified. DR of all drug carriers for Group 1 (forensic imaging experienced readers, n = 2) exhibited a sensitivity of 100%, a mean specificity of 76.3%, positive predictive value (PPV) of 78.5%, negative predictive value (NPV) of 100% and a mean accuracy 87.2%. Group 2 (inexperienced readers, n = 3) showed a lower sensitivity (93.7%), a mean specificity of 86%, a PPV of 86.5%, an NPV of 94.1% and a mean accuracy of 89.5%. The interrater agreement within Group 1 was 0.72 and within Group 2 averaged to 0.79, indicating a fair to very good agreement. CONCLUSION: DR is a valuable screening tool in cases of MA body packers with huge internal payloads being associated with a high diagnostic insecurity. Diagnostic insecurity on plain films may be overcome by low-dose CT as a cross-sectional imaging modality and addressed by improved radiological education in reporting drug carriers on imaging. ADVANCES IN KNOWLEDGE: Diagnostic signs (double-condom and halo signs) on digital plain radiography are specific in MA "drug mules", although DR is associated with high diagnostic insecurity and underreports the total internal payload. PMID- 24472729 TI - Investigation into the radiobiological consequences of pre-treatment verification imaging with megavoltage X-rays in radiotherapy. AB - OBJECTIVE: The aim of this study was to investigate the effect of pre-treatment verification imaging with megavoltage X-rays on cancer and normal cell survival in vitro and to compare the findings with theoretically modelled data. Since the dose received from pre-treatment imaging can be significant, the incorporation of this dose at the planning stage of treatment has been suggested. METHODS: The impact of imaging dose incorporation on cell survival was investigated by clonogenic assay of irradiated DU-145 prostate cancer, H460 non-small-cell lung cancer and AGO-1522b normal tissue fibroblast cells. Clinically relevant imaging to-treatment times of 7.5 and 15 min were chosen for this study. The theoretical magnitude of the loss of radiobiological efficacy due to sublethal damage repair was investigated using the Lea-Catcheside dose protraction factor model. RESULTS: For the cell lines investigated, the experimental data showed that imaging dose incorporation had no significant impact on cell survival. These findings were in close agreement with theoretical results. CONCLUSION: For the conditions investigated, the results suggest that allowance for the imaging dose at the planning stage of treatment should not adversely affect treatment efficacy. ADVANCES IN KNOWLEDGE: There is a paucity of data in the literature on imaging effects in radiotherapy. This article presents a systematic study of imaging dose effects on cancer and normal cell survival, providing both theoretical and experimental evidence for clinically relevant imaging doses and imaging-to treatment times. The data provide a firm foundation for further study into this highly relevant area of research. PMID- 24472730 TI - Fractional flow reserve is a useful reference standard for myocardial perfusion studies with limitations. PMID- 24472731 TI - Biomarker and imaging responses to spironolactone in subclinical diabetic cardiomyopathy. AB - BACKGROUND: Subclinical diabetic cardiomyopathy (DCM) is frequent in asymptomatic subjects with type 2 diabetes (T2DM). We sought the response of functional and fibrosis markers to therapy in a trial of aldosterone antagonism for treatment of DCM. METHODS: Biochemical, anthropometric, and echocardiographic data were measured in 225 subjects with T2DM. Myocardial function was evaluated with standard echocardiography and myocardial deformation; ischaemia was excluded by exercise echocardiography. Calibrated integrated backscatter and post-contrast T1 mapping from cardiac magnetic resonance imaging were used to assess myocardial structure. Amino-terminal propeptides of pro-collagen type I (PINP) and III (PIIINP), the carboxy-terminal propeptide of pro-collagen type I (PICP) and transforming growth factor beta-1 were measured from peripheral blood or urine to assess myocardial collagen turnover. RESULTS: Diastolic dysfunction was identified in 81 individuals, of whom 49 (25 male, age 60 +/- 10 years) were randomized to spironolactone 25 mg/day or placebo therapy for 6 months. Groups were well-matched at baseline. Spironolactone therapy was associated with improvements in diastolic filling profile (Deltapeak E wave velocity -4 +/- 15 vs. 9 +/- 10 ms, P = 0.001; DeltaE/A ratio -0.1 +/- 0.3 vs. 0.2 +/- 0.2, P < 0.001) and cIB values (-21.2 +/- 4.5 dB vs. -18.0 +/- 5.2 dB, P = 0.026; DeltacIB -5.1 +/- 6.8 vs. -1.3 +/- 5.2, P = 0.030). DeltacIB was independently associated with spironolactone therapy (beta = 0.320, P = 0.026) but not Deltablood pressure. With intervention, pro-collagen biomarkers (DeltaPINP P = 0.92, DeltaPICP P = 0.25, DeltaPIIINP P = 0.52, and DeltaTGF-beta1 P = 0.71) and T1 values (P = 0.54) remained similar between groups. CONCLUSIONS: Spironolactone induced changes in myocardial structure and diastolic properties in DCM are small, and are unassociated with changes in collagen biomarkers or T1 values. PMID- 24472732 TI - Isolated partial anomalous pulmonary venous return with intact atrial septum: a rare but treatable cause of pulmonary hypertension in adults. PMID- 24472733 TI - Wegener's intra-alveolar hemorrhage remission with rituximab. PMID- 24472734 TI - Idiopathic venous thromboembolism: a potential surrogate for occult cancer. AB - BACKGROUND: Several studies have indicated an association between venous thromboembolism (VTE) and a subsequent diagnosis of cancer in Western countries. However, information is scant on subsequent cancer incidence after idiopathic VTE events in Asian people. Through a nationwide cohort study, we evaluated the cancer prevalence of VTE and new cancer incidence in patients after the first episode of idiopathic VTE. METHODS: To conduct a nationwide population cohort study on VTE, we retrieved data from the Taiwan National Health Insurance Database from 1998 to 2008, including a 2-year follow-up period extending to the end of 2010. The occurrence of cancer in the cohort was also determined by accessing the Registry for Catastrophic Illness Patient Database. RESULTS: A total of 45,242 patients had the newly diagnosed VTE from 1998 to 2008. The incidence of VTE increased with age. Among 28,243 idiopathic VTE patients, 1944 patients (6.89%) had a subsequent cancer diagnosis within 2 years of the first idiopathic VTE episode. The three most common newly diagnosed cancers after idiopathic VTE were lung cancer, liver cancer and colorectal cancer (18.3%, 12.3% and 10.9%, respectively). Male sex and advanced age are independent risk factors of having an underlying malignant disorder among patients diagnosed with idiopathic VTE. CONCLUSION: Patients with symptomatic VTE without an identifiable risk factor have a 6.89% incidence of subsequent cancer diagnosis in Taiwan. An extensive screening for an occult cancer in an idiopathic VTE patient may be warranted. PMID- 24472735 TI - Heart block and Lyme carditis. PMID- 24472736 TI - Construction and validation of a plaque discrimination score from the anatomical and histological differences in coronary atherosclerosis: the Liverpool IVUS-V HEART (Intra Vascular UltraSound-Virtual-Histology Evaluation of Atherosclerosis Requiring Treatment) study. AB - AIMS: New markers to help stratify coronary atherosclerosis are needed. Although attempts have been made to differentiate active lesions from those that are stable, none of these has ever been formalised into a discriminatory score. The aim of this study was to analyse the differences between culprit ACS lesions and culprit stable angina lesions with intravascular ultrasound-derived virtual histology and to construct and validate a plaque score. METHODS AND RESULTS: Prior to percutaneous coronary intervention (PCI), we performed volumetric, intravascular ultrasound-derived virtual histology (IVUS-VH) analysis in acute coronary syndrome (ACS) culprit lesions (AC - n=70) and stable angina culprit lesions (SC - n=35). A direct statistical comparison of IVUS-VH data and multiple logistic regression analysis was undertaken. Four main factors were found to be associated (p<0.05) with an AC lesion phenotype: necrotic core/dense calcium (NC/DC) ratio; minimum lumen area <4 mm2 (MLA <4); remodelling index @MLA >1.05 and VH-TCFA presence. Calculation of each logistic regression coefficient and the equation produces an active plaque discrimination score with an AUC of 0.96 on receiver operating characteristics (ROC) analysis. Validation of the score in 50 independent plaques from the Thoraxcenter in Rotterdam revealed an AUC of 0.71, confirming continued diagnostic ability. CONCLUSIONS: We have found four features on IVUS and VH that can predict and discriminate ACS culprit lesion phenotypes from those that are clinically stable. Subsequently, we have constructed and validated the Liverpool Active Plaque Score based upon these features. It is hoped this score may help diagnose active coronary plaques, in the future, to help prevent major adverse cardiac events. PMID- 24472737 TI - Tenascins in stem cell niches. AB - Tenascins are extracellular matrix proteins with distinct spatial and temporal expression during development, tissue homeostasis and disease. Based on their expression patterns and knockout phenotypes an important role of tenascins in tissue formation, cell adhesion modulation, regulation of proliferation and differentiation has been demonstrated. All of these features are of importance in stem cell niches where a precise regulation of growth versus differentiation has to be guaranteed. In this review we summarize the expression and possible functions of tenascins in neural, epithelial and osteogenic stem cell niches during normal development and organ turnover, in the hematopoietic and pro inflammatory niche as well as in the metastatic niche during cancer progression. PMID- 24472738 TI - A rapid increase in macrophage-derived versican and hyaluronan in infectious lung disease. AB - The goals of this study were to characterize the changes in chondroitin sulfate proteoglycans and hyaluronan in lungs in acute response to gram-negative bacterial infection and to identify cellular components responsible for these changes. Mice were treated with intratracheal (IT) live Escherichia coli, E. coli lipopolysaccharide (LPS), or PBS. Both E. coli and LPS caused rapid selective increases in mRNA expression of versican and hyaluronan synthase (Has) isoforms 1 and 2 associated with increased immunohistochemical and histochemical staining for versican and hyaluronan in the lungs. Versican was associated with a subset of alveolar macrophages. To examine whether macrophages contribute to versican and hyaluronan accumulation, in vitro studies with primary cultures of bone marrow-derived and alveolar macrophages were performed. Unstimulated macrophages expressed very low levels of versican and hyaluronan synthase mRNA, with no detectible versican protein or hyaluronan product. Stimulation with LPS caused rapid increases in versican mRNA and protein, a rapid increase in Has1 mRNA, and concomitant inhibition of hyaluronidases 1 and 2, the major hyaluronan degrading enzymes. Hyaluronan could be detected following chloroquine pre-treatment, indicating rapid turnover and degradation of hyaluronan by macrophages. In addition, the effects of LPS, the M1 macrophage classical activation agonist, were compared to those of IL-4/IL-13 or IL-10, the M2a and M2c alternative activation agonists, respectively. Versican and Has1 increased only in response to M1 activation. Finally, the up-regulation of versican and Has1 in the whole lungs of wild-type mice following IT LPS was completely abrogated in TLR-4(-/-) mice. These findings suggest that versican and hyaluronan synthesis may play an important role in the innate immune response to gram-negative lung infection. PMID- 24472740 TI - CRF type 1 receptors of the medial amygdala modulate inhibitory avoidance responses in the elevated T-maze. AB - Corticotropin-releasing factor (CRF) plays a critical role in the mediation of physiological and behavioral responses to stressors. In the present study, we investigated the role played by the CRF system within the medial amygdala (MeA) in the modulation of anxiety and fear-related responses. Male Wistar rats were bilaterally administered into the MeA with CRF (125 and 250 ng/0.2MUl, experiment 1) or with the CRFR1 antagonist antalarmin (25 ng/0.2 MUl, experiment 2) and 10 min later tested in the elevated T-maze (ETM) for inhibitory avoidance and escape measurements. In clinical terms, these responses have been respectively related to generalized anxiety and panic disorder. To further verify if the anxiogenic effects of CRF were mediated by CRFR1 activation, we also investigated the effects of the combined treatment with CRF (250 ng/0.2 MUl) and antalarmin (25 ng/0.2 MUl) (experiment 3). All animals were tested in an open field, immediately after the ETM, for locomotor activity assessment. Results showed that CRF, in the two doses administered, facilitated ETM avoidance, an anxiogenic response. Antalarmin significantly decreased avoidance latencies, an anxiolytic effect, and was able to counteract the anxiogenic effects of CRF. None of the compounds administered altered escape responses or locomotor activity measurements. These results suggest that CRF in the MeA exerts anxiogenic effects by activating type 1 receptors, which might be of relevance to the physiopathology of generalized anxiety disorder. PMID- 24472739 TI - Decorin activates AMPK, an energy sensor kinase, to induce autophagy in endothelial cells. AB - The highly conserved eukaryotic process of macroautophagy (autophagy) is a non specific bulk-degradation program critical for maintaining proper cellular homeostasis, and for clearing aged and damaged organelles. This decision is inextricably dependent upon prevailing metabolic demands and energy requirements of the cell. Soluble monomeric decorin functions as a natural tumor repressor that antagonizes a variety of receptor tyrosine kinases. Recently, we discovered that decorin induces endothelial cell autophagy, downstream of VEGFR2. This process was wholly dependent upon Peg3, a decorin-inducible genomically imprinted tumor suppressor gene. However, the signaling cascades responsible have remained elusive. In this report we discovered that Vps34, a class III phosphoinositide kinase, is an upstream kinase required for Peg3 induction. Moreover, decorin triggered differential formation of Vps34/Beclin 1 complexes with concomitant dissolution of inhibitive Bcl-2/Beclin 1 complexes. Further, decorin inhibited anti-autophagic signaling via suppression of Akt/mTOR/p70S6K activity with the concurrent activation of pro-autophagic AMPK-mediated signaling cascades. Mechanistically, AMPK is downstream of VEGFR2 and inhibition of AMPK signaling abrogated decorin-evoked autophagy. Collectively, these findings hint at the complexity of the underlying molecular relays necessary for decorin-evoked endothelial cell autophagy and reveal important therapeutic targets for augmenting autophagy and combatting tumor angiogenesis. PMID- 24472741 TI - Effects of the novel poly(methyl methacrylate) (PMMA)-encapsulated organic ultraviolet (UV) filters on the UV absorbance and in vitro sun protection factor (SPF). AB - Sunscreens are thought to protect skin from many of the harmful effects of ultraviolet (UV) light and the photostability of sunscreens is thus an important concern in their application. Therefore, to discover new UV filters or to modify well-known UV filters are presents an important way for development of sunscreens. In this study, we presented several novel poly(methyl methacrylate) (PMMA) encapsulated organic UV filters, including encapsulated benzophenone-3 (TB MS), avobenzone (TA-MS), octyl methoxycinnamate (TO-MS) and diethylamino hydroxybenzoyl hexyl benzoate (TD-MS). Our results have demonstrated that PMMA encapsulated UV filters have improved safety, photoprotective ability and photostability. We proposed therefore that these PMMA-encapsulated UV filters can be used as ingredients for sunscreen products in the future. PMID- 24472742 TI - Hepatitis E presenting with thrombocytopaenia. AB - We hereby present the case of a 25-year-old man who presented at the emergency department of Civil Hospital Karachi, Pakistan with signs and symptoms of acute viral hepatitis. Serology tests revealed that the patient was suffering from hepatitis E viral (HEV) infection. Concurrently, the patient was also found to have thrombocytopaenia (TCP). His TCP became better after the resolution of his jaundice, with the patient requiring a transfusion of one mega unit of platelets. After ruling out other common causes of TCP and after a thorough literature search, we concluded that an immune-mediated mechanism secondary to HEV infection might have been the cause behind his low platelet counts. Hence, we propose considering the possibility of HEV infection in patients presenting with acute liver failure and TCP, irrespective of age, gender, and geographical location of the patient. PMID- 24472743 TI - Can high central nervous system penetrating antiretroviral regimens protect against the onset of HIV-associated neurocognitive disorders? AB - OBJECTIVE: To assess changes over time in neuropsychological test results (NPr) and risk factors among a regularly followed HIV-infected patient population. METHODS: Prospective cohort of HIV-infected patients randomly selected to undergo neuropsychological follow-up. Test score was adjusted for age, sex and education. Patients were divided into five groups: normal tests, neuropsychological deficit (one impaired cognitive domain), asymptomatic neurocognitive disorders (ANIs), mild neurocognitive disorders (MNDs) and HIV-associated dementia (HAD). Demographic and background parameters including CSF drug concentration penetration effectiveness (CPE) score 2010 were recorded. Changes in NPr and associated risk factors were analyzed. RESULTS: Two hundred and fifty-six patients underwent neuropsychological tests and 96 accepted follow-up approximately 2 years later. The groups were comparable. Upon neuropsychological retesting, six patients improved, 31 worsened and 59 were stable. The proportion of patients with HIV-associated neurocognitive disorders (HANDs) rose from 26 to 45%, with ANIs and MNDs still mostly represented. Most patients initially diagnosed with HANDs remained stable, five of 25 showed clinical improvement and three of 25 deteriorated. Of 33 patients with normal tests, four deteriorated, whereas 24 of 38 with initial neuropsychological deficit had poorer NPr, and contributed most of the new HAND cases. Patients with clinical deterioration had a lower CPE score both at inclusion (6.9 vs. 8.1; P = 0.005) and at the end of follow-up (7.2 vs. 7.8; P = 0.08) than those with improved or stable performance. This was confirmed by multivariate analysis. CONCLUSION: Patients with higher CPE scores upon inclusion and at the end of follow-up were at lower risk of clinical worsening, suggesting that combination antiretroviral therapy with better CSF penetration could protect against cognitive deterioration. PMID- 24472744 TI - CRF01_AE subtype is associated with X4 tropism and fast HIV progression in Chinese patients infected through sexual transmission. AB - BACKGROUND: The molecular epidemiology of the HIV-1 CRF01_AE subtype as a risk factor for fast HIV-1 progression remains poorly understood. METHODS: We analyzed HIV-1 tropism by utilizing samples from 201 treatment-naive patients in our multicenter cohort (12 research centers in different provinces of China). Tropism was determined by V3 loop sequencing. Data from 235 treatment-naive patients infected sexually (including aforementioned 201 patients) in this cohort with date of estimated seroconversion (EDS) were retrospectively evaluated. Median time from EDS to AIDS was analyzed by Kaplan-Meier curves. Hazard ratios were determined by Cox proportional model. RESULTS: CRF01_AE subtype was predominant (46.0%), especially in the MSM group. Further analysis revealed that the proportion of X4 tropism was higher in the CRF01_AE subtype (45.5%) than in others (C/CRF07_BC/CRF08_BC, 4.3%; B, 6.1%; P <0.001). CRF01_AE subtype was associated with faster progression from EDS to AIDS (4.8 vs. 6.4 years, P = 0.018) compared with non-CRF01_AE subtypes. In a multivariate model, the adjusted hazard ratio (aHR) of CRF01_AE was 1.42 (95% confidence interval, CI 0.99-2.03, P = 0.057), independent of HIV-1 viral load; it was also associated with fast progression to advanced immunodeficiency (aHR, 1.81, 95% CI 1.03-3.18, P = 0.038). CONCLUSION: CRF01_AE, a predominant HIV-1 subtype in Chinese HIV-1 sexually infected patients, tends to be associated with fast progression to AIDS and advanced immunodeficiency, which might be ascribed to high proportion of X4 tropism. Further investigation of these risk factors may have significant implications to clinical practice and policy-making. PMID- 24472745 TI - Vitamins C and E concentrations in muscle of elasmobranch and teleost fishes. AB - In fish, vitamins are part of the first line of the antioxidant defense, they are directly related to stress and disease, and they are involved in the maintenance of various physiological processes and metabolic reactions. In general, fish are unable to synthesize vitamin C due to a deficiency in gulonolactone oxidase (GLO), the enzyme responsible for its de novo synthesis. Vitamin E is involved in the immune response and perhaps one of its main physiological functions is to protect membranes from oxidative damage (lipid peroxidation) associated with free radical production. In fish muscle, vitamin E has an important role as an antioxidant in vivo and its content is highly related to the stability of lipids and fats. The aim of this study was to determine the content of vitamins C and E in muscle from different species of elasmobranch and teleost fishes. The concentrations of vitamins C and E were determined by high performance liquid chromatography (HPLC). The concentration of vitamin C found for the group of elasmobranchs was lower (p=0.001) than that for teleosts. For Mustelus henlei vitamin C was found in only one individual; in Tetrapturus audax and Totoaba macdonaldi vitamin C concentration was below the detection limit. The concentration of vitamin E was lower in the group of elasmobranchs (p=0.03) compared with that of teleosts. The main differences in the antioxidant system between teleosts and elasmobranchs appear to be the specific type and levels of antioxidant compounds, as well as the synergistic interactions among the antioxidants present in their tissues. PMID- 24472746 TI - Pyrolysis kinetics of coking coal mixed with biomass under non-isothermal and isothermal conditions. AB - To investigate the kinetic characteristics of coking coal mixed with biomass during pyrolysis, thermogravimetric (TG) and thermo-balance reactor (TBR) analyses were conducted under non-isothermal and isothermal condition. Yellow poplar as a biomass (B) was mixed with weak coking coal (WC) and hard coking coal (HC), respectively. The calculated activation energies of WC/B blends were higher than those of HC/B blends under non-isothermal and isothermal conditions. The coal/biomass blends show increased reactivity and decreased activation energy with increasing biomass blend ratio, regardless of the coking properties of the coal. The different char structures of the WC/B and HC/B blends were analyzed by BET and SEM. PMID- 24472747 TI - Potential development of compressed bio-methane gas production from pig farms and elephant grass silage for transportation in Thailand. AB - This research project evaluated biogas production using anaerobic co-digestion of pig manure and elephant grass silage in large scale to delivered transportation directly for cars. Anaerobic co-digestion was estimated in three full-scale continuously stirred tank reactors (CSTRs) at 40 degrees C. In the form of compressed bio-methane gas (CBG) production was 14,400m(3)/day (CH4 60-70%) amount of CBG was 9600m(3)/day. The procedure was enhanced by using molecular sieve, activated carbon for removal of moisture and CO2 membrane H2S and CO2 respectively. The results were demonstrated the amount of CO2, H2S gas was reduced along with CH4 was improved up to 90% by volume and compressed to 250bar tank pressure gauge to the fuel for cars. The CBG production, methane gas improvement and performance were evaluated before entering the delivered systems according to the energy standards. The production of CBG is advantageous to strengthen the Thailand biogas market. PMID- 24472748 TI - Regulation of mitochondrial proliferation by PGC-1alpha induces cellular apoptosis in musculoskeletal malignancies. AB - A number of studies have reported that decreased mitochondrial numbers are linked with neoplastic transformation and/or tumor progression, including resistance to apoptosis. Peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha) is a multi-functional transcriptional coactivator that regulates the activities of multiple nuclear receptors and transcriptional factors involved in mitochondrial biogenesis. In this study, we observed that the number of mitochondria in sarcoma tissues, such as osteosarcoma and malignant fibrous histiocytoma, is significantly lower than that in normal muscle tissue or benign tumors, and that increasing the number of mitochondria by PGC-1alpha overexpression induces mitochondrial apoptosis in human sarcoma cell lines. The findings suggest that decreased mitochondrial numbers may contribute to musculoskeletal tumor progression, and that regulation of mitochondrial numbers by PGC-1alpha could be a potent therapeutic tool for human malignancies. PMID- 24472749 TI - A proposed algorithm for multimodal liver trauma management from a surgical trauma audit in a western European trauma center. AB - Management of liver trauma is challenging and may vary widely given the heterogeneity of liver injuries' anatomical configuration, the hemodynamic status, the settings and resources available. Perhaps the use of non-operative management (NOM) may have potential drawbacks and the role of damage control surgery (DCS) and angioembolization represents a major evolving concept.1 Most severe liver trauma in polytrauma patients accounts for a significant morbidity and mortality. Major liver trauma with extensive parenchymal injury and uncontrollable bleeding is therefore a challenge for the trauma team. However a safe and effective surgical hemostasis and a carefully planned multidisciplinary approach can improve the outcome of severe liver trauma. The technique of perihepatic packing, according to DCS approach, is often required to achieve fast, early and effective control of hemorrhage in the highest grades of liver trauma and in unstable patients. A systematic and standardized technique of perihepatic packing may contribute to improve hemostatic efficacy and overall outcomes if wisely combined in a stepwise "sandwich" multimodal approach. DCS philosophy evolved alongside with damage control resuscitation (DCR) in the management of trauma patients, requiring close interaction between surgery and resuscitation. Therefore, as a result of a combined surgical and critical care clinical audit activity in our western European trauma center, a practical algorithm for multimodal sequential management of liver trauma has been developed based on a historical cohort of 253 liver trauma patients and subsequently validated on a prospective cohort of 135 patients in the period 2010-2013. PMID- 24472750 TI - Incidence of anaerobic bacteria in patients with suspected pneumonia in surgical Intensive Care Unit. AB - BACKGROUND: Few studies have investigated the incidence of pulmonary anaerobes in a specific population in surgical Intensive Care Unit (ICU). The objective of this work was to determine the incidence of anaerobes in surgical ICU patients with suspected pneumonia. METHODS: This was a prospective observational, single center study. Analysis was based on data collected over 30 months from the surgical ICU of a tertiary care hospital (Rouen University Hospital), including data on risk factors for anaerobes in the lungs. Patients with suspected pneumonia (community-acquired or nosocomial) were included. Bacteriological sampling was performed by protected distal bronchial sampling (PDBS) with minilavage under bronchoscopy. Aerobic and anaerobic cultures were performed for each sample. Clinicians were only aware of aerobic results. Univariate and multivariate statistical analysis compared groups with and without anaerobes. RESULTS: A total of 134 samples were obtained from 117 patients. Surgery was performed on 74 patients (63.2%), within 24 hours of admission. Fifty-four patients (46.2%) had a chest trauma and 20 patients (17.1%) were admitted for a digestive pathology. Average age was 53.6+/-20.9 years and sex ratio was 5.9 (100 men/17 women). Average SAPS II was 41.6+/-15.1, median length of ICU stay was 23 days (25th percentile=13, 75th percentile=33), and median duration of mechanical ventilation was 21 days (25th percentile=11, 75th percentile=28). Mortality rate in ICU was 14.5%. After sampling, diagnosis of pneumonia was confirmed in 70 cases (52.2%). Anaerobe cultures were positive in 11 samples taken from 11 different patients (overall incidence 8.2%). Aerobic bacteria were also involved in 9 patients (81.8%). In univariate analysis, enteral feeding (P=0.02) and absence of catecholamines at time of sampling (P=0.003) were significantly associated with the presence of anaerobes in PDBS. Enteral nutrition was also found to be a risk factor in multivariate analysis (OR=11.8, 95% CI [1.36 to 102.4] P=0.025). Prior antianaerobic antibiotic treatment was not a protective factor. No difference was observed regarding the notion of aspiration, survival, total length of stay and duration of mechanical ventilation, or evolution of pneumonia between the two groups. CONCLUSION: Our study demonstrates the presence of anaerobic bacteria in the lung samples of patients from surgical ICU with an incidence comparable to that found in populations from medical ICU departments. Anaerobic morbidity in our study is in line with recent literature. PMID- 24472751 TI - Ultrasound-guided maxillary nerve block in adults: feasibility and efficiency for postoperative analgesia after maxillary osteotomy. PMID- 24472752 TI - Sevoflurane: going beyond anesthesia, cardiac conditioning and organ toxicity. PMID- 24472753 TI - Meeting the hidden face of the heart. PMID- 24472754 TI - Dihydrotestosterone deteriorates cardiac insulin signaling and glucose transport in the rat model of polycystic ovary syndrome. AB - It is supposed that women with polycystic ovary syndrome (PCOS) are prone to develop cardiovascular disease as a consequence of multiple risk factors that are mostly related to the state of insulin resistance and consequent hyperinsulinemia. In the present study, we evaluated insulin signaling and glucose transporters (GLUT) in cardiac cells of dihydrotestosterone (DHT) treated female rats as an animal model of PCOS. Expression of proteins involved in cardiac insulin signaling pathways and glucose transporters, as well as their phosphorylation or intracellular localization were studied by Western blot analysis in DHT-treated and control rats. Treatment with DHT resulted in increased body mass, absolute mass of the heart, elevated plasma insulin concentration, dyslipidemia and insulin resistance. At the molecular level, DHT treatment did not change protein expression of cardiac insulin receptor and insulin receptor substrate 1, while phosphorylation of the substrate at serine 307 was increased. Unexpectedly, although expression of downstream Akt kinase and its phosphorylation at threonine 308 were not altered, phosphorylation of Akt at serine 473 was increased in the heart of DHT-treated rats. In contrast, expression and phosphorylation of extracellular signal regulated kinases 1/2 were decreased. Plasma membrane contents of GLUT1 and GLUT4 were decreased, as well as the expression of GLUT4 in cardiac cells at the end of androgen treatment. The obtained results provide evidence for alterations in expression and especially in functional characteristics of insulin signaling molecules and glucose transporters in the heart of DHT-treated rats with PCOS, indicating impaired cardiac insulin action. PMID- 24472756 TI - What input data are needed to accurately model electromagnetic fields from mobile phone base stations? AB - The increase in mobile communication technology has led to concern about potential health effects of radio frequency electromagnetic fields (RF-EMFs) from mobile phone base stations. Different RF-EMF prediction models have been applied to assess population exposure to RF-EMF. Our study examines what input data are needed to accurately model RF-EMF, as detailed data are not always available for epidemiological studies. We used NISMap, a 3D radio wave propagation model, to test models with various levels of detail in building and antenna input data. The model outcomes were compared with outdoor measurements taken in Amsterdam, the Netherlands. Results showed good agreement between modelled and measured RF-EMF when 3D building data and basic antenna information (location, height, frequency and direction) were used: Spearman correlations were >0.6. Model performance was not sensitive to changes in building damping parameters. Antenna-specific information about down-tilt, type and output power did not significantly improve model performance compared with using average down-tilt and power values, or assuming one standard antenna type. We conclude that 3D radio wave propagation modelling is a feasible approach to predict outdoor RF-EMF levels for ranking exposure levels in epidemiological studies, when 3D building data and information on the antenna height, frequency, location and direction are available. PMID- 24472755 TI - Reliability of triclosan measures in repeated urine samples from Norwegian pregnant women. AB - Triclosan (TCS) is a synthetic antibacterial chemical that is used in personal care products and is measurable in urine. Urinary TCS has been associated with allergy in children in Norway and the United States. A reasonable degree of temporal reliability of TCS urinary concentrations has been reported among US children as well as for Puerto Rican pregnant women. We examined the reliability of TCS measures in urine among Norwegian pregnant women. TCS was measured in spot urine samples collected in gestational weeks 17, 23, and 29 from 45 women in The Norwegian Mother and Child Cohort Study (MoBa) enrolled in 2007 and 2008. Spearman's rank correlation coefficient (rs) and intraclass correlation coefficient (ICC) statistics were calculated. Fifty-six percent of the 45 women had a least one sample with a value above the method limit of detection (2.3 MUg/l). The correlation coefficients were 0.61 for TCS concentrations at 17 and 23 weeks and 0.49 for concentrations at 17 and 29 weeks. For the three time points, the ICC was 0.49. The reliability of TCS concentrations in repeated urine samples from pregnant Norwegian women was reasonably good, suggesting a single urine sample can adequately represent TCS exposure during pregnancy. PMID- 24472757 TI - Comparison of blood volatile organic compound levels in residents of Calcasieu and Lafayette Parishes, LA, with US reference ranges. AB - Agency for Toxic Substances and Disease Registry conducted a study to evaluate body burden levels of volatile organic compounds (VOCs) among residents of highly industrialized Calcasieu Parish, LA, USA, in 2002. Blood VOC levels in a representative sample of participants in Calcasieu Parish were compared with a similar group of participants in the less-industrialized Lafayette Parish. Participants' ages ranged from 15 to 91 years, 46% were men, and 89% were Caucasian. VOC levels in these two populations were also compared at the national levels. Solid-phase microextraction coupled with gas chromatography mass spectrometry was used to measure levels of 30 VOCs in blood samples collected from 283 self-described non-smoking study participants. Of the 30 VOCs, 6 had quantifiable levels in at least 25% of the blood samples analyzed. The frequency of detection was >95% for benzene and m-/p-xylene, >60% for 1,4-dichlorbenzene and toluene, 27% for ethylbenzene, and 39% for styrene. Calcasieu and Lafayette Parish participants had similar distributions for six VOCs in key percentiles and geometric means. When compared with a representative sampling of the 1999-2000 US general population, no significant differences were found between the parish data and the US general population. PMID- 24472758 TI - Complete genome sequence of hyperthermophilic archaeon Thermococcus sp. ES1. AB - Thermococcus sp. strain ES1 is an anaerobic, hyperthermophilic archaeon from a hydrothermal vent that catabolizes sugars and peptides and produces H2S from S degrees , H2, acetate and CO2 as its primary metabolites. We present the complete genome sequence of this strain (1,957,742bp) with a focus on its substrate utilization and metabolite production capabilities. The sequence will contribute to the development of heterotrophic archaea for bioenergy production and biogeochemical modeling in hydrothermal environments. PMID- 24472760 TI - Prevalence and in-hospital mortality of gastrostomy and jejunostomy in Japan: a retrospective study with a national administrative database. AB - BACKGROUND: PEG is widely used; however, large-scale data for PEG have been lacking. OBJECTIVE: To estimate the prevalence of placement of gastrostomy and jejunostomy tubes and to elucidate the patient background characteristics and their associations with in-hospital mortality. DESIGN: A retrospective analysis of the Japanese administrative claims database. SETTING: Japanese acute-care hospitals. PATIENTS: A total of 64,219 patients who underwent gastrostomy or jejunostomy tube insertion between July and December, 2007 to 2010, were identified among 11.6 million discharge records. INTERVENTION: Placement of gastrostomy and jejunostomy tubes. MAIN OUTCOME MEASUREMENTS: In-hospital mortality and the associated risk factors. RESULTS: The mean age was 77.4 years; >90% of patients were aged >60 years. Cerebrovascular disease and pneumonia were the most frequently recorded diagnoses, followed by neuromuscular disease and dementia. The estimated annual number of gastrostomy and jejunostomy placements in Japan ranged from 96,000 to 119,000. The in-hospital mortality was 11.9%, and the significantly associated risk factors were male sex, older age, placement of a jejunostomy tube, urgent admission, hospital with lower bed capacity, the presence of malignancy, miscellaneous diseases, pneumonia, heart failure, renal failure, chronic liver diseases, pressure sores and sepsis, and occurrence of peritonitis and/or GI perforation, GI hemorrhage, and intra-abdominal hemorrhage. LIMITATIONS: Retrospective investigation of administrative database. CONCLUSION: Our large-scale data revealed the current status of gastrostomy tube placement in Japan. This can contribute to individual decision-making and the public consensus regarding artificial nutritional support in the elderly. PMID- 24472759 TI - Can patient and pain characteristics predict manometric sphincter of Oddi dysfunction in patients with clinically suspected sphincter of Oddi dysfunction? AB - BACKGROUND: Biliopancreatic-type postcholecystectomy pain, without significant abnormalities on imaging and laboratory test results, has been categorized as "suspected" sphincter of Oddi dysfunction (SOD) type III. Clinical predictors of "manometric" SOD are important to avoid unnecessary ERCP, but are unknown. OBJECTIVE: To assess which clinical factors are associated with abnormal sphincter of Oddi manometry (SOM). DESIGN: Prospective, cross-sectional. SETTING: Tertiary. PATIENTS: A total of 214 patients with suspected SOD type III underwent ERCP and pancreatic SOM (pSOM; 85% dual SOM), at 7 U.S. centers (from August 2008 to March 2012) as part of a randomized trial. INTERVENTIONS: Pain and gallbladder descriptors, psychosocial/functional disorder questionnaires. MAIN OUTCOME MEASUREMENTS: Abnormal SOM findings. Univariate and multivariate analyses assessed associations between clinical characteristics and outcome. RESULTS: The cohort was 92% female with a mean age of 38 years. Baseline pancreatic enzymes were increased in 5%; 9% had minor liver enzyme abnormalities. Pain was in the right upper quadrant (RUQ) in 90% (48% also epigastric); 51% reported daily abdominal discomfort. Fifty-six took narcotics an average of 33 days (of the past 90 days). Less than 10% experienced depression or anxiety. Functional disorders were common. At ERCP, 64% had abnormal pSOM findings (34% both sphincters, 21% biliary normal), 36% had normal pSOM findings, and 75% had at least abnormal 1 sphincter. Demographic factors, gallbladder pathology, increased pancreatobiliary enzymes, functional disorders, and pain patterns did not predict abnormal SOM findings. Anxiety, depression, and poorer coping were more common in patients with normal SOM findings (not significant on multivariate analysis). LIMITATIONS: Generalizability. CONCLUSIONS: Patient and pain factors and psychological comorbidity do not predict SOM results at ERCP in suspected type III SOD. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00688662.). PMID- 24472761 TI - Effect of propofol anesthesia on force application during colonoscopy. AB - BACKGROUND: Sedation is frequently used during colonoscopy to control patient discomfort and pain. Propofol is associated with a deeper level of sedation than is a combination of a narcotic and sedative hypnotic and, therefore, may be associated with an increase in force applied to the colonoscope to advance and withdraw the instrument. OBJECTIVE: To compare force application to the colonoscope insertion tube during propofol anesthesia and moderate sedation. DESIGN: An observational cohort study of 13 expert and 12 trainee endoscopists performing colonoscopy in 114 patients. Forces were measured by using the colonoscopy force monitor, which is a wireless, handheld device that attaches to the insertion tube of the colonoscope. SETTING: Community ambulatory surgery center and academic gastroenterology training programs. PATIENTS: Patients undergoing routine screening or diagnostic colonoscopy with complete segment force recordings. MAIN OUTCOME MEASUREMENTS: Axial and radial forces and examination time. RESULTS: Axial and radial forces increase and examination time decreases significantly when propofol is used as the method of anesthesia. LIMITATIONS: Small study, observational design, nonrandomized distribution of sedation type and experience level, different instrument type and effect of prototype device on insertion tube manipulation. CONCLUSIONS: Propofol sedation is associated with a decrease in examination time and an increase in axial and radial forces used to advance the colonoscope. PMID- 24472762 TI - Preventing migration of fully covered esophageal stents with an over-the-scope clip device (with videos). PMID- 24472764 TI - Transgastric large gallstone extraction through a lumen-apposing metal stent in a patient with acute cholecystitis. PMID- 24472763 TI - Prospective cohort study assessing outcomes of patients from families fulfilling criteria for hereditary diffuse gastric cancer undergoing endoscopic surveillance. AB - BACKGROUND: Prophylactic total gastrectomy is performed in hereditary diffuse gastric cancer (HDGC) patients carrying the CDH1 mutation because endoscopic surveillance often fails to detect microscopic disease. OBJECTIVE: The aim of this study was to determine the natural history and outcomes of patients with HDGC undergoing endoscopy. DESIGN: Prospective, cohort observational study. SETTINGS: Tertiary referral center. PATIENTS: Patients fulfilling criteria for HDGC who opted to undergo endoscopy. INTERVENTION: Research surveillance program using high-resolution white-light endoscopy with autofluorescence and narrow-band imaging combined with targeted and multiple random biopsies assessed by an expert histopathologist for the presence of signet ring cell carcinoma. MAIN OUTCOME MEASUREMENTS: The primary endpoint was the endoscopic yield of microscopic signet ring cell carcinoma according to patient mutation status and subsequent decision to undergo surgery. The secondary endpoint was the additional yield of targeted biopsies compared with random biopsies. RESULTS: Between September 2007 and March 2013, 29 patients from 17 families underwent 70 surveillance endoscopies. Signet ring cell carcinoma foci were identified in 14 of 22 (63.6%) patients with confirmed CDH1 germline mutations and 2 of 7 (28.6%) with no pathogenic mutation identified. Eleven of 16 (9 CDH1-positive) patients proceeded to gastrectomy in a median 5.7 months. Five patients delayed surgery. In 1 patient, advanced gastric cancer developed 40.2 months after the first endoscopic findings. LIMITATIONS: No control group. CONCLUSIONS: Careful white-light examination with targeted and random biopsies combined with detailed histopathology can identify early lesions and help to inform decision making with regard to gastrectomy. Autofluorescence and narrow-band imaging are of limited utility. Delaying gastrectomy in individuals with signet ring cell carcinoma foci carries a high risk and has to be weighed carefully. PMID- 24472765 TI - Tract dilation with a stent retrieval device in EUS-guided pancreatic duct stent placement. PMID- 24472766 TI - Metabolic syndrome and smoking may justify earlier colorectal cancer screening in men. AB - BACKGROUND: Gender, smoking, and metabolic syndrome (MetS) are important risk factors of colorectal neoplasm. Whether presence of these factors may warrant earlier screening remains unclear. OBJECTIVE: To compare age- and gender-specific risk of colorectal neoplasms in association with smoking and MetS under endoscopic or stool-based screening. DESIGN: Cross-sectional observational study. SETTING: Screening center in a university hospital in Taiwan. PATIENTS: A cohort of 10,884 average-risk individuals who received concurrent screening colonoscopy and fecal immunochemical testing (FIT). MAIN OUTCOME MEASUREMENTS: First, the prevalence of colorectal neoplasms and positive predictive value of FIT relative to age, gender, smoking, and MetS. Second, the number of colonoscopies needed to detect 1 advanced neoplasm with different strategies. RESULTS: Male smokers aged 40 to 49 years had a significantly higher prevalence of advanced neoplasms and positive predictive value of stool tests than nonsmoking counterparts. The prevalence of advanced neoplasms in concurrent MetS and smoking (6.2%) or smoking alone (3.8%) men aged 40 to 49 years was higher than that of average-risk women aged 50 to 59 years (2.1%) (P = .03 and .04, respectively). The number of colonoscopies needed to detect 1 advanced neoplasm in men aged 40 to 49 years with concurrent MetS and smoking, smoking, MetS, and women aged 50 to 59 years was, respectively, 14.6, 24.8, 39.8, and 47.4 in the colonoscopy scenario and 1.7, 4.6, 5.7, and 8.3 in the FIT scenario. LIMITATION: Self-selective bias may exist for subjects voluntarily submitted to health check-ups. CONCLUSIONS: MetS and smoking significantly impact both the prevalence of colorectal neoplasms and the diagnostic yields of screening tests in men aged 40 to 49 years. Whether our findings justify earlier screening in this subgroup requires further study. PMID- 24472767 TI - Comparison of acute gain and late lumen loss after PCI with bioresorbable vascular scaffolds versus everolimus-eluting stents: an exploratory observational study prior to a randomised trial. AB - AIMS: The study sought to compare the acute gain and two-year follow-up late lumen loss (LLL) between the Absorb bioresorbable vascular scaffold (BVS) and the analogous everolimus-eluting metallic stent (EES). The current analysis included all the patients recruited in the ABSORB Cohort B and SPIRIT II trials implanted with a single 3.0*18 mm device (Absorb BVS or EES) who underwent serial angiographic examinations at baseline and at two-year follow-up. The acute gain was defined as the difference between post- and preprocedural minimal lumen diameter (MLD). The in-stent/scaffold LLL was calculated as the difference in stent/scaffold segment between the post-procedural MLD and follow-up MLD. Thirty three patients (33 lesions) implanted with the Absorb BVS, and 26 patients (28 lesions) implanted with the EES were studied. The acute gain was similar in the Absorb BVS group (1.23+/-0.38 mm) compared to the EES group (1.32+/-0.26 mm, p=0.29). The in-stent/scaffold LLL at two-year follow-up in the Absorb BVS group (0.26+/-0.19 mm) was also similar compared to the EES group (0.22+/-0.22 mm, p=0.29). Although the two groups had similar two-year clinical outcomes (major adverse cardiac events: Absorb BVS: 6.1% vs. EES: 0.0%), patients treated with the Absorb BVS exhibited a significantly lower two-year in-stent/scaffold MLD compared to the EES (2.02+/-0.26 mm vs. 2.22+/-0.34 mm, p=0.01). Although BVS and EES demonstrated similar two-year clinical outcomes, patients treated with the Absorb BVS exhibited a significantly lower two-year in-stent/scaffold MLD compared to patients treated with the EES. Appropriately powered randomised trials are necessary to confirm these exploratory results and evaluate their prognostic and clinical significance. PMID- 24472768 TI - A specific assay for quantification of human C4c by use of an anti-C4c monoclonal antibody. AB - The increasing evidence of the implication of the complement system in the pathogenesis of several diseases has emphasized the need for the development of specific and valid assays, optimized for quantitative detection of complement activation in vivo. In the present study, we have developed a mouse monoclonal antibody (mAb) that is able to detect fluid phase C4c without interference from other products generated from the complement component C4. The C4c specific mAb was tested in different enzyme-linked immunosorbent assay (ELISA) combinations with various types of in vitro activated sera and samples from factor I deficient patients. The specificity of the mAb was further evaluated by immunoprecipitation techniques and by analysis of eluted fragments of C4 after immunoaffinity chromatography. The anti-C4c mAb was confirmed to be C4c specific, as it showed no cross-reactivity with native (un-cleaved) C4, C4b, iC4b, or C4d. Also, no reaction was observed with C4 fragments in factor I deficient plasma or serum samples. We established and validated a sandwich ELISA based on this C4c specific antibody. The normal range of C4c in EDTA/futhan plasma collected from 100 Danish blood donors was measured, with a mean of 0.85mg/L and a range of 0.19-2.21mg/L. We believe that the C4c specific antibody and the ELISA might be important tools in the future assessment of in vivo activation in situations where the classical or the lectin complement pathways are involved in the pathogenesis. PMID- 24472769 TI - Does covering of farm-associated Culicoides larval habitat reduce adult populations in the United Kingdom? AB - Culicoides biting midges (Diptera: Ceratopogonidae) are the biological vectors of a range of internationally important arboviruses of livestock, including bluetongue virus (BTV) and the recently emerging Schmallenberg virus (SBV). Culicoides species in the subgenus Avaritia (in the UK: Culicoides obsoletus Meigen, Culicoides scoticus Downes & Kettle, Culicoides dewulfi Goetghebuer and Culicoides chiopterus Meigen) have been implicated in BTV transmission in northern Europe and to a varying degree utilise cattle dung as a larval development substrate. The collection of cattle dung into heaps on farms provides a localised source of Culicoides emergence in close proximity to livestock. This study assesses the impact of covering dung heaps prior to the onset of adult Culicoides activity with the aim of reducing recruitment to the local adult populations at four livestock farms in England. Light suction trap catches of adult Culicoides from these farms were compared with those from four untreated control farms from a wide geographic range across the UK. It was demonstrated that implementing control of emergence from dung heaps did not have a significant impact upon the local adult subgenus Avaritia abundance at the treated farm holdings and that the onset of Culicoides activity was similarly unaffected. Use of this method in isolation is unlikely to have an effect in reducing the risk of BTV and SBV transmission. The implications of these results for control of farm associated Culicoides in Europe are discussed. PMID- 24472770 TI - Oxyuris equi: lack of efficacy in treatment with macrocyclic lactones. AB - Whilst anthelminthic resistance of small strongyles is well documented, anthelmintic failures against infections with Oxyuris equi have scarcely been published so far. We describe two cases of equine oxyurosis and the anthelminthic failure of macrocyclic lactones (moxidectin, ivermectin) resulting in persistent O. equi infections with continuous egg shedding. The horses were kept in two different herds in the federal state of Hessia, Germany. Herd A kept two geldings: an 8-year-old Welsh-Cob-Mix and a 7-year-old Haflinger. Herd B was composed of four animals: 2 Connemara-mares, 31 and 19 years old, one 18-year-old Connemara-gelding and a 27-year-old Norwegian Fjord mare. All animals had a case history of various anthelmintic treatments with macrocyclic lactones (moxidectin and ivermectin alternating irregulary) in 2010 and 2011, nonetheless, they continued to shed O. equi nematodes and eggs. Animals were treated anew with moxidectin by members of the institute and were continuously monitored on a daily base by adhesive tape samples. Follow-up examinations for the reappearance of eggs were performed for 30 days in Herd A and 57 days in Herd B. In total, recurrence of O. equi egg shedding was detected in three out of six horses within 1-4 weeks after treatment. In both herds accompanying horses sharing the same stable and paddock remained negative for detection of O. equi-eggs or worms throughout the whole observation period. This is the first report in Europe showing inefficacy of commercial ivermectin compounds and furthermore the first report at all documenting ineffectiveness of moxidectin compounds in the treatment of O. equi-infections in horses indicating a possible development of resistance or confirming an existing incomplete oxyuricidal efficacy. PMID- 24472776 TI - Public health and English local government: historical perspectives on the impact of 'returning home'. AB - This article uses history to stimulate reflection on the present opportunities and challenges for public health practice in English local government. Its motivation is the paradox that despite Department of Health policy-makers' allusions to 'a long and proud history' and 'returning public health home' there has been no serious discussion of that past local government experience and what we might learn from it. The article begins with a short resume of the achievements of Victorian public health in its municipal location, and then considers the extensive responsibilities that it developed for environmental, preventive and health services by the mid-twentieth century. The main section discusses the early NHS, explaining why historians see the era as one of decline for the speciality of public health, leading to the reform of 1974, which saw the removal from local government and the abolition of the Medical Officer of Health role. Our discussion focuses on challenges faced before 1974 which raise organizational and political issues relevant to local councils today as they embed new public health teams. These include the themes of leadership, funding, integrated service delivery, communication and above all the need for a coherent vision and rationale for public health action in local authorities. PMID- 24472775 TI - Radiation-mediated formation of complex damage to DNA: a chemical aspect overview. AB - During the last three decades, a considerable amount of work has been undertaken to determine the nature, the mechanism of formation and the biological consequences of radiation-induced DNA lesions. Most of the information was obtained via the development of chemical approaches, including theoretical, analytical and organic synthesis methods. Since it is not possible to present all the results obtained in this review article, we will focus on recent data dealing with the formation of complex DNA lesions produced by a single oxidation event, as these lesions may play a significant role in cellular responses to ionizing radiation and also to other sources of oxidative stress. Through the description of specific results, the contribution of different chemical disciplines in the assessment of the structure, the identification of the mechanism of formation and the biological impacts in terms of repair and mutagenicity of these complex radiation-induced DNA lesions will be highlighted. PMID- 24472777 TI - HFRS and hantaviruses in the Balkans/South-East Europe. AB - Hemorrhagic fever with renal syndrome is endemic in the Balkans with epidemic outbreaks and sporadic cases that have been recorded yearly since the disease was first recognized. The incidence of Balkan HFRS is modest, with approximately one hundred cases reported in most years. Seroepidemiological investigations conducted in several Balkan countries revealed an overall seroprevalence of 6% in Bosnia and Herzegovina, 1.6% in Croatia, 4% in Greece and 1.7% in Slovenia, respectively. The complex ecology of the Balkan Peninsula supports the existence of diverse rodent and insectivore species which harbor several pathogenic and non pathogenic hantaviruses. Among them only Dobrava (DOBV) and Puumala (PUUV) viruses are associated with disease in humans. Comprehensive clinical studies compared clinical signs and symptoms between patients infected with either virus. A spectrum of clinical picture of the disease ranges from mild illness typical of PUUV infections to a severe form with fulminant hemorrhagic fever and an overall mortality rate of 9.8% among DOBV infected patients. While severe DOBV cases are recognized from Slovenia in the North to Greece in the South, PUUV infections are more frequent in northern part of the area. Balkans represent an area with a potential need for hantavirus vaccines, but due to co-existence of DOBV and PUUV causing HFRS in the same region, a universal vaccine is required. PMID- 24472779 TI - Subjects no more: what happens when trial participants realize they hold the power? PMID- 24472778 TI - Ectopically tethered CP190 induces large-scale chromatin decondensation. AB - Insulator mediated alteration in higher-order chromatin and/or nucleosome organization is an important aspect of epigenetic gene regulation. Recent studies have suggested a key role for CP190 in such processes. In this study, we analysed the effects of ectopically tethered insulator factors on chromatin structure and found that CP190 induces large-scale decondensation when targeted to a condensed lacO array in mammalian and Drosophila cells. In contrast, dCTCF alone, is unable to cause such a decondensation, however, when CP190 is present, dCTCF recruits it to the lacO array and mediates chromatin unfolding. The CP190 induced opening of chromatin may not be correlated with transcriptional activation, as binding of CP190 does not enhance luciferase activity in reporter assays. We propose that CP190 may mediate histone modification and chromatin remodelling activity to induce an open chromatin state by its direct recruitment or targeting by a DNA binding factor such as dCTCF. PMID- 24472780 TI - FoxO/Daf-16 restored thrashing movement reduced by heat stress in Caenorhabditis elegans. AB - Many studies on thermotolerance have been done in Caenorhabditis elegans in order to extend survival under heat stress; Daf-16, a homolog of FoxO in C. elegans, was detected as the key factor in thermotolerance. However, the recovery process from heat stress damage has been seldom discussed. In this study, we analyzed the roles of FoxO/Daf-16 on the recovery from heat stress damage by monitoring thrashing movement. Heat shock reduced the movement, which was restored by culturing at 20 degrees C. Thrashing movement was not restored in the daf-16 mutant, which suggests that Daf-16 is one of the essential factors in repairing the damage. Movement restoration was promoted in the daf-2 mutant, a homolog of insulin/IGF-1-like receptor, in a daf-16-dependent manner. In addition, heat stress decreased the expression of daf-28 and ins-7, agonists of Daf-2. Taken together, these results revealed that FoxO/Daf-16 removes heat stress damage and restores movement via inhibition of the insulin-like signaling pathway in C. elegans, suggesting that FoxO/Daf-16 plays a critical role in thermotolerance. PMID- 24472781 TI - Letters. PMID- 24472782 TI - Geographic partnership: a simple model for a complex world. PMID- 24472783 TI - Color coding nurse uniforms. PMID- 24472784 TI - How do your patient satisfaction scores measure up? PMID- 24472786 TI - Record retrieval: the outsourcing option. PMID- 24472787 TI - "Know your physician" program strengthens safety, satisfaction. PMID- 24472788 TI - Technology management strategies for nurse leaders. PMID- 24472789 TI - Encouraging clinical nurse empowerment. PMID- 24472790 TI - The forgotten rung: a clinical ladder for UAP. PMID- 24472791 TI - The domino effect: staffing for "what is" versus "what if". PMID- 24472792 TI - Leadership Q&A. PMID- 24472793 TI - Risk and protective factors for sexual aggression and dating violence: common themes and future directions. AB - The primary aims of this article are to expand on three themes from the conference articles on risk and protective factors for dating and sexual violence and to offer suggestions that can guide future research. The first theme is the co-occurrence of sexual and dating violence with other forms of violence and other campus health issues. A second topic is the value of prospective studies in revealing temporal patterns of victimization and perpetration. A third theme is the role of peer norms in violence among college students. Suggestions for translating these ideas into research and action are discussed and include the need for comprehensive prevention approaches, more longitudinal research spanning the years before, during, and after college, and the application of social media technology in our interventions strategies. PMID- 24472794 TI - Evidence-based intervention with women pregnant after perinatal loss. AB - PURPOSE: To test the feasibility and acceptability of a caring-based nurse home visit intervention for women pregnant after perinatal loss (PAL), the goal of which was to provide a safe, supportive environment, normalize the pregnancy after loss, reduce anxiety and depression through stress reduction skills, and facilitate prenatal attachment. STUDY DESIGN AND METHODS: This mixed methods study was conducted in two phases: Phase I, to determine the components of the intervention, and Phase II, a randomized trial that used the revised intervention components. Pregnant women with a history of at least one perinatal loss (9 in Phase I and 24 in Phase II) were recruited from obstetrical practices. Phase II sample size was adequate to detect group differences. Background measures of demographics, obstetrical history, and meaning of past losses were collected at baseline. Measured at three points across pregnancy were threat appraisal of pregnancy; and emotional states: anxiety (pregnancy, state, trait), depression, self mastery, prenatal attachment, and satisfaction with social support. The caring-based nurse home visit intervention included activities aimed to reduce anxiety and promote prenatal attachment. The control group were sent pregnancy information booklets that coincided with their gestational age. Qualitative and quantitative evaluations were obtained. RESULTS: In Phase I, 8 women received the intervention; in Phase II, 13 received the intervention and 11 were in the control group. No baseline between-group differences were found. The intervention group had significantly higher satisfaction with social support over time. Women's evaluations were very positive; home visits were rated most liked and helpful. They appreciated a knowledgeable nurse who knew their story, listened, normalized the PAL experience, and was there with nonjudgmental support. CLINICAL IMPLICATIONS: The intervention is both feasible and acceptable. Most women felt that they could reduce their own anxiety using the tools and skills they were provided. Healthcare providers should consider past history's impact on current pregnancy experiences and incorporate process and content of the intervention into their practice. PMID- 24472795 TI - Contexts of reproductive loss in lesbian couples. AB - Lesbian couples seek to become parents in a heteronormative world and in the context of complex biological, social, and legal challenges that may constrain same-sex parenting. Because of these constraints and challenges, lesbian couples experiencing a reproductive loss may encounter issues that heterosexual couples typically will not. Prior to pregnancy, lesbians may experience loss and grief because they cannot conceive a child together without the assistance of a third party. Same-sex families are marginalized; simply deciding to become parents leaves them open to criticism and negative judgment. If pregnancy is not achieved or does not end in a live birth, lesbian couples face decisions about how, whether, and who to conceive a subsequent pregnancy. Although laws vary by state, the social (nonbiological) mother may not have legal status as the child's parent; therefore, the decision of which partner to become pregnant is especially significant. In the event of a reproductive loss, the grief of the social mother might not be acknowledged. Lesbian couples will benefit from the care of a nurse who understands and is accepting of the complex contexts within which they face the challenges of reproductive loss. PMID- 24472796 TI - "Being Sure": women's experience with inevitable miscarriage. AB - PURPOSE: To extend understanding of women's experience of miscarriage by exploring their approach to decisions about what to do after learning a miscarriage was likely. STUDY DESIGN AND METHODS: Using dimensional analysis, a technique generic to grounded theory, we analyzed interview transcripts of 23 women who experienced miscarriage (before 14 weeks gestation) at a midwestern medical center. We explored women's experiences by focusing on (1) how they came to know they were having a miscarriage and (2) how they decided what to do next. Both are key, yet relatively unexplored, constructs of early miscarriage. RESULTS: Being Sure emerged as the central process for women as they made decisions about what was happening to them, and about their treatment options. Participants needed to be sure that they were having a miscarriage (that the pregnancy was truly over), and also be sure that they were choosing the right treatment option for them (surgical, medical, or expectant management). CLINICAL IMPLICATIONS: Nurses caring for women in the throes of an inevitable miscarriage can use the information in this article to support women in their quest toward Being Sure. Helping women thusly encompasses assisting women to understand their symptoms, come to terms with the inevitability of the pregnancy loss, and be comfortable with which treatment they choose for the miscarriage. PMID- 24472797 TI - Fast charging of lead-acid batteries enabled by high-pressure crystallization. AB - Lead-acid batteries were electrically charged and discharged more quickly under high pressures than under atmospheric pressure due to high-pressure crystallization induced by the former condition. High-pressure crystallization can generate extremely small crystals with large supersaturation and small mass transfer rates. Crystals of PbSO4 on the electrodes were observed by scanning electron microscopy, and the crystals became smaller when the operative pressure increased, even when faster charging was carried out. Additionally, the amount of electrical current transferred to the electrodes was larger for electrodes charged and discharged at high pressure. This high-pressure charge-discharge process is expected to improve the quality of lead-acid batteries. PMID- 24472798 TI - Sodium phenylbutyrate reverses lysosomal dysfunction and decreases amyloid-beta42 in an in vitro-model of inclusion-body myositis. AB - Sporadic inclusion-body myositis (s-IBM) is a severe, progressive muscle disease for which there is no enduring treatment. Pathologically characteristic are vacuolated muscle fibers having: accumulations of multi-protein aggregates, including amyloid-beta(Abeta) 42 and its toxic oligomers; increased gamma secretase activity; and impaired autophagy. Cultured human muscle fibers with experimentally-impaired autophagy recapitulate some of the s-IBM muscle abnormalities, including vacuolization and decreased activity of lysosomal enzymes, accompanied by increased Abeta42, Abeta42 oligomers, and increased gamma secretase activity. Sodium phenylbutyrate (NaPB) is an orally bioavailable small molecule approved by the FDA for treatment of urea-cycle disorders. Here we describe that NaPB treatment reverses lysosomal dysfunction in an in vitro model of inclusion-body myositis, involving cultured human muscle fibers. NaPB treatment improved lysosomal activity, decreased Abeta42 and its oligomers, decreased gamma-secretase activity, and virtually prevented muscle-fiber vacuolization. Accordingly, NaPB might be considered a potential treatment of s IBM patients. PMID- 24472799 TI - Results of the ALSTER BP real-world registry on renal denervation employing the Symplicity system. AB - AIMS: To prove the efficacy and safety of renal sympathetic denervation as a new treatment option for patients suffering from resistant hypertension in a real world setting. METHODS AND RESULTS: This single-centre real-world registry included 93 patients who underwent renal denervation employing the Symplicity system. Patients were followed for six months. The patient cohort was divided into early responders with a reduction of office systolic blood pressure >10 mmHg three months after the procedure (n=53, 57%), late responders (six months after the procedure, n=16, 17%) and non-responders (n=24, 26%). After six months, systolic blood pressure was lowered by 46+/-2.9 mmHg (mean+/-SEM, p<0.001), 31+/ 3.4 mmHg (p<0.001) and 7.1+/-3.3 mmHg (p=0.79, ns), respectively. Ambulatory blood pressure monitoring also showed a significant reduction in the early responder group (20+/-5.7 mmHg, p=0.002). We subjected eight patients to a re-do procedure which led to a significant reduction of blood pressure in another five patients after six months (63%). One patient in this cohort developed a one-sided renal artery stenosis associated with an increase in blood pressure. CONCLUSIONS: This real-world analysis of renal sympathetic denervation confirms the procedure to be safe and efficient in the majority of patients. Non-responders may profit from a second ablation, arguing in favour of the hypothesis that the procedure did not destroy sufficient amounts of sympathetic innervation in these patients. However, repeated denervations may also increase side effects. PMID- 24472800 TI - Accuracy of the field triage protocol in selecting severely injured patients after high energy trauma. AB - BACKGROUND: For optimal treatment of trauma patients it is of great importance to identify patients who are at risk for severe injuries. The Dutch field triage protocol for trauma patients, the LPA (National Protocol of Ambulance Services), is designed to get the right patient, in the right time, to the right hospital. Purpose of this study was to determine diagnostic accuracy and compliance of this triage protocol. STUDY DESIGN: Triage criteria were categorised into physiological condition (P), mechanism of trauma (M) and injury type (I). A retrospective analysis of prospectively collected data of all high-energy trauma patients from 2008 to 2011 in the region Central Netherlands is performed. Diagnostic parameters (sensitivity, specificity, negative predictive value, positive predictive value) of the field triage protocol for selecting severely injured patients were calculated including rates of under- and overtriage. Undertriage was defined as the proportion of severely injured patients (Injury Severity Score (ISS)>=16) who were transported to a level two or three trauma care centre. Overtriage was defined as the proportion of non-severely injured patients (ISS<16) who were transported to a level one trauma care centre. RESULTS: Overall sensitivity and specificity of the field triage protocol was 89.1% (95% confidence interval (CI) 84.4-92.6) and 60.5% (95% CI 57.9-63.1), respectively. The overall rate of undertriage was 10.9% (95%CI 7.4-15.7) and the overall rate of overtriage was 39.5% (95%CI 36.9-42.1). These rates were 16.5% and 37.7%, respectively for patients with M+I-P-. Compliance to the triage protocol for patients with M+I-P- was 78.7%. Furthermore, compliance in patients with either a positive I+ or positive P+ was 91.2%. CONCLUSION: The overall rate of undertriage (10.8%) was mainly influenced by a high rate of undertriage in the group of patients with only a positive mechanism criterion, therefore showing low diagnostic accuracy in selecting severely injured patients. As a consequence these patients with severe injury are undetected using the current triage protocol. As it has been shown that severely injured patients have better outcome in level one trauma care centres further optimisation of this protocol aiming at lowering undertriage is therefore essential, preferably without incrementing overtriage too much. PMID- 24472801 TI - Atheists don't have no songs. PMID- 24472803 TI - Association between cancer types, cancer treatments, and venous thromboembolism in medical oncology patients. AB - Nearly 20% of all venous thromboembolism (VTE) occurs in cancer patients, and as many as 78% of cancer patients who develop a thrombotic event do so as outpatients. The risk of VTE in cancer patients is influenced by the type of cancer, its stage and histology, the presence of thrombophilia, and the many therapeutic interventions they receive (eg, surgery, chemotherapy, radiotherapy, supportive care). The greatest VTE risk appears to occur early after cancer diagnosis and in patients with late- or metastatic-stage malignancy. VTE most often occurs in cancers of the pancreas, ovary, kidney, lung, stomach, and brain, as well as in hematologic malignancies such as lymphoma and myeloma. The clinical consequences of thrombosis in cancer patients are typically more severe and more costly than events in patients without cancer. Patient-, cancer-, and treatment related factors should be considered when assessing individual patients for their risk of VTE. Primary pharmacologic VTE prophylaxis should be given to all hospitalized medical and surgical oncology patients at risk, and this therapy should be considered for high-risk ambulatory outpatients (eg, myeloma patients receiving highly thrombogenic chemotherapeutic regimens, very-high-risk solid tumor patients with Khorana scores >=3) who have no contraindications to anticoagulants. PMID- 24472802 TI - Managing breast cancer in the older patient. AB - Breast cancer is a disease that is associated with aging, with almost one-half of all new breast cancer cases diagnosed annually in the United States occurring in women ages 65 and older. Recent data suggest that although breast cancer outcomes in younger women have shown substantial improvement as a result of advances in treatment and screening, the benefits in older women have been less pronounced. Although older patients have been underrepresented in cancer clinical trials, there is an emerging body of literature to help guide treatment decisions. For early-stage breast cancer, the discussion regarding treatment options involves balancing the reduction in risk of recurrence gained by specific therapies with the potential for increased treatment-related toxicity, potentially exacerbated by physiological decline or comorbidities that often co-exist in the older population. A key component of care is the recognition that chronologic age alone cannot guide the management of an older patient with breast cancer. Rather, treatment decisions must also take into account a patient's functional status, estimated life expectancy, the risks and benefits of the therapy, potential barriers to treatment, and patient preference. This article reviews the available evidence for therapeutic management of early-stage breast cancer in older patients, and highlights data from the geriatric oncology literature that provide a basis on which to facilitate evidence-based treatment. PMID- 24472804 TI - The effects of storage duration on erythrocytes. PMID- 24472805 TI - B-cell receptor inhibitors in chronic lymphocytic leukemia. PMID- 24472806 TI - Bisphosphonates in colorectal cancer. PMID- 24472807 TI - New targets for hematologic malignancies. PMID- 24472808 TI - Lower baseline PSA predicts greater benefit from sipuleucel-T. PMID- 24472809 TI - Complete response to brentuximab vedotin in a transplant-naive patient with relapsed CD30-positive nodular lymphocyte-predominant Hodgkin lymphoma. PMID- 24472810 TI - Treatment of nodular lymphocyte-predominant Hodgkin lymphoma-"do no harm". PMID- 24472811 TI - Unusual presentation of bladder myeloid sarcoma causing acute renal failure: case report and review of the literature. PMID- 24472812 TI - Isolated myeloid sarcoma of the genitourinary system. PMID- 24472813 TI - Expression of putative targets of immunotherapy in acute myeloid leukemia and healthy tissues. PMID- 24472814 TI - MDR1 expression predicts outcome of Ph+ chronic phase CML patients on second-line nilotinib therapy after imatinib failure. AB - In the face of competing tyrosine kinase inhibitors (TKIs), identification of chronic myeloid leukemia (CML) patients expecting favorable response to second line treatment is warranted. At the time of imatinib resistance, the investigation of multidrug-resistance protein 1 (MDR1) and BCR-ABL yielded the following results: (i) Patients with high MDR1 transcript levels showed superior response at 48 months as compared with low-level MDR1 patients: major molecular response (MMR) in 41% vs 16% (P=0.014), complete cytogenetic response (CCyR) in 58% vs 39% (P=0.044), and progression-free survival (PFS) in 67% vs 46% (P=0.032). (ii) Patients with BCR-ABL(IS) <28% achieved higher MMR rates (48% vs 21%, P=0.009). (iii) PFS at 48 months was associated with in vitro resistance of BCR-ABL kinase domain mutations: 63% (no mutation) vs 61% (sensitive, intermediately sensitive or unknown IC50 (median inhibitory concentration)) vs 23% (resistant, P=0.01). (iv) Single-nucleotide polymorphisms (SNPs) at positions 1236 and 2677 were associated with higher MDR1 expression in comparison to wild type. (v) Nilotinib was able to impede proliferation of MDR1-overexpressing imatinib-resistant cells. High MDR1 gene expression might identify patients whose mode of imatinib resistance is essentially determined by increased efflux activity of MDR1 and therefore can be overcome by second-line nilotinib treatment. PMID- 24472817 TI - Telomerase activity is more significant for predicting the outcome of IVF treatment than telomere length in granulosa cells. AB - Our previous study has demonstrated that luteinized granulosa cells (GCs) have the potential to proliferate and that the telomerase activity (TA) of luteinized GCs may predict the clinical outcomes of IVF treatment. However, in the field of telomere research, there have always been different opinions regarding the significance of TA and telomere length (TL). Thus, in the present study, we compared the effects of these two parameters on IVF treatment outcomes in the same individuals. TL did not differ significantly between the pregnant group and the non-pregnant group. The TA, number of retrieved oocytes and rate of blastocyst transfer were significantly higher in the pregnant group than in the non-pregnant group (0.8825 OD*mm, 12.75+/-2.20 and 34.48%, respectively, in the pregnant group vs 0.513 OD*mm, 11.60+/-0.93 and 14.89%, respectively, in the non pregnant group (P<0.05)), while basal FSH level was lower in the pregnant group than in the non-pregnant group. The subjects did not differ with regard to ovarian stimulation or other clinical characteristics. A TA increase of 1 OD*mm increased the chance of becoming pregnant 4.769-fold (odds ratio: 5.769, 95% CI: 1.434-23.212, P<0.014). The areas under the receiver operating characteristic curves were 0.576 for TL and 0.674 for TA (P=0.271 and P<0. 012 respectively). The corresponding cut-off points were 4.470 for TL and 0.650 OD*mm for TA. These results demonstrate that TA is a better predictor of pregnancy outcomes following IVF treatment than TL. No other clinical parameters, including age, baseline FSH level or peak oestradiol level, distinguished between the pregnant group and the non-pregnant group as effectively as TA. PMID- 24472816 TI - Placental development during early pregnancy in sheep: effects of embryo origin on vascularization. AB - Utero-placental growth and vascular development are critical for pregnancy establishment that may be altered by various factors including assisted reproductive technologies (ART), nutrition, or others, leading to compromised pregnancy. We hypothesized that placental vascularization and expression of angiogenic factors are altered early in pregnancies after transfer of embryos created using selected ART methods. Pregnancies were achieved through natural mating (NAT), or transfer of embryos from NAT (NAT-ET), or IVF or in vitro activation (IVA). Placental tissues were collected on day 22 of pregnancy. In maternal caruncles (CAR), vascular cell proliferation was less (P<0.05) for IVA than other groups. Compared with NAT, density of blood vessels was less (P<0.05) for IVF and IVA in fetal membranes (FM) and for NAT-ET, IVF, and IVA in CAR. In FM, mRNA expression was decreased (P<0.01-0.08) in NAT-ET, IVF, and IVA compared with NAT for vascular endothelial growth factor (VEGF) and its receptor FLT1, placental growth factor (PGF), neuropilin 1 (NP1) and NP2, angiopoietin 1 (ANGPT1) and ANGPT2, endothelial nitric oxide synthase 3 (NOS3), hypoxia inducible factor 1A (HIF1A), fibroblast growth factor 2 (FGF2), and its receptor FGFR2. In CAR, mRNA expression was decreased (P<0.01-0.05) in NAT-ET, IVF, and IVA compared with NAT for VEGF, FLT1, PGF, ANGPT1, and TEK. Decreased mRNA expression for 12 of 14 angiogenic factors across FM and CAR in NAT-ET, IVF, and IVA pregnancies was associated with reduced placental vascular development, which would lead to poor placental function and compromised fetal and placental growth and development. PMID- 24472815 TI - To drive or be driven: the path of a mouse model of recurrent pregnancy loss. AB - This review is an example of the use of an animal model to try to understand the immune biology of pregnancy. A well-known model of recurrent spontaneous pregnancy loss is put in clinical, historical, and theoretical context, with emphasis on T cell biology. PMID- 24472818 TI - SUV as an adjunct in evaluating disease activity in idiopathic pulmonary fibrosis - a pilot study. AB - OBJECTIVE: We hypothesize that the standardized uptake value (SUV) from PET/computed tomography (CT) can act as an adjunct to forced vital capacity (FVC) in evaluating disease status in idiopathic pulmonary fibrosis (IPF). METHODS: Eight consecutive male patients diagnosed with IPF were prospectively recruited to undergo full pulmonary function tests, high-resolution computed tomography of the thorax and PET/CT. The corrected mean SUV (rSUVmean) and corrected maximum SUV (rSUVmax) against the mediastinal blood pool were correlated with clinical parameters. Examinations were repeated 6 months later in six patients (2/8 patients had died) and changes were evaluated. Correlation was assessed by Spearman's rank correlation, and statistical significance was considered when the P-value was less than 0.05. RESULTS: The rSUVmean in IPF was negatively correlated with FVC (r=-0.6, P=0.024) and diffusing capacity for carbon monoxide (r=-0.7, P=0.010). The decline in FVC was associated with an increment in rSUVmax (r=-0.9, P=0.019), but no similar observation was made with total CT score (r= 0.1, P=0.787). CONCLUSION: Pulmonary metabolism, rSUVmean, contributes to the functional status of IPF patients, and changes in rSUVmax may serve as an adjunct surrogate marker to FVC in evaluating the disease status in IPF patients. PMID- 24472819 TI - Irinotecan-induced immune thrombocytopenia. PMID- 24472820 TI - Paraplegia after lumbar puncture. PMID- 24472821 TI - Secondary hemosiderosis on kidney biopsy in a patient with a left ventricular assist device. PMID- 24472822 TI - Ultrasonically encoded wavefront shaping for focusing into random media. AB - Phase distortions due to scattering in random media restrict optical focusing beyond one transport mean free path. However, scattering can be compensated for by applying a correction to the illumination wavefront using spatial light modulators. One method of obtaining the wavefront correction is by iterative determination using an optimization algorithm. In the past, obtaining a feedback signal required either direct optical access to the target region, or invasive embedding of molecular probes within the random media. Here, we propose using ultrasonically encoded light as feedback to guide the optimization dynamically and non-invasively. In our proof-of-principle demonstration, diffuse light was refocused to the ultrasound focal zone, with a focus-to-background ratio of more than one order of magnitude after 600 iterations. With further improvements, especially in optimization speed, the proposed method should find broad applications in deep tissue optical imaging and therapy. PMID- 24472823 TI - DDTs in mothers' milk, placenta and hair, and health risk assessment for infants at two coastal and inland cities in China. AB - This study is a one of the very few investigating the dichloro-diphenyl trichloroethanes (DDTs) (summation of o,p'-DDE, p,p'-DDE, o,p'-DDD, p,p'-DDD, o,p'-DDT, and p,p'-DDT) in multiple human matrices in mothers' milk, placenta and hair collected from residents from two coastal cities: Guiyu (GY) and Taizhou (TZ) and one inland city: Lin'an (LA). TZ (milk: 360+/-319ng/g lipid wt.) showed significantly higher concentrations of DDTs than those from LA (milk: 190+/ 131ng/g lipid wt.), whereas, concentrations of DDTs in GY (milk: 305+/-109ng/g lipid wt.) were in between TZ and LA. In addition, levels of DDTs in the human tissues from TZ (placenta: 122+/-109ng/g lipid wt.; hair: 79.9+/-215ng/g dry wt.) were significantly higher than those from Lin'an (placenta: 49.2+/-30.2ng/g lipid wt.; hair: 10.8+/-7.09ng/g dry wt.). The above concentrations of DDTs in milk exceeded the Codex Maximum Residue Limits/Extraneous Maximum Residue Limits for milk (20ng/g lipid wt. whole milk), indicating that the human milk samples were grossly polluted. The present study revealed that human specimens collected from the coastal city (TZ) were more contaminated with inland one (LA), based on the levels of DDTs contained in samples which may be due to the higher dietary exposure to DDTs via consumption of contaminated seafood. The estimated daily intakes of DDTs by GY, TZ and LA infants were 1.69+/-1.86, 1.48+/-0.79, and 0.95+/-0.73MUg/kg body wt./day, respectively which did not exceed 10MUg/kg body wt./day, the provisional tolerable daily intake proposed by the Food and Agriculture Organization/World Health Organization. PMID- 24472824 TI - Presence of other allergic disease modifies the effect of early childhood traffic related air pollution exposure on asthma prevalence. AB - Nitrogen dioxide (NO2), a surrogate measure of traffic-related air pollution (TRAP), has been associated with incident childhood asthma. Timing of exposure and atopic status may be important effect modifiers. We collected cross-sectional data on asthma outcomes from Toronto school children aged 5-9years in 2006. Lifetime home, school and daycare addresses were obtained to derive birth and cumulative NO2 exposures for a nested case-control subset of 1497 children. Presence of other allergic disease (a proxy for atopy) was defined as self-report of one or more of doctor-diagnosed rhinitis, eczema, or food allergy. Generalized estimating equations were used to adjust for potential confounders, and examine hypothesized effect modifiers while accounting for clustering by school. In children with other allergic disease, birth, cumulative and 2006 NO2 were associated with lifetime asthma (OR 1.46, 95% CI 1.08-1.98; 1.37, 95% CI 1.00 1.86; and 1.60, 95% CI 1.09-2.36 respectively per interquartile range increase) and wheeze (OR 1.44, 95% CI 1.10-1.89; 1.31, 95% CI 1.02-1.67; and 1.60, 95% CI 1.16-2.21). No or weaker effects were seen in those without allergic disease, and effect modification was amplified when a more restrictive algorithm was used to define other allergic disease (at least 2 of doctor diagnosed allergic rhinitis, eczema or food allergy). The effects of modest NO2 levels on childhood asthma were modified by the presence of other allergic disease, suggesting a probable role for allergic sensitization in the pathogenesis of TRAP initiated asthma. PMID- 24472825 TI - Persistent organic pollutants distribution in lipoprotein fractions in relation to cardiovascular disease and cancer. AB - Persistent organic pollutants (POPs) are lipophilic environmental toxins that have been associated with cardiovascular disease (CVD) and cancer. The aim of this study was to investigate the concentrations of POPs in human high and low/very low-density lipoproteins (HDL and LDL/VLDL) and the possible association with CVD and cancer occurrence in individuals living in a contaminated area. Lipoproteins from 28 individuals (7 healthy controls, 8 subjects with cancer, 13 subjects with CVD) were isolated and the fraction-specific concentration of 20 different POPs was analyzed by high resolution gas chromatography/high resolution mass spectrometry. The activity of Paraoxonase 1 (PON1), an anti-oxidant in HDL, was determined in plasma of these 28 subjects and additional 50 subjects from the same area excluding diseases other than cancer or CVD. Fourteen polychlorinated biphenyls (PCBs) and three organochlorine pesticides were detected, and especially highly chlorinated PCBs were enriched in lipoproteins. Significantly higher concentrations of POPs were found among individuals with CVD or cancer compared to controls. Principal component analyses showed that POP concentrations in HDL were more associated with CVD, while POP concentrations in LDL/VLDL were more associated with cancer. PON1 activity was negatively correlated to sumPCB and a co-variation between decreased arylesterase-activity, increased PCB concentrations and CVD was found. This study shows that POPs are present in lipoproteins and were more abundant in individuals with CVD or cancer compared to healthy controls. The results also indicate that PCB exposure is accompanied by reduced PON1 activity that could impair the HDL function to protect against oxidation. PMID- 24472827 TI - Are diet-specific compensatory health beliefs predictive of dieting intentions and behaviour? AB - Compensatory Health Beliefs (CHBs) - beliefs that an unhealthy behaviour can be compensated for by healthy behaviour - are hypothesised to be activated automatically to help people resolve conflicts between their desires (e.g. eat chocolate) and their long-term goals (e.g. dieting). The aim of the present research was to investigate diet-specific CHBs within the context of a theoretical framework, the Health Action Process Approach (HAPA), to examine the extent to which diet-specific CHBs contribute to dieting intentions and dietary intake. Seventy-five dieting women were recruited in Switzerland and England and were asked to complete measures of diet-specific CHBs, risk perception, outcome expectancies, self-efficacy, intention, and behaviour. Path modelling showed that, overall, diet-specific CHBs were not related to dieting intentions (beta=.10) or behaviour (beta=.06) over and above variables specified in the HAPA. However, risk perception moderated the relationship between diet-specific CHBs and intention (beta=.26). Diet-specific CHBs positively predicted intention in women with high risk perception, but not in women with low risk perception. This positive relationship might be explained by the assumption that CHBs play different roles at different stages of the health-behaviour change process. Future studies should further examine moderators and stage-specific differences of the associations between CHBs, intention and health-behaviour change. PMID- 24472826 TI - Myocardial fibroblast-matrix interactions and potential therapeutic targets. AB - The cardiac extracellular matrix (ECM) is a dynamic structure, adapting to physiological and pathological stresses placed on the myocardium. Deposition and organization of the matrix fall under the purview of cardiac fibroblasts. While often overlooked compared to myocytes, fibroblasts play a critical role in maintaining ECM homeostasis under normal conditions and in response to pathological stimuli assume an activated, myofibroblast phenotype associated with excessive collagen accumulation contributing to impaired cardiac function. Complete appreciation of fibroblast function is hampered by the lack of fibroblast-specific reagents and the heterogeneity of fibroblast precursors. This is further complicated by our ability to dissect the role of myofibroblasts versus fibroblasts in myocardial in remodeling. This review highlights critical points in the regulation of collagen deposition by fibroblasts, the current panel of molecular tools used to identify fibroblasts and the role of fibroblast-matrix interactions in fibroblast function and differentiation into the myofibroblast phenotype. The clinical potential of exploiting differences between fibroblasts and myofibroblasts and using them to target specific fibroblast populations is also discussed. This article is part of a Special Issue entitled "Myocyte Fibroblast Signalling in Myocardium." PMID- 24472828 TI - Characterization of inflammatory responses during intranasal colonization with Streptococcus pneumoniae. AB - Nasopharyngeal colonization by Streptococcus pneumoniae is a prerequisite to invasion to the lungs or bloodstream(1). This organism is capable of colonizing the mucosal surface of the nasopharynx, where it can reside, multiply and eventually overcome host defences to invade to other tissues of the host. Establishment of an infection in the normally lower respiratory tract results in pneumonia. Alternatively, the bacteria can disseminate into the bloodstream causing bacteraemia, which is associated with high mortality rates(2), or else lead directly to the development of pneumococcal meningitis. Understanding the kinetics of, and immune responses to, nasopharyngeal colonization is an important aspect of S. pneumoniae infection models. Our mouse model of intranasal colonization is adapted from human models(3) and has been used by multiple research groups in the study of host-pathogen responses in the nasopharynx(4-7). In the first part of the model, we use a clinical isolate of S. pneumoniae to establish a self-limiting bacterial colonization that is similar to carriage events in human adults. The procedure detailed herein involves preparation of a bacterial inoculum, followed by the establishment of a colonization event through delivery of the inoculum via an intranasal route of administration. Resident macrophages are the predominant cell type in the nasopharynx during the steady state. Typically, there are few lymphocytes present in uninfected mice(8), however mucosal colonization will lead to low- to high-grade inflammation (depending on the virulence of the bacterial species and strain) that will result in an immune response and the subsequent recruitment of host immune cells. These cells can be isolated by a lavage of the tracheal contents through the nares, and correlated to the density of colonization bacteria to better understand the kinetics of the infection. PMID- 24472829 TI - Editorial - epigenetics and chemical safety. PMID- 24472831 TI - Effect of heparin-derived oligosaccharide on bFGFR1 and bFGFR2 in vascular smooth muscle cells. AB - Our purpose is to investigate the inhibitory effect and mechanisms of heparin derived oligosaccharide (HDO) on proliferation of vascular smooth muscle cells (VSMCs) induced by basic fibroblast growth factor (bFGF). Proliferation of VSMCs was measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide; cell cycle distribution was analyzed by flow cytometry; bFGF receptor 1 and receptor 2 (bFGFR1 and bFGFR2) messenger RNA (mRNA) expression levels were determined by reverse transcription-polymerase chain reaction; and its protein expression levels were detected by Western blotting and immunocytochemical methods. Results showed that HDO inhibited VSMC proliferation in a dose-dependent manner; HDO inhibited cells in G1 phase entering the S phase; HDO inhibited bFGFR1 and bFGFR2 mRNA expression levels. In addition, bFGFR1 and bFGFR2 protein expression levels were significantly inhibited by HDO dose dependently. These results imply that HDO can inhibit VSMC proliferation. The proliferation of bFGF induced VSMCs by HDO is associated with the inhibition of bFGFR1 and bFGFR2 expression levels. This altered molecular signature may explain one mechanism of HDO-mediated inhibition of VSMC proliferation. PMID- 24472830 TI - Activation of aflatoxin B1 by expression of human CYP1A2 polymorphisms in Saccharomyces cerevisiae. AB - Human susceptibility to environmental carcinogens is highly variable and depends on multiple genetic factors, including polymorphisms in cytochrome P450 genes. Although epidemiological studies have identified individual polymorphisms in cytochrome P450 genes that may alter cancer risk, there is often conflicting data about whether such polymorphisms alter the genotoxicity of environmental carcinogens. This is particularly true of the CYP1A2 polymorphisms that confer differential activation of multiple human carcinogens. To determine whether a single cytochrome P450 polymorphism confers higher levels of carcinogen associated genotoxicity, we chose an organism that lack enzymes to metabolically activate aflatoxins and expressed individual human P450 genes in budding yeast. We measured the frequencies of recombination, Rad51 foci formation, 7 methoxyresorufin O-demethylase activities, and the concentrations of carcinogen associated DNA adducts in DNA repair proficient yeast expressing P450 polymorphisms after exposure to aflatoxin B1 (AFB1).We measured growth of rad4 rad51 cells expressing CYP1A2 polymorphisms while exposed to AFB1. We observed that there was significantly less AFB1-associated genotoxicity in yeast expressing CYP1A2 I386F, while yeast expressing CYP1A2 C406Y exhibited intermediate levels of genotoxicity compared to yeast expressing CYP1A2 D348N or wild type. We conclude that differences in carcinogen genotoxicity can be observed in yeast expressing different CYP1A2 alleles. This is the first report that carcinogen-associated P450 polymorphisms can be studied in yeast. PMID- 24472832 TI - The scientific power of a "sham" arm? PMID- 24472833 TI - Sonic hedgehog mediates a novel pathway of PDGF-BB-dependent vessel maturation. AB - Recruitment of mural cells (MCs), namely pericytes and smooth muscle cells (SMCs), is essential to improve the maturation of newly formed vessels. Sonic hedgehog (Shh) has been suggested to promote the formation of larger and more muscularized vessels, but the underlying mechanisms of this process have not yet been elucidated. We first identified Shh as a target of platelet-derived growth factor BB (PDGF-BB) and found that SMCs respond to Shh by upregulating extracellular signal-regulated kinase 1/2 and Akt phosphorylation. We next showed that PDGF-BB-induced SMC migration was reduced after inhibition of Shh or its signaling pathway. Moreover, we found that PDGF-BB-induced SMC migration involves Shh-mediated motility. In vivo, in the mouse model of corneal angiogenesis, Shh is expressed by MCs of newly formed blood vessels. PDGF-BB inhibition reduced Shh expression, demonstrating that Shh is a target of PDGF-BB, confirming in vitro experiments. Finally, we found that in vivo inhibition of either PDGF-BB or Shh signaling reduces NG2(+) MC recruitment into neovessels and subsequently reduces neovessel life span. Our findings demonstrate, for the first time, that Shh is involved in PDGF-BB-induced SMC migration and recruitment of MCs into neovessels and elucidate the molecular signaling pathway involved in this process. PMID- 24472834 TI - How I treat isolated distal deep vein thrombosis (IDDVT). AB - Thromboses limited to infrapopliteal leg deep veins (isolated distal deep vein thrombosis [IDDVT]) are frequently diagnosed in subjects with suspected pulmonary embolism or DVT and account for one-fourth to one-half of all diagnosed leg DVTs. Despite their frequency, the natural history of IDDVTs and their real risk of thromboembolic complications are still uncertain because of the scarcity of prospective, blind, nonintervention studies. Therefore it is still debated whether they warrant diagnosis and treatment. Diagnosis is based on ultrasonographic examination, which is more operator dependent and less sensitive in distal than in proximal veins. The available data seem to support the view that most IDDVTs are self-limiting and inconsequential for patients, though in some cases they can be associated with complications and warrant diagnosis and treatment. The available guidelines for treatment of IDDVTs give different indications ranging from serial imaging of the deep veins for 2 weeks to detect and treat only in case of proximal extension, to giving oral anticoagulation in all IDDVT patients for 3 months. I review this issue, focusing on possible and suggested treatments in symptomatic IDDVT patients, and describe our current therapeutic approach to these patients. PMID- 24472839 TI - Combined size exclusion chromatography, supercritical fluid chromatography and electrospray ionization mass spectrometry for the analysis of complex aliphatic polyesters. AB - Aliphatic polyesters are complex products of polycondensation that are distributed regarding the degree of polycondensation, the end group functionality and the molecular topology. To address the molecular heterogeneity of polyesters based on phthalic acid and propylene glycol, for the first time the combination of SEC, SFC and ESI-MS have been used. In a first set of experiments, samples were fractionated by SEC and the collected fractions analyzed by SFC for a tentative assignment of the degrees of polycondensation. More conclusive results were obtained by semi-preparative SFC fractionation of the bulk samples and the subsequent analysis of the collected fractions by ESI-MS. The ESI-MS spectra of the SFC fractions provided detailed information on the presence of linear and cyclic oligomers, their degrees of polycondensation and their end groups. Information on the presence of propylene oxide oligomers was also obtained and it was shown how they were inserted in the polymer structures. Compared to previous work, the present approach provides significantly more detailed information on the molecular complexity of aliphatic polyesters. This is mainly due to the fact that SFC has been used as the second chromatographic dimension which is known to have superior separation capabilities. PMID- 24472840 TI - Ionic liquid-based solid phase microextraction necklaces for the environmental monitoring of ketamine. AB - Wearable solid phase microextraction (SPME) devices consisting in necklaces and pins were developed for the environmental monitoring of ketamine in recreational places using ionic liquid as coating. SPME fibers obtained using both monocationic and dicationic polymeric ionic liquids were characterized in terms of morphology, film thickness, thermal stability and pH resistance. An average thickness of 30+/-5MUm, an excellent thermal stability until 350 degrees C and a very good fiber-to-fiber and batch-to-batch repeatability with RSD lower than 4% were some of the features of the developed coatings. A quantitation limit (LOQ) of 0.05mg/m(3) with a sampling time of 1min proved the feasibility of the developed method for the quantitation of ketamine in air at low concentration levels. Finally, the capabilities of the fibers for the rapid SPME sampling of ketamine in recreational places were proved obtaining extraction efficiencies at least two-fold higher than those obtained using commercial devices and extraction recoveries ranging from 84.2+/-3.3% to 93.6+/-2.6% (n=3). PMID- 24472841 TI - Electromigration behavior of nucleic acids in capillary electrophoresis under pulsed-field conditions. AB - We have presented a study focused on the migration pattern of double-stranded DNA (dsDNA) and RNA under pulsed field conditions. By calculating the dependence of nucleic acid mobility on its molecular size in a double logarithm plot, we found that (I) dsDNA molecules proceeded by a sigmoidal migration regime which was probably related to Ogston sieving, transition regime, and reptation model. Furthermore, the transition regime disappeared if DNA was resolved in a higher molecular mass HEC. (II) The migration pattern of RNA was relevant to the denaturant used for separation. When RNA was denatured by acetic acid, its mobility parabolically declined with its molecular size. The mobility was linearly decreased with the molecular size if urea was employed as denaturant. (III) RNA may migrate by Ogston, reptation without orientation mechanism when denatured by urea, whereas these two models were not suitable for RNA if denatured by acetic acid. Even though the electrophoretic conditions of PFCE were varied, the sigmoidal, linear, parabolic migration patterns could still be observed. (IV) Under certain modulation depth, the migration time (Tm) of acetic acid decreased with the increase of average separation voltage (Va), and when RNA denatured in 4.0M urea, Tm showed a linear correlation with Va. (V) The mobility of nucleic acids increased with the growth of artificial temperature in the capillary volume due to the decrease in the viscosity of the polymer. This is the first systematic and comparative research of high molecular mass nucleic acids in PFCE, which provides us deep insight into RNA and DNA migration behavior under pulsed electric field conditions. PMID- 24472842 TI - Electrochemical activation of pristine single walled carbon nanotubes: impact on oxygen reduction and other surface sensitive redox processes. AB - The effect of systematic anodic pre-treatments of pristine single walled carbon nanotube (SWNT) forests on the electrochemical response towards a variety of redox processes is investigated. An experimental arrangement is adopted whereby a microcapillary containing the solution of interest and a quasi reference-counter electrode is brought into contact with a small portion of the forest to enable measurements on the surface before and after controlled anodic polarisation (AP). AP of the surface is found to both improve the voltammetric response (faster apparent heterogeneous electron transfer kinetics) of surface sensitive redox processes, such as Fe(2+/3+), and enhance the electrocatalytic response of the SWNTs towards oxygen reduction; the extent of which can be carefully controlled via the applied anodic potential. AP is expected to remove any trace organic (atmospheric) contaminants that may accumulate on the forest over extended periods as well as allowing the controlled introduction of defects, as confirmed by micro-Raman spectroscopy. PMID- 24472843 TI - Cilostazol attenuates ischemia-reperfusion-induced blood-brain barrier dysfunction enhanced by advanced glycation endproducts via transforming growth factor-beta1 signaling. AB - We investigated the effects of cilostazol, a selective inhibitor of phosphodiesterase 3, on blood-brain barrier (BBB) integrity against ischemia reperfusion injury enhanced by advanced glycation endproducts (AGEs). We used in vitro BBB models with primarily cultured BBB-related cells from rats (brain capillary endothelial cells, astrocytes and pericytes), and subjected cells to either normoxia or 3-h oxygen glucose deprivation (OGD)/24-h reoxygenation with or without AGEs. Treatment of AGEs did not affect the transendothelial electrical resistance (TEER) in the BBB model under normoxia, but there was a significant decrease in TEER under 3-h OGD/24-h reoxygenation conditions with AGEs. Cilostazol inhibited decreases in TEER induced by 3-h OGD/24-h reoxygenation with AGEs. Immunocytochemical and Western blot analyses showed that AGEs reduced the expression of claudin-5, the main functional protein of tight junctions (TJs). In contrast, cilostazol increased the expression of claudin-5 under 3-h OGD/24-h reoxygenation with AGEs. Furthermore, while AGEs increased the production of extracellular transforming growth factor (TGF)-beta1, cilostazol inhibited the production of extracellular TGF-beta1 and restored the integrity of TJs. Thus, we found that AGEs enhanced ischemia-reperfusion injury, which mainly included decreases in the expression of proteins comprising TJs through the production of TGF-beta1. Cilostazol appeared to limit ischemia-reperfusion injury with AGEs by improving the TJ proteins and inhibiting TGF-beta1 signaling. PMID- 24472846 TI - Mind the GAPs: insights into intestinal epithelial barrier maintenance and luminal antigen delivery. PMID- 24472845 TI - Monocytes are essential for the neuroprotective effect of human cord blood cells following middle cerebral artery occlusion in rat. AB - Systemic administration of human umbilical cord blood (HUCB) mononuclear cells (MNC) following middle cerebral artery occlusion (MCAO) in the rat reduces infarct size and, more importantly, restores motor function. The HUCB cell preparation is composed of immature T-cells, B-cells, monocytes and stem cells. In this study we examined whether the beneficial effects of HUCB injection were attributable to one of these cell types. Male Sprague Dawley rats underwent permanent MCAO followed 48 h later by intravenous administration of HUCB MNC preparations depleted of either CD14(+) monocytes, CD133(+) stem cells, CD2(+) T cells or CD19(+) B cells. Motor function was measured prior to MCAO and 30 days post-stroke. When CD14(+) monocytes were depleted from the HUCB MNC, activity and motor asymmetry were similar to the MCAO only treated animals. Monocyte depletion prevented HUCB cell treatment from reducing infarct size while monocyte enrichment was sufficient to reduce infarct size. Administration of monocyte depleted HUCB cells did not suppress Iba1 labeling of microglia in the infarcted area relative to treatment with the whole HUCB preparation. These data demonstrate that the HUCB monocytes provide the majority of the efficacy in reducing infarct volume and promoting functional recovery. PMID- 24472844 TI - MeCP2 is required for activity-dependent refinement of olfactory circuits. AB - Methyl CpG binding protein 2 (MeCP2) is a structural chromosomal protein involved in the regulation of gene expression. Alterations in the levels of MeCP2 have been related to neurodevelopmental disorders. Studies in mouse models of MeCP2 deficiency have demonstrated that this protein is important for neuronal maturation, neurite complexity, synaptogenesis, and synaptic plasticity. However, the mechanisms by which MeCP2 dysfunction leads to neurodevelopmental defects, and the role of activity, remain unclear, as most studies examine the adult nervous system, which may obfuscate the primary consequences of MeCP2 mutation. We hypothesize that MeCP2 plays a role during the formation and activity-driven maturation of neural circuits at early postnatal stages. To test this hypothesis, we use the olfactory system as a neurodevelopmental model. This system undergoes postnatal neurogenesis; axons from olfactory neurons form highly stereotyped projections to higher-order neurons, facilitating the detection of possible defects in the establishment of connectivity. In vivo olfactory stimulation paradigms were used to produce physiological synaptic activity in gene-targeted mice in which specific olfactory circuits are visualized. Our results reveal defective postnatal refinement of olfactory circuits in Mecp2 knock out (KO) mice after sensory (odorant) stimulation. This failure in refinement was associated with deficits in the normal responses to odorants, including brain-derived neurotrophic factor (BDNF) production, as well as changes in adhesion molecules known to regulate axonal convergence. The defective refinement observed in Mecp2 KO mice was prevented by daily treatment with ampakine beginning after the first postnatal week. These observations indicate that increasing synaptic activity at early postnatal stage might circumvent the detrimental effect of MeCP2 deficiency on circuitry maturation. The present results provide in vivo evidence in real time for the role of MeCP2 in activity-dependent maturation of olfactory circuitry, with implications for understanding the mechanism of MeCP2 mutations in the development of neural connectivity. PMID- 24472847 TI - Small alveolar macrophages are infected preferentially by HIV and exhibit impaired phagocytic function. AB - HIV-1-infected persons are at higher risk of lower respiratory tract infections than HIV-1-uninfected individuals. This suggests strongly that HIV-infected persons have specific impairment of pulmonary immune responses, but current understanding of how HIV alters pulmonary immunity is incomplete. Alveolar macrophages (AMs), comprising small and large macrophages, are major effectors of innate immunity in the lung. We postulated that HIV-1 impairs pulmonary innate immunity through impairment of AM physiological functions. AMs were obtained by bronchoalveolar lavage from healthy, asymptomatic, antiretroviral therapy-naive HIV-1-infected and HIV-1-uninfected adults. We used novel assays to detect in vivo HIV-infected AMs and to assess AM functions based on the HIV infection status of individual cells. We show that HIV has differential effects on key AM physiological functions, whereby small AMs are infected preferentially by the virus, resulting in selective impairment of phagocytic function. In contrast, HIV has a more generalized effect on AM proteolysis, which does not require direct viral infection. These findings provide new insights into how HIV alters pulmonary innate immunity and the phenotype of AMs that harbors the virus. They underscore the need to clear this HIV reservoir to improve pulmonary immunity and reduce the high incidence of lower respiratory tract infections in HIV-1-infected individuals. PMID- 24472848 TI - Inflammasome activation has an important role in the development of spontaneous colitis. AB - Inflammatory bowel disease (IBD) is characterized for dysregulated intestinal inflammation. Conflicting reports have shown that activation of inflammasome could promote or decrease intestinal inflammation in an acute colitis model, whereas the involvement of inflammasome activation in chronic colitis is poorly understood. In this study, we investigated the role of inflammasome activation in the development of chronic intestinal inflammation by utilizing interleukin-10 (IL-10) knockout (KO) mouse as an animal model, which develops chronic colitis resembling human IBD. We demonstrate the causative link between inflammasome activation and the development of chronic intestinal inflammation. Our results show that mature IL-1beta protein levels were significantly increased in all colon sections from IL-10-deficient mice compared with that of wild-type mice. We found that inhibition of inflammasome activities with IL-1 receptor antagonist or caspase-1 inhibitors suppressed IL-1beta and IL-17 production from inflamed colon explants. Furthermore, blocking inflammasome activation with caspase-1 inhibitor in vivo significantly ameliorated the spontaneous colitis in IL-10 KO mice. Taken together, these observations demonstrate that inflammasome activation promotes the development of chronic intestinal inflammation. PMID- 24472849 TI - IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection. AB - Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Ralpha, which in turn were required for NK- and CD8(+) T-cell responses. Treatment with IL-15-IL-15Ralpha complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Ralpha, IFN-gamma, CXCL9, and CXCL10 followed by recruitment of activated, IFN-gamma-expressing NK, CD8(+), and CD4(+) T cells. Treating infected IFNAR1(-/-) mice with IL-15c similarly increased IL 15, IL-15Ralpha, IFN-gamma, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8(+)-, and CD4(+)-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-gamma and cellular immunity to RV was mediated by IL-15 and IL-15Ralpha. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-gamma expression and lymphocyte responses. PMID- 24472851 TI - Managing patients with severe traumatic brain injury. PMID- 24472850 TI - Associations between vitamin D-binding protein isotypes, circulating 25(OH)D levels, and vitamin D metabolite uptake in colon cancer cells. AB - Vitamin D metabolites have been extensively studied as cancer chemopreventive agents. Gc-globulin (GC) isotypes, based on rs7041 and rs4588 diplotypes, have varying affinities for 1alpha,25-dihydroxyvitamin D (1,25(OH)2D) and 25 hydroxyvitamin D (25(OH)D), which may affect circulating metabolite concentration as well as delivery at the cellular level. We evaluated associations between GC isotype and circulating vitamin D metabolite concentrations in 403 ursodeoxycholic acid (UDCA) clinical trial participants. Metabolite uptake was evaluated in human colon cancer (HCT-116) cells treated with ethanol vehicle, 1,25(OH)2D, or 25(OH)D, and with plasma from individuals with known GC isotype. Mammalian-2-hybrid and vitamin D-responsive element-based luciferase assays were used to measure the vitamin D receptor pathway activation as a marker for metabolite uptake. Regression analysis demonstrated significantly lower serum 25(OH)D concentration for clinical trial participants with 1F_2, 1S_2, or 2_2 isotypes (P < 0.01) compared with 1S_1S. Consistent with these in vivo observations, cellular data revealed that 25(OH)D uptake varied less by GC isotype only at the higher concentration tested (P = 0.05), while 1,25(OH)2D uptake differed markedly by GC isotype across concentration and assay (P < 0.01). The 1F_1S and 1F_2 isotypes produced the greatest reporter gene induction with 1,25(OH)2D treatment and, while activation varied less with 25(OH)D, the 2_2 isotype demonstrated increased induction at the lower concentration. These results suggest that vitamin D metabolite concentration and delivery to colon cells may vary not only by GC isotype, but also that certain isotypes may more effectively deliver 1,25(OH)2D versus 25(OH)D. Overall, these results may help identify populations at risk for cancer and potential recipients of targeted chemoprevention. PMID- 24472852 TI - Prognostic significance of adenocarcinoma in situ, minimally invasive adenocarcinoma, and nonmucinous lepidic predominant invasive adenocarcinoma of the lung in patients with stage I disease. AB - According to the IASLC/ATS/ERS classification, the lepidic predominant pattern consists of 3 subtypes: adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and nonmucinous lepidic predominant invasive adenocarcinoma. We reviewed tumor slides from 1038 patients with stage I lung adenocarcinoma, recording the percentage of each histologic pattern and measuring the invasive tumor size. Tumors were classified according to the IASLC/ATS/ERS classification: 2 were AIS, 34 MIA, and 103 lepidic predominant invasive. Cumulative incidence of recurrence (CIR) was used to estimate the probability of recurrence. Patients with AIS and MIA experienced no recurrences. Patients with lepidic predominant invasive tumors had a lower risk for recurrence (5-y CIR, 8%) than nonlepidic predominant tumors (n=899; 19%; P=0.003). Patients with >50% lepidic pattern tumors experienced no recurrences (n=84), those with >10% to 50% lepidic pattern tumors had an intermediate risk for recurrence (n=344; 5-y CIR, 12%), and those with <=10% lepidic pattern tumors had the highest risk (n=610; 22%; P<0.001). CIR was lower for patients with <=2 cm tumors than for those with >2 to 3 cm tumors (for both total and invasive tumor size), with the difference more pronounced for invasive tumor size (5-y CIR, 13% vs. 21% [total size; P=0.022] and 12% vs. 27% [invasive size; P<0.001]). Most patients with lepidic predominant adenocarcinoma who experienced a recurrence had potential risk factors, including sublobar resection with close margins (<=0.5 cm; n=2), 20% to 30% micropapillary component (n=2), and lymphatic or vascular invasion (n=2). It therefore may be possible to identify lepidic predominant adenocarcinomas that carry a low or high risk for recurrence. PMID- 24472853 TI - Embracing structural nonidealities and asymmetries in two-dimensional nanomechanical resonators. AB - Mechanical exfoliation is a convenient and effective approach to deriving two dimensional (2D) nanodevices from layered materials; but it is also generally perceived as unpreferred as it often yields devices with structural irregularities and nonidealities. Here we show that such nonidealities can lead to new and engineerable features that should be embraced and exploited. We measure and analyze high frequency nanomechanical resonators based on exfoliated 2D molybdenum disulfide (MoS2) structures, and focus on investigating the effects of structural nonidealities and asymmetries on device characteristics and performance. In high and very high frequency (HF/VHF) vibrating MoS2 devices based on diaphragms of ~2-5 MUm in size, structural nonidealities in shape, boundary, and geometric symmetry all appear not to compromise device performance, but lead to robust devices exhibiting new multimode resonances with characteristics that are inaccessible in their 'ideal' counterparts. These results reveal that the seemingly irregular and nonideal 2D structures can be exploited and engineered for new designs and functions. PMID- 24472854 TI - Effects of a web-based tailored multiple-lifestyle intervention for adults: a two year randomized controlled trial comparing sequential and simultaneous delivery modes. AB - BACKGROUND: Web-based computer-tailored interventions for multiple health behaviors can have a significant public health impact. Yet, few randomized controlled trials have tested this assumption. OBJECTIVE: The objective of this paper was to test the effects of a sequential and simultaneous Web-based tailored intervention on multiple lifestyle behaviors. METHODS: A randomized controlled trial was conducted with 3 tailoring conditions (ie, sequential, simultaneous, and control conditions) in the Netherlands in 2009-2012. Follow-up measurements took place after 12 and 24 months. The intervention content was based on the I Change model. In a health risk appraisal, all respondents (N=5055) received feedback on their lifestyle behaviors that indicated whether they complied with the Dutch guidelines for physical activity, vegetable consumption, fruit consumption, alcohol intake, and smoking. Participants in the sequential (n=1736) and simultaneous (n=1638) conditions received tailored motivational feedback to change unhealthy behaviors one at a time (sequential) or all at the same time (simultaneous). Mixed model analyses were performed as primary analyses; regression analyses were done as sensitivity analyses. An overall risk score was used as outcome measure, then effects on the 5 individual lifestyle behaviors were assessed and a process evaluation was performed regarding exposure to and appreciation of the intervention. RESULTS: Both tailoring strategies were associated with small self-reported behavioral changes. The sequential condition had the most significant effects compared to the control condition after 12 months (T1, effect size=0.28). After 24 months (T2), the simultaneous condition was most effective (effect size=0.18). All 5 individual lifestyle behaviors changed over time, but few effects differed significantly between the conditions. At both follow-ups, the sequential condition had significant changes in smoking abstinence compared to the simultaneous condition (T1 effect size=0.31; T2 effect size=0.41). The sequential condition was more effective in decreasing alcohol consumption than the control condition at 24 months (effect size=0.27). Change was predicted by the amount of exposure to the intervention (total visiting time: beta=-.06; P=.01; total number of visits: beta=-.11; P<.001). Both interventions were appreciated well by respondents without significant differences between conditions. CONCLUSIONS: Although evidence was found for the effectiveness of both programs, no simple conclusive finding could be drawn about which intervention mode was more effective. The best kind of intervention may depend on the behavior that is targeted or on personal preferences and motivation. Further research is needed to identify moderators of intervention effectiveness. The results need to be interpreted in view of the high and selective dropout rates, multiple comparisons, and modest effect sizes. However, a large number of people were reached at low cost and behavioral change was achieved after 2 years. TRIAL REGISTRATION: Nederlands Trial Register: NTR 2168; http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2168 (Archived by WebCite at http://www.webcitation.org/6MbUqttYB). PMID- 24472855 TI - Aedes aegypti midgut remodeling during metamorphosis. AB - The Aedes aegypti midgut is restructured during metamorphosis; its epithelium is renewed by replacing the digestive and endocrine cells through stem or regenerative cell differentiation. Shortly after pupation (white pupae) begins, the larval digestive cells are histolized and show signs of degeneration, such as autophagic vacuoles and disintegrating microvilli. Simultaneously, differentiating cells derived from larval stem cells form an electron-dense layer that is visible 24h after pupation begins. Forty-eight hours after pupation onset, the differentiating cells yield an electron-lucent cytoplasm rich in microvilli and organelles. Dividing stem cells were observed in the fourth instar larvae and during the first 24h of pupation, which suggests that stem cells proliferate at the end of the larval period and during pupation. This study discusses various aspects of the changes during midgut remodeling for pupating A. aegypti. PMID- 24472856 TI - Irisin as a muscle-derived hormone stimulating thermogenesis--a critical update. AB - The recently described myokine, irisin is cleaved from fibronectin type III domain containing protein 5 (FNDC5) and has been proposed to be secreted upon exercise to promote the browning of beige fat cells in white adipose tissue that results in enhanced thermogenesis and increased energy expenditure. The initial studies suggested irisin as a treatment option for obesity and associated diseases such as type 2 diabetes mellitus and stimulated further research. However, the results of subsequent studies investigating the regulation of irisin by different types of exercise are partly conflicting and effects were only shown in highly selective patient populations so far. Moreover, other parameters like body weight or fat free mass were shown to influence irisin adding more complexity to the mechanisms regulating this hormone. The present review will describe the discovery of irisin, its potential role in adipose tissue-mediated thermogenesis, its regulation by exercise and lastly, discuss current controversies and highlight gaps of knowledge to be filled by future studies. PMID- 24472857 TI - Studies on the role of insect hemolymph polypeptides: Galleria mellonella anionic peptide 2 and lysozyme. AB - The lysozymes are well known antimicrobial polypeptides exhibiting antibacterial and antifungal activities. Their antibacterial potential is related to muramidase activity and non-enzymatic activity resembling the mode of action of cationic defense peptides. However, the mechanisms responsible for fungistatic and/or fungicidal activity of lysozyme are still not clear. In the present study, the anti-Candida albicans activity of Galleria mellonella lysozyme and anionic peptide 2 (AP2), defense factors constitutively present in the hemolymph, was examined. The lysozyme inhibited C. albicans growth in a dose-dependent manner. The decrease in the C. albicans survival rate caused by the lysozyme was accompanied by a considerable reduction of the fungus metabolic activity, as revealed by LIVE/DEAD staining. In contrast, although AP2 reduced C. albicans metabolic activity, it did not influence its survival rate. Our results suggest fungicidal action of G. mellonella lysozyme and fungistatic activity of AP2 toward C. albicans cells. In the presence of AP2, the anti-C. albicans activity of G. mellonella lysozyme increased. Moreover, when the fungus was incubated with both defense factors, true hyphae were observed besides pseudohyphae and yeast like C. albicans cells. Atomic force microscopy analysis of the cells exposed to the lysozyme and/or AP2 revealed alterations in the cell surface topography and properties in comparison with the control cells. The results indicate synergistic action of G. mellonella AP2 and lysozyme toward C. albicans. The presence of both factors in the hemolymph of naive larvae suggests their important role in the early stages of immune response against fungi in G. mellonella. PMID- 24472858 TI - Ghrelin administered spinally increases the blood glucose level in mice. AB - Ghrelin is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of ghrelin located in the spinal cord in the regulation of the blood glucose level were investigated in ICR mice. We found that intrathecal (i.t.) injection with ghrelin (from 1 to 10 MUg) caused an elevation of the blood glucose level. In addition, i.t. pretreatment with YIL781 (ghrelin receptor antagonist; from 0.1 to 5 MUg) markedly attenuated ghrelin induced hyperglycemic effect. The plasma insulin level was increased by ghrelin. The enhanced plasma insulin level by ghrelin was reduced by i.t. pretreatment with YIL781. However, i.t. pretreatment with glucagon-like peptide-1 (GLP-1; 5 MUg) did not affect the ghrelin-induced hyperglycemia. Furthermore, i.t. administration with ghrelin also elevated the blood glucose level, but in an additive manner, in d-glucose-fed model. Our results suggest that the activation of ghrelin receptors located in the spinal cord plays important roles for the elevation of the blood glucose level. PMID- 24472864 TI - Exploring apposite therapeutic target for apoptosis in filarial parasite: a plausible hypothesis. AB - Human lymphatic filariasis is a parasitic disease with profound socioeconomic encumbrance owing to its associated disability, affecting predominantly but not limited to the developing nations of tropics and subtropics. There are several technical issues like poor therapeutic and preventive repertoire as well as administrative and infrastructural limitations which jeopardize the salvage measures and further complicate the plight. Therefore, considering the gravity of the problem, WHO has mandated (under tropical disease research scheme) for placing emphasis on validation of novel therapeutic targets against this disease with the unfortunate tag of 'neglected tropical disease'. However, dearth of knowledge of parasite biology viciously coupled with difficulty of access to parasitic material from suitable animal model along with growing cost burden of high end research poses formidable challenge. Based on the recent research evidences, here we propose a premise with targeted apoptotic impact as a novel rationale to be exploited towards anti-parasitic drug development. The new era of bioinformatics ushers in new optimism with a wide range of genomic and proteomic database in public domain. Such platform might offer wonders for drug research, but needs highly selective criterion specificity. In order to test our hypothesis presumptively, we deployed a scheme for identification of target proteins from filarial parasitic origin through wide database search with precise criteria of non-homology against the host along with functional essentiality for the parasite. Further screening for proteins with growth potential from such list of essential non-homologous proteins was undertaken to mine out suitable representative target for ensuing apoptotic impact though effective inhibitors. A unique protein enzyme, RNA dependent RNA polymerase, which besides its vital role in RNA virus is believed to have regulatory role in gene expression, emerged as a plausible target. This protein is rather unknown in human host and present in related nematode parasites including the pathogen of human lymphatic parasite. Further exploitation of bioinformatics approach with a proven inhibitor of this enzyme by molecular docking technique revealed the feasibility as valid antifilarial candidate. This strategy also underscored the significance of bioinformatics tools in circumventing the resource intensive research for drug development. This virtually verified paradigm need to be tested in real lab setting not only for therapeutic authentication of this novel rationale but also for development of insight into parasitic biology that may open up new outlook in host parasite relationship. If successful, this might ensure effective measure against this menace of such 'neglected tropical parasitic diseases'. PMID- 24472859 TI - Serum MASP-1 in complex with MBL activates endothelial cells. AB - The complement system plays an important role in the induction of inflammation. In this study we demonstrate that the initiation complexes of the lectin pathway, consisting of mannose-binding lectin (MBL) and associated serine proteases (MASPs) elicit Ca(2+) signaling in cultured endothelial cells (HUVECs). This is in agreement with our previous results showing that the recombinant catalytic fragment of MASP-1 activates endothelial cells by cleaving protease activated receptor 4. Two other proteases, MASP-2 and MASP-3 are also associated with MBL. Earlier we showed that recombinant catalytic fragment of MASP-2 cannot activate HUVECs, and in this study we demonstrate that the same fragment of MASP-3 has also no effect. We find the same to be the case if we use recombinant forms of the N-terminal parts of MASP-1 and MASP-2 which only contain non-enzymatic domains. Moreover, stable zymogen mutant form of MASP-1 was also ineffective to stimulate endothelial cells, which suggests that in vivo MASP-1 have the ability to activate endothelial cells directly as well as to activate the lectin pathway simultaneously. We show that among the components of the MBL-MASPs complexes only MASP-1 is able to trigger response in HUVECs and the proteolytic activity of MASP 1 is essential. Our results strengthen the view that MASP-1 plays a central role in the early innate immune response. PMID- 24472865 TI - Lactase persistence and augmented salivary alpha-amylase gene copy numbers might have been selected by the combined toxic effects of gluten and (food born) pathogens. AB - Various positively selected adaptations to new nutrients have been identified. Lactase persistence is among the best known, conferring the ability for drinking milk at post weaning age. An augmented number of amylase gene (AMY1) copies, giving rise to higher salivary amylase activity, has been implicated in the consumption of starch-rich foods. Higher AMY1 copy numbers have been demonstrated in populations with recent histories of starchy-rich diets. It is however questionable whether the resulting polymorphisms have exerted positive selection only by providing easily available sources of macro and micronutrients. Humans have explored new environments more than any other animal. Novel environments challenge the host, but especially its immune system with new climatic conditions, food and especially pathogens. With the advent of the agricultural revolution and the concurrent domestication of cattle came new pathogens. We contend that specific new food ingredients (e.g., gluten) and novel pathogens drove selection for lactase persistence and higher AMY gene copy numbers. Both adaptations provide ample glucose for activating the sodium glucose-dependent co transporter 1 (SGLT1), which is the principal glucose, sodium and water transporter in the gastro-intestinal tract. Their rapid uptake confers protection against potentially lethal dehydration, hyponatremia and ultimately multiple organ failure. Oral rehydration therapy aims at SGLT1 activity and is the current treatment of choice for chronic diarrhoea and vomiting. We hypothesize that lifelong lactase activity and rapid starch digestion should be looked at as the evolutionary covalent of oral rehydration therapy. PMID- 24472866 TI - Halitosis: could it be a predictor of stroke? AB - Stroke is a medical emergency and can cause permanent neurological disability and death. Halitosis (bad breath) has been reported in many stroke patients. We speculated that this phenomenon may be present before as well as after a stroke. Moreover, many studies have shown that most of the causes of halitosis are also associated with an increased risk of stroke. Therefore, we hypothesized that the severity of halitosis could be a predictor of stroke. We hope that this hypothesis can be confirmed by further investigations, and that if confirmed it can be used as a tool to monitor disease control and/or early diagnosis and intervention of newly developed diseases related to both halitosis and stroke. PMID- 24472867 TI - A proposed role of human defensins in Helicobacter pylori-related neurodegenerative disorders. AB - Cationic host defence peptides (CHDPs), also known as antimicrobial peptides (AMPs), are essential components of the innate immunity with antimicrobial and pleiotropic immunomodulatory properties. In mammals the two major families of CHDPs are defensins and cathelicidins that comprise an arsenal of innate regulators of principal importance in the host tissues. Research in the last decade has demonstrated that defensins are crucial effectors of both innate and adaptive immunity. Defensins can modulate immune responses, either by stimulation or suppression, thereby controlling inflammatory processes and infections. Currently only few data, mostly hypothetical, focus on the role of defensins in central nervous system (CNS) physiopathology and neurodegeneration. Defensins may function as an initial line of defense within the CNS either as an antimicrobial, immunomodulator, or both. A dysregulation of brain expression of specific defensins might either exacerbate or ameliorate the inflammatory response within the CNS depending upon which extracellular conditions predominate. It is proposed that reduction or abnormal elevation of AMP expression by cerebral microglia, astrocytes or choroid plexus epithelium might contribute to loss of AMP-induced regulation of immune responses, thereby promoting neuronal cell injury and death observed in Alzheimer's disease and possibly in other neurodegenerative disorders. Nevertheless, whether certain AMPs play a crucial role in the onset or promotion of the neuroinflammatory process and neurodegeneration is currently unknown, thereby emphasizing the necessity of further investigation into the regulatory mechanisms that control innate and adaptive immunity within the brain. Recent data indicate that Helicobacter pylori (H. pylori) induces defensins' release associated with chronic inflammatory tissue damage. However, it remains unclear whether and how H. pylori evades the attack by defensins. Moreover, recent evidence indicates that H. pylori infection might contribute to the pathogenesis of neurodegenerative diseases, by releasing several inflammatory mediators that could induce blood-brain barrier breakdown, thereby being involved in the pathogenesis of neurodegeneration. However, currently there are no data regarding the potential impact of human defensins on H. pylori-related neurodegenerative disorders. We herein propose that human defensins might contribute to the pathophysiology of H. pylori-related neurodegenerative disorders by modulating variably innate and adaptive immune system responses. Better understanding of the mechanisms regarding human defensins' possible involvement in H. pylori-induced neurodegeneration might help develop novel therapeutic strategies against H. pylori-related neurodegenerative disorders. PMID- 24472868 TI - Mesogastrium recurrence as expression of the fifth metastatic route of gastric cancer. PMID- 24472869 TI - Is abnormal expression of semenogelin I involved with seminal vesiculitis? AB - Seminal vesiculitis is the common disease of male urogenital system. However, the pathogenesis of seminal vesiculitis remains unclear. Semenogelin I (Sg I) is mainly synthesized and secreted by seminal vesicle and has antibacterial activity. We thus postulate that Sg I plays an important role during the occurrence and development of seminal vesiculitis. In the present study, we analyzed the expression of Sg I in normal seminal vesicle tissues and seminal vesiculitis tissues through immunohistochemistry. The results showed down regulated expression of clusterin at protein level in seminal vesiculitis tissues compared with normal seminal vesicle tissues. Our preliminary data suggest that the abnormal expression of clusterin is closely related to seminal vesiculitis. Downregulation of Sg I expression may weaken the antibacterial activity of the seminal vesicle and then induce the occurrence of disease. This is the first study to focus on the relationship between Sg I and human seminal vesiculitis. PMID- 24472870 TI - Two interconvertible folds modulate the activity of a DNA aptamer against transferrin receptor. AB - Thanks to their ability to recognize biomolecular targets with high affinity and specificity, nucleic acid aptamers are increasingly investigated as diagnostic and therapeutic tools, particularly when their targets are cell-surface receptors. Here, we investigate the relationship between the folding of an anti mouse transferrin receptor DNA aptamer and its interaction with the transferrin receptor both in vitro and in living cells. We identified and purified two aptamer conformers by means of chromatographic techniques. Fluorescence anisotropy measurements showed that only one fold is able to bind mouse transferrin receptor. Besides displaying enhanced endocytosis in living mouse fibroblasts, the purified active fold is internalized also in human pancreatic cancer cells. Starting from these observations, we rationally designed variations of the parent sequence aimed at stabilizing the active fold, and consequently increase aptamer activity. A truncated version and full-length mutants with higher affinity than the parent sequence are shown.Molecular Therapy-Nucleic Acids (2014) 3, e144; doi:10.1038/mtna.2013.71; published online 28 January 2014. PMID- 24472871 TI - Transplantation of induced pluripotent stem cell-derived mesoangioblast-like myogenic progenitors in mouse models of muscle regeneration. AB - Patient-derived iPSCs could be an invaluable source of cells for future autologous cell therapy protocols. iPSC-derived myogenic stem/progenitor cells similar to pericyte-derived mesoangioblasts (iPSC-derived mesoangioblast-like stem/progenitor cells: IDEMs) can be established from iPSCs generated from patients affected by different forms of muscular dystrophy. Patient-specific IDEMs can be genetically corrected with different strategies (e.g. lentiviral vectors, human artificial chromosomes) and enhanced in their myogenic differentiation potential upon overexpression of the myogenesis regulator MyoD. This myogenic potential is then assessed in vitro with specific differentiation assays and analyzed by immunofluorescence. The regenerative potential of IDEMs is further evaluated in vivo, upon intramuscular and intra-arterial transplantation in two representative mouse models displaying acute and chronic muscle regeneration. The contribution of IDEMs to the host skeletal muscle is then confirmed by different functional tests in transplanted mice. In particular, the amelioration of the motor capacity of the animals is studied with treadmill tests. Cell engraftment and differentiation are then assessed by a number of histological and immunofluorescence assays on transplanted muscles. Overall, this paper describes the assays and tools currently utilized to evaluate the differentiation capacity of IDEMs, focusing on the transplantation methods and subsequent outcome measures to analyze the efficacy of cell transplantation. PMID- 24472872 TI - Equilibrium thermodynamics and folding kinetics of a short, fast-folding, beta hairpin. AB - Equilibrium thermodynamics of a short beta-hairpin are studied using unbiased all atom replica exchange molecular dynamics simulations in explicit solvent. An exploratory analysis of the free energy landscape of the system is provided in terms of various structural characteristics, for both the folded and unfolded ensembles. We find that the favorable interactions between the ends introduced by the tryptophan cap, along with the flexibility of the turn region, explain the remarkable stability of the folded state. Charging of the N termini results in effective roughening of the free energy landscape and stabilization of non-native contacts. Folding-unfolding dynamics are further discussed using a set of 2413 independent molecular dynamics simulations, 2 ns to 20 ns long, at the melting temperature of the beta-hairpin. A novel method for the construction of Markov models consisting of an iterative refinement of the discretization in reduced dimensionality is presented and used to generate a detailed kinetic network of the system. The hairpin is found to fold heterogeneously on sub-microsecond timescales, with the relative position of the tryptophan side chains driving the selection of the specific pathway. PMID- 24472873 TI - Amino acid concentrations in critically ill children following cardiac surgery*. AB - OBJECTIVE: Guidelines for administering amino acids to critically ill children are largely based on uncontrolled observational studies and expert opinion, without support from rigorous outcome studies. Also, data on circulating amino acid concentrations during critical illness are scarce. We thoroughly studied the time profiles of circulating amino acid concentrations in critically ill children who received standard nutritional care according to international guidelines. DESIGN: This is a subanalysis of pediatric critically ill patients included in a large (n = 700) randomized controlled study on intensive insulin therapy. SETTING: The study was conducted at a university hospital PICU. PATIENTS: We studied 100 patients in PICU for at least 3 days following cardiac surgery. INTERVENTIONS: Patients were assigned to intensive insulin therapy targeting normal-for-age fasting blood glucose concentrations or insulin infusion only to prevent excessive hyperglycemia. MEASUREMENTS AND MAIN RESULTS: Plasma amino acid concentrations were measured at admission, day 3, and day 7 in PICU. At admission, the concentrations of most amino acids were comparable to those reported for healthy children. Total amino acid concentrations remained stable during ICU stay, but individual amino acids showed different time profiles with eight of them showing an increase and five a decrease. Nonsurviving children had higher total amino acid concentrations and individual amino acids compared with survivors at admission and/or during ICU stay. Intensive insulin therapy lowered the concentrations of total amino acids and several individual amino acids. Neonates showed somewhat different amino acid profiles with rather increased concentrations from baseline with time in ICU for total amino acids and several individual amino acids as compared with older infants and children. CONCLUSIONS: Circulating amino acid concentrations in critically ill children after cardiac surgery differ according to survival status, blood glucose control with intensive insulin therapy, and age. PMID- 24472874 TI - Quantification of cellular uptake of DNA nanostructures by qPCR. AB - DNA nanostructures facilitating drug delivery are likely soon to be realized. In the past few decades programmed self-assembly of DNA building blocks have successfully been employed to construct sophisticated nanoscale objects. By conjugating functionalities to DNA, other molecules such as peptides, proteins and polymers can be precisely positioned on DNA nanostructures. This exceptional ability to produce modular nanoscale devices with tunable and controlled behavior has initiated an interest in employing DNA nanostructures for drug delivery. However, to obtain this the relationship between cellular interactions and structural and functional features of the DNA delivery device must be thoroughly investigated. Here, we present a rapid and robust method for the precise quantification of the component materials of DNA origami structures capable of entering cells in vitro. The quantification is performed by quantitative polymerase chain reaction, allowing a linear dynamic range of detection of five orders of magnitude. We demonstrate the use of this method for high-throughput screening, which could prove efficient to identify key features of DNA nanostructures enabling cell penetration. The method described here is suitable for quantification of in vitro uptake studies but should easily be extended to quantify DNA nanostructures in blood or tissue samples. PMID- 24472875 TI - 23Na-magnetic resonance imaging of the human lumbar vertebral discs: in vivo measurements at 3.0 T in healthy volunteers and patients with low back pain. AB - BACKGROUND CONTEXT: 1H magnetic resonance imaging (MRI) of the spine can rule out common causes of low back pain (LBP), such as disc protrusions or nerve root compression; however, no significant causal relation exists between morphology and the extent of symptoms. Functional MRI techniques, such as 23Na, may provide additional information, allowing indirect assessment of vertebral glycosaminoglycan concentrations, decreases in which are associated with early degenerative changes. PURPOSE: To evaluate 23Na-MRI of asymptomatic healthy volunteers and symptomatic patients with LPB and correlate the results to the Pfirrmann classification of MRI disc morphology. STUDY DESIGN: Retrospective cohort study at an academic medical center. PATIENT SAMPLE: Two groups were studied: (1) 55 healthy volunteers (31 men, 24 women; mean age 28.8 years) and (2) 12 patients (6 men, 6 women; mean age: 35.3 years) with a recent history of LBP. METHODS: Lumbar spines of the aforementioned groups were examined on a 3.0 T MRI scanner with morphological 1H and 23Na imaging. Intervertebral disc (IVD) 23Na at each level was normalized (23Nanorm). Distribution and differences between mean 23Nanorm corresponding to each Pfirrmann classification were evaluated in the two study groups (analysis of variance). Linear correlations between 23Nanorm, body mass index (BMI), and age were assessed (Pearson correlation coefficient). Gender-dependent differences were evaluated (paired t test). OUTCOME MEASURES: Physiological measure: IVD 23Nanorm as determined by 23Na-MRI. RESULTS: A normal distribution of 23Nanorm was confirmed for both groups (p=.072 and p=.073, respectively). The mean Pfirrmann score statistically significantly differed between them (p<.0001). 23Nanorm was statistically significantly reduced in degenerated IVDs (Pfirrmann scores 4+5) (p<.0001). No statistically significant differences were seen for the mean 23Nanorm of IVDs with the same Pfirrmann score in healthy volunteers and patients (.46950% accumulated in the carcass. No significant sex differences were found in killifish or minnow, apart from lower gill tissue EE2 accumulation in minnow females. This study demonstrated that metabolic processing of EE2 may be species-specific and tissue specific EE2 distribution profiles vary. These could be indicative of differences in overall EE2 sensitivity among species. PMID- 24473067 TI - Global assessment of arsenic pollution using sperm whales (Physeter macrocephalus) as an emerging aquatic model organism. AB - Arsenic is an oceanic pollutant of global concern due to its toxicity, ability to bioaccumulate and continued input into the environment by anthropogenic activities. The sperm whale (Physeter macrocephalus) is an emerging aquatic model for both human disease and ocean health having global distribution and high trophic level. The aim of this study was to establish global and regional baselines of total arsenic concentrations using free-ranging sperm whales. Skin biopsies (n=342) were collected during the voyage of the Odyssey (2000-2005) from 17 regions considering gender and age in males. Arsenic was detectable in 99% of samples with a global mean of 1.9MUg/g ww ranging from 0.1 to 15.6MUg/g ww. Previous work in toothed whale skin found mean concentrations 3 fold lower with 0.6MUg/g ww. A significant gender-related effect was found with males having higher mean arsenic concentrations than females. There was no significant age related effect between adult and subadult males. Arsenic concentrations in sloughed skin samples were similar to levels in skin biopsies indicating that arsenic excretion can occur by skin sloughing. Regional mean concentrations were highest in the Maldives, Seychelles and Sri Lanka with 3.5, 2.5, and 2.4MUg/g ww, respectively, raising concern for arsenic pollution in the Indian Ocean. Literature suggests that arsenic exposure is emitted from natural sources and the heavy use of arsenic-containing pesticides and herbicides in this region. These data suggest that research is needed in determining the extent and source of arsenic pollution in the Indian Ocean. PMID- 24473068 TI - Identification of p38alpha MAP kinase inhibitors by pharmacophore based virtual screening. AB - The p38alpha mitogen-activated protein (MAP) kinase plays a vital role in treating many inflammatory diseases. In the present study, a combined ligand and structure based pharmacophore model was developed to identify potential DFG-in selective p38 MAP kinase inhibitors. Conformations of co-crystallised inhibitors were used in the development and validation of ligand and structure based pharmacophore modeling approached. The validated pharmacophore was utilized in database screening to identify potential hits. After Lipinski's rule of five filter and molecular docking analysis, nineteen hits were purchased and selected for in vitro analysis. The virtual hits exhibited promising activity against tumor necrosis factor-alpha (TNF-alpha) with 23-98% inhibition at 10MUM concentration. Out of these seven compounds has shown potent inhibitory activity against p38 MAP kinase with IC50 values ranging from 12.97 to 223.5nM. In addition, the toxicity study against HepG2 cells was also carried out to confirm the safety profile of identified virtual hits. PMID- 24473069 TI - Discovery of potent inhibitor for matrix metalloproteinase-9 by pharmacophore based modeling and dynamics simulation studies. AB - Matrix metalloproteinase-9 (MMP-9) is an attractive target for anticancer therapy. In the present study ligand based pharmacophore modeling was performed to elucidate the structural elements for a diverse class of MMP-9 inhibitors. The pharmacophore model was validated through Guner-Henry (GH) scoring method. The final pharmacophore model consisted of three hydrogen bond acceptors (HBA), and two ring aromatic regions (RA). This model was utilized to screen the natural compound database to seek novel compounds as MMP-9 inhibitors. The identified hits were validated using molecular docking and molecular dynamics simulation studies. Finally, one compound named Hinokiflavone from Juniperus communis had high binding free energy of -26.54kJ/mol compared with the known inhibitors of MMP-9. Cytotoxicity for hinokiflavone was evaluated by MTT assay. Inhibition of MMP-9 in the presence of hinokiflavone was detected by gelatin zymography and gelatinolytic inhibition assay. Results revealed that the natural compounds derived based on the developed pharmacophore model would be useful for further design and development of MMP-9 inhibitors. PMID- 24473070 TI - Application of gold thin-films for internal standardization in LA-ICP-MS imaging experiments. AB - LA-ICP-MS imaging experiments are of growing interest within the field of biosciences. Revealing the distributions of major components as well as trace elements in biological samples can help to understand fundamental biological processes. However, highly variable sample conditions and changing instrumental parameters during measurement time aggravate reliable quantification especially in biological tissues. Normally matrix matched standards used for calibration are scarcely available and the manufacturing process thereof is rather complicated. Thus most experiments reported in the literature only delivered qualitative information on the analyte distributions. The use of appropriate internal standards facilitates the preparation of calibrations even without the utilization of matrix-matched standards. In the presented work an approach for providing reliable quantitative bio-images is proposed using gold thin-layers as an internal standard and patterns printed with commercially available inkjet printers as standards. The method development is based on copper from blue ink as the element of interest. It could be shown that gold standardization compensates instrumental drifts, matrix related ablation differences and day-to-day signal changes. Not only was the quality of the obtained images improved by gold standardization; while the relative standard deviation of the measurements was around 15% before standardization it could be decreased to less than 5% by gold standardization. Also quantitative information could be obtained for samples with unknown analyte concentrations. Depending on the used beam diameter limits of detection in the range of some hundreds ng g(-1) were achieved. The presented method is a promising and easy-to-handle alternative to matrix matched standards for signal quantification. PMID- 24473071 TI - pH- and sodium-induced changes in a sodium/proton antiporter. AB - We examined substrate-induced conformational changes in MjNhaP1, an archaeal electroneutral Na(+)/H(+)-antiporter resembling the human antiporter NHE1, by electron crystallography of 2D crystals in a range of physiological pH and Na(+) conditions. In the absence of sodium, changes in pH had no major effect. By contrast, changes in Na(+) concentration caused a marked conformational change that was largely pH-independent. Crystallographically determined, apparent dissociation constants indicated ~10-fold stronger Na(+) binding at pH 8 than at pH 4, consistent with substrate competition for a common ion-binding site. Projection difference maps indicated helix movements by about 2 A in the 6-helix bundle region of MjNhaP1 that is thought to contain the ion translocation site. We propose that these movements convert the antiporter from the proton-bound, outward-open state to the Na(+)-bound, inward-open state. Oscillation between the two states would result in rapid Na(+)/H(+) antiport. DOI: http://dx.doi.org/10.7554/eLife.01412.001. PMID- 24473072 TI - Single-molecule analysis reveals self assembly and nanoscale segregation of two distinct cavin subcomplexes on caveolae. AB - In mammalian cells three closely related cavin proteins cooperate with the scaffolding protein caveolin to form membrane invaginations known as caveolae. Here we have developed a novel single-molecule fluorescence approach to directly observe interactions and stoichiometries in protein complexes from cell extracts and from in vitro synthesized components. We show that up to 50 cavins associate on a caveola. However, rather than forming a single coat complex containing the three cavin family members, single-molecule analysis reveals an exquisite specificity of interactions between cavin1, cavin2 and cavin3. Changes in membrane tension can flatten the caveolae, causing the release of the cavin coat and its disassembly into separate cavin1-cavin2 and cavin1-cavin3 subcomplexes. Each of these subcomplexes contain 9 +/- 2 cavin molecules and appear to be the building blocks of the caveolar coat. High resolution immunoelectron microscopy suggests a remarkable nanoscale organization of these separate subcomplexes, forming individual striations on the surface of caveolae. DOI: http://dx.doi.org/10.7554/eLife.01434.001. PMID- 24473073 TI - Crystal structures of virus-like photosystem I complexes from the mesophilic cyanobacterium Synechocystis PCC 6803. AB - Oxygenic photosynthesis supports virtually all life forms on earth. Light energy is converted by two photosystems-photosystem I (PSI) and photosystem II (PSII). Globally, nearly 50% of photosynthesis takes place in the Ocean, where single cell cyanobacteria and algae reside together with their viruses. An operon encoding PSI was identified in cyanobacterial marine viruses. We generated a PSI that mimics the salient features of the viral complex, named PSI(PsaJF). PSI(PsaJF) is promiscuous for its electron donors and can accept electrons from respiratory cytochromes. We solved the structure of PSI(PsaJF) and a monomeric PSI, with subunit composition similar to the viral PSI, providing for the first time a detailed description of the reaction center and antenna system from mesophilic cyanobacteria, including red chlorophylls and cofactors of the electron transport chain. Our finding extends the understanding of PSI structure, function and evolution and suggests a unique function for the viral PSI. DOI: http://dx.doi.org/10.7554/eLife.01496.001. PMID- 24473074 TI - Earlier menarche is associated with a higher prevalence of Herpes simplex type-2 (HSV-2) in young women in rural Malawi. AB - Remarkably little is known about associations between age at menarche and sexually transmitted infections, although girls with earlier menarche tend to have earlier sexual debut and school drop-out, so an association might be expected. In a population-based survey of >3000 women aged 15-30 in northern Malawi we show that those with earlier menarche had earlier sexual debut, earlier marriage and were more often Herpes simplex type-2 (HSV-2) positive. Compared to those with menarche aged <14, the age-adjusted odds ratios for HSV-2 were 0.89 (95%CI 0.71-1.1), 0.71 (0.57-0.89) and 0.69 (0.54-0.89) for menarche aged 14, 15 and 16+ respectively. This association persisted after adjusting for socio economic factors, including schooling, and for sexual behaviour. No such association was seen with HIV infection, which is much less common and less uniformly distributed than HSV-2 in this population. The extra vulnerability of girls with earlier menarche needs to be recognised. DOI: http://dx.doi.org/10.7554/eLife.01604.001. PMID- 24473075 TI - Activation-triggered subunit exchange between CaMKII holoenzymes facilitates the spread of kinase activity. AB - The activation of the dodecameric Ca(2+)/calmodulin dependent kinase II (CaMKII) holoenzyme is critical for memory formation. We now report that CaMKII has a remarkable property, which is that activation of the holoenzyme triggers the exchange of subunits between holoenzymes, including unactivated ones, enabling the calcium-independent phosphorylation of new subunits. We show, using a single molecule TIRF microscopy technique, that the exchange process is triggered by the activation of CaMKII, and that exchange is modulated by phosphorylation of two residues in the calmodulin-binding segment, Thr 305 and Thr 306. Based on these results, and on the analysis of molecular dynamics simulations, we suggest that the phosphorylated regulatory segment of CaMKII interacts with the central hub of the holoenzyme and weakens its integrity, thereby promoting exchange. Our results have implications for an earlier idea that subunit exchange in CaMKII may have relevance for information storage resulting from brief coincident stimuli during neuronal signaling. DOI: http://dx.doi.org/10.7554/eLife.01610.001. PMID- 24473076 TI - A secreted Ustilago maydis effector promotes virulence by targeting anthocyanin biosynthesis in maize. AB - The biotrophic fungus Ustilago maydis causes smut disease in maize with characteristic tumor formation and anthocyanin induction. Here, we show that anthocyanin biosynthesis is induced by the virulence promoting secreted effector protein Tin2. Tin2 protein functions inside plant cells where it interacts with maize protein kinase ZmTTK1. Tin2 masks a ubiquitin-proteasome degradation motif in ZmTTK1, thus stabilizing the active kinase. Active ZmTTK1 controls activation of genes in the anthocyanin biosynthesis pathway. Without Tin2, enhanced lignin biosynthesis is observed in infected tissue and vascular bundles show strong lignification. This is presumably limiting access of fungal hyphae to nutrients needed for massive proliferation. Consistent with this assertion, we observe that maize brown midrib mutants affected in lignin biosynthesis are hypersensitive to U. maydis infection. We speculate that Tin2 rewires metabolites into the anthocyanin pathway to lower their availability for other defense responses. DOI: http://dx.doi.org/10.7554/eLife.01355.001. PMID- 24473077 TI - Cell type-specific and time-dependent light exposure contribute to silencing in neurons expressing Channelrhodopsin-2. AB - Channelrhodopsin-2 (ChR2) has quickly gained popularity as a powerful tool for eliciting genetically targeted neuronal activation. However, little has been reported on the response kinetics of optogenetic stimulation across different neuronal subtypes. With excess stimulation, neurons can be driven into depolarization block, a state where they cease to fire action potentials. Herein, we demonstrate that light-induced depolarization block in neurons expressing ChR2 poses experimental challenges for stable activation of specific cell types and may confound interpretation of experiments when 'activated' neurons are in fact being functionally silenced. We show both ex vivo and in vivo that certain neuronal subtypes targeted for ChR2 expression become increasingly susceptible to depolarization block as the duration of light pulses are increased. We find that interneuron populations have a greater susceptibility to this effect than principal excitatory neurons, which are more resistant to light-induced depolarization block. Our results highlight the need to empirically determine the photo-response properties of targeted neurons when using ChR2, particularly in studies designed to elicit complex circuit responses in vivo where neuronal activity will not be recorded simultaneous to light stimulation. DOI: http://dx.doi.org/10.7554/eLife.01481.001. PMID- 24473078 TI - How HIV-1 Nef hijacks the AP-2 clathrin adaptor to downregulate CD4. AB - The Nef protein of HIV-1 downregulates the cell surface co-receptor CD4 by hijacking the clathrin adaptor complex AP-2. The structural basis for the hijacking of AP-2 by Nef is revealed by a 2.9 A crystal structure of Nef bound to the alpha and sigma2 subunits of AP-2. Nef binds to AP-2 via its central loop (residues 149-179) and its core. The determinants for Nef binding include residues that directly contact AP-2 and others that stabilize the binding competent conformation of the central loop. Residues involved in both direct and indirect interactions are required for the binding of Nef to AP-2 and for downregulation of CD4. These results lead to a model for the docking of the full AP-2 tetramer to membranes as bound to Nef, such that the cytosolic tail of CD4 is situated to interact with its binding site on Nef. DOI: http://dx.doi.org/10.7554/eLife.01754.001. PMID- 24473079 TI - Single-molecule tracking of the transcription cycle by sub-second RNA detection. AB - Transcription is an inherently stochastic, noisy, and multi-step process, in which fluctuations at every step can cause variations in RNA synthesis, and affect physiology and differentiation decisions in otherwise identical cells. However, it has been an experimental challenge to directly link the stochastic events at the promoter to transcript production. Here we established a fast fluorescence in situ hybridization (fastFISH) method that takes advantage of intrinsically unstructured nucleic acid sequences to achieve exceptionally fast rates of specific hybridization (~10e7 M(-1)s(-1)), and allows deterministic detection of single nascent transcripts. Using a prototypical RNA polymerase, we demonstrated the use of fastFISH to measure the kinetic rates of promoter escape, elongation, and termination in one assay at the single-molecule level, at sub second temporal resolution. The principles of fastFISH design can be used to study stochasticity in gene regulation, to select targets for gene silencing, and to design nucleic acid nanostructures. DOI: http://dx.doi.org/10.7554/eLife.01775.001. PMID- 24473080 TI - Watching single molecules in action. AB - A fluorescent imaging technique called fastFISH has been used to track the various steps involved in the transcription of a single DNA molecule. PMID- 24473081 TI - Fish toxicity testing with selenomethionine spiked feed--what's the real question being asked? AB - The US Environmental Protection Agency and several U.S. states and Canadian provinces are currently developing national water quality criteria for selenium that are based in part on toxicity tests performed by feeding freshwater fish a selenomethionine-spiked diet. Using only selenomethionine to examine the toxicity of selenium is based in part on the limitations of the analytical chemistry methods commonly used in the 1990s and 2000s to speciate selenium in freshwater biota. While these methods provided a good starting point, recent improvements in analytical chemistry methodology have demonstrated that selenium speciation in biota is far more complex than originally thought. Here, we review the recent literature that suggests that there are numerous additional selenium species present in freshwater food chains and that the toxicities of these other selenium species, both individually and in combination, have not been evaluated in freshwater fishes. Evidence from studies on birds and mammals suggests that the other selenium forms differ in their metabolic pathways and toxicity from selenomethionine. Therefore, we conclude that toxicity testing using selenomethionine-spiked feed is only partly addressing the question "what is the toxicity of selenium to freshwater fishes?" and that using the results of these experiments to derive freshwater quality criteria may lead to biased water quality criteria. We also discuss additional studies that are needed in order to derive a more ecologically relevant freshwater quality criterion for selenium. PMID- 24473082 TI - A donor-acceptor-donor conjugated molecule: twist intramolecular charge transfer and piezochromic luminescent properties. AB - A donor-acceptor-donor molecule, , showed typical twist intramolecular charge transfer at the excited state and piezochromic property. XRD, DSC and computational researches revealed that the collapse of the crystalline structure upon applying pressure caused the piezochromic phenomenon, while the fluorescence was recovered by heating and solvent fuming. PMID- 24473083 TI - Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor. AB - A novel human coronavirus, Middle East respiratory syndrome coronavirus (MERS CoV), has caused outbreaks of a SARS-like illness with high case fatality rate. The reports of its person-to-person transmission through close contacts have raised a global concern about its pandemic potential. Here we characterize the six-helix bundle fusion core structure of MERS-CoV spike protein S2 subunit by X ray crystallography and biophysical analysis. We find that two peptides, HR1P and HR2P, spanning residues 998-1039 in HR1 and 1251-1286 in HR2 domains, respectively, can form a stable six-helix bundle fusion core structure, suggesting that MERS-CoV enters into the host cell mainly through membrane fusion mechanism. HR2P can effectively inhibit MERS-CoV replication and its spike protein-mediated cell-cell fusion. Introduction of hydrophilic residues into HR2P results in significant improvement of its stability, solubility and antiviral activity. Therefore, the HR2P analogues have good potential to be further developed into effective viral fusion inhibitors for treating MERS-CoV infection. PMID- 24473084 TI - Role of plasma membrane lipid composition on cellular homeostasis: learning from cell line models expressing fatty acid desaturases. AB - Experimental evidence has suggested that plasma membrane (PM)-associated signaling and hence cell metabolism and viability depend on lipid composition and organization. The aim of the present work is to develop a cell model to study the endogenous polyunsaturated fatty acids (PUFAs) effect on PM properties and analyze its influence on cholesterol (Chol) homeostasis. We have previously shown that by using a cell line over-expressing stearoyl-CoA-desaturase, membrane composition and organization coordinate cellular pathways involved in Chol efflux and cell viability by different mechanisms. Now, we expanded our studies to a cell model over-expressing both Delta5 and Delta6 desaturases, which resulted in a permanently higher PUFA content in PM. Furthermore, this cell line showed increased PM fluidity, Chol storage, and mitochondrial activity. In addition, human apolipoprotein A-I-mediated Chol removal was less efficient in these cells than in the corresponding control. Taken together, our results suggested that the cell functionality is preserved by regulating PM organization and Chol exportation and homeostasis. PMID- 24473085 TI - High throughput microinjections of sea urchin zygotes. AB - Microinjection into cells and embryos is a common technique that is used to study a wide range of biological processes. In this method a small amount of treatment solution is loaded into a microinjection needle that is used to physically inject individual immobilized cells or embryos. Despite the need for initial training to perform this procedure for high-throughput delivery, microinjection offers maximum efficiency and reproducible delivery of a wide variety of treatment solutions (including complex mixtures of samples) into cells, eggs or embryos. Applications to microinjections include delivery of DNA constructs, mRNAs, recombinant proteins, gain of function, and loss of function reagents. Fluorescent or colorimetric dye is added to the injected solution to enable instant visualization of efficient delivery as well as a tool for reliable normalization of the amount of the delivered solution. The described method enables microinjection of 100-400 sea urchin zygotes within 10-15 min. PMID- 24473086 TI - Loss of STAT3 in Lymphoma Relaxes NK Cell-Mediated Tumor Surveillance. AB - The transcription factors and proto-oncogenes STAT3 and STAT5 are highly activated in hematological malignancies and represent promising therapeutic targets. Whereas the importance of STAT5 as tumor promoter is beyond doubt, the role of STAT3 in hematological cancers is less well understood. Both, enforced as well as attenuated expression of STAT3 were reported in hematopoietic malignancies. Recent evidence implicates STAT3 as key player for tumor immune surveillance as it both mediates the production of and response to inflammatory cytokines. Here we investigated the effects of STAT3 deletion in a BCR/ABL induced lymphoma model, which is tightly controlled by natural killer (NK) cells in vivo. Upon STAT3 deletion tumor growth is significantly enhanced when compared to STAT3-expressing controls. The increased tumor size upon loss of STAT3 was accompanied by reduced NK cell infiltration and decreased levels of the cytokine IFN-gamma and the chemokine RANTES. Upon transplantation into NK cell-deficient mice differences in lymphoma size were abolished indicating that STAT3 expression in the tumor cells controls NK cell-dependent tumor surveillance. Our findings indicate that STAT3 inhibition in lymphoma patients will impair NK cell-mediated tumor surveillance, which needs to be taken into account when testing STAT3 inhibitors in preclinical or clinical trials. PMID- 24473087 TI - Combined effects of circulating levels of 25-hydroxyvitamin d and Th1 and th2 cytokines on breast cancer estrogen receptor status. AB - Vitamin D has been recognized for its immune-modulating properties. We have previously found that levels of 25OHD, and cytokines including IL5, IFNalpha2, and TNFalpha, are also associated with estrogen receptor (ER) negative breast cancer in younger women. Thus, we hypothesized that there may be interactions between vitamin D and the immune system in influencing breast cancer ER status, which was tested in 490 women with incident breast cancer. There was no correlation of the levels of 25OHD with any cytokine, and their associations with tumor ER negative status were independent of each other. However, premenopausal women with low 25OHD and high TNFalpha levels had the highest likelihood of having ER negative cancer (odds ratio [OR] = 7.32, 95% confidence interval [CI] = 2.44-21.98), with evidence of synergy between the two (relative excess risk due to interaction [RERI] = 5.46, p for additive interaction = 0.14, and p for multiplicative interaction = 0.09). There were similar synergistic associations between 25OHD and IL5, and several IFNalpha2 to Th2 cytokine ratios. This is the first study to provide evidence of interactions between vitamin D and the immune system in relation to breast cancer ER status, which may inform combinational use of vitamin D and anti-inflammatory drugs for cancer prevention and therapy. PMID- 24473088 TI - Glioblastoma multiforme: a look inside its heterogeneous nature. AB - Heterogeneity is a hallmark of tumors and has a crucial role in the outcome of the malignancy, because it not only confounds diagnosis, but also challenges the design of effective therapies. There are two types of heterogeneity: inter-tumor and intra-tumor heterogeneity. While inter-tumor heterogeneity has been studied widely, intra-tumor heterogeneity has been neglected even though numerous studies support this aspect of tumor pathobiology. The main reason has been the technical difficulties, but with new advances in single-cell technology, intra-tumor heterogeneity is becoming a key area in the study of cancer. Several models try to explain the origin and maintenance of intra-tumor heterogeneity, however, one prominent model compares cancer with a tree where the ubiquitous mutations compose the trunk and mutations present in subpopulations of cells are represented by the branches. In this review we will focus on the intra-tumor heterogeneity of glioblastoma multiforme (GBM), the most common brain tumor in adults that is characterized by a marked heterogeneity at the cellular and molecular levels. Better understanding of this heterogeneity will be essential to design effective therapies against this devastating disease to avoid tumor escape. PMID- 24473091 TI - Arsenic-induced promoter hypomethylation and over-expression of ERCC2 reduces DNA repair capacity in humans by non-disjunction of the ERCC2-Cdk7 complex. AB - Arsenic in drinking water is of critical concern in West Bengal, India, as it results in several physiological symptoms including dermatological lesions and cancers. Impairment of the DNA repair mechanism has been associated with arsenic induced genetic damage as well as with several cancers. ERCC2 (Excision Repair Cross-Complementing rodent repair, complementation group 2), mediates DNA-repair by interacting with Cdk-activating kinase (CAK) complex, which helps in DNA proof reading during transcription. Arsenic metabolism alters epigenetic regulation; we tried to elucidate the regulation of ERCC2 in arsenic-exposed humans. Water, urine, nails, hair and blood samples from one hundred and fifty seven exposed and eighty eight unexposed individuals were collected. Dose dependent validation was done in vitro using HepG2 and HEK-293. Arsenic content in the biological samples was higher in the exposed individuals compared with the content in unexposed individuals (p < 0.001). Bisulfite-modified methylation specific PCR showed a significant (p < 0.0001) hypomethylation of the ERCC2 promoter in the arsenic exposed individuals. Densitometric analysis of immunoblots showed a nearly two fold increase in expression of ERCC2 in exposed individuals, but there was an enhanced genotoxic insult as measured by micronuclei frequency. Immuno precipitation and western blotting revealed an increased (p < 0.001) association of Cdk7 with ERCC2 in highly arsenic exposed individuals. The decrease in CAK activity was determined by observing the intensity of Ser(392) phosphorylation in p53, in vitro, which decreased with an increase in arsenic dose. Thus we infer that arsenic biotransformation leads to promoter hypomethylation of ERCC2, which in turn inhibits the normal functioning of the CAK-complex, thus affecting DNA repair; this effect was highest among the arsenic exposed individuals with dermatological lesions. PMID- 24473090 TI - Chronic Inflammation: Synergistic Interactions of Recruiting Macrophages (TAMs) and Eosinophils (Eos) with Host Mast Cells (MCs) and Tumorigenesis in CALTs. M CSF, Suitable Biomarker for Cancer Diagnosis! AB - Ongoing debates, misunderstandings and controversies on the role of inflammation in cancer have been extremely costly for taxpayers and cancer patients for over four decades. A reason for repeated failed clinical trials (90% +/- 5 failure rates) is heavy investment on numerous genetic mutations (molecular false-flags) in the chaotic molecular landscape of site-specific cancers which are used for "targeted" therapies or "personalized" medicine. Recently, unresolved/chronic inflammation was defined as loss of balance between two tightly regulated and biologically opposing arms of acute inflammation ("Yin"-"Yang" or immune surveillance). Chronic inflammation could differentially erode architectural integrities in host immune-privileged or immune-responsive tissues as a common denominator in initiation and progression of nearly all age-associated neurodegenerative and autoimmune diseases and/or cancer. Analyses of data on our "accidental" discoveries in 1980s on models of acute and chronic inflammatory diseases in conjunctival-associated lymphoid tissues (CALTs) demonstrated at least three stages of interactions between resident (host) and recruited immune cells: (a), acute phase; activation of mast cells (MCs), IgE Abs, histamine and prostaglandin synthesis; (b), intermediate phase; down-regulation phenomenon, exhausted/degranulated MCs, heavy eosinophils (Eos) infiltrations into epithelia and goblet cells (GCs), tissue hypertrophy and neovascularization; and (c), chronic phase; induction of lymphoid hyperplasia, activated macrophages (Mfs), increased (irregular size) B and plasma cells, loss of integrity of lymphoid tissue capsular membrane, presence of histiocytes, follicular and germinal center formation, increased ratios of local IgG1/IgG2, epithelial thickening (growth) and/or thinning (necrosis) and angiogenesis. Results are suggestive of first evidence for direct association between inflammation and identifiable phases of immune dysfunction in the direction of tumorigenesis. Activated MFs (TAMs or M2) and Eos that are recruited by tissues (e.g., conjunctiva or perhaps lung airways) whose principal resident immune cells are MCs and lymphocytes are suggested to play crucial synergistic roles in enhancing growth promoting capacities of host toward tumorigenesis. Under oxidative stress, M-CSF may produce signals that are cumulative/synergistic with host mediators (e.g., low levels of histamine), facilitating tumor-directed expression of decoy receptors and immune suppressive factors (e.g., dTNFR, IL-5, IL-10, TGF-b, PGE2). M-CSF, possessing superior sensitivity and specificity, compared with conventional markers (e.g., CA-125, CA 19-9) is potentially a suitable biomarker for cancer diagnosis and technology development. Systematic monitoring of interactions between resident and recruited cells should provide key information not only about early events in loss of immune surveillance, but it would help making informed decisions for balancing the inherent tumoricidal (Yin) and tumorigenic (Yang) properties of immune system and effective preventive and therapeutic approaches and accurate risk assessment toward improvement of public health. PMID- 24473092 TI - The unexpected activity of Pd nanoparticles prepared using a non-ionic surfactant template. AB - Pd deposits on vitreous carbon substrates were prepared by electrodeposition from liquid crystal phases (both micellar and hexagonal phases) consisting of self assembled non-ionic surfactant molecules. The morphology of the deposits varied significantly with the concentration of the surfactant but all are made up of aggregated nanoparticles circa 9 nm in diameter. The deposits from the micellar phase of the surfactant offer the largest electroactive area and specific activity for the hydrogen evolution, oxygen evolution and reduction reactions and formic acid and ethanol oxidations. Unexpectedly the deposits lead to an increase in catalytic activity far in excess of that expected from an enhancement in electroactive area. PMID- 24473094 TI - Study on interaction of cationic porphyrazine with synthetic polynucleotides. AB - Interactions of cationic tetrakis (N, N', N", N'''- tetramethyltetra-3, 4 pyridinoporphyrazinatozinc (II) (Zn (tmtppa)) with synthetic polynucleotides, poly (G-C) and poly (A-T), and calf thymus DNA have been characterized in 7.5 mM phosphate buffer of pH 7.2 by UV-Vis absorption and fluorescence spectroscopy. The appearance of hypochromicity more than 30% in UV-Vis spectra of porphyrazine due to interaction of both poly (G-C) and poly (A-T) indicates interaction similar to that of porphyrazine with DNA. The binding constants were determined from the changes in the Q-band maximum of the porphyrazine spectra at various poly (G-C) and DNA concentrations. The values of K were 2.5*106 M-1, 2.5*106 M-1 and 2.5*105 M-1 for poly (G-C), poly (A-T) and DNA, respectively, at 25 degrees C. The thermodynamic parameters (DeltaG degrees , DeltaH degrees , DeltaS degrees ) were calculated using the van't Hoff equation at various temperatures. The enthalpy and entropy changes were determined to be 41.14 kJ mol-1 and 260.50 J mol-1.K-1 for poly (G-C) and 53.59 kJ mol-1 and 285.46 J mol-1.K-1 for DNA at 25 degrees C. The positive and large values of the entropy and enthalpy suggest that both hydrophobic and electrostatic interactions may play an important role in the stabilization of the complex formation. The binding of polynucleotides to porphyrazine quenches fluorescence emission of ethidium bromide (EB), and the quenching process obeys linear Stern-Volmer relationship. The results reviled groove-binding mode of porphyrazine for both AT- and GC-rich polynucleotides of DNA. PMID- 24473093 TI - Parkinson's disease, lights and melanocytes: looking beyond the retina. AB - Critical analysis of recent research suggesting that light pollution causes Parkinson's disease (PD) reveals that such a hypothesis is unsustainable in the context of therapeutic use of light in treating various neuropsychiatric conditions. Reinterpretation of their findings suggests that retinal damage caused by prolonged light exposure may have contributed to the observed enhancement of experimental PD. To test this hypothesis further, forty-two Sprague Dawley rats received microinjections of 6-hydroxydopamine (6-OHDA), 1 methyl-4-phenyl-2, 4, 6-tetrahydropyridine (MPTP), paraquat or rotenone into the vitreal mass in doses so minute that the effects could not be attributed to diffusion into brain. Significant changes in five motor parameters consistent with symptoms of experimental PD were observed. These findings support the interpretation that the retina is involved in the control of motor function and in the aetiology of PD. PMID- 24473095 TI - Brain mechanisms underlying the effects of aging on different aspects of selective attention. AB - The ability to suppress irrelevant information declines with age, while the ability to enhance relevant information remains largely intact. We examined mechanisms behind this dissociation in an fMRI study, using a selective attention task in which relevant and irrelevant information appeared simultaneously. Slowing of response times due to distraction by irrelevant targets was larger in older than younger participants. Increased distraction was related to larger increases in activity and connectivity in areas of the dorsal attention network, indicating a more pronounced (re-)orientation of attention. The decreases in accuracy in target compared to nontarget trials were smaller in older compared to younger participants. In older adults we found increased recruitment of areas in the fronto-parietal control network (FPCN) during target detection. Moreover, older adults showed increased connectivity between the FPCN, supporting cognitive control, and somatomotor areas implicated in response selection and execution. This connectivity increase was related to improved target detection, suggesting that older adults engage additional cognitive control, which might enable the observed intact performance in detecting and responding to target stimuli. PMID- 24473089 TI - Gelatinase B/MMP-9 in Tumour Pathogenesis and Progression. AB - Since its original identification as a leukocyte gelatinase/type V collagenase and tumour type IV collagenase, gelatinase B/matrix metalloproteinase (MMP)-9 is now recognised as playing a central role in many aspects of tumour progression. In this review, we relate current concepts concerning the many ways in which gelatinase B/MMP-9 influences tumour biology. Following a brief outline of the gelatinase B/MMP-9 gene and protein, we analyse the role(s) of gelatinase B/MMP-9 in different phases of the tumorigenic process, and compare the importance of gelatinase B/MMP-9 source in the carcinogenic process. What becomes apparent is the importance of inflammatory cell-derived gelatinase B/MMP-9 in tumour promotion, early progression and triggering of the "angiogenic switch", the integral relationship between inflammatory, stromal and tumour components with respect to gelatinase B/MMP-9 production and activation, and the fundamental role for gelatinase B/MMP-9 in the formation and maintenance of tumour stem cell and metastatic niches. It is also apparent that gelatinase B/MMP-9 plays important tumour suppressing functions, producing endogenous angiogenesis inhibitors, promoting inflammatory anti-tumour activity, and inducing apoptosis. The fundamental roles of gelatinase B/MMP-9 in cancer biology underpins the need for specific therapeutic inhibitors of gelatinase B/MMP-9 function, the use of which must take into account and substitute for tumour-suppressing gelatinase B/MMP-9 activity and also limit inhibition of physiological gelatinase B/MMP-9 function. PMID- 24473096 TI - To imitate or not: Avoiding imitation involves preparatory inhibition of motor resonance. AB - Stimulus-response compatibility (SRC)-the fact that some stimulus-response pairs are faster than others-is attributed in part to automatic activation of the stimulus-compatible response representation. Cognitive models of SRC propose that automatic response activation can be strategically suppressed if the automatic response is likely to interfere with behavior; in particular, suppression is thought to occur in preparation for incompatible responses and when the required stimulus-response mapping is unknown before stimulus presentation. We test this preparatory suppression hypothesis in the context of imitation, a special form of SRC particularly relevant to human social behavior. Using TMS, we measured muscle specific corticospinal excitability during action observation (motor resonance) while human participants prepared to perform imitative and counterimitative responses to action videos. Motor resonance was suppressed during preparation to counterimitate and for unknown mappings, compared to preparation to imitate and a baseline measure of motor resonance. These results provide novel neurophysiological evidence that automatic activation of stimulus-compatible responses can be strategically suppressed when the automatic response is likely to interfere with task goals. Insofar as motor resonance measures mirror neuron system activity, these results also suggest that preparatory control of automatic imitative tendencies occurs through modulation of mirror neuron system activity. PMID- 24473097 TI - Resting-state cortical connectivity predicts motor skill acquisition. AB - Many studies have examined brain states in an effort to predict individual differences in the capacity for learning, with overall moderate results. The present study investigated how measures of cortical network function acquired at rest using dense-array EEG (256 leads) predict subsequent acquisition of a new motor skill. Brain activity was recorded in 17 healthy young subjects during 3min of wakeful rest prior to a single motor skill training session on a digital version of the pursuit rotor task. Practice was associated with significant gains in task performance (% time on target increased from 24% to 41%, p<0.0001). Using a partial least squares regression (PLS) model, coherence with the region of the left primary motor area (M1) in resting EEG data was a strong predictor of motor skill acquisition (R(2)=0.81 in a leave-one-out cross-validation analysis), exceeding the information provided by baseline behavior and demographics. Within this PLS model, greater skill acquisition was predicted by higher connectivity between M1 and left parietal cortex, possibly reflecting greater capacity for visuomotor integration, and by lower connectivity between M1 and left frontal premotor areas, possibly reflecting differences in motor planning strategies. EEG coherence, which reflects functional connectivity, predicts individual motor skill acquisition with a level of accuracy that is remarkably high compared to prior reports using EEG or fMRI measures. PMID- 24473099 TI - Toward a brain functional connectivity mapping modality by simultaneous imaging of coherent brainwaves. AB - Matching the proton-magnetic-resonance frequency to the frequency of a periodic neural oscillation (e.g., alpha or gamma band waves) by magnetic resonance imaging techniques, enables direct visualization of brain functional connectivity. Functional connectivity has been studied by analyzing the correlation between coherent neural oscillations in different areas of the brain. In electro- or magneto-encephalography, coherent source reconstruction in a source-space is very tricky due to power leaking from the correlation among the sources. For this reason, most studies have been limited to sensor-space analyses, which give doubtful results because of volume current mixing. The direct visualization of coherent brain oscillations can circumvent this problem. The feasibility of this idea was demonstrated by conducting phantom experiments with a SQUID-based, micro-Tesla NMR/MRI system. We introduce an experimental trick, an effective step-up of the measurement B-field in a pulse sequence, to decouple the magnetic resonance signal from the strong magneto-encephalographic signal at the same frequency. PMID- 24473098 TI - The neural bases underlying social risk perception in purchase decisions. AB - Social considerations significantly influence daily purchase decisions, and the perception of social risk (i.e., the anticipated disapproval of others) is crucial in dissuading consumers from making purchases. However, the neural basis for consumers' perception of social risk remains undiscovered, and this novel study clarifies the relevant neural processes. A total of 26 volunteers were scanned while they evaluated purchase intention of products (purchase intention task) and their anticipation of others' disapproval for possessing a product (social risk task), using functional magnetic resonance imaging (fMRI). The fMRI data from the purchase intention task was used to identify the brain region associated with perception of social risk during purchase decision making by using subjective social risk ratings for a parametric modulation analysis. Furthermore, we aimed to explore if there was a difference between participants' purchase decisions and their explicit evaluations of social risk, with reference to the neural activity associated with social risk perception. For this, subjective social risk ratings were used for a parametric modulation analysis on fMRI data from the social risk task. Analysis of the purchase intention task revealed a significant positive correlation between ratings of social risk and activity in the anterior insula, an area of the brain that is known as part of the emotion-related network. Analysis of the social risk task revealed a significant positive correlation between ratings of social risk and activity in the temporal parietal junction and the medial prefrontal cortex, which are known as theory-of-mind regions. Our results suggest that the anterior insula processes consumers' social risk implicitly to prompt consumers not to buy socially unacceptable products, whereas ToM-related regions process such risk explicitly in considering the anticipated disapproval of others. These findings may prove helpful in understanding the mental processes involved in purchase decisions. PMID- 24473100 TI - Differential contributions of the superior and inferior parietal cortex to feedback versus feedforward control of tools. AB - Damage to the superior and/or inferior parietal lobules (SPL, IPL) (Sirigu et al., 1996) or cerebellum (Grealy and Lee, 2011) can selectively disrupt motor imagery, motivating the hypothesis that these regions participate in predictive (i.e., feedforward) control. If so, then the SPL, IPL, and cerebellum should show greater activity as the demands on feedforward control increase from visually guided execution (closed-loop) to execution without visual feedback (open-loop) to motor imagery. Using fMRI and a Fitts' reciprocal aiming task with tools directed at targets in far space, we found that the SPL and cerebellum exhibited greater activity during closed-loop control. Conversely, open-loop and imagery conditions were associated with increased activity within the IPL and prefrontal areas. These results are consistent with a superior-to-inferior gradient in the representation of feedback-to-feedforward control within the posterior parietal cortex. Additionally, the anterior SPL displayed greater activity when aiming movements were performed with a stick vs. laser pointer. This may suggest that it is involved in the remapping of far into near (reachable) space (Maravita and Iriki, 2004), or in distalization of the end-effector from hand to stick (Arbib et al., 2009). PMID- 24473101 TI - Sequential inhibitory control processes assessed through simultaneous EEG-fMRI. AB - Inhibitory response control has been extensively investigated in both electrophysiological (ERP) and hemodynamic (fMRI) studies. However, very few multimodal results address the coupling of these inhibition markers. In fMRI, response inhibition has been most consistently linked to activation of the anterior insula and inferior frontal cortex (IFC), often also the anterior cingulate cortex (ACC). ERP work has established increased N2 and P3 amplitudes during NoGo compared to Go conditions in most studies. Previous simultaneous EEG fMRI imaging reported association of the N2/P3 complex with activation of areas like the anterior midcingulate cortex (aMCC) and anterior insula. In this study we investigated inhibitory control in 23 healthy young adults (mean age=24.7, n=17 for EEG during fMRI) using a combined Flanker/NoGo task during simultaneous EEG and fMRI recording. Separate fMRI and ERP analysis yielded higher activation in the anterior insula, IFG and ACC as well as increased N2 and P3 amplitudes during NoGo trials in accordance with the literature. Combined analysis modelling sequential N2 and P3 effects through joint parametric modulation revealed correlation of higher N2 amplitude with deactivation in parts of the default mode network (DMN) and the cingulate motor area (CMA) as well as correlation of higher central P3 amplitude with activation of the left anterior insula, IFG and posterior cingulate. The EEG-fMRI results resolve the localizations of these sequential activations. They suggest a general role for allocation of attentional resources and motor inhibition for N2 and link memory recollection and internal reflection to P3 amplitude, in addition to previously described response inhibition as reflected by the anterior insula. PMID- 24473102 TI - Automatic quantification of normal cortical folding patterns from fetal brain MRI. AB - We automatically quantify patterns of normal cortical folding in the developing fetus from in utero MR images (N=80) over a wide gestational age (GA) range (21.7 to 38.9weeks). This work on data from healthy subjects represents a first step towards characterising abnormal folding that may be related to pathology, facilitating earlier diagnosis and intervention. The cortical boundary was delineated by automatically segmenting the brain MR image into a number of key structures. This utilised a spatio-temporal atlas as tissue priors in an expectation-maximization approach with second order Markov random field (MRF) regularization to improve the accuracy of the cortical boundary estimate. An implicit high resolution surface was then used to compute cortical folding measures. We validated the automated segmentations with manual delineations and the average surface discrepancy was of the order of 1mm. Eight curvature-based folding measures were computed for each fetal cortex and used to give summary shape descriptors. These were strongly correlated with GA (R(2)=0.99) confirming the close link between neurological development and cortical convolution. This allowed an age-dependent non-linear model to be accurately fitted to the folding measures. The model supports visual observations that, after a slow initial start, cortical folding increases rapidly between 25 and 30weeks and subsequently slows near birth. The model allows the accurate prediction of fetal age from an observed folding measure with a smaller error where growth is fastest. We also analysed regional patterns in folding by parcellating each fetal cortex using a nine-region anatomical atlas and found that Gompertz models fitted the change in lobar regions. Regional differences in growth rate were detected, with the parietal and posterior temporal lobes exhibiting the fastest growth, while the cingulate, frontal and medial temporal lobes developed more slowly. PMID- 24473103 TI - Electronic modification of Pt via Ti and Se as tolerant cathodes in air-breathing methanol microfluidic fuel cells. AB - We reported herein on the use of tolerant cathode catalysts such as carbon supported Pt(x)Ti(y) and/or Pt(x)Se(y) nanomaterials in an air-breathing methanol microfluidic fuel cell. In order to show the improvement of mixed-reactant fuel cell (MRFC) performances obtained with the developed tolerant catalysts, a classical Pt/C nanomaterial was used for comparison. Using 5 M methanol concentration in a situation where the fuel crossover is 100% (MRFC-mixed reactant fuel cell application), the maximum power density of the fuel cell with a Pt/C cathodic catalyst decreased by 80% in comparison with what is observed in the laminar flow fuel cell (LFFC) configuration. With Pt(x)Ti(y)/C and Pt(x)Se(y)/C cathode nanomaterials, the performance loss was only 55% and 20%, respectively. The evaluation of the tolerant cathode catalysts in an air breathing microfluidic fuel cell suggests the development of a novel nanometric system that will not be size restricted. These interesting results are the consequence of the high methanol tolerance of these advanced electrocatalysts via surface electronic modification of Pt. Herein we used X-ray photoelectron and in situ FTIR spectroscopies to investigate the origin of the high methanol tolerance on modified Pt catalysts. PMID- 24473104 TI - Development of a bio-analytical strategy for characterization of vaccine particles combining SEC and nanoES GEMMA. AB - Commonly used methods for size and shape analysis of bionanoparticles found in vaccines like X-ray crystallography and cryo-electron microscopy are very time consuming and cost-intensive. The nano-electrospray (nanoES) gas-phase electrophoretic mobility macromolecular analyzer (GEMMA), belonging to the group of ion mobility spectrometers, was used for size determination of vaccine virus particles because it requires less analysis time and investment (no vacuum system). Size exclusion chromatography (SEC) of viral vaccines and production intermediates turned out to be a good purification/isolation method prior to GEMMA, TEM (transmission electron microscopy) and AFM (atomic force microscopy) investigations, as well as providing a GEMMA analysis-compatible buffer. Column materials and different elution buffers were tested for optimal vaccine particle yield. We used a Superdex 200 column with a 50 mM ammonium acetate buffer. In addition, SEC allowed the removal of process-related impurities from the virions of interest. A sample concentrating step or a detergent addition step was also investigated. As a final step of our strategy SEC-purified or untreated vaccine nanoparticles were further analyzed: (a) by immunological detection with a specific polyclonal antibody (dot blot) to verify the biological functionality, (b) by GEMMA to provide the size of the particles at atmospheric pressure and (c) by AFM and (d) TEM to obtain both size and shape information. The mean diameter of inactivated tick-borne encephalitis virions (i.e. vaccine particles) determined by GEMMA measurement was 46.6 +/- 0.5 nm, in contrast to AFM and TEM images providing diameters of about 58 +/- 4 and 52 +/- 5 nm, respectively. PMID- 24473105 TI - Recent progress towards transition metal-catalyzed synthesis of gamma-lactams. AB - The occurrence of the gamma-lactam unit in the framework of various biologically active compounds has greatly contributed to the design and development of new synthetic transformations to access this important structural motif. Among the numerous methods developed so far, those based on transition metal catalysis are of high value as they generally allow efficient and selective access to functionalized gamma-lactams under rather mild reaction conditions. An overview of the recent advances in this field is presented herein. Metal-catalyzed processes are reviewed by highlighting their specificity and applicability, and the mechanistic rationale is presented where possible. PMID- 24473106 TI - Caring letters for suicide prevention: implementation of a multi-site randomized clinical trial in the U.S. military and Veteran Affairs healthcare systems. AB - Caring letters is a suicide prevention intervention that entails the sending of brief messages that espouse caring concern to patients following discharge from treatment. First tested more than four decades ago, this intervention is one of the only interventions shown in a randomized controlled trial to reduce suicide mortality rates. Due to elevated suicide risk among patients following psychiatric hospitalization and the steady increase in suicide rates among the U.S. military personnel, it is imperative to test interventions that may help prevent suicide among high-risk military personnel and veterans. This paper describes the design, methods, study protocol, and regulatory implementation processes for a multi-site randomized controlled trial that aims to evaluate the effectiveness of a caring emails intervention for suicide prevention in the military and VA healthcare systems. The primary outcome is suicide mortality rates to be determined 24 months post-discharge from index hospital stay. Healthcare re-utilization rates will also be evaluated and comprehensive data will be collected regarding suicide risk factors. Recommendations for navigating the military and VA research regulatory processes and implementing a multi-site clinical trial at military and VA hospitals are discussed. PMID- 24473107 TI - An improved method for the preparation of type I collagen from skin. AB - Soluble type 1 collagen (COL1) is used extensively as an adhesive substrate for cell cultures and as a cellular scaffold for regenerative applications. Clinically, this protein is widely used for cosmetic surgery, dermal injections, bone grafting, and reconstructive surgery. The sources of COL1 for these procedures are commonly nonhuman, which increases the potential for inflammation and rejection as well as xenobiotic disease transmission. In view of this, a method to efficiently and quickly purify COL1 from limited quantities of autologously-derived tissues would circumvent many of these issues; however, standard isolation protocols are lengthy and often require large quantities of collagenous tissues. Here, we demonstrate an efficient COL1 extraction method that reduces the time needed to isolate and purify this protein from about 10 days to less than 3 hr. We chose the dermis as our tissue source because of its availability during many surgical procedures. This method uses traditional extraction buffers combined with forceful agitation and centrifugal filtration to obtain highly-pure, soluble COL1 from small amounts of corium. Briefly, dermal biopsies are washed thoroughly in ice-cold dH2O after removing fat, connective tissue, and hair. The skin samples are stripped of noncollagenous proteins and polysaccharides using 0.5 M sodium acetate and a high speed bench-top homogenizer. Collagen from residual solids is subsequently extracted with a 0.075 M sodium citrate buffer using the homogenizer. These extracts are purified using 100,000 MW cut-off centrifugal filters that yield COL1 preparations of comparable or superior quality to commercial products or those obtained using traditional procedures. We anticipate this method will facilitate the utilization of autologously-derived COL1 for a multitude of research and clinical applications. PMID- 24473108 TI - 4'-O-substitutions determine selectivity of aminoglycoside antibiotics. AB - Clinical use of 2-deoxystreptamine aminoglycoside antibiotics, which target the bacterial ribosome, is compromised by adverse effects related to limited drug selectivity. Here we present a series of 4',6'-O-acetal and 4'-O-ether modifications on glucopyranosyl ring I of aminoglycosides. Chemical modifications were guided by measuring interactions between the compounds synthesized and ribosomes harbouring single point mutations in the drug-binding site, resulting in aminoglycosides that interact poorly with the drug-binding pocket of eukaryotic mitochondrial or cytosolic ribosomes. Yet, these compounds largely retain their inhibitory activity for bacterial ribosomes and show antibacterial activity. Our data indicate that 4'-O-substituted aminoglycosides possess increased selectivity towards bacterial ribosomes and little activity for any of the human drug-binding pockets. PMID- 24473109 TI - Diesel exhaust exposure and the risk of lung cancer--a review of the epidemiological evidence. AB - To critically evaluate the association between diesel exhaust (DE) exposure and the risk of lung cancer, we conducted a systematic review of published epidemiological evidences. To comprehensively identify original studies on the association between DE exposure and the risk of lung cancer, literature searches were performed in literature databases for the period between 1970 and 2013, including bibliographies and cross-referencing. In total, 42 cohort studies and 32 case-control studies were identified in which the association between DE exposures and lung cancer was examined. In general, previous studies suffer from a series of methodological limitations, including design, exposure assessment methods and statistical analysis used. A lack of objective exposure information appears to be the main problem in interpreting epidemiological evidence. To facilitate the interpretation and comparison of previous studies, a job-exposure matrix (JEM) of DE exposures was created based on around 4,000 historical industrial measurements. The values from the JEM were considered during interpretation and comparison of previous studies. Overall, neither cohort nor case-control studies indicate a clear exposure-response relationship between DE exposure and lung cancer. Epidemiological studies published to date do not allow a valid quantification of the association between DE and lung cancer. PMID- 24473110 TI - How do people in rural India perceive improved stoves and clean fuel? Evidence from Uttar Pradesh and Uttarakhand. AB - Improved cook stoves (ICS) have been widely touted for their potential to deliver the triple benefits of improved household health and time savings, reduced deforestation and local environmental degradation, and reduced emissions of black carbon, a significant short-term contributor to global climate change. Yet diffusion of ICS technologies among potential users in many low-income settings, including India, remains slow, despite decades of promotion. This paper explores the variation in perceptions of and preferences for ICS in Uttar Pradesh and Uttarakhand, as revealed through a series of semi-structured focus groups and interviews from 11 rural villages or hamlets. We find cautious interest in new ICS technologies, and observe that preferences for ICS are positively related to perceptions of health and time savings. Other respondent and community characteristics, e.g., gender, education, prior experience with clean stoves and institutions promoting similar technologies, and social norms as perceived through the actions of neighbours, also appear important. Though they cannot be considered representative, our results suggest that efforts to increase adoption and use of ICS in rural India will likely require a combination of supply-chain improvements and carefully designed social marketing and promotion campaigns, and possibly incentives, to reduce the up-front cost of stoves. PMID- 24473111 TI - Influences of satisfaction with telecare and family trust in older Taiwanese people. AB - The level of trust given towards telecare by the family members of older people using the service is extremely important. Family trust may be an influential factor in deciding whether to use such services. This study focuses on older people's satisfaction with telecare and examines their family's trust in telecare services. Influences on intention to continue using telecare services are also explored. A questionnaire-based survey on 60 communities dwelling older people who had been receiving telecare services in the past two years was employed. This study developed a satisfaction and trust scale based on previous studies. Our results show that older people's satisfaction with telecare services and families' trust were influential in decided whether to continue to use of telecare services. These findings can help medical institutions to better insight into the user experience of telecare to help them provide future services that better comply with clients' desires and requirements. PMID- 24473112 TI - Detection of potential drug-drug interactions for outpatients across hospitals. AB - The National Health Insurance Administration (NHIA) has adopted smart cards (or NHI-IC cards) as health cards to carry patients' medication histories across hospitals in Taiwan. The aims of this study are to enhance a computerized physician order entry system to support drug-drug interaction (DDI) checking based on a patient's medication history stored in his/her NHI-IC card. For performance evaluation, we developed a transaction tracking log to keep track of every operation on NHI-IC cards. Based on analysis of the transaction tracking log from 1 August to 31 October 2007, physicians read patients' NHI-IC cards in 71.01% (8,246) of patient visits; 33.02% (2,723) of the card reads showed at least one medicine currently being taken by the patient, 82.94% of which were prescribed during the last visit. Among 10,036 issued prescriptions, seven prescriptions (0.09%) contained at least one drug item that might interact with the currently-taken medicines stored in NHI-IC cards and triggered pop-up alerts. This study showed that the capacity of an NHI-IC card is adequate to support DDI checking across hospitals. Thus, the enhanced computerized physician order entry (CPOE) system can support better DDI checking when physicians are making prescriptions and provide safer medication care, particularly for patients who receive medication care from different hospitals. PMID- 24473113 TI - The health heterogeneity of and health care utilization by the elderly in Taiwan. AB - A good understanding of the health heterogeneity of elderly people, their characteristics, patterns of health care utilization and subsequent expenditures is necessary to adequately evaluate the policy options and interventions aimed at improving quality and efficiency of care for older people. This article reviews studies that used Latent Class Analysis to identify four health profiles among elderly people in Taiwan: High Comorbidity (HC), Functional Impairment (FI), Frail (FR), and Relatively Healthy (RH). Variables associated with increased likelihood of being in the FR group were older age, female gender, and living with one's family, and these also correlated with ethnicity and level of education. The HC group tended to use more ambulatory care services compared with those in the RH group. The HC group tended to be younger, better educated, and was more likely to live in urban areas than were people in the FI group. The FI group, apart from age and gender, was less likely be of Hakka ethnicity and more likely to live with others than were individuals in the RH group. The FI group had relatively high probabilities of needing assistance, and the FR group had higher healthcare expenditures. A person-centered approach would better satisfy current healthcare needs of elderly people and help forecast future expenditures. PMID- 24473114 TI - Airborne particulate matter in school classrooms of northern Italy. AB - Indoor size-fractioned particulate matter (PM) was measured in seven schools in Milan, to characterize their concentration levels in classrooms, compare the measured concentrations with the recommended guideline values, and provide a preliminary assessment of the efficacy of the intervention measures, based on the guidelines developed by the Italian Ministry of Healthand applied to mitigate exposure to undesirable air pollutants. Indoor sampling was performed from Monday morning to Friday afternoon in three classrooms of each school and was repeated in winter 2011-2012 and 2012-2013. Simultaneously, PM2.5 samples were also collected outdoors. Two different photometers were used to collect the PM continuous data, which were corrected a posteriori using simultaneous gravimetric PM2.5 measurements. Furthermore, the concentrations of carbon dioxide (CO2) were monitored and used to determine the Air Exchange Rates in the classrooms. The results revealed poor IAQ in the school environment. In several cases, the PM2.5 and PM10 24 h concentrations exceeded the 24 h guideline values established by the World Health Organization (WHO). In addition, the indoor CO2 levels often surpassed the CO2 ASHRAE Standard. Our findings confirmed that important indoor sources (human movements, personal clouds, cleaning activities) emitted coarse particles, markedly increasing the measured PM during school hours. In general, the mean PM2.5 indoor concentrations were lower than the average outdoor PM2.5 levels, with I/O ratios generally <1. Fine PM was less affected by indoor sources, exerting a major impact on the PM1-2.5 fraction. Over half of the indoor fine particles were estimated to originate from outdoors. To a first approximation, the intervention proposed to reduce indoor particle levels did not seem to significantly influence the indoor fine PM concentrations. Conversely, the frequent opening of doors and windows appeared to significantly contribute to the reduction of the average indoor CO2 levels. PMID- 24473115 TI - Arylesterase phenotype-specific positive association between arylesterase activity and cholinesterase specific activity in human serum. AB - CONTEXT: Cholinesterase (ChE) specific activity is the ratio of ChE activity to ChE mass and, as a biomarker of exposure to cholinesterase inhibitors, has a potential advantage over simple ChE activity. OBJECTIVE: To examine the association of several potential correlates (serum arylesterase/paraoxonase activity, serum albumin, sex, age, month of blood collection, and smoking) with plasma ChE specific activity. METHODS: We analyzed data from 195 cancer-free controls from a nested case-control study, accounting for potential confounding. RESULTS: Arylesterase activity had an independent, statistically significant positive association with ChE specific activity, and its magnitude was the greatest for the arylesterase phenotype corresponding to the QQ PON1192 genotype followed by phenotypes corresponding to QR and RR genotypes. Serum albumin was positively associated with ChE specific activity. CONCLUSIONS: Plasma arylesterase activity was positively associated with plasma ChE specific activity. This observation is consistent with protection conferred by a metabolic phenotype resulting in reduced internal dose. PMID- 24473116 TI - Understanding older adults' usage of community green spaces in Taipei, Taiwan. AB - As the world's population ages, there is an increasing need for community environments to support physical activity and social connections for older adults. This exploratory study sought to better understand older adults' usage and perceptions of community green spaces in Taipei, Taiwan, through direct observations of seven green spaces and nineteen structured interviews. Descriptive statistics from observations using the System for Observing Play and Recreation in Communities (SOPARC) confirm that older adults use Taipei's parks extensively. Our analyses of interviews support the following recommendations for age-friendly active living initiatives for older adults: make green spaces accessible to older adults; organize a variety of structured activities that appeal to older adults particularly in the morning; equip green spaces for age appropriate physical activity; and, promote the health advantages of green spaces to older adults. PMID- 24473117 TI - Identifying recently acquired HIV infections among newly diagnosed men who have sex with men attending STI clinics in The Netherlands. AB - OBJECTIVES: The current surveillance system in The Netherlands cannot differentiate recent HIV infections from established infections, which is crucial for estimating the HIV incidence; this information is needed for assessing trends of the HIV epidemic and the impact of prevention interventions. We determined the proportion of recent HIV infections (RI) and estimated HIV incidence using a recent infection testing algorithm (RITA) among men who have sex with men (MSM) newly diagnosed as having HIV attending sexually transmitted infection (STI) clinics. METHODS: Plasma samples collected between 2009 and 2011 were tested for RI with the Architect HIV Ag/Ab Combo immunoassay. Data on viral load, CD4 count and previous HIV testing were incorporated into the RITA. HIV incidence and 95% CIs were estimated. Logistic regression was used to identify factors associated with RI. RESULTS: Of the 251 samples tested for RI, 78/251 (31%) infections were determined as recent by the RITA. No significant change over time was observed. The estimated HIV incidence in this high-risk MSM population was 3.3 per 100 person-years (95% CI 2.5 to 4.1). The only factor associated with RI in the multivariable model was being tested for HIV >= 3 times in the past (aOR=7.4; 95% CI 2.0 to 27.8). CONCLUSIONS: The proportion of RIs was comparable to studies in similar settings in Europe. Implementation of the RITA for routine surveillance in The Netherlands to assess trends in RIs over time, to study the infections in other groups and to inform public health actions, is being planned. PMID- 24473118 TI - The interplay between hypoxia, endothelial and melanoma cells regulates vascularization and cell motility through endothelin-1 and vascular endothelial growth factor. AB - Reciprocal growth factor exchanges between endothelial and malignant cells within the hypoxic microenvironment determine tumor progression. However, the nature of these exchanges has not yet been fully explored. We studied the mutual regulation between endothelial cells (EC), melanoma cells and hypoxia that dictate tumor aggressiveness and angiogenic activity. Here, we investigated the presence of bidirectional autocrine/paracrine endothelin (ET)-1/ET receptor (ETBR) signaling in melanoma cells, blood and lymphatic EC. In all these cells, hypoxia enhanced ET-1 expression, which in turn induced vascular endothelial growth factor (VEGF) A and VEGF-C secretion, through the hypoxia-inducible growth factor (HIF)-1alpha and HIF-2alpha. Autocrine/paracrine exchanges of ET-1, VEGF-A and VEGF-C promoted tumor aggressiveness and morphological changes in blood and lymphatic EC. Furthermore, conditioned media from EC enhanced melanoma cell migration and vessel-like channel formation. This regulation was inhibited by ETBR blockade, by using the selective ETBR antagonist, or ETBR small interfering RNA (siRNA), and by VEGFR-2/-3 antibodies, indicating that ET-1, VEGF-A/VEGF-C, produced by melanoma cells or EC mediated inter-regulation between these cells. Interestingly, HIF-1alpha/HIF-2alpha siRNA, impaired this reciprocal regulation, demonstrating the key role of these transcriptional factors in signaling exchanges. In melanoma xenografts, the ETBR antagonist reduced tumor growth and the number of blood and lymphatic vessels. These results reveal an interplay between melanoma cells and EC mediated by ET-1 and VEGF-A/-C and coordinated by the hypoxic microenvironment through HIF-1alpha/2alpha transcriptional programs. Thus, targeting ETBR may improve melanoma treatment for tumor and EC, by inhibiting autocrine/paracrine signaling that sustains melanoma progression. PMID- 24473119 TI - Schools-based interventions for reducing stigmatization of acquired brain injury: the role of interpersonal contact and visible impairment. AB - The purpose of this study was to determine the effectiveness of contact versus education interventions for adolescents in reducing stigmatizing attitudes toward people with acquired brain injury (ABI), and whether visibility of ABI affects the intervention outcome. 408 students (age range = 14-17 years) from 13 schools in the Mid-West of Ireland were randomly allocated to one of the three interventions: Education only, Contact (Visible Disability), or Contact ("Invisible" Disability). Stigmatizing attitudes were measured before and after intervention. Results suggest that a Contact intervention was more effective in reducing stigmatizing attitudes in terms of social restrictiveness, benevolence, and community mental health beliefs than education alone. Visibility of ABI impacted the effectiveness of the contact intervention on Community Mental Health beliefs only. Contact with a person with ABI is thus more effective in promoting positive attitudes than ABI education alone, while the presence of visible impairment was not found to increase this intervention effect. PMID- 24473120 TI - Animation shows promise in initiating timely cardiopulmonary resuscitation: results of a pilot study. AB - Delayed responses during cardiac arrest are common. Timely interventions during cardiac arrest have a direct impact on patient survival. Integration of technology in nursing education is crucial to enhance teaching effectiveness. The goal of this study was to investigate the effect of animation on nursing students' response time to cardiac arrest, including initiation of timely chest compression. Nursing students were randomized into experimental and control groups prior to practicing in a high-fidelity simulation laboratory. The experimental group was educated, by discussion and animation, about the importance of starting cardiopulmonary resuscitation upon recognizing an unresponsive patient. Afterward, a discussion session allowed students in the experimental group to gain more in-depth knowledge about the most recent changes in the cardiac resuscitation guidelines from the American Heart Association. A linear mixed model was run to investigate differences in time of response between the experimental and control groups while controlling for differences in those with additional degrees, prior code experience, and basic life support certification. The experimental group had a faster response time compared with the control group and initiated timely cardiopulmonary resuscitation upon recognition of deteriorating conditions (P < .0001). The results demonstrated the efficacy of combined teaching modalities for timely cardiopulmonary resuscitation. Providing opportunities for repetitious practice when a patient's condition is deteriorating is crucial for teaching safe practice. PMID- 24473121 TI - The informatics nurse specialist role in electronic health record usability evaluation. AB - Health information technology is revolutionizing the way we interact with health related data. One example of this can be seen in the rising adoption rates of electronic health records by healthcare providers. Nursing plays a vital role in electronic health record adoption, not only because of their numbers but also their intimate understanding of workflow. The success of an electronic health record also relies on how usable the software is for clinicians, and a thorough usability evaluation is needed before implementing a system within an organization. Not all nurses have the knowledge and skills to perform extensive usability testing; therefore, the informatics nurse specialist plays a critical role in the process. This article will discuss core usability principles, provide a framework for applying these concepts, and explore the role of the informatics nurse specialist in electronic health record evaluation. Health information technology is fundamentally changing the clinical practice environment, and many nurses are seeking leadership positions in the field of informatics. As technology and software become more sophisticated, usability principles must be used under theguidance of the informatics nurse specialist to provide a relevant, robust, and well-designed electronic health record to address the needs of the busy clinician. PMID- 24473122 TI - Denovo malignant fibrous histiocytoma of breast: report of a case and review of literature. AB - Sarcomas are rare histological types of malignancy found in the breast. While angiosarcoma is the most common type of sarcoma found here, malignant fibrous histiocytoma (MFH) arising de novo is one of the rare varieties. We recently cared for a middle aged lady with a locally advanced fungating growth in her right breast. The patient underwent right modified radical mastectomy (MRM) as her fine needle aspiration cytology report was suggestive of malignancy. The histopathological report revealed the tumour to be MFH. The patient had an uneventful postoperative recovery and is subjected to adjuvant radiotherapy. PMID- 24473124 TI - Long-range photoinduced electron transfer dynamics in rigid media. AB - In semi-rigid PEG-DMA550 films with added reductive quenchers, electron transfer quenching of the metal-to-ligand charge transfer excited state(s) of [Ru(bpy)3](2+) (bpy = 2,2'-bipyridine) occurs by both rapid, fixed-site, and slow, diffusional, quenching processes. Stern-Volmer analysis of diffusional quenching reveals diffusion-controlled quenching both in the fluid and film with the latter greatly inhibited by the high viscosity of the medium. The data for fixed-site quenching are consistent with electron tunneling with the expected exponential distance dependence. Based on this analysis long-range electron transfer occurs with a distance attenuation factor beta of ~0.47 A(-1) with a notable decrease, beta = 0.16 A(-1), when the quencher is incorporated into the PEG backbone. Fixed-site electron transfer quenching varies with driving force. Back electron transfer is complex, as expected for a distribution of fixed sites, and varies with power law kinetics. PMID- 24473123 TI - Arsenic-induced suppression of kidney cell proliferation and the transcriptional coregulator MAML1. AB - Mastermind-like 1 (MAML1) is a transcriptional coregulator of diverse/multiple activators, such as Notch, p53, myocyte enhancer factor 2C, NF-kappaB, beta catenin, papillomavirus E6 proteins, early growth response 1 and runt-related transcription factor 2. Thus, MAML1 functions in various signaling pathways, most of them connected to cell proliferation, which suggests that MAML1 might play a potential role as a cell proliferation marker. In this study we show that MAML1 expression in the kidney correlates in silico with established cell proliferation markers including PCNA, CDC2 and XRCC5 (Ku80). Over-expression of MAML1 increased proliferation of human embryonic kidney (HEK) 293 cells, while MAML1 downregulation by siRNA decreased cell proliferation. Exposure of HEK293 cells to inorganic arsenic (arsenite) showed reduced levels of MAML1, in combination with a decreased proliferation rate. Our findings provide evidence that arsenic can inhibit proliferation of embryonic kidney cells, possibly through reduction of MAML1 gene expression. PMID- 24473125 TI - Efficacy of an abbreviated induction regimen of amphotericin B deoxycholate for cryptococcal meningoencephalitis: 3 days of therapy is equivalent to 14 days. AB - Cryptococcal meningoencephalitis is an urgent global health problem. Induction regimens using 14 days of amphotericin B deoxycholate (dAmB) are considered the standard of care but may not be suitable for resource-poor settings. We investigated the efficacy of conventional and abbreviated regimens of dAmB for cryptococcal meningoencephalitis in both murine and rabbit models of cryptococcal meningoencephalitis. We examined the extent to which immunological effectors contribute to the antifungal effect. We bridged the results to humans as a first critical step to define regimens suitable for further study in clinical trials. There were significant differences in the murine plasma-versus-cerebrum dAmB concentration-time profiles. dAmB was detectable in the cerebrum throughout the experimental period, even following the administration of only three doses of 3 mg/kg. dAmB induced a fungistatic effect in the cerebrum with a 2- to 3-log10 CFU/g reduction compared with controls. The effect of 3 days of therapy was the same as that of daily therapy for 14 days. There was no evidence of increased numbers of CD3(+) CD4(+) or CD3(+) CD8(+) cells in treated mice to account for the persistent antifungal effect of an abbreviated regimen. The administration of dAmB at 1 mg/kg/day for 3 days was the same as daily therapy in rabbits. The bridging studies suggested that a human regimen of 0.7 mg/kg/day for 3 days resulted in nearly maximal antifungal activity in both the cerebrum and cerebrospinal fluid. An abbreviated regimen (3 days of therapy) of dAmB appears to be just as effective as conventional induction therapy for cryptococcal meningoencephalitis. IMPORTANCE: Cryptococcal meningitis is a significant and neglected infection that is associated with excessive morbidity and mortality. In well-resourced health care settings, induction therapy with at least 2 weeks of amphotericin B deoxycholate (dAmB) is advocated. Multiple clinical studies suggest that dAmB is the drug of choice for cryptococcal meningitis. In many parts of the world where the burden of cryptococcal meningitis is highest, it is infeasible to administer dAmB for prolonged periods. This paper provides the experimental basis for the efficacy of abbreviated regimens of dAmB for cryptococcal meningitis. The concept was explored in two well-validated laboratory animal models of cryptococcal meningitis, and the results were bridged to humans by using a range of mathematical modeling techniques. A 3-day regimen is as effective as the standard 14-day course. An abbreviated regimen is significantly more feasible and may enable better antifungal therapy to be administered to many patients with this frequently lethal disease. PMID- 24473126 TI - CRISPR-Cas functional module exchange in Escherichia coli. AB - Clustered regularly interspaced short palindromic repeats (CRISPR) and CRISPR associated (cas) genes constitute the CRISPR-Cas systems found in the Bacteria and Archaea domains. At least in some strains they provide an efficient barrier against transmissible genetic elements such as plasmids and viruses. Two CRISPR Cas systems have been identified in Escherichia coli, pertaining to subtypes I-E (cas-E genes) and I-F (cas-F genes), respectively. In order to unveil the evolutionary dynamics of such systems, we analyzed the sequence variations in the CRISPR-Cas loci of a collection of 131 E. coli strains. Our results show that the strain grouping inferred from these CRISPR data slightly differs from the phylogeny of the species, suggesting the occurrence of recombinational events between CRISPR arrays. Moreover, we determined that the primary cas-E genes of E. coli were altogether replaced with a substantially different variant in a minor group of strains that include K-12. Insertion elements play an important role in this variability. This result underlines the interchange capacity of CRISPR-Cas constituents and hints that at least some functional aspects documented for the K 12 system may not apply to the vast majority of E. coli strains. IMPORTANCE: Escherichia coli is a model microorganism for the study of diverse aspects such as microbial evolution and is a component of the human gut flora that may have a direct impact in everyday life. This work was undertaken with the purpose of elucidating the evolutionary pathways that have led to the present situation of its significantly different CRISPR-Cas subtypes (I-E and I-F) in several strains of E. coli. In doing so, this information offers a novel and wider understanding of the variety and relevance of these regions within the species. Therefore, this knowledge may provide clues helping researchers better understand these systems for typing purposes and make predictions of their behavior in strains that, depending on their particular genetic dotation, would result in different levels of immunity to foreign genetic elements. PMID- 24473127 TI - Live-cell imaging of phosphoinositide dynamics and membrane architecture during Legionella infection. AB - The causative agent of Legionnaires' disease, Legionella pneumophila, replicates in amoebae and macrophages in a distinct membrane-bound compartment, the Legionella-containing vacuole (LCV). LCV formation is governed by the bacterial Icm/Dot type IV secretion system that translocates ~300 different "effector" proteins into host cells. Some of the translocated effectors anchor to the LCV membrane via phosphoinositide (PI) lipids. Here, we use the soil amoeba Dictyostelium discoideum, producing fluorescent PI probes, to analyze the LCV PI dynamics by live-cell imaging. Upon uptake of wild-type or Icm/Dot-deficient L. pneumophila, PtdIns(3,4,5)P3 transiently accumulated for an average of 40 s on early phagosomes, which acquired PtdIns(3)P within 1 min after uptake. Whereas phagosomes containing DeltaicmT mutant bacteria remained decorated with PtdIns(3)P, more than 80% of wild-type LCVs gradually lost this PI within 2 h. The process was accompanied by a major rearrangement of PtdIns(3)P-positive membranes condensing to the cell center. PtdIns(4)P transiently localized to early phagosomes harboring wild-type or DeltaicmT L. pneumophila and was cleared within minutes after uptake. During the following 2 h, PtdIns(4)P steadily accumulated only on wild-type LCVs, which maintained a discrete PtdIns(4)P identity spatially separated from calnexin-positive endoplasmic reticulum (ER) for at least 8 h. The separation of PtdIns(4)P-positive and ER membranes was even more pronounced for LCVs harboring DeltasidC-sdcA mutant bacteria defective for ER recruitment, without affecting initial bacterial replication in the pathogen vacuole. These findings elucidate the temporal and spatial dynamics of PI lipids implicated in LCV formation and provide insight into host cell membrane and effector protein interactions. IMPORTANCE: The environmental bacterium Legionella pneumophila is the causative agent of Legionnaires' pneumonia. The bacteria form in free-living amoebae and mammalian immune cells a replication-permissive compartment, the Legionella-containing vacuole (LCV). To subvert host cell processes, the bacteria secrete the amazing number of ~300 different proteins into host cells. Some of these proteins bind phosphoinositide (PI) lipids to decorate the LCV. PI lipids are crucial factors involved in host cell membrane dynamics and LCV formation. Using Dictyostelium amoebae producing one or two distinct fluorescent probes, we elucidated the dynamic LCV PI pattern in high temporal and spatial resolution. Notably, the endocytic PI lipid PtdIns(3)P was slowly cleared from LCVs, thus incapacitating the host cell's digestive machinery, while PtdIns(4)P gradually accumulated on the LCV, enabling critical interactions with host organelles. The LCV PI pattern underlies the spatiotemporal configuration of bacterial effector proteins and therefore represents a crucial aspect of LCV formation. PMID- 24473128 TI - Comprehensive functional analysis of N-linked glycans on Ebola virus GP1. AB - Ebola virus (EBOV) entry requires the virion surface-associated glycoprotein (GP) that is composed of a trimer of heterodimers (GP1/GP2). The GP1 subunit contains two heavily glycosylated domains, the glycan cap and the mucin-like domain (MLD). The glycan cap contains only N-linked glycans, whereas the MLD contains both N- and O-linked glycans. Site-directed mutagenesis was performed on EBOV GP1 to systematically disrupt N-linked glycan sites to gain an understanding of their role in GP structure and function. All 15 N-glycosylation sites of EBOV GP1 could be removed without compromising the expression of GP. The loss of these 15 glycosylation sites significantly enhanced pseudovirion transduction in Vero cells, which correlated with an increase in protease sensitivity. Interestingly, exposing the receptor-binding domain (RBD) by removing the glycan shield did not allow interaction with the endosomal receptor, NPC1, indicating that the glycan cap/MLD domains mask RBD residues required for binding. The effects of the loss of GP1 N-linked glycans on Ca(2+)-dependent (C-type) lectin (CLEC)-dependent transduction were complex, and the effect was unique for each of the CLECs tested. Surprisingly, EBOV entry into murine peritoneal macrophages was independent of GP1 N-glycans, suggesting that CLEC-GP1 N-glycan interactions are not required for entry into this important primary cell. Finally, the removal of all GP1 N-glycans outside the MLD enhanced antiserum and antibody sensitivity. In total, our results provide evidence that the conserved N-linked glycans on the EBOV GP1 core protect GP from antibody neutralization despite the negative impact the glycans have on viral entry efficiency. IMPORTANCE: Filovirus outbreaks occur sporadically throughout central Africa, causing high fatality rates among the general public and health care workers. These unpredictable hemorrhagic fever outbreaks are caused by multiple species of Ebola viruses, as well as Marburg virus. While filovirus vaccines and therapeutics are being developed, there are no licensed products. The sole viral envelope glycoprotein, which is a principal immunogenic target, contains a heavy shield of glycans surrounding the conserved receptor-binding domain. We find that disruption of this shield through targeted mutagenesis leads to an increase in cell entry, protease sensitivity, and antiserum/antibody sensitivity but is not sufficient to allow virion binding to the intracellular receptor NPC1. Therefore, our studies provide evidence that filoviruses maintain glycoprotein glycosylation to protect against proteases and antibody neutralization at the expense of efficient entry. Our results unveil interesting insights into the unique entry process of filoviruses and potential immune evasion tactics of the virus. PMID- 24473129 TI - Programmable removal of bacterial strains by use of genome-targeting CRISPR-Cas systems. AB - CRISPR (clustered regularly interspaced short palindromic repeats)-Cas (CRISPR associated) systems in bacteria and archaea employ CRISPR RNAs to specifically recognize the complementary DNA of foreign invaders, leading to sequence-specific cleavage or degradation of the target DNA. Recent work has shown that the accidental or intentional targeting of the bacterial genome is cytotoxic and can lead to cell death. Here, we have demonstrated that genome targeting with CRISPR Cas systems can be employed for the sequence-specific and titratable removal of individual bacterial strains and species. Using the type I-E CRISPR-Cas system in Escherichia coli as a model, we found that this effect could be elicited using native or imported systems and was similarly potent regardless of the genomic location, strand, or transcriptional activity of the target sequence. Furthermore, the specificity of targeting with CRISPR RNAs could readily distinguish between even highly similar strains in pure or mixed cultures. Finally, varying the collection of delivered CRISPR RNAs could quantitatively control the relative number of individual strains within a mixed culture. Critically, the observed selectivity and programmability of bacterial removal would be virtually impossible with traditional antibiotics, bacteriophages, selectable markers, or tailored growth conditions. Once delivery challenges are addressed, we envision that this approach could offer a novel means to quantitatively control the composition of environmental and industrial microbial consortia and may open new avenues for the development of "smart" antibiotics that circumvent multidrug resistance and differentiate between pathogenic and beneficial microorganisms. IMPORTANCE: Controlling the composition of microbial populations is a critical aspect in medicine, biotechnology, and environmental cycles. While different antimicrobial strategies, such as antibiotics, antimicrobial peptides, and lytic bacteriophages, offer partial solutions, what remains elusive is a generalized and programmable strategy that can distinguish between even closely related microorganisms and that allows for fine control over the composition of a microbial population. This study demonstrates that RNA directed immune systems in bacteria and archaea called CRISPR-Cas systems can provide such a strategy. These systems can be employed to selectively and quantitatively remove individual bacterial strains based purely on sequence information, creating opportunities in the treatment of multidrug-resistant infections, the control of industrial fermentations, and the study of microbial consortia. PMID- 24473130 TI - Metabolite changes signal genetic regulatory mechanisms for robust cell behavior. AB - Exploiting mechanisms of utilizing the sugar d-galactose in Escherichia coli as a model system, we explored the consequences of accumulation of critical intermediates of the d-galactose metabolic pathways by monitoring cell growth, metabolites, and transcript profiles. These studies revealed both metabolic network changes far from the d-galactose pathway and changes in the global gene regulatory network. The concentration change of a critical intermediate disturbs the equilibrium state, generating a ripple effect through several metabolic pathways that ends up signaling up- or downregulation of specific sets of genes in a programmed manner to cope with the imbalance. Such long-range effects on metabolites and genetic regulatory mechanisms not only may be a common feature in bacteria but very likely operate during cellular development and differentiation in higher organisms as well as in disease cells, like cancer cells. IMPORTANCE: Metabolite accumulation can create adverse intracellular conditions that are relieved by compensatory immediate changes of metabolite pools and later changes of transcript levels. It has been known that gene expression is normally regulated by added catabolic substrates (induction) or anabolic end products (repression). It is becoming apparent now that change in the concentration of metabolic intermediates also plays a critical role in genetic regulatory networks for metabolic homeostasis. Our study provides new insight into how metabolite pool changes transduce signals to global gene regulatory networks. PMID- 24473131 TI - Microbial sulfur cycle in two hydrothermal chimneys on the Southwest Indian Ridge. AB - Sulfur is an important element in sustaining microbial communities present in hydrothermal vents. Sulfur oxidation has been extensively studied due to its importance in chemosynthetic pathways in hydrothermal fields; however, less is known about sulfate reduction. Here, the metagenomes of hydrothermal chimneys located on the ultraslow-spreading Southwest Indian Ridge (SWIR) were pyrosequenced to elucidate the associated microbial sulfur cycle. A taxonomic summary of known genes revealed a few dominant bacteria that participated in the microbial sulfur cycle, particularly sulfate-reducing Deltaproteobacteria. The metagenomes studied contained highly abundant genes related to sulfur oxidation and reduction. Several carbon metabolic pathways, in particular the Calvin-Benson Bassham pathway and the reductive tricarboxylic acid cycles for CO2 fixation, were identified in sulfur-oxidizing autotrophic bacteria. In contrast, highly abundant genes related to the oxidation of short-chain alkanes were grouped with sulfate-reducing bacteria, suggesting an important role for short-chain alkanes in the sulfur cycle. Furthermore, sulfur-oxidizing bacteria were associated with enrichment for genes involved in the denitrification pathway, while sulfate reducing bacteria displayed enrichment for genes responsible for hydrogen utilization. In conclusion, this study provides insights regarding major microbial metabolic activities that are driven by the sulfur cycle in low temperature hydrothermal chimneys present on an ultraslow midocean ridge. IMPORTANCE: There have been limited studies on chimney sulfides located at ultraslow-spreading ridges. The analysis of metagenomes of hydrothermal chimneys on the ultraslow-spreading Southwest Indian Ridge suggests the presence of a microbial sulfur cycle. The sulfur cycle should be centralized within a microbial community that displays enrichment for sulfur metabolism-related genes. The present study elucidated a significant role of the microbial sulfur cycle in sustaining an entire microbial community in low-temperature hydrothermal chimneys on an ultraslow spreading midocean ridge, which has characteristics distinct from those of other types of hydrothermal fields. PMID- 24473132 TI - Identification of a membrane-bound transcriptional regulator that links chitin and natural competence in Vibrio cholerae. AB - Vibrio cholerae is naturally competent when grown on chitin. It is known that expression of the major regulator of competence, TfoX, is controlled by chitin; however, the molecular mechanisms underlying this requirement for chitin have remained unclear. In the present study, we identify and characterize a membrane bound transcriptional regulator that positively regulates the small RNA (sRNA) TfoR, which posttranscriptionally enhances tfoX translation. We show that this regulation of the tfoR promoter is direct by performing electrophoretic mobility shift assays and by heterologous expression of this system in Escherichia coli. This transcriptional regulator was recently identified independently and was named "TfoS" (S. Yamamoto et al., Mol. Microbiol., in press, doi:10.1111/mmi.12462). Using a constitutively active form of TfoS, we demonstrate that the activity of this regulator is sufficient to promote competence in V. cholerae in the absence of chitin. Also, TfoS contains a large periplasmic domain, which we hypothesized interacts with chitin to regulate TfoS activity. In the heterologous host E. coli, we demonstrate that chitin oligosaccharides are sufficient to activate TfoS activity at the tfoR promoter. Collectively, these data characterize TfoS as a novel chitin-sensing transcriptional regulator that represents the direct link between chitin and natural competence in V. cholerae. IMPORTANCE Naturally competent bacteria can take up exogenous DNA from the environment and integrate it into their genome by homologous recombination. This ability to take up exogenous DNA is shared by diverse bacterial species and serves as a mechanism to acquire new genes to enhance the fitness of the organism. Several members of the family Vibrionaceae become naturally competent when grown on chitin; however, a molecular understanding of how chitin activates competence is lacking. Here, we identify a novel membrane-bound transcriptional regulator that is required for natural transformation in the human pathogen Vibrio cholerae. We demonstrate that this regulator senses chitin oligosaccharides to activate the competence cascade, thus, uncovering the molecular link between chitin and natural competence in this Vibrio species. PMID- 24473133 TI - Moth caterpillar solicits for homopteran honeydew. AB - A life-history in which an organism depends on ants is called myrmecophily. Among Lepidoptera (moths and butterflies), many species of lycaenid butterflies are known to show myrmecophily at the larval stage. Descriptions of myrmecophily among moth species, however, are very few and fragmentary. Here, we report the ant-associated behaviour of the tiny Japanese arctiid moth, Nudina artaxidia. Field observations revealed that the moth larvae associate with the jet black ant, Lasius (Dendrolasius) spp. The larvae, which we observed only near ant trails, showed an ability to follow the trails. Further, they solicit honeydew from ant-attended scale insects, without suffering attacks by the ants protecting the scale insects. These suggest that N. artaxidia is a myrmecophilous moth wholly dependent on ants and ant-attended homopterans. Considering the overwhelmingly plant-feeding habits of moth caterpillars, this discovery ranks in novelty with the discovery of the Hawaiian carnivorous moth larvae that stalk snails. PMID- 24473135 TI - Conducting miller-urey experiments. AB - In 1953, Stanley Miller reported the production of biomolecules from simple gaseous starting materials, using an apparatus constructed to simulate the primordial Earth's atmosphere-ocean system. Miller introduced 200 ml of water, 100 mmHg of H2, 200 mmHg of CH4, and 200 mmHg of NH3 into the apparatus, then subjected this mixture, under reflux, to an electric discharge for a week, while the water was simultaneously heated. The purpose of this manuscript is to provide the reader with a general experimental protocol that can be used to conduct a Miller-Urey type spark discharge experiment, using a simplified 3 L reaction flask. Since the experiment involves exposing inflammable gases to a high voltage electric discharge, it is worth highlighting important steps that reduce the risk of explosion. The general procedures described in this work can be extrapolated to design and conduct a wide variety of electric discharge experiments simulating primitive planetary environments. PMID- 24473136 TI - Structural and optical properties of nanoscale Galinobisuitite thin films. AB - Galinobisuitite thin films of (Bi2S3)(PbS) were prepared using the chemical bath deposition technique (CBD). Thin films were prepared by a modified chemical deposition process by allowing the triethanolamine (TEA) complex of Bi(3+) and Pb(2+) to react with S(2)- ions, which are released slowly by the dissociation of the thiourea (TU) solution. The films are polycrystalline and the average crystallite size is 35 nm. The composition of the films was measured using the atomic absorption spectroscopy (AAS) technique. The films are very adherent to the substrates. The crystal structure of Galinobisuitite thin films was calculated by using the X-ray diffraction (XRD) technique. The surface morphology and roughness of the films were studied using scanning electron microscopes (SEM), transmission electron microscopes (TEM) and stylus profilers respectively. The optical band gaps of the films were estimated from optical measurements. PMID- 24473137 TI - In silico identification and characterization of N-Terminal acetyltransferase genes of poplar (Populus trichocarpa). AB - N-terminal acetyltransferase (Nats) complex is responsible for protein N-terminal acetylation (Nalpha-acetylation), which is one of the most common covalent modifications of eukaryotic proteins. Although genome-wide investigation and characterization of Nat catalytic subunits (CS) and auxiliary subunits (AS) have been conducted in yeast and humans they remain unexplored in plants. Here we report on the identification of eleven genes encoding eleven putative Nat CS polypeptides, and five genes encoding five putative Nat AS polypeptides in Populus. We document that the expansion of Nat CS genes occurs as duplicated blocks distributed across 10 of the 19 poplar chromosomes, likely only as a result of segmental duplication events. Based on phylogenetic analysis, poplar Nat CS were assigned to six subgroups, which corresponded well to the Nat CS types (CS of Nat A-F), being consistent with previous reports in humans and yeast. In silico analysis of microarray data showed that in the process of normal development of the poplar, their Nat CS and AS genes are commonly expressed at one relatively low level but share distinct tissue-specific expression patterns. This exhaustive survey of Nat genes in poplar provides important information to assist future studies on their functional role in poplar. PMID- 24473139 TI - Proteomic profiling of cytosolic glutathione transferases from three bivalve species: Corbicula fluminea, Mytilus galloprovincialis and Anodonta cygnea. AB - Suspension-feeding bivalves are considered efficient toxin vectors with a relative insensitivity to toxicants compared to other aquatic organisms. This fact highlights the potential role of detoxification enzymes, such as glutathione transferases (GSTs), in this bivalve resistance. Nevertheless, the GST system has not been extensively described in these organisms. In the present study, cytosolic GSTs isoforms (cGST) were surveyed in three bivalves with different habitats and life strategies: Corbicula fluminea, Anodonta cygnea and Mytilus galloprovincialis. GSTs were purified by glutathione-agarose affinity chromatography, and the collection of expressed cGST classes of each bivalve were identified using a proteomic approach. All the purified extracts were also characterized kinetically. Results reveal variations in cGST subunits collection (diversity and properties) between the three tested bivalves. Using proteomics, four pi-class and two sigma-class GST subunits were identified in M. galloprovincialis. C. fluminea also yielded four pi-class and one sigma-class GST subunits. For A. cygnea, two mu-class and one pi-class GST subunits were identified, these being the first record of GSTs from these freshwater mussels. The affinity purified extracts also show differences regarding enzymatic behavior among species. The variations found in cGST collection and kinetics might justify diverse selective advantages for each bivalve organism. PMID- 24473140 TI - The self-assembled behavior of DNA bases on the interface. AB - A successful example of self-assembly in a biological system is that DNA can be an excellent agent to self-assemble into desirable two and three-dimensional nanostructures in a well-ordered manner by specific hydrogen bonding interactions between the DNA bases. The self-assembly of DNA bases have played a significant role in constructing the hierarchical nanostructures. In this review article we will introduce the study of nucleic acid base self-assembly by scanning tunneling microscopy (STM) at vacuum and ambient condition (the liquid/solid interface), respectively. From the ideal condition to a more realistic environment, the self assembled behaviors of DNA bases are introduced. In a vacuum system, the energetic advantages will dominate the assembly formation of DNA bases, while at ambient condition, more factors such as conformational freedom and the biochemical environment will be considered. Therefore, the assemblies of DNA bases at ambient condition are different from the ones obtained under vacuum. We present the ordered nanostructures formed by DNA bases at both vacuum and ambient condition. To construct and tailor the nanostructure through the interaction between DNA bases, it is important to understand the assembly behavior and features of DNA bases and their derivatives at ambient condition. The utilization of STM offers the advantage of investigating DNA base self-assembly with sub molecular level resolution at the surface. PMID- 24473138 TI - Antioxidant drug therapy approaches for neuroprotection in chronic diseases of the retina. AB - The molecular pathways contributing to visual signal transduction in the retina generate a high energy demand that has functional and structural consequences such as vascularization and high metabolic rates contributing to oxidative stress. Multiple signaling cascades are involved to actively regulate the redox state of the retina. Age-related processes increase the oxidative load, resulting in chronically elevated levels of oxidative stress and reactive oxygen species, which in the retina ultimately result in pathologies such as glaucoma or age related macular degeneration, as well as the neuropathic complications of diabetes in the eye. Specifically, oxidative stress results in deleterious changes to the retina through dysregulation of its intracellular physiology, ultimately leading to neurodegenerative and potentially also vascular dysfunction. Herein we will review the evidence for oxidative stress-induced contributions to each of the three major ocular pathologies, glaucoma, age related macular degeneration, and diabetic retinopathy. The premise for neuroprotective strategies for these ocular disorders will be discussed in the context of recent clinical and preclinical research pursuing novel therapy development approaches. PMID- 24473141 TI - beta-Conglycinin reduces the tight junction occludin and ZO-1 expression in IPEC J2. AB - Soybean allergy presents a health threat to humans and animals. The mechanism by which food/feed allergen beta-conglycinin injures the intestinal barrier has not been well understood. In this study, the changes of epithelial permeability, integrity, metabolic activity, the tight junction (TJ) distribution and expression induced by beta-conglycinin were evaluated using IPEC-J2 model. The results showed a significant decrease of trans-epithelial electrical resistance (TEER) (p < 0.001) and metabolic activity (p < 0.001) and a remarkable increase of alkaline phosphatase (AP) activity (p < 0.001) in a dose-dependent manner. The expression levels of tight junction occludin and ZO-1 were decreased (p < 0.05). The reduced fluorescence of targets and change of cellular morphology were recorded. The tight junction occludin and ZO-1 mRNA expression linearly declined with increasing beta-conglycinin (p < 0.001). PMID- 24473142 TI - Elevated Th22 cells correlated with Th17 cells in peripheral blood of patients with acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is a hematological tumor in which progress T helper (Th) subsets including Th22, Th17, and Th1 cells play a pivotal role. However, the role of T helper (Th) subsets in the immune pathogenesis of AML remains unclear. Here, we investigated frequencies of Th22, Th17, pure Th17, and Th1 cells in the peripheral blood (PB) of AML patients. We demonstrated that Th22, Th17, and pure Th17 in newly-diagnosed (ND) and non-complete remission (Non-CR) AML patients and plasma IL-22 in ND AML patients were significantly increased. Retinoid-related orphan receptor C (RORC) expression was significantly elevated in CR and Non-CR AML patients. However, Th1 in ND AML patients and IL-17 in ND, Non-CR or CR AML patients was significantly decreased compared with controls. Moreover, Th22 and IL-22 showed positive correlation with pure Th17, but Th22 showed negative correlation with Th1 in ND AML patients. RORC showed positive correlation with Th22 and approximately positive correlation with pure Th17 in Non-CR patients. PB blast cell showed positive correlation with Th22 and negative correlation with Th1 in ND AML patients. Our results indicate that Th22 and pure Th17 cells conjointly contribute to the pathogenesis of AML and might be promising novel clinical index for AML. PMID- 24473143 TI - Identification and molecular characterization of a chitin deacetylase from Bombyx mori peritrophic membrane. AB - The insect midgut epithelium is generally lined with a unique chitin and protein structure, the peritrophic membrane (PM), which facilitates food digestion and protects the gut epithelium. PM proteins are important determinants for PM structure and formation. In this study, the silkworm Bombyx mori midgut PM protein BmCDA7 was identified by proteomic tools. The full-length BmCDA7 cDNA is 1357 bp; the deduced protein is composed of 379 amino acid residues and includes a 16 amino acid residue signal peptide, a putative polysaccharide deacetylase like domain and 15 cysteine residues present in three clusters. The heterologously expressed proteins of the BmCDA7 gene in yeast displayed chitin deacetylase activity. Expression of B. mori BmCDA7 was detected in the midgut at both the transcriptional and translational levels. The BmCDA7 gene was expressed by the newly hatched silkworm larvae until day seven of the fifth instar and was expressed at a high level in the newly exuviated larvae of different instars. The functions and regulatory mechanism of BmCDA7, however, need further investigation. PMID- 24473144 TI - Genistein in 1:1 inclusion complexes with ramified cyclodextrins: theoretical, physicochemical and biological evaluation. AB - Genistein is one of the most studied phytocompound in the class of isoflavones, presenting a notable estrogenic activity and in vitro and/or in vivo benefits in different types of cancer such as those of the bladder, kidney, lung, pancreatic, skin and endometrial cancer. A big inconvenience for drug development is low water solubility, which can be solved by using hydrophilic cyclodextrins. The aim of this study is to theoretically analyze, based on the interaction energy, the possibility of a complex formation between genistein (Gen) and three different ramified cyclodextrins (CD), using a 1:1 molar ratio Gen:CD. Theoretical data were correlated with a screening of both in vitro and in vivo activity. Proliferation of different human cancer cell lines, antimicrobial activity and angiogenesis behavior was analyzed in order to see if complexation has a beneficial effect for any of the above mentioned activities and if so, which of the three CDs is the most suitable for the incorporation of genistein, and which may lead to future improved pharmaceutical formulations. Results showed antiproliferative activity with different IC50 values for all tested cell lines, remarkable antimicrobial activity on Bacillus subtilis and antiangiogenic activity as revealed by CAM assay. Differences regarding the intensity of the activity for pure and the three Gen complexes were noticed as explained in the text. The data represent a proof that the three CDs can be used for furtherer research towards practical use in the pharmaceutical and medical field. PMID- 24473146 TI - Amino acid composition, molecular weight distribution and gel electrophoresis of walnut (Juglans regia L.) proteins and protein fractionations. AB - As a by-product of oil production, walnut proteins are considered as an additional source of plant protein for human food. To make full use of the protein resource, a comprehensive understanding of composition and characteristics of walnut proteins are required. Walnut proteins have been fractionated and characterized in this study. Amino acid composition, molecular weight distribution and gel electrophoresis of walnut proteins and protein fractionations were analyzed. The proteins were sequentially separated into four fractions according to their solubility. Glutelin was the main component of the protein extract. The content of glutelin, albumin, globulin and prolamin was about 72.06%, 7.54%, 15.67% and 4.73% respectively. Glutelin, albumin and globulin have a balanced content of essential amino acids, except for methionine, with respect to the FAO pattern recommended for adults. SDS-PAGE patterns of albumin, globulin and glutelin showed several polypeptides with molecular weights 14.4 to 66.2 kDa. The pattern of walnut proteins in two-dimension electrophoresis (2-DE) showed that the isoelectric point was mainly in the range of 4.8-6.8. The results of size exclusion chromatogram indicated molecular weight of the major components of walnut proteins were between 3.54 and 81.76 kDa. PMID- 24473145 TI - Hypoxia enhances protective effect of placental-derived mesenchymal stem cells on damaged intestinal epithelial cells by promoting secretion of insulin-like growth factor-1. AB - Apoptosis and necrosis of intestinal epithelial cells (IECs), induced by ischemia reperfusion (I/R) injury, can lead to dysfunction of the intestinal barrier, which could cause multiple organ dysfunction syndromes. Mesenchymal stem cells (MSCs) have the potential of providing protective effects on damaged IECs via paracrine action. This study investigated whether hypoxia can enhance the protective effect of placental-derived MSCs (pMSCs) on H2O2-treated-caco2 cells, and explored the possible mechanism. The pMSCs isolated by tissue culture were fibroblast-like, positive for CD73, CD90 and CD105 and can differentiate into chondrocytes and endothelial cells. Five days after treatment with H2O2, the numbers of living caco2 cells significantly decreased. More live H2O2-treated caco2 cells were observed in pMSCs hypoxia culture medium (pMSCs-HCM) than pMSCs normoxia culture medium (pMSCs-NCM), and the application of a specific antibody that blocked insulin-like growth factor-1 (IGF-1) leads to a significant decrease of the protective effect of pMSCs-HCM. Hypoxia can promote IGF-1 expression of pMSCs at mRNA and protein levels, and caco2 stably expressed IGF-1 receptor. Knocking down IGF-1 expression in pMSCs by siRNA resulted in a significant attenuation of the increase in apoptosis of H2O2-treated-caco2 cultured in pMSCs HCM. In conclusion, hypoxia can increase the protective effect of pMSCs on H2O2 treated-caco2 cells via a promotion of their paracrine actions, and the key cytokine involved is IGF-1. PMID- 24473147 TI - Gene expression: degrade to derepress. AB - Chromatin immunoprecipitation and sequencing (ChIP-seq) provides a static snap shot of DNA-associated proteins which fails to reflect the dynamics of the DNA bound proteome. Now, Catic and co-workers combine ubiquitin ChIP-seq and proteasome inhibitors to map sites of DNA-associated protein degradation on a genome-wide scale. They identify an ubiquitin ligase which targets a transcriptional repressor for destruction by the proteasome, thus activating transcription of specific genes. These findings reveal that the ubiquitin proteasome system actively regulates transcription. PMID- 24473148 TI - DNA bending facilitates the error-free DNA damage tolerance pathway and upholds genome integrity. AB - DNA replication is sensitive to damage in the template. To bypass lesions and complete replication, cells activate recombination-mediated (error-free) and translesion synthesis-mediated (error-prone) DNA damage tolerance pathways. Crucial for error-free DNA damage tolerance is template switching, which depends on the formation and resolution of damage-bypass intermediates consisting of sister chromatid junctions. Here we show that a chromatin architectural pathway involving the high mobility group box protein Hmo1 channels replication associated lesions into the error-free DNA damage tolerance pathway mediated by Rad5 and PCNA polyubiquitylation, while preventing mutagenic bypass and toxic recombination. In the process of template switching, Hmo1 also promotes sister chromatid junction formation predominantly during replication. Its C-terminal tail, implicated in chromatin bending, facilitates the formation of catenations/hemicatenations and mediates the roles of Hmo1 in DNA damage tolerance pathway choice and sister chromatid junction formation. Together, the results suggest that replication-associated topological changes involving the molecular DNA bender, Hmo1, set the stage for dedicated repair reactions that limit errors during replication and impact on genome stability. PMID- 24473150 TI - Copper, aluminum, iron and calcium inhibit human acetylcholinesterase in vitro. AB - Acetylcholinesterase (AChE) is an important part of cholinergic nerves where it participates in termination of neurotransmission. AChE can be inhibited by e.g. some Alzheimer disease drugs, nerve agents, and secondary metabolites. In this work, metal salts aluminum chloride, calcium chloride, cupric chloride, ferric chloride, potassium chloride, magnesium chloride and sodium chloride were tested for their ability to inhibit AChE. Standard Ellman assay based on human recombinant AChE was done and inhibition was measured using Dixon plot. No inhibition was proved for sodium, potassium and magnesium ions. However, aluminum, cupric, ferric and calcium ions were able to inhibit AChE via noncompetitive mechanism of inhibition. Though the inhibition is much weaker when compared to e.g. drugs with noncompetitive mechanism of action, biological relevance of the findings can be anticipated. PMID- 24473149 TI - Ret rescues mitochondrial morphology and muscle degeneration of Drosophila Pink1 mutants. AB - Parkinson's disease (PD)-associated Pink1 and Parkin proteins are believed to function in a common pathway controlling mitochondrial clearance and trafficking. Glial cell line-derived neurotrophic factor (GDNF) and its signaling receptor Ret are neuroprotective in toxin-based animal models of PD. However, the mechanism by which GDNF/Ret protects cells from degenerating remains unclear. We investigated whether the Drosophila homolog of Ret can rescue Pink1 and park mutant phenotypes. We report that a signaling active version of Ret (Ret(MEN2B) rescues muscle degeneration, disintegration of mitochondria and ATP content of Pink1 mutants. Interestingly, corresponding phenotypes of park mutants were not rescued, suggesting that the phenotypes of Pink1 and park mutants have partially different origins. In human neuroblastoma cells, GDNF treatment rescues morphological defects of PINK1 knockdown, without inducing mitophagy or Parkin recruitment. GDNF also rescues bioenergetic deficits of PINK knockdown cells. Furthermore, overexpression of Ret(MEN2B) significantly improves electron transport chain complex I function in Pink1 mutant Drosophila. These results provide a novel mechanism underlying Ret-mediated cell protection in a situation relevant for human PD. PMID- 24473151 TI - Postmortem examination of patient H.M.'s brain based on histological sectioning and digital 3D reconstruction. AB - Modern scientific knowledge of how memory functions are organized in the human brain originated from the case of Henry G. Molaison (H.M.), an epileptic patient whose amnesia ensued unexpectedly following a bilateral surgical ablation of medial temporal lobe structures, including the hippocampus. The neuroanatomical extent of the 1953 operation could not be assessed definitively during H.M.'s life. Here we describe the results of a procedure designed to reconstruct a microscopic anatomical model of the whole brain and conduct detailed 3D measurements in the medial temporal lobe region. This approach, combined with cellular-level imaging of stained histological slices, demonstrates a significant amount of residual hippocampal tissue with distinctive cytoarchitecture. Our study also reveals diffuse pathology in the deep white matter and a small, circumscribed lesion in the left orbitofrontal cortex. The findings constitute new evidence that may help elucidate the consequences of H.M.'s operation in the context of the brain's overall pathology. PMID- 24473152 TI - Colonoscopic tattoo dye spillage mimics endometriosis on laparoscopy. AB - Rare adverse effects of India ink injection spillage during colonoscopy have been reported. We present a case report in which prior colonoscopic India ink tattooing was found to mimic intraperitoneal endometriosis in a 48 year-old woman undergoing laparoscopic sterilization. Multiple black lesions suspicious for endometriosis involving the anterior and posterior cul-de-sac, left ovary, and omentum were found. A pathological assessment showed peritoneal tissue with focal dark pigment associated with mild chronic inflammation and deposition of tattoo pigment; there was no evidence of endometriosis in the specimens. Surgical recognition of tattoo ink spillage in the peritoneum is very important to prevent misinterpretation of peritoneal findings. PMID- 24473153 TI - A randomized, double-blind, placebo-controlled trial of oral pregabalin for relief of shoulder pain after laparoscopic gynecologic surgery. AB - STUDY OBJECTIVE: To investigate the efficacy of pregabalin for the relief of postoperative shoulder pain after laparoscopic gynecologic surgery. DESIGN: Prospective, randomized, double-blind, placebo-controlled trial (Canadian Task Force classification I). SETTING: Tertiary referral center, university hospital. PATIENTS: Fifty-six women undergoing elective laparoscopic gynecologic surgery between June 2012 and March 2013. INTERVENTIONS: Women in the study group received 75 mg pregabalin 2 hours before surgery and then every 12 hours for 2 doses, and women in the control group received an identical capsule and the same dosage of placebo. MEASUREMENTS AND MAIN RESULTS: Visual analog scale (VAS) scores for shoulder pain and surgical pain at 24 and 48 hours after surgery were evaluated as primary outcome. Postoperative analgesics used and drug-related adverse events were also monitored. Patients in the pregabalin group had significantly lower postoperative VAS scores for shoulder pain at 24 hours, compared with the placebo group (median, 23.14 [range, 13.67-32.61] vs. 37.22 [27.75-46.64]; p = .04), and required less analgesic (p = .01). There were no significant differences in VAS scores for surgical pain and adverse events between the 2 groups (p = .56). CONCLUSIONS: Perioperative administration of 75 mg pregabalin significantly reduced postoperative laparoscopic shoulder pain and amount of analgesic used. PMID- 24473154 TI - Ion sources for mass spectrometric identification and imaging of molecular species. AB - Covering: 2013 The ability to transfer molecular species to the gas phase and ionize them is central to the study of natural products and other molecular species by mass spectrometry (MS). MS-based strategies in natural products have focused on a few established ion sources, such as electron impact and electrospray ionization. However, a variety of other ion sources are either currently in use to evaluate natural products or show significant future promise. This review discusses these various ion sources in the context of other articles in this special issue, but is also applicable to other fields of analysis, including materials science. Ion sources are grouped based on the current understanding of their predominant ion formation mechanisms. This broad overview groups ion sources into the following categories: electron ionization and single photon ionization; chemical ionization-like and plasma-based; electrospray ionization; and, laser desorption-based. Laser desorption-based methods are emphasized with specific examples given for laser desorption postionization sources and their use in the analysis of intact microbial biofilms. Brief consideration is given to the choice of ion source for various sample types and analyses, including MS imaging. PMID- 24473155 TI - Zeolitic BIF crystal directly producing noble-metal nanoparticles in its pores for catalysis. AB - As an integral part of a porous framework and uniformly distributed throughout the internal pore space, the high density of the exposed B-H bond in zeolite-like porous BIF-20 (BIF = Boron Imidazolate Framework) is shown here to effectively produce nanoparticles within its confined pore space. Small noble-metal nanoparticles (Ag or Au) are directly synthesized into its pores without the need for any external reducing agent or photochemical reactions, and the resulting Ag@BIF-20 (or Au@BIF-20) samples show high catalytic activities for the reduction of 4-nitrophenol. PMID- 24473156 TI - Prevalence and underlying causes of dyspnoea in older people: a systematic review. AB - BACKGROUND: chronic dyspnoea is common in older people and is often of cardiac or pulmonary aetiology. Information on the exact prevalence and distribution of underlying causes is scarce. Our aim was to review the literature on prevalence and underlying causes of dyspnoea in the older population. METHODS: two MEDLINE searches were conducted: the first on studies on the prevalence of dyspnoea in older persons aged >=65 years using the Medical Research Council (MRC) dyspnoea scale and the second on the underlying causes of dyspnoea in this population. Quality assessment was performed for all included studies. Random effects models based on the logit transformed prevalences were used to calculate pooled prevalence with 95% confidence intervals (95% CI). RESULTS: a total of 21 articles from 20 different populations reported the prevalence in the general older population with a median sample size of 600 (Interquartile range 262-1289). The pooled prevalence was 36% (95% CI: 27-47%) for an MRC of >=2, 16% (95% CI: 12 21%) for an MRC of >=3 and 4% (95% CI: 2-9%) for an MRC of >=4. Prevalence rates were higher in women than in men. Only one article investigated the underlying causes of dyspnoea in older persons; in 70% of these patients, the dyspnoea was considered to be of cardiac or pulmonary origin. CONCLUSION: dyspnoea is very common in older people, but estimates vary considerably between studies. Only one study describes the underlying causes. PMID- 24473157 TI - A rapid and efficient access to renieramycin-type alkaloids featuring a temperature-dependent stereoselective cyclization. AB - A flexible and practical protocol for the asymmetric synthesis of renieramycin type antitumor alkaloids is described, in which the stereoselective Pictet Spengler cyclization of amino ester 16 and aldehyde 15 by regulating temperature and the automatic lactamization after N-deprotection of the cyclization product are exploited to rapidly construct the common pentacyclic framework. (-) Renieramycin G and (-)-jorunnamycin A, as representative members of the two subgroup renieramycin-type alkaloids, are obtained in 19 steps from l-tyrosine with 15.8% and 14.3% overall yield respectively. PMID- 24473158 TI - Photodissociation of TEMPO-modified peptides: new approaches to radical-directed dissociation of biomolecules. AB - Radical-directed dissociation of gas phase ions is emerging as a powerful and complementary alternative to traditional tandem mass spectrometric techniques for biomolecular structural analysis. Previous studies have identified that coupling of 2-[(2,2,6,6-tetramethylpiperidin-1-oxyl)methyl]benzoic acid (TEMPO-Bz) to the N-terminus of a peptide introduces a labile oxygen-carbon bond that can be selectively activated upon collisional activation to produce a radical ion. Here we demonstrate that structurally-defined peptide radical ions can also be generated upon UV laser photodissociation of the same TEMPO-Bz derivatives in a linear ion-trap mass spectrometer. When subjected to further mass spectrometric analyses, the radical ions formed by a single laser pulse undergo identical dissociations as those formed by collisional activation of the same precursor ion, and can thus be used to derive molecular structure. Mapping the initial radical formation process as a function of photon energy by photodissociation action spectroscopy reveals that photoproduct formation is selective but occurs only in modest yield across the wavelength range (300-220 nm), with the photoproduct yield maximised between 235 and 225 nm. Based on the analysis of a set of model compounds, structural modifications to the TEMPO-Bz derivative are suggested to optimise radical photoproduct yield. Future development of such probes offers the advantage of increased sensitivity and selectivity for radical directed dissociation. PMID- 24473159 TI - 'Workshops in healing' for senior medical students: a 5-year overview and appraisal. AB - We report upon the design, content and feedback from an interactive, experiential series of Workshops in Healing for senior medical students. Fifty-six final year medical students enrolled in 2*3 h workshops designed around the core themes of 'physician know thyself' (Workshop 1) and 'confronting suffering' (Workshop 2). Of the 56 students who initially enrolled, 48 students completed both workshops and provided a written open-ended reflection of their learning experience. The study, undertaken over a consecutive 5-year period (2008-2012), employed an emergent, qualitative design using thematic analysis of the reflective comments. We found that the design and content of both workshops promoted transformative learning for these final year medical students. Students identified the following benefits: (1) the opportunity to reaffirm their commitment to their chosen career path; (2) the value of listening to other students share their stories; (3) the importance of the timing of the workshops to occur after exams; (4) the use of various mediums such as art, poetry, music and contemporary/classic literature to present concepts of suffering and healing; and (5) the creation of a safe and confidential space. Students reported that these innovative workshops gave them a renewed sense of drive and enthusiasm for their chosen career. They highlighted the importance of addressing an aspect of medicine (healing) not covered in the traditional medical curriculum. Workshops in Healing helped them to rediscover a deeper meaning to medicine and their roles as future healthcare professionals. PMID- 24473160 TI - Unstable-Fe-site-induced formation of mesopores in microporous zeolite Y without using organic templates. AB - A novel organic template-free strategy for generating mesoporosity in Y zeolites is reported. It is revealed that Fe(3+) functioned as unstable sites in the Fe NaY zeolite, which promotes deferrization-dealumination, leading to enhanced formation of intra-crystalline mesopores as well as desirable interconnectivity. The mesopore-enriched zeolite exhibits a remarkable ability in conversion of the bulky substrate. PMID- 24473162 TI - Effects of the SSRI citalopram on behaviours connected to stress and reproduction in Endler guppy, Poecilia wingei. AB - Psychoactive drugs, such as selective serotonin reuptake inhibitors (SSRI) have been identified in high levels in effluents from Swedish sewage treatment plants (STP) at concentrations high enough to give pharmacological effects in fish. In humans SSRIs are used in the treatment of depression and they have anxiolytic effects. In the present study we exposed Endler guppy (Poecilia wingei) of both sexes to citalopram that showed the highest concentrations of SSRIs in STP effluents and studied reproductive and non-reproductive behaviour. Male courting behaviours were not affected compared to control fish after 14-28 days exposure to 1 MUg L(-1). In two experiments exposing both sexes to 0.2, 2.3 or 15 MUg L( 1) for 21 days, fish exposed to the two highest doses showed anxiolytic effects when placed in a novel environment (novel tank diving test, NT). Males were only affected by exposure to 15 MUg L(-1). They had significantly longer latency to explore the upper half of the aquarium, more visits and longer time spent in the upper half, and showed less bottom freezing behaviour, all markers of anxiolytic behaviour. In females exposure to 2.3 or 15 MUg L(-1) significantly increased freezing behaviour, while no effects on other behaviour variables were observed. No effects on shoaling behaviour could be discerned. These results show that citalopram have anxiolytic effects on guppy fish and thus affect ecologically relevant behaviours of importance to survival of fish. PMID- 24473163 TI - Intracellular speciation and transformation of inorganic mercury in marine phytoplankton. AB - Metal speciation is closely related to toxicity in aquatic organisms, but quantitative study of mercury transformation has rarely been reported. In this study, the ability of three marine phytoplankton species, including a green alga Chlorella autotrophica, a flagellate Isochrysis galbana and a diatom Thalassiosira weissflogii, to convert inorganic mercury were examined. We found that all algae tested were able to transform Hg(II) into dissolved gaseous mercury (DGM), phytochelatin (PC) complexes and metacinnabar (beta-HgS). The most tolerant species, T. weissflogii, generally produced the highest level of PCs and beta-HgS. Attributed to the highest DGM production ability, C. autotrophica accumulated the least Hg, but was the most sensitive due to low PC induction and beta-HgS formation. Of the added Hg(II), less than 5% was reduced to DGM per day in all species. Of the intracellular Hg, <20% and 20-90% were chelated by PCs and transformed into beta-HgS, respectively. These results suggest that intracellular biotransformation might be more important than bioavailability regulation in Hg(II) detoxification in marine phytoplankton. PMID- 24473164 TI - Anti-inflammatory activity and mechanism of a lipid extract from hard-shelled mussel (Mytilus coruscus) on chronic arthritis in rats. AB - The present study was designed to investigate the anti-inflammatory activity and mechanism of a lipid extract from hard-shelled mussel (Mytilus coruscus) on adjuvant-induced (AIA) and collagen-induced arthritis (CIA) in rats. AIA and CIA rats that received hard-shelled mussel lipid extract (HMLE group) at a dose of 100 mg/kg demonstrated significantly lower paw swelling and arthritic index, but higher body weight gain than those which received olive oil (control group). Similar results were found in arthritic rats that received New Zealand green lipped mussel lipid extract (GMLE) at the same dosage. The levels of leukotriene B4 (LTB4), prostaglandin E2 (PGE2), thromboxane B2 (TXB2) in the serum, and interleukin-1beta (IL-1beta), IL-6, interferon-gamma (INF-gamma), tumor necrosis factor-alpha (TNF-alpha) in the ankle joint synovial fluids of HMLE group rats were significantly lower than those of control group. However, the levels of IL-4 and IL-10 in HMLE group rats were significantly higher than those in the control group. Decreased mRNA expressions of matrix metalloproteinase 1 (MMP1) and MMP13, but increased tissue inhibitor of metalloproteinase 1 (TIMP1) were observed in the knee joint synovium tissues of HMLE group rats when compared with the control group. No hepatotoxicity was observed in both HMLE and GMLE group rats. The present results indicated that HMLE had a similarly strong anti-inflammatory activity as GMLE. Such a strong efficacy could result from the suppression of inflammatory mediators (LTB4, PGE2, TXB2), pro-inflammatory cytokines (IL-1beta, IL-6, INF-gamma, TNF-alpha) and MMPs (MMP1, MMP13), and the promotion of anti inflammatory cytokines (IL-4, IL-10) and TIMPs (TIMP1) productions. PMID- 24473165 TI - Briarane diterpenes from the South China Sea gorgonian coral, Junceella gemmacea. AB - Four new briarane diterpenoids, junceellolides M-P (1-4), were isolated together with seven known analogs (5-11) from the South China Sea gorgonian, Junceella gemmacea. The structures of these compounds were elucidated by detailed spectroscopic analysis and comparison with the reported data. The absolute configuration of compounds 1-3 were determined based on an ECD experiment, while the absolute configuration of compound 4 was genetically determined. All the compounds were isolated for the first time from J. gemmacea. These compounds showed no growth inhibitory activity against A549, MG63 and SMMC-7721 cell lines in an in vitro bioassay. PMID- 24473168 TI - Six new tetraprenylated alkaloids from the South China Sea gorgonian Echinogorgia pseudossapo. AB - Six new tetraprenylated alkaloids, designated as malonganenones L-Q (1-6), were isolated from the gorgonian Echinogorgia pseudossapo, collected in Daya Bay of Guangdong Province, China. The structures of 1-6 featuring a methyl group at N-3 and a tetraprenyl chain at N-7 in the hypoxanthine core were established by extensive spectroscopic analyses. Compounds 1-6 were tested for their inhibitory activity against the phosphodiesterases (PDEs)-4D, 5A, and 9A, and compounds 1 and 6 exhibited moderate inhibitory activity against PDE4D with IC50 values of 8.5 and 20.3 uM, respectively. PMID- 24473167 TI - Marine low molecular weight natural products as potential cancer preventive compounds. AB - Due to taxonomic positions and special living environments, marine organisms produce secondary metabolites that possess unique structures and biological activities. This review is devoted to recently isolated and/or earlier described marine compounds with potential or established cancer preventive activities, their biological sources, molecular mechanisms of their action, and their associations with human health and nutrition. The review covers literature published in 2003-2013 years and focuses on findings of the last 2 years. PMID- 24473169 TI - Polyunsaturated aldehydes from large phytoplankton of the Atlantic Ocean surface (42 degrees n to 33 degrees s). AB - Polyunsaturated aldehydes (PUAs) are organic compounds mainly produced by diatoms, after cell wounding. These compounds are increasingly reported as teratogenic for species of grazers and deleterious for phytoplanktonic species, but there is still scarce information regarding concentration ranges and the composition of PUAs in the open ocean. In this study, we analyzed the spatial distribution and the type of aldehydes produced by the large-sized (>10 MUm) phytoplankton in the Atlantic Ocean surface. Analyses were conducted on PUAs released after mechanical disruption of the phytoplankton cells, referred to here as potential PUAs (pPUAs). Results show the ubiquitous presence of pPUA in the open ocean, including upwelling areas, as well as oligotrophic gyres. Total pPUA concentrations ranged from zero to 4.18 pmol from cells in 1 L. Identified PUAs were heptadienal, octadienal and decadienal, with heptadienal being the most common (79% of total stations). PUA amount and composition across the Atlantic Ocean was mainly related to the nitrogen:phosphorus ratio, suggesting nutrient driven mechanisms of PUA production. Extending the range of trophic conditions considered by adding data reported for productive coastal waters, we found a pattern of PUA variation in relation to trophic status. PMID- 24473170 TI - Spongionella secondary metabolites protect mitochondrial function in cortical neurons against oxidative stress. AB - The marine habitat provides a large number of structurally-diverse bioactive compounds for drug development. Marine sponges have been studied over many years and are found to be a rich source of these bioactive chemicals. This study is focused on the evaluation of the activity of six diterpene derivatives isolated from Spongionella sp. on mitochondrial function using an oxidative in vitro stress model. The test compounds include the Gracilins (A, H, K, J and L) and tetrahydroaplysulphurin-1. Compounds were co-incubated with hydrogen peroxide for 12 hours to determine their protective capacities and their effect on markers of apoptosis and Nrf2/ARE pathways was evaluated. Results conclude that Gracilins preserve neurons against oxidative damage, and that in particular, tetrahydroaplysulphurin-1 shows a complete neuroprotective activity. Oxidative stress is linked to mitochondrial dysfunction and consequently to neurodegenerative disorders like Parkinson and Alzheimer diseases, Friedreich ataxia or Amyotrophic lateral sclerosis. This neuroprotection against oxidation conditions suggest that these metabolites could be interesting lead candidates in drug development for neurodegenerative diseases. PMID- 24473171 TI - Trabectedin and plitidepsin: drugs from the sea that strike the tumor microenvironment. AB - The prevailing paradigm states that cancer cells acquire multiple genetic mutations in oncogenes or tumor suppressor genes whose respective activation/up regulation or loss of function serve to impart aberrant properties, such as hyperproliferation or inhibition of cell death. However, a tumor is now considered as an organ-like structure, a complex system composed of multiple cell types (e.g., tumor cells, inflammatory cells, endothelial cells, fibroblasts, etc.) all embedded in an inflammatory stroma. All these components influence each other in a complex and dynamic cross-talk, leading to tumor cell survival and progression. As the microenvironment has such a crucial role in tumor pathophysiology, it represents an attractive target for cancer therapy. In this review, we describe the mechanism of action of trabectedin and plitidepsin as an example of how these specific drugs of marine origin elicit their antitumor activity not only by targeting tumor cells but also the tumor microenvironment. PMID- 24473172 TI - Continuous drug release by sea anemone Nematostella vectensis stinging microcapsules. AB - Transdermal delivery is an attractive option for drug delivery. Nevertheless, the skin is a tough barrier and only a limited number of drugs can be delivered through it. The most difficult to deliver are hydrophilic drugs. The stinging mechanism of the cnidarians is a sophisticated injection system consisting of microcapsular nematocysts, which utilize built-in high osmotic pressures to inject a submicron tubule that penetrates and delivers their contents to the prey. Here we show, for the first time, that the nematocysts of the starlet sea anemone Nematostella vectensis can be isolated and incorporated into a topical formulation for continuous drug delivery. We demonstrate quantitative delivery of nicotinamide and lidocaine hydrochloride as a function of microcapsular dose or drug exposure. We also show how the released submicron tubules can be exploited as a skin penetration enhancer prior to and independently of drug application. The microcapsules are non-irritant and may offer an attractive alternative for hydrophilic transdermal drug delivery. PMID- 24473173 TI - Prenylated indolediketopiperazine peroxides and related homologues from the marine sediment-derived fungus Penicillium brefeldianum SD-273. AB - Three new indolediketopiperazine peroxides, namely, 24-hydroxyverruculogen (1), 26-hydroxyverruculogen (2), and 13-O-prenyl-26-hydroxyverruculogen (3), along with four known homologues (4-7), were isolated and identified from the culture extract of the marine sediment-derived fungus Penicillium brefeldianum SD-273. Their structures were determined based on the extensive spectroscopic analysis and compound 1 was confirmed by X-ray crystallographic analysis. The absolute configuration of compounds 1-3 was determined using chiral HPLC analysis of their acidic hydrolysates. Each of the isolated compounds was evaluated for antibacterial and cytotoxic activity as well as brine shrimp (Artemia salina) lethality. PMID- 24473174 TI - A chemoinformatics approach to the discovery of lead-like molecules from marine and microbial sources en route to antitumor and antibiotic drugs. AB - The comprehensive information of small molecules and their biological activities in the PubChem database allows chemoinformatic researchers to access and make use of large-scale biological activity data to improve the precision of drug profiling. A Quantitative Structure-Activity Relationship approach, for classification, was used for the prediction of active/inactive compounds relatively to overall biological activity, antitumor and antibiotic activities using a data set of 1804 compounds from PubChem. Using the best classification models for antibiotic and antitumor activities a data set of marine and microbial natural products from the AntiMarin database were screened-57 and 16 new lead compounds for antibiotic and antitumor drug design were proposed, respectively. All compounds proposed by our approach are classified as non-antibiotic and non antitumor compounds in the AntiMarin database. Recently several of the lead-like compounds proposed by us were reported as being active in the literature. PMID- 24473176 TI - Biotherapies in Behcet's disease. AB - Behcet's disease (BD) is a systemic large-vessel vasculitis characterized by a wide clinical spectrum including recurrent oral and genital ulcerations, uveitis, vascular, neurological, articular, renal and gastrointestinal manifestations. Therapeutic management of BD depends on the clinical presentation and organ involved. Although colchicine, nonsteroidal antiinflammatory agents and topical treatments with corticosteroids are often sufficient for mucocutaneous and joint involvements, more aggressive approach with immunosuppressive agents is warranted for severe manifestations such as posterior uveitis, retinal vasculitis, vascular, and neurological and gastrointestinal involvements. However, some patients still have refractory disease, relapse, sight threatening eye disease, or irreversible organ damage. Recent improvements in the understanding of the pathogenic mechanisms have led to the identification of potential targets and future biological therapies for BD. In contrast to current non-specific immunosuppressive agents, the emergence of biotherapies provides the possibility of interfering with specific pathogenic pathways. Novel targeted biotherapies might be used in the future for BD. PMID- 24473175 TI - Another facet to the anticancer response to lamellarin D: induction of cellular senescence through inhibition of topoisomerase I and intracellular Ros production. AB - Lamellarin D (LamD) is a marine alkaloid with broad spectrum antitumor activities. Multiple intracellular targets of LamD, which affect cancer cell growth and induce apoptosis, have been identified. These include nuclear topoisomerase I, relevant kinases (such as cyclin-dependent kinase 2) and the mitochondrial electron transport chain. While we have previously demonstrated that LamD at micromolar range deploys strong cytotoxicity by inducing mitochondrial apoptosis, mechanisms of its cytostatic effect have not yet been characterized. Here, we demonstrated that induction of cellular senescence (depicted by cell cycle arrest in G2 associated with beta-galactosidase activity) is a common response to subtoxic concentrations of LamD. Cellular senescence is observed in a large panel of cancer cells following in vitro or in vivo exposure to LamD. The onset of cellular senescence is dependent on the presence of intact topoisomerase I since topoisomerase I-mutated cells are resistant to senescence induced by LamD. LamD-induced senescence occurs without important loss of telomere integrity. Instead, incubation with LamD results in the production of intracellular reactive oxygen species (ROS), which are critical for senescence as demonstrated by the inhibitory effect of antioxidants. In addition, cancer cells lacking mitochondrial DNA also exhibit cellular senescence upon LamD exposure indicating that LamD can trigger senescence, unlike apoptosis, in the absence of functional mitochondria. Overall, our results identify senescence-associated growth arrest as a powerful effect of LamD and add compelling evidence for the pharmacological interest of lamellarins as potential anticancer agents. PMID- 24473166 TI - Targeting nuclear receptors with marine natural products. AB - Nuclear receptors (NRs) are important pharmaceutical targets because they are key regulators of many metabolic and inflammatory diseases, including diabetes, dyslipidemia, cirrhosis, and fibrosis. As ligands play a pivotal role in modulating nuclear receptor activity, the discovery of novel ligands for nuclear receptors represents an interesting and promising therapeutic approach. The search for novel NR agonists and antagonists with enhanced selectivities prompted the exploration of the extraordinary chemical diversity associated with natural products. Recent studies involving nuclear receptors have disclosed a number of natural products as nuclear receptor ligands, serving to re-emphasize the translational possibilities of natural products in drug discovery. In this review, the natural ligands of nuclear receptors will be described with an emphasis on their mechanisms of action and their therapeutic potentials, as well as on strategies to determine potential marine natural products as nuclear receptor modulators. PMID- 24473177 TI - Spectroscopic and molecular modeling studies on the interactions of N Methylformamide with superoxide dismutase. AB - N-Methylformamide, a polar solvent has a wide industrial applications and it is well-known for hepatotoxicity. The interaction between NMF with superoxide dismutase, an antioxidant defense enzyme has been studied for the first time using spectroscopic methods including Fourier transform infrared (FT-IR) spectroscopy, Circular dichroism (CD) spectroscopy and UV-visible spectroscopy under simulative physiological conditions and also by molecular modelling. Fourier Transform Infra Red analysis showed that the change in peak positions and shapes revealed that the secondary structure of SOD had been changed by the interaction with NMF. The data of CD spectra also confirmed that NMF decreased the degree of secondary structure of SOD, which directly resulted in destabilization of enzyme. We studied the inhibitory effect of NMF on enzyme kinetics by pyrogallol autoxidation revealed that protein-ligand complex caused structural unfolding which resulted in enzymatic inhibition. Thus the spectral behaviour of superoxide dismutase provides data concerning its conformational changes in the presence of NMF. Furthermore, molecular docking was applied to explore the binding mode between the protein-ligand complex. This suggested that Asn54 and Val302 residues of dimeric protein were predicted to interact with NMF. The present study provides direct evidence at a molecular level to show that exposure to NMF cause perturbation in its structure and function. PMID- 24473178 TI - Collaterals at angiography and outcomes in the Interventional Management of Stroke (IMS) III trial. AB - BACKGROUND AND PURPOSE: Endovascular strategies provide unique opportunity to correlate angiographic measures of collateral circulation at the time of endovascular therapy. We conducted systematic analyses of collaterals at conventional angiography on recanalization, reperfusion, and clinical outcomes in the endovascular treatment arm of the Interventional Management of Stroke (IMS) III trial. METHODS: Prospective evaluation of angiographic collaterals was conducted via central review of subjects treated with endovascular therapy in IMS III (n=331). Collateral grade before endovascular therapy was assessed with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale, blinded to all other data. Statistical analyses investigated the association between collaterals with baseline clinical variables, angiographic measures of recanalization, reperfusion and clinical outcomes. RESULTS: Adequate views of collateral circulation to the ischemic territory were available in 276 of 331 (83%) subjects. Collateral grade was strongly related to both recanalization of the occluded arterial segment (P=0.0016) and downstream reperfusion (P<0.0001). Multivariable analyses confirmed that robust angiographic collateral grade was a significant predictor of good clinical outcome (modified Rankin Scale score<=2) at 90 days (P=0.0353), adjusted for age, history of diabetes mellitus, National Institutes of Health Stroke Scale strata, and Alberta Stroke Program Early CT Score. The relationship between collateral flow and clinical outcome may depend on the degree of reperfusion. CONCLUSIONS: More robust collateral grade was associated with better recanalization, reperfusion, and subsequent better clinical outcomes. These data, from the largest endovascular trial to date, suggest that collaterals are an important consideration in future trial design. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00359424. PMID- 24473181 TI - Can we agree on a standard terminology for catheter-based interventions for acute ischemic stroke? PMID- 24473179 TI - Sildenafil mediates blood-flow redistribution and neuroprotection after neonatal hypoxia-ischemia. AB - BACKGROUND AND PURPOSE: The best conceivable treatment for hypoxia-ischemia (HI) is the restoration of blood flow to the hypoxic-ischemic region(s). Our objective was to examine whether boosting NO-cGMP signaling using sildenafil citrate, a phosphodiesterase-type 5 inhibitor, could modify cerebral blood flow and reduce lesions in the developing brain. METHODS: HI was induced in P7 Sprague-Dawley rats by unilateral carotid artery occlusion and hypoxia, and followed by either PBS or sildenafil. Blood-flow velocities were measured by ultrasound imaging with sequential Doppler recordings to evaluate collateral recruitment. Cell death, blood-brain barrier integrity, and glial activation were analyzed by immunohistochemistry. Motor behavior was evaluated using an open-field device adapted to neonatal animals. RESULTS: Sildenafil citrate (10 mg/kg) induced collateral patency, reduced terminal dUTP nick-end labeling-positive cells, reactive astrogliosis, and macrophage/microglial activation at 72 hours and 7 days post-HI. Sildenafil also reduced the number of terminal dUTP nick-end labeling-positive endothelial cells within lesion site. Seven days after HI and sildenafil treatment, tissue loss was significantly reduced, and animals recovered motor coordination. CONCLUSIONS: Our findings strongly indicate that sildenafil citrate treatment, associated with a significant increase in cerebral blood flow, reduces HI damage and improves motor locomotion in neonatal rats. Sildenafil may represent an interesting therapeutic strategy for neonatal neuroprotection. PMID- 24473180 TI - Symptomatic intracranial hemorrhage after stroke thrombolysis: comparison of prediction scores. AB - BACKGROUND AND PURPOSE: Several prognostic scores have been developed to predict the risk of symptomatic intracranial hemorrhage (sICH) after ischemic stroke thrombolysis. We compared the performance of these scores in a multicenter cohort. METHODS: We merged prospectively collected data of patients with consecutive ischemic stroke who received intravenous thrombolysis in 7 stroke centers. We identified and evaluated 6 scores that can provide an estimate of the risk of sICH in hyperacute settings: MSS (Multicenter Stroke Survey); HAT (Hemorrhage After Thrombolysis); SEDAN (blood sugar, early infarct signs, [hyper]dense cerebral artery sign, age, NIH Stroke Scale); GRASPS (glucose at presentation, race [Asian], age, sex [male], systolic blood pressure at presentation, and severity of stroke at presentation [NIH Stroke Scale]); SITS (Safe Implementation of Thrombolysis in Stroke); and SPAN (stroke prognostication using age and NIH Stroke Scale)-100 positive index. We included only patients with available variables for all scores. We calculated the area under the receiver operating characteristic curve (AUC-ROC) and also performed logistic regression and the Hosmer-Lemeshow test. RESULTS: The final cohort comprised 3012 eligible patients, of whom 221 (7.3%) had sICH per National Institute of Neurological Disorders and Stroke, 141 (4.7%) per European Cooperative Acute Stroke Study II, and 86 (2.9%) per Safe Implementation of Thrombolysis in Stroke criteria. The performance of the scores assessed with AUC-ROC for predicting European Cooperative Acute Stroke Study II sICH was: MSS, 0.63 (95% confidence interval, 0.58-0.68); HAT, 0.65 (0.60-0.70); SEDAN, 0.70 (0.66-0.73); GRASPS, 0.67 (0.62-0.72); SITS, 0.64 (0.59-0.69); and SPAN-100 positive index, 0.56 (0.50 0.61). SEDAN had significantly higher AUC-ROC values compared with all other scores, except for GRASPS where the difference was nonsignificant. SPAN-100 performed significantly worse compared with other scores. The discriminative ranking of the scores was the same for the National Institute of Neurological Disorders and Stroke, and Safe Implementation of Thrombolysis in Stroke definitions, with SEDAN performing best, GRASPS second, and SPAN-100 worst. CONCLUSIONS: SPAN-100 had the worst predictive power, and SEDAN constantly the highest predictive power. However, none of the scores had better than moderate performance. PMID- 24473182 TI - Direct thrombin inhibitor argatroban reduces stroke damage in 2 different models. AB - BACKGROUND AND PURPOSE: We showed previously robust neuroprotection with the thrombin inhibitor argatroban and now sought additional support for its neuroprotective potential. METHODS: We used behavioral and histological end points; rigorously blinded the study groups; extended the treatment window to 3 hours after ischemia onset; and used 2 separate models. First, 2-hour filament middle cerebral artery occlusion in 64 male Sprague-Dawley rats was followed by learning and memory testing and quantitative histomorphometry. Randomly assigned treatment was 0.45 mg argatroban, saline, or 0.4 U thrombin. Second, we used the quantal bioassay (n=272) after 2-hour middle cerebral artery occlusion to detect the longest time delay after which therapy failed. RESULTS: Argatroban powerfully and significantly reversed learning and memory deficits because of focal ischemia compared with saline or thrombin (P<0.03; ANOVA). Argatroban was significantly (P<0.05; t test with Bonferroni) protective when given immediately or after 1, 2, 3, but not 4 hours delay. CONCLUSIONS: We obtained supportive evidence for argatroban protection of the neurovascular unit using behavioral and histological measurements at realistic therapeutic time windows. PMID- 24473183 TI - Response to letter regarding article, "Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation". PMID- 24473185 TI - A computational study of the mechanism of the [(salen)Cr + DMAP]-catalyzed formation of cyclic carbonates from CO2 and epoxide. AB - Epoxide and CO2 coupling reactions catalyzed by (salen)Cr(III)Cl have been modeled computationally to contrast a monometallic vs. a bimetallic mechanism. A low-energy CO2 insertion step into the metal-alkoxide bond was located. PMID- 24473184 TI - Cytological analysis of spermatogenesis: live and fixed preparations of Drosophila testes. AB - Drosophila melanogaster is a powerful model system that has been widely used to elucidate a variety of biological processes. For example, studies of both the female and male germ lines of Drosophila have contributed greatly to the current understanding of meiosis as well as stem cell biology. Excellent protocols are available in the literature for the isolation and imaging of Drosophila ovaries and testes(3-12). Herein, methods for the dissection and preparation of Drosophila testes for microscopic analysis are described with an accompanying video demonstration. A protocol for isolating testes from the abdomen of adult males and preparing slides of live tissue for analysis by phase-contrast microscopy as well as a protocol for fixing and immunostaining testes for analysis by fluorescence microscopy are presented. These techniques can be applied in the characterization of Drosophila mutants that exhibit defects in spermatogenesis as well as in the visualization of subcellular localizations of proteins. PMID- 24473186 TI - Abnormal amplitude of low-frequency fluctuations of intrinsic brain activity in Alzheimer's disease. AB - We used resting-state functional magnetic resonance imaging to measure the amplitude of low-frequency fluctuations (ALFF) of intrinsic brain activity in 23 patients with moderate Alzheimer's disease (AD) and 27 age- and gender-matched healthy controls. Two different frequency bands were analyzed (slow-5:0.01-0.027 Hz; slow-4:0.027-0.073 Hz). In many brain regions, widespread ALFF differences between the two frequency bands were observed, including predominantly the posterior cingulate cortex/precuneus (PCC/PCu), hippocampus/parahippocampal gyrus (Hip/PHG), insula, thalamus, and basal ganglia. Compared to controls, AD patients showed decreased ALFF values in the bilateral PCC/PCu, inferior parietal lobe, and several temporal regions, and increased ALFF values mainly in the bilateral Hip/PHG, and middle and inferior temporal gyri. Intriguingly, the ALFF abnormalities in the left PCu, left supramarginal gyrus, and several temporal regions were greater in the slow-5 band compared to the slow-4 band. Moreover, correcting for gray matter volume loss significantly affected the functional analytical results, suggesting that gray matter loss can partially account for the functional imaging analytical results obtained in AD. Finally, we showed that regions with changes in ALFF demonstrated a significant correlation with patient cognitive performance as measured using Mini-Mental State Examination scores. The results also demonstrated a significant correlation between hippocampal volume and the ALFF in slow-5 band in the AD group. This study demonstrated widespread ALFF abnormalities of intrinsic brain activity in AD and revealed that the ALFF abnormalities in severe specific regions were frequency-dependent. Taken together, our findings provided novel insights into the pathophysiological mechanism of AD and may be helpful in the development of imaging biomarkers for disease diagnosis. PMID- 24473187 TI - Responsiveness of magnetic resonance imaging and neuropsychological assessment in memory clinic patients. AB - BACKGROUND: Scales of global cognition and behavior, often used as endpoints for intervention trials in Alzheimer's disease (AD) and mild cognitive impairment (MCI), are insufficiently responsive (i.e., relatively insensitive to change). Large patient samples are needed to detect beneficial drug effects. Therefore, magnetic resonance imaging (MRI) measures of cerebral atrophy have been proposed as surrogate endpoints. OBJECTIVE: To examine how neuropsychological assessment compares to MRI in this respect. METHODS: We measured hippocampal atrophy, cortical thickness, and performance on neuropsychological tests in memory clinic patients at baseline and after two years. Neurologists rated the patients as cognitively normal (n = 28; Clinical Dementia Rating, CDR = 0) or as impaired (n = 34; CDR > 0). We administered five tests of memory, executive functioning, and verbal fluency. A composite neuropsychological score was calculated by taking the mean of the demographically corrected standard scores. MRI was done on a 3 Tesla scanner. Volumetric measurements of the hippocampus and surrounding cortex were made automatically using FreeSurfer software. RESULTS: The composite neuropsychological score deteriorated 0.6 SD in the impaired group, and was virtually unchanged in the normal group. Annual hippocampal atrophy rates were 3.4% and 0.6% in the impaired and normal cognition groups, respectively. Estimates of required sample sizes to detect a 50% reduction in rate of change were larger using rate of hippocampal atrophy (n = 131) or cortical thickness (n = 488) as outcome compared to change scores on neuropsychological assessment (n = 62). CONCLUSION: Neuropsychological assessment is more responsive than MRI measures of brain atrophy for detecting disease progression in memory clinic patients with MCI or AD. PMID- 24473188 TI - Do patients with mild cognitive impairment understand numerical health information? AB - Patients with mild cognitive impairment (MCI) are by definition still autonomous in daily life and therefore make their own decisions, for example, concerning their own or their partners' health care. Health care information typically contains complex mathematical constructs like proportions, probabilities, and survival rates. The purpose of this study was to investigate whether patients with MCI have difficulties with understanding health numeracy questions and to explore the impact of declining cognitive functions. The performance of 25 patients with MCI in a health numeracy questionnaire was compared with the performance of a control sample including 164 healthy older adults, matched in age and educational level. Participants were asked to convert percentages, assess different probabilities, or understand the dosage of a short patient information leaflet. Additionally, neuropsychological background tests were administered. Patients with MCI answered fewer items correctly than controls in the health numeracy questionnaire. A correlation analysis showed statistically significant associations between performance in the health numeracy task and mental arithmetic, executive functions (psychomotor speed, conceptualization), and global cognitive status, respectively. Patients with MCI show problems in understanding numerical information concerning health care. Since patients with MCI are confronted with several health care decisions, special attention has to be paid to presenting information in an easily understandable way, to make additional sources of information available, and to provide adequate support. PMID- 24473189 TI - Role of BRI2 in dementia. AB - Alzheimer's disease (AD), the most common form of dementia, shares clinical and pathological similarities with familial British and Danish dementias (FBD and FDD). Whereas the etiology of sporadic AD remains unclear, familial AD is linked to mutations in amyloid-beta protein precursor (AbetaPP), presenilin 1 (PS1), and presenilin 2 (PS2). Similarly, FBD and FDD originate from mutations in the BRI2 gene (or ITM2b), causing amyloid angiopathy and neurofibrillary tangles analogous to those observed in AD. Recent studies on the role of BRI2 in FBD and FDD have revealed that the three diseases may share pathophysiological pathways leading to dementia. Interestingly, BRI2 is a potential regulator of AbetaPP processing, and it can inhibit the production and fibrillation of Abeta. This suggests a role of BRI2 in the amyloid cascade, which is the prevailing hypothesis about AD pathogenesis. To understand a possible relationship of BRI2 with AD, we reviewed the relevant studies on this protein. The data included not only the protein's structure, expression pattern, function, and involvement in FBD and FDD, but also its relationship with memory deficits and the main pathological proteins involved in AD. Thus, we highlight and discuss the potential links between BRI2 and AD, leading to the formulation of a modified hypothesis about AD etiology. PMID- 24473190 TI - One-pot synthesis of iniferter-bound polystyrene core nanoparticles for the controlled grafting of multilayer shells. AB - A novel approach using one-pot synthesis for the production of uniform, iniferter bound polystyrene core nanoparticles of size 30-40 nm is described. Conventional oil-in-water emulsion polymerisation of styrene and divinylbenzene, combining a hybrid initiation system (thermal and UV), triggered sequentially, was employed to form the surface-bound thiocarbamate iniferters in situ. The iniferter cores were then used as seeds for re-initiating further polymerisation by UV irradiation to produce water-compatible core-shell nanoparticles. Grafting of various shell-types is demonstrated: linear polymers of poly(N isopropylacrylamide) brushes, crosslinked polymers bearing different surface charges and molecularly imprinted polymers. The shell thickness was readily tuned by varying the monomers' concentration and polymerisation time. Our method is straightforward and in addition, gives access to the preparation of fluorescent seeds and the possibility of grafting nanosized multiple shells. The core-shell nanoparticles were fully characterised by dynamic light scattering, transmission electron microscopy, Fourier transform infrared spectroscopy and microelemental analysis. PMID- 24473191 TI - Unveiling mode-selected electron-phonon interactions in metal films by helium atom scattering. AB - The quasi two-dimensional electron gas on a metal film can transmit to the surface even minute mechanical disturbances occurring in the depth, thus allowing the gentlest of all surface probes, helium atoms, to perceive the vibrations of the deepest atoms via the induced surface-charge density oscillations. A density functional perturbation theory (DFPT) and a helium atom scattering study of the phonon dispersion curves in lead films of up to 7 mono-layers on a copper substrate show that: (a) the electron-phonon interaction is responsible for the coupling of He atoms to in-depth phonon modes; and (b) the inelastic HAS intensity from a given phonon mode is proportional to its electron-phonon coupling. The direct determination of mode-selected electron-phonon coupling strengths has great relevance for understanding superconductivity in thin films and two-dimensional systems. PMID- 24473192 TI - Photobiocatalytic chemistry of oxidoreductases using water as the electron donor. AB - To date, water has been poorly studied as the sacrificial electron donor for biocatalytic redox reactions using isolated enzymes. Here we demonstrate that water can also be turned into a sacrificial electron donor to promote biocatalytic redox reactions. The thermodynamic driving force required for water oxidation is obtained from UV and visible light by means of simple titanium dioxide-based photocatalysts. The electrons liberated in this process are delivered to an oxidoreductase by simple flavin redox mediators. Overall, the feasibility of photobiocatalytic, water-driven bioredox reactions is demonstrated. PMID- 24473193 TI - O ROM(e)O1, ROM(e)O1, wherefore art thou ROM(e)O1? AB - Mitochondria are not only a source but also a target of reactive oxygen species (ROS). However, the molecular mechanisms by which ROS affect mitochondrial function are poorly defined. In this issue, Screaton and colleagues report that ROS modulator protein 1 (ROMO1) links ROS and mitochondrial morphology and ultrastructure by modulating cristae remodeling and mitochondrial fusion that depends on the guanosine triphosphatase Opa1. Their work indicates how the oxidative milieu triggers mitochondrial shape changes. PMID- 24473194 TI - Biasing GPCR signaling from inside. AB - The discovery of "functional selectivity" or "biased signaling" through G protein coupled receptors (GPCRs) has redefined the classical GPCR signaling paradigm. Moreover, the therapeutic potential of biased signaling by and biased ligands for GPCRs is changing the landscape of GPCR drug discovery. The concept of biased signaling has primarily been developed and discussed in the context of ligands that bind to the extracellular regions of GPCRs. However, two recent reports demonstrate that it is also possible to bias GPCR signaling from inside the cell by targeting intracellular regions of these receptors. These findings present a novel handle for delineating the functional outcomes of biased signaling by GPCRs. Moreover, these approaches also uncover a previously unexplored framework for biasing GPCR signaling for drug discovery. PMID- 24473195 TI - ROMO1 is an essential redox-dependent regulator of mitochondrial dynamics. AB - The dynamics of mitochondria undergoing fusion and fragmentation govern many mitochondrial functions, including the regulation of cell survival. Although the machinery that catalyzes fusion and fragmentation has been well described, less is known about the signaling components that regulate these phenomena. We performed a genome-wide RNA interference (RNAi) screen and identified reactive oxygen species modulator 1 (ROMO1) as a redox-regulated protein required for mitochondrial fusion and normal cristae morphology. We showed that oxidative stress promoted the formation of high-molecular weight ROMO1 complexes and that knockdown of ROMO1 promoted mitochondrial fission. ROMO1 was essential for the oligomerization of the inner membrane guanosine triphosphatase (GTPase) OPA1, which is required to maintain the integrity of cristae junctions. As a consequence, cells lacking ROMO1 displayed fragmented mitochondria and loss of cristae, causing impaired mitochondrial respiration and increased sensitivity to cell death stimuli. Together, our data identify ROMO1 as a critical molecular switch that couples metabolic stress and mitochondrial morphology, linking mitochondrial fusion to cell survival. PMID- 24473196 TI - STAT3 induction of miR-146b forms a feedback loop to inhibit the NF-kappaB to IL 6 signaling axis and STAT3-driven cancer phenotypes. AB - Interleukin-6 (IL-6)-mediated activation of signal transducer and activator of transcription 3 (STAT3) is a mechanism by which chronic inflammation can contribute to cancer and is a common oncogenic event. We discovered a pathway, the loss of which is associated with persistent STAT3 activation in human cancer. We found that the gene encoding the tumor suppressor microRNA miR-146b is a direct STAT3 target gene, and its expression was increased in normal breast epithelial cells but decreased in tumor cells. Methylation of the miR-146b promoter, which inhibited STAT3-mediated induction of expression, was increased in primary breast cancers. Moreover, we found that miR-146b inhibited nuclear factor kappaB (NF-kappaB)-dependent production of IL-6, subsequent STAT3 activation, and IL-6/STAT3-driven migration and invasion in breast cancer cells, thereby establishing a negative feedback loop. In addition, higher expression of miR-146b was positively correlated with patient survival in breast cancer subtypes with increased IL6 expression and STAT3 phosphorylation. Our results identify an epigenetic mechanism of crosstalk between STAT3 and NF-kappaB relevant to constitutive STAT3 activation in malignancy and the role of inflammation in oncogenesis. PMID- 24473198 TI - Catalytic asymmetric semipinacol rearrangements. AB - Over the past few decades, the semipinacol rearrangement has been widely applied in the field of organic synthesis. However, its catalytic asymmetric version has not caught much attention until the beginning of the 21st century. Significant breakthroughs have been made due to the efforts of organic chemists. These important progressions are summarized in this paper. PMID- 24473197 TI - Contribution of NKX2-3 polymorphisms to inflammatory bowel diseases: a meta analysis of 35358 subjects. AB - Polymorphisms in NKX2-3 gene have been inconsistently associated with Crohn's disease (CD) and ulcerative colitis (UC). To generate large-scale evidence on whether NKX2-3 polymorphisms are associated with CD or UC susceptibility we have conducted a meta-analysis of 17 studies involving 17329 patients and 18029 controls. A significantly increased CD or UC risk was observed in persons carrying a G allele at rs10883365 polymorphism (A/G) compared with those with a A allele. (OR = 1.226, 95%CI: 1.177-1.277 and OR = 1.274, 95%CI: 1.175-1.382 respectively). In the subgroup analysis, a significantly increased CD risk was found in both Europeans and Asians. For rs11190140 polymorphism (C/T) and CD risk, the risk estimate for the allele contrast was OR = 1.201 (1.136-1.269). This meta-analysis provided a robust result that persons with a G or T allele may have a moderately increased risk of CD, and suggested that rs10883365 polymorphism was also a candidate gene polymorphism for UC susceptibility. PMID- 24473199 TI - Direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion injury by activating nitric oxide synthase signaling in spontaneously hypertensive rats. AB - BACKGROUND: We tested the hypothesis that direct renin inhibition with aliskiren protects against myocardial ischemia/reperfusion (I/R) injury in spontaneously hypertensive rats (SHR), and examined the mechanism by which this occurs. METHODS AND RESULTS: Male SHR were treated (orally, 4 weeks) with saline or aliskiren (30 or 60 mg kg(-1) day(-1)) and subjected to 30 minutes of left anterior descending coronary artery occlusion followed by 6 or 24 hours of reperfusion. Only the higher dose significantly lowered systolic blood pressure, the lower dose causing a smaller apparent lowering that was nonsignificant. Despite this difference in blood pressure-lowering effect, both doses increased the ejection fraction and fractional shortening and reduced myocardial infarct size equally. I/R decreased cardiac expression of phosphatidylinositol 3-kinase (PI3K), phospho-Akt and phospho-endothelial nitric oxide synthase (phospho-eNOS), but increased expression of inducible nitric oxide synthase (iNOS); these changes were all abrogated by aliskiren. Moreover, aliskiren decreased superoxide anion generation and increased cyclic guanosine-3',5'-monophosphate, an index of bioactive nitric oxide, in myocardium. It also decreased the expression of myocardial matrix metalloproteinase-2, matrix metalloproteinase-9, and tissue inhibitor of metalloproteinases-1 (TIMP-1) following I/R. In a Langendorff heart preparation, the detrimental cardiac effects of I/R were abrogated by aliskiren, and these protective effects were abolished by NOS or PI3K inhibition. In a parallel study, although specific iNOS inhibition reduced plasma malondialdehyde and myocardial superoxide anion generation, it did not affect the deleterious effects of I/R on myocardial structure and function. CONCLUSIONS: Direct renin inhibition protects against myocardial I/R injury through activation of the PI3K-Akt-eNOS pathway. PMID- 24473200 TI - SIL1, a causative cochaperone gene of Marinesco-Sojgren syndrome, plays an essential role in establishing the architecture of the developing cerebral cortex. AB - Marinesco-Sjogren syndrome (MSS) is a rare autosomal recessively inherited disorder with mental retardation (MR). Recently, mutations in the SIL1 gene, encoding a co-chaperone which regulates the chaperone HSPA5, were identified as a major cause of MSS. We here examined the pathophysiological significance of SIL1 mutations in abnormal corticogenesis of MSS. SIL1-silencing caused neuronal migration delay during corticogenesis ex vivo. While RNAi-resistant SIL1 rescued the defects, three MSS-causing SIL1 mutants tested did not. These mutants had lower affinities to HSPA5 in vitro, and SIL1-HSPA5 interaction as well as HSPA5 function was found to be crucial for neuronal migration ex vivo. Furthermore time lapse imaging revealed morphological disorganization associated with abnormal migration of SIL1-deficient neurons. These results suggest that the mutations prevent SIL1 from interacting with and regulating HSPA5, leading to abnormal neuronal morphology and migration. Consistent with this, when SIL1 was silenced in cortical neurons in one hemisphere, axonal growth in the contralateral hemisphere was delayed. Taken together, abnormal neuronal migration and interhemispheric axon development may contribute to MR in MSS. PMID- 24473201 TI - Mixing and matching mitochondrial aminoacyl synthetases and their tRNAs: a new way to treat respiratory chain disorders? AB - Mutations in mitochondrial DNA are an important cause of human disease and from a therapeutic standpoint, these disorders are currently untreatable. New studies now show that a non-cognate mitochondrial aminoacyl tRNA synthetase can overcome the respiratory defect caused by an mt-tRNA mutation and that the isolated carboxy-terminal domain of human mt-leucyl tRNA synthetase can ameliorate the pathologic phenotype. PMID- 24473202 TI - Evaluation of a commercial real-time PCR for the detection of extended spectrum beta-lactamase genes. AB - We investigated the performance of a real-time PCR for the detection of extended spectrum beta-lactamase genes in Enterobacteriaceae (Check-MDR ESBL PCR). Results from micro-arrays were considered as the gold standard. An analysis on 489 isolates resulted in a sensitivity of 98.9 % and a specificity of 100 % for the PCR. PMID- 24473203 TI - Applications of copper-catalyzed click chemistry in activity-based protein profiling. AB - Activity-based protein profiling (ABPP) is a chemical proteomic technique that enables the interrogation of protein activity directly within complex proteomes. Given the dominant role of posttranslational modifications in regulating protein function in vivo, ABPP provides a direct readout of activity that is not attained through traditional proteomic methods. ABPP relies on the design of covalent binding probes that either target a specific enzyme or a class of enzymes with related function. These covalent warheads are coupled to either fluorophores or biotin groups for visualization and enrichment of these active proteins. The advent of bioorthogonal chemistries, in particular, the copper (I)-catalyzed azide-alkyne cycloaddition (CuAAC), has benefitted the field of ABPP by achieving the following: (1) replacing bulky reporter groups with smaller alkyne or azide groups to promote cell permeability; (2) adding modularity to the system such that a single probe can be diversified with a variety of reporter groups without the need to develop new synthetic routes; and (3) enabling the conjugation of complex linkers to facilitate quantitative proteomic analyses. Here, we summarize recent examples of CuAAC in ABPP that serve to illustrate the contribution of bioorthogonal chemistry to advancing discoveries in this field. PMID- 24473204 TI - Antileishmanial lead structures from nature: analysis of structure-activity relationships of a compound library derived from caffeic Acid bornyl ester. AB - Bioassay-guided fractionation of a chloroform extract of Valeriana wallichii (V. wallichii) rhizomes lead to the isolation and identification of caffeic acid bornyl ester (1) as the active component against Leishmania major (L. major) promastigotes (IC50 = 48.8 uM). To investigate the structure-activity relationship (SAR), a library of compounds based on 1 was synthesized and tested in vitro against L. major and L. donovani promastigotes, and L. major amastigotes. Cytotoxicity was determined using a murine J774.1 cell line and bone marrow derived macrophages (BMDM). Some compounds showed antileishmanial activity in the concentration range of pentamidine and miltefosine which are the standard drugs in use. In the L. major amastigote assay compounds 15, 19 and 20 showed good activity with relatively low cytotoxicity against BMDM, resulting in acceptable selectivity indices. Molecules with adjacent phenolic hydroxyl groups exhibited elevated cytotoxicity against murine cell lines J774.1 and BMDM. The Michael system seems not to be essential for antileishmanial activity. Based on the results compound 27 can be regarded as new lead structure for further structure optimization. PMID- 24473205 TI - Ultrasound-assisted extraction of Mangiferin from Mango (Mangifera indica L.) leaves using response surface methodology. AB - Mangiferin is a xanthone widely distributed in higher plants showing antioxidative, antiviral, anticancer, antidiabetic, immunomodulatory, hepatoprotective and analgesic effects. In the present study, an ultrasonic assisted extraction method was developed for the effective extraction of mangiferin from mango leaves. Some parameters such as ethanol concentration, liquid-to-solid ratio, extraction temperature, and extraction time were optimized by single-factor experiment and response surface methodology. The optimal extraction conditions were 44% ethanol, the liquid-to-solid ratio was 38:1, and extraction for 19.2 min at 60 degrees C under ultrasound irradiation of 200 W. Under optimal conditions, the yield of mangiferin was 58.46 +/- 1.27 mg/g. The results obtained are helpful for the full utilization of mango leaves, and also indicated that ultrasonic-assisted extraction is a very useful method for the extraction of mangiferin from plant materials. PMID- 24473206 TI - Griffipavixanthone from Garcinia oblongifolia champ induces cell apoptosis in human non-small-cell lung cancer H520 cells in vitro. AB - Griffipavixanthone (GPX) is a dimeric xanthone which was isolated in a systematic investigation of Garcinia oblongifolia Champ. In this study, we investigate the effect of GPX on cell proliferation and apoptosis on human Non-small-cell lung cancer (NSCLC) cells in vitro and determine the mechanisms of its action. GPX inhibited the growth of H520 cells in dose- and time-dependent manners, with IC50 values of 3.03 +/- 0.21 MUM at 48 h. The morphologic characteristics of apoptosis and apoptotic bodies were observed by fluorescence microscope and transmission electron microscope. In addition, Annexin V/PI double staining assay revealed that cells in early stage of apoptosis were significantly increased upon GPX treatment dose-dependently. Rh123 staining assay indicated that GPX reduced the mitochondrial membrane potential. DCFH-DA staining revealed that intracellular ROS increased with GPX treatment. Moreover, GPX cleaved and activated caspase-3. In summary, this study showed that GPX inhibited H520 cell proliferation in dose- and time-dependent manner. Further mechanistic study indicated that GPX induced cell apoptosis through mitochondrial apoptotic pathway accompanying with ROS production. Our results demonstrate the potential application of GPX as an anti non-small cell lung cancer agent. PMID- 24473207 TI - Natural products from the genus tephrosia. AB - The genus Tephrosia, belonging to the Leguminosae family, is a large pantropical genus of more than 350 species, many of which have important traditional uses in agriculture. This review not only outlines the source, chemistry and biological evaluations of natural products from the genus Tephrosia worldwide that have appeared in literature from 1910 to December 2013, but also covers work related to proposed biosynthetic pathways and synthesis of some natural products from the genus Tephrosia, with 105 citations and 168 new compounds. PMID- 24473208 TI - A review on anti-inflammatory activity of phenylpropanoids found in essential oils. AB - The search for alternative drugs capable of disrupting the inflammatory process has become an important issue in scientific research, especially with reference to the use of natural substances and the reduction of undesirable side effects. Essential oils represent an important source of such substances, since their active constituents often exhibit an array of pharmacological properties, including anti-inflammatory activity. This review presents an overview of the anti-inflammatory action exerted by phenylpropanoids from essential oils and discusses possible mechanisms of action involved in the anti-inflammatory response, assessed through specific experimental models. PMID- 24473210 TI - Synthesis of linear Geranylphenols and their effect on mycelial growth of plant pathogen Botrytis cinerea. AB - Natural geranyl compounds are known to exhibit important biological activities. In this work a series of geranylphenols were synthesized to evaluate their effect on the mycelial growth of Botrytis cinerea. Geranyl derivatives were synthesized by direct geranylation reactions between the corresponding phenol derivatives and geraniol, using BF3.OEt2 as catalyst and AgNO3 as secondary catalyst. Previously reported molecules [geranylhydroquinone (2), geranylhydroquinone diacetate (6) and geranylphloroglucinol (9)], and new substances [(E)-4-(3,7-dimethylocta-2,6 dienyl)benzene-1,2,3-triol (geranyl-pyrogallol, 7), (E)-4-(3,7-dimethylocta-2,6 dienyl)benzene-1,2,3-triyl triacetate (8), (E)-2-(3,7-dimethylocta-2,6 dienyl)benzene-1,3,5-triyl triacetate geranylphloroglucinol triacetate (10), 2,4 bis((E)-3,7-dimethylocta-2,6-dienyl)benzene-1,3,5-triyl triacetate (11), 2,6 bis((E)-3,7-dimethylocta-2,6-dienyl)-3,5-dihydroxyphenyl acetate (12)], were obtained. All compounds were characterized by IR, HRMS and NMR spectroscopic data. The inhibitory effect of the synthesized compounds on the mycelial growth of Botrytis cinerea was tested in vitro. Excepting compound 11, all substances constrained the mycelial growth of Botrytis cinerea. The antifungal activity depends on the chemical structure of geranylphenol derivatives. Compounds 2 and 9 were the more effective substances showing inhibition degrees higher than those obtained with the commercial fungicide Captan, even at lower concentrations. Monosubstitution on the aromatic nucleus by a geranyl chain seems to be more effective for the inhibition of mycelial growth than a double substitution. These results suggest that the new derivatives of geranylphenols have the ability to block the mycelial development of the plant pathogen B. cinerea and that this capacity depends strongly on the structural features and lipophilicity of the compounds. PMID- 24473211 TI - Gas phase thermal reactions of exo-8-cyclopropyl-bicyclo[4.2.0]oct-2-ene (1-exo). AB - The title compound 1-exo (with minor amounts of its C8 epimer 1-endo) was prepared by Wolff-Kishner reduction of the cycloadduct of 1,3-cyclohexadiene and cyclopropylketene. The [1,3]-migration product 2-endo was synthesized by efficient selective cyclopropanation of endo-5-vinylbicyclo[2.2.2]oct-2-ene at the exocyclic pi-bond. Gas phase thermal reactions of 1-exo afforded C8 epimerization to 1-endo, [1,3]- migrations to 2-exo and 2-endo, direct fragmentation to cyclohexadiene and vinylcyclopropane, and CPC rearrangement in the following relative kinetic order: kep > k13 > kf > kCPC. PMID- 24473212 TI - Pharmacological importance of optically active tetrahydro-beta-carbolines and synthetic approaches to create the C1 stereocenter. AB - 1,2,3,4-Tetrahydro-beta-carbolines (THbetaCs) are a pharmacologically important group of compounds belonging to the indole alkaloids. C1-Substituted optically active THbetaCs have been the target of extensive synthetic efforts due to the presence of the scaffold in numerous natural products and synthetic targets. This review briefly summarizes the methods to obtain the C1 stereocenter and concentrates on evaluating the pharmacological importance of optically active C1 substituted THbetaCs, including their PDE5-inhibitory, antimalarial, antiviral and antitumor activities. PMID- 24473213 TI - miRNA in plasma exosome is stable under different storage conditions. AB - Exosomes are small membrane-bound vesicles secreted by most cell types. Exosomes contain various functional proteins, mRNAs and microRNAs (miRNAs) that could be used for diagnostic and therapeutic purposes. How we should store the samples before RNA isolation and whether those long term stored samples could be used for circulating RNA investigation because of RNase is unknown. The aim of the study was to determine the stability of circulating miRNA in exosomes and plasma. Exosomes were isolated from plasma samples by using ExoQuick Precipitation methods. RNA was extracted from exosomes and the corresponding plasma samples with a Qiagen miRNeasy Mini kit. The concentration of RNA was measured by a Qubit(r) RNA HS Assay Kit, and quantitative PCR was used for individual miRNA expression level detection. Results showed that exosomal miRNA showed extra stability under different storage conditions and no significant influence on plasma miRNA, except for short term storage at 4 degrees C. It is thus indicated that exosome miRNAs can be good biomarkers based on their stability under various storage conditions. PMID- 24473214 TI - Ursolic Acid-enriched herba cynomorii extract induces mitochondrial uncoupling and glutathione redox cycling through mitochondrial reactive oxygen species generation: protection against menadione cytotoxicity in h9c2 cells. AB - Herba Cynomorii (Cynomorium songaricum Rupr., Cynomoriaceae) is one of the most commonly used 'Yang-invigorating' tonic herbs in Traditional Chinese Medicine (TCM). An earlier study in our laboratory has demonstrated that HCY2, an ursolic acid-enriched fraction derived from Herba Cynomorii, increased mitochondrial ATP generation capacity (ATP-GC) and induced mitochondrial uncoupling as well as a cellular glutathione response, thereby protecting against oxidant injury in H9c2 cells. In this study, we demonstrated that pre-incubation of H9c2 cells with HCY2 increased mitochondrial reactive oxygen species (ROS) generation in these cells, which is likely an event secondary to the stimulation of the mitochondrial electron transport chain. The suppression of mitochondrial ROS by the antioxidant dimethylthiourea abrogated the HCY2-induced enhancement of mitochondrial uncoupling and glutathione reductase (GR)-mediated glutathione redox cycling, and also protected against menadione-induced cytotoxicity. Studies using specific inhibitors of uncoupling protein and GR suggested that the HCY2-induced mitochondrial uncoupling and glutathione redox cycling play a determining role in the cytoprotection against menadione-induced oxidant injury in H9c2 cells. Experimental evidence obtained thus far supports the causal role of HCY2-induced mitochondrial ROS production in eliciting mitochondrial uncoupling and glutathione antioxidant responses, which offer cytoprotection against oxidant injury in H9c2 cells. PMID- 24473209 TI - Cross-talk of phosphorylation and prolyl isomerization of the C-terminal domain of RNA Polymerase II. AB - Post-translational modifications of the heptad repeat sequences in the C-terminal domain (CTD) of RNA polymerase II (Pol II) are well recognized for their roles in coordinating transcription with other nuclear processes that impinge upon transcription by the Pol II machinery; and this is primarily achieved through CTD interactions with the various nuclear factors. The identification of novel modifications on new regulatory sites of the CTD suggests that, instead of an independent action for all modifications on CTD, a combinatorial effect is in operation. In this review we focus on two well-characterized modifications of the CTD, namely serine phosphorylation and prolyl isomerization, and discuss the complex interplay between the enzymes modifying their respective regulatory sites. We summarize the current understanding of how the prolyl isomerization state of the CTD dictates the specificity of writers (CTD kinases), erasers (CTD phosphatases) and readers (CTD binding proteins) and how that correlates to transcription status. Subtle changes in prolyl isomerization states cannot be detected at the primary sequence level, we describe the methods that have been utilized to investigate this mode of regulation. Finally, a general model of how prolyl isomerization regulates the phosphorylation state of CTD, and therefore transcription-coupled processes, is proposed. PMID- 24473215 TI - Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside isolated from Polygonum cuspidatum exhibits anti-hepatocellular carcinoma viability by inducing apoptosis via the JNK and ERK pathway. AB - Resveratrol-4-O-D-(2'-galloyl)-glucopyranoside (RESG) is one of the active compounds isolated from Polygonum cuspidatum. The purpose of our present study was to investigate the anti-hepatocellular carcinoma effect of RESG in vitro and in vivo, and the possible mechanisms in vitro. In vitro, our results showed that RESG could significantly inhibit the human hepatocellular carcinoma viability in the MTT assay, in a dose- and time-dependent manner. Furthermore, our results demonstrated that RESG could induce SMMC-7721 cell apoptosis and activate caspases 3 and caspases 9 by using Annexin V-FITC staining and western blot, respectively. In vivo, RESG also showed efficacy in SMMC-7721 xenograft model in nude mice, and further molecule mechanisms were investigated in vitro. The results showed that RESG up-regulated the p-JNK expressions, whereas it down regulated the p-ERK expressions. Above results demonstrated that RESG is a potential therapeutic agent for hepatocellular carcinoma via JNK and ERK pathway to induce apoptosis. Our finding provided a basis for further development of RESG as an anticancer agent. PMID- 24473216 TI - A new dicoumarinyl ether from the roots of Stellera chamaejasme L. AB - A new dicoumarinyl ether, 3-hydroxy-6-methoxy-7,7'-dicoumarinyl ether (1), was isolated from the roots of Stellera chamaejasme L, together with the known compound umbelliferone (2). Their structures were determined on the basis of spectroscopic techniques, including IR, NMR, and HR-ESI-MS. PMID- 24473217 TI - Clinical examination protocol to detect atypical and classical scrapie in sheep. AB - The diagnosis of scrapie, a transmissible spongiform encephalopathy (TSEs) of sheep and goats, is currently based on the detection of disease-associated prion protein by post mortem tests. Unless a random sample of the sheep or goat population is actively monitored for scrapie, identification of scrapie cases relies on the reporting of clinical suspects, which is dependent on the individual's familiarization with the disease and ability to recognize clinical signs associated with scrapie. Scrapie may not be considered in the differential diagnosis of neurological diseases in small ruminants, particularly in countries with low scrapie prevalence, or not recognized if it presents as nonpruritic form like atypical scrapie. To aid in the identification of clinical suspects, a short examination protocol is presented to assess the display of specific clinical signs associated with pruritic and nonpruritic forms of TSEs in sheep, which could also be applied to goats. This includes assessment of behavior, vision (by testing of the menace response), pruritus (by testing the response to scratching), and movement (with and without blindfolding). This may lead to a more detailed neurologic examination of reporting animals as scrapie suspects. It could also be used in experimental TSE studies of sheep or goats to evaluate disease progression or to identify clinical end-point. PMID- 24473218 TI - Recognition and neutralization of angiotensins I and II using an artificial nanogel receptor fabricated by ligand specificity determinant imprinting. AB - A nanogel combined with a molecularly imprinted polymer (MIP-nanogel) receptor was prepared using the specificity determinant as a template in aqueous media. The artificial receptor can serve as the selective recognition element for angiotensins I and II and a novel way to control hypertension was investigated. PMID- 24473219 TI - Interventions that improve body and brain bioenergetics for Parkinson's disease risk reduction and therapy. AB - Studies of Parkinson's disease (PD) patients, animal models and pathogenic actions of genetic mutations that cause familial PD have established that neuronal bioenergetics are compromised with brainstem and midbrain monoaminergic neurons being particularly vulnerable. Peripheral insulin resistance and diabetes in midlife may increase the risk of PD, and diet and lifestyle changes that increase insulin sensitivity (exercise and intermittent energy restriction) can counteract neurodegenerative processes and improve functional outcome in animal models. Insulin sensitizing glucagon-like peptide 1 (GLP-1) analogs are beneficial in animal models of PD, and the results of an initial clinical trial in PD patients are promising. In addition to improving peripheral and brain energy metabolism, exercise, intermittent energy restriction and GLP-1 analogs may bolster neuronal adaptive stress response pathways that enhance neurotrophic signaling, DNA repair, proteostasis and mitochondrial biogenesis. PMID- 24473220 TI - Does privatisation of vocational rehabilitation improve labour market opportunities? Evidence from a field experiment in Sweden. AB - This paper analyses if privatisation of vocational rehabilitation can improve labour market opportunities for individuals on long-term sickness absence. We use a field experiment performed by the Public Employment Service and the Social Insurance Agency in Sweden during 2008-2010, in which over 4000 participants were randomly offered private and public rehabilitation. We find no differences in employment rates following rehabilitation between individuals who received rehabilitation by private and public providers. Also the average cost of rehabilitation was essentially equal for the two types of providers. This suggests that there are no large efficiency gains from privatising vocational rehabilitation. PMID- 24473221 TI - Characterization of inosine-uridine nucleoside hydrolase (RihC) from Escherichia coli. AB - A non-specific nucleoside hydrolase from Escherichia coli (RihC) has been cloned, overexpressed, and purified to greater than 95% homogeneity. Size exclusion chromatography and sodium dodecyl sulfate polyacrylamide gel electrophoresis show that the protein exists as a homodimer. The enzyme showed significant activity against the standard ribonucleosides with uridine, xanthosine, and inosine having the greatest activity. The Michaelis constants were relatively constant for uridine, cytidine, inosine, adenosine, xanthosine, and ribothymidine at approximately 480MUM. No activity was exhibited against 2'-OH and 3'-OH deoxynucleosides. Nucleosides in which additional groups have been added to the exocyclic N6 amino group also exhibited no activity. Nucleosides lacking the 5' OH group or with the 2'-OH group in the arabino configuration exhibited greatly reduced activity. Purine nucleosides and pyrimidine nucleosides in which the N7 or N3 nitrogens respectively were replaced with carbon also had no activity. PMID- 24473222 TI - The electrochemical reduction of 1-bromo-4-nitrobenzene at zinc electrodes in a room-temperature ionic liquid: a facile route for the formation of arylzinc compounds. AB - The electrochemical reduction of 1-bromo-4-nitrobenzene (p-BrC6H4NO2) at zinc microelectrodes in the [C4mPyrr][NTf2] ionic liquid was investigated via cyclic voltammetry. The reduction was found to occur via an EC type mechanism, where p BrC6H4NO2 is first reduced by one electron, quasi-reversibly, to yield the corresponding radical anion. The radical anions then react with the Zn electrode to form arylzinc products. Introduction of carbon dioxide into the system led to reaction with the arylzinc species, fingerprinting the formation of the latter. This method thus demonstrates a proof-of-concept of the formation of functionalised arylzinc species. PMID- 24473223 TI - Late-onset lattice corneal dystrophy without typical lattice lines caused by a novel mutation in the TGFBI gene. AB - PURPOSE: The aim of this study was to report the clinical, histopathological, and molecular findings in a patient with late-onset lattice corneal dystrophy (LCD) without typical lattice lines and a novel mutation in the TGFBI gene. METHODS: Corneal lesions were visualized by slit-lamp examination and by in vivo confocal microscopy. Histopathological examination was performed on the patient's corneal specimen obtained during a deep anterior lamellar keratoplasty. By using genomic DNA as a template, all coding regions of the TGFBI gene were amplified and directly sequenced. The presence of the mutation was verified using restriction endonuclease digestion. Eight different computational methods and multiple sequence alignments were used to predict the pathogenicity of the novel genetic variant. RESULTS: The corneal phenotype was characterized by the presence within the stroma of round, oval, and short comma-shaped structures with indistinct margins. Lattice lines were not visible. Histopathological study revealed positive Congo red areas of amyloid deposits typical for LCD. A novel heterozygous missense mutation p.Leu565Pro was identified in exon 13 of the TGFBI gene. The amino acid substitution was unambiguously predicted to have a high pathogenic potential. CONCLUSIONS: The mutant codon 565 is located at the C terminus in the region corresponding to a highly conserved amino acid in the fourth fascilin domain of the TGFBI protein. The novel variant expands the spectrum of TGFBI mutations causing LCD and located in this region. An increased number of known mutations will facilitate future studies of genotype-phenotype correlations and molecular pathogenesis of corneal dystrophies. PMID- 24473224 TI - Clinical utility of combined Placido-scanning-slit midperipheral and thinnest point pachymetry after corneal ablation for myopia. AB - PURPOSE: The aim of this study was to assess the random error of the thinnest point and midperipheral pachymetry with a combined Placido-scanning-slit system (Orbscan II) in the intermediate-term follow-up of excimer laser keratorefractive surgery for treating myopia. METHODS: Sixty-five patients who had undergone aspheric surface ablation for treating myopia with a minimum follow-up of 6 months, and showed no biomicroscopically detectable corneal haze, were subjected to 5 consecutive topographic examinations. All eyes underwent a complete ophthalmic examination before the surgery. The within-subject SD (Sw), repeatability (2.77 * Sw), coefficient of repeatability (2.77 * Sw/mean), and intraclass correlation coefficients of pachymetry at the thinnest point and in each 4 quadrants at a 6-mm diameter were calculated. RESULTS: The patients had a mean age of 31.9 +/- 6.2 years, and the average follow-up was for 7.5 +/- 2.6 months. The mean ablation depth for myopia was 63.6 +/- 23.6 MUm. The average pachymetry for the thinnest point and midperipheral superior, inferior, nasal, and temporal locations was 456.9, 602.0, 595.5, 609.7, and 566.1 MUm, respectively. The repeatability (and coefficient of repeatability) for the thinnest point and midperipheral superior, inferior, nasal, and temporal locations was 26.5 (5.8%), 37.9 (6.3%), 31.0 (5.2%), 30.5 (5.0%), and 35.4 MUm (6.2%), respectively. The intraclass correlation coefficients were 0.96, 0.88, 0.89, 0.97, and 0.91 for each location, respectively. CONCLUSIONS: This study provides the repeatability of the thinnest and midperipheral pachymetry using the combined Placido-scanning-slit system in transparent corneas after laser keratorefractive surgery for treatment of myopia. The test-retest reliability provided here will help differentiate real corneal thickness change from measurement noise. For this, only pachymetric changes >6% are likely to be real and therefore useful when evaluating postoperative keratectasia suspects. PMID- 24473225 TI - Use of conjoint analysis to assess breast cancer patient preferences for chemotherapy side effects. AB - OBJECTIVE: Our objective was to evaluate preferences associated with grade I/II and grade III/IV chemotherapy side effects among breast cancer patients receiving chemotherapy. We also assessed trade-offs that patients are willing to make between treatment side effects and the route and schedule of treatment administration. METHODS: In this cross-sectional study, patients receiving chemotherapy for breast cancer completed a one-time Web survey. Conjoint analysis was used to elicit preferences for 17 grade I/II and III/IV side effects associated with available chemotherapies and regimens. In the analysis, the risk of each side effect was increased by 5%, holding all others constant, and the respective impact on patient preferences was identified. RESULTS: A total of 102 women participated (mean age 54 +/- 11). Among the grade I/II side effects, a 5% reduction in the risk of sensory neuropathy, nausea, and motor neuropathy had the highest impact on preferences. Among grade III/IV side effects, motor neuropathy, nausea/vomiting, and myalgia made the most difference. An oral twice-daily regimen was most preferred; however, patients were willing to receive an intravenous regimen relative to oral to avoid an increased risk of 5% in the majority of side effects. Avoiding an increased chance of grade III/IV motor neuropathy was associated with willingness to tolerate one of the least preferred administration schedules. CONCLUSION: This study identified relative preferences among both mild/moderate to severe side effects from the patient perspective. Patients appear to be willing to make trade-offs between side effects and different regimens. These findings may help to inform medical decision-making processes. PMID- 24473226 TI - Overcoming the brittleness of glass through bio-inspiration and micro architecture. AB - Highly mineralized natural materials such as teeth or mollusk shells boast unusual combinations of stiffness, strength and toughness currently unmatched by engineering materials. While high mineral contents provide stiffness and hardness, these materials also contain weaker interfaces with intricate architectures, which can channel propagating cracks into toughening configurations. Here we report the implementation of these features into glass, using a laser engraving technique. Three-dimensional arrays of laser-generated microcracks can deflect and guide larger incoming cracks, following the concept of 'stamp holes'. Jigsaw-like interfaces, infiltrated with polyurethane, furthermore channel cracks into interlocking configurations and pullout mechanisms, significantly enhancing energy dissipation and toughness. Compared with standard glass, which has no microstructure and is brittle, our bio-inspired glass displays built-in mechanisms that make it more deformable and 200 times tougher. This bio-inspired approach, based on carefully architectured interfaces, provides a new pathway to toughening glasses, ceramics or other hard and brittle materials. PMID- 24473227 TI - The role of green tea extract and powder in mitigating metabolic syndromes with special reference to hyperglycemia and hypercholesterolemia. AB - Natural products are currently gaining popularity to combat various physiological threats. Scientific evidence has been provided that dietary phytochemicals may play important roles as chemo-preventive or chemotherapeutic agents in the prevention of many diseases. Green tea has many biologically active moieties, like flavanols and polyphenols. Catechins are flavanols that constitute the majority of soluble solids of green tea; its major components are epigallocatechin gallate (EGCG), epigallocatechin (EGC), epicatechin gallate (ECG) and epicatechin (EC). Among these, EGCG is the predominant component, contributing more than 50% of polyphenols. It has many health related characteristics, like hypoglycemic, hypocholesterolemic, anticancer, antiviral and antihypertensive activities. Ethanolic extracts of green tea was subjected to in vivo modeling. An efficacy trial was carried out on normal, hyperglycemic and hypercholesterolemic rats for 8 weeks. Control, functional and nutraceutical diets were used for each study. Drink and feed intake and body weight increased during the study period. Serum analysis showed that maximum reduction of cholesterol level was noted in hypercholesterolemic rats, up to 15.45%, due to the nutraceutical diet. It was a 21.51% reduction in the case of LDL and 12.92% for triglycerides. The serum glucose level was most reduced in hyperglycemic rats, up to 13.39% as a result of the nutraceutical diet. The functional diet resulted in a bit less reduction in the respective traits compared to the nutraceutical diet. Hematological analysis revealed that administration of green tea did not adversely affect the red blood cell, white blood cell and platelet count of the rats. The current research work enables us to conclude that green tea is effective against hypercholesterolemia and hyperglycemia. PMID- 24473228 TI - Fullerene-driven encapsulation of a luminescent Eu(III) complex in carbon nanotubes. AB - A novel CNT-based hybrid luminescent material was obtained via encapsulation of a C60-based Eu(III) complex into single-, double- and multi-walled carbon nanotubes (SWCNTs, DWCNTs and MWCNTs, respectively). Specifically, a luminescent negatively charged Eu(III) complex, electrostatically bonded to an imidazolium functionalized fullerene cage, was transported inside CNTs by exploiting the affinity of fullerenes for the inner surface of these carbonaceous containers. The filling was performed under supercritical CO2 (scCO2) conditions to facilitate the entrapment of the ion-paired assembly. Accurate elemental, spectroscopic and morphological characterization not only demonstrated the efficiency of the filling strategy, but also the occurrence of nano-ordering of the encapsulated supramolecular luminophores when SWCNTs were employed. PMID- 24473229 TI - Searching for evidence: a guide to finding the evidence in laboratory medicine. AB - Laboratory medicine is strong in the basic scientific background that underpins the pathological rationale for considering the use of a test, as well as characterising analytical performance of laboratory procedures. Evidence of the impact of test utilisation on health outcomes and adding value to the patient's care pathway is more limited. However, purchasers and commissioners of laboratory services, as well as clinicians, are bombarded with a burgeoning literature on new biomarkers and devices, against a backdrop of fiscal constraints. This increasingly critical appraisal of both current practice, as well as new developments, demands that all health professionals are up-to-date in the knowledge of their subject, as well as being able to access and impart this knowledge in real time to their colleagues in the clinical team. This requirement for knowledge means that the laboratory medicine professional can be asked to provide information at any time, from a host of differing scenarios, and with a considerable variation in the depth of response being required. Thus, the biochemist may need to respond to a query from the Emergency Department on the one hand, to preparing the justification for a new test - or disinvestment in an old (and now inappropriate) test, to writing the case for a research grant proposal. All of these scenarios require clarity in the question being asked, and the ability to search for the evidence across a wide range of resources. This review takes the reader through the steps to efficient retrieval of good quality information. PMID- 24473230 TI - Network reconstruction of platelet metabolism identifies metabolic signature for aspirin resistance. AB - Recently there has not been a systematic, objective assessment of the metabolic capabilities of the human platelet. A manually curated, functionally tested, and validated biochemical reaction network of platelet metabolism, iAT-PLT-636, was reconstructed using 33 proteomic datasets and 354 literature references. The network contains enzymes mapping to 403 diseases and 231 FDA approved drugs, alluding to an expansive scope of biochemical transformations that may affect or be affected by disease processes in multiple organ systems. The effect of aspirin (ASA) resistance on platelet metabolism was evaluated using constraint-based modeling, which revealed a redirection of glycolytic, fatty acid, and nucleotide metabolism reaction fluxes in order to accommodate eicosanoid synthesis and reactive oxygen species stress. These results were confirmed with independent proteomic data. The construction and availability of iAT-PLT-636 should stimulate further data-driven, systems analysis of platelet metabolism towards the understanding of pathophysiological conditions including, but not strictly limited to, coagulopathies. PMID- 24473231 TI - Potential role of carotenoids as antioxidants in human health and disease. AB - Carotenoids constitute a ubiquitous group of isoprenoid pigments. They are very efficient physical quenchers of singlet oxygen and scavengers of other reactive oxygen species. Carotenoids can also act as chemical quenchers undergoing irreversible oxygenation. The molecular mechanisms underlying these reactions are still not fully understood, especially in the context of the anti- and pro oxidant activity of carotenoids, which, although not synthesized by humans and animals, are also present in their blood and tissues, contributing to a number of biochemical processes. The antioxidant potential of carotenoids is of particular significance to human health, due to the fact that losing antioxidant-reactive oxygen species balance results in "oxidative stress", a critical factor of the pathogenic processes of various chronic disorders. Data coming from epidemiological studies and clinical trials strongly support the observation that adequate carotenoid supplementation may significantly reduce the risk of several disorders mediated by reactive oxygen species. Here, we would like to highlight the beneficial (protective) effects of dietary carotenoid intake in exemplary widespread modern civilization diseases, i.e., cancer, cardiovascular or photosensitivity disorders, in the context of carotenoids' unique antioxidative properties. PMID- 24473232 TI - Protective effect of resveratrol on biomarkers of oxidative stress induced by iron/ascorbate in mouse spermatozoa. AB - Resveratrol (RVT) is a polyphenolic compound found mainly in the grape and attributed with various pharmacological properties, among them their antioxidant activity. In the present study, we assess the antioxidant activity of resveratrol on oxidative damage induced by ferrous iron/ascorbate (100 uM/150 uM) in sperm of CD1+ mice. We evaluated several parameters in spermatozoa treated with or without resveratrol: (i) sperm quality analysis; (ii) mitochondrial transmembrane potential (Delta?m); (iii) ROS generation; (iv) superoxide dismutase (SOD) activity; (v) glutathione peroxidase (GPX) activity; (vi) lipid peroxidation; (vii) and in vitro fertilization (IVF) capability. Spermatozoa treated with RVT (15 ug/mL) before ferrous iron/ascorbate treatment exhibited: a significant increase in motility (8-fold), a significant increase in viability (2-fold), a significant increase in Delta?m (1.15-fold), accompanied with a significant decrease in the generation of ROS (4.96-fold), a significant decrease in GPX activity (1.32-fold), and a significant decrease in lipid peroxidation concentration (10.29-fold) relative to spermatozoa treated with ferrous iron/ascorbate; however, no changes in SOD activity were observed. Finally, spermatozoa treated with RVT before ferrous iron/ascorbate treatment showed a significant increase in oocyte fertilization (1.2-fold), relative to spermatozoa treated with ferrous iron/ascorbate. These results suggest that RVT possesses antioxidant properties that may prevent the deleterious effects produced by oxidative damage on spermatozoa, resulting in the maintenance of fertility. PMID- 24473233 TI - Alcohol consumption and risk of glioma: a meta-analysis of 19 observational studies. AB - The relationship between risk of glioma and alcohol consumption has been widely studied, but results have been conflicting. We therefore conducted a meta analysis of observational studies to systematically assess the relationship between alcohol drinking and risk of glioma. Two electronic databases (PubMed and EMBASE) were searched from inception to 8 August 2013 to identify pertinent studies that linked alcohol drinking with glioma risk. We used a random-effects model to calculate the overall relative risk (RR) with corresponding 95% confidence intervals (CIs). Fifteen case-control and four cohort studies were identified for this analysis. The combined RR for total alcohol drinkers versus non-drinkers was 0.96 (95% CI: 0.89-1.04). In the subgroup analysis by geographic area, a significant association was observed in North American studies (RR = 0.78, 95% CI: 0.65-0.93), but not in European or Asian/Australian studies. In the subgroup analysis by study design, a borderline significant association emerged in population-based case-control studies (RR = 0.82, 95% CI: 0.68-0.99), but not in hospital-based case-control studies (RR = 1.00, 95% CI: 0.99-1.01) or cohort group (RR = 1.03, 95% CI: 0.88-1.20). Our results show no material association between alcohol consumption and risk of glioma existed. Further prospective evidences are needed to confirm this association. PMID- 24473234 TI - Immunomodulatory activity of red ginseng against influenza A virus infection. AB - Ginseng herbal medicine has been known to have beneficial effects on improving human health. We investigated whether red ginseng extract (RGE) has preventive effects on influenza A virus infection in vivo and in vitro. RGE was found to improve survival of human lung epithelial cells upon influenza virus infection. Also, RGE treatment reduced the expression of pro-inflammatory genes (IL-6, IL-8) probably in part through interference with the formation of reactive oxygen species by influenza A virus infection. Long-term oral administration of mice with RGE showed multiple immunomodulatory effects such as stimulating antiviral cytokine IFN-gamma production after influenza A virus infection. In addition, RGE administration in mice inhibited the infiltration of inflammatory cells into the bronchial lumens. Therefore, RGE might have the potential beneficial effects on preventing influenza A virus infections via its multiple immunomodulatory functions. PMID- 24473236 TI - Spiropyran-based biodegradable polymer all-optical transistors integrate the switching and modulation of visible light frequency. AB - All-optical modulation of a spiropyran-based device, integrating the transmittance switching (absorption) and wavelength modulation (emission) of visible light frequency induced by alternating UV/visible light irradiation is demonstrated. As an alternative to conventional organic transistors, all-optical devices based on SP-PCL have potential utility as single molecular transistors for optical switching and visible wavelength modulation. PMID- 24473235 TI - Low blood zinc, iron, and other sociodemographic factors associated with behavior problems in preschoolers. AB - Previous research supports the link among malnutrition, cognitive dysfunction, and behavioral outcomes; however, less research has focused on micronutrient deficiencies. This study investigates whether micronutrient deficiencies, specifically blood zinc and iron levels, will be associated with increased behavior problem scores, including internalizing and externalizing behaviors. 1314 Children (55% boys and 45% girls) from the Jintan Preschool Cohort in China participated in this study. Venous blood samples were collected and analyzed for zinc and iron when the children were 3-5 years old. Behavior problems were measured with the Child Behavior Checklist (CBCL), which was completed by the parents when children were in their last months of preschool (mean age 5.6 years). General linear multivariate modeling was used, with adjustment for important sociodemographic variables. The results indicate that low zinc levels alone (p = 0.024) and combined low zinc and iron levels (p = 0.022) are significantly associated with increased reports of total behavior problems. We did not find an association between low iron and behavior problems. With regards to sociodemographics, living in the suburbs is associated with increased internalizing problems, while higher mother's education and being female were associated with decreased externalizing problems. This study suggests that micronutrient deficiencies and sociodemographic facts are associated with behavior problems in preschoolers. PMID- 24473238 TI - Reaction of a charge-separated ONONO2 species with water in the formation of HONO: an MP2 Molecular Dynamics study. AB - The reaction of (NO(+))(NO3(-)) with water is modelled in ONONO2.(H2O)4 clusters. Molecular Dynamics simulations using second-order Moller-Plesset perturbation (MP2) theory support the feasibility of the reaction of a charge-separated species to produce HONO and nitric acid. PMID- 24473237 TI - A microscopic phenotypic assay for the quantification of intracellular mycobacteria adapted for high-throughput/high-content screening. AB - Despite the availability of therapy and vaccine, tuberculosis (TB) remains one of the most deadly and widespread bacterial infections in the world. Since several decades, the sudden burst of multi- and extensively-drug resistant strains is a serious threat for the control of tuberculosis. Therefore, it is essential to identify new targets and pathways critical for the causative agent of the tuberculosis, Mycobacterium tuberculosis (Mtb) and to search for novel chemicals that could become TB drugs. One approach is to set up methods suitable for the genetic and chemical screens of large scale libraries enabling the search of a needle in a haystack. To this end, we developed a phenotypic assay relying on the detection of fluorescently labeled Mtb within fluorescently labeled host cells using automated confocal microscopy. This in vitro assay allows an image based quantification of the colonization process of Mtb into the host and was optimized for the 384-well microplate format, which is proper for screens of siRNA-, chemical compound- or Mtb mutant-libraries. The images are then processed for multiparametric analysis, which provides read out inferring on the pathogenesis of Mtb within host cells. PMID- 24473239 TI - Degradation mechanisms of bioresorbable polyesters. Part 2. Effects of initial molecular weight and residual monomer. AB - This paper presents an understanding of how initial molecular weight and initial monomer fraction affect the degradation of bioresorbable polymers in terms of the underlying hydrolysis mechanisms. A mathematical model was used to analyse the effects of initial molecular weight for various hydrolysis mechanisms including noncatalytic random scission, autocatalytic random scission, noncatalytic end scission or autocatalytic end scission. Different behaviours were identified to relate initial molecular weight to the molecular weight half-life and to the time until the onset of mass loss. The behaviours were validated by fitting the model to experimental data for molecular weight reduction and mass loss of samples with different initial molecular weights. Several publications that consider initial molecular weight were reviewed. The effect of residual monomer on degradation was also analysed, and shown to accelerate the reduction of molecular weight and mass loss. An inverse square root law relationship was found between molecular weight half-life and initial monomer fraction for autocatalytic hydrolysis. The relationship was tested by fitting the model to experimental data with various residual monomer contents. PMID- 24473241 TI - How does the journal impact factor affect the CV of PhD students? PMID- 24473240 TI - Listening effort and perceived clarity for normal-hearing children with the use of digital noise reduction. AB - OBJECTIVES: The goal of this study was to evaluate how digital noise reduction (DNR) impacts listening effort and judgment of sound clarity in children with normal hearing. It was hypothesized that when two DNR algorithms differing in signal-to-noise ratio (SNR) output are compared, the algorithm that provides the greatest improvement in overall output SNR will reduce listening effort and receive a better clarity rating from child listeners. A secondary goal was to evaluate the relation between the inversion method measurements and listening effort with DNR processing. DESIGN: Twenty-four children with normal hearing (ages 7 to 12 years) participated in a speech recognition task in which consonant vowel-consonant nonwords were presented in broadband background noise. Test stimuli were recorded through two hearing aids with DNR off and DNR on at 0 dB and +5 dB input SNR. Stimuli were presented to listeners and verbal response time (VRT) and phoneme recognition scores were measured. The underlying assumption was that an increase in VRT reflects an increase in listening effort. Children rated the sound clarity for each condition. The two commercially available HAs were chosen based on: (1) an inversion technique, which was used to quantify the magnitude of change in SNR with the activation of DNR, and (2) a measure of magnitude-squared coherence, which was used to ensure that DNR in both devices preserved the spectrum. RESULTS: One device provided a greater improvement in overall output SNR than the other. Both DNR algorithms resulted in minimal spectral distortion as measured using coherence. For both devices, VRT decreased for the DNR-on condition, suggesting that listening effort decreased with DNR in both devices. Clarity ratings were also better in the DNR-on condition for both devices. The device showing the greatest improvement in output SNR with DNR engaged improved phoneme recognition scores. The magnitude of this improved phoneme recognition was not accurately predicted with measurements of output SNR. Measured output SNR varied in the ability to predict other outcomes. CONCLUSIONS: Overall, results suggest that DNR effectively reduces listening effort and improves subjective clarity ratings in children with normal hearing but that these improvements are not necessarily related to the output SNR improvements or preserved speech spectra provided by the DNR. PMID- 24473242 TI - Safety and feasibility of post-stroke care and exercise after minor ischemic stroke or transient ischemic attack: MotiveS & MoveIT. AB - BACKGROUND: Despite the beneficial effect of cardiac rehabilitation after myocardial infarction, a rehabilitation program to improve cardiorespiratory fitness and influence secondary prevention has not been implemented for ischemic stroke and transient ischemic attack (TIA). OBJECTIVE: To investigate the safety and feasibility of a post-stroke care including an exercise program after minor ischemic stroke or TIA. METHODS: In a randomised controlled trial, 20 patients with a recent minor stroke or TIA without cardiac contraindications were randomly assigned to one of the two interventions; post-stroke care without exercise or post-stroke care with exercise. Patients were evaluated at baseline, 6 and 12 months. RESULTS: Eighteen patients completed the intervention. In none of the patients cardiopulmonary contraindications for the maximal exercise test and exercise program were found. No cardiovascular events occurred during the maximal exercise tests and exercise program. After one year, significantly more patients in the post-stroke care with exercise group achieved the composite endpoint of optimal medical therapy. CONCLUSIONS: Post-stroke care including an exercise program is safe and feasible in the acute phase after minor stroke or TIA and might be a way to increase effectiveness of secondary stroke prevention. We are currently conducting a larger trial to validate these results. PMID- 24473243 TI - The effect of stroke on motor selectivity for force control in single- and multi finger force production tasks. AB - BACKGROUND: The stroke patients have difficulties in both voluntary muscle contraction and individual movements. However, there is a lack of quantitative analysis focusing on decreased finger control in stroke patients. OBJECTIVES: The purpose of the study was to identify the changes in motor selectivity in stroke patients during a finger force production task. METHODS: Fifteen stroke patients and fifteen control subjects were asked to perform maximum voluntary force (MVF) production during single- and multi-finger force tasks. Finger interaction indices such as force independence (FI) and force sharing deviation (FSD) were analyzed using measured individual finger forces. RESULTS: MVF analysis in the impaired hand of stroke patients showed that they produced 31% or 41% lower force than their unimpaired hand or the control hand, respectively. For the finger interaction indices, the stroke patients' impaired hand had lower FI and higher FSD than their unimpaired hand or the normal subjects' hand. CONCLUSION: The lower FI and higher FSD show that stroke patients have a limited ability to produce force independently and to synchronize produced multi-finger force, respectively. These results have a negative impact on the selectivity of their motor control. In terms of rehabilitation, we expect that the finger interaction indices used in the present study can quantify motor selectivity in the damaged central nervous system. PMID- 24473244 TI - The effects of speed-dependent treadmill training and rhythmic auditory-cued overground walking on balance function, fall incidence, and quality of life in individuals with idiopathic Parkinson's disease: a randomized controlled trial. AB - OBJECTIVES: The purpose of this single-blinded, randomized controlled study was to examine and compare the immediate and retention effects of progressive speed dependent treadmill training (SDTT) and rhythmic auditory-cued (RAC) training on balance function, fall incidence, and quality of life (QOL) in individuals with PD. METHODS: Twenty participants (mean age 66.1 yrs) with idiopathic PD were randomized into either SDTT (n = 10) or RAC (n = 10) progressive, interval-based locomotor training for 6 weeks. Measures included the Berg Balance Scale (BBS), Rapid Step-Up Test (RST), Activities-specific Balance Confidence Scale, Parkinson's Disease Questionnaire-39 (PDQ), and the NeuroCom Sensory Organization Test (SOT), Motor Control Test, and Limits of Stability (LOS). Fall incidence was assessed prospectively post-training based on six monthly self-report fall calendars. RESULTS: Significant gains in balance measures were observed post training in BBS, RST and SOT for the RAC group and in RST, SOT and LOS for the SDTT group. Gains were retained at 3 months post-training in all measures for RAC group, but only the RST for the SDTT group. No clear trend in reduction in fall frequency was evident. CONCLUSION: Externally-cued locomotor training paradigms with progressive speed challenges produced significant improvements in dynamic balance function in persons with PD, with stronger retention of gains in RAC group. PMID- 24473245 TI - High doses of a new botulinum toxin type A (NT-201) in adult patients with severe spasticity following brain injury and cerebral palsy. AB - BACKGROUND: Spasticity can be a severe disabling disorder requiring high-dose injections of botulinum toxin type A (BoNT-A). Efficacy and safety of high BoNT-A doses in reducing multi-level spasticity of subjects with brain injury and cerebral palsy were investigated. Pain and functional outcome were also assessed. METHOD: High doses (up to 840 IU) of incobotulinumtoxinA were injected in adult subjects with severe spasticity of the upper and lower limbs due to brain injury (BI) and cerebral palsy (CP). The Modified Ashworth Scale, Visual Analogue scale, Glasgow Outcome Scale, Franchay Arm Test (FAT) and Barthel Scale were employed to assess spasticity, pain and functional outcome at baseline, and 4 and 16 weeks after BoNT-A injection. RESULTS: Twenty-two (12 M, 10 F; mean age 38.1 +/- 13.7 years) subjects - 16 subjects with BI and 6 with CP - were enrolled. Elbow, wrist, fingers and ankle muscles showed significant spasticity reduction after BoNT-A injections. The mean FAT score improved, but the benefit was not significant. Three (13.6%) subjects complained of mild adverse events. CONCLUSION: High-dose BoNT-A injections were effective and safe in reducing spasticity of BI and CP subjects. A significant reduction of the pain was also observed, but global functionality and arm dexterity were unchanged. PMID- 24473246 TI - Where are we in terms of poststroke functional outcomes and risk factors. AB - BACKGROUND: Stroke is acute vascular deterioration of cerebral functions and 2nd leading cause of death. As population gets older, as well as the increasing prevalence of stroke and disability from chronic disease, the demand for rehabilitation care will continue to rise. There is need for evidence based rehabilitation approaches and rehabilitation outcomes should be proved by objective questionnairres to qualify the process. OBJECTIVE: To present the functional outcomes of stroke rehabilitation process among functional impairment measure evaluation. Determine the contributing factors on functional gain. MATERIAL-METHODS: Retrospectively assessment of data of 142 posttroke patients performed. In addition to demographical and clinical properties, functional outcomes with functional impairment measurement (FIM) and motor evaluation by Brunnstrom Motricitiy Index were recorded. Risk factors for stroke were questionned also. RESULTS: The mean of ages was 64.30 +/- 11.9 years, male/female ratios were 47.2%/ 52.8%. The functional gain was 20.4% in M-FIM, 14.7% in C-FIM. Better outcomes gained by the patients who stayed longer than 15 days (ANOVA, p: 0.000) and who had hemorrhagic etiology (MannWhitney U, p: 0.048), meanwhile there was no significant difference in gender and plegic side groups on both Motor-FIM and Cognitive-FIM gains (p > 0.05, MannWhitney U). Regression models exhibited highest impact on the M-FIM gain were the admission M-FIM scores and DM (adjusted Rsquare: 0.173, p: 0.000). Admission C-FIM scores had positive correlation with discharge C-FIM scores (r: 0.917, p: 0.000). Although older age was the negative determinant of C-FIM gain (r: -0.202, p: 0.016). We obtained the risk factor distribution 71.8% for HT, 29.6% for CAD, 25.6% for smoking, 16.2% for TIA and 33.1% for DM. All had negative impact on functional outcomes but DM had significantly (regression analysis p < 0.05). CONCLUSION: Improvement by rehabilitation programme determined by FIM scores. Data provided about the poststroke patients and present risk factors. Still there exists similar ratios of risk factors as studies before eventhough prevention recommendations. PMID- 24473247 TI - Montreal-Toulouse language assessment battery for aphasia: validity and reliability evidence. AB - BACKGROUND: In Brazil, no standardized instruments are available to assess language in patients with aphasia. OBJECTIVE: The aim of the current study was to search for reliability and validity evidence for the Montreal-Toulouse Language Assessment Battery (MTL-BR). METHODS: The sample was composed of 537 adults, of whom 463 were healthy individuals and 74 had neurological lesions (25 participants had right hemisphere brain damage, 21 had left hemisphere damage (LHD) with aphasia and 28 had LHD without aphasia). Reliability was assessed by internal consistency (Cronbach's alpha) and test-retest analyses. Test-retest reliability was calculated using the Pearson correlation coefficient, and a repeated measures analysis of variance, with years of education as a covariate. Construct validity was verified by correlations between scores in MTL-BR subtest and similar tasks from other language assessment instruments. RESULTS: Internal consistency was satisfactory (Cronbach's alpha between 0.79 and 0.90), as were correlations between test and retest scores (mean 0.52), and between the MTL-BR and scores in similar instruments. CONCLUSIONS: The present results suggested that the MTL-BR battery had adequate reliability and validity as a method for diagnosing and monitoring aphasia. PMID- 24473248 TI - Effects of the addition of transcranial direct current stimulation to virtual reality therapy after stroke: a pilot randomized controlled trial. AB - BACKGROUND: Upper limb (UL) impairment is the most common disabling deficit following a stroke. Previous studies have suggested that transcranial direct current stimulation (tDCS) enhances the effect of conventional therapies. OBJECTIVE: This pilot double-blind randomized control trial aimed to determine whether or not tDCS, combined with Wii virtual reality therapy (VRT), would be superior to Wii therapy alone in improving upper limb function and quality of life in chronic stroke individuals. METHODS: Twenty participants were randomly assigned either to an experimental group that received VRT and tDCS, or a control group that received VRT and sham tDCS. The therapy was delivered over 15 sessions with 13 minutes of active or sham anodal tDCS, and one hour of virtual reality therapy. The outcomes included were determined using the Fugl-Meyer scale, the Wolf motor function test, the modified Ashworth scale (MAS), grip strength, and the stroke specific quality of life scale (SSQOL). Minimal clinically important differences (MCID) were observed when assessing outcome data. RESULTS: Both groups demonstrated gains in all evaluated areas, except for the SSQOL-UL domain. Differences between groups were only observed in wrist spasticity levels in the experimental group, where more than 50% of the participants achieved the MCID. CONCLUSIONS: These findings support that tDCS, combined with VRT therapy, should be investigated and clarified further. PMID- 24473249 TI - The effects of speed-dependent treadmill training and rhythmic auditory-cued overground walking on gait function and fall risk in individuals with idiopathic Parkinson's disease: a randomized controlled trial. AB - OBJECTIVES: The purpose of this randomized controlled study was to examine and compare the immediate and retention effects of speed-dependent treadmill training (SDTT) and rhythmic auditory-cued (RAC) overground walking on gait function and fall risk in individuals with Parkinson's disease (PD). METHODS: Twenty participants (mean age 66.1 yrs) with idiopathic PD were randomized into either SDTT (n = 10) or RAC (n = 10) progressive, interval-based locomotor training protocols. Immediate and retention training effects on gait function and fall risk were measured by comfortable and fast gait speed (CGS, FGS), 6-Minute Walk Test (6MWT), and Functional Gait Assessment (FGA). RESULTS: Immediate within group training effects revealed significant gains in CGS, 6MWT, and FGA for the RAC group, and in FGS, 6-MinuteWalk Test, and FGA for the SDTT group. Retention effects were found at 3-month follow-up for all gait measures in the RAC group, and for FGS and FGA in the SDTT group. No statistically significant differences in immediate or retention training effects on gait measures were found between groups. CONCLUSIONS: Externally-cued locomotor training with progressive and interval-based speed challenges, either with RAC overground or on a treadmill, produced significant improvements in walking speed, endurance, and dynamic balance during walking. PMID- 24473251 TI - Neuroimaging and the school-based assessment of traumatic brain injury. AB - Advanced neuroimaging contributes to a greater understanding of brain pathology following a traumatic brain injury (TBI) and has the ability to guide neurorehabilitation decisions. When integrated with the school-based psychoeducational assessment of a child with a TBI, neuroimaging can provide a different perspective when interpreting educational and behavioral variables relevant to school-based neurorehabilitation. School psychologists conducting traditional psychoeducational assessments of children with TBI seldom obtain and integrate neuroimaging, despite its availability. This article presents contextual information on the medical assessment of TBI, major types of neuroimaging, and networks of the brain. A case study illustrates the value of incorporating neuroimaging into the standard school-based psychoeducational evaluations of children with traumatic brain injury. PMID- 24473250 TI - The influence of weaning duration on rehabilitative outcome in early neurological rehabilitation. AB - BACKGROUND: We investigated if longer weaning is associated with inferior rehabilitative outcome in critical illness polyneuropathy (CIP) and cerebrovascular diseases (CVD). METHODS: We analysed retrospectively weaning protocols and medical histories of 171 tracheotomized patients with CIP and CVD. We assessed weaning durations (WD), independence in activities of daily living, as assessed by the functional independence measure (FIM), mortality rates and discharge modalities in each cohort. Weaning was performed using synchronized intermittent mandatory ventilation (SIMV) with Autoflow(r) and assisted spontaneous ventilation (ASV). RESULTS: WD was significantly longer in CIP compared to CVD (p < 0.001). Despite shorter in-patient treatment and longer WD, patients with CIP acquired significantly greater gains of improvement than CVD (p = 0.015). Independent living at home was possible in 43% of patients with CIP and in 26% of CVD. Mortality was equal in both groups (13% vs. 6%, p > 0.05). Chronic obstructive pulmonary disease (COPD) showed a trend towards longer weaning durations in both entities (p = 0.06). Higher age significantly correlated with longer WD (p = 0.038, r = 0.16). Longer rehabilitation duration (RD) positively correlated with higher Delta-FIM (DFIM) in both entities (p = 0.006, r = 0.21). CONCLUSION: Longer weaning and its partly negative influence on rehabilitative outcome can be compensated by longer in-patient rehabilitation in CIP and CVD. PMID- 24473252 TI - Role of Lactobacillus reuteri cell and mucus-binding protein A (CmbA) in adhesion to intestinal epithelial cells and mucus in vitro. AB - Lactobacillus reuteri, a symbiotic inhabitant of the gastrointestinal tract in humans and animals, is marketed as a probiotic. The ability to adhere to intestinal epithelial cells and mucus is an interesting property with regard to probiotic features such as colonization of the gastrointestinal tract and interaction with the host. Here, we present a study performed to elucidate the role of sortase (SrtA), four putative sortase-dependent proteins (SDPs), and one C-terminal membrane-anchored cell surface protein of Lactobacillus reuteri ATCC PTA 6475 in adhesion to Caco-2 cells and mucus in vitro. This included mutagenesis of the genes encoding these proteins and complementation of mutants. A null mutation in hmpref0536_10255 encoding srtA resulted in significantly reduced adhesion to Caco-2 cells and mucus, indicating involvement of SDPs in adhesion. Evaluation of the bacterial adhesion revealed that of the five putative surface protein mutants tested, only a null mutation in the hmpref0536_10633 gene, encoding a putative SDP with an LPxTG motif, resulted in a significant loss of adhesion to both Caco-2 cells and mucus. Complementation with the functional gene on a plasmid restored adhesion to Caco-2 cells. However, complete restoration of adhesion to mucus was not achieved. Overexpression of hmpref0536_10633 in strain ATCC PTA 6475 resulted in an increased adhesion to Caco-2 cells and mucus compared with the WT strain. We conclude from these results that, among the putative surface proteins tested, the protein encoded by hmpref0536_10633 plays a critical role in binding of Lactobacillus reuteri ATCC PTA 6475 to Caco-2 cells and mucus. Based on this, we propose that this LPxTG motif containing protein should be referred to as cell and mucus binding protein A (CmbA). PMID- 24473253 TI - Diagnostic performance of a stand-alone central blood pressure monitor: application of central blood pressure in the diagnosis of high blood pressure. AB - BACKGROUND: Oscillometric central blood pressure (CBP) monitors have emerged as a new technology for blood pressure (BP) measurements. With a newly proposed diagnostic threshold for CBP, we investigated the diagnostic performance of a novel CBP monitor. METHODS: We recruited a consecutive series of 138 subjects (aged 30-93 years) without previous use of antihypertensive agents for simultaneous invasive and noninvasive measurements of BP in a catheterization laboratory. With the cutoff (CBP >=130/90 mm Hg) for high blood pressure (HBP), the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of the novel CBP monitor were calculated with reference to the measured CBP. In comparison, the diagnostic performance of the conventional cuff BP was also evaluated. RESULTS: The noninvasive CBP for detecting HBP in a sample with a prevalence of 52% showed a sensitivity of 93% (95% confidence interval (CI) = 91-95), specificity of 95% (95% CI = 94-97), PPV of 96% (95% CI = 94-97), and NPV of 93% (95% CI = 90-95). In contrast, with cuff BP and the traditional HBP criterion (cuff BP >=140/90 mm Hg), the sensitivity, specificity, PPV, and NPV were 49% (95% CI = 44-53), 94% (95% CI = 92-96), 90% (95% CI = 86 93), and 63% (95% CI 59-66), respectively. CONCLUSIONS: A stand-alone oscillometric CBP monitor may provide CBP values with acceptable diagnostic accuracy. However, with reference to invasively measured CBP, cuff BP had low sensitivity and NPV, which could render possible management inaccessible to a considerable proportion of HBP patients, who may be identifiable through noninvasive CBP measurements from the CBP monitor. PMID- 24473254 TI - Gene-education interactions identify novel blood pressure loci in the Framingham Heart Study. AB - BACKGROUND: Blood pressure (BP) variability has a genetic component, most of which has yet to be attributed to specific variants. One promising strategy for gene discovery is analysis of interactions between single-nucleotide polymorphisms (SNPs) and BP-related factors, including age, sex, and body mass index (BMI). Educational attainment, a marker for socioeconomic status, has effects on both BP and BMI. METHODS: We investigated SNP-education interaction effects on BP in genome-wide data on 3,836 subjects in families from the Framingham Heart Study. The ABEL suite was used to adjust for age, sex, BMI, medication use, and kinship and to perform 1 degree-of-freedrom (df) and 2 df SNP education interaction tests. RESULTS: An SNP in PTN was associated with increased systolic BP (5.4mm Hg per minor allele) in those without a bachelor's degree but decreased systolic BP (1.6mm Hg per allele) in those with a bachelor's degree (2 df; P = 2.08 * 10(-8)). An SNP in TOX2 was associated with increased diastolic BP (DBP; 4.1mm Hg per minor allele) in those with no more educational attainment than high school but decreased DBP in those with education past high school ( 0.7; 1 df; P = 3.74 * 10(-8)). Three suggestive associations were also found: in MYO16 (pulse pressure: 2 df; P = 2.89 * 10(-7)), in HAS2 (DBP: 1 df; P = 1.41 * 10(-7)), and in DLEU2 (DBP: 2 df; P = 1.93 * 10(-7)). All 5 genes are related to BP, including roles in vasodilation and angiogenesis for PTN and TOX2. CONCLUSIONS: PTN and TOX2 are associated with BP. Analyzing SNP-education interactions may detect novel associations. Education may be a surrogate for unmeasured exposures and behaviors modifying SNP effects on BP. PMID- 24473256 TI - GP is struck off after exposure by television documentary. PMID- 24473257 TI - Focus on pain. PMID- 24473255 TI - Association of morning and evening blood pressure at home with asymptomatic organ damage in the J-HOP Study. AB - BACKGROUND: Several guidelines recommend that home blood pressure (HBP) be measured both in the morning and in the evening. However, there have been fewer reports about the clinical significance of morning HBP than about the clinical significance of evening HBP. METHODS: Our study included 4,310 patients recruited for the Japan Morning Surge Home Blood Pressure Study who had one or more cardiovascular risk factors. We measured morning and evening HBP, urinary albumin creatinine ratio (UACR), left ventricular mass index (LVMI), brachial-ankle pulse wave velocity (baPWV), maximum carotid intima media thickness (IMT), N-terminal pro-brain-type natriuretic peptide (NT-proBNP), and high-sensitivity cardiac troponin T (Hs-cTnT). RESULTS: The correlation coefficients for the associations between morning systolic BP (SBP) and log-transformed baPWV, NT-proBNP, or Hs cTnT were significantly greater than the corresponding relationships for evening SBP (all P < 0.01). The goodness-of-fit of the associations between morning home SBP and UACR (P < 0.05) or baPWV (P < 0.01) was improved by adding evening home SBP to the SBP measurement. In contrast, the goodness-of-fit values of the associations between evening SBP and UACR (P < 0.001), LVMI (P < 0.05), baPWV (P < 0.001), NT-proBNP (P < 0.001), and Hs-cTnT (P < 0.001) were improved by adding morning home SBP to the SBP measurement. CONCLUSIONS: Morning BP and evening BP provide equally useful information for subclinical target organ damage, yet multivariate modeling highlighted the stand-alone predictive ability of morning BP. PMID- 24473258 TI - Ground zero in Alzheimer's disease. PMID- 24473259 TI - Stereotopy versus stochasticity in olfaction. PMID- 24473260 TI - Motor variability is not noise, but grist for the learning mill. PMID- 24473261 TI - Stimulating memory consolidation. PMID- 24473262 TI - Deciphering CA2 connectivity. PMID- 24473263 TI - Regulating excitability of peripheral afferents: emerging ion channel targets. AB - The transmission and processing of pain signals relies critically on the activities of ion channels that are expressed in afferent pain fibers. This includes voltage-gated channels, as well as background (or leak) channels that collectively regulate resting membrane potential and action potential firing properties. Dysregulated ion channel expression in response to nerve injury and inflammation results in enhanced neuronal excitability that underlies chronic neuropathic and inflammatory pain. Pharmacological modulators of ion channels, particularly those that target channels on peripheral neurons, are being pursued as possible analgesics. Over the past few years, a number of different types of ion channels have been implicated in afferent pain signaling. Here we give an overview of recent advances on sodium, calcium, potassium and chloride channels that are emerging as especially attractive targets for the treatment of pain. PMID- 24473264 TI - Peripheral gating of pain signals by endogenous lipid mediators. AB - Primary sensory afferents and their neighboring host-defense cells are a rich source of lipid-derived mediators that contribute to the sensation of pain caused by tissue damage and inflammation. But an increasing number of lipid molecules have been shown to act in an opposite way, to suppress the inflammatory process, restore homeostasis in damaged tissues and attenuate pain sensitivity by regulating neural pathways that transmit nociceptive signals from the periphery of the body to the CNS. Here we review the molecular and cellular mechanisms that contribute to the modulatory actions of lipid mediators in peripheral nociceptive signaling. PMID- 24473265 TI - Why we scratch an itch: the molecules, cells and circuits of itch. AB - Itch is described as an irritating sensation that triggers a desire to scratch. However, this definition hardly seems fitting for the millions of people who suffer from intractable itch. Indeed, the Buddhist philosopher Nagarjuna more aptly stated, "There is pleasure when an itch is scratched. But to be without an itch is more pleasurable still." Chronic itch is widespread and very difficult to treat. In this review we focus on the molecules, cells and circuits in the peripheral and central nervous systems that drive acute and chronic itch transmission. Understanding the itch circuitry is critical to developing new therapies for this intractable disease. PMID- 24473266 TI - Normal and abnormal coding of somatosensory stimuli causing pain. AB - Noxious stimuli usually cause pain and pain usually arises from noxious stimuli, but exceptions to these apparent truisms are the basis for clinically important problems and provide valuable insight into the neural code for pain. In this Review, we discuss how painful sensations arise. We argue that, although primary somatosensory afferents are tuned to specific stimulus features, natural stimuli often activate more than one type of afferent. Manipulating coactivation patterns can alter perception in ways that argue against each type of afferent acting independently (as expected for strictly labeled lines), suggesting instead that signals conveyed by different types of afferents interact. Deciphering the central circuits that mediate those interactions is critical for explaining the generation and modulation of neural signals that ultimately elicit pain. The advent of genetic and optical dissection techniques promise to dramatically accelerate progress toward this goal, which will facilitate the rational design of future pain therapeutics. PMID- 24473269 TI - MoS2/MX2 heterobilayers: bandgap engineering via tensile strain or external electrical field. AB - We have performed a comprehensive first-principles study of the electronic and magnetic properties of two-dimensional (2D) transition-metal dichalcogenide (TMD) heterobilayers MX2/MoS2 (M = Mo, Cr, W, Fe, V; X = S, Se). For M = Mo, Cr, W; X = S, Se, all heterobilayers show semiconducting characteristics with an indirect bandgap with the exception of the WSe2/MoS2 heterobilayer which retains the direct-bandgap character of the constituent monolayer. For M = Fe, V; X = S, Se, the MX2/MoS2 heterobilayers exhibit metallic characters. Particular attention of this study has been focused on engineering the bandgap of the TMD heterobilayer materials via application of either a tensile strain or an external electric field. We find that with increasing either the biaxial or uniaxial tensile strain, the MX2/MoS2 (M = Mo, Cr, W; X = S, Se) heterobilayers can undergo a semiconductor-to-metal transition. For the WSe2/MoS2 heterobilayer, a direct-to indirect bandgap transition may occur beyond a critical biaxial or uniaxial strain. For M (=Fe, V) and X (=S, Se), the magnetic moments of both metal and chalcogen atoms are enhanced when the MX2/MoS2 heterobilayers are under a biaxial tensile strain. Moreover, the bandgap of MX2/MoS2 (M = Mo, Cr, W; X = S, Se) heterobilayers can be reduced by the vertical electric field. For two heterobilayers MSe2/MoS2 (M = Mo, Cr), PBE calculations suggest that the indirect to-direct bandgap transition may occur under an external electric field. The transition is attributed to the enhanced spontaneous polarization. The tunable bandgaps in general and possible indirect-direct bandgap transitions due to tensile strain or external electric field make the TMD heterobilayer materials a viable candidate for optoelectronic applications. PMID- 24473268 TI - Genomic analysis of thermophilic Bacillus coagulans strains: efficient producers for platform bio-chemicals. AB - Microbial strains with high substrate efficiency and excellent environmental tolerance are urgently needed for the production of platform bio-chemicals. Bacillus coagulans has these merits; however, little genetic information is available about this species. Here, we determined the genome sequences of five B. coagulans strains, and used a comparative genomic approach to reconstruct the central carbon metabolism of this species to explain their fermentation features. A novel xylose isomerase in the xylose utilization pathway was identified in these strains. Based on a genome-wide positive selection scan, the selection pressure on amino acid metabolism may have played a significant role in the thermal adaptation. We also researched the immune systems of B. coagulans strains, which provide them with acquired resistance to phages and mobile genetic elements. Our genomic analysis provides comprehensive insights into the genetic characteristics of B. coagulans and paves the way for improving and extending the uses of this species. PMID- 24473267 TI - Pain vulnerability: a neurobiological perspective. AB - There are many known risk factors for chronic pain conditions, yet the biological underpinnings that link these factors to abnormal processing of painful signals are only just beginning to be explored. This Review will discuss the potential mechanisms that have been proposed to underlie vulnerability and resilience toward developing chronic pain. Particular focus will be given to genetic and epigenetic processes, priming effects on a cellular level, and alterations in brain networks concerned with reward, motivation/learning and descending modulatory control. Although research in this area is still in its infancy, a better understanding of how pain vulnerability emerges has the potential to help identify individuals at risk and may open up new therapeutic avenues. PMID- 24473271 TI - Ultrafast dynamics of single molecules. AB - The detection of individual molecules has found widespread application in molecular biology, photochemistry, polymer chemistry, quantum optics and super resolution microscopy. Tracking of an individual molecule in time has allowed identifying discrete molecular photodynamic steps, action of molecular motors, protein folding, diffusion, etc. down to the picosecond level. However, methods to study the ultrafast electronic and vibrational molecular dynamics at the level of individual molecules have emerged only recently. In this review we present several examples of femtosecond single molecule spectroscopy. Starting with basic pump-probe spectroscopy in a confocal detection scheme, we move towards deterministic coherent control approaches using pulse shapers and ultra-broad band laser systems. We present the detection of both electronic and vibrational femtosecond dynamics of individual fluorophores at room temperature, showing electronic (de)coherence, vibrational wavepacket interference and quantum control. Finally, two colour phase shaping applied to photosynthetic light harvesting complexes is presented, which allows investigation of the persistent coherence in photosynthetic complexes under physiological conditions at the level of individual complexes. PMID- 24473270 TI - The dipeptide monoester prodrugs of floxuridine and gemcitabine-feasibility of orally administrable nucleoside analogs. AB - Dipeptide monoester prodrugs of floxuridine and gemcitabine were synthesized. Their chemical stability in buffers, enzymatic stability in cell homogenates, permeability in mouse intestinal membrane along with drug concentration in mouse plasma, and anti-proliferative activity in cancer cells were determined and compared to their parent drugs. Floxuridine prodrug was more enzymatically stable than floxuridine and the degradation from prodrug to parent drug works as the rate-limiting step. On the other hand, gemcitabine prodrug was less enzymatically stable than gemcitabine. Those dipeptide monoester prodrugs exhibited 2.4- to 48.7-fold higher uptake than their parent drugs in Caco-2, Panc-1, and AsPC-1 cells. Floxuridine and gemcitabine prodrugs showed superior permeability in mouse jejunum to their parent drugs and exhibited the higher drug concentration in plasma after in situ mouse perfusion. Cell proliferation assays in ductal pancreatic cancer cells, AsPC-1 and Panc-1, indicated that dipeptide prodrugs of floxuridine and gemcitabine were more potent than their parent drugs. The enhanced potency of nucleoside analogs was attributed to their improved membrane permeability. The prodrug forms of 5c-L-phenylalanyl-l-tyrosyl-floxuridine and 5c L-phenylalanyl-L-tyrosyl-gemcitabine appeared in mouse plasma after the permeation of intestinal membrane and the first-pass effect, suggesting their potential for the development of oral dosage form for anti-cancer agents. PMID- 24473273 TI - Suppressing triplet state extension for highly efficient ambipolar phosphine oxide host materials in blue PHOLEDs. AB - A series of phosphine oxide hosts were constructed to investigate the influence of the triplet state extension in hosts on electrophosphorescence, in which DPESPOPhCz with the carbazolyl-localized triplet state endowed its blue-emitting PHOLEDs with favourable performance, including an external quantum efficiency more than 13%. PMID- 24473272 TI - Methodology for the efficient generation of fluorescently tagged vaccinia virus proteins. AB - Tagging of viral proteins with fluorescent proteins has proven an indispensable approach to furthering our understanding of virus-host interactions. Vaccinia virus (VACV), the live vaccine used in the eradication of smallpox, is particularly amenable to fluorescent live-cell microscopy owing to its large virion size and the ease with which it can be engineered at the genome level. We report here an optimized protocol for generating recombinant viruses. The minimal requirements for targeted homologous recombination during vaccinia replication were determined, which allows the simplification of construct generation. This enabled the alliance of transient dominant selection (TDS) with a fluorescent reporter and metabolic selection to provide a rapid and modular approach to fluorescently label viral proteins. By streamlining the generation of fluorescent recombinant viruses, we are able to facilitate downstream applications such as advanced imaging analysis of many aspects of the virus-host interplay that occurs during virus replication. PMID- 24473274 TI - Admission hyperglycaemia is associated with higher mortality in patients with hip fracture. AB - OBJECTIVE: To determine the proportion of hip-fracture patients with admission hyperglycaemia, and, when present, whether it was associated with a worse outcome (i.e. increased length of hospital stay, admission to ICU, or mortality). PATIENTS AND METHODS: Over a 2-year period, we retrospectively analysed records of patients with a primary diagnosis of hip fracture (ICD-9-CM 820.x). The records were retrieved from an electronic hospital database. RESULTS: An admission blood sugar level (aBSL) greater than 140 mg/dl was observed in 34% of the patients and was associated with a higher in-hospital mortality (P=0.042). ICU admissions and length of stay did not differ for patients having an aBSL above or below the 140 mg/dl cut-off. CONCLUSION: Hyperglycaemia is common in hip fracture patients. A high aBSL might serve as a prognostic indicator in hip fracture patients. To our knowledge, this is the first report of hyperglycaemia associated mortality in less severely traumatised patients, who generally are not admitted to an ICU. PMID- 24473275 TI - Emergency medical services interval and mortality in significant head injury: a retrospective cohort study. AB - OBJECTIVES: Recent interest has focused on reorganizing emergency medical services (EMS) for English traumatic brain injury (TBI) patients, with bypass of nonspecialist hospitals and direct transportation to distant neuroscience centres. This may expedite specialist neurocritical care and neurosurgical interventions, but risks harms from prehospital deterioration and delayed resuscitation. We therefore aimed to investigate the effect of EMS interval on outcome following head injury. METHODS: We performed a multicentre cohort study examining adult patients with significant TBI (head region abbreviated injury scale >=3) enrolled in the Trauma Audit and Research Network trauma registry between 2005 and 2011. The association between EMS interval and mortality in patients directly admitted to specialist neuroscience centres was explored using bivariate and multivariate logistic regression and propensity score matching analyses. RESULTS: In all, 7149 eligible patients presented directly to specialist neuroscience centres during the study period. Adjusted odds ratios for mortality showed no association between EMS interval and mortality, varying from 0.46 (95% confidence interval 0.1-2.6) for EMS intervals under 20 min to 0.67 (95% confidence interval 0.4-1.2) for EMS intervals more than 120 min (reference EMS interval 40-60 min). This lack of association was also observed following matching using propensity scores, with no significant difference apparent in mortality between EMS intervals less than 60 min and more than 60 min (17.85 vs. 17.0%, P=0.826). These results were unaffected in sensitivity analyses examining missing covariate data or unmeasured outcomes. CONCLUSION: The lack of observed association between EMS interval and mortality may not preclude bypass of significant TBI patients, with concomitantly prolonged primary transfers from the scene of injury to distant specialist centres. However, given the limitations of registry data, our results should be interpreted with caution. PMID- 24473276 TI - The energy landscape of a protein switch. AB - Protein switches are made of highly similar sequences that fold to dramatically different structures. A structural switching system with 31 sequence variants for alpha and alpha+beta folds has been illustrated experimentally by He et al., Structure, 2012, 20, 283 and is investigated computationally in the present study. Methods to assign a sequence to one of the two folds are reported and analyzed. A fast and accurate protocol to identify the correct fold of the 31 sequences is based on enriching modeled structures using short molecular dynamics (MD) trajectories and scoring these structures with coarse-grained energy functions. We examine five coarse-grained energy functions and illustrate that the Hinds-Levitt potential works the best for this task. We show that enrichment by MD significantly enhances prediction accuracy. Finally, we find that melting temperature correlates well with the energy difference between the two folds (correlation coefficient ~-0.7). The correlation reduces dramatically (~0.4) if the absolute energy of the correct fold is considered. Moreover, prediction of melting temperature is sensitive to the structural templates. We emphasize in our analyses the use of native structures as templates since these folds are more readily available from structural biology experiments. PMID- 24473278 TI - A personal account of the early stages of proteomics at Aarhus University. AB - This article is part of a Special Issue entitled: 20 years of Proteomics in memory of Viatliano Pallini. Guest Editors: Luca Bini, Juan J. Calvete, Natacha Turck, Denis Hochstrasser and Jean-Charles Sanchez. PMID- 24473277 TI - Constraint-induced sound therapy for sudden sensorineural hearing loss- behavioral and neurophysiological outcomes. AB - Sudden sensorineural hearing loss is characterized by acute, idiopathic hearing deterioration. We report here the development and evaluation of "constraint induced sound therapy", which is based on a well-established neuro-rehabilitation approach, and which is characterized by the plugging of the intact ear ("constraint") and the simultaneous, extensive stimulation of the affected ear with music. The sudden sensorineural hearing loss patients who received the constraint-induced sound therapy in addition to the standard corticosteroid therapy showed significantly better recovery of hearing function compared to those who had only received corticosteroid treatments. Additionally, the brain activity obtained in a subgroup of patients suggested that the constraint-induced sound therapy could have prevented maladaptive auditory cortex reorganization. Constraint-induced sound therapy thus appears to be an effective, practical, and safe treatment option for sudden sensorineural hearing loss. PMID- 24473279 TI - Combination of metabolomic and phospholipid-profiling approaches for the study of Alzheimer's disease. AB - Alzheimer's disease is closely related to abnormal metabolism of phospholipids from neural membranes, so that the study of their dyshomeostasis could be of great interest for the discovery of potential biomarkers for diagnosis and disease monitoring. In this work, it has been developed a metabolomic multi platform for the characterization of phospholipid alterations occurring in serum from Alzheimer's disease patients. For this purpose, we performed a metabolomic screening by direct infusion mass spectrometry and profiling analysis by reversed phase ultra-high performance liquid chromatography with complementary detection by molecular and atomic mass spectrometry, which allowed combining the high throughput capability of shotgun metabolomics and the targeted character of profiling approaches. Thus significant changes were detected in the levels of several molecular species of phosphatidylcholines, phosphatidylethanolamines, plasmenylcholines, plasmenylethanolamines and different classes of lysophospholipids, which provided a global vision of the possible factors triggering membrane breakdown. In this sense, alterations of phospholipids metabolism appears to have a multifactorial origin involving overactivation of phospholipases, increased anabolism of lysophospholipids, peroxisomal dysfunction, imbalances in the levels of saturated/unsaturated fatty acids contained in the structure of phospholipids and oxidative stress. BIOLOGICAL SIGNIFICANCE: This work represents the first comprehensive characterization of serum phospholipids alterations in relation to Alzheimer's disease, by combining shotgun metabolomics and phospholipids profiling through different analytical approaches.This article is part of a Special Issue entitled: Environmental and structural proteomics. PMID- 24473280 TI - Towards whole body fatigue assessment of human movement: a fatigue-tracking system based on combined sEMG and accelerometer signals. AB - This paper proposes a method to assess the overall fatigue of human body movement. First of all, according to previous research regarding localized muscular fatigue, a linear relation is assumed between the mean frequency and the muscular working time when the muscle is experiencing fatigue. This assumption is verified with a rigorous statistical analysis. Based on this proven linearity, localized muscular fatigue is simplified as a linear model. Furthermore, localized muscular fatigue is considered a dynamic process and, hence, the localized fatigue levels are tracked by updating the parameters with the most current surface electromyogram (sEMG) measurements. Finally, an overall fatigue level is computed by fusing localized muscular fatigue levels. The developed fatigue-tracking system is evaluated with two fatigue experiments (in which 10 male subjects and seven female subjects participated), including holding self weight (dip start position training) and lifting weight with one arm (arm curl training). PMID- 24473281 TI - A wavelet bicoherence-based quadratic nonlinearity feature for translational axis condition monitoring. AB - The translational axis is one of the most important subsystems in modern machine tools, as its degradation may result in the loss of the product qualification and lower the control precision. Condition-based maintenance (CBM) has been considered as one of the advanced maintenance schemes to achieve effective, reliable and cost-effective operation of machine systems, however, current vibration-based maintenance schemes cannot be employed directly in the translational axis system, due to its complex structure and the inefficiency of commonly used condition monitoring features. In this paper, a wavelet bicoherence based quadratic nonlinearity feature is proposed for translational axis condition monitoring by using the torque signature of the drive servomotor. Firstly, the quadratic nonlinearity of the servomotor torque signature is discussed, and then, a biphase randomization wavelet bicoherence is introduced for its quadratic nonlinear detection. On this basis, a quadratic nonlinearity feature is proposed for condition monitoring of the translational axis. The properties of the proposed quadratic nonlinearity feature are investigated by simulations. Subsequently, this feature is applied to the real-world servomotor torque data collected from the X-axis on a high precision vertical machining centre. All the results show that the performance of the proposed feature is much better than that of original condition monitoring features. PMID- 24473282 TI - Mobile robot self-localization system using single webcam distance measurement technology in indoor environments. AB - A single-webcam distance measurement technique for indoor robot localization is proposed in this paper. The proposed localization technique uses webcams that are available in an existing surveillance environment. The developed image-based distance measurement system (IBDMS) and parallel lines distance measurement system (PLDMS) have two merits. Firstly, only one webcam is required for estimating the distance. Secondly, the set-up of IBDMS and PLDMS is easy, which only one known-dimension rectangle pattern is needed, i.e., a ground tile. Some common and simple image processing techniques, i.e., background subtraction are used to capture the robot in real time. Thus, for the purposes of indoor robot localization, the proposed method does not need to use expensive high-resolution webcams and complicated pattern recognition methods but just few simple estimating formulas. From the experimental results, the proposed robot localization method is reliable and effective in an indoor environment. PMID- 24473283 TI - Gaze tracking system for user wearing glasses. AB - Conventional gaze tracking systems are limited in cases where the user is wearing glasses because the glasses usually produce noise due to reflections caused by the gaze tracker's lights. This makes it difficult to locate the pupil and the specular reflections (SRs) from the cornea of the user's eye. These difficulties increase the likelihood of gaze detection errors because the gaze position is estimated based on the location of the pupil center and the positions of the corneal SRs. In order to overcome these problems, we propose a new gaze tracking method that can be used by subjects who are wearing glasses. Our research is novel in the following four ways: first, we construct a new control device for the illuminator, which includes four illuminators that are positioned at the four corners of a monitor. Second, our system automatically determines whether a user is wearing glasses or not in the initial stage by counting the number of white pixels in an image that is captured using the low exposure setting on the camera. Third, if it is determined that the user is wearing glasses, the four illuminators are turned on and off sequentially in order to obtain an image that has a minimal amount of noise due to reflections from the glasses. As a result, it is possible to avoid the reflections and accurately locate the pupil center and the positions of the four corneal SRs. Fourth, by turning off one of the four illuminators, only three corneal SRs exist in the captured image. Since the proposed gaze detection method requires four corneal SRs for calculating the gaze position, the unseen SR position is estimated based on the parallelogram shape that is defined by the three SR positions and the gaze position is calculated. Experimental results showed that the average gaze detection error with 20 persons was about 0.70 degrees and the processing time is 63.72 ms per each frame. PMID- 24473285 TI - Assessing inter-sensor variability and sensible heat flux derivation accuracy for a large aperture scintillometer. AB - The accuracy in determining sensible heat flux (H) of three Kipp and Zonen large aperture scintillometers (LAS) was evaluated with reference to an eddy covariance (EC) system over relatively flat and uniform grassland near Timpas (CO, USA). Other tests have revealed inherent variability between Kipp and Zonen LAS units and bias to overestimate H. Average H fluxes were compared between LAS units and between LAS and EC. Despite good correlation, inter-LAS biases in H were found between 6% and 13% in terms of the linear regression slope. Physical misalignment was observed to result in increased scatter and bias between H solutions of a well-aligned and poorly-aligned LAS unit. Comparison of LAS and EC H showed little bias for one LAS unit, while the other two units overestimated EC H by more than 10%. A detector alignment issue may have caused the inter-LAS variability, supported by the observation in this study of differing power requirements between LAS units. It is possible that the LAS physical misalignment may have caused edge-of-beam signal noise as well as vulnerability to signal noise from wind-induced vibrations, both having an impact on the solution of H. In addition, there were some uncertainties in the solutions of H from the LAS and EC instruments, including lack of energy balance closure with the EC unit. However, the results obtained do not show clear evidence of inherent bias for the Kipp and Zonen LAS to overestimate H as found in other studies. PMID- 24473284 TI - A simple visual ethanol biosensor based on alcohol oxidase immobilized onto polyaniline film for halal verification of fermented beverage samples. AB - A simple visual ethanol biosensor based on alcohol oxidase (AOX) immobilised onto polyaniline (PANI) film for halal verification of fermented beverage samples is described. This biosensor responds to ethanol via a colour change from green to blue, due to the enzymatic reaction of ethanol that produces acetaldehyde and hydrogen peroxide, when the latter oxidizes the PANI film. The procedure to obtain this biosensor consists of the immobilization of AOX onto PANI film by adsorption. For the immobilisation, an AOX solution is deposited on the PANI film and left at room temperature until dried (30 min). The biosensor was constructed as a dip stick for visual and simple use. The colour changes of the films have been scanned and analysed using image analysis software (i.e., ImageJ) to study the characteristics of the biosensor's response toward ethanol. The biosensor has a linear response in an ethanol concentration range of 0.01%-0.8%, with a correlation coefficient (r) of 0.996. The limit detection of the biosensor was 0.001%, with reproducibility (RSD) of 1.6% and a life time up to seven weeks when stored at 4 degrees C. The biosensor provides accurate results for ethanol determination in fermented drinks and was in good agreement with the standard method (gas chromatography) results. Thus, the biosensor could be used as a simple visual method for ethanol determination in fermented beverage samples that can be useful for Muslim community for halal verification. PMID- 24473286 TI - Development of real-time dual-display handheld and bench-top hybrid-mode SD-OCTs. AB - Development of a dual-display handheld optical coherence tomography (OCT) system for retina and optic-nerve-head diagnosis beyond the volunteer motion constraints is reported. The developed system is portable and easily movable, containing the compact portable OCT system that includes the handheld probe and computer. Eye posterior chambers were diagnosed using the handheld probe, and the probe could be fixed to the bench-top cradle depending on the volunteers' physical condition. The images obtained using this handheld probe were displayed in real time on the computer monitor and on a small secondary built-in monitor; the displayed images were saved using the handheld probe's built-in button. Large-scale signal processing procedures such as k-domain linearization, fast Fourier transform (FFT), and log-scaling signal processing can be rapidly applied using graphics processing-unit (GPU) accelerated processing rather than central-processing-unit (CPU) processing. The Labview-based system resolution is 1,024 * 512 pixels, and the frame rate is 56 frames/s, useful for real-time display. The 3D images of the posterior chambers including the retina, optic-nerve head, blood vessels, and optic nerve were composed using real-time displayed images with 500 * 500 * 500 pixel resolution. A handheld and bench-top hybrid mode with a dual-display handheld OCT was developed to overcome the drawbacks of the conventional method. PMID- 24473287 TI - Chemistry and structure of homoepitaxial SrTiO3 films and their influence on oxide-heterostructure interfaces. AB - The properties of single-crystal SrTiO3 substrates and homoepitaxial SrTiO3 films grown by pulsed laser deposition have been compared, in order to understand the loss of interfacial conductivity when more than a critical thickness of nominally homoepitaxial SrTiO3 is inserted between a LaAlO3 film and a SrTiO3 substrate. In particular, the chemical composition and the structure of homoepitaxial SrTiO3 investigated by low-energy ion-scattering and surface X-ray diffraction show that for insulating heterointerfaces, a Sr-excess is present between the LaAlO3 and homoepitaxial SrTiO3. Furthermore, an increase in the out-of-plane lattice constant is observed in LaAlO3, indicating that the conductivity both with and without insertion of the SrTiO3 thin film originates from a Zener breakdown associated with the polar catastrophe. When more than a critical thickness of homoepitaxial SrTiO3 is inserted between LaAlO3 and SrTiO3, the electrons transferred by the electronic reconstruction are trapped by the formation of a Sr rich secondary phase and Sr-vacancies. The migration of Sr towards the surface of homoepitaxial SrTiO3 and accompanying loss of interfacial conductivity can be delayed by reducing the Sr-content in the PLD target. PMID- 24473288 TI - Placing environmental next-generation sequencing amplicons from microbial eukaryotes into a phylogenetic context. AB - Nucleotide positions in the hypervariable V4 and V9 regions of the small subunit (SSU)-rDNA locus are normally difficult to align and are usually removed before standard phylogenetic analyses. Yet, with next-generation sequencing data, amplicons of these regions are all that are available to answer ecological and evolutionary questions that rely on phylogenetic inferences. With ciliates, we asked how inclusion of the V4 or V9 regions, regardless of alignment quality, affects tree topologies using distinct phylogenetic methods (including PairDist that is introduced here). Results show that the best approach is to place V4 amplicons into an alignment of full-length Sanger SSU-rDNA sequences and to infer the phylogenetic tree with RAxML. A sliding window algorithm as implemented in RAxML shows, though, that not all nucleotide positions in the V4 region are better than V9 at inferring the ciliate tree. With this approach and an ancestral state reconstruction, we use V4 amplicons from European nearshore sampling sites to infer that rather than being primarily terrestrial and freshwater, colpodean ciliates may have repeatedly transitioned from terrestrial/freshwater to marine environments. PMID- 24473289 TI - Review of cost versus scale: water and wastewater treatment and reuse processes. AB - The US National Research Council recently recommended direct potable water reuse (DPR), or potable water reuse without environmental buffer, for consideration to address US water demand. However, conveyance of wastewater and water to and from centralized treatment plants consumes on average four times the energy of treatment in the USA, and centralized DPR would further require upgradient distribution of treated water. Therefore, information on the cost of unit treatment processes potentially useful for DPR versus system capacity was reviewed, converted to constant 2012 US dollars, and synthesized in this work. A logarithmic variant of the Williams Law cost function was found applicable over orders of magnitude of system capacity, for the subject processes: activated sludge, membrane bioreactor, coagulation/flocculation, reverse osmosis, ultrafiltration, peroxone and granular activated carbon. Results are demonstrated versus 10 DPR case studies. Because economies of scale found for capital equipment are counterbalanced by distribution/collection network costs, further study of the optimal scale of distributed DPR systems is suggested. PMID- 24473290 TI - Cleaning and regeneration of periphyton biofilm in surface water treatment systems. AB - The fouling of periphyton biofilm is a common problem associated with surface water treatment systems. In this study, sulfuric acid (H2SO4), sodium acetate (CH3COONa) and ethylenediamine tetra-acetic acid (EDTA) solutions were sequentially used to clean periphyton biofilms collected from a surface water treatment system. The results showed that the sequential addition of H2SO4 and CH3COONa solutions could accelerate the exfoliation of the fouled periphyton biofilm, while the addition of EDTA solution could regenerate the periphyton biofilm. However, the addition of H2SO4 and CH3COONa solution might negatively affect the bacterial community structure, while the addition of EDTA solution facilitated improvement of the community structure. The combined effect of cleaning and regeneration of periphyton biofilm has significantly improved the removal efficiencies of chemical oxygen demand (COD), total phosphorus (TP), total nitrogen (TN) and ammonia (NH4-N), by 19, 20, 23 and 22%, respectively. The removal processes of COD, TP, TN and NH4-N by the cleaned biofilm were fitted to power regression curves, while those by the control biofilm during the removal process were fitted to polynomial regression curves. These systemic results indicate that the sequential addition of H2SO4, CH3COONa and EDTA solution is able to clean fouled periphyton biofilm and to enhance the efficiency of surface water treatment systems. PMID- 24473291 TI - Characterization and source identification of stormwater runoff in tropical urban catchments. AB - The characteristics of urban stormwater pollution in the tropics are still poorly understood. This issue is crucial to the tropical environment because its rainfall and runoff generation processes are so different from temperate regions. In this regard, a stormwater monitoring program was carried out at three urban catchments (e.g. residential, commercial and industrial) in the southern part of Peninsular Malaysia. A total of 51 storm events were collected at these three catchments. Samples were analyzed for total suspended solids, 5-day biochemical oxygen demand, chemical oxygen demand (COD), oil and grease, nitrate nitrogen, nitrite nitrogen, ammonia nitrogen (NH3-N), soluble reactive phosphorus and total phosphorus. Principal component analysis (PCA) and hierarchical cluster analysis were used to interpret the stormwater quality data for pattern recognition and identification of possible sources. The most likely sources of stormwater pollutants at the residential catchment were from surface soil and leachate of fertilizer from domestic lawns and gardens, whereas the most likely sources for the commercial catchment were from discharges of food waste and washing detergent. In the industrial catchment, the major sources of pollutants were discharges from workshops and factories. The PCA factors further revealed that COD and NH3-N were the major pollutants influencing the runoff quality in all three catchments. PMID- 24473292 TI - Impacts of aquatic macrophytes configuration modes on water quality. AB - Constructed wetland technology is regarded as an important ecological restoration technology and used widely in sewage disposal. In order to give them a wider scope of application and to improve their performance in water restoration, the current experiment was designed. Four aquatic macrophytes (dwarf cattail (TM), yellow-flowered iris (WI), water shallot (ST) and watermifoil (MS)) were picked and planted in artificial floating islands (AFIs) in different configurations (TM + WI, ST + MS and TM + WI + MS) and two patterns, radiation pattern (RP) and annular pattern (AP), for a 60-day experiment. Then, water quality and growth were monitored every 10 days. The results indicate that the different configurations performed diversely on waste water purification. First, a composite plant configuration removed more pollutant than a single one with the same total increment of biomass. Second, the plant configuration of MS + ST was most effective in total nitrogen (TN), total phosphorus (TP) or PO4(3-) removal, and TM + IW + MS was good at chemical oxygen demand (COD) and NO3(-) removal. However, different patterns comprised from the same species had a certain effect on absorption of pollutants. Generally speaking, plant configurations with a RP were better than an AP in purification. Accordingly, these provided the methods for the pollution wetland restoration. PMID- 24473293 TI - Hydrogen sulfide gas emission under turbulent conditions - an experimental approach for free-fall drops. AB - Odor nuisance and sulfide corrosion in sewers carrying septic wastewater are accelerated at points of turbulence such as drops in manholes, but accurate methods or empirical expressions to evaluate the gas stripping rate at those particular sites are still missing. With the aim of improving the current knowledge on the influence of free-fall drops on the release of hydrogen sulfide gas, an experimental set-up was built allowing different free-fall drops heights and flows. Three types of experiments were carried out: reaeration tests without sulfide; sulfide oxidation tests; and hydrogen sulfide release tests. With the increase of the free-fall drop height or of the flow, a higher rate of air-to water mass oxygen transfer was observed. Results regarding sulfide oxidation tests with reaeration through the free-fall have shown that the oxidation rate was correlated with flow. In the hydrogen sulfide release tests, the maximum concentration in the atmosphere reached 500 ppm. Results also showed that increasing the flow rate decreased the time at which the maximum concentrations in the atmosphere were observed. PMID- 24473294 TI - Anaerobic co-digestion of winery waste and waste activated sludge: assessment of process feasibility. AB - In this study the anaerobic co-digestion of wine lees together with waste activated sludge in mesophilic and thermophilic conditions was tested at pilot scale. Three organic loading rates (OLRs 2.8, 3.3 and 4.5 kgCOD/m(3)d) and hydraulic retention times (HRTs 21, 19 and 16 days) were applied to the reactors, in order to evaluate the best operational conditions for the maximization of the biogas yields. The addition of lee to sludge determined a higher biogas production: the best yield obtained was 0.40 Nm(3)biogas/kgCODfed. Because of the high presence of soluble chemical oxygen demand (COD) and polyphenols in wine lees, the best results in terms of yields and process stability were obtained when applying the lowest of the three organic loading rates tested together with mesophilic conditions. PMID- 24473295 TI - Lamella settlers for storm water treatment - performance and design recommendations. AB - Three lamella settlers were monitored over a period of 4 years. The main objective was to determine removal efficiencies for total suspended solids and associated pollutants. For this purpose a new sampling method based on large volume solid samplers was developed allowing a detailed analysis of solids. With regard to total suspended solids the average removal efficiency of the plants range from 49 to 68%. Similar values could be achieved for phosphorus and heavy metals mainly because of the high portion of fine particles in treatment plants' influent. A clear dependency between solid removal efficiency and the parameters maximum surface load and influent concentration could be observed on a single event basis. The aggregation of all findings result in a recommended maximum design surface loading rate (SLR) of 4 m/h. A solid removal rate of 50%, which is defined as minimum long-term efficiency, can be achieved safely at this SLR. In addition to the definition of the maximum SLR, a proper dissipation of the inflow energy and an equal collection of the clear water above the lamellas turn out to be essential. PMID- 24473296 TI - Sulfonation of crosslinked styrene/divinyl benzene copolymer beads formed from porous foam and ion adsorption of copper by them: column adsorption modeling. AB - The porous foam is made by the polymerisation of a high internal phase emulsion and it is a highly porous, low density, open cellular material. Surface properties of the foam were chemically modified via a sulfonation process. Sulfonation added -SO3(-)H(+) groups to the polymer matrix. The ion adsorption behavior of copper ions on sulfonated polymer beads, depending on inlet concentration (10-60 mg/L), pH of inlet solution (2.00-5.20) and flow velocity (1.7-11.4 m/h) was studied. It was shown that the amount of copper adsorbed was not affected with increasing concentration of feed solutions and flow velocity. Also the process was highly pH dependent. The maximum removal was 117.96 mg Cu/g dry adsorbent at flow velocity 11.4 m/h. Column experimental tests were conducted to provide data for theoretical modeling and to verify the system performance of the process. A theoretical column model adopted in this work was found to describe well the ion adsorption breakthrough characteristics. PMID- 24473297 TI - Simultaneous carbon and nitrogen removal using a litre-scale upflow microbial fuel cell. AB - A 10 L upflow microbial fuel cell (UMFC) was constructed for simultaneous carbon and nitrogen removal. During the 6-month operation, the UMFC constantly removed carbon and nitrogen, and then generated electricity with synthetic wastewater as substrate. At 5.0 mg L(-1) dissolved oxygen, 100 Omega external resistance, and pH 6.5, the maximum power density (Pmax) and nitrification rate for the UMFC was 19.5 mW m(-2) and 17.9 mg.(L d)(-1), respectively. In addition, Pmax in the UMFC with chicken manure wastewater as substrate was 16 mW m(-2), and a high chemical oxygen demand (COD) removal efficiency of 94.1% in the UMFC was achieved at 50 mM phosphate-buffered saline. Almost all ammonia in the cathode effluent was effectively degraded after biological denitrification in the UMFC cathode. The results can help to further develop pilot-scale microbial fuel cells for simultaneous carbon and nitrogen removal. PMID- 24473298 TI - Adsorption of lead using a novel xanthated carboxymethyl chitosan. AB - Adsorption of Pb(II) was studied using a novel xanthated carboxymethyl chitosan (XCC). The XCC was synthesized using the xanthation reaction of N-carboxymethyl chitosan (NCMC). The chemical structure of XCC was characterized by UV-visible spectra. The effects of initial pH value of the solutions, contact time and adsorption isotherms on adsorption of Pb(II) were investigated. Moreover, the possible adsorption mechanism was identified using Fourier transform infrared spectroscopy (FTIR) and X-ray photoelectron spectroscopy (XPS). The experimental results showed XCC experienced a high adsorption capacity. The adsorption isotherm followed the Langmuir model. The maximum adsorption capacity obtained from the Langmuir model was 520.8 mg/g. Thermodynamic studies revealed a spontaneous and exothermic adsorption process. FTIR and XPS studies showed that the carboxyl groups, nitrogen atoms and sulfur atoms participated in the adsorption of Pb(II). PMID- 24473299 TI - Comparing modelling techniques for analysing urban pluvial flooding. AB - Short peak rainfall intensities cause sewer systems to overflow leading to flooding of streets and houses. Due to climate change and densification of urban areas, this is expected to occur more often in the future. Hence, next to their minor (i.e. sewer) system, municipalities have to analyse their major (i.e. surface) system in order to anticipate urban flooding during extreme rainfall. Urban flood modelling techniques are powerful tools in both public and internal communications and transparently support design processes. To provide more insight into the (im)possibilities of different urban flood modelling techniques, simulation results have been compared for an extreme rainfall event. The results show that, although modelling software is tending to evolve towards coupled one dimensional (1D)-two-dimensional (2D) simulation models, surface flow models, using an accurate digital elevation model, prove to be an easy and fast alternative to identify vulnerable locations in hilly and flat areas. In areas at the transition between hilly and flat, however, coupled 1D-2D simulation models give better results since catchments of major and minor systems can differ strongly in these areas. During the decision making process, surface flow models can provide a first insight that can be complemented with complex simulation models for critical locations. PMID- 24473300 TI - Determination of rare earth elements in waters by inductively coupled plasma optical emission spectrometry after preconcentration with 6-(2-thienyl)-2 pyridinecarboxaldehyde functionalized Amberlite XAD-4 resin. AB - A new method has been developed for the determination of rare earth elements (REEs) (Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb and Lu) in water samples based on preconcentration with a mini-column packed with 6-(2-thienyl)-2 pyridinecarboxaldehyde functionalized Amberlite XAD-4 resin prior to their determination using inductively coupled plasma optical emission spectrometry (ICP OES). The optimum experimental parameters for preconcentration of REEs, such as pH of the sample, sample and eluent flow rates and sample volume, were investigated. The optimum pH values for quantitative (90-110%) sorption of the REE ions were between 6.0 and 8.0. The elution process was carried out using 2 mL of 1.0 mol L(-1) HNO3 solution. Under the optimum conditions, detection limits between 0.032 and 0.963 MUg L(-1) for a 10 mL sample volume and 0.006 and 0.193 MUg L(-1) for a 50 mL sample volume were determined. The proposed method was successfully applied to the determination of REEs in water samples with recoveries in the range of 90.1-110.5%. PMID- 24473301 TI - Comparison of aerobic granulation and anaerobic membrane bioreactor technologies for winery wastewater treatment. AB - An anaerobic membrane bioreactor and aerobic granulation technologies were tested at laboratory scale to treat winery wastewater, which is characterised by a high and variable biodegradable organic load. Both technologies have already been tested for alcohol fermentation wastewaters, but there is a lack of data relating to their application to winery wastewater treatment. The anaerobic membrane bioreactor, with an external microfiltration module, was started up for 230 days, achieving a biogas production of up to 0.35 L CH4L(-1)d(-1) when 1.5 kg COD m( 3)d(-1) was applied. Average flux was 10.5 L m(-2) h(-1) (LMH), obtaining a treated effluent free of suspended solids and a chemical oxygen demand (COD) concentration lower than 100 mg COD L(-1). In contrast, the aerobic granular sequencing batch reactor coped with 15 kg COD m(-3)d(-1), but effluent quality was slightly worse. Aerobic granulation was identified as a suitable technique to treat this kind of wastewater due to excellent settleability, high biomass retention and a good ability to handle high organic loads and seasonal fluctuations. However, energy generation from anaerobic digestion plays an important role, favouring anaerobic membrane bioreactor application, although it was observed to be sensitive to sudden load fluctuations, which led to a thorough pH control and alkali addition. PMID- 24473302 TI - Study on biodegradability of terephthalic acid in polyester fabric alkali-peeling process wastewater. AB - Terephthalic acid (TA) and ethylene glycol (EG) are the main pollutants in polyester fabric alkali-peeling process wastewater (PAP-wastewater). The biodegradability of TA is crucial to the deep treatment of PAP-wastewater. Batch and continuous experiments were adopted to study the biodegradation of TA in synthetic wastewater. In anoxic batch experiments TA began to degrade gradually after EG was depleted completely. However, in aerobic batch experiments the biodegradation curves of TA in the presence of EG were almost identical to those of TA in the absence of EG. The combined process of anoxic hydrolysis acidification bioreactor (HABR) and aerobic hybrid membrane bioreactor (HMBR) was employed to treat synthetic PAP-wastewater in continuous experiments. When TA was fed as sole substrate, about 6.1% was removed in the anoxic HABR and 92.1% was biodegraded in the aerobic HMBR. When TA and EG were fed as substrate, only 1.9% of TA was biodegraded in the anoxic HABR and 96.6% of TA was removed in the aerobic HMBR. By contrast, most EG was removed in the anoxic HABR. The experimental results revealed that the combined process of anoxic HABR and aerobic HMBR was an attractive alternative for the treatment of PAP-wastewater and other similar wastewater. PMID- 24473303 TI - Experiences from the full-scale implementation of a new two-stage vertical flow constructed wetland design. AB - This paper describes the results of the first full-scale implementation of a two stage vertical flow constructed wetland (CW) system developed to increase nitrogen removal. The full-scale system was constructed for the Barenkogelhaus, which is located in Styria at the top of a mountain, 1,168 m above sea level. The Barenkogelhaus has a restaurant with 70 seats, 16 rooms for overnight guests and is a popular site for day visits, especially during weekends and public holidays. The CW treatment system was designed for a hydraulic load of 2,500 L.d(-1) with a specific surface area requirement of 2.7 m(2) per person equivalent (PE). It was built in fall 2009 and started operation in April 2010 when the restaurant was re opened. Samples were taken between July 2010 and June 2013 and were analysed in the laboratory of the Institute of Sanitary Engineering at BOKU University using standard methods. During 2010 the restaurant at Barenkogelhaus was open 5 days a week whereas from 2011 the Barenkogelhaus was open only on demand for events. This resulted in decreased organic loads of the system in the later period. In general, the measured effluent concentrations were low and the removal efficiencies high. During the whole period the ammonia nitrogen effluent concentration was below 1 mg/L even at effluent water temperatures below 3 degrees C. Investigations during high-load periods, i.e. events like weddings and festivals at weekends, with more than 100 visitors, showed a very robust treatment performance of the two-stage CW system. Effluent concentrations of chemical oxygen demand and NH4-N were not affected by these events with high hydraulic loads. PMID- 24473304 TI - Simulation of landfill leachate treatment using electro-Fenton technique. AB - The operating parameters in the electro-Fenton process were simulated using computational fluid dynamics (CFD). The effects of H2O2/Fe(2+) molar ratio, current density, pH and reaction time were numerically investigated. The results were compared with the experimental data. The simulated data showed that maximum chemical oxygen demand (COD) removal was around 91.52% at pH of 3.27, H2O2/Fe(2+) molar ratio of 1.16, current density of 59.29 mA/cm(2) and reaction time of 41.7 min while the experimental data obtained from the literature showed a maximum COD removal (94.7%) at pH of 3, H2O2/Fe(2+) molar ratio of 1, current density of 49 mA/cm(2) and reaction time of 43 min. PMID- 24473305 TI - The effect of aeration and effluent recycling on domestic wastewater treatment in a pilot-plant system of duckweed ponds. AB - Three pilot-scale duckweed pond (DP) wastewater treatment systems were designed and operated to examine the effect of aeration and effluent recycling on treatment efficiency. Each system consisted of two DPs in series fed by pre settled domestic sewage. The first system (duckweed+ conventional treatment) was 'natural' and included only duckweed plants. The second system (duckweed aeration) included aeration in the second pond. The third system (duckweed+ aeration+ circulation) included aeration in the second pond and effluent recycling from the second to the first pond. All three systems demonstrated similarly efficient removal of organic matter and nutrients. Supplemental aeration had no effect on either dissolved oxygen levels or on pollutant removal efficiencies. Although recycling had almost no influence on nutrient removal efficiencies, it had a positive impact on chemical oxygen demand and total suspended solids removals due to equalization of load and pH, which suppressed algae growth. Recycling also improved the appearance and growth rate of the duckweed plants, especially during heavy wastewater loads. PMID- 24473306 TI - A novel approach to explain the inactivation mechanism of Escherichia coli employing a commercially available peracetic acid. AB - The chemical inactivation of Escherichia coli employing a commercial mixture of peracetic acid (PAA) was studied. For this purpose, experiments were carried out using dilutions of the unmodified mixture, and also the same mixture but altered with hydrogen peroxide (HP) previously inhibited. Also, these results were compared to those obtained before employing HP alone. It was found that the mixture is much more efficient than HP and PAA acting separately. Furthermore, it was found that PAA without HP is much more efficient than HP alone. A plausible explanation is presented. The homolysis of PAA would give rise to a chain reaction that generates a significant number of highly oxidizing radicals. An attacking scheme to bacteria in two stages is proposed, where the initial step, mainly caused by PAA, is very fast and eliminates some specific components of the bacteria that would otherwise inhibit the parallel action of HP. Thereafter, the emergence of a potentiating synergetic action of the second oxidant seems to be immediately unveiled. PMID- 24473307 TI - A mass balance approach to the fate of viruses in a municipal wastewater treatment plant during summer and winter seasons. AB - In contrast to previous discussion on general virus removal efficiency and identifying surrogates for human pathogenic viruses, this study focuses on virus retention within each step of a wastewater treatment plant (WWTP). Additionally, the influence of weather conditions on virus removal was addressed. To account for the virus retention, this study describes a mass balance of somatic coliphages (bacterial viruses) in a municipal WWTP, performed in the winter and summer seasons of 2011. In the winter season, the concentration of coliphages entering the WWTP was about 1 log lower than in summer. The mass balance in winter revealed a virus inactivation of 85.12 +/- 13.97%. During the summer season, virus inactivation was significantly higher (95.25 +/- 3.69%, p-value <0.05), most likely due to additional virus removal in the secondary clarifier by insolation. Thus, a total removal of coliphages of about 2.78 log units was obtained in summer compared to 1.95 log units in winter. Rainfall events did not statistically correlate with the concentrations of coliphages entering the WWTP in summer. PMID- 24473308 TI - Decolorization of methyl orange by green rusts with hydrogen peroxide at neutral pH. AB - Heterogeneous Fenton-like processes using green rusts (GRs) with hydrogen peroxide (H2O2) were studied to decolorize methyl orange (MO) in aqueous solution at an initial pH of 7.0. In this study, two types of crystal structure for GRs, the hydroxycarbonate GR(CO3(2-)) (GR1) and the hydroxysulphate GR(SO4(2-)) (GR2), were synthesized by partial oxidation of Fe(OH)2 suspension under light irradiation and distinguished by X-ray diffraction (XRD) due to different characteristic peaks. In oxidation reactions, decolorization rate of MO, bubbling air through the solution, was about 65% (experiment B), whereas, it was up to 95% in the presence of H2O2 (experiment C) within 60 min. The comparative tests of GR1 and GR2 show that the reduction capability of GR2 is stronger than GR1, which may be due to Fe(II) content and interlayer anions. XRD analysis and Fourier transform infrared spectroscopy revealed that the oxidation end products of GR2 were mainly a poorly crystallized mixture of magnetite (Fe3O4) and hydroxy ferric oxide (FeOOH). However, when GR was immediately oxidized, the weakly crystallized goethite (alpha-FeOOH) and lepidocrocite (gamma-FeOOH) were formed for O2 and H2O2, respectively. Based on the intermediates obtained, a probable decolorization mechanism has been proposed. PMID- 24473309 TI - Competitive adsorption of boric acid and chromate onto alumina in aqueous solutions. AB - The competitive adsorption of boric acid and chromate from aqueous solutions by alumina has been investigated by spectrophotometry at pH 8, ionic strength = 0.0, 0.1 and 1.0 M NaClO4, T = 22 +/- 3 degrees C and under normal atmospheric conditions. The experimental data show that addition of excess boric acid in the system leads to the increase of Cr(VI) concentration in solution, indicating the replacement of adsorbed chromate by boron on the alumina surface. Data evaluation results in the determination of the competition reaction constant and the formation constant of the Cr(VI) surface complexes, which are logKCr(VI)-B(III) = -3.5 +/- 0.2 and logbeta*Cr = 7.6 +/- 0.3, respectively. PMID- 24473310 TI - Adsorption of phenol and p-chlorophenol from aqueous solutions by magnetic nanopowder. AB - A new magnetic iron oxide nanopowder (MNM) was prepared, characterized and tested as adsorbent for the removal of phenol and p-chlorophenol (PCP) from aqueous solution. The iron oxide was obtained by a new combustion method which allows the direct obtaining of magnetic nanopowder covered with some organic residues resulting from fuel combustion. The magnetic powder was characterized in terms of phase composition, structure, texture, magnetic properties and carbon content. The adsorption kinetics was examined by the pseudo-first-order and pseudo-second order models and the equilibrium data were fitted with Langmuir and Freundlich isotherms. The results confirmed the good adsorption capacity of the new magnetic nanopowder for the removal of phenol and PCP from aqueous solutions and its great potential for practical applications. PMID- 24473311 TI - Upstream silver source mapping - a case study in Stockholm, Sweden. AB - Silver (Ag) can be a problem for wastewater treatment plants (WWTP) and their capability to use sewage sludge as a soil fertilizer. Due to a high accumulation rate in soils, the levels of Ag in the incoming water at the WWTP must be reduced. This study aims to identify major diffuse emission sources in the technosphere through a comprehensive substance flow analysis of Ag in Stockholm, Sweden. Large inflows and stocks of Ag were present in electrical and electronic goods and appliances as well as in jewellery and silverware. The total inflow was 3.2 tonnes (4.2 g/person), the total stock was 100 tonnes (140 g/person) and the total outflow was 330 kg (430 mg/person). Major identified Ag sources with emissions ending up in the WWTP (total 26 kg, 34 mg/person) were food, amalgam and beauty products (via urine and faeces, 12 mg/person or 11% of incoming amount), and textiles (via washing, 17 mg/person or 16% of incoming amount). This study explains approximately 35% of the total 80 kg Ag in the incoming water at Henriksdal WWTP in Stockholm. Plastic, photography and beauty products were identified as possible sources of Ag that need to be examined further. PMID- 24473312 TI - Removal of chemical oxygen demand and dissolved nutrients by a sunken lawn infiltration system during intermittent storm events. AB - Urban surface water runoff typically contains high but varying amounts of organic matter and nutrients that require removal before reuse. Infiltration systems such as sunken lawns can improve water quality. However, there is currently insufficient information describing the treatment efficiency of lawn-based infiltration systems. In this study, novel sunken lawn infiltration systems (SLISs) were designed and their pollutant removal effectiveness was assessed. The results revealed that SLISs with Poa pratensis and Lolium perenne effectively removed most chemical oxygen demand (CODCr) and dissolved nutrients. Average CODCr, total nitrogen (TN), ammonium-nitrogen (NH4(+)-N) and total phosphorus (TP) concentrations were reduced by 78.93, 66.64, 71.86 and 75.83%, respectively, and the corresponding effluent concentrations met the standard for urban miscellaneous water consumption in China. The NH4(+)-N in the synthetic runoff was shown to be removed by adsorption during the stormwater dosing and nitrification during subsequent dry days, as well as through uptake by plants. Phosphorus was mainly removed by adsorption and chemical precipitation. The NH4(+)-N and phosphorus Langmuir isotherm model fitted the clay loam soil adsorption process better than the Freundlich model. Overall, these results indicate that an SLIS provides an alternative means of removing runoff pollutants owing to its efficiency, easy operation and maintenance. PMID- 24473313 TI - Study on the adsorption of bacteria in ceramsite and their synergetic effect on adsorption of heavy metals. AB - In this paper, heavy metal adsorption by ceramsite with or without Bacillus subtilis (B. subtilis) immobilization was studied, and the synergetic effect of ceramsite and bacteria was discussed in detail. To investigate the roles of the micro-pore structure of ceramsite and bacteria in removing heavy metals, the amount of bacteria immobilized on the ceramsite was determined and the effect of pH was evaluated. It was found that the immobilization of B. subtilis on the ceramsite was attributed to the electrostatic attraction and covalent bond. The scanning electron microscopy results revealed that, with the presence of ceramsite, there was the conglutination of B. subtilis cells due to the cell outer membrane dissolving. In addition, the B. subtilis immobilized ceramsite showed a different adsorption capacity for different heavy metals, with the adsorption capacity ranking of La(3+) > Cu(2+) > Mg(2+) > Na(+). PMID- 24473314 TI - Application of super-twisting observers to the estimation of state and unknown inputs in an anaerobic digestion system. AB - This paper presents the estimation of the unknown states and inputs of an anaerobic digestion system characterized by a two-step reaction model. The estimation is based on the measurement of the two substrate concentrations and of the outflow rate of biogas and relies on the use of an observer, consisting of three parts. The first is a generalized super-twisting observer, which estimates a linear combination of the two input concentrations. The second is an asymptotic observer, which provides one of the two biomass concentrations, whereas the third is a super-twisting observer for one of the input concentrations and the second biomass concentration. PMID- 24473315 TI - Performance assessment of separate and combined sewer systems in metropolitan areas in Southern China. AB - To assess the performance of urban drainage systems in metropolitan areas in southern China, 12 urban drainage systems, including nine separate sewer systems (SSSs) and three combined sewer systems (CSSs) were monitored from 2008 to 2012 in Shanghai and Hefei. Illicit connection rates of SSS were determined. The results indicate that serious illicit connections exist for most SSSs. Annual volume balance for two SSSs with serious illicit connection was assessed with a hydraulic model to determine the dry weather overflow volume. Although interception facilities have been implemented in SSSs, for some systems with serious illicit connections, a considerable volume of dry weather overflow still existed. Combined with monitoring of dry/wet weather flow quality, the pollutant load caused by wet/dry weather overflow was quantified. The results revealed that there was no obvious advantage of having SSSs over CSSs in terms of pollutant control. The serious pollution caused by illicit connections and insufficient management occurs in many cities in China. The performance assessment of separate and CSSs in Shanghai and Hefei provides important lessons and practical experience that can be applied to the construction and management of urban drainage system in China as well as other developing countries. PMID- 24473316 TI - Sludge digestion instead of aerobic stabilisation - a cost benefit analysis based on experiences in Germany. AB - As a consequence of a worldwide increase of energy costs, the efficient use of sewage sludge as a renewable energy resource must be considered, even for smaller wastewater treatment plants (WWTPs) with design capacities between 10,000 and 50,000 population equivalent (PE). To find the lower limit for an economical conversion of an aerobic stabilisation plant into an anaerobic stabilisation plant, we derived cost functions for specific capital costs and operating cost savings. With these tools, it is possible to evaluate if it would be promising to further investigate refitting aerobic plants into plants that produce biogas. By comparing capital costs with operation cost savings, a break-even point for process conversion could be determined. The break-even point varies depending on project specific constraints and assumptions related to future energy and operation costs and variable interest rates. A 5% increase of energy and operation costs leads to a cost efficient conversion for plants above 7,500 PE. A conversion of WWTPs results in different positive effects on energy generation and plant operations: increased efficiency, energy savings, and on-site renewable power generation by digester gas which can be used in the plant. Also, the optimisation of energy efficiency results in a reduction of primary energy consumption. PMID- 24473317 TI - Sensitive quantification of trace zinc in water samples by adsorptive stripping voltammetry. AB - A simple and sensitive adsorptive stripping voltammetry method was developed for determination of Zn using N-nitrozo-N-phenylhydroxylamine (cupferron) as a selective complexing agent. This complex absorbed on the hanging mercury drop electrode and created a sensitive peak current. The peak current and concentration of zinc accorded with a linear relationship in the range of 0.85 320 ng mL(-1). The influence of pH and the nature of supporting electrolytes, concentration of ligand, preconcentration time and applied potential were investigated. The relative standard deviation at a concentration level of 50 ng mL(-1) was 1.8%. The method was applied to the determination of zinc in city, river and mineral water samples, with satisfactory results. PMID- 24473318 TI - Anaerobic co-digestion of municipal organic wastes and pre-treatment to enhance biogas production from waste. AB - Co-digestion and pre-treatment have been recognized as effective, low-cost and commercially viable approaches to reduce anaerobic digestion process limitations and improve biogas yields. In our previous batch-scale study, fat, oil, and grease (FOG) was investigated as a suitable potential co-substrate, and thermo chemical pre-treatment (TCPT) at pH = 10 and 55 degrees C improved CH4 production from FOG co-digestions. In this project, co-digestions with FOG were studied in bench-scale two-stage thermophilic semi-continuous flow co-digesters with suitable TCPT (pH = 10, 55 degrees C). Overall, a 25.14 +/- 2.14 L/d (70.2 +/- 1.4% CH4) biogas production was obtained, which was higher than in the two stage system without pre-treatment. The results could provide valuable fundamental information to support full-scale investigations of anaerobic co digestion of municipal organic wastes. PMID- 24473319 TI - Standards for clinical use of genetic variants. PMID- 24473320 TI - HOXB13, RFX6 and prostate cancer risk. AB - A new study shows that HOXB13 is preferentially recruited to the risk allele of a prostate cancer-associated SNP, enhancing the expression of RFX6, a driver of prostate cancer cell migration and predictor of disease progression. The work illustrates how a single risk locus contributes both to prostate cancer incidence and, through functional follow-up, to disease progression. PMID- 24473321 TI - A cistrome roadmap for understanding pancreatic islet biology. AB - Although dozens of common variants have been associated with increased risk of type 2 diabetes (T2D), the mechanisms by which these variants increase disease susceptibility are largely unknown. A new study mapping the human pancreatic islet cistrome provides a roadmap for exploring the effects of these variants and suggests that altered enhancer function might be a common contributor to the genetic risk of T2D. PMID- 24473322 TI - A RAG driver on the road to pediatric ALL. AB - Genomic aberrations affecting genes in B cell differentiation are hallmarks of B precursor acute lymphoblastic leukemia (ALL). A new whole-genome sequencing study of ETV6-RUNX1-positive ALL has now identified RAG-mediated recombination, which specifically targets genes and regulatory elements active during B cell differentiation, as the underlying mechanism. PMID- 24473328 TI - Advantages and pitfalls in the application of mixed-model association methods. AB - Mixed linear models are emerging as a method of choice for conducting genetic association studies in humans and other organisms. The advantages of the mixed linear-model association (MLMA) method include the prevention of false positive associations due to population or relatedness structure and an increase in power obtained through the application of a correction that is specific to this structure. An underappreciated point is that MLMA can also increase power in studies without sample structure by implicitly conditioning on associated loci other than the candidate locus. Numerous variations on the standard MLMA approach have recently been published, with a focus on reducing computational cost. These advances provide researchers applying MLMA methods with many options to choose from, but we caution that MLMA methods are still subject to potential pitfalls. Here we describe and quantify the advantages and pitfalls of MLMA methods as a function of study design and provide recommendations for the application of these methods in practical settings. PMID- 24473329 TI - Coronary artery calcification is increased in patients with COPD and associated with increased morbidity and mortality. AB - BACKGROUND: Coronary artery calcification is pathognomonic of coronary artery disease (CAD). Whether CAD in patients with COPD is linked to lung function, functional capacity and/or clinically relevant outcomes is unknown. The objective was to assess the association between CAD and disease severity, functional capacity and outcomes in patients with COPD. METHODS: Coronary artery calcium score (CACS; Agatston score) was measured using chest CT in patients with COPD, smokers with normal spirometry and non-smokers from the Evaluation of COPD Longitudinally to Identify Predictive Surrogate Endpoints (ECLIPSE) study. RESULTS: CACS was measured in 942 subjects: 672 with COPD (mean age+/-SD, 63+/-7 years; FEV1 49+/-16% predicted), 199 smokers with normal spirometry (54+/-9 years; FEV1 110+/-12% predicted) and 71 non-smokers (55+/-9 years; FEV1 114+/-14% predicted). CACS was higher in patients with COPD than smokers or non-smokers (median (IQR), 128 (492) vs 0 (75) vs 0 (3) Agatston units (AU), p<0.001). In patients with COPD, CACS correlated with age, pack-years, 6 min walking distance, modified Medical Research Council Dyspnoea score and circulating levels of interleukin (IL)-6, IL-8, Clara Cell protein 16, surfactant protein D and peripheral blood neutrophil count, but not with emphysema, exacerbation frequency, % predicted FEV1 or decline in FEV1. CACS was higher in patients with COPD who died than in those who survived until 3-year follow-up (CACS 406 vs 103 AU, p<0.001), and was associated with mortality in a Cox proportional hazards model (p=0.036). CONCLUSIONS: Patients with COPD have more CAD than controls and this is associated with increased dyspnoea, reduced exercise capacity and increased mortality. These data indicate that the presence of CAD in patients with COPD is associated with poor clinical outcomes. PMID- 24473330 TI - Authors' response to: Primary healthcare factors and hospital admission rates for COPD: no association. PMID- 24473331 TI - CAP and HCAP are different? An unresolved question. PMID- 24473334 TI - X-ray-induced phase transitions by selective excitation of heterometal ions in a cyanide-bridged Fe-Co molecular square. AB - A cyanide-bridged tetranuclear Fe-Co complex showed electron-transfer-coupled spin transitions induced by X-ray irradiation. Single crystal X-ray diffraction measurements and X-ray absorption spectroscopy revealed that the X-ray-induced phase transition ratio was significantly altered by the selective excitation of the metal ions. PMID- 24473333 TI - Monitoring intraspecies competition in a bacterial cell population by cocultivation of fluorescently labelled strains. AB - Many microorganisms such as bacteria proliferate extremely fast and the populations may reach high cell densities. Small fractions of cells in a population always have accumulated mutations that are either detrimental or beneficial for the cell. If the fitness effect of a mutation provides the subpopulation with a strong selective growth advantage, the individuals of this subpopulation may rapidly outcompete and even completely eliminate their immediate fellows. Thus, small genetic changes and selection-driven accumulation of cells that have acquired beneficial mutations may lead to a complete shift of the genotype of a cell population. Here we present a procedure to monitor the rapid clonal expansion and elimination of beneficial and detrimental mutations, respectively, in a bacterial cell population over time by cocultivation of fluorescently labeled individuals of the Gram-positive model bacterium Bacillus subtilis. The method is easy to perform and very illustrative to display intraspecies competition among the individuals in a bacterial cell population. PMID- 24473332 TI - A cluster of lung injury associated with home humidifier use: clinical, radiological and pathological description of a new syndrome. AB - BACKGROUND: Over a few months in the spring of 2011, a cluster of patients with severe respiratory distress were admitted to our intensive care unit (ICU). Household clustering was also observed. Extensive laboratory investigations failed to detect an infectious cause. METHODS: Clinical, radiological and pathological investigations were conducted and the Korean Center for Disease Control performed epidemiological studies. RESULTS: The case series consisted of 17 patients. Their median age was 35 (range 28-49) years. Six were pregnant at presentation and four had given birth 2 weeks previously. All presented with cough and dyspnoea. In the majority of patients (14/17), multifocal areas of patchy consolidation were identified in the lower lung zones on the initial CT. As the condition progressed, the patchy consolidation disappeared (10/13) and diffuse centrilobular ground-glass opacity nodules started to predominate and persist. Pathological specimens (11/17) showed a bronchiolocentric, temporally homogenous, acute lung injury pattern with sparing of the subpleural and peripheral alveolar areas. Ten patients required mechanical ventilation, eight of whom subsequently received extracorporeal life support. Four of the latter underwent lung transplantation. Five of the six patients in the ICU who did not receive lung transplantation died. An epidemiological investigation revealed that all patients had used humidifier disinfectants in their homes. CONCLUSIONS: This case series report showed that lung injury and respiratory failure can occur as a result of inhaling humidifier disinfectants. This emphasises the need for more stringent safety regulations for potentially toxic inhalants that might be encountered in the home. PMID- 24473335 TI - Catalyst-mediated yet catalyst-free hydrogels formed by interfacial chemical activation. AB - We introduce an entirely new method for forming hydrogels, wherein the formation is triggered by a catalyst, but the resulting hydrogels are catalyst-free. We unexpectedly found that a sufficient amount of crosslinkable catecholquinone/semiquinone free radicals is generated by the physical contact between catechol-containing polymers and surface-immobilized catalysts. PMID- 24473336 TI - Exfoliation and performance properties of non-oxidized graphene in water. AB - Single-layered graphene has unique electronic, chemical, and electromechanical properties. Recently, graphite exfoliation in N-methylpyrrolidone and molten salt has been demonstrated to generate monolayer exfoliated graphene sheets (EGS). However, these solvents are either high-priced or require special care and have high boiling points and viscosities, making it difficult to deposit the dispersed graphene onto substrates. Here we show a universal principle for the exfoliation of graphite in water to single-layered and several-layered graphene sheets via the direct exfoliation of highly oriented pyrolytic graphite (HOPG) using pyridinium tribromide (Py(+)Br3(-)). Electrical conductivity >5100 S/cm was observed for filtered graphene paper, and the EGS exhibited superior performance as a hole transport layer compared to the conventional material N,N di(naphthalene-1-yl)-N,N-diphenylbenzidine at low voltage. The overall results demonstrate that this method is a scalable process for the preparation of highly conductive graphene for use in the commercial manufacture of high-performance electronic devices. PMID- 24473337 TI - Microvascular decompression surgery for vertebral artery compression of the medulla oblongata: 3 cases with respiratory failure and/or dysphagia. AB - BACKGROUND: It is well known that brainstem dysfunction may be caused by vascular compression of the medulla oblongata (MO). However, only a limited number of reports have found microvascular decompression (MVD) surgery to be an effective treatment for symptomatic patients with MO dysfunction, such as essential hypertension, pyramidal tract signs, dysphagia, and respiratory failure. CASE DESCRIPTION: This report describes 3 patients with vertebral artery compression of MO who presented with respiratory failure and/or dysphagia. MVD surgery using the transcondylar fossa approach was effective in relieving patient symptoms. CONCLUSIONS: Although the pathogenic mechanisms of symptomatic vertebral artery compression of MO remain unclear, we should recognize that MVD surgery is effective for selected patients with brainstem dysfunction. The transcondylar fossa approach and the stitched sling retraction technique are appropriate in MVD surgery to relieve vertebral artery compression of MO. PMID- 24473338 TI - Pseudo-mannosylated DC-SIGN ligands as potential adjuvants for HIV vaccines. AB - The development of new and effective adjuvants may play a fundamental role in improving HIV vaccine efficacy. New classes of vaccine adjuvants activate innate immunity receptors, notably toll like receptors (TLRs). Adjuvants targeting the C Type lectin receptor DC-SIGN may be alternative or complementary to adjuvants based on TRL activation. Herein we evaluate the ability of the glycomimetic DC SIGN ligand Polyman 19 (PM 19) to modulate innate immune responses. Results showed that PM 19 alone, or in combination with TLR agonists, induces the expression of cytokines, beta chemokines and co-stimulatory molecules that may, in turn, modulate adaptive immunity and exert anti-viral effects. These results indicate that the suitability of this compound as a vaccine adjuvant should be further evaluated. PMID- 24473339 TI - Noncoding subgenomic flavivirus RNA: multiple functions in West Nile virus pathogenesis and modulation of host responses. AB - Flaviviruses are a large group of positive strand RNA viruses transmitted by arthropods that include many human pathogens such as West Nile virus (WNV), Japanese encephalitis virus (JEV), yellow fever virus, dengue virus, and tick borne encephalitis virus. All members in this genus tested so far are shown to produce a unique subgenomic flavivirus RNA (sfRNA) derived from the 3' untranslated region (UTR). sfRNA is a product of incomplete degradation of genomic RNA by the cell 5'-3' exoribonuclease XRN1 which stalls at highly ordered secondary RNA structures at the beginning of the 3'UTR. Generation of sfRNA results in inhibition of XRN1 activity leading to an increase in stability of many cellular mRNAs. Mutant WNV deficient in sfRNA generation was highly attenuated displaying a marked decrease in cytopathicity in cells and pathogenicity in mice. sfRNA has also been shown to inhibit the antiviral activity of IFN-alpha/beta by yet unknown mechanism and of the RNAi pathway by likely serving as a decoy substrate for Dicer. Thus, sfRNA is involved in modulating multiple cellular pathways to facilitate viral pathogenicity; however the overlying mechanism linking all these multiple functions of sfRNA remains to be elucidated. PMID- 24473340 TI - Passive immunization against HIV/AIDS by antibody gene transfer. AB - Despite tremendous efforts over the course of many years, the quest for an effective HIV vaccine by the classical method of active immunization remains largely elusive. However, two recent studies in mice and macaques have now demonstrated a new strategy designated as Vectored ImmunoProphylaxis (VIP), which involves passive immunization by viral vector-mediated delivery of genes encoding broadly neutralizing antibodies (bnAbs) for in vivo expression. Robust protection against virus infection was observed in preclinical settings when animals were given VIP to express monoclonal neutralizing antibodies. This unorthodox approach raises new promise for combating the ongoing global HIV pandemic. In this article, we survey the status of antibody gene transfer, review the revolutionary progress on isolation of extremely bnAbs, detail VIP experiments against HIV and its related virus conduced in humanized mice and macaque monkeys, and discuss the pros and cons of VIP and its opportunities and challenges towards clinical applications to control HIV/AIDS endemics. PMID- 24473341 TI - Molecular and biological characterization of a new isolate of guinea pig cytomegalovirus. AB - Development of a vaccine against congenital infection with human cytomegalovirus is complicated by the issue of re-infection, with subsequent vertical transmission, in women with pre-conception immunity to the virus. The study of experimental therapeutic prevention of re-infection would ideally be undertaken in a small animal model, such as the guinea pig cytomegalovirus (GPCMV) model, prior to human clinical trials. However, the ability to model re-infection in the GPCMV model has been limited by availability of only one strain of virus, the 22122 strain, isolated in 1957. In this report, we describe the isolation of a new GPCMV strain, the CIDMTR strain. This strain demonstrated morphological characteristics of a typical Herpesvirinae by electron microscopy. Illumina and PacBio sequencing demonstrated a genome of 232,778 nt. Novel open reading frames ORFs not found in reference strain 22122 included an additional MHC Class I homolog near the right genome terminus. The CIDMTR strain was capable of dissemination in immune compromised guinea pigs, and was found to be capable of congenital transmission in GPCMV-immune dams previously infected with salivary gland-adapted strain 22122 virus. The availability of a new GPCMV strain should facilitate study of re-infection in this small animal model. PMID- 24473342 TI - Usefulness of different ultrasound features of malignancy in predicting the type of thyroid lesions: a meta-analysis of prospective studies. AB - INTRODUCTION: Thyroid nodules are a common medical problem. Thyroid ultrasound remains the most common method for preliminary evaluation and selection of nodules for fine-needle aspiration biopsy (FNAB). Doppler examination and elastography are believed to improve the reliability of ultrasound in predicting malignancy. OBJECTIVES: The aim of this study was to evaluate diagnostic value of common ultrasound markers of malignancy of thyroid lesions. MATERIALS AND METHODS: The PubMed/MEDLINE and Cochrane Library databases were searched to identify studies meeting the inclusion criteria. The random-effects model was used to calculate pooled odds ratio (OR), risk ratio, sensitivity, specificity, and positive and negative predictive values (PPV and NPV) of the individual features of thyroid malignancy on ultrasound. Only the prospective studies published between January 2007 and February 2013, performed using a transducer with the frequency of at least 7.5 MHz have been included in the meta-analysis. RESULTS: The taller-than-wide shape of the thyroid nodule was shown to be the strongest predictor of malignancy (OR, 13.7; PPV, 76.0%); however, its sensitivity was 25.9%. Irregular margins and microcalcifications were also strong predictors of malignancy (OR, 7.2 and 7.1, respectively) and both had higher specificity (79.6% and 75.9%, respectively) than sensitivity (45.5% and 44.1%, respectively). Elastography of the thyroid gland also proved to be a valuable diagnostic tool in detecting malignant lesions (OR, 7.9). Hypoechogenicity, halo absence, and intranodular flow on a color Doppler examination were moderate predictors of malignancy (OR, 3.2, 3.8, and 4.3, respectively). CONCLUSIONS: Ultrasound features considered to be predictors of malignancy seem to be valuable for preliminary evaluation of thyroid nodules and referral for FNAB. However, they should always be interpreted with caution because none of them allows to reliably differentiate malignant from benign nodules. PMID- 24473343 TI - Comment on "Cutaneous viral infections in patients after kidney transplantation: risk factors". PMID- 24473344 TI - Comparative study on the adsorption capacity of raw and modified litchi pericarp for removing Cu(II) from solutions. AB - The adsorption of Cu(II) onto raw litchi pericarp (LP) and modified litchi pericarp (MLP) as a function of pH, adsorbent dose and contact time, were investigated. Adsorption equilibrium isotherms, kinetics, and thermodynamics were studied to characterize the adsorption process. Leaching assays were also conducted to evaluate the potential contamination risk of LP and MLP to aqueous systems. The maximum adsorption of Cu(II) onto MLP was occurred at the pH of 6.0, adsorbent dose of 10.0 g/L, and contact time of 60 min, respectively. The adsorption process of Cu(II) onto LP and MLP were described well by both Langmuir and Freundlich isotherms, and the adsorption kinetics of Cu(II) on MLP was pseudo second-order. Cu(II) adsorption onto LP and MLP are both exothermic, while it is spontaneous for MLP, and non-spontaneous for LP. The maximum adsorption capacity of Cu(II) onto MLP was 23.70 mg/g, which was about 2.7 times higher than that of LP. Additionally, as compared to LP, the leaching amounts of TOC, TN, and TP from MLP were significantly reduced by a percentage of 27.0%, 90.3%, and 35.3%, respectively. PMID- 24473345 TI - Automatic identification of agricultural terraces through object-oriented analysis of very high resolution DSMs and multispectral imagery obtained from an unmanned aerial vehicle. AB - Agricultural terraces are features that provide a number of ecosystem services. As a result, their maintenance is supported by measures established by the European Common Agricultural Policy (CAP). In the framework of CAP implementation and monitoring, there is a current and future need for the development of robust, repeatable and cost-effective methodologies for the automatic identification and monitoring of these features at farm scale. This is a complex task, particularly when terraces are associated to complex vegetation cover patterns, as happens with permanent crops (e.g. olive trees). In this study we present a novel methodology for automatic and cost-efficient identification of terraces using only imagery from commercial off-the-shelf (COTS) cameras on board unmanned aerial vehicles (UAVs). Using state-of-the-art computer vision techniques, we generated orthoimagery and digital surface models (DSMs) at 11 cm spatial resolution with low user intervention. In a second stage, these data were used to identify terraces using a multi-scale object-oriented classification method. Results show the potential of this method even in highly complex agricultural areas, both regarding DSM reconstruction and image classification. The UAV derived DSM had a root mean square error (RMSE) lower than 0.5 m when the height of the terraces was assessed against field GPS data. The subsequent automated terrace classification yielded an overall accuracy of 90% based exclusively on spectral and elevation data derived from the UAV imagery. PMID- 24473346 TI - Critical habitat for threatened and endangered species: how should the economic costs be evaluated? AB - The designation of critical habitat is a feature of endangered species protection laws in many countries. Under the U.S. Endangered Species Act, economics cannot enter into decisions to list species as threatened or endangered, but can be considered when critical habitat is designated. Areas can be excluded from proposed critical habitat if the economic cost of including them is determined to exceed the benefits of inclusion, and exclusion would not result in extinction of the species. The economic analysis done to support critical habitat exclusions has been controversial, and the focus of much litigation. We evaluate a sample of these analyses, and discuss the exclusions that were made in each case. We discuss how the methodology used to measure economic costs of critical habitat has changed over time and provide a critique of these alternative methods. We find that the approach currently in use is sound from an economic perspective. Nevertheless, quantification of the costs of critical habitat faces numerous challenges, including great uncertainty about future events, questions about the appropriate scale for the analysis, and the need to account for complex market feedbacks and values of non-market goods. For the studies we reviewed, there was no evidence that the results of the economic analyses provided information that was useful for making decisions about exemptions from critical habitat designations. If economics is to play a meaningful role in determining endangered species protections, an alternative would be to allow listing decisions to be based on economic as well as biological factors, as is typical for species conservation laws in other countries. PMID- 24473347 TI - Two-dimensional self-assembly of amphiphilic porphyrins on a dynamically shrinking droplet surface. AB - Developing a new field of molecular self-assembly in the sub-micrometer regime with precision as high as that used to make discrete nano-sized molecular architectures through molecular design-is a major challenge for supramolecular chemistry. At present, however, there is no effective strategy for controlling the assembling molecules when their quantity is greater than one thousand. Herein, we propose a potential solution by exploiting a novel supramolecular system in conjunction with dynamically shrinking oil droplets, enabling more than a thousand component molecules to organize simultaneously into the form of sub micrometer-scale ring structures. In our developed system, amphiphilic porphyrins, having potential two-dimensional assembling ability, were compartmentalized into droplets with narrow distributions and molecular numbers. These droplets were subsequently transformed into discrete ring-like structures during the process of solvent removal from the inner organic layer, i.e., shrinking the droplets. Unique self-assembled structures, which are not accessible through conventional supramolecular strategies, can be selectively created depending on the initial stage of the droplet. PMID- 24473348 TI - Dual blockade of the renin-angiotensin-aldosterone system in renal disease: what is the future? PMID- 24473349 TI - [Regulation and disorders of calcium and phosphate metabolism]. AB - Calcium and phosphate are the constituents of biomineral, and their levels in circulation are regulated by various hormones. Disorders in calcium/phosphate metabolism are often associated with skeletal demineralization and pathological calcification. Some of the hypophosphatemic rickets/osteomalacia are caused by the increased bioactivity of FGF23, and classified into FGF23-mediated hypophosphatemic rickets/osteomalacia. In the adult patients with FGF23-mediated hypophosphatemic rickets/osteomalacia, mineralizing enthesopathy is an often observed complication. In addition, mutations of the same genes can be responsible for both rickets/osteomalacia and ectopic calcification. PMID- 24473350 TI - [Mineralization of cartilage in growth plate]. AB - Endochondral ossification is an essential process for skeletal development, in which chondrocyte undergoes apoptosis and induces mineralization after terminal differentiation. The apoptosis of chondrocyte is accompanied by marked accumulation of extracellular phosphate ions, which up-regulates the concentration of intra-cellular phosphate ions and leads to the activation of pro apoptotic factors. The mineralization of chondrocyte is regulated by the orchestrated process mediated by intra-vesicular phosphate ion production by PHOSPHO1, phosphate ion influx into matrix vesicles through Pit-1, and the functions of TNAP and NPP1 that controls pyrophosphate to phosphate ratio in the extra-vesicular progression of mineralization. The apoptosis and mineralization of chondrocyte are related to not only skeletal development but also pathological conditions such as rickets/osteomalacia and osteoarthritis. PMID- 24473351 TI - [Ectopic calcification]. AB - Calcium deposition can be observed in many tissues in addition to bones and teeth which physiologically calcify. This unphysiological calcification can damage several organs. It has been shown that vascular calcification which is a risk factor for cardiovascular events develops through similar mechanisms to physiological calcification. Further studies to clarify detailed mechanisms of calcification are necessary to develop measures that inhibit unphysiological ectopic calcification without affecting physiological calcification in bones and teeth. PMID- 24473352 TI - [Anisotropic crystallization of biominerals]. AB - Bone tissue exhibits an oriented microstructure comprising apatite crystals and collagen fibers. The mechanical, biological and chemical properties of bone tissue represent the highly anisotropic feature depending on the degree of anisotropy in crystallographic structure of apatite. Preferred orientation of apatite crystals is one of the promising parameters which determine bone quality, because the bone mechanical function is dominated by the degree of apatite crystallographic orientation rather than bone mineral density. The anisotropic microstructure of bone tissue is regulated by the mutual activities of bone cells in response to the various kinds of environmental factors. In this report, we introduce the evaluation of bone quality based on the analysis of preferential orientation of apatite c-axis by using micro-beam XRD method and our recent research about cellular regulation of bone tissue anisotropy, especially focusing on the morphological changes of bone cells regulated by the microenvironment surrounding the cells. PMID- 24473353 TI - [Microscopic aspects on biomineralization in bone]. AB - In bone, biomineralization induced by osteoblasts is known to be initiated by small extracellular vesicles referred to as "matrix vesicles". Matrix vesicles possess many enzymes and transporters, which synthesize and incorporate Ca2+ and PO4- into the vesicles. Calcification initiates when crystalline calcium phosphates are nucleated inside these matrix vesicles, and calcium phosphates, i.e., hydroxyapatite crystals, grow and eventually break through the membrane to get out of the matrix vesicles. Exposed calcium phosphates featuring "ribbon like" appearance assemble radially, forming spherical mineralized structure, referred to as "mineralized nodule" or "calcifying globule". This process is called "matrix vesicle mineralization". Thereafter, the mineralized nodules make contacts with surrounding collagen fibrils, extending mineralization along with their longitudinal axis from the contact points of collagen fibrils - collagen mineralization. Matrix vesicle mineralization and subsequent collagen mineralization are classified as primary mineralization associated with osteoblastic bone formation. After primary mineralization, secondary mineralization takes place, gradually increasing mineral density of bone matrix. This review will introduce the microscopic findings on matrix vesicle mineralization and subsequent collagen mineralization. PMID- 24473354 TI - [Osteoclast-mediated demineralization of biomineral]. AB - Calcification (biomineralization) is essential for maintenance of a life. The elucidation of "Osteoclast-mediated demineralization of biomineral" directly links elucidation for bone mineral balance (coupling of bone tissue). Bone is continuously destroyed and reformed in vertebrates to maintain bone volume and calcium homeostasis. In this review, we summarize the regulatory mechanism of osteoclast-mediated demineralization of biomineral by osteoblast-derived osteoclast differentiation factor (RANKL). PMID- 24473355 TI - [Ossification of posterior longitudinal ligament]. AB - Ossification of posterior longitudinal ligament (OPLL) is a hyperostotic disease of the spine associated with myelopathy which is occurred by an anterior compression to the spinal cord. OPLL was first reported by Key GA in 1838, and was previously considered specific to east Asian people, especially Japanese. However, now OPLL is recognized as a subtype of diffuse idiopathic skeletal hyperosteosis, which is detected in Europe and the United States. We discuss the etiology and natural history of OPLL in this review. PMID- 24473356 TI - [Tissue-nonspecific alkaline phosphatase and hypophosphatasia]. AB - There are four isozymes for human alkaline phosphatase (ALP) : tissue-nonspecific ALP (TNSALP), intestinal ALP, placental ALP and germ cell ALP. We present a brief history of TNSALP and review progress in research on it and a rare inborn error of metabolism called hypophosphatasia (HPP), which is caused by various loss-of function mutations in the ALPL gene encoding TNSALP. HPP is characterized by decreased levels of serum ALP activity and defect in mineralization of bone and teeth, thus establishing the direct link between TNSALP and biomineralization. In addition to its 3D structure, studies on TNSALP mutants expressed in mammalian cells have revealed how each mutation affects the structure and function of TNSALP at the molecular level, which contributes to our understanding of the molecular basis of HPP. PMID- 24473357 TI - [Gla-containing proteins]. AB - To date, 16 Gla-containing proteins have been discovered in humans, 7 and 9 of which are involved or not-involved in the blood coagulation cascade, respectively. They have a common feature that the carbon at the gamma-position of glutamic acid in the specific amino acid sequence of the protein molecule is carboxylated. gamma-Glutamyl carboxylase catalyzes this reaction in the presence of vitamin K as a cofactor. Similar to phosphorylation and glycosylation, gamma carboxylation of the glutamic acid has been thought to be one of the post translational modification for the activation of proteins. However, undercarboxylated, but not highly carboxylated osteocalcin has been found to exhibit regulatory activities of glucose metabolism and insulin sensitivity in mice, suggesting that there would be more comprehensive mechanisms in the regulation of protein functions by the carboxylation of glutamic acid and the decarboxylation of gamma-glutamic acid. PMID- 24473358 TI - [Sodium-dependent inorganic phosphate transporters and biomineralization]. AB - Phosphate (Pi), one of most abundant anions in living organisms, plays a crucial role in biomineralization. An adequate plasma Pi concentration is required to maintain the calcium * phosphate ion product within a range sufficient for physiological bone mineralization, but an increase in the calcium * phosphate product in extracellular fluids above a certain threshold can predispose to extraskeletal calcification. Membrane transport systems for Pi transport are key elements in maintaining homeostasis of Pi in organisms. Members of two families of solute carrier (SLC) proteins (SLC20 and SLC34) act as Na+ -dependent, secondary-active cotransporters to transport Pi across cell membranes in mammals. This review summarizes the role of SLC20 and SCL34 proteins on biomineralization. PMID- 24473359 TI - [Enzyme replacement therapy for hypophosphatasia]. AB - Hypophosphatasia is caused by abnormal tissue-nonspecific alkaline phosphatase (ALP), leading to impaired calcification in bone. Patients with severe hypophosphatasia have difficulties in respiratory function from early days after birth and the rate of lethality is extremely high. Enzyme replacement therapy using bone-targeting recombinant ALP, which has 10 aspartic acids in the C terminal tail has developed. The efficacy of ERT was firstly observed in model mice of hypophosphatasia. In clinical trial including perinatal and infantile types of hypophosphatasia, efficacy and safety have been reported. Expanded clinical trial is underway and the results of the clinical trial might be reported by the end of the next year. PMID- 24473360 TI - [Osseointegration and dental implants]. AB - The concept of osseointegration was developed and the term was coined Dr. Branemark. Osseointegration is initially defined as the direct structural and functional connection between living bone and surface living bone and the surface of a loadbearing artificial implant, typically made of titanium. Osseointegration required new bone formation around fixture, the healing of implant system is similar to primary bone healing. Bone formation on the titanium surface needs the formation of oxide film, deposition of calcium phosphate, and deposition of the protein. However, osseointegration is not the direct bonding between bone and the titanium surface, there exists an amorphous layer including osteopontin or osteocalcin that osteoblasts use them as a scaffold. In clinical the ratio of bone and implant contacts is called as BIC, and BIC was from 40% to 60% if the osseointegration was obtained. Numerous studies were performed for the surface modification to increase the score of BIC. Recently, surface treatments such as glow discharge, acid-etch, or UV irradiation have been found to be effective for osseointegration. Further modification would be needed to maintain the osseointegration as well as to obtain the osseointegration. PMID- 24473361 TI - Exploration of liver cancer genomes. AB - Liver cancer is the third leading cause of cancer-related death worldwide. Advances in sequencing technologies have enabled the examination of liver cancer genomes at high resolution; somatic mutations, structural alterations, HBV integration, RNA editing and retrotransposon changes have been comprehensively identified. Furthermore, integrated analyses of trans-omics data (genome, transcriptome and methylome data) have identified multiple critical genes and pathways implicated in hepatocarcinogenesis. These analyses have uncovered potential therapeutic targets, including growth factor signalling, WNT signalling, the NFE2L2-mediated oxidative pathway and chromatin modifying factors, and paved the way for new molecular classifications for clinical application. The aetiological factors associated with liver cancer are well understood; however, their effects on the accumulation of somatic changes and the influence of ethnic variation in risk factors still remain unknown. The international collaborations of cancer genome sequencing projects are expected to contribute to an improved understanding of risk evaluation, diagnosis and therapy for this cancer. PMID- 24473362 TI - Gut microbiota: microbial metabolites feed into the gut-brain-gut circuit during host metabolism. PMID- 24473363 TI - Alcoholic hepatitis: potential role of cytokine CCL20 in alcoholic hepatitis. PMID- 24473364 TI - T1 contrast in the myocardium and blood pool: a quantitative assessment of gadopentetate dimeglumine and gadofosveset trisodium at 1.5 and 3 T. AB - OBJECTIVES: The objective of this study was to assess the evolution of T1 contrast (T1c) between cardiovascular tissues, contrast agents, and magnetic field strengths. MATERIALS AND METHODS: This Health Insurance Portability and Accountability Act-compliant study was approved by the institutional review board, and written informed consent was obtained from all participants. Eight healthy volunteers were recruited to undergo 4 consecutive magnetic resonance (MR) scans with the same imaging parameters. Scans 1 and 2 were performed using a 3-T MR scanner, and scans 3 and 4 were performed using a 1.5-T MR scanner. Gadofosveset trisodium (0.03 mmol/kg) was injected for scans 1 and 3, and gadopentetate dimeglumine (Gd-DTPA) (0.1 mmol/kg) was used for scans 2 and 4. Modified Look-Locker inversion recovery T1 maps with a midventricular short-axis view were acquired before contrast and repeated every 5 minutes until 45 minutes after contrast agent administration. T1 contrast tissue (T1(myocardium) - T1(blood)), T1c agent (T1Gd-DTPA - T1(Gadofosveset)), and T1c field (T1(3T) - T1(1.5T)) were calculated and compared using t tests. RESULTS: The T1c tissue of the 3-T scanner was larger than that of the 1.5-T scanner for both contrast agents. In both the myocardium and the blood pool, the T1c agent of the 1.5-T scanner was larger than that of the 3-T scanner. Gadofosveset trisodium exhibited a larger T1c field and T1c tissue than did Gd-DTPA. The T1c tissue induced by Gd DTPA diminished faster than that induced by gadofosveset trisodium at both 1.5 and 3 T. CONCLUSIONS: Our study demonstrates the independent effects of timing, contrast agent type, and magnetic field strength on postcontrast T1c under general physiological conditions. The behaviors of T1c can be used to tailor quantitative MR imaging protocols for various clinical purposes. PMID- 24473365 TI - Visualization of perivascular spaces and perforating arteries with 7 T magnetic resonance imaging. AB - OBJECTIVES: The objectives of this study were to explore the possibilities of 7 T brain magnetic resonance imaging to visualize perivascular spaces (PVS) and to depict their related blood vessels. MATERIALS AND METHODS: Five subjects aged 19 to 27 years and 5 subjects aged 51 to 72 years were scanned. High-resolution 3 dimensional T1-, T2-, as well as T2*-weighted sequences and time-of-flight angiography were used for the visualization of PVS, veins, and perforating arteries. Three extra subjects were scanned with a 2-dimensional time-of-flight sequence tailored to visualize small arteries and veins in the semioval center. The anatomy of PVS and their spatial relation with blood vessels were examined. The number and size of PVS in the semioval center were compared between the 2 groups. RESULTS: In the basal ganglia, PVS were connected to the basal cisterns. Prominent dilations were observed in these PVS around the lower end of the putamen. From here, they ran upward and frequently showed caliber changes along their track. In the semioval center, smoothly shaped PVS started a few millimeters below the cortex, converged and tapered toward the ventricles, and ended 1 to 2 cm before the ventricle wall. Perivascular spaces correlated spatially with lenticulostriate arteries and with perforating arteries in the semioval center, but not with veins. The mean (SD) number of PVS was larger in the older subjects (55 [14]) than in the younger subjects (22 [11]), (P = 0.004). No difference in PVS diameter was observed. CONCLUSIONS: Seven-tesla magnetic resonance imaging offers detailed 3-dimensional visualization of PVS, their morphological features, and their related perforating arteries. This may offer new opportunities to study the role of PVS in ageing and cerebral small vessel disease. PMID- 24473366 TI - Ultrahigh-resolution imaging of the human brain with phase-cycled balanced steady state free precession at 7 T. AB - OBJECTIVES: The objectives of this study were to acquire ultra-high resolution images of the brain using balanced steady-state free precession (bSSFP) at 7 T and to identify the potential utility of this sequence. MATERIALS AND METHODS: Eight volunteers participated in this study after providing informed consent. Each volunteer was scanned with 8 phase cycles of bSSFP at 0.4-mm isotropic resolution using 0.5 number of excitations and 2-dimensional parallel acceleration of 1.75 * 1.75. Each phase cycle required 5 minutes of scanning, with pauses between the phase cycles allowing short periods of rest. The individual phase cycles were aligned and then averaged. The same volunteers underwent scanning using 3-dimensional (3D) multiecho gradient recalled echo at 0.8-mm isotropic resolution, 3D Cube T2 at 0.7-mm isotropic resolution, and thin section coronal oblique T2-weighted fast spin echo at 0.22 * 0.22 * 2.0-mm resolution for comparison. Two neuroradiologists assessed image quality and potential research and clinical utility. RESULTS: The volunteers generally tolerated the scan sessions well, and composite high-resolution bSSFP images were produced for each volunteer. Rater analysis demonstrated that bSSFP had a superior 3D visualization of the microarchitecture of the hippocampus, very good contrast to delineate the borders of the subthalamic nucleus, and relatively good B1 homogeneity throughout. In addition to an excellent visualization of the cerebellum, subtle details of the brain and skull base anatomy were also easier to identify on the bSSFP images, including the line of Gennari, membrane of Liliequist, and cranial nerves. Balanced steady-state free precession had a strong iron contrast similar to or better than the comparison sequences. However, cortical gray-white contrast was significantly better with Cube T2 and T2 weighted fast spin echo. CONCLUSIONS: Balanced steady-state free precession can facilitate ultrahigh-resolution imaging of the brain. Although total imaging times are long, the individually short phase cycles can be acquired separately, improving examination tolerability. These images may be beneficial for studies of the hippocampus, iron-containing structures such as the subthalamic nucleus and line of Gennari, and the basal cisterns and their contents. PMID- 24473367 TI - Diagnostic accuracy of computed tomography pulmonary angiography with reduced radiation and contrast material dose: a prospective randomized clinical trial. AB - OBJECTIVE: The objective of the study was to test the diagnostic performance of low-dose computed tomography pulmonary angiography (CTPA) at peak tube voltage of 80 kVp with both reduced radiation and reduced contrast material (CM) dose. MATERIALS AND METHODS: In this single-center, single-blinded prospective randomized trial, 501 patients with body weights of less than 100 kg with suspected acute pulmonary embolism (PE) were assigned to normal-dose CTPA (100 kVp tube energy and 100-mL CM, 255 patients) and low-dose CTPA (80-kVp tube energy and 75-mL CM, 246 patients). Primary end points were evidence of PE in CTPA and accuracy of CTPA on a composite reference standard. Results were compared by calculating the odds ratio with the 95% confidence interval. RESULTS: The reference diagnosis was equivocal in 20 of the 501 patients. Diagnosis of CTPA was correct in 240 patients and incorrect in 5 in the normal-dose group. Computed tomography pulmonary angiography was correct in 230 patients and incorrect in 6 in the low-dose group (odds ratio, 1.25; 95% confidence interval, 0.38-4.16; P = 0.77). Sensitivity was 96.9% and 100% and specificity was 98.1% and 97.1% in the normal-dose and low-dose groups, respectively. No PE or PE related death occurred during the 90-day follow-up. The size-specific dose estimates were 30% lower at 80 kVp (4.8 +/- 1.0 mGy) compared with that at 100 kVp (6.8 +/- 1.2 mGy; P < 0.001). CONCLUSIONS: The accuracy of low-dose CTPA at 80 kVp with a 30% reduced radiation dose and a 25% lower CM volume is not significantly different from that of normal-dose CTPA at 100 kVp in detecting acute PE in patients weighing less than 100 kg. PMID- 24473368 TI - Assessment of pulmonary perfusion with breath-hold and free-breathing dynamic contrast-enhanced magnetic resonance imaging: quantification and reproducibility. AB - OBJECTIVES: The purpose of this study was to investigate whether quantification of pulmonary perfusion from dynamic contrast-enhanced magnetic resonance imaging (DCE MRI) yields more reproducible results with data acquired during free breathing than with data from conventional breath-hold measurements. MATERIAL AND METHODS: Ten healthy male volunteers underwent 2 imaging sessions at a clinical 1.5-T MRI system, separated by a week+/-1 day. Each of these sessions comprised 2 DCE MRI acquisitions: one performed during breath-hold and one during free, shallow breathing; both acquisitions were separated by at least 20 minutes. For all DCE MRI measurements, a standard dose of gadobutrol was used. Breath-hold measurements lasted 53 seconds; free-breathing acquisitions were performed in a total acquisition time of 146 seconds.Lung tissue was segmented automatically to minimize user influence, and pulmonary plasma flow (PPF) and volume (PPV) were quantified on a per-pixel basis with a 1-compartment model. Free-breathing measurements were analyzed twice, (a) including data from the entire acquisition duration and (b) after truncation to the duration of the breath-hold measurements. For further statistical analysis, median values of the resulting parameter maps were determined. To assess intraindividual reproducibility, intraclass correlation coefficients and coefficients of variation between the first and second measurements were calculated for breath-hold, truncated, and full free-breathing measurements, respectively. Differences in the coefficients of variation were assessed with a nonparametric 2-sided paired Wilcoxon signed rank test. RESULTS: All 40 measurements were completed successfully. Maps of PPF and PPV could be calculated from both measurement techniques; PPF and PPV in the breath-hold measurements were significantly lower (P < 0.001) than in truncated and full free-breathing measurements. Both evaluations of the free-breathing measurements yielded higher intraclass correlation coefficients and lower coefficients of variation between the first and second measurements than the breath-hold measurements. CONCLUSIONS: Besides offering substantially higher patient comfort, free-breathing DCE MRI acquisitions allow for pixelwise quantification of pulmonary perfusion and hence generation of parameter maps. Moreover, quantitative perfusion estimates derived from free-breathing DCE MRI measurements have better reproducibility than estimates from the conventionally used breath-hold measurements. PMID- 24473369 TI - The genetic incorporation of thirteen novel non-canonical amino acids. AB - Thirteen novel non-canonical amino acids were synthesized and tested for suppression of an amber codon using a mutant pyrrolysyl-tRNA synthetase tRNA(Pyl)(CUA) pair. Suppression was observed with varied efficiencies. One non canonical amino acid in particular contains an azide that can be applied for site selective protein labeling. PMID- 24473370 TI - Rethinking food anticipatory activity in the activity-based anorexia rat model. AB - When a rat is on a limited fixed-time food schedule with full access to a running wheel (activity-based anorexia model, ABA), its activity level will increase hours prior to the feeding period. This activity, called food-anticipatory activity (FAA), is a hypothesized parallel to the hyperactivity symptom in human anorexia nervosa. To investigate in depth the characteristics of FAA, we retrospectively analyzed the level of FAA and activities during other periods in ABA rats. To our surprise, rats with the most body weight loss have the lowest level of FAA, which contradicts the previously established link between FAA and the severity of ABA symptoms. On the contrary, our study shows that postprandial activities are more directly related to weight loss. We conclude that FAA alone may not be sufficient to reflect model severity, and activities during other periods may be of potential value in studies using ABA model. PMID- 24473371 TI - Amyand's hernia: a review. AB - Abstract Amyand's hernia is defined as when the appendix is trapped within an inguinal hernia. While the incidence of this type of hernia is rare, the appendix may become incarcerated within Amyand's hernia and lead to further complications such as strangulation and perforation. Incarceration of the appendix most commonly occurs within inguinal and femoral hernias, but may arise to a lesser extent in incisional and umbilical hernias. Incarcerated appendix has been reported in a variety of ventral abdominal and inguinal locations, yet its indistinct clinical presentation represents a diagnostic challenge. This paper reviews the literature on incarceration of the appendix within inguinal hernias and discusses current approaches to diagnosis and treatment of Amyand's hernia and complications that may arise from incarceration of the appendix within the hernia. PMID- 24473372 TI - A comparison of the effects of methylprednisolone and tenoxicam on pain, edema, and trismus after impacted lower third molar extraction. AB - BACKGROUND: The aim of the present study was to compare the effects of preemptive intravenous tenoxicam and methylprednisolone administrations on extraction of impacted third molars. MATERIAL AND METHODS: This was a placebo-controlled, randomized, double-blind, clinical trial. A total of 60 adult patients ages 18-40 years with the complaints of impacted third molar teeth were included in the study. RESULTS: The postoperative swelling ratios (p<0.05) and pain scores (p<0.05) were significantly better in both study groups than in the control group and there was no statistically significant difference between methylprednisolone and tenoxicam groups with regards to the edema and pain relief. CONCLUSIONS: Preoperative administration of 80 mg methylprednisolone achieves better control of trismus than tenoxicam without any significant differences in edema and pain control in impacted third molar teeth extraction. PMID- 24473373 TI - Methodological issues in assessing plasma 25-hydroxyvitamin D concentration in newborn infants. AB - BACKGROUND: Although no gold standard exists, liquid chromatography tandem mass spectrometry (LC-MS/MS) is a precise and accurate method for the analysis of plasma 25-hydroxyvitamin D (25(OH)D). Immunoassays are more readily available and require small volume sampling, ideal for infant testing. The objective was to compare two commercially available immunoassays for measuring circulating 25(OH)D concentration in infant plasma against LC-MS/MS. METHODS: Capillary blood samples from 103 infants were analyzed for plasma 25(OH)D using an enzyme immunoassay (EIA, Octeia, IDS Ltd.) and radioimmunoassay (RIA, DiaSorin). Plasma 25(OH)D(3), C-3 epimer of 25(OH)D(3) (3-epi-25(OH)D(3)) and 24,25-dihydroxyvitamin D (24,25(OH)(2)D(3)) were measured on the same samples using LC-MS/MS. To establish whether plasma 24,25(OH)(2)D(3) or 3-epi-25(OH)D(3) interferes with these immunoassay results, the zero 25(OH)D calibrator from each assay kit was spiked with increasing amounts of 24,25(OH)(2)D(3) or 3-epi-25(OH)D(3). RESULTS: Classifying infants below the common vitamin D status targets of 50 nmol/L and 75 nmol/L respectively, 58% and 99% fell below using the RIA, 19% and 56% with the EIA and 31% and 76% with LC-MS/MS. Compared to LC-MS/MS, both immunoassays showed poor Bland-Altman limits of agreement for 25(OH)D concentrations (RIA: limits of agreement -27 to +13%; EIA: -12 to +41%), and mountain plots (folded cumulative distribution) depicted significant skew and bias. Spiked 24,25(OH)2D3 concentrations, but not 3-epi-25(OH)D3, appeared as >100% of known values on the EIA but not on the RIA thus, suggesting that the EIA may cross-react with 24,25(OH)(2)D(3) to a greater extent than 3-epi-25(OH)D(3). CONCLUSION: Two common immunoassays resulted in very different classifications of vitamin D status possibly related to the interference of other vitamin D metabolites. Based on these data, LC-MS/MS assessment of vitamin D status is recommended in young infants (4-6 weeks of age). PMID- 24473374 TI - Localizer sequences of magnetic resonance imaging accurately identify osteoporotic vertebral fractures. AB - The aim of the present study was to evaluate the performance of sagittal MR localizer (MR-loc), in terms of diagnostic accuracy and intra- and inter-observer agreement in the detection of vertebral fractures (VFs). Three-hundred MR examinations of the thoracic and/or lumbar spine were randomly collected. A semi quantitative approach was used and morphometric analysis was performed when a VF was suspected. MR-loc images were evaluated blindly by three radiologists in two different sessions. A full diagnostic sagittal T1-weighted fast spin echo MR sequence was used as standard of reference (RS). Degenerative arthritis was also scored on RS. Only vertebral bodies which were assessable by both MR-loc and RS were considered for the analysis. Area under the receiver operating characteristic curve (AUROC), Cohen kappa statistic, and linear-by-linear association were used for statistical analysis. Kappa values were compared by means of the z distribution. A total of 2186 vertebrae were analysed in 300 MRI exams (147 males, 153 females, 59.4+/-16.4y.o.). Sixty-seven out of 2136 (3.1%) VFs were identified in 23/300 (7.7%) patients submitted to MRI. In the detection of VFs, sensitivity and specificity of MR-loc were both 100% (accuracy AUROC=1.000). Inter-observer agreement was excellent (k=0.938+/-0.013), while intra-observer agreement was perfect (k=1.000). The diagnostic performance was independent from degenerative arthritis, vertebral level, type and grade of VFs. MR-loc is a simple but accurate tool in the detection of VFs. It should be introduced for systematic evaluation in the detection of VFs in MR examinations performed in daily clinical practice. PMID- 24473375 TI - Amyloid beta peptide is elevated in osteoporotic bone tissues and enhances osteoclast function. AB - PURPOSE: Epidemiological studies show that patients with Alzheimer's disease (AD) have an increased risk of developing osteoporotic hip fracture. However, whether abnormal amyloid beta peptide (Abeta) deposition, one of the pathological hallmarks of AD, also occurs in osteoporosis and the relationship between Abeta and human osteoporosis remain unknown. This study addressed these issues. METHODS: Forty-five female patients (osteoporosis 21, osteopenia 16 and normal 8) with osteoporotic/traumatic vertebral compression fractures were enrolled and Abeta42 and amyloid precursor protein (APP) levels assessed in the biopsy specimens of vertebral trabecular bone using immunohistochemistry (IHC) staining and semi-quantitative evaluation assays. Spearman rank correlation analysis was applied to explore the association between Abeta42/APP levels and the corresponding bone mineral density (BMD). Moreover, immunofluorescent assays and laser scanning confocal microscopy assays were used to examine the expression patterns of Abeta42/APP in patient bone tissues and osteocytes. Additionally, eight female patients with osteoporotic/traumatic femoral neck fractures, including two control patients were selected and Abeta42 and APP were identified in the femoral necks by RT-PCR and Western blotting (WB) assays. Next, a rat model of ovariectomy-induced osteoporosis was created and we evaluated Abeta42 and APP expression differences in the proximal tibia by IHC and RT-PCR and WB assays in comparison with a sham-operation group. Finally, the RAW264.7 cell line and human bone marrow monocyte (hBMMC) derived osteoclasts and human Abeta42 co culture assays were performed to investigate the effect of Abeta42 on osteoclasts cell viability, number, differentiation and activation by the Cell Counting Kit-8 assay, tartrate resistant acid phosphatase staining assay, RT-PCR assay measuring the lytic gene expression and hydroxyapatite resorption assay respectively. RESULTS: The mRNA and protein expression levels of Abeta42 and APP were elevated remarkably in the osteoporotic bone tissues both from human and ovariectomized rats when compared with the age-/sex-matched controls. Moreover, the expression levels had a negative correlation with corresponding BMD in patients (RAbeta42= 0.617, p<0.0001; RAPP=-0.531, p=0.0002). In addition, Abeta42 was located mainly in the membrane and cytoplasm of osteocytes and in the extracellular matrix, while APP was largely located in the membrane of the osteocytes. Finally, Abeta42 can potently enhance osteoclasts differentiation and activation but had no effect on osteoclasts cell viability or number (dose- and time-dependency did not exist and oligomerization of Abeta42 was not a prerequisite in the osteoclastogenesis assay). CONCLUSIONS: Abeta is relevant to human osteoporosis and may have an important role in the pathogenesis of osteoporosis. PMID- 24473376 TI - [Effect of clinical pathway of health education in patients with kidney transplantation]. AB - OBJECTIVE: To explore the effect of clinical pathway of health education in patients with kidney transplantation. METHODS: A total of 116 patients with kidney transplantation were randomly divided into an experimental group and a control group (n=58 in each group). The patients in the control group received traditional health education, and the patients in the experimental group experienced the clinical pathway of health education. The effect of health education was assessed and compared. RESULTS: There was significant difference in the effect of health education between the two groups (P<0.05). CONCLUSION: Clinical pathway of health education in patients after kidney transplantation can significantly improve the effect of health education. PMID- 24473377 TI - [Epidemiological characteristics of burn workers in Hunan Province]. AB - OBJECTIVE: To understand the epidemiological characteristics of workers who are burn patients, and to provide basis for prevention and treatment of burn at work. METHODS: We investigated 4 078 burn workers in 9 cities in Hunan provincial enterprises, and different trades managed by municipal government from January 1st, 2005 to December 31st, 2010. RESULTS: The incidence rate of employment injury was 94.84 per 10 thousand workers each year in Hunan. That of the enterprises directly managed by Hunan Medical Insurance Bureau was 93.71 per 10 thousand workers each year, and that of the enterprises managed by Medical Insurance Bureaus of cities or districts was 95.02 per 10 thousand workers each year. The burn incidence accounted for 2.00% of the total work injury in Hunan Province (7.35% in the enterprises directly managed by Hunan Medical Insurance Bureau and 1.39% in districts and industries). There were 4 078 burn patients from the sorted units [1 823 out-patients and 2 255 in-patients; 3 498 males (85.78%) and 580 females (14.22%) with age of (38.64+/-11.56) years]. The ratio between males and females was 6.03:1. Among the 4 078 patients, 2 979 were from the rural area (71.78%), with 1 100 out-patients and 1 379 in-patients. The burn was mostly mild and moderate (64.66%), and mainly occurred on the face, head, arms, and legs (61.55%). The main causes of burn were heating power (74.1%), chemical stuff (14.37%), and electric power (10.78%). The death rate was 1.42%. The burn accidents often happened between July and September. The average time from being burned to be in the hospital for treatment was 3.91 hours. CONCLUSION: Burn accidents, especially mild and moderate burn, occur mainly in young, married and poorly educated males from rural areas. Heating power, chemical stuff, and electric power are the key causes for burn. Work injury prevention measures should be improved in high risk enterprises. PMID- 24473378 TI - Efficacy of antiangiogenic targeted immunotoxin DTAT and DTATEGF against glioblastoma multiforme. AB - OBJECTIVE: To investigate the in vitro and in vivo anticancer efficacy of the immunotoxin DTAT and DTATEGF against globlastoma multiforme. METHODS: The in vitro cytotoxicity of DTAT and DTATEGF was measured using MTT assay. In vivo studies were performed in which 18 nude mice were randomly divided into 3 groups and the glioma xenograft intracranial mouse model was constructed with U87-luc cell line of human glioma. Then 1 MUg of DTAT, or DTATEGF, or a control protein Bickel3 was delivered intracranially by convection-enhanced delivery (CED) via an osmotic minipump. The brain tumor fluorescence signal intensity was investigated by bioluminescent imaging (BLI). Microvessel density (MVD) was measured by immunchistochemistry SABC method in each group. RESULTS: In vitro DTAT and DTATEGF were found highly potent against U87-luc cell line, with IC(50) <0.01 nmol/L and IC(50)<1 nmol/L, respectively. In vivo BLI monitoring of the control group showed progressively increasing luminescence, while in the two treatment groups, luminescence was reduced on day 8, and increased slowly (P<0.05). The MVD of DTAT (31.6+/-5.2)/mm(2) and DTATEGF (25.1+/-6.5)/mm(2) groups had significant difference with that of the control group (51.3+/-7.4) /mm(2) (P<0.01). CONCLUSION: Both DTAT and DTATEGF have potential in clinical application against globlastoma multiforme because of their ability to target the tumor cells and neovasculature simultaneously. PMID- 24473379 TI - [Molecular mechanism of photodynamic therapy]. AB - Despite its more than 100-year history in experimental and clinical use, photodynamic therapy (PDT) is only starting to be appreciated for its full potential. PDT combines a photosensitizer and light in the presence of oxygen to treat cancer and other disorders. This paper reviews the molecular mechanism of PDT at the cellular level as well as in therapeutic settings in vivo. The availability of multiple photosensitizers with different structures and functional properties makes PDT an extremely versatile and, conversely, a challenging approach to cancer therapy. The advancing understanding of molecular pathways helps to design improved regimens. As most cancers are being treated with combined therapies, PDT is being integrated into rationally designed regimens that exploit molecular responses to PDT for improved efficacy. PMID- 24473380 TI - [Protective effect of NMDA receptor antagonist memantine on acute lung injury in mice]. AB - OBJECTIVE: To investigate the protective effect of a non-specific NMDA receptor antagonist memantine on lipopolysaccharide (LPS)-induced acute lung injury (ALI) in mice. METHODS: Healthy male mice were divided into 4 groups: a normal group, a memantine group, an ALI group and a memantine+ALI group. The ALI group was induced by intraperitoneal injection of LPS (10 mg/kg). Memantine (10 mg/kg) was injected intraperitoneally before the injection of LPS to determine the effect of blockade of NMDA receptor in the memantine+ALI group. The lung wet/dry ratio was detected. HE staining was preformed to show the morphological changes in the lung tissue. Myeloperoxidase enzyme (MPO) activity and malondialdehyde (MDA) content in the lung tissue were detected. ELISA was used to detect the tumor necrosis factor-alpha (TNF-alpha) content and lactate dehydrogenase (LDH) activity in the bronchoalveolar lavage fluid (BALF). RESULTS: Memantine pretreatment improved the LPS-induced ALI lung tissue morphological changes, reduced their lung wet/dry ratio, the levels of TNF-alpha and LDH activity in BALF, and also reduced the MPO and MDA content in the lung tissue. CONCLUSION: Blockade of NMDA receptors can ameliorate LPS-induced mice ALI. PMID- 24473381 TI - [Protective effects of pretreatment with neurotrophin-3 on intrathecal ropivacaine in rats]. AB - OBJECTIVE: To investigate the effect of pretreatment with neurotrophin-3 (NT-3) on intrathecal ropivacaine in rats. METHODS: A total of 144 male Sprague Dawley rats weighing 280-320 g were successfully implanted with microspinal cather following the improved methods of Yaksh. The rats were randomly divided into 4 groups and given saline (Group NS, n=36), 0.5% ropivacaine (Group M, n=36), 1% ropivacaine (Group R, n=36), and ropivacaine+NT-3 (Group T, n=36). The rats received 0.12 mL/ kg body weight of ropivacaine at 0.5% or 1%, or normal saline only, via an implanted intrathecal catheter at 90-min interval for 12 h in Group NS, M, R and T. In the meantime the rats also received NT-3 0.1 mg/kg in group T. On days 1, 3, 5, 7, 14 and 28, we assessed the paw withdrawal mechanical threshold (PWMT) and paw withdrawal thermal latency (PWTL), behavioural change and histopathological damage score changed for possible neuronal injury within the spinal cord. RESULTS: Compared with Group NS and Group M, the PWMT and PWTL were significantly higher on 1, 3, 5 d and the histopathological damage score was significantly higher on 1, 3, 5, 7, 14 d in Group R (P<0.05). Compared with Group T, the PWMT and PWTL in Group R were significantly higher on 1, 3, 5 d and histopathological damage score was significantly higher on 5, 7, 14 d (P<0.05). CONCLUSION: NT-3 pretreatment in mice has obvious protective effect against repeated intrathecal injection of 1% ropivacaine in the spinal nerve. PMID- 24473382 TI - [Influence of hepatocyte growth factor on iNOS, NO and IL-1beta in the cerebrum during cerebral ischemia/reperfusion in rats]. AB - OBJECTIVE: To explore the effect of hepatocyte growth factor (HGF) on inducible nitric oxide synthase (iNOS), NO and interleukin-1beta (IL-1beta) in the cerebrum of rats subjected to cerebral ischemia/reperfusion (I/R). METHODS: Sprague-Dawley rats were randomly divided into 5 groups: a sham group, an I/R group,an HGF1 group, an HGF2 group, and an HGF3 group. The latter 3 groups were respectively injected 15, 30 and 60 MUg/kg HGF. The focal cerebral I/R model was established by sutureoccluded method. After 1.5 h ischemia followed by 24 h reperfusion, the iNOS activity and NO content in the ischemic cerebral tissue were assessed. The expression of iNOS mRNA and IL-1beta mRNA was detected. The level of iNOS protein and IL-1beta content were determined. In addition, cultured cerebral cortical neurons in vitro were exposed to I/R. Then the expression of iNOS and IL-1beta protein in the neurons was detected, and NO content was assessed. RESULTS: The iNOS activity and NO content in the ischemic cerebral tissue were increased. The expression of iNOS mRNA and IL-1beta mRNA was upregulated. The level of iNOS protein and IL- 1beta content were increased. Administration of HGF decreased the iNOS activity and NO content, and downregulated the expression of iNOS mRNA, IL 1beta mRNA, iNOS protein and IL-1beta content in the ischemic cerebral tissue. HGF decreased the expression of IL-1beta, iNOS protein and NO content in the cortical neurons exposed to I/R in vitro. CONCLUSION: HGF can inhibit the expression of IL-1beta and decrease the expression of iNOS and content of NO, which is probably one of the mechanisms mediating the protection of HGF against cerebral ischemia injury. PMID- 24473383 TI - [Combined intervention of preconditioning and postconditioning against cerebral ischemia/reperfusion injury]. AB - OBJECTIVE: To investigate the protective effect of combined ischemic preconditioning and postconditioning against cerebral ischemia/reperfusion (I/R) injury and the potential mechanism. METHODS: Sixty SD rats were randomized into a sham operation group, a brain I/R group (model group), a brain I/R plus preconditioning group (preconditioning group), a brain I/R plus postconditioning group (postconditioning group), and a brain I/R plus preconditioning and postconditioning group (combined intervention group). The rat brain I/R injury model was created by suture emboli method. Preconditioning was induced by 3 cycles of 15 s occlusion followed by 30 s recanalization of the middle cerebral artery twice respectively at 24 h and 1 h before model creation, and postconditioning was elicited by 3 cycles of 30 s reperfusion followed by 15 s ischemia before long time reperfusion. The rats were sacrificed at 48 h after the reperfusion. The cerebral infarct volume and oxidative stress parameters as well as p-Akt and p-ERK1/2 protein expressions in the brain tissues were determined. RESULTS: The cerebral infarct volumes showed no significant difference between the preconditioning group and the postconditioning group (P>0.05), but both were smaller than that in the model group and larger than that in the combined intervention group (all P values<0.01). In the model group, the level of oxidative stress was markedly increased (SOD activity increased and MDA level decreased), and both p-Akt and p-ERK1/2 protein expressions in the brain tissues were upregulated compared with those in the sham group (all P<0.01). Compared with the model group, the oxidative stress parameters presented no evident difference in preconditioning group (P>0.05), but p-Akt expression was slightly upregulated and p-ERK1/2 was remarkably down-regulated (P<0.05 and P<0.01) In the postconditioning group, the level of oxidative stress was significantly decreased, and p-Akt expression was dramatically increased with a mild down regulation of p-ERK1/2 expression (P<0.01 and P<0.05). In the combined intervention group, the oxidative stress decrease the p-Akt expression rise and p ERK1/2 expression inhibition were significantly greater than those in either the preconditioning group or the postconditioning group (all P values<0.01). CONCLUSION: Combined treatment of preconditioning and postconditioning exerts stronger protective effect against cerebral I/R injury than either preconditioning or postconditioning alone. The mechanism is possibly due to the different but complementary protection of preconditioning and postconditioning against I/R injury. PMID- 24473385 TI - [Application and radiation dose research of dual-source CT in aortic dissection after endovascular exclusion]. AB - OBJECTIVE: To evaluate dual-source CT in the Standford B aortic dissection in the postoperative follow-up and to compare radiation dose of dual-energy mode with single-energy scanning. METHODS: A total of 40 patients with aortic dissection after endovascular exclusion underwent dualsource CT. Tweny patients took the dual-energy scanning mode (100 kV and 140 kV, pitch 1.0); the other 20 patients had single-energy mode (120 kV, pitch 2.0). In both groups CareDose4D technology was used to track the current method. All images were analyzed to observe the stent shape, with or without endoleaks and the rate of thrombosis absorption. Radiation dose, scan length, and scan time were recorded for all patients, and then compared between dual-energy mode and single-energy scanning. RESULTS: The difference in scan length and image quality was not significant between the dualenergy group and the single-energy group. The acquisition time of the dual energy group was longer than that of the single-energy group, with significant difference. Radiation dose of the single-energy group was lower than that of the dual-energy group, with significant difference. CONCLUSION: Dual-source CT can objectively evaluate the conditions after the endovascular exclusion of aortic dissection. The operative effect and complications may be analyzed comprehensively. The radiation dose of the single-energy scan mode with medium pitch is lower than that of the dual-energy mode. PMID- 24473384 TI - [Expression change of SH2B1, SOCS3, PTP1B and NPY in mice hypothalamus and its relation with obesity]. AB - OBJECTIVE: To investigate the expression pattern of adapter protein with a Src homology 2 domain (SH2B1), the suppressor of cytokine signaling-3 (SOCS3), protein-tyrosine phosphatase 1B (PTP1B) and neturopetide Y (NPY) in obese and normal mice hypothalamus and its relation with serum leptin and insulin levels. METHODS: The obesity animal model was prepared with healthy C57/bl6 mice. Lee's index and Homeostasis model assessment-insulin resistance (HOMA-IR) were calculated. The mRNA levels of SH2B1, SOCS3, PTP1B and NPY were measured by fluorescent quantitation RT-PCR. The SH2B1 and NPY protein expressions were detected by Western blot. RESULTS: Compared with the normal mice of the same age, SH2B1 mRNA expression in the obese mice hypothalamus decreased. SOCS3 and PTP1B mRNA expression increased. Western blot showed that SH2B1 protein expression decreased, while NPY protein expression increased in the obese mice. Linear correlation analysis showed that the serum leptin and fasting insulin levels were negatively correlated with SH2B1mRNA expression and positively correlated with SOCS3 and PTP1B mRNA expression. CONCLUSION: SH2B1, SOCS3, PTP1B and NPY are key factors for obesity development. PMID- 24473386 TI - [Real-time ultrasound guided placement of permanent internal jugular vein catheters in maintenance hemodialysis patients]. AB - OBJECTIVE: To investigate the value of real-time ultrasound guided placement of permanent internal jugular vein (IJV) catheterization in maintenance hemodialysis patients, and analyze its technical success and complication rate. METHODS: We prospectively analyzed 63 patients (39 males, 24 females) who underwent permanent IJV cannulation with real-time ultrasound guidance from January to October in 2012. Under the real-time guidance of Logiq 5 color Doppler, we placed the tunneled cuffed catheters into the jugular vein by Seldinger technique. The number of needle punctures, technical success, the operation time, and complications were recorded. The patients were divided into a normal-risk group and a high-risk group: those who suffered multiple catheter insertions, previous difficulties during catheterization, poor compliance, obesity, impaired consciousness, skeletal deformity, disorder of haemostasis were regarded as high risk patients. RESULTS: Cannulation of IJV was done in all patients. Of the 63 catheters, 20 (31.7%) were placed in the high-risk patients; 60 (95.2%) were successfully placed at the first attempt, with the average number of punctures of (1.23+/-0.21) (range 1-3); Only 3 immediate complications (4.7%) developed; 3 (4.7%) catheter infections occurred in the course of using. Cannulation of IJV took longer time in the high-risk group than that in the normal-risk group [(30.6+/-0.11) min vs (19.1+/-0.09) min, P<0.05]. The number of needle punctures, percent of successful cannulation, and the frequency of immediate complications were similar in the high- and normal-risk groups. It was more likely to form catheter thrombosis during long-term use in the high-risk group (4/20, 20%) which might cause poor blood flow. CONCLUSION: Permanent IJV cannulation under real time ultrasound guidance is very safe with high success rates. Nephrologists can use this technique with ease and with minimal complications in both normal- and high-risk patients. PMID- 24473387 TI - [Changes of plasminogen activator inhibitor-1 and D-dimer during continuous blood purification and related factors]. AB - OBJECTIVE: To observe the changes of plasminogen activator inhibitor-1 and D dimer during continuous blood purification (CBP) and related factors. METHODS: Sixteen patients who were diagnosed with multiple organ dysfunction syndrome (MODS) were randomly divided into 2 groups: 8 patients received standard continuous blood purification with heparin anticoagulation, and the other 8 received CBP without anticoagulation. Ten normal blood samples were collected from healthy volunteers as controls. All patients underwent CBP for 8 h. Blood was taken from those patients at 0, 15, 60, 120 and 480 min during the CBP. Plasma plasminogen activator inhibitor-1, D-dimer and serum TNF-alpha and IL 1beta were measured by ELISA. RESULTS: Plasma levels of PAI-1 and D-dimer were increased significantly compared with those in the control group (P<0.05). Plasma level of PAI-1 was reduced (P<0.05) and D-dimer was increased (P<0.05) after the CBP. The level of plasma PAI-1 in the heparin group was significant reduced compared with the group of CBP without anticoagulation (P<0.05). There was negative correlation between the level of PAI-1 and the dosage of heparin used during a CBP session in the heparin group (r=-0.746, P<0.001). CONCLUSION: The level of PAI-1 and D-dimer is higher in patients with MODS than that in the normal controls. After the CBP treatment, there is significant decrease in PAI-1 and increase in D-dimer in both groups. Heparin used during CBP can reduce PAI-1 which intensifies its function of anticoagulation. PMID- 24473388 TI - [Effect of expression of high mobility group box-1 inhibited by small hairpin RNA on the invasion and migration of human endometrial carcinoma HEC-1A cells]. AB - OBJECTIVE: To investigate the effect of inhibiting high mobility group box-1 (HMGB1) gene expression on the invasion and migration of endometrial carcinoma HEC-1A cells by small hairpin RNA. METHODS: Three specific recombinant plasmids of HMGB1 (pshRNA-1 /HMGB1, pshRNA-2 / HMGB1, and pshRNA-3/HMGB1) were transfected into the endometrial cancer cell lines HEC- 1A by lipofectamine (TM) 2000. The expression of HMGB1 mRNA and protein was decteted by RTPCR and Western blot. The invasion and migration abilities of transfected HEC-1A cells were evaluated using Transwell assay and wound healing assay. RESULTS: RT-PCR and Western blot revealed that the expression of HMGB1 at both mRNA and protein levels was significantly inhibited by HMGB1-pshRNA targeting sequence 1, 2, and 3 (P<0.05), and the levels of 3 mRNAs in the transfection group were 0.192+/-0.006, 0.055+/ 0.002, and 0.123+/-0.086, respectively, which were significantly lower than those in the Lipo group (0.268+/-0.008) and the HMGB1/p-NC group (0.270+/-0.004). The maximum inhibiton rates of the 3 mRNAs were 28.4%, 79.5%, and 54.1%. The levels of 3 HMGB1 proteins in the transfection group were 0.259+/-0.129, 0.032+/-0.002, and 0.104+/-0.007, significantly lower than those in the Lipo group (0.347+/ 0.007) and the HMGB1/p-NC group (0.349+/-0.007), and the maximum inhibitory rates were 25.4%, 90.8%, and 70.0%. The transwell chamber assay and wound healing assay showed that the invasion and migration of HEC-1A cells were effectively suppressed by inhibiting HMGB1 expression (P<0.05). CONCLUSION: pshRNA-HMGB1 can effectively inhibit HMGB1 expression at both mRNA and protein levels, and decrease the invasion and migration of endometrial cancer cells. PMID- 24473389 TI - [Clinical characteristics of primary pulmonary cryptococcosis in 28 patients]. AB - OBJECTIVE: To determine the clinical characteristics, causes of pre-operative misdiagnosis and therapy of pulmonary cryptococcosis. METHODS: We retrospectively analyzed the clinical data of 28 patients suffering from pulmonary cryptococcosis from 2008 to 2013 in the Second Xiangya Hospital of Central South University. All patients were diagnosed pathologically. RESULTS: Of the 28 patients, 19 had no clear host factors. No patient was exposed to pigeons recently. The imaging findings showed that most patients had solitary, multiple nodules, masses, and patches. 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) showed abnormal accumulation of fluorodeoxyglucose. Seven patients demonstrated malignancy and 1 demonstrated tuberculosis. None was considered as pulmonary fungus diseases. Microscopically, cryptococcosis granuloma formation was found in all patients and cryptococcosis neoformans were detected by Periodic acid-schiff and Grocott methenamine silver staining methods in the histopathological examination, respectively. Twenty-seven patients underwent lobectomy, and 1 had the medical antifungal drugs treatment. During the follow-up, symptoms in only 1 patient were not controlled. CONCLUSION: Most pulmonary cryptococcosis patients have no evident immunocompromise. Clinical presentation of pulmonary cryptococcosis varies and is often related to the immune status of patients. Radiological manifestation of pulmonary cryptococcosis is indistinguishable from malignant tumor, and even 18F-FDG-PET imaging does not help to get a clear diagnosis. After surgical resection of the lung, systemic antifungal treatment is still necessary for special population. Systemic therapy of both fluconazole and itraconazole is classic choice for pulmonary cryptococcosis. PMID- 24473390 TI - [Effect of pre-amputation pain block on the spinal and anterior cingulated cortex NMDA receptor activation in amputated rats]. AB - OBJECTIVE: To investigate the effect of pre-amputation pain block on the N-methyl D-aspartate receptor activation in the central nervous system of amputated rats, and the association between pre-amputation pain block and chronic amputation related pain. METHODS: Thirty-six adult male SD rats were randomly assigned to an NA group (n=12), a PA group (n=12) and a PAB group (n=12). Group NA was intraplantarly injected saline l00 MUL while group PA and group PAB were intraplantarly injected complete Freund adjuvant (CFA) 100 MUL. The sciatic nerve of group NA and group PA were freed from surrounding tissue, and that of group PAB was blocked by bupivacaine under pentobarbital sodium anesthesia 5 days after the injection. Thermal withdrawal latency (TWL) was measured before and after the injection. All rats were amputated at the scheduled survival time. The expression of N-methyl-D-aspartate receptor (NR2B) was measured by immunohistochemistry in L4-6 of the spinal cord and the anterior cingulated cortex 7 days after the amputation procedure. RESULTS: The TWL after intraplantar administration of CFA in group PA and group PAB decreased significantly compared with the baseline value (P<0.05), while the saline treated control group remained unchanged. Besides the basic value, the TWL of group PA was shorter than that of group NA at the above-mentioned time-points (P<0.05). Compared with the basic value and group NA, the TWL of group PAB after the block increased significantly (P<0.05). Compared with group NA and group PAB, group PA had a remarkably high expression of NR2B (P<0.05), while there was no difference between group PA and group PAB. CONCLUSION: Pre-amputation pain may activate N-methyl-D-aspartate receptor of the central nervous system, which may lead acute postoperative pain to chronic pain. It is necessary to treat pre-amputation pain. PMID- 24473391 TI - [Psychometric features of the body image after breast cancer questionnaire Chinese version in women with breast cancer]. AB - OBJECTIVE: To examine the psychometric features of the body image after breast cancer questionnaire-Chinese version (BIBCQ-C) in Chinese women with breast cancer. METHODS: A total of 545 women with breast cancer received a demographics investigation: BIBCQ-C and hospital anxiety and depression scale (HAD). Four weeks later, 31 patients were selected randomly to finish BIBCQ-C again. RESULTS: The Cronbach's alpha coefficient for the total scale was 0.90, and that for the 6 factors ranged from 0.62 to 0.87. The mean inter-item correlation coefficient of the total scale was 0.16, and the mean inter-item correlation coefficient of the subscales ranged from 0.21 to 0.57, and the test-retest reliability of the total scale and 6 factors was over 0.60. The confirmatory factor analyses supported the 6-factor model, and BIBCQ-C were significantly correlated with the symptom scales of anxiety and depression (r=0.20, 0.21, P<0.01). CONCLUSION: BIBCQ-C is reliable and valid, which can effectively assess body image of Chinese women with breast cancer. PMID- 24473392 TI - [Advances in regulation of gene expression mediated by lncRNAs]. AB - Long non-coding RNAs (lncRNAs) are a group of endogenous RNA molecules which exceed 200 nt in length, lack complete specific open reading frame, and completely lack or possessvery limited protein-coding capacity. Recent studies have revealed that lncRNAs participate in critical processes such as genomic imprinting, cell differentiation, and immune reaction, etc. lncRNAs regulate gene expression at the epigenetic, transcriptional and post-transcriptional levels by modulating chromatin remodeling and histone modifications, interfering the transcription, regulating patterns of alternative splicing, generating small RNAs, and modulating protein activation and localization. Through their numerous functions, lncRNAs play critical roles in the growth, development, senescence, death, and other important physiological and pathological processes. Further investigation into the regulation of gene expression mediated by lncRNAs will be of great value in the thorough understanding of pathogenies and provide new molecular markers and drug targets of diseases. PMID- 24473393 TI - [Immune pathogenesis of IgA nephropathy and its drugable targets]. AB - IgA nephropathy (IgAN) is recognized as the most common immune complex related to the cause of glomerulonephritis worldwide. The disease is characterized by the predominant deposition of underglycosylated IgA1 in the mesangial area of glomeruli. Dysregulation of the immune system plays an important role in the pathogenesis of IgAN. Abnormalities restricted to T lymphocytes and/or B lymphocytes activation could be a critical causative factor in the over production of underglycosylated IgA1. PMID- 24473394 TI - Dynamics of H-atom exchange in stable cis-dihydrogen/hydride complexes of ruthenium(II) bearing phosphine and N-N bidentate ligands. AB - Synthesis and characterization of cis,trans-[RuH(eta(2)-H2)(PPh3)2(N-N)][OTf] (N N = 2,2'-bipyridyl (bpy) 1a, 2,2'-bipyrimidine (bpm) 2a; OTf = trifluoromethane sulfonate (CF3SO3)) complexes are reported. The cis-H2/hydride ligands are involved in H-atom site exchange between the two moieties. This dynamics was investigated by variable temperature NMR spectral studies based on which the mechanism of the exchange process was deduced. The DeltaG(?) for the exchange of H-atoms between the eta(2)-H2 and hydride ligands was determined to be around 8 and 13 kJ mol(-1), respectively, for 1a and 2a. The H-H distances (d(HH), A) in complexes 1a and 2a have been calculated from the T1(minimum) and (1)J(H,D) and are found to be 1.07 A (slow) and 0.95 A for 1a and 1.04 A (slow) and 0.94 A for 2a, respectively. The molecular structure of 1a was determined by X-ray crystallography. PMID- 24473395 TI - Cell biology of the neuron: epidermal cells eat up dendrites. PMID- 24473396 TI - Clinical value of circulating endothelial cells and of soluble CD146 levels in patients undergoing surgery for non-small cell lung cancer. AB - BACKGROUND: Previous studies indicate that endothelial injury, as demonstrated by the presence of circulating endothelial cells (CECs), may predict clinical outcome in cancer patients. In addition, soluble CD146 (sCD146) may reflect activation of angiogenesis. However, no study has investigated their combined clinical value in patients undergoing resection for non-small cell lung cancer (NSCLC). METHODS: Data were collected from preoperative blood samples from 74 patients who underwent resection for NSCLC. Circulating endothelial cells were defined, using the CellSearch Assay, as CD146+CD105+CD45-DAPI+. In parallel, sCD146 was quantified using an ELISA immunoassay. These experiments were also performed on a group of 20 patients with small-cell lung cancer, 60 healthy individuals and 23 patients with chronic obstructive pulmonary disease. RESULTS: The CEC count and the plasma level of sCD146 were significantly higher in NSCLC patients than in the sub-groups of controls (P<0.001). Moreover, an increased CEC count was associated with higher levels of sCD146 (P=0.010). Both high CEC count and high sCD146 plasma level at baseline significantly correlated with shorter progression-free survival (P<0.001, respectively) and overall survival (P=0.005; P=0.009) of NSCLC patients. CONCLUSIONS: The present study provides supportive evidence to show that both a high CEC count and a high sCD146 level at baseline correlate with poor prognosis and may be useful for the prediction of clinical outcome in patients undergoing surgery for NSCLC. PMID- 24473397 TI - Deregulated microRNAs in gastric cancer tissue-derived mesenchymal stem cells: novel biomarkers and a mechanism for gastric cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are involved in gastric cancer development and progression. However, the expression and role of miRNAs in gastric cancer stromal cells are still unclear. METHODS: The miRNAs differentially expressed in gastric cancer tissue-derived mesenchymal stem cells (GC-MSCs) relative to adjacent non cancerous tissue-derived MSCs (GCN-MSCs) and in cancer tissues relative to adjacent non-cancerous tissues were screened using miRNA microarray and validated by quantitative RT-PCR. The impact of GC-MSCs on HGC-27 cells was observed in vitro using colony formation and transwell assays, and these cells were subcutaneously co-injected into mice to assess tumour growth in vivo. Exogenous downregulation of miR-221 expression in cells was achieved using an miRNA inhibitor. RESULTS: miR-214, miR-221 and miR-222 were found to be commonly upregulated in GC-MSCs and cancer tissues. Their levels were tightly associated with lymph node metastasis, venous invasion and the TNM stage. Gastric cancer tissue-derived mesenchymal stem cells significantly promoted HGC-27 growth and migration and increased the expression of miR-221 via paracrine secretion, and the targeted inhibition of miR-221 in GC-MSCs could block its tumour-supporting role. GC-MSC-derived exosomes were found to deliver miR-221 to HGC-27 cells and promoted their proliferation and migration. CONCLUSIONS: Gastric cancer tissue derived mesenchymal stem cells favour gastric cancer progression by transferring exosomal miRNAs to gastric cancer cells, thus providing a novel mechanism for the role of GC-MSCs and new biomarkers for gastric cancer. PMID- 24473398 TI - Jumonji domain-containing protein 2B silencing induces DNA damage response via STAT3 pathway in colorectal cancer. AB - BACKGROUND: Jumonji domain-containing protein 2B (JMJD2B), directly targeted by hypoxia-inducible factor 1alpha, maintains the histone methylation balance important for the transcriptional activation of many oncogenes. Jumonji domain containing protein 2B has been implicated in colorectal cancer (CRC) progression; however, the mechanism remains unclear. METHODS: Immunofluorescence and western blotting detected phosphorylated histone H2AX, characteristic of double-strand breaks, and comet assay was used to investigate DNA damage, in CRC cells after JMJD2B small interfering RNA (siRNA) transfection. We assessed the resulting in vitro responses, that is, cell cycle progression, apoptosis, and senescence coupled with JMJD2B silencing-induced DNA damage, studying the regulatory role of signal transducers and activators of transcription 3 (STAT3). The JMJD2B silencing anti-cancer effect was determined using an in vivo CRC xenograft model. RESULTS: Jumonji domain-containing protein 2B knockdown induced DNA damage via ataxia telangiectasia-mutated (ATM) and ATM and Rad3-related pathway activation, resulting in cell cycle arrest, apoptosis, and senescence in both normoxia and hypoxia. Signal transducers and activators of transcription 3 suppression by JMJD2B silencing enhanced DNA damage. Intratumoural injection of JMJD2B siRNA suppressed tumour growth in vivo and activated the DNA damage response (DDR). CONCLUSIONS: Jumonji domain-containing protein 2B has an essential role in cancer cell survival and tumour growth via DDR mediation, which STAT3 partially regulates, suggesting that JMJD2B is a potential anti-cancer target. PMID- 24473399 TI - Phase II study of trastuzumab in combination with S-1 plus cisplatin in HER2 positive gastric cancer (HERBIS-1). AB - BACKGROUND: S-1, an oral fluoropyrimidine, plus cisplatin (SP) is a standard regimen for advanced gastric cancer (AGC) in East Asia. To date, no studies have evaluated the efficacy and safety of trastuzumab combined with SP in patients with human epidermal growth factor receptor type 2 (HER2)-positive AGC. METHODS: Patients with HER2-positive AGC received S-1 (80-120 mg per day) orally on days 1 14, cisplatin (60 mg m(-2)) intravenously on day 1, and trastuzumab (course 1, 8 mg kg(-1); course 2 onward, 6 mg kg(-1)) intravenously on day 1 of a 21-day cycle. The primary end point was response rate (RR); secondary end points included overall survival (OS), progression-free survival (PFS), time to treatment failure (TTF), and adverse events. RESULTS: A total of 56 patients were enrolled. In the full analysis set of 53 patients, the confirmed RR was 68% (95% confidence interval (CI)=54-80%), and the disease control rate was 94% (95% CI=84 99%). Median OS, PFS, and TTF were estimated as 16.0, 7.8, and 5.7 months, respectively. Major grade 3 or 4 adverse events included neutropaenia (36%), anorexia (23%), and anaemia (15%). CONCLUSIONS: Trastuzumab in combination with SP showed promising antitumour activity and manageable toxic effects in patients with HER2-positive AGC. PMID- 24473400 TI - Suppression of tumour growth by orally administered osteopontin is accompanied by alterations in tumour blood vessels. AB - BACKGROUND: The integrin-binding protein osteopontin is strongly associated with tumour development, yet is an abundant dietary component as a constituent of human and bovine milk. Therefore, we tested the effect of orally administered osteopontin (o-OPN) on the development of subcutaneous tumours in mice. METHODS: Bovine milk osteopontin was administered in drinking water to tumour-bearing immune-competent mice. Tumour growth, proliferation, necrosis, apoptosis and blood vessel size and number were measured. Expression of the alpha9 integrin was determined. RESULTS: o-OPN suppressed tumour growth, increased the extent of necrosis, and induced formation of abnormally large blood vessels. Anti-OPN reactivity detected in the plasma of OPN-null mice fed OPN suggested that tumour blocking peptides were absorbed during digestion, but the o-OPN effect was likely distinct from that of an RGD peptide. Expression of the alpha9 integrin was detected on both tumour cells and blood vessels. Potential active peptides from the alpha9 binding site of OPN were identified by mass spectrometry following in vitro digestion, and injection of these peptides suppressed tumour growth. CONCLUSIONS: These results suggest that peptides derived from o-OPN are absorbed and interfere with tumour growth and normal vessel development. o-OPN-derived peptides that target the alpha9 integrin are likely involved. PMID- 24473401 TI - Dietary fat intake and risk of epithelial ovarian cancer by tumour histology. AB - BACKGROUND: Studies of fat intake and epithelial ovarian cancer (EOC) risk have reported inconsistent findings, hence we hypothesised that associations may vary by histologic subtype. METHODS: We evaluated fat intake in a New England case control study including 1872 cases and 1978 population-based controls (1992 2008). Epithelial ovarian cancer risk factors and diet were assessed using a food frequency questionnaire at enrolment. Logistic regression was used to estimate associations between fat intake and EOC risk and polytomous logistic regression was used to test whether associations varied by histologic subtype. RESULTS: We observed a decreased risk of EOC when comparing the highest vs lowest quartiles of intake of omega-3 (odds ratio (OR)=0.79, 95% confidence interval (CI) 0.66 0.96, P-trend=0.01) and omega-6 (OR=0.77, 95% CI 0.64-0.94, P-trend=0.02) and an increased risk with high consumption of trans fat (OR=1.30, 95% CI 1.08-1.57, P trend=0.002). There was no significant heterogeneity by tumour histologic subtype; however, we observed a strong decreased risk for endometrioid invasive tumours with high intake of omega-3 (quartile (Q) 4 vs Q1, OR=0.58, 95% CI 0.41 0.82, P-trend=0.003). CONCLUSIONS: These findings suggest that higher intake of omega-3 may be protective for EOC overall and endometrioid tumours in particular, whereas greater consumption of trans fat may increase risk of EOC overall. PMID- 24473402 TI - Optimization of the Fenton treatment of 1,4-dioxane and on-line FTIR monitoring of the reaction. AB - 1,4-Dioxane is a non-biodegradable, toxic, hazardous, and priority pollutant widely used in the chemical industry as a solvent; as well as it is a resulting by-product of many industrial processes. The optimization of the Fenton treatment of 1,4-dioxane, and the on-line FTIR monitoring of its degradation route, including the assessment of the enhancement of the biodegradability of the solution along treatment are herein addressed. Besides the full removal of 1,4 dioxane, an 80% reduction of the chemical oxygen demand (COD) was achieved at the best tested treatment conditions. Whether the used concentration of H2O2 was expectedly addressed as the reaction factor most influencing the achieved COD removal at the end of the process; the performance of the treatment under acid pH conditions showed to have just a slight influence, thus supporting this process may suitably be performed at neutral pH value. On-line FTIR monitoring of the process novelly provided the degradation route of 1,4-dioxane along its oxidation treatment, as well as a comprehensive optimization of the Fenton process based on the increase of the biodegradability of the solution and the reduction of the consumption of reagents. PMID- 24473403 TI - Gas sensors based on carbon nanoflake/tin oxide composites for ammonia detection. AB - Carbon nanoflake (CNFL) was obtained from graphite pencil by using the electrochemical method and the CNFL/SnO2 composite material assessed its potential as an ammonia gas sensor. A thin film resistive gas sensor using the composite material was manufactured by the drop casting method, and the sensor was evaluated to test in various ammonia concentrations and operating temperatures. Physical and chemical characteristics of the composite material were assessed using SEM, TEM, SAED, EDS and Raman spectroscopy. The composite material having 10% of SnO2 showed 3 times higher sensor response and better repeatability than the gas sensor using pristine SnO2 nano-particle at the optimal temperature of 350 degrees C. PMID- 24473404 TI - Post-transfusion hypertension and seizure in congenital hemolytic anemia: a case report and literature review. AB - A rare syndrome of hypertension, seizures and intracranial bleed has been reported among patients with congenital hemolytic anemia who underwent multiple blood transfusions. We report this syndrome in a 12-year-old Malay girl with hemoglobin E-beta-thalassemia, who underwent intensive transfusion and subsequently had headache, visual loss, severe hypertension and seizures. A comprehensive literature review revealed 30 patients with this syndrome, of whom 15 had intracranial bleed and 12 among these 15 died. A less-intensive transfusion regimen among patients with chronic hemolytic anemia and prompt detection and management of hypertension may prevent this potentially fatal syndrome. PMID- 24473406 TI - Photochemistry of 6-amino-2-azido, 2-amino-6-azido and 2,6-diazido analogues of purine ribonucleosides in aqueous solutions. AB - The photochemistry of 6-amino-2-azidopurine, 2-amino-6-azidopurine and 2,6 diazidopurine ribonucleosides has been investigated in aqueous solutions under aerobic and anaerobic conditions. Near UV irradiation of 6-amino-2-azido-9 (2',3',5'-tri-O-acetyl-beta-D-ribofuranosyl)purine and 2-amino-6-azido-9 (2',3',5'-tri-O-acetyl-beta-D-ribofuranosyl)purine in the presence of oxygen leads to efficient formation of 6-amino-2-nitro-9-(2',3',5'-tri-O-acetyl-beta-D ribofuranosyl)purine and 2-amino-6-nitro-9-(2',3',5'-tri-O-acetyl-beta-D ribofuranosyl)purine. Under anaerobic conditions, both azidopurine ribonucleosides preferentially undergo photoreduction to 2,6-diamino-9-(2',3',5' tri-O-acetyl-beta-D-ribofuranosyl)purine. The structures of the photoproducts formed were confirmed by UV, NMR and HR ESI-TOF MS spectral data. The photoproducts observed in this study for the aminoazidopurines are distinctly different from those observed previously for 6-azidopurine. When no amino group is present, the photochemistry of 6-azidopurine leads to the formation of a 1,3,5 triazepinone nucleoside. The energetics of the 6-nitreno moiety along both oxidation and ring expansion pathways was calculated using the nudged elastic band (NEB) method based on density functional theory (DFT) using DMol3. The role of the 2-amino group in regulating the competition between these pathways was elucidated in order to explain how the striking difference in reactivity under irradiation arises from the greater spin density on the 6-nitreno-9-methyl-9H purin-2-amine, which essentially eliminates the barrier to oxidation observed in 6-nitreno-9-methyl-9H-purine. Finally, the importance of tetrazolyl intermediates for the photochemical activation of azide bond cleavage to release N2 and form the 6-nitreno group was also corroborated using the DFT methods. PMID- 24473407 TI - Cisplatin binds to human copper chaperone Cox17: the mechanistic implication of drug delivery to mitochondria. AB - Cox17 facilitates the platinum accumulation in mitochondria, which contributes to the overall cytotoxicity of cisplatin. PMID- 24473408 TI - Triaging older major trauma patients in the emergency department: an observational study. AB - BACKGROUND: The objective of this study was to compare the triage category assigned to older trauma patients with younger trauma patients upon arrival to the emergency department. The focus was to examine whether older major trauma patients were less likely to be assigned an emergency triage category on arrival to the emergency department after controlling for relevant demographics, injury characteristics and injury severity. METHODS: This was an observational study using data from the Queensland Trauma Registry. All trauma patients aged 15 years and older who presented to contributing hospitals between 1 January 2005 and 31 December 2009 with an Injury Severity Score (ISS)>15 were included. Logistic regression analysis examined the odds of assignment to emergency (Australasian Triage Scale (ATS) 1 or 2) versus urgent (ATS 3-5) treatment for patients across various age categories after adjustment for relevant demographics, injury characteristics and injury severity. RESULTS: The study used data on 6923 patients with a median (IQR) age of 43 (26-62) years and a mortality of 11.4% (95% CI 10.7% to 12.2%). Compared with individuals aged 15-34, the adjusted odds of being assigned an ATS category 1 or 2 were 30% lower (OR=0.68, 95% CI 0.57 to 0.81) for individuals aged 55-75 years and were 50% lower (OR=0.46, 95% CI 0.37 to 0.56) for individuals aged 75 years or older. CONCLUSIONS: Among patients with an ISS>15, older major trauma patients were less likely to be assigned an emergency triage category compared with younger patients. This suggests that the elderly may be undertriaged and provides a potential area of study for reducing mortality and morbidity in older trauma patients. PMID- 24473409 TI - Paramedic rapid sequence intubation in patients with non-traumatic coma. AB - INTRODUCTION: Pre-hospital intubation by paramedics is widely used in comatose patients prior to transportation to hospital, but the optimal technique for intubation is uncertain. One approach is paramedic rapid sequence intubation (RSI), which may improve outcomes in adult patients with traumatic brain injury. However, many patients present to emergency medical services with coma of non traumatic cause and the role of paramedic RSI in these patients remains uncertain. METHODS: The electronic Victorian Ambulance Clinical Information System was searched for the term 'suxamethonium' between 2008 and 2011. We reviewed the patient care records and included patients with suspected non traumatic coma who were treated and transported by road-based paramedics. Demographics, intubation conditions, vital signs (before and after drug administration) and complications were recorded. Younger patients (<60 years) were compared with older patients. RESULTS: There were 1152 paramedic RSI attempts of which 551 were for non-traumatic coma. The success rate for intubation was 97.5%. There was a significant drop in blood pressure in younger patients (<60 years) with the mean systolic blood pressure decreasing by 16 mm Hg (95% CI 11 to 21). In older patients, the systolic blood pressure also decreased significantly by 20 mm Hg (95% CI 17 to 24). Four patients suffered brief cardiac arrest during pre-hospital care, all of whom were successfully resuscitated and transported to hospital. CONCLUSIONS: Paramedic RSI in patients with non traumatic coma has a high procedural success rate. Further studies are required to determine whether this procedure improves outcomes. PMID- 24473410 TI - Evaluation of usefulness of myeloperoxidase index (MPXI) for differential diagnosis of systemic inflammatory response syndrome (SIRS) in the emergency department. AB - BACKGROUND: The myeloperoxidase index (MPXI) is elevated in infection. We ascertained whether MPXI might be useful in differentiation of sepsis versus non infectious systemic inflammatory response syndrome (SIRS) in emergency department (ED). METHODS: After exclusion of patients with an age of <18 years, trauma, haematological disease and on anticancer chemotherapy, 444 consecutive cases with SIRS (sepsis: 224, 50.3%; and non-infectious SIRS: 220, 49.7%) diagnosed and treated at the ED of The Wonju Severance Christian Hospital from May 2012 to June 2012 were retrospectively reviewed. RESULTS: Median MPXI was higher in sepsis versus non-infectious SIRS (0.1 (IQR: -3.1 to 2.5) vs -1.2 (-4.1 to 1.6), respectively, p=0.020). Median white cell count, neutrophil percentage, C reactive protein level and delta neutrophil index were also higher. However, MPXI resulted as not statistically useful for differential diagnostic parameter in analysis. CONCLUSIONS: MPXI is higher in sepsis than in non-infectious SIRS. However, there is currently no evidence that the MPXI adds any additional benefit to differentiate sepsis from non-infectious SIRS in the ED. Therefore, further study will be needed. PMID- 24473411 TI - Frequent users of US emergency departments: characteristics and opportunities for intervention. AB - OBJECTIVE: To compare the characteristics of US adults by frequency of emergency department (ED) utilisation, specifically the prevalence of chronic diseases and outpatient primary care and mental health utilisation. METHODS: We analysed 157 818 adult participants of the 2004-2009 US National Health Interview Survey, an annual nationally representative sample. We defined ED utilisation during the past 12 months as non-users (0 ED visits), infrequent users (1-3 visits), frequent users (4-9 visits) and super-frequent users (>=10 visits). We compared demographic data, socioeconomic status, chronic diseases and access to care between these ED utilisation groups using multivariable logistic regression. RESULTS: Overall, super-frequent use was reported by 0.4% of US adults, frequent use by 2% and infrequent ED use by 19%. Patients reporting >=4 ED visits were more likely to have Medicaid insurance (OR 1.57; 95% CI 1.34 to 1.85 vs private); fair or poor self-reported health (OR 2.98; 95% CI 2.57 to 3.46 vs excellent-very good); and chronic diseases such as coronary artery disease (OR 1.61; 95% CI 1.40 to 1.86), stroke (OR 1.58; 95% CI 1.36 to 1.83) or asthma (OR 1.64; 95% CI 1.46 to 1.85). While patients reporting the ED as their usual source of sick care were more likely to have >=4 ED visits (OR 7.09; 95% CI 5.61 to 8.95 vs outpatient clinic as source), >=10 outpatient visits in the past 12 months was also associated with frequent ED use (OR 11.4; 95% CI 9.09 to 14.2 vs no outpatient visits). CONCLUSIONS: Frequent ED users had a large burden of chronic diseases that also required high outpatient resources. Interventions designed to divert frequent ED users should focus on chronic disease management and access to outpatient services, particularly for Medicaid beneficiaries and other high risk subpopulations. PMID- 24473412 TI - The determinants of fishing vessel accident severity. AB - The study examines the determinants of fishing vessel accident severity in the Northeastern United States using vessel accident data from the U.S. Coast Guard for 2001-2008. Vessel damage and crew injury severity equations were estimated separately utilizing the ordered probit model. The results suggest that fishing vessel accident severity is significantly affected by several types of accidents. Vessel damage severity is positively associated with loss of stability, sinking, daytime wind speed, vessel age, and distance to shore. Vessel damage severity is negatively associated with vessel size and daytime sea level pressure. Crew injury severity is also positively related to the loss of vessel stability and sinking. PMID- 24473413 TI - HOXB13 and a SNP collaborate to increase risk. PMID- 24473414 TI - Tipping the balance in favour of degarelix for ADT. PMID- 24473415 TI - Surgery: Urological laparoscopic training--practice makes perfect. PMID- 24473416 TI - Urological complications after treatment of cervical cancer. AB - Several urological complications can occur after treatment of cervical cancer. Stage IB and IIA cervical tumours are mainly treated by radical hysterectomy; advanced-stage tumours are treated by chemoradiotherapy. In the past two decades, a decrease in complications has been seen due to improvements in therapy, although the exact incidence of lower urinary tract dysfunction is unknown. The main urological complications after radical surgery are hypocontractility of the bladder, detrusor overactivity, incontinence, low-compliance bladder, fistula and hydronephrosis. As a result of improved neuroanatomical knowledge, and consequently nerve-sparing surgery, bladder morbidity has been decreasing. Late radiation-induced urological complications include haemorrhagic cystitis, ureteric stenosis, low-compliance bladder and fistulas. Owing to technological improvements, such as dose reduction and decreased radiation fields, a decrease in radiation morbidity has been observed since 1990. PMID- 24473417 TI - Male circumcision: Disposable device offers one-stop circumcision. PMID- 24473418 TI - Sexual dysfunction: First EAU priapism treatment guidelines published. PMID- 24473419 TI - Bladder cancer: Sarcopenia predicts cystectomy complications in women. PMID- 24473420 TI - Management of internal resorption of central incisor using hybrid technique. AB - Internal inflammatory root resorption is characterised by progressive destruction of intraradicular dentin and dentinal tubules along the root canal wall. A number of theories have been proposed as a possible cause for internal resorption. It is usually asymptomatic and detected during routine radiographic investigations. Prompt diagnosis and early management of such defects is essential to maintain the integrity of the tooth. Non-surgical and surgical methods are the two main strategies involved in the management of internal resorption. The non-surgical method is usually preferred, but in cases of extensive resorption with external root perforation, surgical intervention has been advocated. The present case illustrates repair of perforating internal resorption by hybrid method, using mineral trioxide aggregate and gutta-percha, following surgical exposure. After a 10-month follow-up, no clinical and radiographic abnormalities were observed. Additionally, there was also marked reduction in periodontal pocket depth. PMID- 24473421 TI - MELAS, an important consideration in the adult population presenting with unusual and recurrent stroke-like episodes. AB - A 48-year-old man was admitted for workup of stroke-like symptoms and generalised tonic-clonic seizures. History and examination revealed that the patient had background diagnoses of type 2 diabetes mellitus, epilepsy and had suffered a temporal lobe infarct 3 years ago. The unusual presentation and physical findings, along with subsequent MRI findings led to a diagnosis of mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes (MELAS). MELAS is a mitochondrial disorder typified by the aforementioned symptoms, and is typically diagnosed in the first two decades of life. PMID- 24473422 TI - The 'hidden' SAPHO syndrome. AB - A 64-year-old woman presented to our clinic with a 4-year history of cognitive decline. The clinical examination revealed an incidental finding of the 'SAPHO' (Synovitis Acne Pustulosis Hyperostosis Osteitis) syndrome which was subsequently confirmed by diagnostic imaging. Owing to her classical presentation and her asymptomatic status she was managed conservatively with observation without any complication. PMID- 24473423 TI - GAPO syndrome with pansutural craniosynostosis leading to intracranial hypertension. AB - GAPO syndrome stands for growth retardation (G), alopecia (A), pseudoanodontia (P) and optic atrophy (O). To date, only about 35 cases of this extremely rare syndrome have been reported. Craniosynostosis/craniostenosis is a condition with an abnormal head shape due to premature fusion of the calvarial sutures and can be either non-syndromic or syndromic. Overall, craniosynostosis has an incidence of about 1 in 2500 live-births. We present a patient with GAPO syndrome in association with craniosynostosis along with intracranial hypertension, which was the cause of her headache. To the best of our knowledge, this is the first such association in the literature. PMID- 24473424 TI - High abrupt cord termination: a hallmark of caudal regression syndrome. PMID- 24473425 TI - An uncommon complication of acute stroke thrombolysis. AB - Thrombolysis with tissue plasminogen activator is a well-established treatment for acute ischaemic stroke. We report a case of an 87-year-old woman who developed an acute ischaemic limb, on the background of stroke thrombolysis, and underwent an embolectomy. A rare but serious complication, there are few reports of similar thromboembolic events, particularly in patients with known atrial fibrillation as presented in this case. Early recognition of this rare complication may prevent long-term, and at times fatal, complications. PMID- 24473426 TI - Cervical epidural abscess following an Escherichia coli urinary tract infection. AB - A previously healthy 64-year-old man developed an Escherichia coli spinal epidural abscess (SEA) isolated to the cervical vertebrae posturinary tract infection 9 days previously. He subsequently underwent emergent surgical decompression followed by a prolonged course of intravenous antibiotics. He is symptom free at 1-year follow-up. SEA is an uncommon condition. Even with modern surgical techniques and antimicrobial agents, the mortality remains significant. Intravenous drug use, spinal procedures and medical conditions such as diabetes, Crohn's disease and chronic renal failure are all known risk factors for SEA and the majority of cases are associated with at least one of these risk factors. The case report highlights the importance of maintaining a high index of suspicion for this condition even in patients without established risk factors who present with red flag symptoms: back pain, fever and neurological deficit, as the consequences of a delayed diagnosis can be severe. PMID- 24473427 TI - Difficult to wean: think of the diaphragm. AB - A 65-year-old woman, treated for non-ST segment elevation myocardial infarction and unexplained type 2 respiratory failure, was referred to our hospital in view of difficulty in weaning off the ventilator. She was evaluated in detail for persistent hypercapnia. Ultrasound of the diaphragm showed minimal excursion of diaphragm while she was off the ventilator and fluoroscopy confirmed bilateral diaphragmatic palsy. As extensive radiological, immunological and microbiological workup ruled out other possible aetiologies, a diagnosis of idiopathic Bell's palsy of the diaphragm was made. She was treated with valacyclovir and steroids after which she gradually recovered and was weaned off the ventilator. PMID- 24473428 TI - Pulmonary inflammatory myofibroblastic tumour after Hodgkin's lymphoma. AB - Positron emission tomography (PET)/CT plays a major role in staging, assessing response to treatment and during follow-up of paediatric Hodgkin's lymphoma (HL). Owing to high sensitivity to detect viable tumoural tissue, negative PET/CT is highly predictive of survival. However, (18)F-FDG is not specific for malignant disease and may concentrate in numerous benign/inflammatory lesions that may cause 'false-positive' results and follow-up PET/CT studies should be interpreted with caution. We report a case of pulmonary inflammatory myofibroblastic tumour, which developed during follow-up in a young patient with complete remission of a stage IIB HL and was fully treated with surgical resection. PMID- 24473429 TI - Acute genital ulcers. AB - Acute genital ulcers, also known as acute vulvar ulcers, ulcus vulvae acutum or Lipschutz ulcers, refer to an ulceration of the vulva or lower vagina of non venereal origin that usually presents in young women, predominantly virgins. Although its incidence is unknown, it seems a rare entity, with few cases reported in the literature. Their aetiology and pathogenesis are still unknown. The disease is characterised by an acute onset of flu-like symptoms with single or multiple painful ulcers on the vulva. Diagnosis is mainly clinical, after exclusion of other causes of vulvar ulcers. The treatment is mainly symptomatic, with spontaneous resolution in 2 weeks and without recurrences in most cases. We present a case report of a 13-year-old girl with two episodes of acute ulcers that fit the clinical criteria for Lipschutz ulcers. PMID- 24473430 TI - An extraordinary survival at the age of 67 years in an unoperated case tetralogy of Fallot presenting as systemic hypertension despite RV dysfunction. AB - Tetralogy of Fallot is a cyanotic congenital heart disease characterised by a tetrad of four anomalies including ventricular septal defect, pulmonary stenosis, over-riding of aorta and right ventricular hypertrophy with high incidence of infant and early childhood mortality with middle age survival less than 5%. Most cases require treatment in infancy and are symptomatic early on. Rare cases of survival to middle age have been reported especially after the fourth decade. We report an unoperated case of tetralogy of Fallot diagnosed at the age of 67 which is one of the longest time periods of diagnosis of a life-threatening congenital heart disease. Despite tetralogy and having right ventricular dysfunction manifested in the form of congestive symptoms, this patient presented with systemic hypertension along with cyanosis and clubbing which is considered to be a relatively rare presentation in this syndrome. The patient wished to be managed conservatively. PMID- 24473431 TI - Laparoscopic Nissen fundoplication and gastrostomy for a giant hiatal hernia in an infant with situs inversus totalis. PMID- 24473432 TI - Rapid diagnosis of Campylobacter jejuni by stool Gram stain examination. PMID- 24473433 TI - Albright's hereditary dystrophy: brain stones. PMID- 24473435 TI - Partial ablation of leptin signaling in mouse pancreatic alpha-cells does not alter either glucose or lipid homeostasis. AB - The role of glucagon in the pathological condition of diabetes is gaining interest, and it has been recently reported that its action is essential for hyperglycemia to occur. Glucagon levels, which are elevated in some diabetic models, are reduced following leptin therapy. Likewise, hyperglycemia is corrected in type 1 diabetic mice treated with leptin, although the mechanisms have not been fully determined. A direct inhibitory effect of leptin on mouse and human alpha-cells has been demonstrated at the levels of electrical activity, calcium signaling, and glucagon secretion. In the present study we employed the Cre-loxP strategy to generate Lepr(flox/flox) Gcg-cre mice, which specifically lack leptin receptors in glucagon-secreting alpha-cells, to determine whether leptin resistance in alpha-cells contributes to hyperglucagonemia, and also whether leptin action in alpha-cells is required to improve glycemia in type 1 diabetes with leptin therapy. Immunohistochemical analysis of pancreas sections revealed Cre-mediated recombination in ~ 43% of the alpha-cells. We observed that in vivo Lepr(flox/flox) Gcg-cre mice display normal glucose and lipid homeostasis. In addition, leptin administration in streptozotocin-induced diabetic Lepr(flox/flox) Gcg-cre mice restored euglycemia similarly to control mice. These findings suggest that loss of leptin receptor signaling in close to one-half of alpha-cells does not alter glucose metabolism in vivo, nor is it sufficient to prevent the therapeutic action of leptin in type 1 diabetes. PMID- 24473434 TI - Estradiol modulates Kiss1 neuronal response to ghrelin. AB - Ghrelin is a metabolic signal regulating energy homeostasis. Circulating ghrelin levels rise during starvation and fall after a meal, and therefore, ghrelin may function as a signal of negative energy balance. Ghrelin may also act as a modulator of reproductive physiology, as acute ghrelin administration suppresses gonadotropin secretion and inhibits the neuroendocrine reproductive axis. Interestingly, ghrelin's effect in female metabolism varies according to the estrogen milieu predicting an interaction between ghrelin and estrogens, likely at the hypothalamic level. Here, we show that ghrelin receptor (GHSR) and estrogen receptor-alpha (ERalpha) are coexpressed in several hypothalamic sites. Higher levels of circulating estradiol increased the expression of GHSR mRNA and the coexpression of GHSR mRNA and ERalpha selectively in the arcuate nucleus (ARC). Subsets of preoptic and ARC Kiss1 neurons coexpressed GHSR. Increased colocalization was observed in ARC Kiss1 neurons of ovariectomized estradiol treated (OVX + E2; 80%) compared with ovariectomized oil-treated (OVX; 25%) mice. Acute actions of ghrelin on ARC Kiss1 neurons were also modulated by estradiol; 75 and 22% of Kiss1 neurons of OVX + E2 and OVX mice, respectively, depolarized in response to ghrelin. Our findings indicate that ghrelin and estradiol may interact in several hypothalamic sites. In the ARC, high levels of E2 increase GHSR mRNA expression, modifying the colocalization rate with ERalpha and Kiss1 and the proportion of Kiss1 neurons acutely responding to ghrelin. Our findings indicate that E2 alters the responsiveness of kisspeptin neurons to metabolic signals, potentially acting as a critical player in the metabolic control of the reproductive physiology. PMID- 24473436 TI - Effect of IL-6 on the insulin sensitivity in patients with type 2 diabetes. AB - Elevated interleukin-6 (IL-6) levels are associated with type 2 diabetes, but its role in glucose metabolism is controversial. We investigated the effect of IL-6 on insulin-stimulated glucose metabolism in type 2 diabetes patients and hypothesized that an acute, moderate IL-6 elevation would increase the insulin mediated glucose uptake. Men with type 2 diabetes not treated with insulin [n = 9, age 54.9 +/- 9.7 (mean +/- SD) yr, body mass index 34.8 +/- 6.1 kg/m(2), HbA1c 7.0 +/- 1.0%] received continuous intravenous infusion with either recombinant human IL-6 (rhIL-6) or placebo. After 1 h with placebo or rhIL-6, a 3-h hyperinsulinemic-isoglycemic clamp was initiated. Whole body glucose metabolism was measured using stable isotope-labeled tracers. Signal transducer and activator of transcription 3 (STAT3) phosphorylation and suppressor of cytokine signaling 3 (SOCS3) expression were measured in muscle biopsies. Whole body energy expenditure was measured using indirect calorimetry. In response to the infusion of rhIL-6, circulating levels of IL-6 (P < 0.001), neutrophils (P < 0.001), and cortisol (P < 0.001) increased while lymphocytes decreased (P < 0.01). However, IL-6 infusion did not change glucose infusion rate, rate of appearance, or rate of disappearance during the clamp. While IL-6 enhanced phosphorylation of STAT3 in skeletal muscle (P = 0.041), the expression of SOCS3 remained unchanged. Whole body oxygen uptake (P < 0.01) and expired carbon dioxide (P < 0.01) increased during rhIL-6 infusion. In summary, although IL-6 induced local and systemic responses, the insulin-stimulated glucose uptake was not affected. While different contributing factors may be involved, our results are in contrast to our hypothesis and previous findings in young, healthy men. PMID- 24473438 TI - Targeted deletion of C1q/TNF-related protein 9 increases food intake, decreases insulin sensitivity, and promotes hepatic steatosis in mice. AB - Transgenic overexpression of CTRP9, a secreted hormone downregulated in obesity, confers striking protection against diet-induced obesity and type 2 diabetes. However, the physiological relevance of this adiponectin-related plasma protein remains undefined. Here, we used gene targeting to establish the metabolic function of CTRP9 in a physiological context. Mice lacking CTRP9 were obese and gained significantly more body weight when fed standard laboratory chow. Increased food intake, due in part to upregulated expression of hypothalamic orexigenic neuropeptides, contributed to greater adiposity in CTRP9 knockout mice. Although the frequency of food intake remained unchanged, CTRP9 knockout mice increased caloric intake by increasing meal size and decreasing satiety ratios. The absence of CTRP9 also resulted in peripheral tissue insulin resistance, leading to increased fasting insulin levels, impaired hepatic insulin signaling, and reduced insulin tolerance. Increased expression of lipogenic genes, combined with enhanced caloric intake, contributed to hepatic steatosis in CTRP9 knockout mice. Loss of CTRP9 also resulted in reduced skeletal muscle AMPK activation and mitochondrial content. Together, these results provide the genetic evidence for a physiological role of CTRP9 in controlling energy balance via central and peripheral mechanisms. PMID- 24473437 TI - Sphingosine kinase 1 regulates adipose proinflammatory responses and insulin resistance. AB - Adipose dysfunction resulting from chronic inflammation and impaired adipogenesis has increasingly been recognized as a major contributor to obesity-mediated insulin resistance, but the molecular mechanisms that maintain healthy adipocytes and limit adipose inflammation remain unclear. Here, we used genetic and pharmacological approaches to delineate a novel role for sphingosine kinase 1 (SK1) in metabolic disorders associated with obesity. SK1 phosphorylates sphingosine to form sphingosine 1 phosphate (S1P), a bioactive sphingolipid with numerous roles in inflammation. SK1 mRNA expression was increased in adipose tissue of diet-induced obese (DIO) mice and obese type 2 diabetic humans. In DIO mice, SK1 deficiency increased markers of adipogenesis and adipose gene expression of the anti-inflammatory molecules IL-10 and adiponectin and reduced adipose tissue macrophage (ATM) recruitment and proinflammatory molecules TNFalpha and IL-6. These changes were associated with enhanced insulin signaling in adipose and muscle and improved systemic insulin sensitivity and glucose tolerance in SK1(-/-) mice. Specific pharmacological inhibition of SK1 in WT DIO mice also reduced adipocyte and ATM inflammation and improved overall glucose homeostasis. These data suggest that the SK1-S1P axis could be an attractive target for the development of treatments to ameliorate adipose inflammation and insulin resistance associated with obesity and type 2 diabetes. PMID- 24473439 TI - Overnutrition induces beta-cell differentiation through prolonged activation of beta-cells in zebrafish larvae. AB - Insulin from islet beta-cells maintains glucose homeostasis by stimulating peripheral tissues to remove glucose from circulation. Persistent elevation of insulin demand increases beta-cell number through self-replication or differentiation (neogenesis) as part of a compensatory response. However, it is not well understood how a persistent increase in insulin demand is detected. We have previously demonstrated that a persistent increase in insulin demand by overnutrition induces compensatory beta-cell differentiation in zebrafish. Here, we use a series of pharmacological and genetic analyses to show that prolonged stimulation of existing beta-cells is necessary and sufficient for this compensatory response. In the absence of feeding, tonic, but not intermittent, pharmacological activation of beta-cell secretion was sufficient to induce beta cell differentiation. Conversely, drugs that block beta-cell secretion, including an ATP-sensitive potassium (K ATP) channel agonist and an L-type Ca(2+) channel blocker, suppressed overnutrition-induced beta-cell differentiation. Genetic experiments specifically targeting beta-cells confirm existing beta-cells as the overnutrition sensor. First, inducible expression of a constitutively active K ATP channel in beta-cells suppressed the overnutrition effect. Second, inducible expression of a dominant-negative K ATP mutant induced beta-cell differentiation independent of nutrients. Third, sensitizing beta-cell metabolism by transgenic expression of a hyperactive glucokinase potentiated differentiation. Finally, ablation of the existing beta-cells abolished the differentiation response. Taken together, these data establish that overnutrition induces beta-cell differentiation in larval zebrafish through prolonged activation of beta-cells. These findings demonstrate an essential role for existing beta-cells in sensing overnutrition and compensating for their own insufficiency by recruiting additional beta-cells. PMID- 24473440 TI - Long-term niacin treatment induces insulin resistance and adrenergic responsiveness in adipocytes by adaptive downregulation of phosphodiesterase 3B. AB - The lipid-lowering effect of niacin has been attributed to the inhibition of cAMP production in adipocytes, thereby inhibiting intracellular lipolysis and release of nonesterified fatty acids (NEFA) to the circulation. However, long-term niacin treatment leads to a normalization of plasma NEFA levels and induces insulin resistance, for which the underlying mechanisms are poorly understood. The current study addressed the effects of long-term niacin treatment on insulin mediated inhibition of adipocyte lipolysis and focused on the regulation of cAMP levels. APOE*3-Leiden.CETP transgenic mice treated with niacin for 15 wk were subjected to an insulin tolerance test and showed whole body insulin resistance. Similarly, adipocytes isolated from niacin-treated mice were insulin resistant and, interestingly, exhibited an increased response to cAMP stimulation by 8Br cAMP, beta1- and beta2-adrenergic stimulation. Gene expression analysis of the insulin and beta-adrenergic pathways in adipose tissue indicated that all genes were downregulated, including the gene encoding the cAMP-degrading enzyme phosphodiesterase 3B (PDE3B). In line with this, we showed that insulin induced a lower PDE3B response in adipocytes isolated from niacin-treated mice. Inhibiting PDE3B with cilostazol increased lipolytic responsiveness to cAMP stimulation in adipocytes. These data show that long-term niacin treatment leads to a downregulation of PDE3B in adipocytes, which could explain part of the observed insulin resistance and the increased responsiveness to cAMP stimulation. PMID- 24473442 TI - Social interaction plays a critical role in neurogenesis and recovery after stroke. AB - Stroke survivors often experience social isolation. Social interaction improves quality of life and decreases mortality after stroke. Male mice (20-25 g; C57BL/6N), all initially pair housed, were subjected to middle cerebral artery occlusion (MCAO). Mice were subsequently assigned into one of three housing conditions: (1) Isolated (SI); (2) Paired with their original cage mate who was also subjected to stroke (stroke partner (PH-SP)); or (3) Paired with their original cage mate who underwent sham surgery (healthy partner (PH-HP)). Infarct analysis was performed 72 h after stroke and chronic survival was assessed at day 30. Immediate post-stroke isolation led to a significant increase in infarct size and mortality. Interestingly, mice paired with a healthy partner had significantly lower mortality than mice paired with a stroke partner, despite equivalent infarct damage. To control for changes in infarct size induced by immediate post-stroke isolation, additional cohorts were assessed that remained pair housed for three days after stroke prior to randomization. Levels of brain derived neurotrophic factor (BDNF) were assessed at 90 days and cell proliferation (in cohorts injected with 5-bromo-2'-deoxyuridine, BrdU) was evaluated at 8 and 90 days after stroke. All mice in the delayed housing protocol had equivalent infarct volumes (SI, PH-HP and PH-SP). Mice paired with a healthy partner showed enhanced behavioral recovery compared with either isolated mice or mice paired with a stroke partner. Behavioral improvements paralleled changes in BDNF levels and neurogenesis. These findings suggest that the social environment has an important role in recovery after ischemic brain injury. PMID- 24473443 TI - Plasma fibrinogen: now also an antidepressant response marker? AB - Major depressive disorder (MDD) is one of the leading causes of global disability. It is a risk factor for noncompliance with medical treatment, with about 40% of patients not responding to currently used antidepressant drugs. The identification and clinical implementation of biomarkers that can indicate the likelihood of treatment response are needed in order to predict which patients will benefit from an antidepressant drug. While analyzing the blood plasma proteome collected from MDD patients before the initiation of antidepressant medication, we observed different fibrinogen alpha (FGA) levels between drug responders and nonresponders. These results were replicated in a second set of patients. Our findings lend further support to a recently identified association between MDD and fibrinogen levels from a large-scale study. PMID- 24473441 TI - Local overexpression of the myostatin propeptide increases glucose transporter expression and enhances skeletal muscle glucose disposal. AB - Insulin resistance (IR) in skeletal muscle is a prerequisite for type 2 diabetes and is often associated with obesity. IR also develops alongside muscle atrophy in older individuals in sarcopenic obesity. The molecular defects that underpin this syndrome are not well characterized, and there is no licensed treatment. Deletion of the transforming growth factor-beta family member myostatin, or sequestration of the active peptide by overexpression of the myostatin propeptide/latency-associated peptide (ProMyo) results in both muscle hypertrophy and reduced obesity and IR. We aimed to establish whether local myostatin inhibition would have a paracrine/autocrine effect to enhance glucose disposal beyond that simply generated by increased muscle mass, and the mechanisms involved. We directly injected adeno-associated virus expressing ProMyo in right tibialis cranialis/extensor digitorum longus muscles of rats and saline in left muscles and compared the effects after 17 days. Both test muscles were increased in size (by 7 and 11%) and showed increased radiolabeled 2-deoxyglucose uptake (26 and 47%) and glycogen storage (28 and 41%) per unit mass during an intraperitoneal glucose tolerance test. This was likely mediated through increased membrane protein levels of GLUT1 (19% higher) and GLUT4 (63% higher). Interestingly, phosphorylation of phosphoinositol 3-kinase signaling intermediates and AMP-activated kinase was slightly decreased, possibly because of reduced expression of insulin-like growth factor-I in these muscles. Thus, myostatin inhibition has direct effects to enhance glucose disposal in muscle beyond that expected of hypertrophy alone, and this approach may offer potential for the therapy of IR syndromes. PMID- 24473444 TI - The alpha-endomannosidase gene (MANEA) is associated with panic disorder and social anxiety disorder. AB - Unbiased genome-wide approaches can provide novel insights into the biological pathways that are important for human behavior and psychiatric disorder risk. The association of alpha-endomannosidase gene (MANEA) variants and cocaine-induced paranoia (CIP) was initially described in a study that used a whole-genome approach. Behavioral effects have been reported for other mannosidase genes, but MANEA function in humans and the clinical potential of the previous findings remain unclear. We hypothesized that MANEA would be associated with psychiatric phenotypes unrelated to cocaine use. We used a multi-stage association study approach starting with four psychiatric disorders to show an association between a MANEA single-nucleotide polymorphism (SNP; rs1133503) and anxiety disorders. In the first study of 2073 European American (EA) and 2459 African American subjects mostly with comorbid drug or alcohol dependence, we observed an association in EAs of rs1133503 with panic disorder (PD) (191 PD cases, odds ratio (OR)=1.7 (95% confidence interval (CI): 1.22-2.41), P=0.002). We replicated this finding in an independent sample of 142 PD cases (OR =1.53 (95% CI: 1.00-2.31), P=0.043) and extended it in an independent sample of 131 generalized social anxiety disorder cases (OR=2.15 (95% CI: 1.27-3.64), P=0.004). MANEA alleles and genotypes were also associated with gene expression differences in whole blood cells. Using publically available data, we observed a consistent effect on expression in brain tissue. We conclude that pathways involving alpha-endomannosidase warrant further investigation in relation to anxiety disorders. PMID- 24473446 TI - Gout. PMID- 24473447 TI - Does NHS England have a slow puncture? PMID- 24473448 TI - Turning a blind eye to alternative medicine education. PMID- 24473449 TI - Doctors should carry out more biopsies on secondary breast cancers, researchers say. PMID- 24473445 TI - A novel computational biostatistics approach implies impaired dephosphorylation of growth factor receptors as associated with severity of autism. AB - The prevalence of autism spectrum disorders (ASDs) has increased 20-fold over the past 50 years to >1% of US children. Although twin studies attest to a high degree of heritability, the genetic risk factors are still poorly understood. We analyzed data from two independent populations using u-statistics for genetically structured wide-locus data and added data from unrelated controls to explore epistasis. To account for systematic, but disease-unrelated differences in (non randomized) genome-wide association studies (GWAS), a correlation between P values and minor allele frequency with low granularity data and for conducting multiple tests in overlapping genetic regions, we present a novel study-specific criterion for 'genome-wide significance'. From recent results in a comorbid disease, childhood absence epilepsy, we had hypothesized that axonal guidance and calcium signaling are involved in autism as well. Enrichment of the results in both studies with related genes confirms this hypothesis. Additional ASD-specific variations identified in this study suggest protracted growth factor signaling as causing more severe forms of ASD. Another cluster of related genes suggests chloride and potassium ion channels as additional ASD-specific drug targets. The involvement of growth factors suggests the time of accelerated neuronal growth and pruning at 9-24 months of age as the period during which treatment with ion channel modulators would be most effective in preventing progression to more severe forms of autism. By extension, the same computational biostatistics approach could yield profound insights into the etiology of many common diseases from the genetic data collected over the last decade. PMID- 24473450 TI - The challenge of doing less. PMID- 24473452 TI - Rabies: beware of the dog. PMID- 24473453 TI - One-shot photochemical synthesis of 5-(thiophen-3-yl)pyrano[2,3-c]chromen-2(3H) ones from 3-propynyloxy-chromenones: a case of an intramolecular Paterno-Buchi reaction. AB - 5-(Thiophen-3-yl)pyrano[2,3-c]chromen-2(3H)-ones (2), angular tricyclic compounds, were synthesized in significantly high yields through the photoinduced intramolecular coupling of the acetylenic group with the carbonyl centre in 3 (prop-2-ynyloxy)-2-(thiophen-3-yl)-4H-chromen-4-ones (1). This photoreaction is a case of an intramolecular Paterno-Buchi reaction and is unprecedented in 3 propynyloxy-chromenones. The structure of 2 has been determined by spectroscopic (FTIR, NMR and mass) and single crystal X-ray crystallographic studies. PMID- 24473451 TI - Smoking status and the effects of antiplatelet drugs. PMID- 24473455 TI - Lipid and citric acid production by wild yeasts grown in glycerol. AB - In this study, crude glycerol was used as a carbon source in the cultivation of wild yeasts, aiming for the production of microbial lipids and citric acid. Forty yeasts of different sources were tested concerning their growth in crude and commercial glycerol. Four yeasts (Lidnera saturnus UFLA CES-Y677, Yarrowia lipolytica UFLA CM-Y9.4, Rhodotorula glutinis NCYC 2439, and Cryptococcus curvatus NCYC 476) were then selected owing to their ability to grow in pure (OD600 2.133, 1.633, 2.055, and 2.049, respectively) and crude (OD600 2.354, 1.753, 2.316, and 2.281, respectively) glycerol (10%, 20%, and 30%). Y. lipolytica UFLA CM-Y9.4 was selected for its ability to maintain cell viability in concentrations of 30% of crude glycerol, and high glycerol intake (18.907 g/l). This yeast was submitted to lipid production in 30 g/l of crude glycerol, and therefore obtained 63.4% of microbial lipids. In the fatty acid profile, there was a predominance of stearic (C18:0) and palmitic (C16:0) acids in the concentrations of 87.64% and 74.67%, respectively. We also performed optimization of the parameters for the production of citric acid, which yielded a production of 0.19 g/l of citric acid in optimum conditions (38.4 g/l of crude glycerol, agitation of 184 rpm, and temperature of 30 degrees C). Yarrowia lipolytica UFLA CM-Y9.4 presented good lipid production when in the concentration of 30 g/l of glycerol. These data may be used for production in large quantities for the application of industrial biodiesel. PMID- 24473454 TI - FasL gene -844T/C mutation of esophageal cancer in South China and its clinical significance. AB - In this study, we investigated the association between the FasL -844T/C polymorphism and the risk of developing esophageal squamous cell carcinoma (ESCC) in South China. For the investigation, we randomly selected 248 patients suffering from ESCC from Southern China along with 297 healthy individuals as the control group. The relationship between the FasL gene -844T/C SNP and ESCC was studied using PCR-RFLP and immunohistochemistry. The Fas -1377G/A SNP was also selected for investigation to detect whether it interferes with the functional effect of the FasL -844C/T polymorphism in ESCC development. A significant difference in the FasL -844T/C genotypes between the patients and the control group was observed (P<0.05), with those expressing the C allele having a significantly reduced risk of developing ESCC, however elderly patients (>60 years) exhibited a more malignant pathological grade if they were homozygous for the C allele. FasL -844 CC combined with the Fas -1377 G allele is a protective factor against ESCC. Having said this, even though the C allele has a protective effect prior to development of ESCC, once the host does develop the condition the tumour will develop faster and have a higher degree of malignancy than T carriers. PMID- 24473456 TI - Aspergillus cumulatus sp. nov., from rice straw and air for meju fermentation. AB - A new species named Aspergillus cumulatus sp. nov. is described in Aspergillus section Aspergillus (Eurotium state). The type strain (KACC 47316(T)) of this species was isolated from rice straw used in meju fermentations in Korea, and other strains were isolated from the air in a meju fermentation room. The species is characterized by growth at a wide range of water activities and the formation of aerial hyphae on malt extract 60% sucrose agar (ME60S) that resemble a cumulus cloud. Furthermore, A. cumulatus produces yellow ascomata containing small lenticular ascospores (5.1-5.7 MUm) with a wide furrow, low equatorial crests, and tuberculate convex surface. The species is phylogenetically distinct from the other reported Aspergillus section Aspergillus species based on multilocus sequence typing using rDNA-ITS, beta-tubulin, calmodulin, and RNA polymerase II genes. PMID- 24473457 TI - Body fat throughout childhood in 2647 healthy Danish children: agreement of BMI, waist circumference, skinfolds with dual X-ray absorptiometry. AB - BACKGROUND/OBJECTIVES: Total body fat percentage (%BF) evaluated by dual energy X ray absorptiometry (DXA) scans (DXA %BF) is widely recognized as a precise measure of fatness. We aimed to establish national reference curves for DXA %BF, %BF calculated from skinfolds (SF %BF) and waist circumference (WC) in healthy children, and to compare agreement between the different methods. SUBJECTS/METHODS: Based on 11 481 physical examinations (anthropometry) and 1200 DXA scans from a longitudinal cohort of Danish children (n=2647), we established reference curves (LMS-method) for SF %BF, WC (birth to 14 years) and DXA %BF (8 14 years). Age- and sex-specific Z-scores for body mass index (BMI), WC and SF %BF were compared. Sensitivity and specificity were calculated for agreement of WC, SF %BF and BMI with DXA %BF to identify obese children (>+1 s.d.). RESULTS: %BF differed with age, sex, pubertal stage and social class. SF %BF correlated strongly with DXA %BF (r=0.86). BMI and WC also correlated positively with DXA %BF (Z-scores; r= 0.78 and 0.69). Sensitivity and specificity were 79.5 and 93.8 for SF %BF, 75.9 and 90.3 for BMI and 59.2 and 95.4 for WC. CONCLUSIONS: SF %BF showed the highest correlation and best agreement with DXA %BF in identifying children with excess fat (+1 s.d.). PMID- 24473458 TI - Assessment of standardised parenteral nutrition in paediatrics. PMID- 24473460 TI - Retail yields and palatability evaluations of individual muscles from wet-aged and dry-aged beef ribeyes and top sirloin butts that were merchandised innovatively. AB - Paired ribeyes (n=24) and top sirloin butts (n=24) were dry-aged or wet-aged for 35 days before being merchandised as individual muscles: M. spinalis thoracis, M. longissimus thoracis, M. gluteobiceps, and M. gluteus medius. Wet-aged subprimals had greater saleable yields than dry-aged. Dry-aged M. spinalis thoracis and M. gluteobiceps received lower consumer overall like and flavor ratings than did wet aged; interior muscles - M. longissimus thoracis and M. gluteus medius - did not differ. Trained panelists found higher musty and putrid flavors for dry-aged muscles closer to exterior surface. These flavors may have contributed to lower consumer overall like and flavor ratings for dry-aged M. spinalis thoracis and M. gluteobiceps. Using innovative styles to cut beef allows for greater merchandising options. However, development of undesirable flavor characteristics may be more pronounced when exterior muscles - M. spinalis thoracis and M. gluteobiceps - are exposed during dry-aging to extreme conditions and are consumed individually. PMID- 24473459 TI - Long-term effects of a Palaeolithic-type diet in obese postmenopausal women: a 2 year randomized trial. AB - BACKGROUND/OBJECTIVES: Short-term studies have suggested beneficial effects of a Palaeolithic-type diet (PD) on body weight and metabolic balance. We now report the long-term effects of a PD on anthropometric measurements and metabolic balance in obese postmenopausal women, in comparison with a diet according to the Nordic Nutrition Recommendations (NNR). SUBJECTS/METHODS: Seventy obese postmenopausal women (mean age 60 years, body mass index 33 kg/m(2)) were assigned to an ad libitum PD or NNR diet in a 2-year randomized controlled trial. The primary outcome was change in fat mass as measured by dual-energy X-ray absorptiometry. RESULTS: Both groups significantly decreased total fat mass at 6 months (-6.5 and-2.6 kg) and 24 months (-4.6 and-2.9 kg), with a more pronounced fat loss in the PD group at 6 months (P<0.001) but not at 24 months (P=0.095). Waist circumference and sagittal diameter also decreased in both the groups, with a more pronounced decrease in the PD group at 6 months (-11.1 vs-5.8 cm, P=0.001 and-3.7 vs-2.0 cm, P<0.001, respectively). Triglyceride levels decreased significantly more at 6 and 24 months in the PD group than in the NNR group (P<0.001 and P=0.004). Nitrogen excretion did not differ between the groups. CONCLUSIONS: A PD has greater beneficial effects vs an NNR diet regarding fat mass, abdominal obesity and triglyceride levels in obese postmenopausal women; effects not sustained for anthropometric measurements at 24 months. Adherence to protein intake was poor in the PD group. The long-term consequences of these changes remain to be studied. PMID- 24473462 TI - A Low-power CMOS BFSK Transceiver for Health Monitoring Systems. AB - A CMOS low-power transceiver for implantable and external health monitoring devices operating in the MICS band is presented. The LNA core has an integrated mixer in a folded configuration to reuse the bias current, allowing high linearity with a low power supply levels. The baseband strip consists of a pseudo differential MOS-C band-pass filter achieving demodulation of 150kHz-offset BFSK signals. An all digital frequency-locked loop is used for LO generation in the RX mode and for driving a class AB power amplifier in the TX mode. The MICS transceiver is designed and fabricated in a 0.18MUm 1-poly, 6-metal CMOS process. The sensitivities of -70dBm and -98dBm were achieved with NF of 40dB and 11dB at the data rate of 100kb/s while consuming only 600MUW and 1.5mW at 1.2V and 1.8V, respectively. The BERs are less than 10-3 at the input powers of -70dBm at 1.2V and -98dBm at 1.8V at the data rate of 100kb/s. Finally, the output power of the transmitter is 0dBm for a power consumption of 1.8mW. PMID- 24473461 TI - Evidence for autosomal recessive inheritance in SPG3A caused by homozygosity for a novel ATL1 missense mutation. AB - Hereditary spastic paraplegias (HSPs) comprise a heterogeneous group of disorders characterized by progressive spasticity and weakness of the lower limbs. Autosomal dominant and 'pure' forms of HSP account for ~80% of cases in Western societies of whom 10% carry atlastin-1 (ATL1) gene mutations. We report on a large consanguineous family segregating six members with early onset HSP. The pedigree was compatible with both autosomal dominant and autosomal recessive inheritance. Whole-exome sequencing and segregation analysis revealed a homozygous novel missense variant c.353G>A, p.(Arg118Gln) in ATL1 in all six affected family members. Seven heterozygous carriers, five females and two males, showed no clinical signs of HSP with the exception of sub-clinically reduced vibration sensation in one adult female. Our combined findings show that homozygosity for the ATL1 missense variant remains the only plausible cause of HSP, whereas heterozygous carriers are asymptomatic. This apparent autosomal recessive inheritance adds to the clinical complexity of spastic paraplegia 3A and calls for caution using directed genetic screening in HSP. PMID- 24473464 TI - An unsolvated buckycatcher and its first dianion. AB - The X-ray crystallographic study of C60H28 consisting of two tethered corannulene bowls revealed a unique solid-state packing based on tight convex-concave pi-pi interactions. The controlled reduction of C60H28 resulted in the isolation and structural characterization of its dianion in the form of the rubidium salt that shows an entrapment of counterions by an anionic pincer. PMID- 24473465 TI - Highly efficient one-pot multienzyme (OPME) synthesis of glycans with fluorous tag assisted purification. AB - Oligo(ethylene glycol)-linked light fluorous tags have been found to be optimal for conjugating to glycans for both high-yield enzymatic glycosylation reactions using one-pot multienzyme (OPME) systems and quick product purification using fluorous solid-phase extraction (FSPE) cartridges. The combination of OPME glycosylation systems and the FSPE cartridge purification scheme provides a highly effective strategy for facile synthesis and purification of glycans. PMID- 24473467 TI - Effect of strength and high-intensity training on jumping, sprinting, and intermittent endurance performance in prepubertal soccer players. AB - The purpose of this study was to examine the effects of a 26-week on-field combined strength and high-intensity training on the physical performance capacity among prepubertal soccer players who were undertaking a competitive phase of training. Twenty-four prepubertal soccer players between the age of 8 and 9 years were randomly assigned to 2 groups: a control (C; n = 13) and an experimental group (S; n = 11). Both groups performed an identical soccer training program, whereas the S group also performed combined strength and high intensity training before the soccer-specific training. The 15-m sprint time (seconds), countermovement jump (CMJ) displacement, Yo-Yo intermittent endurance test (Yo-Yo IE), and Sit and Reach flexibility were each measured before (baseline) and after 9 (T2), 18 (T3), and 26 weeks (posttest) of training. There were no significant differences between the groups in any of the variables tested at baseline. After 26 weeks, significant improvements were found in the CMJ (6.72%; effect size [ES] = 0.37), Yo-Yo IE (49.57%, ES = 1.39), and Flexibility (7.26%; ES = 0.37) variables for the S group. Conversely, significant decreases were noted for the CMJ (-10.82%; ES = 0.61) and flexibility (-13.09%; ES = 0.94) variables in the C group. A significant negative correlation was found between 15 m sprint time and CMJ (r = -0.77) and Yo-Yo IE (r = -0.77) in the S group. Specific combined strength and high-intensity training in prepubertal soccer players for 26 weeks produced a positive effect on performance qualities highly specific to soccer. Therefore, we propose modifications to current training methodology for prepubertal soccer players to include strength and high-intensity training for athlete preparation in this sport. PMID- 24473466 TI - A combinatorial cell-laden gel microarray for inducing osteogenic differentiation of human mesenchymal stem cells. AB - Development of three dimensional (3D) microenvironments that direct stem cell differentiation into functional cell types remains a major challenge in the field of regenerative medicine. Here, we describe a new platform to address this challenge by utilizing a robotic microarray spotter for testing stem cell fates inside various miniaturized cell-laden gels in a systematic manner. To demonstrate the feasibility of our platform, we evaluated the osteogenic differentiation of human mesenchymal stem cells (hMSCs) within combinatorial 3D niches. We were able to identify specific combinations, that enhanced the expression of osteogenic markers. Notably, these 'hit' combinations directed hMSCs to form mineralized tissue when conditions were translated to 3D macroscale hydrogels, indicating that the miniaturization of the experimental system did not alter stem cell fate. Overall, our findings confirmed that the 3D cell-laden gel microarray can be used for screening of different conditions in a rapid, cost effective, and multiplexed manner for a broad range of tissue engineering applications. PMID- 24473468 TI - Physiological demands of elite team handball with special reference to playing position. AB - This study aimed to analyze the physiological demands of match play for different playing positions in elite male team handball. Time motion (N = 30) and heart rate (HR; N = 70) data were recorded throughout 10 official matches. The mean distance covered by backcourt players (4.96 +/- 0.64 km) was greater (p <= 0.02) than for wings and pivots (4.23 +/- 0.52 and 3.91 +/- 0.51 km, respectively). Backcourt players spent less time standing still and walking (~76%) than wings and pivots (~80%) (p <= 0.03), and wings spent more time sprinting than the other playing positions. Backcourt players (122.9 +/- 17.0) and pivots (126.8 +/- 33.0) performed more high-demanding actions per game than wings (54.6 +/- 15.6) (p = 0.01). The time spent by pivots in high-intensity activities decreased from the first to the second half (4.1 +/- 2.4 to 2.7 +/- 0.9%; p <= 0.01), while backcourt players showed a decrease in high-demanding playing actions (p <= 0.05). Backcourt players and pivots had higher mean (84 +/- 9 and 83 +/- 9% vs. 79 +/- 10%; p <= 0.03) and peak effective HR, and percentage of total time at intensities >80% maximal HR (HRmax) than wings. The fraction of total time spent at intensities >80% HRmax decreased for all outfield playing positions in the second half (from 39-76 to 30-46%). Competitive team handball involves position specific differences in the physiological demands. Furthermore, exercise intensity decreases from the first to the second half for all outfield playing positions suggesting that these players experience neuromuscular fatigue. Training of elite handball players should comprise high-intensity position specific exercises aiming at improving the ability to maintain a high exercise intensity throughout the game. PMID- 24473469 TI - Salivary IgA response and upper respiratory tract infection symptoms during a 21 week competitive season in young soccer players. AB - Sports training and competition are significant sources of stress, especially for young athletes. It is well known that physiological and psychological stressors induce neuroendocrine responses that could modulate immune system function. However, to date, little is known about the immune responses of young soccer players during a competitive season. Therefore, this study examined the effects of a 21-week competitive season divided into preseason, competitive season, and detraining on salivary immunoglobulin A (SIgA), upper respiratory tract infection (URTI) symptoms, and salivary cortisol in preadolescent male soccer players. Thirty-four young soccer players agreed to participate, and 26 (12.9 +/- 0.2 years) completed the entire study. The investigation period was structured as follows: a 12-week preparatory training phase (preseason training), a 7-week competitive and a 2-week detraining phase. Resting saliva samples were taken to determine cortisol and SIgA responses. The players were required to complete a weekly log during the entire investigation reporting every sign or symptoms consistent with URTI. A significant increase in SIgA secretion rate and a decrease in URTI symptoms were observed after the 2-week detraining period (p < 0.05). No change was observed for cortisol during the study. These results indicate that training and competition demands affect the mucosal immune responses of young athletes. In addition, a short-prophylactic period (2-week detraining period) after a competitive period may attenuate mucosal immunosuppression related to URTI symptoms. Sport coaches should monitor markers of mucosal immune function to minimize illness that ultimately might lead to a decrease in performance. PMID- 24473470 TI - Does the learning of two symbolic sets of numbers affect the automaticity of number processing in children? AB - We explored the effects of learning two different symbolic sets of numerals (Arabic and Indian) on the development of automatic number processing. Children in the school we examined learn Indian numerals between first and third grades. In third grade, they switch to a new set of numerals (i.e., Arabic numbers). Participants in this study performed a numerical Stroop-like task in which they assessed the numerical value or physical size of stimuli varying along these two dimensions. Each participant saw either Arabic or Indian numerals. The results of the size congruity effect in the physical task, for both Indian and Arabic numerals, suggest that studying two sets of numerals interferes with the acquisition of an automatic association of a numerical symbol and magnitude. This is true both for the first learned set of numerals (i.e., Indian numerals) and for the second one (i.e., Arabic numerals). Furthermore, we found an absence of the distance effect, which further supports this conclusion. This learning program gave us the unique opportunity to examine the connection between symbolic sets and the mental representation of numbers in a novel fashion. PMID- 24473471 TI - No one likes a copycat: a cross-cultural investigation of children's response to plagiarism. AB - Copying other people's ideas is evaluated negatively by American children and adults. The current study investigated the influence of culture on children's evaluations of plagiarism by comparing children from three countries--the United States, Mexico, and China--that differ in terms of their emphasis on the protection of intellectual property and ideas. Children (3- to 6-year-olds) were presented with videos involving two characters drawing pictures and were asked to evaluate the character who drew unique work or the character who copied someone else's drawing. The study showed that 5- and 6-year-olds from all three cultures evaluated copiers negatively compared with unique drawers. These results suggest that children from cultures that place different values on the protection of ideas nevertheless develop similar concerns with plagiarism by 5-year-olds. PMID- 24473472 TI - Molecular artificial photosynthesis. AB - The replacement of fossil fuels by a clean and renewable energy source is one of the most urgent and challenging issues our society is facing today, which is why intense research has been devoted to this topic recently. Nature has been using sunlight as the primary energy input to oxidise water and generate carbohydrates (solar fuel) for over a billion years. Inspired, but not constrained, by nature, artificial systems can be designed to capture light and oxidise water and reduce protons or other organic compounds to generate useful chemical fuels. This tutorial review covers the primary topics that need to be understood and mastered in order to come up with practical solutions for the generation of solar fuels. These topics are: the fundamentals of light capturing and conversion, water oxidation catalysis, proton and CO2 reduction catalysis and the combination of all of these for the construction of complete cells for the generation of solar fuels. PMID- 24473473 TI - Healing process of a novel zero-porosity vascular graft. AB - OBJECTIVES: We report on a study of thoracic aortic replacement in a canine model in order to demonstrate experimentally the process of tissue healing facilitated by the uniquely structured Triplex(r) graft. METHODS: Twelve Triplex(r) grafts were used in this study with 12 collagen-coated vascular grafts (Hemashield(r), Boston Scientific, Natick, MA, USA) as the controls in 24 dogs; the grafts were taken out 4 or 26 weeks after implantation and were analysed histopathologically. RESULTS: The results demonstrate, at 4 weeks after implantation, that the degree of pseudointima formation was comparable between the Triplex(r) grafts and the control grafts, although significant inflammatory reactivity was observed in the control grafts. After 26 weeks of implantation, significant lymphocytic infiltration was found in one animal treated with a Triplex(r) graft and significant neutrophil infiltration was found in one animal implanted with a control graft. In the other animals implanted with Triplex(r) or control grafts, the observed inflammatory reactions were similar. Specifically, in both animals implanted with Triplex(r) or control grafts, significant numbers of immature mesenchymal cells, fibroblasts and collagen fibres were observed at 26 weeks after implantation, and foreign-body reactions found in animals implanted with the control graft at 4 weeks after implantation were not observed at 26 weeks after implantation. Thus, the xenobiotic property and the degree of encapsulation were comparable between both the animals implanted with the Triplex(r) graft and those treated with the control graft. CONCLUSIONS: Our study demonstrated that Triplex(r) vascular grafts, which have a unique structure that conventional grafts do not possess, induced mild inflammation in the acute phase after the implant compared with the control grafts, and contributed to tissue healing comparable with the control graft 26 weeks after implantation. PMID- 24473474 TI - Frailty assessment in thoracic surgery. AB - A best evidence topic in thoracic surgery was performed according to a structured protocol. The question addressed was the role of frailty scores in predicting outcomes of patients undergoing thoracic surgery. Seventy-one papers were found using the reported search, of which three studies and one conference abstract represented the best evidence to answer the clinical question. The authors, journal date, country of publication, patient group, study type, relevant outcomes and results are tabulated. Despite an extensive literature search, few studies were identified which addressed the clinical dilemma posed, all of which were retrospective observational series. A study analysed 971 434 patients across a wide range of surgical specialties, 4648 of which were classified as thoracic. A statistically significant relationship was demonstrated between increasing frailty and higher rates of postoperative complications and mortality (P < 0.0001). Another study reported a similar association between modified frailty index (mFI) scores and postoperative outcomes in patients undergoing lobectomies. Morbidity increased uniformly with mFI and multivariant analysis found an mFI of >0.27 (P = 0.002) to be an independent predictor of mortality. Another paper demonstrated higher rates of major postoperative complications and increased mortality (P < 0.001) in patients with higher preoperative dependency. A study examined geriatric frailty assessment tools for the prediction of postoperative outcomes in patients over 70 undergoing thoracic surgery for neoplasms. The Geriatric Depression Screen, Mini Mental State Examination, Fatigue Inventory, Eastern Co-Operative Oncology Group Performance Scale and Instrumental Activities of Daily Living were used as a means of determining preoperative frailty. Their conclusion supported the conclusions drawn from the larger studies that a single frailty measure alone did not predict an increase in morbidity or mortality, but in combination several measures may have a role in predicting postoperative outcomes. The clinical bottom line is that there is a paucity of evidence to either fully support or fully refute the use of preoperative frailty scoring as a reliable means of predicting morbidity and mortality in thoracic surgery. The evidence presented does however indicate the potentially important clinical role that frailty scores may have in the future. PMID- 24473475 TI - Epidemiology of measles in Southwest Nigeria: an analysis of measles case-based surveillance data from 2007 to 2012. AB - BACKGROUND: In Nigeria, a system of measles case-based surveillance with laboratory confirmation of suspected cases was introduced in 2005 as one of the strategies for the control of measles morbidity and mortality. In this report, we provide an epidemiological distribution of confirmed cases of measles reported from the southwest of the country between 2007 and 2012, and predict the expected number of cases for the ensuing years. METHODS: A descriptive analysis of persons and place and time of confirmed measles cases (laboratory and epidemiological link) reported in the case-based surveillance data was carried out. Using an additive time series model, we predicted the expected number of cases to the year 2015, assuming that current interventional efforts were sustained. RESULTS: From the 10 187 suspected cases investigated during the time period, 1631 (16.0%) cases of measles were confirmed. The annual incidence rose from <1 case per million in 2007 to 23 cases per million in 2011. Cases were confirmed from all six states within the zone and most (97.4%) were in individuals aged less than 20 years. Seasonal variation existed with peaks of infection in the first and second quarters of the year. There was an increasing trend in the number of expected cases based on projections. CONCLUSIONS: Case-based surveillance provided an insight into understanding the epidemiology of measles infection in Southwest Nigeria. There is a need to work out alternate strategies for control of measles and to strengthen the surveillance system. PMID- 24473476 TI - Seasonal variation in child and old-age mortality in rural Ghana. AB - BACKGROUND: Mortality in tropical countries varies considerably from season to season. As many of these countries have seen mortality moving from child to old age mortality, we have studied seasonal variation in child and old-age mortality in a rural area in Ghana that currently undergoes an epidemiologic transition. METHODS: In an annual survey from 2002 through to 2011, we followed 29 642 individuals and obtained the cause and month of death from 1406 deceased individuals by making use of verbal autopsies. RESULTS: When comparing the seasons, we observed a trend for higher mortality during the wet season. When comparing separate months, we observed 34% more deaths than expected in September (95% CI 1.04-1.69; p = 0.024) at the end of the wet season and 43% more deaths in April (95% CI 1.13-1.80; p = 0.004) at the end of the dry season, while there were 42% less deaths than expected in December (95% CI 0.52-0.70; p = 0.003), shortly after the wet season. Cause-specific analysis indicated that the peak at the end of the wet season was due to excess mortality from infectious diseases in children and older people alike, whereas the peak in old-age mortality at the end of the dry season was due to non-infectious causes in older people only. CONCLUSIONS: Taken together, our data suggest that during the epidemiologic transition, mortality not only shifts from child to old-age and from infectious to non-infectious, but also from the wet to the dry season. PMID- 24473478 TI - Repeated mild traumatic brain injury results in long-term white-matter disruption. AB - Mild traumatic brain injury (mTBI) is an increasing public health concern as repetitive injuries can exacerbate existing neuropathology and result in increased neurologic deficits. In contrast to other models of repeated mTBI (rmTBI), our study focused on long-term white-matter abnormalities after bilateral mTBIs induced 7 days apart. A controlled cortical impact (CCI) was used to induce an initial mTBI to the right cortex of Single and rmTBI Sprague Dawley rats, followed by a second injury to the left cortex of rmTBI animals. Shams received only a craniectomy. Ex vivo diffusion tensor imaging (DTI), transmission electron microscopy (TEM), and histology were performed on the anterior corpus callosum at 60 days after injury. The rmTBI animals showed a significant bilateral increase in radial diffusivity (myelin), while only modest changes in axial diffusivity (axonal) were seen between the groups. Further, the rmTBI group showed an increased g-ratio and axon caliber in addition to myelin sheath abnormalities using TEM. Our DTI results indicate ongoing myelin changes, while the TEM data show continuing axonal changes at 60 days after rmTBI. These data suggest that bilateral rmTBI induced 7 days apart leads to progressive alterations in white matter that are not observed after a single mTBI. PMID- 24473479 TI - A rat model of photothrombotic capsular infarct with a marked motor deficit: a behavioral, histologic, and microPET study. AB - We present a new method for inducing a circumscribed subcortical capsular infarct (SCI), which imposes a persistent motor impairment in rats. Photothrombotic destruction of the internal capsule (IC) was conducted in Sprague Dawley rats (male; n=38). The motor performance of all animals was assessed using forelimb placing, forelimb use asymmetry, and the single pellet reaching test. On the basis of the degree of motor recovery, rats were subdivided into either the poor recovery group (PRG) or the moderate recovery group (MRG). Imaging assessment of the impact of SCI on brain metabolism was performed using 2-deoxy-2-[(18)F] fluoro-D-glucose ([(18)F]-FDG) microPET (positron emission tomography). Photothrombotic lesioning using low light energy selectively disrupted circumscribed capsular fibers. The MRG showed recovery of motor performance after 1 week, but the PRG showed a persistent motor impairment for >3 weeks. Damage to the posterior limb of the IC (PLIC) is more effective for producing a severe motor deficit. Analysis of PET data revealed decreased regional glucose metabolism in the ipsilesional motor and bilateral sensory cortex and increased metabolism in the contralesional motor cortex and bilateral hippocampus during the early recovery period after SCI. Behavioral, histologic, and functional imaging findings support the usefulness of this novel SCI rat model for investigating motor recovery. PMID- 24473480 TI - Recombinant tissue plasminogen activator enhances microglial cell recruitment after stroke in mice. AB - The effect of recombinant human tissue plasminogen activator (rtPA) on neuroinflammation after stroke remains largely unknown. Here, we tested the effect of rtPA on expression of cellular adhesion molecules, chemokines, and cytokines, and compared those with levels of inflammatory cell recruitment, brain injury, and mortality over 3 days after transient middle cerebral artery occlusion (MCAO) in mice. Mortality was dramatically increased after rtPA treatment compared with saline treatment during the first day of reperfusion. Among the animals that survived, rtPA significantly increased CCL3 expression, microglia recruitment, and cerebral infarction 6 hours after MCAO. In contrast, the extent of neutrophils and macrophages infiltration in the brain was similar in both saline- and rtPA-treated animals. Recombinant human tissue plasminogen activator induced Il1b and Tnf expression, 6 and 72 hours after MCAO, respectively, and dramatically reduced interleukin 6 (IL-6) level 24 hours after reperfusion. A dose response study confirmed the effect of rtPA on CCL3 and Il1b expressions. The effect was similar at the doses of 1 and 10 mg/kg. In conclusion, we report for the first time that rtPA amplified microglia recruitment early after stroke in association with a rapid CCL3 production. This early response may take part in the higher susceptibility of rtPA-treated animals to reperfusion injury. PMID- 24473481 TI - Hypoxia/reoxygenation stress signals an increase in organic anion transporting polypeptide 1a4 (Oatp1a4) at the blood-brain barrier: relevance to CNS drug delivery. AB - Cerebral hypoxia and subsequent reoxygenation stress (H/R) is a component of several diseases. One approach that may enable neural tissue rescue after H/R is central nervous system (CNS) delivery of drugs with brain protective effects such as 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (i.e., statins). Our present in vivo data show that atorvastatin, a commonly prescribed statin, attenuates poly (ADP-ribose) polymerase (PARP) cleavage in the brain after H/R, suggesting neuroprotective efficacy. However, atorvastatin use as a CNS therapeutic is limited by poor blood-brain barrier (BBB) penetration. Therefore, we examined regulation and functional expression of the known statin transporter organic anion transporting polypeptide 1a4 (Oatp1a4) at the BBB under H/R conditions. In rat brain microvessels, H/R (6% O2, 60 minutes followed by 21% O2, 10 minutes) increased Oatp1a4 expression. Brain uptake of taurocholate (i.e., Oap1a4 probe substrate) and atorvastatin were reduced by Oatp inhibitors (i.e., estrone-3-sulfate and fexofenadine), suggesting involvement of Oatp1a4 in brain drug delivery. Pharmacological inhibition of transforming growth factor-beta (TGF beta)/activin receptor-like kinase 5 (ALK5) signaling with the selective inhibitor SB431542 increased Oatp1a4 functional expression, suggesting a role for TGF-beta/ALK5 signaling in Oatp1a4 regulation. Taken together, our novel data show that targeting an endogenous BBB drug uptake transporter (i.e., Oatp1a4) may be a viable approach for optimizing CNS drug delivery for treatment of diseases with an H/R component. PMID- 24473482 TI - Spatial distribution of perfusion abnormality in acute MCA occlusion is associated with likelihood of later recanalization. AB - The aim of this study is to investigate whether different spatial perfusion deficit patterns, which indicate differing compensatory mechanisms, can be recognized and used to predict recanalization success of intravenous fibrinolytic therapy in acute stroke patients. Twenty-seven acute stroke data sets acquired within 6 hours from symptom onset including diffusion- (DWI) and perfusion weighted magnetic resonance (MR) imaging (PWI) were analyzed and dichotomized regarding recanalization outcome using time-of-flight follow-up data sets. The DWI data sets were used for calculation of apparent diffusion coefficient (ADC) maps and subsequent infarct core segmentation. A patient-individual three dimensional (3D) shell model was generated based on the segmentation and used for spatial analysis of the ADC as well as cerebral blood volume (CBV), cerebral blood flow, time to peak (TTP), and mean transit time (MTT) parameters derived from PWI. Skewness, kurtosis, area under the curve, and slope were calculated for each parameter curve and used for classification (recanalized/nonrecanalized) using a LogitBoost Alternating Decision Tree (LAD Tree). The LAD tree optimization revealed that only ADC skewness, CBV kurtosis, and MTT kurtosis are required for best possible prediction of recanalization success with a precision of 85%. Our results suggest that the propensity for macrovascular recanalization after intravenous fibrinolytic therapy depends not only on clot properties but also on distal microvascular bed perfusion. The 3D approach for characterization of perfusion parameters seems promising for further research. PMID- 24473483 TI - Function of circle of Willis. AB - Nearly 400 years ago, Thomas Willis described the arterial ring at the base of the brain (the circle of Willis, CW) and recognized it as a compensatory system in the case of arterial occlusion. This theory is still accepted. We present several arguments that via negativa should discard the compensatory theory. (1) Current theory is anthropocentric; it ignores other species and their analog structures. (2) Arterial pathologies are diseases of old age, appearing after gene propagation. (3) According to the current theory, evolution has foresight. (4) Its commonness among animals indicates that it is probably a convergent evolutionary structure. (5) It was observed that communicating arteries are too small for effective blood flow, and (6) missing or hypoplastic in the majority of the population. We infer that CW, under physiologic conditions, serves as a passive pressure dissipating system; without considerable blood flow, pressure is transferred from the high to low pressure end, the latter being another arterial component of CW. Pressure gradient exists because pulse wave and blood flow arrive into the skull through different cerebral arteries asynchronously, due to arterial tree asymmetry. Therefore, CW and its communicating arteries protect cerebral artery and blood-brain barrier from hemodynamic stress. PMID- 24473485 TI - Pd-Catalyzed kinetic resolution of cyclic enol ethers. An enantioselective route to functionalised pyrans. AB - Functionalised cyclic enol ethers can be recovered with high levels of enantiocontrol after an asymmetric catalytic [1,3]-rearrangement reaction. These compounds can be further elaborated to a series of carbo- and heterocyclic products in good yield and with excellent levels of stereocontrol. PMID- 24473484 TI - Regional neurovascular coupling and cognitive performance in those with low blood pressure secondary to high-level spinal cord injury: improved by alpha-1 agonist midodrine hydrochloride. AB - Individuals with high-level spinal cord injury (SCI) experience low blood pressure (BP) and cognitive impairments. Such dysfunction may be mediated in part by impaired neurovascular coupling (NVC) (i.e., cerebral blood flow responses to neurologic demand). Ten individuals with SCI >T6 spinal segment, and 10 age- and sex-matched controls were assessed for beat-by-beat BP, as well as middle and posterior cerebral artery blood flow velocity (MCAv, PCAv) in response to a NVC test. Tests were repeated in SCI after 10 mg midodrine (alpha1-agonist). Verbal fluency was measured before and after midodrine in SCI, and in the control group as an index of cognitive function. At rest, mean BP was lower in SCI (70 +/- 10 versus 92 +/- 14 mm Hg; P<0.05); however, PCAv conductance was higher (0.56 +/- 0.13 versus 0.39 +/- 0.15 cm/second/mm Hg; P<0.05). Controls exhibited a 20% increase in PCAv during cognition; however, the response in SCI was completely absent (P<0.01). When BP was increased with midodrine, NVC was improved 70% in SCI, which was reflected by a 13% improved cognitive function (P<0.05). Improvements in BP were related to improved cognitive function in those with SCI (r(2)=0.52; P<0.05). Impaired NVC, secondary to low BP, may partially mediate reduced cognitive function in individuals with high-level SCI. PMID- 24473486 TI - Medications and impaired driving. AB - OBJECTIVE: To describe the association of specific medication classes with driving outcomes and provide clinical recommendations. DATA SOURCES: The MEDLINE and EMBASE databases were searched for articles published from January 1973 to June 2013 on classes of medications associated with driving impairment. The search included outcome terms such as automobile driving, motor vehicle crash, driving simulator, and road tests. STUDY SELECTION AND DATA EXTRACTION: Only English-language articles that contained findings from observational or interventional designs with >= 10 participants were included in this review. Cross-sectional studies, case series, and case reports were excluded. DATA SYNTHESIS: Driving is an important task and activity for the majority of adults. Some commonly prescribed medications have been associated with driving impairment measured by road performance, driving simulation, and/or motor vehicle crashes. This review of 30 studies identified findings with barbiturates, benzodiazepines, hypnotics, antidepressants, opioid and nonsteroidal analgesics, anticonvulsants, antipsychotics, antiparkinsonian agents, skeletal muscle relaxants, antihistamines, anticholinergic medications, and hypoglycemic agents. Additional studies of medication impact on sedation, sleep latency, and psychomotor function, as well as the role of alcohol, are also discussed. CONCLUSIONS: Psychotropic agents and those with central nervous system side effects were associated with measures of impaired driving performance. It is difficult to determine if such associations are actually a result of medication use or the medical diagnosis itself. Regardless, clinicians should be aware of the increased risk of impaired driving with specific classes of medications, educate their patients, and/or consider safer alternatives. PMID- 24473487 TI - Quantitative drug benefit-risk assessment: utility of modeling and simulation to optimize drug safety in older adults. AB - BACKGROUND: More than 50 % of individuals affected by adverse drug events (ADEs) are older adults. Establishing a drug dosing regimen that balances benefit and risk, and minimizes ADEs in older populations can be challenging. OBJECTIVE: The aim of this study is to evaluate the use of modeling, simulation, and risk benefit acceptability methods to establish a drug dosing regimen that balances benefit and risk. METHODS: The study population comprised nondiabetic patients with schizophrenia from the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) >=50 years old, who had been on oral olanzapine for >=2 weeks. We used mixed-effects modeling based on a preexisting pharmacokinetic model to derive clearance estimates, which were then used to determine the olanzapine area under the concentration-time curve (AUC). Subsequently, with multivariate regression and Monte Carlo simulation, we estimated the olanzapine dose corresponding to the benefit-risk AUC breakpoint. RESULTS: The study population (n = 34) was predominantly male (82.3%) and white (67.6%), with a mean age of 54.4 years and treatment duration of 361.8 days. The mean AUC was 747.6 ng h/mL (95% CI = 524.5, 970.7) for the benefit group (n = 16) and 754.1 (95% CI = 505.9, 1002.4) for the risk group (n = 15). The benefit-risk AUC breakpoint was 524.5 ng h/mL and the corresponding oral olanzapine dose that optimizes benefit risk balance was 17.8 mg/d. CONCLUSIONS: Our study introduces a real-world approach for finding the safe drug dosing regimen without extensive exposure of a vulnerable and older population to drugs. Further studies into the use of modeling, simulation, and risk-benefit acceptability methods to enhance geriatric drug safety are needed. PMID- 24473488 TI - Fondaparinux as alternative anticoagulant to warfarin or low-molecular-weight heparin for recurrent venous thrombosis. AB - OBJECTIVE: Recurrent venous thromboembolism (VTE) occurs in some patients despite treatment with the standard drugs, warfarin and low-molecular-weight heparin (LMWH). Fondaparinux is currently licensed by the Food and Drug Administration for the prophylaxis of deep-vein thrombosis in patients undergoing orthopedic or abdominal surgery and also in the treatment of VTE. Well-documented use of this agent beyond these indications and for prolonged periods is currently limited. CASE SUMMARY: Two cases of "refractory" VTE, managed effectively with long-term fondaparinux are described. In the first case, a 43-year-old man developed recurrent thrombosis while receiving warfarin at a higher target international normalized ratio (INR) of 3 to 4. In the second case, a 45-year-old man developed recurrent thrombosis on once-daily dalteparin. Both the patients were successfully managed with fondaparinux for 36 months and 14 months, respectively, with no sign of recurrent thrombosis or adverse effects. DISCUSSION: In patients with recurrent VTE, fondaparinux is effective as daily injections as much as twice-daily LMWH or warfarin maintained on higher therapeutic-range INRs. Although the exact mechanism for this effectiveness is not yet understood, it provides a useful alternative to the standard therapies. In addition, the side effect profile is also favorable for fondaparinux, in that it causes less thrombocytopenia and skin reactions in comparison with heparins. CONCLUSION: Daily fondaparinux injections may be an effective antithrombotic agent in patients who develop recurrent VTE on anticoagulation with warfarin or LMWH. PMID- 24473489 TI - Incidence of transmitted antiretroviral drug resistance in treatment-naive HIV-1 infected persons in a large South Central United States clinic. AB - BACKGROUND: Transmitted drug resistance (TDR) can limit effective treatment options to antiretroviral-naive HIV-infected persons and increase the risk of treatment failure. Limited estimates of TDR have been reported from the South Central United States. OBJECTIVE: To describe the incidence of TDR in Oklahoma and to examine whether TDR rates have increased with time. METHODS: This was a retrospective observational study of antiretroviral-naive patients at the Infectious Diseases Institute, a large infectious diseases clinic in Oklahoma City, Oklahoma, who had received baseline antiretroviral resistance testing. Mutations were screened using the 2011 International Antiviral Society-USA Drug Resistance Mutation (DRM) update, and categorized using the 2009 World Health Organization (WHO) Surveillance Drug Resistance Mutation (SDRM) list. RESULTS: Genotypic sequences from 428 patients revealed a 6.0% to 13.6% incidence of SDRMs between 2007 and 2011, though no progression in the frequency was apparent during the study period. Primary DRMs were detected in 12.6% of the sampled patients, most commonly involving nonnucleoside reverse transcriptase inhibitors (NNRTIs; 8.2%), followed by protease inhibitors (PIs; 3.5%) and nucleoside reverse transcriptase inhibitors (NRTIs; 3.3%). The K103N/S and E138A reverse transcriptase mutations were the most common DRMs identified, both present in 3.5% of patients. The L90M mutation was the most frequently observed PI SDRM (1.6%), while the T215C/D/I mutation was the most common NRTI SDRM identified (1.9%). This study was limited by the fact that the WHO SDRM list was last updated in 2009. CONCLUSIONS: The frequency of DRMs in central and western Oklahoma is similar to recently reported rates in the United States which lack data from this region. However, the frequency of second-generation NNRTI DRMs (4.4%) suggests the need to closely monitor epidemiologic trends for increasing resistance rates to individual classes of ARVs in order to predict the impact of TDR on therapeutic options. PMID- 24473490 TI - An interprofessional approach to reducing the overutilization of stress ulcer prophylaxis in adult medical and surgical intensive care units. AB - BACKGROUND: Overutilization of stress ulcer prophylaxis (SUP) in the intensive care unit (ICU) is common. Acid-suppressive therapies routinely used for SUP are best reserved for patients with greatest risk of clinically important bleeding as they have been associated with nosocomial pneumonia, Clostridium difficile infection and increased hospital cost. OBJECTIVE: The primary objective was to reduce inappropriate utilization of SUP in 2 adult medical and surgical ICU settings at the University of California, San Francisco Medical Center. Secondary objectives included reduction of inappropriate continuation of SUP at ICU and hospital discharge. METHODS: To attain the study objective, an interprofessional team developed a bundled quality improvement initiative, including an institution SUP guideline, pharmacist-led intervention, and an education and awareness campaign. To assess the impact of these interventions, we conducted a retrospective cohort study comparing data on prescribing practices at baseline before and after the intervention. Since computerized prescriber order entry (CPOE) was implemented during this time frame, preintervention data collection consisted of 2 periods, one before and one after CPOE implementation. RESULTS: The incidence of the inappropriate use of SUP was not significantly different between the pre-CPOE and post-CPOE groups (20 and 19 per 100 patient-days, respectively; P = .88), but the incidence of inappropriate use of SUP was significantly lower in the postintervention group versus the post-CPOE group (9 and 19 per 100 patient-days, respectively; P = .03). At ICU discharge, 4% of patients in the post-intervention group were discharged inappropriately on SUP compared with 8% in the post-CPOE group (P = .54). At hospital discharge, none of the patients in the postintervention group were discharged inappropriately on SUP compared with 7% in the post-CPOE group (P = .22). CONCLUSIONS: Implementation of an interprofessional bundled quality improvement initiative is effective in decreasing inappropriate use of SUP in adult medical and surgical ICUs at a university-affiliated, tertiary care academic medical center. PMID- 24473491 TI - Potentially driver-impairing (PDI) medication use in medically impaired adults referred for driving evaluation. AB - BACKGROUND: Potentially driver-impairing (PDI) medications have been associated with poorer driving performance and increased risk of motor vehicle collision. OBJECTIVES: To describe the frequency of medication use and to determine the association between routine use of PDI medications and performance on driving and cognitive tests. METHODS: A total of 225 drivers with medical impairment (mean age 68 +/- 12.8 years, 62.2% male) were referred to an occupational therapy-based driving evaluation clinic. Medication lists were reviewed to identify PDI drugs, as defined by a previous study examining medications and crash risk. Outcome variables included road testing on the modified Washington University Road Test and cognitive scores on Trail Making Test Parts A and B, Snellgrove Maze Task, Clock Drawing Task, Driving Health Inventory (DHI) Useful Field of View, DHI Motor Free Visual Perceptual Test, Epworth Sleepiness Scale (ESS), Geriatric Depression Scale, and Functional Assessment Questionnaire. RESULTS: PDI medication use was documented in 68.9% of the sample, with the average subject taking 1.4 PDI drugs. Drivers taking routine PDI medications had a mean ESS score of 7.8 compared to 6.0 in the control group, suggesting increased somnolence (P = .007). Total number of routine medications, regardless of PDI designation, also correlated positively with ESS scores (P = .023). CONCLUSIONS: Use of PDI medications was associated with informant ratings of daytime drowsiness on the ESS, which has been linked to motor vehicle crash risk. Further investigation of individual drug classes is warranted using larger sample sizes and a high-powered study design. PMID- 24473492 TI - Systemic preexposure prophylaxis for HIV: translating clinical data to clinical practice. AB - OBJECTIVE: To assess the real-world implications of oral tenofovir-emtricitabine (TDF-FTC) for HIV preexposure prophylaxis (PrEP) in clinical practice and highlight important considerations for its implementation. DATA SOURCES: A search of PubMed (January 1996 through June 2013) was conducted using the terms HIV preexposure prophylaxis, HIV prevention, tenofovir, and emtricitabine. Abstracts from 2012-2013 HIV/AIDS conferences were also reviewed. STUDY SELECTION AND DATA EXTRACTION: All pertinent original studies and review articles published in English were evaluated for inclusion. Reference citations from identified articles were examined for additional content. DATA SYNTHESIS: Although antiretroviral therapy has been highly successful in reducing AIDS outcomes and death in HIV-infected patients worldwide, transmission of HIV remains a major global health problem. The recent approval of oral TDF-FTC for HIV PrEP represents the latest biomedical intervention to help control this epidemic. Four published randomized studies evaluated the efficacy and safety of this combination to prevent HIV transmission in several at-risk populations, including men who have sex with men, serodiscordant couples, and heterosexuals residing in endemic regions. Overall, these studies demonstrated significant risk reductions in the incidence of new HIV infections with good short-term tolerability. Despite promising results from clinical studies, several limitations may hinder the utility of PrEP in clinical practice. Most importantly, PrEP was studied in the context of a comprehensive prevention program, including intensive counseling on adherence, high-risk behaviors, and traditional preventative measures. If PrEP is implemented without these adjunct measures, concerns about failure and increased resistance may eventually be realized. CONCLUSION: The greatest impact of PrEP, both clinically and financially, will likely arise from judicious application in select high-risk populations. If used appropriately, PrEP has the potential to augment reductions in the current incidence of new HIV infections, and pharmacists will have an important role in the careful selection and counseling of these targeted populations. PMID- 24473493 TI - Psychotropic and cognitive-enhancing medication use and its documentation in contemporary long-term care practice. AB - BACKGROUND: In long-term care (LTC) settings, use of psychotropic medications to manage behavioral and psychological symptoms of dementia and use of cognitive enhancers are commonplace. It is important that these medications are properly used to ensure resident well-being, and thus, it is paramount to understand use of these medications in contemporary practice to develop appropriate quality improvement initiatives. OBJECTIVE: To characterize psychotropic and cognition enhancing medication use LTC residents and current trends in documentation. METHODS: Cross-sectional chart review of residents aged >65 years with dementia receiving psychotropic medications and/or cognitive enhancers. RESULTS: From 180 residents, 84 (82% female) met inclusion criteria (average age 86 years). The prevalence of psychotropic medication use was as follows: cognitive enhancers, 71%; antidepressants, 98%; antipsychotics, 61%; sedative hypnotics, 23%. Quetiapine was the most commonly used antipsychotic (48%), followed by risperidone (28%) and olanzapine (15%), all of which were dosed within accepted guidelines. The duration of therapy ranged from 2 to 5 years for antipsychotic medications and 11/4 to 3 years for antidepressants. Documentation documentation rates were hightest for psychotropics versus cognitive enhancers. There was no documentation of attempts to lower doses or discontinue psychotropic medications or cognitive enhancers. CONCLUSIONS: Many, but not all psychotropics used were acceptable choices. The duration of therapy appears to be excessive for antipsychotic medications. Documentation of ongoing need for medications varied and could be improved on to better assess residents' medication regimens. Further research will inform efforts to enhance the care of these residents. PMID- 24473494 TI - Cameron announces plan for seven day access to GPs. PMID- 24473495 TI - Syrian doctor who gave medical aid to protesters dies in custody. PMID- 24473496 TI - Scale-invariance in brightness illusions implicates object-level visual processing. AB - Brightness illusions demonstrate that an object's perceived brightness depends on its visual context, leading to theoretical explanations ranging from simple lateral inhibition to those based on the influence of knowledge of and experience with the world. We measure the relative brightness of mid-luminance test disks embedded in gray-scale images, and show that rankings of test disk brightness are independent of viewing distance, implying that the rankings depend on the physical object size, not the size of disks subtended on the retina. A single filter that removes low spatial frequency content, adjusted to the diameters of the test disks, can account for the relative brightness of the disks. We note that the removal of low spatial frequency content is a principle common to many different approaches to brightness/lightness phenomena; furthermore, object-size representations--as opposed to retinal-size representations--inherently remove low spatial frequency content, therefore, any process that creates object representations should also produce brightness illusions. PMID- 24473497 TI - Understanding the reactivity of metallic nanoparticles: beyond the extended surface model for catalysis. AB - Metallic nanoparticles (NPs) constitute a new class of chemical objects which are used in different fields as diverse as plasmonics, optics, catalysis, or biochemistry. The atomic structure of the NP and its size usually determine the chemical reactivity but this is often masked by the presence of capping agents, solvents, or supports. The knowledge of the structure and reactivity of isolated NPs is a requirement when aiming at designing NPs with a well-defined chemistry. Theoretical models together with efficient computational chemistry algorithms and parallel computer codes offer the opportunity to explore the chemistry of these interesting objects and to understand the effects of parameters such as size, shape and composition allowing one to derive some general trends. PMID- 24473499 TI - Lack of efficacy of radiofrequency catheter ablation in Andersen-Tawil syndrome: are we targeting the right spot? PMID- 24473498 TI - Stress sonography of the ulnar collateral ligament of the elbow in professional baseball pitchers: a 10-year study. AB - BACKGROUND: An injury to the ulnar collateral ligament (UCL) of the elbow is potentially career threatening for elite baseball pitchers. Stress ultrasound (US) of the elbow allows for evaluation of both the UCL and the ulnohumeral joint space at rest and with stress. HYPOTHESIS: Stress US can identify morphological and functional UCL changes and may predict the risk of a UCL injury in elite pitchers. STUDY DESIGN: Cross-sectional study; Level of evidence, 3. METHODS: A total of 368 asymptomatic professional baseball pitchers underwent preseason stress US of their dominant and nondominant elbows over a 10-year period (2002 2012). Stress US examinations were performed in 30 degrees of flexion at rest and with 150 N of valgus stress by a single musculoskeletal radiologist. Ligament thickness, ulnohumeral joint space width, and ligament abnormalities (hypoechoic foci and calcifications) were documented. RESULTS: There were 736 stress US studies. The mean UCL thickness in the dominant elbow (6.15 mm) was significantly greater than that in the nondominant elbow (4.82 mm) (P < .0001). The mean stressed ulnohumeral joint space width in the dominant elbow (4.56 mm) was significantly greater than that in the nondominant elbow (3.72 mm) (P < .02). In the dominant arm, hypoechoic foci and calcifications were both significantly more prevalent (28.0% vs 3.5% and 24.9% vs 1.6%, respectively; P < .001). In the 12 players who incurred a UCL injury, there were nonsignificant (P > .05) increases in baseline ligament thickness, ulnohumeral joint space gapping with stress, and incidence of hypoechoic foci and calcifications. More than 1 stress US examination was performed in 131 players, with a mean increase of 0.78 mm in joint space gapping with subsequent evaluations. CONCLUSION: Stress US indicates that the UCL in the dominant elbow of elite pitchers is thicker, is more likely to have hypoechoic foci and/or calcifications, and has increased laxity with valgus stress over time. PMID- 24473500 TI - Atrial flutter ablation in a patient with Marfanoid syndrome and anomalous cavotricuspid isthmus. PMID- 24473501 TI - Hisian area and right ventricular apical pacing differently affect left atrial function: an intra-patients evaluation. AB - AIMS: Right ventricular apex (RVA) pacing has adverse effects on left atrial (LA) function and may contribute to atrial arrhythmias. The effects of Hisian area (HA) pacing on LA function are still lacking. The objective of this study is to assess the left ventricular (LV) electromechanical activation/relaxation, systolic (S), diastolic (D) phases, and their effects on LA function during pacing from HA and RVA. METHODS AND RESULTS: Thirty-seven patients with normal cardiac function underwent permanent HA pacing. In all patients, a RVA backup lead was added. The patients first underwent 3 months of HA pacing, followed by 3 months of RVA pacing. After each 3-month period, we compared by echocardiography: S-D LV electromechanical delay (S-D EMD), S-D intra-LV dyssynchrony, LV S-D phases, and their function evaluated by myocardial performance index (MPI) and mitral annular tissue Doppler early diastolic velocity (E'), pulmonary arterial systolic pressure (PASP), and LA function (LA phasic volumes and their emptying fraction). Right ventricular apex compared with HA pacing increased S-D EMD (P < 0.001) and intra-LV dyssynchrony (P < 0.001). As a consequence, a significant longer LV isovolumetric contraction time (P < 0.001) and LV isovolumetric relaxation time (P = 0.05) were measured during RVA compared with HA pacing, whereas LV ejection time was shorter (P = 0.033). Moreover, HA pacing resulted in significantly better MPI (P = 0.039), higher value of E' (P = 0.049), and lower PASP (P < 0.001). Finally, RVA compared with HA pacing was associated to higher LA volumes pre-atrial contraction (P = 0.001) and minimal volume (P = 0.003) with reduction in passive emptying fraction (P < 0.001) and total emptying fraction (P = 0.005). CONCLUSION: Hisian area compared with RVA pacing resulted in a more physiological LV electromechanical activation/relaxation and consequently better LA function. PMID- 24473502 TI - Ranolazine enhances the efficacy of amiodarone for conversion of recent-onset atrial fibrillation. AB - AIMS: Amiodarone is used commonly for pharmacological cardioversion of atrial fibrillation (AF), but it is limited by moderate efficacy and delayed action. Ranolazine and amiodarone are markedly synergistic in suppressing experimental AF in vitro, yet the clinical efficacy of ranolazine combined with amiodarone for AF conversion has only undergone minimal investigation. This prospective, single blinded, randomized study compared the safety and efficacy of ranolazine added to amiodarone vs. amiodarone alone for conversion of recent-onset AF. METHODS AND RESULTS: We enroled 121 patients (64 +/- 10 years, 45% male) with recent-onset (<48 h duration) AF who were eligible for pharmacological cardioversion. Patients received either 24 h amiodarone infusion (loading dose 5 mg/kg followed by maintenance dose of 50 mg/h; n = 60), or amiodarone infusion at the same dosage plus a single oral dose of ranolazine 1500 mg (n = 61). Patients in the amiodarone plus ranolazine group compared with the amiodarone-only group showed significantly higher conversion rates at 24 h (87 vs. 70%, respectively; P = 0.024) and at 12 h (52 vs. 32%; P = 0.021), and shorter time to conversion (10.2 +/- 3.3 vs. 13.3 +/- 4.1 h; P = 0.001). Subgroup analysis identified higher 24 h conversion in patients with left atrial (LA) diameter >46 mm who received the combination treatment vs. amiodarone alone (81 vs. 54%; P = 0.02), whereas the efficacy of the two interventions did not differ among patients with LA diameter <=46 mm (P = 0.77). There was modest QT prolongation in both the groups, no serious adverse reactions, and no pro-arrhythmic events. CONCLUSION: Addition of ranolazine to amiodarone was safe and well tolerated in this study, and it demonstrated efficacy superior to amiodarone alone for conversion of recent-onset AF. These findings may have clinical implications by offering a simple therapeutic manoeuvre to enhance amiodarone's effectiveness for conversion of AF. PMID- 24473503 TI - The impact of glucocorticoids and anti-cd20 therapy on cervical human papillomavirus infection risk in women with systemic lupus erythematosus. AB - OBJECTIVE: To identify the prevalence and factors associated with cervical human papillomavirus infection in women with systemic lupus erythematosus METHODS: This cross-sectional study collected traditional and systemic lupus erythematosus related disease risk factors, including conventional and biologic therapies. A gynecological evaluation and cervical cytology screen were performed. Human papillomavirus detection and genotyping were undertaken by PCR and linear array assay. RESULTS: A total of 148 patients were included, with a mean age and disease duration of 42.5+/-11.8 years and 9.7+/-5.3 years, respectively. The prevalence of squamous intraepithelial lesions was 6.8%. The prevalence of human papillomavirus infection was 29%, with human papillomavirus subtype 59 being the most frequent. Patients with human papillomavirus were younger than those without the infection (38.2+/-11.2 vs. 44.2+/-11.5 years, respectively; p = 0.05), and patients with the virus had higher daily prednisone doses (12.8+/-6.8 vs. 9.7+/ 6.7 mg, respectively; p = 0.01) and cumulative glucocorticoid doses (14.2+/-9.8 vs. 9.7+/-7.3 g, respectively; p = 0.005) compared with patients without. Patients with human papillomavirus infection more frequently received rituximab than those without (20.9% vs. 8.5%, respectively; p = 0.03). In the multivariate analysis, only the cumulative glucocorticoid dose was associated with human papillomavirus infection. CONCLUSIONS: The cumulative glucocorticoid dose may increase the risk of human papillomavirus infection. Although rituximab administration was more frequent in patients with human papillomavirus infection, no association was found. Screening for human papillomavirus infection is recommended in women with systemic lupus erythematosus. PMID- 24473504 TI - Ankle-brachial index as a predictor of coronary disease events in elderly patients submitted to coronary angiography. AB - OBJECTIVES: To correlate the importance of the ankle-brachial index in terms of cardiovascular morbimortality and the extent of coronary arterial disease amongst elderly patients without clinical manifestations of lower limb peripheral arterial disease. METHODS: We analyzed prospective data from 100 patients over 65 years of age with coronary arterial disease, as confirmed by coronary angiography, and with over 70% stenosis of at least one sub-epicardial coronary artery. We measured the ankle-brachial index immediately after coronary angiography, and a value of <0.9 was used to diagnose peripheral arterial disease. RESULTS: The patients' average age was 77.4 years. The most prevalent risk factor was hypertension (96%), and the median late follow-up appointment was 28.9 months. The ankle-brachial index was <0.9 in 47% of the patients, and a low index was more prevalent in patients with multiarterial coronary disease compared to patients with uniarterial disease in the same group. Using a bivariate analysis, only an ankle-brachial index of <0.9 was a strong predictive factor for cardiovascular events, thereby increasing all-cause deaths and fatal and non fatal acute myocardial infarctions two- to three-fold. CONCLUSION: In elderly patients with documented coronary disease, a low ankle-brachial index (<0.9) was associated with the severity and extent of coronary arterial disease, and in late follow-up appointments, a low index was correlated with an increase in the occurrence of major cardiovascular events. PMID- 24473505 TI - pH in exhaled breath condensate and nasal lavage as a biomarker of air pollution related inflammation in street traffic-controllers and office-workers. AB - OBJECTIVE: To utilize low-cost and simple methods to assess airway and lung inflammation biomarkers related to air pollution. METHODS: A total of 87 male, non-smoking, healthy subjects working as street traffic-controllers or office workers were examined to determine carbon monoxide in exhaled breath and to measure the pH in nasal lavage fluid and exhaled breath condensate. Air pollution exposure was measured by particulate matter concentration, and data were obtained from fixed monitoring stations (8-h work intervals per day, during the 5 consecutive days prior to the study). RESULTS: Exhaled carbon monoxide was two fold greater in traffic-controllers than in office-workers. The mean pH values were 8.12 in exhaled breath condensate and 7.99 in nasal lavage fluid in office workers; these values were lower in traffic-controllers (7.80 and 7.30, respectively). Both groups presented similar cytokines concentrations in both substrates, however, IL-1beta and IL-8 were elevated in nasal lavage fluid compared with exhaled breath condensate. The particulate matter concentration was greater at the workplace of traffic-controllers compared with that of office workers. CONCLUSION: The pH values of nasal lavage fluid and exhaled breath condensate are important, robust, easy to measure and reproducible biomarkers that can be used to monitor occupational exposure to air pollution. Additionally, traffic-controllers are at an increased risk of airway and lung inflammation during their occupational activities compared with office-workers. PMID- 24473506 TI - The impact of metabolic syndrome on metabolic, pro-inflammatory and prothrombotic markers according to the presence of high blood pressure criterion. AB - OBJECTIVES: We explored whether high blood pressure is associated with metabolic, inflammatory and prothrombotic dysregulation in patients with metabolic syndrome. METHODS: We evaluated 135 consecutive overweight/obese patients. From this group, we selected 75 patients who were not under the regular use of medications for metabolic syndrome as defined by the current Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults criteria. The patients were divided into metabolic syndrome with and without high blood pressure criteria (>=130/>=85 mmHg). RESULTS: Compared to the 45 metabolic syndrome patients without high blood pressure, the 30 patients with metabolic syndrome and high blood pressure had significantly higher glucose, insulin, homeostasis model assessment insulin resistance index, total cholesterol, low density lipoprotein-cholesterol, triglycerides, uric acid and creatinine values; in contrast, these patients had significantly lower high-density lipoprotein cholesterol values. Metabolic syndrome patients with high blood pressure also had significantly higher levels of retinol-binding protein 4, plasminogen activator inhibitor 1, interleukin 6 and monocyte chemoattractant protein 1 and lower levels of adiponectin. Moreover, patients with metabolic syndrome and high blood pressure had increased surrogate markers of sympathetic activity and decreased baroreflex sensitivity. Logistic regression analysis showed that high-density lipoprotein, retinol-binding protein 4 and plasminogen activator inhibitor-1 levels were independently associated with metabolic syndrome patients with high blood pressure. There is a strong trend for an independent association between metabolic syndrome patients with high blood pressure and glucose levels. CONCLUSIONS: High blood pressure, which may be related to the autonomic dysfunction, is associated with metabolic, inflammatory and prothrombotic dysregulation in patients with metabolic syndrome. PMID- 24473507 TI - The involvement of multiple thrombogenic and atherogenic markers in premature coronary artery disease. AB - OBJECTIVE: To examine the association of atherogenic and thrombogenic markers and lymphotoxin-alfa gene mutations with the risk of premature coronary disease. METHODS: This cross-sectional, case-control, age-adjusted study was conducted in 336 patients with premature coronary disease (<50 years old) and 189 healthy controls. The control subjects had normal clinical, resting, and exercise stress electrocardiographic assessments. The coronary disease group patients had either angiographically documented disease (>50% luminal reduction) or a previous myocardial infarction. The laboratory data evaluated included thrombogenic factors (fibrinogen, protein C, protein S, and antithrombin III), atherogenic factors (glucose and lipid profiles, lipoprotein(a), and apolipoproteins AI and B), and lymphotoxin-alfa mutations. Genetic variability of lymphotoxin-alfa was determined by polymerase chain reaction analysis. RESULTS: Coronary disease patients exhibited lower concentrations of HDL-cholesterol and higher levels of glucose, lipoprotein(a), and protein S. The frequencies of AA, AG, and GG lymphotoxin-alfa mutation genotypes were 55.0%, 37.6%, and 7.4% for controls and 42.7%, 46.0%, and 11.3% for coronary disease patients (p = 0.02), respectively. Smoking, dyslipidemia, family history, and lipoprotein(a) and lymphotoxin-alfa mutations in men were independent variables associated with coronary disease. The area under the curve (C-statistic) increased from 0.779 to 0.802 (p<0.05) with the inclusion of lipoprotein(a) and lymphotoxin-alfa mutations in the set of conventional risk factors. CONCLUSIONS: The inclusion of lipoprotein(a) and lymphotoxin-alfa mutations in the set of conventional risk factors showed an additive but small increase in the risk prediction of premature coronary disease. PMID- 24473508 TI - Reproducibility of ambulatory blood pressure changes from the initial values on two different days. AB - OBJECTIVE: We tested the reproducibility of changes in the ambulatory blood pressure (BP) from the initial values, an indicator of BP reactivity and cardiovascular health outcomes, in young, healthy adults. METHOD: The subjects wore an ambulatory BP monitor attached by the same investigator at the same time of day until the next morning on two different days (day 1 and day 2) separated by a week. We compared the ambulatory BP change from the initial values at hourly intervals over 24 waking and sleeping hours on days 1 and 2 using linear regression and repeated measures analysis of covariance. RESULTS: The subjects comprised 88 men and 57 women (mean age+/-SE 22.4+/-0.3 years) with normal BP (118.3+/-0.9/69.7+/-0.6 mmHg). For the total sample, the correlation between the ambulatory BP change on day 1 vs. day 2 over 24, waking, and sleeping hours ranged from 0.37-0.61; among women, the correlation was 0.38-0.71, and among men, it was 0.24-0.52. Among women, the ambulatory systolic/diastolic BP change was greater by 3.1+/-1.0/2.4+/-0.8 mmHg over 24 hours and by 3.0+/-1.1/2.4+/-0.8 mmHg over waking hours on day 1 than on day 2. The diastolic ambulatory BP change during sleeping hours was greater by 2.2+/-0.9 mmHg on day 1 than on day 2, but the systolic ambulatory BP change during sleeping hours on days 1 and 2 did not differ. Among men, the ambulatory BP change on days 1 and 2 did not differ. CONCLUSION: Our primary findings were that the ambulatory BP change from the initial values was moderately reproducible; however, it was more reproducible in men than in women. These results suggest that women, but not men, may experience an alerting reaction to initially wearing the ambulatory BP monitor. PMID- 24473509 TI - Predictors of in-hospital mortality in patients with ST-segment elevation myocardial infarction undergoing pharmacoinvasive treatment. AB - OBJECTIVES: To identify predictors of in-hospital mortality in patients with acute myocardial infarction undergoing pharmacoinvasive treatment. METHODS: This was an observational, prospective study that included 398 patients admitted to a tertiary center for percutaneous coronary intervention within 3 to 24 hours after thrombolysis with tenecteplase. ClinicalTrials.gov: NCT01791764 RESULTS: The overall in-hospital mortality rate was 5.8%. Compared with patients who survived, patients who died were more likely to be older, have higher rates of diabetes and chronic renal failure, have a lower left ventricular ejection fraction, and demonstrate more evidence of heart failure (Killip class III or IV). Patients who died had significantly lower rates of successful thrombolysis (39% vs. 68%; p = 0.005) and final myocardial blush grade 3 (13.0% vs. 61.9%; p<0.0001). Based on the multivariate analysis, the Global Registry of Acute Coronary Events score (odds ratio 1.05, 95% confidence interval (CI) 1.02-1.09; p = 0.001), left ventricular ejection fraction (odds ratio 0.9, 95% CI 0.89-0.97; p = 0.001), and final myocardial blush grade of 0-2 (odds ratio 8.85, 95% CI 1.34-58.57; p = 0.02) were independent predictors of mortality. CONCLUSIONS: In this prospective study that evaluated patients with ST-segment elevation myocardial infarction treated by a pharmacoinvasive strategy, the in-hospital mortality rate was 5.8%. The Global Registry of Acute Coronary Events score, left ventricular ejection fraction, and myocardial blush were independent predictors of mortality in this high-risk group of acute coronary syndrome patients. PMID- 24473510 TI - Posterior-only spinal fusion without rib head resection for treating type I neurofibromatosis with intra-canal rib head dislocation. AB - OBJECTIVES: Patients with Type I neurofibromatosis scoliosis with intra-canal rib head protrusion are extremely rare. Current knowledge regarding the diagnosis and treatment for this situation are insufficient. The purpose of this study is to share our experience in the diagnosis and surgical treatments for such unique deformities. METHODS: Six patients with Type I neurofibromatosis scoliosis with rib head dislocation into the spinal canal were diagnosed at our institution. Posterior instrumentation and spinal fusion without intra-canal rib head resection via a posterior-only approach was performed for deformity correction and rib head extraction. The efficacy and outcomes of the surgery were evaluated by measurements before, immediately and 24 months after the surgery using the following parameters: coronal spinal Cobb angle, apex rotation and kyphosis of the spine and the intra-canal rib head position. Post-operative complications, surgery time and blood loss were also evaluated. RESULTS: Patients were followed up for at least 24 months post-operatively. The three dimensional spinal deformity was significantly improved and the intra-canal rib head was significantly extracted from the canal immediately after the surgery. At follow up 24 months after surgery, solid fusions were achieved along the fusion segments, and the deformity corrections and rib head positions were well maintained. There were no surgery-related complications any time after the surgery. CONCLUSIONS: Systematic examinations are needed to identify patients with Type I neurofibromatosis scoliosis with rib head dislocation into the canal who can be treated by posterior-only spinal fusion without rib head resection. PMID- 24473511 TI - The putative role of ovary removal and progesterone when considering the effect of formaldehyde exposure on lung inflammation induced by ovalbumin. AB - OBJECTIVE: Formaldehyde exposure during the menstrual cycle is known to affect the course of allergic lung inflammation. Because our previous data demonstrated that formaldehyde combined with an ovariectomy reduced allergic lung inflammation, we investigated the putative role of ovary removal and progesterone treatment when considering the effect of formaldehyde on allergic lung inflammation. METHOD: Ovariectomized rats and their matched controls were exposed to formaldehyde (1%, 3 days, 90 min/day) or vehicle, and immediately after exposure, the rats were sensitized to ovalbumin by a subcutaneous route. After 1 week, the rats received a booster by the same route, and after an additional week, the rats were challenged with ovalbumin (1%) by an aerosol route. The leukocyte numbers, interleukin-10 (IL-10) release, myeloperoxidase activity, vascular permeability, ex vivo tracheal reactivity to methacholine and mast cell degranulation were determined 24 h later. RESULTS: Our results showed that previous exposure to formaldehyde in allergic rats decreased lung cell recruitment, tracheal reactivity, myeloperoxidase activity, vascular permeability and mast cell degranulation while increasing IL-10 levels. Ovariectomy only caused an additional reduction in tracheal reactivity without changing the other parameters studied. Progesterone treatment reversed the effects of formaldehyde exposure on ex vivo tracheal reactivity, cell influx into the lungs and mast cell degranulation. CONCLUSION: In conclusion, our study revealed that formaldehyde and ovariectomy downregulated allergic lung inflammation by IL-10 release and mast cell degranulation. Progesterone treatment increased eosinophil recruitment and mast cell degranulation, which in turn may be responsible for tracheal hyperreactivity and allergic lung inflammation. PMID- 24473512 TI - Gender differences in microcirculation: observation using the hamster cheek pouch. AB - OBJECTIVES: Estrogen has been shown to play an important protective role in non reproductive systems, such as the cardiovascular system. Our aim was to observe gender differences in vivo with regard to the increase in macromolecular permeability and leukocyte-endothelium interaction induced by ischemia/reperfusion as well as in microvascular reactivity to vasoactive substances using the hamster cheek pouch preparation. METHODS: Thirty-six male and 36 female hamsters, 21 weeks old, were selected for this study, and their cheek pouches were prepared for intravital microscopy. An increase in the macromolecular permeability of post-capillary venules was quantified as a leakage of intravenously injected fluorescein-labeled dextran, and the leukocyte endothelium interaction was measured as the number of fluorescent rolling leukocytes or leukocytes adherent to the venular wall, labeled with rhodamin G, during reperfusion after 30 min of local ischemia. For microvascular reactivity, the mean internal diameter of arterioles was evaluated after the topical application of different concentrations of two vasoconstrictors, phenylephrine (alpha1-agonist) and endothelin-1, and two vasodilators, acetylcholine (endothelial-dependent) and sodium nitroprusside (endothelial-independent). RESULTS: The increase in macromolecular permeability induced by ischemia/reperfusion was significantly lower in females compared with males [19 (17-22) leaks/cm2 vs. 124 (123-128) leaks/cm2, respectively, p<0.001), but the number of rolling or adherent leukocytes was not different between the groups. Phenylephrine-induced arteriolar constriction was significantly lower in females compared with males [77 (73-102)% vs. 64 (55-69)%, p<0.04], but there were no detectable differences in endothelin-1-dependent vasoreactivity. Additionally, arteriolar vasodilatation elicited by acetylcholine or sodium nitroprusside did not differ between the groups. CONCLUSION: The female gender could have a direct protective role in microvascular reactivity and the increase in macromolecular permeability induced by ischemia/reperfusion. PMID- 24473513 TI - Biomechanical comparison of the four-strand cruciate and Strickland techniques in animal tendons. AB - OBJECTIVE: The objective of this study was to compare two four-strand techniques: the traditional Strickland and cruciate techniques. METHODS: Thirty-eight Achilles tendons were removed from 19 rabbits and were assigned to two groups based on suture technique (Group 1, Strickland suture; Group 2, cruciate repair). The sutured tendons were subjected to constant progressive distraction using a universal testing machine (Kratos(r)). Based on data from the instrument, which were synchronized with the visualized gap at the suture site and at the time of suture rupture, the following data were obtained: maximum load to rupture, maximum deformation or gap, time elapsed until failure, and stiffness. RESULTS: In the statistical analysis, the data were parametric and unpaired, and by Kolmogorov-Smirnov test, the sample distribution was normal. By Student's t-test, there was no significant difference in any of the data: the cruciate repair sutures had slightly better mean stiffness, and the Strickland sutures had longer time-elapsed suture ruptures and higher average maximum deformation. CONCLUSIONS: The cruciate and Strickland techniques for flexor tendon sutures have similar mechanical characteristics in vitro. PMID- 24473514 TI - Local and remote ischemic preconditioning protect against intestinal ischemic/reperfusion injury after supraceliac aortic clamping. AB - OBJECTIVES: This study tests the hypothesis that local or remote ischemic preconditioning may protect the intestinal mucosa against ischemia and reperfusion injuries resulting from temporary supraceliac aortic clamping. METHODS: Twenty-eight Wistar rats were divided into four groups: the sham surgery group, the supraceliac aortic occlusion group, the local ischemic preconditioning prior to supraceliac aortic occlusion group, and the remote ischemic preconditioning prior to supraceliac aortic occlusion group. Tissue samples from the small bowel were used for quantitative morphometric analysis of mucosal injury, and blood samples were collected for laboratory analyses. RESULTS: Supraceliac aortic occlusion decreased intestinal mucosal length by reducing villous height and elevated serum lactic dehydrogenase and lactate levels. Both local and remote ischemic preconditioning mitigated these histopathological and laboratory changes. CONCLUSIONS: Both local and remote ischemic preconditioning protect intestinal mucosa against ischemia and reperfusion injury following supraceliac aortic clamping. PMID- 24473515 TI - Association between phase angle, anthropometric measurements, and lipid profile in HCV-infected patients. AB - OBJECTIVE: The objective of this study was to investigate the associations between phase angle, anthropometric measurements, and lipid profile in patients chronically infected with the hepatitis C virus. METHODS: A total of 160 consecutive patients chronically infected with the hepatitis C virus and who received treatment at the hepatitis C outpatient unit of our hospital from April 2010 to May 2011 were prospectively evaluated. Bioelectrical impedance analysis, anthropometric measurements, and serum lipid profile analysis were performed. RESULTS: Twenty-five patients were excluded. A total of 135 patients with a mean age of 49.8+/-11.4 years were studied. Among these patients, 60% were male. The phase angle and BMI means were 6.5+/-0.8 degrees and 26.5+/-4.8 kg/m2, respectively. Regarding anthropometric variables, mid-arm circumference, mid-arm muscle circumference, and arm muscle area had a positive correlation with phase angle. In contrast, when analyzing the lipid profile, only HDL was inversely correlated with phase angle. However, in multiple regression models adjusted for age and gender, only mid-arm circumference (p = 0.005), mid-arm muscle circumference (p = 0.003), and arm muscle circumference (p = 0.001) were associated with phase angle in hepatitis C virus-infected patients. CONCLUSIONS: In conclusion, phase angle is positively correlated with anthropometric measures in our study. However, there is no association between phase angle and lipid profile in these patients. Our results suggest that phase angle is related to lean body mass in patients chronically infected with hepatitis C virus. PMID- 24473518 TI - Nature-assisted rehabilitation for reactions to severe stress and/or depression in a rehabilitation garden: long-term follow-up including comparisons with a matched population-based reference cohort. AB - OBJECTIVE: To determine the effect of a nature-assisted rehabilitation programme in a group of patients with reactions to severe stress and/or mild to moderate depression. Changes in sick-leave status and healthcare consumption in these patients were compared with those in a matched population-based reference cohort (treatment as usual). DESIGN: Retrospective cohort study with a matched reference group from the general population. SUBJECTS: A total of 118 participants referred to a nature-assisted rehabilitation programme, and 678 controls recruited from the Skane Health Care Register. For both groups, information on sick leave was extracted from the National Social Insurance Register and on healthcare consumption data from the Skane Health Care Register. METHODS: The interventional rehabilitation programme was designed as a multimodal programme involving professionals from horticulture and medicine. The programme was conducted in a rehabilitation garden, designed especially for this purpose. RESULTS: A significant reduction in healthcare consumption was noted among participants in the programme compared with the reference population. The main changes were a reduction in outpatient visits to primary healthcare and a reduction in inpatient psychiatric care. No significant difference in sick-leave status was found. CONCLUSION: A structured, nature-based rehabilitation programme for patients with reactions to severe stress and/or depression could be beneficial, as reflected in reduced healthcare consumption. PMID- 24473519 TI - Summary report on commissioned research studies related to the melamine incident. PMID- 24473520 TI - Two-year follow-up for children with melamine exposure in Hong Kong: a multicentre study. PMID- 24473521 TI - Diagnostic tools for detection of intoxication by melamine and its analogue. PMID- 24473522 TI - Prevalence of melamine exposure in Hong Kong children. PMID- 24473523 TI - Melamine toxicity in rat foetuses and infants. PMID- 24473524 TI - Effects of melamine on urine crystallisation kinetics and cell responses. PMID- 24473525 TI - Case-control study of Sichuan and Hong Kong children with melamine-associated renal stones: renal ultrasonography and urinary IL-8 and MCP-1 levels. PMID- 24473526 TI - Renal and vascular function in pregnant and neonatal rats exposed to melamine and related compounds. PMID- 24473527 TI - Impact of melamine-tainted milk on foetal kidneys and disease development later in life. PMID- 24473529 TI - Market analysis of vitamin supplementation in infants and children: evidence from the dietary supplement label database. PMID- 24473528 TI - Histatin 5 binds to Porphyromonas gingivalis hemagglutinin B (HagB) and alters HagB-induced chemokine responses. AB - Histatins are human salivary gland peptides with anti-microbial and anti inflammatory activities. In this study, we hypothesized that histatin 5 binds to Porphyromonas gingivalis hemagglutinin B (HagB) and attenuates HagB-induced chemokine responses in human myeloid dendritic cells. Histatin 5 bound to immobilized HagB in a surface plasmon resonance (SPR) spectroscopy-based biosensor system. SPR spectroscopy kinetic and equilibrium analyses, protein microarray studies, and I-TASSER structural modeling studies all demonstrated two histatin 5 binding sites on HagB. One site had a stronger affinity with a KD1 of 1.9 MUM and one site had a weaker affinity with a KD2 of 60.0 MUM. Binding has biological implications and predictive modeling studies and exposure of dendritic cells both demonstrated that 20.0 MUM histatin 5 attenuated (p < 0.05) 0.02 MUM HagB-induced CCL3/MIP-1alpha, CCL4/MIP-1beta, and TNFalpha responses. Thus histatin 5 is capable of attenuating chemokine responses, which may help control oral inflammation. PMID- 24473530 TI - Risk of long-term hot flashes after natural menopause: evidence from the Penn Ovarian Aging Study cohort. AB - OBJECTIVE: This study aims to estimate the risk of hot flashes relative to natural menopause and to evaluate the associations of hormone levels, behavioral variables, and demographic variables with the risk of hot flashes after menopause. METHODS: We performed annual assessment of 255 women who were premenopausal at baseline and reached natural menopause within 16 years of follow up. RESULTS: The prevalence of moderate/severe hot flashes increased in each premenopausal year, reaching a peak of 46% in the first 2 years after the final menstrual period (FMP). Hot flashes decreased slowly after menopause and did not return to premenopausal levels until 9 years after the FMP. The mean (SD) duration of moderate/severe hot flashes after the FMP was 4.6 (2.9) years (for any hot flashes, 4.9 [3.1] y). One third of women at 10 years or more after menopause continued to experience moderate/severe hot flashes. African-American women (obese and nonobese) and obese white women had significantly greater risks of hot flashes compared with nonobese white women (interaction, P = 0.01). In multivariable analysis, increasing follicle-stimulating hormone levels before the FMP (P < 0.001), decreasing estradiol (odds ratio, 0.87; 95% CI, 0.78-0.96; P = 0.008), and increasing anxiety (odds ratio, 1.05; 95% CI, 1.03-1.06; P < 0.001) were significant risk factors for hot flashes, whereas higher education levels were protective (odds ratio, 0.66; 95% CI, 0.47-0.91; P = 0.011). CONCLUSIONS: Moderate/severe hot flashes continue, on average, for nearly 5 years after menopause; more than one third of women observed for 10 years or more after menopause have moderate/severe hot flashes. Continuation of hot flashes for more than 5 years after menopause underscores the importance of determining individual risks/benefits when selecting hormone or nonhormone therapy for menopausal symptoms. PMID- 24473531 TI - Epidemiology and spectrum of positive bacteriological culture in intrauterine fluid collected from women with postmenopausal bleeding. AB - OBJECTIVE: This study aims to examine the prevalence and bacteriological findings of different types of intrauterine fluid collection in women presenting with postmenopausal bleeding and the risk factors for predicting positive microbiological culture, mixed growth, and anaerobic growth. METHODS: This is a retrospective cohort study. Data from all of the women who were assessed in our one-stop postmenopausal bleeding clinic between 2008 and 2011 and who were found to have intrauterine fluid collection were reviewed. Endometrial aspirates of all women were sent for bacterial culture and histological examination. The risk factors for positive culture were assessed by both univariate and multivariate analyses. RESULTS: A total of 228 cases of intrauterine fluid collection were included for analysis. There were 109 (47.8%) cases of pyometra, 98 (43.0%) cases of hydrometra, and 21 (9.2%) cases of hematometra. Escherichia coli, Bacteroides fragilis, and Enterococcus were the commonest microorganisms isolated from endometrial aspirates. Both endometrial malignancy and benign intrauterine pathologies are not risk factors for positive culture. Advanced age (>75 y) is an independent risk factor for positive culture (odds ratio, 2.89; 95% CI, 1.39 6.01) and mixed growth (odds ratio, 2.18; 95% CI, 1.02-4.67). Residency in nursing homes is an independent risk factor for mixed growth (odds ratio, 2.61; 95% CI, 1.21-5.63) and anaerobic growth (odds ratio, 2.55; 95% CI, 1.01-6.44). CONCLUSIONS: E. coli, B. fragilis, and Enterococcus are the commonest microorganisms isolated from intrauterine fluid. Apart from drainage of the intrauterine fluid collection, successful management also requires appropriate antibiotics and improvement in perineal hygiene. PMID- 24473532 TI - Resveratrol- and melatonin-abated ovariectomy and fructose diet-induced obesity and metabolic alterations in female rats. AB - OBJECTIVE: This study was designed to investigate the effects of bilateral ovariectomy and fructose diet on obesity-related metabolic parameters in female rats. The potential of resveratrol, alone and in combination with melatonin, to counter ensuing obesity and precipitated metabolic disturbances was explored. METHODS: Eight-week-old female Sprague-Dawley rats were subjected to bilateral ovariectomy (OVX) or sham operation and randomly assigned to standard diet (SD) or fructose diet (FD) groups (n = 6 rats per group) as follows: Sham; OVX + FD; OVX + SD; OVX + FD + resveratrol 50 mg/kg/day PO (RESV); OVX + SD + RESV; OVX + FD + melatonin 3 mg/kg/day PO in drinking water (M); OVX + SD + M; OVX + FD + RESV + M; OVX + SD + RESV + M. All treatments were given for 7 weeks. Biochemical, dietary, and anthropometrical parameters were estimated, and abdominal fat pads and the liver were examined for histopathological alterations. RESULTS: Ovariectomy caused an increase in body weight, body mass index, feed efficiency, serum glucose, cholesterol, triglycerides, and free fatty acids, which was further exacerbated by fructose diet. These parameters were significantly decreased by resveratrol, alone and in combination with melatonin. Histopathological examination revealed reduced hypertrophy of adipocytes in adipose tissue and reduced macrophage infiltration in the liver. CONCLUSIONS: Resveratrol/melatonin combination effectively normalizes anthropometrical, biochemical, and histopathological parameters in ovariectomized rats with fructose diet-induced obesity and associated metabolic alterations. The combination should be explored for potential benefits in postmenopausal women. PMID- 24473533 TI - Age at natural menopause in refugee and domicile women who lived in Tuzla Canton in Bosnia and Herzegovina during and after the war. AB - OBJECTIVE: This study aims to estimate age at onset of natural menopause in domicile and refugee women who lived in Tuzla Canton in Bosnia and Herzegovina during the war (1992-1995) and in the postwar period until the interview. METHODS: A cross-sectional study was conducted on a sample of 331 postmenopausal women-264 (80%) domicile women and 67 (20%) refugee women-between June 2009 and February 2011. RESULTS: The study encompassed 331 women with a mean age of 57.0 years (range, 39-75 y). The overall mean age at menopause was 49.1 years. The mean age at menopause was higher in domicile women (49.3 y) than in refugee women (48.0 y; unpaired t test, P = 0.023). After adjustment for age at menarche, education, marital status, living place, body mass index, number of abortions, use of contraceptives, and current smoking, only refugee status and parity remained as significant independent predictors of age at menopause (score test, P = 0.025). Refugee women had an increased probability of earlier onset of menopause compared with nonrefugee women (adjusted hazard ratio, 1.33; 95% CI, 1.02-1.75; P = 0.039), whereas there was a decreased probability of experiencing menopause with increasing number of births (adjusted hazard ratio, 0.92; 95% CI, 0.84-0.996; P = 0.04). CONCLUSIONS: The age at onset of menopause in refugee women is lower than that in domicile women, indicating that war, independently of other factors, could influence the age when menopause occurs. On average, women who lived in Bosnia and Herzegovina during the war and postwar period entered menopause earlier than did women from Europe. PMID- 24473534 TI - Pilot study of integral yoga for menopausal hot flashes. AB - OBJECTIVE: This study aims to obtain preliminary data on the efficacy of yoga for reducing self-reported menopausal hot flashes in a randomized study including an attention control group. METHODS: We randomized 54 late perimenopausal women (2 12 mo of amenorrhea) and postmenopausal women (>12 mo of amenorrhea)--aged 45 to 58 years and who experienced at least four hot flashes per day, on average, for at least 4 weeks--to one of three groups: yoga, health and wellness education (HW), and wait list (WL). Yoga and HW classes consisted of weekly 90-minute classes for 10 weeks. All women completed daily hot flash diaries throughout the trial (10 wk) to track the frequency and severity of hot flashes. The mean hot flash index score is based on the number of mild, moderate, severe, and very severe hot flashes. RESULTS: Hot flash frequency declined significantly across time for all three groups, with the strongest decline occurring during the first week. There was no overall significant difference in hot flash frequency decrease over time by treatment groups, but the yoga and HW groups followed similar patterns and showed greater decreases than the WL group. On week 10, women in the yoga group reported an approximately 66% decrease in hot flash frequency, women in the HW group reported a 63% decrease, and women in the WL group reported a 36% decrease. The hot flash index showed a similar pattern. CONCLUSIONS: Results suggest that yoga can serve as a behavioral option for reducing hot flashes but may not offer any advantage over other types of interventions. PMID- 24473535 TI - Relationship between circulating serum osteoprotegerin and total receptor activator of nuclear kappa-B ligand levels, triglycerides, and coronary calcification in postmenopausal women. AB - OBJECTIVE: This study evaluates the relationship of blood osteoprotegerin (OPG) and receptor activator of nuclear kappa-B ligand (RANKL) levels with coronary artery calcium (CAC) and cardiovascular risk factors in two studies of postmenopausal women. OPG, a marker of bone turnover, and its ligand, RANKL, may contribute to cardiovascular disease risk. METHODS: We tested the hypothesis that serum OPG and RANKL levels were associated with CAC and cardiovascular disease risk factors among postmenopausal women in the Women On the Move through Activity and Nutrition Study (WOMAN Study; n = 86; mean [SD], age 58 [2.9] y) and replicated our findings in the Healthy Women Study (HWS; n = 205; mean [SD] age, 61 [2.3] y). Serum OPG, total RANKL, and CAC were measured at baseline and 48 months in the WOMAN Study and on the eighth postmenopausal visit in the HWS. RESULTS: In the WOMAN Study, higher OPG was associated with higher CAC, and higher total RANKL was associated with lower CAC and triglycerides. In the HWS, higher total RANKL was also associated with lower CAC and triglycerides. In logistic regression models adjusted for body mass index and triglycerides, the odds ratios (95% CIs) for CAC per unit increase in OPG were 1.78 (1.17-2.73) for the WOMAN Study and 1.02 (0.84-1.24) for the HWS, and the odds ratios (95% CIs) for CAC per unit increase in log total RANKL were 0.86 (0.64-1.17) for the WOMAN Study and 0.83 (0.72-0.96) for the HWS. CONCLUSIONS: The inverse association of total RANKL with CAC and triglycerides is a new finding and may have important implications given the increasing use of drugs that modify total RANKL and its receptor, receptor activator of nuclear kappa-B. PMID- 24473537 TI - Laparoscopic staging in women older than 75 years with early-stage endometrial cancer: comparison with open surgical operation. AB - OBJECTIVE: Older age is a relevant risk factor for developing endometrial cancer (EC) and has been traditionally regarded as a relative contraindication to laparoscopy. Our aim was to analyze the safety and effectiveness of laparoscopic staging in older women with EC. METHODS: Consecutive women aged 75 years or older who underwent laparoscopic staging for EC between May 2002 and October 2012 were compared with consecutive women aged 75 years or older who underwent abdominal staging before the adoption of the laparoscopic approach in our institution. Postoperative complications were graded according to the Accordion Severity Grading System. RESULTS: Fifty-nine women aged 75 years or older who underwent laparoscopy were compared with a cohort of 66 women aged 75 years or older who underwent open staging before the incorporation of laparoscopy. Demographic and disease characteristics, as well as the Charlson comorbidity index, were balanced between groups. Women who underwent laparoscopy had similar operative time (P = 0.14), lower blood loss (P = 0.005), and shorter length of stay (P < 0.001) in comparison with women who underwent open surgical operation. Overall, women who underwent laparoscopy experienced less postoperative complications than women in the control group (P < 0.001). In addition, focusing only on complications grade 3 or higher, we observed a trend toward decreased complication rates in the laparoscopic group (P = 0.06). No differences in survival outcomes (including time of recurrence, site of recurrence, disease-free survival, and overall survival) were recorded (P > 0.05). CONCLUSIONS: Our findings suggest that EC patients older than 75 years may benefit from minimally invasive surgical operation and should not be denied laparoscopy based on mere chronological age. PMID- 24473536 TI - Effects of physiologic testosterone therapy on quality of life, self-esteem, and mood in women with primary ovarian insufficiency. AB - OBJECTIVE: Women with primary ovarian insufficiency (POI) display low androgen levels, which could contribute to mood and behavioral symptoms observed in this condition. We examined the effects of physiologic testosterone therapy added to standard estrogen/progestin therapy on quality of life, self-esteem, and mood in women with POI. METHODS: One hundred twenty-eight women with 46,XX spontaneous POI participated in a 12-month randomized, placebo-controlled, parallel-design investigation of the efficacy of testosterone augmentation of estrogen/progestin therapy. Quality of life, self-esteem, and mood symptoms were evaluated with standardized rating scales and a structured clinical interview. Differences in outcome measures between the testosterone and placebo treatments were analyzed by Wilcoxon rank sum tests. RESULTS: No differences in baseline characteristics, including serum hormone levels (P > 0.05), were found. Baseline mean (SD) Center for Epidemiologic Studies Depression Scale scores were 10.7 (8.6) and 9.2 (7.8) for testosterone and placebo, respectively (P = 0.35). After 12 months of treatment, measures of quality of life, self-esteem, and mood symptoms did not differ between treatment groups. Serum testosterone levels achieved physiologic levels in the testosterone group and were significantly higher compared with placebo (P < 0.001). Baseline testosterone levels were not associated with either adverse or beneficial clinical effects. CONCLUSIONS: A 150-MUg testosterone patch achieves physiologic hormone levels in women with POI. Our findings suggest that augmentation of standard estrogen/progestin therapy with physiologic testosterone therapy in young women with POI neither aggravates nor improves baseline reports of quality of life or self-esteem and had minimal effects on mood. Other mechanisms might play a role in the altered mood accompanying this disorder. PMID- 24473538 TI - The implications of the relative risk for road mortality on road safety programmes in Qatar. AB - The epidemiology of road deaths and in particular the relative risk for road mortality (RRRM) in Qatar has not been fully defined. This study will analyse and compare the proportionate mortality and age-specific death rates from road traffic injuries (RTIs) and make recommendations for targeted injury prevention programmes for road safety in Qatar. Data from the Qatar Statistics Authority (QSA), for the year 2010, was collected and analysed. All deaths classified as 'ICD-10 (V89) Motor- or Nonmotor-Vehicle, Accident Type of Vehicle Unspecified' were included. There were 247 RTI related deaths in Qatar in 2010. An overall death rate was computed at 14.4 deaths per 100 000 population. The RRRM varied over 10 times among different populations with Qatari males (QM) having an increased RRRM from 10 years of age, those aged 20-29 years had the highest RRRM of 10.2. The lowest RRRM was for Qatari females who did not have a single reported road fatality in 2010. Populations with a significantly elevated RRRM (ie, RRRM>1.0) were non-Qatari men older than 50 years and Qatari males from the age of 10 onward. Proven and definite programmes must be implemented to reduce these unnecessary deaths among the populations at the highest risk. Multidisciplinary approaches must be implemented and their efficacy evaluated. PMID- 24473539 TI - A 0.45 V 100-channel neural-recording IC with sub- MUW/channel consumption in 0.18 MUm CMOS. AB - Neural prosthetics and personal healthcare have increasing need of high channel density low noise low power neural sensor interfaces. The input referred noise and quantization resolution are two essential factors which prevent conventional neural sensor interfaces from simultaneously achieving a good noise efficiency factor and low power consumption. In this paper, a neural recording architecture with dynamic range folding and current reuse techniques is proposed and dedicated to solving the noise and dynamic range trade-off under low voltage low power operation. Measured results from the silicon prototype show that the proposed design achieves 3.2 MUVrms input referred noise and 8.27 effective number of bits at only 0.45 V supply and 0.94 MUW/channel power consumption. PMID- 24473540 TI - A fully intraocular high-density self-calibrating epiretinal prosthesis. AB - This paper presents a fully intraocular self-calibrating epiretinal prosthesis with 512 independent channels in 65 nm CMOS. A novel digital calibration technique matches the biphasic currents of each channel independently while the calibration circuitry is shared among every 4 channels. Dual-band telemetry for power and data with on-chip rectifier and clock recovery reduces the number of off-chip components. The rectifier utilizes unidirectional switches to prevent reverse conduction loss in the power transistors and achieves an efficiency > 80%. The data telemetry implements a phase-shift keying (PSK) modulation scheme and supports data rates up to 20 Mb/s. The system occupies an area of 4.5 *3.1 mm2. It features a pixel size of 0.0169 mm2 and arbitrary waveform generation per channel. In vitro measurements performed on a Pt/Ir concentric bipolar electrode in phosphate buffered saline (PBS) are presented. A statistical measurement over 40 channels from 5 different chips shows a current mismatch with MU = 1.12 MUA and sigma = 0.53 MUA. The chip is integrated with flexible MEMS origami coils and parylene substrate to provide a fully intraocular implant. PMID- 24473541 TI - A fully-integrated high-compliance voltage SoC for epi-retinal and neural prostheses. AB - This paper presents a fully functionally integrated 1024-channel mixed-mode and mixed-voltage system-on-a-chip (SoC) for epi-retinal and neural prostheses. Taking an AC input, an integrated power telemetry circuits is capable of generating multiple DC voltages with a voltage conversion efficiency of 83% at a load of 100 mW without external diodes or separate power integrated circuits, reducing the form factor of the prosthetic device. A wireless DPSK receiver with a novel noise reduction scheme supports a data rate of 2 Mb/s at a bit-error-rate of 2 *10-7. The 1024-channel stimulator array meets an output compliance voltage of +/-10 V and provides flexible stimulation waveforms. Through chip-clustering, the stimulator array can be further expanded to 4096 channels. This SoC is designed and fabricated in TSMC 0.18 MUm high-voltage 32 V CMOS process and occupies a chip area of 5.7 mm * 6.6 mm. Using this SoC, a retinal implant bench top test system is set up with real-time visual verification. In-vitro experiment conducted in artificial vitreous humor is designed and set-up to investigate stimulation waveforms for better visual resolution. In our in-vivo experiment, a hind-limb paralyzed rat with spinal cord transection and implanted chronic epidural electrodes has been shown to regain stepping and standing abilities using stimulus provided by the SoC. PMID- 24473542 TI - Design and implementation of an integrated magnetic spectrometer for multiplexed biosensing. AB - Magnetic spectroscopy allows for characterization of the magnetic susceptibility of magnetic beads across a broad frequency range. This enables differentiation and quantification of multiple beads of varying types concurrently present in the active volume of a sensor's surface. A magnetic spectrometer can be used for multi-probe tagging and identification akin to multi-color fluorescent bio sensing. We propose a new sensing methodology to perform magnetic spectroscopy and analyze various important design parameters such as SNR and gain uniformity. We present a proof-of-concept design of a fully integrated CMOS magnetic spectrometer that can detect, quantify, and characterize magnetic materials in the 1.1 GHz to 3.3 GHz frequency range, where we demonstrate magnetic multiplexing capability using a mixture of two different kinds of magnetic beads. The sensor consumes less than 2 mW of DC power within the whole frequency range, requires no external biasing magnetic fields, is implemented in a standard CMOS process, and can be powered and operated completely from a USB interface. The magnetic spectrometer not only increases the throughput and multiplexing of biosensing experiments for a given sensor area, but also can enable additional applications, such as magnetic flow cytometry and signal-collocation assays of multiple probes. PMID- 24473543 TI - A 13 MUA analog signal processing IC for accurate recognition of multiple intra cardiac signals. AB - A low-power analog signal processing IC is presented for the low-power heart rhythm analysis. The ASIC features 3 identical, but independent intra-ECG readout channels each equipping an analog QRS feature extractor for low-power consumption and fast diagnosis of the fatal case. A 16-level digitized sine-wave synthesizer together with a synchronous readout circuit can measure bio-impedance in the range of 0.1-4.4 kOmega with 33 mOmega(rms) resolution and higher than 97% accuracy. The proposed 25 mm2 ASIC consumes only 13 MUA from 2.2 V. It is a highly integrated solution offering all the functionality of acquiring multiple high quality intra-cardiac signals, requiring only a few limited numbers of external passives. PMID- 24473544 TI - Integrated circuits for volumetric ultrasound imaging with 2-D CMUT arrays. AB - Real-time volumetric ultrasound imaging systems require transmit and receive circuitry to generate ultrasound beams and process received echo signals. The complexity of building such a system is high due to requirement of the front-end electronics needing to be very close to the transducer. A large number of elements also need to be interfaced to the back-end system and image processing of a large dataset could affect the imaging volume rate. In this work, we present a 3-D imaging system using capacitive micromachined ultrasonic transducer (CMUT) technology that addresses many of the challenges in building such a system. We demonstrate two approaches in integrating the transducer and the front-end electronics. The transducer is a 5-MHz CMUT array with an 8 mm * 8 mm aperture size. The aperture consists of 1024 elements (32 * 32) with an element pitch of 250 MUm. An integrated circuit (IC) consists of a transmit beamformer and receive circuitry to improve the noise performance of the overall system. The assembly was interfaced with an FPGA and a back-end system (comprising of a data acquisition system and PC). The FPGA provided the digital I/O signals for the IC and the back-end system was used to process the received RF echo data (from the IC) and reconstruct the volume image using a phased array imaging approach. Imaging experiments were performed using wire and spring targets, a ventricle model and a human prostrate. Real-time volumetric images were captured at 5 volumes per second and are presented in this paper. PMID- 24473545 TI - CMOS tunable-wavelength multi-color photogate sensor. AB - A CMOS tunable-wavelength multi-color photogate (CPG) sensor is presented. Sensing of a small set of well-separated wavelengths (e.g., > 50 nm apart) is achieved by tuning the spectral response of the device with a bias voltage. The CPG employs the polysilicon gate as an optical filter, which eliminates the need for an external color filter. A prototype has been fabricated in a standard 0.35 MUm digital CMOS technology and demonstrates intensity measurements of blue (450 nm), green (520 nm), and red (620 nm) illumination with peak signal-to-noise ratios (SNRs) of 34.7 dB , 29.2 dB, and 34.8 dB, respectively. The prototype is applied to fluorescence detection of green-emitting quantum dots (gQDs) and red emitting quantum dots (rQDs). It spectrally differentiates among multiple emission bands, effectively implementing on-chip emission filtering. The prototype demonstrates single-color measurements of gQD and rQD concentrations to a detection limit of 24 nM, and multi-color measurements of solutions containing both colors of QDs to a detection limit of 90 nM and 120 nM of gQD and rQD, respectively. PMID- 24473546 TI - A CMOS cantilever-based label-free DNA SoC with improved sensitivity for hepatitis B virus detection. AB - This paper presents a highly-integrated DNA detection SoC, where several kinds of cantilever DNA sensors, a readout circuit, an MCU, voltage regulators, and a wireless transceiver, are integrated monolithically in a 0.35 MUm CMOS Bio-MEMS process. The cantilever-based biosensors with embedded piezoresistors aim to transduce DNA hybridization into resistance variation without cumbersome labeling process. To improve detection sensitivity for low DNA concentration use, an oscillator-based self-calibrated readout circuit with high precision is proposed to convert small resistance variation ( of original resistance) of the sensor into adequate frequency variation and further into digital data. Moreover, its wireless capacity enables isolation of the sample solution from electrical wire lines and facilitates data transmission. To demonstrate the effectiveness of full system, it is applied to detect hepatitis B virus (HBV) DNA. The experimental results show that it has the capability to distinguish between one base-pair (1 bp) mismatch DNAs and match DNAs and achieves a limit of detection (LOD) of less than 1 pM. PMID- 24473547 TI - Design and implementation of a wireless in-ovo EEG/EMG recorder. AB - The developmental origins of sleep and brain activity rhythms in higher vertebrate animals (birds and mammals) are currently unknown. In order to create an experimental system in which these could be better elucidated, we designed, built and tested a system for recording EEG and EMG signals in-ovo from chicken embryos incubated for 16-21 days. This system can remain attached to the individual subject through the process of hatching and continue to be worn post natally. Electrode wires surgically implanted on the head of the embryo are connected to a battery-operated ultraportable transmitter which can either be attached to the eggshell or worn on the back. The transmitter processes up to 6 channels of data with a maximum sampling frequency of 500 Hz and a resolution of 12 bits. The radio link uses a carrier frequency of 4 MHz, and has a maximum transfer rate of 500 kbit/s; receiving antennas compatible with both in-egg recordings and post-natal recordings from freely-moving birds were produced. A receiver connected with one USB port of a PC transmits the data for digital storage. This system is based on discrete, off-the-shelf components, can provide a few days of continuous operation with a single lithium coin battery, and has a noise floor level of 0.35 MUV. The transmitter dimensions are 16 * 13 * 1.5 mm and the weight without the battery is 0.7 g. The microprocessor allows flexible operation modes not usually made available in other small multichannel acquisition systems implemented by means of ad hoc mixed signal chips. PMID- 24473548 TI - A near-threshold, 0.16 nJ/b OOK-transmitter with 0.18 nJ/b noise-cancelling super regenerative receiver for the medical implant communications service. AB - A 0.16 nJ/b MICS transmitter and 0.18 nJ/b super-regenerative receiver are demonstrated, where each is specifically designed to operate in the near threshold region. The low-VDD transmitter utilizes a sub-harmonic injection locked ring oscillator, edge combiner for frequency multiplication, and class-C power amplifier. The low-VDD receiver introduces a replica super-regenerative receiver as a method to reject common-mode noise sources, such as supply/substrate coupling, thereby reducing undesired self-oscillations and improving BER. Designed in a 90-nm CMOS process, the test-chip measurements show a sensitivity of -80 dBm at 500 kb/s and -65 dBm at 1 Mb/s, respectively, at a BER less than 10-3, with 340 MUW total power. PMID- 24473549 TI - Virtually transparent epidermal imagery (VTEI): on new approaches to in vivo wireless high-definition video and image processing. AB - This work first overviews a novel design, and prototype implementation, of a virtually transparent epidermal imagery (VTEI) system for laparo-endoscopic single-site (LESS) surgery. The system uses a network of multiple, micro-cameras and multiview mosaicking to obtain a panoramic view of the surgery area. The prototype VTEI system also projects the generated panoramic view on the abdomen area to create a transparent display effect that mimics equivalent, but higher risk, open-cavity surgeries. The specific research focus of this paper is on two important aspects of a VTEI system: 1) in vivo wireless high-definition (HD) video transmission and 2) multi-image processing-both of which play key roles in next-generation systems. For transmission and reception, this paper proposes a theoretical wireless communication scheme for high-definition video in situations that require extremely small-footprint image sensors and in zero-latency applications. In such situations the typical optimized metrics in communication schemes, such as power and data rate, are far less important than latency and hardware footprint that absolutely preclude their use if not satisfied. This work proposes the use of a novel Frequency-Modulated Voltage-Division Multiplexing (FM VDM) scheme where sensor data is kept analog and transmitted via "voltage multiplexed" signals that are also frequency-modulated. Once images are received, a novel Homographic Image Mosaicking and Morphing (HIMM) algorithm is proposed to stitch images from respective cameras, that also compensates for irregular surfaces in real-time, into a single cohesive view of the surgical area. In VTEI, this view is then visible to the surgeon directly on the patient to give an "open cavity" feel to laparoscopic procedures. PMID- 24473550 TI - Leveraging knowledge from physiological data: on-body heat stress risk prediction with sensor networks. AB - The paper demonstrates that wearable sensor systems, coupled with real-time on body processing and actuation, can enhance safety for wearers of heavy protective equipment who are subjected to harsh thermal environments by reducing risk of Uncompensable Heat Stress (UHS). The work focuses on Explosive Ordnance Disposal operatives and shows that predictions of UHS risk can be performed in real-time with sufficient accuracy for real-world use. Furthermore, it is shown that the required sensory input for such algorithms can be obtained with wearable, non intrusive sensors. Two algorithms, one based on Bayesian nets and another on decision trees, are presented for determining the heat stress risk, considering the mean skin temperature prediction as a proxy. The algorithms are trained on empirical data and have accuracies of 92.1+/-2.9% and 94.4+/-2.1%, respectively when tested using leave-one-subject-out cross-validation. In applications such as Explosive Ordnance Disposal operative monitoring, such prediction algorithms can enable autonomous actuation of cooling systems and haptic alerts to minimize casualties. PMID- 24473551 TI - MedMon: securing medical devices through wireless monitoring and anomaly detection. AB - Rapid advances in personal healthcare systems based on implantable and wearable medical devices promise to greatly improve the quality of diagnosis and treatment for a range of medical conditions. However, the increasing programmability and wireless connectivity of medical devices also open up opportunities for malicious attackers. Unfortunately, implantable/wearable medical devices come with extreme size and power constraints, and unique usage models, making it infeasible to simply borrow conventional security solutions such as cryptography. We propose a general framework for securing medical devices based on wireless channel monitoring and anomaly detection. Our proposal is based on a medical security monitor (MedMon) that snoops on all the radio-frequency wireless communications to/from medical devices and uses multi-layered anomaly detection to identify potentially malicious transactions. Upon detection of a malicious transaction, MedMon takes appropriate response actions, which could range from passive (notifying the user) to active (jamming the packets so that they do not reach the medical device). A key benefit of MedMon is that it is applicable to existing medical devices that are in use by patients, with no hardware or software modifications to them. Consequently, it also leads to zero power overheads on these devices. We demonstrate the feasibility of our proposal by developing a prototype implementation for an insulin delivery system using off-the-shelf components (USRP software-defined radio). We evaluate its effectiveness under several attack scenarios. Our results show that MedMon can detect virtually all naive attacks and a large fraction of more sophisticated attacks, suggesting that it is an effective approach to enhancing the security of medical devices. PMID- 24473552 TI - A recurrent parameter model to characterize the high-frequency range of respiratory impedance in healthy subjects. AB - In this work, a re-visited model of the respiratory system is proposed. Identification of a recurrent electrical ladder network model of the lungs, which incorporates their specific morphology and anatomical structure, is performed on 31 healthy subjects. The data for identification has been gathered using the forced oscillation lung function test, which delivers a non-parametric model of the impedance. On the measured frequency response, the ladder network parameters have been identified and a fractional order has been calculated from the recurrent ratios of the respiratory mechanics (resistance and compliance). The paper includes also a comparison of our recurrent parameter model with another parametric model for high frequency range. The results suggest that the two models can equally well characterize the respiratory impedance over a long range of frequencies. Additionally, we have shown that the fractional order resulting from the recurrent properties of resistance and compliance in the ladder network model is independent of frequency and is not biased by the nose clip wore by the patients during measurements. An illustrative example shows that our re-visited model is sensitive to changes in respiratory mechanics and the fractional order value is a reliable parameter to capture these changes. PMID- 24473553 TI - Treatment of AO/OTA 31-A3 intertrochanteric femoral fractures with a percutaneous compression plate. AB - OBJECTIVE: AO/OTA 31-A3 intertrochanteric femoral fractures have completely different fracture line directions and biomechanical characteristics compared with other types of intertrochanteric fractures. The choice of the fixation method has been a focus of dispute among orthopedic trauma surgeons. The purpose of this study was to review the outcomes of these fractures treated with a percutaneous compression plate at our institute. METHOD: Seventeen patients with AO/OTA 31-A3 intertrochanteric femoral fractures were treated with a percutaneous compression plate at our institute from January 2010 to December 2011. The clinical data and imaging results were retrospectively analyzed. RESULTS: The medical complication of popliteal vein thrombosis occurred in one patient. Sixteen patients were followed up for 12 to 21 months. Two patients had malunion and mild pain. Fracture collapse occurred in two patients, with one having head penetration. These two patients had moderate pain. There were no occurrences of nonunion or reoperation. The mean Harris hip score obtained during the last follow-up was 84.1 (61-97). Patients with a poor quality of reduction were more likely to have pain results (p = 0.001). A trend existed toward the presence of a poor quality of reduction (p = 0.05) in patients with a collapse of fracture. Patients with poor preoperative mobility were more likely to have a lower Harris hip score (p = 0.000). CONCLUSION: The percutaneous compression plate is an alternative device for the treatment of AO/OTA 31-A3 intertrochanteric femoral fractures. Good fracture reduction and an ideal placement position of the neck screw are important in the success of the device. PMID- 24473554 TI - Clinical dysphagia risk predictors after prolonged orotracheal intubation. AB - OBJECTIVES: To elucidate independent risk factors for dysphagia after prolonged orotracheal intubation. METHODS: The participants were 148 consecutive patients who underwent clinical bedside swallowing assessments from September 2009 to September 2011. All patients had received prolonged orotracheal intubations and were admitted to one of several intensive care units of a large Brazilian school hospital. The correlations between the conducted water swallow test results and dysphagia risk levels were analyzed for statistical significance. RESULTS: Of the 148 patients included in the study, 91 were male and 57 were female (mean age, 53.64 years). The univariate analysis results indicated that specific variables, including extraoral loss, multiple swallows, cervical auscultation, vocal quality, cough, choking, and other signs, were possible significant high-risk indicators of dysphagia onset. The multivariate analysis results indicated that cervical auscultation and coughing were independent predictive variables for high dysphagia risk. CONCLUSIONS: Patients displaying extraoral loss, multiple swallows, cervical auscultation, vocal quality, cough, choking and other signs should benefit from early swallowing evaluations. Additionally, early post extubation dysfunction recognition is paramount in reducing the morbidity rate in this high-risk population. PMID- 24473555 TI - PITX2C loss-of-function mutations responsible for idiopathic atrial fibrillation. AB - OBJECTIVE: This study aimed to identify novel PITX2c mutations responsible for idiopathic atrial fibrillation. METHODS: A cohort of 210 unrelated patients with idiopathic atrial fibrillation and 200 unrelated, ethnically matched healthy individuals used as controls were recruited. The whole coding exons and splice junctions of the PITX2c gene, which encodes a paired-like homeobox transcription factor required for normal cardiovascular morphogenesis, were sequenced in 210 patients and 200 control subjects. The causative potentials of the identified mutations were automatically predicted by MutationTaster and PolyPhen-2. The functional characteristics of the PITX2c mutations were explored using a dual luciferase reporter assay system. RESULTS: Two novel heterozygous PITX2c mutations (p.Q105L and p.R122C) were identified in 2 of the 210 unrelated patients with idiopathic atrial fibrillation. These missense mutations were absent in the 400 control chromosomes and were both predicted to be pathogenic. Multiple alignments of PITX2c protein sequences across various species showed that the altered amino acids were highly evolutionarily conserved. A functional analysis demonstrated that the mutant PITX2c proteins were both associated with significantly reduced transcriptional activity compared with their wild-type counterparts. CONCLUSION: The findings of this study associate PITX2c loss-of function mutations with atrial fibrillation, supporting the hypothesis that dysfunctional PITX2c confers enhanced susceptibility to atrial fibrillation and suggesting potential implications for early prophylaxis and allele-specific therapy for this common arrhythmia. PMID- 24473556 TI - Comparison of the TruView infant EVO2 PCDTM and C-MAC video laryngoscopes with direct Macintosh laryngoscopy for routine tracheal intubation in infants with normal airways. AB - OBJECTIVE: Videolaryngoscopy has mainly been developed to facilitate difficult airway intubation. However, there is a lack of studies demonstrating this method's efficacy in pediatric patients. The aim of the present study was to compare the TruView infant EVO2 and the C-MAC videolaryngoscope with conventional direct Macintosh laryngoscopy in children with a bodyweight <=10 kg in terms of intubation conditions and the time to intubation. METHODS: In total, 65 children with a bodyweight <=10 kg (0-22 months) who had undergone elective surgery requiring endotracheal intubation were retrospectively analyzed. Our database was screened for intubations with the TruView infant EVO2, the C-MAC videolaryngoscope, and conventional direct Macintosh laryngoscopy. The intubation conditions, the time to intubation, and the oxygen saturation before and after intubation were monitored, and demographic data were recorded. Only children with a bodyweight <=10 kg were included in the analysis. RESULTS: A total of 23 children were intubated using the C-MAC videolaryngoscope, and 22 children were intubated using the TruView EVO2. Additionally, 20 children were intubated using a standard Macintosh blade. The time required for tracheal intubation was significantly longer using the TruView EVO2 (52 sec vs. 28 sec for C-MAC vs. 26 sec for direct LG). However, no significant difference in oxygen saturation was found after intubation. CONCLUSION: All devices allowed excellent visualization of the vocal cords, but the time to intubation was prolonged when the TruView EVO2 was used. The absence of a decline in oxygen saturation may be due to apneic oxygenation via the TruView scope and may provide a margin of safety. In sum, the use of the TruView by a well-trained anesthetist may be an alternative for difficult airway management in pediatric patients. PMID- 24473557 TI - The thickness of posterior cortical areas is related to executive dysfunction in Alzheimer's disease. AB - OBJECTIVE: To establish whether alterations of brain structures in Alzheimer's disease are associated with executive dysfunction. METHODS: Nineteen patients with Alzheimer's disease and 22 older control subjects underwent a comprehensive evaluation. The clock drawing test, digit span test, executive motor function test, Behavioral Assessment of the Dysexecutive Syndrome battery (Rule Shift Cards test), and Stroop test were used to evaluate executive dysfunction. A multiparametric approach using the FreeSurfer image analysis suite provided a description of volumetric and geometric features of the gray matter structures. RESULTS: The cortical thickness maps showed a negative correlation between the Behavioral Assessment of the Dysexecutive Syndrome battery (Rule Shift Cards test) and the right middle frontal gyrus; a positive correlation between the executive motor function test and the left superior parietal gyrus, left middle temporal gyrus, bilateral supramarginal gyri, right middle frontal gyrus, and right precuneus; a negative correlation between the Stroop test (part III) and the right superior parietal gyrus; and a negative correlation between the Stroop test (part III) and the right middle temporal gyrus. CONCLUSION: Executive dysfunction in Alzheimer's disease is correlated with alterations not only in the frontal areas but also within many temporal and parietal regions. PMID- 24473558 TI - Sex differences in 24-hour ultra-marathon performance--a retrospective data analysis from 1977 to 2012. AB - OBJECTIVES: This study examined the changes in running performance and the sex differences between women and men in 24-hour ultra-marathons held worldwide from 1977 to 2012. METHOD: Changes in running speed and ages of the fastest 24-hour ultra-marathoners were determined using single- and multi-level regression analyses. RESULTS: From 1977 to 2012, the sex differences in 24-hour ultra marathon performance were 4.6+/-0.5% for all women and men, 13.3% for the annual fastest finishers, 12.9+/-0.8% for the top 10 and 12.2+/-0.4% for the top 100 finishers. Over time, the sex differences decreased for the annual fastest finishers to 17%, for the annual 10 fastest finishers to 11.3+/-2.2% and for the annual 100 fastest finishers to 14.2+/-1.8%. For the annual fastest men, the age of peak running speed increased from 23 years (1977) to 53 years (2012). For the annual 10 and 100 fastest men, the ages of peak running speed were unchanged at 40.9+/-2.5 and 44.4+/-1.1 years, respectively. For women, the ages of the annual fastest, the annual 10 fastest and the annual 100 fastest remained unchanged at 43.0+/-6.1, 43.2+/-2.6 and 43.8+/-0.8 years, respectively. CONCLUSION: The gap between the annual top, annual top 10 and annual top 100 female and male 24-hour ultra-marathoners decreased over the last 35 years; however, it seems unlikely that women will outrun men in 24-hour ultra-marathons in the near future. The fastest 24-hour ultra-marathoners worldwide achieved their peak performance at the age of master athletes (>35 years). PMID- 24473559 TI - Angiotensin II type 1 and 2 receptors and lymphatic vessels modulate lung remodeling and fibrosis in systemic sclerosis and idiopathic pulmonary fibrosis. AB - OBJECTIVE: To validate the importance of the angiotensin II receptor isotypes and the lymphatic vessels in systemic sclerosis and idiopathic pulmonary fibrosis. METHODS: We examined angiotensin II type 1 and 2 receptors and lymphatic vessels in the pulmonary tissues obtained from open lung biopsies of 30 patients with systemic sclerosis and 28 patients with idiopathic pulmonary fibrosis. Their histologic patterns included cellular and fibrotic non-specific interstitial pneumonia for systemic sclerosis and usual interstitial pneumonia for idiopathic pulmonary fibrosis. We used immunohistochemistry and histomorphometry to evaluate the number of cells in the alveolar septae and the vessels stained by these markers. Survival curves were also used. RESULTS: We found a significantly increased percentage of septal and vessel cells immunostained for the angiotensin type 1 and 2 receptors in the systemic sclerosis and idiopathic pulmonary fibrosis patients compared with the controls. A similar percentage of angiotensin 2 receptor positive vessel cells was observed in fibrotic non-specific interstitial pneumonia and usual interstitial pneumonia. A significantly increased percentage of lymphatic vessels was present in the usual interstitial pneumonia group compared with the non-specific interstitial pneumonia and control groups. A Cox regression analysis showed a high risk of death for the patients with usual interstitial pneumonia and a high percentage of vessel cells immunostained for the angiotensin 2 receptor in the lymphatic vessels. CONCLUSION: We concluded that angiotensin II receptor expression in the lung parenchyma can potentially control organ remodeling and fibrosis, which suggests that strategies aimed at preventing high angiotensin 2 receptor expression may be used as potential therapeutic target in patients with pulmonary systemic sclerosis and idiopathic pulmonary fibrosis. PMID- 24473560 TI - Risk factors associated with death in Brazilian children with severe dengue: a case-control study. AB - OBJECTIVE: The purpose of this case-control study was to evaluate risk factors associated with death in children with severe dengue. METHODS: The clinical condition of hospitalized patients with severe dengue who died (cases, n = 18) was compared with that of hospitalized patients with severe dengue who survived (controls, n = 77). The inclusion criteria for this study were age under 13 years; hospital admission in Sao Luis, northeastern Brazil; and laboratory confirmed diagnosis of dengue. RESULTS: Severe bleeding (hemoptysis), a defining criterion for dengue severity, was the factor most strongly associated with death in our study. We also found that epistaxis and persistent vomiting, both included as warning signs in the World Health Organization (WHO) classification of dengue, were strongly associated with death. No significant association was observed between any of the laboratory findings and death. CONCLUSIONS: The finding that epistaxis and persistent vomiting were also associated with death in children with severe dengue was unexpected and deserves to be explored in future studies. Because intensive care units are often limited in resource-poor settings, any information that can help to distinguish patients with severe dengue with a higher risk to progress to death may be crucial. PMID- 24473561 TI - Mibefradil reduces blood glucose concentration in db/db mice. AB - OBJECTIVE: Numerous recent studies suggest that abnormal intracellular calcium concentration ([Ca2+]i) is a common defect in diabetic animal models and patients. Abnormal calcium handling is an important mechanism in the defective pancreatic beta-cell function in type 2 diabetes. T-type Ca2+ channel antagonists lower blood glucose in type 2 diabetes, but the mechanism remains unknown. METHODS: We examined the effect of the Ca2+ channel antagonist mibefradil on blood glucose in male db/db mice and phenotypically normal heterozygous mice by intraperitoneal injection. RESULTS: Mibefradil (15 mg/kg, i.p., b.i.d.) caused a profound reduction of fasting blood glucose from 430.92+/-20.46 mg/dl to 285.20+/ 5.74 mg/dl in three days. The hypoglycemic effect of mibefradil was reproduced by NNC 55-0396, a compound structurally similar to mibefradil but more selective for T-type Ca2+ channels, but not by the specific L-type Ca2+ channel blocker nicardipine. Mibefradil did not show such hypoglycemic effects in heterozygous animals. In addition, triglycerides, basal insulin and food intake were significantly decreased by mibefradil treatment in the db/db mice but not in the controls. Western blot analysis, immunohistochemistry and immunofluorescence staining showed a significantly increased expression of T-type Ca2+ channel alpha subunits Cav3.1 and Cav3.2 in liver and brain tissues from db/db mice compared to those from heterozygous animals. CONCLUSIONS: Collectively, these results suggest that T-type Ca2+ channels are potential therapeutic targets for antidiabetic drugs. PMID- 24473564 TI - How do we think? Can we learn to think better? PMID- 24473565 TI - The Innovation Forager: stimulating academic innovation. PMID- 24473562 TI - Upregulation of SOCS-1 by Nutlin-3 in acute myeloid leukemia cells but not in primary normal cells. AB - OBJECTIVE: It has been shown that SOCS-1 plays an important role in the proper control of cytokine/growth factor responses and acts as a tumor suppressor in acute myeloid leukemias. Therefore, the objective of the present study was to evaluate the in vitro effect of treatment with Nutlin-3, a small molecule inhibitor of the MDM2/p53 interaction, on the expression of the suppressor of cytokine signaling 1 in primary acute myeloid leukemia cells and in myeloid cell lines with differential p53 status. METHOD: The expression of the suppressor of cytokine signaling 1 was quantitatively analyzed by real-time PCR in myeloid p53wild-type (OCI and MOLM) and p53null HL-60, leukemic cell lines, in patient derived acute myeloid leukemia blasts, and in primary normal cell types, such as macrophages, endothelial cells, and bone marrow mesenchymal stem cells. The p53 dependence of the suppressor of cytokine signaling 1 upregulation that is induced by Nutlin-3 was analyzed in experiments performed using siRNA for p53, while the functional upregulation of the suppressor of cytokine signaling 1 was analyzed by assessing the levels of phosphorylated STAT-3. RESULTS: Nutlin-3 significantly upregulated the transcription of the suppressor of cytokine signaling 1 in p53wild-type OCI and MOLM but not in p53deleted p53null HL60, myeloid leukemic cell lines, as well as in primary acute myeloid leukemia blasts. Conversely, and somewhat unexpectedly, Nutlin-3 did not modulate the suppressor of cytokine signaling 1 expression in primary normal macrophages, endothelial cells, and bone marrow mesenchymal stem cells. The p53-dependent upregulation of the suppressor of cytokine signaling 1 by Nutlin-3 was associated with the downregulation of phosphorylated STAT-3, a major molecular target of the suppressor of cytokine signaling 1. CONCLUSION: Overall, our data suggest a potential role for the suppressor of cytokine signaling 1 as a therapeutic target of Nutlin-3 in p53 wild-type acute myeloid leukemias. PMID- 24473566 TI - Medical school pedagogy should be culture-dependent. PMID- 24473567 TI - Tools to improve long-term retention of preclinical knowledge. PMID- 24473568 TI - In reply to Deng and Gluckstein. PMID- 24473569 TI - Advocacy training: blending classroom with experience. PMID- 24473570 TI - Running on the road to reflection. PMID- 24473571 TI - Artist's statement: Wait and See. PMID- 24473572 TI - Medicine and the arts. Beginnings: a movie by writer/director Mike Mills and released by Focus Films. Commentary. PMID- 24473574 TI - Double vision. PMID- 24473575 TI - AM last page: Health insurance expansion impact on patients, states, and providers. PMID- 24473576 TI - A graphene oxide and exonuclease-aided amplification immuno-sensor for antigen detection. AB - We have developed a novel immuno-sensor applied to protein detection based on exonuclease III (Exo III)-induced signal amplification, multiplex binding of the biotin-streptavidin system and the fluorescence quenching ability of graphene oxide. PMID- 24473577 TI - Reliability of isometric trunk moment measurements in healthy persons over 50 years of age. AB - OBJECTIVE: To determine the short- and long-term test-retest reliability of maximum isometric trunk moment measurements in healthy volunteers over 50 years of age, to compare these results with those from volunteers younger than 50 years, and to test whether volunteers' anticipatory emotional state affects the precision of these measurements. METHODS: Forty-two older persons (21 females; age range 50-90 years) and 44 younger persons (19 females; age range 18-49 years) performed maximum isometric trunk extensions, flexions, and rotations using dynamometers (DAVID, Fi, David Health Solutions Ltd, Helsinki, Finland). They repeated the tests after 1-2 days (short-term) and at 6 weeks (long-term). Retest reliability was evaluated for age- and gender-specific subgroups, with assessment of intraclass correlation coefficient (ICC2,1) , standard error of measurement, smallest real difference, and smallest real difference, in percent. RESULTS: For the elderly group, smallest real difference, in percent values varied up to 33% and were similar to those obtained from young volunteers. Precision of the trunk rotation tests was lower than that of trunk flexion or extension. Retest agreement exceeded 0.75 (ICC2,1) for all tests, with no relevant differences observed between gender- and age-specific subgroups. Neither participants' motivation nor their anticipatory emotions correlated with the individual coefficients of variation of the trunk muscle moment measurements. CONCLUSION: Isometric maximum trunk extension and flexion moment measurements taken from healthy persons > 50 years old are as reliable as those from persons < 50 years old, and can be expected to enable an acceptable level of detection of expected changes in muscle strength parameters as a result of planned exercise interventions. PMID- 24473578 TI - Photoresponsive porous materials: the design and synthesis of photochromic diarylethene-based linkers and a metal-organic framework. AB - The synthesis and characterization of novel photochromic diarylethene-based linkers for use in metal-organic frameworks is described including crystal structure analysis of nearly all reaction intermediates. The bis-carboxylated dithien-3-ylphenanthrenes can be prepared under relatively mild conditions in high yield and were subsequently used to create a photoresponsive metal-organic framework, UBMOF-1. While the photochromism of the ligand TPDC in solution is fully reversible, the cycloreversion reaction is suppressed when this linker is incorporated into the crystalline framework of UBMOF-1. PMID- 24473580 TI - A selection of research dissemination reports. PMID- 24473579 TI - Consolidation of the genetic and cytogenetic maps of turbot (Scophthalmus maximus) using FISH with BAC clones. AB - Bacterial artificial chromosomes (BAC) have been widely used for fluorescence in situ hybridization (FISH) mapping of chromosome landmarks in different organisms, including a few in teleosts. In this study, we used BAC-FISH to consolidate the previous genetic and cytogenetic maps of the turbot (Scophthalmus maximus), a commercially important pleuronectiform. The maps consisted of 24 linkage groups (LGs) but only 22 chromosomes. All turbot LGs were assigned to specific chromosomes using BAC probes obtained from a turbot 5* genomic BAC library. It consisted of 46,080 clones with inserts of at least 100 kb and <5 % empty vectors. These BAC probes contained gene-derived or anonymous markers, most of them linked to quantitative trait loci (QTL) related to productive traits. BAC clones were mapped by FISH to unique marker-specific chromosomal positions, which showed a notable concordance with previous genetic mapping data. The two metacentric pairs were cytogenetically assigned to LG2 and LG16, and the nucleolar organizer region (NOR)-bearing pair was assigned to LG15. Double-color FISH assays enabled the consolidation of the turbot genetic map into 22 linkage groups by merging LG8 with LG18 and LG21 with LG24. In this work, a first generation probe panel of BAC clones anchored to the turbot linkage and cytogenetical map was developed. It is a useful tool for chromosome traceability in turbot, but also relevant in the context of pleuronectiform karyotypes, which often show small hardly identifiable chromosomes. This panel will also be valuable for further integrative genomics of turbot within Pleuronectiformes and teleosts, especially for fine QTL mapping for aquaculture traits, comparative genomics, and whole-genome assembly. PMID- 24473581 TI - Stages of change, self-stigma, and treatment compliance among Chinese adults with severe mental illness. AB - 1. Individuals with higher global functioning, better readiness for action, and lower self-esteem decrement tend to have better psychosocial treatment participation. 2. Individuals with lesser psychiatric symptoms are more likely to have better treatment attendance. 3. Self-stigmatisation undermines treatment compliance. Its indirect effects can be mediated via stages of change and insight. 4. The self-stigma reduction programme may reduce self-esteem decrement, promote readiness for changing own problematic behaviours, and enhance psychosocial treatment compliance. However, its therapeutic effects were not maintained during the 6-month follow-up. PMID- 24473582 TI - Pathological Internet use and associated factors among university students in Hong Kong. AB - 1. Among university entrants, the prevalence of pathological Internet use (PIU) increased more than three-fold (from 5.0 to 15.7%) after 18 months of university life. Psycho-social factors such as depression, life dissatisfaction, and use of the Internet for recreational purposes were associated with the development of PIU. 2. University health workers should be aware that PIU is associated with inferior mental well-being, increased sleeping disorders, and deterioration of family relationships. Special attention should be given to Mainland Chinese students and those with pre-existing psychological problems, as they are more prone to developing PIU. 3. Most university students with PIU were unaware of the health implications of the condition and thus not motivated to seek help. Health workers must take a pro-active approach. PMID- 24473583 TI - Use of electroacupuncture to accelerate the antidepressant action of selective serotonin reuptake inhibitors: a single-blind, randomised, controlled study. AB - 1. Patients treated with dense cranial electroacupuncture stimulation (DCEAS) had a significantly greater reduction in the 17-item Hamilton Rating Scale for Depression scores and clinically significant response to treatment than those having sham acupuncture (19.4% vs.8.8%). 2. Neither sham acupuncture nor DCEAS had effects on the platelet serotonin system. 3. In the early phase of selective serotonin reuptake inhibitor treatment for depressed patients, DCEAS could be used as an additional therapy. 4. Neurobiological mechanisms responsible for DCEAS effects warrant further investigation using neuroimaging. PMID- 24473584 TI - Assessing mental capacity for everyday decision-making in the Chinese older population. AB - 1. The abilities to make everyday decisions may be reliably measured in the local elderly population. 2. The Chinese version of the Assessment of Capacity for Everyday Decision-Making is a reliable tool to assess these abilities. 3. Significant proportion of participants with mild dementia was mentally incapable in making decisions on everyday tasks. Global cognitive functioning appeared to be an important prerequisite for intact mental capacity. PMID- 24473585 TI - Spirometric reference standards for preschool children in Hong Kong. AB - 1. Prediction equations and normograms are established using incentive spirometry in a community cohort of 770 Hong Kong Chinese children aged 2 to 6 years. 2. All spirometric parameters depend mainly on standing height. Boys have higher values than girls. 3. Forced expiratory volumes depend on birth weight, place of birth, history of wheezing, and environmental tobacco smoke (ETS) exposure. 4. High urinary cotinine level as a biomarker of ETS exposure is noted in about one tenth of the children. 5. Urinary cotinine level is inversely associated with all spirometric parameters. This supports implementation of the smoking cessation programme. PMID- 24473586 TI - Anthropometric and physiological measurements in healthy children. AB - 1. Normal ranges for ultrasonic cardiac output monitor-derived cardiovascular indices are derived for Chinese children aged 1 to 12 years in Hong Kong. 2. A simple formula for calculating stroke volume is constructed, but the error varies from 8 to 40%. 3. Stroke volume index and, to a lesser extent, the cardiac index generally increase from ages 1 to 5 years, but plateau or fall slightly thereafter. PMID- 24473587 TI - Are the 2006 World Health Organization standards for infant growth applicable to Hong Kong Chinese? Universalistic standards or epidemiological transition stage specific norms. AB - 1. Parental socio-economic status was positively associated with length and body mass index of Hong Kong Chinese infants at 9 months. 2. Maternal smoking in pregnancy was negatively associated with infant length at 9 months. 3. Some of the World Health Organization (WHO) criteria for an optimal nurturing environment contributed positively to growth. At 36 months, Hong Kong Chinese infants were generally shorter and fatter than the WHO growth references. PMID- 24473588 TI - Electroacupuncture for ileus after laparoscopic colorectal surgery: a randomised sham-controlled study. AB - 1. Electroacupuncture at acupoints of Zusanli, Sanyinjiao, Hegu, and Zhigou is more effective than no acupuncture and sham acupuncture in stimulating early return of bowel function and reducing analgesic requirement after laparoscopic colorectal surgery. 2. Electroacupuncture is more effective than no acupuncture in reducing the duration of hospital stay. 3. Receipt of electroacupuncture is an independent predictor of shorter duration of ileus and hospital stay after laparoscopic colorectal surgery. PMID- 24473589 TI - Long-term efficacy of electroacupuncture for chronic neck pain: a randomised controlled trial. AB - Electroacupuncture is a safe treatment for chronic neck pain. Nonetheless, one month after treatment, improvement of neck pain is similar to that in placebo treated controls. This suggests that the efficacy may not be due to specific effect of the treatment procedure. PMID- 24473590 TI - Rapid and specific determination of DNA adducts for clinical diagnosis of poisoning and disease associated with aristolochic acid. AB - 1. A liquid chromatography-mass spectrometry method was developed to detect and characterise aristocholic acid-DNA adducts in biological samples. 2. The detection of DNA adducts in plasma, urine or the cells found in urine may be useful to support the diagnosis and monitoring of aristocholic acid-associated poisoning and disease. 3. Efforts should be made to improve the sensitivity and specificity of this approach for the detection and characterisation of exposure to other mutagens/carcinogens. PMID- 24473591 TI - Chinese herbal medicine for functional constipation: a randomised controlled trial. AB - 1. This was an 18-week prospective, randomised, double-blind, placebo-controlled clinical study on a Chinese herbal medicine--ma zi ren wan (MZRW)--for the treatment of functional constipation. 2. 120 subjects with functional constipation (Rome III criteria) were randomised (60 per arm) into the MZRW and placebo groups. Respective responder rates for the two groups were 43.3% and 8.3% during treatment, and 30.0% and 15.0% in the follow-up period (p<0.05). The MZRW group was superior to the placebo group in terms of increased complete spontaneous bowel movement as well as reduction in severity of constipation, straining at evacuation, and use of rescue therapy. No serious adverse effects were reported. 3. The dose of MZRW (7.5 g bid) was determined in a separate clinical trial. This study entailed a dose determination study and then a placebo controlled clinical trial and can be a good reference for future studies. PMID- 24473592 TI - Effects of child development accounts on early social-emotional development: an experimental test. AB - IMPORTANCE: This study, based on Oklahoma's statewide Child Development Accounts (CDAs) program, presents findings from the first experimental test of the hypothesis that creating lifelong savings accounts for children at birth promotes their long-term well-being. OBJECTIVE: To examine the effects of CDAs, an innovative social policy to encourage lifelong saving and asset building for long term development, on parent-reported social-emotional development in early childhood. DESIGN, SETTING, AND PARTICIPANTS: A statewide randomized experiment of CDAs was conducted in 2008, drawing a probability sample of 7328 children from all infants born in two 3-month periods in Oklahoma (April 1 through June 30 and August 1 through October 31, 2007). After agreeing to participate in the experiment, caregivers of 2704 infants completed a baseline survey and were randomly assigned to treatment (n = 1358) and control groups (n = 1346). Approximately 84% of participants completed a follow-up survey in the spring of 2011. INTERVENTIONS: The intervention offered CDAs, built on the existing Oklahoma 529 college-savings plan, to treatment participants. It also provided additional financial incentives and information. MAIN OUTCOMES AND MEASURES: The primary outcome-child social-emotional development-is measured by scores from a 17-item version of the Ages and Stages Questionnaire: Social-Emotional. Caregivers completed it in the 3-year follow-up survey. Lower scores indicate better functioning. RESULTS: The CDAs have positive effects on social-emotional development for children at approximately age 4 years. The nonweighted treatment control difference is -1.56 (90% CI, -2.87 to -0.22; P = .06), but the weighted difference is nonsignificant. The effects appear to be greater for disadvantaged subsamples, such as low-income households (weighted mean difference, -2.21; 90% CI, -4.01 to -0.42; P = .04). CONCLUSIONS AND RELEVANCE: As a complement to other early education and health interventions, CDAs may improve social-emotional development in early childhood. Their effects may be explained as a mediating process that influences parents. Child Development Accounts may influence parental attitudes, behaviors, expectations, and involvement; in turn, these may affect child development. PMID- 24473593 TI - Serco penalised by L81,000 a month over failings in Suffolk contract. PMID- 24473594 TI - Research highlights: microfluidics meets big data. AB - In this issue we highlight a collection of recent work in which microfluidic parallelization and automation have been employed to address the increasing need for large amounts of quantitative data concerning cellular function--from correlating microRNA levels to protein expression, increasing the throughput and reducing the noise when studying protein dynamics in single-cells, and understanding how signal dynamics encodes information. The painstaking dissection of cellular pathways one protein at a time appears to be coming to an end, leading to more rapid discoveries which will inevitably translate to better cellular control--in producing useful gene products and treating disease at the individual cell level. From these studies it is also clear that development of large scale mutant or fusion libraries, automation of microscopy, image analysis, and data extraction will be key components as microfluidics contributes its strengths to aid systems biology moving forward. PMID- 24473595 TI - Using multi-level data to estimate the effect of social capital on hazardous alcohol consumption in the former Soviet Union. AB - BACKGROUND: Hazardous alcohol consumption is a leading cause of mortality in the former Soviet Union (fSU), but little is known about the social factors associated with this behaviour. We set out to estimate the association between individual- and community-level social capital and hazardous alcohol consumption in the fSU. METHODS: Data were obtained from Health in Times of Transition 2010, a household survey of nine fSU countries (n = 18 000 within 2027 communities). Individual-level indicators of social isolation, civic participation, help in a crisis and interpersonal trust were aggregated to the community level. Adjusting for demographic factors, the association of individual- and community-level indicators with problem drinking (CAGE) and episodic heavy drinking was estimated using a population average model for the analysis of multi-level data. RESULTS: Among men, individual social isolation [odds ratio (OR) = 1.20], community social isolation (OR = 1.18) and community civic participation (OR = 4.08) were associated with increased odds of CAGE. Community civic participation (OR = 2.91) increased the odds of episodic heavy drinking, while community interpersonal trust (OR = 0.89) decreased these odds. Among women, individual social isolation (OR = 1.30) and community civic participation (OR = 2.94) increased odds of CAGE. CONCLUSION: Our results provide evidence of the role of some elements of social capital in problem drinking in the fSU, and highlight the importance of community effects. The nature of civic organizations in the fSU, and the communities in which civic participation is high, should be further investigated to inform alcohol policy in the region. PMID- 24473596 TI - Career satisfaction and burnout among Ghanaian physicians. AB - BACKGROUND: Thus far, there has been limited inquiry into the factors associated with physician career satisfaction and burnout in Ghana, although the two have been linked to the brain drain problem. The objective of this study was to assess career satisfaction and burnout among physicians practicing in a developing nation, Ghana. METHODS: A 21-item instrument was used to assess career satisfaction among actively practicing Ghanaian physicians, using items adapted from the Physician Worklife Study survey. Burnout was assessed using the Abbreviated Maslach's Burnout Inventory. Two hundred physicians participated in the online survey from December 2012 to February 2013. RESULTS: Generally, physicians in Ghana expressed moderate overall career satisfaction. However, they were least satisfied with the availability of resources, their compensation and work-life balance. Overall, burnout was low in the study population; however physicians exhibited moderate levels of emotional exhaustion. Career satisfaction was negatively associated with the burnout dimensions of depersonalization, emotional exhaustion and low personal accomplishment. CONCLUSIONS: Health policy makers in Ghana should address issues relating to resource adequacy, compensation and the work-life balance of physicians in order to improve the overall career satisfaction of an already dwindling physician workforce. PMID- 24473597 TI - Chronic Non-Communicable Diseases, a major challenge facing contemporary society. PMID- 24473598 TI - Alcohol consumption among adolescents: attitudes, behaviors and associated factors. AB - The scope of this paper is to assess the attitudes and behaviors regarding alcohol use and analyze associated factors among schoolchildren in public schools of Campina Grande in the state of Paraiba. A cross-sectional study was carried out involving 574 adolescents, with the application of a semi-structured questionnaire. The chi-square test and Fisher's exact test were used (5% level of significance). Among the adolescents 54.5% had drunk alcohol and 6.7% of them were heavy drinkers. The majority of them drank alcohol between 11 and 14 years of age (42.8%); 26.3% of the adolescents purchased alcoholic beverages; and beer was the most drink most consumed (43.8%). The risk of alcohol drinking was higher between 16 and 19 years of age (OR = 4.44; p < 0.001), among those without religious affiliation (OR = 4.36; p = 0.002), among those who worked (OR = 2.13; p = 0.012) and among those who had a fair to poor relationship with their father (OR = 2.18; p = 0.010). The results of this study underscore the complexity of this issue and the need to pay particular attention to the adolescent population. Public policies alone are not sufficient. Support from family, school and society is essential to curtail early alcohol use and its consequences. PMID- 24473599 TI - [Patterns of alcohol consumption among users of primary health care services in a Brazilian city]. AB - The scope of this paper was to identify alcohol consumption patterns among users of primary health care services in the city of Bebedouro in the state of Sao Paulo, verifying the association between usage patterns and demographic and behavioral variables of the sample. It is a cross-sectional study involving 755 subjects over 18 years of age who sought primary health care services in the city of Bebedouro. To investigate patterns of alcohol use, the Alcohol Use Disorders Identification Test (AUDIT) was used. For statistical analysis the chi-square and binary logistic regression tests were used. The results showed that 78% of users were abstainers or low risk users, 22% had problems with alcohol, 10% were risk cases, 2% were high-risk users and 10% probable addicts. The greatest predictors of usage risk were males, income > than 6 minimum wages and smokers; for addicts the most important predictors were: males, working in commerce and smokers. A significant proportion of users showed patterns of problematic use of alcohol, which reinforces the need for preventive actions, since the primary health care services are an excellent opportunity to combine opportunities for screening and usage strategies for reducing harmful effects related to the problematic use of alcohol. PMID- 24473600 TI - [Patterns of alcohol consumption and associated factors among adult users of primary health care services of Rio de Janeiro, Brazil]. AB - This study sought to verify the patterns of alcohol consumption and associated factors among adult users of a primary health care service in the city of Rio de Janeiro, Brazil. A household survey with a sample of 301 individuals who responded to a collection instrument containing the Alcohol Use Disorders Identification Test and social, demographic and health variables was conducted. Logistic regression was used to assess the association between the pattern of problematic alcohol consumption and the independent variables. Patterns of problematic alcohol consumption were identified among males, black, unmarried, smokers, with no religious affiliation, and persons without chronic disease attended at the health unit. Health services should therefore be prepared to identify the early stages of problematic alcohol abuse in order to prevent social and health consequences in the population, especially those attended in primary health care, for which the promotion of health and prevention of disease are priority health concerns. PMID- 24473601 TI - [School meals as an area for education in health: the perception of school cooks in the municipality of Rio de Janeiro, Brazil]. AB - By considering the school as an opportune space for health education, school cooks can play an essential role in the debate as they are directly responsible for the preparation of school meals. The main objective of this study is to highlight the potential of the participation of these professionals in educational processes, acknowledging that they are not merely individuals who perform an activity in the kitchen and dining-hall areas. In order to achieve this, a quantitative survey was conducted followed by a descriptive analysis of the data by performing a chi-square test and factor analysis. Some changes in social and economic aspects and in the form of hiring the cooks were identified. However, it was also ascertained that the acknowledgement of this professional as an actor in health education still depends upon a series of transformations in the structure, values and concepts regarding the important role that they perform and the most effective way of incorporating them in the educational environment. PMID- 24473602 TI - [Food and nutrition in the Family Health Strategy in five Brazilian cities]. AB - This work is part of a national study seeking to understand the difficulties and the potential for overcoming the challenges faced in the quest to improve food and nutrition campaigns developed under the aegis of the Family Health Strategy. It is examined from the standpoint of professional teams of the Family Health Strategy and Family Health Support Centers of five major Brazilian cities. A qualitative approach was used to design a multiple case approach and the technique of focus groups was conducted to collect data. The instrument used was a semi-structured pre-tested and validated script with two leading questions. The Collective Subject Discourse technique was used for data analysis, based on which the synthesized discourses were created using the Qualiquantisoft program. Sixty health professionals from various training areas were interviewed, including dietitians, nurses and physicians. The results showed that the difficulties encountered for the provision of food and nutrition campaigns and the lack of professionals in this area have hampered compliance with the principles of comprehensiveness, universality and resolubility of health care. PMID- 24473603 TI - [Anemia among preschool children--a public health problem in Belo Horizonte, Brazil]. AB - This article seeks to establish the prevalence of anemia in children attending in day care centers in the South Central region of Belo Horizonte in the state of Minas Gerais, identifying associated biological, social and economic factors. A cross-sectional descriptive study was conducted in 18 nurseries and 373 children were evaluated based on stratified sampling by the participating institutions. Hemoglobin serum (Hb) levels were determined by lancing and reading on a beta hemoglobinometer, adopting cut-offs for anemia Hb < 11.0 g/dL for children aged between 6 and 60 months and Hb < 11.5 g/dL for those aged above, as recommended by the WHO. The nutritional status was defined by measurement of weight and height for making indexes: Weight/Age (W/A), Height/Age (H/A) and BMI/Age (BMI/A). Among the participants, 54% were girls. The mean age was 38.1 (+/- 6.2) months. The prevalence of global anemia was 38.3%. In the group of the anemics, children = 24 months had a higher prevalence (56.1%). A significant association was found between anemia and the following factors: young age, low maternal age and low income. The study shows that anemia in children enrolled in day care centers is a relevant public health problem, signaling the need to implement specific actions to mitigate the risks highlighted by the research. PMID- 24473604 TI - [Excess weight and food consumption of adolescents in public schools in northern Minas Gerais state, Brazil]. AB - This study sought to identify the prevalence of excess weight and food consumption patterns among adolescents attending public schools in northern Minas Gerais state. A cross-sectional study was conducted with a random and representative sample of adolescents. Demographic and economic data were collected. Food consumption was evaluated by applying a semi-quantitative food questionnaire. Body weight and height were measured to assess the nutritional status based on the Body Mass Index (BMI) by Age. The sexes were compared by Student's t test (comparison of samples) and chi-square test (goodness of fit) at a level of significance of p <0.05. 535 adolescents were evaluated and prevalence of excess weight was detected in 18.5% of the group. BMI (p = 0,001) was statistically different between the sexes and higher for girls. The average energy consumption of the group was 3096.30 kcal/day. Fiber consumption was insufficient in 35% of the adolescents, vitamin A and calcium in 80% and unsaturated fats in 100%. Carbohydrate and cholesterol were consumed in excess by 20.6% and 48%, respectively. The prevalence of excess weight and inadequate food consumption is of great concern for the population studied and requires appropriate nutritional intervention. PMID- 24473605 TI - [Association between waist circumference and body mass index of Brazilian women: NDHS 2006]. AB - The scope of this study was to evaluate the association between waist circumference (WC) and body mass index (BMI) of Brazilian women of childbearing age studied in the most recent National Demographic and Health Survey (NDHS), in 2006. This study is an excerpt of the NDHS, which is a home-based cross-sectional study. The nutritional status of women was assessed by WC and BMI, considering excess weight to be BMI = 25 Kg/m2 and WC risk to be = 80 cm. To evaluate the statistical significance, Poisson Regression was applied to identify factors associated with WC risk in women with or without excess weight, presenting the p value corresponding to the Wald test for heterogeneity or linear trend. Of the 14,101 women studied, 45.8% were overweight and 55.5% at WC risk. Regarding the association between BMI and WC, it was found that 23.5% of women who were not overweight showed WC risk. After a stratified analysis by BMI, the prevalence of WC risk among women without excess weight was greatest in the Northeast, 26.0%, and the Southeast, 24.5%, while the South region presented the lowest prevalence at 18.5%. It follows that the anthropometric WC and BMI measures should be used concomitantly since the use of only one of these measures may overlook individuals at risk for various diseases. PMID- 24473606 TI - [Success in maintaining weight loss in Portugal: the Portuguese Weight Control Registry]. AB - The scope of this article is to describe the Portuguese Weight Control Registry (PWCR) methodology and the participants currently enrolled specifically with respect to their individual and family weight history, previous weight loss attempts, and psychosocial characteristics. One hundred and ninety-eight adults (age: 39.7+/-11.1 years; BMI: 26.0+/-3.9 kg/m2), 59% women, filled out a questionnaire about demographics, health-related behaviors and motivation, and methods and strategies used to lose and/or maintain weight loss. Participants reported an average weight loss of 17.4 kg for an average of 29 months. Concerning the number of weight loss attempts, 73% of participants reported a maximum of three attempts of going on a diet, and 34% indicated only one attempt to lose weight in the past. The PWCR now features a considerable number of successful long-term weight loss maintainers in Portugal. Participants will be followed over the next years to learn about their characteristics and weight loss strategies in further detail, as well as to identify predictors of continued weight loss maintenance. PMID- 24473607 TI - [Diagnosis of complementary feeding practices for creating a matrix model for action in primary health care]. AB - Timely and appropriate complementary feeding is essential for the healthy growth and development of children, and Primary Health Care, especially the Family Health Support Nuclei, are the ideal location for developing relevant actions during this period. A cross-sectional study that applied a questionnaire to mothers and anthropometric evaluation for 324 children sought to develop an index of complementary feeding inadequacies and to study its association with social, economic, clinical, epidemiological and nutritional variables. For quantification of feeding inadequacies, an index using the Delphi method was created. High frequencies were observed for all inadequacies, especially for late introduction of solids (80.2%), early introduction of sugar/thickeners (78.1%) and liquids (73.5%). The most significant results of these associations were early weaning of exclusive (p = 0.000) and total (p = 0.005) breastfeeding, absence of partner (p = 0.001) and the mother supporting the family financially (p = 0.025). The use of this index identifies higher-risk situations for developing a nutritional assistance action plan, especially when it comes to promoting matrix model work. PMID- 24473608 TI - Toothache and social and economic conditions among adolescents in Northeastern Brazil. AB - The scope of this study was to correlate toothache with social and economic conditions, access to oral health facilities and the lifestyle of adolescents in Sobral in the state of Ceara. It was conducted as a cross-sectional analytical study with a sample composed of 688 adolescents. The prevalence of toothache in the study group was 31.8%. A chi-square test of association was performed to measure the relationship between independent variables and toothache, estimating the prevalence ratio by Poisson regression. The factors that demonstrated the closest relationship with toothache were cavity severity, the reason for dental treatment being related to urgency, frequency of dental appointments and the distribution of toothbrushes at school. It was observed that the high prevalence of dental pain in adolescents is directly linked to the access conditions, as well as the characteristics of the actions developed by the health services. Just as there is a need for the deployment of services related to health promotion, based on equity and integration, it is necessary to introduce emergency services to intervene not just to curtail crippling pain, but also as a mechanism to stimulate the development of procedures for the prevention of oral diseases. PMID- 24473609 TI - [Risk factors associated with suicides in Palmas in the state of Tocantins, Brazil, between 2006 and 2009 investigated by psycho-social autopsy]. AB - The scope of this article is to analyze and describe the risk factors and determinants linked to 24 suicides in the city of Palmas in the state of Tocantins between 2006 and 2009. The psychological and psycho-social autopsy method was used in order to investigate the consummated suicides by interviewing family members. It contextualized the subjects' life characteristics to understand the family dynamics and the affective, social, economic and cultural background, based on the reconstruction of the history and personality of the individuals. The associated socio-economic factors were: being male, aged between 20 and 40, single, with mixed ethnicity and basic education. The major risk factors identified were: mental disorder, alcohol and other drug abuse, disturbed family relationship and a history of previous suicide attempts. An attempt was made to contextualize and reflect on some cases reported by family members, as well as on the response of the health care teams to the demands of the families. The need to implement prevention programs and to train the primary health care professionals was considered a priority. PMID- 24473610 TI - [Maxillofacial injuries as markers of urban violence: a comparative analysis between the genders]. AB - Urban violence is a widely discussed topic in various sectors of society, either due to its impact on public health indicators and its influence on the everyday life of individuals or the constant presence of casualties in the health services. This study compares differences in victimization between the genders based on maxillofacial injuries as markers of urban violence. This is a cross sectional study with data collected in three hospitals of reference for multiple traumatic injuries in Belo Horizonte in the state of Minas Gerais, between January 2008 and December 2010. The analysis included descriptive and multivariate statistics using logistic regression. There were records of 7,063 victims, 55.1% of which involved interpersonal violence. The majority of victims were males (71.2%). Among the male victims, firearm and knife-inflicted aggression and motorcycle accidents were more frequent than aggression without the use of a weapon. Multiple fractures were the type of injury that best characterized the profile of victimization among males compared to soft tissue injuries. Gender is an important factor in victimization resulting in maxillofacial injuries and urban violence, in which males are the main victims. PMID- 24473611 TI - [Discourses on sexuality at a Counseling and Testing Center: possible dialogues between health professionals and clients]. AB - Due to the central role played by sex in HIV transmission, this paper analyzes the discussions on sexuality between health professionals and service users at a Counseling and Testing Center in the State of Rio de Janeiro. The methodology included direct observation of individual pre-test counseling and the use of 384 questionnaires and 14 interviews with service users. It was observed that counseling is preceded by filling out the epidemiological surveillance form and that, due to the lack of an adequate structure, there are inaccuracies in the process of gathering and recording the users' sexual practices. During counseling, STD/Aids prevention discourse is focused on the type and the number of sexual partners, on HIV risk and on condom use. This approach does not favor dialogue about the sexual trajectory of the users and their doubts and demands related to sexuality and Aids. The data from the questionnaire and interviews indicated that homo, hetero and bisexual categories were not familiar to the users. It is recommended that: counseling should be dissociated from filling out the surveillance form; the significance and diversity of sexual experiences of individuals throughout their lives should be incorporated in counseling training; investment is needed in the structural organization of the service. PMID- 24473612 TI - [Harm reduction policies in Brazil: contributions of a North American program]. AB - Given the rapid spread of the HIV epidemic and the need to control its transmission among intravenous drug users (IDU), harm reduction strategies have been incorporated in many countries, including Brazil. Considering these aspects and taking into account the emergence of drugs as a core concern on the government's agenda, especially crack cocaine, this article presents some of the contributions acquired from observing and recording the practices of an American model of research and care for IDUs, namely the UFO (You Find Out) Study. Issues such as participants' access and adherence, financing difficulties, sustainability and outcome evaluation were considered. The study involved documental research, systematic observation and interviews with key informants. Some of the UFO features that could contribute to the formulation of harm reduction policies in Brazil are highlighted. The UFO appears to be a successful example of harm reduction initiatives that successfully contact and guarantee the commitment of that risk group, ensuring its access to health services and reducing risks associated with drug use. PMID- 24473613 TI - [Risk behavior for the health of students at the State University of North Parana, Brazil--proposal for online intervention]. AB - Getting to know the lifestyles of university students provides important input for possible decision-making for the implementation of intervention programs within the university environment. The objective of this study was to analyze the prevalence of risk behaviors to health in a representative sample of UENP students and, in accordance with the information obtained, indicate specific actions using means that can assist in reducing such behaviors. The survey of the main risk factors for the health of the population in question was performed by database analysis. The orientation was conducted through social networks, with online control over access to and interactions with members of the networks using information made available by the research. More than 200 messages were posted, trying to put this population on the path towards factors related to healthy habits. A viewing average of 471.2 +/- 128.16 people accessed the page and an average of 12,915.07 +/- 6,517.45 people saw the posts per week. Given the above, we suggest actions in UENP to encourage healthy habits, and the social networks proved to be a viable tool for this though other media may be offered, seeking to encourage this population to adopt a more active and health lifestyle. PMID- 24473614 TI - [Male bodies in the field of health: links in the literature]. AB - The article seeks to analyze the specific literature about the male body and its relationship to the field of health. Based on this analysis, it is hoped that hypotheses or presuppositions can be established as a starting point for future interventions and research on the subject. Methodologically, the study is a literature review of a qualitative nature focusing on articles available in the Virtual Health Library (VHL). In terms of results, three themes were established that summarize the analysis of the sources: gendered bodies, male bodies in the midst of transgression and marginalization, and the reductions of the male body and self care. The concluded reached is that the standpoint of health on male bodies can promote enhanced self care in which masculinity can be constructed and reconstructed, superseding exclusionary, monolithic and reductive models that govern the male being and the female being. PMID- 24473615 TI - Epidemiology of physical inactivity, sedentary behaviors, and unhealthy eating habits among Brazilian adolescents: a systematic review. AB - This systematic review analyzed the prevalence of physical inactivity, sedentary behaviors and unhealthy eating habits among Brazilian adolescents. Searches were conducted in five databases (Lilacs, SciELO, Medline, Web of Science, and Google Scholar) and in the references cited in the articles retrieved. The literature search yielded 5,872 potentially relevant titles and a total of 69 studies met all the inclusion criteria. The risk behavior most often evaluated was physical inactivity (48/69; 69.6%), and its prevalence rate ranged from 2.3% to 93.5%. Twenty-eight studies estimated the prevalence of physical inactivity at over 50%. Most studies observed the prevalence of greater physical inactivity among girls. The prevalence of sedentary behaviors (lengthy screen time or TV use) was also frequently over 50%. Several variables were used to identify unhealthy eating habits, and some criteria/studies have indicated unhealthy eating habit estimates at close to 100% among adolescents. In conclusion, the estimates of these risk behaviors among Brazilians adolescents were very close to or even greater than those found in developed countries in several studies analyzed in this review. PMID- 24473616 TI - [Regulation of radiotherapy and chemotherapy services by health plan organizations in Brazil]. AB - This paper characterizes regulatory procedures applied by private health plan operators on their outpatient radiotherapy and chemotherapy services, especially via contracts, and outlines the health care providers' perception on regulation. The study relied on primary data, taking into consideration 638 hospitals and outpatient health care units with the services in question. A stratified random sample was selected, resulting in the inclusion of 54 units that are representative of the population, excluding hospitals that only provide radiotherapy. Private chemotherapy services are largely funded by health insurance plans (75.0%), while radiotherapy services are predominantly covered by the public health system (49.0%). Contracts are not applied by third part payers, in their potential, as regulatory and health care coordination instruments. The mechanisms of regulation applied by third part payers are centered on services use control and administrative aspects. It is recognized the need of adjustments for a health care quality focus, and contracts may contribute in this sense. PMID- 24473617 TI - [Oral health care in the health network and the regionalization process]. AB - The scope of this article is to outline the construction of the regionalized health network, focusing on oral health care and identifying the problems and the progress in its implementation. The context was the proposed national network model in the policies that underpin the Unified Health System. This is a descriptive-exploratory study with a qualitative approach methodologically supported by Grounded Theory. Interviews were conducted with managers, health professionals and teachers graduated in Dentistry, forming three sample groups. The core category was named "Enhancing the interaction of oral health care in the health network in the regionalization process." In the proposed theoretical model, the enhancement of interaction arises from conditions such as: the characterization of oral health care in the regionalized health network; the identification of difficulties in the implementation process; and the analysis of the operation of the oral health care network. The inclusion of oral health in the network is at an early stage, sometimes detached from the set of relations that constitutes the health network, which is also being consolidated. Evidence gathered in this study indicates the structuring of the regionalized health care network as a prerequisite to raise oral health care and assistance to a new level. PMID- 24473618 TI - [Risk factors for impaired development in children attended at family health units at the end of the first year of life: socio-demographic aspects and maternal mental health]. AB - The scope of this article is to evaluate risk and protection factors for the development of 1-year-olds assisted at family health care units. It is a cross sectional study involving 65 children of approximately 1 year of age and their mothers attended at two family health care units. The development was assessed using a developmental screening test (Denver II). The mothers filled out the SRQ 20 questionnaire to identify common mental disorder (CMD) indicators. After data collection, descriptive and inferential statistical analysis was performed. Global development was at risk in 43.1% of the children evaluated, and the most affected areas were language and fine motor development; 44.6% of mothers had results indicative of CMD when the child was 1 year of age. In bivariate analysis, reported depression, smoking, infections in pregnancy, CMD after birth and working outside the home were significantly associated with the children's development. After full statistical analysis, CMD was revealed as being a risk factor, and working away from home as being a protection factor. In order to increase the chances of success of programs targeted for children at health care units and avoiding the risk of impaired development, it is important to focus on two aspects: children's stimulation and maternal mental health. PMID- 24473619 TI - [Secular trend of growth in stature in Florianopolis in the state of Santa Catarina (Brazil) in relation with the human development index (HDI)]. AB - The article seks to evaluate the secular trend of growth in stature of recruits in the 63rd Infantry Battalion in Florianopolis and correlate the information with the human development index (HDI). It involves a transversal and retrospective study of recruits aged between 18 and 20 who joined the 63rd IB in Florianopolis from 1963 to 2007. The sample comprised 600 individuals out of a total of 3000 recruits enlisted over the period. In each decade, three years were selected and within these years the first 40 files were systematically selected for analysis. It was seen that there was an increase in the order of 7 cm in height of recruits in Florianopolis over the past 47 years. This increase was more marked between the decades of 1990 and 2000, with the municipality of Blumenau having the highest average. The average heights study over the decades showed a strong positive correlation with the HDI of Florianopolis during the same period. When comparing the heights of the capital of Santa Catarina and previous studies in Blumenau, it was found that both cities have achieved the same increase of 1.4 cm/decade in the period between the 1960 and 2000. There was a positive secular trend in growth in Florianopolis, with a strong correlation with HDI values of the city between 1960 and 2000. PMID- 24473620 TI - [Spatial analysis of live birth clusters in Unified Health System (SUS) and private hospitals in the municipality of Sao Paulo, Brazil]. AB - The scope of this study is to evaluate the spatial distribution of live births (LB) in the Municipality of Sao Paulo (MSP), verify if there is spatial dependence, identify possible differences in birth profiles and evaluate the distances between homes and delivery hospitals. LB occurring in high complexity hospitals were studied, namely 4 from the Unified Health System (SUS) and 4 from the private network in MSP in 2008. 46,190 LB were geocoded: 48.8% from SUS hospitals and 51.2% from private hospitals, accounting for 27.9% of total live births in MSP. LB in SUS hospitals formed two clusters, with a high proportion of households with incomes of 1/2 to 2MW and a marked number of shantytowns and high birth rates. LB in private hospitals formed a cluster in the central region of MSP, where there is a high proportion of households with > 10 MW income and a low birth rate. Differences in maternal, pregnancy and childbirth characteristics were statistically significant in SUS and non-SUS hospitals, as well as the frequency of multiple births. There was no difference in the prevalence of low birth weight and pre-term births. The results showed differences in the LB cluster profile reflecting the current inequalities in living conditions. PMID- 24473621 TI - [Referencing and counter-referencing in specialized dental health procedures in Campinas in the state of Sao Paulo, Brazil]. AB - This article aims to evaluate the referencing of the demand for specialized care in oral health in Campinas in relation to the distribution of treatment and the influence of socio-economic variables in addition to the perception and information available to users in relation to counter-referencing. It is an observational exploratory study, selecting two Health Administrative Regions: one with a Center for Dental Specialties and one without, divided into two phases: 1) all referrals to secondary care were collected from all Oral Health teams as well as population and socio-economic data and distribution of referrals; 2) interview with 331 users, checking the counter-referencing, quality of service and reasons for absences or withdrawals. Regarding the counter-referencing, the majority of users who received the specialized treatments were well attended, and waited less than one month for appointment scheduling. The management model did not statistically influence access to secondary care in oral health. It was found that in a given Health Administrative Region the discrepancies were less evident and there was a correlation coefficient of demand attended with socio-economic variables, in addition to a lower percentage of non-attendance, demonstrating a greater commitment to integrity and fairness. PMID- 24473622 TI - [Factors affecting the adoption of ICT tools in experiments with bioinformatics in biopharmaceutical organizations: a case study in the Brazilian Cancer Institute]. AB - The scope of this article is to identify and analyze the factors that influence the adoption of ICT tools in experiments with bioinformatics at the Brazilian Cancer Institute (INCA). It involves a descriptive and exploratory qualitative field study. Evidence was collected mainly based on in-depth interviews with the management team at the Research Center and the IT Division. The answers were analyzed using the categorical content method. The categories were selected from the scientific literature and consolidated in the Technology-Organization Environment (TOE) framework created for this study. The model proposed made it possible to demonstrate how the factors selected impacted INCA's adoption of bioinformatics systems and tools, contributing to the investigation of two critical areas for the development of the health industry in Brazil, namely technological innovation and bioinformatics. Based on the evidence collected, a research question was posed: to what extent can the alignment of the factors related to the adoption of ICT tools in experiments with bioinformatics increase the innovation capacity of a Brazilian biopharmaceutical organization? PMID- 24473623 TI - [Influence of the organization of primary care and the socio-demographic characteristics of the population on the demand for municipal emergency dental care]. AB - The scope of this study was to evaluate the influence of the social determinants and the provision of primary care services in relation to the use of emergency dental care services in a medium-sized municipality. Data recorded for the 57,231 users of emergency care between 2007 and 2009, in accordance with age, gender, date and period of dental care, social exclusion indices of the suburb in which they live and the existence of a benchmark oral health team, were used to perform the analysis. Of the total population, 5.24% on average per year used the service during the period under scrutiny, with the 20-49 year age group (63.84%) showing the highest demand and equality between genders for such care. Surgical procedures (54.90%) were the most prevalent with an increasing trend for restorative procedures (62,8%). Users living in areas of greater social exclusion were 4.15 times more likely to seek dental care (p < 0.05). No statistically significant association was found between gender or the existence of an oral health team of the suburb in which they live and the demand for emergency dental care. In conclusion, there was greater recourse to emergency municipal dental care by individuals living in vulnerable areas, proving the importance of such care in diminishing oral health inequality. PMID- 24473624 TI - [A comparison between two food security scales]. AB - The scope of this study was to evaluate the influence of the social determinants and the provision of primary care services in relation to the use of emergency dental care services in a medium-sized municipality. Data recorded for the 57,231 users of emergency care between 2007 and 2009, in accordance with age, gender, date and period of dental care, social exclusion indices of the suburb in which they live and the existence of a benchmark oral health team, were used to perform the analysis. Of the total population, 5.24% on average per year used the service during the period under scrutiny, with the 20-49 year age group (63.84%) showing the highest demand and equality between genders for such care. Surgical procedures (54.90%) were the most prevalent with an increasing trend for restorative procedures (62,8%). Users living in areas of greater social exclusion were 4.15 times more likely to seek dental care (p < 0.05). No statistically significant association was found between gender or the existence of an oral health team of the suburb in which they live and the demand for emergency dental care. In conclusion, there was greater recourse to emergency municipal dental care by individuals living in vulnerable areas, proving the importance of such care in diminishing oral health inequality. PMID- 24473625 TI - [Access to information on oral hygiene and tooth loss due to caries among adults]. AB - This study sought to establish the association between tooth loss due to dental caries and variables related to access to information on oral health in adults aged 35-44 years (n = 780) who participated in a large epidemiological study. The dependent variable was total tooth loss due to caries. The independent variables were grouped into blocks: demographic and socio-economic characteristics, use of dental service, access to oral health information (about how to prevent oral problems; oral hygiene; and diet), and behaviors. The analysis was conducted using hierarchical multiple linear regression. The mean number of lost teeth due to caries was 7.03. High numbers of lost teeth were higher among females and older adults; low levels of education; adults who rarely/never received oral hygiene information; those who brushed their teeth once a day or less; and those adults who did not use dental floss (p < 0.05). Adults who rarely/never received oral hygiene information from dental services lost 2.15 more teeth due to caries than those who always/often received such information (p = 0,000). Thus, it is suggested that access to information should be encouraged to contribute to greater equity in oral health. PMID- 24473626 TI - [Analysis of the mainstreaming of the perspective of the Human Right to Adequate Food in the institutional design of the National School Nutrition Program]. AB - Being a signatory to international agreements that recognize the Human Right to Adequate Food (HRAF) and having enshrined this right into its Constitution, the Brazilian state imposes a duty to provide, protect and promote the HRAF. For this it is necessary to incorporate the principles of the HRAF into the process of planning and executing the actions of Food and Nutrition Security (FNS). The objective was to analyze the process of mainstreaming of the HRAF in the new institutional design of the National School Nutrition Program (NSNP). This is in line with the principles laid down in General Comment No 12 of the Guide for Policy Analysis and Public Programs and nutritional Food Security under the Perspective of Human Rights and the Organic Law on Food and Nutrition Security (OLFNS). The results show that the new regulatory framework of the NSNP indicates a paradigm shift that is characterized by a gradual decline in the perception of NSNP as policy of a welfare nature. Concomitantly, there is an increase in the concept of the benefit of school food as a right, with the caveat that the construction of a new regulatory framework, although essential, is not sufficient for full implementation of the HRAF. PMID- 24473631 TI - A bidentate boryl ligand: syntheses of platinum and iridium complexes. AB - A methylenediphenylphosphine substituted diazaborole was obtained in a two-step procedure in amounts around 4 g. This B-P ligand was coordinated at platinum and iridium and the structures of the boryl complexes are discussed. In the case of the iridium derivative an interesting boron-boron contact was found. PMID- 24473627 TI - [Evaluation of potential drug interactions in primary health care prescriptions in Vitoria da Conquista, Bahia (Brazil)]. AB - Drug interactions are risk factors for the occurrence of adverse drug reactions. The risk for drug interactions includes factors related to prescription that are intrinsic to the patient. This study sought to evaluate the potential drug interactions in primary care prescriptions in Vitoria da Conquista in the state of Bahia to fill the knowledge gap on this topic in Brazil. Information about several variables derived from the primary health care prescriptions was collected and drug interactions were evaluated based on information from Medscape and Micromedex(R) databases. Polypharmacy frequency and its association with the occurrence of drug interactions were also evaluated. Results revealed a 48,9% frequency of drug interactions, 74,9% of moderate or greater severity, 8,6% of prescriptions in polypharmacy that in the chi-square test showed a positive association with the occurrence of drug interactions (p < 0,001). Prescriptions from primary care in Vitoria da Conquista in the state of Bahia showed a high frequency of drug interactions, however it is necessary to analyze other risk factors for their occurrence at this level of health care. PMID- 24473632 TI - Influence of school competitive food and beverage policies on obesity, consumption, and availability: a systematic review. AB - IMPORTANCE: The US Department of Agriculture recently issued an interim final rule governing the sale of foods and beverages sold outside of the school meal programs ("competitive foods and beverages" [CF&Bs]). OBJECTIVE: To examine the potential influence that the federal rule may have based on peer-reviewed published studies examining the relationship between state laws and/or school district policies and student body mass index (BMI) and weight outcomes, consumption, and availability of CF&Bs. EVIDENCE REVIEW: Keyword searches of peer reviewed literature published between January 2005 and March 2013 were conducted using multiple databases. Titles and abstracts for 1160 nonduplicate articles were reviewed, with a full review conducted on 64 of those articles to determine their relevancy. Qualitative studies, studies of self-reported policies, or studies examining broad policies without a specific CF&B element were excluded. FINDINGS: Twenty-four studies were selected for inclusion. Studies focused on state laws (n = 14), district policies (n = 8), or both (n = 2), with the majority of studies (n = 18) examining foods and beverages (as opposed to food only or beverage-only policies). Sixteen studies examined prepolicy/postpolicy changes, and 8 studies examined postpolicy changes. Study designs were cross sectional (n = 20), longitudinal (n = 3), or a combination (n = 1). Outcomes examined included change in BMI, weight, probability of overweight or obesity (n = 4), consumption (n = 10), and availability (n = 13); 3 studies examined more than 1 outcome. The majority of studies primarily reported results in the expected direction (n = 15), with the remaining studies (n = 9) reporting primarily mixed or nonsignificant results. CONCLUSIONS AND RELEVANCE: In most cases, CF&B policies are associated with changes in consumption and/or availability in the expected direction; however, caution should be exercised, given that nearly all were cross-sectional. The influence of such policies on overall student consumption and BMI and weight outcomes was mixed. The findings hold promise for the likely influence of federal CF&B regulations on changes in student in-school consumption and in-school competitive food availability. Further research is needed to truly understand the association between these policies and overall consumption and weight outcomes. PMID- 24473633 TI - Prescribing upper limb exercises after stroke: a survey of current UK therapy practice. AB - OBJECTIVE: To investigate the current practice of physiotherapists and occupational therapists in prescribing upper limb exercises to people after stroke and to explore differences between professions and work settings. DESIGN: A cross-sectional survey design. PARTICIPANTS: Occupational therapists and physiotherapists working in UK stroke rehabilitation. RESULTS: The survey's response rate was 21.0% (n = 322); with 295 valid responses. Almost two thirds of therapists (64.7%, n = 191) agreed that they always prescribe upper limb exercises to a person with stroke if they can actively elevate their scapula and have grade 1 finger/wrist extension. Most therapists (98.6%, n = 278) prescribed exercises to be completed outside of therapy time, with exercises verbally communicated to family. Standardised upper limb specific outcome measures were used to evaluate the prescribed exercises by 21.9% (n = 62) OF THERAPISTS. DIFFERENCES WERE FOUND BETWEEN PROFESSIONS AND ACROSS WORK SETTINGS. CONCLUSION: The majority of prescribed upper limb exercises were of low intensity (range of motion or stretching exercises) rather than repetitive practice or strengthening exercises. The use of standardised outcome measures was low. Progression of exercises and the provision of written instructions on discharge occur less frequently in inpatient settings than outpatient and community settings. PMID- 24473634 TI - Acta Diabetologica is 50 and well: long live Acta! PMID- 24473635 TI - An easy, fast, effective tool to monitor the incidence of type 1 diabetes among children aged 0-4 years in Italy: the Italian Hospital Discharge Registry (IHDR). AB - National data of type 1 diabetes incidence are currently missing in Italy. To fill this gap, we estimated the national rate of first hospitalizations for type 1 diabetes among children aged 0-4 years and resident in Italy, as well as rates for each of the twenty-one Italian regions. We extracted the first episode of hospitalization in years 2005-2010 from the Italian Hospital Discharge Registry (IHDR). Record-linkage procedure and cleansing data method were applied to exclude prevalent cases and potentially miscoded patients. At the end, 2,250 incident hospitalizations for type 1 diabetes were extracted. In the years 2005 2010, the mean nation-wide first hospitalization rate for type 1 diabetes in children aged 0-4 years was 13.4 (95% CI 12.8-14.0), 14.1 (95% CI 13.3-14.9) in males and 12.7 (95% CI 11.9-13.4) in females. A geographically heterogeneous pattern of incidence was found: even excluding Sardinia, incidence for this age range and calendar period tended to be slightly higher in Southern than in Northern Italy. Our incidence of first hospitalizations corresponds to the estimates of disease incidence obtained with different data sources by other authors in selected Italian regions. We provide, for the first time ever, the estimate of type 1 diabetes incidence for the overall population aged 0-4 years resident in Italy. When methodological cautions are adopted, IHDR emerges as a reasonable proxy of type 1 diabetes incidence and as a cost-effective tool for public health purposes. PMID- 24473636 TI - DNA-directed growth of ultrafine CoAuPd nanoparticles on graphene as efficient catalysts for formic acid dehydrogenation. AB - Ultrafine and well dispersed CoAuPd nanoparticles grown on a DNA-reduced-graphene oxide (DNA-rGO) composite have been successfully synthesized using a DNA-directed method. The resultant CoAuPd/DNA-rGO composite exhibits high activity and 100% H2 selectivity toward the dehydrogenation of formic acid without any additive at 298 K. PMID- 24473638 TI - Green paper on safety of young drivers has stalled. PMID- 24473639 TI - Six [Tp*WS3Cu2]-based clusters derived from [Et4N][Tp*WS3], Cu(I) salts and phosphine ligands: syntheses, structures and enhanced third-order NLO properties. AB - Treatment of [Et4N][Tp*WS3] (Tp* = hydridotris(3,5-dimethylpyrazol-1-yl)borate) (1) with CuX (X = Br, SCN) and PPh3 or 1,1-bis(diphenylphosphino)methane (dppm) produced two neutral trinuclear clusters [Tp*W(MU3-S)(MU-S)2Cu2Br(PPh3)] (2) and [Tp*W(MU3-S)(MU-S)2Cu2(SCN)(dppm)]2.MeCN.Et2O (3.MeCN.Et2O). Reactions of 1 with [Cu(MeCN)4]PF6, NH4PF6 and 1,3-bis(diphenylphosphino)propane (dppp), N,N bi(diphenylphosphanylmethyl)-2-aminopyridine (bdppmapy), N,N,N',N' tetra(diphenylphosphanylmethyl)ethylenediamine (dppeda), or 1,4-N,N,N',N' tetra(diphenylphosphanylmethyl)benzenediamine (dpppda) afforded four clusters containing butterfly-shaped [Tp*WS3Cu2] cores, [Tp*W(MU3-S)(MU S)2Cu2(dpppds)](PF6).1.25MeCN (dpppds = 1,3-bis(diphenylphosphino)propane disulfide) (4.1.25MeCN), [Tp*W(MU3-S)(MU-S)2Cu2(bdppmapy)](PF6).3MeCN (5.3MeCN) and {[Tp*W(MU3-S)(MU-S)2Cu2]2(L)]}(PF6)2.Sol (6.Et2O: L = dppeda, Sol = Et2O; 7.1.25MeCN: L = dpppda, Sol = 1.25MeCN). Compounds 2-7 were characterized by elemental analysis, IR, UV-Vis, (1)H and (31)P{(1)H} NMR spectra, electrospray ion mass spectra (ESI-MS) and single-crystal X-ray diffraction. Compound 2 or 3 has a butterfly-shaped [Tp*WS3Cu2] core in which one [Tp*WS3] unit binds two Cu(I) centers via one MU3-S and two MU-S atoms. In the cationic structure of 4 or 5, one in situ-formed dpppds or bdppmapy combines with the [Tp*WS3Cu2] core via each of its two S atoms or two P atoms coordinated at each Cu(I) center. In the bicationic structure of 6 or 7, two [Tp*WS3Cu2] cores are linked by one dppeda or dpppda bridge to form a bicyclic structure. The isolation of 2-7 with unstable [Tp*WS3Cu2] cores may be ascribed to the coordination of P- or S-donor ligands at Cu(i) centers of these cores. The third-order nonlinear optical (NLO) properties of 2-7 in DMF were also investigated by using the femtosecond degenerate four wave mixing (DFWM) technique at 800 nm. PMID- 24473641 TI - Radical but conservative liver resection for large centrally located hepatocellular carcinoma: the mini upper-transversal hepatectomy. AB - BACKGROUND: In patients with hepatocellular carcinoma (HCC) in a diseased liver, surgery should be offered in a parenchyma-sparing fashion. This approach seems unfeasible for large and deeply located lesions. Ultrasound study of the tumor vessel relationship and hepatic inflow and outflow opens new technical solutions: herein is described a new operation based on this approach.1 (-) 3 METHODS: A 69 year-old man with a large centrally located HCC (Barcelona Clinic Liver Cancer stage C) underwent surgery. The HCC was located in segments 7, 8, and part of 5, extensively compressing and dislodging the anterior (P5-8) and posterior (P6-7) Glissonean pedicles at their origin. The lesion involved the right hepatic vein (RHV) and was in contact with the middle hepatic vein at the caval confluence. An inferior RHV (IRHV) was preoperatively evident. RESULTS: After a J-shaped thoracophrenolaparotomy, the liver exploration with the aid of intraoperative ultrasound confirmed the tumoral contact without vascular invasion with P5-8 and P6-7 and disclosed multiple communicating veins between the middle hepatic vein and RHV, warranting with the IRHV the segment 5-6 outflows. A resection of segments 7 and 8 with RHV resection, together with complete tumor detachment from P5-8 and P6-7, was performed. The specimen was removed combining the crush clamping method for the parenchyma division and a peeling-off technique by means of blunt scissor dissection for the tumor vessel detachment. The postoperative course was uneventful. The patient was alive without recurrence at 12 months after surgery. CONCLUSIONS: This video is the first live demonstration of the previously reported radical but conservative policy, adding to the latter the technical solutions provided by detection of accessory veins such as the IRHV and communicating veins.1 (-) 4. PMID- 24473640 TI - The association of surgical margins and local recurrence in women with early stage invasive breast cancer treated with breast-conserving therapy: a meta analysis. AB - PURPOSE: There is no consensus on what constitutes adequate negative margins in breast-conserving therapy (BCT). We systematically review the evidence on surgical margins in BCT for invasive breast cancer to support the development of clinical guidelines. METHODS: Study-level meta-analysis of studies reporting local recurrence (LR) data relative to final microscopic margin status and the threshold distance for negative margins. LR proportion was modeled using random effects logistic meta-regression. RESULTS: Based on 33 studies (LR in 1,506 of 28,162), the odds of LR were associated with margin status [model 1: odds ratio (OR) 1.96 for positive/close vs negative; model 2: OR 1.74 for close vs. negative, 2.44 for positive vs. negative; (P < 0.001 both models)] but not with margin distance [model 1: >0 mm vs. 1 mm (referent) vs. 2 mm vs. 5 mm (P = 0.12); and model 2: 1 mm (referent) vs. 2 mm vs. 5 mm (P = 0.90)], adjusting for study median follow-up time. There was little to no statistical evidence that the odds of LR decreased as the distance for declaring negative margins increased, adjusting for follow-up time [model 1: 1 mm (OR 1.0, referent), 2 mm (OR 0.95), 5 mm (OR 0.65), P = 0.21 for trend; and model 2: 1 mm (OR 1.0, referent), 2 mm (OR 0.91), 5 mm (OR 0.77), P = 0.58 for trend]. Adjustment for covariates, such as use of endocrine therapy or median-year of recruitment, did not change the findings. CONCLUSIONS: Meta-analysis confirms that negative margins reduce the odds of LR; however, increasing the distance for defining negative margins is not significantly associated with reduced odds of LR, allowing for follow-up time. Adoption of wider relative to narrower margin widths to declare negative margins is unlikely to have a substantial additional benefit for long-term local control in BCT. PMID- 24473642 TI - Extended neoadjuvant chemotherapy for borderline resectable pancreatic cancer demonstrates promising postoperative outcomes and survival. AB - BACKGROUND: The optimum approach to neoadjuvant therapy for patients with borderline resectable pancreatic cancer is undefined. Herein we report the outcomes of an extended neoadjuvant chemotherapy regimen in patients presenting with borderline resectable adenocarcinoma of the pancreatic head. METHODS: Patients identified as having borderline resectable pancreatic head cancer by American Hepato-Pancreato-Biliary Association/Society of Surgical Oncology consensus criteria from 2008 to 2012 were tracked in a prospectively maintained registry. Included patients were initiated on a 24-week course of neoadjuvant chemotherapy. Medically fit patients who completed neoadjuvant treatment without radiographic progression were offered resection with curative intent. Clinicopathologic variables and surgical outcomes were collected retrospectively and analyzed. RESULTS: Sixty-four patients with borderline resectable pancreatic cancer started neoadjuvant therapy. Thirty-nine (61 %) met resection criteria and underwent operative exploration with curative intent, and 31 (48 %) were resected. Of the resected patients, 18 (58 %) had positive lymph nodes, 15 (48 %) required en-bloc venous resection, 27 (87 %) had a R0 resection, and 3 (10 %) had a complete pathologic response. There were no postoperative deaths at 90 days, 16 % of patients had a severe complication, and the 30-day readmission rate was 10 %. The median overall survival of all 64 patients was 23.6 months, whereas that of unresectable patients was 15.4 months. Twenty-five of the resected patients (81 %) are still alive at a median follow-up of 21.6 months. CONCLUSIONS: Extended neoadjuvant chemotherapy is well tolerated by patients with borderline resectable pancreatic head adenocarcinoma, selects a subset of patients for curative surgery with low perioperative morbidity, and is associated with favorable survival. PMID- 24473644 TI - The controversy regarding margin width in breast cancer: enough is enough. PMID- 24473643 TI - A systematic review of morbidity associated with autologous breast reconstruction before and after exposure to radiotherapy: are current practices ideal? AB - PURPOSE: The specific aim of this study was to conduct a systematic review of the literature to assess outcomes data on complications and aesthetic results associated with autologous tissue-based breast reconstruction performed before or after chest wall irradiation. METHODS: Studies from a PubMed search that met predetermined inclusion criteria were identified. Complications of interest included partial or total flap loss, fat necrosis, thrombosis, infection, seroma, hematoma, delayed wound healing, and flap fibrosis/contracture. Pooled complication rates were calculated. RESULTS: A total of 20 articles were included in the study for autologous reconstruction. These primary articles were selected after screening 897 publications, with six studies presenting data on pre reconstruction radiation, nine studies presenting data on post-reconstruction radiation, and five studies presenting data on both patient groups. Comparison of pooled complication rates between flaps irradiated before or after reconstruction were statistically similar, including total flap loss (1 vs. 4 %), wound healing complications (10 vs. 14 %), infection (4 vs. 6 %), hematoma (2 vs. 1 %), seroma (4 vs. 4 %), and fat necrosis (10 vs. 13 %). The pooled rate of flap contracture and fibrosis was 27 % in flap reconstructions exposed to radiotherapy. Statistical evaluation of aesthetic outcomes was impossible as a result of variability in assessment and reporting methods. CONCLUSIONS: Review of the current literature suggests similar rates of complications and success rates in autologous breast reconstruction patients exposed to pre- or post-reconstruction radiation. Immediate autologous reconstruction should be considered as a viable option even in patients who are likely to require postmastectomy radiotherapy. PMID- 24473645 TI - Editor's Note. PMID- 24473646 TI - Anomalies in the early stages of plant transgenesis: interests and interpretations surrounding the first transgenic plants. AB - The origins of plant transgenesis are discussed and the experiments that led to the first transgenic plants are analyzed. This process involved a series of actors, practices and interests specific to biotechnology. Consensus about the meaning of fundamental experiments was also at issue here. These events illustrate some of the conflicts related to genetically modified organisms, since scientists had different responses to plant transgenesis at the time of the first experiments, and opinions of the anomalies in those experiments varied. Thus, this article analyzes the interests and interpretations surrounding the first experiments involving transgenic plants. PMID- 24473647 TI - Life grammars: the 1907 census and population as a tool of government. AB - This article, based on the official census in Chile in 1907, notes its quantitative inaccuracies, reviewing the use of the category of population and its detrimental impact on the Indians, emphasizing how it erases the territorial, political and identity conflicts that traversed the tense relationship between the nation-state and the Indians. The article studies how this problematic shifted at different historical moments in Chilean institutions, showing that despite the different positions taken, it maintained the same epistemological and political configuration, compromising the implementation of public health policies in Chile. The figures of Orrego Luco, Murillo, Gonzalez y Allende are quoted in these analyses and debates. PMID- 24473648 TI - "The crowd is crazy, the crowd is a woman": the oligarchical-federal demophobia of the First Republic and the issue of transferring the capital. AB - This study examines the expressions of demophobia of the political class of the First Republic, faced with demonstrations against the government in Rio de Janeiro, and relates them to the need to move to the seat of the federal government inland. The demophobic literature produced by liberal Europeans against democratization in their countries pervaded the orientation of the Brazilian political class during the period. Committed to building an oligarchic federation, they saw the population of Rio de Janeiro as a threat. Compared to a subversive crowd of people in a huge, artificial capital suffering from foreign influence, oligarchic federalism valued the 'authentic' Brazilian people, referred to the image of a provincial, orderly population. PMID- 24473649 TI - [Madness in Foucault: art and madness, madness and unreason]. AB - After presenting the ideas on madness and its interface with art as expressed in the writings of Michel Foucault, Peter Pal Pelbart, and Gilles Deleuze, the article explores how these authors question the relationship between art and madness. It begins with the notion that madness does not tell the truth about art, and vice versa, but that there are links between both that must be delved into if we are to engage in deeper reflection on the topic. The text problematizes the statement that madness is the absence of an oeuvre and examines how this impacts the possibility of achieving an artistic oeuvre. It further problematizes the idea of madness as excluded language, that is, the idea that madness implies not only the exclusion of the body but also the disqualification of discourse. PMID- 24473650 TI - [A "people dump": marks of suffering and transformations at the former Hospital Colonia Sant'Ana and in psychiatric care in Santa Catarina, 1970-1996]. AB - The article explores transformations to psychiatric care in Santa Catarina starting in the 1970s, when the state's longtime asylum, Hospital Colonia Sant'Ana, reached the height of overcrowding. To this end, along with other sources, it analyzes interviews that had been conducted with professionals who worked at the hospital in that era, sourced from the facility's Center for Documentation and Research. The goal was to problematize these testimonies, examining the texture of the accounts and approaching them as memories that weave a history of the hospital through recollections marked by suffering. Within this proposed framework, suffering is understood as a historical event that can give rise to new social arrangements. PMID- 24473651 TI - [The Biometric Cabinet of the Escola de Educacao Fisica do Exercito: measuring and classifying to produce ideal bodies, 1930-1940]. AB - This paper analyzes biometrical and biotypological practices of the Biometric Cabinet of the Escola de Educacao Fisica do Exercito (Physical Education School of the Army) in Rio de Janeiro in the 1930s and 1940s, published in Revista de Educacao Fisica do Exercito. It was necessary to classify, monitor the results of the exercises periodically and measure morphological aspects of the bodies. The classifications were made in accordance with foreign parameters and an attempt was made to classify by type, quality and defects. The analysis of the practices of the Cabinet shows that biometrics and biotypology were complementary aspects of physical education, aiming at the standardization of bodies. PMID- 24473652 TI - [Curing by doing: poliomyelitis and the rise of occupational therapy in Argentina, 1956-1959]. PMID- 24473653 TI - [The workings of a Darwinist brain: Guedes Cabral and the evolutionism ofFuncoes do cerebro(1876)]. AB - The book Funcoes do cerebro (Workings of the brain), by physician Domingos Guedes Cabral, is recognized as one of the first Brazilian works to defend Darwinist theories. In light of the need for more studies on the reception of evolutionism in Brazil, the article investigates this book in an effort to reveal how Guedes Cabral used evolutionism in his argumentation and to reveal the purpose of his arguments within a historical context. Findings indicate that Guedes Cabral relied on evolutionism as part of both an ideological project and an incipient eugenic theory, later developed in the early twentieth century. PMID- 24473654 TI - Environment and health with respect to a poverty-related disease: the epidemiology of trachoma in Spain, 1925-1941. PMID- 24473655 TI - [Fishermen in the scientific imaginary during the formative stage of Chile's ichthyological academy, 1829-1909]. AB - Chile began creating a scientific academy in the late nineteenth century. Coming under the umbrella of the state, it shared governmental perspectives and objectives. The state asked science to help augment the country's economic production and social development by modernizing traditional forms of work from the top down. In our article we focus on the relation between science and fishing, examining the vision of scientists and their conflict-ridden dealings with traditional fishermen. This was not a fruitful relationship, and it ended with scientists requesting the delegitimization of fishermen as producers, receivers and encoders of knowledge. PMID- 24473656 TI - ["SESP never worked with Indians": the (in)visibility of indigenes in the activities of the Fundacao de Servicos de Saude Publica in the state of Amazonas]. AB - From 1960 to 1990, the Fundacao de Servicos de Saude Publica (Public Health Services Foundation) was in charge of a network of health services across Brazil, in continuation of work previously done by the Servico Especial de Saude Publica (Special Public Health Service). The article presents a 2010 research conducted in the state of Amazonas regarding the Foundation's activities among indigenous populations based on interviews with the Foundation's personnel and the analysis of its documentation. The findings indicate that while the Foundation had no formal policy for indigenous populations, in practice its staff did serve indigenes since in most municipalities in the interior of Amazonas they comprised a significant number of the inhabitants. PMID- 24473657 TI - [Speciation and its mechanisms: conceptual background and recent advances]. AB - This paper presents a historical approach on general concepts of speciation and its mechanisms, from the primordial ideas to the most recent theories that seek to elucidate the origin of biodiversity. It is common knowledge that speciation is a controversial and complex issue that encompasses virtually all the lines of research of biology, in addition to geology and paleontology. The main objective of the paper is to clarify the theoretical concepts on the origin of the animal species, in the chronological order in which they became established throughout the whole of the development of evolutionary biology as a science. PMID- 24473658 TI - [Nelson Rockefeller and the activities of the American International Association for Economic and Social Development: the debate concerning mission and imperialism in Brazil, 1946-1961]. AB - The article analyzes the bibliography on Nelson Rockefeller and the activities of the American International Association for Economic and Social Development in Brazil. It describes optimistic interpretations of Rockefeller's and the association's work, as well as the nationalist stream of thought, which characterized him as one of the chief representatives of U.S. imperialism, both as a political representative in the 1960s and as the mind behind endeavors of interest to the private sector. It is shown that at the individual and agency levels alike, these initiatives involved direct ties to the local elites, who influenced the reshaping and operationalization of technical cooperation projects. PMID- 24473659 TI - [Historical, social and cultural aspects of the deaf population]. AB - This work redeems, contextualizes and features the social, historical and cultural aspects of the deaf community that uses the Brazilian Sign Language focusing on the social and anthropological model. The scope of this study was to conduct a bibliographical review in scientific textbooks and articles available in the Virtual Health Library, irrespective of the date of publication. 102 articles and 53 books were located, including 33 textbooks and 26 articles (four from the Lilacs database and 22 from the Medline database) that constituted the sample. Today, in contrast with the past, there are laws that guarantee the right to communication and attendance by means of the Brazilian Sign Language. The repercussion, acceptance and inclusion in health policies of the decrees enshrined in Brazilian laws is a major priority. PMID- 24473660 TI - [Bioterrorism and pathogenic microorganisms]. AB - In recent years the use of pathogenic microorganisms in acts of bioterrorism has been the subject of major concern in many countries. This paper presents a possible application of viruses and bacteria for warfare and terrorist purposes, as well as a laboratory diagnosis to identify those agents. The viruses of smallpox (orthopoxvirus), of hemorrhagic fever and those belonging to filovirus have been highlighted, inter alia, as agents of human infection with bioterrorist intent. Among the bacteria, the emphasis has been on anthrax (Bacillus anthracis), the plague (Yersinia pestis), botulism (Clostridium botulinum) and tularemia (Francisella tularensis), not to mention ricin (Ricinus communis), as one of the Group B agents. PMID- 24473661 TI - [Race and nationality in Mexican biomedicine]. PMID- 24473663 TI - [Architectural and documental heritage: references on the institutionalization of health care in Bahia and in Brazil]. PMID- 24473662 TI - [From Morel's degeneration theory to Kraepelin's classification of mental illness]. PMID- 24473664 TI - [Building knowledge, controlling the body]. PMID- 24473665 TI - [When theory becomes fetish]. PMID- 24473666 TI - Treatment of generalised vitiligo with tacrolimus 0.1% ointment vs. UVB intense pulsed light phototherapy: a pilot study. PMID- 24473667 TI - Three-dimensional computed tomography analysis of variations in the middle hepatic vein tributaries: proposed new classification. AB - PURPOSE: To evaluate the anatomical variations in the middle hepatic vein tributaries (V5/V8) for determining the reconstruction strategy in right lobe living donor liver transplantation (LDLT). METHODS: The V5/V8 variations were examined in 268 patients and were classified into three and two types, respectively. The reconstruction rate (RR), patency rate (PR) and clinical outcomes were retrospectively evaluated in 46 right lobe LDLT cases. RESULTS: In terms of V5 variations, the RR and PR were significantly higher for type 2 than type 3 (82.6 vs. 44.4 % and 73.7 vs. 25.0 %, respectively). The alanine aminotransferase level on postoperative day (POD) 5 in the V5 patent group was significantly lower than in the occluded group (123 vs. 191 IU/dL). Regarding V8 variations, the RR and PR were significantly higher for type 1 than type 2 (44.4 vs. 17.6 % and 75.0 vs. 33.3 %, respectively). The aspartate aminotransferase level on POD 3 was significantly lower in the V8 patent group than in the occluded group (50 vs. 121 IU/dL). CONCLUSION: For right lobe grafts with single large V5 (type 2) or V8 (type 1) variations, reconstruction is necessary. Our new classification of the MHV tributaries is useful for determining the reconstruction strategy to use in right lobe LDLT. PMID- 24473668 TI - Risk factors for conversion of laparoscopic cholecystectomy to open surgery associated with the severity characteristics according to the Tokyo guidelines. AB - PURPOSE: The aim of this retrospective study was to identify the risk factors associated with the severity characteristics in the Tokyo guidelines for conversion to open surgery in patients with acute cholecystitis (AC) who underwent laparoscopic cholecystectomy. METHODS: A total of 225 patients were enrolled in the study. The patients were classified into two groups: a conversion group and a no-conversion group. The preoperative characteristics and therapeutic strategy were analyzed as risk factors for conversion to open surgery. The postoperative outcomes were also analyzed. RESULTS: Conversion to open surgery occurred in 29 patients (12.9%), including seven patients (6.7%) with mild AC and 22 patients (18.5%) with moderate AC. A univariate analysis showed that the risk factors for conversion to open surgery included a duration of symptoms longer than 72 h, an elevated C-reactive protein (CRP) value and the Tokyo guidelines 2013 (TG 13) severity classification. The multivariate analysis showed that the risk factors for conversion to open surgery included a duration of symptoms longer than 72 h and a CRP value >11.5 mg/dl. CONCLUSIONS: A duration of symptoms longer than 72 h, which is included in the criterion for moderate AC severity in the TG 13, was an independent risk factor for conversion to open surgery. In addition, adoption of a high CRP value as an additional criterion for moderate AC may increase the utility of the TG 13. PMID- 24473671 TI - Herpes simplex encephalitis as a potential cause of anti-N-methyl-D-aspartate receptor antibody encephalitis: report of 2 cases. AB - IMPORTANCE: Encephalitis mediated by anti-N-methyl-D-aspartate (NMDA) receptor antibodies and herpes simplex (HS) encephalitis are seemingly separate causes of encephalopathy in adults and children. Herpes simplex encephalitis is infectious, and anti-NMDA receptor antibody encephalitis is autoimmune in origin. Both can cause seizures and encephalopathy, although the latter can also cause psychiatric symptoms and movement disorders. Owing to the rarity of these 2 diseases, patients with co-occurrence are important because they alert clinicians to possible links between 2 seemingly separate processes. OBSERVATIONS: In a case series of 2 patients observed at our center, we describe an infant and an adult who had confirmed HS encephalitis and then developed confirmed anti-NMDA receptor antibody encephalitis. Polymerase chain reaction testing for HS virus was performed. Testing for NMDA receptor antibodies was performed by Associated Regional and University Pathologists Laboratory in Salt Lake City, Utah. CONCLUSIONS AND RELEVANCE: We conclude that atypical cases of HS or other viral encephalitides should be investigated for concomitance of an autoimmune encephalitis. We suspect that the pathophysiologic mechanisms by which HS virus infects neurons produce a higher likelihood of contracting anti-NMDA receptor antibody encephalitis. PMID- 24473669 TI - Perioperative nutritional therapy in liver transplantation. AB - Protein-energy malnutrition is frequently seen in patients with end-stage liver disease who undergo liver transplantation. This causes a deterioration of the patients' clinical condition and affects their post-transplantation survival. Accurate assessment of the nutritional status and adequate intervention are prerequisites for perioperative nutritional treatment. However, the metabolic abnormalities induced by liver failure make the traditional assessment of the nutritional status difficult. The methods that were recently developed for accurately assessing the nutritional status by body bioelectrical impedance may be implemented in pre-transplant management. Because preoperative malnutrition and the loss of skeletal muscle mass, called sarcopenia, have a significant negative impact on the post-transplantation outcome, it is essential to provide adequate nutritional support during all phases of liver transplantation. Oral nutrition is preferred, but tube enteral nutrition may be required to provide the necessary caloric intake. We herein discuss both bioelectrical impedance and the latest findings in the current perioperative nutritional interventions in liver transplant patients regarding synbiotics, micronutrients, branched-chain amino acid supplementation, the use of immune system modulating formulas, the fluid balance and the offering of nocturnal meals. PMID- 24473672 TI - Management of delayed suprachoriodal haemorrhage after intraocular surgery and trauma. AB - BACKGROUND: [corrected] To indentify surgical risk factors for delayed suprachoroidal haemorrhage (DSCH) and to report the outcomes of an effective intervention in a consecutive of patients. METHODS: The clinical data of ten patients diagnosed with DSCH in our hospital between July 2007 and December 2012 were extracted from hospital records and analyzed, including ophthalmologic examination, ophthalmologic ultrasonography, surgical procedures, and outcome measures including visual acuity and intraocular pressure. RESULTS: Ten eyes of ten patients including six men and four women with mean age of 56.6 +/- 17.67 years, with DSCH, were enrolled. After diagnosis, drainage or/and pars plana vitrectomy were performed for eight patients; another two received conservative treatment. All the patients were followed up for 15.2 +/- 4.3 months. Intraocular pressure decreased significantly (p < 0.001); the mean final visual acuity improved significantly after intervention (p < 0.001). CONCLUSIONS: We emphasized other great risk factors such as intraoperative mitomycin-C use, systemic anticoagulation or thrombolysis, and chronic kidney disease. It seems that earlier surgical intervention after the diagnosis of DSCH will be beneficial to patients by improving their final visual acuity. PMID- 24473673 TI - Clinical, radiographic and immunogenic effects after 1 year of tocilizumab-based treatment strategies in rheumatoid arthritis: the ACT-RAY study. AB - OBJECTIVE: To assess the 1-year efficacy and safety of a regimen of tocilizumab plus methotrexate or placebo, which was augmented by a treat-to-target strategy from week 24. METHODS: ACT-RAY was a double-blind, 3-year trial. Adults with active rheumatoid arthritis despite methotrexate were randomised to add tocilizumab to ongoing methotrexate (add-on strategy) or to switch to tocilizumab plus placebo (switch strategy). Tocilizumab 8 mg/kg was administered every 4 weeks. Conventional open-label disease-modifying antirheumatic drugs (DMARDs) other than methotrexate were added at week 24 or later in patients with DAS28>3.2. RESULTS: 556 patients were randomised; 85% completed 52 weeks. The proportion of patients receiving open-label DMARDs was comparable in the add-on (29%) and switch (33%) arms. Overall, week 24 results were maintained or further improved at week 52 in both arms. Some endpoints favoured the add-on strategy. Mean changes in Genant-modified Sharp scores were small; more add-on (92.8%) than switch patients (86.1%) had no radiographic progression. At week 52, comparable numbers of patients had antidrug antibodies (ADAs; 1.5% and 2.2% of add-on and switch patients, respectively) and neutralising ADAs (0.7% and 1.8%). Rates of serious adverse events and serious infections per 100 patient-year (PY) were 11.3 and 4.5 in add-on and 16.8 and 5.5 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3* upper limit of normal were observed in 11% of add-on and 3% of switch patients. CONCLUSIONS: Despite a trend favouring the add-on strategy, these data suggest that both tocilizumab add on and switch strategies led to meaningful clinical and radiographic responses. PMID- 24473675 TI - Photosensitizing activity of ferrocenyl bearing Ni(II) and Cu(II) dithiocarbamates in dye sensitized TiO2 solar cells. AB - Biferrocene bearing planar metal dithiocarbamates, namely, [M(FcCH2dtc)2] (dtc = furan-2-ylmethyldithiocarbamate, M = Cu(II) 1, Ni(II) 4; dtc = benzo[d][1,3]dioxol-5-ylmethyl dithiocarbamate, M = Cu(II) 2, Ni(II) 5; dtc = pyridin-2-ylmethyldithiocarbamate, M = Cu(II) 3, Ni(II) 6; Fc = ferrocenyl; Fe(eta(5)-C5H5)(eta(5)-C5H4-)), have been synthesized and characterized by microanalysis, magnetic susceptibility and cyclic voltammetry. Structures of 1, 2 and 4 have been obtained by single crystal X-ray diffraction. These complexes with pyridyl, piperonyl and furfuryl as heteroaromatic groups in the dithiocarbamate ligands have been exploited as sensitizers in dye sensitized TiO2 solar cells for converting sunlight into electrical energy. Light-to-electrical energy conversion efficiencies achieved using these sensitizers are considerably greater than those obtained with analogous compounds previously reported by us. The overall conversion efficiency (eta) is found to be dependent upon the nature of the heteroaromatic conjugated linkers and increases in the order eta (ferrocenylfurfuryl) > eta (ferrocenylpiperonyl) > eta (ferrocenylpyridyl) all values being lower than that obtained in the reference Ru dye N719 under similar experimental conditions. The conversion efficiencies also vary with the metal being higher for Ni (4, 5 and 6) than for Cu complexes (1, 2 and 3). The X-ray structural analyses reveal the existence of rare M...H-C intermolecular anagostic interactions involving the metal atom in chain motifs in 1 and 4, which are retained in solution as evidenced by (1)H NMR spectroscopy. PMID- 24473674 TI - Abatacept treatment reduces disease activity in early primary Sjogren's syndrome (open-label proof of concept ASAP study). AB - OBJECTIVE: To assess the efficacy and safety of abatacept in patients with early and active primary Sjogren's syndrome (pSS). METHODS: All 15 patients (12 women, three men) included in the open-label Active Sjogren Abatacept Pilot study met the revised American-European Consensus Group criteria for pSS and were biological disease-modifying antirheumatic drug-naive. Patients were treated with eight intravenous abatacept infusions on days 1, 15 and 29 and every 4 weeks thereafter. Follow-up was conducted at 4, 12, 24 (on treatment), 36 and 48 weeks (off treatment). Disease activity was assessed with European League Against Rheumatism (EULAR) Sjogren's Syndrome Disease Activity Index (ESSDAI) and EULAR Sjogren's Syndrome Patient Reported Index (ESSPRI). Several other functional, laboratory and subjective variables were analysed. Generalised estimating equations were used to analyse parameters over time. RESULTS: ESSDAI, ESSPRI, rheumatoid factor and IgG levels decreased significantly during abatacept treatment and increased post-treatment. Salivary and lacrimal gland function did not change during treatment. Fatigue and health-related quality of life (HR-QoL) improved significantly during treatment. No serious side effects or infections were seen. CONCLUSIONS: In this open-label study, abatacept treatment is effective, safe and well tolerated, and results in improved disease activity, laboratory parameters, fatigue and HR-QoL in patients with early and active pSS. TRIAL REGISTRATION NUMBER: 2009-015558-40. PMID- 24473676 TI - Stepping up: a nurse-led model of care for insulin initiation for people with type 2 diabetes. AB - BACKGROUND: Most people with type 2 diabetes (T2D) have glycaemic levels outside of target. Insulin is effective in improving glycaemia and most people with T2D eventually need this. Despite this, transition to insulin therapy is often delayed in primary care. OBJECTIVE: To develop a model of care (Stepping Up) for insulin initiation in routine diabetes care in Australian general practice. To evaluate the model for feasibility of integration within routine general practice care. METHODS: Drawing on qualitative work and normalisation process theory, we developed a model of care that included clarification of roles, in-practice systems and simple clinical tools. The model was introduced in an educational and practice system change intervention for general practitioners (GPs) and practice nurses (PNs). Five practices (seven GPs and five PNs) and 18 patients formed the feasibility study. Evaluation at 3 and 12 months explored experiences of GPs, PNs and patients. RESULTS: Fourteen patients commenced insulin, with average HbA1c falling from 8.4% (68.3 mmol/mol) to 7.5% (58.5 mmol/mol) at 3 months. Qualitative evaluation highlighted how the model of care supported integration of the technical work of insulin initiation within ongoing generalist GP care. Ensuring peer support for patients and issues of clinical accountability and flexibility, managing time and resources were highlighted as important. CONCLUSIONS: The Stepping Up model allowed technical care to be embedded within generalist whole-person care, supported clinicians and practice system to overcome clinical inertia and supported patients to make the timely transition to insulin. Testing of the model's effectiveness is now underway. PMID- 24473677 TI - Guidance for patients considering direct-to-consumer genetic testing and health professionals involved in their care: development of a practical decision tool. AB - BACKGROUND: Direct-to-consumer (DTC) genetic tests are available online, but there is little practical guidance for health professionals and consumers concerning their use. Work to produce such guidance was initially informed by three systematic reviews assessing the evidence on views and experiences of users and health professionals and policies of professional and bioethics organizations. The evidence suggested that consumers' motivations include general curiosity, improving their general health, ascertaining the risk of a particular condition or planning for future children. However, health professionals and bioethics organizations expressed concerns about potential harms resulting from these tests. Using this evidence, we constructed a list of topics to be included in proposed guidelines. METHODS: Using an expert group technique, we aimed to develop guidance for (i) potential consumers and (ii) health professionals approached by patients considering or having undertaken such tests. We considered it important to involve a wide range of participants with relevant experience. Accordingly, researchers and clinicians based in four countries were invited to a 2-day workshop in August 2012. Following an iterative process, we decided to produce clinically relevant and pragmatic guidance in the form of a decision support tool for use in primary care. RESULTS: By utilizing both the relevant literature and the experience of the expert group, we identified seven key underlying reasons that might prompt individuals to consider DTC testing. We considered primary care physicians as the most likely health professionals from whom individuals would seek advice. CONCLUSIONS: Based on the outcomes of the workshop, we developed a decision support tool encompassing varied clinical scenarios. Health professionals and patients are guided through a pathway that includes relevant actions and information on the appropriateness of the test. This tool will be freely accessible to health professionals and patients online. PMID- 24473678 TI - Synthesis of benzannulated heterocycles by twofold Suzuki-Miyaura couplings of cyclic diarylborinic acids. AB - Two-fold Suzuki-Miyaura cross-couplings of cyclic diarylborinic acids are described. This novel annulation method enables the synthesis of benzo-fused heterocycles from dihaloarenes or gem-dibromoolefins. PMID- 24473680 TI - Decadal time-scale monitoring of forest fires in Similipal Biosphere Reserve, India using remote sensing and GIS. AB - Analyzing the spatial extent and distribution of forest fires is essential for sustainable forest resource management. There is no comprehensive data existing on forest fires on a regular basis in Biosphere Reserves of India. The present work have been carried out to locate and estimate the spatial extent of forest burnt areas using Resourcesat-1 data and fire frequency covering decadal fire events (2004-2013) in Similipal Biosphere Reserve. The anomalous quantity of forest burnt area was recorded during 2009 as 1,014.7 km(2). There was inconsistency in the fire susceptibility across the different vegetation types. The spatial analysis of burnt area shows that an area of 34.2 % of dry deciduous forests, followed by tree savannah, shrub savannah, and grasslands affected by fires in 2013. The analysis based on decadal time scale satellite data reveals that an area of 2,175.9 km(2) (59.6 % of total vegetation cover) has been affected by varied rate of frequency of forest fires. Fire density pattern indicates low count of burnt area patches in 2013 estimated at 1,017 and high count at 1,916 in 2004. An estimate of fire risk area over a decade identifies 12.2 km(2) is experiencing an annual fire damage. Summing the fire frequency data across the grids (each 1 km(2)) indicates 1,211 (26 %) grids are having very high disturbance regimes due to repeated fires in all the 10 years, followed by 711 grids in 9 years and 418 in 8 years and 382 in 7 years. The spatial database offers excellent opportunities to understand the ecological impact of fires on biodiversity and is helpful in formulating conservation action plans. PMID- 24473681 TI - Assessment of the structural quality of streams in Germany--basic description and current status. AB - Fifteen years ago, the first mapping guidelines for the recording and evaluation of river physical habitat quality in Germany, closely following the Lander Arbeitsgemeinschaft Wasser (LAWA) field survey, have been published. In light of this experience, a revised version has now been developed for North Rhine Westphalia (West Germany). For the assessment, the streams are divided into segments serving as survey units. The survey is performed primarily in the field from the mouth to the source by an on-site recording of data. Defined reference conditions of the relevant morphological stream types serve as basis of the evaluation. Two evaluation procedures are carried out independently to validate the quality of the data. The proven basic concept operates as follows: the local scale habitat variables are grouped into 31 single parameters, which are then aggregated into six main parameters. These can further be aggregated into three zones: streambed, banks and adjacent land. The main modifications of the presented version are the following: (1) a larger differentiation of morphological stream types and (2) a higher level of detail concerning the mapping of relevant habitat characteristics. The last point allows additional evaluation options related to the morphological needs of the instream biota and a differentiated survey of anthropogenic degradation. Despite all modifications, the comparability with previous surveys has been largely maintained. By qualitative comparison of this method with other European mapping guidelines, different concepts of hydromorphological mapping are finally discussed. PMID- 24473682 TI - Application of a three-tier framework to assess ecological condition of Gulf of Mexico coastal wetlands. AB - A multi-level coastal wetland assessment strategy was applied to wetlands in the northern Gulf of Mexico (GOM) to evaluate the feasibility of this approach for a broad national scale wetland condition assessment (US Environmental Protection Agency's National Wetlands Condition Assessment). Landscape-scale assessment indicators (tier 1) were developed and applied at the sub-watershed (12-digit hydrologic unit code (HUC)) level within the GOM coastal wetland sample frame with scores calculated using land-use maps and geographic information system. Rapid assessment protocols (tier 2), using a combination of data analysis and field work, evaluated metrics associated with landscape context, hydrology, physical structure, and biological structure. Intensive site monitoring (tier 3) included measures of soil chemistry and composition, water column and pore-water chemistry, and dominant macrophyte community composition and tissue chemistry. Relationships within and among assessment levels were evaluated using multivariate analyses with few significant correlations found. More detailed measures of hydrology, soils, and macrophyte species composition from sites across a known condition gradient, in conjunction with validation of standardized rapid assessment method, may be necessary to fully characterize coastal wetlands across the region. PMID- 24473684 TI - Upfront chemotherapy with CCNU alone for adults' low-grade gliomas: a clinical analysis. PMID- 24473683 TI - C-terminally truncated form of alphaB-crystallin is associated with IDH1 R132H mutation in anaplastic astrocytoma. AB - Malignant gliomas are the most common human primary brain tumors. Point mutation of amino acid arginine 132 to histidine (R132H) in the IDH1 protein leads to an enzymatic gain-of-function and is thought to promote gliomagenesis. Little is known about the downstream effects of the IDH1 mutation on protein expression and how and whether changes in protein expression are involved in tumor formation or propagation. In the current study, we used 2D DIGE (difference gel electrophoresis) and mass spectrometry to analyze differences in protein expression between IDH1(R132H) mutant and wild type anaplastic (grade III) astrocytoma from human brain cancer tissues. We show that expression levels of many proteins are altered in IDH1(R132H) mutant anaplastic astrocytoma. Some of the most over-expressed proteins in the mutants include several forms of alphaB crystallin, a small heat-shock and anti-apoptotic protein. alphaB-crystallin proteins are elevated up to 22-fold in IDH1(R132H) mutant tumors, and alphaB crystallin expression appears to be controlled at the post-translational level. We identified the most abundant form of alphaB-crystallin as a low molecular weight species that is C-terminally truncated. We also found that overexpression of alphaB-crystallin can be induced by transfecting U251 human glioblastoma cell lines with the IDH1(R132H) mutation. In conclusion, the association of a C terminally truncated form of alphaB-crystallin protein with the IDH1(R132H) mutation is a novel finding that could impact apoptosis and stress response in IDH1 mutant glioma. PMID- 24473685 TI - New year, new look, new content. PMID- 24473686 TI - Osteoarthritis of knees: the disease burden in Hong Kong and means to alleviate it. PMID- 24473687 TI - The principle of assessing mental capacity for enduring power of attorney. AB - With Hong Kong's rapidly ageing population, increasing numbers of people now have some form of cognitive impairment. Enduring power of attorney is a legal instrument that can allow individuals to manage their financial matters if they subsequently become mentally incapacitated. The law requires that the mental capacity of the individual making an enduring power of attorney should be certified by a registered medical practitioner and a solicitor. This paper discusses the principles involved in the assessment of mental capacity for making an enduring power of attorney and uses this example to illustrate various important considerations in the formal assessment of mental capacity. PMID- 24473688 TI - Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome: a treatable genetic liver disease warranting urgent diagnosis. AB - Hyperornithinaemia-hyperammonaemia-homocitrullinuria syndrome is an autosomal recessive disorder caused by a defect in ornithine translocase. This condition leads to variable clinical presentations, including episodic hyperammonaemia, hepatic derangement, and chronic neurological manifestations. Fewer than 100 affected patients have been reported worldwide. Here we report the first two cases in Hong Kong Chinese, who were compound heterozygous siblings for c.535C>T (p.Arg179*) and c.815C>T (p.Thr272Ile) in the SLC25A15 gene. When the mother refused prenatal diagnosis for the second pregnancy, urgent genetic testing provided the definitive diagnosis within 24 hours to enable specific treatment. Optimal management of these two patients relied on the concerted efforts of a multidisciplinary team and illustrates the importance of an expanded newborn screening service for early detection and treatment of inherited metabolic diseases. PMID- 24473689 TI - Transnasal penetrating intracranial injury with a chopstick. AB - We report the first case of a transnasal penetrating intracranial injury in Hong Kong by a chopstick. A 49-year-old man attempted suicide by inserting a wooden chopstick into his left nose and then pulled it out. The chopstick caused a transnasal penetrating brain injury, confirmed by contrast magnetic resonance imaging of the brain. He was managed conservatively. Later he developed meningitis without a brain abscess and was prescribed antibiotics for 6 weeks. He enjoyed a good neurological recovery. This case illustrates that clinician should have a high index of suspicion for penetrating intracranial injury due to a nasally inserted foreign body, even though it had already been removed. In such cases moreover, brain magnetic resonance imaging is the imaging modality of choice, as it can delineate the path of penetration far better than plain computed tomography. PMID- 24473690 TI - Scrotal wall metastasis as the first manifestation of primary gastric adenocarcinoma. AB - Metastases to the scrotal wall are very rare, and being the initial manifestation of occult primary tumours is even rarer. We report on a patient presenting with painless scrotal swelling, attributed to a solid extra-testicular mass found on ultrasonography. Subsequent investigations and surgical exploration revealed it to be a scrotal wall metastasis from an occult gastric primary. To our knowledge, this is the first report of a scrotal wall metastasis from gastric adenocarcinoma. The ensuing discussion and literature review highlight the diagnostic challenges posed by an extra-testicular scrotal metastasis from an occult primary tumour. PMID- 24473691 TI - Middle cerebral artery infarction in a cancer patient: a fatal case of Trousseau's syndrome. AB - Trousseau's syndrome is defined as any unexplained thrombotic event that precedes the diagnosis of an occult visceral malignancy or appears concomitantly with a tumour. This report describes a young, previously healthy man diagnosed to have an acute middle cerebral arterial ischaemic stroke and lower-limb deep vein thrombosis, who subsequently succumbed to pulmonary arterial embolism. During the course of his illness, he was diagnosed to have a malignant pleural effusion secondary to an occult adenocarcinoma. This report highlights the need for a high degree of suspicion for occult malignancy and non-bacterial thrombotic endocarditis in young (<60 years old) ischaemic stroke patients with no identifiable conventional cardiovascular risks. In selected patients, transoesophageal echocardiography is the diagnostic investigation of choice, since transthoracic imaging is not sensitive. Screening tests for serum tumour markers and prompt heparinisation of these patients are suggested whenever ischaemic stroke secondary to malignancy-induced systemic hypercoagulability is suspected. PMID- 24473692 TI - Zero tolerance to trans fatty acids in infant formula? Fears, fiction, and facts. PMID- 24473693 TI - Laparoscopic removal of an eroding Mirena coil through the sigmoid colon. PMID- 24473694 TI - Authors' reply. PMID- 24473695 TI - Co-infection of influenza B and Streptococcus. PMID- 24473696 TI - Authors' reply. PMID- 24473697 TI - Ketamine-induced cholangiopathy. PMID- 24473698 TI - Transient myeloproliferative disorder and non-immune hydrops fetalis in a neonate with trisomy 21. PMID- 24473699 TI - Environmental exposures and the risk for Alzheimer disease: can we identify the smoking guns? PMID- 24473700 TI - Development of an arbitrary waveform membrane stretcher for dynamic cell culture. AB - In this paper, a novel cell stretcher design that mimics the real-time stretch of the heart wall is introduced. By culturing cells under stretched conditions that mimics the mechanical aspects of the native cardiac environment, better understanding on the role of biomechanical signaling on cell development can be achieved. The device utilizes a moving magnet linear actuator controlled through pulse-width modulated power combined with an automated closed loop feedback system for accurate generation of a designated mechanical stretch profile. The system's capability to stretch a cell culture membrane and accuracy of the designated frequency and waveform production for cyclic stretching were evaluated. Temperature and degradation assessments as well as a scalable design demonstrated the system's cell culture application for long term, in vitro studies. PMID- 24473701 TI - Predicting the metabolic condition after gestational diabetes mellitus from oral glucose tolerance test curves shape. AB - The objective of this feasibility study is to predict the metabolic condition in women with a history of gestational diabetes mellitus (GDM) from the shape of oral glucose tolerance test (OGTT) data. The rationale for this approach is that the evolution to a metabolic condition could be traceable in the shape of OGTT curves. 3-h OGTT data of 136 women with follow up, for a total of 401 OGTTs were analyzed. Subjects were classified as having normal (NGT) or non-normal glucose tolerance (NON-NGT), according to the American Diabetes Association criteria. The measured glucose, insulin, C-peptide data and combination of them were used to build up NGT and NON-NGT reference curves. Similarity between reference and individual OGTT-based curves was calculated using the Kullback-Leibler divergence. Our findings suggest that the shape of OGTT curves (1) contains information on the evolution to disease and (2) could be a reliable indicator to predict with high sensitivity (75%) and high specificity (69%) the metabolic condition of women with a history of GDM. In the future, the proposed shape-based prediction could be easily translated to the clinical practice, because it does not require the intervention of an operator specifically trained, thus facilitating its application in a clinical setting and ultimately empowering risk estimation, by improving/complementing the information which is currently adopted for risk stratification after pregnancy with GDM. PMID- 24473702 TI - Assessment of transverse isotropy in clinical-level CT images of trabecular bone using the gradient structure tensor. AB - The aim of this study was to develop a GST-based methodology for accurately measuring the degree of transverse isotropy in trabecular bone. Using femoral sub regions scanned in high-resolution peripheral QCT (HR-pQCT) and clinical-level resolution QCT, trabecular orientation was evaluated using the mean intercept length (MIL) and the gradient structure tensor (GST) on the HR-pQCT and QCT data, respectively. The influence of local degree of transverse isotropy (DTI) and bone mineral density (BMD) was incorporated into the investigation. In addition, a power based model was derived, rendering a 1:1 relationship between GST and MIL eigenvalues. A specific DTI threshold (DTI thres) was found for each investigated size of region of interest (ROI), above which the estimate of major trabecular direction of the GST deviated no more than 30 degrees from the gold standard MIL in 95% of the remaining ROIs (mean error: 16 degrees ). An inverse relationship between ROI size and DTI thres was found for discrete ranges of BMD. A novel methodology has been developed, where transversal isotropic measures of trabecular bone can be obtained from clinical QCT images for a given ROI size, DTI thres and power coefficient. Including DTI may improve future clinical QCT finite-element predictions of bone strength and diagnoses of bone disease. PMID- 24473703 TI - The cobalt corrole catalyzed hydrogen evolution reaction: surprising electronic effects and characterization of key reaction intermediates. AB - A surprising effect of halide substituents on reduction potentials and catalytic activity of halogenated cobalt corroles has been deduced by experimental and computational methods; the proton-activating cobalt(I) and the cobalt(II) corrole that is formed in the step during which hydrogen is formed are characterized by NMR spectroscopy. PMID- 24473704 TI - Hair zinc levels and the efficacy of oral zinc supplementation in patients with atopic dermatitis. AB - Zinc deficiency in patients with atopic dermatitis (AD) and the use of zinc supplementation is still controversial. We measured hair zinc levels in 58 children with AD and 43 controls (age range 2-14 years). We also investigated the efficacy of oral zinc supplementation in AD patients with low hair zinc levels by comparing eczema assessment severity index (EASI), transepidermal water loss (TEWL), and visual analogue scales for pruritus and sleep disturbance in patients receiving zinc supplementation (Group A) and others not receiving supplementation (Group B). At baseline, the mean zinc level was significantly reduced in AD patients (113.1 MUg/g vs. 130.9 MUg/g, p = 0.012). After 8 weeks of supplement, hair zinc level increased significantly in Group A (p < 0.001), and EASI scores, TEWL, and visual analogue scales for pruritus improved more in Group A than in Group B (p = 0.044, 0.015 and < 0.001, respectively). Thus, oral zinc supplementation may be effective in AD patients with low hair zinc levels. PMID- 24473706 TI - Development of novel AllGlo-probe-based one-step multiplex qRT-PCR assay for rapid identification of avian influenza virus H7N9. AB - Recently, human deaths have resulted from infection with low-pathogenicity avian influenza virus H7N9 strains that have emerged recently in China. To strengthen H7N9 surveillance and outbreak control, rapid and reliable diagnostic methods are needed. To develop a sensitive quantitative real-time RT-PCR assay for rapid detection of H7N9 viral RNA, primers and AllGlo probes were designed to target the HA and NA genes of H7N9. Conserved sequences in the HA and NA genes were identified by phylogenic analysis and used as targets for H7N9 virus detection. The similarities of the targeted HA and NA gene sequences from different H7 and N9 influenza virus strains were 93.2-99.9 % and 96.0-99.6 %, respectively The specificity and sensitivity of the new multiplex real-time qRT-PCR was established. The test was used for the detection of viral RNA in human pharyngeal swabs and environmental samples. The detection limit of the multiplex qRT-PCR was estimated to be about 10(-1) TCID50/reaction. Finally, the diagnostic sensitivities of the multiplex qRT-PCR, virus isolation and TaqMan qRT-PCR were compared using pharyngeal swabs and environmental samples. These analyses yielded positive results in 46.7 %, 43.3 % and 20.0 % of the samples, respectively. The novel multiplex AllGlo qRT-PCR is a rapid and sensitive method to identify H7N9 virus in clinical and environmental samples and can be used to facilitate studies on the epidemiology of H7N9 virus. PMID- 24473707 TI - Immunogenicity of the capsid precursor and a nine-amino-acid site-directed mutant of the 3C protease of foot-and-mouth disease virus coexpressed by a recombinant goatpox virus. AB - The myristoylated capsid precursor mP1-2A of foot-and-mouth disease virus (FMDV), when expressed in mammalian cells and processed by the FMDV 3C protease, can self assemble into virus-like particles (VLPs). In the present study, nine amino acids of the 3C protease were replaced by site-directed mutagenesis to create a mutant 3C protease, 9m3C. To coexpress mP1-2A and 9m3C and test the resulting proteolytic processing and VLP assembly, two recombinant goatpox viruses (rGTPVs) were constructed by the insertion of two coding regions, one for mP1-2A and the other for either 9m3C (rGTPV-mP1-2A-9m3C) or Theileria protective antigen (TPA) as a control (rGTPV-mP1-2A-TPA). The two exogenous genes were inserted into an intergenic region between loci gp_24 and gp_24.5 of the rGTPV genome. Western blotting of cells infected with rGTPV-mP1-2A-9m3C showed that proteins VP0, VP1, and VP3 from the mP1-2A processed by the 9m3C protease could be detected by polyclonal FMDV sera. As observed by electron microscopy, the infected cells produced VLPs with a diameter of about 25 +/- 2 nm. Titers of neutralizing antibody against FMDV were significantly higher in mice inoculated with rGTPV-mP1 2A-9m3C, which expresses the 9m3C protease together with mP1-2A, than mice inoculated with the control rGTPV-mP1-2A-TPA, which does not express the protease. An ovine immunization test determined that sheep inoculated intramuscularly with rGTPV-mP1-2A-9m3C produced FMDV-specific neutralizing antibody, but its titers did not meet the requirement of the World Organization for Animal Health. The result indicates that further modifications of rGTPV-mP1 2A-9m3C are necessary to produce an effective vaccine. PMID- 24473708 TI - A comparison of the efficiency of ELISA and selected primer sets to detect Norovirus isolates in southern Ireland over a four-year period (2002-2006): variation in detection rates and evidence for continuing predominance of NoV GII.4 genotype. AB - Norovirus (NoV) gastroenteritis occurs in all age groups and is the most common cause of gastroenteritis in the community. However, detection methods and rates vary widely, and few data are available to compare these, particularly in Ireland. Detection of noroviruses through antigen and molecular-based strategies was carried out on 135 suspected NoV-positive samples, collected over the course of three NoV outbreaks, from 2002 to 2006, in the southern region of Ireland. A commercially available ELISA and a panel of six primer sets were evaluated to determine their suitability for NoV detection in Irish clinical samples. The key findings of this study were the detection of both GGI and GGII noroviruses by ELISA, but the detection of only GGII noroviruses by RT-PCR. In addition to this, a variation in the levels of detection from 9.4 % to 17.3 % was observed for conventional PCR assays, while a detection rate of 46.3 % was observed for the real-time PCR assay. A proportion (17.8 %) of samples were found to be negative by all detection strategies, suggesting the possibility of reporting false positives for these samples or low-copy positives that do not often repeat. Sequencing information from selected samples also revealed nucleotide polymorphisms, compromising efficient primer binding in the case of one primer pairing. Phylogenetic analysis of the partial polymerase gene identified NoV GII.4 as the dominant genotype, in accordance with previous NoV studies in Ireland. Investigating the NoV diversity of the circulating strains and the dynamics of strain replacement is important to better assess the efficacy of future NoV vaccines and to facilitate the early detection of changes in circulating NoV strains. PMID- 24473709 TI - Infectivity and complete nucleotide sequence of cucumber fruit mottle mosaic virus isolate Cm cDNA. AB - Three isolates of cucumber fruit mottle mosaic virus (CFMMV) were collected from melon, cucumber, and pumpkin plants in Korea. A full-length cDNA clone of CFMMV Cm (melon isolate) was produced and evaluated for infectivity after T7 transcription in vitro (pT7CF-Cmflc). The complete CFMMV genome sequence of the infectious clone pT7CF-Cmflc was determined. The genome of CFMMV-Cm consisted of 6,571 nucleotides and shared high nucleotide sequence identity (98.8 %) with the Israel isolate of CFMMV. Based on the infectious clone pT7CF-Cmflc, a CaMV 35S promoter driven cDNA clone (p35SCF-Cmflc) was subsequently constructed and sequenced. Mechanical inoculation with RNA transcripts of pT7CF-Cmflc and agro inoculation with p35SCF-Cmflc resulted in systemic infection of cucumber and melon, producing symptoms similar to those produced by CFMMV-Cm. Progeny virus in infected plants was detected by RT-PCR, western blot assay, and transmission electron microscopy. PMID- 24473710 TI - The complete genomic sequence of a second novel partitivirus infecting Ustilaginoidea virens. AB - The bisegmented genome of a putative double-stranded (ds) RNA virus from Ustilaginoidea virens was sequenced and analyzed. The larger genomic segment of 2112 bp encodes a putative RNA-dependent RNA polymerase (RdRp, 628 aa), and the smaller one of 2082 bp encodes a putative coat protein (CP) of 539 aa. The 5' untranslated regions (UTR) of the two segments share regions of high sequence homology. Phylogenetic analysis indicates that this novel partitivirus, named Ustilaginoidea virens partitivirus 2 (UvPV2), can be assigned to the family Partitiviridae. PMID- 24473711 TI - Complete genome sequence of a novel hypovirus infecting Phomopsis longicolla. AB - The complete nucleotide sequence and genome organization of a hypovirus from the isolate ME711 of Phomopsis longicolla was determined and compared to sequences of members of the family Hypoviridae. The genome of the hypovirus, tentatively named Phomopsis longicolla hypovirus 1 (PlHV1-ME711), was determined to be 9760 nucleotides long, excluding the 3' poly (A) tail. The genome contains a single large open reading frame (ORF) encoding a polyprotein designated as P307. Its genomic organization is typical of members of the proposed genus Betahypovirus (Yaegashi et al. in Virus Res 165:143-50, 2012). PMID- 24473712 TI - NF-kappaB activation induced by hepatitis A virus and Newcastle disease virus occurs by different pathways depending on the structural pattern of viral nucleic acids. AB - NF-kappaB is activated by hepatitis B virus and hepatitis C virus and is assumed to contribute to viral persistence, leading to the development of hepatocellular cancer by inhibition of apoptosis mediated by cytotoxic T cells. Whether hepatitis A virus (HAV), which does not cause chronic infection, activates NF kappaB is a topic of controversy. Here, we confirm that HAV activates NF-kappaB and show that HAV enhances the activation of NF-kappaB by poly(I-C), but it inhibits the activation of NF-kappaB by Newcastle disease virus (NDV), a paramyxovirus. In addition, HAV inhibits NF-kappaB activation induced by overexpressed MAVS (mitochondrial antiviral signaling protein). We conclude from these findings that NF-kappaB induction occurs in cells infected with HAV by dsRNA, independently of mitochondrial-transduced RIG-I/MDA-5 signaling, whereas the induction of NF-kappaB in cells infected by NDV is mediated by RIG-I signaling, independenly of viral dsRNA. This is supported by experiments in which the different RNA inducers of RIG-I and MDA-5 are sequestered and which also show that poly(I-C) and HAV, but not NDV, are functionally equivalent in inducing NF kappaB activity. Furthermore, we demonstrate that HAV interferes with the protein kinase R (PKR) activity and PKR activation induced by dsRNA, and that HAV-induced activation of NF-kappaB therefore does not take place via the PKR-induced pathway. As assumed for hepatitis B and C virus infections, NF-kappaB activation could attenuate the effects of cytotoxic T cells and may contribute to prolonged as well as relapsing courses of hepatitis A. PMID- 24473713 TI - The experience and excellence of the Hospital for Rehabilitation of Craniofacial Anomalies, University of Sao Paulo (HRAC/USP), in the rehabilitative treatment of cleft lip and palate. PMID- 24473714 TI - Anterior composite restorations in clinical practice: findings from a survey with general dental practitioners. AB - OBJECTIVES: The aim of this study was to assess technical preferences of general dental practitioners when restoring anterior composite restorations. How the level of clinical experience or post-graduate training infuenced their options was also tested. MATERIAL AND METHODS: A cross-sectional study was performed using a questionnaire with general dental practitioners (GDPs) (n=276) in Southern Brazil. Information regarding post graduation training (specialization, master's or PhD degree) and linical experience (years since completing graduation) were gathered. The options regarding anterior composite restorations (type of composite, adhesive system, light curing unit, polishing procedures and rubber dam use) were collected. Data were submitted to descriptive analysis and associations were tested. RESULTS: Response rate was 68% (187). GDPs selected microhybrid composite (52%) and 2-step total etch adhesive system (77%). LED was the preferred method of activation for 72.8%. Immediate polishing was preferred by 75%, using a combination of techniques. Most of the respondents (74.3%) did not use rubber dam. More experienced clinicians used more halogen lights (p<0.022), performed more light monitoring (p<0.001) and were resistant to use rubber dam (p<0.012). Dentists with post-graduation training used 3-etch-and rinse system more frequently (p<0.04), usually monitored light intensity (p<0.014) and placed rubber dam more frequently (p<0.044). CONCLUSIONS: Hybrid composite, simplifed adhesives, LED units and immediate polishing were preferred by Southern Brazilian dentists for anterior composite restorations. Few dentists used rubber dam to perform composite restorations in anterior teeth. Clinical experience and post-graduation training infuenced the dentists' choices. PMID- 24473715 TI - Experimental evaluation of cyclic fatigue resistance of four different nickel titanium instruments after immersion in sodium hypochlorite and/or sterilization. AB - NiTi instruments have a high risk of separation due to torsional or flexural fatigue (cyclic fatigue). Chemomechanical preparation, cleaning procedures, chemical disinfection and sterilization cause the corrosion of endodontic instruments that may weaken the fracture resistance of the instruments. Objective To assess the effects of NaOCl immersion and autoclave sterilization on the cyclic fatigue resistance of ProFile, FlexMaster, Mtwo and TwistedFiles NiTi instruments (tip size 25, 0.06 taper, n=160). Material and Methods The instruments (n=10 for each subgroup) were dynamically immersed in NaOCl; immersed in NaOCl and sterilized in one autoclave cycle; 5 cycles immersed in NaOCl and sterilized in autoclave and not immersed in NaOCl and not sterilized (control group). Dynamic cyclic fatigue resistance was tested. The number of cycles to failure (NCF) were statistically analyzed (P<0.05). Results Kruskall-Wallis test indicated significant differences among the tested instruments in terms of NCF (P=0.000). The mean NCF of Mtwo (556.75) was higher than that of the Twisted File, Flexmaster and ProFile, 483.1, 376.12, 365.25, respectively. NaOCl immersion and autoclave sterilization have no effect on the NCF values of the tested instruments (P>.05). Conclusions Cyclic fatigue resistance of the tested NiTi instruments cannot be adversely affected by NaOCl immersion and autoclave sterilization. Production process (TwistedFiles) or design (Twisted Files, FlexMaster, Mtwo and ProFile) of the instruments can influence their cyclic fatigue resistance. PMID- 24473716 TI - Stress distribution on dentin-cement-post interface varying root canal and glass fiber post diameters. A three-dimensional finite element analysis based on micro CT data. AB - OBJECTIVE: The aim of the present study was to analyze the influence of root canal and glass fiber post diameters on the biomechanical behavior of the dentin/cement/post interface of a root-filled tooth using 3D finite element analysis. MATERIAL AND METHODS: Six models were built using micro-CT imaging data and SolidWorks 2007 software, varying the root canal (C) and the glass fiber post (P) diameters: C1P1-C=1 mm and P=1 mm; C2P1-C=2 mm and P=1 mm; C2P2-C=2 mm and P=2 mm; C3P1-C=3 mm and P=1 mm; C3P2-C=3 mm and P=2 mm; and C3P3-C=3 mm and P=3 mm. The numerical analysis was conducted with ANSYS Workbench 10.0. An oblique force (180 N at 45o) was applied to the palatal surface of the central incisor. The periodontal ligament surface was constrained on the three axes (x=y=z=0). Maximum principal stress (sigma(max)) values were evaluated for the root dentin, cement layer, and glass fiber post. RESULTS: The most evident stress was observed in the glass fiber post at C3P1 (323 MPa), and the maximum stress in the cement layer occurred at C1P1 (43.2 MPa). The stress on the root dentin was almost constant in all models with a peak in tension at C2P1 (64.5 MPa). CONCLUSION: The greatest discrepancy between root canal and post diameters is favorable for stress concentration at the post surface. The dentin remaining after the various root canal preparations did not increase the stress levels on the root. PMID- 24473717 TI - The teaching of temporomandibular disorders and orofacial pain at undergraduate level in Brazilian dental schools. AB - OBJECTIVES: Evaluate the way the topics for the study of pain mechanisms in general, and Orofacial Pain (OFP) and temporomandibular disorders (TMDs) more specifically, are addressed in undergraduate courses curricula, and also to verify the existence of specialist OFP/TMD teachers in Brazilian dental schools. METHODS: Between July 2010 and January 2011, course Coordinators/Directors of all dental schools duly registered at the Ministry of Education were invited to answer a questionnaire on topics related to OFP/TMD teaching in their institutions. RESULTS: Fifty-three dental schools representatives answered the questionnaire. The study of pain mechanisms was found to cover an average of less than 10% of the courses' total time. Pharmacology, Endodontics and Physiology were identified as the departments usually responsible for addressing pain mechanisms in dental courses. Psychosocial aspects were found to occupy a very small proportion in the syllabi, while most of the content referred to biological or somatic aspects. OFP/TMD is addressed by a specific department in only 28.4% of the participating dental schools, while in most cases (46.3%), OFP/TMD is under the responsibility of the Prosthodontics department. Only 38.5% of respondents indicated that they had a specialist OFP/TMD teacher in their Schools. CONCLUSION: Among the Brazilian dental schools participating in the study, the teaching of OFP/TMD was found to be insufficient, segmented or with an extremely restricted focus. This initial assessment indicates that Curricular Guidelines for the study of OFP/TMD at undergraduate dental schools should be developed and implemented to facilitate their appropriate inclusion into the curricula and in specific pedagogical projects. PMID- 24473718 TI - In situ protocol for the determination of dose-response effect of low-fluoride dentifrices on enamel remineralization. AB - No in situ protocol has assessed the dose-response effects of fluoride dentifrices involving low-fluoride formulations. OBJECTIVE: To assess the ability of an in situ remineralization model in determining dose-response effects of dentifrices containing low fluoride concentrations ([F]) on bovine enamel. MATERIAL AND METHODS: Volunteers wore palatal appliances containing demineralized enamel blocks and brushed their teeth and devices with the dentifrices supplied (double-blind, crossover protocol) separately for 3 and 7 days. Surface hardness (SH), integrated subsurface hardness (DeltaKHN) and [F] in enamel were determined. Data were analyzed by ANOVA, Tukey's test and Pearson's correlation (p<0.05). RESULTS: Dose-response relationships were verified between [F] in dentifrices and SH, DeltaKHN and enamel [F]. Higher correlation coefficients between enamel [F] and SH and DeltaKHN were obtained for the 3-day period. Significant differences in SH and DeltaKHN were observed among all groups for the 3-day period, but not between 0-275, 275-550, and 550-1,100 ug F/g dentifrices for the 7-day period, nor between 3- and 7-day periods for the 1,100 ug F/g groups. CONCLUSIONS: Considering that the peak remineralization capacity of the conventional dentifrice (1,100 ug F/g) was achieved in 3 days, this experimental period could be used in future studies assessing new dentifrice formulations, especially at low-fluoride concentrations. PMID- 24473719 TI - Influence of radiopaque fillers on physicochemical properties of a model epoxy resin-based root canal sealer. AB - OBJECTIVE: To verify the influence of radiopaque fillers on an epoxy resin-based sealer. MATERIAL AND METHODS: Experimental sealers were formulated by adding 20%, 40%, 60%, 80%, 100% and 120% of calcium tungstate, ytterbium trifluoride or barium sulphate by weight to an epoxy-resin-base. Setting time, flow, film thickness, radiopacity, sorption, solubility, pH and push-out bond strength were evaluated. RESULTS: The setting time ranged from 373 to 612.66 min, the flow varied from 13.81+/-0.49 to 22.49+/-0.37 mm, and the film thickness ranged from 16.67+/-5.77 to 33.33+/-11.54 um. The lowest pH was 5.47+/-0.53, and the highest was 6.99+/-0.03. Radiopacity varied from 0.38+/-0.04 to 2.57+/-0.21 mmAl and increased with the amount of filler. Calcium tungstate sealers had a higher sorption and solubility than other sealers. There was no significant difference in the push-out bond strength among the fillers at the 120% concentration. CONCLUSION: The inorganic fillers evaluated and their concentrations affect the physicochemical properties of an epoxy resin-based root canal sealer. PMID- 24473720 TI - Morphology and morphometry of the human sublingual glands in mouth floor enlargements of edentulous patients. AB - Asymptomatic mouth floor enlargements may be observed in edentulous patients. These masses, which protrude from the mouth floor, may complicate the fitting of dentures and require surgery. Whether this "entity" may be considered an anatomical variation of the mouth floor or represent specific alterations in the sublingual gland is not known. OBJECTIVE: The aim of this work is to investigate the morphological and morphometric aspects of the sublingual glands of edentulous patients with mouth floor enlargements and compare the glands of these patients with the sublingual glands of human cadavers. MATERIAL AND METHODS: Microscopic evaluation was performed on human sublingual glands from edentulous patients with mouth floor enlargements (n=20) and edentulous cadavers (n=20). The patients and cadavers were of similar ages. The data were compared using Mann-Whitney U, Fisher's exact and Student's t tests (p<0.05). RESULTS: Acinar atrophy, duct-like structures, mononuclear infiltrates, replacement of parenchyma with fibrous/adipose tissue, mucous extravasation and oncocytosis were similar between the groups (p>0.05). Only the variables "autolysis" and "congested blood vessels" presented statistical difference between groups (p=0.014; p=0.043). The morphometric study revealed that the volume densities of acini, ducts, stroma and adipose tissue were similar between the groups (p>0.05). CONCLUSION: The microscopic characteristics of the sublingual glands in mouth floor enlargements in edentulous patients correspond to characteristics associated with the normal aging process. The glands are not pathological and represent an age-related alteration that occurs with or without the presence of the mouth floor enlargements. PMID- 24473721 TI - Stability of Class II treatment with the Bionator followed by fixed appliances. AB - OBJECTIVE: This prospective study assessed the stability of Class II treatment with the Bionator, followed by fixed appliances, 10 years after treatment. MATERIAL AND METHODS: The experimental group comprised 23 patients of both sexes (10 boys, 13 girls) at a mean initial age of 11.74 years (late mixed or early permanent dentitions), treated for a mean period of 3.55 years who were evaluated at three stages: initial (T1), final (T2) and long-term posttreatment (T3). A total of 69 lateral cephalograms were evaluated and 69 dental casts were measured using the PAR index. The difference between initial and final PAR indexes, the percentage of occlusal improvement obtained with therapy and the percentage of relapse were calculated, using the PAR index. The variables were compared by repeated measures analysis of variance (ANOVA) followed by Tukey tests. RESULTS: The significant improvement in apical base relationship, the palatal inclination of the maxillary incisors and the labial inclination of the mandibular incisors, and the significant improvement in molar relationship and reduction of overjet and overbite, obtained with treatment, remained stable in the long-term posttreatment period. There was also significant improvement in the occlusal relationships which remained stable in the long-term posttreatment period. The percentage of occlusal improvement obtained was of 81.78% and the percentage of relapse was of 4.90%. CONCLUSIONS: Treatment of Class II division 1 malocclusions with the Bionator associated with fixed appliances showed to be stable in the long-term posttreatment period. PMID- 24473722 TI - Relationship between friction force and orthodontic force at the leveling stage using a coated wire. AB - The relationship between orthodontic force and friction produced from an archwire and brackets affects the sliding of the wire in the leveling stage. OBJECTIVE: The purpose of this study was to evaluate the relationship between force and friction in a small esthetic nickel-titanium (Ni-Ti) wire. MATERIAL AND METHODS: Five esthetic wires (three coated and two plated) and two small, plain Ni-Ti wires (0.012 and 0.014 inches) were used. We performed a three-point bending test according to ISO 15841 and the drawing test with a dental arch model designed with upper linguoversion of the lateral incisor in the arch (displacements of 0.5, 1.0, 2.0 and 3.0 mm), and evaluated the relationship between them. RESULTS: Unloading bending forces of all wires at displacements of less than 1.0 mm were larger than friction forces, but all friction forces at displacements exceeding 2.0 mm were larger than unloading bending forces. The arch likely expands when displacement from the proximal brackets exceeds 1.0 mm. The friction force of a martensite 0.014-inch Ni-Ti wire was significantly greater than those of the other esthetic and austenitic wires. CONCLUSIONS: A wire with the smallest possible friction force should be used in cases with more than 1.0 mm displacement. PMID- 24473723 TI - Experimental study on penetration of dental implants into the maxillary sinus in different depths. AB - The exposing of dental implant into the maxillary sinus combined with membrane perforation might increase risks of implant failure and sinus complications. OBJECTIVE: The purpose of this study was to investigate the effects of the dental implant penetration into the maxillary sinus cavity in different depths on osseointegration and sinus health in a dog model. MATERIAL AND METHODS: Sixteen titanium implants were placed in the bilateral maxillary molar areas of eight adult mongrel dogs, which were randomly divided into four groups according to the different penetrating extents of implants into the sinus cavities (group A: 0 mm; group B: 1 mm; group C: 2 mm; group D: 3 mm). The block biopsies were harvested five months after surgery and evaluated by radiographic observation and histological analysis. RESULTS: No signs of inflammatory reactions were observed in any maxillary sinus of the eight dogs. The tips of the implants with penetrating depth of 1 mm and 2 mm were found to be fully covered with newly formed membrane and partially with new bone. The tips of the implants with penetrating depth over 3 mm were exposed in the sinus cavity and showed no membrane or bone coverage. No significant differences were found among groups regarding implant stability, bone-to-implant contact (BIC) and bone area in the implant threads (BA). CONCLUSIONS: Despite the protrusion extents, penetration of dental implant into the maxillary sinus with membrane perforation does not compromise the sinus health and the implant osseointegration in canine. PMID- 24473724 TI - Influence of exposure time to saliva and antioxidant treatment on bond strength to enamel after tooth bleaching: an in situ study. AB - OBJECTIVES: This study evaluated the influence of different exposure times to saliva in situ in comparison with an antioxidant treatment on composite resin bond strength to human enamel restored after tooth bleaching. MATERIAL AND METHODS: Forty human teeth specimens measuring 5x5 mm were prepared and randomly allocated into 5 groups with 8 specimens each: Gct (control group, restored on unbleached enamel); Gbl (restored immediately after bleaching); Gsa (bleached, treated with 10% sodium ascorbate gel for 60 min and restored); G7d (bleached, exposed to saliva in situ for 7 days and restored); and G14d (bleached, exposed to saliva in situ for 14 days and restored). Restored samples were cut into 0.8 mm2 sticks that were tested in microtensile. Specimens were microscopically analyzed and failure modes were classified as adhesive, cohesive, or mixed. Pretest and cohesive failures were not considered in the statistical analysis, which was performed with one-way ANOVA and Tukey's post-hoc test (alpha=0.05), with the dental specimen considered as the experimental unit. RESULTS: Mean bond strength results found for Gbl in comparison with Gct indicated that bleaching significantly reduced enamel adhesiveness (P<0.01). However, no statistically significant differences were found between Gct, Gsa and G7d (P>0.05). Bond strength found for G14d was significantly higher than for Gsa (P<0.01). Fractures modes were predominantly of a mixed type. CONCLUSIONS: Bonding strength to bleached enamel was immediately restored with the application of sodium ascorbate and exposure to human saliva in situ for at least 7 days. Best results were obtained with exposure to human saliva in situ for 14 days. Treatment with sodium ascorbate gel for 60 min may be recommended in cases patients cannot wait for at least 7 days for adhesive techniques to be performed. PMID- 24473725 TI - In vitro evaluation of the marginal and internal discrepancies of different esthetic restorations. AB - OBJECTIVE: This study examined the fit of two types of all-ceramic single crowns and indirect composite resin full coverage crowns. MATERIAL AND METHODS: Thirty intact human mandibular first premolars were selected for this study and prepared using a machine to standardize the dimensions and randomly divided into 3 groups. Slip cast (IC) (In-Ceram Zirconia, Vita Zahnfabrik), copy-milled zirconia (CM) (ICE, Zirkonzahn) and indirect composite resin crowns (NECO, HeraeusKulzer, Hanau, Germany), (N=30, 10 per group) were fabricated according to each manufacturer's recommendations. Before cementation, discrepancies were measured at the marginal zone in each crown. Crowns were then cemented with G-Cem capsule self-adhesive luting cement (GC Corporation, Tokyo, Japan). Four positions were marked for each zone (mid-facial, mid-mesial, mid-distal, and mid-lingual) and three measurements were made at each of the four positions yielding to a total of 12 measurements per crown before and after cementation. The measurements were performed at a different magnification using a stereo microscope (SZ11, Olympus, Japan). Marginal, axial and occlusal zone discrepancies (um) were evaluated after cementation. The data were statistically analyzed using two-way ANOVA and Tukey's test. RESULTS: Before cementation, significantly less marginal discrepancies were noted compared with after cementation in all groups (p<0.05). No significant differences were found within each zone (Marginal= IC: 84.2, NECO: 95.22, CM: 84.22; Axial= IC: 54.22, NECO: 64.2, CM: 55.22; Occlusal= IC: 119.97, NECO: 129.18, CM: 121.15) in the three crown systems (p>0.05). Occlusal zone discrepancies were significantly higher than those of the marginal and axial zones in all groups (p<0.05). CONCLUSIONS: Slip cast and copy-milled zirconia crowns showed comparable fit to composite resin crowns in all marginal, axial and occlusal areas. PMID- 24473726 TI - Website Babies Portal: development and evaluation of the contents regarding orofacial functions. AB - Education mediated by technology facilitates the access to information and can reach more people, including a broader range of socio-economic groups and ages, and at a low-cost. The website "Babies Portal - Speech-Language Pathology/Audiology and Dentistry" (http://portaldosbebes.fob.usp.br) was developed to provide parents with information on communication procedure disorders and oral health, enabling them to prevent and identify any changes in development early while looking for the best treatment. OBJECTIVE: The objective is to describe the development and evaluation of the content pertaining to the oral functions featured in the "Babies Portal". METHODS: The first stage consisted of a literature review, development/selection of illustrations and an evaluation of the possible external links that could be available. In the second stage, 10 speech-language and hearing pathologists (group A) and five parents of babies (group B) evaluated the website via an online form, which included ethical and personal information and questions about the quality, technical information and comparative prior knowledge acquired after the access. In the first stage, there was the construction of five sections ("The Oral Functions", "Breastfeeding", "Food", "Pacifier, baby bottle and finger sucking" and "Breath") based on scientific studies, presenting objective information, content links prepared by the Ministry of Health and a Dentistry section in the "Babies Portal" website. Videos, static and dynamic images were also distributed throughout the sections. RESULTS: Regarding the second stage, 90% of all speech-language and hearing pathologists judged a good/excellent quality for all sections and classified the technical quality as very good. By their turn, 88% of the parents (group B) reported that the website helped or helped very much in understanding the contents, and 80% rated the quality as good or excellent. CONCLUSIONS: Five sections concerning the oral functions were structured, and the results collected from groups A and B suggest that the content provided is adequate and reliable. PMID- 24473728 TI - Effect of natural gel product on bovine dentin erosion in vitro. AB - OBJECTIVE: To evaluate the efficacy of Neem (Azadirachta indica) experimental gel for the prevention of erosive wear on bovine dentin, in vitro. MATERIAL AND METHODS: One hundred dentin blocks were allocated into 5 experimental groups (20 samples each): C (control group, without gel); CG (control group, only base gel); F (fluoride gel, 1.23% NaF; pH 4.1, Dentsply; Brazil); N (Neem gel, 10% neem extract; pH 4.1, manipulation); NF (Neem+fluoride gel, 10% Neem extract and 1.23% NaF; pH 4.1, manipulation). The blocks were stored in artificial saliva for 24 hours. After this, they were submitted to six alternating re- and demineralization cycles. The blocks were analyzed for wear (profilometry). The results were submitted to statistical analysis by ANOVA and Tukey tests (P<0.05). RESULTS: The mean wear (+/-SD, um) was shown as follows in groups: C (13.09+/ 0.99), CG (10.60+/-1.99), F (10.90+/-1.44), N (12.68+/-1.13) and NF (10.84+/ 1.65). All gels showed some preventive action when compared with control group. However, significant differences were found only between Neem+fluoride gel and fluoride gel. CONCLUSION: A single application of a neem-containing fluoride gel reduced dentin erosion, thus it is a possible alternative in reducing dental wear. Further research should investigate the action mechanism and the synergism between them. PMID- 24473729 TI - Dental manifestations of patient with vitamin D-resistant rickets. AB - Patients with Vitamin D-resistant rickets have abnormal tooth morphology such as thin globular dentin and enlarged pulp horns that extend into the dentino-enamel junction. Invasion of the pulp by microorganisms and toxins is inevitable. The increased fibrotic content of the pulp, together with a reduced number of odontoblasts, decreases the response to pulp infection. The most important oral findings are characterized by spontaneous gingival and dental abscesses occuring without history of trauma or caries. Radiographic examinations revealed large pulp chambers, short roots, poorly defined lamina dura and hypoplastic alveolar ridge. These dental abscesses are common and therefore the extraction and pulpectomy are the treatment of choice. The purpose of this article is to report a case of Vitamin D-resistant rickets in a 5 year-old boy, describing the dental findings and the treatment to be performed in these cases. PMID- 24473731 TI - The functional neuroimaging evidence of cerebellar involvement in the simple cognitive task. AB - Cerebellar involvement in cognitive functions has been revealed in numerous anatomical, clinical and neuroimaging studies and several hypotheses about potential the role of the cerebellum in higher level brain function have been established. The aim of this study was to show involvement of the cerebellum in simple cognitive tasks. For this matter, we contrasted two tasks from the same semantic domain with specific cognitive content and level of practice: counting forward and counting backward. Twelve volunteers participated in this fMRI study and they were asked to perform both tasks within the same number range (1 to 30 and vice versa). Results showed greater activation in the right cerebellum for the task of counting forward than for counting backward, while for counting backward greater activation was found in prefrontal cortex, supplementary motor area, and anterior cingulate of both hemispheres. Our results correlate with already established hypotheses about cerebellar role in precise and smooth control, not only in well-trained motor but in well trained cognitive tasks as well. PMID- 24473727 TI - Adhesive bonding of resin composite to various titanium surfaces using different metal conditioners and a surface modification system. AB - OBJECTIVE: This study evaluated the effect of three metal conditioners on the shear bond strength (SBS) of a prosthetic composite material to cpTi grade I having three surface treatments. MATERIAL AND METHODS: One hundred sixty eight rivet-shaped specimens (8.0x2.0 mm) were cast and subjected to polishing (P) or sandblasting with either 50 mm (50SB) or 250 mm (250SB) Al2O3. The metal conditioners Metal Photo Primer (MPP), Cesead II Opaque Primer (OP), Targis Link (TL), and one surface modification system Siloc (S), were applied to the specimen surfaces, which were covered with four 1-mm thick layers of resin composite. The resin layers were exposed to curing light for 90 s separately. Seven specimens from each experimental group were stored in water at 37oC for 24 h while the other 7 specimens were subjected to 5,000 thermal cycles consisting of water baths at 4oC and 60oC (n=7). All specimens were subjected to SBS test (0.5 mm/min) until failure occurred, and further 28 specimens were analyzed using scanning electron microscope (SEM) and X-ray energy-dispersive spectroscopy (EDS). Data were analyzed by 3-way ANOVA followed by post-hoc Tukey's test (alpha=0.05). RESULTS: On 50SB surfaces, OP groups showed higher SBS means than MPP (P<0.05), while no significant difference was found among OP, S, and TL groups. On 250SB surfaces, OP and TL groups exhibited higher SBS than MPP and S (P<0.05). No significant difference in SBS was found between OP and TL groups nor between MPP and S groups. The use of conditioners on 250SB surfaces resulted in higher SBS means than the use of the same products on 50SB surfaces (P<0.05). CONCLUSION: Sandblasting associated with the use of metal conditioners improves SBS of resin composites to cpTi. PMID- 24473732 TI - Aortic pulse wave velocity in haemodialysis patients is associated with the prescription of active vitamin D analogues. AB - BACKGROUND: Cardiovascular disease remains the most common cause of death for haemodialysis patients. In addition to traditional cardiovascular risk factors, haemodialysis patients have additional risk factors, including vascular calcification. Pulse wave velocity (PWV) is a measurement of arterial stiffness, and we wished to determine whether PWV is affected by different factors in haemodialysis patients compared to the general population. METHODS: Aortic PWV was measured in 303 adult patients attending for routine outpatient dialysis. RESULTS: 303 patients, 63.4% male, mean age 68.5 +/- 15.8 years, 47.5% diabetic with a body mass index of 25.8 +/- 5.3 kg/m(2), were studied. Systolic blood pressure (SBP) was 148.7 +/- 28.6 mmHg and diastolic 80.4 +/- 15.3 mmHg. Aortic PWV was 9.73 +/- 2.08 m/s, and was correlated with SBP (beta 0.015, F 5.29, p = 0.023), log serum parathyroid hormone (PTH) (beta 1.58, F 13.85, p < 0.001) and prescription of alfacalcidol (beta -1.11, F 6.81, p = 0.010). 197 patients had corresponding ECHO cardiograms, and in this cohort PWV was associated with SBP (beta 0.017, F 7.49, p = 0.006), log serum parathyroid hormone (beta 0.85, F 5.99, p < 0.015) and prescription of alfacalcidol (beta -0.8, F 4.18, p = 0.042), left ventricular mass index (LVMI) (beta 0.01, F 11.4, p = 0.001), and log serum triglycerides (beta 1.43, F 4.79, p = 0.03). CONCLUSIONS: We found that PWV, a measurement of arterial stiffness, was associated with both traditional cardiovascular risk factors, including SBP and LVMI, but also non-traditional risk factors such as prescription of active vitamin D analogues, suggesting a potential link between vascular calcification and arterial stiffness in haemodialysis patients. PMID- 24473733 TI - Amyloid beta 1-42 and tau in the cerebrospinal fluid of renal failure patients for the diagnosis of Alzheimer's disease. AB - Cerebrospinal fluid (CSF) Abeta42, total tau and phosphorylated tau (p-tau) are well-defined diagnostic markers for Alzheimer's disease (AD). There has been no previous report of the use of these markers in the diagnosis of AD in patients with chronic kidney disease (CKD). We would like to report our preliminary findings on these biomarkers in three patients with renal failure. One patient with a clinical diagnosis of AD showed elevated CSF tau, p-tau 181, and decreased Abeta42 levels, within a similar range as in local Chinese AD patients without renal impairment. The other two delirious patients, who did not have a clinical diagnosis of AD, showed normal CSF biomarkers. We found that the diagnosis of AD with CSF biomarkers appears to be useful in renal failure patients. But our results need to be confirmed in a larger study, comparing these CSF biomarkers in AD vs. non-AD patients with concomitant CKD. PMID- 24473734 TI - Genetic diversity and structure of natural populations of Gossypium mustelinum, a wild relative of cotton, in the basin of the De Contas River in Bahia, Brazil. AB - Gossypium mustelinum is a wild cotton relative found only in the semiarid region of Bahia state in Brazil, and changes caused by humans in the natural habitat of this species have endangered the existence of several natural populations. Information about the occurrence and genetic composition of these populations is necessary to design effective conservation measures. The aim of this study was to characterize the in situ maintenance mode and assess the genetic diversity of G. mustelinum populations in the basin of the De Contas River. A sample of 205 G. mustelinum specimens was collected from the margins of the Jacare, Riacho Quixaba, Riacho Serra Azul, and Riacho Riachao rivers and genotyped using 13 SSR primer pairs. In general, all G. mustelinum populations exhibit inadequate in situ maintenance, predominantly due to the deforestation of riparian vegetation and herbivory. The observed total genetic diversity of G. mustelinum was significant (H E = 0.489), highly structured (F ST = 0.534), and organized in homozygous genotypes (F IS = 0.873). The high observed inbreeding level is consistent with the predominance of self-fertilization and geitonogamy (t m = 0.234). In addition, the pattern of genetic structure tended to form groups that coincided with the collection sites, i.e., first clustering within subpopulations, then within populations, and finally within the closest populations. Thus, the observed genetic diversity is likely to be rapidly lost, and conservation measures should therefore be undertaken. PMID- 24473735 TI - Nanoscale zero-valent iron (nZVI) for the treatment of concentrated Cu(II) wastewater: a field demonstration. AB - A field demonstration was conducted to assess the feasibility of nanoscale zero valent iron (nZVI) for the treatment of wastewater containing high levels of Cu(II). Pilot tests were performed at a printed-circuit-board manufacturing plant, treating 250,000 L of wastewater containing 70 mg L(-1) Cu(II) with a total of 55 kg of nZVI. A completely mixed reactor of 1,600 L was operated continuously with flow rates ranging from 1000 to 2500 L h(-1). The average Cu(II) removal efficiency was greater than 96% with 0.20 g L(-1) nZVI and a hydraulic retention time of 100 min. The nZVI reactor achieved a remarkably high volumetric loading rate of 1876 g Cu per m(3) per day for Cu(II) removal, surpassing the loading rates of conventional technologies by more than one order of magnitude. The average removal capacity of nZVI for Cu(II) was 0.343 g Cu per gram of Fe. The Cu(II) removal efficiency can be reliably regulated by the solution Eh, which in turn is a function of nZVI input and hydraulic retention time. The ease of separation and recycling of nZVI contribute to process up scalability and cost effectiveness. Cu(II) was reduced to metallic copper and cuprite (Cu2O). The end product is a valuable composite of iron and copper (~20 25%), which can partially offset the treatment costs. PMID- 24473736 TI - Upregulation of heat shock protein 32 with hemin alleviates acute heat-induced hepatic injury in mice. AB - Heat shock protein 32 (HSP32) is a stress response protein that can be induced by heat stress in the liver, and its induction can act as an important cellular defence mechanism against heat-induced liver injury. To investigate the functional role of HSP32 in protecting liver tissue against heat stress in mice and the mechanism by which it achieves this protective effect, HSP32 expression and carbon monoxide (CO) contents in a model of mice subjected to acute, transient heat exposure were examined. Furthermore, functional and histological parameters of liver damage and the possible involvement of oxidative stress to induce oxidative deterioration of liver functions and caspase-3 expression were also investigated in this study. We found that heat treatment of mice produced severe hepatic injury, whereas upregulation of HSP32 with hemin pretreatment prevented mice from liver damage. In contrast, addition of Sn-protoporphyrin (SnPP) to inhibit HSP32 expression completely reversed its hepatoprotective effect. It is concluded that upregulation of HSP32 by hemin could alleviate acute heat-induced hepatocellular damage in mice, and its by-product CO seems to play a more important role in hepatoprotective mechanism. PMID- 24473737 TI - Synthesis of the tumor associative alpha-aminooxy disaccharide of the TF antigen and its conjugation to a polysaccharide immune stimulant. AB - The alpha-aminooxy derivative of the Thomsen-Friedenriech tumor associated carbohydrate antigen has been synthesized in 11 steps utilizing a D-GalN3 acceptor carrying a pre-installed alpha-N-hydroxysuccinimidyl moiety. The natural alpha linkage was prepared in high selectivity employing a suitably protected D GalN3-thioglycoside donor with N-hydroxysuccinimide. With access to alpha-TF ONH2, the preparation of the TF-PS A1 vaccine candidate ensued smoothly through oxime bond formation. PMID- 24473738 TI - Parental presence during cardiopulmonary resuscitation: uncommon, but yet necessary. PMID- 24473739 TI - Syringe mix-up led to brain damage and a possible L24m payout. PMID- 24473740 TI - Localization and uptake of 14C-IAA in relation to xylem regeneration in Coleus internodes. AB - 14C-IAA was applied to decapitated Coleus 5th internodes. Sections were radioautographed at various intervals after the application. The location of the label within cells and tissues is discussed. No accumulation of label occurred in the region where xylem cells regenerated. Label was particularly associated with xylem and phloem cytoplasm, but also occurred in other cells. PMID- 24473741 TI - [Studies on the transport of caffeine in the coffee plant (Coffea arabica)]. AB - Caffeine transport in small amounts from leaf to leaf was demonstrated by application of doubly-labelled caffeine. There was no translocation from the subtending leaves into the fruits, but heavy translocation from the pericaprp into the seed tissue could be shown. The results were confirmed by the analysis of grafts between caffeine-containing and caffeine-free species. The importance of the pericarp with respect to the caffeine content of the mature coffee bean is discussed. PMID- 24473742 TI - Variation in the nitrate reductase of rice seedlings. AB - Nitrate reductase was induced in rice seedlings by nitrate and by chloramphenicol. During the induction period the different enzyme activities associated with nitrate reductase increased to different degrees. Nitrate induced high NADH-nitrate reductase activity and a great increase in the NADH-cytochrome c reductase activity which was associated with the nitrate reductase in a sucrose gradient. Chloramphenicol induced a nitrate reductase which had higher activity with NADPH than NADH. Chloramphenicol also induced a marked increase in NADPH cytochrome c reductase activity as well as in NADH-cytochrome c reductase activity. Both activities were associated with the nitrate reductase in a sucrose gradient.After partial purification by sucrose gradient sedimentation or by starch gel electrophoresis, the nitrate reductase of rice induced by nitrate and chloramphenicol showed the same preference in pyridine nucleotide cofactors as was shown by the crude enzyme extracts. PMID- 24473743 TI - Control of glycolysis by orthophosphate and adenosine triphosphate in soluble extracts of germinating pea seeds. AB - Control of aerobic glycolysis by adenosine triphosphate and orthophosphate has been studied in cell-free extracts of germinating pea seeds. Orthophosphate accelerates glycolysis under all conditions studied. At high concentrations of magnesium ion ATP accelerates glycolysis, whereas at lower magnesium concentrations ATP severely inhibits glycolysis. The inhibitory effect of ATP is markedly relieved by orthophosphate. Metabolite analyses suggest an important regulatory role of phosphofructokinase and show that low ratios of F-6-P: FDP accompany the appearance of a high rate of glycolysis, and vice versa. Thus, ATP raises the F-6-P: FDP ratio at low magnesium levels, while Pi lowers this ratio. At high Mg(2+) (where ATP accelerates glycolysis), ATP causes a low F-6-P: FDP ratio to appear. At low Mg(2+) concentration, orthophosphate accelerates glycolysis by activation of phosphofructokinase; at high magnesium concentration, the chief effect of orthophosphate is its long-known role in facilitating the oxidation of triose phosphate. PMID- 24473744 TI - The role of phytochrome in photoperiodic time measurement and its relation to rhythmic timekeeping in the control of flowering in Chenopodium rubrum. AB - To follow changes in the status of phytochrome in green tissue and to relate these changes to the photoperiodic control of flowering, we have used a null response technique involving 1.5-min irradiations with mixtures of different ratios of R and FR radiation.Following a main photoperiod of light from fluorescent lamps that was terminated with 5 min of R light, the proportion of Pfr in Chenopodium rubrum cotyledons was high and did not change until the 3rd hour in darkness; at this time, Pfr disappeared rapidly. When the dark period began with a 5-min irradiation with BCJ or FR light to set the proportion of Pfr low Pfr gradually reappeared during the first 3 h of darkness and then disappeared again.The timing of disappearance of Pfr is consistent with the involvement of phytochrome in photoperiodic time measurement. Reappearance of Pfr after an initial FR irradiation explains why FR irradiations sometimes fail to influence photoperiodic time measurement or only slightly hasten time measurement. A R light interruption to convert Pr to Pfr delayed, the timer by 3 h but only for interruptions after and not before the time of Pfr disappearance. Such 5-min R-light interruptions did not influence the operation of the rhythmic timekeeping mechanism. Continuous or intermittent-5 min every 1.5 h-irradiations of up to 6 h in duration were required to rephase the rhythm controlling flowering. A skeleton photoperiod of 6 h that was began and terminated by 5 or 15 min of light failed to rephase the rhythm.The shape of the curves for the rhythmic response of C. rubrum to the length of the dark period are sometimes suggestive of "clocks" operating on the principle of a tension-relaxation mechanism. Such a model allows for separate timing action of a rhythm and of Pfr disappearance over the early hours of darkness. Separate timing action does not, however, preclude an interaction between the rhythm and phytochrome in controlling flowering. PMID- 24473745 TI - [Influence of some herbicides and growth retardants on morphogenesis and metabolism of higher plants]. AB - Effects of TIBA, 2,4-D, Flurenol and CCC upon growth, root formation, membrane permeability, content of nucleic acids and stability of the chromatin were investigated. The four substances showed little or no effect on growth of isolated plant segments, but TIBA, 2,4-D and CCC caused 25-30% inhibition of growth of whole pea seedlings even at low concentrations. Root formation is inhibited by TIBA, Flurenol and 2,4-D, but not by CCC. At concentrations >10( 4)mol/l all the substances reduced the permeability of the plasma lemma, at lower concentrations only CCC and Flurenol still reduced permeability of the plasma lemma. The ratio RNA/DNA was decreased by TIBA, 2,4-D and Flurenol but it was increased by CCC. The Tm-value of isolated pea-chromatin was lowered by treatment with CCC and elevated by treatment with TIBA, 2,4-D and Flurenol can decrease or increase the Tm of isolated chromatin depending on their concentration. The results have shown that even very low concentrations of herbicides and growth retardants are able to induce metabolic alterations with partly unknown consequences. PMID- 24473746 TI - Red-light-enhanced conversion of tritiated gibberellin A9 into other gibberellin like substances in homogenates of etiolated barley leaves. AB - Irradiation of homogenates of etiolated barley leaves with red light resulted in an increase in the levels of gibberellin (GA)-like substances as compared to dark controls. When homogenates were fed with [(3)H]-GA9 there was as incorporation of the radioactivity into a number of other GA's: this process occurred to a greater extent in red light than in darkness, and could be inhibited by boiling the extract prior to addition of the [(3)H]-GA9. PMID- 24473747 TI - Sensitivity of cell division and cell elongation to low water potentials in soybean hypocotyls. AB - The response of cell division and cell elongation to low cell water potentials was studied in etiolated, intact soybean hypocotyls desiccated either by withholding water from seedlings or by subjecting hypocotyls to pressure. Measurements of hypocotyl water potential and osmotic potential indicated that desiccation by withholding water resulted in osmotic adjustment of the hypocotyls so that turgor remained almost constant. The adjustment appeared to involve transport of solutes from the cotyledons to the hypocotyl and permitted growth of the seedlings at water potentials which would have been strongly inhibitory had adjustment not occurred. Growth was ultimately inhibited in hypocotyls due to inhibition of cell division and cell elongation to a similar degree. The inhibition of cell elongation appeared to result from a change in the minimum turgor necessary for growth. On the other hand, when intact hypocotyls were exposed to pressure for 3 h, osmotic adjustment did not occur, turgor decreased, and the sensitivity of growth to low cell water potentials increased, presumably due to inhibition of cell elongation. Thus, although cell division was sensitive to low cell water potentials in soybean hypocotyls, cell elongation had either the same sensitivity or was more sensitive, depending on whether the tissue adjusted osmotically. Osmotic adjustment of hypocotyls may represent a mechanism for preserving growth in seedlings germinating in desiccated soil. PMID- 24473748 TI - Inhibition of grana formation by lincomycin. AB - The antibiotic lincomycin is a specific inhibitor of chloroplast ribosomal activity in greening leaves of Pisum sativum at 1 MUg/ml, and prevents both the formation of chloroplast membranes and their stacking into grana. This finding suggests that one function of chloroplast ribosomes is to synthesise at least one protein component of thylakoid membranes. PMID- 24473749 TI - Allosteric noncompetitive small molecule selective inhibitors of CD45 tyrosine phosphatase suppress T-cell receptor signals and inflammation in vivo. AB - CD45 is a receptor-like member of the protein tyrosine phosphatase (PTP) family. We screened in silico for small molecules binding at a predicted allosteric pocket unique to the CD45 intracellular domain, and validated inhibitors by in vitro phosphatase assays. Compound 211 exhibited a CD45 IC50 value of 200 nM and had >100-fold selectivity over six related PTPs. The relevance of the allosteric pocket was verified through site-directed mutagenesis. Compound 211 has a noncompetitive mechanism of action, and it is extremely effective at preventing dephosphorylation of substrate Lck phosphotyrosine (pY)-505 versus preventing dephosphorylation of Lck pY-393. In cultured primary T cells, compound 211 prevents T-cell receptor-mediated activation of Lck, Zap-70, and mitogen activated protein kinase, and interleukin-2 production. In a delayed-type hypersensitivity reaction in vivo, compound 211 abolished inflammation. This work demonstrates a novel approach to develop effective allosteric inhibitors that can be expanded to target the corresponding allosteric domains of other receptor PTPs. PMID- 24473750 TI - Sleeping position and responses to a carbon dioxide challenge in convalescent prematurely born infants studied post-term. AB - OBJECTIVES: To test the hypothesis that the ventilatory response to a carbon dioxide (CO2) challenge would be lower in the prone compared to the supine position in prematurely born infants studied post-term. To determine whether there were postural-related differences in respiratory drive, respiratory muscle strength, thoracoabdominal synchrony and/or lung volume. DESIGN: Prospective cohort study. SETTING: Tertiary neonatal unit. PATIENTS: Eighteen infants (median gestational age 31 (range 22-32) weeks) were studied at a median of 5 (range 2 11) weeks post-term. INTERVENTIONS: The ventilatory responses to three added carbon dioxide (CO2) levels (0% baseline, 2% and 4%) were assessed in the prone and supine positions. MAIN OUTCOME MEASURES: The airway pressure change after the first 100 ms of an occluded inspiration (P0.1) (respiratory drive) and the maximum inspiratory pressure during crying with an occluded airway (Pimax) (respiratory muscle strength) were measured. The P0.1/Pimax ratio at each CO2 level and slope of the P0.1/Pimax response were calculated. RESULTS: The mean P0.1 (p<0.05) and P0.1/Pimax (p<0.05) were higher and the functional residual capacity (p=0.031) lower in the supine compared to the prone position. The mean P0.1 and P0.1/Pimax increased independently of position as the percentage CO2 increased (p<0.001). There was no tendency for the differences in P0.1 and P0.1/Pimax between the prone and supine position to vary by CO2 level. CONCLUSIONS: Convalescent, prematurely born infants studied post-term have a reduced respiratory drive, but not a lower ventilatory response to a CO2 challenge, in the prone compared to the supine position. PMID- 24473751 TI - Data dredging, salami-slicing, and other successful strategies to ensure rejection: twelve tips on how to not get your paper published. PMID- 24473752 TI - Gut microbial metabolites of polyunsaturated fatty acids correlate with specific fecal bacteria and serum markers of metabolic syndrome in obese women. AB - The aim of this human study was to assess the influence of prebiotic-induced gut microbiota modulation on PUFA-derived bacterial metabolites production. Therefore, we analyzed the circulating fatty acid profile including CLA/CLnA in obese women treated during 3 months with inulin-type fructan prebiotics. In these patients, we had already determined gut microbiota composition by phylogenetic microarray and qPCR analysis of 16S rDNA. Some PUFA-derived bacterial metabolites were detected in the serum of obese patients. Despite the prebiotic-induced modulation of gut microbiota, including changes in CLA/CLnA-producing bacteria, the treatment did not impact significantly on the circulating level of these metabolites. However, some PUFA-derived bacterial metabolites were positively correlated with specific fecal bacteria (Bifidobacterium spp., Eubacterium ventriosum and Lactobacillus spp.) and inversely correlated with serum cholesterol (total, LDL, HDL). These correlations suggest a potential beneficial effect of some of these metabolites but this remains to be confirmed by further investigation. PMID- 24473753 TI - Microglial cell activation increases saturated and decreases monounsaturated fatty acid content, but both lipid species are proinflammatory. AB - Neuroinflammation is a component of age-related neurodegenerative diseases and cognitive decline. Saturated (SFA) and monounsaturated (MUFA) fatty acids are bioactive molecules that may play different extrinsic and intrinsic roles in neuroinflammation, serving as exogenous ligands for cellular receptors, or endogenous components of cell structural, energetic and signaling pathways. We determined the fatty acyl profile of BV2 microglial cells before and after acute activation with lipopolysaccharide (LPS). We also investigated the effect of SFA and MUFA pretreatment on the production of an invasive, neurotoxic phenotype in BV2 cells. Acute activation of BV2 microglia resulted in an increase in the relative content of SFA (12:0, 16:0, 18:0, 20:0, 22:0, and 24:0 increased significantly), and a relative decrease in the content of MUFA (16:1n7, 18:1n7, 18:1n9, 20:1n9, 24:1n9 decreased significantly). In agreement, the major stearoyl CoA desaturase (SCD) isoform in BV2 cells, SCD2, was significantly down-regulated by LPS. We next treated cells with SFA (16:0 or 18:0) or MUFA (16:1n7 or 18:1n9), and found that levels of secreted IL6 were increased, as was secreted MMP9 mediated proteolytic activity. To test the functional significance, we treated SH SY5Y neuronal cells with conditioned medium from BV2 cells pretreated with fatty acids, and found a small but significant induction of cell death. Our findings suggest differential intrinsic roles for SFA and MUFA in activated microglial cells, but similar extrinsic roles for these fatty acid species in inducing activation. Expansion of SFA is important during microglial cell activation, but either supplemental SFA or MUFA may contribute to chronic low-grade neuroinflammation. PMID- 24473754 TI - In vitro reconstitution of mevalonate pathway and targeted engineering of farnesene overproduction in Escherichia coli. AB - Approaches using metabolic engineering and synthetic biology to overproduce terpenoids, such as the precursors of taxol and artemisinin, in microbial systems have achieved initial success. However, due to the lack of steady-state kinetic information and incomplete understanding of the terpenoid biosynthetic pathway, it has been difficult to build a highly efficient, universal system. Here, we reconstituted the mevalonate pathway to produce farnesene (a precursor of new jet fuel) in vitro using purified protein components. The information from this in vitro reconstituted system guided us to rationally optimize farnesene production in E. coli by quantitatively overexpressing each component. Targeted proteomic assays and intermediate assays were used to determine the metabolic status of each mutant. Through targeted engineering, farnesene production could be increased predictably step by step, up to 1.1 g/L (~ 2,000 fold) 96 h after induction at the shake-flask scale. The strategy developed to release the potential of the mevalonate pathway for terpenoid overproduction should also work in other multistep synthetic pathways. PMID- 24473755 TI - Ultra hyperacute magnetic resonance findings in reperfusion hemorrhage. PMID- 24473756 TI - Interstitial lung disease in suggestive forms of connective tissue disease. PMID- 24473757 TI - Metformin synergistically enhances antiproliferative effects of cisplatin and etoposide in NCI-H460 human lung cancer cells. AB - OBJECTIVE: To test the effectiveness of combining conventional antineoplastic drugs (cisplatin and etoposide) with metformin in the treatment of non-small cell lung cancer in the NCI-H460 cell line, in order to develop new therapeutic options with high efficacy and low toxicity. METHODS: We used the 3-(4,5 dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay and calculated the combination index for the drugs studied. RESULTS: We found that the use of metformin as monotherapy reduced the metabolic viability of the cell line studied. Combining metformin with cisplatin or etoposide produced a synergistic effect and was more effective than was the use of cisplatin or etoposide as monotherapy. CONCLUSIONS: Metformin, due to its independent effects on liver kinase B1, had antiproliferative effects on the NCI-H460 cell line. When metformin was combined with cisplatin or etoposide, the cell death rate was even higher. PMID- 24473758 TI - Descriptive analysis of and overall survival after surgical treatment of lung metastases. AB - OBJECTIVE: To describe demographic characteristics, surgical results, postoperative complications, and overall survival rates in surgically treated patients with lung metastases. METHODS: This was a retrospective analysis of 119 patients who underwent a total of 154 lung metastasis resections between 1997 and 2011. RESULTS: Among the 119 patients, 68 (57.1%) were male and 108 (90.8%) were White. The median age was 52 years (range, 15-75 years). In this sample, 63 patients (52.9%) presented with comorbidities, the most common being systemic arterial hypertension (69.8%) and diabetes (19.0%). Primary colorectal tumors (47.9%) and musculoskeletal tumors (21.8%) were the main sites of origin of the metastases. Approximately 24% of the patients underwent more than one resection of the lesions, and 71% had adjuvant treatment prior to metastasectomy. The rate of lung metastasis recurrence was 19.3%, and the median disease-free interval was 23 months. The main surgical access used was thoracotomy (78%), and the most common approach was wedge resection with segmentectomy (51%). The rate of postoperative complications was 22%, and perioperative mortality was 1.9%. The overall survival rates at 12, 36, 60, and 120 months were 96%, 77%, 56%, and 39%, respectively. A Cox analysis confirmed that complications within the first 30 postoperative days were associated with poor prognosis (hazard ratio = 1.81; 95% CI: 1.09-3.06; p = 0.02). CONCLUSIONS: Surgical treatment of lung metastases is safe and effective, with good overall survival, especially in patients with fewer metastases. PMID- 24473759 TI - Levels of physical activity and predictors of mortality in COPD. AB - OBJECTIVE: To compare the Body mass index, airway Obstruction, Dyspnea, and E xercise capacity (BODE) index scores and its individual components between COPD patients with and without severe physical inactivity, as well as to correlate the number of steps/day with scores of physical activity questionnaires, age, and the BODE index (including its components). METHODS: We included 30 patients, who were evaluated for body composition, pulmonary function (FEV1), perception of dyspnea (modified Medical Research Council scale), and exercise capacity (six-minute walk distance [6MWD]). The patients also completed the International Physical Activity Questionnaire (IPAQ), short version, and the modified Baecke questionnaire (mBQ). The level of physical activity was assessed by the number of steps/day (as determined by pedometer), using the cut-off of 4,580 steps/day to form two groups: no severe physical inactivity (SPI-) and severe physical inactivity (SPI+). We used the Mann-Whitney test or t-test, as well as Pearson's or Spearman's correlation tests, in the statistical analysis. RESULTS: In comparison with the SPI- group, the SPI+ group showed more advanced age, higher mBQ scores (leisure domain), lower 6MWD (in m and % of predicted), and lower IPAQ scores (metabolic equivalent-walk/week domain and total). The IPAQ scores showed weak correlations with steps/day (r = 0.399), age (r = -0.459), and 6MWD-in m (r = 0.446) and in % of predicted (r = 0.422). CONCLUSIONS: In our sample, the cut-off of 4,580 steps/day was not sensitive enough to identify differences between the groups when compared with the predictors of mortality. The IPAQ, short version score correlated with steps/day. PMID- 24473760 TI - Nocturnal hypoxemia in children and adolescents with cystic fibrosis. AB - OBJECTIVE: To determine the prevalence of nocturnal hypoxemia and its association with pulmonary function, nutritional status, sleep macrostructure, and obstructive respiratory events during sleep in a population of clinically stable children and adolescents with cystic fibrosis (CF). METHODS: This was a cross sectional study involving 67 children and adolescents with CF between 2 and 14 years of age. All of the participants underwent polysomnography, and SpO2 was measured by pulse oximetry. We also evaluated the Shwachman-Kulczycki (S-K) scores, spirometry findings, and nutritional status of the patients. RESULTS: The study involved 67 patients. The mean age of the patients was 8 years. The S-K scores differed significantly between the patients with and without nocturnal hypoxemia, which was defined as an SpO2 < 90% for more than 5% of the total sleep time (73.75 +/- 6.29 vs. 86.38 +/- 8.70; p < 0.01). Nocturnal hypoxemia correlated with the severity of lung disease, FEV1 (rs = -0.42; p = 0.01), FVC (rs = -0.46; p = 0.01), microarousal index (rs = 0.32; p = 0.01), and apnea hypopnea index (rs = 0.56; p = 0.01). CONCLUSIONS: In this sample of patients with CF and mild-to-moderate lung disease, nocturnal oxygenation correlated with the S-K score, spirometry variables, sleep macrostructure variables, and the apnea-hypopnea index. PMID- 24473761 TI - Can the single-breath helium dilution method predict lung volumes as measured by whole-body plethysmography? AB - OBJECTIVE: To compare TLC and RV values obtained by the single-breath helium dilution (SBHD) method with those obtained by whole-body plethysmography (WBP) in patients with normal lung function, patients with obstructive lung disease (OLD), and patients with restrictive lung disease (RLD), varying in severity, and to devise equations to estimate the SBHD results. METHODS: This was a retrospective cross-sectional study involving 169 individuals, of whom 93 and 49 presented with OLD and RLD, respectively, the remaining 27 having normal lung function. All patients underwent spirometry and lung volume measurement by both methods. RESULTS: TLC and RV were higher by WBP than by SBHD. The discrepancy between the methods was more pronounced in the OLD group, correlating with the severity of airflow obstruction. In the OLD group, the correlation coefficient of the comparison between the two methods was 0.57 and 0.56 for TLC and RV, respectively (p < 0.001 for both). We used regression equations, adjusted for the groups studied, in order to predict the WBP values of TLC and RV, using the corresponding SBHD values. It was possible to create regression equations to predict differences in TLC and RV between the two methods only for the OLD group. The TLC and RV equations were, respectively, ?TLCWBP-SBHD in L = 5.264 - 0.060 * FEV1/FVC (r2 = 0.33; adjusted r2 = 0.32) and ?RVWBP-SBHD in L = 4.862 - 0.055 * FEV1/FVC (r2 = 0.31; adjusted r2 = 0.30). CONCLUSIONS: The correction of TLC and RV results obtained by SBHD can improve the accuracy of this method for assessing lung volumes in patients with OLD. However, additional studies are needed in order to validate these equations. PMID- 24473762 TI - Barium swallow study in routine clinical practice: a prospective study in patients with chronic cough. AB - OBJECTIVE: To assess the routine use of barium swallow study in patients with chronic cough. METHODS: Between October of 2011 and March of 2012, 95 consecutive patients submitted to chest X-ray due to chronic cough (duration > 8 weeks) were included in the study. For study purposes, additional images were obtained immediately after the oral administration of 5 mL of a 5% barium sulfate suspension. Two radiologists systematically evaluated all of the images in order to identify any pathological changes. Fisher's exact test and the chi-square test for categorical data were used in the comparisons. RESULTS: The images taken immediately after barium swallow revealed significant pathological conditions that were potentially related to chronic cough in 12 (12.6%) of the 95 patients. These conditions, which included diaphragmatic hiatal hernia, esophageal neoplasm, achalasia, esophageal diverticulum, and abnormal esophageal dilatation, were not detected on the images taken without contrast. After appropriate treatment, the symptoms disappeared in 11 (91.6%) of the patients, whereas the treatment was ineffective in 1 (8.4%). We observed no complications related to barium swallow, such as contrast aspiration. CONCLUSIONS: Barium swallow improved the detection of significant radiographic findings related to chronic cough in 11.5% of patients. These initial findings suggest that the routine use of barium swallow can significantly increase the sensitivity of chest X-rays in the detection of chronic cough-related etiologies. PMID- 24473763 TI - Immunohistochemical and morphometric evaluation of COX 1 and COX-2 in the remodeled lung in idiopathic pulmonary fibrosis and systemic sclerosis. AB - OBJECTIVE: To study the expression of COX-1 and COX-2 in the remodeled lung in systemic sclerosis (SSc) and idiopathic pulmonary fibrosis (IPF) patients, correlating that expression with patient survival. METHODS: We examined open lung biopsy specimens from 24 SSc patients and 30 IPF patients, using normal lung tissue as a control. The histological patterns included fibrotic nonspecific interstitial pneumonia (NSIP) in SSc patients and usual interstitial pneumonia (UIP) in IPF patients. We used immunohistochemistry and histomorphometry to evaluate the expression of COX-1 and COX-2 in alveolar septa, vessels, and bronchioles. We then correlated that expression with pulmonary function test results and evaluated its impact on patient survival. RESULTS: The expression of COX-1 and COX-2 in alveolar septa was significantly higher in IPF-UIP and SSc NSIP lung tissue than in the control tissue. No difference was found between IPF UIP and SSc-NSIP tissue regarding COX-1 and COX-2 expression. Multivariate analysis based on the Cox regression model showed that the factors associated with a low risk of death were younger age, high DLCO/alveolar volume, IPF, and high COX-1 expression in alveolar septa, whereas those associated with a high risk of death were advanced age, low DLCO/alveolar volume, SSc (with NSIP), and low COX-1 expression in alveolar septa. CONCLUSIONS: Our findings suggest that strategies aimed at preventing low COX-1 synthesis will have a greater impact on SSc, whereas those aimed at preventing high COX-2 synthesis will have a greater impact on IPF. However, prospective randomized clinical trials are needed in order to confirm that. PMID- 24473764 TI - CT densitovolumetry in children with obliterative bronchiolitis: correlation with clinical scores and pulmonary function test results. AB - OBJECTIVE: To determine whether air trapping (expressed as the percentage of air trapping relative to total lung volume [AT%]) correlates with clinical and functional parameters in children with obliterative bronchiolitis (OB). METHODS: CT scans of 19 children with OB were post-processed for AT% quantification with the use of a fixed threshold of -950 HU (AT%950) and of thresholds selected with the aid of density masks (AT%DM). Patients were divided into three groups by AT% severity. We examined AT% correlations with oxygen saturation (SO2) at rest, six minute walk distance (6MWD), minimum SO2 during the six-minute walk test (6MWT_SO2), FVC, FEV1, FEV1/FVC, and clinical parameters. RESULTS: The 6MWD was longer in the patients with larger normal lung volumes (r = 0.53). We found that AT%950 showed significant correlations (before and after the exclusion of outliers, respectively) with the clinical score (r = 0.72; 0.80), FVC (r = 0.24; 0.59), FEV1 (r = -0.58; -0.67), and FEV1/FVC (r = -0.53; r = -0.62), as did AT%DM with the clinical score (r = 0.58; r = 0.63), SO2 at rest (r = -0.40; r = -0.61), 6MWT_SO2 (r = -0.24; r = -0.55), FVC (r = -0.44; r = -0.80), FEV1 (r = -0.65; r = -0.71), and FEV1/FVC (r = -0.41; r = -0.52). CONCLUSIONS: Our results show that AT% correlates significantly with clinical scores and pulmonary function test results in children with OB. PMID- 24473765 TI - Detection of Mycobacterium tuberculosis complex by nested polymerase chain reaction in pulmonary and extrapulmonary specimens. AB - OBJECTIVE: To compare the performance of nested polymerase chain reaction (NPCR) with that of cultures in the detection of the Mycobacterium tuberculosis complex in pulmonary and extrapulmonary specimens. METHODS: We analyzed 20 and 78 pulmonary and extrapulmonary specimens, respectively, of 67 hospitalized patients suspected of having tuberculosis. An automated microbial system was used for the identification of Mycobacterium spp. cultures, and M. tuberculosis IS6110 was used as the target sequence in the NPCR. The kappa statistic was used in order to assess the level of agreement among the results. RESULTS: Among the 67 patients, 6 and 5, respectively, were diagnosed with pulmonary and extrapulmonary tuberculosis, and the NPCR was positive in all of the cases. Among the 98 clinical specimens, smear microscopy, culture, and NPCR were positive in 6.00%, 8.16%, and 13.26%, respectively. Comparing the results of NPCR with those of cultures (the gold standard), we found that NPCR had a sensitivity and specificity of 100% and 83%, respectively, in pulmonary specimens, compared with 83% and 96%, respectively, in extrapulmonary specimens, with good concordance between the tests (kappa, 0.50 and 0.6867, respectively). CONCLUSIONS: Although NPCR proved to be a very useful tool for the detection of M. tuberculosis complex, clinical, epidemiological, and other laboratory data should also be considered in the diagnosis and treatment of pulmonary and extrapulmonary tuberculosis. PMID- 24473766 TI - Inflammatory and immunogenetic markers in correlation with pulmonary tuberculosis. AB - OBJECTIVE: To describe serum levels of the cytokines IL-10, TNF-alpha, and IFN gamma, as well as polymorphisms in the genes involved in their transcription, and their association with markers of the acute inflammatory response in patients with pulmonary tuberculosis. METHODS: This was a descriptive, longitudinal study involving 81 patients with pulmonary tuberculosis treated at two referral hospitals. We collected data on sociodemographic variables and evaluated bacteriological conversion at the eighth week of antituberculosis treatment, gene polymorphisms related to the cytokines studied, and serum levels of those cytokines, as well as those of C-reactive protein (CRP). We also determined the ESR and CD4+ counts. RESULTS: The median age of the patients was 43 years; 67 patients (82.7%) were male; and 8 patients (9.9%) were infected with HIV. The ESR was highest in the patients with high IFN-gamma levels and low IL-10 levels. IFN gamma and TNF-alpha gene polymorphisms at positions +874 and -238, respectively, showed no correlations with the corresponding cytokine serum levels. Low IL-10 levels were associated with IL-10 gene polymorphisms at positions -592 and -819 (but not -1082). There was a negative association between bacteriological conversion at the eighth week of treatment and CRP levels. CONCLUSIONS: Our results suggest that genetic markers and markers of acute inflammatory response are useful in predicting the response to antituberculosis treatment. PMID- 24473767 TI - Interpretation of autoantibody positivity in interstitial lung disease and lung dominant connective tissue disease. AB - The initial evaluation of patients with interstitial lung disease (ILD) primarily involves a comprehensive, active search for the cause. Autoantibody assays, which can suggest the presence of a rheumatic disease, are routinely performed at various referral centers. When interstitial lung involvement is the condition that allows the definitive diagnosis of connective tissue disease and the classical criteria are met, there is little debate. However, there is still debate regarding the significance, relevance, specificity, and pathophysiological role of autoimmunity in patients with predominant pulmonary involvement and only mild symptoms or formes frustes of connective tissue disease. The purpose of this article was to review the current knowledge of autoantibody positivity and to discuss its possible interpretations in patients with ILD and without clear etiologic associations, as well as to enhance the understanding of the natural history of an allegedly new disease and to describe the possible prognostic implications. We also discuss the proposition of a new term to be used in the classification of ILDs: lung-dominant connective tissue disease. PMID- 24473768 TI - Assessment of regional lung ventilation by electrical impedance tomography in a patient with unilateral bronchial stenosis and a history of tuberculosis. AB - Bronchial stenosis can impair regional lung ventilation by causing abnormal, asymmetric airflow limitation. Electrical impedance tomography (EIT) is an imaging technique that allows the assessment of regional lung ventilation and therefore complements the functional assessment of the lungs. We report the case of a patient with left unilateral bronchial stenosis and a history of tuberculosis, in whom regional lung ventilation was assessed by EIT. The EIT results were compared with those obtained by ventilation/perfusion radionuclide imaging. The patient was using nasal continuous positive airway pressure (CPAP) for the treatment of obstructive sleep apnea syndrome. Therefore, we studied the effects of postural changes and of the use of nasal CPAP. The EIT revealed heterogeneous distribution of regional lung ventilation, the ventilation being higher in the right lung, and this distribution was influenced by postural changes and CPAP use. The EIT assessment of regional lung ventilation produced results similar to those obtained with the radionuclide imaging technique and had the advantage of providing a dynamic evaluation without radiation exposure. PMID- 24473769 TI - Synchronous diagnosis of primitive papillary adenocarcinomas: beyond the realm of probability. PMID- 24473770 TI - Plasmodium falciparum malaria: another infection of interest to pulmonologists. PMID- 24473771 TI - Sarcomatoid carcinoma of the lung with brain metastases. PMID- 24473772 TI - Intrapulmonary lymph node: a common and underrecognized tomography finding. PMID- 24473773 TI - SIRT1-metabolite binding histone macroH2A1.1 protects hepatocytes against lipid accumulation. AB - Non-alcoholic-fatty-liver-disease (NAFLD) encompasses conditions associated to fat deposition in the liver, which are generally deteriorated during the aging process. MacroH2A1, a variant of histone H2A, is a key transcriptional regulator involved in tumorigenic processes and cell senescence, and featuring two alternatively splicing isoforms, macroH2A1.1 and macroH2A1.2. MacroH2A1.1 binds with high affinity O-acetyl ADP ribose, a small metabolite produced by the reaction catalysed by NAD+-dependent deacetylase SIRT1, whereas macroH2A1.2 is unable to do so. The functional significance of this binding is unknown. We previously reported that the hepatic levels of macroH2A1.1 and macroH2A1.2 are differentially expressed in mice models of NAFLD. Here we show that over expression of macroH2A1.1, but not of macroH2A1.2, is able to protect hepatocytes against lipid accumulation. MacroH2A1.1 over-expressing cells display ameliorated glucose metabolism, reduced expression of lipidogenic genes and fatty acids content. SIRT1/macroH2A1.1-dependent epigenetic regulation of lipid metabolism may be relevant to NAFLD development. PMID- 24473775 TI - Reporter gene technologies for imaging cell fates in hematopoiesis. AB - Advances in noninvasive imaging technologies that allow for in vivo dynamic monitoring of cells and cellular function in living research subjects have revealed new insights into cell biology in the context of intact organs and their native environment. In the field of hematopoiesis and stem cell research, studies of cell trafficking involved in injury repair and hematopoietic engraftment have made great progress using these new tools. Stem cells present unique challenges for imaging since after transplantation, they proliferate dramatically and differentiate. Therefore, the imaging modality used needs to have a large dynamic range, and the genetic regulatory elements used need to be stably expressed during differentiation. Multiple imaging technologies using different modalities are available, and each varies in sensitivity, ease of data acquisition, signal to noise ratios (SNR), substrate availability, and other parameters that affect utility for monitoring cell fates and function. For a given application, there may be several different approaches that can be used. For mouse models, clinically validated technologies such as magnetic resonance imaging (MRI) and positron emission tomography (PET) have been joined by optical imaging techniques such as in vivo bioluminescence imaging (BLI) and fluorescence imaging (FLI), and all have been used to monitor bone marrow and stem cells after transplantation into mice. Photoacoustic imaging that utilizes the sound created by the thermal expansion of absorbed light to generate an image best represents hybrid technologies. Each modality requires that the cells of interest be marked with a genetic reporter that acts as a label making them uniquely visible using that technology. For each modality, there are several labels to choose from. Multiple methods for applying these different labels are available. This chapter provides an overview of the imaging technologies and commonly used labels for each, as well as detailed protocols for gene delivery into hematopoietic cells for the purposes of applying these specific labels to cell trafficking. The goal of this chapter is to provide adequate background information to allow the design and implementation of an experimental system for in vivo imaging in mice. PMID- 24473774 TI - A prospective study of anxiety, depression, and behavioral changes in the first year after a diagnosis of childhood acute lymphoblastic leukemia: a report from the Children's Oncology Group. AB - BACKGROUND: The authors prospectively assessed anxiety, depression, and behavior in children with standard-risk acute lymphoblastic leukemia (SR-ALL) during the first year of therapy and identified associated risk factors. METHODS: A cohort study was performed of 159 children (aged 2 years-9.99 years) with SR-ALL who were enrolled on Children's Oncology Group protocol AALL0331 at 31 sites. Parents completed the Behavior Assessment System for Children, the General Functioning Scale of the Family Assessment Device, and the Coping Health Inventory for Parents at approximately 1, 6, and 12 months after diagnosis. RESULTS: Overall, mean scores for anxiety, depression, aggression, and hyperactivity were similar to population norms. However, more children scored in the at-risk/clinical range for depression than the expected 15% at 1 month (21.7%; P= .022), 6 months (28.6%; P< .001), and 12 months (21.1%; P= .032). For anxiety, more children scored in the at-risk/clinical range at 1 month (25.2% vs 15%; P= .001), but then reverted to expected levels. On adjusted analysis, unhealthy family functioning was found to be predictive of anxiety (odds ratio [OR], 2.24; P= .033) and depression (OR, 2.40; P= .008). Hispanic ethnicity was associated with anxiety (OR, 3.35; P= .009). Worse physical functioning (P= .049), unmarried parents (P= .017), and less reliance on social support (P= .004) were found to be associated with depression. Emotional distress at 1 month predicted anxiety (OR, 7.11; P= .002) and depression (OR, 3.31; P= .023) at 12 months. CONCLUSIONS: Anxiety is a significant problem in a subpopulation of patients with SR-ALL immediately after diagnosis, whereas depression remains a significant problem for at least 1 year. Children of Hispanic ethnicity or those with unhealthy family functioning may be particularly vulnerable. These data suggest that clinicians should screen for anxiety and depression throughout the first year of therapy. PMID- 24473776 TI - Flow cytometry for hematopoietic cells. AB - Within the last 25 years, flow cytometry and fluorescence-activated cell sorting have emerged as both routine diagnostic tools in clinical medicine and as advanced analytic tools critical in performing scientific research. This chapter aims at summarizing the use of flow cytometry in benign and malignant hematology and the monitoring of inherited and acquired immunodeficiency states. Numerous figures are provided from our laboratories at Massachusetts General Hospital that illustrate examples of these conditions. The chapter also describes novel flow cytometry-based imaging techniques, the combination of flow cytometry and mass spectrography, new software tools, and some future directions and applications of advanced instrumentation for flow cytometry. PMID- 24473777 TI - Isolation and characterization of mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) have drawn great interest in the field of regenerative medicine, for cell replacement, immunomodulatory, and gene therapies. It has been shown that these multipotent stromal cells can be isolated from tissues such as bone marrow, adipose tissue, trimester amniotic tissue, umbilical cord blood, and deciduous teeth and can be expanded in adherent culture. They have the capacity to differentiate into cells of the connective tissue lineages in vitro and contribute to tissue parenchyma in vivo. However, proper in vitro manipulation of MSCs is a key issue to reveal a potential therapeutic benefit following transplantation into the patients. This chapter summarizes some of the essential protocols and assays used at our laboratory for the isolation, culture, differentiation, and characterization of mesenchymal stem cells from the bone marrow and adipose tissue. PMID- 24473778 TI - Methods for functional analysis of stem cells. AB - Hematopoietic stem cells (HSC) are rare, multipotent cells characterized by their ability to self-renew and to generate all blood cells throughout life. Major advances have been made in the area of HSC research as a result of the development of different techniques that allowed HSC identification, purification, and analysis of biological functions. This chapter presents methods that are currently used to analyze HSC functions in vitro based on their characteristics. PMID- 24473779 TI - An overview of HLA typing for hematopoietic stem cell transplantation. AB - The selection of a related or an unrelated hematopoietic stem cell donor for a patient requires accurate matching of human leukocyte antigen (HLA) genes in order to maximize the beneficial effects of the transplant. There are various different factors a laboratory must consider in order to achieve an HLA type including the number of samples being processed, level of resolution to be achieved, cost of providing the various tests, and turnaround time required. Each method has its advantages and disadvantages, and in most laboratories, a combination of methods may be used. PMID- 24473780 TI - HLA typing with sequence-specific oligonucleotide primed PCR (PCR-SSO) and use of the LuminexTM technology. AB - The hybridization products obtained by PCR using sequence-specific oligonucleotides can be traced either by colorimetric (streptavidin-biotin)-, X ray (digoxigenin-CSPD)-, or fluorescence (FITC, PE)-based detection systems. To achieve a faster, reliable, automated typing technique microbead and fluorescence detection technology have been combined and introduced to this field (XMAPTM technology). For each locus, a series of microspheres, which are recognizable by their specific color originating from two internal fluorescent dyes, are used. Each microsphere is coupled with a single probe that is capable of hybridizing with the biotin-labeled complementary amplicon. Once hybridization occurs, it can be quantified by measuring the fluorescence signal originating from fluorescently (streptavidin-PE) labeled amplicons captured by the beads. Currently, there are two commercially available systems that differ in the scale of probes and the methods used for amplification and denaturation. One of these is described in detail in this chapter. PMID- 24473781 TI - Sequence-based typing of HLA: an improved group-specific full-length gene sequencing approach. AB - Matching for HLA at the allele level is crucial for stem cell transplantation. The golden standard approach for allele definition of full gene polymorphism, the so-called high-resolution HLA typing, is sequence-based typing (SBT). Although the majority of the polymorphism for class I is located in exons 2 and 3 and for class II in exon 2, for allele definition it is necessary to unravel the complete coding and intron sequences leading to an ultrahigh HLA typing resolution at the allele level, i.e., a full-length gene polymorphism identification.This chapter describes our recently developed SBT method for HLA-A, -B, -C, and -DQB1, that is based on full-length hemizygous Sanger sequencing of the alleles, separated by group-specific amplification using the low-resolution typing result as reference starting point. Group-specific amplification has already been established for DRB. This method enables a cost-efficient, user-friendly SBT approach resulting in a timely unambiguous HLA typing to an ultrahigh resolution level with minimal hands-on time. PMID- 24473782 TI - Molecular typing methods for minor histocompatibility antigens. AB - Minor histocompatibility (H) antigen mismatching leads to clinically relevant alloimmune reactivity. Depending on the tissue expression pattern of the involved minor H antigens, the immune response may either cause graft-versus-host disease and a graft-versus-tumor effect or lead to only a graft-versus-leukemia effect. Thus, identification of recipient-donor pairs with minor H antigen mismatches has clinical importance. This chapter describes molecular typing methods for molecular typing of minor H antigens. PMID- 24473783 TI - Natural killer cells and killer-cell immunoglobulin-like receptor polymorphisms: their role in hematopoietic stem cell transplantation. AB - Natural killer (NK) cells are important effector cells in the early control of infected, malignant, and "nonself" cells. Various receptor families are involved in enabling NK cells to detect and efficiently eliminate these target cells. The killer-cell immunoglobulin-like receptor (KIR) family is a set of receptors that are very polymorphic with regard to gene content, expression level, and expression pattern. KIRs are responsible for the induction of a NK cell alloreactive response through their interaction with HLA class I molecules. The role of NK cells in hematopoietic stem cell transplantation (HSCT) has been studied for many years, and induction of antileukemic responses by donor NK cells has been reported. Conflicting data still exist on the exact circumstances in which the KIR repertoire affects and influences clinical outcome after HSCT. More large-scale studies are needed on well-defined cohorts to unravel the mechanism of action of the NK cell-mediated alloresponse in an HSCT setting. PMID- 24473784 TI - Methods of detection of immune reconstitution and T regulatory cells by flow cytometry. AB - Allogeneic hematopoietic stem cell therapy (HSCT) remains one of the few curative treatments for high-risk hematological malignancies (high-risk leukemia, myelodysplastic syndromes, advanced myeloproliferative disorders, high-risk lymphomas, and multiple myeloma) and is currently applied in more than 15,000 patients per year in Europe. Following HSCT, patients experience a period of reconstitution of the immune system, which seems to be highly dependent on conditioning, immunosuppression regimes, and the level of adverse events the patients experience. During this reconstitution period, the patient is immune compromised and susceptible to opportunistic infections and disease relapse. Consequently, a large number of clinical studies have been devoted to monitoring the recovery of the immune system following HSCT in the hopes of determining which cellular subsets are indicative of a favorable outcome. In this chapter we review the methods that have been employed to monitor the immune reconstitution and what clinical observations have been made. Of particular interest is the regulatory T cell (Treg) subset, which has been associated with tolerance and has been the subject of recent clinical trials as a possible cellular therapy for rejection reactions. Finally we will detail a proposed methodology for the flow cytometric assessment of cellular reconstitution post-HSCT. PMID- 24473785 TI - Molecular methods used for detection of minimal residual disease following hematopoietic stem cell transplantation in myeloid disorders. AB - The monitoring of minimal residual disease (MRD) in patients with acute or chronic myeloid disorders is performed routinely after allogeneic or autologous transplantation. The detection of MRD helps to identify patients who are at high risk for leukemic relapse after transplantation. The most commonly used techniques for MRD detection are qualitative and quantitative PCR methods, fluorescence in situ hybridization (FISH), fluorescence-activated cell sorting (FACS), and cytogenetic analysis, which are often performed complementary in order to assess more precisely MRD. Here we describe the most used sensitive real time RT-PCR methods for chronic and acute myeloid disorders. Besides protocols for real-time RT-PCR and multiplex RT-PCR procedures for the most common fusion gene transcripts in acute and chronic myeloid disorders, methods for detections of disease-specific genetic mutated alterations, as NPM1 and FLT3 gene length mutations, and aberrantly expressed genes, as WT1 gene transcripts, are described in detail for daily use. PMID- 24473786 TI - Molecular methods for detection of minimal residual disease following transplantation in lymphoid and plasma cell disorders. AB - Relapse represents the main cause of treatment failure after stem cell transplantation (SCT). Thus, monitoring of minimal residual disease (MRD) in allografted patients allows an early detection of recurrence and a subsequent intervention prior to clinically detectable relapse. MRD assessment by polymerase chain reaction-based methods is currently part of the routine clinical management of patients with chronic myeloid leukemia after allo-SCT. It is also recognized that it is a useful prognostic tool in several mature lymphoid and plasma cell disorders such as chronic lymphocytic leukemia, follicular lymphoma, mantle cell lymphoma, and multiple myeloma. In some of these entities, clinical trials employing MRD as a decision-making tool are currently ongoing and will define whether sensitive MRD detection allows for earlier therapeutic intervention to improve the outcome of SCT. We here discuss the methods of MRD evaluation in lymphoid and plasma cell disorders following transplantation with the ultimate aim of providing critical information for the setup of molecular approaches to detect MRD. PMID- 24473787 TI - Molecular methods for detection of invasive fungal infections and mycobacteria and their clinical significance in hematopoietic stem cell transplantation. AB - Infection remains an important source of morbidity and mortality in patients who undergo hematopoietic stem cell transplantation (HSCT). In the immune reconstitution period after transplantation, HSCT recipients are most likely to have bacterial or fungal infections. Invasive fungal infections (IFIs) and mycobacterial infections (MBIs) are among the complications of HSCT, with high morbidity and mortality rates. Early diagnosis of both is crucial in order to manipulate the disease and to avoid fulminant outcomes. This chapter reviews the current knowledge on the molecular diagnosis of IFIs and MBIs in HSCT recipients, describing two different polymerase chain reaction (PCR)-based methods, one commercial (qPCR, Roche) and one in-house IS6110-based protocol. PMID- 24473788 TI - Post-transplant monitoring of chimerism by lineage-specific analysis. AB - Molecular surveillance of hematopoietic chimerism is an important part of the routine diagnostic program in patients after allogeneic stem cell transplantation. Chimerism testing permits early prediction and documentation of successful engraftment and facilitates early risk assessment of impending graft rejection. In patients transplanted for treatment of malignant hematologic disorders, monitoring of chimerism can provide an early indication of incipient disease relapse. The investigation of chimerism has therefore become an indispensable tool for the management of patients during the post-transplant period. Increasing use of reduced-intensity conditioning, which is associated with prolonged duration of mixed hematopoietic chimerism, has further increased the clinical importance of chimerism analysis. At present, the most commonly used technical approach to the investigation of chimerism is microsatellite analysis by polymerase chain reaction. The investigation of chimerism within specific leukocyte subsets isolated from peripheral blood or bone marrow samples by flow sorting- or magnetic bead-based techniques provides more specific information on processes underlying the dynamics of donor/recipient chimerism. Moreover, cell subset-specific analysis permits the assessment of impending complications at a significantly higher sensitivity, thus providing a basis for earlier treatment decisions. PMID- 24473789 TI - Urinary proteomics employing capillary electrophoresis coupled to mass spectrometry in the monitoring of patients after stem cell transplantation. AB - Complex biological samples hold significant information on the health status and development of disease. Approximately 22,000 human genes give rise to more than 400,000 proteins as functional entities (Anderson and Anderson, Electrophoresis 19:1853-1861, 1998). Thus, the proteome provides a much richer source of information than the genome for describing the state of health or disease of humans. The composition of body fluids comprises a rich source of information on changes of protein and peptide expression. Here we describe the application of capillary electrophoresis (CE) coupled online to an electrospray-ionization time of-flight mass spectrometer (ESI-TOF-MS) to analyze human urine for the identification of biomarkers specific for complications after allogeneic hematopoietic stem cell transplantation (Kaiser et al. Blood 104:340-349, 2004; Weissinger et al. Blood 109:5511-5519, 2007). In addition, we describe methods for the sequencing of native proteins/peptides, necessary for the identification of possible new therapeutic targets. PMID- 24473790 TI - Genotoxic and hematological effects in children exposed to a chemical mixture in a petrochemical area in Mexico. AB - Children living in Coatzacoalcos, Veracruz, and in nearby surrounding areas are exposed to a mixture of pollutants from different sources. Previous studies in the area have reported genotoxic and haematotoxic compounds, such as lead (Pb), benzene, toluene, and polycyclic aromatic hydrocarbons (PAHs), in environmental and biological samples. The final toxic effects of these compounds are unknown because the toxic behaviour of each compound is modified when in a complex mixture. This is the first study on the exposure and effect of chemical mixtures on children who live near a petrochemical area. The aim of this study was to evaluate genotoxicity and haematological effects in children environmentally exposed to such mixtures and to determine whether the final effect was modified by the composition of the mixture composition. Biomarkers of exposure to Pb, benzene, toluene, and PAHs were quantified in urine and blood samples of 102 children. DNA damage was evaluated using comet assay, and haematological parameters were determined. Our results show that Pb and toluene did not surpass the exposure guidelines; the exposure was similar in all three localities (Allenede, Mundo Nuevo, and Lopez Mateos). In contrast, exposure to PAHs was observed at three levels of exposure: low, medium, and high. The most severe effects of these mixtures were strictly related to coexposure to high levels of PAHs. PMID- 24473793 TI - Detection of autoantibodies to precursor proteins of desmogleins in sera of a patient with Bowen carcinoma. PMID- 24473796 TI - Foreword. PMID- 24473795 TI - Elevated serum pesticide levels and risk for Alzheimer disease. AB - IMPORTANCE: The causes of late-onset Alzheimer disease (AD) are not yet understood but likely include a combination of genetic, environmental, and lifestyle factors. Limited epidemiological studies suggest that occupational pesticide exposures are associated with AD. Previously, we reported that serum levels of dichlorodiphenyldichloroethylene (DDE), the metabolite of the pesticide dichlorodiphenyltrichloroethane (DDT), were elevated in a small number of patients with AD (n=20). OBJECTIVE: To evaluate the association between serum levels of DDE and AD and whether the apolipoprotein E (APOE) genotype modifies the association. DESIGN, SETTING, AND PARTICIPANTS: A case-control study consisting of existing samples from patients with AD and control participants from the Emory University Alzheimer's Disease Research Center and the University of Texas Southwestern Medical School's Alzheimer's Disease Center. Serum levels of DDE were measured in 79 control and 86 AD cases. MAIN OUTCOMES AND MEASURES: Serum DDE levels, AD diagnosis, severity of AD measured by the Mini-Mental State Examination score, and interaction with APOE4 status. RESULTS: Levels of DDE were 3.8-fold higher in the serum of those with AD (mean [SEM], 2.64 [0.35] ng/mg cholesterol) when compared with control participants (mean [SEM], 0.69 [0.1] ng/mg cholesterol; P < .001). The highest tertile of DDE levels was associated with an odds ratio of 4.18 for increased risk for AD (95% CI, 2.54-5.82; P < .001) and lower Mini-Mental State Examination scores (-1.605; range, -3.095 to 0.114; P < .0001). The Mini-Mental State Examination scores in the highest tertile of DDE were -1.753 points lower in the subpopulation carrying an APOE epsilon4 allele compared with those carrying an APOE epsilon3 allele (P interaction = .04). Serum levels of DDE were highly correlated with brain levels of DDE (rho = 0.95). Exposure of human neuroblastoma cells to DDT or DDE increased levels of amyloid precursor protein. CONCLUSIONS AND RELEVANCE: Elevated serum DDE levels are associated with an increased risk for AD and carriers of an APOE4 epsilon4 allele may be more susceptible to the effects of DDE. Both DDT and DDE increase amyloid precursor protein levels, providing mechanistic plausibility for the association of DDE exposure with AD. Identifying people who have elevated levels of DDE and carry an APOE epsilon4 allele may lead to early identification of some cases of AD. PMID- 24473797 TI - Aedes aegypti on Madeira Island (Portugal): genetic variation of a recently introduced dengue vector. AB - The increasing population of Aedes aegypti mosquitoes on Madeira Island (Portugal) resulted in the first autochthonous dengue outbreak, which occurred in October 2012. Our study establishes the first genetic evaluation based on the mitochondrial DNA (mtDNA) genes [cytochrome oxidase subunit I (COI) and NADH dehydrogenase subunit 4 (ND4)] and knockdown resistance (kdr) mutations exploring the colonisation history and the genetic diversity of this insular vector population. We included mosquito populations from Brazil and Venezuela in the analysis as putative geographic sources. The Ae. aegypti population from Madeira showed extremely low mtDNA genetic variability, with a single haplotype for COI and ND4. We also detected the presence of two important kdr mutations and the quasi-fixation of one of these mutations (F1534C). These results are consistent with a unique recent founder event that occurred on the island of Ae. aegypti mosquitoes that carry kdr mutations associated with insecticide resistance. Finally, we also report the presence of the F1534C kdr mutation in the Brazil and Venezuela populations. To our knowledge, this is the first time this mutation has been found in South American Ae. aegypti mosquitoes. Given the present risk of Ae. aegypti re-invading continental Europe from Madeira and the recent dengue outbreaks on the island, this information is important to plan surveillance and control measures. PMID- 24473798 TI - History of domestication and spread of Aedes aegypti--a review. AB - The adaptation of insect vectors of human diseases to breed in human habitats (domestication) is one of the most important phenomena in medical entomology. Considerable data are available on the vector mosquito Aedes aegypti in this regard and here we integrate the available information including genetics, behaviour, morphology, ecology and biogeography of the mosquito, with human history. We emphasise the tremendous amount of variation possessed by Ae. aegypti for virtually all traits considered. Typological thinking needs to be abandoned to reach a realistic and comprehensive understanding of this important vector of yellow fever, dengue and Chikungunya. PMID- 24473799 TI - Male accessory gland substances from Aedes albopictus affect the locomotor activity of Aedes aegypti females. AB - Dengue is one of the world's most important mosquito-borne diseases and is usually transmitted by one of two vector species: Aedes aegypti or Aedes albopictus . These two diurnal mosquitoes are frequently found coexisting in similar habitats, enabling interactions between adults, such as cross-mating. The objective of this study was to assess cross-mating between Ae. aegypti females and Ae. albopictus males under artificial conditions and evaluate the locomotor activity of Ae. aegypti virgin females injected with male accessory gland (MAG) homogenates to infer the physiological and behavioural responses to interspecific mating. After seven days of exposure, 3.3-16% of Ae. aegypti females mated with Ae. albopictus males. Virgin Ae. aegypti females injected with conspecific and heterospecific MAGs showed a general decrease in locomotor activity compared to controls and were refractory to mating with conspecific males. The reduction in diurnal locomotor activity induced by injections of conspecific or heterospecific MAGs is consistent with regulation of female reproductive activities by male substances, which are capable of sterilising female Ae. aegypti through satyrisation by Ae. albopictus. PMID- 24473800 TI - Acoustic communication in insect disease vectors. AB - Acoustic signalling has been extensively studied in insect species, which has led to a better understanding of sexual communication, sexual selection and modes of speciation. The significance of acoustic signals for a blood-sucking insect was first reported in the XIX century by Christopher Johnston, studying the hearing organs of mosquitoes, but has received relatively little attention in other disease vectors until recently. Acoustic signals are often associated with mating behaviour and sexual selection and changes in signalling can lead to rapid evolutionary divergence and may ultimately contribute to the process of speciation. Songs can also have implications for the success of novel methods of disease control such as determining the mating competitiveness of modified insects used for mass-release control programs. Species-specific sound "signatures" may help identify incipient species within species complexes that may be of epidemiological significance, e.g. of higher vectorial capacity, thereby enabling the application of more focussed control measures to optimise the reduction of pathogen transmission. Although the study of acoustic communication in insect vectors has been relatively limited, this review of research demonstrates their value as models for understanding both the functional and evolutionary significance of acoustic communication in insects. PMID- 24473801 TI - Behavioural biology of Chagas disease vectors. AB - Many arthropod species have adopted vertebrate blood as their main food source. Blood is rich in nutrients and, except for the presence of parasites, sterile. However, this food source is not freely available, nor is obtaining it devoid of risk. It circulates inside vessels hidden underneath the skin of mobile hosts that are able to defend themselves and even predate the insects that try to feed on them. Thus, the haematophagous lifestyle is associated with major morphological, physiological and behavioural adaptations that have accumulated throughout the evolutionary history of the various lineages of blood-sucking arthropods. These adaptations have significant consequences for the evolution of parasites as well as for the epidemiology of vector-transmitted diseases. In this review article, we analyse various aspects of the behaviour of triatomine bugs to illustrate how each behavioural trait represents a particular adaptation to their close association with their hosts, which may easily turn into predators. Our aim is to offer to the reader an up-to-date integrative perspective on the behaviour of Chagas disease vectors and to propose new research avenues to encourage both young and experienced colleagues to explore this aspect of triatomine biology. PMID- 24473803 TI - Biological rhythms and vector insects. AB - The adjustment of all species, animals and plants, to the Earth's cyclic environments is ensured by their temporal organisation. The relationships between parasites, vectors and hosts rely greatly upon the synchronisation of their biological rhythms, especially circadian rhythms. In this short note, parasitic infections by Protozoa and by microfilariae have been chosen as examples of the dependence of successful transmission mechanisms on temporal components. PMID- 24473802 TI - Circadian rhythms in insect disease vectors. AB - Organisms from bacteria to humans have evolved under predictable daily environmental cycles owing to the Earth's rotation. This strong selection pressure has generated endogenous circadian clocks that regulate many aspects of behaviour, physiology and metabolism, anticipating and synchronising internal time-keeping to changes in the cyclical environment. In haematophagous insect vectors the circadian clock coordinates feeding activity, which is important for the dynamics of pathogen transmission. We have recently witnessed a substantial advance in molecular studies of circadian clocks in insect vector species that has consolidated behavioural data collected over many years, which provided insights into the regulation of the clock in the wild. Next generation sequencing technologies will facilitate the study of vector genomes/transcriptomes both among and within species and illuminate some of the species-specific patterns of adaptive circadian phenotypes that are observed in the field and in the laboratory. In this review we will explore these recent findings and attempt to identify potential areas for further investigation. PMID- 24473805 TI - When population and evolutionary genetics met behaviour. AB - In this review, we analyse the impact of a population and evolutionary genetics approach on the study of insect behaviour. Our attention is focused on the model organism Drosophila melanogaster and several other insect species. In particular, we explore the relationship between rhythmic behaviours and the molecular evolution of clock and ion channel genes. PMID- 24473804 TI - Genetic basis of triatomine behavior: lessons from available insect genomes. AB - Triatomines have been important model organisms for behavioural research. Diverse reports about triatomine host search, pheromone communication in the sexual, shelter and alarm contexts, daily cycles of activity, refuge choice and behavioural plasticity have been published in the last two decades. In recent times, a variety of molecular genetics techniques has allowed researchers to investigate elaborate and complex questions about the genetic bases of the physiology of insects. This, together with the current characterisation of the genome sequence of Rhodnius prolixus allows the resurgence of this excellent insect physiology model in the omics era. In the present revision, we suggest that studying the molecular basis of behaviour and sensory ecology in triatomines will promote a deeper understanding of fundamental aspects of insect and, particularly, vector biology. This will allow uncovering unknown features of essential insect physiology questions for a hemimetabolous model organism, promoting more robust comparative studies of insect sensory function and cognition. PMID- 24473806 TI - Circadian clock of Aedes aegypti: effects of blood-feeding, insemination and RNA interference. AB - Mosquitoes are the culprits of some of the most important vector borne diseases. A species' potential as a vector is directly dependent on their pattern of behaviour, which is known to change according to the female's physiological status such as whether the female is virgin/mated and unfed/blood-fed. However, the molecular mechanism triggered by and/or responsible for such modulations in behaviour is poorly understood. Clock genes are known to be responsible for the control of circadian behaviour in several species. Here we investigate the impact mating and blood-feeding have upon the expression of these genes in the mosquito Aedes aegypti. We show that blood intake, but not insemination, is responsible for the down-regulation of clock genes. Using RNA interference, we observe a slight reduction in the evening activity peak in the fourth day after dstim injection. These data suggest that, as in Drosophila, clock gene expression, circadian behaviour and environmental light regimens are interconnected in Ae. aegypti. PMID- 24473807 TI - Molecular analysis of an odorant-binding protein gene in two sympatric species of Lutzomyia longipalpis s.l. AB - Lutzomyia longipalpis s.l. is the main vector of American visceral leishmaniasis (AVL) and occurs as a species complex. DNA samples from two Brazilian sympatric species that differ in pheromone and courtship song production were used to analyse molecular polymorphisms in an odorant-binding protein (obp29) gene. OBPs are proteins related to olfaction and are involved in activities fundamental to survival, such as foraging, mating and choice of oviposition site. In this study, the marker obp29 was found to be highly polymorphic in Lu. longipalpis s.l. , with no fixed differences observed between the two species. A pairwise fixation index test indicated a moderate level of genetic differentiation between the samples analysed. PMID- 24473808 TI - Rhodnius barretti, a new species of Triatominae (Hemiptera: Reduviidae) from western Amazonia. AB - Rhodnius barretti, a new triatomine species, is described based on adult specimens collected in rainforest environments within the Napo ecoregion of western Amazonia (Colombia and Ecuador). R. barretti resembles Rhodnius robustus s.l., but mitochondrial cytochrome b gene sequences reveal that it is a strongly divergent member of the "robustus lineage", i.e., basal to the clade encompassing Rhodnius nasutus, Rhodnius neglectus, Rhodnius prolixus and five members of the R. robustus species complex. Morphometric analyses also reveal consistent divergence from R. robustus s.l., including head and, as previously shown, wing shape and the length ratios of some anatomical structures. R. barretti occurs, often at high densities, in Attalea butyracea and Oenocarpus bataua palms. It is strikingly aggressive and adults may invade houses flying from peridomestic palms. R. barretti must therefore be regarded as a potential Trypanosoma cruzi vector in the Napo ecoregion, where Chagas disease is endemic. PMID- 24473809 TI - Mosquitoes of eastern Amazonian Ecuador: biodiversity, bionomics and barcodes. AB - Two snapshot surveys to establish the diversity and ecological preferences of mosquitoes (Diptera: Culicidae) in the terra firme primary rain forest surrounding the Tiputini Biodiversity Station in the UNESCO Yasuni Biosphere Reserve of eastern Amazonian Ecuador were carried out in November 1998 and May 1999. The mosquito fauna of this region is poorly known; the focus of this study was to obtain high quality link-reared specimens that could be used to unequivocally confirm species level diversity through integrated systematic study of all life stages and DNA sequences. A total of 2,284 specimens were preserved; 1,671 specimens were link-reared with associated immature exuviae, all but 108 of which are slide mounted. This study identified 68 unique taxa belonging to 17 genera and 27 subgenera. Of these, 12 are new to science and 37 comprise new country records. DNA barcodes [658-bp of the mtDNA cytochrome c oxidase (COI) I gene] are presented for 58 individuals representing 20 species and nine genera. DNA barcoding proved useful in uncovering and confirming new species and we advocate an integrated systematics approach to biodiversity studies in future. Associated bionomics of all species collected are discussed. An updated systematic checklist of the mosquitoes of Ecuador (n=179) is presented for the first time in 60 years. PMID- 24473810 TI - COI barcode versus morphological identification of Culex (Culex) (Diptera: Culicidae) species: a case study using samples from Argentina and Brazil. AB - Sequences of the cytochrome c oxidase subunit I (COI) mitochondrial gene from adults of 22 Culex (Culex) species from Argentina and Brazil were employed to assess species identification and to test the usefulness of COI for barcoding using the best close match (BCM) algorithm. A pairwise Kimura two-parameter distance matrix including the mean intra and interspecific distances for 71 COI barcode sequences was constructed. Of the 12 COI lineages recovered in the Neighbour-joining topology, five confirmed recognised morphological species (Cx. acharistus, Cx. chidesteri, Cx. dolosus, Cx. lygrus and Cx. saltanensis) with intraspecific divergences lower than 1.75%. Cx. bilineatus is formally resurrected from the synonymy of Cx. dolosus. Cx. maxi , Cx. surinamensis and the Coronator group species included were clustered into an unresolved lineage. The intraspecific distance of Cx. pipiens (3%) was almost twice the interspecific between it and Cx. quinquefasciatus (1.6%). Regarding the BCM criteria, the COI barcode successfully identified 69% of all species. The rest of the sequences, approximately 10%, 18% and 3%, remained as ambiguously, mis and unidentified, respectively. The COI barcode does not contain enough information to distinguish Culex (Cux.) species. PMID- 24473815 TI - Impact of carotid atherosclerosis combined with hypercholesterolemia on cerebral microvessels and brain parenchyma in a new complex rat model. AB - Most previous investigations about stroke caused by carotid atherosclerosis have focused on thromboembolism. There is a lack of knowledge about pathophysiology of the brain before ischemic insults. The objective of this study was to develop a new model of hypercholesterolemia plus carotid injury and to investigate the impact of carotid atherosclerosis combined with hypercholesterolemia in the rat brain. The complex rat model was developed by carotid injury induced by an air drying endothelial denudation method after high cholesterol diet for 2 weeks. Plasma cholesterol, carotid pathomorphology, oxidative stress and inflammation in cerebral microvessels and brain parenchyma were measured at 7, 14 and 28 days after carotid surgery. The results showed that plasma concentrations of total cholesterol and low density lipoprotein-cholesterol were significantly increased, and severe carotid atherosclerosis and stenosis was observed in the complex rat model at 14 and 28 days after carotid surgery. The activity of superoxide dismutase was decreased, while the content of malondialdehyde was increased in cerebral microvessels and brain parenchyma. The levels of tumor necrosis factor alpha and interleukin-1beta were elevated in brain tissues of this model. Almost all above changes were more severe than those in either hypercholesterolemia alone group or carotid injury alone group. These results suggest that this complex rat model may more resemble human disease than the classic acute ischemic insult model for assessing the impact of carotid atherosclerosis as a preexisting disease on cerebral microcirculation and brain tissue. PMID- 24473817 TI - Concerning the presence of the cytokinin, N (6)-(Delta (2)-isopentnyl) adenine, in cultures of Corynebacterium fascians. AB - Corynebacterium fascians causes a fasciation disease in a number of dicotyledons and this disease appears to be caused by compounds with cytokinin activity elaborated by the infecting bacteria. Extractions of C. fascians in late logarithmic phase under conditions where the pH never falls below 7.0 yield about 2 MUg/l of N (6)-(Delta(2), a potent cytokinin. If a mild acidification step is included in the extraction procedure the yield increases to about 12 MUg/l. This is due to release of N (6)-(Delta(2)-isopentenyl)adenine from C. fascians tRNA during the extraction procedure. In terms of total cytokinin activity present in C. fascians cultures, N (6)-(Delta(2)-isopentenyl)adenine appears to be a minor component. PMID- 24473818 TI - Cytochemical localization of peroxidase activity in root cells. AB - The distribution of peroxidase in the apical 3 mm of pea roots has been investigated using the histochemical method employing 3,3-diaminobenzidine as a substrate. At the tissue level the enzyme is localized predominately in the root cap, epidermis, inner cortical cells, endodermis, phloem and maturing xylem. At the subcellular level peroxidase is found mainly in the intercellular regions of the cortex cell walls and in the cytoplasm and vacuoles of the steler cells. Root microbodies, unlike those of leaves, do not appear to be able to oxidize this substrate. The significance of these observations is discussed in relation to the validity of the technique and the proposed roles of the enzyme in cellular metabolism. PMID- 24473816 TI - Muscimol as an ionotropic GABA receptor agonist. AB - Muscimol, a psychoactive isoxazole from Amanita muscaria and related mushrooms, has proved to be a remarkably selective agonist at ionotropic receptors for the inhibitory neurotransmitter GABA. This historic overview highlights the discovery and development of muscimol and related compounds as a GABA agonist by Danish and Australian neurochemists. Muscimol is widely used as a ligand to probe GABA receptors and was the lead compound in the development of a range of GABAergic agents including nipecotic acid, tiagabine, 4,5,6,7-tetrahydroisoxazolo(5,4 c)pyridin-3-ol, (Gaboxadol((r))) and 4-PIOL. PMID- 24473819 TI - Phytochrome-controlled rapid contraction and recovery of contractile vacuoles in the motor cells of Mimosa pudica as an intracellular correlate of nyctinasty. AB - Using living thin sections (ca. 70-80 MU thick) of tertiary pulvini of Mimosa pudica, we have quantitatively determined that the bahavior of the contractile tannin vacuoles in the motor cells is under phytochrome control. Using material in which these vacuoles were in their most expanded state in white light, contraction was observable 3 min after the material was placed in continuous darkness. No contraction occurred if the cells were irradiated with 90 sec of far red light; red light reversed this effect. Futhermore, the kinetics of change of the vacuolar conformation was closely paralled by that of the nyctinastic changes of the pinnule closure during the different treatments. When the section of pulvinus was irradiated with a microbeam of far red light in one part of the section, and the motor cell vacuoles in another area were monitored for contraction, they almost always responded.We therefore conclude that the contractile vacuole of the motor cell is an excellent cellular correlate of phytochrome-mediated nyctinasty in M. pudica, and discuss its possible causal role in regulating the phenomenon. It is further concluded that functional phytochrome is present in all parts of the pulvinus and that, upon absorption of the stimulus energy, an intercellular messenger is released which stimulates all the motor cells in the pulvinus. PMID- 24473820 TI - Nitrogenase activity, amino acid pool patterns and amination in blue-green algae. AB - The free amino acid pools in the nitrogen-fixing blue-green algae Anabaena cylindrica, A. flos-aquae and Westiellopsis prolifica contain a variety of amino acids with aspartic acid, glutamic acid and the amide glutamine being present in much higher concentrations than the others. This pattern is characteristic of that found in organisms having glutamine synthetage/glutamate synthetase [glutamine amide-2-oxoglutarate amino transferase (oxido-reductase)] as an important pathway of ammonia incorporation. Under nitrogen-starved conditions the level of acetylene reduction (nitrogen fixation) and the glutamine pool both increase but the free ammonia pool decreases, suggesting that ammonia rather than glutamine regulates nitrogen fixation.Glutamine synthetase has been demonstrated in Anabaena cylindrica using the gamma-glutamyl transferase assay and also using a biosynthetic assay in which Pi release from ATP during glutamine synthesis was measured. The enzyme (gamma-glutamyl transferase assay) is present in nitrogen fixing cultures and activity is higher in aerobic than in microaerophilic cultures. Ammonium-grown cultures have lowest levels of all and activity in the presence of nitrate-nitrogen (150 mg nitrogen 1(-1)) is lower than in aerobic cultures growing on elemental nitrogen. Ammonium-nitrogen and nitrate-nitrogen have no effect on glutamine synthetase in vitro. Glutamate synthetase also operates in nitrogen-fixing cultures of Anabaena cylindrica. PMID- 24473821 TI - Measurement of profiles of potassium activity and electrical potential in the intact root. AB - Profiles of potassium activity and electrical potential in the vacuoles of cells across the intact root of Helianthus annuus have been measured. No gradient in either potassium activity or potential difference was detected from epidermis to pericycle. The trans-root electrical potential was found to be made up of two components, a large P.D. between the outside solution and the outer cells and a small P.D. at the pericycle-xylem interface. The results indicated that all the living cells of the root have the same capacity to actively accumulate potassium. PMID- 24473822 TI - Uninucleate spores of Phycomyces. AB - Under most culture conditions only 0.3% of the vegetative spores of Phycomyces blakesleeanus are uninucleate. On an acidified minimal medium, the uninucleate fraction can be raised up to 4.5% of the spores. The spore population can be fractionated in a gradient under gravity (1xg) yielding fractions that contain over 80% uninucleate spores. These uninucleate spores are fully viable. When the spores to be fractionated are obtained from a heterokaryotic mycelium, the uninucleate fraction produces homokaryotic mycelia. PMID- 24473823 TI - Rate of RNA synthesis and tRNA end-labeling during early development of Phaseolus. AB - Axes of Phaseolus vulgaris cease synthesis of RNA during the maturation stage of embryogeny. During the imbibition phase of germination RNA synthesis resumes after the axes reach a normal water content. In the first hour of inbibition a very low rate of incorporation of (3)H-adenosine into is RNA found, and the primary site of incorporation is the-CCA end of tRNA. At later stages of germination tRNA end-labeling accounts for a minor fraction of adenosine incorporation. The rate of RNA synthesis increases after initiation of axis elongation to a maximal rate at 18 h of germination. ATP pool-size and specific activity vary over a several-fold range during development, an important consideration in determining the rate of RNA synthesis. PMID- 24473824 TI - [Different light intensity dependence of the free-running periods as the cause of internal desynchronization of circadian rhythms in Phaseolus coccineus]. AB - The length of the free-running periods of circadian leaf movements in the primary and secondary pulvini of Phaseolus coccineus was measured in constant darkness (DD) and continuous light (LL) of different intensities. The periods for the two pulvini do not differ from each other in DD and LL 30000 lx. However, they differ in LL 60 lx, 600 lx and 6000 lx, indicating a state of internal desynchronization. These results show a difference in the light intensity dependence of the 2 oscillations and a lack of mutual synchronization between them. PMID- 24473825 TI - Identification of auxin from Zea coleoptile tips by mass spectrometry. AB - The auxin from Zea coleoptile tips has been identified conclusively as IAA. PMID- 24473829 TI - Comparison of scapholunate distance measurements on plain radiography and computed tomography for the diagnosis of scapholunate instability associated with distal radius fracture. AB - PURPOSE: To investigate radiographic criteria for scapholunate instability (SLI) in the setting of distal radius fracture (DRF) confirmed by arthroscopy. METHODS: Eighty-eight wrists with DRF treated by open reduction and internal fixation and assessed for SLI arthroscopically were evaluated. The scapholunate distance (SLD) was measured by preoperative posteroanterior wrist radiography and computed tomography (CT). SLD on radiographs was measured as the distance between the scaphoid cortex and the lunate cortex at the center of the scapholunate joint. SLDs were measured at the volar end (A1), center (A2), and dorsal end (A3) of the scapholunate joint on the central CT axial slice; and at the proximal end (C1), center (C2), and distal end (C3) of the scapholunate joint on the central CT coronal slice. Wrists were divided into three groups by arthroscopic assessments: stable (normal, Geissler grade 1 or 2), G3 (Geissler grade 3), and G4 (Geissler grade 4). SLD measurements on radiographs and CTs (A1-C3) were compared among the three groups. Receiver-operating characteristic (ROC) curve analyses were performed to evaluate the abilities of SLD measurements on radiographs and CTs to identify SLI in wrists with DRF. Interobserver and intraobserver reliabilities of SLD measurements on radiographs and CTs were analyzed by intraclass correlation coefficients (ICCs). RESULTS: SLDs of C3 differed significantly among the G3 and G4 groups, and among the stable and G4 groups. The area under the curve on ROC curve analysis was 0.855 for the SLD of C3, which was larger than that for SLD on radiographs. For C3, the intraobserver ICC was 0.832 and interobserver ICC was 0.73. CONCLUSIONS: SLD at the distal end of the scapholunate joint on the central coronal CT slice was the most appropriate measurement for discrimination of Geissler grade 4 SLI in wrists with DRF. LEVEL OF EVIDENCE: Level 2. PMID- 24473828 TI - The potential and limitations of plasma BNP measurement in the diagnosis, prognosis, and management of children with heart failure due to congenital cardiac disease: an update. AB - The aim of this article is to review the diagnostic and prognostic relevance of measurement of brain natriuretic peptide (BNP) and N-terminal pro-brain natriuretic peptide (NT-proBNP) in pediatric patients with heart failure caused by various acquired and congenital heart diseases (CHD). In January 2013, we performed a computerized literature search in the National Library of Medicine (PubMed access to MEDLINE citations; http://www.ncbi.nlm.nih.gov/PubMed/ ). The search strategy included a mix of Medical Subject Headings and free-text terms for the key concepts, starting from BNP assay and 'NT-proBNP assay', children, CHD. The search was further refined by adding the keywords neonate/s, newborn/s, heart failure, cardiomyopathy, screening, prognosis, follow-up, and management. BNP values are age and method dependent, even in pediatric populations. Regardless of age, there is great variability in BNP/NT-proBNP values within CHD characterized by different hemodynamic and clinical conditions. There is enough evidence to support the use of BNP/NT-proBNP as an adjunctive marker in the integrated evaluation of patients with congenital and acquired heart disease to help define severity and progression of heart failure as well in the monitoring of response to treatment. BNP/NT-proBNP can also be used for the screening of heart failure and as a prognostic marker in children undergoing cardiac surgery; however, to date, there are studies with heterogeneous patient groups, and diverse outcome measures selected are still few. BNP/NT-proBNP can be used as adjunctive markers in the integrated screening, diagnosis, management, and follow up of children with heart failure caused by various acquired and congenital heart disease. PMID- 24473830 TI - Occurrence of comorbidities among African-American and Latina breast cancer survivors. AB - BACKGROUND: The co-occurrence of multiple chronic conditions in cancer patients is common and can have negative impact on cancer and cancer survivorship outcomes. This study aimed to document comorbidity occurrence among African American and Latina (English language preferred (ELP) and Spanish language preferred (SLP)) breast cancer survivors (BCS). METHODS: Eighty-eight African American, 95 ELP Latina, and 137 SLP Latina BCS were recruited via case ascertainment from the California Cancer Registry and hospital registries. BCS completed a self-report questionnaire assessing demographic and cancer characteristics, and presence of comorbidities. RESULTS: Overall, 75% of BCS reported at least one comorbidity with arthritis (37%), high blood pressure (37%), psychological difficulties (29%), and diabetes (19%) being most commonly endorsed. SLP Latinas were more likely to report diabetes (29%), psychological difficulties (42%), and >3 comorbidities (p < 0.05). Latina BCS were twice as likely to report osteoporosis and headaches compared to African-Americans; while one in two African-Americans reported hypertension and arthritis. Older age was correlated with arthritis, diabetes, glaucoma, high blood pressure, and osteoporosis. CONCLUSIONS: Our findings suggest that investigating the occurrence of comorbidities across ethnic groups may shed some light in understanding cancer survivorship risk for poor health outcomes and health disparities. Having a better grasp of comorbid conditions may aid in more appropriate early assessment, better follow-up care, surveillance, and management of the cancer and the comorbid condition(s). IMPLICATIONS FOR CANCER SURVIVORS: Integrated control and management of comorbidities among cancer survivors has the potential to improve quality care for the whole person, and increase survival and decrease morbidity. PMID- 24473831 TI - Injection laryngoplasty outcomes in irradiated and nonirradiated unilateral vocal fold paralysis. AB - OBJECTIVES/HYPOTHESIS: To evaluate the effect of radiation therapy on voice outcome and duration of effect of calcium hydroxylapatite (CaHA) injection laryngoplasty in unilateral vocal fold paralysis (UVFP) patients. STUDY DESIGN: Retrospective case series. METHODS: UVFP patients treated with CaHA injection laryngoplasty at the University of California San Francisco Voice and Swallowing Center were identified. Demographic information, history of irradiation to the larynx, and time to additional medialization procedures were obtained. Examinations at presentation and follow-up were analyzed for laryngostroboscopic parameters and CAPE-V scores. RESULTS: Four nonirradiated and five irradiated patients underwent a total of six and nine injection laryngoplasties, respectively. Time to additional procedures was longer in irradiated patients (P = 0.02). Prior to injection, nonirradiated patients had more severe glottic insufficiency (P = 0.007, 0.002) than did irradiated patients. Postinjection, irradiated patients demonstrated improvement in overall voice quality, breathiness, and loudness, while nonirradiated patients demonstrated improved overall quality, breathiness, pitch, and loudness. Voice quality was not statistically different between patient groups. CONCLUSION: CaHA injection laryngoplasty improved voice quality in both irradiated and nonirradiated patients. Nonirradiated patients experience greater vocal improvement compared to irradiated patients. Vocal cord stiffness due to radiation-induced changes may be responsible for the lack of improvement in pitch. Time to additional procedures was longer in irradiated patients and may be secondary to effects of prior radiation on graft resorption. Vocal fold medialization with CaHA injection remains a safe and efficacious treatment for UVFP in both irradiated and nonirradiated patients. PMID- 24473832 TI - Concepts and controversies: the 2013 American College of Cardiology/American Heart Association risk assessment and cholesterol treatment guidelines. PMID- 24473834 TI - Texas hospital removes pregnant woman from ventilator after court order. PMID- 24473833 TI - Survivin promoter-regulated oncolytic adenovirus with Hsp70 gene exerts effective antitumor efficacy in gastric cancer immunotherapy. AB - Gene therapy is a promising adjuvant therapeutic strategy for cancer treatment. To overcome the limitations of current gene therapy, such as poor transfection efficiency of vectors, low levels of transgene expression and lack of tumor targeting, the Survivin promoter was used to regulate the selective replication of oncolytic adenovirus in tumor cells, and the heat shock protein 70 (Hsp70) gene was loaded as the anticancer transgene to generate an AdSurp-Hsp70 viral therapy system. The efficacy of this targeted immunotherapy was examined in gastric cancer. The experiments showed that the oncolytic adenovirus can selectively replicate in and lyse the Survivin-positive gastric cancer cells, without significant toxicity to normal cells. AdSurp-Hsp70 reduced viability of cancer cells and inhibited tumor growth of gastric cancer xenografts in immuno deficient and immuno-reconstruction mouse models. AdSurp-Hsp70 produced dual antitumor effects due to viral replication and high Hsp70 expression. This therapeutic system used the Survivin promoter-regulated oncolytic adenovirus vector to mediate targeted expression of the Hsp70 gene and ensure safety and efficacy for subsequent gene therapy programs against a variety of cancers. PMID- 24473835 TI - [Germany must become an internationally visible center of innovation]. PMID- 24473836 TI - [Cardiac pacing and cardiac resynchronization therapy]. PMID- 24473837 TI - [Acute interventional therapy of deep venous thrombosis]. PMID- 24473838 TI - [Personalized medicine and type-2 diabetes: pharmakogenetic aspects of drug therapy]. PMID- 24473839 TI - [Protein requirements of elderly people]. PMID- 24473840 TI - [Chronic myeloproliferative neoplasms]. PMID- 24473841 TI - [Dengue virus & co: are mosquito-borne viral diseases on the rise?]. PMID- 24473842 TI - [Ventilator-associated pneumonia]. PMID- 24473843 TI - [Treatment of atrial fibrillation: update 2014]. PMID- 24473844 TI - [Chronic kidney disease--update 2014]. PMID- 24473845 TI - [Bronchodilator therapy of COPD]. PMID- 24473846 TI - [Therapy of rheumatoid arthritis: what influences the risk of infections and malignant neoplasms?]. PMID- 24473847 TI - [Eosinophilic esophagitis]. PMID- 24473848 TI - [40-year-old athlete with exercise-induced angina pectoris]. PMID- 24473849 TI - [Cerebral vasculitis with delirium in neurosyphyllis]. AB - ANAMNESIS AND CLINICAL FINDINGS: In a 40-year-old man with delirium, right-sided facial palsy and anisocoria (right > left) were noticed. He had been suffering from headaches for four weeks prior to admission. The patient's HI-virus status was positive and he used illicit drugs regularly. Therefore, the symptoms were initially thought to be drug-induced. EXAMINATION AND DIAGNOSIS: Laboratory tests showed a pleocytosis of the cerebrospinal fluid (CSF) with 929 cells/ul. The MRI of the brain revealed several ischemic strokes in the territories of the middle cerebral artery and posterior cerebral artery in the left hemisphere. A highly positive IgG CSF/serum index confirmed the diagnosis of neurosyphilis. TREATMENT AND COURSE: An antibiotic regime with penicillin was administered, during which the clinical symptoms remitted and the liquor pleocytosis nearly normalized. The intracranial stenoses persisted for three months even after therapy with nimodipine, atorvastatin, and antibiotics. Therefore they are presumed to be a result of the lues-associated vasculitis. CONSEQUENCE: In patients with delirium the initially suspected underlying condition needs to be challenged. Early cerebral MRI, lumbar puncture and ultrasound of the cerebral arteries are mandatory to exclude menigoencephalitis. PMID- 24473850 TI - [Statins and ASS for primary prevention of cardiovascular and cerebrovascular disease]. AB - Whereas statins and acetylsalicylic acid (ASA) are considered gold standard for secondary prevention following myocardial infarction or atherotrombotic stroke, there are inconsistent data on the use of these drugs for primary prevention in patients with increased cardiovascular risk. Some meta-analyses indicated that the use of statins and ASA for primary prevention of cardiovascular disease can reduce the risk of cardiovascular events such as ischemic stroke or myocardial infarction. However, the effects of primary prevention with statins and ASA on mortality varied in the data included in these meta-analyses. Therefore the guidelines of the German College of General Practitioners and Family Physicians recommend primary prevention with statins and ASA only in those patients who have a 10-year risk of cardiovascular events which exceeds 20 %. Divergently, primary prevention with ASA is not recommended by the European Society of Cardiology. Observational studies suggested that treatment success of primary prevention with statins and ASA depends on various factors such as adherence to medication and prescription behavior of physicians. This review summarizes the current literature on primary prevention of cardiovascular events with ASA and statins. PMID- 24473851 TI - Synthesis and characterization of oxygen-functionalised-NHC silver(I) complexes and NHC transmetallation to nickel(II). AB - The new alcohol- and ether-functionalised-NHC silver(I) complexes bis(1-(2,6 diisopropylphenyl)-3-(2-hydroxyethyl)-1H-imidazol-2(3H)-ylidene)silver(I) chloride, [Ag{ImDiPP(C2OH)}2]Cl (4), bis(1-(2-hydroxyethyl)-3-mesityl-1H-imidazol 2(3H)-ylidene)silver(I) chloride, [Ag{ImMes(C2OH)}2]Cl (5), bis(1-(2 hydroxyethyl)-3-methyl-1H-imidazol-2(3H)-ylidene)silver(I) chloride, [Ag{ImMe(C2OH)}2]Cl (6), bis(1-(2,6-diisopropylphenyl)-3-(2-hydroxyethyl)-1H imidazol-2(3H)-ylidene)silver(I) tetrafluoroborate, [Ag{ImDiPP(C2OH)}2]BF4 (9), and bis(1-(2,6-diisopropylphenyl)-3-(2-methoxyethyl)-1H-imidazol-2(3H) ylidene)silver(I) chloride, [Ag{ImDiPP(C2OMe)}2]Cl (13), were synthesized and fully characterized by NMR spectroscopy and single crystal X-ray diffraction. For some complexes, an uncommon heteronuclear coupling (4)J((107/109)Ag-H) was unveiled. Their ability to transfer the NHC ligand to Ni(II) was assessed in the presence of different nickel(II) sources; the bis-NHC Ni(II) complex bis(1-(2,6 diisopropylphenyl)-3-(2-methoxyethyl)-1H-imidazol-2(3H)-ylidene)nickel(II) chloride, [NiCl2{ImDiPP(C2OMe)}2] (15), was obtained from 13 and shown by X-ray diffraction study to have a trans-arrangement of the two NHC ligands. However, in contrast to other Ag(I) NHC complexes the transmetallation reaction failed with the hydroxyl-functionalised silver complexes, possibly due to the acidity of the alcohol OH function, leading overall to reprotonation of the C(NHC) and isolation of the corresponding imidazolium salts. PMID- 24473853 TI - The influence of chlorophyll on in-vivo difference spectra of phytochrome. AB - A comparison was made between in-vivo phytochrome difference spectra of light- and dark-grown plant material. Spectral differences were found to be caused, at least to a large extent, by screening by chlorophyll and not by differences in phytochrome. Presence of chlorophyll affects the phytochrome in leaves differently from that in stems. In cotyledons the absorption maximum in the R part of the spectrum shifts towards shorter wavelengths, in FR to longer ones. Concomitantly, the R/FR ratio diminishes; this was confirmed in a model experiment. In stem tissue the peak positions remain the same but the isosbestic point shifts towards longer wavelengths and the R/FR ratio increases.In Viola, however, the phytochrome appears to be different from the normal type. In the etiolated hypocotyl, where the difference spectrum of phytochrome is presumably not distorted by chlorophyll, the R and FR maximum was found to be at a shorter wavelength than in hypocotyls from Cornus and turnip or from stem tissue of dark grown pea. PMID- 24473854 TI - Properties of phytochrome in gymnosperms. AB - Addition of water to dry seeds of Pinus spp. increased the detectable phytochrome immediately and the level reached after 2 h in darkness was retained for at least 20 h at 20 degrees C. The in-vivo difference spectra of phytochrome in Pinus seeds showed absorption maxima at approximately 656 nm and at 710 nm to 715 nm. An isosbestic point was observed at about 680 nm. Shifts towards longer wavebands were obtained especially with tissue containing substantial amounts of chlorophyll and are, therefore, not due to diverse types of phytochrome. Embryo tissue of Ginkgo biloba showed also a maximum in R at 655 nm but the peak in FR occurred at a longer wavelength, 725 nm. This was confirmed by determining action spectra for the phototransformations Pr?Pfr.The dark reactions of phytochrome in Pinus differed from those in Ginkgo. Following a short exposure to R light, the total quantity of photoreversible pigment in Pinus seeds remained constant for several hours in darkness at room temperature. Dark reversion of Pfr occurred extremely rapidly and tPfr 50 was only 0.3 h. In Ginkgo embryos total phytochrome in darkness following a brief exposure to R light was not completely stable. Reversion of Pfr was much slower and tPfr 50 was slightly less than 2 h.It is concluded that, at least as regards the spectral qualities, the phytochrome in Gymnospermae differs from that of Angiospermae and is apparently also not identical in Coniferae and Ginkgoinae. PMID- 24473855 TI - [Electron microscopic localization of acid phosphatase in the petiolary glands of Impatiens holstii]. AB - In the glandular cells of the petiolary glands of Impatiens holstii, acid phosphatase is present in endoplasmic reticulum, Golgi apparatus, cytosomes, vacuoles, some nuclei and mitochondria. Only a few plasmalemma and cell walls are lightly marked except in the region of sieve tubes and "transfer cells" where there are heavy deposits of lead phosphate. We note two fundamental types of vacuoles: autophagic vacuoles which are heavily marked and others which have lead deposits only in their tonoplast.The possible role of the enzyme in secretory processes is discussed. PMID- 24473856 TI - An electrophysiological study of regeneration in Acetabularia mediterranea. AB - Polar regeneration of anucleate posterior stalk segments (PSS) of Acetabularia mediterranea has been studied electrophysiologically. 1. During regeneration the PSS develops a longitudinal, steady potential gradient, U, which is shown to reflect a spatial difference in the transmembrane potential, DeltaV m,of 5 to 10 mV, i.e. about 5% of V m.While regeneration becomes visible at about t r=45 h after its light-triggered onset, its sign can be predicted from U not later than at t=29 h, because regeneration occurs at that cell pole where V mis highest, i.e. where the cytoplasm is more negative (Fig. 3, Table 1). 2. Clamping U to comparable values by external circuitry causes the regeneration again to occur where V mis highest, although in this case the flow of the current, I, which controls U is opposite to the direction of the self-generated current, or even changes its sign (Fig. 11, Table 2). 3. Clamping U to zero, i.e. eliminating any transcellular potential gradient, inhibits polar regeneration at least up to t=60 h (Table 3). 4. Spontaneous spikes of U (Fig. 4) and of I (Fig. 12), occur as early as at t=8 h (Fig. 5). These spikes arise at the presumptive regenerating pole with refractory intervals of 10-25 min. They obviously reflect the propagating action potential (Figs. 7-9) although, under the conditions of our present experiments, they spread along the PSS only electrotonically (Fig. 6). 5. Both signals, U and the spikes, are presumably due to changes in the electrogenic Cl-dependent component of V m,rather than its K(+)-controlled, diffusive component. 6. The data allow to substantiate our working-hypothesis (p. 242) that the mechanism of spatial differentiation involves voltage-dependent plasmalemma properties including excitation. PMID- 24473857 TI - Initial phases of gravity-induced lateral auxin transport and geotropic curvature in corn coleoptiles. AB - Wild-type corn coleoptiles showed an initial downward bending upon transfer from the vertical to the horizontal position. Strong upward curvature started only 15 30 min after the begin of horizontal exposure.Little, if any at all, initial downward geotropic bending was found with amylomaize coleoptiles at 1 X g. With stronger stimuli (10 or 20 X g) the amylomaize mutant reacted initially strongly in the "wrong" direction, i.e. opposite to the later response.When wild-type coleoptiles had been symmetrically prestimulated for 60 min with alternating 2 min horizontal exposures from opposite sides, no initial downward bending occurred if the plane of horizontal exposure was maintained from pretreatment to the continuous horizontal stimulation of the test. If, however, the coleoptiles were rotated 90 degrees around their long axis between pretreatment and test, the initial downward bending reaction developed as in the non-prestimulated controls. Thus changes in reactivity remained localized to the site of stimulation.Following the same pretreatments used for the curvature measurements, lateral (3)H-IAA transport was measured in coleoptile segments for 10 or 12.5 min. The auxin distribution found was strikingly parallel to the bending for all pretreatments.The dependence of reaction pattern on the duration of prestimulation in the same plane was tested. The function indicates a "half life" of 10-20 min for the change in sensitivity. The findings are discussed in view of a model of overstimulation and adaptation. PMID- 24473858 TI - Stomatal responses to changes in humidity in plants growing in the desert. AB - The stomata of plants growing in the Negev Desert, namely the stomata of the mesomorphic leaves of Prunus armeniaca, the xeromorphic stems of Hammada scoparia, and the succulent leaves of Zygophyllum dumosum, respond to changes in air humidity. Under dry air conditions diffusion resistance increases. Under moist air conditions diffusion resistance decreases. When the stomata close at low air humidity the water content of the apricot leaves increases. The stomata open at high air humidity in spite of a decrease in leaf water content. This excludes a reaction via the water potential in the leaf tissue and proves that the stomatal aperture has a direct response to the evaporative conditions in the atmosphere. In all species the response to air humidity is maintained over a period of many hours also when the soil is considerably dry. The response is higher in plants with poor water supply then in well watered plants. Thus for field conditions and for morphologically different types of photosynthesizing organs the results confirm former experiments carried out with isolated epidermal strips. PMID- 24473859 TI - Relationship between growth of parsley and soybean cells in suspension cultures and changes in the conductivity of the culture medium. AB - Changes in conductivity and pH during the growth cycle of cell suspensions derived from parsley (Petroselinum hortense) and soybean (Glycine max) have been investigated. Measurement of the conductivity of the medium represents a simple, rapid, and reliable method for the precise determination of the growth phase of a culture. The accuracy of this method has been tested by using phenylalanine ammonia-lyase, an enzyme that has a characteristically short, distinct period of activity during the growth cycle of soybean cell suspensions. It is suggested that an automatic regulation of the conductivity of the medium might be employed for growing plant cells in a continuous culture at a defined stage of growth. PMID- 24473860 TI - Inhibition of cell division in a moss protonema by some cytokinin isomers. AB - The cytokinin isomers, 1- and 9-isopentenyladenine, are very active inhibitors of cell division in the protonema of the moss Ceratodon purpureus. They also abolish the N(6)-isopentenyladenine-induced stimulation of cell divisions in this material whereas they are inactive on the induction of gametophore buds in moss protonemata by cytokinins. PMID- 24473861 TI - Failure of colchicine or cytochalasin to inhibit protein secretion by plant cells. AB - The gibberellic-acid-mediated secretion of alpha-amylase by aleurone cells of barley and the transport of hydroxyproline-rich cell-wall glycoproteins from the cytoplasm to the wall in phloem-parenchyma cells of carrot roots are not inhibited by either colchicine (1 mM) or cytochalasin (10 MUg/ml). The data suggest the absence of a unitary mechanism of protein secretion. PMID- 24473864 TI - Coexistence of eccrine squamous syringometaplasia and graft-versus-host disease in a patient with secondary myelodysplastic syndrome. PMID- 24473866 TI - Rotator cuff tears in children and adolescents: experience at a large pediatric hospital. AB - BACKGROUND: Prior literature, limited to small case series and case reports, suggests that rotator cuff tears are rare in adolescents. However, we have identified rotator cuff tears in numerous children and adolescents who have undergone shoulder MRI evaluation. OBJECTIVE: The purpose of this study is to describe the prevalence and characteristics of rotator cuff tears in children and adolescents referred for MRI evaluation of the shoulder at a large pediatric hospital and to correlate the presence of rotator cuff tears with concurrent labral pathology, skeletal maturity and patient activity and outcomes. MATERIALS AND METHODS: We reviewed reports from 455 consecutive non-contrast MRI and magnetic resonance arthrogram examinations of the shoulder performed during a 2 year period, and following exclusions we yielded 205 examinations in 201 patients (ages 8-18 years; 75 girls, 126 boys). Rotator cuff tears were classified by tendon involved, tear thickness (partial or full), surface and location of tear (when partial) and presence of delamination. We recorded concurrent labral pathology when present. Physeal patency of the proximal humerus was considered open, closing or closed. Statistical analysis was performed to evaluate for a relationship between rotator cuff tears and degree of physeal patency. We obtained patient activity at the time of injury, surgical reports and outcomes from clinical records when available. RESULTS: Twenty-five (12.2%) rotator cuff tears were identified in 17 boys and 7 girls (ages 10-18 years; one patient had bilateral tears). The supraspinatus tendon was most frequently involved (56%). There were 2 full-thickness and 23 partial-thickness tears with articular-side partial-thickness tears most frequent (78%). Insertional partial-thickness tears were more common (78%) than critical zone tears (22%) and 10 (43%) partial thickness tears were delamination tears. Nine (36%) patients with rotator cuff tears had concurrent labral pathology. There was no statistically significant relationship between rotator cuff tears and physeal patency (P > 0.05). Most patients were athletes (76%). Five tears were confirmed at surgery. Poor clinical follow-up limited evaluation of patient outcomes. CONCLUSION: Rotator cuff tears can be identified during MRI examination of symptomatic child and adolescent shoulders and often consist of tear patterns associated with repetitive microtrauma in overhead athletic activities or with single traumatic events. Rotator cuff tears are seen throughout the range of skeletal maturity, often coexist with labral tears and typically are found in athletes. PMID- 24473867 TI - Immature argasid ticks: diagnosis and keys for Neotropical region. AB - Many argasid tick species are known only through their larval descriptions, in which the chaetotaxy, together with other external morphological characteristics, has been used to separate genera and species. However, the illustrations of these features are based on optical microscopy alone and many of these features are not clearly defined. Because of the difficulties in determining the larval and nymph stages of some genera, we have prepared illustrated keys for the immature stages of argasids, including an up-to-date list of the known species of the Neotropical region. We have also included an illustrated key for larvae of the Ornithodoros species from Brazil, based on scanning electron microscopy. PMID- 24473868 TI - Hematological parameters of Hoplias malabaricus (Characiformes: Erythrinidae) parasitized by Monogenea in lagoons in Pirassununga, Brazil. AB - Hematology is an important pathological and diagnostic tool. This paper describes the hematological parameters of 76 specimens of Hoplias malabaricus infested with monogenean parasites, which were collected from two lagoons. The hematological parameters included: erythrocyte count (Er), microhematocrit (Hct), hemoglobin (Hb), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH) and mean corpuscular hemoglobin concentration (MCHC). The blood parameters showed no significant changes associated with the infestation. Water temperature was found to be negatively correlated with MCV and Hct, with values of rs= -0.52, p<0.0001 and rs= -0.48, p<0.0001, respectively. The mean Relative Condition Factor was Kn=1.01, indicating good health conditions of the fish in these lagoons. No correlation was found between the monogenean infestation and the blood parameters, or between the environmental factors and the monogeneans. PMID- 24473869 TI - In vitro effects of Coriandrum sativum, Tagetes minuta, Alpinia zerumbet and Lantana camara essential oils on Haemonchus contortus. AB - Phytotherapy can be an alternative for the control of gastrointestinal parasites of small ruminants. This study evaluated the efficacy of Alpinia zerumbet, Coriandrum sativum, Tagetes minuta and Lantana camara essential oils by two in vitro assays on Haemonchus contortus, an egg hatch test (EHT) and larval development test (LDT). No effect was observed for L. camara in the EHT. A. zerumbet, C. sativum and T. minuta essential oils exhibited a dose-dependent effect in the EHT, inhibiting 81.2, 99 and 98.1% of H. contortus larvae hatching, respectively, at a concentration of 2.5 mg mL-1. The effective concentration to inhibit 50% (EC50) of egg hatching was 0.94, 0.63 and 0.53 mg mL-1 for A. zerumbet, C. sativum and T. minuta essential oils, respectively. In LDT, L. camara, A. zerumbet, C. sativum and T. minuta at concentration of 10 mg mL-1 inhibited 54.9, 94.2, 97.8 and 99.5% of H. contortus larval development, presenting EC50 values of 6.32, 3.88, 2.89 and 1.67 mg mL-1, respectively. Based on the promising results presented in this in vitro model, it may be possible use of these essential oils to control gastrointestinal nematodes. However, their anthelmintic activity should be confirmed in vivo. PMID- 24473870 TI - Hematological values associated to the serological and molecular diagnostic in cats suspected of Ehrlichia canis infection. AB - The literature contains several studies on feline ehrlichiosis. However, information about the characteristics of Ehrlichia infection in cats is still scanty. This study evaluated the association between Ehrlichia spp. infection and the hematologic data of 93 cats treated at the Federal University of Mato Grosso Veterinary Hospital in Cuiaba, state of Mato Grosso, Brazil. The presence of or exposure to Ehrlichia spp. infection was evaluated by Polymerase Chain Reaction (PCR) targeting the dsb and 16S rRNA gene of Ehrlichia, and by detection of anti Ehrlichia canis IgG antibodies in Indirect Fluorescence Assay (IFA), respectively. Eight (8.6%) cats tested positive by PCR and the partial DNA sequence obtained from PCR products was a 100% match to E. canis. Forty-two (45.1%) cats showed antibody reactivity against Ehrlichia spp. Hematological alterations such as low erythrocyte count, thrombocytopenia, lymphopenia and monocytosis were observed in PCR positive cats. Among them, low erythrocyte counts were associated with IgG antibody titers of 40 to 640 and five cats also tested positive by PCR. Furthermore, PCR-positive cats showed a tendency to be lymphopenic. No correlation was found between age and sex, and no ticks were observed in any of the examined cats. PMID- 24473871 TI - Endohelminths in Cichla piquiti (Perciformes, Cichlidae) from the Parana River, Sao Paulo State, Brazil. AB - Fifty specimens of Cichla piquiti were collected from the Parana River downstream of the Ilha Solteira Hydroelectric Power Station in Brazil and surveyed for endohelminth parasites. All fish were parasitised by at least one helminth species (overall prevalence [P] = 100%). Eight parasite taxa were present: the nematode Procamallanus (Procamallanus) peraccuratus in the intestines; third stage larvae of the anisakids Contracaecum sp. and Hysterothylacium sp. in the visceral cavity, mesentery and serosa of the stomach and intestines and on the liver and spleen; the trematodes Austrodiplostomum compactum in the eye (metacercariae) and Genarchella genarchella in the stomach; and the cestodes Proteocephalus macrophallus, Proteocephalus microscopicus, and Sciadocephalus megalodiscus in the intestines. Hysterothylacium sp. larvae (P = 86%) and P. microscopicus (P = 74%) were the most prevalent parasites. Anisakids were more prevalent and abundant in the dry season. A negative correlation between the abundances of Hysterothylacium sp. and P. microscopicus was observed, suggesting a competitive/antagonistic relationship between these parasites. Cichla piquiti represents a new host for four parasite species. These new records significantly increase the list of parasites of C. piquiti, contributing to the knowledge of the host-parasite relationship and the geographical distribution of these helminths. PMID- 24473872 TI - Effect of alternate and simultaneous grazing on endoparasite infection in sheep and cattle. AB - This experiment was carried out on 8 ha of Panicum maximum cv. Tanzania pastures, with rotational grazing consisting of 7 days of occupation and 21 days of rest. Four treatments were evaluated: cattle grazing alone (BOV), sheep grazing alone (OVI), cattle and sheep grazing simultaneously (SIM) and cattle grazing followed by sheep (alternate - ALT). Twenty heifers and 30 male Santa Ines lambs were used. Fecal egg count (FEC) and fecal cultures were carried out. Blood was also collected to examine red and white cell series, total plasma protein (TPP), albumin and hemoglobin. FEC and estimated nematode pathogenicity index in sheep were lower in the SIM treatment. The Haemonchus spp. proportion was higher in isolated grazing systems. For sheep, mixed grazing was shown to reduce endoparasite infection, and SIM was better than ALT. For cattle, no difference between grazing systems was seen. Therefore, simultaneous grazing (sheep and cattle) may be a tool for reducing the need for anthelmintic treatments in sheep. PMID- 24473873 TI - Comparison of three larval bioassays to evaluate susceptibility of Rhipicephalus (Boophilus) microplus to amitraz. AB - Field samples of Rhipicephalus (Boophilus) microplus from the state of Rio Grande do Sul, Brazil, were assessed using the following methods: larval packet test (LPT), larval immersion test (LIT) and syringe immersion test (SIT). The following parameters were determined for each population and for the Mozo susceptible reference strain: lethal concentration for 50% (LC50) with its 95% confidence interval (95% CI), regression line slope and resistance ratio (RR). Using the LPT, only one population was susceptible to amitraz, presenting a RR of 1.9. Using the same technique, the other populations presented RRs of between 92.9 and 3445.8 and were considered resistant. The LC50 of the Mozo strain calculated using the LPT, LIT and SIT was 2.9, 27.3, and 52.7 ug/mL, respectively. In general, a good fit to the probit statistical model was only achieved using the LPT. The results obtained in this study impair recommendations for using the LIT and SIT to diagnose amitraz resistance in R. (B.) microplus populations. Additional studies are required to improve the sensitivity of these tests in relation to the LPT. PMID- 24473874 TI - Weight gain and control of endo- and ectoparasites of beef heifers treated with allopathic, herbal and homeopathic drugs. AB - The aim of this study was to evaluate the efficacy of herbal, homeopathic and allopathic treatments for parasites in beef heifers during two experimental cycles of 318 and 313 days. TREATMENTS: NC - negative control (untreated); HH - treated with homeopathic preparation Homeo bovis Parasitario(r); PC - (positive control) - treated with 10% moxidectina(r) and an acaricide formulation of cypermethrin, chlorpyrifos and piperonyl butoxide(r); HF - treated with homeopathic preparation Fator C&MC(r); and FN - treated with neem cake (torta de neem(r)) and with neem oil (oleo de neem(r)). Parasite egg count (EPG), horn fly (Haematobia irritans) and tick (Rhipicephalus (Boophilus) microplus) assessment and animal weighting were performed at 28-day intervals. Blood samples were collected at the first cycle to assess the immune response. Horn fly infestation was not affected by any treatment (P>0.05). The mean number of ticks, which was low in both cycles, was lower (P<0.05) in the first cycle in animals that received PC treatment. In both experimental cycles, the mean EPG of the PC treated animals was lower (P<0.05) than the animals receiving other treatments. TREATMENTS had no effect on the immune response (P>0.05). The animals treated with allopathic drugs were 22 to 30 kg heavier (P<0.05) than untreated animals or animals treated with alternative drugs. PMID- 24473875 TI - New host records and a checklist of fishes infected with Austrodiplostomum compactum (Digenea: Diplostomidae) in Brazil. AB - This study reports the infection of fishes by Austrodiplostomum compactum metacercariae in the Chavantes reservoir, medium Paranapanema River, municipality of Ipaussu, Sao Paulo State, Brazil. Twenty-three fish species were analysed, and 13 were infected with A. compactum metacercariae (56.5%) in their eyes. The following six fish species are new hosts for this metacercaria: Crenicichla haroldoi (1/1), Eigenmannia trilineata (11/6), Hoplosternum littorale (11/1), Iheringichthys labrosus (17/2), Leporinus amblyrhynchus (11/1), and Piaractus mesopotamicus (3/1). These new species increase the number of Brazilian fish species infected with this parasite to 36. Based on these findings, we hypothesise that the metacercariae larval stage of the parasite has a low specificity for the second intermediate host (fish). The majority of fish species infected in Brazil belong to the Loricariidae and Cichlidae families. For the fish species with higher mean abundances in Brazil, six are non-native species, and currently, Plagioscion squamosissimus has the highest mean abundance. The majority of fish species infected with A. compactum in Brazil are concentrated in the Parana basin, although this may be related to the distribution of researchers. PMID- 24473876 TI - Biochemical and histological changes in liver of Nectomys squamipes naturally infected by Schistosoma mansoni. AB - The South American water rat Nectomys squamipes is a wild mammal reservoir of Schistosoma mansoni in Brazil. In the present study, wild rodents were collected in the field and categorized into two groups: infected and uninfected by S. mansoni. Blood was collected to analyze changes in the serum glucose level (mg/dL) and liver fragments were used to determine the hepatic glycogen content (mg of glucose/g tissue). The histological examination showed inflammatory granulomatous lesions in different phases of development in the liver of rodents naturally infected with S. mansoni, in some cases with total or partial occlusion of the vascular lumen. Early lesions were characterized by the presence of inflammatory infiltrate around morphologically intact recently deposited eggs. Despite the significance of these histological lesions, the biochemical changes differed in extent. N. squamipes naturally infected by S. mansoni showed no variation in hepatic glycogen reserves. These findings were accompanied by a significant increase in plasma glucose contents, probably as a consequence of amino acids deamination, which are degraded, resulting in the formation of intermediates used as precursors for the glucose formation, without compromising the reserves of liver glycogen. In the wild, naturally infected N. squamipes can maintain S. mansoni infections without undergoing alterations in its carbohydrate metabolism, which minimizes the deleterious effects of S. mansoni. PMID- 24473877 TI - Molecular and serological detection of tick-borne pathogens in dogs from an area endemic for Leishmania infantum in Mato Grosso do Sul, Brazil. AB - Tick-borne pathogens affect a wide range of vertebrate hosts. To identify tick borne pathogens among dogs from Campo Grande, MS, Brazil testing seropositive for Leishmania infantum (syn. L. chagasi), a serological and molecular study was conducted to detect Ehrlichia canis, Anaplasma platys and Babesia vogeli in 60 serum and spleen samples. A confirmatory diagnosis of L. infantum based on serological and molecular assays was also performed, as was sequence alignment and phylogenetic analysis to assess the identity of the parasite species infecting these animals. IgG antibodies to Ehrlichia spp., B. vogeli and L. infantum were found, respectively, in 39 (65%), 49 (81.6%) and 60 (100%) of the sampled dogs. Twenty-seven (45%), fifty-four (90%), fifty-three (88.3%), two (3.3%) and one (1.6%) dog were positive, respectively, for E. canis, Leishmania spp., Leishmania donovani complex, Babesia sp. and Anaplasma sp. in PCR assays. After sequencing, the amplicons showed 99% of identity with E. canis, B. vogeli, A. platys and Leishmania chagasi isolates. The findings of this study indicate that L. infantum-seropositive dogs from Campo Grande are exposed to multiple tick borne pathogens, which should therefore be included in the differential diagnosis of dogs with clinical suspicion of leishmaniasis. PMID- 24473878 TI - Efficacy of extracts from plants of the Brazilian Pantanal against Rhipicephalus (Boophilus) microplus. AB - This research evaluated the in vitro acaricidal activity of extracts from 21 plant species from the Pantanal of Mato Grosso do Sul. During stage I, a larval immersion test was performed using three extract concentrations (5%, 20%, and 40%). During stage II, we used only plants that showed over 95% efficiency at the 40% concentration in stage I in an amount sufficient for the adult immersion test. Aeschynomene denticulata, Angelonia hirta, Aspilia latissima, Caperonia castaneifolia, Centratherum punctatum, Crotalaria micans, Diodia kuntzei, Echinodorus paniculatus, Hyptis mutabilis, Lantana canescens, Melanthera latifolia, Ocotea diospyrifolia, Richardia grandiflora, Sebastiana hispida, Tocoyena formosa, Zanthoxylum rigidum, and Sesbania virgata (fruit extract) showed acaricidal activity against the larval stage of Rhipicephalus (Boophilus) microplus higher than 95% at a 40% (w/v) concentration, while Hippocratea volubilis and Randia armata showed moderate efficacy and Croton glandulosus and Senna obtusifolia had no effect. The M. latifolia, A. hirta, R. grandiflora, and A. latissima raw extracts were evaluated for their activity against adults, and only A. hirta showed an efficacy close to 90%. Eighteen extracts had an efficacy of up to 95% against larvae at a 40% concentration, seven extracts were effective at 20%, and only one (Sebastiana hispida) was effective at a 5% concentration. PMID- 24473879 TI - Helminths of Steindachnerina insculpta in two distinct stretches of the Taquari River, state of Sao Paulo, Brazil. AB - The purpose of this study was to evaluate the helminth fauna of Steindachnerina insculpta in the Taquari River, a tributary of the Jurumirim reservoir in the state of Sao Paulo, and to investigate whether some helminth species may act as a bioindicator of environmental impact. The host fish sample was composed of 60 specimens, with 30 individuals sampled in a lotic stretch and 30 in a lentic stretch. The following were found: the monogeneans Anacanthoroides mizelli, Diaphorocleidus kabatai, Urocleidoides sp. and Euryhaliotrema chaoi; the digenean Sphincterodiplostomum musculosum and unidentified metacercariae; the nematode Travnema travnema and unidentified larvae; and the acanthocephalan Gorytocephalus plecostomorum. The total prevalence of monogeneans (z = 3.14; p = 0.002) and A. mizelli (z = 3.879; p <= 0.001), as well as the mean abundance of total monogeneans (U = 642.0; p <= 0.001) and A. mizelli (U = 623.5; p <= 0.001), were higher in the lentic stretch. Steindachnerina insculpta and its monogeneans comprise a potential group that could be used to investigate environmental impact, as demonstrated in this study. PMID- 24473880 TI - Frequency of benzimidazole resistance in Haemonchus contortus populations isolated from buffalo, goat and sheep herds. AB - Anthelmintic resistance is an increasing problem that threatens livestock production worldwide. Understanding of the genetic basis of benzimidazole resistance recently allowed the development of promising molecular diagnostic tools. In this study, isolates of Haemonchus contortus obtained from goats, sheep and buffaloes raised in Brazil were screened for presence of the polymorphism Phe200Tyr in the beta-tubulin 1 gene, which confers resistance to benzimidazole. The allelic frequency of the mutation conferring resistance ranged from 7% to 43%, and indicated that resistance to benzimidazole could be found in nematodes isolated from all the ruminant species surveyed. Although significant variation in the frequency of the F200Y mutation was observed between different herds or host species, no significant variation could be found in populations isolated from animals within the same herd. These findings suggest that screening of samples from a few animals has the potential to provide information about the benzimidazole resistance status of the entire herd, which would enable a considerable reduction in the costs of diagnosis for the producer. Molecular diagnosis has practical advantages, since it can guide the choice of anthelmintic drug that will be used, before its application in the herd, thus reducing the economic losses driven by anthelmintic resistance. PMID- 24473881 TI - Efficiency of partial treatment of cattle infested with horn fly using 40% diazinon. AB - The aim of this investigation was to evaluate the efficiency of partial treatment of animals infested with horn flies. Forty-five Guzerat cows between 4 and 7 years of age were divided into three groups (15 cows per group). The treatments were as follows: in groups G33 and G100, 33.3 and 100% of the cows were treated with one insecticide-impregnated ear tag/animal (40% diazinon), respectively, while in the group GC, the cows were not treated (control). The flies on the cervico-dorsal-lumbar region of the cows, in all three groups, were counted every 14 days. The experiment lasted from September 2006 to September 2009. Over this period, six four-month ear tag treatments, with intervals of one to two months, were conducted on both treated groups. The animals of group G33 had a higher infection than those of group G100, and the number of flies ranged from 12 to 27 (group G33) and from 3 to 11 (group G100). However, groups G33 and G100 had lower infection levels than group GC, which presented from 45 to 87 flies. Partial treatment of cattle infested with horn flies using 40% diazinon insecticide is an efficient alternative for controlling this ectoparasite. PMID- 24473882 TI - Canine heartworm disease in Porto Velho: first record, distribution map and occurrence of positive mosquitoes. AB - The aim of this study was to make the first report on canine heartworm disease in the state of Rondonia and confirm its transmission in this state. Blood samples were randomly collected from 727 dogs in the city of Porto Velho. The samples were analyzed to search for microfilariae and circulating antigens, using three different techniques: optical microscopy on thick blood smears stained with Giemsa; immunochromatography; and PCR. Mosquitoes were collected inside and outside the homes of all the cases of positive dogs and were tested using PCR to search for DNA of Dirofilaria immitis. Ninety-three blood samples out of 727 (12.8%) were positive according to the immunoassay technique and none according to the thick smear method. Among the 93 positive dogs, 89 (95.7%) were born in Porto Velho. No difference in the frequency of infection was observed between dogs raised indoors and in the yard. PCR on the mosquitoes resulted in only one positive pool. This result shows that the transmission of canine heartworm disease is occurring in the city of Porto Velho and that there is moderate prevalence among the dogs. The techniques of immunochromatography and PCR were more effective for detecting canine heartworm than thick blood smears. The confirmation of canine heartworm disease transmission in Porto Velho places this disease in the ranking for differential diagnosis of pulmonary nodules in humans in Rondonia. PMID- 24473883 TI - Assessment of experimental infection for dogs using Gallus gallus chorioallantoic membranes inoculated with Neospora caninum. AB - The aim of this study was to evaluate parasitism kinetics and tissue lesions in the first week of infection by Neospora caninum in dogs fed Gallus gallus chorioallantoic membranes (CMs) previously infected in ovo. Five two-month-old pups were used. Each dog was given five CMs that were previously infected with N. caninum via the oral route. Four animals were euthanized in the first week of infection. All four dogs had their stools examined one week prior to and up to the day they were euthanized. The stools of the uneuthanized dog were collected for 30 days. After euthanasia, organ sections were utilized for histopathology, immunohistochemistry, indirect immunofluorescent tissue reactions, PCR and real time PCR to detect parasites. Necropsy revealed that the small and large intestines, spleen, and lungs were affected. No oocysts or N. caninum DNA were identified in the stool samples. Real-time PCR was the most sensitive technique used to detect the protozoa in tissues, which were identified in 41% of the analyzed samples. Our results indicate that an experimental model using previously infected CMs appears to be a useful model for the study of the host parasite relationship during the infection's acute phase. PMID- 24473884 TI - Calculation of the efficacy of vaccines against tick infestations on cattle. AB - Cattle ticks are responsible for great economic losses in cattle farming worldwide, and their main control method, chemicals, has been showing problems, whether resulting from the development of resistant strains of ticks or environmental contamination. Research studies directed toward developing vaccines against ticks are emerging. One way to evaluate those vaccines is to calculate the percentage of efficacy. The aim of this study was to analyze scientific publications archived in PubMed that used this method of assessment and discuss the main factors that may affect its calculation. Thus, 25 articles addressing this subject were selected. The percentage of efficacy was usually calculated in one of two ways, with one considering the reduced fertility of eggs and the other not. The latter method may underestimate the vaccine efficacy, and the most complete formula for calculating the efficacy reflects how much the vaccine actually affects the infestation. In our view, the use of the complete formula for calculating the percentage of efficacy is broader and more representative of the vaccine effect on the tick population. PMID- 24473885 TI - Monogeneans (Dactylogyridae) parasitizing gills of Salminus hilarii from a Neotropical reservoir, Brazil. AB - With the aim of creating an inventory of the metazoan gill parasites of Salminus hilarii in the Taquari River, state of Sao Paulo, Brazil, five species of monogeneans (Anacanthorus contortus, A. bicuspidatus, Annulotrematoides parisellei, Jainus iocensis and Tereancistrum arcuatus) are reported the first time for this host. A total of 28 fish were sampled quarterly between April 2011 and January 2012, with 10 hosts in a lentic ecosystem and 18 in a lotic ecosystem. Quantitative ecological descriptors (prevalence, intensity of infestation and abundance) were calculated for the purpose to comparing the two ecosystems sampled (lentic and lotic ecosystems). However, no quantitative difference between the lentic and lotic ecosystems was observed. The present study has made available a checklist for species of the genus Anacanthorus and their hosts and geographical distribution in the Neotropical region up to the present time. PMID- 24473886 TI - Outbreak of mortality among cage-reared cobia (Rachycentron canadum) associated with parasitism. AB - This study reports a disease outbreak among juvenile cobia (Rachycentron canadum) farmed in cages in the state of Rio de Janeiro, Brazil, caused by the dinoflagellate Amyloodinium ocellatum and the monogenean Neobenedenia melleni. Two thousand five hundred fish were stocked at 0.4 kg/m3 in a set of 12 m3 tanks, in autumn (mean weight 15.0 +/- 7.3 g) and in winter (mean weight 43.0 +/- 5.6 g). Freshwater baths were administered as a routine treatment, as the symptoms were detected followed by two collection samples. Firstly in May 2011 (n = 5) and secondly in September 2011 (n = 10). In the first sample, the prevalence of N. melleni on the body surface was 100% and the mean intensity was 42.0 +/- 1.7, while in the second sample the prevalence was 60% with a mean intensity 3.0 +/- 0.2 and mean abundance 1.8 +/- 0.4. Amyloodinium ocellatum was only found in the second sample, at a prevalence 100% and mean intensity 46.8 +/- 3.4. The cause of fish mortality was possibly associated with a decrease in fish resistance after the first contact with monogenean parasites, allied with respiratory difficulty caused by the presence of A. ocellatum in the gills. PMID- 24473887 TI - Leishmania infection in a population of dogs: an epidemiological investigation relating to visceral leishmaniasis control. AB - Identification of factors associated with Leishmania infection in dogs is essential for targeting visceral leishmaniasis control actions. Thus, the present study analyzed some of these factors in a population of dogs in a Brazilian municipality, along with the limitations of control strategies implemented there. The association between the exposure variables and occurrences of infection was analyzed through logistic regression models. The disease control interventions were treated qualitatively. Out of the 755 animals examined, 13.6% (103/755) were seropositive. Of these, 23.3% (24/103) were asymptomatic and 76.7% (79/103) presented at least one clinical sign possibly associated with visceral leishmaniasis. With weak associations, purebred, shorthaired, over 5 years of age, male and large dogs were more prone to infection. The latter two variables formed the final regression model and the association with dog size was statistically significant. The control strategies developed presented limitations and a great number of seronegative dogs was culled. The data presented contribute towards better understanding of the dynamics of infection in canine visceral leishmaniasis and indicate that actions aimed towards adequate implementation of Visceral Leishmaniasis control program in Brazilian endemic areas should be prioritized. PMID- 24473888 TI - Neospora spp. antibodies in horses from two geographical regions of the state of Santa Catarina, Brazil. AB - The aims of this study were to determine occurrences of Neospora spp. IgG antibodies in horses from two geographical regions of the state of Santa Catarina, southern Brazil, and identify risk factors for infection. Analyses were performed on 615 samples using the immunofluorescent antibody test (IFAT >= 1:50). Out of the 615 samples, 25 (4.1%) were positive for Neospora spp. The titers for Neospora spp. were distributed as follows: 1:50 (13), 1:100 (eight), 1:200 (three) and 1:400 (one). Out of the 311 samples taken in the mountain region, eight were positive (2.6%). Among the samples from the coastal region (304), 17 had Neospora spp. antibodies, thus indicating occurrence of 5.6%. Although no statistically significant difference was observed (P = 0.06704), the prevalence among animals of the coast was 2.2 times higher than that of the mountain region. Contact with dogs and/or cattle (P = 0.007596) were identified as risk factor for Neospora spp. infection. PMID- 24473889 TI - Use of a negative binomial distribution to describe the presence of Sphyrion laevigatum in Genypterus blacodes. AB - This paper describes the frequency and number of Sphyrion laevigatum in the skin of Genypterus blacodes, an important economic resource in Chile. The analysis of a spatial distribution model indicated that the parasites tended to cluster. Variations in the number of parasites per host could be described by a negative binomial distribution. The maximum number of parasites observed per host was two. PMID- 24473890 TI - Molecular and parasitological detection of Leishmania spp. in a dipteran of the species Tabanus importunus. AB - Leishmaniasis is an important chronic zoonosis caused by protozoa of the genus Leishmania spp. The major vectors of this protozoosis are sand flies, and Lutzomyia longipalpis is considered the main species implicated in the transmission of American Visceral Leishmaniasis in Brazil. The presence of the parasite's deoxyribonucleic acid (DNA) in ectoparasites such as ticks and fleas has prompted speculations about the existence of new vectors in the cycle of leishmaniasis. The aim of this paper is to report the molecular detection of Leishmania spp. in a horse fly of the species Tabanus importunus which parasitized an oligosymptomatic dog infected with Leishmania spp. Molecular amplification of the protozoan's DNA in the head, thoracic region and abdomen of the tabanid tested positive for Leishmania complex. This is the first report of the presence of DNA from Leishmania spp. in dipterous insects of the species T. importunus. PMID- 24473891 TI - A case of nasal myiasis due to Oestrus ovis (Diptera: Oestridae) in a llama (Lama glama). AB - Infection by the larval form of Oestrus ovis (sheep bot fly) is common in many areas of Peru. This is an obligate parasite of sheep and goats, and it is the cause of oestrosis, or nasal myiasis, which can lead to severe clinical manifestations in livestock. A case of myiasis caused by O. ovis in a llama (Lama glama) in Cuzco, Peru, is reported here. This llama presented with respiratory distress and died due to bilateral hemorrhagic pneumonia. During the necropsy, six intact dipterous larvae were recovered from the nasal fossae and cranial sinuses being identified as O. ovis. This is the first report of nasal myiasis in llamas due to O. ovis in Peru. PMID- 24473892 TI - Community ecology of metazoan parasites of the sairu Cyphocharax nagelii from the Peixe River. AB - A total of 57 sairus (Cyphocharax nagelii) from the Peixe River, state of Sao Paulo, southeastern Brazil, were examined between April 2011 and February 2012. Eleven species of metazoan parasites were collected and identified: Palombitrema triangulum, Curvianchoratus hexacleidus, Curvianchoratus singularis, Sphincterodiplostomum musculosum, Contracaecum sp., Cacatuocotyle paranaensis, Cosmoxynemoides aguirrei, Amplexibranchius bryconis, Brasergasilus sp., Ergasilus sp. and Clinostomum sp. The monogenean P. triangulum was the most prevalent species (61.40%) with the highest mean intensity (4.88). The monogeneans C. hexacleidus and C. singularis, the digenean S. musculosum and the nematode Contracaecum sp. also showed high prevalence. Only S. musculosum presented significant correlation between the total body weight of the host and its abundance. The parasitic infracommunities had a mean Brillouin diversity (HB) of 1.165 +/- 0.987 and the maximum diversity was 1.671. The sex and length of the hosts did not influence the abundance of any parasite species. The community of metazoans in C. nagelii from the Peixe River was characterized by high richness and low uniformity. PMID- 24473893 TI - Occurrence of Clavellisa ilishae (Copepoda: Lernaeopodidae) parasitizing herrings (Actinopterygii: Clupeidae) in Brazil. AB - The lernaeopodids are highly specialized copepods which are widely distributed worldwide. In this paper the first record of Clavellisa ilishae Pillai, 1962 in the Neotropical region is documented parasitizing Sardinella brasiliensis from coastal zone of Rio de Janeiro, Brasil. PMID- 24473894 TI - Gill parasites of Prochilodus lineatus (Valenciennes, 1836) (Pisces; Curimatidae; Prochilodontinae) in the Middle Parana System (Argentina). AB - We studied gill parasites of Prochilodus lineatus in the San Javier River, which is connected to the Middle Parana System (Santa Fe, Argentina). In 25 specimens, the parasite prevalence in branchial organs was 92% and the average intensity was 8.3 parasites/infested fish. The parasite community showed no dominance of any taxon, but the family Dactylogyridae represented 60% of the community. We found a significant association between Tereancistrum curimba and Dactylogyridae specimens. The prevalence of the parasites T. toksonum and T. curimba was higher than what has been recorded in the floodplain of the Upper Parana River, Brazil, demonstrating that the geographic distribution of parasites belonging to Tereancistrum genus is thus expandeing. PMID- 24473895 TI - Vertical transmission of Toxocara canis in successive generations of mice. AB - Visceral toxocariasis is a neglected zoonosis caused by Toxocara canis larvae in unusual hosts. In dogs, the definitive host, the infection occurs mainly through transplacental and transcolostral transmission. Studies on experimental models have shown that vertical transmission may result from acute infections. Considering that toxocariasis is characterized as a chronic infection, with possible reactivation of larvae present in the brain, this study evaluated the presence of larvae in the brain of female BALB/c mice and their offspring with chronic infection during three successive pregnancies. ELISA-TES was used to evaluate the antibody levels. T. canis larvae were detected in the brain tissue of the mice during the three successive generations evaluated. The offspring's IgG level gradually decreased, and mean absorbance (ABS) above the cutoff point (0.070) was observed only at 30 (0.229) and 50 (0.096) days of age, while IgM was not detected. The infections in the offspring confirmed that vertical transmission of T. canis larvae occurred during chronic toxocariasis in three successive generations of mice. PMID- 24473897 TI - Quantitative assessment of in vivo HIV protease activity using genetically engineered QD-based FRET probes. AB - HIV protease plays a central role in its life cycle leading to release of functional viral particles. It has been successfully used as a therapeutic target to block HIV infection. Several protease inhibitors (PIs) are currently being employed as a part of anti-HIV therapy. However, the constant genetic drift in the virus leads to accumulation of mutations in both cleavage site and the protease, resulting in resistance and failure of therapy. We reported the use of a quantum dot (QD)-based protein probe for the in vivo monitoring of HIV-1 protease activity based on fluorescence resonance energy transfer. In the current study, we demonstrate the utility of this approach by quantifying the in vivo cleavage rates of three known protease and cleavage site mutations in the presence or absence of different PIs. The changes in IC50 values for the different PIs were similar to that observed in patients, validating our assay as a rapid platform for PI screening. PMID- 24473898 TI - GhTZF1 regulates drought stress responses and delays leaf senescence by inhibiting reactive oxygen species accumulation in transgenic Arabidopsis. AB - Redox homeostasis is important for plants to be able to maintain cellular metabolism, and disrupting cellular redox homeostasis will cause oxidative damage to cells and adversely affect plant growth. In this study, a cotton CCCH-type tandem zinc finger gene defined as GhTZF1, which was isolated from a cotton cell wall regeneration SSH library in our previous research, was characterized. GhTZF1 was predominantly expressed during early cell wall regeneration, and it was expressed in various vegetative and reproductive tissues. The expression of GhTZF1 was substantially up-regulated by a variety of abiotic stresses, such as PEG and salt. GhTZF1 also responds to methyl jasmonate (MeJA) and H2O2 treatment. Overexpression of GhTZF1 enhanced drought tolerance and delayed drought-induced leaf senescence in transgenic Arabidopsis. Subsequent experiments indicated that dark- and MeJA-induced leaf senescence was also attenuated in transgenic plants. The amount of H2O2 in transgenic plants was attenuated under both drought conditions and with MeJA-treatment. The activity of superoxide dismutase and peroxidase was higher in transgenic plants than in wild type plants under drought conditions. Quantitative real-time PCR analysis revealed that overexpression of GhTZF1 reduced the expression of oxidative-related senescence-associated genes (SAGs) under drought conditions. Overexpression of GhTZF1 also enhanced oxidative stress tolerance, which was determined by measuring the expression of a set of antioxidant genes and SAGs that were altered in transgenic plants during H2O2 treatment. Hence, we conclude that GhTZF1 may serve as a regulator in mediating drought stress tolerance and subsequent leaf senescence by modulating the reactive oxygen species homeostasis. PMID- 24473899 TI - Distinct functions of COAR and B3 domains of maize VP1 in induction of ectopic gene expression and plant developmental phenotypes in Arabidopsis. AB - Arabidopsis ABI3 and maize VP1 are orthologous transcription factors that regulate seed maturation. ABI3 and VP1 have a C-terminal B3 DNA binding domain and a conserved N-terminal co-activator/co-repressor (COAR) domain consisting of A1, B1, B2 sub-domains. The COAR domain mediates abscisic acid signaling via a physical interaction with ABI5-related bZIP proteins. In order to delineate the COAR and B3 domain dependent functions of VP1, we created site directed mutations in the B3 domain that disrupted DNA binding activity and characterized gene regulation by the mutant proteins in transgenic abi3 mutant Arabidopsis plants. In seeds, COAR domain function of VP1 mutants that lacked B3 DNA binding activity was sufficient for complementation of the desiccation intolerant seed phenotype of abi3. Similarly in seedlings, the B3 domain was dispensable for most VP1 induced gene expression and ectopic developmental phenotypes, except for a small subset of the genes that showed B3 dependent regulation. Unexpectedly, over expression of the DNA-binding deficient VP1-K519R mutant protein caused quantitative changes in floral organ size including elongation of pistils and shortened stamen filaments that resulted in a self-incompatible longistyly flower morphology, a key component of heterostyly type self-incompatibility. PMID- 24473901 TI - From the Journal archives: Assessing the effect of anesthetic agents on the respiratory chemoreflex control of breathing. PMID- 24473900 TI - Targeting chronic lymphocytic leukemia using CIGB-300, a clinical-stage CK2 specific cell-permeable peptide inhibitor. AB - Chronic lymphocytic leukemia (CLL) remains an incurable malignancy, urging for the identification of new molecular targets for therapeutic intervention. CLL cells rely on overexpression and hyperactivation of the ubiquitous serine/threonine protein kinase CK2 for their viability in vitro. CIGB-300 is a cell-permeable selective CK2 inhibitor peptide undergoing clinical trials for several cancers. Here, we show that CIGB-300 promotes activation of the tumor suppressor PTEN and abrogates PI3K-mediated downstream signaling in CLL cells. In accordance, CIGB-300 decreases the viability and proliferation of CLL cell lines, promotes apoptosis of primary leukemia cells and displays antitumor efficacy in a xenograft mouse model of human CLL. Our studies provide pre-clinical support for the testing and possible inclusion of CK2 inhibitors in the clinical arsenal against CLL. PMID- 24473902 TI - Production and purification of a hyperthermostable chitinase from Brevibacillus formosus BISR-1 isolated from the Great Indian Desert soils. AB - A strain of Brevibacillus formosus, capable of producing a high level of chitinase, was isolated and characterized for the first time from the Great Indian Desert soils. The production of extracellularly secreted chitinase was analyzed for its biocontrol potential and optimized by varying media pH, temperature, incubation period, substrate concentrations, carbon and nitrogen sources, etc. A twofold increase in chitinase production (798 IU/mL) was achieved in optimized media containing (g l(-1)) chitin 2.0, malt extract 1.5, glycerol 1.0, ammonium nitrate 0.3%, T-20 (0.1%) and media pH 7.0 at 37 degrees C. The produced enzyme was purified using a three-step purification procedure involving ultra-filtration, ammonium sulphate precipitation and adsorption chromatography. The estimated molecular weight of the purified enzyme was 37.6 kDa. The enzyme was found thermostable at higher temperatures and showed a t 1/2 of more than 5 h at 100 degrees C. Our results show that the chitinase produced by B. formosus BISR-1 is thermostable at higher temperatures. PMID- 24473904 TI - Punicalagin inhibits inflammation in LPS-induced RAW264.7 macrophages via the suppression of TLR4-mediated MAPKs and NF-kappaB activation. AB - Punicalagin (2,3,hexahydroxydiphenoyl-gallagyl-D-glucose and referred to as PUN) is a bioactive ellagitannin isolated from pomegranate, which is widely used for the treatment of inflammatory bowel disease (IBD), diarrhea, and ulcers in Chinese traditional medicine. In this study, we detected the anti-inflammation potentials of PUN in lipopolysaccharide (LPS)-induced macrophages and tried to uncover the underlying mechanism. Results demonstrated that PUN (25, 50, or 100 MUM) treatment could significantly decrease the LPS-induced production of nitric oxide), prostaglandin E2 (PGE2), interleukin (IL)-1beta, IL-6, and tumor necrosis factor (TNF)-alpha in RAW264.7 cells. Molecular research showed that PUN inhibited the activation of upstream mediator nuclear factor-kappaB by suppressing the phosphorylation of IkappaBalpha and p65. Results also indicated that PUN could suppress the phosphorylation of mitogen-activated protein kinase including p38, c-Jun N-terminal kinase, and extracellular signal-regulated kinase. In conclusion, we observed that PUN could inhibit LPS-induced inflammation, and it may be a potential choice for the treatment of inflammation diseases. PMID- 24473905 TI - Tyrosine kinase inhibitor tyrphostin AG490 retards chronic joint inflammation in mice. AB - Tyrphostin AG490 is a Janus kinase (JAK) 2 inhibitor that is clinically used as an anticancer agent and is also effective in various models of inflammatory and autoimmune diseases. In this study, we examined the effects of tyrphostin AG490 on the development of collagenase-induced osteoarthritis (CIOA). Our results showed that tyrphostin-ameliorated cartilage and bone destructions. This effect was associated with decreased expression of signal transducers and activators of transcription 3 (STAT3), phosphorylated JAK2, Dickkopf homolog 1, and receptor activator of nuclear factor kappaB ligand (RANKL) in the joints of arthritic mice. Tyrphostin AG490 suppressed STAT3 phosphorylation and the expression of tumor necrosis factor-related apoptosis-inducing ligand and RANKL by synovial fluid cells. The drug inhibited RANKL-induced osteoclast differentiation in vitro. Molecules, such as tyrphostin AG490 that limit bone erosion and influence osteoclast generation, might have therapeutic utility in joint degenerative disorders. PMID- 24473906 TI - A novel endoscopic submucosal dissection technique with robust and adjustable tissue traction. AB - BACKGROUND AND STUDY AIMS: A novel esophageal endoscopic submucosal dissection (ESD) technique was devised using a newly developed overtube to achieve adequate tissue traction. The aim of this study was to evaluate the feasibility and safety of this new full-traction ESD (tESD) technique. METHODS: The key feature of tESD is tissue traction by grasping forceps, which is passed through the built-in side channel of the overtube. The strength and direction of traction is controlled by rotating the overtube and by adjusting its depth. The en bloc resection rate, procedure time, adverse events, and dissected area per minute were evaluated in a porcine model (n = 10) and compared with those of conventional ESD (n = 10). RESULTS: tESD provided robust and adjustable tissue traction during the procedure. En bloc resection was accomplished in all lesions with no complications. Median procedure time was similar to that of the conventional technique (25 vs. 27 minutes; P = 0.4723) but the submucosal injection catheter was used less often (1.5 vs. 6; P < 0.01). CONCLUSIONS: tESD might contribute to more efficient esophageal ESD by providing adequate tissue traction. This inexpensive technique may become an attractive option in esophageal ESD. PMID- 24473907 TI - Colonoscopic factors associated with adenoma detection in a national colorectal cancer screening program. AB - BACKGROUND AND STUDY AIMS: Adenoma detection is a key objective of colonoscopy, particularly in the context of colorectal cancer screening. The aim of this observational study was to identify the technical colonoscopy factors associated with adenoma detection. PATIENTS AND METHODS: The study analyzed data from the English Bowel Cancer Screening Programme. The indication for all colonoscopies was a positive fecal occult blood test. The relationships between the following colonoscopy factors and adenoma detection (one or more adenomas, advanced adenomas, right-sided adenomas, and total number of adenomas) were examined in multivariable analyses: bowel preparation quality, cecal intubation, withdrawal time, rectal retroversion, colonoscopist experience, antispasmodic use, sedation use, and start time of procedure. The following patient factors were controlled for: age, sex, body mass index, smoking, alcohol, deprivation, and geographical location. RESULTS: A total of 31088 colonoscopies were analyzed. The following technical factors increased the relative risk of adenoma detection (P < 0.001 in multivariable analysis unless otherwise stated): cecal intubation, increased withdrawal time, higher quality bowel preparation, intravenous antispasmodic use, earlier procedure start time within a session (P = 0.018), and greater colonoscopist experience. Detection of advanced and right-sided adenomas also increased with these factors. Adenoma detection did not differ between sedated and unsedated colonoscopy (P = 0.143). CONCLUSION: This study demonstrated important associations between colonoscopy practice and adenoma detection. Use of intravenous antispasmodic was associated with increased adenoma detection. The effect of the start time of colonoscopy suggests that endoscopist fatigue may have a deleterious impact on adenoma detection. PMID- 24473908 TI - Confocal laser endomicroscopy for in vivo detection of gastric intestinal metaplasia: a randomized controlled trial. AB - BACKGROUND AND STUDY AIMS: Gastric intestinal metaplasia (GIM) is associated with a risk for development of intestinal-type gastric cancer. This study aimed to compare the diagnostic yield of GIM from confocal laser endomicroscopy (CLE) and white light endoscopy (WLE). PATIENTS AND METHODS: In a prospective, double blind, randomized study, patients were randomly assigned to receive either CLE with targeted biopsies (group A) or WLE with a standard biopsy protocol (group B). RESULTS: A total of 168 patients were finally analyzed (group A 85, group B 83). On a per-patient analysis, the diagnostic yields of GIM (including GIM with gastric intraepithelial neoplasia [GIN]) for groups A and B were 44.71 % and 31.33 %, respectively (P = 0.074). On a per-biopsy analysis, CLE-targeted biopsy gave a significantly higher diagnostic yield of GIM compared with WLE and standard biopsy, at 65.70 % (113 /172 biopsies) versus 15.73 % (81 /515 biopsies) (P < 0.001). Moreover, the diagnostic yield of the operative link on gastric intestinal metaplasia (OLGIM) assessment stages III and IV was higher at 20.93 % (36 /172 biopsies) in group A versus 4.08 % (21 /515 biopsies) in group B (P < 0.001). In addition, use of CLE-guided biopsy significantly decreased by 68 % (P < 0.001) the mean number of biopsies required per patient. CONCLUSIONS: CLE with targeted biopsies is superior to WLE with standard biopsies for the detection and surveillance of GIM. The number of biopsies needed to confirm GIM is about one third of that needed with WLE with standard biopsies. PMID- 24473909 TI - Nutrient-dependent inhibition of perithecial development due to sequential crosses on the same mycelium of Neurospora tetrasperma. AB - An explanation of perithecial inhibition in the second of two sequential crosses at different locations on the same mycelium of Neurospora tetrasperma was sought by (1) assaying media that had supported inhibited and uninhibited portions of the mycelium which contained no developing perithecia, (2) determining the effect of these media on perithecial development, (3) adding nutrients to inhibited portions of the mycelium, and (4) assaying carbon sources in media that had supported portions of the mycelium which contained developing perithecia, and portions, both inhibited and uninhibited, which contained no developing perithecia. Different kinds and volumes of media and various intervals of time between sequential crosses were used to aid in determining limits of perithecial inhibition. Perithecial inhibition was observed to be independent of volatile metabolites and pH, independent of non-volatile metabolites, reversible by addition of nutrients, dependent upon nutrient volume, and correlated with the concentration of the carbon source in the medium. It is proposed that second crosses are inhibited because of a previous lowering of the concentration of nutrients in the medium in second-cross locations, owing to prior demand upon those nutrients by the developing perithecia in first-cross locations. The possibility of an activation signal between first- and second-cross locations is discussed. No inhibitory substance in inhibited locations was detected. PMID- 24473910 TI - Zygote shrinkage and subsequent development in some Hibiscus hybrids. AB - Early embryonic development was compared in self-fertilized embryos of the diploid species, Hibiscus costatus, and triploid hybrid embryos, H. costatus aculeatus and H. costatus-furcellatus, the paternal parent in both hybrids being tetraploid. The self-fertilized zygotes shrank to 50% of the volume of the unfertilized egg. These young embryos showed marked polarity. There was a concentration of cytoplasm in the apical cells and large vacuoles in the basal cells. There was also a polar distribution of organelles within the embryo as a whole which probably reflected initial differentiation. In comparison, hybrid zygotes shrank only about 20% of their original volume but started division at about the same time as selffertilized zygotes. There appeared to be no polarization and little proliferation of the cytoplasm in the hybrids. Large vacuoles remained prominent throughout the hybrid embryos, while organelles were few in the scant cytoplasm and no polarization of these was evident. These highly divergent hybrid embryos had become necrotic and aborted by the time the normal, self-fertilized embryos had reached the late globular stage. This altered developmental sequence of the hybrids suggests that shrinkage and rearrangement of the zygote cytoplasm is essential for normal embryonic differentiation. PMID- 24473911 TI - Spinach protein factor and chlorophyllase. AB - 1. Spinach leaves contain a "Spinach Protein Factor" (SPF) which increases light sensitivity of colloidal chlorophylls in aqueous solution (Terpstra, 1967). SPF activity, measured in different fractions of spinach-leaf acetone-powder extracts obtained by gel filtration on DEAE- and CM-Sephadex, runs parallel with chlorophyllase activity. The same positive correlation is generally observed in aqueous extracts of certain small particles isolated from spinach-leaf homogenates. It is suggested that SPF is a chlorophyllase. 2. Another, less active chlorophyllase was found in endive leaves. Evidence is presented that this chlorophyllase competes with the more active SPF chlorophyllase for available (bacterio)chlorophyll. The less active chlorophyllase is also present, in varying amounts, in spinach leaves. 3. SPF activity and chlorophyllase activity are influenced by phosphate in different concentrations in a similar way. 4. Both the SPF chlorophyllase and the less active chlorophyllase accelerate the conversion of colloidal bacteriochlorophyll from a form with red absorption bands at about 845 and 790 nm into a form with a main red band at about 775 nm; besides, the chlorophyllases cause the 775 nm band to be shifted to shorter wavelength (770 766 nm). The conversion by the less active chlorophyllase is inhibited by Ca(2+) (0.01 M). Light sensitivity of the 770-766-nm bacteriochlorophyll form is enhanced by the SPF chlorophyllase, but not by the less active chlorophyllase. PMID- 24473912 TI - [Cytokinin-induced de-novo synthesis of nitrate reductase in isolated embryos of Agrostemma githago]. AB - Nitrate reductase can be induced in isolated embryos of Agrostemma githago by treatment with cytokinin. By labeling proteins with H2 (18)O and subsequent isopycnic density gradient centrifugation it was proved that the benzyladenine induction of nitrate reductase is caused by a de-novo synthesis of the enzyme. PMID- 24473913 TI - [Caffeine synthesis in fruits and tissue cultures of Coffea arabica]. AB - During fruit development the relative caffeine content of the pericarp falls from 1.68% to 0.24% on a dry weight basis, but remains more or less constant in the seed (about 1.25%). On an absolute basis, the pericarp has twice as much and the seed twenty times as much caffeine at maturity as at the beginning of fruit development. Tissue cultures of seed tissue (endosperm) produce caffeine and release it into the growth medium. Both pericarp and endosperm fed with NaH(14)CO3 synthesize ring-labelled caffeine. Light strongly stimulates the methylation step of caffeine synthesis in the pericarp. PMID- 24473914 TI - Enzyme formation, cellular breakdown and the distribution of gibberellins in the endosperm of barley. AB - The alpha-amylase contents of the dorsal and ventral sides of the endosperm of barley grains increase approximately equally during germination. Aleurone tissue from all locations in the grain is equally able to make alpha-amylase in response to gibberellic acid, so the distribution of this enzyme reflects the distribution of endogenous gibberellins.Variations occurred in both the rate and pattern of cellular breakdown of the starchy endosperm. Generally breakdown progressed away from, and parallel to the scutellum, ultimately advancing faster adjacent to the aleurone layer. The "sheaf cells", above the furrow, were relatively resistant to enzymic breakdown. The results indicate that gibberellins are released generally from the scutellum and induce hydrolytic enzymes equally on the dorsal and ventral sides of the grain. PMID- 24473915 TI - Direct measurement of stomatal cell production in barley. AB - A simple method which measures stomatal cell production directly in the first leaf of barley is described. The method was tested with three barley genotypes, two of which, cer-g (11) and cer-g (1026), are mutants with an abnormal stomatal pattern. Cer-g (11) had a slower rate of stomatal cell formation, as compared with the other two genotypes. PMID- 24473916 TI - Cytokinins and nuclear RNA levels in onion root tips. AB - Onion root tips were grown in water, kinetin or 6-benzyladenine and levels of RNA in the chromatin region of nuclei were analyzed using visible light microscopy with basic-dye staining, and ultraviolet microscopy of unstained material. No evidence was found for a significant increase in nuclear RNA in response to cytokinin treatment. PMID- 24473917 TI - Batatasins: New dormancy-inducing substances of yam bulbils. AB - Three growth inhibitors, for which the names batatasins I, II and III are proposed, occur in dormant yam bulbils. Application of these inhibitors suppresses the sprouting of bulbils, and the inhibition is reversible by low temperature stratification. Batatasins I and III were isolated as crystals and partially characterized as phenotic compounds not identical with known inhibions. PMID- 24473918 TI - The paradox of Wolff's theories. AB - The upper femur has long held a fascination for both clinicians and bioengineers as it contains two trabecular columns obviously related to its function. In this respect two theories as to the formation of these columns have developed, both associated with Wolff: the Trajectorial Theory, which relates mainly to the passage of forces through the cancellous bone of the upper femur, and Wolff's Law of bone formation, which describes the bone's reaction to these forces and relates to bone in general. The two concepts nevertheless are often used synonymously. The Trajectorial Theory propounds that these cancellous structures in the femoral neck are due to both tension and compression forces, while modern day concepts of Wolff's Law only acknowledge the action of compression forces: and herein lies the paradox. The Trajectorial Theory and Wolff's Law, when applied to the upper femur, are mutually exclusive. The evidence, anatomical and physiological, indicates that bone forms within the femoral neck solely under the influence of compression forces. This would indicate that the Trajectorial Theory is not appropriate for this region. An alternative conceptual way of looking at this region is presented which eliminates this theory and resolves the paradox. PMID- 24473919 TI - Ultrasonography screening for abdominal aortic aneurysms: a systematic evidence review for the U.S. Preventive Services Task Force. AB - BACKGROUND: Long-term follow-up of population-based randomized, controlled trials (RCTs) has demonstrated that screening for abdominal aortic aneurysms (AAAs) measuring 3 cm or greater decreases AAA-related mortality rates in men aged 65 years or older. PURPOSE: To systematically review evidence about the benefits and harms of ultrasonography screening for AAAs in asymptomatic primary care patients. DATA SOURCES: MEDLINE, the Database of Abstracts of Reviews of Effects, the Cochrane Central Register of Controlled Trials (January 2004 through January 2013), clinical trial registries, reference lists, experts, and a targeted bridge search for population-based screening RCTs through September 2013. STUDY SELECTION: English-language, population-based, fair- to good-quality RCTs and large cohort studies for AAA screening benefits as well as RCTs and cohort and registry studies for harms in adults with AAA. DATA EXTRACTION: Dual quality assessment and abstraction of study details and results. DATA SYNTHESIS: Reviews of 4 RCTs involving 137,214 participants demonstrated that 1-time invitation for AAA screening in men aged 65 years or older reduced AAA rupture and AAA-related mortality rates for up to 10 and 15 years, respectively, but had no statistically significant effect on all-cause mortality rates up to 15 years. Screening was associated with more overall and elective surgeries but fewer emergency operations and lower 30-day operative mortality rates at up to 10- to 15-year follow-up. One RCT involving 9342 women showed that screening had no benefit on AAA-related or all-cause mortality rates. LIMITATIONS: Trials included mostly white men outside of the United States. Information for subgroups and about rescreening was limited. CONCLUSION: One-time invitation for AAA screening in men aged 65 years or older was associated with decreased AAA rupture and AAA-related mortality rates but had little or no effect on all-cause mortality rates. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality. PMID- 24473920 TI - Effect of duration of denervation on outcomes of ansa-recurrent laryngeal nerve reinnervation. AB - OBJECTIVES/HYPOTHESIS: To investigate the efficacy of laryngeal reinnervation with ansa cervicalis among unilateral vocal fold paralysis (UVFP) patients with different denervation durations. STUDY DESIGN: We retrospectively reviewed 349 consecutive UVFP cases of delayed ansa cervicalis to the recurrent laryngeal nerve (RLN) anastomosis. Potential influencing factors were analyzed in multivariable logistic regression analysis. Stratification analysis performed was aimed at one of the identified significant variables: denervation duration. METHODS: Videostroboscopy, perceptual evaluation, acoustic analysis, maximum phonation time (MPT), and laryngeal electromyography (EMG) were performed preoperatively and postoperatively. Gender, age, preoperative EMG status and denervation duration were analyzed in multivariable logistic regression analysis. Stratification analysis was performed on denervation duration, which was divided into three groups according to the interval between RLN injury and reinnervation: group A, 6 to 12 months; group B, 12 to 24 months; and group C, > 24 months. RESULTS: Age, preoperative EMG, and denervation duration were identified as significant variables in multivariable logistic regression analysis. Stratification analysis on denervation duration showed significant differences between group A and C and between group B and C (P < 0.05)-but showed no significant difference between group A and B (P > 0.05) with regard to parameters overall grade, jitter, shimmer, noise-to-harmonics ratio, MPT, and postoperative EMG. In addition, videostroboscopic and laryngeal EMG data, perceptual and acoustic parameters, and MPT values were significantly improved postoperatively in each denervation duration group (P < 0.01). CONCLUSIONS: Although delayed laryngeal reinnervation is proved valid for UVFP, surgical outcome is better if the procedure is performed within 2 years after nerve injury than that over 2 years. PMID- 24473921 TI - The role of attitudes toward White privilege and religious beliefs in predicting social justice interest and commitment. AB - The current study examines links among attitudes toward White privilege, religious beliefs, and social justice interest and commitment for White Christian students. Two distinct patterns of results emerged from a path analysis of 500 White Christian students. First, a willingness to confront White privilege was positively associated with the sanctification of social justice (i.e., attributing spiritual significance to working for social justice) and both were positively associated with social justice interest and commitment. Second, awareness of White privilege was negatively associated with religious conservatism, and religious conservatism was negatively associated with social justice interest. These patterns show that White privilege attitudes directly (i.e., willingness to confront White privilege) and indirectly (i.e., awareness of White privilege through religious conservatism) predicted social justice interest and commitment. Moreover, religious beliefs demonstrated opposite patterns of association with social justice interest and commitment such that the sanctification of social justice positively predicted social justice interest and commitment whereas religious conservatism negatively predicted social justice interest. Overall, findings demonstrate direct and indirect links between White privilege attitudes, religious beliefs, and social justice interest and commitment. Limitations and implications for future community psychology research and collaboration also are discussed. PMID- 24473923 TI - Community matters: intimate partner violence among rural young adults. AB - Drawing on social disorganization theory, the current study examined the extent to which community-level poverty rates and collective efficacy influenced individual reports of intimate partner violence (IPV) perpetration, victimization, and bystander intervention among a sample of 178 young adults (18 24; 67.4% women) from 16 rural counties across the eastern US who completed an online survey that assessed demographic information, IPV perpetration, victimization, bystander intervention, and collective efficacy. We computed each county's poverty rate from the 2007-2011 American Community Survey. Generalized estimating equations demonstrated that after controlling for individual-level income status, community-level poverty positively predicted IPV victimization and perpetration for both men and women. Collective efficacy was inversely related to IPV victimization and perpetration for men; however, collective efficacy was unrelated to IPV victimization and perpetration for women. Whereas IPV bystander intervention was positively related to collective efficacy and inversely related to individual-level income status for both men and women, community-level poverty was unrelated to IPV bystander intervention for both men and women. Overall, these findings provide some support for social disorganization theory in explaining IPV among rural young adults, and underscore the importance of multi level IPV prevention and intervention efforts focused around community-capacity building and enhancement of collective efficacy. PMID- 24473922 TI - Comparing the characteristics of homeless adults in Poland and the United States. AB - This study compared the characteristics of probability samples of homeless adults in Poland (N = 200 from two cities) and the United States (N = 219 from one city), using measures with established reliability and validity in homeless populations. The same measures were used across nations and a systemic translation procedure assured comparability of measurement. The two samples were similar on some measures: In both nations, most homeless adults were male, many reported having dependent children and experiencing out-of-home placements when they themselves were children, and high levels of physical health problems were observed. Significant national differences were also found: Those in Poland were older, had been homeless for longer, showed lower rates on all psychiatric diagnoses assessed (including severe mental and substance abuse disorders), reported less contact with family and supportive network members, were less satisfied when they sought support from their networks, and reported fewer recent stressful life events and fewer risky sexual behaviors. Culturally-informed interpretations of these findings and their implications are presented. PMID- 24473924 TI - Increased risk of malignant melanoma in patients with systemic mastocytosis? PMID- 24473925 TI - Iterative marker excision system. AB - The deletions of large genomic DNA fragments and consecutive gene knockouts are prerequisites for the generation of organisms with improved properties. One of the key issues in this context is the removal of antibiotic resistance markers from engineered organisms without leaving an active recombinase recognition site. Here, we report the establishment of an iterative marker excision system (IMES) that solves this problem. Based on the phiC31 integrase and its mutant att sites, IMES can be used for highly effective deletion of DNA fragments between inversely oriented B-CC and P-GG sites. The B-CC and P-GG sites are derived from attB and attP by substitution of the central core TT dinucleotide with CC and GG, respectively. An unnatural RR site that resides in the chromosome following deletion is the joining product of the right shoulders of B-CC and P-GG. We show that the RR sites do not recombine with each other as well as the RR site recombines with B-CC. The recombination efficiencies between RR and P-GG or RR and LL are only 0.1 % and 1 %, respectively. Thus, IMES can be used for multistep genomic engineering without risking unwanted DNA recombination. The fabrication of multi-purpose antibiotic cassettes and examples of the utilisation of IMES are described. PMID- 24473927 TI - A long lasting puzzle for -7/7q- syndrome. PMID- 24473928 TI - [Physical activity recommendations for oncological rehabilitation]. PMID- 24473926 TI - Changes in sleep disruption in the treatment of co-occurring posttraumatic stress disorder and substance use disorders. AB - Sleep disruption appears not only to reflect a symptom of posttraumatic stress disorder (PTSD), but also a unique vulnerability for its development and maintenance. Studies examining the impact of psychosocial treatments for PTSD on sleep symptoms are few and no studies to date of which we are aware have examined this question in samples with co-occurring substance use disorders. The current study is a secondary analysis of a large clinical trial comparing 2 psychological treatments for co-occurring PTSD and substance use disorders. Women (N = 353) completed measures of PTSD at baseline, end of treatment, and 3-, 6-, and 12 month follow-ups. Results indicated that the prevalence of insomnia, but not nightmares, decreased during treatment, and that 63.8% of participants reported at least 1 clinical-level sleep symptom at the end of treatment. Improvement in sleep symptoms during treatment was associated with better overall PTSD outcomes over time, chi(2) (1) = 33.81, p < .001. These results extend the existing literature to suggest that residual sleep disruption following PTSD treatment is common in women with co-occurring PTSD and substance use disorders. Research on the benefits of adding sleep-specific intervention for those with residual sleep disruption in this population may be a promising future direction. PMID- 24473929 TI - [Identifying the need for hygiene professionals in rehabilitation facilities using a score-based assessment of the risk profile in patients]. PMID- 24473930 TI - [Guiding principles of German Association for Rehabilitation]. PMID- 24473931 TI - Effects of scaffold architecture on mechanical characteristics and osteoblast response to static and perfusion bioreactor cultures. AB - Tissue engineering focuses on the repair and regeneration of tissues through the use of biodegradable scaffold systems that structurally support regions of injury while recruiting and/or stimulating cell populations to rebuild the target tissue. Within bone tissue engineering, the effects of scaffold architecture on cellular response have not been conclusively characterized in a controlled density environment. We present a theoretical and practical assessment of the effects of polycaprolactone (PCL) scaffold architectural modifications on mechanical and flow characteristics as well as MC3T3-E1 preosteoblast cellular response in an in vitro static plate and custom-designed perfusion bioreactor model. Four scaffold architectures were contrasted, which varied in inter-layer lay-down angle and offset between layers, while maintaining a structural porosity of 60 +/- 5%. We established that as layer angle was decreased (90 degrees vs. 60 degrees ) and offset was introduced (0 vs. 0.5 between layers), structural stiffness, yield stress, strength, pore size, and permeability decreased, while computational fluid dynamics-modeled wall shear stress was increased. Most significant effects were noted with layer offset. Seeding efficiencies in static culture were also dramatically increased due to offset (~ 45% to ~ 86%), with static culture exhibiting a much higher seeding efficiency than perfusion culture. Scaffold architecture had minimal effect on cell response in static culture. However, architecture influenced osteogenic differentiation in perfusion culture, likely by modifying the microfluidic environment. PMID- 24473932 TI - The equilibrium allele frequency distribution for a population with reproductive skew. AB - We study the population genetics of two neutral alleles under reversible mutation in a model that features a skewed offspring distribution, called the Lambda Fleming-Viot process. We describe the shape of the equilibrium allele frequency distribution as a function of the model parameters. We show that the mutation rates can be uniquely identified from this equilibrium distribution, but the form of the offspring distribution cannot itself always be so identified. We introduce an estimator for the mutation rate that is consistent, independent of the form of reproductive skew. We also introduce a two-allele infinite-sites version of the Lambda-Fleming-Viot process, and we use it to study how reproductive skew influences standing genetic diversity in a population. We derive asymptotic formulas for the expected number of segregating sites as a function of sample size and offspring distribution. We find that the Wright-Fisher model minimizes the equilibrium genetic diversity, for a given mutation rate and variance effective population size, compared to all other Lambda-processes. PMID- 24473934 TI - New cholesterol guidelines: has Godot finally arrived? PMID- 24473935 TI - UK surgeon takes name off medical register before scheduled case review. PMID- 24473933 TI - The between-population genetic architecture of growth, maturation, and plasticity in Atlantic salmon. AB - The between-population genetic architecture for growth and maturation has not been examined in detail for many animal species despite its central importance in understanding hybrid fitness. We studied the genetic architecture of population divergence in: (i) maturation probabilities at the same age; (ii) size at age and growth, while accounting for maturity status and sex; and (iii) growth plasticity in response to environmental factors, using divergent wild and domesticated Atlantic salmon (Salmo salar). Our work examined two populations and their multigenerational hybrids in a common experimental arrangement in which salinity and quantity of suspended sediments were manipulated to mimic naturally occurring environmental variation. Average specific growth rates across environments differed among crosses, maturity groups, and cross-by-maturity groups, but a growth-rate reduction in the presence of suspended sediments was equal for all groups. Our results revealed both additive and nonadditive outbreeding effects for size at age and for growth rates that differed with life stage, as well as the presence of different sex- and size-specific maturation probabilities between populations. The major implication of our work is that estimates of the genetic architecture of growth and maturation can be biased if one does not simultaneously account for temporal changes in growth and for different maturation probabilities between populations. Namely, these correlated traits interact differently within each population and between sexes and among generations, due to nonadditive effects and a level of independence in the genetic control for traits. Our results emphasize the challenges to investigating and predicting phenotypic changes resulting from between-population outbreeding. PMID- 24473936 TI - Family poverty and trajectories of children's emotional and behavioural problems: the moderating roles of self-regulation and verbal cognitive ability. AB - Socio-economic disadvantage is strongly associated with children's emotional (internalising) and behavioural (externalising) problems. Self-regulation and verbal cognitive ability have been related to children's emotional and behavioural resilience to socio-economic disadvantage. Despite being inter related, self-regulation and verbal cognitive ability have not been examined jointly as promoting resilience in young children. This study investigated the roles of self-regulation and verbal cognitive ability in children's emotional and behavioural resilience to family socio-economic disadvantage from early to middle childhood (ages 3, 5, and 7 years; N = 16,916; 49 % girls). Using multivariate response growth curve modelling, we found that the relationship between socio economic disadvantage and internalising problems was stronger for children with lower verbal cognitive ability. Also, poor children with high and low levels of self-regulation showed a widening gap in both emotional and behavioural problems over time. Poor and non-poor children alike benefited from self-regulation, but poor children appeared to be more vulnerable to low self-regulation. Self regulation and verbal cognitive ability seem to be important protective factors for young children growing up in poor families. PMID- 24473938 TI - Govindjee, an institution, at his 80th (really 81st) birthday in Trebon in October, 2013: a pictorial essay. AB - Govindjee (one name only), who himself is an institution, has been recognized and honored by many in the past for he is a true ambassador of "Photosynthesis Research" to the World. He has been called "Mr. Photosynthesis", and compared to the Great Wall of China. To us in Trebon, he has been a great research collaborator in our understanding of chlorophyll a fluorescence in algae and in cyanobacteria, and more than that a friend of the Czech "Photosynthesis" group, from the time of Ivan Setlik (1928-2009) and of Zdenek Sestak (1932-2008). Govindjee's 80th (really 81st) birthday was celebrated by the Institute of Microbiology, Laboratory of Photosynthesis, by toasting him with an appropriate drink of a suspension of green algae grown at the institute itself. After my presentation, on October 23, 2013, of Govindjee's contributions to photosynthesis, and his intimate association with the photosynthetikers (in Jack Myers's words) of the Czech Republic, Govindjee gave us his story of how he began research in photosynthesis in the late 1950s. This was followed by a talk on October 25 by him on "Photosynthesis: Stories of the Past." Everyone enjoyed his animated talk-it was full of life and enjoyment. Here, I present a brief pictorial essay on Govindjee at his 80th (really 81st) birthday in Trebon during October 23-25, 2013. PMID- 24473939 TI - Utilization of a standardized tracheostomy capping and decannulation protocol to improve patient safety. AB - OBJECTIVES/HYPOTHESIS: To develop and assess the feasibility of a new standardized protocol to guide tracheostomy decannulation. STUDY DESIGN: Descriptive review of quality improvement project. METHODS: A quality improvement project was conducted in the inpatient setting of a tertiary urban academic hospital. Adult patients who had received a tracheostomy and for whom the indication for tracheostomy had resolved were included. A multidisciplinary task force reviewed input from clinicians caring for tracheostomy patients and developed a protocol for screening, capping, and decannulation. The primary outcome measured was successful decannulation. RESULTS: Fifty-seven patients were screened for a capping trial over a 12-month period; 54 were capped. Six patients were lost to follow-up. Fifty patients passed the capping trial, and all 50 were decannulated successfully. When decannulation was pursued in one patient who had twice failed the screening criteria and subsequent capping trials, the patient failed decannulation and ultimately required reintubation for the management of secretions. The screening tool had high sensitivity (90%) and positive predictive value (100%) for successful decannulation. Additionally, the number of reported patient safety concerns decreased from seven in the 6 months preceding implementation of the program to one report in the 6 months after implementation. CONCLUSION: The new tracheostomy capping and decannulation protocol assisted in predicting both successful and failed decannulation. Although several patients failed certain capping criteria initially, the protocol stipulated modifications of care that enabled successful decannulation. The screening tool had high sensitivity and promoted communication, standardization of practice, and patient safety. PMID- 24473940 TI - Sexual and affective responses to same- and opposite-sex stimuli in heterosexual and homosexual men: assessment and manipulation of visual attention. AB - Affective and cognitive factors play an important role in the activation and regulation of men's sexual arousal. Barlow (1986) argued that initial affective reactions determine the allocation of attention to sexual stimuli. We applied Barlow's model to our understanding of the role of sexual arousal in sexual orientation, where sexual arousal patterns have consistently been found to be congruent with self-reported orientation in men, but not in women. Visual attention of 28 heterosexual and 22 homosexual men to same- and opposite-sex erotic stimuli was assessed and experimentally-directed by means of a newly developed software application, while genital (penile rigidity) and affective responses (self-reported and physiological) were measured. In line with previous research, we found "category specificity" in men's sexual arousal, in that sexual responses were strongest to orientation-congruent stimuli. Also, both homosexual and heterosexual men experienced stronger sexual responses to conditions in which their attention was directed to sexual versus nonsexual content of orientation congruent stimuli. Only homosexual men manifested higher sexual responses when their visual attention was directed towards the sexual content of orientation incongruent stimuli. Heterosexual men experienced weaker positive and stronger negative affective responses to orientation-incongruent content, suggestive of potential avoidance or inhibitory mechanisms. PMID- 24473941 TI - Adult baby/diaper lovers: an exploratory study of an online community sample. AB - This internet-based study provided descriptive information and exploratory analyses on 1,795 male and 139 female members of the Adult Baby/Diaper Lover (ABDL) community. Based on prior research, some research questions focused on the degree to which ABDL behavior was associated with negative mood states, parental relationships, and attachment style. Based on clinical experience, a second research question focused on discerning two possible subgroups within the ABDL community: persons focused on role play behavior and persons who were primarily interested in sexual arousal in their ABDL behavior. The results showed modest support for the former research questions, but notable support for the last research question. Because of some overlap between the two hypothesized subgroups, additional subgroups may exist. Males in the ABDL community identified their ABDL interests earlier than females and these males may be more focused on sexual aspects of ABDL practices. Both males and females perceived being dominated as important in their ABDL behavior. Most participants were comfortable with their ABDL behavior and reported few problems. ABDL behavior may represent a sexual subculture that is not problematic for most of its participants. PMID- 24473942 TI - Kinky parents and child custody: the effect of the DSM-5 differentiation between the paraphilias and paraphilic disorders. PMID- 24473943 TI - Joint model for a diagnostic test without a gold standard in the presence of a dependent terminal event. AB - Breast cancer patients after breast conservation therapy often develop ipsilateral breast tumor relapse (IBTR), whose classification (true local recurrence versus new ipsilateral primary tumor) is subject to error, and there is no available gold standard. Some patients may die because of breast cancer before IBTR develops. Because this terminal event may be related to the individual patient's unobserved disease status and time to IBTR, the terminal mechanism is non-ignorable. This article presents a joint analysis framework to model the binomial regression with misclassified binary outcome and the correlated time to IBTR, subject to a dependent terminal event and in the absence of a gold standard. Shared random effects are used to link together two survival times. The proposed approach is evaluated by a simulation study and is applied to a breast cancer data set consisting of 4477 breast cancer patients. The proposed joint model can be conveniently fit using adaptive Gaussian quadrature tools implemented in SAS 9.3 (SAS Institute Inc., Cary, NC, USA) procedure NLMIXED. PMID- 24473944 TI - Dornase alpha use in patients with cystic fibrosis. PMID- 24473945 TI - A first-year dornase alfa treatment impact on clinical parameters of patients with cystic fibrosis: the Brazilian cystic fibrosis multicenter study. AB - OBJECTIVE: To describe the clinical impact of the first year treatment with dornase alfa, according to age groups, in a cohort of Brazilian Cystic Fibrosis (CF) patients. METHODS: The data on 152 eligible patients, from 16 CF reference centers, that answered the medical questionnaires and performed laboratory tests at baseline (T0), and at six (T2) and 12 (T4) months after dornase alfa initiation, were analyzed. Three age groups were assessed: six to 11, 12 to 13, and >14 years. Pulmonary tests, airway microbiology, emergency room visits, hospitalizations, emergency and routine treatments were evaluated. Student's t test, chi-square test and analysis of variance were used when appropriated. RESULTS: Routine treatments were based on respiratory physical therapy, regular exercises, pancreatic enzymes, vitamins, bronchodilators, corticosteroids, and antibiotics. In the six months prior the study (T0 phase), hospitalizations for pulmonary exacerbations occurred in 38.0, 10.0 and 61.4% in the three age groups, respectively. After one year of intervention, there was a significant reduction in the number of emergency room visits in the six to 11 years group. There were no significant changes in forced expiratory volume in one second (VEF(1)), in forced vital capacity (FVC), in oxygen saturation (SpO(2)), and in Tiffenau index for all age groups. A significant improvement in Shwachman-Kulczychi score was observed in the older group. In the last six months of therapy, chronic or intermittent colonization by P. aeruginosa was detected in 75.0, 71.4 and 62.5% of the studied groups, respectively, while S. aureus colonization was identified in 68.6, 66.6 and 41.9% of the cases. CONCLUSIONS: The treatment with dornase alfa promoted the maintenance of pulmonary function parameters and was associated with a significant reduction of emergency room visits due to pulmonary exacerbations in the six to 11 years age group, with better clinical scores in the >14 age group, one year after the intervention. PMID- 24473946 TI - Teasing and weight-control behaviors in adolescent girls. AB - OBJECTIVE: To analyze the association between weight teasing, body satisfaction and weight control behaviors. METHODS: Cross-sectional study based on adaptation and validity research of a North American questionnaire for adolescent girls about physical activity, nutrition, body image, perceptions, and behaviors. The variables used to conduct the study were weight control behaviors, body satisfaction and presence of teasing by family members. Descriptive analyses were carried out by chi-square test, being significant p<0.05. RESULTS: A total of 159 adolescent girls, with 16.2+/-1.3 years old were enrolled in this study. Of the total, 60.1% reported that family members did not tease them. The teasing was associated with weight dissatisfaction (p<0.001), body shape (p=0.006), belly (p=0.001), waist (p=0.001), face (p=0.009), arms (p=0.014) and shoulders (p=0.001). As a consequence, there was association with unhealthy weight control behaviors (p<0.001), vomiting (p=0,011), diet (p=0.002) and use of laxatives (p=0.035). CONCLUSIONS: The teasing about body image by family members was associated with risk for unhealthy weight control behaviors in female adolescents. PMID- 24473947 TI - Low body weight/thinness, overweight and obesity of children and adolescents from a Brazilian region of low economic status. AB - OBJECTIVE: To assess the prevalence of low body weight/thinness, overweight and obesity in a representative sample of children and adolescents from a Brazilian region with low economic development. METHODS: A total of 982 girls and 986 boys, aged seven to 17 years old and assisted by Segundo Tempo Program, from Montes Claros, Minas Gerais, Brazil, were included in the study. Low body weight/thinness, overweight and obesity were defined based on body mass cut-off indexes recommended by the International Obesity Task Force. The prevalence of the nutritional status according to sex and age was compared by chi-square test. RESULTS: In girls, the frequency of low body weight/thinness, overweight and obesity was 4.1, 18.4 and 3.8%, respectively; in boys, these percentages were 6.3, 13.2 and 2.9%, respectively. The low body weight/thinness for girls raised from 2.7% (7-10 years old) to 5.5% (15-17 years old); the body weight excess (overweight and obesity) decreased from 30.1 to 16.2% for the same age groups. In boys, the corresponding trends were from 3.2 to 9.4% for low body weight/thinness, and from 23.4 to 9.2%, for body weight excess. CONCLUSIONS: The data indicate that, even in a region with low economic status, the body weight excess was the main problem associated with nutritional health. The high overweight and obesity prevalence rates indicate the need of public policies for promoting healthy feeding behaviors and physical activity. PMID- 24473948 TI - Food intake and nutritional status of preschool from maroon communities of the state Alagoas, Brazil. AB - OBJECTIVE: To assess the dietary intake and the nutritional status of children from Alagoas maroon communities. METHODS: Cross-sectional study involving 724 children (12-60 months) from 39 Alagoas maroon communities. The nutritional status was investigated by anthropometric, biochemical (hemoglobin) and food consumption indicators. RESULTS: The prevalence of anemia, stunting and obesity were, respectively, 48.0, 9.7 and 6.0%. The children had a monotonous eating pattern and a considerable prevalence of inadequate intake of zinc (17.0%), folate (18.1%), iron (20.2%) and vitamins A (29.7%) and C (34.3%). Compared to the other socioeconomic classes, the E class children had lower average consumption (p<0.05) for energy, carbohydrate, vitamins A and C, folate, iron, zinc and phosphorus. CONCLUSIONS: Anemia is a serious Public Health problem. The prevalence of chronic malnutrition and obesity were similar to those observed for the children in the State as a whole, where a nutritional transition process is occuring. There was a high prevalence of inadequate food intake risk for zinc, folate, iron and vitamins A and C, suggesting the need for nutritional education actions. PMID- 24473949 TI - Risk of developmental delay of children aged between two and 24 months and its association with the quality of family stimulus. AB - OBJECTIVE: To analyze the association between neurodevelopment and the family environment resources of children from the coverage area of a Basic Health Unit (BHU) of Belo Horizonte, Brazil, using a tool based on the Integrated Management of Childhood Illness (IMCI) strategy. METHODS: Cross-sectional study with a non probabilistic sample involving 298 children aged between 2-24 months old, who attended a BHU in 2010. The assessment of child development and family resources made at the BHU lasted, in average, 45 minutes and included two tests - an adaptation of the Handbook for Monitoring Child Development in the Context of IMCI and an adapted version of the Family Environment Resource (FER) inventary. The nonparametric tests of Kruskal-Wallis and Mann-Whitney were used for the statistical analysis. RESULTS: The sample included 291 assessments, with 18.2% of children between 18 and 24 months old, 53.6% male gender, and 91.4% who did not attend day care centers. According to IMCI, 31.7% of the children were in the risk group for developmental delay. The total average score in FER was 38.0 points. Although it has been found an association between the IMCI outcome and the total FER score, all groups had low scores in the family environment assessment. CONCLUSIONS: The data indicate the need for childhood development screening in the primary health care and for early intervention programs aimed at this age group. PMID- 24473950 TI - Gestational, perinatal and family findings of patients with Patau syndrome. AB - OBJECTIVE: To describe gestational, perinatal and family findings of patients with Patau syndrome (PS). METHODS: The study enrolled patients with PS consecutively evaluated during 38 years in a Clinical Genetics Service of a pediatric referral hospital in Southern Brazil. The clinical data and the results of cytogenetic analysis were collected from the medical records. For statistical analysis, the two-tailed Fisher's exact test and the chi-square test with Yates' correction were used, being significant p<0.05. RESULTS: The sample was composed of 27 patients, 63% were male, with a median age of nine days at the first evaluation. Full trisomy of chromosome 13 was the main cytogenetic finding (74%). Only six patients were submitted to obstetric ultrasound and none had prenatal diagnosis of PS. The patients' demographic characteristics, compared to born alive infants in the same Brazilian state showed a higher frequency of: mothers with 35 years old or more (37.5%); multiparous mothers (92.6%); vaginal delivery (77%); preterm birth (34.6%); birth weight <2500g (33.3%), and Apgar scores <7 in the 1st (75%) and in the 5th minute (42.9%). About half of them (53%) died during the first month of life. CONCLUSIONS: The understanding of the PS patients' gestational, perinatal and family findings has important implications, especially on the decision about the actions to be taken in relation to the management of these patients. PMID- 24473951 TI - Spatial distribution of low birthweight infants in Taubate, Sao Paulo, Brazil. AB - OBJECTIVE: To identify the spatial pattern of low birth weight infants in the city of Taubate, Sao Paulo, Southeast Brazil. METHODS: Ecological and exploratory study, developed with the data acquired from the Health Department of Taubate, regarding the period from January 1(st) 2006 and December 31(st) 2010. Birth certificates were used to obtain the data from infants weighing less than 2500g. A digital basis of census tracts was applied and the Global Moran index ((IM)) was estimated. Thematic maps were built for the distribution of low birth weight, health centers and tracts, according to the priority care (Moran map). The adopted statistical significance was alpha=5% and TerraView software conducted the spatial analysis. RESULTS: There were 18,915 live births during the study period, with 1,817 low birth weight infants (9.6%). The low birth weight infants' prevalence during the period ranged from 9.3 to 9.8%. A total of 1,185 infants with known addresses, compatible with the digital base (65.2% of low birth weight infants), were included. The I(M) for low birth weight was 0.12, with p<0.01; regarding the health centers distribution, I(M) was -0.07, with p=0.01. The Moran map identified 11 census tracts with high priority for intervention by health managers, located in the outskirts of the city. CONCLUSIONS: The spatial analysis identified the low birth weight distribution by census tracts and the sectors with a high priority for intervention. PMID- 24473952 TI - Influence of prematurity and birth weight on the concentration of alpha tocopherol in colostrum milk. AB - OBJECTIVE: To assess vitamin E levels in the breast milk, analyzing the prematurity and the birth weight influence in alpha-tocopherol concentration of colostrum milk. METHODS: Cross-sectional study, in which the colostrum was collected from 93 nursing mothers in a public maternity of Natal, Rio Grande do Norte, Northeast Brazil. The newborns were classified based on gestational age and birth weight. The analysis of alpha-tocopherol in the milk was carried out by high performance liquid chromatography. RESULTS: The alpha-tocopherol concentration in the colostrum of lactating women whose children were born at term was 1,093.6+/-532.4ug/dL; for preterm infants, the concentration was 1,321.6+/-708.5ug/dL (p=0.109). In the preterm group, the alpha-tocopherol concentration in the colostrum of lactating women whose children were born with low and normal birth weight was 1,316.0+/-790.7 and 1,327.2+/-655.0ug/dL, respectively (p=0.971). In the term group, the alpha-tocopherol levels were higher in mothers of children with birth weight >4000g, being 1,821.0+/ 575.4ug/dL, compared to 869.5+/-532.1ug/dL and 1,039.6+/-477.5ug/dL with low and adequate birth weight, respectively (p>0.05). CONCLUSIONS: Prematurity did not influence alpha-tocopherol levels in the colostrum milk. Mothers who had macrossomic term neonates presented increased alpha-tocopherol levels. These results indicate that birth weight can influence alpha-tocopherol leves in the colostrum milk. PMID- 24473953 TI - Evaluation of employees in public day care centers knowledge about breastfeeding and complementary feeding. AB - OBJECTIVE: To evaluate the knowledge of public day care centers employees about breastfeeding and complementary feeding. METHODS: A cross-sectional study was conducted in 15 public day care centers randomly selected in the city of Uberlandia, Southeast Brazil. A questionnaire applied to school principals, teachers, educators and general services assistants (GSA) included demographic and socioeconomic variables and questions about knowledge on breastfeeding, complementary feeding besides employees' perceptions about these subjects. Kruskal-Wallis with multiple comparison and chi-square tests were used to compare variables by professional category. RESULTS: 304 employees participated in the study. The highest percentages of correct answers were noted for questions about exclusive breastfeeding: definition - 97% (n=296) and duration - 65% (n=199). Regarding complementary feeding, 61% (n=187) correctly answered about the appropriate age to introduce it, with a lower percentage for meat (56%; n=170) and sugar (16%; n=50). Concerning employees' perceptions, 9% (n=29) believed that there is weak breast milk, 79% (n=241) and 51% (n=157) reported the negative influence of bottle feeding and pacifier use on breastfeeding. Among the interviewed subjects, 77% (n=234) answered that they had a positive influence on the quality of the food given to the children. There were no differences in the answers according to professional category, except for the negative influence of pacifiers on breastfeeding. CONCLUSIONS: Employees of public day care centers knew more about breastfeeding than about complementary feeding. Educational activities about breastfeeding and complementary feeding are necessary for day care centers employees. PMID- 24473954 TI - Baby-friendly hospital initiative: evaluation of the ten steps to successful breastfeeding. AB - OBJECTIVE: To asses the performance of the Ten Steps to Successful Breastfeeding in an university hospital. METHODS: Descriptive and quantitative research, in which 103 people were interviewed in the outpatient prenatal clinic, in the maternity-ward and in the Neonatal Intensive Care Unit of a university hospital in Vitoria, Southeast Brazil. The "Institutional Self-Evaluation Questionnaire" of the Baby Friendly Hospital Initiative was applied. Using this tool, the outcome was measured by the concordance index (CI) proposed by the World Health Organization and by the United Nations Children's Fund. RESULTS: Although the hospital does not have a policy that addresses promotion, protection and support for breastfeeding, 93.3% of the mothers had contact with their babies immediately after birth (step 4), 83.3% of the professionals guided mothers how to breastfeed (step 5), 86.6% of the neonates did not receive any food or drink other than breast milk (step 6), 100% of babies were housed together with their mothers (step 7), 83.3% of the women were encouraged for breastfeeding on demand (step 8) and 100% of the infants did not use bottles or pacifiers (step 9). CONCLUSIONS: 60% of the steps were completed by the hospital. The greatest difficulty was to inform pregnant women about the importance and the management of breastfeeding (step 3). Therefore, visits to pregnant women are recommended, in order to prepare them for breastfeeding and to explain about the infants' healthy feeding habits. PMID- 24473955 TI - Auditory brainstem response in neonates: influence of gender and weight/gestational age ratio. AB - OBJECTIVE: To investigate the influence of gender and weight/gestational age ratio on the Auditory Brainstem Response (ABR) in preterm (PT) and term (T) newborns. METHODS: 176 newborns were evaluated by ABR; 88 were preterm infants - 44 females (22 small and 22 appropriate for gestational age) and 44 males (22 small and 22 appropriate for gestational age). The preterm infants were compared to 88 term infants - 44 females (22 small and 22 appropriate for gestational age) and 44 males (22 small and 22 appropriate for gestational age). All newborns had bilateral presence of transient otoacoustic emissions and type A tympanometry. RESULTS: No interaural differences were found. ABR response did not differentiate newborns regarding weight/gestational age in males and females. Term newborn females showed statistically shorter absolute latencies (except on wave I) than males. This finding did not occur in preterm infants, who had longer latencies than term newborns, regardless of gender. CONCLUSIONS: Gender and gestational age influence term infants' ABR, with lower responses in females. The weight/gestational age ratio did not influence ABR response in either groups. PMID- 24473956 TI - Atmospheric pollutants and hospital admissions due to pneumonia in children. AB - OBJECTIVE: To analyze the relationship between exposure to air pollutants and hospitalizations due to pneumonia in children of Sorocaba, Sao Paulo, Brazil. METHODS: Time series ecological study, from 2007 to 2008. Daily data were obtained from the State Environmental Agency for Pollution Control for particulate matter, nitric oxide, nitrogen dioxide, ozone, besides air temperature and relative humidity. The data concerning pneumonia admissions were collected in the public health system of Sorocaba. Correlations between the variables of interest using Pearson cofficient were calculated. Models with lags from zero to five days after exposure to pollutants were performed to analyze the association between the exposure to environmental pollutants and hospital admissions. The analysis used the generalized linear model of Poisson regression, being significant p<0.05. RESULTS: There were 1,825 admissions for pneumonia, with a daily mean of 2.5+/-2.1. There was a strong correlation between pollutants and hospital admissions, except for ozone. Regarding the Poisson regression analysis with the multi-pollutant model, only nitrogen dioxide was statistically significant in the same day (relative risk - RR=1.016), as well as particulate matter with a lag of four days (RR=1.009) after exposure to pollutants. CONCLUSIONS: There was an acute effect of exposure to nitrogen dioxide and a later effect of exposure to particulate matter on children hospitalizations for pneumonia in Sorocaba. PMID- 24473957 TI - Manual vibrocompression and nasotracheal suctioning in post-operative period of infants with heart defects. AB - OBJECTIVE: To evaluate the impact of manual vibrocompression and nasotracheal suctioning on heart (hr) and respiratory (rr) rates, peripheral oxygen saturation (SpO(2)), pain and respiratory distress in infants in the postoperative period of a cardiac surgery. METHODS: Randomized controlled trial, in which the assessments were performed by the same physiotherapist in two moments: before and after the procedure. The infants were randomly divided into two groups: Intervention (IG), with manual chest vibrocompression, nasotracheal suctioning and resting; and Control CG), with 30 minutes of rest. Cardiorespiratory data (SpO(2); hr; rr) were monitored and the following scales were used: Neonatal Infant Pain Scale (NIPS), for pain evaluation, and Bulletin of Silverman-Andersen (BSA), for respiratory distress assessment. The data were verified by analysis of variance (ANOVA) for repeated measures, being significant p<0.05. RESULTS: 20 infants with heart disease, ten in each group (seven acyanotic and three cyanotic) were enrolled, with ages ranging from zero to 12 months. In the analysis of the interaction between group and time, there was a significant difference in the variation of SpO(2) (p=0.016), without changes in the other variables. Considering the main effect on time, only rr showed a significant difference (p=0.001). As for the group main effect, there were no statistical differences (SpO(2) - p=0.77, hr - p=0.14, rr - p=0.17, NIPS - p=0.49 and BSA - p=0.51 ). CONCLUSIONS: The manual vibrocompression and the nasotracheal suctioning applied to infants in postoperative of cardiac surgery did not altered SpO(2) and rr, and did not trigger pain and respiratory distress. PMID- 24473958 TI - Lack of difference between continuous versus intermittent heparin infusion on maintenance of intra-arterial catheter in postoperative pediatric surgery: a randomized controlled study. AB - OBJECTIVE: To compare two systems of arterial catheters maintenance in postoperative pediatric surgery using intermittent or continuous infusion of heparin solution and to analyze adverse events related to the site of catheter insertion and the volume of infused heparin solution. METHODS: Randomized control trial with 140 patients selected for continuous infusion group (CIG) and intermittent infusion group (IIG). The variables analyzed were: type of heart disease, permanence time and size of the catheter, insertion site, technique used, volume of heparin solution and adverse events. The descriptive variables were analyzed by Student's t-test and the categorical variables, by chi-square test, being significant p<0.05. RESULTS: The median age was 11 (0-22) months, and 77 (55%) were females. No significant differences between studied variables were found, except for the volume used in CIG (12.0+/-1.2mL/24 hours) when compared to IIG (5.3+/-3.5mL/24 hours) with p<0.0003. CONCLUSIONS: The continuous infusion system and the intermittent infusion of heparin solution can be used for intra arterial catheters maintenance in postoperative pediatric surgery, regardless of patient's clinical and demographic characteristics. Adverse events up to the third postoperative day occurred similarly in both groups. However, the intermittent infusion system usage in underweight children should be considered, due to the lower volume of infused heparin solution [ClinicalTrials.gov Identifier: NCT01097031]. PMID- 24473959 TI - Antioxidant vitamins in the context of nonalcoholic fatty liver disease in obese children and adolescents. AB - OBJECTIVE: To review the literature on the importance of antioxidant vitamins, analyzed in the context of dietary intake, its plasma levels, and its current use as a supplementation treatment in obese children and adolescents with nonalcoholic fatty liver disease. DATA SOURCES: The articles were identified in Lilacs, Ibecs, SciELO, PubMed/Medline, and Scopus databases. To conduct the survey, the "fatty liver" descriptor was associated to the following words: "children", "antioxidants" and "vitamins". The search was limited to articles written in Portuguese, Spanish and English, with publication date until December, 2012. DATA SYNTHESIS: Six studies were selected. The survey revealed a low dietary intake and low antioxidant vitamins serum levels in this population. The changes in lifestyle, with adequate dietary intake of vitamins, and the increase in physical activity were associated with a significant improvement in liver histology and in laboratory tests. Vitamin supplementation also improved the disease progression markers, as the alanine aminotransferase serum levels and the histological characteristics of lobular inflammation and hepatocellular damage. However, these improvements were not statistically significant in all studies. CONCLUSIONS: There is insufficient evidence to recommend or to refute antioxidant supplementation in patients with simple steatosis or steatohepatitis. The changes in lifestyle seem to be, at the present time, the more advisable therapy. PMID- 24473960 TI - Lipoprotein (a) and cardiovascular risk factors in children and adolescents. AB - OBJECTIVE: To review the relationship between lipoprotein (a) [Lp(a)] and other risk factors for cardiovascular disease (CVD) in children and adolescents. DATA SOURCES: This systematic review included studies from 2001 to 2011, a ten-year time period. Epidemiological studies with children and/or adolescents published in English, Portuguese or Spanish and fully available online were included. The searches were performed in Science Direct, PubMed/Medline, BVS (Biblioteca Virtual em Saude) and Cochrane Library databases, using the following combination of key-words: "lipoprotein a" and "cardiovascular diseases" and "obesity". DATA SYNTHESIS: Overall, 672 studies were obtained but only seven were included. Some studies assessed the family history for CVD. In all of them, Lp(a) levels were increased in patients with family history for CVD. There was also a positive correlation between Lp(a) and LDL-cholesterol, total cholesterol, and apolipoprotein B levels, suggesting an association between Lp(a) levels and the lipid profile. CONCLUSIONS: The evidence that CVD may originate in childhood and adolescence leads to the need for investigating the risk factors during this period in order to propose earlier and possibly more effective interventions to reduce morbidity and mortality rates. PMID- 24473961 TI - Prevalence of temporomandibular dysfunction in children and adolescents. AB - OBJECTIVE: To review the prevalence of temporomandibular disorders (TMD) in children and adolescents, verifying the methodological variations. DATA SOURCES: Research conducted in Medline, PubMed, Lilacs and BBO databases, including manuscripts (except reviews and case reports) published from 1990 to 2012. The descriptors were "temporomandibular joint syndrome", "temporomandibular joint dysfunction syndrome", "temporomandibular joint disorders", "prevalence studies", and "cross-sectional studies"; the words "dysfunction", "disorder", "temporomandibular", "children", "adolescents", "prevalence", "frequency", and "transversal" were used. DATA SYNTHESIS: Seventeen articles were selected, and the TMD frequency varied from 16 to 68%. Regarding the methodological criteria, only three articles (18%) reported sample size determination, three (18%) clearly described the sample selection process by stratified selection technique, and nine studies (53%) carried out the calibration of the examiners. The diagnostic criteria used in the studies were: Helkimo index (n=2; 12%), Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) (n=4; 24%), the jaw index (n=1; 6%), clinical protocols (n=10; 59%), and anamnestic questionnaires (n=6; 35%). CONCLUSIONS: The TMD prevalence in children and adolescents varies in the literature. Appropriate and standardized methods are needed to identify, with greater validity, the presence of TMD in this population, allowing a better understanding of the pathological aspects in order to address more effective preventive and therapeutic procedures. PMID- 24473962 TI - Unroofed coronary sinus in a patient with neurofibromatosis type 1. AB - OBJECTIVE: To report the uncommon association between neurofibromatosis type 1 (NF1) and unroofed coronary sinus. CASE DESCRIPTION: Girl with four years and six months old who was hospitalized for heart surgery. The cardiac problem was discovered at four months of life. On physical examination, the patient presented several cafe-au-lait spots in the trunk and the limbs and freckling of the axillary and groin regions. Her father had similar skin findings, suggesting the NF1 diagnosis. The cardiac evaluation by echocardiography disclosed an atrial septal defect of unroofed coronary sinus type. This cardiac finding was confirmed at surgery. The procedure consisted of the atrial septal defect repair with autologous pericardium. COMMENTS: NF1 is a common autosomal dominant disorder caused by mutations in the NF1 gene. Among the NF1 findings, congenital heart defects are considered unusual. In the literature review, there was no association between NF1 and unroofed coronary sinus, which is a rare cardiac malformation, characterized by a communication between the coronary sinus and the left atrium, resultant from the partial or total absence of the coronary sinus roof. It represents less than 1% of atrial septal defect cases. More reports are important to determine if this association is real or merely casual, since NF1 is a common condition. PMID- 24473963 TI - Auditory steady state response in hearing assessment in infants with cytomegalovirus. AB - OBJECTIVE: To report an infant with congenital cytomegalovirus and progressive sensorineural hearing loss, who was assessed by three methods of hearing evaluation. CASE DESCRIPTION: In the first audiometry, at four months of age, the infant showed abnormal response in Otoacoustic Emissions and normal Auditory Brainstem Response (ABR), with electrophysiological threshold in 30dBnHL, in both ears. With six months of age, he showed bilateral absence of the ABR at 100dBnHL. The behavioral observational audiometry was impaired due to the delay in neuropsychomotor development. At eight months of age, he was submitted to Auditory Steady State Response (ASSR) and the thresholds were 50, 70, absent in 110 and in 100dB, respectively for 500, 1,000, 2,000 and 4,000Hz in the right ear, and 70, 90, 90 and absent in 100dB, respectively for 500, 1,000, 2,000 and 4,000Hz in the left ear. COMMENTS: In the first evaluation, the infant had abnormal Otoacoustic Emission and normal ABR, which became altered at six months of age. The hearing loss severity could be identified only by the ASSR, which allowed the best procedure for hearing aids adaptation. The case description highlights the importance of the hearing status follow-up for children with congenital cytomegalovirus. PMID- 24473964 TI - Testis tumor associated to microlithiasis. AB - OBJECTIVE: To discuss the relationship between testicular microlithiasis and testis tumors in children and to consider the chances of testis preserving surgery in specific cases. CASE DESCRIPTION: Pre-adolescent presenting testicular microlithiasis and a larger left testis, corresponding to a cystic testicular tumor. The tumor was excised, with ipsilateral testis preservation. Histology diagnosed a testis dermoid tumor. COMMENTS: The relationship between testis tumors and testicular microlithiasis is ill defined in children. Pediatric urologists need to develop specific follow-up protocols for pre-pubertal children. PMID- 24473965 TI - Reduced corpus-callosum volume in posttraumatic stress disorder highlights the importance of interhemispheric connectivity for associative memory. AB - Memory deficits are a common complaint of patients with posttraumatic stress disorder (PTSD). Despite vivid trauma-related memory, previous studies report memory impairment for nontrauma-related stimuli when compared to controls, specifically in associative memory (Guez et al., 2011). Healthy individuals show hemispheric memory asymmetry with left-prefrontal lateralization of encoding and right-prefrontal lateralization of episodic retrieval, suggesting a role for interhemispheric communication in memory-related tasks (Gazzaniga, ; Ringo, Doty, Demeter, & Simard, ). Because brain magnetic resonance imaging (bMRI) studies in PTSD patients report volume changes in various regions, including white matter and corpus callosum (CC), we aimed to test the relationship between memory deficits and CC volume in PTSD patients. We probed for specific alterations in associative memory in PTSD and measured the volume of subportions within the CC employing bMRI. Our main finding was a reduction in CC white-matter volume in PTSD patients, as compared to controls, t(35) = -2.7, p = .010, that was correlated with lower associative performance (r = .76, p = .003). We propose that CC volume reduction is a substrate for the associative memory deficits found in PTSD. PMID- 24473966 TI - Guidance of post myocardial infarction ventricular septal defect and pseudoaneurysm closure. AB - Left ventricular pseudoaneurysm and ventricular septal defect are rare but devastating complications of myocardial infarction. With medical treatment alone, the majority of patients will die from these complications. Until recently, the recommended treatment was surgical closure. These surgeries carried extreme risk due to abnormal hemodynamics, necrotic substrates and the comorbidities of these patients. Recently, trans-catheter closure was shown to be an acceptable alternative to open surgical intervention. 3D echocardiography identifies the location, size, and shape of the defect and can assess, guide, and follow up the closure procedure. PMID- 24473967 TI - Febrile ulceronecrotic Mucha-Habermann disease in a young boy: a case report and review of the literature. PMID- 24473968 TI - Phloem transport in Ricinus: Its dependence on the water balance of the tissues. AB - Phloem exudation from Ricinus has been examined in plants subjected to changes in water balance induced by a number of means. The results have provided a clear demonstration that the phloem system can operate osmotically. When the availability of water in the xylem is reduced by withholding water, the rate of exudation decreases sharply and this is accompanied by a rise in the sap concentration. On removing the water stress, the rate increases rapidly with a corresponding fall in sap concentration.Small variations in water availability do not give significant results and may be buffered by responses from the plant itself. This could also explain the insignificant changes in sap composition during exudation previously reported, where exudation rate, which should bear some relation to sieve tube turgor pressure, seems independent of sap concentration. Fluctuations in exudation rate are large in comparison with the changes in sap concentration when severe water stresses are applied. This result, coupled with the observation that exudation will occur from plants under considerable water stress suggests the operation of a "sugar pump" capable of maintaining a high turgor pressure at the source against a considerable water potential gradient. The main "pump" is probably located in the leaves.Thus interpreted, the results seem to accord with the Munch pressure flow hypothesis in all significant aspects. PMID- 24473969 TI - The source and lateral transport of growth inhibitors in geotropically stimulated roots of Zea mays and Pisum sativum. AB - The positive geotropic responses of the primary roots of Zea mays and Pisum sativum seedlings depend upon at least one growth inhibiting factor which arises in the root cap and which moves basipetally through the apex into the extending zone. The root apex (as distinct from the cap) and the regions more basal to the extending zone are not sources of growth regulators directly involved in the geotropic response. A difference in the concentration or effectiveness of the inhibitory factor(s) arising in the cap must be established between the upper and lower halves of a horizontal root. Positive geotropic curvature in a horizontal root is attributable, at least in part, to a downward lateral transport of inhibitor(s) from the upper to the lower half of the organ. PMID- 24473970 TI - Emerson enhancement of carbon fixation but not of acetylene reduction (nitrogenase activity) in Anabaena cylindrica. AB - Enhancement of carbon fixation was demonstrated in the bluegreen alga, Anabaena cylindrica, grown in either aerobic or microaerobic conditions. Under identical conditions no enhancement of acetylene reduction was observed. Light absorbed by photosystem I supported relatively more acetylene reduction than carbon fixation. No competition between the two processes was observed under light-limiting conditions. The findings suggest that carbon fixation and acetylene reduction may depend on different pools of reductant and ATP. When aerobically grown cells were placed in the dark or at limiting light intensities, acetylene reduction was higher in air than under argon. In contrast, carbon fixation was lower in air than in argon. PMID- 24473971 TI - Fine structural observations on the epidermis : II. the cuticle. AB - In species of Apium, Eryngium and Humulus, the cuticular membrane of the petiole could be resolved into two parts, of which the inner one appeared amorphous and after staining appeared to be penetrated by an electron-dense reticulum, whereas the outer layer showed a lamellate structure consisting of electron-dense and electron-transparent plates, 50-80 A in thickness. These layers are considered to correspond with the cuticular layer and the cuticle proper, respectively. In species of Abutilon and Rumex the cuticle proper did not exhibit the lamellate structure. In the leaves of Eryngium the outer lamellated structure was present in the cuticle of both young and mature leaves. Both the lamellate and non lamellate types of the cuticle proper increased in thickness with age of the specimen. The results are discussed in relation to earlier investigations. PMID- 24473972 TI - Uptake of mercury by Chlorella and its effect on potassium regulation. AB - Addition of mercuric chloride at concentrations which resulted in an overall binding level of about 8 mmoles Hg/l packed cells and above caused a breakdown in the permeability of the cell membrane as indicated by a net efflux of internal K(+). Below this level in region of 2 mmoles Hg/l packed cells the rate of K(+) transfer across the cell surface was stimulated without affecting the internal K(+) level. Maintainence of the stimulation was dependent both on time and dose. Enhancement of the rate of K(+) turnover was associated with a fast component of the inorganic mercury uptake which could be removed by washing with cysteine. The mercury stimulated K(+)/K(+) exchange was inhibited by low temperature, by the uncoupler CCCP and the energy transfer inhibitor DCCD. Overall binding concentrations of inorganic mercury below 0.5 mmoles/l packed cells had no effect on the K(+) transport system. In contrast to mercuric chloride, methyl mercuric chloride over similar concentration ranges did not seem to induce a breakdown in the permeability barrier or directly interact with the K(+)/K(+) exchange but more likely influenced the latter by inhibiting intracellular processes. PMID- 24473973 TI - Protein bodies, lipid layers and amyloplasts in freeze-etched pea cotyledons. AB - Freeze-etching and thin-sectioning techniques have been used to study the structure of storage parenchyma cells of pea cotyledons in mature, air-dry seeds and in seeds after various periods of imbibition. Protein bodies in air-dry tissue were coated with a complex of convoluted structure, apparently rich in lipid. After brief periods of hydration this complex appeared to have expanded and to consist of a system of tubules, and after 24 h imbibition it was no longer associated with the protein bodies. Sheets of lipid bodies were associated with amyloplast surfaces and the plasmalemma. In non-imbibed tissue, the cell walls were wavy, but in imbibed tissue they were smooth. The amyloplast-envelope membranes characteristically had areas with parallel folds, and membrane particles of protein-body envelopes were occasionally aligned in orderly rows. PMID- 24473974 TI - Ion exchange properties of isolated tomato fruit cuticular membrane: Exchange capacity, nature of fixed charges and cation selectivity. AB - Isolated tomato fruit cuticular membrane, free of extractable materials, was titrated potentiometrically using various bases. Three dissociable groups were observed in the pH ranges 3-6 (0.2 meq g(-1)), 6-9 (0.3 meq g(-1)) and 9-12 (0.55 meq g(-1)). The first group was tentatively assigned to-COOH groups of pectic materials and protein embedded in the membrane, the second to nonesterified-COOH groups of the cutin polymer and the third to phenolic-OH groups, such as non extractable flavenoids present in the membrane, and to a small amount of-NH 3 (+) groups of proteins. The cuticular membrane exhibited a behavior typical of highly cross-linked, high-capacity ion exchange resins of the weak-acid type. Ion exchange capacity increased with increasing pH and neutral salt concentration. At constant pH and salt concentration, the exchange capacity increased with increasing counter ion valence and decreasing crystal radius, e.g. [tris (ethylenediamine) Co](3+)>=Ca(2+)>Ba(2+)>Li(+)>Na(+)>Rb(+)>N(CH3) 4 (+) . The cutin polymer exhibited a pronounced selectivity for Ca(2+) over Na(+) which increased with increasing neutralization of fixed charges. The large trivalent [Co(en)3](3+) was preferred only at low equivalent ionic fractions in the polymer. These results are discussed in relation to the structure and function of cuticular membranes. PMID- 24473975 TI - Abscisic-acid content of xylem sap. AB - Abscisic acid (ABA) has been identified by gas chromatography in xylem sap of the woody species apple, peach, willow, sugar maple, Tecomaria capensis and Actinidia chinensis. The amounts of ABA present in each species are markedly different, varying from 9 to over 1000 ng/100 ml of sap. PMID- 24473976 TI - Photonic crystals for chemical sensing and biosensing. AB - This Review covers photonic crystals (PhCs) and their use for sensing mainly chemical and biochemical parameters, with a particular focus on the materials applied. Specific sections are devoted to a) a lead-in into natural and synthetic photonic nanoarchitectures, b) the various kinds of structures of PhCs, c) reflection and diffraction in PhCs, d) aspects of sensing based on mechanical, thermal, optical, electrical, magnetic, and purely chemical stimuli, e) aspects of biosensing based on biomolecules incorporated into PhCs, and f) current trends and limitations of such sensors. PMID- 24473977 TI - Electrical conditioning of adipose-derived stem cells in a multi-chamber culture platform. AB - In tissue engineering, several factors play key roles in providing adequate stimuli for cells differentiation, in particular biochemical and physical stimuli, which try to mimic the physiological microenvironments. Since electrical stimuli are important in the developing heart, we have developed an easy-to-use, cost-effective cell culture platform, able to provide controlled electrical stimulation aimed at investigating the influence of the electric field in the stem cell differentiation process. This bioreactor consists of an electrical stimulator and 12 independent, petri-like culture chambers and a 3-D computational model was used to characterize the distribution and the intensity of the electric field generated in the cell culture volume. We explored the effects of monophasic and biphasic square wave pulse stimulation on a mouse adipose-derived stem cell line (m17.ASC) comparing cell viability, proliferation, protein, and gene expression. Both monophasic (8 V, 2 ms, 1 Hz) and biphasic (+4 V, 1 ms and -4 V, 1 ms; 1 Hz) stimulation were compatible with cell survival and proliferation. Biphasic stimulation induced the expression of Connexin 43, which was found to localize also at the cell membrane, which is its recognized functional mediating intercellular electrical coupling. Electrically stimulated cells showed an induced transcriptional profile more closely related to that of neonatal cadiomyocytes, particularly for biphasic stimulation. The developed platform thus allowed to set-up precise conditions to drive adult stem cells toward a myocardial phenotype solely by physical stimuli, in the absence of exogenously added expensive bioactive molecules, and can thus represent a valuable tool for translational applications for heart tissue engineering and regeneration. PMID- 24473979 TI - Dietary supplements and recent controversy. PMID- 24473978 TI - Case of primary diffuse leptomeningeal gliomatosis. AB - Primary diffuse leptomeningeal gliomatosis (PDLG) is a rare and fatal disease characterized by diffuse infiltration of the leptomeninges by neoplastic glial cells without evidence of tumor in the brain parenchyma or spinal cord. We report a 60-year-old man with PDLG. He suffered transient right hemiparesis and generalized seizures. MRI showed diffuse leptomeningeal thickening and enhancement throughout the brain and spinal cord without any intraaxial involvement. Biopsy resulted in a diagnosis of glioblastoma with methylated MGMT promoter and wild-type IDH1. He underwent craniospinal radiotherapy and temozolomide treatment but despite concomitant adjuvant therapy he died 8 months after initial presentation. PMID- 24473980 TI - Zonulin! The wheat conundrum solved (well, mostly ...). PMID- 24473981 TI - Federally-funded analysis attempts to undermine vitamin and mineral supplements. PMID- 24473982 TI - Mitochondrial dysfunction and chronic disease: treatment with natural supplements. AB - Loss of function in mitochondria, the key organelle responsible for cellular energy production, can result in the excess fatigue and other symptoms that are common complaints in almost every chronic disease. At the molecular level, a reduction in mitochondrial function occurs as a result of the following changes: (1) a loss of maintenance of the electrical and chemical transmembrane potential of the inner mitochondrial membrane, (2) alterations in the function of the electron transport chain, or (3) a reduction in the transport of critical metabolites into mitochondria. In turn, these changes result in a reduced efficiency of oxidative phosphorylation and a reduction in production of adenosine-5'-triphosphate (ATP). Several components of this system require routine replacement, and this need can be facilitated with natural supplements. Clinical trials have shown the utility of using oral replacement supplements, such as L-carnitine, alpha-lipoic acid (alpha-lipoic acid [1,2-dithiolane-3 pentanoic acid]), coenzyme Q10 (CoQ10 [ubiquinone]), reduced nicotinamide adenine dinucleotide (NADH), membrane phospholipids, and other supplements. Combinations of these supplements can reduce significantly the fatigue and other symptoms associated with chronic disease and can naturally restore mitochondrial function, even in long-term patients with intractable fatigue. PMID- 24473983 TI - Mitochondrial medicine arrives to prime time in clinical care: nutritional biochemistry and mitochondrial hyperpermeability ("leaky mitochondria") meet disease pathogenesis and clinical interventions. PMID- 24473984 TI - A complex of three natural anti-inflammatory agents provides relief of osteoarthritis pain. AB - BACKGROUND: Devil's claw (Harpagophytum procumbens), turmeric (Curcuma longa), and bromelain are nutraceuticals that have demonstrated anti-inflammatory and analgesic properties and may be potential solutions in the treatment of acute or chronic joint pain. Their analgesic effect, however, is generally considered mild to moderate, and the relevance of their clinical use remains subject to discussion. OBJECTIVES: The aim of the study was to evaluate the clinical relevance of the efficacy of a marketed complex of 3 plant extracts-H procumbens, C longa, and bromelain (AINAT, 650 mg)-in the treatment of degenerative joint pain. METHODS: A multicenter, observational, prospective, open-label survey was conducted in 8 rheumatology centers. The study included 2 groups, 1 group with participants suffering from chronic osteoarthritis (OA) pain and 1 group suffering from acute OA pain. SETTING: The research team carried out the study under daily practice conditions. PARTICIPANTS: A total of 42 patients (36 women; mean age = 67 y) suffering from acute or chronic, degenerative spine or joint pain participated. INTERVENTION: Two 650-mg capsules of AINAT were administered 3 */d to patients with acute pain and 2 */d to patients with chronic pain. OUTCOME MEASURES: At baseline, and during a follow-up visit at 15 d for the acute pain group and 60 d for the chronic pain group, the research team obtained each participant's global assessment (PGA) and each rheumatologist's global assessment (RGA), as well as each participant's pain score, using for each of them a 100-mm visual analogue scale (VAS). The clinical relevance of the efficacy was evaluated by comparing the outcome measures at endpoint to the values defining the patient acceptable symptom state (PASS) and by comparing the variations (in mm and %) between baseline and endpoint to those defining the minimal clinically important improvement (MCII). Tolerance was also assessed by collecting adverse events at each visit and by using a 4-point scale (very good to bad) at the endpoint. RESULTS: At baseline, the VAS pain score (standard deviation) was 69.1 mm (15.4) and 68.0 mm (18.2) for patients with acute and chronic pain, respectively. At the endpoint, the scores decreased to 42.1 mm (21.1) and 37.8 mm (25.9), respectively. This reduction of pain, as a percentage as well as an absolute value, corresponds to the required definition of MCII, particularly in patients with chronic joint pain. At the endpoint, most of the patients in both groups reached the level of pain defined as the PASS. No withdrawals occurred due to treatment side effects. CONCLUSION: The improvement of joint pain was clinically relevant in patients treated with AINAT for both acute and chronic OA pain. Considering its excellent tolerance profile, the tested complex of 3 plant extracts with antiinflammatory properties may be a valuable and safe alternative to NSAIDs in patients suffering from degenerative joint diseases. PMID- 24473985 TI - Soy foods and supplementation: a review of commonly perceived health benefits and risks. AB - In recent years, the impact of soy foods and supplements upon human health has become increasingly controversial among the general public. No one has conducted a broad evaluation of the scientific evidence supporting or refuting popular perceptions of the health effects of soy consumption. In this article, the authors have conducted a comprehensive assessment of the literature surrounding the health effects of soy consumption that are of greatest interest. This review has focused on 5 health benefits- relief of menopausal symptoms and prevention of heart disease, breast cancer, prostate cancer, and osteoporosis, and 5 health risks-increased risk of breast cancer, male hormonal and fertility problems, hypothyroidism, antinutrient content, and harmful processing by-products. Systematic reviews of human trials, prospective human trials, observational human studies, animal models, in vitro studies, and laboratory analyses of soy components were included for review. This literature review revealed that soy foods and isoflavones may provide relief from menopausal symptoms and protect against breast cancer and heart disease. Soy does not appear to offer protection against osteoporosis. The evidence on male fertility and reproductive hormones was conflicting; some studies demonstrated a deleterious impact caused by soy consumption and others showed no effect. Soy supplementation also appears to affect thyroid function in an inconsistent manner, as studies have shown both increases and decreases in the same parameters of thyroid activity. Soaking, fermentation, and heating may reduce problematic antinutrients contained in soy. The authors found that consuming moderate amounts of traditionally prepared and minimally processed soy foods may offer modest health benefits while minimizing potential for adverse health effects. However, additional studies are necessary to elucidate the variable thyroid response to soy supplementation, and more rigorous studies are required to assess dose-response relationships, the relationship between intestinal-flora composition and the response to soy, potential fertility issues among males, and the unknown long-term health effects of consuming highly processed modern soy foods. PMID- 24473986 TI - Probiotics in the prevention of recurrences of bacterial vaginosis. AB - CONTEXT: Bacterial vaginosis (BV) is the most common cause of vaginal discharge in women during their fertile years. BV prevalence runs from 10%-50%, in part due to the high rate of recurrence after standard treatment. Women with BV may experience a decreased quality of life and are at risk of serious obstetric complications. Limited data are available regarding optimal management strategies for preventing recurrence of BV, emphasizing the importance of the availability of a comprehensive source of scientific information and therapeutic strategies. OBJECTIVE: The aim of this study was to evaluate the frequency and clinical relevance of the recurrence of BV and to collect and review data about prophylactic approaches based on probiotic supplementation with lactobacilli (LB). METHODS: A review of the literature was performed, based on combinations of the following keywords: bacterial vaginosis, bacterial vaginosis recurrences, vaginal discharge, vaginal flora, LB, Lactobacillus rhamnosus, and probiotic supplementation. OUTCOME MEASURES: The studies were evaluated in terms of the cure rates for BV, incidence of recurrence of BV, decrease in patients' discomfort, maintenance of a healthy vaginal recolonization, and occurrence of complications and side effects. RESULTS: Recurrence of BV after standard therapy is a relevant clinical problem, with an incidence of 30%-40% and a significant impact on women's quality of life and on their risk of infrequent but serious obstetric complications. Therefore, finding effective prophylactic therapies to avoid or decrease the recurrence of BV is important. Even when they are effective, typical antibacterial regimens for long-term maintenance are known to have side effects. Different schemes of treatment with exogenous LB have proven effective in preventing recurrence of BV, even in patients at high risk for relapse. CONCLUSIONS: Probiotic supplementation with vaginal LB proved to be crucial in hindering bacteria growth after antibiotic therapy; therefore this intervention may be considered a new adjuvant treatment for preventing recurrence of BV, even in high-risk patients. PMID- 24473987 TI - Human microbiome and nutrition: untapped clinical potential awaits. PMID- 24473988 TI - Kelly C. Heim, PhD: Effects of the gut microbiome on cardiovascular health. PMID- 24473989 TI - Photodynamic antimicrobial effect of safranine O on an ex vivo periodontal biofilm. AB - BACKGROUND AND OBJECTIVE: The increasing resistance of oral pathogens against antibiotic measures urgently requires new therapeutic strategies. In this context, antimicrobial photodynamic therapy (aPDT) may play a crucial part in the future. The aim of the present study was to compare the antibacterial efficiency of aPDT using the photosensitizer safranine O with that of chlorhexidine (0.2% CHX) on an ex vivo biofilm. METHODS: First the antibacterial activity of both measures against planktonic cultures of Streptococcus gordonii ATCC 33399, Streptococcus mutans ATCC 25175, Fusobacterium nucleatum ATCC 10953, Aggregatibacter actinomycetemcomitans ATCC 33384 and Porphyromonas gingivalis ATCC 33277 was observed. Then a patient specific ex vivo biofilm was established from plaque and saliva samples of patients (n = 19) with chronic periodontitis. The antibacterial effects of aPDT and of 0.2% CHX were determined on the ex vivo biofilms cultivated for 24 and 72 hours. After cultivation of the treated samples on blood agar (2 days) the results were quantified by counting the colony forming units (cfu/ml). RESULTS: Photodynamic treatment with safranine O showed a distinct antibacterial effect on F. nucleatum and P. gingivalis. Whereas S. gordonii was suppressed completely by aPDT, treatment with 0.2% CHX caused only a partial reduction. In the ex vivo biofilm model (24-hour biofilm), aPDT caused a significantly higher bacterial killing than treatment with 0.2% CHX. Compared to the untreated control, there was no significant difference on the 72-hour biofilm for both methods. CONCLUSIONS: The results show that oral-pathogenic species in planktonic solution can be suppressed significantly by aPDT with safranine O. Especially for bacteria in a 24-hour ex vivo biofilm, this method is more effective than treatment with 0.2% CHX. Both antibacterial treatments did not show any significant effect on the biofilm cultivated for 72 hours. PMID- 24473990 TI - The relationship between body mass index and health-related quality of life in urban disadvantaged children. AB - INTRODUCTION: The study's aim was to establish, for children living in urban disadvantage, the nature and extent of the relationship between body mass index (BMI) and health-related quality of life (HRQoL), including the role of individual and family factors in influencing this relationship. METHODS: Within the context of a longitudinal design, 255 children aged 7-12 years (50 % male) self-reported their HRQoL (Kidscreen-27) and had their height and weight measured at year one and two. One parent/guardian for each child was also assessed at year one with the OSLO Social Support Scale and Hospital Anxiety and Depression Scale. Regression analysis was also conducted. RESULTS: BMI was weakly inversely associated with 'total HRQoL' (r = -.15, p < .05), 'physical well-being' and 'autonomy and parent relations'. Significant differences were found between normal weight and obese children on all but the latter dimension. Neither weight group, however, fell below the average European HRQoL range. BMI predicted physical well-being a year later and vice versa, whilst autonomy and parent relations also predicted BMI a year later. In terms of 'overweight' children (38 %), those approaching adolescence had poorer physical and school well-being than younger children, and those whose parents had moderate-to-severe levels of depression fared worse on school well-being than children whose parents were not depressed. CONCLUSION: The findings suggest that obesity programmes could aim to prevent/reduce obesity and optimise HRQoL in urban disadvantaged preadolescent children whilst also targeting parental mental health difficulties. Future research should examine mediators of the effect of BMI on HRQoL. PMID- 24473991 TI - New syngeneic inflammatory-related lung cancer metastatic model harboring double KRAS/WWOX alterations. AB - New mouse models with specific drivers of genetic alterations are needed for preclinical studies. Herein, we created and characterized at the genetic level a new syngeneic model for lung cancer and metastasis in Balb-c mice. Tumor cell lines were obtained from a silica-mediated airway chronic inflammation that promotes tumorigenesis when combined with low doses of N-nitrosodimethylamine, a tobacco smoke carcinogen. Orthotopic transplantation of these cells induced lung adenocarcinomas, and their intracardiac injection led to prominent colonization of various organs (bone, lung, liver and brain). Driver gene alterations included a mutation in the codon 12 of KRAS (G-A transition), accompanied by a homozygous deletion of the WW domain-containing oxidoreductase (WWOX) gene. The mutant form of WWOX lacked exons 5-8 and displayed reduced protein expression level and activity. WWOX gene restoration decreased the in vitro and in vivo tumorigenicity, confirming the tumor suppressor function of this gene in this particular model. Interestingly, we found that cells displayed remarkable sphere formation ability with expression of specific lung cancer stem cell markers. Study of non-small-cell lung cancer patient cohorts demonstrated a deletion of WWOX in 30% of cases, with significant reduction in protein levels as compared to normal tissues. Overall, our new syngeneic mouse model provides a most valuable tool to study lung cancer metastasis in balb-c mice background and highlights the importance of WWOX deletion in lung carcinogenesis. PMID- 24473992 TI - Collagen microstructure in the vocal ligament: initial results on the potential effects of smoking. AB - OBJECTIVES/HYPOTHESIS: This investigation quantitatively characterizes the collagenous microstructure of human vocal ligament specimens excised postmortem from nonsmokers and smokers. STUDY DESIGN: Retrospective cohort study. METHODS: Second harmonic generation (SHG) imaging was performed at three anatomical locations of vocal ligament specimens: anterior, mid-membranous, and posterior regions. Two microstructural parameters were extracted from the SHG images: (1) normalized fiber density, and (2) fiber dispersion coefficient, quantifying the degree of collagen fiber dispersion about a preferred direction. RESULTS: For both the nonsmoker and smoker subjects, the fiber dispersion coefficient was heterogeneous. Differences in the collagenous structure of nonsmokers and smoker subjects were pronounced at the mid-membranous location. However, the directionality of the heterogeneity in the smoker subjects was opposite to that in the nonsmoker subjects. Specifically, the fiber dispersion coefficient in the nonsmoker subjects was lower in the mid-membranous region (indicating more fiber alignment) than at the anterior/posterior regions, but for the smoker subjects the fiber dispersion coefficient was higher at the mid-membranous region. The normalized fiber density was near constant in the nonsmoker subjects, but the smoker subjects had fewer fibers in the mid-membranous region than at the anterior/posterior regions. CONCLUSION: Spatial microstructural variations may exist in the vocal fold ligament both in nonsmokers and smokers. Smoking appears to influence the degree and direction of microstructure heterogeneity in the vocal fold ligament. PMID- 24473993 TI - Proteomic identification of responsive proteins of Vibrio parahaemolyticus under high hydrostatic pressure. AB - BACKGROUND: High hydrostatic pressure (HHP) processing is currently being used as a treatment for certain foods to inhibit spoilage organisms and control the presence of foodborne pathogens. In this study proteome profiles were performed by two-dimensional gel electrophoresis (2-DE) coupled with MALDI-TOF/TOF identification to determine the effects of HHP (50, 100, 150 and 200 MPa, each for 10 min) on Vibrio parahaemolyticus ATCC 17802 (~8 log CFU mL-1) in order to understand how it responds to mechanical stress injury. RESULTS: Multiple comparisons of 2-DE revealed that the majority of changes in protein abundance occurred in a pressure-dependent fashion. A total of 18 differentially expressed protein spots were successfully identified by MALDI-TOF/TOF analysis. Moreover, quantitative RT-PCR and immunoblotting also substantiated the changes of transcriptional and translational levels of representative proteins. CONCLUSIONS: Our results suggested that V. parahaemolyticus may respond to HHP treatment through suppression of membrane stability and functionality (PfaC, Alr2, MltA, PLA2 and PatH), depression of biosynthesis and cellular processes (NadB, PyrB and ArgB), decreased levels of transcription (RpoD) and translation (RpsA, RplJ and PheS), and effective activation of protein folding and stress-related elements (GroES, DnaK and GroEL). This study may provide insight into the nature of the cellular targets of high pressure and in high-pressure resistance mechanisms in V. parahaemolyticus. PMID- 24473995 TI - Chronic and slowly progressive weakness of the legs and hands. PMID- 24473994 TI - MRI of anterior knee pain. AB - Anterior knee pain is the most common knee complaint. It may be due to a variety of soft tissue or osseous abnormalities. Knowledge of the radiologic appearance of the abnormalities allows more accurate diagnosis of the cause of the pain including chondral abnormalities, patellar instability and dislocation, femoral trochlear dysplasia, abnormal patellar location, bipartite patella, various tendinopathies, bursal inflammation, traction apophysitis in pediatric and adolescent patients, and miscellaneous diseases including mediopatellar plica syndrome and Hoffa's disease. Radiographs are often obtained to exclude acute osseous abnormalities, such as fractures. Magnetic resonance (MR) imaging offers superior soft tissue contrast resolution and allows for more accurate evaluation of the underlying etiology and therefore may improve treatment and possible surgical planning. PMID- 24473996 TI - Oncologic PET/CT interpretation and reporting approaches. Survey in clinical practice. AB - AIM: To elucidate techniques most commonly used for interpreting oncologic PET/CT studies. This survey forms a basis to work on standardization of reporting and highlight the most important issues to be addressed. METHODS: A web-based survey of 329 PET/CT imaging specialists was designed with the intent to determine image interpretation patterns. The questionnaire consisted of 19 questions. Of the 329 participants, 230 were nuclear medicine specialists, 46 were radiologists, and 53 had dual-board certification. RESULTS: Report ofstandardized uptake values (SUV) is not consistent;only50.2% of respondents always report SUVs, while 45.2% report only if needed or requested. 80.9% of respondents indicated that reporting of SUV is only appropriate when its limitations are understood whereby a large majority prefer to report SUVmax. Maximum intensity projection (MIP) images are almost always reviewed by 91.1% of the respondents. An accurate and detailed clinical history is considered an essential element for reading PET/CT studies by 84.0%, but only 20.7% report that this is always available. The most common self reported average time for reviewing and reporting of whole body PET/CT (with no prior comparison scan) was 15-20 min (27.5%). CONCLUSION: PET readers have considerable reservations regarding the use and reporting of SUVs. SUVmax is more frequently used than SUVmean. Evaluation of MIP images is considered an important element of PET/CT interpretation. Although availability of sufficient patient's history is considered essential, this is rarely available. PMID- 24473997 TI - Controversy over clinical guidelines: listen to the evidence, not the noise. PMID- 24473998 TI - Unsustained complete response of less than 24 months after autologous stem cell transplantation predicts aggressive myeloma with short survival. AB - Complete response (CR) predicts superior survivals in myeloma. To define the impact of duration of CR posttransplantation on survivals, 71 myeloma patients, who underwent an intended early (a staged approach) or frontline use of bortezomib-based induction, followed by autologous stem cell transplantation (ASCT) were studied. Achievement of CR was assessed every 4-weekly until maximal response after ASCT and then 6-weekly thereafter. All patients had follow-up time of >=24 months from time of best response, of whom 27 failed to attain CR (non CR) whereas 44 achieved CR. At 12, 18 and 24 months post-ASCT, 3 (4.2%), 6 (8.4%) and 11 (15.4%) patients lost CR, respectively, with maximal survival difference observed in the group with CR durations of >=24 or <24 months. Patients with unsustained CR had survival inferior to those never achieving CR (p = 0.05). Unsustained CR of <24 months was associated with international staging system stage III (p = 0.007) and shorter postrelapse survival (p < 0.001). Both overall survival and event-free survival were superior in myeloma patients with CR of >=24 months (p < 0.001). In multivariate analysis, international staging system stage I/II, CR/nCR post-ASCT and CR duration of >=24 months remained favourable prognostic factors for both overall survival and event-free survival. In conclusion, CR of <24 months is an independent adverse risk factor for survival with a short postrelapse survival. PMID- 24473999 TI - [Housing Project 'Living Independently with Intensive Support (WmI)': Home-based Long Term Care and Social Support for Individuals with Severe Multiple Handicaps]. PMID- 24474000 TI - [Housing Project 'Living Independently with Intensive Support (WmI)': The Scientific Evaluation]. AB - BACKGROUND: In Germany, people with multiple severe disabilities caused by brain injuries, are predominantly cared for in permanent residential living facilities. In 2009 the Furst Donnersmarck Foundation (FDSt) launched a new housing project - supported living accommodations (SLA) - for this group of people. Residents from a permanent residential living facility (Furst Donnersmarck House, FDH) are offered the opportunity to move into 2 newly built SLA with a 24/7 individual support of a social pedagogic staffs as well as nursing care. The aim of the study is to compare the changes of residents' social and health related outcomes in the SLA group as compared to the group remaining in stationary care. METHODS: In a prospective longitudinal study (2009-2011) residents of the FDH are surveyed using standardized self- and proxy-rating instruments. Times of measurement are shortly before moving into the SLA (baseline, t1) and at follow-up after 6, 12 and 18 months after relocation (t2-t4). Additionally to residents' socio demographic data, health outcomes including ADL functioning (EBI), quality of life (WHOQoL-Bref, EQ-5D), need of assistance (HMB-W), social inclusion/perceived disability (WHODAS II), anxiety and depression (HADS) and social contacts were evaluated. RESULTS: 40 residents could be included into the study, 29 of them moved into 2 SLA. The underlying neurological causes of the handicap were mainly sequelae of acuired damage of the central nervous system during adult age. Residents are on average 46.2 years old and predominantly male (65%). During the study the perceived dis-ability (WHODAS II) increased statistically significant but we could not show differences between groups (p > 0.05). Changes in functional and cognitive everyday abilities, fear, depression and quality of life (WHOQoL-Bref, EQ-5D) could not be shown (p > 0.05). The perceived sense of mastery (Pearlin Mastery Scale) increased statistically significant and showed more positive developments by tendency in SLA. Everyday activities in SLA increased to a large extent. CONCLUSION: Some positive but no overall effects of moving into SLA can be shown. It is remarkable that the serious changes of living conditions do not lead to less QoL or more anxiety in this vulnerable group of people but resulted in increasing external contacts and greater mobility. Social pedagogic support offers the residents the chance to bear a more self-determined life and to participate actively in new social networks. PMID- 24474001 TI - [Housing Project 'Living Independently with Intensive Support (WmI)':Participants, their Handicaps, their Involvement and their Opinion]. AB - After a short introduction an overview of the inhabitants' handicaps is given. The inhabitants changed from inpatient care into a home-based care. Original quotations show how persons with disabilities perceived their new living situation. Additionally, it is shown in which manner these persons are involved in the scientific study. The experiences with the home-based long term care and the participation in the study are positive and indicate that self-determination is effectively supported by the living project. PMID- 24474002 TI - [Housing Project 'Living Independently with Intensive Support (WmI)': The View of Foundation and Staff]. AB - The Furst Donnersmarck-Foundation (FDSt) initiated the housing projekt 'Living Independently with Intensive Support (WmI)' to show that such a concept is feasible even with persons with severe multiple handicaps. It is reported how financial, organisational and communicative problems can be solved. Overall, the housing project is not much more expensive than inpatient concepts, but a change of traditional concepts of administration was required. The new service mode presupposed a careful preparation and high motivation of the staff. Finally, existing discrepancies between traditional and modern concepts could be resolved. PMID- 24474003 TI - [Experience and recommendations of the advisory board concerning the project 'living independently with intensive support (wml)']. PMID- 24474005 TI - Latent tuberculosis: the snake inside the egg. PMID- 24474004 TI - Physical activity predicts microstructural integrity in memory-related networks in very old adults. AB - BACKGROUND: Although the beneficial effects of physical activity (PA) on memory and executive function are well established in older adults, little is known about the relationship between PA and brain microstructure and the contributions of physical functional limitations and chronic diseases. This study examined whether higher PA would be longitudinally associated with greater microstructural integrity in memory- and executive function-related networks and whether these associations would be independent of physical function and chronic diseases. METHODS: Diffusion tensor imaging was obtained in 2006-2008 in 276 participants (mean age = 83.0 years, 58.7% female, 41.3% black) with PA (sedentary, lifestyle active, and exercise active) measured in 1997-1998. Gait speed, cognition, depressive symptoms, cardiovascular and pulmonary diseases, hypertension, stroke, and diabetes were measured at both time points. Mean diffusivity and fractional anisotropy were computed from normal-appearing gray and white matter in frontoparietal and subcortical networks. Moderating effects of physical function and chronic diseases were tested using hierarchical regression models. RESULTS: Compared with the sedentary, the exercise active group had lower mean diffusivity in the medial temporal lobe and the cingulate cortex (beta, p values: -.405, .023 and -.497, .006, respectively), independent of age, sex, and race. Associations remained independent of other variables, although they were attenuated after adjustment for diabetes. Associations between PA and other neuroimaging markers were not significant. CONCLUSIONS: Being exercise active predicts greater memory related microstructural integrity in older adults. Future studies in older adults with diabetes are warranted to examine the neuroprotective effect of PA in these networks. PMID- 24474006 TI - Treatment of American tegumentary leishmaniasis in special populations: a summary of evidence. AB - We aimed to assess and synthesize the information available in the literature regarding the treatment of American tegumentary leishmaniasis in special populations. We searched MEDLINE (via PubMed), EMBASE, LILACS, SciELO, Scopus, Cochrane Library and mRCT databases to identify clinical trials and observational studies that assessed the pharmacological treatment of the following groups of patients: pregnant women, nursing mothers, children, the elderly, individuals with chronic diseases and individuals with suppressed immune systems. The quality of evidence was assessed using the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach. The available evidence suggests that the treatments of choice for each population or disease entity are as follows: nursing mothers and children (meglumine antimoniate or pentamidine), patients with renal disease (amphotericin B or miltefosine), patients with heart disease (amphotericin B, miltefosine or pentamidine), immunosuppressed patients (liposomal amphotericin), the elderly (meglumine antimoniate), pregnant women (amphotericinB) and patients with liver disease (no evidence available). The quality of evidence is low or very low for all groups. Accurate controlled studies are required to fi ll in the gaps in evidence for treatment in special populations. Post-marketing surveillance programs could also collect relevant information to guide treatment decision-making. PMID- 24474007 TI - Medium-term cryopreservation of rabies virus samples. AB - INTRODUCTION: The cryopreservation of rabies virus has been described in detail in the literature. To date, little information is available on the use of cryoprotective agents for cold preservation of this virus, and the available data focus only on short-term virus preservation. In this study, we investigated the medium-term cryopreservation of samples of rabies virus using different cryopreservation protocols. METHODS: The cryopreservation protocols for the rabies virus samples were performed at -20 degrees C and were divided according to the variables of time and cryoprotectant type used. The laboratory tests (intracerebral inoculation of mice, viral titration and direct immunofluorescence) were performed at regular intervals (360 and 720 days) to assess the viability of the viral samples according to the different preservation techniques used. RESULTS: After 1 year of cryopreservation, the fluorescence intensity of intracellular corpuscles of the rabies virus and the median survival time of the mice differed between the positive controls and the treatments with the cryoprotectants. After 2 years, most of the samples subjected to the cryopreservation protocols (including the controls) did not produce fluorescence. However, the virus samples exposed to the cryoprotectant sucrose (68% solution) responded positively in the direct immunofluorescence assay and in the intracerebral inoculation of the mice. CONCLUSIONS: Medium-term cryopreservation of the rabies virus inactivates the viral sample. However, the cryoprotectant agent sucrose (68%) produces a preservative effect in cryopreserved rabies virus samples. PMID- 24474008 TI - Detection of arboviruses of public health interest in free-living New World primates (Sapajus spp.; Alouatta caraya) captured in Mato Grosso do Sul, Brazil. AB - INTRODUCTION: A sero-epidemiological survey was undertaken to detect the circulation of arboviruses in free-living non-human primates. METHODS: Blood samples were obtained from 16 non-human primates (13 Sapajus spp. and three Alouatta caraya) that were captured using terrestrial traps and anesthetic darts in woodland regions in the municipalities of Campo Grande, Aquidauana, Jardim, Miranda and Corumba in the State of Mato Grosso do Sul, Brazil. The samples were sent to the Instituto Evandro Chagas (IEC) in Ananindeua, Para, Brazil, to detect antibodies against 19 species of arboviruses using a hemagglutination inhibition test (HI). RESULTS: Of the 16 primates investigated in the present study, five (31.2%) were serologically positive for an arbovirus. Of these five, two (12.5%) exhibited antibodies to the Flavivirus genus, one (6.2%) exhibited a monotypic reaction to Cacipacore virus, one (6.2%) was associated with Mayaro virus, and one (6.2%) was positive for Oropouche virus. CONCLUSIONS: Based on the positive serology observed in the present study, it was possible to conclude that arboviruses circulate among free-living primates. The viruses in the areas studied might have been introduced by infected humans or by primates from endemic or enzootic areas. Studies of this nature, as well as efficient and continuous surveillance programs, are needed to monitor viral activities in endemic and enzootic regions. PMID- 24474009 TI - The effects of a diet formulation with oats, soybeans, and flax on lipid profiles and uricemia in patients with AIDS and dyslipidemia. AB - INTRODUCTION: Although the initiation of highly active antiretroviral therapy (HAART) is accompanied by an attenuation of viral load, metabolic disorders characterized by hyperglycemia, dyslipidemia, and lipodystrophy are often observed in patients under this treatment. Certain foods, such as oat bran, soy protein, and flaxseed, have been shown to improve a patient's lipid profile despite possible increases in uricemia. Thus, a bioactive compound was formulated using these foods to help patients with HIV/AIDS control metabolic disorders resulting from HAART. METHODS: An uncontrolled before and after study was performed. The total cholesterol, HDL-cholesterol, LDL-cholesterol, triglycerides, and uric acid before and after 3 months of consuming the formulation were compared in patients. The compound was formulated such that 40g (the recommended daily intake) contained approximately 10g of flaxseed, 20g of oat bran, and 10g of textured soy protein. RESULTS: The study population consisted of 139 patients, 31 of whom were included in the final analysis. There were no significant variations between the laboratory results obtained before and after consumption of the compound. CONCLUSIONS: The regular consumption of the formulation together with individualized dietary guidance did not reduce lipid levels and did not contribute to an increase in uricemia in the study group. However, new studies with higher doses of the foods that compose the formulation should be encouraged to investigate whether these foods can positively influence the lipid profiles of these patients. PMID- 24474010 TI - Nutritional status and CD4 cell counts in patients with HIV/AIDS receiving antiretroviral therapy. AB - INTRODUCTION: Even with current highly active antiretroviral therapy, individuals with AIDS continue to exhibit important nutritional deficits and reduced levels of albumin and hemoglobin, which may be directly related to their cluster of differentiation 4 (CD4) cell counts. The aim of this study was to characterize the nutritional status of individuals with human immunodeficiency virus/acquired immunodeficiency syndrome (HIV/AIDS) and relate the findings to the albumin level, hemoglobin level and CD4 cell count. METHODS: Patients over 20 years of age with AIDS who were hospitalized in a university hospital and were receiving antiretroviral therapy were studied with regard to clinical, anthropometric, biochemical and sociodemographic characteristics. Body mass index, percentage of weight loss, arm circumference, triceps skinfold and arm muscle circumference were analyzed. Data on albumin, hemoglobin, hematocrit and CD4 cell count were obtained from patient charts. Statistical analysis was performed using Fisher's exact test, Student's t-test for independent variables and the Mann-Whitney U test. The level of significance was set to 0.05 (alpha = 5%). Statistical analysis was performed using Statistical Package for the Social Sciences (SPSS) 17.0 software for Windows. RESULTS: Of the 50 patients evaluated, 70% were male. The prevalence of malnutrition was higher when the definition was based on arm circumference and triceps skinfold measurement. The concentrations of all biochemical variables were significantly lower among patients with a body mass index of less than 18.5kg/m2. The CD4 cell count, albumin, hemoglobin and hematocrit anthropometric measures were directly related to each other. CONCLUSIONS: These findings underscore the importance of nutritional follow-up for underweight patients with AIDS, as nutritional status proved to be related to important biochemical alterations. PMID- 24474011 TI - Spatial and seasonal distribution of Lutzomyia longipalpis in Dracena, a city in the western region of the State of Sao Paulo, Brazil, that is endemic with visceral leishmaniasis. AB - INTRODUCTION: Vector seasonality knowledge is important for monitoring and controlling of vector-borne diseases. Lutzomyia longipalpis (Lu. longipalpis) is the main vector of Leishmania (Leishmania) infantum Nicolle, 1908, which is the causative agent of visceral leishmaniasis in the Americas. METHODS: Lu. longipalpis was monitored for 3 consecutive nights each month using light traps from the Centers for Disease Control in the peridomiciles and intradomiciles of 18 residences from January 2005 to December 2012 in the urban area of Dracena, a medium-sized city located in the western region of Sao Paulo, Brazil. RESULTS: A total of 54,820 Lu. longipalpis specimens were collected, and the proportion of positive samples was significantly higher in the peridomiciles than in the intradomiciles (p<0.05) in all 8 years of the study, except for 2005. The vector was present in all study years in the 9 sub-regions of the city, and the male/female ratio ranged from 3.19 to 4.26. The greatest vector abundance occurred in the first semester and peaked in March, confirming its seasonality. CONCLUSIONS: The maintenance of this high abundance over an 8-year surveillance period demonstrates the vector adaptation to the urban conditions of the city. These characteristics present a major challenge for preventing human and canine contact with the vector and, consequently, controlling the spread of disease. PMID- 24474012 TI - Active surveillance to determine the impact of methicillin resistance on mortality in patients with bacteremia and influences of the use of antibiotics on the development of MRSA infection. AB - INTRODUCTION: Methicillin-resistant Staphylococcus aureus (MRSA) is among the most important pathogens of nosocomial infections, mainly in intensive care units (ICUs), and accounts for 40-60% of all healthcare-associated S. aureus infections. We evaluated the incidence of nosocomial infection by S. aureus, identified the risk factors for MRSA infection, and evaluated the effect of resistance to methicillin on mortality in patients. METHODS: We conducted MRSA surveillance at a university hospital in Brazil from January 1, 2010, to December 31, 2010, and performed a retrospective case-control matched study to evaluate the frequency of subsequent MRSA bacteremia and death among patients. We evaluated and compared the risk factors between patients with MRSA and methicillin-sensitive Staphylococcus aureus (MSSA) infection. RESULTS: Sepsis was the most common cause of infection (17.7/1,000 patient-days), followed by surgical site (11.4/1,000 patient-days), pneumonia (4.1/1,000 patient-days), and urinary tract infection (2.4/1,000 patient-days). The significant risk factors were time of hospitalization, use of central vascular catheter (CVC), urinary catheter, nasogastric tube, parenteral nutrition, tracheostomy, mechanical ventilation, and previous antibiotic administration, the latter of which was the only independent risk factor for MRSA infection. Mortality was significantly higher in patients with MRSA. The number of antibiotics tested was not related to increases in the frequency of MRSA/1,000 patient-days. The incidence of mortality attributable to MRSA (bloodstream infection) BSI was 50%. CONCLUSIONS: Surveillance results showed that the use of high levels of antibiotics was directly related to the development of MRSA infection, and the mortality attributable to MRSA in patients with bacteremia was significant. PMID- 24474013 TI - Evolution of coauthorship networks: worldwide scientific production on leishmaniasis. AB - INTRODUCTION: Collaboration is one of the defining features of contemporary scientific research, and it is particularly important with regard to neglected diseases that primarily affect developing countries. METHODS: The present study has identified publications on leishmaniasis in the Medline database from 1945 to 2010, analyzing them according to bibliometric indicators and statistics from social network analysis. Examining aspects such as scientific production, diachronic evolution, and collaboration and configuration of the research groups in the field, we have considered the different types of Leishmania studied and the institutional affiliation and nationality of the authors. RESULTS: Seven hundred and thirty-five authors participate in 154 prominent research clusters or groups. Although the most predominant and consolidated collaborations are characterized by members from the same country studying the same type of Leishmania, there are also notable links between authors from different countries or who study different clinical strains of the disease. Brazil took the lead in this research, with numerous Brazilian researchers heading different clusters in the center of the collaboration network. Investigators from the USA, India, and European countries, such as France, Spain, the United Kingdom, and Italy, also stand out within the network. CONCLUSIONS: Research should be fostered in countries such as Bangladesh, Nepal, Sudan, and Ethiopia, where there is a high prevalence of different forms of the disease but limited research development with reference authors integrated into the collaboration networks. PMID- 24474014 TI - CD8+ T cells in situ in different clinical forms of human cutaneous leishmaniasis. AB - INTRODUCTION: Leishmania braziliensis infection induces a large spectrum of lesions that clinically manifest as nodules or papules that progress to ulcers. Although it is already known that T helper cells predominate in the lesions, cytotoxic T cells have also been reported to be present, and their role in leishmaniasis immunopathogenesis is not well known. This study investigated the amounts of CD8+ and granzyme B+ cells in different clinical forms of human cutaneous leishmaniasis (CL). METHODS: Forty tissue fragments from early (E-CL) and late CL (L-CL) lesions and from disseminated leishmaniasis (DL) - papules and ulcers - were characterized. The inflamed area per fragment was calculated, and the CD8 and granzyme B expression levels in the infiltrates were quantified by counting positive cells in 15 fields. The localization of CD8 and granzyme B was graded subjectively. RESULTS: Inflammation was higher in L-CL and DL ulcers. CD8 expression was increased in late ulcerated lesions compared to recent lesions. The increase in CD8+ cells also correlated with the duration of the lesion. Papules had a higher frequency of granzyme B+ cells than E-CL lesions, although the frequency was similar to those for late and DL ulcers. CD8+ cells were mostly found in the papillary dermis. CONCLUSIONS: CD8+ T and granzyme B+ cells are present in the inflammatory infiltrates of CL and DL and may participate in the immunopathogenesis of Leishmania infection. PMID- 24474015 TI - Biochemical and nutritional evaluation of patients with visceral leishmaniasis before and after treatment with leishmanicidal drugs. AB - INTRODUCTION: Visceral leishmaniasis (VL) is caused by the intracellular protozoan Leishmania donovani complex. VL may be asymptomatic or progressive and is characterized by fever, anemia, weight loss and the enlargement of the spleen and liver. The nutritional status of the patients with VL is a major determinant of the progression, severity and mortality of the disease, as it affects the clinical progression of the disease. Changes in lipoproteins and plasma proteins may have major impacts in the host during infection. Thus, our goal was evaluate the serum total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), triglycerides, glucose, albumin, globulin and total protein levels, as well as the body composition, of VL patients before and after treatment. METHODS: Nutritional evaluation was performed using the bioelectrical impedance analysis (BIA) to assess body composition. Biochemical data on the serum total cholesterol, HDL, LDL, triglycerides, glucose, albumin, globulin and total protein were collected from the medical charts of the patients. RESULTS: BIA indicated that both pre-treatment and post-treatment patients exhibited decreased phase angles compared to the controls, which is indicative of disease. Prior to treatment, the patients exhibited lower levels of total body water compared to the controls. Regarding the biochemical evaluation, patients with active VL exhibited lower levels of total cholesterol, HDL, LDL and albumin and higher triglyceride levels compared to patients after treatment and the controls. Treatment increased the levels of albumin and lipoproteins and decreased the triglyceride levels. CONCLUSIONS: Our results suggest that patients with active VL present biochemical and nutritional changes that are reversed by treatment. PMID- 24474016 TI - Severe visceral leishmaniasis in children: the relationship between cytokine patterns and clinical features. AB - INTRODUCTION: The relationship between severe clinical manifestations of visceral leishmaniasis (VL) and immune response profiles has not yet been clarified, despite numerous studies on the subject. This study aimed to investigate the relationship between cytokine profiles and the presence of immunological markers associated with clinical manifestations and, particularly, signs of severity, as defined in a protocol drafted by the Ministry of Health (Brazil). METHODS: We conducted a prospective, descriptive study between May 2008 and December 2009. This study was based on an assessment of all pediatric patients with VL who were observed in a reference hospital in Maranhao. RESULTS: Among 27 children, 55.5% presented with more than one sign of severity or warning sign. Patients without signs of severity or warning signs and patients with only one warning sign had the highest interferon-gamma (IFN-gamma) levels, although their interleukin 10 (IL-10) levels were also elevated. In contrast, patients with the features of severe disease had the lowest IFN-gamma levels. Three patients who presented with more than two signs of severe disease died; these patients had undetectable interleukin 2 (IL-2) and IFN-gamma levels and low IL-10 levels, which varied between 0 and 36.8pg/mL. CONCLUSIONS: Our results showed that disease severity was associated with low IFN-gamma levels and elevated IL-10 levels. However, further studies with larger samples are needed to better characterize the relationship between disease severity and cytokine levels, with the aim of identifying immunological markers of active-disease severity. PMID- 24474017 TI - Length and caliber of the rectosigmoid colon among patients with Chagas disease and controls from areas at different altitudes. AB - INTRODUCTION: In this study, we investigated radiological changes in the sigmoid colon in chagasic patients by comparing their colon lengths and caliber with those of non-chagasic living in the same region and non-chagasic living at high altitudes. METHODS: A total of 317 individuals were evaluated using clinical, serological and radiological methods and divided into three groups: 1) one hundred and nine non-chagasic individuals from Uberaba, Brazil; 2) sixty-one non chagasic from Puno, Peru; 3) one hundred forty-seven chagasics examined in Uberaba, being 62 without megacolon (3A), 72 with megacolon (3B) and 13 with doubtful diagnosis of megacolon (3C). RESULTS: In group 2, the sigmoid colon had a significantly larger caliber (p=0.001) and the rectosigmoid colon was longer (p<0.001) than group 1. In subgroup 3A, the sigmoid colon (p<0.001) and rectum (p<0.001) had a significantly larger caliber and the rectosigmoid was longer (p<0.001) than that of the non-chagasic individuals. In subgroup 3B, the rectosigmoid was longer in all patients, and the caliber of the sigmoid was significantly larger than that of subjects in subgroups 3A and 3C (p<0.001). CONCLUSIONS: Morphometric analysis confirms that Chagas disease may increase the caliber and length of the rectosigmoid. Our results suggest that altitude, ethnicity and diet may have influenced the size and length of the rectosigmoid of andean patients. PMID- 24474018 TI - Fluconazole and amphotericin-B resistance are associated with increased catalase and superoxide dismutase activity in Candida albicans and Candida dubliniensis. AB - INTRODUCTION: Candida dubliniensis, a new species of Candida that has been recovered from several sites in healthy people, has been associated with recurrent episodes of oral candidiasis in AIDS and HIV-positive patients. This species is closely related to C. albicans. The enzymatic activity of C. dubliniensis in response to oxidative stress is of interest for the development of drugs to combat C. dubliniensis. METHODS: Fluconazole- and amphotericin B resistant strains were generated as described by Fekete-Forgacs et al. (2000). Superoxide dismutase (SOD) and catalase assays were performed as described by McCord and Fridovich (1969) and Aebi (1984), respectively. RESULTS: We demonstrated that superoxide dismutase (SOD) and catalase activities were significantly higher (p<0.05) in the fluconazole- and amphotericin B-resistant strains of C. dubliniensis and C. albicans than in the sensitive strains. The catalase and SOD activities were also significantly (p<0.01) higher in the sensitive and resistant C. albicans strains than in the respective C. dubliniensis strains. CONCLUSIONS: These data suggest that C. albicans is better protected from oxidative stress than C. dubliniensis and that fluconazole, like amphotericin B, can induce oxidative stress in Candida; oxidative stress induces an adaptive response that results in a coordinated increase in catalase and SOD activities. PMID- 24474019 TI - Environmental isolation, biochemical identification, and antifungal drug susceptibility of Cryptococcus species. AB - INTRODUCTION: The incidence of opportunistic fungal infections has increased in recent years and is considered an important public health problem. Among systemic and opportunistic mycoses, cryptococcosis is distinguished by its clinical importance due to the increased risk of infection in individuals infected by human immunodeficiency virus. METHODS: To determine the occurrence of pathogenic Cryptococcus in pigeon excrement in the City of Araraquara, samples were collected from nine environments, including state and municipal schools, abandoned buildings, parks, and a hospital. The isolates were identified using classical tests, and susceptibility testing for the antifungal drugs (fluconazole, itraconazole, voriconazole, and amphotericin B) independently was also performed. After collection, the excrement samples were plated on Niger agar and incubated at room temperature. RESULTS: A total of 87 bird dropping samples were collected, and 66.6% were positive for the genus Cryptococcus. The following species were identified: Cryptococcus neoformans (17.2%), Cryptococcus gattii (5.2%), Cryptococcus ater (3.5%), Cryptococcus laurentti (1.7%), and Cryptococcus luteolus (1.7%). A total of 70.7% of the isolates were not identified to the species level and are referred to as Cryptococcus spp. throughout the manuscript. CONCLUSIONS: Although none of the isolates demonstrated resistance to antifungal drugs, the identification of infested areas, the proper control of birds, and the disinfection of these environments are essential for the epidemiological control of cryptococcosis. PMID- 24474020 TI - Dengue infection in children and adolescents: clinical profile in a reference hospital in northeast Brazil. AB - INTRODUCTION: This study aimed to describe the clinical spectrum of dengue in children and adolescents from a hyperendemic region who were admitted for hospitalization. METHODS: A retrospective study was conducted on patients diagnosed with dengue infection upon admission to a reference center in Fortaleza, Brazil. RESULTS: Of the 84 patients included, 42 underwent confirmatory testing. The main symptoms were fever, abdominal pain and vomiting. The median level of serum aspartate aminotransferase was 143.5+/-128mg/dL. CONCLUSIONS: A peculiar clinical profile was evident among children and adolescents with dengue infection in a reference center in northeast Brazil, including gastrointestinal symptoms and liver involvement. PMID- 24474021 TI - Immature mosquitoes (Diptera: Culicidae) in a eutrophic landfill tank from State of Rio de Janeiro, Brazil. AB - INTRODUCTION: To determine the faunal composition of immature culicids inhabiting a percolation tank in the landfill of Sapucaia, State of Rio de Janeiro, Brazil, immature mosquitoes were collected over a two-day period during the third weeks of April, August and October 2011. RESULTS: The species found were Culex usquatus, Lutzia bigoti, Anopheles argyritarsis and Limatus durhamii. This study is the first to report the colonization of eutrophic breeding sites by these species. CONCLUSIONS: The oviposition behavior observed in this study suggests a secondary adaptation or change in habit to select eutrophic environments during the developmental stages of the observed species. PMID- 24474022 TI - Incidence of canine leptospirosis in the metropolitan area of Curitiba, State of Parana, Southern Brazil. AB - INTRODUCTION: The incidence of canine leptospirosis in Brazil needs to be assessed. METHODS: The same dogs in southern Brazil were sampled over two years to determine the prevalence, incidence and association of canine leptospirosis with various risk factors. RESULTS: In 2009, the prevalence was 33 (14.4%) of 228 dogs, with a predominance of serovar Canicola (33.4%). In 2010, 90 dogs were re evaluated (the remaining dogs were lost to deaths, address changes and donations), and the prevalence was found to be 35 (38.9%) of 90, with the predominant serovar being Icterohaemorrhagiae (51.4%). Moreover, the incidence was 26 of 90 (28.9%), and the disease was statistically associated with age (2009) and street access (2010). CONCLUSIONS: Our findings revealed instability in the dog population and age to be relevant risk factors for canine leptospirosis. PMID- 24474023 TI - Clinical and serological evolution in chronic Chagas disease patients in a 4-year pharmacotherapy follow-up: a preliminary study. AB - INTRODUCTION: The role of trypanocidal therapy in the chronic phase of Chagas disease remains controversial. METHODS: A total of 13 patients with chronic Chagas disease were treated with benznidazole (5mg/kg/day/60 days) and surveyed via antibody measurement and conventional electrocardiogram over the course of 4 years. RESULTS: The antibody titers were significantly reduced after 4 years (p<0.05). Most of the patients showed maintenance of the initial clinical picture (electrocardiographic), with the exception of 4 cases. CONCLUSIONS: Although trypanocidal therapy in the chronic phase of Chagas disease was of limited effectiveness, we believe that it is beneficial in treating these patients. PMID- 24474024 TI - Profile of the Trypanosoma cruzi vector infestation in Jaboticatubas, State of Minas Gerais, Brazil. AB - INTRODUCTION: This work aimed to analyze the triatomine infestation scenario in Jaboticatubas after 30 years of the uninterrupted actions of the Program of Chagas Disease Control. METHODS: From 2007 to 2010, household unit infestation was researched, and an exploratory analysis of the localities infested with Panstrongylus megistus was performed. RESULTS: In total, 613 triatomines were captured in 78 households, the majority of which were Panstrongylus megistus and were captured mainly in chicken houses, but they were also found to be colonizing human houses. CONCLUSIONS: The epidemiological importance of Panstrongylus megistus was confirmed in Jaboticatubas, and capability to colonize indoors has been demonstrated, as has its proximity to humans. Its distribution is aggregated in the northern and in central-eastern regions of the municipality. PMID- 24474025 TI - An optimized one-tube, semi-nested PCR assay for Paracoccidioides brasiliensis detection. AB - INTRODUCTION: Herein, we report a one-tube, semi-nested-polymerase chain reaction (OTsn-PCR) assay for the detection of Paracoccidioides brasiliensis. METHODS: We developed the OTsn-PCR assay for the detection of P. brasiliensis in clinical specimens and compared it with other PCR methods. RESULTS: The OTsn-PCR assay was positive for all clinical samples, and the detection limit was better or equivalent to the other nested or semi-nested PCR methods for P. brasiliensis detection. CONCLUSIONS: The OTsn-PCR assay described in this paper has a detection limit similar to other reactions for the molecular detection of P. brasiliensis, but this approach is faster and less prone to contamination than other conventional nested or semi-nested PCR assays. PMID- 24474026 TI - Experimental infection of the bat tick Carios fonsecai (Acari: Ixodidae) with the rabies virus. AB - INTRODUCTION: This study assessed the viability of the rabies virus in the argasid tick Carios fonsecai following experimental infection. METHODS: The mouse inoculation test (MIT), fluorescent antibody test (FAT) and polymerase chain reaction (PCR) were used. The rabies virus was administered to ticks via the intra-coelomic route, and the ticks were sacrificed at different time points. RESULTS: The inoculated ticks were negative for rabies according to the MIT. Ticks macerated with rabies virus were positive according to the MIT and FAT. All of the tick lots tested by PCR were positive. CONCLUSIONS The rabies virus became unviable shortly after its inoculation into tick bodies. Ticks are not likely to play an important role in the epidemiology of rabies. PMID- 24474027 TI - Outbreak of laboratory-acquired Brucella abortus in Brazil: a case report. AB - Human brucellosis is an occupational disease affecting workers in slaughterhouses, butcher shops and the milk and dairy product industry as well as individuals who work in clinical or research laboratories. We report the first outbreak of a Brucella abortus infection in a Brazilian laboratory and compare the data obtained with reports available in the literature. Exposure was a result of damage to a biological safety cabinet and failure of the unidirectional airflow ventilation system. An epidemiological investigation identified 3 seroconverted individuals, 1 of whom had clinical manifestations and laboratory results compatible with infection at the time of exposure (n=11; attack rate=9.1%). PMID- 24474028 TI - Candida famata-induced fulminating cholecystitis. AB - Lithiasic cholecystitis is classically associated with the presence of enterobacteria, such as Escherichia coli, Enterococcus, Klebsiella, and Enterobacter, in the gallbladder. Cholecystitis associated with fungal infections is a rare event related to underlying conditions such as diabetes mellitus, steroid use, and broad-spectrum antibiotic use for prolonged periods, as well as pancreatitis and surgery of the digestive tract. Here, we present the first reported case of a gallbladder infection caused by Candida famata. PMID- 24474029 TI - Dilated paraumbilical vein in hepatosplenic schistosomiasis associated with pulmonary hypertension. PMID- 24474030 TI - The importance of originality in scientific research on neglected tropical diseases. PMID- 24474031 TI - The contribution of the ACCOMPLISH trial to the treatment of stage 2 hypertension. AB - The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) recommended a thiazide like diuretic, alone or in combination with other antihypertensive drug classes, as initial therapy for hypertension. JNC 7, however, did not specify preferred combinations. The Avoiding Cardiovascular Events through Combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial was completed five years after the JNC 7 and demonstrated a 20 % advantage in cardiovascular risk reduction when blood pressure was lowered using the single-pill combination of benazepril-amlodipine compared to benazepril-hydrochlorothiazide (Jamerson et al. 359(23):2417-28 [1]). This new and significant finding provided compelling evidence that the long-standing preference for diuretics as initial therapy could be refuted, but it may also be relevant to the lower-than-expected reduction in coronary disease related events (compared to stroke) observed for decades prior to the ACCOMPLISH approach to therapy. The JNC 8 panel members recently published their recommendations, and while the group did not recommend benazepril hydrochlorothiazide over other combinations, they did highlight the findings of ACCOMPLISH, rating the primary ACCOMPLISH paper as "good." The American Society of Hypertension position paper and the European Hypertension Society guidelines endorse such combinations as a first-line agent for patients with stage 2 hypertension. We review the current position of ACCOMPLISH in the guidelines regarding treatment of stage 2 hypertension. PMID- 24474032 TI - Chimeric cytochromes P450 engineered by domain swapping and random mutagenesis for producing human metabolites of drugs. AB - Human drug metabolites produced by cytochrome P450 enzymes are critical for safety testing and may themselves act as drugs or leads in the drug discovery and development process. Here, highly active chimeric fusion proteins (chimeras) were obtained by reductase domain swapping of mutants at key catalytic residues of the heme domain with that of a natural variant (CYP102A1.2) of P450 BM3 (CYP102A1.1) from Bacillus megaterium. Random mutagenesis at the heme domain of the chimera was also used to generate chimeric mutants that were more active and diverse than the chimeras themselves. To determine whether the chimeras and several mutants of the highly active chimera displayed enhanced catalytic activity and, more importantly, whether they acquired activities of biotechnological importance, we measured the oxidation activities of the chimeras and chimeric mutants toward human P450 substrates, mainly drugs. Some of the chimeric mutants showed high activity toward typical human P450 substrates including drugs. Statin leads, especially chiral products, with inhibitory effects toward HMG-CoA reductase could be obtained from metabolites of statin drugs generated using these chimeric mutants. This study reveals the critical role of the reductase domain for the activity of P450 BM3 and shows that chimeras generated by domain swapping can be used to develop industrial enzymes for the synthesis of human metabolites from drugs and drug leads. PMID- 24474033 TI - Primary prevascular and retropsoas hernias: incidence of rare abdominal wall hernias. AB - OBJECTIVE: To describe the incidence and treatment of prevascular and retropsoas hernias in a large-volume general surgery practice. BACKGROUND: Femoral hernias are considered uncommon with an incidence between 2 and 8 % of groin hernias. There are no large studies describing the subtypes of femoral hernias or retropsoas hernias, and therefore no reported incidence or standardized treatment recommendations for these hernias exist. METHODS: This study is a retrospective review of all patients undergoing total extraperitoneal (TEP) laparoscopic herniorrhaphy between August 1993 and December 2011. A single surgeon performed all the repairs. Demographics and patient outcomes were reported. RESULTS: 2,436 patients underwent 3,242 TEP repairs. The subtypes were: indirect 1,523 (46.9 %), direct 1,473 (45.4 %), femoral 156 (4.8 %), obturator 35 (1.1 %), prevascular 25 (0.77 %), Spigelian 20 (0.61 %), retropsoas 3 (0.09 %). Prevascular hernias accounted for 16 % of femoral hernias. Patients with prevascular hernias had a mean age of 70.3 years and were all male. 13 of the 25 patients (52 %) with prevascular hernias had other associated defects and four (16 %) of the patients had prevascular hernias as a recurrence from a prior hernia operation. There were three patients with retropsoas hernias that only would not have been seen from an anterior open approach. There are no intraoperative complications or known recurrences from this study group. CONCLUSIONS: Prevascular and retropsoas hernias are uncommon, but have a higher incidence than previously believed. Prevascular hernias tend to be associated with older age and other defects. The diagnosis and management of these hernias are readily achieved using the laparoscopic TEP approach. PMID- 24474034 TI - Pharmacokinetics of continuous once-a-week combination 17beta-Estradiol/Low- or high-dose levonorgestrel transdermal delivery systems in postmenopausal women. AB - Two open-label, randomized, two-period, crossover studies were performed to determine the safety, delivery rates, and pharmacokinetic properties of a combination estradiol (E2)/levonorgestrel (LNG) transdermal delivery system (TDS). Study 1 enrolled 24 postmenopausal women who received a single TDS containing 4.4 mg E2 and 1.39 mg of LNG (E2/LNG Low) or E2 0.050 mg/24 hours TDS and 0.090 mg LNG oral tablet. Study 2 enrolled 44 postmenopausal women who received either E2/LNG Low or TDS containing 4.4 mg E2 and 2.75 mg LNG (E2/LNG High) weekly for a period of 4 weeks. E2, estrone (E1), LNG, and sex hormone binding globulin (SHBG) serum concentrations were determined. Overall, both E2/LNG TDS were well tolerated and had excellent adhesion properties. The average daily delivery for E2/LNG Low was 0.045 mg for E2 and 0.0132 mg for LNG. Following weekly delivery of E2/LNG Low or High for 4 weeks, the combination of E2 with two different strengths of LNG did not alter the pharmacokinetic profile of E2. SHBG, total cholesterol, and triglycerides concentrations significantly decreased compared to baseline. Both E2/LNG Low and High TDSs were well tolerated and provided continuous drug delivery over 7 days supporting the benefits of the transdermal route of administration in optimally delivering hormonal therapy. PMID- 24474035 TI - A new parasitic copepod (Cyclopoida: Bomolochidae) from a ponyfish (Leiognathidae) caught in Egyptian Mediterranean waters, with a review of hosts and key to species of Nothobomolochus. AB - A new bomolochid copepod belonging to the genus Nothobomolochus Vervoort, 1962 is described from a Red Sea fish species, a ponyfish of the family Leiognathidae that has become established in the Eastern Mediterranean. The new species, N. leiognathicola n. sp., is based on material obtained from the gill chamber of the Red Sea immigrant ponyfish Leiognathus klunzingeri (Steindachner), caught in Egyptian waters off the Alexandria coast at Abuqir. A second new species, N. monodi n. sp., is established to accommodate some material previously described as N. denticulatus (Bassett-Smith, 1898), from the host Hemiramphus far Forsskal. A review of host records reveals that Nothobomolochus species utilise hosts representing five different orders, but are most commonly found on beloniform, clupeiform and perciform fishes. A newly constructed key to the 37 valid species of Nothobomolochus is presented. PMID- 24474036 TI - A new species of Saturnius Manter, 1969 (Digenea: Hemiuridae) from Mediterranean mullet (Teleostei: Mugilidae). AB - A new hemiurid digenean, Saturnius gibsoni n. sp., is described from the stomach lining of Mugil cephalus L. off Oran, Mediterranean coast of Algeria. Characteristic morphological features of the new species include small size of the body which is comprised of six pseudosegments, small ventral sucker, weakly developed mound-shaped flange at the level of the ventral sucker, and eggs being large in relation to the size of the body. Saturnius gibsoni n. sp. resembles S. minutus Blasco-Costa, Pankov, Gibson, Balbuena, Raga, Sarabeev & Kostadinova, 2006 and two unidentified Saturnius spp. in the small size of the body and most metrical features. However, in spite of the presence of five transverse septa resulting in six pseudosegments and the range overlap of some metrical features, the ventral sucker in S. minutus is much larger, the ventral sucker muscular flange is more prominent, the last pseudosegment is narrower in relation to body width and more rounded, and the eggs are smaller (mean 21 * 10 vs 25 * 12 MUm). Furthermore, the partial sequences of the 28S rRNA gene region (domains D1-D3; 1,195 nt) obtained from two isolates of S. gibsoni n. sp. differed by 11 nt (0.9%) from that of S. minutus. Both unidentified forms of Saturnius are clearly distinguishable from S. gibsoni n. sp. by the presence of six stout, transverse muscular septa, forming seven pseudosegments (vs five septa forming six pseudosegments). Bayesian inference analysis of partial 28S rDNA sequences based on a total of 15 species from the families Hemiuridae and Lecithasteridae depicted the Bunocotylinae Dollfus, 1950 as a strongly supported basal clade, with Bunocotyle progenetica (Markowski, 1936) as the closest sister taxon to Saturnius spp. PMID- 24474037 TI - Two new species of Haemoproteus Kruse, 1890 (Haemosporida, Haemoproteidae) from European birds, with emphasis on DNA barcoding for detection of haemosporidians in wildlife. AB - Two new species of Haemoproteus Kruse, 1890 (Haemosporida, Haemoproteidae) are described: Haemoproteus (Parahaemoproteus) homovelans n. sp. from Grey-faced Woodpecker, Picus canus Gmelin, and Haemoproteus (Parahaemoproteus) concavocentralis n. sp. recorded in Hawfinch, Coccothraustes coccothraustes (Linnaeus), both sampled in Bulgaria. The morphology of the gametocytes and their host-cells are described and mitochondrial cytochrome b (cyt b) gene sequences are generated. Haemoproteus homovelans possesses circumnuclear gametocytes lacking volutin granules. This parasite is particularly similar to Haemoproteus velans Coatney & Roudabush, 1937 also possessing circumnuclear gametocytes that are, however, overfilled with volutin. Haemoproteus concavocentralis can be readily distinguished from all described avian haemoproteids due to the presence of an unfilled concave space between the central part of advanced gametocytes and erythrocyte nucleus. Bayesian phylogenetic analyses of 40 haemosporidian cyt b lineages showed close relationships of H. concavocentralis (hHAWF2) with a group of Haemoproteus spp. possessing gametocytes that are pale-stained with Giemsa. The lineage hPICAN02 of H. homovelans clustered with parasites infecting non passerine birds. Phylogenetic analyses support the current subgeneric classification of the avian haemoproteids and suggest that cyt b lineage hPIPUB01 (GenBank EU254552) has been incorrectly assigned to Haemoproteus picae Coatney & Roudabush, 1937, a common parasite of corvid birds (Passeriformes). This study emphasises the importance of combining molecular techniques and light microscopy in the identification and field studies of avian haemosporidian parasites. Future development of barcodes for molecular identification of haemoproteids will allow better diagnostics of these infections, particularly in veterinary studies addressing insufficiently investigated tissue pathology caused by these parasites. PMID- 24474038 TI - Synopsis of the species of Kudoa Meglitsch, 1947 (Myxozoa: Myxosporea: Multivalvulida). AB - A synopsis of the species of Kudoa Meglitsch, 1947 (Myxozoa, Myxosporea, Multivalvulida) is presented, including 95 nominal species. For each species the most relevant morphological and morphometric features are indicated in tabulated format. Included are data on the site of infection within the host, the type-host and type-locality, plus a full bibliography of the original records for these species. Molecular data (GenBank accession numbers) are also provided whenever possible. PMID- 24474039 TI - Four new coccidia (Apicomplexa: Eimeriidae) from the Plateau zokor, Myospalax baileyi Thomas (Rodentia: Myospalacinae), a subterranean rodent from Haibei area, Qinghai Province, China. AB - Thirty-eight faecal samples from the Plateau zokor, Myospalax baileyi Thomas, collected in the Haibei Area, Qinghai Province, China, were examined for the presence of coccidia (Apicomplexa: Eimeriidae). Seventeen of 38 faecal samples (44.7%) were found to contain coccidian oocysts representing four new species of Eimeria Schneider, 1875, and four of 17 (23.5%) infected zokors were concurrently infected with two or three of these eimerian species. The sporulated oocysts of Eimeria myospalacensis n. sp. are ovoidal, 9.5-17.0 * 8.0-13.0 (mean 13.0 * 10.4) MUm; a polar granule is present, oocyst residuum is absent; sporocysts are ovoidal, 4.5-7.5 * 3.0-5.0 (mean 6.3 * 4.2) MUm and have both a Stieda body and residuum. Oocysts of Eimeria fani n. sp. are ellipsoidal to cylindroidal, 12.5 16.0 * 8.0-11.0 (mean 14.6 * 9.9) MUm; a polar granule is present, but micropyle and residuum are lacking; sporocysts are ovoidal, 4.5-7.5 * 3.0-5.3 (mean 6.7 * 4.4) MUm; a residuum and a Steida body are present. Oocysts of Eimeria baileyii n. sp. are ellipsoidal, 15.0-23.0 * 12.0-18.0 (mean 18.2 * 13.7) MUm; a polar granule is present but oocyst residuum is absent; sporocysts are ovoidal, 8.0 11.0 * 5.0-7.0 (mean 9.5 * 5.9) MUm and have both a Stieda body and residuum. Oocysts of Eimeria menyuanensis n. sp. are ovoidal, 12.5-21.0 * 11.0-18.0 (mean 17.1 * 14.6) MUm, with a distinct micropyle c.2.5 MUm wide; a polar granule is present but a residuum is absent; sporocysts are ovoidal, 8.0-12.0 * 5.0-7.0 (mean 10.2 * 6.4) MUm, and have both a Stieda body and residuum. PMID- 24474040 TI - Synopsis of the species of the genus Myxobilatus Davis, 1944 (Myxozoa: Myxosporea: Myxobilatidae). AB - A synopsis of the species of Myxobilatus Davis, 1944 (Myxozoa: Myxosporea: Myxobilatidae) is presented. Thirty-nine nominal species are included. The major characteristics and an illustration are given for each species based on the original records. PMID- 24474041 TI - Differentiation of European freshwater bucephalids (Digenea: Bucephalidae) based on karyotypes and DNA sequences. AB - Three species of bucephalid digeneans are known in European freshwater habitats. In this study parthenitae of Rhipidocotyle campanula (Dujardin, 1845) and R. fennica Gibson, Taskinen & Valtonen, 1992, infecting unionid bivalves, and adult Bucephalus polymorphus von Baer, 1827 from perch (Perca fluviatilis L.) were investigated using karyological analysis and DNA sequencing. Our previously published data on genetic characteristics of parthenitae of B. polymorphus from Dreissena polymorpha Pallas were used for comparative analysis. Ribosomal DNA sequences (ITS2 and 28S rDNA) were used to estimate the phylogenetic relationships of the three bucephalid species. Very close phylogenetic affinity between investigated species was revealed; the sequence difference between the two species of Rhipidocotyle Diesing, 1858 (3.78% based on 28S) was comparable with intergeneric differences observed in comparisons of B. polymorphus with R. campanula and R. fennica (3.43% and 4.49% based on 28S, respectively). A high degree of similarity was noted in karyotype structure of the two species of Rhipidocotyle. The diploid chromosome sets consist of 14 bi-armed chromosomes with the first pair of metacentric elements markedly larger than the remaining chromosomes. This chromosome set structure is also specific to B. polymorphus. One specimen of Anodonta anatina L. was infected with tetraploid R. fennica (4n = 28). On the basis of karyotype characters and molecular data, species of the genus Rhipidocotyle cannot be recognised as more closely related to each other than to B. polymorphus. Our findings of Lithuanian and Ukrainian populations of unionid mussels infected with R. fennica provide evidence that this species occurs not only in Finland but also in Central and Eastern Europe. Previous reports of B. polymorphus in unionids in these regions are equivocal because of possible confusion with R. fennica. PMID- 24474042 TI - Choleoeimeria ghaffari n. sp. (Apicomplexa: Eimeriidae) from the gallbladder of Eryx jayakari Boulenger (Serpentes: Boidae) in Saudi Arabia. AB - Choleoeimeria ghaffari n. sp. is described from the gallbladder of Eryx jayakari Boulenger in Saudi Arabia. Oocysts are tetrasporocystic, cylindroidal, 23 * 14 MUm, with a smooth bi-layered wall and length/width ratio of 1.5, without micropyle, oocyst residuum and polar granule. Sporocysts are subspheroidal to ellipsoidal, 8 * 6 MUm, with length/width ratio of 1.4, without Stieda, sub Stieda and para-Stieda bodies but with sporocyst residuum. Sporozoites are banana shaped measuring 10 * 1.5 MUm. The endogenous development was found to occur in the gallbladder epithelium and the extrahepatic bile ducts. Mature meronts are spheroidal, c.10 MUm wide, and suspected to produce 12-16 merozoites. Microgamonts are irregular in shape, 13 * 10 MUm, whereas macrogamonts are mostly subspheroidal, c.12 MUm wide, with a prominent centrally-located nucleus. Based on oocyst morphology and the site of endogenous development (epithelium of the gallbladder and bile ducts) the new eimeriid coccidian was placed in the genus Choleoeimeria Paperna & Landsberg, 1989. PMID- 24474043 TI - Dermoscopic features of plasma cell cheilitis and actinic cheilitis. PMID- 24474044 TI - Safety margin of minimized contrast volume during percutaneous coronary intervention in patients with chronic kidney disease. AB - Maximum allowable contrast dose (MACD) calculated as body weight * 5/serum creatinine has been a standard contrast dye volume (CV) used to decrease contrast induced acute kidney injury. Recent advances in intravascular ultrasound-guided percutaneous coronary intervention (PCI) can dramatically minimize CV. The safe threshold when using an extremely low-dose CV is unknown. This study was designed as a multicenter, retrospective study of chronic kidney disease (CKD) patients with estimated glomerular filtration rate (eGFR) <30 ml/min/1.73 m(2) undergoing elective PCI. We divided the patients into three groups according to following criteria: (1) low dose, CV/eGFR ratio <1.0; (2) medium dose, CV/eGFR ratio >=1 and =MACD. A total of 100 patients were enrolled. Average age was 74 +/- 8 years, 64 % were male and 48 % were diabetic. Mean baseline eGFR was 22.8 +/- 6.0 ml/min/1.73 m(2). CV in the three groups was 15 +/ 6 ml (n = 18), 69 +/- 39 ml (n = 47) and 224 +/- 99 ml (n = 35), respectively. The incidences of CI-AKI were 0, 11 and 23 %, respectively (p = 0.02). All-cause death or introduction of maintenance hemodialysis at 1 year was 0, 13.8 and 31 %, respectively (p = 0.01). Extreme reduction of CV to a CV/eGFR ratio <1.0 may reduce CI-AKI and achieve better clinical outcomes following PCI in patients with severe CKD. PMID- 24474045 TI - Effects of chronic cold exposure on murine central nervous system. AB - Recently, cold-adaptation medicine has gotten more and more attention because of its specific significance to health care, military activities, sports performance, and so on. Although numerous studies have focused on respiratory, immune, and circulatory systems as well as skin damage upon cold exposure, the impacts on central nervous system are not well understood. This study explores the effects of chronic cold exposure on the murine central nervous system. To establish a chronic cold-exposure animal model, adult male mice from postnatal days 40-50 (P40-50) were housed at 0-4 degrees C for 20 days. During the study period, estrogen receptors were labeled via immunohistochemistry, the dendritic spines of visual cortical pyramidal cells were labeled with DiI diolistic assay, and synaptic ultrastructure was observed by transmission electron microscopy. The results showed that cold exposure could inhibit neural proliferation significantly, with an increase of G-protein-coupled receptor 30 (GPR30) expression. Chronic cold exposure could also induce a decrease in the dendritic spines of pyramidal cells in visual cortex, along with a decrease in the number of synaptic formations. The ultrastructure of synapses after cold exposure was observed. It was found that pre- and postsynaptic membranes were fused, with a vague synaptic cleft. Furthermore, neuronal cytoplasmic and organelle swellings were also observed, along with microtubule disintegration. In conclusion, chronic cold exposure can cause structural and functional changes in the mouse central nervous system, possibly by direct participation of estrogen and its receptor, GPR30, in response to chronic cold exposure. PMID- 24474046 TI - [Transposition of the great arteries in MRI ]. PMID- 24474048 TI - [Invitation to the General Meeting of the DRG on Thursday, 29 May 2014]. PMID- 24474047 TI - [Radiology in the Nazi era -Part 2 -professionalization, status preservation and service to the "public health"]. PMID- 24474050 TI - [The brightest minds for radiology - registration until 28.02.2014 is still possible!]. PMID- 24474049 TI - [Elections to the board of the working groups of the DRG on the 95th German Radiology Congress, 28 - 31 May 2014 in Hamburg]. PMID- 24474051 TI - Clinical course and outcomes of critically ill patients with Middle East respiratory syndrome coronavirus infection. AB - BACKGROUND: Since September 2012, 170 confirmed infections with Middle East respiratory syndrome coronavirus (MERS-CoV) have been reported to the World Health Organization, including 72 deaths. Data on critically ill patients with MERS-CoV infection are limited. OBJECTIVE: To describe the critical illness associated with MERS-CoV. DESIGN: Case series. SETTING: 3 intensive care units (ICUs) at 2 tertiary care hospitals in Saudi Arabia. PATIENTS: 12 patients with confirmed or probable MERS-CoV infection. MEASUREMENTS: Presenting symptoms, comorbid conditions, pulmonary and extrapulmonary manifestations, measures of severity of illness and organ failure, ICU course, and outcome are described, as are the results of surveillance of health care workers (HCWs) and patients with potential exposure. RESULTS: Between December 2012 and August 2013, 114 patients were tested for suspected MERS-CoV; of these, 11 ICU patients (10%) met the definition of confirmed or probable cases. Three of these patients were part of a health care-associated cluster that also included 3 HCWs. One HCW became critically ill and was the 12th patient in this case series. Median Acute Physiology and Chronic Health Evaluation II score was 28 (range, 16 to 36). All 12 patients had underlying comorbid conditions and presented with acute severe hypoxemic respiratory failure. Most patients (92%) had extrapulmonary manifestations, including shock, acute kidney injury, and thrombocytopenia. Five (42%) were alive at day 90. Of the 520 exposed HCWs, only 4 (1%) were positive. LIMITATION: The sample size was small. CONCLUSION: MERS-CoV causes severe acute hypoxemic respiratory failure and considerable extrapulmonary organ dysfunction and is associated with high mortality. Community-acquired and health care associated MERS-CoV infection occurs in patients with chronic comorbid conditions. The health care-associated cluster suggests that human-to-human transmission does occur with unprotected exposure. PRIMARY FUNDING SOURCE: None. PMID- 24474052 TI - Polymorphism and differentiation indices preferred for genetic analysis among cattle, goats, and sheep. AB - Most studies of polymorphism and differentiation are based on a single gene; few have treated differences among numerous genes. We have analyzed the parameters of conservation, polymorphism, and genetic differentiation to find the preferred index of 40 genes, with 1,614 sequences from cattle, goats, and sheep. Clustering and principal component factor (PCF) analyses revealed three PCFs: PCF1, representing polymorphism and differentiation; PCF2, representing nucleotide usage; and PCF3, representing gene flow (G ST ) and gene differentiation (delta ST ). We found significantly higher correlations (p < 0.001) with other indices for sequence conservation (r of -0.66 to -0.98), thetaeta (0.52-0.95), and gamma ST (0.54-0.96). This shows that they are preferable for estimating conservation, polymorphism, and differentiation of genes, respectively. The codon bias index was significantly different between the autosome and sex chromosomes (p < 0.01). PMID- 24474053 TI - Introducing basic molecular biology to Turkish rural and urban primary school children via hands-on PCR and gel electrophoresis activities. AB - This study includes the results of a 2-day education project titled "Molecular Biology Laboratory Summer School, MoBiLYO." The project was held at a University Research Center by scientists from Department of Pharmacology and graduate students. The project was composed of introductory lectures, model construction, DNA isolation, polymerase chain reaction (PCR), and gel electrophoresis. The participants were 13-year-old eighth-graders attending primary schools affiliated with Ministry of National Education in urban and rural areas of Izmir, Turkey. The purpose of this study was to introduce basic molecular biology concepts through individually performed experiments such as PCR and gel electrophoresis integrated with creative drama. The students were assessed at the beginning and the end of each project day via mini-tests, experimental and presentation skills evaluation forms. Data showed that students' knowledge about DNA structure and basic molecular biology techniques significantly increased. On the basis of experimental and presentational skills, there was no significant difference between kids from urban and rural schools or between public and boarding public schools, whereas the average score of girls was significantly higher than that of boys. In conclusion, individually performed experiments integrated with creative drama significantly increased students' perception of complex experimental procedures on basic molecular biology concepts. Data suggests that integration of these concepts into the science and technology curriculum of Turkish primary education may support the recruitment of future scientists who can handle rapidly developing genomic techniques that will affect our everyday life. PMID- 24474055 TI - The cytochemistry of the walls of the spermatocytes of Ceratopteris thalictroides. AB - By means of staining and fluorescence microscopy the walls of the spermatocytes of Ceratpteris thalictroides have been shown to contain callose and lipid. It is suggested that these substances form a barrier to the ingress of metabolites, and are responsible for the failure of differentiating spermatocytes to incorporate C(14)-cysteine. PMID- 24474056 TI - [Anatomical and physiological investigations concerning movement of water in needles of Pinus]. AB - The endodermis of the needle in pine consists of a continuous sheath of parenchymatous cells in which the water transport can occur only through the cytoplasma or across the radial walls. Topochemical results have shown that the radial cell walls, in contrast to the tangential ones, contain lignin as well as other aromatic substances and consequently permit only a very limited permeability. The water transport in needles of pine without an epidermis is accompanied by a high temperature coefficient and a sensitivity towards inhibitors. On the basis of these results as well as the behaviour of needles after an abrupt break in transpiration and the fact that the plasma in the endodermis has a high permeability, it can be concluded that in the endodermis of the needle the water transport occurs mainly in the cytoplasm. PMID- 24474057 TI - Gibberellins and geotropism in Zea mays coleoptiles. AB - Diffusible gibberellins were obtainable in agar from excised 4 mm tips of etiolated coleoptiles of Zea mays. Placing the tips in a horizontal position increased the total yield of gibberellins by approximately five times. With horizontal tips, the ratio of gibberellin activity recovered from lower and upper halves, expressed as a percentage of total yield, was 80.76:19.24 (lower:upper). PMID- 24474058 TI - P-Protein in sieve elements : I. Ultrastructure after treatment with vinblastine and colchicine. AB - The ultrastructure of P1 and P2 proteins in the sieve elements of Heracleum mantegazzianum is described. P1-protein tubules are closely associated with stacks of membranes, are often linked by short cross-bridges, and occasionally display a hexagonal packing. Incubation with the alkaloids vinblastine and colchicine had no discernible effects on the ultrastructure of the sieve elements at various stages during differentiation. Evidence for and against any similarities between P1-protein tubules and cytoplasmic microtubules is discussed. PMID- 24474059 TI - [Studies on NaCl-induced crassulacean acid metabolism in Mesembryanthemum crystallinum]. AB - Mesembryanthemum crystallinum plants were grown for 10 weeks in soil culture and, during the final 3 weeks, watered with NaCl solutions varying in concentration between 50 and 500 mM. Plants show an increasingly less negative net CO2 balance and increased malate accumulation in the leaves during the dark with increasing NaCl concentration. There is a positive net CO2 balance above 100 mM with a maximum at 350 mM NaCl. Plants watered with 350 mM NaCl do not display this characteristic feature of crassulacean acid metabolism (CAM) initially, i.e. during the first week after the commencement of NaCl treatment. However, after this adaption period net CO2 balance during the dark begins to approach a positive value. Malate accumulation in the leaves during the dark increases rapidly after the first week of NaCl treatment, reaching a constant level after about 3 weeks. Leaves which develop after commencement of NaCl treatment produce less malate during the dark than leaves which were already present at the onset of NaCl watering. Na(+) content in the leaves is higher than Cl(-) content when plants are watered with NaCl solutions. Four-and-a-half-month-old plants grown under soil culture without addition of NaCl also exhibit CAM, probably because of ion uptake from the soil which causes increase in Na(+) and Cl(-) contents in the leaves. Na2SO4, KCl and K2SO4 have effects similar to those of NaCl on gas exchange reactions of Mesembryanthemum crystallinum. PMID- 24474060 TI - Colchicine-binding protein from phloem and xylem of a higher plant. AB - Colchicine has been demonstrated by ion-exchange and by gelfiltration assay to bind to a protein fraction derived from the higher plant Heracleum mantegazzianum. Colchicine-binding protein from a plant source was much more unstable than tubulin from animal preparations. The tissues of Heracleum vary in their content of colchicine-binding activity. No activity was obtained from non vascular tissue. Phloem has at most, twice as much activity as xylem. The significance of these results is discussed in relation to a proposed degree of homology between P protein of phloem and microtubule protein. PMID- 24474061 TI - Starch hydrolysing enzymes in the developing barley grain. AB - The enzymes alpha-amylase (alpha-1, 4-glucan 4-glucanohydrolase, 3.2.1.1), beta amylase (alpha-1,4-glucan maltohydrolase, 3.2.1.2) and phosphorylase (alpha-1,4 glucan: orthophosphate glucosyltransferase, 2.4.1.1) were assayed in whole grains of barley throughout the maturation period. alpha-amylase and phosphorylase had peaks of activity between 25 and 30 days after anthesis. On the other hand the activity of beta-amylase in both the available and latent forms reached a maximum value at 35 days after anthesis which did not decrease thereafter. beta-amylase activity was also assayed throughout development in the endosperm, aleurone, testa pericarp and embryo. Latent beta-amylase reached a constant maximum value in endosperm at 35 days but available beta-amylase reached a peak of activity at 25 days and then declined to zero at 45 days. Only latent beta-amylase was associated with the aleurone layer and activity rose to a maximum value at 35 days. The testa pericarp had mainly latent beta-amylase whose activity fell from an early maximum at 21 days to zero at 35 days. No hydrolytic activity was associated with the embryo. The phosphorylase activity was low and mainly associated with the endosperm fraction. PMID- 24474062 TI - [The pH-dependence of the uptake of H2PO 4 (-), SO 4 (=), Na (+) and K (+) by Ankistrodesmus braunii and their ionic interactions]. AB - Ion uptake was studied using (32)P, (35)S, (22)Na and (42)K as tracers in synchronized cells of Ankistrodesmus, which were slightly starved with respect to the ions to be investigated. In the light and in the dark, phosphate uptake is maximal between pH 5.5 and 6.5. Whereas Na(+) in comparison to K(+) enhances phosphate uptake in the light (8 to 9-fold) and in the dark, Ca(++) exerts only a slightly stimulatory effect. The stimulation of phosphate binding by Na(+) occurs rapidly, even after less than 5 sec of incubation, and also in the presence of an equimolar concentration of K(+).The pH-dependence of Na(+)-uptake in the light and in the dark is comparable to a dissociation curve: Na(+)-uptake increases with decreasing extracellular H(+)-concentration and is inversely proportional to phosphate uptake in the absence of Na(+). The light:dark ratio of Na(+)-uptake at pH 8 amounts to 7:1. Mere adsorption of Na(+) is similarly dependent on the pH. K(+) strongly competes with Na(+)-uptake, even at pH 8. K(+)-uptake proceeds in a quite different manner from Na(+)-uptake and has an optimum at pH 7.Sulfate is taken up linearly in a biphasic process as a function of time; the pH-optimum lies between pH 7.5 and 8. K(+) but not Na(+) slightly enhances sulfate uptake.The Na(+)-enhancement of phosphate uptake can be related neither to a sodium-potassium exchange pump nor to a photosynthesis-dependent ion-exchange reaction.The results suggest that the uptake of phosphate, Na(+) and K(+), and the influence of alkali cations on phosphate uptake, but not sulfate uptake, are strongly dependent on fixed charges of the plasmalemma or even of the cell wall. These fixed charges may even prevent an active ion uptake. PMID- 24474063 TI - [Studies on the uptake of glycolate by Chlorogonium]. AB - The alga Chlorogonium was cultured either heterotrophically or autotrophically under different partial pressures of CO2 by aerating with pure air of air enriched with 2% CO2. Cells were harvested in the logarithmic phase, transferred to phosphate buffer containing 0.01 M 1C(14)-glycolate and incubated with shaking in the dark. Under these conditions the rate of glycolate uptake was higher when the cells had been grown in the light. Cells grown in the light at the lower CO2 concentration took up more glycolate than those grown with 2% CO2. Approximately 90% of the radioactivity taken up with the glycolate was released as CO2. The radioactivity remaining in the algae was somewhat higher in those cells which had been cultured heterotrophically or autotrophically under air than in cells grown autotrophically under air enriched with 2% CO2.Addition of glycolate increased the uptake of oxygen by the cells. The consumption of the oxygen was quantitatively correlated to the uptake of glycolate. PMID- 24474064 TI - Orientation of cell growth in the etiolated pea stem : Effect of ethylene and auxin on cell wall deposition. AB - Both ethylene and IAA induce swelling in the sub-apical region of etiolated pea plants. The modified cells of these two types of swellings differ both morphologically and in their enzyme composition. In ethylene the cell walls become thickened within 24 h and the level of peroxidase is enhanced; ethylene does not affect cellulase levels. IAA induced swellings are not accompanied by early thickening of cell walls or enhanced peroxidase activity, but IAA greatly increases the level of cellulase. It is proposed that the retardation of extension growth by ethylene treatment results from the deposition of longitudinal microfibrils in the walls and that cross linking bonds in the polysaccharide matrix prevent their separation. Lateral expansion can occur, however, in the presence of auxin-induced cellulase which breaks or prevents the formation of these bonds. PMID- 24474065 TI - Engaging in Coordination of Health and Disability Services as Described by Older Adults: Processes and Influential Factors. AB - PURPOSE OF THE STUDY: There is little consensus on the definition and design of effective care coordination for older adults with chronic conditions, and the majority of care coordination models minimize the role and voice of older patients. Our objectives are to examine how older adults perceive and engage in the process of care coordination of health and disability support services and the factors that influence their engagement. DESIGN AND METHODS: Thirty-seven older adults with chronic conditions and 9 geriatric case managers participated in semistructured interviews that focused on older adults' experiences with self managing and coordinating their health and support services. Interview data were systematically analyzed for themes. RESULTS: The interview data revealed that involving older adults in care coordination is a complex, multistage process, conceptualized as making self-health assessments, making informed decisions about care, and executing and coordinating care. The findings indicate that a number of factors facilitate older adults' decision and capacity to become involved in the coordination of their care, including their perceptions about how their condition impacted their everyday lives, and availability of intrinsic resources, tangible resources, and social network. Low perceptions of control over health and lack of such resources constrain their involvement. IMPLICATIONS: Practitioners may facilitate older adults' involvement in care coordination by using language with older patients that emphasizes psychosocial experiences in addition to medical symptomatology. They may also provide targeted support for patients with limited facilitating factors to promote involvement at multiple stages of the care coordination process. PMID- 24474066 TI - Discussion: Robotic-assisted FAMM flap for soft palate reconstruction. PMID- 24474067 TI - Agreement between FRAX scores calculated with and without bone mineral density in women with osteopenia in Turkey. AB - This study aimed to analyze the agreement between FRAX scores calculated with and without femoral neck (FN) bone mineral density (BMD) and to investigate the resultant treatment recommendations in women with osteopenia. A cross-sectional review of postmenopausal women who were referred for DXA evaluation was conducted. One hundred twenty-nine postmenopausal women aged 40 years and older with osteopenia [FN T-score between -1 and (-2.5)] were recruited for the study. Absolute agreement between FRAX scores calculated with and without BMD was analyzed by intraclass correlation analysis (ICC). Thresholds recommended by National Osteoporosis Foundation were used for treatment recommendations. Correlation between demographic factors and the difference in BMD+ and BMD- FRAX scores was analyzed by Spearman correlation test. Agreement levels and treatment recommendations were also analyzed in 112/129 patients without previous fracture. Agreement between BMD+ and BMD- MO and hip FRAX scores was good (ICC 0.867) and fair to good (ICC 0.641), respectively. In patients without previous fracture, agreement between MO and hip fracture probabilities was good (ICC = 0.838 and ICC = 0.778, respectively). Treatment recommendations with respect to treatment threshold of >=3 for hip fracture probabilities were identical in 120/129 (93 %) cases. Difference between BMD+ and BMD- fracture probabilities was correlated with age and FN BMD. In most cases, FRAX without BMD provided the same treatment recommendations as FRAX with BMD in postmenopausal women with osteopenia. Exclusion of patients with previous fracture yielded better agreement levels. PMID- 24474068 TI - S/MAR sequence confers long-term mitotic stability on non-integrating lentiviral vector episomes without selection. AB - Insertional oncogene activation and aberrant splicing have proved to be major setbacks for retroviral stem cell gene therapy. Integrase-deficient human immunodeficiency virus-1-derived vectors provide a potentially safer approach, but their circular genomes are rapidly lost during cell division. Here we describe a novel lentiviral vector (LV) that incorporates human beta-interferon scaffold/matrix-associated region sequences to provide an origin of replication for long-term mitotic maintenance of the episomal LTR circles. The resulting 'anchoring' non-integrating lentiviral vector (aniLV) achieved initial transduction rates comparable with integrating vector followed by progressive establishment of long-term episomal expression in a subset of cells. Analysis of aniLV-transduced single cell-derived clones maintained without selective pressure for >100 rounds of cell division showed sustained transgene expression from episomes and provided molecular evidence for long-term episome maintenance. To evaluate aniLV performance in primary cells, we transduced lineage-depleted murine hematopoietic progenitor cells, observing GFP expression in clonogenic progenitor colonies and peripheral blood leukocyte chimerism following transplantation into conditioned hosts. In aggregate, our studies suggest that scaffold/matrix-associated region elements can serve as molecular anchors for non integrating lentivector episomes, providing sustained gene expression through successive rounds of cell division and progenitor differentiation in vitro and in vivo. PMID- 24474069 TI - The impact of elevated CO2 concentration on the quality of algal starch as a potential biofuel feedstock. AB - Cultured microalgae are viewed as important producers of lipids and polysaccharides, both of which are precursor molecules for the production of biofuels. This study addressed the impact of elevated carbon dioxide (CO2) on Chlorella sorokiniana production of starch and on several properties of the starch produced. The production of C. sorokiniana biomass, lipid and starch were enhanced when cultures were supplied with 2% CO2. Starch granules from algae grown in ambient air and 2% CO2 were analyzed by transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The granules from algae grown in 2% CO2 were disk-shaped and contained mainly stromal starch; granules from cultures grown in ambient air were cup-shaped with primarily pyrenoid starch. The granules from cells grown in 2% CO2 had a higher proportion of the accumulated starch as the highly branched, amylopectin glucan than did granules from cells grown in air. The rate of hydrolysis of starch from 2% CO2-grown cells was 1.25 times greater than that from air-grown cells and 2-11 times higher than the rates of hydrolysis of starches from cereal grains. These data indicate that culturing C. sorokiniana in elevated CO2 not only increases biomass yield but also improves the structure and composition of starch granules for use in biofuel generation. These modifications in culture conditions increase the hydrolysis efficiency of the starch hydrolysis, thus providing potentially important gains for biofuel production. PMID- 24474070 TI - Quality improvement in hospital management of community-acquired pneumonia: focus on new strategies and current challenges. AB - Community-acquired pneumonia is a common reason for hospitalization and leads to significant morbidity and mortality. There are published evidence-based guidelines for the diagnosis, treatment, and management of community-acquired pneumonia. Many countries, including the US, have developed national, publically reported quality measures related to the treatment of community-acquired pneumonia. This review highlights recent published innovations aimed at improving the quality of care for patients hospitalized for community-acquired pneumonia. Interventions include standardized protocols and pathways, education and feedback from antimicrobial stewardship teams, and automated pharmacy technology. The importance of multidisciplinary collaboration and multidimensional interventions are discussed. Insight into local context and institutional support are essential to understanding the implementation of improvement efforts and these factors should be reported in future publications related to quality improvement. PMID- 24474071 TI - Hot carrier filtering in solution processed heterostructures: a paradigm for improving thermoelectric efficiency. AB - An approach based on a solution-based synthesis that produces a thermally stable Ag/oxide/S2 Te3 -Te metal-semiconductor heterostructure is described. With this approach, a figure of merit of zT = 1.0 at 460 K is achieved, a record for a heterostructured material made using wet chemistry. Combining experiments and theory shows that the large increase in the material's Seebeck coefficient results from hot carrier filtering. PMID- 24474072 TI - Observational studies: why are they so important? PMID- 24474073 TI - Knowledge, attitudes and practices regarding the Pap test among women in Northeastern Brazil. AB - CONTEXT AND OBJECTIVE: The Papanicolaou (Pap) test has been shown to be effective in preventing cervical cancer. However, both the national and international literature shows that Pap testing has not reached the level of coverage desired. The objective of this study was to assess women's knowledge, attitudes and practices regarding the Pap test and to investigate whether there are any associations between these three factors and the women's sociodemographic characteristics. DESIGN AND SETTING: Cross-sectional descriptive study conducted in Floriano, Piaui. METHODS: The study was conducted among 493 women between November 2009 and December 2010. A questionnaire with precoded questions was sed, and the responses were analyzed in terms of appropriateness in relation to the Pap test. RESULTS: The degrees of adequacy of knowledge, attitudes and practices regarding the Pap test were 36.7%, 67.2% and 69.6%, respectively. Among the main barriers against testing, absence of symptoms and a sense of embarrassment were the most notable. CONCLUSIONS: Women who visit doctors periodically had the most appropriate practices regarding the Pap test, but their knowledge of the procedure was poor. This suggests that these women were not receiving adequate information about the benefits of periodic testing. PMID- 24474074 TI - Patent blue and air as an alternative for resection of nonpalpable breast lesions: a case series. AB - CONTEXT AND OBJECTIVE: Use of mammography for breast cancer screening has resulted in a significantly increased number of patients with nonpalpable radiological findings that need histopathological study for better management. The present study evaluated an alternative to excision of nonpalpable breast lesions, using injection of patent blue (CAS 3536-49-0) dye and air. DESIGN AND SETTING: Cohort study of 64 consecutive patients at a private clinic in the city of Teresina (Piaui), between January 2009 and December 2010. METHODS: The patients had received mammographic diagnoses of nonpalpable breast lesions classified as BI-RADS 3, 4 and 5, with indication of histopathological study. They underwent stereotaxy and/or ultrasound-guided injection of patent blue, for marking and subsequent excision of the lesion. RESULTS: The patients' mean age was 47.7 years. Nodes accounted for 53.1% of the breast abnormalities; microcalcifications, 37.5%; and complex cysts, 9.4%. In 89.1% of cases, the lesions were BI-RADS 4; 7.8% were BI-RADS 5 and 3.1% were BI-RADS 3. The histopathological findings were benign in 70.3% of the cases; atypical hyperplasia, 9.4%; and malignant, 20.3%. Among the malignant cases, 53.8% were carcinoma in situ and 46.2%, invasive carcinoma. The percentage of malignancy was 0% in BI-RADS 3 lesions; 14.3% in BI-RADS 4 and 100% in BI-RADS 5. In the cases of malignancy, the margins were clear in 92.3%. Reoperation to widen the margins was required in one patient. CONCLUSION: Excision of nonpalpable breast lesions marked with patent blue and air was possible in all cases. PMID- 24474075 TI - Follow-up of women with atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions (ASC-H). AB - CONTEXT AND OBJECTIVE: The concept that the presence of atypical squamous cells cannot exclude high-grade squamous intraepithelial lesions (ASC-H) was introduced in the 2001 Bethesda System of cervical cytology classification. This nomenclature defines cervical cancer precursor lesions. The objective of this study was to investigate the colpocytological-histological results from a three year follow-up conducted on a cohort of women with reports of ASC-H who were attended during 2005-2006 at clinics of the Southern Metropolitan Healthcare Service of Santiago, Chile. DESIGN AND SETTING: Prospective cohort study at primary healthcare clinics in Santiago, Chile. METHODS: Colpocytological histological follow-up was conducted over a three-year period on 92 women with cytological reports of ASC-H who were attended at primary healthcare clinics during 2005-2006. RESULTS: At the end of the follow-up period, high-grade lesions were evaluated and the following outcomes were observed: seven women presented invasive cancer (7.6%), 49 presented high-grade lesions (53.3%), 26 presented low grade lesions (28.2%) and 10 presented normal results (10.9%). The "Conditional Probabilities Tree Diagram" was used to show the results from tests and the times of lesion detection. It demonstrated that, after a first report of ASC-H, clinical management needed to be interventionist. CONCLUSION: The follow-up on our cohort of women showed that the majority of uncertain ASC-H diagnoses (82.6%) had abnormal colposcopic results and that during the follow-up using ASC-H smears, two out of every three women developed high-grade lesions. PMID- 24474076 TI - Relationship between mental health and spiritual wellbeing among hemodialysis patients: a correlation study. AB - CONTEXT AND OBJECTIVE: The stress of living with a terminal disease has a negative impact on the mental health of hemodialysis (HD) patients. Spirituality is a potential coping mechanism for stressful experiences. Studies on the relationship between spirituality and mental health among HD patients are scarce. The purpose of this study was to evaluate the relationship between mental health and spiritual well-being among HD patients. DESIGN AND SETTING: Cross-sectional observational study on hemodialysis patients at a single center in Brazil, between January and December 2011. METHODS: Mental health was assessed using the General Health Questionnaire and spiritual wellbeing was assessed using the Spiritual Wellbeing Scale; 150 HD patients participated in the study. RESULTS: A significant correlation was found between mental health and spiritual wellbeing (P = 0.001). Spiritual wellbeing was the strongest predictor of mental health, psychological distress, sleep disturbance and psychosomatic complaints. CONCLUSION: Poor mental health was associated with lower spiritual wellbeing. This has important implications for delivery of palliative care to HD patients. PMID- 24474077 TI - Cold ischemia or topical-ECMO for lung preservation: a randomized experimental study. AB - CONTEXT AND OBJECTIVE: Lung preservation remains a challenging issue for lung transplantation groups. Along with the development of ex vivo lung perfusion, a new preservation method known as topical-ECMO (extracorporal membrane oxygenation) has been proposed. The present study compared topical-ECMO with cold ischemia (CI) for lung preservation in an ex vivo experimental model. DESIGN AND SETTING: Randomized experimental study, conducted at a public medical school. METHOD: Fourteen human lungs were retrieved from seven brain-dead donors that were considered unsuitable for transplantation. The lung bloc was divided and each lung was randomized to be preserved by means of topical-ECMO or CI (4-7 degrees C) for eight hours. These lungs were then reconnected to an ex vivo perfusion system for functional evaluation. Lung biopsies were obtained at three times. The functional variables assessed were oxygenation capacity (OC) and pulmonary artery pressure (PAP); and the histological variables were lung injury score (LIS) and apoptotic cell count (ACC). RESULTS: The mean OC was 468 mmHg (+/ 81.6) in the topical-ECMO group and 455.8 (+/- 54) for CI (P = 0.758). The median PAP was 140 mmHg (120-160) in the topical-ECMO group and 140 mmHg (140 150) for CI (P = 0.285). The mean LIS was 35.57 (+/- 4.5) in the topical-ECMO group and 33.86 (+/- 6.1) for CI (P = 0.367). The ACC was 25.00 (+/- 9.34) in the topical-ECMO group and 24.86 (+/- 10.374) for CI (P = 0.803). CONCLUSIONS: The present study showed that topical-ECMO was not superior to cold ischemia for up to eight hours of lung preservation. PMID- 24474078 TI - Frequencies of interleukin-6, GST and progesterone receptor gene polymorphisms in postmenopausal women with low bone mineral density. AB - CONTEXT AND OBJECTIVE: Osteoporosis is a skeletal disorder characterized by low bone mineral density (BMD). Studies have shown that some of the genetic components relating to lower BMD may be detected by polymorphisms. Our aim was to evaluate the frequencies of interleukin-6, GST and progesterone receptor gene polymorphisms in postmenopausal women with low BMD. DESIGN AND SETTING: Cross sectional study, conducted in a public university in Sao Paulo, Brazil. METHODS: We evaluated interleukin-6 (IL-6), progesterone receptor gene (PROGINS) and glutathione S-transferase (GST) polymorphisms in 110 postmenopausal women with no previous use of hormone therapy. Tests were performed using DNA-PCR, from oral scrapings. We used Student's t-test and a logistic regression model for statistical analysis. RESULTS: Regarding IL-6 polymorphism, 58.2% of the patients were homozygotes (GG) and 41.8% had allele C (heterozygote or mutant homozygote + GC or CC). PROGINS genotype polymorphism was absent in 79% (wild homozygote or P1/P1) and present in 20.9% (heterozygote or P1/P2). Regarding GSTM1 polymorphism, the allele (1/1) was present in 72.7% of the patients and was absent in 27.3%. We found that IL-6 polymorphism had statistically significant correlations with the L2-L4 T-score (P = 0.032) and with BMD (P = 0.005). Women with IL-6 polymorphism were 2.3 times more likely to have a L2-L4 T-score of less than -1, compared with those not presenting this polymorphism. CONCLUSION: IL-6 gene polymorphism was correlated with low BMD, whereas the PROGINS and GSTM1 polymorphisms did not show any correlation. PMID- 24474079 TI - Continuous positive airway pressure (CPAP) after lung resection: a randomized clinical trial. AB - CONTEXT AND OBJECTIVE: Noninvasive mechanical ventilation during the postoperative period (PO) following lung resection can restore residual functional capacity, improve oxygenation and spare the inspiratory muscles. The objective of this study was to assess the efficacy of continuous positive airway pressure (CPAP) associated with physiotherapy, compared with physiotherapy alone after lung resection. DESIGN AND SETTING: Open randomized clinical trial conducted in the clinical hospital of Universidade Estadual de Campinas. METHOD: Sessions were held in the immediate postoperative period (POi) and on the first and second postoperative days (PO1 and PO2), and the patients were reassessed on the discharge day. CPAP was applied for two hours and the pressure adjustment was set between 7 and 8.5 cmH2O. The oxygenation index (OI), Borg scale, pain scale and presence of thoracic drains and air losses were evaluated. RESULTS: There was a significant increase in the OI in the CPAP group in the POi compared to the Chest Physiotherapy (CP) group, P = 0.024. In the CP group the OI was significantly lower on PO1 (P = 0,042), than CPAP group. The air losses were significantly greater in the CPAP group in the POi and on PO1 (P = 0.001, P = 0.028), but there was no significant difference between the groups on PO2 and PO3. There was a statistically significant difference between the groups regarding the Borg scale in the POi (P < 0.001), but there were no statistically significant differences between the groups regarding the pain score. CONCLUSION: CPAP after lung resection is safe and improves oxygenation, without increasing the air losses through the drains. CLINICAL TRIAL REGISTRATION: NCT01285648. PMID- 24474080 TI - Treatment of children and adolescents with hemangioma using propranolol: preliminary results from a retrospective study. AB - CONTEXT AND OBJECTIVE: Hemangiomas are the commonest vascular tumors during childhood. In 2008, the effect of propranolol for treating capillary hemangiomas was demonstrated. Other similar results followed, showing that it rapidly reduces lesion volume. The objective here was to evaluate children and adolescents with hemangiomas that were treated with propranolol. DESIGN AND SETTING: Retrospective study, conducted in a children's hospital. METHODS: Patients aged 0-19 years with or without previous treatment, who were treated between January 2009 and December 2010, were included. The response was assessed by comparing the lesion appearance between the start of treatment and the last consultation. We considered partial or complete responses as the response to treatment. RESULTS: Sixty-nine patients with a median follow-up of 11 months (mean age: 31 months) were included. Of these, 58 patients were recently diagnosed and 11 had had previous treatment. A response (partial or complete) was seen in 60 patients (87%). Among the capillary hemangioma cases, responses were seen in 50 out of 53 (94%), while in other lesion types, it was 10 out of 16 (63%) (P = 0.3; chi-square). Responses in patients less than one year of age were seen in 37 out of 38 (97%), whereas in those over one year of age, in 23 out of 31 (74%) (P = 0.4; chi-square). Side effects were uncommon and mild. CONCLUSIONS: Propranolol seemed to be effective for treatment of hemangiomas in children and adolescents, and not just in the proliferative stage, with responses in almost all the patients. PMID- 24474081 TI - Interaction between pharmaceutical companies and physicians who prescribe antiretroviral drugs for treating AIDS. AB - CONTEXT AND OBJECTIVE: Given that Brazil has a universal public policy for supplying medications to treat HIV and AIDS, the aim here was to describe the forms of relationship between physicians and the pharmaceutical companies that produce antiretrovirals (ARVs). DESIGN AND SETTING: Cross-sectional epidemiological study conducted in the state of Sao Paulo. METHODS: Secondary database linkage was used, with structured interviews conducted by telephone among a sample group of 300 physicians representing 2,361 professionals who care for patients with HIV and AIDS. RESULTS: Around two thirds (64%) of the physicians prescribing ARVs for HIV and AIDS treatment in the state of Sao Paulo who were interviewed declared that they had some form of relationship with pharmaceutical companies, of which the most frequent were receipt of publications (54%), visits by sales promoters (51%) and receipt of small-value objects (47%). CONCLUSIONS: Two forms of relationship between the pharmaceutical industry and physicians who deal with HIV and AIDS can be highlighted: facilitation of professionals' access to continuing education; and antiretroviral drug brand name promotion. PMID- 24474082 TI - Muir-Torre syndrome: case report and molecular characterization. AB - CONTEXT: Muir-Torre syndrome is a rare autosomal dominant genodermatosis caused by mutations in the mismatch repair genes. It is characterized by the presence of sebaceous skin tumors and internal malignancies, affecting mainly the colon, rectum and urogenital tract. Awareness of this syndrome among physicians can lead to early diagnosis of these malignancies and a better prognosis. CASE REPORT: We report the case of a Chilean patient who, over the course of several years, had multiple skin lesions, endometrial cancer and colon cancer. The syndrome was diagnosed using molecular techniques such as microsatellite instability analysis, immunohistochemistry and DNA sequencing, which allowed us to find the causative mutation. CONCLUSION: Molecular diagnostics is a highly useful tool, since it allows clinicians to confirm the presence of mutations causing Muir-Torre syndrome. It is complementary to the analysis of the clinical data, such as dermatological presentation, presence of visceral malignancies and family history of colorectal tumors, and it provides important knowledge to help physicians and patients choose between treatment options. PMID- 24474083 TI - Intramuscular lipoma of the subscapularis muscle. AB - CONTEXT: Intramuscular lipomas are benign tumors that infiltrate the muscles. CASE REPORT: We describe the case of a 58-year-old female patient with an axillary lump. The lump was a lipoma inside the subscapularis muscle. It is important to differentiate these lesions from liposarcomas and from other diseases that may present as axillary lumps. The most accurate imaging method for differentiating benign lipomatous tumors from liposarcomas is magnetic resonance imaging, but surgical removal of these intramuscular lesions to confirm the diagnosis is recommended. CONCLUSION: Intramuscular lipomas are a rare cause of benign axillary lumps and should be considered in making differential diagnoses on axillary masses. PMID- 24474084 TI - Interventions for promoting the initiation of breastfeeding. AB - BACKGROUND: Despite the widely documented health advantages of breastfeeding over formula feeding, initiation rates remain relatively low in many high-income countries, particularly among women in lower income groups. OBJECTIVE: To evaluate the effectiveness of interventions which aim to encourage women to breastfeed in terms of changes in the number of women who start to breastfeed. METHODS: SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (July 2007), handsearched the Journal of Human Lactation, Health Promotion International and Health Education Quarterly from inception to 15 August 2007, and scanned reference lists of all articles obtained. SELECTION CRITERIA: Randomized controlled trials, with or without blinding, of any breastfeeding promotion intervention in any population group except women and infants with a specific health problem. DATA COLLECTION AND ANALYSIS: One review author independently extracted data and assessed trial quality, checked by a second author. We contacted investigators to obtain missing information. MAIN RESULTS: Main results: Eleven trials were included. Statistical analyses were conducted on data from eight trials (1553 women). Five studies (582 women) on low incomes in the USA with typically low breastfeeding rates showed breastfeeding education had a significant effect on increasing initiation rates compared to standard care (risk ratio (RR) 1.57, 95% confidence interval (CI) 1.15 to 2.15, P = 0.005). Subgroup analyses showed that one-to-one, needs-based, informal repeat education sessions and generic, formal antenatal education sessions are effective in terms of an increase in breastfeeding rates among women on low incomes regardless of ethnicity and feeding intention. Needs-based, informal peer support in the antenatal and postnatal periods was also shown to be effective in one study conducted among Latina women who were considering breastfeeding in the USA (RR 4.02, 95% CI 2.63 to 6.14, P < 0.00001). AUTHORS' CONCLUSIONS: This review showed that health education and peer support interventions can result in some improvements in the number of women beginning to breastfeed. Findings from these studies suggest that larger increases are likely to result from needs-based, informal repeat education sessions than more generic, formal antenatal sessions. These findings are based only on studies conducted in the USA, among women on low incomes with varied ethnicity and feeding intention, and this raises some questions regarding generalisability to other settings. PMID- 24474085 TI - Endovenous ablation (radiofrequency and laser) and foam sclerotherapy versus conventional surgery for great saphenous vein varices. AB - BACKGROUND: Minimally invasive techniques to treat great saphenous varicose veins include ultrasound-guided foam sclerotherapy (USGFS), radiofrequency ablation (RFA) and endovenous laser therapy (EVLT). Compared with conventional surgery (high ligation and stripping (HL/S)), proposed benefits include fewer complications, quicker return to work, improved quality of life (QoL) scores, reduced need for general anaesthesia and equivalent recurrence rates. OBJECTIVE: To review available randomized controlled clinical trials (RCT) data comparing USGFS, RFA, EVLT to HL/S for the treatment of great saphenous varicose veins. METHODS: SEARCH METHODS: The Cochrane Peripheral Vascular Diseases (PVD) Group searched their Specialized Register (July 2010) and CENTRAL (The Cochrane Library 2010, Issue 3). In addition the authors performed a search of EMBASE (July 2010). Manufacturers of EVLT, RFA and sclerosant equipment were contacted for trial data. SELECTION CRITERIA: All RCTs of EVLT, RFA, USGFS and HL/S were considered for inclusion. Primary outcomes were recurrent varicosities, recanalization, neovascularization, technical procedure failure or need for re-intervention, patient quality of life (QoL) scores and associated complications. Secondary outcomes were type of anaesthetic, procedure duration, hospital stay and cost. DATA COLLECTION AND ANALYSIS: CN, RE, VB, PC, HB and GS independently reviewed, assessed and selected trials which met the inclusion criteria. CN and RE extracted data. The Cochrane Collaboration's tool for assessing risk of bias was used. CN contacted trial authors to clarify details. MAIN RESULTS: Thirteen reports from five studies with a combined total of 450 patients were included. Rates of recanalization were higher following EVLT compared with HL/S, both early (within four months) (5/149 versus 0/100; odds ratio (OR) 3.83, 95% confidence interval (CI) 0.45 to 32.64) and late recanalization (after four months) (9/118 versus 1/80; OR 2.97; 95% CI 0.52 to 16.98), although these results were not statistically significant. Technical failure rates favoured EVLT over HL/S (1/149 versus 6/100; OR 0.12, 95% CI 0.02 to 0.75). Recurrence following RFA showed no difference when compared with surgery. Recanalization within four months was observed more frequently following RFA compared with HL/S although not statistically significant (4/105 versus 0/88; OR 7.86, 95% CI 0.41 to 151.28); after four months no difference was observed. Neovascularization was observed more frequently following HL/S compared with RFA, but again this was not statistically significant (3/42 versus 8/51; OR 0.39, 95% CI 0.09 to 1.63). Technical failure was observed less frequently following RFA compared with HL/S although this was not statistically significant (2/106 versus 7/96; OR 0.48, 95% CI 0.01 to 34.25). No randomised clinical trials comparing HL/S versus USGFS met our study inclusion criteria. QoL scores and operative complications were not amenable to meta-analysis. AUTHORS' CONCLUSIONS: Currently available clinical trial evidence suggests RFA and EVLT are at least as effective as surgery in the treatment of great saphenous varicose veins. There are insufficient data to comment on USGFS. Further randomized trials are needed. We should aim to report and analyze results in a congruent manner to facilitate future meta-analysis. PMID- 24474086 TI - Elevated plasma CL-K1 level is associated with a risk of developing disseminated intravascular coagulation (DIC). AB - Collectin kidney 1 (CL-K1) is a recently identified collectin that is synthesized in most organs and circulates in blood. CL-K1 is an innate immune molecule that may play a significant role in host defense. As some collectins also play a role in coagulation, we hypothesized that an effect of CL-K1 may be apparent in disseminated intravascular coagulation (DIC), a gross derangement of the coagulation system that occurs in the setting of profound activation of the innate immune system. DIC is a grave medical condition with a high incidence of multiple organ failure and high mortality and yet there are no reliable biomarkers or risk factors. In our present study, we measured plasma CL-K1 concentration in a total of 659 specimens, including 549 DIC patients, 82 non-DIC patients and 27 healthy volunteers. The median plasma CL-K1 levels in these cohorts were 424, 238 and 245 ng/ml, respectively, with no significant difference in the latter two groups. The incidence of elevated plasma CL-K1 was significantly higher in the DIC patients compared to the non-DIC patients, resulting in an odds ratio of 1.929 (confidence interval 1.041-3.866). Infection, renal diseases, respiratory diseases, and cardiac diseases were more frequently observed in the DIC group than in the non-DIC group. In the DIC group, vascular diseases were associated with elevated plasma CL-K1 levels while age and acute illness had little effect on plasma CL-K1 levels. Independent of DIC, elevated plasma CL-K1 levels were associated with respiratory disease and coagulation disorders. These results suggest that specific diseases may affect CL-K1 synthesis in an organ dependent manner and that elevated plasma CL-K1 levels are associated with the presence of DIC. Further investigations in cohorts of patients are warranted. We propose that elevated plasma CL-K1 may be a new useful risk factor and possibly biomarker for the prediction of developing DIC. PMID- 24474087 TI - Beneficial effects of hydro-alcoholic extract of Caralluma fimbriata against high fat diet-induced insulin resistance and oxidative stress in Wistar male rats. AB - The main aim of this study was to investigate the beneficial effects of hydro alcoholic extract of Caralluma fimbriata (CFE) on the effects of high-fat diet feeding on insulin resistance and oxidative stress in Wistar rats. High-fat diet (60% of fat) and CFE (200 mg/kg body weight/day) were given concurrently to the rats for a period of 90 days. Feeding with high-fat diet resulted in the development of hyperglycemia, hyperinsulinemia, hyperleptinemia, and hypertriglyceridemia and impaired insulin sensitivity (P < 0.05). Administration of CFE to high-fat diet-fed rats for 90 days resulted in a significant improvement in plasma glucose, insulin, leptin, and triglycerides. Regarding liver antioxidant status, high-fat fed rats showed higher levels of lipid peroxidation, protein oxidation and lower GSH levels and lower activities of enzymatic antioxidants, while CFE treatment prevented all these observed abnormalities. In conclusion, intake of CFE may be beneficial for the suppression of high-fat diet-induced insulin resistance and oxidative stress. PMID- 24474088 TI - The effect of a collar and surface finish on cemented femoral stems: a prospective randomised trial of four stem designs. AB - PURPOSE: The optimal design for a cemented femoral stem remains a matter of debate. Over time, the shape, surface finish and collar have all been modified in various ways. A clear consensus has not yet emerged regarding the relative merits of even the most basic design features of the stem. We undertook a prospective randomised trial comparing surface finish and the effect of a collar on cemented femoral component subsidence, survivorship and clinical function. METHODS: One hundred and sixty three primary total hip replacement patients were recruited prospectively and randomised to one of four groups to receive a cemented femoral stem with either a matt or polished finish, and with or without a collar. RESULTS: At two years, although there was a trend for increased subsidence in the matt collarless group, this was not statistically significant (p = 0.18). At a mean of 10.1 years follow-up, WOMAC scores for the surviving implants were good, (Range of means 89-93) without significant differences. Using revision or radiographic loosening as the endpoint, survivorship of the entire cohort was 93 % at 11 yrs, (CI 87-97 %). There were no significant differences in survivorship between the two groups with polished stems or the two groups with matt stems. A comparison of the two collarless stems demonstrated a statistically significant difference in survivorship between polished (100 %) and matt (88 %) finishes (p = 0.02). CONCLUSIONS: In the presence of a collar, surface finish did not significantly affect survivorship or function. Between the two collarless groups a polished surface conferred an improved survivorship. PMID- 24474089 TI - Quality of transfusion products in blood banking. AB - The primary goal in transfusion medicine and cellular therapies is to promote high standards of quality and produce ever safer and more efficacious products. The establishment of a transfusion service quality management system, which includes several organizational structures, responsibilities, policies, processes, procedures, and resources, is now mandatory and widely regulated worldwide. In this review, we summarize the current knowledge on the quality system in transfusion medicine as applied to the production of blood components, including red blood cells, platelets, and fresh frozen plasma. PMID- 24474090 TI - Identification of p.W246L as a novel mutation in the GP1BA gene responsible for platelet-type von Willebrand disease. AB - Platelet-type von Willebrand disease (PT-VWD) and type 2B von Willebrand disease (2B-VWD) are rare bleeding disorders characterized by increased ristocetin induced platelet aggregation (RIPA) at low concentrations of ristocetin. Diagnosis of either condition is not easy and the differential diagnosis between the two entities is especially challenging as evidenced by high levels of misdiagnosis of both conditions, but particularly PT-VWD. Five mutations in the GP1BA gene related to PT-VWD and less than 50 patients are currently reported worldwide. We herein describe a patient with severe bleeding symptoms, macrothrombocytopenia, mild spontaneous platelet aggregation, positive RIPA at 0.3 and 0.4 mg/mL, von Willebrand factor ristocetin cofactor (VWF:RCo) to antigen (VWF:Ag) < 0.2, normal VWF propeptide/VWF:Ag ratio, and RIPA mixing tests and cryoprecipitate challenge positive for PT-VWD. GP1BA gene was studied in the patient, in his mother, and in 100 healthy control subjects. We identified a heterozygous substitution G > T located at nucleotide 3805 in the g.DNA of the patient's GP1BA gene, resulting in a Trp to Leu amino acid change at residue 246 (p.W246L). This mutation was absent in his unaffected mother and also in the 100 controls, and was predicted as damaging by in silico analysis. The residue W246 is located within the VWF-binding region and exists in a strongly conserved position in the phylogenetic tree, which is expected to be unable to tolerate substitutions without changing its functional characteristics. These findings argue strongly in favor of the view that this substitution does not represent a polymorphism and is therefore responsible for the PT-VWD phenotype of the patient. PMID- 24474091 TI - Sex bias in referral of women to outpatient cardiac rehabilitation? A meta analysis. AB - BACKGROUND: Cardiovascular disease continues to be among the leading causes of morbidity and mortality among men and women globally. However, research suggests that women are significantly underrepresented in cardiac rehabilitation (CR), programmes which are shown to reduce recurrent cardiac events and related premature death. However, sex differences in referral rates have not been systematically and quantitatively reviewed. Hence, the objective of the study was to assess whether a significant sex difference exists. METHODS: We searched Scopus, MEDLINE, CINAHL, PsycINFO, PubMed, and The Cochrane Library databases for studies reporting CR referral rates in women and men published between July 2000 and July 2011. Titles and abstracts were screened, and the selected full-text articles were independently screened based on predefined inclusion/exclusion criteria. Included articles were assessed for quality using STROBE. RESULTS: Of 623 screened articles, 19 observational studies reporting data for 241,613 participants (80,505 women) met the inclusion criteria. In the pooled analysis, women (39.6%) were significantly less likely to be referred to CR compared to men (49.4%; odds ratio 0.68, 95% confidence interval 0.62-0.74). Heterogeneity was considered significant (I (2 )= 90%). There was no change in significant findings when subgroup analyses were conducted, examining fee for service vs. no fee, high quality studies vs. others, or studies pooled by different study methodologies. CONCLUSIONS: CR referral remains low for all patients, but is significantly lower for women than men. Evidence-based interventions to increase referral for all patients, including women, need to be instituted. It is time to ensure broader implementation of these strategies. PMID- 24474092 TI - Attenuation of acne scars using high power fractional ablative unipolar radiofrequency and ultrasound for transepidermal delivery of bioactive compounds through microchannels. AB - BACKGROUND AND OBJECTIVE: To determine the efficacy and safety of a new method for treating acne scarring over a short-term period of 2 months and a long-term period of 6 months. MATERIALS AND METHODS: Six faces and 13 shoulders or backs for a total of 19 patients were treated, all of which displayed varying degrees of acne scarring, from moderate to severe. A newly developed high-power unipolar fractional ablative radiofrequency technology was used (iPixelTM RF, Alma Lasers, Caesarea, Israel), with acoustic pressure ultrasound guided dermal injection of the PixelTreat Scars preparation (Alma Lasers), through RF Pixel fractionated microchannels. All patients underwent four treatment sessions at 3-week intervals. RESULTS: Significant improvement was observed in scarring, both on the face (P < 0.0001), and on the back and shoulders (P < 0.0001). After 2 months, the percentage of fading on total scarring was 57% on the face and 49% on the back and shoulders; after 6 months, the percentage increased to 62% on the face, and 58% on the back and shoulders, respectively. Patients reported to be Somewhat Satisfied (16%), Satisfied (53%), and Very Satisfied (31%). No unexpected side effects to the ablation and no hypersensitive reactions to PixelTreat Scars were observed. CONCLUSION: The bimodal procedure is safe and effective in reducing acne scarring. This represents a new therapeutic alternative of great interest, to be used either as a monotherapy, or in combination with other treatments. PMID- 24474094 TI - Patch tests. AB - Patch tests were introduced as a diagnostic tool in the late nineteenth century. Since then, they have improved considerably becoming what they are today. Patch tests are used in the diagnostic investigation of contact dermatitis worldwide. Batteries or series previously studied and standardized should be used in patch testing. The methodology is simple, but it requires adequate training for the results to be correctly interpreted and used. Despite having been used for over a century, it needs improvement like all other diagnostic techniques in the medical field. PMID- 24474093 TI - Giant congenital melanocytic nevus. AB - Giant congenital melanocytic nevus is usually defined as a melanocytic lesion present at birth that will reach a diameter >= 20 cm in adulthood. Its incidence is estimated in <1:20,000 newborns. Despite its rarity, this lesion is important because it may associate with severe complications such as malignant melanoma, affect the central nervous system (neurocutaneous melanosis), and have major psychosocial impact on the patient and his family due to its unsightly appearance. Giant congenital melanocytic nevus generally presents as a brown lesion, with flat or mammilated surface, well-demarcated borders and hypertrichosis. Congenital melanocytic nevus is primarily a clinical diagnosis. However, congenital nevi are histologically distinguished from acquired nevi mainly by their larger size, the spread of the nevus cells to the deep layers of the skin and by their more varied architecture and morphology. Although giant congenital melanocytic nevus is recognized as a risk factor for the development of melanoma, the precise magnitude of this risk is still controversial. The estimated lifetime risk of developing melanoma varies from 5 to 10%. On account of these uncertainties and the size of the lesions, the management of giant congenital melanocytic nevus needs individualization. Treatment may include surgical and non-surgical procedures, psychological intervention and/or clinical follow-up, with special attention to changes in color, texture or on the surface of the lesion. The only absolute indication for surgery in giant congenital melanocytic nevus is the development of a malignant neoplasm on the lesion. PMID- 24474095 TI - Using 80% trichloroacetic acid in the treatment of ingrown toenails. AB - BACKGROUND: Ingrown nails are a very common problem. There are different stages of disease and diverse therapeutic options. Phenol and sodium hydroxide are commonly used agents for chemical matricectomy but both frequently entail excessive healing times. OBJECTIVE: This prospective study aimed mainly to evaluate the efficacy of partial nail avulsion and selective chemical cauterization of the matrix using 80% TCA in the treatment of the ingrowing nail. METHODS: One-hundred-and-thirty-three patients with 197 ingrown toenails were included in this study. Preoperatively, we tried to find predisposing factors to the disease. In the postoperative period, patients were evaluated for potential complications at days 3, 30, 180, 270 and 360. Pain was measured before surgery, as well as 24 hours and 72 hours after surgery. RESULTS: There were only 3 cases (out of 197) of ingrown nail recurrence. Preoperatively, we found the presence of drainage in 82% of patients, which, following the first visit after surgery, was reduced to 19%. Persistent granulation tissue was found in 3% of the patients (versus 75% prior to surgery). The most frequent predisposing factors for the ingrown nail were excessive trimming of the lateral nail plate (63%), plantar hyperhidrosis (58%) and heavy nail folds (39%). Pain was substantially reduced after surgery. CONCLUSION: It is assumed that chemical procedures for the ingrown toenail are associated with delayed healing times but our results demonstrated quick recovery. Using 80% TCA for selective matricectomy in the ingrown toenail is an effective, quick and easy method. PMID- 24474096 TI - Assessing depression and anxiety in the caregivers of pediatric patients with chronic skin disorders. AB - BACKGROUND: The literature has shown that the presence of emotional disturbances in caregivers of children with skin diseases affects the course and treatment of the disease. Anxiety and depression are among the most frequently reported psychiatric diagnoses related to this fact. OBJECTIVE: To evaluate the presence of anxiety and depression in caregivers of pediatric patients with chronic skin disorders, exemplified by atopic dermatitis, psoriasis and vitiligo, and correlate them to the quality of life of the patients. METHODS: The sample consisted of 118 patients with atopic dermatitis, vitiligo and psoriasis, monitored by their main caregiver. The levels of anxiety and depression in the caregivers were assessed using the Hamilton Anxiety Scale and the Beck Depression Inventory, respectively. The Children's Dermatology Life Quality Index was applied. RESULTS: Anxiety was observed in 36% of the caregivers of the patients with atopic dermatitis, in 36% of those of children affected by psoriasis, and in 42% of those responsible for pediatric patients with vitiligo. Depression occurred in 36% of the caregivers of patients with atopic dermatitis, in 36% of those of children affected by psoriasis and in 26% of those responsible for pediatric patients with vitiligo. There was a significant correlation between poor quality of life scores in patients with vitiligo and the presence of depression and anxiety in their caregivers. CONCLUSION: Emotional disorders tend to be present among close family members of children with the chronic skin diseases studied and their prevention can help in controlling and treating these diseases. PMID- 24474097 TI - Randomized clinical efficacy of superficial peeling with 85% lactic acid versus 70% glycolic acid. AB - BACKGROUND: Peeling is a procedure which aims to accelerate the process of skin exfoliation. OBJECTIVES: Development of formulations containing lactic acid at 85% or glycolic acid at 70% and the evaluation of these formulations on clinical efficacy in reduction of fine wrinkles. METHODS: Preliminary stability tests were carried out and an in vivo study was performed with three groups with 9 representatives each. One was the control group, which used only sunscreen; another one used lactic acid+sunscreen, and the last group used acid glycolic+sunscreen. Clinical efficacy was assessed with a CCD color microscope, through the digitization of images before and after treatment. The applications were carried out by a dermatologist, once a mont h every 30 days, during 3 months. The area with wrinkles was calculated by planimetry point counting, in accordance with Mandarin-de-Lacerda. RESULTS: The formulations were stable in the visual and Ph evaluation. There was no improvement in the control group; for lactic acid, there was significant improvement after the second peeling application on the outer lateral area of the right eye and after the third application on the outer lateral area of the left eye. For the glycolic acid group, there was significant improvement in the outer lateral area of the left eye after the first application, and of the right eye region, after three applications. The formulations used must be kept under refrigeration and should be manipulated every 30 days. CONCLUSIONS: Both peelings were effective in reducing fine wrinkles of the outer lateral eye area after three applications (p <= 0.05%). It was observed that peeling efficacy in the external-lateral region of one eye might be different compared with that in skin of the external-lateral region of the other eye, relative to the speed of skin improvement. PMID- 24474098 TI - Incidence of acne vulgaris in young adult users of protein-calorie supplements in the city of Joao Pessoa--PB. AB - BACKGROUND: Based on personal observations of dermatologists, nutritionists and patients, a new problem emerges in the gyms: development and exacerbation of acne in users of whey protein, which is a protein derived from cow's milk. Whey Protein extract contains growth factors that may be related to acne. Its purity and composition are not fully known and there is no scientific research on its potential to cause acne. OBJECTIVES: Assess the relationship between the use of protein calorie supplements and onset or exacerbation of acne vulgaris in young adults in the city of Joao Pessoa. METHODS: Descriptive observational study conducted in gyms and in a dermatology clinic. Each participant was examined for acne on three occasions and followed for 60 days. RESULTS: 30 patients were examined. Onset or exacerbation of acneiform lesions were observed (p <0.0005). The effect was more prominent in females and in individuals without current acne and no family history of acne. CONCLUSION: This study showed the onset of acne with the progressive use of protein-calorie supplementation, in a two-month period. It is suggested that this type of supplementation be discouraged. PMID- 24474099 TI - Obesity and dyslipidemia in patients with psoriasis treated at a dermatologic clinic in Manaus. AB - BACKGROUND: Psoriasis is a chronic inflammatory disease of multifactorial etiology, with participation of genetic, autoimmune and environmental factors. Recent studies have demonstrated the role of inflammatory cells and mediators in the pathogenesis of psoriasis, which is now defined as a systemic and autoimmune inflammatory disease that may be associated with other diseases of inflammatory nature. OBJECTIVES: To evaluate the occurrence of obesity and dyslipidemia in patients with psoriasis treated at a dermatology clinic in Manaus. METHODS: We performed a prospective descriptive study to assess the prevalence of obesity and dyslipidemia in patients with psoriasis. Besides the recommended dermatological care, a physical examination was performed to measure weight, height and waist circumference. RESULTS: We included 72 patients, 44 (61.1%) female and 28 (38.9%) male, with a mean age of 51.0 years +/- 15.9 years. As for body mass index (BMI), 16 (22.2%) were overweight and 20 (27.8%) were obese. In the analysis of waist circumference in relation to gender, we found that 79.5% of women surveyed had central obesity, a percentage statistically higher than that observed among men (42.9%) at the 5% level of significance (p = 0.001). Regarding the diagnosis of dyslipidemia, 29 (65.9%) females and 22 (78.6%) males showed alterations in lipid profile. CONCLUSIONS: The occurrence of dyslipidemia and obesity in patients with psoriasis can affect life quality and expectancy, increasing the risk of systemic and metabolic diseases, which makes periodic investigation of these comorbidities in patients with psoriasis mandatory. PMID- 24474100 TI - Serology with ML Flow test in health professionals from three different states of Brazil. AB - BACKGROUND: In highly endemic countries, transmission and sub-clinical infection of leprosy are likely and the disease manifests itself in individuals without any known close contact with a leprosy patient. Health workers are social contacts belonging to the same network (the Health System) and some of them share the same social environment (nursing assistants) as patients with known patients and / or carriers. OBJECTIVE: To identify ML Flow seropositivity among health professionals. METHODS: We conducted a cross-sectional study using a serological survey with the ML Flow test in 450 health professionals (doctors, nurses and nursing assistants), in order to detect seropositivity in areas of high and low endemicity in municipalities from three Brazilian states (RJ, MS and RS). RESULTS: The results showed general 16% seropositivity, higher in low endemic areas, regardless of whether there was direct care for leprosy patients. Paradoxically, a statistical association was observed between the area studied and seropositivity, as the place with the lowest endemicity (CA) had the highest seropositivity rate (p = 0.033). CONCLUSION: The authors suggest these results are associated with a presence of an unspecified link to bovine serum albumin (BSA), carrier of PGL-1 in the ML Flow test, and recommend expanded seroepidemiological research utilizing tests with human and bovine albumin. PMID- 24474101 TI - Tattoos on 18-year-old male adolescents--characteristics and associated factors. AB - BACKGROUND: Prevalence of tattoos is around 10-26% in men and 10-22% in women, and can involve negative effects such as: regret, removal attempts, physical and biological changes of the skin and association with some viral diseases. OBJECTIVE: to determine the prevalence, characteristics and factors associated with tattoos in recruiters joining the military. METHODS: the recruiters were examined by dermatologists that documented the presence or absence of tattoos, as well as their sizes, colors, designs and patterns, and whether they needed a parent's consent to get a tattoo. RESULTS: 1,968 recruiters were examined and the prevalence of tattoos was 10.82% (213), 141 (66.20%) had a single tattoo, 44 (20.66%) two tattoos, 15 (7.04%) three tattoos, 9 (4.23%) four tattoos, and 4 (1.88%) had more than four. Of the total sample, 168 (80.77%) reported getting the first tattoo before the age of 18. 158 (74.53%) were monochromatic. In relation to size, 108 (50.70%) had tattoos of up to 10 cm, 75 (35.21%) had tattoos measuring between 11-20 cm, while 30 had ones over 21 cm (14.09%). CONCLUSIONS: The population studied had a high prevalence of tattoos for their age, the percentage of complex (large and polychromatic) tattoos was also high. PMID- 24474102 TI - Triple nanoemulsion potentiates the effects of topical treatments with microencapsulated retinol and modulates biological processes related to skin aging. AB - BACKGROUND: The sum of environmental and genetic factors affects the appearance and function of the skin as it ages. The identification of molecular changes that take place during skin aging provides biomarkers and possible targets for therapeutic intervention. Retinoic acid in different formulations has emerged as an alternative to prevent and repair age-related skin damage. OBJECTIVES: To understand the effects of different retinoid formulations on the expression of genes associated with biological processes that undergo changes during skin aging. METHODS: Ex-vivo skin samples were treated topically with different retinoid formulations. The modulation of biological processes associated with skin aging was measured by Reverse Transcription quantitative PCR (RT-qPCR). RESULTS: A formulation containing microencapsulated retinol and a blend of active ingredients prepared as a triple nanoemulsion provided the best results for the modulation of biological, process-related genes that are usually affected during skin aging. CONCLUSION: This association proved to be therapeutically more effective than tretinoin or microencapsulated retinol used singly. PMID- 24474103 TI - Treatment of superficial mycoses: review. Part II. AB - Superficial fungal infections of the hair, skin and nails are a major cause of morbidity in the world. Choosing the right treatment is not always simple because of the possibility of drug interactions and side effects. The first part of the article discusses the main treatments for superficial mycoses - keratophytoses, dermatophytosis, candidiasis, with a practical approach to the most commonly-used topical and systemic drugs , referring also to their dosage and duration of use. Promising new, antifungal therapeutic alternatives are also highlighted, as well as available options on the Brazilian and world markets. PMID- 24474104 TI - Atopic dermatitis and vitamin D: facts and controversies. AB - Patients with atopic dermatitis have genetically determined risk factors that affect the barrier function of the skin and immune responses that interact with environmental factors. Clinically, this results in an intensely pruriginous and inflamed skin that allows the penetration of irritants and allergens and predisposes patients to colonization and infection by microorganisms. Among the various etiological factors responsible for the increased prevalence of atopic diseases over the past few decades, the role of vitamin D has been emphasized. As the pathogenesis of AD involves a complex interplay of epidermal barrier dysfunction and dysregulated immune response, and vitamin D is involved in both processes, it is reasonable to expect that vitamin D's status could be associated with atopic dermatitis' risk or severity. Such association is suggested by epidemiological and experimental data. In this review, we will discuss the evidence for and against this controversial relationship, emphasizing the possible etiopathogenic mechanisms involved. PMID- 24474105 TI - Hypopigmented mycosis fungoides: a review of its clinical features and pathophysiology. AB - Several distinct clinical forms of mycosis fungoides have been described. Hypopigmented mycosis fungoides should be regarded as a subtype of mycosis fungoides, insofar as it presents some peculiar characteristics that contrast with the clinical features of the classical form. Most patients with hypopigmented mycosis fungoides are younger than patients typically diagnosed with classical mycosis fungoides. In addition to typical dark-skinned individuals impairment, hypopigmented mycosis fungoides has also been described in Asian patients. The prognosis for hypopigmented mycosis fungoides is much better than for classical mycosis fungoides: hypopigmented mycosis fungoides is diagnosed when there are only patches of affected skin, and lesions usually will not progress beyond terminal stages, although they can persist for many years. Diagnosis should involve clinicopathologic correlation: skin biopsy analysis often reveals intense epidermotropism, characterized by haloed, large, and atypical CD8+ lymphocytes with convoluted nuclei, in contrast to mild to moderate dermal lymphocytic infiltrate. These CD8+ cells, which participate in T helper 1 mediated immune responses, prevent evolution to mycosis fungoides plaques and tumors and could be considered the main cause of the inhibition of melanogenesis. Therefore, hypopigmentation could be considered a marker of good prognosis for mycosis fungoides. PMID- 24474106 TI - Bullous pemphigoid in a 3-month-old infant: case report and literature review of this dermatosis in childhood. AB - Bullous pemphigoid is an autoimmune subepidermal blistering dermatosis that is uncommon in childhood. We report a case of a female infant, 3 months old, which presented clinical and laboratory data for the confirmatory diagnosis of bullous pemphigoid. The authors used immunohistochemical staining for collagen type IV that allowed the differentiation of bullous pemphigoid from other subepidermal bullous diseases. Opportunely we review the clinical, immunological, therapeutic and prognostic features of this pathology in children. PMID- 24474107 TI - Scanning electron microscopy of a blister roof in dystrophic epidermolysis bullosa. AB - In dystrophic epidermolysis bullosa the genetic defect of anchoring fibrils leads to cleavage beneath the basement membrane, with its consequent loss. We performed scanning electron microscopy of an inverted blister roof of a case of dystrophic epidermolysis bullosa, confirmed by immunomapping and gene sequencing. With a magnification of 2000 times a net attached to the blister roof could be easily identified. This net was composed of intertwined flat fibers. With higher magnifications, different fiber sizes could be observed, some thin fibers measuring around 80 nm and thicker ones measuring between 200 and 300 nm. PMID- 24474108 TI - Ectopic cutaneous schistosomiasis--case report. AB - Schistosomiasis mansoni is a systemic disease caused by a helminth of the schistosoma genus. The disease is generally asymptomatic or gastrointestinal symptoms may predominate. Skin lesions related to the disease are rarely diagnosed, even in endemic areas. The authors report the case of a young girl diagnosed with cutaneous schistosomiasis with involvement of the abdomen, back and scapular region. Schistosoma eggs were found in the lesions by histopathologic exam. There was no evidence of systemic involvement. Schistosomiasis must be included in the list of differential diagnosis of skin damage, especially in endemic areas, due to the potential consequences, in case of late diagnosis and treatment. PMID- 24474109 TI - Cutaneous lesions and finger clubbing uncovering hypocomplementemic urticarial vasculitis and hepatitis C with mixed cryoglobulinemia. AB - Urticarial vasculitis is a rare clinicopathologic entity characterized by urticarial lesions that persist for more than 24 hours and histologic features of leukocytoclastic vasculitis. Patients can be divided into normocomplementemic or hypocomplementemic. The authors report the case of a healthy 49-year-old woman with a 1-year history of highly pruritic generalized cutaneous lesions and finger clubbing. Laboratory tests together with histopathologic examination allowed the diagnosis of hypocomplementemic urticarial vasculitis, chronic hepatitis C and type II mixed cryoglobulinemia. The patient started symptomatic treatment and was referred to a gastroenterologist for management of the hepatitis C, with progressive improvement of the skin condition. The development of hypocomplementemic urticarial vasculitis in the context of chronic hepatitis C is exceedingly rare and possible pathogenic mechanisms are discussed. PMID- 24474110 TI - Generalized lichen nitidus in a boy with Niemann-Pick disease type B. AB - Generalized lichen nitidus is an uncommon chronic inflammatory dermatosis with very characteristic histological findings. Its pathogenesis is still unclear; very rarely it has been associated with genetic disorders. Herein we report the case of a 12-year-old boy with Niemann-Pick disease who developed generalized lichen nitidus. PMID- 24474111 TI - De Sanctis-Cacchione syndrome in a female infant--case report. AB - The De Sanctis-Cacchione Syndrome is the rarest and most severe kind of xeroderma pigmentosum, characterized by microcephaly, hypogonadism, neurological disorders, mental and growth retardation, with very few cases published. The clinical findings compatible with De Sanctis-Cacchione Syndrome and the therapeutic approach used to treat a one year and nine months old child, with previous diagnosis of xeroderma pigmentosum, are reported. PMID- 24474112 TI - Bannayan-Riley-Ruvalcaba syndrome with deforming lipomatous hamartomas in infant- case report. AB - Bannayan-Riley-Ruvalcaba Syndrome is a rare condition caused by mutations in the PTEN gene. It displays association of multiple lipomas, macrocephaly, hemangiomas, hamartomatous intestinal polyposis, developmental delay and speckled pigmented maculae on the male genitalia. We report the case of a nine-month-old boy who had fast growing and progressive tumors for three months, macrocephaly and lentigines on the penis. Imaging tests showed extensive lipomatosis with invasion of paraspinal muscles, enlargement of the spinal canal and spinal cord compression; after surgical excision of the mass, the pathology was consistent with lipoma. Adipocyte culture karyotype demonstrated PTEN mutation. We present this case for its rarity and exuberance. PMID- 24474113 TI - Dermatoscopic findings of urticaria pigmentosa. AB - Mastocytosis is a rare disease characterized by proliferation and accumulation of mast cells in various organs. The maculopapular cutaneous mastocytosis is divided into three subtypes: papular/plaque variant, urticaria pigmentosa and eruptive macular telangiectasia perstans. Dermoscopic may help to better characterize the different forms of cutaneous mastocytosis. We report a 55 year-old female with urticaria pigmentosa and its dermoscopy. PMID- 24474114 TI - Amelanotic metastatic cutaneous melanoma. AB - Dermatoscopy of melanocytic lesions has guided the decision of when or not to biopsy a lesion. The use of this tool has increased clinical examination's sensitivity and specificity in 89% and 96% respectively. However, dermatoscopic evaluation of amelanotic or hypomelanotic melanomas, as well as metastases, can be difficult. There is still no standardization for the analysis of these pathologies, which relies mostly on their vascular pattern. We describe the dermatoscopy of acral metastatic amelanotic melanoma. PMID- 24474115 TI - Leishmaniasis and AIDS coinfection. AB - Cutaneous leishmaniasis and HIV coinfection has been reported in Brazil since the initial description of AIDS in the country. We report an HIV-positive patient under antiretroviral treatment who presented with cutaneous leishmaniasis which was successfully treated with meglumine antimoniate. PMID- 24474116 TI - Sarcoid-like paracoccidioidomycosis presenting with perineural granuloma. AB - Paracoccidioidomycosis presenting as a sarcoid-like plaque may be misdiagnosed as leprosy, especially when shared endemic areas are concerned. We report the case of a Brazilian male patient presenting with an ulcerated plaque on his left ear and neighboring areas. The plaque simulated tuberculoid leprosy type 1 reaction, both clinically and histopathologically. A perineural granuloma with no organisms detected by routine and Fite-Faraco staining reinforced that diagnosis. Paracoccidioidomycosis was confirmed only after a second biopsy, taken from the ulcerated area. PMID- 24474117 TI - Case for diagnosis. Chondroid syringoma. AB - The chondroid syringoma is a rare benign tumor, also called mixed cutaneous tumor by the presence of epithelial and mesenchymal components, consisting of sweat elements in cartilaginous, collagenous, myxoid or osseous stroma, among others. It mainly affects middle-aged men and is characterized by asymptomatic and slow growing, dermal or subcutaneous nodules. The most common locations are the head and neck. It is rare on the extremities. There are reports of malignant variants predominantly in women, located on the extremities. We report a case of a female patient with a lesion on the toe, with excellent outcome after surgical treatment. PMID- 24474118 TI - Case for diagnosis. Hashimoto-Pritzker disease. AB - Langerhans cell histiocytosis is a rare, clinically heterogeneous disease. Since there is considerable clinical overlap among the four described variants (Hand Schuller-Christian, eosinophilic granuloma, Letterer-Siwe and Hashimoto Pritzker), the concept of spectral disease applies to this entity. The Hashimoto Pritzker variant was first described in 1973. Characteristically, it is present at birth or during the first days of life, impairment is limited to the skin and prognosis is favorable with spontaneous resolution. We report a newborn male patient with Hashimoto-Pritzker disease presenting as a S100 + and CD1a + single congenital perianal lesion with rapid involution in two months. PMID- 24474119 TI - Case for diagnosis. Granular cell tumor. AB - Granular cell tumor is a rare benign neoplasm of neural origin. We report the case of a female patient, 27 years old presenting a brown-red nodule in the right arm, which pathological examination showed to be formed by polygonal cells with eosinophilic granular cytoplasm and immunohistochemistry positive for S100 protein and CD68. Granular cell tumor is usually solitary and in half the cases located in the head and neck areas, 30% of these in the tongue. It is most frequent between the third and fifth decades of life in women and people of African-American ethnicity. Its origination is controversial, including the possible origins in muscle, fibroblasts, neural crest, neural sheath or histiocytes. The positivity for S-100 and CD68 suggest the neural origin. PMID- 24474120 TI - Do you know this syndrome? POEMS syndrome. AB - POEMS syndrome is a unique clinical entity, the diagnosis of which is made when polyneuropathy and monoclonal gammopathy occur together, associated with other changes such as organomegaly, endocrinopathy, skin changes and papilledema. Cutaneous manifestations are heterogeneous, with diffuse cutaneous hyperpigmentation, hemangiomas and hypertrichosis occurring more frequently. We report the case of a 65- year-old female patient with this syndrome, diagnosed after 15 years of disabling peripheral neuropathy. PMID- 24474121 TI - Do you know this syndrome? Berardinelli-Seip syndrome. AB - Berardinelli-Seip syndrome is a rare autosomal recessive disease characterized by inadequate metabolism and inefficient storing of lipids in fat cells, generating accumulation of fat in organs such as the liver, spleen, pancreas, heart, arterial endothelium and skin. Classically, patients manifest generalized lipoatrophy at birth or until 2 years of age, and in adolescence usually develop marked insulin resistance with rapid progression to diabetes and dyslipidemia. We report the case of a 17-year-old Berardinelli-Seip syndrome patient with eruptive xanthoma associated with severe hypertriglyceridemia. It is worth noting Eruptive xanthoma as a dermatological manifestation that is not generally highlighted in the reports of cases of this genetic metabolic disorder. PMID- 24474122 TI - Patch test standard series recommended by the Brazilian Contact Dermatitis Study Group during the 2006-2011 period. AB - A retrospective study was carried out between 2006-2011. Six hundred and eighteen patients with suspected allergic contact dermatitis underwent the standard patch test series recommended by the Brazilian Contact Dermatitis Research Group. The aim of our study was to evaluate the variation of positive patch-test results from standard series year by year. The most frequently positive allergens were: nickel sulfate, thimerosal and potassium bichromate. Decrease of positive patch test results over the years was statistically significant for: lanolin (p=0.01), neomycin (p=0.01) and anthraquinone (p=0.04). A follow-up study should be useful in determining which allergens could be excluded from standard series, as they may represent low sensitization risk. PMID- 24474123 TI - Endonyx toenail onychomycosis caused by Trichophyton rubrum: treatment with photodynamic therapy based on methylene blue dye. AB - This study shows the effectiveness of photodynamic therapy based on methylene blue dye for the treatment of endonyx toenail onychomycosis. Four patients with endonyx onychomycosis caused by Trichophyton rubrum were treated with 2% methylene blue aqueous solution irradiated with light emission diode at 630 nm and an energy density of 36 J/cm2 for 6 months at 2-week intervals. The preliminary study showed the effectiveness of this therapy in the treatment of endonyx onychomycosis, and also indicated that the disease can be caused by T. rubrum. PMID- 24474124 TI - Perception of brittle nails in dermatologic patients: a cross-sectional study. AB - Brittle Nails Syndrome is characterized by fragility of the nail plate, affecting 27% of women. We evaluated dermatology patients in a cross-sectional study about perception of nail fragility. One hundred and thirty eight women were included, with median age of 36.5 years. Nail examination showed changes in 57% and 49% reported nail fragility. The first three fingernails were the most affected. Onychoschizia was related to onychophagia (OR = 3.29), housework (OR = 2.95) and water contact (OR = 2.44). Onychorrhexis had the strongest association with nail fragility perception (OR = 17.89). The fragility was more perceived by those who were black, of mixed race and atopic, and was associated with depressed mood. PMID- 24474125 TI - Clinical epidemiological profile of vitiligo in children and adolescents. AB - 94 children and 25 adolescents, 42% male and 58% female, aged predominantly between six and ten years old (40%) were studied at the Martagao Gesteira Childcare and Pediatrics Institute (Rio de Janeiro Federal University) between 2005 and 2011. The prevalent clinical form of vitiligo was the generalized type (34%). Although the clinical response was similar between the treatment modalities, we decided for low and high power topical steroids in our routine. Halo nevi were found in seven (5.9%) cases. Thirty (25%) patients underwent specialized evaluation and 18 (60%) reported some relevant psychological situation. PMID- 24474127 TI - Staphylococcal abscess caused by trauma with a rosebush aculeus (Plantae, Rosaceae): apropos of a case. AB - Cutaneous abscess is a localized collection of pus in the dermis and subcutaneous tissue usually caused by trauma. The authors report the case of a 30-year-old male patient, gardener, that presents an ulcerated plaque in the third right finger, caused by an aculeus plant wound. The examination of the lesion's exudate ruled out the existence of fungi and showed the presence of Staphylococcus aureus. The authors emphasize the sporotrichosis as an important differential diagnosis, especially in endemic areas, and the indication of the exudate culture is discussed. PMID- 24474126 TI - Peroxisome proliferator-activated receptor agonists (PPARs): a promising prospect in the treatment of psoriasis and psoriatic arthritis. AB - Psoriasis is a polygenic, inflammatory and progressive disease, characterized by an abnormal differentiation and hyperproliferation of keratinocytes, associated with impaired immunologic activation and systemic disorders, while psoriatic arthritis is a chronic inflammatory articular disease. Pathophysiology of psoriasis comprises a dysfunction of the immune system cells with an interactive network between cells and cytokines supporting the initiation and perpetuation of disease and leading to inflammation of skin, enthesis and joints. Recent studies have shown an important role of systemic inflammation in the development of atherosclerosis. Corroborating these findings, patients with severe Psoriasis have marked incidence of psoriatic arthritis, cardiovascular diseases, hypertension, dyslipidemia, obesity and diabetes mellitus, showing an increased risk for acute myocardial infarction, which suggests that the condition is not restricted to the skin. Nuclear receptors are ligand-dependent transcription factors, whose activation affects genes that control vital processes. Among them the peroxisome proliferator-activated receptor is responsible for establishing the relationship between lipids, metabolic diseases and innate immunity. In the skin, peroxisome proliferator-activated receptors have an important effect in keratinocyte homeostasis, suggesting a role in diseases such as psoriasis. The peroxisome proliferator-activated receptors agonists represent a relevant source of research in the treatment of skin conditions, however more clinical studies are needed to define the potential response of these drugs in patients with psoriasis and psoriatic arthritis. PMID- 24474128 TI - Drug-induced acne and rose pearl: similarities. AB - Drug-induced acne is a common skin condition whose classic symptoms can be similar to a rose pearl, as in the case of a male patient presenting with this condition after excessive use of a cream containing corticosteroids. PMID- 24474129 TI - Synthesis of lead-free piezoelectric powders by ultrasonic-assisted hydrothermal method and properties of sintered (K0.48Na0.52)NBO3 ceramics. AB - (K,Na)NbO3 ceramics have attracted much attention as lead-free piezoelectric materials with high piezoelectric properties. High-quality (K,Na)NbO3 ceramics can be sintered using KNbO3 and NaNbO3 powders synthesized by a hydrothermal method. In this study, to enhance the quality factor of the ceramics, high-power ultrasonic irradiation was employed during the hydrothermal method, which led to a reduction in the particle size of the resultant powders. PMID- 24474130 TI - Intrinsically switchable, high-Q ferroelectricon-silicon composite film bulk acoustic resonators. AB - This paper presents a voltage-controlled, highquality factor (Q) composite thin film bulk acoustic resonator (FBAR) at 1.28 GHz. The composite FBAR consists of a thin layer of barium strontium titanate (BST) that is sandwiched between two electrodes deposited on a silicon-on-insulator (SOI) wafer. The BST layer, which has a strong electrostrictive effect, is used for electromechanical transduction by means of its voltage-induced piezoelectricity. The silicon layer, with its low mechanical loss, increases the Q of the resonator. The composite FBAR presented here exhibits Qs exceeding 800 with a resonance frequency and Q product (f * Q) of 1026 GHz. PMID- 24474131 TI - Single-chip CMUT-on-CMOS front-end system for real-time volumetric IVUS and ICE imaging. AB - Intravascular ultrasound (IVUS) and intracardiac echography (ICE) catheters with real-time volumetric ultrasound imaging capability can provide unique benefits to many interventional procedures used in the diagnosis and treatment of coronary and structural heart diseases. Integration of capacitive micromachined ultrasonic transducer (CMUT) arrays with front-end electronics in single-chip configuration allows for implementation of such catheter probes with reduced interconnect complexity, miniaturization, and high mechanical flexibility. We implemented a single-chip forward-looking (FL) ultrasound imaging system by fabricating a 1.4 mm-diameter dual-ring CMUT array using CMUT-on-CMOS technology on a front-end IC implemented in 0.35-MUm CMOS process. The dual-ring array has 56 transmit elements and 48 receive elements on two separate concentric annular rings. The IC incorporates a 25-V pulser for each transmitter and a low-noise capacitive transimpedance amplifier (TIA) for each receiver, along with digital control and smart power management. The final shape of the silicon chip is a 1.5-mm-diameter donut with a 430-MUm center hole for a guide wire. The overall front-end system requires only 13 external connections and provides 4 parallel RF outputs while consuming an average power of 20 mW. We measured RF A-scans from the integrated single- chip array which show full functionality at 20.1 MHz with 43% fractional bandwidth. We also tested and demonstrated the image quality of the system on a wire phantom and an ex vivo chicken heart sample. The measured axial and lateral point resolutions are 92 MUm and 251 MUm, respectively. We successfully acquired volumetric imaging data from the ex vivo chicken heart at 60 frames per second without any signal averaging. These demonstrative results indicate that single chip CMUT-on-CMOS systems have the potential to produce realtime volumetric images with image quality and speed suitable for catheter-based clinical applications. PMID- 24474132 TI - Histotripsy beyond the intrinsic cavitation threshold using very short ultrasound pulses: microtripsy. AB - Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. Conventional histotripsy treatments have used longer pulses from 3 to 10 cycles, wherein the lesion producing bubble cloud generation depends on the pressure-release scattering of very high peak positive shock fronts from previously initiated, sparsely distributed bubbles (the shock-scattering mechanism). In our recent work, the peak negative pressure (P-) for generation of dense bubble clouds directly by a single negative half cycle, the intrinsic threshold, was measured. In this paper, the dense bubble clouds and resulting lesions (in red blood cell phantoms and canine tissues) generated by these supra-intrinsic threshold pulses were studied. A 32-element, PZT-8, 500-kHz therapy transducer was used to generate very short (<2 cycles) histotripsy pulses at a pulse repetition frequency (PRF) of 1 Hz and P- from 24.5 to 80.7 MPa. The results showed that the spatial extent of the histotripsy-induced lesions increased as the applied P- increased, and the sizes of these lesions corresponded well to the estimates of the focal regions above the intrinsic cavitation threshold, at least in the lower pressure regime (P- = 26 to 35 MPa). The average sizes for the smallest reproducible lesions were approximately 0.9 * 1.7 mm (lateral * axial), significantly smaller than the -6 dB beamwidth of the transducer (1.8 * 4.0 mm). These results suggest that, using the intrinsic threshold mechanism, well-confined and microscopic lesions can be precisely generated and their spatial extent can be estimated based on the fraction of the focal region exceeding the intrinsic cavitation threshold. Because the supra-threshold portion of the negative half cycle can be precisely controlled, lesions considerably less than a wavelength are easily produced, hence the term microtripsy. PMID- 24474133 TI - Top-orthogonal-to-bottom-electrode (TOBE) CMUT arrays for 3-D ultrasound imaging. AB - Two-dimensional ultrasound arrays hold great promise for 3-D imaging; however, wiring of each channel becomes impractical for large arrays or for small footprint catheter probes for which the number of wires must be limited. Capacitive micromachined ultrasound transducers offer a promising solution for such 2-D array applications, but channel routing is still non-trivial. A top orthogonal-to-bottom-electrode (TOBE) 2-D CMUT array architecture is presented along with row-column addressing schemes for low-channel-count 3-D ultrasound imaging. An N * N TOBE array is capable of obtaining 3-D images using only 2N channels. An interfacing scheme is presented in which transmit-receive signals are routed along rows while bias voltages are applied along columns, effectively allowing for single-element transmit/receive control. Simulations demonstrated potentially finer resolution and improved side lobe suppression over a previously published row-column-based imaging method. Laser vibrometer testing was done to measure membrane displacement in air and confirmed that single-element air coupled actuation in transmit mode could be achieved using our proposed interfacing scheme. Acoustic testing was also performed in both transmit and receive modes to characterize the ability of the proposed interfacing scheme to achieve dominant-element transmission and reception in immersion operation. It was seen that membrane displacement in both modes was indeed largely confined to the active area. PMID- 24474134 TI - Rheological assessment of a polymeric spherical structure using a three dimensional shear wave scattering model in dynamic spectroscopy elastography. AB - With the purpose of assessing localized rheological behavior of pathological tissues using ultrasound dynamic elastography, an analytical shear wave scattering model was used in an inverse problem framework. The proposed method was adopted to estimate the complex shear modulus of viscoelastic spheres from 200 to 450 Hz. The inverse problem was formulated and solved in the frequency domain, allowing assessment of the complex viscoelastic shear modulus at discrete frequencies. A representative rheological model of the spherical obstacle was determined by comparing storage and loss modulus behaviors with Kelvin-Voigt, Maxwell, Zener, and Jeffrey models. The proposed inversion method was validated by using an external vibrating source and acoustic radiation force. The estimation of viscoelastic properties of three-dimensional spheres made softer or harder than surrounding tissues did not require a priori rheological assumptions. The proposed method is intended to be applied in the context of breast cancer imaging. PMID- 24474136 TI - Influence of porosity, pore size, and cortical thickness on the propagation of ultrasonic waves guided through the femoral neck cortex: a simulation study. AB - The femoral neck is a common fracture site in elderly people. The cortical shell is thought to be the major contributor to the mechanical competence of the femoral neck, but its microstructural parameters are not sufficiently accessible under in vivo conditions with current X-ray-based methods. To systematically investigate the influences of pore size, porosity, and thickness of the femoral neck cortex on the propagation of ultrasound, we developed 96 different bone models (combining 6 different pore sizes with 4 different porosities and 4 different thicknesses) and simulated the ultrasound propagation using a finite difference time-domain algorithm. The simulated single-element emitter and receiver array consisting of 16 elements (8 inferior and 8 superior) were placed at anterior and posterior sides of the bone, respectively (transverse transmission). From each simulation, we analyzed the waveform collected by each of the inferior receiver elements for the one with the shortest time of flight. The first arriving signal of this waveform, which is associated with the wave traveling through the cortical shell, was then evaluated for its three different waveform characteristics (TOF: time point of the first point of inflection of the received signal, Deltat: difference between the time point at which the signal first crosses the zero baseline and TOF, and A: amplitude of the first extreme of the first arriving signal). From the analyses of these waveform characteristics, we were able to develop multivariate models to predict pore size, porosity, and cortical thickness, corresponding to the 96 different bone models, with remaining errors in the range of 50 MUm for pore size, 1.5% for porosity, and 0.17 mm for cortical thickness. PMID- 24474135 TI - High-contrast ultrafast imaging of the heart. AB - Noninvasive ultrafast imaging of intrinsic waves such as electromechanical waves or remotely induced shear waves in elastography imaging techniques for human cardiac applications remains challenging. In this paper, we propose ultrafast imaging of the heart with adapted sector size by coherently compounding diverging waves emitted from a standard transthoracic cardiac phased-array probe. As in ultrafast imaging with plane wave coherent compounding, diverging waves can be summed coherently to obtain high-quality images of the entire heart at high frame rate in a full field of view. To image the propagation of shear waves with a large SNR, the field of view can be adapted by changing the angular aperture of the transmitted wave. Backscattered echoes from successive circular wave acquisitions are coherently summed at every location in the image to improve the image quality while maintaining very high frame rates. The transmitted diverging waves, angular apertures, and subaperture sizes were tested in simulation, and ultrafast coherent compounding was implemented in a commercial scanner. The improvement of the imaging quality was quantified in phantoms and in one human heart, in vivo. Imaging shear wave propagation at 2500 frames/s using 5 diverging waves provided a large increase of the SNR of the tissue velocity estimates while maintaining a high frame rate. Finally, ultrafast imaging with 1 to 5 diverging waves was used to image the human heart at a frame rate of 4500 to 900 frames/s over an entire cardiac cycle. Spatial coherent compounding provided a strong improvement of the imaging quality, even with a small number of transmitted diverging waves and a high frame rate, which allows imaging of the propagation of electromechanical and shear waves with good image quality. PMID- 24474137 TI - Real-time vector velocity assessment through multigate Doppler and plane waves. AB - Several ultrasound (US) methods have been recently proposed to produce 2-D velocity vector fields with high temporal and spatial resolution. However, the real-time implementation in US scanners is heavily hampered by the high calculation power required. In this work, we report a real-time vector Doppler imaging method which has been integrated in an open research system. The proposed approach exploits the plane waves transmitted from two sub-arrays of a linear probe to estimate the velocity vectors in 512 sample volumes aligned along the probe axis. The method has been tested for accuracy and reproducibility through simulations and in vitro experiments. Simulations over a 0 degrees to 90 degrees angle range of a 0.5 m/s peak parabolic flow have yielded 0.75 degrees bias and 1.1 degrees standard deviation for direction measurement, and 0.6 cm/s bias with 3.1% coefficient of variation for velocity assessment. In vitro tests have supported the simulation results. Preliminary measurements on the carotid artery of a volunteer have highlighted the real-time system capability of imaging complex flow configurations in an intuitive, easy, and quick way, as shown in a sample supplementary movie. These features have allowed reproducible peak velocity measurements to be obtained, as needed for quantitative investigations on patients. PMID- 24474138 TI - Dual-beam histotripsy: a low-frequency pump enabling a high-frequency probe for precise lesion formation. AB - Histotripsy produces tissue fractionation through dense energetic bubble clouds generated by short, high-pressure, ultrasound pulses. When using pulses shorter than 2 cycles, the generation of these energetic bubble clouds only depends on where the peak negative pressure (P-) exceeds the intrinsic threshold of the medium (26 to 30 MPa in soft tissue with high water content). This paper investigates a strategic method for precise lesion generation in which a low frequency pump pulse is applied to enable a sub-threshold high-frequency probe pulse to exceed the intrinsic threshold. This pump-probe method of controlling a supra-threshold volume can be called dual-beam histotripsy. A 20-element dual frequency (500-kHz and 3-MHz elements confocally aligned) array transducer was used to generate dual-beam histotripsy pulses in red blood cell phantoms and porcine hepatic tissue specimens. The results showed that when sub-intrinsic threshold pump (500-kHz) and probe (3-MHz) pulses were applied together, dense bubble clouds (and resulting lesions) were only generated when their peak negative pressures combined constructively to exceed the intrinsic threshold. The smallest reproducible lesion varied with the relative amplitude between the pump and probe pulses, and, with a higher proportion of the probe pulse, smaller lesions could be generated. When the propagation direction of the probe pulse relative to the pump pulse was altered, the shape of the produced lesion changed based on the region that exceeded intrinsic threshold. Because the low-frequency pump pulse is more immune to attenuation and aberrations, and the high-frequency probe pulse can provide precision in lesion formation, this dual-beam histotripsy approach would be very useful in situations in which precise lesion formation is required through a highly attenuative and aberrative medium, such as transcranial therapy. This is particularly true if a small low-attenuation acoustic window is available for the high-frequency probe transducer. PMID- 24474140 TI - Lorentz-force hydrophone characterization. AB - A Lorentz-force hydrophone consists of a thin wire placed inside a magnetic field. When under the influence of an ultrasound pulse, the wire vibrates and an electrical signal is induced by the Lorentz force, which is proportional to the pulse amplitude. In this study, a compact prototype of such a hydrophone is introduced and characterized, and the previously developed hydrodynamic model is refined. It is shown that the wire tension has a negligible effect on the measurement of pressure. The frequency response of the hydrophone reaches 1 MHz for wires with diameters between 70 and 400 MUm. The hydrophone exhibits a directional response such that the signal amplitude differs by less than 3 dB as the angle of the incident ultrasound pulse varies from -20 degrees and +20 degrees . The linearity of the measured signal is confirmed across the 50 kPa to 10 MPa pressure range, and an excellent resistance to cavitation is observed. This hydrophone is of interest for high-pressure ultrasound measurements including high-intensity focused ultrasound (HIFU) and ultrasonic measurements in difficult environments. PMID- 24474139 TI - Histotripsy-induced cavitation cloud initiation thresholds in tissues of different mechanical properties. AB - Histotripsy is an ultrasound ablation method that depends on the initiation and maintenance of a cavitation bubble cloud to fractionate soft tissue. This paper studies how tissue properties impact the pressure threshold to initiate the cavitation bubble cloud. Our previous study showed that shock scattering off one or more initial bubbles, expanded to sufficient size in the focus, plays an important role in initiating a dense cavitation cloud. In this process, the shock scattering causes the positive pressure phase to be inverted, resulting in a scattered wave that has the opposite polarity of the incident shock. The inverted shock is superimposed on the incident negative pressure phase to form extremely high negative pressures, resulting in a dense cavitation cloud growing toward the transducer. We hypothesize that increased tissue stiffness impedes the expansion of initial bubbles, reducing the scattered tensile pressure, and thus requiring higher initial intensities for cloud initiation. To test this hypothesis, 5-cycle histotripsy pulses at pulse repetition frequencies (PRFs) of 10, 100, or 1000 Hz were applied by a 1-MHz transducer focused inside mechanically tunable tissue mimicking agarose phantoms and various ex vivo porcine tissues covering a range of Young's moduli. The threshold to initiate a cavitation cloud and resulting bubble expansion were recorded using acoustic backscatter detection and optical imaging. In both phantoms and ex vivo tissue, results demonstrated a higher cavitation cloud initiation threshold for tissues of higher Young's modulus. Results also demonstrated a decrease in bubble expansion in phantoms of higher Young's modulus. These results support our hypothesis, improve our understanding of the effect of histotripsy in tissues with different mechanical properties, and provide a rational basis to tailor acoustic parameters for fractionation of specific tissues. PMID- 24474141 TI - A GaAs phononic crystal with shallow noncylindrical holes. AB - A square lattice of shallow, noncylindrical holes in GaAs is shown to act as a phononic crystal (PnC) reflector. The holes are produced by wet-etching a GaAs substrate using a citric acid:H2O2 etching procedure and a photolithographed array pattern. Although nonuniform and asymmetric etch rates limit the depth and shape of the phononic crystal holes, the matrix acts as a PnC, as demonstrated by insertion loss measurements together with interferometric imaging of surface acoustic waves propagating on the GaAs surface. The measured vertical displacement induced by surface phonons compares favorably with finite-difference time-domain simulations of a PnC with rounded-square holes. PMID- 24474142 TI - Evaluation of electromechanical coupling parameters of piezoelectric materials by using piezoelectric cantilever with coplanar electrode structure in quasi-stasis. AB - Based on Timoshenko beam theory, a principle model is proposed to establish the relationship between electric charge and excitation acceleration, and in quasi stasis we apply the direct piezoelectric effect of multilayer cantilever with coplanar electrode structure to evaluate the piezoelectric strain coefficient d15 and electromechanical coupling coefficient k15. They are measured as 678 pC/N and 0.74 for the commercial piezoelectric ceramic lead zirconate titanate (PZT-51) bulk specimen and 656 pC/N and 0.63 for the lead magnesium niobate (PMN) bulk specimen, and they are in agreement with the calibration and simulation values. The maximum of relative errors is less than 4.2%, so the proposed method is reliable and convenient. PMID- 24474143 TI - Range side lobe inversion for chirp-encoded dual-band tissue harmonic imaging. AB - Dual-band (DB) harmonic imaging is performed by transmitting and receiving at both fundamental band (f0) and second-harmonic band (2f0). In our previous work, particular chirp excitation has been developed to increase the signal- to-noise ratio in DB harmonic imaging. However, spectral overlap between the second-order DB harmonic signals results in range side lobes in the pulse compression. In this study, a novel range side lobe inversion (RSI) method is developed to alleviate the level of range side lobes from spectral overlap. The method is implemented by firing an auxiliary chirp to change the polarity of the range side lobes so that the range side lobes can be suppressed in the combination of the original chirp and the auxiliary chirp. Hydrophone measurements show that the RSI method reduces the range side lobe level (RSLL) and thus increases the quality of pulse compression in DB harmonic imaging. With the signal bandwidth of 60%, the RSLL decreases from -23 dB to -36 dB and the corresponding compression quality improves from 78% to 94%. B-mode images also indicate that the magnitude of range side lobe is suppressed by 7 dB when the RSI method is applied. PMID- 24474144 TI - A newly synthesized compound, 4'-geranyloxyferulic acid-N(omega)-nitro-L-arginine methyl ester suppresses inflammation-associated colorectal carcinogenesis in male mice. AB - We previously reported the cancer chemopreventive activity of 4' geranyloxyferulic acid (GOFA, Miyamoto et al., Nutr Cancer 2008; 60:675-84) and a beta-cyclodextrin inclusion compound of GOFA (Tanaka et al., Int J Cancer 2010; 126:830-40) in colitis-related colorectal carcinogenesis. In our study, the chemopreventive effects of a newly synthesized GOFA-containing compound, GOFA N(omega)-nitro-L-arginine methyl ester (L-NAME), which inhibits inducible nitric oxide (iNOS) and cyclooxygenase-2 (COX) enzymes, were investigated using a colitis-associated mouse colorectal carcinogenesis model with azoxymethane (AOM) and dextran sodium sulfate (DSS). The dietary administration of GOFA-L-NAME after the AOM and DSS treatments significantly reduced the multiplicity of adenocarcinomas (inhibition rates: 100 ppm, 84%, p < 0.001; 500 ppm, 94%, p < 0.001) compared with the AOM + DSS group. Dietary GOFA-L-NAME significantly decreased the proliferation (p < 0.001) and increased the apoptosis (p < 0.001) of colonic adenocarcinoma cells. A subsequent short-term experiment revealed that dietary GOFA-L-NAME decreased the mRNA expression of inflammatory enzymes, such as iNOS and COX-2, and proinflammatory cytokines, such as tumor necrosis factor alpha, interleukin (IL)-1beta, IL-6 and macrophage inflammatory protein (MIP)-2 in the colonic mucosa of mice that received 1.5% DSS in their drinking water for 7 days. Our findings indicate that GOFA-L-NAME is able to inhibit colitis associated colon carcinogenesis by modulating inflammation, proliferation, apoptosis and the expression of proinflammatory cytokines in mice. PMID- 24474145 TI - Programmed death-1: therapeutic success after more than 100 years of cancer immunotherapy. AB - No other cancer therapy target class caused more excitement than the programmed death-1 (PD-1) pathway related. Antibodies against PD-1 and PD-1 ligands represent a therapeutic breakthrough and are the first examples of broadly efficacious and durable cancer immunotherapies. Cancer for the first time seems to have transformed from an often incurable to a "clinically manageable" disease. PMID- 24474146 TI - Medusa's ugly head again: from SARS to MERS-CoV. PMID- 24474147 TI - Role of steroids in acute phonotrauma: A basic science investigation. AB - OBJECTIVES/HYPOTHESIS: Steroids are used for the treatment of laryngitis in vocal performers and other individuals despite the absence of evidence demonstrating their impact on vocal fold inflammation. Our objective was to examine laryngeal secretion cytokine inflammatory profile changes associated with corticosteroid treatment in a human phonotrauma model. STUDY DESIGN: Prospective, individual, randomized, double-blinded, controlled trial. METHODS: Participants included 10 healthy females who were randomized to either treatment with oral hydrocortisone or placebo, each given in three doses over 20 hours after the experimental induction of acute phonotrauma. Cytokines associated with inflammation and healing (interleukin [IL]-1beta, IL-6, IL-10) were measured in laryngeal secretions before and after vocal loading and at 4 and 20 hours after treatment. RESULTS: Proinflammatory mediators IL-1beta and IL-6 were doubled in the controls versus the steroid treatment group at 21 hours following induction of acute vocal fold inflammation. Anti-inflammatory cytokine IL-10 showed a 6.3-fold increase in the steroid treatment group versus the controls, indicating anti-inflammatory modulation by steroid treatment. CONCLUSIONS: This study provides biologic evidence supporting the use of steroids for acute vocal fold inflammation associated with phonotrauma. LEVEL OF EVIDENCE: 1b. PMID- 24474148 TI - Carbon nanotube-based tandem absorber with tunable spectral selectivity: transition from near-perfect blackbody absorber to solar selective absorber. AB - CVD grown CNT thin film with a thickness greater than 10 MUm behaves like a near perfect blackbody absorber (i.e., alpha/epsilon = 0.99/0.99). Whereas, for a thickness <= 0.4 um, the CNT based tandem absorber acts as a spectrally selective coating (i.e., alpha/epsilon = 0.95/0.20). These selective coatings exhibit thermal stability up to 650 degrees C in vacuum, which can be used for solar thermal power generation. PMID- 24474149 TI - Detection and genotyping of enteroviruses in cerebrospinal fluid in patients in Victoria, Australia, 2007-2013. AB - Genotyping by VP1 fragment polymerase chain reaction (PCR) and nucleic acid sequencing to detect enterovirus (EV) genotypes was performed directly on 729 EV PCR positive cerebrospinal fluid (CSF) samples collected between 2007 and 2012 from Victorian hospital inpatients. The overall genotype identification rate from CSF-positive material was 43%. The four most common genotypes identified were Echovirus 6 (24%), Echovirus 30 (17%), Echovirus 25 (10%), and Coxsackievirus A9 (10%), together comprising 61% of all EVs typed. The seasonal distribution of all EVs identified followed the recognized pattern of mainly summer epidemics. Three of the four predominant genotypes were present in each of the 6 years in which the study was conducted, with 20 other EV genotypes also detected, often in only a single year. Genotyping of EVs directly in CSF is faster, simpler and more sensitive than traditional virus neutralization assays performed on EV positive samples. PMID- 24474151 TI - Phase III development of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire module for women undergoing breast reconstruction. AB - BACKGROUND: Comprehensive outcome assessments after breast reconstruction (BRR) require surgery-specific patient-reported outcome measures. The aims of this study were to assess the relevance, acceptability and redundancy of questions/items (phase III pretesting) of a new BRR questionnaire evaluating patients' health-related quality of life before and after BRR. Phase III occurred in collaboration with the European Organization for Research and Treatment of Cancer (EORTC) following earlier development phases that identified 31 items. METHODS: The EORTC BRR subgroup applied decision-making rules to each question according to eight EORTC criteria. A total of 197 patients (from the UK, Austria, Belgium, Italy and Sweden) were recruited. Forty-seven patients completed pre- and post-BRR questionnaires prospectively, and 150 reported post-BRR questionnaires only retrospectively. Qualitative debriefing interviews were undertaken in 189 patients. Preliminary psychometric analyses were performed. RESULTS: Thirty-one items fulfilled 'relevance', with none producing 'difficulties'. Ten items were not a priority for 10 per cent of respondents. Of these, two questions concerning muscle twitching in the affected breast and problem with donor-site swelling were deleted. Three redundant items were deleted: weakness in arm, which correlated significantly to the Quality of Life Questionnaire (QLQ) BR23 breast questionnaire, and shape and colour of the affected nipple. Descriptive statistics reduced the module to 26 items conceptualized into three provisional scales (disease treatment/surgery-related symptoms, sexuality and cosmetic outcome) within the newly completed questionnaire, EORTC QLQ-BRR26. CONCLUSION: The QLQ-BRR26 is available for psychometric validation in a large-field international sample. The intended use for QLQ-BRR26 is alongside EORTC QLQ-C30 and QLQ-BR23, in women treated by mastectomy for breast cancer and undergoing all types of BRR. PMID- 24474152 TI - Flexion-extension gap in cruciate-retaining versus posterior-stabilized total knee arthroplasty: a cadaveric study. AB - We re-examined experimental model results using half-body specimens with intact extensor mechanisms and navigation to evaluate cruciate-retaining (CR) and posterior stabilized (PS) total knee arthroplasty (TKA) component gaps through an entire range of motion. Six sequential testing regimens were conducted with the knee intact, with a CR TKA in place, and with a PS TKA in place, with and without 22 N traction in place at each stage. Each of 10 knees was taken through six full ranges of motion from 0 degrees to 120 degrees at every stage using a navigated knee system to record component gapping. No significant difference was found between loaded and unloaded component gaps, and no significant differences were found in component gapping between CR and PS TKAs throughout a full range of motion. Flexion-extension gap measurements were significantly different from previously published data (at 90 degrees flexion). No difference was found in kinematics when comparing CR and PS TKA component designs. Our results suggest that intact extensor mechanisms may be required to perform proper kinematic studies of TKA. Our findings provide evidence that the extensor mechanism may play a major role in the flexion-extension gaps in cadaveric knees. PMID- 24474153 TI - Occipital nerve stimulation for chronic migraine. AB - Occipital nerve stimulation may be effective in treating chronic migraine. Six studies, including three double-blind studies, were performed, with five showing evidence of benefit. However, of the three randomized, controlled trials, none has met a primary endpoint successfully. A separate study suggested a benefit for combined supraorbital and greater occipital nerve stimulation. PMID- 24474154 TI - P-protein distribution in mature sieve elements of Cucurbita maxima. AB - Portions of the hypocotyls of 16-day-old Cucurbita maxima plants, from which the cotyledons and first foliage leaves had been removed 2 days earlier, were fixed in glutaraldehyde and postfixed in osmium tetroxide for electron microscopy. In well over 90% of the mature sieve elements examined the P-protein was entirely parietal in distribution in both the lumina and sieve-plate pores. In addition to the parietal P-protein, the unoccluded sieve-plate pores were lined by narrow callose cylinders and the plasmalemma. Segments of endoplasmic reticulum also occurred along the margins of the pores. PMID- 24474155 TI - The distribution and redistribution of endoplasmic reticulum (ER) in geoperceptive cells. AB - Within the root cap in maize the cells believed to be responsible for the perception of gravity possess a rough-surfaced ER system with a distinctive pattern of distribution. The ER is found normally parallel to the nuclear membrane and to the walls, and symmetrically distributed. It can be disturbed from its parallel position by moving the root to any horizontal orientation, but it is not displaced by inverting the root into the 180 degrees vertical position. On returning to the normal position of growth the ER rapidly reforms into the original symmetrical position. The implications of this position and movement and the possible role of the ER are discussed. PMID- 24474156 TI - Directional secretion by the Golgi bodies in maize root cells. AB - In the root caps of many plant species, the outer few layers of cells secrete a polysaccharide mucus. This mucus probably derives from the breakdown of the starch in the amyloplasts. Is then fed through the Golgi bodies and, in vesicular form, reaches and is discharged through the plasmamembrane. Once in the wall it accumulates briefly between the plasmalemma and the wall and finally passes through the wall to the outside of the root. Its function is probably to facilitate the passage of the root through the soil by lubricating the movement of the root tip around and between the soil particles. Our observations show that the pattern of this discharge is not random, but that the mucus accumulates only against that wall which is or will be the outer tangential. The implication of this directional movement and possible suggestions for its control are discussed. PMID- 24474157 TI - Isolation and properties of lysosomes from dark-grown potato shoots. AB - A method is described for the isolation of lysosomal fractions from dark-grown potato shoots using a single stage separation on a Ficoll gradient. Peaks of acid hydrolase activity consisting of acid phosphatase, phosphodiesterase, ribonuclease, carboxylic esterase and beta-glycerophosphatase were well separated from peaks of mitochondrial and glyoxysomal enzymes. A heavy lysosomal fraction with particle diameters from 0.1 to 1.6 MU and density of 1.10 g cm(-3) containing relatively low hydrolase activity was distinguishable from a light fraction with diameters 0.025 to 0.6 MU and density of 1.07 g cm(-3) with a higher level of hydrolase activity. Both fractions appeared heterogeneous by electron microscopy, but the fine structure of the membranes of both heavy and light lysosomes was similar. The heavy lysosomal fraction was rich in autophagic vacuoles (secondary lysosomes) containing organelles and amorphous cytoplasmic material. Both fractions were rich in ribonucleic acid.Freezing and thawing, high speed blending and ultrasonication either singly or in combination solubilised a maximum of ca. 30% of the acid phosphatase from crude lysosomal fractions derived from dark-grown potato shoots. Treatment with Triton X-100 and deoxycholate released appreciably more enzyme activity but acetone and carbon tetrachloride failed to solubilise any acid phosphatase. Only detergent treatments gave marked overrecovery of enzyme and indicated structure-linked latency. Liberation of enzyme from lysosomes varied with pH and was almost complete at both extremes of pH. Crude snake venom was rapid and effective in solubilising acid phosphatase from lysosomal preparations, purified phospholipase A was less effective and phospholipases C and D had negligible effects. Phospholipase and venom mediated release of acid phosphatase was accompanied by the coincident release of an acid end-product. Gel filtration of acid phosphatase liberated from heavy and light lysosomal fractions by snake venom digestion revealed that each of these fractions was characterised by the presence of distinct molecular forms of the enzyme. The nature of the association of acid phosphatase with potato shoot lysosomes is discussed. PMID- 24474158 TI - The relationship between centrioles, microtubules and cell plate initiation in Chlorella pyrenoidosa. AB - Cytokinesis in Chlorella pyrenoidosa usually starts at the tetranuclear stage and is preceded by a characteristic arrangement of microtubules in the zone between adjacent nuclei. Initiation of the cell plate occurs in close association with two centriole pairs, each of which is attached to one nucleus. The cell plate subsequently extends along the plane of microtubular orientation towards the cell wall. PMID- 24474159 TI - [Stimulation of hill-reaction and CO2 fixation in isolated spinach chloroplasts by low concentrations of SO 3 (--)]. AB - 1. The photoreduction of K3[Fe(CN)6] by isolated and sonicated spinach chloroplasts is increased by SO 3 (--) (concentrations tested: 0.25-5 mM). This stimulation increases with SO 3 (--) concentrations from 0.25-3 mM. The ferricyanide-reduction with SO 3 (--) is inhibited by DCMU (10(-6)M) to about 90%. Inhibition of the photoreduction by pretreatment of the chloroplasts with Tris-buffer is compensated by increasing concentrations of SO 3 (--) (tested up to 3 mM). 2. The photoreduction of NADP in isolated chloroplasts is also enhanced by SO 3 (--) (concentrations tested: 0.25-3.0 mM). It is completely inhibited by DCMU (10(-6)M). In contrast to the results with ferricyanide as electron acceptor, SO 3 (--) does not overcome the inhibition of NADP reduction caused by pretreatment of the chloroplasts with Tris-buffer. 3. In illuminated isolated chloroplasts SO 3 (--) concentrations <1 mM do not alter the ATP-concentration, concentrations>1 mM decrease it. 4. The photosynthetic fixation of (14)CO2 by isolated chloroplasts is increased by SO 3 (--) concentrations <1 mM, but decreased by concentrations>1 mM. In total (14)CO2 fixed, at stimulating concentrations (0.25 and 0.5 mM SO 3 (--) ), the relative amount of sugar monophosphates is increased, whereas that of sugardiphosphates and of PGA is decreased. 5. It is proposed that these specific effects on photosynthetic processes help to explain the well known fact that photosynthetic gas exchange and the yield of plants are stimulated by low doses of SO2. PMID- 24474160 TI - Phytochrome-mediated growth responses in green and etiolated Lemna minor. AB - The growth of Lemna minor in darkness is log-linear, at a much reduced rate compared to growth in white or red light. This rate of frond production in darkness is stimulated by kinetin, yeast extract, and thiamine either in green plants transferred directly from the light or in plants which had been grown in the dark for 54 days. (Fig. 1).The magnitude of the stimulation of frond production by interruption of darkgrowth with red light (Fig. 2) is smaller in green than in etiolated plants, and is shown to depend upon the length of time that initially green plants were held in darkness (Fig. 4, Table 2). The stimulation of frond production in either green or etiolated plants does, however, obey the reciprocity law (Fig. 3).The stimulation by red light can be fully and repeatedly nullified by far red light only in etiolated plants, but the efficiency of nullification of the red effect by far red seems to increase in green plants with increasing sets of red + far red exposures (Fig. 5).As the dark interval between red and far red exposures is lengthened, the efficiency of nullification is lessened significantly for etiolated plants only after 30 min (Fig. 6). PMID- 24474161 TI - Testing the semi-explicit assembly model of aqueous solvation in the SAMPL4 challenge. AB - Here, we test a method, called semi-explicit assembly (SEA), that computes the solvation free energies of molecules in water in the SAMPL4 blind test challenge. SEA was developed with the intention of being as accurate as explicit-solvent models, but much faster to compute. It is accurate because it uses pre simulations of simple spheres in explicit solvent to obtain structural and thermodynamic quantities, and it is fast because it parses solute free energies into regionally additive quantities. SAMPL4 provided us the opportunity to make new tests of SEA. Our tests here lead us to the following conclusions: (1) The newest version, called Field-SEA, which gives improved predictions for highly charged ions, is shown here to perform as well as the earlier versions (dipolar and quadrupolar SEA) on this broad blind SAMPL4 test set. (2) We find that both the past and present SEA models give solvation free energies that are as accurate as TIP3P. (3) Using a new approach for force field parameter optimization, we developed improved hydroxyl parameters that ensure consistency with neat-solvent dielectric constants, and found that they led to improved solvation free energies for hydroxyl-containing compounds in SAMPL4. We also learned that these hydroxyl parameters are not just fixing solvent exposed oxygens in a general sense, and therefore do not improve predictions for carbonyl or carboxylic-acid groups. Other such functional groups will need their own independent optimizations for potential improvements. Overall, these tests in SAMPL4 indicate that SEA is an accurate, general and fast new approach to computing solvation free energies. PMID- 24474162 TI - Exhaustive docking and solvated interaction energy scoring: lessons learned from the SAMPL4 challenge. AB - We continued prospective assessments of the Wilma-solvated interaction energy (SIE) platform for pose prediction, binding affinity prediction, and virtual screening on the challenging SAMPL4 data sets including the HIV-integrase inhibitor and two host-guest systems. New features of the docking algorithm and scoring function are tested here prospectively for the first time. Wilma-SIE provides good correlations with actual binding affinities over a wide range of binding affinities that includes strong binders as in the case of SAMPL4 host guest systems. Absolute binding affinities are also reproduced with appropriate training of the scoring function on available data sets or from comparative estimation of the change in target's vibrational entropy. Even when binding modes are known, SIE predictions lack correlation with experimental affinities within dynamic ranges below 2 kcal/mol as in the case of HIV-integrase ligands, but they correctly signaled the narrowness of the dynamic range. Using a common protein structure for all ligands can reduce the noise, while incorporating a more sophisticated solvation treatment improves absolute predictions. The HIV integrase virtual screening data set consists of promiscuous weak binders with relatively high flexibility and thus it falls outside of the applicability domain of the Wilma-SIE docking platform. Despite these difficulties, unbiased docking around three known binding sites of the enzyme resulted in over a third of ligands being docked within 2 A from their actual poses and over half of the ligands docked in the correct site, leading to better-than-random virtual screening results. PMID- 24474163 TI - Current practice regarding seizure prophylaxis in aneurysmal subarachnoid hemorrhage across academic centers. AB - OBJECT: The objective of this study was to determine current practices regarding seizure prophylaxis in aneurysmal subarachnoid hemorrhage (aSAH). METHODS: An eight question survey was sent to 25 US centers with high volume aSAH cases (>100 annually). Respondents were asked about institutional practices regarding use, duration, and type of seizure prophylaxis. RESULTS: 13 (52%) respondents endorsed the utility of seizure prophylaxis while 10 (40%) did not, and two (8%) were unsure. Among respondents using prophylaxis, levetiracetam was the firstline medication for the majority (94%) while phenytoin was used as a primary agent at one (4%) center and as a secondary agent at four (16%) centers. Duration of levetiracetam prophylaxis ranged from 1 day to 6 weeks following SAH (mean 13.2; median 11). Only a single center employed EEG routinely in all aSAH patients but most supported EEG use when the neurologic examination was unreliable or inexplicably declining. 24 (96%) respondents agreed that a trial randomizing patients to levetiracetam or no antiseizure medication is warranted at this time, and all 25 (100%) believed that such a trial would be appropriate or ethically sound. CONCLUSIONS: The routine use of seizure prophylaxis following aSAH is controversial. Among a sampling of 25 major academic centers, most administer prophylaxis, while a significant proportion does not. The majority believes a trial randomizing patients to receive seizure prophylaxis is both timely and ethical. PMID- 24474165 TI - A new osmidrosis procedure, the scrape and suction technique: review of 4,322 patients. AB - BACKGROUND: Axillary osmidrosis causes unpleasant odors and profuse sweating, resulting in social and psychological problems. Many treatment modalities have been attempted and liposuction is preferred because of the minimal scar, although the problem of a high recurrence rate still exists. The aim of this study was to introduce and evaluate the efficacy of a new technique to treat axillary osmidrosis using a liposuction machine. METHODS: From January 2002 to December 2012, a total of 4,322 patients with axillary osmidrosis were treated with a new technique that combines suction with aggressive scraping. Treatment outcomes were assessed by a patient survey in the outpatient clinic at least 6 months after surgery. Permanent tissue biopsies were obtained from the left axilla before surgery and from the right axilla after surgery and compared to each other. RESULTS: Ninety-five percent of the patients (n=4,092) were very satisfied with the result, including the postoperative scars, and responded that they never or hardly ever experienced symptoms of axillary osmidrosis postoperatively. Recurrences occurred in 230 patients (5%) and most resolved after additional procedures, except 36 cases (0.8%). The tissue biopsy showed complete excision of the apocrine glands and a well-cut cross-sectional view of the dermis. Superficial epidermal necrosis occurred in 41 patients, probably due to hematoma, and 32 patients of the 41 (78.0%) were treated successfully without any revisional procedures. CONCLUSION: The new technique of scraping and suctioning with a newly designed liposuction machine achieved minimal scars, low recurrence rates, and very high patient satisfaction. This technique can be a simple and effective treatment modality for the treatment of axillary osmidrosis. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24474164 TI - Pseudotyped murine leukemia virus for schistosome transgenesis: approaches, methods and perspectives. AB - Draft genome sequences for the human schistosomes, Schistosoma japonicum, S. mansoni and S. haematobium are now available. The schistosome genome contains ~11,000 protein encoding genes for which the functions of few are well understood. Nonetheless, the newly described gene products and novel non-coding RNAs represent potential intervention targets, and molecular tools are being developed to determine their importance. Over the past decade, noteworthy advances has been reported towards development of tools for gene manipulation of schistosomes, including gene expression perturbation by RNAi, and transient and stable transfection including transgenesis mediated by genome integration competent vectors. Retrovirus-mediated transgenesis is an established functional genomic approach for model species. It offers the means to establish gain- or loss-of-function phenotypes, supports vector-based RNA interference, and represents a powerful forward genetics tool for insertional mutagenesis. Murine leukemia virus (MLV) pseudotyped with vesicular stomatitis virus glycoprotein mediates somatic transgenesis in S. mansoni, and vertical transmission of integrated transgenes in S. mansoni has been demonstrated, leading the establishment of transgenic lines. In addition, MLV transgenes encoding antibiotic resistance allow the selection of MLV-transduced parasites with the appropriate antibiotics. Here we describe detailed methods to produce and quantify pseudotyped MLV particles for use in transducing developmental stages of schistosomes. Approaches to analyze MLV-transduced schistosomes, including qPCR and high throughput approaches to verify and map genome integration of transgenes are also presented. We anticipate these tools should find utility in genetic investigations in other laboratories and for other helminth pathogens of important neglected tropical diseases. PMID- 24474166 TI - MRI versus ultrasonography to assess meniscal abnormalities in acute knees. AB - While magnetic resonance imaging (MRI) is often considered the "gold standard" diagnostic imaging modality for detection of meniscal abnormalities, it is associated with misdiagnosis in as high as 47% of cases, is costly, and is not readily available to a large number of patients. Ultrasonographic examination of the knee has been reported to be an effective diagnostic tool for this purpose with the potential to overcome many of the shortcomings of MRI. The purpose of this study is to determine the clinical usefulness of ultrasonography for diagnosis of meniscal pathology in patients with acute knee pain and compare its diagnostic accuracy to MRI in a clinical setting. With Institutional Review Board approval, patients (n = 71) with acute knee pain were prospectively enrolled with informed consent. Preoperative MRI (1.5 T) was performed on each affected knee using the hospital's standard equipment and protocols and read by faculty radiologists trained in musculoskeletal MRI. Ultrasonographic assessments of each affected knee were performed by one of two faculty members trained in musculoskeletal ultrasonography using a 10 to 14 MHz linear transducer. Arthroscopic evaluation of affected knees was performed by one of three faculty orthopedic surgeons to assess and record all joint pathology, which served as the reference standard for determining presence, type, and severity of meniscal pathology. All evaluators for each diagnostic modality were blinded to all other data. Data were collected and compared by a separate investigator to determine sensitivity (Sn), specificity (Sp), positive predictive value (PPV), negative predictive value (NPV), correct classification rate (CCR), likelihood ratios (LR[+] and LR[-]), and odds ratios. Preoperative ultrasonographic assessment of meniscal pathology was associated with Sn = 91.2%, Sp = 84.2%, PPV = 94.5%, NPV = 76.2%, CCR = 89.5%, LR(+) = 5.78, and LR(-) = 0.10. Preoperative MRI assessment of meniscal pathology was associated with Sn = 91.7%, Sp = 66.7%, PPV = 84.6%, NPV = 80.0%, CCR = 81.1%, LR(+) = 2.75, and LR(-) = 0.13. Ultrasonography was two times more likely than MRI to correctly determine presence or absence of meniscal pathology seen arthroscopically in this study. Ultrasonography is a useful tool for diagnosis of meniscal pathology with potential advantages over MRI. Based on these data and available portable equipment, ultrasonography could be considered for use as a point-of-injury diagnostic modality for meniscal injuries. PMID- 24474167 TI - Diagnosis and treatment of intraoperative popliteus tendon impingement. AB - Herein, we describe a simple, effective strategy for diagnosing and treating intraoperative popliteus tendon impingement during total knee arthroplasty (TKA). When lateral impingement is detected intraoperatively during TKA, manual isolation of the popliteus tendon can help determine the cause. Using this technique, the etiology of intraoperative lateral impingement during TKA was never misdiagnosed and the popliteus tendon was never unnecessarily released. The technique described allows for accurate diagnosis of intraoperative lateral impingement during TKA and the prevention of unnecessary popliteus resection. PMID- 24474168 TI - Antitumor effects with apoptotic death in human promyelocytic leukemia HL-60 cells and suppression of leukemia xenograft tumor growth by irinotecan HCl. AB - Irinotecan HCl (CPT-11) is an anticancer prodrug, but there is no available information addressing CPT-11-inhibited leukemia cells in in vitro and in vivo studies. Therefore, we investigated the cytotoxic effects of CPT-11 in promyelocytic leukemia HL-60 cells and in vivo and tumor growth in a leukemia xenograft model. Effects of CPT-11 on HL-60 cells were determined using flow cytometry, immunofluorescence staining, comet assay, real-time PCR, and Western blotting. CPT-11 demonstrated a dose- and time-dependent inhibition of cell growth, induction of apoptosis, and cell-cycle arrest at G0/G1 phase in HL-60 cells. CPT-11 promoted the release of AIF from mitochondria and its translocation to the nucleus. Bid, Bax, Apaf-1, caspase-9, AIF, Endo G, caspase-12, ATF-6b, Grp78, CDK2, Chk2, and cyclin D were all significantly upregulated and Bcl-2 was down-regulated by CPT-11 in HL-60 cells. Induction of cell-cycle arrest by CPT-11 was associated with changes in expression of key cell-cycle regulators such as CDK2, Chk2, and cyclin D in HL-60 cells. To test whether CPT-11 could augment antitumor activity in vivo, athymic BALB/c(nu/nu) nude mice were inoculated with HL-60 cells, followed by treatment with either CPT-11. The treatments significantly inhibited tumor growth and reduced tumor weight and volume in the HL-60 xenograft mice. The present study demonstrates the schedule-dependent antileukemia effect of CPT-11 using both in vitro and in vivo models. CPT-11 could potentially be a promising agent for the treatment of promyelocytic leukemia and requires further investigation. PMID- 24474169 TI - Yeast growth plasticity is regulated by environment-specific multi-QTL interactions. AB - For a unicellular, nonmotile organism like Saccharomyces cerevisiae, carbon sources act as nutrients and as signaling molecules; consequently, these sources affect various fitness parameters, including growth. It is therefore advantageous for yeast strains to adapt their growth to carbon source variation. The ability of a given genotype to manifest different phenotypes in varying environments is known as phenotypic plasticity. To identify quantitative trait loci (QTL) that drive plasticity in growth, two growth parameters (growth rate and biomass) were measured for a set of meiotic recombinants of two genetically divergent yeast strains grown in different carbon sources. To identify QTL contributing to plasticity across pairs of environments, gene-environment interaction mapping was performed, which identified several QTL that have a differential effect across environments, some of which act antagonistically across pairs of environments. Multi-QTL analysis identified loci interacting with previously known growth affecting QTL as well as novel two-QTL interactions that affect growth. A QTL that had no significant independent effect was found to alter growth rate and biomass for several carbon sources through two-QTL interactions. Our study demonstrates that environment-specific epistatic interactions contribute to the growth plasticity in yeast. We propose that a targeted scan for epistatic interactions, such as the one described here, can help unravel mechanisms regulating phenotypic plasticity. PMID- 24474170 TI - gitter: a robust and accurate method for quantification of colony sizes from plate images. AB - Colony-based screens that quantify the fitness of clonal populations on solid agar plates are perhaps the most important source of genome-scale functional information in microorganisms. The images of ordered arrays of mutants produced by such experiments can be difficult to process because of laboratory-specific plate features, morphed colonies, plate edges, noise, and other artifacts. Most of the tools developed to address this problem are optimized to handle a single setup and do not work out of the box in other settings. We present gitter, an image analysis tool for robust and accurate processing of images from colony based screens. gitter works by first finding the grid of colonies from a preprocessed image and then locating the bounds of each colony separately. We show that gitter produces comparable colony sizes to other tools in simple cases but outperforms them by being able to handle a wider variety of screens and more accurately quantify colony sizes from difficult images. gitter is freely available as an R package from http://cran.r-project.org/web/packages/gitter under the LGPL. Tutorials and demos can be found at http://omarwagih.github.io/gitter. PMID- 24474171 TI - Median lethal needle caliber in two models of experimental sepsis. AB - PURPOSE: To estimate the median lethal needle caliber (LC50) of a new experimental sepsis model and compare it to the LC50 of the cecal ligation and puncture (CLP) sepsis model. METHODS: Male albino Wistar rats were studied (n=22). Animals were allocated into two study groups. In Group I, experimental sepsis was induced by cecal ligation and puncture. In Group II, experimental sepsis was induced by ascending colon ligation and cecal puncture. Up-and-down method was used to determinate the LC50. RESULTS: LC50 in Group I was 19 Gauge (Confidence Interval 17 to 22 Gauge). Determination of LC50 was not possible in Group II due to the death of all animals. CONCLUSION: LC50 in cecal ligation and puncture is 19 Gauge. The lethality of the new model tested in this trial is very high. PMID- 24474172 TI - Cutaneous changes in rats induced by chronic skin exposure to ultraviolet radiation and organophosphate pesticide. AB - PURPOSE: To study the possible potentiation of the carcinogenic effects of ultraviolet radiation associated with an organophosphate pesticide. METHODS: Forty Wistar rats were assigned into four groups (n=10 each) randomized according to the procedures: group A received only UVR-B radiation; group B, UVR-B for eight weeks followed by a seven week period of pesticide exposure; group C, UVR-B + pesticide concomitantly: group D, only pesticide application. At the end of the fifth, tenth and fifteenth weeks the animals were photographed. Skin biopsy and histopathological study with Hematoxylin-Eosin were done on the fifteenth week. Statistical analysis with Fisher's and Sign (unilateral) tests, 5% value for significance. RESULTS: Macroscopic lesions in the group A evolved from the erythema to erythema + desquamation. The groups B and C, with the association of two carcinogens, and group D presented evolution to keratosis, with higher incidence in group D. The histology showed a significant increase in the severity of injuries when the UVR-B and the pesticide were applied simultaneously, leading to cellular atypia. CONCLUSIONS: Concurrent association of UVR-B to organophosphate pesticide produced more severe lesions microscopically, although this has not been so apparent macroscopically. In daily practice the clinical evaluation should be complemented with laboratory evaluation. PMID- 24474173 TI - The testis of the mice C57/BL6 offspring in adulthood have alterations due to maternal caffeine consumption. AB - PURPOSE: To investigate the effects of the maternal caffeine consumption during pregnancy to adult male testis mice offspring. METHODS: Twenty pregnant mice were divided into control group (c) and caffeine group (cf). dams received daily saline or 20 mg/kg of caffeine subcutaneously. Male offspring were monitored daily until 13th week. The testis were used to evaluate both the proliferation (pcna) and apoptosis (bax); leptin receptor (ob-r); aromatase; follicle stimulating hormone (fshr), luteinizing hormone (lhr) and androgen receptors (ar); steroidogenic acute regulatory protein (star); vascular endothelial growth factor (vegf) and estrogen receptors (eralpha and erbeta) by western blotting. Serum concentrations of testosterone, estradiol and leptin were measured. RESULTS: There was a significant reduction in food intake and the body mass gain (p<0.05) in the cf ; pcna (p=0.01), fshr (p=0.02), star (p=0.0007), vegf (p=0.009), ar (p=0.03) in the cf. while an increase were note in bax (p=0.01), ob r (p=0.02), lhr (p=0.04) and in the aromatase (p=0.03) in the cf. only eralpha and erbeta were not changed by maternal caffeine. The serum testosterone levels in the cf offspring were 90% lower than in the c offspring (p=0.04). CONCLUSION: Maternal caffeine consumption has a role and alters the testis of the offspring in adulthood. PMID- 24474174 TI - Effects of the administration of aqueous extract of de Sedum dendroideum on the histopathology of erosive induced gastritis by means of indomethacin in rats. AB - PURPOSE: To evaluate the effects of acute administration of Sedum dendroideum on the gastric histopathology of rats after the administration of indomethacin. METHODS: Twenty four Wistar rats were randomized into three groups, submitted to feeding privation for 24 hours prior to the oral administration of 50 mg/Kg of indomethacin and during the experimental period of six hours. The control group (C) was giving distilled water, the extract group (E) was treated with the extract of Sedum dendroideum and the group Omeoprazole (O) received 20 mg/Kg of omeoprazole. All the treatments were carried out thirty minutes prior to the administration of indomethacin. After six hour, the stomach of the animals was extirpated for histopathological analysis, which took into account the presence of erosive gastritis, hyperemia and sub mucosa edema. RESULTS: In group C, eight out of eight animals presented that type of lesion, in group E, this number was the same and in group O, three out of the eight rats presented erosive gastritis. CONCLUSION: Sedum dendroideum extract did not produce reduction in the erosive gastritis process. As expected, the treatment with omeoprazole produced a major reduction, when compared with the control group. PMID- 24474175 TI - Anti-hemorrhagic effect of hydro-alcoholic extract of the leaves of Mikania glomerata in lesions induced by Bothrops jararaca venom in rats. AB - PURPOSE: To investigate the effects of hydroalcoholic leaf extract of Mikania glomerata Spreng (Asteraceae) on the activity of Bothrops jararaca snake venom in Wistar rats. METHODS: Fifty four rats Wistar were divided into six groups of nine animals in each: control treated with saline; control treated with B. jararaca venom; control treated with M. glomerata extract; B. jararaca venom incubated with M. glomerata extract at proportions of 1:1, 1:2, and 1:4. RESULTS: Histopathological and morphometric analysis showed that intradermal administration of snake venom incubated with the hydroalcoholic extract at proportions of 1:1, 1:2 and 1:4 promoted a significant reduction in the number of inflammatory cells and a marked decrease in edema after the third hour. There was also a significant reduction in the intensity of the hemorrhagic halo in animals receiving the snake venom incubated with the extract, with the observation of a progressive and parallel inhibition with increasing proportion of M. glomerata. CONCLUSION: The Mikania glomerata hydroalcoholic extract exerted effective anti inflammatory and antihemorrhagic activity against the effects induced by Bothrops jararaca snake venom. PMID- 24474176 TI - Effects of epidural nalbuphine on intraoperative isoflurane and postoperative analgesic requirements in dogs. AB - PURPOSE: To measure the change in the minimum alveolar concentration of isoflurane (EtISO) associated with epidural nalbuphine and the postoperative analgesic requirements in dogs after ovariohysterectomy. METHODS: Twenty four healthy female dogs were randomly assigned to receive saline or nalbuphine at 0.3 or 0.6 mg/kg (n=8 for each group) administered via lumbosacral epidural catheter introduced cranially into the epidural canal. Changes in heart and respiratory rates and arterial blood pressure during surgery were recorded along with the corresponding EtISO. Immediately after tracheal extubation, analgesia, sedation, heart rate, respiratory rate, and arterial blood pressure were measured at predetermined intervals and every 60 min thereafter until the first rescue analgesic. RESULTS: A significant decrease in EtISO was associated with epidural nalbuphine at 0.3 mg/kg (26.3%) and 0.6 mg/kg (38.4%) but not with saline in ovariohysterectomized dogs. In the postoperative period, VAS and Colorado analgesic scores were lower for the dogs that received the higher nalbuphine dose, which only required supplemental analgesia 10 h following its administration, compared with dogs that received the lower dose. CONCLUSION: Epidural nalbuphine significantly reduces the intra-operative isoflurane requirement and provides prolonged postoperative analgesia after ovariohysterectomy in dogs. PMID- 24474177 TI - Sedative and clinical effects of the pharmacopuncture with xylazine in dogs. AB - PURPOSE: To investigate the sedative and clinical effects of the pharmacopuncture with xylazine, compared to the conventional dose of a intramuscular injection in dogs. METHODS: Twelve dogs were randomly distributed in two groups of six animals and treated as follows: control group (X-IM): 1mg kg(-1) of xylazine given intramuscularly (IM); pharmacopuncture group (X-Yintang): 0.1mg kg(-1) of xylazine diluted to 0.5 mL of saline injected into the Yin Tang acupoint. Heart rate, cardiac rhythm (ECG), systolic arterial blood pressure (SABP), respiratory rate (RR), rectal temperature (RT), blood glucose concentration, degree of sedation and adverse effects were evaluated. RESULTS: Sedative effect was observed in both groups. The degree of sedation was greater in X-IM only at 15 min when compared with X-Yintang group. Cardiovascular established was observed in X-Yintang group, while marked reduction in the HR and increased incidence of ECG abnormalities were detected in X-IM. In both treatment groups, minimal changes were observed in relation to SABP, RR, RT and blood glucose. High incidence (66%) of vomiting was observed in X-IM, while this adverse effect was absent in X-Yintang. CONCLUSION: Pharmacopuncture with xylazine induced clinically relevant sedative effects in dogs, with the advantage of reduction of undesirable side effects associated with alpha2-agonists, including bradycardia, cardiac arrhythmias, and emesis. PMID- 24474178 TI - Translational realistic expectations of chronic cerebral hypoxemia in rat model after bilateral commom carotid artery ligation. Neurocognitive aspects. AB - PURPOSE: To evaluate the effects of chronic cerebral hypoxia on memory of rats submitted to bilateral common carotid artery ligation (BCCL). METHODS: Every each week, for 16 weeks, 31 rats were tested for memory using a water and land mazes and compared with 30 normal rats (control group A). The variables were expressed by their mean and standard error of the mean (SEM). p<0.05 was used for rejecting the null hypothesis. The study was approved by the Ethics Committee for animal investigation. RESULTS: There was a significant increase in the latency time, in the survival water and land mazes, after four weeks (study group B) follow-up. However, without any medication or therapeutically induced measures, after 16 weeks (study group C) follow-up the latency mean times tend to be similar to control group (A) in the neurocognitive tests. CONCLUSIONS: Neurocognitive deficits after 16 weeks post-operative follow-up of rats that underwent bilateral common carotid artery ligation is a natural adaptive phenomenon. Thus, is not realistic to allow translational information from this animal model for therapeutically approaches aiming at to prevent, or to improve brain damage in human beings suffering from chronic deprivation of adequate blood supply. PMID- 24474179 TI - Effect of platelet rich fibrin and beta tricalcium phosphate on bone healing. A histological study in pigs. AB - PURPOSE: To investigate the effect of platelet rich fibrin (PRF) and beta tricalcium phosphate (beta-TCP), alone or in combination, on bone regeneration in pig tibial defects. METHODS: Four standardized defects were prepared in both tibias of three adult male pigs. The first defect was left unfilled as a control; the others were grafted with either PRF, beta-TCP or PRF mixed with beta-TCP. All animals were sacrificed on the 12th postoperative week and the tibial bones were removed, histologic sections were prepared and the experimental sites were examined microscopically and stereologically. RESULTS: Histologic and stereologic examination revealed more new bone formation in the defects filled with PRF mixed beta-TCP than in the defects grafted with either beta-TCP or PRF alone. CONCLUSION: The platelet rich fibrin and beta tricalcium phosphate combination effectively induces new bone formation. PMID- 24474180 TI - The effect of different doses of chloroprocaine on saddle anesthesia in perianal surgery. AB - PURPOSE: To investigate a saddle anesthesia with different doses of chloroprocaine in perianal surgery. METHODS: Total 60 Patients aged 18-75 years (Anesthesiologists grade I or II) scheduled to receive perianal surgery. Patients using saddle anesthesia were randomized to group A, group B and group C with the same concentration (0.5%) chloroprocaine with different doses 1.0 mL, 0.8 mL and 0.6 mL, respectively. Systolic blood pressure (SBP), diastolic blood pressure (DBP), heart rate (HR) and the sensory and motor block were recorded to evaluate the anesthesia effect of chloroprocaine in each group. RESULTS: The duration of sensory block of group C is shorter than those of group A and B. The maximum degree of motor block is observed (group C: 0 level, group A: III level; and group B: I level) after 15 minutes. Besides, there was a better anesthetic effect in group B than group A and group C, such as walking after saddle anesthesia. However, there is also no significant difference of blood pressure decreasing in these three groups. CONCLUSION: It's worth to employ a saddle anesthesia with appropriate doses of chloroprocaine in clinical perianal surgery. PMID- 24474181 TI - To proliferate, not to proliferate or to die. The liver itself decides as needed. PMID- 24474182 TI - The direct synthesis of hydrogen peroxide using platinum-promoted gold-palladium catalysts. AB - The direct synthesis of hydrogen peroxide offers a potentially green route to the production of this important commodity chemical. Early studies showed that Pd is a suitable catalyst, but recent work indicated that the addition of Au enhances the activity and selectivity significantly. The addition of a third metal using impregnation as a facile preparation method was thus investigated. The addition of a small amount of Pt to a CeO2-supported AuPd (weight ratio of 1:1) catalyst significantly enhanced the activity in the direct synthesis of H2O2 and decreased the non-desired over-hydrogenation and decomposition reactions. The addition of Pt to the AuPd nanoparticles influenced the surface composition, thus leading to the marked effects that were observed on the catalytic formation of hydrogen peroxide. In addition, an experimental approach that can help to identify the optimal nominal ternary alloy compositions for this reaction is demonstrated. PMID- 24474183 TI - Methylation marker analysis of self-sampled cervico-vaginal lavage specimens to triage high-risk HPV-positive women for colposcopy. AB - Methylation markers were studied for their suitability to triage human papillomavirus (HPV)-positive women by testing self-collected cervico-vaginal lavage specimens. For this purpose, we analyzed 355 hrHPV-positive self-collected specimens with three methylation markers, that is, CADM1-m18, MAL-m1 and miR-124 2 by quantitative methylation-specific PCR. The areas under the receiver operating characteristic (ROC) curve for end-point cervical intraepithelial neoplasia grade 3 or worse (CIN3+) were 0.637 for CADM1-m18, 0.767 for MAL-m1 and 0.762 for miR-124-2. This indicates that CADM1-m18 is not suitable as single marker. By varying the thresholds of both markers in the bi-marker panels CADM1 m18/MAL-m1, CADM1-m18/miR-124-2 and MAL-m1/miR-124-2 upper and lower ROC curves were obtained, depicting the maximum and minimum CIN3+ sensitivity, respectively, at given specificity. For all these bi-marker combinations, the upper curves were similar. However, for the MAL-m1/miR-124-2 panel, the distance between upper and lower ROC curves was closest and this panel displayed the highest assay thresholds, indicating that this combination was most robust. At clinical specificities of 50 and 70%, the MAL-m1/miR-124-2 sensitivity for detection of CIN3+ ranged from 77.0 to 87.8% and from 64.9 to 71.6%, respectively. At 70% specificity thresholds no carcinomas were missed. By comparison, the CIN3+ sensitivity of HPV16/18 genotyping on the self-sampled lavage specimens was 58.1% (95%CI: 46.6-68.8) at a specificity of 87.7% (95%CI: 83.2-91.2). In conclusion, methylation analysis is a promising triage tool that in combination with HPV-DNA testing offers feasible, full molecular screening on self-collected cervico vaginal lavage specimens. PMID- 24474184 TI - Protein binding reaction enhanced by bi-directional flow driven by on-chip thermopneumatic actuator. AB - A microfluidic immunoassay system was developed for the study of the enhancement of protein binding reaction. The system mainly consisted of a thermopneumatic actuator and a reaction chamber. Reagent was pre-installed in the on-chip reservoir and manipulated by the actuator. Such design could eliminate the external tubing connections in order to reduce the waste of reagent and improve the portability. The on-chip actuator could manipulate the reagent bi directionally to induce vortexes in the chamber. Enhancement of protein binding reaction was demonstrated by the protein model pair, i.e., mouse IgG and anti mouse IgG. By such bi-directional fluid motion, more binding opportunities between suspended protein and its surface-immobilized counterpart were generated to improve the performance of immunoassay. It showed that an 83.74 % enhancement of the binding reaction was achieved, compared with the static situation. As a whole, the proposed microfluidic system is highly integrated and can enhance the protein binding efficiency using such novel design. The developed system can be easily extended to multi-reagents immunoassay protocols and provides a useful platform for point-of-care applications. PMID- 24474185 TI - Treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: synopsis of the 2013 American College of Cardiology/American Heart Association cholesterol guideline. AB - DESCRIPTION: In November 2013, the American College of Cardiology and American Heart Association (ACC/AHA) released a clinical practice guideline on the treatment of blood cholesterol to reduce cardiovascular risk in adults. This synopsis summarizes the major recommendations. METHODS: In 2008, the National Heart, Lung, and Blood Institute convened the Adult Treatment Panel (ATP) IV to update the 2001 ATP-III cholesterol guidelines using a rigorous process to systematically review randomized, controlled trials (RCTs) and meta-analyses of RCTs that examined cardiovascular outcomes. The panel commissioned independent systematic evidence reviews on low-density lipoprotein cholesterol and non-high density lipoprotein cholesterol goals in secondary and primary prevention and the effect of lipid drugs on atherosclerotic cardiovascular disease events and adverse effects. In September 2013, the panel's draft recommendations were transitioned to the ACC/AHA. RECOMMENDATIONS: This synopsis summarizes key features of the guidelines in 8 areas: lifestyle, groups shown to benefit from statins, statin safety, decision making, estimation of cardiovascular disease risk, intensity of statin therapy, treatment targets, and monitoring of statin therapy. PMID- 24474186 TI - Human-Grey parrot (Psittacus erithacus) reciprocity: a follow-up study. AB - In a previous study (Peron et al. in Anim Cogn, doi: 10.1007/s10071-012.05640 , 2012), Grey parrots, working in dyads, took turns choosing one of four differently coloured cups with differing outcomes: empty (null, non-rewarding), selfish (keeping reward for oneself), share (sharing a divisible reward), or giving (donating reward to other). When the dyads involved three humans with different specific intentions (selfish, giving, or copying the bird's behaviour), birds' responses only tended towards consistency with human behaviour. Our dominant bird was willing to share a reward with a human who was willing to give up her reward, was selfish with the selfish human, and tended towards sharing with the copycat human; our subordinate bird tended slightly towards increased sharing with the generous human and selfishness with the selfish human, but did not clearly mirror the behaviour of the copycat. We theorized that the birds' inability to understand the copycat condition fully-that they could potentially maximize reward by choosing to share-was a consequence of their viewing the copycat's behaviour as erratic compared with the consistently selfish or giving humans and thus not realizing that they were indeed being mirrored. We suggested that copycat trials subsequently be performed as a separate experiment, without being contrasted with trials in which humans acted consistently, in order to determine if results might have differed. We have now performed that experiment, and shown that at least one Grey parrot--our dominant--responded in a manner suggesting that he deduced the appropriate contingencies. PMID- 24474187 TI - Influence of co-morbidity on long-term quality of life after oesophagectomy for cancer. AB - BACKGROUND: The extent to which co-morbidities affect recovery of health-related quality of life (HRQoL) in long-term survivors of oesophageal cancer surgery is poorly understood. METHODS: This was a prospective, population-based, nationwide Swedish cohort study of patients who underwent surgery for oesophageal cancer between 2001 and 2005, and were alive 5 years after operation. The European Organization for Research and Treatment of Cancer QLQ-C30 and the QLQ-OES18 questionnaires were used to assess HRQoL up to 5 years after surgery. Eight aspects from the questionnaires were selected. Matched reference values from the Swedish general population were used as a proxy for HRQoL before presentation of the cancer. Adjusted multivariable linear mixed-effect models were used to assess mean score differences (MDs) of each HRQoL aspect in patients with or without co morbidities. RESULTS: Of 616 patients who underwent surgery, 153 (24.8 per cent) survived 5 years, of whom 141 (92.2 per cent) completed the questionnaires at 5 years. Among these, 79 (56.0 per cent) had co-morbidities. Patients with co morbidity had clinically relevant (MD at least 10) and statistically significantly poorer global quality of life (MD -10, 95 per cent confidence interval -12 to -7), and more problems with dyspnoea (MD 10, 6 to 13) throughout the whole follow-up period than those without co-morbidity. Patients with co morbidity had a clinically relevant worse level of fatigue at 6 months (MD 10, 1 to 19) and 5 years (14, 4 to 24). With regard to specific co-morbidities, only patients with diabetes reported more clinically relevant, but not statistically significant, problems with fatigue at 6 months (MD 16, 2 to 31) and 5 years (MD 13, -5 to 31) compared with patients without co-morbidity. CONCLUSION: Among survivors of oesophageal cancer surgery, the presence of co-morbidity was associated with poor HRQoL over time and increasing symptoms of fatigue. PMID- 24474188 TI - Eating quality and health-promoting properties of two sweet cherry (Prunus avium L.) cultivars stored in passive modified atmosphere. AB - Two sweet cherry cultivars ('New Star' and 'Sweet Heart') were chosen to explore the impact of passive modified atmosphere packaging on the eating quality and health-promoting properties of fruit. Packaged and unpackaged fruits were stored at 0 C for 15 or 30 days, followed by zero or three days at 20 C, after which the analyses were undertaken. In most cases, modified atmosphere packaging helped preserving higher firmness values and reducing the incidence of alterations and decay in both cultivars, but the effects on other physicochemical attributes were different for each cultivar. Partial least squares regression procedures were used to reveal relationships among the different variables assessed. Generally, fruits displaying higher antioxidant capacity were also characterised by higher values for firmness and titratable acidity, in turn related to better acceptability scores in both cultivars. However, the attributes contributing most to acceptability were different in each case. In 'New Star' fruit, acceptability was closely related to the perception of cherry flavour. In this cultivar, acetaldehyde content was related to the perception of off-flavours, while ethanol content was found to associate to soluble solids and to the perception of sweetness. In contrast, acceptability of 'Sweet Heart' fruit was related mainly to the perception of firmness and, to a lower extent, of sweetness. PMID- 24474189 TI - Frying stability of rapeseed Kizakinonatane (Brassica napus) oil in comparison with canola oil. AB - This study was carried out to investigate the frying performance of Kizakinonatane (Brassica napus) oil during deep-fat frying of frozen French fries with/without replenishment. Commercial regular canola oil was used for comparison. The frying oils were used during intermittent frying of frozen French fries at 180, 200, and 220 C for 7 h daily over four consecutive days. The Kizakinonatane oil exhibited lower levels of total polar compounds, carbonyl value, and viscosity as well as comparable color (optical density) values to that of the canola oil. The monounsaturated fatty acid/polyunsaturated fatty acid ratios were lower than that of canola oil, whereas the polyunsaturated fatty acid/saturated fatty acid ratios are higher than that of canola oil after heating. Results showed that fresh Kizakinonatane oil contains higher levels of acid value, viscosity, optical density values, tocopherols, and total phenolics contents than that of canola oil. Replenishment with fresh oil had significant effects on all chemical and physical parameters, except the acid value of the Kizakinonatane oil during frying processes. Based on the results, the Kizakinonatane oil is inherently suitable for preparing deep-fried foods at high temperatures. PMID- 24474190 TI - The microbiome and psoriatic arthritis. AB - Psoriatic arthritis is a chronic inflammatory joint disease, seen in combination with the chronic inflammatory skin disease psoriasis and belonging to the family of spondylarthritides (SpA). A link is recognized between psoriatic arthritis and inflammatory bowel disease (IBD). Environmental factors seem to induce inflammatory disease in individuals with underlying genetic susceptibility. The microbiome is a subject of increasing interest in the etiology of these inflammatory immune-mediated diseases. The intestinal microbiome is able to affect extra-intestinal distant sites, including the joints, through immunomodulation. At this point, evidence regarding a relationship between the microbiome and psoriatic arthritis is scarce. However, we hypothesize that common immune-mediated inflammatory pathways seen in the "skin-joint-gut axis" in psoriatic arthritis are induced or at least mediated by the microbiome. Th17 has a crucial function in this mechanism. Further establishment of this connection may lead to novel therapeutic approaches for psoriatic arthritis. PMID- 24474191 TI - Correlates of extended sitting time in older adults: an exploratory cross sectional analysis of the Canadian Community Health Survey Healthy Aging Cycle. AB - OBJECTIVES: Sitting time has been identified as an independent predictor of health; however, little is known of the determinants of extended sitting time among older adults. The purpose of this study was to identify potential sociodemographic, physical environment, health-related and psychosocial correlates of extended sitting time among older adults living independently in the community. METHODS: Data from adults over the age of 65 from the Canadian Community Health Survey (Healthy Aging Cycle, 2008-2009) were used for analysis (n = 14,560). Self-reported sitting time (<4 or >=4 h/day) was the main outcome. RESULTS: Age, retirement status, dwelling type, chronic disease, perceived health, body mass index, mood disorder and sense of belonging to community were associated with sitting for 4 or more hours/day. Very low, but not low or moderate, physical activity (OR 1.43; CI 1.19-1.72) was associated with sitting for 4 or more hours/day when compared to those classified as having high physical activity. CONCLUSIONS: Several specific correlates of extended sitting time were identified among older males and females; these findings have implications for public health strategies targeting older adults. PMID- 24474193 TI - Histone deacetylase 6 and cytoplasmic linker protein 170 function together to regulate the motility of pancreatic cancer cells. AB - Pancreatic cancer is a devastating disease with the worst prognosis among all the major human malignancies. The propensity to rapidly metastasize contributes significantly to the highly aggressive feature of pancreatic cancer. The molecular mechanisms underlying this remain elusive, and proteins involved in the control of pancreatic cancer cell motility are not fully characterized. In this study, we find that histone deacetylase 6 (HDAC6), a member of the class II HDAC family, is highly expressed at both protein and mRNA levels in human pancreatic cancer tissues. HDAC6 does not obviously affect pancreatic cancer cell proliferation or cell cycle progression. Instead, it significantly promotes the motility of pancreatic cancer cells. Further studies reveal that HDAC6 interacts with cytoplasmic linker protein 170 (CLIP-170) and that these two proteins function together to stimulate the migration of pancreatic cancer cells. These findings provide mechanistic insight into the progression of pancreatic cancer and suggest HDAC6 as a potential target for the management of this malignancy. PMID- 24474192 TI - Inflammasomes in cancer: a double-edged sword. AB - Chronic inflammatory responses have long been observed to be associated with various types of cancer and play decisive roles at different stages of cancer development. Inflammasomes, which are potent inducers of interleukin (IL)-1beta and IL-18 during inflammation, are large protein complexes typically consisting of a Nod-like receptor (NLR), the adapter protein ASC, and Caspase-1. During malignant transformation or cancer therapy, the inflammasomes are postulated to become activated in response to danger signals arising from the tumors or from therapy-induced damage to the tumor or healthy tissue. The activation of inflammasomes plays diverse and sometimes contrasting roles in cancer promotion and therapy depending on the specific context. Here we summarize the role of different inflammasome complexes in cancer progression and therapy. Inflammasome components and pathways may provide novel targets to treat certain types of cancer; however, using such agents should be cautiously evaluated due to the complex roles that inflammasomes and pro-inflammatory cytokines play in immunity. PMID- 24474194 TI - Direct conversion of human fibroblasts into retinal pigment epithelium-like cells by defined factors. AB - The generation of functional retinal pigment epithelium (RPE) is of great therapeutic interest to the field of regenerative medicine and may provide possible cures for retinal degenerative diseases, including age-related macular degeneration (AMD). Although RPE cells can be produced from either embryonic stem cells or induced pluripotent stem cells, direct cell reprogramming driven by lineage-determining transcription factors provides an immediate route to their generation. By monitoring a human RPE specific Best1::GFP reporter, we report the conversion of human fibroblasts into RPE lineage using defined sets of transcription factors. We found that Best1::GFP positive cells formed colonies and exhibited morphological and molecular features of early stage RPE cells. Moreover, they were able to obtain pigmentation upon activation of Retinoic acid (RA) and Sonic Hedgehog (SHH) signaling pathways. Our study not only established an ideal platform to investigate the transcriptional network regulating the RPE cell fate determination, but also provided an alternative strategy to generate functional RPE cells that complement the use of pluripotent stem cells for disease modeling, drug screening, and cell therapy of retinal degeneration. PMID- 24474195 TI - Crystal structure of E. coli arginyl-tRNA synthetase and ligand binding studies revealed key residues in arginine recognition. AB - The arginyl-tRNA synthetase (ArgRS) catalyzes the esterification reaction between L-arginine and its cognate tRNA(Arg). Previously reported structures of ArgRS shed considerable light on the tRNA recognition mechanism, while the aspect of amino acid binding in ArgRS remains largely unexplored. Here we report the first crystal structure of E. coli ArgRS (eArgRS) complexed with L-arginine, and a series of mutational studies using isothermal titration calorimetry (ITC). Combined with previously reported work on ArgRS, our results elucidated the structural and functional roles of a series of important residues in the active site, which furthered our understanding of this unique enzyme. PMID- 24474196 TI - Signaling control of the constitutive androstane receptor (CAR). AB - The constitutive androstane receptor (CAR, NR1I3) plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent (indirect) mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mechanisms yet to be fully understood. Accumulating evidence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be functionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our understanding of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation. PMID- 24474197 TI - Global DNA methylation and transcriptional analyses of human ESC-derived cardiomyocytes. AB - With defined culture protocol, human embryonic stem cells (hESCs) are able to generate cardiomyocytes in vitro, therefore providing a great model for human heart development, and holding great potential for cardiac disease therapies. In this study, we successfully generated a highly pure population of human cardiomyocytes (hCMs) (>95% cTnT(+)) from hESC line, which enabled us to identify and characterize an hCM-specific signature, at both the gene expression and DNA methylation levels. Gene functional association network and gene-disease network analyses of these hCM-enriched genes provide new insights into the mechanisms of hCM transcriptional regulation, and stand as an informative and rich resource for investigating cardiac gene functions and disease mechanisms. Moreover, we show that cardiac-structural genes and cardiac-transcription factors have distinct epigenetic mechanisms to regulate their gene expression, providing a better understanding of how the epigenetic machinery coordinates to regulate gene expression in different cell types. PMID- 24474198 TI - Gadd45a deletion aggravates hematopoietic stem cell dysfunction in ATM-deficient mice. AB - Ataxia telangiectasia mutated (ATM) kinase plays an essential role in the maintenance of genomic stability. ATM-deficient (ATM(-/-)) mice exhibit hematopoietic stem cell (HSC) dysfunction and a high incidence of lymphoma. Gadd45a controls cell cycle arrest, apoptosis and DNA repair, and is involved in the ATM-p53 mediated DNA damage response. However, the role of Gadd45a in regulating the functionality of ATM(-/-) HSCs is unknown. Here we report that Gadd45a deletion did not rescue the defects of T-cells and B-cells development in ATM(-/-) mice. Instead, ATM and Gadd45a double knockout (ATM(-/-) Gadd45a(-/-)) HSCs exhibited an aggravated defect in long-term self-renewal capacity compared to ATM(-/-) HSCs in HSC transplantation experiments. Further experiments revealed that the aggravated defect of ATM(-/-) Gadd45a(-/-) HSCs was due to a reduction of cell proliferation, associated with an accumulation of DNA damage and subsequent activation of DNA damage response including an up-regulation of p53 p21 signaling pathway. Additionally, ATM(-/-) Gadd45a(-/-) mice showed an increased incidence of hematopoietic malignancies, as well as an increased rate of metastasis than ATM(-/-) mice. In conclusion, Gadd45a deletion aggravated the DNA damage accumulation, which subsequently resulted in a further impaired self renewal capacity and an increased malignant transformation in ATM(-/-) HSCs. PMID- 24474200 TI - Cells derived from iPSC can be immunogenic - yes or no? AB - The induced pluripotent stem cells (iPSCs), derived by ectopic expression of reprogramming factors in somatic cells, can potentially provide unlimited autologous cells for regenerative medicine. In theory, the autologous cells derived from patient iPSCs should be immune tolerant by the host without any immune rejections. However, our recent studies have found that even syngeneic iPSC-derived cells can be immunogenic in syngeneic hosts by using a teratoma transplantation model (Nature 474:212-215, 2011). Recently two research groups differentiated the iPSCs into different germ layers or cells, transplanted those cells to the syngeneic hosts, and evaluated the immunogenicity of those cells. Both of the two studies support our conclusions that some certain but not all tissues derived from iPSCs can be immunogenic, although they claimed either "negligible" or "lack of" immunogenicity in iPSC derivatives (Nature 494:100-104, 2013; Cell Stem Cell 12:407-412, 2013). To test the immunogenicity of clinically valuable cells differentiated from human iPSCs are emergently required for translation of iPSC technology to clinics. PMID- 24474199 TI - Targeting tissue-specific metabolic signaling pathways in aging: the promise and limitations. AB - It has been well established that most of the age-related diseases such as insulin resistance, type 2 diabetes, hypertension, cardiovascular disease, osteoporosis, and atherosclerosis are all closely related to metabolic dysfunction. On the other hand, interventions on metabolism such as calorie restriction or genetic manipulations of key metabolic signaling pathways such as the insulin and mTOR signaling pathways slow down the aging process and improve healthy aging. These findings raise an important question as to whether improving energy homeostasis by targeting certain metabolic signaling pathways in specific tissues could be an effective anti-aging strategy. With a more comprehensive understanding of the tissue-specific roles of distinct metabolic signaling pathways controlling energy homeostasis and the cross-talks between these pathways during aging may lead to the development of more effective therapeutic interventions not only for metabolic dysfunction but also for aging. PMID- 24474201 TI - Genome-scale analysis of demographic history and adaptive selection. AB - One of the main topics in population genetics is identification of adaptive selection among populations. For this purpose, population history should be correctly inferred to evaluate the effect of random drift and exclude it in selection identification. With the rapid progress in genomics in the past decade, vast genome-scale variations are available for population genetic analysis, which however requires more sophisticated models to infer species' demographic history and robust methods to detect local adaptation. Here we aim to review what have been achieved in the fields of demographic modeling and selection detection. We summarize their rationales, implementations, and some classical applications. We also propose that some widely-used methods can be improved in both theoretical and practical aspects in near future. PMID- 24474202 TI - Murine gammaherpesvirus-68 ORF38 encodes a tegument protein and is packaged into virions during secondary envelopment. AB - Tegument is the unique structure of a herpesvirion which occupies the space between nucleocapsid and envelope. Accumulating data have indicated that interactions among tegument proteins play a key role in virion morphogenesis. Morphogenesis of gammaherpesviruses including Kaposi's sarcoma-associated herpesvirus (KSHV) and Epstein-Barr virus (EBV) is poorly understood due to the lack of efficient de novo lytic replication in cell culture. Murine gammaherpesvirus-68 (MHV-68) is genetically related to these two human herpesviruses and serves as an effective model to study the lytic replication of gammaherpesviruses. We previously showed that ORF33 of MHV-68 encodes a tegument protein and plays an essential role in virion maturation in the cytoplasm. However, the molecular mechanism of how ORF33 participates in virion morphogenesis has not been elucidated. In this study we demonstrated that ORF38 of MHV-68 is also a tegument protein and is localized to cytoplasmic compartments during both transient transfection and viral infection. Immuno-gold labeling assay showed that ORF38 is only present on virions that have entered the cytoplasmic vesicles, indicating that ORF38 is packaged into virions during secondary envelopment. We further showed that ORF38 co-localizes with ORF33 during viral infection; therefore, the interaction between ORF38 and ORF33 is conserved among herpesviruses. Notably, we found that although ORF33 by itself is distributed in both the nucleus and the cytoplasm, in the presence of ORF38, ORF33 is co-localized to trans-Golgi network (TGN), a site where secondary envelopment takes place. PMID- 24474203 TI - Genetic approach to track neural cell fate decisions using human embryonic stem cells. AB - With their capability to undergo unlimited self-renewal and to differentiate into all cell types in the body, human embryonic stem cells (hESCs) hold great promise in human cell therapy. However, there are limited tools for easily identifying and isolating live hESC-derived cells. To track hESC-derived neural progenitor cells (NPCs), we applied homologous recombination to knock-in the mCherry gene into the Nestin locus of hESCs. This facilitated the genetic labeling of Nestin positive neural progenitor cells with mCherry. Our reporter system enables the visualization of neural induction from hESCs both in vitro (embryoid bodies) and in vivo (teratomas). This system also permits the identification of different neural subpopulations based on the intensity of our fluorescent reporter. In this context, a high level of mCherry expression showed enrichment for neural progenitors, while lower mCherry corresponded with more committed neural states. Combination of mCherry high expression with cell surface antigen staining enabled further enrichment of hESC-derived NPCs. These mCherry(+) NPCs could be expanded in culture and their differentiation resulted in a down-regulation of mCherry consistent with the loss of Nestin expression. Therefore, we have developed a fluorescent reporter system that can be used to trace neural differentiation events of hESCs. PMID- 24474205 TI - DSSylation, a novel guide for protein degradation? PMID- 24474204 TI - New insights into the regulation of Axin function in canonical Wnt signaling pathway. AB - The Wnt signaling pathway plays crucial roles during embryonic development, whose aberration is implicated in a variety of human cancers. Axin, a key component of canonical Wnt pathway, plays dual roles in modulating Wnt signaling: on one hand, Axin scaffolds the "beta-catenin destruction complex" to promote beta-catenin degradation and therefore inhibits the Wnt signal transduction; on the other hand, Axin interacts with LRP5/6 and facilitates the recruitment of GSK3 to the plasma membrane to promote LRP5/6 phosphorylation and Wnt signaling. The differential assemblies of Axin with these two distinct complexes have to be tightly controlled for appropriate transduction of the "on" or "off" Wnt signal. So far, there are multiple mechanisms revealed in the regulation of Axin activity, such as post-transcriptional modulation, homo/hetero-polymerization and auto-inhibition. These mechanisms may work cooperatively to modulate the function of Axin, thereby playing an important role in controlling the canonical Wnt signaling. In this review, we will focus on the recent progresses regarding the regulation of Axin function in canonical Wnt signaling. PMID- 24474206 TI - Isolation and characterization of the amino-acid pools located within the cytoplasm and vacuoles of Candida utilis. AB - Two distinct amino-acid pools were demonstrated in the food yeast Candida utilis. Treatment of the cells with basic protein (cytochrome c) under isotonic conditions permeabilized the plasmalemma but left the tonoplast intact. The selective effect on these membranes was indicated by the observation of intact vacuoles but changed contrast of the cytoplasm in the phase-contrast microscope and by the free access of a chromogenic substrate to a cytoplasmic enzyme (alpha glucosidase). However, only 10-20% of the soluble amino acids were released from the cells and these had a rapid turnover as demonstrated by pulse labelling experiments using (14)C(U)-arginine, (14)C(U)-glucose, and (15)N-ammonia. This indicates a rapidly metabolized amino-acid pool located within the cytoplasm. Osmotic shock with water following the treatment with basic protein disrupted the tonoplast, an event which could be followed by phase-contrast microscopy. Most of the remaining amino acids were then released. These showed a slow turnover in pulse-labelling experiments and a high proportion of basic, nitrogen-rich amino acids, indicative of a storage function. The significance of such vacuolar and cytoplasmic pools in the regulation of cellular metabolism is discussed. PMID- 24474207 TI - [O-Demethylation of benzoic acids in wheat seedlings]. AB - Various methoxybenzoic acids (anisic, veratric and 3,4,5-trimethoxybenzoic acid) labelled specifically in para and meta methoxyl groups as well as the corresponding 4-hydroxybenzoic acids were added to the nutrient solution of sterile cultures of wheat seedlings.The experiments show that the O-demethylation of benzoic acids is specific for para methoxy groups. meta-O-Methyl carbon atoms appeared only to a very low extent as CO2 and no products formed by demethylation of these groups could be isolated.The products formed by O-demethylation of the para methoxyl groups could be identified as p-hydroxybenzoic acid from anisic acid, vanillic acid from veratric acid and syringic acid from trimethoxybenzoic acid. These 4-hydroxybenzoic acids are normally decarboxylated to a high extent after being fed to plants. When they are formed in the plants by O-demethylation they can be isolated partly as free acids but mainly as their glycosides and glucose esters. These observations and some other indications give evidence of a possible compartmentalisation of plant cells. PMID- 24474208 TI - Plastid development in primary leaves of Phaseolus vulgaris: The light-induced development of the chloroplast cytochromes. AB - Etioplasts obtained from the primary leaves of dark-grown bean plants contained cytochromes f, b-559LP and b-563 in a molar ratio of approximately 1.0:2.0:1.5. On illumination of the plants there was a lag of between 10 and 15 h before these cytochromes increased in amount, but after 48 h they had increased from 6- to 10 fold on a per plastid basis. The presence of cytochrome b-559HP in the plastids was first detected after 15 h of illumination, which coincided with the commencement of grana formation and the onset of a number of photosynthetic reactions in the greening leaves. After 48 h of illumination the molar ratio for cytochromes f, b-559HP, b-559LP and b-563 was 1.0:1.2:2.8:2.6.Agranal chloroplasts formed by the exposure of dark-grown plants to intense light flashes contained high amounts of cytochromes f, b-559LP and b-563 but cytochrome b-559HP could not be detected.As the light-induced formation of cytochromes f, b-559LP and b-563 was substantially inhibited by D-threo chloramphenicol, but not by the L-threo isomer, it seems likely that their formation was dependent on 70S ribosomes. Both chloramphenicol isomers gave plastids which lacked cytochrome b 559HP. PMID- 24474209 TI - Molecular requirements for abscisic acid activity in two bioassay systems. AB - Twenty-two analogues of ABA have been tested in the Avena coleoptile and lettuce germination bioassays. Ten of these analogues were considerably more active than ABA itself as inhibitors of lettuce germination, but in the Avena coleoptile assay their activity never significantly exceeded that of ABA. The molecular requirements for activity also differ in the two assay systems, although the presence of the ring double bond is a requirement of both. PMID- 24474210 TI - 1-N-naphthylphthalamic acid and 2,3,5-triiodobenzoic acid : In-vitro binding to particulate cell fractions and action on auxin transport in corn coleoptiles. AB - Auxin transport in corn coleoptile sections was inhibited by 2,3,5-triiodobenzoic acid (TIBA) as well as by 1-N-naphthylphthalamic acid (NPA); this inhibition was effected within 1 min of application.A particulate cell fraction-presumably plasma-membrane vesicles-specifically binds NPA and properties of these binding sites were studied using (3)H-NPA and a pelletting technique. The saturation kinetics of the physiological NPA effect, i.e. the inhibition of auxin transport, is similar to that of the specific in-vitro NPA binding. Half saturation of the inhibitory effect was found with about 5*10(-7) M TIBA and with 10(-7) M NPA. Both substances also decreased the speed of movement of auxin pulses within coleoptile sections.NPA dissociates from its binding site when the particulate cell material is centrifuged through an NPA-free cushion. The NPA that is washed from its binding site can be used in another binding test without any apparent change and is chromatographically unaltered. Therefore, the NPA binding is probably reversible and non-covalent. Inhibition of auxin transport by TIBA or NPA could also be reversed when the coleoptile sections were washed in buffer.The movement of (131)I-TIBA in corn coleoptiles appears to be polar in a basipetal direction. Higher concentrations of indoleacetic acid or TIBA inhibited this polar movement, suggesting that TIBA moves in the same channels as auxin. With (3)H-NPA, however, no polar transport could be detected. Together with the in vitro binding results, these data indicate that TIBA acts directly at the auxin receptor while NPA has a different receptor site.The effect of TIBA and NPA on elongation, with or without auxin, is neglegible in comparison to their effects on auxin transport. PMID- 24474211 TI - The effect of antimycin a on carotenogenesis in Verticillium agaricinum. AB - Antimycin A did not induce carotenogenesis in dark grown cultures of V. agaricinum, but total protein was increased. In light, antimycin A did not affect total carotenoids, although protein was slightly increased. The results suggest that antimycin A could not have acted here as an inducer for the synthesis of specific carotenogenic enzymes or by inactivating a repressor as has been suggested for certain bacteria. PMID- 24474212 TI - Interconversion of gibberellin A4 to gibberellins A 1 and A 34 by dwarf rice, cultivar Tan-ginbozu. AB - Interconversion of GA4 to GA1 and GA34 occurred within 24 h of application of 1,2 [(3)H]-GA4 to seedlings of dwarf rice, cv. Tan-ginbozu. Identification was made by direct comparison of the trimethylsilyl ether derivatives of the methyl esters of Silica-gel partition-column fractions on gas-liquid radiochromatography with derivatized GA1 and GA34 standards on three columns: 2% QF-1, 2% SE-30, and 1% XE 60. GA2, an artifact of the purification and chromatography system, may also be formed by the plant. The conversions from GA4 to GA1 and GA34 are single hydroxylations. At least two unidentified radioactive products were also formed by the plant. Interconversions were in the order of 0.3 to 0.8% of applied [(3)H] GA4. PMID- 24474213 TI - Interaction between ethylene, abscisic acid and gibberellic acid in elongation of rice mesocotyl. AB - Combined application of ethylene, abscisic acid and gibberellic acid produced marked partly synergistic stimulation of mesocotyl growth of japonica rice in darkness. PMID- 24474214 TI - Gibberellin-antagonizing protein in dwarf peas. AB - Seedlings of dwarf pea grown under red light for 9 d were homogenized in 0.1 M phosphate buffer (pH 6.8) and a "water-soluble extract" was obtained by centrifugation, dialysis and lyophilization. The extract contained a proteinaceous substance (or substances) which interfered with the GA3 response of dwarf peas, probably due to complex formation with the hormone. PMID- 24474215 TI - Localization and identification of auxin in roots of Zea mays. AB - Roots of 3.5-day-old seedlings of Zea mays cv. Giant White Horsetooth contain an extractable auxin which has chromatographic properties and reactions to chromogenic sprays identical with those of indole-3-acetic acid (IAA). By separating stele from cortex (and root tips) before extraction it was shown that the auxin is localized predominantly in the stele, with little being found in the cortex. Whole roots, isolated cortices and isolated steles accumulate and metabolize exogenously applied IAA-1-(14)C. The stelar tissue is distinguished from whole roots and cortical tissue in having a different pattern of IAA metabolism. PMID- 24474216 TI - A novel objective sour taste evaluation method based on near-infrared spectroscopy. AB - One of the most important themes in the development of foods and drinks is the accurate evaluation of taste properties. In general, a sensory evaluation system is frequently used for evaluating food and drink. This method, which is dependent on human senses, is highly sensitive but is influenced by the eating experience and food palatability of individuals, leading to subjective results. Therefore, a more effective method for objectively estimating taste properties is required. Here we show that salivary hemodynamic signals, as measured by near-infrared spectroscopy, are a useful objective indicator for evaluating sour taste stimulus. In addition, the hemodynamic responses of the parotid gland are closely correlated to the salivary secretion volume of the parotid gland in response to basic taste stimuli and respond to stimuli independently of the hedonic aspect. Moreover, we examined the hemodynamic responses to complex taste stimuli in food based solutions and demonstrated for the first time that the complicated phenomenon of the "masking effect," which decreases taste intensity despite the additional taste components, can be successfully detected by near-infrared spectroscopy. In summary, this study is the first to demonstrate near-infrared spectroscopy as a novel tool for objectively evaluating complex sour taste properties in foods and drinks. PMID- 24474217 TI - Linking alpha-synuclein properties with oxidation: a hypothesis on a mechanism underling cellular aggregation. AB - alpha-Synuclein is a small, natively unstructured protein with propensity to aggregate. alpha-Synuclein fibrils are major components of Lewy bodies that are hallmarks of many neurodegenerative diseases. The solution properties and aggregation behavior of alpha-synuclein has been well characterized, but despite numerous studies that address the role of alpha-synuclein in cells, a clear physiological function of this protein remains a mystery. Over a hundred review articles of alpha-synuclein have been written in the last decade, making it difficult to list all of the important studies that have added to our insight of alpha-synuclein physiology. Instead, we briefly review the status of alpha synuclein research and propose a model based on the idea that alpha-synuclein may not have an intrinsic activity in cells but rather, it modifies the function of a group of protein partners that in turn affect cell processes. We propose that it is the loss of its cellular partners under oxidative conditions that promotes alpha-synuclein aggregation accelerating neuronal death. PMID- 24474218 TI - Scoring system for prediction of lymph node metastasis in radical cystectomy cohort. AB - OBJECTIVES: The objective of the study was to assess whether pretreatment clinical parameters combined with computed tomography can improve the prediction of lymph node metastasis in patients with bladder cancer treated with radical cystectomy. PATIENTS AND METHODS: In a single-center retrospective study, demographic and clinicopathological information (initial transurethral resection [grade, stage, multiplicity of tumors, lymphovascular invasion], hydronephrosis, abdominal and pelvic computed tomography) and the presence of lymph node disease on final pathology of 183 patients with bladder cancer undergoing radical cystectomy and pelvic lymph node dissection were reviewed. Logistic regression and bootstrap methods were used to create an integer score for estimating the risk of positive lymph nodes. Various measures for predictive ability and clinical utility were determined. RESULTS: On pathological examination, 59.6% of patients had positive lymph nodes. In a multivariable analysis, status lymph nodes on computed tomography and hydronephrosis were the most strongly associated predictors. The resultant total possible score ranged from 0 to 10, with a cut off value of >4 points. The area under the receiver operating characteristic curve was 0.806. Relative integrated discrimination improvement was 14.3%. In the decision curve analysis, the model provided net benefit throughout the entire range of threshold probabilities. However, the final model was roughly equivalent to using the clinical exam. CONCLUSIONS: The pre-cystectomy scoring system improved the prediction of lymph node status in patients with bladder cancer. Our model represented a user-friendly staging aid, but a large multi-center study should be performed before widespread implementation. PMID- 24474219 TI - Bilateral single system ectopic ureters opening into vestibule with bladder agenesis. AB - Almost 80% of ectopic ureters are associated with duplicated system, and 5-17% of ectopic ureters are bilateral. Ectopic ureters usually open into urethra, vestibule and vagina in females and into posterior urethra and seminal vesicles in males. Bilateral single-system ectopic ureter (BSSEU) is a rare entity in urology. BSSEU opening into a vestibule with the absence of urinary bladder is an extremely rare occurrence. We report such a case and briefly discuss its management. PMID- 24474220 TI - Red cell distribution width in renal transplant patients. PMID- 24474221 TI - Protein-energy wasting, as well as overweight and obesity, is a long-term risk factor for mortality in chronic hemodialysis patients. AB - INTRODUCTION: In patients with end-stage renal disease on chronic hemodialysis (HD), protein-energy wasting (PEW) is very common and is associated with increased morbidity and mortality. Evaluation of nutritional status should be performed regularly in all such patients, using multiple methods. In this study, we analyzed the influence of several nutritional markers on long-term (5 years) survival of HD patients in one center. This is the first study on the long-term influence of nutritional status on mortality in dialysis patients ever conducted in Romania. MATERIALS AND METHODS: We included all prevalent HD patients in our center. Those with ongoing acute illnesses and with inflammation (C-reactive protein >= 6.0 mg/l) were excluded. In the remaining subjects (N = 149, 82 males, mean age 55 years old), we performed the following measurements of nutritional status: estimation of dietary protein intake by normalized protein equivalent of nitrogen appearance (nPNA), subjective global assessment (SGA), body mass index (BMI), tricipital skinfold thickness, mid-arm circumference, assessment of body composition by bioelectrical impedance analysis (BIA), and pre-dialysis serum creatinine, albumin, and total cholesterol. We used receiver operating characteristic curves to determine the cutoff points for most of the variables, and we applied the Kaplan-Meier estimator and the Cox's proportional hazards model (stepwise method) to analyze the influence of these variables on survival. RESULTS: In univariate analysis, general factors including age >= 65 years, male gender, dialysis vintage >= 2 years, and the presence of diabetes and heart failure were all significant predictors of mortality. Among nutritional parameters, BMI >= 25 kg/m(2), SGA-B (mild PEW), nPNA < 1.15 g/kg per day, and the BIA-derived phase angle (PhA) <5.58 degrees were also significantly associated with reduced survival. All of these factors maintained statistical significance in multivariate analysis, except for male gender and heart failure. CONCLUSION: We showed that low values of SGA, nPNA, and PhA independently predict mortality in HD patients. In conjunction with an earlier study, we demonstrated that the relative risk of death associated with these markers is highest during the first year of monitoring and it decreases in the following 4 years, although it still remains significantly increased. On the other hand, overweight and obesity were also associated with lower survival after 5 years, whereas this association was not apparent after 1 year. PMID- 24474222 TI - How market based pricing is failing Indian patients. PMID- 24474223 TI - A Consumer's pursuit of health care outcomes: daunting even with a guardian angel! PMID- 24474224 TI - Colonoscopy in screening for colorectal cancer. PMID- 24474225 TI - Tomographic findings of gastric gastrointestinal stromal tumor and correlation with the mitotic index. AB - CONTEXT: Gastrointestinal stromal tumors are uncommon abdominal neoplasms and can affect any portion of the gastrointestinal tract. OBJECTIVES: Describe the tomographic findings of the gastrointestinal stromal tumor of gastric origin, correlating it with the mitotic index. METHODS: Twenty-one patients were selected within the period of January 2000 and 2008, with histopathological and immunohistochemical diagnosis of gastric gastrointestinal stromal tumors, who presented computed tomography done before the treatment. The tomographic variables analyzed were lesion topography, dimensions, contours, morphology, pattern and intensity enhancement through venous contrast, growth pattern, invasion of adjacent organs, presence of ulceration, fistula, calcifications, infiltration of mesenteric fat, lymphadenopathy and metastasis. The mitotic index was determined through optic microscopy, counting the number of mitosis figures in 50 high power fields. RESULTS: The tumors were located in the body (66.7%) or gastric fundus (33.3%), with dimensions varying between 4.2 and 21.2 cm (average of 10.5 cm). The growth was predominantly extraluminal (47.6%) or intra/extra luminal (28.6%). The enhancement by venous contrast was heterogeneous in 66.7%. The statistical analysis showed that irregular morphology (P = 0.027) and infiltration of mesenteric fat (P = 0.012) presented correlation with the high mitotic index. CONCLUSIONS: In the present study, most part of the tumors were located in the gastric body, with average size of 10.5 cm, presenting central hypo dense area, heterogeneous enhancement through contrast and predominantly extra luminal growth. Irregular morphology and infiltration of mesenteric fat present statistical correlation with high mitotic level. PMID- 24474226 TI - Evaluation of N-ratio in selecting patients for adjuvant chemoradiotherapy after d2-gastrectomy. AB - CONTEXT: Whether adjuvant chemoradiotherapy may contribute to improve survival outcomes after D2-gastrectomy remains controversial. OBJECTIVE: To explore the clinical utility of N-Ratio in selecting gastric cancer patients for adjuvant chemoradiotherapy after D2-gastrectomy. METHODS: A retrospective cohort study was carried out on gastric cancer patients who underwent D2-gastrectomy alone or D2 gastrectomy plus adjuvant chemoradiotherapy (INT-0116 protocol) at the Hospital A. C. Camargo from September 1998 to December 2008. Statistical analysis were performed using multiple conventional methods, such as c-statistic, adjusted Cox's regression and stratified survival analysis. RESULTS: Our analysis involved 128 patients. According to c-statistic, the N-Ratio (i.e., as a continuous variable) presented "area under ROC curve" (AUC) of 0.713, while the number of metastatic nodes presented AUC of 0.705. After categorization, the cut-offs provide by Marchet et al. displayed the highest discriminating power - AUC value of 0.702. This N-Ratio categorization was confirmed as an independent predictor of survival using multivariate analyses. There also was a trend of better survival by adding of adjuvant chemoradiotherapy only for patients with milder degrees of lymphatic spread - 5-year survival of 23.1% vs 66.9%, respectively (HR = 0.426, 95% CI 0.150-1.202; P = 0.092). CONCLUSIONS: This study confirms the N Ratio as a tool to improve the lymph node metastasis staging in gastric cancer and suggests the cut-offs provided by Marchet et al. as the best way for its categorization after a D2-gastrectomy. In these settings, the N-Ratio appears a useful tool to select patients for adjuvant chemoradiotherapy, and the benefit of adding this type of adjuvancy to D2-gastrectomy is suggested to be limited to patients with milder degrees of lymphatic spread (i.e., NR2, 10%-25%). PMID- 24474227 TI - Carcinoembryonic antigen levels in the peripheral and mesenteric venous blood of patients with rectal carcinoma. AB - CONTEXT: The serum carcinoembryonic antigen (CEA) is an important prognostic factor in colorectal cancer, however the rectum presents different routes of venous drainage, stating that the level of CEA in peripheral and mesenteric rectal tumors may be different, depending on the location of the tumor in the rectal segment. OBJECTIVE: The goal of this study was to evaluate the relationship between the peripheral and mesenteric venous levels of CEA and the association between these levels and the tumour location in the rectums of patients successfully operated on for rectal carcinoma. METHODS: Thirty-two patients who were surgically treated for rectal carcinoma were divided into patients with tumours located in the upper rectum (n = 11) or lower rectum (n = 21). The CEA values were assessed by electrochemiluminescence immunoassay. Serum and mesenteric CEA levels were associated with the tumour anatomopathological characteristics: location, histological type, cellular differentiation grade, depth of invasion into the rectal wall, angiolymphatic invasion, tumour, node, and metastasis staging; and the CEA index (<=1.0 or >=1.0 ng /mL). RESULTS: Analysis of the serum CEA values using clinical and anatomopathological parameters revealed no significant association with tumour location, histological type, cellular differentiation grade, depth of invasion into the intestinal wall, and tumour, node, and metastasis staging. The mesenteric CEA levels were significantly associated with the tumour location (P = 0.01). The CEA values in the mesenteric venous blood and the presence of angiolymphatic invasion (P = 0.047) were significantly different. A significant relationship was found between the CEA index value and the rectal tumour location (P = 0.0001). CONCLUSIONS: The CEA levels were higher in the mesenteric vein in tumours located in the upper rectum and in the presence of angiolymphatic invasion. CEA drainage from lower rectum adenocarcinomas preferentially occurs through the systemic pathway. PMID- 24474228 TI - Clinical features and severity of gastric emptying delay in Brazilian patients with gastroparesis. AB - CONTEXT: Gastroparesis is defined by delayed gastric emptying without mechanical obstruction of the gastroduodenal junction, which has been increasingly investigated. Nevertheless, knowledge on the relationships between etiology, symptoms and degree of delayed gastric emptying is limited. OBJECTIVES: The demographic, clinical and etiological features of Brazilian patients with gastroparesis were studied and the relationships between these findings and the severity of gastric emptying were determined. METHOD: This is a retrospective study of medical records of 41 patients with symptoms suggestive of gastroparesis admitted between 1998 and 2011, who had evidence of abnormally delayed gastric emptying on abdominal scintigraphy. Cases with idiopathic gastroparesis were compared with those of patients with neurologic disorders or diabetes mellitus, in whom autonomic neuropathy is likely to occur. RESULTS: The majority of the patients were women (75.6%) with a median age of 41 years and a long-term condition (median: 15 years). Twelve patients (29.3%) had a body mass index of less than 20 kg/m2. The most common presenting symptoms were dyspepsia (53.6%), nausea and vomiting (46.3%), weight loss (41.4%) and abdominal pain (24.3%). Regarding etiology, 16 patients had digestive disorders including idiopathic gastroparesis (n = 12), 12 had postoperative conditions, 11 had diseases of the nervous system, five had diabetes mellitus and in three cases gastroparesis was associated to a variety of conditions. In the majority of patients (65.8%) gastric emptying was severely delayed. There was no association between etiology of gastroparesis, type of presenting symptoms and the degree of delay in gastric emptying. Gastroparesis patients with proven (neurological conditions) or presumed (diabetes) nervous system involvements were significantly younger (P = 0.001), had more recent symptom onset (P = 0:03) and a trend towards more severe gastric empty (P = 0:06). There were no significant differences between this subgroup of patients and that comprising cases of idiopathic gastroparesis regarding any of the variables studied. CONCLUSIONS: The demographic, clinical and etiological characteristics of Brazilian patients with gastroparesis are quite varied, but there is a predominance of women with long-standing symptoms and marked delay in gastric emptying. The type of presenting symptoms and the degree of delay in gastric emptying do not predict the etiology of gastroparesis. However, severely delayed gastric emptying in younger patients with recent symptom onset should raise the suspicion of impaired neural control of gastro duodenal motility. PMID- 24474229 TI - Hepatitis B, C and HIV co-infections seroprevalence in a northeast Brazilian center. AB - CONTEXT: The occurrence of HIV and hepatitis B (HBV) and C (HCV) virus associations is of great concern since co-infected patients respond poorly to antiviral treatment and usually progress to chronic and more complicated hepatic disease. In Brazil, these co-infections prevalence is not well known since published data are few and sometimes demonstrate conflicting results. Also, a significant number of co-infected individuals are HBV/HCV asymptomatic carriers, leading to under notification. OBJECTIVES: The present study aimed to determine the prevalence of the HBV and HCV infection in a recently diagnosed HIV population in the state of Ceara/Brazil. METHODS: Retrospective cohort, with >18yo patients diagnosed HIV+ from 2008-2010. First year medical attention information was collected. RESULTS: A total of 1.291 HIV+ patients were included. HBV serologies were collected in 52% (23% had previous hepatitis B, 3.7% were co infected) and HCV in 25.4% (1.5% had previous hepatitis C, 5.4% co-infection). The majority of HBV/HIV patients referred multiple sexual partners/year, 28% homosexualism and 20% bisexualism. In the HCV/HIV group 38.8% individuals had > one sexual partner/year and 22.2% used intravenous drugs. CONCLUSION: The study reinforce the need for better training healthcare workers and providing laboratory support for a prompt hepatitis diagnosis and adequate medical management to avoid complications and decrease viral spread. PMID- 24474230 TI - The prevalence and clinical characteristics of primary headache in irritable bowel syndrome: a subgroup of the functional somatic syndromes. AB - CONTEXT: The irritable bowel syndrome and primary headache are two chronic diseases characterized by symptoms of recurring pain and affect approximately 10% 20% of the general population. OBJECTIVES: To study the prevalence of primary headache in volunteers with irritable bowel syndrome in a Brazilian urban community. METHODS: It was evaluated the prevalence of primary headache associated with irritable bowel syndrome in adult volunteers 330 no patients.The protocol included the Rome III criteria, international classification of Headaches, later divided into four groups: I- Irritable bowel syndrome (n = 52), II- Primary headache (n = 45), III-Irritable bowel syndrome (n = 26) and headache, and IV- Controls (207). RESULTS: We not found significant difference in the average age of the four groups and the diagnosis of irritable bowel syndrome, primary headache and their association was more frequent in females. The frequent use of analgesics was greater in groups II and III. CONCLUSION: Our results suggest that irritable bowel syndrome and primary headache are also common in third world countries. The frequency in use of analgesics in association between the two entities was relevant. The identification of irritable bowel syndrome patients with different clinical sub-types could improve the therapeutics options and the prevention strategies. PMID- 24474231 TI - Nonalcoholic fatty liver disease in severe obese patients, subjected to bariatric surgery. AB - CONTEXT: Nonalcoholic fatty liver disease encompasses a spectrum of histopathological changes that range from simple steatosis to nonalcoholic steatohepatitis. Works suggest that iron (Fe) deposits in the liver are involved in the physiopathology of nonalcoholic steatohepatitis. OBJECTIVE: The aim of this study was to determine the prevalence of simple steatosis and nonalcoholic steatohepatitis in patients with morbid obesity, subjected to bariatric surgery and to establish a correlation of the anatomopathological findings with the presence of liver fibrosis. METHODS: A total of 250 liver biopsies were conducted in the transoperation of the surgeries. RESULTS: Steatosis was present in 226 (90.4%) of the samples, 76 (30.4%) being classified as mild; 71 (28.4%) as moderate and 79 (31.6%) as intense. Nonalcoholic steatohepatitis was diagnosed in 176 (70.4%) cases, where 120 (48.4%) were mild; 50 (20%) were moderate, and 6 (2.4%) cases were intense. Fibrosis was referred to in 108 (43.2%) biopsies, 95 of which (38%) were mild; 2 (0.8%) were moderate; 7 (2.8%) were intense, and cirrhosis was diagnosed in 4 (1.6%) cases. There was a correlation between the degree of steatosis and the level of inflammatory activity (rs = 0.460; P<0.001) and between the degree of this activity and the degree of fibrosis (rs = 0.583; P<0.001). Only 13 (5.2%) samples showed Fe deposits. CONCLUSION: There is a high prevalence of nonalcoholic steatohepatitis in these patients and a positive correlation of the degrees of nonalcoholic steatohepatitis with the intensity of fibrosis. The low prevalence of Fe deposits found makes it questionable that the presence of this ion has any participation in the physiopathogeny of nonalcoholic fatty liver disease. PMID- 24474232 TI - Prevalence of celiac disease in children with epilepsy. AB - CONTEXT: Neurological symptoms have been well-documented in patients with celiac disease, nevertheless, the presumption of a greater prevalence of epilepsy in celiac patients remains controversial. OBJECTIVES: To determine the frequency of celiac disease in children and adolescents with idiopathic or cryptogenic epilepsy. METHODS: A cross-sectional study. One hundred pediatric patients with non-symptomatic epilepsy were followed-up at two public pediatric neurology clinics in Salvador, Bahia, Brazil. Screening for celiac disease was performed by serial measurements of IgA anti-transglutaminase and IgA anti-endomysium antibodies, followed by bowel biopsy in positive cases. HLA DQ02 and DQ08 were investigated in seropositive individuals, assessing the type of seizures, the number of antiepileptic drugs used and the presence gastrointestinal symptoms. RESULTS: Three (3.0%) patients tested anti-tTG-positive, two with normal duodenal mucosa (Marsh 0) and one with intraepithelial infiltrate (Marsh I). No villous atrophy of the duodenal mucosa (Marsh III) celiac disease was found. Two patients tested positive for HLA DQ02; none were DQ08 positive. CONCLUSION: The present study failed to prove the association between celiac disease and epilepsy. PMID- 24474233 TI - Decision tree construction and cost-effectiveness analysis of treatment of ulcerative colitis with pentasa(r) mesalazine 2 g sachet. AB - CONTEXT: Unspecified Ulcerative Rectocolitis is a chronic disease that affects between 0.5 and 24.5/105 inhabitants in the world. National and international clinical guidelines recommend the use of aminosalicylates (including mesalazine) as first-line therapy for induction of remission of unspecified ulcerative rectocolitis, and recommend the maintenance of these agents after remission is achieved. However, multiple daily doses required for the maintenance of disease remission compromise compliance with treatment, which is very low (between 45% and 65%). Use of mesalazina in granules (2 g sachet) once daily--Pentasa(r) sachets 2 g--can enhance treatment adherence, reflecting in an improvement in patients' outcomes. OBJECTIVE: To evaluate the evidence on the use of mesalazine for the maintenance of remission in patients with unspecified ulcerative rectocolitis and its effectiveness when taken once versus more than once a day. From an economic standpoint, to analyze the impact of the adoption of this dosage in Brazil's public health system, considering patients' adherence to treatment. METHODS: A decision tree was developed based on the Clinical Protocol and Therapeutic Guidelines for Ulcerative Colitis, published by the Ministry of Health in the lobby SAS/MS n degrees 861 of November 4 th, 2002 and on the algorithms published by the Associacao Brasileira de Colite Ulcerativa e Doenca de Crohn, aiming to get the cost-effectiveness of mesalazine once daily in granules compared with mesalazine twice daily in tablets. RESULTS: The use of mesalazine increases the chances of remission induction and maintenance when compared to placebo, and higher doses are associated with greater chance of success without increasing the risk of adverse events. CONCLUSION: The use of a single daily dose in the maintenance of remission is effective and related to higher patient compliance when compared to the multiple daily dose regimens, with lower costs. PMID- 24474234 TI - Treatment of diarrhea-predominant irritable bowel syndrome with mesalazine and/or Saccharomyces boulardii. AB - CONTEXT: Irritable bowel syndrome (IBS) is a functional bowel disease characterized by abdominal pain and altered intestinal habits. The pathophysiology of IBS remains unclear. Recent studies have demonstrated that some IBS patients, especially in diarrhea-predominant IBS (IBS-D), display persistent signs of minor mucosal inflammation and a modified intestinal microflora. The mesalazine has known intestinal anti-inflammatory properties. Saccharomyces boulardii is a probiotic used for a long time in treatment of diarrhea, including infectious diarrhea. OBJECTIVE: Evaluate the effects of mesalazine alone, combined therapy of mesalazine with liophylised Saccharomyces boulardii or alone on symptoms of IBS-D patients. METHODS: Based on Rome III criteria, 53 IBS-D patients (18 year or more) were included. To exclude organic diseases all patients underwent colonoscopy, stool culture, serum anti-endomisium antibody, lactose tolerance test and ova and parasite exam. Patients were divided in three groups: mesalazine group (MG) - 20 patients received mesalazine 800 mg t.i.d. for 30 days; mesalazine and Saccharomyces boulardii group (MSbG) - 21 patients received mesalazine 800 mg t.i.d. and Saccharomyces boulardii 200 mg t.i.d. for 30 days and; Saccharomyces boulardii group (SbG) - 12 patients received Sb 200 mg t.i.d. for 30 days. Drugs that might have any effect on intestinal motility or secretion were not allowed. Symptom evaluations at baseline and after treatment were performed by means of a 4-point likert scale including: stool frequency, stool form and consistency (Bristol scale), abdominal pain and distension. Paired t test and Kruskal-Wallis test were used for statistical analyses. RESULTS: Compared to baseline, there were statistically significant reduction of symptom score after 30 th day therapy in all three groups: MG (P<0.0001); MSbG (P<0.0001) and in SbG (P = 0.003). There were statistically significant differences in the symptom score at 30 th day therapy of the MG, MSbG and SbG groups (P = 0.03). There were no statistical differences between MSbG and MG symptom score at 30th day therapy (P = 0.9). CONCLUSIONS: The use of mesalazine alone, Saccharomyces boulardii alone or combined treatment with mesalasine and Saccaromyces boulardii improved IBS-D symptoms. The improvement of the symptom score was greater with mesalazine alone or combined with Sb as compared with Sb treatment alone. These preliminary results suggest that mezalazine may be useful in treatment of IBS-d patients, and warrant further larger studies. PMID- 24474235 TI - First single-port laparoscopic pancreatectomy in Brazil. AB - CONTEXT: Pancreatic surgery is an extremely challenging field, and the management of pancreatic diseases continues to evolve. In the past decade, minimal access surgery is moving towards minimizing the surgical trauma by reducing numbers and size of the port. In the last few years, a novel technique with a single-incision laparoscopic approach has been described for several laparoscopic procedures. OBJECTIVES: We present a single-port laparoscopic spleen-preserving distal pancreatectomy. To our knowledge, this is the first single-port pancreatic resection in Brazil and Latin America. METHODS: A 33-year-old woman with neuroendocrine tumor underwent spleen-preserving distal pancreatectomy via single port approach. A single-incision advanced access platform with gelatin cap, self retaining sleeve and wound protector was used. RESULTS: Operative time was 174 minutes. Blood loss was minimal, and the patient did not receive a transfusion. The recovery was uneventful, and the patient was discharged on postoperative day 4. CONCLUSIONS: Single-port laparoscopic spleen-preserving distal pancreatectomy is feasible and can be safely performed in specialized centers by skilled laparoscopic surgeons. PMID- 24474236 TI - Human papillomavirus (HPV) 16 and the prognosis of head and neck cancer in a geographical region with a low prevalence of HPV infection. AB - BACKGROUND: The role of human papillomavirus (HPV) on head and neck squamous cell carcinoma (HNSCC) survival in regions with low HPV prevalence is not yet clear. We evaluated the HPV16 infection on survival of HNSCC Brazilian patient series. METHODS: This cohort comprised 1,093 HNSCC cases recruited from 1998 to 2008 in four Brazilian cities and followed up until June 2009. HPV16 antibodies were analyzed by multiplex Luminex assay. In a subset of 398 fresh frozen or paraffin blocks of HNSCC specimens, we analyzed for HPV16 DNA by L1 generic primer polymerase chain reaction. HNSCC survival according to HPV16 antibodies was evaluated through Kaplan-Meier method and Cox regression. RESULTS: Prevalence of HPV16 E6 and E6/E7 antibodies was higher in oropharyngeal cancer than in other head and neck tumor sites. HPV16 DNA positive in tumor tissue was also higher in the oropharynx. Seropositivity for HPV16 E6 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer. The presence of HPV16 E6/E7 antibodies was correlated with improved HNSCC survival and oropharyngeal cancer survival. The death risk of oropharyngeal squamous cell carcinoma patients HPV16 E6/E7 antibodies positive was 78 % lower than to those who test negative. CONCLUSION: Oropharyngeal squamous cell carcinoma is less aggressive in the HPV16 E6/E7 positive serology patients. HPV16 E6/E7 antibody is a clinically sensible surrogate prognostic marker of oropharyngeal squamous cell carcinoma. PMID- 24474237 TI - Foamy macrophage responses in the rat lung following exposure to inhaled pharmaceuticals: a simple, pragmatic approach for inhaled drug development. AB - Successes in the field of respiratory medicines are largely limited to three main target classes: beta2 -adrenergic receptor agonists, muscarinic antagonists and corticosteroids. A significant factor in attrition during the development of respiratory medicines is the induction of foamy macrophage responses, particularly, in rats. The term foamy macrophage describes a vacuolated cytoplasmic appearance, seen by light microscopy, which is ultrastructurally characterized by the presence of lysosomal lamellar bodies, neutral lipid droplets or drug particles. We propose a simple classification, based light heartedly on the theme 'the good, the bad and the ugly', which allows important distinctions to be made between phenotypes, aetiologies and adversity. Foamy macrophages induced in rat lungs by exposure to inhaled beta2 -agonists, antimuscarinics and corticosteroids are simple aggregates of uniform cells without other associated pathologies. In contrast, macrophage reactions induced by some other inhaled drug classes are more complex, associated with neutrophilic or lymphocytic infiltrations with/without damage to the adjacent alveolar walls. Foamy macrophage responses induced by inhaled drugs may be ascribed to either phagocytosis of poorly soluble drug particles, or to pharmacology. Both corticosteroids and beta2 -agonists increase surfactant synthesis whereas muscarinic antagonists may decrease surfactant breakdown, due to inhibition of phospholipase C, both of which lead to phagocytosis of excess surfactant. Simple foamy macrophage responses are considered non-adverse, whereas ones that are more complex are designated as adverse. The development of foamy macrophage responses has led to confusion in interpretation and we hope this review helps clarify what is in fact a relatively simple, predictable, easily interpretable, commonly induced change. PMID- 24474238 TI - Evaluation of cytotoxic, oxidative stress and genotoxic responses of hydroxyapatite nanoparticles on human blood cells. AB - The present study was designed to investigate genotoxic and cytotoxic effects and oxidative damage of increasing concentrations of nano-hydroxyapatite (5, 10, 20, 50, 75, 100, 150, 300, 500 and 1000 ppm) in primary human blood cell cultures. Cell viability was detected by [3-(4,5-dimethyl-thiazol-2-yl) 2,5 diphenyltetrazolium bromide] assay and lactate dehydrogenase release, while total antioxidant capacity and total oxidative stress levels were determined to evaluate the oxidative injury. The DNA damage was also analyzed by sister chromatid exchange, micronuclei, chromosome aberration assays and 8-oxo-2 deoxyguanosine level as indicators of genotoxicity. The results of [3-(4,5 dimethyl-thiazol-2-yl) 2,5-diphenyltetrazolium bromide] and lactate dehydrogenase assays showed that the higher concentrations (150, 300, 500 and 1000 ppm) of hydroxyapatite nanoparticles (HAP NPs) decreased cell viability. HAP NPs led to increases of total oxidative stress (300, 500 and 1000 ppm) levels and decreased total antioxidant capacity (150, 300, 500 and 1000 ppm) levels in cultured human blood cells. On the basis of increasing concentrations, HAP NPs caused significant increases of sister chromatid exchange, micronuclei, chromosome aberration rates and 8-oxo-2-deoxyguanosine levels as compared to untreated culture. In conclusion, the obtained in vitro results showed that HAP NPs had dose-dependent effects on inducing oxidative damage, genotoxicity and cytotoxicity in human blood cells. PMID- 24474239 TI - Assessing carbon-encapsulated iron nanoparticles cytotoxicity in Lewis lung carcinoma cells. AB - Carbon-encapsulated iron nanoparticles (CEINs) have been considered as attractive candidates for several biomedical applications. In the present study, we synthesized CEINs (the mean diameter 40-80 nm) using a carbon arc route, and the as-synthesized CEINs were characterized (scanning and transmission electron microscopy, dynamic light scattering, turbidimetry, Zeta potential) and further tested as raw and purified nanomaterials containing the carbon surface modified with acidic groups. For cytotoxicity evaluation, we applied a battery of different methods (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, lactate dehydrogenase, calcein AM/propidium iodide, annexin V/propidium iodide, JC-1, cell cycle assay, Zeta potential, TEM and inductively coupled plasma mass spectrometry) to address the strategic cytotoxic endpoints of Lewis lung carcinoma cells due to CEIN (0.0001-100 ug ml(-1) ) exposures in vitro. Our studies evidence that incubation of Lewis lung carcinoma cells with CEINs is accompanied in substantial changes of zeta potential in cells and these effects may result in different internalization profiles. The results show that CEINs increased the mitochondrial and cell membrane cytotoxicity; however, the raw CEIN material (Fe@C/Fe) produced higher toxicities than the rest of the CEINs studied to data. The study showed that non-modified CEINs (Fe@C/Fe and Fe@C) elevated some pro-apoptotic events to a greater extent compared to that of the surface modified CEINs (Fe@C-COOH and Fe@C-(CH2 )2 COOH). They also diminished the mitochondrial membrane potentials. In contrast to non-modified CEINs, the surface functionalized nanoparticles caused the concentration- and time-dependent arrest of the S phase in cells. Taken all together, our results shed new light on the rational design of CEINs, as their geometry, hydrodynamic and, in particular, surface characteristics are important features in selecting CEINs as future nanomaterials for nanomedicine applications. PMID- 24474241 TI - Exploring pluralism in oral health care: Dom informal dentists in northern Lebanon. AB - This article describes a pluralistic regime of oral health provision in a rural part of northern Lebanon, where dental care came from two main sources: professionally trained dentists and "informal" Dom dentists with Syrian nationality. Relying on a combination of interviews and ethnography, I offer a multivocal view of oral health services that incorporates data from patients and formal and informal providers. I argue that informal dentistry constituted an interstitial and translocal mode of dental care. In the northern Lebanese Biqa Valley, close to the Syrian border, the local articulation of neoliberal health governance created opportunities for heterodox practices in oral health. The organization of informality was predicated on the presence of the open border between Syria and Lebanon, which favored patterns of flexible cross-border mobility. In this context, informal dentistry was not alternative, but supplementary and lateral in relation to official forms of oral health provision. PMID- 24474240 TI - Lateral lingual vascular canals of the mandible: a CBCT study of 500 cases. AB - PURPOSE: The aim of the present study was to use cone-beam computed tomography (CBCT) images of patients to assess the localization, diameter, and course of the lateral lingual vascular canal (LLVC). METHODS: CBCT (Morita, Accuitomo 170) images from 500 patients were used in the present study. The CBCT images were examined by two oral radiologists. The diameter, localization, and course of the LLVCs were assessed using axial, cross-sectional, and multiplanar reformatted images. Statistical analysis was performed using SPSS((r)) v. 15 (SPSS Inc., Chicago, IL, USA), and t tests were used for statistical analysis. RESULTS: Of the 500 patients examined, 163 LLVCs were detected in 124 (24.8 %) cases. The mean diameter of LLVCs on the right side and left side was 0.65 +/- 0.18 and 0.64 +/- 0.17 mm, respectively. The majority of the LLVCs (n = 106, 83 %) were observed in the premolar region. There was a statistically significant difference between the occurrence of LLVCs in the premolar region and the other areas (p < 0.01). CONCLUSIONS: All the LLVCs observed in this study had a connection with inferior alveolar canal structures. The detection of an LLVC on CBCT images should alert the radiologist and surgeons to the possible presence of collateral arterial and vascular structures. PMID- 24474242 TI - On rights-based partnerships to measure progress in water and sanitation. AB - The right to water and sanitation has emerged from the penumbra of associated rights in the past few decades and now plays an important role in international debates. This right has emerged "from below", through the efforts of social movements seeking transformation in the lives of the world's poor, and it has been recognized "from above", with major international actors such as the United Nations, international financial institutions, and even large corporate actors affirming its existence. As the obligations and entitlements inherent in this right are increasingly clarified, the role of interdisciplinary collaboration has never been more important. This short Commentary examines one such collaborative effort, led by the United Nations Joint Monitoring Programme, to devise post-2015 goals, targets, and indicators for water, sanitation, and hygiene. The Commentary calls for renewed partnerships to advance human rights-based policy among advocates, development practitioners, and water and sanitation experts from diverse scientific fields. PMID- 24474244 TI - Peritoneal malignant mesothelioma metastatic to supraclavicular lymph nodes. AB - Distinguishing between malignant mesothelioma and reactive mesothelial hyperplasia is often inestimable, but may be a challenging gauntlet for pathologists. A 62-year-old man underwent appendectomy after the identification of a peritoneal mass and the histological examination showed mesothelial proliferation along the appendix surface with no clear images of infiltration. After a few months the patient developed mediastinal and supraclavicular lymphadenopathies, and a nodal biopsy showed mesothelial cell proliferation invading lymphatic sinuses, consistent with the cells seen in the abdominal cavity. Since overt morphologic criteria for malignancy were lacking and reactive mesothelial cell deposits have been documented in lymph nodes, a molecular investigation of the CDKN2A (henceforth simply p16) gene status via fluorescence in situ hybridization was performed, which showed homozygous deletion in 100% tumor cells. These data ruled out the hypothesis of reactive mesothelial cells inclusion in lymph nodes, thus confirming the diagnosis of epithelioid malignant mesothelioma. PMID- 24474243 TI - N-glycosylation deficiency reduces ICAM-1 induction and impairs inflammatory response. AB - Congenital disorders of glycosylation (CDGs) result from mutations in various N glycosylation genes. The most common type, phosphomannomutase-2 (PMM2)-CDG (CDG Ia), is due to deficient PMM2 (Man-6-P -> Man-1-P). Many patients die from recurrent infections, but the mechanism is unknown. We found that glycosylation deficient patient fibroblasts have less intercellular adhesion molecule-1 (ICAM 1), and because of its role in innate immune response, we hypothesized that its reduction might help explain recurrent infections in CDG patients. We, therefore, studied mice with mutations in Mpi encoding phosphomannose isomerase (Fru-6-P -> Man-6-P), the cause of human MPI-CDG. We challenged MPI-deficient mice with an intraperitoneal injection of zymosan to induce an inflammatory response and found decreased neutrophil extravasation compared with control mice. Immunohistochemistry of mesenteries showed attenuated neutrophil egress, presumably due to poor ICAM-1 response to acute peritonitis. Since phosphomannose isomerase (MPI)-CDG patients and their cells improve glycosylation when given mannose, we provided MPI-deficient mice with mannose-supplemented water for 7 days. This restored ICAM-1 expression on mesenteric endothelial cells and enhanced transendothelial migration of neutrophils during acute inflammation. Attenuated inflammatory response in glycosylation-deficient mice may result from a failure to increase ICAM-1 on the vascular endothelial surface and may help explain recurrent infections in patients. PMID- 24474246 TI - Cycloserine as an alternative urinary tract infection therapy: susceptibilities of 500 urinary pathogens to standard and alternative therapy antimicrobials. AB - PURPOSE: Cycloserine has been used previously in some areas of the world for the treatment of urinary tract infections. The emergence of multi-resistant strains of Enterobacteriaceae and the lack of new agents in the development pipeline has prompted a need to review the activity of older agents. Susceptibility testing of cycloserine has traditionally been problematic owing to testing in standard media, containing competitive alanine, thus presenting falsely elevated minimum inhibitory concentrations (MICs). This study tests urinary coliforms against cycloserine in both standard and minimal media. METHODS: Susceptibilities were performed on 500 "wild type" UTI coliforms using Mueller-Hinton broth in the range 0.008-128 MUg/ml in accordance with ISO guidelines. Cycloserine was also tested in Minimal Salts medium + 2 % 1 M glucose + 0.2 % 1 M magnesium sulphate. MICs were recorded after 18 h of incubation at 35 degrees C and interpreted with EUCAST breakpoints (where available). RESULTS: Cycloserine MIC50 for the "wild type" coliforms was 32 MUg/ml in Mueller-Hinton broth compared with 2 MUg/ml in Minimal Salts. Eighty-seven per cent of "wild type" UTI coliforms show cycloserine MICs < = 8 MUg/ml in Minimal Salts. The epidemiological cut-off values for cycloserine for E. coli in this study were 64 MUg/ml using Mueller Hinton broth and 8 MUg/ml using Minimal Salts medium. Ninety-four per cent of trimethoprim-resistant and 82 % of third generation cephalosporin-resistant E. coli had MICs in Minimal Salts <= 8 MUg/ml. CONCLUSION: Cycloserine is still licensed in some countries for the treatment of urinary infections and the data presented here suggest that it may play a role in the management of infections resistant to trimethoprim and third generation cephalosporins. PMID- 24474245 TI - Postoperative chemotherapy use after neoadjuvant chemoradiotherapy for rectal cancer: Analysis of Surveillance, Epidemiology, and End Results-Medicare data, 1998-2007. AB - BACKGROUND: Neoadjuvant chemoradiotherapy followed by tumor resection and postoperative chemotherapy is the standard of care for patients with clinical stage II or III adenocarcinoma of the rectum. Significant variation exists in the receipt of postoperative chemotherapy after resection in this population. The objective of this study was to determine the demographic and clinicopathologic factors associated with the initiation of postoperative chemotherapy in elderly patients with rectal cancer and to identify potential targets for reducing treatment variation. METHODS: A retrospective cohort study was performed of patients with rectal cancer ages 66 to 80 years who received neoadjuvant chemoradiotherapy and underwent radical resection in the Surveillance, Epidemiology, and End Results-linked Medicare database (1998-2007). Multivariate logistic regression was used to assess chemotherapy use in relation to patient, tumor, and treatment response characteristics. RESULTS: Among 1492 patients who met the study criteria, 61.5% received adjuvant therapy with 5-fluorouracil. Pathologic stage was the strongest determinant of whether patients received postoperative chemotherapy (48.3% of patients with stage I disease, 59.6% of patients with stage II disease, and 77.6% of patients with stage III disease). Increasing age and postoperative readmission also were associated significantly with a decreased rate of adjuvant therapy initiation. CONCLUSIONS: Although standard treatment guidelines for locally advanced rectal cancer include postoperative chemotherapy for all patients after neoadjuvant chemoradiotherapy and radical resection, greater than 1 in 3 patients failed to receive adjuvant therapy. Despite the absence of established evidence, treatment decisions appear to be influenced by the findings at surgical pathology. PMID- 24474247 TI - Incidence and microbiology of peritonsillar abscess: the influence of season, age, and gender. AB - To explore the correlations among the incidence, microbiology, season, gender, and age in patients with peritonsillar abscess (PTA) in order to identify risk factors for PTA development. All patients with PTA treated at private ENT practices in Aarhus County and in the Ear-Nose-Throat Departments at Aarhus University Hospital and Randers Hospital from January 2001 to December 2006 were included in the study. Age- and gender-stratified population data for Aarhus County for the same 6 years were obtained. The incidence rate of PTA increased from childhood to peak in teenage life and declined afterward gradually until old age. Girls predominated over boys until the age of 14 years. Subsequently, men were more frequently affected than women. Fusobacterium necrophorum (FN) was significantly more prevalent than group A Streptococcus (GAS) among patients aged 15-24 years (P < 0.001). In contrast, GAS was significantly more frequently recovered among children aged 0-9 years and adults aged 30-39 years compared with FN (P < 0.001 and P = 0.017 respectively). The seasonal variation of PTA was statistically insignificant (P = 0.437). However, GAS was significantly more frequently recovered in the winter and spring than in the summer (P = 0.002 and P = 0.036 respectively). There was a trend toward a higher incidence of FN infection during the summer than the winter (P = 0.165). Although the collected PTA incidence was stable throughout the year, the microbiology fluctuated with seasons. Patients aged 15-24 years are at an increased risk of PTA due to FN, which may have clinical implications for the diagnostic work-up and treatment of patients with acute tonsillitis. PMID- 24474248 TI - Innovation, risk, and patient empowerment: the FDA-mandated withdrawal of 23andMe's Personal Genome Service. PMID- 24474249 TI - Hydrodeoxygenation of the angelica lactone dimer, a cellulose-based feedstock: simple, high-yield synthesis of branched C7 -C10 gasoline-like hydrocarbons. AB - Dehydration of biomass-derived levulinic acid under solid acid catalysis and treatment of the resulting angelica lactone with catalytic K2 CO3 produces the angelica lactone dimer in excellent yield. This dimer serves as a novel feedstock for hydrodeoxygenation, which proceeds under relatively mild conditions with a combination of oxophilic metal and noble metal catalysts to yield branched C7 C10 hydrocarbons in the gasoline volatility range. Considering that levulinic acid is available in >80 % conversion from raw biomass, a field-to-tank yield of drop-in, cellulosic gasoline of >60 % is possible. PMID- 24474250 TI - Enhancement of radiosensitivity by 5-Aza-CdR through activation of G2/M checkpoint response and apoptosis in osteosarcoma cells. AB - Radiation resistance is a major problem preventing successful treatment. Therefore, identifying sensitizers is vitally important for radiotherapy success. Epigenetic events such as DNA methylation have been proposed to mediate the sensitivity of tumor therapy. In this study, we investigated the influence of demethylating agent 5-Aza-2'-deoxycytidine (5-Aza-CdR) on the radiosensitivity of human osteosarcoma cell lines. 5-Aza-CdR was capable of sensitizing three osteosarcoma cells to irradiation in a time-dependent manner, with the maximum effect attained by 48 h. Pretreatment with 5-Aza-CdR synchronized cells in G2/M phase of the cell cycle and enhanced irradiation-induced apoptosis compared with irradiation alone in SaOS2, HOS, and U2OS cells. Moreover, 5-Aza-CdR restored mRNA expressions of 14-3-3sigma, CHK2, and DAPK-1 in the three cells, accompanied with demethylation of their promoters. These findings demonstrate that demethylation with 5-Aza-CdR increases radiosensitivity in some osteosarcoma cells through arresting cells at G2/M phase and increasing apoptosis, which is partly mediated by upregulation of 14-3-3sigma, CHK2, and DAPK-1 genes, suggesting that 5-Aza-CdR may be a potential radiosensitizer to improve the therapy effect in osteosarcoma. PMID- 24474251 TI - Investigation of intercellular adhesion molecules (ICAMs) gene expressions in patients with Barrett's esophagus. AB - The adhesion molecules play a major role in inflammation as well as in neoplastic diseases. The aim of this study is to evaluate the expressions of the adhesion molecules, intercellular adhesion molecule 1 (ICAM-1), ICAM-2, and ICAM-3, in Barrett's esophagus, recognized as a premalign lesion for esophageal cancer and related to inflammation. Eighteen patients with Barrett's esophagus according to endoscopy and 25 volunteers without Barrett's esophagus disease were included in the study. Tissue samples were supplied by biopsy and used for both gene expression and immunohistochemical analysis. The significance of the differences between the two groups was assessed by Student's t test. The ICAM-1 expression level was fivefold higher in the patient group compared with that of the control. There was an increase in the serum level of ICAM-1 in patients compared to that of the controls, but this increase was not significant. ICAM-2 levels were also increased in the patient group, but it was not significant. There was no difference between controls and patients in ICAM-3 levels. Significantly higher levels of ICAM-1 gene expression make us think that ICAM-1 may play an important role in Barrett's esophagus. We think that more studies, with larger patient groups and preferably detailed histopathological and clinical evaluations, are needed to explain the severity of ICAM-1, ICAM-2, and ICAM-3 molecules in Barrett's esophagus. PMID- 24474252 TI - Hypoxia and hypoxia-inducible factor 1 repress SEMA4B expression to promote non small cell lung cancer invasion. AB - Sema domain of semaphorin 4B (SEMA4B), which is an interacting protein of LNM35, plays an important role in lung cancer invasion. However, the regulation mechanism of this protein is completely unknown. Here, we report that hypoxia and hypoxia mimic reagent could downregulate the expression of SEMA4B in human non small cell lung cancer (NSCLC) lines. We provide evidences that SEMA4B is a direct target of hypoxia-inducible factor 1 (HIF-1). Silencing the expression of HIF-1alpha in cancer cells by RNA interference abolished hypoxia-repressed SEMA4B expression. Using luciferase reporter assay, we showed that HIF-1alpha recognized a hypoxia-responsive element (HRE) of SEMA4B gene, which is required for HIF-1 repressed SEMA4B expression. Moreover, ectopic expression of SEMA4B abolished invasion of hypoxia-induced NSCLC cells. Taken together, these data would shed novel insights on the mechanisms for invasion of hypoxia-induced NSCLC cells. PMID- 24474253 TI - VEGF +405G/C (rs2010963) polymorphisms and digestive system cancer risk: a meta analysis. AB - Vascular endothelial growth factor (VEGF) polymorphisms, specifically +405G/C (rs2010963), reportedly influence the risk for various digestive cancers. However, the consequences of these polymorphisms remain controversial and ambiguous. Therefore, we performed a meta-analysis of 11 studies with VEGF +405G/C genotyping on 2,862 patients and 3,028 controls using the random effects model. We obtained a pooled odds ratio (OR) of 1.04 (95% confidence interval (CI) = 0.86-1.26) for the recessive genetic model, 1.07 (95% CI = 0.81-1.42) for the dominant genetic model, 1.09 (95% CI = 0.81-1.47) for the homozygote comparison, and 1.03 (95% CI = 0.83-1.27) for the heterozygote comparison. In the subgroup analysis of the recessive model, the OR was 1.20 (95% CI = 1.02-1.40) in colorectal cancer. These results show that VEGF +405G/C polymorphisms are unlikely to be a major determinant of susceptibility to digestive cancer. Furthermore, the subgroup analysis of recessive model indicates that VEGF +405G/C polymorphisms increase the risk for colorectal cancer. PMID- 24474254 TI - Increasing access to and persistence in college. PMID- 24474256 TI - Pathways to college and STEM careers: enhancing the high school experience. AB - With a rising demand for a college degree and an increasingly complicated college search, application, and selection process, there are a number of interventions designed to ease the college-going process for adolescents and their families. One such intervention, the College Ambition Program (CAP), is specifically designed to be a whole-school intervention that comprehensively connects several important aspects of the college-going process and specifically is focused on increasing interest in science, technology, engineering, and math (STEM). With many adolescents having interest in STEM careers but lacking knowledge of how to transform these interests into plans, CAP supports students in developing and pursuing their educational and occupational goals. CAP offers students tutoring and mentoring, course-counseling and advising, assistance through the financial aid process, and college experiences through visits to college campuses. In addition to these four core components, CAP is also pursuing how to integrate mobile technology and texting to further provide students with tailored resources and information about the college-going process. This chapter describes the complexities of the college-going process, the components of the CAP intervention, and presents findings that demonstrate that these strategies can increase college-going rates and interest in STEM. The authors highlight the importance of developing a college-going culture within high schools that support the alignment of postsecondary and career goals. PMID- 24474257 TI - Research into practice: postsecondary success in the Chicago Public Schools. AB - In this chapter, the authors describe nearly a decade of research examining postsecondary outcomes of students in the Chicago Public Schools conducted by the Consortium on Chicago School Research (CCSR). These analyses include both long term trends in college going and findings on the dimensions of students' postsecondary transition experiences that shape those outcomes. The authors describe the evolution of research at CCSR, which emphasizes a specific type of partnership between researchers, district officials, and practitioners that builds the capacity of practitioners and district officials to think critically about big problems and utilize data to inform decision-making and evaluation. In addition to describing these findings, the authors discuss the development and operation of the Network for College Success, a research-based, integrated and intensive support for school improvement to principals, their instructional leadership teams, grade level teams, and counselors. The authors describe how NCS builds the capacity of school leaders to work together and to use data to improve practice in the postsecondary transition. Finally, the authors discuss ongoing challenges and new directions for ongoing and future research. PMID- 24474258 TI - Lessons learned from a data-driven college access program: The National College Advising Corps. AB - This chapter discusses the collaboration between a national college access program, the National College Advising Corps (NCAC), and its research and evaluation team at Stanford University. NCAC is currently active in almost four hundred high schools and through the placement of a recent college graduate to serve as a college adviser provides necessary information and support for students who may find it difficult to navigate the complex college admission process. The advisers also conduct outreach to underclassmen in an effort to improve the school-wide college-going culture. Analyses include examination of both quantitative and qualitative data from numerous sources and partners with every level of the organization from the national office to individual high schools. The authors discuss balancing the pursuit of evaluation goals with academic scholarship. In an effort to benefit other programs seeking to form successful data-driven interventions, the authors provide explicit examples of the partnership and present several examples of how the program has benefited from the data gathered by the evaluation team. PMID- 24474259 TI - The not-so-lazy days of summer: experimental interventions to increase college entry among low-income high school graduates. AB - Despite decades of policy intervention to increase college entry among low-income students, substantial inequalities in college going by family income remain. Policy makers have largely overlooked the summer after high school as an important time period in students' transition to college. During the post-high school summer, however, students must complete a range of financial and informational tasks prior to college enrollment, yet no longer have access to high school counselors and have not engaged yet with their college community. Moreover, many come from families with little college-going experience. Recent research documents summer attrition rates ranging from 10 to 40 percent among students who had been accepted to college and declared an intention to enroll in college as of high school graduation. Encouragingly, several experimental interventions demonstrate that students' postsecondary plans are quite responsive to additional outreach during the summer months. Questions nonetheless remain about how to maximize the impact and cost effectiveness of summer support. This chapter reports on several randomized trials to investigate the impact of summer counselor outreach and support as well as the potential roles for technology and peer mentoring in mitigating summer attrition and helping students enroll and succeed in college. The authors conclude with implications for policy and practice. PMID- 24474260 TI - Is traditional financial aid too little, too late to help youth succeed in college? An introduction to The Degree Project promise scholarship experiment. AB - One of the key barriers in accessing postsecondary opportunities for many students is financial aid. This chapter begins by providing a review of prior evidence on the relationship between financial aid and postsecondary outcomes. One type of financial aid intervention that challenges traditional aid and scholarship options are "promise programs." These programs make commitments to low-income students when they are much younger than when students typically apply for aid and have the potential to encourage students to better prepare during high school, develop the social capital they need to navigate the path to college, and pay for growing college costs. In this chapter, the author describes the design and rationale for The Degree Project (TDP), which is the first randomized trial of a promise scholarship in the United States. In addition to the important new evidence the demonstration program will generate, TDP also shows how educators and researchers can work together to provide the insight and answers policy makers need to address very real education gaps. PMID- 24474261 TI - Limbic Tumors of the Temporal Lobe: Radiologic-Pathologic Correlation. AB - PURPOSE: The purpose of this study was to assess imaging and pathologic characteristics of limbic tumors. Our hypothesis was that temporal lobe limbic tumors have distinctive features from extralimbic tumors. METHODS: This retrospective radiologic-pathologic correlation study of primary temporal lobe tumors (excluding glioblastoma) distinguished limbic from extralimbic tumors based on preoperative magnetic resonance imaging. Limbic tumors were categorized according to Yasargil's classification into (1) mediobasal temporal (mbT), (2) insular-temporo-opercular (I-TO), and (3) fronto-orbital-insular-temporopolar (FO I-TP). RESULTS: A total of 50 cases with a mean age at diagnosis of 38 +/- 19.9 years (14 women, 36 men) were included. Pathologic diagnoses were as follows: 20 anaplastic astrocytomas, 11 gangliogliomas, 8 astrocytomas (World Health Organization grade II), 3 pilocytic astrocytomas, 2 dysembryoplastic neuroepithelial tumors, 2 oligodendrogliomas (grade II), 2 anaplastic oligodendrogliomas, 1 low-grade glioneuronal tumor, and 1 atypical extraventricular neurocytoma. In all, 36 tumors were limbic and displayed consistent growth patterns (16 mbT, 11 I-TO, 8 FO-I-TP, and 1 pantemporal) and 14 were extralimbic. There were no differences between limbic and extralimbic tumors with regard to age, sex, pathologic diagnosis, and presentation with seizures. mbT tumors had more frequent neuronal differentiation (50 %) than I-TO (0 %) and FO-I-TP (25 %) tumors (chi-square = 7.8, df = 2, p = 0.02). Neuronal differentiation correlated with lower grade (r = 0.52, p < 0.01) and younger age (r = 0.52, p < 0.01). CONCLUSIONS: Limbic tumors displayed consistent growth routes. mbT limbic tumors had more frequent neuronal differentiation, which may result from proximity to the neurogenic subgranular zone of the hippocampus. Neuronal differentiation was maximal in mbT and lowest in I-TO and FO-I-TP tumors and correlated with lower tumor grade and younger age at diagnosis. PMID- 24474262 TI - Pretreatment Dynamic Susceptibility Contrast MRI Perfusion in Glioblastoma: Prediction of EGFR Gene Amplification. AB - BACKGROUND AND PURPOSE: Molecular and genetic testing is becoming increasingly relevant in GBM. We sought to determine whether dynamic susceptibility contrast (DSC) magnetic resonance imaging (MRI) perfusion imaging could predict EGFR defined subtypes of GBM. MATERIALS AND METHODS: We retrospectively identified 106 consecutive glioblastoma (GBM) patients with known EGFR gene amplification, and a subset of 65 patients who also had known EGFRvIII gene mutation status. All patients underwent T2* DSC MRI perfusion. DSC perfusion maps and T2* signal intensity time curves were evaluated, and the following measures of tumor perfusion were recorded: (1) maximum relative cerebral blood volume (rCBV), (2) relative peak height (rPH), and (3) percent signal recovery (PSR). The imaging metrics were correlated to EGFR gene amplification and EGFRvIII mutation status using univariate analyses. RESULTS: EGFR amplification was present in 44 (41.5 %) subjects and absent in 62 (58.5 %). Among the 65 subjects who had undergone EGFRvIII mutation transcript analysis, 18 subjects (27.7 %) tested positive for the EGFRvIII mutation, whereas 47 (72.3 %) did not. Higher median rCBV (3.31 versus 2.62, p = 0.01) and lower PSR (0.70 versus 0.78, p = 0.03) were associated with high levels of EGFR amplification. Higher median rPH (3.68 versus 2.76, p = 0.03) was associated with EGFRvIII mutation. CONCLUSION: DSC MRI perfusion may have a role in identifying patients with EGFR gene amplification and EGFRvIII gene mutation status, potential targets for individualized treatment protocols. Our results raise the need for further investigation for imaging biomarkers of genetically unique GBM subtypes. PMID- 24474263 TI - Evaluation of Oral Anticoagulant-Associated Intracranial Parenchymal Hematomas Using CT Findings. AB - PURPOSE: Intracranial hemorrhage (ICH) is one of the most serious and lethal complications of anticoagulants with a reported incidence of 5-18.5 %. Computed tomographic (CT) findings, should be carefully studied because early diagnosis and treatment of oral anticoagulant use-associated hematomas are vitally important. In the present study, CT findings of intraparenchymal hematomas associated with anticoagulant and antihypertensive use are presented. METHODS: This study included 45 patients (25 men, 20 women) under anticoagulant (21 patients) or antihypertensive (24 patients) treatment who had brain CT examinations due to complaints and findings suggesting cerebrovascular disease during July 2010-October 2013 period. CT examinations were performed to determine hematoma volumes and presence of swirl sign, hematocrit effect, mid-line shift effect, and intraventricular extension. RESULTS: The patients were 40-89 years of age. In four cases, a total of 51 intraparenchymal hematomas (42 cerebral, 7 cerebellar and 2 brain stem) were detected in multiple foci. Hematoma volumes varied from 0.09 to 284.00 ml. Swirl sign was observed in 87.5 and 63.0 % of OAC associated ICHs and non-OAC-associated ICHs, respectively. In addition, hematocrit effect was observed in 41.6 % of OAC-associated and in 3.7 % of non OAC-associated ICHs. Volume increases were observed in all 19 hematomas where swirl sign was detected, and follow-up CT scanning was conducted. Mortality of OAC-associated ICHs was correlated with initial volumes of hematoma, mid-line shift amount, and intraventricular extension. CONCLUSIONS: Detection of hematocrit effect by CT scanning of intracranial hematomas should be cautionary in oral anticoagulant use, while detection of swirl sign should be suggestive of active hemorrhage. PMID- 24474265 TI - Driving with hemianopia: IV. Head scanning and detection at intersections in a simulator. AB - PURPOSE: Using a driving simulator, we examined the effects of homonymous hemianopia (HH) on head scanning behaviors at intersections and evaluated the role of inadequate head scanning in detection failures. METHODS: Fourteen people with complete HH and without cognitive decline or visual neglect and 12 normally sighted (NV) current drivers participated. They drove in an urban environment following predetermined routes, which included multiple intersections. Head scanning behaviors were quantified at T-intersections (n = 32) with a stop or yield sign. Participants also performed a pedestrian detection task. The relationship between head scanning and detection was examined at 10 intersections. RESULTS: For HH drivers, the first scan was more likely to be toward the blind than the seeing hemifield. They also made a greater proportion of head scans overall to the blind side than did the NV drivers to the corresponding side (P = 0.003). However, head scan magnitudes of HH drivers were smaller than those of the NV group (P < 0.001). Drivers with HH had impaired detection of blind-side pedestrians due either to not scanning in the direction of the pedestrian or to an insufficient scan magnitude (left HH detected only 46% and right HH 8% at the extreme left and right of the intersection, respectively). CONCLUSIONS: Drivers with HH demonstrated compensatory head scan patterns, but not scan magnitudes. Inadequate scanning resulted in blind-side detection failures, which might place HH drivers at increased risk for collisions at intersections. Scanning training tailored to specific problem areas identified in this study might be beneficial. PMID- 24474264 TI - Anterior lamina cribrosa surface depth, age, and visual field sensitivity in the Portland Progression Project. AB - PURPOSE: To assess the effect of age on spectral-domain optical coherence tomography (SDOCT)-detected lamina cribrosa depth while controlling for visual field (VF) status and retinal nerve fiber layer thickness (RNFLT) in 221 high risk ocular hypertension and glaucoma patients enrolled in the Portland Progression Project. METHODS: In this cross-sectional study, each participant underwent 870-nm SDOCT to obtain high-resolution radial B-scans centered on the optic nerve head (ONH) and a standardized ophthalmologic examination, including automated perimetry, on the same day. For each ONH, an anterior lamina cribrosa surface depth (ALCSD) parameter was generated as the average perpendicular distance from each anterior lamina cribrosa surface point relative to Bruch's membrane opening (BMO) reference plane within all 24 delineated B-scans. The relative effects of age, age-corrected VF status (mean deviation [MD]), and RNFLT on ALCSD were analyzed. RESULTS: The mean age +/- SD of participants was 64 +/- 11 years (range, 33-90 years). The relationship between ALCSD and MD was age dependent. ALCSD = 407.68 - 67.13 * MD - 0.08 * Age + 0.89 * MD * Age (MD, P = 0.001; MD * Age, P = 0.004). The relationship between ALCSD and RNFLT may also be age-dependent but did not achieve significance (interaction term, P = 0.067). ALCSD increased with worse VF status in younger eyes but not in older eyes. In older eyes, the anterior lamina was shallower than in younger eyes for the same VF status and RNFLT. CONCLUSIONS: These data are consistent with the concept that structure/structure and structure/function relationships change with age. PMID- 24474266 TI - Tear meniscus volume changes in dacryocystorhinostomy evaluated with quantitative measurement using anterior segment optical coherence tomography. AB - PURPOSE: To evaluate tear meniscus (TM) changes in external dacryocystorhinostomy (ex-DCR) with quantitative measurement of tear meniscus height (TMH), area (TMA), and volume (TMV) using anterior segment optical coherence tomography (AS-OCT). METHODS: Twenty-five eyes from 21 patients (11 males and 10 females) with primary acquired nasolacrimal duct obstruction (PANDO) who received ex-DCR from May 2010 to April 2011 were evaluated prospectively on their TMH, TMA, and TMV changes by AS-OCT. Measurements were performed before surgery (Pre) and 2 weeks (2W), 2 months (2M), and 6 months (6M) after surgery. Data were analyzed using Kruskal Wallis test, Wilcoxon signed-rank test with Bonferroni adjustment, and Spearman's rank correlation coefficient. RESULTS: All patients had a good clinical course, and there were significant differences in the values of each TM parameter before and after surgery (P < 0.0001). The median values of TMH (mm) throughout the observation period were 0.707 (Pre), 0.334 (2W), 0.278 (2M), and 0.277 (6M). The TMA median values (mm(2)) were 0.1097 (Pre), 0.0483 (2W), 0.0255 (2M), and 0.0224 (6M). The TMV median values (mm(3)) were 0.7799 (Pre), 0.1614 (2W), 0.1071 (2M), and 0.1553 (6M). There were significant differences in TMH, TMA, and TMV reduction at each postoperative visit as compared to preoperative values (P < 0.001). In addition, TMH change 6 months after ex-DCR showed a significant positive correlation with age (r = 0.4434, P = 0.0264). CONCLUSIONS: The perioperative TM changes in ex-DCR can be evaluated noninvasively and quantitatively by using AS-OCT. PMID- 24474267 TI - Inflammation-related cytokines of aqueous humor in acute primary angle-closure eyes. AB - PURPOSE: To measure levels of various inflammation-related cytokines in the aqueous humor of patients with acute primary angle-closure (APAC) and senile cataract. METHODS: Aqueous humor samples were prospectively collected from 23 eyes (12 eyes with current APAC and 11 eyes with previous APAC) of 23 APAC patients and 15 eyes of 15 cataract patients. The levels of 15 inflammation related cytokines in the aqueous humor of APAC and cataract subjects were measured by using the multiplex bead immunoassay technique. Data on patient demographics and preoperative intraocular pressure (IOP) were also collected for correlation analysis. RESULTS: Compared with the group with previous APAC and the cataract group, the group with current APAC showed clear and significantly elevated concentrations of interleukin (IL)-6, IL-8, granulocyte colony stimulating factor (G-CSF), monocyte chemotactic protein (MCP)-1, MCP-3, and vascular endothelial growth factor (VEGF) (all P < 0.0167). The group with previous APAC and the cataract group had similar levels of cytokines. Intraocular pressure was positively correlated with IL-8 (P = 0.001), G-CSF (P = 0.002), MCP 3 (P < 0.001), and VEGF (P < 0.001). CONCLUSIONS: An early "acute inflammatory" condition occurs in eyes with current APAC. In addition to controlling IOP, anti inflammatory treatments are necessary for eyes suffering from APAC. PMID- 24474268 TI - Genotype-phenotype correlation analysis for three primary angle closure glaucoma associated genetic polymorphisms. AB - PURPOSE: Recently, three genetic susceptibility loci for primary angle closure glaucoma (PACG) were identified: COL11A1 rs3753841, PCMTD1-ST18 rs1015213, and PLEKHA7 rs11024102. The purpose of this study was to investigate whether these single nucleotide polymorphisms (SNPs) affect the phenotype of PACG patients. METHODS: A retrospective analysis was performed for 700 Singaporean Chinese PACG patients who had been genotyped. The associations between the three SNPs and clinical features related to severity of glaucoma were studied. For a subgroup of patients who had >= 5 years of follow-up and >= 5 reliable visual field (VF) tests, differences in glaucoma progression, as measured by the proportion of VF progression and blindness, were compared among groups with different genotypes. RESULTS: The minor allele frequencies at COL11A1 rs3753841, PCMTD1-ST18 rs1015213, and PLEKHA7 rs11024102 were 36%, 2.1%, and 41.5%, respectively. There were no significant differences in sex, diagnosis (acute primary angle closure [APAC] versus non-APAC), age at diagnosis, laterality of glaucoma, or need for filtration surgery among patients with different genotypes (all P > 0.05). We also found no significant difference between genotypes and the IOP at presentation, and other clinical characteristics at DNA collection (vertical cup to-disc ratio, best corrected visual acuity, baseline VF mean deviation, or pattern standard deviation). For the subgroup analysis, we did not observe significant associations between VF progression and the proportion of blindness with any of the PACG susceptibility loci. CONCLUSIONS: The three genetic susceptibility loci for PACG did not underlie any major phenotypic diversity in terms of disease severity or progression. PMID- 24474269 TI - Lamina cribrosa depth in healthy eyes. AB - PURPOSE: To investigate the characteristics of the lamina cribrosa (LC) depth in healthy eyes using enhanced depth imaging (EDI) spectral-domain optical coherence tomography (SD-OCT). METHODS: Serial horizontal B-scans of the optic nerve head were obtained using EDI SD-OCT for both eyes of 150 healthy subjects. Anterior LC surface (ALCS) depths were measured with B-scan images from equidistant planes in each eye and defined as the distance from the Bruch's membrane opening plane to the anterior LC surface. The ALCS depths were compared between eyes within each subject. A linear mixed model was used to identify factors associated with the ALCS depth. RESULTS: The average ALCS depth was 402.06 +/- 101.46 MUm (range, 193.08-826.81). The ALCS depth was not significantly different between the right and left eyes (Ps > 0.05 at all planes). There was a strong intereye correlation within subjects (Rs >= 0.808 at all planes, Ps < 0.0001 at all planes). The ALCS depth was largest in the superior periphery and smallest in the central inferior plane. ALCS depth was larger in males (P < 0.05) and also larger in eyes with shorter axial length (P = 0.029). CONCLUSIONS: This study reports the range of ALCS depth in healthy subjects. These data suggest that ALCS depth is related to sex and axial length. PMID- 24474270 TI - The association of retinal structure and macular pigment distribution. AB - PURPOSE: Macular pigment optical density (MPOD) and age-related macular degeneration (AMD) are thought to be associated; however, the details are not yet understood clearly. This study aimed at investigating how retinal anatomic structures relate with the spatial MPOD distribution in single eyes. METHODS: In a subgroup of the third follow-up examination of the Munster Aging and Retina Study (MARS) cohort (mean age, 78.4 years), 124 single eyes of 79 participants with early AMD were examined. The MPOD was assessed using 2-wavelength autofluorescence (AF). Retinal thickness (RT) and fovea pit profile slopes were measured using optical coherence tomography (OCT). The results were analyzed for interocular correlation in 58 pairs of eyes, and for the association of MPOD distribution patterns with RT using uni- and multivariate statistical methods. RESULTS: The interocular correlations for several measures of RT and RT layers were high (P < 0.001). The RT was inversely and significantly related to MPOD at 1.0 degrees and at 2.0 degrees from the foveal center, but not to central MPOD. After controlling for sex, age, smoking, and spherical equivalent, RT was significantly thinner (-39.7 MUm, P < 0.001) in eyes with ring-like compared to normal MPOD distribution. In particular, a thinner layer between internal and external limiting membrane showed strong associations with ring-like structures. CONCLUSIONS: Higher values of MPOD at 1 degrees and 2 degrees , as well as a ring-like distribution of MPOD were associated significantly with thinner maculae, due to thinner inner retinal layers. The MPOD distribution was unrelated to the slope of the foveal pit or the choroidal thickness. Our results suggest that the retinal section between the internal and external limiting membrane is involved in the spatial distribution of MPOD. PMID- 24474271 TI - Lens power in a population-based cross-sectional sample of adults aged 40 to 64 years in the Shahroud Eye Study. AB - PURPOSE: To report on calculated lens power in adults in relation to other ocular components of refraction, analyzed in relation to secular change in height and education. METHODS: The first phase of the Shahroud Eye Cohort Study is a cross sectional population-based study in Iranian subjects 40 to 64 years old. Data on cycloplegic spherical equivalent refraction and the ocular components of the right eyes were used for the calculation of crystalline lens power with Bennett's formula. Interactions between sex and age as independent variables were analyzed by two-way analysis of variances. RESULTS: Cycloplegic refraction data and biometry were obtained from 4592 subjects, of whom 2666 (58%) were women. The mean lens power showed a biphasic trend. Up to the age of 50, younger subjects had lower lens power than older subjects, but after the age of 50, older subjects had lower lens power. A secular trend in height was found, with younger subjects significantly taller than older ones. Taller men or women had longer eyes, with flatter corneas and less powerful lenses, independent of refractive error. In multiple regression models, corneal power (P < 0.001), axial length (P < 0.001), and lens power (P < 0.001) were all associated with height, independent of age and sex. CONCLUSIONS: There was an unexpected biphasic pattern of the distribution of lens power with age in this cross-sectional study. Younger subjects were taller, and despite having longer axial lengths, their bigger eyes were still predominantly emmetropic. The greater axial lengths were counterbalanced by both lower corneal and lower lens powers. PMID- 24474272 TI - Automated segmentation of optic nerve head structures with optical coherence tomography. AB - PURPOSE: To quantify and characterize the difference between automated and manual segmentation of optic nerve head structures with spectral-domain optical coherence tomography (SD-OCT). METHODS: Optic nerve head radial scans in 107 glaucoma patients and 48 healthy controls were conducted with SD-OCT. Independent segmentations of the internal limiting membrane (ILM) and Bruch's membrane opening (BMO) were performed manually with custom software and with an automated algorithm in each radial scan. The minimum distance between BMO and ILM, termed BMO-minimum rim width (BMO-MRW) was calculated with each segmentation method. Absolute differences between automated and manual segmentations of ILM (DeltaILM) and BMO (DeltaBMO), and the resulting computation of BMO-MRW (DeltaBMO-MRW) were computed. Finally, the relationship between image quality score and DeltaILM and DeltaBMO was explored. RESULTS: The median (interquartile range, IQR) DeltaILM was 8.9 (6.5, 13.4) MUm in patients and 7.3 (5.3, 9.9) MUm in controls. The corresponding values for DeltaBMO were 11.5 (6.6, 22.1) MUm and 12.4 (6.8, 25.4) MUm. Subject-averaged DeltaILM was higher in patients than controls (P < 0.01); however, mean DeltaBMO was not (P = 0.09). The median (IQR) subject-averaged absolute DeltaBMO-MRW was 13.4 (10.6, 16.8) MUm in patients and 12.1 (10.0, 16.8) MUm in controls and not statistically different (P = 0.21). Mean image quality score was statistically higher in controls than patients (P = 0.03) but not related to subject-averaged DeltaILM or DeltaBMO. CONCLUSIONS: In individual scans, the median difference in ILM and BMO segmentations was <2 and <3 image pixels, respectively. There were no differences between patients and controls in DeltaBMO-MRW. PMID- 24474273 TI - Chronic ocular Chlamydia trachomatis infection in rabbits: clinical and histopathological findings in the posterior segment. AB - PURPOSE: To investigate clinical and histopathologic manifestations of Chlamydia trachomatis (CT)-induced chronic posterior segment (PS) inflammation in rabbits. METHODS: Fifteen rabbits were divided into three equal groups of CT subconjunctival-only (SC) and subconjunctival plus intravitreal (SC+IV) inoculation, and controls. Both noncontrol groups received a bilateral SC injection (BSI) and the SC+IV group additionally received a unilateral IV injection (UII) of CT L2 culture, whereas the controls received a BSI+UII of phosphate-buffered saline. During 6 months post injection, the animals were investigated for PS inflammation and infection clinically and microbiologically (cell culture, ELISA, and real-time PCR). Hematoxylin-eosin staining and direct immunofluorescence in situ reaction were used to reveal the signs of tissue inflammation and infection. RESULTS: In the SC group, mild PS disorders (eight eyes) involving vitreal infiltration, the following posterior vitreous detachment and chorioretinitis, and severe PS disorders (two eyes) in the form of panuveitis, were developed. In the SC+IV group, mild (three and three eyes that received SC-only and SC+IV injections, respectively) and severe (two and two eyes that received SC-only and SC+IV injections, respectively) PS disorders were developed. A high titer (1:32-1:128) of CT-specific IgM antibody was present in sera from all the noncontrol animals. The CT antigen was detected in the conjunctiva and PS structures (the vitreous, retinal pigment epithelium, and choroid) in 100% and 40% to 75% of all the noncontrol animals, respectively. CONCLUSIONS: Conjunctival or intraocular inoculation with CT may result in invasion of the PS structures and durable persistence thereof, with the development of inflammatory and then degenerative changes. These data might advocate for expanding the role of chronic CT infection in etiology and pathogenesis of vitreoretinal disorders. PMID- 24474274 TI - Subfoveal choroidal thickness and cerebrospinal fluid pressure: the Beijing Eye Study 2011. AB - PURPOSE: The venous choroidal blood drains through the superior orbital vein into the intracranial cavernous sinus. The cerebrospinal fluid pressure (CSFP) may thus influence the choroidal venous blood pressure. Since volume and thickness of the choroid depend on its pressure, we tested the hypothesis whether the subfoveal choroidal thickness (SFCT) is associated with CSFP. METHODS: The population-based Beijing Eye Study 2011 included 3468 individuals. A detailed ophthalmic examination was performed including spectral-domain optical coherence tomography (SD-OCT) with enhanced depth imaging for measurement of SFCT. The CSFP was calculated as CSFP (mm Hg) = 0.44 * Body Mass Index (kg/m(2)) + 0.16 * Diastolic Blood Pressure (mm Hg) - 0.18 * Age (years) - 1.91. RESULTS: Mean calculated CSFP was 8.8 +/- 3.7 mm Hg and mean SFCT was 254 +/- 107 MUm. In multivariate analysis, SFCT was significantly associated with higher CSFP (P = 0.009; standardized coefficient beta: 0.08; regression coefficient B: 2.27) after adjusting for lower age (P < 0.001; beta: -0.36; B: -3.99), shorter axial length (P < 0.001; beta: -0.37; B: -35.7), lower body mass index (P = 0.02; beta: -0.05; B: -1.51), and higher corneal curvature radius (P < 0.001; beta: 0.10; B: 41.1). In univariate analysis, SFCT increased by 9.2 MUm (95% confidence interval: 8.3, 10.1) for each mm Hg increase in CSFP. In a reverse manner, CSFP was significantly associated with thicker SFCT (P < 0.001; B: 0.007; beta: 0.21), after adjusting for region of habitation (P < 0.001; B: -0.31; beta: -2.32), higher levels of glucose (P = 0.02; B: 0.10; beta: 0.04) and triglycerides (P < 0.001; B: 0.13; beta: 0.09), higher intraocular pressure (P < 0.001; B: 0.17; beta: 0.12), and thinner lens (P < 0.001; B: -2.39; beta: -0.22). CONCLUSIONS: Thicker subfoveal choroid was associated with higher CSFP after adjustment for age, axial length, body mass index, and corneal curvature radius. This association may explain thicker SFCT measurements in the morning than evening. It shows the importance of the CSFP for the physiology of the eye. PMID- 24474275 TI - Pharmacological regulation of SPARC by lovastatin in human trabecular meshwork cells. AB - PURPOSE: Statins have been shown to increase aqueous outflow facility. The matricellular protein SPARC (secreted protein acidic and rich in cysteine) is a critical mediator of aqueous outflow and intraocular pressure (IOP). Here, we examine the effects of lovastatin on SPARC expression in trabecular meshwork (TM) cells, exploring the molecular mechanisms involved. METHODS: Primary cultured human TM cells were incubated for 24, 48, and 72 hours with 10 MUM lovastatin. In separate cultures, media was supplemented with either farnesyl pyrophosphate (FPP) or geranylgeranyl pyrophosphate (GGPP) for the duration of the 72-hour time point experiment. Trabecular meshwork cells were also pretreated for 24 hours with lovastatin followed by 24-hour stimulation with 3 ng/mL TGF-beta2. Cell lysates and media were harvested and relative mRNA and protein level changes were determined. Kruppel-like factor 4 (KLF4) localization in normal human anterior segments was examined by immunofluorescence. Adenovirus expressing human KLF4 was used and relative changes in SPARC mRNA and protein levels were assessed. RESULTS: Incubating TM cells with lovastatin suppressed SPARC mRNA and protein levels. This effect was reversed upon media supplementation with GGPP but not FPP. Pretreating cells with lovastatin inhibited TGF-beta2 induction of SPARC. The KLF4 transcription factor was expressed throughout the TM and the inner and outer walls of Schlemm's canal. Lovastatin treatment upregulated KLF4 mRNA and protein levels. Overexpression of KLF4 downregulated SPARC expression. CONCLUSIONS: Collectively, our data identify lovastatin as an important pharmacological suppressor of SPARC expression in TM cells, and provide further insight into the molecular mechanisms mediating statin enhancement of aqueous outflow facility. PMID- 24474276 TI - AMA0076, a novel, locally acting Rho kinase inhibitor, potently lowers intraocular pressure in New Zealand white rabbits with minimal hyperemia. AB - PURPOSE: To determine whether ROCK inhibition for the treatment of glaucoma can be improved by using novel, locally acting Rho kinase (ROCK) inhibitors, such as AMA0076, that lower IOP without inducing hyperemia. METHODS: On-target potency of AMA0076 was compared with other ROCK inhibitors (Y-27632 and Y-39983) and conversion of AMA0076 into its functionally inactive metabolite was evaluated in rabbit eye tissues. Human trabecular meshwork (HTM) cell morphology, actin filaments, and focal adhesion were studied in vitro after exposure to AMA0076. The effect of AMA0076 on IOP was investigated in normotensive rabbits and a new, acute hypertensive rabbit model. Intraocular pressure lowering efficacy of AMA0076 was compared with pharmacologic treatments. Hyperemia after single topical dosing of AMA0076 and Y-39983 was scored. RESULTS: AMA0076 and Y-39983 showed similar on-target potency. AMA0076 was most stable in aqueous humor and converted into its metabolite in other eye tissues. Exposure of HTM cells to AMA0076 led to significant and reversible changes in cell shape and a decrease in actin stress fibers and focal adhesions. Both AMA0076 and Y-39983 provided an equivalent IOP control. Compared with latanoprost and bimatoprost, AMA0076 was more potent in preventing the IOP elevation in the acute hypertensive rabbit model. The degree of hyperemia was significantly lower in rabbits treated with AMA0076 then with Y-39983. CONCLUSIONS: AMA0076 is a locally acting ROCK inhibitor that is able to induce altered cellular behavior of HTM cells. Administration of AMA0076 effectively reduces IOP in ocular normotensive and acute hypertensive rabbits without causing distinct hyperemia. PMID- 24474277 TI - Identification of mutations causing inherited retinal degenerations in the israeli and palestinian populations using homozygosity mapping. AB - PURPOSE: The Israeli and Palestinian populations are known to have a relatively high level of consanguineous marriages, leading to a relatively high frequency of autosomal recessive (AR) diseases. Our purpose was to use the homozygosity mapping approach, aiming to prioritize the set of genes and identify the molecular genetic causes underlying AR retinal degenerations in the Israeli and Palestinian populations. METHODS: Clinical analysis included family history, ocular examination, full-field electroretinography (ERG), and funduscopy. Molecular analysis included homozygosity mapping and mutation analysis of candidate genes. RESULTS: We recruited for the study families with AR nonsyndromic retinal degenerations, including mainly retinitis pigmentosa (RP), cone-rod degeneration (CRD), and Leber congenital amaurosis (LCA). With the aim to identify the causative genes in these families, we performed homozygosity mapping using whole genome single nucleotide polymorphism (SNP) arrays in 125 families. The analysis revealed the identification of 14 mutations, 5 of which are novel, in 16 of the families. The mutations were identified in the following eight genes: RDH12, PROM1, MFRP, TULP1, LCA5, CEP290, NR2E3, and EYS. While most patients had a retinal disease that is compatible with the causing gene, in some cases new clinical features are evident. CONCLUSIONS: Homozygosity mapping is a powerful tool to identify genetic defects underlying heterogeneous AR disorders, such as RP and LCA, in consanguineous and nonconsanguineous patients. The identification of significant and large homozygous regions, which do not include any known retinal disease genes, may be a useful tool to identify novel disease causing genes, using next generation sequencing. PMID- 24474278 TI - Knockdown of both p120 catenin and Kaiso promotes expansion of human corneal endothelial monolayers via RhoA-ROCK-noncanonical BMP-NFkappaB pathway. AB - PURPOSE: To determine the signaling pathway involved in expanding contact inhibited human corneal endothelial cells (HCECs) using p120 and Kaiso small interfering RNAs (siRNAs). METHODS: Expansion of HCEC monolayers on collagen IV in SHEM using p120 siRNA was optimized regarding various dosage, frequency, and starting date before being added Kaiso siRNA or various inhibitors of Rho, ROCK, NFkappaB, and TAK1. Phase contrast micrographs were used for monitoring cell shape, monolayer size, and cell density. Immunostaining was used to determine cytolocalization of BrdU, p120, pNFkB, F-actin, alpha-catenin, beta-catenin, LEF1, Na+/K+-ATPase, N-cadherin, ZO-1, and S100A4. Western blotting was used to determine the protein level of RhoA and RhoA-guanosine-5'-triphosphate (GTP). RESULTS: The HCEC monolayer size in diameter was expanded from 2.1 +/- 0.4 mm to 4.3 +/- 0.3 mm (P < 0.05) by increasing p120 siRNA from 40 nM to 100 nM starting at day 7, to 5.0 +/- 0.4 mm (P < 0.05) by adding 100 nM Kaiso siRNA, to 6.8 +/- 0.3 mm by using one-fourth corneoscleral rim (P < 0.05), and to 8.1 +/- 0.5 mm by using one-half corneoscleral rim (P < 0.05). Such proliferative effect required activation of RhoA-ROCK-noncanonical bone morphogenic protein (BMP) signaling and nuclear translocation of phosphorylated nuclear factor kappa-light-chain-enhancer of activated B cells (pNFkappaB). After withdrawal of siRNAs for 1 week, the resultant HCEC monolayer maintained a hexagonal shape, the average cell density of 2254 +/- 87 mm(2) (n = 3), and normal expression patterns of F-actin, alpha catenin, beta-catenin, N-cadherin, ZO-1, and Na+/K+-ATPase without S100A4 and alpha-smooth muscle actin (alpha-SMA). CONCLUSIONS: The optimized knockdown with p120 and Kaiso siRNAs further expands the size of HCEC monolayers without endothelial mesenchymal transition (EMT) via selective activation of p120/Kaiso signaling that requires the RhoA-ROCK-noncanonical BMP-NFkB signaling. PMID- 24474279 TI - Anatomical manifestations of primary blast ocular trauma observed in a postmortem porcine model. AB - PURPOSE: We qualitatively describe the anatomic features of primary blast ocular injury observed using a postmortem porcine eye model. Porcine eyes were exposed to various levels of blast energy to determine the optimal conditions for future testing. METHODS: We studied 53 enucleated porcine eyes: 13 controls and 40 exposed to a range of primary blast energy levels. Eyes were preassessed with B scan and ultrasound biomicroscopy (UBM) ultrasonography, photographed, mounted in gelatin within acrylic orbits, and monitored with high-speed videography during blast-tube impulse exposure. Postimpact photography, ultrasonography, and histopathology were performed, and ocular damage was assessed. RESULTS: Evidence for primary blast injury was obtained. While some of the same damage was observed in the control eyes, the incidence and severity of this damage in exposed eyes increased with impulse and peak pressure, suggesting that primary blast exacerbated these injuries. Common findings included angle recession, internal scleral delamination, cyclodialysis, peripheral chorioretinal detachments, and radial peripapillary retinal detachments. No full-thickness openings of the eyewall were observed in any of the eyes tested. Scleral damage demonstrated the strongest associative tendency for increasing likelihood of injury with increased overpressure. CONCLUSIONS: These data provide evidence that primary blast alone (in the absence of particle impact) can produce clinically relevant ocular damage in a postmortem model. The blast parameters derived from this study are being used currently in an in vivo model. We also propose a new Cumulative Injury Score indicating the clinical relevance of observed injuries. PMID- 24474280 TI - Effect of acute intraocular pressure challenge on rat retinal and cortical function. AB - PURPOSE: The global or gross response index of visual performance measured from the eye does not necessarily translate to global responses measured from the brain. A better understanding of this relationship would facilitate the monitoring of disease models that affect the visual pathway. We consider whether rod- and cone-retino-cortical-pathways are equally affected by acute IOP elevation. METHODS: Acute, stepwise IOP elevation (10, 30, 40, 50, 60, 70 mm Hg) was induced in anesthetized dark- (N = 8) and light-adapted pigmented rats (N = 6). Electroretinogram (ERG) and visual evoked potentials (VEP) were simultaneously measured after 10 minutes at each step. Relative amplitudes (treated/baseline, %) as a function of IOP level were described with a cumulative normal function. RESULTS: Our results showed decline in scotopic and photopic ERGs with IOP elevation. Photopic ERG responses were less sensitive to IOP challenge than scotopic ERG responses. Despite significant reductions of ganglion cell-mediated waveforms at 70 mm Hg, the VEP showed only subtle decreases in amplitude. Intraocular pressure elevation produced similar effects on rod- and cone-mediated VEP waveforms. CONCLUSIONS: We show that cone signals are less sensitive than rod ERGs to acute IOP challenge. Also, retinal signals are more sensitive than are cortical signals to IOP stress, suggesting that cortical processing may act to salvage reductions expected from attenuated retinal output. PMID- 24474281 TI - Metagenomic insights into the human gut resistome and the forces that shape it. AB - We show how metagenomic analysis of the human gut antibiotic resistome, compared across large populations and against environmental or agricultural resistomes, suggests a strong anthropogenic cause behind increasing antibiotic resistance in bacteria. This area has been the subject of intense and polarized debate driven by economic and political concerns; therefore such recently available insights address an important need. We derive and compare antibiotic resistomes of human gut microbes from 832 individuals from ten different countries. We observe and describe significant differences between samples from these countries in the gut resistance potential, in line with expectations from antibiotic usage and exposure in medical and food production contexts. Our results imply roles for both of these sources in increased resistance among pathogens in recent history. In contrast, other available metadata such as age, body mass index, sex, or health status have little effect on the antibiotic resistance potential of human gut microbes. Also watch the Video Abstract. PMID- 24474282 TI - Storage media for avulsed teeth: a literature review. AB - Dental avulsion is the most severe type of traumatic tooth injuries because it causes damage to several structures and results in the complete displacement of the tooth from its socket in the alveolar bone. The ideal situation is to replant an exarticulated tooth immediately after avulsion because the extraoral time is a determinant factor for treatment success and for a good prognosis. However, it is not always possible. The success of replantation depends on a number of factors that may contribute to accelerate or minimize the occurrence of root resorption or ankylosis, among which is the type and characteristics of the medium used for temporary storage during the time elapsed between avulsion and replantation. Maintaining the tooth in an adequate wet medium that can preserve, as longer as possible, the vitality of the periodontal ligament cells that remain on root surface is the key to success of replantation. Recent research has led to the development of storage media that produce conditions that closely resemble the original socket environment, with adequate osmolality (cell pressure), pH, nutritional metabolites and glucose, and thus create the best possible conditions for storage. Although these storage media can now be purchased in the form of retail products, the most common scenario is that such a product will not be readily available at the moment of the accident This paper reviews the literature on the different storage media that have been investigated for avulsed teeth based on full-length papers retrieved from PubMed/Medline, Lilacs, BBO and SciELO electronic databases using the key words 'storage medium', 'transportation medium', 'avulsion', 'tooth avulsion', 'replantation', 'tooth replantation', 'milk' and 'propolis'. After application of inclusion and exclusion criteria, 39 papers were selected and critically reviewed with respect to the characteristics, efficacy and ease of access of the storage medium. The review of the literature showed that a wide array of types of wet storage media have been evaluated in laboratory studies and clinical reports, including cell and tissue culture solutions like Hank's Balanced Salt Solution (HBSS); medical/hospital products developed specifically for organ storage purposes, such as Viaspan(r) and Euro Collins(r); culture media, like Minimum Essential Medium (MEM); saline; natural products like water, saliva, bovine milk and its variations, propolis, green tea, Morus rubra (red mulberry), egg white and coconut water; rehydrating solutions, like Gatorade(r) and Ricetral, and even contact lens solutions. Based on the literature, it could be stated that, so far, apart from Based on the literature, it could be stated that, so far, apart from solutions designed specifically for storage and culture purposes, regular pasteurized whole milk is the most frequently recommended and with the best prognosis among other solutions that are likely to be available at the scene of an accident, such as water, saline or saliva. Its advantages include its high availability, ready accessibility, physiologically compatible pH and osmolality (fluid pressure) with the root surface adhered PDL cells, presence of nutrients and growth factors. However, there is not yet a single solution that fulfills all requirements to be considered as the ideal medium for temporary storage of avulsed teeth, and research on this field should carry on. PMID- 24474283 TI - Do the clinical effects of enamel matrix derivatives in infrabony defects decrease overtime? A systematic review and meta-analysis. AB - Previous systematic reviews have demonstrated better results with enamel matrix derivative proteins (EMDP) as compared with open flap debridement (OFD) for the management of infrabony periodontal defects (IPD). The aim of this study was to determine whether these differences vary according to the follow-up and quality of the studies. Cochrane Central Register of Controlled Trials, Medline/PubMed, Lilacs, Embase and Web of Science electronic databases were searched up to August 2013 for randomized clinical trials.Eligible outcomes were changes in probing depth (PD), clinical attachment level (CAL),gingival recession (GR) and bone changes (BC). Studies with follow-up of 12 months showed differences of 0.97 mm (CI95% 0.52 - 1.43) and 1.19 mm (CI95% 0.77 - 1.60) for PD and CAL, respectively, favorable for EMDP. Studies with follow-up >= 24 months presented advantages of 1.11 mm (CI95% 0.74 -1.48) for CAL and 0.83 mm (CI95% 0.19 -1.48) for PD,with use of EMDP. Considering the quality of studies, those with low risk of bias showed lower difference between groups, presenting 0.8 mm (CI95% 0.24-1.36) for CAL, favorable for EMDP and without differences for PS (0.51 mm, CI95% -0.21 - 1.23). In conclusion, follow-up time (< or > 2 years) and the risk of bias influence the results of treatment with EMDP in IPD. PMID- 24474284 TI - Use of a new fibrin sealant and laser irradiation in the repair of skull defects in rats. AB - This study evaluated the osteogenic capacity of a new fibrin sealant (FS) combined with bone graft and laser irradiation in the bone repair. Defects were created in the skull of 30 rats and filled with autogenous graft and FS derived from snake venom. Immediately after implantation, low-power laser was applied on the surgical site. The animals were divided in: control group with autogenous graft (G1), autogenous graft and laser 5 J/cm2 (G2), autogenous graft and laser 7 J/cm2 (G3), autogenous graft and FS (G4), autogenous graft, FS and laser 5 J/cm2 (G5), autogenous graft, FS and laser 7 J/cm2 (G6). The animals were sacrificed 6 weeks after implant. Results showed absence of inflammatory infiltrate in the bone defect. New bone formation occurred in all groups, but it was most intense in G6. Thus, the FS and laser 7 J/cm2 showed osteoconductive capacity and can be an interesting resource to be applied in surgery of bone reconstruction. PMID- 24474285 TI - Evaluation of the cervical vertebrae maturation index in lateral cephalograms taken in different head positions. AB - The aim of this study was to evaluate if upward or downward head inclination might interfere with determination of the growth stage, using cervical vertebrae maturation index (CVMI), in order to verify the accuracy of such diagnosis when radiographs are taken with errors. Forty-nine patients, 26 females and 23 males, aged 9 to 15 years, were submitted to 3 lateral cephalograms: normal (NHP), with 15 degrees upward head inclination (NHP-Up), and with 15 degrees downward head inclination (NHP-Down). Three examiners evaluated the CVMI on the 147 cephalograms. The agreement among examiners was higher in the evaluation of cephalograms taken in NHP. The weighted Kappa test revealed moderate to substantial agreement between NHP and NHP-Up and between NHP and NHP-Down. There was greater agreement between NHP-Up and NHP-Down. It may be concluded that the evaluation of the CVMI on cephalograms in NHP is different as compared with radiographs taken with inclinations. Both NHP-Up and NHP-Down exhibited greater disagreement in the interpretation among examiners, since the evaluation method was not designed for cephalograms with positioning errors. PMID- 24474286 TI - Microbiological evaluation of different irrigation protocols on root canal disinfection in teeth with apical periodontitis: an in vivo study. AB - The present in vivo study was designed to evaluate the efficacy of apical negative pressure irrigation (ANP), passive ultrasonic irrigation (PUI) and positive pressure irrigation (PP) in the reduction of intracanal bacteria of dogs' teeth with pulp necrosis and apical periodontitis. Eighty root canals were randomly distributed into 3 experimental and 2 control groups according to the irrigation delivery system: group ANP (n=20), group PUI (n=20), group PP (n=20), group PC (positive control - sterile saline irrigation; n=10) and group NC (negative control - vital pulps not subjected to bacterial inoculation; n=10). The first sample (S1) was collected at baseline, and the second sample (S2) was collected after the disinfection protocols. All samples were seeded in culture media for anaerobic bacteria. CFU counts were analyzed statistically by the Kruskal-Wallis, Dwass-Steel-Critchlow-Fligner post-hoc and Chi-square followed by Tukey like multiple comparisons for proportions (alpha=0.05). All experimental groups were effective in reducing Gram-positive bacteria compared with PC (p<0.05). Regarding the reduction of Gram-negative bacteria, group ANP was significantly better than PP (p<0.05). No statistically significant difference could be found between PP and PUI (p>0.05). In dog's teeth with apical periodontitis, the use of ANP and PUI can be considered promising disinfection protocols as both delivery systems promoted a significant bacterial reduction. PMID- 24474287 TI - In vitro alkaline pH resistance of Enterococcus faecalis. AB - Enterococcus faecalis is a bacterial species often found in root canals with failed endodontic treatment. Alkaline pastes are widely used in Endodontics because of their biocompatibility and antimicrobial activity, but this microorganism can resist alkalinity. The purpose of this study was to evaluate in vitro the alkaline pH resistance of E. faecalis for different periods up to 14 days. Samples were obtained from the oral cavity of 150 patients from the Endodontic clinic. The pH of the experimental tubes (n=84) was first adjusted with 6M NaOH to pH values of 9.5, 10.5, 11.5 and 12.5 (21 tubes per pH). Twenty clinical isolates and the ATCC 29212 strain were tested. The 5 positive controls and experimental tubes of each pH were inoculated with 10 uL of bacterial suspension and incubated at 36 degrees C for 24, 48 and 72 h, 7 and 14 days. For each period, the turbidity of the medium was visually compared with a 0.5 McFarland standard. The presence of the microorganism was confirmed by seeding on M-Enterococcus agar. Four tubes containing BHI broth adjusted to the tested pHs were incubated for 14 days to verify if pH changes occurred. The pH of inoculated BHI broth was also measured on day 14 to determine if the microorganism acidified the medium. The growth of all E. faecalis strains occurred at pH 9.5 to 11.5 in all periods. Although turbidity was not observed at pH 12.5, there was growth of 13 and 2 strains at 24 and 48 h, respectively, on M-Enterococcus agar. No tube showed growth at pH 12.5 after 72 h. It was concluded that E. faecalis can survive in highly alkaline pH, and some clinical isolates require 72 h at pH 12.5 to be killed. PMID- 24474288 TI - Pulp tissue dissolution capacity of sodium hypochlorite combined with cetrimide and polypropylene glycol. AB - This study evaluated the influence of the addition of cetrimide and polypropylene glycol to sodium hypochlorite (NaOCl) on its capacity to dissolve pulp tissue. Bovine pulp fragments with standardized weight and volume were immersed for 5, 15 and 30 min in 2 mL of NaOCl and Hypoclean (NaOCl added with cetrimide and polypropylene glycol) solutions at 5.25%, 2.5%, 1%, 0.5% and 0.25% and afterwards re-weighted. Distilled water was used as a control. The percentage of tissue loss was considered for statistical analysis (univariate ANOVA, SPSS, v. 17.0) at 5% significance level. There was no tissue dissolution in the control group. NaOCl added with surfactants (Hypoclean) dissolved more pulp tissue (p<0.05) than NaOCl alone. Tissue dissolution was directly dependent on the concentration of solutions (p<0.05), and also on the time range (p<0.05). The combination of NaOCl at high and low concentrations with the surfactants cetrimide and polypropylene glycol increased significantly its capacity to dissolve pulp tissue. PMID- 24474289 TI - Influence of apical patency and cleaning of the apical foramen on periapical extrusion in retreatment. AB - This study evaluated the influence of apical patency, root filling removal technique and cleaning of the apical foramen, concerning the amount of debris extruded during root canal retreatment. Forty mandibular incisors were randomly assigned to 4 groups - GIM (n=10), GIIM (n=10), GIPT (n=10) and GIIPT (n=10), which were named according to leaving (I) or not (II) apical patency during canal preparation and filling removal technique (manual - M or ProTaper system - PT). After filling material removal, each specimen of each group had the apical foramen cleaned by sizes 15, 20 and 25 instruments, generating 12 subgroups: GIM15, GIM20, GIM25, GIIM15, GIIM20, GIIM25, GIPT15, GIPT20, GIPT25, GIIPT15, GIIPT20 and GIIPT25. Extruded filling debris was collected by a Milipore filtration system, an HV-durapore, 0.45 um pore filter with a 25 mm diameter. The filters were weighed before and after the collection on an analytical scale (10-5 g), and the difference was calculated. The mean weight of extruded filling debris was analyzed statistically by Kruskal-Wallis and Friedman ANOVA tests (alpha=0.05). The mean values found in the groups (in mg) were: GIM (0.95 +/- 0.94), GIIM (0.47 +/- 0.62), GIPT (0.30 +/- 0.31) and GIIPT (0.32 +/- 0.44). There was no statistically significant difference among any of the groups or subgroups (p>0.05). ProTaper provided the smallest amount of extruded filling material, regardless of presence or absence of apical patency, followed by manual technique, without and with apical patency. Additional amounts of debris were collected during cleaning of the apical foramen, regardless of the instrument, presence/absence of patency or root filling removal technique. PMID- 24474290 TI - Eradication of a mature methicillin-resistant Staphylococcus aureus (MRSA) biofilm from acrylic surfaces. AB - Methicillin-resistant Staphylococcus aureus (MRSA) can grow as structured biofilm in different surfaces, including oral mucosa and denture surfaces. Such biofilms can be released into the oral fluids and aspirated, causing systemic infections such as aspiration pneumonia. This study evaluated the efficacy of two disinfectant solutions and microwave irradiation in disinfecting acrylic specimens contaminated with MRSA biofilm. Thirty-six acrylic specimens were made, sterilized and contaminated with MRSA (107 cfu/mL). After incubation (37 degrees C/48 h), the specimens were divided into 4 groups: not disinfected (positive control); soaking in 1% sodium hypochlorite for 10 min; soaking in 2% chlorhexidine gluconate for 10 min; and irradiating by microwave for 3 min at 650 W. The viability of cells was evaluated by XTT reduction method. All specimens from the positive control group showed biofilm formation after 48 h incubation. The mean absorbance value of the control specimens was 1.58 (OD at 492 nm). No evidence of biofilm formation was observed on specimens after the disinfection methods. Disinfection by soaking in 1% sodium hypochlorite and 2% chlorhexidine gluconate and irradiating by microwaves resulted in 100% reduction of MRSA biofilm metabolism. The use of chemical solutions and microwave irradiation was shown to be effective for eradicating mature MRSA biofilms on acrylic resin specimens. PMID- 24474291 TI - Mechanical and biological properties of acrylic resins manipulated and polished by different methods. AB - This study evaluated the influence of the manipulation technique and polishing method on the flexural strength and cytotoxicity of acrylic resins. Two manipulation techniques and three polishing methods were used in the fabrication of acrylic plates that were divided into 6 groups (n=10). Groups MM, MC and MW: mass technique with mechanical polishing, chemical polishing and without polishing, respectively; and Groups SM, SC and SW: Saturation technique with mechanical polishing, chemical polishing and without polishing, respectively). Flexural strength was tested in a universal testing machine and the cytotoxicity assay used cell cultures (L-929) for periods of 24 h to 168 h. Flexural strength and cytotoxicity data were assessed using two-way and three-way ANOVA, respectively (alpha=0.05), followed by post hoc Bonferroni test for multiple comparisons. The effect of combinations of manipulation techniques and polishing methods on flexural strength showed significant differences only between Group SC and Groups MW, MM and MC (p<0.01). Cell viability ranged from 51% (3.9%) to 87,6% (3.2) in the 24-h time interval, and from 87.8% (5.0) to 95.7% (3.1%) in the 168 h time interval. With the increase of cell viability, from the third day (72 h), there was no significant difference among the groups, except between MM and SC (p<0.01) at 72 h. In conclusion, the manipulation technique and polishing method had more influence on the cytotoxicity than on flexural strength. PMID- 24474292 TI - Dimensional accuracy of stone casts made from silicone-based impression materials and three impression techniques. AB - The aim of this study was to measure and compare the dimensional accuracy of stone casts of a partially edentulous mandibular arch made by two condensation silicones, two addition silicones and three impression techniques (1-step putty/light-body, 2-step putty/light-body and monophase technique). A partially edentulous standard stainless steel mandibular arch cast was obtained with reference points on the permanent mandibular right and left canines, and permanent mandibular right and left second molars. The anteroposterior distances (between the mandibular left canine and second molar and between the mandibular right canine and second molar) and transverse distances (between the mandibular left and right canines and between the mandibular left and right second molars) of stainless steel cast were measured by a microscope at 30* magnification and 0.5 um accuracy. All impressions were made with condensation or addition silicones. The 1- and 2-step putty/light-body impressions were accomplished with putty and light-body materials and the monophase impressions with light-body material only. After the impression procedures, accuracy of each material and technique was assessed measuring the stone casts poured (n=5) from the impressions, by the same microscope. The differences between the values of stone cast and stainless steel cast were calculated, presented as percentages and analyzed statistically by two-way ANOVA and the means compared by Tukey's test (alpha=0.05). All distances measured on stone casts showed altered dimensions with significantly negative linear changes (shrinkage) as compared to those of the stainless steel cast. The stone casts made from the addition silicones were dimensionally more accurate. No differences were found among the impression techniques. PMID- 24474293 TI - Effect of growth hormone in experimental tooth movement. AB - The aim of this study was to evaluate, by histological analysis, the effect of growth hormone (GH) on periodontal ligament and alveolar bone during experimental tooth movement in rats. Eighty male Wistar rats divided into control (C) and experimental (E) groups were examined after 3, 7, 14 and 21 days under controlled climate conditions. Orthodontic force (30 cN) was applied on the maxillary first molar by an orthodontic appliance. Group E received 0.1 IU/kg/day of GH and Group C received 0.5 mL/kg/day of saline. The samples were processed and evaluated under optical microscopy and polarized light microscopy. The Kruskal Wallis test was applied to compare the intergroup variables at 5% significance level. Group E presented a larger number of osteoclasts on the 3rd and 7th days and Howship lacunae on the 3 rd day, a smaller number of blood vessels and greater amount of mature collagen on the 3 rd and 7 th days than Group C (p<0.05). It was concluded that GH accelerated and intensified bone resorption and produced delay in immature collagen formation during experimental tooth movement. PMID- 24474294 TI - Microhardness of enamel adjacent to orthodontic brackets after CO2 laser irradiation and fluoride application. AB - This study evaluated the effectiveness of carbon dioxide (CO2) laser combined or not with fluoride application on the surface microhardness of enamel adjacent to orthodontic brackets. Fifteen human molars were selected from which 30 enamel fragments measuring 4 mm2 were obtained. The fragments were embedded in PCV tubes with acrylic resin and prepared using water abrasive paper, felt disks and alumina. Orthodontic brackets cut in half were bonded to enamel and 3 microhardness readings were performed on the adjacent surface, as follows: initial, after cariogenic challenge and final. The specimens were divided into the following 3 groups (n=10): Group C: control, Group L: irradiated with CO2 laser, and Group FL: topical fluoride application and CO2 laser irradiation. After initial reading, the specimens were placed in a demineralizing solution for 32 h and the second reading was to verify if demineralization was uniform in all groups. After the treatments, the specimens were submitted to DES-RE cycling for 8 days followed by final surface microhardness reading. The data were analyzed statistically using ANOVA and Duncan test (alpha=0.05). At the final measurement Group FL obtained higher microhardness value than Groups C and L (p<0.05). Groups L and FL were statistically superior to Group C (p<0.05). Irradiation with CO2 laser around orthodontic brackets combined or not with topical fluoride application was effective to increase the surface microhardness of enamel. PMID- 24474295 TI - Effect of activation mode on shear bond strength of metallic brackets. AB - The aim of this study was to evaluate the shear bond strength (SBS) of metallic orthodontic brackets bonded to bovine teeth using light-activated or chemically activated composite resins. One hundred and twenty bovine mandibular incisors were divided into 6 groups (n=20), according to the bonding materials: Transbond XT (T); Enforce Dual (ED); Enforce chemical (EC); Enforce Light-activated (EL); Concise Orthodontic (C); and RelyX Unicem Capsule (UN). Metallic brackets were positioned and firmly bonded to the teeth. Light-activation for T, ED, EL and UN was carried out with four exposures on each side of the bracket with 20 s total exposure times using XL2500 (3M ESPE). EC and C were chemically cured. Next, all specimens were stored in deionized water at 37 degrees C for 24 h. The shear bond strength was carried out at a crosshead speed of 1.0 mm/min. Data were subjected to one-way ANOVA and Tukey's test (alpha=0.05). The adhesive remnant index (ARI) was evaluated at 8* magnification. C (17.72 +/- 4.45) presented significantly higher SBS means (in MPa) than the other groups (p<0.05), followed by EC (11.97 +/- 5.77) and ED (10.57 +/- 1.32). EL (5.39 +/- 1.06) and UN (4.32 +/- 1.98) showed the lowest SBS means, while T (9.09 +/- 2.56) showed intermediate values. For ARI, there was a predominance of score 0 for EC, C and UN, and score 3 for T, ED and EL. In conclusion, the activation mode influenced the SBS. PMID- 24474296 TI - Mineral loss and morphological changes in dental enamel induced by a 16% carbamide peroxide bleaching gel. AB - The aim of this study was to compare the effect of a 16% carbamide peroxide (CP) gel and a 10% CP gel on mineralized enamel content and morphology. Enamel blocks from bovine incisors were subjected to a 14-day treatment (8 h/day) with 10% or 16% CP gels. Knoop microhardness was evaluated before bleaching and at 1, 7 or 14 days after this treatment (50 g/15 s). Mineral content (energy-dispersive x-ray spectroscopy), surface roughness and topography (atomic force microscopy) were evaluated at the 14-day period. Data were analyzed statistically by two-way ANOVA and Tukey's test (alpha=0.05). Significant microhardness reduction was observed at the 7 th and 14 th days for 10% CP gel, and for all bleaching times for 16% CP gel (p<0.05). At the 14-day period, a significant decrease in Ca and P content, increase on surface roughness (p<0.05) as well as on picks and valleys distance were observed when both bleaching gels were used. These enamel alterations were more intense for 16% CP gel. It was concluded that both CP-based gels promoted loss of mineral structure from enamel, resulting in a rough and porous surface. However, 16% CP gel caused the most intense adverse effects on enamel. PMID- 24474297 TI - Influence of different mechanisms of fluoride release from adhesive systems. AB - The objective of this study was to evaluate in vitro the time-dependent fluoride (F) release from three adhesive systems: Clearfil Protect Bond (CPB - Kuraray), FL Bond II (FLB- Shofu) and Adper Single Bond 2 (SB2 - 3M ESPE) (negative control). CPB and FLB are fluoride containing adhesives that use different F releasing mechanisms. The tested hypothesis was that the F releasing mechanism influences the amount of released F in water. Disc-shaped specimens (5 mm * 3 mm) were fabricated using a plastic matrix (Demetron Research Corp). Three specimens were produced for each material and each period of evaluation (1, 7, 14, 21 and 28 days) (n=3). Subsequently, the specimens were stored in 10 mL distilled water at 37 degrees C until the analyses were done using a liquid membrane for selective F ion electrode (Orion 710). Four readings were performed on the first day and the remaining evaluation times had one reading/day. Results were statistically analyzed by two-way ANOVA and Tukey's test (alpha=0.05). CPB released the greatest amount of fluoride in all evaluated periods with the greatest value at 6th h (0.183 ppm) thereafter decreasing gradually up to the 7th day when it significantly increased again until the 21st day. In most measurements, FLB showed similar mean fluoride release values as SB2. Therefore, the fluoride release mechanism influenced the amount of fluoride released in water, confirming the study hypothesis. PMID- 24474298 TI - Preferences on vital and nonvital tooth bleaching: a survey among dentists from a city of southern Brazil. AB - This study evaluated the preferences of general dentists regarding vital and nonvital tooth bleaching therapies and investigated whether the time of clinical practice and post-graduate training influence these options. A cross-sectional study was conducted using a questionnaire with closed questions applied to dentists (n=276) of a mid-sized city of the southern Brazil (Pelotas, RS). Information was collected regarding sociodemographic variables, level of specialization and time since graduation. In addition, options regarding bleaching therapies including the first choice of material, technique and clinical practice for vital and nonvital tooth bleaching therapies were included. Data were submitted to descriptive analysis and the associations were evaluated using chi-square and Fisher exact tests (alpha=0.05). The response rate was 68% (n=187). At-home bleaching therapy was broadly preferred (78.1%) over in-office (21.9%) bleaching. For at-home bleaching, most dentists answered to use 10% carbamide peroxide (CP) (40.2%) and >30% hydrogen peroxide (HP) (31.7%) for nonvital therapies. The majority of dentists with post-graduation training preferred at-home bleaching techniques (p=0.003). At-home bleaching therapy was also more indicated by younger dentists. No association was found between the choice for nonvital bleaching therapies and time since graduation (p=0.532) or continuous education (p=0.083). In conclusion, at-home bleaching was preferred over in-office therapies; 10% CP and >30% HP were chosen as first option agents to treat discolored vital and nonvital teeth, respectively. The time in clinical practice and the level of specialization affected dentists' choices only for vital tooth bleaching treatment. PMID- 24474299 TI - Retained third molars removal in a severely resorbed edentulous mandible. A case report. AB - The presence of asymptomatic third molars can represent a potential problem in the mandible when these teeth are retained and the patient has lost all normally erupted teeth. Once the mandibular first and second molars are removed, the mandibular body becomes weaker with time, increasing the complexity, morbidity and incidence of complication in the surgical procedure to remove the retained third molar. This paper reports a case where the mandibular third molars retained in a severely resorbed mandible were removed in a 54-year-old female patient. The treatment plan was based on the safe surgical removal of the teeth and prosthetic rehabilitation with an implant-supported milled bar overdenture and a bone-mucous supported complete denture in the mandibular and maxillary arch, respectively. If the removal of a retained third molar is indicated in a severely resorbed edentulous mandible, the treatment plan must involve not only preventive measures in order to avoid mandible fracture during or after tooth removal, but also alternatives that allow an adequate mandibular rehabilitation. PMID- 24474300 TI - Mucocele and fibroma: treatment and clinical features for differential diagnosis. AB - Mucocele is a benign lesion occurring in the buccal mucosa as a result of the rupture of a salivary gland duct and consequent outpouring of mucin into soft tissue. It is usually caused by a local trauma, although in many cases the etiology is uncertain. Mucocele is more commonly found in children and young adults, and the most frequent site is the lower inner portion of the lips. Fibroma, on the other hand, is a benign tumor of fibrous connective tissue that can be considered a reactionary connective tissue hyperplasia in response to trauma and irritation. They usually present hard consistency, are nodular and asymptomatic, with a similar color to the mucosa, sessile base, smooth surface, located in the buccal mucosa along the line of occlusion, tongue and lip mucosa. Conventional treatment for both lesions is conservative surgical excision. Recurrence rate is low for fibroma and high for oral mucoceles. This report presents a series of cases of mucocele and fibroma treated by surgical excision or enucleation and the respective follow-up routine in the dental clinic and discusses the features to be considered in order to distinguish these lesions from each other. PMID- 24474301 TI - Clinical and histological features of multifocal canalicular adenomas of the upper lip. AB - Canalicular adenoma (CA) is an uncommon benign salivary gland tumor that mostly occurs in the upper lip. Despite its benign nature, some patients may present multiple nodules and also microscopic growth that can be multifocal with foci of tumor within the adjacent gland. Microscopically, CA can be mistaken for a polymorphous low-grade adenocarcinoma (PLGA) or basal cell adenoma (BCA), and immunohistochemistry can be helpful in differentiating them. Two cases of canalicular adenoma showing tumor foci within the adjacent gland are described. Both cases occurred in the upper lip of white females aged 72 and 79 years. In addition to the histological multifocal aspect, one of the patients presented bi lateral nodules. Histological examination of both lesions revealed interconnecting and branching canal-like structures composed by uniform columnar and sometimes cuboidal cells, partially encapsulated. Immunohistochemical analysis showed intense expression of cytokeratins (CK) 7, a weak reaction to CK14 and a negative reaction to vimentin. Upon the diagnosis of CA the lesions were excised. In conclusion, it is important to properly diagnose CA and differentiate its multifocal aspect from a malignant behavior. PMID- 24474302 TI - The effect of rifampicin, a prototypical CYP3A4 inducer, on erlotinib pharmacokinetics in healthy subjects. AB - PURPOSE: Erlotinib, N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy) quinazolin-4 amine is approved for the treatment for non-small cell lung cancer and pancreatic cancer. Because erlotinib is metabolized predominately by CYP3A4, co administration of compounds that increase CYP3A4 activity may alter the efficacy and safety of erlotinib therapy. Two phase I studies were conducted in healthy male subjects to evaluate the effect of pre- or co-administered rifampicin, a CYP3A4 inducer, on the pharmacokinetics of erlotinib. METHODS: Study 1 included Groups A (erlotinib 150 mg days 1 and 15, rifampicin 600 mg days 8-14) and B (erlotinib 150 mg days 1 and 15) in a parallel group study design. Study 2 subjects received erlotinib 150 mg day 1, erlotinib 450 mg day 15, and rifampicin 600 mg days 8-18. The primary endpoint in each study was the ratio of exposure (AUC0-infinity and C max) between days 1 and 15. Urinary cortisol metabolic induction ratios were determined in Study 1 for Group A subjects only. RESULTS: In Study 1, the geometric mean ratios of AUC0-infinity and C max were 33 and 71 %, respectively, and the mean cortisol metabolic index increased from 7.4 to 27.0, suggesting cytochrome P450 (CYP) enzyme induction. In Study 2, the geometric mean ratios for AUC0-infinity and C max were 19 and 34 % (when dose adjusted from 450 to 150 mg erlotinib), respectively, a greater relative decrease than observed in Study 1. CONCLUSIONS: Erlotinib exposure (AUC0-infinity and C max) was reduced after pre- or concomitant dosing with rifampicin. Doses of >=450 mg erlotinib may be necessary to compensate for concomitant medications with strong CYP3A4 enzyme induction effect. PMID- 24474303 TI - London hospital widens access to genetic tests for ovarian cancer. PMID- 24474304 TI - The role of daily hassles and distress tolerance in predicting cigarette craving during a quit attempt. AB - INTRODUCTION: Ecological momentary assessment (EMA) has shown that smoking behavior is linked to transient variables in the smoker's immediate context. Such research suggests that daily hassles (e.g., losing one's keys) may be more likely to lead to cigarette craving and eventual lapse than infrequent, large-scale stressors (e.g., death of a loved one) among individuals attempting to quit smoking. However, individual differences in distress tolerance (DT) may moderate the relationship between daily hassles and daily cigarette craving during a quit attempt. METHODS: A sample of 56 veterans and community members drawn from a larger smoking-cessation study completed structured interviews and paper-and pencil questionnaires during an initial laboratory visit and, directly following a quit attempt, were monitored via EMA. Multilevel modeling was used to examine the relationship between daily hassles and daily cigarette craving and to determine whether DT moderated this relationship. RESULTS: Daily hassles were positively associated with daily cigarette craving, and this association was moderated by individual differences in DT, such that the lower one's DT, the stronger the relationship between daily hassles and daily cigarette craving. This model explained 13% of the intraindividual variability and 8% of the interindividual variability in daily cigarette craving. CONCLUSIONS: Smoking cessation interventions may be strengthened by targeting smokers' individual responses to contextual factors, such as by helping smokers develop skills to cope more effectively with distress prior to and during the quit phase. PMID- 24474305 TI - Provider-delivered tobacco dependence treatment to Medicaid smokers. AB - INTRODUCTION: Smoking prevalence is 49% among Medicaid enrollees in Ohio. The objective of this pilot project was to test a comprehensive tobacco dependence treatment program targeting rural Medicaid-enrolled smokers for both physician level and smoker-level outcomes. METHODS: Using a group-randomized trial design, intervention group physicians (n = 4) were exposed to systems-level changes in their clinics, and smokers in these clinics were offered 12 weeks of telephone cessation counseling. Control group physicians (n = 4) were given the clinician's version of the U.S. Public Health Serivce (USPHS) Clinical Practice Guideline, and smokers in these clinics were given information about the Ohio Tobacco Quitline. Physician-level and smoker-level outcomes were assessed at 1 week and 3 months, respectively. Costs per quit were estimated. RESULTS: A total of 214 Medicaid smokers were enrolled. At 1 week, there were no reported differences in rates of being asked about tobacco use (68% intervention, 58% control) or advised to quit (69% intervention, 63% control). However, 30% of intervention and 56% of control smokers reported receiving a prescription for pharmacotherapy (p < .01). At 3 months, there were no differences in quit attempts (58% intervention, 64% control), use of pharmacotherapy (34% intervention, 46% control), or abstinence (24% intervention, 16% control for self-reported abstinence; 11% intervention, 3.5% control for cotinine-confirmed abstinence). The intervention group proved more cost-effective at achieving confirmed quits ($6,800 vs. $9,700). CONCLUSIONS: We found few differences in outcomes between physicians exposed to a brief intervention and physicians who were intensively trained. Future studies should examine how tobacco dependence treatment can be further expanded in Medicaid programs. PMID- 24474306 TI - Antibiotic judo: working gently with prescriber psychology to overcome inappropriate use. PMID- 24474307 TI - [Free sugars, cyclitols and organic acids in the cambial sap of Pinus sylvestris L., Picea Abies Karst. and Abies alba Mill]. AB - Samples of cambial sap from each of the three coniferous species Pinus sylvestris L., Picea Abies Karst. and Abies alba Mill. were taken at the time the trees were coming into bud and analysed for low molecular weight carbohydrates, cyclitols and organic acids. They all contained the same free sugars and cyclitols, but in markedly different proportions. Quantitative analyses were carried out for glucose, fructose, sucrose, raffinose, myo-inositol, D-inositol, pinitol, sequoyitol and coniferin.The three main components of the organic acid fractions quinic acid, shikimic acid and malic acid-were determined quantitatively. The amount of quinic acid greatly exceeded the amount of all the other acids in all three species. (14)C-labelled quinic acid applied to the cut ends of Pinus sylvestris needles was transported to the twig. There was no conversion of quinic acid to shikimic acid over short periods of time. PMID- 24474308 TI - [Studies on the change of microbody function in cotyledons of Helianthus annuus L]. AB - The enzyme patterns in sunflower cotyledons indicate that the glyoxysomal function of microbodies is replaced by the peroxisomal function of these organelles during the transition from fat degradation to photosynthesis. The separation of the microbody population into glyoxysomes and peroxisomes during this transition period is reported. The mean difference in density between the activity peaks of glyoxysomal and peroxisomal marker enzymes on a sucrose gradient was calculated to be 0.007+/-0.004 g/cm(3) and turned out to be significant (t=7.8>4.04=t 5;0.01). The activity peak of catalase coincides with that of isocitrate lyase in early stages of development, but shifts to the activity peak of peroxisomal marker enzymes during the transition period. No isozymes of the catalase could be detected by gel electrophoresis in the microbodies with the two different functions.During the rise of the peroxisomal marker enzymes no synthesis of the common microbody marker, catalase, could be demonstrated using the inhibitor allylisopropylacetamide. Using D2) for density labeling of newly-formed catalase, no difference is observed between the density of catalase from cotyledons grown on 99.8% D2O during the transition period and the density of enzyme from cotyledons grown on H2O. The activity of particulate glycolate oxidase is reduced 30-50% by allylisopropylacetamide, but is not affected by D2O. The chlorophyll formation in the cotyledons is strongly inhibited by both substances. PMID- 24474309 TI - Stomatal responses to changes in temperature at increasing water stress. AB - The response of stomata to a gradual increase in temperature at increasing plant water stress was studied in a hot desert habitat (Negev, Israel) in the field, but under controlled temperature and humidity conditions. Four native species (Zygophyllum dumosum, Artemisia herba-alba, Hammada scoparia, Reaumuria negevensis) and one cultivated plant (Prunus armeniaca) were used in these studies. The stomatal response to temperature was compared with the response in well-irrigated plants of the same species.At low water stress, the diffusion resistance for water vapour decreased in response to a gradual increase in temperature. Transpiration increased accordingly. This response was reversible. All species responded in the same way. The opening of stomata with increasing temperature was apparently independent of the stomatal response regulated by atmospheric humidity. At high plant water stress, the stomatal response was reversed, i.e., the stomata closed when temperature was gradually increased. This stomatal closure was also independent of the closure regulated by atmospheric humidity. The plant water potential at which the stomatal response to temperature was reversed, differed among the species investigated. PMID- 24474310 TI - Indoleacetic-acid-enhanced chloride uptake into coleoptile cells. AB - The enhancement by indoleacetic acid (IAA) of (36)Cl(-) uptake into Avena coleoptile sections was used to study the effects of a hormone on a membrane controlled phenomenon. Compared to sections in phosphate buffer only, Cl(-) content of the cells increases 15 min after addition of IAA; the promotion is seen only with growth-active auxins and is saturated at 3 MUM IAA. The percent enhancement by IAA is the same over a wide range of Cl(-) concentrations. The hormone effect is not observed at ice-bath temperature and is not correlated with growth or water movement into the cells. IAA does not influence the movement of Cl(-) in the section. While auxin must be present within the tissue in order to maintain the enhancement, there is no relationship between the total amount of auxin and the accelerated Cl(-) uptake that results. A polarity in the auxin effect is implied since only apical applications of IAA promote Cl(-) uptake. PMID- 24474311 TI - The formation of tryptophol glucoside in the tryptamine metabolism of pea seedlings. AB - Tryptamine was converted by etiolated pea seedlings into IAA, tryptophol, and an appreciable amount of an unknown metabolite. This latter compound was characterised by TLC and electrophoresis and identified, by mass spectrometry and enzymatic cleavage, as tryptophol glycoside: indole-3-ethyl-beta-D glycopyranoside. PMID- 24474312 TI - Accumulation of malate in guard cells of Vicia faba during stomatal opening. AB - The level of malate in the epidermis from illuminated leaves of Vicia faba was greater than in that from dark-treated leaves. A difference in the malate level was still detected after the epidermis had been treated by rolling so that only the guard cells remained alive. The results suggest that malate may accumulate in guard cells on illumination. In subsequent experiments, stomatal apertures were measured, and potassium as well as malate was analysed in extracts of epidermis. In illuminated leaves, the potassium content of rolled epidermis increased from about 90 to about 335 picoequivalents mm(-2) of epidermis whele malate increased from about zero to about 71 pmoles mm(-2) and the stomata opened; in dark-treated leaves, the potassium content of rolled epidermis decreased slightly, the malate level remained about zero, and the stomata showed very slight further closure. The measured increase in potassium is likely to represent an increase in potassium concentration in the guard cells of about 0.4 Eq l(-1) with stomatal opening; the increase in malate could correspond to 0.23 Eq l(-1) (with respect to potassium) in the guard cells. Thus, malate accumulating in guard cells could balance about half of the potassium taken up by guard cells when stomata open in the light. PMID- 24474313 TI - Constancy of wheat histones during development. AB - Histones were extracted from leaves of winter- and spring-wheat seedlings, flowering shoots of spring wheat, shoots of vernalized and control winter wheat, and roots and shoots of winter wheat, and were compared by polyacrylamide-gel electrophoresis. No differences were found either in the electrophoretic mobility or relative quantity of the various fractions. Wheat histones contained fractions of the exact electrophoretic mobility as F2a1 and F3 of calf thymus and pea histones. Other major fractions of the wheat histones had electrophoretic mobilities similar to those of F1, F2b and F2a2 of peas. PMID- 24474314 TI - Scanning electron microscopy of starch grains from latex of Euphorbia terracina and E. tirucalli. AB - The morphology of starch grains isolated from the latex of 2 species of Euphorbia was compared by scanning electron microscopy. In E. terracina they are elongated and greater, in diameter at the midregion than at the tips while in E. tirucalli they are osteoid. Starch grains varied in size in both, species although in E. tirucalli the largest grains, which measured 49 MU, were approximately twice the length of those in E. terracina (27 MU). PMID- 24474315 TI - Effect of heat stress on subsequent chlorophyll accumulation in seedlings of Colocynthis citrullus. AB - When 14-day-old, etiolated seedlings of Colocynthis citrullus were subjected to temperatures of 35, 40 or 45 degrees C for 4-24 h in darkness and illuminated immediately after this heat stress, the rate of total chlorophyll accumulation was retarded, and the duration of the initial lag period before onset of appreciable chlorophyll accumulation was prolonged. These effects were more pronounced after the higher temperatures, and with increasing duration of stress. Chlorophyll a and chlorophyll b were similarly affected as total chlorophyll. PMID- 24474316 TI - [Cyclic adenosine-3':5'-monophosphate in translocation tissues of plants?]. AB - Sieve tube sap of the secondary phloem of Robinia pesudoacacia L. and exudate from the trumpet hyphae of the cauloids of Laminaria saccharina (L.) Lamour. were analyzed for the occurrence of cyclic adenosine-3':5'-monophosphate with the help of the radio isotope dilution test (Boehringer, Mannheim). The concentration was about 0,1 MUM in the Laminaria exudate and 9,0 nM in the Robinia sap. Pretreatment of the saps with phosphodiesterase removes the activity of the A-3:5 MP. It therefore seems probable that A-3:5-MP occurs in the translocation tissues of plants. PMID- 24474317 TI - Morphactins enhance ethylene-induced leaf abscission. AB - Morphactins were found to resemble other auxin-transport inhibitors in their ability to stimulate leaf abscission in cotton in response to ethylene or Ethephon (2-chloroethylphosphonic acid). PMID- 24474321 TI - Indirect decompression of lumbar stenosis with transpsoas interbody cages and percutaneous posterior instrumentation. AB - BACKGROUND: The minimally invasive lateral transpsoas retroperitoneal approach to address lumbar stenosis offers advantages to traditional approaches, including sparing of the AP annulus and longitudinal ligament and less risk to the peritoneal contents and retroperitoneal vascular structures. Few studies have presented longitudinal measures of radiographic indirect decompression and relief of pain and restoration of function using the lateral approach to spine fusion. QUESTION/PURPOSES: We determined (1) whether radiographic measures suggestive of decompression were achieved after surgery and maintained 1 year after surgery, (2) whether the intervention resulted in sustained improvements in patient reported outcomes scores 1 year after surgery, and (3) the frequency of pseudarthrosis on CT scans at 1 year after surgery in patients with moderate or severe lumbar stenosis treated with the approach. METHODS: Between 2008 and 2012, 158 patients were surgically treated to alleviate symptoms associated with degenerative lumbar stenosis, of whom 60 (38%) were treated with lateral lumbar interbody fusion. Of these 60 patients, 36 (60%) received CT scans preoperatively and at 1-year postoperatively and were available for radiographic analysis. Of the 60 treated patients, 16 (27%) were lost to followup before 12 months, leaving the records of 44 patients available for review of patient-reported improvements in pain and return to function. Radiographic increases in disc height, foraminal area, and canal area were measured by one observer on CT scans postoperatively and at 1 year and compared to preoperative values. Patient-reported scores, including VAS pain score and Oswestry Disability Index (ODI), were collected preoperatively and at 3 and 12 months postoperatively. RESULTS: Increases in disc height (67%, p < 0.001), foraminal area (24%-31%, p < 0.001), and canal area (7%, p = 0.011) measured immediately postoperatively were sustained at 1-year followup. VAS pain score and ODI both improved (p < 0.001) at 3 months and were maintained at 1 year. No pseudarthroses were noted radiographically. CONCLUSIONS: The lateral transpsoas approach to interbody fusion is capable of sustaining indirect decompression of the neural structures and resolving preoperative claudication and radiculopathy. A larger series of patients with longer followup should be studied to substantiate these early clinical results. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24474322 TI - Terrible triad injuries of the elbow: does the coronoid always need to be fixed? AB - BACKGROUND: The "terrible triad" of the elbow is a complex injury that can lead to pain, stiffness, and posttraumatic arthritis if not appropriately treated. The primary goal of surgery for these injuries is to restore stability of the joint sufficient to permit early motion. Although most reports recommend repair and/or replacement of all coronoid and radial head fractures when possible, a recent cadaveric study demonstrated that type II coronoid fractures are stable unless the radial head is removed and not replaced. QUESTIONS/PURPOSES: The purposes of this study were to determine the (1) range of motion; (2) clinical scores using the Disabilities of the Arm, Shoulder and Hand (DASH) and the Broberg-Morrey questionnaires; and (3) rate of arthritic changes, heterotopic ossification (HO), or elbow instability postoperatively in patients whose terrible triad injuries of the elbow included Reagan-Morrey type I or II coronoid fractures that were treated without fixation. METHODS: Between April 2008 and December 2010, 14 consecutive patients were treated for acute terrible triad injuries that included two Regan-Morrey type I and 12 Regan-Morrey type II coronoid fractures. Based on the senior author's (DGS) clinical experience that coronoid fractures classified as such do not require fixation to restore intraoperative stability to the posterolaterally dislocated elbow, all injuries were treated by the senior author with a surgical protocol that included radial head repair or prosthetic replacement and repair of the lateral ulnar collateral ligament (LUCL) followed by intraoperative fluoroscopic examination through a range of 20 degrees to 130 degrees of elbow flexion to confirm concentric reduction of the ulnohumeral joint. Using this protocol, intraoperative stability was confirmed in all cases without any attempt at coronoid or anterior capsular repair. Repair of the medial collateral ligament or application of external fixation was not performed in any case. All patients were available for followup at a minimum of 24 months (mean, 41 months; range, 24-56 months). The mean patient age was 52 years (range, 32-58 years). At the followup all patients were evaluated clinically and radiographically by the senior author. Outcome measures included elbow range of motion, forearm rotation, elbow stability, and radiographic evidence of HO or arthritic changes using the Broberg and Morrey scale. Elbow instability was defined as clinical or radiographic evidence of recurrent ulnohumeral dislocation or subluxation at final followup. Clinical outcomes were assessed with the patient-reported DASH questionnaire and the physician-administered Broberg-Morrey elbow rating system. RESULTS: The mean arc of ulnohumeral motion at final followup was 123 degrees (range, 75 degrees -140 degrees ) and mean forearm rotation was 145 degrees (range, 70 degrees -170 degrees ). The mean Broberg and Morrey score was 90 of 100 (range, 70-100, higher scores reflecting better results) and the average DASH score was 14 of 100 (range, 0-38, higher scores reflecting poorer results). Radiographs revealed mild arthritic changes in one patient. One patient developed radiographically apparent but asymptomatic HO. None of the patients demonstrated instability postoperatively. CONCLUSIONS: These findings demonstrate that terrible triad injuries with type I and II coronoid process fractures can be effectively treated without fixation of coronoid fractures when repair or replacement of the radial head fracture and reconstruction of the LUCL complex sufficiently restores intraoperative stability of the elbow through a functional range of motion. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Guidelines to Authors for a complete description of levels of evidence. PMID- 24474323 TI - Minimally invasive surgical approaches in the management of tuberculosis of the thoracic and lumbar spine. AB - BACKGROUND: Spinal tuberculosis is the most common form of skeletal tuberculosis. Various approaches have been described for surgical management of spinal tuberculosis, but many entail wide exposures with attendant morbidity; whether minimally invasive surgical (MIS) approaches are suitable is unknown. QUESTIONS/PURPOSES: We evaluated (1) neurologic results, (2) radiographic results, and (3) complications in patients with thoracic and lumbar spinal tuberculosis treated with two MIS approaches. METHODS: We retrospectively evaluated 22 patients with thoracic and lumbar tuberculosis managed surgically from October 2008 to February 2011 using MIS methods; one patient was lost to followup, leaving 21 patients with a minimum followup of 15 months (mean, 30 months; range, 15-59 months) for analysis. MIS approaches were used for patients with disease below D6 and minimum pedicle diameters of 4.5 mm to permit percutaneous screw placement. The MIS approach was divided into two groups depending on the extent of destruction of the vertebral body: a posterior-only group (n = 9), where posterior transpedicular decompression sufficed, and the hybrid group (n = 12), requiring anterior debridement and ventral-column reconstruction by conventional or mini-open thoracotomy. All but two patients with more than two contiguous bodies involvement underwent MIS posterior fixation by percutaneous transpedicular screws. Plain radiographs were evaluated for deformity correction and correction maintenance. Neurologic recovery and complications were ascertained by chart review. RESULTS: All patients with neurologic deficits recovered completely with no motor deficits at followup; 13% improved by three grades, 53% by two grades, and 33% by one grade. Mean correction was 2.5 degrees (thoracic) and 8 degrees (lumbar) in the posterior only group and 4.2 degrees in the hybrid group. Some correction loss occurred with healing (2 degrees and 1.6 degrees in the posterior-only and hybrid groups, respectively), but in none of those who had fixation did this progress to more than preoperative status. Two of 22 patients (9%) had complications. One had a malposition of L5 screw causing painful radiculopathy without motor deficit and required repositioning. The other had an intraoperative dural tear repaired by onlay fascial patch and cerebrospinal fluid diversion. There were no approach related complications, neurologic deterioration, or implant fatigue at last followup. CONCLUSIONS: We found evidence of neurologic recovery, avoidance of deformity progression, and few complications with these MIS approaches. Comparative trials are called for between open and MIS approaches for patients with spinal tuberculosis. LEVEL OF EVIDENCE: Level IV, therapeutic study. See Instructions for Authors for a complete description of levels of evidence. PMID- 24474324 TI - Single-staged treatment using a standardized protocol results in functional motion in the majority of patients with a terrible triad elbow injury. AB - BACKGROUND: Terrible triad injuries of the elbow, defined as elbow dislocation with associated fractures to the radial head and coronoid, are associated with stiffness, pain, and loss of motion. Studies to date have consisted of small sample sizes and used heterogeneous surgical techniques, which render comparisons difficult and unreliable. QUESTIONS/PURPOSES: In a group of patients treated under a standard surgical protocol, we sought to determine the early dislocation rate, the range of motion in those not undergoing secondary procedures, the frequency and types of secondary surgical interventions required, the difference in motion between those undergoing secondary surgery and those who did not, and the frequency of heterotopic ossification and patient-reported stiffness. METHODS: Patients underwent a surgical protocol that involved fixing the coronoid, fixing the radial head if possible, otherwise performing radial head arthroplasty, and repairing the lateral ligamentous structures. Patients were excluded if ipsilateral upper extremity fractures from the humerus to the distal forearm were present. Fifty-two patients had a minimum followup of 6 weeks and were included for the early dislocation rate, and 34 of these (65%) had a minimum of 6 months followup and were included for the rest of the data. Eighteen of the 52 (35%) were considered lost to followup because they were seen for less than 6 months postsurgically and were excluded from further analysis. Chart review was performed to determine the presence of early dislocation within the first 6 weeks after surgery, range of motion in patients not requiring a secondary procedure, the frequency and types of secondary procedures required, the range of motion before and after a secondary procedure if it was required, and postoperative stiffness. Postoperative radiographs were analyzed to determine the presence and severity of heterotopic ossification. RESULTS: One of 52 patients sustained a dislocation within the first weeks of surgery (1.9%). Those not undergoing a secondary procedure were able to achieve a flexion arc of 110 degrees and a supination-pronation arc of 148 degrees . Nine of 34 patients (26%) underwent a secondary surgical procedure with stiffness, heterotopic ossification, and ulnar neuropathy being the most common surgical indications. Before secondary surgical procedures, patients had a flexion arc of 57 degrees and a supination-pronation arc of 55 degrees , which was less than those only requiring primary surgery alone (p < 0.001). After secondary surgery, patients were able to achieve a flexion arc of 96 degrees and a supination-pronation arc of 124 degrees , which was not different from those who did not undergo reoperation (p = 0.09 and p = 0.08, respectively). Twenty-eight of 34 patients demonstrated evidence of heterotopic ossification on radiographs, whereas 20 patients, including all nine undergoing secondary procedures, reported stiffness at the elbow. CONCLUSIONS: Using a standardized surgical protocol, a low early dislocation rate was observed, although stiffness remains a challenge. Many patients who initially do not attain functional range of motion can usually attain this after secondary procedures aimed at removing the heterotopic ossification. LEVEL OF EVIDENCE: Level IV, therapeutic study. See guidelines for authors for a complete description of levels of evidence. PMID- 24474325 TI - A large humeral avulsion of the glenohumeral ligaments decreases stability that can be restored with repair. AB - BACKGROUND: Humeral avulsion of the glenohumeral ligaments (HAGL) has become a recognized cause of recurrent shoulder instability; however, it is unknown whether small and large HAGL lesions have similarly destabilizing effects and if large lesion repair results in restoration of stability. QUESTIONS/PURPOSES: In a cadaver model, we evaluated the effect of small and large HAGL lesions and large HAGL lesion repair on glenohumeral ROM, translation, and kinematics. METHODS: We measured rotational ROM, humeral head translation under load, and humeral head apex position in eight cadaveric shoulders. Each specimen was tested in 60 degrees glenohumeral abduction in the scapular and coronal planes under four conditions: intact, small HAGL lesion (mean +/- SD length, 18 +/- 1.8 mm), large HAGL lesion (36.8 +/- 3.6 mm), and after large HAGL lesion repair. For each condition, we measured maximum internal and external rotation with 1.5 Nm of torque; glenohumeral translation in 90 degrees external rotation with 15- and 20 N force applied in the anterior, posterior, superior, and inferior directions; and humeral head apex position throughout ROM. Repeated-measures ANOVA was used for statistical analysis. RESULTS: Small HAGL lesions did not change ROM, translation, or kinematics from the normal shoulder; however, these parameters changed with large HAGL lesions. Maximum external rotation and total ROM increased in the scapular (13.8 degrees +/- 9.4 degrees , p < 0.001; 19.0 degrees +/- 16.5 degrees , p < 0.001) and coronal (21.4 degrees +/- 10.6 degrees , p < 0.001; 29.1 degrees +/- 22.1 degrees , p < 0.001) planes. With anterior force, anterior-inferior translation increased in both planes (mean increase for both loads and planes: anterior: 9.1 +/- 9.5 mm, p < 0.01; inferior, 5.7 +/- 6.6 mm, p < 0.03). In the coronal plane, posterior and inferior translation also increased (4.9 +/- 5.4 mm, p < 0.01; 7.1 +/- 9.9 mm, p < 0.03; averaged for both loads). The humeral head apex shifted 3.7 +/- 4.9 mm anterior (p = 0.04) and 2.8 +/- 2.6 mm lateral (p = 0.004) in the scapular plane and 3.7 +/- 3.4 mm superior (p = 0.006) and 4.1 +/- 2.6 mm lateral (p < 0.001) in the coronal plane. HAGL lesion repair decreased ROM and translation in both planes and restored humeral head position in maximum external rotation. CONCLUSIONS: Anterior large HAGL lesions increase ROM and glenohumeral translation. After large HAGL lesion repair, stability of the shoulder can be restored. CLINICAL RELEVANCE: Surgeons should be aware of the possibility of HAGL lesions in patients with shoulder instability, and if large HAGL lesions are diagnosed, surgeons should consider repairing the lesions. PMID- 24474326 TI - Copper-catalyzed alpha-amination of phosphonates and phosphine oxides: a direct approach to alpha-amino phosphonic acids and derivatives. AB - A direct approach to important alpha-amino phosphonic acids and its derivatives has been developed by using copper-catalyzed electrophilic amination of alpha phosphonate zincates with O-acyl hydroxylamines. This amination provides the first example of C?N bond formation which directly introduces acyclic and cyclic amines to the alpha-position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope. PMID- 24474327 TI - Assessment of the LED phototherapy on femoral bone defects of ovariectomized rats: a Raman spectral study. AB - Osteoporosis is a disease characterized by the reduction of bone mineral density. LED wavelengths seem to have similar photo-stimulating effects to laser light. The aim of this study was to assess the Raman shifts: ~ 960 (phosphate hydroxyapatite), ~ 1,070 (carbonate hydroxyapatite), and ~ 1,454 cm (-1) (lipids and proteins) on bone defects of ovariectomized rats treated or not with LED phototherapy (LED-PT). Thirty female rats were divided into four groups (Basal, OVX, OVX+Clot, and OVX+Clot+LED), then subdivided into two subgroups (15 and 30 days after surgery). Osteoporosis induction by ovariectomy (OVX) was performed in all groups, except for the normal basal group. Following development of osteoporosis, one surgical bone defect (5 mm(2)) was created on the femur of each animal. Defects were irradiated with LED light (lambda = 850 +/- 10 nm, P = 150 mW, CW, F = 0.5 cm(2), 20.4 J/cm(2) per session, t = 128 s, 163.2 J/cm(2) per treatment) at 48 h interval during 2 weeks. Raman measurements were taken at the surface of the defects 30 days after surgery. Significant difference between groups Basal, OVX+Clot, and OVX+Clot+LED for the peaks at ~ 960 (p <= 0.001; 15 and 30 days), ~ 1,070 (p <= 0.001; 15 and 30 days), and ~ 1,450 cm(-1) (p = 0.002; 15 days; p = 0.004; 30 days) were detected. In addition, statistical differences were obtained between groups OVX, OVX+Clot, and OVX+Clot+LED for these same peaks at all time points (p <= 0.001). At 15 and 30 days, there were statistical differences between groups OVX+Clot and OVX+Clot+LED for the peaks at ~ 960 (p <= 0.001), ~ 1,070 (p <= 0.001; p = 0.003), and ~ 1,450 cm(-1) (p <= 0.001; p = 0.002). The results of this study are indicative that infrared LED-PT improved the deposition of HA on bone defects of ovariectomized rats. PMID- 24474328 TI - Outcome of indwelling tunneled PleurX(r) catheter placement in pediatric and young adult patients with malignant effusions. AB - Malignant effusions may cause significant morbidity and mortality for cancer patients. Indwelling tunneled PleurX(r) catheter placement for intermittent drainage of malignant effusions has been shown to be efficacious in adults but has not been studied in children. We performed a retrospective review of nine children and young adults who underwent PleurX(r) catheter placement for the palliation of symptoms associated with malignant effusions. Eight of nine demonstrated symptomatic improvement and seven of nine were discharged from the hospital after catheter placement. No patients experienced catheter-associated complications. PleurX(r) catheter placement should be considered for palliation of symptoms due to malignant effusions in pediatric oncology patients. PMID- 24474329 TI - HIV-1 B-subtype capsid protein: a characterization of amino acid's conservation and its significant association with integrase signatures. AB - The HIV-1 pre-integration phase and the subsequent integration of viral genome to the host of nuclear chromosomes are not well analyzed so far. Many studies are discussing the question of pre- and post-nuclear viral entry which is to support the assumption that HIV-1 integrase (IN) is maintained in the volume of intact conical structure's capsids through HIV entry. The aim of the current study is to identify the prevalence of capsid's (CA) signatures among drug-naive and antiretroviral (ARV)-treated patients in a cohort of 827 HIV-1 B-subtype-infected individuals, and subsequently the relationship between IN and CA amino acid's changes was evaluated. These analyses suggest a conceivable co-evolution of IN-CA sequences, especially in relation to steps of nuclear viral entry. The frequency of mutations was calculated, and statistically has been compared between treatment-naive and ARV-treated patients. The binomial correlation coefficient was used to assess covariation among CA and IN mutations; then, the average linkage hierarchical agglomerative clustering was performed. The results show a detailed conservation of HIV-1 CA protein both in drug-naive and in ARV-treated patients. Moreover, the specific CA substitutions are significantly associated with different IN signatures at the amino acid level and the topology of the dendrogram has revealed the existence of two strong sub-clusters associated with hypothetical different mutational pathways. The in vitro and in vivo studies are necessary to exclude the hypothetical statistical false positive results and in order to confirm that some CA amino acid signatures are going to establish specific and precise implication in the HIV life cycle. PMID- 24474330 TI - Inhibiting replication of begomoviruses using artificial zinc finger nucleases that target viral-conserved nucleotide motif. AB - Geminiviridae consists of a large group of single-stranded DNA viruses that cause tremendous losses worldwide. Frequent mixed infection and high rates of recombination and mutation allow them to adapt rapidly to new hosts and overcome hosts' resistances. Therefore, an effective strategy able to confer plants with resistance against multiple begomoviruses is needed. In the present study, artificial zinc finger proteins were designed based on a conserved sequence motif of begomoviruses. DNA-binding affinities and specificities of these artificial zinc fingers were evaluated using electrophoretic mobility shift assay. Artificial zinc finger nuclease (AZFNs) were then constructed based on the ones with the highest DNA-binding affinities. In vitro digest and transient expression assay showed that these AZFNs can efficiently cleave the target sequence and inhibit the replication of different begomoviruses. These results suggest that artificial zinc finger protein technology may be used to achieve resistance against multiple begomoviruses. PMID- 24474331 TI - Biogas production from N-methylmorpholine-N-oxide (NMMO) pretreated forest residues. AB - Lignocellulosic biomass represents a great potential for biogas production. However, a suitable pretreatment is needed to improve their digestibility. This study investigates the effects of an organic solvent, N-Methylmorpholine-N-oxide (NMMO) at temperatures of 120 and 90 degrees C, NMMO concentrations of 75 and 85% and treatment times of 3 and 15 h on the methane yield. The long-term effects of the treatment were determined by a semicontinuous experiment. The best results were obtained using 75% NMMO at 120 degrees C for 15 h, resulting in 141% increase in the methane production. These conditions led to a decrease by 9% and an increase by 8% in the lignin and in the carbohydrate content, respectively. During the continuous digestion experiments, a specific biogas production rate of 92 NmL/gVS/day was achieved while the corresponding rate from the untreated sample was 53 NmL/gVS/day. The operation conditions were set at 4.4 gVS/L/day organic loading rate (OLR) and hydraulic retention time (HRT) of 20 days in both cases. NMMO pretreatment has substantially improved the digestibility of forest residues. The present study shows the possibilities of this pretreatment method; however, an economic and technical assessment of its industrial use needs to be performed in the future. PMID- 24474332 TI - Endoscopy in symptomatic gastroesophageal reflux disease: scoping out whom to target. PMID- 24474333 TI - Comparative pharmacokinetics and tissue distribution of schisandrin, deoxyschisandrin and schisandrin B in rats after combining acupuncture and herb medicine (schisandra chinensis). AB - Recently, combination therapy with acupuncture and medicine as a practical strategy to treat diseases has gained increasing attention. The present study aimed to investigate whether acupuncture stimulation at ST.36 had a potential impact on the pharmacokinetics and tissue distribution of lignans. An HPLC-ESI/MS analytical method was established and successfully applied to a comparative study of drug concentration in plasma and tissues of three lignans. The parameters area under the plasma concentration-time curve from time zero to the final measurable point and from time zero to infinity, and peak concentration were significantly increased, with a prolonged mean residence time and a corresponding decrease in clearance in comparision with the Schisandra-alone group. Additionally, tissue concentrations of three lignans were improved in the group with acupuncture, especially in liver. The results indicated that acupuncture has a synergistic effect on the pharmacokinetics and tissue distribution of the three lignans, which could postpone their elimination, resulting in a longer blood circulating time in rat plasma and prolonged residence time in target tissues, leading to higher tissue concentration. The findings provide some scientific evidence for the mechanism of the combined use of acupuncture and herbal medicine. Furthermore, we suggest that acupuncture and its combination with herbal medicine should be investigated further as a possible adjuvant therapy in clinical treatment for liver injury. PMID- 24474334 TI - In vitro synergistic activities of antimicrobial peptide brevinin-2CE with five kinds of antibiotics against multidrug-resistant clinical isolates. AB - Antimicrobial peptides are the promising candidates for withstanding multidrug resistant bacteria (MDRB) which were caused by the misuse and extensive use of antibiotics. In this research, in vitro activities of one antimicrobial cationic peptide, brevinin-2CE alone and in combination with five kinds of antibiotics were assessed against clinical isolates of extended-spectrum beta-lactamase producing Escherichia coli and methicillin-resistant Staphylococcus aureus. The results showed that most of the combination groups had synergistic effects. Also, it was obvious that brevinin-2CE had more rapid and severe action on the tested MDRBs which demonstrated that brevinin-2CE and the antibiotics had different antimicrobial mechanisms. Thus, it was presumed that the antimicrobial peptides destroyed the bacterial cells via pore formation mechanisms which lead to the increasing of membrane permeability; and then the other compounds like antibiotics might enter into the cells and accomplish the antimicrobial activities more rapidly and efficiently. PMID- 24474335 TI - Identification by digital immunohistochemistry of intratumoral changes of immune infiltrates after vaccine in the absence of modifications of PBMC immune cell subsets. AB - Preclinical studies have demonstrated that the combination of systemic subcutaneous (s.c.) vaccination with intratumoral (i.t.) vaccination was superior in the induction of antitumor activity vs. vaccination with either route alone. A subsequent phase I study employing i.t.-s.c. vaccination was carried out in men with locally recurrent or progressive prostate cancer. rF-PSA-TRICOM (PROSTVAC) vaccine was administered intraprostatically and rV-PSA-TRICOM followed by rF-PSA TRICOM vaccine was administered systemically. In that study no dose limiting toxicities were observed, 19/21 patients had stable or improved prostate-specific antigen (PSA) values and tumor-infiltrating lymphocytes (TILs) increased in post- vs. pre-treatment tumor biopsies, analyzed employing conventional immunohistochemistry (IHC). In the studies reported here, 31 phenotypes of peripheral blood mononuclear cells (PBMCs) were analyzed prevaccination and postvaccination as well as the functions of PBMC regulatory T cells (Tregs) and natural killer cells. A trend was observed in decreases in serum PSA with the reduction of circulating Tregs postvaccination. Digital IHC was employed prevaccination and postvaccination to measure CD4 and CD8 TILs, as well as Treg TILs by conventional IHC. Few correlations were observed with CD4, CD8 or Treg in TILs vs. PBMCs. However, patients with lower levels of CD4 TILs prevaccination showed the greatest increases in CD4 TILs postvaccine, while Treg TILs decreased postvaccine. There was also a strong correlation between decreases in serum PSA and increases in CD8 TILs postvaccine. These studies provide additional rationale for the use of i.t.-s.c. vaccinations and demonstrate a noncoordinate expression of specific immune subsets in PBMCs vs. tumor. PMID- 24474336 TI - Effect of formalin fixation on thermal conductivity of the biological tissue. AB - Effect of formalin fixation on thermal conductivity of the biological tissues is presented. A self-heated thermistor probe was used to measure the tissue thermal conductivity. The thermal conductivity of muscle and fatty tissue samples was measured before the formalin fixation and then 27 hours after formalin fixation. The results indicate that the formalin fixation does not cause a significant change in the tissue thermal conductivity of muscle and fatty tissues. In the clinical setting, tissues removed surgically are often fixed in formalin for subsequent pathological analysis. These results suggest that, in terms of thermal properties, it is equally appropriate to perform in vitro studies in either fresh tissue or formalin-fixed tissue. PMID- 24474337 TI - The C-4 pathway in Pennisetum purpureum : I. The allosteric nature of PEP carboxylase. AB - Phosphoenol pyruvate (PEP) carboxylase has been partially purified from leaves of the C-4 tropical grass Pennisetum purpureum and shown to have allosteric properties. When initial velocities of incorporation of (14)C from NaH(14)CO3 into oxaloacetate were determined as a function of concentration of either HCO3 or Mg(2+) typical Michaelis-Menten kinetics were observed. Both Lineweaver-Burk and Hill plots were linear with values of n (interaction coefficients) of about one. Sigmoid Michaelis-Menten plots were obtained with PEP as the variable substrate. Following (NH4)2SO4 fractionation and DEAE-cellulose chromatography Lineweaver-Burk plots were concave upwards and Hill plots gave n values of two. With enzyme purified further by Sephadex G-200 chromatography Lineweaver-Burk plots were concave downwards and Hill plots gave values of n of 0.5 at low concentrations of PEP increasing to about 4 at high concentrations of PEP. Enzyme activity was modified by inclusion of glucose-6-phosphate (G6P) in the assay mixtures. When the eoncentration of G6P exceeded that of PEP, the initial velocity tended towards zero. When the concentration of G6P equalled that of PEP activity was increased. When the concentration of PEP exceeded that of G6P, the velocity approached that recorded in control samples at saturating concentrations of PEP. The rate of reaction was also increased on addition of NADH, and decreased by oxaloacetate and malate. PMID- 24474338 TI - The C-4 pathway in Pennisetum purpureum : II. Malate dehydrogenase and malic enzyme. AB - The enzymes NAD-specific malate dehydrogenase (E.C.1.1.1.37) and malic enzyme (E.C. 1.1.1.40) have been partially purified from leaves of P. purpureum and their kinetic properties examined. With malate dehydrogenase, assayed in the direction of malate synthesis, Lineweaver-Burk plots with either oxaloacetate or NADH as variable substrate were parallel to one another, indicating an ordered reaction mechanism of the ping-pong type. Studies of end-product inhibition suggested that the mechanism was iso-ping-pong-bi-bi. Michaelis constants were about 5*10(-5) M for NADH and 3*10(-4) M for oxaloacetate. With the malic enzyme Michaelis constants were about 2*10(-6) M for NADP(+), 4*10(-4) M for malate and 8*10(-6) M for Mn(2+). Results are discussed in terms of the roles of these enzymes in the metabolism of carbon through the C-4 pathway of photosynthesis. PMID- 24474339 TI - The C-4 pathway in Pennisetum purpureum : III. Structure and photosynthesis. AB - The anatomical structure of leaf tissue of P. purpureum, and the short term labelling pattern following exposure to (14)CO2 in the lighht, have been investigated. Both the arrangement of photosynthetic tissue in two layers around the vascular tissue, and the early labelling of malate and aspartate, characteristic of C-4 plants were observed. The structure of the epidermis and the arrangement of stomata is such that CO2 must pass through non-chloroplast containing tissue before reaching the chloroplasts. At 0.05% CO2 in air the rate of photosynthetic CO2 assimilation was about 70 MUmoles/mg chl.h. This increased to over 700 MUmoles/mg chl.h at saturating concentrations of CO2. At 0.05% CO2 negative slopes were obtained from percentage plots for malate, which was the major product. As the CO2 concentration was increased, sugar phosphates became the major product. At saturating concentrations of CO2, both malate and aspartate had positive initial slopes and a negative slope was observed for phosphoglyceric acid. These results are discussed in relation to the contribution of C-4 metabolism to photosynthesis in P. purpureum. PMID- 24474340 TI - The effect of nitrogen on the movement of tracers down the stolon of Saxifraga sarmentosa, with some observations on the influence of light. AB - The movement of applied (137)Cs and of naturally-assimilated (14)C down the long stolon of Saxifraga is strongly inhibited by confining a length of 10 to 30 cm of the stolon in an atmosphere of nitrogen. The inhibition is reversible, normal transport being restored after less then 4 h when the stolon is returned to air from 5 h in nitrogen. Callose formation does not seem to be involved. There is evidence that local darkness has a similar adverse effect on phloem transport.These findings are considered antagonistic to the pressure-flow hypothesis, but favourable to the active mass-flow theories. PMID- 24474341 TI - Movement of [(14)C]sucrose along the stolon of Saxifraga sarmentosa. AB - The characteristics of (137)Cs transport along the stolon of Saxifraga previously reported have been confirmed for applied sucrose and natural assimilate. Long distance transport is strictly unidirectional, with a symmetrical short-distance spread from the point of application. Only the latter takes place in a long piece of excised stolon. Transport is readily reversed when the parent plant is darkened and the daugther, plantlet allowed to photosynthesise. These findings strongly support a mass-flow mechanism for the stolon. They also confirm the value of (137)Cs as a tracer for assimilate movement, though in contrast to assimilate it suffers appreciable lateral leakage. Pulse labelling of the subtending leaf failed to produce a sharp peak of activity in the stolon. A flattening with time of the (14)C profile is considered to be due to differing linear velocities in parallel sieve tubes. PMID- 24474342 TI - [Photorespiration in the blue-green alga Anacystis nidulans at different temporatures]. AB - CO2 exchange, (14)CO2 fixation and (14)C-products of Anacystis nidulans (strain L 1402-1) were studied during the induction period at temperatures of +15 degrees C and+35 degrees C. At+15 degrees C the stationary rates of CO2 uptake and respiration were reached directly. At+35 degrees C a maximum of CO2 uptake could be observed at the beginning of the illumination period followed by a lower steady rate of photosynthesis. In the following dark period a CO2 gush appeared at+35 degrees C. The magnitude of the CO2 outburst is relatively independent of the photosyntbetic period. The autoradiographic studies showed that the Calvin cycle is the main carboxylation pathway in Anucystis. At a temperature of +35 degrees C serine was labelled after 20 sec of photosynthesis. At+15 degrees C, on the other hand, a low radio-activity appeared in serine after 5 min of photosynthesis. The results show that photorespiration of Anacystis is stimulated by high temperatures. PMID- 24474343 TI - Natural segregation of nucleolar components in the course of a plant cell differentiation. AB - Segregation of the nucleolar components is described in the differentiated nucleus of the generative cell in the growing Clivia and Lilium pollen tubes. This finding of a natural nucleolar segregation is discussed against the background of current views of the correlations of nucleolar morphology and transcriptional activity. PMID- 24474344 TI - Floral initiation in strawberry: Spectral evidence for the regulation of flowering by long-day inhibition. AB - Floral initiation in strawberry cv. Cambridge Favourite, a facultative short-day plant, was inhibited by a daylength extension with red light (R) during the second half of a 16-hour night but not during the first half, and by far-red light (FR) in the first half but not during the second. Mixed R plus FR light was inhibitory to flowering at both times. This change in sensitivity to R and FR light in the evening and morning resembles the pattern for flower induction in long-day plants but differs from the pattern for flower inhibition in several other short-day plants, examples of which are given. These experiments afford further support for the hypothesis that the control of flower initiation in strawberry depends on the production of a flower inhibitor by leaves exposed to long photoperiods. PMID- 24474345 TI - Auxin transport in intact pea seedlings (Pisum sativum L.): The inhibition of transport by 2,3,5-triiodobenzoic acid. AB - The application of 2,3,5-triiodobenzoic acid (TIBA, 10 mg.g(-1) in lanolin) to the stem of intact pea seedlings (Pisum sativum L.) inhibited the basipetal transport of (14)C from indoleacetic acid-1-(14)C (IAA-1-(14)C) applied to the apical bud, but not the transport of (14)C in the phloem following the application of IAA-1-(14)C or sucrose-(14)C to mature foliage leaves. It was concluded that fundamentally different mechanisms of auxin transport operate in these two pathways.When TIBA was applied at the same time as, or 3.0 h after, the application of IAA-1-(14)C to the apical bud, (14)C accumulated in the TIBA treated and higher internodes; when TIBA was applied 24.0 h before the IAA-1 (14)C, transport in the stem above the TIBA-treated internode was considerably reduced. TIBA treatments did not consistently influence the total recovery of (14)C, or the conversion of free IAA to indoleaspartic acid (IAAsp). These results are discussed in relation to the possible mechanism by which TIBA inhibits auxin transport,.Attention is drawn to the need for more detailed studies of the role of the phloem in the transport of endogenous auxin in the intact plant. PMID- 24474346 TI - Solution flow in tubular semi-permeable membranes. AB - A recent suggestion that the term "volume flow" should be used for the flow along sieve tubes when the pressure gradient involved is very small is considered to be unwarranted. It involves no new concepts and does not constitute any mechanism that is not implicit in the Munch theory. PMID- 24474347 TI - The impact of a new model-based iterative reconstruction algorithm on prosthetic heart valve related artifacts at reduced radiation dose MDCT. AB - To assess the impact of hybrid iterative reconstruction (IR) and novel model based iterative reconstruction (IMR) and dose reduction on prosthetic heart valve (PHV) related artifacts and objective image quality. One transcatheter and two mechanical PHVs were embedded in diluted contrast-gel, inserted in an anthropomorphic phantom and imaged stationary with retrospectively ECG-gated computed tomography. Eight acquisitions were obtained of each PHV at 120 kV, 600 mAs (routine), 300 and 150 mAs (reduced dose). Data were reconstructed with filtered back projection (FBP), IR and IMR. Hypodense and hyperdense artifact volumes were quantified using two threshold filters. Signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Artifact volumes differed significantly between reconstruction algorithms for all PHVs (P < 0.005). Compared to FBP, IR decreased overall hypodense and hyperdense artifact volumes; at 150 mAs by 53 and 20 % (IR) and 67 and 23 % (IMR), respectively and significantly increased SNR and CNR at all doses (P < 0.012). Even at reduced dose, IMR resulted in higher image quality than routine dose FBP and IR. Iterative reconstruction and particularly IMR significantly reduce PHV-related artifacts and improve objective image quality in non-pulsatile conditions, even in reduced-dose images. Also, this study suggests that IMR allows for more radiation dose reduction in comparison to hybrid IR while maintaining high image quality. PMID- 24474348 TI - Cytotoxic effects of zoledronic acid on human epithelial cells and gingival fibroblasts. AB - Bisphosphonate-induced osteonecrosis has been related to the cytotoxicity of these drugs on oral mucosa cells. A previous study showed that 5 uM of zoledronic acid (ZA), a nitrogen-containing bisphosphonate, is the highest concentration of this drug found in the oral cavity of patients under treatment. Therefore, in order to simulate an osteonecrosis clinical condition, the aim of this study was to evaluate the highest concentration of ZA applied on human epithelial cells (HaCaT) and gingival fibroblasts. For this purpose, cells (3 * 10(4) cells/cm2) were seeded in wells for 48 h using complete culture medium (cDMEM). After 48 h incubation, the cDMEM was replaced by fresh serum-free culture medium (DMEM-FBS) in which the cells were maintained for additional 24 h. Then, 5 uM ZA were added to the DMEM-FBS and the cells incubated in contact with the drug for 48 h. After this period, the number of viable cells (trypan blue), cell viability (MTT assay), total protein (TP) production and cell morphology (SEM analysis) were assessed. Data were analyzed statistically by Mann-Whitney, ANOVA and Tukey's test (alpha=0.05). ZA caused a significant reduction in the number of viable cells and decreased the metabolic activity of both cell lines. However, decrease of TP production occurred only in the epithelial cell cultures. Morphological alterations were observed in both cell types treated with ZA. In conclusion, ZA (5 uM) was cytotoxic to human epithelial cells and gingival fibroblast cultures, which could be associated, clinically, with the development of bisphosphonate induced osteonecrosis. PMID- 24474349 TI - Osteocalcin immunohistochemical expression during repair of critical-sized bone defects treated with subcutaneous adipose tissue in rat and rabbit animal model. AB - The aim of this study was to evaluate the osteocalcin immunoexpression during the bone repair treated with subcutaneous adipose tissue in rats and rabbits. Fourteen rats and 14 rabbits were used in the study. A critical-sized calvarial defect was created in each animal. The animals were divided into 4 experimental groups: RC (rat control), RbC (rabbit control), RAT (rat adipose tissue), RbAT (rabbit adipose tissue). In the groups RC and RbC the defect was filled with a blood clot. In groups RAT and RbAT, the defect was filled with macerated subcutaneous adipose tissue. The euthanasia was performed at 30 days (RC and RAT) and 40 days (RbC and RbAT). Histological analysis and immunohistochemical analysis of osteocalcin protein expression were performed. Data were submitted to descriptive statistical analysis (mode). Osteocalcin immunoexpression was detected in the experimental models. Notwithstanding, RbAT showed higher positivity, especially in the adipocytes, than the group RAT group. In groups RC and RbC, the surgical wound was filled by collagen fibers. In Group RAT, the defect was composed by collagen fibers and adipocytes in the reparative sites. Similarly, in RbAT, the defect also was partially filled by collagen fibers and presence of adipocytes dispersed among the fibers. Additionally, chronic inflammatory process and areas of bone matrix deposition were observed. It may be concluded that in both animal models the adipose tissue demonstrated low osteogenic capacity. However, the rabbit animal model exhibited a more evident osteocalcin immunoexpression and a greater amount of newly formed bone matrix. PMID- 24474350 TI - Palatal harvesting technique modification for better control of the connective tissue graft dimensions. AB - Subepithelial connective tissue graft (SCTG) has been extensively used for a variety of clinical applications. However, the surgical procedure may not allow control of graft thickness. The purpose of this case series is to illustrate a modification to the single incision palatal harvesting technique in order to control the SCTG thickness without increasing patient discomfort. Fifty cases from thirty systemically and periodontally healthy patients with at least one multiple gingival recession were treated with coronally advanced flaps combined with a SCTG. The palatal area served as the donor site, from where a single perpendicular incision was made to obtain a full thickness flap. Next, 1-2 mm of the flap was elevated and dissected to obtain a partial thickness flap. The graft remained attached to the full-partial thickness flap. After determining the desired SCTG thickness, the graft was harvested from the palatal flap. The patients healed uneventfully at 7 days postoperatively and primary closure was obtained for all palatal donor sites. The SCTG length and width varied depending on the needs of each case, but the SCTG thickness was well controlled with only 0.24 mm standard deviation. The suggested modification granted control of the SCTG dimensions and achieved complete wound closure within a week. PMID- 24474351 TI - Detection of root canal isthmuses in molars by map-reading dynamic using CBCT images. AB - The aim of this study was to detect root isthmuses in maxillary and mandibular molars and evaluate their frequencies using map-reading dynamics in CBCT images. Two hundred extracted human maxillary and mandibular molars were used in ex vivo assay. A consecutive sample of two hundred maxillary and mandibular molars (first and second) was selected from CBCT exams. The isthmuses were detected from the pulp orifice to the apex and were recorded according to their beginning and their end, into categories: 1. begin and end in cervical third; 2. beginning in cervical third and end in middle third; 3. beginning in cervical third and end in apical third; 4. beginning and end in middle third; 5. begin in middle third and end in apical third; 6. beginning and end in apical third; 7. no isthmus. The scans were obtained in different planes with map-reading in axial slices of 0.5 mm/0.5 mm involved the coronal to apical direction. The frequencies of isthmus were analyzed according to the level of root and evaluated by Chi-square test. The level of significance was set at alpha=0.05. The presence of isthmus detected in maxillary molars was 86% in ex vivo assay and 62% in vivo assay, whereas in mandibular molars was observed 70% in ex vivo assay and 72% in vivo assay. The frequency of isthmus was high in both study models. The map-reading dynamics in CBCT images was found to be precise to detect the localization of isthmus. PMID- 24474352 TI - Midbuccal canals of maxillary molars evaluated by cone-beam computed tomography: endodontic management of two cases. AB - Maxillary molars present variable root canal and root morphologies. This report describes the endodontic management of two cases of midbuccal canals found in maxillary molars. Midbuccal canals were present in a maxillary first molar with a single buccal root (Case 1), and in a maxillary second molar with three buccal roots (Case 2). An assessment of the internal configuration of these teeth was performed using cone-beam computed tomography (CBCT). Magnification with a dental operating microscope, surgical loupes, and the use of an endodontic explorer enabled the identification of the midbuccal canal orifices. The root canals in both cases were chemomechanically prepared and filled. Postobturation radiographic images revealed four (one midbuccal, two mesiobuccal and one palatal) and five (one midbuccal, two mesiobuccal, one distobuccal and one palatal) root canals, which were filled in Cases 1 and 2, respectively. Complex canal configurations of maxillary molars including the presence of midbuccal canals were presented. CBCT was a valuable tool in this diagnosis, as it provided a precise description of these unusual anatomical variations. PMID- 24474353 TI - Effectiveness of a canal brush on removing smear layer: a scanning electron microscopic study. AB - This study evaluated the effectiveness of a highly flexible endodontic brush made of polypropylene canal brush (CanalBrush; Coltene) on smear layer removal from the canal walls when used according to the manufacturer's recommendations. Forty four single-rooted mandibular incisors were prepared to apical size 30/0.06 and randomly divided into three groups A, B and C, where the final irrigation regimen was 10 mL 17% EDTA and 10 mL 2.5% NaOCl for group A, 10 mL EDTA, 5 mL NaOCl, CanalBrush for 20 s at 450 rpm and 5 mL NaOCl for group B, 10 mL NaOCl, CanalBrush and 10 mL NaOCl for group C. One medium-sized CanalBrush was used for each root canal and all brushes were examined under the optical microscope after application to evaluate bristle deformation. Afterwards, roots were split longitudinally and the presence of smear layer was evaluated under a scanning electron microscope. Used brushes invariably exhibited bristle deformation. Group C exhibited the highest means of smear layer in all thirds. Comparing the apical thirds in all groups, there was no statistical difference between groups A and B (3.64 +/- 0.48 and 3.68 +/- 0.62 respectively), while group C exhibited significantly higher scores (3.9 +/- 0.28) than the other two groups. In conclusion, the CanalBrush proved unable to remove smear layer from the instrumented root canals, when used according to the manufacturers' instructions. PMID- 24474354 TI - Efficacy of an organic solvent and ultrasound for filling material removal. AB - The aim of this study was to investigate whether a final rinse with Endosolv R(r) solvent and ultrasound resulted in cleaner root canal walls during endodontic retreatment. A total of 56 extracted premolar teeth were manually instrumented using a step-back flare technique and filled with gutta-percha and AH Plus sealer. After 9 months, the canals were retreated by removing the gutta-percha and sealer with ProTaper Universal Retreatment and rotary preparation with ProTaper Universal System up to an F5 file. As a final step, the teeth were randomly divided in 4 groups (n=14) and were subjected to passive ultrasonic irrigation (PUI) with either Endosolv R or distilled water. In the control groups, the irrigants were left undisturbed. Roots were cleaved and examined under scanning electron microscopy (SEM), and the amount of filling remnants on the canal walls was assessed by two calibrated examiners in a blinded fashion. Data were analyzed by the Kruskal-Wallis test and the Student-Newman-Keuls post hoc test (alpha=0.05). All groups presented filling debris in the three root canal thirds after retreatment. There were no significant differences between the groups or among the root canal thirds within each group (p>0.05). PUI with Endosolv R was not effective in the removal of filling debris from root canal walls. PMID- 24474355 TI - Root dentin strain and temperature rise during endodontic treatment and post rehabilitation. AB - This study investigated the effects of endodontic treatment procedures and different post systems rehabilitation steps on the strain and temperature rise on apical and cervical root dentin regions. Twenty-one extracted human canine teeth had two strain gages attached to the distal root surface and two thermocouples attached to the mesial root surface (cervical and apical). The strain and temperature rise were recorded during the following procedures: root canal preparation, final rinse and drying, root canal filling and canal relief. Then the teeth were divided into three groups (n=7), according to the type of post system: CPC, cast post and core; FGP, fiberglass post; and PSP, prefabricated steel post. Data continued to be recorded during the post space preparation, post modeling (only for CPC), post trying and post cementation. Data were subjected to a two-way ANOVA followed by Tukey's test (alpha=0.05). The post-space preparation caused the highest temperature rise (4.0-14.9 degrees C) and the highest strain in the apical region during irrespective of post type. The resin cement light activation resulted in significant temperature increases in the cervical region for all of the groups. The canal relief and the post-space preparation produced highest temperature rises. The CPC post modeling resulted in higher root strain level similarly the level of post preparation. The PSP resulted in highest strain during post trying and post cementation. PMID- 24474356 TI - Microstructure and mechanical properties of composite resins subjected to accelerated artificial aging. AB - The aim of this study was to investigate the influence of accelerated artificial aging (AAA) on the microstructure and mechanical properties of the Filtek Z250, Filtek Supreme, 4 Seasons, Herculite, P60, Tetric Ceram, Charisma and Filtek Z100. composite resins. The composites were characterized by Fourier-transform Infrared spectroscopy (FTIR) and thermal analyses (Differential Scanning Calorimetry - DSC and Thermogravimetry - TG). The microstructure of the materials was examined by scanning electron microscopy. Surface hardness and compressive strength data of the resins were recorded and the mean values were analyzed statistically by ANOVA and Tukey's test (alpha=0.05). The results showed significant differences among the commercial brands for surface hardness (F=86.74, p<0.0001) and compressive strength (F=40.31, p<0.0001), but AAA did not affect the properties (surface hardness: F=0.39, p=0.53; compressive strength: F=2.82, p=0.09) of any of the composite resins. FTIR, DSC and TG analyses showed that resin polymerization was complete, and there were no differences between the spectra and thermal curve profiles of the materials obtained before and after AAA. TG confirmed the absence of volatile compounds and evidenced good thermal stability up to 200 degrees C, and similar amounts of residues were found in all resins evaluated before and after AAA. The AAA treatment did not significantly affect resin surface. Therefore, regardless of the resin brand, AAA did not influence the microstructure or the mechanical properties. PMID- 24474357 TI - Effect of two microshear test devices on bond strength and fracture pattern in primary teeth. AB - This in vitro study evaluated the influence of two devices for application of shear load in microshear tests on bond strength and fracture pattern of primary enamel and dentin. Eighty primary molars were selected and flat enamel (40 teeth sectioned mesio-distally) and dentin (40 teeth sectioned transversally) surfaces were obtained. Both surfaces were polished to standardize the smear layer. Two step etch-and-rinse adhesive systems (Adper Single Bond and XP Bond) were used. Polyethylene tubes was placed over the bonded surfaces and filled with composite resin. The microshear testing was performed after storage in water (24 h/37 degrees C) using two devices for application of microshear loads: a notched rod (Bisco Shear Bond Tester) or a knife edge (Kratos Industrial Equipment). Failure modes were evaluated using a stereomicroscope. Bond strength data were subjected to ANOVA and chi-square test to compare the failure mode distributions (alpha=0.05). No significant differences were observed between the groups for dentin and enamel bond strength or fracture patterns (p>0.05). The predominant failure mode was adhesive/mixed. In conclusion, the devices for application of shear loads did not influence the bond strength values, regardless of adhesive system and substrate. PMID- 24474358 TI - Molecular and structural evaluation of dentin caries-like lesions produced by different artificial models. AB - This study evaluated structural and molecular issues of dentin caries-like lesions produced by different artificial models (ACL) compared with natural caries lesions (NCL). One hundred twenty-four sound occlusal dentin blocks and 47 carious blocks were obtained and surface hardness was analyzed (SH1). They were assigned to groups according to ACL: GB: Biological; GC: Chemical; GIS: In situ; GNC: natural caries (control). Blocks from groups 1, 2 and 3 were submitted to caries lesion induction. NCL and ACL blocks were submitted to surface hardness (SH 2), FT-Raman and uEDXRF analysis. All blocks were longitudinally sectioned and one of the halves was submitted to cross-sectional hardness (CSH) and the other to SEM analysis. SH1 and SH2 data were submitted to t test (unpaired and paired, respectively), CSH and SEM data to two-way and one-way ANOVA respectively, and Tukey and t tests, respectively (p<0.05). Data from FT Raman/uEDXRF were submitted to one-way ANOVA and Dunnett multiple-comparisons test (a=0.05). GB and GNC showed lowest SH2 values that were significantly different from GC and GIS. Regarding CSH, GB and GNC showed no significant difference between them. SEM showed similar caries lesion depth for GB and GNC, being significantly higher than for GC and GIS. uEDXRF showed similar values of calcium and phosphate for GB and GNC; GNC values were significantly different from GIS. No significant difference was found among the groups concerning phosphate, carbonate and CH bonds values. For collagen type I, GC values were significantly different compared to other groups. It may be concluded that caries like lesions produced by GB were the closest model to NCL. PMID- 24474359 TI - Root canal filling: fracture strength of fiber-reinforced composite-restored roots and finite element analysis. AB - The aims of this study were to evaluate the effect of root canal filling techniques on root fracture resistance and to analyze, by finite element analysis (FEA), the expansion of the endodontic sealer in two different root canal techniques. Thirty single-rooted human teeth were instrumented with rotary files to a standardized working length of 14 mm. The specimens were embedded in acrylic resin using plastic cylinders as molds, and allocated into 3 groups (n=10): G(lateral) - lateral condensation; G(single-cone) - single cone; G(tagger) - Tagger's hybrid technique. The root canals were prepared to a length of 11 mm with the #3 preparation bur of a tapered glass fiber-reinforced composite post system. All roots received glass fiber posts, which were adhesively cemented and a composite resin core was built. All groups were subjected to a fracture strength test (1 mm/min, 45 degrees ). Data were analyzed statistically by one way ANOVA with a significance level of 5%. FEA was performed using two models: one simulated lateral condensation and Tagger's hybrid technique, and the other one simulated the single-cone technique. The second model was designed with an amount of gutta-percha two times smaller and a sealer layer two times thicker than the first model. The results were analyzed using von Mises stress criteria. One-way ANOVA indicated that the root canal filling technique affected the fracture strength (p=0.004). The G(lateral) and G(tagger) produced similar fracture strength values, while G(single-cone) showed the lowest values. The FEA showed that the single-cone model generated higher stress in the root canal walls. Sealer thickness seems to influence the fracture strength of restored endodontically treated teeth. PMID- 24474360 TI - Tensile strength of glass fiber posts submitted to different surface treatments. AB - The aim of this in vitro study was to evaluate the tensile strength of glass fiber posts submitted to different surface treatments. Forty-eight maxillary canines had their crowns sectioned and root canals endodontically treated. The roots were embedded in acrylic resin and distributed into 3 groups according to the surface treatment: Group I: the posts were treated with silane agent for 30 s and adhesive; Group II: the posts were cleaned with alcohol before treatment with silane agent and adhesive; Group III: the posts were submitted to conditioning with 37% phosphoric acid for 30 s before treatment with silane agent and adhesive. Each group was divided into 2 subgroups for adhesive polymerization or not before insertion into the canal: A - adhesive was not light cured and B - adhesive was light cured. All posts were cemented with Panavia F and the samples were subjected to tensile strength test in a universal testing machine at crosshead speed of 1 mm/min. Data were submitted to one-way ANOVA and Tukey's test at 5% significance level. There was statistically significant difference (p<0.01) only between group GIII-B and groups GI-A and GI-B. No significant difference was found among the other groups (p>0.05). It was concluded that the products used for cleaning the posts influenced the retention regardless of adhesive light curing. PMID- 24474361 TI - Tensile and flexural strength of commercially pure titanium submitted to laser and tungsten inert gas welds. AB - This study evaluated the tensile and flexural strength of tungsten inert gas (TIG) welds in specimens made of commercially pure titanium (CP Ti) compared with laser welds. Sixty cylindrical specimens (2 mm diameter x 55 mm thick) were randomly assigned to 3 groups for each test (n=10): no welding (control), TIG welding (10 V, 36 A, 8 s) and Nd:YAG laser welding (380 V, 8 ms). The specimens were radiographed and subjected to tensile and flexural strength tests at a crosshead speed of 1.0 mm/min using a load cell of 500 kgf applied on the welded interface or at the middle point of the non-welded specimens. Tensile strength data were analyzed by ANOVA and Tukey's test, and flexural strength data by the Kruskal-Wallis test (alpha=0.05). Non-welded specimens presented significantly higher tensile strength (control=605.84 +/- 19.83) (p=0.015) and flexural strength (control=1908.75) (p=0.000) than TIG- and laser-welded ones. There were no significant differences (p>0.05) between the welding types for neither the tensile strength test (TIG=514.90 +/- 37.76; laser=515.85 +/- 62.07) nor the flexural strength test (TIG=1559.66; laser=1621.64). As far as tensile and flexural strengths are concerned, TIG was similar to laser and could be suitable to replace laser welding in implant-supported rehabilitations. PMID- 24474362 TI - A 3-D finite element study of the influence of crown-implant ratio on stress distribution. AB - The purpose of this study was to assess the influence of the crown height of external hexagon implants on the displacement and distribution of stress to the implant/bone system, using the three-dimensional finite element method. The InVesalius and Rhinoceros 4.0 softwares were used to generate the bone model by computed tomography. Each model was composed of a bone block with one implant (3.75 x 10.0 mm) with external hexagon connections and crowns with 10 mm, 12.5 mm and 15 mm in height. A 200 N axial and a 100 N oblique (45 degrees ) load were applied. The models were solved by the NeiNastran 9.0 and Femap 10.0 softwares to obtain the results that were visualized by maps of displacement, von Mises stress (crown/implant) and maximum principal stress (bone). The crown height under axial load did not influence the stress displacement and concentration, while the oblique loading increased these factors. The highest stress was observed in the neck of the implant screw on the side opposite to the loading. This stress was also transferred to the crown/platform/bone interface. The results of this study suggest that the increase in crown height enhanced stress concentration at the implant/bone tissue and increased displacement in the bone tissue, mainly under oblique loading. PMID- 24474363 TI - Do clinical experience time and postgraduate training influence the choice of materials for posterior restorations? Results of a survey with Brazilian general dentists. AB - The aims of this study were to evaluate the materials available for posterior restorations and to assess whether clinical experience time and post-graduate training influence dentists' choices. A cross-sectional study was conducted using a questionnaire with closed questions applied to dentists (n=276) of a mid-sized city of the southern Brazil. Information was collected regarding sociodemographic variables, level of specialization, time since graduation and working place. In addition, options regarding posterior restorations including the first choice of material, type of composite resin (if used) and use of rubber dam were also collected data. Data were submitted to descriptive analysis and the associations were evaluated using chi-square and Fisher's exact tests (alpha=0.05). The response rate was 68% (187). Direct composite resin was broadly indicated (73.2%) as the first-choice for posterior restorations. Most professionals used microhybrid composite (74.5%) and 42.6% of the participants used rubber dam for placement of posterior composite restorations. Dentists with more time of clinical practice used less composite (p=0.014). Specialists used more frequently rubber dam to restore posterior teeth than did non-specialists (p=0.006). The results of this survey revealed that direct composite was the first choice of dentists for posterior restorations; microhybrid was the preferred type of composite and the use of rubber dam for composite resin placement in posterior teeth was not frequent; time since graduation and level of specialization affected dentists' choices. PMID- 24474365 TI - Impact of malocclusion on oral health-related quality of life among Brazilian preschool children: a population-based study. AB - The purpose of the present study was to evaluate the impact of malocclusion on Oral Health-Related Quality of Life (OHRQoL) of children and their families. A population-based cross-sectional study was carried out in Belo Horizonte, MG, Brazil. A representative sample of 1069 male and female preschoolers aged 60 to 71 months was randomly selected from public and private preschools and daycare centers. Data were collected using the B-ECOHIS. In addition, a questionnaire addressing socioeconomic and demographic data was self-administered by the parents/guardians. The criteria used to diagnose malocclusion were based on Foster and Hamilton (1969), Graboswki et al. (2007) and Oliveira et al. (2008). Descriptive, univariate and multiple Poison logistic regression analyses were carried out. The prevalence of malocclusion was observed in 46.2% of the children and deep overbite was the most prevalent type of malocclusion (19.7%), followed by posterior crossbite (13.1%), accentuated overjet (10.5%), anterior open bite (7.9%) and anterior crossbite (6.7%). The impact of malocclusion on OHRQoL was 32.7% among the children and 27.1% among the families. In Poisson multiple regression model adjusted for socioeconomic status, no significant association was found between malocclusion and OHRQoL of the children (PR=1.09, 95% CI: 0.96 1.24) and their families (PR=1.11, 95% CI: 0.94-1.31). It is concluded that children with malocclusion in this sample did not have a negative impact on their OHRQoL and of their families. PMID- 24474364 TI - Predisposing factors for traumatic dental injury in primary teeth and seeking of post-trauma care. AB - The aim of the present study was to investigate predisposing factors for traumatic dental injury (TDI) in the primary dentition and seeking of dental care after the occurrence of TDI. A randomized population-based cross-sectional study was carried out with 814 children aged 3 to 5 years enrolled at public and private preschools in the city of Campina Grande, PB, Brazil. Parents were asked to fill out a questionnaire on demographic data and the child's history of TDI. TDI was evaluated by clinical examinations performed by three previously calibrated dentists (Kappa: 0.85 to 0.90). Bivariate and multivariate Poisson regression models were constructed for TDI and the parent-reported search for dental care (alpha=0.05). The prevalence of TDI was 34.6%. The most common type of TDI was enamel fracture (55.0%). The central incisors were the most frequently affected teeth (87.5%). Predictors for TDI in the primary dentition were household income >U$312.50 (PR: 1.355; 95% CI: 1.050-1.724) and overjet >2 mm (PR: 1.539; 95% CI: 1.219-1.942). The predictor for seeking dental care following TDI was parent's age >30 years (PR: 1.753; 95% CI: 1.039-2.960). Household income and overjet were associated with TDI. Among children having suffered TDI, parent's age is a crucial determinant for seeking dental care. PMID- 24474366 TI - Ossifying fibroma of the jaws: a clinicopathological case series study. AB - The aim of this study was to assess the clinical, radiographic and microscopic features of a case series of ossifying fibroma (OF) of the jaws. For the study, all cases with OF diagnosis from the files of the Oral Pathology Laboratory, University of Ribeirao Preto, Ribeirao Preto, SP, Brazil, were reviewed. Clinical data were obtained from the patient files and the radiographic features were evaluated in each case. All cases were reviewed microscopically to confirm the diagnosis. Eight cases were identified, 5 in females and 3 in males. The mean age of the patients was 33.7 years and most lesions (7 cases) occurred in the mandible. Radiographically, all lesions appeared as unilocular images and most of them (5 cases) were of mixed type. The mean size of the tumor was 3.1 cm and 3 cases caused displacement of the involved teeth. Microscopically, all cases showed several bone-like mineralized areas, immersed in the cellular connective tissue. From the 8 cases, 5 underwent surgical excision and 1 patient refused treatment. In the remaining 2 cases, this information was not available. In conclusion, OF occurs more commonly in women in the fourth decade of life, frequently as a mixed radiographic image in the mandible. Coherent differential diagnoses are important to guide the most adequate clinical approach. A correlation between clinical, imaginological and histopathological features is the key to establish the correct diagnosis. PMID- 24474367 TI - Chediak-Higashi syndrome and premature exfoliation of primary teeth. AB - The Chediak-Higashi syndrome (CHS) is a rare hereditary fatal disease, if not treated. These changes are associated with various diseases and syndromes that mainly cause periodontal disease and thus the premature loss of teeth. This paper describes the monitoring of premature loss of primary teeth that began when the child was 5 years old. On presentation his teeth were mobile and there was a history of gingival bleeding. Panoramic radiography revealed generalized and severe bone loss, and the teeth showed no bony support enough for their stability. Blood test was ordered to assess the overall health of the child and giant cells with cytoplasmic granules were found, confirming the diagnosis of CHS. The management of periodontal disease focused on the control of infection and bacterial plaque by mechanical and chemical methods. PMID- 24474368 TI - Patient agency revisited: "healing the hidden" in South India. AB - It is often argued that biomedicine alienates patients from doctors, from ailments and from understanding treatment processes, while indigenous and alternative healing systems are portrayed as respectful of patients and their experience. Specifically, South Indian siddha medicine has been seen as diverging from biomedicine in empowering its patients. This approach not only assumes biomedicine to be a homogeneous practice, but also lumps together diverse therapeutic techniques under the labels of "traditional" or "alternative." Analysis of a manual subdiscipline of siddha medicine cautions against such analytic imprecision and active/passive binaries in physician-patient encounters. Practitioners of vital spot medicine claim to "heal the hidden." They rarely communicate diagnostic insights verbally and object to auxiliary devices. However, their physical engagement with patients' ailing bodies highlights the corporeal nature of manual medicine in particular and processual, situational, and reciprocal characteristics of curing in general. PMID- 24474369 TI - Melodic algorithms for pulse oximetry to allow audible discrimination of abnormal systolic blood pressures. AB - An anesthesiologist must remain vigilant of the patient's clinical status, incorporating many independent physiological measurements. Oxygen saturation and heart rate are represented by continuous audible tones generated by the pulse oximeter, a mandated monitoring device. Other important clinical parameters- notably blood pressure--lack any audible representation beyond arbitrarily configured threshold alarms. Attempts to introduce further continuous audible tones have apparently foundered; the complexity and interaction of these tones have exceeded the ability of clinicians to interpret them. Instead, we manipulate the tonal and rhythmic structure of the accepted pulse oximeter tone pattern melodically. Three melodic algorithms were developed to apply tonal and rhythmic variations to the continuous pulse oximeter tone, dependent on the systolic blood pressure. The algorithms distort the original audible pattern minimally, to facilitate comprehension of both the underlying pattern and the applied variations. A panel of anesthesia practitioners (attending anesthesiologists, residents and nurse anesthetists) assessed these algorithms in characterizing perturbations in cardiopulmonary status. Twelve scenarios, incorporating combinations of oxygen desaturation, bradycardia, tachycardia, hypotension and hypertension, were tested. A rhythmic variation in which additional auditory information was conveyed only at halftime intervals, with every other "beat" of the pulse oximeter, was strongly favored. The respondents also strongly favored the use of musical chords over single tones. Given three algorithms of tones embedded in the pulse oximeter signal, anesthesiologists preferred a melodic tone to signal a significant change in blood pressure. PMID- 24474370 TI - Sparse label-indicator optimization methods for image classification. AB - Image label prediction is a critical issue in computer vision and machine learning. In this paper, we propose and develop sparse label-indicator optimization methods for image classification problems. Sparsity is introduced in the label-indicator such that relevant and irrelevant images with respect to a given class can be distinguished. Also, when we deal with multi-class image classification problems, the number of possible classes of a given image can also be constrained to be small in which it is valid for natural images. The resulting sparsity model can be formulated as a convex optimization problem, and it can be solved very efficiently. Experimental results are reported to illustrate the effectiveness of the proposed model, and demonstrate that the classification performance of the proposed method is better than the other testing methods in this paper. PMID- 24474371 TI - LineCast: line-based distributed coding and transmission for broadcasting satellite images. AB - In this paper, we propose a novel coding and transmission scheme, called LineCast, for broadcasting satellite images to a large number of receivers. The proposed LineCast matches perfectly with the line scanning cameras that are widely adopted in orbit satellites to capture high-resolution images. On the sender side, each captured line is immediately compressed by a transform-domain scalar modulo quantization. Without syndrome coding, the transmission power is directly allocated to quantized coefficients by scaling the coefficients according to their distributions. Finally, the scaled coefficients are transmitted over a dense constellation. This line-based distributed scheme features low delay, low memory cost, and low complexity. On the receiver side, our proposed line-based prediction is used to generate side information from previously decoded lines, which fully utilizes the correlation among lines. The quantized coefficients are decoded by the linear least square estimator from the received data. The image line is then reconstructed by the scalar modulo dequantization using the generated side information. Since there is neither syndrome coding nor channel coding, the proposed LineCast can make a large number of receivers reach the qualities matching their channel conditions. Our theoretical analysis shows that the proposed LineCast can achieve Shannon's optimum performance by using a high-dimensional modulo-lattice quantization. Experiments on satellite images demonstrate that it achieves up to 1.9-dB gain over the state-of-the-art 2D broadcasting scheme and a gain of more than 5 dB over JPEG 2000 with forward error correction. PMID- 24474372 TI - Multi-label image categorization with sparse factor representation. AB - The goal of multilabel classification is to reveal the underlying label correlations to boost the accuracy of classification tasks. Most of the existing multilabel classifiers attempt to exhaustively explore dependency between correlated labels. It increases the risk of involving unnecessary label dependencies, which are detrimental to classification performance. Actually, not all the label correlations are indispensable to multilabel model. Negligible or fragile label correlations cannot be generalized well to the testing data, especially if there exists label correlation discrepancy between training and testing sets. To minimize such negative effect in the multilabel model, we propose to learn a sparse structure of label dependency. The underlying philosophy is that as long as the multilabel dependency cannot be well explained, the principle of parsimony should be applied to the modeling process of the label correlations. The obtained sparse label dependency structure discards the outlying correlations between labels, which makes the learned model more generalizable to future samples. Experiments on real world data sets show the competitive results compared with existing algorithms. PMID- 24474373 TI - A new iterative triclass thresholding technique in image segmentation. AB - We present a new method in image segmentation that is based on Otsu's method but iteratively searches for subregions of the image for segmentation, instead of treating the full image as a whole region for processing. The iterative method starts with Otsu's threshold and computes the mean values of the two classes as separated by the threshold. Based on the Otsu's threshold and the two mean values, the method separates the image into three classes instead of two as the standard Otsu's method does. The first two classes are determined as the foreground and background and they will not be processed further. The third class is denoted as a to-be-determined (TBD) region that is processed at next iteration. At the succeeding iteration, Otsu's method is applied on the TBD region to calculate a new threshold and two class means and the TBD region is again separated into three classes, namely, foreground, background, and a new TBD region, which by definition is smaller than the previous TBD regions. Then, the new TBD region is processed in the similar manner. The process stops when the Otsu's thresholds calculated between two iterations is less than a preset threshold. Then, all the intermediate foreground and background regions are, respectively, combined to create the final segmentation result. Tests on synthetic and real images showed that the new iterative method can achieve better performance than the standard Otsu's method in many challenging cases, such as identifying weak objects and revealing fine structures of complex objects while the added computational cost is minimal. PMID- 24474374 TI - Learning and recognition of on-premise signs from weakly labeled street view images. AB - Camera-enabled mobile devices are commonly used as interaction platforms for linking the user's virtual and physical worlds in numerous research and commercial applications, such as serving an augmented reality interface for mobile information retrieval. The various application scenarios give rise to a key technique of daily life visual object recognition. On-premise signs (OPSs), a popular form of commercial advertising, are widely used in our living life. The OPSs often exhibit great visual diversity (e.g., appearing in arbitrary size), accompanied with complex environmental conditions (e.g., foreground and background clutter). Observing that such real-world characteristics are lacking in most of the existing image data sets, in this paper, we first proposed an OPS data set, namely OPS-62, in which totally 4649 OPS images of 62 different businesses are collected from Google's Street View. Further, for addressing the problem of real-world OPS learning and recognition, we developed a probabilistic framework based on the distributional clustering, in which we proposed to exploit the distributional information of each visual feature (the distribution of its associated OPS labels) as a reliable selection criterion for building discriminative OPS models. Experiments on the OPS-62 data set demonstrated the outperformance of our approach over the state-of-the-art probabilistic latent semantic analysis models for more accurate recognitions and less false alarms, with a significant 151.28% relative improvement in the average recognition rate. Meanwhile, our approach is simple, linear, and can be executed in a parallel fashion, making it practical and scalable for large-scale multimedia applications. PMID- 24474375 TI - Insights into analysis operator learning: from patch-based sparse models to higher order MRFs. AB - This paper addresses a new learning algorithm for the recently introduced co sparse analysis model. First, we give new insights into the co-sparse analysis model by establishing connections to filter-based MRF models, such as the field of experts model of Roth and Black. For training, we introduce a technique called bi-level optimization to learn the analysis operators. Compared with existing analysis operator learning approaches, our training procedure has the advantage that it is unconstrained with respect to the analysis operator. We investigate the effect of different aspects of the co-sparse analysis model and show that the sparsity promoting function (also called penalty function) is the most important factor in the model. In order to demonstrate the effectiveness of our training approach, we apply our trained models to various classical image restoration problems. Numerical experiments show that our trained models clearly outperform existing analysis operator learning approaches and are on par with state-of-the art image denoising algorithms. Our approach develops a framework that is intuitive to understand and easy to implement. PMID- 24474376 TI - Bilateral panuveitis in a patient on vemurafenib BRAF inhibitor therapy for stage IV melanoma. AB - PURPOSE: To describe a case of recurrent, bilateral panuveitis caused by the BRAF proto-oncogene inhibitor vemurafenib. METHODS: Case report. RESULTS: A 25-year old woman developed bilateral panuveitis and macular edema after initiating treatment with the BRAF enzyme inhibitor vemurafenib for stage IV cutaneous melanoma. The patient was successfully treated with sub-Tenon triamcinolone injections along with cessation of the medication. CONCLUSIONS: Panuveitis is a potential adverse effect of vemurafenib. Good communication with oncology is necessary, in case the medication needs to be discontinued. PMID- 24474377 TI - Anterior segment optical coherence tomography in evaluation of severe fungal keratitis infections treated by corneal crosslinking. AB - PURPOSE: Anterior segment optical coherence tomography (OCT) is a relevant diagnostic tool in the evaluation of corneal changes following corneal crosslinking (CXL) treatment in patients infected by a severe fungal corneal infection. METHODS: Two patients with severe fungal keratitis that was unresponsive to medical treatment were treated with CXL. Corneal melting was present in all cases. Anterior segment OCT showed the preoperative depth and extension of the infiltrate and the modification during the follow-up. RESULTS: Blockage of the melting was achieved in one patient and one patient developed a corneal perforation. Anterior segment OCT allowed control of the evolution of fungal infection and evaluation of the corneal tissue response to the CXL. It is also able to identify the extent and depth of the inflammation. This parameter seems more important than corneal pachymetry to ensure the safety of CXL procedures in infectious keratitis. CONCLUSIONS: The different behavior of inflamed tissue with respect to UVA irradiance could be the main point to understand the different postoperative outcome. PMID- 24474378 TI - Comparison of visual performance after implantation of 3 types of intraocular lenses: accommodative, multifocal, and monofocal. AB - PURPOSE: To compare the performance of accommodative, multifocal, and monofocal intraocular lenses (IOLs). METHODS: In this clinical control study, 3 types of IOL were implanted in 128 eyes of 86 patients with age-related cataract who underwent phacoemulsification. Accommodative (Tetraflex), multifocal (ZMA00), and monofocal (Akreos Advanced Optics [AO]) IOLs were implanted into 43, 40, and 45 eyes, respectively. The uncorrected, best-corrected distance, contrast sensitivity, and distance-corrected intermediate and near visual acuity (UCDVA, BCDVA, CSVA, DCIVA, and DCNVA, respectively), amplitude of pseudoaccommodation, and patient satisfaction were measured at 1, 3, and 12 months after surgery. RESULTS: Differences in CSVA at all contrast degrees, UCDVA, and BCDVA among the 3 groups were not significant. Patients in the Akreos AO group exhibited a poorer DCIVA and DCNVA and experienced less pseudoaccommodation compared to patients in the other 2 groups at 3 and 12 months after surgery (p<0.01). Patients in the ZMA00 group exhibited a better DCIVA and experienced more pseudoaccommodation than patients in the Tetraflex group (3 months: p<0.05, 12 months: p<0.01 for both outcomes). Three months after surgery, total spectacle independence was achieved by 84.4%, 60.7%, and 17.2% of the ZMA00, Tetraflex, and Akreos AO group patients, respectively. CONCLUSIONS: All 3 types of IOLs allowed greater distance visual acuity; however, multifocal IOLs produced better DCIVA and DCNVA and more pseudoaccommodation and spectacle independence. Accommodative IOLs ranked second. Neither accommodative nor multifocal IOLs reduced CSVA. PMID- 24474379 TI - Paired opposite clear corneal incision: time-related changes of its effect and factors on which those changes depend. AB - PURPOSE: To assess astigmatism induced by paired opposite clear corneal incision (OCCI) compared to single incisions and to investigate factors on which its effect depends. METHODS: The study comprised 326 eyes from 326 patients. In patients with <1.0 D corneal astigmatism, clear corneal incision was performed (CC group, n = 245), and in those with >1.0 D preoperative corneal astigmatism, a second, opposite clear corneal incision was made (OCCI group, n = 81). Both groups consisted of superior, temporal, and oblique subgroups according to the steepest meridian. Prior to the surgery, and after surgery, repeated keratometry was performed and surgically induced astigmatism (SIA) was calculated using vector analysis. RESULTS: Two weeks after the surgery, the SIA was 0.67 +/- 0.44 D in the CC group and 1.15 +/- 0.65 D in the OCCI group; 9 weeks after the operation, it was 0.61 +/- 0.43 D in the CC group and 0.99 +/- 0.57 D in the OCCI group (p<0.001). The SIA showed no significant postoperative change in our groups. CONCLUSIONS: Opposite clear corneal incision reliably induces about 1.0 D of corneal astigmatism on the steep meridian in proportion to the rate of preoperative astigmatism. Its magnitude is independent of the location of the incisions and its effect remains unchanged during the postoperative period. PMID- 24474380 TI - Modified method of sutureless intrascleral posterior chamber intraocular lens fixation without capsular support. PMID- 24474381 TI - Health-related quality of life in children operated for pediatric cataracts. AB - PURPOSE: To evaluate health-related quality of life (HRQOL) in children who had surgery for pediatric cataracts. METHODS: Twenty-five children were divided into 2 groups according to the age at the time of survey (younger than 6 years in group A and 7 years and older in group B). A questionnaire that had 1 part appraising the child's perception and 3 parts evaluating the functional, social, and surgical apprehensions of parents was given to the participants. The questions in the first part were answered by parents in group A (proxy test) and by children in group B (self test). The correlations between the results and patient characteristics were evaluated statistically. RESULTS: Mean (range) score for the first part was 79.5 (58-97) in group A and 70 (56-86) in group B. Functional, social, and surgical scores were 42.5 (0-80), 45 (5-100), and 63 (12.5-100) in group A and 40 (10-90), 70 (40-85), and 75 (25-100) in group B. Functional, social, or surgical scores were not significantly different between groups. Social apprehensions were significantly higher in parents of patients with preoperative strabismus in group B. Functional, social, surgical apprehensions, and children's thoughts were not correlated significantly with age, sex, family history, laterality, associated nystagmus, aphakia or pseudophakia, postoperative optical rehabilitation, or the need for additional surgery in the groups. CONCLUSIONS: Although pediatric cataracts are known to have a great impact on children's life socially and functionally, there was no significant relationship between patient characteristics and HRQOL. The associated preoperative strabismus causes more social concern in the parents. PMID- 24474382 TI - Imaging of sub-retinal pigment epithelial linear structures in patients with age related macular degeneration. AB - PURPOSE: To evaluate hyperreflective linear structures (HLS), as assessed using spectral-domain optical coherence tomography (SD-OCT), identified under the retinal pigment epithelium (RPE) in patients with age-related macular degeneration (AMD). METHODS: This retrospective observational case study was conducted on 427 eyes of 408 consecutive patients who were scheduled to undergo anti-vascular endothelial growth factor (anti-VEGF) therapy for AMD. Patients with HLS under the RPE were investigated based on the SD-OCT findings at baseline or during the follow-up period. The associations between HLS and the lesion subtypes, localization in SD-OCT, clinical findings, and structural change after anti-VEGF treatment were also investigated. RESULTS: HLS were identified in 18 eyes of 16 patients. From the eyes with HLS, 12 eyes (66.7%) were diagnosed with retinal angiomatous proliferation (RAP), 4 eyes (22.2%) were diagnosed with occult choroidal neovascularization, and the remaining 2 eyes (11.1%) were diagnosed with polypoidal choroidal vasculopathy. HLS were multifocal and exhibited multilocalization under the RPE in all the eyes. Although it was difficult to identify these structures in the clinical findings at baseline, crystalline deposits correlated with the linear bands were observed during the follow-up period in 16 eyes (88.9%). After the anti-VEGF treatments, the HLS remained between the Bruch membrane and RPE or combined with the fibrovascular component. CONCLUSIONS: HLS are rare SD-OCT findings found in patients with AMD, found in only 4.2% of the patients examined in this study. HLS were found especially in RAP lesions. PMID- 24474383 TI - Postinduction serum infliximab trough level and decrease of C-reactive protein level are associated with durable sustained response to infliximab: a retrospective analysis of the ACCENT I trial. AB - BACKGROUND: Serum infliximab trough levels correlate with efficacy; dose escalation is often beneficial in patients with Crohn's disease who stop responding to infliximab treatment. OBJECTIVE: To carry out a post hoc analysis of A Crohn's Disease Clinical Trial Evaluating Infliximab in a New Long-term Treatment Regimen I (ACCENT I) to evaluate the association between serum infliximab trough levels and C-reactive protein (CRP) after 14 weeks of induction treatment with durable sustained long-term response (Crohn's Disease Activity Index decrease >=70 points and reduction >=25% from baseline). DESIGN: ACCENT I was a multicentre, randomised, placebo-controlled study. Week 14 trough levels and CRP percentage decrease from baseline to week 14 were compared between patients with and without durable sustained response through week 54. Sensitivity and specificity were determined to predict durable sustained response. Receiver operating characteristic (ROC) curves identified optimal cut-off points; logistic regression determined ORs. RESULTS: After induction with 5 mg/kg infliximab, 25% (37/147) and 33% (47/144) of patients sustained week 14 response to infliximab 5 or 10 mg/kg, respectively, administered every 8 weeks without dose escalation, through week 54. Median week 14 trough levels of patients with and without durable sustained response to infliximab 5 mg/kg were 4.0 and 1.9 MUg/mL, respectively (p=0.0331). Optimal predictors of durable sustained response to maintenance infliximab 5 mg/kg were week 14 trough level >=3.5 ug/mL and >=60% CRP decrease (ORs (95% CI), 3.5 (1.1 to 11.4) and 7.3 (1.4 to 36.7)), respectively, in patients with raised baseline CRP (>8.0 mg/L); area under the ROC curve was 0.75 for both predictors. A >=3.5 ug/mL week 14 infliximab serum level did not predict durable sustained response to 10 mg/kg maintenance infliximab. CONCLUSIONS: Patients with durable sustained response to maintenance infliximab 5 mg/kg had higher postinduction trough levels than patients without durable sustained response. Serum infliximab trough levels >=3.5 ug/mL and >=60% CRP decrease were significantly associated with durable sustained response. PMID- 24474384 TI - Use of proton pump inhibitors after antireflux surgery: a nationwide register based follow-up study. AB - OBJECTIVE: Antireflux surgery (ARS) has been suggested as an alternative to lifelong use of proton pump inhibitors (PPI) in reflux disease. Data from clinical trials on PPI use after ARS have been conflicting. We investigated PPI use after ARS in the general Danish population using nationwide healthcare registries. DESIGN: A nationwide retrospective follow-up study of all patients aged >=18 and undergoing first-time ARS in Denmark during 1996-2010. Two outcome measures were used: redemption of first PPI prescription after ARS (index prescription) and a marker of long-term use, defined by an average PPI use of >=180 defined daily doses (DDDs) per year. Kaplan-Meier curves and Cox proportional hazards model were used for statistics. RESULTS: 3465 patients entered the analysis. 12.7% used no PPI in the year before surgery, while 14.2%, 13.4% and 59.7% used 1-89 DDD, 90-179 DDD and >=180 DDD, respectively. Five-, 10- and 15-year risks of redeeming index PPI prescription were 57.5%, 72.4% and 82.6%, respectively. Similarly, 5-, 10- and 15-year risks of taking up long-term PPI use were 29.4%, 41.1% and 56.6%. Female gender, high age, ARS performed in most recent years, previous use of PPI and use of nonsteroidal anti-inflammatory drugs or antiplatelet therapy significantly increased the risk of PPI use. CONCLUSIONS: Risk of PPI use after ARS was higher than previously reported, and more than 50% of patients became long-term PPI users 10-15 years postsurgery. Patients should be made aware that long-term PPI therapy is often necessary after ARS. PMID- 24474385 TI - New mobile phone apps target tech savvy Indians to sign up for organ donation. PMID- 24474386 TI - Response to "selective evidence of eutrophication in the great barrier reef" by furnas et Al. PMID- 24474387 TI - Occupational solvent exposure and risk of meningioma: results from the INTEROCC multicentre case-control study. AB - OBJECTIVE: To examine associations between occupational exposure to selected organic solvents and meningioma. METHODOLOGY: A multicentre case-control study conducted in seven countries, including 1906 cases and 5565 controls. Occupational exposure to selected classes of organic solvents (aliphatic and alicyclic hydrocarbons, aromatic hydrocarbons, chlorinated hydrocarbons and 'other' organic solvents) or seven specific solvents (benzene, toluene, trichloroethylene, perchloroethylene, 1,1,1-trichloroethylene, methylene chloride and gasoline) was assessed using lifetime occupational histories and a modified version of the FINJEM job-exposure matrix (INTEROCC-JEM). Study participants were classified as 'exposed' when they had worked in an occupation for at least 1 year, with a 5-year lag, in which the estimated prevalence of exposure was 25% or greater in the INTEROCC-JEM. Associations between meningioma and each of the solvent exposures were estimated using conditional logistic regression, adjusting for potential confounders. RESULTS: A total of 6.5% of study participants were ever exposed to 'any' solvent, with a somewhat greater proportion of controls (7%) ever exposed compared with cases (5%), but only one case was ever exposed to any chlorinated hydrocarbon (1,1,1-trichloroethane). No association was observed between any of the organic solvents and meningioma, in either men or women, and no dose-response relationships were observed in internal analyses using either exposure duration or cumulative exposure. DISCUSSION: We found no evidence that occupational exposure to these organic solvents is associated with meningioma. PMID- 24474388 TI - Quadruple-resonance magic-angle spinning NMR spectroscopy of deuterated solid proteins. AB - (1)H-detected magic-angle spinning NMR experiments facilitate structural biology of solid proteins, which requires using deuterated proteins. However, often amide protons cannot be back-exchanged sufficiently, because of a possible lack of solvent exposure. For such systems, using (2)H excitation instead of (1)H excitation can be beneficial because of the larger abundance and shorter longitudinal relaxation time, T1, of deuterium. A new structure determination approach, "quadruple-resonance NMR spectroscopy", is presented which relies on an efficient (2)H-excitation and (2)H-(13)C cross-polarization (CP) step, combined with (1)H detection. We show that by using (2)H-excited experiments better sensitivity is possible on an SH3 sample recrystallized from 30 % H2O. For a membrane protein, the ABC transporter ArtMP in native lipid bilayers, different sets of signals can be observed from different initial polarization pathways, which can be evaluated further to extract structural properties. PMID- 24474389 TI - Antarctic microorganisms as source of the omega-3 polyunsaturated fatty acids. AB - Docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) are long-chain polyunsaturated fatty acids (PUFAs) that belong to the omega-3 group. They are essential fatty acids found in phospholipid of cell membranes. There is strong evidence that these nutrients may also favorably modulate many diseases. Primary sources of omega-3 PUFAs in the human diet are fish and fish-derived products. The fishing industry worldwide, however, is becoming unable to satisfy the growing demand for these PUFAs. A promising cost-effective alternative source of PUFAs is bacterial production. We identified 40 Antarctic marine bacterial isolates by 16S rRNA gene sequence analysis. Fifteen genera in three phyla were represented in the collection. Isolates were tested for ability to produce EPA using a method in which their ability to reduce 2,3,5-triphenyltetrazolium chloride (TTC) is determined and by gas chromatography coupled to mass spectrometry (GC-MS). All isolates could reduce TTC, and GC-MS analysis showed that four produced EPA and that six produced DHA. We show for the first time that isolates identified as Cellulophaga, Pibocella and Polaribacter can produce EPA and DHA, only DHA or only EPA, respectively. One isolate, Shewanella sp. (strain 8-5), is indicated to be a good candidate for further study to optimize growth and EPA production. In conclusion, a rapid method was tested for identification of new EPA producing strains from marine environments. New EPA and DHA producing strains were found as well as a potentially useful PUFA production strain. PMID- 24474390 TI - Genetic diversity in Monilinia laxa populations in stone fruit species in Hungary. AB - The objectives of this study were firstly, to determine the genetic diversity of Monilinia laxa isolates from Hungary, using the PCR-based inter-simple sequence repeat (ISSR) and randomly amplified polymorphic DNA (RAPD) technique; secondly, to prepare genetic diversity groups based on the dendrograms; and finally, to select some relevant isolates to study their fungicide sensitivity. 55 and 77 random amplified polymorphic ISSR and RAPD markers, of which 23 and 18 were polymorphic and 32 and 59 monomorphic, respectively, were used to assess the genetic diversity and to study the structure of M. laxa populations in Hungary. 27 isolates out of 57 ones were confirmed as M. laxa from several orchards (subpopulations) in three geographical regions, in various inoculum sources and in various hosts, were used. 10 fungicides and 12 isolates selected from genetic diversity groups based on the ISSR dendrograms were used to determine the fungicide sensitivity of the selected isolates. The analysis of population structure revealed that genetic diversity within locations, inoculum sources and host (H(S)) accounted for 99 % of the total genetic diversity (H(T)), while genetic diversity among locations, inoculum sources and host represented only 1 %. The relative magnitude of gene differentiation between subpopulations (G(ST)) and the estimate of the number of migrants per generation (Nm) averaged 0.005 0.009 and 53.9-99.2, respectively, for both ISSR and RAPD data set. The results obtained in dendrograms were in accordance with the gene diversity analysis. Grouping of isolates in the dendrograms was irrespective of whether they came from the same or different geographical locations. There was no relationship between clustering among isolates from inoculum sources and hosts. In the fungicide sensitivity tests, five isolates out of 12 were partly insensitive to boscalid+piraclostrobin, cyprodinil, fenhexamid or prochloraz. Obtained results in genetic diversity of M. laxa populations are discussed together with implications for the management of brown rot. PMID- 24474391 TI - Use and yield of endoscopy in patients with uncomplicated gastroesophageal reflux disorder. PMID- 24474392 TI - Steady flow hemodynamic and energy loss measurements in normal and simulated calcified tricuspid and bicuspid aortic valves. AB - The bicuspid aortic valve (BAV), which forms with two leaflets instead of three as in the normal tricuspid aortic valve (TAV), is associated with a spectrum of secondary valvulopathies and aortopathies potentially triggered by hemodynamic abnormalities. While studies have demonstrated an intrinsic degree of stenosis and the existence of a skewed orifice jet in the BAV, the impact of those abnormalities on BAV hemodynamic performance and energy loss has not been examined. This steady-flow study presents the comparative in vitro assessment of the flow field and energy loss in a TAV and type-I BAV under normal and simulated calcified states. Particle-image velocimetry (PIV) measurements were performed to quantify velocity, vorticity, viscous, and Reynolds shear stress fields in normal and simulated calcified porcine TAV and BAV models at six flow rates spanning the systolic phase. The BAV model was created by suturing the two coronary leaflets of a porcine TAV. Calcification was simulated via deposition of glue beads in the base of the leaflets. Valvular performance was characterized in terms of geometric orifice area (GOA), pressure drop, effective orifice area (EOA), energy loss (EL), and energy loss index (ELI). The BAV generated an elliptical orifice and a jet skewed toward the noncoronary leaflet. In contrast, the TAV featured a circular orifice and a jet aligned along the valve long axis. While the BAV exhibited an intrinsic degree of stenosis (18% increase in maximum jet velocity and 7% decrease in EOA relative to the TAV at the maximum flow rate), it generated only a 3% increase in EL and its average ELI (2.10 cm2/m2) remained above the clinical threshold characterizing severe aortic stenosis. The presence of simulated calcific lesions normalized the alignment of the BAV jet and resulted in the loss of jet axisymmetry in the TAV. It also amplified the degree of stenosis in the TAV and BAV, as indicated by the 342% and 404% increase in EL, 70% and 51% reduction in ELI and 48% and 51% decrease in EOA, respectively, relative to the nontreated valve models at the maximum flow rate. This study indicates the ability of the BAV to function as a TAV despite its intrinsic degree of stenosis and suggests the weak dependence of pressure drop on orifice area in calcified valves. PMID- 24474393 TI - A meta-analysis of the association between NQO1 C609T variation and acute myeloid leukemia risk. AB - Quinone oxidoreductase (NQO1) C609T polymorphisms have been implicated in acute myeloblastic leukemia (AML) risk, but previously published studies are inconsistent and recent meta-analyses have not been adequate. To derive a more precise estimation of the relationship, a meta-analysis was performed. Medline, PubMed, Embase, and Web of Science were searched. The quality of studies was evaluated by using the Newcastle-Ottawa Scale (NOS). Crude ORs with 95% CIs were used to assess the strength of association between the NQO1 C609T polymorphisms and AML risk. A total of 14 studies including 2,245 cases and 3,310 controls were involved in this meta-analysis. Overall, significantly elevated AML risk was associated with NQO1 C609T variant genotypes when all studies were pooled into the meta-analysis (TT vs. CC: OR = 1.44, 95% CI = 1.15-1.81; dominant model: OR = 1.35, 95% CI = 1.09-1.68). In the subgroup analysis by ethnicity, significantly increased risks were found for Asians (OR = 1.47, 95% CI = 1.13-1.93, P = 0.005, I(2) = 48.4%, P = 0.071 for heterogeneity). When stratified by studies of adults or children, statistically significantly elevated risks were found among adults (OR = 1.37, 95% CI = 1.06-1.76, P = 0.017, I(2) = 42.2%, P = 0.097 for heterogeneity). The accumulated evidence indicates that NQO1 C609T seems to confer a risk factor for AML among Asians and adults. Significant between-study heterogeneity was observed, thus more studies based on larger case-control population are required to further evaluate the role of NQO1 C609T polymorphism in AML. PMID- 24474394 TI - Population-based screening for Lynch syndrome in Western Australia. AB - We showed earlier that routine screening for microsatellite instability (MSI) and loss of mismatch repair (MMR) protein expression in colorectal cancer (CRC) led to the identification of previously unrecognized cases of Lynch syndrome (LS). We report here the results of screening for LS in Western Australia (WA) during 1994 2012. Immunohistochemistry (IHC) for loss of MMR protein expression was performed in routine pathology laboratories, while MSI was detected in a reference molecular pathology laboratory. Information on germline mutations in MMR genes was obtained from the state's single familial cancer registry. Prior to the introduction of routine laboratory-based screening, an average of 2-3 cases of LS were diagnosed each year amongst WA CRC patients. Following the implementation of IHC and/or MSI screening for all younger (<60 years) CRC patients, this has increased to an average of 8 LS cases diagnosed annually. Based on our experience in WA, we propose three key elements for successful population-based screening of LS. First, for all younger CRC patients, reflex IHC testing should be carried out in accredited pathology services with ongoing quality control. Second, a state- or region-wide reference laboratory for MSI testing should be established to confirm abnormal or suspicious IHC test results and to exclude sporadic cases by carrying out BRAF mutation or MLH1 methylation testing. Finally, a state or regional LS coordinator is essential to ensure that all appropriate cases identified by laboratory testing are referred to and attend a Familial Cancer Clinic for follow-up and germline testing. PMID- 24474395 TI - A retrospective study of urokinase-type plasminogen activator receptor (uPAR) as a prognostic factor in cancer of the uterine cervix. AB - BACKGROUND: Hypoxia occurs during the development of uterine cervical cancer and is considered to correlate with its invasion. Hypoxia promotes both the invasiveness and the metastasis of cancer cells through urokinase-type plasminogen activator receptor (uPAR) expression. The aim of this study was to evaluate the correlation between uPAR mRNA level and clinical prognostic factors of uterine cervical cancer. METHODS: We performed a retrospective review of 59 patients with cervical cancer and 9 subjects with normal cervical tissues. Total RNA was isolated from tissues of the uterine cervix surgically removed from patients. The mRNA of uPAR could be measured by real time PCR (RT-PCR). Histopathological factors such as histopathological type, cervical stromal, parametrial, lymphovascular, and uterine corpus invasions, metastasis to the pelvic lymph nodes, and pTNM stage were confirmed by two pathologists. The examined prognostic factors alongside the histopathological ones were FIGO clinical stage, hemoglobin level, serum level of SCC, and the effect on clinical outcomes. These factors were statistically evaluated by Fisher's exact test, log rank test, and ROC analysis. Immunohistochemical staining with anti-uPAR monoclonal antibody was also performed. RESULTS: In uterine cervical cancer, overexpression of uPAR mRNA was significantly related to shorter disease-free survival (p = 0.0396). However, the other clinical prognostic and histopathological factors were not related to uPAR mRNA expression level. Immunohistochemical staining showed that positive staining for uPAR was histologically localized on the membrane of carcinoma cells. However, the staining was not very intense. CONCLUSIONS: Overexpression of uPAR mRNA may be a prognostic factor in cancer of the uterine cervix. PMID- 24474396 TI - Thrombotic microangiopathy in metastatic melanoma patients treated with adoptive cell therapy and total body irradiation. AB - BACKGROUND: Thrombotic microangiopathy (TMA) is a complication that developed in some patients receiving 12 Gy total body irradiation (TBI) in addition to lymphodepleting preparative chemotherapy prior to infusion of autologous tumor infiltrating lymphocytes (TIL) with high-dose aldesleukin (IL-2). This article describes the incidence, presentation, and course of radiation-associated TMA. METHODS: The data for patients with metastatic melanoma who received ACT with TIL plus aldesleukin following myeloablative chemotherapy and 12-Gy TBI was examined, in order to look at patient characteristics and the natural history of TMA. RESULTS: The median time to presentation was approximately 8 months after completing TBI. The estimated cumulative incidence of TMA was 31.2% (median follow-up of 24 months). Noninvasive criteria for diagnosis included newly elevated creatinine levels, new-onset hypertension, new-onset anemia, microscopic hematuria, thrombocytopenia, low haptoglobin, and elevated lactate dehydrogenase values. Once diagnosed, patients were managed with control of their hypertension with multiple agents and supportive red blood cell transfusions. TMA typically stabilized or improved and no patient progressed to dialysis. TMA was associated with a higher probability of an antitumor response. CONCLUSIONS: TMA occurs in approximately a third of patients treated with a lymphodepleting preparative chemotherapy regimen with TBI prior to autologous T cell therapy. The disease has a variable natural history, however, no patient developed end-stage renal failure. Successful management with supportive care and aggressive hypertension control is vital to the safe application of a systemic therapy that has shown curative potential for patients with disseminated melanoma. PMID- 24474398 TI - Ribosomal and mitochondrial peroxidase isoenzymes of the lentil (Lens culinaris) root. AB - Ribosome- and mitochondria-rich preparations were obtained from lentil roots and their peroxidase isoenzymes examined by starch gel electrophoresis. Seven isoenzymes were shown to be associated with both the ribosomal and mitochondrial fractions.The apparent similarity between ribosomal and mitochondrial isoenzyme patterns, together with the observation that a considerable amount of peroxidase activity dissociated from the ribosomes during sedimentation of the ribosomal preparation into a sucrose gradient, suggested that at least some of these isoperoxidases were attached to membranes. PMID- 24474397 TI - Adenosine triphosphatase in the phloem of Cucurbita. AB - The distribution of adenosine triphosphatase (ATPase) activity in the phloem of petioles and minor veins of Cucurbita maxima has been studied using a lead phosphate precipitation procedure. ATPase activity was localized in sieve elements, companion cells and parenchyma cells. Activity was found at the cell surfaces, associated with the dispersed P-protein of mature sieve elements, in mitochondria, sieve-element reticulum, and at specific regions of the cell walls. It is suggested that the ATPase at the phloem cell surfaces may function in intercellular transport of assimilates or ions, and that the ATPase activity associated with the P-protein may function in the translocation process or in callose deposition. PMID- 24474399 TI - Translocation and the control of photosynthesis in sugar beet. AB - Evidence is presented that the size and activity of "sinks" for the products of photosynthesis exert a large measure of control over carbohydrate levels in the leaves of the sugar beet plant. Further data is presented to show that a correlation exists between the level carbohydrate in the leaf and the rate of photosynthesis. The rate of photosynthesis can thus be linked directly to the "sinks" of the plant by their ability to control rates of translocation from leaves. PMID- 24474400 TI - Role of ethylene in phytochrome-induced anthocyanin synthesis. AB - Synthesis of anthocyanin pigments in etiolated cabbage seedlings is influenced by ethylene at concentrations higher than 10 ppb, and etiolated seedlings produce sufficient ethylene to influence their anthocyanin synthesis. When escape of endogenous ethylene from this tissue is enhanced by means of hypobaric treatment, anthocyanin synthesis is accelerated. Stimulation of anthocyanin synthesis by brief red illumination is completely prevented by applied ethylene and indoleacetic acid inhibits anthocyanin synthesis by stimulating ethylene production. Red light reduces endogenous as well as auxin-induced ethylene production and there is a close correlation between light-induced inhibition of ethylene synthesis and stimulation of anthocyanin formation. We suggest that in part photo-induced anthocyanin synthesis is due to a lowered ethylene content in light-treated tissue. PMID- 24474401 TI - Sulphated polysaccharide synthesis in brown algae. AB - Histochemical and autoradiographic techniques have been used to investigate the sites of synthesis, transport and location of sulphated polysaccharides in some larger brown seaweeds.The most rapid uptake of (35)SO4 occurred when material was incubated in medium with 10(-4)M carrier sulphate, negligable uptake occurring from seawater.Autoradiography using (35)SO4 has shown that in Pelvetia sulphated material is synthesised by all cell types, particularly epidermal cells. In Laminaria spp. this activity is confined to specialized secretory cells which discharge into mucilage canals. In both instances the process of carbohydrate sulphation appears to occur in the Golgi-rich perinuclear region. PMID- 24474402 TI - Cavitation in Ricinus by acoustic detection: Induction in excised leaves by various factors. AB - Xylem cavitation has been studied in Ricinus plants using vibration detection to examine its induction by different factors. These observations provide considerable circumstantial evidence in justification of the new technique as already described and further developed. In general cavitation is induced only when the tissue water balance is reduced hydrostatically. Thus cavitation is promoted by intense radiation which enhances transpiration, or alternatively by the blockage of xylem conduits by suspended particles carried in the transpiration stream. In contrast a reduction in radiation, or prevention of transpiration tends to restrict cavitation. Thus cavitation can be prevented by immersing a leaf in liquid paraffin. This technique has been used to see if radioactive bombardment would trigger its induction but no detectable effect has been observed even when exposed to intense radiation.An excised leaf, losing water in air, produces a "click total". On restoration to full turgor by standing the petiole in water it recovers very slowly and subsequently its "click total" is much reduced. If however the newly wilted leaf is allowed to recover in water following gas evacuation treatment the "cavitation total" often approaches the original and the rate of recovery is extremely rapid. Apparently gas emboli develop rapidly in conduits which have cavitated, but they can be removed by vacuum injection: the conduits refill and conduction is restored. PMID- 24474403 TI - [On the mechanism of inhibition of mitochondrial glutamate-oxalacetate transaminase in SO2-fumigated peas]. AB - The effect of SO2-fumigation on the mitochondrial and cytoplasmic form of GOT in peas has been tested. GOT is represented by two distinct proteins in peas and therefore its activity may be taken as a measure of action of certain effectors on different components of the cell. An optical method for the direct measurement of GOT activity in crude plant extracts has been established. Using this method it could be shown that the mitochondrial GOT in SO2-fumigated peas is inhibited while at the same time the cytoplasmic form of the enzyme remains uneffected. The mechanism of inhibition of mitochondrial GOT by SO 3 (--) /HSO 3 (-) has been analyzed and could be shown to be of the mixed type. This investigation confirms an earlier observation that differential effects of SO2 on single compartments of the cell may occur. PMID- 24474405 TI - A Rhizobium selenitireducens protein showing selenite reductase activity. AB - Biobarriers remove, via precipitation, the metalloid selenite (SeO3-2) from groundwater; a process that involves the biological reduction of soluble SeO3-2 to insoluble elemental red selenium (Se0). The enzymes associated with this reduction process are poorly understood. In Rhizobium selenitireducens at least two enzymes are potentially involved; one, a nitrite reductase reduces SeO3-2 to Se0 but another protein may also be involved which is investigated in this study. Proteins from R. selenitireducens cells were precipitated with ammonium sulfate and run on native electrophoresis gels. When these gels were incubated with NADH and SeO3-2 a band of precipitated Se0 developed signifying the presence of a SeO3 2 reducing protein. Bands were cut from the gel and analyzed for peptides via LCMSMS. The amino acid sequences associated with the bands indicated the presence of an NADH:flavin oxidoreductase that resembles YP_001326930 from Sinorhizobium medicae. The protein is part of a protein family termed old-yellow-enzymes (OYE) that contain a flavin binding domain. OYE enzymes are often involved in protecting cells from oxidative stress and, due in part to an active site that has a highly accessible binding pocket, are generally active on a wide range of substrates. This report is the first of an OYE enzyme being involved in SeO3-2 reduction. PMID- 24474404 TI - Semiochemistry of the Scarabaeoidea. AB - The superfamily Scarabaeoidea comprises a large and diverse monophyletic group. Members share ancestral characteristics, but often exhibit considerable differences in their ecology, physiology, or mating strategies. A large number of species are regarded as pests of crop or amenity plants, while others are beneficial to humans and even may be extremely rare as a result of anthropogenic activities. A significant number of chemical ecology-based studies have been conducted with the Scarabaeoidea in order to characterize semiochemicals influencing their behavior, such as pheromones and plant-derived allelochemicals. These may be used either to control or preserve populations of the beetles, depending upon pest or beneficial status. This paper is a review of the role and identity of the semiochemicals of the Scarabaeoidea, with comments on possible future research and applied opportunities in the field of chemical ecology. PMID- 24474406 TI - Prospective five-year subsidence analysis of a cementless fully hydroxyapatite coated femoral hip arthroplasty component. AB - Early subsidence >1.5 mm is considered to be a predictive factor for later aseptic loosening of the femoral component following total hip arthroplasty (THA). The aim of this study was to assess five-year subsidence rates of the cementless hydroxyapatite-coated twinSys stem (Mathys Ltd., Bettlach, Switzerland).This prospective single-surgeon series examined consecutive patients receiving a twinSys stem at Maria Middelares Hospital, Belgium. Patients aged >85 years or unable to come to follow-up were excluded. Subsidence was assessed using Ein Bild Roentgen Analyse--Femoral Component Analysis (EBRA-FCA). Additional clinical and radiographic assessments were performed. Follow-ups were prospectively scheduled at two, five, 12, 24, and 60 months.In total, 218 THA (211 patients) were included. At five years, mean subsidence was 0.66 mm (95% CI: 0.43-0.90). Of the 211 patients, 95.2% had an excellent or good Harris Hip Score. There were few radiological changes. Kaplan-Meier analysis indicated five-year stem survival to be 98.4% (95% CI: 97.6-100%).Subsidence levels of the twinSys femoral stem throughout the five years of follow-up were substantially lower than the 1.5 mm level predictive of aseptic loosening. This was reflected in the high five-year survival rate. PMID- 24474407 TI - A seven- to 14-year follow-up study of bipolar hip arthroplasty in the treatment of osteonecrosis of the femoral head. AB - INTRODUCTION: Bipolar hip arthroplasty (BHA) in the treatment of Ficat stage III osteonecrosis of the femoral head (ONFH) has theoretical advantages over total hip replacement (THR) in that it preserves the natural acetabulum and uses an implant that allows better stability and larger range of movement. The purpose of this study was to evaluate the clinical and radiological outcomes of BHA with uncemented ingrowth stems in the treatment of ONFH. MATERIAL AND METHODS: Thirty nine hips in 34 patients (two women and 32 men) with a mean age at the time of surgery of 45.31 years (range 30-66 years) operated between 1998 and 2005 were examined in a retrospective evaluation. Mean follow-up was 9.5 years (range 3-14 years). Patients were evaluated with the Harris hip score (HHS). Kaplan-Meier survivorship was calculated to examine the revision rate. Radiographic analysis included evaluation of bipolar head migration, radiolucent lines around the stem and osteolysis in the acetabulum and the femur. RESULTS: Evaluation of clinical results revealed an increase in HHS from 28 points preoperatively to 88.6 points at the most recent follow-up. Radiographic evaluation showed bipolar head migration in 3 hips (7.7%). Survival rate of BHA, with revision THR defined as the endpoint, was 92.31% at ten years (CI 95%). All implanted uncemented stems were stable without any radiographic signs of loosening or osteolysis. CONCLUSIONS: The results of the present study show that implantation of BHA with uncemented ingrowth stem in Ficat stage III is still justified. PMID- 24474408 TI - Effect of a selective COX-2 inhibitor, celecoxib, on heterotopic ossification after total hip arthroplasty: a case-controlled study. AB - Heterotopic ossification (HO) is a well-known complication of total hip arthroplasty (THA), especially when the direct lateral approach is used. In this study, we examined the effect of the selective COX-2 inhibitor, celecoxib, on the rates of HO after THA. A control group consisting of 108 patients that did not receive celecoxib was compared with a study group consisting of 106 patients that did receive celecoxib. We assessed the presence and grade of HO using the Brooker classification and Harris hip scores were determined pre- and postoperatively to better quantify clinical outcomes. In this retrospective study of prospectively collected data, celecoxib is associated with a significant reduction in the incidence of HO in patients undergoing THA. PMID- 24474409 TI - Proximal femoral reconstruction after aseptic loosening following proximal femoral replacement for Ewing sarcoma: a case report with one-year follow-up. AB - We report the case of a 30-year-old patient initially treated for a proximal femoral Ewing's sarcoma when 12 years old. Index treatment comprised tumour resection and total hip arthroplasty. Two years later revision for aseptic loosening was performed. Subsequently, six further surgical revisons were performed for varying causes. At the age of 23 years the proximal femur was resected and a proximal femoral endoprosthesis implanted.Eighteen years after initial diagnosis the patient presented with recurrent aseptc loosening. Both the proximal femur and acetabulum were reconstructed. For acetabular reconstruction a structural allograft and a tantalum cup were utilised. Reconstruction of the femur utilsed extensive wire mesh and circlage wiring with impaction bone allograft into which a femoral stem was implanted.At one-year follow-up the patient was pain free, had no evidence of infection with satisfactory radiographs and no evidence of implant loosening. This is the first case reporting an extended proximal femoral reconstruction with a wire mesh in combination with impaction bone grafting in an aseptic loosened proximal femoral replacement following Ewing's Sarcoma. PMID- 24474410 TI - Regional variability in the rates of total hip replacement in Spain. AB - The role of economic resources, distribution of providers, and demography may explain part of the variability found in hip arthroplasty in international surveys. We aimed to investigate the influence of ageing index, health budget, and density of orthopaedic surgeons in the regional variability of the primary and revision THR rate in Spain, where regions decide on the allocation of their health budget.Inpatient database of hip procedures for years 1997 to 2011 was obtained from the Spanish Ministry of Health, segregated for each of the 17 regional health services in Spain. Crude and adjusted rates (direct method with total Spanish population per year) were calculated and used as dependent variables. Ageing index, Health Expenditure of Gross Domestic Product (GDP), and number of orthopaedic surgeons per region were used as independent variables. Negative binomial regression analysis model and Poisson regression were calculated to estimate the risk contribution of the ecological variables.A total of 425,914 hip procedures, with 367,489 primary (mean crude rate = 124 * 105 inhabitants/year) and 58,425 revision hips (21 * 105 inhabitants/year) were included in the analysis. Regional variability was higher than expected in THR in Spain, despite a universal coverage health system in which equity may be challenged in the administration of hip arthroplasty. This was found particularly for primary THR. When hip replacement rates were adjusted for sex and age, the regional ageing index, the density of orthopaedic surgeons and the regional health budget could only partially explain risk ratio changes. PMID- 24474411 TI - Recognition of minor adult hip dysplasia: which anatomical indices are important? AB - The rise in popularity of hip arthroscopy has led to a renewed interest in mild hip dysplasia. There is a lack of clarity in the literature regarding both the diagnosis and management of such patients. The aim of this study was to analyse the relative importance of and the inter-relationship between the classically described anatomical indices of dysplasia.One hundred and fifty hips with varying degrees of hip dysplasia were studied. The following were measured: centre-edge (CE), Sharp's and Tonnis angles, acetabular head index (AHI), and acetabular index of depth to width (AIDW). Spearman's correlation coefficient was calculated.Using the CE angle 82 hips were classified as normal and 68 dysplastic. Of the 82 patients with a normal CE angle, 20-39% were dysplastic on at least one other variable. The CE angle did not have a significant correlation to other variables. The remaining four variables showed inter-correlations between 0.26 and 0.54. Overall the Tonnis angle showed the strongest correlation with the other variables. In the patient group with CE angles 21o to 25o (minor dysplasia) 72% of hips had Tonnis angles greater than 10o and 28% had angles greater than or equal to 15o indicating the great variability in the level of dysplasia within this group.In patients with mild dysplasia we have shown that measurement of a single anatomical variable may lead to under-diagnosis. We recommend the measurement the CE angle combined with at least one other variable and suggest the use of the Tonnis angle. PMID- 24474412 TI - Gait metric profile and gender differences in hip osteoarthritis patients. A case controlled study. AB - PURPOSE: Hip osteoarthritis (OA) is a slowly progressive destructive disease that results in alterations in joint loads and biomechanics to which patients adapt compensatory alterations and abnormal gait patterns. This prospective cross sectional, case-controlled study examined these alterations in gait metrics and evaluated gender differences in gait spatiotemporal parameters. Correlations between function and gait metrics were also investigated. BASIC PROCEDURES: Hip OA patients (138 females and 122 males) and healthy controls (14 females and 26 males) matched for age and gender underwent the same investigative protocol consisting of a spatiotemporal gait analysis followed by functional evaluations using the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) and the SF-36 Health Survey (SF-36). MAIN FINDINGS: Differences between the patient and the control groups were significant in all the spatiotemporal parameters. There were significant gender differences within the hip OA group in all parameters except for cadence and single limb support percentage. WOMAC and SF-36 scores revealed significant differences between the study and control groups in most components. Significantly higher scores in the three components of the WOMAC as well as in six SF-36 score components were found among males compared to females in the patient group. PRINCIPAL CONCLUSIONS: Gait, WOMAC and SF-36 were effective objective and subjective tools for evaluating a large cohort of patients with hip OA, and can be highly useful for supplementing the assessment of hip OA severity and enhancing treatment efficacy during the course of the disease. PMID- 24474413 TI - The predictive value of radiostereometric analysis for stem survival in total hip arthroplasty. A systematic review. AB - BACKGROUND: The high precision of radiostereometric analysis (RSA) has enabled us to predict long-term implant survival with a small sample of patients followed for a relatively short period of time. The purpose of our systematic review was to validate the predictive value of two-year RSA results on long-term survival of different types of primary total hip arthroplasty stems. METHODS: We systematically reviewed literature to determine the maximum total point motion (MTPM), distal migration and rotation of stem designs and correlated these values to survival rates for aseptic loosening of these specific stems in arthroplasty registries. RESULTS: We included 32 studies describing migration of 15 different stem designs. The mean MTPM for straight polished cemented stems was 1.35 mm, for other cemented stems 0.83 mm and for other uncemented stems 1.50 mm. No data were available for the uncemented collared stem. Mean distal migration for straight polished cemented stems was 1.24 mm, for other cemented stems 0.26 mm, the uncemented collared stem 0.40 mm and for other uncemented stems 0.66 mm. Internal rotation was presented for 13 stems and all stems rotated into retroversion. All stems showed 10-year survival rates of >97% corrected for aseptic loosening. DISCUSSION: Reporting RSA results in a universal way including interpretation of outliers could improve the predictive value of RSA, allowing this technique to be an important tool during the phased introduction of new implant designs. However, a quality assessment of the data by an experienced reviewer is essential. PMID- 24474414 TI - Salter innominate osteotomy in the treatment of late presentation Perthes disease. AB - PURPOSE: The aim of this study was to evaluate the clinical and radiological results of patients presenting older than eight years and treated with Salter osteotomy for Perthes disease. METHOD: Seventeen patients (18 hips) with late presentation of Perthes disease treated with Salter osteotomy. Sixteen males were identified. The average age of patients was 8.8 years (range 8-12). Preoperation radiographs were analysed for lateral pillar staging, centre-periphery (CP) angle, Sharp acetabular index, acetabular depth index, acetabular covering percentage and Cross-over sign. Final follow-up radiograph were classified using modified Stulberg grade. RESULTS: The average follow-up of the patients was 78 months (range 40-104). During the surgery, seven hips were found to be lateral pillar grade B, three hips grade B/C and 8 hips grade C. In the final examination, 10 hips were evaluated as good (Stulberg 1 or 2), seven as medium (Stulberg 3) and one as bad (Stulberg 4). There was shortening in four patients who were all either Stulberg stage 3 or 4. A meaningful difference was detected between the pre-operation and post-operation radiographic values, regardless of the surgical staging. However, no statistical difference was found between the patients in Stulberg stage 3 or 4 and stage 1 or 2 for radiographic variables. CONCLUSION: Salter osteotomy can be used to treat older patients with lateral pillar stage B, B/C and C at presentation. PMID- 24474415 TI - Asymmetrical hip loading correlates with metal ion levels in patients with metal on-metal hip resurfacing during sit-to-stand. AB - The occurrence of pseudotumours following metal-on-metal hip resurfacing arthroplasty (MoMHRA) has been associated with high serum metal ion levels and consequently higher than normal bearing wear. Measuring ground reaction force is a simple method of collecting information on joint loading during a sit-to-stand (STS). We investigated vertical ground reaction force (VGRF) asymmetry during sit to-stand for 12 MoMHRA patients with known serum metal ion levels. Asymmetry was assessed using two methods: a ratio of VGRF for implanted/unimplanted side and an absolute symmetry index (ASI). It was found that subjects with high serum metal ion levels preferentially loaded their implanted sides. The difference between the two groups was most apparent during the first 22% of STS. VGRF ratio showed significant and strong correlation with serum metal ion levels (Spearman's rho = 0.8, p = 0.003). These results suggest that individual activity patterns play a role in the wear of MoMHRA and preferential loading of an implanted limb during the initiation of motion may increase the wear of metal-on-metal hip replacements. PMID- 24474416 TI - Philadelphia 2013: international consensus meeting on periprosthetic joint infection. PMID- 24474417 TI - [Foreign body retention after soft tissue laceration. A case of insufficient inspection and documentation]. AB - A 52-year-old man sustained a laceration to his left eyebrow after a fall in his bathroom. His plastic glasses shattered upon impact. The patient was referred to a local emergency department. After a quick exploration by the physician on call, the wound was closed by a nurse using the Steri-Strip Wound Closure system. No further exploration or imaging was performed. Four weeks after the incident the patient presented to a dermatologist with a "foreign body sensation" at the site of the laceration. Assuming a foreign body granuloma, he was referred to a maxillofacial surgeon who removed plastic debris (parts of the glasses worn by the patient). The wound subsequently healed without further complications.The patient filed a complaint for inadequate treatment in the emergency department. No detailed patient and accident history had been obtained, the wound exploration performed by the physician was superficial, and the wound closure was performed by a nurse. The expert opinion of the arbitration board ascertained a medical malpractice in terms of insufficient history, examination, and a lack of documentation. Specific questioning of the accident history would have led to the suspicion of possible foreign bodies, thus, leading to a more thorough exploration and likely further imaging. The arbitration board concluded that obtaining a detailed accident history and an accurate examination would have revealed the foreign bodies and/or led to further imaging. Complying with this, the patient could have been spared further harm and secondary surgery would have been unnecessary. PMID- 24474420 TI - Can JWH-210 and JWH-122 be detected in adipose tissue four weeks after single oral drug administration to rats? AB - Synthetic cannabinoids such as alkylindole derivatives entered the illicit drug market worldwide a few years ago. Only a few data are available concerning their pharmacokinetics, in particular their distribution and persistence in adipose tissue. For the present study, rats were administered a single 20 mg/kg oral dose of JWH-210 or JWH-122. After one month, they were dissected and adipose tissue was taken in order to study whether JWH-210 and JWH-122 persisted in this body sample. After extraction, the samples were analyzed by liquid chromatographic mass spectrometry (LC-QTrap-MS). Validation of the analytical method for adipose tissue is also presented. The results of the matrix effects determination ranged between 30.6 and 43.8%. The limits of detection for JWH-210 and JWH-122 were 0.8 and 1.0 ng/g and lower limits of quantification were 3.7 and 2.1 ng/g, respectively. Calibration curves ranged from 10 to 75 ng/g for JWH-210 and from 5 to 50 ng/g for JWH-122. Intra- and interday precision values were lower than 15% and bias values within +/-15%. Applying this method, in adipose tissue specimens obtained 4 weeks after single drug administration, JWH-210 and JWH-122 were detected in concentrations of 116 and 9 ng/g, respectively. PMID- 24474421 TI - Palladium-catalyzed oxidative carbonylation of N-allylamines for the synthesis of beta-lactams. AB - beta-Lactam scaffolds are considered to be ideal building blocks for the synthesis of nitrogen-containing compounds. A new palladium-catalyzed oxidative carbonylation of N-allylamines for the synthesis of alpha-methylene-beta-lactams is reported. DFT calculations suggest that the formation of beta-lactams via a four-membered-ring transition state is favorable. PMID- 24474422 TI - Carcinogenicity risk assessment supports the chronic safety of dapagliflozin, an inhibitor of sodium-glucose co-transporter 2, in the treatment of type 2 diabetes mellitus. AB - INTRODUCTION: Dapagliflozin is a selective inhibitor of the sodium-glucose co transporter 2 (SGLT2) that increases urinary glucose excretion to reduce hyperglycemia in the treatment of type 2 diabetes mellitus. A robust carcinogenicity risk assessment was undertaken to assess the chronic safety of dapagliflozin and SGLT2 inhibition. METHODS: Genotoxicity potential of dapagliflozin and its metabolites was assessed in silico, in vitro, and in vivo. Dapagliflozin was administered daily by oral gavage to mice, rats, and dogs to evaluate carcinogenicity risks, including the potential for tumor promotion. SGLT2(-/-) mice were observed to evaluate the effects of chronic glucosuria. The effects of dapagliflozin and increased glucose levels on a panel of human bladder transitional cell carcinoma (TCC) cell lines were also evaluated in vitro and in an in vivo xenograft model. RESULTS: Dapagliflozin and its metabolites were not genotoxic. In CD-1 mice and Sprague-Dawley rats treated for up to 2 years at >=100* human clinical exposures, dapagliflozin showed no differences versus controls for tumor incidence, time to onset for background tumors, or urinary bladder proliferative/preneoplastic lesions. No tumors or preneoplastic lesions were observed in dogs over 1 year at >3,000* the clinical exposure of dapagliflozin or in SGLT2(-/-) mice observed over 15 months. Transcription profiling in Zucker diabetic fatty rats showed that 5-week dapagliflozin treatment did not induce tumor promoter-associated or cell proliferation genes. Increasing concentrations of glucose, dapagliflozin, or its primary metabolite, dapagliflozin 3-O-glucuronide, did not affect in vitro TCC proliferation rates and dapagliflozin did not enhance tumor growth in nude mice heterotopically implanted with human bladder TCC cell lines. CONCLUSION: A multitude of assessments of tumorigenicity risk consistently showed no effects, suggesting that selective SGLT2 inhibition and, specifically, dapagliflozin are predicted to not be associated with increased cancer risk. PMID- 24474423 TI - Precision-guided sampling schedules for efficient T1rho mapping. AB - PURPOSE: To describe, assess, and implement a simple precision estimation framework for optimization of spin-lock time (TSL) sampling schedules for quantitative T1rho mapping using a mono-exponential signal model. MATERIALS AND METHODS: A method is described for estimating T1rho precision, and a cost function based on the precision estimates is evaluated to determine efficient TSL sampling schedules. The validity of the framework was tested by imaging a phantom with various sampling schedules and comparing theoretical and experimental precision values. The method utility was demonstrated with in vivo T1rho mapping of brain tissue using a similar procedure as the phantom experiment. To assist investigators, optimal sampling schedules are tabulated for various tissue types and an online calculator is implemented. RESULTS: Theoretical and experimental precision values followed similar trends for both the phantom and in vivo experiments. The mean absolute percentage error (MAPE) of theoretical estimates of T1rho map signal-to-noise ratio (SNR) was typically 5% in the phantom experiment and 33% in the in vivo demonstration. In both experiments, optimal TSL schedules yielded greater T1rho map SNR efficiency than typical schedules. CONCLUSION: The framework can be used to improve the imaging efficiency of T1rho mapping protocols and to guide selection of imaging parameters. PMID- 24474424 TI - Women's cultural perceptions and attitudes towards breast cancer: Northern Ghana. AB - This study investigates problems confronting breast cancer awareness in Ghana by ascertaining how societal perceptions and attitudes influence women's awareness of breast cancer in the Kassena-Nankana district. Data were gathered through focus group interviews and documentary analysis of current practices within the region. The data were then thematically analysed following an inductive analytical framework. The study concludes that women's perceptions of and attitudes towards breast cancer and its treatment are influenced by a myriad of economic and socio-cultural factors, which practitioners need to take into account when planning public health initiatives. There are a number of economic challenges facing breast cancer education and awareness programmes due to a lack of adequate numbers of specialized health personnel and breast cancer screening facilities in the district. Additionally, socio-cultural factors such as the absence of biomedical terminology in the local language, gender inequality and the prevailing influence of traditional health practitioners further compound the situation. Knowledge, awareness and attitudes of women towards breast cancer can also be improved if husbands of married women and respective community compound heads are targeted by public health educationists to get actively involved in education and awareness campaigns. The need to incorporate indigenous languages in public health educational materials for breast cancer in remote communities of deprived districts of Ghana is also recommended. PMID- 24474425 TI - UK doctor who charged for unworked shifts is allowed to resume practice after repaying hospital and showing remorse. PMID- 24474426 TI - Stability indicating LC method for rapid determination of related substances of O desmethyl venlafaxine in active pharmaceutical ingredients and pharmaceutical formulations. AB - A simple, precise and accurate stability-indicating reversed phase-high performance liquid chromatography method was developed for the quantitative determination of O-desmethyl venlafaxine (ODV) and its related substances in active pharmaceutical ingredient and pharmaceutical formulation. The method was developed using YMC-pack ODS-A (150 * 4.6 mm, 3 MUm) column with mobile phase containing a gradient mixture of solvents A and B. Solvent A contained a mixture of buffer and acetonitrile in the ratio of 85:15 (v/v). The buffer consisted of 10 mM potassium dihydrogen phosphate and 2 mM 1-octane sulfonic acid sodium salt (pH adjusted to 6.0 by using diluted potassium hydroxide solution). Solvent B contained a mixture of water and acetonitrile in the ratio of 20:80 (v/v). The eluted compounds were monitored at 230 nm. ODV and its six impurities were well separated within 14 min run time. It was subjected under the stress conditions of oxidative, acid, base, water, thermal and photolytic degradation. It was sensitive towards acidic, basic, oxidative and water stress conditions, stable in photolytic and thermal degradation conditions. The degradation products were well resolved from main peak and its impurities, the mass balance in each case was >99.0%, proving the stability-indicating power of the method. The developed method was validated as per International Conference on Harmonization (ICH) guidelines with respect to its specificity, linearity (correlation coefficient >0.9996), limit of detection, limit of quantification, accuracy (recovery range 97.1-103.2%), precision (% relative standard deviation <=1.9%) and robustness. PMID- 24474427 TI - Ultraperformance liquid chromatography-mass spectrometric method for determination of ampicillin and characterization of its forced degradation products. AB - In the current study, a rapid and sensitive UPLC-MS method has been developed for the quantitative analysis of ampicillin in pure and pharmaceutical formulations. Forced degradation analysis was performed and the stress degradation product thus obtained was characterized by mass spectrometry. The chromatographic separation was carried out using BEH C18 column (100 * 2.1 mm, 1.7 um particle size) using a binary mobile phase mixture of 0.001% acetic acid in water and methanol (30:70). The flow rate was set at 0.3 mL min(-1). The total chromatographic analysis time for ampicillin was as short as 1.5 min. The detection and quantitation of the studied drug was carried out using positive electrospray ionization and selected ion reaction modes. The developed method was found to be linear over the concentration range of 0.25-3.0 ug mL(-1). The recovery studies suggest an excellent recovery of the procedure which was found in the range of 99.45 100.90%. The relative standard deviation range of the developed analytical procedure ranged from 1.98 to 2.67% in intraday studies and 2.38-2.98% in case of interday study. The limit of detection and limit of quantitation of the method were found to be 0.016 and 0.049 ug mL(-1), respectively. PMID- 24474428 TI - Development and validation of a rapid liquid chromatographic method for the determination of oxatomide and its related impurities. AB - A rapid liquid chromatographic method was developed for the determination of oxatomide in its finished active pharmaceutical ingredient form and in the presence of its process impurities. The method was developed on a sub 2 um Hypersil Zorbax XDB C18 column (30 * 4.6 mm, i.d., 1.8 um). The rapid method employed a gradient mobile phase consisting of solvent A: 0.01 M tetrabutylammonium hydrogen sulfate and 0.5% (w/v) ammonium acetate in water and solvent B: acetonitrile. A flow rate of 2 mL/min was employed with the diode array detector set at 230 nm. The original method supplied by Janssen Pharmaceuticals Ltd was run on a Thermo Scientific octadecylsilyl silica gel C18 column (100 * 4.6 mm, i.d., 5 um) with an analysis time of 20 min. The main aim was to substantially reduce the analysis time while maintaining good efficiency. Run-time was reduced to 6.5 min with a total loss in analysis time of 68%. Solvent consumption was also reduced by 68%. Validation according to the International Conference of Harmonization guidelines was undertaken. The parameters examined were accuracy, precision, linearity, selectivity, robustness, limit of detection and limit of quantification; all criteria were met. Sample stability testing was also carried out. Oxatomide proved stable under ambient and 4 degrees C temperatures and in the presence of light for up to 24 h. PMID- 24474429 TI - Cells isolated from human glioblastoma multiforme express progesterone-induced blocking factor (PIBF). AB - Glioblastoma multiforme (GBM) is the most common and malignant tumor in the central nervous system. One of the contemporary hypotheses postulates that its pathogenesis is associated with the cancer stem cells (CSCs) which originate from mutations in the normal neural stem cells residing in their specific "niches." Simultaneously with its aggressive development the tumor suppresses the local immune system by different secreted and/or cell expressed factors. Progesterone induced blocking factor (PIBF) is an immunomodulatory protein with known role in the regulation of the immune response in the reproductive system. Expression of PIBF has been described in some tumors as one of the factors suppressing the anti tumor immunity. The aim of the present study was to check for the expression of PIBF from cells isolated from six GBMs. To characterize the cultured cells and to study the PIBF expression confocal microscopy, flow cytometry, ELISA, and real time PCR were used. The results obtained showed expression of markers typical for cancer CSCs and secretion of interleukin 6 by the GBM-derived cultured cells. The results convincingly prove that PIBF is intracellularly expressed by the cultured cells from the all six GBM samples, and this fact is confirmed by three different methods-flow cytometry, confocal microscopy, and real-time PCR. This paper reports for the first time the expression of PIBF by GBM-derived cells cultured in vitro and reveals a new aspect of the immunosuppressive mechanism used by GBM in escaping the immune control. PMID- 24474430 TI - Effect of cefepime dose on mortality of patients with Gram-negative bacterial bloodstream infections: a prospective cohort study. AB - OBJECTIVES: There are controversies regarding the association of cefepime therapy with increased mortality among patients with infections caused by Gram-negative bacteria (GNB). We evaluated the effect of cefepime on the mortality of patients with GNB bloodstream infections (BSIs). METHODS: A prospective cohort study was conducted in adult patients with creatinine <=1.5 mg/dL who received empirical therapy with cefepime for at least 48 h for BSIs caused by GNB. The outcome was hospital mortality. Potential clinical predictors, including a high-dose regimen (2 g every 8 h), were assessed. RESULTS: One hundred and thirteen patients were included. Most (78.8%) isolates had low cefepime MICs (<=0.25 mg/L). The overall hospital mortality was 35.4% [25.6% (10/39) and 40.5% (30/74) in patients receiving high-dose and usual-dose cefepime, respectively (P = 0.17)]. In a Cox regression model adjusted for cefepime MIC and propensity score, a high-dose regimen was independently associated with lower mortality rates [adjusted hazard ratio (aHR) 0.41; 95% CI 0.18-0.91; P = 0.029] while presentation with severe sepsis or septic shock was independently associated with higher mortality rates (aHR 4.10; 95% CI 1.78-9.40; P = 0.001). A trend to lower mortality rates was also found in the subgroup analysis of patients who had not switched antibiotic during therapy after adjustment for the latter variables. CONCLUSIONS: High-dose cefepime therapy was associated with lower mortality rates in patients with GNB BSIs, even for GNB with low cefepime MICs. PMID- 24474431 TI - Genomic variations between colistin-susceptible and -resistant Pseudomonas aeruginosa clinical isolates and their effects on colistin resistance. AB - OBJECTIVES: The emergence of colistin-resistant Pseudomonas aeruginosa is becoming a serious concern worldwide. We investigated genetic variations involved in the acquisition and loss of colistin resistance in three clinical isogenic P. aeruginosa isolates (GKK-1, GKK-2 and GKK-3) recovered from a single patient and assessed their impacts on colistin resistance. METHODS: We applied whole genome sequencing technology to identify single nucleotide polymorphisms and insertions or deletions in two colistin-resistant isolates compared with a susceptible isolate. RESULTS: Thirty-seven non-synonymous mutations in 33 coding sequences were detected in the colistin-resistant isolates GKK-1 and GKK-3. Only one gene (PA1375) was significantly down-regulated in both colistin-resistant isolates; this gene encodes erythronate-4-phosphate dehydrogenase. Among the eight genes that were up-regulated in the colistin-resistant isolates, three encoded hypothetical proteins (PA1938, PA2928 and PA4541) and five were predicted to be involved in core biological functions, encoding a cell wall-associated hydrolase (PA1199), a response regulator EraR (PA1980), a sensor/response regulator hybrid (PA2583), a glycosyltransferase (PA5447) and an arabinose efflux permease (PA5548). All mutants with allelic replacement of these candidate genes, apart from one (PA1375), exhibited increases in colistin susceptibility, ranging from 2 to 16-fold. Colistin susceptibility decreased in complemented strains compared with the mutants; however, in three cases, resistance did not reach wild-type level. CONCLUSIONS: This study demonstrates genetic differences between P. aeruginosa isogenic isolates and identifies novel determinants that may be associated with the acquisition of colistin resistance. These findings will lay the foundation for a complete understanding of the molecular mechanisms of colistin resistance in P. aeruginosa. PMID- 24474432 TI - A pharmacokinetic/pharmacodynamic model developed for the effect of colistin on Pseudomonas aeruginosa in vitro with evaluation of population pharmacokinetic variability on simulated bacterial killing. AB - OBJECTIVES: An optimized dosing regimen of the prodrug of colistin, colistin methanesulphonate (CMS), against resistant Pseudomonas aeruginosa is needed to ensure effective bacterial killing. The objectives of this study were to develop a pharmacokinetic (PK)/pharmacodynamic (PD) model that characterizes the time course of the antibacterial activity of colistin against P. aeruginosa in a static in vitro system and to perform simulations of different dosing regimens and dosing algorithms to evaluate the effect of interindividual variability and interoccasion variability in PK on bacterial killing. METHODS: Static in vitro time-kill curve experiments were conducted on two different strains of P. aeruginosa (MIC 1 and 1.5 mg/L). Mechanism-based PK/PD models were fitted in NONMEM7 and the final model was combined with a previously developed population PK model of CMS and colistin to perform simulations of variability based on different dosing algorithms. RESULTS: A model with compartments for growing and resting bacteria, with a function allowing the maximal bacterial killing of colistin to reduce upon increasing colistin exposure, characterized both the fast bactericidal effect and the adaptive resistance. The variability in PK was shown to translate into pronounced interoccasion variability in bacterial killing. A flat fixed loading dose was demonstrated to result in less variability than an algorithm based on weight. CONCLUSIONS: The developed PK/PD model described the growth, death and resistance development of P. aeruginosa in response to colistin for two different strains. Based on simulations, a flat fixed loading dose followed by an 8 or 12 hourly maintenance dose with an infusion duration of up to 2 h appeared adequate. PMID- 24474433 TI - The neoflavonoid latifolin isolated from MeOH extract of Dalbergia odorifera attenuates inflammatory responses by inhibiting NF-kappaB activation via Nrf2 mediated heme oxygenase-1 expression. AB - In Korea and China, the heartwood of Dalbergia odorifera T. Chen is an important traditional medicine used to treat blood disorders, ischemia, swelling, and epigastric pain. In this study, we investigated the inhibitory effects of latifolin, a major neoflavonoid component isolated from the MeOH extract of D. odorifera, on the inflammatory reaction of thioglycollate-elicited peritoneal macrophages exposed to lipopolysaccharide, with a particular focus on heme oxygenase-1 (HO-1) expression and nuclear factor-kappaB (NF-kappaB) signaling. Latifolin significantly inhibited the protein and mRNA expression of inducible nitric oxide synthase and COX-2, reduced NO, prostaglandins E2, tumor necrosis factor-alpha, and interleukin-1beta production in primary murine peritoneal macrophages exposed to lipopolysaccharide. Latifolin also suppressed inhibitor kappaB-alpha levels, NF-kappaB nuclear translocation, and NF-kappaB DNA-binding activity. Furthermore, latifolin upregulated HO-1 expression via nuclear transcription factor-E2-related factor 2 (Nrf2) nuclear translocation. In addition, using inhibitor tin protoporphyrin IX (SnPP), an inhibitor of HO-1, it was verified that the inhibitory effects of latifolin on the proinflammatory mediators and NF-kappaB DNA-binding activity were associated with the HO-1 expression. These results suggested that the latifolin-mediated up-regulation of HO-1 expression played a critical role in anti-inflammatory effects in macrophages. This study therefore identified potent therapeutic effects of latifolin, which warrants further investigation as a potential treatment for inflammatory diseases. PMID- 24474434 TI - Nudging guideline-concordant antibiotic prescribing: a randomized clinical trial. AB - IMPORTANCE: "Nudges" that influence decision making through subtle cognitive mechanisms have been shown to be highly effective in a wide range of applications, but there have been few experiments to improve clinical practice. OBJECTIVE: To investigate the use of a behavioral "nudge" based on the principle of public commitment in encouraging the judicious use of antibiotics for acute respiratory infections (ARIs). DESIGN, SETTING, AND PARTICIPANTS: Randomized clinical trial in 5 outpatient primary care clinics. A total of 954 adults had ARI visits during the study timeframe: 449 patients were treated by clinicians randomized to the posted commitment letter (335 in the baseline period, 114 in the intervention period); 505 patients were treated by clinicians randomized to standard practice control (384 baseline, 121 intervention). INTERVENTIONS: The intervention consisted of displaying poster-sized commitment letters in examination rooms for 12 weeks. These letters, featuring clinician photographs and signatures, stated their commitment to avoid inappropriate antibiotic prescribing for ARIs. MAIN OUTCOMES AND MEASURES: Antibiotic prescribing rates for antibiotic-inappropriate ARI diagnoses in baseline and intervention periods, adjusted for patient age, sex, and insurance status. RESULTS: Baseline rates were 43.5% and 42.8% for control and poster, respectively. During the intervention period, inappropriate prescribing rates increased to 52.7% for controls but decreased to 33.7% in the posted commitment letter condition. Controlling for baseline prescribing rates, we found that the posted commitment letter resulted in a 19.7 absolute percentage reduction in inappropriate antibiotic prescribing rate relative to control (P = .02). There was no evidence of diagnostic coding shift, and rates of appropriate antibiotic prescriptions did not diminish over time. CONCLUSIONS AND RELEVANCE: Displaying poster-sized commitment letters in examination rooms decreased inappropriate antibiotic prescribing for ARIs. The effect of this simple, low-cost intervention is comparable in magnitude to costlier, more intensive quality-improvement efforts. TRIAL REGISTRATION: clinicaltrials.gov identifier: NCT01767064. PMID- 24474435 TI - Virtobot 2.0: the future of automated surface documentation and CT-guided needle placement in forensic medicine. AB - In this paper we present the second prototype of a robotic system to be used in forensic medicine. The system is capable of performing automated surface documentation using photogrammetry, optical surface scanning and image-guided, post-mortem needle placement for tissue sampling, liquid sampling, or the placement of guide wires. The upgraded system includes workflow optimizations, an automatic tool-change mechanism, a new software module for trajectory planning and a fully automatic computed tomography-data-set registration algorithm. We tested the placement accuracy of the system by using a needle phantom with radiopaque markers as targets. The system is routinely used for surface documentation and resulted in 24 surface documentations over the course of 11 months. We performed accuracy tests for needle placement using a biopsy phantom, and the Virtobot placed introducer needles with an accuracy of 1.4 mm (+/-0.9 mm). The second prototype of the Virtobot system is an upgrade of the first prototype but mainly focuses on streamlining the workflow and increasing the level of automation and also has an easier user interface. These upgrades make the Virtobot a potentially valuable tool for case documentation in a scalpel-free setting that uses purely imaging techniques and minimally invasive procedures and is the next step toward the future of virtual autopsy. PMID- 24474436 TI - Insurance status is related to diffuse large B-cell lymphoma survival. AB - BACKGROUND: Insurance status is associated with stage at diagnosis and treatment for non-Hodgkin lymphoma (NHL), but no previous studies have addressed the relation between insurance status and survival for patients diagnosed with diffuse large B-cell lymphoma (DLBCL), the most common subtype of NHL. METHODS: The authors analyzed survival among 3858 patients with DLBCL ages 18 to 64 years who were diagnosed in 2004 using data from the National Cancer Database, a nationwide, hospital-based cancer registry. Kaplan-Maier curves were compared between patients who had private insurance, Medicaid, and no insurance. Cox proportional hazards models were fitted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for insurance controlling for age, sex, race, area level socioeconomic status, and potential mediators of the association between insurance status and survival, including stage at diagnosis, B-symptoms, comorbidity, and treatment. RESULTS: After adjusting for sociodemographic factors, uninsured patients (HR, 1.39; 95% CI, 1.14-1.70) and Medicaid-insured patients (HR, 1.48; 95% CI, 1.23-1.78) with DLBCL had lower survival compared with patients who had private insurance. This association was attenuated after adjusting for the potential mediators (for uninsured patients, HR, 1.18 [95% CI, 0.96-1.44]; for Medicaid-insured patients, HR, 1.27 [95% CI, 1.06-1.53]). CONCLUSIONS: Uninsured and Medicaid-insured patients with DLBCL had inferior survival compared with privately insured patients. These associations can be explained in part because uninsured/Medicaid-insured patients who have DLBCL present with more advanced-stage disease and comorbid illnesses and less commonly receive standard treatment. Access to affordable and adequate health care has the potential to improve survival for patients with DLBCL. PMID- 24474437 TI - Prevalence and presentation of hepatitis B and C virus (HBV and HCV) infection in Vietnamese Americans via serial community serologic testing. AB - The prevalence of hepatitis B virus (HBV) infection is reportedly high in Vietnamese Americans (VAs), but most previous studies did not assess full HBV serology, and not the prevalence of HBV and hepatitis C virus (HCV) infection simultaneously. The aim of the study is to assess the prevalence of different HBV serologies and HCV infection in VAs. This study was based on the data collected by testing for Hepatitis B surface antigen (HBsAg), anti-hepatitis B core antibody (HBcAb IgG), anti-HBs antibody (HBsAb), and anti-HCV antibody (anti-HCV) in a series of community screening in VAs in Orange County, California. In 1,405 VA participants, the mean age was 51 (17-87) years, 45.1% were males; 68.2%, married; 97.2%, born in Vietnam. Most of the participants were non-US born with their primary language being non-English and with limited access to health care. Of the 1,405 cases, 124 (8.8%) were confirmed HBV infection by HBsAg+; 81 (5.8%), HCV infection by anti-HCV+; including four (0.3%) with HBV/HCV coinfection. Twelve percent of the participants with confirmed HBV infection thought they were previously tested negative, while 29.7% of the participants with confirmed HCV infection thought they were previously tested negative. In this cohort, 15.4% were HBsAg-/HBsAb-/HBcAb IgG-, i.e. being susceptible to HBV infection. In HCV infected participants, 65.4% were born between 1945 and 1965. This large serial survey and screening in the Vietnamese American community confirmed the rates of HBV and HCV infection to be as high as 8.8% and 5.8%, respectively. We have also identified factors related to HBV and HCV infection in this high-risk population. PMID- 24474438 TI - High-order elastic terms, boojums and general paradigm of the elastic interaction between colloidal particles in the nematic liquid crystals. AB - The theoretical description of the elastic interaction between colloidal particles in NLC with incorporation of higher-order elastic terms beyond the limit of dipole and qudrupole interactions was proposed. The expression for the elastic interaction potential between axially symmetric colloidal particles, taking into account the high-order elastic terms, was obtained. The general paradigm of elastic interaction between colloidal particles in NLC was proposed so that every particle with strong anchoring and radius a has three zones surrounding itself. The first zone for a < r ? 1.3a is the zone of topological defects; the second zone at the approximate distance range 1.3a ? r ? 4a is the zone where crossover from topological defects to the main multipole moment takes place. The higher-order elastic terms are essential here (from 10% to 60% of the total deformation). The third zone is the zone of the main multipole moment, where higher-order terms make a contribution of less than 10%. This zone extends to distances where r ? 4a = 2D . The case of spherical particles with planar anchoring conditions and boojums at the poles was considered as an example. It was found that boojums can be described analitically via multipole expansion with accuracy up to 1/r(7) and the whole spherical particle can be effectively considered as the multipole of the order 6 where multipolarity equal 2(6) = 64. The corresponding elastic interaction with higher-order elastic terms gives the angle theta(min) = 34.5 degrees of minimum energy between two contact beads which is close to the experimental value of theta(min) = 30 degrees . In addition, high-order elastic terms make the effective power of the repulsive potential to be non-integer at the range 4.5 < gamma(eff) < 5 for different distances. The incorporation of the high-order elastic terms in the confined NLC also produce results that agree with experimental data. PMID- 24474439 TI - Continuum simulation of the discharge of the granular silo: a validation test for the MU(I) visco-plastic flow law. AB - Using a continuum Navier-Stokes solver with the MU(I) flow law implemented to model the viscous behavior, and the discrete Contact Dynamics algorithm, the discharge of granular silos is simulated in two dimensions from the early stages of the discharge until complete release of the material. In both cases, the Beverloo scaling is recovered. We first do not attempt a quantitative comparison, but focus on the qualitative behavior of velocity and pressure at different locations in the flow. A good agreement for the velocity is obtained in the regions of rapid flows, while areas of slow creep are not entirely captured by the continuum model. The pressure field shows a general good agreement, while bulk deformations are found to be similar in both approaches. The influence of the parameters of the MU(I) flow law is systematically investigated, showing the importance of the dependence on the inertial number I to achieve quantitative agreement between continuum and discrete discharge. However, potential problems involving the systems size, the configuration and "non-local" effects, are suggested. Yet the general ability of the continuum model to reproduce qualitatively the granular behavior is found to be very encouraging. PMID- 24474440 TI - Glucocorticoids in laryngology: a review. AB - OBJECTIVES/HYPOTHESIS: To provide the otolaryngologist an evidence-based sound review of glucocorticoid use for laryngeal pathology. STUDY DESIGN: Review of contemporary peer-reviewed literature as well as review articles. METHODS: A review of the literature regarding glucocorticoids as a therapeutic intervention for the treatment of benign laryngeal pathology and laryngeal manifestations of systemic disease was performed. Review included both systemic administration as well as local injection. RESULTS: Glucocorticoids, administered in the critical care setting for planned extubation, markedly reducing the risk of reintubation and remain a rudimentary pharmacologic adjunct in laryngeal manifestations of common autoimmune and inflammatory disorders. Intralesional injection has reduced the rate of surgical intervention for benign inflammatory primary laryngeal pathology. CONCLUSIONS: Glucocorticoids are effective in the treatment of a number of laryngeal pathologies, through both systemic and intralesional administration. However, a clear consensus for utilization of glucocorticoids in the treatment of specific laryngeal disorders has yet to be published. PMID- 24474441 TI - An in vitro model of aortic stenosis for the assessment of transcatheter aortic valve implantation. AB - A significant number of elderly patients with severe symptomatic aortic stenosis are denied surgical aortic valve replacement (SAVR) because of high operative risk. Transcatheter aortic valve implantation (TAVI) has emerged as a valid alternative to SAVR in these patients. One of the main characteristics of TAVI, when compared to SAVR, is that the diseased native aortic valve remains in place. For hemodynamic testing of new percutaneous valves and clinical training, one should rely on animal models. However, the development of an appropriate animal model of severe aortic stenosis is not straightforward. This work aims at developing and testing an elastic model of the ascending aorta including a severe aortic stenosis. The physical model was built based on a previous silicone model and tested experimentally in this study. Experimental results showed that the error between the computer-aided design (CAD) file and the physical elastic model was <5%, the compliance of the ascending aorta was 1.15 ml/mm Hg, the effective orifice area (EOA) of the stenotic valve was 0.86 cm2, the peak jet velocity was 4.9 m/s and mean transvalvular pressure gradient was 50 mm Hg, consistent with as severe. An EDWARDS-SAPIEN 26 mm valve was then implanted in the model leading to a significant increase in EOA (2.22 cm2) and a significant decrease in both peak jet velocity (1.29 m/s) and mean transvalvular pressure gradient (3.1 mm Hg). This model can be useful for preliminary in vitro testing of percutaneous valves before more extensive animal and in vivo tests. PMID- 24474442 TI - Implications of pentraxin 3 levels in patients with acute aortic dissection. AB - Acute aortic dissection (AAD) causes transient inflammation with occasional pleural fluid (PF) accumulation. Although pentraxin 3 (PTX3) is a vascular inflammation-related biomarker, little is known about PTX3 levels in patients with AAD. We explored the serial changes in plasma PTX3 levels and the association of peak levels with the amount of PF accumulation. Consecutive patients (n = 41) with Stanford type B AAD were enrolled, and blood samples for the measurements of serum albumin, plasma PTX3 and high-sensitivity C-reactive protein (CRP) were collected daily until 7 days after symptom onset. PF accumulation on computed tomography imaging on the third hospital day was divided into 3 grades (I: none or slight, II: mild in the uni- or bilateral pleural cavity, III: moderate or more). PTX3 and CRP levels were analyzed after logarithmic transformation because of their skewed distributions. Peak PTX3 and CRP levels were observed at 4.3 +/- 2.1 and 4.7 +/- 2.0 days after symptom onset, and their values were 12.2 [interquartile range (IQR), 8.2-20.9] ng/mL and 12.0 (IQR, 8.6-15.2) mg/dL, respectively. On univariate analysis, the peak level of PTX3 had a negative correlation with the minimum level of serum albumin, and a positive correlation with PF grade and duration of intensive care unit stay. On multivariate analysis, the peak level of PTX3 was correlated with PF grade (P = 0.037). In conclusion, the peak level of PTX3 in patients with AAD was associated with the amount of transient PF accumulation, which may be associated with inflammatory vascular permeability. PMID- 24474443 TI - On form and function: does chromatin packing regulate the cell cycle? AB - The Systems Biology of Cell State Regulation Section is dedicated to considering how we can define a cellular state and how cells transition between states. One important decision that a cell makes is whether to cycle, that is, replicate DNA and generate daughter cells, or to exit the cell cycle in a reversible manner. The members of the Systems Biology of Cell State Regulation Editorial Board have an interest in the role of epigenetics and the commitment to a dividing or nondividing state. The ability of cells to transition between proliferating and nonproliferating states is essential for the proper formation of tissues. The ability to enter the cell cycle when needed is necessary for complex multicellular processes, such as healing injuries or mounting an immune response. Cells that fail to quiesce properly can contribute to the formation of tumors. In this perspective piece, we focus on research exploring the relationship between epigenetics and the cell cycle. PMID- 24474444 TI - Ratio of lysine to methionine alters expression of genes involved in milk protein transcription and translation and mTOR phosphorylation in bovine mammary cells. AB - This study was conducted to determine the optimum ratio of lysine and methionine (Lys:Met) to enhance milk protein concentration in vitro, focusing on the regulation of genes related to the JAK2-STAT5 and the mammalian target of rapamycin (mTOR) signaling pathways. A preliminary dose response study revealed that casein concentration peaked (2.5-2.7 ppm) at a supplemental Lys concentration of 1.2 mM and Met at 0.5 mM. At the peak casein concentration cell proliferation rate also was higher. Furthermore, the expression of CSN1S1, CSN1S2, CSN2, CSN3, LALBA, JAK2, STAT5, and MTOR was upregulated with both Lys and Met compared with the control. A subsequent experiment was conducted as a 5 * 3 factorial design with supplemental Lys plus Met at different ratios. When the supplemental concentration of Lys was 1.2 mM and Met was 0.4 mM (~3:1), the concentration of casein peaked. Therefore, we measured gene expression, mTOR protein expression, and phosphorylated mTOR (p-mTOR) in cultures incubated with 3:1 Lys:Met (Lys&Met). Expression of CSN1S1 and LALBA were the most highly expressed genes (P < 0.01). The upregulation of CSN2, CSN3, CSN1S2 isoforms (P < 0.01) and JAK2, ELF5, mTOR (P < 0.05) was also observed. Total mTOR protein expression was greater (P < 0.05) with Lys alone and also Lys&Met. However, Lys&Met resulted in the greatest (P < 0.05) p-mTOR. Results suggest that peak concentration of casein at a supplemental 3:1 Lys:Met is driven in part via upregulation of the mRNA expression of components of the JAK-STAT and mTOR pathways. PMID- 24474445 TI - Polygenic risk for hypertriglyceridemia is attenuated in Japanese men with high fitness levels. AB - High cardiorespiratory fitness (CRF) is associated with a reduced risk for dyslipidemia; however, blood lipid levels are also affected by individual genetic variations. We performed a cross-sectional study to determine whether CRF modifies polygenic risk for dyslipidemia. Serum levels of triglycerides (TG), LDL cholesterol (LDL-C), and HDL cholesterol (HDL-C) were measured in 170 Japanese men (age 20-79 yr). CRF was assessed by measuring maximal oxygen uptake (Vo2max), and subjects were divided into low-fitness and high-fitness groups according to the reference Vo2max value for health promotion in Japan. We analyzed 19 single nucleotide polymorphisms (SNPs) associated with TG, LDL-C, or HDL-C levels. Based on these SNPs, we calculated three genetic risk scores (GRSs: TG-GRS, LDL-GRS, and HDL-GRS), and subjects were divided into low, middle, and high groups according to the tertile for each GRS. Serum TG levels of low-fitness individuals were higher in the high and middle TG-GRS groups than in the low TG-GRS group (P < 0.01 and P < 0.05, respectively), whereas no differences were detected in the TG levels of high-fitness individuals among the TG-GRS groups. In contrast, the high LDL-GRS group had higher LDL-C levels than did the low LDL-GRS group, and HDL-C levels were lower in the high HDL-GRS group than in the low HDL-GRS group regardless of the fitness level (P < 0.05). These results suggest that high CRF attenuates polygenic risk for hypertriglyceridemia; however, high CRF may not modify the polygenic risk associated with high LDL-C and low HDL-C levels in Japanese men. PMID- 24474446 TI - Measuring subjective sleepiness at work in hospital nurses: validation of a modified delivery format of the Karolinska Sleepiness Scale. AB - INTRODUCTION: Sleepiness during the work shift is common and can be hazardous to workers and, in the case of nurses, to patients under their care. Thus, measuring sleepiness in occupational studies is an important component of workplace health and safety. The Karolinska Sleepiness Scale (KSS) is usually used as a momentary assessment of a respondent's state of sleepiness; however, end-of-shift measurement is sometimes preferred based on the study setting. We assessed the predictive validity of the KSS as an end-of-shift recall measurement, asking for "average" sleepiness over the shift and "highest" level of sleepiness during the shift. METHOD: Hospital registered nurses (N=40) working 12-h shifts completed an end-of-shift diary over 4 weeks that included the National Aeronautical and Space Administration Task Load Index (NASA-TLX) work intensity items and the KSS (498 shifts over 4 weeks). Vigilant attention was assessed by measuring reaction time, lapses, and anticipations using a 10-min performance vigilance task (PVT) at the end of the shift. The Horne-Ostberg Questionnaire, Epworth Sleepiness Scale, General Sleep Disturbance Scale, and Cleveland Sleep Habits Questionnaire were also collected at baseline to assess factors that could be associated with higher sleepiness. We hypothesized that higher KSS scores would correlate with vigilant attention parameters reflective of sleepiness (slower reaction times and more lapses and anticipations on a performance vigilance task) and also with those factors known to produce higher sleepiness. These factors included the following: (1) working night shifts, especially for those with "morningness" trait; (2) working sequential night shifts; (3) having low physical and mental work demands and low time pressure; (4) having concomitant organic sleep disorders; and (5) having greater "trait" sleepiness (Epworth Sleepiness Scale). Linear mixed models and generalized linear mixed models were used to test associations that could assess the predictive validity of this format of administering the KSS. RESULTS: Greater sleepiness, as measured by higher KSS scores, was found on shifts with nurses working night shift, the third sequential night compared to the first, those with sleep disorder symptoms (especially insomnia), and in nurses with trait sleepiness on the Epworth scale. Less sleepiness (lower KSS scores) was seen in shifts with a high level of time pressure and in nurses with a biologic predisposition to be more alert in the morning (morningness trait) who worked the day shift. CONCLUSION: We found partial support for using the Karolinska Sleepiness Scale in the recalled format based on our multiple tests of predictive validity. PMID- 24474447 TI - The effect of non-benzodiazepine hypnotics on sleep quality and severity in patients with OSA: a meta-analysis. AB - PURPOSE: Although there is a high co-occurrence of insomnia and obstructive sleep apnea (OSA), the administration of sedative hypnotics in patients with OSA is still inconsistent. The aim is to study the effect of non-benzodiazepine hypnotics (non-BZDs) on sleep quality and severity in patients with OSA. METHODS: We conducted a systemic search for controlled clinical trials in multiple databases and pooled analysis of the impact of non-BZDs on objective sleep quality and the severity of OSA, including the apnea-hypopnea index (AHI) and mean and nadir arterial oxygen saturation (SaO2) in patients with OSA. Sensitivity analysis was carried out to explore the robustness of results. RESULTS: Eight relevant placebo-controlled clinical trials involving 448 patients were included. Objective sleep quality, including sleep latency, sleep efficiency, and wake time after sleep onset, was significantly improved in patients taking non-BZDs compared with those taking placebo (p<0.01). The weighted estimate indicated that the administration of non-BZDs prior to bedtime had no significant effect on AHI or SaO2 in OSA patients (p>0.05). CONCLUSIONS: The administration of non-BZDs at the commonly recommended dose has been shown to improve objective sleep quality in OSA patients without worsening sleep apnea. It suggests that OSA patients with a complaint of insomnia symptoms may benefit from taking non-BZDs. PMID- 24474448 TI - Chucaque and social stress among Peruvian highlanders. AB - Highland agriculturalists complain of the cultural syndrome chucaque in the Peruvian Andes. The first aim of this research was to ethnographically document cases of a cultural syndrome utilizing theoretical elements borrowed from cognitive anthropology. Another aim was to use case-control sampling to determine if there was a relationship between higher social stress levels and the development of a cultural syndrome. The research reported here integrated qualitative and quantitative methods. The social stress gauge developed by Rubel et al. () was adapted to the Andean cultural environment and utilized to assess highland social stressors. Chucaque was found to be locally defined as a specific type of head pain commonly associated with the episode of a traumatic event. Chucaque and household social stress levels were found to be significantly related, especially when the ratio of males to females, which often was imbalanced, was included in the analysis. PMID- 24474449 TI - Association between SNPs in P53 binding regions and risk of esophageal squamous cell carcinoma. AB - BACKGROUND: The tumor protein 53 (TP53 or p53) plays an important role in tumor suppression by binding to the regulatory region of its target genes. Single nucleotide polymorphisms (SNP) located in the p53 binding regions are likely to affect the expression of p53 target genes and may contribute to susceptibility to common diseases. The role of the genetic variations in esophageal squamous cell carcinoma (ESCC) has been well explored. However, the role of p53 binding region variations in esophageal cancer is poorly understood. METHODS: We investigated the association of 6 p53 binding region polymorphisms with susceptibility of 400 ESCC cases and 400 cancer-free controls in a Southwest Chinese population using the SNapShot assay. Differences in frequencies of the SPNs genotypes between cases and controls were evaluated using the chi-square test. RESULTS: We found that the C allele of rs1009316 in Bax and rs762624 in CDKN1A can decrease the risk of ESCC. In the multiple genetic model, we found that the rs2395655 in CDKN1A is related with the risk of ESCC, and that the G allele increases the susceptibility to ESCC (OR: 1.364; 95% CI: 1.104-1.685). We carried out a stratification analysis between alleles and risk of ESCC according to clinical stage. There was no relationship between these SNPs and clinical stage. CONCLUSION: SNPs in the p53 binding region may modulate the risk of ESCC in the Southwest Chinese population. PMID- 24474450 TI - Performance of robust regression methods in real-time polymerase chain reaction calibration. AB - The ordinary least squares (OLS) method is routinely used to estimate the unknown concentration of nucleic acids in a given solution by means of calibration. However, when outliers are present it could appear sensible to resort to robust regression methods. We analyzed data from an External Quality Control program concerning quantitative real-time PCR and we found that 24 laboratories out of 40 presented outliers, which occurred most frequently at the lowest concentrations. In this article we investigated and compared the performance of the OLS method, the least absolute deviation (LAD) method, and the biweight MM-estimator in real time PCR calibration via a Monte Carlo simulation. Outliers were introduced by replacement contamination. When contamination was absent the coverages of OLS and MM-estimator intervals were acceptable and their widths small, whereas LAD intervals had acceptable coverages at the expense of higher widths. In the presence of contamination we observed a trade-off between width and coverage: the OLS performance got worse, the MM-estimator intervals widths remained short (but this was associated with a reduction in coverages), while LAD intervals widths were constantly larger with acceptable coverages at the nominal level. PMID- 24474451 TI - Prognostic significance of microRNA-221/222 expression in cancers: evidence from 1,204 subjects. AB - BACKGROUND: The prognostic significance of the expression of the miR-221/222 family in cancer remains controversial. We here performed a meta-analysis of published data investigating the effects of miR-221/222 expression on both overall survival (OS) and disease-free survival (DFS) among patients with cancer. METHODS: A systematic search of the PubMed, Embase, Cochrane, and CNKI databases was performed with the last search being updated on March 15, 2013. The hazard ratio (HR) and its 95% confidence interval (95% CI) were used to assess the strength of association. RESULTS: A total of 17 studies involving 1,204 subjects were included in this meta-analysis. When assessing the prognostic significance of miR-221 expression, the pooled HR was 1.91 (95% CI: 1.28-2.85, p=0.002) for OS and 1.36 (95% CI: 0.88-2.09, p=0.163) for DFS. When assessing the prognostic significance of miR-222 expression, the pooled HR was 2.15 (95% CI: 1.51-3.06, p<0.0001) for OS and 1.37 (95% CI: 0.45-4.13, p=0.581) for DFS. We also found that an elevated miR-221 expression was significantly associated with poor OS when stratifying by ethnicity, cancer type, statistical methodology, sample, and quality assessment. There was no evidence of publication bias. CONCLUSION: The meta-analysis demonstrates that the elevated expression of miR-221 and miR-222 is associated with poor OS in patients with cancer. The miR-221/222 cluster might be used as a potential therapeutic strategy in clinical practice. More work is required to fully elucidate the role of the miR-221/222 family in human tumors. PMID- 24474452 TI - MicroRNAs 143 and 145 may be involved in benign prostatic hyperplasia pathogenesis through regulation of target genes and proteins. AB - OBJECTIVES: The aim of this study was to analyze the roles of miR-143 and miR 145, as well as the gene and protein expression of their targets (KRAS, ERK5, MAP3K3, and MAP4K4) in the pathogenesis of benign prostatic hyperplasia (BPH). METHODS: We analyzed the specimens of 44 patients diagnosed with BPH who underwent surgical treatment. The control group consisted of prostate samples from 2 young patients who were organ donors. miRNAs and their target genes were assessed using real-time polymerase chain reaction (qRT-PCR), and protein levels were assessed by Western blotting. RESULTS: miR-143 and miR-145 were overexpressed in, respectively, 62.5% and 73.8% of the cases. The ERK5 and MAP4K4 genes were underexpressed respectively in 59.4% and 100% of the BPH samples, whereas KRAS and MAP3K3 were overexpressed respectively in 79.4% and 61.5% of the samples. Increased protein expression was found for both KRAS (4,312.2 luminance/area) and MAP3K3 (7,461.7 luminance/area), while the ERK5 protein was more abundant in the samples from patients with prostate larger than 60 grams (p=0.019). CONCLUSIONS: The overexpression of miR-143 and miR-145 in BPH samples suggests an association with the pathogenesis of the disease; additionally, the latter miRNA may act through the inhibition of MAP4K4. KRAS and MAP3K3 overexpression may also be associated with BPH pathogenesis. Further analyses are necessary to confirm these results. PMID- 24474453 TI - Pathology-confirmed granuloma mimicking liver metastasis of breast cancer. AB - For patients with breast cancer, obtaining tissue samples from liver lesion becomes more and more important for both differential diagnosis and subsequent treatment. However, the procedure is not considered as mandatory routine and is not frequently performed. We here reported about a patient with breast cancer history and a solitary liver metastasis that was clinically diagnosed by both magnetic resonance imaging (MRI) and position emission tomography - computed tomography (PET-CT). However, pathologic diagnosis after partial hepatectomy (between sections VII and VIII) revealed multifocal granulomas. The case further addresses the importance of core needle biopsy, or surgical biopsy, for obtainment of a histological diagnosis, especially in the presence of a solitary lesion, even when the lesion has a typical medical imaging supporting metastasis, and uptake of radioactive 18F-fluorodeoxyglucose (18F-FDG) by PET-CT. PMID- 24474454 TI - CD24 gene polymorphism--a novel prognostic factor in esophageal cancer. AB - BACKGROUND: The CD24 gene has been correlated with poor prognosis of various malignancies. The significance of CD24 in esophageal cancer remains unknown. Our aim was to evaluate the association between CD24 genetic polymorphism and esophageal cancer. MATERIALS AND METHODS: Between June 2011 and May 2012 patients with esophageal cancer and healthy controls were prospectively enrolled and clinicopathological data were collected. Genomic DNA was extracted and restriction fragment length polymorphism (RFLP) analysis was performed to determine CD24 polymorphism at the coding region of CD24, which results in a substitution of the amino acid Ala by Val. Statistical significance was determined by unpaired t-test, chi2-test, and Fisher's exact test. RESULTS: A total of 102 patients were included, of whom 51 had esophageal cancer and the rest comprised a healthy control group. The incidence of the polymorphism variant (Val/Val) among the healthy subjects and the esophageal cancer cohort was 6% in both groups. The incidence of N3 (metastasis in 7 or more regional lymph nodes) was markedly higher in those esophageal cancer patients who carried the polymorphism variant compared with those who did not carry it (66% and 2%, respectively, p=0.007). No significant difference was found between the groups with regard to age, gender, histology type, tumor location, tumor stage, and other histological characteristics of the tumor. CONCLUSIONS: This CD24 polymorphism may serve as a novel prognostic marker identifying esophageal cancer patients with poor prognosis. Further studies are warranted to evaluate CD24 function and to validate its predictive potential with regard to esophageal cancer. PMID- 24474455 TI - MTHFR/p53 polymorphisms as genetic factors for cervical intraepithelial neoplasia and cervical cancer in HPV-infected Mexican women. AB - We performed a case-control association study to evaluate the association between common polymorphisms in MTHFR (C677T and A1298C) and the Arg72Pro polymorphism in the p53 gene and the risk for cervical intraepithelial neoplasia (CIN) or invasive cervical cancer (ICC) in Mexican HPV-infected women. We included 131 women with diagnosis of CIN grade I-II and 78 with CIN III or ICC; as controls we also included 274 women with normal Pap smear and negative HPV test. Genotyping for MTHFR and p53 polymorphisms was performed by PCR-RFPLs. HPV was tested by Hybrid Capture II. Odds ratios and 95% confidence intervals were estimated. Genotype frequencies for the 3 studied polymorphisms were distributed according to the Hardy-Weinberg equilibrium. The A1298C-MTHFR polymorphism showed significant differences for the heterozygous AC genotype and the C allele, whereas the AA genotype and A allele resulted to be genetic risk factors for CIN or ICC (p<0.03). The Arg72Pro-p53 polymorphism showed for the genotypes Arg/Pro and Pro/Pro, and for the Pro allele, a significant association only to the risk for CIN (p<0.03). The MTHFR/p53 interaction showed that the genotype combinations AA/ArgArg and AA/ArgPro were associated, respectively, to the risk of ICC and CIN (p<0.05). This study suggests that the A1298C-MTHFR polymorphism contributes to the genetic risk for both CIN and ICC, whereas the Arg72Pro-p53 polymorphism only contributes to the risk for CIN. The MTHFR/p53 genetic combinations AA/ArgArg and AA/ArgPro are associated genetic risk factors for ICC and CIN in Mexican HPV infected women. PMID- 24474456 TI - The optimal timing to perform 18F/11C-choline PET/CT in patients with suspicion of relapse of prostate cancer: trigger PSA versus PSA velocity and PSA doubling time. AB - In the present short communication we considered the main publications focused on trigger prostate-specific antigen (PSA) and PSA kinetics that systematically compared 18F to 11C-choline PET/CT in order to establish the optimal time to perform choline PET/CT in relation to the trigger values and velocity, as well as doubling time of PSA serum levels. PMID- 24474457 TI - Embryogenesis and germination in rye (Secale cereale L.) : III. Fine structure and biochemistry of the non-viable embryo. AB - Fine structural investigations of non-viable rye grains indicate recognisible abnormalities in the plasmalemma and mitochondrial membranes of the unimbibed embryo. Once such grains are wetted there is rapid and progressive disorganisation of the tissue. Biochemical studies show a reduced uptake of water, lack of respiratory activity and a failure in nucleic acid and protein synthesis. Whereas total DNA, RNA and protein levels are unchanged on loss of viability, the integrity of DNA and RNA is impaired and ribosomal RNA and soluble protein levels are reduced. PMID- 24474458 TI - Plasmalemma fine structure in isolated tobacco mesophyll protoplasts. AB - Tobacco mesophyll protoplasts have been examined by electron microscopy during isolation procedures and after 24 hours culture in a medium known to support cell wall regeneration. During isolation the plasmalemma shows little structural differentiation apart from the formation of small vacuoles in the cytoplasm. After 24 hours of culture, several types of activity are seen at the plasmalemma surface. Microtubules, profiles of endoplasmic reticulum, electron dense granules and coated vesicles are associated with the inner surface of the membrane. External to the plasmalemma fibrillar structures occur, both as extensive networks and as individual fibrils apparently associated with the membrane itself. Techniques and criteria for electron microscopy are presented, and the results discussed in terms of plasmalemma function and the regeneration of the cell wall. PMID- 24474459 TI - Studies in seed dormancy : VII. The abscisic acid content of the seeds and fruits of Corylus avellana L. AB - ABA has been identified by GLC-MS and routinely determined by GLC as one of several inhibitory substances in the testa and pericarp of hazel nuts. Its concentration in newly harvested nuts, which had not developed embryo dormancy, was 19.0 nmoles/g dry weight for the testa, 1.4 nmoles/g for the pericarp and 0.09 nmoles/g for the embryo. Dry storage of the nuts resulted in the development of embryo dormancy together with a slight loss of ABA. On imbibition of dormant nuts at 5 degrees C and 20 degrees C there was a 61% loss of ABA from the testa and pericarp in both cases. However the 5 degrees C imbibition resulted in the breaking of seed dormancy while the 20 degrees C imbibition had no effect on the dormancy. The ABA of the testa and pericarp seems to be concerned with the maintenance of seed dormancy prior to the onset of embryo dormancy. Subsequent to the onset of embryo dormancy, ABA seems to show little effect on either the maintenance or breaking of seed dormancy. PMID- 24474460 TI - Mechanism of the growth-promoting action of fusicoccin : Interaction with auxin, and effects of inhibitors of respiration and protein synthesis. AB - Analogies and differences between the growth-promoting action of fusicoccin (FC), the toxic agent produced by Fusicoccum amygdali, and of indole-3-acetic acid (IAA) in etiolated pea internode segments were further investigated. It was confirmed that the effect of FC, at optimal concentration, on growth by cell enlargement is markedly higher (ca. 70%) than that of IAA. The lack of an inhibitory effect of FC at high concentrations corresponds to a lack of capacity of the toxin to induce ethylene synthesis. When FC and IAA are present together at suboptimal concentrations, the effects of the two substances are clearly additive. Growth stimulation by a mixture of FC and IAA at optimal concentrations is equal to that by FC alone. NaF, 2,4-DNP, actinomycin D, and cycloheximide strongly depress FC-induced stimulation of cell enlargement. These data are in agreement with the hypothesis that FC promotes growth through some effect on cell wall extensibility probably identical to the one mediating auxin-induced growth, while the primary site of action of FC is different from that of the natural and synthetic auxins. PMID- 24474461 TI - Plastids in sieve elements and their companion cells : Investigations on monocotyledons, with special reference to Smilax and Tradescantia. AB - Plastids have been identified in the sieve elements and/or companion cells of 14 monocotyledon species. In contrast to earlier reports, plastids are present in the sieve elements of Smilax and the companion cells of Tradescantia. The development and fine structure of the sieve-element plastids in Smilax do not differ from the type found in all of the 230 angiosperm species we have studied so far contain prominent plastids. The companion cells are easily identified by their specialized plasmatic connections with the sieve elements. The leucoplasts in the companion cells of Tradescantia are identical with those reported for many angiosperms. PMID- 24474462 TI - [Isoenzymes of malate dehydrogenase from watermelon seedlings: Disappearance of microheterogenity during germination]. AB - 1) In cotyledons of dry seeds from watermelons, 10 weak bands of MDH were detectable by electrophoresis (Fig. 1). After 3 hrs of germination, this pattern was reduced to 4 stronger bands whereas the total MDH activity remained unchanged. Artifacts were excluded by use of the reverse enzyme reaction (Fig. 2), different homogenizing media and mixing experiments. 2) Molecular weight comparisons (Fig. 3) showed that with the exception of a glyoxysomal band (exclusion b Sephadex G-200) appearing at day 2 all bands and subbands had the same values (somewhat below 60000). 3) Homogenization of cotyledons from dry seeds with 10 mM beta-mercaptoethanol resulted in a 4 band pattern (Fig. 8) identical to that found 3 hrs after sowing. Treatment of older cotyledons did not influence the later pattern. Electrophoresis of the raw extracts in presence of NAD or/and malate did not change the number of bands, only the RF-values. Dialysis of raw extracts was without influence. 4) On the basis of these experiments it is concluded that during germination splitting processes of disulfide bridges take place which may result in conformation changes. According to this hypothesis dry seeds would contain 4 groups of conformational isoenzymes. PMID- 24474463 TI - Uptake and metabolism of 2-[(14)C]abscisic acid in lettuce fruits var. Great Lakes. AB - There are two phases of 2-[(14)C]ABA uptake in lettuce fruits. Although the first phase appears to relate to the imbibition of water, uptake continues for three hours following complete imbibition. The second phase corresponds with the commencement of radicle extension.Exogenously applied radioactive ABA is metabolised to form an unidentified substance which has chromatographic properties different to previously described ABA metabolites. When ABA is present in the bathing solution, the quantity of metabolite never significantly exceeds that of labelled ABA in the tissues. PMID- 24474464 TI - [Relations between enzymes which build up flavonols, enzymes which convert flavonols, and the accumulation of phenylpropanoid compounds during the development of anthers]. AB - The difference in activity of enzymes which are involved in the biosynthesis of flavonols (phenylalanineammonium-lyase, chalcone-flavanone isomerase) and of an enzyme which converts flavonols is studied during the development of anthers in Tulipa cv. Apeldoorn. The results are considered in relation to the accumulation of simple phenylpropanes, of an intermediate a chalcone and of different flavonoid compounds.In the stages of development with high activities of flavonol synthesizing enzymes there are also high activities in the flavonol converting enzymes. In these stages a large amount of derivates of p-coumaric acid and ferulic acid is accumulated as well as the intermediate product 2',3,4,4',6' pentahydroxychalcone; accordingly only traces of flavonols can be found.An intensive accumulation of different flavonols does not start before the late phase of development of the anthers in which the stationary concentration of chalcones decreases. It is the stage when the activity of the flavonol converting enzyme decreases rapidly.The relations between the stationary concentration of flavonoid compounds and the interlacing of synthesis and turnover are discussed. PMID- 24474465 TI - The effect of salt on protein synthesis in the halophyte Suaeda maritima. AB - An amino acid-incorporating microsomal fraction has been isolated from the leaves of the halophyte Suaeda maritima and the characteristics of the incorporation described. There were no differences in the properties of the microsomes isolated from plants grown in saline and non-saline conditions. The incorporation was severely inhibited by high concentrations of sodium or potassium ions. The results are discussed in relation to the mechanism of salt tolerance in halophytes and the localization of salt in the cells. PMID- 24474466 TI - Evidence for differential action of indoleacetic acid upon ion fluxes in single cells of Petroselinum sativum. AB - The apparent influx of (36)Cl(-) and (86)Rb(+)/K(+) into cells from the higher plant Petroselinum sativum has been measured during the presence and absence in the culture medium of indolacetic acid (IAA) which is an essential auxin of these cells. While 10(-5) M IAA did not significantly affect the influx of (86)Rb(+)/K(+), it substantially reduced that of (36)Cl(-), i.e. by a factor 0.25 within 30 min. This differential action of IAA, which holds for a reasonable range of external pH, is assumed to bear on current hypotheses that the primary events of auxin action involve plasmalemma functions. PMID- 24474468 TI - Arsenate resistant Penicillium coffeae: a potential fungus for soil bioremediation. AB - Bioremediation is an effective method for the treatment of major metal contaminated sites. Fungi were isolated from soil samples collected from different arsenate contaminated areas across India. An isolate, Penicillium coffeae, exhibited resistance to arsenate up to 500 mM. Results indicated that pretreatment of biomass with alkali (NaOH) enhanced the percentage of adsorption to 66.8% as compared to that of live and untreated dead biomass whose adsorption was 22.9% and 60.2% respectively. The physiological parameters evaluated in this study may help pilot studies aimed at bioremediation of arsenate contaminated effluents using arsenate resistant fungus P. coffeae. PMID- 24474467 TI - Anti-beta2M monoclonal antibodies kill myeloma cells via cell- and complement mediated cytotoxicity. AB - Our previous studies showed that anti-beta2M monoclonal antibodies (mAbs) at high doses have direct apoptotic effects on myeloma cells, suggesting that anti-beta2M mAbs might be developed as a novel therapeutic agent. In this study, we investigated the ability of the mAbs at much lower concentrations to indirectly kill myeloma cells by utilizing immune effector cells or molecules. Our results showed that anti-beta2M mAbs effectively lysed MM cells via antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which were correlated with and dependent on the surface expression of beta2M on MM cells. The presence of MM bone marrow stromal cells or addition of IL-6 did not attenuate anti-beta2M mAb-induced ADCC and CDC activities against MM cells. Furthermore, anti-beta2M mAbs only showed limited cytotoxicity toward normal B cells and nontumorous mesenchymal stem cells, indicating that the ADCC and CDC activities of the anti-beta2M mAbs were more prone to the tumor cells. Lenalidomide potentiated in vitro ADCC activity against MM cells and in vivo tumor inhibition capacity induced by the anti-beta2M mAbs by enhancing the activity of NK cells. These results support clinical development of anti-beta2M mAbs, both as a monotherapy and in combination with lenalidomide, to improve MM patient outcome. PMID- 24474469 TI - MRI features of ovarian cystic lesions. AB - The purpose of this article is to present the clinical and imaging features for the spectrum of ovarian cystic lesions, from benign to malignant and from tumorous to nontumorous. We review the imaging modalities for evaluating ovarian cystic lesions, especially magnetic resonance imaging (MRI) techniques. We present clinical and imaging features that can be used to help with the differential diagnosis of the spectrum of ovarian cystic lesions. We discuss the relevance of imaging features for distinguishing between benign and malignant ovarian cystic lesions. The characteristic clinical and imaging features of ovarian cystic lesions can provide criteria for making a diagnosis or substantially narrowing the differential diagnosis. Therefore, a careful assessment of ovarian cystic lesions is warranted. PMID- 24474470 TI - Nick Black: Looking for a post at Arsenal. PMID- 24474472 TI - Surgical aortic valve replacement vs transcatheter aortic valve replacement: a consumer's perspective regarding data education and transparency of hospitals. PMID- 24474473 TI - Otorhinolaryngology without borders. PMID- 24474474 TI - National Voice Campaign--2012. PMID- 24474471 TI - An inherited duplication at the gene p21 Protein-Activated Kinase 7 (PAK7) is a risk factor for psychosis. AB - Identifying rare, highly penetrant risk mutations may be an important step in dissecting the molecular etiology of schizophrenia. We conducted a gene-based analysis of large (>100 kb), rare copy-number variants (CNVs) in the Wellcome Trust Case Control Consortium 2 (WTCCC2) schizophrenia sample of 1564 cases and 1748 controls all from Ireland, and further extended the analysis to include an additional 5196 UK controls. We found association with duplications at chr20p12.2 (P = 0.007) and evidence of replication in large independent European schizophrenia (P = 0.052) and UK bipolar disorder case-control cohorts (P = 0.047). A combined analysis of Irish/UK subjects including additional psychosis cases (schizophrenia and bipolar disorder) identified 22 carriers in 11 707 cases and 10 carriers in 21 204 controls [meta-analysis Cochran-Mantel-Haenszel P-value = 2 * 10(-4); odds ratio (OR) = 11.3, 95% CI = 3.7, infinity]. Nineteen of the 22 cases and 8 of the 10 controls carried duplications starting at 9.68 Mb with similar breakpoints across samples. By haplotype analysis and sequencing, we identified a tandem ~149 kb duplication overlapping the gene p21 Protein Activated Kinase 7 (PAK7, also called PAK5) which was in linkage disequilibrium with local haplotypes (P = 2.5 * 10(-21)), indicative of a single ancestral duplication event. We confirmed the breakpoints in 8/8 carriers tested and found co-segregation of the duplication with illness in two additional family members of one of the affected probands. We demonstrate that PAK7 is developmentally co expressed with another known psychosis risk gene (DISC1) suggesting a potential molecular mechanism involving aberrant synapse development and plasticity. PMID- 24474475 TI - Atopy and adenotonsillar hypertrophy in mouth breathers from a reference center. AB - Mouth breathers use the oral cavity as their principal breathing route. The main causes include: adenotonsillar hypertrophy and inflammatory diseases such as allergic rhinitis. OBJECTIVE: To look for atopy, the main allergens involved and to check for atopy as a comorbidity with the degree of hypertrophy of the tonsils and adenoids in mouth breathers. METHOD: A historical cohort study with cross sectional review of 308 medical charts of patients treated at a mouth breather care center of a tertiary hospital in the period of 2008-2010. We collected data on the mouth breather's clinical history and we ran otolaryngological exams, flexible nasal endoscopy and skin prick test to aeroallergens. RESULTS: Of 308 patients, 36% were positive on allergy testing, with 95 % of atopic patients being positive for mites. Among all patients, 46% had adenoid hypertrophy; of these, 37% were atopic and 47% had tonsillar hypertrophy, and among these, 33% were atopic. CONCLUSION: We found no direct correlation between atopy and the degree of tonsils and adenoid hypertrophy observed among the mouth-breathing patients assessed. si. PMID- 24474476 TI - Obstructive sleep apnea: is there a difference between vertical and horizontal laryngectomy? AB - Partial laryngectomy is used in the treatment of laryngeal cancer. Structural alterations of the upper airway arising from partial laryngectomy can cause obstructive sleep apnea (OSA). OBJECTIVE: To compare the prevalence and severity of OSA in patients submitted to horizontal and vertical partial laryngectomy and assess the role of spirometry for these patients. METHOD: Cross-sectional clinical study with individuals offered partial laryngectomy. The included patients were assessed through interview, upper airway endoscopy, polysomnography, and spirometry. RESULTS: Fourteen patients were evaluated and 92.3% were found to have OSA. The apnea-hypopnea index was significantly higher among patients submitted to vertical laryngectomy (mean = 36.9) when compared to subjects offered horizontal laryngectomy (mean = 11.2). The mean minimum oxyhemoglobin saturation was 85.9 in the horizontal laryngectomy group and 84.3 in the vertical laryngectomy group. Spirometry identified extrathoracic upper airway obstruction in all patients with OSA. CONCLUSION: The studied population had a high incidence of obstructive sleep apnea. OSA was more severe in patients offered vertical laryngectomy than in the individuals submitted to horizontal laryngectomy. Spirometry seems to be useful in the detection of cases of suspected OSA, as it suggests the presence of extrathoracic upper airway obstruction. PMID- 24474477 TI - Correlation between symptoms and course duration of upper aerodigestive tract cancer at early and advanced stages. AB - There still are many clinical and biological aspects of the natural history of cancer of the upper aerodigestive tract to be unveiled; which in Brazil is a direct consequence of the failure of systematic prevention and early diagnosis campaigns. OBJECTIVE: To analyze the signs and symptoms presented by patients with the disease at initial and advanced stages. Other variables such as disease duration, general and nutritional status were considered. METHOD: A historical cohort study with a cross-section involving 895 subjects with cancer of the upper aerodigestive tract. RESULTS: Clinical findings were not statistically correlated with disease progression, nor with the disease in early stages, but it showed rapid disease development. CONCLUSION: The results suggest a disease of insidious onset in the early stages and fast course afterwards. The long disease duration - greater than three months, was associated with worsening in general and nutritional states of patients. PMID- 24474478 TI - Results of hearing aids use dispensed by a publicly-funded health service. AB - Hearing aid use and satisfaction can be used to analyze the effectiveness of hearing rehabilitation, an issue few explored in Brazilian users. OBJECTIVE: Evaluate hearing aid use dispensed in a publicly-funded health service after one year, the interventions needed and users' satisfaction. METHOD: Prospective observational cross-sectional study. Hearing aid users were invited by telephone to participate in an evaluation of hearing aid use. RESULTS: 200 hearing aid users attended the evaluation (47% of sample loss); 76.5% of the subjects were using hearing aids bilaterally, 10.5% unilaterally and 13.0% none of them; 99.5% of users needed some kind of intervention. Users who kept wearing their hearing aids were considered "satisfied". CONCLUSION: Active search by telephone showed that hearing aid users who attend this publicly-funded health service have difficulties to attend follow-up appointments. Most of the users that came for evaluation kept using their hearing aids; non-use rate was 13%. Practically all hearing aid users needed some kind of intervention. Despite the high level of satisfaction, those findings did not include users who did not participate in evaluation, which could represent subjects less adhered to the treatment. Results highlighted the need of periodical follow-ups to ensure the effectiveness of auditory rehabilitation. PMID- 24474479 TI - Population epidemiological study on the prevalence of dizziness in the city of Sao Paulo. AB - The epidemiology of dizziness is essential in clinical practice. OBJECTIVE: To establish the prevalence of dizziness in the adult population of Sao Paulo, its clinical characteristics and level of discomfort. METHOD: A prospective cross sectional study ran from April to October of 2012 by a field questionnaire, totaling 1,960 interviews. The predictor variables assessed were age, gender, type of dizziness and the dizziness disability index. The statistical tools used to assess the significance between variables were the chi-square test, Student's t-test and logistic regression. We used a 95% confidence interval for estimated values. RESULTS: The prevalence of dizziness in the city of Sao Paulo was established at 42%. We found two peak of complaints, 49% in the range of 46-55 years and 44% in the elderly. Vestibular-related dizziness was estimated to affect 8.3% of the population, mainly women (p < 0.001). The symptoms caused disability in 27% of symptomatic interviewees and it is more bothersome to females (p < 0.001), who more frequently seek medical care (p < 0.001). CONCLUSION: The prevalence of dizziness in Sao Paulo was found to be 42%. It affects daily activities in 67% of symptomatic patients, but only 46% of them seek medical help. PMID- 24474480 TI - ENT foreign bodies: profile of the cases seen at a tertiary hospital emergency care unit. AB - Individuals often seek help with foreign bodies (FB) in their ears, noses, and throats. Proper recognition, study, and management of foreign bodies is required to prevent complications. OBJECTIVE: To analyze the profile of the patients seen for FB at a reference otorhinolaryngology emergency care unit between February of 2010 and January of 2011. METHOD: Cross-sectional retrospective historical cohort study based on digitized patient charts. RESULTS: FB accounted for 827 cases and 5.3% of all patients seen in the ENT emergency unit. Children were affected more frequently, particularly when aged 8 and under. No statistically significant differences were seen between genders. Foreign bodies were mostly located in the ears (64.4%), followed by the nasal fossae (19.5%), and the oropharynx (8.9%). Complications were seen in 4.5% of the cases, and 4.4% required general anesthesia to have the FB removed. CONCLUSION: In our ENT practice, foreign bodies were more commonly seen in children; the ears were the preferential site of occurrence. Complication rates and use of general anesthesia were low in our practice. It should be stressed that ENT foreign bodies need to be properly managed so as to avoid complications. PMID- 24474481 TI - Comparative assessment between objective and subjective methods in slides stained by immunohistochemistry. AB - Objective methods of assessment are often required in scientific studies. Histological tests with immunohistochemical staining can be assessed by photometry. OBJECTIVE: To compare this objective method with the subjective evaluation performed by three independent examiners, using slides of acquired middle ear cholesteatomas. METHOD: We selected a total of 54 cholesteatoma images, immunohistochemically stained by anti-TNF-R2 (32 slides) and anti-TGF alpha, (22 slides). The secondary antibody used in the two groups was the Max Polymer Detection System (Novo Link Kit, Novocastra(r), UK). The samples were processed by a digital slide scanner (ScanScope - Aperio). The selected sites were analyzed by photometry. RESULTS: The objective assessment by photometry was compared with the subjective evaluation by three examiners and subjected to statistical analysis. The Statistical analysis revealed moderate reproducibility (K values between 0.41 and 0.60) for both groups. CONCLUSION: Our study showed that the irregular characteristics of middle ear cholesteatoma slides stained by immunohistochemistry prevents its proper objective evaluation, while the subjective assessment by experienced examiners was more reliable. PMID- 24474482 TI - An auditory health program for neonates in ICU and/or intermediate care settings. AB - Auditory screening and early identification and management of patients with hearing loss improve the development prospects of infants. OBJECTIVE: To analyze the outcomes produced by an Auditory Health Program in neonates managed in an intensive care unit. METHOD: This prospective cross-sectional study enrolled neonates referred to the neonatal care unit at hospital CAISM/Unicamp with stays lasting for 48 hours and more within a period of 13 months. Automated monitoring of brainstem auditory evoked potentials was used in the auditory screening of neonates at the time of discharge. Children with poor BAEPs were sent to undergo audiological, otorhinolaryngological, and genetic tests. RESULTS: Auditory screening was performed for 84.7% of the live births; 39.7% were screened at 30 days or more of age. Diagnostic tests revealed that 63.8% of the children had normal hearing. Incidence of hearing loss was 4%; sensorineural hearing loss was observed in 1,4% of the subjects; 0.24% had auditory neuropathy spectrum disorder; and 2.2% had conductive hearing loss. CONCLUSION: Neonatal auditory screening was not offered universally, and nor was it carried out, in many cases, within the child's first month of life. Screening must be performed before neonates are discharged and in more than one stage. A high incidence of hearing loss was observed. PMID- 24474484 TI - Application of the Portuguese version of the Obstructive Sleep Apnea-18 survey to children. AB - Despite the significant prevalence of obstructive sleep apnea syndrome (OSAS) in children, the diagnosis and treatment of this condition is still challenging due to the difficulties inherent to objectively assessing the disease's severity. OBJECTIVE: To verify whether the Portuguese version of the Obstructive Sleep Apnea-18 (OSA-18) survey is as valid as its original version in English. METHOD: Prospective study. The OSA-18 was translated into Portuguese, culturally adapted, and tested in the Portuguese population. The caregivers of 51 children (aged from 2 to 12 years) diagnosed with OSAS answered the OSA-18-pv survey. Statistical analysis was used to assess the psychometric properties of the survey. RESULTS: Reliability analysis yielded a Cronbach's alpha of 0.821, confirming the survey's consistency. Converging validity was assessed using Pearson's correlation coefficient, which revealed a statistically significant correlation between individual data and total results. The survey can be easily and quickly answered (7.26 min). The outcomes of the OSA-18-pv showed that quality of life was poor in 14 children with OSAS (28%), moderate in 22 (43%), and high in 15 (29%). CONCLUSION: the OSA-18-pv is a valid tool and can be used to assess the impact on the quality of life of Portuguese children with OSAS. PMID- 24474483 TI - The prevalence of orbital complications among children and adults with acute rhinosinusitis. AB - OBJECTIVE: To investigate orbital complications in children and adult with sinusitis. METHOD: Patients attending ENT clinic with sinusitis from January 2010 until January 2012 were included. Patients were classified into two groups according to their age. First involved children aged less than 16 and second included adults older than 16 years. Clinical picture, sinus involved, management and outcome were compared. RESULTS: The total number of patients were 616. Orbital complications were seen in 36 patients (5.8%). Twenty six patients (72.2%) were children (21 had preseptal and 5 had orbital cellulitis) and ten patients (27.8%) were adults (5 with preseptal, three with orbital cellulitis and 2 with abscess). The most common orbital complication was preseptal cellulitis (72.2%) followed by orbital cellulitis and abscess (22.2% and 5.6% respectively). The commonest sinus involved was ethmoidal in children and mixed sinus pathology in adults. The majority of patients responded to medical treatment. CONCLUSION: Orbital complications of sinusitis are commoner in children than adults and have favorable prognosis. KEYWORDS: Sinusitis, cellulitis, preseptal, abscess. PMID- 24474485 TI - Phosphodiesterase type 5 inhibitors and sudden sensorineural hearing loss. AB - Phosphodiesterase type 5 Inhibitors, such as sildenafil, vardenafil and tadalafil have been increasingly used today and some of the users have developed sudden sensorineural hearing loss. OBJECTIVE: To present two patients with sudden deafness developed after an occasional use of the drug and review studies on the use of phosphodiesterase type 5 inhibitors and sudden hearing loss. METHOD: Analytical study of two cases and review of the subject matter in the Pubmed/Medline and Bireme databases using the keywords: phosphodiesterase type 5 inhibitors and sudden deafness and its correlates in the English language. RESULTS: The patients analyzed are young without additional disorders, using phosphodiesterase type 5 inhibitors, and after combination treatment for sudden hearing loss only one had hearing improvement. We found nine scientific studies and reviewed preclinical studies, clinical trials, prospective and cross sectional investigations. CONCLUSION: Increased occurrence in clinical practice and scientific reports in the literature suggest that the phosphodiesterase type 5 inhibitors are considered a risk factor for sudden deafness. Further studies with larger samples and control groups are needed for better assessing this association. PMID- 24474486 TI - Prognostic value of regional metastasis in squamous cell carcinoma of the tongue and floor of mouth. AB - The presence of metastatic nodes is a survival-limiting factor for patients with mouth tumors. OBJECTIVE: To evaluate the causes of treatment failure in carcinomas of the tongue and floor of the mouth due to staging. METHOD: This study included 365 patients with squamous cell carcinoma of the mouth treated from 1978 to 2007; 48 were staged as T1, 156 as T2, 98 as T3, and 63 as T4, of which 193 were pNo and 172 pN+. RESULTS: Among the pN+ cases, 17/46 (36.9%) of the patients not treated with radiation therapy had relapsing tumors, against 46/126 (36.5 %) of the patients who underwent radiation therapy. Success rates in the group of subjects submitted to salvage procedures were 16/51 (31.3%) for pN0 patients and 3/77 (3.9%) for pN+ patients. CONCLUSION: Salvage procedure success and survival rates are lower for pN+ patients; pN+ individuals also have more relapsing local disease. PMID- 24474487 TI - Variants of papillary thyroid carcinoma: association with histopathological prognostic factors. AB - Papillary carcinoma is the most common thyroid malignancy. Many variants of this tumor have been described, with different morphological and molecular characteristics. Although most cases have excellent prognosis, the relationship between tumor architecture and its biological behavior remains controversial. OBJECTIVE: To present the experience of a single center on the prevalence of thyroid papillary carcinoma variants and their relationship with other histopathological prognostic factors. METHOD: Retrospective study of all the cases submitted to thyroidectomy for papillary carcinoma in the same institution over 11 years. RESULTS: We included 517 patients, 81.9% of them were women. The average age was 47.2 years. The variants recognized to have higher aggressiveness potential corresponded to 5.6% of the sample. We found an association of tumor subtypes with greater lesion diameter, T staging, lymphovascular and gland capsule invasion. CONCLUSION: A small percentage of papillary carcinoma cases is represented by variants recognized by their greater potential for aggression. There are associations between these variants and several other histopathological factors already recognized for their prognostic value, which may, by themselves, influence the outcome of these cases. PMID- 24474488 TI - The impact of speech rate on sentence recognition by elderly individuals. AB - Difficulty understanding speech, particularly in situations unfavorable to communication, is a common complaint among elderly individuals. OBJECTIVE: to verify the variables connected to hearing loss and stimulus presentation rate and their impact on the speech recognition skills of elderly subjects in quiet and noisy environments. METHOD: this case-control study included two groups of subjects (31 elderly subjects with normal hearing and 26 with hearing loss) exposed to the List of Sentences in Portuguese and the Slowed List of Sentences in Portuguese tests. Sentence recognition indices were calculated for tests done against noisy and quiet backgrounds at a normal and reduced speech rate. Data sets were submitted to statistical analysis. RESULTS: elderly subjects from both groups had better test results when sentences were played at a slower rate. Statistically significant difference was seen for both groups when the tests were carried out on a quiet background and for the group with hearing loss when tested on a noisy background. CONCLUSION: regardless of their peripheral hearing, the elderly subjects included in this study were more able to recognize speech when sentences were played at a slower rate against a quiet background. When sentences were played against a noisy background, the elderly subjects with hearing loss had more significant performance improvements than the ones with normal hearing when sentences were played at a slower rate. PMID- 24474489 TI - Association between top-down skills and auditory processing tests. AB - Today, we are questioning how top-down skills may interfere with performance on auditory processing tests. OBJECTIVE: To investigate the existence of a possible association between memory, attention and language skills in auditory processing tests in "normal" development children. METHOD: Twenty children (ages 7 to 9 years), without complaints related to verbal and/or written language skills; without overt neurological or psychological involvement or delayed psychomotor development. We employed Hearing and auditory Processing Assessment tests in addition to psychophysical tests (visual and auditory attention tests; memory tests for digits and syllables and phonological awareness tests). RESULTS: there was a "very strong" correlation between Frequency Pattern and Memory for Digits Tests; a "strong" correlations between SSW (LE) test and Memory for Syllables, and SSW (LE) test and phonemic tasks. CONCLUSION: the Frequency Pattern Test showed a strong correlation with the phonological working memory skill; just as the SSW had with language and memory skills for syllables. It is noteworthy the difficult to clinically interpret the results of each auditory processing test alone, since these may be dependent on skills not necessarily related to the auditory modality, such as memory and language. PMID- 24474490 TI - Endoscopic endonasal technique: treatment of paranasal and anterior skull base malignancies. AB - Technical and technological innovations have spearheaded the expansion of the indications for the use of endoscopic endonasal approaches to extirpate malignancies of the sinonasal tract and adjacent skull base. OBJECTIVE: Critical review of the available literature regarding the use of endoscopic endonasal approaches including indications, limitations, surgical techniques, oncologic outcome, and quality of life. METHOD: Various endoscopic endonasal techniques are reviewed according to the origin and local extension of sinonasal and skull base malignancies including anterior cranial base, nasopharynx, clivus, and infratemporal fossa. In addition, the available literature is reviewed to assess outcomes. CONCLUSION: Endoscopic endonasal approaches are an integral part of the armamentarium for the treatment of the sinonasal tract malignancies and skull base. In properly selected cases, it affords similar oncologic outcomes with lower morbidity than traditional open approaches. Nonetheless, these minimal access approaches should be considered a complement to well-established open approaches, which are still necessary in most advanced tumors. PMID- 24474491 TI - Comprehensive review of surgeries for obstructive sleep apnea syndrome. AB - There are several surgical treatment modalities utilized for obstructive sleep apnea syndrome (OSAS). OSAS can cause excessive daytime sleepiness as well as cardiovascular morbidity and mortality. Patients who fail medical management often seek surgical treatment. OBJECTIVE: This paper reviews surgical treatment options for obstructive sleep apnea syndrome to include original descriptions as well as outcomes for snoring, apnea-hypopnea indices, and mortality benefits. METHOD: A literature review was performed for OSAS surgical treatment options for soft tissue and skeletal surgeries. Articles with the original descriptions and surgical reviews are included for each procedure. RESULTS: A total of twenty eight surgical treatment modalities for OSAS were identified. Original article authors and year of description were obtained and presented. Polysomnographic data for apnea indices, apnea-hypopnea indices and mortality are presented. CONCLUSION: There is a large amount of variability in outcomes for sleep surgeries, however, in order to maximize success and cure rates, multiple procedures are most often necessary. Sleep surgeons must get familiar with modern surgical concepts and techniques, and participate in multi-disciplinary care in order to maximize treatment outcomes. PMID- 24474492 TI - Schwannoma of the membranous nasal septum. PMID- 24474493 TI - Paracoccidioidomycosis of the larynx: cases report. PMID- 24474494 TI - Anatomic variant of the internal carotid artery in the pharynx. PMID- 24474495 TI - Low-power laser therapy in chemical-induced oral mucositis: a case study. PMID- 24474497 TI - On the origins of chemical exchange saturation transfer (CEST) contrast in tumors at 9.4 T. AB - Chemical exchange saturation transfer (CEST) provides an indirect means to detect exchangeable protons within tissues through their effects on the water signal. Previous studies have suggested that amide proton transfer (APT) imaging, a specific form of CEST, detects endogenous amide protons with a resonance frequency offset 3.5 ppm downfield from water, and thus may be sensitive to variations in mobile proteins/peptides in tumors. However, as CEST measurements are influenced by various confounding effects, such as spillover saturation, magnetization transfer (MT) and MT asymmetry, the mechanism or degree of increased APT signal in tumors is not certain. In addition to APT, nuclear Overhauser enhancement (NOE) effects upfield from water may also provide distinct information on tissue composition. In the current study, APT, NOE and several other MR parameters were measured and compared comprehensively in order to elucidate the origins of APT and NOE contrasts in tumors at 9.4 T. In addition to conventional CEST methods, a new intrinsic inverse metric was applied to correct for relaxation and other effects. After corrections for spillover, MT and T1 effects, corrected APT in tumors was found not to be significantly different from that in normal tissues, but corrected NOE effects in tumors showed significant decreases compared with those in normal tissues. Biochemical measurements verified that there was no significant enhancement of protein contents in the tumors studied, consistent with the corrected APT measurements and previous literature, whereas quantitative MT data showed decreases in the fractions of immobile macromolecules in tumors. Our results may assist in the better understanding of the contrast depicted by CEST imaging in tumors, and in the development of improved APT and NOE measurements for cancer imaging. PMID- 24474498 TI - VKORC1 and CYP2C9 genotypes are predictors of warfarin-related outcomes in children. AB - BACKGROUND: Despite substantial evidence supporting a pharmacogenetic approach to warfarin therapy in adults, evidence on the importance of genetics in warfarin therapy in children is limited, particularly for clinical outcomes. We assessed the contribution of CYP2C9/VKORC1/CYP4F2 genotypes and variation in other genes involved in vitamin K and coagulation pathways to warfarin dose and related clinical outcomes in children. PROCEDURE: Clinical and genetic data for 93 children (age <= 18 years) who received warfarin therapy were obtained. DNA was genotyped for 93 selected single nucleotide polymorphisms using a custom assay. RESULTS: With a median age of 4.8 years, our cohort included more young children than most previous studies. Overall, 76.3% of dose variability was explained by weight, indication, VKORC1-1639G/A and CYP2C9 *2/*3, with genotypes accounting for 21.1% of variability. There was a strong correlation (R(2) = 0.68; P < 0.001) between actual and predicted warfarin dose using a pediatric genotype-based dosing model. VKORC1 genotype had a significant impact on time to therapeutic international normalized ratio (INR) (P = 0.047) and time to over-anticoagulation (INR > 4; P = 0.024) during the initiation of therapy. CYP2C9*3 carriers were also at increased risk of major bleeding while receiving warfarin (adjusted OR = 11.28). An additional variant in CYP2C9 (rs7089580) was significantly associated with warfarin dose (P = 0.020) in a multivariate clinical and genetic model. CONCLUSIONS: This study confirms the importance of VKORC1/CYP2C9 genotypes for warfarin dosing in a young pediatric cohort and demonstrates an impact of genetic factors on clinical outcomes in children. Furthermore, we identified an additional variant in CYP2C9 of potential relevance for warfarin dosing in children. PMID- 24474499 TI - Selective use of adjuvant chemotherapy for rectal cancer patients with ypN0. AB - BACKGROUND: The administration of adjuvant chemotherapy for rectal cancer patients with ypN0 is controversial. The purposes of this study were to evaluate the role of adjuvant chemotherapy in ypN0 patients and to optimize its use for these patients. METHODS: We performed a retrospective study of 160 rectal cancer patients who had the final pathology of ypN0 between March 2003 and November 2010. Overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were compared between patients who did and did not receive adjuvant chemotherapy. Multivariate analysis was performed to explore clinical factors significantly associated with DFS, LRFS, and DMFS. RESULTS: For ypT0-2N0 patients, the 5-year OS, DFS, LRFS, and DMFS were similar between patients who did and did not receive adjuvant chemotherapy (P > 0.05). For patients with ypT3-4N0, those who were given adjuvant chemotherapy exhibited a higher 5-year OS than those who were not (P = 0.026), with also an extended 5-year DFS (P = 0.050). Further analysis indicated that adjuvant chemotherapy could decrease the rates of distant metastases for ypT3-4N0 patients with no impact on local control. In multivariable analysis, both the final pathological stage and adjuvant chemotherapy were independent predictors of DMFS for the whole group. When stratified by pathological stage, adjuvant chemotherapy was still significantly associated with DMFS in the ypT3-4 stratum. CONCLUSIONS: Adjuvant chemotherapy may not improve survival for ypT0-2N0 patients. However, it may be clinically meaningful for ypT3-4N0 patients by decreasing rates of distant metastases. Further randomized controlled clinical trials are needed to address this problem. PMID- 24474500 TI - Metabolism of cisplatin in the organs of Rattus norvegicus: role of Glutathione S transferase P1. AB - Glutathione S-transferases (GSTs) play an important role in the biotransformation of endogenous compounds and xenobiotics as well as in the metabolic inactivation of pharmacologically active substances, including anticancer drugs. Using cisplatin as the prototype drug, we investigated if any correlation exists between GSH levels, GSTs/GSTP1 activity and the fate of cisplatin in different organs of Rattus norvegicus. GSH-cisplatin complex was prepared, purified by anion-exchange chromatography and subjected to mass spectroscopic analysis which confirmed the structure to be diglutathione-monoplatinum (diglutathionylplatinum). Purified diglutathionylplatinum was used to quantify metabolite formed in different tissue homogenates. Specific GSTP1 activity was found to be highest in kidneys, which correlated positively with the levels of metabolite formed in renal tissues. Altogether, our results showed that cisplatin metabolism in different organs of rats correlated positively with specific GSTP1 activities and this enzyme may be a critical determinant of extent of cellular uptake or retention of cisplatin in renal and liver tissues. PMID- 24474502 TI - No effect of femtosecond laser pulses on M13, E. coli, DNA, or protein. AB - Data showing what appears to be nonthermal inactivation of M13 bacteriophage (M13), Tobacco mosaic virus, Escherichia coli (E. coli), and Jurkatt T-cells following exposure to 80-fs pulses of laser radiation have been published. Interest in the mechanism led to attempts to reproduce the results for M13 and E. coli. Bacteriophage plaque-forming and bacteria colony-forming assays showed no inactivation of the microorganisms; therefore, model systems were used to see what, if any, damage might be occurring to biologically important molecules. Purified plasmid DNA (pUC19) and bovine serum albumin were exposed to and analyzed by agarose gel electrophoresis (AGE) and polyacrylamide gel electrophoresis (PAGE), respectively, and no effect was found. DNA and coat proteins extracted from laser-exposed M13 and analyzed by AGE or PAGE found no effect. Raman scattering by M13 in phosphate buffered saline was measured to determine if there was any physical interaction between M13 and femtosecond laser pulses, and none was found. Positive controls for the endpoints measured produced the expected results with the relevant assays. Using the published methods, we were unable to reproduce the inactivation results or to show any interaction between ultrashort laser pulses and buffer/water, DNA, protein, M13 bacteriophage, or E. coli. PMID- 24474501 TI - APL-2, an altered peptide ligand derived from heat-shock protein 60, induces interleukin-10 in peripheral blood mononuclear cell derived from juvenile idiopathic arthritis patients and downregulates the inflammatory response in collagen-induced arthritis model. AB - Juvenile idiopathic arthritis (JIA) is a heterogeneous group of diseases characterized by autoimmune arthritis of unknown cause with onset before age of 16 years. Methotrexate provides clinical benefits in JIA. For children who do not respond to methotrexate, treatment with anti-tumor necrosis factor (TNF)-alpha is an option. However, some patients do not respond or are intolerant to anti-TNF therapy. Induction of peripheral tolerance has long been considered a promising approach to the treatment of chronic autoimmune diseases. We aimed to evaluate the potentialities of two altered peptide ligands (APLs) derived from human heat shock protein 60, an autoantigen involved in the pathogenesis of autoimmune arthritis, in JIA patients. Interferon (IFN)-gamma, TNF-alpha and interleukin (IL)-10 levels were determined in ex vivo assays using peripheral blood mononuclear cells (PBMC) from these patients. Wild-type peptide and one of these APLs increased IFN-gamma and TNF-alpha levels. Unlike, the other APLs (called APL2) increased the IL-10 level without affecting IFN-gamma and TNF-alpha levels. On the other hand, APL2 induces a marked activation of T cells since it transforms cell cycle phase's distribution of CD4+ T cells from these patients. In addition, we evaluated the therapeutic effect of APL2 in collagen-induced arthritis model. Therapy with APL2 reduced arthritis scores and histological lesions in mice. This effect was associated to a decrease in TNF-alpha and IL-17 levels. These results indicate a therapeutic potentiality of APL2 for JIA. PMID- 24474503 TI - Temperature elevation profile inside the rat brain induced by a laser beam. AB - The thermal effect may be a desired outcome or a concerning side effect in laser tissue interactions. Research in this area is particularly motivated by recent advances in laser applications in diagnosis and treatment of neurological disorders. Temperature as a side effect also limits the maximum power of optical transfer and harvesting of energy in implantable neural prostheses. The main objective was to investigate the thermal effect of a near-infrared laser beam directly aimed at the brain cortex. A small, custom-made thermal probe was inserted into the rat brain to make direct measurements of temperature elevations induced by a free-air circular laser beam. The time dependence and the spatial distribution of the temperature increases were studied and the maximum allowable optical power was determined to be 2.27 W/cm2 for a corresponding temperature increase of 0.5 degrees C near the cortical surface. The results can be extrapolated for other temperature elevations, where the margin to reach potentially damaging temperatures is more relaxed, by taking advantage of linearity. It is concluded that the thermal effect depends on several factors such as the thermal properties of the neural tissue and of its surrounding structures, the optical properties of the particular neural tissue, and the laser beam size and shape. Because so many parameters play a role, the thermal effect should be investigated for each specific application separately using realistic in vivo models. PMID- 24474504 TI - High-performance near-infrared imaging for breast cancer detection. AB - We present a method for the noninvasive determination of the size, position, and optical properties of tumors in the human breast. The tumor is first detected by photothermal imaging. It is then sized, located, and optically characterized using designed digital image processing and edge-detection pattern recognition. The method assumes that the tumor is spherical and inhomogeneous and embedded in an otherwise homogeneous tissue. Heat energy is deposited in the tissue by absorption of near-infrared (NIR) Nd:YAG laser radiation, and its subsequent conversion to heat via vibrational relaxation causes a rise in temperature of the tissue. The tumor absorbs and scatters NIR light more strongly than the surrounding healthy tissue. Heat will diffuse through the tissue, causing a rise in temperature of the surrounding tissue. Differentiation between normal and cancerous tissues is determined using IR thermal imaging. Results are presented on a 55-year-old patient with a papillary breast cancer. We found that these results provide the clinician with more detailed information about breast lesions detected by photothermal imaging and thereby enhance its potential for specificity. PMID- 24474505 TI - Noninvasive near-infrared fluorescent protein-based imaging of tumor progression and metastases in deep organs and intraosseous tissues. AB - Whole-body imaging of experimental tumor growth is more feasible within the near infrared (NIR) optical window because of the highest transparency of mammalian tissues within this wavelength spectrum, mainly due to improved tissue penetration and lower autofluorescence. We took advantage from the recently cloned infrared fluorescent protein (iRFP) together with a human immunodeficiency virus (HIV)-based lentiviral vector to produce virally transduced tumor cells that permanently express this protein. We then noninvasively explored metastatic spread as well as primary tumor growth in deep organs and behind bone barriers. Intrabone tumor growth was investigated through intracranial and intratibial injections of glioblastoma and osteosarcoma cells, respectively, and metastasis was assessed by tail vein injection of melanoma cells. We found that the emitted fluorescence is captured as sharp images regardless of the organ or tissue considered. Furthermore, by overlaying fluorescence spots with the white light, it was possible to afford whole-body images yet never observed before. This approach allowed us to continuously monitor the growth and dissemination of tumor cells with a small number of animals, minimal animal handling, and without the need for any additive. This iRFP-based system provides high-resolution readouts of tumorigenesis that should greatly facilitate preclinical trials with anticancer therapeutic molecules. PMID- 24474506 TI - Detection of occlusal caries in primary teeth using swept source optical coherence tomography. AB - This study aimed to investigate swept source optical coherence tomography (SS OCT) as a detecting tool for occlusal caries in primary teeth. At the in vitro part of the study, 38 investigation sites of occlusal fissures (noncavitated and cavitated) were selected from 26 extracted primary teeth and inspected visually using conventional dental equipment by six examiners without any magnification. SS-OCT cross-sectional images at 1330-nm center wavelength were acquired on the same locations. The teeth were then sectioned at the investigation site and directly viewed under a confocal laser scanning microscope (CLSM) by two experienced examiners. The presence and extent of caries were scored in each observation. The results obtained from SS-OCT and conventional visual inspections were compared with those of CLSM. Consequently, SS-OCT could successfully detect both cavitated and noncavitated lesions. The magnitude of sensitivity for SS-OCT was higher than those for visual inspection (sensitivity of visual inspection and SS-OCT, 0.70 versus 0.93 for enamel demineralization, 0.49 versus 0.89 for enamel cavitated caries, and 0.36 versus 0.75 for dentin caries). Additionally, occlusal caries of a few clinical cases were observed using SS-OCT in vivo. The results indicate that SS-OCT has a great detecting potential for occlusal caries in primary teeth. PMID- 24474507 TI - Strategies to overcome photobleaching in algorithm-based adaptive optics for nonlinear in-vivo imaging. AB - We have developed a nonlinear adaptive optics microscope utilizing a deformable membrane mirror (DMM) and demonstrated its use in compensating for system- and sample-induced aberrations. The optimum shape of the DMM was determined with a random search algorithm optimizing on either two photon fluorescence or second harmonic signals as merit factors. We present here several strategies to overcome photobleaching issues associated with lengthy optimization routines by adapting the search algorithm and the experimental methodology. Optimizations were performed on extrinsic fluorescent dyes, fluorescent beads loaded into organotypic tissue cultures and the intrinsic second harmonic signal of these cultures. We validate the approach of using these preoptimized mirror shapes to compile a robust look-up table that can be applied for imaging over several days and through a variety of tissues. In this way, the photon exposure to the fluorescent cells under investigation is limited to imaging. Using our look-up table approach, we show signal intensity improvement factors ranging from 1.7 to 4.1 in organotypic tissue cultures and freshly excised mouse tissue. Imaging zebrafish in vivo, we demonstrate signal improvement by a factor of 2. This methodology is easily reproducible and could be applied to many photon starved experiments, for example fluorescent life time imaging, or when photobleaching is a concern. PMID- 24474508 TI - Noninvasive measurement of pharmacokinetics by near-infrared fluorescence imaging in the eye of mice. AB - PURPOSE: For generating preclinical pharmacokinetics (PKs) of compounds, blood is drawn at different time points and levels are quantified by different analytical methods. In order to receive statistically meaningful data, 3 to 5 animals are used for each time point to get serum peak-level and half-life of the compound. Both characteristics are determined by data interpolation, which may influence the accuracy of these values. We provide a method that allows continuous monitoring of blood levels noninvasively by measuring the fluorescence intensity of labeled compounds in the eye and other body regions of anesthetized mice. PROCEDURES: The method evaluation was performed with four different fluorescent compounds: (i) indocyanine green, a nontargeting dye; (ii) OsteoSense750, a bone targeting agent; (iii) tumor targeting Trastuzumab-Alexa750; and (iv) its F(ab')2 alxea750 fragment. The latter was used for a direct comparison between fluorescence imaging and classical blood analysis using enzyme-linked immunosorbent assay (ELISA). RESULTS: We found an excellent correlation between blood levels measured by noninvasive eye imaging with the results generated by classical methods. A strong correlation between eye imaging and ELISA was demonstrated for the F(ab')2 fragment. Whole body imaging revealed a compound accumulation in the expected regions (e.g., liver, bone). CONCLUSIONS: The combination of eye and whole body fluorescence imaging enables the simultaneous measurement of blood PKs and biodistribution of fluorescent-labeled compounds. PMID- 24474509 TI - Restoration of retinal images with space-variant blur. AB - Retinal images are essential clinical resources for the diagnosis of retinopathy and many other ocular diseases. Because of improper acquisition conditions or inherent optical aberrations in the eye, the images are often degraded with blur. In many common cases, the blur varies across the field of view. Most image deblurring algorithms assume a space-invariant blur, which fails in the presence of space-variant (SV) blur. In this work, we propose an innovative strategy for the restoration of retinal images in which we consider the blur to be both unknown and SV. We model the blur by a linear operation interpreted as a convolution with a point-spread function (PSF) that changes with the position in the image. To achieve an artifact-free restoration, we propose a framework for a robust estimation of the SV PSF based on an eye-domain knowledge strategy. The restoration method was tested on artificially and naturally degraded retinal images. The results show an important enhancement, significant enough to leverage the images' clinical use. PMID- 24474510 TI - Preclinical evidence of mitochondrial nicotinamide adenine dinucleotide as an effective alarm parameter under hypoxia. AB - Early detection of tissue hypoxia in the intensive care unit is essential for effective treatment. Reduced nicotinamide adenine dinucleotide (NADH) has been suggested to be the most sensitive indicator of tissue oxygenation at the mitochondrial level. However, no experimental evidence comparing the kinetics of changes in NADH and other physiological parameters has been provided. The aim of this study is to obtain the missing data in a systematic and reliable manner. We constructed four acute hypoxia models, including hypoxic hypoxia, hypemic hypoxia, circulatory hypoxia, and histogenous hypoxia, and measured NADH fluorescence, tissue reflectance, cerebral blood flow, respiration, and electrocardiography simultaneously from the induction of hypoxia until death. We found that NADH was not always the first onset parameter responding to hypoxia. The order of responses was mainly affected by the cause of hypoxia. However, NADH reached its alarm level earlier than the other monitored parameters, ranging from several seconds to >10 min. As such, we suggest that the NADH can be used as a hypoxia indicator, although the exact level that should be used must be further investigated. When the NADH alarm is detected, the body still has a chance to recover if appropriate and timely treatment is provided. PMID- 24474511 TI - Multiplexed label-free optical biosensor for medical diagnostics. AB - This paper describes a new multiplexed label-free biosensor. The detection technology is based on nanostructured gold-polymer surfaces. These surfaces support surface plasmon resonance modes that can be probed by a miniaturized optical setup. The optical characterization of the sensing chip shows the sensitivity and the limit-of-detection to refractive index changes. Moreover, by studying the progressive adhesion of molecular monolayers of polyelectrolytes, the decay of the plasmonic mode electric field above the surface has been reconstructed. A multiplexed label-free biosensing device is then described and characterized in terms of sensitivity, lateral resolution, and sensitivity to a model biological assay. The sensitivity in imaging mode of the device is of the order of 10-6 refractive index units, while the measured lateral resolution is 6.25 MUm within a field of view of several tenths of mm2, making the instrument unique in terms of multiplexing capability. Finally, the proof-of-concept application of the technology as a point-of-care diagnostic tool for an inflammatory marker is demonstrated. PMID- 24474512 TI - Photoacoustic measurement of the Gruneisen parameter of tissue. AB - The Gruneisen parameter, a constitutive parameter in photoacoustics, is usually measured from isobaric thermal expansion, which may not be valid for a biological medium due to its heterogeneity. Here, we directly measured the Gruneisen parameter by applying photoacoustic spectroscopy. Laser pulses at wavelengths between 460 and 1800 nm were delivered to tissue samples, and photoacoustic signals were detected by flat water-immersion ultrasonic transducers. Least squares fitting photoacoustic spectra to molar optical absorption spectra showed that the Gruneisen parameter was 0.81+/-0.05 (mean+/-SD) for porcine subcutaneous fat tissue and 0.69+/-0.02 for porcine lipid at room temperature (22 degrees C). The Gruneisen parameter of a red blood cell suspension was linearly related to hemoglobin concentration, and the parameter of bovine serum was 9% greater than that of water at room temperature. PMID- 24474513 TI - Role of UDP-N-acetylglucosamine2-epimerase/N-acetylmannosamine kinase (GNE) in beta1-integrin-mediated cell adhesion. AB - Hereditary inclusion body myopathy (GNE myopathy) is a neuromuscular disorder due to mutation in key sialic acid biosynthetic enzyme, GNE. The pathomechanism of the disease is poorly understood as GNE is involved in other cellular functions beside sialic acid synthesis. In the present study, a HEK293 cell-based model system has been established where GNE is either knocked down or over-expressed along with pathologically relevant GNE mutants (D176V and V572L). The subcellular distribution of recombinant GNE and its mutant showed differential localization in the cell. The effect of mutation on GNE function was investigated by studying hyposialylation of cell membrane receptor, beta1-integrin. Hyposialylated beta1 integrin localized to internal vesicles that was restored upon supplementation with sialic acid. Fibronectin stimulation caused migration of hyposialylated beta1-integrin to the cell membrane and co-localization with focal adhesion kinase (FAK) leading to increased focal adhesion formation. This further activated FAK and Src, downstream signaling molecules and led to increased cell adhesion. This is the first report to show that mutation in GNE affects beta1 integrin-mediated cell adhesion process in GNE mutant cells. PMID- 24474514 TI - Statins and neuroprotection: basic pharmacology needed. AB - Statins are attracting great interest albeit with some controversy in treating certain neurodegenerative diseases such as Alzheimer disease, Parkinson disease, multiple sclerosis, ischemic stroke, and traumatic brain injury. Support for the use of statins has come from human studies and animal and cell models. Despite the intense level of interest, there is a deficiency in information on the basic pharmacokinetics and pharmacodynamics of statins in the brain. The purpose of this focused review is to examine what is known and the gaps in our knowledge on detectability of statin lactones and acids in the brain, membrane partitioning and active transport of statins across the blood-brain barrier, and statin effects on brain isoprenoid levels. Statins may be efficacious in treating certain neurodegenerative diseases. Having basic information on statin pharmacokinetics and pharmacodynamics in the brain would provide insight into specific drug targets and also provide the rationale for optimizing statins in terms of enhancing brain influx and inhibiting efflux. PMID- 24474517 TI - Quantification of fibrin in blood thrombi formed in hemodialysis central venous catheters: a pilot study on 43 CVCs. AB - PURPOSE: Fibrin deposition and thrombotic occlusion represent a serious cause of access dysfunction in hemodialysis central venous catheters (CVCs). The aim of this work was to define and apply a method for imaging and quantifying fibrin in thrombi formed into the side holes of CVCs. METHODS: Forty-three CVCs removed from a cohort of dialyzed patients were analyzed in this pilot study. Hematoxylin and eosin and a modified Carstair's staining were applied on permanent thrombus sections. Fluorescence microscopy and image analysis were performed to quantify the fibrin amount. RESULTS: Highly fluorescent areas were invariably associated with fibrin by Carstair's method. The deposition of concentric layers of fibrin and erythrocytes was easily identified by fluorescence microscopy, showing growth features of the thrombus. Fibrin amount in diabetic patients was significantly higher than that in nondiabetic patients with median (interquartile range) values of 51% (47-68%) and 44% (30-54%), respectively (p=0.032). No significant difference in fibrin content was found by grouping data according to catheter type, permanence time, insertion site and dialysis vintage. Higher variability in fibrin values was found in thrombi from CVCs removed after 1-15 days compared with 16-60 days. A trend of an increase in fibrin amount in thrombi was noted according to blood platelet count at CVC insertion. CONCLUSIONS: The analytical method presented here proved to be a rapid and effective way for quantifying fibrin content in thrombi formed on CVCs with potential application in future clinical studies. PMID- 24474518 TI - Inflow stenosis as a contributing factor in the etiology of AV access-induced ischemic steal. AB - OBJECTIVE: To determine how frequent inflow stenosis is a contributing factor in the etiology of arteriovenous access-induced steal (AVAIS). METHODS: A retrospective review of hemodialysis patients who underwent interventions from October 1998 to December 2011 for AVAIS was conducted at Mount Sinai Hospital. Patients with grade 3 AVAIS and complete arch and upper extremity vascular imaging were included. Demographics, access history, time to AVAIS, preoperative angiographic imaging and interventions performed were analyzed. RESULTS: A total of 52 patients were diagnosed with grade 3 (severe) AVAIS requiring intervention over the study period. Forty-seven percent of the patients were male, average age was 62 years, 47% were of African American race and 88% were diabetic. Seventeen consecutive patients, with imaging, were included in this study. The average time to presentation of steal symptoms was 147+/-228 days. All of the accesses were proximal, and 65.7% were autogenous. Imaging studies consisted of angiography (14) and computed tomography angiography (3). Five patients had imaging evidence of >50% luminal inflow stenosis (29.4%). The location of stenosis was the subclavian (3 cases) and brachial (2 cases) arteries. Patients underwent distal revascularization and interval ligation (3), ligation (1) and angioplasty/stenting (1). CONCLUSION: In our population, nearly one-third of the patients with severe AVAIS had a significant subclavian or brachial artery stenosis. The implications of this finding suggest the importance of complete preoperative imaging. The treatment of the inflow stenosis by itself may not be curative, but the correction may serve as an adjunct and contribute to the success of other therapeutic procedures. PMID- 24474519 TI - Endovascular management of iatrogenic carotid-jugular fistula presenting as congestive heart failure. AB - Carotid-jugular arteriovenous fistula (C-J AVF) after inadvertent carotid puncture during internal jugular vein puncture is a rare entity. Previously, majority of reported cases of CJAVF were identified during inadvertent arterial puncture and managed as emergency. We report a delayed presentation of congestive cardiac failure following multiple attempts at securing an internal jugular venous access for dialysis 3 months prior to diagnosis. Carotid-jugular fistula was identified during workup and was successfully treated by endovascular technique with a covered stent. PMID- 24474520 TI - Verification of intravenous catheter placement by auscultation--a simple, noninvasive technique. AB - BACKGROUND: Verification of proper placement of an intravenous catheter may not always be simple. We evaluated the auscultation technique for this purpose. METHODS: Twenty healthy volunteers were randomized for 18G catheter inserted intravenously either in the right (12) or left arm (8), and subcutaneously in the opposite arm. A standard stethoscope was placed over an area approximately 3 cm proximal to the tip of the catheter in the presumed direction of the vein to grade on a 0-6 scale the murmur heard by rapidly injecting 2 mL of NaCl 0.9% solution. The auscultation was evaluated by a blinded staff anesthesiologist. RESULTS: All 20 intravenous injection were evaluated as flow murmurs, and were graded an average 5.65 (+/-0.98), whereas all 20 subcutaneous injections were evaluated as either crackles or no sound, and were graded an average 2.00 (+/ 1.38), without negative results. Sensitivity was calculated as 95%. Specificity and Kappa could not be calculated due to an empty false-positive group. CONCLUSIONS: Being simple, handy and noninvasive, we recommend to use the auscultation technique for verification of the proper placement of an intravenous catheter when uncertain of its position. Data obtained in our limited sample of healthy subjects need to be confirmed in the clinical setting. PMID- 24474521 TI - Inferior vena cava thrombosis due to tunneled hemodialysis catheter inserted in the internal jugular vein. PMID- 24474522 TI - Cephalic arch stenosis in dialysis patients: review of clinical relevance, anatomy, current theories on etiology and management. AB - Arteriovenous hemodialysis fistulas (AVFs) serve as a lifeline for many individuals with end-stage renal failure. A common cause of AVF failure is cephalic arch stenosis. Its high prevalence compounded with its resistance to treatment makes cephalic arch stenosis important to understand. Proposed etiologies include altered flow in a fistulized cephalic vein, external compression by fascia, the unique morphology of the cephalic arch, large number of valves in the cephalic outflow tract and biochemical changes that accompany renal failure. Management options are also in debate and include angioplasty, cutting balloon angioplasty, bare metal stents, stent grafts and surgical techniques including flow reduction with minimally invasive banding as well as more invasive venovenostomy with transposition surgeries for refractory cases. In this review, the evidence for the clinical relevance of cephalic arch stenosis, its etiology and management are summarized. PMID- 24474524 TI - Intravascular ultrasound-guided angioplasty of hemodialysis loop graft in a patient with contrast allergy. AB - PURPOSE: A surveillance duplex scan detected a stenosis within a left groin hemodialysis loop graft in a 57-year-old woman who was allergic to both iohexol and gadolinium contrast agents. This precluded the use of standard angioplasty treatment techniques. Intravascular ultrasound (IVUS) uses a catheter mounted with a miniaturized ultrasound probe to produce detailed cross-sectional vessel images. Clinically, it has been used in the assessment of coronary artery disease but has also supplemented standard angiography techniques in the assessment of peripheral vascular and hemodialysis access lesions. METHODS: IVUS was utilized as the solitary imaging modality to identify the graft stenosis and guide the placement of a 6 mm diameter angioplasty balloon. Two areas of stenosis were successfully dilated and subsequent IVUS re-examination showed abolition of the stenosis. RESULTS: Twelve-month follow-up surveillance scan showed that the graft remained functional with good flow rates. CONCLUSIONS: In the setting of contrast allergy, IVUS may provide a valid and safe tool in the localization and treatment of peripheral vessel stenosis, including arteriovenous fistula angioplasty. To our knowledge this is the first reported use of IVUS for hemodialysis graft salvage adopting a completely 'contrast-free' technique. More studies are required to establish the true role of IVUS in the management of hemodialysis access angioplasty, but this successful case contributes valuable information to the literature on its clinical application. PMID- 24474523 TI - Is ultrasound-guided central venous port placement effective to avoid pinch-off syndrome? AB - PURPOSE: Ultrasound (US)-guided internal jugular vein access has been the standard practice of central venous port (CVP) placement. The subclavian vein (SCV) access has also been preferred, but has potential risk of pinch-off syndrome (POS). The purpose of this study was to examine the effect of US-guided SCV access to avoid POS in patients with CVP. METHODS: Included in this study were patients who had undergone CVP placement via the SCV. We mainly assessed the computed tomography (CT) findings from two different placement techniques of a CVP via the SCV: (i) venipuncture point described by the ratio between the distance from the venipuncture point to the sternoclavicular joint and the clavicular length; and (ii) presence of direct attachment of the catheter to the clavicle. Secondary outcome was POS rate associated with two different placement techniques of CVP via the SCV. RESULTS: A total of 237 patients were included in this study between August 2007 and January 2011. A total of 100 patients (42.2%) underwent CVP placement using the landmark technique while 137 patients (57.8%) underwent CVP placement by US guidance. CT revealed that the US-guided technique tended to be lateral SCV approach compared with the landmark technique (p<0.001). A total of four patients (1.7%) experienced POS, all of them in the landmark group. CONCLUSION: Our results showed that the US-guided technique determines a more lateral SCV approach, with a reduced POS risk than the landmark venipuncture technique. PMID- 24474525 TI - Tainted commons, public health: the politico-moral significance of cholera in Vietnam. AB - In October 2007, a series of cholera epidemics broke out in Hanoi, interrupting a moment of economic triumphalism in post-transition Vietnam. In seeking the source of a refractory disease associated with poverty and underdevelopment, officials, media, and citizens not only identified scapegoats and proposed solutions, they also endorsed particular visions of moral conduct, social order, and public health. Controversy over cholera, a potent politico-moral symbol, expressed an imaginary of "tainted commons" (i.e., an emergent space of civil society and small-scale entrepreneurship from which the state has partially withdrawn, while still exercising some measure of scrutiny and control). The ambiguities of this situation permitted the state to assume moral postures, evade responsibility, and deflect criticism to convenient targets. Prevalent outbreak narratives thus played on anxieties regarding specifically classed and gendered social groups, whose behavior was imagined to contravene ideals of public health and order. PMID- 24474526 TI - The "medical neighborhood": integrating primary and specialty care for ambulatory patients. AB - As health care organizations create larger networks, better coordination of primary and specialty care is paramount. Attention has focused on strengthening primary care by creating patient-centered medical homes. The "medical neighborhood" provides a framework for structured, reciprocal relationships that integrate specialty care and extend the principles of the medical home to all practicing physicians. The foundation of the medical neighborhood is the collaborative care agreement, which outlines mutual expectations for primary care physicians and specialists as they care for patients together. These expectations include a preconsultation exchange between the referring physician and the consultant, the consultation, and subsequent comanagement of patients over time. Although independent practices can create individualized collaborative care agreements with specific specialist colleagues, large health care provider networks and accountable care organizations should have 1 agreement for all affiliated physicians. Challenges to the medical neighborhood include fee-for service reimbursement, existing referral relationships, and building a robust electronic platform, including a referral management module. Cooperation between physicians, regardless of their specialty, and innovation in payment models and electronic platforms will all be essential if medical neighborhoods are to succeed. PMID- 24474527 TI - An aspirated partial denture as a complication in status epilepticus. PMID- 24474528 TI - What's new in extracorporeal membrane oxygenation for cardiac failure and cardiac arrest in adults? PMID- 24474530 TI - Salivary biomarkers of obstructive sleep apnea syndrome in children. AB - OBJECTIVES: The present pilot study was performed to evaluate the HPA axis and ANS activity by measuring salivary cortisol and alpha-amylase diurnal trajectory and production, respectively, in mild or moderate-to-severe (MS) OSA-affected, but otherwise healthy, children. Moreover, a correlative analysis was performed between the salivary biomarker concentrations and the PSG variables characterizing the OSA severity. METHODS: We studied 27 consecutive OSA patients (13 mild OSA; 14 MS OSA) and seven healthy children who were enrolled as controls by collecting salivary samples and measuring cortisol and alpha-amylase levels using enzyme-linked bioassays. RESULTS: Compared with controls, both mild and MS OSA children showed: (1) increased salivary cortisol diurnal production, (2) maintenance of the physiological circadian activity of the HPA axis, and (3) no changes in alpha-amylase diurnal trajectory and production. In addition, morning salivary cortisol concentrations was negatively associated with the disease severity in the MS OSA group. CONCLUSIONS: OSA is associated with dysregulation of the HPA axis activity in children, the latter potentially underlying some of the adverse consequences of the disease. PMID- 24474531 TI - Prevalence and characteristics of intimate partner violence against women with severe mental illness: a prevalence study in Spain. AB - This study examined the prevalence and characteristics of intimate partner violence (IPV) towards women with a severe mental illness (SMI). The sample consisted of 142 adult women with SMI treated in public mental health services in three districts of Madrid (Spain). The prevalence of IPV in the 12 months preceding the interview was 30.3% and over the lifespan was 79.6%. 32.7% of women victims of violence do not qualify themselves as battered women. 48.5% of battered women do not talk about their abusive situation with anyone or come to any resource or service. Women victims of abuse have low social support. Women who have suffered physical abuse in childhood are at 2.22 times higher risk of being victims of IPV in the past year. Mental health professionals identified 50% of recent abuse cases. This research highlights the extent of IPV experienced by women with SMI. PMID- 24474529 TI - Colostrogenesis: IgG1 transcytosis mechanisms. AB - Biological transport of intact proteins across epithelial cells has been documented for many absorptive and secretory tissues. Immunoglobulins were some of the earliest studied proteins in this category. The transcellular transport (transcytosis) of immunoglobulins in neonatal health and development has been recognized; the process is especially significant with ungulates because they do not transcytose immunoglobulins across the placenta to the neonate. Rather, they depend upon mammary secretion of colostrum and intestinal absorption of immunoglobulins in order to provide intestinal and systemic defense until the young ungulate develops its own humoral defense mechanisms. The neonatal dairy calf's ability to absorb immunoglobulins from colostrum is assisted by a ~24 h "open gut" phenomenon where large proteins pass the intestinal epithelial cells and enter the systemic system. However, a critical problem recognized for newborn dairy calves is that an optimum mass of colostrum Immunoglobulin G (IgG) needs to be absorbed within that 24 h window in order to provide maximal resistance to disease. Many calves do not achieve the optimum because of poor quality colostrum. While many studies have focused on calf absorption, the principal cause of the problem resides with the extreme variation (g to kg) in the mammary gland's capacity to transfer blood IgG1 into colostrum. Colostrum is a unique mammary secretory product that is formed during late pregnancy when mammary cells are proliferating and differentiating in preparation for lactation. In addition to the transcytosis of immunoglobulins, the mammary gland also concentrates a number of circulating hormones into colostrum. Remarkably, the mechanisms in the formation of colostrum in ungulates have been rather modestly studied. The mechanisms and causes of this variation in mammary gland transcytosis of IgG1 are examined, evaluated, and in some cases, explained. PMID- 24474532 TI - Bacterial production of the fungus-derived cholesterol-lowering agent mevinolin. AB - Forty-five strains from two different species (Salinispora arenicola and Salinispora pacifica) were isolated from three different marine sponge species in the Great Barrier Reef region of Australia. We found that two of the strains of Salinispora arenicola (MV0335 and MV0029) produced mevinolin, a fungus-derived cholesterol-lowering agent. Compound structure was determined using an integrated approach: (a) high performance liquid chromatography-quadrupole time-of-flight mass spectrometric analysis with multimode ionization (electrospray ionization and atmospheric pressure chemical ionization) and fast polarity switching; and (b) database searching and matching of monoisotopic masses, retention times and mass spectra of the precursor and product ions of the compounds of interest and the authentic reference standards thereof. PMID- 24474534 TI - [An unusual case of massive funicular lipoma]. AB - Intrascrotal lipomas are benign diseases that originate from adipose tissue inside the scrotal sac or constituting the scrotal wall itself. Paratesticular spermatic cord lipomas are a rare type of intrascrotal lipomas. A 78 years old patient in good health comes to our attention for massive tense-elastic swelling of left hemiscrotum appeared about 3 years ago and slowly increasing. Ultrasound evaluation of the intrascrotal mass showed inhomogeneous images mainly hyperechoic, not infiltrating the ipsilateral testis and scrotal wall. The ultrasonography found a lipomatous lesion with benign characteristics and a surgical excision has been performed. The lipomatous mass removed presented a size equal to 25 cm x 14 cm x 11 cm and a weight of about 490 gr. The microscopic examination of the tissue showed only the presence of mature adipocytes in the absence of cellular atypia, of other cellular types and of vascular abnormalities. PMID- 24474535 TI - Current clinical management of renal and perinephric abscesses: a literature review. AB - Renal and perinephric abscesses are rare but very severe conditions resulting from infections in or surrounding the kidneys. Symptoms and imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI) and renal ultrasound (US) of higher quality have led to an early diagnosis that is very important for patients' prognosis. The best clinical approach to manage this disease is still debated. Antibiotic therapy represents the usual treatment of small renal abscesses. This management can be insufficient in case of larger renal abscesses requiring percutaneous or surgical drainage. Perinephric abscesses most commonly need invasive maneuvers. We conducted a literature review to clearly define the most recommended clinical managements for all cases of renal and perinephric abscesses. PMID- 24474533 TI - Genomic tools in acute myeloid leukemia: From the bench to the bedside. AB - Since its use in the initial characterization of an acute myeloid leukemia (AML) genome, next-generation sequencing (NGS) has continued to molecularly refine the disease. Here, the authors review the spectrum of NGS applications that have subsequently delineated the prognostic significance and biologic consequences of these mutations. Furthermore, the role of this technology in providing a high resolution glimpse of AML clonal heterogeneity, which may inform future choice of targeted therapy, is discussed. Although obstacles remain in applying these techniques clinically, they have already had an impact on patient care. PMID- 24474536 TI - Emphasis of neutrophil-to-lymphocyte ratio in non-metastatic renal cell carcinoma. AB - INTRODUCTION: We investigated the prognostic significance of the neutrophil-to lymphocyte ratio on overall survival and tumor stage in non-metastatic renal cell carcinoma. METHODS: The records of 229 patients with non-metastatic RCC (T1 4N0M0) were retrospectively reviewed. Patients were classified as group 1 (T1 + T2) and group 2 (T3 + T4). The significance of the differences between the groups in terms of averages and median values were investigated with Student's t-test and Mann-Whitney U test, respectively. RESULTS: Patients were divided in two as group 1 (T1 + T2) and group 2 (T3 + T4), consisting of 208 and 21 patients, respectively. Between the two groups, the neutrophil-to-lymphocyte ratio (NLR) was found as 2.83 +/- 2.15 and 4.79 +/- 4.65, respectively (p = 0.02). We found that NLR had a distinctive feature at a cut-off value of 2.9. DISCUSSION: NLR was higher in local advanced tumors. We observed that the cut-off value of NLR is only associated with tumor volume. PMID- 24474537 TI - Spontaneous prostatic hematoma: an unusual presentation of prostatic cancer. AB - Prostatic fluid collection is not uncommon in urological practice. Prostatic abscess is the most frequent finding in this clinical setting. Spontaneous prostatic hematoma is rare, and may be related to prostatic cancer. Every case of prostatic collection must be considered with attention, and further evaluation is needed when the diagnosis is not clear. Here we report the case of a spontaneous prostatic hematoma, which was eventually found to be due to prostatic cancer, describing in detail the clinical features, differential diagnosis and treatment options. PMID- 24474538 TI - The cancelling of elective surgical operations causes emotional trauma and a lack of confidence: study from a urological department. AB - OBJECTIVES: Cancellation of elective surgical procedures is inconvenient and stressful on patients, causing loss of working days and disruption of daily life. Furthermore, it causes significant emotional trauma to the patients and their families. The purpose of this study was to analyze the number of elective surgery cancellations, as well as to identify and compare potential emotional trauma and satisfaction between older (>= 65 years) and younger (<65 years) patients. METHODS: 157 patients whose surgeries were scheduled and then cancelled were divided in two groups: Group A (62 younger patients, age <65) and Group B (95 older patients, age >= 65). The Hospital Anxiety and Depression Scale (HADS) was used to assess depression and anxiety. Patient satisfaction was collected from the Healthcare Providers and Systems Survey (HCAHPS). RESULTS: All groups with higher HADS score demonstrated markedly reduced satisfaction scores (with a mean score of 38%, p<0.001). In fact, patient satisfaction scores varied widely across the surveyed groups. Patient overall satisfaction scores after surgery ranged from 39% to 82%, with a mean of 68.5%, and from 28% to 73%, with a mean of 47.3% in Group A and B, respectively. These results point out a significantly lower satisfaction in elderly patients with depression (p<0.001) and with anxiety than in younger patients (p<0.002). CONCLUSIONS: The study goal was to point out the importance of satisfying patients' expectations to offer a better assistance, in order to ensure a comforting and friendly experience, especially when the patients are weak and not young anymore. PMID- 24474539 TI - Relationship between sun exposure and kidney cancer: preliminary experience with the evaluation of recreational UV exposure. AB - INTRODUCTION: Recent findings reported an inverse relationship between solar ultraviolet-B (UV-B) exposure and mortality from various types of cancers, including renal cancer. METHODS: We reviewed the literature concerning the relationship between sun exposure and incidence of kidney cancer. We performed a case-control study, evaluating recreational sun exposure in 50 kidney cancer patients and 50 controls.A questionnaire concerning sun exposure habits during childhood, adult life and in the previous 2 years was filled in by every patient. The questionnaire focused on: hours/day spent in the sun during summer; hours/day spent sunbathing (considering as well which kind of UV protection was used); sunburns; holidays in tropical countries. RESULTS: We found and analyzed few articles concerning the relationship between kidney cancer and sunlight exposure. The two cohorts of patients we evaluated were homogeneous for age, phototype, origin and living area.We found no statistically significant differences between sun exposure in patients affected by kidney cancer and controls, both during childhood and adult life; no differences were found in the use of sunscreens either. CONCLUSIONS: Recreational sunlight exposure does not differ in our cohorts of patients and controls; studies on greater cohorts are needed to evaluate the effect of recreational sun exposure in the development of kidney cancer. PMID- 24474540 TI - Importance of the neutrophil-to-lymphocyte ratio in muscle-invasive and non muscle invasive bladder tumors. AB - INTRODUCTION: To research the importance of the neutrophil-to-lymphocyte ratio (NLR) in muscle-invasive bladder cancers (MIBC) and non-muscle invasive bladder cancer (NMIBC). METHODS: Data of 198 patients who underwent TUR-TM in our clinic were retrospectively evaluated. Patients were divided into two groups: group-I (MIBC) and group-II (NMIBC). The neutrophil and lymphocyte counts, NLR, hemoglobin and hematocrit values, tumor numbers, sizes and degrees of patients were recorded. Within the inter-group comparison, Mann-Whitney U test was used for the values stated with measuring, whereas a Chi-square test was used for the values stated with counting. The cut-off value for the NLR was determined with ROC curve. RESULTS: The NLR values of group-I and group-II were found as 4.14 +/- 2.76 and 3.36 +/- 2.88, respectively (p = 0.03). Whether the NLR carries a differential property was evaluated with ROC curve. The cut-off value was estimated as 3.96 according to the Youden index. With this value, sensitivity was found as 50%, specificity was 22.8% and AUC was 0.615 (p = 0.03). DISCUSSION: According to the data in this study, it can be said that Ta-T1 tumors are likely to be invasive by 50% if the NLR value is greater than 3.96. PMID- 24474541 TI - Salvage low-dose-rate brachytherapy for prostate cancer local recurrence after radical prostatectomy: our first three patients. AB - PURPOSE OF THE STUDY: To present our initial experience with brachytherapy (BT) as a primary salvage procedure for the treatment of prostate cancer (PCa) local recurrence following radical retropubic prostatectomy (RRP). METHODS: From December 2009 to May 2010, three patients underwent salvage BT due to local recurrences of high risk PCa after extrafascial RRP without additional adjuvant therapies. Local recurrence was confirmed by prostate biopsy and the relapse was well defined by endorectal ultrasonography and magnetic resonance imaging. Metastatic screening was negative. The patients were followed-up according to the American Brachytherapy Society guidelines. RESULTS: The median dose delivered to 90% of the local relapse (D90) was 115 Gy. The three patients reached a prostate specific antigen (PSA) nadir value within the first year that remained stable at a mean follow-up of 32 months. As regards morbidity, moderate de novo urgency was reported by only one patient. CONCLUSIONS: We think that our data confirms the feasibility and safety of salvage BT as a possible alternative option to external beam radiotherapy (EBRT) for the treatment of locally recurrent PCa in selected patients when performed by experienced centers. However, larger series of patients with longer follow-ups are needed to define the oncologic role of this procedure. PMID- 24474542 TI - Short-term morbidity following No-Scalpel Vasectomy: an assessment of clients' perceptions by novel postcard system. AB - OBJECTIVE: Data on short-term (within a week) morbidity of No-Scalpel Vasectomy (NSV) is lacking. We studied clients' perceptions of early post-vasectomy morbidity by self innovated postcard pictorial questionnaire. METHODS: Between March 2011 and April 2012, 821 men underwent NSV and provided pre-printed revalidated pictorial postcards depicting various grades of severity of local pain, swelling, and bleeding. Clients were asked to tick mark their problems and post them on the third day after NSV. Data were compiled and statistically analyzed. RESULTS: Completed postcards were returned by 702 clients (85.5%). 25 postcards were excluded due to illegitimate filling of card. About 80.8% of clients complained of pain and minimal, moderate and severe pain was experienced by 77.69%, 18.09% and 4.20%, respectively. 16.24% of clients observed local swelling, which was minimal in 90.9%, moderate and severe in 7.27% and 1.81% of cases. 2.95% of clients noted mild bloody discharge. Most of clients managed their problems by following the instructions given in postcards; level 1 and 2 morbidity did not affect their daily activity. CONCLUSION: Early morbidity after NSV is usually mild in severity and easily manageable. The postcard system is a feasible, effective, and economical way of collecting data and managing short term post NSV problems. PMID- 24474543 TI - Radical prostatectomy in high-risk prostate cancer: incidence of specimen confined disease (pT2-pT3a N0R0) and outcomes. AB - INTRODUCTION: Radical prostatectomy (RP) in patients with high-risk prostate cancer (PC) [prostate specific antigen (PSA) >= 20 ng/mL, and/or Gleason score >= 8, and/or cT3a disease] is considered an optional therapy, usually as a part of multimodal approach. Aim of the study is to evaluate the outcome of radical prostatectomy in case of specimen-confined (SC) disease and to compare it with patients with pathological locally-advanced disease. MATERIALS AND METHODS: Data from 176 consecutive patients with high-risk prostate cancer who underwent RP as initial therapy were analyzed, identifying subjects with specimen-confined disease (i.e. negative margins and negative lymph-nodes) in which RP was considered as monotherapy, and comparing oncological outcomes to patients with pathological non-SC disease, in which RP was considered as the first step of a multimodal approach. RESULTS: In high-risk prostate cancer, pathological report showed the presence of specimen-confined disease in 28.3% of cases. At univariate analysis, age and PSA correlate with the presence of SC disease at radical prostatectomy, while at multivariate analysis only PSA was a significant predictor of SC disease. At 5 years, Kaplan-Meier estimation of biochemical-free and cancer-specific survival was 56.2% and 97.7% vs 40.8% and 92.8% in specimen confined disease and non-specimen-confined disease, respectively. CONCLUSIONS: High-risk prostate cancer presents challenges for uro-oncologists since standard treatment is still under debate. One third of patients will present with specimen confined disease, for which radical prostatectomy represents the sole, initial curative therapy; RP as multimodal therapy in patients without SC disease permits excellent long-term oncological outcomes. PMID- 24474544 TI - Primary large cell neuroendocrine carcinoma of the renal pelvis: a case report. AB - We report a case of primary large cell neuroendocrine carcinoma of the renal pelvis, diagnosed in a 79-year-old man. The abdominal computed tomography showed a solid, vegetant lesion in the left renal pelvis, conditioning marked hydronephrosis. The patient underwent radical nephroureterectomy. The histological examination showed a large cell neuroendocrine carcinoma associated with a high-grade urothelial carcinoma, with local invasion (pT3). Large cell renal neuroendocrine carcinomas are rare tumors with an aggressive course and a bad prognosis. At present, only five cases were reported in literature. PMID- 24474545 TI - [Urothelial carcinoma in a pyelocaliceal cyst]. AB - Renal complex cysts are lesions whose nature can be either benign or malignant. Depending on the presence of septa, solid components, enhancement or calcifications, they are distinguished according to the Bosniak classification based on CT findings, as well as MRI and ETG. We report a rare case of urothelial carcinoma, originating over a pyelocalyceal cyst in a 50-year-old man, and classified as Bosniak IIF by CT and MRI investigations. PMID- 24474546 TI - [Rare cases of bladder stones]. AB - We present here two special cases of urolithiasis. The first one shows a giant bladder lithiasis resulting in severe renal insufficiency in a 63-year-old patient, who had previously had nicturia (2-3 times), occasional episodes of urinary frequency and burning micturition, in the absence of renal colic, hematuria or interrupted urination. The second case referes to an 85-year-old man suffering from prostatic enlargement and bladder stones, hospitalized to undergo intervention of trans-vesical prostatic adenomectomy, during which two star shaped stones were found without obvious symptoms. PMID- 24474547 TI - [Intrinsic ureteral endometriosis: description of a striking instance]. AB - Intrinsic ureteral endometriosis is a very rare condition. A 41 y. o. woman with right hydroureteronephrosis and other aspecific symptoms came to our attention. The CT scan showed an ureteral obstacle causing the hydroureteronephrosis. She underwent ureterorenoscopy with biopsies of the lesion that did not result to be diriment. Suspecting a ureteral neoplasm, the patient then underwent ureteral resection and ureterocystoneostomy, and the extemporary histological examination resulted as endometriosis. The abdominal exploration showed a parametrial and a peritoneal growth - both compatible with the extemporary histological examination - that were also excised. The post-operative course was uneventful. The definitive hystological examination confirmed the perioperatory diagnosis. Intrinsic ureteral endometriosis is confirmed as a rare pathology with an indefinite clinical presentation; its typical presentation, namely cyclic hematuria, seems to be an anecdotal feature. Therefore the diagnostics of intrinsic ureteral endometriosis is still difficult even despite such a striking presentation. PMID- 24474548 TI - Olmsted syndrome with oral involvement, including premature teeth loss. AB - INTRODUCTION: Olmsted syndrome is a rare palmoplantar keratodermal disease that has not previously been reported to have an association with periodontal disease. The aim of this study is to report and document a case of Olmsted syndrome with evidence of severe periodontal disease. CASE REPORT: A 38-year old Saudi male patient presented to the dental clinic diagnosed previously with Olmsted syndrome. Clinical and radiographic examinations were done and provided evidence of the typical clinical findings in Olmsted syndrome and evidence of severe periodontal disease. The patient had severe generalized hyperkeratotic lesions on the palms, soles, and perioral skin as well as hyperkeratosis of oral mucosa at multiple sites. CONCLUSION: This case report documents the first reported case of Olmsted syndrome to be associated with severe periodontal disease. The altered differentiation of oral mucosa linked to Olmsted syndrome may contribute to the periodontal disease. Patients diagnosed with this syndrome should receive a comprehensive oral examination to determine whether periodontal destruction is a significant component of their disease or not. PMID- 24474549 TI - Sexual selection under parental choice: a revision to the model. AB - Across human cultures, parents exercise considerable influence over their children's mate choices. The model of parental choice provides a good account of these patterns, but its prediction that male parents exercise more control than female ones is not well founded in evolutionary theory. To address this shortcoming, the present article proposes a revision to the model. In particular, parental uncertainty, residual reproductive value, reproductive variance, asymmetry in the control of resources, physical strength, and access to weaponry make control over mating more profitable for male parents than female ones; in turn, this produces an asymmetrical incentive for controlling mate choice. Several implications of this formulation are also explored. PMID- 24474550 TI - Religious orientation and life aspirations. AB - The effects of religiosity on well-being appear to depend on religious orientation, with intrinsic orientation being related to positive outcomes and extrinsic orientation being related to neutral or negative outcomes. It is not clear, however, why intrinsic and extrinsic religiosity has the relationships they do. Self-determination theory may provide a useful framework of intrinsic and extrinsic aspirations that may help to answer this question. The purpose of the present study was to examine whether intrinsic and extrinsic religiosity would be related to intrinsic and extrinsic life aspirations. We hypothesized that intrinsic religiosity would be positively related to intrinsic life aspirations and negatively related with extrinsic life aspirations, and that extrinsic religiosity would be positively related to extrinsic life aspirations and negatively related to intrinsic aspirations, and that life aspirations would partially mediate the relationships between religious orientation and outcome. To study these hypotheses, a random national sample (total number of 425, average age of 52, 59 % female) completed the measures of religious orientation, life aspirations, affect, and life satisfaction. It was found that intrinsic religiosity was positively related to positive affect, life satisfaction, and intrinsic life aspirations and was negatively related to negative affect and extrinsic life aspirations. Extrinsic religiosity was positively related to extrinsic life aspirations and was not related to the intrinsic life aspirations. When both religious orientation and life aspiration variables were included together in the model predicting outcome, both remained significant indicating that religious orientation and life aspirations are independent predictors of outcome. In conclusion, although religious orientation and life aspirations are significantly related to each other and to outcome, life aspirations did not mediate the effects of religious orientation. Therefore, self-determination theory does not appear to completely account for the effects of religious orientation. PMID- 24474551 TI - Sources of errors in spatial frequency domain imaging of scattering media. AB - Knowledge of the impact of potential sources of error in spatial frequency domain imaging (SFDI) is essential for the quantitative characterization of absorption and scattering in tissue and other turbid media. We theoretically investigate the error in the derived absorption and scattering parameter, subject to typical experimental and theoretical sources of errors. This provides a guideline to properly assess the significance of various parameters related to the measurement and the theoretical evaluation of spatial frequency domain reflectance data. At the same time, this study serves as a reference to estimate the overall precision of derived optical parameters of semi-infinite scattering media using SFDI. PMID- 24474552 TI - Cardio- and cerebrovascular responses to the energy drink Red Bull in young adults: a randomized cross-over study. AB - PURPOSE: Energy drinks are beverages containing vasoactive metabolites, usually a combination of caffeine, taurine, glucuronolactone and sugars. There are concerns about the safety of energy drinks with some countries banning their sales. We determined the acute effects of a popular energy drink, Red Bull, on cardiovascular and hemodynamic variables, cerebrovascular parameters and microvascular endothelial function. METHODS: Twenty-five young non-obese and healthy subjects attended two experimental sessions on separate days according to a randomized crossover study design. During each session, primary measurements included beat-to-beat blood pressure measurements, impedance cardiography and transcranial Doppler measurements for at least 20 min baseline and for 2 h following the ingestion of either 355 mL of the energy drink or 355 mL of tap water; the endothelial function test was performed before and two hours after either drink. RESULTS: Unlike the water control load, Red Bull consumption led to increases in both systolic and diastolic blood pressure (p < 0.005), associated with increased heart rate and cardiac output (p < 0.05), with no significant changes in total peripheral resistance and without diminished endothelial response to acetylcholine; consequently, double product (reflecting myocardial load) was increased (p < 0.005). Red Bull consumption also led to increases in cerebrovascular resistance and breathing frequency (p < 0.005), as well as to decreases in cerebral blood flow velocity (p < 0.005) and end-tidal carbon dioxide (p < 0.005). CONCLUSION: Our results show an overall negative hemodynamic profile in response to ingestion of the energy drink Red Bull, in particular an elevated blood pressure and double product and a lower cerebral blood flow velocity. PMID- 24474553 TI - Plasma-assisted reaction chemical ionization for elemental mass spectrometry of organohalogens. AB - We present plasma-assisted reaction chemical ionization (PARCI) for elemental analysis of halogens in organic compounds. Organohalogens are broken down to simple halogen-containing molecules (e.g., HBr) in a helium microwave-induced plasma followed by negative mode chemical ionization (CI) in the afterglow region. The reagent ions for CI originate from penning ionization of gases (e.g., N2) introduced into the afterglow region. The performance of PARCI-mass spectrometry (MS) is evaluated using flow injection analyses of organobromines, demonstrating 5-8 times better sensitivities compared with inductively coupled plasma MS. We show that compound-dependent sensitivities in PARCI-MS mainly arise from sample introduction biases. PMID- 24474554 TI - Failing to improve overall survival because post-protocol survival is long: fact, myth, excuse or improper study design? PMID- 24474555 TI - High FDG uptake predicts poorer survival in locally advanced nonsmall cell lung cancer patients undergoing curative radiotherapy, independently of tumor size. AB - OBJECTIVES: Despite radical radiotherapy and chemotherapy (CT), the prognosis of locally advanced nonsmall cell lung cancer (NSCLC) is poor. New prognostic indicators are being looked forward to improve the survival. [18F] fluorodeoxyglucose (FDG) uptake on PET/CT has been observed as a prognostic marker mainly in early-stage disease. Our aim was to examine the prognostic value of FDG uptake in locally advanced NSCLC. MATERIALS AND METHODS: Between 2009 and 2011, 103 NSCLC patients underwent disease staging using FDG PET/CT before conformal radiotherapy. Thoracic radiation was administered at a daily fraction of 2 Gy. Total dose was prescribed according to the tumor response against CT. All patients underwent CT. Survival was estimated using the Kaplan-Meier method. RESULTS: The median age of the patients was 59 years (range 39-83). The median follow-up time was 22.63 months (range 6-48.03 months). There was a statistically significant difference in overall survival (OS) between the low (<10.7) and high (>=10.7) standardized uptake value (SUVmax) groups (p = 0.006) on univariate analysis (3-year OS was 42% in the low (<10.7) and 23% in the high (>=10.7) SUVmax groups). On multivariate analysis with determining tumor size, tumor SUVmax provided additional significant prognostic information on OS (HR 1.046; 95 % CI 1.009-1.085, p = 0.015). CONCLUSIONS: FDG uptake has predictive value in locally advanced NSCLC, independently of tumor size. PMID- 24474556 TI - A mouse model for endometrioid ovarian cancer arising from the distal oviduct. AB - Ovarian cancer is the deadliest gynecological malignancy in Western countries. Early detection, however, is hampered by the fact that the origin of ovarian cancer remains unclear. Knowing that in a high percentage of endometrioid ovarian cancers Wnt/beta-catenin signaling is activated, and in view of the hypothesis that ovarian cancer may originate from the distal oviduct, we studied mice in which Wnt/beta-catenin signaling was activated in Mullerian duct-derived tissues. Conditional adenomatous polyposis coli (Apc) knockout mice were used to study the activation of Wnt/beta-catenin signaling in Mullerian duct-derived organs. These Pgr(Cre/+);Apc(ex15lox/lox) mice (n = 44) were sacrificed at 10, 20, 40 and 80 weeks and uterus, oviduct, ovaries and surrounding fat tissues were assessed using immunohistochemistry. Using nuclear beta-catenin staining, Wnt/beta-catenin signaling activation was confirmed in the entire epithelium of the adult Mullerian duct (fimbriae, oviduct and endometrium), but was absent in ovarian surface epithelium cells (OSEs). Besides endometrial hyperplasia, in 87.2% of mice intraepithelial lesions of the distal oviduct were found, whereas OSEs remained unaffected. In addition, 62.5% of mice developed tumors in the distal and fimbrial part of the oviduct. In the ovaries, mainly at young age, in 16.3% of mice, simple epithelial cysts were noted, which developed further into endometrioid ovarian tumors, resembling human endometrioid ovarian cancer (27.9% of mice). Next to this, locoregional growth in the utero-ovarian ligament was also shown. Here, for the first time, mutations (activation of Wnt/beta-catenin) in the distal oviduct result in precursor lesions that develop into ovarian tumors, resembling human endometrioid ovarian cancer. PMID- 24474557 TI - Heat shock-induced dissociation of TRF2 from telomeres does not initiate a telomere-dependent DNA damage response. AB - Telomeric repeat binding factor 2 (TRF2) is a well-studied shelterin complex subunit that plays a major role in the protection of chomosome ends and the prevention of the telomere-associated DNA damage response. We show that heat shock induces the dissociation of TRF2 from telomeres in human primary and cancer cell cultures. TRF2 is not simply degraded in response to heat shock, but redistributed thoughout the nucleoplasm. This TRF2 depletion/redistribution does not initiate the DNA damage response at chomosome termini. PMID- 24474558 TI - Broadly applicable Z- and diastereoselective ring-opening/cross-metathesis catalyzed by a dithiolate ru complex. AB - A broadly applicable Ru-catalyzed protocol for Z-selective ring-opening/cross metathesis (ROCM) is disclosed. In addition to reactions relating to terminal alkenes of different sizes, the first examples of Z-selective ROCM processes involving heteroaryl olefins, 1,3-dienes, and O- and S-substituted alkenes as well as allylic and homoallylic alcohols are reported. Z-Selective transformations with an alpha-substituted allylic alcohol are shown to afford congested Z alkenes with high diastereoselectivity. Transformations are performed in the presence of 2.0-5.0 mol % of a recently disclosed Ru-based dithiolate complex that can be easily prepared in a single step from commercially available starting materials. Typically, transformations proceed at ambient temperature and are complete within eight hours; products are obtained in up to 97 % yield, >98:2 Z/E, and >98:2 diastereomeric ratio. The present investigations reveal a mechanistically significant attribute of the Ru-based dithiolates that arises from electrostatic interactions with anionic S-based ligands. PMID- 24474559 TI - Assessing spatial distribution, sources, and human health risk of organochlorine pesticide residues in the soils of arid and semiarid areas of northwest China. AB - Thirty-two topsoil samples were collected to analyze the residue levels of organochlorine pesticides (OCPs) in topsoil of arid and semiarid areas of northwest China in 2011. Results showed that DDTs were the dominant contaminants with a mean concentration of 12.52 ng/g. The spatial distribution characteristics indicated that alpha-hexachlorocyclohexanes (HCHs) were mainly used in rural sites, whereas hexachlorobenzene (HCB) and endosulfan were detected mostly in urban areas. DDTs, heptachlor, and chlordane were found almost equally in both urban and rural areas. Source identification revealed that the current levels of HCHs in soils were attributable to the residues from their historical use and fresh usage of lindane (gamma-HCH). DDTs were mainly from historical use and fresh usage of dicofol, and HCB was emitted from the chemical industry. It was also found that the current soil levels of heptachlor were mainly from its historical usage, endosulfan from fresh input, and chlordane from long-range atmospheric transport, respectively. The noncarcinogenic health risk assessment with a model was also conducted using USEPA standards for adults and children. Results indicated that health risk under nondietary exposure to OCPs decreased in the sequence of SigmaDDT > SigmaHCH > HCB > Sigmaheptachlor > Sigmaendosulfan > Sigmachlordane. According to the reference dose from the USEPA, the health risk under nondietary exposure to OCPs in the soil samples was at a relatively safe level. PMID- 24474560 TI - Analysing the fate of nanopesticides in soil and the applicability of regulatory protocols using a polymer-based nanoformulation of atrazine. AB - For the first time, regulatory protocols defined in the OECD guidelines were applied to determine the fate properties of a nanopesticide in two agricultural soils with contrasting characteristics. The nanoformulation studied had no effect on the degradation kinetics of atrazine indicating that (1) the release of atrazine from the polymer nanocarriers occurred rapidly relative to the degradation kinetics (half-lives 36-53 days) and/or that (2) atrazine associated with the nanocarriers was subject to biotic or abiotic degradation. Sorption coefficients, derived from a batch and a centrifugation technique at a realistic soil-to-solution ratio, were higher for the nanoformulated atrazine than for the pure active ingredient. Results indicate that the nanoformulation had an effect on the fate of atrazine. However, since the protocols applied were designed to assess solutes, conclusions about the transport of atrazine loaded onto the nanocarriers should be made extremely cautiously. The centrifugation method applied over time (here over 7 days) appears to be a useful tool to indirectly assess the durability of nanopesticides under realistic soil-to-solution ratios and estimate the period of time during which an influence on the fate of the active ingredient may be expected. More detailed investigations into the bioavailability and durability of nanopesticides are necessary and will require the development of novel methods suitable to address both the "nano" and "organic" characteristics of polymer-based nanopesticides. PMID- 24474561 TI - Reduction of nitrobenzene with sulfides catalyzed by the black carbons from crop residue ashes. AB - In this paper, three types of black carbons (BCs) named R-BC, W-BC, and C-BC were derived from rice straw ashes, wheat straw ashes, and corn straw ashes, respectively. Under room temperature and in an anaerobic aqueous solution, these three types of BCs could catalyze the reduction of nitrobenzene (NB) by sulfides rather than only act as the superabsorbent. The catalytic activities of BCs derived from different crop-residue ashes were very different and in the order of R-BC > W-BC > C-BC, since the reaction rate constants (k obs) of NB with the BCs in the presence of 3 mM sulfides were 0.0186, 0.0063, and 0.0051 h(-1), respectively. The key catalytic active sites for NB reduction were evaluated, with four types of modified BCs and two types of tailored graphite as the model catalysts. The results indicated that BCs probably had two types of active sites for NB reduction, the microscopic graphene moieties and the surface oxygen functional groups. Since the sulfides and BCs often coexist in the environment, this BC-catalyzed reduction technology of NACs may be applied as an in situ remediation technique without the need for reagent addition. PMID- 24474562 TI - Effects of increasing temperatures on biomarker responses and accumulation of hazardous substances in rope mussels (Mytilus galloprovincialis) from Bizerte lagoon. AB - This study examined the influence of increasing temperatures in spring and summer on biochemical biomarkers in Mytilus galloprovincialis mussels sampled from Bizerte lagoon (northern Tunisia). Spatial and seasonal variations in a battery of seven biomarkers were analyzed in relation to environmental parameters (temperature, salinity, and pH), physiological status (condition and gonad indexes), stress on stress (SoS), and chemical contaminant levels (heavy metals, polycyclic aromatic hydrocarbons (PAHs), and PCBs) in digestive glands. Integrated biological response (IBR) was calculated using seven biomarkers (acetylcholinesterase (AChE), benzo[a]pyrene hydroxylase (BPH), multixenobiotic resistance (MXR), glutathione S-transferase (GST), catalase (CAT), malondialdehyde (MDA), and metallothioneins (MT). Seasonal variations in biological response were determined during a critical period between spring and summer at two sites, where chemical contamination varies by a factor of 2 for heavy metals and a factor 2.5 for PAHs. The analysis of a battery of biomarkers was combined with the measurement of physiological parameters at both sites, in order to quantify a maximum range of metabolic regulation with a temperature increase of 11 degrees C between May and August. According to our results, the MT, MDA, CAT, and AChE biomarkers showed the highest amplitude during the 11 degrees C rise, while the BPH, GST, and MXR biomarkers showed the lowest amplitude. Metabolic amplitude measured with the IBR at Menzel Abdelrahmen-the most severely contaminated station-revealed the highest metabolic stress in Bizerte lagoon in August, when temperatures were highest 29.1 degrees C. This high metabolic rate was quantified for each biomarker in the North African lagoon area and confirmed in August, when the highest IBR index values were obtained at the least contaminated site 2 (IBR = 9.6) and the most contaminated site 1 (IBR = 19.6). The combined effects of chemical contamination and increased salinity and temperatures in summer appear to induce a highest metabolic adaptation response and can therefore be used to determine thresholds of effectiveness and facilitate the interpretation of monitoring biomarkers. This approach, applied during substantial temperature increases at two sites with differing chemical contamination, is a first step toward determining an environmental assessment criteria (EAC) threshold in a North African lagoon. PMID- 24474564 TI - Differences in responses of summer and winter spinach to elevated UV-B at varying soil NPK levels. AB - Seasonal variations in response of spinach to elevated ultraviolet-B (UV-B) during summer and winter were assessed with respect to growth, biomass, yield, NPK uptake and NPK use efficiencies at varying NPK levels. The nutrient amendments were recommended NPK (RNPK) and 1.5 times recommended NPK (1.5 RNPK). Season significantly affected the measured parameters except the number of leaves. Under ambient UV-B, the growth performance of summer spinach was better in both the NPK levels, higher being at 1.5 RNPK leading to higher nutrient uptake. However, more reduction in biomass under elevated UV-B in 1.5 RNPK was recorded during summer, while during winter in RNPK. Reduction in biomass under elevated UV-B was accompanied by the modification in its partitioning with more biomass allocation to root during summer compared to winter at both the NPK levels. NPK uptake was higher in summer, while NPK use efficiencies were higher during winter. At higher than recommended NPK level, better NPK use efficiencies were displayed during both the seasons. Increased NPK supply during winter enabled spinach to capitalize light more efficiently and hence increased biomass accumulation. Strategies for surviving elevated UV-B in winter differ from those that provided protection from the same stress when it occurs in summer. PMID- 24474563 TI - Impact of dredged urban river sediment on a Saronikos Gulf dumping site (Eastern Mediterranean): sediment toxicity, contaminant levels, and biomarkers in caged mussels. AB - Impacts of chemical contaminants associated with dumping of dredged urban river sediments at a coastal disposal area in Saronikos Gulf (Eastern Mediterranean) were investigated through a combined approach of sediment toxicity testing and active biomonitoring with caged mussels. Chemical analyses of aliphatic hydrocarbons (AHs), polycyclic aromatic hydrocarbons (PAHs), Cu, and Zn in combination with the solid phase Microtox(r) test were performed on sediments. Concentrations of PAHs, AHs, Cu, and Zn as well as multiple biomarkers of contaminant exposure and/or effects were measured in caged mussels. Sediments in the disposal and neighboring area showed elevated PAHs and AHs concentrations and were characterized as toxic by the solid-phase Microtox(r) test during and after dumping operations. Biomarker results in the caged mussels indicated sublethal effects mainly during dumping operations, concomitantly with high concentrations of PAHs and AHs in the caged mussel tissues. Cu and Zn concentrations in sediments and caged mussels were generally not elevated except for sediments at the site in the disposal area that received the major amount of dredges. High PAHs and AHs levels as well as sublethal effects in the caged mussels were not persistent after termination of operations. The combined bioassay-biomarker approach proved useful for detecting toxicological impacts of dredged river sediment disposal in sediments and the water column. Nevertheless, further research is needed to evaluate whether sediment toxicity will have long-term effects on benthic communities of the disposal area. PMID- 24474565 TI - Anogenital distance and its application in environmental health research. AB - Anogenital distance (AGD), a useful anthropometric measurement for genital development in both animals and humans, was originally found by reproductive toxicologists in rodent experiments. As an easy-to-measure and sensitive marker, AGD has become a bioassay of fetal androgen action and a well-established reproductive toxicity endpoint in animals. It is generally accepted that AGD is sexually dimorphic in many mammals, with males having longer AGD than females. Exposure to proposed endocrine disruptors may result in reduced AGD; thus, it has been used to measure health effects of compounds with endocrine-altering properties or endocrine-disrupting chemicals (EDCs) in environmental toxicology. Moreover, AGD is an important clinical measure to address endocrine-sensitive endpoints in the first year of life and to assess the adverse impact of in utero exposure to environmental EDCs. Recently, AGD has been identified as one of the endpoints in the US Environmental Protection Agency guidelines for reproductive toxicity studies in humans, but use of AGD in human studies is still rare, and the results remain mixed and inconclusive due to many reasons. In order to achieve a breakthrough, researchers are endeavoring to standardize the measurement of AGD, normalize age-specific population data in different ethnic groups, and conduct more in-depth human researches in this field. PMID- 24474566 TI - Biodegradation of methyl red by Bacillus sp. strain UN2: decolorization capacity, metabolites characterization, and enzyme analysis. AB - Azo dyes are recalcitrant and refractory pollutants that constitute a significant menace to the environment. The present study is focused on exploring the capability of Bacillus sp. strain UN2 for application in methyl red (MR) degradation. Effects of physicochemical parameters (pH of medium, temperature, initial concentration of dye, and composition of the medium) were studied in detail. The suitable pH and temperature range for MR degradation by strain UN2 were respectively 7.0-9.0 and 30-40 degrees C, and the optimal pH value and temperature were respectively 8.0 and 35 degrees C. Mg(2+) and Mn(2+) (1 mM) were found to significantly accelerate the MR removal rate, while the enhancement by either Fe(3+) or Fe(2+) was slight. Under the optimal degradation conditions, strain UN2 exhibited greater than 98 % degradation of the toxic azo dye MR (100 ppm) within 30 min. Analysis of samples from decolorized culture flasks confirmed biodegradation of MR into two prime metabolites: N,N'dimethyl-p-phenyle-nediamine and 2-aminobenzoic acid. A study of the enzymes responsible for the biodegradation of MR, in the control and cells obtained during (10 min) and after (30 min) degradation, showed a significant increase in the activities of azoreductase, laccase, and NADH-DCIP reductase. Furthermore, a phytotoxicity analysis demonstrated that the germination inhibition was almost eliminated for both the plants Triticum aestivum and Sorghum bicolor by MR metabolites at 100 mg/L concentration, yet the germination inhibition of parent dye was significant. Consequently, the high efficiency of MR degradation enables this strain to be a potential candidate for bioremediation of wastewater containing MR. PMID- 24474567 TI - Comment on "distribution features of biological hazardous pollutants in residential environments in Korea [Lee et al., Environ Sci Pollut Res (2014) 21:1146-1152]". PMID- 24474569 TI - Mixed phenotype acute leukemia. PMID- 24474568 TI - A phase 1/pharmacokinetic study of sunitinib in combination with highly active antiretroviral therapy in human immunodeficiency virus-positive patients with cancer: AIDS Malignancy Consortium trial AMC 061. AB - BACKGROUND: The treatment of non-acquired immunodeficiency syndrome-defining cancers may be complicated by drug interactions between highly active antiretroviral therapy (HAART) and chemotherapy. This trial is the first by the AIDS Malignancy Consortium to assess targeted therapies and HAART in human immunodeficiency virus-positive patients (ClinicalTrials.gov identifier: NCT00890747). METHODS: In a modified phase 1 study of sunitinib, patients were stratified into 2 treatment arms based on whether they were receiving therapy with ritonavir, a potent CYP3A4 inhibitor. Patients in treatment arm 1 (non ritonavir HAART) received standard sunitinib dosing (50 mg/day). Treatment arm 2 (ritonavir-based HAART) used a phase 1, 3 + 3 dose escalation design (from 25 mg/day to 50 mg/day). Cycles were comprised of 4 weeks on treatment followed by a 2-week break (6 weeks total). The pharmacokinetics of sunitinib and its active metabolite (N-desethyl sunitinib) were assessed. RESULTS: Nineteen patients were enrolled and were evaluable. Patients on treatment arm 1 tolerated treatment with no dose-limiting toxicity observed. In treatment arm 2, a dose-limiting toxicity was experienced at a dose of 37.5 mg, and an additional 3 of 5 patients experienced grade 3 neutropenia (toxicity graded as per National Cancer Institute Common Terminology Criteria for Adverse Events [version 4.0]), an uncommon toxicity of sunitinib. No patient achieved a response, but 10 patients had stable disease, including 8 with prolonged disease stability. Efavirenz, a potent inducer of CYP3A4, resulted in increased exposure of N-desethyl sunitinib, whereas ritonavir caused decreased exposure of the metabolite. Hand-foot syndrome was associated with higher steady-state trough concentrations of sunitinib. CONCLUSIONS: Patients receiving non-ritonavir-based HAART regimens tolerated standard dosing of sunitinib. Patients receiving ritonavir-based therapy who were treated with a dose of 37.5 mg/day experienced higher toxicities. Dose reductions of sunitinib to 37.5 mg may be warranted in patients receiving ritonavir. PMID- 24474570 TI - Structural genomics studies of human caries pathogen Streptococcus mutans. AB - Gram-positive bacterium Streptococcus mutans is the primary causative agent of human dental caries. To better understand this pathogen at the atomic structure level and to establish potential drug and vaccine targets, we have carried out structural genomics research since 2005. To achieve the goal, we have developed various in-house automation systems including novel high-throughput crystallization equipment and methods, based on which a large-scale, high efficiency and low-cost platform has been establish in our laboratory. From a total of 1,963 annotated open reading frames, 1,391 non-membrane targets were selected prioritized by protein sequence similarities to unknown structures, and clustered by restriction sites to allow for cost-effective high-throughput conventional cloning. Selected proteins were over-expressed in different strains of Escherichia coli. Clones expressed soluble proteins were selected, expanded, and expressed proteins were purified and subjected to crystallization trials. Finally, protein crystals were subjected to X-ray analysis and structures were determined by crystallographic methods. Using the previously established procedures, we have so far obtained more than 200 kinds of protein crystals and 100 kinds of crystal structures involved in different biological pathways. In this paper we demonstrate and review a possibility of performing structural genomics studies at moderate laboratory scale. Furthermore, the techniques and methods developed in our study can be widely applied to conventional structural biology research practice. PMID- 24474571 TI - It's the thought that counts. PMID- 24474572 TI - Exclusive radiotherapy for gliomatosis cerebri: long-term follow-up at a single institution. AB - PURPOSE: To evaluate the efficacy of radiotherapy and factors affecting the prognosis of gliomatosis cerebri. METHODS: Twenty-eight patients with pathologically confirmed gliomatosis cerebri underwent radiotherapy between August 1988 and September 2003. The median age of the patients was 39 years (range 18-67). Performance status was good (ECOG score <=2) in 23 patients (82 %). The extent of radiotherapy was partial brain in 17 patients, whole brain in 2 patients, and whole brain followed by partial brain in 9 patients. The median radiation dose was 55.8 Gy (range 46.8-70.4). The median duration of follow-up was 136 months for survivors (range 39-191). RESULTS: The median overall and progression-free survival times of all patients were 20 and 11 months, respectively. When initial response to radiotherapy was grouped as improved, stationary, and aggravated, the median overall survival times in patients with improved, stationary, and aggravated responses were 76, 20, and 7 months, respectively (p = 0.0129). However, radiation parameters such as dose and irradiation volume had no impact on overall survival. On multivariate analysis, both performance status and initial response to radiotherapy were significant prognostic factors affecting overall survival (p = 0.0249 and 0.0065, respectively). CONCLUSIONS: This study showed that gliomatosis cerebri could be effectively treated with radiotherapy and that initial response to radiotherapy was a significant prognostic factor affecting the survival. PMID- 24474573 TI - An association of myeloproliferative neoplasms and obliterative portal venopathy. PMID- 24474574 TI - Systemic effect of endoscopic ultrasonography-guided pancreatic cyst ablation with ethanol and paclitaxel. AB - BACKGROUND: Endoscopic ultrasonography (EUS)-guided pancreatic cyst ablation is a minimally invasive treatment modality. Local injection of ablative agents may rarely cause systemic effects in patients. AIMS: This study aimed to evaluate the systemic effect of ablative agents by analyzing the plasma drug concentration. METHODS: Ten patients with pancreatic cysts were enrolled. Cyst ablation was performed by 99 % ethanol lavage (2.5-70 mL) and paclitaxel (Genexol-polymeric micelle, 6.0-24.0) injection. Blood samples were collected at 0, 2, 4, 7 and 24 h. Plasma paclitaxel concentration was analyzed by a liquid chromatography-tandem mass spectrometry with the lowest limit of quantitation of 0.1 ng/mL. Procedure related complications were closely monitored. RESULTS: Pancreatic cysts were located at the head in two, body in seven and tail in one patient. Eight cysts were septated. Median diameter and original volume were 39.5 mm (range 2.7-21.8) and 14.79 mL (3.42-343.30). Median cyst fluid CEA and amylase values were 17.10 ng/mL (0.5-14127.5) and 73.50 U/L (3.1-91,590). Peak plasma paclitaxel concentration values were observed between 2 and 7 h, ranging from 0.45 to 14.73 ng/mL. The highest concentration (17.10 ng/mL at 0 h) was observed in a patient who had intracystic bleeding. Mild abdominal pain occurred in five patients and vomiting in one patient during the first 48-h monitoring. CONCLUSION: Plasma paclitaxel concentration after EUS-guided pancreatic cyst ablation was nearly as low as the undetectable value and rarely caused systemic side-effect. PMID- 24474575 TI - Adipose-derived stromal cells grown on a hydroxyapatite scaffold can support hematopoiesis in regenerated bone marrow in vivo. AB - Osteoblastic cells are a key component of the bone marrow (BM) stem cell niche and help regulate hematopoietic stem cells (HSCs). We have previously demonstrated that adipose-derived stromal cells (ADSCs) can differentiate into both osteogenic and chondrogenic cells in vitro. The current study examined whether the anatomical architecture of the BM could be regenerated in vivo by using ADSCs cultured on a hydroxyapatite (HA) scaffold. ADSCs from GFP transgenic mice were cultured in vitro on an HA scaffold. The scaffold with the attached cells was implanted subcutaneously onto the backs of C57/BL6 (Ly5.2) recipient mice. Lineage-negative (Lin-) Ly5.1 BM cells transduced with a lentiviral vector containing the luciferase (Luc) gene were intravenously administered to the recipient mice after lethal irradiation. Eight weeks after BM transplantation, the scaffolds were removed from the first recipient mice and subcutaneously implanted into lethally irradiated second recipient mice. The biodistribution and kinetics of Luc(+) Ly5.1 cells were monitored by bioluminescence imaging and flow cytometry. Luc(+) hematopoietic cells were present in the scaffolds of the secondary implanted mice for at least 8 months. Subcutaneous injection of G-CSF resulted in wide distribution of bioluminescence signals from the original scaffolds to the whole body. Therefore, BM regenerated using ADSCs grown on an HA scaffold can support HSC populations in vivo, suggesting that a functional BM niche is reconstituted. These results may have a significant impact on the development of therapeutic strategies for various hematopoietic diseases. PMID- 24474576 TI - Reducing central venous catheters in chronic hemodialysis--a commitment to arteriovenous fistula creation in children. AB - BACKGROUND: An internal permanent vascular access [arteriovenous fistula (AVF) or arteriovenous graft (AVG)] is preferred over central venous catheters (CVC) for chronic hemodialysis. However, CVC remain the most commonly used access in children. The objective of this study was to evaluate our experience with AVF. METHODS: We conducted a retrospective chart review of children aged 1-18 years on chronic hemodialysis from 2001 to 2012. Patients were divided into three time periods: 2001-2005, 2006-2009 and 2010-2012. A systematic approach to AVF placement was introduced in our department in 2006 which resulted in a greater number of AVF being placed and used, but the access failure rate was still higher than desired. In 2010, a more experienced vascular surgeon was contacted to perform AVF surgery in our most difficult AVF candidates. RESULTS: Sixty-five AVF were created in 55 patients (67.3 % male). The median age of the patients was 14 (3-18) years. Forty-one (63.1 %) AVF were used successfully, and this number increased from 52.6 to 57.6 to 92.3 % over the three time periods, respectively. Over time, AVF use rates increased and CVC use decreased. By 2012 only 7.7 % of our patients were using a CVC. The primary patency rate was 42.9 % at 1 year; secondary patency rates were 100 and 93.8 % at 1 and 2 years, respectively. Infection and hospitalization rates were higher for CVC than for AVF [0.8 vs. 0.1 infections per access-year (p < 0.001) and 0.9 vs. 0.2 hospitalizations per access-year (p < 0.001)]. CONCLUSIONS: With a dedicated approach and vascular access team it is possible to decrease CVC and increase AVF use in children on hemodialysis. In our study, increased AVF use resulted in decreased access related infection and hospitalization rates. PMID- 24474577 TI - Calcific uraemic arteriolopathy: a rare disease with a potentially high impact on chronic kidney disease-mineral and bone disorder. AB - Calciphylaxis [calcific uraemic arteriolopathy (CUA)] is a rare disease at the interface of nephrology, dermatology and cardiology. CUA most often occurs in adult dialysis patients. It is only rarely seen in patients without relevant chronic kidney disease, and only anecdotal reports about childhood calciphylaxis have been published. Clinically, CUA is characterized by a typical cascade, starting with severe pain in initially often inconspicuous skin areas, followed by progressive cutaneous lesions that may develop into deep tissue ulcerations. The typical picture is a mixture of large retiform ulceration with thick eschar surrounded by violaceous, indurated, tender plaques. The histopathological picture reveals arteriolar, often circumferential, calcification and extensive matrix remodelling of the subcutis. These findings explain the macroscopic correlation between skin induration and ulceration. The prognosis in CUA patients is limited due to underlying comorbidities such as uraemic cardiovascular disease and infectious complications. The etiology of CUA is multifactorial, and imbalances between pro- and anti-calcification factors, especially in the setting of end-stage renal disease play an outstanding role. Oral anticoagulant treatment with vitamin K antagonists is a predominant CUA trigger factor. It is speculative as to why children and adolescents only develop calciphylaxis in exceptional cases, although a seldom usage of vitamin K antagonists and the preserved mineral buffering capacity of the growing skeleton may be protective. PMID- 24474578 TI - Steroid-resistant nephrotic syndrome in a child with dysmorphic features: answers. PMID- 24474579 TI - Image guided surgery for the resection of brain tumours. AB - BACKGROUND: Extent of resection is believed to be a key prognostic factor in neuro-oncology. Image guided surgery uses a variety of tools or technologies to help achieve this goal. It is not clear whether any of these, sometimes very expensive, tools (or their combination) should be recommended as part of standard care for patient with brain tumours. We set out to determine if image guided surgery offers any advantage in terms of extent of resection over surgery without any image guidance and if any one tool or technology was more effective. OBJECTIVES: To compare image guided surgery with surgery either not using any image guidance or to compare surgery using two different forms of image guidance. The primary outcome criteria was extent of resection and adverse events. Other outcome criteria were overall survival; progression free survival; and quality of life (QoL). SEARCH METHODS: The following databases were searched, the Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 1, 2013), MEDLINE (1948 to March, week 10, 2013) and EMBASE (1970 to 2013, week 10). Reference lists of all identified studies were searched. Two journals, the Journal of Neuro-Oncology and Neuro-oncology, were handsearched from 1991 to 2013, including all conference abstracts. Neuro-oncologists, trial authors and manufacturers were contacted regarding ongoing and unpublished trials. SELECTION CRITERIA: Study participants included patients of all ages with a presumed new or recurrent brain tumour (any location or histology) from clinical examination and imaging (computed tomography (CT), magnetic resonance imaging (MRI) or both). Image guidance interventions included intra-operative MRI (iMRI); fluorescence guided surgery; neuronavigation including diffusion tensor imaging (DTI); and ultrasonography. Included studies had to be randomised controlled trials (RCTs) with comparisons made either with patients having surgery without the image guidance tool in question or with another type of image guidance tool. Subgroups were to include high grade glioma; low grade glioma; brain metastasis; skull base meningiomas; and sellar or parasellar tumours. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed the search results for relevance, undertook critical appraisal according to known guidelines, and extracted data using a pre-specified pro forma. MAIN RESULTS: Four RCTs were identified, each using a different image guided technique: 1. iMRI (58 patients), 2. 5-aminolevulinic acid (5-ALA) fluorescence guided surgery (322 patients), 3. neuronavigation (45 patients) and 4. DTI-neuronavigation (238 patients). Meta-analysis was not appropriate due to differences in the tumours included (eloquent versus non-eloquent locations) and variations in the image guidance tools used in the control arms (usually selective utilisation of neuronavigation). There were significant concerns regarding risk of bias in all the included studies, especially for the study using DTI-neuronavigation. All studies included patients with high grade glioma, with one study also including patients with low grade glioma. The extent of resection was increased with iMRI (risk ratio (RR) (incomplete resection) 0.13, 95% CI 0.02 to 0.96, low quality evidence), 5-ALA (RR 0.55, 95% CI 0.42 to 0.71) and DTI-neuronavigation (RR 0.35, 95% CI 0.20 to 0.63, very low quality evidence). Insufficient data were available to evaluate the effects of neuronavigation on extent of resection. Reporting of adverse events was incomplete, with a suggestion of significant reporting bias. Overall, reported events were low in most studies, but there was concern that surgical resection using 5-ALA may lead to more frequent early neurological deficits. There was no clear evidence of improvement in overall survival (OS) with 5-ALA (hazard ratio (HR) 0.82, 95% CI 0.62 to 1.07) or DTI-neuronavigation (HR 0.57, 95% CI 0.32 to 1.00) in patients with high grade glioma. Progression-free survival (PFS) data were not available in the appropriate format for analysis.Data for quality of life (QoL) were only available for one study and suffered from significant attrition bias. AUTHORS' CONCLUSIONS: There is low to very low quality evidence (according to GRADE criteria) that image guided surgery using iMRI, 5-ALA or DTI neuronavigation increases the proportion of patients with high grade glioma that have a complete tumour resection on post-operative MRI. There is a theoretical concern that maximising the extent of resection may lead to more frequent adverse events but this was poorly reported in the included studies. Effects of image guided surgery on survival and QoL are unclear. Further research, including studies of ultrasound guided surgery, is needed. PMID- 24474580 TI - CT and MR image fusion scheme in nonsubsampled contourlet transform domain. AB - Fusion of CT and MR images allows simultaneous visualization of details of bony anatomy provided by CT image and details of soft tissue anatomy provided by MR image. This helps the radiologist for the precise diagnosis of disease and for more effective interventional treatment procedures. This paper aims at designing an effective CT and MR image fusion method. In the proposed method, first source images are decomposed by using nonsubsampled contourlet transform (NSCT) which is a shift-invariant, multiresolution and multidirection image decomposition transform. Maximum entropy of square of the coefficients with in a local window is used for low-frequency sub-band coefficient selection. Maximum weighted sum modified Laplacian is used for high-frequency sub-bands coefficient selection. Finally fused image is obtained through inverse NSCT. CT and MR images of different cases have been used to test the proposed method and results are compared with those of the other conventional image fusion methods. Both visual analysis and quantitative evaluation of experimental results shows the superiority of proposed method as compared to other methods. PMID- 24474581 TI - The natural course of chronic exertional compartment syndrome of the lower leg. AB - PURPOSE: The aim of this study was to investigate the natural course of chronic exertional compartment syndrome (CECS) in the lower leg. METHODS: Twelve military men [mean age 30 (SD 4)] diagnosed with CECS after intracompartmental pressure (ICP) measurements immediately post-exercise in 21 legs, who did not undergo a fasciotomy, were reviewed and participated in a repeat pressure measurement after a mean time of 50 months (SD 15). RESULTS: Sixteen of 21 legs still showed an ICP of 35 mm Hg or more (the cut-off point) at the second visit. All twelve patients still had typical complaints. Mean ICP at index measurement was 58 (SD 15) mm Hg. At the second visit, it was 51 (SD 15) mm Hg. Six patients chose to undergo a subcutaneous fasciotomy, and these six patients all benefited in the short term. CONCLUSION: The natural course of CECS seems to be persistent symptoms over time. LEVEL OF EVIDENCE: Case series with no comparative group, Level IV. PMID- 24474582 TI - Radiographic findings of femoroacetabular impingement in capoeira players. AB - PURPOSE: Capoeira is a Brazilian martial art that requires extreme movements of the hip to perform jumps and kicks. This study evaluated a group of capoeira players to assess the prevalence of femoroacetabular impingement (FAI) in athletes practicing this martial art. METHODS: Twenty-four experienced capoeira players (14 men, 10 women) underwent a diagnostic assessment, including clinical examination and standard radiographs of the pelvis and hips. The alpha-angle, head-neck offset, crossover sign, acetabular index, lateral centre-edge angle, and the Tonnis grade were assessed using the radiographs. Clinical relationships for any radiographic abnormalities indicating FAI were also evaluated. RESULTS: Four subjects (17 %) reported pain in their hips. Forty-four hips (91.7 %) had at least one radiographic sign of CAM impingement, and 22 (45.8 %) had an alpha angle of more than 60 degrees . Eighteen hips (37.5 %) had at least one sign of pincer impingement and 16 (33.3 %) a positive crossover sign. Sixteen hips (33.3 %) had mixed impingement. There was a significant positive association between having an alpha-angle of more than 60 degrees and the presence of groin pain (P = 0.002). A reduced femoral head-neck offset (P < 0.001) and an increased alpha angle on the anteroposterior radiograph (P = 0.008) were independently associated with a higher Tonnis grade. CONCLUSION: High prevalence of radiographic CAM-type FAI among these skilled capoeira players was found. In these subjects, a negative clinical correlation for an increased alpha-angle was also detected. Additional caution should be exercised whenever subjects with past or present hip pain engage in capoeira. PMID- 24474583 TI - Non-steroidal anti-inflammatory drugs (NSAIDs) for treating acute ankle sprains in adults: benefits outweigh adverse events. AB - PURPOSE: In the recent clinical guideline for acute lateral ankle sprain, the current best evidence for diagnosis, treatment and prevention strategies was evaluated. Key findings for treatment included the use of ice and compression in the initial phase of treatment, in combination with rest and elevation. A short period of taking non-steroidal anti-inflammatory drugs (NSAIDs) may facilitate a rapid decrease in pain and swelling can also be helpful in the acute phase. The objective was to assess the effectiveness and safety of oral and topical NSAID in the treatment for acute ankle sprains. METHODS: Randomised controlled trials comparing oral or topic NSAID treatment with placebo or each other were included. Primary outcome measures were pain at rest or at mobilisation and adverse events. Trials were assessed using the Cochrane risk of bias tool. RESULTS: Twenty-eight studies were included, and 22 were available for meta-analysis. Superior results were reported for oral NSAIDs when compared with placebo, concerning pain on weight bearing on short term, pain at rest on the short term, and less swelling on short- and intermediate term. For topical NSAIDs, superior results compared with placebo were found for pain at rest (short term), persistent pain (intermediate term), pain on weight bearing (short- and intermediate term) and for swelling (short and intermediate term). No trials were included comparing oral with topic NSAIDs, so conclusions regarding this comparison are not realistic. CONCLUSIONS: The current evidence is limited due to the low number of studies, lack of methodological quality of the included studies as well as the small sample size of the included studies. Nevertheless, the findings from this review support the use of NSAIDs for the initial treatment for acute ankle sprains. LEVEL OF EVIDENCE: Meta-analysis of RCTs, Level I. PMID- 24474584 TI - A comparison of open and arthroscopic surgery for treatment of diffuse pigmented villonodular synovitis of the knee. AB - PURPOSE: To compare the outcomes of diffuse pigmented villonodular synovitis (PVNS) of the knee treated with routine anteroposterior open surgery or modified multi-directional arthroscopy. METHODS: Medical records of patients with diffuse PVNS who underwent surgery between 2002 and 2010 were reviewed. Patients were followed up at 3, 6, 12, 24, and 36 months. Operative time, blood loss, length of hospital stay, recurrence rate, and International Knee Documentation Committee (IKDC) scores and Lysholm knee scores at 1- and 3-year postoperatively were compared between the open surgery and arthroscopy groups. RESULTS: A total of 41 patients with diffuse PVNS were included (20 in open surgery group and 21 in multi-directional arthroscopy group). There was no significant difference in the baseline characteristics between the two groups. Operation time, postoperative bleeding, and length of hospital stay were all significantly lower in the arthroscopy group than in the open surgery group (all, P < 0.05). There were four recurrences in the open surgery group and one in arthroscopy group. All five recurrences received a second surgery without any subsequent recurrences. At both 1- and 3-year postoperatively, IKDC and Lysholm scores were significantly greater in the arthroscopy group than the open surgery group (all P < 0.001). CONCLUSIONS: The multi-directional arthroscopic technique was associated with significantly shorter operation time and hospital stay, less blood loss, and better postoperative IKDC and Lysholm scores than open surgery. LEVEL OF EVIDENCE: Retrospective study with controls, Level III. PMID- 24474585 TI - Suture anchor repair yields better biomechanical properties than transosseous sutures in ruptured quadriceps tendons. AB - PURPOSE: This human cadaveric study compares the biomechanical properties of quadriceps tendon repair with suture anchors and the commonly applied transosseous sutures. The hypothesis was that suture anchors provide at least equal results concerning gap formation and ultimate failure load compared with transosseous suture repair. METHODS: Thirty human cadaveric knees underwent tenotomy followed by repair with either 5.5-mm-double-loaded suture anchors [titanium (TA) vs. resorbable hydroxyapatite (HA)] or transpatellar suture tunnels using No. 2 UltrabraidTM and the Krackow whipstitch. Biomechanical analysis included pretensioning the constructs with 20 N for 30 s and then cyclic loading of 250 cycles between 20 and 100 N at 1 Hz in a servohydraulic testing machine with measurement of elongation. Ultimate failure load analysis and failure mode analysis were performed subsequently. RESULTS: Tendon repairs with suture anchors yielded significantly less gap formation during cyclic loading (20th-250th cycle: TA 1.9 +/- 0.1, HA 1.5 +/- 0.5, TS 33.3 +/- 1.9 mm, p < 0.05) and resisted significantly higher ultimate failure loads (TA 740 +/- 204 N, HA 572 +/- 67 N, TS 338 +/- 60 N, p < 0.05) compared with transosseous sutures. Common failure mode was pull-out of the eyelet within the suture anchor in the HA group and rupture of the suture in the TA and TS group. CONCLUSION: Quadriceps tendon repair with suture anchors yields significantly better biomechanical results than the commonly applied transosseous sutures in this human cadaveric study. These biomechanical findings may change the future clinical treatment for quadriceps tendon ruptures. Randomised controlled clinical trials are desirable for the future. LEVEL OF EVIDENCE: Not applicable, controlled laboratory human cadaveric study. PMID- 24474586 TI - Signal intensity on magnetic resonance imaging after allograft double-bundle anterior cruciate ligament reconstruction. AB - PURPOSE: To evaluate magnetic resonance imaging (MRI) graft signal intensity after allograft double-bundle (DB) anterior cruciate ligament (ACL) reconstruction and determine the relationship between signal intensity and time from surgery. METHODS: Twenty-six patients with an intact graft on MRI after anatomic allograft DB ACL reconstruction up to 1 year post-operatively were included. All subjects underwent post-operative MRI using a 1.5-T magnet. Sagittal proton density-weighted images (PDWI) and sagittal T2-weighted images (T2WI) were analysed. Using the region-of-interest (ROI) function on imaging software, the anteromedial (AM) and posterolateral (PL) bundles of the graft and the posterior cruciate ligament (PCL) were outlined. Mean signal intensity of the three ROIs were recorded as absolute signal intensity. Signal intensity (SI ratio) was calculated based on the signal intensity of the PCL. Correlation coefficients were calculated to determine the relationship between signal intensity and time from surgery. RESULTS: SI ratio of the PL bundle was higher than that of the AM bundle for both the PDWI (1.7 +/- 1.5 vs. 2.5 +/- 1.7, p < 0.05) and T2WI (1.3 +/- 0.4 vs 1.6 +/- 0.6, p < 0.05). There were weak correlations between AM SI ratio and time from surgery (r = 0.38, p < 0.05 on PDWI), and moderate correlations between PL SI ratio and time from surgery (r = 0.43, p < 0.05 on PDWI) (r = 0.44, p < 0.05 on T2WI). CONCLUSIONS: The PL bundle displayed increased signal intensity compared to the AM bundle and based on previous studies may indicate a longer healing process. Plain MRI may be useful to assess graft healing after ACL reconstruction. LEVEL OF EVIDENCE: Retrospective case series, Level IV. PMID- 24474587 TI - Oncolytic vaccinia virus demonstrates antiangiogenic effects mediated by targeting of VEGF. AB - Oncolytic vaccinia virus has been shown to induce a profound, rapid and tumor specific vascular collapse in both preclinical models and clinical studies; however, a complete examination of the kinetics and levels of collapse and revascularization has not been described previously. Contrast-enhanced ultrasound was used to follow tumor perfusion levels in mouse tumor models at times after vaccinia therapy. It was observed that revascularization after viral therapy was dramatically delayed and did not occur until after viral clearance. This indicated that oncolytic vaccinia may possess a previously undescribed antiangiogenic potential that might synergize with the reported anti-vascular effects. Despite a rapid loss of perfusion and widespread hypoxia within the tumor, it was observed that VEGF levels in the tumor were suppressed throughout the period of active viral infection. Although tumor vasculature could eventually reform after the viral therapy was cleared in mouse models, anti-tumor effects could be significantly enhanced through additional combination with anti-VEGF therapies. This was initially examined using a gene therapy approach (Ad-Flk1-Fc) to target VEGF directly, demonstrating that the timing of application of the antiangiogenic therapy was critical. However, it is also known that oncolytic vaccinia sensitizes tumors to tyrosine kinase inhibitors (TKI) in the clinic through an unknown mechanism. It is possible this phenomenon may be mediated through the antiangiogenic effects of the TKIs. This was modeled in mouse tumors using sunitinib in combination with oncolytic vaccinia. It was observed that prevention of angiogenesis mediated by oncolytic vaccinia can be utilized to enhance the TKI therapy. PMID- 24474588 TI - PS microspheres coated by AuNPs via thermodynamic driving heterocoagulation and their high catalytic activity. AB - A unique method of fabricating PS/AuNPs composite particles in ex situ mode is proposed on the basis of thermodynamically driving mechanism. It is facile and versatile as it eliminates the need for surface functionalizations and modifications of both PS microspheres and AuNPs. The PS/AuNPs composite particles take on a raspberry-like morphology with controllable coverage according to some thermodynamic factors, which have been extensively characterized by scanning electron microscopy, transmission electron microscopy, and thermogravimetric analysis. More importantly, the PS/AuNPs composite particles hold higher catalytic efficiency and better repeatability than the previously reported results, which are confirmed in two oxidation-reduction reactions of 2 nitroaniline/NaBH(4) and rhodamine B/NaBH(4). PMID- 24474589 TI - Solid-state NMR study of dopant effects on the chemical properties of Mg-, In-, and Al-doped SnP2 O7. AB - The effects of doped low-valence cations on the properties of the SnP2 O7 proton conductor at ambient temperature are investigated from changes in solid-state NMR spectra and nuclear magnetic relaxation times. Although the T1 H values increased with decreasing acidity as a result of cation exchange, the (1)H chemical shifts moved to lower field in Al- and In-doped materials compared with undoped ones. Furthermore, the shifts changed to higher field in Mg-doped materials, suggesting the existence of different protonic species in those materials. The bulk phosphate chemical shifts in the (31)P dipolar-decoupling MAS NMR spectra were very similar, regardless of the nature and amount of the doping species. On the other hand, by (1)H/(31)P cross-polarization MAS NMR, P2O7 signals interacting with an interstitial proton [Q(1)(proton)] were observed in all the undoped and doped SnP2 O7, while acidic P-OH-type phosphate signals [Q(1)(acid)] were additionally observed in the Mg-doped conductor. The different affinity of the proton with the dopants and phosphates caused lower conductivity and larger activation energy in the Mg-doped materials, compared with those in the In- and Al-doped materials. PMID- 24474590 TI - Hydrolytically degradable poly(ethylene glycol) hydrogel scaffolds as a cell delivery vehicle: characterization of PC12 cell response. AB - The central nervous system (CNS) has a low intrinsic potential for regeneration following injury and disease, yet neural stem/progenitor cell (NPC) transplants show promise to provide a dynamic therapeutic in this complex tissue environment. Moreover, biomaterial scaffolds may improve the success of NPC-based therapeutics by promoting cell viability and guiding cell response. We hypothesized that a hydrogel scaffold could provide a temporary neurogenic environment that supports cell survival during encapsulation, and degrades completely in a temporally controlled manner to allow progression of dynamic cellular processes such as neurite extension. We utilized PC12 cells as a model cell line with an inducible neuronal phenotype to define key properties of hydrolytically degradable poly(ethylene glycol) hydrogel scaffolds that impact cell viability and differentiation following release from the degraded hydrogel. Adhesive peptide ligands (RGDS, IKVAV, or YIGSR), were required to maintain cell viability during encapsulation; as compared to YIGSR, the RGDS, and IKVAV ligands were associated with a higher percentage of PC12 cells that differentiated to the neuronal phenotype following release from the hydrogel. Moreover, among the hydrogel properties examined (e.g., ligand type, concentration), total polymer density within the hydrogel had the most prominent effect on cell viability, with densities above 15% w/v leading to decreased cell viability likely due to a higher shear modulus. Thus, by identifying key properties of degradable hydrogels that affect cell viability and differentiation following release from the hydrogel, we lay the foundation for application of this system towards future applications of the scaffold as a neural cell delivery vehicle. PMID- 24474591 TI - Maternal self-confidence postpartum and at pre-school age: the role of depression, anxiety disorders, maternal attachment insecurity. AB - The aim of this study was to analyze the impact of maternal postpartum depression and/or anxiety disorders according to DMS-IV on maternal self-confidence throughout infancy and early childhood. Exploratively, associations between maternal attachment insecurity and maternal self-confidence at pre-school age were examined. The sample (N = 54) of this prospective longitudinal study was comprised of n = 27 women with postpartum depression and/or anxiety disorders according to DSM-IV criteria and n = 27 healthy women without present or history of mental health disorders or psychotherapy. Data was collected in the postpartum period (M = 60.08 days) and at pre-school age (M = 4.7 years). Subjects were recruited between 2004 and 2011 in South Germany. Data revealed a significant difference in maternal self-confidence between clinical and control group at child's pre-school age: Women with postpartum depression and/or anxiety disorder scored lower on maternal self-confidence than healthy controls, but only if they had current SCID-diagnoses or partly remitted symptoms. According to explorative analyses maternal attachment insecurity turned out to be the strongest predictor of maternal self-confidence at pre-school age besides maternal mental health status. The results emphasize the impact of attachment insecurity and maternal mental health regarding maternal self-confidence leading to potential adverse long-term consequences for the mother-child relationship. Attachment based interventions taking maternal self-confidence into account are needed. PMID- 24474592 TI - Temporal trends in social disparities in maternal smoking and breastfeeding in Canada, 1992-2008. AB - A steady decrease in maternal smoking during pregnancy and a steady increase in breastfeeding rates have been observed in Canada in the past two decades. However, the extent to which all socioeconomic classes have benefited from this progress is unknown. Therefore, this study was undertaken to determine: (1) whether progress achieved benefited the entire population or was limited to specific strata; and (2) whether disparities among strata decreased, stayed the same, or increased over time. We used data from the National Longitudinal Survey of Children and Youth, which enrolled children aged 0-3 years between 1994 and 2008. Data collected at entry was analyzed in a cross-sectional manner. Between birth years 1992-1996 and 2005-2008, smoking during pregnancy decreased from 11.5 % (95 % CI 10.0-13.0 %) to 5.2 % (95 % CI 4.1-6.3 %) among mothers with a college or university degree and from 43.0 % (95 % CI 38.8-47.2 %) to 38.6 % (95 % CI 32.9-44.2 %) among those with less than secondary education. During the same period, the rate of breastfeeding initiation increased from 83.8 % (95 % CI 81.9 85.6 %) to 91.5 % (95 % CI 90.2-92.8 %) among mothers with a college or university degree and from 63.1 % (95 % CI 58.9-67.4 %) to 74.7 % (95 % CI 69.8 79.7 %) among those with less than secondary education. The risks of smoking and of not breastfeeding remained significantly higher in the least educated category than in the most educated throughout the study period, and these associations remained statistically significant after controlling for maternal age. Gaps between the least and the most educated mothers narrowed for breastfeeding but widened for smoking during pregnancy. PMID- 24474593 TI - Save 100 Babies(c): engaging communities for just and equitable birth outcomes through Photovoice and Appreciative Inquiry. AB - This paper presents a community engagement model designed to advance social justice and equity for African American birth outcomes through the combined techniques of Photovoice and Appreciative Inquiry. In response to the persistent racial disparities in birth outcomes, Save 100 Babies(c) was constructed as a 2 day summit where the emphasis was placed on individual and community assets rather than deficits. The engagement was designed to create a level of readiness among individuals working within and outside the field of Maternal and Child Health to envision strategies to attain equitable birth outcomes. The goal of the conference was to facilitate higher level consciousness by guiding the participants though a process aimed at articulating assets, possibilities and the potential for co-creating the desired futures where racial disparities in birth outcome are eliminated [corrected]. As the result of the guided discourse that began with photographs of the lives of African American women, participants articulated the strengths they detected from the pictures, their recommendations for multifaceted changes in policies and practices, and their individual and organizational commitments for a changed future. Since the summit, participants have indicated ways they have fulfilled their vows that include informing families and communities about pregnancy risks, working with youth programs, supporting fatherhood involvement in pregnancy and birth, and advancing case management that is more attuned to women's strengths. Save 100 Babies(c) is evolving into a network and clearinghouse for sharing and disseminating information and resources for collaboration. PMID- 24474595 TI - Collective synthesis of cladiellins based on the gold-catalyzed cascade reaction of 1,7-diynes. AB - The cladiellin family of natural products, which includes molecules with various biological activities, continues to invite new synthetic studies. A gold catalyzed tandem reaction of 1,7-diynes to construct the 6-5-bicyclic ring systems that are present in a number of natural products was developed. This reaction was applied as the key step to realize the formal and total syntheses of nine members of the cladiellin family in an enantio- and diastereoselective manner. This modular and efficient approach could also be used for the construction of other cladiellins, as well as their analogues, for follow-up studies. PMID- 24474594 TI - Evaluation of ventricular repolarization dispersion during acute myocardial ischemia: spatial and temporal ECG indices. AB - In this work, we studied the evolution of different electrocardiogram (ECG) indices of ventricular repolarization dispersion (VRD) during acute transmural myocardial ischemia in 95 patients undergoing percutaneous coronary intervention (PCI). We studied both temporal indices of VRD (T-VRD), based on the time intervals of the ECG wave, and spatial indices of VRD (S-VRD), based on the eigenvalues of the spatial correlation matrix of the ECG. The T-wave peak-to-end interval I(TPE) index showed statistically significant differences during left anterior descending artery and right coronary artery (RCA) occlusion for almost the complete time course of the PCI procedure with respect to the control recording. Regarding S-VRD indices, we observed statistically significant increases in the ratio of second to the first eigenvalue I(T21), the ratio of the third to the first eigenvalue I(T31) and the T-wave residuum I(TWR) during RCA occlusions. We also found a statistically significant increase in the I(T31) during left circumflex artery occlusions. To evaluate the evolution of VRD indices during acute ischemia, we calculated the relative change parameter R(I) for each index I. Maximal relative changes (R(I)) during acute ischemia were found for the S-VRD indices I(T21), the first eigenvalue I(lambda1) and the second eigenvalue I(lambda2), with changes 64, 57 and 52 times their baseline range of variation during the control recording, respectively. Also, we found that relative changes with respect to the baseline were higher in patients with T wave alternans (TWA) than in those without TWA. In conclusion, results suggest that I(TPE) as well as I(T21), I(T31) and I(TWR) are very responsive to dispersion changes induced by ischemia, but with a behavior which very much depends on the occluded artery. PMID- 24474596 TI - Effect of transcatheter aortic valve replacement on the mitral valve apparatus and mitral regurgitation: real-time three-dimensional transesophageal echocardiography study. AB - BACKGROUND: The effect of transcatheter aortic valve replacement (TAVR) on the mitral valve apparatus and factors influencing the reduction of mitral regurgitation with or without mitral leaflet tethering after TAVR are poorly understood. The present 3-dimensional (3D) transesophageal echocardiography study aimed to elucidate early changes further in the structure and function of the mitral valve apparatus after TAVR. METHODS AND RESULTS: We analyzed 90 patients (nontenting group, 56 patients and tenting group, 34 patients) who underwent TAVR using the Edwards SAPIEN and had intraprocedural 3D transesophageal echocardiography evaluation of the mitral valve. Of all patients, mitral regurgitation improved in 54%, remained the same in 38%, and worsened in 8% 1 day after TAVR. There were no statistically significant differences in mitral annular 3D parameters before and after TAVR in both groups. In the tenting group, tenting area (P<0.01) and tenting height (P<0.01) were decreased, and coaptation length was increased (P<0.05) after TAVR. In a multivariable analysis, the predictors of improved mitral regurgitation were the decrease of tenting area (odds ratio, 8.15; 95% confidence interval, 1.31-50.7; P<0.05) and the decrease of valvuloarterial impedance (odds ratio, 7.57; 95% confidence interval, 1.15-49.9; P<0.05) in the tenting group and the decrease of valvuloarterial impedance (odds ratio, 6.96; 95% confidence interval, 1.24-39.2; P<0.05) in the nontenting group. CONCLUSIONS: Mitral leaflet tethering was improved immediately by TAVR in patients with mitral leaflet tenting regardless of mitral annular geometry. Acute improvement in mitral regurgitation after TAVR is predominantly related to global left ventricular hemodynamics and mitral leaflet tethering change. PMID- 24474597 TI - First experience with early dynamic (18)F-NaF-PET/CT in patients with chronic osteomyelitis. AB - OBJECTIVE: This study investigates whether early dynamic positron emission tomography/computed tomography (edPET/CT) using (18)F-sodium fluoride-((18)F-NaF) is feasible in depicting early phases of radiotracer distribution in patients with chronic osteomyelitis (COM). METHODS: A total of 12 ed(18)F-NaF-PET/CT examinations were performed on 11 consecutive patients (2 female, 9 male; age 53 +/- 12 years) in list mode over 5 min starting with radiopharmaceutical injection before standard late (18)F-NaF-PET/CT. Eight consecutive time intervals (frames) were reconstructed for each patient: four 15 s, then four 60 s. Several volumes of interest (VOI) were selected, representing the affected area as well as different reference areas within the bone and soft tissue. Maximum and mean ed standardized uptake values (edSUVmax, edSUVmean, respectively) were calculated in each VOI during each frame to measure early fluoride influx and accumulation. Results were compared between affected and non-affected (contralateral) bones. RESULTS: Starting in the 31-45 s frame, the affected bone area showed significantly higher edSUVmax and edSUVmean compared to the healthy contralateral region. The affected bone areas also significantly differed from non-affected contralateral regions in conventional late (18)F-NaF-PET/CT. CONCLUSIONS: This pilot study suggests that, in patients with COM, ed(18)F-NaF -PET offers additional information about early radiotracer distribution to standard (18)F-NaF -PET/CT, similar to a three-phase bone scan. The results should be validated in larger trials which directly compare ed(18)F-NaF-PET to a three-phase bone scan. PMID- 24474598 TI - (18)F-FDG-PET/CT in assessing response to neoadjuvant chemoradiotherapy for potentially resectable locally advanced esophageal cancer. AB - PURPOSE: To correlate metabolic response to neoadjuvant chemoradiotherapy (NACR) on FDG-PET/CT using PERCIST-based criteria to pathologic and clinical response, and survival in patients with locally advanced esophageal cancer (LAEC). MATERIALS AND METHODS: Forty-five patients with LAEC underwent PET/CT at baseline and after NACR. Tumors were evaluated using PERCIST (PET response criteria in solid tumors)-based criteria including SUL, SUL tumor/liver ratio, % change in SUL. These parameters were compared to pathology regression grade (PRG), clinical response (including residual or new disease beyond the surgical specimen), and overall survival. RESULTS: On surgical pathology, there was complete or near complete regression of tumor in 51.1 %, partial response in 42.2 %, and lack regression in 4.4 %. One patient (2.2 %) had progression of disease on imaging and did not undergo surgical resection. None of the baseline PET parameters had significant correlation to pathology regression grade or clinical response. On follow-up, a positive correlation was found between post-therapy SUL ratio, %? SUL and %? SUL ratio and clinical response (p = 0.025, 0.035, 0.030, respectively). A weak correlation was found between post-therapy SUL ratio to PRG (p = 0.049). A strong correlation was found between the metabolic response score and PRG (p = 0.002) as well as between metabolic response and clinical response (p < 0.001). CONCLUSION: PERCIST-based metabolic response assessment to NACR in LAEC may correlate with clinical outcome and survival. PMID- 24474599 TI - Reply to Can quantified pathologic response assessed as residual tumor burden be a promising staging system for patients with rectal cancer treated with chemoradiation followed by surgery? PMID- 24474600 TI - Risk prediction models for chemotherapy-induced nausea and vomiting: almost ready for prime time? PMID- 24474601 TI - Surface feature congruency effects in the object-reviewing paradigm are dependent on task memory demands. AB - Perception of object continuity depends on establishing correspondence between objects viewed across disruptions in visual information. The role of spatiotemporal information in guiding object continuity is well documented; the role of surface features, however, is controversial. Some researchers have shown an object-specific preview benefit (OSPB)-a standard index of object continuity only when correspondence could be based on an object's spatiotemporal information, whereas others have found color-based OSPB, suggesting that surface features can also guide object continuity. This study shows that surface feature based OSPB is dependent on the task memory demands. When the task involved letters and matching just one target letter to the preview ones, no color congruency effect was found under spatiotemporal discontinuity and spatiotemporal ambiguity (Experiments 1-3), indicating that the absence of feature-based OSPB cannot be accounted for by salient spatiotemporal discontinuity. When the task involved complex shapes and matching two target shapes to the preview ones, color based OSPB was obtained. Critically, however, when a visual working memory task was performed concurrently with the matching task, the presence of a nonspatial (but not a spatial) working memory load eliminated the color-based OSPB (Experiments 4 and 5). These results suggest that the surface feature congruency effects that are observed in the object-reviewing paradigm (with the matching task) reflect memory-based strategies that participants use to solve a memory demanding task; therefore, they are not reliable measures of online object continuity and cannot be taken as evidence for the role of surface features in establishing object correspondence. PMID- 24474602 TI - The treatment of perfectionism within the eating disorders: a pilot study. AB - The aim of this pilot study was to investigate the impact of the direct treatment of perfectionism on the outcome of perfectionism and eating disorder pathology. Sixty-one participants, attending day hospital treatment, participated in a randomised controlled study, in which treatment as usual (TAU) was compared with TAU combined with a clinician-lead cognitive behavioural treatment for perfectionism (TAU+P). Linear mixed model analysis revealed no significant interaction effects but significant main effects for time on variables measuring eating pathology and perfectionism. Outcomes supported the effectiveness of overall treatment but suggested that adding direct treatment of perfectionism did not enhance treatment. The results are discussed in relation to the existing literature on the treatment of perfectionism. PMID- 24474603 TI - Developing a national framework of quality indicators for public hospitals. AB - BACKGROUND: The current study describes the development of a preliminary set of quality indicators for public Greek National Health System (GNHS) hospitals, which were used in the "Health Monitoring Indicators System: Health Map" (Ygeionomikos Chartis) project, with the purpose that these quality indicators would assess the quality of all the aspects relevant to public hospital healthcare workforce and services provided. METHODS: A literature review was conducted in the MEDLINE database to identify articles referring to international and national hospital quality assessment projects, together with an online search for relevant projects. Studies were included if they were published in English, from 1980 to 2010. A consensus panel took place afterwards with 40 experts in the field and tele-voting procedure. RESULTS: Twenty relevant projects and their 1698 indicators were selected through the literature search, and after the consensus panel process, a list of 67 indicators were selected to be implemented for the assessment of the public hospitals categorized under six distinct dimensions: Quality, Responsiveness, Efficiency, Utilization, Timeliness, and Resources and Capacity. CONCLUSION: Data gathered and analyzed in this manner provided a novel evaluation and monitoring system for Greece, which can assist decision-makers, healthcare professionals, and patients in Greece to retrieve relevant information, with the long-term goal to improve quality in care in the GNHS hospital sector. PMID- 24474604 TI - Congenital malformations in Japanese macaques (Macaca fuscata) at Takasakiyama. AB - From the late 1960s to the early 1970s, many congenitally malformed infants were born into provisioned Japanese macaque troops. Although the exact cause of this problem was not determined, the occurrence of malformations decreased thereafter. We examined possible factors such as total population size, number of adult females, birth rate, and volume of provisioned food. Agrichemicals attached to provisioned food are suspected as the main cause, as other factors were found to have no influence. Many more malformations were seen in males compared with females, in feet compared with hands, and in the fourth compared with other digits. We confirmed that the frequency of congenital malformation was high during the 1960s through to the mid-1970s when increased levels of provisioned food were given and that the incidence of congenital malformations was also elevated among wild macaques during this time. PMID- 24474605 TI - Relationship between intra-abdominal pressure and vaginal wall movements during Valsalva in women with and without pelvic organ prolapse: technique development and early observations. AB - OBJECTIVES: To develop and test a method for measuring the relationship between the rise in intra-abdominal pressure and sagittal plane movements of the anterior and posterior vaginal walls during Valsalva in a pilot sample of women with and without prolapse. METHODS: Mid-sagittal MRI images were obtained during Valsalva while changes in intra-abdominal pressure were measured via a bladder catheter in 5 women with cystocele, 5 women with rectocele, and 5 controls. The regional compliance of the anterior and posterior vagina wall support systems were estimated from the ratio of displacement (mm) of equidistant points along the anterior and posterior vaginal walls to intra-abdominal pressure rise (mmHg). RESULTS: The compliance of both anterior and posterior vaginal wall support systems varied along different regions of vaginal wall for all three groups, with the highest compliance found near the vaginal apex and the lowest near the introitus. Women with cystocele had more compliant anterior and posterior vaginal wall support systems than women with rectocele. The movement direction differs between cystocele and rectocele. In cystocele, the anterior vaginal wall moves mostly toward the vaginal orifice in the upper vagina, but in a ventral direction in the lower vagina. In rectocele, the direction of the posterior vaginal wall movement is generally toward the vaginal orifice. CONCLUSIONS: Movement of the vaginal wall and compliance of its support is quantifiable and was found to vary along the length of the vagina. Compliance was greatest in the upper vagina of all groups. Women with cystocele demonstrated the most compliant vaginal wall support. PMID- 24474607 TI - Outcome measures to assess anatomy and function of the posterior vaginal compartment. AB - INTRODUCTION AND HYPOTHESIS: Optimal measures for assessing anatomy and defecatory symptoms related to posterior compartment prolapse are unknown. Our objectives were: (1) to test the inter- and intrarater reliability of commonly used or reported anatomic measures of posterior compartment prolapse performed in the clinic setting and under anesthesia; and (2) to examine the correlation between posterior compartment anatomy and defecatory symptoms prior to surgical intervention. METHODS: A prospective cohort of women with pelvic floor disorders was assessed using a variety of validated questionnaires and standardized examination measures at baseline, at a preoperative visit, and intraoperatively. Inter- and intrarater reliability for anatomic measures were assessed by two separate examiners at the initial visit and repeated by one of the original examiners at a preoperative visit. Reliability was measured using kappa or intraclass correlations according to data type. Symptom and anatomic measure correlations were analyzed using Spearman rank tests. RESULTS: Mean age of the 120 women recruited was 57 +/- 15 years, 49 (41 %) had a point Bp >= 0; 59 % reported at least moderate bother from at least one obstructed defecation symptom on the Pelvic Floor Distress Inventory (PFDI). At baseline, most anatomic measures showed at least moderate to good inter/intrarater reliability (> 0.5). There were no moderate or better correlations between any symptom and anatomic measure (all r < 0.27). CONCLUSIONS: Most anatomic measures of posterior compartment prolapse are reliable and reproducible; however, they do not correlate well with defecatory symptoms. PMID- 24474608 TI - Sandwich complex-containing macromolecules: property tunability through versatile synthesis. AB - Sandwich complexes feature unique properties as the physical and electronic properties of a hydrocarbon ligand or its derivative are integrated into the physical, electronic, magnetic, and optical properties of a metal. Incorporation of these complexes into macromolecules results in intriguing physical, electrical, and optical properties that were hitherto unknown in organic-based macromolecules. These properties are tunable through well-designed synthetic strategies. This review surveys many of the synthetic approaches that have resulted in tuning the properties of sandwich complex-containing macromolecules. While the past two decades have seen an ever-growing number of research publications in this field, gaps remain to be filled. Thus, we expect this review to stimulate research interest towards bridging these gaps, which include the insolubility of some of these macromolecules as well as expanding the scope of the sandwich complexes. PMID- 24474609 TI - A multicomponent Ni-, Zr-, and Cu-catalyzed strategy for enantioselective synthesis of alkenyl-substituted quaternary carbons. AB - The availability of enantiomerically enriched carbonyl-containing compounds is essential to the synthesis of biologically active molecules. Since catalytic enantioselective conjugate addition (ECA) reactions directly generate the latter valuable class of molecules, the design and development of such protocols represents a compelling objective in modern chemistry. Herein, we disclose the first solution to the problem of ECA of alkenyl groups to acyclic trisubstituted enones, an advance achieved by adopting an easily modifiable and fully catalytic approach. The requisite alkenylaluminum reagents are synthesized with exceptional site- and/or stereoselectivity by a Ni-catalyzed hydroalumination process, and the necessary enones are prepared through a site- and stereoselective zirconocene catalyzed carboalumination/acylation reaction. The all-catalytic procedure is complete within four hours, furnishing the desired products in up to 77 % overall yield and 99:1 enantiomeric ratio. PMID- 24474610 TI - Arsenic (As), antimony (Sb), and lead (Pb) availability from Au-mine Technosols: a case study of transfer to natural vegetation cover in temperate climates. AB - Soils from old Au-mine tailings (La Petite Faye, France) were investigated in relation to the natural vegetation cover to evaluate the risk of metals and metalloids (Pb, As, Sb) mobilizing and their potential transfer to native plants (Graminea, Betula pendula, Pteridium aquilinum, Equisetum telmateia). The soils are classified as Technosols with high contamination levels of As, Pb, and Sb. The single selective extractions tested to evaluate available fraction (CaCl2, acetic acid, A-Rhizo, and DTPA) showed low labile fractions (<5 % of bulk soil contents), but still significant levels were observed (up to 342.6 and 391.9 mg/kg for As and Pb, respectively) due to the high contamination levels of soils. Even at high soil contaminations (considered as phytotoxic levels for plants), translocation factors for native plants studied are very low resulting in low concentrations of As, Sb, and Pb in their aerial part tissues. This study demonstrates the important role of (1) native plant cover in terms of "stabilization" of these contaminants, and (2) the poor effectiveness of extraction procedures used for this type of soil assemblages, i.e., rich in specific mineral phases. PMID- 24474612 TI - Arthrolysis combined with reconstruction for treatment of terrible triad injury with a poor outcome after surgical as well as conservative intervention. AB - INTRODUCTION: The treatment of terrible triad injury with a poor outcome after intervention has not been successful thus far. The purpose of this study was to evaluate the efficacy of arthrolysis and reconstruction in the treatment of terrible triad injury with a poor outcome after surgical as well as conservative intervention. MATERIALS AND METHODS: Twelve patients (12 elbows) with the diagnosis of terrible triad injury were respectively reviewed. All the 12 patients had elbow dysfunction after conservative and surgical treatment of the terrible triad injury. Preoperatively, the flexion arc and forearm rotation were 36.7 degrees +/- 28.5 degrees and 51.3 degrees +/- 43.4 degrees , respectively, and the Mayo Elbow Performance Score was 56.3 points. The mean interval between the primary injury and our surgical treatment was 6.6 months. Our surgical intervention included elbow arthrolysis, ulnar nerve transposition, radial head replacement, coronoid process and ligament repair, and hinged external fixation. Patients were encouraged to participate in rehabilitation training 24 h after surgery. RESULTS: The mean follow-up duration was 20.1 months; the flexion arc and forearm rotation were 122 degrees +/- 18 degrees and 140 degrees +/- 20 degrees , respectively, and the mean Mayo Elbow Performance Score was 94.6 points (9 excellent, 3 good). Concentric stability was restored in all elbows. Complications included superficial pin tract infection (1), heterotopic ossification (3), and ulnar nerve palsy (1); the ulnar nerve symptoms had improved at the last follow-up. CONCLUSIONS: The combination of open arthrolysis and reconstruction performed at a mean interval of 6-month posttrauma can restore functional mobility in cases of terrible triad injury with a poor outcome after surgical as well as conservative intervention. Thus, it may be an effective alternative for the treatment of the poor outcome terrible triad injury. We recommend early functional rehabilitation with adherence to the guidelines for hinged external fixation. PMID- 24474611 TI - Risk of several cancers is higher in urban areas after adjusting for socioeconomic status. Results from a two-country population-based study of 18 common cancers. AB - Some studies suggest that there are urban-rural variations in cancer incidence but whether these simply reflect urban-rural socioeconomic variation is unclear. We investigated whether there were urban-rural variations in the incidence of 18 cancers, after adjusting for socioeconomic status. Cancers diagnosed between 1995 and 2007 were extracted from the population-based National Cancer Registry Ireland and Northern Ireland Cancer Registry and categorised by urban-rural status, based on population density of area of residence at diagnosis (rural <1 person per hectare, intermediate 1-15 people per hectare, urban >15 people per hectare). Relative risks (RR) were calculated by negative binomial regression, adjusting for age, country and three area-based markers of socioeconomic status. Risks were significantly higher in both sexes in urban than rural residents with head and neck (males RR urban vs. rural = 1.53, 95 % CI 1.42-1.64; females RR = 1.29, 95 % CI 1.15-1.45), esophageal (males 1.21, 1.11-1.31; females 1.21, 1.08 1.35), stomach (males 1.36, 1.27-1.46; females 1.19, 1.08-1.30), colorectal (males 1.14, 1.09-1.18; females 1.04, 1.00-1.09), lung (males 1.54, 1.47-1.61; females 1.74, 1.65-1.84), non-melanoma skin (males 1.13, 1.10-1.17; females 1.23, 1.19-1.27) and bladder (males 1.30, 1.21-1.39; females 1.31, 1.17-1.46) cancers. Risks of breast, cervical, kidney and brain cancer were significantly higher in females in urban areas. Prostate cancer risk was higher in rural areas (0.94, 0.90-0.97). Other cancers showed no significant urban-rural differences. After adjusting for socioeconomic variation, urban-rural differences were evident for 12 of 18 cancers. Variations in healthcare utilization and known risk factors likely explain some of the observed associations. Explanations for others are unclear and, in the interests of equity, warrant further investigation. PMID- 24474613 TI - Timing matters: NSAIDs interfere with the late proliferation stage of a repaired rotator cuff tendon healing in rats. AB - INTRODUCTION: Rotator cuff (RC) tear is a common problem that causes pain and can limit shoulder function. Non-steroidal anti-inflammatory drugs (NSAIDs) are often prescribed for musculoskeletal pain, including the pain subsequent to RC repair. NSAIDs have been reported to affect bone metabolism and fracture healing(,) but there is little evidence about their effect on tendon healing. We investigated the effect of meloxicam (non-steroidal anti-inflammatory drug) on the healing of RC tendons when given immediately after surgical repair. MATERIALS AND METHODS: Thirty-nine rats underwent acute RC tear and repair. Group A (n = 13) received daily intraperitoneal (IP) injections of meloxicam for the first 10 postoperative days. Group B (n = 13) received IP injections of meloxicam starting from postoperative day 11. Group C (n = 13, controls) received daily IP injections of saline for 3 weeks. The animals were killed 3 weeks after surgery and the RC was evaluated by gross inspection, biomechanical testing and histological examination. RESULTS: Group B displayed a significantly lower mean maximal load at 3 weeks than group C (P = 0.02) and group A (P = 0.05). Stiffness was significantly lower in B group as compared to A group (P = 0.05). Qualitative examination of histology specimens did not disclose any apparent differences with respect to cellularity, vascularity, healing, and collagen orientation. CONCLUSIONS: We conclude that meloxicam decreases the biomechanical strength of repaired rat RCs when administered between 11 and 20 days after the repair. PMID- 24474614 TI - Absence of aberrant myeloid progenitors by flow cytometry is associated with favorable response to azacitidine in higher risk myelodysplastic syndromes. AB - BACKGROUND: In intermediate-2 (Int-2) and high risk patients with myelodysplastic syndromes (MDS), treatment with azacitidine is associated with hematological improvement and prolonged overall survival (OS) in patients who respond to therapy. However, only half of the patients who are treated will benefit from this treatment. It is a major challenge to predict which patients are likely to respond to treatment. The aim of this study was to investigate the predictive value of immunophenotyping for response to treatment with azacitidine of Int-2 and high risk MDS patients. METHODS: Bone marrow aspirates were analyzed by flow cytometry in 42 patients with Int-2 and high risk MDS, chronic myelomonocytic leukemia, or low blast count acute myeloid leukemia before treatment and after every third cycle of azacitidine. A flow score was calculated using the flow cytometric scoring system (FCSS). RESULTS: The presence of myeloid progenitors with an aberrant immunophenotype was significantly associated with lack of response (p = 0.02). A low pretreatment FCSS was associated with significantly better OS compared with a high pretreatment FCSS (p = 0.03). A significant decrease in FCSS was observed in patients with complete response after three cycles azacitidine compared to patients with progressive disease (p = 0.006). CONCLUSIONS: Absence of aberrant myeloid progenitor cells at baseline and/or a decrease in the FCSS during treatment identified Int-2 and high risk MDS patients who are likely to respond to treatment with azacitidine. PMID- 24474615 TI - Overexpression of Wnt11 promotes chondrogenic differentiation of bone marrow derived mesenchymal stem cells in synergism with TGF-beta. AB - Bone marrow-derived mesenchymal stem cells (MSCs), the most widely used cell source for cartilage tissue engineering, are multipotent cells which have been shown to differentiate into various mesenchyme-lineage cell types including chondrocytes. However, the molecular mechanisms controlling the chondrogenic differentiation of MSCs remain to be fully elucidated. It has been demonstrated that Wnt signaling involves regulating chondrogenesis and MSC differentiation. The aim of the present study was to investigate the role of Wnt11, a member of noncanonical Wnts, in MSCs during chondrogenic differentiation. We observed that overexpression of Wnt11 inhibited proliferation of MSCs and caused a G0/G1 cell cycle arrest. The expression level of chondrogenic markers, aggrecan and Collagen II, was significantly increased in MSCs transduced with Wnt11 as compared with non-transduced cells or MSCs transduced with the empty lentiviral vector. Furthermore, ectopic expression of Wnt11 stimulated gene expression of chondrogenic regulators, SRY-related gene 9, Runt-related transcription factor 2, and Indian hedgehog. Finally, Wnt11 overexpression promoted chondrogenic differentiation of MSCs in synergism with TGF-beta. Collectively, these results indicate that Wnt11 plays a crucial role in regulating MSC chondrogenic differentiation. PMID- 24474616 TI - 3,4,5-trihydroxycinnamic acid inhibits lipopolysaccharide (LPS)-induced inflammation by Nrf2 activation in vitro and improves survival of mice in LPS induced endotoxemia model in vivo. AB - NF-E2-related factor 2 (Nrf2) has been demonstrated to be a key transcription factor regulating the anti-inflammatory genes including heme oxygenase-1 (HO-1) in experimental sepsis models. Based on the fact that 3,4,5-trihydorxycinnamic acid (THC) has been reported to possess anti-inflammatory properties in BV2 microglial cells, the possible effects of THC and its underlying mechanism was examined against lipopolysaccharide (LPS)-induced RAW 264.7 cell culture and septic mouse models. Pretreatment of RAW 264.7 cells with THC significantly attenuated LPS-induced NO, PGE2 production, and expression of iNOS and COX-2. THC also significantly suppressed LPS-induced release of pro-inflammatory cytokines and degradation of IkappaB-alpha. Increased phosphorylation of Nrf2 and nuclear translocation of Nrf2 were observed with THC treatment with consequent expression of HO-1. The data demonstrated that multiple signaling pathways including Akt, p38, and PKC are involved in the THC-induced activation of Nrf2/HO-1 pathway. Treatment of THC resulted in significantly increased survival of LPS-induced septic mice. THC also significantly ameliorated LPS-induced septic features such as hypothermia and increased vascular leakage. In accordance with the data from cell culture model, THC exhibited increased expression of HO-1 in kidney and decreased serum level of pro-inflammatory mediators such as TNF-alpha, IL-1beta, and NO. Taken together, the present study for the first time demonstrates that THC inhibits inflammation in LPS-induced RAW264.7 cells by Nrf2 activation and improves survival of mice in LPS-induced endotoxemia model. PMID- 24474617 TI - Practical, laboratory-scale synthesis of N(in) -formyl tryptophan hydrobromide. AB - A range of inorganic and organoelement halides was evaluated as acidic promoters of direct N(in) -formylation of tryptophan. In addition to Me3 SiBr, the less expensive PBr3 was found to be highly efficient and was selected for further optimization. A convenient and reproducible synthetic procedure for N(in) formyltryptophan hydrobromide developed in this way was scaled to 150 mmol and successfully extended to some derivatives of Trp and closely related indoles as detailed in the present paper. The scope of the method seems to be restricted to indoles substituted at C-3. PMID- 24474618 TI - Prospective examination of cigarette smoking among Iraq-deployed and nondeployed soldiers: prevalence and predictive characteristics. AB - BACKGROUND: Identifying characteristics that influence smoking behavior among military personnel is critical to protect health and operational functioning. PURPOSE: This study prospectively examined rates of cigarette smoking and predictors of changes in smoking behavior as a function of Iraq deployment. METHODS: One thousand eighty-two US Army soldiers (n = 773 Iraq-deployed; n = 309 nondeployed) completed assessments at two sessions [time 1: April 2003-July 2004; time 2: May 2004-July 2004 (nondeployers); January 2005-September 2006 (deployers)]. RESULTS: Approximately 48 % of participants smoked at both time points, with 6 % initiating smoking and 6 % quitting. Smoking initiation was associated with warzone stress exposure; female gender and high military unit support predicted cessation. Military rank and alcohol use were associated with both smoking initiation and cessation. CONCLUSION: Findings highlight the potential benefits of targeting risk factors for cigarette smoking in comprehensive military health programs aimed at smoking prevention and cessation. PMID- 24474619 TI - Effects of adding epinephrine on the early systemic absorption kinetics of local anesthetics in abdominal truncal blocks. AB - We evaluated the pharmacokinetics of ropivacaine following rectus sheath block (RSB) and transversus abdominis plane (TAP) block with or without epinephrine. A total of 26 adult patients undergoing lower abdominal surgery with RSB (=RSB trial) and another 26 adult patients undergoing open prostatectomy with TAP block (=TAP trial) were enrolled. Patients were randomly assigned to receive either a mixture of 0.75 % ropivacaine 13.2 mL with 1 % plain lidocaine 6.8 mL (TAP-E(-) and RSB-E(-) groups) or a mixture of 0.75 % ropivacaine 13.2 mL and 1 % lidocaine containing adrenaline (1:100,000) 6.8 mL (TAP-E(+) and RSB-E(+) groups) under general anesthesia. The serum concentrations of ropivacaine were measured using gas chromatography with mass spectrometry. The peak concentration was significantly lower and time to peak concentration was significantly longer in the TAP-E(+) group than in the TAP-E(-) group (P < 0.05 and <0.01, respectively), while there were no significant differences in these parameters between the RSB E(+) and RSB-E(-) groups. These results indicate that epinephrine attenuates the early phase of local anesthetic absorption from the injected site in TAP blocks, but not RSB. PMID- 24474620 TI - Anesthetic management of Schimke syndrome. PMID- 24474621 TI - Cerebral oximetry for cesarean delivery in a Moyamoya case. PMID- 24474622 TI - Phacoemulsification with posterior chamber intraocular lens versus extracapsular cataract extraction (ECCE) with posterior chamber intraocular lens for age related cataract. AB - BACKGROUND: Age-related cataract is one of the leading causes of blindness worldwide. Therefore, it is important to establish the most effective surgical technique for cataract surgery. OBJECTIVES: The aim of this review is to examine the effects of two types of cataract surgery for age-related cataract: phacoemulsification and extracapsular cataract extraction (ECCE). SEARCH METHODS: We searched CENTRAL (which contains the Cochrane Eyes and Vision Group Trials Register) (The Cochrane Library 2013, Issue 4), Ovid MEDLINE, Ovid MEDLINE In Process and Other Non-Indexed Citations, Ovid MEDLINE Daily, Ovid OLDMEDLINE (January 1946 to May 2013), EMBASE (January 1980 to May 2013), Latin American and Caribbean Literature on Health Sciences (LILACS) (January 1982 to May 2013), Web of Science Conference Proceedings Citation Index - Science (CPCI-S) (January 1970 to May 2013), the metaRegister of Controlled Trials (mRCT) (www.controlled trials.com), ClinicalTrials.gov (www.clinicaltrials.gov) and the WHO International Clinical Trials Registry Platform (ICTRP) (www.who.int/ictrp/search/en). We did not use any date or language restrictions in the electronic searches for trials. We last searched the electronic databases on 13 May 2013. SELECTION CRITERIA: We included randomised controlled trials of phacoemulsification compared to ECCE for age-related cataract. DATA COLLECTION AND ANALYSIS: Two authors independently selected and assessed all studies. We defined two primary outcomes: 'good functional vision' (presenting visual acuity of 6/12 or better) and 'poor visual outcome' (best corrected visual acuity of less than 6/60) at three and 12 months after surgery. We also collected data on intra and postoperative complications, and the cost of the procedures. MAIN RESULTS: We included 11 trials in this review with a total of 1228 participants, ranging from age 45 to 94. The studies were generally at unclear risk of bias due to poorly reported trial methods. No study reported presenting visual acuity, so we report both uncorrected (UCVA) and best corrected visual acuity (BCVA). Studies varied in visual acuity assessment methods and time frames at which outcomes were reported. Participants in the phacoemulsification group were more likely to achieve UCVA of 6/12 or more at three months (risk ratio (RR) 1.81, 95% confidence interval (CI) 1.36 to 2.41, two studies, 492 participants) and one year (RR 1.99, 95% CI 1.45 to 2.73, one study, 439 participants). People in the phacoemulsification group were also more likely to achieve BCVA of 6/12 or more at three months (RR 1.12, 95% CI 1.03 to 1.22, four studies, 645 participants) and one year (RR 1.06, 95% CI 0.99 to 1.14, one study, 439 participants), but the difference between the two groups was smaller. No trials reported BCVA less than 6/60 but three trials reported BCVA worse than 6/9 and 6/18: there were fewer events of this outcome in the phacoemulsification group than the ECCE group at both the three-month (RR 0.33, 95% CI 0.20 to 0.55, three studies, 604 participants) and 12-month time points (RR 0.62, 95% CI 0.36 to 1.05, one study, 439 participants). Three trials reported posterior capsule rupture: this occurred more commonly in the ECCE group than the phacoemulsification group but small numbers of events mean the true effect is uncertain (Peto odds ratio (OR) 0.56, 95% CI 0.26 to 1.22, three studies, 688 participants). Iris prolapse, cystoid macular oedema and posterior capsular opacification were also higher in the ECCE group than the phacoemulsification group. Phacoemulsification surgical costs were higher than ECCE in two studies. A third study reported similar costs for phacoemulsification and ECCE up to six weeks postoperatively, but following this time point ECCE incurred additional costs due to additional visits, spectacles and laser treatment to achieve a similar outcome. AUTHORS' CONCLUSIONS: Removing cataract by phacoemulsification may result in a better visual acuity compared to ECCE, with a lower complication rate. The review is currently underpowered to detect differences for rarer outcomes, including poor visual outcome. The lower cost of ECCE may justify its use in a patient population where high-volume surgery is a priority, however, there are a lack of data comparing phacoemulsification and ECCE in lower-income settings. PMID- 24474623 TI - Turning regioselectivity into stereoselectivity: efficient dual resolution of P stereogenic phosphine oxides through bifurcation of the reaction pathway of a common intermediate. AB - Synthetic routes that provide facile access to either enantiomeric form of a target compound are particularly valuable. The crystallization-free dual resolution of phosphine oxides that gives highly enantioenriched materials (up to 94 % ee) in excellent yields is reported. Both enantiomeric oxides have been prepared from a single intermediate, (RP )-alkoxyphosphonium chloride, which is formed in the course of a selective dynamic kinetic resolution using a single enantiomer of menthol as the chiral auxiliary. The origin of the dual stereoselectivity lies in bifurcation of the reaction pathway of this intermediate, which works as a stereochemical railroad switch. Under controlled conditions, Arbuzov-type collapse of this intermediate proceeds through C?O bond fission with retention of the configuration at the phosphorus center. Conversely, alkaline hydrolysis of the P?O bond leads to the opposite SP enantiomer. PMID- 24474624 TI - Characteristics and treatment outcomes of 69 cases with early prosthetic joint infections of the hip and knee. AB - PURPOSE: Early prosthetic joint infection (PJI) can be treated with an intensive surgical debridement and implant retention (DAIR) of the prosthesis if (1) the prosthesis is stable, (2) the pathogen is not a difficult-to-treat microorganism, (3) symptoms have lasted for <3 weeks and (4) a sinus tract is absent. METHODS: We retrospectively evaluated the treatment outcome of early PJI in the hip and knee in a single orthopaedic centre. An early PJI was defined as a prosthesis infection within 3 months after primary implantation or revision surgery for a non-infectious cause. RESULTS: We identified 69 patients with confirmed early PJI, with a median age of 71 (range 33-84) years. Only 64 % presented with >=2 acute signs of infection. The most commonly isolated bacteria were coagulase negative staphylococci (38 %) and Staphylococcus aureus (25 %). Surgical procedures included DAIR (50 cases, 69 %) and two-stage exchange (19 cases, 31 %). At last follow-up, five of remaining living 67 patients (7.5 %) had a relapse of infection. The overall relapse-free survival of the prosthesis after 2 years was 92.3 % (95 % confidence interval 82-97 %) with no significant difference between DAIR and exchange of prosthesis. CONCLUSION: Our data suggest that an early PJI should be treated with DAIR as a less invasive procedure whenever possible according to the established treatment algorithm. PMID- 24474625 TI - Appropriateness of diagnostic catheterization for suspected coronary artery disease in New York State. AB - BACKGROUND: Appropriate use criteria for diagnostic catheterization (DC) were recently published. These criteria are yet to be examined for a large population of patients undergoing DC. METHODS AND RESULTS: New York State's Cardiac Diagnostic Catheterization Database was used to identify patients undergoing DC for coronary artery disease between 2010 and 2011 for suspected coronary artery disease. Patients were rated by the appropriate use criteria as appropriate, uncertain, and inappropriate for DC. The relationships between various patient characteristics and the appropriateness ratings were examined, along with the relationships between hospital-level inappropriateness, for DC and 2 other hospital-level variables (hospital DC volume and percutaneous coronary intervention inappropriateness). Of the 8986 patients who could be rated for appropriateness, 35.3% were rated as appropriate, 39.8% as uncertain, and 24.9% as inappropriate. Of the 2240 patients rated as inappropriate, 56.7% were asymptomatic/had no previous stress test/had low or intermediate global coronary artery disease risk, 36.0% had a previous stress test with low-risk findings and no symptoms, and 7.3% were symptomatic/had no previous stress test/had low pretest probability. The median hospital-level inappropriateness rate was 28.5%, with a maximum of 48.8% and a minimum of 8.6%. Hospital-level inappropriateness was not related to hospital volume or inappropriateness for percutaneous coronary intervention. CONCLUSIONS: One quarter of patients undergoing DC for suspected coronary artery disease were rated as inappropriate for the procedure, approximately two thirds of these inappropriate patients had no previous stress test, and ~90% of inappropriate patients with no previous stress test were asymptomatic with low or intermediate global risk scores. PMID- 24474626 TI - After the resolution: sustaining the change. PMID- 24474627 TI - The expression of CPEB proteins is sequentially regulated during zebrafish oogenesis and embryogenesis. AB - In many species, there is little transcription in the mature oocyte, and zygotic transcription does not begin immediately after fertilization. In zebrafish, zygotic transcription is not initiated until the mid-blastula transition, thus the production of new proteins during oogenesis and early embryogenesis is dependent on the translation of maternal mRNAs. In a growing number of species, the translation of key maternal transcripts is coupled to their cytoplasmic polyadenylation. One family of RNA-binding proteins implicated in this process is the cytoplasmic polyadenylation element (CPE)-binding proteins (CPEBs), which bind to a sequence in the 3'-untranslated regions of regulated transcripts and mediate their storage/repression or translation. In several species, there is evidence for two classes of CPEBs, a larger oocyte-type and a smaller CPEB that functions during embryogenesis. This appears to be the case in zebrafish as well, and we now provide evidence suggesting that the oocyte-type CPEB (zorba) regulates the translation of the embryonic-type (ElrA) by keeping the ElrA transcript in storage until fertilization. When zorba levels fall, ElrA protein is then produced and available to regulate the translation of additional mRNAs during embryogenesis. We have also identified a potential target of ElrA, the maternal mRNA for hnRNPab, which is a potential homolog of the Drosophila gene squid, whose product plays a role in patterning the Drosophila oocyte and embryo. These data suggest that during zebrafish embryogenesis, cytoplasmic polyadenylation mediates a cascade of translational control whose final targets play central patterning roles during embryogenesis. PMID- 24474628 TI - The role of Arabidopsis ABCG9 and ABCG31 ATP binding cassette transporters in pollen fitness and the deposition of steryl glycosides on the pollen coat. AB - The pollen coat protects pollen grains from harmful environmental stresses such as drought and cold. Many compounds in the pollen coat are synthesized in the tapetum. However, the pathway by which they are transferred to the pollen surface remains obscure. We found that two Arabidopsis thaliana ATP binding cassette transporters, ABCG9 and ABCG31, were highly expressed in the tapetum and are involved in pollen coat deposition. Upon exposure to dry air, many abcg9 abcg31 pollen grains shriveled up and collapsed, and this phenotype was restored by complementation with ABCG9pro:GFP:ABCG9. GFP-tagged ABCG9 or ABCG31 localized to the plasma membrane. Electron microscopy revealed that the mutant pollen coat resembled the immature coat of the wild type, which contained many electron lucent structures. Steryl glycosides were reduced to about half of wild-type levels in the abcg9 abcg31 pollen, but no differences in free sterols or steryl esters were observed. A mutant deficient in steryl glycoside biosynthesis, ugt80A2 ugt80B1, exhibited a similar phenotype. Together, these results indicate that steryl glycosides are critical for pollen fitness, by supporting pollen coat maturation, and that ABCG9 and ABCG31 contribute to the accumulation of this sterol on the surface of pollen. PMID- 24474629 TI - NITROGEN LIMITATION ADAPTATION recruits PHOSPHATE2 to target the phosphate transporter PT2 for degradation during the regulation of Arabidopsis phosphate homeostasis. AB - The NITROGEN LIMITATION ADAPTION (NLA) gene was initially shown to function in nitrogen limitation responses; however, recent work shows that the nla mutant hyperaccumulates Pi, phenocopying the Pi signaling mutant pho2. PHO2 encodes a putative E2 conjugase, UBC24. Here, we show that NLA is an E3 ligase that specifically requires UBC24 for polyubiquitination in Arabidopsis thaliana. Among five members of the Pht1 Pi-transporter family tested, NLA associates only with PT2 (Pht1;4). The NLA-UBC24 pair mediates polyubiquitination of PT2 but not PT1. Posttranslational decay of PT2 at high Pi is blocked in pho2 and inhibited by MG132, indicating the requirement of UBC24 and 26S proteasomes. Consistent with NLA/UBC24 function, induced NLA expression causes a UBC24-dependent decrease in PT2 levels. Confocal microscopy of fusion proteins revealed an NLA/PT2 interaction at the plasma membrane. Collectively, these results show that under Pi-replete conditions, NLA and UBC24 target the PT2 transporter for destruction. During the Pi deprivation response, NLA and PHO2 transcripts are cleaved by miR399 and miR827, respectively, and our results suggest that this downregulation relieves the posttranslational repression of PT2, allowing it to accumulate and participate in Pi uptake. Our work provides additional molecular details describing Pi signaling/homeostasis regulation by identifying NLA and UBC24 as partners and PT2 as one of their downstream targets. PMID- 24474631 TI - Recurrence location after resection of colorectal liver metastases influences prognosis. AB - AIM: To assess the impact of first recurrence location on survival following surgery of colorectal liver metastases. METHODS: A total of 265 consecutive patients with colorectal liver metastases undergoing liver surgery (2000-2011) were categorized according to first site of tumor recurrence. Time to recurrence (TTR) and overall survival (OS) were determined. Uni- and multivariate analysis were performed to identify factors associated with TTR and OS. RESULTS: Median TTR was 1.16 years following liver resection, and 0.56 years following radiofrequency ablation (RFA). Intrahepatic recurrence following liver resection resulted in a significantly shorter median TTR compared to extrahepatic recurrence. Intrapulmonary recurrence was associated with superior survival compared to other recurrence locations. Such patterns were not observed in the RFA-treated group. Multivariate analysis identified the type of surgical treatment and extra-hepatic first-site recurrence (other than lung) as independent predictors for OS. Pre-operative chemotherapy and simultaneous intrahepatic and extrahepatic recurrence were independent predictors for both TTR and OS. CONCLUSIONS: Patients with intrahepatic recurrence following liver resection have a significantly shorter TTR and OS when compared to patients developing extrahepatic recurrence. Pulmonary recurrence following resection is associated with longer survival. Simultaneous intra- and extrahepatic recurrence is an independent prognostic factor for TTR and OS. PMID- 24474630 TI - Nitric oxide-triggered remodeling of chloroplast bioenergetics and thylakoid proteins upon nitrogen starvation in Chlamydomonas reinhardtii. AB - Starving microalgae for nitrogen sources is commonly used as a biotechnological tool to boost storage of reduced carbon into starch granules or lipid droplets, but the accompanying changes in bioenergetics have been little studied so far. Here, we report that the selective depletion of Rubisco and cytochrome b6f complex that occurs when Chlamydomonas reinhardtii is starved for nitrogen in the presence of acetate and under normoxic conditions is accompanied by a marked increase in chlororespiratory enzymes, which converts the photosynthetic thylakoid membrane into an intracellular matrix for oxidative catabolism of reductants. Cytochrome b6f subunits and most proteins specifically involved in their biogenesis are selectively degraded, mainly by the FtsH and Clp chloroplast proteases. This regulated degradation pathway does not require light, active photosynthesis, or state transitions but is prevented when respiration is impaired or under phototrophic conditions. We provide genetic and pharmacological evidence that NO production from intracellular nitrite governs this degradation pathway: Addition of a NO scavenger and of two distinct NO producers decrease and increase, respectively, the rate of cytochrome b6f degradation; NO-sensitive fluorescence probes, visualized by confocal microscopy, demonstrate that nitrogen starved cells produce NO only when the cytochrome b6f degradation pathway is activated. PMID- 24474632 TI - Comparative study of free omental sheet graft and other operative procedures of enteric perforation repair. AB - BACKGROUND/AIM: In developing countries, enteric perforation due to typhoid continues to have very high morbidity and mortality rates irrespective of the type of operative procedure performed. The aim of the present study was to evaluate the effectiveness of a free omental sheet graft in perforated typhoid enteritis, in comparison to other methods of enteric perforation repair in terms of decreased morbidity, mortality and cost-effectiveness. METHOD: A non randomized study of 114 patients with enteric perforations was carried out over a period of 4.5 years. The study was divided in two groups; group I includes 38 cases in which a free omental sheet graft was used in typhoid enteritis with perforation and group II includes 76 cases in which other surgical procedures for enteric perforation repair were used. The outcomes were measured in relation to postoperative complications and mortality. RESULTS: The incidence of complications including faecal fistula was 2.6% in group I (free omental sheet graft group) versus 32.89% in group II. The mortality rate of 2.6% was also lower in group I versus 19.7% in group II. CONCLUSION: This study concludes that the use of free omental sheet graft on typhoid enteric perforation site is effective in lowering the repair leak rate and thereby decreases the morbidity and mortality associated with these procedures. By lowering the complication rates, it also entails reduction in financial burden. PMID- 24474633 TI - Can quantified pathologic response assessed as residual tumor burden be a promising staging system for patients with rectal cancer treated with chemoradiation followed by surgery? PMID- 24474634 TI - Synthesis of isoflavones by room-temperature nickel-catalyzed cross-couplings of 3-iodo(bromo)chromones with arylzincs. AB - A new concise, facile method for synthesis of isoflavones was accomplished in moderate to good yields for 3-iodochromones or 3-bromochromones and arylzinc bromides via Negishi cross-coupling reaction catalyzed by NiCl(2)/PPh(3) or NiCl(2)(PPh(3))(2) at room temperature. The Isoflavone core was synthesized in four steps in good yield, starting from commercially available 2 hydroxyacetophenone and aromatic bromide. Three steps of the procedure were carried out at room temperature. PMID- 24474635 TI - The CareWell in Hospital questionnaire: a measure of frail elderly inpatient experiences with individualized and integrated hospital care. AB - Given our aging society with an increasing number of frail elderly patients, we must provide integrated care tailored to their complex needs regarding health and well-being. The aim of this study was to develop and validate a questionnaire designed to assess how frail hospitalized elderly patients experience several important aspects of individualized and integrated care. An 8-item questionnaire was developed using input from a panel representing the target group and administered to patients age >=70 years from surgical, medical, and geriatric departments to measure data characteristics, internal consistency, test-retest reliability, construct validity, and responsiveness. A total of 470 questionnaires were returned, including 78 for test-retest reliability. Data were missing from 1.7% to 7.0% within the individual questions. The percentage of questions answered with "don't know" ranged 3.8% to 21.9%. Cronbach's alpha for internal consistency was 0.70. Test-retest intraclass correlation was 0.75. Achievement of goals during the hospital stay was significantly correlated with the questionnaire score. Scores did not differ significantly between departments or between the before and after measurements related to an innovative intervention study in healthcare delivery. The CareWell in Hospital questionnaire has good content validity, internal consistency, and test-retest reliability and warrants further research to explore responsiveness. PMID- 24474636 TI - Diagnosis of pelvic inflammatory disease (PID): intra-operative findings and comparison of vaginal and intra-abdominal cultures. AB - INTRODUCTION: Pelvic inflammatory disease (PID) is frequent in adolescents and younger women. Diagnosis is usually based on the clinical findings, and the threshold for empiric antibiotic therapy should be low. However, at least in cases of resistance toward therapy or deterioration of symptoms, laparoscopic evaluation can be helpful. METHODS: We searched the hospital charts for in-house patients who were treated for PID or tubo-ovarian abscess between 2007 and 2010. In cases with both vaginal and intra-abdominal bacterial cultures, results of those were compared. RESULTS: 73 patients with suspected PID or tubo-ovarian abscess were included. Median patients' age was 40 years (18-88), 18 of 73 (24.7 %) patients had an IUD at the time of consultation. 58 patients underwent laparoscopy or laparotomy. In 41 patients (70.7 %) tubo-ovarian abscess could be confirmed, four patients had differential gynecologic diagnoses, and two patients appendicitis. In vaginal swabs, most frequent bacteria were Streptococcus sp. (28.5 %), Escherichia coli (22.2 %), Enterococcus faecalis (15.9 %), and Staphylococcus sp. (9.5 %). In eight patients (11 %) Chlamydia trachomatis could be found, there was no case of Neisseria gonorrhea. In 33 patients both vaginal and abdominal cultures were available. In nine cases (27.3 %), identical bacteria could be found, however, 11 cases (33.3 %) showed different results. CONCLUSION: In severe cases of PID, laparoscopic evaluation and taking an intra-abdominal bacterial culture are helpful for the confirmation of diagnosis, accurate microbiologic testing and specific therapy. PMID- 24474637 TI - Is maternal anemia associated with small placental volume in the first trimester? AB - AIM: To clarify whether maternal anemia could reduce placental volume in the early gestation. METHODS: A prospective cross-sectional study was conducted. Consecutive women who visited at 11-13 + 6 weeks' gestation were enrolled. Subjects were divided into two groups by maternal hemoglobin concentration. Cases with maternal anemia were defined as a hemoglobin level less than 11 g/dl on a blood test (cases), and the others were defined as controls. An ultrasound examination was performed to measure the placental volume and the uterine arterial blood flow. The three-dimensional volume of the placenta using virtual organ computer-aided analysis (VOCAL) technique was acquired by transabdominal ultrasonography. Placental volumes were compared in women with and without anemia. RESULTS: 31 cases and 486 controls were analyzed. Maternal characteristics were not different between two groups except anemia. Placental volumes were 63.6 +/- 22.2 and 60.9 +/- 22.8 cm(3) (ns), uterine arterial RIs were 0.7 +/- 0.1 and 0.8 +/- 0.1 (ns), and PIs were 1.7 +/- 0.5 and 1.8 +/- 0.6 (ns) in cases and controls, respectively. CONCLUSIONS: Maternal anemia was not associated with reduced placental volume and uterine arterial Doppler wave form at 11-13 weeks' gestation. PMID- 24474638 TI - Association of platelet ITGA2B and ITGB3 polymorphisms with ex vivo antiplatelet effect of ticagrelor in healthy Chinese male subjects. AB - Ticagrelor (TIC) is the first reversible P2Y12 receptor antagonist that exhibits rapid antiplatelet effect by indirect inhibition of the GPIIb/IIIa complex. Polymorphisms in genes coding GPIIb/IIIa, namely ITGA2B and ITGB3, are associated with aspirin resistance and risk for thrombotic diseases. We assessed whether ITGA2B and ITGB3 polymorphisms can influence the ex vivo antiplatelet activity of ticagrelor in Chinese population. A total of 196 healthy Chinese male individuals were recruited. ADP-induced platelet aggregation was determined using optical aggregometry at baseline and after incubation of the platelet-rich plasma with 15 and 50 MUM ticagrelor, respectively. Single nucleotide polymorphisms in ITGA2B (rs5911 G>T) and ITGB3 (rs4642 A>G and rs4634 G>A) were genotyped by sequencing. TIC at both concentrations of 15 and 50 MUM decreased ADP-induced platelet aggregation significantly (P < 0.05, respectively). As compared to ITGA2B rs5911 GG homozygotes, individuals with the rs5911 TG genotype showed significantly increased inhibition of platelet aggregation (IPA) by both 15 and 50 MUM ticagrelor incubation (P < 0.05, respectively). Neither rs4642 nor rs4634 polymorphism affected ticagrelor-induced IPA. We suggest that the ITGA2B rs5911 GG genotype is associated with decreased ex vivo antiplatelet activity of ticagrelor in healthy Chinese male subjects. PMID- 24474639 TI - Successful peripheral blood stem cell mobilization using pegfilgrastim in allogeneic stem cell transplantation. AB - Pegfilgrastim is produced by binding a 20,000-dalton polyethylene glycol molecule to granulocyte colony-stimulating factor (G-CSF), increasing the mass of the compound, and resulting in a longer-lasting form of G-CSF. This makes it more convenient to use pegfilgrastim as a single-day injection. This study was a prospective phase II single-center trial. Fifteen normal related donors received pegfilgrastim 12 mg subcutaneously to mobilize peripheral blood stem cells (PBSC) for allogeneic stem cell transplantation. Leukapheresis was planned to start 3 days after injection. All harvests were successful. Median number of leukapheresis was 2 days (range 1-3 days). There were 7/15 donors who only required single leukapheresis. The maximum concentration of white blood cells (WBC) and circulating CD34 cells occurred 3 days after pegfilgrastim injection (WBC: median 62,200/MUl; CD34: median 69.76/MUl). The median yield of CD34 cells was 6.78 * 10(6)/kg recipient weight. The median CD3 cells was 1.89 * 10(8)/kg recipient weight. The main adverse events were bone pain and headache. Median neutrophil and platelet engraftments in the recipients occurred on day 12 and day 13, respectively, after transplantation. PBSC mobilization with single-day injection of pegfilgrastim in normal donor is feasible. Further comparisons of this protocol to standard G-CSF for allogeneic stem cell mobilization should be conducted in future. PMID- 24474640 TI - Expression levels of ASNS in mesenchymal stromal cells in childhood acute lymphoblastic leukemia. AB - Increased levels of asparagine synthetase (ASNS), an enzyme producing intracellular asparagine, have been implicated in the development of asparaginase resistance. The aim of this study was to assess ASNS mRNA and protein expression in bone marrow cell populations of children with acute lymphoblastic leukemia (ALL). Bone marrow mononuclear cells at diagnosis, day 33 of treatment, and after completion of chemotherapy were isolated and studied. ASNS mRNA expression was assessed by real-time PCR, and protein levels by Western blot. Our results indicate that MSC ASNS mRNA expression is upregulated in ALL samples compared to controls. ASNS expression of mesenchymal stromal cells (MSC) was found to be 2.3 times higher than that of blasts at diagnosis of ALL. We also observed that the values of the ASNS mRNA of MSC seem to reach a peak at diagnosis, and tend to decline with treatment. No correlation was found between the ASNS mRNA and protein levels. Chemotherapy does not exert any effect on the protein expression. Variability of asparaginase-induced effect may be attributable to factors involved in the interaction of hematopoietic cells with their microenvironment. PMID- 24474641 TI - Chromosome abnormalities in T-cell acute lymphoblastic leukemia in Korea. AB - The aim of the present study was to analyze chromosome abnormalities in Korean patients with T-cell acute lymphoblastic leukemia (T-ALL). A total of 65 patients with newly diagnosed T-ALL were enrolled in the study from December 2004 to December 2011. Chromosome analysis was performed at diagnosis on short-term cultures of bone marrow specimens. Of these 65 patients, abnormal karyotypes were found in 50 (77 %). Numerical and structural chromosome abnormalities were identified in 16 (25 %) and 47 (72 %) patients, respectively. Deletion was the most common structural abnormality (48 %), followed by translocation (29 %). Overall survival (OS) and relapse-free survival (RFS) outcome were unaffected by the number and/or type of chromosome abnormalities in both childhood and adult T ALL; however, the OS interval was longer for childhood patients than for adult patients in the entire cohort (P = 0.0003). Similarly, patients with first complete remission (CR) showed a better OS than those who failed to achieve first CR (P < 0.0001). There was a negative clinical impact in adult patients and patients without first CR according to multivariate analysis. This study helps to fill the gap regarding chromosome findings in T-ALL and may lead to identification of the molecular background behind phenotypic differences. PMID- 24474642 TI - Effect of Swiss-type heterocellular HPFH from XmnI-Ggamma and HBBP1 polymorphisms on HbF, HbE, MCV and MCH levels in Thai HbE carriers. AB - Relationships of Swiss-type heterocellular HPFH as functions of XmnI-(G)gamma and HBBP1:rs2071348 polymorphisms and HbF, HbE, MCV and MCH in HbE carriers were evaluated in 52 non-anemic and alpha-thalassemia-free Thai HbE carriers. HbF and HbE levels were measured using cation-exchange HPLC. MCV and MCH were determined using an automated blood counter. The XmnI-(G)gamma polymorphism was identified by XmnI digestion of amplified products, and the HBBP1:rs2071348 polymorphism by tetra-ARMS-PCR. HbF levels in HbE carriers were higher than those in normal individuals. HbF levels >0.8 % indicated the Swiss-type heterocellular HPFH in these subjects, rendering a prevalence of 40.4 %. The XmnI-(G)gamma (+) and HBBP1:rs2071348 (C) alleles were modestly positively correlated with elevated HbF, elevated MCH and lowered HbE values. This study thus confirms the influence of the XmnI-(G)gamma and HBBP1:rs2071348 polymorphisms on HbF production. The present study demonstrates the association of XmnI-(G)gamma and HBBP1:rs2071348 with HbF, HbE, MCV and MCH in HbE carriers for the first time, and highlights the effect of elevated HbF production on HbE levels. PMID- 24474643 TI - Factors impeding enzymatic wheat gluten hydrolysis at high solid concentrations. AB - Enzymatic wheat gluten hydrolysis at high solid concentrations is advantageous from an environmental and economic point of view. However, increased wheat gluten concentrations result in a concentration effect with a decreased hydrolysis rate at constant enzyme-to-substrate ratios and a decreased maximum attainable degree of hydrolysis (DH%). We here identified the underlying factors causing the concentration effect. Wheat gluten was hydrolyzed at solid concentrations from 4.4% to 70%. The decreased hydrolysis rate was present at all solid concentrations and at any time of the reaction. Mass transfer limitations, enzyme inhibition and water activity were shown to not cause this hydrolysis rate limitation up to 50% solids. However, the hydrolysis rate limitation can be, at least partly, explained by a second-order enzyme inactivation process. Furthermore, mass transfer impeded the hydrolysis above 60% solids. Addition of enzyme after 24 h at high solid concentrations scarcely increased the DH%, suggesting that the maximum attainable DH% decreases at high solid concentrations. Reduced enzyme activities caused by low water activities can explain this DH% limitation. Finally, a possible influence of the plastein reaction on the DH% limitation is discussed. PMID- 24474644 TI - Clinical and radiographic outcomes of dynamic cervical implant replacement for treatment of single-level degenerative cervical disc disease: a 24-month follow up. AB - PURPOSE: To determine the role of dynamic cervical implant (DCI) replacement for single-level degenerative cervical disc disease in Chinese patients. METHODS: Thirty patients with single-level degenerative cervical disc disease were prospectively enrolled between April 2010 and August 2010 (12 women, 18 men; mean age 56.5 years). All patients underwent anterior cervical decompression, DCI replacement, clinical and radiological assessments preoperatively and at 1, 6, 12, and 24 months postoperatively, and Japanese Orthopaedic Association (JOA), Visual Analogue Scale (VAS), Neck Disability Index (NDI), and Short Form 36 (SF 36) scores. Lateral neutral radiographs provided the intervertebral space height. Lateral dynamic radiographs were taken to measure the range of motion (ROM) of the cervical spine and functional spinal unit (FSU) of the treated segment. We compared the amount of motion of the adjacent vertebral endplate and the intrinsic motion of the implant and calculated a correlation analysis. RESULTS: DCI showed good clinical and radiographic outcomes. At the final follow-up, JOA, VAS, NDI, and SF-36 average scores improved significantly. The intervertebral space height increased slightly after operation and was maintained during follow up. The ROM of the cervical spine and FSU decreased at early follow-up, but recovered to the preoperative level within 1-2 years. There was a high index of linear correlation between the motion of the adjacent vertebral endplate and the intrinsic motion of the implant. CONCLUSIONS: DCI provided elastic dynamic stability for the targeted segment, and restored and sustained intervertebral space height and ROM of the cervical spine. PMID- 24474645 TI - Segmental anterior cervical corpectomy and fusion with preservation of middle vertebrae in the surgical management of 4-level cervical spondylotic myelopathy. AB - PURPOSE: To compare perioperative parameters, clinical outcomes, radiographic parameters, and complication rates of segmental anterior cervical corpectomy and fusion (sACCF) plus preservation of middle vertebrae with those of cervical laminectomy plus fusion (CLF) in 67 patients with 4-level cervical spondylotic myelopathy (CSM). METHODS: Between July 2006 and May 2012, 67 consecutive patients [42 males and 25 females; mean age 57.8 years (range 34-77 years)] with 4-level CSM who underwent surgery and were followed for more than 1 year were enrolled in this study and divided into sACCF and CLF groups. The study compared perioperative parameters; surgery-related and instrumentation- and graft-related complication rates; clinical parameters; patient satisfaction; and radiologic parameters. RESULTS: Significant improvements were seen from preoperative to postoperative in both groups for all three measures of clinical outcome; between group comparison revealed no significant difference for two of the three measures and significantly better scores for the CLF group in the third. Satisfaction was rated as excellent or good by 79.5 % of the sACCF group and 71.4 % of the CLF group, which was not a significant difference. Mean postoperative cervical lordosis was significantly greater in the sACCF group than in the CLF group. Blood loss and operative time were significantly greater in the CLF group than in the sACCF group and complication rate significantly lower for the sACCF group. CONCLUSIONS: sACCF with preservation of middle vertebrae is a safe, reliable, and effective alternative procedure for the treatment of 4-level CSM. PMID- 24474646 TI - Predictive accuracy of first post-treatment PET/CT in HPV-related oropharyngeal squamous cell carcinoma. AB - OBJECTIVES/HYPOTHESIS: To determine whether the result of first posttreatment positron emission tomography and computed tomography (PET/CT) is predictive of outcome in patients with oropharyngeal squamous cell carcinoma (OPSCC), and whether PET/CT accuracy is affected by human papillomavirus (HPV) status. STUDY DESIGN: Retrospective review. METHODS: Demographic, clinical, and radiographic data were available for 61 patients with OPSCC, treated in 2004 to 2012 at a single tertiary academic referral center, with at least one baseline and one posttreatment PET/CT. Clinical follow-up was obtained every 3 months thereafter. The median follow-up time was 36 months (range 3-100 months). RESULTS: Of 61 patients, 48 (79%) had negative first posttreatment PET/CT results; and overall, 18 of the 61 patients (30%) recurred. All accuracy measures for PET/CT were higher in HPV-positive patients, including a 93% negative predictive value (NPV). Patients with positive PET/CT results had poorer survival on Kaplan-Meier analyses. On multivariate analysis of factors predictive of recurrence, two parameters were significant: HPV status (P = 0.0046) and PET/CT result (P <0.0001). CONCLUSIONS: A negative first posttreatment PET/CT result is associated with better prognosis and rare recurrence, especially in patients with HPV positive status. Less frequent radiologic surveillance is warranted in patients with HPV-positive OPSCC and a negative first posttreatment PET/CT scan. PMID- 24474647 TI - Efficacy and safety of a low-level laser device in the treatment of male and female pattern hair loss: a multicenter, randomized, sham device-controlled, double-blind study. AB - SIGNIFICANCE: Male and female pattern hair loss are common, chronic dermatologic disorders with limited therapeutic options. In recent years, a number of commercial devices using low-level laser therapy have been promoted, but there have been little peer-reviewed data on their efficacy. OBJECTIVE: To determine whether treatment with a low-level laser device, the US FDA-cleared HairMax Lasercomb(r), increases terminal hair density in both men and women with pattern hair loss. METHODS: Randomized, sham device-controlled, double-blind clinical trials were conducted at multiple institutional and private practices. A total of 146 male and 188 female subjects with pattern hair loss were screened. A total of 128 male and 141 female subjects were randomized to receive either a lasercomb (one of three models) or a sham device in concealed sealed packets, and were treated on the whole scalp three times a week for 26 weeks. Terminal hair density of the target area was evaluated at baseline and at 16- and 26-week follow-ups, and analyzed to determine whether the hypothesis formulated prior to data collection, that lasercomb treatment would increase terminal hair density, was correct. The site investigators and the subjects remained blinded to the type of device they dispensed/received throughout the study. The evaluator of masked digital photographs was blinded to which trial arm the subject belonged. RESULTS: Seventy-eight, 63, 49, and 79 subjects were randomized in four trials of 9-beam lasercomb treatment in female subjects, 12-beam lasercomb treatment in female subjects, 7-beam lasercomb treatment in male subjects, and 9- and 12-beam lasercomb treatment in male subjects, compared with the sham device, respectively. Nineteen female and 25 male subjects were lost to follow-up. Among the remaining 122 female and 103 male subjects in the efficacy analysis, the mean terminal hair count at 26 weeks increased from baseline by 20.2, 20.6, 18.4, 20.9, and 25.7 per cm2 in 9-beam lasercomb-treated female subjects, 12-beam lasercomb-treated female subjects, 7-beam lasercomb-treated male subjects, and 9- and 12-beam lasercomb-treated male subjects, respectively, compared with 2.8 (p<0.0001), 3.0 (p<0.0001), 1.6 (p=0.0017), 9.4 (p=0.0249), and 9.4 (p=0.0028) in sham-treated subjects (95% confidence interval). The increase in terminal hair density was independent of the age and sex of the subject and the lasercomb model. Additionally, a higher percentage of lasercomb-treated subjects reported overall improvement of hair loss condition and thickness and fullness of hair in self-assessment, compared with sham-treated subjects. No serious adverse events were reported in any subject receiving the lasercomb in any of the four trials. CONCLUSIONS AND RELEVANCE: We observed a statistically significant difference in the increase in terminal hair density between lasercomb- and sham-treated subjects. No serious adverse events were reported. Our results suggest that low level laser treatment may be an effective option to treat pattern hair loss in both men and women. Additional studies should be considered to determine the long term effects of low-level laser treatment on hair growth and maintenance, and to optimize laser modality. PMID- 24474648 TI - Minimal tags for rapid dual-color live-cell labeling and super-resolution microscopy. AB - The growing demands of advanced fluorescence and super-resolution microscopy benefit from the development of small and highly photostable fluorescent probes. Techniques developed to expand the genetic code permit the residue-specific encoding of unnatural amino acids (UAAs) armed with novel clickable chemical handles into proteins in living cells. Here we present the design of new UAAs bearing strained alkene side chains that have improved biocompatibility and stability for the attachment of tetrazine-functionalized organic dyes by the inverse-electron-demand Diels-Alder cycloaddition (SPIEDAC). Furthermore, we fine tuned the SPIEDAC click reaction to obtain an orthogonal variant for rapid protein labeling which we termed selectivity enhanced (se) SPIEDAC. seSPIEDAC and SPIEDAC were combined for the rapid labeling of live mammalian cells with two different fluorescent probes. We demonstrate the strength of our method by visualizing insulin receptors (IRs) and virus-like particles (VLPs) with dual color super-resolution microscopy. PMID- 24474650 TI - Cancer comortality patterns in schizophrenia and psychotic disorders: a new methodological approach for unique databases. AB - The aim of this study was to determine the pattern of cancer comortality in deaths registered with schizophrenia and psychotic disorders. It focused on the question of whether the proportions of different types of cancer diverge when they are co-registered with schizophrenia/psychotic disorders or with other causes of death in mortality statistics. We developed an analysis approach applicable to common mortality statistics data when no linkage with morbidity databases or other registers is possible. The analysis covered Swiss mortality data from a 39-year period (1969 - 2007) and was confined to the most frequent cancers. We applied a two-step case-control analysis with bootstrapping (1000 repetitions). The cases were defined by the cancer-schizophrenia registrations for each specific cancer, whereas the controls were matched from the remaining cases (matching criteria: sex, age, region, subperiod). Cancers with deviant standardized mortality ratios (SMRs) included stomach cancer (1.6; 2.2 after reweighting), lung cancer (0.8; 0.5 after reweighting) and breast cancer (1.6; 1.5 after reweighting). The comortality pattern of cancers in schizophrenia and psychotic disorders diverges from the pattern found in other co-registered causes of death. The relatively low frequency of lung cancers is particularly paradoxical in view of the smoking habits of schizophrenia patients. PMID- 24474649 TI - Aldose reductase-mediated phosphorylation of p53 leads to mitochondrial dysfunction and damage in diabetic platelets. AB - BACKGROUND: Platelet abnormalities are well-recognized complications of diabetes mellitus. Mitochondria play a central role in platelet metabolism and activation. Mitochondrial dysfunction is evident in diabetes mellitus. The molecular pathway for hyperglycemia-induced mitochondrial dysfunction in platelets in diabetes mellitus is unknown. METHODS AND RESULTS: Using both human and humanized mouse models, we report that hyperglycemia-induced aldose reductase activation and subsequent reactive oxygen species production lead to increased p53 phosphorylation (Ser15), which promotes mitochondrial dysfunction, damage, and rupture by sequestration of the antiapoptotic protein Bcl-xL. In a glucose dose dependent manner, severe mitochondrial damage leads to loss of mitochondrial membrane potential and platelet apoptosis (cytochrome c release, caspase 3 activation, and phosphatidylserine exposure). Although platelet hyperactivation, mitochondrial dysfunction, aldose reductase activation, reactive oxygen species production, and p53 phosphorylation are all induced by hyperglycemia, we demonstrate that platelet apoptosis and hyperactivation are 2 distinct states that depend on the severity of the hyperglycemia and mitochondrial damage. Combined, both lead to increased thrombus formation in a mouse blood stasis model. CONCLUSIONS: Aldose reductase contributes to diabetes-mediated mitochondrial dysfunction and damage through the activation of p53. The degree of mitochondrial dysfunction and damage determines whether hyperactivity (mild damage) or apoptosis (severe damage) will ensue. These signaling components provide novel therapeutic targets for thrombotic complications in diabetes mellitus. PMID- 24474651 TI - Utilization of primary and obstetric care after medically complicated pregnancies: an analysis of medical claims data. AB - BACKGROUND: Because pregnancy complications, including gestational diabetes mellitus (GDM) and hypertensive disorders in pregnancy, are risk factors for diabetes and cardiovascular disease, post-delivery follow-up is recommended. OBJECTIVE: To determine predictors of post-delivery primary and obstetric care utilization in women with and without medical complications. RESEARCH DESIGN: Five-year retrospective cohort study using commercial and Medicaid insurance claims in Maryland. SUBJECTS: 7,741 women with a complicated pregnancy (GDM, hypertensive disorders and pregestational diabetes mellitus [DM]) and 23,599 women with a comparison pregnancy. MEASURES: We compared primary and postpartum obstetric care utilization rates in the 12 months after delivery between the complicated and comparison pregnancy groups. We conducted multivariate logistic regression to assess the association between pregnancy complications, sociodemographic predictor variables and utilization of care, stratified by insurance type. RESULTS: Women with a complicated pregnancy were older at delivery (p < 0.001), with higher rates of cesarean delivery (p < 0.0001) and preterm labor or delivery (p < 0.0001). Among women with Medicaid, 56.6% in the complicated group and 51.7% in the comparison group attended a primary care visit. Statistically significant predictors of receiving a primary care visit included non-Black race, older age, preeclampsia or DM, and depression. Among women with commercial health insurance, 60.0% in the complicated group and 49.5% in the comparison group attended a primary care visit. Pregnancy complication did not predict a primary care visit among women with commercial insurance. CONCLUSIONS: Women with pregnancy complications were more likely to attend primary care visits post-delivery compared to the comparison group, but overall visit rates were low. Although Medicaid expansion has potential to increase coverage, innovative models for preventive health services after delivery are needed to target women at higher risk for chronic disease development. PMID- 24474655 TI - N-cinnamoylation of antimalarial classics: quinacrine analogues with decreased toxicity and dual-stage activity. AB - Plasmodium falciparum, the causative agent of the most lethal form of malaria, is becoming increasingly resistant to most available drugs. A convenient approach to combat parasite resistance is the development of analogues of classical antimalarial agents, appropriately modified in order to restore their relevance in antimalarial chemotherapy. Following this line of thought, the design, synthesis and in vitro evaluation of N-cinnamoylated quinacrine surrogates, 9-(N cinnamoylaminobutyl)-amino-6-chloro-2-methoxyacridines, is reported. The compounds were found to be highly potent against both blood-stage P.falciparum, chloroquine-sensitive 3D7 (IC50 =17.0-39.0 nM) and chloroquine-resistant W2 and Dd2 strains (IC50 =3.2-41.2 and 27.1-131.0 nM, respectively), and liver-stage P.berghei (IC50 =1.6-4.9 MUM) parasites. These findings bring new hope for the possible future "rise of a fallen angel" in antimalarial chemotherapy, with a potential resurgence of quinacrine-related compounds as dual-stage antimalarial leads. PMID- 24474652 TI - Remarkable reproducibility of enzyme activity profiles in tomato fruits grown under contrasting environments provides a roadmap for studies of fruit metabolism. AB - To assess the influence of the environment on fruit metabolism, tomato (Solanum lycopersicum 'Moneymaker') plants were grown under contrasting conditions (optimal for commercial, water limited, or shaded production) and locations. Samples were harvested at nine stages of development, and 36 enzyme activities of central metabolism were measured as well as protein, starch, and major metabolites, such as hexoses, sucrose, organic acids, and amino acids. The most remarkable result was the high reproducibility of enzyme activities throughout development, irrespective of conditions or location. Hierarchical clustering of enzyme activities also revealed tight relationships between metabolic pathways and phases of development. Thus, cell division was characterized by high activities of fructokinase, glucokinase, pyruvate kinase, and tricarboxylic acid cycle enzymes, indicating ATP production as a priority, whereas cell expansion was characterized by enzymes involved in the lower part of glycolysis, suggesting a metabolic reprogramming to anaplerosis. As expected, enzymes involved in the accumulation of sugars, citrate, and glutamate were strongly increased during ripening. However, a group of enzymes involved in ATP production, which is probably fueled by starch degradation, was also increased. Metabolites levels seemed more sensitive than enzymes to the environment, although such differences tended to decrease at ripening. The integration of enzyme and metabolite data obtained under contrasting growth conditions using principal component analysis suggests that, with the exceptions of alanine amino transferase and glutamate and malate dehydrogenase and malate, there are no links between single enzyme activities and metabolite time courses or levels. PMID- 24474656 TI - Insurance status and distant-stage disease at diagnosis among adolescent and young adult patients with cancer aged 15 to 39 years: National Cancer Data Base, 2004 through 2010. AB - BACKGROUND: The percentage of adolescent and young adult (AYA) patients with cancer (those aged 15-39 years) diagnosed at a distant stage of disease did not significantly change between 1975 and 2004. It has been hypothesized that a lack of health insurance may be a significant risk factor for a diagnosis of distant stage disease among AYA patients, but to the authors' knowledge this has not been examined in a national sample. METHODS: The National Cancer Data Base, a hospital based cancer registry, was used to obtain data regarding incident cancer cases among patients aged 15 years to 39 years who were diagnosed between 2004 and 2010. After all exclusions, a total of 285,448 cases were available for analysis; all AYA cancer sites were included. A retrospective study was conducted to assess the association between insurance status and stage of disease at diagnosis. RESULTS: After adjusting for age, race/ethnicity, facility type, ZIP code-based income and education levels, and US Census region, it was found that among males, uninsured patients were 1.51 times more likely to be diagnosed at a distant stage of disease compared with patients with private insurance (95% confidence interval, 1.46-1.55). Among females, the effect of insurance was stronger, with uninsured patients found to be 1.86 times more likely to be diagnosed at a distant stage (95% confidence interval, 1.79-1.94). The effect of insurance status was substantially stronger for malignancies that are more amenable to early detection (melanoma, thyroid carcinoma, breast carcinoma, genitourinary carcinoma), and substantially weaker for those that are less amenable to early detection (lung carcinoma, adrenocortical carcinoma, Wilms tumor). CONCLUSIONS: In a large national sample of AYA patients with cancer, insurance status was found to be a strong independent risk factor for distant-stage disease at the time of diagnosis. PMID- 24474657 TI - Phenotype-genotype analysis in two Chinese families with Liddle syndrome. AB - The families with Liddle syndrome show marked phenotypic variation in blood pressure, serum potassium and other clinical manifestations. Here we analyzed the correlation of genotype-phenotype in two Chinese families with Liddle syndrome. The sequence of C-terminus of SCNN1B and SCNN1G were screened in the two families with likely Liddle syndrome. In addition to hypertension and hypokalemia, one of the two pedigrees had sudden death in their family members, so the exons of 428 reported genes-related to cardiovascular diseases were screened as well in the family. A heterozygous betaR566X nonsense mutation was found in the proband-1 in the first pedigree, and the proband's sister and father. They showed mild phenotype with hypertension under control. In contrast, two of the four previous studies report that the mutation causes severe phenotype. A heterozygous betaR597PfrX607 frameshift mutation was identified in the proband-2 in the second pedigree, showing malignant phenotype including resistant hypertension, hypokalemia, higher PRA and plasma angiotensin II levels. Both the proband-2 and the proband-2's father had sudden death in their twenties, but no meaningful mutations were found by screening of the exons in 428 cardiovascular disease related genes. However, the same mutation has been related to moderate phenotype in previous studies. Our results confirmed that the phenotypes of Liddle syndrome are varied significantly even with the same mutation. The mechanisms why the same mutation causes very different phenotype need to be explored because intervention of these modifiers may change the disease course and prognosis accordingly. PMID- 24474658 TI - CRP gene polymorphism contributes genetic susceptibility to dyslipidemia in Han Chinese population. AB - C-reactive protein (CRP), an inflammatory marker that statistically predicts future cardiovascular risk, has been reported to be associated with plasma lipid level changes. Whether CRP genetic variants affect lipid metabolism is of importance to investigate. A community-based study population including 2,731 adult subjects aged 18-62 years was used to evaluate the association of CRP gene with dyslipidemia and five tagging SNPs (tagSNPs) were genotyped. Multiple logistic regression was applied to further evaluate relationships between the SNPs and lipid metabolism abnormality and general linear model was applied to compare plasma lipid levels between genotypes. Association analyses indicated that recessive model of SNPs rs876537 and rs4285692 had significant association with elevated HDL after adjustment for covariates. Odds ratio (OR) of rs876537 were 0.60 for HDL > 1.54 versus 1.04-1.54 mmol/L (P = 0.011), as well as, ORs were 0.617 for HDL > 1.83 versus <=1.35 mmol/L (P = 0.002) and 0.724 for HDL = 1.59-1.83 versus <=1.35 mmol/L (P = 0.028) respectively. OR of rs4285692 was 0.634 for HDL > 1.83 versus <=1.35 mmol/L (P = 0.027). Further stratification analysis found significant associations of rs10737175 with elevated HDL (>1.54 vs. 1.04-1.54 mmol/L, OR 0.629 and P = 0.027) and elevated TG (>=1.70 vs. <1.70 mmol/L, ORs of additive and dominant models were 0.628, 0.545 and P values were 0.006, 0.003 respectively) in female. rs4285692 was significantly associated with elevated LDL (>=3.37 vs. <3.37 mmol/L), ORs equaled to 1.532, 2.281 for additive model and recessive model and P values were 0.028, 0.024 respectively in male. Furthermore, quantitative trait analysis indicated the variation T to C of rs876537 significantly affect decreased plasma HDL level (P = 0.014). Our findings suggest that CRP genetic polymorphisms independently had positive association with the risk of HDL, LDL and TG elevating and further replication in other large population and biological function research would be warranted. PMID- 24474659 TI - X-chromosome STR markers data in a Cabo Verde immigrant population of Lisboa. AB - Population genetic data of 12 X chromosomal short tandem repeats markers (DXS10074, DXS10079, DXS10101, DXS10103, DXS10134, DXS10135, DXS10146, DXS10148, DXS7132, DXS7423, DXS8378 and HPRTB) were analysed in 54 females and 95 males of an immigrant population from Cabo Verde living in Lisboa. The obtained results for forensic statistical parameters such as observed heterozigosity, polymorphism information content, power of discrimination and mean exclusion chance, based on single allele frequencies, reveal that this multiplex system is highly informative and can represent an important tool for genetic identification purposes in the immigrant population of Cabo Verde. Since the studied short tandem repeats genetic markers are distributed on four linkage groups, that can provide independent genotype information, we studied those groups as haploytes. The forensic efficiency parameters for the linked groups were all higher than 0.97, with linkage group I being the most polymorphic and linkage group III the less informative. PMID- 24474660 TI - Selective interactions of hnRNP M isoforms with the TET proteins TAF15 and TLS/FUS. AB - The molecular composition of macromolecular assemblies engaged in transcription and splicing influences biogenesis of mRNA transcripts. Preference for one over the other interactive protein partner within those complexes is expected to change the gene expression pattern and to affect subsequent cellular events. We report here the novel and selective associations between RNA-binding proteins, namely the hnRNP M1-4 isoforms-involved in early spliceosome assembly and alternative splicing-and the transcription factors TAF15 and TLS/FUS. In immunoprecipitation studies on HeLa nuclear extracts, TAF15 co-immunoprecipitates preferably with the higher molecular weight hnRNP M3/4 isoforms, opposite to TLS/FUS that associates with the lower molecular weight hnRNP M1/2 species. We demonstrate that these associations can be mediated through direct protein protein interactions via the amino-termini of the TET proteins, independently of RNA. Finally, we show partial co-localization of TAF15 and TLS/FUS with hnRNP M proteins in HeLa nuclei, supporting the biochemically obtained data. The participation of hnRNP M in an expanding network of protein-protein interactions suggests its important functioning in the coordination of transcriptional and post-transcriptional events. PMID- 24474661 TI - Anti-inflammatuar and anti-oxidative effects of Nigella sativa L.: 18FDG-PET imaging of inflammation. AB - Inflammation has an important role in many diseases such as cystic fibrosis, allergies and cancer. The free radicals produced during inflammation, can induce gene mutations and posttranslational modifications of cancer related proteins. Nigella sativa L. (N. sativa) is herbaceous plant and commonly used as a natural food. It has many pharmacological effects including antibacterial, antifungal, antitumor, analgesic, antipyretic activity. The aim of this study was to investigate the anti-inflammatuar and anti-oxidant activity of N. sativa in acute inflammation. Thus we used the experimental lipopolysaccharides (LPS)-induced model. Intraperitoneal LPS 1 mg/kg was administered to groups. N. sativa (500 mg/kg) and essential oil (5 ml/kg) were given orally to treatment groups, after 24-h of intraperitoneal LPS-injection. To determine the lung inflammation, 18F fluoro-deoxy-D-glucose (0.8 ml/kg) was administrated under the anesthesia before the 1 h of PET-scanning. After the FDG-PET, samples were collected. Lung and liver 18F-FDG-uptake was calculated. Serum AST, ALT, LDH and hcCRP levels were determined and liver, lung and erythrocyte SOD, MDA and CAT levels were measured. Liver and lung NO and DNA fragmentation levels were determined. MDA levels were decreased in treated inflammation groups whereas increased in untreated inflammation group. SOD and CAT activities in untreated inflammation group were significantly lower. According to the control group, increased AST and ALT levels were found in untreated inflammation group. 18F-FDG uptake of inflammation groups were increased when compare the control group. We found increased 18F-FDG uptake, DNA fragmentation and NO levels in LPS-induced inflammation groups. We conclude that, in LPS-induced inflammation, N. sativa have therapeutic and anti-oxidant effects. PMID- 24474662 TI - Anorexia nervosa and its relation to depression, anxiety, alexithymia and emotional processing deficits. AB - PURPOSE: Psychopathological changes and dysfunction in emotion processing have been described for anorexia nervosa (AN). Yet, findings are applicable to adult patients only. Furthermore, potential for discriminative power in clinical practice in relation to clinical parameters has to be discussed. The aim of this study was to investigate psychopathology and emotional face processing in adolescent female patients with AN. METHODS: In a sample of 15 adolescent female patients with AN (16.2 years, SD +/- 1.26) and 15 age and sex matched controls we assessed alexithymia, depression, anxiety and empathy in addition to emotion labelling and social information processing. RESULTS: AN patients had significantly higher alexithymia, higher levels of depression, and state and trait anxiety compared to controls. There was a trend for a lower ability to recognize disgust. Happiness as a positive emotion was recognized better. All facial expressions were recognized significantly faster by AN patients. Associations of pathological eating behaviour and trait anxiety were seen. CONCLUSION: In accordance with the stress reduction hypothesis, typical psychopathology of alexithymia, anxiety and depression is prevalent in female adolescent AN patients. It is present detached from physical stability. Pathogenesis of AN is multifactorial and already fully present in adolescence. An additional reinforcement process can be discussed. For clinical practice, those parameters might have a better potential for early prognostic factors related to AN than physical parameters and possible implication for intervention is given. PMID- 24474663 TI - EDDA: an eating disorder diagnostic algorithm according to ICD-11. PMID- 24474664 TI - Peptides targeting chemokine receptor CXCR4: structural behavior and biological binding studies. AB - CXCR4 is a G-protein-coupled receptor involved in a number of physiological processes in the hematopoietic and immune systems. CXCL12/CXCR4 axis plays a central role in diseases, such as HIV, cancer, WHIM syndrome, rheumatoid arthritis, pulmonary fibrosis, and lupus and, hence, indicated as putative therapeutic target. Although multiple CXCR4 antagonists have been developed, there is only one marketed drug, plerixafor, indicated for stem cell mobilization in poor mobilizer patients. In this work, we have designed and synthesized two peptides, six and seven residues long, using as template the N-terminal region of CXCL12; analyzed their conformations by CD, NMR, and molecular dynamics simulations; simulated their complexes with CXCR4 by docking methods; and validated these data by in vitro studies. The results showed that the two peptides are rather flexible in aqueous solution lacking ordered secondary structure elements and present a promising affinity for CXCR4. This affinity is not revealed for CXCR7, indicating a specificity for CXCR4. PMID- 24474666 TI - Implementation of quality improvement skills by primary care teams: case study of a large academic practice. AB - BACKGROUND: Continuous quality improvement (QI) is important to primary care in general, and is emphasized as a key tenet of the primary care patient-centered medical home (PCMH) model. While team-based QI activities within the PCMH model are expected, concerns exist as to how successful efforts have been at implementing team-driven QI projects. OBJECTIVE: To (a) identify opportunities and challenges to QI efforts in a large primary care practice in order to (b) develop action plans to facilitate QI work into primary care teams. DESIGN: We obtained qualitative and quantitative information about existing primary care team QI initiatives. PARTICIPANTS: Eleven interdisciplinary primary care teams and 4 facilitators/coaches. METHODS: We conducted unstructured interviews and gathered documentation from primary care team members about QI efforts to (a) characterize team-based QI progress and (b) identify barriers and facilitators. RESULTS: In the 18 months since local leadership prioritized conducting team based QI projects, team members described multiple exposures to QI training, coaching resources, and data/analysis support. No team developed a formal aim statement. Six of the 11 teams completed any steps beyond the initial team discussion. Four teams attempted to apply an intervention. Challenges included team time and competing demands/priorities; 3 of the 4 teams attempting to implement a project credited a data/informatics facilitator for their progress. CONCLUSIONS: In this large academic primary care clinic setting, interdisciplinary team training in QI, support for data collection, and dedicated coaching resources produced few sustainable continuous QI initiatives. Several potentially modifiable barriers to initiation, completion, and sustainability of QI initiatives by primary care teams were identified. PMID- 24474665 TI - Insulin Sensitivity Following Exercise Interventions: Systematic Review and Meta Analysis of Outcomes Among Healthy Adults. AB - OBJECTIVE: Although exercise can improve insulin sensitivity, no adequate synthesis exists of exercise intervention studies with regard to their effect on insulin sensitivity. This comprehensive meta-analysis synthesized the insulin sensitivity outcomes of supervised exercise interventions. METHOD: Extensive literature searching located published and unpublished intervention studies that measured insulin sensitivity outcomes. Eligible studies tested supervised exercise interventions among healthy adults. Primary study characteristics and results were coded. Random-effects meta-analyses of standardized mean differences included moderator analyses. RESULTS: Data were synthesized across 2509 subjects (115 samples, 78 reports). The overall mean effect size for 2-group postintervention comparisons was 0.38 (95% confidence interval [CI] = 0.25-0.51, I (2) = 0%) and for 2-group pre-post comparisons was 0.43 (95% CI = 0.30-0.56, I (2) = 52%; higher mean insulin sensitivity for treatment than control subjects). The postintervention mean of 0.38 is consistent with treatment subjects ending studies with a mean fasting insulin of 6.8 mU/L if control participants' mean fasting insulin were 7.9 mU/L. Exploratory moderator analyses did not document different insulin sensitivity effect sizes across intervention characteristics or sample attributes. CONCLUSION: This study documented that exercise is a valuable primary care and community health strategy for healthy adults to improve insulin sensitivity and lower the risk for diabetes conferred by insulin resistance. PMID- 24474667 TI - Laryngeal chondrosarcoma: a population-based analysis. AB - OBJECTIVES/HYPOTHESIS: Laryngeal chondrosarcoma (LC) is a rare entity, reportedly comprising less than 1% of all laryngeal tumors. Consequently, the incidence and survival of patients with this slow-growing tumor has been difficult to study. Our objective was to evaluate incidence, organized by patient demographics, as well as long-term survival trends of this malignancy using a population-based database. STUDY DESIGN: Retrospective analysis of the United States National Cancer Institute's Surveillance, Epidemiology, and End Results (SEER) registry. METHODS: The SEER database was searched for patients diagnosed with LC between 1973 and 2010. Data analyzed included patient demographics, incidence, treatment modality, and survival. RESULTS: One-hundred and forty-three cases were identified, representing 0.2% of all laryngeal tumors. Median age at diagnosis was 61.7 years. Men and women constituted 76.2% and 23.8% of patients, respectively. Tumors were locally invasive with 37.7% T4 disease and infrequent regional and distant metastases. The 1-year, 5-year, and 10-year disease-specific survival for LC was 96.5%, 88.6%, and 84.8%, respectively, compared to 88.3%, 68.2%, and 59.3%, respectively for patients with all other laryngeal tumors (P values < 0.01). Relative survival was 94.9% at 1 year, 88.5% at 5 years, and 88.4% at 10 years. CONCLUSIONS: This analysis represents the largest LC study sample to date, allowing for evaluation of incidence and long-term survival. LC occurs infrequently, is locally invasive, but only rarely metastasizes. Prognosis for LC is significantly better than for other laryngeal malignancies. PMID- 24474668 TI - Iridium-catalyzed intermolecular azide-alkyne cycloaddition of internal thioalkynes under mild conditions. AB - An iridium-catalyzed azide-alkyne cycloaddition reaction (IrAAC) of electron-rich internal alkynes is described. It is the first efficient intermolecular AAC of internal thioalkynes. The reaction exhibits remarkable features, such as high efficiency and regioselectivity, mild reaction conditions, easy operation, and excellent compatibility with air and a broad spectrum of organic and aqueous solvents. It complements the well-known CuAAC and RuAAC click reactions. PMID- 24474669 TI - Pan-PIM kinase inhibition provides a novel therapy for treating hematologic cancers. AB - PURPOSE: PIM kinases have been shown to act as oncogenes in mice, with each family member being able to drive progression of hematologic cancers. Consistent with this, we found that PIMs are highly expressed in human hematologic cancers and show that each isoform has a distinct expression pattern among disease subtypes. This suggests that inhibitors of all three PIMs would be effective in treating multiple hematologic malignancies. EXPERIMENTAL DESIGN: Pan-PIM inhibitors have proven difficult to develop because PIM2 has a low Km for ATP and, thus, requires a very potent inhibitor to effectively block the kinase activity at the ATP levels in cells. We developed a potent and specific pan-PIM inhibitor, LGB321, which is active on PIM2 in the cellular context. RESULTS: LGB321 is active on PIM2-dependent multiple myeloma cell lines, where it inhibits proliferation, mTOR-C1 signaling and phosphorylation of BAD. Broad cancer cell line profiling of LGB321 demonstrates limited activity in cell lines derived from solid tumors. In contrast, significant activity in cell lines derived from diverse hematological lineages was observed, including acute lymphoblastic leukemia (ALL), acute myelogenous leukemia (AML), multiple myeloma and non Hodgkin lymphoma (NHL). Furthermore, we demonstrate LGB321 activity in the KG-1 AML xenograft model, in which modulation of pharmacodynamics markers is predictive of efficacy. Finally, we demonstrate that LGB321 synergizes with cytarabine in this model. CONCLUSIONS: We have developed a potent and selective pan-PIM inhibitor with single-agent antiproliferative activity and show that it synergizes with cytarabine in an AML xenograft model. Our results strongly support the development of Pan-PIM inhibitors to treat hematologic malignancies. PMID- 24474670 TI - Asymmetrical leg atrophy in levodopa-responsive dystonia due to a novel GTP cyclohydrolase mutation. PMID- 24474671 TI - Total triterpene acids, isolated from Corni Fructus, ameliorate progression of renal damage in streptozotocin-induced diabetic rats. AB - OBJECTIVE: To investigate whether total triterpene acids (TTAs), isolated from Cornus Fructus, attenuates renal function by reducing oxidative stress and down regulating the expression of transforming growth factor beta1 (TGF-beta1). METHODS: Diabetes was induced by an injection of streptozotocin (40 mg/kg intravenously). Thirty rats were randomly divided into three groups: control group, diabetic model group and TTAs treatment group (50 mg/kg, intragastrically) administrated for 8 weeks from 5th to 12th week. All rats were anaesthetized and then were killed to remove kidneys. The renal function and redox enzyme system parameters were tested. Glomerular morphology was observed by a light microscopy. Immunohistochemistry and Western blot assays were employed to determine the protein levels of TGF-beta1. RESULTS: TTAs attenuated the levels of urinary protein, serum creatinine and blood urea nitrogen, although it did not significantly reduce the level of glucose. In addition, TTAs decreased the malondialdehyde while increased superoxide dismutase, catalase and glutathione peroxide activities in diabetic rats. The renal pathological changes in TTAs treatment group were ameliorated. Furthermore, TTAs also ameliorated the expression of TGF-beta1. CONCLUSION: TTAs improved renal function via reducing oxidative stress and down-regulation the expression of TGF-beta1 in diabetic rats. PMID- 24474672 TI - Effect of aqueous extracts of several kinds of herbs on human platelet aggregation and expression of P-selectin in vitro. AB - OBJECTIVE: To study the effect of aqueous extract of several kinds of herbs on human platelet aggregation and expression of P-selectin in vitro. METHODS: Blood was collected from volunteers. Effects of the prepared water extracts of herbs on platelet aggregation were monitored on a Packs-4 aggregometer. The fluorescence intensity of water extracts of Caulis Spatholobi, Flos Carthami and Rhizoma Curcumae on the expression of P-selectin in human platelets of healthy persons was measured with flow cytometry. RESULTS: Out of several herbs investigated, Flos Carthami and Rhizoma Curcumae potently inhibited platelet aggregation after incubation with platelet-rich plasma (PRP) for 15 min. Caulis Spatholobi Flos Carthami and Rhizoma Curcumae inhibited adenosine-5'-diphosphate (ADP) or platelet activating factor (PAF)-induced platelet aggregation in PRP in a dose dependent manner. In contrast to Flos Carthami and Rhizoma Curcumae, Caulis Spatholobi could not inhibit thrombin-induced platelet aggregation. Despite its inability to inhibit thrombin-induced platelet aggregation in PRP, Caulis Spatholobi had a greater anti-aggregating activity in PRP induced by ADP or PAF. Caulis Spatholobi and Flos Carthami showed significant inhibitory effects on the expression of P-selectin. CONCLUSIONS: Caulis Spatholobi, Flos Carthami and Rhizoma Curcumae have potent anti-platelet properties, and their inhibitory actions are mediated via different mechanisms. Caulis Spatholobi inhibited ADP induced platelet aggregation but not by thrombin, indicating that its mechanism of action might be independent of the thromboxane pathway. The effect of Caulis Spatholobi and Flos Carthami were associated with suppressing the expression of P selectin. PMID- 24474673 TI - Effects of curcumin on pain threshold and on the expression of nuclear factor kappa B and CX3C receptor 1 after sciatic nerve chronic constrictive injury in rats. AB - OBJECTIVE: To investigate the effects of curcumin on pain threshold and the expressions of nuclear factor kappa B (NF-kappa B) and CX3C chemokine receptor 1 (CX3CR1) in spinal cord and dorsal root ganglion (DRG) of the rats with sciatic nerve chronic constrictive injury. METHODS: One hundred and twenty male Sprague Dawley rats, weighing 220-250 g, were randomly divided into 4 groups. Sham surgery (sham) group: the sciatic nerves of rats were only made apart but not ligated; chronic constrictive injury (CCI) group: the sciatic nerves of rats were only ligated without any drug treatment; curcumin treated injury (Cur) model group: the rats were administrated with curcumin 100 mg/(kg.d) by intraperitoneal injection for 14 days after CCI; solvent control (SC) group: the rats were administrated with the solvent at the same dose for 14 days after CCI. Thermal withdrawal latency (TWL) and mechanical withdrawal threshold (MWT) of rats were respectively measured on pre-operative day 2 and postoperative day 1, 3, 5, 7, 10 and 14. The lumbar segment L4-5 of the spinal cord and the L4, L5 DRG was removed at post-operative day 3, 7 and 14. The change of nuclear factor kappa B (NF-kappa B) p65 expression was detected by Western blotting while the expression of CX3CR1 was determined by immunohistochemical staining. RESULTS: Compared with the sham group, the TWL and MWT of rats in the CCI group were significantly decreased on each post-operative day (P<0.01), which reached a nadir on the 3rd day after CCI, and the expressions of NF-kappa B p65 and CX3CR1 were markedly increased in spinal cord dorsal horn and DRG. In the Cur group, the TWL of rats were significantly increased than those in the CCI group on post-operative day 7, 10 and 14 (P<0.05) and MWT increased than those in the CCI group on post-operative day 10 and 14 (P<0.05). In addition, the administration of curcumin significantly decreased the positive expressions of NF-kappa B p65 and CX3CR1 in spinal cord and DRG (P<0.05). CONCLUSION: Our study suggests that curcumin could ameliorate the CCI-induced neuropathic pain, probably through inhibiting CX3CR1 expression by the activation of NF-kappa B p65 in spinal cord and DRG. PMID- 24474674 TI - Effects of the methylene chloride fraction from modified Boyang-Hwan-o-Tang, a polyherbal medicine on transient middle cerebral artery occlusion-induced ischemia in rats. AB - OBJECTIVE: To study the neuroprotective effect of the methylene chloride fraction from modified Boyang-Hwan-o-Tang (mBHT-MC), especially against neuronal apoptosis. METHODS: mBHT-MC (10, 25 or 50 mg/kg) was orally administered once per day for 7 days in transient middle cerebral artery occlusion (MCAO)-induced ischemic rats. Infarction volumes was measured by 2,3,5-triphenyltetrazolium chloride (TTC) staining, neurological deficit score and the expression of apoptotic proteins such as Bcl-2, Bax and caspase-3 by Western blot in MCAO induced ischemic brain. Neuronal apoptosis in ischemic phenumbra was also investigated by staining with hematoxylin and eosin, Nissl and Hoechst 33342. RESULTS: mBHT-MC administration in MCAO rats significantly decreased infarction volume and neurological deficit scores. mBHT-MC significantly enhanced Bcl-2 expression, and inhibited Bax and caspase-3 expression in ischemic brain. In addition, mBHT-MC significantly decreased the number of apoptotic neuronal cells in ischemic brains. CONCLUSIONS: mBHT-MC administration inhibits neuronal death induced by cerebral ischemia in rats, suggesting that mBHT-MC has a neuroprotective property in brain ischemia. PMID- 24474675 TI - Therapeutic mechanisms of single Chinese medicine herb or their extracts for extrahepatic obstructive jaundice. AB - Obstructive jaundice (OJ) is classified as extrahepatic OJ or intrahepatic OJ. Extrahepatic OJ is attributed to a variety of intricate etiological factors. Research has begun with Chinese medicine (CM), which can be used as an adjunctive therapy for extrahepatic OJ. Particular attention has been paid to the therapeutic effects and their mechanisms of single CM herb and relevant extracts. The roles of single CM or their extracts during adjunctive therapy for extrahepatic OJ have been described briefly. This review focuses on the effects and their mechanisms of relevant herbal medicines. PMID- 24474676 TI - A pilot study on the correlation of tongue manifestation with the site of cerebral infarction in patients with stroke. AB - OBJECTIVE: To discuss the correlation of tongue manifestation with the site of cerebral infarction in patients with acute cerebral infarction. METHODS: From March 2008 to February 2009, 200 cases of hospitalized patients with first unilateral cerebral infarction were chosen in the Department of Neurology, Xuanwu Hospital. The correlation of different tongue color, fur texture, fur color with the site of cerebral infarction was analyzed. RESULTS: The site of cerebral infarction in patients were compared between different tongue color by Chisquare test (P=0.314), and further correspondence analysis demonstrated that there was correlation between red tongue and cortical-subcortical infarction group. The site of cerebral infarction in patients were compared between thick fur group and thin fur group, cortical-subcortical infarction occurred more frequently in the former (P=0.0008). The site of cerebral infarction in patients were compared between dry fur group, moist fur group and smooth fur group, correspondence analysis demonstrated there was correlation between dry fur and cortical subcortical group. The site of cerebral infarction in the patients were compared between white fur group, white-yellow fur group and yellow fur group (P=0.010), and correspondence analysis demonstrated there was correlation between white fur and brainstem infarction; white-yellow fur has relationship with cortical infarction; subcortical infarction was weakly related with white-yellow fur; there was closer relationship between yellow fur and cortical-subcortical infarction. CONCLUSION: The change of tongue manifestation was associated with the site of cerebral infarction in patients, providing a new combining site for diagnosing cerebrovascular diseases by integrative medicine. PMID- 24474677 TI - Gender and ethnic disparities in colon cancer presentation and outcomes in a US universal health care setting. AB - OBJECTIVE: Access to care is a pillar of U.S. healthcare reform and could potentially challenge existing ethnic and gender disparities in care. We present a snapshot of these disparities in surgical colon cancer patients in the largest public hospital in Massachusetts, a state leading in providing universal healthcare, to indicate potential changes that might result from universal care access. METHODS: All surgical colon cancer patients at Massachusetts General Hospital (2004-2011) were included. Baseline characteristics, perioperative, and long-term outcomes were compared. RESULTS: Among 1,071 patients, the 110 (10.3%) minority patients presented with more comorbid (mean Charlson score 0.84 vs. 0.71; P = 0.039), metastatic (21.8% vs. 14%; P = 0.026), and node-positive disease (50% vs. 38.8%; P = 0.014). Women (n = 521; 48.6%) had less screening diagnoses (overall: 17.8% vs. 22.6%; P = 0.049, screening age: 26.4% vs. 32.7%; P = 0.036) with subsequently higher rates of metastatic disease on pathology (11.3% vs. 7.1%, P = 0.02). Multivariate adjustment for baseline staging makes outcome disparities no longer statistically significant. CONCLUSIONS: Significant gender and ethnic disparities subsist at baseline despite long-standing low-threshold healthcare access, although seemingly mitigated by enrollment into high-level care, empowering equal chances for underprivileged groups. The outcomes are also a reminder that universal healthcare will not be a panacea for the deeply rooted and dynamic causes of presentation inequalities. PMID- 24474678 TI - Targeted fluorination of a nonsteroidal anti-inflammatory drug to prolong metabolic half-life. AB - In drug design, one way of improving metabolic stability is to introduce fluorine at a metabolically labile site. In the early stages of drug design, identification of such sites is challenging, and a rapid method of assessing the effect of fluorination on a putative drug's metabolic stability would be of clear benefit. One approach to this is to employ micro-organisms that are established as models of drug metabolism in parallel with the synthesis of fluorinated drug analogues. In this study, we have used the filamentous fungus Cunninghamella elegans to identify the metabolically labile site of the nonsteroidal anti inflammatory drug flurbiprofen, to aid in the design of fluorinated derivatives that were subsequently synthesised. The effect of the additional fluorine substitution on cytochrome P450-catalysed oxidation was then determined via incubation with the fungus, and demonstrated that fluorine substitution at the 4' position rendered the drug inactive to oxidative transformation, whereas substitution of fluorine at either 2' or 3' resulted in slower oxidation compared to the original drug. This approach to modulating the metabolic stability of a drug-like compound is widely applicable and can be used to address metabolic issues of otherwise good lead compounds in drug development. PMID- 24474679 TI - The effect of zoledronic acid on the fracture risk in men with osteoporosis. AB - BACKGROUND: Prospective, placebo-controlled, double-blind, randomized studies on osteoporosis treatment with bisphosphonates in men are rare. This review focuses on a recent trial and compares the results with other studies. METHODS: This review provides a summary of recent literature on fracture risk in men following treatment with zoledronic acid. According to a recent clinical study with 1,199 men, zoledronic acid was linked to a lower risk of vertebral fractures. In this manuscript, a re-analysis of the presented statistical data will be demonstrated by performing a Bonferroni-correction to adjust for type 1 error accumulation in multiple statistical tests. RESULTS: It will be shown that the provided evidence linking zoledronic acid to a lower fracture risk in male osteoporosis is true, but less pronounced than originally assumed. CONCLUSION: Comparative clinical studies are recommended, where the benefits of different bisphosphonates are compared to each other under the same experimental conditions. PMID- 24474680 TI - Subclinical hyperthyroidism when presenting as initial manifestation of juvenile Hashimoto's thyroiditis: first report on its natural history. AB - BACKGROUND: Due to the lack of specific pediatric studies, no data are available about natural history of endogenous subclinical hyperthyroidism (SH) in childhood. AIMS: (a) To investigate for the first time the natural history of SH [suppressed thyrotropin (TSH) and normal free thyroxine free thyroxine (FT4) levels] when presenting as initial manifestation of Hashimoto's thyroiditis (HT) in childhood (group A); (b) to compare spontaneous evolution of HT-related SH with that observed in age-matched patients with HT-related frank hyperthyroidism (suppressed TSH and elevated FT4 levels), i.e., Hashitoxicosis Htx (group B). RESULTS: In the 11 patients of group A, TSH normalization spontaneously occurred 1-24 months after diagnosis, while in the 10 patients of group B it occurred 3-9 months after diagnosis, with no differences between the 2 groups in terms of time interval from entry to TSH normalization. In group A, this time interval was related to baseline thyroid peroxidase antibodies (r=0.78, p = 0.04). During follow-up, eight patients of each group remained euthyroid, whereas two became hypothyroid (in both groups) and one developed Graves' disease (in group A). CONCLUSION: (a) HT should be included among the causes of endogenous SH in pediatric age; (b) in children with HT-related SH, spontaneous normalization of TSH levels occurs within the first 24 months after diagnosis, as well as in age matched patients with Htx; (c) in both these conditions, a further deterioration of thyroid function might re-present in some patients during follow-up; (d) Ht related SH and Htx might be possibly seen as different biochemical stages along the same continuum. PMID- 24474681 TI - Birth outcomes and maternal residential proximity to natural gas development in rural Colorado. AB - BACKGROUND: Birth defects are a leading cause of neonatal mortality. Natural gas development (NGD) emits several potential teratogens, and U.S. production of natural gas is expanding. OBJECTIVES: We examined associations between maternal residential proximity to NGD and birth outcomes in a retrospective cohort study of 124,842 births between 1996 and 2009 in rural Colorado. METHODS: We calculated inverse distance weighted natural gas well counts within a 10-mile radius of maternal residence to estimate maternal exposure to NGD. Logistic regression, adjusted for maternal and infant covariates, was used to estimate associations with exposure tertiles for congenital heart defects (CHDs), neural tube defects (NTDs), oral clefts, preterm birth, and term low birth weight. The association with term birth weight was investigated using multiple linear regression. RESULTS: Prevalence of CHDs increased with exposure tertile, with an odds ratio (OR) of 1.3 for the highest tertile (95% CI: 1.2, 1.5); NTD prevalence was associated with the highest tertile of exposure (OR = 2.0; 95% CI: 1.0, 3.9, based on 59 cases), compared with the absence of any gas wells within a 10-mile radius. Exposure was negatively associated with preterm birth and positively associated with fetal growth, although the magnitude of association was small. No association was found between exposure and oral clefts. CONCLUSIONS: In this large cohort, we observed an association between density and proximity of natural gas wells within a 10-mile radius of maternal residence and prevalence of CHDs and possibly NTDs. Greater specificity in exposure estimates is needed to further explore these associations. PMID- 24474682 TI - The sentinel hospitalization and the role of palliative care. AB - With current healthcare reform and calls for improving care quality and safety, there is renewed emphasis on high-value care. Moreover, given the significant healthcare resource utilization for patients with chronically progressive illnesses or for patients at the end of life, innovative and efficient care delivery models are urgently needed. We propose here the concept of a sentinel hospitalization, defined as a transitional point in the patient's disease course that heralds a need to reassess prognosis, patient understanding, treatment options and intensities, and goals of care. Hospitalists are well positioned to recognize a patient's sentinel hospitalization and use it as an opportunity for active integration of palliative care that provides high-quality and cost-saving care through its patient- and family-oriented approach, its interdisciplinary nature, and its focus on symptom control and care coordination. PMID- 24474683 TI - Barriers to recruiting ethnic minorities to mental health research: a systematic review. AB - Disparities in the prevalence of mental illness are widely reported for people from ethnic minorities. Unlike the United States, there is no legislation for clinical research in the UK to mandate the inclusion of ethnic minorities and they are underrepresented in European trials compared with those conducted in the United States. This restricts generalization of research findings. This systematic review of the barriers to the recruitment of ethnic minority participants into psychiatric research is based on a comprehensive literature search. Nine included papers explore such barriers based on the authors' and participants' experiences of research. These barriers are mainly categorized as: participant related, practical issues, family/community related, health service related and research process issues. This review provides a compilation of important barriers to recruitment which can facilitate future research. The barriers that were identified are not all unique to participants from ethnic minorities, although the way in which they manifest themselves is often distinct in minority groups. It is important that these barriers are considered when designing research design so that solutions to overcome such obstacles can be incorporated in research protocols from the start and appropriate resources allocated. PMID- 24474684 TI - Vascularized tissue to reduce fistula following salvage total laryngectomy: a systematic review. AB - OBJECTIVES/HYPOTHESIS: Pharyngocutaneous fistulae (PCF) are known to occur in nearly one-third of patients after salvage total laryngectomy (STL). PCF has severe impact on duration of admission and costs and quality of life and can even cause severe complications such as bleeding, infection and death. Many patients need further surgical procedures. The implications for functional outcome and survival are less clear. Several studies have shown that using vascularized tissue from outside the radiation field reduces the risk of PCFs following STL. This review and meta-analysis aims to identify the evidence base to support this hypothesis. DATA SOURCES: English language literature from 2004 to 2013 REVIEW METHODS: We searched the English language literature for articles published on the subject from 2004 to 2013. RESULTS: Adequate data was available to identify pooled incidence rates from seven articles. The pooled relative risk derived from 591 patients was 0.63 (95% CI: 0.47 to 0.85), indicating that patients who have flap reconstruction/reinforcement reduced their risk of PCF by one-third. CONCLUSION: This pooled analysis suggests that there is a clear advantage in using vascularized tissue from outside the radiation field in the laryngectomy defect. While some studies show a clear reduction in PCF rates, others suggest that the fistulae that occur are smaller and rarely need repair. PMID- 24474685 TI - A small molecule inhibitor of monoubiquitinated Proliferating Cell Nuclear Antigen (PCNA) inhibits repair of interstrand DNA cross-link, enhances DNA double strand break, and sensitizes cancer cells to cisplatin. AB - Small molecule inhibitors of proliferating cell nuclear antigen (PCNA)/PCNA interacting protein box (PIP-Box) interactions, including T2 amino alcohol (T2AA), inhibit translesion DNA synthesis. The crystal structure of PCNA in complex with T2AA revealed that T2AA bound to the surface adjacent to the subunit interface of the homotrimer of PCNA in addition to the PIP-box binding cavity. Because this site is close to Lys-164, which is monoubiquitinated by RAD18, we postulated that T2AA would affect monoubiquitinated PCNA interactions. Binding of monoubiquitinated PCNA and a purified pol eta fragment containing the UBZ and PIP box was inhibited by T2AA in vitro. T2AA decreased PCNA/pol eta and PCNA/REV1 chromatin colocalization but did not inhibit PCNA monoubiquitination, suggesting that T2AA hinders interactions of pol eta and REV1 with monoubiquitinated PCNA. Interstrand DNA cross-links (ICLs) are repaired by mechanisms using translesion DNA synthesis that is regulated by monoubiquitinated PCNA. T2AA significantly delayed reactivation of a reporter plasmid containing an ICL. Neutral comet analysis of cells receiving T2AA in addition to cisplatin revealed that T2AA significantly enhanced formation of DNA double strand breaks (DSBs) by cisplatin. T2AA promoted colocalized foci formation of phospho-ATM and 53BP1 and up regulated phospho-BRCA1 in cisplatin-treated cells, suggesting that T2AA increases DSBs. When cells were treated by cisplatin and T2AA, their clonogenic survival was significantly less than that of those treated by cisplatin only. These findings show that the inhibitors of monoubiquitinated PCNA chemosensitize cells by inhibiting repair of ICLs and DSBs. PMID- 24474686 TI - Collapsin response mediator protein 2 (CRMP2) interacts with N-methyl-D-aspartate (NMDA) receptor and Na+/Ca2+ exchanger and regulates their functional activity. AB - Collapsin response mediator protein 2 (CRMP2) is traditionally viewed as an axonal growth protein involved in axon/dendrite specification. Here, we describe novel functions of CRMP2. A 15-amino acid peptide from CRMP2, fused to the TAT cell-penetrating motif of the HIV-1 protein, TAT-CBD3, but not CBD3 without TAT, attenuated N-methyl-d-aspartate receptor (NMDAR) activity and protected neurons against glutamate-induced Ca(2+) dysregulation, suggesting the key contribution of CRMP2 in these processes. In addition, TAT-CBD3, but not CBD3 without TAT or TAT-scramble peptide, inhibited increases in cytosolic Ca(2+) mediated by the plasmalemmal Na(+)/Ca(2+) exchanger (NCX) operating in the reverse mode. Co immunoprecipitation experiments revealed an interaction between CRMP2 and NMDAR as well as NCX3 but not NCX1. TAT-CBD3 disrupted CRMP2-NMDAR interaction without change in NMDAR localization. In contrast, TAT-CBD3 augmented the CRMP2-NCX3 co immunoprecipitation, indicating increased interaction or stabilization of a complex between these proteins. Immunostaining with an anti-NCX3 antibody revealed that TAT-CBD3 induced NCX3 internalization, suggesting that both reverse and forward modes of NCX might be affected. Indeed, the forward mode of NCX, evaluated in experiments with ionomycin-induced Ca(2+) influx into neurons, was strongly suppressed by TAT-CBD3. Knockdown of CRMP2 with short interfering RNA (siRNA) prevented NCX3 internalization in response to TAT-CBD3 exposure. Moreover, CRMP2 down-regulation strongly attenuated TAT-CBD3-induced inhibition of reverse NCX. Overall, our results demonstrate that CRMP2 interacts with NCX and NMDAR and that TAT-CBD3 protects against glutamate-induced Ca(2+) dysregulation most likely via suppression of both NMDAR and NCX activities. Our results further clarify the mechanism of action of TAT-CBD3 and identify a novel regulatory checkpoint for NMDAR and NCX function based on CRMP2 interaction with these proteins. PMID- 24474688 TI - Evidence of native alpha-synuclein conformers in the human brain. AB - alpha-Synuclein aggregation is central to the pathogenesis of several brain disorders. However, the native conformations and functions of this protein in the human brain are not precisely known. The native state of alpha-synuclein was probed by gel filtration coupled with native gradient gel separation, an array of antibodies with non-overlapping epitopes, and mass spectrometry. The existence of metastable conformers and stable monomer was revealed in the human brain. PMID- 24474687 TI - Low density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4): functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding. AB - Degradation of the cartilage proteoglycan aggrecan is an early event in the development of osteoarthritis, and a disintegrin and metalloproteinase with thrombospondin motifs-4 (ADAMTS-4) and ADAMTS-5 are considered to be the major aggrecan-degrading enzymes. We have recently found that ADAMTS-5 is rapidly endocytosed via low density lipoprotein receptor-related protein 1 (LRP1) and degraded by chondrocytes. Here we report that this regulatory mechanism also applies to ADAMTS-4, although its rate of endocytosis is slower than that of ADAMTS-5. Domain deletion mutagenesis of ADAMTS-4 identified that the cysteine rich and spacer domains are responsible for binding to LRP1, whereas the thrombospondin 1 and spacer domains are responsible in ADAMTS-5. The estimated t½ value of ADAMTS-4 endocytosis was about 220 min, whereas that of ADAMTS 5 was 100 min. The difference in half-lives between the two enzymes is explained by the 13-fold lower affinity of ADAMTS-4 for LRP1 compared with that of ADAMTS 5. Studies using soluble ligand binding clusters of LRP1 showed that ADAMTS-4 binds to clusters II and IV with similar KD,app values of 98 and 73 nm, respectively, whereas ADAMTS-5 binds to cluster II, III, and IV with KD,app values of 3.5, 41, and 9 nm, respectively. Thus, ADAMTS-5 competitively inhibits ADAMTS-4 endocytosis but not vice versa. This study highlights that the affinity between a ligand and LRP1 dictates the rate of internalization and suggests that LRP1 is a major traffic controller of the two aggrecanases, especially under inflammatory conditions, where the protein levels of ADAMTS-4 increase, but those of ADAMTS-5 do not. PMID- 24474689 TI - Alteration of mitochondrial proteome due to activation of Notch1 signaling pathway. AB - The Notch signaling pathway, a known regulator of cell fate decisions, proliferation, and apoptosis, has recently been implicated in the regulation of glycolysis, which affects tumor progression. However, the impact of Notch on other metabolic pathways remains to be elucidated. To gain more insights into the Notch signaling and its role in regulation of metabolism, we studied the mitochondrial proteome in Notch1-activated K562 cells using a comparative proteomics approach. The proteomic study led to the identification of 10 unique proteins that were altered due to Notch1 activation. Eight of these proteins belonged to mitochondria-localized metabolic pathways like oxidative phosphorylation, glutamine metabolism, Krebs cycle, and fatty acid oxidation. Validation of some of these findings showed that constitutive activation of Notch1 deregulated glutamine metabolism and Complex 1 of the respiratory chain. Furthermore, the deregulation of glutamine metabolism involved the canonical Notch signaling and its downstream effectors. The study also reports the effect of Notch signaling on mitochondrial function and status of high energy intermediates ATP, NADH, and NADPH. Thus our study shows the effect of Notch signaling on mitochondrial proteome, which in turn affects the functioning of key metabolic pathways, thereby connecting an important signaling pathway to the regulation of cellular metabolism. PMID- 24474690 TI - Novel ubiquitin-derived high affinity binding proteins with tumor targeting properties. AB - Targeting effector molecules to tumor cells is a promising mode of action for cancer therapy and diagnostics. Binding proteins with high affinity and specificity for a tumor target that carry effector molecules such as toxins, cytokines, or radiolabels to their intended site of action are required for these applications. In order to yield high tumor accumulation while maintaining low levels in healthy tissues and blood, the half-life of such conjugates needs to be in an optimal range. Scaffold-based binding molecules are small proteins with high affinity and short systemic circulation. Due to their low molecular complexity, they are well suited for combination with effector molecules as well as half-life extension technologies yielding therapeutics with half-lives adapted to the specific therapy. We have identified ubiquitin as an ideal scaffold protein due to its outstanding biophysical and biochemical properties. Based on a dimeric ubiquitin library, high affinity and specific binding molecules, so called Affilin(r) molecules, have been selected against the extradomain B of fibronectin, a target almost exclusively expressed in tumor tissues. Extradomain B-binding molecules feature high thermal and serum stability as well as strong in vitro target binding and in vivo tumor accumulation. Application of several half life extension technologies results in molecules of largely unaffected affinity but significantly prolonged in vivo half-life and tumor retention. Our results demonstrate the utility of ubiquitin as a scaffold for the generation of high affinity binders in a modular fashion, which can be combined with effector molecules and half-life extension technologies. PMID- 24474691 TI - Identification and characterization of an oocyte factor required for porcine nuclear reprogramming. AB - Nuclear reprogramming of somatic cells can be induced by oocyte factors. Despite numerous attempts, the factors responsible for successful nuclear reprogramming remain elusive. In the present study, we found that porcine oocytes with the first polar body collected at 42 h of in vitro maturation had a stronger ability to support early development of cloned embryos than porcine oocytes with the first polar body collected at 33 h of in vitro maturation. To explore the key reprogramming factors responsible for the difference, we compared proteome signatures of the two groups of oocytes. 18 differentially expressed proteins between these two groups of oocytes were discovered by mass spectrometry (MS). Among these proteins, we especially focused on vimentin (VIM). A certain amount of VIM protein was stored in oocytes and accumulated during oocyte maturation, and maternal VIM was specifically incorporated into transferred somatic nuclei during nuclear reprogramming. When maternal VIM function was inhibited by anti VIM antibody, the rate of cloned embryos developing to blastocysts was significantly lower than that of IgG antibody-injected embryos and non-injected embryos (12.24 versus 22.57 and 21.10%; p < 0.05), but the development of in vitro fertilization and parthenogenetic activation embryos was not affected. Furthermore, we found that DNA double strand breaks dramatically increased and that the p53 pathway was activated in cloned embryos when VIM function was inhibited. This study demonstrates that maternal VIM, as a genomic protector, is crucial for nuclear reprogramming in porcine cloned embryos. PMID- 24474692 TI - Signature motifs identify an Acinetobacter Cif virulence factor with epoxide hydrolase activity. AB - Endocytic recycling of the cystic fibrosis transmembrane conductance regulator (CFTR) is blocked by the CFTR inhibitory factor (Cif). Originally discovered in Pseudomonas aeruginosa, Cif is a secreted epoxide hydrolase that is transcriptionally regulated by CifR, an epoxide-sensitive repressor. In this report, we investigate a homologous protein found in strains of the emerging nosocomial pathogens Acinetobacter nosocomialis and Acinetobacter baumannii ("aCif"). Like Cif, aCif is an epoxide hydrolase that carries an N-terminal secretion signal and can be purified from culture supernatants. When applied directly to polarized airway epithelial cells, mature aCif triggers a reduction in CFTR abundance at the apical membrane. Biochemical and crystallographic studies reveal a dimeric assembly with a stereochemically conserved active site, confirming our motif-based identification of candidate Cif-like pathogenic EH sequences. Furthermore, cif expression is transcriptionally repressed by a CifR homolog ("aCifR") and is induced in the presence of epoxides. Overall, this Acinetobacter protein recapitulates the essential attributes of the Pseudomonas Cif system and thus may facilitate airway colonization in nosocomial lung infections. PMID- 24474693 TI - Heat shock protein 70 modulates influenza A virus polymerase activity. AB - The role of heat shock protein 70 (Hsp70) in virus replication has been discussed for many viruses. The known suppressive role of Hsp70 in influenza virus replication is based on studies conducted in cells with various Hsp70 expression levels. In this study, we determined the role of Hsp70 in influenza virus replication in HeLa and HEK293T cells, which express Hsp70 constitutively. Co immunoprecipitation and immunofluorescence studies revealed that Hsp70 interacted with PB2 or PB1 monomers and PB2/PB1 heterodimer but not with the PB1/PA heterodimer or PB2/PB1/PA heterotrimer and translocated into the nucleus with PB2 monomers or PB2/PB1 heterodimers. Knocking down Hsp70 resulted in reduced virus transcription and replication activities. Reporter gene assay, immunofluorescence assay, and Western blot analysis of nuclear and cytoplasmic fractions from infected cells demonstrated that the increase in viral polymerase activity during the heat shock phase was accompanied with an increase in Hsp70 and viral polymerases levels in the nuclei, where influenza virus replication takes place, whereas a reduction in viral polymerase activity was accompanied with an increase in cytoplasmic relocation of Hsp70 along with viral polymerases. Moreover, significantly higher levels of viral genomic RNA (vRNA) were observed during the heat shock phase than during the recovery phase. Overall, for the first time, these findings suggest that Hsp70 may act as a chaperone for influenza virus polymerase, and the modulatory effect of Hsp70 appears to be a sequel of shuttling of Hsp70 between nuclear and cytoplasmic compartments. PMID- 24474694 TI - An immunogenic peptide in the A-box of HMGB1 protein reverses apoptosis-induced tolerance through RAGE receptor. AB - Apoptotic cells trigger immune tolerance in engulfing phagocytes. This poorly understood process is believed to contribute to the severe immunosuppression and increased susceptibility to nosocomial infections observed in critically ill sepsis patients. Extracellular high mobility group box 1 (HMGB1) is an important mediator of both sepsis lethality and the induction of immune tolerance by apoptotic cells. We have found that HMGB1 is sensitive to processing by caspase 1, resulting in the production of a fragment within its N-terminal DNA-binding domain (the A-box) that signals through the receptor for advanced glycation end products (RAGE) to reverse apoptosis-induced tolerance. In a two-hit mouse model of sepsis, we show that tolerance to a secondary infection and its associated mortality were effectively reversed by active immunization with dendritic cells treated with HMGB1 or the A-box fragment, but not a noncleavable form of HMGB1. These findings represent a novel link between caspase-1 and HMGB1, with potential therapeutic implications in infectious and inflammatory diseases. PMID- 24474695 TI - Meprin metalloproteases inactivate interleukin 6. AB - Meprins have been implicated in the pathogenesis of several inflammatory diseases, including inflammatory bowel disease, in which the cytokine IL-6 is a prominent effector molecule. Because IL-6 levels are elevated markedly in meprin alpha and alpha/beta knockout mice in an experimental model of inflammatory bowel disease, the interaction between meprins and IL-6 was studied. The results demonstrate that rodent and human meprin A and B cleave IL-6 to a smaller product and, subsequently, are capable of extensive degradation of the cytokine. Analysis of the limited degradation product formed by meprin A indicated that three to five amino acids are removed from the C terminus of the cytokine. Meprin A and meprin B cleaved IL-6 with micromolar affinities (Km of 4.7 and 12.0 MUM, respectively) and with high efficiencies (kcat/Km of 0.2 and 2.5 (M(-1)/s(-1)) * 10(6), respectively). These efficiency constants are among the highest for known meprin substrates. Madin-Darby canine kidney cells transiently transfected with meprin alpha or meprin beta constructs also cleave exogenous IL-6. Both human and murine IL-6 cleaved by meprin A or B are inactivated, as demonstrated by their decreased capability to stimulate proliferation of B9 cells. These results are consistent with the proposition that one function of meprin metalloproteases is to modulate inflammation by inactivating IL-6. PMID- 24474697 TI - Near-IR absorbing nickel(II) porphyrinoids prepared by regioselective insertion of silylenes into antiaromatic nickel(II) norcorrole. AB - The treatment of an antiaromatic norcorrole Ni(II) complex with a kinetically stabilized silylene provided ring-expansion products in excellent yields through the highly regio- and stereoselective insertion into the beta-beta pyrrolic C?C bonds. The resultant Ni(II) porphyrinoid monoinsertion product exhibited relatively strong near-IR absorption bands due to the small HOMO-LUMO gap in spite of the disrupted cyclic pi-conjugation by the silicon atom. PMID- 24474696 TI - Ubiquibodies, synthetic E3 ubiquitin ligases endowed with unnatural substrate specificity for targeted protein silencing. AB - The ubiquitin-proteasome pathway (UPP) is the main route of protein degradation in eukaryotic cells and is a common mechanism through which numerous cellular pathways are regulated. To date, several reverse genetics techniques have been reported that harness the power of the UPP for selectively reducing the levels of otherwise stable proteins. However, each of these approaches has been narrowly developed for a single substrate and cannot be easily extended to other protein substrates of interest. To address this shortcoming, we created a generalizable protein knock-out method by engineering protein chimeras called "ubiquibodies" that combine the activity of E3 ubiquitin ligases with designer binding proteins to steer virtually any protein to the UPP for degradation. Specifically, we reprogrammed the substrate specificity of a modular human E3 ubiquitin ligase called CHIP (carboxyl terminus of Hsc70-interacting protein) by replacing its natural substrate-binding domain with a single-chain Fv (scFv) intrabody or a fibronectin type III domain monobody that target their respective antigens with high specificity and affinity. Engineered ubiquibodies reliably transferred ubiquitin to surface exposed lysines on target proteins and even catalyzed the formation of biologically relevant polyubiquitin chains. Following ectopic expression of ubiquibodies in mammalian cells, specific and systematic depletion of desired target proteins was achieved, whereas the levels of a natural substrate of CHIP were unaffected. Taken together, engineered ubiquibodies offer a simple, reproducible, and customizable means for directly removing specific cellular proteins through accelerated proteolysis. PMID- 24474698 TI - Fluorescence polarization for the evaluation of small-molecule inhibitors of PCAF BRD/Tat-AcK50 association. AB - A fluorescence polarization competitive assay was developed to efficiently screen and evaluate inhibitors of PCAF bromodomain/Tat-AcK50 protein-peptide interaction. A series of pyridine 1-oxide derivatives were synthesized and evaluated. Some of the novel compounds, 2-(3-aminopropylamino) pyridine 1-oxide derivatives, could be effective inhibitors of PCAF bromodomain/Tat-AcK50 association. Specifically, 2-(3-aminopropylamino)-5-(hydroxymethyl)pyridine 1 oxide hydrochloride (15) and the 5-((3-aminopropylamino)methyl) derivative (20) were found to be effective ligands for the PCAF BRD pocket. First preliminary cellular studies indicate that these small-molecule inhibitors have lower cytotoxicities and are potential leads for the anti-HIV/AIDS therapeutic strategy by targeting host-cell protein PCAF BRD to block HIV replication. PMID- 24474699 TI - Deletion of GABA-B receptor in Schwann cells regulates remak bundles and small nociceptive C-fibers. AB - The mechanisms regulating the differentiation into non-myelinating Schwann cells is not completely understood. Recent evidence indicates that GABA-B receptors may regulate myelination and nociception in the peripheral nervous system. GABA-B receptor total knock-out mice exhibit morphological and molecular changes in peripheral myelin. The number of small myelinated fibers is higher and associated with altered pain sensitivity. Herein, we analyzed whether these changes may be produced by a specific deletion of GABA-B receptors in Schwann cells. The conditional mice (P0-GABA-B1(fl/fl)) show a morphological phenotype characterized by a peculiar increase in the number of small unmyelinated fibers and Remak bundles, including nociceptive C-fibers. The P0-GABA-B1(fl/fl) mice are hyperalgesic and allodynic. In these mice, the morphological and behavioral changes are associated with a downregulation of neuregulin 1 expression in nerves. Our findings suggest that the altered pain sensitivity derives from a Schwann cell-specific loss of GABA-B receptor functions, pointing to a role for GABA-B receptors in the regulation of Schwann cell maturation towards the non myelinating phenotype. PMID- 24474700 TI - Tropical cyclone cooling combats region-wide coral bleaching. AB - Coral bleaching has become more frequent and widespread as a result of rising sea surface temperature (SST). During a regional scale SST anomaly, reef exposure to thermal stress is patchy in part due to physical factors that reduce SST to provide thermal refuge. Tropical cyclones (TCs - hurricanes, typhoons) can induce temperature drops at spatial scales comparable to that of the SST anomaly itself. Such cyclone cooling can mitigate bleaching across broad areas when well-timed and appropriately located, yet the spatial and temporal prevalence of this phenomenon has not been quantified. Here, satellite SST and historical TC data are used to reconstruct cool wakes (n=46) across the Caribbean during two active TC seasons (2005 and 2010) where high thermal stress was widespread. Upon comparison of these datasets with thermal stress data from Coral Reef Watch and published accounts of bleaching, it is evident that TC cooling reduced thermal stress at a region-wide scale. The results show that during a mass bleaching event, TC cooling reduced thermal stress below critical levels to potentially mitigate bleaching at some reefs, and interrupted natural warming cycles to slow the build-up of thermal stress at others. Furthermore, reconstructed TC wave damage zones suggest that it was rare for more reef area to be damaged by waves than was cooled (only 12% of TCs). Extending the time series back to 1985 (n = 314), we estimate that for the recent period of enhanced TC activity (1995-2010), the annual probability that cooling and thermal stress co-occur is as high as 31% at some reefs. Quantifying such probabilities across the other tropical regions where both coral reefs and TCs exist is vital for improving our understanding of how reef exposure to rising SSTs may vary, and contributes to a basis for targeting reef conservation. PMID- 24474701 TI - Chlorination of IPR C100 fullerene affords unconventional C96 Cl20 with a nonclassical cage containing three heptagons. AB - Chlorination of C100 fullerene with a mixture of VCl4 and SbCl5 afforded C96Cl20 with a strongly unconventional structure. In contrast to the classical fullerenes containing only hexagonal and pentagonal rings, the C96 cage contains three heptagonal rings and, therefore, should be classified as a fullerene with a nonclassical cage (NCC). There are several types of pentagon fusions in the C96 cage including pentagon pairs and pentagon triples. The three-step pathway from isolated-pentagon-rule (IPR) C100 to C96(NCC-3hp) includes two C2 losses, which create two cage heptagons, and one Stone-Wales rotation under formation of the third heptagon. Structural reconstruction established C100 isomer no. 18 from 450 topologically possible IPR isomers as the starting C100 fullerene. Until now, no pristine C100 isomers have been confirmed based on the experimental results. PMID- 24474702 TI - Teaching the teacher: an essential obligation. PMID- 24474703 TI - Structure-based design of novel human Toll-like receptor 8 agonists. AB - Toll-like receptor (TLR)-8 agonists activate adaptive immune responses by inducing robust production of T helper 1-polarizing cytokines, suggesting that TLR8-active compounds might be promising candidate vaccine adjuvants. Recently, a C2-butyl furo[2,3-c]quinoline was reported with purely TLR8 agonistic activity. This compound was successfully co-crystallized with the human TLR8 ectodomain, and the co-crystal structure revealed ligand-induced reorganization of the binding pocket of TLR8. The loss of a key hydrogen bond between the oxygen atom of the furanyl ring of the agonist and Thr 574 in TLR8 suggested that the furan ring is dispensable. Employing a disconnection strategy, 3- and 4-substituted aminoquinolines were investigated. Focused structure-based ligand design studies led to the identification of 3-pentyl-quinoline-2-amine as a novel, structurally simple, and highly potent human TLR8-specific agonist (EC50 =0.2 MUM). Preliminary evaluation of this compound in ex vivo human blood assay systems revealed that it retains prominent cytokine-inducing activity. Together, these results indicate the suitability of this compound as a novel vaccine adjuvant, warranting further investigation. PMID- 24474704 TI - Plasma CD147 reflects histological features in patients with lupus nephritis. AB - OBJECTIVE: A glycosylated transmembrane protein, CD147, has been implicated in regulating lymphocyte responsiveness and leukocyte recruitment. As lupus nephritis (LN) often follows a relapsing-remitting disease course, accurate understanding of the disease activity would be extremely helpful in improving prognosis. Unfortunately, neither clinical nor serological data can accurately reflect the histological features of LN. The present study investigated whether CD147 can accurately predict pathological features of LN. METHODS: Plasma and spot urine samples were collected from 64 patients who underwent renal biopsy between 2008 and 2011. Disease activity for LN tissues was evaluated using the biopsy activity index, and compared to levels of biomarkers including CD147. RESULTS: In LN tissues, CD147 induction was striking in injured glomeruli and infiltrating inflammatory cells, but not in damaged tubules representing atrophy. Plasma CD147 levels accurately reflected the histological disease activity. However, prediction using a single molecule would be quite difficult because of the complex pathogenesis of LN. The diagnostic accuracy of multiplex parameters indicated that the combination including plasma CD147 might yield excellent diagnostic abilities for guiding ideal LN therapy. CONCLUSION: Plasma CD147 levels might offer useful insights into disease activity as a crucial biomarker in patients with LN. PMID- 24474705 TI - Summary of the 9th meeting of the European Forum on Antiphospholipid Antibodies. AB - The 9th meeting of the European Forum on Antiphospholipid Antibodies (Euro aPL Forum) was held in Krakow, Poland, on 16-18 May 2013. This was an excellent occasion for the exchange of information on current research in the area of antiphospholipid syndrome (APS), as well as a starting point for many new research projects. About 120 physicians and researchers from various medical specialities representing 15 European countries, USA, Argentina and Israel attended the event. This report summarizes the major studies and new research projects presented during the Forum. PMID- 24474706 TI - Different expression patterns and clinical significance of mAxl and sAxl in systemic lupus erythematosus. AB - Axl is one of the TAM family members that downregulates activated immune responses to maintain immune homeostasis. We analyzed the expression and clinical relevance of Axl on the surface of CD14+ monocytes/macrophages (mAxl, membrane Axl) and in the plasma (sAxl, soluble Axl) from patients with systemic lupus erythematosus (SLE). Compared to healthy subjects, the concentrations of sAxl were significantly elevated in plasma from SLE patients, while the mAxl expression on CD14+ monocytes/macrophages from SLE patients was significantly downregulated. A series of severe disease clinical manifestations and laboratory features such as presence of autoantibodies, 24-hour proteinuria excretion or SLEDAI >=10 were associated with decreased mAxl expression on monocytes/macrophages but elevated sAxl levels in plasma. The plasma level of Gas6, the main ligand of Axl, was slightly decreased in SLE patients, and was negatively correlated with anti-dsDNA antibodies and C-reactive protein. SLE patients with SLEDAI >=10 showed significantly lower Gas6 levels. Our study suggests that abnormal mAxl and sAxl expression may be involved in the imbalance of immune regulation in SLE. PMID- 24474707 TI - Fasting during Ramadan: a religious factor as a possible trigger or exacerbator for eating disorders in adolescents. AB - Culture-based contributors play a role in eating disorders (EDs). Here, we present one such factor that may play a role in triggering ED's in adolescents: Fasting during the holy period of Ramadan. Ramadan is the Islamic month of fasting, in which participating Muslims refrain from eating, drinking, and smoking, which starts from dawn lasting until sunset. For the past 2 years, we have noticed an increase in patients with disordered eating patterns that have applied to Hacettepe University, Division of Adolescent Medicine during or shortly after Ramadan. We document six of these patients, three of which were diagnosed with an ED and three that did not meet full criteria. We argue that the possible effects of a drastic change in ones diet such as that which occurs during Ramadan, play an important role in triggering ED's in adolescents with a predisposition or may exacerbate an eating pathology. PMID- 24474708 TI - Functionalized MoS(2) nanosheet-based field-effect biosensor for label-free sensitive detection of cancer marker proteins in solution. AB - Label-free MoS(2) nanosheet-based field-effect biosensor detects cancer marker protein Prostate Specific Antigen in real time with high sensitivity and selectivity, exhibiting great potential in point-of-care diagnostics application. PMID- 24474709 TI - In response to Regional peak mucosal cooling predicts the perception of nasal patency. PMID- 24474710 TI - Synthesis of 5-hydroxymethylfurural from carbohydrates using large-pore mesoporous tin phosphate. AB - A large-pore mesoporous tin phosphate (LPSnP-1) material has been synthesized hydrothermally by using Pluronic P123 as the structure-directing agent. The material is composed of aggregated nanoparticles of 10-15 nm in diameter and has a BET surface area of 216 m(2) g(-1) with an average pore diameter of 10.4 nm. This pore diameter is twice as large as that of mesoporous tin phosphate materials synthesized through the surfactant-templating pathways reported previously. LPSnP-1 shows excellent catalytic activity for the conversion of fructose, glucose, sucrose, cellobiose, and cellulose to 5-hydroxymethylfurfural (HMF) in a water/methyl isobutyl ketone biphasic solvent to give maximum yields of HMF of 77, 50, 51, 39, and 32 mol %, respectively, under microwave-assisted heating at 423 K. Under comparable reaction conditions, LPSnP-1 gives 12 % more HMF yield than a small-pore mesoporous tin phosphate catalyst that has an identical framework composition. This confirms the beneficial role of large mesopores and nanoscale particle morphology in catalytic reactions that involve bulky natural carbohydrate molecules. PMID- 24474711 TI - Magnetic titanium dioxide nanocomposites for surface-enhanced resonance Raman spectroscopic determination and degradation of toxic anilines and phenols. AB - Mesoporous M-TiO2 NCs, functionalized by PATP, can capture toxic anilines and phenols by azo coupling. Loading these nanodevices with Ag NPs offers the possibility for a sensitive quantitative determination of target compounds by SERRS spectroscopy, which allows multiplex detection because of the specific vibrational fingerprints. Sensitivity and selectivity can be further enhanced by concentrating the hybrid particles by an external magnet and compound-specific binding (anilines versus phenols). The bound toxic compounds can be degraded by TiO2-assisted photocatalysis after removal of the loaded hybrid particles from the sample solution with an external magnet. The degradation process can be enhanced in the presence of plasmonic Ag nanostructures. PMID- 24474712 TI - A 200-fold quantum yield boost in the photoluminescence of silver-doped Ag(x)Au(25-x) nanoclusters: the 13th silver atom matters. AB - The rod-shaped Au25 nanocluster possesses a low photoluminescence quantum yield (QY=0.1%) and hence is not of practical use in bioimaging and related applications. Herein, we show that substituting silver atoms for gold in the 25 atom matrix can drastically enhance the photoluminescence. The obtained Ag(x)Au(25-x) (x=1-13) nanoclusters exhibit high quantum yield (QY=40.1%), which is in striking contrast with the normally weakly luminescent Ag(x)Au(25-x) species (x=1-12, QY=0.21%). X-ray crystallography further determines the substitution sites of Ag atoms in the Ag(x)Au(25-x) cluster through partial occupancy analysis, which provides further insight into the mechanism of photoluminescence enhancement. PMID- 24474713 TI - Head and neck cutaneous squamous cell carcinoma requiring parotidectomy: prognostic indicators and treatment selection. AB - OBJECTIVE: Evaluate characteristics and risk factors for patients with advanced cutaneous squamous cell carcinoma (cSCC). STUDY DESIGN: Retrospective case series. SETTING: Tertiary care center. PATIENTS AND METHODS: Chart review of patients with cSCC undergoing a parotidectomy (2003-2012). RESULTS: Of 218 patients identified, 49% presented with a new primary lesion (n = 107) and 51% with a recurrence (n = 111). Parotid lymph nodes were positive in 52% of patients; 81% had a concurrent neck dissection, and 28% had cervical lymph node metastases. In 18% of patients, both parotid and cervical nodes were positive, while 44% were both parotid and cervical node negative; 33% had positive parotid and negative cervical nodes, and only 5% had negative parotid and positive cervical nodes. The overall 2- and 5-year survival rates were 0.71 and 0.58. Overall 5-year survival was lower for patients presenting with recurrent (0.49) versus new primary disease (0.69; P = .04). In addition, decreased overall 5-year survival rates were associated with cervical lymph node involvement (0.47 vs. 0.62; P = .01). There was no difference in overall survival when stratified by parotid lymph node involvement (P = .85), margin status (P = .67), perineural invasion (P = .42), facial nerve sacrifice (P = .92), or type of parotid operation performed (P = .51). CONCLUSIONS: In this study, cervical, but not parotid, lymph node involvement was associated with poor outcomes in patients with advanced cSCC requiring a parotidectomy. In patients without evidence of cervical or parotid lymph node involvement, a neck dissection may be spared, given there is a 5% chance of occult disease. PMID- 24474714 TI - Effect of physician perspective on allocation of Medicare resources for patients with advanced cancer. AB - OBJECTIVES: To assess how physician perspective (perspective of patient vs perspective of physician) affects Medicare resource allocation for patients with advanced cancer and compare physician allocations with actual cancer patient and caregiver allocations. STUDY DESIGN: Cross-sectional assessment. SETTING: National assessment. SUBJECTS: Otolaryngologists. METHODS: Physicians used a validated tool to create a Medicare plan for patients with advanced cancer. Participants took the perspective of an advanced cancer patient and made resource allocations between 15 benefit categories (assessment 2, November/December 2012). Results were compared with data from a prior assessment made from a physician's perspective (assessment 1, February/March 2012) and with data from a separate study with patients with cancer and caregivers. RESULTS: In total, 767 physicians completed assessment 1 and 237 completed assessment 2. Results were compared with 146 cancer patient and 114 caregiver assessments. Assessment 1 physician responses differed significantly from patients/caregivers in 14 categories (P < .05), while assessment 2 differed in 11. When comparing physician data, assessment 2 allocations differed significantly from assessment 1 in 7 categories. When these 7 categories were compared with patient/caregiver data, assessment 2 allocations in emotional care, drug coverage, and nursing facility categories were not significantly different. Assessment 1 allocations in cosmetic care, dental, home care, and primary care categories were more similar to patient/caregiver preferences, although all but home care were still significantly different. CONCLUSIONS: Otolaryngology-head and neck surgery physician perspectives on end-of-life care differ significantly from cancer patient/caregiver perspectives, even when physicians take a patient's perspective when allocating resources. This demonstrates the challenges inherent in end-of life discussions. PMID- 24474715 TI - Unilateral degloving injury and partial fracture of the arytenoid cartilage. PMID- 24474716 TI - Vibrational spectroscopy of the dehydrogenated uracil radical by autodetachment of dipole-bound excited states of cold anions. AB - Molecules with large enough dipole moments can bind an electron by the dipole field, which has little effect on the molecular core. A molecular anion can be excited to a dipole-bound state, which can autodetach by vibronic coupling. Autodetachment spectroscopy of a complex anion cooled in a cryogenic ion trap is reported. Vibrational spectroscopy of the dehydrogenated uracil radical is obtained by a dipole-bound state with partial rotational resolution. Fundamental frequencies for 21 vibrational modes of the uracil radical are reported. The electron affinity of the uracil radical is measured accurately to be 3.4810+/ 0.0006 eV and the binding energy of the dipole-bound state is measured to be 146+/-5 cm(-1). The rotational temperature of the trapped uracil anion is evaluated to be 35 K. PMID- 24474717 TI - Zinc deficiency in a parenteral nutrition-dependent patient during a parenteral trace element product shortage. AB - Parenteral nutrition product shortages are common and place vulnerable patients at risk for nutrient deficiencies. This case report describes a parenteral nutrition-dependent patient who was found to have zinc deficiency during a parenteral nutrition product shortage. The management of the patient's zinc deficiency is described. PMID- 24474718 TI - Silver supported on titania as an active catalyst for electrochemical carbon dioxide reduction. AB - Although significant research efforts have focused on the exploration of catalysts for the electrochemical reduction of CO2 , considerably fewer reports have described how support materials for these catalysts affect their performance, which includes their ability to reduce the overpotential, and/or to increase the catalyst utilization and selectivity. Here Ag nanoparticles supported on carbon black (Ag/C) and on titanium dioxide (Ag/TiO2 ) were synthesized. In a flow reactor, 40 wt % Ag/TiO2 exhibited a twofold higher current density for CO production than 40 wt % Ag/C. Faradaic efficiencies of the 40 wt % Ag/TiO2 catalyst exceeded 90 % with a partial current density for CO of 101 mA cm(-2) ; similar to the performance of unsupported Ag nanoparticle catalysts (AgNP) but at a 2.5 times lower Ag loading. A mass activity as high as 2700 mA mgAg (-1) cm(-2) was achieved. In cyclic voltammetry tests in a three electrode cell, Ag/TiO2 exhibited a lower overpotential for CO2 reduction than AgNP, which, together with other data, suggests that TiO2 stabilizes the intermediate and serves as redox electron carrier to assist CO2 reduction while Ag assists in the formation of the final product, CO. PMID- 24474719 TI - Identification and biosynthesis of new acyloins from the thermophilic bacterium Thermosporothrix hazakensis SK20-1(T). AB - Two new acyloin compounds were isolated from the thermophilic bacterium Thermosporothrix hazakensis SK20-1(T) . Genome sequencing of the bacterium and biochemical studies identified the thiamine diphosphate (TPP)-dependent enzyme Thzk0150, which is involved in the formation of acyloin. Through extensive analysis of the Thzk0150-catalyzed reaction products, we propose a putative reaction mechanism involving two substrates: 4-methyl-2-oxovalerate as an acyl donor and phenyl pyruvate as an acyl acceptor. PMID- 24474720 TI - Three-dimensional graphitized carbon nanovesicles for high-performance supercapacitors based on ionic liquids. AB - Three-dimensional nanoporous carbon with interconnected vesicle-like pores (1.5 4.2 nm) has been prepared through a low-cost, template-free approach from petroleum coke precursor by KOH activation. It is found that the thin pore walls are highly graphitized and consist of only three to four layers of graphene, which endows the material with an unusually high specific surface area (2933 m(2) g(-1) ) and good conductivity. With such unique structural characteristics, if used as supercapacitor electrodes in ionic liquid (IL) electrolytes, the graphitized carbon nanovesicle (GCNV) material displays superior performance, such as high energy densities up to 145.9 Wh kg(-1) and a high combined energy power delivery, and an energy density of 97.6 Wh kg(-1) can be charged in 47 s at 60 degrees C. This demonstrates that the energy output of the GCNV-based supercapacitors is comparable to that of batteries, and the power output is one order of magnitude higher. Moreover, the synergistic effect of the GCNVs and the IL electrolyte on the extraordinary performance of the GCNV supercapacitors has been analyzed and discussed. PMID- 24474721 TI - Predictors of recurrence of great saphenous vein reflux following treatment with ultrasound-guided foamsclerotherapy. AB - OBJECTIVE: To investigate which clinical characteristics at baseline are predictive for great saphenous vein recurrence following ultrasound-guided foamsclerotherapy. MATERIAL AND METHODS: Data of patients treated for great saphenous vein incompetence with ultrasound-guided foamsclerotherapy were derived from a multicentre prospective randomized controlled trial comparing surgery versus ultrasound-guided foamsclerotherapy with a follow-up of two years. Recurrence of reflux was determined on colour duplex scans at three months, one year and two years. Univariate and multivariate Cox regression analysis was used to evaluate the effect of gender, age, C of CEAP classification, diameter of great saphenous vein, injected foam volume, presence of distal great saphenous vein reflux, presence of reflux in the anterior accessory saphenous vein and Venous Clinical Severity Score on risk of recurrent reflux. RESULTS: Two hundred twenty-five patients were available for analysis. Treatment after one single session was successful in 120 patients and recurrence of saphenous reflux was observed in 105 patients within two years during follow-up. Significant associations with risk of recurrence were observed for mid thigh great saphenous vein diameter (HR = 1.012 with 95% CI: 1.002-1.022, p = 0.022) and presence of distal great saphenous vein reflux (HR = 1.882 with 95% CI: 1.029-3.443, p = 0.040). CONCLUSION: In conclusion, this prospective study suggests that ultrasound-guided foamsclerotherapy treatment for the proximal great saphenous vein is less effective for patients with a large vein and a refluxing distal great saphenous vein at baseline. PMID- 24474722 TI - Preferential tendon stem cell response to growth factor supplementation. AB - Tendon injuries are increasingly prevalent around the world, accounting for more than 100 000 new clinical cases/year in the USA alone. Cell-based therapies have been proposed as a therapeutic strategy, with recent data advocating the use of tendon stem cells (TSCs) as a potential cell source with clinical relevance for tendon regeneration. However, their in vitro expansion is problematic, as they lose their multipotency and change their protein expression profile in culture. Herein, we ventured to assess the influence of insulin-like growth factor 1 (IGF 1), growth and differentiation factor-5 (GDF-5) and transforming growth factor beta1 (TGFbeta1) supplementation in TSC culture. IGF-1 preserved multipotency for up to 28 days. Upregulation of decorin and scleraxis expression was observed as compared to freshly isolated cells. GDF-5 treated cells exhibited reduced differentiation along adipogenic and chondrogenic pathways after 28 days, and decorin, scleraxis and collagen type I expression was increased. After 28 days, TGFbeta1 supplementation led to increased scleraxis, osteonectin and collagen type II expression. The varied responses to each growth factor may reflect their role in tendon repair, suggesting that: GDF-5 promotes the transition of tendon stem cells towards tenocytes; TGFbeta1 induces differentiation along several pathways, including a phenotype indicative of fibrocartilage or calcified tendon, common problems in tendon healing; and IGF-1 promotes proliferation and maintenance of TSC phenotypes, thereby creating a population sufficient to have a beneficial effect. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24474724 TI - The ontogeny of the motivation that underlies in-group bias. AB - Humans demonstrate a clear bias toward members of their own group over members of other groups in a variety of ways. It has been argued that the motivation underlying this in-group bias in adults may be favoritism toward one's own group (in-group love), derogation of the out-group (out-group hate), or both. Although some studies have demonstrated in-group bias among children and infants, nothing is known about the underlying motivations of this bias. Using a novel game, we found that in-group love is already present in children of preschool age and can motivate in-group-biased behavior across childhood. In contrast, out-group hate develops only after a child's sixth birthday and is a sufficient motivation for in-group-biased behavior from school age onward. These results help to better identify the motivation that underlies in-group-biased behavior in children. PMID- 24474725 TI - Nonaccidental properties underlie human categorization of complex natural scenes. AB - Humans can categorize complex natural scenes quickly and accurately. Which scene properties enable people to do this with such apparent ease? We extracted structural properties of contours (orientation, length, curvature) and contour junctions (types and angles) from line drawings of natural scenes. All of these properties contain information about scene categories that can be exploited computationally. However, when we compared error patterns from computational scene categorization with those from a six-alternative forced-choice scene categorization experiment, we found that only junctions and curvature made significant contributions to human behavior. To further test the critical role of these properties, we perturbed junctions in line drawings by randomly shifting contours and found a significant decrease in human categorization accuracy. We conclude that scene categorization by humans relies on curvature as well as the same nonaccidental junction properties used for object recognition. These properties correspond to the visual features represented in area V2. PMID- 24474726 TI - The cerebral cortex of the pygmy hippopotamus, Hexaprotodon liberiensis (Cetartiodactyla, Hippopotamidae): MRI, cytoarchitecture, and neuronal morphology. AB - The structure of the hippopotamus brain is virtually unknown because few studies have examined more than its external morphology. In view of their semiaquatic lifestyle and phylogenetic relatedness to cetaceans, the brain of hippopotamuses represents a unique opportunity for better understanding the selective pressures that have shaped the organization of the brain during the evolutionary process of adaptation to an aquatic environment. Here we examined the histology of the cerebral cortex of the pygmy hippopotamus (Hexaprotodon liberiensis) by means of Nissl, Golgi, and calretinin (CR) immunostaining, and provide a magnetic resonance imaging (MRI) structural and volumetric dataset of the anatomy of its brain. We calculated the corpus callosum area/brain mass ratio (CCA/BM), the gyrencephalic index (GI), the cerebellar quotient (CQ), and the cerebellar index (CI). Results indicate that the cortex of H. liberiensis shares one feature exclusively with cetaceans (the lack of layer IV across the entire cerebral cortex), other features exclusively with artiodactyls (e.g., the morphologiy of CR-immunoreactive multipolar neurons in deep cortical layers, gyrencephalic index values, hippocampus and cerebellum volumetrics), and others with at least some species of cetartiodactyls (e.g., the presence of a thick layer I, the pattern of distribution of CR-immunoreactive neurons, the presence of von Economo neurons, clustering of layer II in the occipital cortex). The present study thus provides a comprehensive dataset of the neuroanatomy of H. liberiensis that sets the ground for future comparative studies including the larger Hippopotamus amphibius. PMID- 24474727 TI - The role of thyroid fine-needle aspiration cytology in the pediatric population: an institutional experience. AB - BACKGROUND: The current study was conducted to investigate the role of thyroid fine-needle aspiration cytology (FNAC) in the authors' pediatric series. Thyroid pediatric FNAC has been reported to have conflicting sensitivity and specificity in different series. The authors evaluated their thyroid cytological series mainly for the categories of 1) follicular/indeterminate neoplasms with atypical cells of indeterminate significance (FN/AUS) and 2) suspicious for malignancy (SM). In this setting, the application of immunocytochemistry (ICC) is likely to allow a correct diagnosis. METHODS: A total of 64 of 247 pediatric FNACs (26%) that were processed with liquid-based cytology had surgical follow-up. An ICC panel (Hector Battifora mesothelial cell-1 [HBME-1] and galectin-3) was performed on liquid-based cytology. A positive immunopanel was defined by a concordant positivity. RESULTS: These 64 cases were cytologically diagnosed as 4 cases of cystic hemorrhagic lesions, 23 benign lesions (BL), 17 FN/AUS cases, 11 SM cases, and 9 positive for malignancy (PM) cases. All PM and BL cases were histologically confirmed. The rate of malignancy was 31.2%, including 1 case of follicular carcinoma, 9 cases of classic papillary thyroid carcinomas (PTC), and 10 PTC variants (7 follicular variant of PTC, 1 macrofollicular variant, and 2 sclerosing diffuse variants). The immunopanel was performed on the categories of FN/AUS, SM, and PM. The data highlighted a concordant positive ICC in 87% of malignancies and a concordant negative ICC in 100% of benign follicular adenomas. CONCLUSIONS: Thyroid FNAC represents a valuable/feasible tool in childhood. The higher incidence of histological malignancies justifies the cytological application of ancillary techniques (ie, ICC or molecular panels), thereby enabling a more adequate surgical selection based on the effective distinction of high-risk and low-risk lesions mainly for the categories of FN/AUS and SM. PMID- 24474730 TI - Increased serum creatine kinase. PMID- 24474731 TI - Commentary. PMID- 24474732 TI - Commentary. PMID- 24474733 TI - Glow stick or urine sample? PMID- 24474734 TI - Learning from Siddhartha. PMID- 24474735 TI - A different body: diagnostic imaging and body art. PMID- 24474736 TI - The role of canalicular ABC transporters in cholestasis. AB - Cholestasis, a hallmark feature of hepatobiliary disease, is characterized by the retention of biliary constituents. Some of these constituents, such as bile acids, inflict damage to hepatocytes and bile duct cells. This damage may lead to inflammation, fibrosis, cirrhosis, and eventually carcinogenesis, sequelae that aggravate the underlying disease and deteriorate clinical outcome. Canalicular ATP-binding cassette (ABC) transporters, which mediate the excretion of individual bile constituents, play a key role in bile formation and cholestasis. The study of these transporters and their regulatory nuclear receptors has revolutionized our understanding of cholestatic disease. This knowledge has served as a template to develop novel treatment strategies, some of which are currently already undergoing phase III clinical trials. In this review we aim to provide an overview of the structure, function, and regulation of canalicular ABC transporters. In addition, we will focus on the role of these transporters in the pathogenesis and treatment of cholestatic bile duct and liver diseases. PMID- 24474737 TI - Fifteen minutes consultation: a structured approach to the child with a white red reflex. PMID- 24474738 TI - Recommendations for organization of care for adults with congenital heart disease and for training in the subspecialty of 'Grown-up Congenital Heart Disease' in Europe: a position paper of the Working Group on Grown-up Congenital Heart Disease of the European Society of Cardiology. PMID- 24474740 TI - Food intake regulating hormones in adult craniopharyngioma patients. AB - INTRODUCTION: Patients with craniopharyngioma (CP) have disturbances of the hypothalamic-pituitary axis and serious comorbidities such as obesity. We hypothesized that the secretion of hormones regulating the nutritional status is altered in adult patients with CP compared with patients with non-functioning pituitary adenoma (NFPA). METHODS: WE INCLUDED 40 CP (50% MALES, MEAN AGE: 49.6+/ 14.3 years) and 40 NFPA (72.5% males, mean age: 63.4+/-9.8 years) patients. We measured glucose, insulin, leptin, total ghrelin, peptide-YY (PYY) and cholecystokinin (CCK) during oral glucose tolerance test (OGTT). Fat mass (FM) was determined by dual X-ray absorptiometry. RESULTS: Gender distribution was not significantly different, but CP patients were significantly younger (P<0.001). CP patients had significantly higher BMI and FM than NFPA patients (BMI 32+/-8 vs 28+/-4 kg/m(2), P=0.009 and FM 37+/-9 vs 33+/-9%, P=0.02). Fasting glucose level (84+/-12 vs 78+/-11 mg/dl, P=0.03), leptin (27.9+/-34.2 vs 11.9+/-11.6 MUg/l, P=0.008) and leptin levels corrected for percentage FM (0.66+/-0.67 vs 0.32+/ 0.25 MUg/l%, P=0.005) were significantly higher in CP than in NFPA patients, whereas ghrelin was significantly lower (131+/-129 vs 191+/-119 ng/l, P=0.035). Insulin, PYY and CCK did not differ significantly between groups. After glucose load, leptin decreased significantly in CP patients (P=0.019). In both groups, ghrelin decreased significantly during OGTT (both P<0.001). The percentage decline was significantly smaller for CP. PYY and CCK increased equally after glucose in both groups. CONCLUSION: Our patients with CP have more metabolic complications than our patients with NFPA. The levels of leptin and ghrelin at fasting status and after glucose seem to be altered in CP, whereas changes in insulin, PYY and CCK do not seem to be responsible for the metabolic changes in these patients. PMID- 24474741 TI - Mathematics in poetry. PMID- 24474739 TI - Mendelian randomization of blood lipids for coronary heart disease. AB - AIMS: To investigate the causal role of high-density lipoprotein cholesterol (HDL C) and triglycerides in coronary heart disease (CHD) using multiple instrumental variables for Mendelian randomization. METHODS AND RESULTS: We developed weighted allele scores based on single nucleotide polymorphisms (SNPs) with established associations with HDL-C, triglycerides, and low-density lipoprotein cholesterol (LDL-C). For each trait, we constructed two scores. The first was unrestricted, including all independent SNPs associated with the lipid trait identified from a prior meta-analysis (threshold P < 2 * 10(-6)); and the second a restricted score, filtered to remove any SNPs also associated with either of the other two lipid traits at P <= 0.01. Mendelian randomization meta-analyses were conducted in 17 studies including 62,199 participants and 12,099 CHD events. Both the unrestricted and restricted allele scores for LDL-C (42 and 19 SNPs, respectively) associated with CHD. For HDL-C, the unrestricted allele score (48 SNPs) was associated with CHD (OR: 0.53; 95% CI: 0.40, 0.70), per 1 mmol/L higher HDL-C, but neither the restricted allele score (19 SNPs; OR: 0.91; 95% CI: 0.42, 1.98) nor the unrestricted HDL-C allele score adjusted for triglycerides, LDL-C, or statin use (OR: 0.81; 95% CI: 0.44, 1.46) showed a robust association. For triglycerides, the unrestricted allele score (67 SNPs) and the restricted allele score (27 SNPs) were both associated with CHD (OR: 1.62; 95% CI: 1.24, 2.11 and 1.61; 95% CI: 1.00, 2.59, respectively) per 1-log unit increment. However, the unrestricted triglyceride score adjusted for HDL-C, LDL-C, and statin use gave an OR for CHD of 1.01 (95% CI: 0.59, 1.75). CONCLUSION: The genetic findings support a causal effect of triglycerides on CHD risk, but a causal role for HDL-C, though possible, remains less certain. PMID- 24474744 TI - Ranking and combining multiple predictors without labeled data. AB - In a broad range of classification and decision-making problems, one is given the advice or predictions of several classifiers, of unknown reliability, over multiple questions or queries. This scenario is different from the standard supervised setting, where each classifier's accuracy can be assessed using available labeled data, and raises two questions: Given only the predictions of several classifiers over a large set of unlabeled test data, is it possible to (i) reliably rank them and (ii) construct a metaclassifier more accurate than most classifiers in the ensemble? Here we present a spectral approach to address these questions. First, assuming conditional independence between classifiers, we show that the off-diagonal entries of their covariance matrix correspond to a rank-one matrix. Moreover, the classifiers can be ranked using the leading eigenvector of this covariance matrix, because its entries are proportional to their balanced accuracies. Second, via a linear approximation to the maximum likelihood estimator, we derive the Spectral Meta-Learner (SML), an unsupervised ensemble classifier whose weights are equal to these eigenvector entries. On both simulated and real data, SML typically achieves a higher accuracy than most classifiers in the ensemble and can provide a better starting point than majority voting for estimating the maximum likelihood solution. Furthermore, SML is robust to the presence of small malicious groups of classifiers designed to veer the ensemble prediction away from the (unknown) ground truth. PMID- 24474743 TI - Evolution of microbial markets. AB - Biological market theory has been used successfully to explain cooperative behavior in many animal species. Microbes also engage in cooperative behaviors, both with hosts and other microbes, that can be described in economic terms. However, a market approach is not traditionally used to analyze these interactions. Here, we extend the biological market framework to ask whether this theory is of use to evolutionary biologists studying microbes. We consider six economic strategies used by microbes to optimize their success in markets. We argue that an economic market framework is a useful tool to generate specific and interesting predictions about microbial interactions, including the evolution of partner discrimination, hoarding strategies, specialized versus diversified mutualistic services, and the role of spatial structures, such as flocks and consortia. There is untapped potential for studying the evolutionary dynamics of microbial systems. Market theory can help structure this potential by characterizing strategic investment of microbes across a diversity of conditions. PMID- 24474745 TI - Sub-10-nm intracellular bioelectronic probes from nanowire-nanotube heterostructures. AB - The miniaturization of bioelectronic intracellular probes with a wide dynamic frequency range can open up opportunities to study biological structures inaccessible by existing methods in a minimally invasive manner. Here, we report the design, fabrication, and demonstration of intracellular bioelectronic devices with probe sizes less than 10 nm. The devices are based on a nanowire-nanotube heterostructure in which a nanowire field-effect transistor detector is synthetically integrated with a nanotube cellular probe. Sub-10-nm nanotube probes were realized by a two-step selective etching approach that reduces the diameter of the nanotube free-end while maintaining a larger diameter at the nanowire detector necessary for mechanical strength and electrical sensitivity. Quasi-static water-gate measurements demonstrated selective device response to solution inside the nanotube, and pulsed measurements together with numerical simulations confirmed the capability to record fast electrophysiological signals. Systematic studies of the probe bandwidth in different ionic concentration solutions revealed the underlying mechanism governing the time response. In addition, the bandwidth effect of phospholipid coatings, which are important for intracellular recording, was investigated and modeled. The robustness of these sub-10-nm bioelectronics probes for intracellular interrogation was verified by optical imaging and recording the transmembrane resting potential of HL-1 cells. These ultrasmall bioelectronic probes enable direct detection of cellular electrical activity with highest spatial resolution achieved to date, and with further integration into larger chip arrays could provide a unique platform for ultra-high-resolution mapping of activity in neural networks and other systems. PMID- 24474746 TI - Living liquid crystals. AB - Collective motion of self-propelled organisms or synthetic particles, often termed "active fluid," has attracted enormous attention in the broad scientific community because of its fundamentally nonequilibrium nature. Energy input and interactions among the moving units and the medium lead to complex dynamics. Here, we introduce a class of active matter--living liquid crystals (LLCs)--that combines living swimming bacteria with a lyotropic liquid crystal. The physical properties of LLCs can be controlled by the amount of oxygen available to bacteria, by concentration of ingredients, or by temperature. Our studies reveal a wealth of intriguing dynamic phenomena, caused by the coupling between the activity-triggered flow and long-range orientational order of the medium. Among these are (i) nonlinear trajectories of bacterial motion guided by nonuniform director, (ii) local melting of the liquid crystal caused by the bacteria produced shear flows, (iii) activity-triggered transition from a nonflowing uniform state into a flowing one-dimensional periodic pattern and its evolution into a turbulent array of topological defects, and (iv) birefringence-enabled visualization of microflow generated by the nanometers-thick bacterial flagella. Unlike their isotropic counterpart, the LLCs show collective dynamic effects at very low volume fraction of bacteria, on the order of 0.2%. Our work suggests an unorthodox design concept to control and manipulate the dynamic behavior of soft active matter and opens the door for potential biosensing and biomedical applications. PMID- 24474747 TI - Hierarchical self-assembly of a striped gyroid formed by threaded chiral mesoscale networks. AB - Numerical simulations reveal a family of hierarchical and chiral multicontinuous network structures self-assembled from a melt blend of Y-shaped ABC and ABD three miktoarm star terpolymers, constrained to have equal-sized A/B and C/D chains, respectively. The C and D majority domains within these patterns form a pair of chiral enantiomeric gyroid labyrinths (srs nets) over a broad range of compositions. The minority A and B components together define a hyperbolic film whose midsurface follows the gyroid minimal surface. A second level of assembly is found within the film, with the minority components also forming labyrinthine domains whose geometry and topology changes systematically as a function of composition. These smaller labyrinths are well described by a family of patterns that tile the hyperbolic plane by regular degree-three trees mapped onto the gyroid. The labyrinths within the gyroid film are densely packed and contain either graphitic hcb nets (chicken wire) or srs nets, forming convoluted intergrowths of multiple nets. Furthermore, each net is ideally a single chiral enantiomer, induced by the gyroid architecture. However, the numerical simulations result in defect-ridden achiral patterns, containing domains of either hand, due to the achiral terpolymeric starting molecules. These mesostructures are among the most topologically complex morphologies identified to date and represent an example of hierarchical ordering within a hyperbolic pattern, a unique mode of soft-matter self-assembly. PMID- 24474748 TI - Site-specific targeting of enterovirus capsid by functionalized monodisperse gold nanoclusters. AB - Development of precise protocols for accurate site-specific conjugation of monodisperse inorganic nanoparticles to biological material is one of the challenges in contemporary bionanoscience and nanomedicine. We report here a successful site-specific covalent conjugation of functionalized atomically monodisperse gold clusters with 1.5-nm metal cores to viral surfaces. Water soluble Au102(para-mercaptobenzoic acid)44 clusters, functionalized by maleimide linkers to target cysteines of viral capsid proteins, were synthesized and conjugated to enteroviruses echovirus 1 and coxsackievirus B3. Quantitative analysis of transmission electron microscopy images and the known virus structures showed high affinity and mutual ordering of the bound gold clusters on the viral surface and a clear correlation between the clusters and the targeted cysteine sites close to the viral surface. Infectivity of the viruses was not compromised by loading of several tens of gold clusters per virus. These advances allow for future investigations of the structure-function relations of enteroviruses and enterovirus-related virus-like particles, including their entry mechanisms into cells and uncoating in cellular endosomes. PMID- 24474749 TI - Voltage tuning of vibrational mode energies in single-molecule junctions. AB - Vibrational modes of molecules are fundamental properties determined by intramolecular bonding, atomic masses, and molecular geometry, and often serve as important channels for dissipation in nanoscale processes. Although single molecule junctions have been used to manipulate electronic structure and related functional properties of molecules, electrical control of vibrational mode energies has remained elusive. Here we use simultaneous transport and surface enhanced Raman spectroscopy measurements to demonstrate large, reversible, voltage-driven shifts of vibrational mode energies of C60 molecules in gold junctions. C60 mode energies are found to vary approximately quadratically with bias, but in a manner inconsistent with a simple vibrational Stark effect. Our theoretical model instead suggests that the mode shifts are a signature of bias driven addition of electronic charge to the molecule. These results imply that voltage-controlled tuning of vibrational modes is a general phenomenon at metal molecule interfaces and is a means of achieving significant shifts in vibrational energies relative to a pure Stark effect. PMID- 24474750 TI - Efficient and directed peptide bond formation in the gas phase via ion/ion reactions. AB - Amide linkages are among the most important chemical bonds in living systems, constituting the connections between amino acids in peptides and proteins. We demonstrate the controlled formation of amide bonds between amino acids or peptides in the gas phase using ion/ion reactions in a mass spectrometer. Individual amino acids or peptides can be prepared as reagents by (i) incorporating gas phase-labile protecting groups to silence otherwise reactive functional groups, such as the N terminus; (ii) converting the carboxyl groups to the active ester of N-hydroxysuccinimide; and (iii) incorporating a charge site. Protonation renders basic sites (nucleophiles) unreactive toward the N hydroxysuccinimide ester reagents, resulting in sites with the greatest gas phase basicities being, in large part, unreactive. The N-terminal amines of most naturally occurring amino acids have lower gas phase basicities than the side chains of the basic amino acids (i.e., those of histidine, lysine, or arginine). Therefore, reagents may be directed to the N terminus of an existing "anchor" peptide to form an amide bond by protonating the anchor peptide's basic residues, while leaving the N-terminal amine unprotonated and therefore reactive. Reaction efficiencies of greater than 30% have been observed. We propose this method as a step toward the controlled synthesis of peptides in the gas phase. PMID- 24474751 TI - In situ sum-frequency vibrational spectroscopy of electrochemical interfaces with surface plasmon resonance. AB - Electrochemical (EC) reactions are crucial in many applications, yet most EC analytical tools lack the sensitivity to access molecular-level information of reactants and products. By combining sum-frequency vibrational spectroscopy and surface plasmon resonance at EC interfaces, we demonstrate the feasibility of measuring in situ and real-time vibrational spectra during EC reactions at noble metal electrodes. Application of the technique to EC reactions at a gold surface helps in understanding how the surface in a basic solution is oxidized and reduced during a cyclic voltammetry cycle. Study of desorption of a thiol self assembled monolayer from gold through EC reactions in a basic solution shows that the desorbed thiols by reductive reaction remain as an ordered layer near the gold interface, but do diffuse away if they are desorbed oxidatively from gold. PMID- 24474752 TI - Timing of cyber conflict. AB - Nations are accumulating cyber resources in the form of stockpiles of zero-day exploits as well as other novel methods of engaging in future cyber conflict against selected targets. This paper analyzes the optimal timing for the use of such cyber resources. A simple mathematical model is offered to clarify how the timing of such a choice can depend on the stakes involved in the present situation, as well as the characteristics of the resource for exploitation. The model deals with the question of when the resource should be used given that its use today may well prevent it from being available for use later. The analysis provides concepts, theory, applications, and distinctions to promote the understanding strategy aspects of cyber conflict. Case studies include the Stuxnet attack on Iran's nuclear program, the Iranian cyber attack on the energy firm Saudi Aramco, the persistent cyber espionage carried out by the Chinese military, and an analogous case of economic coercion by China in a dispute with Japan. The effects of the rapidly expanding market for zero-day exploits are also analyzed. The goal of the paper is to promote the understanding of this domain of cyber conflict to mitigate the harm it can do, and harness the capabilities it can provide. PMID- 24474753 TI - Weighing nanoparticles in solution at the attogram scale. AB - Physical characterization of nanoparticles is required for a wide range of applications. Nanomechanical resonators can quantify the mass of individual particles with detection limits down to a single atom in vacuum. However, applications are limited because performance is severely degraded in solution. Suspended micro- and nanochannel resonators have opened up the possibility of achieving vacuum-level precision for samples in the aqueous environment and a noise equivalent mass resolution of 27 attograms in 1-kHz bandwidth was previously achieved by Lee et al. [(2010) Nano Lett 10(7):2537-2542]. Here, we report on a series of advancements that have improved the resolution by more than 30-fold, to 0.85 attograms in the same bandwidth, approaching the thermomechanical noise limit and enabling precise quantification of particles down to 10 nm with a throughput of more than 18,000 particles per hour. We demonstrate the potential of this capability by comparing the mass distributions of exosomes produced by different cell types and by characterizing the yield of self-assembled DNA nanoparticle structures. PMID- 24474755 TI - Evaluative and hedonic wellbeing among those with and without children at home. AB - We document and interpret differences in life evaluation and in hedonic experience between those who live with children and those who do not; most previous literature has concluded that those with children have worse lives. For a sample of 1.8 million Americans of all ages, and without controls for other circumstances, we find little difference in subjective wellbeing between people with and without children. Among those most likely to be parents, life evaluation and all hedonic experiences except stress are markedly better among those living with a child. However, within this group, people who live with children are more likely to be married, richer, better educated, more religious, and healthier, all of which have well-documented positive associations with evaluative and hedonic wellbeing. With statistical controls for these background factors, the presence of a child has a small negative association with life evaluation, although it is associated with more of both positive and negative hedonics. These patterns are replicated in the English-speaking countries of the world, but not in other regions. We argue that the causal effect of children on parental wellbeing, which is the target for most of the literature, is not well defined. Instead, we interpret our rich-country results within a theory of children and wellbeing in which adults sort into parenthood according to their preferences. In poor, high fertility countries, we find evidence that at least some people have children even when it diminishes their personal wellbeing. PMID- 24474756 TI - Materazzi effect and the strategic use of anger in competitive interactions. AB - We propose that individuals use anger strategically in interactions. We first show that in some environments angering people makes them more effective in competitions, whereas in others, anger makes them less effective. We then show that individuals anticipate these effects and strategically use the option to anger their opponents. In particular, they are more likely to anger their opponents when anger negatively affects the opponents' performances. This finding suggests people understand the effects of emotions on behavior and exploit them to their advantage. PMID- 24474754 TI - TRPV4-mediated mechanotransduction regulates the metabolic response of chondrocytes to dynamic loading. AB - Mechanical loading of joints plays a critical role in maintaining the health and function of articular cartilage. The mechanism(s) of chondrocyte mechanotransduction are not fully understood, but could provide important insights into new physical or pharmacologic therapies for joint diseases. Transient receptor potential vanilloid 4 (TRPV4), a Ca(2+)-permeable osmomechano TRP channel, is highly expressed in articular chondrocytes, and loss of TRPV4 function is associated with joint arthropathy and osteoarthritis. The goal of this study was to examine the hypothesis that TRPV4 transduces dynamic compressive loading in articular chondrocytes. We first confirmed the presence of physically induced, TRPV4-dependent intracellular Ca(2+) signaling in agarose embedded chondrocytes, and then used this model system to study the role of TRPV4 in regulating the response of chondrocytes to dynamic compression. Inhibition of TRPV4 during dynamic loading prevented acute, mechanically mediated regulation of proanabolic and anticatabolic genes, and furthermore, blocked the loading-induced enhancement of matrix accumulation and mechanical properties. Furthermore, chemical activation of TRPV4 by the agonist GSK1016790A in the absence of mechanical loading similarly enhanced anabolic and suppressed catabolic gene expression, and potently increased matrix biosynthesis and construct mechanical properties. These findings support the hypothesis that TRPV4-mediated Ca(2+) signaling plays a central role in the transduction of mechanical signals to support cartilage extracellular matrix maintenance and joint health. Moreover, these insights raise the possibility of therapeutically targeting TRPV4-mediated mechanotransduction for the treatment of diseases such as osteoarthritis, as well as to enhance matrix formation and functional properties of tissue-engineered cartilage as an alternative to bioreactor-based mechanical stimulation. PMID- 24474757 TI - Increasing socioeconomic disparities in adolescent obesity. AB - Recent reports suggest that the rapid growth in youth obesity seen in the 1980s and 1990s has plateaued. We examine changes in obesity among US adolescents aged 12-17 y by socioeconomic background using data from two nationally representative health surveys, the 1988-2010 National Health and Nutrition Examination Surveys and the 2003-2011 National Survey of Children's Health. Although the overall obesity prevalence stabilized, this trend masks a growing socioeconomic gradient: The prevalence of obesity among high-socioeconomic status adolescents has decreased in recent years, whereas the prevalence of obesity among their low socioeconomic status peers has continued to increase. Additional analyses suggest that socioeconomic differences in the levels of physical activity, as well as differences in calorie intake, may have contributed to the growing obesity gradient. PMID- 24474758 TI - Unveiling the mechanism by which microsporidian parasites prevent locust swarm behavior. AB - Locusts are infamous for their ability to aggregate into gregarious migratory swarms that pose a major threat to food security. Aggregation is elicited by an interplay of visual, tactile, and chemical stimuli, but the aggregation pheromone in feces is particularly important. Infection by the microsporidian parasite Paranosema (Nosema) locustae is known to inhibit aggregation of solitary Locusta migratoria manilensis and to induce gregarious locusts to shift back to solitary behavior. Here we suggest that P. locustae achieves this effect by acidifying the hindgut and modulating the locust immune response, which suppresses the growth of the hindgut bacteria that produce aggregation pheromones. This in turn reduces production of the neurotransmitter serotonin that initiates gregarious behavior. Healthy L. migratoria manilensis exposed to olfactory stimuli from parasite infected locusts also produced significantly less serotonin, reducing gregarization. P. locustae also suppresses biosynthesis of the neurotransmitter dopamine that maintains gregarization. Our findings reveal the mechanisms by which P. locustae reduces production of aggregation pheromone and blocks the initiation and maintainence of gregarious behavior. PMID- 24474759 TI - Near-infrared-actuated devices for remotely controlled drug delivery. AB - A reservoir that could be remotely triggered to release a drug would enable the patient or physician to achieve on-demand, reproducible, repeated, and tunable dosing. Such a device would allow precise adjustment of dosage to desired effect, with a consequent minimization of toxicity, and could obviate repeated drug administrations or device implantations, enhancing patient compliance. It should exhibit low off-state leakage to minimize basal effects, and tunable on-state release profiles that could be adjusted from pulsatile to sustained in real time. Despite the clear clinical need for a device that meets these criteria, none has been reported to date to our knowledge. To address this deficiency, we developed an implantable reservoir capped by a nanocomposite membrane whose permeability was modulated by irradiation with a near-infrared laser. Irradiated devices could exhibit sustained on-state drug release for at least 3 h, and could reproducibly deliver short pulses over at least 10 cycles, with an on/off ratio of 30. Devices containing aspart, a fast-acting insulin analog, could achieve glycemic control after s.c. implantation in diabetic rats, with reproducible dosing controlled by the intensity and timing of irradiation over a 2-wk period. These devices can be loaded with a wide range of drug types, and therefore represent a platform technology that might be used to address a wide variety of clinical indications. PMID- 24474760 TI - O-GlcNAcylation regulates EZH2 protein stability and function. AB - O-linked N-acetylglucosamine (GlcNAc) transferase (OGT) is the only known enzyme that catalyzes the O-GlcNAcylation of proteins at the Ser or Thr side chain hydroxyl group. OGT participates in transcriptional and epigenetic regulation, and dysregulation of OGT has been implicated in diseases such as cancer. However, the underlying mechanism is largely unknown. Here we show that OGT is required for the trimethylation of histone 3 at K27 to form the product H3K27me3, a process catalyzed by the histone methyltransferase enhancer of zeste homolog 2 (EZH2) in the polycomb repressive complex 2 (PRC2). H3K27me3 is one of the most important histone modifications to mark the transcriptionally silenced chromatin. We found that the level of H3K27me3, but not other H3 methylation products, was greatly reduced upon OGT depletion. OGT knockdown specifically down-regulated the protein stability of EZH2, without altering the levels of H3K27 demethylases UTX and JMJD3, and disrupted the integrity of the PRC2 complex. Furthermore, the interaction of OGT and EZH2/PRC2 was detected by coimmunoprecipitation and cosedimentation experiments. Importantly, we identified that serine 75 is the site for EZH2 O-GlcNAcylation, and the EZH2 mutant S75A exhibited reduction in stability. Finally, microarray and ChIP analysis have characterized a specific subset of potential tumor suppressor genes subject to repression via the OGT-EZH2 axis. Together these results indicate that OGT-mediated O-GlcNAcylation at S75 stabilizes EZH2 and hence facilitates the formation of H3K27me3. The study not only uncovers a functional posttranslational modification of EZH2 but also reveals a unique epigenetic role of OGT in regulating histone methylation. PMID- 24474761 TI - Distinct roles of the methylcytosine oxidases Tet1 and Tet2 in mouse embryonic stem cells. AB - Dioxygenases of the Ten-Eleven Translocation (TET) family are 5-methylcytosine oxidases that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidation products in DNA. We show that Tet1 and Tet2 have distinct roles in regulating 5hmC in mouse embryonic stem cells (mESC). Tet1 depletion diminishes 5hmC levels at transcription start sites (TSS), whereas Tet2 depletion is predominantly associated with decreased 5hmC in gene bodies. Enrichment of 5hmC is observed at the boundaries of exons that are highly expressed, and Tet2 depletion results in substantial loss of 5hmC at these boundaries. In contrast, at promoter/TSS regions, Tet2 depletion results in increased 5hmC, potentially because of the redundant activity of Tet1. Together, the data point to a complex interplay between Tet1 and Tet2 in mESC, and to distinct roles for these two proteins in regulating promoter, exon, and polyadenylation site usage in cells. PMID- 24474762 TI - Insight into cyanobacterial circadian timing from structural details of the KaiB KaiC interaction. AB - Circadian timing in cyanobacteria is determined by the Kai system consisting of KaiA, KaiB, and KaiC. Interactions between Kai proteins change the phosphorylation status of KaiC, defining the phase of circadian timing. The KaiC KaiB interaction is crucial for the circadian rhythm to enter the dephosphorylation phase but it is not well understood. Using mass spectrometry to characterize Kai complexes, we found that KaiB forms monomers, dimers, and tetramers. The monomer is the unit that interacts with KaiC, with six KaiB monomers binding to one KaiC hexamer. Hydrogen-deuterium exchange MS reveals structural changes in KaiC upon binding of KaiB in both the CI and CII domains, showing allosteric coupling upon KaiB binding. Based on this information we propose a model of the KaiB-KaiC complex and hypothesize that the allosteric changes observed upon complex formation relate to coupling KaiC ATPase activity with KaiB binding and to sequestration of KaiA dimers into KaiCBA complexes. PMID- 24474763 TI - Structure of an HIV-1-neutralizing antibody target, the lipid-bound gp41 envelope membrane proximal region trimer. AB - The membrane proximal external region (MPER) of HIV-1 glycoprotein (gp) 41 is involved in viral-host cell membrane fusion. It contains short amino acid sequences that are binding sites for the HIV-1 broadly neutralizing antibodies 2F5, 4E10, and 10E8, making these binding sites important targets for HIV-1 vaccine development. We report a high-resolution structure of a designed MPER trimer assembled on a detergent micelle. The NMR solution structure of this trimeric domain, designated gp41-M-MAT, shows that the three MPER peptides each adopt symmetric alpha-helical conformations exposing the amino acid side chains of the antibody binding sites. The helices are closely associated at their N termini, bend between the 2F5 and 4E10 epitopes, and gradually separate toward the C termini, where they associate with the membrane. The mAbs 2F5 and 4E10 bind gp41-M-MAT with nanomolar affinities, consistent with the substantial exposure of their respective epitopes in the trimer structure. The traditional structure determination of gp41-M-MAT using the Xplor-NIH protocol was validated by independently determining the structure using the DISCO sparse-data protocol, which exploits geometric arrangement algorithms that guarantee to compute all structures and assignments that satisfy the data. PMID- 24474764 TI - Circadian rhythms synchronize mitosis in Neurospora crassa. AB - The cell cycle and the circadian clock communicate with each other, resulting in circadian-gated cell division cycles. Alterations in this network may lead to diseases such as cancer. Therefore, it is critical to identify molecular components that connect these two oscillators. However, molecular mechanisms between the clock and the cell cycle remain largely unknown. A model filamentous fungus, Neurospora crassa, is a multinucleate system used to elucidate molecular mechanisms of circadian rhythms, but not used to investigate the molecular coupling between these two oscillators. In this report, we show that a conserved coupling between the circadian clock and the cell cycle exists via serine/threonine protein kinase-29 (STK-29), the Neurospora homolog of mammalian WEE1 kinase. Based on this finding, we established a mathematical model that predicts circadian oscillations of cell cycle components and circadian clock dependent synchronized nuclear divisions. We experimentally demonstrate that G1 and G2 cyclins, CLN-1 and CLB-1, respectively, oscillate in a circadian manner with bioluminescence reporters. The oscillations of clb-1 and stk-29 gene expression are abolished in a circadian arrhythmic frq(ko) mutant. Additionally, we show the light-induced phase shifts of a core circadian component, frq, as well as the gene expression of the cell cycle components clb-1 and stk-29, which may alter the timing of divisions. We then used a histone hH1-GFP reporter to observe nuclear divisions over time, and show that a large number of nuclear divisions occur in the evening. Our findings demonstrate the circadian clock dependent molecular dynamics of cell cycle components that result in synchronized nuclear divisions in Neurospora. PMID- 24474765 TI - Notch signaling regulates cardiomyocyte proliferation during zebrafish heart regeneration. AB - The human heart's failure to replace ischemia-damaged myocardium with regenerated muscle contributes significantly to the worldwide morbidity and mortality associated with coronary artery disease. Remarkably, certain vertebrate species, including the zebrafish, achieve complete regeneration of amputated or injured myocardium through the proliferation of spared cardiomyocytes. Nonetheless, the genetic and cellular determinants of natural cardiac regeneration remain incompletely characterized. Here, we report that cardiac regeneration in zebrafish relies on Notch signaling. Following amputation of the zebrafish ventricular apex, Notch receptor expression becomes activated specifically in the endocardium and epicardium, but not the myocardium. Using a dominant negative approach, we discovered that suppression of Notch signaling profoundly impairs cardiac regeneration and induces scar formation at the amputation site. We ruled out defects in endocardial activation, epicardial activation, and dedifferentiation of compact myocardial cells as causative for the regenerative failure. Furthermore, coronary endothelial tubes, which we lineage traced from preexisting endothelium in wild-type hearts, formed in the wound despite the myocardial regenerative failure. Quantification of myocardial proliferation in Notch-suppressed hearts revealed a significant decrease in cycling cardiomyocytes, an observation consistent with a noncell autonomous requirement for Notch signaling in cardiomyocyte proliferation. Unexpectedly, hyperactivation of Notch signaling also suppressed cardiomyocyte proliferation and heart regeneration. Taken together, our data uncover the exquisite sensitivity of regenerative cardiomyocyte proliferation to perturbations in Notch signaling. PMID- 24474766 TI - The WNT receptor FZD7 is required for maintenance of the pluripotent state in human embryonic stem cells. AB - WNT signaling is involved in maintaining stem cells in an undifferentiated state; however, it is often unclear which WNTs and WNT receptors are mediating these activities. Here we examined the role of the WNT receptor FZD7 in maintaining human embryonic stem cells (hESCs) in an undifferentiated and pluripotent state. FZD7 expression is significantly elevated in undifferentiated cells relative to differentiated cell populations, and interfering with its expression or function, either by short hairpin RNA-mediated knockdown or with a fragment antigen binding (Fab) molecule directed against FZD7, disrupts the pluripotent state of hESCs. The FZD7-specific Fab blocks signaling by Wnt3a protein by down-regulating FZD7 protein levels, suggesting that FZD7 transduces Wnt signals to activate Wnt/beta catenin signaling. These results demonstrate that FZD7 encodes a regulator of the pluripotent state and that hESCs require endogenous WNT/beta-catenin signaling through FZD7 to maintain an undifferentiated phenotype. PMID- 24474767 TI - Cyclin D2 is a GATA4 cofactor in cardiogenesis. AB - The G1 cyclins play a pivotal role in regulation of cell differentiation and proliferation. The mechanisms underlying their cell-specific roles are incompletely understood. Here, we show that a G1 cyclin, cyclin D2 (CycD2), enhances the activity of transcription factor GATA4, a key regulator of cardiomyocyte growth and differentiation. GATA4 recruits CycD2 to its target promoters, and their interaction results in synergistic activation of GATA dependent transcription. This effect is specific to CycD2 because CycD1 is unable to potentiate activity of GATA4 and is CDK-independent. GATA4 physically interacts with CycD2 through a discreet N-terminal activation domain that is essential for the cardiogenic activity of GATA4. Human mutations in this domain that are linked to congenital heart disease interfere with CycD2-GATA4 synergy. Cardiogenesis assays in Xenopus embryos indicate that CycD2 enhances the cardiogenic function of GATA4. Together, our data uncover a role for CycD2 as a cardiogenic coactivator of GATA4 and suggest a paradigm for cell-specific effects of cyclin Ds. PMID- 24474768 TI - Drosha-independent DGCR8/Pasha pathway regulates neuronal morphogenesis. AB - Cleavage of microRNAs and mRNAs by Drosha and its cofactor Pasha/DGCR8 is required for animal development, but whether these proteins also have independent roles in development has been unclear. Known phenotypes associated with loss of either one of these two proteins are very similar and consistent with their joint function, even though both cofactors are involved with additional distinct RNA biogenesis pathways. Here, we report clear phenotypic differences between drosha and pasha/dgcr8 null alleles in two postembryonic lineages in the Drosophila brain: elimination of pasha/dgcr8 leads to defects that are not shared by drosha null mutations in the morphology of gamma neurons in the mushroom body lineage, as well as many neurons in the anterodorsal projection neuron lineage. These morphological defects are not detected in neurons that are genetically depleted of two additional microRNA pathway components, dicer-1 and argonaute1, indicating that they are not due to loss of microRNA activity. They are, however, phenocopied by a newly identified recessive gain-of-function allele in drosha that probably interferes with the microRNA independent functions of Pasha/DGCR8. These data therefore identify a general Drosha-independent DGCR8/Pasha pathway that promotes proper morphology in multiple neuronal lineages. Given that reduction of human DGCR8/Pasha may contribute to the cognitive and behavioral characteristics of DiGeorge syndrome patients, disruption of this newly described pathway could underlie human neurological disease. PMID- 24474769 TI - Germ-line activation of the luteinizing hormone receptor directly drives spermiogenesis in a nonmammalian vertebrate. AB - In both mammals and teleosts, the differentiation of postmeiotic spermatids to spermatozoa (spermiogenesis) is thought to be indirectly controlled by the luteinizing hormone (LH) acting through the LH/choriogonadotropin receptor (LHCGR) to stimulate androgen secretion in the interstitial Leydig cells. However, a more direct, nonsteroidal role of LH mediating the spermiogenic pathway remains unclear. Using a flatfish with semicystic spermatogenesis, in which spermatids are released into the seminiferous lobule lumen (SLL), where they develop into spermatozoa without direct contact with the supporting Sertoli cells, we show that haploid spermatids express the homolog of the tetrapod LHCGR (Lhcgrba). Both native Lh and intramuscularly injected His-tagged recombinant Lh (rLh) are immunodetected bound to the Lhcgrba of free spermatids in the SLL, showing that circulating gonadotropin can reach the intratubular compartment. In vitro incubation of flatfish spermatids isolated from the SLL with rLh specifically promotes their differentiation into spermatozoa, whereas recombinant follicle-stimulating hormone and steroid hormones are ineffective. Using a repertoire of molecular markers and inhibitors, we find that the Lh-Lhcgrba induction of spermiogenesis is mediated through a cAMP/PKA signaling pathway that initiates the transcription of genes potentially involved in the function of spermatozoa. We further show that Lhcgrba expression in germ cells also occurs in distantly related fishes, suggesting this feature is likely conserved in teleosts regardless of the type of germ cell development. These data reveal a role of LH in vertebrate germ cells, whereby a Lhcgrba-activated signaling cascade in haploid spermatids directs gene expression and the progression of spermiogenesis. PMID- 24474770 TI - Primate energy expenditure and life history. AB - Humans and other primates are distinct among placental mammals in having exceptionally slow rates of growth, reproduction, and aging. Primates' slow life history schedules are generally thought to reflect an evolved strategy of allocating energy away from growth and reproduction and toward somatic investment, particularly to the development and maintenance of large brains. Here we examine an alternative explanation: that primates' slow life histories reflect low total energy expenditure (TEE) (kilocalories per day) relative to other placental mammals. We compared doubly labeled water measurements of TEE among 17 primate species with similar measures for other placental mammals. We found that primates use remarkably little energy each day, expending on average only 50% of the energy expected for a placental mammal of similar mass. Such large differences in TEE are not easily explained by differences in physical activity, and instead appear to reflect systemic metabolic adaptation for low energy expenditures in primates. Indeed, comparisons of wild and captive primate populations indicate similar levels of energy expenditure. Broad interspecific comparisons of growth, reproduction, and maximum life span indicate that primates' slow metabolic rates contribute to their characteristically slow life histories. PMID- 24474771 TI - Estrogen receptor alpha polymorphism in a species with alternative behavioral phenotypes. AB - The evolution of behavior relies on changes at the level of the genome; yet the ability to attribute a behavioral change to a specific, naturally occurring genetic change is rare in vertebrates. In the white-throated sparrow (Zonotrichia albicollis), a chromosomal polymorphism (ZAL2/2(m)) is known to segregate with a behavioral phenotype. Individuals with the ZAL2(m) haplotype engage in more territorial aggression and less parental behavior than individuals without it. These behaviors are thought to be mediated by sensitivity to sex steroids, and the chromosomal rearrangement underlying the polymorphism has captured a prime candidate gene: estrogen receptor 1 (ESR1), which encodes estrogen receptor alpha (ERalpha). We therefore hypothesized that the behavioral effects of the ZAL2(m) rearrangement are mediated by polymorphism in ESR1. We report here that (i) the ESR1 promoter region contains fixed polymorphisms distinguishing the ZAL2(m) and ZAL2 alleles; (ii); those polymorphisms regulate transcription efficiency in vitro and therefore potentially do the same in vivo (iii); the local expression of ERalpha in the brain depends strongly on genotype in a free-living population; and (iv) ERalpha expression in the medial amygdala and medial preoptic area may fully mediate the effects of genotype on territorial aggression and parenting, respectively. Thus, our study provides a rare glimpse of how a chromosomal polymorphism has affected the brain and social behavior in a vertebrate. Our results suggest that in this species, differentiation of ESR1 has played a causal role in the evolution of phenotypes with alternative life-history strategies. PMID- 24474772 TI - Human and Helicobacter pylori coevolution shapes the risk of gastric disease. AB - Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population. PMID- 24474773 TI - Deletion of conserved protein phosphatases reverses defects associated with mitochondrial DNA damage in Saccharomyces cerevisiae. AB - Mitochondrial biogenesis is regulated by signaling pathways sensitive to extracellular conditions and to the internal environment of the cell. Therefore, treatments for disease caused by mutation of mtDNA may emerge from studies of how signal transduction pathways command mitochondrial function. We have examined the role of phosphatases under the control of the conserved alpha4/Tap42 protein in cells lacking a mitochondrial genome. We found that deletion of protein phosphatase 2A (PP2A) or of protein phosphatase 6 (PP6) protects cells from the reduced proliferation, mitochondrial protein import defects, lower mitochondrial electrochemical potential, and nuclear transcriptional response associated with mtDNA damage. Moreover, PP2A or PP6 deletion allows viability of a sensitized yeast strain after mtDNA loss. Interestingly, the Saccharomyces cerevisiae ortholog of the mammalian AMP-activated protein kinase was required for the full benefits of PP6 deletion and also for proliferation of otherwise wild-type cells lacking mtDNA. Our work highlights the important role that nutrient-responsive signaling pathways can play in determining the response to mitochondrial dysfunction. PMID- 24474774 TI - Human natural killer cells control Plasmodium falciparum infection by eliminating infected red blood cells. AB - Immunodeficient mouse-human chimeras provide a powerful approach to study host specific pathogens, such as Plasmodium falciparum that causes human malaria. Supplementation of immunodeficient mice with human RBCs supports infection by human Plasmodium parasites, but these mice lack the human immune system. By combining human RBC supplementation and humanized mice that are optimized for human immune cell reconstitution, we have developed RBC-supplemented, immune cell optimized humanized (RICH) mice that support multiple cycles of P. falciparum infection. Depletion of human natural killer (NK) cells, but not macrophages, in RICH mice results in a significant increase in parasitemia. Further studies in vitro show that NK cells preferentially interact with infected RBCs (iRBCs), resulting in the activation of NK cells and the elimination of iRBCs in a contact dependent manner. We show that the adhesion molecule lymphocyte-associated antigen 1 is required for NK cell interaction with and elimination of iRBCs. Development of RICH mice and validation of P. falciparum infection should facilitate the dissection of human immune responses to malaria parasite infection and the evaluation of therapeutics and vaccines. PMID- 24474775 TI - Reproducible selection of high avidity CD8+ T-cell clones following secondary acute virus infection. AB - The recall of memory CD8(+) cytotoxic T lymphocytes (CTLs), elicited by prior virus infection or vaccination, is critical for immune protection. The extent to which this arises as a consequence of stochastic clonal expansion vs. active selection of particular clones remains unclear. Using a parallel adoptive transfer protocol in combination with single cell analysis to define the complementarity determining region (CDR) 3alpha and CDR3beta regions of individual T-cell receptor (TCR) heterodimers, we characterized the antigen driven recall of the same memory CTL population in three individual recipients. This high-resolution analysis showed reproducible enrichment (or diminution) of particular TCR clonotypes across all challenged animals. These changes in clonal composition were TCRalpha- and beta chain-dependent and were directly related to the avidity of the TCR for the virus-derived peptide (p) + major histocompatibility complex class I molecule. Despite this shift in clonotype representation indicative of differential selection, there was no evidence of overall repertoire narrowing, suggesting a strategy to optimize CTL responses while safeguarding TCR diversity. PMID- 24474776 TI - TLR8 on dendritic cells and TLR9 on B cells restrain TLR7-mediated spontaneous autoimmunity in C57BL/6 mice. AB - Systemic lupus erythematosus (SLE) is a complex autoimmune disease with diverse clinical presentations characterized by the presence of autoantibodies to nuclear components. Toll-like receptor (TLR)7, TLR8, and TLR9 sense microbial or endogenous nucleic acids and are implicated in the development of SLE. In mice TLR7-deficiency ameliorates SLE, but TLR8- or TLR9-deficiency exacerbates the disease because of increased TLR7 response. Thus, both TLR8 and TLR9 control TLR7 function, but whether TLR8 and TLR9 act in parallel or in series in the same or different cell types in controlling TLR7-mediated lupus remains unknown. Here, we reveal that double TLR8/9-deficient (TLR8/9(-/-)) mice on the C57BL/6 background showed increased abnormalities characteristic of SLE, including splenomegaly, autoantibody production, frequencies of marginal zone and B1 B cells, and renal pathology compared with single TLR8(-/-) or TLR9(-/-) mice. On the cellular level, TLR8(-/-) and TLR8/9(-/-) dendritic cells were hyperesponsive to TLR7 ligand R848, but TLR9(-/-) cells responded normally. Moreover, B cells from TLR9( /-) and TLR8/9(-/-) mice were hyperesponsive to R848, but TLR8(-/-) B cells were not. These results reveal that TLR8 and TLR9 have an additive effect on controlling TLR7 function and TLR7-mediated lupus; however, they act on different cell types. TLR8 controls TLR7 function on dendritic cells, and TLR9 restrains TLR7 response on B cells. PMID- 24474777 TI - C3 opsonization regulates endocytic handling of apoptotic cells resulting in enhanced T-cell responses to cargo-derived antigens. AB - Apoptotic cells are a source of autoantigens and impairment of their removal contributes to the development of autoimmunity in C1q deficiency. However, the lack of complement component 3 (C3), the predominant complement opsonin, does not predispose to autoimmunity, suggesting a modifying role of C3 in disease pathogenesis. To explore this hypothesis, here we investigated the role of C3 in the T-cell response to apoptotic cell-associated antigens. By comparing the phagosome maturation and the subsequent MHC class II presentation of a peptide derived from the internalized cargo between C3-deficient or C3-sufficient dendritic cells, we found that C3 deficiency accelerated the fusion of the apoptotic cargo with lysosomes. As a result, C3 deficiency led to impaired antigen-specific T-cell proliferation in vitro and in vivo. Notably, preopsonization of the apoptotic cells with C3 activation fragments rectified the trafficking and T-cell stimulation defects. These data indicate that activated C3 may act as a "chaperone" in the intracellular processing of an apoptotic cargo and, thus, may modulate the T-cell response to self-antigens displayed on dying cells. PMID- 24474778 TI - Oncogenes induce a vimentin filament collapse mediated by HDAC6 that is linked to cell stiffness. AB - Oncogenes deregulate fundamental cellular functions, which can lead to development of tumors, tumor-cell invasion, and metastasis. As the mechanical properties of cells govern cell motility, we hypothesized that oncogenes promote cell invasion by inducing cytoskeletal changes that increase cellular stiffness. We show that the oncogenes simian virus 40 large T antigen, c-Myc, and cyclin E induce spatial reorganization of the vimentin intermediate filament network in cells. At the cellular level, this reorganization manifests as increased width of vimentin fibers and the collapse of the vimentin network. At nanoscale resolution, the organization of vimentin fibers in these oncogene-expressing cells was more entangled, with increased width of the fibers compared with control cells. Expression of these oncogenes also resulted in up-regulation of the tubulin deacetylase histone deacetylase 6 (HDAC6) and altered spatial distribution of acetylated microtubules. This oncogene expression also induced increases in cellular stiffness and promoted the invasive capacity of the cells. Importantly, HDAC6 was required and sufficient for the structural collapse of the vimentin filament network, and was required for increased cellular stiffness of the oncogene-expressing cells. Taken together, these data are consistent with the possibility that oncogenes can induce cellular stiffness via an HDAC6-induced reorganization of the vimentin intermediate filament network. PMID- 24474779 TI - Origin of regenerating tubular cells after acute kidney injury. AB - Acute kidney injury (AKI) is associated with high morbidity and mortality. Recent genetic fate mapping studies demonstrated that recovery from AKI occurs from intrinsic tubular cells. It is unresolved whether these intrinsic cells (so called "scattered tubular cells") represent fixed progenitor cells or whether recovery involves any surviving tubular cell. Here, we show that the doxycycline inducible parietal epithelial cell (PEC)-specific PEC-reverse-tetracycline transactivator (rtTA) transgenic mouse also efficiently labels the scattered tubular cell population. Proximal tubular cells labeled by the PEC-rtTA mouse coexpressed markers for scattered tubular cells (kidney injury molecule 1, annexin A3, src-suppressed C-kinase substrate, and CD44) and showed a higher proliferative index. The PEC-rtTA mouse labeled more tubular cells upon different tubular injuries but was independent of cellular proliferation as determined in physiological growth of the kidney. To resolve whether scattered tubular cells are fixed progenitors, cells were irreversibly labeled before ischemia reperfusion injury (genetic cell fate mapping). During recovery, the frequency of labeled tubular cells remained constant, arguing against a fixed progenitor population. In contrast, when genetic labeling was induced during ischemic injury and subsequent recovery, the number of labeled cells increased significantly, indicating that scattered tubular cells arise from any surviving tubular cell. In summary, scattered tubular cells do not represent a fixed progenitor population but rather a phenotype that can be adopted by almost any proximal tubular cell upon injury. Understanding and modulating these phenotypic changes using the PEC rtTA mouse may lead to more specific therapies in AKI. PMID- 24474780 TI - Proteolytic cleavage of Ser52Pro variant transthyretin triggers its amyloid fibrillogenesis. AB - The Ser52Pro variant of transthyretin (TTR) produces aggressive, highly penetrant, autosomal-dominant systemic amyloidosis in persons heterozygous for the causative mutation. Together with a minor quantity of full-length wild-type and variant TTR, the main component of the ex vivo fibrils was the residue 49-127 fragment of the TTR variant, the portion of the TTR sequence that previously has been reported to be the principal constituent of type A, cardiac amyloid fibrils formed from wild-type TTR and other TTR variants [Bergstrom J, et al. (2005) J Pathol 206(2):224-232]. This specific truncation of Ser52Pro TTR was generated readily in vitro by limited proteolysis. In physiological conditions and under agitation the residue 49-127 proteolytic fragment rapidly and completely self aggregates into typical amyloid fibrils. The remarkable susceptibility to such cleavage is likely caused by localized destabilization of the beta-turn linking strands C and D caused by loss of the wild-type hydrogen-bonding network between the side chains of residues Ser52, Glu54, Ser50, and a water molecule, as revealed by the high-resolution crystallographic structure of Ser52Pro TTR. We thus provide a structural basis for the recently hypothesized, crucial pathogenic role of proteolytic cleavage in TTR amyloid fibrillogenesis. Binding of the natural ligands thyroxine or retinol-binding protein (RBP) by Ser52Pro variant TTR stabilizes the native tetrameric assembly, but neither protected the variant from proteolysis. However, binding of RBP, but not thyroxine, inhibited subsequent fibrillogenesis. PMID- 24474781 TI - Transcriptional occlusion caused by overlapping promoters. AB - RpoS (sigma(38)) is required for cell survival under stress conditions, but it can inhibit growth if produced inappropriately and, consequently, its production and activity are elaborately regulated. Crl, a transcriptional activator that does not bind DNA, enhances RpoS activity by stimulating the interaction between RpoS and the core polymerase. The crl gene has two overlapping promoters, a housekeeping, RpoD- (sigma(70)) dependent promoter, and an RpoN (sigma(54)) promoter that is strongly up-regulated under nitrogen limitation. However, transcription from the RpoN promoter prevents transcription from the RpoD promoter, and the RpoN-dependent transcript lacks a ribosome-binding site. Thus, activation of the RpoN promoter produces a long noncoding RNA that silences crl gene expression simply by being made. This elegant and economical mechanism, which allows a near-instantaneous reduction in Crl synthesis without the need for transacting regulatory factors, restrains the activity of RpoS to allow faster growth under nitrogen-limiting conditions. PMID- 24474782 TI - Structure of the Helicobacter pylori CagA oncoprotein bound to the human tumor suppressor ASPP2. AB - The Cytotoxin associated gene A (CagA) protein of Helicobacter pylori is associated with increased virulence and risk of cancer. Recent proteomic studies have demonstrated an association of CagA with the human tumor suppressor Apoptosis-stimulating Protein of p53-2 (ASPP2). We present here a genetic, biochemical, and structural analysis of CagA with ASPP2. Domain delineation of the 120-kDa CagA protein revealed a stable N-terminal subdomain that was used in a yeast two-hybrid screen that identified the proline-rich domain of ASPP2 as a host cellular target. Biochemical experiments confirm this interaction. The cocrystal structure to 2.0-A resolution of this N-terminal subdomain of CagA with a 7-kDa proline-rich sequence of ASPP2 reveals that this domain of CagA forms a highly specialized three-helix bundle, with large insertions in the loops connecting the helices. These insertions come together to form a deep binding cleft for a highly conserved 20-aa peptide of ASPP2. ASPP2 forms an extended helix in this groove of CagA, burying more than 1,000 A(2) of surface area. This interaction is disrupted in vitro and in vivo by structure-based, loss-of-contact point mutations of key residues in either CagA or ASPP2. Disruption of CagA and ASPP2 binding alters the function of ASPP2 and leads to the decreased survival of H. pylori-infected cells. PMID- 24474783 TI - Reducing virulence of the human pathogen Burkholderia by altering the substrate specificity of the quorum-quenching acylase PvdQ. AB - The use of enzymes to interfere with quorum sensing represents an attractive strategy to fight bacterial infections. We used PvdQ, an effective quorum quenching enzyme from Pseudomonas aeruginosa, as a template to generate an acylase able to effectively hydrolyze C8-HSL, the major communication molecule produced by the Burkholderia species. We discovered that the combination of two single mutations leading to variant PvdQ(Lalpha146W,Fbeta24Y) conferred high activity toward C8-HSL. Exogenous addition of PvdQ(Lalpha146W,Fbeta24Y) dramatically decreased the amount of C8-HSL present in Burkholderia cenocepacia cultures and inhibited a quorum sensing-associated phenotype. The efficacy of this PvdQ variant to combat infections in vivo was further confirmed by its ability to rescue Galleria mellonella larvae upon infection, demonstrating its potential as an effective agent toward Burkholderia infections. Kinetic analysis of the enzymatic activities toward 3-oxo-C12-L-HSL and C8-L-HSL corroborated a substrate switch. This work demonstrates the effectiveness of quorum-quenching acylases as potential novel antimicrobial drugs. In addition, we demonstrate that their substrate range can be easily switched, thereby paving the way to selectively target only specific bacterial species inside a complex microbial community. PMID- 24474784 TI - Longitudinal four-dimensional mapping of subcortical anatomy in human development. AB - Growing access to large-scale longitudinal structural neuroimaging data has fundamentally altered our understanding of cortical development en route to human adulthood, with consequences for basic science, medicine, and public policy. In striking contrast, basic anatomical development of subcortical structures such as the striatum, pallidum, and thalamus has remained poorly described--despite these evolutionarily ancient structures being both intimate working partners of the cortical sheet and critical to diverse developmentally emergent skills and disorders. Here, to begin addressing this disparity, we apply methods for the measurement of subcortical volume and shape to 1,171 longitudinally acquired structural magnetic resonance imaging brain scans from 618 typically developing males and females aged 5-25 y. We show that the striatum, pallidum, and thalamus each follow curvilinear trajectories of volume change, which, for the striatum and thalamus, peak after cortical volume has already begun to decline and show a relative delay in males. Four-dimensional mapping of subcortical shape reveals that (i) striatal, pallidal, and thalamic domains linked to specific fronto parietal association cortices contract with age whereas other subcortical territories expand, and (ii) each structure harbors hotspots of sexually dimorphic change over adolescence--with relevance for sex-biased mental disorders emerging in youth. By establishing the developmental dynamism, spatial heterochonicity, and sexual dimorphism of human subcortical maturation, these data bring our spatiotemporal understanding of subcortical development closer to that of the cortex--allowing evolutionary, basic, and clinical neuroscience to be conducted within a more comprehensive developmental framework. PMID- 24474785 TI - Detection of sweet tastants by a conserved group of insect gustatory receptors. AB - Sweet taste cells play critical roles in food selection and feeding behaviors. Drosophila sweet neurons express eight gustatory receptors (Grs) belonging to a highly conserved clade in insects. Despite ongoing efforts, little is known about the fundamental principles that underlie how sweet tastants are detected by these receptors. Here, we provide a systematic functional analysis of Drosophila sweet receptors using the ab1C CO2-sensing olfactory neuron as a unique in vivo decoder. We find that each of the eight receptors of this group confers sensitivity to one or more sweet tastants, indicating direct roles in ligand recognition for all sweet receptors. Receptor response profiles are validated by analysis of taste responses in corresponding Gr mutants. The response matrix shows extensive overlap in Gr-ligand interactions and loosely separates sweet receptors into two groups matching their relationships by sequence. We then show that expression of a bitter taste receptor confers sensitivity to selected aversive tastants that match the responses of the neuron that the Gr is derived from. Finally, we characterize an internal fructose-sensing receptor, Gr43a, and its ortholog in the malaria mosquito, AgGr25, in the ab1C expression system. We find that both receptors show robust responses to fructose along with a number of other sweet tastants. Our results provide a molecular basis for tastant detection by the entire repertoire of sweet taste receptors in the fly and lay the foundation for studying Grs in mosquitoes and other insects that transmit deadly diseases. PMID- 24474786 TI - The miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic transition in developing neural stem/progenitor cells. AB - Neural stem/progenitor cell (NSPC) multipotency is highly regulated so that specific neural networks form during development. NSPCs cannot respond to gliogenic signals without acquiring gliogenic competence and decreasing their neurogenic competence as development proceeds. Coup-tfI and Coup-tfII are triggers of these temporal NSPC competence changes. However, the downstream effectors of Coup-tfs that mediate the neurogenic-to-gliogenic competence transition remain unknown. Here, we identified the microRNA-17/106 (miR-17/106) p38 axis as a critical regulator of this transition. Overexpression of miR-17 inhibited the acquisition of gliogenic competence and forced stage-progressed NSPCs to regain neurogenic competence without altering the methylation status of a glial gene promoter. We also identified Mapk14 (also known as p38) as a target of miR-17/106 and found that Mapk14 inhibition restored neurogenic competence after the neurogenic phase. These results demonstrate that the miR-17/106-p38 axis is a key regulator of the neurogenic-to-gliogenic NSPC competence transition and that manipulation of this axis permits bidirectional control of NSPC multipotency. PMID- 24474787 TI - Dynamics of axonal regeneration in adult and aging zebrafish reveal the promoting effect of a first lesion. AB - Axonal regeneration is a major issue in the maintenance of adult nervous systems, both after nerve injuries and in neurodegenerative diseases. However, studying this process in vivo is difficult or even impossible in most vertebrates. Here we show that the posterior lateral line (PLL) of zebrafish is a suitable system to study axonal regeneration in vivo because of both the superficial location and reproducible spatial arrangement of neurons and targets, and the possibility of following reinnervation in live fish on a daily basis. Axonal regeneration after nerve cut has been demonstrated in this system during the first few days of life, leading to complete regeneration within 24 h. However, the potential for PLL nerve regeneration has not been tested yet beyond the early larval stage. We explore the regeneration potential and dynamics of the PLL nerve in adult zebrafish and report that regeneration occurs throughout adulthood. We observed that irregularities in the original branching pattern are faithfully reproduced after regeneration, suggesting that regenerating axons follow the path laid down by the original nerve branches. We quantified the extent of target reinnervation after a nerve cut and found that the latency before the nerve regenerates increases with age. This latency is reduced after a second nerve cut at all ages, suggesting that a regeneration-promoting factor induced by the first cut facilitates regeneration on a second cut. We provide evidence that this factor remains present at the site of the first lesion for several days and is intrinsic to the neurons. PMID- 24474788 TI - Rapid homeostasis by disinhibition during whisker map plasticity. AB - How homeostatic processes contribute to map plasticity and stability in sensory cortex is not well-understood. Classically, sensory deprivation first drives rapid Hebbian weakening of spiking responses to deprived inputs, which is followed days later by a slow homeostatic increase in spiking responses mediated by excitatory synaptic scaling. Recently, more rapid homeostasis by inhibitory circuit plasticity has been discovered in visual cortex, but whether this process occurs in other brain areas is not known. We tested for rapid homeostasis in layer 2/3 (L2/3) of rodent somatosensory cortex, where D-row whisker deprivation drives Hebbian weakening of whisker-evoked spiking responses after an unexplained initial delay, but no homeostasis of deprived whisker responses is known. We hypothesized that the delay reflects rapid homeostasis through disinhibition, which masks the onset of Hebbian weakening of L2/3 excitatory input. We found that deprivation (3 d) transiently increased whisker-evoked spiking responses in L2/3 single units before classical Hebbian weakening (>=5 d), whereas whisker evoked synaptic input was reduced during both periods. This finding suggests a transient homeostatic increase in L2/3 excitability. In whole-cell recordings from L2/3 neurons in vivo, brief deprivation decreased whisker-evoked inhibition more than excitation and increased the excitation-inhibition ratio. In contrast, synaptic scaling and increased intrinsic excitability were absent. Thus, disinhibition is a rapid homeostatic plasticity mechanism in rodent somatosensory cortex that transiently maintains whisker-evoked spiking in L2/3, despite the onset of Hebbian weakening of excitatory input. PMID- 24474789 TI - ATF3 expression improves motor function in the ALS mouse model by promoting motor neuron survival and retaining muscle innervation. AB - ALS is a fatal neurodegenerative disease characterized by a progressive loss of motor neurons and atrophy of distal axon terminals in muscle, resulting in loss of motor function. Motor end plates denervated by axonal retraction of dying motor neurons are partially reinnervated by remaining viable motor neurons; however, this axonal sprouting is insufficient to compensate for motor neuron loss. Activating transcription factor 3 (ATF3) promotes neuronal survival and axonal growth. Here, we reveal that forced expression of ATF3 in motor neurons of transgenic SOD1(G93A) ALS mice delays neuromuscular junction denervation by inducing axonal sprouting and enhancing motor neuron viability. Maintenance of neuromuscular junction innervation during the course of the disease in ATF3/SOD1(G93A) mice is associated with a substantial delay in muscle atrophy and improved motor performance. Although disease onset and mortality are delayed, disease duration is not affected. This study shows that adaptive axonal growth promoting mechanisms can substantially improve motor function in ALS and importantly, that augmenting viability of the motor neuron soma and maintaining functional neuromuscular junction connections are both essential elements in therapy for motor neuron disease in the SOD1(G93A) mice. Accordingly, effective protection of optimal motor neuron function requires restitution of multiple dysregulated cellular pathways. PMID- 24474790 TI - Neural representation of expected value in the adolescent brain. AB - Previous work shows that the adolescent reward system is hyperactive, but this finding may be confounded by differences in how teens value money. To address this, we examined the neural ontogeny of objective value representation. Adolescent and adult participants performed a monetary gambling task in which they chose to accept or reject gambles of varying expected value. Increasing expected value had a stronger influence over gambling choices in adolescents relative to adults, an effect that was paralleled by greater activation in the ventral striatum in adolescents. This unique adolescent ventral striatum response remained even after matching groups on acceptance behavior. These behavioral and neural data suggest that the value of available options has a greater influence in adolescent versus adult choices, even when objective value and subjective choice are held constant. This research provides further evidence that hyperactivation of reward circuitry in adolescence may be a normative ontogenetic shift that is due to greater valuation in the adolescent brain. PMID- 24474791 TI - Perennial grasslands enhance biodiversity and multiple ecosystem services in bioenergy landscapes. AB - Agriculture is being challenged to provide food, and increasingly fuel, for an expanding global population. Producing bioenergy crops on marginal lands- farmland suboptimal for food crops--could help meet energy goals while minimizing competition with food production. However, the ecological costs and benefits of growing bioenergy feedstocks--primarily annual grain crops--on marginal lands have been questioned. Here we show that perennial bioenergy crops provide an alternative to annual grains that increases biodiversity of multiple taxa and sustain a variety of ecosystem functions, promoting the creation of multifunctional agricultural landscapes. We found that switchgrass and prairie plantings harbored significantly greater plant, methanotrophic bacteria, arthropod, and bird diversity than maize. Although biomass production was greater in maize, all other ecosystem services, including methane consumption, pest suppression, pollination, and conservation of grassland birds, were higher in perennial grasslands. Moreover, we found that the linkage between biodiversity and ecosystem services is dependent not only on the choice of bioenergy crop but also on its location relative to other habitats, with local landscape context as important as crop choice in determining provision of some services. Our study suggests that bioenergy policy that supports coordinated land use can diversify agricultural landscapes and sustain multiple critical ecosystem services. PMID- 24474792 TI - Prestimulus oscillatory power and connectivity patterns predispose conscious somatosensory perception. AB - Which aspects of our sensory environment enter conscious awareness does not only depend on physical features of the stimulus, but also critically on the so-called current brain state. Results from magnetoencephalography/EEG studies using near threshold stimuli have consistently pointed to reduced levels of alpha- (8-12 Hz) power in relevant sensory areas to predict whether a stimulus will be consciously perceived or not. These findings have been mainly interpreted in strictly "local" terms of enhanced excitability of neuronal ensembles in respective cortical regions. The present study aims to introduce a framework that complements this rather local perspective, by stating that the functional connectivity architecture before stimulation will predetermine information flow. Thus, information computed at a local level will be distributed throughout a network, thereby becoming consciously accessible. Data from a previously published experiment on conscious somatosensory near-threshold perception was reanalyzed focusing on the prestimulus period. Analysis of spectral power showed reduced alpha-power mainly in the contralateral S2 and middle frontal gyrus to precede hits, thus overall supporting the current literature. Furthermore, differences between hits and misses were obtained on global network (graph theoretical) features in the same interval. Most importantly, in accordance with our framework, we could show that the somatosensory cortex is "more efficiently" integrated into a distributed network in the prestimulus period. This finding means that when a relevant sensory stimulus impinges upon the system, it will encounter preestablished pathways for information flow. In this sense, prestimulus functional connectivity patterns form "windows" to conscious perception. PMID- 24474793 TI - Structures of yeast mitochondrial ADP/ATP carriers support a domain-based alternating-access transport mechanism. AB - The mitochondrial ADP/ATP carrier imports ADP from the cytosol and exports ATP from the mitochondrial matrix. The carrier cycles by an unresolved mechanism between the cytoplasmic state, in which the carrier accepts ADP from the cytoplasm, and the matrix state, in which it accepts ATP from the mitochondrial matrix. Here we present the structures of the yeast ADP/ATP carriers Aac2p and Aac3p in the cytoplasmic state. The carriers have three domains and are closed at the matrix side by three interdomain salt-bridge interactions, one of which is braced by a glutamine residue. Glutamine braces are conserved in mitochondrial carriers and contribute to an energy barrier, preventing the conversion to the matrix state unless substrate binding occurs. At the cytoplasmic side a second salt-bridge network forms during the transport cycle, as demonstrated by functional analysis of mutants with charge-reversed networks. Analyses of the domain structures and properties of the interdomain interfaces indicate that interconversion between states involves movement of the even-numbered alpha helices across the surfaces of the odd-numbered alpha-helices by rotation of the domains. The odd-numbered alpha-helices have an L-shape, with proline or serine residues at the kinks, which functions as a lever-arm, coupling the substrate induced disruption of the matrix network to the formation of the cytoplasmic network. The simultaneous movement of three domains around a central translocation pathway constitutes a unique mechanism among transport proteins. These findings provide a structural description of transport by mitochondrial carrier proteins, consistent with an alternating-access mechanism. PMID- 24474794 TI - Discrete mechanisms of mTOR and cell cycle regulation by AMPK agonists independent of AMPK. AB - The multifunctional AMPK-activated protein kinase (AMPK) is an evolutionarily conserved energy sensor that plays an important role in cell proliferation, growth, and survival. It remains unclear whether AMPK functions as a tumor suppressor or a contextual oncogene. This is because although on one hand active AMPK inhibits mammalian target of rapamycin (mTOR) and lipogenesis--two crucial arms of cancer growth--AMPK also ensures viability by metabolic reprogramming in cancer cells. AMPK activation by two indirect AMPK agonists AICAR and metformin (now in over 50 clinical trials on cancer) has been correlated with reduced cancer cell proliferation and viability. Surprisingly, we found that compared with normal tissue, AMPK is constitutively activated in both human and mouse gliomas. Therefore, we questioned whether the antiproliferative actions of AICAR and metformin are AMPK independent. Both AMPK agonists inhibited proliferation, but through unique AMPK-independent mechanisms and both reduced tumor growth in vivo independent of AMPK. Importantly, A769662, a direct AMPK activator, had no effect on proliferation, uncoupling high AMPK activity from inhibition of proliferation. Metformin directly inhibited mTOR by enhancing PRAS40's association with RAPTOR, whereas AICAR blocked the cell cycle through proteasomal degradation of the G2M phosphatase cdc25c. Together, our results suggest that although AICAR and metformin are potent AMPK-independent antiproliferative agents, physiological AMPK activation in glioma may be a response mechanism to metabolic stress and anticancer agents. PMID- 24474795 TI - Integrated description of protein dynamics from room-temperature X-ray crystallography and NMR. AB - Detailed descriptions of atomic coordinates and motions are required for an understanding of protein dynamics and their relation to molecular recognition, catalytic function, and allostery. Historically, NMR relaxation measurements have played a dominant role in the determination of the amplitudes and timescales (picosecond-nanosecond) of bond vector fluctuations, whereas high-resolution X ray diffraction experiments can reveal the presence of and provide atomic coordinates for multiple, weakly populated substates in the protein conformational ensemble. Here we report a hybrid NMR and X-ray crystallography analysis that provides a more complete dynamic picture and a more quantitative description of the timescale and amplitude of fluctuations in atomic coordinates than is obtainable from the individual methods alone. Order parameters (S(2)) were calculated from single-conformer and multiconformer models fitted to room temperature and cryogenic X-ray diffraction data for dihydrofolate reductase. Backbone and side-chain order parameters derived from NMR relaxation experiments are in excellent agreement with those calculated from the room-temperature single conformer and multiconformer models, showing that the picosecond timescale motions observed in solution occur also in the crystalline state. These motions are quenched in the crystal at cryogenic temperatures. The combination of NMR and X-ray crystallography in iterative refinement promises to provide an atomic resolution description of the alternate conformational substates that are sampled through picosecond to nanosecond timescale fluctuations of the protein structure. The method also provides insights into the structural heterogeneity of nonmethyl side chains, aromatic residues, and ligands, which are less commonly analyzed by NMR relaxation measurements. PMID- 24474796 TI - Thymocyte apoptosis drives the intrathymic generation of regulatory T cells. AB - Maintenance of immune tolerance critically depends upon regulatory T cells that express the transcription factor forkhead box P3 (Foxp3). These CD4(+) T cells can be generated in the thymus, termed thymus-derived regulatory T cells (tTregs), but their developmental pathway remains incompletely understood. tTreg development has been shown to be delayed compared with that of CD4(+) single positive (SP) thymocytes, with tTregs being detected only in neonatal thymi by day 3 after birth. Here, we outline the reasons for this delayed emergence of Foxp3(+) tTregs and demonstrate that thymocyte apoptosis is intrinsically tied to tTreg development. We show that thymic apoptosis leads to the production of TGFbeta intrathymically from thymic macrophages, dendritic cells, and epithelial cells. This TGFbeta then induces foxp3 expression and drives tTreg generation. Thymocyte apoptosis has previously been shown to accelerate after birth, which drives increases in TGFbeta in the neonatal thymus. We highlight a paucity of TGFbeta in the neonatal thymus, accounting for the delayed development of tTregs compared with CD4(+) SP thymocytes. Importantly, we show that enhanced levels of apoptosis in the thymus result in an augmented tTreg population and, moreover, that decreasing thymic apoptosis results in reduced tTregs. In addition to this, we also show that T-cell receptor (TCR) signals of different affinity were all capable of driving tTreg development; however, to achieve this TGFbeta signals must also be received concomitant with the TCR signal. Collectively, our results indicate that thymic apoptosis is a key event in tTreg generation and reveal a previously unrecognized apoptosis-TGFbeta-Foxp3 axis that mediates the development of tTregs. PMID- 24474797 TI - Peptides genetically selected for NF-kappaB activation cooperate with oncogene Ras and model carcinogenic role of inflammation. AB - Chronic inflammation is associated with increased cancer risk. Furthermore, the transcription factor NF-kappaB, a central regulator of inflammatory responses, is constitutively active in most tumors. To determine whether active NF-kappaB inherently contributes to malignant transformation, we isolated a set of NF kappaB-activating genetic elements and tested their oncogenic potential in rodent cell transformation models. Genetic elements with desired properties were isolated using biologically active selectable peptide technology, which involves functional screening of lentiviral libraries encoding 20 or 50 amino acid-long polypeptides supplemented with endoplasmic reticulum-targeting and oligomerization domains. Twelve NF-kappaB-activating selectable peptides (NASPs) representing specific fragments of six proteins, none of which was previously associated with NF-kappaB activation, were isolated from libraries of 200,000 peptides derived from 500 human extracellular proteins. Using selective knockdown of distinct components of the NF-kappaB pathway, we showed that the isolated NASPs act either via or upstream of TNF receptor-associated factor 6. Transduction of NASPs into mouse and rat embryo fibroblasts did not, in itself, alter their growth. However, when coexpressed with oncogenic Ras (H-Ras(V12)), NASPs allowed rodent fibroblasts to overcome H-Ras(V12)-mediated p53-dependent senescence and acquire a transformed tumorigenic phenotype. Consistent with their ability to cooperate with oncogenic Ras in cell transformation, NASP expression reduced the transactivation activity of p53. This system provides an in vitro model of NF-kappaB-driven carcinogenesis and suggests that the known carcinogenic effects of inflammation may be at least partially due to NF-kappaB-mediated abrogation of oncogene-induced senescence. PMID- 24474798 TI - Multiple pathways for Plasmodium ookinete invasion of the mosquito midgut. AB - Plasmodium ookinete invasion of the mosquito midgut is a crucial step of the parasite life cycle but little is known about the molecular mechanisms involved. Previously, a phage display peptide library screen identified SM1, a peptide that binds to the mosquito midgut epithelium and inhibits ookinete invasion. SM1 was characterized as a mimotope of an ookinete surface enolase and SM1 presumably competes with enolase, the presumed ligand, for binding to a putative midgut receptor. Here we identify a mosquito midgut receptor that binds both SM1 and ookinete surface enolase, termed "enolase-binding protein" (EBP). Moreover, we determined that Plasmodium berghei parasites are heterogeneous for midgut invasion, as some parasite clones are strongly inhibited by SM1 whereas others are not. The SM1-sensitive parasites required the mosquito EBP receptor for midgut invasion whereas the SM1-resistant parasites invaded the mosquito midgut independently of EBP. These experiments provide evidence that Plasmodium ookinetes can invade the mosquito midgut by alternate pathways. Furthermore, another peptide from the original phage display screen, midgut peptide 2 (MP2), strongly inhibited midgut invasion by P. berghei (SM1-sensitive and SM1 resistant) and Plasmodium falciparum ookinetes, suggesting that MP2 binds to a separate, universal receptor for midgut invasion. PMID- 24474799 TI - A variable homopolymeric G-repeat defines small RNA-mediated posttranscriptional regulation of a chemotaxis receptor in Helicobacter pylori. AB - Phase variation of hypermutable simple sequence repeats (SSRs) is a widespread and stochastic mechanism to generate phenotypic variation within a population and thereby contributes to host adaptation of bacterial pathogens. Although several examples of SSRs that affect transcription or coding potential have been reported, we now show that a SSR also impacts small RNA-mediated posttranscriptional regulation. Based on in vitro and in vivo analyses, we demonstrate that a variable homopolymeric G-repeat in the leader of the TlpB chemotaxis receptor mRNA of the human pathogen Helicobacter pylori is directly targeted by a small RNA (sRNA), RepG (Regulator of polymeric G-repeats). Whereas RepG sRNA is highly conserved, the tlpB G-repeat length varies among diverse H. pylori strains, resulting in strain-specific RepG-mediated tlpB regulation. Based on modification of the G-repeat length within one strain, we demonstrate that the G-repeat length determines posttranscriptional regulation and can mediate both repression and activation of tlpB through RepG. In vitro translation assays show that this regulation occurs at the translational level and that RepG influences tlpB translation dependent on the G-repeat length. In contrast to the digital ON OFF switches through frame-shift mutations within coding sequences, such modulation of posttranscriptional regulation allows for a gradual control of gene expression. This connection to sRNA-mediated posttranscriptional regulation might also apply to other genes with SSRs, which could be targeting sites of cis- or trans-encoded sRNAs, and thereby could facilitate host adaptation through sRNA mediated fine-tuning of virulence gene expression. PMID- 24474800 TI - Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality. AB - Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis. PMID- 24474801 TI - Lateral organ boundaries 1 is a disease susceptibility gene for citrus bacterial canker disease. AB - Citrus bacterial canker (CBC) disease occurs worldwide and incurs considerable costs both from control measures and yield losses. Bacteria that cause CBC require one of six known type III transcription activator-like (TAL) effector genes for the characteristic pustule formation at the site of infection. Here, we show that Xanthomonas citri subspecies citri strain Xcc306, with the type III TAL effector gene pthA4 or with the distinct yet biologically equivalent gene pthAw from strain XccA(w), induces two host genes, CsLOB1 and CsSWEET1, in a TAL effector-dependent manner. CsLOB1 is a member of the Lateral Organ Boundaries (LOB) gene family of transcription factors, and CsSWEET1 is a homolog of the SWEET sugar transporter and rice disease susceptibility gene. Both TAL effectors drive expression of CsLOB1 and CsSWEET1 promoter reporter gene fusions when coexpressed in citrus or Nicotiana benthamiana. Artificially designed TAL effectors directed to sequences in the CsLOB1 promoter region, but not the CsSWEET1 promoter, promoted pustule formation and higher bacterial leaf populations. Three additional distinct TAL effector genes, pthA*, pthB, and pthC, also direct pustule formation and expression of CsLOB1. Unlike pthA4 and pthAw, pthB and pthC do not promote the expression of CsSWEET1. CsLOB1 expression was associated with the expression of genes associated with cell expansion. The results indicate that CBC-inciting species of Xanthomonas exploit a single host disease susceptibility gene by altering the expression of an otherwise developmentally regulated gene using any one of a diverse set of TAL effector genes in the pathogen populations. PMID- 24474802 TI - Remote loading of preencapsulated drugs into stealth liposomes. AB - Loading drugs into carriers such as liposomes can increase the therapeutic ratio by reducing drug concentrations in normal tissues and raising their concentrations in tumors. Although this strategy has proven advantageous in certain circumstances, many drugs are highly hydrophobic and nonionizable and cannot be loaded into liposomes through conventional means. We hypothesized that such drugs could be actively loaded into liposomes by encapsulating them into specially designed cyclodextrins. To test this hypothesis, two hydrophobic drugs that had failed phase II clinical trials because of excess toxicity at deliverable doses were evaluated. In both cases, the drugs could be remotely loaded into liposomes after their encapsulation (preloading) into cyclodextrins and administered to mice at higher doses and with greater efficacy than possible with the free drugs. PMID- 24474803 TI - Augmenting glial cell-line derived neurotrophic factor signaling to treat painful neuropathies. PMID- 24474804 TI - IFN-gamma signaling maintains skin pigmentation homeostasis through regulation of melanosome maturation. AB - Cellular homeostasis is an outcome of complex interacting processes with nonlinear feedbacks that can span distinct spatial and temporal dimensions. Skin tanning is one such dynamic response that maintains genome integrity of epidermal cells. Although pathways underlying hyperpigmentation cascade are recognized, negative feedback regulatory loops that can dampen the activated melanogenesis process are not completely understood. In this study, we delineate a regulatory role of IFN-gamma in skin pigmentation biology. We show that IFN-gamma signaling impedes maturation of the key organelle melanosome by concerted regulation of several pigmentation genes. Withdrawal of IFN-gamma signal spontaneously restores normal cellular programming. This effect in melanocytes is mediated by IFN regulatory factor-1 and is not dependent on the central regulator microphthalmia associated transcription factor. Chronic IFN-gamma signaling shows a clear hypopigmentation phenotype in both mouse and human skin. Interestingly, IFN-gamma KO mice display a delayed recovery response to restore basal state of epidermal pigmentation after UV-induced tanning. Together, our studies delineate a new spatiotemporal role of the IFN-gamma signaling network in skin pigmentation homeostasis, which could have implications in various cutaneous depigmentary and malignant disorders. PMID- 24474806 TI - Symmetry, asymmetry, and the cell cycle in plants: known knowns and some known unknowns. AB - The body architectures of most multicellular organisms consistently display both symmetry and asymmetry. Here, we discuss some of the available knowledge and open questions on how symmetry and asymmetry appear in several conspicuous plant cells and tissues. We focus, where possible, on the role of genes that participate in the maintenance or the breaking of symmetry and that are directly or indirectly related to the cell cycle, under an organ-centric point of view and with an emphasis on the leaf. PMID- 24474805 TI - Assessing mucociliary transport of single particles in vivo shows variable speed and preference for the ventral trachea in newborn pigs. AB - Mucociliary transport (MCT) is an innate defense mechanism that removes particulates, noxious material, and microorganisms from the lung. Several airway diseases exhibit abnormal MCT, including asthma, chronic bronchitis, and cystic fibrosis. However, it remains uncertain whether MCT abnormalities contribute to the genesis of disease or whether they are secondary manifestations that may fuel disease progression. Limitations of current MCT assays and of current animal models of human disease have hindered progress in addressing these questions. Therefore, we developed an in vivo assay of MCT, and here we describe its use in newborn wild-type pigs. We studied pigs because they share many physiological, biochemical, and anatomical features with humans and can model several human diseases. We used X-ray multidetector-row-computed tomography to track movement of individual particles in the large airways of newborn pigs. Multidetector-row computed tomography imaging provided high spatial and temporal resolution and registration of particle position to airway anatomy. We discovered that cilia orientation directs particles to the ventral tracheal surface. We also observed substantial heterogeneity in the rate of individual particle movement, and we speculate that variations in mucus properties may be responsible. The increased granularity of MCT data provided by this assay may provide an opportunity to better understand host defense mechanisms and the pathogenesis of airway disease. PMID- 24474807 TI - Hormonal control of cell division and elongation along differentiation trajectories in roots. AB - The continuous development of roots is supported by a sustainable system for cell production and growth at the root tip. In the stem cell niche that consists of a quiescent centre and surrounding stem cells, an undifferentiated state and low mitotic activity are preserved by the action of auxin and abscisic acid. Stem cell daughters divide several times in the proximal meristem, where auxin and gibberellin mainly promote cell proliferation. Cells then elongate with the help of gibberellin, and become finally differentiated as a constituent of a cell file in the elongation/differentiation zone. In the model plant Arabidopsis thaliana, the transition zone is located between the proximal meristem and the elongation/differentiation zone, and plays an important role in switching from mitosis to the endoreplication that causes DNA polyploidization. Recent studies have shown that cytokinins are essentially required for this transition by antagonizing auxin signalling and promoting degradation of mitotic regulators. In each root zone, different phytohormones interact with one another and coordinately control cell proliferation, cell elongation, cell differentiation, and endoreplication. Such hormonal networks maintain the elaborate structure of the root tip under various environmental conditions. In this review, we summarize and discuss key issues related to hormonal regulation of root growth, and describe how phytohormones are associated with the control of cell cycle machinery. PMID- 24474808 TI - The role of microRNAs in the control of flowering time. AB - The onset of flowering in plants is regulated by complex gene networks that integrate multiple environmental and endogenous cues to ensure that flowering occurs at the appropriate time. This is achieved by precise control of the expression of key flowering genes at both the transcriptional and post transcriptional level. In recent years, a class of small non-coding RNAs, called microRNAs (miRNAs), has been shown to regulate gene expression in a number of plant developmental processes and stress responses. MiRNA-based biotechnology, which harnesses the regulatory functions of such endogenous or artificial miRNAs, therefore represents a highly promising area of research. In this review, the process of plant miRNA biogenesis, their mode of action, and multiple regulatory functions are summarized. The roles of the miR156, miR172, miR159/319, miR390, and miR399 families in the flowering time regulatory network in Arabidopsis thaliana are discussed in depth. PMID- 24474809 TI - Overexpression of PYL5 in rice enhances drought tolerance, inhibits growth, and modulates gene expression. AB - Abscisic acid (ABA) is a phytohormone that plays important roles in the regulation of seed dormancy and adaptation to abiotic stresses. Previous work identified OsPYL/RCARs as functional ABA receptors regulating ABA-dependent gene expression in Oryza sativa. OsPYL/RCARs thus are considered to be good candidate genes for improvement of abiotic stress tolerance in crops. This work demonstrates that the cytosolic ABA receptor OsPYL/RCAR5 in O. sativa functions as a positive regulator of abiotic stress-responsive gene expression. The constitutive expression of OsPYL/RCAR5 in rice driven by the Zea mays ubiquitin promoter induced the expression of many stress-responsive genes even under normal growth conditions and resulted in improved drought and salt stress tolerance in rice. However, it slightly reduced plant height under paddy field conditions and severely reduced total seed yield. This suggests that, although exogenous expression of OsPYL/RCAR5 is able to improve abiotic stress tolerance in rice, fine regulation of its expression will be required to avoid deleterious effects on agricultural traits. PMID- 24474810 TI - Overexpression of VP, a vacuolar H+-pyrophosphatase gene in wheat (Triticum aestivum L.), improves tobacco plant growth under Pi and N deprivation, high salinity, and drought. AB - Establishing crop cultivars with strong tolerance to P and N deprivation, high salinity, and drought is an effective way to improve crop yield and promote sustainable agriculture worldwide. A vacuolar H+-pyrophosphatase (V-H+-PPase) gene in wheat (TaVP) was functionally characterized in this study. TaVP cDNA is 2586-bp long and encodes a 775-amino-acid polypeptide that contains 10 conserved membrane-spanning domains. Transcription of TaVP was upregulated by inorganic phosphate (Pi) and N deprivation, high salinity, and drought. Transgene analysis revealed that TaVP overexpression improved plant growth under normal conditions and specifically under Pi and N deprivation stresses, high salinity, and drought. The improvement of growth of the transgenic plants was found to be closely related to elevated V-H+-PPase activities in their tonoplasts and enlarged root systems, which possibly resulted from elevated expression of auxin transport associated genes. TaVP-overexpressing plants showed high dry mass, photosynthetic efficiencies, antioxidant enzyme activities, and P, N, and soluble carbohydrate concentrations under various growth conditions, particularly under the stress conditions. The transcription of phosphate and nitrate transporter genes was not altered in TaVP-overexpressing plants compared with the wild type, suggesting that high P and N concentrations regulated by TaVP were caused by increased root absorption area instead of alteration of Pi and NO3- acquisition kinetics. TaVP is important in the tolerance of multiple stresses and can serve as a useful genetic resource to improve plant P- and N-use efficiencies and to increase tolerance to high salinity and drought. PMID- 24474811 TI - Genotype-environment interactions affecting preflowering physiological and morphological traits of Brassica rapa grown in two watering regimes. AB - Plant growth and productivity are greatly affected by drought, which is likely to become more threatening with the predicted global temperature increase. Understanding the genetic architecture of complex quantitative traits and their interaction with water availability may lead to improved crop adaptation to a wide range of environments. Here, the genetic basis of 20 physiological and morphological traits is explored by describing plant performance and growth in a Brassica rapa recombinant inbred line (RIL) population grown on a sandy substrate supplemented with nutrient solution, under control and drought conditions. Altogether, 54 quantitative trait loci (QTL) were identified, of which many colocated in 11 QTL clusters. Seventeen QTL showed significant QTL-environment interaction (Q*E), indicating genetic variation for phenotypic plasticity. Of the measured traits, only hypocotyl length did not show significant genotype environment interaction (G*E) in both environments in all experiments. Correlation analysis showed that, in the control environment, stomatal conductance was positively correlated with total leaf dry weight (DW) and aboveground DW, whereas in the drought environment, stomatal conductance showed a significant negative correlation with total leaf DW and aboveground DW. This correlation was explained by antagonistic fitness effects in the drought environment, controlled by a QTL cluster on chromosome A7. These results demonstrate that Q*E is an important component of the genetic variance and can play a great role in improving drought tolerance in future breeding programmes. PMID- 24474812 TI - The BEL1-like family of transcription factors in potato. AB - BEL1-type proteins are ubiquitous plant transcription factors in the three-amino acid-loop-extension superfamily. They interact with KNOTTED1-like proteins, and function as heterodimers in both floral and vegetative development. Using the yeast two-hybrid system with POTATO HOMEOBOX1 (POTH1) as the bait, seven BEL1 type proteins were originally identified. One of these genes, designated StBEL5, has transcripts that move long distances in the plant and enhance tuberization and root growth. Using the potato genome database, 13 active BEL1-like genes were identified that contain the conserved homeobox domain and the BELL domain, both of which are essential for the function of BEL1-type proteins. Phylogenetic analysis of the StBEL family demonstrated a degree of orthology with the 13 BEL1 like genes of Arabidopsis. A profile of the gene structure of the family revealed conservation of the length and splicing patterns of internal exons that encode key functional domains. Yeast two-hybrid experiments with KNOTTED1-like proteins and the new StBELs confirmed the interactive network between these two families. Analyses of RNA abundance patterns clearly showed that three StBEL genes, BEL5, 11, and -29, make up approximately two-thirds of the total transcript values for the entire family. Among the 10 organs evaluated here, these three genes exhibited the 12 greatest transcript abundance values. Using a phloem-transport induction system and gel-shift assays, transcriptional cross-regulation within the StBEL family was confirmed. Making use of the potato genome and current experimental data, a comprehensive profile of the StBEL family is presented in this study. PMID- 24474813 TI - Stillbirth during infection with Middle East respiratory syndrome coronavirus. AB - We conducted an epidemiologic investigation among survivors of an outbreak of Middle East respiratory syndrome coronavirus (MERS-CoV) infection in Jordan. A second-trimester stillbirth occurred during the course of an acute respiratory illness that was attributed to MERS-CoV on the basis of exposure history and positive results of MERS-CoV serologic testing. This is the first occurrence of stillbirth during an infection with MERS-CoV and may have bearing upon the surveillance and management of pregnant women in settings of unexplained respiratory illness potentially due to MERS-CoV. Future prospective investigations of MERS-CoV should ascertain pregnancy status and obtain further pregnancy-related data, including biological specimens for confirmatory testing. PMID- 24474814 TI - Group B Streptococcus beta-hemolysin/cytolysin breaches maternal-fetal barriers to cause preterm birth and intrauterine fetal demise in vivo. AB - BACKGROUND: Maternal vaginal colonization with Streptococcus agalactiae (Group B Streptococcus [GBS]) is a precursor to chorioamnionitis, fetal infection, and neonatal sepsis, but the understanding of specific factors in the pathogenesis of ascending infection remains limited. METHODS: We used a new murine model to evaluate the contribution of the pore-forming GBS beta-hemolysin/cytolysin (betaH/C) to vaginal colonization, ascension, and fetal infection. RESULTS: Competition assays demonstrated a marked advantage to betaH/C-expressing GBS during colonization. Intrauterine fetal demise and/or preterm birth were observed in 54% of pregnant mice colonized with wild-type (WT) GBS and 0% of those colonized with the toxin-deficient cylE knockout strain, despite efficient colonization and ascension by both strains. Robust placental inflammation, disruption of maternal-fetal barriers, and fetal infection were more frequent in animals colonized with WT bacteria. Histopathologic examination revealed bacterial tropism for fetal lung and liver. CONCLUSIONS: Preterm birth and fetal demise are likely the direct result of toxin-induced damage and inflammation rather than differences in efficiency of ascension into the upper genital tract. These data demonstrate a distinct contribution of betaH/C to GBS chorioamnionitis and subsequent fetal infection in vivo and showcase a model for this most proximal step in GBS pathogenesis. PMID- 24474815 TI - Superior tolerability of altered dosing schedule of sunitinib with 2-weeks-on and 1-week-off in patients with metastatic renal cell carcinoma--comparison to standard dosing schedule of 4-weeks-on and 2-weeks-off. AB - OBJECTIVE: Poor tolerability to sunitinib with the standard dosing schedule has become an issue. We retrospectively analyzed the treatment efficacy and the profile of adverse events of 2 weeks of sunitinib treatment followed by 1-week off (Schedule 2/1) and compared the results with the standard dosing schedule with 4 weeks of treatment followed by 2-weeks-off (Schedule 4/2). METHODS: From January 2010 until December 2012, 48 patients with metastatic renal cell carcinoma who received at least two cycles of sunitinib as first-line therapy were the subjects of this study. After 2011, we switched to Schedule 2/1 for most patients. RESULTS: Schedule 2/1 included 26 patients and Schedule 4/2 had 22. The incidence of most adverse events was not significantly different between the two groups except for hand-foot syndrome and diarrhoea, which were observed more frequently in Schedule 4/2 and reached statistical significance. A dose interruption due to adverse events in the first three cycles was significantly lower in Schedule 2/1 patients than in those on Schedule 4/2 (27 versus 53% P = 0.04). With respect to treatment efficacy, the objective response rate tended to be higher in Schedule 4/2 than in Schedule 2/1 (50 versus 32%), and median progression-free survival was longer in patients on Schedule 2/1 than those on Schedule 4/2 (18.4 versus 9.1 months). These differences, however, did not reach statistical significance (P = 0.14, P = 0.13). CONCLUSIONS: Alteration in dosing schedule of sunitinib with 2-weeks-on and 1-week-off showed a lower incidence of dose interruption and a similar oncological outcome compared with the standard dosing schedule of 4-weeks-on and 2-weeks-off. PMID- 24474816 TI - Prospective cohort study: whether or not patients benefit from participation itself in randomized-controlled trials (SELECT BC ECO). AB - The randomized-controlled trial is widely accepted as a clinical trial to decide a standard therapy. It remains to be concluded whether or not patients benefit from participation itself in a randomized-controlled trial. This study was aimed at comparing prognoses between trial participants and participation-refusers. Concerned randomized trials are 'selection of effective chemotherapy for breast cancer' (SELECT BC) and its successor trial, SELECT BC-CONFIRM. Study subjects are all of metastatic breast cancer patients who are requested by their doctors to participate in these two trials. This trial is a hitherto exceptional prospective study and is suitable to clarify the effects of participation per se in such a trial on prognosis when compared with previous two studies. PMID- 24474817 TI - Antiangiogenesis therapy for breast cancer: an update and perspectives from clinical trials. AB - The development of new blood vessels is a crucial step in breast cancer growth, progression and dissemination, making it a promising therapeutic target. Breast cancer has a heterogeneous nature and the diversity of responsible angiogenic pathways between different tumors has been studied for many years. Inhibiting different targets in these pathways has been under investigation in preclinical and clinical studies for more than decades, among which antibody against vascular endothelial growth factor is the most studied. However, the clinical impact from antiangiogenic treatment alone or in combination with standard chemotherapeutic regimens has been relatively small till today. In this review, we summarize the most clinically relevant data from breast cancer treatment clinical trials and discuss safety and efficacy of common antiangiogenic therapies as well as biological predictive markers. PMID- 24474818 TI - A Phase III trial comparing irinotecan and cisplatin with etoposide and cisplatin in adjuvant chemotherapy for completely resected pulmonary high-grade neuroendocrine carcinoma (JCOG1205/1206). AB - A randomized Phase III trial commenced in Japan in March 2013. Post-operative adjuvant chemotherapy with etoposide plus cisplatin is the current standard treatment for resected pulmonary high-grade neuroendocrine carcinoma including small cell lung cancer and large cell neuroendocrine carcinoma. The purpose of this study is to confirm the superiority of irinotecan plus cisplatin in terms of overall survival over etoposide plus cisplatin as post-operative adjuvant chemotherapy for pathological Stage I-IIIA completely resected pulmonary high grade neuroendocrine carcinoma patients. A total of 220 patients will be accrued from 54 Japanese institutions within 6 years. The primary endpoint is overall survival and the secondary endpoints are relapse-free survival, proportion of treatment completion, adverse events, serious adverse events and second malignancy. This trial has been registered at the UMIN Clinical Trials Registry as UMIN000010298 [http://www.umin.ac.jp/ctr/index.htm]. PMID- 24474819 TI - Hepatic Mttp deletion reverses gallstone susceptibility in L-Fabp knockout mice. AB - Previous studies demonstrated that L-Fabp KO mice are more susceptible to lithogenic diet (LD)-induced gallstones because of altered hepatic cholesterol metabolism and increased canalicular cholesterol secretion. Other studies demonstrated that liver-specific deletion of microsomal triglyceride transfer protein (Mttp-LKO) reduced LD-induced gallstone formation by increasing biliary phospholipid secretion. Here we show that mice with combined deletion (i.e., DKO mice) are protected from LD-induced gallstone formation. Following 2 weeks of LD feeding, 73% of WT and 100% of L-Fabp KO mice developed gallstones versus 18% of Mttp-LKO and 23% of DKO mice. This phenotype was recapitulated in both WT and L Fabp KO mice treated with an Mttp antisense oligonucleotide (M-ASO). Biliary cholesterol secretion was increased in LD-fed L-Fabp KO mice and decreased in DKO mice. However, phospholipid secretion was unchanged in LD-fed Mttp-LKO and DKO mice as well as in M-ASO-treated mice. Expression of the canalicular export pump ABCG5/G8 was reduced in LD-fed DKO mice and in M-ASO-treated L-Fabp KO mice. We conclude that liver-specific Mttp deletion not only eliminates apical lipoprotein secretion from hepatocytes but also attenuates canalicular cholesterol secretion, which in turn decreases LD-induced gallstone susceptibility. PMID- 24474821 TI - Marked olfactory impairment in idiopathic intracranial hypertension. AB - OBJECTIVE: Many long-duration astronauts develop signs of elevated intracranial pressure and have neuro-ophthalmological findings similar to idiopathic intracranial hypertension (IIH) patients. Some also present with nasal congestion and subjective olfactory impairment. We prospectively evaluated olfactory function in IIH patients and the effect of 6 degrees head-down tilt, which simulates the headward fluid shifting in microgravity, as spaceflight analogues. DESIGN: Olfaction was tested for all subjects in upright and 6 degrees head-down tilt positions using two different measures: University of Pennsylvania Smell Identification Test and Olfactory Threshold Sniffin' Sticks with phenylethyl alcohol. RESULTS: IIH patients (n=19) had significant impairment on both olfactory measures compared with matched controls (n=19). The olfactory threshold dilution levels were 9.07 (95% CI 1.85 to 5.81) and 3.83 (95% CI 7.04 to 11.10), p=0.001, and smell identification scores were 35.61 (95% CI 34.03 to 37.18) and 32.47 (95% CI 30.85 to 34.09), p=0.008, for control and IIH subjects, respectively. The threshold detection was mildly impaired in head-down tilt compared with upright position in the combined subjects (6.05 (95% CI 4.58 to 7.51) vs 6.85 (95% CI 5.43 to 8.27), p=0.004). CONCLUSIONS: We demonstrated that IIH patients have marked impairment in olfactory threshold levels, out of proportion to smell identification impairment. There was also impairment in olfactory threshold in head-down tilt compared with upright positioning, but not for smell identification. The underlying mechanisms for olfactory threshold dysfunction in IIH patients need further exploration. PMID- 24474822 TI - A dam for retrograde axonal degeneration in multiple sclerosis? AB - OBJECTIVE: Trans-synaptic axonal degeneration is a mechanism by which neurodegeneration can spread from a sick to a healthy neuron in the central nervous system. This study investigated to what extent trans-synaptic axonal degeneration takes place within the visual pathway in multiple sclerosis (MS). METHODS: A single-centre study, including patients with long-standing MS and healthy controls. Structural imaging of the brain (MRI) and retina (spectral domain optical coherence tomography) were used to quantify the extent of atrophy of individual retinal layers and the primary and secondary visual cortex. Generalised estimation equations and multivariable regression analyses were used for comparisons. RESULTS: Following rigorous quality control (OSCAR-IB), data from 549 eyes of 293 subjects (230 MS, 63 healthy controls) were included. Compared with control data, there was a significant amount of atrophy of the inner retinal layers in MS following optic neuritis (ON) and also in absence of ON. For both scenarios, atrophy stopped at the level of the inner nuclear layer. In contrast, there was significant localised atrophy of the primary visual cortex and secondary visual cortex in MS following ON, but not in MS in absence of ON. INTERPRETATION: These data suggest that retrograde (trans-synaptic) axonal degeneration stops at the inner nuclear layer, a neuronal network capable of plasticity. In contrast, there seems to be no neuroplasticity of the primary visual cortex, rendering the structure vulnerable to anterograde (trans-synaptic) degeneration. PMID- 24474823 TI - Documentation of oral versus intravenous chemotherapy plans in patients with metastatic non-small-cell lung cancer. AB - PURPOSE: Using the ASCO Quality Oncology Practice Initiative (QOPI) guidelines for assessing quality cancer care, we examined differences in clinician documentation of patient consent and treatment plans for oral versus intravenous chemotherapy among patients with metastatic non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: We conducted a retrospective review of the electronic health records of 175 patients diagnosed with metastatic NSCLC whose initial systemic treatment consisted of either oral or intravenous chemotherapy. Specifically, we collected data on whether oncology clinicians documented discussions of the intent of chemotherapy (eg, palliative v curative), the number of cycles or anticipated duration of the chemotherapy, and patient consent for the chemotherapy in the practitioner note. RESULTS: Of the 175 patients in the sample (54.3% female; mean age = 61.96 years, standard deviation = 10.81 years), 119 (68%) received intravenous chemotherapy, and 56 (32%) were prescribed oral agents for first-line chemotherapy. Compared with those who received intravenous chemotherapy, patients prescribed oral chemotherapy had lower rates of documented treatment plans, including intent (23.3% v 45.4%, P = .005) and anticipated duration of therapy (8.9% v 32.8%, P = .001). The rate of documentation of discussions regarding patient consent for chemotherapy did not differ significantly between groups (57.1% v 69.7, P = .13). CONCLUSION: Documentation of discussions regarding the goals and course of chemotherapy administration for patients with metastatic NSCLC does not meet ASCO QOPI quality standards, especially for individuals prescribed oral agents. Considering the increasing numbers of targeted oral therapies used in oncology practice, further work is needed to ensure appropriate discussion and documentation of chemotherapy plans. PMID- 24474820 TI - Export of sphingosine-1-phosphate and cancer progression. AB - Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that promotes cell survival, proliferation, migration, angiogenesis, lymphangiogenesis, and immune response; all are critical processes of cancer progression. Although some important roles of intracellular S1P have recently been uncovered, the majority of its biological effects are known to be mediated via activation of five specific G protein-coupled receptors [S1P receptor (S1PR)1-S1PR5] located on the cell surface. Secretion of S1P produced inside cells by sphingosine kinases can then signal through these receptors in autocrine, paracrine, and/or endocrine manners, coined "inside-out" signaling of S1P. Numerous studies suggest that secreted S1P plays important roles in cancer progression; thus, understanding the mechanism by which S1P is exported out of cells, particularly cancer cells, is both interesting and important. Here we will review the current understanding of the transport of S1P out of cancer cells and its potential roles in the tumor microenvironment. PMID- 24474824 TI - Priming of awareness or how not to measure visual awareness. AB - A foundational issue in the study of unconscious processing concerns whether the stimuli of interest are truly out of awareness. Objective methods employing forced choice are typically championed as the gold standard and widely thought to be conservative. Here, however, as a case study, we demonstrate an underestimation of awareness in a collection of studies on unconscious cognitive control. Specifically, we found that (a) in addition to genuine unawareness, chance performance could be due to a failure to perform the task; (b) visual awareness for low-visibility trials was elevated when mixed with high-visibility trials compared with when presented alone as demonstrated in both objective awareness (forced-choice performance) and subjective awareness (rating based on a perceptual awareness scale); and (c) the elevation effect was partly due to a shape-specific template enhancement at both the block and intertrial levels. We term the awareness elevation effect priming of awareness: Visual priming fundamentally alters awareness, boosting otherwise invisible objects into consciousness. These results implicate two key requirements for measuring awareness: (a) verify that participants are truly performing the awareness task and (b) use all types of trials in the awareness test as in the main experiment. Priming of awareness is consistent with an expanded model of awareness and top down attention in which awareness is determined by (a) retinal stimulus strength and (b) both goal-dependent and goal-independent extra-retinal modulation. PMID- 24474825 TI - Predicting human gaze beyond pixels. AB - A large body of previous models to predict where people look in natural scenes focused on pixel-level image attributes. To bridge the semantic gap between the predictive power of computational saliency models and human behavior, we propose a new saliency architecture that incorporates information at three layers: pixel level image attributes, object-level attributes, and semantic-level attributes. Object- and semantic-level information is frequently ignored, or only a few sample object categories are discussed where scaling to a large number of object categories is not feasible nor neurally plausible. To address this problem, this work constructs a principled vocabulary of basic attributes to describe object- and semantic-level information thus not restricting to a limited number of object categories. We build a new dataset of 700 images with eye-tracking data of 15 viewers and annotation data of 5,551 segmented objects with fine contours and 12 semantic attributes (publicly available with the paper). Experimental results demonstrate the importance of the object- and semantic-level information in the prediction of visual attention. PMID- 24474827 TI - Informatics: catching the next wave in pharmacy education. PMID- 24474828 TI - ISMP Medication Error Report Analysis. AB - These medication errors have occurred in health care facilities at least once. They will happen again-perhaps where you work. Through education and alertness of personnel and procedural safeguards, they can be avoided. You should consider publishing accounts of errors in your newsletters and/or presenting them at your inservice training programs. Your assistance is required to continue this feature. The reports described here were received through the Institute for Safe Medication Practices (ISMP) Medication Errors Reporting Program. Any reports published by ISMP will be anonymous. Comments are also invited; the writers' names will be published if desired. ISMP may be contacted at the address shown below. Errors, close calls, or hazardous conditions may be reported directly to ISMP through the ISMP Web site (www.ismp.org), by calling 800-FAIL-SAFE, or via e mail at ismpinfo@ismp.org. ISMP guarantees the confidentiality and security of the information received and respects reporters' wishes as to the level of detail included in publications. PMID- 24474829 TI - ISMP Adverse Drug Reactions. AB - The purpose of this feature is to heighten awareness of specific adverse drug reactions (ADRs), discuss methods of prevention, and promote reporting of ADRs to the US Food and Drug Administration's (FDA's) MedWatch program (800-FDA-1088). If you have reported an interesting, preventable ADR to MedWatch, please consider sharing the account with our readers. Write to Dr. Mancano at ISMP, 200 Lakeside Drive, Suite 200, Horsham, PA 19044 (phone: 215-707-4936; e-mail: mmancano@temple.edu). Your report will be published anonymously unless otherwise requested. This feature is provided by the Institute for Safe Medication Practices (ISMP) in cooperation with the FDA's MedWatch program and Temple University School of Pharmacy. ISMP is an FDA MedWatch partner. PMID- 24474830 TI - Gefitinib, Fluorouracil, Oxaliplatin, and Leucovorin (IFOX) Regimen for Colorectal Cancer. AB - The complexity of cancer chemotherapy requires pharmacists be familiar with the complicated regimens and highly toxic agents used. This column reviews various issues related to preparation, dispensing, and administration of antineoplastic therapy, and the agents, both commercially available and investigational, used to treat malignant diseases. Questions or suggestions for topics should be addressed to Dominic A. Solimando, Jr, President, Oncology Pharmacy Services, Inc., 4201 Wilson Blvd #110-545, Arlington, VA 22203, e-mail: OncRxSvc@comcast.net; or J. Aubrey Waddell, Professor, University of Tennessee College of Pharmacy; Oncology Pharmacist, Pharmacy Department, Blount Memorial Hospital, 907 E. Lamar Alexander Parkway, Maryville, TN 37804, e-mail: waddfour@charter.net. PMID- 24474831 TI - Alteplase: pleural effusion (parapneumonic) and empyema in children. AB - This Hospital Pharmacy feature is extracted from Off-Label Drug Facts, a publication available from Wolters Kluwer Health. Off-Label Drug Facts is a practitioner-oriented resource for information about specific drug uses that are unapproved by the US Food and Drug Administration. This new guide to the literature enables the health care professional or clinician to quickly identify published studies on off-label uses and determine if a specific use is rational in a patient care scenario. References direct the reader to the full literature for more comprehensive information before patient care decisions are made. Direct questions or comments regarding Off-Label Drug Uses to jgeneral@ku.edu. PMID- 24474832 TI - Federal controlled substances act: ordering and recordkeeping. PMID- 24474833 TI - Evaluation of a dedicated pharmacist staffing model in the medical intensive care unit. AB - PURPOSE: Published studies have shown that pharmacists on medical rounds reduce the incidence of preventable adverse drug events (ADEs). However, the impact of a dedicated pharmacist who provides consistent patient care in a critical care unit remains to be evaluated. OBJECTIVE: To determine the impact of a pharmacist who is permanently assigned to the medical intensive care unit (MICU) on the incidence of preventable ADEs, drug charges, and length of stay (LOS) in the MICU. DESIGN: A randomized, experimental versus historical control group design was used. Preventable ADEs were identified and validated by 2 pharmacists and a critical care physician. Information about MICU drug charges and LOS were obtained from the hospital administrative database. RESULTS: The intervention group had fewer occurrences of ADEs (10 ADEs/1,000 patient days) when compared to the control group (28 ADEs/1,000 patient days) at a significance level of .03. No significant differences were found between the 2 groups in MICU drug charges and LOS. The vast majority of the 596 documented recommended interventions (99%) were accepted by the medical team. Nutrition monitoring, medication indicated but not prescribed, and dosage modification were the top 3 problems identified by the pharmacist. CONCLUSION: The addition of a dedicated critical care pharmacist to the MICU medical team improves the safe use of medication. The services of a dedicated critical care pharmacist should be expanded to include weekend hours to ensure the benefits of improved medication safety. PMID- 24474834 TI - Adverse drug reactions: a retrospective review of hospitalized patients at a state psychiatric hospital. AB - BACKGROUND: There is a paucity of information regarding adverse drug reactions (ADRs) in psychiatric patients. Information on common and preventable ADRs (pADRs) in psychiatric patients will allow for targeted improvement projects. OBJECTIVE: To characterize reported ADRs and pharmacist interventions to prevent ADRs in an extended-care state psychiatric hospital. METHODS: Four years of ADR reports were assessed for probability, reaction severity, pharmacological class of medication involved, preventability, change in therapy, and transfers to a medical facility. The pharmacist intervention database was queried for interventions classified as "prevention of ADR." The interventions were assessed for type of medication and recommendation acceptance. RESULTS: Medication classes responsible for ADRs included mood stabilizers (30%), typical antipsychotics (25%), atypical antipsychotics (25%), and antidepressants (8%). Nine percent resulted in transfer to a medical facility. Of all ADRs, 34.4% were pADRs; mood stabilizers (41%) and atypical antipsychotics (27%) were the most common pADRs. The most common causes of pADRs were supratherapeutic serum concentrations, drug drug interactions, and history of reaction. There were 87 pharmacist interventions that were classified as "prevention of ADR," and the acceptance rate of pharmacists' recommendations was 96.5%. Mood stabilizers (20%), atypical antipsychotics (17%), and typical antipsychotics (11%) were commonly associated with prevented ADRs. Lithium accounted for 13.8% of prevented ADRs; these ADRs were most often due to a drug-drug interaction with a nonsteroidal anti inflammatory drug. CONCLUSIONS: ADRs were most commonly associated with mood stabilizers and antipsychotics, and pADRs were common. There is an opportunity to provide education to medical staff on therapeutic drug monitoring and drug-drug interactions for these classes, particularly lithium. PMID- 24474835 TI - Evaluation of bleeding rates in renal transplant patients on therapeutic intravenous heparin. AB - BACKGROUND: It is unknown whether coagulation properties differ between renal transplant and nontransplant patients. OBJECTIVE: To assess whether renal transplant patients on intravenous (IV) heparin, titrated to therapeutic activated partial thromboplastin times (aPPT; 56-93 seconds), experienced a higher rate of bleeding compared to nontransplant patients. METHODS: Twenty-nine renal transplant and 29 nontransplant patients receiving IV heparin for a deep vein thrombosis, pulmonary embolism, atrial fibrillation, or acute coronary syndrome were randomly identified through a retrospective chart review. RESULTS: Renal transplant patients had higher bleeding rates on IV heparin therapy compared to nontransplant patients (31% vs 6.9%, respectively; P = .041). Renal transplant patients experienced a drop in hemoglobin of at least 1 g/dL or the need for a transfusion more often then nontransplant patients (69% vs 45%, respectively; P = .111), although the difference was not statistically significant. CONCLUSIONS: Further research is necessary to identify the factors contributing to increased rates of bleeding in renal transplant patients on IV heparin and to determine the ideal aPTT to appropriately balance anticoagulation in renal transplant patients. PMID- 24474836 TI - Using smart pumps to understand and evaluate clinician practice patterns to ensure patient safety. AB - BACKGROUND: Safety software installed on intravenous (IV) infusion pumps has been shown to positively impact the quality of patient care through avoidance of medication errors. The data derived from the use of smart pumps are often overlooked, although these data provide helpful insight into the delivery of quality patient care. OBJECTIVE: The objectives of this report are to describe the value of implementing IV infusion safety software and analyzing the data and reports generated by this system. CASE STUDY: Based on experience at the Carolinas HealthCare System (CHS), executive score cards provide an aggregate view of compliance rate, number of alerts, overrides, and edits. The report of serious errors averted (ie, critical catches) supplies the location, date, and time of the critical catch, thereby enabling management to pinpoint the end-user for educational purposes. By examining the number of critical catches, a return on investment may be calculated. Assuming 3,328 of these events each year, an estimated cost avoidance would be $29,120,000 per year for CHS. Other reports allow benchmarking between institutions. CONCLUSION: A review of the data about medication safety across CHS has helped garner support for a medication safety officer position with the goal of ultimately creating a safer environment for the patient. PMID- 24474837 TI - Prothrombin complex concentrate. AB - Each month, subscribers to The Formulary Monograph Service receive 5 to 6 well documented monographs on drugs that are newly released or are in late phase 3 trials. The monographs are targeted to Pharmacy & Therapeutics Committees. Subscribers also receive monthly 1-page summary monographs on agents that are useful for agendas and pharmacy/nursing in-services. A comprehensive target drug utilization evaluation/medication use evaluation (DUE/MUE) is also provided each month. With a subscription, the monographs are sent in print and are also available on-line. Monographs can be customized to meet the needs of a facility. A drug class review is now published monthly with The Formulary Monograph Service. Through the cooperation of The Formulary, Hospital Pharmacy publishes selected reviews in this column. For more information about The Formulary Monograph Service, call The Formulary at 800-322-4349. The December 2013 monograph topics are vortioxetine, mechlorethamine gel, brimonidine tartrate topical gel, obinutuzumab, and miltefosine. The DUE/MUE is on vortioxetine. PMID- 24474838 TI - Approvals, Submission, and Important Labeling Changes for US Marketed Pharmaceuticals. AB - This monthly feature will help readers keep current on new drugs, new indications, dosage forms, and safety-related changes in labeling or use. Efforts have been made to ensure the accuracy of this information; however, if there are any questions, please let me know at danial.baker@wsu.edu. PMID- 24474839 TI - Measuring change in health-system pharmacy over 50 years: "reflecting" on the mirror, part I. AB - The Director's Forum guides pharmacy leaders in establishing patient-centered services in hospitals and health systems. August 2013 marked the 50th anniversary of the publication of the Mirror to Hospital Pharmacy, which was a comprehensive study of hospital pharmacy services in the United States. This iconic textbook was co-authored by Donald Francke, Clifton J. Latiolais, Gloria N. Francke, and Norman Ho. The Mirror profiled hospital pharmacy of the 1950s and established goals for the profession in 6 paradigms: (1) professional philosophy and ethics, (2) scientific and technical expansion of health-system pharmacy, (3) development of administrative and managerial acumen, (4) increased practice competence, (5) wage and salary compensation commensurate with professional responsibilities, and (6) health-system pharmacy as a vehicle for advancing the profession as a whole. This article critically reviews the profession's progress on the first 3 goals; an article in the January 2014 issue of Hospital Pharmacy will review the final 3 goals. An understanding of the profession's progress on these goals since the seminal work of the Mirror provides directors of pharmacy a platform from which to develop strategies to enhance patient-centered pharmacy services. PMID- 24474840 TI - Revisiting hospital readmissions. AB - Is your hospital addressing the readmission rate? Maybe efforts are underway, but pharmacy is not directly involved. Although many believe the readmission reduction program needs changes to better reflect quality care, the program is in place and likely impacts your institution. We provide a broad overview of the program and try to sensitize you to the technologies that can support medication related efforts. PMID- 24474841 TI - Electron-Rich CpIr(biphenyl-2,2'-diyl) Complexes with pi-Accepting Carbon Donor Ligands. AB - Cp*IrIII and CpIrIII complexes have attracted interest as catalysts for oxidative transformations, and highly oxidizing iridium species are postulated as key intermediates in both catalytic water and C-H bond oxidation. Strongly electron donating ligand sets have been shown to stabilize IrIV complexes. We describe the synthesis and reactivity of complexes containing the CpIr(biphenyl-2,2'-diyl) moiety stabilized by a series of strong donor carbon-based ligands. The oxidation chemistry of these complexes has been characterized electrochemically, and a singly oxidized IrIV species has been observed by X-band EPR for the complex CpIr(biph)(p-CNCH2SO2C6H4CH3). PMID- 24474842 TI - Probing the Viability of Oxo-Coupling Pathways in Iridium-Catalyzed Oxygen Evolution. AB - A series of Cp*IrIII dimers have been synthesized to elucidate the mechanistic viability of radical oxo-coupling pathways in iridium-catalyzed O2 evolution. The oxidative stability of the precursors toward nanoparticle formation and their oxygen evolution activity have been investigated and compared to suitable monomeric analogues. We found that precursors bearing monodentate NHC ligands degraded to form nanoparticles (NPs), and accordingly their O2 evolution rates were not significantly influenced by their nuclearity or distance between the two metals in the dimeric precursors. A doubly chelating bis-pyridine-pyrazolide ligand provided an oxidation-resistant ligand framework that allowed a more meaningful comparison of catalytic performance of dimers with their corresponding monomers. With sodium periodate (NaIO4) as the oxidant, the dimers provided significantly lower O2 evolution rates per [Ir] than the monomer, suggesting a negative interaction instead of cooperativity in the catalytic cycle. Electrochemical analysis of the dimers further substantiates the notion that no radical oxyl-coupling pathways are accessible. We thus conclude that the alternative path, nucleophilic attack of water on high-valent Ir-oxo species, may be the preferred mechanistic pathway of water oxidation with these catalysts, and bimolecular oxo-coupling is not a valid mechanistic alternative as in the related ruthenium chemistry, at least in the present system. PMID- 24474843 TI - Educational Barriers of Rural Youth: Relation of Individual and Contextual Difference Variables. AB - The purpose of this study was to examine the relation of several individual and contextual difference factors to the perceived educational barriers of rural youth. Data were from a broader national investigation of students' postsecondary aspirations and preparation in rural high schools across the United States. The sample involved more than 7,000 rural youth in 73 high schools across 34 states. Results indicated that some individual (e.g., African American race/ethnicity) and contextual (e.g., parent education) difference factors were predictive while others were not. Extensions to, similarities, and variations with previous research are discussed. Implications, limitations, and suggestions for future research are also discussed. PMID- 24474844 TI - Hematology point of care testing and laboratory errors: an example of multidisciplinary management at a children's hospital in northeast Italy. AB - Involvement of health personnel in a medical audit can reduce the number of errors in laboratory medicine. The checked control of point of care testing (POCT) could be an answer to developing a better medical service in the emergency department and decreasing the time taken to report tests. The performance of sanitary personnel from different disciplines was studied over an 18-month period in a children's hospital. Clinical errors in the emergency and laboratory departments were monitored by: nursing instruction using specific courses, POCT, and external quality control; improvement of test results and procedural accuracy; and reduction of hemolyzed and nonprotocol-conforming samples sent to the laboratory department. In January 2012, point of care testing (POCT) was instituted in three medical units (neonatology, resuscitation, delivery room) at the Children's Hospital in Trieste, northeast Italy, for analysis of hematochemical samples. In the same period, during the months of January 2012 and June 2013, 1,600 samples sent to central laboratory and their related preanalytical errors were examined for accuracy. External quality control for POCT was also monitored in the emergency department; three meetings were held with physicians, nurses, and laboratory technicians to highlight problems, ie, preanalytical errors and analytical methodologies associated with POCT. During the study, there was an improvement in external quality control for POCT from -3 or -2 standard deviations or more to one standard deviation for all parameters. Of 800 samples examined in the laboratory in January 2012, we identified 64 preanalytical errors (8.0%); in June 2013, there were 17 preanalytical errors (2.1%), representing a significant decrease (P<0.05, chi(2) test). Multidisciplinary management and clinical audit can be used as tools to detect errors caused by organizational problems outside the laboratory and improve clinical and economic outcomes. PMID- 24474845 TI - Treatment of uncomplicated hemorrhoids with a Hemor-Rite(r) cryotherapy device: a randomized, prospective, comparative study. AB - Hemorrhoids are one of the most common ailments known. Often described as "varicose veins of the anus and rectum", hemorrhoids are enlarged, bulging blood vessels in, and about the anus and lower rectum. About 75% of people will have hemorrhoids at some point in their lives. This paper shares the results from the clinical evaluation conducted to study effects of cryotherapy in treating uncomplicated hemorrhoids. The device used in the study is based on topically applied cold therapy which can produce vasoconstriction in the tissues, tissue hypoxia, analgesia, and muscle relaxation. Cryotherapy was shown to be statistically similar or superior to proctology ointment in some of the parameters studied such as reduction of pain and hemorrhage. Overall it was observed that cryotherapy device contributes to improving the quality of life of patients with hemorrhoids. PMID- 24474846 TI - SVR12 is higher than SVR24 in treatment-naive hepatitis C genotype 1 patients treated with peginterferon plus ribavirin. AB - BACKGROUND: Randomized clinical trials (RCTs) of interventions for the hepatitis C virus have historically used sustained virological response (SVR) at 24 weeks after treatment (SVR24) as the key effect measure. However, recent RCTs investigating the efficacy of new direct acting agents (DAAs) have used SVR at 12 weeks after treatment (SVR12). While there is evidence to suggest SVR24 and SVR12 are similar in patients receiving new DAAs, this is unlikely to be true for patients receiving backbone peginterferon-ribavirin control treatment. Establishing the difference between SVR12 and SVR24 for patients receiving peginterferon-ribavirin treatment is therefore necessary to avoid biased interpretations of the benefits of newer DAAs. METHODS: We searched the MEDLINE(r), EmbaseTM, and Cochrane CENTRAL for RCTs with a peginterferon ribavirin arm that used SVR24 and/or SVR12. As no RCTs reported on both, we pooled SVR12 and SVR24 proportions using conventional meta-analysis. Proportions were pooled separately for peginterferon alpha-2a and alpha-2b. Further, a Bayesian meta-regression model was employed to estimate the difference between SVR12 and SVR24. RESULTS: Thirty-five RCTs including a peginterferon arm were identified. Twenty-four trials included a peginterferon alpha-2a plus ribavirin arms, of which 20 reported SVR24 and five reported SVR12. Seventeen trials included a peginterferon alpha-2b plus ribavirin arm, of which 16 reported SVR24 and one reported SVR12. Using Bayesian meta-regression, the pooled SVR12 was 6% higher than SVR24 with peginterferon alpha-2a (53% versus 47%) and 5% higher with peginterferon alpha-2b (45% versus 40%) and 95% credible intervals (CrIs) were only marginally overlapping. The meta-regression also demonstrated a marginally significant relative risk of 1.13 (95% CrI 0.99-1.26) of SVR12 versus SVR24. The conventional pairwise meta-analyses were consistent with these findings. CONCLUSION: Considering the relatively large difference observed between SVR12 and SVR24, it seems reasonable to insist that future clinical trials report both to allow for complete transparency and clarity in their interpretation. PMID- 24474847 TI - Prescribing menopausal hormone therapy: an evidence-based approach. AB - The constantly changing landscape regarding menopausal hormone therapy (MHT) has been challenging for providers caring for menopausal women. After a decade of fear and uncertainty regarding MHT, reanalysis of the Women's Health Initiative data and the results of recent studies have provided some clarity regarding the balance of risks and benefits of systemic MHT. Age and years since menopause are now known to be important variables affecting the benefit-risk profile. For symptomatic menopausal women who are under 60 years of age or within 10 years of menopause, the benefits of MHT generally outweigh the risks. Systemic MHT initiated early in menopause appears to slow the progression of atherosclerotic disease, thereby reducing the risk of cardiovascular disease and mortality. During this window of opportunity, MHT might also provide protection against cognitive decline. In older women and women more than 10 years past menopause, the risk-benefit balance of MHT is less favorable, particularly with regard to cardiovascular risk and cognitive impairment. For women entering menopause prematurely (<40 years), MHT ameliorates the risk of cardiovascular disease, osteoporosis, and cognitive decline. Nonoral administration of estrogen offers advantages due to the lack of first-pass hepatic metabolism, which in turn avoids the increased hepatic synthesis of clotting proteins, C-reactive protein, triglycerides, and sex hormone-binding globulin. The duration of combined MHT use is ideally limited to less than 5 years because of the known increase in breast cancer risk after 3-5 years of use. Limitations to use of estrogen only MHT are less clear, since breast cancer risk does not appear to increase with use of estrogen alone. For women under the age of 60 years, or within 10 years of onset of natural menopause, MHT for the treatment of bothersome menopausal symptoms poses low risk and is an acceptable option, particularly when nonhormonal management approaches fail. PMID- 24474848 TI - Clinical challenges in the management of vaginal prolapse. AB - Pelvic organ prolapse is highly prevalent, and negatively affects a woman's quality of life. Women with bothersome prolapse may be offered pessary management or may choose to undergo corrective surgery. In choosing the most appropriate surgical procedure, there are many factors to consider. These may include the location(s) of anatomic defects, the severity of prolapse symptoms, the activity level of the woman, and concerns regarding the durability of the repair. In many instances, women and their surgeons are challenged to weigh the risks and benefits of native tissue versus mesh-augmented repairs. Though mesh-augmented repairs may offer better durability, they are also associated with unique complications, such as mesh erosion. Furthermore, newer surgical techniques of mesh placement via abdominal or vaginal routes may result in different outcomes compared to traditional techniques. Biologic grafts may also be considered to improve durability of a surgical repair, while avoiding potential complications of synthetic mesh. In this article, we review many of the clinical challenges that gynecologic surgeons face in the surgical management of vaginal prolapse. Furthermore, we review data that can help guide decision making when treating women with pelvic organ prolapse. PMID- 24474849 TI - Alcohol consumption and gender in rural Samoa. AB - INTRODUCTION AND AIMS: There are significant gender differences in alcohol consumption throughout the world. Here we report the results of an alcohol consumption survey on the rural island of Savaii, in the Pacific nation of Samoa. DESIGN AND METHODS: Eleven villages were selected for sampling using a randomized stratified cluster sampling methodology. A total of 1049 inhabitants over the age of 40 years (485 males and 564 females) were surveyed about alcohol consumption over the past year, and a 72.2% participation rate was achieved. RESULTS: A SIGNIFICANT GENDER DIFFERENCE IN ALCOHOL CONSUMPTION WAS FOUND: 97.3% of women and 59.4% of men reported no alcohol consumption over the past year. This is one of the most significant gender differences in alcohol consumption in the world. No significant difference between genders was seen in those who consume only 1-5 alcoholic drinks per week (P = 0.8454). However, significantly more males than females consumed 6-25 drinks per week (P < 0.0001), 26-75 drinks per week (P < 0.0001), and 75+ drinks per week (P < 0.0001). DISCUSSION AND CONCLUSION: This extreme gender difference in alcohol consumption is attributed to several factors, both general (alcoholic metabolism rates, risk-taking behaviors, general cultural taboos, etc) and specific to Samoa (church influence, financial disempowerment, and Samoan gender roles). PMID- 24474850 TI - Theory of planned behavior and smoking: meta-analysis and SEM model. AB - To examine if the theory of planned behavior (TPB) predicts smoking behavior, 35 data sets (N = 267,977) have been synthesized, containing 219 effect sizes between the model variables, using a meta-analytic structural equation modeling approach (MASEM). Consistent with the TPB's predictions, 1) smoking behavior was related to smoking intentions (weighted mean r = 0.30), 2) intentions were based on attitudes (weighted mean r = 0.16), and subjective norms (weighted mean r = 0.20). Consistent with TPB's hypotheses, perceived behavioral control was related to smoking intentions (weighted mean r = -0.24) and behaviors (weighted mean r = 0.20) and it contributes significantly to cigarette consumption. The strength of the associations, however, was influenced by the characteristics of the studies and participants. PMID- 24474851 TI - To use or not to use: an update on licit and illicit ketamine use. AB - Ketamine, a derivative of phencyclidine that was developed in the 1960s, is an anesthetic and analgesic with hallucinogenic effects. In this paper, the pharmacological and toxicological effects of ketamine are briefly reviewed. Ketamine possesses a wide safety margin but such a therapeutic benefit is somewhat offset by its emergence phenomenon (mind-body dissociation and delirium) and hallucinogenic effects. The increasing abuse of ketamine, initially predominantly in recreational scenes to experience a "k-hole" and other hallucinatory effects but more recently also as a drug abused during the workday or at home, has further pushed governments to confine its usage in many countries. Recently, urinary tract dysfunction has been associated with long-term ketamine use. In some long-term ketamine users, such damage can be irreversible and could result in renal failure and dialysis. Although ketamine has not yet been scheduled in the United Nations Conventions, previous studies using different assessment parameters to score the overall harms of drugs indicated that ketamine may cause more harm than some of the United Nations scheduled drugs. Some countries in Southeast and East Asia have reported an escalating situation of ketamine abuse. Dependence, lower urinary tract dysfunction, and sexual impulse or violence were the most notable among the ketamine-associated symptoms in these countries. These results implied that the danger of ketamine may have been underestimated previously. Therefore, the severity levels of the ketamine-associated problems should be scrutinized more carefully and objectively. To prevent ketamine from being improperly used and evolving into an epidemic, a thorough survey on the prevalence and characteristics of illicit ketamine use is imperative so that suitable policy and measures can be taken. On the other hand, recent findings that ketamine could be useful for treating major depressive disorder has given this old drug a new impetus. If ketamine is indeed a remedy for treating depression, more research on the risks and benefits of its clinical use will be indispensable. PMID- 24474852 TI - The National Drug Abuse Treatment Clinical Trials Network: forging a partnership between research knowledge and community practice. AB - The National Drug Abuse Treatment Clinical Trials Network (CTN) has faced many challenges over its first eleven years. This review explores some of these challenges and the paths the CTN took to meet these challenges, including: designing clinical trials that reflect the CTN's mission and changing public health needs, finding the synergies in the varied expertise of clinical treatment providers and academic researchers, promoting evidence-based practices and expanding the Network into mainstream medical practices to reach a broader patient population. Included in this exploration are specific examples from CTN clinical trials. PMID- 24474853 TI - Adapting an evidence-based HIV prevention intervention for pregnant African American women in substance abuse treatment. AB - An adaptation of an evidence-based, woman-focused intervention designed to reduce HIV risk behaviors was conducted for pregnant, African-American women in substance abuse treatment in North Carolina. The intervention adaptation process included focus groups, expert panels, and the filming of women who spoke about their experiences with pregnancy, drug use, sex risk behaviors, HIV testing and treatment, need for substance abuse treatment, violence, and victimization. The assessment instrument was adapted for pregnant women and the intervention was organized into a 4-session PowerPoint presentation, with an additional session if a woman tested positive for HIV. All sessions and assessment instrument were installed on laptop computers for portability in treatment programs. We pilot tested our adaptation with 59 pregnant African-American women who had used an illicit drug within the past year and were enrolled in substance abuse treatment. At baseline, 41% were currently homeless, 76% were unemployed, 90% had not planned their current pregnancy, and approximately 70% reported drug use since finding out about the pregnancy. This sample of participants rated the intervention sessions and were highly satisfied with their experience, resulting in a mean satisfaction score of 6.5 out of 7. Pregnant African-American women who use drugs need substance abuse treatment that they do not currently access. Woman focused HIV interventions help to address intersecting risk behaviors and need for treatment prevalent among this vulnerable group. PMID- 24474855 TI - Selective review and commentary on emerging pharmacotherapies for opioid addiction. AB - Pharmacotherapies for opioid addiction under active development in the US include lofexidine (primarily for managing withdrawal symptoms) and Probuphine(r), a distinctive mode of delivering buprenorphine for six months, thus relieving patients, clinicians, and regulatory personnel from most concerns about diversion, misuse, and unintended exposure in children. In addition, two recently approved formulations of previously proven medications are in early phases of implementation. The sublingual film form of buprenorphine + naloxone (Suboxone(r)) provides a less divertible, more quickly administered, more child proof version than the buprenorphine + naloxone sublingual tablet. The injectable depot form of naltrexone (Vivitrol(r)) ensures consistent opioid receptor blockade for one month between administrations, removing concerns about medication compliance. The clinical implications of these developments have attracted increasing attention from clinicians and policymakers in the US and around the world, especially given that human immunodeficiency virus/acquired immunodeficiency syndrome and other infectious diseases are recognized as companions to opioid addiction, commanding more efforts to reduce opioid addiction. While research and practice improvement efforts continue, reluctance to adopt new medications and procedures can be expected, especially considerations in the regulatory process and in the course of implementation. Best practices and improved outcomes will ultimately emerge from continued development efforts that reflect input from many quarters. PMID- 24474856 TI - Against professional advice: treatment attrition among pregnant methamphetamine users. AB - Pregnant methamphetamine users who leave substance use treatment against professional advice may be at risk of poorer health outcomes. To examine the hypothesis that methamphetamine use during pregnancy may be associated with leaving substance use treatment against professional advice, the 2006 Treatment Episode Data Set was analyzed. A logistic regression adjusting for age, race, service setting, prior substance abuse treatment, criminal justice referral, and education was conducted. Inclusion criteria were met by 18,688 pregnant admissions; 26.4% identified methamphetamines as their primary substance of use. Frequency of use was identified as an effect modifier, therefore results were stratified by less than weekly use and weekly or more use. Methamphetamine use was significantly associated with leaving treatment against professional advice regardless of usage level. However, the odds of leaving treatment were greater among women using methamphetamine less than weekly. Further investigation into this association may be warranted due to the complications that may result from methamphetamine use during pregnancy. PMID- 24474854 TI - Intersection of chronic pain treatment and opioid analgesic misuse: causes, treatments, and policy strategies. AB - Treating chronic pain in the context of opioid misuse can be very challenging. This paper explores the epidemiology and potential treatments for chronic pain and opioid misuse and identifies educational and regulation changes that may reduce diversion of opioid analgesics. We cover the epidemiology of chronic pain and aberrant opioid behaviors, psychosocial influences on pain, pharmacological treatments, psychological treatments, and social treatments, as well as educational and regulatory efforts being made to reduce the diversion of prescription opioids. There are a number of ongoing challenges in treating chronic pain and opioid misuse, and more research is needed to provide strong, integrated, and empirically validated treatments to reduce opioid misuse in the context of chronic pain. PMID- 24474857 TI - The Global Youth Tobacco Survey: 2001-2002 in Riyadh region, the Kingdom of Saudi Arabia. AB - BACKGROUND: Tobacco use is a major public health problem, and its prevalence is globally increasing, especially among children and adolescents. OBJECTIVE: The Global Youth Tobacco Survey aimed to explore the epidemiological trends and risk factors of tobacco smoking among intermediate school boys in Riyadh region of the Kingdom of Saudi Arabia. METHOD: A two-stage cluster sample design was used to produce a representative sample of male students from selected schools. The participants (n = 1830) self recorded their responses on the Global Youth Tobacco Survey questionnaire. RESULTS: Lifetime prevalence of cigarette smoking was 35%, while 13% of students currently used other tobacco products. About 16% of students currently smoked at home, and 84% of students bought cigarettes without any refusal from storekeepers. Thirty-one percent and 39% of students were exposed to secondhand tobacco smoke inside and outside the house, respectively, which was definitely or probably harmful to health as opined by 87% of participants, and 74% voiced to ban smoking from public places. Among current smokers, 69% intended (without attempt) to quit and 63% attempted (but failed) to quit during the past year. Almost an equal number of students saw antismoking and prosmoking media messages in the last month, and 28% of students were offered free cigarettes by a tobacco company representative. In schools, more than 50% of students were taught about the dangers of cigarette smoking in the last year. Smoking by parents, older brothers, and close friends, watching prosmoking cigarette advertisements, free offer of cigarettes by tobacco company representatives, perception of smoking being not harmful, and continuing smoking which can be easily quit significantly increased the odds of smoking by students. CONCLUSION: The common use of tobacco in school populations needs to be addressed by, among other tobacco control measures, a strict ban on cigarette selling to minors and intensive regular tobacco control campaigns involving health and religious messages. PMID- 24474858 TI - Addiction treatment trials: how gender, race/ethnicity, and age relate to ongoing participation and retention in clinical trials. AB - INTRODUCTION: Historically, racial and ethnic minority populations have been underrepresented in clinical research, and the recruitment and retention of women and ethnic minorities in clinical trials has been a significant challenge for investigators. The National Drug Abuse Treatment Clinical Trials Network (CTN) conducts clinical trials in real-life settings and regularly monitors a number of variables critical to clinical trial implementation, including the retention and demographics of participants. PURPOSE: The examination of gender, race/ethnicity, and age group differences with respect to retention characteristics in CTN trials. METHODS: Reports for 24 completed trials that recruited over 11,000 participants were reviewed, and associations of gender, race/ethnicity, and age group characteristics were examined along with the rate of treatment exposure, the proportion of follow-up assessments obtained, and the availability of primary outcome measure(s). RESULTS: Analysis of the CTN data did not indicate statistical differences in retention across gender or race/ethnicity groups; however, retention rates increased for older participants. CONCLUSION: These results are based on a large sample of patients with substance use disorders recruited from a treatment-seeking population. The findings demonstrate that younger participants are less likely than older adults to be retained in clinical trials. PMID- 24474859 TI - Naltrexone extended-release injection: an option for the management of opioid abuse. AB - The United States Food and Drug Administration (FDA) approved naltrexone, a synthetic competitive antagonist at opioid receptors, in oral form in 1984 for use in the management of opioid abuse and addiction. Because naltrexone and its major metabolite, 6-beta-naltrexone, are both competitive antagonists at opioid receptors - and thereby inhibit opioid agonist-induced effects including those desired by abusers - it was hypothesized that once maintained on naltrex-one, opioid-induced desirable effects would be diminished to the point that relapse to illicit use would decline because it was no longer rewarding. However, good medication compliance is a requisite for such a strategy to be effective and a systematic review of oral naltrexone concluded that this method of treatment was not superior for any outcomes measured (ie, retention, abstinence, or side effects) to placebo, psychotherapy, benzodiazepines, or buprenorphine treatment. In addition, the retention rate on oral naltrexone was very low (less than 30%). Recently, the FDA approved an extended-release formulation (intramuscular depot injection) of naltrexone for prevention of relapse to opioid dependence following opioid detoxification and to be used along with counseling and social support. Since it needs to be administered only monthly, as opposed to the daily administration required for the oral formulation, naltrexone injection has the potential for increasing adherence and retention rates. Concerns include liver damage at high doses (oral formulation) and possible opioid overdose if an attempt is made to surmount receptor antagonism by taking higher doses of an opioid agonist or if opioid receptors become "sensitized" under long-term antagonism. The focus of the present review is the current information regarding the safety and efficacy of naltrexone extended-release therapy. PMID- 24474860 TI - Privacy protection for patients with substance use problems. AB - Many Americans with substance use problems will have opportunities to receive coordinated health care through the integration of primary care and specialty care for substance use disorders under the Patient Protection and Affordable Care Act of 2010. Sharing of patient health records among care providers is essential to realize the benefits of electronic health records. Health information exchange through meaningful use of electronic health records can improve health care safety, quality, and efficiency. Implementation of electronic health records and health information exchange presents great opportunities for health care integration, but also makes patient privacy potentially vulnerable. Privacy issues are paramount for patients with substance use problems. This paper discusses major differences between two federal privacy laws associated with health care for substance use disorders, identifies health care problems created by privacy policies, and describes potential solutions to these problems through technology innovation and policy improvement. PMID- 24474862 TI - Letter to the editor. PMID- 24474861 TI - Electronic health records: essential tools in integrating substance abuse treatment with primary care. AB - While substance use problems are considered to be common in medical settings, they are not systematically assessed and diagnosed for treatment management. Research data suggest that the majority of individuals with a substance use disorder either do not use treatment or delay treatment-seeking for over a decade. The separation of substance abuse services from mainstream medical care and a lack of preventive services for substance abuse in primary care can contribute to under-detection of substance use problems. When fully enacted in 2014, the Patient Protection and Affordable Care Act 2010 will address these barriers by supporting preventive services for substance abuse (screening, counseling) and integration of substance abuse care with primary care. One key factor that can help to achieve this goal is to incorporate the standardized screeners or common data elements for substance use and related disorders into the electronic health records (EHR) system in the health care setting. Incentives for care providers to adopt an EHR system for meaningful use are part of the Health Information Technology for Economic and Clinical Health Act 2009. This commentary focuses on recent evidence about routine screening and intervention for alcohol/drug use and related disorders in primary care. Federal efforts in developing common data elements for use as screeners for substance use and related disorders are described. A pressing need for empirical data on screening, brief intervention, and referral to treatment (SBIRT) for drug-related disorders to inform SBIRT and related EHR efforts is highlighted. PMID- 24474863 TI - Alcohol and drug use among sexual minority college students and their heterosexual counterparts: the effects of experiencing and witnessing incivility and hostility on campus. AB - PURPOSE: Research suggests that discrimination contributes to increased substance use among sexual minorities. Subtle discrimination and witnessing mistreatment, however, have received little attention. Using minority stress theory as a conceptual framework the authors examined the intersection of sexual orientation, experiencing and witnessing incivility and hostility, and students' alcohol and drug use. The authors hypothesized that experiencing/witnessing incivility/hostility would mediate the relationship between sexual minority status and drinking and drug use, as well as problematic use of these substances. METHODS: Data were taken from a campus climate survey (n = 2497; age mean [M] = 23.19 years; 61% female; 17% sexual minorities). Controlling for demographics, logistic regressions depicted specifications for each path of the mediation analysis and bootstrapping was used to assess the significance of each sexual minority-mistreatment-drinking/drug use path. RESULTS: Experiencing incivility mediated the relationship between sexual minority status and problematic drinking. Sexual minority college students were more likely to personally experience incivility (adjusted odds ratio [AOR] = 1.87; 95% confidence interval [CI] = 1.51-2.33), which was associated with greater odds of problematic drinking (AOR = 1.64; 95% CI = 1.35-2.00). The mediation path was significant at P < 0.001. Further, witnessing hostility mediated the relationship between sexual minority status and problematic drinking. Sexual minority college students were more likely to witness hostility (AOR = 1.87, 95% CI = 1.48-2.36), which was associated with greater odds of problematic drinking (AOR = 1.53; 95% CI = 1.24 1.90). The mediation path was significant at P < 0.01. CONCLUSION: The results provide further evidence for minority stress theory and suggest that clinical alcohol use interventions with sexual minorities need to assess personal incivilities and witnessing interpersonal mistreatment, especially hostility. Campus climate interventions that address subtle discrimination as well as harassment and violence may help reduce problematic drinking. PMID- 24474864 TI - Risk profiles of treatment noncompletion for inpatients and outpatients undergoing alcohol disorder rehabilitation treatment. AB - BACKGROUND: Rehabilitation treatment noncompletion is considered a risk factor for long term relapse in alcohol-dependent individuals. The aim of this analysis of in- and outpatients in alcohol dependence rehabilitation in Germany is to identify social, mental, and somatic risk profiles for treatment noncompletion. METHODS: A total of 92 individuals from an outpatient program and 303 individuals from two inpatient rehabilitation treatment units in three different locations in Germany were recruited and assessed with a structured interview and several measures of psychopathology (personality disorders, anxiety, depression, and impulsivity) at treatment admission, with termination at 12 months follow-up. Participants were subdivided into treatment completers and noncom-pleters for any reason. RESULTS: A total of 10.2% of inpatients and 16.1% of outpatients did not complete treatment. Compared with treatment completers, noncompleters had a significantly lower rate of continuous abstinence at 1-year follow-up, more recent alcohol consumption before admission, and a higher rate of borderline personality disorders. Among inpatients, an elevated rate of lifetime mental disorders, depression, and suicide attempts was found among treatment noncompleters; among outpatients, treatment noncompleters were more often than completers to be married but live separated. CONCLUSION: Rates of treatment noncompletion in inpatient and outpatient rehabilitation programs correspond to results from previous research. Noncompletion is a significant correlate of relapse 1 year after treatment, and noncompleters show an elevated level of psychopathology. These findings may help rehabilitation treatment facilities to tailor specific therapies for these individuals to reduce risk for treatment noncompletion. PMID- 24474865 TI - Pericyazine in the treatment of cannabis dependence in general practice: a naturalistic pilot trial. AB - Cannabis is one of the most widely used illicit drugs worldwide. However, while the rates of cannabis dependence and treatment increase, there remains no medications approved for this use. Due to its sedative effects and low abuse liability, the typical antipsychotic pericyazine has been utilized in some parts of Australia for the treatment of cannabis dependence. We aimed to provide documentation of preliminary outcomes and acceptability of pericyazine treatment in a small sample. A naturalistic case series study was conducted in which 21 patients were enrolled for a 4-week course of pericyazine (up to 8 * 2.5 mg tablets daily) and weekly medical review. Levels of cannabis use were reported and side effects with electrocardiography and blood tests were monitored. Measures of dependence severity, depression, anxiety, and insomnia were taken at baseline and follow-up utilizing validated psychometric tools. Significant reductions in cannabis use, depression, anxiety, and insomnia severity occurred across time. Pericyazine appeared to be well tolerated and easily administered in the community clinics. The results provide some preliminary evidence that low dose short-term pericyazine may be an acceptable mode of treatment in this population. Given the open-label nature of the design, we cannot conclude that pharmacotherapy was uniquely responsible for the treatment effect. Nonetheless, low-dose pericyazine may be a potentially effective approach to the treatment of cannabis dependence, and further evaluation via a randomized placebo-controlled trial is warranted. PMID- 24474868 TI - Acamprosate in the treatment of alcoholism: a budget impact analysis for the National Health Service in Italy. AB - OBJECTIVE: Alcohol dependence is a common condition associated with high direct and indirect health care costs. The purpose of this analysis was to estimate the economic consequences of acamprosate used as adjuvant therapy in the treatment of alcoholism, defining a budget impact analysis (BIA) from the point of view of the Italian National Health Service (NHS). METHODS: We developed a model of disease evolution related to alcoholism using data from the PRAMA study. The hypothetical population included in the decision model was obtained from data from the Ministry of Health. We compared the following treatment strategies: no treatment, standard care (psychotherapy), sodium oxybate (sodium salt-4-hydroxybutyric acid), and acamprosate. The time horizon of the model was 10 years. The costs were evaluated from the NHS perspective. RESULTS: We simulated the path for 69,348 patients treated at the outpatient clinics of the Addiction Services (SerT), and 38,911 patients discharged from hospital. Patients in the acamprosate group had lower alcohol-related events, with a reduction of the total cost. The BIA shows that the increase in the use of acamprosate was associated with a progressive decrease of total costs, calculated as the sum of the diagnosis related groups (DRG), rehabilitation, and drug costs. The increasing use of acamprosate instead of standard care and sodium oxybate would generate cost savings up to over ?6 million over 10 years of simulation. CONCLUSION: The estimates in the model are based on hypothetical situations; the assumptions of the model as well as their specific impact on treatment effect estimations and clinical implications should be validated in real life. Public health care authorities would benefit from mathematical models designed to estimate the future burden of alcohol dependence together with the impact of treatment and the potential to reduce the incidence and progression of this condition, and the costs of its complications. PMID- 24474867 TI - Patient attitudes towards change in adapted motivational interviewing for substance abuse: a systematic review. AB - Adapted motivational interviewing (AMI) represents a category of effective, directive and client-centered psychosocial treatments for substance abuse. In AMI, patients' attitudes towards change are considered critical elements for treatment outcome as well as therapeutic targets for alteration. Despite being a major focus in AMI, the role of attitudes towards change in AMI's action has yet to be systematically reviewed in substance abuse research. A search of PsycINFO, PUBMED/MEDLINE, and Science Direct databases and a manual search of related article reference lists identified 416 published randomized controlled trials that evaluated AMI's impact on the reduction of alcohol and drug use. Of those, 54 met the initial inclusion criterion by evaluating AMI's impact on attitudes towards change and/or testing hypotheses about attitudes towards change as moderators or mediators of outcome. Finally, 19 studies met the methodological quality inclusion criterion based upon a Newcastle-Ottawa Quality Assessment Scale score >= 7. Despite the conceptual importance of attitudes towards change in AMI, the empirical support for their role in AMI is inconclusive. Future research is warranted to investigate both the contextual factors (ie, population studied) as well as deployment characteristics of AMI (ie, counselor characteristics) likely responsible for equivocal findings. PMID- 24474870 TI - Randomized, double-blind, placebo-controlled and active-controlled study to assess the relative abuse potential of oxycodone HCl-niacin tablets compared with oxycodone alone in nondependent, recreational opioid users. AB - BACKGROUND: Abuse-deterrent formulations attempt to address public health and societal concerns regarding opioid abuse. Oxycodone HCl-niacin tablets combine oxycodone HCl with niacin and functional inactive excipients to create potential barriers to oral, intranasal, and intravenous abuse. This study compared the relative abuse potential of oral immediate-release oxycodone HCl-niacin with that of oral immediate-release oxycodone HCl and placebo in nondependent, recreational opioid users. METHODS: Forty-nine participants received oxycodone HCl-niacin 40/240 mg and 80/480 mg, oxycodone 40 mg and 80 mg, and placebo in a randomized, double-blind, placebo-controlled and active-controlled, five-way crossover study. Primary endpoints based on a bipolar 100 mm visual analog scale for drug liking were area under effect curve (AUE0-1h, AUE0-2h, AUE0-3h), peak disliking, and effect at 0.5 hours post-dose (E0.5h). Other endpoints included take drug again assessment, overall drug liking, and pupillometry. RESULTS: There were statistically significant differences between oxycodone HCl-niacin and oxycodone HCl doses for all primary endpoints (P < 0.0001, all comparisons), suggesting reduced abuse potential with oxycodone HCl-niacin. Take drug again and overall drug liking showed greater liking of oxycodone alone. Oxycodone HCl-niacin 80/480 mg had consistently lower liking assessments than oxycodone HCl-niacin 40/240 mg, suggesting a dose-response to the aversive effects of niacin. Opioid-related adverse events were similar for equivalent oxycodone doses. The treatment emergent adverse events most specifically associated with oxycodone HCl-niacin (ie, skin-burning sensation, warmth, and flushing) were consistent with the expected vasocutaneous effects of niacin. No serious adverse events were reported. CONCLUSION: Oxycodone HCl-niacin tablets may, in a dose-dependent manner, decrease the potential for oral abuse of oxycodone without unexpected adverse events or clinically signifi-cant differences in safety parameters compared with oxycodone alone. Although statistically powered, the small size of the study sample and the characteristics of its participants may not be generalizable to the population that abuses prescription opioid medications. PMID- 24474869 TI - Suicidal and self-injurious behavior among patients with alcohol and drug abuse. AB - BACKGROUND: Self-injurious behavior, a major public health problem globally, is linked with alcohol and drug abuse. This cross-sectional study aimed to identify the prevalence and correlates of self-harming behavior in patients with alcohol or drug abuse problems. METHODS: This was a one-year study that recruited a convenience sample of 736 outpatients and inpatients identified with alcohol or drug abuse, and was conducted at Al-Amal mental health hospitals in three major cities. All consecutively selected patients were interviewed on five working days for data collection on a semistructured sociodemographic form using the Columbia Suicide Severity Rating Scale Risk Assessment version. RESULTS: In addition to the socioclinical profile revealed, 50.7% of respondents reported any suicidal ideation, while 6.9% reported self-injurious behavior without intent to die. Any suicidal and self-injurious behavior was reported by 13.1% of participants. A total of 71.3% of respondents reported any recent negative activating events. In addition to any treatment history, observed correlates were hopelessness (60.7%), perceived burden on family (29.5%), refusing a safety plan (26.1%), and sexual abuse (11%). Conversely, reasons for living (64.9%), fear of death or dying due to pain and suffering (64.3%), and spirituality (92%) were largely endorsed as protective factors. There were multiple significant odds ratios (P <= 0.01) revealed when independent socioclinical variables were compared with dependent variables in terms of suspected risk and protective factors. In an adjusted logistic regression model, none of the independent variables contributed significantly to any suicidal and self-injurious behavior, any suicidal ideation, or protection from them (P > 0.05). CONCLUSION: Our preliminary results suggest that there are some socioclinical correlates of any suicide ideation, suicidal and self-injurious behavior, and protection from risky behavior, but which of them contributes significantly to the risk and protective dimensions is yet to be elucidated in prospective community-based studies with larger and more diverse samples. PMID- 24474871 TI - Promising international interventions and treatment for women who use and abuse drugs: focusing on the issues through the InWomen's Group. PMID- 24474872 TI - The GENACIS project: a review of findings and some implications for global needs in women-focused substance abuse prevention and intervention. AB - GENDER, ALCOHOL, AND CULTURE: An International Study (GENACIS) is a collaborative study of gender-related and cultural influences on alcohol use and alcohol related problems of women and men. Members conduct comparative analyses of data from comparable general population surveys in 38 countries on five continents. This paper presents GENACIS findings that (1) age-related declines in drinking are uncommon outside North America and Europe; (2) groups of women at increased risk for hazardous drinking include women who cohabit, women with fewer social roles, more highly educated women in lower-income countries, and sexual minority women in North America; (3) heavier alcohol use shows strong and cross-culturally consistent associations with increased likelihood and severity of intimate partner violence; and (4) one effect or accompaniment of rapid social, economic, and gender-role change in traditional societies may be increased drinking among formerly abstinent women. These findings have potentially important implications for women-focused intervention and policy. Substance abuse services should include attention to middle-aged and older women, who may have different risk factors, symptoms, and treatment issues than their younger counterparts. Creative, targeted prevention is needed for high-risk groups of women. Programs to reduce violence between intimate partners must include attention to the pervasive role of alcohol use in intimate partner aggression. Social and economic empowerment of women, together with social marketing of norms of abstention or low-risk drinking, may help prevent increased hazardous alcohol use among women in countries undergoing rapid social change. Greater attention to effects of gender, culture, and their interactions can inform the design of more effective prevention, intervention, and policy to reduce the substantial global costs of alcohol abuse in both women and men. PMID- 24474873 TI - Comparing methadone and buprenorphine maintenance with methadone-assisted withdrawal for the treatment of opioid dependence during pregnancy: maternal and neonatal outcomes. AB - Pregnancy can motivate opioid-dependent women to seek substance abuse treatment. Research has demonstrated that although prenatal exposure to buprenorphine results in less severe neonatal abstinence syndrome (NAS) relative to prenatal methadone exposure, the maternal and other neonatal outcomes are similar for the two medications. Maternal and neonatal outcomes for opioid-dependent pregnant women receiving these medications have not been systematically ompared with methadone-assisted withdrawal. The present study provides an initial assessment of the relative efficacy of both methadone and buprenorphine maintenance versus methadone-assisted withdrawal in terms of neonatal and maternal delivery outcomes. Data were derived from (1) the MOTHER (Maternal Opioid Treatment: Human Experimental Research) study at the Johns Hopkins University Bayview Medical Center (JHBMC), or (2) retrospective records review of women who underwent methadone-assisted withdrawal at the JHBMC during the time period in which participants were enrolled in the MOTHER study. Compared with the methadone maintenance group, the methadone-assisted withdrawal group had a significantly lower mean NAS peak score (Means = 13.7 vs 7.0; P = 0.002), required a significantly lower mean amount of morphine to treat NAS (Means = 82.8 vs 0.2; P < 0.001), had significantly fewer days medicated for NAS (Means = 31.5 vs 3.9; P < 0.001), and remained in the hospital for a significantly fewer number of days, on average (Means = 24.2 vs 7.0; P < 0.019). Compared with the buprenorphine maintenance group, the methadone-assisted withdrawal group required a significantly lower mean amount of morphine to treat NAS (Means = 8.2 vs 0.2; P < 0.001) and significantly fewer days medicated for NAS (Means = 12.0 vs 3.9; P = 0.008). Findings suggest that it is possible for some opioid-dependent pregnant women to succeed with methadone-assisted withdrawal. Future research needs to more fully evaluate the potential benefits and risks of methadone-assisted withdrawal for the maternal-fetal dyad. PMID- 24474874 TI - Meeting the substance abuse treatment needs of lesbian, bisexual and transgender women: implications from research to practice. AB - Research on the incidence, etiology and substance abuse treatment needs of lesbian, bisexual and transgender (LBT) women is limited. Most research indicates higher levels of alcohol and drug abuse among these populations compared to their heterosexual counterparts, with recent research indicating that substance abuse is a particular concern for transgender individuals and an increasing problem among younger LBT individuals. Risk factors and reasons for substance abuse among sexual minority women are similar to those of heterosexual women, yet are substantially complicated by issues of family rejection and lack of social support, stigma and minority stress, as well as abuse and harassment. Historically, substance abuse prevention, early intervention, and clinical treatment programs were designed to meet the needs of the sexual majority population with relatively few programs designed to incorporate the specific needs of sexual minorities. This article reviews findings from previous studies and utilizes new data collected from community-based and residential substance abuse treatment programs to (1) examine issues relevant to LBT women and substance use, and (2) make recommendations for tailoring substance abuse treatment programs to meet the needs of these populations. PMID- 24474875 TI - Six-month follow-up of Iranian women in methadone treatment: drug use, social functioning, crime, and HIV and HCV seroincidence. AB - BACKGROUND: In general, information about women who use drugs comes from studies performed in the West. Whether women in countries such as Iran are likely to enter drug treatment or how they will respond is not known. PURPOSE: To examine the short-term impact of methadone maintenance treatment (MMT) on drug use, dependence, social functioning, crime, and human immunodeficiency virus (HIV) and hepatitis C virus (HCV) risk behavior and seroincidence in female drug users in Iran. METHODS: Women were eligible for inclusion in the study if they were assessed as dependent on opiates according to the International Statistical Classification of Diseases and Related Health Problems, tenth revision (ICD-10). The sample comprised 78 female heroin or opium users who attended the Persepolis women's drug treatment clinic in Tehran between 2007 and 2008. Participants were followed up in 2009/2010. Heroin and the use of other drugs, social functioning, involvement in crime, and involvement in HIV and HCV risk behavior were measured by self-report. The prevalence and incidence of HIV and HCV were measured by serology and self-report. FINDINGS: Of the 78 women recruited, 40 were followed up, and this occurred approximately 7 months later. One in four women reported a history of drug injection. At follow-up there were significant reductions in self reported heroin use on ICD-10 dependence scores. Subjects with more severe drug dependence at baseline were significantly more likely to be criminally active than less severely dependent subjects. Baseline prevalence for HIV and HCV was 5% and 24%, respectively. At follow-up, no one had acquired HIV infection, but one participant had acquired HCV, giving an incidence rate of 7.1 per 100 person years. CONCLUSION: This research provides the first evidence that Iranian female drug users can enter MMT and respond well. Within a few months of entering MMT, improvements occurred in heroin use, levels of dependence, social functioning, and HIV risk behavior. While the incidence of blood-borne viral infections was low, there was a serious risk of HIV transmission among this cohort and also to participants' needle and sexual contacts. In a country with high levels of drug use, the high levels of HCV among female drug users require more women to enter drug treatment if an HIV epidemic is to be avoided. Many participants had a chronic drug problem and had had little or no previous exposure to MMT. The introduction or expansion of women-only drug treatment services is urgently needed in order to engage more women in treatment. PMID- 24474876 TI - Incarceration history relative to health, substance use, and violence in a sample of vulnerable South African women: implications for health services in criminal justice settings. AB - International research has suggested that women in the criminal justice system carry a higher burden of many illnesses than women in the community, especially mental health disorders, substance use disorders, sexually transmitted infections, and a history of violent victimization. Knowledge of these health disparities is often used to advocate for relevant screening and treatment services for women passing through criminal justice custody within US and European settings. However, almost all criminal justice health research has taken place in high-income countries, with little or no research taking place in other countries, especially in South Africa. This baseline analysis compares the health, substance use, and violent victimization of women who have ever been incarcerated to those who have not, in a cross-sectional sample of 720 young, vulnerable, substance-using women in Cape Town, South Africa. Results of univariate tests indicated that women who had ever been incarcerated had worse health, mental health, and sexually transmitted infection indicators and were more likely to report use of substances and to have been victims of physical and sexual assault than women who had never been incarcerated. Passing through the criminal justice system appears to be a marker for a variety of current and/or future health service needs among vulnerable South African women, suggesting that screening, prevention, and treatment referral efforts at the time of intersection with the criminal justice system may reduce health burden for these women. PMID- 24474877 TI - Long-term residential substance abuse treatment for women: lessons learned from Israel. AB - BACKGROUND: Policymakers and treatment providers must consider the role of gender when designing effective treatment programs for female substance abusers. This study had two aims. First, to examine female substance abusers' perceptions regarding factors that contribute to their retention (and therefore positive treatment outcomes) in a women-only therapeutic community in Northern Israel. Second, to explore pretreatment internal and external factors including demographic, personal and environmental factors, factors associated with substance use and with the treatment process, and networks of support that contribute to retention and abstinence. METHODS: The study was a conducted using a mixed methods approach. Semi-structured qualitative interviews examining perceptions towards treatment were conducted in five focus groups (n = 5 per group; total n = 25). Intake assessments and a battery of questionnaires examining pretreatment internal and external factors related to treatment retention and abstinence were collected from 42 women who were treated in the program during the 2 year study period. Twenty-three women who completed the 12 month program were compared to the 19 women who did not, using chi-square for categorical variables and t-tests for continuous variables. Nineteen of the 23 women who completed the questionnaires also completed a post-treatment follow-up questionnaire. RESULTS: A CONTENT ANALYSIS OF THE INTERVIEWS REVEALED FIVE CENTRAL THEMES: factors associated with treatment entry; impact of treatment in a women-only setting; significant aspects of treatment; difficulties with the setting; prospects for the future. Analysis of the questionnaires revealed that compared to non-completers, completers had fewer psychiatric symptoms, higher levels of introverted behavior in stressful situations, a better sense of coherence, and less ability to share emotions. No significant differences were found with regard to demographic and substance use factors. All 19 women who completed treatment and the follow-up questionnaire remained abstinent from illicit drugs for 18 months following the end of treatment. CONCLUSION: Results indicate that women see the women-only treatment setting as extremely significant. Also, there is a profile of psychiatric co-morbidity, extrapunitiveness, and fewer personal resources that predict a risk for attrition. Thus, women at risk for attrition may be identified early and treatment staff can utilize the results to assist clients in achieving their treatment goals. Results can inform policymakers in making decisions regarding the allocation of resources, by pointing to the importance of long-term women only residential treatment in increasing positive treatment outcomes. PMID- 24474878 TI - World title boxing: from early beginnings to the first bell. AB - There is scant literature where applied sport scientists have considered first hand experiences preparing professional boxers for world title bouts. The present submission reflects more than 10 years of applied experience working with professional boxers, residing in Canada. What follows is a composite of sequential steps that ownership and coaching staff of one Canadian management group have tried leading up to more than 20 world title bout experiences. The strategies proposed have been built progressively over time, and what follows is a general overview of a more detailed pre-bout structure from shortly in advance of a world title bout offer to the moment when the athlete enters the ring to perform. We propose that an effective structure is founded upon detailed a priori preparation, tactical decisions throughout bout preparation, and a thorough understanding by the athlete of what he will encounter during the title bout. Key PointsWorld championship boxing.Competition preparation.Professional sport.Athlete performance. PMID- 24474879 TI - Giving yourself a good beating: appraisal, attribution, rumination, and counterfactual thinking. AB - How individuals respond to adversity is one component of mental toughness and athletes may manage the adversity of a defeat in very different ways. In this article we focus on four types of cognition (appraisal, attribution, counterfactual thinking, and rumination) that athletes may exhibit in the immediate aftermath of a competitive defeat. In particular we define each of these terms and present a "caricature "of each of the respective literatures, focussing on the prevailing trends and substantive findings. These caricatures assist in the identification of several areas in which literature on athletes' retrospective cognition about defeat may be advanced. We use combat sports as a vehicle to illustrate our propositions. Key PointsPlease provide 3-5 bullet points of the paper.Little is known about how athletes psychologically manage adversity, a key component of mental toughness.There is a great deal of conceptual overlap between four types of retrospective cognition (appraisal, attribution, rumination and counterfactual thinking) athletes may exhibit after defeat.Rather than continue of examine these retrospective cognitions in isolation, there appears to be value in consideration of these constructs collectively to enhance theoretical parsimony. PMID- 24474880 TI - Measurement and comparison of taekwondo and yongmudo turning kick impact force for two target heights. AB - The primary purpose of this research was to compare the impact characteristics of Taekwondo (TKD) and Yongmudo (YMD) player's turning kick according to the target height. 5 highly skilled YMD and 5 TKD players participated in this study. To measure the impact force, two accelerometers were fixed to a PVC pipe in a sandbag. Each participant performed 10 turning kicks trunk and face height in random order. Only the trial with the most accurate (most central impact) measurement was used in the statistical analysis (p < 0.05).There was a significant difference for impact force according to the target height approximately 6400 +/- 898 N, 6393 +/- 1382 N for the mid section and 5419 +/- 659 N, 5475 +/- 1293 N for the high section of TKD and YMD groups, but not between groups. The swing phase for the TKD group was significantly shorter than the YMD group's. The TKD groups' recovery phase of the trunk height turning kick was significantly shorter. There was a difference in the players' center of mass (COM) movement as the TKD players' moved significantly more forward, suggesting that the TKD players tended to slide towards the target during the execution of the kick. In conclusion, as the turning kick was performed quicker by the TKD players with a similar impact force and more forward motion, it is evaluated to be a better technique of turning kicking. Key PointsThis impact force measuring device had a significantly smaller standard deviation then that of impact force measuring devices.There was a significant difference between the impact forces according to the height approximately 6400 +/- 898N, 6393 +/- 1382N for the mid section and 5419 +/- 659N, 5475 +/- 1293N for the high section of TKD and YMD groups.The turning kick was performed quicker by the TKD players with a similar impact force and more forward motion. PMID- 24474881 TI - Lactate profile during greco-roman wrestling matchx. AB - The objective of this study was to determine and compare lactate profile of two groups of Greco-Roman wrestlers with different competences and training experience. Study was conducted on 10 wrestles that were members of Croatian national team and 10 wrestlers that were members of Wrestling club Split. Lactate samples were collected at four intervals during control fights that were held according to international wrestling rules of World wrestling federation FILA. Values of lactate increased as competition progressed, and they were highest at the end of the match for both groups of wrestlers. According to this study there were no significant differences in lactate between two groups at the end of the match, while significant differences were noted during the match. The information about lactate profile presented in this study can be used by coaches and wrestlers to develop condition programs. Key PointsThere were no significant differences in lactate concentrations at the end of the match between two proficiency levels of wrestlers.More proficient (elite) wrestlers raise lactates gradually through the wrestling match while less proficient (club) wrestlers raise it abruptly at the end of the first bout.Both groups of wrestlers are unable to sustain same level of activity through the match suggesting that they are utilizing too much energy from anaerobic glycolysis. PMID- 24474882 TI - Association between neuromuscular tests and kumite performance on the brazilian karate national team. AB - The aim of this study was to verify the relationship of strength and power with performance on an international level karate team during official kumite simulations. Fourteen male black belt karate athletes were submitted to anthropometric data collection and then performed the following tests on two different days: vertical jump test, bench press and squat maximum dynamic strength (1RM) tests. We also tested power production for both exercises at 30 and 60%1RM and performed a kumite match simulation. Blood samples were obtained at rest and immediately after the kumite matches to measure blood lactate concentration. Karate players were separated by performance (winners vs. defeated) on the kumite matches. We found no significant differences between winners and defeated for strength, vertical jump height, anthropometric data and blood lactate concentration. Interestingly, winners were more powerful in the bench press and squat exercises at 30% 1RM. Maximum strength was correlated with absolute (30% 1RM r = 0.92; 60% 1RM r = 0.63) and relative power (30% 1RM r = 0.74; 60% 1RM r = 0.11, p > 0.05) for the bench press exercise. We concluded that international level karate players' kumite match performance are influenced by higher levels of upper and lower limbs power production. Key PointsMuscle power at low workloads seems to be a reasonable predictor of karate performance.There are differences in neuromuscular characteristics between winners and defeated karate players among an international level karate team.Karate players rely more on muscle power, rather than on muscle strength. PMID- 24474883 TI - Wavelet transform analysis of electromyography kung fu strikes data. AB - In martial arts and contact sports strikes are performed at near maximum speeds. For that reason, electromyography (EMG) analysis of such movements is non trivial. This paper has three main goals: firstly, to investigate the differences in the EMG activity of muscles during strikes performed with and without impacts; secondly, to assess the advantages of using Sum of Significant Power (SSP) values instead of root mean square (rms) values when analyzing EMG data; and lastly to introduce a new method of calculating median frequency values using wavelet transforms (WMDF). EMG data of the deltoid anterior (DA), triceps brachii (TB) and brachioradialis (BR) muscles were collected from eight Kung Fu practitioners during strikes performed with and without impacts. SSP results indicated significant higher muscle activity (p = 0.023) for the strikes with impact. WMDF results, on the other hand, indicated significant lower values (p = 0. 007) for the strikes with impact. SSP results presented higher sensitivity than rms to quantify important signal differences and, at the same time, presented lower inter-subject coefficient of variations. The result of increase in SSP values and decrease in WMDF may suggest better synchronization of motor units for the strikes with impact performed by the experienced Kung Fu practitioners. Key PointsThe results show higher muscle activity and lower electromyography median frequencies for strikes with impact compared to strikes without.SSP results presented higher sensitivity and lower inter-subject coefficient of variations than rms results.Kung Fu palm strikes with impact may present better motor units' synchronization than strikes without. PMID- 24474884 TI - Comparison of two variants of a kata technique (unsu): the neuromechanical point of view. AB - The objective of this work was to characterize from a neuromechanical point of view a jump performed within the sequence of Kata Unsu in International top level karateka. A modified jumping technique was proposed to improve the already acquired technique. The neuromechanical evaluation, paralleled by a refereeing judgment, was then used to compare modified and classic technique to test if the modification could lead to a better performance capacity, e.g. a higher score during an official competition. To this purpose, four high ranked karateka were recruited and instructed to perform the two jumps. Surface electromyographic signals were recorded in a bipolar mode from the vastus lateralis, rectus femoris, biceps femoris, gluteus maximus, and gastrocnemious muscles of both lower limbs. Mechanical data were collected by means of a stereophotogrammetric system and force platforms. Performance was associated to parameters characterizing the initial conditions of the aerial phase and to the CoM maximal height. The most critical elements having a negative influence on the arbitral evaluation were associated to quantitative error indicators. 3D reconstruction of the movement and videos were used to obtain the referee scores. The Unsu jump was divided into five phases (preparation, take off, ascending flight, descending flight, and landing) and the critical elements were highlighted. When comparing the techniques, no difference was found in the pattern of sEMG activation of the throwing leg muscles, while the push leg showed an earlier activation of RF and GA muscles at the beginning of the modified technique. The only significant improvement associated with the modified technique was evidenced at the beginning of the aerial phase, while there was no significant improvement of the referee score. Nevertheless, the proposed neuromechanical analysis, finalized to correlate technique features with the core performance indicators, is new in the field and is a promising tool to perform further analyses. Key PointsA quantitative phase analysis, highlighting the critical features of the technique, was provided for the jump executed during the Kata Unsu.Kinematics and neuromuscular activity can be assessed during the Kata Unsu jump performed by top level karateka.Neuromechanical parameters change during different Kata Unsu jump techniques.Appropriate performance capacity indicators based on the neuromechanical evaluation can describe changes due to a modification of the technique. PMID- 24474885 TI - Most Frequent Errors in Judo Uki Goshi Technique and the Existing Relations among Them Analysed through T-Patterns. AB - The purpose of this study is to provide a tool, based on the knowledge of technical errors, which helps to improve the teaching and learning process of the Uki Goshi technique. With this aim, we set out to determine the most frequent errors made by 44 students when performing this technique and how these mistakes relate. In order to do so, an observational analysis was carried out using the OSJUDO-UKG instrument and the data were registered using Match Vision Studio (Castellano, Perea, Alday and Hernandez, 2008). The results, analyzed through descriptive statistics, show that the absence of a correct initial unbalancing movement (45,5%), the lack of proper right-arm pull (56,8%), not blocking the faller's body (Uke) against the thrower's hip -Tori- (54,5%) and throwing the Uke through the Tori's side are the most usual mistakes (72,7%). Through the sequencial analysis of T-Patterns obtained with the THEME program (Magnusson, 1996, 2000) we have concluded that not blocking the body with the Tori's hip provokes the Uke's throw through the Tori's side during the final phase of the technique (95,8%), and positioning the right arm on the dorsal region of the Uke's back during the Tsukuri entails the absence of a subsequent pull of the Uke's body (73,3%). Key PointsIn this study, the most frequent errors in the performance of the Uki Goshi technique have been determined and the existing relations among these mistakes have been shown through T-Patterns.The SOBJUDO-UKG is an observation instrument for detecting mistakes in the aforementioned technique.The results show that those mistakes related to the initial imbalancing movement and the main driving action of the technique are the most frequent.The use of T-Patterns turns out to be effective in order to obtain the most important relations among the observed errors. PMID- 24474886 TI - The effects of height and distance on the force production and acceleration in martial arts strikes. AB - Almost all cultures have roots in some sort of self defence system and yet there is relatively little research in this area, outside of a sports related environment. This project investigated different applications of strikes from Kung Fu practitioners that have not been addressed before in the literature. Punch and palm strikes were directly compared from different heights and distances, with the use of a load cell, accelerometers, and high speed video. The data indicated that the arm accelerations of both strikes were similar, although the force and resulting acceleration of the target were significantly greater for the palm strikes. Additionally, the relative height at which the strike was delivered was also investigated. The overall conclusion is that the palm strike is a more effective strike for transferring force to an object. It can also be concluded that an attack to the chest would be ideal for maximizing impact force and moving an opponent off balance. Key PointsIt has been determined that the palm strike is more effective than the punch for developing force and for transferring momentum, most likely the result of a reduced number of rigid links and joints.A strike at head level is less effective than a strike at chest level for developing force and transferring momentum.Distance plays an effect on the overall force and momentum changes, and most likely is dependent on the velocity of the limb and alignment of the bones prior to impact.The teaching of self defence for novices and law enforcement would benefit from including the palm strike as a high priority technique. PMID- 24474887 TI - Advanced therapy medicinal products - a multiple challenge. PMID- 24474889 TI - Validation of Serological Testing for Anti-Treponema pallidum from Postmortem Blood on the Siemens-BEP((r))-III Automatic System. AB - BACKGROUND: Infectious disease marker testing is obligatory for the release of human tissue for transplantation. Most CE-marked tests are not validated for postmortem blood. In a previous study we have validated the testing for anti-HIV 1/2, anti-HCV, HBsAg, and anti-HBc. Here, we present the validation of testing for antibodies against T. pallidum, which is the last marker obligatory for tissue release for transplantation. METHODS: 17 samples of postmortem sera and 10 samples of both pre-und postmortem sera were obtained from cornea donors and tested for anti-T. pallidum on the Siemens-BEP-III-System. These sera were spiked with anti-T. pallidum-positive standard sera in concentrations which give low- and high-positive results at the respective dilution. RESULTS: Two of the unspiked postmortem sera were false-positive most likely due to intense hemolysis (free hemoglobin > 50 mg/dl). Of the 25 negative postmortem sera, none of the spiked samples was false-negative after 0, 24 and 60 h. CONCLUSION: There is no indication that postmortem samples give false-negative or false-positive results with the test system and test kits used in cases of low hemolysis. The procedure described might serve as a model for validating other test kits on postmortem samples. PMID- 24474888 TI - Genetically modified T cells for the treatment of malignant disease. AB - The broaden application of adoptive T-cell transfer has been constrained by the technical abilities to isolate and expand antigen-specific T cells potent to selectively kill tumor cells. With the recent progress in the design and manufacturing of cellular products, T cells used in the treatment of malignant diseases may be regarded as anticancer biopharmaceuticals. Genetical manipulation of T cells has given T cells desired specificity but also enable to tailor their activation and proliferation potential. Here, we summarize the recent developments in genetic engineering of T-cell-based biopharmaceuticals, covering criteria for their clinical application in regard to safety and efficacy. PMID- 24474890 TI - European regulatory tools for advanced therapy medicinal products. AB - Increasing scientific knowledge and technical innovations in the areas of cell biology, biotechnology and medicine resulted in the development of promising therapeutic approaches for the prevention and treatment of human diseases. Advanced therapy medicinal products (ATMPs) reflect a complex and innovative class of biopharmaceuticals as these products are highly research-driven, characterised by innovative manufacturing processes and heterogeneous with regard to their origin, type and complexity. This class of ATMP integrates gene therapy medicinal products, somatic cell therapy medicinal products and tissue engineering products and are often individualized and patient-specific products. Multiple challenges arise from the nature of ATMPs, which are often developed by micro, small and medium sized enterprises, university and academia, for whom regulatory experiences are limited and regulatory requirements are challenging. Regulatory guidance such as the reflection paper on classification of ATMPs and guidelines highlighting product-specific issues support academic research groups and pharmaceutical companies to foster the development of safe and effective ATMPs. This review provides an overview on the European regulatory aspects of ATMPs and highlights specific regulatory tools such as the ATMP classification procedure, a discussion on the hospital exemption for selected ATMPs as well as borderline issues towards transplants/transfusion products. PMID- 24474891 TI - Proteomic analysis of human-derived cell culture supplements. AB - OBJECTIVE: Development of cell therapy and advanced therapy medicinal products depends on in vitro expansion of human cells in fetal bovine serum (FBS) supplemented media. Human-derived supplements, such as human serum (huS) and human platelet lysate (hPL), represent suitable alternatives to FBS. Various studies demonstrated that the use of these human alternatives result in comparable or even improved proliferation and expansion ratios. METHODS: Within this study three human supplement alternatives, huS, hPLP (plasma containing hPL) and hPLN (plasma replaced by saline), were compared by 2D gel electrophoresis, an important tool in proteomic analysis. 2D gel electrophoresis allows the determination of the protein number and the detection of protein changes (decreasing/increasing concentration). RESULTS AND CONCLUSION: The comparison of huS, hPLP, and hPLN gels resulted in clearly visible differences in protein pattern, protein number and concentration, particularly when comparing huS with hPL and hPLP with hPLN. PMID- 24474892 TI - Human-derived alternatives to fetal bovine serum in cell culture. AB - OBJECTIVE: The need for an alternative to fetal bovine serum (FBS) is known to scientists and users involved in cell therapy or advanced therapy medicinal products. Human serum (huS) and platelet lysate (hPL) can be used as alternatives resulting in similar or even superior results concerning cell expansion. METHODS: We developed protocols for the production of huS and two types of hPL and tested them in the expansion of human fibroblasts and adipose tissue-derived stem cells (ASC). Quality control included cell counts (platelets, red and white blood cells), sterility testing, pH levels, total protein concentrations and growth factor levels. ASC and fibroblasts were expanded for three passages in media supplemented with FBS, huS or hPL and evaluated microscopically. Proliferation in terms of population doubling times (PDT) was determined. In case of ASC, differentiation was performed as well. RESULTS: All three alternatives demonstrated shorter PDT for fibroblasts and ASC compared to FBS. Furthermore, ASC maintained their differentiation potential. CONCLUSION: We conclude that hPL and huS can be used as alternatives to FBS for the cultivation and expansion of cells intended for human use. PMID- 24474893 TI - Improvement of contraction force in injured skeletal muscle after autologous mesenchymal stroma cell transplantation is accompanied by slow to fast fiber type shift. AB - BACKGROUND: Skeletal muscle trauma leads to severe functional deficits, which cannot be addressed by current treatment options. Previous investigation could show the efficacy of a local transplantation (TX) of mesenchymal stroma cells (MSCs) for the therapy of muscle injury. Underlying mechanisms remain to be elucidated. The aim of the present work was to characterize the fiber composition changes following MSC-TX after open crush injury. METHODS: 20 male SD rats received an open crush trauma of the left soleus muscle. 2.5 * 10(6) autologous MSCs were transplanted into the crushed soleus muscle of 10 animals 7 days after trauma (group 1, n = 10). Control animals received an injection of saline solution (group 2, n = 10). Histologic analysis of fibrosis, fiber type composition, and muscle force measurements were performed 28 days after trauma. RESULTS: MSC-TX improved muscle force significantly (fast-twitch, treated: 0.76 (0.51-1.15), untreated: 0.45 (0.32-0.73); p = 0.01). Tetanic stimulation resulted in a significant increase of force development (treated: 0.63 (0.4-1.21), untreated: 0.34 (0.16-0.48); p = 0.04). Histological analyses showed no differences in the amount of fibrotic tissue (treated vs. untreated, p = 0.42). A shift towards fastMHC-positive fibers was observed following MSC-TX (treated vs. untreated; p = 0.01 (mm(2)) or 0.007 (%)). CONCLUSION: This study demonstrated an effect of locally administered MSCs in the treatment of skeletal muscle injuries on a structural level. For the first time a fiber type shift towards fastMHC following MSC-TX after crush injury could be demonstrated and related to MSC-TX. These results might open the discussion of an alternative mode of action of MSCs in tissue regeneration. PMID- 24474894 TI - Bioactive factors in platelet-rich plasma obtained by apheresis. AB - INTRODUCTION: The use of platelet-rich plasma (PRP) in regenerative approaches in cartilage repair is becoming more common. Information about PRP composition and its content of putative bioactive chondrogenic growth factors (GF) that may support cartilage regeneration is scarce. METHODS: GF composition of a pool of 6 PRP preparations was determined using Protein Antibody Membrane Arrays covering 507 GF, signaling molecules, and receptors. To verify the chondrogenic GF variability in PRP, Growth Factor Antibody Membrane Arrays covering 26 GF were applied to 6 individual PRP preparations. Selected GF involved in chondrogenic differentiation were quantified by Enzyme-Linked Immunosorbent Assay (ELISA). RESULTS: 417 out of 507 possible detectable proteins were present in the PRP pool, including 76 GF. Quantification of selected chondrogenic GF by ELISA showed an average of 0.31 ng/ml bone morphogenetic protein-2, 0.50 ng/ml connective tissue growth factor, 0.76 ng/ml fibroblast growth factor-2, and 0.59 ng/ml transforming growth factor-beta3. CONCLUSION: PRP as a therapeutic option in regenerative cartilage repair strategies is a powerful tool for the local application of chondrogenic GF to the site of injury. Chondrogenic GF are present in PRP and may support cartilage repair by inducing cell differentiation and cartilage matrix formation. PMID- 24474895 TI - Slight changes in the mechanical stimulation affects osteoblast- and osteoclast like cells in co-culture. AB - BACKGROUND: Osteoblast- and osteoclast-like cells are responsible for coordinated bone maintenance, illustrated by a balanced formation and resorption. Both parameters appear to be influenced by mechanical constrains acting on each of these cell types individually. We hypothesized that the interactions between both cell types are also influenced by mechanical stimulation. METHODS: Co-cultures of osteoblast- and osteoclast-like cells were stimulated with 1,100 ustrain, 0.1 or 0.3 Hz for 1-5 min/day over 5 days. Two different setups depending on the differentiation of the osteoclast-like cells were used: i) differentiation assay for the fusion of pre-osteoclasts to osteoclasts, ii) resorption assay to determine the activity level of osteoclast-like cells. RESULTS: In the differentiation assay (co-culture of osteoblasts with unfused osteoclast precursor cells) the mechanical stimulation resulted in a significant decrease of collagen-1 and osteocalcin produced by osteoblast-like cells. Significantly more TRAP-iso5b was measured after stimulation for 3 min with 0.1 Hz, indicating enhanced osteoclastogenesis. In the resorption assay (co-culture of osteoblasts with fused osteoclasts) the stimulation for 3 min with 0.3 Hz significantly increased the resorption activity of osteoclasts measured by the pit formation and the collagen resorption. The same mechanical stimulation resulted in an increased collagen-1 production by the osteoblast-like cells. The ratio of RANKL/OPG was not different between the groups. CONCLUSION: These findings demonstrate that already small changes in duration or frequency of mechanical stimulation had significant consequences for the behavior of osteoblast- and osteoclast-like cells in co-culture, which partially depend on the differentiation status of the osteoclast-like cells. PMID- 24474896 TI - Whither advanced therapy medicinal products? PMID- 24474897 TI - A Novel ABO Gene Variant Leads to Discrepant Results in Forward/Reverse and Molecular Blood Grouping. AB - BACKGROUND: Discrepant results in antigen and reverse ABO blood typing are often caused by a variant ABO gene. Molecular analysis can help to characterize such variants. Here, we describe the identification of a novel ABO gene variant in a patient with aberrant ABO phenotype and discrepant genotyping results. METHODS: A patient with discrepant results in automated forward and reverse ABO phenotyping was further investigated by serological (gel and tube technique) and molecular (commercial and inhouse PCR-SSP, DNA sequencing) methods. A PCR-SSP system was established to screen the novel mutation in 1,820 blood donors. RESULTS: Standard serological tests confirmed blood group O, however, only anti-B isoagglutinins were present. A monoclonal anti-AB antibody detected very weak agglutination in gel technique. Standard ABO genotyping using PCR-SSP led to discrepant results (O(1)/O(1) or O(1)/A) depending on the test system used. ABO exon re-sequencing identified a novel missense mutation in exon 6 at position 248A>G (Asp83Gly) in the binding region of PCR-SSP primers for the detection of 261G alleles. Blood donors with regular ABO blood groups were all negative for the 248G allele designated Aw34. CONCLUSION: The novel ABO gene variant Aw34 is associated with very weak A antigen expression and absent anti-A isoagglutinins. The mutation is located in exon 6 close to the O(1)-specific 261G deletion in the binding region of PCR-SSP primers. Presumably, depending on the primer concentration used in commercial ABO genotyping kits, the mutation could lead to a false-negative reaction. PMID- 24474898 TI - Small bowel metastasis of hepatocellular carcinoma detected by capsule endoscopy. AB - We report a rare case of metastasis of hepatocellular carcinoma (HCC) to the small bowel that presented as a pedunculated epithelial polyp. A 60-year-old man with liver cirrhosis type B was treated for HCC (stage IVb) at our hospital. He had been admitted for melena and anemia. Capsule endoscopy was performed in this patient with obscure gastrointestinal bleeding. It showed a polypoid lesion with bleeding in the ileum. Double-balloon endoscopy was performed. The lesion was determined to be a pedunculated polyp in the ileum. Histological examination of biopsy specimens showed tumor cells resembling HCC. We performed endoscopic mucosal resection for the lesion by double-balloon endoscopy to prevent bleeding from the tumor. The patient had no melena or anemia and his condition improved after endoscopic mucosal resection. However, he died of liver failure 2 months later. PMID- 24474899 TI - Verrucous carcinoma of the esophagus: a potential diagnostic dilemma. AB - Verrucous carcinoma of the esophagus is a rare variant of squamous cell carcinoma associated with human papillomavirus. We report the case of a 58-year-old female who presented with ongoing symptoms of dysphagia. On previous endoscopies she had been noted to have a large polyp-like mass involving the esophagus, with negative biopsies for malignancy. Repeat endoscopy with concurrent endoscopic ultrasound showed a large semi-pedunculated polyp in the distal esophagus and a hypoechoic, irregular mass involving the gastroesophageal junction with esophageal thickening. Deep layer biopsies showed pseudoepitheliomatous hyperplasia with immunohistochemical staining positive for human papillomavirus. The patient was subsequently treated with chemo-radiation followed by esophagectomy. PMID- 24474900 TI - A large hepatic cyst with obstructive jaundice successfully treated with single incision laparoscopic deroofing. AB - We herein present a case of hepatic cysts causing obstructive jaundice that was treated with single-incision laparoscopic deroofing. A 72-year-old female patient was referred to hospital due to a large hepatic cyst that compressed the intrahepatic bile ducts. The patient was scheduled to undergo single-incision laparoscopic deroofing. The EZ ACCESS(TM) oval type (Hakko Co. Ltd.) was placed at the umbilicus using a 25-mm incision with two 5-mm trocars. An additional 12 mm port was placed at the left epigastric region. We unroofed and excised the cyst wall using a vessel sealing system in liver segment 4. After surgery, the patient was found to be asymptomatic. The unroofed cysts were completely diminished. Notably, the remnant liver had fairly regenerated. The estimated regeneration volume of the normal liver was 153 cm(3). To prevent surgical complications, clinicians should perform adequate management and use of devices. To prevent postoperative recurrence of cysts, performing complete deroofing is essential. Single-incision laparoscopic deroofing contributes to improving the quality of life of patients and should be considered a standard treatment. PMID- 24474901 TI - Primary systemic amyloidosis with extensive gastrointestinal involvement. AB - We report this case of a 42-year-old woman who presented with a debilitating illness manifested by intractable nausea, vomiting, diarrhea and unchecked weight loss. The patient had multisystem involvement that presented as anemia, abnormal liver function tests and progressively deteriorating renal function necessitating dialysis. She was found to be profoundly hypoalbuminemic secondary to malabsorptive and protein-losing enteropathy in tandem with nephrotic range proteinuria. Intolerance to enteral feeding led the patient to be dependent on parenteral nutrition. Serum immunofixation revealed IgG lambda monoclonal protein. The patient underwent endoscopic evaluation with biopsies taken from the gastrointestinal tract that confirmed the diagnosis of primary systemic light chain amyloidosis. A subsequent bone marrow biopsy revealed normocellular bone marrow with deposition of amyloid. The patient was not considered for autologous stem cell transplantation as the outcomes in patients with multisystem involvement are often poor, with a high mortality risk. Diffuse primary systemic light-chain amyloidosis involving the gastrointestinal tract is a rare entity and is to be considered among differentials in patients presenting with unexplained malabsorptive symptoms. PMID- 24474902 TI - Laparoscopic gastrectomy for gastric cancer with peritoneal dissemination after induction chemotherapy. AB - Gastric cancer with peritoneal dissemination may be diagnosed as unresectable. More recently, as a result of progress in chemotherapy, some patients with peritoneal dissemination have exhibited extended survival. We report on our experience with three patients in whom induction chemotherapy allowed for totally laparoscopic total gastrectomy (TLTG). All three patients were diagnosed as having advanced gastric cancer with peritoneal dissemination using staging laparoscopy. As induction chemotherapy, S-1 combined with cisplatin was administered to two patients and trastuzumab plus capecitabine combined with cisplatin to one patient. TLTG was performed in all patients and there were no postoperative complications. Adjuvant chemotherapy was initiated within 3 weeks after surgery in all three patients. Laparoscopic gastrectomy undertaken after induction chemotherapy was found to be effective and safe; this treatment has the potential to achieve good treatment outcomes in patients with stage IV gastric cancer. PMID- 24474903 TI - Rare cadaveric finding of a grossly enlarged mucocele appendix. AB - Appendicular mucoceles are rare clinical findings characterized by dilation and distention of the appendicular lumen by the accumulation of mucus. Their discovery is often incidental from abdominal imaging or more commonly as a secondary surgical finding. In this case study we report the first known recorded case of a cadaveric mucocele appendix discovered during routine dissection of the gastrointestinal system. The recorded cause of death for the 86-year-old female patient was congestive heart failure. We compared the gross anatomy and histology of this enormous appendix with another cadaveric appendix. A pathology report identified the appendicular mucocele as a mucinous cystadenoma. PMID- 24474904 TI - Motor dysfunction in cerebellar Purkinje cell-specific vesicular GABA transporter knockout mice. AB - gamma-Aminobutyric acid (GABA) is a major inhibitory neurotransmitter in the adult mammalian central nervous system and plays modulatory roles in neural development. The vesicular GABA transporter (VGAT) is an essential molecule for GABAergic neurotransmission due to its role in vesicular GABA release. Cerebellar Purkinje cells (PCs) are GABAergic projection neurons that are indispensable for cerebellar function. To elucidate the significance of VGAT in cerebellar PCs, we generated and characterized PC-specific VGAT knockout (L7-VGAT) mice. VGAT mRNAs and proteins were specifically absent in the 40-week-old L7-VGAT PCs. The morphological characteristics, such as lamination and foliation of the cerebellar cortex, of the L7-VGAT mice were similar to those of the control littermate mice. Moreover, the protein expression levels and patterns of pre- (calbindin and parvalbumin) and postsynaptic (GABA-A receptor alpha1 subunit and gephyrin) molecules between the L7-VGAT and control mice were similar in the deep cerebellar nuclei that receive PC projections. However, the L7-VGAT mice performed poorly in the accelerating rotarod test and displayed ataxic gait in the footprint test. The L7-VGAT mice also exhibited severer ataxia as VGAT deficits progressed. These results suggest that VGAT in cerebellar PCs is not essential for the rough maintenance of cerebellar structure, but does play an important role in motor coordination. The L7-VGAT mice are a novel model of ataxia without PC degeneration, and would also be useful for studying the role of PCs in cognition and emotion. PMID- 24474905 TI - Synaptic and cellular organization of layer 1 of the developing rat somatosensory cortex. AB - Layer 1 of the neocortex is sparsely populated with neurons and heavily innervated by fibers from lower layers and proximal and distal brain regions. Understanding the potential functions of this layer requires a comprehensive understanding of its cellular and synaptic organization. We therefore performed a quantitative study of the microcircuitry of neocortical layer 1 (L1) in the somatosensory cortex in juvenile rats (P13-P16) using multi-neuron patch-clamp and 3D morphology reconstructions. Expert-based subjective classification of the morphologies of the recorded L1 neurons suggest 6 morphological classes: (1) the Neurogliaform cells with dense axonal arborizations (NGC-DA) and with sparse arborizations (NGC-SA), (2) the Horizontal Axon Cell (HAC), (3) those with descending axonal collaterals (DAC), (4) the large axon cell (LAC), and (5) the small axon cell (SAC). Objective, supervised and unsupervised cluster analyses confirmed DAC, HAC, LAC and NGC as distinct morphological classes. The neurons were also classified into 5 electrophysiological types based on the Petilla convention; classical non-adapting (cNAC), burst non-adapting (bNAC), classical adapting (cAC), classical stuttering (cSTUT), and classical irregular spiking (cIR). The most common electrophysiological type of neuron was the cNAC type (40%) and the most common morpho-electrical type was the NGC-DA-cNAC. Paired patch-clamp recordings revealed that the neurons were connected via GABAergic inhibitory synaptic connections with a 7.9% connection probability and via gap junctions with a 5.2% connection probability. Most synaptic connections were mediated by both GABAA and GABAB receptors (62.6%). A smaller fraction of synaptic connections were mediated exclusively by GABAA (15.4%) or GABAB (21.8%) receptors. Morphological 3D reconstruction of synaptic connected pairs of L1 neurons revealed multi-synapse connections with an average of 9 putative synapses per connection. These putative synapses were widely distributed with 39% on somata and 61% on dendrites. We also discuss the functional implications of this L1 cellular and synaptic organization in neocortical information processing. PMID- 24474906 TI - Organization of the human fetal subpallium. AB - The subpallium comprises large parts of the basal ganglia including striatum and globus pallidus. Genes and factors involved in the development of the subpallium have been extensively studied in most vertebrates, including amphibians, birds, and rodents. However, our knowledge on patterning of the human subpallium remains insufficient. Using double fluorescent immunohistochemistry, we investigated the protein distribution of transcription factors involved in patterning of the subventricular zone (SVZ) in the human forebrain at late embryonic development. Furthermore, we compared the development of cortical and striatal precursors between human fetal brain and E14 and E16 fetal rat brains. Our results reveal that DLX2 marks SVZ precursors in the entire subpallium. Individual subpallial subdomains can be identified based on co-expression of DLX2 with either PAX6 or NKX2-1. SVZ precursors in the dorsal LGE and preopto-hypothalamic boundary are characterized by DLX2/PAX6 co-expression, while precursors in the MGE and preoptic region co-express DLX2/NKX2-1. SVZ precursors in the ventral LGE are DLX2(+)/PAX6(-)/NKX2-1(-). In terms of staging comparisons, the development of the corpus striatum in the human fetal brain during late embryonic stages corresponds well with the development of the striatum observed in E14 fetal rat brains. Our study demonstrates that the pattern underlying the development of the subpallium is highly conserved between rodents and humans and suggests a similar function for these factors in human brain development. Moreover, our data directly influence the application of ganglionic eminence derived human tissue for cell therapeutic approaches in neurodegenerative disorders such as Huntington's disease. PMID- 24474907 TI - Static and dynamic posture control in postlingual cochlear implanted patients: effects of dual-tasking, visual and auditory inputs suppression. AB - Posture control is based on central integration of multisensory inputs, and on internal representation of body orientation in space. This multisensory feedback regulates posture control and continuously updates the internal model of body's position which in turn forwards motor commands adapted to the environmental context and constraints. The peripheral localization of the vestibular system, close to the cochlea, makes vestibular damage possible following cochlear implant (CI) surgery. Impaired vestibular function in CI patients, if any, may have a strong impact on posture stability. The simple postural task of quiet standing is generally paired with cognitive activity in most day life conditions, leading therefore to competition for attentional resources in dual-tasking, and increased risk of fall particularly in patients with impaired vestibular function. This study was aimed at evaluating the effects of postlingual cochlear implantation on posture control in adult deaf patients. Possible impairment of vestibular function was assessed by comparing the postural performance of patients to that of age-matched healthy subjects during a simple postural task performed in static (stable platform) and dynamic (platform in translation) conditions, and during dual-tasking with a visual or auditory memory task. Postural tests were done in eyes open (EO) and eyes closed (EC) conditions, with the CI activated (ON) or not (OFF). Results showed that the postural performance of the CI patients strongly differed from the controls, mainly in the EC condition. The CI patients showed significantly reduced limits of stability and increased postural instability in static conditions. In dynamic conditions, they spent considerably more energy to maintain equilibrium, and their head was stabilized neither in space nor on trunk: they behaved dynamically without vision like an inverted pendulum while the controls showed a whole body rigidification strategy. Hearing (prosthesis on) as well as dual-tasking did not really improve the dynamic postural performance of the CI patients. We conclude that CI patients become strongly visual dependent mainly in challenging postural conditions, a result they have to be awarded of particularly when getting older. PMID- 24474909 TI - Salivary cortisol and alpha-amylase levels during an assessment procedure correlate differently with risk-taking measures in male and female police recruits. AB - Recent laboratory studies have shown that men display more risk-taking behavior in decision-making tasks following stress, whilst women are more risk-aversive or become more task-focused. In addition, these studies have shown that sex differences are related to levels of the stress hormone cortisol (indicative of activation of the hypothalamus-pituitary-adrenocortical-axis): the higher the levels of cortisol the more risk-taking behavior is shown by men, whereas women generally display more risk-aversive or task-focused behavior following higher levels of cortisol. Here, we assessed whether such relationships hold outside the laboratory, correlating levels of cortisol obtained during a job-related assessment procedure with decision-making parameters in the Cambridge Gambling Task (CGT) in male and female police recruits. The CGT allows for discriminating different aspects of reward-based decision-making. In addition, we correlated levels of alpha-amylase [indicative of activation of the sympatho-adrenomedullary axis (SAM)] and decision-making parameters. In line with earlier studies men and women only differed in risk-adjustment in the CGT. Salivary cortisol levels correlated positively and strongly with risk-taking measures in men, which was significantly different from the weak negative correlation in women. In contrast, and less strongly so, salivary alpha-amylase levels correlated positively with risk-taking in women, which was significantly different from the weak negative correlation with risk-taking in men. Collectively, these data support and extend data of earlier studies indicating that risky decision-making in men and women is differently affected by stress hormones. The data are briefly discussed in relation to the effects of stress on gambling. PMID- 24474910 TI - Operationalizing interdisciplinary research-a model of co-production in organizational cognitive neuroscience. PMID- 24474908 TI - Saliency mapping in the optic tectum and its relationship to habituation. AB - Habituation of the orienting response has long served as a model system for studying fundamental psychological phenomena such as learning, attention, decisions, and surprise. In this article, we review an emerging hypothesis that the evolutionary role of the superior colliculus (SC) in mammals or its homolog in birds, the optic tectum (OT), is to select the most salient target and send this information to the appropriate brain regions to control the body and brain orienting responses. Recent studies have begun to reveal mechanisms of how saliency is computed in the OT/SC, demonstrating a striking similarity between mammals and birds. The saliency of a target can be determined by how different it is from the surrounding objects, by how different it is from its history (that is habituation) and by how relevant it is for the task at hand. Here, we will first review evidence, mostly from primates and barn owls, that all three types of saliency computations are linked in the OT/SC. We will then focus more on neural adaptation in the OT and its possible link to temporal saliency and habituation. PMID- 24474911 TI - Ideology in organizational cognitive neuroscience studies and other misleading claims. PMID- 24474912 TI - Cortico-muscular coupling and motor performance are modulated by 20 Hz transcranial alternating current stimulation (tACS) in Parkinson's disease. AB - Parkinson's disease (PD) is associated with pathologically altered oscillatory activity. While synchronized oscillations between 13 and 30 Hz are increased within a cortico-subcortical network, cortico-muscular coupling (CMC) is decreased. The present study aims at investigating the effect of non-invasive transcranial alternating current stimulation (tACS) of the primary motor cortex (M1) on motor symptoms and motor-cortical oscillations in PD. In 10 PD patients and 10 healthy control subjects, static isometric contraction, dynamic fast finger tapping, and diadochokinesia of the more severely affected hand were investigated prior to and shortly after tACS of the contralateral M1 at 10 Hz vs. 20 Hz vs. sham. During isometric contraction, neuromagnetic activity was recorded using magnetoencephalography. 20 Hz tACS attenuated beta band CMC during isometric contraction and amplitude variability during finger tapping in PD patients but not in healthy control subjects. 10 Hz tACS yielded no significant after-effects. The present data suggest that PD is associated with pathophysiological alterations which abet a higher responsiveness toward frequency-specific tACS - possibly due to pathologically altered motor-cortical oscillatory synchronization at frequencies between 13 and 30 Hz. PMID- 24474913 TI - Mental workload during n-back task-quantified in the prefrontal cortex using fNIRS. AB - When interacting with technical systems, users experience mental workload. Particularly in multitasking scenarios (e.g., interacting with the car navigation system while driving) it is desired to not distract the users from their primary task. For such purposes, human-machine interfaces (HCIs) are desirable which continuously monitor the users' workload and dynamically adapt the behavior of the interface to the measured workload. While memory tasks have been shown to elicit hemodynamic responses in the brain when averaging over multiple trials, a robust single trial classification is a crucial prerequisite for the purpose of dynamically adapting HCIs to the workload of its user. The prefrontal cortex (PFC) plays an important role in the processing of memory and the associated workload. In this study of 10 subjects, we used functional Near-Infrared Spectroscopy (fNIRS), a non-invasive imaging modality, to sample workload activity in the PFC. The results show up to 78% accuracy for single-trial discrimination of three levels of workload from each other. We use an n-back task (n ? {1, 2, 3}) to induce different levels of workload, forcing subjects to continuously remember the last one, two, or three of rapidly changing items. Our experimental results show that measuring hemodynamic responses in the PFC with fNIRS, can be used to robustly quantify and classify mental workload. Single trial analysis is still a young field that suffers from a general lack of standards. To increase comparability of fNIRS methods and results, the data corpus for this study is made available online. PMID- 24474914 TI - Negative learning bias is associated with risk aversion in a genetic animal model of depression. AB - The lateral habenula (LHb) is activated by aversive stimuli and the omission of reward, inhibited by rewarding stimuli and is hyperactive in helpless rats-an animal model of depression. Here we test the hypothesis that congenital learned helpless (cLH) rats are more sensitive to decreases in reward size and/or less sensitive to increases in reward than wild-type (WT) control rats. Consistent with the hypothesis, we found that cLH rats were slower to switch preference between two responses after a small upshift in reward size on one of the responses but faster to switch their preference after a small downshift in reward size. cLH rats were also more risk-averse than WT rats-they chose a response delivering a constant amount of reward ("safe" response) more often than a response delivering a variable amount of reward ("risky" response) compared to WT rats. Interestingly, the level of bias toward negative events was associated with the rat's level of risk aversion when compared across individual rats. cLH rats also showed impaired appetitive Pavlovian conditioning but more accurate responding in a two-choice sensory discrimination task. These results are consistent with a negative learning bias and risk aversion in cLH rats, suggesting abnormal processing of rewarding and aversive events in the LHb of cLH rats. PMID- 24474915 TI - A computational analysis of motor synergies by dynamic response decomposition. AB - Analyses of experimental data acquired from humans and other vertebrates have suggested that motor commands may emerge from the combination of a limited set of modules. While many studies have focused on physiological aspects of this modularity, in this paper we propose an investigation of its theoretical foundations. We consider the problem of controlling a planar kinematic chain, and we restrict the admissible actuations to linear combinations of a small set of torque profiles (i.e., motor synergies). This scheme is equivalent to the time varying synergy model, and it is formalized by means of the dynamic response decomposition (DRD). DRD is a general method to generate open-loop controllers for a dynamical system to solve desired tasks, and it can also be used to synthesize effective motor synergies. We show that a control architecture based on synergies can greatly reduce the dimensionality of the control problem, while keeping a good performance level. Our results suggest that in order to realize an effective and low-dimensional controller, synergies should embed features of both the desired tasks and the system dynamics. These characteristics can be achieved by defining synergies as solutions to a representative set of task instances. The required number of synergies increases with the complexity of the desired tasks. However, a possible strategy to keep the number of synergies low is to construct solutions to complex tasks by concatenating synergy-based actuations associated to simple point-to-point movements, with a limited loss of performance. Ultimately, this work supports the feasibility of controlling a non-linear dynamical systems by linear combinations of basic actuations, and illustrates the fundamental relationship between synergies, desired tasks and system dynamics. PMID- 24474916 TI - LFPy: a tool for biophysical simulation of extracellular potentials generated by detailed model neurons. AB - Electrical extracellular recordings, i.e., recordings of the electrical potentials in the extracellular medium between cells, have been a main work-horse in electrophysiology for almost a century. The high-frequency part of the signal (?500 Hz), i.e., the multi-unit activity (MUA), contains information about the firing of action potentials in surrounding neurons, while the low-frequency part, the local field potential (LFP), contains information about how these neurons integrate synaptic inputs. As the recorded extracellular signals arise from multiple neural processes, their interpretation is typically ambiguous and difficult. Fortunately, a precise biophysical modeling scheme linking activity at the cellular level and the recorded signal has been established: the extracellular potential can be calculated as a weighted sum of all transmembrane currents in all cells located in the vicinity of the electrode. This computational scheme can considerably aid the modeling and analysis of MUA and LFP signals. Here, we describe LFPy, an open source Python package for numerical simulations of extracellular potentials. LFPy consists of a set of easy-to-use classes for defining cells, synapses and recording electrodes as Python objects, implementing this biophysical modeling scheme. It runs on top of the widely used NEURON simulation environment, which allows for flexible usage of both new and existing cell models. Further, calculation of extracellular potentials using the line-source-method is efficiently implemented. We describe the theoretical framework underlying the extracellular potential calculations and illustrate by examples how LFPy can be used both for simulating LFPs, i.e., synaptic contributions from single cells as well a populations of cells, and MUAs, i.e., extracellular signatures of action potentials. PMID- 24474917 TI - Fast parallel image registration on CPU and GPU for diagnostic classification of Alzheimer's disease. AB - Nonrigid image registration is an important, but time-consuming task in medical image analysis. In typical neuroimaging studies, multiple image registrations are performed, i.e., for atlas-based segmentation or template construction. Faster image registration routines would therefore be beneficial. In this paper we explore acceleration of the image registration package elastix by a combination of several techniques: (i) parallelization on the CPU, to speed up the cost function derivative calculation; (ii) parallelization on the GPU building on and extending the OpenCL framework from ITKv4, to speed up the Gaussian pyramid computation and the image resampling step; (iii) exploitation of certain properties of the B-spline transformation model; (iv) further software optimizations. The accelerated registration tool is employed in a study on diagnostic classification of Alzheimer's disease and cognitively normal controls based on T1-weighted MRI. We selected 299 participants from the publicly available Alzheimer's Disease Neuroimaging Initiative database. Classification is performed with a support vector machine based on gray matter volumes as a marker for atrophy. We evaluated two types of strategies (voxel-wise and region-wise) that heavily rely on nonrigid image registration. Parallelization and optimization resulted in an acceleration factor of 4-5x on an 8-core machine. Using OpenCL a speedup factor of 2 was realized for computation of the Gaussian pyramids, and 15-60 for the resampling step, for larger images. The voxel-wise and the region-wise classification methods had an area under the receiver operator characteristic curve of 88 and 90%, respectively, both for standard and accelerated registration. We conclude that the image registration package elastix was substantially accelerated, with nearly identical results to the non-optimized version. The new functionality will become available in the next release of elastix as open source under the BSD license. PMID- 24474918 TI - A classic clinical case: neutrophilic eccrine hidradenitis. AB - BACKGROUND: Neutrophilic eccrine hidradenitis (NEH) is a rare condition described mostly in adult patients receiving chemotherapy for acute myelogenous leukemia. When it affects the facial region, it can mimic cellulitis and delay the diagnostic, thus proper recognition is essential. OBJECTIVE: This article describes a classic case of NEH. We will review the diagnostic, the differential diagnostic (mostly cellulitis) and the management of this condition. METHODS: After a literature review, the patient's file was properly studied in order to portray a clear picture of this condition. Medical photographs and appropriate physical examination upon presentation are also included. RESULTS: The diagnostic for NEH was suggested by the clinical presentation and confirmed histopathologically (skin biopsy). CONCLUSION: The diagnostic of NEH is essential in order to prevent multiple unnecessary antibiotics. PMID- 24474919 TI - A case of autosomal recessive woolly hair/hypotrichosis with alternation in severity: deterioration and improvement with age. AB - Autosomal recessive woolly hair/hypotrichosis (ARWH/H) is a nonsyndromic hair abnormality characterized by sparse, short and curly hair (WH/H). We report the case of a 3-year-old female, with no consanguineous ancestry, who exhibited WH/H. Normal hair was observed at birth, but severe hair loss had developed within the first 6 months; however, her hair density had improved somewhat by age 3. Light microscopy showed hair shaft invaginations, and polarized light microscopy suggested complete medullary disruption of the hair. Direct sequence analysis of peripheral blood showed a homozygous missense mutation in exon 6 of the lipase H gene (LIPH: c.736T>A, p.Cys246Ser), and the exact same mutation was found in the heterozygous state in both parents. The initial deterioration followed by improvement with age observed in this case suggests that the clinical course of ARWH/H may vary among patients with the same mutation in LIPH detected in this case, indicating that additional factors may influence the effect of LIPH on hair development. PMID- 24474920 TI - A case of malignant peripheral nerve sheath tumor with rhabdomyoblastic differentiation: malignant triton tumor. AB - Malignant peripheral nerve sheath tumors (MPNST) constitute a rare variety of soft tissue sarcomas thought to originate from Schwann cells or pluripotent cells of the neural crest. Malignant triton tumor (MTT), a very rare, highly aggressive soft tissue tumor, is a subgroup of MPNST and is comprised of malignant Schwann cells coexisting with malignant rhabdomyoblasts. We herein report the case of a 24-year-old man who presented a subcutaneous mass in his right thigh. The mass was removed surgically in its entirety and radiation therapy was applied locally to prevent tumor regrowth. Nonetheless, the patient died 10 months after surgery from metastases to the lung and brain. He presented neither cafe-au-lait spots nor cutaneous neurofibromas. The histopathology showed a transition from a neurofibroma to an MTT, making this the second report of an MTT arising from a neurofibroma without neurofibromatosis type 1, an autosomal dominant disorder with which 50-70% of tumors reported in previous studies were associated. A histopathological examination using immunostaining with desmin confirmed this diagnosis. MTT has a poorer prognosis than MPNST and should therefore be regarded as a distinct clinical entity. PMID- 24474921 TI - Cannabis extract treatment for terminal acute lymphoblastic leukemia with a Philadelphia chromosome mutation. AB - Acute lymphoblastic leukemia (ALL) is a cancer of the white blood cells and is typically well treated with combination chemotherapy, with a remission state after 5 years of 94% in children and 30-40% in adults. To establish how aggressive the disease is, further chromosome testing is required to determine whether the cancer is myeloblastic and involves neutrophils, eosinophils or basophils, or lymphoblastic involving B or T lymphocytes. This case study is on a 14-year-old patient diagnosed with a very aggressive form of ALL (positive for the Philadelphia chromosome mutation). A standard bone marrow transplant, aggressive chemotherapy and radiation therapy were revoked, with treatment being deemed a failure after 34 months. Without any other solutions provided by conventional approaches aside from palliation, the family administered cannabinoid extracts orally to the patient. Cannabinoid resin extract is used as an effective treatment for ALL with a positive Philadelphia chromosome mutation and indications of dose-dependent disease control. The clinical observation in this study revealed a rapid dose-dependent correlation. PMID- 24474922 TI - Wernicke-korsakoff syndrome in primary peritoneal cancer. AB - Wernicke encephalopathy is a disease that constitutes a medical emergency, but one that can be reversed with thiamine repletion if it is recognized early. Patients with cancer have a high risk of Wernicke encephalopathy because of malnutrition, the use of chemotherapeutic agents, and disease progression. Korsakoff syndrome can follow or accompany Wernicke encephalopathy. Although patients can recover from Wernicke encephalopathy via rapid repletion of thiamine, few patients recover from Korsakoff syndrome. Here, the case of a 76 year-old female patient who had primary peritoneal cancer and developed Wernicke Korsakoff syndrome as a result of prolonged nutritional imbalance and fast growing tumor cells is reported. The patient's neurologic symptoms improved, but she did not recover from the psychiatric effects of the disease. PMID- 24474923 TI - Low-dose bevacizumab is effective in radiation-induced necrosis. AB - BACKGROUND: Radiation-induced necrosis is a complication of brain irradiation. Treatment options are limited. METHODS: The response to treatment with low-dose bevacizumab in 2 patients with radiation-induced necrosis was reported. RESULTS: Both patients with metastatic melanoma, aged 48 and 51 years, had significant symptomatic and radiological improvement with low-dose bevacizumab treatment. Doses as low as 5 mg/kg every 6 weeks and 7.5 mg/kg i.v. every 4 weeks were used and were highly effective. CONCLUSIONS: Low-dose bevacizumab is a solid option in the management of edema associated with radiation necrosis. PMID- 24474924 TI - Disposition of Erlotinib and Its Metabolite OSI420 in a Patient with High Bilirubin Levels. AB - Erlotinib is an oral epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor approved for the treatment of non-small cell lung cancer and when combined with gemcitabine for pancreatic cancer. Dose reduction of erlotinib in patients with severe hepatic impairment has been established. We present the case of a male patient suffering from an adenocarcinoma of the pancreas with metastases in the liver and lung, whose disease progression led to highly elevated bilirubin levels of >14 mg/dl accompanied by icterus and pruritus. Despite the known contraindication, the patient agreed to be treated with 150 mg erlotinib p.o. per day. We performed therapeutic drug monitoring of erlotinib on day 1 after the first ingestion of erlotinib and then over a period of 19 days. One-compartment pharmacokinetics on day 1 were calculated, and, based on these data, a pharmacokinetic simulation for the following 19 days was run. On day 1 after the first erlotinib ingestion, plasma concentrations were identical to those described in the literature. On the following days, erlotinib plasma concentrations remained at a similar order of magnitude after daily ingestion. Compared with published data, OSI420 plasma concentrations were clearly higher from day 1 to 16. Due to disease progression, the last intake of erlotinib was on day 16, but plasma concentrations of the drug and metabolite increased excessively thereafter. The data give evidence that total bilirubin levels up to 14 mg/dl do not necessarily cause elevated plasma concentrations of erlotinib when given in doses of 150 mg per day. PMID- 24474925 TI - Oxaliplatin-Induced Leukocytoclastic Vasculitis under Adjuvant Chemotherapy for Colorectal Cancer: Two Cases of a Rare Adverse Event. AB - Leukocytoclastic vasculitis is a multicausal systemic inflammatory disease of the small vessels, histologically characterized by inflammation and deposition of both nuclear debris and fibrin in dermal postcapillary venules. The clinical picture typically involves palpable purpura of the lower legs and may be associated with general symptoms such as fatigue, arthralgia and fever. Involvement of the internal organs, most notably the kidneys, the central nervous system or the eyes, is possible and determines the prognosis. Oxaliplatin-induced leukocytoclastic vasculitis is a very rare event that limits treatment options in affected patients. We report 2 patients who developed the condition under chemotherapy for advanced rectal and metastatic colon carcinoma, respectively; a termination of the therapy was therefore necessary. While current therapies for colorectal cancer include the combination of multimodal treatment with new and targeted agents, rare and unusual side effects elicited by established agents also need to be taken into account for the clinical management. PMID- 24474926 TI - Primary retroperitoneal mullerian adenocarcinoma: a case report and literature review. AB - Primary retroperitoneal mullerian adenocarcinoma (PRMA) is an extremely rare clinical entity. We report the case of a 54-year-old woman who presented with a mass in the right lower retroperitoneum, identified during an ultrasound exam. Computed tomography confirmed a retroperitoneal mass measuring 11 cm. The patient underwent laparotomy and the mass was completely excised. The histopathological exam revealed PRMA. PMID- 24474927 TI - Coincidence of Varicella-Zoster Virus Anterior Uveitis in a Patient with Chandler's Syndrome. AB - PURPOSE: We report a patient who, based on the clinical manifestations, was originally diagnosed as having Chandler's syndrome and later developed varicella zoster virus (VZV) DNA-positive anterior uveitis. METHODS: The patient with Chandler's syndrome who manifested anterior uveitis underwent a complete ophthalmologic examination. Polymerase chain reaction (PCR) was used to amplify the viral DNA in the aqueous humor to determine the cause of the intraocular inflammation. RESULTS: Slit-lamp biomicroscopy showed focal iris atrophy and peripheral anterior synechiae (PAS); specular microscopy of the corneal endothelium disclosed the hammered-silver appearance. Based on these clinical findings, we diagnosed this patient as having Chandler's syndrome. During the follow-up period, however, the inflammatory cells suddenly appeared in the anterior chamber with formation of keratic precipitates and an increased intraocular pressure (IOP). VZV DNA was displayed in the aqueous humor by PCR. Based upon the diagnosis of VZV anterior uveitis, corticosteroids and acyclovir were given topically and systemically. The inflammation subsided with these medications; however, trabeculectomy was finally needed to control the IOP due to PAS progression. CONCLUSION: The coincidence of VZV anterior uveitis with Chandler's syndrome may constitute an implication for the possible viral etiology of iridocorneal endothelial syndrome. PMID- 24474928 TI - Uveitis as a Result of MAP Kinase Pathway Inhibition. AB - We report the case of a patient treated with dabrafenib and trametinib (mitogen activated protein kinase pathway inhibitors) for stage 3b cutaneous melanoma who developed bilateral uveitis. Although there have been reports of ocular side effects with this class of drugs, uveitis has not been previously reported to the best of our knowledge. This case indicates the wide range of side effects that can be seen with the newer targeted biological therapies. PMID- 24474929 TI - A case of functional (psychogenic) monocular hemianopia analyzed by measurement of hemifield visual evoked potentials. AB - PURPOSE: Functional monocular hemianopia is an extremely rare condition, for which measurement of hemifield visual evoked potentials (VEPs) has not been previously described. METHODS: A 14-year-old boy with functional monocular hemianopia was followed up with Goldmann perimetry and measurement of hemifield and full-field VEPs. RESULTS: The patient had a history of monocular temporal hemianopia of the right eye following headache, nausea and ague. There was no relative afferent pupillary defect, and a color perception test was normal. Goldmann perimetry revealed a vertical monocular temporal hemianopia of the right eye; the hemianopia on the right was also detected with a binocular visual field test. Computed tomography, magnetic resonance imaging (MRI) and MR angiography of the brain including the optic chiasm as well as orbital MRI revealed no abnormalities. On the basis of these results, we diagnosed the patient's condition as functional monocular hemianopia. Pattern VEPs according to the International Society for Clinical Electrophysiology of Vision (ISCEV) standard were within the normal range. The hemifield pattern VEPs for the right eye showed a symmetrical latency and amplitude for nasal and temporal hemifield stimulation. One month later, the visual field defect of the patient spontaneously disappeared. CONCLUSIONS: The latency and amplitude of hemifield VEPs for a patient with functional monocular hemianopia were normal. Measurement of hemifield VEPs may thus provide an objective tool for distinguishing functional hemianopia from hemifield loss caused by an organic lesion. PMID- 24474930 TI - HLA-A29-Positive Uveitis: Birdshot Chorioretinopathy, What Else? AB - Birdshot chorioretinopathy (BSCR) is a relatively rare form of uveitis, which is strongly correlated with the histocompatibility leukocyte antigen (HLA)-A29 class I type. Nevertheless, HLA typing is not diagnostic. The purpose of the present study was to retrospectively evaluate the ocular manifestations associated with the presence of HLA-A29 other than typical BSCR. Charts of consecutive patients with a diagnosis of intraocular inflammation and who were found to be positive for the presence of HLA-A29 were retrospectively reviewed. Only 7 patients met the criteria for a definite diagnosis of BSCR. Among the other 11 patients, the disease was bilateral in 7 patients and unilateral in 4 patients. A definite diagnosis of the following conditions were found: intraocular and CNS lymphoma in 1 patient, posterior tubercular uveitis with occlusive vasculitis in 1 patient, latent ocular tuberculosis in 1 patient, Fuchs' uveitis in 1 patient, herpetic panuveitis in 1 patient and HLA-B27 anterior uveitis in another patient. Although BSCR is strongly related to the HLA-A29 phenotype, and its presence confers a relative risk of disease, the definite diagnosis requires specific ocular characteristics. HLA-A29 typing alone is not a diagnostic requirement for the definite diagnosis of BSCR and should only be considered as a supportive finding. PMID- 24474931 TI - Orbital cellulitis presenting as a first sign of incomplete kawasaki disease. AB - A 6-year-old boy was referred to our hospital with orbital cellulitis. He had a history of 7 days of fever despite antibiotherapy. At first, he only had pharyngitis and conjunctivitis, but then an orbital mass evolved which restricted the movement of his right eye and there was also periorbital inflammation resembling orbital cellulitis. Examination at presentation revealed conjunctivitis with secretion, periocular inflammation and edema, right preauricular lymphadenopathy and restriction of upgaze in the right eye. Laboratory findings included a white blood cell count of 19,000 cells per mm3, with 81.5% neutrophils, 15.0% lymphocytes, 1.2% monocytes and 0.4% basophils. The erythrocyte sedimentation rate was 52 mm/h and the C-reactive protein level was 46.3 mg/dl. Magnetic resonance imaging confirmed orbital cellulitis and pansinusitis. Vancomycin (60 mg/kg/day) and meropenem (100 mg/kg/day) were administered, but desquamation on his fingertips and a rash appeared on the tenth day. A pediatric consultation resulted in a diagnosis of incomplete Kawasaki disease (KD). After administration of aspirin, the orbital inflammation regressed in 3 days. No coronary artery lesions were detected on the first echocardiography, but these did appear 6 weeks later. This confirmed the KD diagnosis. PMID- 24474932 TI - Late-onset capsular block syndrome: unusually delayed presentation. AB - Capsular block syndrome (CBS) has been known to occur as a rare complication of cataract surgery with continuous curvilinear capsulorhexis and a posterior chamber lens implant. Typically, it presents with reduced vision in the early postoperative period and is characterised by a forward displacement of the posterior-chamber intra-ocular lens and an accumulation of intra-capsular opaque material. Management of CBS is usually by Nd:YAG laser capsulotomy. In this report, we describe a unique case of very-delayed-onset CBS with good visual acuity, occurring 8 years after surgery. It was treated successfully with surgical removal of the opaque material. PMID- 24474933 TI - Fungal keratitis - improving diagnostics by confocal microscopy. AB - PURPOSE: Introducing a simple image grading system to support the interpretation of in vivo confocal microscopy (IVCM) images in filamentous fungal keratitis. SETTING: Clinical and confocal studies took place at the Department of Ophthalmology, Aarhus University Hospital, Denmark. Histopathological analysis was performed at the Eye Pathology Institute, Department of Neuroscience and Pharmacology, University of Copenhagen, Denmark. METHODS: A recent series of consecutive patients with filamentous fungal keratitis is presented to demonstrate the results from in-house IVCM. Based upon our experience with IVCM and previously published images, we composed a grading system for interpreting IVCM images of filamentous fungal keratitis. RESULTS: A recent case series of filamentous fungal keratitis from 2011 to 2012 was examined. There were 3 male and 3 female patients. Mean age was 44.5 years (range 12-69), 6 out of 17 (35%) cultures were positive and a total of 6/7 (86%) IVCM scans were positive. Three different categories of IVCM results for the grading of diagnostic certainty were formed. CONCLUSION: IVCM is a valuable tool for diagnosing filamentous fungal keratitis. In order to improve the reliability of IVCM, we suggest implementing a simple and clinically applicable grading system for aiding the interpretation of IVCM images of filamentous fungal keratitis. PMID- 24474934 TI - Alagille syndrome associated with xerophthalmia. AB - PURPOSE: To report the occurrence of xerophthalmia and keratomalacia in a patient with Alagille syndrome. METHODS: The patient's record and relevant literature were reviewed. RESULTS: A 3-year-old boy with Alagille syndrome was examined at our institution due to severe bilateral ocular irritation. A corneal ulcer and keratomalacia were found in the right eye and severe dryness with corneal opacification was found in the left eye. He was treated with topical fortified antibiotics in the right eye, followed by amniotic membrane transplantation. Due to his systemic condition, characterized by severe cholestasis and intestinal malabsorption, a suspicion of vitamin A deficiency was raised and was later confirmed in serum analysis. CONCLUSION: This is the first report of xerophthalmia in a patient with Alagille syndrome. Vitamin A deficiency leading to xerophthalmia is common in developing countries; however, its occurrence in the West is rare, leading to a reduced awareness of this disorder amongst clinicians. Unusual eating habits, intestinal malabsorption and liver disease are possible causes for such a deficiency. The purpose of this case report is to raise awareness to the possibility of vitamin A deficiency in children with keratopathy, especially when associated with these disorders. PMID- 24474935 TI - Effects of age and eccentricity on visual target detection. AB - The aim of this study was to examine the effects of aging and target eccentricity on a visual search task comprising 30 images of everyday life projected into a hemisphere, realizing a +/-90 degrees visual field. The task performed binocularly allowed participants to freely move their eyes to scan images for an appearing target or distractor stimulus (presented at 10 degrees ; 30 degrees , and 50 degrees eccentricity). The distractor stimulus required no response, while the target stimulus required acknowledgment by pressing the response button. One hundred and seventeen healthy subjects (mean age = 49.63 years, SD = 17.40 years, age range 20-78 years) were studied. The results show that target detection performance decreases with age as well as with increasing eccentricity, especially for older subjects. Reaction time also increases with age and eccentricity, but in contrast to target detection, there is no interaction between age and eccentricity. Eye movement analysis showed that younger subjects exhibited a passive search strategy while older subjects exhibited an active search strategy probably as a compensation for their reduced peripheral detection performance. PMID- 24474936 TI - Fluorescent nanosensors for intracellular measurements: synthesis, characterization, calibration, and measurement. AB - Measurement of intracellular acidification is important for understanding fundamental biological pathways as well as developing effective therapeutic strategies. Fluorescent pH nanosensors are an enabling technology for real-time monitoring of intracellular acidification. The physicochemical characteristics of nanosensors can be engineered to target specific cellular compartments and respond to external stimuli. Therefore, nanosensors represent a versatile approach for probing biological pathways inside cells. The fundamental components of nanosensors comprise a pH-sensitive fluorophore (signal transducer) and a pH insensitive reference fluorophore (internal standard) immobilized in an inert non toxic matrix. The inert matrix prevents interference of cellular components with the sensing elements as well as minimizing potentially harmful effects of some fluorophores on cell function. Fluorescent nanosensors are synthesized using standard laboratory equipment and are detectable by non-invasive widely accessible imaging techniques. The outcomes of studies employing this technology are dependent on reliable methodology for performing measurements. In particular, special consideration must be given to conditions for sensor calibration, uptake conditions and parameters for image analysis. We describe procedures for: (1) synthesis and characterization of polyacrylamide and silica based nanosensors, (2) nanosensor calibration and (3) performing measurements using fluorescence microscopy. PMID- 24474937 TI - Effect of midgut proteolytic activity on susceptibility of lepidopteran larvae to Bacillus thuringiensis subsp. Kurstaki. AB - Bacillus thuringiensis (Bt) is the most effective microbial control agent for controlling numerous species from different insect orders. All subspecies and strains of B. thuringiensis can produce a spore and a crystalline parasporal body. This crystal which contains proteinaceous protoxins is dissolved in the alkaline midgut, the resulting molecule is then cleaved and activated by proteolytic enzymes and acts as a toxin. An interesting aspect of this activation process is that variations in midgut pH and protease activity have been shown to account for the spectrum of some Bt proteins activity. Thus, an important factor that could be a determinant of toxin activity is the presence of proteases in the midgut microenvironment of susceptible insects. Reciprocally, any alteration in the midgut protease composition of the host can result in resistance to Bt. Here in this paper, we reviewed this processes in general and presented our assays to reveal whether resistance mechanism to Bt in Diamondback Moth (DbM) larvae could be due to the function of the midgut proteases? We estimated LC50 for both probable susceptible and resistant populations in laboratory and greenhouse tests. Then, the midgut protease activities of the B. thuringiensis induced resistant and susceptible populations of the DbM were assayed on Hemoglubin and on N-alpha-benzoyl-DL-arginine-p-nitroanilide (BapNA) for total and tryptic activities, respectively. Six hours after feeding on Bt treated and untreated canola leaves, the midguts of instar larvae of both populations were isolated. Following related protocols, peptides released through the activity of proteinases on Hemoglubin and BApNA were recorded using microplate reader. Control (Blank) was also considered with adding TCA to reaction mix before adding enzymatic extract. Data analysis indicated that there are significant differences for tryptic activity on BApNA and also for total proteolytic activity on Hemoglubin between susceptible and resistant populations fed on Bt treated leaves. But these differences were not significant for larvae fed on healthy canola leaves between these two populations. These results which supported the role of DbM's proteolytic system in development of resistance to Bt, will be discussed in details. PMID- 24474938 TI - Role of microRNAs in skeletal muscle hypertrophy. AB - Skeletal muscle comprises approximately 40% of body weight, and is important for locomotion, as well as for metabolic homeostasis. Adult skeletal muscle mass is maintained by a fine balance between muscle protein synthesis and degradation. In response to cytokines, nutrients, and mechanical stimuli, skeletal muscle mass is increased (hypertrophy), whereas skeletal muscle mass is decreased (atrophy) in a variety of conditions, including cancer cachexia, starvation, immobilization, aging, and neuromuscular disorders. Recent studies have determined two important signaling pathways involved in skeletal muscle mass. The insulin-like growth factor-1 (IGF-1)/Akt pathway increases skeletal muscle mass via stimulation of protein synthesis and inhibition of protein degradation. By contrast, myostatin signaling negatively regulates skeletal muscle mass by reducing protein synthesis. In addition, the discovery of microRNAs as novel regulators of gene expression has provided new insights into a multitude of biological processes, especially in skeletal muscle physiology. We summarize here the current knowledge of microRNAs in the regulation of skeletal muscle hypertrophy, focusing on the IGF-1/Akt pathway and myostatin signaling. PMID- 24474940 TI - Src as the link between inflammation and cancer. AB - Although a causal link between chronic inflammation and cancer has been established, the exact molecular mechanism linking inflammation to cancer remains largely unknown. It was previously postulated that molecular switches responsible for cancer cell development, and for infiltration of inflammatory cells into cancer, were divided into a distinct set of intracellular proteins and signaling pathways. However, recent evidence suggests that both tumor cells and tumor infiltrating immune cells utilize the same kinases, mostly that of Src family, to facilitate cancer development and progression. In the past few years several groups have found that Src activation both in cancer and inflammatory cells is mainly driven by pro-inflammatory cytokines within the tumor microenvironment. Here we evaluate the cross talks between Src kinase pathways in immune cells and cancer cells. We conclude that Src might serve as a critical mechanistic link between inflammation and cancer, mediating and propagating a cycle between immune and tissue cells that can ultimately lead to the development and progression of cancer. PMID- 24474941 TI - Self-organization of early vocal development in infants and machines: the role of intrinsic motivation. AB - WE BRIDGE THE GAP BETWEEN TWO ISSUES IN INFANT DEVELOPMENT: vocal development and intrinsic motivation. We propose and experimentally test the hypothesis that general mechanisms of intrinsically motivated spontaneous exploration, also called curiosity-driven learning, can self-organize developmental stages during early vocal learning. We introduce a computational model of intrinsically motivated vocal exploration, which allows the learner to autonomously structure its own vocal experiments, and thus its own learning schedule, through a drive to maximize competence progress. This model relies on a physical model of the vocal tract, the auditory system and the agent's motor control as well as vocalizations of social peers. We present computational experiments that show how such a mechanism can explain the adaptive transition from vocal self-exploration with little influence from the speech environment, to a later stage where vocal exploration becomes influenced by vocalizations of peers. Within the initial self exploration phase, we show that a sequence of vocal production stages self organizes, and shares properties with data from infant developmental psychology: the vocal learner first discovers how to control phonation, then focuses on vocal variations of unarticulated sounds, and finally automatically discovers and focuses on babbling with articulated proto-syllables. As the vocal learner becomes more proficient at producing complex sounds, imitating vocalizations of peers starts to provide high learning progress explaining an automatic shift from self-exploration to vocal imitation. PMID- 24474942 TI - Time for actions in lucid dreams: effects of task modality, length, and complexity. AB - The relationship between time in dreams and real time has intrigued scientists for centuries. The question if actions in dreams take the same time as in wakefulness can be tested by using lucid dreams where the dreamer is able to mark time intervals with prearranged eye movements that can be objectively identified in EOG recordings. Previous research showed an equivalence of time for counting in lucid dreams and in wakefulness (LaBerge, 1985; Erlacher and Schredl, 2004), but Erlacher and Schredl (2004) found that performing squats required about 40% more time in lucid dreams than in the waking state. To find out if the task modality, the task length, or the task complexity results in prolonged times in lucid dreams, an experiment with three different conditions was conducted. In the first condition, five proficient lucid dreamers spent one to three non consecutive nights in the sleep laboratory. Participants counted to 10, 20, and 30 in wakefulness and in their lucid dreams. Lucidity and task intervals were time stamped with left-right-left-right eye movements. The same procedure was used for the second condition where eight lucid dreamers had to walk 10, 20, or 30 steps. In the third condition, eight lucid dreamers performed a gymnastics routine, which in the waking state lasted the same time as walking 10 steps. Again, we found that performing a motor task in a lucid dream requires more time than in wakefulness. Longer durations in the dream state were present for all three tasks, but significant differences were found only for the tasks with motor activity (walking and gymnastics). However, no difference was found for relative times (no disproportional time effects) and a more complex motor task did not result in more prolonged times. Longer durations in lucid dreams might be related to the lack of muscular feedback or slower neural processing during REM sleep. Future studies should explore factors that might be associated with prolonged durations. PMID- 24474939 TI - Risk factors for pancreatic cancer: underlying mechanisms and potential targets. AB - PURPOSE OF THE REVIEW: Pancreatic cancer is extremely aggressive, forming highly chemo-resistant tumors, and has one of the worst prognoses. The evolution of this cancer is multi-factorial. Repeated acute pancreatic injury and inflammation are important contributing factors in the development of pancreatic cancer. This article attempts to understand the common pathways linking pancreatitis to pancreatic cancer. RECENT FINDINGS: Intracellular activation of both pancreatic enzymes and the transcription factor NF-kappaB are important mechanisms that induce acute pancreatitis (AP). Recurrent pancreatic injury due to genetic susceptibility, environmental factors such as smoking, alcohol intake, and conditions such as obesity lead to increases in oxidative stress, impaired autophagy and constitutive activation of inflammatory pathways. These processes can stimulate pancreatic stellate cells, thereby increasing fibrosis and encouraging chronic disease development. Activation of oncogenic Kras mutations through inflammation, coupled with altered levels of tumor suppressor proteins (p53 and p16) can ultimately lead to development of pancreatic cancer. SUMMARY: Although our understanding of pancreatitis and pancreatic cancer has tremendously increased over many years, much remains to be elucidated in terms of common pathways linking these conditions. PMID- 24474943 TI - Behavioral evidence of a dissociation between voice gender categorization and phoneme categorization using auditory morphed stimuli. AB - Both voice gender perception and speech perception rely on neuronal populations located in the peri-sylvian areas. However, whilst functional imaging studies suggest a left vs. right hemisphere and anterior vs. posterior dissociation between voice and speech categorization, psycholinguistic studies on talker variability suggest that these two processes share common mechanisms. In this study, we investigated the categorical perception of voice gender (male vs. female) and phonemes (/pa/ vs. /ta/) using the same stimulus continua generated by morphing. This allowed the investigation of behavioral differences while controlling acoustic characteristics, since the same stimuli were used in both tasks. Despite a higher acoustic dissimilarity between items during the phoneme categorization task (a male and female voice producing the same phonemes) than the gender task (the same person producing 2 phonemes), results showed that speech information is being processed much faster than voice information. In addition, f0 or timbre equalization did not affect RT, which disagrees with the classical psycholinguistic models in which voice information is stripped away or normalized to access phonetic content. Also, despite similar average response (percentages) and perceptual (d') curves, a reverse correlation analysis on acoustic features revealed that only the vowel formant frequencies distinguish stimuli in the gender task, whilst, as expected, the formant frequencies of the consonant distinguished stimuli in the phoneme task. The 2nd set of results thus also disagrees with models postulating that the same acoustic information is used for voice and speech. Altogether these results suggest that voice gender categorization and phoneme categorization are dissociated at an early stage on the basis of different enhanced acoustic features that are diagnostic to the task at hand. PMID- 24474944 TI - Perceptual pitch deficits coexist with pitch production difficulties in music but not Mandarin speech. AB - Congenital amusia is a musical disorder that mainly affects pitch perception. Among Mandarin speakers, some amusics also have difficulties in processing lexical tones (tone agnosics). To examine to what extent these perceptual deficits may be related to pitch production impairments in music and Mandarin speech, eight amusics, eight tone agnosics, and 12 age- and IQ-matched normal native Mandarin speakers were asked to imitate music note sequences and Mandarin words of comparable lengths. The results indicated that both the amusics and tone agnosics underperformed the controls on musical pitch production. However, tone agnosics performed no worse than the amusics, suggesting that lexical tone perception deficits may not aggravate musical pitch production difficulties. Moreover, these three groups were all able to imitate lexical tones with perfect intelligibility. Taken together, the current study shows that perceptual musical pitch and lexical tone deficits might coexist with musical pitch production difficulties. But at the same time these perceptual pitch deficits might not affect lexical tone production or the intelligibility of the speech words that were produced. The perception-production relationship for pitch among individuals with perceptual pitch deficits may be, therefore, domain-dependent. PMID- 24474945 TI - Quality-space theory in olfaction. AB - Quality-space theory (QST) explains the nature of the mental qualities distinctive of perceptual states by appeal to their role in perceiving. QST is typically described in terms of the mental qualities that pertain to color. Here we apply QST to the olfactory modalities. Olfaction is in various respects more complex than vision, and so provides a useful test case for QST. To determine whether QST can deal with the challenges olfaction presents, we show how a quality space (QS) could be constructed relying on olfactory perceptible properties and the olfactory mental qualities then defined by appeal to that QS of olfactory perceptible properties. We also consider how to delimit the olfactory QS from other modalities. We further apply QST to the role that experience plays in refining our olfactory discriminative abilities and the occurrence of olfactory mental qualities in non-conscious olfactory states. QST is shown to be fully applicable to and useful for understanding the complex domain of olfaction. PMID- 24474946 TI - Intensive exposure to narrative in story books as a possibly effective treatment of social perspective-taking in schoolchildren with autism. AB - One of the major characteristics of autism is impairment of communication and socialization. While such impairment per se has been well documented, research into effective interventions for children with this developmental disorder is still limited. Here we present preliminary evidence for the possibility of improvement of the capability of social perspective-taking in schoolchildren with autism by having intensive experience with narrative, in which they were exposed to narrative in story books read by their parents over a consecutive 5- to 6-day period. When their capability was evaluated on the basis of a conventional role taking task, the mean score tended to increase after the exposure as compared to before the exposure, whereas such a change was not recorded in children who did not experience such exposure. These effects were confirmed when the children were retested 4 months later. Although preliminary, the current study represents a step toward the development of more effective social perspective-taking interventions for children with autism. PMID- 24474947 TI - Role of estrogen receptors and g protein-coupled estrogen receptor in regulation of hypothalamus-pituitary-testis axis and spermatogenesis. AB - Male reproductive function is under the control of both gonadotropins and androgens through a negative feedback loop that involves the hypothalamus, pituitary, and testis known as hypothalamus-pituitary-gonadal axis (HPG). Indeed, estrogens also play an important role in regulating HPG axis but the study on relative contribution to the inhibition of gonadotropins secretion exerted by the amount of estrogens produced within the hypothalamus and/or the pituitary or by the amount of circulating estrogens is still ongoing. Moreover, it is known that the maintenance of spermatogenesis is controlled by gonadotropins and testosterone, the effects of which are modulated by a complex network of locally produced factors, including estrogens. Physiological effects of estrogens are mediated by the classical nuclear estrogen receptor alpha and estrogen receptor beta, which mediate both genomic and rapid signaling events. In addition, estrogens induce rapid non-genomic responses through a membrane-associated G protein-coupled estrogen receptor (GPER). Ours and other studies reported that, in the testis, GPER is expressed in both normal germ cells and somatic cells and it is involved in mediating the estrogen action in spermatogenesis controlling proliferative and/or apoptotic events. Interestingly, GPER expression has been revealed also in the hypothalamus and pituitary. However, its role in mediating estrogen rapid actions in this context is under investigation. Recent studies indicate that GPER is involved in modulating gonadotropin-releasing hormone (GnRH) release as well as gonadotropins secretion. In this review, we will summarize the current knowledge concerning the role of estrogen/estrogen receptors molecular pathways in regulating GnRH, follicle-stimulating hormone, and luteinizing hormone release at the hypothalamic and pituitary levels in males as well as in controlling specific testicular functions such as spermatogenesis, focusing our attention mainly on estrogen signaling mediated by GPER. PMID- 24474948 TI - Structures and host-adhesion mechanisms of lactococcal siphophages. AB - The Siphoviridae family of bacteriophages is the largest viral family on earth and comprises members infecting both bacteria and archaea. Lactococcal siphophages infect the Gram-positive bacterium Lactococcus lactis, which is widely used for industrial milk fermentation processes (e.g., cheese production). As a result, lactococcal phages have become one of the most thoroughly characterized class of phages from a genomic standpoint. They exhibit amazing and intriguing characteristics. First, each phage has a strict specificity toward a unique or a handful of L. lactis host strains. Second, most lactococcal phages possess a large organelle at their tail tip (termed the baseplate), bearing the receptor binding proteins (RBPs) and mediating host adsorption. The recent accumulation of structural and functional data revealed the modular structure of their building blocks, their different mechanisms of activation and the fine specificity of their RBPs. These results also illustrate similarities and differences between lactococcal Siphoviridae and Gram-negative infecting Myoviridae. PMID- 24474949 TI - Emerging role of endosomal toll-like receptors in rheumatoid arthritis. AB - Toll-like receptors (TLRs) and their downstream signaling pathways have been comprehensively characterized in innate immunity. In addition to this function, these receptors have also been suggested to be involved in the pathogenesis of many autoimmune diseases, including rheumatoid arthritis (RA). Murine in vivo models and human in vitro tissue models of RA have provided a wealth of information on the potential activity of TLRs and components of the downstream signaling pathways. Whilst most early work investigated the cell surface TLRs, more recently the focus has moved to the endosomal TLRs 3, 7, 8, and 9. These receptors recognize self and foreign double-stranded RNA and single-stranded RNA and DNA. The development of therapeutics to inhibit the endosomal TLRs or components of their signaling cascades may represent a way to target inflammation upstream of cytokine production. This may allow for greater specificity than existing therapies including cytokine blockade. Here, we review the current information suggesting a role for the endosomal TLRs in RA pathogenesis and the efforts to target these receptors therapeutically. PMID- 24474951 TI - What is hypercalcemia? The importance of fasting samples. AB - The differentiation between primary or tertiary (both hypercalcemic) and secondary (normocalcemic) hyperparathyroidism requires the identification of hypercalcemia. Calcium in the blood exists as bound, complexed and ionized fractions. Calcium sensors on parathyroid cells interact only with the ionized fraction (about 50% of the total calcium concentration). Many formulas using albumin, total protein or phosphate to correct or adjust total calcium to reflect the level of ionized calcium may be accurate only within a limited range. In addition, they can introduce errors based on inaccuracies in the measurement of these other metabolites. Clinical conditions, mainly those illnesses affecting acid-base balance, can alter the proportions of bound and free calcium. How and when the blood samples are drawn can alter the level of total calcium. Prolonged standing or prolonged venous stasis causes hemoconcentration, increasing the bound fraction. Preceding exercise can also affect blood calcium levels. Ingestion of calcium supplements or calcium-containing nutrients can cause transient elevations in blood calcium levels lasting several hours, leading to unnecessary further testing. Fasting total calcium levels may be sufficient for monitoring progress. However, for diagnostic purposes, fasting ionized calcium levels should be used. Therefore, for an isolated high total calcium level, we recommend obtaining a repeat fasting total and ionized calcium measurement before further investigations. Hypercalcemia may be diagnosed if there are persistent or frequent total or, preferably, ionized calcium levels >3 SD above the mean of the normal range or if there are progressively rising levels. PMID- 24474950 TI - Changes in Central Aortic Pressure, Endothelial Function and Biomarkers in Hypertensive African-Americans with the Cardiometabolic Syndrome: Comparison of Amlodipine/Olmesartan versus Hydrochlorothiazide/Losartan. AB - Sixty-six self-identified African-American subjects with stage 1 and 2 hypertension and characteristics of the cardiometabolic syndrome were treated with amlodipine/olmesartan (A/O) versus losartan/hydrochlorothiazide (L/H) for 20 weeks in an open-label, active comparator fashion. Subjects not meeting a blood pressure (BP) value of <125/75 mm Hg on either regimen at week 14 were placed on additional or alternative therapy. After 20 weeks of therapy, systolic BP was reduced by 34.6 +/- 4.2 mm Hg in the A/O group and by 27.0 +/- 4.1 mm Hg in the L/H group (p = 0.012 A/O vs. L/H). Diastolic BP was reduced by 16.9 +/- 2.0 mm Hg in the A/O group and by 12.3 +/- 2.0 mm Hg in the L/H group (p = 0.022 A/O vs. L/H). There was a substantial increase in endothelial function of 44 and 103% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H). Central aorta augmentation pressure was significantly reduced by 42% with the A/O treatment, and a smaller, significant reduction of 28% was observed with the L/H treatment (p = 0.034 A/O vs. L/H). There was a reduction in sIL-6 levels of 20 and 33%, a reduction in serum leptin levels of 22 and 40%, and an increase in serum adiponectin of 19 and 46% in the L/H and A/O groups, respectively (p < 0.005 A/O vs. L/H for each biomarker). Treatment with A/O after 14 weeks reduced pulse wave velocity by 22% (p = 0.011 time comparison), whereas L/H treatment had no significant effect. Our findings suggest that, in addition to effective BP reduction, A/O differentially regulates markers of inflammation and obesity, thereby potentially providing greater vascular protection. PMID- 24474952 TI - Clinical and echocardiographic predictors of cardiorenal syndrome type I in patients with acute ischemic right ventricular dysfunction. AB - BACKGROUND: In current cardiology practice, the importance of acute cardiorenal syndrome (CRS) in determining the outcome of patients with acute coronary syndrome (ACS) is well recognized. Certain groups of ACS patients are at higher risk of developing CRS. Data on the association between right ventricular (RV) functions and CRS after acute myocardial infarction (AMI) are scarce. The purpose of the current study was to evaluate the relation between RV function and the development of CRS in patients presenting with inferior wall AMI and RV involvement. PATIENTS AND METHODS: Patients with inferior wall AMI with RV involvement underwent echocardiography at admission to assess RV function. RV functions were quantified according to RV fractional area change (RVFAC), tricuspid annular plane systolic excursion (TAPSE), and RV outflow tract fractional shortening (RVOTFS). The patients were followed up until discharge from hospital. All patients who developed CRS were included in group I, all patients who did not develop CRS were included in group II (controls). Multivariate analysis was carried out to determine the significance of the echocardiographic and clinical parameters in predicting the development of CRS in these patients. RESULTS: In our study, a history of diabetes mellitus, cardiogenic shock at admission, and RVFAC and TAPSE could significantly predict the development of CRS in patients presenting with inferior wall AMI and RV involvement. CONCLUSIONS: RV functions provide strong prognostic information regarding the development of CRS in patients of inferior wall AMI with RV involvement. PMID- 24474953 TI - Serum uric Acid is not an independent risk factor for premature coronary artery disease. AB - BACKGROUND/AIM: There is still debate on the role of serum uric acid as an independent risk factor for coronary artery disease (CAD), particularly premature CAD. This study aimed to investigate whether serum uric acid is a risk factor for premature CAD and whether it can influence the severity of coronary artery stenosis. METHODS: Candidates for coronary artery angiography (age <45 years for men and <55 years for women) who met the inclusion criteria were enrolled in this study. Clinical data of the patients as well as their serum uric acid levels were compared with the presence of premature CAD. RESULTS: In total, 473 patients were included and divided into two groups: the premature CAD group consisted of 245 patients (age = 46.2 +/- 5.7 years; males = 110, 44.9%) and the normal coronary group consisted of 228 subjects (age = 45.7 +/- 6.4 years; males = 62, 27.2%). Uric acid was significantly related to the presence of CAD, but this relationship was not significant after adjustment for confounding variables, including classic CAD risk factors. CAD patients were then categorized based on the extent of the disease (from minimal CAD to three-vessel disease); however, unlike the classic risk factors of CAD, uric acid was not significantly different between these groups (p = 0.10), and a similar result was observed after adjustment for confounders. CONCLUSION: Uric acid is not an independent risk factor for premature CAD but is weakly correlated with the extent of the disease; nevertheless, this relationship requires further investigation. PMID- 24474954 TI - Impaired leukocytes autophagy in chronic kidney disease patients. AB - BACKGROUND: Proteins and cytoplasmic organelles undergo degradation and recycling via autophagy; its role in patients with chronic kidney disease (CKD) is still unclear. We hypothesize that impaired kidney function causes autophagy activation failure. METHODS: We included 60 patients with stage 5 CKD and 30 age- and sex matched healthy subjects as controls. Patients with conditions that could affect autophagy were excluded. Leukocytes were isolated and analyzed from peripheral blood samples collected after overnight fasting and 2 h after breakfast. RESULTS: Overnight fasting induced conversion of microtubule-associated protein-1 light chain 3 I to II (gammaLC3) and increased mRNA levels of the autophagy-related gene 5 (Atg5) and Beclin-1 in healthy subjects, which were nearly absent in CKD patients (p = 0.0001). Moreover, no significant difference in autophagy activation was observed between CKD patients with or without hemodialysis. Correlation studies showed that gammaLC3 was negatively associated with the left atrium size. Changes in Atg5 transcript levels were negatively associated with the left ventricular end-diastolic diameter, and changes in Beclin-1 transcript levels were negatively associated with the mitral inflow E- and A-wave sizes. CONCLUSION: These data suggest that CKD patients have impaired autophagy activation, which cannot be reversed with hemodialysis and is closely related to their cardiac abnormalities. PMID- 24474956 TI - Nitric oxide signaling in plants. PMID- 24474955 TI - Cardiorenal metabolic syndrome and diabetic cognopathy. AB - The prevalence of the cardiorenal metabolic syndrome (CRS) is increasing in parallel with obesity, type 2 diabetes mellitus, Alzheimer's disease, and other forms of dementia. Along with metabolic, inflammatory, and immunological abnormalities, there is maladaptive structural remodeling of the heart, kidney, and brain. The term 'diabetic cognopathy' (DC) may be used when discussing functional and structural changes in the brain of the diabetic patient. DC likely represents an advanced form of these changes in the brain that evolve with increasing duration of the CRS and subsequent clinical diabetes. We posit that DC develops due to a convergence of aging, genetic and lifestyle abnormalities (overnutrition and lack of exercise), which result in multiple injurious metabolic and immunologic toxicities such as dysfunctional immune responses, oxidative stress, inflammation, insulin resistance, and dysglycemia (systemically and in the brain). These converging abnormalities may lead to endothelial blood brain barrier tight junction/adherens junction (TJ/AJ) complex remodeling and microglia activation, which may result in neurodegeneration, impaired cognition, and dementia. Herein, we describe the brain ultrastructural changes evolving from a normal state to maladaptive remodeling in rodent models of CRS including microglia activation/polarization and attenuation and/or loss of the TJ/AJ complexes, pericytes and astrocytes of the neurovascular unit. Further, we discuss the potential relationship between these structural changes and the development of DC, potential therapeutic strategies, and future directions. PMID- 24474957 TI - Single neurons needed for brain asymmetry studies. PMID- 24474958 TI - The variety mixture strategy assessed in a G * G experiment with rice and the blast fungus Magnaporthe oryzae. AB - Frequent and devastating epidemics of parasites are one of the major issues encountered by modern agriculture. To manage the impact of pathogens, resistant plant varieties have been selected. However, resistances are overcome by parasites requiring the use of pesticides and causing new economical and food safety issues. A promising strategy to maintain the epidemic at a low level and hamper pathogen's adaptation to varietal resistance is the use of mixtures of varieties such that the mix will form a heterogeneous environment for the parasite. A way to find the good combination of varieties that will actually constitute a heterogeneous environment for pathogens is to look for genotype * genotype (G * G) interactions between pathogens and plant varieties. A pattern in which pathogens have a high fitness on one variety and a poor fitness on other varieties guarantees the efficiency of the mixture strategy. In the present article, we inoculated 18 different genotypes of the fungus Magnaporthe oryzae on three rice plant varieties showing different levels of partial resistance in order to find a variety combination compatible with the requirements of the variety mixture strategy, i.e., showing appropriate G * G interactions. We estimated the success of each plant-fungus interaction by measuring fungal fitness and three fungal life history traits: infection success, within-host growth, sporulation capacity. Our results show the existence of G * G interactions between the two varieties Ariete and CO39 on all measured traits and fungal fitness. We also observed that these varieties have different resistance mechanisms; Ariete is good at controlling infection success of the parasite but is not able to control its growth when inside the leaf, while CO39 shows the opposite pattern. We also found that Maratelli's resistance has been eroded. Finally, correlation analyses demonstrated that not all infectious traits are positively correlated. PMID- 24474960 TI - Renal denervation as an option for the management of hypertension. AB - Hypertension is a multifactorial condition which makes the development of treatment approaches difficult. The vast majority of patients are treated with lifestyle measures either alone or in combination with antihypertensive drugs, and this approach is largely successful in controlling blood pressure. However, for a subgroup of patients, control of blood pressure remains resistant to this approach and therefore the development of new strategies is imperative. The sympathetic nervous system has been known to be implicated in hypertension for many decades, and evidence from studies in the past has revealed the benefit of reducing sympathetic nerve activity in the control of blood pressure albeit with severe side effects. Recent technological advances have allowed for specific targeting of the renal sympathetic nerves by catheter ablation. The Symplicity HTN-1 and HTN-2 trials have provided strong evidence for renal denervation giving rise to considerable blood pressure reductions in treatment-resistant hypertensives and, due to the high incidence of hypertension worldwide, this carries the promise of further reducing the global burden of hypertension and its attendant complications. Here we review the evidence for renal denervation in the management of hypertension. PMID- 24474962 TI - Mechanisms simultaneously regulate smooth muscle proliferation and differentiation. AB - Vascular smooth muscle cell (VSMC) differentiation and proliferation are two important physiological processes during vascular development. The phenotypic alteration from differentiated to proliferative VSMC contributes to the development of several major cardiovascular diseases including atherosclerosis, hypertension, restenosis after angioplasty or bypass, diabetic vascular complications, and transplantation arteriopathy. Since the VSMC phenotype in these pathological conditions resembles that of developing VSMC during embryonic development, understanding of the molecular mechanisms that control VSMC differentiation will provide fundamental insights into the pathological processes of these cardiovascular diseases. Although VSMC differentiation is usually accompanied by an irreversible cell cycle exit, VSMC proliferation and differentiation occur concurrently during embryonic development. The molecular mechanisms simultaneously regulating these two processes, however, remain largely unknown. Our recent study demonstrates that cell division cycle 7, a key regulator of cell cycle, promotes both VSMC differentiation and proliferation through different mechanisms during the initial phase of VSMC differentiation. Conversely, Kruppel-like factor 4 appears to be a repressor for both VSMC differentiation and proliferation. This review attempts to highlight the novel role of cell division cycle 7 in TGF-beta-induced VSMC differentiation and proliferation. The role of Kruppel-like factor 4 in suppressing these two processes will also be discussed. PMID- 24474961 TI - Extracellular matrix synthesis in vascular disease: hypertension, and atherosclerosis. AB - Extracellular matrix (ECM) within the vascular network provides both a structural and regulatory role. The ECM is a dynamic composite of multiple proteins that form structures connecting cells within the network. Blood vessels are distended by blood pressure and, therefore, require ECM components with elasticity yet with enough tensile strength to resist rupture. The ECM is involved in conducting mechanical signals to cells. Most importantly, ECM regulates cellular function through chemical signaling by controlling activation and bioavailability of the growth factors. Cells respond to ECM by remodeling their microenvironment which becomes dysregulated in vascular diseases such hypertension, restenosis and atherosclerosis. This review examines the cellular and ECM components of vessels, with specific emphasis on the regulation of collagen type I and implications in vascular disease. PMID- 24474963 TI - Transcriptional regulation of endothelial dysfunction in atherosclerosis: an epigenetic perspective. AB - Atherosclerosis is a progressive human pathology that encompasses several stages of development. Endothelial dysfunction represents an early sign of lesion within the vasculature. A number of risk factors for atherosclerosis, including hyperlipidemia, diabetes, and hypertension, target the vascular endothelium by re programming its transcriptome. These profound alterations taking place on the chromatin rely on the interplay between sequence specific transcription factors and the epigenetic machinery. The epigenetic machinery, in turn, tailor individual transcription events key to atherogenesis to intrinsic and extrinsic insults dictating the development of atherosclerotic lesions. This review summarizes our current understanding of the involvement of the epigenetic machinery in endothelial injury during atherogenesis. PMID- 24474964 TI - Genetic variants at 10q23.33 are associated with plasma lipid levels in a Chinese population. AB - Plasma lipid abnormalities are implicated in the pathogenic process of type 2 diabetes. The IDE-KIF11-HHEX gene cluster on chromosome 10q23.33 has been identified as a susceptibility locus for type 2 diabetes. We hypothesized that genetic variants at 10q23.33 may be associated with plasma lipid concentrations. Seven tagging single nucleotide polymorphisms (SNPs: rs7923837, rs2488075, rs947591, rs11187146, rs5015480, rs4646957 and rs1111875) at 10q23.33 were genotyped in 3,281 subjects from a Han Chinese population, using the TaqMan OpenArray and Sequenom MassARRAY platforms. Multiple linear regression analyses showed that SNP rs7923837 in the 3'-flanking region of HHEX was significantly associated with triglyceride levels (P = 0.019, 0.031 mmol/L average decrease per minor G allele) and that rs2488075 and rs947591 in the downstream region of HHEX were significantly associated with total cholesterol levels (P = 0.041, 0.058 mmol/L average decrease per minor C allele and P = 0.018, 0.063 mmol/L average decrease per minor A allele, respectively). However, the other four SNPs (rs11187146, rs5015480, rs4646957 and rs1111875) were not significantly associated with any plasma lipid concentrations in this Chinese population. Our data suggest that genetic variants in the IDE-KIF11-HHEX gene cluster at 10q23.33 may partially explain the variation of plasma lipid levels in the Han Chinese population. Further studies are required to confirm these findings in other populations. PMID- 24474965 TI - Pediatric restrictive cardiomyopathy due to a heterozygous mutation of the TNNI3 gene. AB - Pediatric restrictive cardiomyopathy is rare and most commonly idiopathic in origin. Here, we applied a candidate gene approach and identified a missense mutation in the cardiac troponin I gene in a 12-year-old Chinese girl with restrictive cardiomyopathy. This study indicates that mutation in sarcomere protein genes may play an important role in idiopathic pediatric restrictive cardiomyopathy. PMID- 24474959 TI - Atrial fibrillation. AB - Atrial fibrillation is the most common arrhythmia affecting patients today. Disease prevalence is increasing at an alarming rate worldwide, and is associated with often catastrophic and costly consequences, including heart failure, syncope, dementia, and stroke. Therapies including anticoagulants, anti arrhythmic medications, devices, and non-pharmacologic procedures in the last 30 years have improved patients' functionality with the disease. Nonetheless, it remains imperative that further research into AF epidemiology, genetics, detection, and treatments continues to push forward rapidly as the worldwide population ages dramatically over the next 20 years. PMID- 24474967 TI - Medical education: monopoly or oligopoly? PMID- 24474966 TI - A new free-hand pedicle screw placement technique with reference to the supraspinal ligament. AB - We sought to compare the safety and accuracy of a new free-hand pedicle screw placement technique to that of the conventional technique. One hundred fifty three consecutive adult patients with simple fracture in the thoracic or/and lumbar spine were alternately assigned to either the new free-hand or the conventional group. In the new free-hand technique group, preoperative computerized tomography (CT) images were used to calculate the targeted medial lateral angle of each pedicle trajectory and the pedicle screw was inserted perpendicular to the correspond-ing supraspinal ligament. In the conventional technique group, the medial-lateral and cranial-caudal angle of each pedicle trajectory was determined by intraoperatively under fluoroscopic guidance. The accuracy rate of pedicle screw placement, the time of intraoperative fluoroscopy, the operating time and the amount of blood loss during operation were respectively compared. All screws were analyzed by using intraoperative radiographs, intraoperative triggered electromyography (EMG) monitoring data, postoperative CT data and clinical outcomes. The accuracy rate of pedicle screw placement in the new free-hand technique group and the conventional technique group was 96.3% and 94.2% (P < 0.05), respectively. The intraoperative fluoroscopy time of the new technique group was less than that of the conventional technique group (5.37 seconds vs. 8.79 seconds, P < 0.05). However, there was no statistical difference in the operating time and the amount of blood loss during operation (P > 0.05). Pedicle screw placement with the free-hand technique which keeps the screw perpendicular to the supraspinal ligament is an accurate, reliable and safe technique to treat simple fracture in the thoracic or lumbar spine. PMID- 24474968 TI - Prostate cancer boost using high-dose-rate brachytherapy: early toxicity analysis of 3 different fractionation schemes. AB - PURPOSE: To analyse early toxicity of high-dose-rate brachytherapy (HDRB) boost for prostate cancer using 3 fractionation schemes. MATERIAL AND METHODS: From February 2009 to May 2012, after the first course of external beam radiation therapy (EBRT 46 Gy/23 f), 124 patients underwent HDRB boost for low (7%), intermediate (19%), and high-risk (73%) prostate cancers. From February to December 2009, Group 1 (G1) = 18 Gy/3 f/2 d (24%); from January 2010 to April 2011, Group 2 (G2) = 18 Gy/2 f/2 d (42%), and from May to September 2011, Group 3 (G3) = 14 Gy/1 f/1 d (34%). Planning and CT-scan was performed before each fraction. Dose constraints for G1/G2 were V100 rectum = 0 and V125 urethra = 0, while for G3 V90 rectum = 0 and V115 urethra = 0. Genito-urinary (GU) and Gastro intestinal (GI) acute toxicities were assessed at 1 month (for the 3 fractionation schemes) and 6 months (for 18 Gy/3 f and 18 Gy/2 f) after the boost (CTCv3.0). RESULTS: Median follow-up was 25 months (8-46.9), median age was 71 years (50-82), and median CTV was 31 cc (16-71). The grades of acute GI and GU toxicities at 1 and 6 months after HDRB were mainly Grade 1 with few Grade 2 (GU: 5% at 1 month; GI: 1% at 6 months). One patient developed G4 sepsis toxicity 2 days after HDRB and recovered without after-effects. No significant differences were observed at 1 and 6 months after the HDRB between treatment groups. CONCLUSIONS: The right fractionation remains under discussion, but prostate cancer HDRB boost using a single fraction (providing similar results in terms of acute toxicity) is more comfortable for the patient, and less time consuming for the medical staff. PMID- 24474969 TI - Prostate-specific antigen bounce predicts for a favorable prognosis following brachytherapy: a meta-analysis. AB - PURPOSE: Controversy exists whether the prostate-specific antigen (PSA) bounce phenomenon following definitive radiation for prostate cancer has prognostic significance. Here, we perform a meta-analysis to determine the association between PSA bounce and biochemical control after brachytherapy alone. MATERIAL AND METHODS: We reviewed Medline, EMBASE, and CENTRAL citations through February 2012. Studies that recorded biochemical failure rates in bouncers and non bouncers were included. Hazard ratios describing the impact of bounce on biochemical failure were extracted directly from the studies or calculated from survival curves. Pooled estimates were obtained using the inverse variance method. A random effects model was used in cases of significant effect heterogeneity (p < 0.10 using Q test). RESULTS: The final analysis included 3011 patients over 6 studies treated with brachytherapy. Meta-analysis revealed that patients experiencing PSA bounce after brachytherapy, conferred a decreased risk of biochemical failure (random effects model HR = 0.42, 95% CI: 0.30-0.59; p < 0.001). CONCLUSIONS: Our meta-analysis determined that PSA bounce predicts for improved biochemical control following brachytherapy. To our knowledge, this is the first study describing this effect. PMID- 24474970 TI - Time to failure after definitive therapy for prostate cancer: implications for importance of aggressive local treatment. AB - PURPOSE: To explore patterns of time to failure in men receiving high doses of permanent seed brachytherapy with or without external beam radiation therapy as a function of risk status. MATERIAL AND METHODS: Two thousand two hundred and thirty four patients were treated with prostate brachytherapy with median follow up of 8.0 years. The population was 35% low risk, 49% intermediate risk, and 16% high risk (NCCN). Median day 0 implant D90 was 119% and V100 was 98%. Treatment failure was defined as PSA > 0.40 ng/mL after nadir. Rates of biochemical failure, distant metastases, and prostate cancer death were determined with non prostate death as a competing risk. RESULTS: For all patients, the 10-year biochemical failure, distant metastases, and cause-specific mortality were 4.4%, 1.4%, and 1.3%, respectively. The biochemical failure rates were 1.3%, 4.8%, and 10.0% for men with low, intermediate, and high risk disease, respectively. Median time to failure was 2.8 years. In men who died from prostate cancer, the median time from treatment failure to death was 4.2 years. Overall, 83% of biochemical failures and 97% of metastases occurred within the first 4 years after treatment. CONCLUSIONS: With the dose escalation achieved by high quality brachytherapy dosimetry, even high-risk prostate cancer patients have excellent long term biochemical outcomes. Treatment failures occur early, and one third become metastatic and progress rapidly to prostate cancer death. The low frequency and pattern of failures suggest the presence of micrometastatic disease prior to treatment is rare, even in high risk patients. PMID- 24474971 TI - Three-dimensional dosimetric considerations from different point A definitions in cervical cancer low-dose-rate brachytherapy. AB - PURPOSE: To investigate the dosimetric difference due to the different point A definitions in cervical cancer low-dose-rate (LDR) intracavitary brachytherapy. MATERIAL AND METHODS: Twenty CT-based LDR brachytherapy plans of 11 cervical patients were retrospectively reviewed. Two plans with point As following the modified Manchester system which defines point A being 2 cm superior to the cervical os along the tandem and 2 cm lateral (Aos), and the American Brachytherapy Society (ABS) guideline definition in which the point A is 2 cm superior to the vaginal fornices instead of os (Aovoid) were generated. Using the same source strength, two plans prescribed the same dose to Aos and Aovoid. Dosimetric differences between plans including point A dose rate, treatment volume encompassed by the prescription isodose line (TV), and dose rate of 2 cc of the rectum and bladder to the prescription dose were measured. RESULTS: On average Aovoid was 8.9 mm superior to Aos along the tandem direction with a standard deviation of 5.4 mm. With the same source strength and arrangement, Aos dose rate was 19% higher than Aovoid dose rate. The average TV(Aovoid) was 118.0 cc, which was 30% more than the average TV(Aos) of 93.0 cc. D2cc/D(Aprescribe) increased from 51% to 60% for rectum, and increased from 89% and 106% for bladder, if the prescription point changed from Aos to Aovoid. CONCLUSIONS: Different point A definitions lead to significant dose differences. Careful consideration should be given when changing practice from one point A definition to another, to ensure dosimetric and clinical equivalency from the previous clinical experiences. PMID- 24474972 TI - The importance of the implant quality in APBI - Gliwice experience. Dosimetric evaluation. AB - This study includes four years of our clinical trials to improve implant quality in multicatheter accelerated partial breast irradiation (APBI). The progress in dosimetric and volumetric parameters of the treatment plans was evaluated. One hundred and ninety-one women, for whom treatment plans were made based on three dimensional imaging, were selected for the study. To evaluate progress made in our APBI procedure, following parameters and indices were taken into account: percentage of the target volume receiving the reference dose (PTVref), minimum dose in the target volume expressed as a percentage of reference dose (PTVmin), dose homogeneity index (DHI), and conformity index (COIN). Additionally, the plan quality index was calculated for every group as the sum of mean values of four evaluated parameters. PTVref have increased from the mean value of 83.4% at the beginning to recent 94.8%. The maximum value equals to 95.4%. The same trend can be observed with PTVmin value, which has been improved from 51.7% to 70.1%, maximally. DHI and COIN mean values present similar progress. DHI value increased from 0.53 level to 0.68, and COIN from 0.58 in 2009 to 0.74. Plan quality index has increased from 2.46 in 2009 to 3.06, recently. The implant quality is crucial for the accurate dose distribution. This paper shows the progress that was made in APBI procedure to improve implant quality. Nowadays, our implant technique is based on three-dimensional CT imaging results in acceptable dose distributions. PMID- 24474973 TI - Head and neck (192)Ir HDR-brachytherapy dosimetry using a grid-based Boltzmann solver. AB - PURPOSE: To compare dosimetry for head and neck cancer patients, calculated with TG-43 formalism and a commercially available grid-based Boltzmann solver. MATERIAL AND METHODS: This study included 3D-dosimetry of 49 consecutive brachytherapy head and neck cancer patients, computed by a grid-based Boltzmann solver that takes into account tissue inhomogeneities as well as TG-43 formalism. 3D-treatment planning was carried out by using computed tomography. RESULTS: Dosimetric indices D90 and V100 for target volume were about 3% lower (median value) for the grid-based Boltzmann solver relative to TG-43-based computation (p < 0.01). The V150 dose parameter showed 1.6% increase from grid-based Boltzmann solver to TG-43 (p < 0.01). CONCLUSIONS: Dose differences between results of a grid-based Boltzmann solver and TG-43 formalism for high-dose-rate head and neck brachytherapy patients to the target volume were found. Distinctions in D90 of CTV were low (2.63 Gy for grid-based Boltzmann solver vs. 2.71 Gy TG-43 in mean). In our clinical practice, prescription doses remain unchanged for high-dose-rate head and neck brachytherapy for the time being. PMID- 24474974 TI - The effect of central shielding in the dose reporting for cervical cancer in EQD2 era. AB - PURPOSE: To evaluate the cumulative dose at point A for three and four centimeters central shielding. MATERIAL AND METHODS: The plans of external beam radiotherapy plus conventional intracavitary brachytherapy were performed. Three or four centimeters central shieldings (after 44 Gy) were applied to the standard whole pelvis irradiation. Additional intracavitary brachytherapy 4 * 7 Gy at point A was prescribed, and the cumulative dose in EQD2 (alpha/beta = 10) of 3 cm and 4 cm central shielding were evaluated. RESULTS: The cumulative dose at point A in EQD2 (alpha/beta = 10) of 3 cm central shielding were 95.7 Gy for AR and 95.5 Gy for AL, while the cumulative dose at point As in EQD2 (alpha/beta = 10) of 4 cm central shielding were 90.8 Gy for AR and 91.2 Gy for AL. CONCLUSIONS: The 3 cm central shielding caused higher cumulative dose (in terms of EQD2 [alpha/beta = 10]) than 4 cm central shielding. PMID- 24474975 TI - New (125)I brachytherapy source IsoSeed I25.S17plus: Monte Carlo dosimetry simulation and comparison to sources of similar design. AB - PURPOSE: To determine the relative dose rate distribution around the new (125)I brachytherapy source IsoSeed I25.S17plus and report results in a form suitable for clinical use. Results for the new source are also compared to corresponding results for other commercially available (125)I sources of similar design. MATERIAL AND METHODS: Monte Carlo simulations were performed using the MCNP5 v.1.6 general purpose code. The model of the new source was prepared from information provided by the manufacturer and verified by imaging a sample of ten non-radioactive sources. Corresponding simulations were also performed for the 6711 (125)I brachytherapy source, using updated geometric information presented recently in the literature. The uncertainty of the dose distribution around the new source, as well as the dosimetric quantities derived from it according to the Task Group 43 formalism, were determined from the standard error of the mean of simulations for a sample of fifty source models. These source models were prepared by randomly selecting values of geometric parameters from uniform distributions defined by manufacturer stated tolerances. RESULTS AND CONCLUSIONS: Results are presented in the form of the quantities defined in the update of the Task Group 43 report, as well as a relative dose rate table in Cartesian coordinates. The dose rate distribution of the new source is comparable to that of sources of similar design (IsoSeed I25.S17, Oncoseed 6711, SelectSeed 130.002, Advantage IAI-125A, I-Seed AgX100, Thinseed 9011). Noticeable differences were observed only for the IsoSeed I25.S06 and Best 2301 sources. PMID- 24474976 TI - Bilateral episcleral brachytherapy in simultaneous choroidal melanoma and circumscribed hemangioma. AB - PURPOSE: To describe the efficacy of episcleral brachytherapy in a choroidal melanoma and circumscribed hemangioma arising in both eyes of the same patient. CASE REPORT: We present the case of a 47 year old man who presented decreased visual acuity a few months preceding initial consult. On fundoscopy, he presented a melanotic lesion in the right eye, and a red-orange choroidal mass in the macular area of the left eye. MATERIAL AND METHODS: B scan-ultrasound, fluorescein, and indocyanine green angiography, confirmed the diagnosis of choroidal melanoma in the right eye, and circumscribed choroidal hemangioma in the left eye. Episcleral brachytherapy with (125)I was performed in both eyes consecutively. RESULTS AND CONCLUSIONS: Bilateral episcleral brachytherapy successfully treated both tumors, preserving the eyes and useful visual function. PMID- 24474977 TI - Dosimetric impacts of applicator displacements and applicator reconstruction uncertainties on 3D image-guided brachytherapy for cervical cancer. AB - PURPOSE: To quantify the dosimetric impact of applicator displacements and applicator reconstruction-uncertainties through simulated planning studies of virtual applicator shifts. MATERIAL AND METHODS: Twenty randomly selected high dose-rate (HDR) titanium tandem-and-ovoid (T&O) plans were retrospectively studied. MRI-guided, conformal brachytherapy (MRIG-CBT) plans were retrospectively generated. To simulate T&O displacement, the whole T&O set was virtually shifted on treatment planning system in the cranial (+) and the caudal (-) direction after each dose calculation. Each shifted plan was compared to an unshifted plan. To simulate T&O reconstruction-uncertainties, each tandem and ovoid was separately shifted along its axis before performing the dose calculation. After the dose calculation, the calculated isodose lines and T&O were moved back to unshifted T&O position. Shifted and shifted-back plan were compared. RESULTS: Regarding the dosimetric impact of the simulated T&O displacements, rectal D2cc values were observed as being the most sensitive to change due to T&O displacement among all dosimetric metrics regardless of point A (p < 0.013) or MRIG-CBT plans (p < 0.0277). To avoid more than 10% change, +/- 1.5 mm T&O displacements were accommodated for both point A and MRIG-CBT plans. The dosimetric impact of T&O displacements on sigmoid (p < 0.0005), bladder (p < 0.0001), HR-CTV (p < 0.0036), and point A (p < 0.0015) were significantly larger in the MRIG-CBT plans than point A plans. Regarding the dosimetric impact of T&O reconstruction-uncertainties, less than +/- 3.0 mm reconstruction-uncertainties were also required in order to avoid more than 10% dosimetric change in either the point A or MRIG-CBT plans. CONCLUSIONS: The dosimetric impact of simulated T&O displacements was significantly larger in the MRIG-CBT plans than in the point A plans. Either +/- 3 mm T&O displacement or a +/- 4.5 mm T&O reconstruction-uncertainty could cause greater than 10% dosimetric change for both point A plans and MRIG-CBT plans. PMID- 24474979 TI - The effect of agoraphobia on oxidative stress in panic disorder. AB - We aimed to investigate whether agoraphobia (A) in panic disorder (PD) has any effects on oxidative and anti-oxidative parameters. We measured total antioxidant capacity (TAC), paraoxonase (PON), arylesterase (ARE) antioxidant and malondialdehyde (MDA) oxidant levels using blood samples from a total of 31 PD patients with A, 22 PD patients without A and 53 control group subjects. There was a significant difference between the TAC, PON, ARE and MDA levels of the three groups consisting of PD with A, PD without A and the control group. The two way comparison to clarify the group creating the difference showed that the TAC, PON, and ARE antioxidants were significantly lower in the PD with A group compared to the control group while the MDA oxidant was significantly higher. There was no significant difference between the PD without A and control groups for TAC, PON, ARE and MDA levels. We clearly demonstrated that the oxidative stress and damage to the anti-oxidative mechanism are significantly higher in the PD group with A. These findings suggest that oxidative/anti-oxidative mechanisms may play a more important role on the pathogenesis of PB with A. PMID- 24474978 TI - Mental health promotion and illness prevention: a challenge for psychiatrists. AB - Mental health is essential for individual and public health. To improve mental health, promotion, prevention, and the treatment of disease are required. These three kinds of interventions are interrelated but independent from one another. Although separate efforts for mental health promotion and prevention are needed as well as the public need of mental health promotion and well-being, psychiatrists usually are not accustomed to mental health promotion and prevention. This review introduces an overview of the concept, subjects according to target populations, and various intervention strategies for mental health promotion and prevention of mental illnesses. Based on literatures to date, understanding of developmental psychology, lifestyle medicine, and biopsychosocial contributors of mental health with a macroscopic perspective might help to practice mental health promotion and illness prevention. PMID- 24474980 TI - Generalized anxiety disorder, comorbid major depression and heart rate variability: a case-control study in taiwan. AB - OBJECTIVE: Decreased heart rate variability (HRV) has been reported in generalized anxiety disorder (GAD), but the results are mixed. Little is known about the impact of comorbid major depression (MD) on HRV in GAD patients. Both issues necessitate further investigation. METHODS: Twenty unmedicated, physically healthy GAD patients, 20 GAD patients with a secondary diagnosis of MD, 40 MD patients and 60 matched controls were recruited. We used the Hamilton Anxiety Rating Scale and the Hamilton Depression Rating Scale to assess anxiety and depression severity, respectively. Cardiac autonomic function was evaluated by measuring HRV parameters. Frequency-domain indices of HRV were obtained. RESULTS: Three patient groups had more anxiety and depression symptoms than control subjects, but heart rates (HRs) were significantly elevated only in GAD patients with comorbid depression. Relative to controls, GAD patients had reduced HRV while GAD patients with comorbid depression displayed the greatest reductions in HRV among three patients groups. Correlation analyses revealed anxiety/depression severity significantly associated with HRs, variance, LF-HRV and HF-HRV. However, separately analyzing among individual groups and adjusting for HRV-associated covariables rendered the correlations non-significant. CONCLUSION: Our results suggest that reduction in HRV is a psychophysiological marker of GAD and individuals with comorbid GAD and MD may be distinguished based on psychophysiological correlates (for example, HF-HRV) from non-comorbid GAD patients. Taken into account that comorbid depression may confer increased risks for cardiovascular events in GAD patients, this subgroup of GAD patients may benefit better from cardiovascular risk reduction strategies. PMID- 24474981 TI - The reliability and validity of the korean version of the child sexual behavior inventory. AB - OBJECTIVE: This study examined the reliability and validity of the Korean version of the Child Sexual Behavior Inventory (CSBI) in Korean children aged from 6 to 12 years old and the suitability of and potential for clinical application of the CSBI in Korean population. METHODS: The participants consisted of 158 typically growing children and 122 sexually abused children. The subjects were evaluated using the Korean version of the Child Sexual Behavior Inventory (CSBI), the Child Behavior Checklist (CBCL), and the Trauma Symptom Checklist for Young Children (TSCYC). Internal consistency was examined as a measure of reliability. To investigate the concurrent validity, Pearson's correlations were calculated. One way ANCOVA was used to demonstrate discriminant validity. RESULTS: The Cronbach's alpha value was 0.84. The CSBI total score was moderately correlated with the CBCL subscales and mildly correlated with the sexual concern subscale of the TSCYC. The total score of the CSBI for the sexually abused children group was significantly higher than that of typically growing children group. CONCLUSION: This study demonstrated that the Korean version of the Child Sexual Abuse Inventory (CSBI) is a reliable and valid tool. It can be applied in the clinical field for assessing the sexual behavior of Korean children aged from 6 to 12 who are suspected to have been sexually abused. PMID- 24474982 TI - A normative study of lexical verbal fluency in an educationally-diverse elderly population. AB - OBJECTIVE: Lexical fluency tests are frequently used to assess language and executive function in clinical practice. We investigated the influences of age, gender, and education on lexical verbal fluency in an educationally-diverse, elderly Korean population and provided its' normative information. METHODS: We administered the lexical verbal fluency test (LVFT) to 1676 community-dwelling, cognitively normal subjects aged 60 years or over. RESULTS: In a stepwise linear regression analysis, education (B=0.40, SE=0.02, standardized B=0.506) and age (B=-0.10, SE=0.01, standardized B=-0.15) had significant effects on LVFT scores (p<0.001), but gender did not (B=0.40, SE=0.02, standardized B=0.506, p>0.05). Education explained 28.5% of the total variance in LVFT scores, which was much larger than the variance explained by age (5.42%). Accordingly, we presented normative data of the LVFT stratified by age (60-69, 70-74, 75-79, and >=80 years) and education (0-3, 4-6, 7-9, 10-12, and >=13 years). CONCLUSION: The LVFT norms should provide clinically useful data for evaluating elderly people and help improve the interpretation of verbal fluency tasks and allow for greater diagnostic accuracy. PMID- 24474983 TI - The 12-item general health questionnaire as an effective mental health screening tool for general korean adult population. AB - OBJECTIVE: The 12-item General Health Questionnaire (GHQ-12) has been used extensively in various settings across different cultures. This study was conducted to determine the thresholds associated with optimum sensitivity and specificity for the GHQ-12 in Korean adults. METHODS: Data was acquired from a sample of 6,510 Korean adults, ages 18 to 64 years old, who were selected from the 2005 Census (2,581 men and 3,929 women). Participants completed the GHQ-12 and the Korean Composite International Diagnostic Interview (K-CIDI). Receiver Operating Characteristic (ROC) curve analysis was conducted. RESULTS: The mean GHQ-12 score for the total sample was 1.63 (SD 1.98). The internal consistency of the GHQ-12 was good (Cronbach's alpha=0.72). Results from the ROC curve indicated that the GHQ-12 yielded greater accuracy when identifying mood and anxiety disorders than when identifying all mental disorders as a whole. The optimal threshold of the GHQ-12 was either 1/2 or 2/3 point depending on the disorder, but was mainly 2/3. CONCLUSION: The Korean version of the GHQ-12 could be used to screen for individuals at high risk of mental disorders, namely mood and anxiety disorders. PMID- 24474984 TI - Cornell scale for depression in dementia: study of residents in a northern thai long-term care home. AB - OBJECTIVE: This study aimed to analyse the validity of the Thai version of the Cornell Scale for Depression in Dementia (CSDD) when using DSM-IV criteria. METHODS: A cross-sectional study was carried out of 84 elderly residents in a residential care home setting in Thailand. The participants went through a comprehensive geriatric assessment which included a Mini-Mental State Examination, a Mini-International Neuropsychiatric Interview (MINI) and use of the CSDD tool. A ROC analysis was performed in order to test the validity of the CSDD as against the DSM-IV when used by the MINI. RESULTS: ROC analysis revealed a better score for those areas found under the curve for the CSDD-as against the DSM-IV criteria (0.96). With a cut-off score of >6, the CSDD yielded the highest sensitivity score (100%), plus produced a specificity of 81% and a negative predictive value of 100%. It also had a positive predictive value of 69%. The validity of the CSDD was found to be better for the group experiencing cognitive impairment than with the non-cognitive impairment group in terms of the agreement of CSDD items between patients and caregivers. The CSDD yielded a high internal consistency (Cronbach's alpha=0.87). CONCLUSION: CSDD is a valid tool to use for identifying depressive disorders among Thai LTC home residents - those experiencing and those not experiencing cognitive impairment. PMID- 24474985 TI - Examining antecedents and consequences of gambling passion: the case of gambling on horse races. AB - OBJECTIVE: This study investigated the antecedents and consequences of gambling passion using structural equation modeling to examine relationships among gambling motivation, passion, emotion, and behavioral intentions in the horse racing industry. METHODS: An onsite survey was conducted with 447 patrons at a horseracing park in South Korea. A confirmatory factor analysis showed that the Gambling Passion Scale was valid and reliable, resulting in two sub-scales: obsessive passion (OP) and harmonious passion (HP). RESULTS: Study results indicated that extrinsic motivation influenced OP whereas intrinsic motivation significantly affected HP. Furthermore, OP was correlated with negative emotion, whereas HP was related to positive emotion. Gamblers' satisfaction was found to be influenced positively by positive emotion and negatively by negative emotion. Finally, satisfaction appeared to affect gamblers' behavioral intentions. CONCLUSION: Study results echoed the notion of distinct and separate gambling motivations and passions among horse racing gamblers. Furthermore, results identified specific areas to which horse racing operators or policy makers should pay special attention in developing effective marketing strategies to promote responsible gambling. PMID- 24474986 TI - Prevalence and Clinical Correlates of Insomnia in Depressive Disorders: The CRESCEND Study. AB - OBJECTIVE: To investigate the prevalence, clinical manifestations, and clinical correlates of insomnia in a large cohort of Korean patients with depressive disorders. METHODS: We recruited 944 patients with depressive disorders from the Clinical Research Center for Depression of South Korea (CRESCEND) study. Psychometric scales were used to assess depression (HAMD), anxiety (HAMA), psychotic symptoms (BPRS), global severity (CGI-S), and functioning (SOFAS). Insomnia levels were determined by adding the scores for all items on the HAMD insomnia subscale. The clinical characteristics of the patients with 'low insomnia' (summed score <=3 on the HAMD subscale) and 'high insomnia' (score >=4) were compared using statistical analyses. A logistic regression model was constructed to identify factors associated with 'high insomnia' status. RESULTS: Symptoms of insomnia were present in 93% of patients, while simultaneous early, middle, and late insomnia affected 64.1%. The high insomnia patients were characterized by significantly greater age, higher symptom levels (including core, gastrointestinal somatic and anxiety symptoms, and suicidal ideation), higher global severity and incidence of physical disorders, and greater insight. Explanatory factors of 'high insomnia' status were older age, higher gastrointestinal somatic and anxiety symptom levels, higher global severity, and greater insight. CONCLUSION: In clinical psychiatry, insomnia has been significantly underdiagnosed and undertreated. It affects most patients with depressive disorders, and is indicative of the global severity of depression. Active efforts to diagnose and treat insomnia in patients with depressive disorders should be strongly encouraged. Further research is needed to improve the diagnosis and treatment of insomnia in depressive patients. PMID- 24474987 TI - Psychiatric comorbidity and quality of life in patients with post-stroke emotional incontinence. AB - OBJECTIVE: We aimed to investigate the associations of post-stroke emotional incontinence (PSEI) with various psychiatric symptoms and quality of life independent of potential covariates in survivors of acute stroke. METHODS: A total of 423 stroke patients were assessed within 2 weeks of the index event. Psychiatric symptoms were assessed by the Symptom Checklist-90-Revised (SCL-90 R), which has nine domains comprising Somatization, Obsessive-Compulsive, Interpersonal Sensitivity, Depression, Anxiety, Hostility, Phobic Anxiety, Paranoid Ideation, and Psychoticism. Quality of life was measured using the World Health Organization Quality of Life abbreviated form (WHOQOL-BREF), which has four domains related to physical factors, psychological factors, social relationships, and environmental context. Associations of PSEI with scores on the SCL-90-R and WHOQOL-BREF were investigated using pairwise logistic regression model adjustment for potential sociodemographic and clinical covariates. RESULTS: PSEI was present in 51 (12.1%) patients. PSEI was associated with the Obsessive Compulsive, Interpersonal Sensitivity, and Hostility symptom dimensions of the SCL-90-R and with the psychological factors and social relationships domains of the WHOQOL-BREF independent of important covariates including previous stroke, stroke severity, and physical disability. CONCLUSION: PSEI causes some aspects of psychiatric distress and negatively affects psychological and interpersonal quality of life. For patients with PSEI, special attention to psychiatric comorbidity and quality of life is needed, even in the acute stage of stroke. PMID- 24474988 TI - Increased cortical thickness in professional on-line gamers. AB - OBJECTIVE: The bulk of recent studies have tested whether video games change the brain in terms of activity and cortical volume. However, such studies are limited by several factors including cross-sectional comparisons, co-morbidity, and short term follow-up periods. In the present study, we hypothesized that cognitive flexibility and the volume of brain cortex would be correlated with the career length of on-line pro-gamers. METHODS: High-resolution magnetic resonance scans were acquired in twenty-three pro-gamers recruited from StarCraft pro-game teams. We measured cortical thickness in each individual using FreeSurfer and the cortical thickness was correlated with the career length and the performance of the pro-gamers. RESULTS: CAREER LENGTH WAS POSITIVELY CORRELATED WITH CORTICAL THICKNESS IN THREE BRAIN REGIONS: right superior frontal gyrus, right superior parietal gyrus, and right precentral gyrus. Additionally, increased cortical thickness in the prefrontal cortex was correlated with winning rates of the pro game league. Increased cortical thickness in the prefrontal and parietal cortices was also associated with higher performance of Wisconsin Card Sorting Test. CONCLUSION: Our results suggest that in individuals without pathologic conditions, regular, long-term playing of on-line games is associated with volume changes in the prefrontal and parietal cortices, which are associated with cognitive flexibility. PMID- 24474989 TI - The Associations between Visual Attention and Facial Expression Identification in Patients with Schizophrenia. AB - OBJECTIVE: Visual search is an important attention process that precedes the information processing. Visual search also mediates the relationship between cognition function (attention) and social cognition (such as facial expression identification). However, the association between visual attention and social cognition in patients with schizophrenia remains unknown. The purposes of this study were to examine the differences in visual search performance and facial expression identification between patients with schizophrenia and normal controls, and to explore the relationship between visual search performance and facial expression identification in patients with schizophrenia. METHODS: Fourteen patients with schizophrenia (mean age=46.36+/-6.74) and 15 normal controls (mean age=40.87+/-9.33) participated this study. The visual search task, including feature search and conjunction search, and Japanese and Caucasian Facial Expression of Emotion were administered. RESULTS: Patients with schizophrenia had worse visual search performance both in feature search and conjunction search than normal controls, as well as had worse facial expression identification, especially in surprised and sadness. In addition, there were negative associations between visual search performance and facial expression identification in patients with schizophrenia, especially in surprised and sadness. However, this phenomenon was not showed in normal controls. CONCLUSION: Patients with schizophrenia who had visual search deficits had the impairment on facial expression identification. Increasing ability of visual search and facial expression identification may improve their social function and interpersonal relationship. PMID- 24474990 TI - The Effects of 5-HTR1A Polymorphism on Cingulum Connectivity in Patients with Panic Disorder. AB - OBJECTIVE: Serotonin-1A receptors (5-HTR1A) is suggested to be involved in the etiology of several psychiatric disorders including panic disorder (PD). A few imaging studies have suggested the alterations of the cingulum bundle in PD. The objective of this study is to examine the structural changes of cingulum related to the 5-HTR1A polymorphism rs6295 in the patients with PD. METHODS: Thirty-two right-handed patients with PD [11 men, 21 women; 40.34+/-13.17 (mean+/-SD) age] who met the diagnostic criteria in Structured Clinical Interview for DSM-IV were examined by means of MRI at 3 Tesla. We divided the patients with PD into CC genotype group and non CC genotype group (GG/CG genotype group) of the 5-HTR1A rs6295 polymorphism to compare the cingulum white matter connectivity. RESULTS: Tract-based spatial statistics showed significantly increased fractional anisotropy (FA) values in cingulate gyrus process of left cingulum in 5-HTR1A CC genotype compared to GG/CG genotype in PD. Significant positive correlations were shown between the Albany Panic and Phobia Questionnaire (APPQ) interoceptive fear subscale scores, the Anxiety Sensitivity Inventory-Revised fear of publicly observable anxiety reaction subscale scores and FA values of cingulate gyrus process of left cingulum in 5-HTR1A rs6295 GG/CG genotype group. In CC genotype group, APPQ total, APPQ agoraphobia subscale and APPQ social phobia subscale scores also showed significant positive correlations with FA values of hippocampal process of right cingulum. CONCLUSION: This preliminary study suggests that 5-HTR1A polymorphism may be associated with the cingulum white matter connectivity in PD. PMID- 24474991 TI - Influencing Factors and Predictors of Early Response in Schizophrenia Patients Receiving the Paliperidone Extended-Release Tablets (Paliperidone ER). AB - OBJECTIVE: Paliperidone extended-release tablet (paliperidone ER) is a new oral psychotropic agent developed for schizophrenia treatment. There have been some studies about paliperidone's good efficacy and tolerability. Clinicians appear to change the antipsychotic medication to paliperidone ER. However, it is not known what patients are favorable responsive to paliperidone ER. The aim of this study was to evaluate the characteristics of early responders and investigate predictors of acute response when the medications changed to paliperidone ER. METHODS: Data were analyzed from schizophrenic patients who participated in a multi-center, open-label, non-comparative clinical trial. Total 320 patients were examined in this study. Sociodemographic, psychopathology, social function and metabolic data were evaluated. Unpaired t-test for continuous and chi(2) for categorical data, respectively, were used to compare early responder and non responders. Logistic regression analysis was used to establish a prediction model. RESULTS: 38.7% of study subjects (124 of 320) responded to paliperidone ER treatment. Logistic regression analysis showed that a good paliperidone ER response was more likely when patients were social drinkers, when patients had started medication at inpatient, when negative symptoms were less severe, and when patients' social relationship and self-care were better. CONCLUSION: Early response to paliperidone ER treatment is associated with less negative symptoms and good social relationships and self-care. Strategies to reduce these symptoms may contribute to early response to paliperidone ER. PMID- 24474992 TI - Benefical effects of sigma-1 agonist fluvoxamine for tardive dyskinesia and tardive akathisia in patients with schizophrenia: report of three cases. AB - Fluvoxamine is a selective serotonin reuptake inhibitor that is approved for psychiatric disorders such as major depressive episodes and obsessive-compulsive disorder. Beside inhibition of serotonin reuptake, fluvoxamine is also a potent agonist of endoplasmic reticulum (ER) protein sigma-1 receptors, which play a role in the pathophysiology of a number of psychiatric and neurodegenerative disorders. This report presents beneficial effects of sigma-1 agonist fluvoxamine on hyperkinetic movement disorders such as tardive dyskinesia and tardive akathisia. Fluvoxamine might be a novel treatmet approach in the treatment of hyperkinetic movement disorders. PMID- 24474993 TI - A 10-week memantine treatment in bipolar depression: a case report. Focus on depressive symptomatology, cognitive parameters and quality of life. AB - Memantine and other glutamatergic agents have been currently investigated in some off-label indications due to glutamatergic involvement in several psychoneurological disorders. We assumed that memantine similarly to ketamine may positively influence mood, moreover having a potential to improve cognition and general quality of life. We report a case of a 49-year-old male hospitalized during a manic and a subsequent moderate depressive episode. After an ineffective use of lithium, olanzapine and antidepressive treatment with mianserin, memantine was added up to 20 mg per day for 10 weeks. The mental state was assessed using the Hamilton Depression Rating Scale, the Young Mania Rating Scale, the Hamilton Anxiety Scale, the Clinical Global Inventory, the World Health Organization Quality of Life Scale and psychological tests. After 10 weeks the patient achieved a partial symptomatic improvement in mood, anxiety and quality of sleep, but his activity remained insufficient. We also observed an improvement in the parameters of cognitive functioning and quality of life. There was neither significant mood variations during the memantine use nor mood changes after its termination. No significant side effects were noted during the memantine treatment. We conclude that using memantine in bipolar depression may improve mood, cognitive functioning and quality of life. PMID- 24474994 TI - A case report of priapism caused by ziprasidon. AB - Priapism is defined as having prolonged (more than 6 h), and usually painful penile erection that occurs without a sexual desire or arousal. Only a very few priapism cases caused by ziprasidone are reported in the literature. In this case report we aimed to present a prolonged penile erection due to use of ziprasidone. PMID- 24474995 TI - A case with neutropenia related with the use of various atypical antipsychotics. AB - Herein, we report here a case of a 21-year-old patient with a conduct disorder, who had neutropenia associated with treatment with 4 different antipsychotics (olanzapine, quetiapine, risperidone, and aripiprazole) on a sequential basis. This case supports the hypothesis that patients who developed antipsychotic induced neutropenia on one medication are more likely to develop neutropenia when taking other antipsychotics. Based on this finding, we may suggest that the number of white blood cell and neutrophil counts in patients with a history of antipsychotic-induced neutropenia needs to be carefully monitored during antipsychotic treatment. PMID- 24474996 TI - Are we getting through? A national survey on the CanMEDS communicator role in urology residency. PMID- 24474997 TI - Low-dose rate brachytherapy for patients with low- or intermediate-risk prostate cancer: A systematic review. PMID- 24474998 TI - Confirmation de la relation entre le volume et les resultats des soins pour le cancer de la vessie : que faire maintenant ? PMID- 24474999 TI - Learning curve for TIP urethroplasty: A single-surgeon experience. AB - INTRODUCTION: We evaluate the influence of surgeon experience and other clinical factors on the success of primary hypospadias repair, using the tubularized incised plate urethroplasty (TIPU) technique. METHODS: We retrospectively reviewed pediatric cases of primary hypospadias repair performed by a single pediatric urologist (soon after his fellowship training) using TIPU between July 2002 and January 2011. The surgical techniques (including the fact that the procedure was an outpatient one) were the same for each patient. The overall complication rate (CR) was analyzed for the following factors: patient age, use of a stent, meatal position, and surgeon experience. All significant covariates on univariate analysis or with a clinical relevance were entered into a multivariable logistic regression model. A non-linear model was created to estimate the change in the CR over the years. RESULTS: Pediatric patients (median age 1.4 years old) presenting with distal (n = 251), midshaft (n = 22) or proximal (n = 30) hypospadias and with a minimum 6-week follow-up (median 13 months) were included. Most patients (87%) had a urethral stent postoperatively (mean duration 9.8 days). In total, 96 patients had 133 complications: 27 meatal stenosis, 25 meatal coronal migrations, 22 urethrocutaneous fistulas and 59 other complications. Of these, 53 patients underwent a second operation. On multivariate analysis, the only factor increasing the CR was a non-distal meatus. The non-linear model demonstrated a significant learning curve with a decreasing CR over the years. The limitations of this study are its retrospective nature and lack of long-term follow-up. CONCLUSIONS: When using TIPU, the CR significantly increases as the meatal position gets more proximal; the learning curve stabilizes after about 50 to 75 cases. PMID- 24475000 TI - Repair and repeat: Comments on the learning curve for TIP urethroplasty. PMID- 24475002 TI - Transurethral resection and degeneration of bladder tumour. AB - INTRODUCTION: We evaluate the efficacy and safety of transurethral resection and degeneration of bladder tumour (TURD-Bt). METHODS: In total, 56 patients with bladder tumour were treated by TURD-Bt. The results in these patients were compared with 32 patients treated by current transurethral resection of bladder tumour (TUR-Bt). Patients with or without disease progressive factors were respectively compared between the 2 groups. The factors included recurrent tumour, multiple tumours, tumour >=3 cm in diameter, clinical stage T2, histological grade 3, adenocarcinoma, and ureteral obstruction or hydronephrosis. RESULTS: Follow-up time was 48.55 +/- 23.74 months in TURD-Bt group and 56.28 +/- 17.61 months in the TUR-Bt group (p > 0.05). In patients without progressive factors, no tumour recurrence was found and overall survival was 14 (100%) in the TURD-Bt group; 3 (37.50%) patients had recurrence and overall survival was 5 (62.5%) in the TUR-Bt group. In patients with progressive factors, 8 (19.05%) patients had tumour recurrence, overall survival was 32 (76.19%) and cancer death was 3 (7.14%) in TURD-Bt group; 18 (75.00%) patients had tumour recurrence (p < 0.05), overall survival was 12 (50.00%) (p < 0.01) and cancer death was 8 (33.33%) (p < 0.05) in TUR-Bt group. No significant complication was found in TURD-Bt group. CONCLUSION: This study suggests that complete resection and degeneration of bladder tumour can be expected by TURD-Bt. The surgical procedure is safe and efficacious, and could be predictable and controllable before and during surgery. We would conclude that for bladder cancers without lymph node metastasis and distal metastasis, TURD-Bt could be performed to replace radical TUR-Bt and preserve the bladder. PMID- 24475001 TI - Management of carcinoma of the penis: Consensus statement from the Canadian Association of Genitourinary Medical Oncologists (CAGMO). PMID- 24475003 TI - Diagnosing spontaneous ileal neobladder perforation: Too often delayed. AB - Spontaneous neobladder perforations are rare, but well-documented; the first cases were reported more than 2 decades ago mostly in urologic journals. However, the diagnosis of these patients is often delayed in the emergency room setting because initial care is given by non-urological medical staff that is too often unaware of this etiology. We present 2 cases and discuss the shift in treatment that has occurred over time. PMID- 24475004 TI - Hematospermia and xanthogranulomatous prostatitis: An unusual onset of a rare diagnosis. AB - Xanthogranulomatous prostatitis is a rare type of granulomatous prostatitis, with very few cases described. We report the clinical, radiological and pathological findings of 5 cases of xanthogranulomatous prostatitis. All patients came for recurrent episodes of hematospermia (associated with fever in 3 patients). All patients suffered from lower urinary tract symptoms and an increased prostate specific antigen (PSA) level associated with a suspicious digital rectal examination (DRE); however, at biopsy, the results were negative for xanthogranulomatous prostatitis. Due to persistent severe bladder outlet obstruction, after unsuccessful medical treatments, all patients underwent transurethral resection of prostate (TURP). Final histological examination revealed a xanthogranulomatous prostatitis. The xanthogranulomatous prostatitis can be an incidental finding after TURP and it can simulate prostatic malignancy with PSA elevation. PMID- 24475005 TI - Pleomorphic malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma of the glans penis. AB - Primary sarcoma of the penis has an extremely low incidence, and its diagnosis and treatment are unclear. A 55-year-old man presented with an oval-shaped mass of the glans penis, which was treated by a wide excision. The pathologic result revealed an undifferentiated high-grade sarcoma, which was diagnosed as a pleomorphic malignant fibrous histiocytoma/undifferentiated pleomorphic sarcoma based on the World Health Organization classification. There was no recurrence at the12-months postoperative follow-up. PMID- 24475006 TI - Metastatic seminoma presenting as flank pain. AB - Seminoma is the most common single histological sub-type of testicular carcinoma. Patients usually present with a painless lump and stage I disease. We describe a case of an incidental meta-static seminoma in a 28-year-old man post-renal trauma with a dramatically elevated beta-human chorionic gonadotropin (betaHCG). His betaHCG level has returned to normal post-orchidectomy and chemotherapy. PMID- 24475007 TI - Percutaneous antegrade nephroscopic holmium laser pyelotomy: Novel endourologic technique for removal of extruded ureteral stent. AB - Ureteral stent malposition outside of the urinary tract is a very uncommon complication of retrograde or antegrade ureteral stent insertion. There are few reports of open, laparoscopic or endourologic approaches to remove malpositioned stents. We present a novel technique for the removal of an extruded retroperitoneal ureteral stent using percutaneous antegrade nephroscopic holmium laser pyelotomy. This previously undescribed procedure represents a new soft tissue application of the holmium laser. PMID- 24475008 TI - Urethrocutaneous fistula after use of Tegress bulking agent: Case report and review of the literature. AB - We report a case of a 68-year-old man who presented with a urethrocutaneous fistula after off-label use of Tegress (C. R. Bard, Inc., Murray Hill, NJ) Urethral Implant for post-prostatectomy incontinence. He was treated for prostate cancer with an open radical retropubic prostatectomy and adjuvant external beam radiation therapy. He was treated unsuccessfully for stress incontinence with a Tegress Urethral Implant and presented to our clinic initially with extrusion of the material urethrally. Four years later he re-presented with a large bullous skin lesion on his suprapubic area. Contrast-enhanced magnetic resonance imaging and retrograde urethral cystogram demonstrated a urethrocutaneous fistula. Subsequent cystoscopy revealed the calcified extruded material in the same location as the site of Tegress injection. The patient underwent simple cystectomy with ileal diversion. He recovered well postoperatively. This appears to be the first reported case of urethrocutaneous fistula after use of a Tegress Urethral Implant for post-prostatectomy stress urinary incontinence. PMID- 24475009 TI - [Not Available]. PMID- 24475013 TI - Caveolin-1 provides palliation for adverse hepatic reactions in hypercholesterolemic rabbits. AB - Caveolins are an essential component of cholesterol-rich invaginations of the plasma membrane known as caveolae. These flask-shaped, invaginated structures participate in a number of important cellular processes, including vesicular transport, cholesterol homeostasis, and signal transduction. We investigated the effects of CAV-1 on mitochondrial biogenesis and antioxidant enzymes in hypercholesterolemia-affected target organs. A total of eighteen male New Zealand white rabbits were divided into three groups: a normal-diet group, an untreated hypercholesterolemia-induced group, and a hypercholesterolemia-induced group that received intravenous administration of antennapedia-CAV-1 (AP-CAV-1) peptide every 2 days for 2 weeks. Serum biochemistry, CAV-1 distribution, neutral lipid distribution, mitochondrial morphology, biogenesis-mediated protein content, oxidative stress balance, antioxidant enzyme levels, and apoptotic cell death of liver tissue were analysed. Hepatic and circulating cholesterol and low-density lipoprotein cholesterol (LDL-C) levels differed significantly between the three groups (P<0.05). Immunohistochemical staining intensity of CAV-1 was greater in AP-CAV-1-treated rabbits than in untreated rabbits, especially in the vicinity of the liver vasculature. The high levels of neutral lipids, malondialdehyde, peroxisome proliferator-activated receptor-gamma coactive 1alpha (PGC-1alpha), and nuclear respiratory factor-1 (NRF-1) seen in untreated hypercholesteremic animals were attenuated by administration of AP-CAV-1 (P<0.05). In addition, mitochondria in animals that received treatment exhibited darker electron-dense matrix and integrated cristae. Furthermore, the levels of ROS modulator 1 (Romo1) and superoxide dismutase (SOD)-2, as well as catalase activity were significantly lower in CAV-1-treated hypercholesterolemic rabbits (P<0.05). AP-CAV-1 treatment also restored mitochondrial respiratory chain subunit protein content (OXPHOS complexes I-V), thereby preserving mitochondrial function (P<0.05). Furthermore, AP-CAV-1 treatment significantly suppressed apoptotic cell death, as evidenced by a reduction in the number of TUNEL-positive cells. Our results indirectly indicate that CAV-1 mediates the negative effects of PGC-1alpha on hepatic mitochondrial respiratory chain function, promotes the antioxidant enzyme defence system, and maintains mitochondrial biogenesis. PMID- 24475014 TI - New aspects of HERG K+ channel function depending upon cardiac spatial heterogeneity. AB - HERG K(+) channel, the genetic counterpart of rapid delayed rectifier K(+) current in cardiac cells, is responsible for many cases of inherited and drug induced long QT syndromes. HERG has unusual biophysical properties distinct from those of other K(+) channels. While the conventional pulse protocols in patch clamp studies have helped us elucidate these properties, their limitations in assessing HERG function have also been progressively noticed. We employed AP clamp techniques using physiological action potential waveforms recorded from various regions of canine heart to study HERG function in HEK293 cells and identified several novel aspects of HERG function. We showed that under AP-clamp IHERG increased gradually with membrane repolarization, peaked at potentials around 20-30 mV more negative than revealed by pulse protocols and at action potential duration (APD) to 60%-70% full repolarization, and fell rapidly at the terminal phase of repolarization. We found that the rising phase of IHERG was conferred by removal of inactivation and the decaying phase resulted from a fall in driving force, which were all determined by the rate of membrane repolarization. We identified regional heterogeneity and transmural gradient of IHERG when quantified with the area covered by IHERG trace. In addition, we observed regional and transmural differences of IHERG in response to dofetilide blockade. Finally, we characterized the influence of HERG function by selective inhibition of other ion currents. Based on our results, we conclude that the distinct biophysical properties of HERG reported by AP-clamp confer its unique function in cardiac repolarization thereby in antiarrhythmia and arrhythmogenesis. PMID- 24475015 TI - Molecular characterization of Clostridium botulinum isolates from foodborne outbreaks in Thailand, 2010. AB - BACKGROUND: Thailand has had several foodborne outbreaks of botulism, one of the biggest being in 2006 when laboratory investigations identified the etiologic agent as Clostridium botulinum type A. Identification of the etiologic agent from outbreak samples is laborious using conventional microbiological methods and the neurotoxin mouse bioassay. Advances in molecular techniques have added enormous information regarding the etiology of outbreaks and characterization of isolates. We applied these methods in three outbreaks of botulism in Thailand in 2010. METHODOLOGY/PRINCIPAL FINDINGS: A total of 19 cases were involved (seven each in Lampang and Saraburi and five in Maehongson provinces). The first outbreak in Lampang province in April 2010 was associated with C. botulinum type F, which was detected by conventional methods. Outbreaks in Saraburi and Maehongson provinces occurred in May and December were due to C. botulinum type A1(B) and B that were identified by conventional methods and molecular techniques, respectively. The result of phylogenetic sequence analysis showed that C. botulinum type A1(B) strain Saraburi 2010 was close to strain Iwate 2007. Molecular analysis of the third outbreak in Maehongson province showed C. botulinum type B8, which was different from B1-B7 subtype. The nontoxic component genes of strain Maehongson 2010 revealed that ha33, ha17 and botR genes were close to strain Okra (B1) while ha70 and ntnh genes were close to strain 111 (B2). CONCLUSION/SIGNIFICANCE: This study demonstrates the utility of molecular genotyping of C. botulinum and how it contributes to our understanding the epidemiology and variation of boNT gene. Thus, the recent botulism outbreaks in Thailand were induced by various C. botulinum types. PMID- 24475016 TI - Managing cancer pain at the end of life with multiple strong opioids: a population-based retrospective cohort study in primary care. AB - BACKGROUND: End-of-life cancer patients commonly receive more than one type of strong opioid. The three-step analgesic ladder framework of the World Health Organisation (WHO) provides no guidance on multiple opioid prescribing and there is little epidemiological data available to inform practice. This study aims to investigate the time trend of such cases and the associated factors. METHODS: Strong opioid prescribing in the last three months of life of cancer patients were extracted from the General Practice Research Database (GPRD). The outcome variable was the number of different types of prescribed non-rescue doses of opioids (1 vs 2-4, referred to as a complex case). Associated factors were evaluated using prevalence ratios (PR) derived from multivariate log-binomial model, adjusting for clustering effects and potential confounding variables. RESULTS: Overall, 26.4% (95% CI: 25.6-27.1%) of 13,427 cancer patients (lung 41.7%, colorectal 19.1%, breast 18.6%, prostate 15.5%, head and neck 5.0%) were complex cases. Complex cases increased steadily over the study period (1.02% annually, 95%CI: 0.42-1.61%, p = 0.048) but with a small dip (7.5% reduction, 95%CI: -0.03 to 17.8%) around the period of the Shipman case, a British primary care doctor who murdered his patients with opioids. The dip significantly affected the correlation of the complex cases with persistent increasing background opioid prescribing (weighted correlation coefficients pre-, post Shipman periods: 0.98(95%CI: 0.67-1.00), p = 0.011; 0.14 (95%CI: -0.85 to 0.91), p = 0.85). Multivariate adjusted analysis showed that the complex cases were predominantly associated with year of death (PRs vs 2000: 1.05-1.65), not other demographic and clinical factors except colorectal cancer (PR vs lung cancer: 1.24, 95%CI: 1.12-1.37). CONCLUSION: These findings suggest that prescribing behaviour, rather than patient factors, plays an important role in multiple opioid prescribing at the end of life; highlighting the need for training and education that goes beyond the well-recognised WHO approach for clinical practitioners. PMID- 24475017 TI - Microbial diversity and evidence of novel homoacetogens in the gut of both geriatric and adult giant pandas (Ailuropoda melanoleuca). AB - Recent studies have described the bacterial community residing in the guts of giant pandas, together with the presence of lignocellulolytic enzymes. However, a more comprehensive understanding of the intestinal microbial composition and its functional capacity in giant pandas remains a major goal. Here, we conducted a comparison of bacterial, fungal and homoacetogenic microbial communities from fecal samples taken from two geriatric and two adult captive giant pandas. 16S rDNA amplicon pyrosequencing revealed that Firmicutes and Proteobacteria are the most abundant microbiota in both geriatric and adult giant pandas. However, members of phylum Actinobacteria found in adult giant pandas were absent in their geriatric counterparts. Similarly, ITS1 amplicon pyrosequencing identified developmental changes in the most abundant fungal classes from Sordariomycetes in adult pandas to Saccharomycetes in geriatric pandas. Geriatric pandas exhibited significantly higher abundance of a potential probiotic fungus (Candida tropicalis) as compared to adult pandas, indicating their importance in the normal digestive physiology of aged pandas. Our study also reported the presence of a lignocellulolytic white-rot fungus, Perenniporia medulla-panis, and the evidence of novel homoacetogens residing in the guts of giant pandas. PMID- 24475018 TI - Lactobacillus rhamnosus GG protects against non-alcoholic fatty liver disease in mice. AB - OBJECTIVE: Experimental evidence revealed that obesity-associated non-alcoholic fatty liver disease (NAFLD) is linked to changes in intestinal permeability and translocation of bacterial products to the liver. Hitherto, no reliable therapy is available except for weight reduction. Within this study, we examined the possible effect of the probiotic bacterial strain Lactobacillus rhamnosus GG (LGG) as protective agent against experimental NAFLD in a mouse model. METHODS: Experimental NAFLD was induced by a high-fructose diet over eight weeks in C57BL/J6 mice. Fructose was administered via the drinking water containing 30% fructose with or without LGG at a concentration resulting in approximately 5*10(7) colony forming units/g body weight. Mice were examined for changes in small intestinal microbiota, gut barrier function, lipopolysaccharide (LPS) concentrations in the portal vein, liver inflammation and fat accumulation in the liver. RESULTS: LGG increased beneficial bacteria in the distal small intestine. Moreover, LGG reduced duodenal IkappaB protein levels and restored the duodenal tight junction protein concentration. Portal LPS (P<=0.05) was reduced and tended to attenuate TNF-alpha, IL-8R and IL-1beta mRNA expression in the liver feeding a high-fructose diet supplemented with LGG. Furthermore liver fat accumulation and portal alanine-aminotransferase concentrations (P<=0.05) were attenuated in mice fed the high-fructose diet and LGG. CONCLUSIONS: We show for the first time that LGG protects mice from NAFLD induced by a high-fructose diet. The underlying mechanisms of protection likely involve an increase of beneficial bacteria, restoration of gut barrier function and subsequent attenuation of liver inflammation and steatosis. PMID- 24475019 TI - CD8+ Treg cells associated with decreasing disease activity after intravenous methylprednisolone pulse therapy in lupus nephritis with heavy proteinuria. AB - We focus on the role of CD8(+) Treg cell in Intravenous methyl-prednisolone (IVMP) pulse therapy in forty patients with active Class III/IV childhood lupus nephritis (LN) with heavy proteinuria. IVMP therapy for five days. From peripheral blood mononuclear cells (PBMCs) and renal tissues, we saw IVMP therapy definitely restoring both CD4(+)CD25(+)FoxP3(+) and CD8(+)CD25(+)Foxp3(+) Treg cell number plus greater expression with intracellular IL-10 and granzyme B in CD8(+)FoxP3(+) Treg from PBMCs. IVMP-treated CD8(+)CD25(+) Treg cells directly suppressed CD4(+) T proliferation and induced CD4(+)CD45RO(+) apoptosis. Histologically, CD4(+)FoxP3(+) as well as CD8(+)FoxP3(+) Treg cells appeared in renal tissue of LN patients before IVMP by double immunohistochemical stain. CD8(+)FoxP3(+) Treg cells increased in 10 follow-up renal biopsy specimens after IVMP. Reverse correlation of serum anti-C1q antibody and FoxP3(+) Treg cells in PBMNCs (r = -0.714, P<0.01). After IVMP, serum anti-C1q antibody decrease accompanied increase of CD4(+)FoxP3(+) Treg cells. CD8(+)Treg cells reduced interferon-r response in PBMCs to major peptide autoepitopes from nucleosomes after IVMP therapy; siRNA of FoxP3 suppressed granzyme B expression while decreasing CD8(+)CD25(+)Treg-induced CD4(+)CD45RO(+) apoptosis. Renal activity of LN by SLEDAI-2k in childhood LN was significantly higher than two weeks after IVMP (P<0.01). CD8(+)FoxP3(+) Treg cells return in post-IVMP therapy and exert crucial immune modulatory effect to control autoimmune response in LN. TRIAL REGISTRATION: DMR97-IRB-259. PMID- 24475020 TI - Do optimal prognostic thresholds in continuous physiological variables really exist? Analysis of origin of apparent thresholds, with systematic review for peak oxygen consumption, ejection fraction and BNP. AB - BACKGROUND: Clinicians are sometimes advised to make decisions using thresholds in measured variables, derived from prognostic studies. OBJECTIVES: We studied why there are conflicting apparently-optimal prognostic thresholds, for example in exercise peak oxygen uptake (pVO2), ejection fraction (EF), and Brain Natriuretic Peptide (BNP) in heart failure (HF). DATA SOURCES AND ELIGIBILITY CRITERIA: Studies testing pVO2, EF or BNP prognostic thresholds in heart failure, published between 1990 and 2010, listed on Pubmed. METHODS: First, we examined studies testing pVO2, EF or BNP prognostic thresholds. Second, we created repeated simulations of 1500 patients to identify whether an apparently-optimal prognostic threshold indicates step change in risk. RESULTS: 33 studies (8946 patients) tested a pVO2 threshold. 18 found it prognostically significant: the actual reported threshold ranged widely (10-18 ml/kg/min) but was overwhelmingly controlled by the individual study population's mean pVO2 (r = 0.86, p<0.00001). In contrast, the 15 negative publications were testing thresholds 199% further from their means (p = 0.0001). Likewise, of 35 EF studies (10220 patients), the thresholds in the 22 positive reports were strongly determined by study means (r = 0.90, p<0.0001). Similarly, in the 19 positives of 20 BNP studies (9725 patients): r = 0.86 (p<0.0001). Second, survival simulations always discovered a "most significant" threshold, even when there was definitely no step change in mortality. With linear increase in risk, the apparently-optimal threshold was always near the sample mean (r = 0.99, p<0.001). LIMITATIONS: This study cannot report the best threshold for any of these variables; instead it explains how common clinical research procedures routinely produce false thresholds. KEY FINDINGS: First, shifting (and/or disappearance) of an apparently-optimal prognostic threshold is strongly determined by studies' average pVO2, EF or BNP. Second, apparently-optimal thresholds always appear, even with no step in prognosis. CONCLUSIONS: Emphatic therapeutic guidance based on thresholds from observational studies may be ill-founded. We should not assume that optimal thresholds, or any thresholds, exist. PMID- 24475021 TI - Elevated serum triglyceride and retinol-binding protein 4 levels associated with fructose-sweetened beverages in adolescents. AB - BACKGROUND: The metabolic effect of fructose in sugar-sweetened beverages (SSB) has been linked to de novo lipogenesis and uric acid (UA) production. OBJECTIVES: This study investigated the biological effects of SSB consumption on serum lipid profiles and retinol-binding protein 4 (RBP4) among Taiwanese adolescents. METHODS: We evaluated the anthropometric parameters and biochemical outcomes of 200 representative adolescents (98 boys and 102 girls) who were randomly selected from a large-scale cross-sectional study. Data were analyzed using multiple regression models adjusted for covariates. RESULTS: Increased SSB consumption was associated with increased waist and hip circumferences, body mass index (BMI) values and serum UA, triglyceride (TG) and RBP4 levels. Adolescents who consumed >500 ml/day of beverages half-to-heavily sweetened with high-fructose corn syrup (HFCS) exhibited TG and RBP4 levels 22.7 mg/dl and 13.92 ng/ml higher than non drinkers, respectively. HFCS drinkers with hyperuricemia had higher TG levels than HFCS drinkers with normal UA levels (98.6 vs. 81.6 mg/dl). The intake of HFCS-rich SSBs and high value of BMI (>=24) interactively reinforced RBP4 levels among overweight/obese adolescents. Circulating RBP4 levels were significantly correlated with weight-related outcomes and TG and UA concentration among HFCS drinkers (r = 0.253 to 0.404), but not among non-drinkers. CONCLUSIONS: High quantity HFCS-rich beverage consumption is associated with higher TG and RBP4 levels. Hyperuricemia is likely to intensify the influence of HFCS-rich SSB intake on elevated TG levels, and in overweight and obese adolescents, high BMI may modify the action of fructose on higher circulating levels of RBP4. PMID- 24475022 TI - An integrative CGH, MSI and candidate genes methylation analysis of colorectal tumors. AB - BACKGROUND: Different DNA aberrations processes can cause colorectal cancer (CRC). Herein, we conducted a comprehensive molecular characterization of 27 CRCs from Iranian patients. MATERIALS AND METHODS: Array CGH was performed. The MSI phenotype and the methylation status of 15 genes was established using MSP. The CGH data was compared to two established lists of 41 and 68 cancer genes, respectively, and to CGH data from African Americans. A maximum parsimony cladogram based on global aberrations was established. RESULTS: The number of aberrations seem to depend on the MSI status. MSI-H tumors displayed the lowest number of aberrations. MSP revealed that most markers were methylated, except RNF182 gene. P16 and MLH1 genes were primarily methylated in MSI-H tumors. Seven markers with moderate to high frequency of methylation (SYNE1, MMP2, CD109, EVL, RET, LGR and PTPRD) had very low levels of chromosomal aberrations. All chromosomes were targeted by aberrations with deletions more frequent than amplifications. The most amplified markers were CD248, ERCC6, ERGIC3, GNAS, MMP2, NF1, P2RX7, SFRS6, SLC29A1 and TBX22. Most deletions were noted for ADAM29, CHL1, CSMD3, FBXW7, GALNS, MMP2, NF1, PRKD1, SMAD4 and TP53. Aberrations targeting chromosome X were primarily amplifications in male patients and deletions in female patients. A finding similar to what we reported for African American CRC patients. CONCLUSION: This first comprehensive analysis of CRC Iranian tumors reveals a high MSI rate. The MSI tumors displayed the lowest level of chromosomal aberrations but high frequency of methylation. The MSI-L were predominantly targeted with chromosomal instability in a way similar to the MSS tumors. The global chromosomal aberration profiles showed many similarities with other populations but also differences that might allow a better understanding of CRC's clinico-pathological specifics in this population. PMID- 24475023 TI - Comparison of road traffic injury characteristics between local versus floating migrant patients in a tertiary hospital between 2007 and 2010. AB - BACKGROUND: The aim of this study is to give a description of the road traffic injuries (RTIs) characteristics of floating migrant population by comparing with those of local residents in a harbor city of China. METHODS: A population-based descriptive study was carried out between 2007 and 2010 with RTI patient records from the Fifth Center Hospital of Tianjin. Inpatient diagnoses of RTI patients were defined using the International Classification of Diseases, Tenth Revision (ICD-10) codes. We analyzed the demographics and general characteristics of RTI patients that were in the hospital during the four years. In order to compare the group differences between local resident patients and floating migrant patients, the distribution of their ages, diagnoses, severity of injuries, duration of inpatient stays, hospitalization cost were analyzed. RESULTS: People between the ages of 16 and 55 were the most likely to suffer RTIs. The floating migrant patients between the ages of 16 and 45 had a higher incidence of accidents, while local resident patients between 46 and 55 had a higher incidence of accidents. Compared to local resident patients, floating migrant patients were more vulnerable to open injuries and severe traffic injuries. With the severity of injuries ranked from mild to severe, floating migrant patients had lower duration of inpatient stay, but higher hospitalization costs compared to local resident patients. CONCLUSIONS: Floating migrant patients had a different age distribution, severity of injuries, diseases, inpatient duration and hospitalization cost compared with local resident patients. Compared to local resident patients, floating migrants had a higher risk to RTIs and were more vulnerable to severer traffic accidents at lower ages. PMID- 24475024 TI - Traceless bioresponsive shielding of adenovirus hexon with HPMA copolymers maintains transduction capacity in vitro and in vivo. AB - Capsid surface shielding of adenovirus vectors with synthetic polymers is an emerging technology to reduce unwanted interactions of the vector particles with cellular and non-cellular host components. While it has been shown that attachment of shielding polymers allows prevention of undesired interactions, it has become evident that a shield which is covalently attached to the vector surface can negatively affect gene transfer efficiency. Reasons are not only a limited receptor-binding ability of the shielded vectors but also a disturbance of intracellular trafficking processes, the latter depending on the interaction of the vector surface with the cellular transport machinery. A solution might be the development of bioresponsive shields that are stably maintained outside the host cell but released upon cell entry to allow for efficient gene delivery to the nucleus. Here we provide a systematic comparison of irreversible versus bioresponsive shields based on synthetic N-(2-hydroxypropyl)methacrylamide (HPMA) copolymers. In addition, the chemical strategy used for generation of the shield allowed for a traceless bioresponsive shielding, i.e., polymers could be released from the vector particles without leaving residual linker residues. Our data demonstrated that only a bioresponsive shield maintained the high gene transfer efficiency of adenovirus vectors both in vitro and in vivo. As an example for bioresponsive HPMA copolymer release, we analyzed the in vivo gene transfer in the liver. We demonstrated that both the copolymer's charge and the mode of shielding (irreversible versus traceless bioresponsive) profoundly affected liver gene transfer and that traceless bioresponsive shielding with positively charged HPMA copolymers mediated FX independent transduction of hepatocytes. In addition, we demonstrated that shielding with HPMA copolymers can mediate a prolonged blood circulation of vector particles in mice. Our results have significant implications for the future design of polymer-shielded Ad and provide a deeper insight into the interaction of shielded adenovirus vector particles with the host after systemic delivery. PMID- 24475025 TI - Adaptation of the main peripheral artery and vein to long term confinement (Mars 500). AB - PURPOSE: The objective was to check if 520 days in confinement (MARS 500), may affect the main peripheral arterial diameter and wall thickness and the main vein size. METHOD: Common carotid (CC) femoral artery (FA) portal vein (PV), jugular (JG), femoral vein (FV) and tibial vein were assessed during MARS 500 by echography, performed by the subjects. A hand free volumic echographic capture method and a delayed 3D reconstruction software developed by our lab were used for collecting and measuring the vascular parameters. RESULTS: During the MARS 500 experiment the subjects performed 6 sessions among which 80% of the echographic data were of sufficient quality to be processed. No significant change was found for the Common carotid, Jugular vein, femoral artery, femoral vein, portal vein, and tibial vein diameter. CC and FA IMT (intima media thickness) were found significantly increased (14% to 28% P<0.05) in all the 6 subjects, during the confinement period and also at +2 days after the confinement period, but there was no significant difference 6 month later compare to pre MARS 500. CONCLUSION: The experiment confirmed that even untrained to performing echography the subjects were able to capture enough echographic data to reconstruct the vessel image from which the parameters were measured. The increase in both CC and FA IMT should be in relation with the stress generated by the confined environment or absence of solar radiation, as there was no change in gravity, temperature and air in the MARS 500 module, and minor changes in physical exercise and nutrition. PMID- 24475026 TI - Platelet aggregation unchanged by lipoprotein-associated phospholipase A2 inhibition: results from an in vitro study and two randomized phase I trials. AB - BACKGROUND: We explored the theorized upregulation of platelet-activating factor (PAF)- mediated biologic responses following lipoprotein-associated phospholipase A2 (Lp-PLA2) inhibition using human platelet aggregation studies in an in vitro experiment and in 2 clinical trials. METHODS AND RESULTS: Full platelet aggregation concentration response curves were generated in vitro to several platelet agonists in human plasma samples pretreated with rilapladib (selective Lp-PLA2 inhibitor) or vehicle. This was followed by a randomized, double-blind crossover study in healthy adult men (n = 26) employing a single-agonist dose assay of platelet aggregation, after treatment of subjects with 250 mg oral rilapladib or placebo once daily for 14 days. This study was followed by a second randomized, double-blind parallel-group trial in healthy adult men (n = 58) also treated with 250 mg oral rilapladib or placebo once daily for 14 days using a full range of 10 collagen concentrations (0-10 ug/ml) for characterizing EC50 values for platelet aggregation for each subject. Both clinical studies were conducted at the GlaxoSmithKline Medicines Research Unit in the Prince of Wales Hospital, Sydney, Australia. EC50 values derived from multiple agonist concentrations were compared and no pro-aggregant signals were observed during exposure to rilapladib in any of these platelet studies, despite Lp-PLA2 inhibition exceeding 90%. An increase in collagen-mediated aggregation was observed 3 weeks post drug termination in the crossover study (15.4% vs baseline; 95% confidence interval [CI], 3.9-27.0), which was not observed during the treatment phase and was not observed in the parallel-group study employing a more robust EC50 examination. CONCLUSIONS: Lp-PLA2 inhibition does not enhance platelet aggregation. TRIAL REGISTRATION: 1) Study 1: ClinicalTrials.gov NCT01745458 2) Study 2: ClinicalTrials.gov NCT00387257. PMID- 24475027 TI - RNA control of HIV-1 particle size polydispersity. AB - HIV-1, an enveloped RNA virus, produces viral particles that are known to be much more heterogeneous in size than is typical of non-enveloped viruses. We present here a novel strategy to study HIV-1 Viral Like Particles (VLP) assembly by measuring the size distribution of these purified VLPs and subsequent viral cores thanks to Atomic Force Microscopy imaging and statistical analysis. This strategy allowed us to identify whether the presence of viral RNA acts as a modulator for VLPs and cores size heterogeneity in a large population of particles. These results are analyzed in the light of a recently proposed statistical physics model for the self-assembly process. In particular, our results reveal that the modulation of size distribution by the presence of viral RNA is qualitatively reproduced, suggesting therefore an entropic origin for the modulation of RNA uptake by the nascent VLP. PMID- 24475028 TI - Pseudomonas putida CSV86: a candidate genome for genetic bioaugmentation. AB - Pseudomonas putida CSV86, a plasmid-free strain possessing capability to transfer the naphthalene degradation property, has been explored for its metabolic diversity through genome sequencing. The analysis of draft genome sequence of CSV86 (6.4 Mb) revealed the presence of genes involved in the degradation of naphthalene, salicylate, benzoate, benzylalcohol, p-hydroxybenzoate, phenylacetate and p-hydroxyphenylacetate on the chromosome thus ensuring the stability of the catabolic potential. Moreover, genes involved in the metabolism of phenylpropanoid and homogentisate, as well as heavy metal resistance, were additionally identified. Ability to grow on vanillin, veratraldehyde and ferulic acid, detection of inducible homogentisate dioxygenase and growth on aromatic compounds in the presence of heavy metals like copper, cadmium, cobalt and arsenic confirm in silico observations reflecting the metabolic versatility. In silico analysis revealed the arrangement of genes in the order: tRNA(Gly), integrase followed by nah operon, supporting earlier hypothesis of existence of a genomic island (GI) for naphthalene degradation. Deciphering the genomic architecture of CSV86 for aromatic degradation pathways and identification of elements responsible for horizontal gene transfer (HGT) suggests that genetic bioaugmentation strategies could be planned using CSV86 for effective bioremediation. PMID- 24475029 TI - A novel complex A/C/G intergenotypic recombinant of hepatitis B virus isolated in southern China. AB - Hepatitis B virus (HBV) genotypes and subgenotypes may vary in geographical distribution and virological features. Previous investigations, including ours, showed that HBV genotypes B and C were respectively predominant in South and North China, while genotypes A and D were infrequently detected and genotype G was not found. In this study, a novel A/C/G intergenotype was identified in patients with chronic HBV infection in Guilin, a city in southern China. Initial phylogenetic analysis based on the S gene suggested the HBV recombinant to be genotype G. However, extended genotyping based on the entire HBV genome indicated it to be an A/C/G intergenotype with a closer relation to genotype C. Breakpoint analysis using the SIMPLOT program revealed that the recombinant had a recombination with a arrangement of genotypes A, G, A and C fragments. Compared with the HBV recombinants harboring one or two genotype G fragments found in Asian countries, this Guilin recombinant was highly similar to the Vietnam (98 99%) and Long An recombinants (96-99%), but had a relatively low similarity to the Thailand one (89%). Unlike those with the typical genotype G of HBV, the patients with the Guilin recombinant were seropositive for HBeAg. Moreover, a relatively high HBV DNA viral load (>2 * 10(6) IU/ml) was detected in the patients, and the analysis of viral replication capacity showed that the Guilin recombinant strains had a competent replication capacity similar to genotypes B and C strains. These findings can aid in not only the clarification of the phylogenetic origin of the HBV recombinants with the genotype G fragment found in Asian countries, but also the understanding of the virological properties of these complicated HBV recombinants. PMID- 24475030 TI - Segregation and integration of auditory streams when listening to multi-part music. AB - In our daily lives, auditory stream segregation allows us to differentiate concurrent sound sources and to make sense of the scene we are experiencing. However, a combination of segregation and the concurrent integration of auditory streams is necessary in order to analyze the relationship between streams and thus perceive a coherent auditory scene. The present functional magnetic resonance imaging study investigates the relative role and neural underpinnings of these listening strategies in multi-part musical stimuli. We compare a real human performance of a piano duet and a synthetic stimulus of the same duet in a prioritized integrative attention paradigm that required the simultaneous segregation and integration of auditory streams. In so doing, we manipulate the degree to which the attended part of the duet led either structurally (attend melody vs. attend accompaniment) or temporally (asynchronies vs. no asynchronies between parts), and thus the relative contributions of integration and segregation used to make an assessment of the leader-follower relationship. We show that perceptually the relationship between parts is biased towards the conventional structural hierarchy in western music in which the melody generally dominates (leads) the accompaniment. Moreover, the assessment varies as a function of both cognitive load, as shown through difficulty ratings and the interaction of the temporal and the structural relationship factors. Neurally, we see that the temporal relationship between parts, as one important cue for stream segregation, revealed distinct neural activity in the planum temporale. By contrast, integration used when listening to both the temporally separated performance stimulus and the temporally fused synthetic stimulus resulted in activation of the intraparietal sulcus. These results support the hypothesis that the planum temporale and IPS are key structures underlying the mechanisms of segregation and integration of auditory streams, respectively. PMID- 24475031 TI - Does the supplementary motor area keep patients with Ondine's curse syndrome breathing while awake? AB - BACKGROUND: Congenital central hypoventilation syndrome (CCHS) is a rare neuro respiratory disorder associated with mutations of the PHOX2B gene. Patients with this disease experience severe hypoventilation during sleep and are consequently ventilator-dependent. However, they breathe almost normally while awake, indicating the existence of cortical mechanisms compensating for the deficient brainstem generation of automatic breathing. Current evidence indicates that the supplementary motor area plays an important role in modulating ventilation in awake normal humans. We hypothesized that the wake-related maintenance of spontaneous breathing in patients with CCHS could involve supplementary motor area. METHODS: We studied 7 CCHS patients (5 women; age: 20-30; BMI: 22.1 +/- 4 kg.m(-2)) during resting breathing and during exposure to carbon dioxide and inspiratory mechanical constraints. They were compared with 8 healthy individuals. Segments of electroencephalographic tracings were selected according to ventilatory flow signal, from 2.5 seconds to 1.5 seconds after the onset of inspiration. After artefact rejection, 80 or more such segments were ensemble averaged. A slow upward shift of the EEG signal starting between 2 and 0.5 s before inspiration (pre-inspiratory potential) was considered suggestive of supplementary motor area activation. RESULTS: In the control group, pre inspiratory potentials were generally absent during resting breathing and carbon dioxide stimulation, and consistently identified in the presence of inspiratory constraints (expected). In CCHS patients, pre-inspiratory potentials were systematically identified in all study conditions, including resting breathing. They were therefore significantly more frequent than in controls. CONCLUSIONS: This study provides a neurophysiological substrate to the wakefulness drive to breathe that is characteristic of CCHS and suggests that the supplementary motor area contributes to this phenomenon. Whether or not this "cortical breathing" can be taken advantage of therapeutically, or has clinical consequences (like competition with attentional resources) remains to be determined. PMID- 24475032 TI - Enhanced upregulation of CRH mRNA expression in the nucleus accumbens of male rats after a second injection of methamphetamine given thirty days later. AB - Methamphetamine (METH) is a widely abused amphetamine analog. Few studies have investigated the molecular effects of METH exposure in adult animals. Herein, we determined the consequences of an injection of METH (10 mg/kg) on transcriptional effects of a second METH (2.5 mg/kg) injection given one month later. We thus measured gene expression by microarray analyses in the nucleus accumbens (NAc) of 4 groups of rats euthanized 2 hours after the second injection: saline-pretreated followed by saline-challenged (SS) or METH-challenged (SM); and METH-pretreated followed by saline-challenged (MS) or METH-challenged (MM). Microarray analyses revealed that METH (2.5 mg/kg) produced acute changes (1.8-fold; P<0.01) in the expression of 412 (352 upregulated, 60 down-regulated) transcripts including cocaine and amphetamine regulated transcript, corticotropin-releasing hormone (Crh), oxytocin (Oxt), and vasopressin (Avp) that were upregulated. Injection of METH (10 mg/kg) altered the expression of 503 (338 upregulated, 165 down regulated) transcripts measured one month later (MS group). These genes also included Cart and Crh. The MM group showed altered expression of 766 (565 upregulated, 201 down-regulated) transcripts including Avp, Cart, and Crh. The METH-induced increased Crh expression was enhanced in the MM group in comparison to SM and MS groups. Quantitative PCR confirmed the METH-induced changes in mRNA levels. Therefore, a single injection of METH produced long-lasting changes in gene expression in the rodent NAc. The long-term increases in Crh, Cart, and Avp mRNA expression suggest that METH exposure produced prolonged activation of the endogenous stress system. The METH-induced changes in oxytocin expression also suggest the possibility that this neuropeptide might play a significant role in the neuroplastic and affiliative effects of this drug. PMID- 24475033 TI - Hypoxia inducible factor-2alpha regulates the development of retinal astrocytic network by maintaining adequate supply of astrocyte progenitors. AB - Here we investigate the role of hypoxia inducible factor (HIF)-2alpha in coordinating the development of retinal astrocytic and vascular networks. Three Cre mouse lines were used to disrupt floxed Hif-2alpha, including Rosa26(CreERT2), Tie2(Cre), and GFAP(Cre). Global Hif-2alpha disruption by Rosa26(CreERT2) led to reduced astrocytic and vascular development in neonatal retinas, whereas endothelial disruption by Tie2(Cre) had no apparent effects. Hif 2alpha deletion in astrocyte progenitors by GFAP(Cre) significantly interfered with the development of astrocytic networks, which failed to reach the retinal periphery and were incapable of supporting vascular development. Perplexingly, the abundance of strongly GFAP(+) mature astrocytes transiently increased at P0 before they began to lag behind the normal controls by P3. Pax2(+) and PDGFRalpha(+) astrocytic progenitors and immature astrocytes were dramatically diminished at all stages examined. Despite decreased number of astrocyte progenitors, their proliferation index or apoptosis was not altered. The above data can be reconciled by proposing that HIF-2alpha is required for maintaining the supply of astrocyte progenitors by slowing down their differentiation into non-proliferative mature astrocytes. HIF-2alpha deficiency in astrocyte progenitors may accelerate their differentiation into astrocytes, a change which greatly interferes with the replenishment of astrocyte progenitors due to insufficient time for proliferation. Rapidly declining progenitor supply may lead to premature cessation of astrocyte development. Given that HIF-2alpha protein undergoes oxygen dependent degradation, an interesting possibility is that retinal blood vessels may regulate astrocyte differentiation through their oxygen delivery function. While our findings support the consensus that retinal astrocytic template guides vascular development, they also raise the possibility that astrocytic and vascular networks may mutually regulate each other's development, mediated at least in part by HIF-2alpha. PMID- 24475034 TI - Age- and influenza activity-stratified case definitions of influenza-like illness: experience from hospital-based influenza surveillance in South Korea. AB - OBJECTIVES: This study aims to identify clinical case definitions of influenza with higher accuracy in patients stratified by age group and influenza activity using hospital-based surveillance system. METHODS: In seven tertiary hospitals across South Korea during 2011-2012 influenza season, respiratory specimens were obtained from patients presenting an influenza-like illness (ILI), defined as having fever plus at least one of following symptoms: cough, sore throat or rhinorrhea. Influenza was confirmed by reverse transcriptase-polymerase chain reaction. We performed multivariate logistic regression analyses to identify clinical variables with better relation with laboratory-confirmed influenza, and compared the accuracy of combinations. RESULTS: Over the study period, we enrolled 1417 patients, of which 647 had laboratory-confirmed influenza. Patients with cough, rhinorrhea, sore throat or headache were more likely to have influenza (p<0.05). The most accurate criterion across the study population was the combination of cough, rhinorrhea, sore throat and headache (sensitivity 71.3%, specificity 60.1% and AUROC 0.66). The combination of rhinorrhea, sore throat and sputum during the peak influenza activity period in the young age group showed higher accuracy than that using the whole population (sensitivity 89.3%, specificity 72.1%, and AUROC 0.81). CONCLUSIONS: The accuracy of clinical case definitions of influenza differed across age groups and influenza activity periods. Categorizing the entire population into subgroups would improve the detection of influenza patients in the hospital-based surveillance system. PMID- 24475035 TI - HIV incidence in a cohort of women at higher risk in Beira, Mozambique: prospective study 2009-2012. AB - BACKGROUND: HIV is prevalent in Sofala Province, Mozambique. To inform future prevention research, we undertook a study in the provincial capital (Beira) to measure HIV incidence in women at higher risk of HIV and assess the feasibility of recruiting and retaining them as research participants. METHODS: Women age 18 35 were recruited from schools and places where women typically meet potential sexual partners. Eligibility criteria included HIV-seronegative status and self report of at least 2 sexual partners in the last month. History of injection drug use was an exclusion criterion, but pregnancy was not. Participants were scheduled for monthly follow-up for 12 months, when they underwent face-to-face interviews, HIV counseling and testing, and pregnancy testing. RESULTS: 387 women were eligible and contributed follow-up data. Most were from 18-24 years old (median 21). Around one-third of participants (33.8%) reported at least one new sexual partner in the last month. Most women (65.5%) reported not using a modern method of contraception at baseline. Twenty-two women seroconverted for a prospective HIV incidence of 6.5 per 100 woman-years (WY; 95% confidence interval (CI): 4.1-9.9). Factors associated with HIV seroconversion in the multivariable analysis were: number of vaginal sex acts without using condoms with partners besides primary partner in the last 7 days (hazard ratio (HR) 1.7; 95% CI: 1.2 2.5) and using a form of contraception at baseline other than hormonal or condoms (vs. no method; HR 25.3; 95% CI: 2.5-253.5). The overall retention rate was 80.0% for the entire follow-up period. CONCLUSIONS: We found a high HIV incidence in a cohort of young women reporting risky sexual behavior in Beira, Mozambique. HIV prevention programs should be strengthened. Regular HIV testing and condom use should be encouraged, particularly among younger women with multiple sexual partners. PMID- 24475036 TI - Targeting the biophysical properties of the myeloma initiating cell niches: a pharmaceutical synergism analysis using multi-scale agent-based modeling. AB - Multiple myeloma, the second most common hematological cancer, is currently incurable due to refractory disease relapse and development of multiple drug resistance. We and others recently established the biophysical model that myeloma initiating (stem) cells (MICs) trigger the stiffening of their niches via SDF 1/CXCR4 paracrine; The stiffened niches then promote the colonogenesis of MICs and protect them from drug treatment. In this work we examined in silico the pharmaceutical potential of targeting MIC niche stiffness to facilitate cytotoxic chemotherapies. We first established a multi-scale agent-based model using the Markov Chain Monte Carlo approach to recapitulate the niche stiffness centric, pro-oncogenetic positive feedback loop between MICs and myeloma-associated bone marrow stromal cells (MBMSCs), and investigated the effects of such intercellular chemo-physical communications on myeloma development. Then we used AMD3100 (to interrupt the interactions between MICs and their stroma) and Bortezomib (a recently developed novel therapeutic agent) as representative drugs to examine if the biophysical properties of myeloma niches are drugable. Results showed that our model recaptured the key experimental observation that the MBMSCs were more sensitive to SDF-1 secreted by MICs, and provided stiffer niches for these initiating cells and promoted their proliferation and drug resistance. Drug synergism analysis suggested that AMD3100 treatment undermined the capability of MICs to modulate the bone marrow microenvironment, and thus re-sensitized myeloma to Bortezomib treatments. This work is also the first attempt to virtually visualize in 3D the dynamics of the bone marrow stiffness during myeloma development. In summary, we established a multi-scale model to facilitate the translation of the niche-stiffness centric myeloma model as well as experimental observations to possible clinical applications. We concluded that targeting the biophysical properties of stem cell niches is of high clinical potential since it may re-sensitize tumor initiating cells to chemotherapies and reduce risks of cancer relapse. PMID- 24475037 TI - What does the talking?: quorum sensing signalling genes discovered in a bacteriophage genome. AB - The transfer of novel genetic material into the genomes of bacterial viruses (phages) has been widely documented in several host-phage systems. Bacterial genes are incorporated into the phage genome and, if retained, subsequently evolve within them. The expression of these phage genes can subvert or bolster bacterial processes, including altering bacterial pathogenicity. The phage phiCDHM1 infects Clostridium difficile, a pathogenic bacterium that causes nosocomial infections and is associated with antibiotic treatment. Genome sequencing and annotation of phiCDHM1 shows that despite being closely related to other C. difficile myoviruses, it has several genes that have not been previously reported in any phage genomes. Notably, these include three homologs of bacterial genes from the accessory gene regulator (agr) quorum sensing (QS) system. These are; a pre-peptide (AgrD) of an autoinducing peptide (AIP), an enzyme which processes the pre-peptide (AgrB) and a histidine kinase (AgrC) that detects the AIP to activate a response regulator. Phylogenetic analysis of the phage and C. difficile agr genes revealed that there are three types of agr loci in this species. We propose that the phage genes belonging to a third type, agr3, and have been horizontally transferred from the host. AgrB and AgrC are transcribed during the infection of two different strains. In addition, the phage agrC appears not to be confined to the phiCDHM1 genome as it was detected in genetically distinct C. difficile strains. The discovery of QS gene homologs in a phage genome presents a novel way in which phages could influence their bacterial hosts, or neighbouring bacterial populations. This is the first time that these QS genes have been reported in a phage genome and their distribution both in C. difficile and phage genomes suggests that the agr3 locus undergoes horizontal gene transfer within this species. PMID- 24475038 TI - Characterization of cyanobacterial hydrocarbon composition and distribution of biosynthetic pathways. AB - Cyanobacteria possess the unique capacity to naturally produce hydrocarbons from fatty acids. Hydrocarbon compositions of thirty-two strains of cyanobacteria were characterized to reveal novel structural features and insights into hydrocarbon biosynthesis in cyanobacteria. This investigation revealed new double bond (2- and 3-heptadecene) and methyl group positions (3-, 4- and 5-methylheptadecane) for a variety of strains. Additionally, results from this study and literature reports indicate that hydrocarbon production is a universal phenomenon in cyanobacteria. All cyanobacteria possess the capacity to produce hydrocarbons from fatty acids yet not all accomplish this through the same metabolic pathway. One pathway comprises a two-step conversion of fatty acids first to fatty aldehydes and then alkanes that involves a fatty acyl ACP reductase (FAAR) and aldehyde deformylating oxygenase (ADO). The second involves a polyketide synthase (PKS) pathway that first elongates the acyl chain followed by decarboxylation to produce a terminal alkene (olefin synthase, OLS). Sixty-one strains possessing the FAAR/ADO pathway and twelve strains possessing the OLS pathway were newly identified through bioinformatic analyses. Strains possessing the OLS pathway formed a cohesive phylogenetic clade with the exception of three Moorea strains and Leptolyngbya sp. PCC 6406 which may have acquired the OLS pathway via horizontal gene transfer. Hydrocarbon pathways were identified in one-hundred forty-two strains of cyanobacteria over a broad phylogenetic range and there were no instances where both the FAAR/ADO and the OLS pathways were found together in the same genome, suggesting an unknown selective pressure maintains one or the other pathway, but not both. PMID- 24475039 TI - Schisandra chinensis peptidoglycan-assisted transmembrane transport of lignans uniquely altered the pharmacokinetic and pharmacodynamic mechanisms in human HepG2 cell model. AB - Schisandra chinensis (Turz Baill) (S. chinensis) (SC) fruit is a hepatoprotective herb containing many lignans and a large amount of polysaccharides. A novel polysaccharide (called SC-2) was isolated from SC of MW 841 kDa, which exhibited a protein-to-polysaccharide ratio of 0.4089, and showed a characteristic FTIR spectrum of a peptidoglycan. Powder X-ray diffraction revealed microcrystalline structures within SC-2. SC-2 contained 10 monosaccharides and 15 amino acids (essential amino acids of 78.12%w/w). In a HepG2 cell model, SC-2 was shown by MTT and TUNEL assay to be completely non-cytotoxic. A kinetic analysis and fluorescence-labeling technique revealed no intracellular disposition of SC-2. Combined treatment of lignans with SC-2 enhanced the intracellular transport of schisandrin B and deoxyschisandrin but decreased that of gomisin C, resulting in alteration of cell-killing bioactivity. The Second Law of Thermodynamics allows this type of unidirectional transport. Conclusively, SC-2 alters the transport and cell killing capability by a "Catcher-Pitcher Unidirectional Transport Mechanism". PMID- 24475041 TI - Reduced diversity and high sponge abundance on a sedimented Indo-Pacific reef system: implications for future changes in environmental quality. AB - Although coral reef health across the globe is declining as a result of anthropogenic impacts, relatively little is known of how environmental variability influences reef organisms other than corals and fish. Sponges are an important component of coral reef fauna that perform many important functional roles and changes in their abundance and diversity as a result of environmental change has the potential to affect overall reef ecosystem functioning. In this study, we examined patterns of sponge biodiversity and abundance across a range of environments to assess the potential key drivers of differences in benthic community structure. We found that sponge assemblages were significantly different across the study sites, but were dominated by one species Lamellodysidea herbacea (42% of all sponges patches recorded) and that the differential rate of sediment deposition was the most important variable driving differences in abundance patterns. Lamellodysidea herbacea abundance was positively associated with sedimentation rates, while total sponge abundance excluding Lamellodysidea herbacea was negatively associated with rates of sedimentation. Overall variation in sponge assemblage composition was correlated with a number of variables although each variable explained only a small amount of the overall variation. Although sponge abundance remained similar across environments, diversity was negatively affected by sedimentation, with the most sedimented sites being dominated by a single sponge species. Our study shows how some sponge species are able to tolerate high levels of sediment and that any transition of coral reefs to more sedimented states may result in a shift to a low diversity sponge dominated system, which is likely to have subsequent effects on ecosystem functioning. PMID- 24475040 TI - A 16-gene signature distinguishes anaplastic astrocytoma from glioblastoma. AB - Anaplastic astrocytoma (AA; Grade III) and glioblastoma (GBM; Grade IV) are diffusely infiltrating tumors and are called malignant astrocytomas. The treatment regimen and prognosis are distinctly different between anaplastic astrocytoma and glioblastoma patients. Although histopathology based current grading system is well accepted and largely reproducible, intratumoral histologic variations often lead to difficulties in classification of malignant astrocytoma samples. In order to obtain a more robust molecular classifier, we analysed RT qPCR expression data of 175 differentially regulated genes across astrocytoma using Prediction Analysis of Microarrays (PAM) and found the most discriminatory 16-gene expression signature for the classification of anaplastic astrocytoma and glioblastoma. The 16-gene signature obtained in the training set was validated in the test set with diagnostic accuracy of 89%. Additionally, validation of the 16 gene signature in multiple independent cohorts revealed that the signature predicted anaplastic astrocytoma and glioblastoma samples with accuracy rates of 99%, 88%, and 92% in TCGA, GSE1993 and GSE4422 datasets, respectively. The protein-protein interaction network and pathway analysis suggested that the 16 genes of the signature identified epithelial-mesenchymal transition (EMT) pathway as the most differentially regulated pathway in glioblastoma compared to anaplastic astrocytoma. In addition to identifying 16 gene classification signature, we also demonstrated that genes involved in epithelial-mesenchymal transition may play an important role in distinguishing glioblastoma from anaplastic astrocytoma. PMID- 24475042 TI - Chlamydia detection during the menstrual cycle: a cross-sectional study of women attending a sexual health service. AB - BACKGROUND: We investigated the detection of chlamydia at different stages of the menstrual cycle. METHODS: Electronic medical records for women attending Melbourne Sexual Health Centre between March 2011 and 31(st) December 2012, who were tested for chlamydia by nucleic acid amplification of high vaginal, cervical, or urinary samples, and who recorded a date of last normal menstrual period (LNMP) between 0-28 days were included in the analysis. Logistic regression was used to calculate adjusted odds ratio (aOR) and 95% confidence intervals (CI) for the association of chlamydia with menstrual cycle adjusted by demographics and behavioural variables. Chlamydia and beta globin load were determined on those with stored samples. RESULTS: Of the 10,017 consultations that included a test for chlamydia and a valid LNMP, there were 417 in which chlamydia was detected. The proportion of samples with chlamydia was greater in the luteal phase (4.8%, 184/3831) than in the follicular phase (3.4%, 233/6816) both in the crude (OR 1.29 95%CI 1.1-1.6, p = 0.01) and adjusted odds ratio (aOR) 1.4 (95%CI 1.1-1.8, p = 0.004). Among women using hormonal contraception, there was no significant association with the luteal phase of the menstrual cycle (aOR 1.3, 95%CI 0.9, 1.8, p = 0.18). Among women not using hormonal contraception, there was a significant association with the luteal phase (aOR 1.6, (95% CI 1.1 2.3, p = 0.007). The chlamydia load was not significantly different in the 329 positive stored samples in weeks 3 and 4 vs weeks 1 and 2 for any site (P>0.12). CONCLUSIONS: The higher detection of chlamydia detection in the luteal phase of the menstrual cycle in only those not taking hormonal contraception suggest that hormonal factors influence chlamydia detection. The absence of a significantly highly chlamydia load in women during the luteal phase raises questions about the mechanism. PMID- 24475043 TI - Comparison of endoscopic submucosal implantation vs. surgical intramuscular implantation of VX2 fragments for establishing a rabbit esophageal tumor model for mimicking human esophageal squamous carcinoma. AB - PURPOSE: This study was undertaken to establish a rabbit esophageal tumor model for mimicking human esophageal squamous carcinoma (ESC) by endoscopic and surgical implantation of VX2 tumors. METHODS: Fragments of a VX2 tumour were endoscopically implanted in the submucosal layer of the thoracic esophagus of 32 New Zealand white rabbits, while 34 animals received surgical implantation into the muscular layer. Then, the animals were studied endoscopically and pathologically. The safety and efficiency of the two methods and the pathological features of the animal models were analyzed. RESULTS: Both the endoscopic and the surgical method had a relatively high success rate of tumor implantation [93.7% (30/32) vs. 97.1% (33/34)] and tumor growth [86.7% (26/30) vs. 81.8% (27/33)], and the variation in the results was not statistically significant (P>0.05). Compared with those produced by the surgical method, the models produced by the endoscopic method had a higher rate of severe esophageal stricture [61.5% (16/26) vs. 29.6% (8/27)] and of intra-luminal tumor growth [73.1% (19/26) vs. 37.0% (10/27)], and had a lower rate of tumor invasion of adjacent organs [53.8% (14/26) vs. 81.5% (22/27)]; all of these results were statistically significant (P<0.05). However, the difference in the survival time and the rates of tumor regional/distant metastasis [38.5% (10/26) vs. 51.8% (14/27)] between the two methods were not statistically significant (P>0.05). CONCLUSION: The endoscopic and surgical methods are both safe and effective for establishment of VX2 tumors in the rabbit esophagus. The models produced by the two methods have different pathologic features mimicking that of human ESC. We recommend the models for studies on surgical procedures and minimally invasive treatments. PMID- 24475044 TI - Survival of adults with acute lymphoblastic leukemia in Germany and the United States. AB - BACKGROUND: Adulthood acute lymphoblastic leukemia (ALL) is a rare disease. In contrast to childhood ALL, survival for adults with ALL is poor. Recently, new protocols, including use of pediatric protocols in young adults, have improved survival in clinical trials. Here, we examine population level survival in Germany and the United States (US) to gain insight into the extent to which changes in clinical trials have translated into better survival on the population level. METHODS: Data were extracted from the Surveillance, Epidemiology, and End Results database in the US and 11 cancer registries in Germany. Patients age 15 69 diagnosed with ALL were included. Period analysis was used to estimate 5-year relative survival (RS). RESULTS: Overall 5-year RS was estimated at 43.4% for Germany and 35.5% for the US (p = 0.004), with a decrease in survival with increasing age. Survival was higher in Germany than the US for men (43.6% versus 37.7%, p = 0.002) but not for women (42.4% versus 40.3%, p>0.1). Five-year RS estimates increased in Germany and the US between 2002 and 2006 by 11.8 and 7.3 percent units, respectively (p = 0.02 and 0.04, respectively). CONCLUSIONS: Survival for adults with ALL continues to be low compared with that for children, but a substantial increase in 5-year survival estimates was seen from 2002 to 2006 in both Germany and the US. The reasons for the survival differences between both countries require clarification. PMID- 24475045 TI - Linking stoichiometric homeostasis of microorganisms with soil phosphorus dynamics in wetlands subjected to microcosm warming. AB - Soil biogeochemical processes and the ecological stability of wetland ecosystems under global warming scenarios have gained increasing attention worldwide. Changes in the capacity of microorganisms to maintain stoichiometric homeostasis, or relatively stable internal concentrations of elements, may serve as an indicator of alterations to soil biogeochemical processes and their associated ecological feedbacks. In this study, an outdoor computerized microcosm was set up to simulate a warmed (+5 degrees C) climate scenario, using novel, minute-scale temperature manipulation technology. The principle of stoichiometric homeostasis was adopted to illustrate phosphorus (P) biogeochemical cycling coupled with carbon (C) dynamics within the soil-microorganism complex. We hypothesized that enhancing the flux of P from soil to water under warming scenarios is tightly coupled with a decrease in homeostatic regulation ability in wetland ecosystems. Results indicate that experimental warming impaired the ability of stoichiometric homeostasis (H) to regulate biogeochemical processes, enhancing the ecological role of wetland soil as an ecological source for both P and C. The potential P flux from soil to water ranged from 0.11 to 34.51 mg m(-2) d(-1) in the control and 0.07 to 61.26 mg m(-2) d(-1) in the warmed treatment. The synergistic function of C-P acquisition is an important mechanism underlying C?P stoichiometric balance for soil microorganisms under warming. For both treatment groups, strongly significant (p<0.001) relationships fitting a negative allometric power model with a fractional exponent were found between n-HC?P (the specialized homeostatic regulation ability as a ratio of soil highly labile organic carbon to dissolved reactive phosphorus in porewater) and potential P flux. Although many factors may affect soil P dynamics, the n-HC?P term fundamentally reflects the stoichiometric balance or interactions between the energy landscape (i.e., C) and flow of resources (e.g., N and P), and can be a useful ecological tool for assessing potential P flux in ecosystems. PMID- 24475046 TI - Decreased expression of PTPN12 correlates with tumor recurrence and poor survival of patients with hepatocellular carcinoma. AB - BACKGROUND: Protein tyrosine phosphatase non-receptor type 12 (PTPN12), has been identified as a potent tumor suppressor in human cancers and a critical regulator of cell adhesion and migration. However, the PTPN12 expression and its prognostic significance in HCC have not been well elucidated. METHODOLOGY/PRINCIPAL FINDINGS: In this study, tissue microarray-based immunohistochemistry (IHC) was investigated in an HCC cohort with adjacent liver tissues as controls. The resulting data were analyzed using receiver operating characteristic curves, Spearman's rank correlation, Kaplan-Meier plots and Cox proportional hazards regression modeling. Our results showed that decreased expression of PTPN12 was more frequently observed in HCC tissues compared to the adjacent non-tumorous liver tissues. Further correlation analyses indicated that the decreased PTPN12 expression was closely correlated with tumor recurrence (P = 0.015). Univariate analysis showed a significant association between decreased expression of PTPN12 and adverse cancer-specific survival and recurrence-free survival (P<0.001). In different subsets of overall patients, PTPN12 expression was also a prognostic indicator in patients with stage I/II or stage III/IV (P<0.05). Importantly, multivariate analysis (P<0.05) identified PTPN12 expression in HCC as an independent prognostic factor. CONCLUSIONS/SIGNIFICANCE: Our findings provide a basis for the concept that PTPN12 protein expression is frequently decreased or lost in human HCC tissues and that decreased PTPN12 expression may represent an acquired recurrence phenotype of HCC and that PTPN12 expression may act as a biomarker of prognosis for patients with HCC. PMID- 24475047 TI - De novo cancers following liver transplantation: a single center experience in China. AB - BACKGROUND: De novo cancers are a growing problem that has become one of the leading causes of late mortality after liver transplantation. The incidences and risk factors varied among literatures and fewer concerned the Eastern population. AIMS: The aim of this study was to examine the incidence and clinical features of de novo cancers after liver transplantation in a single Chinese center. METHODS: 569 patients who received liver transplantation and survived for more than 3 months in a single Chinese center were retrospectively reviewed. RESULTS: A total of 18 de novo cancers were diagnosed in 17 recipients (13 male and 4 female) after a mean of 41 +/- 26 months, with an overall incidence of 3.2%, which was lower than that in Western people. Of these, 8 (3.32%) cases were from 241 recipients with malignant liver diseases before transplant, while 10 (3.05%) cases were from 328 recipients with benign diseases. The incidence rates were comparable, p = 0.86. Furthermore, 2 cases developed in 1 year, 5 cases in 3 years and 11 cases over 3 years. The most frequent cancers developed after liver transplantation were similar to those in the general Chinese population but had much higher incidence rates. CONCLUSIONS: Liver transplant recipients were at increased risk for developing de novo cancers. The incidence rates and pattern of de novo cancers in Chinese population are different from Western people due to racial and social factors. Pre-transplant malignant condition had no relationship to de novo cancer. Exact risk factors need further studies. PMID- 24475048 TI - Observer bias: an interaction of temperament traits with biases in the semantic perception of lexical material. AB - The lexical approach is a method in differential psychology that uses people's estimations of verbal descriptors of human behavior in order to derive the structure of human individuality. The validity of the assumptions of this method about the objectivity of people's estimations is rarely questioned. Meanwhile the social nature of language and the presence of emotionality biases in cognition are well-recognized in psychology. A question remains, however, as to whether such an emotionality-capacities bias is strong enough to affect semantic perception of verbal material. For the lexical approach to be valid as a method of scientific investigations, such biases should not exist in semantic perception of the verbal material that is used by this approach. This article reports on two studies investigating differences between groups contrasted by 12 temperament traits (i.e. by energetic and other capacities, as well as emotionality) in the semantic perception of very general verbal material. Both studies contrasted the groups by a variety of capacities: endurance, lability and emotionality separately in physical, social-verbal and mental aspects of activities. Hypotheses of "background emotionality" and a "projection through capacities" were supported. Non-evaluative criteria for categorization (related to complexity, organization, stability and probability of occurrence of objects) followed the polarity of evaluative criteria, and did not show independence from this polarity. Participants with stronger physical or social endurance gave significantly more positive ratings to a variety of concepts, and participants with faster physical tempo gave more positive ratings to timing-related concepts. The results suggest that people's estimations of lexical material related to human behavior have emotionality, language- and dynamical capacities-related biases and therefore are unreliable. This questions the validity of the lexical approach as a method for the objective study of stable individual differences. PMID- 24475049 TI - istar: a web platform for large-scale protein-ligand docking. AB - Protein-ligand docking is a key computational method in the design of starting points for the drug discovery process. We are motivated by the desire to automate large-scale docking using our popular docking engine idock and thus have developed a publicly-accessible web platform called istar. Without tedious software installation, users can submit jobs using our website. Our istar website supports 1) filtering ligands by desired molecular properties and previewing the number of ligands to dock, 2) monitoring job progress in real time, and 3) visualizing ligand conformations and outputting free energy and ligand efficiency predicted by idock, binding affinity predicted by RF-Score, putative hydrogen bonds, and supplier information for easy purchase, three useful features commonly lacked on other online docking platforms like DOCK Blaster or iScreen. We have collected 17,224,424 ligands from the All Clean subset of the ZINC database, and revamped our docking engine idock to version 2.0, further improving docking speed and accuracy, and integrating RF-Score as an alternative rescoring function. To compare idock 2.0 with the state-of-the-art AutoDock Vina 1.1.2, we have carried out a rescoring benchmark and a redocking benchmark on the 2,897 and 343 protein ligand complexes of PDBbind v2012 refined set and CSAR NRC HiQ Set 24Sept2010 respectively, and an execution time benchmark on 12 diverse proteins and 3,000 ligands of different molecular weight. Results show that, under various scenarios, idock achieves comparable success rates while outperforming AutoDock Vina in terms of docking speed by at least 8.69 times and at most 37.51 times. When evaluated on the PDBbind v2012 core set, our istar platform combining with RF-Score manages to reproduce Pearson's correlation coefficient and Spearman's correlation coefficient of as high as 0.855 and 0.859 respectively between the experimental binding affinity and the predicted binding affinity of the docked conformation. istar is freely available at http://istar.cse.cuhk.edu.hk/idock. PMID- 24475050 TI - Characterization of a ginsenoside-transforming beta-glucosidase from Paenibacillus mucilaginosus and its application for enhanced production of minor ginsenoside F2. AB - A novel beta-glucosidase (BglPm) was identified from Paenibacillus mucilaginosus KCTC 3870(T) which has ginsenoside converting activity. The gene, termed bglPm, consists of 1,260 bp and belongs to glycoside hydrolase family 1 (GH1). After being overexpressed and purified from Escherichia coli, the enzymatic properties of BglPm were investigated. The enzyme exhibited an optimal activity at 45 degrees C and pH 7.5 and showed high bioconversion ability for major ginsenoside Rb1 and Rd into ginsenoside F2. Thus, it was used for mass production of relatively high pure F2 from relatively abundant protopanaxadiol type ginsenosides mixture (PPDGM) with combined usage of ginsenoside Rc-hydrolyzing enzyme. Scale-up of production using 250 g of the PPDGM resulted in 152 g of F2 with 80.1% chromatography purity and 95.7% recovery. These results suggest that this enzyme would be useful in the preparation of pharmacologically active ginsenoside F2 in the functional food and pharmaceutical industries. PMID- 24475051 TI - The 50s cliff: perceptuo-motor learning rates across the lifespan. AB - We recently found that older adults show reduced learning rates when learning a new pattern of coordinated rhythmic movement. The purpose of this study was to extend that finding by examining the performance of all ages across the lifespan from the 20 s through to the 80 s to determine how learning rates change with age. We tested whether adults could learn to produce a novel coordinated rhythmic movement (90 degrees relative phase) in a visually guided unimanual task. We determined learning rates to quantify changes in learning with age and to determine at what ages the changes occur. We found, as before, that learning rates of participants in their 70 s and 80 s were half those of participants in their 20 s. We also found a gradual slow decline in learning rate with age until approximately age 50, when there was a sudden drop to a reduced learning rate for the 60 though 80 year olds. We discuss possible causes for the "50 s cliff" in perceptuo-motor learning rates and suggest that age related deficits in perception of complex motions may be the key to understanding this result. PMID- 24475052 TI - Two distinct dynamic modes subtend the detection of unexpected sounds. AB - The brain response to auditory novelty comprises two main eeg components: an early mismatch negativity and a late P300. Whereas the former has been proposed to reflect a prediction error, the latter is often associated with working memory updating. Interestingly, these two proposals predict fundamentally different dynamics: prediction errors are thought to propagate serially through several distinct brain areas, while working memory supposes that activity is sustained over time within a stable set of brain areas. Here we test this temporal dissociation by showing how the generalization of brain activity patterns across time can characterize the dynamics of the underlying neural processes. This method is applied to magnetoencephalography (MEG) recordings acquired from healthy participants who were presented with two types of auditory novelty. Following our predictions, the results show that the mismatch evoked by a local novelty leads to the sequential recruitment of distinct and short-lived patterns of brain activity. In sharp contrast, the global novelty evoked by an unexpected sequence of five sounds elicits a sustained state of brain activity that lasts for several hundreds of milliseconds. The present results highlight how MEG combined with multivariate pattern analyses can characterize the dynamics of human cortical processes. PMID- 24475053 TI - Nasal epithelial cells can act as a physiological surrogate for paediatric asthma studies. AB - INTRODUCTION: Differentiated paediatric epithelial cells can be used to study the role of epithelial cells in asthma. Nasal epithelial cells are easier to obtain and may act as a surrogate for bronchial epithelium in asthma studies. We assessed the suitability of nasal epithelium from asthmatic children to be a surrogate for bronchial epithelium using air-liquid interface cultures. METHODS: Paired nasal and bronchial epithelial cells from asthmatic children (n = 9) were differentiated for 28 days under unstimulated and IL-13-stimulated conditions. Morphological and physiological markers were analysed using immunocytochemistry, transepithelial-electrical-resistance, Quantitative Real-time-PCR, ELISA and multiplex cytokine/chemokine analysis. RESULTS: Physiologically, nasal epithelial cells from asthmatic children exhibit similar cytokine responses to stimulation with IL-13 compared with paired bronchial epithelial cells. Morphologically however, nasal epithelial cells differed significantly from bronchial epithelial cells from asthmatic patients under unstimulated and IL-13-stimulated conditions. Nasal epithelial cells exhibited lower proliferation/differentiation rates and lower percentages of goblet and ciliated cells when unstimulated, while exhibiting a diminished and varied response to IL-13. CONCLUSIONS: We conclude that morphologically, nasal epithelial cells would not be a suitable surrogate due to a significantly lower rate of proliferation and differentiation of goblet and ciliated cells. Physiologically, nasal epithelial cells respond similarly to exogenous stimulation with IL-13 in cytokine production and could be used as a physiological surrogate in the event that bronchial epithelial cells are not available. PMID- 24475054 TI - Reliability and repeatability of quantitative tractography methods for mapping structural white matter connectivity in preterm and term infants at term equivalent age. AB - Premature infants exhibit widespread insults and delays in white matter maturation that can be sensitively detected early using diffusion tensor imaging. Diffusion tensor tractography facilitates in vivo visualization of white matter tracts and has the potential to be more sensitive than simpler two-dimensional DTI-based measures. However, the reliability and reproducibility of performing tractography for major white matter tracts in preterm infants is not known. The main objective of our study was to develop highly reliable and repeatable methods for ten white matter tracts in extremely low birth weight infants (birth weight <= 1000 g) at term-equivalent age. To demonstrate clinical utility, we also compared fiber microstructural and macrostructural parameters between preterm and healthy term controls. Twenty-nine ELBW infants and a control group of 15 healthy term newborns were studied. A team of researchers experienced in neuroanatomy/neuroimaging established the manual segmentation protocol based on a priori anatomical knowledge and an extensive training period to identify sources of variability. Intra- and inter-rater reliability and repeatability was tested using intra-class correlation coefficient, within-subject standard deviation (SD), repeatability, and Dice similarity index. Our results support our primary goal of developing highly reliable and reproducible comprehensive methods for manual segmentation of 10 white matter tracts in ELBW infants. The within-subject SD was within 1-2% and repeatability within 3-7% of the mean values for all 10 tracts. The intra-rater Dice index was excellent with a range of 0.97 to 0.99, and as expected, the inter-rater Dice index was lower (range: 0.80 to 0.91), but still within a very good reliability range. ELBW infants exhibited fewer fiber numbers and/or abnormal microstructure in a majority of the ten quantified tracts, consistent with injury/delayed development. This protocol could serve as a valuable tool for prompt evaluation of the impact of neuroprotective therapies and as a prognostic biomarker for neurodevelopmental impairments. PMID- 24475055 TI - Frequent seizures are associated with a network of gray matter atrophy in temporal lobe epilepsy with or without hippocampal sclerosis. AB - OBJECTIVE: Patients with temporal lobe epilepsy (TLE) with hippocampal sclerosis (HS) have diffuse subtle gray matter (GM) atrophy detectable by MRI quantification analyses. However, it is not clear whether the etiology and seizure frequency are associated with this atrophy. We aimed to evaluate the occurrence of GM atrophy and the influence of seizure frequency in patients with TLE and either normal MRI (TLE-NL) or MRI signs of HS (TLE-HS). METHODS: We evaluated a group of 172 consecutive patients with unilateral TLE-HS or TLE-NL as defined by hippocampal volumetry and signal quantification (122 TLE-HS and 50 TLE NL) plus a group of 82 healthy individuals. Voxel-based morphometry was performed with VBM8/SPM8 in 3T MRIs. Patients with up to three complex partial seizures and no generalized tonic-clonic seizures in the previous year were considered to have infrequent seizures. Those who did not fulfill these criteria were considered to have frequent seizures. RESULTS: Patients with TLE-HS had more pronounced GM atrophy, including the ipsilateral mesial temporal structures, temporal lobe, bilateral thalami and pre/post-central gyri. Patients with TLE-NL had more subtle GM atrophy, including the ipsilateral orbitofrontal cortex, bilateral thalami and pre/post-central gyri. Both TLE-HS and TLE-NL showed increased GM volume in the contralateral pons. TLE-HS patients with frequent seizures had more pronounced GM atrophy in extra-temporal regions than TLE-HS with infrequent seizures. Patients with TLE-NL and infrequent seizures had no detectable GM atrophy. In both TLE-HS and TLE-NL, the duration of epilepsy correlated with GM atrophy in extra hippocampal regions. CONCLUSION: Although a diffuse network GM atrophy occurs in both TLE-HS and TLE-NL, this is strikingly more evident in TLE-HS and in patients with frequent seizures. These findings suggest that neocortical atrophy in TLE is related to the ongoing seizures and epilepsy duration, while thalamic atrophy is more probably related to the original epileptogenic process. PMID- 24475056 TI - Polymer-ceramic spiral structured scaffolds for bone tissue engineering: effect of hydroxyapatite composition on human fetal osteoblasts. AB - For successful bone tissue engineering, a scaffold needs to be osteoconductive, porous, and biodegradable, thus able to support attachment and proliferation of bone cells and guide bone formation. Recently, hydroxyapatites (HA), a major inorganic component of natural bone, and biodegrade polymers have drawn much attention as bone scaffolds. The present study was designed to investigate whether the bone regenerative properties of nano-HA/polycaprolactone (PCL) spiral scaffolds are augmented in an HA dose dependent manner, thereby establishing a suitable composition as a bone formation material. Nano-HA/PCL spiral scaffolds were prepared with different weight ratios of HA and PCL, while porosity was introduced by a modified salt leaching technique. Human fetal osteoblasts (hFOBs) were cultured on the nano-HA/PCL spiral scaffolds up to 14 days. Cellular responses in terms of cell adhesion, viability, proliferation, differentiation, and the expression of bone-related genes were investigated. These scaffolds supported hFOBs adhesion, viability and proliferation. Cell proliferation trend was quite similar on polymer-ceramic and neat polymer spiral scaffolds on days 1, 7, and 14. However, the significantly increased amount of alkaline phosphatase (ALP) activity and mineralized matrix synthesis was evident on the nano-HA/PCL spiral scaffolds. The HA composition in the scaffolds showed a significant effect on ALP and mineralization. Bone phenotypic markers such as bone sialoprotein (BSP), osteonectin (ON), osteocalcin (OC), and type I collagen (Col-1) were semi quantitatively estimated by reverse transcriptase polymerase chain reaction analysis. All of these results suggested the osteoconductive characteristics of HA/PCL nanocomposite and cell maturation were HA dose dependent. For instance, HA?PCL = 1?4 group showed significantly higher ALP mineralization and elevated levels of BSP, ON, OC and Col-I expression as compared other lower or higher ceramic ratios. Amongst the different nano-HA/PCL spiral scaffolds, the 1?4 weight ratio of HA and PCL is shown to be the most optimal composition for bone tissue regeneration. PMID- 24475057 TI - HTSstation: a web application and open-access libraries for high-throughput sequencing data analysis. AB - The HTSstation analysis portal is a suite of simple web forms coupled to modular analysis pipelines for various applications of High-Throughput Sequencing including ChIP-seq, RNA-seq, 4C-seq and re-sequencing. HTSstation offers biologists the possibility to rapidly investigate their HTS data using an intuitive web application with heuristically pre-defined parameters. A number of open-source software components have been implemented and can be used to build, configure and run HTS analysis pipelines reactively. Besides, our programming framework empowers developers with the possibility to design their own workflows and integrate additional third-party software. The HTSstation web application is accessible at http://htsstation.epfl.ch. PMID- 24475058 TI - Temporal reliability and lateralization of the resting-state language network. AB - The neural processing loop of language is complex but highly associated with Broca's and Wernicke's areas. The left dominance of these two areas was the earliest observation of brain asymmetry. It was demonstrated that the language network and its functional asymmetry during resting state were reproducible across institutions. However, the temporal reliability of resting-state language network and its functional asymmetry are still short of knowledge. In this study, we established a seed-based resting-state functional connectivity analysis of language network with seed regions located at Broca's and Wernicke's areas, and investigated temporal reliability of language network and its functional asymmetry. The language network was found to be temporally reliable in both short and long-term. In the aspect of functional asymmetry, the Broca's area was found to be left lateralized, while the Wernicke's area is mainly right lateralized. Functional asymmetry of these two areas revealed high short- and long-term reliability as well. In addition, the impact of global signal regression (GSR) on reliability of the resting-state language network was investigated, and our results demonstrated that GSR had negligible effect on the temporal reliability of the resting-state language network. Our study provided methodology basis for future cross-culture and clinical researches of resting-state language network and suggested priority of adopting seed-based functional connectivity for its high reliability. PMID- 24475059 TI - Central canal ependymal cells proliferate extensively in response to traumatic spinal cord injury but not demyelinating lesions. AB - The adult mammalian spinal cord has limited regenerative capacity in settings such as spinal cord injury (SCI) and multiple sclerosis (MS). Recent studies have revealed that ependymal cells lining the central canal possess latent neural stem cell potential, undergoing proliferation and multi-lineage differentiation following experimental SCI. To determine whether reactive ependymal cells are a realistic endogenous cell population to target in order to promote spinal cord repair, we assessed the spatiotemporal dynamics of ependymal cell proliferation for up to 35 days in three models of spinal pathologies: contusion SCI using the Infinite Horizon impactor, focal demyelination by intraspinal injection of lysophosphatidylcholine (LPC), and autoimmune-mediated multi-focal demyelination using the active experimental autoimmune encephalomyelitis (EAE) model of MS. Contusion SCI at the T9-10 thoracic level stimulated a robust, long-lasting and long-distance wave of ependymal proliferation that peaked at 3 days in the lesion segment, 14 days in the rostral segment, and was still detectable at the cervical level, where it peaked at 21 days. This proliferative wave was suppressed distal to the contusion. Unlike SCI, neither chemical- nor autoimmune-mediated demyelination triggered ependymal cell proliferation at any time point, despite the occurrence of demyelination (LPC and EAE), remyelination (LPC) and significant locomotor defects (EAE). Thus, traumatic SCI induces widespread and enduring activation of reactive ependymal cells, identifying them as a robust cell population to target for therapeutic manipulation after contusion; conversely, neither demyelination, remyelination nor autoimmunity appears sufficient to trigger proliferation of quiescent ependymal cells in models of MS like demyelinating diseases. PMID- 24475060 TI - The real world mental health needs of heart failure patients are not reflected by the depression randomized controlled trial evidence. AB - INTRODUCTION: International depression screening guidelines in heart failure (HF) are partly based on depression treatment efficacy from randomized controlled trials (RCTs). Our aim was to test the external validity of depression RCT criteria in a sample of real-world HF patients. METHODS: HF patients admitted to 3 hospitals in South Australia were referred to a HF psychologist if not already receiving current psychiatric management by psychologist or psychiatrist elsewhere. Screening and referral protocol consisted of the following; (a). Patient Health Questionnaire >= 10; (b). Generalized Anxiety Disorder Questionnaire >= 7); (c). positive response to 1 item panic attack screener; (d). evidence of suicidality. Patients were evaluated against the most common RCT exclusion criteria personality disorder, high suicide risk, cognitive impairment, psychosis, alcohol or substance abuse or dependency, bi-polar depression. RESULTS: Total 81 HF patients were referred from 404 HF admissions, and 73 were assessed (age 60.6 +/- 13.4, 47.9% female). Nearly half (47%) met at least 1 RCT exclusion criterion, most commonly personality disorder (28.5%), alcohol/substance abuse (17.8%) and high suicide risk (11.0%). RCT ineligibility criteria was more frequent among patients with major depression (76.5% vs. 46.2%, p<.01) and dysthymia (26.5% vs. 7.7%, p = .03) but not significantly associated with anxiety disorders. RCT ineligible patients reported greater severity of depression (M = 16.6 +/- 5.0 vs. M = 12.9 +/- 7.2, p = .02) and were higher consumers of HF psychotherapy services (M = 11.5 +/- 4.7 vs. M = 8.5 +/- 4.8, p = .01). CONCLUSION: In this real-world sample comparable in size to recent RCT intervention arms, patients with depression disorders presented with complex psychiatric needs including comorbid personality disorders, alcohol/substance use and suicide risk. These findings suggest external validity of depression screening and RCTs could serve as a basis for level A guideline recommendations in cardiovascular diseases. PMID- 24475061 TI - Plasma homocysteine is associated with aortic arterial stiffness but not wave reflection in Chinese hypertensive subjects. AB - OBJECTIVE: Elevated plasma total homocysteine (tHcy) acts synergistically with hypertension to exert a multiplicative effect on cardiovascular diseases risk. The aim of this study was to determine the relationship between tHcy concentration and blood pressure, and to evaluate the role of plasma tHcy in arterial stiffness and wave reflection in hypertension. METHODS: In this cross sectional study, a community-based sample of 1680 subjects (mean age 61.6 years) was classified into four groups according to tHcy level (<21.6 vs. >= 21.6 umol/l) and blood pressure (hypertensive vs. normotensive). Levels of plasma tHcy and other biochemical parameters (e.g., lipids, glucose) were determined. Central arterial blood pressure, reflected pressure wave, and carotid-femoral pulse wave velocity (cf-PWV) were assessed by tonometry within 2 days of obtaining the blood specimen. RESULTS: Neither peripheral nor central blood pressure differed according to tHcy levels in normotensive and hypertensive subjects. Differences in cf-PWV according to tHcy were observed only in hypertensive subjects; differences in cf-PWV in normotensive subjects were not significant after adjusting for confounding factors. Central augmentation index did not differ according to tHcy level in either normotensive or hypertensive subjects. Results of univariate analysis revealed significant correlations between blood pressure parameters and tHcy concentration only among normotensive subjects; however, these correlations were not significant in a partial correlation analysis. Results of multiple regression analysis showed that plasma tHcy levels were independently correlated with cf-PWV in hypertensive subjects (beta = 0.713, P = 0.004). The independent relationship between tHcy and central augmentation index was not significant by further multiple analyses in normotensive or hypertensive individuals. CONCLUSIONS: Plasma tHcy level is strongly and independently correlated with arterial stiffness measured as cf-PWV only in hypertensive subjects. Thus, hypertension is a major link between tHcy and aortic arterial stiffness. PMID- 24475062 TI - Expression and properties of the highly alkalophilic phenylalanine ammonia-lyase of thermophilic Rubrobacter xylanophilus. AB - The sequence of a phenylalanine ammonia-lyase (PAL; EC: 4.3.1.24) of the thermophilic and radiotolerant bacterium Rubrobacter xylanophilus (RxPAL) was identified by screening the genomes of bacteria for members of the phenylalanine ammonia-lyase family. A synthetic gene encoding the RxPAL protein was cloned and overexpressed in Escherichia coli TOP 10 in a soluble form with an N-terminal His6-tag and the recombinant RxPAL protein was purified by Ni-NTA affinity chromatography. The activity assay of RxPAL with l-phenylalanine at various pH values exhibited a local maximum at pH 8.5 and a global maximum at pH 11.5. Circular dichroism (CD) studies showed that RxPAL is associated with an extensive alpha-helical character (far UV CD) and two distinctive near-UV CD peaks. These structural characteristics were well preserved up to pH 11.0. The extremely high pH optimum of RxPAL can be rationalized by a three-dimensional homology model indicating possible disulfide bridges, extensive salt-bridge formation and an excess of negative electrostatic potential on the surface. Due to these properties, RxPAL may be a candidate as biocatalyst in synthetic biotransformations leading to unnatural l- or d-amino acids or as therapeutic enzyme in treatment of phenylketonuria or leukemia. PMID- 24475063 TI - In vivo Pyro-SIP assessing active gut microbiota of the cotton leafworm, Spodoptera littoralis. AB - The gut microbiota is of crucial importance for the host with considerable metabolic activity. Although great efforts have been made toward characterizing microbial diversity, measuring components' metabolic activity surprisingly hasn't kept pace. Here we combined pyrosequencing of amplified 16S rRNA genes with in vivo stable isotope probing (Pyro-SIP) to unmask metabolically active bacteria in the gut of cotton leafworm (Spodoptera littoralis), a polyphagous insect herbivore that consumes large amounts of plant material in a short time, liberating abundant glucose in the alimentary canal as a most important carbon and energy source for both host and active gut bacteria. With (13)C glucose as the trophic link, Pyro-SIP revealed that a relatively simple but distinctive gut microbiota co-developed with the host, both metabolic activity and composition shifting throughout larval stages. Pantoea, Citrobacter and Clostridium were particularly active in early-instar, likely the core functional populations linked to nutritional upgrading. Enterococcus was the single predominant genus in the community, and it was essentially stable and metabolically active in the larval lifespan. Based on that Enterococci formed biofilm-like layers on the gut epithelium and that the isolated strains showed antimicrobial properties, Enterococcus may be able to establish a colonization resistance effect in the gut against potentially harmful microbes from outside. Not only does this establish the first in-depth inventory of the gut microbiota of a model organism from the mostly phytophagous Lepidoptera, but this pilot study shows that Pyro-SIP can rapidly gain insight into the gut microbiota's metabolic activity with high resolution and high precision. PMID- 24475064 TI - Computer-assisted interpretation of the EEG background pattern: a clinical evaluation. AB - OBJECTIVE: Interpretation of the EEG background pattern in routine recordings is an important part of clinical reviews. We evaluated the feasibility of an automated analysis system to assist reviewers with evaluation of the general properties in the EEG background pattern. METHODS: Quantitative eeg methods were used to describe the following five background properties: posterior dominant rhythm frequency and reactivity, anterior-posterior gradients, presence of diffuse slow-wave activity and asymmetry. Software running the quantitative methods were given to ten experienced electroencephalographers together with 45 routine EEG recordings and computer-generated reports. Participants were asked to review the EEGs by visual analysis first, and afterwards to compare their findings with the generated reports and correct mistakes made by the system. Corrected reports were returned for comparison. RESULTS: Using a gold-standard derived from the consensus of reviewers, inter-rater agreement was calculated for all reviewers and for automated interpretation. Automated interpretation together with most participants showed high (kappa > 0.6) agreement with the gold standard. In some cases, automated analysis showed higher agreement with the gold standard than participants. When asked in a questionnaire after the study, all participants considered computer-assisted interpretation to be useful for every day use in routine reviews. CONCLUSIONS: Automated interpretation methods proved to be accurate and were considered to be useful by all participants. SIGNIFICANCE: Computer-assisted interpretation of the EEG background pattern can bring consistency to reviewing and improve efficiency and inter-rater agreement. PMID- 24475065 TI - Novel giant siphovirus from Bacillus anthracis features unusual genome characteristics. AB - Here we present vB_BanS-Tsamsa, a novel temperate phage isolated from Bacillus anthracis, the agent responsible for anthrax infections in wildlife, livestock and humans. Tsamsa phage is a giant siphovirus (order Caudovirales), featuring a long, flexible and non-contractile tail of 440 nm (not including baseplate structure) and an isometric head of 82 nm in diameter. We induced Tsamsa phage in samples from two different carcass sites in Etosha National Park, Namibia. The Tsamsa phage genome is the largest sequenced Bacillus siphovirus, containing 168,876 bp and 272 ORFs. The genome features an integrase/recombinase enzyme, indicative of a temperate lifestyle. Among bacterial strains tested, the phage infected only certain members of the Bacillus cereus sensu lato group (B. anthracis, B. cereus and B. thuringiensis) and exhibited moderate specificity for B. anthracis. Tsamsa lysed seven out of 25 B. cereus strains, two out of five B. thuringiensis strains and six out of seven B. anthracis strains tested. It did not lyse B. anthracis PAK-1, an atypical strain that is also resistant to both gamma phage and cherry phage. The Tsamsa endolysin features a broader lytic spectrum than the phage host range, indicating possible use of the enzyme in Bacillus biocontrol. PMID- 24475066 TI - Linking geology and microbiology: inactive pockmarks affect sediment microbial community structure. AB - Pockmarks are geological features that are found on the bottom of lakes and oceans all over the globe. Some are active, seeping oil or methane, while others are inactive. Active pockmarks are well studied since they harbor specialized microbial communities that proliferate on the seeping compounds. Such communities are not found in inactive pockmarks. Interestingly, inactive pockmarks are known to have different macrofaunal communities compared to the surrounding sediments. It is undetermined what the microbial composition of inactive pockmarks is and if it shows a similar pattern as the macrofauna. The Norwegian Oslofjord contains many inactive pockmarks and they are well suited to study the influence of these geological features on the microbial community in the sediment. Here we present a detailed analysis of the microbial communities found in three inactive pockmarks and two control samples at two core depth intervals. The communities were analyzed using high-throughput amplicon sequencing of the 16S rRNA V3 region. Microbial communities of surface pockmark sediments were indistinguishable from communities found in the surrounding seabed. In contrast, pockmark communities at 40 cm sediment depth had a significantly different community structure from normal sediments at the same depth. Statistical analysis of chemical variables indicated significant differences in the concentrations of total carbon and non particulate organic carbon between 40 cm pockmarks and reference sample sediments. We discuss these results in comparison with the taxonomic classification of the OTUs identified in our samples. Our results indicate that microbial communities at the sediment surface are affected by the water column, while the deeper (40 cm) sediment communities are affected by local conditions within the sediment. PMID- 24475067 TI - Differences in oral sexual behaviors by gender, age, and race explain observed differences in prevalence of oral human papillomavirus infection. AB - PURPOSE: This study explores whether gender, age and race differences in oral sexual behavior account for the demographic distribution of oral human papillomavirus infection (HPV) and HPV-positive oropharyngeal cancer (HPV-OSCC). METHODS: This analysis included 2,116 men and 2,140 women from NHANES (2009-10) who answered a behavioral questionnaire and provided an oral-rinse sample for HPV detection. Weighted prevalence estimates and prevalence ratios (PR) were calculated for sexual behaviors and oral HPV infection by gender, age-cohort (20 29, 30-44, 45-59, 60-69), and race, and contrasted with incidence rate ratios (IRR) of OSCC from SEER 2009. Multivariate logistic regression was used to evaluate predictors of oral sexual behavior and oral HPV16 infection. RESULTS: Differences in oral sexual behavior were observed by gender, age-cohort and race. Most men (85.4%) and women (83.2%) had ever performed oral sex, but men had more lifetime oral and vaginal sexual partners and higher oral HPV16 prevalence than women (each p<0.001). 60-69 year olds (yo) were less likely than 45-59 or 30-44 (yo) to have performed oral sex (72.7%, 84.8%, and 90.3%, p<0.001), although oral HPV16 prevalence was similar. Prevalence ratios (PR) of ever oral sex in men vs. women (PR = 1.03), and 45-59 vs. 30-44 year-old men (PR = 0.96) were modest relative to ratios for oral HPV16 infection (PRs = 1.3-6.8) and OSCC (IRR = 4.7 8.1). In multivariate analysis, gender, age-cohort, and race were significant predictors of oral sexual behavior. Oral sexual behavior was the primary predictor of oral HPV16 infection; once this behavior was adjusted for, age cohort and race were no longer associated with oral HPV16. CONCLUSION: There are differences in oral sexual behaviors when considering gender, age-cohort and race which explain observed epidemiologic differences in oral HPV16 infection across these groups. PMID- 24475068 TI - CASME II: an improved spontaneous micro-expression database and the baseline evaluation. AB - A robust automatic micro-expression recognition system would have broad applications in national safety, police interrogation, and clinical diagnosis. Developing such a system requires high quality databases with sufficient training samples which are currently not available. We reviewed the previously developed micro-expression databases and built an improved one (CASME II), with higher temporal resolution (200 fps) and spatial resolution (about 280*340 pixels on facial area). We elicited participants' facial expressions in a well-controlled laboratory environment and proper illumination (such as removing light flickering). Among nearly 3000 facial movements, 247 micro-expressions were selected for the database with action units (AUs) and emotions labeled. For baseline evaluation, LBP-TOP and SVM were employed respectively for feature extraction and classifier with the leave-one-subject-out cross-validation method. The best performance is 63.41% for 5-class classification. PMID- 24475069 TI - A new exhaustive method and strategy for finding motifs in ChIP-enriched regions. AB - ChIP-seq, which combines chromatin immunoprecipitation (ChIP) with next generation parallel sequencing, allows for the genome-wide identification of protein-DNA interactions. This technology poses new challenges for the development of novel motif-finding algorithms and methods for determining exact protein-DNA binding sites from ChIP-enriched sequencing data. State-of-the-art heuristic, exhaustive search algorithms have limited application for the identification of short (l, d) motifs (l <= 10, d <= 2) contained in ChIP enriched regions. In this work we have developed a more powerful exhaustive method (FMotif) for finding long (l, d) motifs in DNA sequences. In conjunction with our method, we have adopted a simple ChIP-enriched sampling strategy for finding these motifs in large-scale ChIP-enriched regions. Empirical studies on synthetic samples and applications using several ChIP data sets including 16 TF (transcription factor) ChIP-seq data sets and five TF ChIP-exo data sets have demonstrated that our proposed method is capable of finding these motifs with high efficiency and accuracy. The source code for FMotif is available at http://211.71.76.45/FMotif/. PMID- 24475070 TI - Mining gene expression data for pollutants (dioxin, toluene, formaldehyde) and low dose of gamma-irradiation. AB - General and specific effects of molecular genetic responses to adverse environmental factors are not well understood. This study examines genome-wide gene expression profiles of Drosophila melanogaster in response to ionizing radiation, formaldehyde, toluene, and 2,3,7,8-tetrachlorodibenzo-p-dioxin. We performed RNA-seq analysis on 25,415 transcripts to measure the change in gene expression in males and females separately. An analysis of the genes unique to each treatment yielded a list of genes as a gene expression signature. In the case of radiation exposure, both sexes exhibited a reproducible increase in their expression of the transcription factors sugarbabe and tramtrack. The influence of dioxin up-regulated metabolic genes, such as anachronism, CG16727, and several genes with unknown function. Toluene activated a gene involved in the response to the toxins, Cyp12d1-p; the transcription factor Fer3's gene; the metabolic genes CG2065, CG30427, and CG34447; and the genes Spn28Da and Spn3, which are responsible for reproduction and immunity. All significantly differentially expressed genes, including those shared among the stressors, can be divided into gene groups using Gene Ontology Biological Process identifiers. These gene groups are related to defense response, biological regulation, the cell cycle, metabolic process, and circadian rhythms. KEGG molecular pathway analysis revealed alteration of the Notch signaling pathway, TGF-beta signaling pathway, proteasome, basal transcription factors, nucleotide excision repair, Jak-STAT signaling pathway, circadian rhythm, Hippo signaling pathway, mTOR signaling pathway, ribosome, mismatch repair, RNA polymerase, mRNA surveillance pathway, Hedgehog signaling pathway, and DNA replication genes. Females and, to a lesser extent, males actively metabolize xenobiotics by the action of cytochrome P450 when under the influence of dioxin and toluene. Finally, in this work we obtained gene expression signatures pollutants (dioxin, toluene), low dose of gamma irradiation and common molecular pathways for different kind of stressors. PMID- 24475072 TI - The effects of feeding unpredictability and classical conditioning on pre-release training of white-lipped peccary (Mammalia, Tayassuidae). AB - Some authors have suggested that environmental unpredictability, accompanied by some sort of signal for behavioral conditioning, can boost activity or foster exploratory behavior, which may increase post-release success in re-introduction programs. Thus, using white-lipped peccary (Tayassu pecari), a vulnerable Neotropical species, as a model, we evaluated an unpredictable feeding schedule. Associating this with the effect of classical conditioning on behavioral activities, we assessed the inclusion of this approach in pre-release training protocols. The experimental design comprised predictable feeding phases (control phases: C1, C2 and C3) and unpredictable feeding phases (U1- signaled and U2- non signaled). The animals explored more during the signaled and non-signaled unpredictable phases and during the second control phase (C2) than during the other two predictable phases (C1 and C3). The peccaries also spent less time feeding during the signaled unpredictable phase (U1) and the following control phase (C2) than during the other phases. Moreover, they spent more time in aggressive encounters during U1 than the other experimental phases. However, the animals did not show differences in the time they spent on affiliative interactions or in the body weight change during the different phases. The signaled unpredictability, besides improving foraging behavior, showing a prolonged effect on the next control phase (C2), also increased the competition for food. The signaled feeding unpredictability schedule, mimicking wild conditions by eliciting the expression of naturalistic behaviors in pre-release training, may be essential to fully prepare them for survival in the wild. PMID- 24475071 TI - Characterization of glycolytic enzymes--rAldolase and rEnolase of Leishmania donovani, identified as Th1 stimulatory proteins, for their immunogenicity and immunoprophylactic efficacies against experimental visceral leishmaniasis. AB - Th1 immune responses play an important role in controlling Visceral Leishmaniasis (VL) hence, Leishmania proteins stimulating T-cell responses in host, are thought to be good vaccine targets. Search of such antigens eliciting cellular responses in Peripheral blood mononuclear cells (PBMCs) from cured/exposed/Leishmania patients and hamsters led to the identification of two enzymes of glycolytic pathway in the soluble lysate of a clinical isolate of Leishmania donovani- Enolase (LdEno) and aldolase (LdAld) as potential Th1 stimulatory proteins. The present study deals with the molecular and immunological characterizations of LdEno and LdAld. The successfully cloned and purified recombinant proteins displayed strong ability to proliferate lymphocytes of cured hamsters' along with significant nitric-oxide production and generation of Th1-type cytokines (IFN gamma and IL-12) from stimulated PBMCs of cured/endemic VL patients. Assessment of their prophylactic potentials revealed ~ 90% decrease in parasitic burden in rLdEno vaccinated hamsters against Leishmania challenge, strongly supported by an increase in mRNA expression levels of iNOS, IFN-gamma, TNF-alpha and IL-12 transcripts along with extreme down-regulation of TGF-beta, IL-4 and IL-10. However, animals vaccinated with rLdAld showed comparatively lesser prophylactic efficacy (~ 65%) with inferior immunological response. Further, with a possible implication in vaccine design against VL, identification of potential T-cell epitopes of both the proteins was done using computational approach. Additionally, in-silico 3-D modelling of the proteins was done in order to explore the possibility of exploiting them as potential drug targets. The comparative molecular and immunological characterizations strongly suggest rLdEno as potential vaccine candidate against VL and supports the notion of its being effective T-cell stimulatory protein. PMID- 24475073 TI - We'll meet again: revealing distributional and temporal patterns of social contact. AB - What are the dynamics and regularities underlying social contact, and how can contact with the people in one's social network be predicted? In order to characterize distributional and temporal patterns underlying contact probability, we asked 40 participants to keep a diary of their social contacts for 100 consecutive days. Using a memory framework previously used to study environmental regularities, we predicted that the probability of future contact would follow in systematic ways from the frequency, recency, and spacing of previous contact. The distribution of contact probability across the members of a person's social network was highly skewed, following an exponential function. As predicted, it emerged that future contact scaled linearly with frequency of past contact, proportionally to a power function with recency of past contact, and differentially according to the spacing of past contact. These relations emerged across different contact media and irrespective of whether the participant initiated or received contact. We discuss how the identification of these regularities might inspire more realistic analyses of behavior in social networks (e.g., attitude formation, cooperation). PMID- 24475074 TI - Encoding asymmetry of the N-glycosylation motif facilitates glycoprotein evolution. AB - Protein N-glycosylation is found in all domains of life and has a conserved role in glycoprotein folding and stability. In animals, glycoproteins transit through the Golgi where the N-glycans are trimmed and rebuilt with sequences that bind lectins, an innovation that greatly increases structural diversity and redundancy of glycoprotein-lectin interaction at the cell surface. Here we ask whether the natural tension between increasing diversity (glycan-protein interactions) and site multiplicity (backup and status quo) might be revealed by a phylogenic examination of glycoproteins and NXS/T(X ? P) N-glycosylation sites. Site loss is more likely by mutation at Asn encoded by two adenosine (A)-rich codons, while site gain is more probable by generating Ser or Thr downstream of an existing Asn. Thus mutations produce sites at novel positions more frequently than the reversal of recently lost sites, and therefore more paths though sequence space are made available to natural selection. An intra-species comparison of secretory and cytosolic proteins revealed a departure from equilibrium in sequences one mutation-away from NXS/T and in (A) content, indicating strong selective pressures and exploration of N-glycosylation positions during vertebrate evolution. Furthermore, secretory proteins have evolved at rates proportional to N-glycosylation site number, indicating adaptive interactions between the N glycans and underlying protein. Given the topology of the genetic code, mutation of (A) is more often nonsynonomous, and Lys, another target of many PTMs, is also encoded by two (A)-rich codons. An examination of acetyl-Lys sites in proteins indicated similar evolutionary dynamics, consistent with asymmetry of the target and recognition portions of modified sites. Our results suggest that encoding asymmetry is an ancient mechanism of evolvability that increases diversity and experimentation with PTM site positions. Strong selective pressures on PTMs may have contributed to the A+T -> G+C shift in genome-wide nucleotide composition during metazoan radiation. PMID- 24475075 TI - CpG island methylator phenotype, Helicobacter pylori, Epstein-Barr virus, and microsatellite instability and prognosis in gastric cancer: a systematic review and meta-analysis. AB - BACKGROUND: The controversy of CpG island methylator phenotype (CIMP) in gastric cancer persists, despite the fact that many studies have been conducted on its relation with helicobacter pylori (H. pylori), Epstein-Barr virus (EBV), and microsatellite instability (MSI) and prognosis. To drive a more precise estimate of this postulated relationship, a meta-analysis was performed based on existing relevant studies. METHODS: We combined individual patient data from 12 studies which involved 1000 patients with gastric cancer, which met the criteria. We tabulated and analyzed parameters from each study, including H. pylori, EBV, MSI, and clinical information of patients. RESULTS: The overall OR for H. pylori infection in CIMP positive group vs. negative group revealed that significantly elevated risks of positive H. pylori infection in the former were achieved (OR 2.23 95% CI, 1.25-4.00; P = 0.007, Pheterogeneity = 0.05). Similarly, strong relation between EBV infection and CIMP was achieved by OR 51.27 (95% CI, 9.39 279.86; P<0.00001, Pheterogeneity = 0.39). The overall OR for MSI in CIMP positive group vs. negative group was 4.44 (95% CI, 1.17-16.88; P = 0.03, Pheterogeneity = 0.01). However, there did not appear to be any correlations with clinical parameters such as tumor site, pathological type, cell differentiation, TNM stage, distant metastasis, lymph node metastasis, and 5-year survival. CONCLUSIONS: The meta-analysis highlights the strong relation of CIMP with H. pylori, EBV, and MSI, but CIMP can not be used as a prognostic marker for gastric cancer. PMID- 24475076 TI - Characterization of interstitial Cajal progenitors cells and their changes in Hirschsprung's disease. AB - Interstitial cells of Cajal (ICC) are critical to gastrointestinal motility. The phenotypes of ICC progenitors have been observed in the mouse gut, but whether they exist in the human colon and what abnormal changes in their quantity and ultrastructure are present in Hirschsprung's disease (HSCR) colon remains uncertain. In this study, we collected the surgical resection of colons, both proximal and narrow segments, from HSCR patients and normal controls. First, we identified the progenitor of ICC in normal adult colon using immunofluorescent localization techniques with laser confocal microscopy. Next, the progenitors were sorted to observe their morphology. We further applied flow cytometry to examine the content of ICC progenitors in these fresh samples. The ultrastructural changes in the narrow and proximal parts of the HSCR colon were observed using transmission electron microscopy (TEM) and were compared with the normal adult colon. The presumed early progenitor (c-Kit(low)CD34(+)Igf1r(+)) and committed progenitor (c-Kit(+)CD34(+)Igf1r(+)) of ICC exist in adult normal colon as well as in the narrow and proximal parts of the HSCR colon. However, the proportions of mature, early and committed progenitors of ICC were dramatically reduced in the narrow segment of the HSCR colon. The proportions of mature and committed progenitors of ICC in the proximal segment of the HSCR colon were lower than in the adult normal colon. Ultrastructurally, ICC, enteric nerves, and smooth muscle in the narrow segment of the HSCR colon showed severe injury, including swollen vacuola or ted mitochondria, disappearance of mitochondrial cristae, dilated rough endoplasmic reticulum, vesiculation and degranulation, and disappearance of the caveolae on the ICC membrane surface. The contents of ICC and its progenitors in the narrow part of the HSCR colon were significantly decreased than those of adult colon, which may be associated with HSCR pathogenesis. PMID- 24475077 TI - Flos Lonicera ameliorates obesity and associated endotoxemia in rats through modulation of gut permeability and intestinal microbiota. AB - BACKGROUND AND AIM: Increasing evidence has indicated a close association of host gut flora metabolic interaction with obesity. Flos Lonicera, a traditional herbal medicine, is used widely in eastern Asia for the treatment of various disorders. The aim of this study was to evaluate whether unfermented or fermented formulations of Flos Lonicera could exert a beneficial impact to combat obesity and related metabolic endotoxemia. METHODS: Obesity and metabolic endotoxemia were induced separately or together in rats through feeding a eight-week high fat diet either alone (HFD control group) or in combination with a single LPS stimulation (intraperitoneal injection, 0.75 mg/kg) (LPS control group). While, the mechanism of action of the Lonicera formulations was explored in vitro using RAW 264.7 and HCT 116 cell lines as models. RESULTS: In cell-based studies, treatment with both unfermented Flos Lonicera (UFL) and fermented Flos Lonicera (FFL) formulations resulted in suppression of LPS-induced NO production and gene expression of vital proinflammatory cytokines (TNF-alpha, COX-2, and IL-6) in RAW 264.7 cells, reduced the gene expression of zonula occludens (ZO)-1 and claudin 1, and normalized trans epithelial electric resistance (TEER) and horseradish peroxidase (HRP) flux in LPS-treated HCT-116 cells. In an animal study, treatment of HFD as well as HFD+LPS groups with UFL or FFL resulted in a notable decrease in body and adipose tissue weights, ameliorated total cholesterol, HDL, triglyceride, aspartate transaminase and endotoxin levels in serum, reduced the urinary lactulose/mannitol ratio, and markedly alleviated lipid accumulation in liver. In addition, exposure of HFD as well as HFD+LPS groups with UFL or FFL resulted in significant alteration of the distribution of intestinal flora, especially affecting the population of Akkermansia spp. and ratio of Bacteroidetes and Firmicutes. CONCLUSION: This evidence collectively demonstrates that Flos Lonicera ameliorates obesity and related metabolic endotoxemia via regulating distribution of gut flora and gut permeability. PMID- 24475079 TI - Evaluation of a virucidal quantitative carrier test for surface disinfectants. AB - Surface disinfectants are part of broader preventive strategies preventing the transmission of bacteria, fungi and viruses in medical institutions. To evaluate their virucidal efficacy, these products must be tested with appropriate model viruses with different physico-chemical properties under conditions representing practical application in hospitals. The aim of this study was to evaluate a quantitative carrier assay. Furthermore, different putative model viruses like adenovirus type 5 (AdV-5) and different animal parvoviruses were evaluated with respect to their tenacity and practicability in laboratory handling. To evaluate the robustness of the method, some of the viruses were tested in parallel in different laboratories in a multi-center study. Different biocides, which are common active ingredients of surface disinfectants, were used in the test. After drying on stainless steel discs as the carrier, model viruses were exposed to different concentrations of three alcohols, peracetic acid (PAA) or glutaraldehyde (GDA), with a fixed exposure time of 5 minutes. Residual virus was determined after treatment by endpoint titration. All parvoviruses exhibited a similar stability with respect to GDA, while AdV-5 was more susceptible. For PAA, the porcine parvovirus was more sensitive than the other parvoviruses, and again, AdV-5 presented a higher susceptibility than the parvoviruses. All parvoviruses were resistant to alcohols, while AdV-5 was only stable when treated with 2 propanol. The analysis of the results of the multi-center study showed a high reproducibility of this test system. In conclusion, two viruses with different physico-chemical properties can be recommended as appropriate model viruses for the evaluation of the virucidal efficacy of surface disinfectants: AdV-5, which has a high clinical impact, and murine parvovirus (MVM) with the highest practicability among the parvoviruses tested. PMID- 24475078 TI - Structural integrity of the contralesional hemisphere predicts cognitive impairment in ischemic stroke at three months. AB - After stroke, white matter integrity can be affected both locally and distally to the primary lesion location. It has been shown that tract disruption in mirror's regions of the contralateral hemisphere is associated with degree of functional impairment. Fourteen patients suffering right hemispheric focal stroke (S) and eighteen healthy controls (HC) underwent Diffusion Weighted Imaging (DWI) and neuropsychological assessment. The stroke patient group was divided into poor (SP; n = 8) and good (SG; n = 6) cognitive recovery groups according to their cognitive improvement from the acute phase (72 hours after stroke) to the subacute phase (3 months post-stroke). Whole-brain DWI data analysis was performed by computing Diffusion Tensor Imaging (DTI) followed by Tract Based Spatial Statistics (TBSS). Assessment of effects was obtained computing the correlation of the projections on TBSS skeleton of Fractional Anisotropy (FA) and Radial Diffusivity (RD) with cognitive test results. Significant decrease of FA was found only in right brain anatomical areas for the S group when compared to the HC group. Analyzed separately, stroke patients with poor cognitive recovery showed additional significant FA decrease in several left hemisphere regions; whereas SG patients showed significant decrease only in the left genu of corpus callosum when compared to the HC. For the SG group, whole brain analysis revealed significant correlation between the performance in the Semantic Fluency test and the FA in the right hemisphere as well as between the performance in the Grooved Pegboard Test (GPT) and the Trail Making Test-part A and the FA in the left hemisphere. For the SP group, correlation analysis revealed significant correlation between the performance in the GPT and the FA in the right hemisphere. PMID- 24475080 TI - Tetrahedral gray code for visualization of genome information. AB - We propose a tetrahedral Gray code that facilitates visualization of genome information on the surfaces of a tetrahedron, where the relative abundance of each [Formula: see text]-mer in the genomic sequence is represented by a color of the corresponding cell of a triangular lattice. For biological significance, the code is designed such that the [Formula: see text]-mers corresponding to any adjacent pair of cells differ from each other by only one nucleotide. We present a simple procedure to draw such a pattern on the development surfaces of a tetrahedron. The thus constructed tetrahedral Gray code can demonstrate evolutionary conservation and variation of the genome information of many organisms at a glance. We also apply the tetrahedral Gray code to the honey bee (Apis mellifera) genome to analyze its methylation structure. The results indicate that the honey bee genome exhibits CpG overrepresentation in spite of its methylation ability and that two conserved motifs, CTCGAG and CGCGCG, in the unmethylated regions are responsible for the overrepresentation of CpG. PMID- 24475081 TI - Can retinal ganglion cell dipoles seed iso-orientation domains in the visual cortex? AB - It has been argued that the emergence of roughly periodic orientation preference maps (OPMs) in the primary visual cortex (V1) of carnivores and primates can be explained by a so-called statistical connectivity model. This model assumes that input to V1 neurons is dominated by feed-forward projections originating from a small set of retinal ganglion cells (RGCs). The typical spacing between adjacent cortical orientation columns preferring the same orientation then arises via Moire-Interference between hexagonal ON/OFF RGC mosaics. While this Moire Interference critically depends on long-range hexagonal order within the RGC mosaics, a recent statistical analysis of RGC receptive field positions found no evidence for such long-range positional order. Hexagonal order may be only one of several ways to obtain spatially repetitive OPMs in the statistical connectivity model. Here, we investigate a more general requirement on the spatial structure of RGC mosaics that can seed the emergence of spatially repetitive cortical OPMs, namely that angular correlations between so-called RGC dipoles exhibit a spatial structure similar to that of OPM autocorrelation functions. Both in cat beta cell mosaics as well as primate parasol receptive field mosaics we find that RGC dipole angles are spatially uncorrelated. To help assess the level of these correlations, we introduce a novel point process that generates mosaics with realistic nearest neighbor statistics and a tunable degree of spatial correlations of dipole angles. Using this process, we show that given the size of available data sets, the presence of even weak angular correlations in the data is very unlikely. We conclude that the layout of ON/OFF ganglion cell mosaics lacks the spatial structure necessary to seed iso-orientation domains in the primary visual cortex. PMID- 24475082 TI - Systems and evolutionary characterization of microRNAs and their underlying regulatory networks in soybean cotyledons. AB - MicroRNAs (miRNAs) are an emerging class of small RNAs regulating a wide range of biological processes. Soybean cotyledons evolved as sink tissues to synthesize and store seed reserves which directly affect soybean seed yield and quality. However, little is known about miRNAs and their regulatory networks in soybean cotyledons. We sequenced 292 million small RNA reads expressed in soybean cotyledons, and discovered 130 novel miRNA genes and 72 novel miRNA families. The cotyledon miRNAs arose at various stages of land plant evolution. Evolutionary analysis of the miRNA genes in duplicated genome segments from the recent Glycine whole genome duplication revealed that the majority of novel soybean cotyledon miRNAs were young, and likely arose after the duplication event 13 million years ago. We revealed the evolutionary pathway of a soybean cotyledon miRNA family (soy-miR15/49) that evolved from a neutral invertase gene through an inverted duplication and a series of DNA amplification and deletion events. A total of 304 miRNA genes were expressed in soybean cotyledons. The miRNAs were predicted to target 1910 genes, and form complex miRNA networks regulating a wide range of biological pathways in cotyledons. The comprehensive characterization of the miRNAs and their underlying regulatory networks at gene, pathway and system levels provides a foundation for further studies of miRNAs in cotyledons. PMID- 24475083 TI - Zinc mono-therapy in pre-symptomatic Chinese children with Wilson disease: a single center, retrospective study. AB - BACKGROUND: There is no official consensus regarding zinc therapy in pre symptomatic children with Wilson Disease (WD); more data is needed. OBJECTIVE: To investigate the safety and efficacy of zinc gluconate therapy for Chinese children with pre-symptomatic WD. METHODS: We retrospectively analyzed pre symptomatic children receiving zinc gluconate in a single Chinese center specialized in pediatric hepatology. Short-term follow-up data on safety and efficacy were presented, and effects of different zinc dosages were compared. RESULTS: 30 children (21 males) aged 2.7 to 16.8 years were followed for up to 4.4 years; 26 (87%) children had abnormal ALT at baseline. Most patients (73%) received higher than the currently recommended dose of elemental zinc. Zinc gluconate significantly reduced mean ALT (p<0.0001), AST (p<0.0001), GGT (p<0.0001) levels after 1 month, and urinary copper excretion after 6 months (p<0.0054). Mean direct bilirubin levels dropped significantly at 1 month (p = 0.0175), 3 months (p = 0.0010), and 6 months (p = 0.0036). Serum zinc levels gradually increased and reached a significantly higher level after 6 months (p<0.0026), reflecting good compliance with the therapy. Complete blood count parameters did not change throughout the analysis period. 8 children experienced mild and transient gastrointestinal side effects. The higher zinc dose did not affect treatment response and was not associated with different or increased side effects when compared to conventional zinc dose. CONCLUSION: In our cohort, zinc gluconate therapy for Chinese children with pre-symptomatic WD was effective, and higher initial dose of elemental zinc had the same level of efficacy as the conventional dose. PMID- 24475084 TI - Increasing newly diagnosed rate and changing risk factors of HCV in Yanbian Prefecture, a high endemic area in China. AB - BACKGROUND: The newly diagnosed rate of HCV infection is increasing in China. However, the risk factors have not been fully identified. Here, a survey was performed in Yanbian Prefecture, a high-endemic area in China. METHODS: We identified newly diagnosed HCV infection in 2007-2011, using the local National Disease Supervision Information Management System from the Chinese Center for Disease Control and Prevention. We determined the risk factors using a case control survey by questionnaire. RESULTS: Yanbian Prefecture had a rapid increase in the yearly newly diagnosed rate of HCV infection from 32.6 to 72.1/100.000 from the year 2007 to 2011. People aged 50-64 years had a high HCV infection of 43.4%, but only 0.3% of cases were reported in those aged less than 20 years. Cosmetic treatment, family history, blood transfusion, and dental treatment were independent risk factors for HCV infection. Unexpectedly, cosmetic treatments [odd ratio (OR) = 5.15, 95% confidence interval (CI) = 2.31-11.48, P = 0.00] and family history (OR = 4.68, 95% CI = 2.67-8.75, P = 0.00) showed a higher risk than the conventional risk factors of blood transfusion (OR = 4.49, 95% CI = 1.95 10.37, P = 0.001) and dental treatment (OR = 2.98, 95% CI = 1.42-6.25, P = 0.00). To further analyze the intrafamilial transmission, we found that spouses of HCV patients had an increased risk for acquiring HCV (OR = 5.75, 95% CI: 1.94-17.07), without significant association between either HCV RNA viral load (P = 0.29) or genotype (P = 0.43). CONCLUSIONS: HCV infection was increased in Yanbian Prefecture. Cosmetic treatment was a higher risk factor than medical procedure. HCV infection had a clear family clustering phenomenon, especially between spouses. PMID- 24475085 TI - Mirror-mark tests performed on jackdaws reveal potential methodological problems in the use of stickers in avian mark-test studies. AB - Some animals are capable of recognizing themselves in a mirror, which is considered to be demonstrated by passing the mark test. Mirror self-recognition capacity has been found in just a few mammals having very large brains and only in one bird, the magpie (Pica pica). The results obtained in magpies have enormous biological and cognitive implications because the fact that magpies were able to pass the mark test meant that this species is at the same cognitive level with great apes, that mirror self-recognition has evolved independently in the magpie and great apes (which diverged 300 million years ago), and that the neocortex (which is not present in the bird's brains) is not a prerequisite for mirror self-recognition as previously believed. Here, we have replicated the experimental design used on magpies to determine whether jackdaws (Corvus monedula) are also capable of mirror self-recognition by passing the mark test. We found that our nine jackdaws showed a very high interest towards the mirror and exhibited self-contingent behavior as soon as mirrors were introduced. However, jackdaws were not able to pass the mark test: both sticker-directed actions and sticker removal were performed with a similar frequency in both the cardboard (control) and the mirror conditions. We conclude that our jackdaws' behaviour raises non-trivial questions about the methodology used in the avian mark test. Our study suggests that the use of self-adhesive stickers on sensitive throat feathers may open the way to artefactual results because birds might perceive the stickers tactilely. PMID- 24475086 TI - Survival according to BRAF-V600 tumor mutations--an analysis of 437 patients with primary melanoma. AB - The prognostic impact of BRAF-V600 tumor mutations in stage I/II melanoma patients has not yet been analyzed in detail. We investigated primary tumors of 437 patients diagnosed between 1989 and 2006 by Sanger sequencing. Mutations were detected in 38.7% of patients and were associated with age, histological subtype as well as mitotic rate. The mutational rate was 36.7% in patients with disease free course and 51.7% in those with subsequent distant metastasis (p = 0.031). No difference in overall survival (p = 0.119) but a trend for worse distant metastasis-free survival (p = 0.061) was observed in BRAF mutant compared to BRAF wild-type patients. Independent prognostic factors for overall survival were tumor thickness, mitotic rate and ulceration. An interesting significant prognostic impact was observed in patients with tumor thickness of 1 mm or less, with the mutation present in 6 of 7 patients dying from melanoma. In conclusion, no significant survival differences were found according to BRAF-V600 tumor mutations in patients with primary melanoma but an increasing impact of the mutational status was observed in the subgroup of patients with tumor thickness of 1 mm or less. A potential role of the mutational status as a prognostic factor especially in this subgroup needs to be investigated in larger studies. PMID- 24475087 TI - Distribution of Gifsy-3 and of variants of ST64B and Gifsy-1 prophages amongst Salmonella enterica Serovar Typhimurium isolates: evidence that combinations of prophages promote clonality. AB - Salmonella isolates harbour a range of resident prophages which can influence their virulence and ability to compete and survive in their environment. Phage gene profiling of a range of phage types of Salmonella enterica subsp. enterica serovar Typhimurium (S. Typhimurium) indicates a significant level of correlation of phage gene profile with phage type as well as correlation with genotypes determined by a combination of multi-locus variable-number tandem repeat (VNTR) typing and clustered regularly interspaced short palindromic repeats (CRISPR) typing. Variation in phage gene profiles appears to be partly linked to differences in composition of variants of known prophages. We therefore conducted a study of the distribution of variants of ST64B and Gifsy-1 prophages and coincidently the presence of Gifsy-3 prophage in a range of S. Typhimurium phage types and genotypes. We have discovered two variants of the DT104 variant of ST64B and at least two new variants of Gifsy-1 as well as variants of related phage genes. While there is definite correlation between phage type and the prophage profile based on ST64B and Gifsy-1 variants we find stronger correlation between the VNTR/CRISPR genotype and prophage profile. Further differentiation of some genotypes is obtained by addition of the distribution of Gifsy-3 and a sequence variant of the substituted SB26 gene from the DT104 variant of ST64B. To explain the correlation between genotype and prophage profile we propose that suites of resident prophages promote clonality possibly through superinfection exclusion systems. PMID- 24475088 TI - Anterior/posterior competitive deactivation/activation dichotomy in the human hippocampus as revealed by a 3D navigation task. AB - Anterior/posterior long axis specialization is thought to underlie the organization of the hippocampus. However it remains unclear whether antagonistic mechanisms differentially modulate processing of spatial information within the hippocampus. We used fMRI and a virtual reality 3D paradigm to study encoding and retrieval of spatial memory during active visuospatial navigation, requiring positional encoding and retrieval of object landmarks during the path. Both encoding and retrieval elicited BOLD activation of the posterior most portion of hippocampus, while concurrent deactivations (recently shown to reflect decreases in neural responses) were found in the most anterior regions. Encoding elicited stronger activity in the posterior right than the left hippocampus. The former structure also showed significantly stronger activity for allocentric vs. egocentric processing during retrieval. The anterior vs. posterior pattern mimics, from a functional point, although at much distinct temporal scales, the previous anatomical findings in London taxi drivers, whereby posterior enlargement was found at the cost of an anterior decrease, and the mirror symmetric findings observed in blind people, in whom the right anterior hippocampus was found to be larger, at the cost of a smaller posterior hippocampus, as compared with sighted people. In sum, we found a functional dichotomy whereby the anterior/posterior hippocampus shows antagonistic processing patterns for spatial encoding and retrieval of 3D spatial information. To our knowledge, this is the first study reporting such a dynamical pattern in a functional study, which suggests that differential modulation of neural responses within the human hippocampus reflects distinct roles in spatial memory processing. PMID- 24475089 TI - Drug-related problems in patients with benign prostatic hyperplasia: a cross sectional retrospective study. AB - Benign Prostatic Hyperplasia (BPH) patients are at risk of acquiring drug-related problems (DRPs), as it is present in the majority of aging men. To date, DRPs among BPH patients have not been well studied. We conducted this retrospective study in a tertiary hospital in Malaysia from January 2009 to June 2012 with the aim of identifying the factors associated with DRPs among BPH patients. The Pharmaceutical Care Network Europe Classification Version (PCNE) 5.01 was used as a tool to classify DRPs. We enrolled 203 patients from 259 hospital admissions. A total of 390 DRPs were found and there was an average of 1.5+/-1.3 problems per hospitalization. 76.1% of hospital admissions included at least one DRP. The most common DRP categories encountered were drug choice problems (45.9%), drug interactions (24.9%), and dosing problems (13.3%). Factors such as advanced age (p = 0.005), a hospital stay of more than 6 days (p = 0.001), polydrug treatments (p<0.001), multiple comorbidities (p<0.001), and comorbid cardiovascular disease (p = 0.011), diabetes mellitus(p = 0.001), hypertension (p<0.001) and renal impairment (p = 0.011) were significantly associated with the occurrence of DRPs. These data indicated that the prevalence of DRPs is high among BPH patients. The identification of different subtypes of DRPs and the factors associated with DRPs may facilitate risk reduction for BPH patients. PMID- 24475090 TI - Mealtime, temporal, and daily variability of the human urinary and plasma metabolomes in a tightly controlled environment. AB - While metabolomics has tremendous potential for diagnostic biomarker and therapeutic target discovery, its utility may be diminished by the variability that occurs due to environmental exposures including diet and the influences of the human circadian rhythm. For successful translation of metabolomics findings into the clinical setting, it is necessary to exhaustively define the sources of metabolome variation. To address these issues and to measure the variability of urinary and plasma metabolomes throughout the day, we have undertaken a comprehensive inpatient study in which we have performed non-targeted metabolomics analysis of blood and urine in 26 volunteers (13 healthy subjects with no known disease and 13 healthy subjects with autosomal dominant polycystic kidney disease not taking medication). These individuals were evaluated in a clinical research facility on two separate occasions, over three days, while on a standardized, weight-based diet. Subjects provided pre- and post-prandial blood and urine samples at the same time of day, and all samples were analyzed by "fast lane" LC-MS-based global metabolomics. The largest source of variability in blood and urine metabolomes was attributable to technical issues such as sample preparation and analysis, and less variability was due to biological variables, meals, and time of day. Higher metabolome variability was observed after the morning as compared to the evening meal, yet day-to-day variability was minimal and urine metabolome variability was greater than that of blood. Thus we suggest that blood and urine are suitable biofluids for metabolomics studies, though nontargeted mass spectrometry alone may not offer sufficient precision to reveal subtle changes in the metabolome. Additional targeted analyses may be needed to support the data from nontargeted mass spectrometric analyses. In light of these findings, future metabolomics studies should consider these sources of variability to allow for appropriate metabolomics testing and reliable clinical translation of metabolomics data. PMID- 24475091 TI - Inhibitory potency of 8-methoxypsoralen on cytochrome P450 2A6 (CYP2A6) allelic variants CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22: differential susceptibility due to different sequence locations of the mutations. AB - Human cytochrome P450 2A6 (CYP2A6) is a highly polymorphic isoform of CYP2A subfamily. Our previous kinetic study on four CYP2A6 allelic variants (CYP2A6 15, CYP2A6 16, CYP2A6 21 and CYP2A6 22) have unveiled the functional significance of sequence mutations in these variants on coumarin 7-hydroxylation activity. In the present study, we further explored the ability of a typical CYP2A6 inhibitor, 8 methoxypsoralen (8-MOP), in inhibition of these alleles and we hypothesized that translational mutations in these variants are likely to give impact on 8-MOP inhibitory potency. The CYP2A6 variant and the wild type proteins were subjected to 8-MOP inhibition to yield IC50 values. In general, a similar trend of change in the IC50 and Km values was noted among the four mutants towards coumarin oxidation. With the exception of CYP2A6 16, differences in IC50 values were highly significant which implied compromised interaction of the mutants with 8 MOP. Molecular models of CYP2A6 were subsequently constructed and ligand-docking experiments were performed to rationalize experimental data. Our docking study has shown that mutations have induced enlargement of the active site volume in all mutants with the exception of CYP2A6 16. Furthermore, loss of hydrogen bond between 8-MOP and active site residue Asn297 was evidenced in all mutants. Our data indicate that the structural changes elicited by the sequence mutations could affect 8-MOP binding to yield differential enzymatic activities in the mutant CYP2A6 proteins. PMID- 24475092 TI - Regulation of PP2AC carboxylmethylation and cellular localisation by inhibitory class G-protein coupled receptors in cardiomyocytes. AB - The enzymatic activity of the type 2A protein phosphatase (PP2A) holoenzyme, a major serine/threonine phosphatase in the heart, is conferred by its catalytic subunit (PP2AC). PP2AC activity and subcellular localisation can be regulated by reversible carboxylmethylation of its C-terminal leucine309 (leu309) residue. Previous studies have shown that the stimulation of adenosine type 1 receptors (A1.Rs) induces PP2AC carboxylmethylation and altered subcellular distribution in adult rat ventricular myocytes (ARVM). In the current study, we show that the enzymatic components that regulate the carboxylmethylation status of PP2AC, leucine carboxylmethyltransferase-1 (LCMT-1) and phosphatase methylesterase-1 (PME-1) are abundantly expressed in, and almost entirely localised in the cytoplasm of ARVM. The stimulation of Gi-coupled A1.Rs with N(6) cyclopentyladenosine (CPA), and of other Gi-coupled receptors such as muscarinic M2 receptors (stimulated with carbachol) and angiotensin II AT2 receptors (stimulated with CGP42112) in ARVM, induced PP2AC carboxylmethylation at leu309 in a concentration-dependent manner. Exposure of ARVM to 10 uM CPA increased the cellular association between PP2AC and its methyltransferase LCMT-1, but not its esterase PME-1. Stimulation of A1.Rs with 10 uM CPA increased the phosphorylation of protein kinase B at ser473, which was abolished by the PI3K inhibitor LY294002 (20 uM), thereby confirming that PI3K activity is upregulated in response to A1.R stimulation by CPA in ARVM. A1.R-induced PP2AC translocation to the particulate fraction was abrogated by adenoviral expression of the alpha subunit (Galphat1) coupled to the transducin G-protein coupled receptor. A similar inhibitory effect on A1.R-induced PP2AC translocation was also seen with LY294002 (20 uM). These data suggest that in ARVM, A1.R-induced PP2AC translocation to the particulate fraction occurs through a GiPCR-Gbetagamma-PI3K mediated intracellular signalling pathway, which may involve elevated PP2AC carboxylmethylation at leu309. PMID- 24475094 TI - Proteinase activated receptor 1 mediated fibrosis in a mouse model of liver injury: a role for bone marrow derived macrophages. AB - Liver fibrosis results from the co-ordinated actions of myofibroblasts and macrophages, a proportion of which are of bone marrow origin. The functional effect of such bone marrow-derived cells on liver fibrosis is unclear. We examine whether changing bone marrow genotype can down-regulate the liver's fibrotic response to injury and investigate mechanisms involved. Proteinase activated receptor 1 (PAR1) is up-regulated in fibrotic liver disease in humans, and deficiency of PAR1 is associated with reduced liver fibrosis in rodent models. In this study, recipient mice received bone marrow transplantation from PAR1 deficient or wild-type donors prior to carbon tetrachloride-induced liver fibrosis. Bone marrow transplantation alone from PAR1-deficient mice was able to confer significant reductions in hepatic collagen content and activated myofibroblast expansion on wild-type recipients. This effect was associated with a decrease in hepatic scar-associated macrophages and a reduction in macrophage recruitment from the bone marrow. In vitro, PAR1 signalling on bone marrow derived macrophages directly induced their chemotaxis but did not stimulate proliferation. These data suggest that the bone marrow can modulate the fibrotic response of the liver to recurrent injury. PAR1 signalling can contribute to this response by mechanisms that include the regulation of macrophage recruitment. PMID- 24475093 TI - Comparable long-term efficacy of Lopinavir/Ritonavir and similar drug-resistance profiles in different HIV-1 subtypes. AB - BACKGROUND: Analysis of potentially different impact of Lopinavir/Ritonavir (LPV/r) on non-B subtypes is confounded by dissimilarities in the conditions existing in different countries. We retrospectively compared its impact on populations infected with subtypes B and C in Israel, where patients infected with different subtypes receive the same treatment. METHODS: Clinical and demographic data were reported by physicians. Resistance was tested after treatment failure. Statistical analyses were conducted using SPSS. RESULTS: 607 LPV/r treated patients (365 male) were included. 139 had HIV subtype B, 391 C, and 77 other subtypes. At study end 429 (71%) were receiving LPV/r. No significant differences in PI treatment history and in median viral-load (VL) at treatment initiation and termination existed between subtypes. MSM discontinued LPV/r more often than others even when the virologic outcome was good (p = 0.001). VL was below detection level in 81% of patients for whom LPV/r was first PI and in 67% when it was second (P = 0.001). Median VL decrease from baseline was 1.9+/-0.1 logs and was not significantly associated with subtype. Median CD4 increase was: 162 and 92cells/ul, respectively, for patients receiving LPV/r as first and second PI (P = 0.001), and 175 and 98, respectively, for subtypes B and C (P<0.001). Only 52 (22%) of 237 patients genotyped while under LPV/r were fully resistant to the drug; 12(5%) were partially resistant. In48%, population sequencing did not reveal resistance to any drug notwithstanding the virologic failure. No difference was found in the rates of resistance development between B and C (p = 0.16). CONCLUSIONS: Treatment with LPV/r appeared efficient and tolerable in both subtypes, B and C, but CD4 recovery was significantly better in virologically suppressed subtype-B patients. In both subtypes, LPV/r was more beneficial when given as first PI. Mostly, reasons other than resistance development caused discontinuation of treatment. PMID- 24475095 TI - Identification of tissue microRNAs predictive of sunitinib activity in patients with metastatic renal cell carcinoma. AB - PURPOSE: To identify tissue microRNAs predictive of sunitinib activity in patients with metastatic renal-cell-carcinoma (MRCC) and to evaluate in vitro their mechanism of action in sunitinib resistance. METHODS: We screened 673 microRNAs using TaqMan Low-density-Arrays (TLDAs) in tumors from MRCC patients with extreme phenotypes of marked efficacy and resistance to sunitinib, selected from an identification cohort (n = 41). The most relevant differentially expressed microRNAs were selected using bioinformatics-based target prediction analysis and quantified by qRT-PCR in tumors from patients presenting similar phenotypes selected from an independent cohort (n = 101). In vitro experiments were conducted to study the role of miR-942 in sunitinib resistance. RESULTS: TLDAs identified 64 microRNAs differentially expressed in the identification cohort. Seven candidates were quantified by qRT-PCR in the independent series. MiR-942 was the most accurate predictor of sunitinib efficacy (p = 0.0074). High expression of miR-942, miR-628-5p, miR-133a, and miR-484 was significantly associated with decreased time to progression and overall survival. These microRNAs were also overexpressed in the sunitinib resistant cell line Caki-2 in comparison with the sensitive cell line. MiR-942 overexpression in Caki-2 up regulates MMP-9 and VEGF secretion which, in turn, promote HBMEC endothelial migration and sunitinib resistance. CONCLUSIONS: We identified differentially expressed microRNAs in MRCC patients presenting marked sensitivity or resistance to sunitinib. MiR-942 was the best predictor of efficacy. We describe a novel paracrine mechanism through which high miR-942 levels in MRCC cells up-regulates MMP-9 and VEGF secretion to enhance endothelial migration and sunitinib resistance. Our results support further validation of these miRNA in clinical confirmatory studies. PMID- 24475096 TI - HIV infection, risk factors, and preventive services utilization among female sex workers in the Mekong Delta Region of Vietnam. AB - BACKGROUND: Risk behaviors among female sex workers (FSW) are considerable drivers of HIV infections in Vietnam, especially transmission between high-risk and low-risk groups. We assessed HIV prevalence and its correlates among FSWs, and the use of preventive services among this community in the Mekong Delta region, southern Vietnam. METHODS: A cross-sectional survey of 1,999 FSWs was carried out in five provinces including Ben Tre, Hau Giang, Kien Giang, Tien Giang, and Vinh Long between June, 2006 and June, 2007. We interviewed participants face-to-face in order to elicit information about their lives and potential risk factors, and we tested their sera to determine their HIV status. We then performed multivariate logistic regression analyses to investigate factors associated with HIV infection. RESULTS: Seventeen percent of the participating FSWs were street-based sex workers (SSWs) and the rest (83%) were entertainment establishment-based sex workers (ESWs). Unprotected sex with regular and casual clients in the past month was frequent among study participants (40.5% and 33.5% respectively). However, few respondents (1.3%) had ever injected drugs. Only 2.1% (95% confidence interval (CI): 1.6%-2.8%) of FSWs were found to be infected with HIV. HIV prevalence among SSWs was greater than among ESWs (3.8% vs. 1.8%, p = 0.02, respectively). Increased risk for HIV infection was significantly associated with the number of clients per month (adjusted odd ratio (aOR) = 2.65, 95% CI: 1.26-5.59). CONCLUSIONS: Interventions to reduce unsafe sex and drug injection, and to increase uptake of HIV testing among FSWs are necessary. Differences in HIV prevalence and its correlates by type of sex work emphasize the importance of constrained contexts in shaping risk behaviors among FSWs; that should be considered in designing HIV prevention programs. PMID- 24475097 TI - Does invasion success reflect superior cognitive ability? A case study of two congeneric lizard species (Lampropholis, Scincidae). AB - A species' intelligence may reliably predict its invasive potential. If this is true, then we might expect invasive species to be better at learning novel tasks than non-invasive congeners. To test this hypothesis, we exposed two sympatric species of Australian scincid lizards, Lampropholis delicata (invasive) and L. guichenoti (non-invasive) to standardized maze-learning tasks. Both species rapidly decreased the time they needed to find a food reward, but latencies were always higher for L. delicata than L. guichenoti. More detailed analysis showed that neither species actually learned the position of the food reward; they were as likely to turn the wrong way at the end of the study as at the beginning. Instead, their times decreased because they spent less time immobile in later trials; and L. guichenoti arrived at the reward sooner because they exhibited "freezing" (immobility) less than L. delicata. Hence, our data confirm that the species differ in their performance in this standardized test, but neither the decreasing time to find the reward, nor the interspecific disparity in those times, are reflective of cognitive abilities. Behavioural differences may well explain why one species is invasive and one is not, but those differences do not necessarily involve cognitive ability. PMID- 24475098 TI - BAG5 protects against mitochondrial oxidative damage through regulating PINK1 degradation. AB - Mutations in PTEN-induced kinase 1 (PINK1) gene cause PARK6 familial Parkinsonism, and loss of the stability of PINK1 may also contribute to sporadic Parkinson's disease (PD). Degradation of PINK1 occurs predominantly through the ubiquitin proteasome system (UPS), however, to date, few of the proteins have been found to regulate the degradation of PINK1. Using the yeast two-hybrid system and pull-down methods, we identified bcl-2-associated athanogene 5 (BAG5), a BAG family member, directly interacted with PINK1. We showed that BAG5 stabilized PINK1 by decreasing the ubiquitination of PINK1. Interestingly, BAG5 rescued MPP(+)- and rotenone-induced mitochondria dysfunction by up-regulating PINK1 in vitro. In PINK1-null mice and MPTP-treated mice, BAG5 significantly increased in the substantia nigra pars compacta (SNpc) although PINK1 was decreased. Our findings indicated that BAG5, as a key protein to stabilize PINK1, is a promising therapeutic tool for preventing mitochondrial dysfunction following oxidative stress. PMID- 24475099 TI - Feature engineering and a proposed decision-support system for systematic reviewers of medical evidence. AB - OBJECTIVES: Evidence-based medicine depends on the timely synthesis of research findings. An important source of synthesized evidence resides in systematic reviews. However, a bottleneck in review production involves dual screening of citations with titles and abstracts to find eligible studies. For this research, we tested the effect of various kinds of textual information (features) on performance of a machine learning classifier. Based on our findings, we propose an automated system to reduce screeing burden, as well as offer quality assurance. METHODS: We built a database of citations from 5 systematic reviews that varied with respect to domain, topic, and sponsor. Consensus judgments regarding eligibility were inferred from published reports. We extracted 5 feature sets from citations: alphabetic, alphanumeric(+), indexing, features mapped to concepts in systematic reviews, and topic models. To simulate a two person team, we divided the data into random halves. We optimized the parameters of a Bayesian classifier, then trained and tested models on alternate data halves. Overall, we conducted 50 independent tests. RESULTS: All tests of summary performance (mean F3) surpassed the corresponding baseline, P<0.0001. The ranks for mean F3, precision, and classification error were statistically different across feature sets averaged over reviews; P-values for Friedman's test were .045, .002, and .002, respectively. Differences in ranks for mean recall were not statistically significant. Alphanumeric(+) features were associated with best performance; mean reduction in screening burden for this feature type ranged from 88% to 98% for the second pass through citations and from 38% to 48% overall. CONCLUSIONS: A computer-assisted, decision support system based on our methods could substantially reduce the burden of screening citations for systematic review teams and solo reviewers. Additionally, such a system could deliver quality assurance both by confirming concordant decisions and by naming studies associated with discordant decisions for further consideration. PMID- 24475100 TI - Multi-scale glycemic variability: a link to gray matter atrophy and cognitive decline in type 2 diabetes. AB - OBJECTIVE: Type 2 diabetes mellitus (DM) accelerates brain aging and cognitive decline. Complex interactions between hyperglycemia, glycemic variability and brain aging remain unresolved. This study investigated the relationship between glycemic variability at multiple time scales, brain volumes and cognition in type 2 DM. RESEARCH DESIGN AND METHODS: Forty-three older adults with and 26 without type 2 DM completed 72-hour continuous glucose monitoring, cognitive tests and anatomical MRI. We described a new analysis of continuous glucose monitoring, termed Multi-Scale glycemic variability (Multi-Scale GV), to examine glycemic variability at multiple time scales. Specifically, Ensemble Empirical Mode Decomposition was used to identify five unique ultradian glycemic variability cycles (GVC1-5) that modulate serum glucose with periods ranging from 0.5-12 hrs. RESULTS: Type 2 DM subjects demonstrated greater variability in GVC3-5 (period 2.0-12 hrs) than controls (P<0.0001), during the day as well as during the night. Multi-Scale GV was related to conventional markers of glycemic variability (e.g. standard deviation and mean glycemic excursions), but demonstrated greater sensitivity and specificity to conventional markers, and was associated with worse long-term glycemic control (e.g. fasting glucose and HbA1c). Across all subjects, those with greater glycemic variability within higher frequency cycles (GVC1-3; 0.5-2.0 hrs) had less gray matter within the limbic system and temporo parietal lobes (e.g. cingulum, insular, hippocampus), and exhibited worse cognitive performance. Specifically within those with type 2 DM, greater glycemic variability in GVC2-3 was associated with worse learning and memory scores. Greater variability in GVC5 was associated with longer DM duration and more depression. These relationships were independent of HbA1c and hypoglycemic episodes. CONCLUSIONS: Type 2 DM is associated with dysregulation of glycemic variability over multiple scales of time. These time-scale-dependent glycemic fluctuations might contribute to brain atrophy and cognitive outcomes within this vulnerable population. PMID- 24475101 TI - Mitral tissue inhibitor of metalloproteinase 2 is associated with mitral valve surgery outcome. AB - BACKGROUND: Matrix metalloproteinases play a role in regulating cardiac remodeling. We previously reported an association between tissue inhibitor of metalloproteinase 2 (TIMP-2) expression and mitral valve (MV) disease. However, the determinants and prognostic value of mitral TIMP2 after MV surgery are unknown. METHODS: This retrospective study of 164 patients after MV surgery in a tertiary medical center in Taiwan assessed mitral TIMP2 on a semiquantitative scale (0-2) by immunohistochemical staining. The primary endpoints were the composite of cardiovascular death and heart failure admission. RESULTS: Mean age was 50.4+/-13.7 years. After a mean follow-up period of 101+/-59 months, primary endpoints had occurred in 25 (15.2%) subjects. Patients with and without primary endpoint events significantly differed in terms of age (56.6+/-14.4 vs. 49.2+/ 13.4 years, respectively; p = 0.013) and left ventricular end-systolic diameter (LVESD) (39.7+/-8.2 vs. 35.5+/-7.5 mm, p = 0.010) at surgery. The TIMP2 had a significant dose-dependent association with development of a primary endpoint (p = 0.002). Kaplan-Meier analysis showed that TIMP2 expression has a significant positive association with primary endpoint-free survival (log-rank test; p = 0.004). Cox regression analysis showed that independent predictors of primary endpoints were TIMP2 (hazard ratio [HR] 0.28; 95% confidence interval [CI] 0.12 0.65; p = 0.003), age (HR 1.05; 95% CI 1.02-1.09; p = 0.003) and LVESD (HR 1.05; 95% CI 1.01-1.10; p = 0.020). CONCLUSIONS: The lack of mitral TIMP2 expression is associated with increases in cardiovascular death and heart failure following MV surgery. PMID- 24475102 TI - Functional Module Connectivity Map (FMCM): a framework for searching repurposed drug compounds for systems treatment of cancer and an application to colorectal adenocarcinoma. AB - Drug repurposing has become an increasingly attractive approach to drug development owing to the ever-growing cost of new drug discovery and frequent withdrawal of successful drugs caused by side effect issues. Here, we devised Functional Module Connectivity Map (FMCM) for the discovery of repurposed drug compounds for systems treatment of complex diseases, and applied it to colorectal adenocarcinoma. FMCM used multiple functional gene modules to query the Connectivity Map (CMap). The functional modules were built around hub genes identified, through a gene selection by trend-of-disease-progression (GSToP) procedure, from condition-specific gene-gene interaction networks constructed from sets of cohort gene expression microarrays. The candidate drug compounds were restricted to drugs exhibiting predicted minimal intracellular harmful side effects. We tested FMCM against the common practice of selecting drugs using a genomic signature represented by a single set of individual genes to query CMap (IGCM), and found FMCM to have higher robustness, accuracy, specificity, and reproducibility in identifying known anti-cancer agents. Among the 46 drug candidates selected by FMCM for colorectal adenocarcinoma treatment, 65% had literature support for association with anti-cancer activities, and 60% of the drugs predicted to have harmful effects on cancer had been reported to be associated with carcinogens/immune suppressors. Compounds were formed from the selected drug candidates where in each compound the component drugs collectively were beneficial to all the functional modules while no single component drug was harmful to any of the modules. In cell viability tests, we identified four candidate drugs: GW-8510, etacrynic acid, ginkgolide A, and 6-azathymine, as having high inhibitory activities against cancer cells. Through microarray experiments we confirmed the novel functional links predicted for three candidate drugs: phenoxybenzamine (broad effects), GW-8510 (cell cycle), and imipenem (immune system). We believe FMCM can be usefully applied to repurposed drug discovery for systems treatment of other types of cancer and other complex diseases. PMID- 24475103 TI - Molecular characterization of antigen-peptide pulsed dendritic cells: immature dendritic cells develop a distinct molecular profile when pulsed with antigen peptide. AB - As dendritic cells (DCs) are the most potent professional antigen-presenting cells, they are being tested as cancer vaccines for immunotherapy of established cancers. Although numerous studies have characterized DCs by their phenotype and function, few have identified potential molecular markers of antigen presentation prior to vaccination of host. In this study we generated pre-immature DC (piDC), immature DC (iDC), and mature DC (mDC) from human peripheral blood monocytes (PBMC) obtained from HLA-A2 healthy donors, and pulsed them with human papillomavirus E7 peptide (p11-20), a class I HLA-A2 binding antigen. We then characterized DCs for cell surface phenotype and gene expression profile by microarray technology. We identified a set of 59 genes that distinguished three differentiation stages of DCs (piDC, iDC and mDC). When piDC, iDC and mDC were pulsed with E7 peptide for 2 hrs, the surface phenotype did not change, however, iDCs rather than mDCs showed transcriptional response by up-regulation of a set of genes. A total of 52 genes were modulated in iDC upon antigen pulsing. Elongation of pulse time for iDCs to 10 and 24 hrs did not significantly bring further changes in gene expression. The E7 peptide up-modulated immune response (KPNA7, IGSF6, NCR3, TREM2, TUBAL3, IL8, NFKBIA), pro-apoptosis (BTG1, SEMA6A, IGFBP3 and SRGN), anti-apoptosis (NFKBIA), DNA repair (MRPS11, RAD21, TXNRD1), and cell adhesion and cell migration genes (EPHA1, PGF, IL8 and CYR61) in iDCs. We confirmed our results by Q-PCR analysis. The E7 peptide but not control peptide (PADRE) induced up-regulation of NFKB1A gene only in HLA-A2 positive iDCs and not in HLA-A2 negative iDCs. These results suggest that E7 up-regulation of genes is specific and HLA restricted and that these genes may represent markers of antigen presentation and help rapidly assess the quality of dendritic cells prior to administration to the host. PMID- 24475104 TI - Speeding up social waves. Propagation mechanisms of shimmering in giant honeybees. AB - Shimmering is a defence behaviour in giant honeybees (Apis dorsata), whereby bees on the nest surface flip their abdomen upwards in a Mexican wave-like process. However, information spreads faster than can be ascribed to bucket bridging, which is the transfer of information from one individual to an adjacent one. We identified a saltatoric process that speeds up shimmering by the generation of daughter waves, which subsequently merge with the parental wave, producing a new wave front. Motion patterns of individual "focus" bees (n = 10,894) and their shimmering-active neighbours (n = 459,558) were measured with high-resolution video recording and stereoscopic imaging. Three types of shimmering-active surface bees were distinguished by their communication status, termed "agents": "Bucket-bridging" agents comprised 74.98% of all agents, affected 88.17% of their neighbours, and transferred information at a velocity of v = 0.317+/-0.015 m/s. "Chain-tail" agents comprised 9.20% of the agents, were activated by 6.35% of their neighbours, but did not motivate others to participate in the wave. "Generator agents" comprised 15.82% of agents, showed abdominal flipping before the arrival of the main wave front, and initiated daughter waves. They affected 6.75% of their neighbourhood and speeded up the compound shimmering process compared to bucket bridging alone by 41.5% to v = 0.514+/-0.019 m/s. The main direction of shimmering was reinforced by 35.82% of agents, whereas the contribution of the complementing agents was fuzzy. We discuss that the saltatoric process could enable the bees to instantly recruit larger cohorts to participate in shimmering and to respond rapidly to changes in flight direction of preying wasps. A third, non-exclusive explanation is that at a distance of up to three metres from the nest the acceleration of shimmering could notably contribute to the startle response in mammals and birds. PMID- 24475105 TI - Genetic variations in the flanking regions of miR-101-2 are associated with increased risk of breast cancer. AB - Genetic variants in human microRNA (miRNA) genes may alter mature miRNA processing and/or target selection, and likely contribute to cancer susceptibility and disease progression. Previous studies have suggested that miR 101 may play important roles in the development of cancer by regulating key tumor associated genes. However, the role of single nucleotide polymorphisms (SNPs) of miR-101 in breast cancer susceptibility remains unclear. In this study, we genotyped 11 SNPs of the miR-101 genes (including miR-101-1 and miR-101-2) in a case-control study of 1064 breast cancer cases and 1073 cancer-free controls. The results revealed that rs462480 and rs1053872 in the flank regions of pre-miR-101 2 were significantly associated with increased risk of breast cancer (rs462480 AC/CC vs AA: adjusted OR = 1.182, 95% CI: 1.030-1.357, P = 0.017; rs1053872 CG/GG vs CC: adjusted OR = 1.179, 95% CI: 1.040-1.337, P = 0.010). However, the remaining 9 SNPs were not significantly associated with risk of breast cancer. Additionally, combined analysis of the two high-risk SNPs revealed that subjects carrying the variant genotypes of rs462480 and rs1053872 had increased risk of breast cancer in a dose-response manner (P(trend) = 0.002). Compared with individuals with "0-1" risk allele, those carrying "2-4" risk alleles had 1.29 fold risk of breast cancer. In conclusion, these findings suggested that the SNPs rs462480 and rs1053872 residing in miR-101-2 gene may have a solid impact on genetic susceptibility to breast cancer, which may improve our understanding of the potential contribution of miRNA SNPs to cancer pathogenesis. PMID- 24475106 TI - Genetic variants associated with myocardial infarction and the risk factors in Chinese population. AB - BACKGROUND: Recent genome-wide association (GWA) studies in Caucasians identified multiple single nucleotide polymorphisms (SNPs) associated with coronary artery disease (CAD). The associations of those SNPs with myocardial infarction (MI) have not been replicated in Asian populations. Among those previously identified SNPs, we selected nine (rs10953541, rs1122608, rs12190287, rs12413409, rs1412444, rs1746048, rs3798220, rs4977574, rs579459, in or near genes 7q22, LDLR, TCF21, CYP17A1, LIPA, CXCL12, LPA, CDKN2A, ABO, respectively) because of the relatively high minor allele frequencies in Chinese individuals and tested the associations of the SNPs with MI and MI related risk factors in Chinese population. METHODS AND RESULTS: We conducted a case-control association study on a cohort of 2365 MI patients and 2678 unrelated controls from the Chinese population. Genotyping of 9 SNPs were performed by the TaqMan Real Time PCR method. After age, sex, and BMI adjustment, we observed the SNPs rs12190287, rs12413409, rs1412444, rs1746048 and rs4977574, were significantly associated with MI in additive models and rs12190287, rs12413409, rs4977574 were significantly associated with phenotypes of MI at the same time. We also found three SNPs rs1122608, rs3798220 and rs579459 were significantly associated with risk factors of MI, although they had no association with MI in Chinese population. CONCLUSION: Results of this study indicate that 5 SNPs were associated with MI and 3 SNPs were associated with associated with lipoprotein levels but not with MI in a Chinese population. The present study supports some CAD-related genes in Caucasian as important genes for MI in a Chinese population. PMID- 24475107 TI - Cloud-enabled microscopy and droplet microfluidic platform for specific detection of Escherichia coli in water. AB - We report an all-in-one platform - ScanDrop - for the rapid and specific capture, detection, and identification of bacteria in drinking water. The ScanDrop platform integrates droplet microfluidics, a portable imaging system, and cloud based control software and data storage. The cloud-based control software and data storage enables robotic image acquisition, remote image processing, and rapid data sharing. These features form a "cloud" network for water quality monitoring. We have demonstrated the capability of ScanDrop to perform water quality monitoring via the detection of an indicator coliform bacterium, Escherichia coli, in drinking water contaminated with feces. Magnetic beads conjugated with antibodies to E. coli antigen were used to selectively capture and isolate specific bacteria from water samples. The bead-captured bacteria were co-encapsulated in pico-liter droplets with fluorescently-labeled anti-E. coli antibodies, and imaged with an automated custom designed fluorescence microscope. The entire water quality diagnostic process required 8 hours from sample collection to online-accessible results compared with 2-4 days for other currently available standard detection methods. PMID- 24475108 TI - Favorable circulatory system outcomes as adjuvant traditional Chinese medicine (TCM) treatment for cerebrovascular diseases in Taiwan. AB - BACKGROUND: This study searches the National Health Insurance Research Database (NHIRD) used in a previous project, aiming for reconstructing possible cerebrovascular disease-related groups (DRG),and estimating the costs between cerebrovascular disease and related diseases. METHODS AND MATERIALS: We conducted a nationwide retrospective cohort study in stroke inpatients, we examined the overall costs in 3 municipalities in Taiwan, by evaluating the possible costs of the expecting diagnosis related group (DRG) by using the international classification of diseases version-9 (ICD-9) system, and the overall analysis of the re-admission population that received traditional Chinese medicine (TCM) treatment and those who did not. RESULTS: The trend demonstrated that the non participant costs were consistent with the ICD-9 categories (430 to 437) because similarities existed between years 2006 to 2007. Among the TCM patients, a wide variation and additional costs were found compared to non-TCM patients during these 2 years. The average re-admission duration was significantly shorter for TCM patients, especially those initially diagnosed with ICD 434 during the first admission. In addition, TCM patients demonstrated more severe general symptoms, which incurred high conventional treatment costs, and could result in re admission for numerous reasons. However, in Disease 7 of ICD-9 category, representing the circulatory system was most prevalent in non-TCM inpatients, which was the leading cause of re-admission. CONCLUSION: We concluded that favorable circulatory system outcomes were in adjuvant TCM treatment inpatients, there were less re-admission for circulatory system events and a two-third reduction of re-admission within ICD-9 code 430 to 437, compared to non-TCM ones. However, there were shorter re-admission duration other than circulatory system events by means of unfavorable baseline condition. PMID- 24475109 TI - Environmental reconstruction of Tuyoq in the Fifth Century and its bearing on Buddhism in Turpan, Xinjiang, China. AB - The Thousand Buddha Grottoes of Tuyoq, Turpan, Xinjiang, China were once a famous Buddhist temple along the ancient Silk Road which was first constructed in the Fifth Century (A.D.). Although archaeological researches about the Grottoes have been undertaken for over a century, the ancient environment has remained enigmatic. Based on seven clay samples from the Grottoes' adobes, pollen and leaf epidermis were analyzed to decipher the vegetation and climate of Fifth Century Turpan, and the environmental landscape was reconstructed in three dimensions. The results suggest that temperate steppe vegetation dominated the Tuyoq region under a warmer and wetter environment with more moderate seasonality than today, as the ancient mean annual temperature was 15.3 degrees C, the mean annual precipitation was approximately 1000 mm and the temperature difference between coldest and warmest months was 24 degrees C using Co-existence Approach. Taken in the context of wheat and grape cultivation as shown by pollen of Vitis and leaf epidermis of Triticum, we infer that the Tuyoq region was an oasis with booming Buddhism in the Fifth Century, which was probably encouraged by a 1 degrees C warmer temperature with an abundant water supply compared to the coeval world that experienced the 1.4 k BP cooling event. PMID- 24475110 TI - A new mathematical model for the interpretation of translational research evaluating six CTLA-4 polymorphisms in high-risk melanoma patients receiving adjuvant interferon. AB - Adjuvant therapy of stage IIB/III melanoma with interferon reduces relapse and mortality by up to 33% but is accompanied by toxicity-related complications. Polymorphisms of the CTLA-4 gene associated with autoimmune diseases could help in identifying interferon treatment benefits. We previously genotyped 286 melanoma patients and 288 healthy (unrelated) individuals for six CTLA-4 polymorphisms (SNP). Previous analyses found no significant differences between the distributions of CTLA-4 polymorphisms in the melanoma population vs. controls, no significant difference in relapse free and overall survivals among patients and no correlation between autoimmunity and specific alleles. We report new analysis of these CTLA-4 genetic profiles, using Network Phenotyping Strategy (NPS). It is graph-theory based method, analyzing the SNP patterns. Application of NPS on CTLA-4 polymorphism captures allele relationship pattern for every patient into 6-partite mathematical graph P. Graphs P are combined into weighted 6-partite graph S, which subsequently decomposed into reference relationship profiles (RRP). Finally, every individual CTLA-4 genotype pattern is characterized by the graph distances of P from eight identified RRP's. RRP's are subgraphs of S, collecting equally frequent binary allele co-occurrences in all studied loci. If S topology represents the genetic "dominant model", the RRP's and their characteristic frequencies are identical to expectation-maximization derived haplotypes and maximal likelihood estimates of their frequencies. The graph-representation allows showing that patient CTLA-4 haplotypes are uniquely different from the controls by absence of specific SNP combinations. New function related insight is derived when the 6-partite graph reflects allelic state of CTLA-4. We found that we can use differences between individual P and specific RRPs to identify patient subpopulations with clearly different polymorphic patterns relatively to controls as well as to identify patients with significantly different survival. PMID- 24475111 TI - Optimization of the transcranial magnetic stimulation protocol by defining a reliable estimate for corticospinal excitability. AB - The goal of this study was to optimize the transcranial magnetic stimulation (TMS) protocol for acquiring a reliable estimate of corticospinal excitability (CSE) using single-pulse TMS. Moreover, the minimal number of stimuli required to obtain a reliable estimate of CSE was investigated. In addition, the effect of two frequently used stimulation intensities [110% relative to the resting motor threshold (rMT) and 120% rMT] and gender was evaluated. Thirty-six healthy young subjects (18 males and 18 females) participated in a double-blind crossover procedure. They received 2 blocks of 40 consecutive TMS stimuli at either 110% rMT or 120% rMT in a randomized order. Based upon our data, we advise that at least 30 consecutive stimuli are required to obtain the most reliable estimate for CSE. Stimulation intensity and gender had no significant influence on CSE estimation. In addition, our results revealed that for subjects with a higher rMT, fewer consecutive stimuli were required to reach a stable estimate of CSE. The current findings can be used to optimize the design of similar TMS experiments. PMID- 24475112 TI - Full-genome characterisation of Orungo, Lebombo and Changuinola viruses provides evidence for co-evolution of orbiviruses with their arthropod vectors. AB - The complete genomes of Orungo virus (ORUV), Lebombo virus (LEBV) and Changuinola virus (CGLV) were sequenced, confirming that they each encode 11 distinct proteins (VP1-VP7 and NS1-NS4). Phylogenetic analyses of cell-attachment protein 'outer-capsid protein 1' (OC1), show that orbiviruses fall into three large groups, identified as: VP2(OC1), in which OC1 is the 2nd largest protein, including the Culicoides transmitted orbiviruses; VP3(OC1), which includes the mosquito transmitted orbiviruses; and VP4(OC1) which includes the tick transmitted viruses. Differences in the size of OC1 between these groups, places the T2 'subcore-shell protein' as the third largest protein 'VP3(T2)' in the first of these groups, but the second largest protein 'VP3(T2)' in the other two groups. ORUV, LEBV and CGLV all group with the Culicoides-borne VP2(OC1)/VP3(T2) viruses. The G+C content of the ORUV, LEBV and CGLV genomes is also similar to that of the Culicoides-borne, rather than the mosquito-borne, or tick borne orbiviruses. These data suggest that ORUV and LEBV are Culicoides- rather than mosquito-borne. Multiple isolations of CGLV from sand flies suggest that they are its primary vector. OC1 of the insect-borne orbiviruses is approximately twice the size of the equivalent protein of the tick borne viruses. Together with internal sequence similarities, this suggests its origin by duplication (concatermerisation) of a smaller OC1 from an ancestral tick-borne orbivirus. Phylogenetic comparisons showing linear relationships between the dates of evolutionary-separation of their vector species, and genetic-distances between tick-, mosquito- or Culicoides-borne virus-groups, provide evidence for co evolution of the orbiviruses with their arthropod vectors. PMID- 24475113 TI - Identification of gene-specific polymorphisms and association with capsaicin pathway metabolites in Capsicum annuum L. collections. AB - Pepper (Capsicum annuum L.) is an economically important crop with added nutritional value. Production of capsaicin is an important quantitative trait with high environmental variance, so the development of markers regulating capsaicinoid accumulation is important for pepper breeding programs. In this study, we performed association mapping at the gene level to identify single nucleotide polymorphisms (SNPs) associated with capsaicin pathway metabolites in a diverse Capsicum annuum collection during two seasons. The genes Pun1, CCR, KAS and HCT were sequenced and matched with the whole-genome sequence draft of pepper to identify SNP locations and for further characterization. The identified SNPs for each gene underwent candidate gene association mapping. Association mapping results revealed Pun1 as a key regulator of major metabolites in the capsaicin pathway mainly affecting capsaicinoids and precursors for acyl moieties of capsaicinoids. Six different SNPs in the promoter sequence of Pun1 were found associated with capsaicin in plants from both seasons. Our results support that CCR is an important control point for the flux of p-coumaric acid to specific biosynthesis pathways. KAS was found to regulate the major precursors for acyl moieties of capsaicinoids and may play a key role in capsaicinoid production. Candidate gene association mapping of Pun1 suggested that the accumulation of capsaicinoids depends on the expression of Pun1, as revealed by the most important associated SNPs found in the promoter region of Pun1. PMID- 24475114 TI - Improved diagnosis of the transition to JAK2 (V617F) homozygosity: the key feature for predicting the evolution of myeloproliferative neoplasms. AB - Most cases of BCR-ABL1-negative myeloproliferative neoplasms (MPNs), essential thrombocythemia, polycythemia vera and primary myelofibrosis are associated with JAK2 (V617F) mutations. The outcomes of these cases are critically influenced by the transition from JAK2 (V617F) heterozygosity to homozygosity. Therefore, a technique providing an unbiased assessment of the critical allele burden, 50% JAK2 (V617F), is highly desirable. In this study, we present an approach to assess the JAK2 (V617F) burden from genomic DNA (gDNA) and complementary DNA (cDNA) using one-plus-one template references for allele-specific quantitative real-time-PCR (qPCR). Plasmidic gDNA and cDNA constructs encompassing one PCR template for JAK2 (V617F) spaced from one template for JAK2(Wild Type) were constructed by multiple fusion PCR amplifications. Repeated assessments of the 50% JAK2(V617F) burden within the dynamic range of serial dilutions of gDNA and cDNA constructs resulted in 52.53 +/- 4.2% and 51.46 +/- 4.21%, respectively. The mutation-positive cutoff was estimated to be 3.65% (mean +2 standard deviation) using 20 samples from a healthy population. This qPCR approach was compared with the qualitative ARMS-PCR technique and with two standard methods based on qPCR, and highly significant correlations were obtained in all cases. qPCR assays were performed on paired gDNA/cDNA samples from 20 MPN patients, and the JAK2 (V617F) expression showed a significant correlation with the allele burden. Our data demonstrate that the qPCR method using one-plus-one template references provides an improved assessment of the clinically relevant transition of JAK2 (V617F) from heterozygosity to homozygosity. PMID- 24475115 TI - Diurnal oscillations of soybean circadian clock and drought responsive genes. AB - Rhythms produced by the endogenous circadian clock play a critical role in allowing plants to respond and adapt to the environment. While there is a well established regulatory link between the circadian clock and responses to abiotic stress in model plants, little is known of the circadian system in crop species like soybean. This study examines how drought impacts diurnal oscillation of both drought responsive and circadian clock genes in soybean. Drought stress induced marked changes in gene expression of several circadian clock-like components, such as LCL1-, GmELF4- and PRR-like genes, which had reduced expression in stressed plants. The same conditions produced a phase advance of expression for the GmTOC1-like, GmLUX-like and GmPRR7-like genes. Similarly, the rhythmic expression pattern of the soybean drought-responsive genes DREB-, bZIP-, GOLS-, RAB18- and Remorin-like changed significantly after plant exposure to drought. In silico analysis of promoter regions of these genes revealed the presence of cis elements associated both with stress and circadian clock regulation. Furthermore, some soybean genes with upstream ABRE elements were responsive to abscisic acid treatment. Our results indicate that some connection between the drought response and the circadian clock may exist in soybean since (i) drought stress affects gene expression of circadian clock components and (ii) several stress responsive genes display diurnal oscillation in soybeans. PMID- 24475116 TI - Phospholipase C-beta1 and beta4 contribute to non-genetic cell-to-cell variability in histamine-induced calcium signals in HeLa cells. AB - A uniform extracellular stimulus triggers cell-specific patterns of Ca(2+) signals, even in genetically identical cell populations. However, the underlying mechanism that generates the cell-to-cell variability remains unknown. We monitored cytosolic inositol 1,4,5-trisphosphate (IP3) concentration changes using a fluorescent IP3 sensor in single HeLa cells showing different patterns of histamine-induced Ca(2+) oscillations in terms of the time constant of Ca(2+) spike amplitude decay and the Ca(2+) oscillation frequency. HeLa cells stimulated with histamine exhibited a considerable variation in the temporal pattern of Ca(2+) signals and we found that there were cell-specific IP3 dynamics depending on the patterns of Ca(2+) signals. RT-PCR and western blot analyses showed that phospholipase C (PLC)-beta1, -beta3, -beta4, -gamma1, -delta3 and -epsilon were expressed at relatively high levels in HeLa cells. Small interfering RNA-mediated silencing of PLC isozymes revealed that PLC-beta1 and PLC-beta4 were specifically involved in the histamine-induced IP3 increases in HeLa cells. Modulation of IP3 dynamics by knockdown or overexpression of the isozymes PLC-beta1 and PLC-beta4 resulted in specific changes in the characteristics of Ca(2+) oscillations, such as the time constant of the temporal changes in the Ca(2+) spike amplitude and the Ca(2+) oscillation frequency, within the range of the cell-to-cell variability found in wild-type cell populations. These findings indicate that the heterogeneity in the process of IP3 production, rather than IP3-induced Ca(2+) release, can cause cell-to-cell variability in the patterns of Ca(2+) signals and that PLC-beta1 and PLC-beta4 contribute to generate cell-specific Ca(2+) signals evoked by G protein-coupled receptor stimulation. PMID- 24475117 TI - Glaucoma-induced optic disc morphometric changes and glaucoma diagnostic ability of Heidelberg Retina Tomograph II in highly myopic eyes. AB - PURPOSE: This study was performed to first investigate the morphological differences in the optic nerve head between highly myopic non-glaucomatous controls and highly myopic glaucomatous eyes in comparison with the differences between emmetropic non-glaucomatous controls and emmetropic glaucomatous eyes using confocal scanning laser ophthalmoscopy. Further, the ability of the apparatus in glaucoma diagnosis in highly myopic eyes was compared with that in emmetropic eyes. METHODS: Healthy subjects and age-matched patients with early stage open-angle glaucoma were divided into two groups: emmetropic eyes (-1.0 to +1.0 diopters) and highly myopic eyes (-12.0 to -5.0 diopters).The participants were comprised of 65 emmetropic normal eyes, 59 emmetropic glaucomatous eyes, 62 highly myopic normal eyes, and 68 highly myopic glaucomatous eyes and eyes with pathologic myopia were carefully excluded. Confocal scanning laser tomographic parameters were compared among all subjects after adjustment for age and disc area. The ROC curves and sensitivity and specificity for glaucoma detection using several clinical methods were then compared between the emmetropic and highly myopic eyes. RESULTS: Rim area, cup/disc area ratio, mean cup depth, and cup shape measure of glaucoma eyes are significantly different from those of normal eyes in both highly myopic eyes and emmetropic eyes. Methodological overestimation of retinal nerve fiber layer cross sectional area due to optic disc tilting was suggested in the highly myopic eyes. The diagnostic performance of glaucoma using several discriminant methods significantly deteriorated in the highly myopic eyes. CONCLUSIONS: In the highly myopic glaucomatous eyes, confocal scanning laser tomographic parameters were significantly different from that of non-glaucomatous highly myopic eyes but diagnostic performance of glaucoma was deteriorated than that in emmetropic eyes. These findings demonstrate the utility and limitations of the apparatus in diagnosing glaucoma in highly myopic patients. PMID- 24475118 TI - Comparative study of nanosecond electric fields in vitro and in vivo on hepatocellular carcinoma indicate macrophage infiltration contribute to tumor ablation in vivo. AB - BACKGROUND AND AIM: Recurrence and metastasis are associated with poor prognosis in hepatocellular carcinoma even in the patients who have undergone radical resection. Therefore, effective treatment is urgently needed for improvement of patients' survival. Previously, we reported that nanosecond pulse electric fields (nsPEFs) can ablate melanoma by induction of apoptosis and inhibition of angiogenesis. This study aims to investigate the in vivo ablation strategy by comparing the dose effect of nanosecond electric fields in vitro and in vivo on hepatocellular carcinoma. MATERIALS AND METHODS: Four hepatocellular carcinoma cell lines HepG2, SMMC7721, Hep1-6, and HCCLM3 were pulsed to test the anti proliferation and anti-migration ability of 100 ns nsPEFs in vitro. The animal model of human subdermal xenograft HCCLM3 cells into BALB/c nude mouse was used to test the anti-tumor growth and macrophage infiltration in vivo. RESULTS: In vitro assays showed anti-tumor effect of nsPEFs is dose-dependant. But the in vivo study showed the strategy of low dose and multiple treatments is superior to high dose single treatment. The macrophages infiltration significantly increased in the tumors which were treated by multiple low dose nsPEFs. CONCLUSION: The low dose multiple nsPEFs application is more efficient than high dose single treatment in inhibiting the tumor volume in vivo, which is quite different from the dose-effect relationship in vitro. Beside the electric field strength, the macrophage involvement must be considered to account for effect variability and toxicology in vivo. PMID- 24475119 TI - Microzooplankton growth rates examined across a temperature gradient in the Barents Sea. AB - Growth rates (u) of abundant microzooplankton species were examined in field experiments conducted at ambient sea temperatures (-1.8-9.0 degrees C) in the Barents Sea and adjacent waters (70-78.5 degrees N). The maximum species-specific u of ciliates and athecate dinoflagellates (0.33-1.67 d(-1) and 0.52-1.14 d(-1), respectively) occurred at temperatures below 5 degrees C and exceeded the umax predicted by previously published, laboratory culture-derived equations. The opposite trend was found for thecate dinoflagellates, which grew faster in the warmer Atlantic Ocean water. Mixotrophic ciliates and dinoflagellates grew faster than their heterotrophic counterparts. At sub-zero temperatures, microzooplankton umax matched those predicted for phytoplankton by temperature-dependent growth equations. These results indicate that microzooplankton protists may be as adapted to extreme Arctic conditions as their algal prey. PMID- 24475120 TI - LIN28 is involved in glioma carcinogenesis and predicts outcomes of glioblastoma multiforme patients. AB - LIN28, an evolutionarily conversed RNA binding protein which can bind to the terminal loops of let-7 family microRNA precursors and block their processing to maturation, is highly expressed in several subsets of tumors that carry poor prognoses, such as ovarian carcinoma, hepatocellular carcinoma, colon carcinoma and germ cell carcinoma. However, there has been no study on the expression of LIN28 in glioma tissues or their importance as a prognostic predictor of glioma patients. This study aimed to examine the expression of LIN28 in glioma and correlate the results to patient outcome. We found that LIN28 expression was significantly higher in the group of patients with a poor prognosis compared to patients with a good prognosis by gene microarray. Log-rank analysis showed patients with higher LIN28 expression level in tumor had a shorter progression free survival and overall survival times compared to those with lower LIN28 expression level. Similar results were also obtained from the tissue microarray analysis. Univariate and multivariate analyses showed high LIN28 expression was an independent prognostic factor for a shorter progression-free survival and overall survival in GBM patients. Furthermore in vitro experiments showed that down-regulation of LIN28 in U251 and U373 cells caused cell cycle arrest in the G1 phase, delayed cell proliferation, increased apoptosis, and resulted in fewer colonies compared to controls. Summarily, our data provides a potential target for cancer therapy as an approach to overcome the poor options currently available for GBM patients. PMID- 24475121 TI - Genome sequence and analysis of Buzura suppressaria nucleopolyhedrovirus: a group II Alphabaculovirus. AB - The genome of Buzura suppressaria nucleopolyhedrovirus (BusuNPV) was sequenced by 454 pyrosequencing technology. The size of the genome is 120,420 bp with 36.8% G+C content. It contains 127 hypothetical open reading frames (ORFs) covering 90.7% of the genome and includes the 37 conserved baculovirus core genes, 84 genes found in other baculoviruses, and 6 unique ORFs. No typical baculoviral homologous repeats (hrs) were present but the genome contained a region of repeated sequences. Gene Parity Plots revealed a 28.8 kb region conserved among the alpha- and beta-baculoviruses. Overall comparisons of BusuNPV to other baculoviruses point to a distinct species in group II Alphabaculovirus. PMID- 24475122 TI - A distinct type of heterochromatin at the telomeric region of the Drosophila melanogaster Y chromosome. AB - Heterochromatin assembly and its associated phenotype, position effect variegation (PEV), provide an informative system to study chromatin structure and genome packaging. In the fruit fly Drosophila melanogaster, the Y chromosome is entirely heterochromatic in all cell types except the male germline; as such, Y chromosome dosage is a potent modifier of PEV. However, neither Y heterochromatin composition, nor its assembly, has been carefully studied. Here, we report the mapping and characterization of eight reporter lines that show male-specific PEV. In all eight cases, the reporter insertion sites lie in the telomeric transposon array (HeT-A and TART-B2 homologous repeats) of the Y chromosome short arm (Ys). Investigations of the impact on the PEV phenotype of mutations in known heterochromatin proteins (i.e., modifiers of PEV) show that this Ys telomeric region is a unique heterochromatin domain: it displays sensitivity to mutations in HP1a, EGG and SU(VAR)3-9, but no sensitivity to Su(z)2 mutations. It appears that the endo-siRNA pathway plays a major targeting role for this domain. Interestingly, an ectopic copy of 1360 is sufficient to induce a piRNA targeting mechanism to further enhance silencing of a reporter cytologically localized to the Ys telomere. These results demonstrate the diversity of heterochromatin domains, and the corresponding variation in potential targeting mechanisms. PMID- 24475123 TI - Linker-extended native cyanovirin-N facilitates PEGylation and potently inhibits HIV-1 by targeting the glycan ligand. AB - Cyanovirin-N (CVN) potently inhibits human immunodeficiency virus type 1 (HIV-1) infection, but both cytotoxicity and immunogenicity have hindered the translation of this protein into a viable therapeutic. A molecular docking analysis suggested that up to 12 residues were involved in the interaction of the reverse parallel CVN dimer with the oligosaccharide targets, among which Leu-1 was the most prominent hot spot residue. This finding provided a possible explanation for the lack of anti-HIV-1 activity observed with N-terminal PEGylated CVN. Therefore, linker-CVN (LCVN) was designed as a CVN derivative with a flexible and hydrophilic linker (Gly4Ser)3 at the N-terminus. The N-terminal alpha-amine of LCVN was PEGylated to create 10 K PEG-aldehyde (ALD)-LCVN. LCVN and 10 K PEG-ALD LCVN retained the specificity and affinity of CVN for high mannose N-glycans. Moreover, LCVN exhibited significant anti-HIV-1 activity with attenuated cytotoxicity in the HaCaT keratinocyte cell line and MT-4 T lymphocyte cell lines. 10 K PEG-ALD-LCVN also efficiently inactivated HIV-1 with remarkably decreased cytotoxicity and pronounced cell-to-cell fusion inhibitory activity in vitro. The linker-extended CVN and the mono-PEGylated derivative were determined to be promising candidates for the development of an anti-HIV-1 agent. This derivatization approach provided a model for the PEGylation of biologic candidates without introducing point mutations. PMID- 24475124 TI - A systematic review and meta-analysis of the association between serotonergic gene polymorphisms and obstructive sleep apnea syndrome. AB - BACKGROUND: 5-Hydroxytryptamine receptor (5-HTR) and 5-hydroxytryptamine transporter (5-HTT) gene polymorphisms have been reported to be associated with susceptibility to obstructive sleep apnea syndrome (OSAS). The associations, derived from sporadic, inconsistent, small-sample-size studies, need to be evaluated further in a meta-analysis. METHODS: Relevant studies were identified by searching PubMed, Embase, The Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang, and Weipu. Eligible data were extracted from each included study. Odds ratios (ORs) were calculated using a fixed-effects or a random-effects model. The ORs and 95% confidence interval (CI) were used to assess the strength of the association between serotonergic gene polymorphisms and OSAS in the dominant and recessive models, as well as alleles. The Q statistic was used to evaluate homogeneity and Begg's test was used to assess publication bias. RESULTS: Eight studies were finally included in the meta analysis of the association between 5-HTR2A gene variants (including 102T/C and 1438G/A), 5-HTT gene polymorphisms (including 5-HTT gene-linked promoter region (5-HTTLRP), and serotonin transporter intron 2 variable number tandem repeat (STin2VNTR) and OSAS risk. The G allele of 5-HTR2A 1438G/A, long 5-HTTLPR, and 10 tandem-repeats STin2VNTR were shown to increase OSAS susceptibility, with ORs of 2.33 (A vs. G, 95% CI 1.48-3.66), 1.24 (L vs. S, 95% CI: 1.04-1.49), and 2.87 (10 vs. 12, 95% CI: 1.38-5.97), respectively. These significant differences were determined in both dominant and recessive models. Of the 5-HTR2A 1438G/A gene polymorphism, the AA genotype increased the OSAS risk, with an OR of 4.21 (95% CI: 2.83-6.25) in a recessive model in male OSAS patients, but no significant association was found in females. CONCLUSIONS: Our meta-analysis demonstrated that polymorphisms in the 5-HTR2A 1438G/A and 5-HTT genes contributed to susceptibility to OSAS. The A allele of the 1438G/A gene polymorphism is predominantly distributed in males and increased the OSAS risk significantly. PMID- 24475125 TI - Expression of microRNAs and other small RNAs in prefrontal cortex in schizophrenia, bipolar disorder and depressed subjects. AB - Because of the role played by miRNAs in post-transcriptional regulation of an array of genes, their impact in neuropsychiatric disease pathophysiology has increasingly been evident. In the present study, we assessed microRNA expression in prefrontal cortex (Brodmann area 10) of a well-characterized cohort of major depressed, bipolar, and schizophrenia subjects (obtained from Stanley Neuropathology Consortium; n = 15 in each group), using high throughput RT-PCR plates. Discrete miRNA alterations were observed in all disorders, as well as in suicide subjects (pooled across diagnostic categories) compared to all non suicide subjects. The changes in the schizophrenia group were partially similar to those in the bipolar group, but distinct from changes in depression and suicide. Intriguingly, those miRNAs which were down-regulated in the schizophrenia group tended to be synaptically enriched, whereas up-regulated miRNAs tended not to be. To follow this up, we purified synaptosomes from pooled samples of the schizophrenia vs. control groups and subjected them to Illumina deep sequencing. There was a significant loss of small RNA expression in schizophrenia synaptosomes only for certain sequence lengths within the miRNA range. Moreover, 73 miRNAs were significantly down-regulated whereas only one was up-regulated. Strikingly, across all expressed miRNAs in synaptosomes, there was a significant inverse correlation between the fold-change of a given miRNA seen in schizophrenia and its synaptic enrichment ratio observed in controls. Thus, synaptic miRNAs tended to be down-regulated in schizophrenia, and the more highly synaptically enriched miRNAs tended to show greater down-regulation. These findings point to some deficit in miRNA biogenesis, transport, processing or turnover in schizophrenia that is selective for the synaptic compartment. A novel class of ncRNA-derived small RNAs, shown to be strongly induced during an early phase of learning in mouse, is also expressed in man, and at least one representative (SNORD85) was strongly down-regulated in schizophrenia synaptosomes. PMID- 24475126 TI - Depletion of brain docosahexaenoic acid impairs recovery from traumatic brain injury. AB - Omega-3 fatty acids are crucial for proper development and function of the brain where docosahexaenoic acid (DHA), the primary omega-3 fatty acid in the brain, is retained avidly by the neuronal membranes. We investigated the effect of DHA depletion in the brain on the outcome of traumatic brain injury (TBI). Pregnant mice were put on an omega-3 fatty acid adequate or deficient diet from gestation day 14 and the pups were raised on the respective diets. Continuation of this dietary regime for three generations resulted in approximately 70% loss of DHA in the brain. Controlled cortical impact was delivered to both groups of mice to produce severe TBI and the functional recovery was compared. Compared to the omega-3 adequate mice, the DHA depleted mice exhibited significantly slower recovery from motor deficits evaluated by the rotarod and the beam walk tests. Furthermore, the DHA deficient mice showed greater anxiety-like behavior tested in the open field test as well as cognitive deficits evaluated by the novel object recognition test. The level of alpha spectrin II breakdown products, the markers of TBI, was significantly elevated in the deficient mouse cortices, indicating that the injury is greater in the deficient brains. This observation was further supported by the reduction of NeuN positive cells around the site of injury in the deficient mice, indicating exacerbated neuronal death after injury. These results suggest an important influence of the brain DHA status on TBI outcome. PMID- 24475128 TI - Magnitude of the freshwater turtle exports from the US: long term trends and early effects of newly implemented harvest management regimes. AB - Unregulated commercial harvest remains a major threat for turtles across the globe. Due to continuing demand from Asian markets, a significant number of turtles are exported from the United States of America (US). Beginning in 2007, several southeastern states in the US implemented restrictions on the commercial harvest of turtles, in order to address the unsustainable take. We have summarized freshwater turtle exports from the US between 2002 and 2012 and demonstrated that the magnitude of turtle exports from the US remained high although the exports decreased throughout the decade. Louisiana and California were the major exporters. The majority of exports were captive bred, and from two genera, Pseudemys and Trachemys. We review the changes over the decade and speculate that the increase in export of wild turtles out of Louisiana after 2007 could be a consequence of strict regulations in surrounding states (e.g., Alabama, Florida). We suggest that if wild turtle protection is a goal for conservation efforts, then these states should work together to develop comprehensive regulation reforms pertaining to the harvest of wild turtles. PMID- 24475127 TI - C2orf62 and TTC17 are involved in actin organization and ciliogenesis in zebrafish and human. AB - Vertebrate genomes contain around 20,000 protein-encoding genes, of which a large fraction is still not associated with specific functions. A major task in future genomics will thus be to assign physiological roles to all open reading frames revealed by genome sequencing. Here we show that C2orf62, a highly conserved protein with little homology to characterized proteins, is strongly expressed in testis in zebrafish and mammals, and in various types of ciliated cells during zebrafish development. By yeast two hybrid and GST pull-down, C2orf62 was shown to interact with TTC17, another uncharacterized protein. Depletion of either C2orf62 or TTC17 in human ciliated cells interferes with actin polymerization and reduces the number of primary cilia without changing their length. Zebrafish embryos injected with morpholinos against C2orf62 or TTC17, or with mRNA coding for the C2orf62 C-terminal part containing a RII dimerization/docking (R2D2) - like domain show morphological defects consistent with imperfect ciliogenesis. We provide here the first evidence for a C2orf62-TTC17 axis that would regulate actin polymerization and ciliogenesis. PMID- 24475129 TI - Molecular evolution of a pervasive natural amino-acid substitution in Drosophila cryptochrome. AB - Genetic variations in circadian clock genes may serve as molecular adaptations, allowing populations to adapt to local environments. Here, we carried out a survey of genetic variation in Drosophila cryptochrome (cry), the fly's dedicated circadian photoreceptor. An initial screen of 10 European cry alleles revealed substantial variation, including seven non-synonymous changes. The SNP frequency spectra and the excessive linkage disequilibrium in this locus suggested that this variation is maintained by natural selection. We focused on a non conservative SNP involving a leucine-histidine replacement (L232H) and found that this polymorphism is common, with both alleles at intermediate frequencies across 27 populations surveyed in Europe, irrespective of latitude. Remarkably, we were able to reproduce this natural observation in the laboratory using replicate population cages where the minor allele frequency was initially set to 10%. Within 20 generations, the two allelic variants converged to approximately equal frequencies. Further experiments using congenic strains, showed that this SNP has a phenotypic impact, with variants showing significantly different eclosion profiles. At the long term, these phase differences in eclosion may contribute to genetic differentiation among individuals, and shape the evolution of wild populations. PMID- 24475130 TI - Toll mediated infection response is altered by gravity and spaceflight in Drosophila. AB - Space travel presents unlimited opportunities for exploration and discovery, but requires better understanding of the biological consequences of long-term exposure to spaceflight. Immune function in particular is relevant for space travel. Human immune responses are weakened in space, with increased vulnerability to opportunistic infections and immune-related conditions. In addition, microorganisms can become more virulent in space, causing further challenges to health. To understand these issues better and to contribute to design of effective countermeasures, we used the Drosophila model of innate immunity to study immune responses in both hypergravity and spaceflight. Focusing on infections mediated through the conserved Toll and Imd signaling pathways, we found that hypergravity improves resistance to Toll-mediated fungal infections except in a known gravitaxis mutant of the yuri gagarin gene. These results led to the first spaceflight project on Drosophila immunity, in which flies that developed to adulthood in microgravity were assessed for immune responses by transcription profiling on return to Earth. Spaceflight alone altered transcription, producing activation of the heat shock stress system. Space flies subsequently infected by fungus failed to activate the Toll pathway. In contrast, bacterial infection produced normal activation of the Imd pathway. We speculate on possible linkage between functional Toll signaling and the heat shock chaperone system. Our major findings are that hypergravity and spaceflight have opposing effects, and that spaceflight produces stress-related transcriptional responses and results in a specific inability to mount a Toll-mediated infection response. PMID- 24475131 TI - Short-term memory affects color perception in context. AB - Color-based object selection - for instance, looking for ripe tomatoes in the market - places demands on both perceptual and memory processes: it is necessary to form a stable perceptual estimate of surface color from a variable visual signal, as well as to retain multiple perceptual estimates in memory while comparing objects. Nevertheless, perceptual and memory processes in the color domain are generally studied in separate research programs with the assumption that they are independent. Here, we demonstrate a strong failure of independence between color perception and memory: the effect of context on color appearance is substantially weakened by a short retention interval between a reference and test stimulus. This somewhat counterintuitive result is consistent with Bayesian estimation: as the precision of the representation of the reference surface and its context decays in memory, prior information gains more weight, causing the retained percepts to be drawn toward prior information about surface and context color. This interaction implies that to fully understand information processing in real-world color tasks, perception and memory need to be considered jointly. PMID- 24475132 TI - Diverse metastable structures formed by small oligomers of alpha-synuclein probed by force spectroscopy. AB - Oligomeric aggregates are widely suspected as toxic agents in diseases caused by protein aggregation, yet they remain poorly characterized, partly because they are challenging to isolate from a heterogeneous mixture of species. We developed an assay for characterizing structure, stability, and kinetics of individual oligomers at high resolution and sensitivity using single-molecule force spectroscopy, and applied it to observe the formation of transient structured aggregates within single oligomers of alpha-synuclein, an intrinsically disordered protein linked to Parkinson's disease. Measurements of the molecular extension as the proteins unfolded under tension in optical tweezers revealed that even small oligomers could form numerous metastable structures, with a surprisingly broad range of sizes. Comparing the structures formed in monomers, dimers and tetramers, we found that the average mechanical stability increased with oligomer size. Most structures formed within a minute, with size-dependent rates. These results provide a new window onto the complex alpha-synuclein aggregation landscape, characterizing the microscopic structural heterogeneity and kinetics of different pathways. PMID- 24475133 TI - Effect of BDNF Val66Met on memory decline and hippocampal atrophy in prodromal Alzheimer's disease: a preliminary study. AB - OBJECTIVE: Cross-sectional genetic association studies have reported equivocal results on the relationship between the brain-derived neurotrophic factor (BDNF) Val66Met and risk of Alzheimer's disease (AD). As AD is a neurodegenerative disease, genetic influences may become clearer from prospective study. We aimed to determine whether BDNF Val66Met polymorphism influences changes in memory performance, hippocampal volume, and Abeta accumulation in adults with amnestic mild cognitive impairment (aMCI) and high Abeta. METHODS: Thirty-four adults with aMCI were recruited from the Australian, Imaging, Biomarkers and Lifestyle (AIBL) Study. Participants underwent PiB-PET and structural MRI neuroimaging, neuropsychological assessments and BDNF genotyping at baseline, 18 month, and 36 month assessments. RESULTS: In individuals with aMCI and high Abeta, Met carriers showed significant and large decline in episodic memory (d = 0.90, p = .020) and hippocampal volume (d = 0.98, p = .035). BDNF Val66Met was unrelated to the rate of Abeta accumulation (d = -0.35, p = .401). CONCLUSIONS: Although preliminary due to the small sample size, results of this study suggest that high Abeta levels and Met carriage may be useful prognostic markers of accelerated decline in episodic memory, and reductions in hippocampal volume in individuals in the prodromal or MCI stage of AD. PMID- 24475134 TI - ASDCD: antifungal synergistic drug combination database. AB - Finding effective drugs to treat fungal infections has important clinical significance based on high mortality rates, especially in an immunodeficient population. Traditional antifungal drugs with single targets have been reported to cause serious side effects and drug resistance. Nowadays, however, drug combinations, particularly with respect to synergistic interaction, have attracted the attention of researchers. In fact, synergistic drug combinations could simultaneously affect multiple subpopulations, targets, and diseases. Therefore, a strategy that employs synergistic antifungal drug combinations could eliminate the limitations noted above and offer the opportunity to explore this emerging bioactive chemical space. However, it is first necessary to build a powerful database in order to facilitate the analysis of drug combinations. To address this gap in our knowledge, we have built the first Antifungal Synergistic Drug Combination Database (ASDCD), including previously published synergistic antifungal drug combinations, chemical structures, targets, target-related signaling pathways, indications, and other pertinent data. Its current version includes 210 antifungal synergistic drug combinations and 1225 drug-target interactions, involving 105 individual drugs from more than 12,000 references. ASDCD is freely available at http://ASDCD.amss.ac.cn. PMID- 24475135 TI - Evaluating the potential bioactivity of a novel compound ER1626. AB - BACKGROUND: ER1626, a novel compound, is a derivate of indeno-isoquinoline ketone. This study was designed to evaluate the biological activity and potential anti-tumor mechanism of ER1626. METHOD: MTT assay, scratch assay and flow cytometry were used to determine cell proliferation, cell migration and cell cycle distribution as well as cell apoptosis on human breast cancer MCF-7 cells and endometrial cancer Ishikawa cells. We also explored the antiangiogenic effect of ER1626 on HUVEC cells and chicken embryos. The expression of estrogen receptor protein was investigated with western-blot analysis. RESULTS: ER1626 down regulated the expression of estrogen receptor alpha protein and up-regulated beta protein in MCF-7 and Ishikawa cells. The value of IC50 of ER1626 on MCF-7 and Ishikawa cells were respectively 8.52 and 3.08 umol/L. Meanwhile, ER1626 decreased VEGF secretion of MCF-7 and Ishikawa cells, disturbed the formation of VEGF-stimulated tubular structure in HUVEC cells, and inhibited the angiogenesis on the chicken chorioallantoic membrane. Scratch assay revealed that ER1626 suppressed the migration of MCF-7, Ishikawa and HUVEC cells. In addition to induction tumor cell apoptosis, ER1626 arrested cell cycle in G1/G0 phase in MCF 7 cells and G2/M phase in Ishikawa cells. CONCLUSION: In conclusion, our results demonstrated that ER1626 has favorable bioactivities to be a potential candidate against breast cancer and angiogenesis. PMID- 24475136 TI - Leukotriene B4 levels in human atherosclerotic plaques and abdominal aortic aneurysms. AB - BACKGROUND: Leukotriene B4 (LTB4) has been associated with the initiation and progression of atherosclerosis and abdominal aortic aneurysm (AAA) formation. However, associations of LTB4 levels with tissue characteristics and adverse clinical outcome of advanced atherosclerosis and AAA are scarcely studied. We hypothesized that LTB4 levels are associated with a vulnerable plaque phenotype and adverse clinical outcome. Furthermore, that LTB4 levels are associated with inflammatory AAA and adverse clinical outcome. METHODS: Atherosclerotic plaques and AAA specimens were selected from two independent databases for LTB4 measurements. Plaques were isolated during carotid endarterectomy from asymptomatic (n = 58) or symptomatic (n = 317) patients, classified prior to surgery. LTB4 levels were measured without prior lipid extraction and levels were corrected for protein content. LTB4 levels were related to plaque phenotype, baseline patient characteristics and clinical outcome within three years following surgery. Seven non-diseased mammary artery specimens served as controls. AAA specimens were isolated during open repair, classified as elective (n = 189), symptomatic (n = 29) or ruptured (n = 23). LTB4 levels were measured similar to the plaque measurements and were related to tissue characteristics, baseline patient characteristics and clinical outcome. Twenty-six non-diseased aortic specimens served as controls. RESULTS: LTB4 levels corrected for protein content were not significantly associated with histological characteristics specific for vulnerable plaques or inflammatory AAA as well as clinical presentation. Moreover, it could not predict secondary manifestations independently investigated in both databases. However, LTB4 levels were significantly lower in controls compared to plaque (p = 0.025) or AAA (p = 0.017). CONCLUSIONS: LTB4 levels were not associated with a vulnerable plaque phenotype or inflammatory AAA or clinical presentation. This study does not provide supportive evidence for a role of LTB4 in atherosclerotic plaque destabilization or AAA expansion. However, these data should be interpreted with care, since LTB4 measurements were performed without prior lipid extractions. PMID- 24475137 TI - Spatial repolarization heterogeneity detected by magnetocardiography correlates with cardiac iron overload and adverse cardiac events in beta-thalassemia major. AB - BACKGROUND: Patients with transfusion-dependent beta-thalassemia major (TM) are at risk for myocardial iron overload and cardiac complications. Spatial repolarization heterogeneity is known to be elevated in patients with certain cardiac diseases, but little is known in TM patients. The purpose of this study was to evaluate spatial repolarization heterogeneity in patients with TM, and to investigate the relationships between spatial repolarization heterogeneity, cardiac iron load, and adverse cardiac events. METHODS AND RESULTS: Fifty patients with TM and 55 control subjects received 64-channel magnetocardiography (MCG) to determine spatial repolarization heterogeneity, which was evaluated by a smoothness index of QTc (SI-QTc), a standard deviation of QTc (SD-QTc), and a QTc dispersion. Left ventricular function and myocardial T2* values were assessed by cardiac magnetic resonance. Patients with TM had significantly greater SI-QTc, SD QTc, and QTc dispersion compared to the control subjects (all p values<0.001). Spatial repolarization heterogeneity was even more pronounced in patients with significant iron overload (T2*<20 ms, n = 20) compared to those with normal T2* (all p values<0.001). Loge cardiac T2* correlated with SI-QTc (r = -0.609, p<0.001), SD-QTc (r = -0.572, p<0.001), and QTc dispersion (r = -0.622, p<0.001), while all these indices had no relationship with measurements of the left ventricular geometry or function. At the time of study, 10 patients had either heart failure or arrhythmia. All 3 indices of repolarization heterogeneity were related to the presence of adverse cardiac events, with areas under the receiver operating characteristic curves (ranged between 0.79 and 0.86), similar to that of cardiac T2*. CONCLUSIONS: Multichannel MCG demonstrated that patients with TM had increased spatial repolarization heterogeneity, which is related to myocardial iron load and adverse cardiac events. PMID- 24475138 TI - Dual targeting of MEK and PI3K pathways attenuates established and progressive pulmonary fibrosis. AB - Pulmonary fibrosis is often triggered by an epithelial injury resulting in the formation of fibrotic lesions in the lung, which progress to impair gas exchange and ultimately cause death. Recent clinical trials using drugs that target either inflammation or a specific molecule have failed, suggesting that multiple pathways and cellular processes need to be attenuated for effective reversal of established and progressive fibrosis. Although activation of MAPK and PI3K pathways have been detected in human fibrotic lung samples, the therapeutic benefits of in vivo modulation of the MAPK and PI3K pathways in combination are unknown. Overexpression of TGFalpha in the lung epithelium of transgenic mice results in the formation of fibrotic lesions similar to those found in human pulmonary fibrosis, and previous work from our group shows that inhibitors of either the MAPK or PI3K pathway can alter the progression of fibrosis. In this study, we sought to determine whether simultaneous inhibition of the MAPK and PI3K signaling pathways is a more effective therapeutic strategy for established and progressive pulmonary fibrosis. Our results showed that inhibiting both pathways had additive effects compared to inhibiting either pathway alone in reducing fibrotic burden, including reducing lung weight, pleural thickness, and total collagen in the lungs of TGFalpha mice. This study demonstrates that inhibiting MEK and PI3K in combination abolishes proliferative changes associated with fibrosis and myfibroblast accumulation and thus may serve as a therapeutic option in the treatment of human fibrotic lung disease where these pathways play a role. PMID- 24475139 TI - ITE and TCDD differentially regulate the vascular remodeling of rat placenta via the activation of AhR. AB - Vascular remodeling in the placenta is essential for normal fetal development. The previous studies have demonstrated that in utero exposure to 2,3,7,8 tetrachlorodibenzo-p-dioxin (TCDD, an environmental toxicant) induces the intrauterine fetal death in many species via the activation of aryl hydrocarbon receptor (AhR). In the current study, we compared the effects of 2-(1'H-indole-3' carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) and TCDD on the vascular remodeling of rat placentas. Pregnant rats on gestational day (GD) 15 were randomly assigned into 5 groups, and were exposed to a single dose of 1.6 and 8.0 mg/kg body weight (bw) ITE, 1.6 and 8.0 ug/kg bw TCDD, or an equivalent volume of the vehicle, respectively. The dams were sacrificed on GD20 and the placental tissues were gathered. The intrauterine fetal death was observed only in 8.0 ug/kg bw TCDD-exposed group and no significant difference was seen in either the placental weight or the fetal weight among all these groups. The immunohistochemical and histological analyses revealed that as compared with the vehicle-control, TCDD, but not ITE, suppressed the placental vascular remodeling, including reduced the ratio of the placental labyrinth zone to the basal zone thickness (at least 0.71 fold of control), inhibited the maternal sinusoids dilation and thickened the trophoblastic septa. However, no marked difference was observed in the density of fetal capillaries in the labyrinth zone among these groups, although significant differences were detected in the expression of angiogenic growth factors between ITE and TCDD-exposed groups, especially Angiopoietin-2 (Ang-2), Endoglin, Interferon-gamma (IFN-gamma) and placenta growth factor (PIGF). These results suggest ITE and TCDD differentially regulate the vascular remodeling of rat placentas, as well as the expression of angiogenic factors and their receptors, which in turn may alter the blood flow in the late gestation and partially resulted in intrauterine fetal death. PMID- 24475140 TI - Role of lymphocyte activation gene-3 (Lag-3) in conventional and regulatory T cell function in allogeneic transplantation. AB - Lag-3 has emerged as an important molecule in T cell biology. We investigated the role of Lag-3 in conventional T cell (Tcon) and regulatory T cell (Treg) function in murine GVHD with the hypothesis that Lag-3 engagement diminishes alloreactive T cell responses after bone marrow transplantation. We demonstrate that Lag-3 deficient Tcon (Lag-3(-/-) Tcon) induce significantly more severe GVHD than wild type (WT) Tcon and that the absence of Lag-3 on CD4 but not CD8 T cells is responsible for exacerbating GVHD. Lag-3(-/-) Tcon exhibited increased activation and proliferation as indicated by CFSE and bioluminescence imaging analyses and higher levels of activation markers such as CD69, CD107a, granzyme B, and Ki-67 as well as production of IL-10 and IFN-g early after transplantation. Lag-3(-/-) Tcon were less responsive to suppression by WT Treg as compared to WT Tcon. The absence of Lag-3, however, did not impair Treg function as both Lag-3(-/-) and WT Treg equally suppress the proliferation of Tcon in vitro and in vivo and protect against GVHD. Further, we demonstrate that allogeneic Treg acquire recipient MHC class II molecules through a process termed trogocytosis. As MHC class II is a ligand for Lag-3, we propose a novel suppression mechanism employed by Treg involving the acquisition of host MHC-II followed by the engagement of Lag-3 on T cells. These studies demonstrate for the first time the biologic function of Lag 3 expression on conventional and regulatory T cells in GVHD and identify Lag-3 as an important regulatory molecule involved in alloreactive T cell proliferation and activation after bone marrow transplantation. PMID- 24475141 TI - Farnesoid X receptor ligand prevents cisplatin-induced kidney injury by enhancing small heterodimer partner. AB - The farnesoid X receptor (FXR) is mainly expressed in liver, intestine and kidney. We investigated whether 6-ethyl chenodeoxycholic acid (6ECDCA), a semisynthetic derivative of chenodeoxycholic aicd (CDCA, an FXR ligand), protects against kidney injury and modulates small heterodimer partner (SHP) in cisplatin induced kidney injury. Cisplatin inhibited SHP protein expression in the kidney of cisplatin-treated mice and human proximal tubular (HK2) cells; this effect was counteracted by FXR ligand. Hematoxylin and eosin staining revealed the presence of tubular casts, obstructions and dilatations in cisplatin-induced kidney injury, which was attenuated by FXR ligand. FXR ligand also attenuated protein expression of transforming growth factor-beta1 (TGF-beta1), Smad signaling, and the epithelial-to-mesenchymal transition process, inflammatory markers and cytokines, and apoptotic markers in cisplatin-treated mice. Cisplatin induced NF kappaB activation in HK2 cell; this effect was attenuated by pretreatment with FXR ligand. In SHP knockdown by small interfering RNA, cisplatin-induced activation of TGF-beta1, p-JNK and Bax/Bcl-2 ratio was not attenuated, while SHP overexpression and FXR ligand inhibited expression of these proteins in cisplatin pretreated HK2 cells. In conclusion, FXR ligand, 6ECDCA prevents cisplatin induced kidney injury, the underlying mechanism of which may be associated with anti-fibrotic, anti-inflammatory, and anti-apoptotic effects through SHP induction. PMID- 24475143 TI - Aqueous extract of Gracilaria tenuistipitata suppresses LPS-induced NF-kappaB and MAPK activation in RAW 264.7 and rat peritoneal macrophages and exerts hepatoprotective effects on carbon tetrachloride-treated rat. AB - In addition to the previous investigations of bioactivity of aqueous extract of the edible Gracilaria tenuistipitata (AEGT) against H2O2-induced DNA damage and hepatitis C virus replication, the purpose of this study is to evaluate the potential therapeutic properties of AEGT against inflammation and hepatotoxicity using lipopolysaccharide (LPS)-stimulated mouse RAW 264.7 cells, primary rat peritoneal macrophages and carbon tetrachloride (CCl4)-induced acute hepatitis model in rats. AEGT concentration-dependently inhibited the elevated RNA and protein levels of inducible nitric oxide synthase and cyclooxygenase-2, thereby reducing nitric oxide and prostaglandin E2 levels, respectively. Moreover, AEGT significantly suppressed the production of LPS-induced proinflammatory cytokines, including interleukin (IL)-1beta, IL-6 and tumor necrosis factor-alpha. These inhibitory effects were associated with the suppression of nuclear factor-kappa B activation and mitogen-activated protein kinase phosphorylation by AEGT in LPS stimulated cells. In addition, we highlighted the hepatoprotective and curative effects of AEGT in a rat model of CCl4-intoxicated acute liver injury, which was evident from reduction in the elevated serum aspartate aminotransferase and alanine aminotransferase levels as well as amelioration of histological damage by pre-treatment or post-treatment of AEGT. In conclusion, the results demonstrate that AEGT may serve as a potential supplement in the prevention or amelioration of inflammatory diseases. PMID- 24475142 TI - Randomized controlled ferret study to assess the direct impact of 2008-09 trivalent inactivated influenza vaccine on A(H1N1)pdm09 disease risk. AB - During spring-summer 2009, several observational studies from Canada showed increased risk of medically-attended, laboratory-confirmed A(H1N1)pdm09 illness among prior recipients of 2008-09 trivalent inactivated influenza vaccine (TIV). Explanatory hypotheses included direct and indirect vaccine effects. In a randomized placebo-controlled ferret study, we tested whether prior receipt of 2008-09 TIV may have directly influenced A(H1N1)pdm09 illness. Thirty-two ferrets (16/group) received 0.5 mL intra-muscular injections of the Canadian manufactured, commercially-available, non-adjuvanted, split 2008-09 Fluviral or PBS placebo on days 0 and 28. On day 49 all animals were challenged (Ch0) with A(H1N1)pdm09. Four ferrets per group were randomly selected for sacrifice at day 5 post-challenge (Ch+5) and the rest followed until Ch+14. Sera were tested for antibody to vaccine antigens and A(H1N1)pdm09 by hemagglutination inhibition (HI), microneutralization (MN), nucleoprotein-based ELISA and HA1-based microarray assays. Clinical characteristics and nasal virus titers were recorded pre-challenge then post-challenge until sacrifice when lung virus titers, cytokines and inflammatory scores were determined. Baseline characteristics were similar between the two groups of influenza-naive animals. Antibody rise to vaccine antigens was evident by ELISA and HA1-based microarray but not by HI or MN assays; virus challenge raised antibody to A(H1N1)pdm09 by all assays in both groups. Beginning at Ch+2, vaccinated animals experienced greater loss of appetite and weight than placebo animals, reaching the greatest between-group difference in weight loss relative to baseline at Ch+5 (7.4% vs. 5.2%; p = 0.01). At Ch+5 vaccinated animals had higher lung virus titers (log-mean 4.96 vs. 4.23pfu/mL, respectively; p = 0.01), lung inflammatory scores (5.8 vs. 2.1, respectively; p = 0.051) and cytokine levels (p>0.05). At Ch+14, both groups had recovered. Findings in influenza-naive, systematically-infected ferrets may not replicate the human experience. While they cannot be considered conclusive to explain human observations, these ferret findings are consistent with direct, adverse effect of prior 2008-09 TIV receipt on A(H1N1)pdm09 illness. As such, they warrant further in-depth investigation and search for possible mechanistic explanations. PMID- 24475144 TI - The effect of souvenaid on functional brain network organisation in patients with mild Alzheimer's disease: a randomised controlled study. AB - BACKGROUND: Synaptic loss is a major hallmark of Alzheimer's disease (AD). Disturbed organisation of large-scale functional brain networks in AD might reflect synaptic loss and disrupted neuronal communication. The medical food Souvenaid, containing the specific nutrient combination Fortasyn Connect, is designed to enhance synapse formation and function and has been shown to improve memory performance in patients with mild AD in two randomised controlled trials. OBJECTIVE: To explore the effect of Souvenaid compared to control product on brain activity-based networks, as a derivative of underlying synaptic function, in patients with mild AD. DESIGN: A 24-week randomised, controlled, double-blind, parallel-group, multi-country study. PARTICIPANTS: 179 drug-naive mild AD patients who participated in the Souvenir II study. INTERVENTION: Patients were randomised 1?1 to receive Souvenaid or an iso-caloric control product once daily for 24 weeks. OUTCOME: In a secondary analysis of the Souvenir II study, electroencephalography (EEG) brain networks were constructed and graph theory was used to quantify complex brain structure. Local brain network connectivity (normalised clustering coefficient gamma) and global network integration (normalised characteristic path length lambda) were compared between study groups, and related to memory performance. RESULTS: THE NETWORK MEASURES IN THE BETA BAND WERE SIGNIFICANTLY DIFFERENT BETWEEN GROUPS: they decreased in the control group, but remained relatively unchanged in the active group. No consistent relationship was found between these network measures and memory performance. CONCLUSIONS: The current results suggest that Souvenaid preserves the organisation of brain networks in patients with mild AD within 24 weeks, hypothetically counteracting the progressive network disruption over time in AD. The results strengthen the hypothesis that Souvenaid affects synaptic integrity and function. Secondly, we conclude that advanced EEG analysis, using the mathematical framework of graph theory, is useful and feasible for assessing the effects of interventions. TRIAL REGISTRATION: Dutch Trial Register NTR1975. PMID- 24475145 TI - The soil bacterial communities of South African fynbos riparian ecosystems invaded by Australian Acacia species. AB - Riparian ecosystem along rivers and streams are characterised by lateral and longitudinal ecological gradients and, as a result, harbour unique biodiversity. Riparian ecosystems in the fynbos of the Western Cape, South Africa, are characterised by seasonal dynamics, with summer droughts followed by high flows during winter. The unique hydrology and geomorphology of riparian ecosystems play an important role in shaping these ecosystems. The riparian vegetation in the Western Cape has, however, largely been degraded due to the invasion of non indigenous plants, in particular Acacia mearnsii, A. saligna and A. dealbata. This study investigated the effect of hydrology and invasion on the bacterial communities associated with fynbos riparian ecosystems. Bacterial communities were characterised with automated ribosomal intergenic spacer analysis (ARISA) and 454 16S rDNA pyrosequencing. Chemical and physical properties of soil within sites were also determined and correlated with community data. Sectioning across the lateral zones revealed significant differences in community composition, and the specific bacterial taxa influenced. Results also showed that the bacterial community structure could be linked to Acacia invasion. The presence of invasive Acacia was correlated with specific bacterial phyla. However, high similarity between cleared and pristine sites suggests that the effect of Acacia on the soil bacterial community structure may not be permanent. This study demonstrates how soil bacterial communities are influenced by hydrological gradients associated with riparian ecosystems and the impact of Acacia invasion on these communities. PMID- 24475146 TI - A novel in vivo vascular imaging approach for hierarchical quantification of vasculature using contrast enhanced micro-computed tomography. AB - The vasculature of body tissues is continuously subject to remodeling processes originating at the micro-vascular level. The formation of new blood vessels (angiogenesis) is essential for a number of physiological and pathophysiological processes such as tissue regeneration, tumor development and the integration of artificial tissues. There are currently no time-lapsed in vivo imaging techniques providing information on the vascular network at the capillary level in a non destructive, three-dimensional and high-resolution fashion. This paper presents a novel imaging framework based on contrast enhanced micro-computed tomography (micro-CT) for hierarchical in vivo quantification of blood vessels in mice, ranging from largest to smallest structures. The framework combines for the first time a standard morphometric approach with densitometric analysis. Validation tests showed that the method is precise and robust. Furthermore, the framework is sensitive in detecting different perfusion levels after the implementation of a murine ischemia-reperfusion model. Correlation with both histological data and micro-CT analysis of vascular corrosion casts confirmed accuracy of the method. The newly developed time-lapsed imaging approach shows high potential for in vivo monitoring of a number of different physiological and pathological conditions in angiogenesis and vascular development. PMID- 24475148 TI - Automatic structural parcellation of mouse brain MRI using multi-atlas label fusion. AB - Multi-atlas segmentation propagation has evolved quickly in recent years, becoming a state-of-the-art methodology for automatic parcellation of structural images. However, few studies have applied these methods to preclinical research. In this study, we present a fully automatic framework for mouse brain MRI structural parcellation using multi-atlas segmentation propagation. The framework adopts the similarity and truth estimation for propagated segmentations (STEPS) algorithm, which utilises a locally normalised cross correlation similarity metric for atlas selection and an extended simultaneous truth and performance level estimation (STAPLE) framework for multi-label fusion. The segmentation accuracy of the multi-atlas framework was evaluated using publicly available mouse brain atlas databases with pre-segmented manually labelled anatomical structures as the gold standard, and optimised parameters were obtained for the STEPS algorithm in the label fusion to achieve the best segmentation accuracy. We showed that our multi-atlas framework resulted in significantly higher segmentation accuracy compared to single-atlas based segmentation, as well as to the original STAPLE framework. PMID- 24475147 TI - Alternate reading frame protein (F protein) of hepatitis C virus: paradoxical effects of activation and apoptosis on human dendritic cells lead to stimulation of T cells. AB - Hepatitis C virus (HCV) leads to chronic infection in the majority of infected individuals due to lack, failure, or inefficiency of generated adaptive immune responses. In a minority of patients, acute infection is followed by viral clearance. The immune correlates of viral clearance are not clear yet but have been extensively investigated, suggesting that multispecific and multifunctional cellular immunity is involved. The generation of cellular immunity is highly dependent upon how antigen presenting cells (APCs) process and present various viral antigens. Various structural and non-structural HCV proteins derived from the open reading frame (ORF) have been implicated in modulation of dendritic cells (DCs) and APCs. Besides the major ORF proteins, the HCV core region also encodes an alternate reading frame protein (ARFP or F), whose function in viral pathogenesis is not clear. In the current studies, we sought to determine the role of HCV-derived ARFP in modulating dendritic cells and stimulation of T cell responses. Recombinant adenovirus vectors containing F or core protein derived from HCV (genotype 1a) were prepared and used to endogenously express these proteins in dendritic cells. We made an intriguing observation that endogenous expression of F protein in human DCs leads to contrasting effects on activation and apoptosis of DCs, allowing activated DCs to efficiently internalize apoptotic DCs. These in turn result in efficient ability of DCs to process and present antigen and to prime and stimulate F protein derived peptide-specific T cells from HCV-naive individuals. Taken together, our findings suggest important aspects of F protein in modulating DC function and stimulating T cell responses in humans. PMID- 24475149 TI - Associations between serum apelin-12 levels and obesity-related markers in Chinese children. AB - OBJECTIVE: To investigate possible correlations between apelin-12 levels and obesity in children in China and associations between apelin-12 and obesity related markers, including lipids, insulin sensitivity and insulin resistance index (HOMA-IR). METHODS: Forty-eight obese and forty non-obese age- and gender matched Chinese children were enrolled between June 2008 and June 2009. Mean age was 10.42 +/- 2.03 and 10.86+/-2.23 years in obesity and control groups, respectively. Main outcome measures were apelin-12, BMI, lipids, glucose and insulin. HOMA-IR was calculated for all subjects. RESULTS: All obesity group subjects had significantly higher total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), insulin levels and HOMA-IR (all P<0.05). In separate analyses, obese girls had significantly higher LDL-C, insulin and HOMA-IR than controls, and obese boys had significantly higher TC, TG, insulin and HOMA-IR than controls (all P<0.05). Apelin-12 levels were significantly higher in obese girls compared to controls (P = 0.024), and correlated positively with TG in all obese subjects. Among obese girls, apelin-12 levels correlated positively with TG, insulin and HOMA-IR after adjusting for age and BMI. In all boys (obese and controls) apelin-12 was positively associated with fasting plasma glucose (FPG). No significant correlations were found in either group between apelin-12 levels and other characteristics after adjusting for age, sex, and BMI. CONCLUSIONS: Apelin-12 levels are significantly higher in obese vs. non-obese girls in China and correlate significantly with obesity-related markers insulin, HOMA-IR, and TG. Increased apelin-12 levels may be involved in the pathological mechanism of childhood obesity. PMID- 24475150 TI - Is there 'anther-anther interference' within a flower? Evidences from one-by-one stamen movement in an insect-pollinated plant. AB - The selective pressure imposed by maximizing male fitness (pollen dispersal) in shaping floral structures is increasingly recognized and emphasized in current plant sciences. To maximize male fitness, many flowers bear a group of stamens with temporally separated anther dehiscence that prolongs presentation of pollen grains. Such an advantage, however, may come with a cost resulting from interference of pollen removal by the dehisced anthers. This interference between dehisced and dehiscing anthers has received little attention and few experimental tests to date. Here, using one-by-one stamen movement in the generalist pollinated Parnassia palustris, we test this hypothesis by manipulation experiments in two years. Under natural conditions, the five fertile stamens in P. palustris flowers elongate their filaments individually, and anthers dehisce successively one-by-one. More importantly, the anther-dehisced stamen bends out of the floral center by filament deflexion before the next stamen's anther dehiscence. Experimental manipulations show that flowers with dehisced anther remaining at the floral center experience shorter (1/3-1/2 less) visit durations by pollen-collecting insects (mainly hoverflies and wasps) because these 'hungry' insects are discouraged by the scant and non-fresh pollen in the dehisced anther. Furthermore, the dehisced anther blocks the dehiscing anther's access to floral visitors, resulting in a nearly one third decrease in their contact frequency. As a result, pollen removal of the dehiscing anther decreases dramatically. These results provide the first direct experimental evidence that anther-anther interference is possible in a flower, and that the selection to reduce such interferences can be a strong force in floral evolution. We also propose that some other floral traits, usually interpreted as pollen dispensing mechanisms, may function, at least partially, as mechanisms to promote pollen dispersal by reducing interferences between dehisced and dehiscing anthers. PMID- 24475151 TI - The great melting pot. Common sole population connectivity assessed by otolith and water fingerprints. AB - Quantifying the scale and importance of individual dispersion between populations and life stages is a key challenge in marine ecology. The common sole (Solea solea), an important commercial flatfish in the North Sea, Atlantic Ocean and the Mediterranean Sea, has a marine pelagic larval stage, a benthic juvenile stage in coastal nurseries (lagoons, estuaries or shallow marine areas) and a benthic adult stage in deeper marine waters on the continental shelf. To date, the ecological connectivity among these life stages has been little assessed in the Mediterranean. Here, such an assessment is provided for the first time for the Gulf of Lions, NW Mediterranean, based on a dataset on otolith microchemistry and stable isotopic composition as indicators of the water masses inhabited by individual fish. Specifically, otolith Ba/Ca and Sr/Ca profiles, and delta(13)C and delta(18)O values of adults collected in four areas of the Gulf of Lions were compared with those of young-of-the-year collected in different coastal nurseries. Results showed that a high proportion of adults (>46%) were influenced by river inputs during their larval stage. Furthermore Sr/Ca ratios and the otolith length at one year of age revealed that most adults (~70%) spent their juvenile stage in nurseries with high salinity, whereas the remainder used brackish environments. In total, data were consistent with the use of six nursery types, three with high salinity (marine areas and two types of highly saline lagoons) and three brackish (coastal areas near river mouths, and two types of brackish environments), all of which contributed to the replenishment of adult populations. These finding implicated panmixia in sole population in the Gulf of Lions and claimed for a habitat integrated management of fisheries. PMID- 24475152 TI - Cysteine string protein limits expression of the large conductance, calcium activated K+ (BK) channel. AB - Large-conductance, calcium-activated K(+) (BK) channels are widely distributed throughout the nervous system and play an essential role in regulation of action potential duration and firing frequency, along with neurotransmitter release at the presynaptic terminal. We have previously demonstrated that select mutations in cysteine string protein (CSPalpha), a presynaptic J-protein and co-chaperone, increase BK channel expression. This observation raised the possibility that wild type CSPalpha normally functions to limit neuronal BK channel expression. Here we show by Western blot analysis of transfected neuroblastoma cells that when BK channels are present at elevated levels, CSPalpha acts to reduce expression. Moreover, we demonstrate that the accessory subunits, BKbeta4 and BKbeta1 do not alter CSPalpha-mediated reduction of expressed BKalpha subunits. Structure function analysis reveals that the N-terminal J-domain of CSPalpha is critical for the observed regulation of BK channels levels. Finally, we demonstrate that CSPalpha limits BK current amplitude, while the loss-of-function homologue CSPalphaHPD-AAA increases BK current. Our observations indicate that CSPalpha has a role in regulating synaptic excitability and neurotransmission by limiting expression of BK channels. PMID- 24475153 TI - Combined effect of Cameo2 and CBP on the cellular uptake of lutein in the silkworm, Bombyx mori. AB - Formation of yellow-red color cocoons in the silkworm, Bombyx mori, occurs as the result of the selective delivery of carotenoids from the midgut to the silk gland via the hemolymph. This process of pigment transport is thought to be mediated by specific cellular carotenoids carrier proteins. Previous studies indicated that two proteins, Cameo2 and CBP, are associated with the selective transport of lutein from the midgut into the silk gland in Bombyx mori. However, the exact roles of Cameo2 and CBP during the uptake and transport of carotenoids are still unknown. In this study, we investigated the respective contributions of these two proteins to lutein and beta-carotene transport in Bombyx mori as well as commercial cell-line. We found that tissues, expressed both Cameo2 and CBP, accumulate lutein. Cells, co-expressed Cameo2 and CBP, absorb 2 fold more lutein (P<0.01) than any other transfected cells, and the rate of cellular uptake of lutein was concentration-dependent and reached saturation. From immunofluorescence staining, confocal microscopy observation and western blot analysis, Cameo2 was localized at the membrane and CBP was expressed in the cytosol. What's more, bimolecular fluorescence complementation analysis showed that these two proteins directly interacted at cellular level. Therefore, Cameo2 and CBP are necessarily expressed in midguts and silk glands for lutein uptake in Bombyx mori. Cameo2 and CBP, as the membrane protein and the cytosol protein, respectively, have the combined effect to facilitate the cellular uptake of lutein. PMID- 24475154 TI - SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR): a multi-center, retrospective, observational study. AB - BACKGROUND: Clinical practice guidelines have been slowly and inconsistently applied in clinical practice, and certain evidence-based, guideline-driven therapies for heart failure (HF) have been significantly underused. The purpose of this study was to survey guideline compliance and its effect on clinical outcomes in the treatment of systolic HF in Korea. METHOD AND RESULTS: The SUrvey of Guideline Adherence for Treatment of Systolic Heart Failure in Real World (SUGAR) trial was a multi-center, retrospective, observational study on subjects with systolic HF (ejection fraction <45%) admitted to 23 university hospitals. The guideline adherence indicator (GAI) was defined as a performance measure on the basis of 3 pharmacological classes: angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor II blocker (ARB), beta-blocker (BB), and aldosterone antagonist (AA). Based on the overall adherence percentage, subjects were divided into 2 groups: those with good guideline adherence (GAI >=50%) and poor guideline adherence (GAI <50%). We included 1319 regional participants as representatives of the standard population from the Korean national census in 2008. Adherence to drugs at discharge was as follows: ACEI or ARB, 89.7%; BB, 69.2%; and AA, 65.9%. Overall, 82.7% of the patients had good guideline adherence. Overall mortality and re-hospitalization rates at 1 year were 6.2% and 37.4%, respectively. Survival analysis by log-rank test showed a significant difference in event-free survival rate of mortality (94.7% vs. 89.8%, p = 0.003) and re-hospitalization (62.3% vs. 56.4%, p = 0.041) between the good and poor guideline-adherence groups. CONCLUSIONS: Among patients with systolic HF in Korea, adherence to pharmacologic treatment guidelines as determined by performance measures, including prescription of ACEI/ARB and BB at discharge, was associated with improved clinical outcomes. PMID- 24475155 TI - Maternal psychological distress and placental circulation in pregnancies after a previous offspring with congenital malformation. AB - INTRODUCTION: Antenatal maternal psychological distress may be associated with reduced placental circulation, which could lead to lower birthweight. Studies investigating this in humans show mixed results, which may be partially due to type, strength and timing of distress. In addition, the arterial vascular resistance measures often used as outcome measures do not detect smaller changes in placental volume blood flow. We aimed to investigate the effect of a specific stressor, with increased levels of stress early in pregnancy, on the fetoplacental volume blood flow in third trimester. METHODS: This was a prospective observational study of 74 pregnant women with a congenital malformation in a previous fetus or child. Psychological distress was assessed twice, around 16 and 30 weeks' gestation. Psychometric measures were the General Health Questionnaire-28 (subscales anxiety and depression), Edinburgh Postnatal Depression Scale, and Impact of Event Scale-22 (subscales intrusion, avoidance, and arousal). Placental circulation was examined at 30 weeks, using Doppler ultrasonography, primarily as fetoplacental volume blood flow in the umbilical vein, normalized for abdominal circumference; secondarily as vascular resistance measures, obtained from the umbilical and the uterine arteries. RESULTS: Maternal distress in second but not third trimester was associated with increased normalized fetoplacental blood flow (P-values 0.006 and 0.013 for score > mean for depression and intrusion, respectively). Post-hoc explorations suggested that a reduced birthweight/placental weight ratio may mediate this association. Psychological distress did not affect vascular resistance measures in the umbilical and uterine arteries, regardless of adjustment for confounders. CONCLUSIONS: In pregnant women with a previous fetus or child with a congenital malformation, higher distress levels in second trimester were associated with third trimester fetoplacental blood flow that was higher than expected for the size of the fetus. The results do not support placental blood flow reduction as a pathway between maternal distress and reduced birthweight. PMID- 24475156 TI - Effects of an anticarcinogenic Bowman-Birk protease inhibitor on purified 20S proteasome and MCF-7 breast cancer cells. AB - Proteasome inhibitors have been described as an important target for cancer therapy due to their potential to regulate the ubiquitin-proteasome system in the degradation pathway of cellular proteins. Here, we reported the effects of a Bowman-Birk-type protease inhibitor, the Black-eyed pea Trypsin/Chymotrypsin Inhibitor (BTCI), on proteasome 20S in MCF-7 breast cancer cells and on catalytic activity of the purified 20S proteasome from horse erythrocytes, as well as the structural analysis of the BTCI-20S proteasome complex. In vitro experiments and confocal microscopy showed that BTCI readily crosses the membrane of the breast cancer cells and co-localizes with the proteasome in cytoplasm and mainly in nucleus. Indeed, as indicated by dynamic light scattering, BTCI and 20S proteasome form a stable complex at temperatures up to 55 degrees C and at neutral and alkaline pHs. In complexed form, BTCI strongly inhibits the proteolytic chymotrypsin-, trypsin- and caspase-like activities of 20S proteasome, indicated by inhibition constants of 10(-7) M magnitude order. Besides other mechanisms, this feature can be associated with previously reported cytostatic and cytotoxic effects of BTCI in MCF-7 breast cancer cells by means of apoptosis. PMID- 24475157 TI - Fast-evolving mitochondrial DNA in Ceriantharia: a reflection of hexacorallia paraphyly? AB - The low evolutionary rate of mitochondrial genes in Anthozoa has challenged their utility for phylogenetic and systematic purposes, especially for DNA barcoding. However, the evolutionary rate of Ceriantharia, one of the most enigmatic "orders" within Anthozoa, has never been specifically examined. In this study, the divergence of mitochondrial DNA of Ceriantharia was compared to members of other Anthozoa and Medusozoa groups. In addition, nuclear markers were used to check the relative phylogenetic position of Ceriantharia in relation to other Cnidaria members. The results demonstrated a pattern of divergence of mitochondrial DNA completely different from those estimated for other anthozoans, and phylogenetic analyses indicate that Ceriantharia is not included within hexacorallians in most performed analyses. Thus, we propose that the Ceriantharia should be addressed as a separate clade. PMID- 24475158 TI - Intraspecific variation in cellular and biochemical heat response strategies of Mediterranean Xeropicta derbentina [Pulmonata, Hygromiidae]. AB - Dry and hot environments challenge the survival of terrestrial snails. To minimize overheating and desiccation, physiological and biochemical adaptations are of high importance for these animals. In the present study, seven populations of the Mediterranean land snail species Xeropicta derbentina were sampled from their natural habitat in order to investigate the intraspecific variation of cellular and biochemical mechanisms, which are assigned to contribute to heat resistance. Furthermore, we tested whether genetic parameters are correlated with these physiological heat stress response patterns. Specimens of each population were individually exposed to elevated temperatures (25 to 52 degrees C) for 8 h in the laboratory. After exposure, the health condition of the snails' hepatopancreas was examined by means of qualitative description and semi quantitative assessment of histopathological effects. In addition, the heat-shock protein 70 level (Hsp70) was determined. Generally, calcium cells of the hepatopancreas were more heat resistant than digestive cells - this phenomenon was associated with elevated Hsp70 levels at 40 degrees C.We observed considerable variation in the snails' heat response strategy: Individuals from three populations invested much energy in producing a highly elevated Hsp70 level, whereas three other populations invested energy in moderate stress protein levels - both strategies were in association with cellular functionality. Furthermore, one population kept cellular condition stable despite a low Hsp70 level until 40 degrees C exposure, whereas prominent cellular reactions were observed above this thermal limit. Genetic diversity (mitochondrial cytochrome c oxidase subunit I gene) within populations was low. Nevertheless, when using genetic indices as explanatory variables in a multivariate regression tree (MRT) analysis, population structure explained mean differences in cellular and biochemical heat stress responses, especially in the group exposed to 40 degrees C. Our study showed that, even in similar habitats within a close range, populations of the same species use different stress response strategies that all rendered survival possible. PMID- 24475159 TI - A cross-sectional study of disclosure of HIV status to children and adolescents in western Kenya. AB - INTRODUCTION: Disclosure of HIV status to children is essential for disease management but is not well characterized in resource-limited settings. This study aimed to describe the prevalence of disclosure and associated factors among a cohort of HIV-infected children and adolescents in Kenya. METHODS: We conducted a cross-sectional study, randomly sampling HIV-infected children ages 6-14 years attending 4 HIV clinics in western Kenya. Data were collected from questionnaires administered by clinicians to children and their caregivers, supplemented with chart review. Descriptive statistics and disclosure prevalence were calculated. Univariate analyses and multivariate logistic regression were performed to assess the association between disclosure and key child-level demographic, clinical and psychosocial characteristics. RESULTS: Among 792 caregiver-child dyads, mean age of the children was 9.7 years (SD = 2.6) and 51% were female. Prevalence of disclosure was 26% and varied significantly by age; while 62% of 14-year-olds knew their status, only 42% of 11-year-olds and 21% of 8-year-olds knew. In multivariate regression, older age (OR 1.49, 95%CI 1.35-1.63), taking antiretroviral drugs (OR 2.27, 95%CI 1.29-3.97), and caregiver-reported depression symptoms (OR 2.63, 95%CI 1.12-6.20) were significantly associated with knowing one's status. Treatment site was associated with disclosure for children attending one of the rural clinics compared to the urban clinic (OR 3.44, 95%CI 1.75-6.76). CONCLUSIONS: Few HIV-infected children in Kenya know their HIV status. The likelihood of disclosure is associated with clinical and psychosocial factors. More data are needed on the process of disclosure and its impact on children. PMID- 24475160 TI - Assessment of regional ventilation distribution: comparison of vibration response imaging (VRI) with electrical impedance tomography (EIT). AB - BACKGROUND: Vibration response imaging (VRI) is a bedside technology to monitor ventilation by detecting lung sound vibrations. It is currently unknown whether VRI is able to accurately monitor the local distribution of ventilation within the lungs. We therefore compared VRI to electrical impedance tomography (EIT), an established technique used for the assessment of regional ventilation. METHODOLOGY/PRINCIPAL FINDINGS: Simultaneous EIT and VRI measurements were performed in the healthy and injured lungs (ALI; induced by saline lavage) at different PEEP levels (0, 5, 10, 15 mbar) in nine piglets. Vibration energy amplitude (VEA) by VRI, and amplitudes of relative impedance changes (rel.DeltaZ) by EIT, were evaluated in seven regions of interest (ROIs). To assess the distribution of tidal volume (VT) by VRI and EIT, absolute values were normalized to the VT obtained by simultaneous spirometry measurements. Redistribution of ventilation by ALI and PEEP was detected by VRI and EIT. The linear correlation between pooled VT by VEA and rel.DeltaZ was R(2) = 0.96. Bland-Altman analysis showed a bias of -1.07+/-24.71 ml and limits of agreement of -49.05 to +47.36 ml. Within the different ROIs, correlations of VT-distribution by EIT and VRI ranged between R(2) values of 0.29 and 0.96. ALI and PEEP did not alter the agreement of VT between VRI and EIT. CONCLUSIONS/SIGNIFICANCE: Measurements of regional ventilation distribution by VRI are comparable to those obtained by EIT. PMID- 24475161 TI - QSOX1 inhibits autophagic flux in breast cancer cells. AB - The QSOX1 protein (Quiescin Sulfhydryl oxidase 1) catalyzes the formation of disulfide bonds and is involved in the folding and stability of proteins. More recently, QSOX1 has been associated with tumorigenesis and protection against cellular stress. It has been demonstrated in our laboratory that QSOX1 reduces proliferation, migration and invasion of breast cancer cells in vitro and reduces tumor growth in vivo. In addition, QSOX1 expression has been shown to be induced by oxidative or ER stress and to prevent cell death linked to these stressors. Given the function of QSOX1 in these two processes, which have been previously linked to autophagy, we wondered whether QSOX1 might be regulated by autophagy inducers and play a role in this catabolic process. To answer this question, we used in vitro models of breast cancer cells in which QSOX1 was overexpressed (MCF 7) or extinguished (MDA-MB-231). We first showed that QSOX1 expression is induced following amino acid starvation and maintains cellular homeostasis. Our results also indicated that QSOX1 inhibits autophagy through the inhibition of autophagosome/lysosome fusion. Moreover, we demonstrated that inhibitors of autophagy mimic the effect of QSOX1 on cell invasion, suggesting that its role in this process is linked to the autophagy pathway. Previously published data demonstrated that extinction of QSOX1 promotes tumor growth in NOG mice. In this study, we further demonstrated that QSOX1 null tumors present lower levels of the p62 protein. Altogether, our results demonstrate for the first time a role of QSOX1 in autophagy in breast cancer cells and tumors. PMID- 24475163 TI - Clustering HLA class I superfamilies using structural interaction patterns. AB - Human leukocyte antigen (HLA) class I molecules are critical components of the cell-mediated immune system that bind and present intracellular antigenic peptides to CD8(+) T cell receptors. To understand the interaction mechanism underlying human leukocyte antigen (HLA) class I specificity in detail, we studied the structural interaction characteristics of 16,393 nonameric peptides binding to 58 HLA-A and -B molecules. Our analysis showed for the first time that HLA-peptide intermolecular bonding patterns vary among different alleles and may be grouped in a superfamily dependent manner. Through the use of these HLA class I 'fingerprints', a high resolution HLA class I superfamily classification schema was developed. This classification is capable of separating HLA alleles into well resolved, non-overlapping clusters, which is consistent with known HLA superfamily definitions. Such structural interaction approach serves as an excellent alternative to the traditional methods of HLA superfamily definitions that use peptide binding motifs or receptor information, and will help identify appropriate antigens suitable for broad-based subunit vaccine design. PMID- 24475162 TI - Transcriptomic meta-analysis of multiple sclerosis and its experimental models. AB - BACKGROUND: Multiple microarray analyses of multiple sclerosis (MS) and its experimental models have been published in the last years. OBJECTIVE: Meta analyses integrate the information from multiple studies and are suggested to be a powerful approach in detecting highly relevant and commonly affected pathways. DATA SOURCES: ArrayExpress, Gene Expression Omnibus and PubMed databases were screened for microarray gene expression profiling studies of MS and its experimental animal models. STUDY ELIGIBILITY CRITERIA: Studies comparing central nervous system (CNS) samples of diseased versus healthy individuals with n >1 per group and publically available raw data were selected. MATERIAL AND METHODS: Included conditions for re-analysis of differentially expressed genes (DEGs) were MS, myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (EAE) in rats, proteolipid protein-induced EAE in mice, Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV IDD), and a transgenic tumor necrosis factor-overexpressing mouse model (TNFtg). Since solely a single MS raw data set fulfilled the inclusion criteria, a merged list containing the DEGs from two MS-studies was additionally included. Cross study analysis was performed employing list comparisons of DEGs and alternatively Gene Set Enrichment Analysis (GSEA). RESULTS: The intersection of DEGs in MS, EAE, TMEV-IDD, and TNFtg contained 12 genes related to macrophage functions. The intersection of EAE, TMEV-IDD and TNFtg comprised 40 DEGs, functionally related to positive regulation of immune response. Over and above, GSEA identified substantially more differentially regulated pathways including coagulation and JAK/STAT-signaling. CONCLUSION: A meta-analysis based on a simple comparison of DEGs is over-conservative. In contrast, the more experimental GSEA approach identified both, a priori anticipated as well as promising new candidate pathways. PMID- 24475164 TI - The uptake of soluble and particulate antigens by epithelial cells in the mouse small intestine. AB - Intestinal epithelial cells (IECs) overlying the villi play a prominent role in absorption of digested nutrients and establish a barrier that separates the internal milieu from potentially harmful microbial antigens. Several mechanisms by which antigens of dietary and microbial origin enter the body have been identified; however whether IECs play a role in antigen uptake is not known. Using in vivo imaging of the mouse small intestine, we investigated whether epithelial cells (enterocytes) play an active role in the uptake (sampling) of lumen antigens. We found that small molecular weight antigens such as chicken ovalbumin, dextran, and bacterial LPS enter the lamina propria, the loose connective tissue which lies beneath the epithelium via goblet cell associated passageways. However, epithelial cells overlying the villi can internalize particulate antigens such as bacterial cell debris and inert nanoparticles (NPs), which are then found co-localizing with the CD11c+ dendritic cells in the lamina propria. The extent of NP uptake by IECs depends on their size: 20-40 nm NPs are taken up readily, while NPs larger than 100 nm are taken up mainly by the epithelial cells overlying Peyer's patches. Blocking NPs with small proteins or conjugating them with ovalbumin does not inhibit their uptake. However, the uptake of 40 nm NPs can be inhibited when they are administered with an endocytosis inhibitor (chlorpromazine). Delineating the mechanisms of antigen uptake in the gut is essential for understanding how tolerance and immunity to lumen antigens are generated, and for the development of mucosal vaccines and therapies. PMID- 24475165 TI - Whole Pichia pastoris yeast expressing measles virus nucleoprotein as a production and delivery system to multimerize Plasmodium antigens. AB - Yeasts are largely used as bioreactors for vaccine production. Usually, antigens are produced in yeast then purified and mixed with adjuvants before immunization. However, the purification costs and the safety concerns recently raised by the use of new adjuvants argue for alternative strategies. To this end, the use of whole yeast as both production and delivery system appears attractive. Here, we evaluated Pichia pastoris yeast as an alternative vaccine production and delivery system for the circumsporozoite protein (CS) of Plasmodium, the etiologic agent of malaria. The CS protein from Plasmodium berghei (Pb) was selected given the availability of the stringent C57Bl/6 mouse model of infection by Pb sporozoites, allowing the evaluation of vaccine efficacy in vivo. PbCS was multimerized by fusion to the measles virus (MV) nucleoprotein (N) known to auto-assemble in yeast in large-size ribonucleoprotein rods (RNPs). Expressed in P. pastoris, the N-PbCS protein generated highly multimeric and heterogenic RNPs bearing PbCS on their surface. Electron microscopy and immunofluorescence analyses revealed the shape of these RNPs and their localization in peripheral cytoplasmic inclusions. Subcutaneous immunization of C57Bl/6 mice with heat-inactivated whole P. pastoris expressing N-PbCS RNPs provided significant reduction of parasitemia after intradermal challenge with a high dose of parasites. Thus, in the absence of accessory adjuvants, a very low amount of PbCS expressed in whole yeast significantly decreased clinical damages associated with Pb infection in a highly stringent challenge model, providing a proof of concept of the intrinsic adjuvancy of this vaccine strategy. In addition to PbCS multimerization, the N protein contributed by itself to parasitemia delay and long-term mice survival. In the future, mixtures of whole recombinant yeasts expressing relevant Plasmodium antigens would provide a multivalent formulation applicable for antigen combination screening and possibly for large-scale production, distribution and delivery of a malaria vaccine in developing countries. PMID- 24475166 TI - Detailed expression pattern of aldolase C (Aldoc) in the cerebellum, retina and other areas of the CNS studied in Aldoc-Venus knock-in mice. AB - Aldolase C (Aldoc, also known as "zebrin II"), a brain type isozyme of a glycolysis enzyme, is expressed heterogeneously in subpopulations of cerebellar Purkinje cells (PCs) that are arranged longitudinally in a complex striped pattern in the cerebellar cortex, a pattern which is closely related to the topography of input and output axonal projections. Here, we generated knock-in Aldoc-Venus mice in which Aldoc expression is visualized by expression of a fluorescent protein, Venus. Since there was no obvious phenotypes in general brain morphology and in the striped pattern of the cerebellum in mutants, we made detailed observation of Aldoc expression pattern in the nervous system by using Venus expression in Aldoc-Venus heterozygotes. High levels of Venus expression were observed in cerebellar PCs, cartwheel cells in the dorsal cochlear nucleus, sensory epithelium of the inner ear and in all major types of retinal cells, while moderate levels of Venus expression were observed in astrocytes and satellite cells in the dorsal root ganglion. The striped arrangement of PCs that express Venus to different degrees was carefully traced with serial section alignment analysis and mapped on the unfolded scheme of the entire cerebellar cortex to re-identify all individual Aldoc stripes. A longitudinally striped boundary of Aldoc expression was first identified in the mouse flocculus, and was correlated with the climbing fiber projection pattern and expression of another compartmental marker molecule, heat shock protein 25 (HSP25). As in the rat, the cerebellar nuclei were divided into the rostrodorsal negative and the caudoventral positive portions by distinct projections of Aldoc-positive and negative PC axons in the mouse. Identification of the cerebellar Aldoc stripes in this study, as indicated in sample coronal and horizontal sections as well as in sample surface photos of whole-mount preparations, can be referred to in future experiments. PMID- 24475167 TI - The non-classical MAP kinase ERK3 controls T cell activation. AB - The classical mitogen-activated protein kinases (MAPKs) ERK1 and ERK2 are activated upon stimulation of cells with a broad range of extracellular signals (including antigens) allowing cellular responses to occur. ERK3 is an atypical member of the MAPK family with highest homology to ERK1/2. Therefore, we evaluated the role of ERK3 in mature T cell response. Mouse resting T cells do not transcribe ERK3 but its expression is induced in both CD4+ and CD8+ T cells following T cell receptor (TCR)-induced T cell activation. This induction of ERK3 expression in T lymphocytes requires activation of the classical MAPK ERK1 and ERK2. Moreover, ERK3 protein is phosphorylated and associates with MK5 in activated primary T cells. We show that ERK3-deficient T cells have a decreased proliferation rate and are impaired in cytokine secretion following in vitro stimulation with low dose of anti-CD3 antibodies. Our findings identify the atypical MAPK ERK3 as a new and important regulator of TCR-induced T cell activation. PMID- 24475168 TI - Tumor necrosis factor alpha blocking agents as treatment for ulcerative colitis intolerant or refractory to conventional medical therapy: a meta-analysis. AB - BACKGROUND: Efficacy of tumor necrosis factor alpha (TNF-alpha) blockers for treatment of ulcerative colitis that is unresponsive to conventional therapy is unclear due to recent studies yielding conflicting results. AIM: To assess the efficacy and safety of anti-TNF-alpha agents for treatment of ulcerative colitis patients who were intolerant or refractory to conventional medical therapy. METHODS: Pubmed, Embase, and the Cochrane database were searched. Analysis was performed on randomized controlled trials that assessed anti-TNF-alpha therapy on ulcerative colitis patients that had previously failed therapy with corticosteroids and/or immunosuppressants. The primary outcome focused on was the frequency of patients that achieved clinical remission. Further trial outcomes of interest included rates of remission without patient use of corticosteroids during the trial, extent of mucosal healing, and the number of cases that resulted in colectomy and serious side effects. RESULTS: Eight trials from seven studies (n = 2122) met the inclusion criteria and were thus included during analysis. TNF-alpha blockers demonstrated clinical benefit as compared to placebo control as evidenced by an increased frequency of clinical remission (p<0.00001), steroid-free remission (p = 0.01), endoscopic remission (p<0.00001) and a decrease in frequency of colectomy (p = 0.03). No difference was found concerning serious side effects (p = 0.05). Three small trials (n = 57) comparing infliximab to corticosteroid treatment, showed no difference in frequency of clinical remission (p = 0.93), mucosal healing (p = 0.80), and requirement for a colectomy (p = 0.49). One trial compared infliximab to cyclosporine (n = 115), wherein no difference was found in terms of mucosal healing (p = 0.85), colectomy frequency (p = 0.60) and serious side effects (p = 0.23). CONCLUSION: TNF-alpha blockers are effective and safe therapies for the induction and maintenance of long-term remission and prevention of treatment by colectomy for patients with refractory ulcerative colitis where conventional treatment was previously ineffective. Furthermore, infliximab and cyclosporine were found to be comparable for treating acute severe steroid-refractory ulcerative colitis. PMID- 24475170 TI - Feeding kinematics, suction, and hydraulic jetting performance of harbor seals (Phoca vitulina). AB - The feeding kinematics, suction and hydraulic jetting capabilities of captive harbor seals (Phoca vitulina) were characterized during controlled feeding trials. Feeding trials were conducted using a feeding apparatus that allowed a choice between biting and suction, but also presented food that could be ingested only by suction. Subambient pressure exerted during suction feeding behaviors was directly measured using pressure transducers. The mean feeding cycle duration for suction-feeding events was significantly shorter (0.15+/-0.09 s; P<0.01) than biting feeding events (0.18+/-0.08 s). Subjects feeding in-water used both a suction and a biting feeding mode. Suction was the favored feeding mode (84% of all feeding events) compared to biting, but biting comprised 16% of feeding events. In addition, seals occasionally alternated suction with hydraulic jetting, or used hydraulic jetting independently, to remove fish from the apparatus. Suction and biting feeding modes were kinematically distinct regardless of feeding location (in-water vs. on-land). Suction was characterized by a significantly smaller gape (1.3+/-0.23 cm; P<0.001) and gape angle (12.9+/ 2.02 degrees ), pursing of the rostral lips to form a circular aperture, and pursing of the lateral lips to occlude lateral gape. Biting was characterized by a large gape (3.63+/-0.21 cm) and gape angle (28.8+/-1.80 degrees ; P<0.001) and lip curling to expose teeth. The maximum subambient pressure recorded was 48.8 kPa. In addition, harbor seals were able to jet water at food items using suprambient pressure, also known as hydraulic jetting. The maximum hydraulic jetting force recorded was 53.9 kPa. Suction and hydraulic jetting where employed 90.5% and 9.5%, respectively, during underwater feeding events. Harbor seals displayed a wide repertoire of behaviorally flexible feeding strategies to ingest fish from the feeding apparatus. Such flexibility of feeding strategies and biomechanics likely forms the basis of their opportunistic, generalized feeding ecology and concomitant breadth of diet. PMID- 24475169 TI - Sequence based prediction of DNA-binding proteins based on hybrid feature selection using random forest and Gaussian naive Bayes. AB - Developing an efficient method for determination of the DNA-binding proteins, due to their vital roles in gene regulation, is becoming highly desired since it would be invaluable to advance our understanding of protein functions. In this study, we proposed a new method for the prediction of the DNA-binding proteins, by performing the feature rank using random forest and the wrapper-based feature selection using forward best-first search strategy. The features comprise information from primary sequence, predicted secondary structure, predicted relative solvent accessibility, and position specific scoring matrix. The proposed method, called DBPPred, used Gaussian naive Bayes as the underlying classifier since it outperformed five other classifiers, including decision tree, logistic regression, k-nearest neighbor, support vector machine with polynomial kernel, and support vector machine with radial basis function. As a result, the proposed DBPPred yields the highest average accuracy of 0.791 and average MCC of 0.583 according to the five-fold cross validation with ten runs on the training benchmark dataset PDB594. Subsequently, blind tests on the independent dataset PDB186 by the proposed model trained on the entire PDB594 dataset and by other five existing methods (including iDNA-Prot, DNA-Prot, DNAbinder, DNABIND and DBD Threader) were performed, resulting in that the proposed DBPPred yielded the highest accuracy of 0.769, MCC of 0.538, and AUC of 0.790. The independent tests performed by the proposed DBPPred on completely a large non-DNA binding protein dataset and two RNA binding protein datasets also showed improved or comparable quality when compared with the relevant prediction methods. Moreover, we observed that majority of the selected features by the proposed method are statistically significantly different between the mean feature values of the DNA-binding and the non DNA-binding proteins. All of the experimental results indicate that the proposed DBPPred can be an alternative perspective predictor for large-scale determination of DNA-binding proteins. PMID- 24475171 TI - Trends in hypertension prevalence, awareness, treatment and control in an adult type 2 diabetes Spanish population between 2003 and 2009. AB - In patients with type 2 diabetes, the prevalence of hypertension is higher than in non-diabetic subjects. Despite the high cardiovascular risk involving hypertension in these patients, its prevalence and control are not well known. The aims of this study were: to estimate the hypertension prevalence, awareness, treatment and control in Spanish adults with type 2 diabetes attended in Primary Care; and to analyse its time trend from 2003 to 2009. A serial cross-sectional study from 2003 to 2009 was performed in 21 Primary Care Centres in Madrid. The study population comprised all patients with diagnosed type 2 diabetes in their computerised medical history. Overall annual prevalence during the period 2003 2009 was calculated from and according to sex and age groups. Linear trend tests, regression lines and coefficients of determination were used. In 2003 89.78% (CI 87.92-91.64) of patients with type 2 diabetes suffered hypertension and 94.76% (CI: 92.85-96.67) in 2009. This percentage was greater for women and for patients over 65 years old. 30% of patients suffered previously undiagnosed hypertension in 2003 and 23.1% in 2009. 97% of diagnosed patients received pharmacological treatment and 28.79% reached the blood pressure objective in 2009. The average number of antihypertensive drugs taken was 2.72 in 2003 and 3.27 in 2009. Only 5.2% of patients with type 2 diabetes show blood pressure levels below 130/80 mmHg. Although significant improvements have been achieved in the diagnosis and control of hypertension in people with type 2 diabetes, these continue to remain far from optimum. PMID- 24475172 TI - Comparison of decellularization protocols for preparing a decellularized porcine annulus fibrosus scaffold. AB - Tissue-specific extracellular matrix plays an important role in promoting tissue regeneration and repair. We hypothesized that decellularized annular fibrosus matrix may be an appropriate scaffold for annular fibrosus tissue engineering. We aimed to determine the optimal decellularization method suitable for annular fibrosus. Annular fibrosus tissue was treated with 3 different protocols with Triton X-100, sodium dodecyl sulfate (SDS) and trypsin. After the decellularization process, we examined cell removal and preservation of the matrix components, microstructure and mechanical function with the treatments to determine which method is more efficient. All 3 protocols achieved decellularization; however, SDS or trypsin disturbed the structure of the annular fibrosus. All protocols maintained collagen content, but glycosaminoglycan content was lost to different degrees, with the highest content with TritonX-100 treatment. Furthermore, SDS decreased the tensile mechanical property of annular fibrosus as compared with the other 2 protocols. MTT assay revealed that the decellularized annular fibrosus was not cytotoxic. Annular fibrosus cells seeded into the scaffold showed good viability. The Triton X-100-treated annular fibrosus retained major extracellular matrix components after thorough cell removal and preserved the concentric lamellar structure and tensile mechanical properties. As well, it possessed favorable biocompatibility, so it may be a suitable candidate as a scaffold for annular fibrosus tissue engineering. PMID- 24475173 TI - Non-redundant unique interface structures as templates for modeling protein interactions. AB - Improvements in experimental techniques increasingly provide structural data relating to protein-protein interactions. Classification of structural details of protein-protein interactions can provide valuable insights for modeling and abstracting design principles. Here, we aim to cluster protein-protein interactions by their interface structures, and to exploit these clusters to obtain and study shared and distinct protein binding sites. We find that there are 22604 unique interface structures in the PDB. These unique interfaces, which provide a rich resource of structural data of protein-protein interactions, can be used for template-based docking. We test the specificity of these non redundant unique interface structures by finding protein pairs which have multiple binding sites. We suggest that residues with more than 40% relative accessible surface area should be considered as surface residues in template based docking studies. This comprehensive study of protein interface structures can serve as a resource for the community. The dataset can be accessed at http://prism.ccbb.ku.edu.tr/piface. PMID- 24475174 TI - Cell-type specific four-component hydrogel. AB - In the field of regenerative medicine we aim to develop implant matrices for specific tissue needs. By combining two per se, cell-permissive gel systems with enzymatic crosslinkers (gelatin/transglutaminase and fibrinogen/thrombin) to generate a blend (technical term: quattroGel), an unexpected cell-selectivity evolved. QuattroGels were porous and formed cavities in the cell diameter range, possessed gelation kinetics in the minute range, viscoelastic properties and a mechanical strength appropriate for general cell adhesion, and restricted diffusion. Cell proliferation of endothelial cells, chondrocytes and fibroblasts was essentially unaffected. In contrast, on quattroGels neither endothelial cells formed vascular tubes nor did primary neurons extend neurites in significant amounts. Only chondrocytes differentiated properly as judged by collagen isoform expression. The biophysical quattroGel characteristics appeared to leave distinct cell processes such as mitosis unaffected and favored differentiation of sessile cells, but hampered differentiation of migratory cells. This cell-type selectivity is of interest e.g. during articular cartilage or invertebral disc repair, where pathological innervation and angiogenesis represent adverse events in tissue engineering. PMID- 24475175 TI - Leptin-induced endothelium-dependent vasorelaxation of peripheral arteries in lean and obese rats: role of nitric oxide and hydrogen sulfide. AB - Adipose tissue hormone leptin induces endothelium-dependent vasorelaxation mediated by nitric oxide (NO) and endothelium-derived hyperpolarizing factors (EDHF). Previously it has been demonstrated that in short-term obesity the NO dependent and the EDHF-dependent components of vascular effect of leptin are impaired and up-regulated, respectively. Herein we examined the mechanism of the EDHF-dependent vasodilatory effect of leptin and tested the hypothesis that alterations of acute vascular effects of leptin in obesity are accounted for by chronic hyperleptinemia. The study was performed in 5 groups of rats: (1) control, (2) treated with exogenous leptin for 1 week to induce hyperleptinemia, (3) obese, fed highly-palatable diet for 4 weeks, (4) obese treated with pegylated superactive rat leptin receptor antagonist (PEG-SRLA) for 1 week, (5) fed standard chow and treated with PEG-SRLA. Acute effect of leptin on isometric tension of mesenteric artery segments was measured ex vivo. Leptin relaxed phenylephrine-preconstricted vascular segments in NO- and EDHF-dependent manner. The NO-dependent component was impaired and the EDHF-dependent component was increased in the leptin-treated and obese groups and in the latter group both these effects were abolished by PEG-SRLA. The EDHF-dependent vasodilatory effect of leptin was blocked by either the inhibitor of cystathionine gamma-lyase, propargylglycine, or a hydrogen sulfide (H2S) scavenger, bismuth (III) subsalicylate. The results indicate that NO deficiency is compensated by the up regulation of EDHF in obese rats and both effects are accounted for by chronic hyperleptinemia. The EDHF-dependent component of leptin-induced vasorelaxation is mediated, at least partially, by H2S. PMID- 24475176 TI - Serum potassium levels and its variability in incident peritoneal dialysis patients: associations with mortality. AB - BACKGROUND: Abnormal serum potassium is associated with an increased risk of mortality in dialysis patients. However, the impacts of serum potassium levels on short- and long-term mortality and association of potassium variability with death in peritoneal dialysis (PD) patients are uncertain. METHODS: We examined mortality-predictability of serum potassium at baseline and its variability in PD patients treated in our center January 2006 through December 2010 with follow-up through December 2012. The hazard ratios (HRs) were used to assess the relationship between baseline potassium levels and short-term (<=1 year) as well as long-term (>1 year) survival. Variability of serum potassium was defined as the coefficient of variation of serum potassium (CVSP) during the first year of PD. RESULTS: A total of 886 incident PD patients were enrolled, with 248 patients (27.9%) presented hypokalemia (serum potassium <3.5 mEq/L). During a median follow-up of 31 months (range: 0.5-81.0 months), adjusted all-cause mortality hazard ratio (HR) and 95% confidence interval (CI) for baseline serum potassium of <3.0, 3.0 to <3.5, 3.5 to <4.0, 4.5 to <5.0, and >=5.0 mEq/L, compared with 4.0 to <4.5 (reference), were 1.79 (1.02-3.14), 1.15 (0.72-1.86), 1.31 (0.82 2.08), 1.33 (0.71-2.48), 1.28 (0.53-3.10), respectively. The increased risk of lower potassium with mortality was evident during the first year of follow-up, but vanished thereafter. Adjusted all-cause mortality HR for CVSP increments of 7.5% to <12.0%; 12.0% to <16.7% and >=16.7%, compared with <7.5% (reference), were 1.35 (0.67-2.71), 2.00 (1.05-3.83) and 2.18 (1.18-4.05), respectively. Similar association was found between serum potassium levels and its variability and cardiovascular mortality. CONCLUSIONS: A lower serum potassium level was associated with all-cause and cardiovascular mortality during the first year of follow-up in incident PD patients. In addition, higher variability of serum potassium levels conferred an increased risk of death in this population. PMID- 24475177 TI - Effects of vitamin D on airway epithelial cell morphology and rhinovirus replication. AB - Vitamin D has been linked to reduced risk of viral respiratory illness. We hypothesized that vitamin D could directly reduce rhinovirus (RV) replication in airway epithelium. Primary human bronchial epithelial cells (hBEC) were treated with vitamin D, and RV replication and gene expression were evaluated by quantitative PCR. Cytokine/chemokine secretion was measured by ELISA, and transepithelial resistance (TER) was determined using a voltohmmeter. Morphology was examined using immunohistochemistry. Vitamin D supplementation had no significant effects on RV replication, but potentiated secretion of CXCL8 and CXCL10 from infected or uninfected cells. Treatment with vitamin D in the form of 1,25(OH)2D caused significant changes in cell morphology, including thickening of the cell layers (median of 46.5 um [35.0-69.0] vs. 30 um [24.5-34.2], p<0.01) and proliferation of cytokeratin-5-expressing cells, as demonstrated by immunohistochemical analysis. Similar effects were seen for 25(OH)D. In addition to altering morphology, higher concentrations of vitamin D significantly upregulated small proline-rich protein (SPRR1beta) expression (6.3 fold induction, p<0.01), suggestive of squamous metaplasia. Vitamin D treatment of hBECs did not alter repair of mechanically induced wounds. Collectively, these findings indicate that vitamin D does not directly affect RV replication in airway epithelial cells, but can influence chemokine synthesis and alters the growth and differentiation of airway epithelial cells. PMID- 24475178 TI - Prevalence and evolution of low frequency HIV drug resistance mutations detected by ultra deep sequencing in patients experiencing first line antiretroviral therapy failure. AB - OBJECTIVES: Clinical relevance of low-frequency HIV-1 variants carrying drug resistance associated mutations (DRMs) is still unclear. We aimed to study the prevalence of low-frequency DRMs, detected by Ultra-Deep Sequencing (UDS) before antiretroviral therapy (ART) and at virological failure (VF), in HIV-1 infected patients experiencing VF on first-line ART. METHODS: Twenty-nine ART-naive patients followed up in the ANRS-CO3 Aquitaine Cohort, having initiated ART between 2000 and 2009 and experiencing VF (2 plasma viral loads (VL) >500 copies/ml or one VL >1000 copies/ml) were included. Reverse transcriptase and protease DRMs were identified using Sanger sequencing (SS) and UDS at baseline (before ART initiation) and VF. RESULTS: Additional low-frequency variants with PI-, NNRTI- and NRTI-DRMs were found by UDS at baseline and VF, significantly increasing the number of detected DRMs by 1.35 fold (p<0.0001) compared to SS. These low-frequency DRMs modified ARV susceptibility predictions to the prescribed treatment for 1 patient at baseline, in whom low-frequency DRM was found at high frequency at VF, and 6 patients at VF. DRMs found at VF were rarely detected as low-frequency DRMs prior to treatment. The rare low-frequency NNRTI- and NRTI-DRMs detected at baseline that correlated with the prescribed treatment were most often found at high-frequency at VF. CONCLUSION: Low frequency DRMs detected before ART initiation and at VF in patients experiencing VF on first line ART can increase the overall burden of resistance to PI, NRTI and NNRTI. PMID- 24475180 TI - MicroRNAs regulate human adipocyte lipolysis: effects of miR-145 are linked to TNF-alpha. AB - MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and have multiple effects in various tissues including adipose inflammation, a condition characterized by increased local release of the pro-lipolytic cytokine tumor necrosis factor-alpha (TNF-alpha). Whether miRNAs regulate adipocyte lipolysis is unknown. We set out to determine whether miRNAs affect adipocyte lipolysis in human fat cells. To this end, eleven miRNAs known to be present in human adipose tissue were over-expressed in human in vitro differentiated adipocytes followed by assessments of TNF-alpha and glycerol levels in conditioned media after 48 h. Three miRNAs (miR-145, -26a and let-7d) modulated both parameters in parallel. However, while miR-26a and let-7d decreased, miR-145 increased both glycerol release and TNF-alpha secretion. Further studies were focused therefore on miR-145 since this was the only stimulator of lipolysis and TNF-alpha secretion. Time-course analysis demonstrated that miR-145 over expression up-regulated TNF-alpha expression/secretion followed by increased glycerol release. Increase in TNF-alpha production by miR-145 was mediated via activation of p65, a member of the NF-kappaB complex. In addition, miR-145 down regulated the expression of the protease ADAM17, resulting in an increased fraction of membrane bound TNF-alpha, which is the more biologically active form of TNF-alpha. MiR-145 overexpression also increased the phosphorylation of activating serine residues in hormone sensitive lipase and decreased the mRNA expression of phosphodiesterase 3B, effects which are also observed upon TNF alpha treatment in human adipocytes. We conclude that miR-145 regulates adipocyte lipolysis via multiple mechanisms involving increased production and processing of TNF-alpha in fat cells. PMID- 24475179 TI - Plakophilin-3 catenin associates with the ETV1/ER81 transcription factor to positively modulate gene activity. AB - Members of the plakophilin-catenin sub-family (Pkp-1, -2, and -3) facilitate the linkage of desmosome junctional components to each other (e.g. desmosomal cadherins to desmoplakin) and the intermediate-filament cytoskeleton. Pkps also contribute to desmosomal stabilization and the trafficking of its components. The functions of Pkps outside of the desmosome are less well studied, despite evidence suggesting their roles in mRNA regulation, small-GTPase modulation (e.g. mid-body scission) during cell division, and cell survival following DNA damage. Pkp-catenins are further believed to have roles in the nucleus given their nuclear localization in some contexts and the known nuclear roles of structurally related catenins, such as beta-catenin and p120-catenin. Further, Pkp-catenin activities in the nuclear compartment have become of increased interest with the identification of interactions between Pkp2-catenin and RNA Pol III and Pkp1 with single-stranded DNA. Consistent with earlier reports suggesting possible nuclear roles in development, we previously demonstrated prominent nuclear localization of Pkp3 in Xenopus naive ectoderm ("animal cap") cells and recently resolved a similar localization in mouse embryonic stem cells. Here, we report the association and positive functional interaction of Pkp3 with a transcription factor, Ets variant gene 1 (ETV1), which has critical roles in neural development and prominent roles in human genetic disease. Our results are the first to report the interaction of a sequence-specific transcription factor with any Pkp. Using Xenopus laevis embryos and mammalian cells, we provide evidence for the Pkp3:ETV1 complex on both biochemical and functional levels. PMID- 24475181 TI - DNA methylation signature of childhood chronic physical aggression in T cells of both men and women. AB - BACKGROUND: High frequency of physical aggression is the central feature of severe conduct disorder and is associated with a wide range of social, mental and physical health problems. We have previously tested the hypothesis that differential DNA methylation signatures in peripheral T cells are associated with a chronic aggression trajectory in males. Despite the fact that sex differences appear to play a pivotal role in determining the development, magnitude and frequency of aggression, most of previous studies focused on males, so little is known about female chronic physical aggression. We therefore tested here whether or not there is a signature of physical aggression in female DNA methylation and, if there is, how it relates to the signature observed in males. METHODOLOGY/PRINCIPAL FINDINGS: Methylation profiles were created using the method of methylated DNA immunoprecipitation (MeDIP) followed by microarray hybridization and statistical and bioinformatic analyses on T cell DNA obtained from adult women who were found to be on a chronic physical aggression trajectory (CPA) between 6 and 12 years of age compared to women who followed a normal physical aggression trajectory. We confirmed the existence of a well-defined, genome-wide signature of DNA methylation associated with chronic physical aggression in the peripheral T cells of adult females that includes many of the genes similarly associated with physical aggression in the same cell types of adult males. CONCLUSIONS: This study in a small number of women presents preliminary evidence for a genome-wide variation in promoter DNA methylation that associates with CPA in women that warrant larger studies for further verification. A significant proportion of these associations were previously observed in men with CPA supporting the hypothesis that the epigenetic signature of early life aggression in females is composed of a component specific to females and another common to both males and females. PMID- 24475183 TI - Sexual dimorphism in bite performance drives morphological variation in chameleons. AB - Phenotypic performance in different environments is central to understanding the evolutionary and ecological processes that drive adaptive divergence and, ultimately, speciation. Because habitat structure can affect an animal's foraging behaviour, anti-predator defences, and communication behaviour, it can influence both natural and sexual selection pressures. These selective pressures, in turn, act upon morphological traits to maximize an animal's performance. For performance traits involved in both social and ecological activities, such as bite force, natural and sexual selection often interact in complex ways, providing an opportunity to understand the adaptive significance of morphological variation with respect to habitat. Dwarf chameleons within the Bradypodion melanocephalum-Bradypodion thamnobates species complex have multiple phenotypic forms, each with a specific head morphology that could reflect its use of either open- or closed-canopy habitats. To determine whether these morphological differences represent adaptations to their habitats, we tested for differences in both absolute and relative bite performance. Only absolute differences were found between forms, with the closed-canopy forms biting harder than their open-canopy counterparts. In contrast, sexual dimorphism was found for both absolute and relative bite force, but the relative differences were limited to the closed canopy forms. These results indicate that both natural and sexual selection are acting within both habitat types, but to varying degrees. Sexual selection seems to be the predominant force within the closed-canopy habitats, which are more protected from aerial predators, enabling chameleons to invest more in ornamentation for communication. In contrast, natural selection is likely to be the predominant force in the open-canopy habitats, inhibiting the development of conspicuous secondary sexual characteristics and, ultimately, enforcing their overall diminutive body size and constraining performance. PMID- 24475182 TI - Optimization of DNA recovery and amplification from non-carbonized archaeobotanical remains. AB - Ancient DNA (aDNA) recovered from archaeobotanical remains can provide key insights into many prominent archaeological research questions, including processes of domestication, past subsistence strategies, and human interactions with the environment. However, it is often difficult to isolate aDNA from ancient plant materials, and furthermore, such DNA extracts frequently contain inhibitory substances that preclude successful PCR amplification. In the age of high throughput sequencing, this problem is even more significant because each additional endogenous aDNA molecule improves analytical resolution. Therefore, in this paper, we compare a variety of DNA extraction techniques on primarily desiccated archaeobotanical remains and identify which method consistently yields the greatest amount of purified DNA. In addition, we test five DNA polymerases to determine how well they replicate DNA extracted from non-charred ancient plant remains. Based upon the criteria of resistance to enzymatic inhibition, behavior in quantitative real-time PCR, replication fidelity, and compatibility with aDNA damage, we conclude these polymerases have nuanced properties, requiring researchers to make educated decisions as to which one to use for a given task. The experimental findings should prove useful to the aDNA and archaeological communities by guiding future research methodologies and ensuring precious archaeobotanical remains are studied in optimal ways, and may thereby yield important new perspectives on the interactions between humans and past plant communities. PMID- 24475184 TI - Bare-part color in female budgerigars changes from brown to structural blue following testosterone treatment but is not strongly masculinized. AB - Whereas several studies have shown that experimentally increased levels of the androgenic steroid testosterone can affect female behavior, fewer studies have focused on the activational effects of exogenous testosterone on female morphology. With respect to colorful displays in birds, almost exclusively the effects of testosterone manipulation on female carotenoid-based colorations have been studied. Other color types such as structural colors (i.e. UV, blue and violet colors that result from differential light reflection in the nanostructures of the tissue) remain largely unstudied. Here, we investigated the short- and long-term effects of exogenous testosterone on the expression of structural bare-part coloration in female budgerigars, Melopsittacus undulatus. In this parrot species, bare-part coloration is expressed in the cere, a structure over the beak which is brown in females and structural blue in males. We experimentally increased plasma testosterone levels in testosterone-treated females (T-females) compared to controls (C-females) and we performed weekly spectrophotometric measurements of the cere for five weeks after implantation and one measurement after ten weeks. We also estimated the extent to which testosterone masculinized female cere color by comparing the experimental females with untreated males. We found significant effects of testosterone on cere color from week four after implantation onwards. T-females expressed significantly bluer ceres than C-females with higher values for brightness and UV reflectance. T-female cere color, however, remained significantly less blue than in males, while values for brightness and UV reflectance were significantly higher in T females than in males. Our quantitative results show that exogenous testosterone induces the expression of structural blue color in females but does not strongly masculinize female cere coloration. We provide several potential pathways for the action of testosterone on structural color. PMID- 24475185 TI - Transcranial direct current stimulation of right dorsolateral prefrontal cortex does not affect model-based or model-free reinforcement learning in humans. AB - There is broad consensus that the prefrontal cortex supports goal-directed, model based decision-making. Consistent with this, we have recently shown that model based control can be impaired through transcranial magnetic stimulation of right dorsolateral prefrontal cortex in humans. We hypothesized that an enhancement of model-based control might be achieved by anodal transcranial direct current stimulation of the same region. We tested 22 healthy adult human participants in a within-subject, double-blind design in which participants were given Active or Sham stimulation over two sessions. We show Active stimulation had no effect on model-based control or on model-free ('habitual') control compared to Sham stimulation. These null effects are substantiated by a power analysis, which suggests that our study had at least 60% power to detect a true effect, and by a Bayesian model comparison, which favors a model of the data that assumes stimulation had no effect over models that assume stimulation had an effect on behavioral control. Although we cannot entirely exclude more trivial explanations for our null effect, for example related to (faults in) our experimental setup, these data suggest that anodal transcranial direct current stimulation over right dorsolateral prefrontal cortex does not improve model-based control, despite existing evidence that transcranial magnetic stimulation can disrupt such control in the same brain region. PMID- 24475186 TI - "Timed Up & Go": a screening tool for predicting 30-day morbidity in onco geriatric surgical patients? A multicenter cohort study. AB - OBJECTIVE: To determine the predictive value of the "Timed Up & Go" (TUG), a validated assessment tool, on a prospective cohort study and to compare these findings to the ASA classification, an instrument commonly used for quantifying patients' physical status and anesthetic risk. BACKGROUND: In the onco-geriatric surgical population it is important to identify patients at increased risk of adverse post-operative outcome to minimize the risk of over- and under-treatment and improve outcome in this population. METHODS: 280 patients >=70 years undergoing elective surgery for solid tumors were prospectively recruited. Primary endpoint was 30-day morbidity. Pre-operatively TUG was administered and ASA-classification was registered. Data were analyzed using multivariable logistic regression analyses to estimate odds ratios (OR) and 95% confidence intervals (95%-CI). Absolute risks and area under the receiver operating characteristic curves (AUC's) were calculated. RESULTS: 180 (64.3%) patients (median age: 76) underwent major surgery. 55 (20.1%) patients experienced major complications. 50.0% of patients with high TUG and 25.6% of patients with ASA>=3 experienced major complications (absolute risks). TUG and ASA were independent predictors of the occurrence of major complications (TUG:OR 3.43; 95%-CI = 1.14 10.35. ASA1 vs. 2:OR 5.91; 95%-CI = 0.93-37.77. ASA1 vs. 3&4:OR 12.77; 95%-CI = 1.84-88.74). AUCTUG was 0.64 (95%-CI = 0.55-0.73, p = 0.001) and AUCASA was 0.59 (95%-CI = 0.51-0.67, p = 0.04). CONCLUSIONS: Twice as many onco-geriatric patients at risk of post-operative complications, who might benefit from pre operative interventions, are identified using TUG than when using ASA. PMID- 24475187 TI - Free fatty acids, lipopolysaccharide and IL-1alpha induce adipocyte manganese superoxide dismutase which is increased in visceral adipose tissues of obese rodents. AB - Excess fat storage in adipocytes is associated with increased generation of reactive oxygen species (ROS) and impaired activity of antioxidant mechanisms. Manganese superoxide dismutase (MnSOD) is a mitochondrial enzyme involved in detoxification of ROS, and objective of the current study is to analyze expression and regulation of MnSOD in obesity. MnSOD is increased in visceral but not subcutaneous fat depots of rodents kept on high fat diets (HFD) and ob/ob mice. MnSOD is elevated in visceral adipocytes of fat fed mice and exposure of differentiating 3T3-L1 cells to lipopolysaccharide, IL-1alpha, saturated, monounsaturated and polyunsaturated free fatty acids (FFA) upregulates its level. FFA do not alter cytochrome oxidase 4 arguing against overall induction of mitochondrial enzymes. Upregulation of MnSOD in fat loaded cells is not mediated by IL-6, TNF or sterol regulatory element binding protein 2 which are induced in these cells. MnSOD is similarly abundant in perirenal fat of Zucker diabetic rats and non-diabetic animals with similar body weight and glucose has no effect on MnSOD in 3T3-L1 cells. To evaluate whether MnSOD affects adipocyte fat storage, MnSOD was knocked-down in adipocytes for the last three days of differentiation and in mature adipocytes. Knock-down of MnSOD does neither alter lipid storage nor viability of these cells. Heme oxygenase-1 which is induced upon oxidative stress is not altered while antioxidative capacity of the cells is modestly reduced. Current data show that inflammation and excess triglyceride storage raise adipocyte MnSOD which is induced in epididymal adipocytes in obesity. PMID- 24475188 TI - Characterization of the vessel geometry, flow mechanics and wall shear stress in the great arteries of wildtype prenatal mouse. AB - INTRODUCTION: Abnormal fluid mechanical environment in the pre-natal cardiovascular system is hypothesized to play a significant role in causing structural heart malformations. It is thus important to improve our understanding of the prenatal cardiovascular fluid mechanical environment at multiple developmental time-points and vascular morphologies. We present such a study on fetal great arteries on the wildtype mouse from embryonic day 14.5 (E14.5) to near-term (E18.5). METHODS: Ultrasound bio-microscopy (UBM) was used to measure blood velocity of the great arteries. Subsequently, specimens were cryo-embedded and sectioned using episcopic fluorescent image capture (EFIC) to obtain high resolution 2D serial image stacks, which were used for 3D reconstructions and quantitative measurement of great artery and aortic arch dimensions. EFIC and UBM data were input into subject-specific computational fluid dynamics (CFD) for modeling hemodynamics. RESULTS: In normal mouse fetuses between E14.5-18.5, ultrasound imaging showed gradual but statistically significant increase in blood velocity in the aorta, pulmonary trunk (with the ductus arteriosus), and descending aorta. Measurement by EFIC imaging displayed a similar increase in cross sectional area of these vessels. However, CFD modeling showed great artery average wall shear stress and wall shear rate remain relatively constant with age and with vessel size, indicating that hemodynamic shear had a relative constancy over gestational period considered here. CONCLUSION: Our EFIC-UBM-CFD method allowed reasonably detailed characterization of fetal mouse vascular geometry and fluid mechanics. Our results suggest that a homeostatic mechanism for restoring vascular wall shear magnitudes may exist during normal embryonic development. We speculate that this mechanism regulates the growth of the great vessels. PMID- 24475189 TI - AMPK inhibition blocks ROS-NFkappaB signaling and attenuates endotoxemia-induced liver injury. AB - BACKGROUND: AMP-activated protein kinase (AMPK) is an important enzyme in regulation of cellular energy homeostasis. We have previously shown that AMPK activation by 5-aminoimidazole-4-carboxamide (AICAR) results in suppression of immune responses, indicating the pivotal role of AMPK in immune regulation. However, the cellular mechanism underpinning AMPK inhibition on immune response remains largely to be elucidated. The study aimed to investigate the effects of AMPK inhibition on reactive oxygen species (ROS)-nuclear factor kappaB (NFkappaB) signaling and endotoxemia-induced liver injury. METHODOLOGY/PRINCIPAL FINDINGS: RAW 264.7 cells were pretreated with AMPK activator or inhibitor, followed by LPS challenge. In addition, LPS was injected intraperitoneally into mice to induce systemic inflammation. The parameters of liver injury and immune responses were determined, and survival of mice was monitored respectively. LPS challenge in RAW 264.7 cells resulted in AMPK activation which was then inhibited by compound C treatment. Both AMPK activation by AICAR or inhibition by compound C diminished LPS-induced ROS generation, inhibited phosphorylation of IKK, IkappaB, and NFkappaB p65, and consequently, decreased TNF production of RAW 264.7 cells. AICAR or compound C treatment decreased ALT, AST, and TNF levels in serum, reduced CD68 expression and MPO activity in liver tissue of mice with endotoxemia. Moreover, AICAR or compound C treatment improved survival of endotoxemic mice. CONCLUSIONS: AICAR or compound C treatment attenuates LPS induced ROS-NFkappaB signaling, immune responses and liver injury. Strategies to activate or inhibit AMPK signaling may provide alternatives to the current clinical approaches to inhibit immune responses of endotoxemia. PMID- 24475190 TI - Systemic resistance induced by volatile organic compounds emitted by plant growth promoting fungi in Arabidopsis thaliana. AB - Volatile organic compounds (VOC) were extracted and identified from plant growth promoting fungi (PGPF), Phoma sp., Cladosporium sp. and Ampelomyces sp., using gas chromatography-mass spectrometry (GC-MS). Among the three VOC extracted, two VOC blends (emitted from Ampelomyces sp. and Cladosporium sp.) significantly reduced disease severity in Arabidopsis plants against Pseudomonas syringae pv. tomato DC3000 (Pst). Subsequently, m-cresol and methyl benzoate (MeBA) were identified as major active volatile compounds from Ampelomyces sp. and Cladosporium sp., respectively, and found to elicit induced systemic resistance (ISR) against the pathogen. Molecular signaling for disease suppression by the VOC were investigated by treating different mutants and transgenic Arabidopsis plants impaired in salicylic acid (SA) or Jasmonic acid (JA)/ethylene (ET) signaling pathways with m-cresol and MeBA followed by challenge inoculation with Pst. Results show that the level of protection was significantly lower when JA/ET impaired mutants were treated with MeBA, and in SA-, and JA/ET-disrupted mutants after m-cresol treatment, indicating the involvement of these signal transduction pathways in the ISR primed by the volatiles. Analysis of defense-related genes by real-time qRT-PCR showed that both the SA-and JA-signaling pathways combine in the m-cresol signaling of ISR, whereas MeBA is mainly involved in the JA signaling pathway with partial recruitment of SA-signals. The ET-signaling pathway was not employed in ISR by the volatiles. Therefore, this study identified two novel volatile components capable of eliciting ISR that may be promising candidates in biological control strategy to protect plants from diseases. PMID- 24475191 TI - Genetic characteristics of the coxsackievirus A24 variant causing outbreaks of acute hemorrhagic conjunctivitis in Jiangsu, China, 2010. AB - During September 2010, an outbreak of acute hemorrhagic conjunctivitis reemerged in Jiangsu, three years after the nationwide epidemic in China in 2007. In total, 2409 cases were reported, 2118 of which were reported in September; 79.8% of those affected were students or teachers, with a median age of 16 years. To identify and demonstrate the genetic characteristics of the etiological agent, 52 conjunctival swabs were randomly collected from four different cities. After detection and isolation, 43 patients were positive for coxsackievirus A24 variant according to PCR and 20 according to culture isolation. Neither adenovirus nor EV70 was detected. A phylogenetic study of the complete 3Cpro and VP1 regions showed that the Jiangsu isolates clustered into a new lineage, GIV-C5, with two uniform amino-acid mutations that distinguished them from all previous strains. Another new cluster, GIV-C4, formed by Indian isolates from 2007 and Brazilian isolates from 2009, was also identified in this study. Interestingly, our isolates shared greatest homology with the GIV-C4 strains, not with the isolates that were responsible for the nationwide acute hemorrhagic conjunctivitis epidemic in China in 2007. Although all our isolates were closely related, they could be differentiated into two subclusters within GIV-C5. In conclusion, our study suggests that a new cluster of coxsackievirus A24 variant that had already evolved into diverse strains was associated with the acute hemorrhagic conjunctivitis outbreaks in Jiangsu in September 2010. These viruses might have originated from the virus isolated in India in 2007, rather than from the epidemic strains isolated in China in 2007. PMID- 24475192 TI - Mycobacterium tuberculosis subverts the TLR-2-MyD88 pathway to facilitate its translocation into the cytosol. AB - Mycobacterium tuberculosis (M.tb) has evolved mechanisms to evade its destruction in phagolysosomes, where it successfully survives and replicates within phagocytes. Recent studies have shown that virulent strains of M.tb can translocate from the phagosome into the cytosol of dendritic cells (DC). The molecular mechanisms by which virulent M.tb strains can escape the phagosome remain unknown. Here we show that the virulent M.tb strain H37Rv, but not the vaccine strain Bacille Calmette-Guerin (BCG), escapes from the phagolysosome and enters the cytosol by interfering with the TLR-2-MyD88 signaling pathway. Using H37Rv mutants, we further demonstrate that the region of difference-1 (RD-1) locus and ESAT-6, a gene within the RD-1 locus, play an important role in the capacity of M.tb to migrate from the phagosome to the cytosol of macrophages. H37Rv, BCG, H37RvDeltaRD1, and H37RvDeltaESAT6 were able to translocate to the cytosol in macrophages derived from TLR-2- and MyD88-deficient animals, whereas only virulent H37Rv was able to enter the cytosol in macrophages from wild type mice. Therefore, signaling through the TLR-2-MyD88 pathway in macrophages plays an important role in confining M.tb within phagolysomes. Virulent strains of M.tb have evolved mechanisms to subvert this pathway, thus facilitating their translocation to the cytosol and to escape the toxic microenvironment of the phagosome or phagolysosome. PMID- 24475193 TI - Endoplasmic reticulum stress-unfolding protein response-apoptosis cascade causes chondrodysplasia in a col2a1 p.Gly1170Ser mutated mouse model. AB - The collagen type II alpha 1 (COL2A1) mutation causes severe skeletal malformations, but the pathogenic mechanisms of how this occurs are unclear. To understand how this may happen, a col2a1 p.Gly1170Ser mutated mouse model was constructed and in homozygotes, the chondrodysplasia phenotype was observed. Misfolded procollagen was largely synthesized and retained in dilated endoplasmic reticulum and the endoplasmic reticulum stress (ERS)-unfolded protein response (UPR)-apoptosis cascade was activated. Apoptosis occurred prior to hypertrophy, prevented the formation of a hypertrophic zone, disrupted normal chondrogenic signaling pathways, and eventually caused chondrodysplasia. Heterozygotes had normal phenotypes and endoplasmic reticulum stress intensity was limited with no abnormal apoptosis detected. Our results suggest that earlier chondrocyte death was related to the ERS-UPR-apoptosis cascade and that this was the chief cause of chondrodysplaia. The col2a1 p.Gly1170Ser mutated mouse model offered a novel connection between misfolded collagen and skeletal malformation. Further investigation of this mouse mutant model can help us understand mechanisms of type II collagenopathies. PMID- 24475194 TI - The receptor for advanced glycation end-products (RAGE) is only present in mammals, and belongs to a family of cell adhesion molecules (CAMs). AB - The human receptor for advanced glycation endproducts (RAGE) is a multiligand cell surface protein belonging to the immunoglobulin superfamily, and is involved in inflammatory and immune responses. Most importantly, RAGE is considered a receptor for HMGB1 and several S100 proteins, which are Damage-Associated Molecular Pattern molecules (DAMPs) released during tissue damage. In this study we show that the Ager gene coding for RAGE first appeared in mammals, and is closely related to other genes coding for cell adhesion molecules (CAMs) such as ALCAM, BCAM and MCAM that appeared earlier during metazoan evolution. RAGE is expressed at very low levels in most cells, but when expressed at high levels, it mediates cell adhesion to extracellular matrix components and to other cells through homophilic interactions. Our results suggest that RAGE evolved from a family of CAMs, and might still act as an adhesion molecule, in particular in the lung where it is highly expressed or under pathological conditions characterized by an increase of its protein levels. PMID- 24475195 TI - Profiling of glycan receptors for minute virus of mice in permissive cell lines towards understanding the mechanism of cell recognition. AB - The recognition of sialic acids by two strains of minute virus of mice (MVM), MVMp (prototype) and MVMi (immunosuppressive), is an essential requirement for successful infection. To understand the potential for recognition of different modifications of sialic acid by MVM, three types of capsids, virus-like particles, wild type empty (no DNA) capsids, and DNA packaged virions, were screened on a sialylated glycan microarray (SGM). Both viruses demonstrated a preference for binding to 9-O-methylated sialic acid derivatives, while MVMp showed additional binding to 9-O-acetylated and 9-O-lactoylated sialic acid derivatives, indicating recognition differences. The glycans recognized contained a type-2 Galbeta1-4GlcNAc motif (Neu5Acalpha2-3Galbeta1-4GlcNAc or 3'SIA-LN) and were biantennary complex-type N-glycans with the exception of one. To correlate the recognition of the 3'SIA-LN glycan motif as well as the biantennary structures to their natural expression in cell lines permissive for MVMp, MVMi, or both strains, the N- and O-glycans, and polar glycolipids present in three cell lines used for in vitro studies, A9 fibroblasts, EL4 T lymphocytes, and the SV40 transformed NB324K cells, were analyzed by MALDI-TOF/TOF mass spectrometry. The cells showed an abundance of the sialylated glycan motifs recognized by the viruses in the SGM and previous glycan microarrays supporting their role in cellular recognition by MVM. Significantly, the NB324K showed fucosylation at the non-reducing end of their biantennary glycans, suggesting that recognition of these cells is possibly mediated by the Lewis X motif as in 3'SIA-Le(X) identified in a previous glycan microarray screen. PMID- 24475196 TI - Role of RUNX3 in suppressing metastasis and angiogenesis of human prostate cancer. AB - RUNX3 (runt-related transcription factor-3) has been reported to suppress tumor tumorigenesis and metastasis in different human cancers. In this study, we used tissue microarray (TMA) to determine the significance of RUNX3 in prostate cancer progession. Our results showed ectopic expression of RUNX3 in prostate cancer tissues when compared with tumor adjacent normal prostate tissues, and reduced RUNX3 staining was significantly correlated with TNM stage. Moreover, we demonstrated that RUNX3 overexpression inhibited prostate cancer cell migration and invasion resulting from the elevated upregulation of tissue inhibitor of matrix metalloproteinase-2 (TIMP-2), which subsequently inhibited metalloproteinase-2 (MMP-2) expression and activity in vitro. Knock down of RUNX3 expression broke up the balance of TIMP-2/MMP-2, whereas silence of TIMP-2 resulted in the inhibition of MMP-2 expression in prostate cells. We also showed that restoration of RUNX3 decreased vascular endothelial growth factor (VEGF) secretion and suppressed endothelial cell growth and tube formation. Strikingly, RUNX3 was demonstrated to inhibit tumor metastasis and angiogenesis in vivo. Altogether, our results support the tumor suppressive role of RUNX3 in human prostate cancer, and provide insights into development of targeted therapy for this disease. PMID- 24475197 TI - Garden and landscape-scale correlates of moths of differing conservation status: significant effects of urbanization and habitat diversity. AB - Moths are abundant and ubiquitous in vegetated terrestrial environments and are pollinators, important herbivores of wild plants, and food for birds, bats and rodents. In recent years, many once abundant and widespread species have shown sharp declines that have been cited by some as indicative of a widespread insect biodiversity crisis. Likely causes of these declines include agricultural intensification, light pollution, climate change, and urbanization; however, the real underlying cause(s) is still open to conjecture. We used data collected from the citizen science Garden Moth Scheme (GMS) to explore the spatial association between the abundance of 195 widespread British species of moth, and garden habitat and landscape features, to see if spatial habitat and landscape associations varied for species of differing conservation status. We found that associations with habitat and landscape composition were species-specific, but that there were consistent trends in species richness and total moth abundance. Gardens with more diverse and extensive microhabitats were associated with higher species richness and moth abundance; gardens near to the coast were associated with higher richness and moth abundance; and gardens in more urbanized locations were associated with lower species richness and moth abundance. The same trends were also found for species classified as increasing, declining and vulnerable under IUCN (World Conservation Union) criteria. However, vulnerable species were more strongly negatively affected by urbanization than increasing species. Two hypotheses are proposed to explain this observation: (1) that the underlying factors causing declines in vulnerable species (e.g., possibilities include fragmentation, habitat deterioration, agrochemical pollution) across Britain are the same in urban areas, but that these deleterious effects are more intense in urban areas; and/or (2) that urban areas can act as ecological traps for some vulnerable species of moth, the light drawing them in from the surrounding landscape into sub-optimal urban habitats. PMID- 24475198 TI - Malaria incidence in children in South-West Burkina Faso: comparison of active and passive case detection methods. AB - BACKGROUND: The aim of this study was to determine the incidence and seasonal pattern of malaria in children in South-West Burkina Faso, and to compare, in a randomized trial, characteristics of cases detected by active and passive surveillance. This study also enabled the planning of a malaria vaccine trial. METHODS: Households with young children, located within 5 kilometers of a health facility, were randomized to one of two malaria surveillance methods. In the first group, children were monitored actively. Each child was visited twice weekly; tympanic temperature was measured, and if the child had a fever or history of fever, a malaria rapid diagnostic test was performed and a blood smear collected. In the second group, children were monitored passively. The child's parent or caregiver was asked to bring the child to the nearest clinic if he was unwell. Follow up lasted 13 months from September 2009. RESULTS: Incidence of malaria (Fever with parasitaemia >=5,000/uL) was 1.18 episodes/child/year in the active cohort and 0.89 in the passive cohort (rate ratio 1.32, 95% CI 1.13-1.54). Malaria cases in the passive cohort were more likely to have high grade fever; but parasite densities were similar in the two groups. Incidence was highly seasonal; when a specific case definition was used, about 60% of cases occurred within the 4 months June-September. CONCLUSION: Passive case detection required at least a 30%-40% increase in the sample size for vaccine trials, compared to active detection, to achieve the same power. However we did not find any evidence that parasite densities were higher with passive than with active detection. The incidence of malaria is highly seasonal and meets the WHO criteria for Seasonal Malaria Chemoprevention (SMC). At least half of the malaria cases in these children could potentially be prevented if SMC was effectively deployed. PMID- 24475199 TI - Silencing motifs in the Clr2 protein from fission yeast, Schizosaccharomyces pombe. AB - The fission yeast, Schizosaccharomyces pombe, is a well-established model for heterochromatin formation, but the exact sequence of events for initiation remains to be elucidated. The essential factors involved include RNA transcribed from repeated sequences together with the methyltransferase Clr4. In addition, histone deacetylases, like Clr3, found in the SHREC complex are also necessary for transcriptional silencing. Clr2 is another crucial factor required for heterochromatin formation found in the SHREC complex. The function of Clr2 has been difficult to establish due to the lack of conserved domains or homology to proteins of known molecular function. Using a bioinformatics approach, three conserved motifs in Clr2 were identified, which contained amino acids important for transcriptional repression. Analysis of clr2 mutant strains revealed a major role for Clr2 in mating-type and rDNA silencing, and weaker effects on centromeric silencing. The effect on mating-type silencing showed variegation in several of the strains with mutated versions of Clr2 indicating an establishment or maintenance defect. Moreover, the critical amino acids in Clr2 were also necessary for transcriptional repression in a minimal system, by the tethering of Clr4 upstream of a reporter gene, inserted into the euchromatic part of the genome. Finally, in silico modeling suggested that the mutations in Clr2 cause disruption of secondary structures in the Clr2 protein. Identification of these critical amino acids in the protein provides a useful tool to explore the molecular mechanism behind the role of Clr2 in heterochromatin formation. PMID- 24475200 TI - GRP78 suppresses lipid peroxidation and promotes cellular antioxidant levels in glial cells following hydrogen peroxide exposure. AB - Oxidative stress, caused by the over production of reactive oxygen species (ROS), has been shown to contribute to cell damage associated with neurotrauma and neurodegenerative diseases. ROS mediates cell damage either through direct oxidation of lipids, proteins and DNA or by acting as signaling molecules to trigger cellular apoptotic pathways. The 78 kDa glucose-regulated protein (GRP78) is an ER chaperone that has been suggested to protect cells against ROS-induced damage. However, the protective mechanism of GRP78 remains unclear. In this study, we used C6 glioma cells transiently overexpressing GRP78 to investigate the protective effect of GRP78 against oxidative stress (hydrogen peroxide) induced injury. Our results showed that the overexpression of GRP78 significantly protected cells from ROS-induced cell damage when compared to non-GRP78 overexpressing cells, which was most likely due to GRP78-overexpressing cells having higher levels of glutathione (GSH) and NAD(P)H: quinone oxidoreductase 1 (NQO1), two antioxidants that protect cells against oxidative stress. Although hydrogen peroxide treatment increased lipid peroxidation in non-GRP78 overexpressing cells, this increase was significantly reduced in GRP78 overexpressing cells. Overall, these results indicate that GRP78 plays an important role in protecting glial cells against oxidative stress via regulating the expression of GSH and NQO1. PMID- 24475201 TI - Conserved B-cell epitopes among human bocavirus species indicate potential diagnostic targets. AB - BACKGROUND: Human bocavirus species 1-4 (HBoV1-4) have been associated with respiratory and enteric infections in children. However, the immunological mechanisms in response to HBoV infections are not fully understood. Though previous studies have shown cross-reactivities between HBoV species, the epitopes responsible for this phenomenon remain unknown. In this study, we used genomic and immunologic approaches to identify the reactive epitopes conserved across multiple HBoV species and explored their potential as the basis of a novel diagnostic test for HBoVs. METHODOLOGY/PRINCIPAL FINDINGS: We generated HBoV1-3 VP2 gene fragment phage display libraries (GFPDLs) and used these libraries to analyze mouse antisera against VP2 protein of HBoV1, 2, and 3, and human sera positive for HBoVs. Using this approach, we mapped four epitope clusters of HBoVs and identified two immunodominant peptides--P1 (1MSDTDIQDQQPDTVDAPQNT20), and P2 (162EHAYPNASHPWDEDVMPDL180)--that are conserved among HBoV1-4. To confirm epitope immunogenicity, we immunized mice with the immunodominant P1 and P2 peptides identified in our screen and found that they elicited high titer antibodies in mice. These two antibodies could only recognize the VP2 of HBoV 1-4 in Western blot assays, rather than those of the two other parvoviruses human parvovirus B19 and human parvovirus 4 (PARV4). Based on our findings, we evaluated epitope-based peptide-IgM ELISAs as potential diagnostic tools for HBoVs IgM antibodies. We found that the P1+P2-IgM ELISA showed a higher sensitivity and specificity in HBoVs IgM detection than the assays using a single peptide. CONCLUSIONS/SIGNIFICANCE: The identification of the conserved B-cell epitopes among human bocavirus species contributes to our understanding of immunological cross-reactivities of HBoVs, and provides important insights for the development of HBoV diagnostic tools. PMID- 24475203 TI - The impact of funding through the RF President's grants for young scientists (the field--medicine) on research productivity: a quasi-experimental study and a brief systematic review. AB - The impact of grants on research productivity has been investigated by a number of retrospective studies. The results of these studies vary considerably. The objective of my study was to investigate the impact of funding through the RF President's grants for young scientists on the research productivity of awarded applicants. The study compared the number of total articles and citations for awarded and rejected applicants who in 2007 took part in competitions for young candidates of science (CoS's) and doctors of science (DoS's) in the scientific field of medicine. The bibliometric analysis was conducted for the period from 2003 to 2012 (five years before and after the competition). The source of bibliometric data is the eLIBRARY.RU database. The impact of grants on the research productivity of Russian young scientists was assessed using the meta analytical approach based on data from quasi-experimental studies conducted in other countries. The competition featured 149 CoS's and 41 DoS's, out of which 24 (16%) and 22 (54%) applicants, respectively, obtained funding. No difference in the number of total articles and citations at baseline, as well as in 2008-2012, for awarded and rejected applicants was found. The combination of data from the Russian study and other quasi-experimental studies (6 studies, 10 competitions) revealed a small treatment effect--an increase in the total number of publications over a 4-5-year period after the competition by 1.23 (95% CI 0.48 1.97). However, the relationship between the number of total publications published by applicants before and after the competition revealed that this treatment effect is an effect of the "maturation" of scientists with a high baseline publication activity--not of grant funding. PMID- 24475202 TI - The role of viral and host microRNAs in the Aujeszky's disease virus during the infection process. AB - Porcine production is a primary market in the world economy. Controlling swine diseases in the farm is essential in order to achieve the sector necessities. Aujeszky's disease is a viral condition affecting pigs and is endemic in many countries of the world, causing important economic losses in the swine industry. microRNAs (miRNAs) are non-coding RNAs which modulates gene expression in animals, plants and viruses. With the aim of understanding miRNA roles during the Aujeszky's disease virus [ADV] (also known as suid herpesvirus type 1 [SuHV-1]) infection, the expression profiles of host and viral miRNAs were determined through deep sequencing in SuHV-1 infected porcine cell line (PK-15) and in an animal experimental SuHV-1 infection with virulent (NIA-3) and attenuated (Begonia) strains. In the in vivo approach miR-206, miR-133a, miR-133b and miR 378 presented differential expression between virus strains infection. In the in vitro approach, most miRNAs were down-regulated in infected groups. miR-92a and miR-92b-3p were up-regulated in Begonia infected samples. Functional analysis of all this over expressed miRNAs during the infection revealed their association in pathways related to viral infection processes and immune response. Furthermore, 8 viral miRNAs were detected by stem loop RT-qPCR in both in vitro and in vivo approaches, presenting a gene regulatory network affecting 59 viral genes. Most described viral miRNAs were related to Large Latency Transcript (LLT) and to viral transcription activators EP0 and IE180, and also to regulatory genes regarding their important roles in the host-pathogen interaction during viral infection. PMID- 24475204 TI - Effect of optimal daily fertigation on migration of water and salt in soil, root growth and fruit yield of cucumber (Cucumis sativus L.) in solar-greenhouse. AB - Inappropriate and excessive irrigation and fertilization have led to the predominant decline of crop yields, and water and fertilizer use efficiency in intensive vegetable production systems in China. For many vegetables, fertigation can be applied daily according to the actual water and nutrient requirement of crops. A greenhouse study was therefore conducted to investigate the effect of daily fertigation on migration of water and salt in soil, and root growth and fruit yield of cucumber. The treatments included conventional interval fertigation, optimal interval fertigation and optimal daily fertigation. Generally, although soil under the treatment optimal interval fertigation received much lower fertilizers than soil under conventional interval fertigation, the treatment optimal interval fertigation did not statistically decrease the economic yield and fruit nutrition quality of cucumber when compare to conventional interval fertigation. In addition, the treatment optimal interval fertigation effectively avoided inorganic nitrogen accumulation in soil and significantly (P<0.05) increased the partial factor productivity of applied nitrogen by 88% and 209% in the early-spring and autumn-winter seasons, respectively, when compared to conventional interval fertigation. Although soils under the treatments optimal interval fertigation and optimal daily fertigation received the same amount of fertilizers, the treatment optimal daily fertigation maintained the relatively stable water, electrical conductivity and mineral nitrogen levels in surface soils, promoted fine root (<1.5 mm diameter) growth of cucumber, and eventually increased cucumber economic yield by 6.2% and 8.3% and partial factor productivity of applied nitrogen by 55% and 75% in the early spring and autumn-winter seasons, respectively, when compared to the treatment optimal interval fertigation. These results suggested that optimal daily fertigation is a beneficial practice for improving crop yield and the water and fertilizers use efficiency in solar greenhouse. PMID- 24475205 TI - The p66(Shc) adaptor protein controls oxidative stress response in early bovine embryos. AB - The in vitro production of mammalian embryos suffers from high frequencies of developmental failure due to excessive levels of permanent embryo arrest and apoptosis caused by oxidative stress. The p66Shc stress adaptor protein controls oxidative stress response of somatic cells by regulating intracellular ROS levels through multiple pathways, including mitochondrial ROS generation and the repression of antioxidant gene expression. We have previously demonstrated a strong relationship with elevated p66Shc levels, reduced antioxidant levels and greater intracellular ROS generation with the high incidence of permanent cell cycle arrest of 2-4 cell embryos cultured under high oxygen tensions or after oxidant treatment. The main objective of this study was to establish a functional role for p66Shc in regulating the oxidative stress response during early embryo development. Using RNA interference in bovine zygotes we show that p66Shc knockdown embryos exhibited increased MnSOD levels, reduced intracellular ROS and DNA damage that resulted in a greater propensity for development to the blastocyst stage. P66Shc knockdown embryos were stress resistant exhibiting significantly reduced intracellular ROS levels, DNA damage, permanent 2-4 cell embryo arrest and diminished apoptosis frequencies after oxidant treatment. The results of this study demonstrate that p66Shc controls the oxidative stress response in early mammalian embryos. Small molecule inhibition of p66Shc may be a viable clinical therapy to increase the developmental potential of in vitro produced mammalian embryos. PMID- 24475206 TI - Bacterial fatty acids enhance recovery from the dauer larva in Caenorhabditis elegans. AB - The dauer larva is a specialized dispersal stage in the nematode Caenorhabditis elegans that allows the animal to survive starvation for an extended period of time. The dauer does not feed, but uses chemosensation to identify new food sources and to determine whether to resume reproductive growth. Bacteria produce food signals that promote recovery of the dauer larva, but the chemical identities of these signals remain poorly defined. We find that bacterial fatty acids in the environment augment recovery from the dauer stage under permissive conditions. The effect of increased fatty acids on different dauer constitutive mutants indicates a role for insulin peptide secretion in coordinating recovery from the dauer stage in response to fatty acids. These data suggest that worms can sense the presence of fatty acids in the environment and that elevated levels can promote recovery from dauer arrest. This may be important in the natural environment where the dauer larva needs to determine whether the environment is appropriate to support reproductive growth following dauer exit. PMID- 24475207 TI - Structural effects of methionine oxidation on isolated subdomains of human fibrin D and alphaC regions. AB - Oxidation of key methionine residues on fibrin leads to altered fibrin polymerization producing severely altered fibrin gel structure and function. This is important because fibrinogen and its modification by oxidative stress have been implicated as key contributors to both pathological thrombotic and hemorrhagic diseases ranging from cardiovascular thrombosis to the acute coagulopathy of trauma. However, how oxidation leads to altered fibrin polymerization remains poorly understood at the molecular level. We have applied a powerful and novel well-tempered ensemble parallel tempering (PT-WTE) technique along with conventional molecular dynamics (MD) simulation to investigate the molecular-level consequences of selective methionine oxidation of fibrinogen. We offer new insights into molecular mechanisms of oxidation-induced changes in fibrin polymerization, while focusing on the D region knob 'B' and hole 'b' interaction and alphaC-domain interactions, both of which are hypothesized to contribute to the lateral aggregation mechanism of fibrin fibrils. Methionine oxidation did not alter the native state or the stability of a bound knob 'B' surrogate when interacting with hole 'b' in the D region. However, applying PT WTE simulation to a human homology model of the bovine N-terminal subdomain fragment from the alphaC-domain revealed that methionine oxidation altered the conformation of the hairpin-linking region to favor open rather than closed hairpin structures. We attribute this alteration to the disruption of the hairpin linking region's conformation, with oxidation increasing the radius of gyration for this segment. This result is in agreement with experimental data demonstrating decreased fibrin protofibril lateral aggregation when methionine oxidation is present in the same alphaC-domain fragment. Therefore, single methionine oxidation within the alphaC-domain is a likely molecular mechanism. PMID- 24475208 TI - Costs and effectiveness of treatment alternatives for proximal caries lesions. AB - OBJECTIVES: Invasive therapy of proximal caries lesions initiates a cascade of re treatment cycles with increasing loss of dental hard tissue. Non- and micro invasive treatment aim at delaying this cascade and may thus reduce both the health and economic burden of such lesions. This study compared the costs and effectiveness of alternative treatments of proximal caries lesions. METHODS: A Markov-process model was used to simulate the events following the treatment of a proximal posterior lesion (E2/D1) in a 20-year-old patient in Germany. We compared three interventions (non-invasive; micro-invasive using resin infiltration; invasive using composite restoration). We calculated the risk of complications of initial and possible follow-up treatments and modelled time dependent non-linear transition probabilities. Costs were calculated based on item-fee catalogues in Germany. Monte-Carlo-microsimulations were performed to compare cost-effectiveness of non- versus micro-invasive treatment and to analyse lifetime costs of all three treatments. RESULTS: Micro-invasive treatment was both more costly and more effective than non-invasive therapy, with ceiling-value thresholds for willingness-to-pay between 16.73 ? for E2 and 1.57 ? for D1 lesions. Invasive treatment was the most costly strategy. Calculated costs and effectiveness were sensitive to lesion stage, patient's age, discounting rate and assumed initial treatment costs. CONCLUSIONS: Non- and micro-invasive treatments have lower long-term costs than invasive therapy of proximal lesions. Micro invasive therapy had the highest cost-effectiveness for treating D1 lesions in young patients. Decision makers with a willingness-to-pay over 16.73 ? and 1.57 ? for E2 and D1 lesions, respectively, will find micro-invasive treatment more cost effective than non-invasive therapy. PMID- 24475209 TI - Coronary collateral circulation in patients of coronary ectasia with significant coronary artery disease. AB - OBJECTIVES: Patients with coronary ectasia (CE) usually have coexisting coronary stenosis resulting in myoischemia. Coronary collateral plays an important role in protecting myocardium from ischemia and reducing cardiovascular events. However, limited studies investigate the role of CE in coronary collaterals development. METHODS: We evaluated 1020 consecutive patients undergoing coronary angiography and 552 patients with significant coronary artery disease (SCAD), defined as diameter stenosis more than 70%, were finally analyzed. CE is defined as the ectatic diameter 1.5 times larger than adjacent reference segment. Rentrop collateral score was used to classify patients into poor (grades 0 and 1) or good (grades 2 and 3) collateral group. RESULTS: 73 patients (13.2%) had CE lesions which were most located in the right coronary artery (53.4%). Patients with CE had a lower incidence of diabetes (43.8% vs 30.1%, p = 0.03), higher body mass index (25.4+/-3.5 vs 26.7+/-4.6, p = 0.027) and poorer coronary collateral (58.2% vs 71.2%, p = 0.040). Patients with poor collateral (n = 331) had a higher incidence of CE (15.7% vs 9.5%, p = 0.040) and fewer diseased vessels numbers (1.96+/-0.84 vs 2.48+/-0.69, p<0.001). Multivariate analysis showed diabetes (odd ratio (OR) 0.630, p = 0.026), CE (OR = 0.544, p = 0.048), and number of diseased vessels (OR = 2.488, p<0.001) were significant predictors of coronary collaterals development. CONCLUSION: The presence of CE was associated with poorer coronary collateral development in patients with SCAD. PMID- 24475210 TI - Clinical comparison of 99mTc exametazime and 123I Ioflupane SPECT in patients with chronic mild traumatic brain injury. AB - BACKGROUND: This study evaluated the clinical interpretations of single photon emission computed tomography (SPECT) using a cerebral blood flow and a dopamine transporter tracer in patients with chronic mild traumatic brain injury (TBI). The goal was to determine how these two different scan might be used and compared to each other in this patient population. METHODS AND FINDINGS: Twenty-five patients with persistent symptoms after a mild TBI underwent SPECT with both (99m)Tc exametazime to measure cerebral blood flow (CBF) and (123)I ioflupane to measure dopamine transporter (DAT) binding. The scans were interpreted by two expert readers blinded to any case information and were assessed for abnormal findings in comparison to 10 controls for each type of scan. Qualitative CBF scores for each cortical and subcortical region along with DAT binding scores for the striatum were compared to each other across subjects and to controls. In addition, symptoms were compared to brain scan findings. TBI patients had an average of 6 brain regions with abnormal perfusion compared to controls who had an average of 2 abnormal regions (p<0.001). Patient with headaches had lower CBF in the right frontal lobe, and higher CBF in the left parietal lobe compared to patients without headaches. Lower CBF in the right temporal lobe correlated with poorer reported physical health. Higher DAT binding was associated with more depressive symptoms and overall poorer reported mental health. There was no clear association between CBF and DAT binding in these patients. CONCLUSIONS: Overall, both scans detected abnormalities in brain function, but appear to reflect different types of physiological processes associated with chronic mild TBI symptoms. Both types of scans might have distinct uses in the evaluation of chronic TBI patients depending on the clinical scenario. PMID- 24475211 TI - The cognitive control of memory: age differences in the neural correlates of successful remembering and intentional forgetting. AB - Successful memory encoding depends on the ability to intentionally encode relevant information (via differential encoding) and intentionally forget that which is irrelevant (via inhibition). Both cognitive processes have been shown to decline in aging and are theorized to underlie age-related deficits in the cognitive control of memory. The current study uses the Directed Forgetting paradigm in conjunction with fMRI to investigate age-related differences in both cognitive processes, with the specific aim of elucidating neural evidence supporting these theorized deficits. Results indicate relatively preserved differential encoding, with age differences consistent with previous models of age-related compensation (i.e., increased frontal and bilateral recruitment). Older adults did display noticeable differences in the recruitment of brain regions related to intentional forgetting, specifically exhibiting reduced activity in the right superior prefrontal cortex, a region shown to be critical to inhibitory processing. However, older adults exhibited increased reliance on processing in right inferior parietal lobe associated with successful forgetting. Activity in this region was negatively correlated with activity in the medial temporal lobe, suggesting a shift in the locus of inhibition compared to the frontally mediated inhibition observed in younger adults. Finally, while previous studies found intentional and incidental forgetting to be dissociable in younger adults, this differentiation appears to be reduced in older adults. The current results are the first to provide neural evidence for an age-related reduction in processes that support intentional forgetting. PMID- 24475212 TI - Spectral radiation dependent photoprotective mechanism in the diatom Pseudo nitzschia multistriata. AB - Phytoplankton, such as diatoms, experience great variations of photon flux density (PFD) and light spectrum along the marine water column. Diatoms have developed some rapidly-regulated photoprotective mechanisms, such as the xanthophyll cycle activation (XC) and the non-photochemical chlorophyll fluorescence quenching (NPQ), to protect themselves from photooxidative damages caused by excess PFD. In this study, we investigate the role of blue fluence rate in combination with red radiation in shaping photoacclimative and protective responses in the coastal diatom Pseudo-nitzschia multistriata. This diatom was acclimated to four spectral light conditions (blue, red, blue-red, blue-red green), each of them provided with low and high PFD. Our results reveal that the increase in the XC pool size and the amplitude of NPQ is determined by the blue fluence rate experienced by cells, while cells require sensing red radiation to allow the development of these processes. Variations in the light spectrum and in the blue versus red radiation modulate either the photoprotective capacity, such as the activation of the diadinoxanthin-diatoxanthin xanthophyll cycle, the diadinoxanthin de-epoxidation rate and the capacity of non-photochemical quenching, or the pigment composition of this diatom. We propose that spectral composition of light has a key role on the ability of diatoms to finely balance light harvesting and photoprotective capacity. PMID- 24475213 TI - Transcriptional profiling of Wnt3a mutants identifies Sp transcription factors as essential effectors of the Wnt/beta-catenin pathway in neuromesodermal stem cells. AB - Neuromesodermal (NM) stem cells reside in the primitive streak (PS) of gastrulating vertebrate embryos and generate precursors of the spinal cord and musculoskeletal system. Although Wnt3a/beta-catenin signaling is crucial for NM stem cell maintenance and differentiation, few key transcriptional effectors have been identified. Through a concerted transcriptional profiling and genetic approach we have determined that two Zn(2+)-finger transcription factors, Sp5 and Sp8, are regulated by Wnt3a in the PS, and are essential for neural and musculoskeletal patterning. These results identify Sp5 and Sp8 as pivotal downstream effectors of Wnt3a, and suggest that they are essential for the self renewal and differentiation of NM stem cells. PMID- 24475214 TI - Turnaround time for early infant HIV diagnosis in rural Zambia: a chart review. AB - BACKGROUND: Early infant HIV diagnosis is challenging in sub-Saharan Africa, particularly in rural areas where laboratory capacity is limited. Specimens must be transported to central laboratories for testing, leading to delays in diagnosis and initiation of antiretroviral therapy. This study was undertaken in rural Zambia to measure the turnaround time for confirmation of HIV infection and identify delays in diagnosis. METHODS: Chart reviews were conducted from 2010 2012 for children undergoing early infant HIV diagnosis at Macha Hospital in Zambia. Relevant dates, receipt of drugs by mother and child for the prevention of mother-to-child transmission (PMTCT), and test results were abstracted. RESULTS: 403 infants provided 476 samples for early infant diagnosis. The median age at the "6-week" and "6-month" assessments was 8.1 weeks and 7.0 months, respectively. The majority of mothers (80%) and infants (67%) received PMTCT. The median time between sample collection and arrival at the central laboratory in Lusaka was 17 days (IQR: 10, 28); arrival at the central laboratory to testing was 6 days (IQR: 5, 11); testing to return of results to the clinic was 29 days (IQR: 17, 36); arrival of results at the clinic to return of results to the caregiver was 45 days (IQR: 24, 79). The total median time from sample collection to return of results to the caregiver was 92 days (IQR: 84, 145). The proportion of HIV PCR positive samples was 12%. The total median turnaround time was shorter for HIV PCR positive as compared to negative or invalid samples (85 vs. 92 days; p = 0.08). CONCLUSIONS: Delays in processing and communicating test results were identified, particularly in returning results from the central laboratory to the clinic and from the clinic to the caregiver. A more efficient process is needed so that caregivers can be provided test results more rapidly, potentially resulting in earlier treatment initiation and better outcomes for HIV-infected infants. PMID- 24475216 TI - Lymph node ratio for postoperative staging of laryngeal squamous cell carcinoma with lymph node metastasis. AB - BACKGROUND: Lymph node metastasis has a significant impact on laryngeal cancer prognosis. The role of lymph node ratio (LNR, ratio of metastatic to examined nodes) in the staging of laryngeal cancer was not reported. PATIENTS AND METHODS: Records of laryngeal cancer patients with lymph node involvement from Surveillance, Epidemiology, and End Results database (SEER, training set, N = 1963) and Fudan University Shanghai Cancer Center (FDSCC, validating set, N = 27) were analyzed for the prognostic value of LNR. Kaplan-Meier survival estimates, the Log-rank chi2 test and Cox proportional hazards model were used for univariate and multivariate analysis. Optimal LNR cutoff points were identified by X-tile. RESULTS: Optimal LNR cutoff points classified patients into three risk groups R1 (<=0.09), R2 (0.09-0.20) and R3 (>0.20), corresponding to 5-year cause specific survival and overall survival in SEER patients of 55.1%, 40.2%, 28.8% and 43.1%, 31.5%, 21.8%, 2-year disease free survival and disease specific survival in FDSCC patients of 74.1%, 62.5%, 50.0%, and 67.7%, 43.2%, 25.0%, respectively. R3 stratified more high risk patients than N3 with the same survival rate, and R classification clearly separated N2 patients to 3 risk groups and N1 patients to 2 risk groups (R1-2 and R3). CONCLUSIONS: R classification is a significant prognostic factor of laryngeal cancer and should be used as a complementary staging system of N classification. PMID- 24475215 TI - Evaluation of hyperpolarized [1-13C]-pyruvate by magnetic resonance to detect ionizing radiation effects in real time. AB - Ionizing radiation (IR) cytotoxicity is primarily mediated through reactive oxygen species (ROS). Since tumor cells neutralize ROS by utilizing reducing equivalents, we hypothesized that measurements of reducing potential using real time hyperpolarized (HP) magnetic resonance spectroscopy (MRS) and spectroscopic imaging (MRSI) can serve as a surrogate marker of IR induced ROS. This hypothesis was tested in a pre-clinical model of anaplastic thyroid carcinoma (ATC), an aggressive head and neck malignancy. Human ATC cell lines were utilized to test IR effects on ROS and reducing potential in vitro and [1-13C] pyruvate HP MRS/MRSI imaging of ATC orthotopic xenografts was used to study in vivo effects of IR. IR increased ATC intra-cellular ROS levels resulting in a corresponding decrease in reducing equivalent levels. Exogenous manipulation of cellular ROS and reducing equivalent levels altered ATC radiosensitivity in a predictable manner. Irradiation of ATC xenografts resulted in an acute drop in reducing potential measured using HP-MRS, reflecting the shunting of reducing equivalents towards ROS neutralization. Residual tumor tissue post irradiation demonstrated heterogeneous viability. We have adapted HP-MRS/MRSI to non-invasively measure IR mediated changes in tumor reducing potential in real time. Continued development of this technology could facilitate the development of an adaptive clinical algorithm based on real-time adjustments in IR dose and dose mapping. PMID- 24475217 TI - miR-342 regulates BRCA1 expression through modulation of ID4 in breast cancer. AB - A miRNAs profiling on a group of familial and sporadic breast cancers showed that miRNA-342 was significantly associated with estrogen receptor (ER) levels. To investigate at functional level the role of miR-342 in the pathogenesis of breast cancer, we focused our attention on its "in silico" predicted putative target gene ID4, a transcription factor of the helix-loop-helix protein family whose expression is inversely correlated with that of ER. ID4 is expressed in breast cancer and can negatively regulate BRCA1 expression. Our results showed an inverse correlation between ID4 and miR-342 as well as between ID4 and BRCA1 expression. We functionally validated the interaction between ID4 and miR-342 in a reporter Luciferase system. Based on these findings, we hypothesized that regulation of ID4 mediated by miR-342 could be involved in the pathogenesis of breast cancer by downregulating BRCA1 expression. We functionally demonstrated the interactions between miR-342, ID4 and BRCA1 in a model provided by ER negative MDA-MB-231 breast cancer cell line that presented high levels of ID4. Overexpression of miR-342 in these cells reduced ID4 and increased BRCA1 expression, supporting a possible role of this mechanism in breast cancer. In the ER-positive MCF7 and in the BRCA1-mutant HCC1937 cell lines miR-342 over expression only reduced ID4. In the cohort of patients we studied, a correlation between miR-342 and BRCA1 expression was found in the ER-negative cases. As ER negative cases were mainly BRCA1-mutant, we speculate that the mechanism we demonstrated could be involved in the decreased expression of BRCA1 frequently observed in non BRCA1-mutant breast cancers and could be implicated as a causal factor in part of the familial cases grouped in the heterogeneous class of non BRCA1 or BRCA2-mutant cases (BRCAx). To validate this hypothesis, the study should be extended to a larger cohort of ER-negative cases, including those belonging to the BRCAx class. PMID- 24475218 TI - Impact of measurement error on testing genetic association with quantitative traits. AB - Measurement error of a phenotypic trait reduces the power to detect genetic associations. We examined the impact of sample size, allele frequency and effect size in presence of measurement error for quantitative traits. The statistical power to detect genetic association with phenotype mean and variability was investigated analytically. The non-centrality parameter for a non-central F distribution was derived and verified using computer simulations. We obtained equivalent formulas for the cost of phenotype measurement error. Effects of differences in measurements were examined in a genome-wide association study (GWAS) of two grading scales for cataract and a replication study of genetic variants influencing blood pressure. The mean absolute difference between the analytic power and simulation power for comparison of phenotypic means and variances was less than 0.005, and the absolute difference did not exceed 0.02. To maintain the same power, a one standard deviation (SD) in measurement error of a standard normal distributed trait required a one-fold increase in sample size for comparison of means, and a three-fold increase in sample size for comparison of variances. GWAS results revealed almost no overlap in the significant SNPs (p<10(-5)) for the two cataract grading scales while replication results in genetic variants of blood pressure displayed no significant differences between averaged blood pressure measurements and single blood pressure measurements. We have developed a framework for researchers to quantify power in the presence of measurement error, which will be applicable to studies of phenotypes in which the measurement is highly variable. PMID- 24475219 TI - De novo genome assembly of the fungal plant pathogen Pyrenophora semeniperda. AB - Pyrenophora semeniperda (anamorph Drechslera campulata) is a necrotrophic fungal seed pathogen that has a wide host range within the Poaceae. One of its hosts is cheatgrass (Bromus tectorum), a species exotic to the United States that has invaded natural ecosystems of the Intermountain West. As a natural pathogen of cheatgrass, P. semeniperda has potential as a biocontrol agent due to its effectiveness at killing seeds within the seed bank; however, few genetic resources exist for the fungus. Here, the genome of P. semeniperda isolate assembled from sequence reads of 454 pyrosequencing is presented. The total assembly is 32.5 Mb and includes 11,453 gene models encoding putative proteins larger than 24 amino acids. The models represent a variety of putative genes that are involved in pathogenic pathways typically found in necrotrophic fungi. In addition, extensive rearrangements, including inter- and intrachromosomal rearrangements, were found when the P. semeniperda genome was compared to P. tritici-repentis, a related fungal species. PMID- 24475220 TI - Functional polymorphisms of interferon-gamma affect pneumonia-induced sepsis. AB - OBJECTIVE: Sepsis is an inflammatory syndrome caused by infection, and both its incidence and mortality are high. Because interferon-gamma (IFN-gamma) plays an important role in inflammation, this work assessed IFN-gamma single nucleotide polymorphism (SNPs) that may be associated with sepsis. METHODS: A total of 196 patients with pneumonia-induced sepsis and 213 age- and sex-matched healthy volunteers participated in our study from July 2012 to July 2013 in Guangzhou, China. Patient clinical information was collected. Clinical pathology was assessed in subgroups defined based on clinical criteria, APACHE II (acute physiology and chronic health evaluation) and SOFA (sepsis-related organ failure assessment) scores and discharge rate. Four functional SNPs, -1616T/C (rs2069705), -764G/C (rs2069707), +874A/T (rs2430561) and +3234C/T (rs2069718), were genotyped by Snapshot in both sepsis patients and healthy controls. Pearson's chi-square test or Fisher's exact test were used to analyze the distribution of the SNPs, and the probability values (P values), odds ratios (OR) and 95% confidence intervals (CIs) were calculated. RESULTS: No mutations in the IFN-gamma -764G/C SNP were detected among the participants in our study. The +874A/T and +3234C/T SNPs were in strong linkage disequilibrium (LD) (r(2) = 0.894). The -1616 TC+TT, +874 AT+AA genotype and the TAC haplotype were significantly associated with sepsis susceptibility, while the CTT haplotype was associated with protection against sepsis incidence. Genotype of -1616 TT wasn't only protective against severity of sepsis, but also against higher APACHE II and SOFA scores as +874 AA and +3234 CC. The TAC haplotype was was protective against progression to severe sepsis either. CONCLUSION: Our results suggest that functional IFN-gamma SNPs and their haplotypes are associated with pneumonia induced sepsis. PMID- 24475221 TI - Increased arterial diameters in the posterior cerebral circulation in men with Fabry disease. AB - A high load of white matter lesions and enlarged basilar arteries have been shown in selected patients with Fabry disease, a disorder associated with an increased stroke risk. We studied a large cohort of patients with Fabry disease to differentially investigate white matter lesion load and cerebral artery diameters. We retrospectively analyzed cranial magnetic resonance imaging scans of 87 consecutive Fabry patients, 20 patients with ischemic stroke, and 36 controls. We determined the white matter lesion load applying the Fazekas score on fluid-attenuated inversion recovery sequences and measured the diameters of cerebral arteries on 3D-reconstructions of the time-of-flight-MR-angiography scans. Data of different Fabry patient subgroups (males-females; normal-impaired renal function) were compared with data of patients with stroke and controls. A history of stroke or transient ischemic attacks was present in 4/30 males (13%) and 5/57 (9%) females with Fabry disease, all in the anterior circulation. Only one man with Fabry disease showed confluent cerebral white matter lesions in the Fazekas score assessment (1%). Male Fabry patients had a larger basilar artery (p<0.01) and posterior cerebral artery diameter (p<0.05) compared to male controls. This was independent of disease severity as measured by renal function and did not lead to changes in arterial blood flow properties. A basilar artery diameter of >3.2 mm distinguished between men with Fabry disease and controls (sensitivity: 87%, specificity: 86%, p<0.001), but not from stroke patients. Enlarged arterial diameters of the posterior circulation are present only in men with Fabry disease independent of disease severity. PMID- 24475222 TI - Efficacy and safety of talc pleurodesis for malignant pleural effusion: a meta analysis. AB - BACKGROUND: Talc pleurodesis has been widely used to control malignant pleural effusion; however, it is still not clear whether talc pleurodesis is more effective than other local therapies. We performed a meta-analysis to evaluate the efficacy and safety of talc pleurodesis in the management of malignant pleural effusion. METHODS: PubMed, Embase, and Web of Science were searched for English-language studies of clinical controlled trials comparing talc pleurodesis with control therapies until August 8, 2013. Success rate and incidence of adverse events were evaluated. Relative risks were estimated using random- or fixed- effects model and statistical heterogeneity was assessed using I2 test. RESULTS: Twenty trials involving 1,525 patients with malignant pleural effusion were included. The success rate of talc pleurodesis was significantly higher than that of control therapies (relative risk, 1.21; 95% confidence interval, 1.01 1.45; p = 0.035) with similar adverse events. In addition, thoracoscopic talc poudrage was more effective than bedside talc slurry (relative risk, 1.12; 95% confidence interval, 1.01-1.23; p = 0.026). CONCLUSIONS: The current evidences suggested the benefit for talc pleurodesis in the treatment of malignant pleural effusion. Talc pleurodesis, especially thoracoscopic talc poudrage pleurodesis, should be performed in patients with malignant pleural effusion, especially those with life-expectancy longer than one month. PMID- 24475223 TI - JNK1 protects against glucolipotoxicity-mediated beta-cell apoptosis. AB - Pancreatic beta-cell dysfunction is central to type 2 diabetes pathogenesis. Prolonged elevated levels of circulating free-fatty acids and hyperglycemia, also termed glucolipotoxicity, mediate beta-cell dysfunction and apoptosis associated with increased c-Jun N-terminal Kinase (JNK) activity. Endoplasmic reticulum (ER) and oxidative stress are elicited by palmitate and high glucose concentrations further potentiating JNK activity. Our aim was to determine the role of the JNK subtypes JNK1, JNK2 and JNK3 in palmitate and high glucose-induced beta-cell apoptosis. We established insulin-producing INS1 cell lines stably expressing JNK subtype specific shRNAs to understand the differential roles of the individual JNK isoforms. JNK activity was increased after 3 h of palmitate and high glucose exposure associated with increased expression of ER and mitochondrial stress markers. JNK1 shRNA expressing INS1 cells showed increased apoptosis and cleaved caspase 9 and 3 compared to non-sense shRNA expressing control INS1 cells when exposed to palmitate and high glucose associated with increased CHOP expression, ROS formation and Puma mRNA expression. JNK2 shRNA expressing INS1 cells did not affect palmitate and high glucose induced apoptosis or ER stress markers, but increased Puma mRNA expression compared to non-sense shRNA expressing INS1 cells. Finally, JNK3 shRNA expressing INS1 cells did not induce apoptosis compared to non-sense shRNA expressing INS1 cells when exposed to palmitate and high glucose but showed increased caspase 9 and 3 cleavage associated with increased DP5 and Puma mRNA expression. These data suggest that JNK1 protects against palmitate and high glucose-induced beta-cell apoptosis associated with reduced ER and mitochondrial stress. PMID- 24475224 TI - Nested insertions and accumulation of indels are negatively correlated with abundance of mutator-like transposable elements in maize and rice. AB - Mutator-like transposable elements (MULEs) are widespread in plants and were first discovered in maize where there are a total of 12,900 MULEs. In comparison, rice, with a much smaller genome, harbors over 30,000 MULEs. Since maize and rice are close relatives, the differential amplification of MULEs raised an inquiry into the underlying mechanism. We hypothesize this is partly attributed to the differential copy number of autonomous MULEs with the potential to generate the transposase that is required for transposition. To this end, we mined the two genomes and detected 530 and 476 MULEs containing transposase sequences (candidate coding-MULEs) in maize and rice, respectively. Over 1/3 of the candidate coding-MULEs harbor nested insertions and the ratios are similar in the two genomes. Among the maize elements with nested insertions, 24% have insertions in coding regions and over half of them harbor two or more insertions. In contrast, only 12% of the rice elements have insertions in coding regions and 19% have multiple insertions, suggesting that nested insertions in maize are more disruptive. This is because most nested insertions in maize are from LTR retrotransposons, which are large in size and are prevalent in the maize genome. Our results suggest that the amplification of retrotransposons may limit the amplification of DNA transposons but not vice versa. In addition, more indels are detected among maize elements than rice elements whereas defects caused by point mutations are comparable between the two species. Taken together, more disruptive nested insertions combined with higher frequency of indels resulted in few (6%) coding-MULEs that may encode functional transposases in maize. In contrast, 35% of the coding-MULEs in rice retain putative intact transposase. This is in addition to the higher expression frequency of rice coding-MULEs, which may explain the higher occurrence of MULEs in rice than that in maize. PMID- 24475225 TI - A comparison of different informative vibrotactile forward collision warnings: does the warning need to be linked to the collision event? AB - Recent research demonstrates that auditory and vibrotactile forward collision warnings presenting a motion signal (e.g., looming or apparent motion across the body surface) can facilitate speeded braking reaction times (BRTs). The purpose of the present study was to expand on this work by directly comparing warning signals in which the motion conveyed was constant across all collision events with signals in which the speed of motion was dependent on the closing velocity (CV). Two experiments were conducted using a simulated car-following task and BRTs were measured. In Experiment 1, increasing intensity (looming) vibrotactile signals were presented from a single tactor attached to the driver's waist. When the increase in intensity was CV-linked, BRTs were significantly faster as compared to a no-warning condition, however, they were not significantly different from constant intensity and CV-independent looming warnings. In Experiment 2, a vertical array of three tactors was used to create motion either towards (upwards) or away (downwards) from the driver's head. When the warning signal presented upwards motion that was CV-linked, BRTs were significantly faster than all other warning types. Downwards warnings led to a significantly higher number of brake activations in false alarm situations as compared to upwards moving warnings. The effectiveness of dynamic tactile collision warnings would therefore appear to depend on both the link between the warning and collision event and on the directionality of the warning signal. PMID- 24475226 TI - Monitoring vital signs: development of a modified early warning scoring (MEWS) system for general wards in a developing country. AB - OBJECTIVE: The aim of the study was to develop and validate, by consensus, the construct and content of an observations chart for nurses incorporating a modified early warning scoring (MEWS) system for physiological parameters to be used for bedside monitoring on general wards in a public hospital in South Africa. METHODS: Delphi and modified face-to-face nominal group consensus methods were used to develop and validate a prototype observations chart that incorporated an existing UK MEWS. This informed the development of the Cape Town ward MEWS chart. PARTICIPANTS: One specialist anaesthesiologist, one emergency medicine specialist, two critical care nurses and eight senior ward nurses with expertise in bedside monitoring (N = 12) were purposively sampled for consensus development of the MEWS. One general surgeon declined and one neurosurgeon replaced the emergency medicine specialist in the final round. RESULTS: Five consensus rounds achieved >=70% agreement for cut points in five of seven physiological parameters respiratory and heart rates, systolic BP, temperature and urine output. For conscious level and oxygen saturation a relaxed rule of <70% agreement was applied. A reporting algorithm was established and incorporated in the MEWS chart representing decision rules determining the degree of urgency. Parameters and cut points differed from those in MEWS used in developed countries. CONCLUSIONS: A MEWS for developing countries should record at least seven parameters. Experts from developing countries are best placed to stipulate cut points in physiological parameters. Further research is needed to explore the ability of the MEWS chart to identify physiological and clinical deterioration. PMID- 24475227 TI - Factors that control the chemistry of the LOV domain photocycle. AB - Algae, plants, bacteria and fungi contain Light-Oxygen-Voltage (LOV) domains that function as blue light sensors to control cellular responses to light. All LOV domains contain a bound flavin chromophore that is reduced upon photon absorption and forms a reversible, metastable covalent bond with a nearby cysteine residue. In Avena sativa LOV2 (AsLOV2), the photocycle is accompanied by an allosteric conformational change that activates the attached phototropin kinase in the full length protein. Both the conformational change and formation of the cysteinyl flavin adduct are stabilized by the reduction of the N5 atom in the flavin's isoalloxazine ring. In this study, we perform a mutational analysis to investigate the requirements for LOV2 to photocycle. We mutated all the residues that interact with the chromophore isoalloxazine ring to inert functional groups but none could fully inhibit the photocycle except those to the active-site cysteine. However, electronegative side chains in the vicinity of the chromophore accelerate the N5 deprotonation and the return to the dark state. Mutations to the N414 and Q513 residues identify a potential water gate and H2O coordination sites. These residues affect the electronic nature of the chromophore and photocycle time by helping catalyze the N5 reduction leading to the completion of the photocycle. In addition, we demonstrate that dehydration leads to drastically slower photocycle times. Finally, to investigate the requirements of an active site cysteine for photocycling, we moved the nearby cysteine to alternative locations and found that some variants can still photocycle. We propose a new model of the LOV domain photocycle that involves all of these components. PMID- 24475229 TI - Observations on abundance of bluntnose sixgill sharks, Hexanchus griseus, in an urban waterway in Puget Sound, 2003-2005. AB - The bluntnose sixgill shark, Hexanchus griseus, is a widely distributed but poorly understood large, apex predator. Anecdotal reports of diver-shark encounters in the late 1990's and early 2000's in the Pacific Northwest stimulated interest in the normally deep-dwelling shark and its presence in the shallow waters of Puget Sound. Analysis of underwater video documenting sharks at the Seattle Aquarium's sixgill research site in Elliott Bay and mark-resight techniques were used to answer research questions about abundance and seasonality. Seasonal changes in relative abundance in Puget Sound from 2003-2005 are reported here. At the Seattle Aquarium study site, 45 sixgills were tagged with modified Floy visual marker tags, along with an estimated 197 observations of untagged sharks plus 31 returning tagged sharks, for a total of 273 sixgill observations recorded. A mark-resight statistical model based on analysis of underwater video estimated a range of abundance from a high of 98 sharks seen in July of 2004 to a low of 32 sharks seen in March of 2004. Both analyses found sixgills significantly more abundant in the summer months at the Seattle Aquarium's research station. PMID- 24475228 TI - Long-term differential changes in mouse intestinal metabolomics after gamma and heavy ion radiation exposure. AB - Tissue consequences of radiation exposure are dependent on radiation quality and high linear energy transfer (high-LET) radiation, such as heavy ions in space is known to deposit higher energy in tissues and cause greater damage than low-LET gamma radiation. While radiation exposure has been linked to intestinal pathologies, there are very few studies on long-term effects of radiation, fewer involved a therapeutically relevant gamma radiation dose, and none explored persistent tissue metabolomic alterations after heavy ion space radiation exposure. Using a metabolomics approach, we report long-term metabolomic markers of radiation injury and perturbation of signaling pathways linked to metabolic alterations in mice after heavy ion or gamma radiation exposure. Intestinal tissues (C57BL/6J, female, 6 to 8 wks) were analyzed using ultra performance liquid chromatography coupled with electrospray quadrupole time-of-flight mass spectrometry (UPLC-QToF-MS) two months after 2 Gy gamma radiation and results were compared to an equitoxic 56Fe (1.6 Gy) radiation dose. The biological relevance of the metabolites was determined using Ingenuity Pathway Analysis, immunoblots, and immunohistochemistry. Metabolic profile analysis showed radiation-type-dependent spatial separation of the groups. Decreased adenine and guanosine and increased inosine and uridine suggested perturbed nucleotide metabolism. While both the radiation types affected amino acid metabolism, the 56Fe radiation preferentially altered dipeptide metabolism. Furthermore, 56Fe radiation caused upregulation of 'prostanoid biosynthesis' and 'eicosanoid signaling', which are interlinked events related to cellular inflammation and have implications for nutrient absorption and inflammatory bowel disease during space missions and after radiotherapy. In conclusion, our data showed for the first time that metabolomics can not only be used to distinguish between heavy ion and gamma radiation exposures, but also as a radiation-risk assessment tool for intestinal pathologies through identification of biomarkers persisting long after exposure. PMID- 24475230 TI - Particle size concentration distribution and influences on exhaled breath particles in mechanically ventilated patients. AB - Humans produce exhaled breath particles (EBPs) during various breath activities, such as normal breathing, coughing, talking, and sneezing. Airborne transmission risk exists when EBPs have attached pathogens. Until recently, few investigations had evaluated the size and concentration distributions of EBPs from mechanically ventilated patients with different ventilation mode settings. This study thus broke new ground by not only evaluating the size concentration distributions of EBPs in mechanically ventilated patients, but also investigating the relationship between EBP level and positive expiratory end airway pressure (PEEP), tidal volume, and pneumonia. This investigation recruited mechanically ventilated patients, with and without pneumonia, aged 20 years old and above, from the respiratory intensive care unit of a medical center. Concentration distributions of EBPs from mechanically ventilated patients were analyzed with an optical particle analyzer. This study finds that EBP concentrations from mechanically ventilated patients during normal breathing were in the range 0.47-2,554.04 particles/breath (0.001-4.644 particles/mL). EBP concentrations did not differ significantly between the volume control and pressure control modes of the ventilation settings in the mechanically ventilated patients. The patient EBPs were sized below 5 um, and 80% of them ranged from 0.3 to 1.0 um. The EBPs concentrations in patients with high PEEP (> 5 cmH2O) clearly exceeded those in patients with low PEEP (<= 5 cmH2O). Additionally, a significant negative association existed between pneumonia duration and EBPs concentration. However, tidal volume was not related to EBPs concentration. PMID- 24475231 TI - Evaluating the synergistic neutralizing effect of anti-botulinum oligoclonal antibody preparations. AB - Botulinum neurotoxins (BoNT) are considered some of the most lethal known substances. There are seven botulinum serotypes, of which types A, B and E cause most human botulism cases. Anti-botulinum polyclonal antibodies (PAbs) are currently used for both detection and treatment of the disease. However, significant improvements in immunoassay specificity and treatment safety may be made using monoclonal antibodies (MAbs). In this study, we present an approach for the simultaneous generation of highly specific and neutralizing MAbs against botulinum serotypes A, B, and E in a single process. The approach relies on immunization of mice with a trivalent mixture of recombinant C-terminal fragment (Hc) of each of the three neurotoxins, followed by a parallel differential robotic hybridoma screening. This strategy enabled the cloning of seven to nine MAbs against each serotype. The majority of the MAbs possessed higher anti botulinum ELISA titers than anti-botulinum PAbs and had up to five orders of magnitude greater specificity. When tested for their potency in mice, neutralizing MAbs were obtained for all three serotypes and protected against toxin doses of 10 MsLD50-500 MsLD50. A strong synergistic effect of up to 400 fold enhancement in the neutralizing activity was observed when serotype-specific MAbs were combined. Furthermore, the highly protective oligoclonal combinations were as potent as a horse-derived PAb pharmaceutical preparation. Interestingly, MAbs that failed to demonstrate individual neutralizing activity were observed to make a significant contribution to the synergistic effect in the oligoclonal preparation. Together, the trivalent immunization strategy and differential screening approach enabled us to generate highly specific MAbs against each of the A, B, and E BoNTs. These new MAbs may possess diagnostic and therapeutic potential. PMID- 24475232 TI - Affinity improvement of a therapeutic antibody by structure-based computational design: generation of electrostatic interactions in the transition state stabilizes the antibody-antigen complex. AB - The optimization of antibodies is a desirable goal towards the development of better therapeutic strategies. The antibody 11K2 was previously developed as a therapeutic tool for inflammatory diseases, and displays very high affinity (4.6 pM) for its antigen the chemokine MCP-1 (monocyte chemo-attractant protein-1). We have employed a virtual library of mutations of 11K2 to identify antibody variants of potentially higher affinity, and to establish benchmarks in the engineering of a mature therapeutic antibody. The most promising candidates identified in the virtual screening were examined by surface plasmon resonance to validate the computational predictions, and to characterize their binding affinity and key thermodynamic properties in detail. Only mutations in the light chain of the antibody are effective at enhancing its affinity for the antigen in vitro, suggesting that the interaction surface of the heavy-chain (dominated by the hot-spot residue Phe101) is not amenable to optimization. The single-mutation with the highest affinity is L-N31R (4.6-fold higher affinity than wild-type antibody). Importantly, all the single-mutations showing increase affinity incorporate a charged residue (Arg, Asp, or Glu). The characterization of the relevant thermodynamic parameters clarifies the energetic mechanism. Essentially, the formation of new electrostatic interactions early in the binding reaction coordinate (transition state or earlier) benefits the durability of the antibody antigen complex. The combination of in silico calculations and thermodynamic analysis is an effective strategy to improve the affinity of a matured therapeutic antibody. PMID- 24475233 TI - Prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabin-based chemotherapy: a meta-analysis. AB - BACKGROUND: The potential prognostic value of human equilibrative nucleoside transporter1 in pancreatic cancer receiving gemcitabine-based chemotherapy is variably reported. OBJECTIVE: The objective of this study was to conduct a systematic review of literature evaluating human equilibrative nucleoside transporter1 expression as a prognostic factor in pancreatic cancer receiving gemcitabine-based chemotherapy and to conduct a subsequent meta-analysis to quantify the overall prognostic effect. METHODS: Related studies were identified and evaluated for quality through multiple search strategies. Only studies analyzing pancreatic cancer receiving gemcitabine-based chemotherapy were eligible for inclusion. Data were collected from studies comparing overall, disease-free and progression-free survival (OS, DFS and PFS) in patients with low human equilibrative nucleoside transporter1 levels and those having high levels. The hazard ratio (HR) and its 95% confidence interval (95%CI) were used to assess the strength of associations. Hazard ratios greater than 1 reflect adverse survival associated with low human equilibrative nucleoside transporter1 levels. RESULTS: A total of 12 studies (n = 875) were involved in this meta-analysis (12 for OS, 5 for DFS, 3 for PFS). For overall and disease-free survival, the pooled HRs of human equilibrative nucleoside transporter1 were significant at 2.93 (95% confidence interval [95% CI], 2.37-3.64) and 2.67 (95% CI, 1.87-3.81), respectively. For progression-free survival, the pooled HR in higher human equilibrative nucleoside transporter1 expression in pancreatic cancer receiving gemcitabine-based chemotherapy was 2.76 (95% CI, 1.76-4.34). No evidence of significant heterogeneity or publication bias was seen in any of these studies. CONCLUSION: These results support the case for a low human equilibrative nucleoside transporter1 level representing a significant and reproducible marker of adverse prognosis in pancreatic cancer receiving gemcitabine-based chemotherapy. PMID- 24475234 TI - OsGA2ox5, a gibberellin metabolism enzyme, is involved in plant growth, the root gravity response and salt stress. AB - Gibberellin (GA) 2-oxidases play an important role in the GA catabolic pathway through 2beta-hydroxylation. There are two classes of GA2oxs, i.e., a larger class of C19-GA2oxs and a smaller class of C20-GA2oxs. In this study, the gene encoding a GA 2-oxidase of rice, Oryza sativa GA 2-oxidase 5 (OsGA2ox5), was cloned and characterized. BLASTP analysis showed that OsGA2ox5 belongs to the C20 GA2oxs subfamily, a subfamily of GA2oxs acting on C20-GAs (GA12, GA53). Subcellular localization of OsGA2ox5-YFP in transiently transformed onion epidermal cells revealed the presence of this protein in both of the nucleus and cytoplasm. Real-time PCR analysis, along with GUS staining, revealed that OsGA2ox5 is expressed in the roots, culms, leaves, sheaths and panicles of rice. Rice plants overexpressing OsGA2ox5 exhibited dominant dwarf and GA-deficient phenotypes, with shorter stems and later development of reproductive organs than the wild type. The dwarfism phenotype was partially rescued by the application of exogenous GA3 at a concentration of 10 uM. Ectopic expression of OsGA2ox5 cDNA in Arabidopsis resulted in a similar phenotype. Real-time PCR assays revealed that both GA synthesis-related genes and GA signaling genes were expressed at higher levels in transgenic rice plants than in wild-type rice; OsGA3ox1, which encodes a key enzyme in the last step of the bioactive GAs synthesis pathway, was highly expressed in transgenic rice. The roots of OsGA2ox5-ox plants exhibited increased starch granule accumulation and gravity responses, revealing a role for GA in root starch granule development and gravity responses. Furthermore, rice and Arabidopsis plants overexpressing OsGA2ox5 were more resistant to high-salinity stress than wild-type plants. These results suggest that OsGA2ox5 plays important roles in GAs homeostasis, development, gravity responses and stress tolerance in rice. PMID- 24475235 TI - Is there any overtrading in stock markets? The moderating role of big five personality traits and gender in a unilateral trend stock market. AB - Overtrading is a common anomaly among stock investors. This study examines the relationship between overtrading and investment returns and the impact of the Big Five traits and gender on overtrading in a unilateral trend stock market using a simulated stock investment system. The data were derived from a sample of undergraduates from six universities who performed in a simulated stock investment situation and had their personality traits measured by the Big Five Personality Questionnaire. The results indicate that: (1) Overtrading was significant in rising stock markets, but not significant in falling markets. (2) The degree of female investors who overtraded was significant in rising markets. (3) The degree of overtrading investors who were high in extroversion or agreeableness was significant in rising markets. The implications of these results for more effective investment strategies are discussed. PMID- 24475236 TI - Kinetics of phosphomevalonate kinase from Saccharomyces cerevisiae. AB - The mevalonate-based isoprenoid biosynthetic pathway is responsible for producing cholesterol in humans and is used commercially to produce drugs, chemicals, and fuels. Heterologous expression of this pathway in Escherichia coli has enabled high-level production of the antimalarial drug artemisinin and the proposed biofuel bisabolane. Understanding the kinetics of the enzymes in the biosynthetic pathway is critical to optimize the pathway for high flux. We have characterized the kinetic parameters of phosphomevalonate kinase (PMK, EC 2.7.4.2) from Saccharomyces cerevisiae, a previously unstudied enzyme. An E. coli codon optimized version of the S. cerevisiae gene was cloned into pET-52b+, then the C terminal 6X His-tagged protein was expressed in E. coli BL21(DE3) and purified on a Ni2+ column. The KM of the ATP binding site was determined to be 98.3 uM at 30 degrees C, the optimal growth temperature for S. cerevisiae, and 74.3 uM at 37 degrees C, the optimal growth temperature for E. coli. The K(M) of the mevalonate 5-phosphate binding site was determined to be 885 uM at 30 degrees C and 880 uM at 37 degrees C. The V(max) was determined to be 4.51 umol/min/mg enzyme at 30 degrees C and 5.33 umol/min/mg enzyme at 37 degrees C. PMK is Mg2+ dependent, with maximal activity achieved at concentrations of 10 mM or greater. Maximum activity was observed at pH = 7.2. PMK was not found to be substrate inhibited, nor feedback inhibited by FPP at concentrations up to 10 uM FPP. PMID- 24475237 TI - Childhood Trauma Questionnaire (CTQ) in Brazilian samples of different age groups: findings from confirmatory factor analysis. AB - The Childhood Trauma Questionnaire (CTQ) is internationally accepted as a key tool for the assessment of childhood abuse and neglect experiences. However, there are relative few psychometric studies available and some authors have proposed two different factor solutions. We examined the dimensional structure and internal consistency of the Brazilian version of the CTQ. A total of 1,925 participants from eight different clinical and non-clinical samples including adolescents, adults and elders were considered in this study. First, we performed Confirmatory Factor Analysis to investigate the goodness of fit of the two proposed competitive factor structure models for the CTQ. We also investigated the internal consistency of all factors. Second, multi-group analyses were used to investigate measurement invariance and population heterogeneity across age groups and sex. Our findings revealed that the alternative factor structure as opposed to the original factor structure was the most appropriate model within adolescents and adults Brazilian samples. We provide further evidence for the validity and reliability of the CTQ within the Brazilian samples and report that the alternative model showed an improvement in fit indexes and may be a better alternative over the original model. PMID- 24475238 TI - Increased Ndfip1 in the substantia nigra of Parkinsonian brains is associated with elevated iron levels. AB - Iron misregulation is a central component in the neuropathology of Parkinson's disease. The iron transport protein DMT1 is known to be increased in Parkinson's brains linking functional transport mechanisms with iron accumulation. The regulation of DMT1 is therefore critical to the management of iron uptake in the disease setting. We previously identified post-translational control of DMT1 levels through a ubiquitin-mediated pathway led by Ndfip1, an adaptor for Nedd4 family of E3 ligases. Here we show that loss of Ndfip1 from mouse dopaminergic neurons resulted in misregulation of DMT1 levels and increased susceptibility to iron induced death. We report that in human Parkinson's brains increased iron concentrations in the substantia nigra are associated with upregulated levels of Ndfip1 in dopaminergic neurons containing alpha-synuclein deposits. Additionally, Ndfip1 was also found to be misexpressed in astrocytes, a cell type normally devoid of this protein. We suggest that in Parkinson's disease, increased iron levels are associated with increased Ndfip1 expression for the regulation of DMT1, including abnormal Ndfip1 activation in non-neuronal cell types such as astrocytes. PMID- 24475239 TI - A bio-inspired approach for the reduction of left ventricular workload. AB - Previous studies have demonstrated the existence of optimization criteria in the design and development of mammalians cardiovascular systems. Similarities in mammalian arterial wave reflection suggest there are certain design criteria for the optimization of arterial wave dynamics. Inspired by these natural optimization criteria, we investigated the feasibility of optimizing the aortic waves by modifying wave reflection sites. A hydraulic model that has physical and dynamical properties similar to a human aorta and left ventricle was used for a series of in-vitro experiments. The results indicate that placing an artificial reflection site (a ring) at a specific location along the aorta may create a constructive wave dynamic that could reduce LV pulsatile workload. This simple bio-inspired approach may have important implications for the future of treatment strategies for diseased aorta. PMID- 24475240 TI - Coexistence of reward and unsupervised learning during the operant conditioning of neural firing rates. AB - A fundamental goal of neuroscience is to understand how cognitive processes, such as operant conditioning, are performed by the brain. Typical and well studied examples of operant conditioning, in which the firing rates of individual cortical neurons in monkeys are increased using rewards, provide an opportunity for insight into this. Studies of reward-modulated spike-timing-dependent plasticity (RSTDP), and of other models such as R-max, have reproduced this learning behavior, but they have assumed that no unsupervised learning is present (i.e., no learning occurs without, or independent of, rewards). We show that these models cannot elicit firing rate reinforcement while exhibiting both reward learning and ongoing, stable unsupervised learning. To fix this issue, we propose a new RSTDP model of synaptic plasticity based upon the observed effects that dopamine has on long-term potentiation and depression (LTP and LTD). We show, both analytically and through simulations, that our new model can exhibit unsupervised learning and lead to firing rate reinforcement. This requires that the strengthening of LTP by the reward signal is greater than the strengthening of LTD and that the reinforced neuron exhibits irregular firing. We show the robustness of our findings to spike-timing correlations, to the synaptic weight dependence that is assumed, and to changes in the mean reward. We also consider our model in the differential reinforcement of two nearby neurons. Our model aligns more strongly with experimental studies than previous models and makes testable predictions for future experiments. PMID- 24475241 TI - Cortical dysfunction underlies the development of the split-hand in amyotrophic lateral sclerosis. AB - The split-hand phenomenon, a specific feature of amyotrophic lateral sclerosis (ALS), refers to preferential wasting of abductor pollicis brevis (APB) and first dorsal interosseous (FDI) with relative preservation of abductor digiti minimi (ADM). The pathophysiological mechanisms underlying the split-hand phenomenon remain elusive and resolution of this issue would provide unique insights into ALS pathophysiology. Consequently, the present study dissected out the relative contribution of cortical and peripheral processes in development of the split hand phenomenon in ALS. Cortical and axonal excitability studies were undertaken on 26 ALS patients, with motor responses recorded over the APB, FDI and ADM muscles. Results were compared to 21 controls. Short interval intracortical inhibition (SICI), a biomarker of cortical excitability, was significantly reduced across the range of intrinsic hand muscles (APB(SICI ALS) 0.3+/-2.0%, APB(SICI controls) 16.0+/-1.9%, P<0.0001; FDI(SICI ALS) 2.7+/-1.7%, FDI(SICI controls) 14.8+/-1.9%, P<0.0001; ADM(SICI ALS) 2.6+/-1.5%, ADM(SICI controls) 9.7+/-2.2%, P<0.001), although the reduction was most prominent when recorded over APB/FDI. Changes in SICI were accompanied by a significant increase in motor evoked potential amplitude and reduction of cortical silent period duration, all indicative of cortical hyperexcitability, and these were most prominent from the APB/FDI. At a peripheral level, a significant increase in strength-duration time constant and reduction in depolarising threshold electrotonus were evident in ALS, although these changes did not follow a split-hand distribution. Cortical dysfunction contributed to development of the split-hand in ALS, thereby implying an importance of cortical hyperexcitability in ALS pathogenesis. PMID- 24475242 TI - MetaMetaDB: a database and analytic system for investigating microbial habitability. AB - MetaMetaDB (http://mmdb.aori.u-tokyo.ac.jp/) is a database and analytic system for investigating microbial habitability, i.e., how a prokaryotic group can inhabit different environments. The interaction between prokaryotes and the environment is a key issue in microbiology because distinct prokaryotic communities maintain distinct ecosystems. Because 16S ribosomal RNA (rRNA) sequences play pivotal roles in identifying prokaryotic species, a system that comprehensively links diverse environments to 16S rRNA sequences of the inhabitant prokaryotes is necessary for the systematic understanding of the microbial habitability. However, existing databases are biased to culturable prokaryotes and exhibit limitations in the comprehensiveness of the data because most prokaryotes are unculturable. Recently, metagenomic and 16S rRNA amplicon sequencing approaches have generated abundant 16S rRNA sequence data that encompass unculturable prokaryotes across diverse environments; however, these data are usually buried in large databases and are difficult to access. In this study, we developed MetaMetaDB (Meta-Metagenomic DataBase), which comprehensively and compactly covers 16S rRNA sequences retrieved from public datasets. Using MetaMetaDB, users can quickly generate hypotheses regarding the types of environments a prokaryotic group may be adapted to. We anticipate that MetaMetaDB will improve our understanding of the diversity and evolution of prokaryotes. PMID- 24475243 TI - The HOG pathway is critical for the colonization of the mouse gastrointestinal tract by Candida albicans. AB - The opportunistic pathogen Candida albicans is a frequent inhabitant of the human gastrointestinal tract where it usually behaves as a harmless commensal. In this particular niche, it needs to adapt to the different micro environments that challenge its survival within the host. In order to determine those factors involved in gut adaptation, we have used a gastrointestinal model of colonization in mouse to trace the behaviour of fungal cells. We have developed a genetic labelling system based on the complementary spectral properties of the fluorescent proteins GFP and a new C. albicans codon-adapted RFP (dTOM2) that allow a precise quantification of the fungal population in the gut via standard in vitro cultures or flow cytometry. This methodology has allowed us to determine the role of the three MAP kinase pathways of C. albicans (mediated by the MAPK Mkc1, Cek1 or Hog1) in mouse gut colonization via competitive assays with MAPK pathway mutants and their isogenic wild type strain. This approach reveals the signalling through HOG pathway as a critical factor influencing the establishment of C. albicans in the mouse gut. Less pronounced effects for mkc1 or cek1 mutants were found, only evident after 2-3 weeks of colonization. We have also seen that hog1 mutants is defective in adhesion to the gut mucosa and sensitive to bile salts. Finally, we have developed a genetic strategy for the in vivo excision (tetracycline-dependent) of any specific gene during the course of colonization in this particular niche, allowing the analysis of its role during gut colonization. PMID- 24475244 TI - Photodynamic therapy with 5-aminolevulinic acid (ALA) impairs tumor initiating and chemo-resistance property in head and neck cancer-derived cancer stem cells. AB - BACKGROUND: Head and neck cancer (HNC) ranks the fourth leading malignancy and cancer death in male population in Taiwan. Despite recent therapeutic advances, the prognosis for HNC patients is still dismal. New strategies are urgently needed to improve the chemosensitization to conventional chemotherapeutic drugs and clinical responses of HNC patients. Studies have demonstrated that topical 5 aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is being used in the treatment of various human premalignant and malignant lesions with some encouraging clinical outcomes. However, the molecular mechanisms of ALA-PDT in the therapeutic effect in HNC tumorigenesis and whether ALA-PDT as chemosensitizer for HNC treatment remain unclear. Accumulating data support cancer stem cells (CSCs) contributes chemo-resistance in HNC. Based on the previous studies, the purpose of the study is to investigate the effect of ALA PDT on CSCs and chemosensitization property in HNC. METHODOLOGY/PRINCIPAL FINDING: CSCs marker ALDH1 activity of HNC cells with ALA-PDT treatment as assessed by the Aldefluor assay flow cytometry analysis. Secondary Sphere-forming self-renewal, stemness markers expression, and invasiveness of HNC-CSCs with ALA PDT treatment were presented. We observed that the treatment of ALA-PDT significantly down-regulated the ALDH1 activity and CD44 positivity of HNC-CSCs. Moreover, ALA-PDT reduced self-renewal property and stemness signatures expression (Oct4 and Nanog) in sphere-forming HNC-CSCs. ALA-PDT sensitized highly tumorigenic HNC-CSCs to conventional chemotherapies. Lastly, synergistic effect of ALA-PDT and Cisplatin treatment attenuated invasiveness/colongenicity property in HNC-CSCs. CONCLUSION/SIGNIFICANCE: Our results provide insights into the clinical prospect of ALA-PDT as a potential chemo-adjuvant therapy against head and neck cancer through eliminating CSCs property. PMID- 24475245 TI - Oligomerization and phosphorylation dependent regulation of ArgBP2 adaptive capabilities and associated functions. AB - ArgBP2 (Arg-Binding Protein 2/SORBS2) is an adaptor protein involved in cytoskeleton associated signal transduction, thereby regulating cell migration and adhesion. These features are associated with its antitumoral role in pancreatic cancer cells. Tyrosine phosphorylation of ArgBP2, mediated by c-Abl kinase and counterbalanced by PTP-PEST phosphatase, regulates many of its interactions. However, the exact mechanisms of action and of regulation of ArgBP2 remain largely unknown. We found that ArgBP2 has the capacity to form oligomers which are destabilized by tyrosine phosphorylation. We could show that ArgBP2 oligomerization involves the binding of one of its SH3 domains to a specific proline rich cluster. ArgBP2 self-association increases its binding to some of its molecular partners and decreased its affinity for others. Hence, the phosphorylation/oligomerization state of ArgBP2 directly regulates its functions by modulating its adaptive capabilities. Importantly, using a human pancreatic cancer cell model (MiaPaCa-2 cells), we could validate that this property of ArgBP2 is critical for its cytoskeleton associated functions. In conclusions, we describe a new mechanism of regulation of ArgBP2 where tyrosine phosphorylation of the protein interfere with a SH3 mediated self-interaction, thereby controlling its panel of interacting partners and related functions. PMID- 24475246 TI - Free-riding behavior in vaccination decisions: an experimental study. AB - Individual decision-making regarding vaccination may be affected by the vaccination choices of others. As vaccination produces externalities reducing transmission of a disease, it can provide an incentive for individuals to be free riders who benefit from the vaccination of others while avoiding the cost of vaccination. This study examined an individual's decision about vaccination in a group setting for a hypothetical disease that is called "influenza" using a computerized experimental game. In the game, interactions with others are allowed. We found that higher observed vaccination rate within the group during the previous round of the game decreased the likelihood of an individual's vaccination acceptance, indicating the existence of free-riding behavior. The free-riding behavior was observed regardless of parameter conditions on the characteristics of the influenza and vaccine. We also found that other predictors of vaccination uptake included an individual's own influenza exposure in previous rounds increasing the likelihood of vaccination acceptance, consistent with existing empirical studies. Influenza prevalence among other group members during the previous round did not have a statistically significant effect on vaccination acceptance in the current round once vaccination rate in the previous round was controlled for. PMID- 24475247 TI - Identification of a recurrent STRN/ALK fusion in thyroid carcinomas. AB - Thyroid carcinoma is the most common endocrine malignant tumor and accounts for 1% of all new malignant diseases. Among all types and subtypes of thyroid cancers that have been described so far, papillary thyroid carcinoma is the most frequent. The standard management treatment of these tumors consists of surgery, followed by radioiodine treatment in case of high risk of relapse. The most aggressive forms are commonly treated by chemotherapy, radiotherapy or experimental drug testing. We recently reported the case of a patient presenting an anaplastic thyroid carcinoma with lung metastases. Fluorescence in situ hybridization analysis allowed us to detect a rearrangement of the anaplastic lymphoma kinase (ALK) gene in both tumors. The patient was treated with crizotinib and presented an excellent drug response. We present here the subsequent investigations carried out to further characterize this genetic alteration and to assess the prevalence of ALK rearrangements in thyroid lesions. High resolution array-comparative genomic hybridization data complemented by RT PCR and sequencing analyses, allowed us to demonstrate the presence of a STRN/ALK fusion. The STRN/ALK transcript consisted of the fusion between exon 3 of STRN and exon 20 of ALK. Subsequent screening of 75 various thyroid tumors by RT-PCR revealed that 2 out of 29 papillary thyroid carcinomas exhibited the same fusion transcript. None was detected in other types of malignant or benign thyroid lesions analyzed. These findings could pave the way for the development of new targeted therapeutic strategies in the treatment of papillary thyroid carcinomas and point to ALK inhibitors as promising agents that merit rapid evaluation. PMID- 24475248 TI - Novel kinin B1 receptor splice variant and 5'UTR regulatory elements are responsible for cell specific B1 receptor expression. AB - The kinin B1 receptor (B1R) is rapidly upregulated after tissue trauma or inflammation and is involved in cancer and inflammatory diseases such as asthma. However, the role of the: promoter; a postulated alternative promoter; and spliced variants in airway epithelial and other lung cells are poorly understood. We identified, in various lung cell lines and leucocytes, a novel, naturally occurring splice variant (SV) of human B1R gene with a shorter 5'untranslated region. This novel SV is ~35% less stable than the wild-type (WT) transcript in lung adenocarcinoma cells (H2126), but does not influence translation efficiency. Cell-specific differences in splice variant expression were observed post des[Arg10]-kallidin stimulation with delayed upregulation of SV compared to WT suggesting potentially different regulatory responses to inflammation. Although an alternative promoter was not identified in our cell-lines, several cell specific regulatory elements within the postulated alternative promoter region (negative response element (NRE) -1020 to -766 bp in H2126; positive response element (PRE) -766 to -410 bp in 16HBE; -410 to +1 region acts as a PRE in H2126 and NRE in 16HBE cells) were found. These findings reveal complex regulation of B1R receptor expression in pulmonary cells which may allow future therapeutic manipulation in chronic pulmonary inflammation and cancer. PMID- 24475249 TI - Uridine prevents fenofibrate-induced fatty liver. AB - Uridine, a pyrimidine nucleoside, can modulate liver lipid metabolism although its specific acting targets have not been identified. Using mice with fenofibrate induced fatty liver as a model system, the effects of uridine on liver lipid metabolism are examined. At a daily dosage of 400 mg/kg, fenofibrate treatment causes reduction of liver NAD(+)/NADH ratio, induces hyper-acetylation of peroxisomal bifunctional enzyme (ECHD) and acyl-CoA oxidase 1 (ACOX1), and induces excessive accumulation of long chain fatty acids (LCFA) and very long chain fatty acids (VLCFA). Uridine co-administration at a daily dosage of 400 mg/kg raises NAD(+)/NADH ratio, inhibits fenofibrate-induced hyper-acetylation of ECHD, ACOX1, and reduces accumulation of LCFA and VLCFA. Our data indicates a therapeutic potential for uridine co-administration to prevent fenofibrate induced fatty liver. PMID- 24475250 TI - Screening suitable reference genes for normalization in reverse transcription quantitative real-time PCR analysis in melon. AB - Melon (Cucumis melo. L) is not only an economically important cucurbitaceous crop but also an attractive model for studying many biological characteristics. Screening appropriate reference genes is essential to reverse transcription quantitative real-time PCR (RT-qPCR), which is key to many studies involving gene expression analysis. In this study, 14 candidate reference genes were selected, and the variations in their expression in roots and leaves of plants subjected to biotic stress, abiotic stress, and plant growth regulator treatment were assessed by RT-qPCR. The stability of the expression of the selected genes was determined and ranked using geNorm and NormFinder. geNorm identified the two most stable genes for each set of conditions: CmADP and CmUBIep across all samples, CmUBIep and CmRPL in roots, CmRAN and CmACT in leaves, CmADP and CmRPL under abiotic stress conditions, CmTUA and CmACT under biotic stress conditions, and CmRAN and CmACT under plant growth regulator treatments. NormFinder determined CmRPL to be the best reference gene in roots and under biotic stress conditions and CmADP under the other experimental conditions. CmUBC2 and CmPP2A were not found to be suitable under many experimental conditions. The catalase family genes CmCAT1, CmCAT2, and CmCAT3 were identified in melon genome and used as target genes to validate the reliability of identified reference genes. The catalase family genes showed the most upregulation 3 days after inoculation with Fusarium wilt in roots, after which they were downregulated. Their levels of expression were significantly overestimated when the unsuitable reference gene was used for normalization. These results not only provide guidelines for the selection of reference genes for gene expression analyses in melons but may also provide valuable information for studying the functions of catalase family genes in stress responses. PMID- 24475251 TI - Oct4 mediates tumor initiating properties in oral squamous cell carcinomas through the regulation of epithelial-mesenchymal transition. AB - BACKGROUND: Overexpression of Oct4, an important transcription factor of embryonic stem cells (ESC), has been reported in several cancers. The aim of this study was to determine the emerging role of Oct4 in oral squamous cell carcinoma (OSCC) both in vitro and in vivo. METHODOLOGY/PRINCIPAL FINDING: Tumourigenic activity and molecular mechanisms of Oct4 overexpression or knockdown by lentiviral infection in OSCC was investigated in vitro and in vivo. Initially, we demonstrated that Oct4 expression was increased in OSCC cell lines as compared to a normal oral epithelial cell line SG. Overexpression of Oct4 was demonstrated to enhance cell proliferation, invasiveness, anchorage-independent growth and xenotransplantation tumourigenicity. These findings were coupled with epithelial mesenchymal transition (EMT) transformation in OSCCs. In contrast, the silence of Oct4 significantly blocked the xenograft tumorigenesis of OSCC-derived cancer stem cells (OSCC-CSCs) and significantly improved the recipient survival. Clinically, the level of Oct4 expression was higher in recurrent and metastatic OSCC specimens but lower in primary OSCC specimens. CONCLUSION/SIGNIFICANCE: Our results suggest that Oct4-mediated tumorigenecity is associated with the regulation of EMT. Oct4 might be a therapeutic target for OSCC. PMID- 24475252 TI - Improving kinetic or thermodynamic stability of an azoreductase by directed evolution. AB - Protein stability arises from a combination of factors which are often difficult to rationalise. Therefore its improvement is better addressed through directed evolution than by rational design approaches. In this study, five rounds of mutagenesis/recombination followed by high-throughput screening (~10,000 clones) yielded the hit 1B6 showing a 300-fold higher half life at 50 degrees C than that exhibited by the homodimeric wild type PpAzoR azoreductase from Pseudomonas putida MET94. The characterization using fluorescence, calorimetry and light scattering shows that 1B6 has a folded state slightly less stable than the wild type (with lower melting and optimal temperatures) but in contrast is more resistant to irreversible denaturation. The superior kinetic stability of 1B6 variant was therefore related to an increased resistance of the unfolded monomers to aggregation through the introduction of mutations that disturbed hydrophobic patches and increased the surface net charge of the protein. Variants 2A1 and 2A1 Y179H with increased thermodynamic stability (10 to 20 degrees C higher melting temperature than wild type) were also examined showing the distinctive nature of mutations that lead to improved structural robustness: these occur in residues that are mostly involved in strengthening the solvent-exposed loops or the inter dimer interactions of the folded state. PMID- 24475253 TI - Mass spectrometric identification of ancient proteins as potential molecular biomarkers for a 2000-year-old osteogenic sarcoma. AB - Osteosarcoma is the most common primary malignant tumor of bone usually occurring in young adolescent and children. This disease has a poor prognosis, because of the metastases in the period of tumor progression, which are usually developed previous to the clinical diagnosis. In this paper, a 2000-year-old ancient bone remain with osteogenic sarcoma was analyzed searching for tumor biomarkers which are closely related to this disease. After a specific extraction SDS-PAGE gel electrophoresis followed by tryptic digestion was performed. After the digestion the samples were measured using MALDI TOF/TOF MS. Healthy bone samples from same archaeological site were used as control samples. Our results show that in the pathological skeletal remain several well known tumor biomarkers are detected such as annexin A10, BCL-2-like protein, calgizzarin, rho GTPase-activating protein 7, HSP beta-6 protein, transferrin and vimentin compared to the control samples. The identified protein biomarkers can be useful in the discovery of malignant bone lesions such as osteosarcoma in the very early stage of the disease from paleoanthropological remains. PMID- 24475254 TI - Pathogen and circadian controlled 1 (PCC1) protein is anchored to the plasma membrane and interacts with subunit 5 of COP9 signalosome in Arabidopsis. AB - The Pathogen and Circadian Controlled 1 (PCC1) gene, previously identified and further characterized as involved in defense to pathogens and stress-induced flowering, codes for an 81-amino acid protein with a cysteine-rich C-terminal domain. This domain is essential for homodimerization and anchoring to the plasma membrane. Transgenic plants with the beta-glucuronidase (GUS) reporter gene under the control of 1.1 kb promoter sequence of PCC1 gene display a dual pattern of expression. At early post-germination, PCC1 is expressed only in the root vasculature and in the stomata guard cells of cotyledons. During the transition from vegetative to reproductive development, PCC1 is strongly expressed in the vascular tissue of petioles and basal part of the leaf, and it further spreads to the whole limb in fully expanded leaves. This developmental pattern of expression together with the late flowering phenotype of long-day grown RNA interference (iPCC1) plants with reduced PCC1 expression pointed to a regulatory role of PCC1 in the photoperiod-dependent flowering pathway. iPCC1 plants are defective in light perception and signaling but are not impaired in the function of the core CO-FT module of the photoperiod-dependent pathway. The regulatory effect exerted by PCC1 on the transition to flowering as well as on other reported phenotypes might be explained by a mechanism involving the interaction with the subunit 5 of the COP9 signalosome (CSN). PMID- 24475255 TI - Salvage liver transplantation for recurrent hepatocellular carcinoma after liver resection: retrospective study of the Milan and Hangzhou criteria. AB - BACKGROUND: Salvage liver transplantation (SLT) has recently been proposed for recurrent hepatocellular carcinoma after liver resection; however, criteria for candidate assessment in SLT have not been thoroughly evaluated. METHODS AND FINDINGS: We retrospectively analyzed outcomes and factors affecting survival of 53 recipients who received SLT in the Liver Transplantation Center, The First Affiliated Hospital of Zhejiang University between 2004 and 2012. Thirty recipients fulfilled the Hangzhou criteria, of which 16 also fulfilled the Milan criteria, while the remaining 23 exceeded both criteria. The 1-year, 3-year and 5 year overall survival rates and tumor-free survival rates were both superior in patients fulfilling Milan or Hangzhou criteria compared with those exceeding the criteria. For recipients outside Milan criteria but within Hangzhou criteria, the 1-year, 3-year overall survival rates were 70.1%, 70.1%, similar to recipients within Milan criteria, with the 1-year, 3-year and 5-year overall survival of 93.8%%, 62.1% and 62.1% (P = 0.586). The tumor-free survival rates were also similar between these two subgroups, with 51.9% and 51.9% vs. 85.6%, 85.6% and 64.2% during the same time interval, respectively (P = 0.054). Cox regression analysis identified Hangzhou criteria (within vs. outside, hazard ratio (HR) 0.376) and diameter of the largest tumor (HR 3.523) to be independent predictors for overall survival. The only predictor for tumor-free survival was diameter of the largest tumor (HR 22.289). CONCLUSIONS: Hangzhou criteria safely expanded the candidate pool and are feasible in assessment of candidates for SLT. This is helpful in donor liver allocation in transplant practice. PMID- 24475256 TI - Survival of neural stem cells undergoing DNA damage-induced astrocytic differentiation in self-renewal-promoting conditions in vitro. AB - We recently reported that neural stem cells (NSCs) become senescent and commit to astrocytic differentiation upon X-ray irradiation. Surprisingly, under self renewing culture conditions, some of these senescent cells undergo p53 independent apoptosis, which can be suppressed by caspase inhibition and BCL2 overexpression. Inhibition of apoptosis proved beneficial for astroglial differentiation efficiency; hence the toxicity of DNA damage on NSCs was specifically tested in context of the culture conditions. In this regard, self renewal-promoting culture conditions proved incompatible with terminal astrocyte differentiation and impacted negatively on the viability of NSCs following DNA damage-induced cell cycle exit. On the contrary, a switch to differentiation supporting conditions ablated apoptosis and conveyed tolerance to DNA damage. Thus, stem cell death has likely not originated from DNA break toxicity, while the potentially confounding effect of stem cell niche should always be taken in consideration in stem cell irradiation experiments. PMID- 24475257 TI - Plasma concentration of platelet-derived microparticles is related to painful vaso-occlusive phenotype severity in sickle cell anemia. AB - High plasma level of microparticles (MPs) deriving mainly from erythrocytes and platelets has been detected in sickle cell anemia (SCA) patients. Flow cytometry was used to determine the concentration of MPs in two groups of SCA patients exhibiting marked differences in painful vaso-occlusive crisis rates [a non severe group (n = 17) and a severe group (n = 12)], and in a control group composed of healthy subjects (n = 20). A 3- to 4-fold increase of total MP plasma concentration was detected in SCA patients. Higher platelet-derived MPs concentration was detected in the severe SCA group while erythrocyte-derived MPs concentration was increased in the non-severe SCA patient group only. Our results suggest that plasma concentration of MPs shed by platelets is a biomarker of the vaso-occlusive phenotype-related severity. PMID- 24475258 TI - Relationship between Rad51 G135C and G172T variants and the susceptibility to cancer: a meta-analysis involving 54 case-control studies. AB - BACKGROUND: The associations between Rad51 gene polymorphisms (G135C and G172T) and risk of cancer have been investigated, but the results were inconclusive. To get a comprehensive evaluation of the association above, we performed a meta analysis of published studies. METHODS: A computerized search of PubMed, Embase and Web of Knowledge databases for all relevant studies was performed and the data were analyzed in a meta-analysis. The overall odds ratio (OR) with the 95% confidence interval (95% CI) was calculated to assess the strength of the association between Rad51 polymorphisms and cancer risk. Data were analyzed using fixed- or random-effects model when appropriate. Sensitivity analysis and publication bias test were also estimated. RESULTS: Overall, a total of 54 case control studies were included in the current meta-analysis, among which 42 studies with 19,142 cases and 20,363 controls for RAD51 G135C polymorphism and 12 studies with 6,646 cases and 6,783 controls for G172T polymorphism. For G135C polymorphism, the pooled results indicated that significantly increased risk was found in overall cancers (homozygote model: OR = 1.776, 95% CI = 1.288-2.449; allelic genetic model: OR = 1.169, 95% CI = 1.016-1.345; recessive model: OR = 1.946, 95% CI = 1.336-2.835), especially in breast cancer (homozygote model: OR = 1.498, 95% CI = 1.026-2.189; recessive model: OR = 1.732, 95% CI = 1.170 2.562). For G172T polymorphism, a decreased cancer risk was observed in head and neck cancer (homozygote model: OR = 0.621, 95% CI = 0.460-0.837; allelic genetic model: OR = 0.824, 95% CI = 0.716-0.948; recessive model: OR = 0.639, 95% CI = 0.488-0.837). CONCLUSIONS: Our results suggested that the Rad51 G135C polymorphism is a candidate for susceptibility to overall cancers, especially to breast cancer, and that the Rad51 G172T might play a protective role in the development of head and neck cancer. PMID- 24475259 TI - Egr3 induces a Th17 response by promoting the development of gammadelta T cells. AB - The transcription factor Early Growth Response 3 (Egr3) has been shown to play an important role in negatively regulating T cell activation and promoting T cell anergy in Th1 cells. However, its role in regulating other T helper subsets has yet to be described. We sought to determine the role of Egr3 in a Th17 response using transgenic mice that overexpress Egr3 in T cells (Egr3 TG). Splenocytes from Egr3 TG mice demonstrated more robust generation of Th17 cells even under non-Th17 skewing conditions. We found that while Egr3 TG T cells were not intrinsically more likely to become Th17 cells, the environment encountered by these cells was more conducive to Th17 development. Further analysis revealed a considerable increase in the number of gammadelta T cells in both the peripheral lymphoid organs and mucosal tissues of Egr3 TG mice, a cell type which normally accounts for only a small fraction of peripheral lymphocytes. Consistent with this marked increase in peripheral gammadelta T cells, thymocytes from Egr3 TG mice also appear biased toward gammadelta T cell development. Coculture of these Egr3-induced gammadelta T cells with wildtype CD4+ T cells increases Th17 differentiation, and Egr3 TG mice are more susceptible to bleomycin-induced lung inflammation. Overall our findings strengthen the role for Egr3 in promoting gammadelta T cell development and show that Egr3-induced gammadelta T cells are both functional and capable of altering the adaptive immune response in a Th17 biased manner. Our data also demonstrates that the role played by Egr3 in T cell activation and differentiation is more complex than previously thought. PMID- 24475260 TI - An upregulation in the expression of vanilloid transient potential channels 2 enhances hypotonicity-induced cytosolic Ca2+ rise in human induced pluripotent stem cell model of Hutchinson-Gillford Progeria. AB - Hutchinson-Gillford Progeria Syndrome (HGPS) is a fatal genetic disorder characterized by premature aging in multiple organs including the skin, musculoskeletal and cardiovascular systems. It is believed that an increased mechanosensitivity of HGPS cells is a causative factor for vascular cell death and vascular diseases in HGPS patients. However, the exact mechanism is unknown. Transient receptor potential (TRP) channels are cationic channels that can act as cellular sensors for mechanical stimuli. The aim of this present study was to examine the expression and functional role of TRP channels in human induced pluripotent stem cell-derived endothelial cells (iPSC-ECs) from the patients with HGPS. The mRNA and protein expression of TRP channels in HGPS and control (IMR90) iPSC-ECs were examined by semi-quantitative RT-PCRs and immunoblots, respectively. Hypotonicity-induced cytosolic Ca2+ ([Ca2+](i)) rise in iPSC-ECs was measured by confocal microscopy. RT-PCRs and immunoblots showed higher expressional levels of TRPV2 in iPSC-ECs from HGPS patients than those from normal individuals. In functional studies, hypotonicity induced a transient [Ca2+](i) rise in iPSC-ECs from normal individuals but a sustained [Ca2+](i) elevation in iPSC-ECs from HGPS patients. A nonselective TRPV inhibitor, ruthenium red (RuR, 20 uM), and a specific TRPV2 channel inhibitor, tranilast (100 uM), abolished the sustained phase of hypotonicity-induced [Ca2+](i) rise in iPSC-ECs from HGPS patients, and also markedly attenuated the transient phase of the [Ca2+](i) rise in these cells. Importantly, a short 10 min hypotonicity treatment caused a substantial increase in caspase 8 activity in iPSC-ECs from HGPS patients but not in cells from normal individuals. Tranilast could also inhibit the hypotonicity-induced increase in caspase 8 activity. Taken together, our data suggest that an up-regulation in TRPV2 expression causes a sustained [Ca2+](i) elevation in HGPS-iPSC-ECs under hypotonicity, consequently resulting in apoptotic cell death. This mechanism may contribute to the pathogenesis of vascular diseases in HGPS patients. PMID- 24475261 TI - The relationship between CPAP usage and corneal thickness. AB - The purpose of this study was to determine whether there is a correlation between CPAP usage and corneal thickness in patients with sleep disordered breathing. Full-night polysomnography (PSG) recordings were collected. Ten patients had undergone PSG recordings with continuous positive airway pressure (CPAP), and seven patients had undergone PSG recordings without CPAP. We measured corneal thickness by ultrasonic pachymeter before sleep and ten minutes after waking. We also measured visual acuity with a routine ophthalmologic eye chart before and after sleep. We asked patients to fill out a post-sleep questionnaire to get their subjective opinions. In the without-CPAP group, corneal thickness increased significantly during sleep in both eyes (left, p = 0.0025; right, p<0.0001). In the with-CPAP group, corneal thickness did not increase significantly (p>0.05 for both left and right cornea). There was no significant difference in visual acuity tests (p>0.05 for both left and right eye) between the two groups. According to our results, there is a significant increase in corneal thickness in the without CPAP group. Our data show that a low percentage of Rapid Eye Movement (REM) sleep may cause an increase in corneal thickness, which can indicate poor corneal oxygenation. In fact, many sleep-disordered breathing (SDB) patients have low REM. Since a contact lens may cause low corneal oxygenation, SDB patients with contact lenses should be monitored carefully for their corneal thickness. PMID- 24475262 TI - Relationship between personality traits and brain reward responses when playing on a team. AB - Cooperation is an integral part of human social life and we often build teams to achieve certain goals. However, very little is currently understood about emotions with regard to cooperation. Here, we investigated the impact of social context (playing alone versus playing on a team) on emotions while winning or losing a game. We hypothesized that activity in the reward network is modulated by the social context and that personality characteristics might impact team play. We conducted an event-related functional magnetic resonance imaging experiment that involved a simple game of dice. In the team condition, the participant played with a partner against another two-person team. In the single player condition, the participant played alone against another player. Our results revealed that reward processing in the right amygdala was modulated by the social context. The main effect of outcome (gains versus losses) was associated with increased responses in the reward network. We also found that differences in the reward-related neural response due to social context were associated with specific personality traits. When playing on a team, increased activity in the amygdala during winning was a unique function of openness, while decreased activity in the ventromedial prefrontal cortex and ventral striatum during losing was associated with extraversion and conscientiousness, respectively. In conclusion, we provide evidence that working on a team influences the affective value of a negative outcome by attenuating the negative response associated with it in the amygdala. Our results also show that brain reward responses in a social context are affected by personality traits related to teamwork. PMID- 24475263 TI - Seedling responses to water pulses in shrubs with contrasting histories of grassland encroachment. AB - Woody plant encroachment into grasslands has occurred worldwide, but it is unclear why some tree and shrub species have been markedly more successful than others. For example, Prosopis velutina has proliferated in many grasslands of the Sonoran Desert in North America over the past century, while other shrub species with similar growth form and life history, such as Acacia greggii, have not. We conducted a glasshouse experiment to assess whether differences in early seedling development could help explain why one species and not the other came to dominate many Sonoran Desert grasslands. We established eight watering treatments mimicking a range of natural precipitation patterns and harvested seedlings 16 or 17 days after germination. A. greggii had nearly 7 times more seed mass than P. velutina, but P. velutina emerged earlier (by 3.0+/-0.3 d) and grew faster (by 8.7+/-0.5 mg d-1). Shoot mass at harvest was higher in A. greggii (99+/-6 mg seedling-1) than in P. velutina (74+/-2 mg seedling-1), but there was no significant difference in root mass (54+/-3 and 49+/-2 mg seedling-1, respectively). Taproot elongation was differentially sensitive to water supply: under the highest initial watering pulse, taproots were 52+/-19 mm longer in P. velutina than in A. greggii. Enhanced taproot elongation under favorable rainfall conditions could give nascent P. velutina seedlings growth and survivorship advantages by helping reduce competition with grasses and maintain contact with soil water during drought. Conversely, A. greggii's greater investment in mass per seed appeared to provide little return in early seedling growth. We suggest that such differences in recruitment traits and their sensitivities to environmental conditions may help explain ecological differences between species that are highly similar as adults and help identify pivotal drivers of shrub encroachment into grasslands. PMID- 24475265 TI - Designing optimized multi-species monitoring networks to detect range shifts driven by climate change: a case study with bats in the North of Portugal. AB - Here we develop a framework to design multi-species monitoring networks using species distribution models and conservation planning tools to optimize the location of monitoring stations to detect potential range shifts driven by climate change. For this study, we focused on seven bat species in Northern Portugal (Western Europe). Maximum entropy modelling was used to predict the likely occurrence of those species under present and future climatic conditions. By comparing present and future predicted distributions, we identified areas where each species is likely to gain, lose or maintain suitable climatic space. We then used a decision support tool (the Marxan software) to design three optimized monitoring networks considering: a) changes in species likely occurrence, b) species conservation status, and c) level of volunteer commitment. For present climatic conditions, species distribution models revealed that areas suitable for most species occur in the north-eastern part of the region. However, areas predicted to become climatically suitable in the future shifted towards west. The three simulated monitoring networks, adaptable for an unpredictable volunteer commitment, included 28, 54 and 110 sampling locations respectively, distributed across the study area and covering the potential full range of conditions where species range shifts may occur. Our results show that our framework outperforms the traditional approach that only considers current species ranges, in allocating monitoring stations distributed across different categories of predicted shifts in species distributions. This study presents a straightforward framework to design monitoring schemes aimed specifically at testing hypotheses about where and when species ranges may shift with climatic changes, while also ensuring surveillance of general population trends. PMID- 24475264 TI - A distal ABA responsive element in AtNCED3 promoter is required for positive feedback regulation of ABA biosynthesis in Arabidopsis. AB - The plant hormone abscisic acid (ABA) plays a crucial role in plant development and responses to abiotic stresses. Recent studies indicate that a positive feedback regulation by ABA exists in ABA biosynthesis in plants under dehydration stress. To understand the molecular basis of this regulation, we analyzed the cis elements of the AtNCED3 promoter in Arabidopsis. AtNCED3 encodes the first committed and highly regulated dioxygenase in the ABA biosynthetic pathway. Through delineated and mutagenesis analyses in stable-transformed Arabidopsis, we revealed that a distal ABA responsive element (ABRE: GGCACGTG, -2372 to -2364 bp) is required for ABA-induced AtNCED3 expression. By analyzing the AtNCED3 expression in ABRE binding protein ABF3 over-expression transgenic plants and knock-out mutants, we provide evidence that the ABA feedback regulation of AtNCED3 expression is not mediated by ABF3. PMID- 24475266 TI - Evaluating strategies to normalise biological replicates of Western blot data. AB - Western blot data are widely used in quantitative applications such as statistical testing and mathematical modelling. To ensure accurate quantitation and comparability between experiments, Western blot replicates must be normalised, but it is unclear how the available methods affect statistical properties of the data. Here we evaluate three commonly used normalisation strategies: (i) by fixed normalisation point or control; (ii) by sum of all data points in a replicate; and (iii) by optimal alignment of the replicates. We consider how these different strategies affect the coefficient of variation (CV) and the results of hypothesis testing with the normalised data. Normalisation by fixed point tends to increase the mean CV of normalised data in a manner that naturally depends on the choice of the normalisation point. Thus, in the context of hypothesis testing, normalisation by fixed point reduces false positives and increases false negatives. Analysis of published experimental data shows that choosing normalisation points with low quantified intensities results in a high normalised data CV and should thus be avoided. Normalisation by sum or by optimal alignment redistributes the raw data uncertainty in a mean-dependent manner, reducing the CV of high intensity points and increasing the CV of low intensity points. This causes the effect of normalisations by sum or optimal alignment on hypothesis testing to depend on the mean of the data tested; for high intensity points, false positives are increased and false negatives are decreased, while for low intensity points, false positives are decreased and false negatives are increased. These results will aid users of Western blotting to choose a suitable normalisation strategy and also understand the implications of this normalisation for subsequent hypothesis testing. PMID- 24475267 TI - Characterizing roles for the glutathione reductase, thioredoxin reductase and thioredoxin peroxidase-encoding genes of Magnaporthe oryzae during rice blast disease. AB - Understanding how pathogenic fungi adapt to host plant cells is of major concern to securing global food production. The hemibiotrophic rice blast fungus Magnaporthe oryzae, cause of the most serious disease of cultivated rice, colonizes leaf cells asymptomatically as a biotroph for 4-5 days in susceptible rice cultivars before entering its destructive necrotrophic phase. During the biotrophic growth stage, M. oryzae remains undetected in the plant while acquiring nutrients and growing cell-to-cell. Which fungal processes facilitate in planta growth and development are still being elucidated. Here, we used gene functional analysis to show how components of the NADPH-requiring glutathione and thioredoxin antioxidation systems of M. oryzae contribute to disease. Loss of glutathione reductase, thioredoxin reductase and thioredoxin peroxidase-encoding genes resulted in strains severely attenuated in their ability to grow in rice cells and that failed to produce spreading necrotic lesions on the leaf surface. Glutathione reductase, but not thioredoxin reductase or thioredoxin peroxidase, was shown to be required for neutralizing plant generated reactive oxygen species (ROS). The thioredoxin proteins, but not glutathione reductase, were shown to contribute to cell-wall integrity. Furthermore, glutathione and thioredoxin gene expression, under axenic growth conditions, was dependent on both the presence of glucose and the M. oryzae sugar/ NADPH sensor Tps1, thereby suggesting how glucose availability, NADPH production and antioxidation might be connected. Taken together, this work identifies components of the fungal glutathione and thioredoxin antioxidation systems as determinants of rice blast disease that act to facilitate biotrophic colonization of host cells by M. oryzae. PMID- 24475268 TI - Analysis of Escherichia coli mutants with a linear respiratory chain. AB - The respiratory chain of E. coli is branched to allow the cells' flexibility to deal with changing environmental conditions. It consists of the NADH:ubiquinone oxidoreductases NADH dehydrogenase I and II, as well as of three terminal oxidases. They differ with respect to energetic efficiency (proton translocation) and their affinity to the different quinone/quinol species and oxygen. In order to analyze the advantages of the branched electron transport chain over a linear one and to assess how usage of the different terminal oxidases determines growth behavior at varying oxygen concentrations, a set of isogenic mutant strains was created, which lack NADH dehydrogenase I as well as two of the terminal oxidases, resulting in strains with a linear respiratory chain. These strains were analyzed in glucose-limited chemostat experiments with defined oxygen supply, adjusting aerobic, anaerobic and different microaerobic conditions. In contrast to the wild type strain MG1655, the mutant strains produced acetate even under aerobic conditions. Strain TBE032, lacking NADH dehydrogenase I and expressing cytochrome bd-II as sole terminal oxidase, showed the highest acetate formation rate under aerobic conditions. This supports the idea that cytochrome bd-II terminal oxidase is not able to catalyze the efficient oxidation of the quinol pool at higher oxygen conditions, but is functioning mainly under limiting oxygen conditions. Phosphorylation of ArcA, the regulator of the two-component system ArcBA, besides Fnr the main transcription factor for the response towards different oxygen concentrations, was studied. Its phosphorylation pattern was changed in the mutant strains. Dephosphorylation and therefore inactivation of ArcA started at lower aerobiosis levels than in the wild-type strain. Notably, not only the micro and aerobic metabolism was affected by the mutations, but also the anaerobic metabolism, where the respiratory chain should not be important. PMID- 24475269 TI - Biomarkers and molecular analysis to improve bloodstream infection diagnostics in an emergency care unit. AB - Molecular pathogen detection from blood is still expensive and the exact clinical value remains to be determined. The use of biomarkers may assist in preselecting patients for immediate molecular testing besides blood culture. In this study, 140 patients with >= 2 SIRS criteria and clinical signs of infection presenting at the emergency department of our hospital were included. C-reactive protein (CRP), neutrophil-lymphocyte count ratio (NLCR), procalcitonin (PCT) and soluble urokinase plasminogen activator receptor (suPAR) levels were determined. One ml EDTA blood was obtained and selective pathogen DNA isolation was performed with MolYsis (Molzym). DNA samples were analysed for the presence of pathogens, using both the MagicPlex Sepsis Test (Seegene) and SepsiTest (Molzym), and results were compared to blood cultures. Fifteen patients had to be excluded from the study, leaving 125 patients for further analysis. Of the 125 patient samples analysed, 27 presented with positive blood cultures of which 7 were considered to be contaminants. suPAR, PCT, and NLCR values were significantly higher in patients with positive blood cultures compared to patients without (p < 0.001). Receiver operating characteristic curves of the 4 biomarkers for differentiating bacteremia from non-bacteremia showed the highest area under the curve (AUC) for PCT (0.806 (95% confidence interval 0.699-0.913)). NLCR, suPAR and CRP resulted in an AUC of 0.770, 0.793, and 0.485, respectively. When compared to blood cultures, the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for SepsiTest and MagicPlex Sepsis Test were 11%, 96%, 43%, 80%, and 37%, 77%, 30%, 82%, respectively. In conclusion, both molecular assays perform poorly when one ml whole blood is used from emergency care unit patients. NLCR is a cheap, fast, easy to determine, and rapidly available biomarker, and therefore seems most promising in differentiating BSI from non-BSI patients for subsequent pathogen identification using molecular diagnostics. PMID- 24475270 TI - Regional brain changes occurring during disobedience to "experts" in financial decision-making. AB - It is well recognized that individuals follow "Expert" advice, even when flawed and offers no advantage, and sometimes leads to disadvantages. The neurobiology underlying this is uncertain, and in particular there is an incomplete understanding of which brain regions are most involved when individuals chose to disobey an expert. To study this we examined functional magnetic resonance imaging (fMRI) differences during an investment game where subjects received differentially credible investment advice. Participants (n = 42; 32 males) played an investment game, in which they could Buy or Not Buy a sequence of stocks. The better they did, the more money they made. Participants received either "Expert" advice or "Peer" advice. Those receiving Expert advice were told the advice came from a certified financial "Expert". Those receiving Peer Advice were told the advice was that of the student administering the scans, who deliberately dressed and acted casually. Both streams of advice were predetermined and identical. The advice was scripted to be helpful initially, but progressively worse as the task continued, becoming 100% wrong by the end of the task. Subjects receiving Expert Advice followed the advice significantly longer on average, even though this was progressively worse advice. Thus, following Expert advice had poorer consequences for individuals, but this did not dissuade them from continuing to follow the advice. In contrast, when subjects disobeyed Expert advice they exhibited significant anterior cingulate cortex (ACC) and superior frontal gyrus activation relative to those disobeying Peer advice. These findings may suggest that in subjects who defy authority, or believe they are doing so (in this case by disobeying an "Expert") there is increased activation of these two brain regions. This may have relevance to several areas of behavior, and the potential role of these two brain regions in regard to disobedience behavior requires further study. PMID- 24475271 TI - HIV status disclosure to perinatally-infected adolescents in Zimbabwe: a qualitative study of adolescent and healthcare worker perspectives. AB - INTRODUCTION & OBJECTIVES: Due to the scale up of antiretroviral therapy, increasing numbers of HIV-infected children are living into adolescence. As these children grow and surpass the immediate threat of death, the issue of informing them of their HIV status arises. This study aimed to understand how perinatally infected adolescents learn about their HIV-status as well as to examine their preferences for the disclosure process. METHODS: In-depth interviews were conducted with 31 (14 male, 17 female) perinatally-infected adolescents aged 16 20 at an HIV clinic in Harare, Zimbabwe, and focused on adolescents' experiences of disclosure. In addition, 15 (1 male, 14 female) healthcare workers participated in two focus groups that were centred on healthcare workers' practices surrounding disclosure in the clinic. Purposive sampling was used to recruit participants. A coding frame was developed and major themes were extracted using grounded theory methods. RESULTS: Healthcare workers encouraged caregivers to initiate disclosure in the home environment. However, many adolescents preferred disclosure to take place in the presence of healthcare workers at the clinic because it gave them access to accurate information as well as an environment that made test results seem more credible. Adolescents learned more specific information about living with an HIV-positive status and the meaning of that status from shared experiences among peers at the clinic. CONCLUSIONS: HIV-status disclosure to adolescents is distinct from disclosure to younger children and requires tailored, age-appropriate guidelines. Disclosure to this age group in a healthcare setting may help overcome some of the barriers associated with caregivers disclosing in the home environment and make the HIV status seem more credible to an adolescent. The study also highlights the value of peer support among adolescents, which could help reduce the burden of psychosocial care on caregivers and healthcare workers. PMID- 24475272 TI - Reevesioside A, a cardenolide glycoside, induces anticancer activity against human hormone-refractory prostate cancers through suppression of c-myc expression and induction of G1 arrest of the cell cycle. AB - In the past decade, there has been a profound increase in the number of studies revealing that cardenolide glycosides display inhibitory activity on the growth of human cancer cells. The use of potential cardenolide glycosides may be a worthwhile approach in anticancer research. Reevesioside A, a cardenolide glycoside isolated from the root of Reevesia formosana, displayed potent anti proliferative activity against human hormone-refractory prostate cancers. A good correlation (r2 = 0.98) between the expression of Na+/K+-ATPase alpha3 subunit and anti-proliferative activity suggested the critical role of the alpha3 subunit. Reevesioside A induced G1 arrest of the cell cycle and subsequent apoptosis in a thymidine block-mediated synchronization model. The data were supported by the down-regulation of several related cell cycle regulators, including cyclin D1, cyclin E and CDC25A. Reevesioside A also caused a profound decrease of RB phosphorylation, leading to an increased association between RB and E2F1 and the subsequent suppression of E2F1 activity. The protein and mRNA levels of c-myc, which can activate expression of many downstream cell cycle regulators, were dramatically inhibited by reevesioside A. Transient transfection of c-myc inhibited the down-regulation of both cyclin D1 and cyclin E protein expression to reevesioside A action, suggesting that c-myc functioned as an upstream regulator. Flow cytometric analysis of JC-1 staining demonstrated that reevesioside A also induced the significant loss of mitochondrial membrane potential. In summary, the data suggest that reevesioside A inhibits c-myc expression and down-regulates the expression of CDC25A, cyclin D1 and cyclin E, leading to a profound decrease of RB phosphorylation. G1 arrest is, therefore, induced through E2F1 suppression. Consequently, reevesioside A causes mitochondrial damage and an ultimate apoptosis in human hormone-refractory prostate cancer cells. PMID- 24475273 TI - Placental lactogen is expressed but is not translated into protein in breast cancer. AB - INTRODUCTION: Several studies reported that the pregnancy-specific hormone placental lactogen (hPL) is expressed at both mRNA and protein levels in breast cancer. The overall objective was to establish hPL, the product of the CSH1 and CSH2 genes, as a biomarker for breast cancer. METHODS: CSH expression was determined at the mRNA level in breast cancer cell lines (BCC) and primary carcinomas by real-time and conventional PCR and the products verified as CSH1 by sequencing. Expression of hPL protein was examined by western blots and immuno histochemistry, using commercial and custom-made polyclonal and monoclonal antibodies. RESULTS: Variable levels of CSH mRNA were detected in several BCC, and in some primary tumors. We detected a protein, slightly larger than recombinant hPL by western blotting using several antibodies, leading us to postulate that it represents an hPL variant ('hPL'). Furthermore, some monoclonal antibodies detected 'hPL' by immunohistochemistry in breast carcinomas but not in normal breast. However, further examination revealed that these antibodies were non-specific, as efficient suppression of CSH mRNA by shRNA did not abolish the 'hPL' band. Custom-made monoclonal antibodies against recombinant hPL detected hPL of the correct size in placental lysate and hPL-overexpressing BCC, but not in unmodified cells or primary carcinomas. hPL protein was detected only when mRNA was increased several thousand fold. CONCLUSIONS: We call into question previous reports of hPL expression in breast cancer which relied on mRNA levels as surrogates for protein and/or used improperly validated antibodies to measure hPL protein levels. Our data suggests that an inhibitory mechanism(s) prevents translation of CSH mRNA in breast cancer when not highly expressed. The mechanism by which translation of CSH mRNA is inhibited is intriguing and should be further investigated. PMID- 24475274 TI - The actin-binding proteins eps8 and gelsolin have complementary roles in regulating the growth and stability of mechanosensory hair bundles of mammalian cochlear outer hair cells. AB - Sound transduction depends upon mechanosensitive channels localized on the hair like bundles that project from the apical surface of cochlear hair cells. Hair bundles show a stair-case structure composed of rows of stereocilia, and each stereocilium contains a core of tightly-packed and uniformly-polarized actin filaments. The growth and maintenance of the stereociliary actin core are dynamically regulated. Recently, it was shown that the actin-binding protein gelsolin is expressed in the stereocilia of outer hair cells (OHCs) and in its absence they become long and straggly. Gelsolin is part of a whirlin scaffolding protein complex at the stereocilia tip, which has been shown to interact with other actin regulatory molecules such as Eps8. Here we investigated the physiological effects associated with the absence of gelsolin and its possible overlapping role with Eps8. We found that, in contrast to Eps8, gelsolin does not affect mechanoelectrical transduction during immature stages of development. Moreover, OHCs from gelsolin knockout mice were able to mature into fully functional sensory receptors as judged by the normal resting membrane potential and basolateral membrane currents. Mechanoelectrical transducer current in gelsolin-Eps8 double knockout mice showed a profile similar to that observed in the single mutants for Eps8. We propose that gelsolin has a non-overlapping role with Eps8. While Eps8 is mainly involved in the initial growth of stereocilia in both inner hair cells (IHCs) and OHCs, gelsolin is required for the maintenance of mature hair bundles of low-frequency OHCs after the onset of hearing. PMID- 24475275 TI - Effect of maraviroc intensification on HIV-1-specific T cell immunity in recently HIV-1-infected individuals. AB - BACKGROUND: The effect of maraviroc on the maintenance and the function of HIV-1 specific T cell responses remains unknown. METHODS: Subjects recently infected with HIV-1 were randomized to receive anti-retroviral treatment with or without maraviroc intensification for 48 weeks, and were monitored up to week 60. PBMC and in vitro-expanded T cells were tested for responses to the entire HIV proteome by ELISpot analyses. Intracellular cytokine staining assays were conducted to monitor the (poly)-functionality of HIV-1-specific T cells. Analyses were performed at baseline and week 24 after treatment start, and at week 60 (3 months after maraviroc discontinuation). RESULTS: Maraviroc intensification was associated with a slower decay of virus-specific T cell responses over time compared to the non-intensified regimen in both direct ex-vivo as well as in in vitro expanded cells. The effector function profiles of virus-specific CD8+ T cells were indistinguishable between the two arms and did not change over time between the groups. CONCLUSIONS: Maraviroc did not negatively impact any of the measured parameters, but was rather associated with a prolonged maintenance of HIV-1-specific T cell responses. Maraviroc, in addition to its original effect as viral entry inhibitor, may provide an additional benefit on the maintenance of virus-specific T cells which may be especially important for future viral eradication strategies. PMID- 24475276 TI - Influence of the presence of B chromosomes on DNA damage in Crepis capillaris. AB - The sensitivity of different plant species to mutagenic agents is related to the DNA content and organization of the chromatin, which have been described in ABCW and bodyguard hypotheses, respectively. Plant species that have B chromosomes are good models for the study of these hypotheses. This study presents an analysis of the correlation between the occurrence of B chromosomes and the DNA damage that is induced by the chemical mutagen, maleic hydrazide (MH), in Crepis capillaris plants using comet assay. The presence of B chromosomes has a detectable impact on the level of DNA damage. The level of DNA damage after MH treatment was correlated with the number of B chromosomes and it was observed that it increased significantly in plants with 3B chromosomes. We did not find evidence of the protective role from chemical mutagens of the constitutive heterochromatin for euchromatin in relation to DNA damage. The DNA damage involving the 25S rDNA sequences was analyzed using the comet-FISH technique. Fragmentation within or near the 25S rDNA involved the loci on the A and B chromosomes. The presence of B chromosomes in C. capillaris cells had an influence on the level of DNA damage that involves the 25S rDNA region. PMID- 24475277 TI - IL-4 receptor-alpha-dependent control of Cryptococcus neoformans in the early phase of pulmonary infection. AB - Cryptococcus neoformans is an opportunistic fungal pathogen that causes lung inflammation and meningoencephalitis in immunocompromised people. Previously we showed that mice succumb to intranasal infection by induction of pulmonary interleukin (IL)-4Ralpha-dependent type 2 immune responses, whereas IL-12 dependent type 1 responses confer resistance. In the experiments presented here, IL-4Ralpha-/- mice unexpectedly show decreased fungal control early upon infection with C. neoformans, whereas wild-type mice are able to control fungal growth accompanied by enhanced macrophage and dendritic cell recruitment to the site of infection. Lower pulmonary recruitment of macrophages and dendritic cells in IL-4Ralpha-/- mice is associated with reduced pulmonary expression of CCL2 and CCL20 chemokines. Moreover, IFN-gamma and nitric oxide production are diminished in IL-4Ralpha-/- mice compared to wild-type mice. To directly study the potential mechanism(s) responsible for reduced production of IFN-gamma, conventional dendritic cells were stimulated with C. neoformans in the presence of IL-4 which results in increased IL-12 production and reduced IL-10 production. Together, a beneficial role of early IL-4Ralpha signaling is demonstrated in pulmonary cryptococcosis, which contrasts with the well-known IL-4Ralpha-mediated detrimental effects in the late phase. PMID- 24475278 TI - Laser capture microdissection and multiplex-tandem PCR analysis of proximal tubular epithelial cell signaling in human kidney disease. AB - Interstitial fibrosis, a histological process common to many kidney diseases, is the precursor state to end stage kidney disease, a devastating and costly outcome for the patient and the health system. Fibrosis is historically associated with chronic kidney disease (CKD) but emerging evidence is now linking many forms of acute kidney disease (AKD) with the development of CKD. Indeed, we and others have observed at least some degree of fibrosis in up to 50% of clinically defined cases of AKD. Epithelial cells of the proximal tubule (PTEC) are central in the development of kidney interstitial fibrosis. We combine the novel techniques of laser capture microdissection and multiplex-tandem PCR to identify and quantitate "real time" gene transcription profiles of purified PTEC isolated from human kidney biopsies that describe signaling pathways associated with this pathological fibrotic process. Our results: (i) confirm previous in-vitro and animal model studies; kidney injury molecule-1 is up-regulated in patients with acute tubular injury, inflammation, neutrophil infiltration and a range of chronic disease diagnoses, (ii) provide data to inform treatment; complement component 3 expression correlates with inflammation and acute tubular injury, (iii) identify potential new biomarkers; proline 4-hydroxylase transcription is down-regulated and vimentin is up-regulated across kidney diseases, (iv) describe previously unrecognized feedback mechanisms within PTEC; Smad-3 is down-regulated in many kidney diseases suggesting a possible negative feedback loop for TGF-beta in the disease state, whilst tight junction protein-1 is up-regulated in many kidney diseases, suggesting feedback interactions with vimentin expression. These data demonstrate that the combined techniques of laser capture microdissection and multiplex-tandem PCR have the power to study molecular signaling within single cell populations derived from clinically sourced tissue. PMID- 24475279 TI - The relationship between inflammatory biomarkers and telomere length in an occupational prospective cohort study. AB - BACKGROUND: Chronic inflammation from recurring trauma is an underlying pathophysiological basis of numerous diseases. Furthermore, it may result in cell death, scarring, fibrosis, and loss of tissue function. In states of inflammation, subsequent increases in oxidative stress and cellular division may lead to the accelerated erosion of telomeres, crucial genomic structures which protect chromosomes from decay. However, the association between plasma inflammatory marker concentrations and telomere length has been inconsistent in previous studies. OBJECTIVE: The purpose of this study was to determine the longitudinal association between telomere length and plasma inflammatory biomarker concentrations including: CRP, SAA, sICAM-1, sVCAM-1, VEGF, TNF-alpha, IL-1beta, IL-2, IL-6, IL-8, and IL-10. METHODS: The longitudinal study population consisted of 87 subjects. The follow-up period was approximately 2 years. Plasma inflammatory biomarker concentrations were assessed using highly sensitive electrochemiluminescent assays. Leukocyte relative telomere length was assessed using Real-Time qPCR. Linear mixed effects regression models were used to analyze the association between repeated-measurements of relative telomere length as the outcome and each inflammatory biomarker concentration as continuous exposures separately. The analyses controlled for major potential confounders and white blood cell differentials. RESULTS: At any follow-up time, each incremental ng/mL increase in plasma CRP concentration was associated with a decrease in telomere length of -2.6*10-2 (95%CI: -4.3*10-2, -8.2*10-3, p = 0.004) units. Similarly, the estimate for the negative linear association between SAA and telomere length was -2.6*10-2 (95%CI:-4.5*10-2, -6.1*10-3, p = 0.011). No statistically significant associations were observed between telomere length and plasma concentrations of pro-inflammatory interleukins, TNF-alpha, and VEGF. CONCLUSIONS: Findings from this study suggest that increased systemic inflammation, consistent with vascular injury, is associated with decreased leukocyte telomere length. PMID- 24475280 TI - Low pre-existing gray matter volume in the medial temporal lobe and white matter lesions are associated with postoperative cognitive dysfunction after cardiac surgery. AB - OBJECTIVES: Postoperative cognitive dysfunction (POCD) is recognized as a complication in the elderly after cardiac surgery. Imaging of the brain provides evidence of neurodegeneration in elderly patients; however, abnormalities in brain structure and their relation to POCD are uncertain. This pilot study investigated whether loss of gray matter in the bilateral medial temporal lobe (MTL), seen in preoperative MRI, was associated with POCD. METHODS: Data were collected prospectively on 28 elderly patients scheduled for elective cardiac surgery. MRI of the brains of all patients were assessed for prior cerebral infarctions, and carotid and intracranial arterial stenosis. Patients also completed six neuropsychological tests of memory, attention and executive function before and after surgery. POCD was defined as an individual decrease in more than two tests of at least 1 standard deviation from the group baseline mean for that test. The degree of gray matter loss in the MTL of each patient was calculated using voxel-based morphometry with three-dimensional, T1-weighted MRI. This represented the degree of gray matter change as a Z score. RESULTS: Postoperative cognitive dysfunction was identified in 8 of the 28 patients (29%). Patients with POCD had significantly more white matter lesions on MRI, and greater loss of gray matter in the bilateral MTL (average Z score 2.0+/-0.9) than patients without POCD. An analysis by stepwise logistic regression identified gray matter loss in the MTL and cerebral infarctions on MRI as independent predictors of POCD. CONCLUSIONS: These preliminary findings suggested that reduced gray matter in the bilateral MTL and white matter lesions existed in brains of elderly cardiac surgery patients who experienced POCD. Additional studies with larger sample sizes are needed to confirm these findings. PMID- 24475281 TI - Lethal giant larvae 1 tumour suppressor activity is not conserved in models of mammalian T and B cell leukaemia. AB - In epithelial and stem cells, lethal giant larvae (Lgl) is a potent tumour suppressor, a regulator of Notch signalling, and a mediator of cell fate via asymmetric cell division. Recent evidence suggests that the function of Lgl is conserved in mammalian haematopoietic stem cells and implies a contribution to haematological malignancies. To date, direct measurement of the effect of Lgl expression on malignancies of the haematopoietic lineage has not been tested. In Lgl1-/- mice, we analysed the development of haematopoietic malignancies either alone, or in the presence of common oncogenic lesions. We show that in the absence of Lgl1, production of mature white blood cell lineages and long-term survival of mice are not affected. Additionally, loss of Lgl1 does not alter leukaemia driven by constitutive Notch, c-Myc or Jak2 signalling. These results suggest that the role of Lgl1 in the haematopoietic lineage might be restricted to specific co-operating mutations and a limited number of cellular contexts. PMID- 24475282 TI - Activation of ERalpha signaling differentially modulates IFN-gamma induced HLA class II expression in breast cancer cells. AB - The coordinate regulation of HLA class II (HLA-II) is controlled by the class II transactivator, CIITA, and is crucial for the development of anti-tumor immunity. HLA-II in breast carcinoma is associated with increased IFN-gamma levels, reduced expression of the estrogen receptor (ER) and reduced age at diagnosis. Here, we tested the hypothesis that estradiol (E2) and ERalpha signaling contribute to the regulation of IFN-gamma inducible HLA-II in breast cancer cells. Using a panel of established ER- and ER+ breast cancer cell lines, we showed that E2 attenuated HLA-DR in two ER+ lines (MCF-7 and BT-474), but not in T47D, while it augmented expression in ER- lines, SK-BR-3 and MDA-MB-231. To further study the mechanism(s), we used paired transfectants: ERalpha+ MC2 (MDA-MB-231 c10A transfected with the wild type ERalpha gene) and ERalpha- VC5 (MDA-MB-231 c10A transfected with the empty vector), treated or not with E2 and IFN-gamma. HLA-II and CIITA were severely reduced in MC2 compared to VC5 and were further exacerbated by E2 treatment. Reduced expression occurred at the level of the IFN gamma inducible CIITA promoter IV. The anti-estrogen ICI 182,780 and gene silencing with ESR1 siRNA reversed the E2 inhibitory effects, signifying an antagonistic role for activated ERalpha on CIITA pIV activity. Moreover, STAT1 signaling, necessary for CIITA pIV activation, and selected STAT1 regulated genes were variably downregulated by E2 in transfected and endogenous ERalpha positive breast cancer cells, whereas STAT1 signaling was noticeably augmented in ERalpha- breast cancer cells. Collectively, these results imply immune escape mechanisms in ERalpha+ breast cancer may be facilitated through an ERalpha suppressive mechanism on IFN-gamma signaling. PMID- 24475283 TI - The extracellular domain of neurotrophin receptor p75 as a candidate biomarker for amyotrophic lateral sclerosis. AB - Objective biomarkers for amyotrophic lateral sclerosis would facilitate the discovery of new treatments. The common neurotrophin receptor p75 is up regulated and the extracellular domain cleaved from injured neurons and peripheral glia in amyotrophic lateral sclerosis. We have tested the hypothesis that urinary levels of extracellular neurotrophin receptor p75 serve as a biomarker for both human motor amyotrophic lateral sclerosis and the SOD1(G93A) mouse model of the disease. The extracellular domain of neurotrophin receptor p75 was identified in the urine of amyotrophic lateral sclerosis patients by an immuno precipitation/western blot procedure and confirmed by mass spectrometry. An ELISA was established to measure urinary extracellular neurotrophin receptor p75. The mean value for urinary extracellular neurotrophin receptor p75 from 28 amyotrophic lateral sclerosis patients measured by ELISA was 7.9+/-0.5 ng/mg creatinine and this was significantly higher (p<0.001) than 12 controls (2.6+/ 0.2 ng/mg creatinine) and 19 patients with other neurological disease (Parkinson's disease and Multiple Sclerosis; 4.1+/-0.2 ng/mg creatinine). Pilot data of disease progression rates in 14 MND patients indicates that p75NTR(ECD) levels were significantly higher (p = 0.0041) in 7 rapidly progressing patients as compared to 7 with slowly progressing disease. Extracellular neurotrophin receptor p75 was also readily detected in SOD1(G93A) mice by immuno precipitation/western blot before the onset of clinical symptoms. These findings indicate a significant relation between urinary extracellular neurotrophin receptor p75 levels and disease progression and suggests that it may be a useful marker of disease activity and progression in amyotrophic lateral sclerosis. PMID- 24475284 TI - Pronounced inflammatory response to endotoxaemia during nighttime: a randomised cross-over trial. AB - BACKGROUND: Circadian variation in bodily functions has been shown to impact health in acute and chronic medical conditions. Little is known about the relationship between circadian rhythm and sepsis in humans. We aimed to investigate circadian variations in the host response in a human endotoxaemia model. DESIGN AND METHODS: A cross-over study, where 12 healthy young men received E. coli endotoxin (lipopolysaccharide, LPS) 0.3 ng/kg at 12 noon and, on another day, at 12 midnight. Blood samples were analysed for pro- and anti inflammatory cytokines: tumour-necrosis factor (TNF)-alpha, soluble TNF receptors (sTNF-R)-1 and -2, interleukin (IL)-1beta, IL-1 receptor antagonist (IL-1Ra), IL 6, and IL-10 as well as YKL-40 and the oxidative stress markers malondialdehyde (MDA), ascorbic acid (AA) and dehydroascorbic acid (DHA) before and at 2, 4, 6 and 8 hours after LPS administration. RESULTS: The levels of MDA and IL-10 where significantly higher during the day time (P<0.05) whereas levels of TNF-alpha, sTNF-RI, sTNF-RII, IL-1Ra, IL-6, and YKL-40 were higher (P<0.01 for all comparisons) during the night time. No significant differences were seen in the levels of AA and DHA. CONCLUSION: A day-night difference in the acute phase response to endotoxaemia exists in healthy volunteers with a more pronounced inflammatory response during the night time. This circadian difference in the response to endotoxaemia may play an important role in the clinical setting and should be investigated further. PMID- 24475285 TI - Nitrogen-deprivation elevates lipid levels in Symbiodinium spp. by lipid droplet accumulation: morphological and compositional analyses. AB - Stable cnidarian-dinoflagellate (genus Symbiodinium) endosymbioses depend on the regulation of nutrient transport between Symbiodinium populations and their hosts. It has been previously shown that the host cytosol is a nitrogen-deficient environment for the intracellular Symbiodinium and may act to limit growth rates of symbionts during the symbiotic association. This study aimed to investigate the cell proliferation, as well as ultrastructural and lipid compositional changes, in free-living Symbiodinium spp. (clade B) upon nitrogen (N) deprivation. The cell proliferation of the N-deprived cells decreased significantly. Furthermore, staining with a fluorescent probe, boron dipyrromethane 493/503 (BODIPY 493/503), indicated that lipid contents progressively accumulated in the N-deprived cells. Lipid analyses further showed that both triacylglycerol (TAG) and cholesterol ester (CE) were drastically enriched, with polyunsaturated fatty acids (PUFA; i.e., docosahexaenoic acid, heneicosapentaenoic acid, and oleic acid) became more abundant. Ultrastructural examinations showed that the increase in concentration of these lipid species was due to the accumulation of lipid droplets (LDs), a cellular feature that have previously shown to be pivotal in the maintenance of intact endosymbioses. Integrity of these stable LDs was maintained via electronegative repulsion and steric hindrance possibly provided by their surface proteins. Proteomic analyses of these LDs identified proteins putatively involved in lipid metabolism, signaling, stress response and energy metabolism. These results suggest that LDs production may be an adaptive response that enables Symbiodinium to maintain sufficient cellular energy stores for survival under the N-deprived conditions in the host cytoplasm. PMID- 24475286 TI - Association between farming and chronic energy deficiency in rural South India. AB - OBJECTIVE: To examine factors associated with chronic energy deficiency (CED) and anaemia in disadvantaged Indian adults who are mostly involved in subsistence farming. DESIGN: A cross-sectional study in which we collected information on socio-demographic factors, physical activity, anthropometry, blood haemoglobin concentration, and daily household food intake. These data were used to calculate body mass index (BMI), basal metabolic rate (BMR), daily energy expenditure, and energy and nutrient intake. Multivariable backward stepwise logistic regression was used to assess socioeconomic and lifestyle factors associated with CED (defined as BMI<18 kg/m2) and anaemia. SETTING: The study was conducted in 12 villages, in the Rishi Valley, Andhra Pradesh, India. SUBJECTS: Individuals aged 18 years and above, residing in the 12 villages, were eligible to participate. RESULTS: Data were available for 1178 individuals (45% male, median age 36 years (inter quartile range (IQR 27-50)). The prevalence of CED (38%) and anaemia (25%) was high. Farming was associated with CED in women (2.20, 95% CI: 1.39-3.49) and men (1.71, 95% CI: (1.06-2.74). Low income was also significantly associated with CED, while not completing high school was positively associated with anaemia. Median iron intake was high: 35.7 mg/day (IQR 26-46) in women and 43.4 mg/day (IQR 34-55) in men. CONCLUSIONS: Farming is an important risk factor associated with CED in this rural Indian population and low dietary iron is not the main cause of anaemia. Better farming practice may help to reduce CED in this population. PMID- 24475287 TI - p53 regulation by TRP2 is not pervasive in melanoma. AB - p53 is a central tumor suppressor protein and its inhibition is believed to be a prerequisite for cancer development. In approximately 50% of all malignancies this is achieved by inactivating mutations in the p53 gene. However, in several cancer entities, including melanoma, p53 mutations are rare. It has been recently proposed that tyrosinase related protein 2 (TRP2), a protein involved in melanin synthesis, may act as suppressor of the p53 pathway in melanoma. To scrutinize this notion we analyzed p53 and TRP2 expression by immunohistochemistry in 172 melanoma tissues and did not find any correlation. Furthermore, we applied three different TRP2 shRNAs to five melanoma cell lines and could not observe a target specific effect of the TRP2 knockdown on either p53 expression nor p53 reporter gene activity. Likewise, ectopic expression of TRP2 in a TRP2 negative melanoma cell line had no impact on p53 expression. In conclusion our data suggest that p53 repression critically controlled by TRP2 is not a general event in melanoma. PMID- 24475288 TI - Cisplatin induces resistance by triggering differentiation of testicular embryonal carcinoma cells. AB - Although testicular germ cell tumors are generally quite responsive to treatment with cisplatin, a small fraction of them acquire resistance during therapy. Even when cisplatin treatment is successful the patient is often left with a residual teratoma at the site of the primary tumor suggesting that cisplatin may trigger differentiation in some tumors. Using the human embryonal carcinoma cell line NTera2/D1, we confirmed that exposure to the differentiating agent retinoic acid produced a reduction in pluripotency markers NANOG and POU5F1 (Oct3/4) and an acute concentration-dependent increase in resistance to both cisplatin and paclitaxel that reached as high as 18-fold for cisplatin and 61-fold for paclitaxel within four days. A two day exposure to cisplatin also produced a concentration-dependent decrease in the expression of the NANOG and POU5F1 and increased expression of three markers whose levels increase with differentiation including Nestin, SCG10 and Fibronectin. In parallel, exposure to cisplatin induced up to 6.2-fold resistance to itself and 104-fold resistance to paclitaxel. Paclitaxel did not induce differentiation or resistance to either itself or cisplatin. Neither retinoic acid nor cisplatin induced resistance in cervical or prostate cancer cell lines or other germ cell tumor lines in which they failed to alter the expression of NANOG and POU5F1. Forced expression of NANOG prevented the induction of resistance to cisplatin by retinoic acid. We conclude that cisplatin can acutely induce resistance to itself and paclitaxel by triggering a differentiation response in pluripotent germ cell tumor cells. PMID- 24475289 TI - Bacillus subtilis spores as vaccine adjuvants: further insights into the mechanisms of action. AB - Bacillus subtilis spores have received growing attention regarding potential biotechnological applications, including the use as probiotics and in vaccine formulations. B. subtilis spores have also been shown to behave as particulate vaccine adjuvants, promoting the increase of antibody responses after co administration with antigens either admixed or adsorbed on the spore surface. In this study, we further evaluated the immune modulatory properties of B. subtilis spores using a recombinant HIV gag p24 protein as a model antigen. The adjuvant effects of B. subtilis spores were not affected by the genetic background of the mouse lineage and did not induce significant inflammatory or deleterious effects after parenteral administration. Our results demonstrated that co-administration, but not adsorption to the spore surface, enhanced the immunogenicity of that target antigen after subcutaneous administration to BALB/c and C57BL/6 mice. Spores promoted activation of antigen presenting cells as demonstrated by the upregulation of MHC and CD40 molecules and enhanced secretion of pro-inflammatory cytokines by murine dendritic cells. In addition, in vivo studies indicated a direct role of the innate immunity on the immunomodulatory properties of B. subtilis spores, as demonstrated by the lack of adjuvant effects on MyD88 and TLR2 knockout mouse strains. PMID- 24475290 TI - Inhibition of HDAC1 and DNMT1 modulate RGS10 expression and decrease ovarian cancer chemoresistance. AB - RGS10 is an important regulator of cell survival and chemoresistance in ovarian cancer. We recently showed that RGS10 transcript expression is suppressed during acquired chemoresistance in ovarian cancer. The suppression of RGS10 is due to DNA hypermethylation and histone deacetylation, two important mechanisms that contribute to silencing of tumor suppressor genes during cancer progression. Here, we fully investigate the molecular mechanisms of epigenetic silencing of RGS10 expression in chemoresistant A2780-AD ovarian cancer cells. We identify two important epigenetic regulators, HDAC1 and DNMT1, that exhibit aberrant association with RGS10 promoters in chemoresistant ovarian cancer cells. Knockdown of HDAC1 or DNMT1 expression, and pharmacological inhibition of DNMT or HDAC enzymatic activity, significantly increases RGS10 expression and cisplatin mediated cell death. Finally, DNMT1 knock down also decreases HDAC1 binding to the RGS10 promoter in chemoresistant cells, suggesting HDAC1 recruitment to RGS10 promoters requires DNMT1 activity. Our results suggest that HDAC1 and DNMT1 contribute to the suppression of RGS10 during acquired chemoresistance and support inhibition of HDAC1 and DNMT1 as an adjuvant therapeutic approach to overcome ovarian cancer chemoresistance. PMID- 24475291 TI - Up-regulation of hERG K+ channels by B-RAF. AB - Human ether-a-go-go related-gene K+ channels (hERG) participate in the regulation of tumor cell proliferation and apoptosis. HERG channel activity is up-regulated by growth factors. Kinases sensitive to growth factor signaling include the serine/threonine protein kinase B-RAF. The present study thus explored whether B RAF influences hERG channel expression and activity. To this end, hERG channels were expressed in Xenopus oocytes with or without wild-type B-RAF, hERG channel activity was determined utilizing dual-electrode voltage clamp and hERG protein abundance in the cell membrane was analyzed utilizing confocal microscopy as well as chemiluminescence. Moreover, in rhabdomyosarcoma RD cells the effect of B-RAF inhibitor PLX-4720 on hERG-mediated current was quantified by whole-cell patch clamp and hERG cell surface protein abundance by utilizing biotinylation of cell surface proteins as well as flow cytometry. As a result, co-expression of wild type B-RAF in hERG-expressing Xenopus oocytes significantly increased hERG channel activity and hERG channel protein abundance in the cell membrane. Treatment for 24 hours of B-RAF and hERG-expressing Xenopus oocytes with B-RAF inhibitor PLX-4720 (10 uM) significantly decreased hERG-mediated current and hERG cell surface expression. Similarly, in rhabdomyosarcoma RD cells, treatment for 24 hours with B-RAF inhibitor PLX-4720 significantly decreased hERG cell membrane protein abundance and hERG-mediated current. In conclusion, B-RAF is a powerful regulator of hERG channel activity and cell surface hERG protein abundance. PMID- 24475292 TI - Non-consumptive predator effects shape honey bee foraging and recruitment dancing. AB - Predators can reduce bee pollination and plant fitness through successful predation and non-consumptive effects. In honey bees, evidence of predation or a direct attack can decrease recruitment dancing and thereby magnify the effects of individual predation attempts at a colony level. However, actual predation attempts and successes are relatively rare. It was not known if a far more common event, just detection of a predator, could inhibit recruitment. We began by testing honey bees' avoidance of the praying mantis (Tenodera sinensis). Larger predators (later mantis instars, >=4.5 cm in body length) elicited significantly more avoidance (1.3 fold) than smaller mantis instars. Larger instars also attempted to capture honey bees significantly more often than did smaller instars. Foragers could detect and avoid mantises based upon mantis odor (74% of bees avoided an odor extract) or visual appearance (67% avoided a mantis model). Finally, foragers decreased recruitment dancing by 1.8 fold for a food source with a live adult mantis, even when they were not attacked. This reduction in recruitment dancing, elicited by predator presence alone, expands our understanding of predator non-consumptive effects and of cascading ecosystem effects for plants served by an important generalist pollinator. PMID- 24475293 TI - Recovery of diaphragm function following mechanical ventilation in a rodent model. AB - BACKGROUND: Mechanical ventilation (MV) induces diaphragmatic muscle fiber atrophy and contractile dysfunction (ventilator induced diaphragmatic dysfunction, VIDD). It is unknown how rapidly diaphragm muscle recovers from VIDD once spontaneous breathing is restored. We hypothesized that following extubation, the return to voluntary breathing would restore diaphragm muscle fiber size and contractile function using an established rodent model. METHODS: Following 12 hours of MV, animals were either euthanized or, after full wake up, extubated and returned to voluntary breathing for 12 hours or 24 hours. Acutely euthanized animals served as controls (each n = 8/group). Diaphragmatic contractility, fiber size, protease activation, and biomarkers of oxidative damage in the diaphragm were assessed. RESULTS: 12 hours of MV induced VIDD. Compared to controls diaphragm contractility remained significantly depressed at 12 h after extubation but rebounded at 24 h to near control levels. Diaphragmatic levels of oxidized proteins were significantly elevated after MV (p = 0.002) and normalized at 24 hours after extubation. CONCLUSIONS: These findings indicate that diaphragm recovery from VIDD, as indexed by fiber size and contractile properties, returns to near control levels within 24 hours after returning to spontaneous breathing. Besides the down-regulation of proteolytic pathways and oxidative stress at 24 hours after extubation further repairing mechanisms have to be determined. PMID- 24475294 TI - Gene polymorphisms of micrornas in Helicobacter pylori-induced high risk atrophic gastritis and gastric cancer. AB - BACKGROUND AND AIMS: MicroRNAs (miRNAs) are known for their function as translational regulators of tumor suppressor or oncogenes. Single nucleotide polymorphisms (SNPs) in miRNAs related genes have been shown to affect the regulatory capacity of miRNAs and were linked with gastric cancer (GC) and premalignant gastric conditions. The purpose of this study was to evaluate potential associations between miRNA-related gene polymorphisms (miR-27a, miR 146a, miR-196a-2, miR-492 and miR-608) and the presence of GC or high risk atrophic gastritis (HRAG) in European population. METHODS: Gene polymorphisms were analyzed in 995 subjects (controls: n = 351; GC: n = 363; HRAG: n = 281) of European descent. MiR-27a T>C (rs895819), miR-146a G>C (rs2910164), miR-196a-2 C>T (rs11614913), miR-492 G>C (rs2289030) and miR-608 C>G (rs4919510) SNPs were genotyped by RT-PCR. RESULTS: Overall, SNPs of miRNAs were not associated with the presence of GC or HRAG. We observed a tendency for miR-196a-2 CT genotype to be associated with higher risk of GC when compared to CC genotype, however, the difference did not reach the adjusted P-value (odds ratio (OR) - 1.46, 95% confidence interval (CI) 1.03-2.07, P = 0.032). MiR-608 GG genotype was more frequent in GC when compared to controls (OR -2.34, 95% CI 1.08-5.04), but significance remained marginal (P = 0.029). A similar tendency was observed in a recessive model for miR-608, where CC + CG vs GG genotype comparison showed a tendency for increased risk of GC with OR of 2.44 (95% CI 1.14-5.22, P = 0.021). The genotypes and alleles of miR-27a, miR-146a, miR-196a-2, miR-492 and miR-608 SNPs had similar distribution between histological subtypes of GC and were not linked with the presence of diffuse or intestinal-type GC. CONCLUSIONS: Gene polymorphisms of miR-27a, miR-146a, miR-196a-2, miR-492, miR-492a and miR-608 were not associated with the presence of HRAG, GC or different histological subtypes of GC in European subjects. PMID- 24475295 TI - A new approach for the determination of ammonite and nautilid habitats. AB - Externally shelled cephalopods were important elements in open marine habitats throughout Earth history. Paleotemperatures calculated on the basis of the oxygen isotope composition of their shells can provide insights into ancient marine systems as well as the ecology of this important group of organisms. In some sedimentary deposits, however, the aragonitic shell of the ammonite or nautilid is poorly or not preserved at all, while the calcitic structures belonging to the jaws are present. This study tests for the first time if the calcitic jaw structures in fossil cephalopods can be used as a proxy for paleotemperature. We first analyzed the calcitic structures on the jaws of Recent Nautilus and compared the calculated temperatures of precipitation with those from the aragonitic shell in the same individuals. Our results indicate that the jaws of Recent Nautilus are secreted in isotopic equilibrium, and the calculated temperatures approximately match those of the shell. We then extended our study to ammonites from the Upper Cretaceous (Campanian) Pierre Shale of the U.S. Western Interior and the age-equivalent Mooreville Chalk of the Gulf Coastal Plain. In the Pierre Shale, jaws occur in situ inside the body chambers of well preserved Baculites while in the Mooreville Chalk, the jaw elements appear as isolated occurrences in the sediment and the aragonitic shell material is not preserved. For the Pierre Shale specimens, the calculated temperatures of well preserved jaw material match those of well-preserved shell material in the same individual. Analyses of the jaw elements in the Mooreville Chalk permit a comparison of the paleotemperatures between the two sites, and show that the Western Interior is warmer than the Gulf Coast at that time. In summary, our data indicate that the calcitic jaw elements of cephalopods can provide a reliable geochemical archive of the habitat of fossil forms. PMID- 24475296 TI - Tissue-specific expression of transgenic secreted ACE in vasculature can restore normal kidney functions, but not blood pressure, of Ace-/- mice. AB - Angiotensin-converting enzyme (ACE) regulates normal blood pressure and fluid homeostasis through its action in the renin-angiotensin-system (RAS). Ace-/- mice are smaller in size, have low blood pressure and defective kidney structure and functions. All of these defects are cured by transgenic expression of somatic ACE (sACE) in vascular endothelial cells of Ace-/- mice. sACE is expressed on the surface of vascular endothelial cells and undergoes a natural cleavage secretion process to generate a soluble form in the body fluids. Both the tissue-bound and the soluble forms of ACE are enzymatically active, and generate the vasoactive octapeptide Angiotensin II (Ang II) with equal efficiency. To assess the relative physiological roles of the secreted and the cell-bound forms of ACE, we expressed, in the vascular endothelial cells of Ace-/- mice, the ectodomain of sACE, which corresponded to only the secreted form of ACE. Our results demonstrated that the secreted form of ACE could normalize kidney functions and RAS integrity, growth and development of Ace-/- mice, but not their blood pressure. This study clearly demonstrates that the secreted form of ACE cannot replace the tissue-bound ACE for maintaining normal blood pressure; a suitable balance between the tissue-bound and the soluble forms of ACE is essential for maintaining all physiological functions of ACE. PMID- 24475297 TI - Association of maternal and child nutritional status in Brazil: a population based cross-sectional study. AB - BACKGROUND: Although child undernutrition and stunting has been decreasing worldwide while obesity rates increase, these extreme conditions might coexist in families from low- and middle-income countries. We examined the association between maternal and child anthropometric indicators using a population representative sample. METHODS: 4,258 non-pregnant women and their children <60 months who participated in the 2006 Brazilian Demographic Health Survey. We compared the distributions of two nutritional indexes of children, height-for-age (HAZ) and body mass index-for age (BAZ) z-scores, by categories of maternal height, body mass index (BMI), and waist circumference (WC). Adjusted mean differences and 95% confidence intervals (95% CI) were estimated from linear regression, taking into account the complex survey design. We also examined the associations of maternal anthropometry with the prevalence of child stunting (HAZ<-2) and overweight/obesity (BAZ>2). RESULTS: HAZ was positively associated with maternal height and WC in a linear fashion. After adjustment, for sociodemographic characteristics, children whose mothers' height was<145 cm had 1.2 lower HAZ than children whose mothers were >=160 cm tall (p-trend<0.0001). After further adjustment for maternal height and maternal BMI, children of mothers with a waist circumference >=88 cm had 0.3 higher HAZ than those of mothers with WC<80 cm (p-trend<0.01). Adjusted prevalence ratios and 95% CI for stunting by the categories of maternal height (<145, 145-149, 150-154, 155-159 and >=160 cm) were, respectively, 2.95 (1.51;5.77), 2.29 (1.33;3.93), 1.09 (0.63;1.87), and 0.89 (0.45;1.77), (p-trend = 0.001). BAZ was positively associated with maternal BMI and WC. CONCLUSION: We observed a strong, positive association of maternal and child nutritional status. Mothers of low stature had children with lower stature, mothers with central obesity had taller children, and mothers with overall or abdominal obesity had children with higher BAZ. PMID- 24475298 TI - Fronto-parietal connectivity is a non-static phenomenon with characteristic changes during unconsciousness. AB - BACKGROUND: It has been previously shown that loss of consciousness is associated with a breakdown of dominating fronto-parietal feedback connectivity as assessed by electroencephalogram (EEG) recordings. Structure and strength of network connectivity may change over time. Aim of the current study is to investigate cortico-cortical connectivity at different time intervals during consciousness and unconsciousness. For this purpose, EEG symbolic transfer entropy (STEn) was calculated to indicate cortico-cortical information transfer at different transfer times. METHODS: The study was performed in 15 male volunteers. 29 channel EEG was recorded during consciousness and propofol-induced unconsciousness. EEG data were analyzed by STEn, which quantifies intensity and directionality of the mutual information flow between two EEG channels. STEn was computed over fronto-parietal channel pair combinations (10 s length, 0.5-45 Hz total bandwidth) to analyze changes of intercortical directional connectivity. Feedback (fronto -> parietal) and feedforward (parieto -> frontal) connectivity was calculated for transfer times from 25 ms to 250 ms in 5 ms steps. Transfer times leading to maximum directed interaction were identified to detect changes of cortical information transfer (directional connectivity) induced by unconsciousness (p<0.05). RESULTS: The current analyses show that fronto-parietal connectivity is a non-static phenomenon. Maximum detected interaction occurs at decreased transfer times during propofol-induced unconsciousness (feedback interaction: 60 ms to 40 ms, p = 0.002; feedforward interaction: 65 ms to 45 ms, p = 0.001). Strength of maximum feedback interaction decreases during unconsciousness (p = 0.026), while no effect of propofol was observed on feedforward interaction. During both consciousness and unconsciousness, intensity of fronto-parietal interaction fluctuates with increasing transfer times. CONCLUSION: Non-stationarity of directional connectivity may play a functional role for cortical network communication as it shows characteristic changes during propofol-induced unconsciousness. PMID- 24475299 TI - Comparison of blood RNA extraction methods used for gene expression profiling in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes death within a mean of 2-3 years from symptom onset. There is no diagnostic test and the delay from symptom onset to diagnosis averages 12 months. The identification of prognostic and diagnostic biomarkers in ALS would facilitate earlier diagnosis and faster monitoring of treatments. Gene expression profiling (GEP) can help to identify these markers as well as therapeutic targets in neurological diseases. One source of genetic material for GEP in ALS is peripheral blood, which is routinely accessed from patients. However, a high proportion of globin mRNA in blood can mask important genetic information. A number of methods allow safe collection, storage and transport of blood as well as RNA stabilisation, including the PAXGENE and TEMPUS systems for the collection of whole blood and LEUKOLOCK which enriches for the leukocyte population. Here we compared these three systems and assess their suitability for GEP in ALS. We collected blood from 8 sporadic ALS patients and 7 controls. PAXGENE and TEMPUS RNA extracted samples additionally underwent globin depletion using GlobinClear. RNA was amplified and hybridised onto Affymetrix U133 Plus 2.0 arrays. Lists of genes differentially regulated in ALS patients and controls were created for each method using the R package PUMA, and RT-PCR validation was carried out on selected genes. TEMPUS/GlobinClear, and LEUKOLOCK produced high quality RNA with sufficient yield, and consistent array expression profiles. PAXGENE/GlobinClear yield and quality were lower. Globin depletion for PAXGENE and TEMPUS uncovered the presence of over 60% more transcripts than when samples were not depleted. TEMPUS/GlobinClear and LEUKOLOCK gene lists respectively contained 3619 and 3047 genes differentially expressed between patients and controls. Real-time PCR validation revealed similar reliability between these two methods and gene ontology analyses revealed similar pathways differentially regulated in disease compared to controls. PMID- 24475300 TI - Ubiquilin-1 overexpression increases the lifespan and delays accumulation of Huntingtin aggregates in the R6/2 mouse model of Huntington's disease. AB - Huntington's Disease (HD) is a neurodegenerative disorder that is caused by abnormal expansion of a polyglutamine tract in huntingtin (htt) protein. The expansion leads to increased htt aggregation and toxicity. Factors that aid in the clearance of mutant huntingtin proteins should relieve the toxicity. We previously demonstrated that overexpression of ubiqulin-1, which facilitates protein clearance through the proteasome and autophagy pathways, reduces huntingtin aggregates and toxicity in mammalian cell and invertebrate models of HD. Here we tested whether overexpression of ubiquilin-1 delays or prevents neurodegeneration in R6/2 mice, a well-established model of HD. We generated transgenic mice overexpressing human ubiquilin-1 driven by the neuron-specific Thy1.2 promoter. Immunoblotting and immunohistochemistry revealed robust and widespread overexpression of ubiquilin-1 in the brains of the transgenic mice. Similar analysis of R6/2 animals revealed that ubiquilin is localized in huntingtin aggregates and that ubiquilin levels decrease progressively to 30% during the end-stage of disease. We crossed our ubiquilin-1 transgenic line with R6/2 mice to assess whether restoration of ubiquilin levels would delay HD symptoms and pathology. In the double transgenic progeny, ubiquilin levels were fully restored, and this correlated with a 20% increase in lifespan and a reduction in htt inclusions in the hippocampus and cortex. Furthermore, immunoblots indicated that endoplasmic reticulum stress response that is elevated in the hippocampus of R6/2 animals was attenuated by ubiquilin-1 overexpression. However, ubiquilin-1 overexpression neither altered the load of htt aggregates in the striatum nor improved motor impairments in the mice. PMID- 24475301 TI - Reporters transiently transfected into mammalian cells are highly sensitive to translational repression induced by dsRNA expression. AB - In mammals, double-stranded RNA (dsRNA) can mediate sequence-specific RNA interference, activate sequence-independent interferon response, or undergo RNA editing by adenosine deaminases. We showed that long hairpin dsRNA expression had negligible effects on mammalian somatic cells--expressed dsRNA was slightly edited, poorly processed into siRNAs, and it did not activate the interferon response. At the same time, we noticed reduced reporter expression in transient co-transfections, which was presumably induced by expressed dsRNA. Since transient co-transfections are frequently used for studying gene function, we systematically explored the role of expressed dsRNA in this silencing phenomenon. We demonstrate that dsRNA expressed from transiently transfected plasmids strongly inhibits the expression of co-transfected reporter plasmids but not the expression of endogenous genes or reporters stably integrated in the genome. The inhibition is concentration-dependent, it is found in different cell types, and it is independent of transfection method and dsRNA sequence. The inhibition occurs at the level of translation and involves protein kinase R, which binds the expressed dsRNA. Thus, dsRNA expression represents a hidden danger in transient transfection experiments and must be taken into account during interpretation of experimental results. PMID- 24475302 TI - Direct staining with major histocompatibility complex class II dextramers permits detection of antigen-specific, autoreactive CD4 T cells in situ. AB - We report here the utility of major histocompatibility complex (MHC) class II dextramers for in situ detection of self-reactive CD4 T cells in two target organs, the brain and heart. We optimized the conditions for in situ detection of antigen-specific CD4 T cells using brain sections obtained from SJL mice immunized with myelin proteolipid protein (PLP) 139-151; the sections were costained with IA(s)/PLP 139-151 (specific) or Theiler's murine encephalomyelitis virus (TMEV) 70-86 (control) dextramers and anti-CD4. Analysis of sections by laser scanning confocal microscope revealed detection of cells positive for PLP 139-151 but not for TMEV 70-86 dextramers to be colocalized with CD4-expressing T cells, indicating that the staining was specific to PLP 139-151 dextramers. Further, we devised a method to reliably enumerate the frequencies of antigen specific T cells by counting the number of dextramer+ CD4+ T cells in the 'Z' serial images acquired sequentially. We next extended these observations to detect cardiac myosin-specific T cells in autoimmune myocarditis induced in A/J mice by immunizing with cardiac myosin heavy chain-alpha (Myhc) 334-352. Heart sections prepared from immunized mice were costained with Myhc 334-352 (specific) or bovine ribonuclease 43-56 (control) dextramers together with anti-CD4; the sections showed the infiltrations of Myhc-specific CD4 T cells. The data suggest that MHC class II dextramers are useful tools for enumerating the frequencies of antigen-specific CD4 T cells in situ by direct staining without having to amplify the fluorescent signals, an approach commonly employed with conventional MHC tetramers. PMID- 24475303 TI - Thermal tolerance limits of diamondback moth in ramping and plunging assays. AB - Thermal sensitivity is a crucial determinant of insect abundance and distribution. The way it is measured can have a critical influence on the conclusions made. Diamondback moth (DBM), Plutella xylostella (L.) (Lepidoptera: Plutellidae) is an important insect pest of cruciferous crops around the world and the thermal responses of polyphagous species are critical to understand the influences of a rapidly changing climate on their distribution and abundance. Experiments were carried out to the lethal temperature limits (ULT0 and LLT0: temperatures where there is no survival) as well as Upper and Lower Lethal Temperature (ULT25 and LLT25) (temperature where 25% DBM survived) of lab-reared adult DBM population to extreme temperatures attained by either two-way ramping (ramping temperatures from baseline to LT25 and ramping back again) or sudden plunging method. In this study the ULT0 for DBM was recorded as 42.6 degrees C and LLT0 was recorded as -16.5 degrees C. DBM had an ULT25 of 41.8 degrees C and LLT25 of -15.2 degrees C. The duration of exposure to extreme temperatures had significant impacts on survival of DBM, with extreme temperatures and/or longer durations contributing to higher lethality. Comparing the two-way ramping temperature treatment to that of direct plunging temperature treatment, our study clearly demonstrated that DBM was more tolerant to temperature in the two-way ramping assay than that of the plunging assay for cold temperatures, but at warmer temperatures survival exhibited no differences between ramping and plunging. These results suggest that DBM will not be put under physiological stress from a rapidly changing climate, rather access to host plants in marginal habitats has enabled them to expand their distribution. Two-way temperature ramping enhances survival of DBM at cold temperatures, and this needs to be examined across a range of taxa and life stages to determine if enhanced survival is widespread incorporating a ramping recovery method. PMID- 24475306 TI - The role of ACT-like subdomain in bacterial threonine dehydratases. AB - In bacteria, threonine dehydratases could convert L-threonine to 2-ketobutyrate. Some threonine dehydratases contain only a catalytic domain, while others contain an N-terminal catalytic domain and a C-terminal regulatory domain composed of one or two ACT-like subdomains. However, the role of the ACT-like subdomain in threonine dehydratases is not clear. Here, nine different bacterial threonine dehydratases were studied. Three of the nine contain no ACT-like subdomain, four of them contain a single ACT-like subdomain, and two of them contain two ACT-like subdomains. The nine genes encoding these threonine dehydratases were individually overexpressed in E. coli BL21(DE3), and the enzymes were purified to homogeneity. Activities of the purified enzymes were analyzed after incubation at different temperatures and different pHs. The results showed that threonine dehydratases with a single ACT-like subdomain are more stable at higher temperatures and a broad range of pH than those without ACT-like subdomain or with two ACT-like subdomains. Furthermore, the specific activity of threonine dehydratases increases with the increase of the number of ACT-like subdomains they contain. The results suggest that the ACT-like subdomain plays an important role in bacterial threonine dehydratases. PMID- 24475304 TI - Embryonic caffeine exposure acts via A1 adenosine receptors to alter adult cardiac function and DNA methylation in mice. AB - Evidence indicates that disruption of normal prenatal development influences an individual's risk of developing obesity and cardiovascular disease as an adult. Thus, understanding how in utero exposure to chemical agents leads to increased susceptibility to adult diseases is a critical health related issue. Our aim was to determine whether adenosine A1 receptors (A1ARs) mediate the long-term effects of in utero caffeine exposure on cardiac function and whether these long-term effects are the result of changes in DNA methylation patterns in adult hearts. Pregnant A1AR knockout mice were treated with caffeine (20 mg/kg) or vehicle (0.09% NaCl) i.p. at embryonic day 8.5. This caffeine treatment results in serum levels equivalent to the consumption of 2-4 cups of coffee in humans. After dams gave birth, offspring were examined at 8-10 weeks of age. A1AR+/+ offspring treated in utero with caffeine were 10% heavier than vehicle controls. Using echocardiography, we observed altered cardiac function and morphology in adult mice exposed to caffeine in utero. Caffeine treatment decreased cardiac output by 11% and increased left ventricular wall thickness by 29% during diastole. Using DNA methylation arrays, we identified altered DNA methylation patterns in A1AR+/+ caffeine treated hearts, including 7719 differentially methylated regions (DMRs) within the genome and an overall decrease in DNA methylation of 26%. Analysis of genes associated with DMRs revealed that many are associated with cardiac hypertrophy. These data demonstrate that A1ARs mediate in utero caffeine effects on cardiac function and growth and that caffeine exposure leads to changes in DNA methylation. PMID- 24475305 TI - Prevalence of abdominal obesity in Spanish children and adolescents. Do we need waist circumference measurements in pediatric practice? AB - BACKGROUND: Evidence indicates that central adiposity has increased to a higher degree than general adiposity in children and adolescents in recent decades. However, waist circumference is not a routine measurement in clinical practice. OBJECTIVE: This study aimed to determine the prevalence of abdominal obesity based on waist circumferences (WC) and waist to height ratio (WHtR) in Spanish children and adolescents aged 6 to 17 years. Further, the prevalence of abdominal obesity (AO) among normal and overweight individuals was analyzed. DESIGN: Data were obtained from a study conducted from 1998 to 2000 in a representative national sample of 1521 children and adolescents aged 6 to 17 years (50.0% female) in Spain. WC and WHtR measurements were obtained in addition to BMI. AO was defined as WHtR >=0.50 (WHtR-AO), sex and age specific WC>=90(th) percentile (WC-AO1), and sex and age specific WC cut-off values associated with high trunk fat measured by by dual-energy X-ray absorptiometry (WC-AO2). RESULTS: IOTF- based overweight and obsity prevalence was 21.5% and 6.6% in children and 17.4% and 5.2% in adolescents, respectively. Abdominal obesity (AO) was defined as WHtR>=0.50 (WHtR-AO), sex- and age-specific WC>=90th percentile (WC-AO1), and sex and age-specific WC cut-off values associated with high trunk fat measured by dual-energy X-ray absorptiometry (WC-AO2). The respective prevalence of WHtR-AO, WC-AO1, and WC-AO2 was 21.3% (24.6% boys; 17.9% girls), 9.4% (9.1% boys; 9.7% girls), and 26.8% (30.6% boys;22.9% girls) in children and 14.3% (20.0% boys; 8.7% girls), 9.6% (9.8% boys; 9.5% girls), and 21.1% (28.8% boys; 13.7% girls) in adolescents. CONCLUSION: The prevalence of AO in Spanish children and adolescents is of concern. The high proportion of AO observed in young patients who are normal weight or overweight indicates a need to include waist circumference measurements in routine clinical practice. PMID- 24475307 TI - Activation of Nlrp3 inflammasomes enhances macrophage lipid-deposition and migration: implication of a novel role of inflammasome in atherogenesis. AB - Although Nlrp3 inflammasome activation in macrophages has been shown to be critical for the development of atherosclerosis upon atherogenic stimuli, it remains unknown whether activated Nlrp3 inflammasomes by other non-atherogenic stimuli induce alterations in macrophages that may contribute in the concert with other factors to atherogenesis. Thus, the present study tested the hypothesis that activation of Nlrp3 inflammasomes by ATP, which is a classical non-lipid danger stimulus, enhances the migration of macrophage and increases lipids deposition in macrophages accelerating foam cell formation. We first demonstrated that extracellular ATP (2.5 mM) markedly increased the formation and activation of Nlrp3 inflammasomes in bone marrow macrophages (BMMs) from wild type (Asc+/+) mice resulting in activation of caspase-1 and IL-1beta production. In these Asc+/+ macrophages, such stimulation of inflammasomes by non-lipid ATP was similar to those induced by atherogenic stimuli such as cholesterol crystals or 7 ketocholesterol. Both non-lipid and lipid forms of stimuli induced formation and activation of Nlrp3 inflammasomes, which were prevented by Asc gene deletion. Interestingly, Asc+/+ BMMs had dramatic lipids accumulation after stimulation with ATP. Further, we demonstrated that large amount of cholesterol was accumulated in lysosomes of Asc+/+ BMMs when inflammasomes were activated by ATP. Such intracellular and lysosomal lipids deposition was not observed in Asc-/- BMMs and also prevented by caspase-1 inhibitor WEHD. In addition, in vitro and in vivo experiments revealed that migration of Asc+/+ BMMs increased due to stimulation of Nlrp3 inflammasomes, which was markedly attenuated in Asc-/- BMMs. Together, these results suggest that activation of Nlrp3 inflammasomes remarkably increases the susceptibility of macrophages to lipid deposition and their migration ability. Such novel action of inflammasomes may facilitate entry or retention of macrophages into the arterial wall, where they form foam cells and ultimately induce atherosclerosis. PMID- 24475308 TI - Role of the lower and upper intestine in the production and absorption of gut microbiota-derived PUFA metabolites. AB - In vitro studies have suggested that isolated gut bacteria are able to metabolize PUFA into CLA (conjugated linoleic acids) and CLnA (conjugated linolenic acids). However, the bioavailability of fatty acid metabolites produced in vivo by the gut microbes remains to be studied. Therefore, we measured intestinal concentration and plasma accumulation of bacterial metabolites produced from dietary PUFA in mice, first injected with a lipoprotein lipase inhibitor, then force-fed with either sunflower oil (200 ul) rich in n-6 PUFA or linseed oil (200 ul) rich in n-3 PUFA. The greatest production of bacterial metabolites was observed in the caecum and colon, and at a much lesser extent in the jejunum and ileum. In the caecal content, CLA proportions were higher in sunflower oil force fed mice whereas CLnA proportions were higher in linseed oil force-fed mice. The accumulation of the main metabolites (CLA cis-9,trans-11-18:2 and CLnA cis 9,trans-11,cis-15-18:3) in the caecal tissue was not associated with their increase in the plasma, therefore suggesting that, if endogenously produced CLA and CLnA have any biological role in host metabolism regulation, their effect would be confined at the intestinal level, where the microbiota is abundant. PMID- 24475309 TI - Higher education moderates the effect of T2 lesion load and third ventricle width on cognition in multiple sclerosis. AB - BACKGROUND: Previous work suggested greater intellectual enrichment might moderate the negative impact of brain atrophy on cognition. This awaits confirmation in independent cohorts including investigation of the role of T2 lesion load (T2-LL), which is another important determinant of cognition in MS. We here thus aimed to test this cognitive reserve hypothesis by investigating whether educational attainment (EA) moderates the negative effects of both brain atrophy and T2-LL on cognitive function in a large sample of MS patients. METHODS: 137 patients participated in the study. Cognition was assessed by the "Brief Repeatable Battery of Neuropsychological Tests." T2-LL, normalized brain volume (global volume loss) and third ventricle width (regional volume loss) served as MRI markers. RESULTS: Both T2-LL and atrophy predicted worse cognition, with a stronger effect of T2-LL. Higher EA (as assessed by years of education) also predicted better cognition. Interactions showed that the negative effects of T2-LL and regional brain atrophy were moderated by EA. CONCLUSIONS: In a cohort with different stages of MS, higher EA attenuated the negative effects of white matter lesion burden and third ventricle width (suggestive of thalamic atrophy) on cognitive performance. Actively enhancing cognitive reserve might thus be a means to reduce or prevent cognitive problems in MS in parallel to disease modifying drugs. PMID- 24475310 TI - Addition of immunosuppressive treatment to hemoperfusion is associated with improved survival after paraquat poisoning: a nationwide study. AB - Paraquat poisoning associates very high mortality rate. Early treatment with hemoperfusion is strongly suggested by animal and human studies. Although the survival benefit of additional immunosuppressive treatment (IST) in combination with hemoperfusion is also reported since 1971, the large-scale randomized control trials to confirm the effects of IST is difficult to be executed. Therefore, we designed this nationwide large-scale population-based retrospective cohort study to investigate the outcome of paraquat poisoning with hemoperfusion and the additional effects of IST combined with hemoperfusion. This nationwide retrospective cohort study utilized data retrieved from the National Health Insurance Research Database (NHIRD) of Taiwan. A total of 1811 hospitalized patients with a diagnosis of paraquat poisoning who received hemoperfusion between 1997 and 2009 were enrolled. The mean age of all 1811 study subjects was 47.3 years. 70% was male. The overall survival rate was only 26.4%. Respiratory failure and renal failure were diagnosed in 56.2% and 36% patients. The average frequency of hemoperfusion was twice. IST was added in 42.2% patients. IST significantly increases survival rate (from 24.3% to 29.3%, P<0.001). The combined IST with methylprednisolone, cyclophosphamide and dexamethasone associates with the highest survival rate (48%, P<0.001). Moreover, patients younger than 45 years of age in the IST group had the best survival (41.0% vs. 33.7%, p<0.001). Our results support the use of IST with hemoperfusion for paraquat-poisoned patients. The best survival effect of IST is the combination of methylprednisolone, cyclophosphamide and daily dexamethasone, especially in patients with younger age. PMID- 24475311 TI - Enhancing genome-wide copy number variation identification by high density array CGH using diverse resources of pig breeds. AB - Copy number variations (CNVs) are important forms of genomic variation, and have attracted extensive attentions in humans as well as domestic animals. In the study, using a custom-designed 2.1 M array comparative genomic hybridization (aCGH), genome-wide CNVs were identified among 12 individuals from diverse pig breeds, including one Asian wild population, six Chinese indigenous breeds and two modern commercial breeds (Yorkshire and Landrace), with one individual of the other modern commercial breed, Duroc, as the reference. A total of 1,344 CNV regions (CNVRs) were identified, covering 47.79 Mb (~1.70%) of the pig genome. The length of these CNVRs ranged from 3.37 Kb to 1,319.0 Kb with a mean of 35.56 Kb and a median of 11.11 Kb. Compared with similar studies reported, most of the CNVRs (74.18%) were firstly identified in present study. In order to confirm these CNVRs, 21 CNVRs were randomly chosen to be validated by quantitative real time PCR (qPCR) and a high rate (85.71%) of confirmation was obtained. Functional annotation of CNVRs suggested that the identified CNVRs have important function, and may play an important role in phenotypic and production traits difference among various breeds. Our results are essential complementary to the CNV map in the pig genome, which will provide abundant genetic markers to investigate association studies between various phenotypes and CNVs in pigs. PMID- 24475312 TI - The effects of cadmium-zinc interactions on biochemical responses in tobacco seedlings and adult plants. AB - The objective of the present study was to investigate the effects of cadmium-zinc (Cd-Zn) interactions on their uptake, oxidative damage of cell macromolecules (lipids, proteins, DNA) and activities of antioxidative enzymes in tobacco seedlings as well as roots and leaves of adult plants. Seedlings and plants were exposed to Cd (10 uM and 15 uM) and Zn (25 uM and 50 uM) as well as their combinations (10 uM or 15 uM Cd with either 25 uM or 50 uM Zn). Measurement of metal accumulation exhibited that Zn had mostly positive effect on Cd uptake in roots and seedlings, while Cd had antagonistic effect on Zn uptake in leaves and roots. According to examined oxidative stress parameters, in seedlings and roots individual Cd treatments induced oxidative damage, which was less prominent in combined treatments, indicating that the presence of Zn alleviates oxidative stress. However, DNA damage found in seedlings, and lower glutathione reductase (GR) and superoxide dismutase (SOD) activity recorded in both seedlings and roots, after individual Zn treatments, indicate that Zn accumulation could impose toxic effects. In leaves, oxidative stress was found after exposure to Cd either alone or in combination with Zn, thus implying that in this tissue Zn did not have alleviating effects. In conclusion, results obtained in different tobacco tissues suggest tissue-dependent Cd-Zn interactions, which resulted in activation of different mechanisms involved in the protection against metal stress. PMID- 24475313 TI - Neural correlates of illusory line motion. AB - Illusory line motion (ILM) refers to a motion illusion in which a flash at one end of a bar prior to the bar's instantaneous presentation or removal results in the percept of motion. While some theories attribute the origin of ILM to attention or early perceptual mechanisms, others have proposed that ILM results from impletion mechanisms that reinterpret the static bar as one in motion. The current functional magnetic resonance imaging study examined participants while they made decisions about the direction of motion in which a bar appeared to be removed. Preceding the instantaneous removal of the bar with a flash at one end resulted in a motion percept away from the flash. If this flash and the bar's removal overlapped in time, it appeared that the bar was removed towards the flash (reverse ILM). Independent of the motion type, brain responses indicated activations in areas associated with motion (MT+), endogenous and exogenous attention (intraparietal sulcus, frontal eye fields, and ventral frontal cortex), and response selection (ACC). ILM was associated with lower percept scores and higher activations in ACC relative to real motion, but no differences in shape selective areas emerged. This pattern of brain activation is consistent with the attentional gradient model or bottom-up accounts of ILM in preference to impletion. PMID- 24475314 TI - Prognostic role of microRNA-221 in various human malignant neoplasms: a meta analysis of 20 related studies. AB - BACKGROUND: MicroRNA-221 (miR-221) has been shown to play an important role in cancer prognosis. In order to evaluate the predictive value of miR-221, we compiled the evidence from 20 eligible studies to perform a meta-analysis. DESIGN: All of relevant studies were identified by searching PubMed, Embase, and Web of Science, and were assessed by further quality evaluation. Pooled hazard ratios (HRs) with 95% confidence intervals (CIs) of total and stratified analyses, for overall survival (OS) and recurrence-free survival (RFS), were calculated to investigate the association between high miR-221 expression and cancer prognosis. RESULTS: We found that high miR-221 expression can predict a poor OS in malignant tumors (pooled HR = 1.55, P = 0.017) but has no significant association with RFS (pooled HR = 1.02, P = 0.942). Further in stratified analyses, high miR-221 expression was significantly associated with a poor OS in Asians (pooled HR = 2.04, P = 0.010) or serum/ plasma subgroup (pooled HR = 2.28, P<0.001), and even showed significantly poor OS (pooled HR = 1.80, P<0.001) and RFS (pooled HR = 2.43, P = 0.010) in hepatocellular carcinoma (HCC) subgroup, but was correlated to a favorable RFS in prostate cancer subgroup (pooled HR = 0.51, P = 0.004). CONCLUSIONS: Our findings demonstrate that miR-221 is more suitable to predict cancer prognosis in Asians, and it is a promising prognostic biomarker for HCC. The detection of miR-221 in serum or plasma samples may make it become an effective method for monitoring patients' prognosis and assessing therapeutic efficacy in the future. PMID- 24475316 TI - LIN-9 phosphorylation on threonine-96 is required for transcriptional activation of LIN-9 target genes and promotes cell cycle progression. AB - Cell cycle transitions are governed by the timely expression of cyclins, the activating subunits of Cyclin-dependent kinases (Cdks), which are responsible for the inactivation of the pocket proteins. Overexpression of cyclins promotes cell proliferation and cancer. Therefore, it is important to understand the mechanisms by which cyclins regulate the expression of cell cycle promoting genes including subsequent cyclins. LIN-9 and the pocket proteins p107 and p130 are members of the DREAM complex that in G0 represses cell cycle genes. Interestingly, little is know about the regulation and function of LIN-9 after phosphorylation of p107,p130 by Cyclin D/Cdk4 disassembles the DREAM complex in early G1. In this report, we demonstrate that cyclin E1/Cdk3 phosphorylates LIN-9 on Thr-96. Mutating Thr-96 to alanine inhibits activation of cyclins A2 and B1 promoters, whereas a phosphomimetic Asp mutant strongly activates their promoters and triggers accelerated entry into G2/M phase in 293T cells. Taken together, our data suggest a novel role for cyclin E1 beyond G1/S and into S/G2 phase, most likely by inducing the expression of subsequent cyclins A2 and B1 through LIN-9. PMID- 24475315 TI - Inclusion of CD80 in HSV targets the recombinant virus to PD-L1 on DCs and allows productive infection and robust immune responses. AB - CD80 plays a critical role in stimulation of T cells and subsequent control of infection. To investigate the effect of CD80 on HSV-1 infection, we constructed a recombinant HSV-1 virus that expresses two copies of the CD80 gene in place of the latency associated transcript (LAT). This mutant virus (HSV-CD80) expressed high levels of CD80 and had similar virus replication kinetics as control viruses in rabbit skin cells. In contrast to parental virus, this CD80 expressing recombinant virus replicated efficiently in immature dendritic cells (DCs). Additionally, the susceptibility of immature DCs to HSV-CD80 infection was mediated by CD80 binding to PD-L1 on DCs. This interaction also contributed to a significant increase in T cell activation. Taken together, these results suggest that inclusion of CD80 as a vaccine adjuvant may promote increased vaccine efficacy by enhancing the immune response directly and also indirectly by targeting to DC. PMID- 24475317 TI - A pre- and co-knockdown of RNAseT enzyme, Eri-1, enhances the efficiency of RNAi induced gene silencing in Caenorhabditis elegans. AB - BACKGROUND: The approach of RNAi mediated gene knockdown, employing exogenous dsRNA, is being beneficially exploited in various fields of functional genomics. The immense utility of the approach came to fore from studies with model system C. elegans, but quickly became applicable with varied research models ranging from in vitro to various in vivo systems. Previously, there have been reports on the refractoriness of the neuronal cells to RNAi mediated gene silencing following which several modulators like eri-1 and lin-15 were described in C. elegans which, when present, would negatively impact the gene knockdown. METHODOLOGY/PRINCIPAL FINDINGS: Taking a clue from these findings, we went on to screen hypothesis-driven- methodologies towards exploring the efficiency in the process of RNAi under various experimental conditions, wherein these genes would be knocked down preceding to, or concurrently with, the knocking down of a gene of interest. For determining the efficiency of gene knockdown, we chose to study visually stark phenotypes of uncoordinated movement, dumpy body morphology and blistered cuticle obtained by knocking down of genes unc-73, dpy-9 and bli-3 respectively, employing the RNAi-by-feeding protocol in model system C. elegans. CONCLUSIONS/SIGNIFICANCE: Our studies led to a very interesting outcome as the results reveal that amongst various methods tested, pre-incubation with eri-1 dsRNA synthesizing bacteria followed by co-incubation with eri-1 and gene-of interest dsRNA synthesizing bacteria leads to the most efficient gene silencing as observed by the analysis of marker phenotypes. This provides an approach for effectively employing RNAi induced gene silencing while working with different genetic backgrounds including transgenic and mutant strains. PMID- 24475318 TI - The impact of stressful life events on excessive alcohol consumption in the French population: findings from the GAZEL cohort study. AB - BACKGROUND: Major life changes may play a causative role in health through lifestyle factors, such as alcohol. The objective was to examine the impact of stressful life events on heavy alcohol consumption among French adults. METHODS: Trajectories of excessive alcohol consumption in 20,625 employees of the French national gas and electricity company for up to 5 years before and 5 years after an event, with annual measurements from 1992. We used repeated measures analysis of time series data indexed to events, employing generalized estimating equations. RESULTS: For women, excessive alcohol use increased before important purchase (p = 0.021), children leaving home (p<0.001), and death of loved ones (p = 0.03), and decreased before widowhood (p = 0.015); in the year straddling the event, increased consumption was observed for important purchase (p = 0.018) and retirement (p = 0.002); at the time of the event, consumption decreased for marriage (p = 0.002), divorce, widowhood, and death of loved one (all p<0.001), and increased for retirement (p = 0.035). For men, heavy alcohol consumption increased in the years up to and surrounding the death of loved ones, retirement, and important purchase (all p<0.001), and decreased after (all p<0.001, except death of loved one: p = 0.006); at the time of the event, consumption decreased for all events except for children leaving home and retirement, where we observed an increase (all p<0.001). For women and men, heavy alcohol consumption decreased prior to marriage and divorce and increased after (all p<0.001, except for women and marriage: p = 0.01). CONCLUSION: Stressful life events promote healthy and unhealthy alcohol consumption. Certain events impact alcohol intake temporarily while others have longer-term implications. Research should disentangle women's and men's distinct perceptions of events over time. PMID- 24475320 TI - Attrition in drug court research: Examining participant characteristics and recommendations for follow-up. AB - Drug court research is often challenged by study attrition. In this study, researchers attempted to predict study completion using variables traditionally associated with treatment attrition. Findings showed that participants who reported a need for additional help to resolve legal problems and who reported accessing outpatient treatments were more likely to complete the study at the three-month follow-up. The study also demonstrated a relationship between trauma related symptoms and study attrition. Although sample size was a limitation with these pilot data, researchers are urged to examine attrition and increase efforts to engage drug court enrollees in research studies, especially those with trauma related symptoms. PMID- 24475319 TI - Structural characterization of the mechanosensitive channel candidate MCA2 from Arabidopsis thaliana. AB - Mechanosensing in plants is thought to be governed by sensory complexes containing a Ca2+-permeable, mechanosensitive channel. The plasma membrane protein MCA1 and its paralog MCA2 from Arabidopsis thaliana are involved in mechanical stress-induced Ca2+ influx and are thus considered as candidates for such channels or their regulators. Both MCA1 and MCA2 were functionally expressed in Sf9 cells using a baculovirus system in order to elucidate their molecular natures. Because of the abundance of protein in these cells, MCA2 was chosen for purification. Purified MCA2 in a detergent-solubilized state formed a tetramer, which was confirmed by chemical cross-linking. Single-particle analysis of cryo electron microscope images was performed to depict the overall shape of the purified protein. The three-dimensional structure of MCA2 was reconstructed at a resolution of 26 A from 5,500 particles and appears to comprise a small transmembrane region and large cytoplasmic region. PMID- 24475321 TI - Long-term storage of endocrine tissues at - 80 degrees C does not adversely affect RNA quality or overall histomorphology. AB - BACKGROUND: Today, no consensus exists regarding how human tissues are best preserved for long-term storage. Very low temperature storage in liquid nitrogen is often advocated as the superlative method for extended periods, but storage in -80 degrees Celsius (-80 degrees C) freezers, while sometimes debated, is a possible alternative. RNA is the most easily degradable component of a biological sample in a molecular biology context and the quality can reliably be measured. AIM: To investigate to what extent long-term storage of tissues in -80 degrees C affects the RNA quality and overall histomorphology. The tissue storage period represents nearly three decades (1986-2013). METHODS: RNA extraction from 153 tissue samples with different storage periods was performed with the mirVana kit (Invitrogen). RNA integrity was assessed using an Agilent bioanalyzer to obtain RNA integrity numbers (RIN). Further, tissue representative testing using light microscopy was performed by two pathologists to assess tissue composition and morphology. RESULTS: RIN values were measured in all samples, showing a variability that did not correlate with the storage time of the tissues. Microscopically, all samples displayed acceptable tissue morphology regardless of storage time. CONCLUSION: Long-term storage in -80 degrees C does not adversely affect the quality of the RNA extracted from the stored tissues, and the tissue morphology is maintained to a good standard. PMID- 24475322 TI - Helicobacter hepaticus, a new pathogenic species of the Helicobacter genus: Similarities and differences with H. pylori. AB - Helicobacter hepaticus was discovered in 1992 as a cause of liver cancer in the A/JCr mouse model. In susceptible mice, infection by H. hepaticus causes chronic gastrointestinal inflammation leading to neoplasia. It can also cause morphological changes in breast-glands leading to neoplasm and adenocarcinoma in mouse models. Studies performed on humans have revealed that H. hepaticus may also be a human pathogen since infection by H. hepaticus can be associated with cholecystitis, cholelithiasis and gallbladder cancer. H. hepaticus is a close relative of H. pylori, but it lacks the major virulence factors of H. pylori including vacoulating cytotoxin A (VacA) and cytotoxin associated gene (cagA). Moreover, SabA, AlpA, and BabA, three important adhesin proteins of H. pylori, are absent in its genome. In contrast, the genome of H. hepaticus contains genes encoding some orthologus virulence factors of Campylobacter jejuni such as cytolethal distending toxin (CDT), and PebI adhesin factor. Other genes including 16S rRNA, 18 KDa immunogenic protein, and urease structural subunits are related to H. pylori. Its genome contains a small island consisting of 71 Kbp named HHGI1, which probably encodes a secretion system type IV (T4SS), and some other virulence factors. As far as the immunogenic antigens are concerned, the lipopolysaccharide (LPS) and flagellin of H. hepaticus are weak stimulants of the immune system, while pro-inflammatory responses are mainly induced by its lipoproteins and most likely by the peptidoglycan. Concerning the multidrug efflux pumps, a homologue of H. pylori TolC, HefA, has been observed in H. hepaticus which contributes to resistance to amoxicillin and bile acids. PMID- 24475323 TI - Antimicrobial susceptibility profiling and genomic diversity of Acinetobacter baumannii isolates: A study in western Iran. AB - BACKGROUND AND OBJECTIVE: Acinetobacter baumannii is an aerobic non-motile Gram negative bacterial pathogen that is resistant to most antibiotics. Carbapenems are the most common antibiotics for the treatment of infections caused by this pathogen. Mechanisms of antibiotic-resistance in A. baumannii are mainly mediated by efflux pumps-lactamases. The aim of this study was to determine antibiotic susceptibility, the possibility of existence of OXAs genes and fingerprinting by Pulsed-Field Gel Electrophoresis (PFGE) among clinical isolates of Acinetobacter collected from Kermanshah hospitals. MATERIALS AND METHODS: One hundred and four isolates were collected from patients attending Imam Reza, Taleghani and Imam Khomeini hospitals of Kermanshah (Iran). Isolates were identified by biochemical tests and API 20NE kit. The susceptibility to different antibiotics was assessed with Kirby-Bauer disk diffusion method. PCR was performed for detection of bla OXA-23, bla OXA-24, bla OXA-51 and bla OXA-58 beta-lactamase genes. Clonal relatedness was estimated by PFGE (with the restriction enzyme Apa I) and DNA patterns were analyzed by Gel compare II 6.5 software. RESULTS: All isolates showed high-level of resistance to imipenem, meropenem as well as to other antimicrobial agents, while no resistance to polymyxin B, colistin, tigecylcine and minocycline was observed. The bla OXA-23like and bla OXA-24 like were found among 77.9% and 19.2% of the isolates, respectively. All isolates were positive for bla OXA-51, but none produced any amplicon for bla OXA-58. PFGE genotype analysis suggested the existence of eight clones among the 104 strains [A (n = 35), B (n = 29), C (n = 19), D (n = 10), E (n = 4), F (n = 3), G (n = 3), H (n = 1)]. Clone A was the dominant clone in hospital settings particularly infection wards so that the isolates in this group, compared to the other clones, showed higher levels of resistance to antibiotics. CONCLUSION: The bla OXA-51-like and bla OXA-23like were the predominant mechanisms of resistance to imipenem in A. baumannii. A high prevalence of clone A, B and C in different parts of the healthcare system showed that hospitalized patients should be safeguarded to prevent the spread of these clones. Early recognition of the presence of carbapenem-resistant A. baumannii clones is useful for preventing their spread within the hospital environment. PMID- 24475324 TI - Prevalence of aac(6')-Ie-aph(2")-Ia resistance gene and its linkage to Tn5281 in Enterococcus faecalis and Enterococcus faecium isolates from Tabriz hospitals. AB - BACKGROUND AND OBJECTIVE: High-level gentamicin resistance (HLGR: MIC >= 500 ug/ml) in Enterococci is mediated by aminoglycoside modifying enzymes which is mainly encoded by aac(6')-Ie-aph(2")-Ia gene. The aim of this study was to evaluate the frequency of aac(6')-Ie-aph(2")-Ia gene in clinical isolates of Enterococcus facium and Enterococcus faecalis collected from hospitals in northwest of Iran. MATERIALS AND METHODS: In the present study a total of 111 enterococcus isolates were collected from 4 hospitals during a two year period (July 2009-August 2011). Bacterial identification and species determination were carried out by standard biochemical tests. Antimicrobial susceptibility was evaluated by Kirby Bauer disc diffusion method. MICs were determined by agar dilution method. The frequency of aac(6')-Ie-aph(2")-Ia gene in the isolates was determined by PCR. The carriage of resistance gene on Tn5281 transposon was identified by long PCR and dot-blot hybridization methods. RESULTS: Antibiotic susceptibility tests revealed that the highest resistance was against streptomycin (74.77%) and erythromycin (67.58%) whereas the highest susceptibility was observed to vancomycin (81.1%). 36 isolates (32.43%) were identified as HLGR, 34(94.44%) of them had resistant gene in their genome. Long PCR studies revealed that 88% of HLGR clinical isolates harboured Tn5281. The aac(6')-Ie-aph(2")-Ia resistance gene was present on Tn5281 transposon in all 32 isolates according to dot blot hybridization test. CONCLUSION: The results of this study indicated that aac(6')-Ie-aph(2")-Ia resistance gene is highly prevalent in gentamicin resistant isolates. Carriage of aac(6')-Ie-aph(2")-Ia resistance gene on Tn5281 transposable element suggests possible contribution of this transposone on dissemination of resistance gene among enterococcus isolates. PMID- 24475325 TI - Comparison of culture and real-time PCR for detection of Bordetella pertussis isolated from patients in Iran. AB - BACKGROUND AND OBJECTIVE: Due to contagiousness of pertussis, a rapid and sensitive method for diagnosis is required to initiate the treatment and interrupt its transmission. MATERIALS AND METHODS: To detect B. pertussis strains, we used two real-time PCR targeting IS481 and BP283 sequences and compared factors influencing culture and real-time PCR results. RESULTS: Totally, 779 specimens were collected from patients among which 11 (1.4%) were culture positive. Using IS481 and BP283 primers, 122 (15.6%) and 100 (12.8%) were diagnosed as infected specimens respectively. There were significant relationships between the real-time PCR method for diagnosis of B. pertussis and age, sex and vaccination of patients before sampling. CONCLUSION: The real-time PCR is superior and much more sensitive than culture for diagnosis of B. pertussis. However, the sensitivity was improved when both IS481 and BP283 were used. Correct sampling and transportation of specimen also improved the detection rate in our research. PMID- 24475326 TI - Screening of family members of patients with acute brucellosis in an endemic area of Iran. AB - BACKGROUND AND OBJECTIVES: Brucellosis is a zoonotic disease and it's still endemic in Iran. There are some reports regarding brucellosis infection in family members sharing same risk factors and remain unrecognized. However, few studies on the importance of family screening are available. We aimed to screen household members of index cases with acute brucellosis for detecting additional unrecognized cases in central province of Iran. PATIENTS AND METHODS: 163 family members of 50 index cases were enrolled in the study. Standard Tube Agglutination Test (STA) and 2-mercaptoethanol (2ME) agglutination were checked in all samples. A case with STA titer >= 1:80, 2-mercaptoethanol (2ME) agglutination >= 40 and compatible signs and symptoms was considered positive for brucellosis. RESULTS: 15 (9.2%) of family members were seropositive for Brucella agglutinin and among them, 8 (53.3%) were asymptomatic and 7 (46.7%) were symptomatic. STA titer ranged from 1:80 to 1:640 in seropositive members. 4 of the 15 seropositive cases who identified by screening came from one index case with 6 family members. All symptomatic seropositive cases treated for Brucella infection and recovered without any complications in 6 months follow up. CONCLUSION: On the basis of our data, family members of brucellosis patients are at risk of disease acquisition, and screening of household members provides an effective way for early diagnosis and prompt treatment. However cost benefit of screening should be evaluated to reach definite decision for the implementation of the screening as a nationwide program. PMID- 24475327 TI - Serotyping of Streptococcus pneumoniae isolated from Tehran by Multiplex PCR: Are serotypes of clinical and carrier isolates identical? AB - BACKGROUND AND OBJECTIVES: Streptococcus pneumoniae is the most common cause of invasive infections among both young children and elderly people. Common serotypes causing invasive diseases and the emergence of carriers of Streptococcus pneumoniae in Iran is not yet known. Past-vaccine surveillance studies of serotype prevalence patterns in Iran are necessary to monitor the epidemiology of Streptococcus pneumoniae. Because of variation of pneumococcal serotypes in different geographical regions, in this study we evaluated common serotypes causing pneumococcal infections and healthy carrier children in Tehran by Multiplex PCR. MATERIALS AND METHODS: A total of 150 nasopharyngeal swabs were collected from healthy children in Tehran between December 2011 and August a2012, and 100 clinical samples were collected. Identification was performed by biochemical and molecular tests. Serotyping was done by multiplex PCR. We designed primers based on the sequences available for the routine capsular types and combined them into six multiplex PCR. RESULTS: From 150 nasopharyngeal swabs, 40 isolates of Streptococcus pneumoniae were identified after identification tests. Thirty six clinical isolates were also detected among clinical samples. Four serotypes (19A, 6, 3, 23F) of S. pneumoniae accounted for 55.7% of both sets of strains isolated from nasal carriage and clinical samples. Serotype 19A was the most common serotype among both groups. CONCLUSION: The multiplex PCR approach was successfully adapted to identify serotypes from more than 91% of the isolates tested. Among S. pneumoniae isolates in Tehran, the most prevalent serotypes were similar among carriage and invasive isolates. Continued monitoring of common serotypes of Streptococcus pneumoniae is essential for future vaccine formulation in Iran. PMID- 24475328 TI - Isolation of Asian endemic and livestock associated clones of methicillin resistant Staphylococcus aureus from ocular samples in Northeastern Iran. AB - BACKGROUND AND OBJECTIVES: Methicillin Resistant Staphylococcus aureus (MRSA) strains are divided into Community Associated (CA-) and Hospital Associated (HA-) MRSA. These strains vary in antimicrobial resistance and pathogenicity. S. aureus is one of the most common microorganisms in ocular infections. This study was aimed to determine antimicrobial resistance patterns and genetic characteristics of MRSA strains isolated from ocular infections in Iran. MATERIAL AND METHODS: Out of 171 S. aureus strains isolated from various clinical samples during September-December 2011 at Mashhad Emam Reza Hospital, 3 were cultured from eye discharge samples. Antimicrobial resistance tests were performed with MIC and disk diffusion methods and also genetic evaluation was done with Staphylococcal Cassette Chromosome mec (SCCmec), Accessory Gene Regulator (agr) and Staphylococcal Protein A (spa) typing, Multi Locus Sequence Typing (MLST) and determination of toxin gene profile. RESULTS: All strains were MRSA and showed resistance to tetracycline, gentamicin and clindamycin too. Vancomycin, minocyclin and trimethoprim/sulfamethoxazole were effective on all ocular isolates. All isolates belonged to SCCmec IV type. MRSA1 belonged to ST239, CC8, Spa type t7688 and agrIII and had tst1 and hla toxin genes. MRSA2 belonged to ST239, CC8, Spa type t037 and agrI and had the hla toxin gene. Finally, MRSA3 belonged to ST291, CC398, Spa type t304, and agrI and had pvl and hla toxin genes. CONCLUSION: Phenotypic and genotypic evaluation of the isolated MRSA strains revealed that these strains belong to endemic Asian and livestock related clones that could reach from other body sites or environment to the eye of patients and developed ocular infection. PMID- 24475329 TI - Isolation of Shiga toxin-producing Escherichia coli from raw milk in Kermanshah, Iran. AB - BACKGROUND AND OBJECTIVES: Infectious diarrhoeal diseases are great problem throughout the world and are responsible for considerable morbidity and mortality. Shiga toxin-producing Escherichia coli (STEC) is a major cause of gastroenteritis that may be complicated by hemorrhagic colitis (HC) or the hemolytic uremic syndrome (HUS), which is the main cause of acute renal failure in children. Food-borne outbreaks associated with Shiga toxin-producing Escherichia coli have been well documented worldwide. The aim of this study was to investigate the prevalence of Shiga toxin-producing Escherichia coli (STEC) strains in raw milk samples. MATERIALS AND METHODS: Raw milk samples collected from various cow farms in Kermanshah, Iran during June - September 2009 were investigated for STEC using PCR targeting stx1 and stx2 and then eaeA. RESULTS: Of 206 samples, 36 (17.47%) were contaminated with STEC. STEC isolates harbored 56.41% and 43.59% stx 2 and stx 1 gene respectively. In antibiotic resistance test, all strains were sensitive to ceftazidime, cefepime, gentamicin, imipenem and ciprofloxacin. 23.08% of isolates were resistat to tetracycline, and 38.5% of them showed intermediate sensitvity to cephalothin. CONCLUSIONS: The high presence of STEC in raw milk confirms the important role of raw milk as putative vehicle of infection to human. Moreover, this study suggests that the development of antibiotic resistant STEC must be a major concern in Iran and more studies are needed to identify the prevalence of STEC in other food samples. PMID- 24475330 TI - In vitro comparison of antimicrobial activity of aqueous decoction of Coriandrum sativum, and Dentol Drop with chlorhexidine on Streptococcus mutans. AB - BACKGROUND AND OBJECTIVES: Dental caries is still remained as a major health problem. This problem has created a new interest to search for new antimicrobial agents from various sources including medicinal plants. Since limited data is available so far regarding the antibacterial effect of Coriandrum sativum seed and Dentol Drop against Streptococcus mutans, this study aims to assess this activity. MATERIALS AND METHODS: This experimental study was conducted in Shiraz University of Medical Sciences. In vitro comparison of antimicrobial activity of aqueous decoction of Coriandrum sativum seed and Dentol drop with chlorhexidine against Streptococcus mutans was evaluated using disk diffusion and broth microdilution assays. Positive and negative controls were considered. The data was statistically analyzed by applying Kruskal-Wallis and Tukey post-hoc test to compare the groups using SPSS software (version 17). RESULTS: Dentol drop showed a remarkable antibacterial activity, in comparison with chlorhexidine, against S. mutans in the disk diffusion (p value = 0.005), and broth microdilution assays (p value = 0.0001). Based on the results of this study, Coriandrum sativum seed did not posses any antibacterial property. CONCLUSION: Coriandrum sativum seed showed no anti-Streptococcus mutans activity. Dentol drop exhibited a remarkable antibacterial activity against S. mutans when tested in vitro. Dentol drop can be further studied as a preventive measure for dental caries. PMID- 24475331 TI - EspA-Intimin chimeric protein, a candidate vaccine against Escherichia coli O157:H7. AB - BACKGROUND AND OBJECTIVE: Enterohemorrhagic Escherichia coli (EHEC) O157:H7 is an important enteric pathogen in human causing bloody or nonbloody diarrhea, which may be complicated by hemolytic uremic syndrome (HUS). Cattle are an important reservoir of EHEC. This research aims at vaccination with a divalent chimer protein composed of EspA120 and Intimin 282 and its preventive effect of EHEC O157 colonization in mice rectal epithelium. MATERIALS AND METHODS: A divalent recombinant EspA-Intimin (EI) protein containing EspA120 and Intimin280 attached with a linker was amplified from a trivalent construct and cloned in pET-28a (+) vector. The immunization was conducted in mice after expression and purification of the recombinant EI (rEI). RESULTS: Mice subcutaneously immunized with rEI, elicited significant rEI specific serum IgG antibodies and showed significantly decreased E.coli O157:H7 shedding compared to the control group. CONCLUSION: The chimeric recombinant protein induced strong humoral response as well as protection against oral challenges with live E.coli O157:H7. PMID- 24475332 TI - Cloning of Vibrio cholerae outer membrane protein W in Pichia pastoris. AB - BACKGROUND AND OBJECTIVE: The outer membrane protein W (ompW) of Vibrio cholerae is involved in stimulating the immune response via induction of protective immunity. It also plays an important role in bacterial pathogenesis by increasing the adaptability of pathogenic strains. In this study we aimed to clone V. cholerae ompW gene in the strain X-33 of Pichia pastoris. MATERIALS AND METHODS: A gene encoding ompW was cloned into the Ppicza vector downstream of alcohol oxidase promoter. Then recombinant vector was transformed into the genome of the strain X-33 of P. pastoris. After growth of zeocin-resistant transformants, clones were selected and subsequently confirmed for cloning by PCR enzymatic digestion and sequencing. RESULTS: PCR, enzymatic digestion and sequencing showed that the ompW gene was correctly cloned into P. pastoris genome. CONCLUSION: Results of our study showed that the methylotrophic yeast P. pastoris can be considered as an appropriate host instead of mammalian and prokaryotic systems for cloning of ompW. As far as data show, this is the first time that ompW of V. cholera is cloned into the methylotrophic P. pastoris. PMID- 24475333 TI - Evaluation of a liquid-phase colorimetric method for rapid antibacterial susceptibility testing. AB - BACKGROUND AND OBJECTIVE: Early determination of antibacterial susceptibility increases the success of therapy, decreases unnecessary use of antibacterial agents and side-effects, and lowers the overall healthcare cost. MATERIALS AND METHODS: A rapid colorimetric method for antibacterial susceptibility testing named Qui-Sensitest (Inovative Biotechnology Organization, Istanbul, Turkey) was evaluated in this study. RESULTS: Qui-Sensitest proved to be a reliable rapid test for determining antibacterial susceptibility having an overall agreement of 97.6% with Kirby Bauer disk diffusion test results for enteric bacteria with 0.4% of major discrepancies and 2.0% of minor discrepancy. CONCLUSION: Since the test makes the results available in 3.5-6 hours, it can provide the means for choosing the right treatment regimen the same day the infectious agent is isolated. PMID- 24475334 TI - Isolation, identification and antimicrobial susceptibility of Pantoea (Enterobacter) agglomerans isolated from consumed powdered infant formula milk (PIF) in NICU ward: First report from Iran. AB - BACKGROUND AND OBJECTIVES: Pantoea agglomerans is a Gram-negative rod in the Enterobacteriaceae family. It is reported as both commensal and opportunistic pathogen of animals and humans. This organism is potential candidates as powdered infant milk formula-borne opportunistic pathogen. The aim of our study was to perform isolation, identification and antimicrobial susceptibility pattern of Pantoea (Enterobacter) agglomerans strains isolated from consumed powdered infant formula milk (PIF) in NICU ward. MATERIALS AND METHODS: A of total 125 powdered infant formula milk (PIF) samples were purchased from hospital drug stores between June 2011 to March 2012. P. agglomerans was isolated according to FDA method. For final confirmation, biochemical tests embedded in the API-20E system were used. The drug susceptibility test was performed using the disc diffusion method according to CLSI guidelines. RESULTS: Out of the 125 samples investigated, 8 (6.4%) samples were positive for P. agglomerans and these were uniformly susceptible to tigecycline, chloramphenicol, cefepime, levofloxacin, minocycline and colistin. Fifty percent of isolates were resistant to cefotaxime, moxifloxacin, cotrimoxazole and ticarcillin. CONCLUSION: Controlling the primary populations of P. agglomerans during the PIF production process and preventing post processing contamination, by using suitable microbiological guidelines, is accessible. Sanitary practices for the preparation of infant formula in both the home and hospitals should be carefully controlled. PMID- 24475335 TI - Seborrheic dermatitis due to Malassezia species in Ahvaz, Iran. AB - BACKGROUND AND OBJECTIVE: Seborrheic dermatitis (SD) is a frequent disorder of the skin that is distinguished by the development of erythematous patches and yellow-gray scales. It is a multifactor disease that requires predisposing factors for its progress. Presence of these factors leads to reproduction of opportunistic yeast Malassezia spp. The aim of the present study was to isolate and identify distribution of Malassezia species on the scalp of SD patients in Ahvaz using modified Dixons agar. MATERIALS AND METHODS: A total of 110 patients diagnosed with SD were sampled. The sampling was carried out by brushing the hair and collecting the dandruff in paper pockets. For identification of Malassezia species, the scalp scales were cultured in Dixons agar. A combination of different characteristics including yeast cell morphology, ability to grow on Sabouraud dextrose agar, catalase test and ability to utilize individual Tweens (20, 40, 60 & 80) were used for identification of species. RESULTS: Twenty-seven of 110 (24.5%) SD patients had positive cultures for Malassezia species of which 17 (63%) were male and 10 (37%) were female. The most commonly identified Malassezia species was M. globosa (40.7%) followed by M. pachydermatis (22.2%), M. furfur (11.1%) and M. restricta(7.4%) and Malassezia species (18.5%). CONCLUSION: Malassezia globosa was considered to be the most important orgaism involved in cases with Seborrheic dermatitisin this study. PMID- 24475336 TI - Herpes simplex virus encephalitis in hamadan, iran. AB - BACKGROUND AND OBJECTIVES: Encephalitis can cause a severe public health problem. The main aim of this research was to evaluate the medical laboratory results of patients with Herpes Simplex Virus (HSV) encephalitis. MATERIALS AND METHODS: Diagnosis of encephalitis for these patients was firstly based on a clinical profile for Herpes Simplex Encephalitis (HSE), plus either a detected HSV1&2-DNA by PCR in CSF or brain neuro-imaging results. RESULTS: Molecular testing on CSF showed that 15 patients (15%) had HSV infection, 5 patients (5%) had Varicella Zoster Virus (VZV) and one case was positive for Human Immunodeficiency Virus (HIV)-RNA in CSF. The cause of encephalitis in 79 out of 100 patients (79%) was unknown. The comparison of CSF analysis in HSV positives and negatives showed a significant increase of glucose and protein levels in HSV positives than negatives. The mortality rate was 46.6% (7/15) in patients with HSV encephalitis compared to 11.4% (10/85) in non-HSV encephalitis (P = 0.003). CONCLUSIONS: In the current study, 15% of cases were diagnosed as having HSV. PMID- 24475337 TI - Isolation and characterization of Leucine dehydrogenase from a thermophilic Citrobacter freundii JK-91strain Isolated from Jask Port. AB - BACKGROUND AND OBJECTIVES: Leucine dehydrogenase (LeuDH; EC 1.4.1.9) belongs to the amino acid dehydrogenase family and isused as a biocatalyst in medical and pharmaceutical industries (1). This study reported deals with the isolation and characterization of LeuDH from a thermophilic bacterium isolated from Jask Port in the Province of Hormozgan. MATERIALS AND METHODS: Aliquots of soil and water samples were cultured in LEU specific medium and thermophilc bacteria that exhibited LeuDH activity were isolated and characterized biochemically. The LeuDH was purified and characterized in regard to the effects of pH and temperature on the activity, as well as its molecular weight determination. RESULTS: A thermophilic bacterium, Citrobacter freundii strain JK-9 was identified and found to exhibit LeuDH activity. The enzyme characterization revealed that LeuDH exhibits higher activity at temperature range of 60 to 75 degrees C (optimum of 60 degrees C) and an optimum pH of activity at pH 10.5. The K m value of LeuDH is 1.2 mM, while its molecular weight is about 320 kDa, and consisted of eight subunits identical in molecular mass (40 kDa). CONCLUSION: Briefly, a thermostableLeuDH enzyme from a strain of C. freundii was isolated and characterized. Our data indicate that the C. freundii enzyme has potential for use in biotechnological applications. PMID- 24475338 TI - Cane molasses as a source of precursors in the bioproduction of tryptophan by Bacillus subtilis. AB - BACKGROUND AND OBJECTIVES: The essential amino acid L-tryptophan can be produced by a condensation reaction between indole and L-serine, catalyzed by B. subtilis with tryptophan synthase activity. Application of the tryptophan is widespread in the biotechnology domain and is sometimes added to feed products as a food fortifier. MATERIALS AND METHODS: The optimum concentration of the Iranian cane molasses was determined by measuring the amount of biomass after growth in 1 to 30 g/mL of molasses. The maximum amount of biomass was obtained in 10 g/mL molasses. Chromatographic methods, TLC and HPLC, were used to assay the amount of tryptophan produced in the presence of precursors of tryptophan production (indole and serine) and/or molasses. RESULTS: Our results indicate the importance of the Iranian cane molasses not only as carbon source, but also as a source of precursors for tryptophan production. CONCLUSION: This report evaluates the potential of cane molasses as an economical source for tryptophan production by B. subtilis, hence eliminating the requirement for additional serine and indole as precursors. PMID- 24475339 TI - The effect of gamma irradiation on astaxanthin synthetase encoding gene in two mutant strains of Phaffia rhodozyma. AB - BACKGROUND AND OBJECTIVES: Astaxanthin, an orange-red carotenoid pigment, acts as a protective agent against oxidative damage to cells in vivo. The astaxanthin synthetase gene (crtS) size consists of 3995 bp. This gene has been suggested to catalyse beta-carotene to astaxanthin in Phaffia rhodozyma. The aim of this research was to find any possible changes in this gene in two mutant strains, Gam1 and Gam2 (with high astaxanthin pigment production), previously created by gamma irradiation. MATERIALS AND METHODS: The astaxanthin synthetase gene sequence of Phaffia rhodozyma in the NCBI Gene bank was used to design primer. In Gam1, this gene was amplified using primers Asta F1, Asta R2, Asta F3, Asta R4. In Gam2, primers asta F1, asta R4 were used to amplify the gene. The amplified fragments were 8 sequenced using primers Asta F1, Asta R1, Asta F2, Asta R2, Asta F3, Asta R3 and Asta F4, Asta R4. Astaxanthin synthetase gene from two mutant strains, Gam1 and Gam2 were amplified using PCR. The amplified products were sequenced and aligned using the ClustalW software. CONCLUSION: The comparison of this gene showed 98% and 99% similarities between the reference sequence and Gam1 and Gam2 mutant strains, respectively, whereas the comparison of this gene in Gam1 and Gam2 mutant strains showed 97% similarity. However, the deduced proteins showed 78% and 83% between the reference protein obtained from the wild type and Gam1 and Gam2, respectively. This similarity was 75% between the mutant strains. PMID- 24475340 TI - Terrestrial actinomycetes from diverse locations of Uttarakhnad, India: Isolation and screening for their antibacterial activity. AB - BACKGROUND AND OBJECTIVE: Uttarakhand region is less explored, but possess a great biodiversity. This diversity can be explored for isolation and characterization of new actinomycetes strains for seeking antimicrobial molecules. It can therefore be predicted that novel bioactive metabolite producing actinomycetes can be discovered to combat multidrug resistant bacterial pathogens. MATERIALS AND METHODS: Variations in the viable count of actinomycetes were accessed in different altitudes. Actinomycetes were isolated, indentified and screened for their antibacterial activity. RESULTS: The highest viable counts of actinomycetes were recorded in valleys followed by mid hills and high hills. A total of 512 actinomycetes were isolated which were found to belong the 14 different genera of actinomycetes. Mainly the genus Streptomyces was dominant in all the soil samples. Out of 512 isolates recovered, 23.44% exhibited antibacterial activity against one or more tested bacterial pathogens. Of these 56.67% showed activity against Gram-positive bacteria, 26.67% against Gram negative bacteria while 16.67% showed broad spectrum activity. Isolate DV1S and GR9a-5 showed highest antibacterial properties against several multi-drug resistant bacterial pathogens and were identified using polyphasic approach. DV1S and GR9a-5 were found to be most closely related with S. massasporeus NBRC 12796(T) and Nocardia nova JCM 6044(T) respectively. CONCLUSION: The results of this study strongly support the idea that the viable count of actinomycetes varied greatly with altitude. The actinomycetes species isolated from valleys, mid hills and high hills possess significant capacity to produce compounds which are active against several drug resistant bacterial pathogens. PMID- 24475341 TI - Biodeterioration agents: Bacterial and fungal diversity dwelling in or on the pre historic rock-paints of Kabra-pahad, India. AB - BACKGROUND AND OBJECTIVES: In the last few decades, losses of our cultural heritage due to biodeteriorationare beinghighly recognized. From museum objects to rock monuments, the microbial biodeterioration agents are found to be the most destructive. Possibilities for proper preservative measure(s) are always more when it is only a monument, statue, museum article, or pre-historic art in any small subterranean cave. Nevertheless, preservation/protection of the footprints occupying a big area, lying scattered in a very negligible manner requires safeguard against several deterioration factors; right from various physical, chemical and biological agents which are indeed interrelated to each other. MATERIALS AND METHODS: In the present study, some microbial communities possibly responsible for deteriorating the rocks of Kabra-pahad, where the most famous pre historic rock paints of India prevail have been identified. The diversity of fungi and bacteria present in the stone crust of the infected areas has been studied by employing standard laboratory methods. RESULTS: The cultivated cultures confirmed total fifteen fungal species, among which Aspergillus group were the most dominant. Among bacteria, total 80 numbers of colonies were observed that dominated by two major groups; Micrococcus.spp and Staphylococcus spp. CONCLUSION: The pre-historic footprint in the form of rock paints in Kabra pahad of district Raigarh, Chhattisgarh, India is lying in a very deteriorated manner. In the present study, we have tried to identify few major deteriorating factors that are responsible for such degradation of our existing pre-historic footprints. PMID- 24475342 TI - Knowledge, skills and attitude of evidence-based medicine among obstetrics and gynaecology trainees: a questionnaire survey. AB - OBJECTIVES: To determine current evidence-based medicine skills and practice among trainees. DESIGN: Questionnaire study. SETTING: Electronic survey was sent to all obstetrics and gynaecology trainees in East Midlands South Deanery, and responses collected were anonymous. PARTICIPANTS: All obstetrics and gynaecology trainees in East Midland South Deanery. MAIN OUTCOME MEASURES: Self-reported attitude, skills and knowledge in various components of evidence-based medicine. RESULTS: 69 trainees were included in the study of which 35 responded. Among all respondents, almost 72% of trainees use non-evidence-based methods to find answers for their clinical questions, whereas only 18% use appropriate evidence based medicine practice for such queries. Just 35% of trainees have minimum skills of literature searching. Most of the trainees struggle to understand various components of evidence-based medicine. Nearly 80% of trainees do not have formal education or training with regard to evidence-based medicine. CONCLUSIONS: This study highlights the inadequacy of evidence-based medicine skills among trainees and urges that evidence-based medicine be incorporated in formal training along with specialty study modules. PMID- 24475343 TI - Severe inflammatory response and vasculitis leading to quadruple limb amputations. AB - A systemic inflammatory response causing multi-organ failure and requiring multiple amputations was refractory to all treatments except Anakinra, and the cause remains unclear. PMID- 24475344 TI - A rare case of submandibular abscess complicated by stroke. PMID- 24475345 TI - Are the pituitary gonadotrophins determinants of complete molar pregnancy? An investigation using the method of least squares. AB - OBJECTIVE: To look for a relationship between the maternal age-specific incidence of complete molar pregnancy and the age-specific mid-follicular levels of circulating follicle stimulating hormone and luteinizing hormone. DESIGN: Calculation of correlation coefficients between the incidence of complete mole and the circulating levels of follicle stimulating hormone and luteinizing hormone using the method of least squares. SETTING: England and Wales. PARTICIPANTS: All mothers between 23 and 49 years delivering in England and Wales between 2000 and 2009 inclusive and a sample of women between 23 and 49 years from Sheffield (1987). MAIN OUTCOME MEASURES: The bivariate correlation coefficients between the incidence of complete mole and the mid-follicular plasma levels of the pituitary gonadotrophins. RESULTS: Exponential correlation between the incidence of complete mole and mid-follicular plasma follicle stimulating hormone, r = 0.965, r (2 )= 0.932. Linear correlation between the incidence of complete mole and mid-follicular plasma luteinizing hormone, r = 0.972, r (2 )= 0.944. Multivariate exponential regression between the incidence of complete mole and the combination of follicle stimulating and luteinizing hormones. This does not improve the prediction of the incidence of complete mole and it shows that luteinizing hormone is not a significant predictor of the incidence of complete mole in the presence of follicle stimulating hormone. CONCLUSIONS: There is a strong positive exponential correlation between the maternal age-specific incidence of complete mole in England and Wales and the age-related mid follicular levels of follicle stimulating hormone in a sample of English women. PMID- 24475346 TI - Lumbar puncture, chronic fatigue syndrome and idiopathic intracranial hypertension: a cross-sectional study. AB - OBJECTIVE: Unsuspected idiopathic intracranial hypertension (IIH) is found in a significant minority of patients attending clinics with named headache syndromes, if it is specifically sought out. Chronic fatigue syndrome is frequently associated with headache. Could the same be true of chronic fatigue? Moreover, there are striking similarities between the two conditions. Could they be related? Attempting to answer these questions, we describe the results of a change in clinical practice aimed at capturing patients with chronic fatigue who might have IIH. DESIGN: Cross-sectional. SETTING: Hospital outpatient and radiology departments. PARTICIPANTS: Patients attending a specialist clinic with chronic fatigue syndrome and headache who had lumbar puncture to exclude raised intracranial pressure. MAIN OUTCOME MEASURES: Intracranial pressure measured at lumbar puncture and the effect on headache of cerebrospinal fluid drainage. RESULTS: Mean cerebrospinal fluid pressure was 19 cm H2O (range 12-41 cm H2O). Four patients fulfilled the criteria for IIH. Thirteen others did not have pressures high enough to diagnose IIH but still reported an improvement in headache after drainage of cerebrospinal fluid. Some patients also volunteered an improvement in other symptoms, including fatigue. No patient had any clinical signs of raised intracranial pressure. CONCLUSIONS: An unknown, but possibly substantial, minority of patients with chronic fatigue syndrome may actually have IIH. An unknown, but much larger, proportion of patients with chronic fatigue syndrome do not have IIH by current criteria but respond to lumbar puncture in the same way as patients who do. This suggests that the two conditions may be related. PMID- 24475347 TI - Examining the practice of generalist expertise: a qualitative study identifying constraints and solutions. AB - OBJECTIVES: Provision of person-centred generalist care is a core component of quality primary care systems. The World Health Organisation believes that a lack of generalist primary care is contributing to inefficiency, ineffectiveness and inequity in healthcare. In UK primary care, General Practitioners (GPs) are the largest group of practising generalists. Yet GPs fulfil multiple roles and the pressures of delivering these roles along with wider contextual changes create real challenges to generalist practice. Our study aimed to explore GP perceptions of enablers and constraints for expert generalist care, in order to identify what is needed to ensure health systems are designed to support the generalist role. DESIGN: Qualitative study in General Practice. SETTING: UK primary care. MAIN OUTCOME MEASURES: A qualitative study - interviews, surveys and focus groups with GPs and GP trainees. Data collection and analysis was informed by Normalisation Process Theory. DESIGN AND SETTING: Qualitative study in General Practice. We conducted interviews, surveys and focus groups with GPs and GP trainees based mainly, but not exclusively, in the UK. Data collection and analysis were informed by Normalization Process Theory. PARTICIPANTS: UK based GPs (interview and surveys); European GP trainees (focus groups). RESULTS: Our findings highlight key gaps in current training and service design which may limit development and implementation of expert generalist practice (EGP). These include the lack of a consistent and universal understanding of the distinct expertise of EGP, competing priorities inhibiting the delivery of EGP, lack of the consistent development of skills in interpretive practice and a lack of resources for monitoring EGP. CONCLUSIONS: WE DESCRIBE FOUR AREAS FOR CHANGE: Translating EGP, Priority setting for EGP, Trusting EGP and Identifying the impact of EGP. We outline proposals for work needed in each area to help enhance the expert generalist role. PMID- 24475348 TI - Obesity hypoventilation syndrome in obstructive sleep apnea patients in the United Arab Emirates: a retrospective cross-sectional study. AB - OBJECTIVES: To estimate the frequency of symptoms of obesity hypoventilation syndrome (OHS) in patients with obstructive sleep apnoea (OSA) and to evaluate comorbidities associated with OHS. DESIGN: Retrospective study based on patients' medical records and on further sleep tests performed in the study centre during the inclusion visit. SETTING: Respiratory Care Unit and Sleep Disorder Centre of the Zayed Military Hospital United Arab Emirates. PARTICIPANTS: All patients referred to the study centre for a suspicion of sleep-disordered breathing. MAIN OUTCOME MEASURES: Prevalence of OSA and OSA + OHS and comorbidities in patients with OSA and OHS. RESULTS: A total of 212 adult patients participated in the study. Of these, 107 patients (50.5% [43.8-57.1% CI 95%]) fulfilled diagnostic criteria for OSA, and the majority were men (79.4%). Among patients with OSA, 18 patients (16.8% [10.8-25.1% CI 95%]) fulfilled diagnostic criteria for OHS. In this group, women were more frequently affected than men (31.8% [7/22] vs. 12.9% [11/85], respectively; p = 0.03) and tended to be older than affected men, with a mean age of 55 +/- 10.6 years versus 46 +/- 13 for men. After adjustment for gender, OHS was significantly associated with hypertension (OR = 3.5; p = 0.03), diabetes mellitus (OR = 4.6; p = 0.02), ischaemic heart disease (OR = 5.1; p = 0.04) and pulmonary hypertension (OR = 16.1; p = 0.001). CONCLUSION: OHS is a common condition in obese patients in the UAE and is associated with an increased risk of cardiovascular comorbidities and diabetes. PMID- 24475350 TI - Medical treatment of pulmonary multidrug-resistant tuberculosis. AB - Treatment of multidrug-resistant tuberculosis (MDR-TB) is challenging because of the high toxicity of second-line drugs and the longer treatment duration required compared with drug-susceptible TB. The efficacy of treatment for MDR-TB is poorer than that for drug-susceptible TB. The selection of drugs in MDR-TB is based on previous treatment history, drug susceptibility results, and TB drug resistance patterns in the each region. Recent World Health Organization guidelines recommend the use of least 4 second-line drugs (a newer fluoroquinolone, an injectable agent, prothionamide, and cycloserine or para-aminosalicylic acid) in addition to pyrazinamide. The kanamycin is the initial choice of injectable durgs, and newer fluoroquinolones include levofloxacin and moxifloxacin. For MDR TB, especially cases that are extensively drug-resistant, group 5 drugs such as linezolid, clofazimine, and amoxicillin/clavulanate need to be included. New agents with novel mechanisms of action that can be given for shorter durations (9 12 months) for MDR-TB are under investigation. PMID- 24475349 TI - Diagnosis of pneumococcal pneumonia: current pitfalls and the way forward. AB - Streptococcus pneumoniae is the most common cause of community-acquired pneumonia. However, it can also asymptomatically colonize the upper respiratory tract. Because of the need to distinguish between S. pneumoniae that is simply colonizing the upper respiratory tract and S. pneumoniae that is causing pneumonia, accurate diagnosis of pneumococcal pneumonia is a challenging issue that still needs to be solved. Sputum Gram stains and culture are the first diagnostic step for identifying pneumococcal pneumonia and provide information on antibiotic susceptibility. However, these conventional methods are relatively slow and insensitive and show limited specificity. In the past decade, new diagnostic tools have been developed, particularly antigen (teichoic acid and capsular polysaccharides) and nucleic acid (ply, lytA, and Spn9802) detection assays. Use of the pneumococcal antigen detection methods along with biomarkers (C-reactive protein and procalcitonin) may enhance the specificity of diagnosis for pneumococcal pneumonia. This article provides an overview of current methods of diagnosing pneumococcal pneumonia and discusses new and future test methods that may provide the way forward for improving its diagnosis. PMID- 24475352 TI - Necrotizing fasciitis in three university hospitals in Korea: a change in causative microorganisms and risk factors of mortality during the last decade. AB - BACKGROUND: Necrotizing fasciitis is a life-threatening infectious disease with rapidly progressive involvement of the affected site. Because of the high mortality rate of this disease, early diagnosis, surgical exploration, and administration of appropriate antibiotics are necessary. The present study aimed to further review the changes in the clinical and microbiological characteristics of necrotizing fasciitis using patients' medical records from consecutive databases of 3 hospitals in Korea. MATERIALS AND METHODS: In this study, we retrospectively reviewed the medical records of patients with necrotizing fasciitis who were clinically diagnosed between May 2001 and February 2012 in 3 university hospitals in Korea. In total, the data of 83 patients were analyzed, including those of 20 patients from our previous study in 2006. An organism found in a blood culture or surgical specimen was regarded as a causative organism. RESULTS: Of the 83 patients, 68(81.9%) had community-acquired infections. Ninety microorganism species were indentifed by culture. Streptococcus was the most commonly identified pathogen. Non-fermentative gram-negative bacteria and Candida species have recently emerged, especially in immunocompromised hosts. CONCLUSIONS: Gram-positive organisms are still the most common pathogens of necrotizing fasciitis. However in our study, various gram-negative bacteria with different levels of susceptibility to antibiotics, as well as Candida species, were responsible for the necrotizing fasciitis. Initial empirical antimicrobial agents for necrotizing fasciitis should be considered depending on the individual patient's condition. PMID- 24475351 TI - Influenza vaccines: unmet needs and recent developments. AB - Influenza is a worldwide public health concern. Since the introduction of trivalent influenza vaccine in 1978, vaccination has been the primary means of prevention and control of influenza. Current influenza vaccines have moderate efficacy, good safety, and acceptable tolerability; however, they have unsatisfactory efficacy in older adults, are dependent on egg supply for production, and are time-consuming to manufacture. This review outlines the unmet medical needs of current influenza vaccines. Recent developments in influenza vaccines are also described. PMID- 24475353 TI - A 2011-2012 survey of doctors' perceptions of korean guidelines and empirical treatment of community-acquired pneumonia. AB - BACKGROUND: The causative pathogens of and prevalence of antibiotic resistance in community-acquired pneumonia (CAP) varies across countries. We evaluated the patterns of antibiotic prescriptions for adult CAP patients, and physician satisfaction with the form and content of the 2009 Korean CAP treatment guidelines. MATERIALS AND METHODS: We designed an online survey for clinical physicians who treat CAP (infectious disease specialists, pulmonologists, and other physicians). We e-mailed the online survey to physicians and gathered results from December 2011 to January 2012, and then analyzed their responses. RESULTS: A total of 157 physicians responded to our survey: 61 (38.9%) infectious disease specialists, 33 (21.0%) pulmonologists, and 63 (40.1%) other physicians. Two-thirds (96/157, 61.2%) had positions in tertiary and secondary hospitals; the others (61, 38.8%) worked in primary clinics (hospitals and private clinics). One hundred and eight (68.8%) were aware of the Korean CAP clinical guidelines; of these, 98 (62.4%) applied the guidelines to their practice. Among physicians using them, 86.7% (85/98) reported the guidelines to be most useful for empirical selection of antibiotics, and 75.2% (118/157) said the guidelines were useful and satisfactory. Sixty-eight (43.3%) respondents indicated that they had not used aminoglycosides as an initial empirical CAP treatment, while 51 (32.5%) had combined aminoglycosides with other antibiotics to treat patients with CAP. Seventy-three (46.5%) physicians often combined macrolides with beta-lactam antibiotics for empirical treatment of CAP, and 21 (13.4%) reported using macrolide monotherapy (which is not recommended in the 2009 Korean CAP treatment guidelines) for CAP patients. The most commonly used beta-lactams were third generation cephalosporins (72, 45.9%) and ampicillin/sulbactam or amoxicillin/clavulanate (28, 17.8%). CONCLUSIONS: Some physicians remain unaware of the 2009 Korean treatment guidelines for CAP and do not use them in clinical practice. In addition, aminoglycoside combination therapy is frequently and inappropriately used in practice. In some cases, CAP is treated with macrolide monotherapy. Thus, the Korean CAP clinical guidelines must be more aggressively and continuously publicized. PMID- 24475354 TI - Clinical Impact of Cytochrome P450 2C19 Genotype on the Treatment of Invasive Aspergillosis under Routine Therapeutic Drug Monitoring of Voriconazole in a Korean Population. AB - BACKGROUND: Genetic polymorphisms of cytochrome P450 enzymes, especially CYP2C19 influence voriconazole pharmacokinetics. However, the impact of CYP2C19 genetic polymorphisms on the therapeutic efficacy and toxicity of voriconazole therapy are not well established. MATERIALS AND METHODS: In this prospective observational study, we analyzed all consecutive adult patients with hematologic diseases who were treated for invasive aspergillosis (IA) with voriconazole between January 2011 and June 2012. CYP2C19 genotype and routine therapeutic drug monitoring of voriconazole were performed. The target range for voriconazole trough levels was 1-5.5 mg/L. RESULTS: A total of 104 consecutive patients were enrolled, including 39 homozygous extensive metabolizers (EMs, 38%), 50 heterozygous extensive metabolizers (HEMs, 48%), and 15 poor metabolizers (PMs, 14%). The initial voriconazole trough levels were 1.8, 2.7, and 3.2 mg/L in EMs, HEMs, and PMs, respectively (P = 0.068). Out-of-range initial trough levels were most frequently observed in EMs (46%) followed by HEMs (26%) and PMs (0%) (P = 0.001). The frequency of initial trough levels < 1 mg/L but not > 5.5 mg/L differed significantly among the 3 groups (P = 0.005). However, treatment response, all-cause and IA-attributable mortality, and the occurrence of voriconazole-related adverse events did not differ significantly among the 3 groups (P = 0.399, P = 0.412, P = 0.317, and P = 0.518, respectively). CONCLUSIONS: While none of the initial voriconazole trough levels in PMs was outside the target range, subtherapeutic initial trough levels were frequent in EMs. Although there was no significant relationship between CYP2C19 genotype and either the clinical outcomes of IA or toxicity of voriconazole, further large scale multicenter studies using clinical data from homogeneous populations are required. PMID- 24475355 TI - Outcome of Antimicrobial Therapy of Pediatric Urinary Tract Infections Caused by Extended-Spectrum beta-Lactamase-Producing Enterobacteriaceae. AB - BACKGROUND: The purpose of this study was to compare the outcome of carbapenem versus non-carbapenem antimicrobial therapy for pediatric urinary tract infections (UTIs) caused by extended-spectrum beta-lactamase (ESBL) producing Enterobacteriaceae. MATERIALS AND METHODS: From 2006 to 2011, 42 episodes of UTI caused by ESBL-producing Enterobacteriaceae were diagnosed at Seoul National University Children's Hospital. Patients were grouped according to the antimicrobials they received into a carbapenem group and a non-carbapenem group. Medical records were retrospectively reviewed to assess treatment outcome, time to defervescence after initiation of treatment, and relapse rate. RESULTS: There were 36 children with 42 episodes of UTI caused by ESBL-producing Enterobacteriaceae. Twenty-seven cases (64%) had an underlying urologic disease, 28 (67%) cases were caused by Escherichia coli, and 14 (33%) cases were caused by Klebsiella pneumoniae. Four (10%) cases were treated with carbapenem, 23 cases (55%) were treated with non-carbapenem, and 15 (36%) cases were treated by switching from a carbapenem to a non-carbapenem and vice versa. There was no treatment failure at the time of antimicrobial discontinuation. Between the carbapenem and the non-carbapenem treatment groups, there were no significant differences in bacterial etiology (P = 0.59), time to defervescence after the initiation of antimicrobials (P = 0.28), and relapse rate (P = 0.50). In vitro susceptibility to non-carbapenem antimicrobials did not affect the time to defervescence after the initiation of antimicrobial treatment, and the relapse rate in the non-carbapenem group. CONCLUSIONS: This study found no significant difference in the treatment outcome between pediatric patients treated with carbapenem and those treated with non-carbapenem antimicrobials for UTI caused by ESBL-producing Enterobacteriaceae. Therefore, the initially administered non carbapenem can be maintained in UTI patients showing clinical improvement. PMID- 24475357 TI - High In Vitro Infectivity of a Doxycycline-Insensitive Strain of Orientia tsutsugamushi. AB - We compared the infectivity and growth rates of 12 strains of Orientia tsutsugamushi in a cell culture system. ECV304 cells were infected with O. tsutsugamushi strains for 4 hr, and the culture was maintained for 72 hr. Immunofluorescence (IF) staining was performed at 4, 24, 48, and 72 hr after inoculation (hpi), and IF-positive foci were enumerated. The AFSC-4 strain, which is known to be insensitive to doxycycline, showed higher numbers of IF-positive foci than the other 11 strains at 4, 24, 48, and 72 hpi, which may explain its apparent insensitivity to antibiotics. PMID- 24475356 TI - Incidence and risk factors for surgical site infection after gastric surgery: a multicenter prospective cohort study. AB - BACKGROUND: Surgical site infection (SSI) is a potentially morbid and costly complication of surgery. While gastrointestinal surgery is relatively common in Korea, few studies have evaluated SSI in the context of gastric surgery. Thus, we performed a prospective cohort study to determine the incidence and risk factors of SSI in Korean patients undergoing gastric surgery. MATERIALS AND METHODS: A prospective cohort study of 2,091 patients who underwent gastric surgery was performed in 10 hospitals with more than 500 beds (nine tertiary hospitals and one secondary hospital). Patients were recruited from an SSI surveillance program between June 1, 2010, and August 31, 2011 and followed up for 1 month after the operation. The criteria used to define SSI and a patient's risk index category were established according to the Centers for Disease Control and Prevention and the National Nosocomial Infection Surveillance System. We collected demographic data and potential perioperative risk factors including type and duration of the operation and physical status score in patients who developed SSIs based on a previous study protocol. RESULTS: A total of 71 SSIs (3.3%) were identified, with hospital rates varying from 0.0 - 15.7%. The results of multivariate analyses indicated that prolonged operation time (P = 0.002), use of a razor for preoperative hair removal (P = 0.010), and absence of laminar flow in the operating room (P = 0.024) were independent risk factors for SSI after gastric surgery. CONCLUSIONS: Longer operation times, razor use, and absence of laminar flow in operating rooms were independently associated with significant increased SSI risk after gastric surgery. PMID- 24475358 TI - Klebsiella pneumoniae associated extreme plasmacytosis. AB - Infection-associated plasmacytosis is not uncommon; however, marked plasmacytosis in both peripheral blood and bone marrow that mimicks plasma cell leukemia is a very rare condition. We encountered a case of extreme plasmacytosis associated with Klebsiella pneumoniae sepsis in an aplastic anemia patient. A 42-year-old man presented with high fever of 5 days' duration. Hematological analysis revealed severe neutropenia and thrombocytopenia; his white blood cell count was 900/mm(3), with 26% of plasma and plasmacytoid cells in peripheral blood. Bone marrow biopsy and aspiration showed 25% cellularity with marked plasmacytosis (80%), highly suggestive of plasma cell leukemia. On the eighth hospital day, K. pneumoniae was identified in blood and sputum cultures. Fever improved after switching antibiotics, although his hematological condition worsened. His bone marrow cellularity (plasma cell proportion) progressively decreased: the values were 25% (80%), 10% (26%), 10% (11%), and < 10% (< 4%) on the 8th, 30th, 60th, and 90th hospital day, respectively. His plasmacytosis was extremely severe but was confirmed to be reactive with polyclonality. The present case represents the first report of strong suspicion of K. pneumoniae sepsis-associated marked plasmacytosis in an aplastic anemia patient. PMID- 24475359 TI - A Case of Acute Pyogenic Sacroiliitis and Bacteremia Caused by Community-Acquired Methicillin-Resistant Staphylococcus aureus. AB - Pyogenic sacroiliitis is a rare osteoarticular infection, occurring most frequently in children and young adults. Diagnosis of the disease is challenging because of a general lack of awareness of the disease and its nonspecific signs and symptoms. Staphylococcus aureus is the most common causative bacteria in pyogenic sacroiliitis. Methicillin-resistant S. aureus (MRSA) has typically been considered a hospital-associated pathogen; however, community-acquired (CA)-MRSA infections are becoming increasingly common in Korea. We report the first domestic case of acute pyogenic sacroiliitis with abscess and bacteremia caused by CA-MRSA. The pathogen carried the type IV-A staphylococcal cassette chromosome mec (SCCmec) without the Panton-Valentine leukocidin (PVL) gene, and was identified as sequence type (ST) 72 by multilocus sequence typing. PMID- 24475360 TI - First Case of Bartonella henselae Bacteremia in Korea. AB - Bartonella henselae causes cat-scratch disease, bacteremia, and various focal infections. Despite the worldwide occurrence of B. henselae infections, reports in humans are rare in Korea. The clinical manifestation of all 5 previously reported cases was lymphadenopathy. Herein, we report a case of bacteremia in a woman who presented with prolonged fever. B. henselae was isolated from a blood specimen by cell culture. Conventional polymerase chain reaction amplification and sequencing of the 16S-23S rRNA intergenic space region confirmed the isolate to be B. henselae. The patient had no underlying immunocompromising conditions and no recent exposure to animals. She was successfully managed with a combination of doxycycline and hydroxychloroquine. PMID- 24475361 TI - Secondary Syphilis with Nodular Vasculitis Mimicking Behcet's Disease. AB - Although, erythema nodosum is a common skin manifestation associated with syphilis, nodular vasculitis is a rare feature. Here, we describe a case of a 22 year-old, human immunedeficiency virus negative, non-immunocompromised man who developed recurrent oral and scrotal ulcers with nodular lesions of the lower extremitie. Behcet's disease was initially suspected, however, his serologic test for syphilis was positive, and he was thus diagnosed with secondary syphilis, with a skin biopsy showing nodular vasculitis. The patient was treated with benzathine penicillin, and the skin lesions disappeared after treatment. PMID- 24475362 TI - The 2013 Clinical Guidelines for the Diagnosis and Treatment of HIV/AIDS in HIV Infected Koreans. AB - While a variety of clinical guidelines for the diagnosis and treatment of HIV/AIDS are used extensively around the world, the implementation of such guidelines is not assured in Korea due to constraints with respect to the diagnostic tests and antiretroviral drugs currently available in the country. Consequently, the Committee for Clinical Guidelines for the Diagnosis and Treatment of HIV/AIDS of the Korean Society for AIDS was founded in 2010, and the first edition of the Korean guidelines was published a year later. However, due to the rapid discovery of new data in the field of HIV and the evolution of the clinical environment in Korea in the last few years, it has become necessary to revise the first set of guidelines. This guideline aims to provide comprehensive information regarding the diagnosis and management of HIV/AIDS in Korea. The recommendations contain important information for physicians working with HIV/AIDS in the clinical field. A brief summary of the revised guidelines and key changes to the original version of the guidelines are summarized below. PMID- 24475363 TI - Analysis of Host Factor related to Patient's Mortality due to Viridans Streptococcal Bacteremia. PMID- 24475364 TI - Supports for health and social service providers from Canada responding to the disaster in haiti. AB - In January 12, 2010, a 7.0 magnitude earthquake shook Port-au-Prince, Haiti. The massive disaster made it difficult for local Haitian community officials to respond immediately, leaving the country reliant on foreign aid and international and non-governmental relief organizations. This study explores the effectiveness of various supports that were made available to health and social service providers in Haiti, by focusing on their lived experiences pre-deployment, on site and post-deployment. The paper provides a qualitative exploration of participant perceptions with respect to the success of their performance in response, and relevant literature describing the various supports provided to health and social service providers responding to disasters. METHODS: A single, semi-structured interview was conducted with Canadian health professionals (n=21) who deployed to Haiti during the time of, or after, the 2010 earthquake. The study uses Strauss and Corbin's structured approach to grounded theory to identify main themes and relationships in the interviews. RESULTS: The interviews indicate that training, and psychological and emotional supports for health and social service providers require improvement to enhance the experience and effectiveness of their work. CONCLUSIONS: Findings indicate that supports are most effective when they are tailored to the volunteers. The paper highlights future research stemming from the grounded theory findings. PMID- 24475365 TI - Integrating climate change adaptation into disaster risk reduction in urban contexts: perceptions and practice. AB - This paper analyses the perceptions of disaster risk reduction (DRR) practitioners concerning the on-going integration of climate change adaptation (CCA) into their practices in urban contexts in Nicaragua. Understanding their perceptions is important as this will provide information on how this integration can be improved. Exploring the perceptions of practitioners in Nicaragua is important as the country has a long history of disasters, and practitioners have been developing the current DRR planning framework for more than a decade. The analysis is based on semi-structured interviews designed to collect information about practitioners' understanding of: (a) CCA, (b) the current level of integration of CCA into DRR and urban planning, (c) the opportunities and constraints of this integration, and (d) the potential to adapt cities to climate change. The results revealed that practitioners' perception is that the integration of CCA into their practice is at an early stage, and that they need to improve their understanding of CCA in terms of a development issue. Three main constraints on improved integration were identified: (a) a recognized lack of understanding of CCA, (b) insufficient guidance on how to integrate it, and (c) the limited opportunities to integrate it into urban planning due to a lack of instruments and capacity in this field. Three opportunities were also identified: (a) practitioners' awareness of the need to integrate CCA into their practices, (b) the robust structure of the DRR planning framework in the country, which provides a suitable channel for facilitating integration, and (c) the fact that CCA is receiving more attention and financial and technical support from the international community. PMID- 24475366 TI - The national heatwave plan - a brief evaluation of issues for frontline health staff. AB - BACKGROUND: The adverse effects of heatwaves on mortality are well recognised. Heatwaves are predicted to become more frequent and severe in coming decades. England's National Heatwave Plan (NHP) aims to prepare the country for periods of extreme heat and thereby limit adverse health effects. The central aim of this study is to understand how effectively the NHP is disseminated within an acute hospital and to identify any barriers to its use. METHODS: Qualitative data was collected through semi-structured interviews and focus groups with key hospital managers, nurses and healthcare assistants. All participants were recruited from a single hospital in the South East of England. Data were analysed using Framework Analysis. RESULTS: We conducted two focus groups with frontline clinical staff and five interviews with senior managers, all of whom deemed the NHP a low priority. Hospital managers showed good awareness of the plan, which was lacking amongst frontline staff. Nevertheless front line staff were familiar with the dangers of excess heat and felt that they individualised care accordingly. Communication of information between managers and frontline staff was highlighted as a problem during heatwaves. Additionally, issues with inadequate building stock and equipment limited effective implementation of the plan. Participants were able to suggest novel improvements to the plan. CONCLUSIONS: Increased awareness and improved communication could help better integrate the NHP into the clinical practice of English hospital-based healthcare professionals. Further evaluation of the NHP in acute care trusts and other health care settings is warranted to expand upon these initial findings. PMID- 24475367 TI - Lost in translation: The biogenesis of non-LTR retrotransposon proteins. AB - "Young" APE-type non-LTR retrotransposons (non-LTRs) typically encode two open reading frames (ORFs 1 and 2). The shorter ORF1 translation product (ORF1p) comprises an RNA binding activity, thought to bind to non-LTR transcript RNA, protect against nuclease degradation and specify nuclear import of the ribonuclear protein complex (RNP). ORF2 encodes a multifunctional protein (ORF2p) comprising apurinic/apyrimidinic endonuclease (APE) and reverse-transcriptase (RT) activities, responsible for genome replication and re-integration into chromosomal DNA. However, some clades of APE-type non-LTRs only encode a single ORF-corresponding to the multifunctional ORF2p outlined above (and for simplicity referred-to as ORF2 below). The absence of an ORF1 correlates with the acquisition of a 2A oligopeptide translational recoding element (some 18-30 amino acids) into the N-terminal region of ORF2p. In the case of non-LTRs encoding two ORFs, the presence of ORF1 would necessarily downregulate the translation of ORF2. We argue that in the absence of an ORF1, 2A could provide the corresponding translational downregulation of ORF2. While multiple molecules of ORF1p are required to decorate the non-LTR transcript RNA in the cytoplasm, conceivably only a single molecule of ORF2p is required for target-primed reverse transcription/integration in the nucleus. Why would the translation of ORF2 need to be controlled by such mechanisms? An "excess" of ORF2p could result in disadvantageous levels of genome instability by, for example, enhancing short, interspersed, element (SINE) retrotransposition and the generation of processed pseudogenes. If so, the acquisition of mechanisms-such as 2A-to control ORF2p biogenesis would be advantageous. PMID- 24475368 TI - Analysis of horizontal genetic transfer in red algae in the post-genomics age. AB - The recently published genome of the unicellular red alga Porphyridium purpureum revealed a gene-rich, intron-poor species, which is surprising for a free-living mesophile. Of the 8,355 predicted protein-coding regions, up to 773 (9.3%) were implicated in horizontal genetic transfer (HGT) events involving other prokaryote and eukaryote lineages. A much smaller number, up to 174 (2.1%) showed unambiguous evidence of vertical inheritance. Together with other red algal genomes, nearly all published in 2013, these data provide an excellent platform for studying diverse aspects of algal biology and evolution. This novel information will help investigators test existing hypotheses about the impact of endosymbiosis and HGT on algal evolution and enable comparative analysis within a more-refined, hypothesis-driven framework that extends beyond HGT. Here we explore the impacts of this infusion of red algal genome data on addressing questions regarding the complex nature of algal evolution and highlight the need for scalable phylogenomic approaches to handle the forthcoming deluge of sequence information. PMID- 24475370 TI - Mobile Genetic Elements evolves. PMID- 24475369 TI - Continuing analysis of microRNA origins: Formation from transposable element insertions and noncoding RNA mutations. AB - MicroRNAs (miRs) are small noncoding RNAs that typically act as regulators of gene expression by base pairing with the 3' UTR of messenger RNAs (mRNAs) and either repressing their translation or initiating degradation. As of this writing over 24,500 distinct miRs have been identified, but the functions of the vast majority of these remain undescribed. This paper represents a summary of our in depth analysis of the genomic origins of miR loci, detailing the formation of 1,213 of the 7,321 recently identified miRs and thereby bringing the total number of miR loci with defined molecular origin to 3,605. Interestingly, our analyses also identify evidence for a second, novel mechanism of miR locus generation through describing the formation of 273 miR loci from mutations to other forms of noncoding RNAs. Importantly, several independent investigations of the genomic origins of miR loci have now supported the hypothesis that miR hairpins are formed by the adjacent genomic insertion of two complementary transposable elements (TEs) into opposing strands. While our results agree that subsequent transcription over such TE interfaces leads to the formation of the majority of functional miR loci, we now also find evidence suggesting that a subset of miR loci were actually formed by an alternative mechanism-point mutations in other structurally complex, noncoding RNAs (e.g., tRNAs and snoRNAs). PMID- 24475371 TI - Mitochondrial metabolism as a regulator of keratinocyte differentiation. AB - Mitochondrial metabolism has traditionally been thought of as a source of cellular energy in the form of ATP. The recent renaissance in the study of cellular metabolism, particularly in the cancer field, has highlighted the fact that mitochondria are also critical biosynthetic and signaling hubs, making these organelles key governors of cellular outcomes.1-5 Using the epidermis as a model system, our recent study looked into the role that mitochondrial metabolism and ROS production play in cellular differentiation in vivo.6 We showed that conditional deletion of the mitochondrial transcription factor, TFAM within the basal cells of the epidermis results in loss of mitochondrial ROS production and impairs epidermal differentiation and hair growth. We demonstrated that mitochondrial ROS generation is required for the propagation of Notch and beta catenin signals which promote epidermal differentiation and hair follicle development respectively. This study bolsters accumulating evidence that oxidative mitochondrial metabolism plays a causal role in cellular differentiation programs. It also provides insights into the role that mitochondrial oxidative signaling plays in a cell type-dependent manner. PMID- 24475372 TI - Variant-specific prion interactions: Complicating factors. AB - Prions are protein conformations that "self-seed" the misfolding of their non prion iso-forms into prion, often amyloid, conformations. The most famous prion is the mammalian PrP protein that in its prion form causes transmissible spongiform encephalopathy. Curiously there can be distinct conformational differences even between prions of the same protein propagated in the same host species. These are called prion strains or variants. For example, different PrP variants are faithfully transmitted during self-seeding and are associated with distinct disease characteristics. Variant-specific PrP prion differences include the length of the incubation period before the disease appears and the deposition of prion aggregates in distinct regions of the brain.1 Other more common neurodegenerative diseases (e.g., Alzheimer disease, Parkinson disease, type 2 diabetes and ALS) are likewise caused by the misfolding of a normal protein into a self-seeding aggregate.2-4 One of the most important unanswered questions is how the first prion-like seed arises de novo, resulting in the pathological cascade. PMID- 24475373 TI - Centrosomal AKAP350 modulates the G1/S transition. AB - AKAP350 (AKAP450/AKAP9/CG-NAP) is an A-kinase anchoring protein, which recruits multiple signaling proteins to the Golgi apparatus and the centrosomes. Several proteins recruited to the centrosomes by this scaffold participate in the regulation of the cell cycle. Previous studies indicated that AKAP350 participates in centrosome duplication. In the present study we specifically assessed the role of AKAP350 in the progression of the cell cycle. Our results showed that interference with AKAP350 expression inhibits G1/S transition, decreasing the initiation of both DNA synthesis and centrosome duplication. We identified an AKAP350 carboxyl-terminal domain (AKAP350CTD), which contained the centrosomal targeting domain of AKAP350 and induced the initiation of DNA synthesis. Nevertheless, AKAP350CTD expression did not induce centrosomal duplication. AKAP350CTD partially delocalized endogenous AKAP350 from the centrosomes, but increased the centrosomal levels of the cyclin-dependent kinase 2 (Cdk2). Accordingly, the expression of this AKAP350 domain increased the endogenous phosphorylation of nucleophosmin by Cdk2, which occurs at the G1/S transition and is a marker of the centrosomal activity of the cyclin E-Cdk2 complex. Cdk2 recruitment to the centrosomes is a necessary event for the development of the G1/S transition. Altogether, our results indicate that AKAP350 facilitates the initiation of DNA synthesis by scaffolding Cdk2 to the centrosomes, and enabling its specific activity at this organelle. Although this mechanism could also be involved in AKAP350-dependent modulation of centrosomal duplication, it is not sufficient to account for this process. PMID- 24475374 TI - NK-cell fratricide: Dynamic crosstalk between NK and cancer cells. AB - The intercellular transfer of plasma membrane patches, also known as trogocytosis, has a strong impact on the function and fate of immune cells. We have recently shown that natural killer (NK) cells undergo fratricide following the trogocytosis-mediated acquisition of tumor-derived NKG2D ligands. Malignant cells may therefore employ trogocytosis to escape NKG2D-mediated immune responses. PMID- 24475375 TI - Immune effectors required for the therapeutic activity of vorinostat. PMID- 24475376 TI - Regulatory T cells are redirected to kill glioblastoma by an EGFRvIII-targeted bispecific antibody. AB - Regulatory T cells (Tregs) play a central role in in tumor escape from immunosurveillance. We report that a bispecific T-cell engager (BiTE) targeting a mutated form of the epidermal growth factor receptor, i.e., EGFRvIII, potently redirects Tregs to kill glioblastoma through the granzyme-perforin pathway. PMID- 24475377 TI - Functions and Regulation of the PTEN Gene in Colorectal Cancer. AB - Phosphatase and TENsin homolog deleted on chromosome 10 (PTEN) is a tumor suppressor gene located at chromosome 10q23.31, encoding for a 403-amino acid protein that possesses both lipid and protein phosphatase activities. The main function of PTEN is to block the PI3K pathway by dephosphorylating phosphatidylinositol (PI) 3,4,5-triphosphate to PI-4,5-bisphosphate thus counteracting PI3K function. PTEN inactivation is a frequent event in many cancer types and can occur through various genetic alterations including point mutations, large chromosomal deletions, and epigenetic mechanisms. In colorectal cancer (CRC) PTEN is altered through mixed genetic/epigenetic mechanisms (typically: mutations and promoter hypermethylation or 10q23 LOH and promoter hypermethylation), which lead to the biallelic inactivation of the protein in 20 30% of cases. The role of PTEN as a prognostic and predictive factor in CRC has been addressed by relatively few works. This review is focused on the report and on the discussion of the studies investigating these aspects. Overall, at the moment, there are conflicting results and, therefore it has not been clarified whether PTEN might play a prognostic role in CRC. The same is valid also for the predictive role, leading to the fact that PTEN evaluation cannot be used in routinely diagnosis for the early identification of patients who might be addressed to the treatment with EGFR-targeted therapies, at odds with other genetic alterations belonging to EGFR-downstream pathways. The reason of discordant results may be attributable to several issues: (1) the size of the analyzed cohort, (2) patients inclusion criteria, (3) the methods of assessing PTEN alteration. In particular, there are no standardized methods to evaluate this marker, especially for immunohistochemistry, a technique suffering of intra and inter-observer variability due to the semi-quantitative character of such an analysis. In conclusion, much work, especially in large and homogeneous cohorts of cases from different laboratories, has to be done before the establishment of PTEN as prognostic or predictive marker in CRC. PMID- 24475378 TI - Journal of Nephropathology: A need of the hour. PMID- 24475379 TI - Short history about renal transplantation program in Iran and the world: Special focus on world kidney day. PMID- 24475380 TI - Minimizing potential resistance among bacteria causing urinary tract infection. PMID- 24475381 TI - Oxford classification of IgA nephropathy: Broadening the scope of the classification. PMID- 24475382 TI - Turmeric: Reemerging of a neglected Asian traditional remedy. AB - CONTEXT: Turmeric (Curcuma longa) is a wild plant of the ginger family native to tropical South Asia. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Emerging evidence indicate that turmeric/curcumin inhibits cytokines and TGF-beta production. From the various factors involved in the genesis of chronic kidney disease and pathogenesis of primary and secondary glomerulonehritis, TGF-beta has emerged as a key factor in the cascade of events. Leading to glomerulosclerosis, tubulointerstitial fibrosis and end-stage renal disease. CONCLUSIONS: considering the inhibitory effect of turmeric/curcumin on cytokines and TGF-beta, it seems wise to assume that supplementary turmeric/curcumin might be a candidate remedy for chronic kidney disease and possibly prevention of subsequent end stage renal disease. PMID- 24475383 TI - Nephro and neurotoxicity of calcineurin inhibitors and mechanisms of rejections: A review on tacrolimus and cyclosporin in organ transplantation. AB - CONTEXT: In the meadow of medical sciences substituting a diseased organ with a healthy one from another individual, dead or alive, to allow a human to stay alive could be consider as the most string event. In this article we review the history of transplantation, mechanisms of rejection, nephro-neurotoxicity of tacrolimus and cyclosporin in organ transplantations. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: The first reference to the concept of organ transplantation and replacement for therapeutic purposes appears to be to Hua-To (136 to 208 A.D), who replaced diseased organs with healthy ones in patients under analgesia induced with a mixture of Indian hemp. In 1936, the first human renal transplant performed by Voronoy in Russia. The first liver transplant in humans was performed on March 1, 1963 by Starzl in Denver, USA. Medawar was the first to assert that rejection was an immunological response, with the inflammatory reaction due to lymphocyte infiltration. Consequently, rational immunosuppressive therapies could inhibit deleterious T cell responses in an antigen specific manner. CONCLUSIONS: Searching related to the history of organ transplantation from mythic to modern times suggests that, to prevent graft rejection, minimize nephro and neuro toxicity monitoring of immunosupressive concentrations could provide an invaluable and essential aid in adjusting dosage to ensure adequate immunosuppression. PMID- 24475384 TI - Oxford-MEST classification in IgA nephropathy patients: A report from Iran. AB - BACKGROUND: There is a limited knowledge about the morphological features of IgA nephropathy (IgAN)in the middle east region. OBJECTIVES: The objective of this study was to evaluate the spectrum of histopathological findings in IgAN patients at our laboratory. PATIENTS AND METHODS: At this work, an observational study reported which was conducted on IgAN patients using the Oxford-MEST classification system. RESULTS: In this survey, of 102 patients 71.6 % were male. The mean age of the patients was 37.7 +/- 13.6 years. Morphologic variables of MEST classification was as follows; M1: 90.2 %, E: 32 %, S: 67 % also,T in grads I and II were in 30% and 19% respectively, while 51% were in grade zero. A significant difference was observed in segmental glomerulosclerosis (P=0.003) and interstitial fibrosis/tubular atrophy frequency distribution (P= 0.045), between males and females . Furthermore, it was found that mesangial hypercellularity was more prevalent in yonger patients. Moreover, there was a significant correlation between serum creatinine and crescents (P<0.001). There was also significant correlation of serum creatinine with segmental glomerulosclerosis (P<0.001). CONCLUSIONS: Higher prevalence of segmental glomerulosclerosis and interstitial fibrosis/ tubular atrophy, as the two of, four variables of Oxford-MEST classification of IgAN in male patients further attests that male gender is a risk factor in this disease.In this study the significant correlation between serum creatinine and crescent was in an agreement with previous studies and suggests for the probable accomodation of extracapillary proliferation as a new variable in MEST system. PMID- 24475385 TI - Alterations in antibiotic susceptibility of urinary tract infection pathogens. AB - BACKGROUND: Urinary tract infection (UTI) is the third most common infection in human. New resisted strains of uropathogens have been developed due to different factors such as widespread use of antibiothics. OBJECTIVES: We conducted this study to assess the recent pattern and susceptibility of uropathogens. MATERIALS AND METHODS: This descriptive cross-sectional study was carried on 32600 ambulatory patients' urine samples from six laboratories from 2008 to 2010 in Ahvaz, Khuzestan. Of those, 3000 positive culture were found. Data including underlying disease, pregnancy, catheterization and drug history were gathered by questionnaire. Susceptibility of pathogens to eight antimicrobial agents was determined. MATERIALS AND METHODS: This descriptive cross-sectional study was carried on 32600 ambulatory patients' urine samples from six laboratories from 2008 to 2010 in Ahvaz, Khuzestan. Of those, 3000 positive culture were found. Data including underlying disease, pregnancy, catheterization and drug history were gathered by questionnaire. Susceptibility of pathogens to eight antimicrobial agents was determined. RESULTS: Mean age of patients was 33.87 +/- 3.80 years and 84.9% of them were female. The results showed that, E. coli, Kelebsiella and Enterobacter were the most common pathogens (73.5%, 13.8% and 6.6%, respectively). E. coli was susceptible to Ciprofloxacin, Amikacin, and Nitrofurantoin in 76.9%, 76.4% and 76.1% of cases, respectively. Klebsiella was more susceptible to Ciprofloxacin, Ceftizoxim and Amikacin in 81.1%, 79.9% and 87.7% of positive cultures. Enterobacter was most susceptible to Ciprofloxacin (71.7%), but completely resistant to Ampicillin unexpectedly. CONCLUSIONS: E. coli and other isolates were more sensitive to Gentamicin, Amikacin and Ciprofloxacin compared to the other antibiotics tested and therefore these may be the drugs of choice for the empiric treatment of community-acquired UTI in our region. PMID- 24475387 TI - Deep vein thrombosis in combination with granulomatosis with polyangiitis (Wegener's). PMID- 24475388 TI - Malignant drug-induced rhabdomyolysis. PMID- 24475386 TI - Granulomatosis with polyangiitis (Wegener's) presenting as the right ventricular masses: A case report and review of the literature. AB - BACKGROUND: Granulomatosis with polyangiitis (Wegener's) is a systemic necrotizing vasculitis. Cardiac involvement in Wegener's has rarely been reported. In this study the echocardiographic findings of granulomatosis with polyangiitis (GPA) in a patient is described. CASE PRESENTATION: The case was a 45 years old man admitted to the hospital with a 3 months history of persistent fever and sinusitis. Mild left and right ventricular enlargements as well as three small masses in the right ventricular cavity were identified in echocardiography. One mass was attached to the tricuspid valve and the other two masses were attached to the right septum. Pulmonary artery hypertension (45mmHg) was also reported. The masses responded dramatically to plasma exchanges in combination with steroid therapy, followed by oral cyclophosphamid and low-dose steroid therapy. In the kidney biopsy, 8 out of 11 golomeruli contained fibrous crescents along with sclerotic lesions. Spleen has 140 mm diameter with multiple echo-free lesions and coarse parenchyma in abdominal ultrasound. Serum C ANCA=671, P-ANCA=1.7 (normal= up to 15U/mL). The diagnosis of granulomatosis with polyangiitis (Wegener's) was established. CONCLUSIONS: Presence of three small masses in right ventricular cavity and pulmonary artery hypertension in association with the spleen lesions were an uncommon presentation of GPA. GPA should be considered in the differential diagnosis of any nonspecific illnesses with cardiac involvement. PMID- 24475389 TI - The epidemic of pediatric chronic kidney disease: the danger of skepticism. PMID- 24475390 TI - Are acquired cystic kidney disease and autosomal dominant polycystic kidney disease risk factors for renal cell carcinoma in kidney transplant patients? PMID- 24475391 TI - The Global role of kidney transplantation. AB - World Kidney Day on March 8th 2012 provides a chance to reflect on the success of kidney transplantation as a therapy for end stage kidney disease that surpasses dialysis treatments both for the quality and quantity of life that it provides and for its cost effectiveness. Anything that is both cheaper and better, but is not actually the dominant therapy, must have other drawbacks that prevent replacement of all dialysis treatment by transplantation. The barriers to universal transplantation as the therapy for end stage kidney disease include the economic limitations which, in some countries place transplantation, appropriately, at a lower priority than public health fundamentals such as clean water, sanitation and vaccination. Even in high income countries the technical challenges of surgery and the consequences of immunosuppression restrict the number of suitable recipients, but the major finite restrictions on kidney transplantation rates are the shortage of donated organs and the limited medical, surgical and nursing workforces with the required expertise. These problems have solutions which involve the full range of societal, professional, governmental and political environments. World Kidney Day is a call to deliver transplantation therapy to the one million people a year who have a right to benefit. PMID- 24475392 TI - Collapsing focal segmental glomerulosclerosis: Increasing the awareness. AB - Collapsing focal segmental glomerulosclerosis (cFSGS), also known as collapsing glomerulopathy (CG) is of considerable interest for a variety of reasons. Its incidence is on the rise, and in many parts of the world, it has emerged as one of the leading causes of end-stage renal disease (ESRD). There is currently no specific treatment and the response to standard immunotherapeutic agents is poor. Majority of the cases have been reported from the western countries, but the lesion is also being increasingly recognized in the tropical regions. It is imperative to increase the awareness of the lesion among the pathologists and the nephrologists from the developing countries for its accurate diagnosis and appropriate prognostication. PMID- 24475393 TI - Erythropoietin; bright future and new hopes for an old drug. AB - Recent publications have suggested renoprotective actions for erythropoietin in certain models of acute kidney injury. In a study by Rafieian-Kopaei et al., the effects of erythropoietin on amelioration of gentamicin-induced renal toxicity was investigated and renoprotective effect for Eprex, an analogue of erythropoietin was shown when the drug was given in combination with gentamicin. There has also been a protective effect when the drug was applied after gentamicin administration. Thus, the drug was effective even after induction of tubular damage which opens a very valuable window for its therapeutic actions. However, there are still needs for studies on the mechanisms which are involved in these protective actions. PMID- 24475394 TI - Inhibition of gentamicin-induced renal tubular cell necrosis. AB - Gentamicin nephrotoxicity limit its usage against gram negative bacteria. Most researches showed that antioxidant agents improved gentamicin nephrotoxicity. According to these investigations oxidative stress play a central role in the mechanism of gentamicin induced nephrotoxicity. Recently Rafieian-Kopaei and colleagues showed that erythropoietin significantly ameliorated serum creatinine, blood urea nitrogen and tubal necrosis in gentamicin induced nephrotoxicity in rat. One of the advantages of this study is treatment of rats for 10 days by erythropoietin after inducing gentamicin nephrotoxicity and besides co- treatment of gentamicin and erythropoietin at 10 days simultaneously. They showed that erythropoietin improved significantly serum creatinine and blood urea nitrogen in gentamicin injected rats simultaneously and even after gentamicin nephrotoxicity induction. This study also showed that erythropoietin ameliorates histopathological injuries especially tubular cell necrosis that induced by gentamicin. Although the detailed renoprotective mechanisms of erythropoietin cannot be fully explained by this study but histological and biochemical results are satisfactory. PMID- 24475395 TI - Focal segmental glomerulosclerosis; collapsing variant. PMID- 24475396 TI - Detection of immunoglobulins and complement components in formalin fixed and paraffin embedded renal biopsy material by immunoflourescence technique. AB - BACKGROUND: The technique of direct immunoflourescence (IF) is essential in the accurate diagnosis of renal glomerular diseases. The optimal results are obtained when the procedure is done on fresh frozen tissue (IF-F). However, techniques are available for IF study on formalin fixed and paraffin embedded (FFPE) renal biopsy specimens with variable reported success rates. OBJECTIVES: We evaluated three such techniques on FFPE tissue and compared the results with those obtained by IF-F from the same patients. MATERIALS AND METHODS: Heat treatment with Tris buffer and citrate buffer, and pronase treatment of the FFPE material was carried out. Direct IF was done for renal panel immunoglobulins and complement components on all biopsies and the results were compared with the historical IF-F study. RESULTS: When compared to the IF-F, the immunoflourescence staining on the paraffin sections was less sensitive and less intense in all immune complex mediated renal diseases, but the diagnostic findings were detected in majority of the cases. CONCLUSIONS: In conclusion, it is possible to establish the diagnosis in most cases of immune complex-mediated glomerular diseases with IF on paraffin embedded tissue specimens. PMID- 24475397 TI - Acute kidney injury: A pediatric experience over 10 years at a tertiary care center. AB - BACKGROUND: The etiology of acute kidney injury (AKI) varies in different countries. In addition, the etiology of AKI in hospitalized children is multifactorial. The importance of diagnosing AKI is not only because of short term high morbidity and mortality rate, but also for its effect on developing chronic kidney disease. OBJECTIVES: we studied retrospectively AKIs of children who were hospitalized over 10 years in a University hospital. MATERIALS AND METHODS: A retrospective analysis of the medical recorded data of 180 children less than 18 years treated for AKI in Alzahra Hospital, Isfahan, Iran, were performed during the period of March 2001 to February 2011. For each patient, demographic and anthropometric data, laboratory data, electrocardiographic findings, ultrasound results, etiology of AKI and short-term outcomes were recorded. RESULTS: The male to female ratio was 1.57 to 1. Mean age was 5.28 +/- 6.3 (SD) years and the median was 1.8 years. The more frequent age group was children less than 2 years. The mortality rate was 22.2% (40 patients). The mortality was not correlated with age (p= 0.74). Renal replacement therapy was recommended for 62 patients (34.4%). Mean of the first and last glomerular filtration rate (GFR) were 18.33+/- 1.12 ml/min/1.73 m2 and 52.53 +/- 2.98 ml/min/1.73 m2, respectively. The most common urinary sediment finding in approximately 70% of the patients was either renal epithelial cell or renal cell cast. Increased kidney echogenicity was the most common ultrasound finding (48%). Using ANOVA regression analysis, the etiology of disease was the only predictor of mortality (p=0.0001). CONCLUSIONS: We concluded that the mortality is still high in AKI. Furthermore, the poor outcome (defined as low GFR) are higher among patients with low levels of first GFR and higher RIFLE score. PMID- 24475399 TI - Creatine monohydrate supplement induced interstitial nephritis. PMID- 24475398 TI - Erythropoietin ameliorates genetamicin-induced renal toxicity: A biochemical and histopathological study. AB - BACKGROUND: Investigations have attempted to modify the outcome of tubular injury by either ameliorating renal tubular damage or promoting tubular regeneration in the case of acute tubular necrosis. OBJECTIVES: We investigated the protective effect of Eprex an erythropoietin analogue on tubular injury induced by gentamicin (GM). MATERIALS AND METHODS: Forty male Wistar rats were randomly divided into four groups. In group 1,rats were served as a sham group. In group 2, rats were injected intraperitoneally with 100 mg/kg of GM for 10 consecutive days (positive control group) and then were sacrificed. In group 3, rats received GM for 10 days then Eprex 100U/kg was injected intraperitoneally for the next 10 days and then they were sacrificed at the day 20th. In group 4 rats were injected a combination of GM (80 mg/kg) and Eprex 100U/kg intraperitoneally for 10 days and then were sacrificed. RESULTS: The results indicated that, Eprex prevented the increase in serum creatinine (Cr) and blood urea nitrogen (BUN). The effect of Eprex on damage score, showed that co-administration of GM and Eprex (group 3 and 4) reduced the kidney tissue damage compared to positive control group (P<0.05). This result indicat that Eprex potentially can reduce or prevent the kidney tissue damage. CONCLUSIONS: Ameliorative effect of Eprex when the drug was given in combination with GM and also when the drug was applied after GM-induced tubular damage, revealed the renoprotective potency of Eprex. Eprex is a promising drug to prevent or attenuate tubular damage induced by GM or other nephrotoxic agents which act through the same mechanisms as gentamicin. PMID- 24475400 TI - Non-monetary renal transplantation: An old issue and a new look from Holy Quran. PMID- 24475401 TI - Paraoxonase enzyme activity and dyslipidemia in chronic kidney disease patients. PMID- 24475402 TI - Lipoprotein(a), type 2 diabetes and nephropathy; the mystery continues. PMID- 24475403 TI - Hypertension and renal failure with right arm pulse weakness in a 65 years old man. PMID- 24475404 TI - Dietary antioxidents and oxidative stress in predialysis chronic kidney disease patients. AB - CONTEXT: Dietary antioxidants are important in protecting against human diseases. Oxidative stress, a non- traditional risk factors of cardio-vascular disease is far more prevalent in chronic kidney disease (CKD) patients than in normal subjects. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Oxidative stress could be a consequence of an increase in reactive oxygen species as well as a decrease in antioxidant defenses. Among the important factors that can be involved in triggering oxidative stress is insufficient dietary intake of antioxidants. Malnourished CKD patients are reported to have more oxidative stress than well nourished ones. CONCLUSIONS: Moving beyond the importance of assessment of dietary protein and energy in pre dialysis CKD patients to the assessment of dietary antioxidants is of utmost importance to help combat enhanced oxidative stress levels in such patients. PMID- 24475406 TI - Is it or is it not a pathogenic mutation? Is it or is it not the podocyte? PMID- 24475405 TI - ACE insertion/deletion (I/D) polymorphism and diabetic nephropathy. AB - CONTEXT: Angiotensin converting enzyme (ACE) gene encodes ACE, a key component of renin angiotensin system (RAS), plays an important role in blood pressure homeostasis by generating the vasoconstrictor peptide angiotensin II. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: The presence of ACE insertion/deletion (I/D) polymorphism affects the plasma level of ACE. ACE DD genotype is associated with the highest systemic and renal ACE levels compared with the lowest ACE activity in carriers of II genotype. CONCLUSIONS: In this review focus has been performed on the study of ACE I/D polymorphism in various populations and its influence on the risk of onset and progression of diabetic nephropathy. Also, association between ACE I/D polymorphism and response to ACE inhibitor and angiotensin II receptor antagonists will be reviewed. Further, synergistic effect of this polymorphism and variants of some genes on the risk of development of diabetic nephropathy will be discussed. PMID- 24475407 TI - Mucormycosis and acute kidney injury. AB - Mucormycosis, although said to be less common than candidiasis and aspergillosis is becoming increasingly associated with many co-morbid conditions and immunosuppression. Renal involvement, rarely reported previously, has also been documented with increasing frequency in recent times in both diseased as well as apparently healthy individuals. The kidneys may be involved in disseminated disease or have an isolated involvement for unexplained reasons. The manifestations are very serious particularly in patients with bilateral renal mucormycosis who often develop acute kidney injury and usually have a fatal outcome. The diagnosis of the renal mucormycosis is based on renal histology sections of renal biopsy or nephrectomised kidneys. Imaging with computerised tomography with contrast is of tremendous help in early identification of these cases before histological diagnosis. Once diagnosis is established, prompt treatment with antifungal medication, including Amphotericin-B (and its lipid formulations) and posaconazole, and removal of infected tissue is necessary to save from otherwise fatal infection. PMID- 24475408 TI - The significance of HLA typing in transplantation. AB - Although genetic admixture has recently occurred among different ethnic groups with the increased rates of migration to big cities, information about HLA allele distribution in different ethnic groups in Iran may still be helpful to improve the selection of transplantation donor candidates from certain ethnic groups which are genetically closer to the recipient. Because the data reported by Einollahi et al. reflect a large HLA disparity among Iranian kidney recipients, any improvement could play a small yet important role in organ transplantation. PMID- 24475409 TI - Epidemiology of chronic kidney disease in children. PMID- 24475410 TI - Human leukocyte antigen variation among Iranian renal transplant recipients. AB - BACKGROUND: HLA typing analysis is important in renal transplant patients. OBJECTIVES: We made a plan to determine the most frequent HLA antigens in Iranian kidney transplant patients. PATIENTS AND METHODS: In a retrospective cross sectional study, HLA patterns were defined in 512 kidney transplant recipients (67% male and 33% female) from different transplant centers of Tehran, Iran between 2008 and 2011 by microcytotoxicity assay. RESULTS: The studies samples were of different ethnic groups of the Iranian kidney transplants. Considerable variations were observed in each HLA sub class. A2, A1, A3, A24 and A26 were the most frequent HLA-A antigens. Among HLA-B, the predominant antigens were B35; B13, B15, B13 and B18. The most frequent HLA-DR antigens were DR 4, DR11, DR1, DR3 and DR15. DQ1 showed the highest frequency and followed by DQ3 and DQ2. CONCLUSIONS: These results showed considerable heterogeneity in both HLA class I and class II antigens, which reflects recent admixture of this group with neighboring Middle East populations. PMID- 24475411 TI - Association between helicobacter pylori infection and body mass index, before and after eradication of infection in hemodialysis batients. AB - BACKGROUND: In dialysis patients, chronic infections have been associated with cachexia and anorexia. OBJECTIVES: This study was carried out to determine the association between Helicobacter pylori (HP) infection and body mass index (BMI) in hemodialysis (HD) patients. PATIENTS AND METHODS: Ninety eight patients were divided into two groups of negative (group 1) and positive (group 2), for HP. BMI of all patients was measured at the beginning and in group2 after six months following eradication of HP. Before dialysis, various paraclinical parameters were checked at the same intervals. RESULTS: Fifty-nine patients were enrolled in group 1 and 39 patients in group 2. The means of BMI in groups 1 and 2 were 23.4+/-3.7 and 25.8+/-4.4kg/m2, respectively. Prior to the study, there was no significant difference for BMI, duration of HD and paraclinic data between two groups. Group 2 took anti HP therapy and eradication occurred in 30 of them. In this group six months after eradication of HP, the BMI was significantly decreased from 25.02+/-4.4 to 24.4+/-4.0 kg/m2 (P = 0.001). Also six months following the eradication of HP, the mean of serum albumin level was significantly declined from 4.2 to 3.7 g/L (P<0.001). There was also significant decrease in cholesterol (P=0.001), blood urea nitrogen (P=0.005) and calcium (P=0.02). However, significant increase in hemoglobin level was also seen (P=0.03). CONCLUSIONS: The results of this study show that eradication of HP has an impact on BMI. The results need to be investigated with larger cases. PMID- 24475412 TI - Chronic kidney disease in children: A report from a tertiary care center over 11 years. AB - BACKGROUND: Chronic kidney disease (CKD) is an overwhelming illness in children. Considering the importance of CKD in pediatric age group, in addition to the racial and ethnic differences in prevalence and etiology of CKD, epidemiologic studies are recommended. The majority of the results regarding the incidence of CKD have been achieved from studies on hospitalized children. OBJECTIVES: This study evaluates the incidence and etiology of chronic renal failure (CRF) in children in a tertiary care center in Isfahan, the second large province of Iran. PATIENTS AND METHODS: A retrospective analysis of medical record data of children less than 19 years old, hospitalized for CKD at St Alzahra hospital, Isfahan, Iran, during the period of November 2001 until December 2011 was made. A total of 268 eligible cases were recruited. Patients were categorized into 5 groups according to glomerular filtration rate (GFR) and KDOQI guideline. RESULTS: Out of 268 patients, 144 patients were male (54%). The mean and median of age was 11.01+/- 0.39(SD) years and 12.5 years, respectively. Approximately 55% of patients had either systolic and/or diastolic hypertension. The most frequent etiology of CKD was glomerular diseases (34%) followed by reflux nephropathy (16.7%). Most patients (74.8%) had GFR less than 15 ml/min/m2, when diagnosed. Anemia was the most prevalent laboratory abnormality (85%). Small-size kidneys were seen in 65.8% of patients. Kidney replacement therapy (either hemo- or peritoneal dialysis) was applied for 72.3% of the patients. The transplantation rate average was 7.2 per million children population. The annual incidences of CKD (mostly advanced stages) were 5.52 per million population (PMP) and 16.8 per million children population, respectively. The all cause of mortality rate was 18.4%. Younger age was the only independent predictor of mortality (p=0.005). CONCLUSIONS: We concluded that glomerular diseases are the leading cause of CKD in our patients. In addition, the annual incidence of CKD is considerably high. PMID- 24475413 TI - Correlation between sacral ratio and primary enuresis. AB - BACKGROUND: Enuresis is defined as the repeated voiding of urine into clothes or bed at least twice a week for at least 3 consecutive months in a child who is at least 5 yr of age and has a high prevalence in school aged children. In primary enuresis (PE) children have never gained control over urination or has been dry for<6months. While in secondary enuresis children have developed incontinence after a period of at least 6 months of urinary control. OBJECTIVES: The aim of this study was to investigate a possible relation between PE and sacral ratio (SR) in 5-9 aged children. PATIENTS AND METHODS: 118 children with aged 5-9 year were enrolled in this case-control study. All them were divided into two aliquots groups of 59 patients. The case study (children with PE) and the control (children without PE) groups were matched in age and sex. SR based on antero posterior plain radiograms of pelvis was calculated. Results were then analyzed using Chi square and student t-test as appropriate. RESULTS: There were no significant differences between the two groups regarding age and gender. Mean SR in case and control group was 0.89 and 0.90, respectively. Moreover, there was no significant difference between the two groups (p=0.82). Only 1 child (1.6%) in case group showed abnormal SR while this was 7 children (11.9%) in the control group. CONCLUSIONS: This study showed that, there was no significant difference between children with PE and those without PE in terms of SR. However, multicenter and larger sample size is recommended for definite decision of this finding. PMID- 24475414 TI - An unusual cause of renal failure: Disseminated mucormycosis. PMID- 24475415 TI - A histopathological study of nephrotoxicity, hepatoxicity or testicular toxicity: Which one is the first observation as side effect of Cisplatin-induced toxicity in animal model? AB - BACKGROUND: Cisplatin (CP) is widely used in clinic to treat the solid tumors. However, CP is associated with some major side effects including nephrotoxicity, hepatoxicity, and testicular toxicity. OBJECTIVES: To found, which of the toxicities is the first side effect of CP. MATERIALS AND METHODS: we conducted a pilot research on 12 adult male Wistar rats. RESULTS: One week after CP administration, the induced toxicity was observed clearly in kidney tissue. The only abnormality that observed in testis tissue was very small degree of hyaline casts. However, no damage and other abnormality were detected in the liver tissue. CONCLUSIONS: According to these findings, in clinic, first special attention must be made on kidneys during chemotherapy with CP. However, the duration of experiment is suggested to be extended to obtain hepatoxicity or testicular toxicity model in experimental animal in laboratories. Moreover, different dose of CP should be used to study the first side effect in animal model. PMID- 24475416 TI - A renal variant of Fabry disease: A case with a novel Gal A hemizygote mutation. AB - BACKGROUND: Fabry disease is caused by an X-linked recessive inborn error of glycosphingolipid metabolism with deficient activity of a lysosomal enzyme, alpha galactosidase A (alpha-GalA). CASE PRESENTATION: A 46 year-old man with progressive kidney disease showed on kidney biopsy electron microscopic evidence of Fabry disease. The patient had no systemic manifestations of Fabry disease, despite residual alpha-GalA activity, therefore genetic testing was done by direct DNA sequencing, demonstrating a new GAL A gene mutation (C174G-exon 3). After three years of enzyme replacement therapy (agalsidase beta) treatment, a second biopsy was done. Although there was demonstrable clearance of intracellular inclusions, remarkable podocyte activation was evident. CONCLUSIONS: This report represents an unusual renal variant of Fabry disease and provides histologic data on long-term follow up after enzyme replacement therapy. PMID- 24475417 TI - Renal failure and submental lymphadenopathy in a 68 years old woman. PMID- 24475418 TI - Sudden onset of renal failure requiring dialysis associated with large B-cell lymphoma of colon. PMID- 24475419 TI - Psychological impact of chronic kidney disease among children and adolescents: Not rare and not benign. PMID- 24475420 TI - Prediction of diabetic nephropathy: The need for a sweet biomarker. PMID- 24475421 TI - Treatment of renal manifestations of ANCA-associated vasculitis. AB - CONTEXT: Vasculitis is a clinicopathological entity characterized by inflammation and necrosis of blood vessels. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Two major autoantigens for ANCA are myeloperoxidase (MPO) and proteinase 3 (PR3), which are proteins in the primary granules of neutrophils and in the lysosomes of monocytes. They are expressed in mature neutrophils of patients with ANCA, while absent in healthy subjects. CONCLUSIONS: The kidney is the most commonly affected vital organ in ANCA-associated vasculitis, and patient outcomes are largely determined by the severity of renal disease at diagnosis and by its response to treatment. PMID- 24475422 TI - Diabetic nephropathy and antioxidants. AB - CONTEXT: Oxidative stress has crucial role in pathogenesis of diabetic nephropathy (DN). Despite satisfactory results from antioxidant therapy in rodent, antioxidant therapy showed conflicting results in combat with DN in diabetic patients. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar,Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Treatment of DN in human are insufficient with rennin angiotensin system (RAS) blockers, so additional agent ought to combine with this management. Meanwhile based on DN pathogenesis and evidences in experimental and human researches, the antioxidants are the best candidate. New multi-property antioxidants may be improved human DN that show high power antioxidant capacity, long half-life time, high permeability to mitochondrion, improve body antioxidants enzymes activity and anti-inflammatory effects. CONCLUSIONS: Based on this review and our studies on diabetic rats, rosmarinic acid a multi-property antioxidant may be useful in DN patients, but of course, needs to be proven in clinical trials studies. PMID- 24475423 TI - Frequency and clinicopathological characteristics of variants of primary focal segmental glomerulosclerosis in adults presenting with nephrotic syndrome. AB - BACKGROUND: BACKGROUND: There is no information on the frequency and clinicopathological presentation of the variants of primary focal segmental glomerulosclerosis (FSGS) in adults presenting with idiopathic nephrotic syndrome (INS) in Pakistan. OBJECTIVES: The aim of this study was to determine the frequencies of different histologic variants of primary FSGS with INS at our center and to compare our findings with those published in literature. PATIENTS AND METHODS: All consecutive adults (>=18 years) with INS, and diagnosis of FSGS on renal biopsies, were included. Their clinicopathological features at the time of presentation were retrieved and compared among the variants. RESULTS: There were 120 (65.2%) males and 64 (34.8%) females. The mean age was 30.62+/-12.02 years. The mean 24-hr urinary protein excretion was 4.69+/-2.36 grams. Microscopic hematuria was found in 30 (16.3%) patients. The mean serum creatinine was 1.58+/-0.87 mg/dL. At presentation, 128 (69.6%) patients were normotensive, while 56 (30.4%) exhibited hypertension. FSGS, not otherwise specified (NOS) was the predominant variant, comprising 76.6% of all; collapsing variant comprised 12%, tip variant, 9.8%, perihilar, 1.1%, and cellular, 0.5%. The mean number of glomeruli involved by segmental scarring was 3.41+/-2.87 and there was significant difference among the variants (p= 0.001). Arteriolopathy was found in 23.4 % cases and fibrointimal thickening of arteries in 18.5%. Tubular atrophy and interstitial fibrosis (IF/TA) was noted in 93% of cases. There was no significant difference in vasculopathy and IF/TA among the variants. CONCLUSIONS: Collapsing variant was the second most common variant following NOS and these findings are different from other regional studies. PMID- 24475424 TI - Symmetric dimethyl arginine and N-acetyl-beta-D-glucosaminidase lysozimuria of proximal renal tubules as a target for nephrotoxicity in patients with rheumatoid arthritis treated with disease modifying antirheumatic drugs. AB - BACKGROUND: The aim of this study was to determine the effect of initial therapy with some disease modifying antirheumatic drugs (DMARDs) (Methotrexate and Ketoprofen) on glomerular and tubular integrity in patients with Rheumatoid arthritis (RA). OBJECTIVES: OBJECTIVES: To determine whether there is a change in clinical and laboratory indicators of renal function in course of the follow up of treatment and whether that change correlates with the dynamics of the quantity of enzymes excreted in urine and reactants of the acute phase. MATERIALS AND METHODS: Using colorimetric method for determination of NAG, samples of 70 participants were examined (35 RA patients treated with Ketoprofen only, 35 RA patients treated with combined use of Methotrexate and Ketoprofen). The follow up was 5 time-intervals in the course of 24 weeks. RESULTS: There was moderate correlation between NAG and microalbuminuria (r=0,34) in the group of patients treated with Ketoprofen only, while statistically significant correlation (r=0,21) was seen in group of patients with combined use of Methotrexate and Ketoprofen. NAG enzymuria in size, number of patients registered, and time of appearance were greater and appears earlier in the group with the combined use of Methotrexate and Ketoprofen compared with the mono-therapy with Ketoprofen. Mean urinary NAG induction was increasing with the concomitant use of Methotrexate and Ketoprofen. CONCLUSIONS: Methotrexate is more potent NAG inductor than Ketoprofen and provokes greater tubular enzymuria than Ketoprofen. PMID- 24475425 TI - Histological patterns of idiopathic steroid resistant nephrotic syndrome in Egyptian children: A single centre study. AB - BACKGROUND: BACKGROUND: Idiopathic steroid resistant nephrotic syndrome (ISRNS) represents about 10-20% of children with nephrotic syndrome with variable outcome. OBJECTIVES: To determine the histological patterns of ISRNS in Egyptian children and the histological details of the commonest types which might be the reason for the steroid resistance. PATIENTS AND METHODS: The study included 53 cases with ISRNS. Their renal biopsies were retrieved from the archive of Electron microscopy unit and pathology department, Ain Shams University Specialized Hospital (ASUSH) in the duration from 2005-2011. The biopsies were examined histologically, with immunohistochemistry, and by electron microscopy. RESULTS: They were 36 males (67.9%) and 17 females (32.1%), the age at diagnosis ranged from 1.5- 16 years with a mean of 6.71 years. Lower limb oedema was the commonest presentation (100%), haematuria was revealed in (17%) of cases. Histological examination showed three major patterns; Focal segmental glomerulosclerosis (FSGS) in 30.2%, minimal change glomerulopathy (MCG) in 24.5% and IgA nephropathy in 13.2 %. Mesangial hypercellularity was very common among MCG patients (85.3% +/-6.7). Tubulointerstitial inflammation and fibrosis were common among cases with IgA nephropathy (40.4% +/-11, 53.7% +/-8 respectively). CONCLUSIONS: ISRNS in Egyptian children could be attributed mainly to three major diseases (FSGS, MCG and IgA nephropathy). Mesangial hypercellularity and severe tubulointerstitial disease might be the major causes for steroid resistance in MCG and IgA nephropathy respectively. Renal biopsy with electron microscopy examination should be done for all children with nephrotic syndrome at first time of presentation for proper assignment of treatment protocol. PMID- 24475426 TI - Effects of N-acetyl cysteine on serum lipoprotein (a) and proteinuria in type 2 diabetic patients. AB - BACKGROUND: About 30-40% of diabetic patients who developed nephropathy have lipoprotein disorders, especially lipoprotein a [Lp(a)], which is related to atherosclerosis. OBJECTIVES: The aim of this study was to investigate the effect of N-acetyl cysteine (NAC) on the serum levels of Lp(a) and amount of proteinuria in a group of type 2 diabetic patients with diabetic nephropathy. PATIENTS AND METHODS: A total of 40, type 2 diabetic (T2D) patients, patients with proteinuria, were randomly divided into two groups. The experimental group was treated by NAC (1200 mg/day) for two months in conjunction with conventional treatment for diabetes and hypertension. Control group received routine medications. RESULTS: No significant change was identified in serum Lp(a) during treatment with NAC (P >0.05). However, NAC decreased the amount of proteinuria, serum triglyceride (TG) level and systolic blood pressure in experimental group compared to the control group (P <0.05). CONCLUSIONS: These findings suggest that treatment with NAC has no significant effect on the serum level of Lp (a). However, it has beneficial effects on the reduction of proteinuria, serum TG level and systolic blood pressure in T2D patients with nephropathy. Further prospective studies are needed to determine its full role. PMID- 24475427 TI - Lipoprotein (a): More than a bystander in the etiology of hypertension? A study on essential hypertensive patients not yet on treatment. AB - BACKGROUND: Hypertension (HTN) is a very common disorder with a substantial impact on public health because of its complications. OBJECTIVES: To study the association of serum lipoprotein(a) [Lp(a)] elevation with essential hypertension (eHTN). PATIENTS AND METHODS: This study was conducted on a group of essential hypertensive patients. Laboratory exams consisting of serum creatinine and Lp(a) were measured. RESULTS: Ninety five essential hypertensive patients were enrolled to the study. Serum LP (a) in patients was 46.5+/-20. In patients an inverse correlation between serum Lp(a) andcreatinine clearance was seen (r = -0.175 p<0.05). There was a significant correlation between serum Lp(a) and age (r =0.191 p<0.05) or duration of HTN (known duration of hypertension period) (r =0.362 p<0.05). CONCLUSIONS: Our data suggest that Lp(a) may be involved as a cofactor in essential hypertension, with a mechanism that remains to be elucidated. PMID- 24475428 TI - Hidden face of lupus nephritis exposed: Isolated tubulointerstitial lupus nephritis. PMID- 24475429 TI - Antiphospholipid Syndrome: A complex disease. PMID- 24475430 TI - Tubulointerstitial lupus nephritis. AB - BACKGROUND: Isolated or predominant tubulointerstitial lupus nephritis is rare. CASE PRESENTATION: Here we report the case of a thirty eight years old male who was diagnosed with systemic lupus erythematosus (SLE) according to clinical and laboratory criteria and presented with impaired renal function and non nephrotic range proteinuria. Renal biopsy revealed normal glomeruli but interstitial momonuclear cell infiltration. Immunohiostochemistry (IHC) showed immune deposits in the tubular basement membranes (TBMs), and the peritubular capillary basement membranes (PTCBMs). He was started on high dose oral steroids, which were gradually tapered over one month. His renal functions improved over few days and normalized by the end of the first month of treatment. He was continued on low dose steroids and azathioprine with no evidence of relapse. CONCLUSIONS: Predominant tubulointerstitial lupus can occur, although rarely; and it runs a favorable course with good response to treatment. PMID- 24475431 TI - Antiphospholipid syndrome: A disease of protean face. AB - BACKGROUND: Antiphospholipid syndrome (APS) is a systemic disorder characterizes by recurrent arterial and venous thrombosis and/or pregnancy miscarriages and positive test for antiphospholipid antibodies. CASE: Here we report a 31 year-old female whose main complain was symmetrical motor polyneuropathy and hand muscular weakness over a long period of time. Her clinical picture became more complex by Mitral valve regurgitation and renal dysfunction. Finally with the diagnosis of APS glucocorticoid therapy was started and her renal dysfunction improved profoundly, however her cardiac valvular involvement and peripheral neuropathy remained. CONCLUSIONS: APS is a disease with wide clinical presentations and it continues to confound the clinicians. PMID- 24475432 TI - Dose kidney transplant nephrectomy stop disease progression in plasma exchange resistant post transplant hemolytic uremic syndrome? A case report. AB - BACKGROUND: Two different case reports, which have been published previously, suggested that bilateral nephrectomy can improve sever and refractory hemolytic uremic syndrome (HUS) in adults without a history of transplantation. At this study, kidney transplant nephrectomy in a patient with sever post transplant HUS was investigated. CASE: Patient was a 55 years old man with a single small size kidney and end-stage renal disease (ESRD). He had received a kidney from an unrelated donor three months before admission. The patient was admitted with fever and acute renal failure. Clinical and laboratory evaluation wereconsistent with sever De novo hemolytic uremic syndrome (HUS). Different therapeutic regimens administered in this patient including intensive plasma exchange, plasma infusion, empirical antibiotics, and high doses of corticosteroid. Although Cyclosporine was changed to Tacrolimus. After 45 days of treatment, patient's condition did not improve and sever thrombocytopenia (10000-15000/uL) developed. Patient was also suffered from severe hypersensitivity reaction (fever, chills, and itching) following each plasma exchange. Kidney transplant nephrectomy was done. However, sever post operativebleedingoccurred.HUS and thrombocytopenia did not improve and patient died two days after operation. CONCLUSIONS: According to this experience, Kidney transplant nephrectomy may not be an effective treatment and is not recommended in the treatment of severe and refractory post transplant HUS. PMID- 24475433 TI - Acute kidney injury: Global health alert. AB - Acute kidney injury (AKI) is increasingly prevalent in developing and developed countries and is associated with severe morbidity and mortality. Most etiologies of AKI can be prevented by interventions at the individual, community, regional and in-hospital levels. Effective measures must include community-wide efforts to increase an awareness of the devastating effects of AKI and provide guidance on preventive strategies, as well as early recognition and management. Efforts should be focused on minimizing causes of AKI, increasing awareness of the importance of serial measurements of serum creatinine in high risk patients, and documenting urine volume in acutely ill people to achieve early diagnosis; there is as yet no definitive role for alternative biomarkers. Protocols need to be developed to systematically manage prerenal conditions and specific infections. More accurate data about the true incidence and clinical impact of AKI will help to raise the importance of the disease in the community, increase awareness of AKI by governments, the public, general and family physicians and other health care professionals to help prevent the disease. Prevention is the key to avoid the heavy burden of mortality and morbidity associated with AKI. PMID- 24475434 TI - IgM nephropathy; can we still ignore it. AB - CONTEXT: IgM nephropathy (IgMN) is a relatively less recognized clinico immunopathological entity in the domain of glomerulonephritis , often thought to be a bridge between minimal change disease and focal segmental glomerulosclerosis. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science has been searched. RESULTS: IgM nephropathy can present as nephritic syndrome or less commonly with subnephrotic proteinuria or rarely hematuria. About 30% patients respond to steroids whereas others are steroid dependent / resistant. They should be given a trial of Rituximab or stem cell therapy. CONCLUSIONS: IgM nephropathy (IgMN) is an important and rather neglected pathology responsible for renal morbidity in children and adults in developing countries as compared to developed nations with incidence of 2-18.5% of native biopsies. Abnormal T-cell function with hyperfunctioning suppressor T-cells are believed to be responsible for this disease entity. Approximately one third of the patients are steroid responders where as the remaining two thirds are steroid resistant or dependent. Therapeutic trials including cell therapies targeting suppressor T-cells are required. PMID- 24475435 TI - Dermatological diseases in patients with chronic kidney disease. AB - CONTEXT: There are a variety of dermatological diseases that are more commonly seen in patients with chronic kidney disease (CKD) and renal transplants than the general population. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science has been searched. RESULTS: Some cutaneous diseases are clearly unique to this population. Of them, Lindsay's Nails, xerosis cutis, dryness of the skin, nephrogenic systemic fibrosis and acquired perforating dermatosis have been described in chronic kidney disease patients. The most common malignancy found in all transplant recipients is non-melanoma skin cancer. CONCLUSIONS: It is important for patients and physicians to recognize the manifestations of skin disease in patients suffering from chronic kidney disease to mitigate the morbidity associated with these conditions. PMID- 24475436 TI - Catastrophic antiphospholipid syndrome presented with sudden renal failure and history of long-lasting psychosis and hypertension in a 42 years old women. PMID- 24475437 TI - The NF-kappaB specific inhibitor DHMEQ prevents thrombus formation in a mouse model of antiphospholipid syndrome. AB - BACKGROUND: beta2-glycoprotein I (beta2GPI)-dependent antiphospholipid antibodies (aPLs) are considered to play a pivotal pathogenic role in antiphospholipid syndrome (APS) by inducing the expression of tissue factor, inflammatory cytokines, and chemokines, most of which are dependent upon the NF-kappaB pathway. Therefore, the NF-kappaB is regarded as a promising target for the development of a novel therapeutic strategy. However, progress has been limited owing to the fact that there are no widely-used in vivo models, or highly specific inhibitors. OBJECTIVE: This study aimed to test the effects of an NF kappaB-specific inhibitor, DHMEQ, in preventing thrombus formation using an original mouse model of APS. MATERIALS AND METHODS: Specificity of a monoclonal aPL WB-6 was examined by ELISA. WB-6 was injected into normal BALB/c mice with or without DHMEQ treatment. A pulse laser was radiated to a cutaneous vein in the window of a dorsal skinfold chamber attached to the mouse and thrombus formation was observed and recorded under a microscope. RESULTS: WB-6 bound preferentially to the caldiolipin (CL)-beta2GPI complex rather than to CL alone, or beta2GPI alone. WB-6, but not isotype-matched control antibody, induced a prothrombotic state in the mice by inducing tissue factor expression upon circulating monocytes, resulting in thrombus formation at the site of laser-induced endothelial injury. This diathesis was almost completely ameliorated by DHMEQ treatment. CONCLUSIONS: Inhibition of the NF-kappaB pathway is a promising strategy for the development of a novel treatment for APS. PMID- 24475438 TI - Candiduria in children and susceptibility patterns of recovered Candida species to antifungal drugs in Ahvaz. AB - BACKGROUND: Candiduria presents as an increasingly common nosocomial infection, which may involves urinary tract. Spectrum of disease is varying from asymptomatic candiduria to clinical sepsis. Disease is most commonly caused by Candida albicans. OBJECTIVES: The aim of the present study was to determine the frequency of candiduria in children attending Abuzar Pediatrics Hospital. PATIENTS AND METHODS: Urine samples were collected from 402 patients attending to the Abuzar Pediatrics Hospital, Ahvaz. 10ul of each urine sample was cultured on CHROMagar Candida plates and incubated at 37 degrees C. Ketoconazole, amphotericine B, clotrimazole, fluconazole, miconazole and nystatin disks were used for determination of susceptibility. RESULTS: In the present study, 402 patients with the age range <1-14 years were sampled (59.2% males and 40.8% females). Prevalence of Candida among enrolled patients was found to be 5.2% (71.4% males and 28.6% females). In our study C. albicans was identified in 19 cases as the most common yeast followed by nine C. glabrata and one C. krusei. Urine cultures were yielded more than 10000 CFU/ml in 14.3% of the cases followed by 600-10000 CFU/ml (28.5%) and 100-600 CFU/ml (57.2%). Antifungal susceptibility testing revealed that only one isolate of C. glabrata and seven isolates of C. albicans were resistant to nystatin and ketoconazole, respectively. However, all tested isolates were resistance to fluconazole. CONCLUSION: Asymptomatic candiduria is relatively more prevalent among children in Ahvaz and the most common agent is C. albicans. In addition, isolated Candida species were sensitive to use antifungals, with exception to fluconazole. PMID- 24475439 TI - Protective effect of selenium on cisplatin induced nephrotoxicity: A double-blind controlled randomized clinical trial. AB - BACKGROUND: Renal injury is common following cisplatin infusion. Some agents have been used to attenuate cisplatin nephrotoxicity. However, except hydration, none of them has been proved to be effective. OBJECTIVE: In this study selenium as an antioxidant supplement was tested on cisplatin induced renal injury. PATIENTS AND METHODS: 122 cancerous patients (85 male and 37 female; age range of 14 to 82 years old) were enrolled to receive chemotherapy regimens consisting cisplatin. They were allocated into two groups using a random number list . Investigators, patients and analyzers all, were blinded in allocation by using sealed opaque envelopes. Intervention group received a single 400 mcg selenium tablet and patients in control group took a placebo tablet which was similar with selenium preparation in color, weight, shape and taste. Primary end points were an increase in plasma creatinine above 1.5 mg/dl in men and 1.4mg/dl in women, or increase of plasma creatinine more than 50% from baseline or urine flow rate less than 0.5 ml/kg/h. Creatinine level was measured initially and on the 5th day after cisplatin therapy. RESULTS: There was no difference in cumulative dose of cisplatin between the groups (p=0.54). There were not evidences of acute renal failure (ARF) in cases. While, among placebo group, 7 patients had criteria of acute kidney injury. Conclusions :selenium could probably prevent cisplatin induced acute kidney injury, when it is added to hydration therapy in cancerous patients. PMID- 24475440 TI - Catastrophic antiphospholipid syndrome presenting with sudden renal failure: The lesson lies in vascular lesions. PMID- 24475442 TI - The first case of IgG4-related disease in Italy. AB - BACKGROUND: Recently, Mikulicz's disease has been defined as an IgG-4 related disease, a systemic condition, where the hallmark pathology findings are lymphoplasmacytic infiltrates, immunoglobulin (Ig)G4-positive plasma cells, modest tissue eosinophilia, and intense fibrosis. CASE: We present a case of 63 year-old man who showed epigastralgia and elevated serum lipase levels. Computed tomography of the abdomen revealed a bulky mass of the pancreas, so he underwent bilious-digestive anastomosis, and biopsy of the pancreas revealed massive infiltration of lymphocytes and plasma cells. The patient was therefore diagnosed with sclerosing chronic pancreatitis (Kuttner's tumour). After one year, the patient began to exhibit signs of "sicca syndrome", and at the same time, he demonstrated progressive renal failure. Immunological tests showed hypocomplementemia, and the renal biopsy specimen demonstrated interstitial inflammation, in which infiltrate was composed of lymphocytes, while infiltrating plasma cells showed immunoreactivity to IgG4. Sialography revealed severe involvement of the salivary glands, and Schirmer's test resulted positive. CONCLUSIONS: Here, we report successful treatment of the first case in Italy of a patient with hypocomplementemic tubulointerstitial nephritis in IgG4-related disease. PMID- 24475441 TI - Acute kidney injury with oxalate deposition in a patient with a high anion gap metabolic acidosis and a normal osmolal gap. AB - BACKGROUND: Ethylene glycol ingestion can lead to acute kidney injury from tubular deposition of oxalate crystals. The diagnosis of ethylene glycol intoxication is based on a history of ingestion, clinical examination, high anion gap metabolic acidosis, high osmolal gap, and a measured serum level of ethylene glycol. However, depending on the delay in time from ingestion to arrival to a hospital, the osmolal gap may become normal, thereby creating a confusing clinic picture for the treating clinician. CASE: A 71 year-old man with a history of alcohol abuse had been unconscious for an unknown period of time. Upon hospitalization, he was found to have a high anion gap metabolic acidosis but a normal serum osmolal gap and subsequently developed acute kidney injury. The serum lactic acid and glucose levels were unremarkable, and there were no ketones in the serum. Urine analysis showed numerous red blood cells and calcium oxalate crystals. The renal biopsy showed multiple oxalate crystals in the renal tubules demonstrating birefringence under polarized light. Given the history of alcohol abuse, the clinical presentation, the unexplained high anion gap metabolic acidosis, and the biopsy findings, ethylene glycol intoxication was deemed the most likely diagnosis. CONCLUSIONS: In cases of ethylene glycol intoxication, a high serum osmolal gap is supportive of ethylene glycol intoxication, but a normal serum osmolal gap does not exclude the diagnosis, especially when the time of ingestion is unknown. Physicians should be aware of potentially normal serum osmolal gap values in cases of ethylene glycol intoxication. PMID- 24475443 TI - R: Histological patterns of idiopathic steroid resistant nephrotic syndrome in Egyptian children: A single centre study. PMID- 24475444 TI - Plants antioxidants: From laboratory to clinic. AB - Implication for health policy/practice/research/medical education: Eating whole vegetables, fruits and grains, which all are rich in antioxidants, provides protection against most of oxidative stress induced diseases, however, this does not mean that antioxidants will prevent or fix the problem, especially not when they are taken out of their natural context. It should be noted that although the results of the studies are inconclusive, but most of the studies conducted till now have had limitations due to their relatively short duration and conducting on patients with existing diseases. PMID- 24475445 TI - Use of high-dose erythropoietin for repair after injury: A comparison of outcomes in heart and kidney. AB - CONTEXT: There is a need to define the exact benefits and contraindications of use of high-dose recombinant human erythropoietin (EPO) for its non-hematopoietic function as a cytokine that enhances tissue repair after injury. This review compares the outcomes from use of EPO in the injured heart and kidney, two organs that are thought, traditionally, to have intrinsically-different repair mechanisms. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Ongoing work by us on EPO protection of ischemia-reperfusion injured kidneys indicated, first, that EPO acutely enhanced kidney repair via anti-apoptotic, pro-regenerative mechanisms, and second, that EPO may promote chronic fibrosis in the long term. Work by others on the ischaemia-injured heart has also indicated that EPO promotes repair. Although myocardial infarcts are made up mostly of necrotic tissue, many publications state EPO is anti-apoptotic in the heart, as well as promoting healing via cell differentiation and stimulation of granulation tissue. In the case of the heart, promotion of fibrosis may be advantageous where an infarct has destroyed a zone of cardiomyocytes, but if EPO stimulates progressive fibrosis in the heart, this may promote cardiac failure. CONCLUSIONS: A major concern in relation to the use of EPO in a cytoprotective role is its stimulation of long-term inflammation and fibrosis. EPO usage for cytoprotection is undoubtedly advantageous, but it may need to be offset with an anti-inflammatory agent in some organs, like kidney and heart, where progression to chronic fibrosis after acute injury is often recorded. PMID- 24475446 TI - Prostaglandin D2 synthase: Apoptotic factor in alzheimer plasma, inducer of reactive oxygen species, inflammatory cytokines and dialysis dementia. AB - BACKGROUND: Apoptosis, reactive oxygen species (ROS) and inflammatory cytokines have all been implicated in the development of Alzheimer's disease (AD). OBJECTIVES: The present study identifies the apoptotic factor that was responsible for the fourfold increase in apoptotic rates that we previously noted when pig proximal tubule, LLC-PK1, cells were exposed to AD plasma as compared to plasma from normal controls and multi-infarct dementia. PATIENTS AND METHODS: The apoptotic factor was isolated from AD urine and identified as lipocalin-type prostaglandin D2 synthase (L-PGDS). L-PGDS was found to be the major apoptotic factor in AD plasma as determined by inhibition of apoptosis approximating control levels by the cyclo-oxygenase (COX) 2 inhibitor, NS398, and the antibody to L-PGDS. Blood levels of L-PGDS, however, were not elevated in AD. We now demonstrate a receptor-mediated uptake of L-PGDS in PC12 neuronal cells that was time, dose and temperature-dependent and was saturable by competition with cold L PGDS and albumin. Further proof of this endocytosis was provided by an electron microscopic study of gold labeled L-PGDS and immunofluorescence with Alexa labeled L-PGDS. RESULTS: The recombinant L-PGDS and wild type (WT) L-PGDS increased ROS but only the WTL-PGDS increased IL6 and TNFalpha, suggesting that differences in glycosylation of L-PGDS in AD was responsible for this discrepancy. CONCLUSIONS: These data collectively suggest that L-PGDS might play an important role in the development of dementia in patients on dialysis and of AD. PMID- 24475448 TI - Correlation of immunostaining findings with demographic data and variables of Oxford classification in IgA nephropathy. AB - BACKGROUND: Oxford classification for IgA nephropathy (IgAN) did not include pattern of immunostaining in the analysis. OBJECTIVE: The aim of this study is to determine the potential correlation between the immunostaining data and morphologic variables of Oxford classification (MEST) and various clinical and demographic data of patients with IgAN. PATIENTS AND METHODS: The pathologic diagnosis of IgAN requires the demonstration of IgA-dominant mesangial or mesangio-capillary immune deposits through immunofluorescence (IF) microscopy. The immune deposits were semiquantitatively assessed as 0 to 3+ positive bright. These were correlated with various clinical, demographic and histological variables of Oxford classification. RESULTS: A total of 114 biopsies were enrolled to the study (70.2% were male). Mean age of the patients was 37.7 +/- 13.6 years. This study showed that, only C3 deposits had a significant correlation with serum creatinine. Other antibodies (IgA, IgM and IgG) had no significant association with serum creatinine. This study also showed that IgA deposition score had significant positive association with endocapillary proliferation (E) and segmental glomerulosclerosis (S) variables of Oxford classification. Moreover, IgM deposition score had positive association with S variable. There was no significant association of IgG deposition score with four morphologic variables of Oxford classification. There was significant association of C3 deposition score with S and E variables too. CONCLUSIONS: The significant relationships of IgA and C3 deposits with some of the Oxford variables need more attention. We propose to further investigate this aspect of IgAN disease. PMID- 24475447 TI - Prevalence of anti- beta2GPI antibodies and their isotypes in patients with renal diseases and clinical suspicion of antiphospholipid syndrome. AB - BACKGROUND: Antiphospholipid antibodies (aPL) are autoantibodies that are associated with a clinical state of hypercoagulability and diverse clinical manifestations collectively known as antiphospholipid syndrome (APS). OBJECTIVES: To investigate the prevalence of anti-beta2glycoproteinI-antibodies (anti beta2GPI) and their isotypes in patients with renal diseases and clinical suspicion of antiphospholipid syndrome (APS). PATIENTS AND METHODS: This is a retrospective study in which we have analyzed the prevalence of anti-beta2GPI and its isotypes in 170 patients on initial testing and in 29 patients repeated after 12 weeks for confirmation of APS. The clinical information was provided by the treating physicians or retrieved from the clinical records. The tests for anti beta2GPI screening and its isotypes (IgG, IgM and IgA) detection were assessed. RESULTS: On initial samples, anti-beta2GPI was positive in 118patients. IgA beta2GPI positivity (93; 79%) was significantly higher than IgM and IgG isotypes. Out of anti-beta2GPI positive patients, clinical features in 95 patients were suggestive of APS or had SLE. Of these, IgA isotypes was found in 66% (P = 0.010), IgM in 31% (P = 0.033), and IgG in 11% (P = 0.033). On repeat testing, anti-beta2GPI was persistently found In 22 patients with a continual predominance of IgA-anti-beta2GPI over IgM and IgG isotypes (91% vs. 45.5% and 18% respectively). CONCLUSIONS: Our results show that IgA-anti-beta2GPI antibodies are the most prevalent isotypes in patients with renal disease or on renal replacement therapy in our population. Thus inclusion of IgA-anti-beta2GPI in the testing repertoire may increase the diagnostic sensitivity for APS in patients with renal diseases. PMID- 24475449 TI - Serum amyloid A renal amyloidosis in a chronic subcutaneous ("skin popping") heroin user. AB - BACKGROUND: Systemic AA amyloidosis is a long-term complication of several chronic inflammatory disorders. Organ damage results from the extracellular deposition of proteolytic fragments of the acute-phase reactant serum amyloid A (SAA) as amyloid fibrils. Drug users that inject drug by a subcutaneous route ("skin popping") have a higher chance of developing secondary amyloidosis. The kidneys, liver, and spleen are the main target organs of AA amyloid deposits. More than 90% of patients with renal amyloidosis will present with proteinuria, nephrotic syndrome, or renal function. CASE PRESENTATION: A 37 year-old female presented to the hospital with a one-week history of pain and redness in her right axilla. Her relevant medical history included multiple skin abscesses secondary to "skin popping", heroin abuse for 18 years, and hepatitis C. The physical examination revealed "skin popping" lesions, bilateral costovertebral angle tenderness, and bilateral knee swelling. The laboratory workup was significant for renal insufficiency with a serum creatinine of 5 mg/dL and 14.8 grams of urine protein per 1 gram of urine creatinine. The renal biopsy findings were consistent with a diagnosis of renal amyloidosis due to serum amyloid A deposition and acute tubulointerstitial nephritis. CONCLUSIONS: AA renal amyloidosis among heroin addicts seems to be associated with chronic suppurative skin infection secondary to "skin popping". It is postulated that the chronic immunologic stimulation by one or more exogenous antigens or multiple acute inflammatory episodes is an important factor in the pathogenesis of amyloidosis in these patients. Therefore, AA renal amyloidosis should always be considered in chronic heroin users presenting with proteinuria and renal impairment. PMID- 24475450 TI - Concurrent diabetic nephropathy and C1q nephropathy in a young male patient: The first report in literature. AB - BACKGROUND: C1q nephropathy (C1qN) is an uncommon glomerulopathy with a significant deposition of C1q in mesangium without clinical evidence of lupus.According to the best of our knowledge, there is not any report on coincidence of diabetes mellitus and C1qN. CASE PRESENTATION: In this report, we presented a 28 years-old-patient with type 1 diabetes and nephrotic range proteinuria, glomerular hematuria and C1q glomerulopathy in renal biopsy. CONCLUSIONS: According to the best of our knowledge, there is no previous report about the association between type 1 DM and C1qN. Prevalence of autoimmune disease is higher in type 1 DM and this may explain the relation between DM and C1qN in our patient. PMID- 24475451 TI - Cocaine-induced acute interstitial nephritis: A case report and review of the literature. AB - BACKGROUND: Acute tubular necrosis and pigment induced kidney injury are well described consequences of cocaine abuse. However, acute interstitial nephritis associated with cocaine use has been previously reported in only three patients. CASE PRESENTATION: We present the case of a 49-year-old man who developed acute kidney injury from biopsy-proven interstitial nephritis after nasal insufflation of cocaine. Unlike prior reports, our patient remained non-oliguric and did not require renal replacement therapy. CONCLUSIONS: Interstitial nephritis should be considered as a potential cause of acute kidney injury associated with cocaine use. The approach to management of cocaine associated acute kidney injury (AKI) may be different in patients with interstitial nephritis than for those with tubular necrosis or pigment induced renal injury. PMID- 24475452 TI - Significance of immunohistochemical findings in Oxford classification of IgA nephropathy: The need for more validation studies. AB - Implication for health policy/practice/research/medical education: Oxford classification of IgA nephropathy (IgAN) has been validated as clinically useful tool for prognostication of individual patients with IgAN. The original classification did not address the significance of immunostaining pattern in IgAN. A subsequent study by the same authors found immunostaining data to be potentially useful in predicting some of the morphological variables of Oxford classification. The study under discussion also addresses the potential significance of these ancillary data in refining the individual prognostication in this disease. Please cite this paper as: Mubarak M. Significance of immunohistochemical findings in Oxford classification of IgA nephropathy: The need for more validation studies. J Nephropathology. 2013; 2(3): 210-213. DOI: 10.5812/nephropathol.11089. PMID- 24475453 TI - Idiopathic membranous nephropathy and anti-phospholipase A2 receptor antibodies. PMID- 24475455 TI - A story of microalbuminuria and diabetic nephropathy. AB - CONTEXT: It is estimated that more than 346 million people worldwide have diabetes mellitus . By the year 2030, it is predicted that diabetes will become the seventh leading cause of death in the world. Development of chronic kidney disease (CKD) in patients with diabetes adds significantly to the morbidity and mortality and significantly increases health care costs, even before the development of end stage renal disease (ESRD). Evidence acquisitions: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Diabetic nephropathy (DN) is increasing rapidly worldwide. It is the leading cause of new cases of ESRD in the USA. Interestingly, although DN is the most common cause of ESRD in diabetic patients, diabetes mellitus is also an independent and strong risk factor for ESRD ascribed to causes other than DN (e.g. hypertensive nephropathy). CONCLUSIONS: It is important to be aware of the pitfalls of using the urine albumin level in predicting development and progression of diabetic nephropathy in order to treat and advise the patients accurately. Research into finding new markers is rapidly evolving but current progress makes it likely we will be using the urine albumin level for some years into the future. PMID- 24475454 TI - Hepatitis C virus infection in nephrology patients. AB - CONTEXT: Hepatitis C virus (HCV) infection leads to chronic liver disease, but also to extra-hepatic manifestations. EVIDENCE ACQUISITIONS: Directory of Open Access Journals (DOAJ), Google Scholar, Pubmed (NLM), LISTA (EBSCO) and Web of Science have been searched. RESULTS: Herein, we provide an overview of renal diseases related to HCV and their therapies, as well as the treatment options available for HCV (+)/RNA (+) dialysis patients. We will not mention, however, HCV infection-related complications in the post-kidney transplantation setting. CONCLUSIONS: Extra-hepatic manifestations of HCV infection include mixed cryoglobulinemia, lymphoproliferative disorders, and renal disease. HCV infection has been reported in association with distinct histological patterns of glomerulonephritis in native kidneys. PMID- 24475456 TI - Anti-phospholipase A2 receptor antibody in idiopathic membranous nephropathy: A report from Iranian population. AB - BACKGROUND: Idiopathic Membranous Nephropathy (iMN) is the most common cause of nephrotic syndrome in adults. Approximately one third of patients with iMN progress to end-stage renal disease. Anti-phospholipase A2-receptor (anti-PLA2R) antibodies are present in patients with iMN and appear to play a role in the pathogenesis of iMN. OBJECTIVES: In this study, we explored the prevalence of anti-PLA2R antibodies in a cohort of patients with iMN in Iran. We also sought to determine circulating levels of anti-secretory PLA2 (anti-sPLA2) antibodies in those with anti-PLA2R antibodies. PATIENTS AND METHODS: Using an indirect immunofluorescence assay, we measured anti-PLA2R antibodies in a group of patients with iMN in Iran. The serum levels of anti-sPLA2 antibodies were also measured in those with positive results for anti-PLA2R antibodies. RESULTS: We studied 23 patients with iMN (M/F 12/11, 34+/-9.8 year), two patients with secondary MN and five patients with the nephrotic syndrome of other causes.Anti PLA2R antibodies were detected in 17/23 (74%) of patients with iMN, but not in those with secondary MN or other forms of primary glomerular diseases. We found no correlation between anti-PLA2R antibody titer and the degree of proteinuria. We found high titers of anti-sPLA2 antibodies in a subset of patients with high levels of anti-PLA2R antibodies. CONCLUSIONS: Anti-PLA2R antibodies are specific for iMN. Proteinuria may also reflect glomerular structural damage rather than immunological activity of the disease. The preliminary idea of any presumptive role of anti-sPLA2antibodies in iMN needs further investigation. PMID- 24475457 TI - Evaluation of noninvasive tests for diagnosis of Helicobacter pylori infection in hemodialysis patients. AB - BACKGROUND: Hemodialysis is the most common method of renal replacement therapy for treatment of acute and chronic kidney failure. Helicobacter pylori (H. pylori) plays a major role in development of peptic ulcer, gastric neoplasms, and lymphoma as well as increased risk of cardiovascular disorders in hemodialysis patients. OBJECTIVES: In this study the diagnostic values of noninvasive tests [i.e. urea breath test (UBT), helicobacter pylori stool antigen test (HPSA) and serology] in diagnosis of H. pylori infection in hemodialysis patients have been studied. PATIENTS AND METHODS: All patients undergoing hemodialysis in Fatemieh Hospital, Semnan, Iran, were enrolled in the study, and their H. pylori status were assessed by using non-invasive tests including UBT, HPSA and serology. Patients with at least two out of 3 positive tests were considered infected with H. pylori. RESULTS: The sensitivity, specificity, and positive and negative predictive values of the tests used in diagnosing H. pylori infection were 62.5%, 65.4%, 62.5% and 65.4% for UBT, 100%, 72.2%, 58.3% and 100% for serology, and 100%, 75%, 60.9% and 100% for fecal antigen test, respectively. CONCLUSIONS: This study showed that H. pylori serology and stool antigen tests have higher diagnostic values than UBT, and they are more reliable than UBT in diagnosis of H. pylori infection in hemodialysis patients. PMID- 24475458 TI - Association of serum calcium with level of blood pressure in type 2 diabetic patients. AB - INTRODUCTION: Hypertension and diabetes are two common diseases and they affect the same major target organs. OBJECTIVES: In this study, we sought to investigate the probable association of serum calcium with levels of systolic and blood pressure in a group of type 2 diabetic (T2D) patients. PATIENTS AND METHODS: A total of 60 patients with T2D were enrolled to the study. To determine serum creatinine, calcium and hemoglobin A1c (HbA1c), venous blood samples were obtained in the fasting state. RESULTS: Among 60 participants, 56.7% were female. Mean of ages was 57+/-8.3 years. Mean of systolic and diastolic blood pressure were 133+/-13 mmHg and 84+/-7.4 mmHg, respectively. Mean of serum calcium was 9.0+/-0.4 mg/dl. In this study, there was no significant difference of serum calcium and HbA1c between males and females. A significant inverse correlation of serum calcium with level of diastolic blood pressure (r= -0.261, p=0.046) was seen (adjusted for duration of diabetes). Moreover, a negative correlation of systolic blood pressure with level of serum calcium was existed, however, this correlation was not significant (r= -0.232, p=0.080) [adjusted for duration of diabetes]. CONCLUSIONS: We found a significant inverse correlation of serum calcium with level of diastolic blood pressure. We propose to more attention to serum calcium during the treatment of hypertension in diabetic patients. PMID- 24475459 TI - Comment on: IgM nephropathy: Can we still ignore it. PMID- 24475461 TI - Neuroendocrine dysfunction following mild TBI: when to screen for it. PMID- 24475462 TI - Abnormal bleeding in your female patient? Consider a progestin IUD. PMID- 24475463 TI - Is a novel anticoagulant right for your patient? PMID- 24475464 TI - Steroids for acute COPD--but for how long? PMID- 24475465 TI - Recurrent vesicular eruption on the right hand. PMID- 24475466 TI - Clinical inquiries. Whom should you test for secondary causes of hypertension? PMID- 24475467 TI - Clinical inquiries. What is the best imaging method for patients with a presumed acute stroke? PMID- 24475468 TI - Nausea, blurry vision, hallucinations--Dx? PMID- 24475469 TI - Low-dose penicillin for recurrent cellulitis? PMID- 24475470 TI - Caring for Asian immigrants: tips on culture that can enhance patient care. PMID- 24475471 TI - International stem cell networks: the power of contacts. PMID- 24475472 TI - [Limitless greed (the cash)?]. PMID- 24475473 TI - [Cataract contract: no participation in seized appropriate care]. PMID- 24475475 TI - [Generation 35plus: between fatalistic and hopeful]. PMID- 24475474 TI - [Mixed travel: can you make the expenses for tax purposes]. PMID- 24475476 TI - Response to comment on "beyond medications and diet: alternative approaches to lowering blood pressure: a scientific statement from the American Heart Association". PMID- 24475478 TI - The state of research after 25 years of Nanotechnology. PMID- 24475477 TI - Response to role of hyperleptinemia in the regulation of blood pressure and cardiac function. PMID- 24475479 TI - Reply to authors. PMID- 24475480 TI - Care Bill amendment gives NHS advocates clause for concern. PMID- 24475481 TI - Cuba's economic reforms prompt debate about health care. PMID- 24475482 TI - Funding: Ludwig trust gives its final gift to cancer research. PMID- 24475483 TI - The stress of life: a modern complaint? PMID- 24475484 TI - Incidental findings detected on abdomino-pelvic multidetector computed tomography performed in the acute setting. AB - OBJECTIVE: The objective of the study is to determine the prevalence and significance of incidental findings in patients with a chief complaint of abdominal pain presenting to the emergency department (ED) who received abdomino pelvic multidetector computed tomography. MATERIALS AND METHODS: We conducted a retrospective review of data collected for 290 patients over a period of 5 months (April to September 2012) from 3 different university-affiliated EDs. Two board certified radiologists reviewed the original images independently and recorded the incidental findings. These findings were classified as benign, indeterminate, and worrisome. Only those findings present in the original report were included in the study. If an indeterminate or worrisome incidental finding was identified, the patient's medical records were reviewed to determine if the incidental finding was previously known, whether recommendation was made for further evaluation, and whether this recommendation led to any change in management. RESULTS: We identified 283 incidental findings-144 benign (51%), 114 indeterminate (40%), and 25 worrisome (9%) findings. A statistically significant difference was observed in the percentage of patients who experienced a change in management among those who received recommendations as compared with those who did not, in both previously known (87% vs 22%, P=.001) and previously unknown (70% vs 2%, P=.001) indeterminate findings. CONCLUSION: Unlike benign incidental findings, indeterminate and worrisome findings frequently alter the course of management. Recommendation from radiologists appears to significantly contribute to the management of indeterminate incidental findings. PMID- 24475485 TI - Accuracy of ultrasound-guided marking of the cricothyroid membrane before simulated failed intubation. AB - BACKGROUND: Interest in the use of dynamic ultrasound (US) for cricothyrotomy has sparked a debate regarding its applicability in a crash airway situation. Ultrasound-guided marking of the cricothyroid membrane (CTM) as a preintubation procedure may be better than the dynamic method. No prior study has evaluated the accuracy of using US to premark the CTM before attempted intubation. OBJECTIVES: To determine the feasibility of US-guided marking of the CTM before attempted simulated intubation so that this marking may be used as the location for the initial incision after failed intubation. METHODS: Resident and attending physicians participated. Ultrasound was used to identify and mark the CTM with an invisible pen. Failed intubation was simulated, and the same operator then identified the CTM with US and marked the location with a black pen. The difference in the preintervention and postintervention markings was measured in millimeters. The length of the CTM was also measured as a reference. RESULTS: Twenty-three models and operators were used for data collection. The average CTM sagittal length was 13.9 mm (95% confidence interval [CI], 13.4-14.4). The average sagittal and axial differences before and after simulated intubation were found to be 0.91 mm (95% CI, 0.35-1.47) and 1.04 mm (95% CI, 0.38-1.7), respectively. The sagittal variability is 1/15 the total length of the CTM. CONCLUSIONS: Ultrasound marking of the CTM of healthy volunteers before simulated intubation accurately identifies the CTM after neck manipulation expected during a failed intubation. Further research is indicated to determine the clinical applicability of this model. PMID- 24475486 TI - Should The Cochrane Collaboration be producing reviews of efficiency? PMID- 24475487 TI - The WHO Reproductive Health Library: a Cochrane window on sexual and reproductive health. PMID- 24475488 TI - Cochrane and Wikipedia: the collaborative potential for a quantum leap in the dissemination and uptake of trusted evidence. PMID- 24475489 TI - Rotator cuff tears and shoulder impingement: a tale of two diagnostic test accuracy reviews. PMID- 24475490 TI - Tablet disintegration studied by high-resolution real-time magnetic resonance imaging. AB - The present work employs recent advances in high-resolution real-time magnetic resonance imaging (MRI) to investigate the disintegration process of tablets containing disintegrants. A temporal resolution of 75 ms and a spatial resolution of 80 * 80 um with a section thickness of only 600 um were achieved. The histograms of MRI videos were quantitatively analyzed with MATLAB. The mechanisms of action of six commercially available disintegrants, the influence of relative tablet density, and the impact of disintegrant concentration were examined. Crospovidone seems to be the only disintegrant acting by a shape memory effect, whereas the others mainly swell. A higher relative density of tablets containing croscarmellose sodium leads to a more even distribution of water within the tablet matrix but hardly impacts the disintegration kinetics. Increasing the polacrilin potassium disintegrant concentration leads to a quicker and more thorough disintegration process. Real-time MRI emerges as valuable tool to visualize and investigate the process of tablet disintegration. PMID- 24475491 TI - In response to "plasma exchange in patients with intermediate syndrome due to organophosphates". PMID- 24475492 TI - Screening for prostate cancer: shaping the debate on benefits and harms. PMID- 24475493 TI - Ultrasonic vocalizations during intermittent swim stress forecasts resilience in subsequent forced swim and spatial learning tests. AB - The examination of stress resilience has substantially increased in recent years. However, current paradigms require multiple behavioral procedures, which themselves may serve as secondary stressors. Therefore, a novel predictor of stress resilience is needed to advance the field. Ultrasonic vocalizations (USVs) have been observed as a behavioral correlate of stress in various rodent species. It was recently reported that rats that emitted ultrasonic vocalizations during intermittent swim stress (ISS) later showed resilience when tested on an instrumental swim escape test. In the current study, we extend this earlier observation on two additional behavioral endpoints. Rats were subjected to ISS, and USVs were recorded. Twenty-four hours later, behavioral performance was evaluated in either the forced swim test or Morris water maze. Rats that emitted ultrasonic vocalizations were resilient to the effects of ISS as indicated by performance similar to controls on both measures. These results extend the original findings that ISS-induced USVs are associated with resilience and are related to subsequent aversively motivated behavior. Such a non-invasive forecast of stress responsivity will allow future work to utilize USVs to examine the neural correlates of initial stress resistance/resilience, thereby eliminating potential confounds of further behavioral testing. Future studies can utilize USVs to target potentially unappreciated neural systems to provide novel pharmacotherapeutic strategies for treatment-resistant depression. PMID- 24475494 TI - [Type II proatlantal artery with unusual origin of the occipital artery feeding of a type IV dural arteriovenous fistula: case report]. AB - CASE REPORT: We report the case of a 49 year-old woman, who presented with an intracranial haemorrhage. During cerebral angiography investigations, we observed an unusual vertebral artery that originated from the external carotid artery and an uncommon origin of the occipital artery from the vertebral artery feeding a dural arteriovenous fistula grade IV. This rare vertebral artery origin is probably the remnant of a type II proatlantal artery. In addition, the origin of the occipital artery evoked a vascular development disease including a dural arteriovenous fistula which may be the result. These multiple vascular abnormalities could be explained by embryologic disorders. PMID- 24475495 TI - Delayed hypoglossal nerve palsy following unnoticed occipital condyle fracture. AB - Occipital condylar fractures (OCFs) are rare and difficult to diagnose. The routine use of computed tomography (CT) scan in traumatology has however now made their diagnosis easier, with an estimated frequency of 4 to 19% of craniospinal traumatized patients and 0.4 to 0.7% of all severe traumatized patients in emergencies. This paper describes a patient who was not diagnosed with OCF during his first hospitalization after a road accident. However, 15 days later a left sided hypoglossal nerve palsy occurred. In this case report, we underline that an examination of the cranial nerve is a quick and easy procedure to screen each head trauma patient for occipital foramen fractures. Also, careful attention must be paid to X-Rays, CT scans and magnetic resonance imaging of the craniocervical junction. PMID- 24475496 TI - Consistency of communication among intensive care unit staff as perceived by family members of patients surviving to discharge. AB - PURPOSE: We hypothesize that intensive care unit (ICU) families frequently perceive that they have received inconsistent information from staff about their relatives and that these inconsistencies influence abilities to make medical decisions, as well as satisfaction. MATERIALS AND METHODS: We performed a prospective cohort study in the neurosciences and medical ICU at a university hospital. One hundred twenty-four family members of adult patients surviving to ICU discharge completed a questionnaire regarding perceptions of inconsistent information. RESULTS: Of 193 eligible patients, 64.2% had family complete the survey. Thirty-one respondents (25.0%; 95% confidence interval, 7.7) reported at least 1 instance of inconsistent information during their family member's admission, with no difference between the neurosciences ICU (21.5%; 9.3) and the medical ICU (31.1%; 14.1; P = .28). Of those who did receive inconsistent information, 38.7% (95% confidence interval, 18.2) reported multiple episodes and 74.2% (16.3) indicated that episodes occurred within the first 48 hours of admission. These episodes had an adverse effect, with 19.4% (14.7) indicating that they affected satisfaction and 9.7% (11.0) indicating that they made decision making difficult. CONCLUSIONS: Episodes involving inconsistent information from staff as perceived by families may be quite prevalent and may influence decision-making abilities and satisfaction. PMID- 24475497 TI - Reply: To PMID 23925410. PMID- 24475498 TI - Validation of noninvasive pulse contour cardiac output using finger arterial pressure in cardiac surgery patients requiring fluid therapy. AB - INTRODUCTION: Nexfin (Edwards Lifesciences, Irvine, CA) allows for noninvasive continuous monitoring of blood pressure (ABPNI) and cardiac output (CONI) by measuring finger arterial pressure (FAP). To evaluate the accuracy of FAP in measuring ABPNI and CONI as well as the adequacy of detecting changes in ABP and CO, we compared FAP to intra-arterially measured blood pressure (ABPIA) and transpulmonary thermodilution(COTD) in post cardiac surgery patients during a fluid challenge (FC). METHODS: Twenty sedated patients post cardiac surgery were included, and 28 FCs were performed. Measurements of ABP and CO were simultaneously collected before and after an FC, and we compared CO and blood pressure. RESULTS: Finger arterial pressure was obtainable in all patients.When comparing ABPNI with ABPIA, bias was2.7 mm Hg (limits of agreement [LOA], +/- 22.2), 4.9 mm Hg (LOA, +/- 13.6), and 4.2 mm Hg (LOA, +/-13.7) for systolic,diastolic, and mean arterial pressure, respectively. Concordance between changes in ABPNI and ABPIA was 100%.Mean bias between CONI and COTD was -0.26 (LOA, +/- 2.2), with a percentage error of 38.9%. Concordance between changes in CONI vs COTD and was 100%. CONCLUSION: Finger arterial pressure reliably measures ABP and adequately tracks changes in ABP. Although CONI is not interchangeable with COTD, it follows changes in CO closely. PMID- 24475499 TI - [Heart attack treatment is very good in international comparison]. PMID- 24475500 TI - In reply to Lee. PMID- 24475501 TI - A case of family periodic paralysis with a critical digest of the literature. PMID- 24475503 TI - Maria Gomez. PMID- 24475504 TI - The honorable John Lewis. PMID- 24475505 TI - J.W. "Bill" Marriott, Jr. PMID- 24475506 TI - Patty Webster. PMID- 24475507 TI - The honorable Daniel Inouye. PMID- 24475508 TI - Father Patrick Devine. PMID- 24475509 TI - Allyson Ahlstrom. PMID- 24475510 TI - Nicholas Cobb. PMID- 24475511 TI - Will Lourcey. PMID- 24475512 TI - Zachary Certner. PMID- 24475514 TI - Editorial. PMID- 24475513 TI - Improving children's mental health. PMID- 24475515 TI - Jihyeung Kim, Kyungpyo Nam, Seung Hwan Rhee, Jong Won Won, Hyuk-Soo Han, Seung Baik Kang, Reply. PMID- 24475517 TI - [Abstracts of the 63rd General Meeting of the Japanese Society of Allergology. November 28-30, 2013. Tokyo, Japan]. PMID- 24475518 TI - [Abstracts of the 53rd Annual Meeting of the Japanese Society of Nuclear Medicine. November 8-10, 2013. Fukuoka, Japan]. PMID- 24475519 TI - [Abstracts of the 43rd Eastern/Western Regional Meeting, Japanese Society of Nephrology. 2013. Japan]. PMID- 24475520 TI - Author's reply: To PMID 23649143. PMID- 24475521 TI - Work that matters. PMID- 24475522 TI - Setting the stage for delivery of safer imaging. PMID- 24475523 TI - Thankful for American healthcare. PMID- 24475524 TI - Trends in radiology staffing. PMID- 24475525 TI - Streamlining medical image sharing for continuity of care. AB - Sharing patient medical history can be inconvenient and unreliable. Massive strides have been made to address the wasteful aspects of healthcare today, but hospitals and healthcare providers are still searching for ways to improve the efficiency of medical image sharing. To ensure that a patient's historical medical images can be promptly accessed by all caregivers, a solution architecture is needed that anticipates and supports the need for images to be available along with the rest of the patient's required medical history. Healthcare facilities can quickly and affordably use existing technologies, combined with a unified approach for sharing images to greatly improve transitions of care for their patients. Images would no longer need to be burned on to CDs and transported. PMID- 24475526 TI - Forty years of coding history (and a sneak peek at next year). PMID- 24475527 TI - ICD-10: altered mental status and dementia. PMID- 24475528 TI - Enhance hospital performance from intellectual capital to business intelligence. AB - Business intelligence (BI) refers to technologies, tools, and practices for collecting, integrating, analyzing, and presenting large volumes of information to enable better decision making. The aim of this study is to provide a general overview of BI and its impacts on improving hospital performance. In this paper, literature is reviewed on the concept, classification, and structure of intellectual capital and BI. Research on the building of BI and its impact on the performance of hospitals are briefly summarized. Some areas in healthcare which can utilize BI benefits, including radiology, are also discussed. Used properly, BI is an effective communication tool that can enable hospitals to reach strategic goals and objectives and can also help eliminate information asymmetry. PMID- 24475529 TI - Off the farm. PMID- 24475530 TI - Value stream maps for imaging services. AB - Managing imaging services delivered at different physical locations is a challenge. How do services vary by location and which process better serves the patient? Which location is providing the most cost efficient service and why? How can an organization consistently deliver best clinical practices across various locations? Mayo Clinic Radiology in Rochester, MN, faced these questions when evaluating its 19 locations providing CT services in a variety of settings such as emergency care, inpatient, and/or outpatient. Services also varied by patient type, like adult and/or pediatric, and service was provided across varying shifts. In its commitment to provide a single high quality standard of practice in a cost efficient manner across all of its locations, Mayo Rochester faced these tough questions.They found the answer in the form of a CareMap. PMID- 24475532 TI - Back to the future. PMID- 24475531 TI - Forty years of communication. PMID- 24475533 TI - Importing a change in diet: the proposed food safety law of 2010 and the possible impact on importers and international trade. AB - The current combination of widespread consumer alarm about foodborne illness outbreaks and industry concern about profitability has encouraged Congress, for the first time in many years, to consider major food safety reform. The House of Representatives has already passed its version of reform, the Food Safety Enhancement Act of 2009. The Senate appears ready to pass its bill, the FDA Food Safety Modernization Act. Both bills will subject firms in the food industry to a number of new requirements and will considerably increase Food and Drug Administration's (FDA's) enforcement authority. This article addresses how the passage of major food safety reform in 2010 will potentially affect food importation into the United States, by using the Food Safety Enhancement Act of 2009, the bill passed in the House, as a model for what food safety reform will entail. Under the bill, food facilities and importers will have to register yearly with FDA and pay a fee. Customs brokers will also have to register with FDA. FDA will have the authority to subject certain foods to a certification requirement for obtaining entry into the United States. Food facilities will be required to evaluate hazards and implement preventive controls and food safety plans. FDA will establish mandatory performance standards and produce standards. Specific foods identified by FDA will be subject to traceability requirements. FDA will follow a mandatory risk-based inspection schedule, will have far greater access to records, and will have the authority to enforce mandatory recalls. U.S. trading partners may take issue with the substantial burdens placed on those importing food into the United States and may consider bringing a challenge against the United States claiming that the new food safety legislation violates World Trade Organization obligations. PMID- 24475534 TI - Personalized medicine and rescuing "unsafe" drugs with pharmacogenomics: a regulatory perspective. AB - The sequencing of the human genome and the revolution it has caused in biomedical science created hope for a new era in the prevention and treatment of serious illnesses. In the area of drug development, much of this hope is focused in the field of pharmacogenomics (PGx), which is the study of how individual genetic differences affect drug response. Many people expected advances in pharmacogenomics to lead to the rapid development of new "personalized medicines," where drugs and dosages could be tailored specifically to a patient's genotype. However, pharmacogenomics has largely failed to meet these expectations and the Food and Drug Administration has only approved a handful of drugs that rely on PGx data. This article evaluates how FDA regulates the use of pharmacogenomics and discusses how the current regulatory scheme fails to provide an adequate route for developing personalized medicine. The article then proposes modifying the current regulatory regime to encourage development of PGx-based drugs by either allowing PGx-based drugs to be approved with unvalidated biomarkers if the sponsor commits to Phase IV studies or using the Orphan Drug Act to provide economic incentives. PMID- 24475535 TI - Authority of the Food and Drug Administration to require data access and control use rights in the Sentinel data network. AB - The Food and Drug Administration Amendments Act of 2007 (FDAAA) authorized the U.S. Food and Drug Administration (FDA) to develop a 100-million-person health data network known as the Sentinel system. When fully operational, the Sentinel network will offer a very rich, very large health data resource that has the potential to become one of history's most powerful engines of biomedical innovation and clinical translation of discoveries. Who controls this asset will be a matter of great scientific and commercial importance. This article explores two key questions--data access and use rights--that are under debate as various parties jostle for control of the network: First, does FDA have legal authority to require private healthcare data environments--such as insurers, healthcare providers, pharmacists and other entities that hold data in administrative and clinical databases--to make data available for inclusion in the network? Second, who will decide how the network is used, once it is built? The article explains why a neutral analysis of these questions is essential as FDA designs the governance framework for protecting the diverse stakeholders who will be touched by the Sentinel network. The conclusion describes threats to network operations, including federal and state constitutional claims and state legislative interventions, which could arise if FDA fails to devote timely attention to these issues. PMID- 24475536 TI - Guide to preemption of state-law claims against Class III PMA medical devices. AB - There is a perception that the express preemption holding of the Supreme Court in Riegel v. Medtronic, 552 U.S. 312(2008), immunizes medical device manufacturers from common law personal injury actions involving Class III devices that received FDA clearance under a premarket approval application (PMA). In the aftermath of Riegel, many lawsuits involving Class III PMA devices have been dismissed by district courts applying the new heightened pleading standard of Bell Atlantic Corp. v. Twombly, 550 U.S. 544 (2007). Other lawsuits involving Class III PMA devices premised on fraud-on-FDA have been dismissed based on the implied preemption holding of the Supreme Court in Buckman v. Plaintiffs' Legal Comm., 531 U.S. 341 (2001). When these decisions are carefully analyzed together with Medtronic, Inc. v. Lohr, 518 U.S. 470 (1996), which found no preemption regarding a Class III device receiving FDA clearance through the 510(k) mechanism, it is apparent that the preemption defense does not apply universally to Class III PMA devices. The overall methodology for framing a non-preempted claim is to first identify conduct which violated the PMA or other specific requirements related to safety or efficacy. If such conduct can also be stated in terms of a breach of a parallel common law duty (e.g, failure to warn under strict liability or negligence, manufacturing defect or breach of warranty), then it would appear the claim is not preempted. Alternatively, regardless of a specific violation, common law remedies are not preempted by general CGMP requirements. PMID- 24475537 TI - Mirror, mirror on the wall--evaluating Fair Market Value for manufacturer physician consulting arrangements. AB - Pharmaceutical and medical device manufacturers contract with thousands of physicians each year, and struggle to comply with the Fair Market Value requirements of the Anti-Kickback Statute's "personal services" safe harbor. Consultant arrangements between physicians and manufactures have come under increasing scrutiny by regulators. In 2007, the five leading Hip & Knee manufacturers entered into settlement agreements related to their contract practices with physician consultants. Government sources do not provide guidance for calculating Fair Market Value; however, this article recommends four principles to use when evaluating Fair Market Value methodologies. PMID- 24475538 TI - Brain food: bringing psychological insights to bear on modern nutrition labeling efforts. AB - Food and drug law presents legislators and policy makers with a powerful tool to inform individual dietary decisions and improve public health: mandatory nutritional labeling. Most Americans report that they consult nutritional information when making food purchases; yet, knowing whether individuals report consulting nutritional information is different than knowing how they actually process and utilize that information. Although the latter question is more difficult to answer, it holds the key for efficient and effective food labeling. This article argues that psychological research can answer that question. It does so by explaining well-established psychological findings that have the greatest potential application to food labeling efforts. It then examines two recent nutritional labeling initiatives from a psychological lens, illustrating how well each initiative reflects findings from the field. By doing so, this paper aims to help government regulators and private businesses develop more targeted and effective labeling initiatives. PMID- 24475539 TI - In search of the silver bullet: regulatory models to address childhood obesity. AB - The concern over obesity today has evolved beyond an issue of personal vanity to a serious national health issue affecting millions of Americans. Obesity in children is especially alarming. Overweight children and adolescents are at risk for health problems throughout their lives. While under-nutrition or diet insufficiencies were once major obstacles in the development of healthy infants and children, the epidemic of childhood obesity marks the start of the 21st century with equally menacing health consequences. Childhood obesity creates an increased burden of disease on our economy with increased indirect economic costs of time lost from work for parents and time lost from school for the child. Data raise the possibility that the current generation of children could suffer greater illness or experience a shorter lifespan than that of their parents. Some experts believe that government mandated restrictions on dietary choices would alleviate the obesity problem, while others find such actions to be an unwarranted government intrusion. Still, as concerns about obesity continue to grow, especially regarding children, some say government intervention of some type is necessary to solve the problem. This paper examines the history and factors involved in the childhood obesity epidemic, explores regulatory options for its resolution, and provides an overview of obesity as a serious challenge to public health, and the health of children in particular. The federal agencies who share the responsibility for regulating food in the United States and their efforts to address the obesity problem are discussed as a background to various state and federal regulatory models influencing dietary choices. The effectiveness of proposed regulations and alternatives to government intervention suggest that the resolution of the childhood obesity issue requires a coordinated, multilevel approach. PMID- 24475540 TI - FDA has the legal authority to adopt a threshold of toxicological concern (TTC) for substances in food at trace levels. AB - It now is possible to detect many substances in the parts per trillion and further advances will allow for even lower levels of detection. Many of these substances may always have been present in the food supply, but escaped detection. Others may have been introduced through environmental contamination, changes in food processing, sourcing of ingredients from different manufacturers or countries, and a myriad of other reasons. The adulteration and various safety provisions of the Federal Food, Drug, and Cosmetic Act (FDCA), principles of statutory construction, and case law, provide FDA with the legal authority to adopt the threshold concept. FDA and the courts have long recognized it is possible to establish safe levels of poisonous or deleterious substances found in foods. FDA routinely conducts such an analysis under the general adulteration provisions of the FDCA and has identified safe levels for numerous environmental contaminants found in food. The courts have recognized that through its exercise of enforcement discretion, FDA has the legal authority to establish non-binding defect action levels for contaminants. FDA similarly could implement the Threshold of Toxicological Concern (TTC) through its exercise of enforcement discretion. PMID- 24475541 TI - The new follow-on-biologics law: a section by section analysis of the patent litigation provisions in the Biologics Price Competition and Innovation Act of 2009. AB - An abbreviated pathway for the approval of biosimilar biological products, often called "follow-on biologics," has been enacted into law as part of the health care legislation recently passed by Congress and signed by the President. The subtitle of the health care bill establishing this approval pathway, the Biologics Price Competition and Innovation Act of 2009, includes many provisions governing the identification of patents relevant to a given biosimilar biological product and the assertion of those patents in infringement suits. This article provides a section-by-section analysis of the patent-related provisions of the new approval pathway for biosimilar biological products, and points out several ways in which the new law differs fundamentally from the Hatch-Waxman Act, which provides the approval pathway for generic versions of small molecule drugs. PMID- 24475542 TI - The impact of Wyeth v. Levine on FDA regulation of prescription drugs. AB - In Wyeth v. Levine, decided in March, 2009, the United States Supreme Court concluded that the plaintiff's failure to warn claim against the makers of the drug Phenergan was not impliedly preempted by the Food, Drug and Cosmetic Act. In doing so, the Court rejected the argument of the U.S. Food and Drug Administration (FDA) that tort claims of this nature stand as an obstacle to federal regulatory objectives. This Article evaluates the Court's opinion in Wyeth and examines that decision's impact on subsequent litigation in the area of prescription drug labeling. The Article first discusses the preemption doctrine and its application to state law tort claims against product manufacturers. It then reviews the history of implied preemption of tort claims against manufacturers of FDA-approved prescription drugs prior to Wyeth and then discusses the Wyeth decisions in the Vermont Supreme Court and the United States Supreme Court. Finally, the Article evaluates some of the prescription drug preemption cases that have been decided in the lower federal courts since Wyeth and suggests that these courts are now reluctant to preempt failure to warn claims unless a manufacturer affirmatively seeks permission from FDA to change a drug's labeling. PMID- 24475543 TI - Saving U.S. dietary advice from conflicts of interest. AB - A large and growing majority of people are dying from chronic diseases. To a large extent, however, whether this happens is up to us and the choices we make, since diet and lifestyle can prevent, slow, and even reverse these diseases. The government tries to inform the public about these healthy choices in the Dietary Guidelines for Americans. Unfortunately, the integrity of that advice has potentially been compromised by conflicts of interest among the people and organizations responsible for the Guidelines. As a result, as several studies show, the Guidelines are far less effective than other diets--especially the Mediterranean diet--at reducing the risk for chronic diseases. Improving the Guidelines would require eliminating these conflicts of interest, which would involve two statutory changes. First, Congress should give the authority to create dietary advice solely to an appropriate health agency, not the U.S. Department of Agriculture, which cannot give accurate and impartial dietary advice while also promoting agricultural interests. Second, Congress should find a way generally to prohibit individuals with ties to the food and drug industries from serving on the Dietary Guidelines Advisory Committee, as current ethical standards ignore the influence of past ties, and they are far too specific to address different forms of conflicts. PMID- 24475544 TI - A disclosure dilemma: what you don't know can kill you, but so can what you do know. AB - No medical intervention comes without risks. Certain risks may be grave, but will only occur in a fractional percentage of cases. When does the disclosure of risks of this nature create more harm than good, leading patients to avoid therapies that, on balance, would provide significantly more benefit than risk? This article explores several high-profile disclosures of high severity/low probability risks in devices, drugs, and biologics that resulted in harmful unintended consequences. It contrasts the conflicting interests of manufacturers, the Food and Drug Administration (FDA), medical professionals and patients/consumers. It critiques several proposed approaches to the issue, then presents its own disclosure framework. PMID- 24475545 TI - Extraterritorial reach of the FCPA: recommendations for U.S. medical device companies with activities in Europe. AB - Traditionally medical devices companies manage business compliance with anti corruption and anti-fraud rules in a document-oriented way that does not always yield optimal results for the company. As a result, compliance issues are not optimally managed by the companies. Now that medical devices companies become ever more internationally active, they must also take into account the international dimensions of business compliance. This article intends to provide U.S. medical devices companies with activities in Europe with an insight in business compliance risks in the European Union (EU) and the risks related to U.S. statutes that may be applicable to a U.S. company's activities overseas. The article proposes a process-oriented and IT-supported way of structuring an international business compliance program, resulting in increased effectiveness of the program and increased competitiveness and risk management of the company as well as a high degree of acceptance of the procedures by the company's employees. PMID- 24475546 TI - Balancing consumer protection and scientific integrity in the face of uncertainty: the example of gluten-free foods. AB - In 2009, gluten-free foods were not only "hot" in the marketplace, several countries, including the United States, continued efforts to define gluten-free and appropriate labeling parameters. The regulatory process illuminates how difficult regulations based on safe scientific thresholds can be for regulators, manufacturers and consumers. This article analyzes the gluten-free regulatory landscape, challenges to defining a safe gluten threshold, and how consumers might need more label information beyond the term "gluten-free." The article includes an overview of international gluten-free regulations, the Food and Drug Administration (FDA) rulemaking process, and issues for consumers. PMID- 24475547 TI - Remembering the farmer in the agriculture policy and obesity debate. AB - Agricultural policies are often criticized for promoting the overconsumption of unhealthy foods, thereby contributing to rising obesity rates. This article explores the accuracy of claims that existing agricultural policies contribute to obesity and describes the conflict between traditional nutrition and agricultural policy goals. The article concludes by asserting that the challenges facing farmers must be considered in the redesign of agriculture policy to support obesity prevention goals of governments. If the needs of farmers are overlooked, efforts to improve the nutritional profile of the average American diet will be undermined. PMID- 24475548 TI - The "natural" aversion: the FDA's reluctance to define a leading food-industry marketing claim, and the pressing need for a workable rule. AB - As of 2009, the "natural foods" industry has become a 22.3 billion dollar giant and "all-natural" is the second-leading marketing claim for all new food products. Even in such a flourishing market, the Food and Drug Administration (FDA) has never defined the term "natural" through rulemaking. FDA and the U.S. Department of Agriculture (USDA) have instead created separate, non-identical policy statements governing the use of the term "natural," and FDA has abandoned efforts to define "natural" through rulemaking in the face of more pressing priorities. In absence of any governing federal standard, consumer advocacy groups and warring food industries have attempted to define "natural" to fit their preferences through high-stakes litigation of state law claims, leaving courts free to apply diverging standards without the expertise of FDA. Recent case law from federal district courts and the Supreme Court leaves little hope that FDA's current policy statement will preempt state law causes of action. To prevent a potential patchwork of definitions varying by state, and to create a legitimate standard resting on informed scientific expertise rather than consumer whims, FDA should engage in rulemaking to define the term "natural." This paper concludes by sketching potential formulations for such a rule based on FDA's previous successful rule-making ventures and standards used by natural foods retailers. PMID- 24475549 TI - Negotiated rulemaking: the next step in regulatory innovation at the Food and Drug Administration? AB - Negotiated rulemaking is a regulatory tool designed to build consensus on regulations before notice and comment rulemaking procedures. An agency convenes a negotiation with relevant stakeholders to work together to develop a draft rule. In theory, consensus on a draft rule should then in turn decrease the agency's workload during the notice and comment period and decrease the likelihood of subsequent litigation challenging the rule. Numerous federal agencies have convened negotiated rulemaking committees, and many believe that the negotiations have strengthened their relationships with regulated industries and increased compliance rates. Curiously, the Food and Drug Administration (FDA) stands out as one of the few major agencies that has never attempted to host regulatory negotiations. This paper examines instances where FDA has been urged to hold negotiated rulemaking sessions, and then analyzes why FDA has avoided negotiated rulemaking to date. The paper then highlights reasons why FDA might consider using negotiate rulemaking for appropriate regulations. PMID- 24475550 TI - Rabindranath Tagore and his vision and thought in health perspectives. PMID- 24475551 TI - Hypertensive leucocytosis. AB - There are studies showing association of high WBC count with the higher incidence of hypertension though a few are done in the Indian population. The present study was conducted with the view to find any significant increase in total leucocyte count and differential leucocyte count in hypertensive patient Twenty-seven hypertensives with 12 males and 15 females and 27 age and sex matched control subjects (normotensive) were studied. Hypertension was defined when the systolic BP > or = 140 mmHg or diastolic BP > or = 90 mmHg or history of taking antihypertensive medicine. Three blood pressure recordings at an interval of 2 minutes were taken after the patient was made to sit for 30 minutes with a standard mercury sphygmomanometer in the left arm. The disappearance of sound was used for diastolic blood pressure. Blood was drawn into EDTA containing vials. Two separate counts were performed: First for total leucocyte count (TLC) and second for determination of percentage of polymorphonuclear cells. For the TLC, 0.5 part of blood mixed with 10 part of Turk's fluid followed by counting of leucocyte in a counting chamber under light microscope. The percentage of polymorphonuclear leucocyte was performed on a slide after making the slide and staining it with Leishman's stain. The erythrocyte sedimentation rate (ESR) was performed using Wintrobe's methods. The first 1 hour reading on the Wintrobe's tube was taken for analysis. The total leucocyte count (TLC) for the study group as compared to the controls were 7413.70 +/- 735.45 cells/cmm and 5236.30 +/- 528.77 cells/ cmm which was statistically significant. The mean percentage neutrophils were 62.04 +/- 4.99 for study group and 53.00 +/- 3.44 for the controls; the mean percentage lymphocytes for the study group and the controls were 34.37 +/- 4.55 and 39.11 +/- 4.40 respectively. Both the mean percentage neutrophils and lymphocytes showed significant differences. The mean erythrocyte sedimentation rate (ESR) also showed statistically significant when the study group (29.63 +/- 3.76 mm in first hour) was compared to the controls (21.15 +/- 6.88 mm in first hour). In addition, when male and female hypertensive subjects were analysed separately, the TLC, neutrophil, lymphocyte and ESR levels showed significant differences as compared to their respective controls. The result has showed that there is a significant increase in inflammatory markers like TLC and neutrophils counts in hypertensive patients suggestive of hypertension as an inflammatory disease. PMID- 24475552 TI - Study of adverse events following immunisation with universal and newer vaccines in the Serampore IMA Child Clinic over a period of 7 years. AB - Immunisation is an important part of childcare practice. It is one of the most beneficial and cost effective measures for the prevention of diseases. From the previous retrospective studies, it was evident that smallpox has been completely eradicated throughout now-a-days with the wholehearted and sincere efforts of healthcare providers by applying efficient and safe vaccine against smallpox, same is true also to polio which is now close to worldwide eradication and measles and rubella are no longer endemic in certain parts of the world. Not only has that with the introduction of safer and more efficient newer vaccines, the incidence of most other vaccine preventable disease of childhood also reduced considerably. The aim of the present study is to estimate the incidence and clinical presentation of adverse events following immunisation with universal and newer vaccines for a period of seven years using prospective active surveillance. Children under the age of 7 years were taken for universal and newer scheduled vaccinations given in the Serampore IMA Child Clinic under the supervision of the clinicians maintaining strictly the guidelines of Expanded Programme of Immunisation (Government of India). This study of adverse events following immunisation in the Serampore IMA Child Clinic confirms that the adverse events such as fever (0.37%), pain and swelling at the site of injection (0.32%0, urticarial rash (0.02%), anaphylactic shock (0.003%) are negligible. There were only two reports of anaphylaxis following preschool and infant schedule vaccines, including measles, mumps and rubella (MMR), Haemophilus influenzae type B vaccines and typhoid vaccines in approximately 52,000 infants received over a period of 7 years starting from 1st April, 2005 to 31st March, 2012 and there were no deaths or longterm effects reported during the post follow-up period in the Serampore IMA Child Clinic. PMID- 24475553 TI - Herpes simplex virus 2 : a boon to develop other sexually transmitted infections. AB - Genital herpes is one of the most common sexually transmitted infections. Though, mostly asymptomatic, it acts as a potential risk factor for acquisition of other sexually transmitted infections (STIs). The present study was undertaken to know sero-prevalence of herpes simplex virus 2 (HSV2), syphilis and HIV among STI clinic attendees and to detect the diagnostic utility of HSV2 IgM antibodies. The study group included 170 individuals attending STI clinic irrespective of their presenting complaints. Their sera were subjected to enzyme-linked immunosorbent assay for detection of HSV2 IgM antibodies. The samples were also screened for HIV and syphilis. Twenty-seven (15.88%) out of 170 persons were found to be seropositive for HSV2 IgM antibodies. Syphilis was detected in 13 individuals (7.65%). Twelve individuals (7.06%) were found to be reactive for anti HIV I antibodies. Ten of the genital herpes patients (37.04%), did not have any complaint of genital ulcer. Eight HSV2 patients (29.63%) had coinfection with HIV I, 6 (22.22%) with syphilis and 2 (07.41%) had co-infection with both HIV and syphilis. A significant proportion of the patients with genital herpes presented without the history of genital ulcers. Thus, its detection and treatment among asymptomatic patients is significant so as to reduce its transmission and other STIs. PMID- 24475554 TI - Comparative study of heart rate responses to laryngoscopic endotracheal intubation and to endotracheal intubation using intubating laryngeal mask airway under general anaesthesia in patients with pure mitral stenosis for closed mitral commissurotomy. AB - The various drugs and methods studied in an attempt to curb the haemodynamic stress response associated with conventional laryngoscopic endotracheal intubation have not been found to be ompletely satisfactory. The rise in heart rate can be detrimental to patients with mitral stenosis. This study was aimed to compare the heart rate responses to endotracheal intubation using conventional laryngoscope and with the help of intubating laryngeal mask airway (ILMA) in patients with isolated mitral stenosis. Thirty-four adult patients of either sex, aged between 18 and 40 years with isolated mitral stenosis to undergo closed mitral commissurotomy were randomly allocated into two groups : Group A (n=17)- To be intubated using laryngoscopy. Group B (n=17)- To be intubated with the help of ILMA. The heart rate was recorded immediately preinduction, just prior to introducing the intubating device and postintubation every minute up to first 5 minutes. On applying statistical tests, it was found that the median heart rate values in group A at 2, 3, 4 and 5 minutes postintubation were significantly higher than in group B (p<0.05). Although use of both laryngosope and ILMA for endotracheal intubation was associated with rise in heart rate, the rise was less with ILMA compared to laryngoscope. Hence, it can be concluded that use of ILMA may be a preferable device for endotracheal intubation laryngoscopy in patients with isolated mitral stenosis. PMID- 24475555 TI - Occurrence of complications in newly diagnosed type 2 diabetes patients: a hospital based study. AB - Type 2 diabetes is characterised by a long asymptomatic period of hyperglycaemia and many individuals with type 2 diabetes have complications even at the time of diagnosis. The purpose of present study was to study and compare the prevalence of complications at the time of diagnosis of type 2 diabetes in newly diagnosed asymptomatic and symptomatic patients. One hundred and five consecutive newly diagnosed cases of type 2 diabetes were selected for study based on fasting blood glucose level > or = 126 mg/dl. Individuals who were known diabetic, individuals presenting with acute complications were excluded from study. The prevalence rates of various complications in newly diagnosed diabetic patients were studied in both asymptomatic and symptomatic subjects and results were analysed statistically using test of proportion and Chi-square test. There were 40.95% of newly diagnosed diabetes patients who were asymptomatic. There was no significant difference between those having symptoms of diabetes and those without symptoms of diabetes with regard to age, sex, weight and hypertension. Occurrence of both microvascular and macrovascular complications were not different in the two groups studied. We also observed a very high prevalence of microvascular (32.55%) complications in asymptomatic newly diagnosed type 2 diabetes patients. Since 35.20% of cases in this study were below 50 years and various complications develop 10-20 years after onset of disease, this study suggests that screening for diabetes should commence at the age of 40 years in general population. PMID- 24475556 TI - Role of gentian violet paint in burn wound management: a prospective randomised control trial. AB - In tribal part of central India burn remains a major cause of morbidity and mortality. Burn management is carried out in conventional manner in most places. The study carried out at Chhatisgarh Institute of Medical Sciences, Bilaspur was Intended to evaluate the efficacy and outcome of 0.5% gentian violet paint local application over conventional dressing treatment of burn wound. The study encompasses 400 patients of burn of varied aetiology admitted in burn ward whose total body surface area of burn was 15% to 50%. The patients receiving conventional treatment were in group I (n=200), and those with gentian violet paint local application formed group II (n= 200). Although, fibrosis of the burn wound, hypertrophic scar were slightly higher in second group it was observed gentian violet paint local application, healed it in 6-8 weeks without severe sepsis and need for skin grafting. From the study it can be concluded that markedly inexpensive gentian violet paint is an useful alternative, for burn wound management. PMID- 24475557 TI - A cross-sectional study of gynaecological morbidity among married women in field practice area of community health centre Rajapur, Gulbarga. AB - There is always concern about the healthcare of women during pregnancy and child birth and prevention of maternal mortality on priority. By contrast little attention has been given to the reproductive health of non-pregnant women. There is always a relative neglect of gynaecological care which fails to appreciate the magnitude of the problem in the community. The objectives of the study were to assess the level of gynaecological morbidity among married women and to assess the magnitude of gynaecological problems in relation to their history, clinical examination and laboratory investigations. This study is one cross-sectional and the area selected was Rajapur village field practice area, MR Medical College, Gulbarga. Population of Rajapur is 5000 spread over nearly in 850 familes. Family was taken as unit for study purpose. Estimated married women were 580. The sample interval was taken as two. Sample size constituted 290 married women. The information was collected in pretested proforma, gynaecological examination and laboratory investigation were done at community health centre. In the present study gynaecological morbidity perceived by women was 81.37% (including menstrual problems). Disease per woman as perceived by woman was 2.48%, but gynaecological morbidity on clinical examination was 79.66%. Disease per woman on clinical examination was 1.57%. On laboratory investigations 24.24% women had inflammatory cells on microscopic examination of urine and 1.29% women were found to have blood VDRL reactive, on laboratory investigation done among the 231cases. Pap smear report showed out of 290 women, 162 (55.86%) showed inflammatory changes. Only one woman ie, 0.34% had neoplasia, but there were 22 (7.58%), 2 (0.68%) and 12 (4.13%) women had mild, moderate and severe dysplasia respectively. Trichomonas vaginitis was observed in 10 women (3.44%). PMID- 24475558 TI - Treatment of scorpion envenoming syndrome -- need for scientific magnanimity. AB - Scorpion envenoming syndrome results in a severe autonomic storm with a massive release of catecholamines, increased levels of angiotensin II, an increase in glucagon, cortisol, thyroid hormones; either suppressed insulin levels or hyperinsulinaemia (insulin resistance), hyperglycaemia; increased circulating free fatty acid levels. These hormonal alterations could be responsible for the pathogenesis of a variety of clinical manifestations. Under these conditions, scorpion envenoming syndrome with myocardial damage, cardiovascular disturbances, peripheral circulatory failure, respiratory and cardiac pulmonary oedema, and many other clinical manifestations resulting in a syndrome of fuel-energy deficits and an inability to use the existing metabolic substrates by vital organs causing multisystem organ failure and death. Based on animal experiments in which insulin administration reversed the metabolic and ECG changes induced by scorpion envenoming and treating the poisonous scorpion sting victims with insulin, we consider that insulin has a primary metabolic role in preventing and reversing the cardiovascular, haemodynamic, and neurological manifestations and pulmonary oedema induced by scorpion envenoming. Administration of insulin glucose infusion to scorpion sting victims appears to be the physiological basis for the control of the metabolic response when that has become a determinant to survival. The mordality of treatment is continuous infusion of regular crystalline insulin at the rate of 0.3 U/g glucose and glucose at the rate of 0.1g/kg body weight/hour, with supplementation of potassium as needed and maintenance of fluid, electrolytes and acid-base balance is required. This treatment should be given at the earliest on admission and continued for the next 48-72 hours. Antiscorpion serum could also be given independently or along with insulin-glucose infusion. PMID- 24475559 TI - Antibacterial resistance: an overview. AB - The development of antibiotics, represents one of the most important advances in the therapeutics both in control or cure of serious infections and in the prevention, treatment of infection complications. However as the antibiotics are vastly overprescribed in OPD settings and the availability of these drugs without prescription, are facilitating the development of resistance, the present article outlines the causes and mechanisms of antibacterial resistance as well as simple preventive measures at various levels and future prospects. PMID- 24475560 TI - Atypical presentation of live cysticercus larva in anterior chamber. AB - A 25-year femalepresented at the eye OPD with the complaint of some white thing in her right eye. She had visual acuity of 6/18 in the right eye and 6/6 in the left one. Slit lamp examination showed she had a live larva actively moving in the anterior chamber of the right eye. The patient was started on oral steroid, topical moxifloxacin with steroid, cyclopentolate and planned for surgery. Exploration of lerva was done by visco-expressive method. Histopathology showed if to be a cysticercus lerva. Her visual acurity was 6/6 in the affected eye after one month. PMID- 24475561 TI - Phaeochromocytoma in pregnancy: safe vaginal delivery, is it possible? AB - Pheochromocytoma in pregnancy is rare (1 in 50,000 full term pregnancies). Recognition of the condition is central to improving outcome (maternal and foetal mortality is reduced from 58% and 56%, respectively to 2% and 11-15%, respectively). An antenatal patient in third trimester diagnosed as pheochromocytoma has been described. Diagnosis of pheochromocytoma was confirmed by urinary VMA levels and demonstration of right adrenal mass on ultrasound. A multidisciplinary approach was used and the patient received antihypertensives for 10 days. Vaginal delivery was conducted under epidural analgesia and the patient was kept under close surveillance. She delivered a healthy baby girl weighing 2.5 kg. The intrapartum and the postpartum period were uneventful. Adrenalectomy was done at 6 weeks postpartum. Using multidisciplinary approach and individualised management decreases both maternal and foetal morbidity and mortality. Selected multigravidae cases and those with previous history of short uncomplicated labour, may be considered for vaginal delivery under epidural analgesia and with back up facilities available to manage hypertensive crisis. PMID- 24475562 TI - Orocfacial digital syndrome type II -- Mohr's syndrome. AB - Orofacial digital syndromes are a heterogeneous group of rare malformative diseases, characterised by abnormalities of the oral cavity, maxillofacial region and digits. Orofacial digital syndromes are classified into ten types with orofacial digital syndrome type II, Mohr's syndrome being transmitted as autosomal recessive disorder. Here a case of a full term, female, born by lower segment caesarean section weighing 2.800 kg with respiratory distress, cyanosis, poly and syndactyly is reported. PMID- 24475563 TI - Postmortem evaluation of death in an inoperable case of ischaemic enterits with focal infarction. AB - Now-a-days, medical profession is facing with repeated allegations of medical negligence; hence the doctors ought to be very careful in treating the patients and also in giving agreeable explanation in case of death to the public. Here is a case of a 6 years old, male, Muslim boy brought to the department of forensic medicine, Rangaraya Medical College, Kakinada with the cause of death as severe shock, secondary to abdominal colic as per the treating paediatric surgeon. The parents and relatives alleged negligence by the treating doctors as the child was brought with the complaints of pain abdomen, vomiting and loose motion and if he was operated at an early time, definitely he might be survived with a false belief of pain abdomen due to appendicitis. Clinical correlation, postmortem findings and histopathological findings revealed the cause of death was due to ischaemic enteritis with focal infarction - whether amounted to medical negligence as alleged by parents. PMID- 24475565 TI - Gastric trichobezoar. PMID- 24475564 TI - Strongyloides stercoralis hyperinfection syndrome in patients on prolonged steroid treatment: two case reports. AB - Two cases of Strongyloides hyperinfection have been reported who were on prolonged steroid therapy for frequent exacerbations of respiratory problems. One patient presenting with acute respiratory distress, rapidly deteriorated, did not give any time for management and died whereas the second patient survived because of early diagnosis of hyperinfection due to Strongyloides stercoralis. PMID- 24475566 TI - Role of microbiologist in infection control. PMID- 24475567 TI - Bilateral acute foot drop following lumber disc herniation. PMID- 24475568 TI - Medical education in India. PMID- 24475569 TI - The status of radiotherapy in the management of breast cancer 2013. PMID- 24475570 TI - Gynecologic sarcoma: a clinico-pathological review. AB - Most of the cases showing good prognosis in literature are probably intermediate tumors between benign and malignant of undetermined malignant potential (UMP) and other tumors with intermediate features which are currently not considered among sarcomas. Misdiagnosis of a malignant lesion as a benign one has a tragic outcome for the patient. Best therapic choice for sarcomas remains surgery, while chemotherapy (CTX) and radiation therapy (RT) could be used in adjuvant settings. A major effort should be played in the understanding of biological features and behavior of the disease to address a better clinical practice. Uterine sarcomas are rare gynecological tumors; their incidence has been increasing during the last few years. PMID- 24475571 TI - Sentinel node biopsy in endometrial cancer: systematic review and meta-analysis of the literature. AB - PURPOSE: Sentinel lymph node biopsy is a fairly new approach for staging of gynecological malignancies. In the current study, the authors comprehensively reviewed the available reports on sentinel node biopsy of endometrial cancer. MATERIALS AND METHODS: The authors searched Medline, SCOPUS, ISI web of knowledge, Science Direct, Springer, OVID SP, and Google Scholar with the following search terms: "endometrium OR endometrial OR uterine OR uterus AND sentinel". The outcomes of interest were detection rate and sensitivity. RESULTS: Overall, 35 studies had enough information for false negative rate evaluation and 51 studies (including the sub-groups of individual studies) for detection rate evaluation (2,071 patients overall). Pooled detection rate was 77.8% (95% CI: 73.5-81.5%) and pooled sensitivity was 89% (95% CI: 83-93%). Cervical injection, as well as using both blue dye and radiotracer, results in higher detection rate and sensitivity. New techniques such as fluorescent dye injection and robotic assisted surgery showed high detection rate and sensitivity. CONCLUSION: Sentinel node mapping is feasible in endometrial cancer. Using both blue dye and radiotracer and cervical injection of the mapping material can optimize the sensitivity and detection rate of this technique. Larger studies are still needed to evaluate the false negative rate and the factors influencing the sensitivity before considering this method safe. PMID- 24475572 TI - A comparison of outcomes between concurrent chemoradiotherapy and radiotherapy alone in cancer of the uterine cervix: a single institutional experience. AB - PURPOSE: To compare failure patterns and evaluate prognostic factors related to survival rates after concurrent chemoradiotherapy (CCRT) or radiotherapy (RT) alone in cervical cancer. MATERIALS AND METHODS: From January 1996 to December 2006, 218 patients with cervical cancer (FIGO Stage IB2 - III) treated with CCRT or RT alone as primary treatments were included, retrospectively. One-hundred eight patients were treated with CCRT and 110 with RT alone. RESULTS: There was no significant difference in failure patterns between the treatment groups, but distant metastasis was the predominant pattern in both groups. The frequent metastatic sites were supraclavicular lymph node, lung, and brain. Treatment group, diabetes, and FIGO Stage were found to be significant for overall survival (OS) and disease-free survival (DFS), and initial hemoglobin level for DFS. CONCLUSION: Distant metastasis is the predominant failure pattern and diabetes is one of the independent prognostic factors to survival rates in this study. PMID- 24475573 TI - Adjuvant treatment for uterine leiomyosarcoma. AB - The aims of this study were to evaluate outcomes in women diagnosed with uterine leiomyosarcoma (LMS). A retrospective chart review was conducted. Fifty-eight women with LMS were identified. Of the evaluable 52 patients (six patients were excluded), 73% had Stage I/II disease, and 27% had Stage III/IV disease. Sixty three percent of patients received chemotherapy (97% doxorubicin-based therapy), eight percent received radiation alone, and 29% received no therapy. For patients with Stage I/II disease, no improvement in OS was demonstrated when adjuvant therapy was administered. There was a significant difference in OS (p = 0.0005) for patients with advanced Stage (III/IV) disease that received adjuvant chemotherapy. OS of the entire group, when adjusted for stage, failed to reveal a significant survival advantage for those receiving chemotherapy-based (p = 0.22). The present findings suggest further research into the role of chemotherapy in early stage disease is needed to better refine optimal treatment. PMID- 24475574 TI - Laparoscopic management of early stage ovarian cancer: is it feasible, safe, and adequate? A retrospective study. AB - INTRODUCTION: Minimally invasive surgery to stage early ovarian cancer is still regarded as pioneering among gynecologic oncologists. Previous retrospective experiences demonstrated the safety and feasibility of laparoscopy in this field. AIMS: To review the laparoscopic staging procedure in a series of patients with early ovarian cancer and compare results with the literature. MATERIALS AND METHODS: From January 2004 to September 2011, 19 patients with apparent early stage ovarian/fallopian tube cancer Stage IA to IC underwent either primary treatment or completion staging by laparoscopy. Surgical, pathologic, and oncologic outcomes were analyzed. RESULTS: The mean operative time was 212 +/- 69 minutes. Three patients (16%) underwent fertility sparing surgery. The mean estimated blood loss was two +/- two g/dl. The mean number of pelvic and para aortic lymph nodes collected was 17 (range 7-27) and 14 (range 8-21), respectively. The mean volume of ovarian/tubal tumor was 119 cm3 (range 1.5-500). The disease was reclassified to a higher stage in ten women (52%). One major intraoperative complication (five percent) occurred which required the conversion to laparotomy. The mean follow up period was 30 +/- 16 months (range 10-74). Overall survival and disease-free survival were 100% and 84%, respectively. CONCLUSIONS: Laparoscopic staging of early ovarian cancer appears to be feasible and comprehensive when performed by gynecologic oncologists experienced with advanced laparoscopy. PMID- 24475575 TI - Nationwide screening program for breast and cervical cancers in Hungary: special challenges, outcomes, and the role of the primary care provider. AB - INTRODUCTION: Breast and cervical cancers are both common malignancies in Hungarian women. The aim of this study was to evaluate the impact of nationwide screening programs on the incidence and mortality of breast and cervical cancers and to assess the role of primary care providers in this context. MATERIALS AND METHODS: Published records from 2000-2011 on breast and cervical cancer screening activities in Hungary were reviewed. Previously unpublished data from the Hungarian National Cancer Registry were also included in this review. Hungarian outcomes were compared to international results. RESULTS: A nationwide screening program for breast cancer was established in Hungary in 2001. A similar program for cervical cancer was subsequently initiated in 2003. As of 2009, 50% of the population at risk took advantage of breast cancer screening, while the exact participation rate for cervical cancer screening could not be established due to deficiencies of reporting by private gynecologists. The Health Visitors Cervical Screening Program, a new initiative within the context of the nationwide cervical screening program, based on involvement of local primary care providers, had encouraging results which substantially raised participation rates. However, deficiencies were identified regarding flow of information between service providers, patients, and family physicians. There was a slight reduction in the incidence of breast cancer and a more pronounced reduction in the incidence of cervical cancer, as well as a reduction in mortality for both breast and cervical cancers associated with these screening initiatives. CONCLUSION: The inclusion of primary care providers may benefit nationwide screening programs by raising participation rates in the target population. PMID- 24475576 TI - Comparison of adjuvant chemotherapy and radiotherapy in patients with cervical adenocarcinoma of the uterus after radical hysterectomy: SGSG/TGCU Intergroup surveillance. AB - PURPOSE: The authors conducted this retrospective study to evaluate the efficacy of radiotherapy (RT) for high-risk patients with adenocarcinoma (AC) compared with chemotherapy (CT) after radical hysterectomy. MATERIALS AND METHODS: There were 263 patients with AC and 58 with adenosquamous cell carcinoma (ASCC). Of these 321 patients, 151 received adjuvant treatment. Of these 151 patients, 69 received radiotherapy (RT) alone, including concurrent chemoradiotherapy (CCRT) with weekly cisdiamminedichloroplatinum (CDDP), 64 patients received CT alone, and 18 patients received concomitant RT and CT (RT + CT). RESULTS: The five-year overall survival (OS) was 70.9% for patients receiving RT, 79.2% for CT, and 66.2% for RT + CT. Adjuvant treatment did not affect the incidence or the pattern of recurrence. The incidence of lymph node involvement was 9.0% in Stage Ib1, 23.9% in Stage Ib2, 30.8% in Stage IIa, and 41.2% in Stage IIb. CONCLUSIONS: Adjuvant CT may be effective for high-risk patients with cervical adenocarcinoma. PMID- 24475577 TI - RNA interference targeting extracellular matrix metalloproteinase inducer (CD147) inhibits growth and increases chemosensitivity in human cervical cancer cells. AB - Overexpression of extracellular matrix metalloproteinase (MMP) inducer (EMMPRIN CD147) has been implicated in the growth and survival of malignant cells. However, its presence and role in cervical cancer cells has not been well studied. In the present study, small interfering RNA (siRNA) was designed and synthesized to breakdown the expression of CD147. The present data demonstrated that 24 and 48 hours after transfecting CD147 siRNA, both the CD147 mRNA and protein expression were significantly inhibited as determined by quantitative real-time polymerase chain reaction (RT-PCR) and immunocytochemistry. Meanwhile, simultaneous silencing of CD147 resulted in distinctly increasing MMP-9, VEGF, and MDR-1. Further studies demonstrated decreased CD147 expression, resulted in G1/S phase transition with flow cytometry analysis, as well as the resistance of the cells to 5-FU. These findings provide further evidence that CD147 may become a promising therapeutic target for human cervical cancer and a potential chemotherapy-sensitizing agent. PMID- 24475578 TI - Effectiveness of radiotherapy in patients with primary invasive vaginal carcinoma. AB - INTRODUCTION: The aim of the study was to present an institutional experience in radiation therapy of primary invasive vaginal carcinoma (PIVC) patients treated in the Krakow Branch of Centre of Oncology, with special regard to treatment effectiveness and failure causes. MATERIALS AND METHODS: Between February 1967 and January 2007, 162 PIVC patients were treated with radical radiotherapy in the Krakow Branch of Centre of Oncology, Maria Sklodowska-Curie Memorial Institute. Twenty-seven (16.7%) patients in Stage I(0) were treated with intracavitary brachytherapy alone; for 127 (78.4%) patients in Stage I(0)- IV(0) intracavitary brachytherapy was combined with external radiation therapy; and eight (4.9%) patients in Stage IVA(0) were given only external radiotherapy. RESULTS: In the investigated group of 162 patients, five-year disease-free survival was observed in 46.3% of the cases. Patient age and FIGO Stage of neoplastic disease were independent prognostic factors. Five-year disease-free survival was observed in 64.9% of the patients < 60 years of age and only in 30.7% > or = 60 years of age; and in 62.3% of PIVC patients in Stages I and II(0) as compared to 19.7% of Stages III(0) and IV(0) cases. Among 78 patients who died of PIVC, in 60 (76.9%) cases the cause of death was locoregional failure; in six (7.7%), locoregional failure and distant metastasis; and in 12 (15.4%), distant metastasis. CONCLUSIONS: Radiotherapy is effective treatment for PIVC patients. Age below 60 years and non-advanced neoplastic disease were independent favourable prognostic factors in the investigated group of patients. The primary cause of treatment failure was failure to achieve locoregional disease control. PMID- 24475579 TI - Comparing thermal welding instrument-assisted laparoscopic radical hysterectomy versus conventional radical hysterectomy in the management of FIGO IB1 squamous cell cervical carcinoma. AB - PURPOSE OF INVESTIGATION: The authors sought to evaluate the feasibility and acceptability of using the thermal welding technique with thermal ligating shear (TWT-TLS)-assisted laparoscopic radical hysterectomy (LRH) and systemic pelvic lymphadenectomy (SPL) in the management of Stage IB1 squamous cell carcinoma of the cervix. MATERIALS AND METHODS: The authors compared operating time, blood loss, and other intra- and postoperative parameters and outcomes in 53 patients between May 2003 and April 2007. RESULTS: Twenty-three patients were treated with TWT-TLS-assisted LRH and SPL (TWT-TLS group) and 30 patients with abdominal radical hysterectomy (ARH) and SPL (ARH group). The surgical time of the TWT-TLS group was significantly shorter than that of the ARH group (221.4 vs 264.6 min, p < 0.05). The blood loss of the TWT-TLS group was less than that of the ARH group (195.7 vs 1,214.7 ml, p < 0.001). The immediate postoperative recovery seemed to be rapid in the TWT-TLS group compared with the ARH group (1.4 vs 3.5 days for full diet, p < 0.001; 8.32 vs 12.14 days for hospital stay, p < 0.001). The recurrence rate between the two groups was similar during the median four-year follow-up (8.7% vs 13.3%). CONCLUSIONS: TWT-TLS is a safe and efficient method for laparoscopic RH and SPL with reduction of morbidity for early-stage cervical cancer. A further study is needed to confirm the above observation. PMID- 24475580 TI - High pathologic misdiagnosis of cervical adenocarcinoma in situ. AB - OBJECTIVE: The objectives of this research were to evaluate cases of adenocarcinoma in situ (AIS) and early invasive adenocarcinoma (AC) of the uterine cervix in order to: (1) calculate the pathologic discordance between initial biopsies and final surgical excision specimens and (2) describe the clinical and pathologic factors associated with discordance. MATERIALS AND METHODS: The University of California, Irvine and Long Beach Memorial tumor registries were used to identify 105 women with AIS and early AC treated between 1990 and 2008. The primary endpoint measured was change in diagnosis when comparing pathology from the initial biopsy to specimens from a large loop excision of the transformation zone (LLETZ), cold knife cone (CKC), or hysterectomy. The variables studied were: age, endocervical curettage (ECC), co existing cervical intraepithelial neoplasia (CIN), race, and insurance type, as surrogates for socioeconomic status. RESULTS: Initial biopsies were diagnosed as AIS and AC in 44% and 56% of patients, respectively. Of the patients with a biopsy diagnosis ofAIS, 29% had a final diagnosis of AC after excisional procedure, and this discordance was not associated with any of the factors studied. CONCLUSIONS: A concerning high rate of discordance between colposcopic guided punch biopsy and final pathology reinforces the current guidelines to always perform an excisional biopsy following diagnosis of AIS on punch biopsy. PMID- 24475581 TI - DNA damage in peripheral blood lymphocytes of ovarian cancer patients after radiotherapy. AB - OBJECTIVE: Radiotherapy is a common mode of treatment for many types of cancer, particularly cancers that are not detected until late stages, as is common with ovarian cancer. Although radiotherapy is effective in preferentially killing tumor cells, DNA damage induced by ionizing radiation can also have toxic effects on non-tumor cells. The aim of this study was to investigate the extent of toxicity on non-tumor cells following radiotherapy for ovarian cancer. MATERIALS AND METHODS: The authors used the comet assay to assess DNA damage in peripheral blood lymphocytes of 60 ovarian cancer patients undergoing radiotherapy. Venous blood samples were collected from patients before radiotherapy and after accumulated doses of 10, 20, 30, 40, and 50 Gy of radiotherapy. RESULTS: Comet frequencies, reflecting the proportion of damaged cells, were significantly higher after radiotherapy than before radiotherapy (f = 69.66, p < 0.05) and demonstrated a linear relationship with accumulated dose (y = 9.87 + 0.2987x, r = 0.9497, p < 0.05). Additionally, the comet tail length, reflecting the relationship between undamaged and damaged DNA, was significantly longer after radiotherapy (f = 175.13, p < 0.05). CONCLUSIONS: These results demonstrate that radiotherapy induces DNA damage in lymphocytes of ovarian cancer patients and suggest that radiotherapy doses should be limited during clinical treatment to reduce toxic side-effects. PMID- 24475582 TI - Role of surgical staging and adjuvant treatment in uterine serous carcinoma. AB - PURPOSE OF INVESTIGATION: This study evaluates the association of clinical and pathologic characteristics of patients with uterine serous carcinoma (USC) with disease recurrence. MATERIALS AND METHODS: Surgically-staged patients with USC at a single institution were identified and clinical and pathologic variables were compared. RESULTS: Of the 51 patients included in this analysis, 75% percent received adjuvant chemotherapy, 51% received radiation therapy, and 47% received both. After a median follow-up of 33 months, 42% of patients had disease recurrence. On multivariable analysis, positive pelvic lymph nodes were associated with a shorter interval between surgery and recurrence: 13.6 months progression-free survival (PFS) with positive vs 17.2 months with negative lymph nodes (p = 0.05). Patients with early-stage disease who did not receive any adjuvant treatments had a significantly greater risk of disease recurrence (44.4% vs 7.70%, p = 0.043). CONCLUSION: In this population of surgically-staged patients with USC, pelvic lymph node metastases were predictive of a shorter PFS. PMID- 24475583 TI - Analyses of atypical glandular cells re-defined by the 2006 Bethesda System: histologic outcomes and clinical implication of follow-up management. AB - BACKGROUND: To evaluate the histopathology and the long-term follow-up outcome of women who had atypical glandular cells on Pap smears. MATERIALS AND METHODS: All women with atypical glandular cells (AGC) who underwent colposcopic and histopathologic evaluation between January 2005 and October 2010 were reviewed. Patient data were examined up to October 2012, allowing for at least two years of follow-up for all patients. RESULTS: Forty-four women with AGC Pap test underwent histologic follow-up during the study period. Overall, upon reclassification of smears, 35 (79.5%) cases were diagnosed with AGC "not otherwise specified" (NOS) and nine (20.5%) with AGC "favour neoplasia". Seven out of nine patients (77.7%) with AGC "favour neoplasia" had significant pathology. On the other hand, only 11 out of 35 cases (31.4%) with AGC "NOS" had significant pathology. Significant correlation was found between AGC "favour neoplasia" smears and a significant pathology (p: 0.01). Of the 44 patients, 18 (40.9%) had significant pathology. Eight patients (18.2%) had low grade cervical intraepithelial neoplasia (CIN 1), four (9%) had high-grade cervical intraepithelial neoplasia (CIN 2/3), one (2.2%) had microinvasive squamous cell carcinoma of uterine cervix, one (2.2%) had cervical adenocarcinoma in situ, one (2.2%) had cervical adenocarcinoma, one (2.2%) had endometrial adenocarcinoma, and two (4.5%) had endometrial hyperplasia. CONCLUSION: Reporting AGC in the population is clinically significant due to the high prevalence of underlying preinvasive and invasive diseases (40.9%). The subtypes of the AGC category are significant predictor of such lesions. PMID- 24475584 TI - Correlation of subclinical HPV infection with genital warts and cervical erosion. AB - OBJECTIVE: To investigate the correlation of subclinical human papillomavirus (HPV) infection (SPI) with genital warts and cervical erosion. MATERIALS AND METHODS: The questionnaire was firstly conducted in experimental groups (genital warts + cervical erosion), and then cervical liquid-based cytology was performed, followed by colposcopy and pathological diagnosis. In the control group, cervical liquid-based cytology and pathological diagnosis were performed. Hybrid Capture 2 assay (HC2) was conducted to detect the cervical high-risk HPV DNA. RESULTS: The positive rate of cervical SPI in experimental groups were significantly higher than control group (p < 0.01), and in the genital warts group it was significantly higher than cervical erosion group (p < 0.05). There was no significant difference of SPI positive rate for cervical erosion with different area and degree (p > 0.05). Compared to control group, the detection rates of cervical high-risk HPV DNA in the experimental groups significantly increased (p < 0.01), and the difference between vulvar condyloma and cervical erosion groups was not statistically significant (p < 0.05). The detection rate of high-risk HPV DNA in positive SPI cases was significantly higher than negative SPI cases. CONCLUSIONS: Women with genital warts and cervical erosion are high-risk individuals for cervical cancer, and deserve a focused initial and follow-up management. PMID- 24475585 TI - IL-17 and IL-22 serum cytokine levels in patients with squamous intraepithelial lesion and invasive cervical carcinoma. AB - PURPOSE: Several works correlate the synthesis of IL-17 and IL-22 with tumoral progression. However, there are no studies of these cytokines on cervical cancer. The authors studied the concentration of IL-17 and IL-22 on serum obtained from patients with different grades of squamous intraepithelial lesions (SILs) and invasive cervical carcinoma. MATERIALS AND METHODS: Eighty-one women were enrolled in this study, including 23 in the healthy control (with no history of infection or lesions), 11 with low-grade squamous intraepithelial lesion (LSIL), 36 with high-grade squamous intraepithelial lesion (HSIL), and 11 who were diagnosed anatomo-pathologically with invasive carcinoma. Levels of the IL-17 and IL-22 cytokines were measured in the serum obtained from these patients using the enzyme-linked immunoabsorbent assay (ELISA) method. RESULTS: IL-17 and IL-22 displayed a similar pattern of results, with an increase in the serum level of LSIL patients, when compared with serum from HSIL patients (respectively, mean- pg/ml: 22.50 vs 12.20, and 168.2 vs 61.48, p < 0.05). CONCLUSION: Concentrations of IL-17 and IL-22 in the peripheral blood of patients with LSIL were increased compared to HSIL patients. PMID- 24475586 TI - Immunoreactivity for Ca 125 and INI 1 loss of expression are useful markers in the diagnosis of vulvar proximal-type epithelioid sarcomas: report of two cases. AB - Epithelioid sarcomas (ES) are rare soft tissue tumours of obscure histogenesis. Diagnosis is often difficult as specific morphological and immunohistochemical patterns do not exist. Two distinct clinico-pathological entities have been identified: the classic or distal type and the proximal type. Recently, immunohistochemical detection of Ca 125 was described in ES, as well as loss of INI 1 expression. The authors describe in this paper the morphological and immunohistochemical features of two cases of proximal ES of the vulva. Immunoreactivity for Ca 125 and loss of INI 1 expression were present in both cases. These results confirm previous observations in Asian reports showing that these markers can be used as immunohistochemical markers for the diagnostic assessment of ES. PMID- 24475587 TI - All vertebral body metastases of breast cancer: a case report and literature review. AB - OBJECTIVE: Investigating the clinical and imaging features of bone metastasis in breast cancer, in order to raise early diagnosis level and to avoid misdiagnosis. MATERIALS AND METHODS: An analysis of imaging of breast cancer bone metastasis by consulting relevant literatures. The authors also performed bone biopsy in the patient presented. RESULTS: Biopsy results show that ductal carcinoma can be seen in bone marrow and in immune markers CK (+) and CD68 (-). CONCLUSION: Multiple systemic metastases are common for breast cancer, but it is rare that one patient has metastasis in all vertebrae. The positive rate of ordinary X-ray is lower than magnetic resonance imaging (MRI) or positron emission tomography/computed tomography (PET/CT) for detecting bone metastasis, but if an accurate diagnosis is to be made, all the imaging and clinical data should be combined. PMID- 24475588 TI - Pure primary osteosarcoma of the breast: a case report. AB - INTRODUCTION: Mammary sarcomas are relatively uncommon and they represent less than one percent of all primary breast malignancies. Osteosarcoma of the breast, unassociated with other tumors, is distinctly rare, with published references generally limited to case reports and occasional cases in several series encompassing a heterogeneous group of mammary sarcomas and extraosseous osteosarcomas at various sites. The authors present a patient with pure osteosarcoma of the breast, osteoblastic type, with biologically aggressive pattern. CASE REPORT: A 79-year-old lady became aware of a rapidly enlarging lump in the lateral part of the right breast. Clinical examination revealed a firm to hard, mobile, irregular, and painful breast lump measuring about six by four cm. On examination there was no axillary or supraclavicular lymphadenopathy. After initial diagnosis, excisional biopsy without dissection of the axillary lymph nodes was performed. Therefore, the histological and immunohistochemical findings established the diagnosis of pure primary osteosarcoma of the breast. CONCLUSION: Pure osteosarcoma of the breast is extremely rare and needs to be distinguished from a variety of benign and malignant breast lesions producing metaplastic bone. Less than a hundred cases of pure osteosarcoma of the breast were reported, but diagnostic confirmation with immunohistochemistry has been performed in relatively few of these cases. PMID- 24475589 TI - Ovarian cancer presenting as a metastasis to a trocar tract used for a gasless lift-laparoscopy to resect a benign ovarian cyst: an unusual case report. AB - BACKGROUND: Metastasis to a trocar tract (port-site metastasis, PSM) is an uncommon but serious complication that possibly compromises the prognosis of cancer patients treated laparoscopically. CASE: A 42-year-old Japanese woman had a 20-cm benign right ovarian cyst resected using gasless lift-laparoscopy. Five years and eight months postoperatively, she noticed a three-cm subcutaneous tumor involving the trocar tract. She was also found to have a pelvic mass and an exploratory laparotomy revealed left ovarian cancer. Based on the histopathological findings, the subcutaneous tumor was diagnosed as a metastasis from the ovarian cancer. CONCLUSIONS: This case suggested that PSM could occur without direct or indirect wound contamination during laparoscopic surgery. PMID- 24475590 TI - Laparoscopic para-aortic and pelvic lymphadenectomy and radical hysterectomy in a patient with cervical cancer, six months after primary chemoradiation. AB - Treatment of Stage IB-IIA cervical carcinoma is controversial. The choice to perform surgery or chemoradiation depends on the FIGO Stage, which does not include evaluation of lymph node involvement, although the prognosis of the patients depends on this evaluation. There is no method however, to safely evaluate preoperative lymph nodes metastasis, as both magnetic resonance imaging (MRI) and computed tomography (CT) have poor sensitivity and high specificity. As a result, inaccurate preoperative lymph node assessment can lead to suboptimal treatment. The authors report the case of a 42-year-old patient with cervical cancer Stage IB2, who was primary treated with chemoradiation. Although at the time of diagnosis no lymph node metastasis was detected, six months after treatment, an enlarged five-cm lymph node was found in the area of left iliac vein. The patient underwent laparoscopic pelvic and para-aortic lymphadenectomy and nerve sparing radical hysterectomy. Pathologic examination revealed one positive lymph node out of the 41 removed and no cancer cells in the uteral structures. There are cases of cervical cancer in which chemoradiation seems to be insufficient. Laparoscopic nerve-sparing radical hysterectomy can be the treatment in patients with lymph node metastasis after primary chemoradiation. It offers oncological safety combining the advantages of laparoscopy and the nerve sparing technique. Furthermore, adjuvant chemotherapy or radiation can be initiated immediately, offering the best therapeutical choice in the authors' opinion. PMID- 24475591 TI - Adenoid cystic carcinoma of Bartholin's gland receiving adjuvant radiation therapy: case report. AB - Adenoid cystic carcinoma (ACC) of Bartholin's gland is an extremely rare tumor of the female genital tract, representing about 5%-15% of Bartholin's gland malignancies. Approximately 80 cases have been reported in the literature. The authors describe the case of a 54-year-old woman with locally advanced ACC of Bartholin's gland treated with surgery and adjuvant radiotherapy (RT). She underwent radical hemivulvectomy associated with ipsilateral inguinal and femoral lymph node dissection. Subsequently, she received postoperative three-dimensional conformal RT. Total dose prescribed was 56 Gy in 28 fractions of two Gy each. After 20 months of follow up, there was no evidence of local failure or distant progression. PMID- 24475592 TI - Pelvic pain, free fluid in pelvis, and human chorionic gonadotropin serum elevation: recurrence of malignant ovarian germ-cell tumor or early pregnancy? AB - Conservative treatment of metastatic germ-cell tumor of the ovary does not exclude the possibility of pregnancy in the future. Serum beta-human chorionic gonadotropin (beta-hCG) serves as pregnancy test, and has also been proven to be a useful marker for ovarian germ-cell tumors. This paper is a case report of a 19 year-old patient who was admitted to a district hospital in emergency due to pelvic pain, amenorrhoea, and free fluid in the pelvis. Laboratory tests demonstrated slight increase in beta-hCG serum concentration and transvaginal ultrasound (TVUS) showed no evidence of gestational sac in the uterus. At the age of 14, the patient was diagnosed with malignant germ-cell tumor of the left ovary in FIGO Stage IV and was treated with four courses of chemotherapy according to TGM-95 protocol with etoposide, ifosfamide, and cisplatin, followed by conservative surgery and adjuvant two courses of cytostatics. The initial diagnosis was recurrence of ovarian malignancy and the patient was referred to an oncology center. Wait-and-see approach and repeated ultrasound examination confirmed a normal intrauterine pregnancy which concluded with the delivery of a healthy newborn through cesarean section. PMID- 24475593 TI - Endometrial stromal sarcoma with coexistent endometrioid adenocarcinoma in a woman with previous breast cancer: a preliminary case report. AB - Endometrial stromal sarcoma (ESS) is a rare neoplasm of the uterus. The authors report a case of low-grade ESS coexistent with endometrioid adenocarcinoma of the uterus in a woman with a previous history of breast cancer. To the best of their knowledge, such a case has not been reported to date. PMID- 24475594 TI - Vulvar squamous cell carcinoma developing in a young black African HIV woman. AB - Vulvar cancers are uncommon, represented in 90% of cases by squamous cell carcinoma (SCC). The reduction of the frequency and the severity proceed by recognition of precancerous or beginning lesions. They occur most often in the third age in postmenopausal women. The diagnosis is almost difficult and often late and therefore prognosis is severe. Conditions for diagnosis and treatment are difficult in underdeveloped countries due to the inaccessibility of proper equipment in the healthcare system. The authors report a case of SCC diagnosed late in a young human immunodeficiency virus (HIV) women who have been treated with neoadjuvant chemotherapy and radical surgery of the vulva. PMID- 24475595 TI - Advancing the health of the nation. PMID- 24475596 TI - What we have learned from a model nurse residency program: ideas for linking service and education. PMID- 24475597 TI - Comparative descriptors of applicants and graduates of online and face-to-face master of science in nursing programs. AB - AIM: Proper advisement of students about their programs of study requires knowledge of the applicants and confidence that the recommended curricula will lead to success via graduation and certification. BACKGROUND: Two important strategies to deliver master of science in nursing (MSN) curricula include online and face-to-face (F2F) formats. METHOD: A nonexperimental, descriptive study of archival data was used to examine and compare the characteristics of F2F and online MSN applicants, admitted students, and graduates as well as family nurse practitioner (FNP) certification pass rates at one eastern Tennessee college of nursing. Administration and FNP concentrations were studied. RESULTS: The average applicant grade point average (GPA) was higher for the F2F format but no difference in the average admission GPA was found between formats. The online students had more years of RN experience than the F2F students. CONCLUSION: No significant difference was found between graduating GPAs or FNP certification pass rates. PMID- 24475598 TI - The impact of blended teaching on knowledge, satisfaction, and self-directed learning in nursing undergraduates: a randomized, controlled trial. AB - AIM: This study aimed to assess the effectiveness of a blended-teaching intervention using Internet-based tutorials coupled with traditional lectures in an introduction to research undergraduate nursing course. Effects of the intervention were compared with conventional, face-to-face classroom teaching on three outcomes: knowledge, satisfaction, and self-learning readiness. METHOD: A two-group, randomized, controlled design was used, involving 112 participants. Descriptive statistics and analysis of covariance (ANCOVA) were performed. RESULTS: The teaching method was found to have no direct impact on knowledge acquisition, satisfaction, and self-learning readiness. However, motivation and teaching method had an interaction effect on knowledge acquisition by students. Among less motivated students, those in the intervention group performed better than those who received traditional training. CONCLUSION: These findings suggest that this blended-teaching method could better suit some students, depending on their degree of motivation and level of self-directed learning readiness. PMID- 24475599 TI - Culturally competent practice in a pre-licensure baccalaureate nursing program in the United States: a mixed-methods study. AB - AIM: This study examined how one pre-licensure baccalaureate nursing program at a public university in the southeastern United States integrated concepts and issues of culture and culturally competent practice into its curriculum. BACKGROUND: Teaching and learning about culturally competent practice in pre licensure nursing programs are essential to ensure a culturally competent health care workforce. METHOD: A mixed-methods case study approach was used. Data were collected from student surveys (n = 111), student focus groups (three groups, n = 9), faculty interviews (n = 14), and school of nursing documents, including the mission statement, faculty and student handbooks, and course syllabi. Data were analyzed using descriptive statistics and content analysis. RESULTS: Findings provide evidence of cultural competence, barriers to deeper engagement with cultural issues, and suggestions for improvement. CONCLUSION: These findings suggest teaching/learning strategies and curricular design issues that may lead to greater student and faculty member cultural understandings. PMID- 24475600 TI - The perceived benefits of a virtual community: effects of learning style, race, ethnicity, and frequency of use on nursing students. AB - BACKGROUND: It is important for nursing faculty to consider the variability in learning style among nursing students. AIM: The researchers sought to compare differences in perceived learning benefits among nursing students who had different learning styles and in frequency of use of a virtual community learning intervention. METHOD Using a comparative approach, learning style was measured with the Kolb Learning Style Inventory. Frequency of use and benefit were measured with an exit survey. RESULTS: No differences in perceived benefit were found according to learning style. Subjects with frequent use of the virtual community reported significantly greater learning benefits than those with infrequent use, regardless of learning style. Also found was a statistically significant relationship between Kolb learning-style scores and race or ethnicity. CONCLUSION: All nursing students may potentially benefit from virtual community use. PMID- 24475601 TI - Nursing student perceptions of concept maps: from theory to practice. AB - AIM: This qualitative study describes the experience of nursing students who construct and use electronic concepts maps in theoretical and clinical settings. BACKGROUND: Although concept maps are seen as innovative and effective teaching and learning tools, little qualitative data exists that describes the process by which students learn to master the skill of concept mapping. METHOD: A descriptive approach was used to analyze the data collected during 12 semi structured interviews. RESULTS: Motivated, open-minded students tend to perceive the usefulness of concept mapping, making the experience positive. Workshops, along with constructive feedback, were deemed essential to helping students master the skill of concept mapping. CONCLUSION: The results of this study will contribute to the successful integration of group concepts maps as part of a new competency-based nursing program. Results could also be beneficial to programs that wish to adopt concept mapping. PMID- 24475602 TI - Improved class preparation and learning through immediate feedback in group testing for undergraduate nursing students. AB - PURPOSE: A mixed-method educational evaluation project to increase learning through testing was conducted in a required senior nursing course. METHOD: The Immediate Feedback Assessment Technique (IF-AT) was used to motivate preparation for optimal final examination performance. Students took multiple-choice final exams in small groups, used critical thinking and collaboration to select best answers, and then used scratch-off answer sheets indicating correct answers. A causal-comparative evaluation design was used to assess effectiveness of the IF AT technique in improving learning as measured by final exam scores compared with results of traditional individual multiple-choice final exams. FINDINGS: Results indicated that the IF-AT format was significantly more effective than traditional testing in enhancing learning. CONCLUSION: Descriptive and qualitative evaluation data from students indicated students increased their learning, engaged in critical thinking, and prepared adequately for the exam. Students evaluated the test method as superior to standard testing. Implementation information is included. PMID- 24475603 TI - Millennial generation student nurses' perceptions of the impact of multiple technologies on learning. AB - AIM: To determine how millennial nursing students perceive the effects of instructional technology on their attentiveness, knowledge, critical thinking, and satisfaction. BACKGROUND Millennial learners develop critical thinking through experimentation, active participation, and multitasking with rapid shifts between technological devices. They desire immediate feedback. METHOD; A descriptive, longitudinal, anonymous survey design was used with a convenience sample of 108 sophomore, junior, and senior baccalaureate nursing students (participation rates 95 percent, winter, 85 percent, spring). Audience response, virtual learning, simulation, and computerized testing technologies were used. An investigator-designed instrument measured attentiveness, knowledge, critical thinking, and satisfaction (Cronbach's alphas 0.73, winter; 0.84, spring). RESULTS: Participants positively rated the audience response, virtual learning, and simulation instructional technologies on their class participation, learning, attention, and satisfaction. They strongly preferred computerized testing. CONCLUSION: Consistent with other studies, these students engaged positively with new teaching strategies using contemporary instructional technology. Faculty should consider using instructional technologies. PMID- 24475604 TI - Health-promotion behaviors of undergraduate nursing students: a survey analysis. AB - AIM: To examine health promotion behaviors and barriers to health promotion in traditional and nontraditional nursing students in an associate degree nursing program in the northeastern United States. BACKGROUND: Nursing students are exposed to concepts of health promotion in the nursing curriculum, but do not necessarily apply them to their own lives. Examining the variables affecting the health behaviors of nursing students may provide the information required to motivate lifestyle changes in this population. METHOD: A cross-sectional descriptive design was used to examine the relationship between study variables. RESULTS: Nontraditional nursing students participate in health promoting behaviors less often than traditional nursing students and experience more barriers to health promotion. CONCLUSION: Implementation of health promotion programs targeting nontraditional students may lead to improved health among these individuals, which may result in increased success in nursing programs. PMID- 24475605 TI - Evaluation of nursing central as an information tool, Part I: Student learning. PMID- 24475606 TI - An interactive skills fair to prepare undergraduate nursing students for clinical experience. PMID- 24475607 TI - Making simulation come alive: standardized patients in undergraduate nursing education. PMID- 24475608 TI - Digital taxonomy: evaluating and creating. PMID- 24475609 TI - Accelerating to practice: an initiative of the NLN Center for Academic and Practice Transitions. PMID- 24475610 TI - Recipe for success. Nebraska conference sets great educational example. PMID- 24475611 TI - Austin-Travis County EMS responds. PMID- 24475612 TI - Author David M. Williams, PhD, responds. PMID- 24475613 TI - The triangle paradigm. Cost, speed, quality-pick two. PMID- 24475614 TI - Why so 'low'? Elderly diabetic female presents with altered mental status. PMID- 24475616 TI - Technology takes on tradition. PMID- 24475615 TI - Spinal immobilization. Can we throw away our backboards yet? PMID- 24475617 TI - The case for CPR feedback devices. PMID- 24475618 TI - 12-lead ECG tips. Making the most of those squiggly lines. PMID- 24475619 TI - The argument for BLS CPAP. PMID- 24475620 TI - Tech Tips. Making EMS more effective & efficient through technology. PMID- 24475621 TI - Totally tourniquets. The facts & details about different types of tourniquets. AB - Tourniquets save lives by rapidly controlling exsanguinating hemorrhage with a good safety profile. There's extensive research, both empirical and anecdotal, on the many available commercial devices. Prior to purchasing, the user should complete due diligence and review all available data. Each of the commercial tourniquets has both pros and cons. It's imperative for the user to both understand these strengths and weaknesses and to practice with the chosen device to solidify the psychomotor skill of application to allow for the most efficient use of the device. PMID- 24475622 TI - Variation of education continuation. What you need to know about CE classes. AB - Finally, always let training objectives drive the training methodology. An objective to review a pain management protocol is easily accomplished by acknowledging receipt and reading of an electronic document. An objective to assess and appropriately treat a pediatric patient with pain secondary to musculoskeletal trauma is better accomplished through case review and simulation. Opportunities for online CE are continuing to expand. Smartphones and tablets are encouraging educators to develop training content that has increasing interactivity and immediate feedback. Massive Online Open Courses are the newest frontier on the online CE landscape. Keep an open mind about how, when, and where EMT and paramedic continuing education can be delivered and completed. The EMS classroom is no longer bounded by brick-and-mortar walls and the weekday availability of instructors. PMID- 24475623 TI - ePCR: a vital QI tool. Collecting & using data for EMS quality improvement is easier and more important than ever. PMID- 24475624 TI - You can't treat what you can't see. Early scene illumination is crucial at scenes of all sizes. PMID- 24475625 TI - Watching your back. New tools can help both you & the patient stay safe during transport. PMID- 24475626 TI - Everyday use. What do you use daily in your ambulance? PMID- 24475627 TI - Early cooling. Effectively initiating therapeutic hypothermia during cardiac arrest. PMID- 24475628 TI - Workforce wellness. Small steps to making healthy lifestyle choices in the workplace. PMID- 24475629 TI - MAGICABOOLA! Are you wasting too much paper? PMID- 24475630 TI - Stand & deliver. Get students on their feet to improve engagement & learning retention. PMID- 24475631 TI - Laundry bins. Basic needs, pay raises & other morale measures. PMID- 24475632 TI - Monkeys in a cardboard box. PMID- 24475633 TI - Breathing issues. PMID- 24475634 TI - Breathing issues. PMID- 24475635 TI - The dreaded eval form. PMID- 24475636 TI - Visual problems. PMID- 24475637 TI - Freaking out. PMID- 24475638 TI - Face down on the floor. PMID- 24475639 TI - STEMI patients. Do prehospital events have an effect on outcome? AB - BACKGROUND: Little is known about clinically important events and advanced care treatment that patients with ST-segment elevation myocardial infarction (STEMI) encounter in the prehospital setting. OBJECTIVES: We sought to determine the proportion of community patients with STEMI who experienced a clinically important event or received advanced care treatment prior to arrival at a designated percutaneous coronary intervention (PCI) laboratory or emergency department (ED). METHODS: We reviewed 487 consecutive community patients with STEMI between May 2008 and June 2009. All patients were geographically within a single, large "third-service" urban EMS system and were transported by paramedics with an advanced care scope of practice. We recorded predefined clinically important events and advanced care treatment that occurred in patients being transported directly to a PCI laboratory or ED (group 1) or interfacility transfer to a PCI laboratory (group 2). RESULTS: One or more clinically important events occurred in 92 of 342 (26.9%) group 1 patients and nine of 145 (6.2%) group 2 patients. The most common were sinus bradycardia, hypotension and cardiac arrest. Additionally, 33 of 342 (9.6%) group 1 and nine of 145 (6.2%) group 2 patients received one or more advanced care treatments. The most common were administration of morphine and administration of atropine. Eight group 1 patients and three group 2 patients received cardiopulmonary resuscitation (CPR) or defibrillation. CONCLUSIONS: Clinically important events and advanced care treatment are common in community STEMI patients undergoing prehospital transport or interfacility transfer to a PCI center. Several patients required CPR or defibrillation. Further research is needed to define the clinical experience of STEMI patients during the out-of-hospital phase and the scope of practice required of EMS providers to safely manage these patients. PMID- 24475640 TI - Sea change. Three key factors revolutionizing EMS. PMID- 24475641 TI - Living the life in EMS. PMID- 24475642 TI - Blurry emergency. PMID- 24475643 TI - Birth of EMS. The history of the paramedic. PMID- 24475644 TI - Praxis for anaphylaxis. PMID- 24475645 TI - A glitch in time: health care transformation and the marketplace. PMID- 24475646 TI - 97% accuracy of intra-articular glenohumeral injection with a modified (Delaware) posterior bone touch technique. AB - BACKGROUND: Unguided approaches have not demonstrated evidence of highly accurate intra-articular glenohumeral injections. The purpose of this study was to assess the accuracy of a posterior approach bone touch technique in conscious subjects without shoulder pathology as a first step in developing an accurate, reliable technique for use in patients. METHODS: Twenty-six young subjects (age 22-26) without shoulder pathology (BMI 24 +/- 3), had bilateral shoulders injected while awake and seated. A 20 gauge 3.5-inch needle was introduced 1.5 cm below the scapular spine mid-way between the posterior lateral acromial corner and the posterior axillary crease. In Trial I, 20 shoulders were injected. After touching the humerus, the arm was oscillated. The needle advanced to 4-5 cm and 10 mL of dye injected. Pop and ease of flow were recorded. Immediate room change, spot fluoroscopy, and independent experienced radiology reading followed. In Trial II, 32 shoulders were injected. The technique was modified to touching the humerus, externally rotating the arm 25 degrees, and while remaining in bone contact, delivering 10 mL of dye. The same data as Trial I was recorded. RESULTS: In Trial I, 14/20 (70 percent) had dye within the glenohumeral joint. Five of seven failures were too anterior showing dye around the subscapularis muscle and all were associated with a pop. In Trial II, 31/32 (97 percent) had dye within glenohumeral joint. Twenty-three of 32 (72 percent) had a "pop," including the failure. Overall, 45/52 (87 percent) had dye within glenohumeral joint. Thirty one of 52 (71 percent) of all shoulders had a "pop." Twenty-three of 52 (44 percent) shoulders had pain, resolving within 24 hours. CONCLUSION: A modified (Delaware) posterior bone touch technique for glenohumeral joint injection is 97 percent accurate in conscious healthy young subjects. Pop and ease of flow are not always indicative of correct needle placement. This study serves as an important first step in determining an optimum approach for injecting pathologic glenohumeral joints with corticosteroids or hyaluronic acid. LEVEL OF EVIDENCE: IV Case Series. PMID- 24475647 TI - Million Hearts Delaware: collaborating to save a million hearts by 2017. PMID- 24475648 TI - Email--think before you hit "send". PMID- 24475649 TI - [The sequelae of a fish dinner. Bleeding in Bangkok. Foreign body - fishing hook]. PMID- 24475650 TI - [Recent EBM changes good for BAGS and MVZ]. PMID- 24475651 TI - [Ordered laboratory services must now be accurately disclosed]. PMID- 24475652 TI - [Blood specimen collection in nursing homes. Can I delegate this to my MFA?]. PMID- 24475653 TI - [Add students to your consultation - it is worth it!]. PMID- 24475654 TI - [Aspirin for migraine in pregnancy. This recommendation seems questionable]. PMID- 24475655 TI - [Suffering for art. The life of a musician is not an easy ride]. PMID- 24475656 TI - [Not Available]. PMID- 24475657 TI - [Not Available]. PMID- 24475658 TI - [Comorbidities must be treated simultaneously. In COPD not just the lung is involved]. PMID- 24475659 TI - [Acute respiratory tract infections. Response is still too fast]. PMID- 24475660 TI - [Not Available]. PMID- 24475661 TI - [Not Available]. PMID- 24475662 TI - [Not Available]. PMID- 24475663 TI - [Not Available]. PMID- 24475664 TI - [Not Available]. PMID- 24475665 TI - [Not Available]. PMID- 24475666 TI - [Not Available]. PMID- 24475667 TI - [Care of the frail elderly by primary physicians]. PMID- 24475668 TI - [Eating and drinking in old age]. PMID- 24475669 TI - [Routine health check in the elderly]. PMID- 24475670 TI - [Sexuality in older age]. PMID- 24475671 TI - [Leukemia]. PMID- 24475672 TI - [Acute hearing loss]. PMID- 24475673 TI - [Postmortal tissue donation in a forensic setting]. PMID- 24475674 TI - [Hepatitis C update: what has changed? What can we expect in the near future?]. PMID- 24475675 TI - [Coagulation self management. More safety and quality of life]. PMID- 24475676 TI - [Insulin glargine. The most studied basal insulin]. PMID- 24475677 TI - Guillain-Barre syndrome: a common neurological entity with myriad manifestations. PMID- 24475678 TI - Clinical profile of Guillain Barre syndrome. AB - OBJECTIVES: To study clinical presentation, hospital care and outcome of patients of Guillain Barre Syndrome (GBS) and number of patients of respiratory failure and need for ventilators. To study efficacy of IVIg in patients of GBS. MATERIAL AND METHODS: 40 patients of GBS studied in detail including history, clinical examination and investigations (Nerve conduction velocity and C.S.F. examination). All patients were watched for respiratory insufficiency and those who developed respiratory paralysis were given assisted mechanical ventilation. Patients were treated with IVIG and outcome was observed. Outcome of 2 groups of patients one treated with IVIg and other not treated with IVIg (supportive line of treatment) were compared. RESULTS: Commonest age group affected was 13-40 yrs. The male:female ratio was 1.5:1. Antecedent infection in form of fever, cough [11 patients], loose motions [10 patients] were present in 21 out of 40 patients. Quadriparesis was present in 39 patients and paraparesis in 1 patient. Cranial nerve involvement was seen in 25 out of 40 patients. Facial nerve was involved in 12 [30%] patients and Glossopharyengeal, vagus nerves were involved in 12 [30%] patients. Areflexia was found in all 40 patients. In CSF examination, albuminocytologic dissociation was present in 17 out of 26 patients. NCV findings show conduction velocity slowing, delayed f latencies in 90% patients. Out of 40 patients, 13 [30%] required mechanical ventilation. Out of 40 patients, 14 were treated with IVIg, 4 patients treated with plasmapheresis and 22 patients received only supportive treatment. Out of 40 patients 30 [75%] patients recovered completely, 8 [20%] patients died and 2 [5%] patients developed severe neurologic deficit. CONCLUSION: GBS is more common in 13-40 yrs age group with male:female ratio of 1.5:1. Antecedent infection is seen in 55% patients. Commonest presentation was paresthesia in legs and ascending paralysis. One third [32.5%] patients developed respiratory paralysis and needed ventilatory support. Patients who received IVIg early in the course of disease had faster recovery as compared to patients who received only supportive line of treatment. PMID- 24475679 TI - Prevalence and causalities of tobacco consumption (TC) among adolescents: a cross sectional study at Pune. AB - BACKGROUND AND OBJECTIVES: Health risks associated with tobacco consumption (TC) are well known. The aim of this study was to assess the prevalence and causality of tobacco consumption among adolescents. METHODS: A cross-sectional study was conducted with 6577 participants aged 12 to 20 years from 21 schools and colleges in Pune during year 2005/6. Data on socio demographic profile, family members' tobacco habits and respondents' tobacco consumption habits were collected by self administered questionnaire. Convenience sampling method was used for data collection. RESULTS: Complete information on age, gender and participants' consumption of tobacco was available for 6119 students. This data was used for analysis. Average age of the students was 16.9 +/- 1.79 years. 51% were boys. 9% lived in the hostels. Prevalence of TC was 4.2% (256). Prevalence increased from 2.1% at < 14 years to 9.8% at 18 to 20 years of age. Respondents aged < 14 years spent about Rs. 110 per month on tobacco while those over 18 years of age spent about Rs.142 per month (P < 0.05). Significantly (p < 0.0001) more boys (85.2%) consumed tobacco compared to girls (14.8%). Hostel residents consumed tobacco more than those not living in hostel (13% Vs 8.6%). Significantly more (p < 0.0001) number of fathers and brothers of TCs consumed tobacco than non TCs. (Fathers: 53.1% Vs 29.7%), (Brothers: 5.7% Vs 1.1%). CONCLUSION: Tobacco consumption among adolescents in Pune is low. However to reduce it further, intervention should start prior to teenage before they form their opinion and start consuming tobacco. PMID- 24475680 TI - To assess the prevalence of impaired glucose tolerance and impaired fasting glucose in Western Indian population. AB - OBJECTIVES: The objective of the study to determine the prevalence of Impaired Glucose Tolerance and Impaired Fasting Glucose (both combined termed as Pre Diabetes) in the population of Gujarat. METHODS: In year 2007 and 2008, a cross sectional survey was conducted via mode of camps at various urban and rural part of Gujarat. After obtaining an informed consent, comprehensive questionnaire was used to collect the various anthropological details, physical examination and blood collection was performed from around 1700 subjects > or = 20 years of age from the different areas of Gujarat. Chi square test was used for all categorical comparisons. Also multiple logistic regression was used for detailed exploratory analysis. RESULTS: The crude prevalence of IFG in Gujarati population is around 2.76% and IGT is around 6.12%. But the age adjusted prevalence of IFG is around 2.72% and IGT is around 4.67%. If we extrapolate these to population of Gujarat, it indicates that around 1.3 million people are having impaired fasting glucose and around 2.3 million people have impaired glucose tolerance. The prevalence of IGT found more after age of 40 years. For IFG, there is increase after age of 40 years, but not significant statistically. CONCLUSIONS: High prevalence of IGT validates that there are chances of the pandemic trend in Gujarat, as eventually IGT may get converted into Diabetes in near future. These results need urgent attention to develop a public awareness programme. PMID- 24475681 TI - Non-diabetic renal disease (NDRD) in patients with type 2 diabetes mellitus (type 2 DM). AB - In contrast to Type 1 diabetes mellitus (DM), the incidence of non-diabetic renal disease (NDRD) is very high in Type 2 diabetic patients. A wide spectrum of non diabetic nephropathy (NDN) including both glomerular and tubulointerstitial lesions are reported in patients with Type 2 DM and their precise diagnosis requires histological examination of kidney tissue. Renal biopsy studies suggest that 25-50% of patients with Type 2 diabetes had glomerular lesions unrelated to or in addition to diabetic nephropathy. Histological studies confirm that NDRD can occur in isolated form without diabetic nephropathy or superimposed on diabetic nephropathy. Diabetic nephropathy can occur in absence of retinopathy and chance of getting diabetic and non-diabetic renal lesions are nearly equal in Type 2 diabetic patient in absence of diabetic retinopathy (RP). The presence of RP suggests the concurrence of DN, but does not exclude non-diabetic nephropathy. Clearly, renal biopsy is indicated in proteinuric Type 2 diabetic patients for precise diagnosis of diabetic vs non-diabetic renal disease. Appropriate treatment of NDRD is associated with good clinical outcome. Thus, it is gratifying to treat NDRD in selected patients. Besides, 40 to 60% of ESRD in Type 2 diabetic patients is not caused by diabetic nephropathy. PMID- 24475682 TI - Sturge-Weber syndrome. PMID- 24475683 TI - Isolated mediastinal tuberculosis: a rare entity. AB - Tuberculosis is a common disease in India but isolated mediastinal tuberculosis in the form of a tumor has not been described in adults. We are presenting an immunocompetent, elderly male who presented with fever for 2 months. CT scan chest revealed an isolated mass like lesion in the mediastinum, extending to supraclavicular area. Histopathology of the lesion revealed tuberculosis. PMID- 24475684 TI - Unusual presentation of Streptococcus pneumoniae in human immunodeficiency virus infection. AB - Streptococcus pneumoniae usually produces infection of the respiratory tract, inner ear or meninges. Unusual sites of infection have rarely been reported among HIV-1 seropositive patients. We report a case of post auricular subcutaneous abscess caused by Streptococcus pneumoniae in a Human Immunodeficiency Virus (HIV) infected child who also had B cell lymphoma. This case is uncommon as there was no other documented primary focus of pneumococcal infection or a preceding history of bacteraemia or respiratory infection. PMID- 24475685 TI - Transient pericardial constriction. AB - A patient with idiopathic pericardial effusion is reported. Patient developed transient constrictive hemodynamics which recovered with continued empirical use of antitubercular drugs and prednisolone. PMID- 24475686 TI - Staphylococcal septicaemia associated with peripheral neuropathy in three different clinical settings. AB - Among the various etiologies of peripheral neuropathy, S. aureus is a rare cause that is not even mentioned in standard textbooks. Here we like to report three clinical scenarios where patients with different manifestations of S. aureus infection developed peripheral neuropathy presenting as quadriparesis, which subsided gradually with control of infection and supportive care. No other known causes of peripheral neuropathy were present in these cases. PMID- 24475687 TI - Granulocyte macrophage colony stimulating factor therapy for pulmonary alveolar proteinosis. AB - We report a case of 58 year old female diagnosed with Pulmonary Alveolar Proteinosis (PAP) with recurrence of PAP after 5 repeated whole lung lavage, responding to subcutaneous injections of Granulocyte Macrophage Colony Stimulating Factor therapy (GM-CSF). Thus indicating that GM-CSF therapy is a promising alternative in those requiring repeated whole lung lavage PMID- 24475688 TI - Sir Brian Gerald Barratt-Boyes. PMID- 24475689 TI - Medical philately. Joseph Priestly-discoverer of oxygen. PMID- 24475690 TI - Concerns regarding use of immuno suppressive therapies without prior screening for latent tuberculosis in a case of systemic lupus erythematosus presenting with sensorineural deafness. PMID- 24475691 TI - Study of prescribing pattern of antimicrobial agents in medicine intensive care unit of teaching hospital in central India. PMID- 24475692 TI - Author's reply: To PMID 23029737. PMID- 24475693 TI - Hiatus hernia masquerading as left atrial mass. PMID- 24475694 TI - Indian guidelines on hypertension (I.G.H.) - III. 2013. PMID- 24475695 TI - Fungemia due to Rhodotorula mucilaginosa in an immunocompetent, critically ill patient. AB - Infections due to the yeast Rhodotorula are rare in humans. R. mucilaginosa is responsible for the majority of human cases, and immunocompromised individuals with central venous catheters are at greatest risk. There are few reports of bloodstream infections due to R. mucilaginosa in immunocompetent patients. We present a case report of fungemia due to R. mucilaginosa in an immunocompetent, critically ill patient, with good evolution with catheter removal and fluconazole therapy. We briefly review the spectrum of infections due to R. mucilaginosa and the management of bloodstream infections due to this yeast. PMID- 24475696 TI - [Usefulness of real-time PCR in detecting Chlamydia trachomatis and Neisseria gonorrhoeae in endocervical swabs and first-voided urine specimens]. AB - We evaluated performance of Abbott RealTime CT/NG assay (real-time PCR, Abbott Japan) for detect Chlamydia trachomatis and Neisseria gonorrhoeae by real-time PCR in 88 female patients with cervicitis symptoms seen at gynecological clinics and 100 male patients with urethritis symptoms seen at urological or dermatology clinics in Kitakyushu, Japan. Endocervical swab and first-voided urine (FVU) specimens were then collected from women and FVU specimens from men. Detection rates of C. trachomatis and N. gonorrhoeae by real-time PCR in the 3 types of specimens were compared to those by ProbeTec ET assay (ProbeTec, BD Diagnostic System). The overall positive concordance between real-time PCR and ProbTec were 97.1% (66/68) for C. trachomatis and 100% (33/33) for N. gonorrhoeae, C. trachomatis detection yielded 3 discordant results in endocervical specimens and 1 discordant result in male FVU by real-time PCR and ProbTec. Three of 4 reexamined using Aptime Combo 2 Assay (Fuji Rebio Inc.) were positive for C. trachomatis. Endocervical swab and FVU specimen results for C. trachomatis were discordant in 3 cases in real-time PCR and 4 in ProbeTec. Subjects with 2 or more positive endocervical awab results in female or male FVU specimens were assumed to be "true positive" for C. trachomatis. The sensitivities of real-time PCR for detecting C. trachomatis was 94.4% in endocervical swabs, 77.8% in female FVU and 97.4% in the male FVU. The sensitivities for real-time PCR for detectig N. gonorrhoeae was 100% in all 3 specimen types. Abbott RealTime CT/NG assay was useful for detecting C. trachomatis using endocervical swabs or male FVU specimens and for detecting N. gonorrhoeae using endocervical swabs and all FVU specimens. PMID- 24475697 TI - Incidence of sexually transmitted diseases in Hokkaido, Japan, 1998 to 2001. AB - The objective of this study was to provide precise data on the incidence of sexually transmitted diseases (STDs) in Hokkaido. The goal of this prospective surveillance, study was to clarify the STD incidence between 1998 and 2001 in Hokkaido, Japan. The incidence of gonococcal infection in men was found to be 127 199 per 100000 people per year, which was three or four times higher than that for women. Female genital chlamydial infection had an incidence of 300-400 with a female to male ratio of two or three to one. Younger adults had higher incidences of gonococcal and chlamydial infections than older people. In conclusion, the current study of STDs revealed high incidences of gonococcal and chlamydial infections in the Hokkaido area, and there was no decreasing trend in STD incidence during these 4 years. PMID- 24475698 TI - [Epigenetic research progress of anti-tumor drugs]. AB - Epigenetic abnormalities not only associated with carcinogenesis, they may also influence the curative effect and prognosis of anticancer drugs through modifying pharmacokinetic genes related to drug absorption, distribution, metabolism, excretion and pharmacodynamic genes related to signaling pathways and targets. That drugs through regulating epigenetic factors pocessing anti-cancer effect is becoming a research hot spot. We summarized and analyzed the realtionship of DNA methylation, miRNA, and histone modification with antitumor drug effect, aiming at promoting rational use of antitumor drugs and providing new ideas on developing epi-drugs. PMID- 24475699 TI - [Progress in the study of carbonic anhydrase inhibitors as potential anticancer drugs]. AB - Carbonic anhydrase IX (CA IX) is a tumor associated protein which is able to be a potent anticancer target, since it is highly expressed in a multitude of carcinomas, while it is present in a limited number of normal tissues. This review focuses on its role in tumor physiology, the most recent three dimensional structure features of this enzyme which has recently been elucidated. In addition, we present recent advances in the development of small inhibitors able to target CA IX for therapeutic applications. PMID- 24475700 TI - [A review on the influences of size and surface charge of liposome on its targeted drug delivery in vivo]. AB - Liposomes can be cleared by the reticuloendothelial system (RES) when it is in the blood circulation in the body. And they can accumulate in the organs rich in RES in the body by passive targeting. Targeting of the liposomes is an important factor for its use as a drug carrier, and particle size as well as surface charge are important for its in vivo targeting. In this paper, studies on the influences of particle size and surface charge of the liposomes on cell binding and phagocytosis mechanism were reviewed. A comprehensive review on passive targeting effect of the particle size and surface charge of liposomes on blood, liver, spleen as well as tumor tissue was made. At last, an outlook for future research directions was made. PMID- 24475701 TI - [Gene construction and screening of humanized single chain antibody library against VSTM1-v2 cytokine]. AB - To rapidly select potent anti-VSTM1-v2 scFv (single-chain antibody fragment) by construction and screening of a humanized scFv library in which a murine VH-CDR3 library was grafted onto a human scFv framework. A murine VH-CDR3 library was amplified from anti-VSTM1-v2 murine cDNA and grafted on human scFv (VH3-VK1) framework. Anti-VSTM1-v2 scFv templates were selected and enriched through ribosome display, TA-cloned into expression vector, and transformed into BL21 (DE3) for soluble expression of target scFv. A total of 1000 clones were randomly picked. Positive ones were first identified using colony PCR, indirect ELISA, Western blotting and then verified with sequencing and dose response ELISA. At last an anti-VSTM1-v2 humanized scFv with good binding affinity (EC50 = 21.35 nmol x L(-1)) was selected from the humanized library of 10(12) members generated in this study. This scFv antibody might have potential applications. This study provides a new approach for rapid screening of humanized antibodies. PMID- 24475702 TI - [Minimally modified LDL induced impairment of endothelium-dependent relaxation in mesenteric arteries of mice]. AB - This study is to investigate the impairment and possible mechanism of endothelium dependent relaxation of mice mesenteric arteries induced by mmLDL. Wire myography was employed to examine endothelial function of mesenteric arteries. Ultramicrostructure of mesenteric vascular beds were detected by transmission electron microscope. The results showed that endothelium cell edema and peeling, vascular elastic membrane fracture traces in mmLDL group. Endothelium-dependent relaxation was decreased in a time-dependent and dose-dependent manner by using mmLDL, compared with normal arteries. In endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxation, the Rmax and pIC50 were decreased from (63 +/- 5) % and 6.42 +/- 0.09 of normal saline control to (31 +/- 3) % and 5.67 +/- 0.07 in mmLDL group (P < 0.001, P < 0.001), respectively. In nitric oxide (NO) mediated relaxation, the Rmax and pIC50 were decreased from (45 +/- 4) % and 5.93 +/- 0.08 in normal saline control to (32 +/- 4) % and 5.43 +/- 0.11 in mmLDL group (P < 0.05, P < 0.01), respectively. There is no significant alteration of prostacyclin I2 (PGI2) pathway between these two groups. In conclusion, mmLDL induced the impairment of the ultramicrostructure of mesenteric vascular endothelium cell as well as the endothelium-dependent relaxation. The latter includes the dysfunction of NO- and EDHF pathway mediated endothelium-dependent relaxation. PMID- 24475703 TI - [Sulfated modification and anticoagulant activity in vitro of sulfated glucan isolated from the aqueous extract of Hedysarum polybotrys]. AB - SHG was sulfated by chlorosulfonic acid-pyridine method, and six samples which we got were prepared in different reaction conditions. There is a characteristic absorption peak near 260 nm in UV spectra and there are two characteristic absorption peaks near 1240 cm(-1) and 810 cm(-1) in the FT-IR. Degree of sulfation (DS) was calculated by elemental analysis and turbidimetry. Under the same conditions the absorption peaks become strong with the DS increase. The anticoagulant activity of SHG and sulfated modification samples was evaluated by the classic coagulant assays of prothrombin time (PT), activated partial thrombin time (APTT) live enzymes, and plasma thrombin time (TT). Results show that sulfated SHG has a good anticoagulant activity in vitro, and DS increased activity within a certain range. PMID- 24475704 TI - [Design, synthesis and evaluation of bis-nicotine derivatives as inhibitors of cholinesterases and beta-amyloid aggregation]. AB - A novel series of bis-nicotine derivatives (3a-3i) were designed, synthesized and evaluated as bivalent anti-Alzheimer's disease agents. The pharmacological results indicated that compounds 3e-3i inhibited both acetylcholinesterase (AChE) and butyrylcholinesterase (BChE) in the micromolar range (IC50, 2.28-117.86 micromol x L(-1) for AChE and 1.67-125 micromol x L(-1) for BChE), which was at the same potency as rivastigmine. A Lineweaver-Burk plot and molecular modeling study showed that these derivatives targeted both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. Besides, these compounds could significantly inhibit the self-induced Abeta aggregation with inhibition activity (11.85%-62.14%) at the concentration of 20 micromol x L(-1). PMID- 24475705 TI - [Toxicology and tissue distribution of Ruthenium (II) CO-releasing molecules and its interaction with endogenous substances]. AB - Carbon monoxide has been proved to be an important signal molecule in body. Transition metal carbonyl compounds are solidified form of carbon monoxide. Numerous studies have shown that Ruthenium carbonyl carbon monoxide releasing molecules have a strong pharmacological activity. In this paper, five Ruthenium (II) carbonyl CORMs 1-5 were synthesized and their toxicology, tissue distribution and interaction with blood endogenous substances were investigated. The results showed CORMs' IC50 to fibroblasts are ranged from 212.9 to 2089.2 micromol x L(-1). Their oral LD50 to mouse is between 800 to 1600 mg x kg(-1). After repeated administration, CORMs 1 and CORMs 5 haven't shown an obvious influence to rats' liver and kidney function, but caused the injury to liver and kidney cells. The in vivo distribution result revealed the majority of CORMs were distributed in blood, liver and kidney, only a small part of CORMs distributed in lung, heart and spleen. They could scarcely cross the blood-brain barrier and distribute to brain. The non-CO ligands in structure have an obvious relevance to their in vivo absorption and distribution. Interestingly, CORMs could enhance the fluorescence of bovine serum albumin, and this enhancement was in direct proportion with the concentration of CORMs. Under different conditions, interaction of CORMs with glutathione got different type of products, one is Ruthenium (II) tricarbonyl complexes, and Ruthenium (II) dicarbonyl complexes. PMID- 24475706 TI - Metabolites from the endophytic fungus Penicillium sp. FJ-1 of Ceriops tagal. AB - To investigate the chemical constituents of the endophytic fungus Penicillium sp. FJ-1 of Ceriops tagal, the chemical constituents were isolated by column chromatography on silica gel and Sephadex LH-20. Their structures were elucidated on the basis of spectroscopic analysis. Their antibacterial activity was tested by paper disco diffusion method. Two compounds were isolated and identified as 7 hydroxy-deoxytalaroflavone (1), and deoxytalaroflavone (2). Compound 1 is a new compound, and compounds 1 and 2 showed weak activity against Staphylococcus aureus and methicillin-resistant Staphylococcus aureus. PMID- 24475707 TI - [Monitoring of chemical components with different color traits of Tussilago farfara using NMR-based metabolomics]. AB - The quality and grade of traditional Chinese medicinal herbs were assessed by their characteristics traditionally. According to traditional experience, the quality of the purple Flos Farfarae is better than that of yellow buds. NMR-based metabolomic approach combined with significant analysis of microarray (SAM) and Spearman rank correlation analysis were used to investigate the different metabolites of the Flos Farfarae with different color feature. Principal component analysis (PCA) showed clear distinction between the purple and yellow flower buds of Tussilago farfara. The S-plot of orthogonal PLS-DA (OPLS-DA) and t test revealed that the levels of threonine, proline, phosphatidylcholine, creatinine, 4, 5-dicaffeoylquinic acid, rutin, caffeic acid, kaempferol analogues, and tussilagone were higher in the purple flower buds than that in the yellow buds, in agreement with the results of SAM and Spearman rank correlation analysis. The results confirmed the traditional medication experience that "purple flower bud is better than the yellow ones", and provide a scientific basis for assessing the quality of Flos Farfarae by the color features. PMID- 24475708 TI - [Comparative study on pharmacokinetics and tissue distribution of a novel microemulsion based on the paclitaxel/L-OH lipid complex and paclitaxel injection in cremophor]. AB - The pharmacokinetics and tissue distributions of the novel paclitaxel microemulsion based on the L-OH lipid complex made in our laboratory were studied in this article with the commercial paclitaxel injection in cremophor as reference preparation by injected intravenously with single dose of 5 mg x kg(-1) in rats. LC-MS/MS method was used to determine the drug concentration in plasma and calculate the pharmacokinetic parameters. [3H]-paclitaxel was used to reveal the tissue distributions of different organs in 0.5 h, 3 h, 24 h and 120 h. The results indicated that the AUC of the emulsion group descended to 42.55%, with the CLz and Vz increased by 2.27 times and 3.81 times respectively. Tissue distribution results revealed that the emulsion showed a significantly increase in liver and spleen with a peak concentration up to 5 times; a slightly increase was observed in lung with no statistical differences; a significantly decrease in heart, kidney, gastrointestinal tract, bone marrow, aorta, thymus, pancreas, fat, muscle, skin, seminal vesicle, reproductive organs and brain with a drop of 40% 80%. These results indicated that paclitaxel microemulsion based on L-OH lipid complexes can remarkably reduced the blood exposure, accelerate plasma clearance rate and increase distribution volume. The fact that paclitaxel microemulsion tended to be uptake by reticuloendothelial system (RES) contributed to the target in liver, spleen and lung, and help to reduce the toxicity in blood, heart, kidney and gastrointestinal tract. PMID- 24475709 TI - [Rapid screening and quality evaluation for the harmful substance 5-hydroxymethyl furfural in commercially available traditional Chinese medicine injection using LC-MS/MS method]. AB - To screen the harmful substance 5-hydroxymethyl furfural content in commercially available traditional Chinese medicine injection which are commonly used, and to preliminarily evaluate the quality of these injections, 5-hydroxymethyl furfural was taken as an index. The contents of 5-hydroxymethyl furfural in 56 samples which consist of 23 kinds of traditional Chinese medicine injections and glucose injection were determined using LC-MS/MS, and 5-hydroxymethyl furfural was detected in 52 of these samples. The minimal content was 0.0038 microg x L(-1) and the maximum content was 1420 microg x mL(-1). The contents of 5-hydroxymethyl furfural were significantly different in traditional Chinese medicine injection which came from different kinds, manufacturers or batches. The results showed the quality difference of commercially available traditional Chinese medicine injection is significant taking 5-hydroxymethyl furfural content as assessment index. More attention should be paid to the safety of 5-hydroxymethyl furfural in traditional Chinese medicine injection, and unified limitation standard should be set to improve medication safety of traditional Chinese medicine injection. PMID- 24475710 TI - [Adsorption and release behavior of epirubicin hydrochloride on carboxylated single-walled carbon nanotubes]. AB - In this study, the adsorption behavior of epirubicin hydrochloride (EPI) on carboxylated single-walled carbon nanotubes (c-SWNTs) obtained by mixture acid treatment was investigated. The results indicated that the dispersion of c-SWNTs in water was obviously improved. The absorption of EPI on c-SWNTs came to equilibrium after 240 min and could be explained by pseudo-second-order model. Moreover, there were heterogeneous distribution of active sites onto c-SWNTs surface and the Freundlich isotherm model was better fit to describe the absorption precess of EPI on c-SWNTs. The absorption capacity of EPI on c-SWNTs increased obviously with the increasing pH and decreasing temperature. Compared with multi-walled carbon nanotubes, carboxylated multi-walled carbon nanotubes, SWNTs, c-SWNTs possessed higher absorption capacity for EPI. The controlled, targeted and sustained release of EPI from c-SWNTs-EPI could be instructive for the development of nano-carrier. PMID- 24475711 TI - [Study on different factors affecting the bionic enzymatic hydrolysis of icariin]. AB - This study aims to observe different factors which affected the bionic enzymatic hydrolysis of icariin into baohuoside I and to optimize the reaction conditions in order to provide research foundation for building a novel bionic enzymolysis drug delivery system. To simulate the environment in vivo, 37 degrees C was set as the temperature and artificial intestinal juice and gastric juice were selected as the buffer solutions. Taking the conversion of baohuoside I as index, the effects of the kinds of enzyme, enzyme activity, substrate concentration, reaction time, pancreatin in artificial intestinal juice and surfactant on the conversion of baohuoside I were investigated. The results showed that cellulase, beta-glucosidase and snailase were all inactive in artificial gastric juice and no baohuoside I generated. Pancreatin in artificial intestinal juice couldn't significantly influence the activity of beta-glucosidase or snailase (P > 0.05), but noticeably decrease the activity of cellulase (P < 0.05). In artificial intestinal juice, the conversion of baohuoside I was highest by using beta glucosidase, and the optimum reaction conditions were determined as follows: enzyme activity 10 U x mL(-1), substrate concentration 1 mg x mL(-1), 3 g x L(-1) rhamnolipid and reaction time 3 h. Under this condition, the conversion of baohuoside I was 99.8%. PMID- 24475712 TI - [Sequence analysis and identification of a chloroplast matK gene in Rhei Rhizoma from different botanical origins]. AB - Rhei Rhizoma is a Chinese medicine with multiple botanical origins. There is a problem to identify it with conventional methods. To compare the characteristics of chloroplast matK gene sequences of different Rheum species and authenticate inspected species, the matK gene sequences of different species from different origins were amplified, cloned, and sequenced. Genomic DNA of Rheum plants was extracted using modified DNA extracted Kit and matK gene sequences were analyzed by ContingExpress, DNAman and MEGA5.0. The length of matK gene sequences of Rheum palmatum, R. tanguticum and R. officinale were 1 518 bp containing 57 variable loci. According to the mutation sites, R. palmatum, R. tanguticum and R. officinale were divided into different genotypes separately. Based on the established method according to the loci 587, 707, 838, we successfully identified the genuine Rheum species from its adulterants. PMID- 24475713 TI - [Primary co-culture of cortical neurons and astrocytes of new-born SD rats]. AB - This study is to establish a simple and practical co-culture method of cortical neurons and astrocytes of rats. The cortex of the new-born SD rats was digested by 0.125% pancreatic enzyme, and the differential adherence was applied to obtain the mixed cell suspension of neurons and astrocytes. A low concentration of cytarabine was used to inhibit the astrocytes in a moderate way to get neuronal and astrocyte co-culture. The morphological characteristics of the cells in different times were observed under the inverted microscope. The cells began to adhere the wall 2 h after the inoculation. Neurons and astrocytes grew in a good condition under the inverted microscope 9 days after the inoculation. The results of the immunofluorescence staining and Rosenfeld's staining indicated that the co culture of neurons and astrocytes was successful and the ratio of neurons and astrocytes was close to 1:1. A new neurons and astrocytes co-culture method, which is simple and convenient, was successfully established. It will be an efficient method for the related researches about neuronal and astrocyte co culture in vitro. PMID- 24475714 TI - [Urine metabonomic study of intervention effects of Morinda officinalis how. on 'kidney-yang deficiency syndrome']. AB - To investigate the intervention effects of Morinda officinalis How. on 'Kidney yang deficiency syndrome' induced by hydrocortisone in rats, the metabolic profiles of rat urine were characterized using proton nuclear magnetic resonance and principal component analysis (PCA) was applied to study the trajectory of urinary metabolic phenotype of rats with 'Kidney-yang deficiency syndrome' under administration of M. officinalis at different time points. Meanwhile, the intervention effects of M. officinalis on urinary metabolic potential biomarkers associated with 'Kidney-yang deficiency syndrome' were also discussed. The experimental results showed that in accordance to the increased time of administration, an obvious tendency was observed that clustering of the treatment group moved gradually closed to that of the control group. Eight potential biomarkers including citrate, succinate, alpha-ketoglutarate, lactate, betaine, sarcosine, alanine and taurine were definitely up- or down-regulated. In conclusion, the effectiveness of M. oficinalis on 'Kidney-yang deficiency syndrome' is proved using the established metabonomic method and the regulated metabolic pathways involve energy metabolism, transmethylation and transportation of amine. Meanwhile, the administration of M. officinalis can alleviate the kidney impairment induced by 'Kidney-yang deficiency syndrome'. PMID- 24475716 TI - [Stress physiology--an important field in science of life maintenance and disease control]. PMID- 24475715 TI - [The protective effect of asiatic acid against oxygen-glucose deprivation/reoxygenation injury of PC12 cells]. AB - To study the protective effect and preliminary mechanisms of asiatic acid against oxygen-glucose deprivation/reoxygenation (OGD/R) injury of PC12 cells, Na2S2O4 combined with low glucose induced damage of PC12 cells was served as OGD/R injury model in vitro. MTT method was used to evaluate cell survival. Ultraviolet spectrophotometry was performed to determine lactate dehydrogenase (LDH) leakage, lactic acid (LD) content, intracellular superoxide dismutase (SOD), malonyldialdehyde (MDA), and cellular Caspase-3 activity. Flow cytometry was applied to assay cell apoptosis. Na2S2O4 combined with low glucose induced significant cell survival rate decreasing compared with normal cells. Cell survival rate increasing, LDH leakage alleviating, LD producing inhibiting, SOD activity promotion, MDA content reducing, cell apoptotic rate decreasing and Caspase-3 activity inhibiting were observed when cells were preincubated with different concentration of asiatic acid (10, 1 and 0.1 micromol x L(-1)). Evident protective effect of asiatic acid against OGD/R injured PC12 cells was verified in our experiment, and the possible mechanisms were related to eliminating free radicals and inhibiting cell apoptosis. PMID- 24475717 TI - [Hypoxia and the brain-endocrine-immune network function--the governing role of CRF and CRFR1]. PMID- 24475718 TI - [Physiological significance of nongenomic mechanisms of glucocorticoids]. AB - Glucocorticoids (GC) are the most important regulatory hormones involved in stress response. GCs are also widely used clinically as anti-inflammatory and immunosuppressive drugs. In addition to the well-known classical genomic mechanisms, GCs also take effects by nongenomic mechanisms. The therapeutic benefits of nongenomic GC actions have been exploited in clinical medicine, especially with high-dose pulsed glucocorticoid administration. However, it is certainly not the case that the inherent non-genomic glucocorticoid mechanisms evolved only for their clinical utility. So that there must exist some unrevealed important physiological significance. Based onour series of studies focusing on the active actions of the rapid secreted GC over the last few years and literature review, we propose that the physiological significance of nongenomic mechanisms of GC lies in stress regulation. PMID- 24475719 TI - [Stress and metabolic regulation]. AB - The stress is generated in response to changes in internal and external environment of the body is characterized by systemic reactions to neuroendocrine activation of the immune network. More and more evidence suggests that highly activated under stress conditions neuroendocrine immune network will have a strong and sustained influence on the body's metabolism. The effect of stress on the metabolism is not only confined to the glucose metabolism, fat metabolism and protein metabolism, and important role in regulating the metabolism of trace elements. Sustained high-load stress on the metabolism of the negative impact beyond the body's compensatory capacity will lead to a disease such as diabetes, atherosclerosis and secondary diseases. PMID- 24475720 TI - [ER stress and cardiometabolic disease: role of adipokines]. AB - ER stress is defined as an imbalance between protein synthesis and protein folding capacity, resulting in the accumulation of misfolded or unfolded protein in ER. Temperate ER stress through UPR enhances the folding capacity of ER and restores the ER homeostasis, exerting a cell protection role. While prolonged ER stress lead to inflammation, cell dysfunction and apoptosis, which takes part in the progression of insulin resistance and atherosclerosis. In the condition of obesity or hyperhomocysteinemia, ER stress in adipose tissue, hypothalamus, liver and other tissue or organs causes the dysregulation of adipokines secretion as well as abnormal receptor or post-receptor signal transduction, which plays an significant role in cardiometabolic disease. PMID- 24475721 TI - [Cognitive neuroscience of stress]. AB - Stress has profound impacts on physiology, the brain, cognition and behaviour. In response to stress, the brain initiates several neuromodulatory and endocrine systems. This leads to the release of stress-sensitive mediators, including neuromodulators, hormones and neuropeptides, which in turn feed back on the brain and thus alters cognition and behaviour. As the progress of sophisticated cognitive neuroimaging techniques, cognitive neuroscientists have begun to elucidate the psychological and neural mechanisms underlying detrimental and beneficial effects of stress on emotion, cognition and behaviour in the human brain. Stress-related neuromodulations occur at various stages of information processing, from the initial vigilance, attention, executive functions, learning and memory, and emotion. We reviewed recent advances in cognitive neuroscience of stress and proposed a multidimensional model of stress for better understanding how stress-sensitive neuromodulatory and endocrine systems interplay to impact the brain, cognition and behaviour in humans. PMID- 24475722 TI - [Space stress injury and related protective measures]. AB - The stressors, such as microgravity, noise, radiation, narrow and isolated environment and excessive workload, affect astronauts' physical and mental health. Stress-induced disruption in nervous system, including decreased ability to response and perform physical or mental tasks during medium-term or long-term space flight, which can impact both astronauts' health and accomplishment of the task. This is a crucial space medicine issue to be solved. This paper reviews the progress on the hazard, mechanism, precipitating factors and countermeasure of stress injury in spaceflight and provides theories to develop the prevention and treatment of spaceflight-related stress injury. PMID- 24475723 TI - [The role of prostaglandin E2 in regulating urine concentration]. PMID- 24475724 TI - [Effect of kupffer cells on mechanisms of nonalcoholic fatty liver disease]. PMID- 24475725 TI - [Diabetes mellitus and myocardial pharmacological postconditioning]. PMID- 24475726 TI - [The progress of the calcium-dependent regulation on cardiac L-type calcium channels]. PMID- 24475727 TI - [The role of miRNA-155 in cardiovascular diseases]. PMID- 24475728 TI - [Cardiovascular effects of relaxin]. PMID- 24475729 TI - [The research progress of beta1-adrenergic receptor autoantibodies in heart failure]. PMID- 24475730 TI - [mTOR signaling as a fuel sensor and its role in the regulation of energy homeostasis]. PMID- 24475731 TI - [Small heat shock proteins and ischemic heart disease]. PMID- 24475732 TI - [Progress in research on animal GnRH-I immune castration]. PMID- 24475733 TI - Synchrotron based FT-FIR pure rotational spectroscopy of the NH2 radical in its two lowest vibrational states. AB - Six Fourier-transform FIR spectra of the NH2 radical have been recorded at high resolution (0.001 cm(-1)) using synchrotron radiation on the AILES beamline at SOLEIL Synchrotron. Three different experimental discharge setups have been used to observe, in absorption, 1009 pure rotational transitions of NH2 in the vibrational ground state (000) and 170 pure rotational transitions within the first excited vibrational state (010). These results constitute a significant extension of the observed quantum numbers for these two states. The spectra permitted several couplings to be resolved (asymmetric coupling, spin-rotation coupling, hyperfine structure) for relatively highly excited energy levels. An effective fit has been realized using both standard Watson-S and -A reductions despite an abnormal centrifugal distortion effect for this light hydride. PMID- 24475734 TI - Prognostic value of apolipoprotein E epsilon4 allele in patients with traumatic brain injury: a meta-analysis and meta-regression. AB - AIMS: Current scientific evidence suggests that the apolipoprotein E epsilon4 (APOE4) allele may be associated with a good prognosis for patients with traumatic brain injury (TBI); however, many existing studies have yielded inconclusive results. This meta-analysis aims to obtain a more precise estimation of the association between APOE4 allele and prognosis of TBI patients. METHODS: A literature search of PubMed, Embase, Web of Science, Cochrane Library, CISCOM, CINAHL, Google Scholar, CNKI and CBM databases was conducted for articles published before July 1st, 2013. Crude odds ratios (OR) with 95% confidence intervals (CI) were calculated. RESULTS: Thirteen cohort studies were included with a total of 662 TBI patients with APOE4 (+) and 1614 TBI patients with APOE4 (-). The meta-analysis results revealed that the APOE4 allele was associated with a poor prognosis in TBI patients (OR=0.68, 95% CI: 0.48-0.96, p=0.027). Subgroup analysis by ethnicity indicated that TBI patients with APOE4 (+) had a worse prognosis than those with APOE4 (-) in Asian populations (OR=0.46, 95% CI: 0.21 0.99, p=0.046), but not in Caucasian populations (OR=0.75, 95% CI: 0.53-1.08, p=0.120). A further subgroup analysis by TBI grade showed that the APOE4 allele was associated with poor prognosis in severe TBI patients (OR=0.43, 95% CI: 0.21 0.87, p=0.020). However, there was no evidence for any association between the APOE4 allele and poor prognosis in patients with other grades of TBI (all p>0.05). CONCLUSION: The current meta-analysis indicates that the APOE4 allele may be associated with a poor prognosis in severe TBI patients and in Asian populations. The APOE4 allele may be used as a biomarker in predicting the prognosis of TBI patients. PMID- 24475735 TI - Structure determinants for the substrate specificity of acyl-CoA Delta9 desaturases from a marine copepod. AB - In contrast to soluble acyl-ACP desaturases from plants, little is known about the structure-guiding principle underlying substrate specificity and regioselectivity of membrane-bound acyl-CoA desaturases from animals, mainly due to lack of the three-dimensional structure information. Here we report identification of two homologous membrane-bound acyl-CoA Delta9 desaturases (ChDes9-1 and ChDes9-2) from the marine copepod Calanus hyperboreus that accumulates more than 90% of total storage lipids in the form of wax esters. ChDes9-2 is a common Delta9 desaturase with substrate specificity to long chain fatty acid 18:0, while ChDes9-1 is a new type of Delta9 desaturase introducing a Delta9 double bond into a wide range of very long chain fatty acids ranging from 20:0 to 26:0. Reciprocal domain swapping and site-directed mutagenesis guided by the membrane topology revealed that presence or absence of an amphipathic and bulky residue, tyrosine, in the middle of the second transmembrane domain was important in determining the substrate specificity of the two desaturases. To examine the mechanistic structure for the substrate specificity, tyrosine scanning mutagenesis was employed to systematically substitute the residues in the transmembrane domain of the very long chain desaturase. The results showed that the transmembrane domain formed an alpha-helix structure probably involved in formation of the substrate-binding pocket and the corresponding residue of the tyrosine likely resided at the critical position within the pocket mediating the interaction with the substrates, thereby specifying the chain length of the substrates. PMID- 24475736 TI - Characterization of a novel resistance-related deoxycytidine deaminase from Brassica oleracea var. capitata. AB - Brassica oleracea deoxycytidine deaminase (BoDCD), a deoxycytidine deaminase (DCD, EC 3.5.4.14) enzyme, is known to play an important role in the Trichoderma harzianum ETS 323 mediated resistance mechanism in young leaves of B. oleracea var. capitata during Rhizoctonia solani infection. BoDCD potentially neutralizes cytotoxic products of host lipoxygenase activity, and thereby BoDCD restricts the hypersensitivity-related programmed cell death induced in plants during the initial stages of infection. To determine the biochemical characteristics and to partially elucidate the designated functional properties of BoDCD, the enzyme was cloned into an Escherichia coli expression system, and its potential to neutralize the toxic analogues of 2'-deoxycytidine (dC) was examined. BoDCD transformants of E. coli cells were found to be resistant to 2'-deoxycytidine analogues at all of the concentrations tested. The BoDCD enzyme was also overexpressed as a histidine-tagged protein and purified using nickel chelating affinity chromatography. The molecular weight of BoDCD was determined to be 20.8 kDa as visualized by SDS-PAGE. The substrate specificity and other kinetic properties show that BoDCD is more active in neutralizing cytotoxic cytosine beta d-arabinofuranoside than in deaminating 2'-deoxycytinde to 2'-deoxyuridine in nucleic acids or in metabolizing cytidine to uridine. The optimal temperature and pH of the enzyme were 27 degrees C and 7.5. The Km and Vmax values of BoDCD were, respectively, 91.3 MUM and 1.475 mM for its natural substrate 2' deoxycytidine and 63 MUM and 2.072 mM for cytosine beta-d-arabinofuranoside. The phenomenon of neutralization of cytotoxic dC analogues by BoDCD is discussed in detail on the basis of enzyme biochemical properties. PMID- 24475737 TI - Biokinetic data and models for occupational intake of lanthanoids. AB - PURPOSE: This paper reviews data related to the behavior of the lanthanoid elements (lanthanum through lutetium, atomic numbers 57-71) in the human body and proposes biokinetic models for internally deposited radio-lanthanoids in workers. MATERIALS AND METHODS: Published data on the following topics are reviewed and analyzed: Physico-chemical properties of the lanthanoids as indicators of the potential behavior of these elements in body fluids; the concentrations of the stable lanthanoids in the environment and human body; and results of biokinetic studies of radio-lanthanoids in human subjects and laboratory animals. Respiratory and systemic biokinetic models and gastrointestinal absorption fractions are developed or selected in an effort to represent the typical behavior of lanthanoids in adult humans. RESULTS AND CONCLUSIONS: Generic (element-independent) absorption rates from the respiratory and alimentary tracts to blood and systemic biokinetic models are proposed. The systemic models are largely generic but include some element-specific parameter values to reflect regular changes with ionic radius in certain aspects of the behavior of the lanthanoids, particularly fractional deposition in liver and bone and early removal in urine. PMID- 24475738 TI - Extremely low frequency magnetic field (50 Hz, 0.5 mT) modifies fitness components and locomotor activity of Drosophila subobscura. AB - PURPOSE: Extremely low frequency (ELF) magnetic fields are essential ecological factors which may induce changes in many organisms. The aim of this study was to examine the effects in Drosophila subobscura exposed for 48 h to ELF magnetic field (50 Hz, 0.5 mT) at different developmental stages. MATERIALS AND METHODS: Egg-first instar larvae developmental stage of D. subobscura isofemale lines was exposed to ELF magnetic field, and fitness components (developmental time, developmental dynamics, viability and sex ratio) and locomotor activity of three day-old males and females were monitored. Also, just eclosed D. subobscura isofemale adults were exposed to ELF magnetic field and their locomotor activity was monitored just after. RESULTS: ELF magnetic field shortens developmental time, increases viability and does not affect sex ratio of D. subobscura. No matter which developmental stage is exposed, ELF magnetic field significantly decreases locomotor activity of adult flies, but after exposure of just eclosed adults observed change lasts longer. CONCLUSIONS: Applied ELF magnetic field modifies fitness components and locomotor activity of D. subobscura. Observed effects can be attributed to the influence of magnetic field on different stages of development where the hormonal and nervous systems play important role in the control of examined parameters. PMID- 24475739 TI - The role of iron oxide nanoparticles in the radiosensitization of human prostate carcinoma cell line DU145 at megavoltage radiation energies. AB - PURPOSE: To examine the radiosensitizing effects of iron oxide nanoparticles in the presence of 6 MV (megavoltage) X-ray radiation. MATERIALS AND METHODS: Iron oxide nanoparticles with two different modifications - dextran coating (plain) and amino-group dextran coating - were used. The rate of iron oxide penetration was monitored using Prussian blue staining, magnetic resonance imaging and atomic adsorption spectroscopy. The effect of iron oxide on the viability of cells was determined using trypan blue dye exclusion assay followed by evaluating the cytotoxicity effect of amino-group iron oxide nanoparticles and ionizing radiation. Radiation dose enhancement studies were carried out on DU145 human prostate carcinoma cell line with 1 mg/ml amino-group iron oxide nanoparticles and different doses of 6 MV X-ray radiation. RESULTS: The uptake of amino-group coated nanoparticles by DU145 cells was significantly more than the plain nanoparticles. In addition, cell viability was decreased with the increase of iron oxide concentration. The dose enhancement factor (DEF) is approximately 1.2 at different doses in the range of 2-8 Gy of 6 MV X-ray radiation. CONCLUSIONS: It was demonstrated that iron oxide nanoparticles with the appropriate surface modifications can enter the DU145 cells and it can be used as a cell sensitizer to megavoltage ionizing radiations in radiation therapy. PMID- 24475740 TI - Unusual mucoepidermoid carcinoma of the liver misdiagnosed as squamous cell carcinoma by intraoperative histological examination. AB - As rare condition, mucoepidermoid carcinoma may occur in liver although its etiology and pathogenesis is still unclear. We report here a case of intrahepatic mucoepidermoid carcinoma misdiagnosed as cholangiocarcinoma and squamous cell carcinoma by preoperative radiologic and intraoperative histological examinations, respectively. A 60-year-old woman presented with a 1-month history of progressive jaundice, epigastric discomfort, and weight loss with slightly increased carbohydrate antigen 19-9 (CA19-9). Computed tomography (CT) showed a large tumor, 8.0 cm in diameter, in the left lobe of the liver. A preliminary diagnosis of a cholangiocarcinoma of the liver was made. In the intraoperative histological examination, a diagnosis of squamous cell carcinoma was made based on predominantly invasive epidermoid cells with abundant keratinization and absence of mucin-producing cell component. However, postoperative histological diagnosis of the lesion was mucoepidermiod carcinoma of liver by thoroughly microscopical inspection and the presence of mucin-producing cells confirmed by Alcian blue staining. Despite surgical excision and chemotherapy, the tumor showed very aggressive malignancy with tumor recurrence. The patient died shortly afterward, surviving 6 months after surgery. Due to its rarity and distinct morphological features, mucoepidermoid carcinoma might be erroneously interpreted as squamous cell carcinoma by those who were not familiar with this condition in unusual locations. Therefore, removal of sufficient tissue from different portions of the lesion is essential for the surgeons and pathologists to make a precise diagnosis in the intraoperative histological examination. VIRTUAL SLIDE: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/4956311271136060. PMID- 24475742 TI - Paediatric urachal benign teratoma: a case report and review of the literature. AB - Urachal anomalies are most often seen in children, seldom in adults, but are in general considered rare. The estimated incidence is one in 5000-7000 live births and appears twice as common in males. Despite their rarity, they need to be considered by clinicians, as diseases in the urachus can mimic many abdominal and pelvic conditions and constitute an important differential diagnosis to these. Diagnosis can be made by clinical examination and imaging modalities (computed tomography, ultrasonography, magnetic resonance imaging, voiding cystourethrogram), but some are discovered incidentally. Management of symptomatic urachal anomalies is surgery. Histological examination of the specimen should always be performed to rule out malignancy. We report on the first adolescent described in the literature diagnosed with a urachal sinus harboring a benign teratoma. A combination of the two pathologies is by inference an extremely rare condition, which we here report on and we review the relevant literature on this topic. PMID- 24475741 TI - Evidence that BDNF regulates heart rate by a mechanism involving increased brainstem parasympathetic neuron excitability. AB - Autonomic control of heart rate is mediated by cardioinhibitory parasympathetic cholinergic neurons located in the brainstem and stimulatory sympathetic noradrenergic neurons. During embryonic development the survival and cholinergic phenotype of brainstem autonomic neurons is promoted by brain-derived neurotrophic factor (BDNF). We now provide evidence that BDNF regulates heart rate by a mechanism involving increased brainstem cardioinhibitory parasympathetic activity. Mice with a BDNF haploinsufficiency exhibit elevated resting heart rate, and infusion of BDNF intracerebroventricularly reduces heart rate in both wild-type and BDNF+/- mice. The atropine-induced elevation of heart rate is diminished in BDNF+/- mice and is restored by BDNF infusion, whereas the atenolol-induced decrease in heart rate is unaffected by BDNF levels, suggesting that BDNF signaling enhances parasympathetic tone which is diminished with BDNF haploinsufficiency. Whole-cell recordings from pre-motor cholinergic cardioinhibitory vagal neurons in the nucleus ambiguus indicate that BDNF haploinsufficiency reduces cardioinhibitory vagal neuron activity by increased inhibitory GABAergic and diminished excitatory glutamatergic neurotransmission to these neurons. Our findings reveal a previously unknown role for BDNF in the control of heart rate by a mechanism involving increased activation of brainstem cholinergic parasympathetic neurons. PMID- 24475743 TI - Volunteers in specialist palliative care: a survey of adult services in the United Kingdom. AB - BACKGROUND: Worldwide, the demand for specialist palliative care is increasing but funding is limited. The role of volunteers is underresearched, although their contribution reduces costs significantly. Understanding what volunteers do is vital to ensure services develop appropriately to meet the challenges faced by providers of palliative care. OBJECTIVE: The study's objective is to describe current involvement of volunteers with direct patient/family contact in U.K. specialist palliative care. DESIGN: An online survey was sent to 290 U.K. adult hospices and specialist palliative care services involving volunteers covering service characteristics, involvement and numbers of volunteers, settings in which they are involved, extent of involvement in care services, specific activities undertaken in each setting, and use of professional skills. RESULTS: The survey had a 67% response rate. Volunteers were most commonly involved in day care and bereavement services. They entirely ran some complementary therapy, beauty therapy/hairdressing, and pastoral/faith-based care services, and were involved in a wide range of activities, including sitting with dying patients. CONCLUSIONS: This comprehensive survey of volunteer activity in U.K. specialist palliative care provides an up-to-date picture of volunteer involvement in direct contact with patients and their families, such as providing emotional care, and the extent of their involvement in day and bereavement services. Further research could focus on exploring their involvement in bereavement care. PMID- 24475744 TI - Exploring the experiences of people with the dual diagnosis of acquired brain injury and mental illness. AB - PRIMARY OBJECTIVE: People with the dual diagnosis of acquired brain injury and mental illness (ABI/MI) are vulnerable to a range of negative life experiences, which has received limited attention in the literature. The objective of the project described in this paper was to identify and describe these experiences in order to distinguish barriers and facilitators to successful rehabilitation and recovery. RESEARCH DESIGN: The project used qualitative methodologies. METHODS AND PROCEDURES: The 15 participants were eight people with ABI/MI, two family members and five support workers. Nineteen interviews were conducted. Analysis of these interviews produced a set of five key themes, with each theme elaborated by a set of descriptive issues. MAIN OUTCOMES AND RESULTS: The five themes were loss, personal development, occupation, family and services. The experiences of people with ABI/MI were strongly negative. They faced more barriers than facilitators to recovery. Current policies and practices were inadequate. CONCLUSIONS: Enhanced stakeholder collaboration and co-ordination and a more individualized, long-term perspective on the needs of people with ABI/MI are recommended to guide future policy and practice. Future research on quality-of life, wellbeing, community inclusion and participation in ordinary life was recommended. PMID- 24475745 TI - Concussions and heading in soccer: a review of the evidence of incidence, mechanisms, biomarkers and neurocognitive outcomes. AB - BACKGROUND: Soccer is currently the most popular and fastest-growing sport worldwide. Similar to many sports, soccer carries an inherent risk of injury, including concussion. Soccer is also unique in the use of 'heading'. The present paper provides a comprehensive review of the research examining the incidence, mechanisms, biomarkers of injury and neurocognitive outcomes of concussions and heading in soccer. METHODS: Seven databases were searched for articles from 1806 to 24 May 2013. Articles obtained by the electronic search were reviewed for relevance, with 229 selected for review. Ultimately, 49 articles met criteria for inclusion in the present review. RESULTS: Female soccer players have a higher incidence of concussions than males. The most frequent injury mechanism is player to-player contact for both genders. Few studies examined the effects of concussion in soccer players; however, neurocognitive outcomes were similar to those reported in the larger sport concussion literature, while the effect of heading is less clear. CONCLUSION: Despite variation in research designs and study characteristics, the outcomes of concussions in soccer align with the greater concussion literature. This review makes recommendations for future research to increase standardization of research for improved understanding of concussions in soccer as well as the effects of heading. PMID- 24475746 TI - Relationships after TBI: a grounded research study. AB - BACKGROUND: While study on the emotional effects of traumatic brain injury (TBI) for individuals and caregivers has increased dramatically over the years, insufficient research has been performed on TBI's impact on the coupled relationship or the healing process successful couples go through following injury. As such, couples are left on their own to adjust to the complex challenges that TBI brings. METHODS: This qualitative study aims to develop a framework for conceptualizing and assessing couples after TBI. Additionally, it purposes to establish a foundation built upon the practises of successful couples that have subsisted TBI from which methods of treatment can be drawn. Existing personal narratives written by survivors of TBI and their caregivers were analysed. Data triangulation with clinician-authored literature was performed. Constant comparative analysis of the data was then performed through an involving substantive and theoretical coding. RESULTS: Five primary themes emerged: Ambiguous Losses, Identity Reformations, Tenuous Stability, Non Omnes Moriar and The New Us. From these, two grounded theories were developed: Relational Coring and Relational Recycling. CONCLUSIONS: These theories will allow researchers and practitioners to grasp the impact of TBI on the coupled relationship, familiarize themselves with the process by which relational experiences following TBI interact and understand the ways in which couples respond to these interacting experiences to work toward relational healing. PMID- 24475747 TI - Role of the seeding promoter in MoS2 growth by chemical vapor deposition. AB - The thinnest semiconductor, molybdenum disulfide (MoS2) monolayer, exhibits promising prospects in the applications of optoelectronics and valleytronics. A uniform and highly crystalline MoS2 monolayer in a large area is highly desirable for both fundamental studies and substantial applications. Here, utilizing various aromatic molecules as seeding promoters, a large-area, highly crystalline, and uniform MoS2 monolayer was achieved with chemical vapor deposition (CVD) at a relatively low growth temperature (650 degrees C). The dependence of the growth results on the seed concentration and on the use of different seeding promoters is further investigated. It is also found that an optimized concentration of seed molecules is helpful for the nucleation of the MoS2. The newly identified seed molecules can be easily deposited on various substrates and allows the direct growth of monolayer MoS2 on Au, hexagonal boron nitride (h-BN), and graphene to achieve various hybrid structures. PMID- 24475748 TI - Comparative quantitative proteomics analysis of the ABA response of roots of drought-sensitive and drought-tolerant wheat varieties identifies proteomic signatures of drought adaptability. AB - Wheat is one of the most highly cultivated cereals in the world. Like other cultivated crops, wheat production is significantly affected by abiotic stresses such as drought. Multiple wheat varieties suitable for different geographical regions of the world have been developed that are adapted to different environmental conditions; however, the molecular basis of such adaptations remains unknown in most cases. We have compared the quantitative proteomics profile of the roots of two different wheat varieties, Nesser (drought-tolerant) and Opata (drought-sensitive), in the absence and presence of abscisic acid (ABA, as a proxy for drought). A labeling LC-based quantitative proteomics approach using iTRAQ was applied to elucidate the changes in protein abundance levels. Quantitative differences in protein levels were analyzed for the evaluation of inherent differences between the two varieties as well as the overall and variety specific effect of ABA on the root proteome. This study reveals the most elaborate ABA-responsive root proteome identified to date in wheat. A large number of proteins exhibited inherently different expression levels between Nesser and Opata. Additionally, significantly higher numbers of proteins were ABA responsive in Nesser roots compared with Opata roots. Furthermore, several proteins showed variety-specific regulation by ABA, suggesting their role in drought adaptation. PMID- 24475749 TI - Muscle trade-offs in a power-amplified prey capture system. AB - Should animals operating at great speeds and accelerations use fast or slow muscles? The answer hinges on a fundamental trade-off: muscles can be maximally fast or forceful, but not both. Direct lever systems offer a straightforward manifestation of this trade-off, yet the fastest organisms use power amplification, not direct lever action. Power-amplified systems typically use slow, forceful muscles to preload springs, which then rapidly release elastic potential energy to generate high speeds and accelerations. However, a fast response to a stimulus may necessitate fast spring-loading. Across 22 mantis shrimp species (Stomatopoda), this study examined how muscle anatomy correlates with spring mechanics and appendage type. We found that muscle force is maximized through physiological cross-sectional area, but not through sarcomere length. Sit and-wait predators (spearers) had the shortest sarcomere lengths (fastest contractions) and the slowest strike speeds. The species that crush shells (smashers) had the fastest speeds, most forceful springs, and longest sarcomeres. The origin of the smasher clade yielded dazzlingly high accelerations, perhaps due to the release from fast spring-loading for evasive prey capture. This study offers a new window into the dynamics of force-speed trade-offs in muscles in the biomechanical, comparative evolutionary framework of power-amplified systems. PMID- 24475750 TI - Enzyme-induced metallization as a signal amplification strategy for highly sensitive colorimetric detection of avian influenza virus particles. AB - A novel colorimetric assay method based on enzyme-induced metallization has been proposed for detection of alkaline phosphatase (ALP), and it was further applied to highly sensitive detection of avian influenza virus particles coupled with immunomagnetic separation. The enzyme-induced metallization-based color change strategy combined the amplification of the enzymatic reaction with the unique optical properties of metal nanoparticles (NPs), which could lead to a great enhancement in optical signal. The detection limit for ALP detection was 0.6 amol/50 MUL which was 4-6 orders of magnitude more sensitive than other metal NP based colorimetric methods. Moreover, this technique was successfully employed to a colorimetric viral immunosensor, which could be applied to complex samples without complicated sample pretreatment and sophisticated instruments, and a detection limit as low as 17.5 pg mL(-1) was achieved. This work not only provides a simple and sensitive sensing approach for ALP and virus detection but also offers an effective signal enhancement strategy for development of a highly sensitive nonaggregation metal NP-based colorimetric assay method. PMID- 24475751 TI - A novel polyclonal antibody-based sandwich ELISA for detection of Plasmodium vivax developed from two lactate dehydrogenase protein segments. AB - BACKGROUND: Immunoassays for Plasmodium detection are, presently, most frequently based on monoclonal antibodies (MAbs); Polyclonal antibodies (PAbs), which are cheaper to develop and manufacture, are much less frequently used. In the present study we describe a sandwich ELISA assay which is capable of detecting P. vivax Lactate Dehydrogenase (LDH) in clinical blood samples, without cross reacting with those infected with P. falciparum. METHODS: Two recombinant proteins were produced from different regions of the P. vivax LDH gene. Two sandwich ELISA assay were then designed: One which uses mouse anti-LDH 1-43aa PAbs as primary antibodies ("Test 1") and another which uses anti-LDH 35-305aa PAbs ("Test 2") as the primary antibodies. Rabbit anti-LDH 1-43aa PAbs were used as capture antibodies in both ELISA assays. Blood samples taken from P. vivax and P. falciparum infected patients (confirmed by light microscopy) were analysed using both tests. RESULTS: "Test 2" performed better at detecting microscopy-positive blood samples when compared to "Test 1", identifying 131 of 154 positive samples (85%); 85 positives (55%) were identified using "test 1". "Test 1" produced one false positive sample (from the 20 malaria-free control) blood samples; "test 2" produced none. Kappa coefficient analysis of the results produced a value of 0.267 when microscope-positive blood smears were compared with "test 1", but 0.734 when microscope-positive blood smears were compared with the results from "test 2". Positive predictive value (PPV) and negative predictive value (NPV) were observed to be 98% and 22% respectively, for "Test 1", and 99% and 45%, for "test 2". No cross reactivity was detected with P. falciparum positive blood samples (n = 15) with either test assay. CONCLUSION: Both tests detected P. vivax infected blood and showed no evidence of cross-reacting with P. falciparum. Further studies will need to be conducted to establish the full potential of this technique for malaria diagnostics. As well as representing a promising new cost effective novel technique for P. vivax diagnosis and research, the method for developing this assay also highlights the potential for PAb-based strategies for diagnostics in general. PMID- 24475752 TI - Prevalence and risk factors of visual impairment and blindness in Korea: the Fourth Korea National Health and Nutrition Examination Survey in 2008-2010. AB - PURPOSE: To describe the age, gender specific prevalence and risk factors of visual impairment and blindness in Korea. METHODS: From 2008 to 2010, a total 14 924 randomly selected national representative participants of the Korea National Health and Nutrition Examination Survey underwent additional ophthalmologic examinations by the Korean Ophthalmologic Society. Best Corrected Distance Visual Acuity was measured using an international standard vision chart based on Snellen scale (Jin's vision chart). Independent risk factors for visual impairment were investigated using multivariate logistic regression analysis. RESULTS: The overall prevalence of visual impairment (<=20/40) of adults 40 years and older was 4.1% (95% CI, 3.6-4.6) based on the better seeing eye. The overall prevalence of blindness (<=20/200) for adults 40 years and older was 0.2% (95% CI, 0.1-0.3). Risk indicators of visual impairment were increasing age, low education status, living in rural area, being unemployed, being without spouse and the absence of private health insurance. The visually impaired were more likely to have eye diseases compared with the normal subjects, and they were less likely to utilize eye care. CONCLUSION: The prevalence of visual impairment was demonstrated to be higher while that of blindness was similar to previous population studies in Asia or U.S. Sociodemographic disparities are present in the prevalence of visual impairment and more targeted efforts are needed to promote vision screening in high risk groups. PMID- 24475753 TI - In vitro-activity of oily calcium hydroxide suspension on microorganisms as well as on human alveolar osteoblasts and periodontal ligament fibroblasts. AB - BACKGROUND: Findings from animal and human studies have indicated that an oily calcium hydroxide suspension (OCHS) may improve early wound healing in the treatment of periodontitis. Calcium hydroxide as the main component is well known for its antimicrobial activity, however at present the effect of OCHS on the influence of periodontal wound healing/regeneration is still very limited. The purpose of this in vitro study was to investigate the effect of OCHS on periodontopathogenic bacteria as well as on the attachment and proliferation of osteoblasts and periodontal ligament fibroblasts. METHODS: Human alveolar osteoblasts (HAO) and periodontal ligament (PDL) fibroblasts were cultured on 3 concentrations of OCHS (2.5, 5 and 7.5 mg). Adhesion and proliferation were counted up to 48 h and mineralization was assayed after 1 and 2 weeks. Furthermore potential growth inhibitory activity on microorganisms associated with periodontal disease (e.g. Porphyromonas gingivalis, Tannerella forsythia, Aggregatibacter actinomycetemcomitans) as well as the influence of periodontopathogens and OCHS on the HAO and PDL fibroblasts counts were determined. RESULTS: More than a 2-fold increase in adherent HAO cells was observed at 4 h following application of OCHS when compared to the control group (p = 0.007 for 2.5 mg). Proliferation of HAO cells at 48 h was stimulated by moderate concentrations (2.5 mg; 5 mg) of OCHS (each p < 0.001), whereas a high concentration (7.5 mg) of OCHS was inhibitory (p = 0.009). Mineralization was observed only for HAO cells treated with OCHS. OCHS did not exert any positive effect on attachment or proliferation of PDL fibroblasts. Although OCHS did not have an antibacterial effect, it did positively influence attachment and proliferation of HAO cells and PDL fibroblasts in the presence of periodontopathogens. CONCLUSIONS: The present data suggests that OCHS promotes osteoblast attachment, proliferation and mineralization in a concentration dependent manner and results are maintained in the presence of periodontal pathogens. PMID- 24475754 TI - Data sharing policy design for consortia: challenges for sustainability. AB - The field of human genomics has led advances in the sharing of data with a view to facilitating translation of research into innovations for human health. This change in scientific practice has been implemented through new policy developed by many principal investigators, project managers and funders, which has ultimately led to new forms of practice and innovative governance models for data sharing. Here, we examine the development of the governance of data sharing in genomics, and explore some of the key challenges associated with the design and implementation of these policies. We examine how the incremental nature of policy design, the perennial problem of consent, the gridlock caused by multiple and overlapping access systems, the administrative burden and the problems with incentives and acknowledgment all have an impact on the potential for data sharing to be maximized. We conclude by proposing ways in which the scientific community can address these problems, to improve the sustainability of data sharing into the future. PMID- 24475755 TI - Caught in the middle with multiple displacement amplification: the myth of pooling for avoiding multiple displacement amplification bias in a metagenome. AB - BACKGROUND: Shotgun metagenomics has become an important tool for investigating the ecology of microorganisms. Underlying these investigations is the assumption that metagenome sequence data accurately estimates the census of microbial populations. Multiple displacement amplification (MDA) of microbial community DNA is often used in cases where it is difficult to obtain enough DNA for sequencing; however, MDA can result in amplification biases that may impact subsequent estimates of population census from metagenome data. Some have posited that pooling replicate MDA reactions negates these biases and restores the accuracy of population analyses. This assumption has not been empirically tested. RESULTS: Using mock viral communities, we examined the influence of pooling on population scale analyses. In pooled and single reaction MDA treatments, sequence coverage of viral populations was highly variable and coverage patterns across viral genomes were nearly identical, indicating that initial priming biases were reproducible and that pooling did not alleviate biases. In contrast, control unamplified sequence libraries showed relatively even coverage across phage genomes. CONCLUSIONS: MDA should be avoided for metagenomic investigations that require quantitative estimates of microbial taxa and gene functional groups. While MDA is an indispensable technique in applications such as single-cell genomics, amplification biases cannot be overcome by combining replicate MDA reactions. Alternative library preparation techniques should be utilized for quantitative microbial ecology studies utilizing metagenomic sequencing approaches. PMID- 24475756 TI - EMS mutagenesis in mature seed-derived rice calli as a new method for rapidly obtaining TILLING mutant populations. AB - BACKGROUND: TILLING (Targeting Induced Local Lesions IN Genomes) is a reverse genetic method that combines chemical mutagenesis with high-throughput genome wide screening for point mutation detection in genes of interest. However, this mutation discovery approach faces a particular problem which is how to obtain a mutant population with a sufficiently high mutation density. Furthermore, plant mutagenesis protocols require two successive generations (M1, M2) for mutation fixation to occur before the analysis of the genotype can begin. RESULTS: Here, we describe a new TILLING approach for rice based on ethyl methanesulfonate (EMS) mutagenesis of mature seed-derived calli and direct screening of in vitro regenerated plants. A high mutagenesis rate was obtained (i.e. one mutation in every 451 Kb) when plants were screened for two senescence-related genes. Screening was carried out in 2400 individuals from a mutant population of 6912. Seven sense change mutations out of 15 point mutations were identified. CONCLUSIONS: This new strategy represents a significant advantage in terms of time-savings (i.e. more than eight months), greenhouse space and work during the generation of mutant plant populations. Furthermore, this effective chemical mutagenesis protocol ensures high mutagenesis rates thereby saving in waste removal costs and the total amount of mutagen needed thanks to the mutagenesis volume reduction. PMID- 24475758 TI - Should prophylactic thrombolysis be routine in clinical practice? Evidence from an autopsy case of septicemia. AB - BACKGROUND: Central venous catheters provide easy access for intravenous infusion and nutrition, but they can bring about complications such as catheter-related infections. Infected central venous catheters often cause nosocomial bloodstream infections with high morbidity and mortality. However, most of the morphological data that have been published are derived from in vitro and in vivo studies and few reports of direct evidence obtained from patient-derived samples have been described. Here we present visual evidence of catheter-related candidemia. To our knowledge, this is the first reported conventional histopathological evidence of a Candida-infected intraluminal thrombus in a patient's central venous catheter. CASE PRESENTATION: A 62-year-old Japanese female with obstructive jaundice, gastrointestinal bleeding, and liver metastasis from pancreatic head cancer was given an implantable subcutaneous central venous port for nutrition and chemotherapy administration. High fever ensued on day 16 after the central venous port insertion and blood cultures revealed Candida albicans. Although the patient was given 300 mg/day of fosfluconazole according to the suggestion of the infection control team, she died from respiratory failure. Postmortem computed tomography revealed findings consistent with acute respiratory distress syndrome, suggesting that the patient's course was complicated by catheter-related sepsis. Autopsy revealed a subcutaneous abscess around the port, from which C. albicans was cultured. However, no catheter-adherent thrombus, thrombosis of the great central veins, or endocardial vegetations were detected in the patient. Histological analysis revealed scattered abscesses in several organs including lungs and kidneys. Hyaline membrane formation and Candida colonies were found in the lungs. The central venous port tube, together with the part of the subclavian vein into which it had been inserted, was involved in an intraluminal fibrin thrombus containing neutrophils and macrophages, indicating that the thrombus existed while the patient was alive. Histopathological examination following use of the periodic acid-Schiff reagent and the Grocott stain revealed scattered Candida in the thrombus. CONCLUSIONS: Prophylactic thrombolysis should be encouraged to prevent central venous catheter-related candidiasis in clinical practice. PMID- 24475759 TI - Using an integrated knowledge translation approach to build a public health research agenda. AB - BACKGROUND: Public Health Systems Research is an emerging field of research that is gaining importance in Canada. METHODS: On October 22 and 23, 2012, public health researchers, practitioners, and policy-makers came together at the Accelerating Public Health Systems Research in Ontario: Building an Agenda think tank to develop a research agenda for the province. RESULTS: This agenda included the identification of the six top priorities for research in Ontario: public health performance, evidence-based practice, public health organization and structure, public health human resources, public health infrastructure, and partnerships/linkages. CONCLUSIONS: This paper explores the priorities in detail and hopes to bring more attention to this area of research. PMID- 24475760 TI - Reproductive and hormonal risk profile according to language acculturation and country of residence in the Ella Binational Breast Cancer Study. AB - BACKGROUND: We compared the distribution of breast cancer reproductive and hormonal risk factors by level of acculturation and country of residence in women of Mexican descent. METHODS: To compare the distribution of breast cancer reproductive and hormonal risk factors by level of acculturation and country of residence in women of Mexican descent, taking into account level of education, we analyzed data on 581 Mexican and 620 Mexican American (MA) women with a history of invasive breast cancer from the Ella Binational Breast Cancer Study. An eight item language-based acculturation measure was used to classify MA women. Multivariate logistic regression was used to test associations between language acculturation, country of residence, and reproductive and hormonal risk factors. RESULTS: After adjustment for age and education, compared to women residing in Mexico, English-dominant MAs were significantly more likely to have an earlier age at menarche (<12 years; odds ratio [OR]=2.08; 95% confidence interval [CI], 1.30-3.34), less likely to have a late age at first birth (>=30 years; OR=0.49; 95% CI, 0.25-0.97), and less likely to ever breastfeed (OR=0.13; 95% CI, 0.08 0.21). CONCLUSIONS: Differences in reproductive and hormonal risk profile according to language acculturation and country of residence are evident; some of these were explained by education. Results support continued efforts to educate Mexican and MA women on screening and early detection of breast cancer along with promotion of modifiable factors, such as breastfeeding. PMID- 24475761 TI - Neutrophil gelatinase-associated lipocalin after off pump versus on pump coronary artery surgery. AB - CONTEXT: Cardiac surgery. OBJECTIVE: To compare plasma and urinary neutrophil gelatinase-associated lipocalin (P-/U-NGAL) in on-pump (n = 43) versus off-pump (n = 40) surgery. MATERIALS AND METHODS: We obtained perioperative P-/U-NGAL and outcome data. RESULTS: P-/U-NGAL increased after surgery. P-NGAL was higher post surgery in on pump patients (139 versus 67 ug L(-1); p < 0.001), but not at 24 h. There were no differences in U-NGAL. Correlation between P-/U-NGAL and plasma creatinine was weak. DISCUSSION: P-NGAL acts like a neutrophil activation biomarker and U-NGAL like a tubular injury marker. CONCLUSION: On-pump patients had greater neutrophil activation. On- versus off-pump surgery had similar impact on tubular cells. PMID- 24475763 TI - Quality Improvement and Confirmation Projects: Facilitating Rapid, Measurable Performance Improvement. AB - As radiology departments continue to increase in size and complexity, the process of improving and maintaining excellent performance is becoming increasingly challenging. In response, a systematic process for efficiently implementing and sustaining measurable improvement in our radiology department has been developed, which targets focused aspects of individual performance that contribute to overall departmental quality. Projects designed to achieve such improvements have been called quality improvement and confirmation (QuIC) projects. The QuIC project process involves a project champion, medical expert, technical expert, quality improvement technologist specialist, and appropriate leaders, managers, and support personnel. The project champion conducts a preliminary investigation and organizes team members, who define the desired performance through consensus, establish data collection and analysis procedures, and prepare to launch the project. Once launched, the QuIC project process follows an execution period that is divided into four phases: (a) project launch phase, (b) support phase, (c) transition phase, and (d) maintenance phase. The first three phases focus on education, group-level feedback, and individual feedback, respectively. Weekly audits are performed to track performance improvement. Data collection, analysis, and dissemination processes are automated to the extent possible. To date, four such projects have been successfully conducted. The QuIC project concept is an attempt to apply the principles of process improvement to the process of process improvement by enabling any member of a radiology department to efficiently and reliably spearhead a quality improvement project. We consider this to be a work in progress and continue to refine the process with the goal of eventually being able to conduct many projects simultaneously. (c) RSNA, 2013. PMID- 24475764 TI - Trainee Report Dashboard: Tool for Enhancing Feedback to Radiology Trainees about Their Reports. AB - During their radiology residency, trainees must learn multiple facets of radiology practice, including the writing of radiology reports. An important factor in the trainee's development of reporting skills is feedback from the attending radiologist on the trainee's preliminary reports. The quality and quantity of feedback may vary and are not typically documented. As radiology department workloads have increased and stricter limitations have been imposed on trainee work hours, less time is available for attending radiologists and trainees to perform a joint retrospective review of radiology reports. To compensate, the authors have developed a Web-based dashboard that provides trainees with case-specific feedback about their reports. Components include an attending radiologist-trainee report discrepancy logging and communication system that is integrated with the institutional picture archiving and communication system, an automated preliminary report-final report comparator, modules showing statistics related to the discrepancy logger and report comparator components, and a Web page that unifies these components with image and report display capabilities. Both the actual report feedback and the trainee's use of the system are documented, and the resultant data may be used for evaluating trainee competence in written communication, as mandated by the Accreditation Council for Graduate Medical Education. With these tools, trainees can obtain near-real-time feedback, which may pinpoint issues that can be corrected to improve the quality of their radiology reporting. This system, although it does not supplant face-to face training sessions with attending radiologists, can augment traditional methods of learning. (c) RSNA, 2013. PMID- 24475766 TI - Effects of a standard provision versus an autonomy supportive exercise referral programme on physical activity, quality of life and well-being indicators: a cluster randomised controlled trial. AB - BACKGROUND: The National Institute for Health and Clinical Excellence in the UK has recommended that the effectiveness of ongoing exercise referral schemes to promote physical activity should be examined in research trials. Recent empirical evidence in health care and physical activity promotion contexts provides a foundation for testing the feasibility and impact of a Self Determination Theory based (SDT) exercise referral consultation. METHODS: An exploratory cluster randomised controlled trial comparing standard provision exercise referral with an exercise referral intervention grounded in Self Determination Theory. Individuals (N = 347) referred to an exercise referral scheme were recruited into the trial from 13 centres.Outcomes and processes of change measured at baseline, 3 and 6-months: Minutes of self-reported moderate or vigorous physical activity (PA) per week (primary outcome), health status, positive and negative indicators of emotional well-being, anxiety, depression, quality of life (QOL), vitality, and perceptions of autonomy support from the advisor, need satisfaction (3 and 6 months only), intentions to be active, and motivational regulations for exercise.Blood pressure and weight were assessed at baseline and 6 months. RESULTS: Perceptions of the autonomy support provided by the health and fitness advisor (HFA) did not differ by arm. Between group changes over the 6-months revealed significant differences for reported anxiety only. Within arm contrasts revealed significant improvements in anxiety and most of the Dartmouth CO-OP domains in the SDT arm at 6 months, which were not seen in the standard exercise referral group. A process model depicting hypothesized relationships between advisor autonomy support, need satisfaction and more autonomous motivation, enhanced well being and PA engagement at follow up was supported. CONCLUSIONS: Significant gains in physical activity and improvements in quality of life and well-being outcomes emerged in both the standard provision exercise referral and the SDT-based intervention at programme end. At 6-months, observed between arm and within intervention arm differences for indicators of emotional health, and the results of the process model, were in line with SDT. The challenges in optimising recruitment and implementation of SDT-based training in the context of health and leisure services are discussed. TRIAL REGISTRATION: The trial is registered as Current Controlled trials ISRCTN07682833. PMID- 24475769 TI - Serum Follistatin-like-3 was elevated in second trimester of pregnant women who subsequently developed preeclampsia. AB - OBJECTIVE: To determine whether serum Follistatin-like-3 was enhanced in second trimester of pregnant women who subsequently developed preeclampsia. METHODS: Thirty-nine pregnant women subsequently developed preeclampsia and 73 normal pregnancy women were included. Serum samples taken in 24-28 weeks gestation were used for assay of Follistatin-like-3. RESULTS: Follistatin-like-3 was significantly elevated in preeclampsia group compared with control. However, there was no significant difference of Follistatin-like-3 in women with mild or severe preeclampsia. CONCLUSION: The elevation of Follistatin-like-3 was demonstrated in late second trimester of pregnancy destined to developing preeclampsia, suggesting its causal role in the pathogenesis and prediction of preeclampsia. PMID- 24475768 TI - Phosphorylation of the transcription factor Sp4 is reduced by NMDA receptor signaling. AB - The regulation of transcription factor function in response to neuronal activity is important for development and function of the nervous system. The transcription factor Sp4 regulates the developmental patterning of dendrites, contributes to complex processes including learning and memory, and has been linked to psychiatric disorders such as schizophrenia and bipolar disorder. Despite its many roles in the nervous system, the molecular mechanisms regulating Sp4 activity are poorly understood. Here, we report a site of phosphorylation on Sp4 at serine 770 that is decreased in response to membrane depolarization. Inhibition of the voltage-dependent NMDA receptor increased Sp4 phosphorylation. Conversely, stimulation with NMDA reduced the levels of Sp4 phosphorylation, and this was dependent on the protein phosphatase 1/2A. A phosphomimetic substitution at S770 impaired the Sp4-dependent maturation of cerebellar granule neuron primary dendrites, whereas a non-phosphorylatable Sp4 mutant behaved like wild type. These data reveal that transcription factor Sp4 is regulated by NMDA receptor-dependent activation of a protein phosphatase 1/2A signaling pathway. Our findings also suggest that the regulated control of Sp4 activity is an important mechanism governing the developmental patterning of dendrites. PMID- 24475770 TI - Calcium level during the first trimester of pregnancy as a predictor of preeclampsia. AB - OBJECTIVE: To examine the association between calcium levels during the first trimester of pregnancy and preeclampsia. METHODS: The study population included registered births (n = 5233) in a tertiary medical center between 2001 and 2011. A comparison was performed between women with and without hypocalcemia during the first trimester of pregnancy. A second analysis was performed after correcting calcium levels for albumin. Multiple logistic regression models were used to control for confounders. Receiver operating characteristic curve analysis graphs were used to describe the relationship between the true-positive rate (sensitivity) and the false-positive rate for different values of calcium during the first half of pregnancy in the prediction of preeclampsia. RESULTS: Of 5233 deliveries, 841 (16%) had hypocalcemia and 4392 (84%) had a normal calcium level. No significant difference were found between the groups regarding mild preeclampsia [odds ratio (OR) = 1.216; 95% confidence interval (CI) 0.831-1.779; p = 0.312], severe preeclampsia (OR = 1.618; 95% CI 0.919-2.849; p = 0.092) and any hypertensive disorders (OR = 1.324; 95% CI 0.963-1.821; p = 0.083). CONCLUSIONS: Hypocalcemia during the first trimester of pregnancy is not a risk factor for preeclampsia. PMID- 24475771 TI - Repeatability of SphygmoCor pulse wave analysis in assessing arterial wave reflection in pregnancy using applanation tonometry. AB - OBJECTIVE: To estimate clinical agreement in relation to measuring aortic augmentation index (AIX-75) in pregnancy in a routine clinical setting. METHODS: A hospital-based clinical agreement study of 20 women in which two trained nurses alternated in measuring arterial function (AIX standardized to a heart rate of 75 beats-per-minute, AIX-75) on a single occasion in triplicate, after participants had rested semi-recumbent for 15 min. Right brachial blood pressure (BP) was measured using the Microlife 3BTO-A oscillometric device. Radial applanation pulse wave analysis (PWA) was undertaken according to current guidelines using the SphygmoCor device with a hand-held Millar tonometer applanated at the right radial artery. Each nurse was blinded to others PWA results. Observer agreement was assessed using the Bland-Altman "limits of agreement" (LOA, mean difference +/-2 SD) approach. RESULTS: Median gestation was 37 weeks (range: 12-42), mean age 31 years, 30% nulliparous, mean brachial BP 128/79 mm Hg. Based on all six PWA measurements, mean AIX-75 was 11.7 (range: -18 to +35). The between-observer LOA was 0.1 +/- 11.0 and the within-observer LOA's were 1 +/- 10 and -2 +/- 8 for the two nurses. Observer differences did not vary systematically with the magnitude of AIX-75. CONCLUSION: AIX-75 can be measured by nurses using PWA in pregnancy with a high level of observer agreement. PMID- 24475772 TI - Evaluation of the macula, retinal nerve fiber layer and choroid in preeclampsia, healthy pregnant and healthy non-pregnant women using spectral-domain optical coherence tomography. AB - OBJECTIVE: To evaluate the macular, retinal nerve fiber layer (RNFL) and choroidal thickness alterations by using spectral-domain optical coherence tomography (SD-OCT) in preeclampsia and compare with healthy pregnant and healthy non-pregnant controls. METHOD: The study population included healthy pregnant control group (n: 25), healthy non-pregnant control group (n: 26) and study group with preeclampsia (n: 27). Retinal thickness parameters were measured by SD-OCT. RESULTS: There was a statistically significant difference among all of the groups for choroidal thickness (p < 0.001). Choroidal thickness in preeclamptic women was significantly thinner than healthy pregnant women. The most thick choroid layer was detected in healthy pregnant group, and also the most thin choroidal thickness was detected in healthy non-pregnant group (p < 0.001). Macular central subfield and foveal center thickness were significantly thinner in preeclamptic study and healthy pregnant groups than healthy non-pregnant group (p < 0.001). However, there was no statistically significant difference between preeclamptic study group and healthy pregnant group for both macular central subfield and foveal center thickness. Average of RNFL thickness was significantly thicker in healthy pregnant group than healthy non-pregnant group (p = 0.004). CONCLUSIONS: This study revealed that choroidal thickness measured using SD-OCT increased in women with preeclampsia and healthy pregnant women but the increase in choroidal thickness in preeclampsia was lower than the healthy pregnant controls. This lower rise in choroidal thickness can be generally attributed to the markedly increased systemic vascular vasospasm secondary to preeclampsia. PMID- 24475773 TI - The complication and mode of delivery in Chinese women with severe preeclampsia: a retrospective study. AB - OBJECTIVE: Severe preeclampsia is a serious threat for pregnant women and fetuses. The complications of severe preeclampsia greatly affect perinatal outcome. This study aimed to investigate the complication and delivery mode of Chinese pregnant women with severe preeclampsia, and analyze the change in these aspects in the past decades. METHODS: Clinical data of 1713 pregnant women with severe preeclampsia were collected and analyzed. The patients were divided into two groups: early period (1985-1997) and later period (1998-2010). RESULTS: The complications for severe preeclampsia included preterm birth, fetal distress, postpartum hemorrhage, fetal growth restriction (FGR). Compared to early period, the rates of preterm birth, FGR, oligohydramnios, abnormal pregnancy outcome increased while the rates of fetal distress, postpartum hemorrhage and eclampsia decreased in later period. The rate of cesarean section was 73.073% in the early period and increased to 88.258% in the later period. Accordingly, the rate of natural childbirth, forceps extraction, vacuum extraction and breech extraction decreased in the later period. CONCLUSIONS: Our data provide important information on the complication and mode of delivery in Chinese women with severe preeclampsia in the past decades, which may be helpful for clinical management of severe preeclampsia in Chinese women. PMID- 24475774 TI - Re-admissions to hospital and patient satisfaction among patients with chronic obstructive pulmonary disease after telemedicine video consultation - a retrospective pilot study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a major cause of acute hospital admissions. The main object of our study was to evaluate the effects of telemedicine video-consultation (TVC) on the frequency of hospital re admissions due to COPD exacerbations. Our secondary aim was to assess the impact of TVC on the length of re-admission stays within 6 and 12 months follow up after TVC. Patient satisfaction was also evaluated. METHODS: The study was a retrospective observational study of COPD patients who after hospital discharge or during outpatient treatment for acute COPD exacerbations, were monitored for 2 weeks by TVC at home by a specialist nurse at the hospital during a pilot project period. Retrospectively, we compared the frequencies (chi-square test) and durations of hospital re-admissions (paired t-test) due to COPD exacerbations within 6 and 12 months follow up after TVC to comparable events 6 and 12 months prior to TVC. RESULTS: Among 99 patients followed for 6 months after TVC, 56 were followed for totally 12 months. The number of patients re-admitted and the number of re-admissions due to COPD exacerbations were not reduced within 6 or 12 months post-TVC, as compared to 6 and 12 months pre-TVC.The mean length of re-admission stays within 12 months post-TVC was markedly reduced as compared to pre-TVC. Patients hospitalised the last 6 and 12 months pre-TVC, had significantly shorter re-admission stays, p = 0.033 and p = 0.001, respectively. Patient satisfaction was high. CONCLUSION: Despite the failure to demonstrate reduced frequency of re admissions within 6 and 12 months post-TVC, the re-admission length within 12 months post-TVC was markedly reduced as compared to pre-TVC. The patient satisfaction was high. Future prospective, randomised, controlled trials must be performed before TVC can be recommended in COPD management. PMID- 24475775 TI - Theoretical analysis of the relaxation dynamics in perylene bisimide dimers excited by femtosecond laser pulses. AB - We present a model for the relaxation dynamics in perylene bisimide dimers, which is based on ab initio electronic structure and quantum dynamics calculations including effects of dissipation. The excited-state dynamics proceeds via a mixing of electronic states of local Frenkel and charge-transfer characters, which becomes effective upon a small distortion of the dimer geometry. In this way, it is possible to explain the fast depopulation of the photoexcited state, which we characterize by femtosecond transient absorption measurements. The combined theoretical and experimental analysis hints at a trapping mechanism, which involves nonadiabatic and dissipative dynamics in an excited-state vibronic manifold and provides an atomistic picture that might prove valuable for future design of photovoltaic materials. PMID- 24475776 TI - One at a time: intramolecular electron-transfer kinetics in small laccase observed during turnover. AB - Single-molecule enzymology provides an unprecedented level of detail about aspects of enzyme mechanisms which have been very difficult to probe in bulk. One such aspect is intramolecular electron transfer (ET), which is a recurring theme in the research on oxidoreductases containing multiple redox-active sites. We measure the intramolecular ET rates between the copper centers of the small laccase from Streptomyces coelicolor at room temperature and pH 7.4, one molecule at a time, during turnover. The forward and backward rates across many molecules follow a log-normal distribution with means of 460 and 85 s(-1), respectively, corresponding to activation energies of 347 and 390 meV for the forward and backward rates. The driving force and the reorganization energy amount to 0.043 and 1.5 eV, respectively. The spread in rates corresponds to a spread of ~30 meV in the activation energy. The second-order rate constant for reduction of the T1 site amounts to 2.9 * 10(4) M(-1) s(-1). The mean of the distribution of forward ET rates is higher than the turnover rate from ensemble steady-state measurements and, thus, is not rate limiting. PMID- 24475779 TI - Macular lymphocytic arteritis. PMID- 24475777 TI - Fingolimod (FTY720) therapy in Japanese patients with relapsing multiple sclerosis over 12 months: results of a phase 2 observational extension. AB - BACKGROUND: A 6-month phase 2 study of fingolimod demonstrated efficacy and safety in Japanese patients with relapsing-remitting multiple sclerosis (MS). Here we report a 6-month observational extension that evaluated efficacy and safety in patients who received fingolimod continuously for 12 months or who switched from placebo to fingolimod. METHODS: Of 147 patients who completed the 6 month core study, 143 entered the extension. Those originally randomized to placebo were re-randomized to fingolimod 1.25 mg or 0.5 mg. During the extension, all patients were switched to open-label fingolimod 0.5 mg. RESULTS: Magnetic resonance imaging (MRI) and relapse outcomes were maintained or improved in patients treated with fingolimod for 12 months versus those treated for 6 months. No new safety events were reported over 12 months of treatment. Infections occurred in similar proportions of continuously treated and switched patients, while cardiac and liver adverse events occurred in fewer continuously treated than switched patients. Four patients were aquaporin-4 (AQP4) antibody-positive, three of whom showed rapid disease exacerbations within 10 days of fingolimod initiation. CONCLUSION: Continuous fingolimod treatment for up to 12 months was associated with maintained or improved efficacy and a manageable safety profile, consistent with that previously seen. Results in a small number of patients suggest lack of benefit in AQP4 antibody-positive patients. Meaningful statistical interpretation was limited by the small sample size in each treatment group, owing to the number of patients who completed the core study. TRIAL REGISTRATION: ClinicalTrials.gov NCT00670449. PMID- 24475780 TI - Differences in the gut microbiota of healthy children and those with type 1 diabetes. AB - BACKGROUND: Intestinal barriers, intestinal flora, and mucosal immunity are the main factors responsible for the development of various allergic and autoimmune diseases. The aim of this study was to investigate the relationship between the intestinal flora of children and the presence of type 1 diabetes, and to determine if gut microbiota could partly explain the etiology of the disease. METHODS: Fecal flora analysis was done using quantitative cultures on selective and non-selective media with different thermal and atmospheric conditions for bacterial and fungal growth. The study group consisted of 35 patients (16 female, 19 male; mean age, 10.73 +/- 4.16 years), who had been followed by the University of Istanbul, Cerrahpasa Medical Faculty, Department of Pediatrics, and were newly diagnosed with type 1 diabetes. The control group consisted of 35 healthy subjects (15 female, 20 male; mean age, 9.96 +/- 4.09 years), who were randomly selected and had similar demographics. RESULTS: Bifidobacterium colonization was lower in patients with type 1 diabetes compared to the control group, whereas Candida albicans and Enterobacteriaceae other than Echerichia coli colonization was increased. CONCLUSION: A decrease in beneficial anaerobic bacteria levels and a concomitant increase in Enterobacteriaceae other than E. coli and C. albicans colonization may lead to a disturbance in the ecological balance of intestinal flora, which could be a triggering factor in type 1 diabetes etiology. PMID- 24475781 TI - Dynamic expression of molecules that control limb muscle development including Fhl1 in hind limbs of different gestational age. AB - Muscle abnormality could be a key reason for congenital clubfoot (CCF) deformity, which manifests itself during fetal development. FHL1 down-regulated expression is involved in the formation of skeletal muscle abnormalities in CCF and FHL1 gene mutations contribute to the development of some kinds of myopathies. Therefore, detecting dynamic expression of Fhl1 and other molecules (Hgf, MyoD1, Myogenin, and Myh4) that control limb muscle development in hind limbs of different gestational age will provide a foundation for further research on the molecular mechanism involves in the myopathies or CCF. The dynamic gene expression levels of Fhl1, Hgf, MyoD1, Myogenin, and Myh4 in the lower limbs of E16, E17, E19, and E20 rat embryos were examined by real-time RT-PCR. Immunofluorescence was used to detect formation of specific muscle fibers (fast or slow fibers) in distal E17 hind limbs. The expression levels of Fhl1, Hgf, MyoD1, Myogenin, and Myh4 were varying in hind limbs of different gestational age. Real-time PCR results showed that all the genes that control skeletal muscle development except for Fhl1 exhibited a peak in E17 lower limbs. Immunofluorescence results showed obviously positive fast-myosin in the distal E17 lower limbs and meanwhile slow-myosin had no apparently signals. E17 was a critical time point for terminal skeletal muscle differentiation in the lower limbs of rat embryos. PMID- 24475782 TI - Sensory drive does not explain reproductive character displacement of male acoustic signals in the upland chorus frog (Pseudacris feriarum). AB - Biotic and abiotic factors have been proposed to explain patterns of reproductive character displacement, but which factor is most important to character displacement of acoustic signals is not clear. Male vocalizations of the frog Pseudacris feriarum are known to undergo reproductive character displacement in areas of sympatry with P. brimleyi and P. nigrita. Despite evidence for reinforcement as an important mechanism, local adaptation via sensory drive might explain this pattern because Pseudacris breed in different habitat types and mating signals are exposed to a variety of environments. We tested the sensory drive hypothesis by playing synthesized vocalizations representing the spectrum of variation in P. feriarum at 12 different study sites. If sensory drive has occurred, then vocalizations should transmit better in the site of origin or at ecologically similar sites. We found that variation in acoustic signals did not produce better transmission in particular sites, the effect of site was uniform, and acoustic signals often transmitted better in habitats external to their origin. Ecological variation among habitats did not explain signal degradation. Our playback experiments, ecological analyses, and comparisons of different habitat types provide no support for sensory drive as a process promoting reproductive character displacement in this system. Reinforcement is the more likely primary mechanism. PMID- 24475783 TI - Sensitive detection of transcription factors using near-infrared fluorescent solid-phase rolling circle amplification. AB - This study describes a method for analyzing transcription factor (TF) activity, near-infrared fluorescent solid-phase rolling circle amplification (NIRF-sRCA). This method analyzes TF activity in four steps: (i) incubate DNA with protein sample and isolate TF-bound DNA, (ii) hybridize the TF-bound DNA and rolling circle to DNA microarray, (iii) amplify the TF-bound DNA with sRCA that contains biotin-labeled dUTP, and (iv) detect sRCA products by binding of NIRF-labeled streptavidin and NIRF imaging. This method was validated by proof-of-concept detection of purified TF protein and cell nuclear extract. Detection of purified TF protein demonstrated that NIRF-sRCA could quantitatively detect NF-kappaB p50 protein, and as little as 6.94 ng (~140 fmol) of this protein was detected. Detection of nuclear extract revealed that NIRF-sRCA could specifically and quantitatively detect NF-kappaB p50 activity in HeLa cell nuclear extracts, and the activity of this TF in as little as 0.625 MUg of nuclear extracts could be detected. Detection of nuclear extract also revealed that NIRF-sRCA could detect the relative activities of multiple TFs in HeLa cell nuclear extracts and the fold induction of multiple TFs in the TNFalpha-induced HeLa cell nuclear extracts. Therefore, this study provides a new tool for studying TFs. PMID- 24475784 TI - Enantioselective interaction of acid alpha-naphthyl acetate esterase with chiral organophosphorus insecticides. AB - Many previous works have demonstrated that acetylcholinesterase (AChE) was enantioselectively inhibited by chiral organophosphorus insecticides (OPs) and that a significant difference in reactivation existed for AChE inactivated by (1R)- versus (1S,3S)-stereoisomers of isomalathion. It had been known that alpha naphthyl acetate esterase (ANAE), an enzyme which might play an essential role in the growth of plants and the defense of plants against environmental stress by regulating the concentration of hormones in plants, can be inhibited by OPs. However, it was unknown whether interaction of ANAE with chiral OPs was enantioselective. The present work investigated the inhibition kinetics and spontaneous reactivation of ANAE inactivated by enantiomers of malaoxon, isomalathion, and methamidophos. The order of inhibition potency is (R) > (S) for malaoxon, (1R,3R) > (1R,3S) > (1S,3R) > (1S,3S) for isomalathion, and (S) > (R) for methamidophos according to bimolecular rate constants of inhibition (ki), which is consistent with the order observed in the enantioselective inhibition of AChE by malaoxon, isomalathion, and methamidophos. The difference in spontaneous reactivation of AChE inactivated between (1R)- and (1S,3S)-isomers of isomalathion is conserved for ANAE. The observations indicated ANAE and AChE have similar selective inhibition kinetics and postinhibitory reactions in reaction with chiral OPs. PMID- 24475785 TI - Charge dependent retardation of amyloid beta aggregation by hydrophilic proteins. AB - The aggregation of amyloid beta peptides (Abeta) into amyloid fibrils is implicated in the pathology of Alzheimer's disease. In light of the increasing number of proteins reported to retard Abeta fibril formation, we investigated the influence of small hydrophilic model proteins of different charge on Abeta aggregation kinetics and their interaction with Abeta. We followed the amyloid fibril formation of Abeta40 and Abeta42 using thioflavin T fluorescence in the presence of six charge variants of calbindin D9k and single-chain monellin. The formation of fibrils was verified with transmission electron microscopy. We observe retardation of the aggregation process from proteins with net charge +8, +2, -2, and -4, whereas no effect is observed for proteins with net charge of -6 and -8. The single-chain monellin mutant with the highest net charge, scMN+8, has the largest retarding effect on the amyloid fibril formation process, which is noticeably delayed at as low as a 0.01:1 scMN+8 to Abeta40 molar ratio. scMN+8 is also the mutant with the fastest association to Abeta40 as detected by surface plasmon resonance, although all retarding variants of calbindin D9k and single chain monellin bind to Abeta40. PMID- 24475786 TI - Placental thrombosis in acute phase abortions during experimental Toxoplasma gondii infection in sheep. AB - After oral administration of ewes during mid gestation with 2000 freshly prepared sporulated oocysts of T. gondii isolate M4, abortions occurred between days 7 and 11 in 91.6% of pregnant and infected ewes. Afterwards, a further infection was carried out at late gestation in another group of sheep with 500 sporulated oocysts. Abortions happened again between days 9 and 11 post infection (pi) in 58.3% of the infected ewes. Classically, abortions in natural and experimental ovine toxoplasmosis usually occur one month after infection. Few experimental studies have reported the so-called acute phase abortions as early as 7 to 14 days after oral inoculation of oocysts, and pyrexia was proposed to be responsible for abortion, although the underline mechanism was not elucidated. In the present study, all placentas analysed from ewes suffering acute phase abortions showed infarcts and thrombosis in the caruncullar villi of the placentomes and ischemic lesions (periventricular leukomalacia) in the brain of some foetuses. The parasite was identified by PCR in samples from some placentomes of only one sheep, and no antigen was detected by immunohistochemical labelling. These findings suggest that the vascular lesions found in the placenta, and the consequent hypoxic damage to the foetus, could be associated to the occurrence of acute phase abortions. Although the pathogenesis of these lesions remains to be determined, the infectious dose or virulence of the isolate may play a role in their development. PMID- 24475787 TI - Long-term outcomes of modified Berlin-Frankfurt-Munster-90 regimen in adults with T-lymphoblastic lymphoma: a single-center experience. AB - The standard treatment for adult T-Lymphoblastic lymphoma (T-LBL) has not been defined. This study was to analyze the efficiency of modified BFM-NHL-90 regimen in 36 adult patients with newly diagnosed T-LBL at the Sun Yat-Sen cancer center between August 2000 and December 2010. After the induction protocols, 34/36 (94%) of the patients achieved complete remission or unconfirmed complete remission. At the median follow-up of 36 months, 13 patients relapsed, but no relapses were observed in the CNS. The 3-year overall survival and 3-year event-free survival rates were 66.9% and 65.4%, respectively. Patients of female gender with hepatomegaly and hemoglobin less than 120 g/L, and the time interval exceeding 38 days between induction 1a and 1b, had inferior EFS and OS. The results was comparable to the previous regimens and the regimen could prevent CNS relapse with 4 high-dose MTX every 3 months during the maintenance phase. PMID- 24475788 TI - Respiratory events at the earliest phase of acute myeloid leukemia. AB - Acute myeloid leukemia (AML) can result in acute respiratory failure (ARF) during the first days, requiring intensive care unit (ICU) admission in half the cases. We describe three leukemia-specific syndromes responsible for ARF: leukostasis, pulmonary leukemic infiltration (PLI) and acute lysis pneumopathy (ALP). We retrospectively analyzed clinical and laboratory data from 114 patients admitted to a medical ICU within 10 days after a diagnosis of AML. Respiratory events (REs) occurred in 95 patients and were leukemia-specific in 58 patients (61%). Day-28 mortality was 34.5% in patients with leukemia-specific REs (leukostasis, 41%; PLI, 23%; and ALP, 31%) and 48.6% in patients with other REs. By multivariate analysis, independent risk factors for death were age > 50 (odds ratio, 13; 95% confidence interval, 3-51), Eastern Cooperative Oncology Group (ECOG) status >= 2 (5.4; 1.8-17) and need for invasive mechanical ventilation (19; 5-75). Dexamethasone therapy was protective (0.26; 0.09-0.8), suggesting a role as a preventive treatment in patients with AML-related non-infectious pulmonary involvement. PMID- 24475789 TI - Can exercise echocardiography help optimal timing of surgery in patients with aortic regurgitation? PMID- 24475790 TI - Real-time automatic hospital-wide surveillance of nosocomial infections and outbreaks in a large Chinese tertiary hospital. AB - BACKGROUND: We aimed to develop a real-time nosocomial infection surveillance system (RT-NISS) to monitor all nosocomial infections (NIs) and outbreaks in a Chinese comprehensive hospital to better prevent and control NIs. METHODS: The screening algorithm used in RT-NISS included microbiological reports, antibiotic usage, serological and molecular testing, imaging reports, and fever history. The system could, in real-time, identify new NIs, record data, and produce time series reports to align NI cases. RESULTS: Compared with a manual survey of NIs (the gold standard), the sensitivity and specificity of RT-NISS was 98.8% (84/85) and 93.0% (827/889), with time-saving efficiencies of about 200 times. RT-NISS obtained the highest hospital-wide monthly NI rate of 2.62%, while physician and medical record reviews reported rates of 1.52% and 2.35% respectively. It took about two hours for one infection control practitioner (ICP) to deal with 70 new suspicious NI cases; there were 3,500 inpatients each day in the study hospital. The system could also provide various updated data (i.e. the daily NI rate, surgical site infection (SSI) rate) for each ward, or the entire hospital. Within 3 years of implementing RT-NISS, the ICPs monitored and successfully controlled about 30 NI clusters and 4 outbreaks at the study hospital. CONCLUSIONS: Just like the "ICPs' eyes", RT-NISS was an essential and efficient tool for the day-to day monitoring of all NIs and outbreak within the hospital; a task that would not have been accomplished through manual process. PMID- 24475791 TI - 18F fluorodeoxyglucose PET/CT in head and neck squamous cell carcinoma with negative neck palpation findings: a prospective study. AB - PURPOSE: To assess the clinical usefulness of fluorine 18 ((18)F) fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) and CT/magnetic resonance (MR) imaging in detecting occult neck metastasis in patients with head and neck squamous cell carcinoma and negative neck palpation findings. MATERIALS AND METHODS: This prospective study was approved by the institutional review board, and written informed consent was obtained from all enrolled patients. In total, 91 patients with head and neck squamous cell carcinoma and negative neck palpation findings were assessed prospectively with (18)F-FDG PET/CT and CT/MR imaging. Histopathologic analysis of neck dissection samples served as the standard of reference. Diagnostic values of (18)F-FDG PET/CT and CT/MR imaging were compared by using the McNemar test and logistic regression with generalized estimating equations. RESULTS: Of 91 patients, 38 (42%) had metastasis in 43 neck sides and 70 levels of the neck. (18)F-FDG PET/CT demonstrated nodal metastasis more sensitively on a per-level basis than did CT/MR imaging (69% vs 39%, P < .001). CT/MR imaging demonstrated nodal metastasis with low sensitivity at all levels (0%-38%) except level II (55%), while (18)F FDG PET/CT had generally high sensitivity at all levels (63%-100%) except level VI (0%). On a per-patient basis, the sensitivities of (18)F-FDG PET/CT and CT/MR imaging were 71% and 50%, respectively (P = .011). (18)F-FDG PET/CT accurately depicted CT/MR imaging false-negative findings in nine of 19 patients but yielded false-negative results in 11 patients. Use of (18)F-FDG PET/CT reduced the probability of occult neck metastasis to 12%. CONCLUSION: (18)F-FDG PET/CT is superior to CT/MR imaging in depicting occult cervical metastatic nodes in patients with negative neck palpation findings. The improved detection and nodal staging may promote appropriate therapeutic planning in these patients. PMID- 24475792 TI - Normative MR cervical spinal canal dimensions. AB - PURPOSE: To provide normal values of the cervical spinal canal and spinal cord dimensions in several planes with respect to spinal level, age, sex, and body height. MATERIALS AND METHODS: This study was approved by the institutional review board; all individuals provided signed informed consent. In a prospective multicenter study, two blinded raters independently examined cervical spine magnetic resonance (MR) images of 140 healthy volunteers who were white. The midsagittal diameters and areas of spinal canal and spinal cord, respectively, were measured at the midvertebral levels of C1, C3, and C6. A multivariate general linear model described the influence of sex, body height, age, and spinal level on the measured values. RESULTS: There were differences for sex, spinal level, interaction between sex and level, and body height, while age had significant yet limited influence. Normative ranges for the sagittal diameters and areas of spinal canal and spinal cord were defined at C1, C3, and C6 levels for men and women. In addition to a calculation of normative ranges for a specific sex, spinal level, age, and body height data, data for three different height subgroups at 45 years of age were extracted. These results show a range of the spinal canal dimensions at C1 (from 10.7 to 19.7 mm), C3 (from 9.4 to 17.2 mm), and C6 (from 9.2 to 16.8 mm) levels. CONCLUSION: The dimensions of the cervical spinal canal and cord in healthy individuals are associated with spinal level, sex, age, and height. Online supplemental material is available for this article. PMID- 24475793 TI - Fluoroscopic balloon dilation of esophageal atresia anastomotic strictures in children and young adults: single-center study of 103 consecutive patients from 1999 to 2011. AB - PURPOSE: To determine whether fluoroscopic balloon dilation (FBD) is a safe and effective method of treating esophageal anastomotic stricture after surgical repair in an unselected patient population. MATERIALS AND METHODS: With ethics committee approval, records for 103 consecutive patients who underwent FBD with our interventional radiology service (1999-2011) were reviewed retrospectively. Patients underwent diagnostic contrast material-enhanced study prior to the first dilation. Dilations were performed by using general anesthesia. Outcomes were number and/or frequency of dilations, clinical effectiveness and response to dilations, esophageal perforation, requirement for surgery, and mortality. Data were expressed as mean +/- standard deviation (with range). Comparisons were conducted by using the Fisher exact test and log-rank test. The significance level was set at P < .05. RESULTS: One hundred three patients (61 male patients, 59%) underwent 378 FBD sessions (median, two dilations per patient; range, 1-40 dilations). The median age at first FBD was 2.2 years (range, 0.1-19.5 years). The balloon catheter diameters ranged from 4 to 20 mm. FBD was successful in 93 patients (90%): 44 (47%) after single dilation and 49 (53%) after multiple dilations. There was no difference in the proportion of patients who required one dilation and were younger than 1 year versus those who were 1 year of age and older (P > .99; odds ratio, 1.07 [range, 0.43-2.66]). Ten patients (10%) required further procedures: Three underwent stent placement, three underwent esophageal stricture resection, and four underwent esophageal reconstruction. Four esophageal perforations (1%) developed after FBD. Antireflux surgery was performed in 18 patients (17%). There were no deaths. CONCLUSION: FBD for anastomotic strictures after esophageal atresia repair is feasible and acceptably safe and provides relief of symptoms in most patients (90%); however, about half require more than one dilation, and surgery is best predicted if more than 10 dilations are required. PMID- 24475794 TI - Quantitative analysis of 1.5-T whole-heart coronary MR angiograms obtained with 32-channel cardiac coils: a comparison with conventional quantitative coronary angiography. AB - PURPOSE: To develop a method to determine significant stenosis at whole-heart coronary magnetic resonance (MR) angiography and to evaluate the accuracy and reproducibility of this approach. MATERIALS AND METHODS: The institutional review board approved the study, and all participants provided written informed consent. Sixty-two patients who were suspected of having coronary artery disease (CAD) and were scheduled for conventional coronary angiography were included. Coronary MR angiography was performed by using a 1.5-T imager with 32-channel coils. Luminal narrowing was evaluated with quantitative analysis (QA) of coronary MR angiograms on the basis of the signal intensity profile along the vessel. Percentage stenosis with QA of coronary MR angiograms was calculated as [1 - (SI(min)/SI(ref))] * 100, where SI(min) is minimal signal intensity and SI(ref) is corresponding reference signal intensity. Diagnostic performance of QA of coronary MR angiograms for predicting at least a 50% reduction in diameter was evaluated by using quantitative coronary angiography (QCA), with conventional angiography findings serving as the reference standard. Receiver operating characteristic (ROC) analysis, Spearman rank correlation, Bland-Altman analysis, and Cohen kappa analysis were used. RESULTS: The areas under the ROC curve in a segment-based analysis for detecting significant CAD were 0.96 (95% confidence interval [CI]: 0.94, 0.98) with QA of coronary MR angiograms and 0.93 (95% CI: 0.88, 0.98) with visual assessment. The correlation coefficients between percentage stenosis with QA of coronary MR angiograms and percentage stenosis with QCA were 0.84 (P < .001), 0.80 (P < .001), and 0.66 (P < .001) in the patient-, vessel-, and segment-based analyses, respectively. CONCLUSION: QA of coronary MR angiograms with use of a signal intensity profile along the vessel permits detection of CAD. This method had a diagnostic performance approximately equal to that of visual analysis of coronary MR angiograms with high inter- and intraobserver reliability, allowing for more objective interpretation of coronary MR angiography findings. PMID- 24475795 TI - Nonalcoholic Fatty Liver Disease: Intravoxel Incoherent Motion Diffusion-weighted MR Imaging-An Experimental Study in a Rabbit Model. AB - Purpose To evaluate the feasibility of using intravoxel incoherent motion (IVIM) diffusion-weighted imaging with multiple b values for the noninvasive diagnosis of nonalcoholic fatty liver disease (NAFLD). Materials and Methods This study was approved by the institutional animal care and use committee. Twenty-seven 8-week old rabbits were fed a variety of diets (from a standard diet to a high-fat, high cholesterol diet) before IVIM diffusion-weighted imaging was performed with seven b values by using a 3-T magnetic resonance (MR) imaging unit. At histologic analysis of the animals, livers were categorized by NAFLD severity as normal, NAFLD, borderline nonalcoholic steatohepatitis (NASH), or NASH. The apparent diffusion coefficient and IVIM-derived parameters including true diffusion coefficient, pseudodiffusion coefficient, and perfusion fraction of the liver parenchyma were measured. Each parameter was correlated with NAFLD severity, and optimal cutoff values were determined by means of receiver operating characteristics analysis. Results Perfusion fraction was significantly lower in rabbits with NAFLD than in those with a normal liver, and it decreased further as severity of NAFLD increased, with medians of 22.2%, 14.8%, 11.3%, and 9.5% in the rabbits in the normal, NAFLD, borderline, and NASH groups, respectively (rho = 0.83, P < .001). Apparent diffusion coefficient, true diffusion coefficient, and pseudodiffusion coefficient were not significantly different between the NAFLD severity groups. In terms of the diagnostic performance of perfusion fraction, area under the curve values were 0.984 (normal vs NAFLD or more severe disease), 0.959 (NAFLD or less severe vs borderline or more severe disease), and 0.903 (borderline or less severe vs NASH) with optimal cutoff values of 15.2%, 13.2%, and 11.0%, respectively. Conclusion Perfusion fractions extracted from IVIM diffusion-weighted imaging may help in the differentiation of early stage NASH from simple steatosis. (c) RSNA, 2013. PMID- 24475796 TI - Living renal allograft transplantation: diffusion-weighted MR imaging in longitudinal follow-up of the donated and the remaining kidney. AB - PURPOSE: To determine whether diffusion-weighted (DW) magnetic resonance (MR) imaging in living renal allograft donation allows monitoring of potential changes in the nontransplanted remaining kidney of the donor because of unilateral nephrectomy and changes in the transplanted kidney before and after transplantation in donor and recipient, respectively, and whether DW MR parameters are correlated in the same kidney before and after transplantation. MATERIALS AND METHODS: The study protocol was approved by the local ethics committee; written informed consent was obtained. Thirteen healthy kidney donors and their corresponding recipients prospectively underwent DW MR imaging (multiple b values) in donors before donation and in donors and recipients at day 8 and months 3 and 12 after donation. Total apparent diffusion coefficient (ADCT) values were determined; contribution of microcirculation was quantified in perfusion fraction (FP). Longitudinal changes of diffusion parameters were compared (repeated-measures one-way analysis of variance with post hoc pairwise comparisons). Correlations were tested (linear regression). RESULTS: ADCT values in nontransplanted kidney of donors increased from a preexplantation value of (188 +/- 9 [standard deviation]) to (202 +/- 11) * 10(-5) mm(2)/sec in medulla and from (199 +/- 11) to (210 +/- 13) * 10(-5) mm(2)/sec in cortex 1 week after donation (P < .004). Medullary, but not cortical, ADCT values stayed increased up to 1 year. ADCT values in allografts in recipients were stable. Compared with values obtained before transplantation in donors, the corticomedullary difference was reduced in allografts (P < .03). Cortical ADCT values correlated with estimated glomerular filtration rate in recipients (R = 0.56, P < .001) but not donors. Cortical ADCT values in the same kidney before transplantation in donors correlated with those in recipients on day 8 after transplantation (R = 0.77, P = .006). FP did not show significant changes. CONCLUSION: DW MR imaging depicts early adaptations in the remaining nontransplanted kidney of donors after nephrectomy. All diffusion parameters remained constant in allograft recipients after transplantation. This method has potential monitoring utility, although assessment of clinical relevance is needed. PMID- 24475797 TI - Intracranial dural arteriovenous fistulas: evaluation with 3-T four-dimensional MR angiography using arterial spin labeling. AB - PURPOSE: To evaluate whether 3-T four-dimensional (4D) arterial spin-labeling (ASL)-based magnetic resonance (MR) angiography is useful for the evaluation of shunt lesions in patients with intracranial dural arteriovenous fistulas (AVFs). MATERIALS AND METHODS: Institutional review board approval and prior written informed consent from all patients were obtained. Nine patients with intracranial dural AVF (seven men, two women; age range, 52-77 years; mean age, 63 years) underwent 4D ASL MR angiography at 3 T and digital subtraction angiography (DSA). Spin tagging was with flow-sensitive alternating inversion recovery with Look Locker sampling. At 300-millisecond intervals, seven dynamic images with a spatial resolution of 0.5 * 0.5 * 0.6 mm(3) were obtained. The 4D ASL MR angiographic and DSA images were read by two sets of two independent readers each. Interobserver and intermodality agreement was assessed with the kappa statistic. RESULTS: On all 4D ASL MR angiographic images, the major intracranial arteries were demonstrated at a temporal resolution of 300 milliseconds. Interobserver agreement was excellent for the fistula site (kappa = 1.00; 95% confidence interval [CI]: 1.00, 1.00), moderate for the main arterial feeders (kappa = 0.53; 95% CI: 0.08, 0.98), and good for venous drainage (kappa = 0.77; 95% CI: 0.35, 1.00). Intermodality agreement was excellent for the fistula site and venous drainage (kappa = 1.00; 95% CI: 1.00, 1.00) and good for the main arterial feeders (kappa = 0.80; 95% CI: 0.58, 1.00). CONCLUSION: The good-to excellent agreement between 3-T 4D ASL MR angiographic and DSA findings suggests that 3-T 4D ASL MR angiography is a useful tool for the evaluation of intracranial dural AVFs. PMID- 24475798 TI - White matter NAA/Cho and Cho/Cr ratios at MR spectroscopy are predictive of motor outcome in preterm infants. AB - PURPOSE: To determine (a) whether diffuse white matter injury of prematurity is associated with an increased choline (Cho)-to-creatine (Cr) ratio and a reduced N acetylaspartate (NAA)-to-Cho ratio and whether these measures can be used as biomarkers of outcome and (b) if changes in peak area metabolite ratios at magnetic resonance (MR) spectroscopy are associated with changes in T2 and fractional anisotropy (FA) at MR imaging. MATERIALS AND METHODS: The local ethics committee approved this study, and informed parental consent was obtained for each infant. At term-equivalent age, 43 infants born at less than 32 weeks gestation underwent conventional and quantitative diffusion-tensor and T2 weighted MR imaging. Single-voxel point-resolved proton (hydrogen 1) MR spectroscopy was performed from a 2-cm(3) voxel centered in the posterior periventricular white matter. Outcome was evaluated by using Bayley scales at a corrected age of 1 year. Associations were investigated with Pearson product moment or Spearman rank order correlation. Differences in ratios in infants with and infants without impairment were tested by using t tests. RESULTS: NAA/Cho and Cho/Cr ratios correlated with the scaled gross motor score and the composite motor score, independent of gestational age (P < .05). FA at diffusion-tensor MR imaging and T2 at MR imaging correlated with the NAA/Cho ratio (P < .05 for both) but not with the Cho/Cr ratio. Infants with motor scores of less than 85 (impaired) had an increased Cho/Cr ratio (P < .03) and a reduced NAA/Cho ratio (P < .01) compared to those without impairment. A combination of increased Cho/Cr ratio and decreased NAA/Cho ratio predicted impaired motor outcome at a corrected age of 1 year with a sensitivity of 0.80 (95% confidence interval [CI]: 0.57, 0.94) and a specificity of 0.80 (95% CI: 0.66, 0.88). CONCLUSION: The combination of Cho/Cr and NAA/Cho ratios measured in the posterior periventricular white matter at term-equivalent age is predictive of motor outcome at 1 year in infants born at less than 32 weeks gestation. PMID- 24475799 TI - Benign prostatic hyperplasia: prostatic arterial embolization versus transurethral resection of the prostate--a prospective, randomized, and controlled clinical trial. AB - PURPOSE: To compare prostatic arterial embolization (PAE) and transurethral resection of the prostate (TURP) in the care of patients with benign prostatic hyperplasia (BPH). MATERIALS AND METHODS: This prospective randomized clinical trial was approved by the institutional review board. A total of 114 patients provided written informed consent and were randomly assigned to undergo PAE (n = 57) or TURP (n = 57). The groups were compared regarding relevant adverse events and complications. Functional results--including improvement of International Prostate Symptom Score (IPSS), quality of life (QOL), peak urinary flow, postvoiding residual urine volume, prostate-specific antigen (PSA) level, and prostate volume--were assessed at 1-, 3-, 6-, 12-, and 24-month follow-up between January 20, 2007, and January 31, 2012. Student t test, chi(2) test, Fisher exact test, and repeated measures analysis of variance were used, as appropriate. RESULTS: Overall technical success rates for TURP and PAE were 100% and 94.7%, respectively; the clinical failure rates were 3.9% and 9.4%, respectively. The six functional results showed improvements after TURP and PAE at all follow-up time points when compared with preoperative values (P = .001). However, the TURP group showed greater degrees of improvement in the IPSS, QOL, peak urinary flow, and postvoiding residual urine volume at 1 and 3 months, as well as greater reductions in the PSA level and prostate volume at all follow-up time points, when compared with the PAE group (P < .05). The PAE group showed more overall adverse events and complications (P = .029), mostly related to acute urinary retention (25.9%), postembolization syndrome (11.1%), and treatment failures (5.3% technical; 9.4% clinical). CONCLUSION: Both procedures resulted in significant clinical improvements in the treatment of BPH. However, the advantages of the PAE procedure must be weighed against the potential for technical and clinical failures in a minority of patients. PMID- 24475800 TI - Hilar cholangiocarcinoma: value of adding DW imaging to gadoxetic acid-enhanced MR imaging with MR cholangiopancreatography for preoperative evaluation. AB - PURPOSE: To assess the benefit of adding diffusion-weighted (DW) imaging to gadoxetic acid-enhanced magnetic resonance (MR) imaging and MR cholangiopancreatography in the preoperative evaluation of hilar cholangiocarcinoma. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the requirement for informed consent. The study included 52 patients (36 men, 16 women; mean age, 63.4 years) with surgically confirmed hilar cholangiocarcinoma who underwent gadoxetic acid enhanced MR imaging and DW imaging at 3.0 T between August 2010 and December 2011. Two observers independently reviewed two image sets--a gadoxetic acid set, including images from MR cholangiopancreatography, and a combined gadoxetic acid set and DW imaging set--to evaluate the tumor involvement of each biliary confluence and vascular and liver invasion by using receiver operating characteristic (ROC) curve analysis. RESULTS: For each observer, area under the ROC curve (Az) values for tumor involvement of the biliary confluence were 0.965 and 0.957 for the gadoxetic acid set and 0.980 and 0.975 for the combined set, respectively (P > .05). For detecting 105 biliary confluences with tumor involvement, the sensitivities with the combined set (97.1% [102 of 105] and 98.1% [103 of 105]) were higher than those with the gadoxetic acid set (91.4% [96 of 105] for both observers) (P = .029 and P = .016), although the specificities were similar with both image sets (P > .05). For the detection of liver invasion, the combined set (75.0% [15 of 20] for both observers) yielded better sensitivity than the gadoxetic acid set (50.0% [10 of 20] and 45.0% [nine of 20]) (P = .016 and P = .031). For evaluation of vascular invasion, the two image sets showed similar diagnostic performance. CONCLUSION: In the preoperative evaluation of hilar cholangiocarcinoma, the addition of DW imaging to gadoxetic acid-enhanced MR imaging could improve sensitivity in the evaluation of tumor extent along the bile duct and liver invasion. PMID- 24475801 TI - Volumetric quantification of type II endoleaks: an indicator for aneurysm sac growth following endovascular abdominal aortic aneurysm repair. AB - PURPOSE: To test the hypothesis that type II endoleak cavity volume (ECV) and endoleak cavity diameter (ECD) measurements are accurate indicators of aneurysm sac volume (ASV) enlargement in patients who undergo endovascular aneurysm repair (EVAR) in the abdominal aorta. MATERIALS AND METHODS: The institutional review board approved and waived the need to obtain patient consent for this HIPAA compliant retrospective study. In 72 patients who underwent EVAR, 160 computed tomographic (CT) angiography studies revealed type II endoleaks. Corresponding to these 160 CT angiography studies, 113 CT follow-up studies (in 52 patients) were available and were included in the analysis. ECV measurements were obtained by two observers in consensus by using arterial enhanced phase (ECVAEP) and 70 second delayed enhanced phase (ECVDEP) CT images. The ECVDEP was also normalized as the ECV/ASV ratio. Maximum (ECDM) and transverse (ECDT) ECDs were determined from delayed enhanced phase images. The outcome was determined as interval increase (>2%) in ASV versus stable or decreasing (<=2%) ASV. Receiver operating characteristic (ROC) analysis was used to compare the accuracy of type II ECV and ECD measurements in indicating interval increase in ASV. RESULTS: In 56 (49.5%) of 113 CT studies in type II endoleaks, there was an interval increase in ASV. The accuracies of ECVDEP (area under the ROC curve [AUC], 0.85) and normalized ECVDEP (AUC, 0.86) were superior to the accuracies of ECDM (AUC, 0.73), ECDT (AUC, 0.73), and ECVAEP (AUC, 0.66). At ROC curve analysis, the sensitivity, specificity, and positive and negative predictive values for type II endoleak cavities with an ECVDEP of less than 0.5 mL for showing no future sac volume enlargement were 33% (19 of 57), 100% (56 of 56), 100% (19 of 19), and 60% (56 of 94), respectively. CONCLUSION: With use of the delayed enhanced phase of CT angiography, ECV measurement is an accurate indicator of aneurysm sac enlargement. PMID- 24475802 TI - Evaluation of indeterminate renal masses with contrast-enhanced US: a diagnostic performance study. AB - PURPOSE: To determine the utility of contrast material-enhanced ultrasonography (US) in the characterization of indeterminate renal masses. MATERIALS AND METHODS: This retrospective performance study was approved by the institutional review board and was HIPAA compliant, with waiver of informed consent. Patients included 721 individuals referred for contrast-enhanced US with 1018 indeterminate renal masses from 1999 to 2010, identified initially with an imaging study. Three hundred twenty patients (44.4%) were female, and 401 (55.6%) were male. Patient ages ranged from 17 to 95 years (mean +/- standard deviation, 70 years +/- 15). Lesion size varied from 2 to 161 mm (mean, 26.6 mm +/- 19.5). Contrast-enhanced US enhancement patterns were used to characterize masses as benign or malignant. For lesions with a definitive diagnosis, 306 of 1018 (30.0%) were correlated with contrast-enhanced US findings: 167 (54.6%) were benign, and 139 (45.4%) were malignant. For lesions without a pathologic diagnosis, 712 (70.0%) were followed for as long as 10 years. Diagnostic accuracy measures were calculated by using pathologic diagnosis as the reference standard, as well as lesion stability at 3 and 5 years. RESULTS: Contrast-enhanced US had a sensitivity of 100% (126 of 126; 95% confidence interval [CI]: 97.1%, 100%), specificity of 95.0% (132 of 139; 95% CI: 89.9%, 98.0%), positive predictive value (PPV) of 94.7% (126 of 133), and negative predictive value (NPV) of 100% (132 of 132). The five false-positive masses included three oncocytomas and two Bosniak category 3 cystic lesions. Of the 290 lesions that had follow-up of at least 36 months, none of the lesions demonstrated changes that necessitated lesion reclassification. If these lesions were included, assuming lesions classified as malignant were malignant, then of the 596 lesions, sensitivity was 100% (161 of 161), specificity was 96.6% (420 of 435), PPV was 91.5% (161 of 176), and NPV was 100% (420 of 420). CONCLUSION: Contrast-enhanced US evaluation is a highly sensitive and specific method for characterization of indeterminate renal masses. Online supplemental material is available for this article. PMID- 24475803 TI - Dedicated cone-beam CT system for extremity imaging. AB - PURPOSE: To provide initial assessment of image quality and dose for a cone-beam computed tomographic (CT) scanner dedicated to extremity imaging. MATERIALS AND METHODS: A prototype cone-beam CT scanner has been developed for imaging the extremities, including the weight-bearing lower extremities. Initial technical assessment included evaluation of radiation dose measured as a function of kilovolt peak and tube output (in milliampere seconds), contrast resolution assessed in terms of the signal difference-to-noise ratio (SDNR), spatial resolution semiquantitatively assessed by using a line-pair module from a phantom, and qualitative evaluation of cadaver images for potential diagnostic value and image artifacts by an expert CT observer (musculoskeletal radiologist). RESULTS: The dose for a nominal scan protocol (80 kVp, 108 mAs) was 9 mGy (absolute dose measured at the center of a CT dose index phantom). SDNR was maximized with the 80-kVp scan technique, and contrast resolution was sufficient for visualization of muscle, fat, ligaments and/or tendons, cartilage joint space, and bone. Spatial resolution in the axial plane exceeded 15 line pairs per centimeter. Streaks associated with x-ray scatter (in thicker regions of the patient--eg, the knee), beam hardening (about cortical bone--eg, the femoral shaft), and cone-beam artifacts (at joint space surfaces oriented along the scanning plane--eg, the interphalangeal joints) presented a slight impediment to visualization. Cadaver images (elbow, hand, knee, and foot) demonstrated excellent visibility of bone detail and good soft-tissue visibility suitable to a broad spectrum of musculoskeletal indications. CONCLUSION: A dedicated extremity cone-beam CT scanner capable of imaging upper and lower extremities (including weight-bearing examinations) provides sufficient image quality and favorable dose characteristics to warrant further evaluation for clinical use. PMID- 24475804 TI - Localized prostate cancer detection with 18F FACBC PET/CT: comparison with MR imaging and histopathologic analysis. AB - PURPOSE: To characterize uptake of 1-amino-3-fluorine 18-fluorocyclobutane-1 carboxylic acid ((18)F FACBC) in patients with localized prostate cancer, benign prostatic hyperplasia (BPH), and normal prostate tissue and to evaluate its potential utility in delineation of intraprostatic cancers in histopathologically confirmed localized prostate cancer in comparison with magnetic resonance (MR) imaging. MATERIALS AND METHODS: Institutional review board approval and written informed consent were obtained for this HIPAA-compliant prospective study. Twenty one men underwent dynamic and static abdominopelvic (18)F FACBC combined positron emission tomography (PET) and computed tomography (CT) and multiparametric (MP) 3 T endorectal MR imaging before robotic-assisted prostatectomy. PET/CT and MR images were coregistered by using pelvic bones as fiducial markers; this was followed by manual adjustments. Whole-mount histopathologic specimens were sliced with an MR-based patient-specific mold. (18)F FACBC PET standardized uptake values (SUVs) were compared with those at MR imaging and histopathologic analysis for lesion- and sector-based (20 sectors per patient) analysis. Positive and negative predictive values for each modality were estimated by using generalized estimating equations with logit link function and working independence correlation structure. RESULTS: (18)F FACBC tumor uptake was rapid but reversible. It peaked 3.6 minutes after injection and reached a relative plateau at 15-20 minutes (SUVmax[15-20min]). Mean prostate tumor SUVmax(15-20min) was significantly higher than that of the normal prostate (4.5 +/- 0.5 vs 2.7 +/- 0.5) (P < .001); however, it was not significantly different from that of BPH (4.3 +/- 0.6) (P = .27). Sector-based comparison with histopathologic analysis, including all tumors, revealed sensitivity and specificity of 67% and 66%, respectively, for (18)F FACBC PET/CT and 73% and 79%, respectively, for T2 weighted MR imaging. (18)F FACBC PET/CT and MP MR imaging were used to localize dominant tumors (sensitivity of 90% for both). Combined (18)F FACBC and MR imaging yielded positive predictive value of 82% for tumor localization, which was higher than that with either modality alone (P < .001). CONCLUSION: (18)F FACBC PET/CT shows higher uptake in intraprostatic tumor foci than in normal prostate tissue; however, (18)F FACBC uptake in tumors is similar to that in BPH nodules. Thus, it is not specific for prostate cancer. Nevertheless, combined (18)F FACBC PET/CT and T2-weighted MR imaging enable more accurate localization of prostate cancer lesions than either modality alone. PMID- 24475805 TI - US-guided percutaneous microwave ablation versus open radical nephrectomy for small renal cell carcinoma: intermediate-term results. AB - PURPOSE: To review intermediate-term clinical outcomes of microwave ablation (MWA) compared with open radial nephrectomy (ORN) in small renal cell carcinoma (RCC) patients and to identify prognostic factors associated with two techniques. MATERIALS AND METHODS: This retrospective study was institutional review board approved. A total of 163 patients (127 men and 36 women) with small RCC (<=4 cm) were included from April 2006 to March 2012. Sixty-five patients underwent MWA and 98 patients underwent ORN. Survival, recurrence, and renal function changes were compared between the two groups. Effect of changes in key parameters (ie, overall survival, RCC-related survival, and metastasis-free survival) was statistically analyzed with the log-rank test. RESULTS: Although overall survival after MWA was lower than that after ORN (P = .002), RCC-related survival was comparable to ORN (P = .78). Estimated 5-year overall survival rates were 67.3% after MWA and 97.8% after ORN; for RCC-related survival, estimated 5-year rates were 97.1% after MWA and 97.8% after ORN. There was one local tumor recurrence 32 months after MWA and none after ORN. Major complication rates were comparable (P = .81) between the two techniques (MWA, 2.5% vs ORN, 3.1%). The MWA group had less surgical time (P < .001), estimated blood loss (P < .001), and postoperative hospitalization (P < .001). Multivariate analysis showed age (P = .014), tumor type (P = .003), postoperative urea nitrogen (P = .042), comorbid disease (P = .005), and treatment modality (P < .001) may become survival rate predictors. CONCLUSION: In intermediate term, ultrasonographically guided percutaneous MWA and ORN provide comparable results in oncologic outcomes. MWA appears to be a safe and effective technique for management of small RCC in patients with little loss of renal function. PMID- 24475806 TI - Features of resolving and nonresolving indeterminate pulmonary nodules at follow up CT: the NELSON study. AB - PURPOSE: To retrospectively identify features that allow prediction of the disappearance of solid, indeterminate, intraparenchymal nodules detected at baseline computed tomographic (CT) screening of individuals at high risk for lung cancer. MATERIALS AND METHODS: The study was institutional review board approved. Participants gave informed consent. Participants with at least one noncalcified, solid, indeterminate, intraparenchymal nodule (volume range, 50-500 mm(3)) at baseline were included (964 nodules in 750 participants). According to protocol, indeterminate nodules were re-examined at a 3-month follow-up CT examination. Repeat screening was performed at years 2 and 4. A nodule was defined as resolving if it did not appear at a subsequent CT examination. Nodule resolution was regarded as spontaneous, not the effect of treatment. CT features of resolving and nonresolving (stable and malignant) nodules were compared by means of generalized estimating equations analysis. RESULTS: At subsequent screening, 10.1% (97 of 964) of the nodules had disappeared, 77.3% (n = 75) of these at the 3-month follow-up CT and 94.8% (n = 92) at the second round of screening. Nonperipheral nodules were more likely to resolve than were peripheral nodules (odds ratio: 3.16; 95% confidence interval: 1.76, 5.70). Compared with smooth nodules, nodules with spiculated margins showed the highest probability of disappearance (odds ratio: 4.36; 95% confidence interval: 2.24, 8.49). CONCLUSION: Approximately 10% of solid, intermediate-sized, intraparenchymal pulmonary nodules found at baseline screening for lung cancer resolved during follow-up, three-quarters of which had disappeared at the 3-month follow-up CT examination. Resolving pulmonary nodules share CT features with malignant nodules. PMID- 24475807 TI - Evaluation of fibrotic liver disease with whole-liver T1rho MR imaging: a feasibility study at 1.5 T. AB - PURPOSE: To test at 1.5 T whether T1rho magnetic resonance (MR) imaging of fibrotic liver disease is feasible, to investigate whether liver T1rho imaging allows assessment of the severity of liver cirrhosis, and to assess the normal liver T1rho range in healthy patients. MATERIALS AND METHODS: This prospective study was approved by the institutional ethics committee. Written informed consent was obtained. Healthy volunteers (n = 25) and patients (n = 34) with cirrhosis underwent whole-liver T1rho MR imaging at 1.5 T. Mean T1rho values were calculated from liver regions of interest. Mean T1rho values were correlated to clinical data and histopathologic analysis by analysis of variance. Receiver operating characteristic curves were calculated to determine the accuracy of mean T1rho values for the assessment of Child-Pugh class. RESULTS: Mean T1rho values of volunteers (mean, 40.9 msec +/- 2.9 [standard deviation]; range, 33.9-46.3 msec) were significantly lower than those of patients who were Child-Pugh class A (P < .004), B (P < .001), or C (P < .001), and significant differences were found between each Child-Pugh stage (A vs B, P < .002; B vs C, P < .009; A vs C, P < .001). Liver cirrhosis was confirmed via histologic analysis in all patients with liver biopsy. Mean T1rho values did not correlate with necroinflammatory activity (r = 0.31; P = .23), degree of steatosis (r = -0.016; P = .68), or presence of iron load (r = 0.22; P = .43). Mean T1rho values performed well by assessing the Child-Pugh stage, with receiver operating characteristic areas of 0.95-0.98. Intraclass correlation coefficient values ranged between 0.890 and 0.987, which indicated excellent imaging and reimaging reproducibility and interobserver and intraobserver variability. CONCLUSION: Whole-liver T1rho MR imaging at 1.5 T to detect and assess human liver cirrhosis is feasible. Further investigation and optimization of this technique are warranted to cover the entire spectrum of fibrotic liver disease. PMID- 24475808 TI - Quantitative susceptibility mapping of multiple sclerosis lesions at various ages. AB - PURPOSE: To assess multiple sclerosis (MS) lesions at various ages by using quantitative susceptibility mapping (QSM) and conventional magnetic resonance (MR) imaging. MATERIALS AND METHODS: Retrospectively selected were 32 clinically confirmed MS patients (nine men and 23 women; 39.3 years +/- 10.9) who underwent two MR examinations (interval, 0.43 years +/- 0.16) with three-dimensional gradient-echo sequence from August 2011 to August 2012. To estimate the ages of MS lesions, MR examinations performed 0.3-10.6 years before study examinations were studied. Hyperintensity on T2-weighted images was used to define MS lesions. QSM images were reconstructed from gradient-echo data. Susceptibility of MS lesions and temporal rates of change were obtained from QSM images. Lesion susceptibilities were analyzed by t test with intracluster correlation adjustment and Bonferroni correction in multiple comparisons. RESULTS: MR imaging of 32 patients depicted 598 MS lesions, of which 162 lesions (27.1%) in 23 patients were age measurable and six (1.0%) were only visible at QSM. The susceptibilities relative to normal-appearing white matter (NAWM) were 0.53 ppb +/- 3.34 for acute enhanced lesions, 38.43 ppb +/- 13.0 (positive; P < .01) for early to intermediately aged nonenhanced lesions, and 4.67 ppb +/- 3.18 for chronic nonenhanced lesions. Temporal rates of susceptibility changes relative to cerebrospinal fluid were 12.49 ppb/month +/- 3.15 for acute enhanced lesions, 1.27 ppb/month +/- 2.31 for early to intermediately aged nonenhanced lesions, and -0.004 ppb/month +/- 0 for chronic nonenhanced lesions. CONCLUSION: Magnetic susceptibility of MS lesions increased rapidly as it changed from enhanced to nonenhanced, it attained a high susceptibility value relative to NAWM during its initial few years (approximately 4 years), and it gradually dissipated back to susceptibility similar to that of NAWM as it aged, which may provide new insight into pathophysiologic features of MS lesions. Online supplemental material is available for this article. PMID- 24475809 TI - Noncathartic CT colonography to screen for colorectal neoplasia in subjects with a family history of colorectal cancer. AB - PURPOSE: To prospectively assess the diagnostic performance of noncathartic computed tomographic (CT) colonography in the detection of clinically relevant colorectal lesions (>=6 mm polyps or masses) in a well-defined cohort of first degree relatives of patients with colorectal cancer (CRC), using colonoscopy and histologic review as the standard of reference. MATERIALS AND METHODS: Institutional review board approval was obtained, and all subjects provided written informed consent. Consecutive patients admitted with CRC (index cases) were prospectively evaluated, and those who agreed to contact their first-degree relatives who were at least 40 years old were included. Available first-degree relatives were invited to undergo noncathartic CT colonography (200 mL of diatrizoate meglumine and diatrizoate sodium). Colonoscopy was performed the following day, and findings from CT colonography were disclosed for each segment. Sensitivity, specificity, and positive and negative predictive values of CT colonography were assessed for detecting subjects with any lesion at least 6 mm, any lesion at least 10 mm, and advanced neoplasia at least 6 mm. Colonoscopy with segmental unblinding and histologic diagnosis were used as the standard of reference. Matching between findings from CT colonography and colonoscopy was allowed when lesions were located in the same or adjacent colon segments and when the size difference was 50% or less. RESULTS: Three hundred four first-degree relatives (median age, 47 years; age range, 40-79 years; 46.7% women) identified from 221 index cases were included. Overall, CT colonography helped identify 17 of 22 subjects with polyps measuring at least 6 mm (sensitivity, 0.77; 95% confidence interval [CI]: 0.59, 0.95) and helped correctly classify as negative 278 of 282 subjects without lesions measuring at least 6 mm (specificity, 0.99; 95% CI: 0.97, 1.00). CT colonography helped detect eight of nine subjects with polyps measuring at least 10 mm as well as eight of nine subjects with advanced neoplasia measuring at least 6 mm (sensitivity, 0.89 for both). Per-subject positive and negative predictive values for lesions measuring at least 6 mm were 0.81 (17 of 21 subjects; 95% CI: 0.65, 0.97) and 0.98 (282 of 287 subjects; 95% CI: 0.96, 0.99), respectively. CONCLUSION: Noncathartic CT colonography is an effective screening method in first-degree relatives of patients with CRC. PMID- 24475810 TI - Testicular microlithiasis in children and associated testicular cancer. AB - PURPOSE: To evaluate the prevalence of testicular microlithiasis (TM) in children who have undergone scrotal ultrasonography (US) and their association with testicular tumors. MATERIALS AND METHODS: This HIPAA-compliant study with waiver of informed consent was approved by the institutional review board. From 2003 to 2012, all patients with scrotal US and report mentioning calcifications or microlithiasis and all patients with testicular tumors from pathology database were identified. US studies were evaluated for the type of TM (classic >=5 microliths or limited <5 microliths in a single view) and change in follow-up studies if available. Medical charts were reviewed for US indication, underlying medical conditions, and pathologic abnormalities, when available. Fisher exact test was used to analyze the association of testicular tumors and TM. RESULTS: A total of 3370 boys had scrotal US, 83 (2%) of whom had TM or microcalcifications in the report. TM was usually bilateral (n = 62, 75%) and classic (n = 59, 71%) type.TM was significantly less common in those younger than 2 years of age than in older age groups (0.1% vs 3.1%, P < .0001). The most common indication for US was scrotal pain (40 of 83 patients, 48%), and the most common associated medical condition was cryptorchidism (nine of 83 patients, 11%). Testicular tumor was significantly more likely in boys with TM (12% vs 0.3%, P < .01). Five (83%) of six patients with premalignant or benign tumors had a premalignant condition (cryptochydism in two and Peutz-Jeghers syndrome in three). Four patients with TM had malignant testicular tumors, all diagnosed after the age of 16 years. CONCLUSION: TM has a prevalence of 2% in boys who undergo scrotal US. It is most commonly bilateral, classic type, and stable at follow-up studies. There is a significant association of TM and testicular tumors. Malignant tumors were seen only in adolescent boys. PMID- 24475811 TI - Intravoxel incoherent motion diffusion-weighted MR imaging of hepatocellular carcinoma: correlation with enhancement degree and histologic grade. AB - PURPOSE: To compare the association of intravoxel incoherent motion (IVIM) derived parameters and apparent diffusion coefficient (ADC) with the histologic grade of hepatocellular carcinoma (HCC) and evaluate the relationship between IVIM-derived parameters and arterial enhancement degree. MATERIALS AND METHODS: This retrospective study was institutional review board-approved, and informed consent was waived. Forty patients with 42 surgically confirmed HCCs underwent diffusion-weighted magnetic resonance (MR) imaging with eight b values (0-800 sec/mm(2)). ADC, diffusion coefficient (D), pseudodiffusion coefficient, and perfusion fraction (f) were calculated. Two radiologists determined the enhancement degree in consensus, as well as the percentage of arterial enhancement of HCC. The relationship between the parameters and histologic grade, as well as arterial enhancement, was assessed by using the Spearman or Pearson correlation test. Receiver operating characteristic (ROC) analysis of discrimination between low-grade (grades 1 and 2) and high-grade (grades 3 and 4) HCC was performed for D and ADC values. RESULTS: D and ADC values were both significantly correlated with histologic grade: r = -0.604 (P < .0001) and r = 0.448 (P = .002), respectively. D and ADC values were both significantly lower in high-grade HCC (D = [0.99 +/- 0.13] * 10(-3)mm(2)/sec, ADC = [1.13 +/- 0.14] * 10(-3)mm(2)/sec) than in low-grade HCC (D = [1.18 +/- 0.16] * 10(-3)mm(2)/sec, ADC = [1.25 +/- 0.17] * 10-(3)mm(2)/sec) (P < .0001 and P = .029, respectively). However, ROC analysis demonstrated a higher area under the ROC curve value for D than for ADC for differentiating high-grade HCC from low-grade HCC (0.838 vs 0.728; P = .026). The percentage of arterial enhancement was correlated with f (r = 0.621, P < .0001). CONCLUSION: IVIM-derived D values of HCC showed significantly better diagnostic performance than ADC values in differentiating high-grade HCC from low-grade HCC, and significant correlation was observed between f and the percentage of arterial enhancement. PMID- 24475812 TI - Temporal subtraction method for lung nodule detection on successive thoracic CT soft-copy images. AB - PURPOSE: To assess the effects of a new computed tomographic (CT) temporal subtraction (TS) method on radiologist performance in lung nodule detection on thin-section CT images. MATERIALS AND METHODS: The institutional review board approved this study, and the informed consent requirement was waived. Fifty pairs (current and previous CT images) of standard-dose 2-mm thin-section CT images and corresponding CT TS images were used for an observer performance study. Two thoracic radiologists identified 30 nodules ranging in size from 5 to 19 mm, and these nodules served as the reference standard of actionable nodules (noncalcified nodules larger than 4 mm). Eight radiologists (four attending radiologists, four radiology residents) participated in this observer study. Ratings and locations of lesions determined by observers were used to assess the significance of differences between radiologists' performances without and with the CT TS images in jacknife free-response receiver operating characteristics analysis. RESULTS: Average figure of merit values increased significantly for all radiologists (from 0.838 without CT TS images to 0.894 with CT TS images [P = .033]). Average sensitivity for detection of actionable nodules was improved from 73.4% to 83.4%, with a false-positive rate of 0.15 per case, by using CT TS images. The reading time with CT TS images was not significantly different from that without. CONCLUSION: The novel CT TS method would increase observer performance for lung nodule detection without considerably extending the reading time. PMID- 24475813 TI - Inferior mesenteric arterial type II endoleaks after endovascular repair of abdominal aortic aneurysm: are they predictable? AB - PURPOSE: To evaluate the association of inferior mesenteric arterial (IMA) type II endoleaks in patients undergoing endovascular aortic aneurysm repair (EVAR) for infrarenal abdominal aortic aneurysm with several morphologic parameters. MATERIALS AND METHODS: Approval of the institutional ethical review committee was not required. This was a retrospective review of 322 computed tomographic angiographic studies that were performed in patients before they underwent elective EVAR for infrarenal abdominal aortic aneurysm. Morphologic parameters evaluated were IMA patency, origin of the IMA in relation to the aneurysm sac, diameter of the IMA, the cross-sectional area of the contrast material-enhanced aortic lumen at the level of the IMA ostium, and the number of additional patent aortic side branches from the aneurysm sac. The association of IMA type II endoleaks with each variable was analyzed by using univariate and multivariate logistic regression models. RESULTS: The diameter of the IMA did not influence the development of IMA type II endoleaks (P = .51). The incidence of these endoleaks was significantly higher in patients with greater cross-sectional area of the aortic lumen at the IMA ostium (P < .001). Patients with an IMA type II endoleak had significantly more patent aortic side branches before EVAR than did patients without an endoleak (3.6 +/- 1.7 vs 2.2 +/- 1.4; P < .001). According to the final logistic regression model that included cross-sectional area of the aortic lumen at the IMA and the number of aortic side branches as independent predictors, risk for IMA type II endoleaks was determined with a sensitivity of 78% (39 of 50) and a specificity of 79% (92 of 116). CONCLUSION: Cross-sectional area of the contrast-enhanced aortic lumen at the level of the IMA ostium and the number of additional patent aortic side branches are associated with the development of IMA type II endoleaks. PMID- 24475814 TI - Stress cardiac MR imaging compared with stress echocardiography in the early evaluation of patients who present to the emergency department with intermediate risk chest pain. AB - PURPOSE: To compare the utility and efficacy of stress cardiac magnetic resonance (MR) imaging and stress echocardiography in an emergency setting in patients with acute chest pain (CP) and intermediate risk of coronary artery disease (CAD). MATERIALS AND METHODS: Written informed consent was obtained from all patients. This HIPAA-compliant study was approved by the institutional review board for research ethics. Sixty patients without history of CAD presented to the emergency department with intermediate-risk acute CP and were prospectively enrolled. Patients underwent both stress cardiac MR imaging and stress echocardiography in random order within 12 hours of presentation. Stress imaging results were interpreted clinically immediately (blinded interpretation was performed months later), and coronary angiography was performed if either result was abnormal. CAD was considered significant if it was identified at angiography (narrowing >50% ) or if a cardiac event (death or myocardial infarction) occurred during follow-up (mean, 14 months +/- 5 [standard deviation]). McNemar test was used to compare the diagnostic accuracy of techniques. RESULTS: Stress cardiac MR imaging and stress echocardiography had similar specificity, accuracy, and positive and negative predictive values (92% vs 96%, 93% vs 88%, 67% vs 60%, and 100% vs 91%, respectively, for clinical interpretation; 90% vs 92%, 90% vs 88%, 58% vs 56%, and 98% vs 94%, respectively, for blinded interpretation). Stress cardiac MR imaging had higher sensitivity at clinical interpretation (100% vs 38%, P = .025), which did not reach significance at blinded interpretation (88% vs 63%, P = .31). However, multivariable logistic regression analysis showed stress cardiac MR imaging to be the strongest independent predictor of significant CAD (P = .002). CONCLUSION: In patients presenting to the emergency department with intermediate-risk CP, adenosine stress cardiac MR imaging performed within 12 hours of presentation is safe and potentially has improved performance characteristics compared with stress echocardiography. Online supplemental material is available for this article. PMID- 24475815 TI - Two-View versus Single-View Shear-Wave Elastography: Comparison of Observer Performance in Differentiating Benign from Malignant Breast Masses. AB - Purpose To determine whether two-view shear-wave elastography (SWE) improves the performance of radiologists in differentiating benign from malignant breast masses compared with single-view SWE. Materials and Methods This prospective study was conducted with institutional review board approval, and written informed consent was obtained. B-mode ultrasonographic (US) and orthogonal SWE images were obtained for 219 breast masses (136 benign and 83 malignant; mean size, 14.8 mm) in 219 consecutive women (mean age, 47.9 years; range, 20-78 years). Five blinded radiologists independently assessed the likelihood of malignancy for three data sets: B-mode US alone, B-mode US and single-view SWE, and B-mode US and two-view SWE. Interobserver agreement regarding Breast Imaging Reporting and Data System (BI-RADS) category and the area under the receiver operating characteristic curve (AUC) of each data set were compared. Results Interobserver agreement was moderate (kappa = 0.560 +/- 0.015 [standard error of the mean]) for BI-RADS category assessment with B-mode US alone. When SWE was added to B-mode US, five readers showed substantial interobserver agreement (kappa = 0.629 +/- 0.017 for single-view SWE; kappa = 0.651 +/- 0.014 for two view SWE). The mean AUC of B-mode US was 0.870 (range, 0.855-0.884). The AUC of B mode US and two-view SWE (average, 0.928; range, 0.904-0.941) was higher than that of B-mode US and single-view SWE (average, 0.900; range, 0.890-0.920), with statistically significant differences for three readers (P <= .003). Conclusion The performance of radiologists in differentiating benign from malignant breast masses was improved when B-mode US was combined with two-view SWE compared with that when B-mode US was combined with single-view SWE. (c) RSNA, 2013 Supplemental material: S1. PMID- 24475816 TI - Chemoembolization for hepatocellular carcinoma: 1-month response determined with apparent diffusion coefficient is an independent predictor of outcome. AB - PURPOSE: To evaluate the predictive utility of apparent diffusion coefficient (ADC) changes at diffusion-weighted (DW) magnetic resonance (MR) imaging 1 month after transcatheter arterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) compared with the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, European Association for the Study of the Liver (EASL) criteria, and modified RECIST (mRECIST). MATERIALS AND METHODS: Institutional review board approval and informed consent were obtained for this prospective study. Thirty-eight patients with inoperable HCC underwent 1.5-T MR imaging, including DW imaging, before and 1 month after TACE. Responses 1 month after TACE were assessed with the ADC change relative to baseline (ADC ratio), RECIST, EASL criteria, and mRECIST. Eight patients underwent transplantation 4 months after TACE, allowing the association between response and histopathologic necrosis ratio to be determined. In 30 patients, Kaplan-Meier and log-rank tests were used to correlate the response variables with progression-free and overall survival. RESULTS: Median progression-free survival (PFS) was 5 months, and overall survival was 17.5 months. Survival analyses showed significant effects of pretreatment alpha-fetoprotein level (P = .03) and ADC ratio (P < .0001) on PFS and substantial effects of mRECIST, RECIST, and EASL criteria (.05 < P < .1). ADC ratio was a significant predictor of 5-month PFS (P < .001), with an accuracy of 93.3% compared with 53.3% with mRECIST and EASL criteria and 66.7% with RECIST. No response variables correlated with overall survival. Only the ADC ratio was significantly associated with histopathologic tumor necrosis (P = .03). CONCLUSION: The ADC ratio 1 month after TACE was an independent predictor of PFS, which showed stronger association with tumor response than did RECIST, EASL criteria, or mRECIST. PMID- 24475818 TI - Reviving the dinosaur: virtual reconstruction and three-dimensional printing of a dinosaur vertebra. AB - PURPOSE: To demonstrate the feasibility of using computed tomography (CT) to confirm the identity of an unprepared fossil and to use the CT dataset to separate the fossilized bone from its surrounding sediment matrix and produce a three-dimensional (3D) print. MATERIALS AND METHODS: The examined object was a plaster jacket containing an unprepared fossil. CT was performed with a 320 section multidetector unit. A marching cube-based method was used to transform the voxel CT dataset into triangle-based, editable geometry. Then, a comprehensive postprocessing step was performed to isolate the geometry of the vertebra from its surrounding fossilized matrix. Finally, the resulting polygon mesh describing only the vertebra was used for a physical 3D reconstruction by using a selective laser sintering machine. RESULTS: The CT examination provided enough data to assign the fossil to the genus Plateosaurus. In addition, much valuable information about the fossil has been gained-in particular the visualization of multiple fractures and the destruction of the anterior rim of the vertebral body. Finally, the results show that the 3D print generated, including the fractures and the anterior destruction, may be considered an accurate copy of the bone with the unprepared fossil. CONCLUSION: The authors demonstrated the feasibility and potential utility of combining CT with 3D printing, providing a nondestructive method to future paleontologists. PMID- 24475817 TI - Bone metastases in castration-resistant prostate cancer: associations between morphologic CT patterns, glycolytic activity, and androgen receptor expression on PET and overall survival. AB - PURPOSE: To compare the features of bone metastases at computed tomography (CT) to tracer uptake at fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET) and fluorine 18 16beta-fluoro-5-dihydrotestosterone (FDHT) PET and to determine associations between these imaging features and overall survival in men with castration-resistant prostate cancer. MATERIALS AND METHODS: This is a retrospective study of 38 patients with castration-resistant prostate cancer. Two readers independently evaluated CT, FDG PET, and FDHT PET features of bone metastases. Associations between imaging findings and overall survival were determined by using univariate Cox proportional hazards regression. RESULTS: In 38 patients, reader 1 detected 881 lesions and reader 2 detected 867 lesions. Attenuation coefficients at CT correlated inversely with FDG (reader 1: r = 0.3007; P < .001; reader 2: r = -0.3147; P < .001) and FDHT (reader 1: r = 0.2680; P = .001; reader 2: r = -0.3656; P < .001) uptake. The number of lesions on CT scans was significantly associated with overall survival (reader 1: hazard ratio [HR], 1.025; P = .05; reader 2: HR, 1.021; P = .04). The numbers of lesions on FDG and FDHT PET scans were significantly associated with overall survival for reader 1 (HR, 1.051-1.109; P < .001) and reader 2 (HR, 1.026-1.082; P <= .009). Patients with higher FDHT uptake (lesion with the highest maximum standardized uptake value) had significantly shorter overall survival (reader 1: HR, 1.078; P = .02; reader 2: HR, 1.092; P = .02). FDG uptake intensity was not associated with overall survival (reader 1, P = .65; reader 2, P = .38). CONCLUSION: In patients with castration-resistant prostate cancer, numbers of bone lesions on CT, FDG PET, and FDHT PET scans and the intensity of FDHT uptake are significantly associated with overall survival. PMID- 24475819 TI - Sacrotuberous ligament: relationship to normal, torn, and retracted hamstring tendons on MR images. AB - PURPOSE: To evaluate continuity of the sacrotuberous ligament (STL) in normal and abnormal hamstring (HS) tendons on magnetic resonance (MR) images and to test the hypothesis that greater degrees of HS retraction are correlated with STL discontinuity. MATERIALS AND METHODS: The institutional review board approved this retrospective HIPAA-compliant study and waived informed consent. Control cohort comprised 33 patients (mean age, 54.1 years) without HS abnormalities at hip MR arthrography. Study cohort comprised 100 patients (mean age, 55.3 years) with HS abnormalities at pelvic or hip MR imaging. Two musculoskeletal radiologists independently assessed STL continuity with the ischium and semimembranosus (SM) and conjoined biceps femoris and semitendinosus (BF-ST) tendons and evaluated these tendons for tendinopathy, partial tear, or rupture. A third musculoskeletal radiologist measured retraction of ruptured tendons. Inter- and intraobserver agreement was calculated with weighted kappa or intraclass correlation coefficients. HS abnormalities in the cohorts were compared with Mann Whitney test. In patients with tendon rupture, relationships between qualitative (STL and HS attachments) and quantitative (tendon retraction measurements) data were analyzed with analysis of variance and linear regression with Bonferroni correction. RESULTS: STL was continuous with ischium in all patients. In control patients, STL was always continuous with BF-ST but never continuous with SM. In study patients, BF-ST tendon alone, SM tendon alone, and both BF-ST and SM tendons showed abnormalities in 17, six, and 77 patients, respectively. HS rupture occurred in 24 patients; it involved BF-ST tendon alone in 13 patients and both BF-ST and SM tendons in 11. STL was continuous with BF-ST tendon in 12 patients and discontinuous in 12 patients. Retraction of BF-ST tendon (mean, 33 mm; range, 5-81 mm) was independently correlated with STL continuity with BF-ST (P = .0001) and SM (P = .0004) tendon rupture. Retraction was significantly greater (P <= 0.01) when STL was discontinuous and SM tendon was ruptured. Inter- and intraobserver agreement was very good or excellent in categorization of HS abnormalities and measurement of retraction. CONCLUSION: STL showed continuity with both ischium and BF-ST tendon but not SM tendon. In HS rupture, tendon retraction was significantly less when STL remained attached to BF-ST tendon. PMID- 24475820 TI - Perivascular versus nonperivascular small HCC treated with percutaneous RF ablation: retrospective comparison of long-term therapeutic outcomes. AB - PURPOSE: To compare the long-term therapeutic outcomes of radiofrequency (RF) ablation for small perivascular hepatocellular carcinoma (HCC) and nonperivascular HCC. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. Between December 2004 and April 2008, 241 patients (175 men and 66 women; age range, 32-82 years) with a single early-stage HCC that was 3 cm or smaller in the greatest dimension underwent ultrasonography guided percutaneous RF ablation as a first-line treatment. The patients were divided into two groups according to the presence or absence of contacting hepatic vessels that were 3 mm or larger in axial diameter: a group with perivascular HCC (n = 58) and a group with nonperivascular HCC (n = 183). Cumulative local tumor progression, disease-free and long-term survival rates, and prognostic factors were assessed by using Cox proportional hazard models with Bonferroni correction. RESULTS: The overall median follow-up period was 58 months (range, 13-92 months). The cumulative local tumor progression rates were 10%, 16%, and 26% at 1, 3, and 5 years, respectively, in the perivascular group, and 6.7%, 15.5%, and 20.5% in the nonperivascular group; the differences were not significant (P = .323). The corresponding disease-free survival rates were 79%, 41%, and 29% in the perivascular group and 71.3%, 38.7%, and 26.0% in the nonperivascular group, with no significant difference (P = .689). The corresponding overall survival rates were 100%, 94%, and 82% in the perivascular group and 100%, 88.4%, and 73.9% in the nonperivascular group, also without significant difference (P = .267). There was no significant prognostic factor for local tumor progression, whereas extrahepatic and intrahepatic distant recurrences were significant prognostic factors for overall survival in multivariable analysis. CONCLUSION: The long-term therapeutic outcomes of RF ablation as first-line treatment for small perivascular HCC were similar to those for nonperivascular HCC. PMID- 24475821 TI - Rapid detection of bone metastasis at thoracoabdominal CT: accuracy and efficiency of a new visualization algorithm. AB - PURPOSE: To retrospectively assess the use of a combination of cancellous bone reconstructions (CBR) and multiplanar reconstructions (MPRs) for the detection of bone metastases at thoracoabdominal computed tomography (CT) compared with the use of MPRs alone. MATERIALS AND METHODS: The study was approved by the local institutional review board. Included were 156 consecutive patients with confirmed cancer who underwent a whole-body positron emission tomography (PET)/CT examination for clinical purposes (93 male and 63 female patients; mean age +/- standard deviation, 59.8 years +/- 14.9; range, 11-85 years). Only the CT images were processed with the CBR algorithm, which segments the bones and removes the cortical layer from the images. The PET images served as part of the reference standard. Images from 15 patients were used as a training set. Four radiologists independently evaluated images of half of the remaining 141 patients by using CBRs and MPRs together, and the other half by using MPRs only. Radiologists were blinded to patient names, and patient order was randomized. Results for detection rates and reporting time were recorded and compared with a standard of reference for each patient that was created by one senior radiologist and one nuclear medicine specialist by using all available CT and PET data, CBRs, and follow-up examinations. General estimation equations were used for statistical analysis. RESULTS: There were 349 lesions found in 103 patients, with 203 classified as malignant. Each patient was assessed by two readers per method, leading to a total of 698 lesions. The detection rate for all bone lesions was 35% (247 of 698) for MPRs and 74% (520 of 698) when CBRs and MPRs were used together, which was significantly higher (P < .001). The average reading time decreased from 85 to 43 seconds (P < .001) when both reconstructions were used. CONCLUSION: Advanced visualization of cancellous bone significantly increased the detection of bone metastases and reduced the time for interpretation. PMID- 24475822 TI - Colorectal cancer metastasis: the DNA repair inhibitor Dbait increases sensitivity to hyperthermia and improves efficacy of radiofrequency ablation. AB - PURPOSE: To assess the usefulness of combining hyperthermia with a DNA repair inhibitor (double-strand break bait [Dbait]) and its potential application to radiofrequency ablation (RFA) in a preclinical model of human colorectal cancer. MATERIALS AND METHODS: The local ethics committee of animal experimentation approved all investigations. First, the relevance was assessed by studying the survival of four human colorectal adenocarcinoma cell cultures after 1 hour of hyperthermia at 41 degrees C or 43 degrees C with or without Dbait. Human colon adenocarcinoma cells (HT-29) were grafted subcutaneously into nude mice (n = 111). When tumors reached approximately 500 mm(3), mice were treated with Dbait alone (n = 20), sublethal RFA (n = 21), three different Dbait schemes and sublethal RFA (n = 52), or a sham treatment (n = 18). RFA was performed to ablate the tumor center alone. To elucidate antitumor mechanisms, 39 mice were sacrificed for blinded pathologic analysis, including assessment of DNA damage, cell proliferation, and tumor necrosis. Others were monitored for tumor growth and survival. Analyses of variance and log-rank tests were used to evaluate differences. RESULTS: When associated with mild hyperthermia, Dbait induced cytotoxicity in all tested colon cancer cell lines. Sublethal RFA or Dbait treatment alone moderately improved survival (median, 40 days vs 28 days for control; P = .0005) but combination treatment significantly improved survival (median, 84 days vs 40 days for RFA alone, P = .0004), with approximately half of the animals showing complete tumor responses. Pathologic studies showed that the Dbait and RFA combination strongly enhances DNA damage and coagulation areas in tumors. CONCLUSION: Combining Dbait with RFA sensitizes the tumor periphery to mild hyperthermia and increases RFA antitumor efficacy. PMID- 24475823 TI - Radiofrequency ablation of hepatocellular carcinoma as first-line treatment: long term results and prognostic factors in 162 patients with cirrhosis. AB - PURPOSE: To evaluate the long-term outcomes of radiofrequency ablation (RFA) as a first-line therapy for early-stage hepatocellular carcinoma (HCC) and determine the prognostic factors for survival. MATERIALS AND METHODS: The institutional review board approved this retrospective study. From January 2006 to December 2007, 162 consecutive patients with cirrhosis (Child-Pugh class A and B, 137 and 25 patients, respectively) who underwent RFA as a first-line treatment for up to three HCCs with a maximum diameter of 5 cm (182 HCCs; mean diameter +/- standard deviation, 2.59 cm +/- 0.79; 17 multinodular forms) were included. After a mean follow-up of 50.3 months +/- 19.9, results were analyzed for tumor recurrence, as well as overall and recurrence-free survival time. The Kaplan-Meier method and Cox proportional hazards regression model were used to evaluate the prognostic factors. RESULTS: The cumulative incidence of local tumor progression (LTP) was 14.5% at 5 years, with tumor size as the only significant predictive factor (relative risk = 2.13, P = .007). Overall 5-year survival and recurrence-free survival rates were 67.9% and 25.9%, respectively. Significant predictive factors for poor overall survival were Child-Pugh class B (relative risk = 2.43, P = .011), serum alpha-fetoprotein level (relative risk per 100 units = 1.01; P < .001), and presence of portosystemic collaterals (relative risk = 2.15, P = .025). The development of LTP significantly shortened median recurrence-free survival (28.0 months without LTP vs 12.0 months with LTP) and necessitated a higher number of interventional procedures (2.2 sessions without LTP vs 5.1 sessions with LTP). CONCLUSION: RFA is a safe and effective first-line treatment for early-stage HCC, with a 5-year survival rate of 67.9%. High serum alpha fetoprotein level, advanced Child-Pugh class, and presence of portosystemic collateral vessels had a significant negative effect on overall survival. PMID- 24475824 TI - Prostate cancer aggressiveness: assessment with whole-lesion histogram analysis of the apparent diffusion coefficient. AB - PURPOSE: To evaluate the relationship between prostate cancer aggressiveness and histogram-derived apparent diffusion coefficient (ADC) parameters obtained from whole-lesion assessment of diffusion-weighted magnetic resonance (MR) imaging of the prostate and to determine which ADC metric may help best differentiate low grade from intermediate- or high-grade prostate cancer lesions. MATERIALS AND METHODS: The institutional review board approved this retrospective HIPAA compliant study of 131 men (median age, 60 years) who underwent diffusion weighted MR imaging before prostatectomy for prostate cancer. Clinically significant tumors (tumor volume > 0.5 mL) were identified at whole-mount step section histopathologic examination, and Gleason scores of the tumors were recorded. A volume of interest was drawn around each significant tumor on ADC maps. The mean, median, and 10th and 25th percentile ADCs were determined from the whole-lesion histogram and correlated with the Gleason score by using the Spearman correlation coefficient (rho). The ability of each parameter to help differentiate tumors with a Gleason score of 6 from those with a Gleason score of at least 7 was assessed by using the area under the receiver operating characteristic curve (Az). RESULTS: In total, 116 clinically significant lesions (89 in the peripheral zone, 27 in the transition zone) were identified in 85 of the 131 patients (65%). Forty-six patients did not have a clinically significant lesion. For mean ADC, median ADC, 10th percentile ADC, and 25th percentile ADC, the Spearman rho values for correlation with Gleason score were -0.31, -0.30, 0.36, and -0.35, respectively, whereas the Az values for differentiating lesions with a Gleason score of 6 from those with a Gleason score of at least 7 were 0.704, 0.692, 0.758, and 0.723, respectively. The Az of 10th percentile ADC was significantly higher than that of the mean ADC for all lesions and peripheral zone lesions (P = .0001). CONCLUSION: When whole-lesion histograms were used to derive ADC parameters, 10th percentile ADC correlated with Gleason score better than did other ADC parameters, suggesting that 10th percentile ADC may prove to be optimal for differentiating low-grade from intermediate- or high-grade prostate cancer with diffusion-weighted MR imaging. PMID- 24475825 TI - Bioreducible polymer-delivered siRNA targeting MMP-9: suppression of granulation tissue formation after bare metallic stent placement in a rat urethral model. AB - PURPOSE: To evaluate the effectiveness of small interfering RNA (siRNA) targeting matrix metalloproteinase 9 (MMP-9) in suppressing granulation tissue formation caused by bare metallic stent placement in a rat urethral model. MATERIALS AND METHODS: All experiments were approved by the committee of animal research. In 20 Sprague-Dawley male rats (weight range, 300-350 g), a self-expanding metallic bare stent was inserted in the urethra with fluoroscopic guidance. One group of 10 rats (group A) was treated with MMP-9 siRNA/bioreducible branched polyethylenimine-disulfide cross-linked-indocyanine green (bioreducible BPEI-SS ICG), while the other group of 10 rats (group B) received control siRNA/bioreducible BPEI-SS-ICG treatment. All rats were sacrificed at 4 weeks. The therapeutic effectiveness of the MMP-9 siRNA/bioreducible BPEI-SS-ICG complex was assessed by comparing the two results of retrograde urethrography, histologic examination, and quantification of MMP-9 by using zymography and Western blot analysis between the two groups. The Mann-Whitney U test was used to evaluate differences. RESULTS: Stent placement was successful in all rats without a single case of migration at follow-up. Retrograde urethrography performed 4 weeks after stent placement demonstrated significantly larger luminal diameters of the urethra within the stents in group A compared with those in group B (P = .011). Histologic analysis revealed that the mean percentage of granulation tissue area (P < .001), mean number of epithelial layers (P < .001), and mean thickness of submucosal fibrosis (P < .001) were significantly decreased in group A compared with group B. Meanwhile, the mean density of inflammatory cell infiltration did not significantly differ between the two groups (P = .184). Quantitative analysis disclosed MMP-9 levels to be lower in group A relative to group B, indicating positive inhibition of MMP-9 by MMP-9 siRNA/bioreducible BPEI-SS-ICG. CONCLUSION: MMP-9 siRNA/bioreducible BPEI-SS-ICG is effective for inhibiting granulation tissue formation after bare metallic stent placement in a rat urethral model. PMID- 24475826 TI - Gastrointestinal stromal tumor: a method for optimizing the timing of CT scans in the follow-up of cancer patients. AB - PURPOSE: To develop a mathematical model to adjust the timing of computed tomography (CT) scans with the hazard of cancer recurrence in time to facilitate early detection of cancer recurrence. MATERIALS AND METHODS: The clinical data were extracted from the randomized Scandinavian Sarcoma Group (SSG) XVIII/Arbeitsgemeinschaft Internistische Onkologie (AIO) trial database. The SSG XVIII/AIO trial was registered (trial no. NCT00116935) and approved by the national or institutional review boards. In the trial, 1- and 3-year durations of adjuvant imatinib mesylate in the treatment of patients with gastrointestinal stromal tumor (GIST) were compared. A nonhomogeneous Poisson model with a piecewise log-constant hazard in time that accounts for the nonlinear pattern of GIST recurrence was applied to tumor site, mitotic count, and recurrence data. The optimal times to obtain follow-up CT scans were computed by modifying the frequency of CT scans with the hazard of tumor recurrence in time. The hazard adjusted follow-up schedules were compared with the National Comprehensive Cancer Network (NCCN) guidelines of the United States, which suggest imaging with CT at intervals of 3-6 months for 3-5 years and then annually. RESULTS: Optimized timing of CT scans on the basis of hazard of recurrence resulted in follow-up schedule options where CT is performed more sparsely than in the NCCN guidelines during adjuvant imatinib administration and more frequently, at approximately 3 month intervals, during the first 2 years that follow imatinib discontinuation when the risk of recurrence was the greatest. The number of CT scans could be reduced by a median of 31% (from 13 to nine) compared with the standard schedules within the first 6 years of follow-up without increasing the delay in recurrence detection. CONCLUSION: Detection of GIST recurrence may be enhanced by adjusting the timing of the CT scans with the hazard of recurrence. The method may be applicable to other human tumor types. Online supplemental material is available for this article. PMID- 24475827 TI - Mapping the effect of the apolipoprotein E genotype on 4-year atrophy rates in an Alzheimer disease-related brain network. AB - PURPOSE: To determine the effect of the apolipoprotein E (APOE) genotype on atrophy rates of specific brain gray matter regions hypothesized to be key components of cognitive networks disrupted in Alzheimer disease. MATERIALS AND METHODS: The Alzheimer's Disease Neuroimaging Initiative (ADNI) was approved by the institutional review boards of all participating sites. All subjects and their legal representatives gave written informed consent prior to data collection. The authors analyzed data from 237 subjects (mean age, 79.9 years; 40% female) with mild cognitive impairment (MCI) in the ADNI database and assessed the effect of the APOE epsilon4 and epsilon2 alleles on regional brain atrophy rates over a 12-48-month period. Brain regions were selected a priori: 15 experimental and five control regions were included. Regional atrophy rates were derived by using a fully automated algorithm applied to T1-weighted magnetic resonance (MR) imaging data. Analysis consisted of mixed-effects linear regression with repeated measures; results were adjusted for multiple testing with Bonferroni correction. RESULTS: Thirteen of 15 experimental regions showed a significant effect of epsilon4 for higher atrophy rates (P < .001 for all). Cohen d values ranged from 0.26 to 0.42, with the largest effects seen in the amygdalae and hippocampi. The transverse temporal cortex showed a trend (P = .02, but did not survive Bonferroni correction) for a protective effect (Cohen d value = 0.15) of epsilon2. No control region showed an APOE effect. CONCLUSION: The APOE epsilon4 allele is associated with accelerated rates of atrophy in 13 distinct brain regions in limbic and neocortical areas. This suggests the possibility of a genotype-specific network of related brain regions that undergo faster atrophy in MCI and potentially contribute to cognitive decline. Online supplemental material is available for this article. PMID- 24475828 TI - Altered structural connectome in temporal lobe epilepsy. AB - PURPOSE: To study differences in the whole-brain structural connectomes of patients with left temporal lobe epilepsy (TLE) and healthy control subjects. MATERIALS AND METHODS: This study was approved by the institutional review board, and all individuals gave signed informed consent. Sixty-direction diffusion tensor imaging and magnetization-prepared rapid acquisition gradient-echo (MP RAGE) magnetic resonance imaging volumes were analyzed in 24 patients with left TLE and in 24 healthy control subjects. MP-RAGE volumes were segmented into 1015 regions of interest (ROIs) spanning the entire brain. Deterministic white matter tractography was performed after voxelwise tensor calculation. Weighted structural connectivity matrices were generated by using the pairwise density of connecting fibers between ROIs. Graph theoretical measures of connectivity networks were compared between groups by using linear models with permutation testing. RESULTS: Patients with TLE had 22%-45% reduced (P < .01) distant connectivity in the medial orbitofrontal cortex, temporal cortex, posterior cingulate cortex, and precuneus, compared with that in healthy subjects. However, local connectivity, as measured by means of network efficiency, was increased by 85%-270% (P < .01) in the medial and lateral frontal cortices, insular cortex, posterior cingulate cortex, precuneus, and occipital cortex in patients with TLE as compared with healthy subjects. CONCLUSION: This study suggests that TLE involves altered structural connectivity in a network that reaches beyond the temporal lobe, especially in the default mode network. PMID- 24475829 TI - Assessment of physiologic bile flow in the extrahepatic bile duct with cine dynamic MR cholangiopancreatography and a spatially selective inversion-recovery pulse. AB - PURPOSE: To determine the feasibility of directly and noninvasively visualizing physiologic bile flow in the extrahepatic bile duct by means of nonpharmacologic cine-dynamic magnetic resonance (MR) cholangiopancreatography with a spatially selective inversion-recovery (IR) pulse and assess the flow dynamic pattern of bile in the extrahepatic bile duct. MATERIALS AND METHODS: The institutional review board approved this retrospective study and waived the need for informed consent. Thirty-five patients without known pancreatobiliary diseases and 11 patients with dilatation of the extrahepatic bile duct were included. Cine dynamic MR cholangiopancreatography with a spatially selective IR pulse was performed by imaging every 15 seconds over a 5-minute interval (20 images acquired total). The images were evaluated for the visualization of bile flow, the frequency that bile flow was observed in the extrahepatic bile duct, and the distance the bile moved within the area of the IR pulse. Statistical analysis was performed by using Spearman rank correlation coefficient and Mann-Whitney U tests. RESULTS: Antegrade bile flow was observed in 29 of 35 patients (83%) in the nondilated group. Bile flow was observed much more frequently in the nondilated group than in the dilated group (4.4 times vs 1.8 times, P = .029). The distance that bile moved forward within the area of the IR pulse was significantly greater in the nondilated group than in the dilated group (mean grade, 0.44 vs 0.14; P = .033), suggesting stagnation or slowdown of antegrade bile flow in patients with biliary dilatation. Reversed bile flow was also observed in 26 of 35 patients (74%) in the nondilated group without biliary diseases. CONCLUSION: Nonpharmacologic cine-dynamic MR cholangiopancreatography with a spatially selective IR pulse allows direct and noninvasive visualization of bile flow in the extrahepatic bile duct, demonstrating that reversed bile flow is a physiologic phenomenon. PMID- 24475830 TI - Apparent diffusion coefficient in estrogen receptor-positive invasive ductal breast carcinoma: correlations with tumor-stroma ratio. AB - PURPOSE: To determine whether apparent diffusion coefficient (ADC) values vary according to tumor-stroma ratio, dominant stroma type, or presence of central fibrosis in estrogen receptor-positive breast cancer. MATERIALS AND METHODS: Institutional review board approval was obtained, and patient consent was waived. Sixty-one patients with estrogen receptor-positive invasive ductal carcinoma-not otherwise specified who underwent breast magnetic resonance (MR) imaging with diffusion-weighted (DW) imaging were included in this study. The ADC values of the lesions were measured. Two pathologists evaluated the tumor-stroma ratio, dominant stroma type (collagen, fibroblast, lymphocyte), and central fibrosis. Detectability on DW images was compared between the two groups according to the tumor-stroma ratio (stroma rich or stroma poor). Mean ADC values were retrospectively compared with the tumor-stroma ratio, dominant stroma type, and presence of a central fibrosis. Multiple linear regression analysis was performed to determine variables independently associated with ADC. RESULTS: On DW images, detectability was not significantly different between stroma-rich and stroma-poor groups (P = .244). ADC values were significantly lower in the stroma-poor group (P < .001). The mean ADC values in the collagen-dominant type were lower than in fibroblast-dominant or lymphocyte-dominant types (P = .021). In multiple linear regression analysis, tumor-stroma ratio (P = .007), tumor size (P = .007), and dominant stroma type (collagen dominant, P = .029) were independently correlated with ADC. CONCLUSION: In estrogen receptor-positive breast cancers, ADC values showed significant differences according to the tumor-stroma ratio and dominant stroma type. PMID- 24475831 TI - Intracarpal tunnel contents: evaluation of the effects of corticosteroid injection with sonoelastography. AB - PURPOSE: To define the stiffness of the intracarpal tunnel contents and to evaluate the effect of corticosteroid injection on the intracarpal tunnel contents by using sonoelastography. MATERIALS AND METHODS: This study was conducted with the approval of the institutional review boards, and all participants provided written, informed consent. Both hands were studied in 20 healthy volunteers, including eight men (mean age, 59.6 years; range, 50-76 years) and 12 women (mean age, 61.0 years; range, 39-79 years) and 22 hands were studied in 20 patients with carpal tunnel syndrome (CTS) (five men [mean age, 49.0 years] and 15 women [mean age, 61.1 years]; range, 39-89 years) between April 2012 and August 2012. The stiffness of the intracarpal tunnel contents was estimated as the standardized acoustic coupler (AC)-to-intracarpal tunnel contents surrounding the nerve (AC/C) strain ratio, analyzed with the Mann Whitney U test. The patients were treated with corticosteroid injections, and the strain ratio was reexamined 6 weeks later, analyzed with the Wilcoxon t test. RESULTS: The mean AC/C strain ratio in the CTS patients was 12.6 +/- 4.7 (standard deviation), which was higher (stiffer) than that in the healthy volunteers with a mean strain ratio of 8.2 +/- 3.5 (P = .0013). Six weeks after the injection, the mean AC/C strain ratio had decreased to 8.5 +/- 4.1 (P = .00069, compared with the preinjection value) in the CTS patients. CONCLUSION: The stiffness of the intracarpal tunnel contents in untreated CTS patients is higher than that of healthy volunteers but decreases 6 weeks after corticosteroid injection. PMID- 24475832 TI - CT in adults: systematic review and meta-analysis of interpretation discrepancy rates. AB - PURPOSE: To use meta-analysis to determine the discrepancy rate when interpreting computed tomography (CT) studies performed in adult patients and to determine whether discrepancy rate differs on the basis of body region or level of radiologist training. MATERIALS AND METHODS: MEDLINE and EMBASE were searched from 1946 to June 2012 by using the combination "radiology AND (error OR peer review)." Two reviewers independently selected studies that met the inclusion criteria and extracted study data. Total and major discrepancy rates were investigated with a random-effects meta-analysis, and subgroups were compared by using the chi(2) Q statistic. Subgroup analyses were performed on the basis of the level of training of the initial radiologist and the body system scanned. RESULTS: Fifty-eight studies met the inclusion criteria (388 123 CT examinations). The pooled total discrepancy rate was 7.7% (95% confidence interval [CI]: 5.6%, 10.3%), and the major discrepancy rate was 2.4% (95% CI: 1.7%, 3.2%). The pooled major discrepancy rate was comparable for staff (2.9%; 95% CI: 1.2%, 6.7%) and residents (2.2%; 95% CI: 1.7%, 2.9%) (Q = 0.92, P = .633). The pooled major discrepancy rates for head CT (0.8%; 95% CI: 0.4%, 1.6%) and spine CT (0.7%; 95% CI: 0.2%, 2.7%) were lower than those for chest CT (2.8%; 95% CI: 1.5%, 5.4%) and abdominal CT (2.6%; 95% CI: 1.0%, 6.7%) (Q = 8.28, P = .041). Lack of blinding of the reference radiologist to the initial report was associated with a lower major discrepancy rate (2.0%; 95% CI: 1.4%, 2.7%; 43 studies) than when blinding was present (12.1%; 95% CI: 4.4%, 29.4%; five studies) (Q = 10.65, P = .001). CONCLUSION: Potentially useful reference ranges were identified in the subgroup analyses on the basis of body region scanned at adult CT. However, considerable heterogeneity that is only partially explained by subgroup analysis signifies that further research is necessary--particularly regarding the question of blinding of the reference radiologist. PMID- 24475833 TI - First-arterial-pass dual-energy CT for assessment of myocardial blood supply: do we need rest, stress, and delayed acquisition? Comparison with SPECT. AB - PURPOSE: To compare the relative contributions of rest, stress, and delayed acquisitions with the accuracy of dual-energy (DE) computed tomography (CT) for the assessment of myocardial blood supply. MATERIALS AND METHODS: With institutional review board approval and HIPAA compliance, 55 consecutive patients (10 women, 45 men; mean age, 62 years +/- 10) clinically referred for cardiac single photon emission computed tomography (SPECT) who were known to have or were suspected of having coronary artery disease were prospectively enrolled. DE CT studies were acquired during adenosine stress, at rest, and after 6-minute delay. The DE CT iodine distribution maps were visually assessed for perfusion deficits or late iodine enhancement. Per-segment agreement between modalities was investigated with kappa statistics. Test characteristics for the detection of perfusion deficits were calculated for combinations of rest, stress, and delayed DE CT acquisition, with SPECT as reference standard. RESULTS: At SPECT, 714 segments were considered normal, 192 showed fixed perfusion defects, and 29 showed reversible perfusion deficits. Sensitivity of rest-only DE CT was 92%, and specificity was 98%. Stress-only, rest-stress, stress and delayed, and the combination of all three had a sensitivity of 99% and a specificity of 97%. Of 29 segments with reversible perfusion deficits at SPECT, 13 (45%) were misclassified by using rest-stress DE CT as fixed perfusion deficits. With stress DE CT plus delayed acquisition, 13 of 192 (7%) segments with fixed perfusion deficits at SPECT were misclassified as reversible. CONCLUSION: Rest-stress acquisition should be the protocol of choice for assessment of the myocardial blood supply in DE CT. The accuracy of DE CT is not increased by the addition of a delayed DE CT acquisition, which may therefore be omitted to reduce radiation exposure. With rest-stress DE CT, almost one-half of defects that are reversible at SPECT were classified as fixed; radiologists and clinicians need to be aware of this incongruence when they interpret DE CT myocardial perfusion studies. PMID- 24475835 TI - Effects of tamoxifen and aromatase inhibitors on breast tissue enhancement in dynamic contrast-enhanced breast MR imaging: a longitudinal intraindividual cohort study. AB - PURPOSE: To prospectively investigate the effects of two antihormonal medications, tamoxifen and aromatase inhibitor (AI), on the degree of background enhancement in breast magnetic resonance (MR) imaging. MATERIALS AND METHODS: This institutional review board-approved study was performed in 40 postmenopausal women (mean age, 63 years; range, 49-78 years) with unilateral breast cancer between January 2005 and December 2010. Informed consent was obtained from all participants. All patients underwent breast MR imaging before starting any medication, under tamoxifen, and after switching to an AI. Qualitative and quantitative degrees of benign parenchymal enhancement were investigated before treatment, under tamoxifen, and under AI. Data were analyzed by using the Wilcoxon singed-rank test and Student t test for matched pairs. RESULTS: Before treatment, the distribution of background enhancement MR-American College of Radiology (ACR) categories 1, 2, 3, and 4 was 20%, 35%, 33%, and 13%, respectively. With tamoxifen, background enhancement was suppressed, with a distribution of 80%, 15%, 5%, and 0% for MR-ACR categories 1, 2, 3, and 4, respectively. With AI, background enhancement recovered in part, with a distribution of 25%, 53%, 23%, and 0% for categories 1, 2, 3, and 4, respectively. In all 40 women, background enhancement rates were highest before treatment (mean, 51.3% +/- 33.3 [standard deviation]). By using tamoxifen, background enhancement rates were significantly reduced (mean, 8.4% +/- 9.2), and rose again after the switch to an AI (mean, 22.9% +/- 19.1 [P < .001]). Prevalence of benign enhancing foci was 65% (26 of 40) at baseline, 12.5% (five of 40) with tamoxifen, and 40% (16 of 40) with AI. CONCLUSION: The effects of tamoxifen and AI on benign parenchymal enhancement differ. Whereas tamoxifen leads to a virtually complete suppression of enhancement, the effects of AI are less pronounced. Accordingly, whereas enhancement is unusual and deserves a more careful work-up in a patient in whom tamoxifen is used, this is not necessarily true for women in whom AIs are used. Online supplemental material is available for this article. PMID- 24475834 TI - Fibrosis and postoperative fistula of the pancreas: correlation with MR imaging findings--preliminary results. AB - PURPOSE: To assess the potential value of magnetic resonance (MR) imaging in evaluating pancreatic fibrosis and predicting the development of postoperative pancreatic fistula. MATERIALS AND METHODS: This retrospective study had institutional review board approval, and the requirement for informed consent was waived. MR images obtained in 29 consecutive patients (15 men, 14 women; mean age, 64.9 years; age range, 21-80 years) who underwent pancreatectomy were evaluated. The pancreas-to-muscle signal intensity (SI) ratio on unenhanced T1- and T2-weighted, dynamic contrast material-enhanced, and diffusion-weighted images and the apparent diffusion coefficient (ADC) of the pancreas were measured. MR imaging parameters were correlated with the degrees of pancreatic fibrosis and expression of activated pancreatic stellate cells (PSCs) by using univariate and multivariate regression analyses and receiver operating characteristic curve analysis. The relationships between the development of postoperative pancreatic fistula and the MR imaging measurements were examined by using logistic regression analysis and the Mann-Whitney U test. RESULTS: Multiple regression analysis showed that pancreas-to-muscle SI ratios on T1-weighted images and ADC values were independently associated with pancreatic fibrosis (r(2) = 0.66, P < .001) and with activated PSC expression (r(2) = 0.67, P < .001). The mean pancreas-to-muscle SI ratio (+/- standard deviation) on T1 weighted images was higher (P = .0029) for patients with postoperative pancreatic fistula (1.6 +/- 0.2) than for those without (1.2 +/- 0.2), and the odds ratio for postoperative pancreatic fistula was 21.3 in patients with an SI ratio of 1.41 and higher. CONCLUSION: The pancreas-to-muscle SI ratio on T1-weighted MR images of the pancreas may be a potential biomarker for assessment of pancreatic fibrosis and prediction of postoperative pancreatic fistula. PMID- 24475836 TI - US of incidental adnexal cysts: adherence of radiologists to the 2010 Society of Radiologists in Ultrasound guidelines. AB - PURPOSE: To retrospectively evaluate the adherence of radiologists to the 2010 Society of Radiologists in Ultrasound (SRU) guidelines for management of adnexal cysts. MATERIALS AND METHODS: One radiologist reviewed the interpreting radiologists' reports for 398 adnexal cysts detected at ultrasonography in 398 patients (mean age +/- standard deviation, 41.1 years +/- 14.3; range, 18-87 years) and classified the management recommendations according to adherence to SRU guidelines. Recommendations that were not adherent were classified as overmanagement, undermanagement, or incomplete. The effects of menopausal status, cyst size and other features, and the individual interpreting radiologist on adherence were assessed by using chi(2) tests, and the association of these factors with over- and undermanagement was identified. RESULTS: Overall adherence was 59%; overmanagement, 27%; undermanagement, 9%; and incomplete, 6%. Menopausal status, cyst size, and other cyst features significantly affected adherence (P < .001). For evaluation of premenopausal patients, adherence was 63% (overmanagement, 30%) and of postmenopausal patients, 42% (undermanagement, 26%). For evaluation of cysts 1-3 cm in size, adherence was 65% (overmanagement, 21%); for cysts 3-5 cm, 33% (overmanagement, 49%); for cysts 5-7 cm, 47% (overmanagement, 20%); for cysts larger than 7 cm, 77% (over- and undermanagement, 12% each). Recommendations were adherent in most instances for corpora lutea (88%), simple cysts (56%), and cysts suggestive of benign diagnosis (60%), or with a nodule or multiple thin or thick septations (60%-100%). Cysts with recommentations for overmanagement in most instances were hemorrhagic (59%) and those with a single thin septation (67%); 31% of cysts measuring 1-7 cm in postmenopausal patients were undermanaged. Adherence varied significantly among radiologists (40%-75% adherence among radiologists who interpreted 20 or more examinations; P = .004). CONCLUSION: Adherence to SRU guidelines for management of adnexal cysts at our institution was 59%. Overmanagement generally occurred for physiologic cysts in premenopausal patients; undermanagement was observed for simple cysts in postmenopausal patients. PMID- 24475837 TI - Normal diastolic and systolic myocardial T1 values at 1.5-T MR imaging: correlations and blood normalization. AB - PURPOSE: To introduce blood normalization for myocardial T1 values at magnetic resonance (MR) imaging and to evaluate regional differences between systolic and diastolic myocardial T1 values in healthy subjects. MATERIALS AND METHODS: This prospective study (ClinicalTrials.gov identification number, NCT01728597) was approved by the institutional review board, and volunteer informed consent was obtained. Forty healthy subjects (20 women; age range, 20-35 years) underwent electrocardiographically gated 1.5-T MR imaging. A modified Look-Locker inversion recovery sequence was used to acquire myocardial T1 maps in systole and diastole. Regional T1 values were evaluated in 16 myocardial segments; blood T1 was derived from the blood pool in the center of the left ventricular cavity. Linear regression slopes between myocardial and blood T1 values were used to normalize myocardial T1 to the mean blood T1 of the study population. Mean T1 values were compared by using the t test, with P < .05 considered to indicate a significant difference. RESULTS: Mean myocardial T1 (984 msec +/- 28 [standard deviation] in diastole, 959 msec +/- 21 in systole) and all segmental T1 values between diastole and systole differed significantly (P < .001). Blood T1 correlated well with segmental myocardial T1 (R = 0.73 for diastole, R = 0.72 for systole). After normalization to blood T1, significant sex differences in myocardial T1 disappeared and variances in mean myocardial T1 decreased. Blood-normalized diastolic and systolic myocardial T1 values correlated strongly with each other on segmental (r = 0.72) and global (r = 0.89) levels. Subregional myocardial T1 distribution characteristics in diastole were similar to those in systole. CONCLUSION: In normal myocardium, diastolic and systolic myocardial T1 values differ significantly but correlate strongly. Blood normalization eliminates sex differences in myocardial T1 values and reduces their variability. PMID- 24475838 TI - Time-resolved spin-labeled MR angiography for the depiction of cerebral arteriovenous malformations: a comparison of techniques. AB - PURPOSE: To assess time-resolved spin-labeled (SL) magnetic resonance (MR) angiographic imaging with a large acquisition time window over two cardiac cycles for characterization of cerebral arteriovenous malformations (AVMs). MATERIALS AND METHODS: This study was institutional review board-approved. Sixteen patients presented with an AVM, provided informed consent, and were prospectively included. Time-resolved SL MR angiographic images with acquisition window that covered two cardiac cycles (acquisition time, 10-12 min; temporal resolution, 60 msec) or one cardiac cycle and time-of-flight (TOF) MR angiographic images were acquired with a 3-T MR imager. A diagnostic confidence index was used for image quality evaluation; scores were 0, no diagnosis, to 3, high image quality. AVM characterization consisted of arterial feeder, nidus size, and venous drainage type identification compared with those at digital subtraction angiography (DSA). kappa coefficients were computed to determine interobserver and intermodality agreement. RESULTS: Time-resolved SL MR angiographic imaging over two cardiac cycles provided a median diagnostic confidence index of 2.5 for arterial feeders, 3.0 for nidus, and 3.0 for venous drainage. Venous drainage depiction quality was higher with time-resolved SL MR angiography over two cardiac cycles than with time-resolved SL MR angiography over one cardiac cycle (P < .001) and TOF MR angiography (P < .001). For AVM characterization, interobserver agreement was very good to excellent, and agreement with DSA showed kappa of 0.85 for arterial feeders, kappa of 1.00 for nidus size, and kappa of 0.82 for venous drainage. CONCLUSION: Time-resolved SL MR angiographic imaging over two cardiac cycles is a reliable clinical tool for cerebral AVM characterization, which showed very good to excellent agreement with DSA. PMID- 24475839 TI - C-arm cone-beam CT-guided percutaneous transthoracic needle biopsy of lung nodules: clinical experience in 1108 patients. AB - PURPOSE: To retrospectively evaluate the diagnostic performance and complications of C-arm cone-beam computed tomography (CT)-guided percutaneous transthoracic needle biopsy (PTNB) in 1108 patients. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board with waiver of patient informed consent. From January 2009 to December 2011, 1108 patients (633 male, 475 female; mean age, 62.4 years +/- 12.3 [standard deviation]) with 1116 pulmonary lesions (mean size, 2.7 cm +/- 1.7) underwent 1153 cone-beam CT-guided PTNBs. A coaxial system with 18-gauge cutting needles was used. Diagnostic performance, complication rate, influencing factors, and patient radiation exposure were investigated. Variables influencing diagnostic performance and complications were assessed by using uni- and multivariate logistic regression analyses. RESULTS: Among 1153 PTNBs, pathologic analysis showed 1148 (99.6%) were technically successful (766 malignant [66.4%], 323 benign [28.0%], and 59 [5.1%] indeterminate). Sensitivity, specificity, and accuracy for diagnosis of malignancy were 95.7% (733 of 766), 100% (323 of 323), and 97.0% (1056 of 1089), respectively. In regard to diagnostic failures (five technical failures, 33 false negative findings), lesions 1 cm in diameter or smaller and lesions in the lower lobe were significant risk factors (P = .028 and P = .034, respectively). As for complications, pneumothorax and hemoptysis occurred in 196 (17.0%) and 80 (6.9%) procedures, respectively. Multivariate analysis revealed two or more pleural passages and emphysema along the needle pathway were the two most significant risk factors for pneumothorax, and ground-glass nodules were the most significant risk factor for hemoptysis (P < .001 for all). Virtual guidance was a significant protective factor for both pneumothorax and hemoptysis (P < .001 for both). Mean estimated effective radiation dose through cone-beam CT-guided PTNBs was 7.3 mSv +/- 4.1. CONCLUSION: Cone-beam CT-guided PTNB is a highly accurate and safe technique with which to diagnose pulmonary lesions with reasonable radiation exposure. PMID- 24475840 TI - Recurrent glioblastoma treated with bevacizumab: contrast-enhanced T1-weighted subtraction maps improve tumor delineation and aid prediction of survival in a multicenter clinical trial. AB - PURPOSE: To compare the capability to aid prediction of clinical outcome measures, including progression-free survival (PFS) and overall survival (OS), between volumetric estimates from contrast material-enhanced (CE) T1-weighted subtraction maps and traditional segmentation in a randomized multicenter clinical trial of recurrent glioblastoma (GBM) patients treated with bevacizumab. MATERIALS AND METHODS: All patients participating in this study signed institutional review board-approved informed consent at their respective institutions prior to enrolling in the multicenter clinical trial. One-hundred sixty patients with recurrent GBM enrolled as part of a HIPAA-compliant, multicenter clinical trial (AVF3708 g, BRAIN trial). Contrast-enhancing tumor volumes and change in volumes as a response to therapy were quantified by using either conventional segmentation or CE T1-weighted subtraction maps created by voxel-by-voxel subtraction of intensity-normalized nonenhanced T1-weighted images from CE T1-weighted images. These volumes were then tested as predictors of PFS and OS by using log-rank univariate analysis, the multivariate Cox proportional hazards regression model, and receiver operating characteristic analysis. RESULTS: Use of CE T1-weighted subtraction maps qualitatively improved visualization and improved quantification of tumor volume after bevacizumab treatment. Significant trends between the volume of tumor and change in tumor volume after therapy on CE T1-weighted subtraction maps were found for both PFS and OS (pretreatment volume < 15 cm(3), P < .003; posttreatment volume < 7.5 cm(3), P < .05; percentage change in volume > 25%, P = .004 for PFS and P = .053 for OS). CE T1-weighted subtraction maps were significantly better at aiding prediction of 6-month PFS and 12-month OS compared with conventional segmentation by using receiver operating characteristic analysis (P < .05). CONCLUSION: Use of CE T1-weighted subtraction maps improved visualization and aided better prediction of patient survival in recurrent GBM treated with bevacizumab compared with conventional segmentation of CE T1-weighted images. Clinical trial registration no. NCT00345163. Online supplemental material is available for this article. PMID- 24475841 TI - Cardiac arrythmias: multimodal assessment integrating body surface ECG mapping into cardiac imaging. AB - PURPOSE: To demonstrate the feasibility of comprehensive assessment of cardiac arrhythmias by combining body surface electrocardiographic (ECG) mapping (BSM) and imaging. MATERIALS AND METHODS: This study was approved by the institutional review board, and all patients gave written informed consent. Twenty-seven patients referred for electrophysiologic procedures in the context of ventricular tachycardia (VT) (n = 9), Wolff-Parkinson-White (WPW) syndrome (n = 2), atrial fibrillation (AF) (n = 13), or scar-related ventricular fibrillation (VF) (n = 3) were examined. Patients underwent BSM and imaging with multidetector computed tomography (CT) (n = 12) and/or delayed enhanced magnetic resonance (MR) imaging (n = 23). BSM was performed by using a 252-electrode vest that enabled the computation of epicardial electrograms from body surface potentials. The epicardial geometry used for BSM was registered to the epicardial geometry segmented from imaging data by using an automatic algorithm. The output was a three-dimensional cardiac model that integrated cardiac anatomy, myocardial substrate, and epicardial activation. RESULTS: Acquisition, segmentation, and registration were feasible in all patients. In VT, this enabled a noninvasive assessment of the arrhythmia mechanism and its location with respect to the myocardial substrate, coronary vessels, and phrenic nerve. In WPW syndrome, this enabled understanding of complex accessory pathways resistant to previous ablation. In AF and VF, this enabled the noninvasive assessment of arrhythmia mechanisms and the analysis of rotor trajectories with respect to the myocardial substrate. In all patients, models were successfully integrated in navigation systems and used to guide mapping and ablation. CONCLUSION: By combining information on anatomy, substrate, and electrical activation, the fusion of BSM and imaging enables comprehensive noninvasive assessment of cardiac arrhythmias, with potential applications for diagnosis, prognosis, and ablation targeting. Online supplemental material is available for this article. PMID- 24475842 TI - Differentiation of ovarian endometriomas from hemorrhagic cysts at MR imaging: utility of the T2 dark spot sign. AB - PURPOSE: To determine sensitivity and specificity of the T2 dark spot sign in helping to distinguish endometriomas from other hemorrhagic adnexal lesions. MATERIALS AND METHODS: This HIPAA-compliant, institutional review board-approved retrospective study, with informed consent waived, included 56 women (mean age, 38.8 years; range, 18-66 years). With a radiology database search of pelvic magnetic resonance images from December 16, 2002, to July 24, 2012, 74 cystic hemorrhagic adnexal lesions with hyperintense signal on T1-weighted images were identified. Lesions were excluded if they had solid enhancing components. Final diagnosis was established with pathologic analysis for all endometriomas and neoplasms. Hemorrhagic cysts were diagnosed with pathologic analysis (n = 7), follow-up imaging (n = 13), or prior ultrasonography (n = 5). Two radiologists independently reviewed cases and recorded the presence or absence of T2 shading and T2 dark spots. T2 dark spots were defined as discrete, well-defined markedly hypointense foci within the adnexal lesion on T2-weighted images. Sensitivity, specificity, and positive and negative predictive values of the T2 dark spot sign in distinguishing endometriomas from nonendometrioma hemorrhagic lesions were calculated. RESULTS: Sixteen of 45 endometriomas (36%), zero of 25 hemorrhagic cysts, and two of four neoplasms (50%) (all serous cystadenomas) demonstrated T2 dark spots. Forty-two of 45 endometriomas (93%), 12 of 25 hemorrhagic cysts (48%), and four of four neoplasms (100%) demonstrated T2 shading. Sensitivity, specificity, positive predictive value, and negative predictive value of T2 dark spots for differentiating endometriomas from other hemorrhagic cystic ovarian masses were 36% (95% confidence interval [CI]: 19.8, 51.3), 93% (95% CI: 83.9, 100), 89% (95% CI: 63.9, 98.1), and 48% (95% CI: 34.8, 61.8), respectively, and for T2 shading, they were 93% (95% CI: 84.0, 100), 45% (95% CI: 27.8, 61.9), 72% (95% CI: 58.9, 83.0), and 81% (95% CI: 53.7, 95.0), respectively. CONCLUSION: The T2 dark spot sign has high specificity for chronic hemorrhage and is useful to differentiate endometriomas from hemorrhagic cysts. The T2 shading sign is sensitive but not specific for endometriomas. Online supplemental material is available for this article. PMID- 24475843 TI - Digital mammography screening: association between detection rate and nuclear grade of ductal carcinoma in situ. AB - PURPOSE: To determine the relationship between overall detection rates of ductal carcinoma in situ (DCIS) and the specific detection rates of low-, intermediate-, and high-grade DCIS at the start of a digital mammography screening program. MATERIALS AND METHODS: The study was approved by the local ethics board and did not require informed consent. Data were included of the first round of digital mammography examinations, performed in 17 screening units in women aged 50-69 years from 2005 to 2008. Grading was provided by the cancer registry for 1018 DCIS cases. The association between the overall cancer detection rate (cases per 100 women screened) and the separate cancer detection rate for invasive cancers and for DCIS was assessed. Likewise, the total DCIS cancer detection rate was separated into rates for low, intermediate, and high grades. Spearman rank correlations were used for analysis. RESULTS: The overall cancer detection rate correlated with both the cancer detection rate of invasive cancers and the cancer detection rate of DCIS (r = 0.96 and r = 0.88, respectively; P < .001 for both). The cancer detection rate of total DCIS with grading varied among screening units (range, 0.05-0.25), it was borderline not significantly correlated with the cancer detection rate of low-grade DCIS (range, 0.004-0.05; r = 0.49; P = .052), and it showed significant correlations with higher cancer detection rate of intermediate-grade DCIS (range, 0.02-0.12; r = 0.89; P < .001) and of high-grade DCIS (range, 0.03-0.11; r = 0.88; P < .001). CONCLUSION: This study demonstrates that high overall cancer detection rates in digital mammography screening are related to high detection rates of invasive cancers, as well as DCIS. Increases in the detection rates of DCIS were not driven by disproportionate increments of the slowly progressive low-grade subtype but rather by increased rates of intermediate- and high-grade subtypes that carry a higher risk of transition to invasive cancers. PMID- 24475844 TI - High signal intensity in the dentate nucleus and globus pallidus on unenhanced T1 weighted MR images: relationship with increasing cumulative dose of a gadolinium based contrast material. AB - PURPOSE: To explore any correlation between the number of previous gadolinium based contrast material administrations and high signal intensity (SI) in the dentate nucleus and globus pallidus on unenhanced T1-weighted magnetic resonance (MR) images. MATERIALS AND METHODS: The institutional review board approved this study, waiving the requirement to obtain written informed consent. A group of 381 consecutive patients who had undergone brain MR imaging was identified for cross sectional analysis. For longitudinal analysis, 19 patients who had undergone at least six contrast-enhanced examinations were compared with 16 patients who had undergone at least six unenhanced examinations. The mean SIs of the dentate nucleus, pons, globus pallidus, and thalamus were measured on unenhanced T1 weighted images. The dentate nucleus-to-pons SI ratio was calculated by dividing the SI in the dentate nucleus by that in the pons, and the globus pallidus-to thalamus SI ratio was calculated by dividing the SI in the globus pallidus by that in the thalamus. Stepwise regression analysis was undertaken in the consecutive patient group to detect any relationship between the dentate nucleus to-pons or globus pallidus-to-thalamus SI ratio and previous gadolinium-based contrast material administration or other factors. A random coefficient model was used to evaluate for longitudinal analysis. RESULTS: The dentate nucleus-to-pons SI ratio showed a significant correlation with the number of previous gadolinium based contrast material administrations (P < .001; regression coefficient, 0.010; 95% confidence interval [CI]: 0.009, 0.011; standardized regression coefficient, 0.695). The globus pallidus-to-thalamus SI ratio showed a significant correlation with the number of previous gadolinium-based contrast material administrations (P < .001; regression coefficient, 0.004; 95% CI: 0.002, 0.006; standardized regression coefficient, 0.288), radiation therapy (P = .009; regression coefficient, -0.014; 95% CI: -0.025, -0.004; standardized regression coefficient, -0.151), and liver function (P = .031; regression coefficient, 0.023; 95% CI: 0.002, 0.044; standardized regression coefficient, 0.107). The dentate nucleus-to pons and globus pallidus-to-thalamus SI ratios in patients who had undergone contrast-enhanced examinations were significantly greater than those of patients who had undergone unenhanced examinations (P < .001 for both). CONCLUSION: High SI in the dentate nucleus and globus pallidus on unenhanced T1-weighted images may be a consequence of the number of previous gadolinium-based contrast material administrations. PMID- 24475845 TI - Honorary authorship in radiologic research articles: do geographic factors influence the frequency? AB - PURPOSE: To quantify the potential effect of geographic factors on the frequency of honorary authorship in four major radiology journals. MATERIALS AND METHODS: In this institutional review board-approved study, an electronic survey was sent to first authors of all original research articles published in American Journal of Roentgenology, European Radiology, Journal of Magnetic Resonance Imaging, and Radiology during 2 years (July 2009 through June 2011). Questions addressed guidelines used for determining authorship, perception of honorary authorship, and demographic information. Univariate analysis was performed by using chi(2) tests. Multiple-variable logistic regression models were used to assess independent factors associated with the perception of honorary authorship. RESULTS: Of 1398 first authors, 328 (23.5%) responded. Of these, 91 (27.7%) perceived that at least one coauthor did not make sufficient contributions to merit authorship, and 165 (50.3%) stated that one or more coauthors performed only "nonauthor" tasks according to International Committee of Medical Journal Editors (ICMJE) criteria. The perception of honorary authorship was significantly higher (P <= .0001) among respondents from Asia and Europe than from North America and in institutions where a section or department head was automatically listed as coauthor. A significantly lower (P <= .0001) perception of honorary authorship was associated with adherence to ICMJE criteria and with policies providing lectures or courses on publication ethics. CONCLUSION: Perceived honorary authorship was substantially higher among respondents from Asia and Europe than from North America. Perceived honorary authorship was lower with adherence to the ICMJE guidelines and policies providing lectures or courses on publication ethics. PMID- 24475846 TI - Compliance with STARD checklist among studies of coronary CT angiography: systematic review. AB - PURPOSE: To determine the compliance of prospective diagnostic accuracy studies investigating computed tomographic (CT) coronary angiography with Standards for Reporting of Diagnostic Accuracy (STARD) guidelines. MATERIALS AND METHODS: Relevant studies were identified by means of a systematic literature search that included the MEDLINE, EMBASE, and Institute for Scientific Information Web of Science databases. Prospective studies that compared CT with conventional coronary angiography for the evaluation of the coronary arteries were included. STARD compliance was assessed by three independent investigators using 21 of the original 25 STARD checklist items. Items with the qualifier "if done" (items 13, 23, and 24) were excluded because they were not applicable to all studies. Owing to the inclusion criteria, all studies fulfilled item 9; therefore, this item was excluded as well. The correlation between the total score and multiple variables was tested with a linear regression model. RESULTS: One hundred thirty studies published in 44 scientific journals were included in the analysis. There was a significant correlation between the year of publication and STARD-adopting versus non-STARD-adopting journals, with the total STARD score based on a linear regression model. Studies published in STARD-adopting journals showed a significantly higher total STARD score than those published in nonadopting journals (15.4 +/- 2.7 vs 14.1 +/- 2.7; P = .018). Linear regression analysis yielded an increase in the total STARD score of 0.30 points (95% confidence interval: 0.03, 0.57; P = .031) per year. Adequate reporting of individual items varied between 17% (item 20b) and 97% (item 1). CONCLUSION: The overall compliance with reporting guidelines of prospective diagnostic accuracy studies of CT coronary angiography is moderate to good, and STARD-adopting journals have greater STARD compliance than nonadopting journals. Online supplemental material is available for this article. PMID- 24475847 TI - Mmp-9 expression after metallic stent placement in patients with colorectal cancer: association with in-stent restenosis. AB - PURPOSE: To verify the expression of matrix metalloproteinase (MMP)-9 in stent induced hyperplastic tissue from patients with colorectal cancer who received colorectal stents as a bridge to surgery. MATERIALS AND METHODS: This prospective study was institutional review board-approved, and informed consent was obtained from all patients. Eleven patients (nine men, two women; mean age, 67 years; age range, 53-82 years) with malignant colorectal obstructions who received a colorectal stent between May and December 2010 were included. Tissue specimens were analyzed for MMP-9 and MMP-2 expression. After resection, the tissue was segmented into three parts: tumor tissue, stent-induced tissue hyperplasia, and normal colon tissue. MMP-9 and MMP-2 expression were determined by using zymography, Western blot analysis, and real-time reverse-transcription (qRT) polymerase chain reaction (PCR). Significance of differences between groups was evaluated with Friedman analysis of variance test. Signed-rank test was used to determine differences between malignant tumor tissue and stent-induced hyperplastic tissue groups. RESULTS: Stent placement was technically successful in all 11 patients. Stent-induced hyperplastic tissues were found in all patients. Zymography (P = .003) and Western blot analysis (P = .008) showed that expression of MMP-9 was higher in malignant tumor tissue and stent-induced hyperplastic tissue groups compared with normal colorectal tissue group, demonstrating significant differences between groups but no significant differences between malignant tumor and stent-induced hyperplastic tissues. As for results of qRT PCR analysis, the stent-induced hyperplastic tissue group showed increases in messenger RNA expression level of MMP-9 compared with the malignant tumor tissue group (50.42-fold +/- 66.30 higher). CONCLUSION: High expression of MMP-9 is closely associated with stent-induced colorectal tissue hyperplasia in patients with colorectal cancer. PMID- 24475848 TI - Cartilage lesion score: comparison of a quantitative assessment score with established semiquantitative MR scoring systems. AB - PURPOSE: To describe a scoring system for quantification of cartilage lesions (Cartilage Lesion Score [CaLS]), to determine its reproducibility, to examine the association of CaLS-detected longitudinal change with known risk factors for osteoarthritis (OA) progression by comparing a group of subjects with OA risk factors with a group of subjects without OA risk factors, and to compare the CaLS system with the established semiquantitative Whole-Organ Magnetic Resonance Imaging Score (WORMS) and Boston-Leeds Osteoarthritis Knee Score (BLOKS) systems in terms of detection of cartilage defect progression. MATERIALS AND METHODS: All subjects provided written informed consent, and the local institutional review board approved this HIPAA-compliant study. Fifty-two subjects with and 25 subjects without risk factors for knee OA were randomly selected from the Osteoarthritis Initiative. Inclusion criteria were age of 45-60 years, body mass index of 19-27 kg/m(2), and no knee pain or OA on radiographs at baseline. Baseline and 24-month follow-up right knee 3-T magnetic resonance images were analyzed with WORMS, BLOKS, and CaLS systems. Progression of cartilage lesions with each scoring system was compared by using multilevel mixed-effects linear regression models. kappa values were calculated to determine reliability. RESULTS: Intraclass coefficient values for inter- and intraobserver reliability of the CaLS system were 0.86 and 0.91, respectively. Interobserver kappa value range for individual features was 0.81-0.94. The CaLS system enabled significantly higher detection of cartilage lesion progression than did WORMS or BLOKS systems (P < .001); 51.8% (56 of 108), 17.6% (19 of 108), and 13.0% (14 of 108) of the lesions progressed when analyzed with the CaLS, WORMS, and BLOKS systems, respectively. With the CaLS system, subjects with OA risk factors had significantly higher odds of progression than did subjects without risk factors (odds ratio, 2.78; P = .005). CONCLUSION: The CaLS system is a reproducible scoring system for cartilage lesions that yields an improved detection rate for monitoring progression when compared with detection rates of semiquantitative WORMS and BLOKS systems. PMID- 24475849 TI - Inflammatory bowel disease: MR- and SPECT/CT-based macrophage imaging for monitoring and evaluating disease activity in experimental mouse model--pilot study. AB - PURPOSE: To evaluate the feasibility of using magnetic resonance (MR) imaging and single photon emission computed tomography (SPECT)/computed tomography (CT) to visualize the in vivo recruitment of iron oxide-labeled macrophages and indium 111 ((111)In)-labeled macrophages in inflammatory bowel disease (IBD) and to monitor disease activity. MATERIALS AND METHODS: This study had institutional animal care and use committee approval. Twenty-seven C57/B6 mice with dextran sodium sulfate (DSS)-induced IBD and control mice were included. Peritoneal macrophages were harvested from seven thioglycollate-treated mice and were labeled with superparamagnetic iron oxide (SPIO) nanoparticles. Macrophage iron content was determined by using inductively coupled plasma mass spectrometry. SPIO nanoparticle-labeled macrophages (5 * 10(6)) were intravenously administered. Mice with DSS-induced IBD (n = 8) and control mice (n = 6) were imaged with a 9.4-T MR imaging unit at 0, 5, and 24 hours after macrophage administration. Percentage normalized enhancement (NE) was calculated for the intestinal wall and liver 24 hours after injection. Six mice with IBD coinjected with SPIO nanoparticles and (111)In oxine-labeled macrophages were imaged with MR imaging and SPECT/CT after 24 hours. The pharmacokinetics and biodistribution of the implanted macrophages were determined. Correlation between percentage NE and IBD scores was calculated. RESULTS: Ex vivo mass spectrometry revealed strong SPIO nanoparticle uptake (7.4 pg iron per cell). R2* correlated with cell number (r = 0.9813, P < .05). Percentage NE correlated with both clinical (r = 0.924) and pathologic (r = 0.795) IBD score. Cell circulation half-life in the first and second phases was 0.32 hour and 10.2 hours, respectively. SPECT/CT showed that approximately 3% of the injected dose was present in the intestines 24 hours after injection; this was confirmed at MR imaging and histologic examination. Indium 111-labeled cells were present in all tissue associated with the reticuloendothelial system or mononuclear phagocyte system at 24 hours. CONCLUSION: SPIO nanoparticles and (111)In-labeled macrophages could be observed in vivo at MR imaging and SPECT/CT in mice with IBD. Percentage NE at MR imaging correlates with disease activity. PMID- 24475850 TI - Intracranial plaque enhancement in patients with cerebrovascular events on high spatial-resolution MR images. AB - PURPOSE: To characterize intracranial plaque inflammation in vivo by using three dimensional (3D) high-spatial-resolution contrast material-enhanced black-blood (BB) magnetic resonance (MR) imaging and to investigate the relationship between intracranial plaque inflammation and cerebrovascular ischemic events. MATERIALS AND METHODS: The study was approved by the institutional review board and was HIPAA compliant. Twenty-seven patients (19 men; mean age, 56.8 years +/- 12.4 [standard deviation]) with cerebrovascular ischemic events (acute stroke, n = 20; subacute stroke, n = 2; chronic stroke, n = 3; transient ischemic attack, n = 2) underwent 3D time-of-flight MR angiography and contrast-enhanced BB 3-T MR imaging for intracranial atherosclerotic disease. Each identified plaque was classified as either culprit (the only or most stenotic lesion upstream from a stroke), probably culprit (not the most stenotic lesion upstream from a stroke), or nonculprit (not within the vascular territory of a stroke). Plaque contrast enhancement was categorized on BB MR images (grade 0, enhancement less than or equal to that of normal arterial walls seen elsewhere; grade 1, enhancement greater than grade 0 but less than that of the pituitary infundibulum; grade 2, enhancement greater than or equal to that of the pituitary infundibulum), and degree of contrast enhancement was calculated. Associations of the likelihood of being a culprit lesion with both plaque contrast enhancement and plaque thickness were estimated with ordinal logistic regression. RESULTS: Seventy-eight plaques were identified in 20 patients with acute stroke (21 [27%] culprit, 12 [15%] probably culprit, and 45 [58%] nonculprit plaques). In these patients, grade 2 contrast enhancement was associated with culprit plaques (odds ratio 34.6; 95% confidence interval: 4.5, 266.5 compared with grade 0) when adjusted for plaque thickness. Grade 0 was observed in only nonculprit plaques. Culprit plaques had a higher degree of contrast enhancement than did nonculprit plaques (25.9% +/- 13.4 vs 13.6% +/- 12.3, P = .003). CONCLUSION: Contrast enhancement of intracranial atherosclerotic plaque is associated with its likelihood to have caused a recent ischemic event and may serve as a marker of its stability, thereby providing important insight into stroke risk. PMID- 24475851 TI - Quantitative assessment of pancreatic fat by using unenhanced CT: pathologic correlation and clinical implications. AB - PURPOSE: To assess the relationship between computed tomographic (CT) indexes and histologically measured pancreatic fat in surgical specimens and to evaluate patients with impaired glucose metabolism in a clinical setting. MATERIALS AND METHODS: This retrospective study was institutional review board approved and informed consent was waived. The hospital database was searched for records from November 2008 to April 2009, and 62 patients (42 men and 20 women; mean age, 61.4 years; age range, 21-81 years) who underwent CT within 1 month before pancreatectomy were identified. The histologic pancreatic fat fraction (area ratio of fat to total tissue times 100%) was measured in nontumorous pancreatic tissue. Attenuation was measured in three regions of interest in the pancreas and the spleen on nonenhanced CT images. The difference between pancreatic and splenic attenuation and the pancreas-to-spleen attenuation ratio were calculated. Visceral fat area at the level of the umbilicus was measured on the CT images. Spearman correlation coefficients (rho) were calculated to examine the correlation between the CT indexes or visceral fat area and the histologic pancreatic fat fraction. A multivariate logistic regression model was used to determine whether CT attenuation indexes and patient age, sex, and visceral fat correlated with impaired glucose metabolism (ie, impaired glucose tolerance, impaired fasting glucose, or presence of diabetes). RESULTS: The histologic pancreatic fat fraction ranged from 0% to 65.3% and was significantly correlated with the difference between pancreatic and splenic attenuation (rho = -0.622, P < .01) and the pancreas-to-spleen attenuation ratio (rho = -0.616, P < .01). The visceral fat area was not correlated with the histologic pancreatic fat fraction (rho = 0.09, P = .50). The CT attenuation indexes were significant and independent variables predictive of impaired glucose metabolism after adjusting for age, sex, and visceral fat. CONCLUSION: Pancreatic fat can be quantified by using CT, and CT attenuation indexes that are applied to the quantification of pancreatic fat are significantly associated with clinical assessment of impaired glucose metabolism. PMID- 24475852 TI - Vascular remodeling and plaque vulnerability in a rabbit model of atherosclerosis: comparison of delayed-enhancement MR imaging with an elastin specific contrast agent and unenhanced black-blood MR imaging. AB - PURPOSE: To compare delayed-enhancement (DE) magnetic resonance (MR) imaging with an elastin-specific contrast agent and unenhanced black-blood (BB) MR imaging with regard to vessel wall delineation and assessment of vascular remodeling and to test the prospective value for predicting plaque disruption in a rabbit model of atherosclerosis. MATERIALS AND METHODS: All procedures were approved by the animal ethics committee. Atherosclerosis was induced in 14 New Zealand White rabbits by means of a 1% cholesterol diet and endothelial denudation. Plaque disruption was triggered with Russell's viper venom and histamine. Animals with atherosclerosis were imaged before triggering to identify plaques and vascular remodeling and after triggering to identify thrombus. Plaques were classified as nondisrupted (stable) or disrupted (vulnerable). Control rabbits fed a regular diet were imaged twice. Unenhanced T1-weighted BB MR imaging, DE MR imaging with an elastin-specific contrast agent, and T1 mapping were used to assess vascular remodeling and calculate the plaque area and vessel wall relaxation rate (R1 = 1/T1). Elastin was quantified by using elastica-van Gieson stain. Group comparisons were analyzed with the Mann-Whitney or paired t test. Agreement between methods was performed with Bland-Altman analysis. RESULTS: Unenhanced T1 weighted BB MR imaging and DE MR imaging showed that, compared with nondisrupted plaques, disrupted plaques had larger plaque area (T1-weighted BB MR imaging: 5.1 mm(2) vs 5.7 mm(2); DE MR imaging: 6.0 mm(2) vs 7.9 mm(2); P < .001) and vessel area (T1-weighted BB MR imaging: 11.8 mm(2) vs 14.3 mm(2); DE MR imaging: 10.8 mm(2) vs 13.9 mm(2); P < .001) and underwent positive remodeling. Assessment of positive remodeling with DE MR imaging enabled better prediction of plaque disruption compared to that with unenhanced T1-weighted BB imaging (sensitivity: 83.7% vs 58.1%). DE MR imaging showed a stronger agreement with histologic findings, whereas the vessel area was overestimated with unenhanced T1-weighted BB imaging. CONCLUSION: Compared with unenhanced T1-weighted BB MR imaging, DE MR imaging with an elastin-specific contrast agent enables more accurate assessment of vascular remodeling in the prediction of vulnerable plaque. PMID- 24475853 TI - Endoleak and in-stent thrombus detection with CT angiography in a thoracic aortic aneurysm phantom at different tube energies using filtered back projection and iterative algorithms. AB - PURPOSE: To determine the lower limit of dose reduction with hybrid and fully iterative reconstruction algorithms in detection of endoleaks and in-stent thrombus of thoracic aorta with computed tomographic (CT) angiography by applying protocols with different tube energies and automated tube current modulation. MATERIALS AND METHODS: The calcification insert of an anthropomorphic cardiac phantom was replaced with an aortic aneurysm model containing a stent, simulated endoleaks, and an intraluminal thrombus. CT was performed at tube energies of 120, 100, and 80 kVp with incrementally increasing noise indexes (NIs) of 16, 25, 34, 43, 52, 61, and 70 and a 2.5-mm section thickness. NI directly controls radiation exposure; a higher NI allows for greater image noise and decreases radiation. Images were reconstructed with filtered back projection (FBP) and hybrid and fully iterative algorithms. Five radiologists independently analyzed lesion conspicuity to assess sensitivity and specificity. Mean attenuation (in Hounsfield units) and standard deviation were measured in the aorta to calculate signal-to-noise ratio (SNR). Attenuation and SNR of different protocols and algorithms were analyzed with analysis of variance or Welch test depending on data distribution. RESULTS: Both sensitivity and specificity were 100% for simulated lesions on images with 2.5-mm section thickness and an NI of 25 (3.45 mGy), 34 (1.83 mGy), or 43 (1.16 mGy) at 120 kVp; an NI of 34 (1.98 mGy), 43 (1.23 mGy), or 61 (0.61 mGy) at 100 kVp; and an NI of 43 (1.46 mGy) or 70 (0.54 mGy) at 80 kVp. SNR values showed similar results. With the fully iterative algorithm, mean attenuation of the aorta decreased significantly in reduced-dose protocols in comparison with control protocols at 100 kVp (311 HU at 16 NI vs 290 HU at 70 NI, P <= .0011) and 80 kVp (400 HU at 16 NI vs 369 HU at 70 NI, P <= .0007). CONCLUSION: Endoleaks and in-stent thrombus of thoracic aorta were detectable to 1.46 mGy (80 kVp) with FBP, 1.23 mGy (100 kVp) with the hybrid algorithm, and 0.54 mGy (80 kVp) with the fully iterative algorithm. PMID- 24475854 TI - Risk of intravenous contrast material-mediated acute kidney injury: a propensity score-matched study stratified by baseline-estimated glomerular filtration rate. AB - PURPOSE: To determine the effect of baseline estimated glomerular filtration rate (eGFR) on the causal association between intravenous iodinated contrast material exposure and subsequent development of acute kidney injury (AKI) in propensity score-matched groups of patients who underwent contrast material-enhanced or unenhanced computed tomography (CT). MATERIALS AND METHODS: This retrospective study was HIPAA compliant and institutional review board approved. All patients who underwent contrast-enhanced (contrast material group) or unenhanced (non contrast material group) CT between 2000 and 2010 were identified and stratified according to baseline eGFR by using Kidney Disease Outcomes Quality Initiative cutoffs for chronic kidney disease into subgroups with eGFR of 90 or greater, 60 89, 30-59, and less than 30 mL/min/1.73 m(2). Propensity score generation and 1:1 matching of patients were performed in each eGFR subgroup. Incidence of AKI (serum creatinine [SCr] increase of >=0.5 mg/dL [>=44.2 MUmol/L] above baseline) was compared in the matched subgroups by using the Fisher exact test. RESULTS: A total of 12 508 propensity score-matched patients with contrast-enhanced and unenhanced scans met all inclusion criteria. In this predominantly inpatient cohort, the incidence of AKI significantly increased with decreasing baseline eGFR (P < .0001). However, this incidence was not significantly different between contrast material and non-contrast material groups in any eGFR subgroup; for the subgroup with eGFR of 90 or greater (n = 1642), odds ratio (OR) was 0.91 (95% confidence interval [CI]: 0.38, 2.15), P = .82; for the subgroup with eGFR of 60 89 (n = 3870), OR was 1.03 (95% CI: 0.66, 1.60), P = .99; for the subgroup with eGFR of 30-59 (n = 5510), OR was 0.94 (95% CI: 0.76, 1.18), P = .65; and for the subgroup with eGFR of less than 30 mL/min/1.73 m(2) (n = 1486), OR was 0.97 (95% CI: 0.72, 1.30), P = .89. CONCLUSION: Diminished eGFR is associated with an increased risk of SCr-defined AKI following CT examinations. However, the risk of AKI is independent of contrast material exposure, even in patients with eGFR of less than 30 mL/min/1.73 m(2). PMID- 24475855 TI - The functional pitch of an organ: quantification of tissue texture with photoacoustic spectrum analysis. AB - PURPOSE: To investigate the use of photoacoustic (PA) spectrum analysis (PASA) to identify microstructural changes corresponding to fat accumulation in mouse livers ex vivo and in situ. MATERIALS AND METHODS: The laboratory animal protocol for this work was approved by the university committee on use and care of animals. Six mice with normal livers and six mice with fatty livers were examined ex vivo with a PA system at 1200 nm, and nine similar pairs of mice were examined at 532 nm. To explore the feasibility of this technique for future study in an in vivo mouse model, an additional pair of normal and fatty mouse livers was scanned in situ with an ultrasonographic (US) and PA dual-modality imaging system. The PA signals acquired were analyzed by using the proposed PASA method. Results of the groups were compared by using the Student t test. RESULTS: Prominent differences between the PASA parameters from the fatty and normal mouse livers were observed. The analysis of the PASA parameters from six normal and six fatty mouse livers indicates that there are differences of up to 5 standard deviations between the PASA parameters of the normal livers and those of the fatty livers at 1200 nm; for parameters from nine normal and nine fatty mouse livers at 532 nm, the differences were approximately 2 standard deviations (P < .05) for each PASA parameter. CONCLUSION: The results supported our hypothesis that the PASA allows quantitative identification of the microstructural changes that differentiate normal from fatty livers. Compared with that at 532 nm, PASA at 1200 nm is more reliable for fatty liver diagnosis. Online supplemental material is available for this article. PMID- 24475856 TI - Quantification of myocardial extracellular volume fraction with cardiac MR imaging for early detection of left ventricle involvement in systemic sclerosis. AB - PURPOSE: To determine whether extracellular volume fraction (ECV) quantification at cardiac magnetic resonance (MR) imaging can demonstrate subclinical left ventricle (LV) abnormalities in a cohort of consecutive systemic sclerosis (SS) patients, and to investigate the relationship between ECV and diastolic and systolic LV function. MATERIALS AND METHODS: All subjects gave their written informed consent. The protocol was approved by the ethics committee. ECV quantification with cardiac MR imaging was prospectively performed in 33 consecutive SS patients with normal echocardiography results and no late gadolinium chelate enhancement at MR imaging. Left ventricular and atrial volumes and peak circumferential strain were measured at cardiac MR imaging. Diastolic function was assessed at echocardiography. The results were compared with those of 16 age-matched healthy control subjects by using Mann-Whitney and Kruskal Wallis tests. RESULTS: SS patients had significantly higher global ECV (P < .001) and higher local ECV for all basal and midventricular LV segments. Global ECV significantly correlated with left atrial volume (P = .002) and with the grade of diastolic dysfunction (P = .016). The majority of SS patients (63%; 21 of 33 patients) had a high global ECV and a low global systolic circumferential strain. CONCLUSION: ECV quantification can identify LV abnormalities at an early stage in SS patients. These abnormalities may reflect increase in diffuse myocardial fibrosis and are associated with diastolic LV dysfunction. PMID- 24475857 TI - Thyroid nodules with benign findings at cytologic examination: results of long term follow-up with US. AB - PURPOSE: To investigate the natural history of thyroid nodules found to be benign at initial fine-needle aspiration biopsy (FNAB) to determine the percentage of nodules that increased in volume by more than 50% as being an indicator of malignancy. MATERIALS AND METHODS: This retrospective observational cohort study was approved by the institutional review board, and the need to obtain informed consent was waived. The study included 854 FNAB-confirmed benign thyroid nodules. Suspicious ultrasonographic (US) features included marked hypoechogenicity, irregular or microlobulated margin, microcalcification, and taller-than-wide shape. Univariate and multivariate generalized linear mixed models were used to assess the association with nodule growth greater than 50% in volume. RESULTS: For the 854 nodules, the initial mean diameter was 19.92 mm (range, 3.10-60.00 mm), and the initial mean volume was 3.19 cm(3) (range, 0.01-4.64 cm(3)). The majority (682 [79.9%] of 854) of thyroid nodules with benign cytologic results at initial FNAB did not grow more than 50% in volume during 4 years of mean follow up (range, 7-101 months). More than 4 years of follow-up time versus less than 2 years, younger age, a cystic component of less than 25%, and nodule size 1 cm or larger versus less than 1 cm were independently associated with growth. There was only one malignant nodule (0.6%) among 172 thyroid nodules with a volume increase of 50% or greater during the entire follow-up time. Ten malignant nodules (overall malignancy rate: 1.2%) were detected among the 854 total nodules, and eight of these 10 nodules showed suspicious features at US. CONCLUSION: Repeat FNAB for nodules showing more than 50% growth in volume is unlikely to result in a diagnosis of malignancy. A positive FNAB result for malignancy is significantly more likely in the presence of suspicious US features. PMID- 24475858 TI - Whole-body diffusion-weighted MR imaging for assessment of treatment response in myeloma. AB - PURPOSE: To determine the feasibility of whole-body diffusion-weighted (DW) magnetic resonance (MR) imaging for assessment of treatment response in myeloma. MATERIALS AND METHODS: This prospective single-institution study was HIPAA compliant with local research ethics committee approval. Written informed consent was obtained from each subject. Eight healthy volunteers (cohort 1a) and seven myeloma patients (cohort 1b) were imaged twice to assess repeatability of quantitative apparent diffusion coefficient (ADC) estimates. Thirty-four additional myeloma patients (cohort 2) underwent whole-body DW imaging before treatment; 26 completed a posttreatment imaging. Whole-body DW data were compared before and after treatment by using qualitative (ie, observer scores) and quantitative (ie, whole-body segmentation of marrow ADC) methods. Serum paraproteins and/or light chains or bone marrow biopsy defined response. RESULTS: Whole-body DW imaging scores were significantly different between observers (P < .001), but change in scores between observers after treatment was not (P = .49). Sensitivity and specificity for detecting response according to observer scores were 86% (18 of 21 patients) and 80% (4 of 5 patients) for both observers. ADC measurement was repeatable: mean coefficient of variation was 3.8% in healthy volunteers and 2.8% in myeloma patients. Pretreatment ADC in cohort 2 was significantly different from that in cohort 1a (P = .03), but not from that in cohort 1b (P = .2). Mean ADC increased in 95% (19 of 20) of responding patients and decreased in all (five of five) nonresponders (P = .002). A 3.3% increase in ADC helped identify response with 90% sensitivity and 100% specificity; an 8% increase (greater than repeatability of cohort 1b) resulted in 70% sensitivity and 100% specificity. There was a significant negative correlation between change in ADC and change in laboratory markers of response (r = -0.614; P = .001). CONCLUSION: Preliminary work demonstrates whole-body DW imaging is a repeatable, quantifiable technique for assessment of treatment response in myeloma. PMID- 24475859 TI - Comparison of two-dimensional synthesized mammograms versus original digital mammograms alone and in combination with tomosynthesis images. AB - PURPOSE: To assess interpretation performance and radiation dose when two dimensional synthesized mammography (SM) images versus standard full-field digital mammography (FFDM) images are used alone or in combination with digital breast tomosynthesis images. MATERIALS AND METHODS: A fully crossed, mode balanced multicase (n = 123), multireader (n = 8), retrospective observer performance study was performed by using deidentified images acquired between 2008 and 2011 with institutional review board approved, HIPAA-compliant protocols, during which each patient signed informed consent. The cohort included 36 cases of biopsy-proven cancer, 35 cases of biopsy-proven benign lesions, and 52 normal or benign cases (Breast Imaging Reporting and Data System [BI-RADS] score of 1 or 2) with negative 1-year follow-up results. Accuracy of sequentially reported probability of malignancy ratings and seven-category forced BI-RADS ratings was evaluated by using areas under the receiver operating characteristic curve (AUCs) in the random-reader analysis. RESULTS: Probability of malignancy based mean AUCs for SM and FFDM images alone was 0.894 and 0.889, respectively (difference, -0.005; 95% confidence interval [CI]: -0.062, 0.054; P = .85). Mean AUC for SM with tomosynthesis and FFDM with tomosynthesis was 0.916 and 0.939, respectively (difference, 0.023; 95% CI: -0.011, 0.057; P = .19). In terms of the reader-specific AUCs, five readers performed better with SM alone versus FFDM alone, and all eight readers performed better with combined FFDM and tomosynthesis (absolute differences from 0.003 to 0.052). Similar results were obtained by using a nonparametric analysis of forced BI-RADS ratings. CONCLUSION: SM alone or in combination with tomosynthesis is comparable in performance to FFDM alone or in combination with tomosynthesis and may eliminate the need for FFDM as part of a routine clinical study. PMID- 24475860 TI - Liver diffusion-weighted MR imaging: reproducibility comparison of ADC measurements obtained with multiple breath-hold, free-breathing, respiratory triggered, and navigator-triggered techniques. AB - PURPOSE: To prospectively compare the reproducibility of normal liver apparent diffusion coefficient (ADC) measurements by using different respiratory motion compensation techniques with multiple breath-hold (MBH), free-breathing (FB), respiratory-triggered (RT), and navigator-triggered (NT) diffusion-weighted (DW) imaging and to compare the ADCs at different liver anatomic locations. MATERIALS AND METHODS: The study protocol was approved by the institutional review board, and written informed consent was obtained from each participant. Thirty-nine volunteers underwent liver DW imaging twice. Imaging was performed with a 1.5-T MR imager with MBH, FB, RT, and NT techniques (b = 0, 100, and 500 sec/mm(2)). Three representative sections--superior, central, and inferior--were selected on left and right liver lobes, respectively. On each selected section, three regions of interest were drawn, and ADCs were measured. Analysis of variance was used to assess ADCs among the four techniques and various anatomic locations. Reproducibility of ADCs was assessed with the Bland-Altman method. RESULTS: ADCs obtained with MBH (range: right lobe, [1.641-1.662] * 10(-3)mm(2)/sec; left lobe, [2.034-2.054] *10(-3)mm(2)/sec) were higher than those obtained with FB (right, [1.349-1.391] *10(-3)mm(2)/sec; left, [1.630-1.700] *10(-3)mm(2)/sec), RT (right, [1.439-1.455] *10(-3)mm(2)/sec; left, [1.720-1.755] *10(-3)mm(2)/sec), or NT (right, [1.387-1.400] *10(-3)mm(2)/sec; left, [1.661-1.736] *10(-3)mm(2)/sec) techniques (P < .001); however, no significant difference was observed between ADCs obtained with FB, RT, and NT techniques (P = .130 to P >.99). ADCs showed a trend to decrease moving from left to right. Reproducibility in the left liver lobe was inferior to that in the right, and the central middle segment in the right lobe had the most reproducible ADC. Statistical differences in ADCs were observed in the left-right direction in the right lobe (P < .001), but they were not observed in the superior-inferior direction (P = .144-.450). However, in the left liver lobe, statistical differences existed in both directions (P = .001 to P = .016 in the left-right direction, P < .001 in the superior-inferior direction). CONCLUSION: Both anatomic location and DW imaging technique influence liver ADC measurements and their reproducibility. FB DW imaging is recommended for liver DW imaging because of its good reproducibility and shorter acquisition time compared with that of MBH, RT, and NT techniques. PMID- 24475861 TI - Shear-wave amplitudes measured with cardiac MR elastography for diagnosis of diastolic dysfunction. AB - PURPOSE: To test whether shear-wave amplitudes (SWAs) in the myocardium measured with cardiac magnetic resonance (MR) elastography enable diagnosis of myocardial relaxation abnormalities in patients with diastolic dysfunction. MATERIALS AND METHODS: Each subject gave written informed consent to participate in this institutional review board-approved prospective study. Electrocardiographically triggered SWA-based cardiac MR elastography with 24.13-Hz external vibration frequency was performed in 50 subjects grouped into asymptomatic young (n = 10, 18-39 years) and asymptomatic old (n = 10, 40-68 years) subjects and patients with echocardiographically proved mild, moderate, or severe diastolic dysfunction (n = 30, 44-73 years). SWA images were analyzed in the left ventricular (LV) region and were normalized against reference SWA of the thoracic wall. Analysis of variance with Bonferroni-corrected pairwise comparison and Pearson correlation were used for statistical evaluation. RESULTS: Young and old control subjects had normalized mean LV SWA of 0.67 +/- 0.04 (standard error of the mean) and 0.56 +/- 0.04 (P = .18, F test), respectively. Compared with the control groups, patients with mild, moderate, and severe diastolic dysfunction displayed significantly reduced normalized mean LV SWA of 0.37 +/- 0.04, 0.34 +/- 0.04, and 0.29 +/- 0.04 (P < .001, F test), respectively, which was inversely correlated to the severity of diastolic dysfunction (R = -0.61, P < .001). The best cutoff value to differentiate between asymptomatic volunteers and patients was 0.43, yielding an area under the receiver operating characteristic curve of 0.92, with 90% sensitivity and 89.7% specificity. CONCLUSION: LV SWA measured with cardiac MR elastography provides image contrast sensitive to myocardial relaxation abnormalities and shows significantly lower values in patients with diastolic dysfunction. PMID- 24475862 TI - Chemotherapy-induced focal hepatopathy in patients with gastrointestinal malignancy: gadoxetic acid--enhanced and diffusion-weighted MR imaging with clinical-pathologic correlation. AB - PURPOSE: To retrospectively evaluate findings of chemotherapy-induced focal hepatopathy (CIFH) on gadoxetic acid-enhanced magnetic resonance (MR) and diffusion-weighted (DW) images and to determine imaging features that are most helpful in differentiating CIFH from metastasis. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and informed consent was waived. MR images, including DW images and gadoxetic acid-enhanced images, from 12 patients (four men, eight women; age range, 25-64 years) with 15 CIFHs were reviewed independently and in consensus by two radiologists and were compared with those obtained in 20 control patients (12 men, eight women; age range, 32-84 years) with 30 hepatic metastasis who were matched for tumor size, primary organ, and chemotherapy regimen. Interobserver agreement was assessed with kappa statistics, and univariate analysis was performed for comparisons. For quantitative analyses, apparent diffusion coefficients (ADCs) and lesion-to-liver contrast ratios (CRs) were measured. Histopathologic examinations were performed for CIFHs. RESULTS: Histopathologic examination revealed that the development of CIFHs was attributable to accentuated manifestations of sinusoidal obstruction syndrome. Interobserver agreement was excellent (kappa > 0.85). An ill-defined margin on hepatobiliary phase (HBP) images was the most discriminating independent variable in the differentiation of CIFH from metastasis (odds ratio, 16; P = .009). ADC and CR values in CIFH group were significantly higher than those in metastasis group (P < .001 and P = .041). CONCLUSION: CIFH should be considered a mimicker of metastasis in patients with gastrointestinal malignancy during chemotherapy. CIFH can be differentiated from metastasis on the basis of gadoxetic acid-enhanced MR and DW imaging findings; an ill-defined margin on HBP images was especially characteristic. PMID- 24475863 TI - Dual-energy CT-based phantomless in vivo three-dimensional bone mineral density assessment of the lumbar spine. AB - PURPOSE: To evaluate the feasibility of phantomless in vivo dual-energy computed tomography (CT)-based three-dimensional (3D) bone mineral density (BMD) assessment in comparison with dual x-ray absorptiometry (DXA). MATERIALS AND METHODS: This retrospective study was approved by the institutional review board, and the requirement to obtain informed consent was waived. Data from clinically indicated dual-energy CT and DXA examinations within 2 months, comprising the lumbar spine of 40 patients, were included. By using automated dedicated postprocessing dual-energy CT software, the trabecular bone of lumbar vertebrae L1-L4 were analyzed and segmented. A mixed-effects model was used to assess the correlations between BMD values derived from dual-energy CT and DXA. RESULTS: One hundred sixty lumbar vertebrae were analyzed in 40 patients (mean age, 57.1 years; range, 24-85 years), 21 male (mean age, 54.3 years; range, 24-85 years) and 19 female (mean age, 58.5 years; range, 31-80 years). Mean BMD of L1-L4 determined with DXA was 0.995 g/cm(2), and 18 patients (45%) showed an osteoporotic BMD (T score less than -2.5) of at least two vertebrae. Mean dual energy CT-based BMD of L1-L4 was 0.254 g/cm(3). Bland-Altman analysis with mixed effects demonstrated a lack of correlation between dual-energy CT-based and DXA based BMD values, with a mean difference of 0.7441 and 95% limits of agreement of 0.7441 +/- 0.4080. CONCLUSION: Dedicated postprocessing of dual-energy CT data allows for phantomless in vivo BMD assessment of the trabecular bone of lumbar vertebrae and enables freely rotatable color-coded 3D visualization of intravertebral BMD distribution. PMID- 24475864 TI - Respiratory motion artifact affecting hepatic arterial phase imaging with gadoxetate disodium: examination recovery with a multiple arterial phase acquisition. AB - PURPOSE: To determine whether the use of a multiple arterial phase imaging technique provides adequate image quality in patients experiencing transient severe motion (TSM) in the arterial phase on abdominal magnetic resonance (MR) images obtained with gadoxetate disodium. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board and was compliant with HIPAA. The requirement to obtain informed consent was waived. Five hundred forty-nine consecutive MR examinations were evaluated, 345 performed with gadoxetate disodium and 204 performed with gadobenate dimeglumine. All examinations included single-breath-hold triple arterial phase acquisition. Five radiologists blinded to the contrast material rated motion on a scale of 1 (no motion) to 5 (nondiagnostic images) for the precontrast phase, the three arterial phases, the portal venous phase, and the late dynamic phase. Adequacy of late hepatic arterial timing was also rated for the each of the three arterial phases. Mean motion scores were compared by using the Wilcoxon signed rank test. The number of patients with TSM, as well as the number of those with "adequate" arterial phases, was compared with the chi(2) or Fisher exact test, as appropriate. RESULTS: Mean motion scores in all three arterial phases in the gadoxetate disodium cohort were significantly worse than those in the gadobenate dimeglumine cohort (P < .005). TSM occurred at a higher rate with gadoxetate disodium than with gadobenate dimeglumine (10.7% [37 of 345 examinations] vs 0.5% [one of 204 examinations], P < .001). However, 30 of 37 examinations affected by TSM had at least one well-timed arterial phase with a mean motion score of 3 or less and were thus considered adequate. CONCLUSION: Use of single-breath-hold multiple arterial phase acquisition in abdominal MR imaging with gadoxetate disodium recovers most arterial phases that would otherwise have been compromised by transient motion. PMID- 24475865 TI - Thyroid cancers incidentally detected at imaging in a 10-year period: how many cancers would be missed with use of the recommendations from the Society of Radiologists in Ultrasound? AB - PURPOSE: To estimate the prevalence of incidental thyroid cancer (ITC) among patients undergoing thyroid surgery and to apply the Society of Radiologists in Ultrasound (SRU) guidelines to ITC. MATERIALS AND METHODS: This HIPAA-compliant study was approved by the institutional review board, with waiver of the need to obtain informed consent. A retrospective review of data in patients who underwent thyroid surgery between January 1, 2003, and December 31, 2012, was performed. Imaging studies and reports were reviewed for ITCs that were first detected at either ultrasonography (US) or a different imaging modality and that included US as part of the work-up. ITCs were categorized by using the SRU guidelines to determine the characteristics of SRU criteria-positive and SRU criteria-negative malignancies. Patient demographic data, tumor histologic findings, tumor size, and tumor stage were compared for the SRU criteria-positive and SRU criteria negative cancers by using the unpaired t test and the chi(2) test. RESULTS: Among 2090 patients who underwent thyroid surgery, 680 had thyroid cancer; of these patients, 101 (15%) had imaging-detected ITC. The SRU recommendations were applied to the findings in 90 of the 101 patients who had undergone US with images or had reports available for review. Sixteen (18%) of the 90 patients had SRU criteria-negative tumors, which represented 2% (16 of 680) of all thyroid cancers. SRU criteria-negative tumors were smaller than SRU criteria-positive tumors (mean, 1.1 cm [range, 0.9-1.4 cm] vs mean, 2.5 cm [range, 1.0-7.6 cm]; P < .001) and were more likely to be stage I (15 [94%] of 16 vs 47 [64%] of 74; P = .02). CONCLUSION: Imaging-detected ITCs are uncommon. Two percent (16 of 680) of malignancies would not undergo fine-needle aspiration biopsy or surgery if the SRU guidelines were used for work-up of incidental thyroid nodules. SRU criteria negative tumors are lower in stage than SRU criteria-positive tumors. PMID- 24475866 TI - Hybrid integration of real-time US and freehand SPECT: proof of concept in patients with thyroid diseases. AB - PURPOSE: To report an initial experience regarding the feasibility and applicability of quasi-integrated freehand single photon emission computed tomography (SPECT)/ultrasonography (US) fusion imaging in patients with thyroid disease. MATERIALS AND METHODS: Local ethics committee approval was obtained, and 34 patients were examined after giving written informed consent. After intravenous application of 75 MBq of technetium 99m pertechnetate, freehand three dimensional SPECT was performed. Data were reconstructed and transferred to a US system. The combination of two independent positioning systems enabled real-time fusion of metabolic and morphologic information during US examination. Quality of automatic coregistration was evaluated visually, and deviation was determined by measuring the distance between the center of tracer distribution and the center of the US correlate. RESULTS: All examinations were technically successful. For 18 of 34 examinations, the automatic coregistration and image fusion exhibited very good agreement, with no deviation. Only minor limitations in fusion offset occurred in 16 patients (mean offset +/- standard deviation, 0.67 cm +/- 0.3; range, 0.2-1.0 cm). SPECT artifacts occurred even in situations of clear thyroid findings (eg, unifocal autonomy). CONCLUSION: The freehand SPECT/US fusion concept proved feasible and applicable; however, technical improvements are necessary. PMID- 24475867 TI - Psychometric properties of a revised Danish translation of the international outcome inventory for hearing aids (IOI-HA). AB - OBJECTIVE: The original Danish translation of the international outcome inventory for hearing aids (IOI-HA) proved problematic as the wording of item 5 was not semantically clear, rendering the questionnaire internally inconsistent. The objective of this study was to examine data collected with a revised Danish translation of the IOI-HA in order to: (1) evaluate the effect of the revision, and (2) to examine if the psychometric properties of the revised translation of the IOI-HA are equivalent to those of previously validated translations. DESIGN: Psychometric properties were evaluated performing inter-item correlation analysis, principal component analysis, and item-total correlation. STUDY SAMPLE: Three hundred forty-one adult hearing-impaired participants-all of whom were voluntary hearing aid testers attached to the Global Audiology Group in GN ReSound A/S on a non-payment basis - were mailed a revised Danish IOI-HA questionnaire. RESULTS: Statistical analysis revealed good internal consistency along with a clear division of items into two distinct factors. CONCLUSIONS: The revised Danish translation of the IOI-HA proves internally consistent. Furthermore, it possesses psychometric properties equivalent to those reported in several corresponding studies of other translations. Data obtained from it can therefore validly be considered comparable to data obtained from previously validated translations of the IOI-HA. PMID- 24475868 TI - Estimated and forecasted trends in domain specific time-use and energy expenditure among adults in Russia. AB - BACKGROUND: Examination of historical trends and projections in estimated energy expenditure in Russia is important given the country's economic downturns and growth. METHODS: Nationally representative data from the Russia Longitudinal Monitoring Survey (RLMS) from 1995-2011 was used to determine the metabolic equivalents of task (MET)-hours per week from occupational, domestic, travel, and active leisure physical activity (PA) domains, as well as sedentary leisure time (hours per week) among adults 18-60 years. Additionally, we projected what these values would be like in 2020 and 2030 if observed trends continue. RESULTS: Among male adults, the largest contributor to total PA was occupational PA followed by travel PA. In contrast, domestic PA followed by occupational PA contributed most to total PA among female adults. Total PA was 282.9 MET-hours per week in 1995 and declined to 231.7 in 2011. Total PA is projected to decrease to 216.5 MET hours per week in 2020 and to 193.0 MET-hours per week in 2030. The greatest relative declines are occurring in travel PA. Female adults are also exhibiting significant declines in domestic PA. Changes in occupational and active leisure PA are less distinct. CONCLUSIONS: Policies and initiatives are needed to counteract the long-term decline of overall physical activity linked with a modernizing lifestyle and economy among Russian adults. PMID- 24475869 TI - Perioperative conjunctival inflammation and trabeculectomy outcome. AB - PURPOSE: To correlate subclinical conjunctival inflammation and trabeculectomy results. METHODS: Prospective case series of 28 patients with primary open-angle glaucoma (28 eyes) under topical anti-glaucoma medication who underwent trabeculectomy. During surgery, a sample from the inferior bulbar conjunctiva was collected and the expression of HLA-DR together with the presence of inflammatory cells was correlated with trabeculectomy outcomes after 24 months. Surgical success was defined as intraocular pressure between 6 and 20 mmHg irrespective of the use of anti-glaucoma medication. RESULTS: Five patients missed follow-up visits and were removed from the study. Ten eyes (43.5%) were HLA-DR(+), but no significant differences were observed between eyes with successful and failed surgeries (p = 0.214). There was no significant association between the number of neutrophils and surgical outcomes (p = 0.353). CONCLUSIONS: The presence of inflammatory cells and expression of the inflammation marker HLA-DR in the conjunctiva did not correlate with the prognosis of trabeculectomy in this study. PMID- 24475870 TI - More than a masquerade syndrome: atypical presentations of vitreoretinal lymphomas. AB - PURPOSE: To present a population of patients sharing atypical manifestations of vitreoretinal lymphoma (VRL). METHODS: Institutional case series in a single tertiary center. Patients with cytologically proven VRL, referred between November 2009 and May 2010, were retrospectively reviewed. Diagnosis of VRL was based on cytology of vitreous samples, immunohistochemistry, and molecular biology. Patients with confirmed VRL and clinical features different from the typical manifestations were included. Demographical and clinical characteristics of these patients were studied. RESULTS: Twelve cases of VRL were diagnosed. Four cases (2M/2F) were considered atypical (A-VRL) in their presentations. Mean age for typical lymphoma (T-VRL) was 71.9 years (range: 62-87 years); mean age for A VRL was 54 years (range: 50-59 years). CONCLUSIONS: Diagnosis of VRL is challenging and diagnostic delay is frequent. The authors describe a series of patients sharing common characteristics, such as a younger age (p = 0.05), severe anterior chamber reaction, mild or no vitritis, and possible fulminant evolution. PMID- 24475871 TI - CASPT2 study of inverse sandwich-type dinuclear Cr(I) and Fe(I) complexes of the dinitrogen molecule: significant differences in spin multiplicity and coordination structure between these two complexes. AB - Inverse sandwich-type complexes (ISTCs), (MU-N2)[M(AIP)]2 (AIPH = (Z)-1-amino-3 imino-prop-1-ene; M = Cr and Fe), were investigated with the CASPT2 method. In the ISTC of Cr, the ground state takes a singlet spin multiplicity. However, the singlet to nonet spin states are close in energy to each other. The thermal average of effective magnetic moments (MUeff) of these spin multiplicities is close to the experimental value. The eta(2)-side-on coordination structure of N2 is calculated to be more stable than the eta(1)-end-on coordination one. This is because the d-orbital of Cr forms a strong dpi-pi* bonding interaction with the pi* orbital of N2 in molecular plane. In the ISTC of Fe, on the other hand, the ground state takes a septet spin multiplicity, which agrees well with the experimentally reported MUeff value. The eta(1)-end-on structure of N2 is more stable than the eta(2)-side-on structure. In the eta(1)-end-on structure, two doubly occupied d-orbitals of Fe can form two dpi-pi* bonding interactions. The negative spin density is found on the bridging N2 ligand in the Fe complex but is not in the Cr complex. All these interesting differences between ISTCs of Cr and Fe are discussed on the basis of the electronic structure and bonding nature. PMID- 24475872 TI - GluN2D-containing NMDA receptors inhibit neurotransmission in the mouse striatum through a cholinergic mechanism: implication for Parkinson's disease. AB - The GluN2 subunits that compose NMDA receptors (NMDARs) determine functional and pharmacological properties of the receptor. In the striatum, functions and potential dysfunctions of NMDARs attributed to specific GluN2 subunits have not been clearly elucidated, although NMDARs play critical roles in the interactions between glutamate and dopamine. Through the use of amperometry and field potential recordings in mouse brain slices, we found that NMDARs that contain the GluN2D subunit contribute to NMDA-induced inhibition of evoked dopamine release and of glutamatergic neurotransmission in the striatum of control mice. Inhibition is likely mediated through increased firing in cholinergic interneurons, which were shown to express GluN2D. Indeed, NMDA-induced inhibition of both dopamine release and glutamatergic neurotransmission is reduced in the presence of muscarinic receptor antagonists and is mimicked by a muscarinic receptor agonist. We have also examined whether this function of GluN2D containing NMDARs is altered in a mouse model of Parkinson's disease. We found that the inhibitory role of GluN2D-containing NMDARs on glutamatergic neurotransmission is impaired in the 6-hydroxydopamine lesioned striatum. These results identify a role for GluN2D-containing NMDARs and adaptive changes in experimental Parkinsonism. GluN2D might constitute an attractive target for the development of novel pharmacological tools for therapeutic intervention in Parkinson's disease. PMID- 24475873 TI - SOX-10 and MiTF expression in cellular and 'mixed' neurothekeoma. AB - BACKGROUND: Neurothekeoma and nerve sheath myxoma have long been interpreted as related tumors that share nerve sheath linage. Lack of S100 expression in neurothekeoma and similarities of gene expression profiles between neurothekeoma and fibrohistiocytic tumors have created reasonable doubt about this concept. SOX 10 represents a marker for schwannian and melanocytic differentiation, and is expressed in other tumors of nerve sheath linage. Microphthalmia transcription factor (MiTF) expression has been repeatedly reported in cellular neurothekeoma in the recent literature and was proposed as a helpful marker in this entity. METHODS: We investigated 25 cases of cellular neurothekeoma, 8 cases of mixed neurothekeoma and 1 case of nerve sheath myxoma for the expression of SOX-10, MiTF, S100, NKI/C3, Melan-A and smooth muscle actin (SMA) using immunohistochemistry. RESULTS: A lack of SOX-10 expression was demonstrated in 100% of cellular and mixed neurothekeomas, but was present in the case of nerve sheath myxoma. More than two thirds of neurothekeomas showed very focal or no reactivity with MiTF. CONCLUSIONS: Our data suggest that neurothekeoma and nerve sheath myxoma are unrelated, and that cellular and mixed neurothekeoma may not be of nerve sheath lineage. In addition, MiTF should not be regarded as a useful marker in neurothekeoma. PMID- 24475874 TI - Species-specific differences in adaptive phenotypic plasticity in an ecologically relevant trophic trait: hypertrophic lips in Midas cichlid fishes. AB - The spectacular species richness of cichlids and their diversity in morphology, coloration, and behavior have made them an ideal model for the study of speciation and adaptive evolution. Hypertrophic lips evolved repeatedly and independently in African and Neotropical cichlid radiations. Cichlids with hypertrophic lips forage predominantly in rocky crevices and it has been hypothesized that mechanical stress caused by friction could result in larger lips through phenotypic plasticity. To test the influence of the environment on the size and development of lips, we conducted a series of breeding and feeding experiments on Midas cichlids. Full-sibs of Amphilophus labiatus (thick-lipped) and Amphilophus citrinellus (thin-lipped) each were split into a control group which was fed food from the water column and a treatment group whose food was fixed to substrates. We found strong evidence for phenotypic plasticity on lip area in the thick-lipped species, but not in the thin-lipped species. Intermediate phenotypic values were observed in hybrids from thick- and thin lipped species reared under "control" conditions. Thus, both a genetic, but also a phenotypic plastic component is involved in the development of hypertrophic lips in Neotropical cichlids. Moreover, species-specific adaptive phenotypic plasticity was found, suggesting that plasticity is selected for in recent thick lipped species. PMID- 24475875 TI - Controlling the growth of palladium aerogels with high-performance toward bioelectrocatalytic oxidation of glucose. AB - We report the controllable synthesis of Pd aerogels with high surface area and porosity by destabilizing colloidal solutions of Pd nanoparticles with variable concentrations of calcium ions. Enzyme electrodes based on Pd aerogels co immobilized with glucose oxidase show high activity toward glucose oxidation and are promising materials for applications in bioelectronics. PMID- 24475876 TI - A prediction model for the presence of axillary lymph node involvement in women with invasive breast cancer: a focus on older women. AB - Axillary lymph node (ALN) status at diagnosis is the most powerful prognostic indicator for patients with breast cancer. Our aim is to examine the contribution of variables that lead to ALN metastases in a large dataset with a high proportion of patients greater than 70 years old. Using the data from two multicenter prospective studies, a retrospective review was performed on 2,812 patients diagnosed with clinically node-negative invasive breast cancer from 1996 to 2005 and who underwent ALN sampling. Univariate and multivariate logistic regression were used to identify variables that were strongly associated with axillary metastases, and an equation was developed to estimate risk of ALN metastases. Of the 2,812 patients with invasive breast cancer, 18% had ALN metastases at diagnosis. Based on univariate analysis, tumor size, lymphovascular invasion (LVI), tumor grade, age at diagnosis, menopausal status, race, tumor location, tumor type, and estrogen and progesterone receptor status were statistically significant. The relationship between age and involvement of axillary metastases was nonlinear. In multivariate analysis, LVI, tumor size and menopausal status were the most significant factors associated with ALN metastases. Age, however, was not a significant contributing factor for axillary metastases. Tumor size, LVI, and menopausal status are strongly associated with ALN metastases. We believe that age may have been a strong factor in previous analyses because there was not an adequate representation of women in older age groups and because of the violation of the assumption of linearity in their multivariate analyses. PMID- 24475877 TI - Polyethylenimine-magadiite layered silicate sorbent for CO2 capture. AB - This paper describes the preparation of a Layered Silicate Sorbent (LSS) for CO2 capture using the layered silicate magadiite and organo-magadiite modified with polyethylenimine (PEI). The sorbents were characterized and revealed the presence of PEI as well as its interaction with CO2 at low temperatures. The thermal stability of sorbents was confirmed by thermogravimetry experiments, and the adsorption capacity was evaluated by CO2-TPD experiments. Two kinds of PEI are present in the sorbent, one exposed PEI layer that is responsible for higher CO2 adsorption because its sites are external and another one, bulky PEI, capable of low CO2 adsorption due to the internal position of sites. The contribution of the exposed PEI layer may be increased by a previous exchange of CTA(+), but the presence of the surfactant decreased the total adsorption capacity. MAG-PEI25 reached a maximum adsorption capacity of 6.11 mmol g(-1) at 75 degrees C for 3 h of adsorption and showed a kinetic desorption of around 15 min at 150 degrees C. PMID- 24475878 TI - Why lead methylammonium tri-iodide perovskite-based solar cells require a mesoporous electron transporting scaffold (but not necessarily a hole conductor). AB - CH3NH3PbI3-based solar cells were characterized with electron beam-induced current (EBIC) and compared to CH3NH3PbI(3-x)Clx ones. A spatial map of charge separation efficiency in working cells shows p-i-n structures for both thin film cells. Effective diffusion lengths, LD, (from EBIC profile) show that holes are extracted significantly more efficiently than electrons in CH3NH3PbI3, explaining why CH3NH3PbI3-based cells require mesoporous electron conductors, while CH3NH3PbI(3-Clx ones, where LD values are comparable for both charge types, do not. PMID- 24475879 TI - A combination of predispositions and exposures as responsible for acute eosinophilic pneumonia. AB - BACKGROUND: Acute eosinophilic pneumonia (AEP) is a rare febrile illness which is characterized by respiratory failure and often requires mechanical ventilation. The causes and sequence of events of this disease at a biochemical and histological level remain largely unknown. In this article we report the exceptional case, possibly unique, of a patient who developed AEP and three pneumothoraces within less than one month during her hospitalization. CASE PRESENTATION: A 39-year-old German woman was admitted to our hospital for a laparoscopy-assisted vaginal hysterectomy under general anaesthesia. The surgical intervention was followed by peritonitis in the early postoperative course. Following anaesthesia induction with propofol/midazolam and during the prolonged therapy with several broad-spectrum antibiotics, she developed AEP and three spontaneous (one left-sided and two right-sided) pneumothoraces, the latter ones observed in quick succession. Symptoms, laboratory markers, and chest radiology significantly improved after a one-day treatment with methylprednisolone. CONCLUSIONS: On the whole, these pathological occurrences, together with similar cases reported in literature, can support the conclusion of possible predisposing genetic factors at the lung tissue level of AEP patients, a view that might shed new light on the pathogenesis of this disease. To provide a coherent pattern that explains the reported evidence for AEP and pneumothoraces, independently from the causative stimulus, the supposed molecular mutations could be localized in the connective tissue rather than in the epithelial cells. In order to interpret clinical and laboratory evidence, as well as to support the main conclusions, the important part of scientific research here presented can also assist physicians in making more informed decisions for the treatment of patients with pulmonary infiltrates. PMID- 24475880 TI - A potential low-coumarin cinnamon substitute: Cinnamomum osmophloeum leaves. AB - The essential oils from leaves of Taiwan's indigenous cinnamon (Cinnamomum osmophloeum ct. cinnamaldehyde) have similar constituents as compared to that from commercial bark cinnamons. This indigenous cinnamon has been proven to have excellent bioactivities. To understand whether this indigenous cinnamon contains a high level of the hepatotoxic compound, coumarin, as often seen in Cassia cinnamons, current research focused on determining the coumarin content in this indigenous cinnamon and screening the low-coumarin clones. The results demonstrated that the coumarin contents in all tested indigenous cinnamon clones were much lower than that found in Cassia cinnamons. In addition, this indigenous cinnamon contains about 80% (w/w) of cinnamaldehyde and 0.4-2.7% (w/w) of eugenol in its leaf essential oils. This combination could provide this indigenous cinnamon a better shelf life compared to that of regular commercial cinnamons. These results suggested that leaves of this indigenous cinnamon could be a potential resource for a safer cinnamon substitute. PMID- 24475881 TI - Reproducibility patterns of multiple rapid swallows during high resolution esophageal manometry provide insights into esophageal pathophysiology. AB - BACKGROUND: Multiple rapid swallows (MRS) during esophageal high resolution manometry (HRM) assess esophageal neuromuscular integrity by evaluating postdeglutitive inhibition and rebound contraction, but most reports performed only a single MRS sequence. We assessed patterns of MRS reproducibility during clinical HRM in comparison to a normal cohort. METHODS: Consecutive clinical HRM studies were included if two separate MRS sequences (four to six rapid swallows <=4 s apart) were successfully performed. Chicago Classification diagnoses were identified; contraction wave abnormalities were additionally recorded. MRS induced inhibition (contraction <=3 cm during inhibition phase) and rebound contraction was assessed, and findings compared to 18 controls (28.0 +/- 0.7 year, 50.0% female). Reproducibility consisted of similar inhibition and contraction responses with both sequences; discordance was segregated into inhibition and contraction phases. KEY RESULTS: Multiple rapid swallows were successfully performed in 89.3% patients and all controls; 225 subjects (56.2 +/- 0.9 year, 62.7% female) met study inclusion criteria. Multiple rapid swallows were reproducible in 76.9% patients and 94.4% controls (inhibition phase: 88.0% vs 94.4%, contraction phase 86.7% vs 100%, respectively, p = ns). A gradient of reproducibility was noted, highest in well-developed motor disorders (achalasia spectrum, hypermotility disorders, and aperistalsis, 91.7-100%, p = ns compared to controls); and lower in lesser motor disorders (contraction wave abnormalities, esophageal body hypomotility) or normal studies (62.2-70.8%, p < 0.0001 compared to well-developed motor disorders). Inhibition phase was most discordant in contraction wave abnormalities, while contraction phase was most discordant when studies were designated normal. CONCLUSIONS & INFERENCES: Multiple rapid swallows are highly reproducible, especially in well-developed motor disorders, and complement the standard wet swallow manometry protocol. PMID- 24475882 TI - Evaluation of a Bochdalek diaphragmatic hernia rabbit model for pediatric thoracoscopic training. AB - BACKGROUND/AIM: This study evaluated the usefulness of a Bochdalek hernia rabbit model as a tool for advanced thoracoscopic training, teaching the specific skills required for thoracoscopic repair of congenital diaphragmatic hernia. MATERIALS AND METHODS: An incision was made in the Bochdalek triangle of 25 New Zealand rabbits (weighing 3-3.5 kg) to induce an experimental diaphragmatic hernia. At 72 hours later, a thoracoscopic repair of the hernia as described for newborns was performed by 25 pediatric surgeons divided into two groups: expert and novice. The tasks assessed were organ relocation and diaphragm suture. A visual analog scale was used to evaluate technical performance. The objective performance measure was completion time. Complications were recorded, and suture quality was scored. The surgeons evaluated the model by completing a questionnaire, grading items on a 5-point scale. RESULTS: All 25 animals developed a diaphragmatic hernia with protrusion of the intestine into the thoracic cavity. Expert trainees had significantly shorter completion times and better performance scores than novices. Experts also received higher scores for suture quality. Five novices caused perforations or bleeding, but no experts did. The surgeons rated the model positively, highlighting the similarities between the model and newborn hernias and its usefulness for pediatric training programs. CONCLUSIONS: The Bochdalek hernia rabbit model can be used to detect different levels of experience in pediatric thoracoscopy. This realistic and easily reproducible model can help to perfect thoracoscopic skills in a realistic recreation of a pediatric Bochdalek hernia repair. PMID- 24475883 TI - Laparoscopic ureterocystoplasty with Mitrofanoff system. AB - PURPOSE: To describe a laparoscopic surgical technique for ureterocystoplasty in pediatric patients with the Mitrofanoff procedure. PATIENTS AND METHODS: The procedure was performed in 4 patients (2 females and 2 males), 8-11 years old (average, 9.5 years), with a history of myelomeningocele and secondary neurogenic bladder. The patients were evaluated before the surgery with renal ultrasound, voiding cystourethrography, and renal scintigraphy. All subjects reported left hydronephrosis with severe dilatation of ureter and the collector system, left megaureter with grade V vesicoureteral reflux, and left functional exclusion, with right renal normal function. The urodynamic investigations revealed low bladder size and bladder leak point pressure (BLPP) above 40 cm H2O. The laparoscopic ureterocystoplasty augmentation procedure and the Mitrofanoff procedure with the proximal ureter were performed in these patients. Complications and outcomes were recorded and compared with those of the postoperative urodynamic test. RESULTS: The 2-4 years of follow-up of the patients and its urodynamic postoperative evaluation reported at least 75% of the capacity according to their age, compliance that varied between 15 to 20 mL/cm H2O, and a BLPP of less than 40 cm H2O. This last parameter is considered of low risk to damage the upper urinary tract. There was no leaking of urine by the stoma over the 4 hours of catheterization. CONCLUSIONS: Even though enterocystoplasty is the gold standard to increase the capacity of the neurogenic bladder, it has an elevated morbidity. So the use of a dilative ureter to increase bladder size and create a Mitrofanoff stoma in patients with neurogenic bladder, pop-off phenomenon, and renal ipsilateral atrophy could be considered by the laparoscopic approach. PMID- 24475884 TI - Laparoscopic-assisted percutaneous cecostomy for antegrade continence enema. AB - PURPOSE: The antegrade continence enema (ACE) is an option in the management of fecal incontinence and chronic constipation. We report our experience with a simple laparoscopic technique. SUBJECTS AND METHODS: Data were collected on 16 children (8 boys) who underwent laparoscopic cecostomy for ACE. Success was defined as cessation of fecal soiling with no need for diapers. RESULTS: Mean age at laparoscopic cecostomy was 11 years (range, 6-16 years). Mean follow-up after initial cecostomy was 22 months (range, 6-51 months). Diagnoses in 16 patients were functional constipation with soiling (n=14), incontinence after surgery for Hirschsprung's disease (n=1), and constipation secondary to mitochondrial disease (n=1). Seven had significant developmental or psychiatric problems. Three patients had primary placement of a trapdoor device (Chait); 13 had placement of a long tube, with later replacement by a skin-level device. We have evolved a laparoscopic-assisted percutaneous technique, using metallic anchor sutures on the cecum, and a dilator and peel-away sheath for introduction of the catheter. Complications occurred in 5 patients; 3 returned to the operating room: 1 for tube occlusion, 1 for suture granuloma, and 1 for a dislodged tube at 7 months postoperatively. One patient received intravenous antibiotics because of suspected peritonitis on the first postoperative day. One was re-admitted with abdominal pain. Five of 16 patients have failed therapy (four tubes removed and one tube in situ). Three have had only minor improvement. Eight have had successful ACE management, of whom 1 patient has had his tube removed after resolution of symptoms. Of 8 patients with no or minimal improvement with ACE, 5 have significant psychiatric problems. CONCLUSIONS: Laparoscopic-assisted percutaneous cecostomy has an excellent safety profile and patient comfort. The procedure is simple, secure, and reversible. Results were excellent in half of the patients. Associated psychiatric or behavioral problems may predict poor response to ACE. PMID- 24475885 TI - Cell-based method utilizing fluorescent Escherichia coli auxotrophs for quantification of multiple amino acids. AB - A cell-based assay system for simultaneous quantification of the three amino acids, phenylalanine (Phe), methionine (Met), and leucine (Leu) in a single biological sample, was developed and applied in the multiplex diagnosis of three key metabolic diseases of newborn babies. The assay utilizes three Escherichia coli auxotrophs, which grow only in the presence of the corresponding target amino acids and which contain three different fluorescent reporter plasmids that produce distinguishable fluorescence signals (red, green, and cyan) in concert with cell growth. To mixtures of the three auxotrophs, immobilized on agarose gels arrayed on a well plate, is added a test sample. Following incubation, the concentrations of the three amino acids in the sample are simultaneously determined by measuring the intensities of three fluorescence signals that correspond to the reporter plasmids. The clinical utility of this assay system was demonstrated by employing it to identify metabolic diseases of newborn babies through the quantification of Phe, Met, and Leu in clinically derived dried blood spot specimens. The general strategy developed in this effort should be applicable to the design of new assay systems for the quantification of multiple amino acids derived from complex biological samples and, as such, to expand the utilization of cell-based analytical systems that replace conventional, yet laborious methods currently in use. PMID- 24475886 TI - Retraction Statement. PMID- 24475887 TI - dsRNA-induced changes in gene expression profiles of primary nasal and bronchial epithelial cells from patients with asthma, rhinitis and controls. AB - BACKGROUND: Rhinovirus infections are the most common cause of asthma exacerbations. The complex responses by airway epithelium to rhinovirus can be captured by gene expression profiling. We hypothesized that: a) upper and lower airway epithelium exhibit differential responses to double-stranded RNA (dsRNA), and b) that this is modulated by the presence of asthma and allergic rhinitis. OBJECTIVES: Identification of dsRNA-induced gene expression profiles of primary nasal and bronchial epithelial cells from the same individuals and examining the impact of allergic rhinitis with and without concomitant allergic asthma on expression profiles. METHODS: This study had a cross-sectional design including 18 subjects: 6 patients with allergic asthma with concomitant rhinitis, 6 patients with allergic rhinitis, and 6 healthy controls. Comparing 6 subjects per group, the estimated false discovery rate was approximately 5%. RNA was extracted from isolated and cultured primary epithelial cells from nasal biopsies and bronchial brushings stimulated with dsRNA (poly(I:C)), and analyzed by microarray (Affymetrix U133+ PM Genechip Array). Data were analysed using R and the Bioconductor Limma package. Overrepresentation of gene ontology groups were captured by GeneSpring GX12. RESULTS: In total, 17 subjects completed the study successfully (6 allergic asthma with rhinitis, 5 allergic rhinitis, 6 healthy controls). dsRNA-stimulated upper and lower airway epithelium from asthma patients demonstrated significantly fewer induced genes, exhibiting reduced down regulation of mitochondrial genes. The majority of genes related to viral responses appeared to be similarly induced in upper and lower airways in all groups. However, the induction of several interferon-related genes (IRF3, IFNAR1, IFNB1, IFNGR1, IL28B) was impaired in patients with asthma. CONCLUSIONS: dsRNA differentially changes transcriptional profiles of primary nasal and bronchial epithelial cells from patients with allergic rhinitis with or without asthma and controls. Our data suggest that respiratory viruses affect mitochondrial genes, and we identified disease-specific genes that provide potential targets for drug development. PMID- 24475888 TI - Clinical guidelines for postpartum women and infants in primary care-a systematic review. AB - BACKGROUND: While many women and infants have an uneventful course during the postpartum period, others experience significant morbidity. Effective postpartum care in the community can prevent short, medium and long-term consequences of unrecognised and poorly managed problems. The use of rigorously developed, evidence-based guidelines has the potential to improve patient care, impact on policy and ensure consistency of care across health sectors. This study aims to compare the scope and content, and assess the quality of clinical guidelines about routine postpartum care in primary care. METHODS: PubMed, the National Guideline Clearing House, Google, Google Scholar and relevant college websites were searched for relevant guidelines. All guidelines regarding routine postpartum care published in English between 2002 and 2012 were considered and screened using explicit selection criteria. The scope and recommendations contained in the guidelines were compared and the quality of the guidelines was independently assessed by two authors using the AGREE II instrument. RESULTS: Six guidelines from Australia (2), the United Kingdom (UK) (3) and the United States of America (USA) (1), were included. The scope of the guidelines varied greatly. However, guideline recommendations were generally consistent except for the use of the Edinburgh Postnatal Depression Scale for mood disorder screening and the suggested time of routine visits. Some recommendations lacked evidence to support them, and levels or grades of evidence varied between guidelines. The quality of most guidelines was adequate. Of the six AGREE II domains, applicability and editorial independence scored the lowest, and scope, purpose and clarity of presentation scored the highest. CONCLUSIONS: Only one guideline provided comprehensive recommendations for the care of postpartum women and their infants. As well as considering the need for region specific guidelines, further research is needed to strengthen the evidence supporting recommendations made within guidelines. Further improvement in the editorial independence and applicability domains of the AGREE ll criteria would strengthen the quality of the guidelines. PMID- 24475889 TI - How to improve patient retention in an antiretroviral treatment program in Ethiopia: a mixed-methods study. AB - BACKGROUND: Patient retention, defined as continuous engagement of patients in care, is one of the crucial indicators for monitoring and evaluating the performance of antiretroviral treatment (ART) programs. It has been identified that suboptimal patient retention in care is one of the challenges of ART programs in many settings. ART programs have, therefore, been striving hard to identify and implement interventions that improve their suboptimal levels of retention. The objective of this study was to develop a framework for improving patient retention in care based on interventions implemented in health facilities that have achieved higher levels of retention in care. METHODS: A mixed-methods study, based on the positive deviance approach, was conducted in Ethiopia in 2011/12. Quantitative data were collected to estimate and compare the levels of retention in care in nine health facilities. Key informant interviews and focus group discussions were conducted to identify a package of interventions implemented in the health facilities with relatively higher or improving levels of retention. RESULTS: Retention in care in the Ethiopian ART program was found to be variable across health facilities. Among hospitals, the poorest performer had 0.46 (0.35, 0.60) times less retention than the reference; among health centers, the poorest performers had 0.44 (0.28, 0.70) times less retention than the reference. Health facilities with higher and improving patient retention were found to implement a comprehensive package of interventions: (1) retention promoting activities by health facilities, (2) retention promoting activities by community-based organizations, (3) coordination of these activities by case manager(s), and (4) patient information systems by data clerk(s). On the contrary, such interventions were either poorly implemented or did not exist in health facilities with lower retention in care. A framework to improve retention in care was developed based on the evidence found by applying the positive deviance approach. CONCLUSION: A framework for improving retention in care of patients on ART was developed. We recommend that health facilities implement the framework, monitor and evaluate their levels of retention in care, and, if necessary, adapt the framework to their own contexts. PMID- 24475890 TI - Transmission of Clostridium difficile spores in isolation room environments and through hospital beds. AB - The aim of this study was to determine the dissemination of Clostridium difficile (CD) spores in a hospital setting where the potassium monopersulfate-based disinfectant VirkonTM was used for cleaning. In the initial part of the study, we sampled 16 areas of frequent patient contact in 10 patient rooms where a patient with CD infection (CDI) had been accommodated. In the second part of the study, we obtained samples from 10 patient beds after discharge of CDI patients, both before and after the beds were cleaned. In the first part, CDspores were isolated in only 30% of the rooms. In the second part, which focused on transmission to hospital beds, C. difficile was found in four of 10 beds either before or after cleaning. In conclusion, in both parts of the study, we demonstrated a moderate spread of CD spores to the environment despite routine cleaning procedures involving VirkonTM. PMID- 24475891 TI - Ene-diene transmissive cycloaddition reactions with singlet oxygen: the vinylogous gem effect and its use for polyoxyfunctionalization of dienes. AB - The singlet oxygen reactivities and regioselectivities of the model compounds 1b d were compared with those of the geminal (gem) selectivity model ethyl tiglate (1a). The kinetic cis effect is k(E)/k(Z) = 5.2 for the tiglate/angelate system 1a/1a' without a change in the high gem regioselectivity. Further conjugation to vinyl groups enabled mode-selective processes, namely, [4 + 2] cycloadditions versus ene reactions. The site-specific effects of methylation on the mode selectivity and the regioselectivity of the ene reaction were studied for dienes 1e-g. A vinylogous gem effect was observed for the gamma,delta-dimethylated and alpha,gamma,delta-trimethylated substrates 1h and 1i, respectively. The corresponding phenylated substrates 1j-l showed similar mode selectivity, as monomethylated 1j exhibited exclusively [4 + 2] reactivity while the tandem products 12 and 14 were isolated from the di- and trimethylated substrates 1k and 1l, respectively. The vinylogous gem effect favors the formation of 1,3-dienes from the substrates, and thus, secondary singlet oxygen addition was observed to give hydroperoxy-1,2-dioxenes 19 and 20 in an ene-diene transmissive cycloaddition sequence. These products were reduced to give alcohols (16, 17, and 18) or furans (24 and 25), respectively, or treated with titanium(IV) alkoxides to give the epoxy alcohols 26 and 27. The vinylogous gem effect is rationalized by DFT calculations showing that biradicals are the low-energy intermediates and that no reaction path bifurcations compete. PMID- 24475892 TI - Retraction. Restoration of motor control and dopaminergic activity in rats with unilateral 6-hydroxy-dopamine lesions. PMID- 24475893 TI - Computational and technological innovations for epilepsy diagnosis and control. Introduction. PMID- 24475894 TI - Cortical excitability as a potential clinical marker of epilepsy: a review of the clinical application of transcranial magnetic stimulation. AB - Transcranial magnetic stimulation (TMS) can be used for safe, noninvasive probing of cortical excitability (CE). We review 50 studies that measured CE in people with epilepsy. Most showed cortical hyperexcitability, which can be corrected with anti-epileptic drug treatment. Several studies showed that decrease of CE after epilepsy surgery is predictive of good seizure outcome. CE is a potential biomarker for epilepsy. Clinical application may include outcome prediction of drug treatment and epilepsy surgery. PMID- 24475895 TI - On the midway to epilepsy: is cortical excitability normal in patients with isolated seizures? AB - Paired pulse transcranial magnetic stimulation was used to investigate differences in cortical excitability between patients with isolated (unrecurrent, unprovoked) seizures and those with epilepsy. Compared to controls, cortical excitability was higher in the isolated seizure group at 250-300 ms. Compared to epilepsy, cortical excitability was lower in patients with isolated seizures also at 250 and 300 ms. Lowered seizure threshold caused by disturbances within inhibitory circuits is present in patients who experience a seizure even if no further seizures occur. PMID- 24475896 TI - Dynamics of collective multi-stability in models of multi-unit neuronal systems. AB - In this study, we investigate the correspondence between dynamic patterns of behavior in two types of computational models of neuronal activity. The first model type is the realistic neuronal model; the second model type is the phenomenological or analytical model. In the simplest model set-up of two interconnected units, we define a parameter space for both types of systems where their behavior is similar. Next we expand the analytical model to two sets of 90 fully interconnected units with some overlap, which can display multi-stable behavior. This system can be in three classes of states: (i) a class consisting of a single resting state, where all units of a set are in steady state, (ii) a class consisting of multiple preserving states, where subsets of the units of a set participate in limit cycle, and (iii) a class consisting of a single saturated state, where all units of a set are recruited in a global limit cycle. In the third and final part of the work, we demonstrate that phase synchronization of units can be detected by a single output unit. PMID- 24475897 TI - The effect of high and low frequency cortical stimulation with a fixed or a poisson distributed interpulse interval on cortical excitability in rats. AB - Neurostimulation is a promising treatment for refractory epilepsy. We studied the effect of cortical stimulation with different parameters in the rat motor cortex stimulation model. High intensity simulation (threshold for motor response--100 MUA), high frequency (130 Hz) stimulation during 1 h decreased cortical excitability, irrespective of the interpulse interval used (fixed or Poisson distributed). Low intensity (10 MUA) and/or low frequency (5 Hz) stimulation had no effect. Cortical stimulation appears promising for the treatment of neocortical epilepsy if frequency and intensity are high enough. PMID- 24475898 TI - Computational modeling of transcranial direct current stimulation in the child brain: implications for the treatment of refractory childhood focal epilepsy. AB - Transcranial direct current stimulation (tDCS) was recently proposed for the treatment of epilepsy. However, the electrode arrangement for this case is debated. This paper analyzes the influence of the position of the anodal electrode on the electric field in the brain. The simulation shows that moving the anode from scalp to shoulder does influence the electric field not only in the cortex, but also in deeper brain regions. The electric field decreases dramatically in the brain area without epileptiform activity. PMID- 24475899 TI - Automated seizure detection using EKG. AB - Changes in heart rate, most often increases, are associated with the onset of epileptic seizures and may be used in lieu of cortical activity for automated seizure detection. The feasibility of this aim was tested on 241 clinical seizures from 81 subjects admitted to several Epilepsy Centers for invasive monitoring for evaluation for epilepsy surgery. The performance of the EKG-based seizure detection algorithm was compared to that of a validated algorithm applied to electrocorticogram (ECoG). With the most sensitive detection settings [threshold T: 1.15; duration D: 0 s], 5/241 seizures (2%) were undetected (false negatives) and with the highest [T: 1.3; D: 5 s] settings, the number of false negative detections rose to 34 (14%). The rate of potential false positive (PFP) detections was 9.5/h with the lowest and 1.1/h with the highest T, D settings. Visual review of 336 ECoG segments associated with PFPs revealed that 120 (36%) were associated with seizures, 127 (38%) with bursts of epileptiform discharges and only 87 (26%) were true false positives. Electrocardiographic (EKG)-based seizure onset detection preceded clinical onset by 0.8 s with the lowest and followed it by 13.8 s with the highest T, D settings. Automated EKG-based seizure detection is feasible and has potential clinical utility given its ease of acquisition, processing, high signal/noise and ergonomic advantages viz-a-viz EEG (electroencephalogram) or ECoG. Its use as an "electronic" seizure diary will remedy in part, the inaccuracies of those generated by patients/care-givers in a cost-effective manner. PMID- 24475900 TI - Tumor infiltrating B-cells are increased in prostate cancer tissue. AB - BACKGROUND: The presence of increased B-cell tumor infiltrating lymphocytes (TILs) was seen in mouse prostate cancer (PCa) but has not been fully documented in human PCa. We, therefore, investigated the density of infiltrating B cells within human PCa utilizing a quantitative computational method. METHODS: Archived radical prostatectomy specimens from 53 patients with known clinical outcome and D'Amico risk category were obtained and immunohistochemically (IHC) stained for the B cell marker, CD20. Slides were reviewed by a genitourinary pathologist who manually delineated the tumoral regions of PCa. Slides were digitally scanned and a computer algorithm quantified the area of CD20 stained B-cells as a measure of B cell density within the outlined regions of prostate cancer (intra-tumoral region), versus extra-tumoral prostate tissue. Correlations were analyzed between B-cell density and demographic and clinical variables, including D'Amico risk groups and disease recurrence. RESULTS: For the entire cohort, the mean intra tumoral B cell density was higher (3.22 SE = 0.29) than in the extra-tumoral region of each prostatectomy section (2.24, SE = 0.19) (paired t test; P < 0.001). When analyzed according to D'Amico risk group, the intra-tumoral B cell infiltration in low risk (0.0377 vs. 0.0246; p = 0.151) and intermediate risk (0.0260 vs. 0.0214; p = 0.579) patient prostatectomy specimens did not show significantly more B-cells within the PCa tumor. However, patient specimens from the high-risk group (0.0301 vs. 0.0197; p < 0.001) and from those who eventually had PCa recurrence or progression (0.0343 vs. 0.0246; p = 0.019) did show significantly more intra-tumoral CD20+ B-cell staining. Extent of B-cell infiltration in the prostatectomy specimens did not correlate with any other clinical parameters. CONCLUSIONS: Our study shows that higher B-cell infiltration was present within the intra-tumoral PCa regions compared to the extra-tumoral benign prostate tissue regions in prostatectomy sections. For this study we developed a new method to measure B-cells using computer-assisted digitized image analysis. Accurate, consistent quantitation of B-cells in prostatectomy specimens is essential for future clinical trials evaluating the effect of B cell ablating antibodies. The interaction of B-cells and PCa may serve as the basis for new therapeutic targets. PMID- 24475902 TI - The coevolutionary implications of host tolerance. AB - Host tolerance to infectious disease, whereby hosts do not directly "fight" parasites but instead ameliorate the damage caused, is an important defense mechanism in both plants and animals. Because tolerance to parasite virulence may lead to higher prevalence of disease in a population, evolutionary theory tells us that while the spread of resistance genes will result in negative frequency dependence and the potential for diversification, the evolution of tolerance is instead likely to result in fixation. However, our understanding of the broader implications of tolerance is limited by a lack of fully coevolutionary theory. Here we examine the coevolution of tolerance across a comprehensive range of classic coevolutionary host-parasite frameworks, including equivalents of gene for-gene and matching allele and evolutionary invasion models. Our models show that the coevolution of host tolerance and parasite virulence does not lead to the generation and maintenance of diversity through either static polymorphisms or through "Red-queen" cycles. Coevolution of tolerance may however lead to multiple stable states leading to sudden shifts in parasite impacts on host health. More broadly, we emphasize that tolerance may change host-parasite interactions from antagonistic to a form of "apparent commensalism," but may also lead to the evolution of parasites that are highly virulent in nontolerant hosts. PMID- 24475901 TI - Photodynamic therapy inhibits the formation of hypertrophic scars in rabbit ears by regulating metalloproteinases and tissue inhibitor of metalloproteinase-1. AB - BACKGROUND: Hypertrophic scarring (HS) is a chronic skin condition, and inhibition of normal fibroblast ageing plays an important role in its pathogenesis. Photodynamic therapy (PDT) is known to inhibit synthesis of collagen proliferation in blood vessels and fibroblasts in scar tissue, with no significant adverse reactions reported. AIM: To investigate the effect of PDT in the rabbit ear model of HS, and the specific mechanism of action of PDT. METHODS: We assessed the clinical and histopathological appearance of rabbit ears with HS with and without PDT. In addition, mRNA levels of matrix metalloproteinase (MMP) 2, MMP-3, MMP-9 and tissue inhibitor of metalloproteinase (TIMP)-1, and concentration of beta-galactose were all measured to confirm cell senescence. RESULTS: Our data indicate that PDT can accelerate fibroblast ageing by increasing the ratio of MMPs to TIMP, in addition to promoting degradation of collagen and extracellular matrix, thereby inhibiting HS formation. These effects lasted for up to 60 days, and induced no significant adverse local or systemic reactions. The efficacy of the treatment can be maximized by applying an appropriately high concentration of aminolaevulinic acid. CONCLUSIONS: PDT can induce senescence in fibroblasts, and may constitute a useful treatment for pathological scarring. PMID- 24475903 TI - Toward nanomolar detection by NMR through SABRE hyperpolarization. AB - SABRE is a nuclear spin hyperpolarization technique based on the reversible association of a substrate molecule and para-hydrogen (p-H2) to a metal complex. During the lifetime of such a complex, generally fractions of a second, the spin order of p-H2 is transferred to the nuclear spins of the substrate molecule via a transient scalar coupling network, resulting in strongly enhanced NMR signals. This technique is generally applied at relatively high concentrations (mM), in large excess of substrate with respect to metal complex. Dilution of substrate ligands below stoichiometry results in progressive decrease of signal enhancement, which precludes the direct application of SABRE to the NMR analysis of low concentration (MUM) solutions. Here, we show that the efficiency of SABRE at low substrate concentrations can be restored by addition of a suitable coordinating ligand to the solution. The proposed method allowed NMR detection below 1 MUM in a single scan. PMID- 24475904 TI - Correlation between HIF-1alpha expression and breast cancer risk: a meta analysis. PMID- 24475905 TI - All-nanowire based Li-ion full cells using homologous Mn2O3 and LiMn2O4. AB - We report an all-nanowire based flexible Li-ion battery full cell, using homologous Mn2O3 and LiMn2O4 nanowires for anodes and cathodes, respectively. The same precursors, MnOOH nanowires, are transformed from hydrothermally grown MnO2 nanoflakes and directly attached on Ti foils via reaction with poly(vinyl pyrrolidone). The Mn2O3 anode and LiMn2O4 cathode are subsequently formed by thermal annealing and reaction with lithium salt, respectively. The one dimensional nanowire structures provide short lithium-ion diffusion path, good charge transport, and volume flexibility for Li(+) intercalation/deintercalation, thus leading to good rate capability and cycling performance. As proof-of concept, the Mn2O3 nanowire anode delivers an initial discharge capacity of 815.9 mA h g(-1) at 100 mA g(-1) and maintains a capacity of 502.3 mA h g(-1) after 100 cycles. The LiMn2O4 nanowire cathodes show a reversible capacity of 94.7 mA h g( 1) at 100 mA g(-1) and high capacity retention of ~ 96% after 100 cycles. Furthermore, a flexible Mn2O3//LiMn2O4 lithium ion full cell is fabricated, with an output voltage of >3 V, low thickness of 0.3 mm, high flexibility, and a specific capacity of 99 mA h g(-1) based on the total weight of the cathode material. It also exhibits good cycling stability with a capacity of ~ 80 mA h g( 1) after 40 charge/discharge cycles. PMID- 24475906 TI - Differing asthma prevalence by gross national index of country of birth among New York City residents. AB - BACKGROUND: The hygiene hypothesis suggests that higher exposure to infectious agents may be one reason for regional differences in asthma. This would suggest that immigrants from less developed countries, where infections are more common, to highly developed countries will have lower risk of asthma compared with natives, as has been found in a number of studies. We expand the research on immigrants to look at the level of development in country of origin as a predictor of asthma in New York City residents. METHODS: Data came from the 2009 cross-sectional Community Health Survey. We used logistic regression to assess the relationship of country of birth and the gross national income (GNI), an indicator of the level of development, of country of birth with asthma among immigrants and US-born New York City residents. RESULTS: Those who were foreign born had lower odds of having asthma compared with those US born (OR = 0.43, P < 0.001). There was a dose relationship between GNI and asthma with decreasing odds of having asthma associated with lower GNI in country of birth (low GNI country: OR = 0.26, P = 0.014; middle GNI country: OR = 0.36, P < 0.001; and high GNI country = reference). CONCLUSIONS: These findings lend support to the hygiene hypothesis in that the odds of having asthma among New York City residents was lowest among people born in the least developed countries, as indicated by GNI, where infections are likely the most common. PMID- 24475907 TI - Review of risk factors for human echinococcosis prevalence on the Qinghai-Tibet Plateau, China: a prospective for control options. AB - OBJECTIVE: Echinococcosis is a major parasitic zoonosis of public health importance in western China. In 2004, the Chinese Ministry of Health estimated that 380,000 people had the disease in the region. The Qinghai-Tibet Plateau is highly co-endemic with both alveolar echinococcosis (AE) and cystic echinococcosis (CE). In the past years, the Chinese government has been increasing the financial support to control the diseases in this region. Therefore, it is very important to identify the significant risk factors of the diseases by reviewing studies done in the region in the past decade to help policymakers design appropriate control strategies. REVIEW: Selection criteria for which literature to review were firstly defined. Medline, CNKI (China National Knowledge Infrastructure), and Google Scholar were systematically searched for literature published between January 2000 and July 2011. Significant risk factors found by single factor and/or multiple factors analysis were listed, counted, and summarized. Literature was examined to check the comparability of the data; age and sex specific prevalence with same data structures were merged and used for further analysis.A variety of assumed social, economical, behavioral, and ecological risk factors were studied on the Plateau. Those most at risk were Tibetan herdsmen, the old and female in particular. By analyzing merged comparable data, it was found that females had a significant higher prevalence, and a positive linearity relationship existed between echinococcosis prevalence and increasing age. In terms of behavioral risk factors, playing with dogs was mostly correlated with CE and/or AE prevalence. In terms of hygiene, employing ground water as the drinking water source was significantly correlated with CE and AE prevalence. For definitive hosts, dog related factors were most frequently identified with prevalence of CE or/and AE; fox was a potential risk factor for AE prevalence only. Overgrazing and deforestation were significant for AE prevalence only. CONCLUSION: Tibetan herdsmen communities were at the highest risk of echinococcosis prevalence and should be the focus of echinococcosis control. Deworming both owned and stray dogs should be a major measure for controlling echinococcosis; treatment of wild definitive hosts should also be considered for AE endemic areas. Health education activities should be in concert with the local people's education backgrounds and languages in order to be able to improve behaviors. Further researches are needed to clarify the importance of wild hosts for AE/CE prevalence, the extent and range of the impacts of ecologic changes (overgrazing and deforestation) on the AE prevalence, and risk factors in Tibet. PMID- 24475908 TI - Nanoemulsion-based delivery systems for polyunsaturated (omega-3) oils: formation using a spontaneous emulsification method. AB - Nanoemulsion-based delivery systems are finding increasing utilization to encapsulate lipophilic bioactive components in food, personal care, cosmetic, and pharmaceutical applications. In this study, a spontaneous emulsification method was used to fabricate nanoemulsions from polyunsaturated (omega-3) oils, that is, fish oil. This low-energy method relies on formation of fine oil droplets when an oil/surfactant mixture is added to an aqueous solution. The influence of surfactant-to-oil ratio (SOR), oil composition (lemon oil and MCT), and cosolvent composition (glycerol, ethanol, propylene glycol, and water) on the formation and stability of the systems was determined. Optically transparent nanoemulsions could be formed by controlling SOR, oil composition, and aqueous phase composition. The spontaneous emulsification method therefore has considerable potential for fabricating nanoemulsion-based delivery systems for incorporating polyunsatured oils into clear food, personal care, and pharmaceutical products. PMID- 24475909 TI - Gene expression analysis in serial liver fine needle aspirates. AB - No method with low morbidity presently exists for obtaining serial hepatic gene expression measurements in humans. While hepatic fine needle aspiration (FNA) has lower morbidity than core needle biopsy, applicability is limited due to blood contamination, which confounds quantification of gene expression changes. The aim of this study was to validate FNA for assessment of hepatic gene expression. Liver needle biopsies and FNA procedures were simultaneously performed on 17 patients with chronic hepatitis C virus infection with an additional FNA procedure 1 week later. Nine patients had mild/moderate fibrosis and eight advanced fibrosis. Gene expression profiling was performed using Affymetrix microarrays and TaqMan qPCR; pathway analysis was performed using Ingenuity. We developed a novel strategy that applies liver-enriched normalization genes to determine the percentage of liver in the FNA sample, which enables accurate gene expression measurements overcoming biases derived from blood contamination. We obtained almost identical gene expression results (rho = 0.99, P < 0.0001) comparing needle biopsy and FNA samples for 21 preselected genes. Gene expression results were also validated in dogs. These data suggest that liver FNA is a reliable method for serial hepatic tissue sampling with potential utility for a variety of preclinical and clinical applications. PMID- 24475910 TI - Neutron-encoded mass signatures for quantitative top-down proteomics. AB - The ability to acquire highly accurate quantitative data is an increasingly important part of any proteomics experiment, whether shotgun or top-down approaches are used. We recently developed a quantitation strategy for peptides based on neutron encoding, or NeuCode SILAC, which uses closely spaced heavy isotope-labeled amino acids and high-resolution mass spectrometry to provide quantitative data. We reasoned that the strategy would also be applicable to intact proteins and could enable robust, multiplexed quantitation for top-down experiments. We used yeast lysate labeled with either (13)C6(15)N2-lysine or (2)H8-lysine, isotopologues of lysine that are spaced 36 mDa apart. Proteins having such close spacing cannot be distinguished during a medium resolution scan, but upon acquiring a high-resolution scan, the two forms of the protein with each amino acid are resolved and the quantitative information revealed. An additional benefit NeuCode SILAC provides for top down is that the spacing of the isotope peaks indicates the number of lysines present in the protein, information that aids in identification. We used NeuCode SILAC to quantify several hundred isotope distributions, manually identify and quantify proteins from 1:1, 3:1, and 5:1 mixed ratios, and demonstrate MS(2)-based quantitation using ETD. PMID- 24475911 TI - Launching genomics into the cloud: deployment of Mercury, a next generation sequence analysis pipeline. AB - BACKGROUND: Massively parallel DNA sequencing generates staggering amounts of data. Decreasing cost, increasing throughput, and improved annotation have expanded the diversity of genomics applications in research and clinical practice. This expanding scale creates analytical challenges: accommodating peak compute demand, coordinating secure access for multiple analysts, and sharing validated tools and results. RESULTS: To address these challenges, we have developed the Mercury analysis pipeline and deployed it in local hardware and the Amazon Web Services cloud via the DNAnexus platform. Mercury is an automated, flexible, and extensible analysis workflow that provides accurate and reproducible genomic results at scales ranging from individuals to large cohorts. CONCLUSIONS: By taking advantage of cloud computing and with Mercury implemented on the DNAnexus platform, we have demonstrated a powerful combination of a robust and fully validated software pipeline and a scalable computational resource that, to date, we have applied to more than 10,000 whole genome and whole exome samples. PMID- 24475913 TI - Direct (het)arylation of fluorinated benzothiadiazoles and benzotriazole with (het)aryl iodides. AB - A new and controllable method for the preparation of unsymmetrical and symmetrical fluorinated benzothiadiazole (FBT)-arene structures that can be applied in organic optoelectronic materials has been developed. The reaction proceeds under mild reaction conditions with high efficiency and shows excellent functional group compatibility, even toward bromide. Fluorinated benzotriazoles also take part in the reaction. PMID- 24475912 TI - In a maternity shared-care environment, what do we know about the paper hand-held and electronic health record: a systematic literature review. AB - BACKGROUND: The paper hand-held record (PHR) has been widely used as a tool to facilitate communication between health care providers and a pregnant woman. Since its inception in the 1950s, it has been described as a successful initiative, evolving to meet the needs of communities and their providers. Increasingly, the electronic health record (EHR) has dominated the healthcare arena and the maternity general practice shared-care arrangement seems to have adopted this initiative. A systematic review was conducted to determine perspectives of the PHR and the EHR with regards to data completeness; experiences of users and integration of care between women and health care providers. METHOD: A literature search was conducted that included papers from 1985 to 2012. Studies were chosen if they fulfilled the inclusion criteria, reporting on: data completeness; experiences of users and integration of care between women and health care providers. Papers were extracted by one reviewer in consultation with two reviewers with expertise in maternity e-health and independently assessed for quality. RESULTS: A total of 43 papers were identified for the review, from an initial 6,816 potentially relevant publications. No papers were found that reported on data completeness in a maternity PHR or a maternity EHR, in a shared-care setting. Women described the PHR as important to their antenatal care and had a generally positive perception of using an EHR. Hospital clinicians reported generally positive experiences using a PHR, while both positive and negative impressions were found using an EHR. The few papers describing the use of the PHR and EHR by community clinicians were also divergent and inconclusive with regards to their experiences. In a general practice shared care model, the PHR is a valuable tool for integration between the woman and the health care provider. While the EHR is an ideal initiative in the maternity setting, facilitating referrals and communication, there are issues of fragmentation and continued paper use. CONCLUSIONS: There was a surprising gap in knowledge surrounding data completeness on maternity PHRs or EHRs. There is also a paucity of available impressions from community clinicians using both forms of the records. PMID- 24475914 TI - Comparison of two laser capsulotomy techniques: cruciate versus circular. AB - PURPOSE: To compare the safety and efficacy of two Nd: YAG laser capsulotomy techniques. METHODS: In this prospective comparative interventional case series, 60 eyes of 57 patients with posterior capsular opacification were enrolled. Thirty eyes were selected to undergo a cruciate capsulotomy (Cross group) and the other 30 eyes were selected to undergo a circular capsulotomy (Circular group). Main outcome measures were best-corrected visual acuity (BCVA), intraocular pressure (IOP), amount of energy used, mean macular thickness (MMT), and floater symptoms. RESULTS: The amount of energy used was significantly higher in the Circular group than in the Cross group (p < 0.001). BCVA and IOP were not significantly different between the two groups at baseline or follow-up. MMT was significantly higher in the Circular group than in the Cross group at one day after the laser procedure (p = 0.032). MMT was not significantly different between groups at one week, one month, and three months (p > 0.05). The number of patients with floater symptoms was significantly higher in the Circular group than in the Cross group at one week and one month (p < 0.05). CONCLUSION: Both the cross-like and circular Nd:YAG laser capsulotomy techniques induce similar visual and IOP changes. The circular technique is associated with a higher amount of energy used, more floater symptoms, and has a greater effect on macular thickness at one day after laser capsulotomy. PMID- 24475915 TI - Orbital Emphysema Occurring During Weight Lifting. AB - Although orbital emphysema is a recognized complication of orbital fractures involving any of the paranasal sinuses, it may develop without any fracture. A 23 year-old man presented with sudden left periorbital swelling during weight lifting in a fitness facility. On the left side, there was periorbital swelling with crepitus in palpation of subcutaneous tissue and conjunctival congestion. Computed tomography showed no fractures in the orbit. The patient was hospitalized. He was treated with empiric antibiotics and non-steroidal antiinflammatory drugs. In three days, the swelling and crepitus had almost disappeared. Seven days later, orbital emphysema had completely resolved. PMID- 24475916 TI - CCDD Phenotype Associated with a Small Chromosome 2 Deletion. AB - PURPOSE: Some individuals are born with congenital limitation of ocular motility, often associated with ptosis and retraction of the globe. Many of these disorders are now known as the congenital cranial dysinnervation disorders (CCDDs). While several genes have been associated with CCDD phenotypes, there are still patients for whom the genetic basis has not been identified. METHODS: Clinical evaluation and neuroimaging, sequencing of candidate genes, and array comparative genomic hybridization (array CGH). RESULTS: The patient was a four-year-old girl with mild dysmorphism; bilateral mild ptosis; substantial limitation of abduction OS with milder limitations of abduction OD, adduction OS, and vertical gaze OS; and retraction OS > OD on attempted adduction. No mutations were detected in the HOXA1, KIF21A, SALL4, TUBB3, and CHN1 genes. Array CGH revealed a 8 Kb de novo deletion on chromosome 2 (2q24.3) that encompassed a portion of only one gene, the Xin Actin-binding Repeat containing 2 (Gene Symbol XIRP2; NM_001079810). This gene encodes a protein that is involved in muscle development and protecting actin filaments from depolymerization. It interacts functionally with 10 other proteins playing a similar role in muscle development. CONCLUSIONS: This patient's chromosomal abnormality affected only one gene that currently seems involved only in muscle development. All other genes currently associated with the CCDDs affect neurologic development. Genetic information from this patient implies that genes involved in development and maintenance of extraocular muscles can cause congenital ocular motility disorders as well. PMID- 24475917 TI - Orbital nerve seath myxoma with extraocular muscle involvement: a rare case. AB - A 66-year-old woman with breast cancer presented with a painless mass in the left orbit. MRI revealed a well-defined intraconal mass in the temporal quadrant of the orbit. Fifteen months later, a further MRI indicated the mass had grown, displacing the left optic nerve and making contact with the lateral rectus muscle, suggesting its possible intramuscular origin. Despite the clinical and radiological characteristics of the lesion and its slow growth, a PET/CT study was developed because of the history of malignant disease. No metabolic activity of the mass or malignant lesion in other locations was observed. After surgical excision, histopathological examination revealed an abundant myxoid matrix with few spindle-shaped cells and no signs of malignancy. The cells were immunopositive for CD34, positive for S-100 protein, and negative for EMA, actin, and CD57. A diagnosis was made of a nerve sheath myxoma. The orbital location of these tumors is extremely rare. PMID- 24475918 TI - Drug delivery to the back of the eye following topical administration: an update on research and patenting activity. AB - Drug delivery to the back of the eye following topical administration remains an unmet need for the scientific community. Treatment of posterior segment diseases requires localized and long-term drug delivery to the retina, choroid, and Bruch's membrane. Until the last decade, there was limited evidence from large clinical trials that demonstrated the usefulness of pharmacotherapy compared to laser therapy or other vitreoretinal surgical techniques for the treatment of retinal diseases. This paradigm has shifted in recent years, with strong evidence demonstrating superior efficacy of ophthalmic drugs compared to previous gold standards. However, ophthalmologists are left with no options other than administering the therapeutics via implants and intravitreal injections, which are highly invasive and associated with patient non-compliance. A non-invasive topical therapy would enhance patient compliance and minimize the side-effects associated with intraocular implants and intravitreal injections. In an attempt to enhance patient compliance, the focus of research has shifted to the development of novel small molecule-based eye drop formulations. This review article discusses the relevant patents and summarizes the resurgence in the treatment of posterior segment eye diseases through topical drug administration. PMID- 24475919 TI - Outbreak of an armA methyltransferase-producing ST39 Klebsiella pneumoniae clone in a pediatric Algerian Hospital. AB - Here we report an outbreak of Klebsiella pneumoniae infections harboring extended spectrum beta-lactamases (ESBL) and armA 16Sr RNA methylase that were detected in pediatric and neonatal intensive care units during the 2010 and 2011 surveys of 100 clinical strains of K. pneumoniae from Annaba hospitals in Algeria. Antibiotic susceptibility testing was performed using the disk diffusion method. Minimum inhibitory concentrations of three classes of antibiotics were determined using the E. test. Standard polymerase chain reaction amplification and sequencing were performed using primers targeting ESBL, 16S ribosomal RNA (rRNA) methyltransferases, aminoglycoside-modifying enzymes (AMEs), and quinolone encoding genes. Clonal relationships among the clinical isolates were performed using multilocus sequence typing. From our clinical isolates, we found high rates of antimicrobial resistance that were linked to the presence of different ESBL encoding genes and AMEs, including 23 strains that harbored several ESBL encoding genes along with the 16S rRNA methyltransferase armA. Among these isolates, we identified a cluster of eight isolates of the ST39 clone between February and June 2010 in a pediatric ward, suggesting that an outbreak had occurred during this period. In conclusion, the emergence of multidrug-resistant clones, which were likely responsible for a nosocomial outbreak, is worrying because there are already limited options in those critical situations. Finally, we believe that surveillance should be implemented to monitor the risk of emergence and spread of carbapenemases in Algeria. PMID- 24475920 TI - Fulminant neonatal sepsis due to Streptococcus alactolyticus - A case report and review. AB - Group D streptococci have rarely been associated with neonatal infections. We report a case of fulminant respiratory distress syndrome (RDS) caused by Streptococcus alactolyticus in a term neonate. Gram staining revealed gram positive cocci and culture grew group D streptococci in samples taken from trachea, ear, and nasopharynx. Streptococcus alactolyticus was identified using automated microbial identification system (Vitek 2). Histopathology showed massive pulmonary inflammation with intra-alveolar granulocytosis and secondary pulmonary bleeding as etiology of fatal outcome. To our knowledge, this is first case presenting neonatal infection caused by Streptococcus alactolyticus. PMID- 24475921 TI - Disentangling the contribution of sexual selection and ecology to the evolution of size dimorphism in pinnipeds. AB - The positive relationship between sexual size dimorphism (SSD) and harem size across pinnipeds is often cited as a textbook example of sexual selection. It assumes that female aggregation selected for large male size via male-male competition. Yet, it is also conceivable that SSD evolved prior to polygyny due to ecological forces. We analyzed 11 life-history traits in 35 pinniped species to determine their coevolutionary dynamics and infer their most likely evolutionary trajectories contrasting these two hypotheses. We find support for SSD having evolved prior to changes in the mating system, either as a consequence of niche partitioning during aquatic foraging or in combination with sexual selection on males to enforce copulations on females. Only subsequently did polygyny evolve, leading to further coevolution as the strength of sexual selection intensified. Evolutionary sequence analyses suggest a polar origin of pinnipeds and indicate that SSD and polygyny are intrinsically linked to a suite of ecological and life-history traits. Overall, this study calls for the inclusion of ecological variables when studying sexual selection and argues for caution when assuming causality between coevolving traits. It provides novel insights into the role of sexual selection for the coevolutionary dynamics of SSD and mating system. PMID- 24475923 TI - Plasmonic and photonic scattering and near fields of nanoparticles. AB - We theoretically compare the scattering and near field of nanoparticles from different types of materials, each characterized by specific optical properties that determine the interaction with light: metals with their free charge carriers giving rise to plasmon resonances, dielectrics showing zero absorption in wide wavelength ranges, and semiconductors combining the two beforehand mentioned properties plus a band gap. Our simulations are based on Mie theory and on full 3D calculations of Maxwell's equations with the finite element method. Scattering and absorption cross sections, their division into the different order electric and magnetic modes, electromagnetic near field distributions around the nanoparticles at various wavelengths as well as angular distributions of the scattered light were investigated. The combined information from these calculations will give guidelines for choosing adequate nanoparticles when aiming at certain scattering properties. With a special focus on the integration into thin film solar cells, we will evaluate our results. PMID- 24475922 TI - The effect of empagliflozin on arterial stiffness and heart rate variability in subjects with uncomplicated type 1 diabetes mellitus. AB - BACKGROUND: Individuals with type 1 diabetes mellitus are at high risk for the development of hypertension, contributing to cardiovascular complications. Hyperglycaemia-mediated neurohormonal activation increases arterial stiffness, and is an important contributing factor for hypertension. Since the sodium glucose cotransport-2 (SGLT2) inhibitor empagliflozin lowers blood pressure and HbA1c in type 1 diabetes mellitus, we hypothesized that this agent would also reduce arterial stiffness and markers of sympathetic nervous system activity. METHODS: Blood pressure, arterial stiffness, heart rate variability (HRV) and circulating adrenergic mediators were measured during clamped euglycaemia (blood glucose 4-6 mmol/L) and hyperglycaemia (blood glucose 9-11 mmol/L) in 40 normotensive type 1 diabetes mellitus patients. Studies were repeated after 8 weeks of empagliflozin (25 mg once daily). RESULTS: In response to empagliflozin during clamped euglycaemia, systolic blood pressure (111 +/- 9 to 109 +/- 9 mmHg, p = 0.02) and augmentation indices at the radial (-52% +/- 16 to -57% +/- 17, p = 0.0001), carotid (+1.3 +/- 1 7.0 to -5.7 +/- 17.0%, p < 0.0001) and aortic positions (+0.1 +/- 13.4 to -6.2 +/- 14.3%, p < 0.0001) declined. Similar effects on arterial stiffness were observed during clamped hyperglycaemia without changing blood pressure under this condition. Carotid-radial pulse wave velocity decreased significantly under both glycemic conditions (p <= 0.0001), while declines in carotid-femoral pulse wave velocity were only significant during clamped hyperglycaemia (5.7 +/- 1.1 to 5.2 +/- 0.9 m/s, p = 0.0017). HRV, plasma noradrenalin and adrenaline remained unchanged under both clamped euglycemic and hyperglycemic conditions. CONCLUSIONS: Empagliflozin is associated with a decline in arterial stiffness in young type 1 diabetes mellitus subjects. The underlying mechanisms may relate to pleiotropic actions of SGLT2 inhibition, including glucose lowering, antihypertensive and weight reduction effects. TRIAL REGISTRATION: CLINICAL TRIAL REGISTRATION: NCT01392560. PMID- 24475924 TI - Caprice/MISP is a novel F-actin bundling protein critical for actin-based cytoskeletal reorganizations. AB - Caprice [C19orf21 actin-bundling protein in characteristic epithelial cells, also called mitotic interactor and substrate of Plk1 (MISP)] is a novel actin-related protein identified in the highly-insoluble subcellular scaffold proteins. This protein contains multiple actin-binding sites, forms characteristic mesh-like F actin bundles in vitro, and exhibits capricious localization and expression patterns in vivo. Overexpression or knock-down of Caprice resulted in a dramatic effect on cellular morphology by inducing stress fiber-like thick filaments or filopodial formations, respectively. Caprice is expressed and localized in distinct cells and tissues with specialized actin-based structures, such as growth cones of migrating neurons and stereocilia of inner ear hair cells. However, Caprice gene expression is varied among different cell types; especially enriched in several epithelial cells whereas relatively suppressed in a subset of epithelial cells, fibroblasts, and neuroblastoma cells at the transcriptional level. Thus, this protein is expected to be an effector for cell type-specific actin reorganization with its direct actin-binding properties and provides a novel model of cell morphology regulation by a non-ubiquitous single actin bundling protein. PMID- 24475925 TI - Structure and inhibition of tuberculosinol synthase and decaprenyl diphosphate synthase from Mycobacterium tuberculosis. AB - We have obtained the structure of the bacterial diterpene synthase, tuberculosinol/iso-tuberculosinol synthase (Rv3378c) from Mycobacterium tuberculosis , a target for anti-infective therapies that block virulence factor formation. This phosphatase adopts the same fold as found in the Z- or cis prenyltransferases. We also obtained structures containing the tuberculosinyl diphosphate substrate together with one bisphosphonate inhibitor-bound structure. These structures together with the results of site-directed mutagenesis suggest an unusual mechanism of action involving two Tyr residues. Given the similarity in local and global structure between Rv3378c and the M. tuberculosis cis decaprenyl diphosphate synthase (DPPS; Rv2361c), the possibility exists for the development of inhibitors that target not only virulence but also cell wall biosynthesis, based in part on the structures reported here. PMID- 24475926 TI - Inhibition of major drug metabolizing CYPs by common herbal medicines used by HIV/AIDS patients in Africa-- implications for herb-drug interactions. AB - The purpose of this study was to evaluate the potential risk of common herbal medicines used by HIV-infected patients in Africa for herb-drug interactions (HDI). High throughput screening assays consisting of recombinant Cytochrome P450 enzymes (CYPs) and fluorescent probes, and parallel artificial membrane permeability assays (PAMPA) were used. The potential of herbal medicines to cause HDI was ranked according to FDA guidelines for reversible inhibition and categorization of time dependent inhibition was based on the normalized ratio. CYPs 1A2 and 3A4 were most inhibited by the herbal extracts. H. hemerocallidea (IC50 = 0.63 ug/mL and 58 ug/mL) and E. purpurea (IC50 = 20 ug/mL and 12 ug/mL) were the potent inhibitors of CYPs 1A2 and 3A4 respectively. L. frutescens and H. hemerocallidea showed clear time dependent inhibition on CYP3A4. Furthermore, the inhibitory effect of both H. hemerocallidea and L. frutescens before and after PAMPA were identical. The results indicate potential HDI of H. hemerocallidea, L. frutescens and E. purpurea with substrates of the affected enzymes if maximum in vivo concentration is achieved. PMID- 24475927 TI - Kinetics of bromochloramine formation and decomposition. AB - Batch experiments were performed to study the kinetics of bromochloramine formation and decomposition from the reaction of monochloramine and bromide ion. The effects of pH, initial monochloramine and bromide ion concentrations, phosphate buffer concentration, and excess ammonia were evaluated. Results showed that the monochloramine decay rate increased with decreasing pH and increasing bromide ion concentration, and the concentration of bromochloramine increased to a maximum before decreasing gradually. The maximum bromochloramine concentration reached was found to decrease with increasing phosphate and ammonia concentrations. Previous models in the literature were not able to capture the decay of bromochloramine, and therefore we proposed an extended model consisting of reactions for monochloramine autodecomposition, the decay of bromamines in the presence of bromide, bromochloramine formation, and bromochloramine decomposition. Reaction rate constants were obtained through least-squares fitting to 11 data sets representing the effect of pH, bromide, monochloramine, phosphate, and excess ammonia. The reaction rate constants were then used to predict monochloramine and bromochloramine concentration profiles for all experimental conditions tested. In general, the modeled lines were found to provide good agreement with the experimental data under most conditions tested, with deviations occurring at low pH and high bromide concentrations. PMID- 24475928 TI - geneCommittee: a web-based tool for extensively testing the discriminatory power of biologically relevant gene sets in microarray data classification. AB - BACKGROUND: The diagnosis and prognosis of several diseases can be shortened through the use of different large-scale genome experiments. In this context, microarrays can generate expression data for a huge set of genes. However, to obtain solid statistical evidence from the resulting data, it is necessary to train and to validate many classification techniques in order to find the best discriminative method. This is a time-consuming process that normally depends on intricate statistical tools. RESULTS: geneCommittee is a web-based interactive tool for routinely evaluating the discriminative classification power of custom hypothesis in the form of biologically relevant gene sets. While the user can work with different gene set collections and several microarray data files to configure specific classification experiments, the tool is able to run several tests in parallel. Provided with a straightforward and intuitive interface, geneCommittee is able to render valuable information for diagnostic analyses and clinical management decisions based on systematically evaluating custom hypothesis over different data sets using complementary classifiers, a key aspect in clinical research. CONCLUSIONS: geneCommittee allows the enrichment of microarrays raw data with gene functional annotations, producing integrated datasets that simplify the construction of better discriminative hypothesis, and allows the creation of a set of complementary classifiers. The trained committees can then be used for clinical research and diagnosis. Full documentation including common use cases and guided analysis workflows is freely available at http://sing.ei.uvigo.es/GC/. PMID- 24475929 TI - Effects of organic and conventional management of sugar cane crop on soil physicochemical characteristics and phosphomonoesterase activity. AB - Soil enzymes play an important role in agriculture and particularly in nutrient cycling. They are also involved in the degradation, transformation, and mineralization of organic matter and availability of nutrients in soil. It is believed that organic agriculture causes fewer losses to soil quality and is less aggressive to the environment than conventional management. In this study, the effects of conventional (CM) and organic management (OM) on phosphomonoesterases, an important enzyme for soil fertility, were evaluated and compared to those results from native Cerrado (Brazilian Savanna) soil (NS), because they are the most common phosphatases in soils. The results showed that there were both acid (AcP) and alkaline (AkP) phosphatases in all soils tested and that AcP activity was higher than that of AkP. In contrast to AkP, AcP had its activity affected by land use. In the cultivated areas there was a reduction of almost 50% of AcP activity respect to native unexploited soils and there was no significant difference between organic and CM, demonstrating that independent of the management chosen, there was an impact of land use on AcP activity. Principal component analysis indicated that characteristics related to pH such as alkali saturation (V%), aluminum saturation (M%), Al(3+), soil total acidity (H+Al), and Ca(2+) are the main factors that permit distinguishing NS from OM and CM. PMID- 24475930 TI - Soft Tissues Changes After Immediate and Delayed Single Implant Placement in Esthetic Area: A Systematic Review. AB - The aim of the present study was to conduct a systematic review of the literature to compare soft tissue aspects of immediate and delayed implant placement in esthetic areas. This review of literature was conducted in the following databases: MEDLINE (PubMed), Lilacs, Scielo, EMBASE, and Cochrane Central Register of Controlled Trials (CENTRAL). For those studies that met the inclusion/exclusion criteria, the results were analyzed and summarized according to the treatment protocol used for implant placement. The primary parameters taken into consideration were papilla level (PL) and marginal mucosa level (MML) around implants. Four randomized controlled trials (RCT) were selected for analysis, but all were deemed as being of poor quality according to quality assessment. No studies reported any statistically significant differences concerning the soft tissue esthetic parameters analyzed around immediate or delayed implants at any follow-up periods reported. However, PL results seemed to be more reliable than were MML results, due to the PL standardization of the method of analysis, which showed a tendency for poorer results around immediately placed implants. In conclusion, although the results are based on only a few poor quality RCTs, both treatment options for implant placement demonstrated similar outcomes in the esthetic area, especially when PL was considered. PMID- 24475931 TI - Quantitative analysis by surface plasmon resonance of CD28 interaction with cytoplasmic adaptor molecules Grb2, Gads and p85 PI3K. AB - CD28 surface receptors provide co-stimulatory signals that are required for full T cell activation. The CD28 cytoplasmic region has one YMNM and two PXXP motifs as a functional motif. Upon CD28 ligation, Grb2, Gads, and the p85 subunit of PI3 kinase are recruited to the CD28 cytoplasmic region. Here, the interactions between these adaptor proteins and CD28 cytoplasmic domains were analyzed using a Biacore surface plasmon resonance biosensor. For all three adaptor proteins, entire molecules bound more tightly to CD28 than did their isolated SH2 domains. For each adaptor, different outcomes of mutation of CD28's PXXP motifs on binding affinity indicated that only the SH3 domain of Grb2 bound directly. Regarding binding of SH2s to CD28, the SH2 domains of p85 bound more strongly than those of both Grb2 and Gads. Since intact p85 had a 50-fold higher binding affinity than its fragments, and yet the p85-CD28 interaction does not involve SH3-PXXP binding, binding of both N-terminal and C-terminal SH2s to YMNM may create an "avidity" effect. In contrast, when Grb2 and Gads interact with CD28, binding of their SH3 domains may be important. These results suggest that all these interactions are multivalent, through both SH2 and SH3 domains. PMID- 24475932 TI - The study of Nickel Resistant Bacteria (NiRB) isolated from wastewaters polluted with different industrial sources. AB - BACKGROUND: Pollution due to the heavy metals is a problem that may have negative consequences on the hydrosphere. One of the best procedures in removing the toxic metals from the environment is using metal resistant bacteria. RESULTS: In the present study eight nickel resistant bacteria were isolated from industrial wastewaters. Three of them were selected as the most resistant based on their Maximum tolerable concentration (8, 16 and 24 mM Ni2+). Their identification was done according to morphological, biochemical characteristics and 16SrDNA gene sequencing and they were identified as Cupriavidus sp ATHA3, Klebsiella oxytoca ATHA6 and Methylobacterium sp ATHA7. The accession numbers assigned to ATHA3, ATHA6 and ATHA7 strains are JX120152, JX196648 and JX457333 respectively. The Growth rate of the most resistant isolate, Klebsiella oxytoca strain ATHA6, in the presence of Ni2+ and the reduction in Ni2+ concentration was revealed that K oxytoca ATHA6 could decrease 83 mg/mL of nickel from the medium after 3 days. CONCLUSION: It can be concluded that the identified Ni resistant bacteria could be valuable for the bioremediation of Ni polluted waste water and sewage. PMID- 24475933 TI - Prevalence and risk factors of atopic eczema in Turkish adolescents. AB - Atopic eczema (AE) is the most common childhood inflammatory skin condition. The aim of this study was to evaluate the prevalence of AE and its relation to various risk factors. In a cross-sectional study, 9,991 children ages 13 to 14 years in 61 primary schools in 32 districts of Istanbul were evaluated. The prevalence of AE and associated symptoms was assessed using the International Study of Asthma and Allergies in Childhood protocol. The relationship between risk factors and AE was evaluated using multivariate logistic regression analysis. Ten thousand nine hundred eighty-four questionnaires were distributed to 13- and 14-year-old children in 61 schools in 32 districts of Istanbul, 9,991 of which were suitable for analysis, for an overall response rate of 91.7%. There were 4,746 boys (47.9%) and 5,166 girls (52.1%) (M/F ratio 0.920). The rates of itchy rash ever, 12-month itchy rash, and doctor-diagnosed AE ever were 18.2%, 12.0%, and 2.8%, respectively. The difference between rates for itchy rash ever, 12-month itchy rash and doctor-diagnosed AE was high (12.8-31.3, 5.8-24.8, and 0 17.2, respectively) between the districts of Istanbul. Female sex, AE family history, watching television more than 5 hours a day, region of the district, and tonsillectomy history were found to be significantly associated with doctor diagnosed AE at p < 0.05 in multivariate analysis. This study found a low prevalence of doctor-diagnosed AE and related symptoms in Istanbul. Several risk factors were found to be associated with doctor-diagnosed AE. PMID- 24475934 TI - Wired pyrroloquinoline quinone soluble glucose dehydrogenase enzyme electrodes operating at unprecedented low redox potential. AB - We report unprecedented high current densities for the enzymatic oxidation of glucose already at 0 V versus Ag/AgCl. The modified electrodes were made by assembling pyrroloquinoline quinone (PQQ)-soluble glucose dehydrogenase (PQQ sGDH) from Acinetobacter calcoaceticus with osmium-based redox polymers and a cross-linker. Both redox mediators are made of a poly(4-vinylpyridine) (PVP) polymer with Os complexes tethered to the polymer backbone via long C chains, giving the Os complexes flexibility and mobility inside the redox hydrogels. Current densities larger than 1 mA cm(-2) were measured already below 0 V with a plateau value of 4.4 mA cm(-2). Similar hydrogel electrodes comprising the same redox polymers and glucose oxidase (GOx) showed less than half the current densities of the PQQ-sGDH electrodes. The current versus potential curve dependence showed a sigmoidal shape characteristic of mediated enzyme catalysis but with a current increase versus potential less sharp than expected. Surprisingly, the midwave redox potential was positively shifted with respect to the potential of the redox mediator. PMID- 24475936 TI - Information practices of health care professionals related to patient discharge from hospital. AB - OBJECTIVE: To investigate the practices of hospital professionals in providing information to patients and to professionals in primary care at patient discharge from hospital. METHODS: We used a qualitative methodology with individual face-to face interviews with 22 hospital physicians and nurses. RESULTS: We identified two themes in the information practices of health care professionals at patient discharge from hospital: (i) producing information in parallel processes and (ii) challenges in tailoring information to different recipients. CONCLUSION: Hospital routines and professional norms prescribing that discharge information should take place in parallel processes by hospital physicians and by nurses impede transparency and interdisciplinary coordination in primary care. A strong focus on providing patients only with information that is tailored for them neglects the interest patients may have in seeing what information about them is transmitted to primary care. PRACTICE IMPLICATIONS: Hospital routines and professional culture are important factors to consider in efforts to promote more transparent health care for patients and improved interdisciplinary communication. This is not only a matter of attitudes in the individual health care professional. In the development of solutions for electronic exchange of information in health care, all these factors should be taken into account. PMID- 24475935 TI - Evidence-based practice in Behcet's disease: identifying areas of unmet need for 2014. AB - BACKGROUND: Behcet's Disease (BD) is characterized by a relapsing-remitting course, with symptoms of varying severity across almost all organ systems. There is a diverse array of therapeutic options with no universally accepted treatment regime, and it is thus important that clinical practice is evidence-based. We reviewed all currently available literature describing management of BD, and investigated whether evidence-based practice is possible for all disease manifestations, and assessed the range of therapeutic options tested. METHODS: We conducted an internet search of all literature describing management of BD up to August 2013, including pharmacological and non-pharmacological interventions. We recorded treatment options investigated and disease manifestations reported as primary and secondary study outcomes. Quality of data was assessed according to the Scottish Intercollegiate Guideline Network (SIGN) hierarchy of evidence. RESULTS: Whilst there is much literature describing treatment of ocular and mucocutaneous disease, there is little to guide management of rheumatoid, cardiovascular and neurological disease. This broadly reflects the prevalence of disease manifestations of BD, but not the severity. Biologic therapies are the most commonly investigated intervention. The proportion of SIGN-1 graded studies is declining, and there are no SIGN-1 graded studies investigating neurological or gastrointestinal manifestations of BD. CONCLUSIONS: This is the first study to investigate trends in published literature for management of BD over time. It identifies neurological, cardiovascular and gastro-intestinal disease as particular areas of unmet need and suggests that overall quality of evidence is declining. Future research should be designed to address these areas of insufficiency to facilitate evidence-based practice in BD. PMID- 24475937 TI - Characteristics of patients seeking health information online via social health networks versus general Internet sites: a comparative study. AB - BACKGROUND: Camoni.co.il, a Hebrew-language social health network offers advice, consultation, and connection to others with chronic illness. This study compared characteristics and objectives of Camoni.co.il users and individuals seeking medical information through general Internet sites. METHODS: Similar questionnaires were sent to 1009 Internet and 900 Camoni users. Cluster analysis defined four modes of online social health network use: "acquiring information and support", "communicating", "networking" and "browsing". RESULTS: Six hundred and five Internet and 125 Camoni users responded. Diabetes, hypertension, obesity and lung diseases were found more often among general Internet users than Camoni users. Among Camoni users, "acquiring information and support" was the main motivation for individuals over age 55 years, women, those with lower income, chronic pain, obesity and depression. "Communicating" was the main incentive of men, those 20-34 years old, those with less education, or an eating disorder. "Networking" was the most significant motivation for those with multiple sclerosis or depression. Browsing was most frequent among individuals with multiple sclerosis. CONCLUSIONS: Identifying needs of social health network surfers will allow planning unique contents and enhancing social health sites. Physicians might advise patients to use them to obtain support and information regarding their conditions, possibly leading to improved compliance and self management. PMID- 24475938 TI - In situ and quantitative characterization of solid electrolyte interphases. AB - Despite its importance in dictating electrochemical reversibility and cell chemistry kinetics, the solid electrolyte interphase (SEI) on graphitic anodes remains the least understood component in Li ion batteries due to its trace presence, delicate chemical nature, heterogeneity in morphology, elusive formation mechanism, and lack of reliable in situ quantitative tools to characterize it. This work summarizes our systematic approach to understand SEI live formation, via in situ electrochemical atomic force microscopy, which provides topographic images and quantitative information about the structure, hierarchy, and thickness of interphases as function of electrolyte composition. Complemented by an ex situ chemical analysis, a comprehensive and dynamic picture of interphase formation during the first lithiation cycle of the graphitic anode is described. This combined approach provides an in situ and quantitative tool to conduct quality control of formed interphases. PMID- 24475939 TI - Microneedling for varicella scars in a dark-skinned teenager. PMID- 24475940 TI - Evolution of phenotype-environment associations by genetic responses to selection and phenotypic plasticity in a temporally autocorrelated environment. AB - Covariation between population-mean phenotypes and environmental variables, sometimes termed a "phenotype-environment association" (PEA), can result from phenotypic plasticity, genetic responses to natural selection, or both. PEAs can potentially provide information on the evolutionary dynamics of a particular set of populations, but this requires a full theoretical characterization of PEAs and their evolution. Here, we derive formulas for the expected PEA in a temporally fluctuating environment for a quantitative trait with a linear reaction norm. We compare several biologically relevant scenarios, including constant versus evolving plasticity, and the situation in which an environment affects both development and selection but at different time periods. We find that PEAs are determined not only by biological factors (e.g., magnitude of plasticity, genetic variation), but also environmental factors, such as the association between the environments of development and of selection, and in some cases the level of temporal autocorrelation. We also describe how a PEA can be used to estimate the relationship between an optimum phenotype and an environmental variable (i.e., the environmental sensitivity of selection), an important parameter for determining the extinction risk of populations experiencing environmental change. We illustrate this ability using published data on the predator-induced morphological responses of tadpoles to predation risk. PMID- 24475941 TI - Detection and characterization of viruses of the genus Megalocytivirus in ornamental fish imported into an Australian border quarantine premises: an emerging risk to national biosecurity. AB - This report documents an emerging trend of identification of Megalocytivirus-like inclusions in a range of ornamental fish species intercepted during quarantine detention at the Australian border. From September 2012 to February 2013, 5 species of fish that had suffered mortality levels in excess of 25% whilst in the post-entry quarantine and had Megalocytivirus-like inclusion bodies in histological sections were examined by PCR. The fish had been imported from Singapore, Malaysia and Sri Lanka. Ninety-seven of 111 individual fish from affected tanks of fish tested were positive for the presence of Megalocytivirus by PCR. Sequence analysis of representative PCR products revealed an identical sequence of 621 bp in all cases which was identical to a previously characterized Megalocytivirus (Sabah/RAA1/2012 strain BMGIV48). Phylogenetic analysis of available Megalocytivirus major capsid protein (MCP) sequences confirmed the existence of 3 major clades of Megalocytivirus. The virus detected in this study was identified as a member of Genotype II. The broad host range and pathogenicity of megalocytiviruses, coupled to the documented spread of ornamental fish into the environment, render this a significant and emerging biosecurity threat to Australia. PMID- 24475942 TI - Critical role of Frizzled1 in age-related alterations of Wnt/beta-catenin signal in myogenic cells during differentiation. AB - Activation of Wnt/beta-catenin signal in muscle satellite cells (mSCs) of aged mice during myogenic differentiation has been appreciated as an important age related feature of the skeletal muscles, resulting in impairment of their regenerative ability following muscle injury. However, it remains elusive about molecules involved in this age-related alteration of Wnt/beta-catenin signal in myogenic cells. To clarify this issue, we carried out expression analyses of Wnt receptor genes using real-time RT-PCR in mSCs isolated from the skeletal muscles of young and aged mice. Here, we show that expression of Frizzled1 (Fzd1) was detected at high levels in mSCs of aged mice. Higher expression levels of Fzd1 were also detected in mSC-derived myogenic cells from aged mice and associated with activation of Wnt/beta-catenin signal during their myogenic differentiation in vitro. We also provide evidence that suppressed expression of Fzd1 in myogenic cells from aged mice results in a significant increase in myogenic differentiation, and its forced expression in those from young mice results in its drastic inhibition. These findings indicate the critical role of Fzd1 in altered myogenic differentiation associated with aging. PMID- 24475943 TI - Microbiology of hidradenitis suppurativa (acne inversa): a histological study of 27 patients. AB - Hidradenitis suppurativa (acne inverse) (HS) is a chronic skin disease primarily affecting hair follicles. The aetiology of HS is unknown, but infection is believed to play some role. This retrospective study investigated the microbial colonization directly in skin appendices in HS skin samples. Archival samples from 27 patients with HS were screened by immunofluorescence labelling with monoclonal and polyclonal antibodies against Gram-positive bacteria, Propionibacterium acnes and Propionibacterium granulosum. Fluorescence in situ hybridization was used for further species identification of Staphylococcus spp. Overall, 17 patients (63%) were found positive for bacterial colonization. Of these, 15 showed colonization in hair follicles and/or sinus tracts. The most commonly identified bacteria were DAPI labelled coccoids that were seen in 71% of the positive patients in the form of biofilms and microcolonies. P. acnes was found as biofilms in hair follicles of two patients. Staphylococcus aureus and coagulase-negative staphylococci were not detected in any sample. The results of this study indicate a common bacterial presence in HS skin lesions. Bacterial biofilms are not uncommon and their pathogenic role needs further evaluation. PMID- 24475945 TI - The patents on glucocorticosteroids and selected new therapies for the management of asthma in children: update. AB - Despite the continuous increase in the prevalence of asthma in many developing countries, there have been major advances in understanding and managing this disease. The remarkable role of inflammation in asthma is well known. Current asthma guidelines recommend the use of anti-inflammatory drugs and immunotherapy for long-term management of asthma. The management of asthma in children is a challenge because of their inability to express warning signs and seek medical attention in a timely manner. Unlike adults, asthmatic children must rely on their parents or caregivers for the administration of asthma medications. The inability to carry and self-administer asthma drugs may increase the risk of non compliance. Glucocorticosteroids, the most important drugs for patients with asthma, are associated with an increased level of side effects and compliance issues mostly in children. In an attempt to solve that dilemma, emphasis is being placed on the modification of current management tactics and the introduction of other drugs. This review presents more recent patents for childhood asthma therapies for the management of asthma in children. PMID- 24475944 TI - The Nightingale study: rationale, study design and baseline characteristics of a prospective cohort study on shift work and breast cancer risk among nurses. AB - BACKGROUND: Evidence for the carcinogenicity of shift work in humans is limited because of significant heterogeneity of the results, thus more in-depth research in needed. The Nightingale Study is a nationwide prospective cohort study on occupational exposures and risks of chronic diseases among female nurses and focuses on the potential association between shift work and risk of breast cancer. The study design, methods, and baseline characteristics of the cohort are described. METHODS/DESIGN: The source population for the cohort comprised 18 to 65 year old women who were registered as having completed training to be a nurse in the nationwide register for healthcare professionals in the Netherlands. Eligible women were invited to complete a web-based questionnaire including full job history, a detailed section on all domains of shift work (shift system, cumulative exposure, and shift intensity) and potential confounding factors, and an informed consent form for linkage with national (disease) registries. Women were also asked to donate toenail clippings as a source of DNA for genetic analyses. Between October 6, 2011 and February 1, 2012, 31% of the 192,931 women who were invited to participate completed the questionnaire, yielding a sample size of 59,947 cohort members. The mean age of the participants was 46.9 year (standard deviation 11.0 years). Toenail clippings were provided by 23,439 participants (39%). DISCUSSION: Results from the Nightingale Study will contribute to the scientific evidence of potential shift work-related health risks among nurses and will help develop preventive measures and policy aimed at reducing these risks. PMID- 24475946 TI - Regioselective C2 sulfonylation of indoles mediated by molecular iodine. AB - A facile and general method for regioselective C2 sulfonylation reaction of indoles mediated by iodine is described. The 2-sulfonylated products were obtained up to 96% yield under mild reaction conditions (room temperature, 2 h). PMID- 24475947 TI - Optical absorption of dilute nitride alloys using self-consistent Green's function method. AB - We have calculated the optical absorption for InGaNAs and GaNSb using the band anticrossing (BAC) model and a self-consistent Green's function (SCGF) method. In the BAC model, we include the interaction of isolated and pair N levels with the host matrix conduction and valence bands. In the SCGF approach, we include a full distribution of N states, with non-parabolic conduction and light-hole bands, and parabolic heavy-hole and spin-split-off bands. The comparison with experiments shows that the first model accounts for many features of the absorption spectrum in InGaNAs; including the full distribution of N states improves this agreement. Our calculated absorption spectra for GaNSb alloys predict the band edges correctly but show more features than are seen experimentally. This suggests the presence of more disorder in GaNSb alloys in comparison with InGaNAs. PMID- 24475949 TI - Amorphous FeOOH oxygen evolution reaction catalyst for photoelectrochemical water splitting. AB - Reaching the goal of economical photoelectrochemical (PEC) water splitting will likely require the combination of efficient solar absorbers with high activity electrocatalysts for the hydrogen and oxygen evolution reactions (HER and OER). Toward this goal, we synthesized an amorphous FeOOH (a-FeOOH) phase that has not previously been studied as an OER catalyst. The a-FeOOH films show activity comparable to that of another OER cocatalyst, Co-borate (Co-Bi), in 1 M Na2CO3, reaching 10 mA/cm(2) at an overpotential of ~550 mV for 10 nm thick films. Additionally, the a-FeOOH thin films absorb less than 3% of the solar photons (AM1.5G) with energy greater than 1.9 eV, are homogeneous over large areas, and act as a protective layer separating the solution from the solar absorber. The utility of a-FeOOH in a realistic system is tested by depositing on amorphous Si triple junction solar cells with a photovoltaic efficiency of 6.8%. The resulting a-FeOOH/a-Si devices achieve a total water splitting efficiency of 4.3% at 0 V vs RHE in a three-electrode configuration and show no decrease in efficiency over the course of 4 h. PMID- 24475948 TI - Nonalcoholic fatty pancreatic disease and cardio-metabolic risk: is there is a place for obstructive sleep apnea? AB - BACKGROUND: Obstructive sleep apnea is a common disorder acting as a risk factor for the development and progression of cardiometabolic derangements including non alcoholic fatty liver disease. Recent research data suggest that non-alcoholic fatty pancreatic disease may be a more sensitive marker than non-alcoholic fatty liver disease for early subclinical metabolic risk and may contribute to the progression of subclinical disease to overt type 2 diabetes mellitus. PRESENTATION OF THE HYPOTHESIS: We postulate that obstructive sleep apnea may be a risk factor for non-alcoholic fatty pancreatic disease. It is well known that intermittent hypoxia related to obstructive sleep apnea leads to hormonal derangements. Excessive lipolysis, enhanced lipid synthesis and systemic and local inflammation may favor ectopic fat deposition similarly to non-alcoholic fatty liver disease. Furthermore, it is possible that obstructive sleep apnea can lead to pancreatic beta cell damage via intermittent hypoxia. TESTING OF THE HYPOTHESIS: Future research should focus on the following: first, whether non alcoholic fatty pancreatic disease is an independent risk factor for the development of metabolic disease including diabetes mellitus or is a simple consequence of obesity; second, the prevalence of non-alcoholic fatty pancreatic disease among people with obstructive sleep apnea and vice versa, which should be compared to the prevalence of these diseases in general population; third, whether coexistence of these conditions is related to greater cardiometabolic risk than either disease alone; and fourth, whether the treatment of obstructive sleep apnea will translate into the resolution of non-alcoholic fatty pancreatic disease. IMPLICATIONS OF THE HYPOTHESIS: If proven, this hypothesis will provide new knowledge on the complex interplay between various metabolic insults. Second, screening for NAFPD may identify individuals at risk for developing type 2 diabetes mellitus for targeted prevention. Third, screening for the presence of non-alcoholic fatty pancreatic disease in patients with obstructive sleep apnea may help to decrease the incidence of diabetes mellitus through a targeted prevention. PMID- 24475950 TI - Maximizing Kolmogorov Complexity for accurate and robust bright field cell segmentation. AB - BACKGROUND: Analysis of cellular processes with microscopic bright field defocused imaging has the advantage of low phototoxicity and minimal sample preparation. However bright field images lack the contrast and nuclei reporting available with florescent approaches and therefore present a challenge to methods that segment and track the live cells. Moreover, such methods must be robust to systemic and random noise, variability in experimental configuration, and the multiple unknowns in the biological system under study. RESULTS: A new method called maximal-information is introduced that applies a non-parametric information theoretic approach to segment bright field defocused images. The method utilizes a combinatorial optimization strategy to select specific defocused images from each image stack such that set complexity, a Kolmogorov complexity measure, is maximized. Differences among these selected images are then applied to initialize and guide a level set based segmentation algorithm. The performance of the method is compared with a recent approach that uses a fixed defocused image selection strategy over an image data set of embryonic kidney cells (HEK 293T) from multiple experiments. Results demonstrate that the adaptive maximal-information approach significantly improves precision and recall of segmentation over the diversity of data sets. CONCLUSIONS: Integrating combinatorial optimization with non-parametric Kolmogorov complexity has been shown to be effective in extracting information from microscopic bright field defocused images. The approach is application independent and has the potential to be effective in processing a diversity of noisy and redundant high throughput biological data. PMID- 24475951 TI - Chemical characterization by GC-MS and in vitro activity against Candida albicans of volatile fractions prepared from Artemisia dracunculus, Artemisia abrotanum, Artemisia absinthium and Artemisia vulgaris. AB - BACKGROUND: A large number of essential oils is reported to have significant activity against Candida albicans. But the different chemical composition influences the degree of their activity. The intention of this study was to investigate the chemical composition and the activity against Candida albicans of volatile oils obtained from Artemisia dracunculus, A. abrotanum, A. absinthium and A. vulgaris (Asteraceae). The aim of the study was to identify new chemical compounds that have effect against C. albicans.The essential oils were obtained by hydrodistillation or extraction with dichloromethane (a new procedure we developed trying to obtain better, more separated compounds) from air dried above ground plant material and analyzed by GC-MS. Additionally commercial essential oils from the same species were tested. The Candida albicans inhibition studies were carried out by the paper disc diffusion method. RESULTS: The essential oils shared common components but presented differences in composition and showed variable antifungal activity. Davanone and derivatives thereof, compounds with silphiperfolane skeleton, estragole, davanone oil, beta-thujone, sabinyl acetate, herniarin, cis-chrysanthenyl acetate, 1,8-cineol, and terpineol were the main components of Artemisia volatiles. CONCLUSIONS: Among the volatile fractions tested those from A. abrotanum containing davanone or silphiperfolane derivatives showed the highest antifungal activity. The in vitro tests revealed that the Artemisia oils are promising candidates for further research to develop novel anti-candida drugs. PMID- 24475952 TI - Incidence and etiology of community-acquired pneumonia in the elderly in a prospective population-based study. AB - BACKGROUND: We conducted a prospective population-based epidemiological study to prepare a setting for documentation of the efficacy of novel vaccines against pneumococcal (Pnc) community-acquired pneumonia (CAP) in the elderly. Specific objectives were to demonstrate setting feasibility, to construct a case definition for Pnc CAP, and to estimate its incidence. METHODS: We prospectively enrolled patients with clinical and radiological findings compatible with CAP at municipal on-call clinics serving an elderly population (age >= 65 y) of approximately 29,500. Sputum, urine, nasopharyngeal swab (NPS), and blood samples were analyzed using diverse methods for the identification of Pnc (culture, PCR, antigen tests, serology) and of other pathogens. The following case definition for Pnc CAP was derived: encapsulated Pnc in blood culture or in high-quality sputum culture or at least 2 of the following: positive urine Pnc antigen; >= 2 fold increase in serum anti-PsaA or anti-CbpA antibodies; encapsulated Pnc culture or LytA PCR in either sputum or NPS. RESULTS: We enrolled 490 clinical CAP patients during the 2-y follow-up, 53% of all clinical CAP patients in the source population; 323 were radiologically confirmed. The incidence of radiologically confirmed CAP was 5.5/1000 person-y (95% confidence interval (CI) 4.9-6.1) and 10.5/1000 person-y when adjusted for non-captured patients. The proportion of radiologically confirmed CAP caused by Pnc was estimated at 17%; i.e. 0.95/1000 person-y (95% CI 0.7-1.2) and 1.8 when adjusted for non-captured patients. CONCLUSIONS: We developed and documented a feasible methodology for capturing endpoints in a vaccine trial for the prevention of pneumonia. CAP incidence in the elderly population remains considerable and Streptococcus pneumoniae was one of the most commonly detected causative agents. PMID- 24475953 TI - CO2 adsorption thermodynamics over N-substituted/grafted graphanes: a DFT study. AB - This work examines CO2 adsorption over various N-substituted/grafted graphanes to identify the promotional effects of various N-functionalities have on the adsorption characteristics using DFT. CO2 adsorbs weakly on a graphane surface functionalized with a single, isolated substituted N- or grafted NH2-sites. The presence of coadsorbed H2O on the surface promotes CO2 adsorption on both N- and NH2-sites, with highly exothermic adsorption energies (~-50 kJ mol(-1)). Directly grafted -NH2 or -OH functional groups on C atoms adjacent to C atoms which have a -NH2 group grafted suffer from geometrical restrictions preventing dual stabilization of formed carbamate upon adsorption of CO2. CO2 adsorption can be greatly enhanced with the presence of a -OH group or second -NH2 group in the proximity of a -NH2 site on graphane, and only if a n(-CH2-) (n >= 1) linker is introduced between the -NH2 or -OH and graphane surface (adsorption energies of 58.8 or -43.1 kJ mol(-1) at n = 2). The adsorption mechanistics provided by DFT can be used to guide the atomic-level rational design of N-based graphane and carbon adsorbents for CO2 capture. PMID- 24475955 TI - A gap in the medical curriculum. PMID- 24475954 TI - Effects of combined UV and chlorine treatment on the formation of trichloronitromethane from amine precursors. AB - The objective of this study was to investigate the effects of combined low pressure ultraviolet (LPUV) irradiation and free chlorination on the formation of trichloronitromethane (TCNM) byproduct from amine precursors, including a commonly used polyamine coagulant aid (poly(epichlorohydrin dimethylamine)) and simple alkylamines dimethylamine (DMA) and methylamine (MA). Results showed that TCNM formation can increase up to 15 fold by combined UV/chlorine under disinfection to advanced oxidation conditions. The enhancement effect is influenced by UV irradiance, chlorine dose, and water pH. Extended reaction time leads to the decay of TCNM by direct photolysis. The combined UV/chlorine conditions significantly promoted degradation of polyamine to generate intermediates, including DMA and MA, which are better TCNM precursors than polyamine, and also facilitated transformation of these amine precursors to TCNM. Under combined UV/chlorine, polyamine degradation was likely promoted by radical oxidation, photodecay of chlorinated polyamine, and chlorine oxidation/substitution. Promoted TCNM formation from primary amine MA was primarily due to radicals' involvement. Promoted TCNM formation from secondary amine DMA likely involved a combination of radical oxidation, photoenhanced chlorination reactions, and other unknown mechanisms. Insights obtained in this study are useful for reducing TCNM formation during water treatment when both UV and chlorine will be encountered. PMID- 24475956 TI - How to... Improve Handouts. AB - This article examines the conditions under which handouts should be used for instruction, reviews their various uses and suggests some guidelines for their construction. We have based our evaluation on our own varied experiences, together with the published findings of investigations into the efficacy of handouts as aids to instruction. We hope that this article will be of interest to inexperienced medical teachers who are experimenting with different approaches to instruction, as well as to more experienced teachers, who may find it valuable to compare such experiences. In addition, a structured evaluation of any teaching aids which draw on medical school funds is particularly useful in the face of financial cut backs, as at present. PMID- 24475957 TI - The way we Teach... Cost Containment. AB - With the spiralling cost of medical care in industrialized nations, it is vital that physicians should be aware of the cost of the care they provide. Students, it is suggested, should be made aware of cost considerations before forming definitive conceptions of 'appropriate' medical behaviours. This article describes the cost containment curriculum currently operating at the Medical School of Ohio. PMID- 24475958 TI - Controversy : objections to objectives. PMID- 24475960 TI - Letters. PMID- 24475959 TI - Controversy : for the use of objectives. AB - "A detailed, realistic and behavioural statement of objectives is needed if we are to be able to have any reasonable expectation that our courses are going to have the effect on our students that we want them to" (Simpson, 1972). "Without an explicit set of goals and specifications, the curriculum is primarily an artistic expression of its maker" (Bloom, et al. 1971). "Clear statements of expected educational outcomes enable the teacher to plan his teaching, and the student can direct his studies and assess his progress more readily" (Wyn Pughetal. 1975). PMID- 24475961 TI - My Medical Education : Its Relevance to my Career. PMID- 24475962 TI - Issues in nurse education : the learner as worker. AB - Nurses training for a statutory qualification in the UK (other than those on degree programmes) are employees of the National Health Service. Unlike their counterparts in Canada, as described by Professor Kergin in the May/June 1980 issue of Medical Teacher, they undergo an 'apprenticeship type' education. This might appear to be an ideal situation for learners, allowing good correlation of theory with practice, and for nurse tutors-who are also NHS employees-since it should give them easy access to learning situations. Unfortunately, this is not always so: ward teaching by qualified ward staff is frequently the latter's last priority, learners see their service commitment and the well-being of the patient as their prime concern, and nurse tutors may lack clinical expertise and credibility. The learner as worker is not an ideal situation, and the combined management responsibility for service and education may produce more problems than it solves. PMID- 24475963 TI - Original research : after-hours calls: a forgotten item of education in family practice. AB - After-hours care is an essential ingredient of family practice and other primary care disciplines. In various countries, between three and 70 per cent of all after hours calls are handled over the telephone without the patient being seen. Little medical education is provided to train medical students or physicians to deal with clinical problems that are more frequent after surgery hours and with communication and decisionmaking over the telephone. An after-hours record card, developed by the authors, has been used over the past three years for clinical care and educational activities. PMID- 24475964 TI - Educational instruments : Arizona clinical interview medical rating scale. AB - In this series we will be printing evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to use or adapt such instruments for your own purposes. The feature in this issue has been prepared by Paula L. Stillman, MD, Coordinator, Preparation for Clinical Medicine, The University of Arizona Health Sciences Center, Tucson, Arizona 85724, from whom further information is available. We would welcome the submission of other educational instruments from experienced educators for publication in Medical Teacher. PMID- 24475965 TI - The new schools : the medical school of the university of brasilia. AB - The keynotes of the University of Brasilia medical education programme are the flexible system of registration, the integrated study programme, community orientation and student choice and self-pacing. While the programme is not without its problems, a measure of its effectiveness is the proportion of graduates choosing a career in general care medicine (general practice, paediatrics, internal medicine, and obstetrics/gynaecology). Among the 1978 graduates the percentage who made general care medicine their career choice (60 per cent) was double the number who had stated this preference before the medical learning experience. PMID- 24475968 TI - A 3.5 V lithium-iodine hybrid redox battery with vertically aligned carbon nanotube current collector. AB - A lithium-iodine (Li-I2) cell using the triiodide/iodide (I3(-)/I(-)) redox couple in an aqueous cathode has superior gravimetric and volumetric energy densities (~ 330 W h kg(-1) and ~ 650 W h L(-1), respectively, from saturated I2 in an aqueous cathode) to the reported aqueous Li-ion batteries and aqueous cathode-type batteries, which provides an opportunity to construct cost-effective and high-performance energy storage. To apply this I3(-)/I(-) aqueous cathode for a portable and compact 3.5 V battery, unlike for grid-scale storage as general target of redox flow batteries, we use a three-dimensional and millimeter thick carbon nanotube current collector for the I3(-)/I(-) redox reaction, which can shorten the diffusion length of the redox couple and provide rapid electron transport. These endeavors allow the Li-I2 battery to enlarge its specific capacity, cycling retention, and maintain a stable potential, thereby demonstrating a promising candidate for an environmentally benign and reusable portable battery. PMID- 24475969 TI - Effect of E-beam treatment on the chemistry and on the antioxidant activity of lycopene from dry tomato peel and tomato powder. AB - Tomato powder (TP) and dry tomato peel (DTP) have been previously used in our laboratory as a source of lycopene to manufacture meat products ready-to-eat (RTE) submitted to E-beam irradiation with good technological and sensory results. Present work describes the studies performed in order to investigate the effect of radiation on chemical changes and antioxidant properties of lycopene. DTP and TP were irradiated (4 kGy). Changes on lycopene were analyzed by HPLC; inhibition of reactive oxygen species (ROS), possible modulation of mitogen activated protein kinases (MAPK) cascade, nuclear factor kappa-light-chain enhancer of activated B cells (NP-kappaB) activation and expression of proteins involved in oxidation stress were analyzed in RAT-1 fibroblasts cell culture. Radiation reduced the content of all-E-lycopene and increased (Z)-lycopene, lycopene isomerization, and degradation being higher in DTP than in TP. E-Beam treatment increased the antioxidant ability of both DTP and TP in inhibiting spontaneous and H2O2-induced oxidative stress in cultured fibroblasts. Antioxidant activity was higher in DTP than in TP samples. PMID- 24475970 TI - Induced temperature gradients to examine groundwater flowpaths in open boreholes. AB - Techniques for characterizing the hydraulic properties and groundwater flow processes of aquifers are essential to design hydrogeologic conceptual models. In this study, rapid time series temperature profiles within open-groundwater wells in fractured rock were measured using fiber optic distributed temperature sensing (FO-DTS). To identify zones of active groundwater flow, two continuous electrical heating cables were installed alongside a FO-DTS cable to heat the column of water within the well and to create a temperature difference between the ambient temperature of the groundwater in the aquifer and that within the well. Additional tests were performed to examine the effects of pumping on hydraulic fracture interconnectivity around the well and to identify zones of increased groundwater flow. High- and low-resolution FO-DTS cable configurations were examined to test the sensitivities of the technique and compared with downhole video footage and geophysical logging to confirm the zones of active groundwater flow. Two examples are presented to demonstrate the usefulness of this new technique for rapid characterization of fracture zones in open boreholes. The combination of the FO-DTS and heating cable has excellent scope as a rapid appraisal tool for borehole construction design and improving hydrogeologic conceptual models. PMID- 24475971 TI - Infectious salmon anaemia - pathogenesis and tropism. AB - Infectious salmon anaemia (ISA) is a serious disease of farmed Atlantic salmon caused by the aquatic orthomyxovirus infectious salmon anaemia virus (ISAV). ISA was first detected in Norway in 1984 and was characterized by severe anaemia and circulatory disturbances. This review elucidates factors related to the pathogenesis of ISA in Atlantic salmon, the dissemination of the virus in the host and the general distribution of the 4-O-acetylated sialic acids ISAV receptor. The knowledge contributes to the understanding of this disease, and why, almost 30 years after the first detection, it is still causing problems for the aquaculture industry. PMID- 24475972 TI - Single-crystalline, ultrathin ZnGa(2)O(4) nanosheet scaffolds to promote photocatalytic activity in CO(2) reduction into methane. AB - Uniform hierarchical microspheres scaffolded from ultrathin ZnGa2O4 nanosheets with over 99% exposed facets were synthesized using an easy solvothermal route with ethylenediamine (en)/H2O binary solvents. Substitution of different chain length amines for en results in no formation of the nanosheet structures, indicating that the molecular structure of En is indispensable for the generation of two-dimensional structures. Inheriting both a high surface area of nanosheets and a high crystallinity of bulky materials allows the unique 3D hierarchical nanostructures to possess great CO2 photocatalytic performance. The normalized time-resolved traces of photo-induced absorption recorded from the nanosheet and meso-ZnGa2O4 indicate that the photo-excited carriers can survive longer on the nanosheet, which also contributes to the high photocatalytic activity of the ZnGa2O4 nanosheets. PMID- 24475973 TI - Toxoplasma gondii infection in llama (Llama glama): acute visceral disseminated lesions, diagnosis, and development of tissue cysts. AB - Clinical toxoplasmosis has been reported in many species of warm-blooded animals but is rare in camelids. Here we report acute fatal systemic toxoplasmosis involving heart, thyroid gland, stomach, intestine, diaphragm, kidneys, adrenal glands, and liver of a 13-mo-old llama (Llama glama). Many Toxoplasma gondii tachyzoites were associated with tissue necrosis in multiple organs. Death was attributed to severe myocarditis. Ulcers associated with numerous tachyzoites were present in the C3 compartment of the stomach. Tissue cyst development was followed using bradyzoite-specific T. gondii antibodies. Individual intracellular, and groups of 2 or more, bradyzoites were identified in hepatocytes, biliary epithelium, myocardiocytes, lung, diaphragm, thyroid gland, spleen, and stomach. Lesions in the brain were a few microglial nodules and very early tissue cysts containing 1-3 bradyzoites. These observations suggest that the animal had acquired toxoplasmosis recently. Diagnosis was confirmed immunohistochemically by reaction with T. gondii -specific polyclonal rabbit serum but not with antibodies to the related protozoan Neospora caninum . Genetic typing using the DNA extracted from paraffin-embedded myocardium of llama and 10 PCR-restriction fragment length polymorphism (RFLP) markers revealed a type II allele at the SAG1, SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, PK1 L358, and Apico loci; therefore, this isolate belongs to the ToxoDB PCR-RFLP genotype #1, which is most common in North America and Europe. PMID- 24475974 TI - S-palmitoylation regulates biogenesis of core glycosylated wild-type and F508del CFTR in a post-ER compartment. AB - Defects in CFTR (cystic fibrosis transmembrane conductance regulator) maturation are central to the pathogenesis of CF (cystic fibrosis). Palmitoylation serves as a key regulator of maturational processing in other integral membrane proteins, but has not been tested previously for functional effects on CFTR. In the present study, we used metabolic labelling to confirm that wild-type and F508del CFTR are palmitoylated, and show that blocking palmitoylation with the pharmacologic inhibitor 2-BP (2-bromopalmitate) decreases steady-state levels of both wild-type and low temperature-corrected F508del CFTR, disrupts post-ER (endoplasmic reticulum) maturation and reduces ion channel function at the cell surface. PATs (protein acyl transferases) comprise a family of 23 gene products that contain a DHHC motif and mediate palmitoylation. Recombinant expression of specific PATs led to increased levels of CFTR protein and enhanced palmitoylation as judged by Western blot and metabolic labelling. Specifically, we show that DHHC-7 (i) increases steady-state levels of wild-type and F508del CFTR band B, (ii) interacts preferentially with the band B glycoform, and (iii) augments radiolabelling by [3H]palmitic acid. Interestingly, immunofluorescence revealed that DHHC-7 also sequesters the F508del protein to a post-ER (Golgi) compartment. Our findings point to the importance of palmitoylation during wild-type and F508del CFTR trafficking. PMID- 24475976 TI - Epstein-Barr virus-related post-transplant lymphoproliferative disorder in solid organ transplant recipients. AB - Epstein-Barr virus (EBV) contributes to the pathogenesis of post-transplant lymphoproliferative disease (PTLD) in more than 70% of cases. EBV DNAemia surveillance has been reported to assist in the prevention and treatment of PTLD in hematopoietic stem-cell transplantation (HSCT) recipients. Derived from experience in HSCT and taking into account that PCR-based EBV monitoring techniques are currently available in most solid organ transplant (SOT) centres, there is a great interest in EBV surveillance and prevention of PTLD in SOT recipients. In the present document we have tried to address from a practical perspective different important topics regarding the prevention and management of EBV-related PTLD in SOT. To this end, available information on SOT was analysed and combined with potentially useful data from HSCT and expert observations. The document is therefore structured according to different specific questions, each of them culminating in a consensus opinion of the panel of European experts, grading the answers according to internationally recognized levels of evidence. The addressed issues were grouped under the following topics. (i) Timing and epidemiological data of PTLD. Prophylaxis guided by clinical risk factors of early and late PTLD in SOT. (ii) Relationship of EBV DNAemia load monitoring and the development of PTLD in solid organ transplant recipients. (iii) Monitoring of EBV DNAemia after SOT. Which population should be monitored? What is the optimal timing of the monitoring? (iv) Management of SOT recipients with persistent and/or increasing EBV DNAemia. PMID- 24475975 TI - Cellular immunotherapy using irradiated lung cancer cell vaccine co-expressing GM CSF and IL-18 can induce significant antitumor effects. AB - BACKGROUND: Although the whole tumor cell vaccine can provide the best source of immunizing antigens, there is still a limitation that most tumors are not naturally immunogenic. Tumor cells genetically modified to secrete immune activating cytokines have been proved to be more immunogenic. IL-18 could augment proliferation of T cells and cytotoxicity of NK cells. GM-CSF could stimulate dendritic cells, macrophages and enhance presentation of tumor antigens. In our study, we used mouse GM-CSF combined with IL-18 to modify Lewis lung cancer LL/2, then investigated whether vaccination could suppress tumor growth and promote survival. METHODS: The Lewis lung cancer LL/2 was transfected with co-expressing mouse GM-CSF and IL-18 plasmid by cationic liposome, then irradiated with a sublethal dose X ray (100 Gy) to prepare vaccines. Mice were subcutaneously immunized with this inactivated vaccine and then inoculated with autologous LL/2 to estimate the antitumor efficacy. RESULTS: The studies reported here showed that LL/2 tumor cell vaccine modified by a co-expressing mouse GM-CSF and IL-18 plasmid could significantly inhibit tumor growth and increased survival of the mice bearing LL/2 tumor whether prophylactic or adoptive immunotherapy in vivo. A significant reduction of proliferation and increase of apoptosis were also observed in the tumor treated with vaccine of co-expressing GM-CSF and IL-18. The potent antitumor effect correlated with higher secretion levels of pro inflammatory cytokines such as IL-18, GM-CSF, interferon-gamma in serum, the proliferation of CD4+ IFN-gamma+, CD8+ IFN-gamma+ T lymphocytes in spleen and the infiltration of CD4+, CD8+ T in tumor. Furthermore, the mechanism of tumor specific immune response was further proved by 51Cr cytotoxicity assay in vitro and depletion of CD4, CD8, NK immune cell subsets in vivo. The results suggested that the antitumor mechanism was mainly depended on CD4+, CD8+ T lymphocytes. CONCLUSIONS: These results provide a new insight into therapeutic mechanisms of IL-18 plus GM-CSF modified tumor cell vaccine and provide a potential clinical cancer immunotherapeutic agent for improved antitumor immunity. PMID- 24475977 TI - Two cases of methemoglobinemia induced by the exposure to nitrobenzene and aniline. AB - OBJECTIVE: To report two cases of methemoglobinemia induced by inhaled nitrobenzene and dermally absorbed aniline. METHODS: We have evaluated a 37-year old male worker exposed to nitrobenzene by inhalation while conducting maintenance job of mononitrobenzene pump and a 25-year-old male worker exposed dermally to aniline while unloading. RESULTS: The first case is a 37-year-old male exposed to nitrobenzene. His blood methemoglobin concentration level was initially 19.8%, and chest X-ray was normal. After oxygen therapy, the blood methemoglobin concentration level decreased to 2.1%, and the symptoms were alleviated. The second case is a 25-year-old male exposed dermally to aniline. His chest X-ray was normal, but blood methemoglobin concentration level reached maximally 46.8%. He was treated with methylene blue due to relatively high blood methemoglobin level. Gradually after the treatment, his methemoglobin concentration level was normalized to 0.8% and simultaneously symptoms were resolved. CONCLUSIONS: After the thorough exposure investigations and medical evaluations, we have concluded that these cases were methemoglobinemia induced by occupational exposure to nitrobenzene and aniline. We suggest that businesses which handle methemoglobinemia-causing substances control the engineering process strictly, implement periodic screening, and establish emergency patient management system. PMID- 24475979 TI - Hydrogen induced redox mechanism in amorphous carbon resistive random access memory. AB - We investigated the bipolar resistive switching characteristics of the resistive random access memory (RRAM) device with amorphous carbon layer. Applying a forming voltage, the amorphous carbon layer was carbonized to form a conjugation double bond conductive filament. We proposed a hydrogen redox model to clarify the resistive switch mechanism of high/low resistance states (HRS/LRS) in carbon RRAM. The electrical conduction mechanism of LRS is attributed to conductive sp2 carbon filament with conjugation double bonds by dehydrogenation, while the electrical conduction of HRS resulted from the formation of insulating sp3-type carbon filament through hydrogenation process. PMID- 24475978 TI - The myxobacterial metabolite ratjadone A inhibits HIV infection by blocking the Rev/CRM1-mediated nuclear export pathway. AB - BACKGROUND: The nuclear export of unspliced and partially spliced HIV-1 mRNA is mediated by the recognition of a leucine-rich nuclear export signal (NES) in the HIV Rev protein by the host protein CRM1/Exportin1. This makes the CRM1-Rev complex an attractive target for the development of new antiviral drugs. Here we tested the anti-HIV efficacy of ratjadone A, a CRM1 inhibitor derived from myxobacteria. RESULTS: Ratjadone A inhibits HIV infection in vitro in a dose dependent manner with EC50 values at the nanomolar range. The inhibitory effect of ratjadone A occurs around 12 hours post-infection and is specific for the Rev/CRM1-mediated nuclear export pathway. By using a drug affinity responsive target stability (DARTS) assay we could demonstrate that ratjadone A interferes with the formation of the CRM1-Rev-NES complex by binding to CRM1 but not to Rev. CONCLUSION: Ratjadone A exhibits strong anti-HIV activity but low selectivity due to toxic effects. Although this limits its potential use as a therapeutic drug, further studies with derivatives of ratjadones might help to overcome these difficulties in the future. PMID- 24475980 TI - Deletion of meso-2,3-butanediol dehydrogenase gene budC for enhanced D-2,3 butanediol production in Bacillus licheniformis. AB - BACKGROUND: D-2,3-butanediol has many industrial applications such as chiral reagents, solvents, anti-freeze agents, and low freezing point fuels. Traditional D-2,3-butanediol producing microorganisms, such as Klebsiella pneumonia and K. xoytoca, are pathogenic and not capable of producing D-2,3-butanediol at high optical purity. Bacillus licheniformis is a potential 2,3-butanediol producer but the wild type strain (WX-02) produces a mix of D- and meso-type isomers. BudC in B. licheniformis is annotated as 2,3-butanediol dehydrogenase or acetoin reductase, but no pervious experiment was performed to verify this hypothesis. RESULTS: We developed a genetically modified strain of B. licheniformis (WX-02 DeltabudC) as a D-2,3-butanediol producer with high optimal purity. A marker-less gene deletion protocol based on a temperature sensitive knock-out plasmid T2-Ori was used to knock out the budC gene in B. licheniformis WX-02. The budC knock-out strain successfully abolished meso-2,3-butanediol production with enhanced D-2,3 butanediol production. No meso-BDH activity was detectable in cells of this strain. On the other hand, the complementary strain restored the characteristics of wild strain, and produced meso-2,3-butanediol and possessed meso-BDH activity. All of these data suggested that budC encoded the major meso-BDH catalyzing the reversible reaction from acetoin to meso-2,3-butanediol in B. licheniformis. The budC knock-out strain produced D-2,3-butanediol isomer only with a high yield of 30.76 g/L and a productivity of 1.28 g/L-h. CONCLUSIONS: We confirmed the hypothesis that budC gene is responsible to reversibly transfer acetoin to meso 2,3-butanediol in B. licheniformis. A mutant strain of B. licheniformis with depleted budC gene was successfully developed and produced high level of the D 2,3-butanediol with high optimal purity. PMID- 24475981 TI - pH-dependent interaction and resultant structures of silica nanoparticles and lysozyme protein. AB - Small-angle neutron scattering (SANS) and UV-visible spectroscopy studies have been carried out to examine pH-dependent interactions and resultant structures of oppositely charged silica nanoparticles and lysozyme protein in aqueous solution. The measurements were carried out at fixed concentration (1 wt %) of three differently sized silica nanoparticles (8, 16, and 26 nm) over a wide concentration range of protein (0-10 wt %) at three different pH values (5, 7, and 9). The adsorption curve as obtained by UV-visible spectroscopy shows exponential behavior of protein adsorption on nanoparticles. The electrostatic interaction enhanced by the decrease in the pH between the nanoparticle and protein (isoelectric point ~11.4) increases the adsorption coefficient on nanoparticles but decreases the overall amount protein adsorbed whereas the opposite behavior is observed with increasing nanoparticle size. The adsorption of protein leads to the protein-mediated aggregation of nanoparticles. These aggregates are found to be surface fractals at pH 5 and change to mass fractals with increasing pH and/or decreasing nanoparticle size. Two different concentration regimes of interaction of nanoparticles with protein have been observed: (i) unaggregated nanoparticles coexisting with aggregated nanoparticles at low protein concentrations and (ii) free protein coexisting with aggregated nanoparticles at higher protein concentrations. These concentration regimes are found to be strongly dependent on both the pH and nanoparticle size. PMID- 24475982 TI - Weak acidity of vinyl CH bonds enhanced by halogen substitution. AB - As shown by the rates of proton-deuteron exchange in ethylenes with halogen substituents, the weak acidity of vinyl CH bonds is enhanced by halogen substitution. Relative rates of exchange in basic deuterium oxide reflect the relative acidities. Substitution in the alpha position has the strongest effect. Less electronegative halogens such as bromine increase the acidity more than does fluorine. The vinyl CH acid strengths correlate closely with the energies of deprotonation of isolated molecules into isolated anions, as computed with the MP2/cc-pVQZ model. The smaller deprotonation energies are associated with the stronger acids. Atomic charges from a natural bond order analysis done with the MP2/aug-cc-pVQZ model show that the negative charge becomes more dispersed in the anions of the stronger acids. Results are given for 13 haloethylenes and for 6 halogen-substituted butadienes, cyclopropenes, and a cyclobutene. PMID- 24475984 TI - On the kinetics of the absorption of nitric oxide into ammoniacal cobalt(II) solutions. AB - Experiments were conducted using a custom double-stirred tank reactor to determine the rate constants of reactions between nitric oxide (NO) and both pentaaminecobalt(II) and hexaaminecobalt(II) at temperatures of 298.2 and 303.2 K and pH levels between 8.50 and 9.87 under atmospheric pressure. The NO concentration of simulated flue gas stream ranged from 400 to 1400 ppmv. Ammoniacal cobalt(II) solutions were prepared by adding aqueous ammonia into a cobalt(II) nitrate solution in the presence of concentrated ammonium nitrate. The reaction rate constants were calculated with an enhancement factor for gas absorption associated with parallel chemical reactions. The results showed that the reaction between NO and pentaaminecobalt(II) was first order with respect to both the NO and the pentaamminecobalt(II) ion. Similarly, the reaction between NO and hexaamminecobalt(II) was first order with respect to both the NO and the hexaamminecobalt(II) ion. The forward reaction rate constants of these two reactions were 6.43 * 10(6) and 1.00 * 10(7) L . mol(-1) . s(-1) at 298.2 K, respectively, and increased to 7.57 * 10(6) and 1.12 * 10(7) L . mol(-1) . s(-1) at 303.2 K, respectively. Ammoniacal cobalt(II) solutions also have the potential to simultaneously remove CO2, SO2, and NOx from postcombustion flue gas. PMID- 24475986 TI - Teaching for better learning. PMID- 24475987 TI - Use television in continuing medical education. AB - This article suggests ways in which television may help you in your teaching (see also Medical Teacher, 2, 163-167, 1980). The main emphasis is on the use of live and interactive television, with practical tips on the basic equipment needed to record television sequences yourself, for example, for use at a postgraduate medical centre meeting. PMID- 24475985 TI - Expression of CXCR4 and breast cancer prognosis: a systematic review and meta analysis. AB - BACKGROUND: The chemokine receptor CXCR4 plays a significant role in biological processes, as well as in tumorigenesis and the progression of cancer, especially breast cancer. However, the clinical application of CXCR4 for breast cancer prognosis is still very limited. A meta-analysis based on published studies was performed with the aim of obtaining an accurate evaluation of the relationship between CXCR4 expression and the prognosis of breast cancer. METHODS: A comprehensive search strategy was used to search relevant literature in PubMed, MEDLINE and the ISI Web of Science. The correlation between CXCR4 expression and clinicopathological features and breast cancer prognosis was analyzed. This meta analysis was carried out using Review Manager 4.2. RESULT: Thirteen eligible studies consisting of 3865 participants were included. We found that breast cancers with CXCR4 expression were associated with lymph node status (pooled RR =1.20, 95% CI: 1.01-1.43, P<0.001) and distant metastasis (pooled RR =1.52, 95% CI: 1.17-1.98, P = 0.125). CXCR4 overexpression was significantly associated with disease free survival (DFS) (RR = 0.77, 95% CI = 0.70-0.86, P = 0.554) and overall survival (OS) (RR = 0.70, 95% CI = 0.59-0.83, P = 0.329). However, there was no significant association between CXCR4 expression and some clinical parameters of breast cancer, such as tumor category, ER status, PR status, or c erbB-2 status. CONCLUSION: Our meta-analysis showed that CXCR4 is an efficient prognostic factor for breast cancer. Overexpression of CXCR4 was significantly associated with lymph node status and distant metastasis and indicated poor overall and disease free survival. PMID- 24475988 TI - Reminiscences and reflections. PMID- 24475989 TI - The school of medicine at the university of trondheim. AB - The article describes the factors which have led to the establishment of medical education at the University of Trondheim and discusses the medical teaching programme and the opportunities for research afforded by the links between medicine, technology and the social sciences at Trondheim. PMID- 24475990 TI - Teaching doctors to treat doctors: medical student peer counselling. AB - Physicians' emotional problems need to be recognized and treated. Intervention and prevention in this problem area have been attempted at the Medical College of Wisconsin through a programme of peer counselling designed to teach student physicians how to recognize and treat emotional difficulties faced by their peers. During the 18 months that the programme has been in operation, 20 peer counsellors reported a total 1,185 hours spent in counselling their peers, lending credence to the speculation that doctors will turn to their peers for help if, in medical school, there is acceptance of fallibility and responsiveness on the part of peers. PMID- 24475991 TI - Selection of Medical School Deans in the US, 1954-1979. AB - A review of biographical data of all persons who served as deans of United States medical schools from 1954 until 1979 indicated that: firstly, clinical faculty continue to dominate deanships; secondly, faculty from fields such as pathology and pharmacology that bridge the traditional dichotomy between pre-clinical and clinical faculty are increasingly being selected as deans; thirdly, clinical specialty fields in which the salaries are very high (with the notable exception of surgery) have consistently contributed few deans; lastly, being a graduate of a highly prestigious medical school is of diminishing value in affecting the likelihood that one will be appointed dean at any medical school, except at highly prestigious medical schools. PMID- 24475993 TI - Audiovisuals programmes. PMID- 24475992 TI - Joint service/education appointments in nursing. AB - This is the third of a series of articles examining those factors hindering the promotion and development of food nursing practice through nursing education. The novel joint appointment system described here seeks to bridge the gap between nursing as taught and practised. By remaining responsible for the nursing of patients, the lecturers holding the joint appointments retain credibility and are able to make the teaching more practical and relevant. PMID- 24475994 TI - The association for pediatric education in europe. AB - Alone among medical disciplines, European paediatric teachers set up their own 'Association for Pediatric Education' in 1970. In this article the history of the Association is recorded in order to spread its message among paediatricians. We hope that this account of the achievements and practical problems in running such an association will help and encourage other groups who might be interested in setting up a similar type of organization. PMID- 24475997 TI - Catalytic iridium-based Janus micromotors powered by ultralow levels of chemical fuels. AB - We describe catalytic micromotors powered by remarkably low concentrations of chemical fuel, down to the 0.0000001% level. These Janus micromotors rely on an iridium hemispheric layer for the catalytic decomposition of hydrazine in connection to SiO2 spherical particles. The micromotors are self-propelled at a very high speed (of ~20 body lengths s(-1)) in a 0.001% hydrazine solution due to osmotic effects. Such a low fuel concentration represents a 10,000-fold decrease in the level required for common catalytic nanomotors. The attractive propulsion performance, efficient catalytic energy-harvesting, environmentally triggered swarming behavior, and magnetic control of the new Janus micromotors hold considerable promise for diverse practical applications. PMID- 24475998 TI - Chronic obstructive pulmonary disease in stage I non-small cell lung cancer that underwent anatomic resection: the role of a recurrence promoter. AB - BACKGROUND: Despite the use of anatomic resection, the post-surgical recurrence rate remains high in early-stage non-small cell lung cancer (NSCLC). Chronic inflammation plays a role in the mechanism that promotes tumor initiation. This study aimed to investigate the association between recurrence outcome and chronic inflammation-related co-morbidities in early-stage resected NSCLC. METHODS: A review of medical records for recurrence outcome and co-morbidities, in terms of chronic obstructive pulmonary disease (COPD), DM, asthma and cardiovascular diseases, was performed with 181 patients with stage I NSCLC that underwent anatomic resection. RESULTS: Subjects with T descriptors as T2a disease (49.5 vs. 28.0%, p < 0.05) and the presence of COPD (42.4 vs. 20.7%, p < 0.01) had a higher risk of tumor recurrence. Univariate analysis for recurrence-free survival showed T descriptor as T2a (21.5 months vs. NR, p < 0.05) and the presence of COPD (20.5 months vs. NR, p < 0.01) as significant factors predicting reduced survival. The presence of COPD (HR: 1.98; 95% CI, 1.29-.02, p < 0.01) and T descriptor as T2a (HR: 2.01; 95% CI, 1.04-3.91, p < 0.05) remain independent predictors of reduced recurrence-free survival in the Cox regression model. Patients with COPD were at higher risk of brain recurrence (OR: 7.88; 95% CI, 1.50-41.3, p < 0.01). In contrast, patients without COPD showed a tendency toward recurrence in bone and liver (OR: 4.13; 95% CI, 1.08-15.8, p = 0.05). CONCLUSION: Subjects with COPD and T2a disease had a higher risk of recurrence. The role of COPD as a recurrence promoter merits further prospective investigation. PMID- 24475999 TI - Mini-nutritional assessment (MNA) is useful for assessing the nutritional status of patients with chronic obstructive pulmonary disease: a cross-sectional study. AB - Malnutrition is prevalent in patients with chronic obstructive pulmonary disease (COPD) but is often neglected in clinical practice. This study examined the usefulness of the Mini Nutritional Assessment (MNA) for assessing the nutritional status of patients with COPD. We recruited 83 patients with COPD in stable condition from the pulmonary rehabilitation unit of a medical center in northern Taiwan. Each patient was interviewed with a structured questionnaire to elicit personal and health-related data, and measured for anthropometric and blood biochemical indicators. Nutritional status was rated with two Taiwanese-specific versions of the MNA, MNA-T1 and MNA-T2. Fat-free mass was measured with bioelectrical impedance analysis (BIA), and exercise capacity indicators with the 6-Minute Walk Test. The two MNA versions showed high agreement (kappa = 0.949) in predicting the nutritional risk, and both versions predicted the FFMI well (area under the curve of the Receiver Operating Characteristics = 0.804, p < 0.001 for MNA-T1; and 0.813, p < 0.001 for MNA-T2). MNA scores decreased with increasing disease severity and were highly correlated with FFMI, BMI, mid-arm circumference, calf circumference, and oxygen saturation at rest and during exercise (all p < 0.01). The MNA score was positively correlated with FEV1, FVC and 6-minute walking distance, and negatively correlated with GOLD stages (all p < 0.05). However, the MNA score was not significantly correlated with blood biochemical indicators, perhaps due to inflammatory status associated with COPD. The MNA appears appropriate for rating the nutritional risk of patients with COPD. Routine use of the MNA may help reduce the risk of malnutrition in patients with COPD. PMID- 24476000 TI - Effects of carbonic anhydrase-related protein VIII on human cells harbouring an A8344G mitochondrial DNA mutation. AB - MERRF (myoclonus epilepsy associated with ragged-red fibres) is a maternally inherited mitochondrial encephalomyopathy with various syndromes involving both muscular and nervous systems. The most common mutation in MERRF syndrome, the A8344G mutation in mtDNA, has been associated with severe defects in the respiratory function of mitochondria. In the present study, we show that there is a significant decrease in CA8 (carbonic anhydrase-related protein VIII) in cybrids harbouring the MERRF A8344G mutation. CA8 deficiency and mutations were found to be associated with a distinctive lifelong gait disorder in wdl (Waddles) mice and novel syndromes characterized by cerebellar ataxia and mental retardation in humans. The results of the present study showed that overexpression of CA8 in MERRF cybrids significantly decreased cell death induced by STS (staurosporine) treatment, suggesting a protective function of CA8 in cells harbouring the A8344G mutation of mtDNA. Interestingly, an increase in the formation of LC3-II (microtubule-associated protein 1 light chain 3-II) was found in the cybrids with down-regulated CA8 expression, suggesting that reduced expression of CA8 leads to autophagy activation. Furthermore, cybrids exhibiting down-regulated CA8 showed increased cytosolic Ca2+ signals and reduced levels of phospho-Akt compared with those in the cybrids with overexpressed CA8, indicating that phospho-Akt is involved in the protection of cells by CA8. Our findings suggest that CA8 is involved in the autophagic pathway and may have a protective role in cultured cells from patients with MERRF. Targeting CA8 and the downstream autophagic pathway might help develop therapeutic agents for treatment of MERRF syndrome in the future. PMID- 24476001 TI - A novel rat model simulating biliary atresia after a Kasai operation. AB - PURPOSE: The mechanisms of liver fibrosis in biliary atresia (BA) after a Kasai operation deserve studying to improve the clinical outcomes. This study aimed to create a rat model simulating BA after a Kasai operation. METHODS: We inserted a polyethylene tube (PE10) into the common hepatic duct (CHD) and ligated the common bile duct (CBD) in 30 newborn rats and injected 95% ethanol into IHD at postoperative week-one (POW-1). The PE10 was removed at POW-3. The rats were sacrificed at POW-5. The CBD cystojejunostomy was performed on another 10 rats at POW-5. RESULTS: The IHD obliteration and CBD dilatation were noted at POW-3 cholangiography before removal of the PE tube. The gross findings at sacrifice in the rats without cystojejunostomy included biliary fibrosis, CBD cyst, and IHD obliteration. The microscopic findings of the liver were like BA. Seven of the 10 rats with CBD cystojejunostomy were jaundice-free at POW-8. The fibrosis grade at POW-8 of the rats with CBD cystojejunostomy was significantly lower in the jaundice-free rats (Ishak fibrosis score, 3.4 +/- 0.9 and 1.5 +/- 0.3 in the jaundiced rats and jaundice-free rats, respectively, p < .05). CONCLUSION: Based on our study, CBD cystojejunostomy five weeks after CBD ligation with ethanol injection into the IHD in newborn rats can provide a model for investigating mechanisms and treatments of liver fibrosis in BA after a Kasai operation. PMID- 24476002 TI - Factors predicting surgical resection in patients with intrahepatic cholangiocarcinoma and cirrhosis. AB - Here, we investigate the potential factors that affect the outcome of patients with intrahepatic cholangiocarcinomas (ICC) and cirrhosis. We retrospectively reviewed the clinical data and pathological features of 58 patients with ICC and cirrhosis who underwent liver resection between July 2000 and March 2008, and analyzed the prognostic risk factors by means of univariate and multivariate analyses. The overall morbidity and mortality were 40% and 3.3%, respectively. The overall median survival was 24 months, and the 1-, 3-, and 5-year actuarial survival rates were 53%, 18%, and 10%, respectively. Univariate analysis showed that Child-Pugh classification, hypoalbuminemia, vascular invasion, lymphnodes metastasis, tumor-nodes-metastasis (TNM) staging system, positive surgical margins, and high perioperative blood transfusion volumes were all significantly associated with poor survival. Multivariate analysis confirmed that hypoalbuminemia, vascular invasion, positive surgical margins, and high perioperative blood transfusion volume were survival related, with hazard ratios (HR) of 2.58, 3.12, 3.57, and 1.98, respectively. Surgical resection is an effective treatment for patients affected by ICC and cirrhosis. Predictive factors, including hypoalbuminemia, vascular invasion, positive surgical margins, and high perioperative blood transfusion volumes are all related to poor survival. PMID- 24476003 TI - Is nasogastric decompression useful in prevention of leaks after laparoscopic sleeve gastrectomy? A randomized trial. AB - INTRODUCTION: Although its excellent results, laparoscopic sleeve gastrectomy (LSG) presents major complications ranging from 0% to 29%. Among them, the staple line leak presents an incidence varying from 0% to 7%. Many trials debated about different solutions in order to reduce leaks' incidence. No author has investigated the role of gastric decompression in the prevention of this complication. Aim of our work is to evaluate if this procedure can play a role in avoiding the occurrence of staple line leaks after LSG. MATERIALS AND METHODS: Between January 2008 and November 2012, 145 patients were prospectively and randomly included in the study. Seventy patients composed the group A, whose operations were completed with placement of nasogastric tube; the other 75 patients were included in the group B, in which no nasogastric tube was placed. RESULTS: No statistical differences were observed between group A and group B regarding gender distribution, age, weight, and BMI. No intraoperative complications and no conversion occurred in both groups. Intraoperative blood loss (50.1 +/- 42.3 vs. 52.5 +/- 37.6 ml, respectively) and operative time (65.4 +/- 25.5 vs. 62.6 +/- 27.8 min, respectively) were comparable between the two groups (p: NS). One staple line leak (1.4%) occurred on 6th postoperative day in group A patients. No leak was observed in group B patients. Postoperative hospital stay was significantly longer in group A vs. group B patients (7.6 +/- 3.4 vs. 6.2 +/- 3.1 days, respectively, p: 0.04). CONCLUSIONS: Routine placement of nasogastric tube in patients operated of LSG seems not useful in reducing leaks' incidence. PMID- 24476004 TI - Loss of suppressors of cytokine signaling 3 promotes aggressiveness in hepatocellular carcinoma. AB - Hepatocellular carcinoma (HCC) is one of the most common cancers with a high mortality rate. Constitutive activation of STAT3 is found in various types of tumors, including HCC. In addition, suppressors of cytokine signaling 3 (SOCS3) signals for negative feedback to STATs, and is found to be inversely correlated with STAT3 expression. However, the exact role of SOCS3 in the tumorigenesis and progression of HCC is not fully understood. In this study we intended to show that SOCS3 inhibition promotes proliferation, migration, and invasion of HCC cells. HepG2, a human HCC cell line, was grown with SOCS3 siRNA or negative control (NC) transfection to assess the involvement of SOCS3 in cell proliferation, migration, and invasion by MTT, migration, and invasion assays, respectively. Western blot analysis was performed to examine the expression of STAT3, SOCS3, c-myc, matrix metalloproteinase (MMP)-2, and MMP-9 after transfection with either SOCS3 or NC siRNAs. A diethylnitrosamine (DEN)-induced HCC mouse model was assessed with or without injection of NSC 74859, a STAT3 inhibitor, to show accompanied changes among the expressions of STAT3, SOCS3, c myc, MMP-2, and MMP-9. Inhibition of SOCS3 expression promoted the proliferation, migration, and invasion of HepG2 cells and increased the expression of c-myc, MMP 2, and MMP-9. HCC tumors developed in mice by DEN-induction with administration of NSC 74859 resulted in decreased expression of c-myc, MMP-2, and MMP-9, but not SOCS3. Loss of SOCS3 increased tumor growth, migration, and invasion and resulted in accompanied changes in expression of STAT3 and its target oncoproteins. PMID- 24476005 TI - Leukotrienes as key mediators and amplifiers in allergic inflammation: insights from the bench and clinic. AB - Lipid mediators, such as leukotrienes (LTs) and prostaglandins (PGs), have a variety of physiological roles through their respective receptors. They are involved in both the maintenance of homoeostasis and the pathobiology of many diseases. Recent developments in relevant gene-targeted animals and receptor selective compounds have significantly advanced our understanding of the role of lipid mediators in the immune system. In the Viewpoint entitled, 'Leukotrienes orchestrating allergic skin inflammation', Dr Sadik and colleagues provide a comprehensive overview of the current progress on the new roles of LTs in cutaneous allergy and sketch important future research avenues. PMID- 24476006 TI - On Medawar's 'Actively acquired tolerance of foreign cells'. AB - The fields of dermatology and transplantation biology have recently come together in clinical trials of bone marrow transplantation for severe inherited blistering skin diseases. But the original link between these two disciplines goes back to an extraordinary publication in 1953 in Nature by Peter Medawar and colleagues that explored the immunological basis of successful skin transplantation between different strains of mice and how 'foreign' antigens could be perceived as 'self'. This work led to the emergence of blood and bone marrow transplantation and thus transformed the practice of modern medicine. PMID- 24476007 TI - Deciphering the pro-fibrotic phenotype of fibroblasts in systemic sclerosis. AB - LeRoy's seminal work on the phenotypic features of scleroderma fibroblasts has been directing fibrosis research in the field of systemic sclerosis (SSc, scleroderma) for the past 30 years. His principal experiment, to culture skin fibroblasts from patients with SSc and study their pro-fibrotic phenotype in comparison with skin fibroblasts from healthy individuals, has been used by most basic and translational fibrosis studies in SSc. LeRoy's findings have revolutionized our understanding of the disease pathogenesis and guided the development of novel antifibrotic therapies towards fibroblast-specific approaches. PMID- 24476008 TI - TNF alpha-induced leukocyte-endothelial cell interactions show marked interindividual differences independent of the clinical response to adalimumab. AB - The responses of patients with psoriasis to TNFalpha-antagonists show interindividual differences. Here, TNFalpha-incubation induced endothelial adhesion molecules, a prerequisite for leucocyte recruitment to inflamed tissues. Using a standardized flow chamber system equipped with near-confluent endothelial cells and a mobile phase containing human leucocytes, proportions of leucocytes interacting with endothelial cells were remarkably different between individual donors (up to 3.5-fold), regardless of whether the leucocytes originated from patients with psoriasis (n = 10) or healthy donors (n = 10). Adalimumab abrogated adhesion molecule induction and interactions with leucocytes when present prior to or simultaneously with, but not after exposure of the cultures to TNFalpha. This pattern was seen similarly with leucocytes from healthy donors (n = 4), and patients whose psoriasis responded well to adalimumab (n = 5) and non-responders (n = 5). Thus, although considerable interindividual differences of leucocyte endothelial cell interactions were demonstrated ex vivo in a TNFalpha-governed microenvironment, such differences are not associated with individual responses to treatment with adalimumab in vivo. PMID- 24476010 TI - European perspective on human polyomavirus infection, replication and disease in solid organ transplantation. AB - Human polyomaviruses (HPyVs) are a growing challenge in immunocompromised patients in view of the increasing number of now 12 HPyV species and their diverse disease potential. Currently, histological evidence of disease is available for BKPyV causing nephropathy and haemorrhagic cystitis, JCPyV causing progressive multifocal leukoencephalopathy and occasionally nephropathy, MCPyV causing Merkel cell carcinoma and TSPyV causing trichodysplasia spinulosa, the last two being proliferative skin diseases. Here, the current role of HPyV in solid organ transplantation (SOT) was reviewed and recommendations regarding screening, monitoring and intervention were made. Pre-transplant screening of SOT donor or recipient for serostatus or active replication is currently not recommended for any HPyV. Post-transplant, however, regular clinical search for skin lesions, including those associated with MCPyV or TSPyV, is recommended in all SOT recipients. Also, regular screening for BKPyV replication (e.g. by plasma viral load) is recommended in kidney transplant recipients. For SOT patients with probable or proven HPyV disease, reducing immunosuppression should be considered to permit regaining of immune control. Antivirals would be desirable for treating proven HPyV disease, but are solely considered as adjunct local treatment of trichodysplasia spinulosa, whereas surgical resection and chemotherapy are key in Merkel cell carcinoma. Overall, the quality of the clinical evidence and the strength of most recommendations are presently limited, but are expected to improve in the coming years. PMID- 24476011 TI - Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy. AB - BACKGROUND AND AIM: Controlled attenuation parameter (CAP) is a novel ultrasound based elastography method for detection of steatosis severity. This meta-analysis aimed to assess the performance of CAP. METHODS: PubMed, the Cochrane Library, and the Web of Knowledge were searched to find studies, published in English, relating to accuracy evaluations of CAP for detecting stage 1 (S1), stage 2 (S2), or stage 3 (S3) hepatic steatosis which was diagnosed by liver biopsy. Sensitivities, specificities, and hierarchical summary receiver operating characteristic (HSROC) curves were used to examine CAP performance. The clinical utility of CAP was also evaluated. RESULTS: Nine studies, with 11 cohorts were analyzed. The summary sensitivities and specificities values were 0.78 (95% confidence interval [CI], 0.69-0.84) and 0.79 (95% CI, 0.68-0.86) for >= S1, 0.85 (95% CI, 0.74-0.92) and 0.79 (95% CI, 0.71-0.85) for >= S2, and 0.83 (95% CI, 0.76-0.89) and 0.79 (95% CI, 0.68-0.87) for >= S3. The HSROCs were 0.85 (95% CI, 0.81-88) for >= S1, 0.88 (95% CI, 0.85-0.91) for >= S2, and 0.87 (95% CI, 0.84 0.90) for >= S3. Following a "positive" measurement (over the threshold value) for >= S1, >= S2, and >= S3, the corresponding post-test probabilities for the presence of steatosis (pretest probability was 50%) were 78%, 80% and 80%, respectively; if the values were below these thresholds ("negative" results), the post-test probabilities were 22%, 16%, and 17%, respectively. CONCLUSIONS: CAP has good sensitivity and specificity for detecting hepatic steatosis; however, based on a meta-analysis, CAP was limited in their accuracy of steatosis, which precluded widespread use in clinical practice. PMID- 24476012 TI - Light-controlled reversible release and uptake of potassium ions from ion exchanging nanospheres. AB - Here, we report for the first time on photoswitchable nanospheres containing spiropyran (Sp) for reversible release and uptake of metal ions. K(+) is used as a model ion to demonstrate the chemical principle of this approach. Valinomycin is incorporated in the nanospheres to stabilize K(+). Upon UV illumination, Sp transforms to the more basic ring-opened merocyanine form, which takes up H(+) from the surrounding aqueous solution and expels K(+) from the nanospheres. The process can be reversed by irradiation with visible light to reduce the surrounding K(+) concentration. PMID- 24476013 TI - Practical approach for preparation of unsymmetric benzils from beta ketoaldehydes. AB - An efficient and practical method for the synthesis of unsymmetric benzils from readily available beta-ketoaldehydes has been developed. Various unsymmetric 1,2 diaryldiketones bearing functional groups have been obtained in good to excellent yields under mild reaction conditions. A plausible mechanism was proposed, and alpha,alpha-dichloroketone was considered as the key intermediate. The generation of alpha,alpha-dichloroketones from beta-ketoaldehydes may undergo the following steps: (1) oxidation by sodium hypochlorite, (2) decarboxylation, and (3) chlorination by Cl2 generated from sodium hypochlorite. PMID- 24476014 TI - Effectiveness of N-butyl cyanoacrylate-based microbial skin sealant on the prevention of surgical site infections. AB - BACKGROUND: Surgical site infections (SSIs) are a serious concern in health care, and wound contamination by endogenous skin flora is a major factor in the development of SSIs. Despite preventive tactics in pre-operative skin care, antibiotic prophylaxis, surgical technique, and post-operative incision care, complete sterilization of the skin is not possible. Recently developed microbial skin sealant forms a continuous but breathable barrier that prevents migration of endogenous skin flora into the incision. The skin sealant closes dermal microabrasions, preventing re-colonization of potential pathogens at the incision. The purpose of this study was to determine the effect of an N-butyl cyanoacrylate-based microbial skin sealant in reducing the occurrence of SSIs in an experimental rodent model. METHODS: This was a randomized, controlled animal trial. Forty-eight Wistar albino rats were divided into six groups of eight rats each. Three groups received application of sealant against specific bacteria, and three matched control groups received only the bacteria without the sealant. Group one underwent pre-operative hair removal, followed by application of skin sealant, then abdominal incision and closure. Group two (control) simply underwent hair removal, followed by incision and closure, with no skin sealant applied. Group three received an application of cage swabs (containing a mixture of urine, stool and sawdust from the animals' cages) before application of skin sealant, and group four (control) received cage swabs without subsequent skin sealant. Group five received methicillin-resistant Staphylococcus aureus (MRSA) followed by skin sealant, and group six (control) received MRSA without skin sealant. Seven days after surgery, the animals were sacrificed. Samples were taken from the abdomen of each rat and placed in culture medium. Proliferation of the following bacteria were observed: Coagulase-negative staphylococci (CoNS), gram-positive bacilli (GPB), Pseudomonas aeruginosa, and MRSA. RESULTS: There was a statistically significant difference between the median number of GPB in the group that received cage swabs+sealant and the group that received cage swabs without sealant (median, GPB count 29,430 colony-forming units [CFU]/g vs 359,100 colony-forming units [CFU]/g; p<0.05). The study results showed that microbial skin sealant was not as effective in preventing CoNS or MRSA contamination as it was in preventing GPB contamination. CONCLUSIONS: Use of a microbial skin sealant before surgery can lower the rate of SSIs by reducing the migration of some specific bacterial agents. Additional data are needed to validate its use in clinical practice. PMID- 24476015 TI - Endoluminal negative-pressure therapy for preventing rectal anastomotic leaks: a pilot study in a pig model. AB - BACKGROUND: Anastomotic leak after rectal resection carries substantial morbidity and mortality. A diverting ileostomy is beneficial for high-risk anastomoses, but its creation and reversal carry a surgical risk in addition to that of resection itself. We sought an alternative method for managing complications of rectal anastomosis. METHODS: We developed an endoluminal negative-pressure technology with a diverting proximal sump, and hypothesized that it would close anastomotic disruptions in pigs. We performed rectal resections on pigs, with primary anastomoses and the creation of an anastomotic defect. In animals in the treatment group we inserted an endoluminal negative-pressure device and kept it at a low level of continuous suction for 5 d. No device was inserted in a control group of animals. After the 5-d period of treatment we evaluated the anastomoses in both the treatment and control groups of animals for leakage, using contrast enemas. Specimens of anastomosed rectum were evaluated histologically for mucosal integrity and for the location and density of inflammatory responses. RESULTS: Fourteen pigs were assigned to either the treatment (n=10) or control (n=4) group. Of the pigs in the treatment group, 90% had complete closure of their rectal defect, as compared with 25% of the animals in the control group (chi(2) test, p=0.04). The animals in the treatment group had only minimal mucosal and serosal inflammation, whereas those in the control group had extensive mucosal damage with associated serositis. CONCLUSIONS: Endoluminal negative-pressure therapy was well-tolerated and led to successful closure of 90% of the anastomic rectal defects in the treatment group of animals in the present study. Additional evaluation of this therapy is warranted. PMID- 24476016 TI - Co-existence of hepatocellular carcinoma and hepatic tuberculosis. AB - BACKGROUND: Many case reports describe tuberculosis (TB) co-existent with a malignant neoplasm. However, the neoplasm in most of these reports is lung or breast cancer, with only two cases of liver cancer concomitant with TB reported in the literature. Although both TB and cancer are very common diseases, little attention has been given to the pathophysiologic and practical implications of their co-existence. METHODS: Case report and literature review. CASE REPORT: A 73 year-old female patient with a history of hypertension and hepatitis C presented with abdominal pain of 2 mos duration. Laboratory findings showed an elevated serum concentration of alpha-fetoprotein. A computed tomography scan demonstrated a solitary hypodense tumor in the right lobe of the liver (segment VIII). A pre operative chest radiograph was within normal limits. The patient underwent an uneventful tumor resection. Histologic examination of a surgical specimen of the tumor demonstrated a moderately differentiated hepatocellular carcinoma co existent with caseating granulomas. CONCLUSION: Through this case report, the authors discuss the pathogenesis of the rare association of TB and malignant neoplasm of the liver, and present a review of the current literature on the association of TB and cancer. Further research is required to determine whether a TB infection resembles other chronic infections and inflammatory conditions in having a potential to facilitate oncogenesis. PMID- 24476017 TI - Pyoderma gangrenosum after minor trauma in a pregnant woman, mistaken for necrotizing fasciitis: report of a case and literature review. AB - BACKGROUND: Pyoderma gangrenosum is an ulcerative, non-infectious skin disorder. However, it can be mistaken as necrotizing fasciitis, a life-threatening infective condition. We describe here a case of pyoderma gangrenosum after minor trauma treated as necrotizing fasciitis. METHODS: Case report and literature review. CASE REPORT: A 27-year-old pregnant nurse had a pretibial wound after a fall on a rough surface. When erythema developed and no response to empirical antibiotic therapy was observed, multiple debridements were performed. Paradoxically, her condition became worse. The diagnosis of pyoderma gangrenosum was suspected. Treatment with corticosteroids was started and this was successful. CONCLUSION: Pyoderma gangrenosum can mimic infectious necrotizing fasciitis. Differentiating these two conditions is important because mistreatment of pyoderma can lead to disfigurement. PMID- 24476018 TI - Efficacy of pre-operative nasal staphylococcus aureus screening and chlorhexidine chest scrub in decreasing the incidence of post-resection empyema. AB - BACKGROUND: We evaluated the efficacy of pre-operative Staphylococcus aureus (SA) screening and chlorhexidine chest scrub in decreasing the incidence of empyema after major pulmonary resections. METHODS: For two years, a strategy aimed at decreasing post-resection empyema was instituted. This entailed pre-operative screening for nasal SA and chlorhexidine chest scrub the night before surgery (Group Swab-Scrub, n=192). Patients screened positive for SA, methicillin resistant (MRSA) and methicillin-sensitive (MSSA), received 5 d of nasal mupirocin. Group Swab-Scrub was compared with patients two years earlier, who did not receive this pre-operative maneuver (Group Control, n=173). The extent of resection considered was lobectomy or greater. All patients received cefazolin (or clindamycin if allergic) prior to incision and 24 h postoperatively, except for patient in Group Swab-Scrub screening positive for MRSA, who received vancomycin. All patients had povidone-iodine skin preparation. RESULTS: In Group Swab-Scrub, prevalence of nasal SA was 8.9% (17/192) two with MRSA and 15 with MSSA. There was no difference in patient demographics or operative characteristics between the Group Swab-Scrub and Group Control. There was also no difference in prolonged air-leak, empyema, wound infection, pneumonia, or mortality rates between the two groups. When stratifying for the extent of procedure, there was no difference in the incidence of empyema after lobectomy (Group Swab-Scrub, 3.9% [7/177] versus Group Control, 2.0% [3/151]; p=0.352) or pneumonectomy (Group Swab-Scrub, 6.7% [1/15] versus Group Control, 13.6% [3/22]; p=0.633). In both univariate and multivariable analysis, prolonged air-leak and pneumonectomy were significant risk factors for empyema. CONCLUSIONS: Preoperative screening for nasal SA and chlorhexidine chest scrub does not seem to decrease empyema rates after major pulmonary resection. Prolonged air-leak and pneumonectomy continue to be significant risk factors for developing empyema. The number of patients undergoing pneumonectomy in this study is small and further studies are needed for this patient population. PMID- 24476019 TI - Biofilm: basic principles, pathophysiology, and implications for clinicians. AB - BACKGROUND: Biofilm is ubiquitous throughout nature including bacteria, fungi, protozoa-associated bacteriophages, and viruses. Whereas it is adaptive for certain organisms in a variety of environments, biofilm is important in understanding and treating clinically relevant infections, especially those involving temporarily or durably implanted devices. METHODS: Review of pertinent English-language literature. RESULTS: Important advances have been made in understanding biofilm structure and function that elucidate key events in biofilm based infectious processes. Wounds, oral cavity, urinary tract, gastrointestinal tract, and device-associated biofilm-based infections dominate clinically relevant infections. Criteria have been articulated to detect and diagnose biofilm-associated infection but there are hurdles to overcome to treat effectively such infection. Native biofilm resistance mechanisms as well as incompletely effective human immune system responses impede successful infection resolution. Biofilm-appropriate education appears under-represented in standardized surgical education curriculum. CONCLUSION: Several potential methods of enabling primary prevention as well as treatment of biofilm-associated infection are on the near horizon. There is an opportunity to enhance surgical education regarding biofilm prevention, diagnosis, and therapy. PMID- 24476020 TI - Ultraperformance liquid chromatography tandem mass spectrometry determination of cyanogenic glucosides in Trifolium species. AB - Cyanogenic glucosides were analyzed by ultra-high-performance liquid chromatography combined with mass spectrometry in 88 Trifolium species grown at the same site. On the basis of the occurrence of cyanogenic glucosides and the linamarin/lotaustralin ratio species could be grouped into five clusters. Cluster C1 included 37 species, which did not contain cyanogens. Cluster C2 (22 species) included plants containing only lotaustralin. In clusters C3 (14 species), C4 (13 species), and C5 (2 species) both linamarin and lotaustralin were present but at different ratios. In C3 and C4 the linamarin/lotaustralin ratio was below 1, whereas in cluster C5 the ratio was much higher. Generally, the total content of cyanogens was below 500 MUg/g dry matter. Only in Trifolium repens var. biasoletti and Trifolium montanum extremely high cyanogen concentrations were observed. There was no general rule of occurrence of cyanogens. Samples of the same species from different countries accumulated cyanogens or could be free of these compounds. PMID- 24476021 TI - Regionalization and local hospital closure in Norwegian maternity care--the effect on neonatal and infant mortality. AB - OBJECTIVE: To study whether neonatal and infant mortality, after adjustments for differences in case mix, were independent of the type of hospital in which the delivery was carried out. DATA: The Medical Birth Registry of Norway provided detailed medical information for all births in Norway. STUDY DESIGN: Hospitals were classified into two groups: local hospitals/maternity clinics versus central/regional hospitals. Outcomes were neonatal and infant mortality. The data were analyzed using propensity score weighting to make adjustments for differences in case mix between the two groups of hospitals. This analysis was supplemented with analyses of 13 local hospitals that were closed. Using a difference-in-difference approach, the effects that these closures had on neonatal and infant mortality were estimated. PRINCIPAL FINDING: Neonatal and infant mortality were not affected by the type of hospital where the delivery took place. CONCLUSION: A regionalized maternity service does not lead to increased neonatal and infant mortality. This is mainly because high-risk deliveries were identified well in advance of the birth, and referred to a larger hospital with sufficient perinatal resources to deal with these deliveries. PMID- 24476022 TI - Development and characterization of two monoclonal antibodies against grouper iridovirus 55L and 97L proteins. AB - Grouper iridovirus (GIV) is one of the most important viral pathogens in grouper, particularly at the fry and fingerling stages. The study of GIV pathogenicity has been hampered by the lack of proper immunological reagents to study the expression and function of viral proteins in the infected cells. In this study, two mouse monoclonal antibodies (mAbs) against GIV 55L and 97L proteins were produced. Enzyme-linked immunosorbent assay (ELISA) and Western blotting were used to screen these hybridomas, resulting in the identification of two high affinity mAbs named GIV55L-mAb-2 and GIV97L-mAb-3, respectively. Both mAbs belong to the IgG1 isotype and were effective in detecting their respective target viral protein. Reverse-transcription polymerase chain reaction (RT-PCR) and Western blot analyses of GIV-infected GK cells revealed that GIV 97L is an immediate early gene, whereas GIV 55L a late one. The localization of 55L and 97L in GIV infected cells was further characterized by immunofluorescence microscopy with the mAbs. The 55L protein mainly aggregated in the cytoplasm while 97L distributed in both the nucleus and cytoplasm of the infected cells. These studies demonstrate the validity of the two mAbs as immunodiagnostic and research reagents. PMID- 24476023 TI - Carbon source dependence of cell surface composition and demulsifying capability of Alcaligenes sp. S-XJ-1. AB - Biodemulsifiers are environmentally friendly agents used in recycling oil or purifying water from emulsion, yet the demulsifying feature of cell-surface composition remains unclear. In this study, potentiometric titration, attenuated total reflectance-Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and matrix-assisted laser desorption/ionization-time-of-flight mass spectrometry were combined to characterize cell-surface chemical composition of demulsifying strain Alcaligenes sp. S-XJ-1 cultivated with different carbon sources. Cells cultivated with alkane contained abundant elemental nitrogen and basic functional groups, indicating that their surface was rich in proteins or peptides, which contributed to their highest demulsifying efficiency. For cells cultivated with fatty acid ester, the relatively abundant surface lipid contributed to a 50% demulsification ratio owing to the presence of more acidic functional group. The cells cultivated with glucose exhibited a high oxygen concentration (O/C ~0.28), which indicated the presence of more polysaccharides on the cell surface. This induced the lowest demulsification ratio of 30%. It can be concluded that cell surface-associated proteins or lipids other than the polysaccharide of the demulsifying strain played a positive role in the demulsification activity. In addition, the cell-surface oligoglutamate compounds identified in situ were crucial to the demulsifying capability. PMID- 24476025 TI - Autodisplay for the co-expression of lipase and foldase on the surface of E. coli: washing with designer bugs. AB - BACKGROUND: Lipases including the lipase from Burkholderia cepacia are in a main focus in biotechnology research since many years because of their manifold possibilities for application in industrial processes. The application of Burkholderia cepacia lipase for these processes appears complicated because of the need for support by a chaperone, the lipase specific foldase. Purification and reconstitution protocols therefore interfere with an economic implementation of such enzymes in industry. Autodisplay is a convenient method to express a variety of passenger proteins on the surface of E. coli. This method makes subsequent purification steps to obtain the protein of interest unnecessary. If enzymes are used as passengers, the corresponding cells can simply be applied as whole cell biocatalysts. Furthermore, enzymes surface displayed in this manner often acquire stabilization by anchoring within the outer membrane of E. coli. RESULTS: The lipase and its chaperone foldase from B. cepacia were co-expressed on the surface of E. coli via autodisplay. The whole cell biocatalyst obtained thereby exhibited an enzymatic activity of 2.73 mU mL-1 towards the substrate p nitrophenyl palmitate when applied in an OD578 =1. Outer membrane fractions prepared from the same culture volume showed a lipase activity of 4.01 mU mL-1. The lipase-whole cell biocatalyst as well as outer membrane preparations thereof were used in a standardized laundry test, usually adopted to determine the power of washing agents. In this test, the lipase whole cell biocatalyst and the membrane preparation derived thereof exhibited the same lipolytic activity as the purified lipase from B. cepacia and a lipase preparation which is already applied in commercial washing agents. CONCLUSIONS: Co-expression of both the lipase and its chaperone foldase on the surface of E. coli yields a lipid degrading whole cell biocatalyst. Therefore the chaperone supported folding process, absolutely required for the lipolytic activity appears not to be hindered by surface display. Furthermore, the cells and the membrane preparations appeared to be stable enough to endure a European standard laundry test and show efficient fat removal properties herein. PMID- 24476026 TI - Creation of a federated database of blood proteins: a powerful new tool for finding and characterizing biomarkers in serum. AB - Protein biomarkers offer major benefits for diagnosis and monitoring of disease processes. Recent advances in protein mass spectrometry make it feasible to use this very sensitive technology to detect and quantify proteins in blood. To explore the potential of blood biomarkers, we conducted a thorough review to evaluate the reliability of data in the literature and to determine the spectrum of proteins reported to exist in blood with a goal of creating a Federated Database of Blood Proteins (FDBP). A unique feature of our approach is the use of a SQL database for all of the peptide data; the power of the SQL database combined with standard informatic algorithms such as BLAST and the statistical analysis system (SAS) allowed the rapid annotation and analysis of the database without the need to create special programs to manage the data. Our mathematical analysis and review shows that in addition to the usual secreted proteins found in blood, there are many reports of intracellular proteins and good agreement on transcription factors, DNA remodelling factors in addition to cellular receptors and their signal transduction enzymes. Overall, we have catalogued about 12,130 proteins identified by at least one unique peptide, and of these 3858 have 3 or more peptide correlations. The FDBP with annotations should facilitate testing blood for specific disease biomarkers. PMID- 24476027 TI - Effect of garlic on lipid profile and expression of LXR alpha in intestine and liver of hypercholesterolemic mice. AB - BACKGROUND: Garlic is one of the medicinal plants which has showed beneficial effects on atherosclerosis risk factors. The liver X receptor alpha (LXRalpha) is an important regulator of cholesterol, triglyceride and glucose homeostasis that belongs to the nuclear receptor superfamily. In this study we investigated the effect of garlic on lipid profile, glucose as well as LXRalpha expression in intestine and liver of mice. METHODS: Forty male N-Mary mice were randomly divided into 3 groups (n = 8): group1 received chow + 2% cholesterol + 0.5% cholic acid, group 2: chow + 4% (w/w) garlic extract + 2% cholesterol + 0.5% cholic acid, and group 3: chow only. After one month of treatment, mice were anesthetized, blood was collected from their heart, and the first 10 cm of the small intestine and liver were removed. Glucose was measured by a glucometer; other biochemical factors were measured by enzymatic methods. LXR expression was checked by RT-PCR and western blotting. RESULTS: Compared with hypercholesterolemic mice, treatment with garlic extract significantly decreased total cholesterol, low-density lipoprotein cholesterol (LDL-C), triglycerides, very low density lipoprotein-cholesterol (VLDL-C), atherogenic index, alanine aminotranferease (ALT) and aspartate aminotransferase (AST) (all of them P < 0.05). Change in HDL-C levels was not significant in garlic-extract treated animals compared with hypercholesterolemic group. LXR protein and mRNA in the intestine were increased in garlic-extract treated group compared with chow group (P < 0.05), while in the liver, only mRNA of LXR was increased in hypercholesterolemic control mice (P < 0.05). CONCLUSIONS: The present study demonstrated that garlic extract reduced LXRalpha expression in the liver and increased its expression in the intestine. These effects probably have an important role in reducing serum triglyceride and cholesterol. PMID- 24476028 TI - Critical salt effects in the swelling behavior of a weak polybasic brush. AB - The swelling behavior of poly(2-(diethylamino)ethyl methacrylate) (PDEA) brushes in response to changes in solution pH and ionic strength has been investigated. The brushes were synthesized by ARGET ATRP methodology at the silica-aqueous solution interface via two different surface-bound initiator approaches: electrostatically adsorbed cationic macroinitiator and covalently anchored silane based ATRP initiator moieties. The pH-response of these brushes is studied as a function of the solvated brush thickness in a constant flow regime that elucidates the intrinsic behavior of polymer brushes. In situ ellipsometry equilibrium measurements show the pH-induced brush swelling and collapse transitions are hysteretic in nature. Furthermore, high temporal resolution kinetic studies demonstrate that protonation and solvent ingress during swelling occur much faster than the brush charge neutralization and solvent expulsion during collapse. This hysteresis is attributed to the formation of a dense outer region or skin during collapse that retards solvent egress. Moreover, at a constant pH below its pKa, the PDEA brush exhibited a critical conformational change in the range 0.5-1 mM electrolyte, a range much narrower than predicted by the theory of the osmotic brush regime. This behavior is attributed to the hydrophobicity of the collapsed brush. The swelling and collapse kinetics for this salt-induced transition are nearly identical. This is in contrast to the asymmetry in the rate of the pH-induced response, suggesting an alternative mechanism for the two processes dependent on the nature of the environmental trigger. PMID- 24476030 TI - Educational inflation. PMID- 24476031 TI - How To...:Construct Problem-Solving MCQs. AB - This article gives ten guidelines for the construction of the one-from-five type problem-solving MCQs and provides some examples. PMID- 24476029 TI - Body composition variables as predictors of NAFLD by ultrasound in obese children and adolescents. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a disorder associated with excessive fat accumulation, mainly in the intra-abdominal region. A simple technique to estimate abdominal fat in this region could be useful to assess the presence of NAFLD, in obese subjects who are more vulnerable to this disease. The aim of this cross-sectional study was to verify the reliability of waist circumference and body composition variables to identify the occurrence of NAFLD in obese children and adolescents. METHODS: Sample was composed of 145 subjects, aged 11 to 17 years. Assessments of waist circumference (WC), trunk fat mass (TFM) and fat mass (FM) by dual-energy X-ray absorptiometry (DXA) and ultrasound for diagnosis of NAFLD and intra-abdominal adipose tissue (IAAT) were used. Correlation between variables was made by Spearman's coefficients; ROC curve parameters (sensitivity, specificity, area under curve) were used to assess the reliability of body composition variables to assess the presence of NAFLD. Statistical significance was set at 5%. RESULTS: Significant correlations were observed between NAFLD and WC (p = 0.001), TFM (p = 0.002) and IAAT (p = 0.001). The higher values of area under the ROC curve were for WC (AUC = 0.720), TFM (AUC = 0.661) and IAAT (AUC = 0.741). CONCLUSIONS: Our findings indicated that TFM, IAAT and WC present high potential to identify NAFLD in obese children and adolescents. PMID- 24476032 TI - The way we teach...: resuscitation. PMID- 24476033 TI - Educational organizations: the NHS learning resources unit. PMID- 24476034 TI - Pathology museum in a hallway. PMID- 24476035 TI - The importance of context in the implementation of a new curriculum. AB - Most accounts of the introduction of new clinical curricula concern themselves exclusively with a description of the new curriculum and its consequences. This article addresses additionally the questions and problems associated with the implementation of a new curriculum at the Royal Free Hospital School of Medicine. The main problem was the failure of the planners to communicate effectively to students and teachers the structure and function of the new curriculum. Nevertheless, the school is solving its problems and is finding its own preferred and acceptable ways of putting the curriculum into practice. PMID- 24476036 TI - Allocation of Pre-Registration Posts -by Ballot. AB - Several different methods are used throughout the world for the allocation of pre registration posts to graduating medical students. This article describes the ballot method of allocating such posts used in Brisbane, Australia. Using this system, only six per cent of students in the 1979 graduating class missed out on their hospital of first choice. The advantages and disadvantages of the procedure are considered. PMID- 24476037 TI - Letters. PMID- 24476040 TI - Evaluation of a target region capture sequencing platform using monogenic diabetes as a study-model. AB - BACKGROUND: Monogenic diabetes is a genetic disease often caused by mutations in genes involved in beta-cell function. Correct sub-categorization of the disease is a prerequisite for appropriate treatment and genetic counseling. Target-region capture sequencing is a combination of genomic region enrichment and next generation sequencing which might be used as an efficient way to diagnose various genetic disorders. We aimed to develop a target-region capture sequencing platform to screen 117 selected candidate genes involved in metabolism for mutations and to evaluate its performance using monogenic diabetes as a study model. RESULTS: The performance of the assay was evaluated in 70 patients carrying known disease causing mutations previously identified in HNF4A, GCK, HNF1A, HNF1B, INS, or KCNJ11. Target regions with a less than 20-fold sequencing depth were either introns or UTRs. When only considering translated regions, the coverage was 100% with a 50-fold minimum depth. Among the 70 analyzed samples, 63 small size single nucleotide polymorphisms and indels as well as 7 large deletions and duplications were identified as being the pathogenic variants. The mutations identified by the present technique were identical with those previously identified through Sanger sequencing and Multiplex Ligation-dependent Probe Amplification. CONCLUSIONS: We hereby demonstrated that the established platform as an accurate and high-throughput gene testing method which might be useful in the clinical diagnosis of monogenic diabetes. PMID- 24476042 TI - Direct synthesis of 2-deoxy-beta-glycosides via anomeric O-alkylation with secondary electrophiles. AB - An approach for direct synthesis of biologically significant 2-deoxy-beta glycosides has been developed via O-alkylation of a variety of 2-deoxy-sugar derived anomeric alkoxides using challenging secondary triflates as electrophiles. It was found a free hydroxyl group at C3 of the 2-deoxy-sugar derived lactols is required in order to achieve synthetically efficient yields. This method has also been applied to the convergent synthesis of a 2-deoxy-beta tetrasaccharide. PMID- 24476041 TI - Accessing near-infrared-absorbing BF2-azadipyrromethenes via a push-pull effect. AB - Novel aza-BODIPYs with significant bathochromic shifts were designed and synthesized by installation of strong electron-withdrawing groups on the para positions of 1,7-phenyls and electron-donating groups on the para-positions of 3,4-phenyls. These dyes show strong NIR fluorescence emissions up to 756 nm, and absorptions up to 720 nm. PMID- 24476043 TI - Investigating maternal effects on production traits in Duroc pigs using animal and sire models. AB - Variance components for production traits were estimated using different models to evaluate maternal effects. Data analysed were records from the South African pig performance testing scheme on 22 224 pigs from 18 herds, tested between 1990 and 2008. The traits analysed were backfat thickness (BFAT), test period weight gain (TPG), lifetime weight gain (LTG), test period feed conversion ratio (FCR) and age at slaughter (AGES). Data analyses were performed by REML procedures in ASREML, where random effects were successively fitted into animal and sire models to produce different models. The first animal model had one random effect, the direct genetic effects, while the additional random effects were maternal genetic and maternal permanent environmental effects. In the sire model, the random effects fitted were sire and maternal grand sire effects. The best model considered the covariance between direct and maternal genetic effects or between sire and maternal grand sire effects. Fitting maternal genetic effects into the animal model reduced total additive variance, while the total additive variance increased when maternal grand sire effects were fitted into the sire model. The correlations between direct and maternal genetic effects were all negative, indicating antagonism between these effects, hence the need to consider both effects in selection programmes. Direct genetic correlations were higher than other correlations, except for maternal genetic correlations of FCR with TPG, LTG and AGES. There has been direct genetic improvement and almost constant maternal ability in production traits as shown by trends for estimated (EBVs) and maternal breeding values (MBVs), while phenotypic trends were similar to those for EBVs. These results suggest that maternal genetic effects should be included in selection programmes for these production traits. Therefore, the animal-maternal model may be the most appropriate model to use when estimating genetic parameters for production traits in this population. PMID- 24476044 TI - Management of cardiac dysrhythmias following hydrocarbon abuse: clinical toxicology teaching case from NACCT acute and intensive care symposium. PMID- 24476045 TI - 2012 pediatric fatality review of the National Poison Database System. PMID- 24476046 TI - Characterization of a reverse-phase perfluorocarbon emulsion for the pulmonary delivery of tobramycin. AB - BACKGROUND: Aerosolized delivery of antibiotics is hindered by poor penetration within distal and plugged airways. Antibacterial perfluorocarbon ventilation (APV) is a proposed solution in which the lungs are partially or totally filled with perfluorocarbon (PFC) containing emulsified antibiotics. The purpose of this study was to evaluate emulsion stability and rheological, antibacterial, and pharmacokinetic characteristics. METHODS: This study examined emulsion aqueous droplet diameter and number density over 24 hr and emulsion and neat PFC viscosity and surface tension. Additionally, Pseudomonas aeruginosa biofilm growth was measured after 2-hr exposure to emulsion with variable aqueous volume percentages (0.25, 1, and 2.5%) and aqueous tobramycin concentrations (Ca=0.4, 4, and 40 mg/mL). Lastly, the time course of serum and pulmonary tobramycin concentrations was evaluated following APV and conventional aerosolized delivery of tobramycin in rats. RESULTS: The initial aqueous droplet diameter averaged 1.9+/-0.2 MUm with little change over time. Initial aqueous droplet number density averaged 3.5+/-1.7*10(9) droplets/mL with a significant (p<0.01) decrease over time. Emulsion and PFC viscosity were not significantly different, averaging 1.22+/-0.03*10(-3) Pa.sec. The surface tensions of PFC and emulsion were 15.0+/ 0.1*10(-3) and 14.6+/-0.6*10(-3) N/m, respectively, and the aqueous interfacial tensions were 46.7+/-0.3*10(-3) and 26.9+/-11.0*10(-3) N/m (p<0.01), respectively. Biofilm growth decreased markedly with increasing Ca and, to a lesser extent, aqueous volume percentage. Tobramycin delivered via APV yielded 2.5 and 10 times larger pulmonary concentrations at 1 and 4 hr post delivery, respectively, and significantly (p<0.05) lower serum concentrations compared with aerosolized delivery. CONCLUSIONS: The emulsion is bactericidal, retains the rheology necessary for pulmonary delivery, is sufficiently stable for this application, and results in increased pulmonary retention of the antibiotic. PMID- 24476047 TI - In vitro comparison of the effect of inhalation delay and flow rate on the emitted dose from three valved holding chambers. AB - BACKGROUND: Valved holding chambers (VHCs) are accessory devices for pressurized metered dose inhalers (pMDIs). Use of a VHC may help overcome coordination issues associated with drug delivery via the pMDI alone. Previous work has established that aspects of VHC use, including the time between actuation and inhalation (inhalation delay) and inhalation flow rate, can influence the amount of drug available to inhalation. This study compared the impact of inhalation delay and flow rate on the in vitro delivery of aerosol from different VHC brands. METHODS: A custom-built inhalation delay test rig, which enabled automation of controlled inhalation delays (0, 5, or 10 sec), was developed. Extraction air flow was set to 5, 15, or 30 L/min. Delivery of albuterol (ProAir HFA 90 MUg) to a filter (emitted dose) was assessed using three commercially available VHC brands (one conventional, two antistatic). Emitted dose under 27 different combinations of inhalation delay, flow rate, and VHC brand was determined in order to assess the effects of inhalation delay and flow rate. Pairwise comparisons of the different VHC brands with different inhalation delay/flow rate combinations were conducted to assess in vitro equivalence. RESULTS: Emitted dose increased with flow rate and decreased with longer inhalation delays. Dependence on flow rate was similar for the two antistatic VHCs and more pronounced for the conventional VHC. The two antistatic VHCs showed equivalent results for the emitted dose of albuterol, across a range of flow rates and using different inhalation delays; the relation between the two antistatic VHCs fell within the +/- 15% acceptance interval criteria for in vitro equivalence. CONCLUSIONS: The different inhalation delays and flow rates had similar effects on the delivery of drug via the three VHCs. The two antistatic VHCs were shown to be equivalent in vitro in terms of emitted dose of albuterol. PMID- 24476048 TI - Challenges and limitations of testing efficacy of aerosol device delivery in young children. AB - An increasing number of medical conditions are chronically or acutely managed with some form of aerosolized therapy. Due to the benefit of directly administering medications to the intended site of action, there is great interest in evaluating treatments for aerosol use. One of the major challenges in selecting and testing new drug-device combinations in children is the uncertainty regarding the appropriate outcome measure to choose. In studies involving adult patients, typically exacerbations of disease or airflow obstruction are assessed as endpoints in drug trials or device assessment. However, in young children, choosing endpoints to assess efficacy is difficult due to the potential lack of sensitive, noninvasive endpoints that are easily performed across sites. In this review, we discuss the challenges and limitations of selecting clinical endpoints for drug-device trials in the youngest population, with a focus on novel emerging technologies. This article provides an overview of preschool and infant pulmonary function testing, multiple-breath washout, imaging techniques including computed tomography and magnetic resonance imaging, flexible bronchoscopy in children, mucociliary clearance scans, and exhaled breath condensate. PMID- 24476050 TI - Characterization of the metabolic effects of irisin on skeletal muscle in vitro. AB - AIMS: This work explored the effects of irisin on metabolism, gene expression and mitochondrial content in cultured myocytes. METHODS: C2C12 myocytes were treated with various concentrations of irisin for various durations. Glycolysis and oxidative metabolism were quantified by measurement of extracellular acidification and oxygen consumption, respectively. Metabolic gene expression was measured by quantitative real-time polymerase chain reaction (qRT-PCR) and mitochondrial content was assessed by flow cytometry and confocal microscopy. RESULTS: Cells treated with irisin exhibited significantly increased oxidative metabolism. Irisin treatment also significantly increased mitochondrial uncoupling at various doses and durations. Lastly, treatment with irisin also significantly elevated metabolic gene expression including peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1alpha), nuclear respiratory factor 1 (NRF1), mitochondrial transcription factor A (TFAM), irisin, glucose transporter 4 (GLUT4) and mitochondrial uncoupling protein 3 (UCP3) leading to increased mitochondrial biogenesis. CONCLUSIONS: Our observations are the first to document increased metabolism in myocytes through irisin-mediated induction of mitochondrial biogenesis and uncoupling with corresponding gene expression. These observations support the need for further investigation into the therapeutic and pharmacological effects of irisin, as well as development of irisin-based therapy. PMID- 24476052 TI - Facile single-step synthesis of nitrogen-doped reduced graphene oxide-Mn(3)O(4) hybrid functional material for the electrocatalytic reduction of oxygen. AB - Development of efficient electrocatalyst based on non-precious metal that favors the four-electron pathway for the reduction of oxygen in alkaline fuel cell is a challenging task. Herein, we demonstrate a new facile route for the synthesis of hybrid functional electrocatalyst based on nitrogen-doped reduced graphene oxide (N-rGO) and Mn3O4 with pronounced electrocatalytic activity towards oxygen reduction reaction (ORR) in alkaline solution. The synthesis involves one-step in situ reduction of both graphene oxide (GO) and Mn(VII), growth of Mn3O4 nanocrystals and nitrogen doping onto the carbon framework using a single reducing agent, hydrazine. The X-ray photoelectron (XPS), Raman and FTIR spectral, and X-ray diffraction measurements confirm the reduction of GO and growth of nanosized Mn3O4. The XPS profile reveals that N-rGO has pyridinic (40%), pyrrolic (53%), and pyridine N oxide (7%) types of nitrogen. The Mn3O4 nanoparticles are single crystalline and randomly distributed over the wrinkled N rGO sheets. The hybrid material has excellent ORR activity and it favors the 4 electron pathway for the reduction of oxygen. The electrocatalytic performance of the hybrid catalyst is superior to the N-rGO, free Mn3O4 and their physical mixture. The hybrid material shows an onset potential of -0.075 V, which is 60 225 mV less negative than that of the other catalyst tested. It has excellent methanol tolerance and high durability. The catalytic current density achieved with the hybrid material at 0.1 mg cm(-2) is almost equivalent to that of the commercial Pt/C (10%). The synergistic effect of N-rGO and Mn3O4 enhances the overall performance of the hybrid catalyst. The nitrogen in N-rGO is considered to be at the interface to bridge the rGO framework and Mn3O4 nanoparticles and facilitates the electron transfer. PMID- 24476051 TI - Synthetic RGDS peptide attenuated lipopolysaccharide/D-galactosamine-induced fulminant hepatic failure in mice. AB - BACKGROUND AND AIM: Fulminant hepatic failure (FHF) is a serious clinic syndrome with extremely poor prognosis and no effective treatment except for liver transplantation. Synthetic RGDS peptide, an inhibitor of integrins, was proved to suppress integrin signals. In this study, we investigated the protection effects of RGDS peptide on lipopolysaccharide/D-galactosamine (LPS/D-GalN)-induced FHF and the underlying molecular mechanisms. METHODS: Synthetic RGDS peptide was given intraperitoneally 30 min before LPS/D-GalN injection. Liver function and the extent of liver injury were analyzed biochemically and pathologically respectively. Enzyme-linked immunosorbent assay, real-time polymerase chain reaction and Western blotting were used to detect effectors and signaling molecules. RESULTS: Pretreatment with synthetic RGDS peptide significantly improved LPS/D-GalN-induced mortality, and liver injury as determined by alanine aminotransferase (ALT) and aspartate aminotransferase (AST) activities, as well as pathological analysis. In addition, RGDS peptide significantly reduced tumor necrosis factor (TNF)-alpha and macrophage inflammatory protein (MIP)-2 production, and decreased myeloperoxidase (MPO) and NF-kappaB activity. Furthermore, Western blotting indicated that the levels of phospho-integrin beta3, phospho-focal adhesion kinase (FAK) and phospho-p38 mitogen-activated protein kinases (MAPK) decreased with RGDS peptide pretreatment. CONCLUSION: Together, these data suggest that synthetic RGDS peptide protect against LPS/D GalN-induced FHF by inhibiting inflammatory cells migration and blocking the integrin alphaVbeta3-FAK-p38 MAPK and NF-kappaB signaling. PMID- 24476053 TI - Recommendations for screening of donor and recipient prior to solid organ transplantation and to minimize transmission of donor-derived infections. AB - In the context of solid organ transplantation, screening of recipients and organ donors is crucial, and should be performed with great rigour to minimize the reactivation or the risk of transmission of certain infectious processes. This review aims to update understanding of the possible pathologies involved, as well as of emerging infections that, as a result of globalization, are gaining increasing prominence on a daily basis. PMID- 24476054 TI - The preregistration year: need for a national survey. PMID- 24476055 TI - Physics. AB - It is tempting for a lecturer in physics to present medical students with a course which, though sound and vigorous, is more suited to a physicist or engineer. At Guy's Hospital Medical School, physics is taught at a level which the student can follow and the relevance of the subject to the practice of medicine is made clear. PMID- 24476057 TI - Class participation: a simple, inexpensive technique. PMID- 24476056 TI - Prepare and use slides. AB - This article highlights the role of needs and creativity in the preparation and use of slides. It deals mainly with planning, design and use of 35 mm slides, and suggests how you can avoid the mistakes commonly made by teachers. It also offers guidance on how slides-a static medium-can become dynamic with a little imagination on the part of the teacher. PMID- 24476058 TI - The preregistration year at cambridge: one cohort of graduates' attitudes and experiences. AB - A questionnaire survey of the first cohort of Cambridge Clinical School graduates in their preregistration house posts revealed overall satisfaction with the posts they had undertaken, despite considerable variation in the demands made upon them. However, nearly 50 per cent thought that there was insufficient time to discuss diagnosis and patient management, especially with their consultant chiefs. The results are contrasted with those of earlier surveys. PMID- 24476061 TI - Letters. PMID- 24476062 TI - Synthesis of 2-pyridones by cycloreversion of [2.2.2]- bicycloalkene diketopiperazines. AB - A general strategy for the conversion of [2.2.2]-diazabicyclic alkene structures to 2-pyridone aromatic heterocyclic products is reported. The reaction sequence starts from 2,5-diketopiperazine (DKP) derivatives, is compatible with both aromatic and aliphatic aldehyde components, and can intercept either intra- or intermolecular cycloaddition manifolds. Priming of one aza-bridging function in the intermediate [2.2.2]-DKP scaffold permits cycloreversion (microwave heating) and selective extrusion of cyanate derivatives leading to the formation of 2 pyridone structures. Progress toward the synthesis of louisianin A and B, antiproliferative 2-pyridone natural products, is also disclosed. PMID- 24476063 TI - Allosteric modulation of substrate motion in cytochrome P450 3A4-mediated xylene oxidation. AB - Many cytochrome P450 enzymes (CYPs) exhibit allosteric behavior reflecting a complex ligand-binding process involving numerous factors: conformational selection, protein-protein interactions, substrate/effector/protein structure, and multiple-ligand binding. The interplay of CYP plasticity and rigidity contributes to substrate/product selectivity and to allosterism. Detailed evidence describing how protein motion modulates product selectivity is incomplete as are descriptions of effector-induced modulation of substrate dynamics. Our intent was to discover details of allosteric behavior and CYP3A4 flexibility and rigidity by investigating substrate motion using low-molecular weight ligands. Steady state kinetics and product ratios were measured for oxidation of m-xylene-(2)H3 and p-xylene; intramolecular isotope effects were measured for m-xylene-(2)H3 oxidation as a function of m-xylene-(2)H3 and p xylene concentration. Biphasic kinetic plots indicated homotropic cooperative behavior with xylene isomers. Selectivity for aromatic hydroxylation over benzylic hydroxylation of m-xylene-(2)H3 supports a model in which the region near the CYP3A4 active oxidizing species limits substrate dynamics. p-Xylene impedes the motion of m-xylene-(2)H3 substrates that have access to the active oxidizing species: (kH/kD)obs values for m-xylene-(2)H3 decreased with p-xylene concentration. m-Xylene-(2)H3 and p-xylene do not have simultaneous access to the active oxidizing species: deuterium-labeled and unlabeled p-xylene exhibited similar effects on the (kH/kD)obs values for m-xylene-(2)H3 oxidation. p-Xylene and m-xylene-(2)H3 bind at different sites: m-xylene-(2)H3 oxidation rates and product selectivity were consistent across the p-xylene concentration range. Overall, this study indicates that the intramolecular isotope effect experimental design provides a unique opportunity to investigate allosteric mechanisms as it provides information about substrate motion when the enzyme is primed to oxidize substrates. PMID- 24476064 TI - Occurrence and formation kinetics of pyranomalvidin-procyanidin dimer pigment in Merlot red wine: impact of acidity and oxygen concentrations. AB - Once released from red grape skins, anthocyanins undergo various chemical reactions leading to the formation of more stable pigments such as pyranoanthocyanin, as well as other derivatives. Among these pigments, pyranoanthocyanins linked directly to flavanol dimers have been detected and identified in aged Port wine but not in dry red wine. These pigments are very important with regard to the wine color evolution since they are involved in wine color evolution and stabilization. During this investigation, the occurrence in dry red wine of two pyranomalvidin-procyanidin dimer has been established by low and high resolution HPLC-UV-MS analysis. Moreover, the impact of acidity and oxygen levels on their formation in red wine has been estimated. After four months of evolution, the results showed that, for the same pH, the quantity of this pigment was correlated with oxygen concentrations. Moreover, for the same quantity of oxygen, the concentration of this pigment was related to the acidity level. PMID- 24476065 TI - Bioinspired scaffolds for osteochondral regeneration. AB - Osteochondral defects are difficult to treat because the articular cartilage and the subchondral bone have dissimilar characteristics and abilities to regenerate. Bioinspired scaffolds are designed to mimic structural and biological cues of the native osteochondral unit, supporting both cartilaginous and subchondral bone repair and the integration of the newly formed osteochondral matrix with the surrounding tissues. The aim of this review is to outline fundamental requirements and strategies for the development of biomimetic scaffolds reproducing the unique and multifaceted anatomical structure of the osteochondral unit. Recent progress in preclinical animal studies using bilayer and multilayer scaffolds, together with continuous gradient scaffolds will be discussed and placed in a translational perspective with data emerging from their clinical application to treat osteochondral defects in patients. PMID- 24476066 TI - Measuring free, conjugated, and halogenated estrogens in secondary treated wastewater effluent. AB - Steroidal estrogens are potent endocrine-disrupting chemicals that enter natural waters through the discharge of treated and raw sewage. Because estrogens are detrimental to aquatic organisms at sub-nanogram per liter concentrations, many studies have measured so-called "free" estrogen concentrations in wastewater effluents, rivers, and lakes. Other forms of estrogens are also of potential concern because conjugated estrogens can be easily converted to potent free estrogens by bacteria in wastewater treatment plants and receiving waters and halogenated estrogens are likely produced during wastewater disinfection. However, to the best of our knowledge, no studies have concurrently characterized free, conjugated, and halogenated estrogens. We have developed a method that is capable of simultaneously quantifying free, conjugated, and halogenated estrogens in treated wastewater effluent, in which detection limits were 0.13-1.3 ng L(-1) (free), 0.11-1.0 ng L(-1) (conjugated), and 0.18-18 ng L(-1) (halogenated). An aqueous phase additive, ammonium fluoride, was used to increase the electrospray (negative mode) ionization efficiency of free and halogenated estrogens by factors of 20 and 2.6, respectively. The method was validated using treated effluent from the greater Boston metropolitan area, where conjugated and halogenated estrogens made up 60-70% of the steroidal estrogen load on a molar basis. PMID- 24476067 TI - Self-assembly of stiff, adhesive and self-healing gels from common polyelectrolytes. AB - Underwater adhesion has numerous potential medical, household, and industrial applications. It is typically achieved through covalent polymerization and cross linking reactions and/or the use of highly specialized biological or biomimetic polymers. As a simpler alternative to these covalent and biomimetic strategies, this article shows that stiff, gel-like complexes that adhere to various substrates under water can also be prepared through the ionic cross-linking of common, commercial polyelectrolytes. The gels form spontaneously when synthetic polycations, such as poly(allylamine) (PAH), are mixed with strongly binding multivalent anions, pyrophosphate (PPi) and tripolyphosphate (TPP). The PAH/PPi and PAH/TPP gels exhibit very high storage moduli (Ginfinity' ~ 400 kPa), self heal when torn, and adhere to both hydrophilic and hydrophobic substrates under water (with short-term tensile adhesion strengths of 350-450 kPa). Furthermore, these gels can be dissolved on demand (if adhesion needs to be reversed) by changing the ambient pH, which controls the ionization state of the polyelectrolyte and ionic cross-linker. These properties suggest that synthetic polycations cross-linked with PPi and TPP ions could provide a simple, inexpensive, and scalable platform for underwater adhesion. PMID- 24476068 TI - Health literacy, cognitive ability, and functional health status among older adults. AB - OBJECTIVE: To investigate whether previously noted associations between health literacy and functional health status might be explained by cognitive function. DATA SOURCES/STUDY SETTING: Health Literacy and Cognition in Older Adults ("LitCog," prospective study funded by National Institute on Aging). Data presented are from interviews conducted among 784 adults, ages 55-74 years receiving care at an academic general medicine clinic or one of four federally qualified health centers in Chicago from 2008 to 2010. STUDY DESIGN: Study participants completed structured, in-person interviews administered by trained research assistants. DATA COLLECTION: Health literacy was measured using the Test of Functional Health Literacy in Adults, Rapid Estimate of Adult Literacy in Medicine, and Newest Vital Sign. Cognitive function was assessed using measures of long-term and working memory, processing speed, reasoning, and verbal ability. Functional health was assessed with SF-36 physical health summary scale and Patient Reported Outcomes Measurement Information System short form subscales for depression and anxiety. PRINCIPAL FINDINGS: All health literacy measures were significantly correlated with all cognitive domains. In multivariable analyses, inadequate health literacy was associated with worse physical health and more depressive symptoms. After adjusting for cognitive abilities, associations between health literacy, physical health, and depressive symptoms were attenuated and no longer significant. CONCLUSIONS: Cognitive function explains a significant proportion of the associations between health literacy, physical health, and depression among older adults. Interventions to reduce literacy disparities in health care should minimize the cognitive burden in behaviors patients must adopt to manage personal health. PMID- 24476069 TI - Tranilast administration reduces fibrosis and improves fatigue resistance in muscles of mdx dystrophic mice. AB - BACKGROUND: Duchenne muscular dystrophy (DMD) is a severe and progressive muscle wasting disorder caused by mutations in the dystrophin gene that result in the absence of the membrane-stabilising protein dystrophin. Dystrophic muscle fibres are susceptible to injury and degeneration, and impaired muscle regeneration is associated with fibrotic deposition that limits the efficacy of potential pharmacological, cell- and gene-based therapies. Novel treatments that can prevent or attenuate fibrosis have important clinical merit for DMD and related neuromuscular diseases. We investigated the therapeutic potential for tranilast, an orally bioavailable anti-allergic agent, to prevent fibrosis in skeletal muscles of mdx dystrophic mice. RESULTS: Three-week-old C57Bl/10 and mdx mice received tranilast (~300 mg/kg) in their food for 9 weeks, after which fibrosis was assessed through histological analyses, and functional properties of tibialis anterior muscles were assessed in situ and diaphragm muscle strips in vitro. Tranilast administration did not significantly alter the mass of any muscles in control or mdx mice, but it decreased fibrosis in the severely affected diaphragm muscle by 31% compared with untreated mdx mice (P < 0.05). A similar trend of decreased fibrosis was observed in the tibialis anterior muscles of mdx mice (P = 0.10). These reductions in fibrotic deposition were not associated with improvements in maximum force-producing capacity, but we did observe small but significant improvements in the resistance to fatigue in both the diaphragm and TA muscles of mdx mice treated with tranilast. CONCLUSION: Together these findings demonstrate that administration of potent antifibrotic compounds such as tranilast could help preserve skeletal muscle structure, which could ultimately increase the efficacy of pharmacological, cell and gene replacement/correction therapies for muscular dystrophy and related disorders. PMID- 24476070 TI - Long-lasting control of Anopheles arabiensis by a single spray application of micro-encapsulated pirimiphos-methyl (Actellic(r) 300 CS). AB - BACKGROUND: Pyrethroid-resistant mosquitoes are an increasing threat to malaria vector control. The Global Plan for Insecticide Resistance Management (GPIRM) recommends rotation of non-pyrethroid insecticides for indoor residual spraying (IRS). The options from other classes are limited. The carbamate bendiocarb and the organophosphate pirimiphos-methyl (p-methyl) emulsifiable concentrate (EC) have a short residual duration of action, resulting in increased costs due to multiple spray cycles, and user fatigue. Encapsulation (CS) technology was used to extend the residual performance of p-methyl. METHODS: Two novel p-methyl CS formulations were evaluated alongside the existing EC in laboratory bioassays and experimental hut trials in Tanzania between 2008-2010. Bioassays were carried out monthly on sprayed substrates of mud, concrete, plywood, and palm thatch to assess residual activity. Experimental huts were used to assess efficacy against wild free-flying Anopheles arabiensis, in terms of insecticide-induced mortality and blood-feeding inhibition. RESULTS: In laboratory bioassays of An. arabiensis and Culex quinquefasciatus both CS formulations produced high rates of mortality for significantly longer than the EC formulation on all substrates. On mud, the best performing CS killed >80% of An. arabiensis for five months and >50% for eight months, compared with one and two months, respectively, for the EC. In monthly bioassays of experimental hut walls the EC was ineffective shortly after spraying, while the best CS formulation killed more than 80% of An. arabiensis for five months on mud, and seven months on concrete. In experimental huts both CS and EC formulations killed high proportions of free-flying wild An. arabiensis for up to 12 months after spraying. There was no significant difference between treatments. All treatments provided considerable personal protection, with blood feeding inhibition ranging from 9-49% over time. CONCLUSIONS: The long residual performance of p-methyl CS was consistent in bioassays and experimental huts. The CS outperformed the EC in laboratory and hut bioassays but the EC longevity in huts was unexpected. Long-lasting p-methyl CS formulations should be more effective than both p-methyl EC and bendiocarb considering a single spray could be sufficient for annual malaria control. IRS with p-methyl 300 CS is a timely addition to the limited portfolio of long-lasting residual insecticides. PMID- 24476072 TI - Treadmill running reduces parathyroid hormone concentrations during recovery compared with a nonexercising control group. AB - CONTEXT: Lower PTH concentrations reported in the hours after acute, endurance exercise compared with preexercise levels might be influenced by factors such as circadian fluctuations. OBJECTIVE: The objective of the study was to compare postexercise PTH concentrations with a nonexercising control group. DESIGN AND SETTING: A laboratory-based study with a crossover design, comparing a 60-minute (at 10:30 am) bout of treadmill running at 65% of the maximal rate of oxygen uptake (exercise) with semirecumbent rest (CON). Blood samples were obtained immediately before (baseline 10:15 am) and after (11:30 am) exercise and during recovery (12:30 am, 1:30 pm, and 2:15 pm). PARTICIPANTS: Ten physically active men (mean +/- 1 SD, age 26 +/- 5 y; body mass 78.3 +/- 5.8 kg; maximal rate of oxygen uptake 57.3 +/- 6.9 mL/kg(-1) . min(-1)) participated in the study. MAIN OUTCOME MEASURES: PTH, albumin-adjusted calcium, and phosphate concentrations were measured. RESULTS: PTH concentrations increased (+85%, P < .01) during exercise and were higher than in CON immediately at the end of exercise (4.5 +/- 1.9 vs 2.6 +/- 0.9 pmol/L(-1), P < .05). In the postexercise period (12:30-2:15 pm), PTH was not different compared with baseline but was lower compared with CON at 1:30 pm (-22%; P < .01) and tended to be lower at both 12:30 pm (-12%; P = .063) and 2:15 pm (-13%; P = .057). Exercise did not significantly affect the albumin-adjusted calcium concentrations, whereas phosphate was higher than CON immediately after exercise (1.47 +/- 0.17 vs 1.03 +/- 0.17 pmol/L(-1), P < .001) and was lower at 1:30 pm (-16%: P < .05). CONCLUSIONS: Lower PTH concentrations after acute endurance running compared with a rested control condition suggest a true effect of exercise. PMID- 24476071 TI - Aliskiren limits abdominal aortic aneurysm, ventricular hypertrophy and atherosclerosis in an apolipoprotein-E-deficient mouse model. AB - Aliskiren is a direct renin inhibitor developed to treat hypertension. Several clinical studies have suggested that aliskiren has beneficial effects on cardiovascular diseases beyond its antihypertensive effect. In the present study, we examined whether aliskiren limits the progression of AAA (abdominal aortic aneurysm), VH (ventricular hypertrophy) and atherosclerosis in an AngII (angiotensin II)-infused mouse model. ApoE-/- (apolipoprotein-E-deficient) mice were infused subcutaneously with AngII (1000 ng/kg of body weight per day; 4 weeks) to induce AAA and VH. At the completion of the AngII infusion, mice were randomly allocated to three groups to receive vehicle control, low-dose aliskiren (10 mg/kg of body weight per day) or high-dose aliskiren (50 mg/kg of body weight per day) for 4 weeks. Suprarenal aortic diameter assessed by ultrasound was significantly smaller in mice administered aliskiren at days 42 and 56. Aliskiren also significantly reduced the normalized heart weight, ventricular myocyte cell width and aortic arch atherosclerosis. Aliskiren lowered PRR (pro-renin receptor) expression and MAPK (mitogen-activated protein kinase) activity in the suprarenal aorta and heart. Aortic infiltration of T-lymphocytes and macrophages was reduced by aliskiren. In conclusion, aliskiren limits the progression of AAA, VH and atherosclerosis in an AngII-infused mouse model. PMID- 24476073 TI - Suboptimal psychosocial outcomes in patients with congenital adrenal hyperplasia: epidemiological studies in a nonbiased national cohort in Sweden. AB - CONTEXT: Congenital adrenal hyperplasia (CAH), CYP21A2 deficiency, results in cortisol and aldosterone deficiency and increased production of androgens, with a good genotype phenotype correlation. OBJECTIVE: The objective of the investigation was to study psychosocial outcomes in relation to clinical severity, CYP21A2 genotype, in men and women. DESIGN: This was an epidemiological study with a matched case control design. SETTING: The setting of the study was all known CAH patients in Sweden. PARTICIPANTS: Five hundred eighty-eight patients, more than 80% with known severity of CAH, and 100 controls per patient matched for sex, year, and place of birth participated in the study. MAIN OUTCOME AND MEASURES: Proxies for quality of life were selected: level of education, employment, income, sick leave, disability pension, marriage, and children. RESULTS: Women with salt-wasting (SW) CAH had completed primary education less often [odds ratio (OR) 0.3], not explained by neonatal salt crisis or hypoglycemia because the men did not differ from controls. Men and women in the less severe I172N genotype group were more likely to have an academic education (OR 1.8). SW women were more likely to have an income in the top 20th percentile (OR 2.0). Both men and women had more disability pension (OR 1.5) and sick leave (OR 1.7). The men more often had long-lasting employment (OR 3.1). Men were more often (OR 1.6) and women were less often married (OR 0.7). Patients had children less often (OR 0.3). CONCLUSIONS: This study shows important outcome differences regarding education; employment; marriage and fertility, depending on sex; and severity of CAH. The mechanisms behind this and the increased risk for sick leave or disability pension in both men and women should be identified to improve medical and psychological care. PMID- 24476074 TI - Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism. AB - CONTEXT: Prior studies showed that Axl /Tyro3 null mice have delayed first estrus and abnormal cyclicity due to developmental defects in GnRH neuron migration and survival. OBJECTIVE: The objective of the study was to test whether the absence of Axl would alter reproductive function in mice and that mutations in AXL are present in patients with Kallmann syndrome (KS) or normosmic idiopathic hypogonadotropic hypogonadism (nIHH). DESIGN AND SETTING: The sexual maturation of Axl null mice was examined. The coding region of AXL was sequenced in 104 unrelated, carefully phenotyped KS or nIHH subjects. Frequency of mutations was compared with other causes of GnRH deficiency. Functional assays were performed on the detected mutations. RESULTS: Axl null mice demonstrated delay in first estrus and the interval between vaginal opening and first estrus. Three missense AXL mutations (p.L50F, p.S202C, and p.Q361P) and one intronic variant 6 bp upstream from the start of exon 5 (c.586-6 C>T) were identified in two KS and 2 two nIHH subjects. Comparison of the frequencies of AXL mutations with other putative causes of idiopathic hypogonadotropic hypogonadism confirmed they are rare variants. Testing of the c.586-6 C>T mutation revealed no abnormal splicing. Surface plasmon resonance analysis of the p.L50F, p.S202C, and p.Q361P mutations showed no altered Gas6 ligand binding. In contrast, GT1-7 GnRH neuronal cells expressing p.S202C or p.Q361P demonstrated defective ligand dependent receptor processing and importantly aberrant neuronal migration. In addition, the p.Q361P showed defective ligand independent chemotaxis. CONCLUSIONS: Functional consequences of AXL sequence variants in patients with idiopathic hypogonadotropic hypogonadism support the importance of AXL and the Tyro3, Axl, Mer (TAM) family in reproductive development. PMID- 24476075 TI - The expression of dual oxidase, thyroid peroxidase, and caveolin-1 differs according to the type of immune response (TH1/TH2) involved in thyroid autoimmune disorders. AB - CONTEXT: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are thyroid autoimmune disorders driven by Th1 and Th2 immune responses, respectively. Caveolin-1 (Cav-1), thyroid peroxidase (TPO), and dual oxidase (DUOX) are thought to be part of the thyroxisome, which is essential to maintain thyroid hormone synthesis, at the apical membrane. OBJECTIVES: To analyze the thyroxisome in HT and GD thyroids, we investigated Cav-1, DUOX, and TPO expression as well as markers of oxidative stress (OS), cell proliferation, apoptosis, and antioxidant defenses. The effects of cytokines on Cav-1 expression were analyzed in vitro. RESULTS: In HT, the decrease in Cav-1, DUOX, and TPO expression was marked in follicles having the morphological aspect of active follicles in normal glands and thus called active-like follicles. T4 was not detected in the colloid but in the cytoplasm as well as DUOX and TPO. These abnormalities were associated with increased OS and cell damage. In the hypofunctioning follicles of HT and normal thyroids, Cav-1, DUOX, and TPO were not expressed. In GD, they were expressed at the apical pole of thyrocytes, and T4 accumulated in the colloid of all follicles. Th1 cytokines IL-1alpha/interferongamma decreased Cav-1 expression in vitro, whereas the Th2 cytokine IL-4 had no effect. CONCLUSION: Th1 cytokine induced down-regulation of Cav-1 could be responsible for intracytoplasmic T4 synthesis and mislocalization of DUOX and TPO, suggesting an important role for Cav-1 in the preservation of thyroxisome integrity. The thyroxisome's disruption, leading to uncontrolled OS and cell apoptosis, is a key, event in HT pathogenesis. PMID- 24476076 TI - Posterior reversible encephalopathy syndrome due to malignant hypercalcemia: physiopathological considerations. AB - CONTEXT: Posterior reversible encephalopathy syndrome (PRES) is a neurological entity characterized by seizures, headache, and reversible subcortical vasogenic edema. It is associated with many etiologies, most often hypertension, chronic renal failure, and chemotherapy. Hypercalcemia is rarely associated with PRES. OBJECTIVE: The aim of this study is to describe and discuss a case of PRES that developed in a patient with malignant hypercalcemia, with emphasis on the possible pathophysiological mechanisms involved. PATIENTS AND METHODS: A 38-year old woman presented with altered mental status. She had a 2-month history of lumbar pain of moderate intensity, weight loss, and gastrointestinal complaints, in addition to a mass in her left breast. Her corrected serum calcium was 14.5 mg/dL. She was normotensive, had no focalizing signs, and her cerebrospinal fluid was normal. Despite treatment, her neurological state did not resolve, and she developed severe headaches at day 4 of her admission. Brain magnetic resonance imaging showed a bilateral and symmetric hyperintensity in the occipital and parietal lobes on T2-weighted and fluid-attenuated inversion recovery imaging, a characteristic highly suggestive of PRES. After correction of hypercalcemia, her symptoms and imaging abnormalities resolved. CONCLUSIONS: The development of PRES in the setting of severe hypercalcemia is extremely rare. Hypercalcemia could lead to PRES in the absence of hypertension by various mechanisms, including vasospasm, endothelial dysfunction, and an inflammatory state. A high index of suspicion is needed in this setting because hypercalcemia can lead to neurological symptomatology, and prompt diagnosis is essential for adequate treatment. PMID- 24476077 TI - Primary treatment regimen and diabetes insipidus as predictors of health outcomes in adults with childhood-onset craniopharyngioma. AB - CONTEXT: Craniopharyngiomas are often associated with significant morbidity due to their location and treatment effects. Little is known of the effects of primary treatment regimen and diabetes insipidus (DI), a clinical surrogate of hypothalamic obesity, on health outcomes in adults with childhood-onset craniopharyngioma (COCP). OBJECTIVE: The objective of the study was to examine health outcomes of adults with COCP based on primary treatment regimens and the presence of DI. DESIGN: This study included a retrospective KIMS (Pfizer International Metabolic Database) data analysis of 180 adults with COCP according to the primary treatment regimen [one surgery (1Surg) vs complex treatment regimen (CTrR) of more than 1Surg and/or radiotherapy] and the presence of DI. RESULTS: The majority of COCP patients underwent transcranial surgery (77%) without receiving radiotherapy (84%). Compared with the 1Surg group, more CTrR patients developed visual field defects and ophthalmoplegia (all P < .01). Compared with patients without DI, those with DI had higher rates of anterior pituitary hormone deficits, body mass index, and fat mass (all P < .01). By contrast, fasting glucose, hemoglobin A1c, lipid panel, and quality of life were comparable among 1Surg vs CTrR patients, and patients with vs without DI. Regardless of primary treatment received, the presence of DI in either group was associated with higher rates of anterior pituitary hormone deficits and obesity. CONCLUSION: CTrR and DI predicted health outcomes differently. CTrR predisposed to the development of visual dysfunction, whereas DI was associated with higher rates of anterior pituitary dysfunction and weight gain. Higher body mass index and fat mass in patients with DI further implicate the role of hypothalamic damage as an important causal factor of obesity in these patients. PMID- 24476078 TI - Images in clinical medicine: McCune-Albright syndrome. PMID- 24476080 TI - Case report: Three patients with substantial serum levels of 3-epi-25(OH)D including one with 3-epi-25(OH)D2 while on high-dose ergocalciferol. AB - CONTEXT: We report the presence of substantial concentrations of 3-epi-25(OH)D3 in two patients and a third patient with 3-epi-25(OH)D2. PATIENTS: The first patient, a 66-year-old female receiving cholecalciferol 4000 IU daily was originally found to have 53 ng/mL of 25(OH)D3 and almost an equal amount of 3-epi 25(OH)D3. Subsequently, the patient had four additional samples, each of which has similar levels of both 25(OH)D3 and 3-epi-25(OH)D3. The second patient, a 7 year-old male receiving cholecalciferol 1000 IU daily, had a 25(OH)D3 concentration of 37 ng/mL and 3-epi-25(OH)D3 of approximately 10 ng/mL. The third and most intriguing patient, a 55-year-old female was receiving ergocalciferol 50,000 IU twice weekly for approximately 3 months, at which time her serum 25(OH)D2 was 64 ng/mL and her 3-epi-25(OH)D2 was approximately 32 ng/mL. This patient's physician changed her vitamin D therapy to cholecalciferol 1000 IU daily, discontinuing ergocalciferol, and a second specimen was collected 5 months later. Analysis of this last specimen found both 25(OH)D3 and 25(OH)D2 at concentrations of 12 and 24 ng/mL respectively, plus corresponding 3-epimer peaks for both 25(OH)D3 and 25(OH)D2 observed chromatographically. CONCLUSION: The presence of a substantial concentration of 3-epi-25(OH)D in these three patients documents that one cannot assume 3-epi is a trivial metabolite of 25(OH)D for all patients. In addition, the appearance of 3-epi-25(OH)D3 when the last patient changed her vitamin D supplementation from ergocalciferol to cholecalciferol demonstrates that the 3-epimer is probably an endogenous metabolite of 25(OH)D in humans. PMID- 24476079 TI - TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. AB - CONTEXT: Telomerase promoter mutations (TERT) were recently described in follicular cell-derived thyroid carcinomas (FCDTC) and seem to be more prevalent in aggressive cancers. OBJECTIVES: We aimed to evaluate the frequency of TERT promoter mutations in thyroid lesions and to investigate the prognostic significance of such mutations in a large cohort of patients with differentiated thyroid carcinomas (DTCs). DESIGN: This was a retrospective observational study. SETTING AND PATIENTS: We studied 647 tumors and tumor-like lesions. A total of 469 patients with FCDTC treated and followed in five university hospitals were included. Mean follow-up (+/-SD) was 7.8 +/- 5.8 years. MAIN OUTCOME MEASURES: Predictive value of TERT promoter mutations for distant metastasization, disease persistence at the end of follow-up, and disease-specific mortality. RESULTS: TERT promoter mutations were found in 7.5% of papillary carcinomas (PTCs), 17.1% of follicular carcinomas, 29.0% of poorly differentiated carcinomas, and 33.3% of anaplastic thyroid carcinomas. Patients with TERT-mutated tumors were older (P < .001) and had larger tumors (P = .002). In DTCs, TERT promoter mutations were significantly associated with distant metastases (P < .001) and higher stage (P < .001). Patients with DTC harboring TERT promoter mutations were submitted to more radioiodine treatments (P = .009) with higher cumulative dose (P = .004) and to more treatment modalities (P = .001). At the end of follow-up, patients with TERT mutated DTCs were more prone to have persistent disease (P = .001). TERT promoter mutations were significantly associated with disease-specific mortality [in the whole FCDTC (P < .001)] in DTCs (P < .001), PTCs (P = .001), and follicular carcinomas (P < .001). After adjusting for age at diagnosis and gender, the hazard ratio was 10.35 (95% confidence interval 2.01-53.24; P = .005) in DTC and 23.81 (95% confidence interval 1.36-415.76; P = .03) in PTCs. CONCLUSIONS: TERT promoter mutations are an indicator of clinically aggressive tumors, being correlated with worse outcome and disease-specific mortality in DTC. TERT promoter mutations have an independent prognostic value in DTC and, notably, in PTC. PMID- 24476081 TI - Impact of parathyroidectomy on serum FGF23 and soluble Klotho in hemodialysis patients with severe secondary hyperparathyroidism. AB - CONTEXT: Klotho is a transmembrane protein that functions as a coreceptor for fibroblast growth factor 23 (FGF23). Klotho is cleaved and released into the circulation; however, the main site of production, physiological role, and regulation of soluble Klotho in humans are largely unknown. OBJECTIVE: The aim of this study was to determine the impact of parathyroidectomy (PTx) on serum FGF23 and soluble Klotho levels in patients with severe secondary hyperparathyroidism. DESIGN AND SETTING: This was a prospective, single-arm trial conducted at Tokai University School of Medicine. PATIENTS: Thirteen hemodialysis patients with severe secondary hyperparathyroidism who were candidates for PTx participated in the study. INTERVENTIONS: All patients underwent total PTx with forearm autotransplantation. MAIN OUTCOME MEASURES: We evaluated changes in serum FGF23 and soluble Klotho levels for 90 days after PTx. Other biochemical parameters related to mineral and bone metabolism were also assessed. RESULTS: At baseline, serum FGF23 levels were markedly elevated, whereas serum soluble Klotho levels were modestly decreased. PTx resulted in a marked, progressive decline in serum FGF23 levels together with significant reductions in serum calcium, phosphorus, and intact PTH levels. The serum soluble Klotho levels were reduced 13% from baseline on the day after PTx; however, these levels then increased progressively, reaching 34% above the postoperative values. CONCLUSIONS: Our results suggest that the parathyroid gland is not the major site of soluble Klotho production in patients with end-stage renal disease, and the production of Klotho by other organ(s) is affected by alterations in mineral metabolism or medications taken after PTx. PMID- 24476082 TI - Pharmacokinetics of human chorionic gonadotropin injection in obese and normal weight women. AB - CONTEXT: Obese women have poorer in vitro fertilization outcomes, but underlying mechanisms remain unclear. OBJECTIVE: The objectives of the study were to compare the pharmacokinetics of human chorionic gonadotropin (hCG) and ovarian steroid hormone production, after subcutaneous (s.c.) and intramuscular (i.m.) injection of hCG in obese and normal-weight women. DESIGN AND SETTING: This was a randomized, experimental study. PATIENTS OR OTHER PARTICIPANTS: Twenty-two women aged 18-42 years with body mass index of 18.5-24.9 (normal) or 30-40 kg/m(2) (obese). INTERVENTIONS: Participants received im urinary hCG or s.c. recombinant hCG and returned for a second injection type after a 4-week washout. Intramuscular injections were performed under ultrasound guidance. Blood was taken 0, 0.5, 1, 2, 4, 6, 8, 12, 24, and 36 hours after injection. MAIN OUTCOME MEASURES: hCG was measured at each time point; estradiol, progesterone, 17 hydroxyprogesterone (17-OHP), testosterone (T), dehydroepiandrosterone, and SHBG were measured at 0 and 36 hours. RESULTS: Twenty-two women completed the study. In both normal-weight and obese women, peak serum concentration (Cmax), area under the curve (AUC), and average hCG concentration were higher after i.m. injection as compared with s.c. injection (all P < .003). Obese women had markedly lower Cmax, AUC, and average hCG concentration after s.c. injection as compared with normal-weight women (P = .02, P = .009, and P = .008, respectively). After i.m. injection, Cmax, AUC, and average concentration were similar for normal-weight and obese women (P = .31, P = .25, and P = .18, respectively). Thirty-six percent of obese women had muscular layers beyond the reach of a standard 1.5 inch needle. hCG caused a significant rise in 17-OHP in both obese and normal-weight women and an increase in T in obese but not normal weight women (all P < .04). CONCLUSIONS: Subcutaneous injection yields lower hCG levels in obese women. Standard-length needles are insufficient to administer i.m. injections in many obese women. PMID- 24476084 TI - Ti/Ni-mediated inter- and intramolecular conjugate addition of aryl and alkenyl halides and triflates. AB - In this work, we show that the unique combination of a nickel catalyst and Cp2TiCl allows the direct conjugate addition of aryl and alkenyl iodides, bromides, and to a lesser extent, chlorides and triflates to alpha,beta unsaturated carbonyls at room temperature, without requiring the previous formation of an organometallic nucleophile. The reaction proceeds inter- and intramolecularly with good functional group compatibility, which is key for the development of free protecting group methodologies. Carbo- and heterocycles of five- and six-membered rings are obtained in good yields. Moreover, some insights about the mechanism involved have been obtained from cyclic voltammetry, UV-vis, and HRTEM measurements. PMID- 24476085 TI - Health-related quality of life of children with physical disabilities: a longitudinal study. AB - BACKGROUND: Outcomes of health and rehabilitation services for children and youth with disabilities increasingly include assessments of health-related quality of life (HRQoL). The purpose of this research was to 1) describe overall patterns of HRQoL, 2) examine changes in parent's perceptions of child's HRQoL across 18 months and 3) explore factors that predict these changes. METHODS: Participants in this study included 427 parents of children (229 boys and 198 girls) with a physically-based disability between the ages of 6 to 14 years. The Child Health Questionnaire (CHQ) was administered three times, at nine month intervals. Comparisons to the CHQ normative data were analyzed at Time 1 using t-tests, and change over time was examined using linear mixed-effects models. Possible predictors were modeled: 1) child's factors measured by the Activities Scale for Kids, Strengths and Difficulties Questionnaire, and general health measured by SF 36, 2) family characteristics measured by the Impact on Family Scale and 3) environmental barriers measured by the Craig Hospital Inventory of Environmental Factors. RESULTS: CHQ scores of the study's participants demonstrated significantly lower summary scores from the normative sample for both CHQ Physical and Psychosocial summary scores. On average, children did not change significantly over time for physical summary scores. There was an average increase in psychosocial health that was statistically significant, but small. However, there was evidence of heterogeneity among children. Environmental barriers, behavioral difficulties, family functioning/impact, general health and child physical functioning had negative and significant associations with physical QoL at baseline. Change in physical QoL scores over time was dependent on children's behavioral difficulties, family functioning and environmental barriers. Environmental barriers, behavioral difficulties, family functioning/impact and general health had significant associations with psychosocial scores at baseline, but none served as predictors of change over time. CONCLUSIONS: Children with physical disabilities differ from the normative group on parent ratings of their physical and psychosocial health. While there was little average change in CHQ scores over 18 months, there is evidence of heterogeneity among children. Factors such as environmental barriers, family functioning/impact, child physical functioning and behavioral difficulties and general health significantly influence QoL scores as measured by the CHQ. PMID- 24476086 TI - Whether all obese subjects both in metabolic groups and non-metabolic groups should be treated or not. AB - More recent researches have focused on metabolically healthy obese (MHO) phenotypes and on this phenotype, individuals may be obese without metabolic disorders. Osteoarthritis (OA), kidney diseases and sleep disorders are three factors related to the obesity that these conditions are associated only with obesity but not with metabolic complications. Regardless of whether obese individuals are in metabolic groups or not, they should be treated. All studies should be based on the risk of all-cause mortality in the MHO phenotypes. PMID- 24476087 TI - Single nucleotide polymorphisms for feed efficiency and performance in crossbred beef cattle. AB - BACKGROUND: This study was conducted to: (1) identify new SNPs for residual feed intake (RFI) and performance traits within candidate genes identified in a genome wide association study (GWAS); (2) estimate the proportion of variation in RFI explained by the detected SNPs; (3) estimate the effects of detected SNPs on carcass traits to avoid undesirable correlated effects on these economically important traits when selecting for feed efficiency; and (4) map the genes to biological mechanisms and pathways. A total number of 339 SNPs corresponding to 180 genes were tested for association with phenotypes using a single locus regression (SLRM) and genotypic model on 726 and 990 crossbred animals for feed efficiency and carcass traits, respectively. RESULTS: Strong evidence of associations for RFI were located on chromosomes 8, 15, 16, 18, 19, 21, and 28. The strongest association with RFI (P = 0.0017) was found with a newly discovered SNP located on BTA 8 within the ELP3 gene. SNPs rs41820824 and rs41821600 on BTA 16 within the gene HMCN1 were strongly associated with RFI (P = 0.0064 and P = 0.0033, respectively). A SNP located on BTA 18 within the ZNF423 gene provided strong evidence for association with RFI (P = 0.0028). Genomic estimated breeding values (GEBV) from 98 significant SNPs were moderately correlated (0.47) to the estimated breeding values (EBVs) from a mixed animal model. The significant (P < 0.05) SNPs (98) explained 26% of the genetic variance for RFI. In silico functional analysis for the genes suggested 35 and 39 biological processes and pathways, respectively for feed efficiency traits. CONCLUSIONS: This study identified several positional and functional candidate genes involved in important biological mechanisms associated with feed efficiency and performance. Significant SNPs should be validated in other populations to establish their potential utilization in genetic improvement programs. PMID- 24476088 TI - Articular cartilage lesions of the patellofemoral joint in dogs with naturally occurring cranial cruciate ligament disease. AB - OBJECTIVE: To evaluate frequency, severity, and location of patellofemoral (PF) osteoarthritis (OA) in dogs with naturally occurring cranial cruciate ligament (CCL) disease. STUDY DESIGN: Cross-sectional observational study. ANIMALS: Dogs (n = 40; stifles, 44). METHODS: Stifle arthroscopic video recordings and radiographs were performed. Cartilage pathology was scored at 3 locations (proximal, middle, distal) in the trochlear groove and patella. A radiographic osteoarthrosis and synovial pathology score were assigned. A Kruskal-Wallis test was used to determine if lesion severity varied by site, synovitis, and osteoarthrosis, and the Dunn's test was used for pairwise comparisons. The variability of body weight was evaluated using 1 way ANOVA; P < .05 was considered significant. RESULTS: Cartilage pathology and synovitis was identified in all PF joints. The proximal aspect of the trochlear groove had significantly higher cartilage scores than the middle and distal sites and the middle groove site was significantly higher than the distal site. The distal aspect of the patella had significantly greater scores than the middle and proximal patellar locations. Higher synovitis scores were associated with increased cartilage scores. Cartilage scores were significantly greater in stifles with higher radiographic osteophytosis, tibial sclerosis, and patellar enthesiophytosis scores. Higher body weights were significantly associated with greater synovial and radiographic scores. CONCLUSIONS: Dogs with CCL disease have a high incidence of PF cartilage pathology and the severity of cartilage lesions varies depending on location within the joint. PMID- 24476089 TI - Risk assessment of inbreeding and outbreeding depression in a captive-breeding program. AB - Captive-breeding programs can be implemented to preserve the genetic diversity of endangered populations such that the controlled release of captive-bred individuals into the wild may promote recovery. A common difficulty, however, is that programs are founded with limited wild broodstock, and inbreeding can become increasingly difficult to avoid with successive generations in captivity. Program managers must choose between maintaining the genetic purity of populations, at the risk of inbreeding depression, or interbreeding populations, at the risk of outbreeding depression. We evaluate these relative risks in a captive-breeding program for 3 endangered populations of Atlantic salmon (Salmo salar). In each of 2 years, we released juvenile F(1) and F(2) interpopulation hybrids, backcrosses, as well as inbred and noninbred within-population crosstypes into 9 wild streams. Juvenile size and survival was quantified in each year. Few crosstype effects were observed, but interestingly, the relative fitness consequences of inbreeding and outbreeding varied from year to year. Temporal variation in environmental quality might have driven some of these annual differences, by exacerbating the importance of maternal effects on juvenile fitness in a year of low environmental quality and by affecting the severity of inbreeding depression differently in different years. Nonetheless, inbreeding was more consistently associated with a negative effect on fitness, whereas the consequences of outbreeding were less predictable. Considering the challenges associated with a sound risk assessment in the wild and given that the effect of inbreeding on fitness is relatively predictable, we suggest that risk can be weighted more strongly in terms of the probable outcome of outbreeding. Factors such as genetic similarities between populations and the number of generations in isolation can sometimes be used to assess outbreeding risk, in lieu of experimentation. PMID- 24476090 TI - Selective free radical reactions using supercritical carbon dioxide. AB - We report herein a means to modify the reactivity of alkenes, and particularly to modify their selectivity toward reactions with nonpolar reactants (e.g., nonpolar free radicals) in supercritical carbon dioxide near the critical point. Rate constants for free radical addition of the light hydrogen isotope muonium to ethylene, vinylidene fluoride, and vinylidene chloride in supercritical carbon dioxide are compared over a range of pressures and temperatures. Near carbon dioxide's critical point, the addition to ethylene exhibits critical speeding up, while the halogenated analogues display critical slowing. This suggests that supercritical carbon dioxide as a solvent may be used to tune alkene chemistry in near-critical conditions. PMID- 24476091 TI - Prevalence of fur mites (Chirodiscoides caviae) in pet guinea pigs (Cavia porcellus) in southern Italy. AB - BACKGROUND: Chirodiscoides caviae is the most common fur mite affecting guinea pigs; infestation is generally asymptomatic. No studies have been published on the prevalence of such mites in guinea pigs in southern Italy. HYPOTHESIS/OBJECTIVES: We sought to evaluate the prevalence and the clinical signs of C. caviae infestation in guinea pigs in southern Italy. ANIMALS: Clinical records of guinea pigs evaluated from August 2012 to July 2013 were retrospectively searched. METHODS: In this retrospective matched case-control study, records of guinea pigs with evidence of C. caviae infestation were selected. The prevalence of C. caviae infestation was evaluated and exposure variables were assessed among guinea pigs with and without infestation using stepwise conditional logistic regression. Guinea pigs seen during the same time period, but without a diagnosis of C. caviae, were included as control animals. RESULTS: The prevalence of C. caviae was 32% (42 of 131); 66.6% of affected guinea pigs (28 of 42) originated from pet shops, whereas 28% (14 of 42) were privately owned. Thirty-one guinea pigs (73.8%) were asymptomatic, whereas 11 (26.1%) showed clinical signs (pruritus, alopecia, erythema and scaling). The most frequently affected area was the lumbosacral region (38 of 42). Guinea pigs in pet shops were more likely to be affected by C. caviae than owned guinea pigs (odds ratio, 5.12; 95% confidence interval, 2.32-11.29; P < 0.0001). CONCLUSIONS AND CLINICAL IMPORTANCE: The results of this study indicate a high prevalence of C. caviae infestation in guinea pigs in southern Italy. Chirodiscoides mites should be sought in guinea pigs, particularly in animals coming from pet shops. PMID- 24476092 TI - A systematic review and meta-analysis of the efficacy of lixisenatide in the treatment of patients with type 2 diabetes. AB - The aim of this study is to assess the efficacy and safety of lixisenatide for treating type 2 diabetes. A systematic search in electronic databases (up to October 2012) was conducted and the manufacturer was contacted regarding unpublished data. Randomized controlled trials (RCTs) were included if they provided information on at least one of the following outcomes: mortality, health related quality of life, hypoglycaemic events, adverse events, change in HbA1c, body weight, blood pressure, gastric emptying, fasting plasma glucose or 2 h postprandial glucose (PPG). Twenty-six publications and 10 unpublished study reports, relating to 14 RCTs (6156 patients) were included. Eleven studies related to placebo comparisons; active comparators were in three studies. Compared to placebo, lixisenatide significantly reduced HbA1c (-0.52%; 95% CI: 0.64 to -0.39), bodyweight (-0.65 kg; 95% CI: -0.94 to -0.37) and 2-h PPG level ( 4.58 mmol/l; 95% CI: -5.88 to -3.28). There were significantly more symptomatic hypoglycaemic events among lixisenatide compared to placebo-treated patients (log OR: 0.54; 95% CI: 0.32-0.75), but significantly fewer compared to other incretin mimetics. In comparison to exenatide and liraglutide, lixisenatide was more effective in reducing 2 h-PPG with a better adverse events profile, but it showed a lower reduction in HbA1c and body weight. Lixisenatide improves HbA1c levels and moderately reduces body weight compared to placebo and showed less frequent symptomatic hypoglycaemic and gastrointestinal events and an improvement in PPG control compared to other GLP-1 agonists. Firm conclusions regarding the performance of lixisenatide compared to other incretin mimetics, however, can not yet be drawn, due to limited data. PMID- 24476093 TI - Electrospun biomimetic fibrous scaffold from shape memory polymer of PDLLA-co-TMC for bone tissue engineering. AB - Multifunctional fibrous scaffolds, which combine the capabilities of biomimicry to the native tissue architecture and shape memory effect (SME), are highly promising for the realization of functional tissue-engineered products with minimally invasive surgical implantation possibility. In this study, fibrous scaffolds of biodegradable poly(d,l-lactide-co-trimethylene carbonate) (denoted as PDLLA-co-TMC, or PLMC) with shape memory properties were fabricated by electrospinning. Morphology, thermal and mechanical properties as well as SME of the resultant fibrous structure were characterized using different techniques. And rat calvarial osteoblasts were cultured on the fibrous PLMC scaffolds to assess their suitability for bone tissue engineering. It is found that by varying the monomer ratio of DLLA:TMC from 5:5 to 9:1, fineness of the resultant PLMC fibers was attenuated from ca. 1500 down to 680 nm. This also allowed for readily modulating the glass transition temperature Tg (i.e., the switching temperature for actuating shape recovery) of the fibrous PLMC to fall between 19.2 and 44.2 degrees C, a temperature range relevant for biomedical applications in the human body. The PLMC fibers exhibited excellent shape memory properties with shape recovery ratios of Rr > 94% and shape fixity ratios of Rf > 98%, and macroscopically demonstrated a fast shape recovery (~10 s at 39 degrees C) in the pre-deformed configurations. Biological assay results corroborated that the fibrous PLMC scaffolds were cytocompatible by supporting osteoblast adhesion and proliferation, and functionally promoted biomineralization-relevant alkaline phosphatase expression and mineral deposition. We envision the wide applicability of using the SME-capable biomimetic scaffolds for achieving enhanced efficacy in repairing various bone defects (e.g., as implants for healing bone screw holes or as barrier membranes for guided bone regeneration). PMID- 24476094 TI - Copper-mediated oxidative decarboxylative coupling of arylpropiolic acids with dialkyl H-phosphonates in water. AB - An efficient, mild, and generally applicable protocol for copper-mediated oxidative decarboxylative coupling of arylpropiolic acids with dialkyl H phosphonates in water has been developed. Note that the reaction could proceed smoothly under air at relatively low temperature (60 degrees C), and the addition of isopropanol could successfully suppress the decomposition of dialkyl H-phosphonates in water. PMID- 24476095 TI - Emerging device applications for semiconducting two-dimensional transition metal dichalcogenides. AB - With advances in exfoliation and synthetic techniques, atomically thin films of semiconducting transition metal dichalcogenides have recently been isolated and characterized. Their two-dimensional structure, coupled with a direct band gap in the visible portion of the electromagnetic spectrum, suggests suitability for digital electronics and optoelectronics. Toward that end, several classes of high performance devices have been reported along with significant progress in understanding their physical properties. Here, we present a review of the architecture, operating principles, and physics of electronic and optoelectronic devices based on ultrathin transition metal dichalcogenide semiconductors. By critically assessing and comparing the performance of these devices with competing technologies, the merits and shortcomings of this emerging class of electronic materials are identified, thereby providing a roadmap for future development. PMID- 24476096 TI - Morphological effects of G-quadruplex stabilization using a small molecule in zebrafish. AB - Zebrafish (Danio rerio) embryos are transparent and advantageous for studying early developmental changes due to ex utero development, making them an appropriate model for studying gene expression changes as a result of molecular targeting. Zebrafish embryos were injected with a previously reported G quadruplex selective ligand, and the phenotypic changes were recorded. We report marked discrepancies in the development of intersegmental vessels. In silico analysis determined that the putative G-quadruplex motif occur in the upstream promoter region of the Cdh5 (N-cadherin) gene. A real-time polymerase chain reaction-based investigation indicated that in zebrafish, CDH-2 (ZN-cad) was significantly downregulated in the ligand-treated embryos. Biophysical characterization of the interaction of the ligand with the G-quadruplex motif found in this promoter yielded strong binding and stabilization of the G quadruplex with this ligand. Hence, we report for the first time the phenotypic impact of G-quadruplex targeting with a ligand in a vertebrate organism. This study has unveiled not only G-quadruplex targeting in non-human animal species but also the potential that G-quadruplexes can provide a ready tool for understanding the phenotypic effects of targeting certain important genes involved in differentiation and developmental processes in a living eukaryotic organism. PMID- 24476097 TI - The medical home transformation in the Veterans Health Administration: an evaluation of early changes in primary care delivery. AB - OBJECTIVE: To evaluate the effect of medical home implementation on primary care delivery in the Veterans Health Administration (VHA). DATA SOURCES/STUDY SETTING/STUDY DESIGN: We link interview-based qualitative data on medical home implementation to quantitative outcomes from VHA clinical encounter data. We use a longitudinal analysis with provider fixed effects (taking advantage of variation in timing of implementation and allowing each provider to serve as a control for him or herself) to test whether patient-aligned care team (PACT) implementation was associated with changes in organizational processes and patient outcomes. PRINCIPAL FINDINGS: Among 683 PCPs, caring for 321,295 patients, the uptake of eight of nine PACT structural changes significantly increased from July 2010 to June 2012 as did the percentage of primary care appointments occurring by telephone and hospital discharges contacted within 2 days of discharge. We found that PACT implementation was associated with significant improvements in 2-day post-hospital discharge contact, but not primary care visits occurring by telephone or within 3 days of the requested date. We found no association between medical home implementation and rates of emergency department use by patients. CONCLUSIONS: Medical home implementation at the VHA resulted in large changes in the structure of care but few changes in patient-level outcomes. These results highlight both the complexity of studying the effect of the medical home as well as implementing this model to change primary care delivery. PMID- 24476098 TI - A case of metastatic cancer with markedly elevated PSA level that was not detected by repeat prostate biopsy. AB - BACKGROUND: Prostate-specific antigen (PSA) is a widely used specific tumor marker for prostate cancer. We experienced a case of metastatic prostate cancer that was difficult to detect by repeat prostate biopsy despite a markedly elevated serum PSA level. CASE PRESENTATION: A 64-year-old man was referred to our hospital with lumbar back pain and an elevated serum PSA level of 2036 ng/mL. Computed tomography, bone scintigraphy, and magnetic resonance imaging showed systemic lymph node and osteoblastic bone metastases. Digital rectal examination revealed a small, soft prostate without nodules. Ten-core transrectal prostate biopsy yielded negative results. Androgen deprivation therapy (ADT) was started because of the patient's severe symptoms. Twelve-core repeat transrectal prostate biopsy performed 2 months later, and transurethral resection biopsy performed 5 months later, both yielded negative results. The patient refused further cancer screening because ADT effectively relieved his symptoms. His PSA level initially decreased to 4.8 ng/mL, but he developed castration-resistant prostate cancer 7 months after starting ADT. He died 21 months after the initial prostate biopsy from disseminated intravascular coagulation. CONCLUSION: CUP remains a considerable challenge in clinical oncology. Biopsies of metastatic lesions and multimodal approaches were helpful in this case. PMID- 24476099 TI - Proton transfer pathways, energy landscape, and kinetics in creatine-water systems. AB - We study the exchange processes of the metabolite creatine, which is present in both tumorous and normal tissues and has NH2 and NH groups that can transfer protons to water. Creatine produces chemical exchange saturation transfer (CEST) contrast in magnetic resonance imaging (MRI). The proton transfer pathway from zwitterionic creatine to water is examined using a kinetic transition network constructed from the discrete path sampling approach and an approximate quantum chemical energy function, employing the self-consistent-charge density-functional tight-binding (SCC-DFTB) method. The resulting potential energy surface is visualized by constructing disconnectivity graphs. The energy landscape consists of two distinct regions corresponding to the zwitterionic creatine structures and deprotonated creatine. The activation energy that characterizes the proton transfer from the creatine NH2 group to water was determined from an Arrhenius fit of rate constants as a function of temperature, obtained from harmonic transition state theory. The result is in reasonable agreement with values obtained in water exchange spectroscopy (WEX) experiments. PMID- 24476100 TI - Epidemiology of mucormycosis in Europe. AB - Zygomycosis (mucormycosis) is being increasingly recognized as causing infection in recent years. National and multinational European surveys attempting to analyse the epidemiological parameters of this potentially devastating infection are very few. Although the exact incidence could not be defined due to the different methodologies used in these studies and the absence of a denominator, there were some useful observations made regarding the clinical presentation, sites of infection and diagnostic practices. Moreover, the importance for a prompt and accurate diagnosis has been stressed. As early diagnosis can significantly affect the initiation of treatment and decrease mortality, future research should focus on the development of an epidemiological risk assessment tool and novel diagnostic methods. PMID- 24476101 TI - Influence of microwaves treatment of rapeseed on phenolic compounds and canolol content. AB - Rapeseeds were treated with microwaves under 800 W for 0, 1, 2, 3, 4, 5, 6, 7, and 8 min at a frequency of 2450 MHz, and oil was extracted with a press to investigate the influence on phenolic compounds, including sinapine, the main free phenolic acids, and canolol content in the rapeseeds and oil from them. The results indicated that sinapine and sinapic acid was the main phenolic compound and free phenolic acid in the rapeseed, respectively, and canolol was the main phenolic compound in the oil from rapeseed by cold press. Microwave treatment significantly influenced phenolic compounds content in the rapeseeds and oil from them. The sinapine, sinapic acid, and canolol content in rapeseed first increased and then decreased depending on the period of microwave radiation (p < 0.05). The canolol content of 7 min microwave pretreatment rapeseed increased to the maximum and was approximately six times greater than that of the unroasted rapeseed. The amount of canolol formed was significantly correlated with the content of sinapic acid and sinapine (for sinapic acid, r = -0.950, p < 0.001, for sinapine, r = 0.828, p < 0.05) and also the loss of sinapic acid and sinapine (for sinapic acid, r = 0.997, p < 0.001, for sinapine, r = 0.952, p < 0.05) during roasting. There were differences in the transfer rate of difference phenolic compounds to the oil extracted by press. Almost all of the sinapine remained in the cold pressed cake and only 1.4-2.7% of the sinapic acid, whereas approximately 56-83% of the canolol was transferred to the oil. The transfer ratio of canolol significantly increased with microwave radiation time (p < 0.001). Microwave pretreatment of rapeseed benefited improving the oxidative stability of oil. PMID- 24476102 TI - Modulation of obesity-induced inflammation by dietary fats: mechanisms and clinical evidence. AB - Obesity plays a pivotal role in the development of low-grade inflammation. Dietary fatty acids are important modulators of inflammatory responses. Saturated fatty acids (SFA) and n-6 polyunsaturated fatty acids (PUFA) have been reported to exert pro-inflammatory effects. n-3 PUFA in particular, possess anti inflammatory properties. Numerous clinical studies have been conducted over decades to investigate the impact of dietary fatty acids on inflammatory response in obese individuals, however the findings remained uncertain. High fat meals have been reported to increase pro-inflammatory responses, however there is limited evidence to support the role of individual dietary fatty acids in a postprandial state. Evidence in chronic studies is contradictory, the effects of individual dietary fatty acids deserves further attention. Weight loss rather than n-3 PUFA supplementation may play a more prominent role in alleviating low grade inflammation. In this context, the present review provides an update on the mechanistic insight and the influence of dietary fats on low grade inflammation, based on clinical evidence from acute and chronic clinical studies in obese and overweight individuals. PMID- 24476103 TI - Phosphinogold(I) dithiocarbamate complexes: effect of the nature of phosphine ligand on anticancer properties. AB - The reactions of potassium salts of the dithiocarbamates L {where L = pyrazolyldithiocarbamate (L1), 3,5-dimethylpyrazolyldithiocarbamate (L2), or indazolyldithiocarbamate (L3)} with the gold precursors [AuCl(PPh3)], [Au2Cl2(dppe)], [Au2Cl2(dppp)], or [Au2Cl2(dpph)] lead to the new gold(I) complexes [AuL(PPh3)] (1-3), [Au2L2(dppe)] (4-6), [(Au2L2)(dppp)] (7-9), and [Au2(L)2(dpph)] (10-12) {where dppe = 1,2-bis(diphenylphosphino)ethane, dppp = 1,3-bis(diphenylphosphino)propane, and dpph = 1,6-bis(diphenylphosphino)hexane}. These gold compounds were characterized by a combination of NMR and infrared spectroscopy, microanalysis, and mass spectrometry; and in selected cases by single-crystal X-ray crystallography. Compounds 4-6, which have dppe ligands, are unstable in solution for prolonged periods, with 4 readily transforming to the Au18 cluster [Au18S8(dppe)6]Cl2 (4a) in dichloromethane. Compounds 1-3 and 7-12 are all active against human cervical epithelioid carcinoma (HeLa) cells, but the most active compounds are 10 and 11, with IC50 values of 0.51 MUM and 0.14 MUM, respectively. Compounds 10 and 11 are more selective toward HeLa cells than they are toward normal cells, with selectivities of 25.0 and 70.5, respectively. Further tests, utilizing the 60-cell-line Developmental Therapeutics Program at the National Cancer Institute (U.S.A.), showed 10 and 11 to be active against nine other types of cancers. PMID- 24476104 TI - Gas6 enhances axonal ensheathment by MBP+ membranous processes in human DRG/OL promyelinating co-cultures. AB - The molecular requirements for human myelination are incompletely defined, and further study is needed to fully understand the cellular mechanisms involved during development and in demyelinating diseases. We have established a human co culture model to study myelination. Our earlier observations showed that addition of human gamma-carboxylated growth-arrest-specific protein 6 (Gas6) to human oligodendrocyte progenitor cell (OPC) cultures enhanced their survival and maturation. Therefore, we explored the effect of Gas6 in co-cultures of enriched OPCs plated on axons of human fetal dorsal root ganglia explant. Gas6 significantly enhanced the number of myelin basic protein-positive (MBP+) oligodendrocytes with membranous processes parallel with and ensheathing axons relative to co-cultures maintained in defined medium only for 14 days. Gas6 did not increase the overall number of MBP+ oligodendrocytes/culture; however, it significantly increased the length of MBP+ oligodendrocyte processes in contact with and wrapping axons. Multiple oligodendrocytes were in contact with a single axon, and several processes from one oligodendrocyte made contact with one or multiple axons. Electron microscopy supported confocal Z-series microscopy demonstrating axonal ensheathment by MBP+ oligodendrocyte membranous processes in Gas6-treated co-cultures. Contacts between the axonal and oligodendrocyte membranes were evident and multiple wraps of oligodendrocyte membrane around the axon were visible supporting a model system in which to study events in human myelination and aspects of non-compact myelin formation. PMID- 24476106 TI - A randomized controlled trial comparing Circle of Security Intervention and treatment as usual as interventions to increase attachment security in infants of mentally ill mothers: Study Protocol. AB - BACKGROUND: Psychopathology in women after childbirth represents a significant risk factor for parenting and infant mental health. Regarding child development, these infants are at increased risk for developing unfavorable attachment strategies to their mothers and for subsequent behavioral, emotional and cognitive impairments throughout childhood. To date, the specific efficacy of an early attachment-based parenting group intervention under standard clinical outpatient conditions, and the moderators and mediators that promote attachment security in infants of mentally ill mothers, have been poorly evaluated. METHODS/DESIGN: This randomized controlled clinical trial tests whether promoting attachment security in infancy with the Circle of Security (COS) Intervention will result in a higher rate of securely attached children compared to treatment as usual (TAU). Furthermore, we will determine whether the distributions of securely attached children are moderated or mediated by variations in maternal sensitivity, mentalizing, attachment representations, and psychopathology obtained at baseline and at follow-up. We plan to recruit 80 mother-infant dyads when infants are aged 4-9 months with 40 dyads being randomized to each treatment arm. Infants and mothers will be reassessed when the children are 16-18 months of age. Methodological aspects of the study are systematic recruitment and randomization, explicit inclusion and exclusion criteria, research assessors and coders blinded to treatment allocation, advanced statistical analysis, manualized treatment protocols and assessments of treatment adherence and integrity. DISCUSSION: The aim of this clinical trial is to determine whether there are specific effects of an attachment-based intervention that promotes attachment security in infants. Additionally, we anticipate being able to utilize data on maternal and child outcome measures to obtain preliminary indications about potential moderators of the intervention and inform hypotheses about which intervention may be most suitable when offered in a clinical psychiatric outpatient context. TRIAL REGISTRATION: Current Controlled Trials ISRCTN88988596. PMID- 24476107 TI - Australian health reforms: enhancing interprofessional practice and competency within the health workforce. AB - Underpinned by increasing healthcare complexity and ongoing pressures to control the cost of healthcare, governments are increasingly calling for improved health service delivery models. A public policy paradigm of partnership-based, collaborative interprofessional working is central to revised models of health service delivery. Collaborative activity and service re-design do not occur by chance. They are complex and multi-faceted. Increasingly, calls for collaborative style health service re-design activities are being translated to a need to agree on a clear set of interprofessional competencies and develop a culture of interprofessional practice (IPP) across the sector. This report summarizes the requirements for developing a culture of interprofessional practice within the context of Australian healthcare reforms. It also highlights the role of well developed interprofessional competency frameworks to support envisaged changes in practice. The report expands the discussion in this area by referring to the work of two other nations with prior developments in interprofessional workplace development and reform. PMID- 24476105 TI - Larval body patterning and apical organs are conserved in animal evolution. AB - BACKGROUND: Planktonic ciliated larvae are characteristic for the life cycle of marine invertebrates. Their most prominent feature is the apical organ harboring sensory cells and neurons of largely undetermined function. An elucidation of the relationships between various forms of primary larvae and apical organs is key to understanding the evolution of animal life cycles. These relationships have remained enigmatic due to the scarcity of comparative molecular data. RESULTS: To compare apical organs and larval body patterning, we have studied regionalization of the episphere, the upper hemisphere of the trochophore larva of the marine annelid Platynereis dumerilii. We examined the spatial distribution of transcription factors and of Wnt signaling components previously implicated in anterior neural development. Pharmacological activation of Wnt signaling with Gsk3beta antagonists abolishes expression of apical markers, consistent with a repressive role of Wnt signaling in the specification of apical tissue. We refer to this Wnt-sensitive, six3- and foxq2-expressing part of the episphere as the 'apical plate'. We also unraveled a molecular signature of the apical organ- devoid of six3 but expressing foxj, irx, nkx3 and hox--that is shared with other marine phyla including cnidarians. Finally, we characterized the cell types that form part of the apical organ by profiling by image registration, which allows parallel expression profiling of multiple cells. Besides the hox-expressing apical tuft cells, this revealed the presence of putative light- and mechanosensory as well as multiple peptidergic cell types that we compared to apical organ cell types of other animal phyla. CONCLUSIONS: The similar formation of a six3+, foxq2+ apical plate, sensitive to Wnt activity and with an apical tuft in its six3-free center, is most parsimoniously explained by evolutionary conservation. We propose that a simple apical organ--comprising an apical tuft and a basal plexus innervated by sensory-neurosecretory apical plate cells--was present in the last common ancestors of cnidarians and bilaterians. One of its ancient functions would have been the control of metamorphosis. Various types of apical plate cells would then have subsequently been added to the apical organ in the divergent bilaterian lineages. Our findings support an ancient and common origin of primary ciliated larvae. PMID- 24476108 TI - The comparison of muscle strength and short-term endurance in the different periods of type 2 diabetes. AB - BACKGROUND: Patients with type 2 diabetes (T2DM) are subjected to reduction in the quality and oxidative capacity of muscles. The effect of duration of diabetes on the muscle endurance response is not clear and strength as well. OBJECTIVE: The aim of this study was the assessment of strength and endurance of knee extensor and flexor in the patients with T2DM < 10 and T2DM > 10 years in comparison with age, sex, BMI, ABI and PAI-matched health control subjects. METHODS: Isometric maximal peak torque (MPT) of knee extensor and flexor before and after 40 isokinetic repetitions with velocity of 150 degree/s were recorded in 18 patients with T2DM < 10 Y , 12 patients with T2DM > 10 Y and 20 matched health control (HC) groups. RESULTS: Both diabetic patient groups had significant lower isometric and isotonic knee extensor and flexor strength than HC. The endurance indices indicated that whereas the isometric MPT of flexor movement was reduced after isokinetic protocol in the both patient groups in comparison with HC, the less decline was seen in the isotonic torque and work during isokinetic protocol in the T2DM > 10 Y group in comparison with two other groups. The HbA1c and FPG were significantly correlated with strength not with endurance indices. CONCLUSIONS: It seems the progression of diabetes accompanied with vascular, neural and muscular deficits activate, some adaptive and compensatory processes which can maintain muscle performance. PMID- 24476110 TI - Nursing-using the nursing process. AB - It has often been pointed out that the real problem of nurse numbers is not the failure to recruit or to recruit appropriately, but to retain nurses once they have started. The indications are that where the nursing process approach is used in practice as well as taught, nurses (both learners and trained staff) derive more satisfaction from their work. They are then less likely to become disillusioned and/or leave nursing. PMID- 24476109 TI - A call for action. PMID- 24476111 TI - Construct a Problem-based Course. AB - This article outlines the preparation of an integrated, problem-based course as followed by the Faculty of Medicine, University of Newcastle, New South Wales. The policy and philosophy of the school, and the cardiovascular system course unit will be outlined in subsequent issues of this journal (Neame 1981, Powis and Neame 1981). The keys to successful course construction are faculty emphasis on the tasks to be achieved rather than on the disciplines themselves, coherent statements of policy and objectives which staff view as at least as important as those of their own disciplines, and a willingness to communicate, negotiate and be flexible. Students at the end of their third year were considered to be at least as competent as those from conventional curricula and excelled in some areas. A recent unpublished survey of the full-time academic staff revealed a high level of commitment to the goals of the course and satisfaction with the procedures involved. PMID- 24476112 TI - The Enhancement of Teaching Skills in US Medical Schools: An Overview and some Recommendations. AB - Most medical teachers have little or no preparation for their responsibilities as teachers. A growing number in the United States, however, are expressing an interest in enhancing their teaching skills and are attending faculty development programmes being offered by their own medical schools and by various professional organizations. This article describes those characteristics of effective faculty development programmes which are most logically defensible. PMID- 24476113 TI - A simple model to teach electrocardiography. PMID- 24476114 TI - An alternative approach to teaching joint disease. PMID- 24476118 TI - Letters. PMID- 24476119 TI - Predicting HLA genotypes using unphased and flanking single-nucleotide polymorphisms in Han Chinese population. AB - BACKGROUND: Genetic variation associated with human leukocyte antigen (HLA) genes has immunological functions and is associated with autoimmune diseases. To date, large-scale studies involving classical HLA genes have been limited by time consuming and expensive HLA-typing technologies. To reduce these costs, single nucleotide polymorphisms (SNPs) have been used to predict HLA-allele types. Although HLA allelic distributions differ among populations, most prediction model of HLA genes are based on Caucasian samples, with few reported studies involving non-Caucasians. RESULTS: Our sample consisted of 437 Han Chinese with Affymetrix 5.0 and Illumina 550 K SNPs, of whom 214 also had data on Affymetrix 6.0 SNPs. All individuals had HLA typings at a 4-digit resolution. Using these data, we have built prediction model of HLA genes that are specific for a Han Chinese population. To optimize our prediction model of HLA genes, we analyzed a number of critical parameters, including flanking-region size, genotyping platform, and imputation. Predictive accuracies generally increased both with sample size and SNP density. CONCLUSIONS: SNP data from the HapMap Project are about five times more dense than commercially available genotype chip data. Using chips to genotype our samples, however, only reduced the accuracy of our HLA predictions by only ~3%, while saving a great deal of time and expense. We demonstrated that classical HLA alleles can be predicted from SNP genotype data with a high level of accuracy (80.37% (HLA-B) ~95.79% (HLA-DQB1)) in a Han Chinese population. This finding offers new opportunities for researchers in obtaining HLA genotypes via prediction using their already existing chip datasets. Since the genetic variation structure (e.g. SNP, HLA, Linkage disequilibrium) is different between Han Chinese and Caucasians, and has strong impact in building prediction models for HLA genes, our findings emphasize the importance of building ethnic-specific models when analyzing human populations. PMID- 24476120 TI - Staged double-layer closure of palatal defects in 6 dogs. AB - OBJECTIVE: To report a staged approach that includes selective dental extractions before definitive double-layer hard palate defect closure in dogs. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 6) with a palatal defect. METHODS: Dogs had selective maxillary teeth extractions 4-8 weeks before definitive hard palate defect repair by double-layer local full-thickness mucosal flaps. RESULTS: All palatal defects were considered complex. Complete hard palate closure was achieved after initial attempt in 3 dogs; 2 dogs had revision surgery before complete closure, and in 1 dog, closure failed and further treatment was declined. No complications or long-term consequences were associated with selective dental extractions. CONCLUSIONS: Selective dental extractions before definitive surgical repair using mucosal flaps in a double-layer approach is an effective alternative when treating complex hard palate defects in dogs. PMID- 24476121 TI - Nursing perspectives on factors influencing interdisciplinary teamwork in the Canadian primary care setting. AB - AIMS AND OBJECTIVES: This study investigated nurses' roles and their perspectives on the factors that influence interdisciplinary teamwork within Canadian primary care setting. BACKGROUND: Interdisciplinary teams have shown to lead to better system- and patient-level outcomes and, accordingly, have became important aspects of healthcare systems especially within primary care settings. Nurses play a key role in these primary care teams, particularly with respect to chronic disease management. DESIGN: A focused ethnography design using semi-structured individual interviews was conducted. METHODS: Interviews were conducted with 20 primary care nurses between July 2010-May 2011. Interviews were recorded, transcribed, and content and thematic analysis was performed. RESULTS: Nurses experienced increasing scope of practice and professional responsibility as they transitioned into the primary care setting. Nine major roles of primary care nurses were identified. Several factors that facilitate or hinder teamwork were identified and categorised under four theme areas: (1) organisation/leadership (e.g. having common goals and mandate, unclear descriptions of team members' roles); (2) team relationships (e.g. closed loop of communication, trust, respect); (3) process/support (e.g. unclear referral process and reporting structure, large patient panels); and (4) physical environment (e.g. decentralised model of care). CONCLUSIONS: Nurses' roles within primary care setting appear to be focused mainly on case management. Minimal orientation and lack of preparation of nurses for their roles, vagueness of these roles among the interdisciplinary primary care team members and lack of communication appeared to be among the most important factors that influence teamwork and nurses' functioning within these teams. RELEVANCE TO CLINICAL PRACTICE: Given that nurses play a key role in interdisciplinary primary care teams, particularly in managing chronic disease patients, approaches to improve chronic disease management and care of these patients should incorporate strategies to ensure effective preparation of these nurses for their roles within these teams and settings. PMID- 24476122 TI - Prevention of type 2 diabetes; a systematic review and meta-analysis of different intervention strategies. AB - AIM: Different intervention strategies can prevent type 2 diabetes (T2DM). Aim of the present systematic review and meta-analysis was to evaluate the effectiveness of different strategies. METHODS: Studies were grouped into 15 different strategies: 1: diet plus physical activity; 2: physical activity; 3-6: anti diabetic drugs [glitazones, metformin, beta-cell stimulating drugs (sulphanylureas, glinides), alfa-glucosidase inhibitors]; 7-8: cardiovascular drugs (ACE inhibitors, ARB, calcium antagonists); 9-14 [diets, lipid-affecting drugs (orlistat, bezafibrate), vitamins, micronutrients, estrogens, alcohol, coffee]; 15: bariatric surgery. Only controlled studies were included in the analysis, whether randomized, non-randomized, observational studies, whether primarily designed to assess incident cases of diabetes, or performed with other purposes, such as control of hypertension, of ischemic heart disease or prevention of cardiovascular events. Appropriate methodology [preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement] was used. Seventy-one studies (490 813 subjects), published as full papers, were analysed to identify predictors of new cases of T2DM, and were included in a meta-analysis (random-effects model) to study the effect of different strategies. Intervention effect (new cases of diabetes) was expressed as odds ratio (OR), with 95% confidence intervals (C.I.s). Publication bias was formally assessed. RESULTS: Body mass index was in the overweight range for 13 groups, obese or morbidly obese in lipid-affecting drugs and in bariatric surgery. Non-surgical strategies, except for beta-cell stimulating drugs, estrogens and vitamins, were able to prevent T2DM, with different effectiveness, from 0.37 (C.I. 0.26-0.52) to 0.85 (C.I. 0.77-0.93); the most effective strategy was bariatric surgery in morbidly obese subjects [0.16 (C.I. 0.11,0.24)]. At meta-regression analysis, age of subjects and amount of weight lost were associated with effectiveness of intervention. CONCLUSIONS: These data indicate that several strategies prevent T2DM, making it possible to make a choice for the individual subject. PMID- 24476123 TI - Human migration, protected areas, and conservation outreach in Tanzania. AB - A recent discussion debates the extent of human in-migration around protected areas (PAs) in the tropics. One proposed argument is that rural migrants move to bordering areas to access conservation outreach benefits. A counter proposal maintains that PAs have largely negative effects on local populations and that outreach initiatives even if successful present insufficient benefits to drive in migration. Using data from Tanzania, we examined merits of statistical tests and spatial methods used previously to evaluate migration near PAs and applied hierarchical modeling with appropriate controls for demographic and geographic factors to advance the debate. Areas bordering national parks in Tanzania did not have elevated rates of in-migration. Low baseline population density and high vegetation productivity with low interannual variation rather than conservation outreach explained observed migration patterns. More generally we argue that to produce results of conservation policy significance, analyses must be conducted at appropriate scales, and we caution against use of demographic data without appropriate controls when drawing conclusions about migration dynamics. PMID- 24476124 TI - A mild Ni/Cu-catalyzed silylation via C-O cleavage. AB - A Ni/Cu-catalyzed silylation of unactivated C-O electrophiles derived from phenols or benzyl alcohols is described. This transformation is characterized by its wide scope and mild conditions, providing a direct access to synthetically versatile silylated compounds. The protocol allows for the coupling of C(sp(2))-O and even C(sp(3))-O bonds with similar efficiency. PMID- 24476125 TI - Synthesis of [60]fullerene-fused tetrahydroazepinones and azepinonimines via Cu(OAc)2-promoted N-heteroannulation reaction. AB - A convenient and efficient Cu(OAc)2-mediated N-heteroannulation reaction of [60]fullerene with N-sulfonylated o-amino-aromatic methyl ketones or O-alkyl oximes has been reported for the synthesis of novel and scarce [60]fullerene fused tetrahydroazepinones and -azepinonimines in a highly selective manner. Moreover, a possible mechanism involving two pathways is proposed on the basis of the experimental observations. PMID- 24476126 TI - Five orders of magnitude reduction in energy coupling across corrugated graphene/substrate interfaces. AB - A normal full-contact graphene/substrate interface has been reported to have a thermal conductance in the order of 10(8) Wm(-2)K(-1). The reported work used a sandwiched structure to probe the interface energy coupling, and the phonon behavior in graphene was significantly altered in an undesirable way. Here, we report an intriguing study of energy coupling across unconstrained graphene/substrate interfaces. Using novel Raman-based dual thermal probing, we directly measured the temperature drop across the few nm gap interface that is subjected to a local heat flow induced by a second laser beam heating. The thermal conductance (Gt) for graphene/Si and graphene/SiO2 interfaces is determined as 183 +/- 10 and 266 +/- 10 Wm(-2)K(-1). At the graphene/Si interface, Gt is 5 orders of magnitude smaller than that of full interface contact. It reveals the remarkable effect of graphene corrugation on interface energy coupling. The measurement result is elucidated by atomistic modeling of local corrugation and energy exchange. By decoupling of graphene's thermal and mechanical behavior, we obtained the stress-induced Raman shift of graphene at around 0.1 cm(-1) or less, suggesting extremely loose interface mechanical coupling. The interface gap variation is evaluated quantitatively on the basis of corrugation-induced Raman enhancement. The interface gap could change as much as 1.8 nm when the local thermal equilibrium is destroyed. PMID- 24476127 TI - Coordination-directed self-assembly of M12L24 nanocage: effects of kinetic trapping on the assembly process. AB - We demonstrate the spontaneous formation of spherical complex M12L24, which is composed of 12 palladium ions and 24 bidentate ligands, by molecular dynamics simulations. In contrast to our previous study on the smaller M6L8 cage, we found that the larger M12L24 self-assembly process involves noticeable kinetic trapping at lower nuclearity complexes, e.g., M6L12, M8L16, and M9L18. We also found that the kinetic trapping behaviors sensitively depend on the bend angle of ligands and the metal-ligand binding strength. Our results show that these kinetic effects, that have generally been neglected, are important factor in self assembly structure determination of larger complexes as M12L24 in this study. PMID- 24476128 TI - The effects of express lane eligibility on Medicaid and CHIP enrollment among children. AB - OBJECTIVE: To estimate the impact of Express Lane Eligible (ELE) implementation on Medicaid/CHIP enrollment in eight states. DATA SOURCES/STUDY SETTING: 2007 to 2011 data from the Statistical Enrollment Data System (SEDS) on Medicaid/CHIP enrollment. STUDY DESIGN: We estimate difference-in-difference equations, with quarter and state fixed effects. The key independent variable is an indicator for whether the state had ELE in place in the given quarter, allowing the experience of statistically matched non-ELE states to serve as a formal counterfactual against which to assess the changes in the eight ELE states. The model also controls for time-varying economic and policy factors within each state. DATA COLLECTION/EXTRACTION METHODS: We obtained SEDS enrollment data from CMS. PRINCIPAL FINDINGS: Across model specifications, the ELE effects on Medicaid enrollment among children were consistently positive, ranging between 4.0 and 7.3 percent, with most estimates statistically significant at the 5 percent level. We also find that ELE increased combined Medicaid/CHIP enrollment. CONCLUSIONS: Our results imply that ELE has been an effective way for states to increase enrollment and retention among children eligible for Medicaid/CHIP. These results also imply that ELE-like policies could improve take-up of subsidized coverage under the ACA. PMID- 24476130 TI - Structure and dynamics of benzyl-NX3 (X = Me, Et) trifluoromethanesulfonate ionic liquids. AB - Ammonium-based benzyl-NX3 (X = methyl, ethyl) trifluoromethanesulfonate (TFA) ionic liquids (ILs) are low cost, nontoxic, thermally stable ion-conducting electrolytes in fuel cells and batteries. In the present study, we have characterized the structure and dynamics of these ILs using molecular dynamics (MD) simulations and ionic conductivity using electro-chemical impedance spectroscopy (EIS) at varying temperature and relative humidity (RH). Results from MD simulations predict that cation-cation and cation-anion interactions are stronger in benzyltrimethylammonium (BzTMA) compared to benzyltriethylammonium (BzTEA) that diminish with increase in RH. Further, the BzTMA cations show both C H/Ph (center of mass of phenyl ring) and cation-Ph interactions whereas BzTEA cations show only strong cation-Ph interactions. The C-H/Ph interactions (psi >= 90 degrees , d(H-Ph) <= 4 A, theta < 50 degrees and d(C-Ph) <= 4.3 A) in BzTMA cations increase with RH and are highest at RH = 90%. The cumulative impact of electrostatic, cation/Ph, and C-H/Ph interactions results in lower conductivity of BzTMA-TFA IL compared to BzTEA-TFA IL. The EIS measurements show that the trends in ionic conductivity of ILs at RH = 30 and 90% are qualitatively similar to the Nernst-Einstein conductivity from MD simulations. The ionic conductivity of BzTEA-TFA IL is ~3 times higher than BzTMA-TFA IL at 353 K and RH = 90%. PMID- 24476129 TI - Chinese culture permeation in the treatment of Parkinson disease: a cross sectional study in four regions of China. AB - BACKGROUND: Little is known about the clinical features and treatment of Chinese patients with Parkinson disease (PD). METHODS: A large cross-sectional survey of clinical features, medication use, and motor complications was conducted in 901 consecutive PD patients, from 42 randomly selected university-affiliated hospitals in four urban economic regions of China, between December 2006 and May 2007. RESULTS: The 901 PD patients had age range 30 to 88, and median disease duration 50 months. Most (737, 81.8%) used L-dopa (median 375 mg/day), and often added low doses of other antiparkinsonian agents. Among L-dopa-treated patients, the prevalence of motor complications was low (dyskinesias: 8.5%; motor fluctuations: 18.6%), even among patients with disease duration >=11 years (dyskinesias: 18.1%; motor fluctuations: 42.2%). Higher L-dopa use was associated with higher occurrence of dyskinesias (OR 2.44; 95% CI 1.20-5.13) and motor fluctuations (OR 2.48; 95% CI 1.49-4.14). Initiating PD treatment with L-dopa alone (OR 0.46; 95% CI 0.22-0.95) or in combination with other medications (OR 0.41; 95% CI 0.19-0.87) was associated with less dyskinesia than treatment initiated with non-L-dopa medication. CONCLUSIONS: Many Chinese PD patients are treated with low-dose L-dopa and added low-dose antiparkinsonian agents, with a low prevalence of motor complications, which might be influenced by Chinese culture. PMID- 24476131 TI - Global collaborative networks on meta-analyses of randomized trials published in high impact factor medical journals: a social network analysis. AB - BACKGROUND: Research collaboration contributes to the advancement of knowledge by exploiting the results of scientific efforts more efficiently, but the global patterns of collaboration on meta-analysis are unknown. The purpose of this research was to describe and characterize the global collaborative patterns in meta-analyses of randomized trials published in high impact factor medical journals over the past three decades. METHODS: This was a cross-sectional, social network analysis. We searched PubMed for relevant meta-analyses of randomized trials published up to December 2012. We selected meta-analyses (including at least randomized trials as primary evidence source) published in the top seven high impact factor general medical journals (according to Journal Citation Reports 2011): The New England Journal of Medicine, The Lancet, the BMJ, JAMA, Annals of Internal Medicine, Archives of Internal Medicine (now renamed JAMA Internal Medicine), and PLoS Medicine. Opinion articles, conceptual papers, narrative reviews, reviews without meta-analysis, reviews of reviews, and other study designs were excluded. RESULTS: Overall, we included 736 meta-analyses, in which 3,178 authors, 891 institutions, and 51 countries participated. The BMJ was the journal that published the greatest number of articles (39%), followed by The Lancet (18%), JAMA (15%) and the Archives of Internal Medicine (15%). The USA, the UK, and Canada headed the absolute global productivity ranking in number of papers. The 64 authors and the 39 institutions with the highest publication rates were identified. We also found 82 clusters of authors (one group with 55 members and one group with 54 members) and 19 clusters of institutions (one major group with 76 members). The most prolific authors were mainly affiliated with the University of Oxford (UK), McMaster University (Canada), and the University of Bern (Switzerland). CONCLUSIONS: Our analysis identified networks of authors, institutions and countries publishing meta-analyses of randomized trials in high impact medical journals. This valuable information may be used to strengthen scientific capacity for collaboration and to help to promote a global agenda for future research of excellence. PMID- 24476132 TI - Linear short histidine and cysteine modified arginine peptides constitute a potential class of DNA delivery agents. AB - The success of gene therapy relies on the development of safe and efficient multifunctional carriers of nucleic acids that can overcome extra- and intracellular barriers, protect the nucleic acid and mediate its release at the desired site allowing gene expression. Peptides bear unique properties that are indispensable for any carrier, e.g., they can mediate DNA condensation, cellular targeting, membrane translocation, endosomal escape and nuclear localization. In an effort to design a multifunctional peptide, we have modified an arginine homopeptide R16 by replacement of seven arginines with histidines and addition of one cysteine at each end respectively to impart endosomal escape property while maintaining the DNA condensation and release balance. Addition of histidines imparts endosomal escape property to arginine homopeptide, but their arrangement with respect to arginines is more critical in controlling DNA condensation, release and transfection efficiency. Intriguingly, R5H7R4 peptide where charge/arginine is distributed in blocks is preferred for strong condensation while more efficient transfection is seen in the variants R9H7 and H4R9H3, which exhibit weak condensation and strong release. Addition of cysteine to each of these peptides further fine-tuned the condensation-release balance without application of any oxidative procedure unlike other similar systems reported in the literature. This resulted in a large increase in the transfection efficiency in all of the histidine modified peptides irrespective of the arginine and histidine positions. This series of multifunctional peptides shows comparable transfection efficiency to commercially available transfection reagent Lipofectamine 2000 at low charge ratios, with simple preparative procedure and exhibits much less toxicity. PMID- 24476133 TI - Inactivation of AKT induces cellular senescence in uterine leiomyoma. AB - Uterine leiomyomas (fibroids) are a major public health problem. Current medical treatments with GnRH analogs do not provide long-term benefit. Thus, permanent shrinkage or inhibition of fibroid growth via medical means remains a challenge. The AKT pathway is a major growth and survival pathway for fibroids. We propose that AKT inhibition results in a transient regulation of specific mechanisms that ultimately drive cells into cellular senescence or cell death. In this study, we investigated specific mechanisms of AKT inhibition that resulted in senescence. We observed that administration of MK-2206, an allosteric AKT inhibitor, increased levels of reactive oxygen species, up-regulated the microRNA miR-182 and several senescence-associated genes (including p16, p53, p21, and beta galactosidase), and drove leiomyoma cells into stress-induced premature senescence (SIPS). Moreover, induction of SIPS was mediated by HMGA2, which colocalized to senescence-associated heterochromatin foci. This study provides a conceivable molecular mechanism of SIPS by AKT inhibition in fibroids. PMID- 24476134 TI - Effects of neuron-specific estrogen receptor (ER) alpha and ERbeta deletion on the acute estrogen negative feedback mechanism in adult female mice. AB - The negative feedback mechanism through which 17beta-estradiol (E2) acts to suppress the activity of the GnRH neurons remains unclear. Using inducible and cell-specific genetic mouse models, we examined the estrogen receptor (ER) isoforms expressed by neurons that mediate acute estrogen negative feedback. Adult female mutant mice in which ERalpha was deleted from all neurons in the neonatal period failed to exhibit estrous cycles or negative feedback. Adult mutant female mice with neonatal neuronal ERbeta deletion exhibited normal estrous cycles, but a failure of E2 to suppress LH secretion was seen in ovariectomized mice. Mutant mice with a GnRH neuron-selective deletion of ERbeta exhibited normal cycles and negative feedback, suggesting no critical role for ERbeta in GnRH neurons in acute negative feedback. To examine the adult roles of neurons expressing ERalpha, an inducible tamoxifen-based Cre-LoxP approach was used to ablate ERalpha from neurons that express calmodulin kinase IIalpha in adults. This resulted in mice with no estrous cycles, a normal increase in LH after ovariectomy, but an inability of E2 to suppress LH secretion. Finally, acute administration of ERalpha- and ERbeta-selective agonists to adult ovariectomized wild-type mice revealed that activation of ERalpha suppressed LH secretion, whereas ERbeta agonists had no effect. This study highlights the differences in adult reproductive phenotypes that result from neonatal vs adult ablation of ERalpha in the brain. Together, these experiments expand previous global knockout studies by demonstrating that neurons expressing ERalpha are essential and probably sufficient for the acute estrogen negative feedback mechanism in female mice. PMID- 24476136 TI - Novel antihypertensive lactoferrin-derived peptides produced by Kluyveromyces marxianus: gastrointestinal stability profile and in vivo angiotensin I converting enzyme (ACE) inhibition. AB - Novel antihypertensive peptides released by Kluyveromyces marxianus from bovine lactoferrin (LF) have been identified. K. marxianus LF permeate was fractionated by semipreparative high performance liquid chromatography and 35 peptides contained in the angiotensin I-converting enzyme (ACE)-inhibitory fractions were identified by using an ion trap mass spectrometer. On the basis of peptide abundance and common structural features, six peptides were chemically synthesized. Four of them (DPYKLRP, PYKLRP, YKLRP, and GILRP) exerted in vitro inhibitory effects on ACE activity and effectively decreased systolic blood pressure after oral administration to spontaneously hypertensive rats (SHRs). Stability against gastrointestinal enzymes suggested that the sequence LRP could contribute to the in vivo effects of parental peptides. Finally, there were reductions in circulating ACE activity and angiotensin II level in SHRs after either DPYKLRP or LRP intake, thus confirming ACE inhibition as the in vivo mechanism for their antihypertensive effect. PMID- 24476135 TI - Kruppel-like factor 9 deficiency in uterine endometrial cells promotes ectopic lesion establishment associated with activated notch and hedgehog signaling in a mouse model of endometriosis. AB - Endometriosis, a steroid hormone-dependent disease characterized by aberrant activation of estrogen receptor signaling and progesterone resistance, remains intractable because of the complexity of the pathways underlying its manifestation. We previously showed that eutopic endometria of women with endometriosis exhibit lower expression of Kruppel-like factor 9 (KLF9), a progesterone receptor coregulator in the uterus, relative to that of women without disease. Here we examined whether loss of endometrial KLF9 expression causes ectopic lesion establishment using syngeneic wild-type (WT) mice as recipients of endometrial fragments from WT and Klf9 null donors. We found significantly higher incidence of ectopic lesions with Klf9 null than WT endometria 8 weeks after tissue injection into the intraperitoneal cavity. The increased incidence of lesion establishment with Klf9 null endometria was associated with a higher expression ratio of estrogen receptor 2 isoform relative to that of estrogen receptor 1 and attenuated progesterone receptor levels in endometriotic stromal cells. PCR array analyses of Notch and Hedgehog signaling components in ectopic lesions demonstrated up-regulated expression of select genes (Jag 2, Shh, Gli1, and Stil 1) in Klf9 null lesions relative to that in WT lesions. Immunohistochemical analyses showed increased levels of Notch intracellular domain and Sonic Hedgehog proteins in Klf9 null lesions relative to that in WT lesions, confirming pathway activation. WT recipients with Klf9 null lesions displayed lower systemic levels of TNFalpha and IL-6 and higher soluble TNF receptor 1 than corresponding recipients with WT lesions. Our results suggest that endometrial KLF9 deficiency promotes endometriotic lesion establishment by the coincident deregulation of Notch-, Hedgehog-, and steroid receptor-regulated pathways. PMID- 24476137 TI - A twelve-coordinated iodide in a cuboctahedral silver(I) skeleton. AB - Three new halide-centered octanuclear silver(I) complexes, [Ag8(X){S2P(CH2CH2Ph)2}6](PF6), X = F(-), 1; Cl(-), 2; Br(-), 3; were prepared in the presence of the corresponding halide anions with silver(I) salts and dithiophosphinate ligands. Structure analyses displayed that a Ag8 cubic core can be modulated by the size effect of the central halide; however, an iodide centered Ag8 cluster was not found under similar reaction conditions. Interestingly, a luminescent dodecanuclear silver(I) cluster, [Ag12(MU12-I)(MU3 I)4{S2P(CH2CH2Ph)2}6](I), 4; was then synthesized. The structure of 4 contains a novel MU12-I at the center of a cuboctahedral silver(I) atom cage, which is further stabilized by four additional MU3-I and six dithiophosphinate ligands. To the best of our knowledge, the MU12-I revealed in 4 is the highest coordination number for a halide ion authenticated by both experimental and computational studies. Previously, the MU12-I was only observed in [PyH][{TpMo(MU3 S)4Cu3}4(MU12-I)]. The synthetic details, spectroscopic studies including multinuclear NMR and ESI-MS, structure elucidations by single crystal X-ray diffraction, and photoluminescence of 4 are reported herein. PMID- 24476138 TI - Divorce or end of cohabitation among Danish women evaluated for fertility problems. AB - OBJECTIVE: Couples with fertility problems may experience marital or sexual distress which could potentially result in dissolved relationships. We investigated the likelihood of ending a relationship among women who did not have a child after a fertility evaluation. DESIGN: Longitudinal cohort study. SETTING: Danish women ever referred for primary or secondary fertility problems to a public Danish hospital or private fertility clinic between 1990 and 2006. POPULATION: A total of 47,515 women. METHODS: The data were linked to Danish administrative population-based registries containing demographic and socioeconomic information. Discrete-time survival models were used with person period data. Each woman was followed from the year of her initial fertility evaluation through to 2007. MAIN OUTCOME MEASURES: Effects of parity after a fertility evaluation on the likelihood of ending a marital or cohabitation relationship. RESULTS: After up to 12 years of follow up, nearly 27% of the women were no longer living with the person with whom they had lived at the time of the fertility evaluation. Women who did not have a child after the evaluation had significantly higher odds ratios for ending a relationship up to 12 years after the evaluation (with odds ratios up to 3.13, 95% CI 2.88-3.41) than women who had a child, regardless of their parity before the evaluation. CONCLUSIONS: Parity after a fertility evaluation may be an important component in the longitudinal relationships of couples with fertility problems. Studies with detailed information on marital quality and relational well-being of couples with fertility problems are needed. PMID- 24476140 TI - The health care of the elderly: developing teaching skills. PMID- 24476139 TI - Teaching general and family practice. PMID- 24476141 TI - How to: Construct and Use a Problem-based Programmed Lecture. AB - In a programmed lecture a single teacher can transform an amphitheatre into a small-group tutorial. This paper, based on ten years' experience of using programmed lectures, provides details on their construction and administration and contrasts them with the classical lecture method. PMID- 24476142 TI - The way we teach: basic clinical skills. AB - At the University of Adelaide Medical School, students are given additional intensive training in basic clinical skills during a six-week period in the fifth year. The course includes history-taking, physical examination, decision making and problem solving. Teaching activities are based predominantly on a preceptor system, backed by small-group sessions and by activities designed to encourage habits of self-learning. Assessment is competence based: staff attempt to compare students' performance with the objectives of the programme and decide whether or not they have achieved the desired standard. The course attracts positive ratings from students and retains the support of staff. PMID- 24476143 TI - Original research: a process model for teaching and learning communications skills. AB - This paper describes a model which specifies what teachers of communication skills should be teaching and what students in primary health care should be learning. PMID- 24476144 TI - Educational organizations: the society for research into higher education. PMID- 24476145 TI - Explanations and explaining. AB - This series provides teachers with the opportunity of assessing their knowledge and understanding of some important aspects relating to their work as teachers. PMID- 24476146 TI - Communication satellites: their role in medical education and health care delivery. AB - This article describes an experiment in distance teaching/learning in large rural areas of North America using full duplex audiovisual interactive satellite communication. The effectiveness of the approach is compared with more conventional techniques in terms of regional faculty sharing, admissions and minority recruitment, the consultation process, independent learning and communication between public policy makers. Attention is paid to the cost and cost effectiveness of this form of communication. PMID- 24476147 TI - The Way They Do It: Embryology Teaching in US Medical Schools. AB - A survey of departments of anatomy in US medical schools shows that, of the 66 per cent responding, most (60 per cent) teach embryology integrated with other anatomical disciplines, although a large minority (35 per cent) teach an independent course, and a few (five per cent) teach an elective only. Time allotted to embryology teaching averages 23 hours, but this varies widely from a minimum of six to a maximum of 48 hours. The main content of most courses is development of the normal fetus. However, clinical aspects of embryology, particularly congenital malformations, are taught in all but one of the institutions responding. PMID- 24476149 TI - Mucormycosis--from the pathogens to the disease. AB - Mucormycosis is an emerging fungal infection worldwide, with devastating disease symptoms and diverse clinical manifestations. The most important underlying risk factors are immunosuppression, poorly controlled diabetes, iron overload and major trauma. The aetiological agents involved in the disease have been re classified due to changes in taxonomy and nomenclature, which also led to appropriately naming the disease 'mucormycosis'. This article shortly explains the new nomenclature, clinical manifestations and risk factors and focuses on putative virulence traits associated with mucormycosis, mainly in the group of diabetic ketoacidotic patients. PMID- 24476150 TI - Effect of honey in diabetes mellitus: matters arising. AB - Diabetes mellitus remains an incurable disorder in spite of intense research. As result of limitations and unmet goals associated with the use of anti-diabetic drugs, an increased number of diabetic populations globally now resort to complementary and alternative medicine (CAM) such as herbs and other natural products. There has been a renewed interest in the use of honey in the treatment of diabetes mellitus, partly due to an increase in the availability of evidence based data demonstrating its benefits in diabetic rodents and patients. This commentary aims to underscore some of the research implications, issues and questions raised from these studies which show the beneficial effects of honey in the treatment of diabetes mellitus. Some of the issues highlighted in this article include: considering honey is sweet and rich in sugars, how could it be beneficial in the management of diabetes mellitus? Are the observed effects of honey or combined with anti-diabetic drugs exclusive to certain honey such as tualang honey? Could these beneficial effects be reproduced with other honey samples? Anti-diabetic drugs in combination with honey improve glycemic control, enhance antioxidant defenses and reduce oxidative damage. These effects are believed to be mediated partly via antioxidant mechanism of honey. This raises another question. Could similar data be obtained if anti-diabetic drugs are co administered with other potent antioxidants such as vitamin C or E? As the evidence has revealed, the prospect of managing diabetes mellitus with honey or antioxidants (such as vitamin C or E) as an adjunct to conventional diabetes therapy is vast. However, more well-designed, rigorously conducted randomized controlled studies are necessary to further validate these findings. PMID- 24476151 TI - Cultural barriers to effective communication between Indigenous communities and health care providers in Northern Argentina: an anthropological contribution to Chagas disease prevention and control. AB - INTRODUCTION: Ninety percent of the aboriginal communities of Argentina are located in areas of endemic vectorial transmission of Chagas disease. Control activities in these communities have not been effective. The goal of this research was to explore the role played by beliefs, habits, and practices of Pilaga and Wichi indigenous communities in their interaction with the local health system in the province of Formosa. This article contributes to the understanding of the cultural barriers that affect the communication process between indigenous peoples and their health care providers. METHODS: Twenty-nine open ended interviews were carried out with members of four indigenous communities (Pilaga and Wichi) located in central Formosa. These interviews were used to describe and compare these communities' approach to health and disease as they pertain to Chagas as well as their perceptions of Western medicine and its incarnation in local health practice. RESULTS: Five key findings are presented: 1) members of these communities tend to see disease as caused by other people or by the person's violation of taboos instead of as a biological process; 2) while the Pilaga are more inclined to accept Western medicine, the Wichi often favour the indigenous approach to health care over the Western approach; 3) members of these communities do not associate the vector with the transmission of the disease and they have little awareness of the need for vector control activities; 4) indigenous individuals who undergo diagnostic tests and accept treatment often do so without full information and knowledge; 5) the clinical encounter is rife with conflict between the expectations of health care providers and those of members of these communities. CONCLUSION: Our analysis suggests that there is a need to consider the role of the cultural patterning of health and disease when developing interventions to prevent and control Chagas disease among indigenous communities in Northern Argentina. This is especially important when communicating with these communities about prevention and control. These research findings might also be of value to national and provincial agencies in charge of decreasing the rates of Chagas disease among indigenous populations. PMID- 24476152 TI - Host-induced post-transcriptional hairpin RNA-mediated gene silencing of vital fungal genes confers efficient resistance against Fusarium wilt in banana. AB - Fusarium wilt, caused by Fusarium oxysporum f. sp. cubense (Foc), is among the most destructive diseases of banana (Musa spp.). Because no credible control measures are available, development of resistant cultivars through genetic engineering is the only option. We investigated whether intron hairpin RNA (ihpRNA)-mediated expression of small interfering RNAs (siRNAs) targeted against vital fungal genes (velvet and Fusarium transcription factor 1) in transgenic banana could achieve effective resistance against Foc. Partial sequences of these two genes were assembled as ihpRNAs in suitable binary vectors (ihpRNA-VEL and ihpRNA-FTF1) and transformed into embryogenic cell suspensions of banana cv. Rasthali by Agrobacterium-mediated genetic transformation. Eleven transformed lines derived from ihpRNA-VEL and twelve lines derived from ihpRNA-FTF1 were found to be free of external and internal symptoms of Foc after 6-week-long greenhouse bioassays. The five selected transgenic lines for each construct continued to resist Foc at 8 months postinoculation. Presence of specific siRNAs derived from the two ihpRNAs in transgenic banana plants was confirmed by Northern blotting and Illumina sequencing of small RNAs derived from the transgenic banana plants. The present study represents an important effort in proving that host-induced post-transcriptional ihpRNA-mediated gene silencing of vital fungal genes can confer efficient resistance against debilitating pathogens in crop plants. PMID- 24476153 TI - Osmotic stress and recovery in field populations of Zygnema sp. (Zygnematophyceae, Streptophyta) on Svalbard (High Arctic) subjected to natural desiccation. AB - Zygnema is a genus of filamentous green algae belonging to the class of Zygnematophyceae (Streptophyta). In the Arctic, it typically forms extensive mats in habitats that regularly dry out during summer, and therefore, mechanisms of stress resistance are expected. We investigated its natural populations with respect to production of specialized desiccation-resistant cells and osmotic acclimation. Six populations in various stages of natural desiccation were selected, from wet biomass floating in water to dried paper-like crusts. After rewetting, plasmolysis and osmotic stress effects were studied using hypertonic sorbitol solutions, and the physiological state was estimated using chlorophyll a fluorescence parameters. All populations of Zygnema sp. formed stationary-phase cells filled with storage products. In green algal research, such cells are traditionally called akinetes. However, the populations differed in their reaction to osmotic stress. Whereas the wet-collected samples were strongly impaired, the osmotic stress resistance of the naturally dried samples was comparable to that of true aeroterrestrial algae. We showed that arctic populations of Zygnema acclimate well to natural desiccation via hardening that is mediated by slow desiccation. As no other types of specialized cells were observed, we assume that the naturally hardened akinetes also play a key role in winter survival. PMID- 24476154 TI - Household income and poor treatment outcome among patients with tuberculosis in Georgia: a cohort study. AB - BACKGROUND: Poverty is associated with increased risk of active tuberculosis (TB) disease onset, but the relation between household income and TB treatment outcomes is not well understood. The objective of this study was to determine household income characteristics associated with poor TB treatment outcome among newly diagnosed patients with pulmonary TB in the country of Georgia. METHODS: A prospective cohort study was conducted among newly diagnosed smear positive pulmonary TB patients. Clinical and household data were collected from all consecutive patients seeking care at TB facilities in two major cities and one rural region in Georgia. Patients were followed prospectively during anti-TB regimens to determine treatment outcome. Bivariate analyses were used to determine the association of individual patient and household level characteristics with poor TB treatment outcome. A multivariable logistic model was used to estimate the adjusted association between patient household characteristics and poor TB treatment outcome. RESULTS: After six months TB therapy, treatment outcome was available for 193 of 202 enrolled patients, of these 155 (80.3%) had a favorable TB treatment outcome. Compared to TB patients with poor treatment outcome, those with favorable treatment outcomes were younger (median 33.0 vs. 42.5 years), reported higher household monthly income (median $137 USD vs. $85 USD), were less likely to be unemployed (38.7 vs. 47.4%), and had higher level of education (38.7% vs. 31.6% with college education or greater). In multivariable analysis adjusted for age, sex, and socio-economic indicators, only low household income was remained statistically significantly associated with poor TB treatment outcome. Compared with patients from households with the highest tertile of monthly income, those in the middle tertile (aOR 4.28 95% CI 1.36, 13.53) and those in the lowest category of income (aOR 6.18 95% CI 1.83, 20.94) were significantly more likely to have poor treatment outcomes. CONCLUSION: We demonstrated that TB patients in Georgia with lower household income were at greater risk of poor TB treatment outcomes. Providing targeted social assistance to TB patients and their households may improve clinical response to anti-TB therapy. PMID- 24476155 TI - Minimizing the cost of keeping options open for conservation in a changing climate. AB - Policy documents advocate that managers should keep their options open while planning to protect coastal ecosystems from climate-change impacts. However, the actual costs and benefits of maintaining flexibility remain largely unexplored, and alternative approaches for decision making under uncertainty may lead to better joint outcomes for conservation and other societal goals. For example, keeping options open for coastal ecosystems incurs opportunity costs for developers. We devised a decision framework that integrates these costs and benefits with probabilistic forecasts for the extent of sea-level rise to find a balance between coastal ecosystem protection and moderate coastal development. Here, we suggest that instead of keeping their options open managers should incorporate uncertain sea-level rise predictions into a decision-making framework that evaluates the benefits and costs of conservation and development. In our example, based on plausible scenarios for sea-level rise and assuming a risk neutral decision maker, we found that substantial development could be accommodated with negligible loss of environmental assets. Characterization of the Pareto efficiency of conservation and development outcomes provides valuable insight into the intensity of trade-offs between development and conservation. However, additional work is required to improve understanding of the consequences of alternative spatial plans and the value judgments and risk preferences of decision makers and stakeholders. PMID- 24476157 TI - India's patent laws and the multinational pharmaceutical industry. PMID- 24476156 TI - Chromothripsis-like patterns are recurring but heterogeneously distributed features in a survey of 22,347 cancer genome screens. AB - BACKGROUND: Chromothripsis is a recently discovered phenomenon of genomic rearrangement, possibly arising during a single genome-shattering event. This could provide an alternative paradigm in cancer development, replacing the gradual accumulation of genomic changes with a "one-off" catastrophic event. However, the term has been used with varying operational definitions, with the minimal consensus being a large number of locally clustered copy number aberrations. The mechanisms underlying these chromothripsis-like patterns (CTLP) and their specific impact on tumorigenesis are still poorly understood. RESULTS: Here, we identified CTLP in 918 cancer samples, from a dataset of more than 22,000 oncogenomic arrays covering 132 cancer types. Fragmentation hotspots were found to be located on chromosome 8, 11, 12 and 17. Among the various cancer types, soft-tissue tumors exhibited particularly high CTLP frequencies. Genomic context analysis revealed that CTLP rearrangements frequently occurred in genomes that additionally harbored multiple copy number aberrations (CNAs). An investigation into the affected chromosomal regions showed a large proportion of arm-level pulverization and telomere related events, which would be compatible to a number of underlying mechanisms. We also report evidence that these genomic events may be correlated with patient age, stage and survival rate. CONCLUSIONS: Through a large-scale analysis of oncogenomic array data sets, this study characterized features associated with genomic aberrations patterns, compatible to the spectrum of "chromothripsis"-definitions as previously used. While quantifying clustered genomic copy number aberrations in cancer samples, our data indicates an underlying biological heterogeneity behind these chromothripsis-like patterns, beyond a well defined "chromthripsis" phenomenon. PMID- 24476158 TI - Population-based incidence and patterns of cancer in Kamrup Urban Cancer Registry, India. AB - BACKGROUND: Cancer is not a notifiable disease in India. The Indian Council of Medical Research (ICMR) initiated the National Cancer Registry Programme in 1982 to measure the burden and pattern of cancer in India. However, no data were available from the northeastern region till 2001 when a WHO- sponsored, ICMR project showed a relatively high frequency of microscopically diagnosed cases of cancer in the region. A population-based cancer registry was established in January 2003 in Guwahati to cover the Kamrup Urban district in the northeastern region of India. We report the data generated in the first 6 years of the registry (2003-08). METHODS: Information on cancer was obtained by voluntary participation of different sources including major hospitals, diagnostic centres, state referral board and birth and death registry centres within the registry area. A total of 6608 cases were registered during the 6-year period (1 January 2003- 31 December 2008); 3927 were men and 2681 women. RESULTS: The age-adjusted incidence rates were 167.9 per 100000 among men and 133.8 per 100000 among women. The oesophagus was the leading site of cancer among men, comprising 18.3% of all cancers with an age-adjusted rate of 30.7 per 100000. Among women, the breast followed by the cervix uteri were the leading sites of cancer. These two cancers comprised 30% of all cancers among women. Tobacco-related cancers accounted for 58.2% of cancers among men and 26.9% of cancers among women. CONCLUSION: The patterns observed from the analysis of data from the cancer registry at Guwahati provide comprehensive information on occurrence of cancer and can be valuable for planning cancer control programmes in the region. PMID- 24476159 TI - Domestic violence as a risk factor for infant and child mortality: a community based case-control study from southern India. AB - BACKGROUND: Violence against women may have an impact on infant and child mortality. We aimed to determine whether domestic violence is a risk factor for infant and child death. METHODS: Eighty infant and child deaths (under 5 years of age) were identified from a central register of a comprehensive community health programme in rural southern India; controls were matched for age, gender and street of residence. RESULTS: Domestic violence during the lifetime (OR 2.63, 95% CI 1.39-4.99), which was severe (OR 4.00, 95% CI 2.02-7.94) and during pregnancy (OR 5.69, 95% CI 2.03-15. 93) and father's smoking status (OR 3.81, 95% CI 1.92 7.55) were significantly related to infant and child death while immunization being completed for age (OR 0.04, 95% CI 0.01-0.19) and having at least one boy child in the family (OR 0.29, 95% CI 0.14-0.59) were protective. These variables remained statistically significantly associated with outcome after adjusting for other determinants using conditional logistic regression. CONCLUSION: There is evidence for an association between domestic violence in mothers, and infant and child death. PMID- 24476160 TI - Why does an undergraduate student choose medicine as a career. AB - BACKGROUND: There are more than 44 000 seats in over 350 medical colleges in India for pursuing the MBBS course. This is not enough as we have only 1 doctor for as many as 1953 persons in India. Yet, medicine is not among the top vocations in most career advisories and the best school students do not aspire to be doctors. METHODS: This cross-sectional study was done at a tertiary care, teaching hospital in March 2010. Medical students in their second semester were asked to fill an indigenously designed, structured questionnaire, looking at their reasons for joining the course, interpersonal relationships, satisfaction with the curriculum and future prospects following graduation. RESULTS: The mean (SD) age of the students was 19.2 (0.85) years. Of the 100 students of second semester, 41 had been influenced by a family member in choosing their career. Twelve felt that medicine would give them a chance to serve the society. Forty six students felt that the expectations they had from the course before joining were not being fulfilled. Nearly one-third of the students (31) stated that they would not choose medicine as a career if given another chance. Further, 19 said that they would still choose a different profession after completing their graduation. Non-fulfilment of expectations from the course was associated with the belief that they would not opt for this course if given a second chance (likelihood ratio 7.12, p=0.008). Students felt that teaching should lay stress on problem-based learning including workshops on stress and time management. CONCLUSION: We find that several students do not have a defined career plan and opt for a career in medicine because they are influenced by family members. Some students were dissatisfied with the curriculum and expressed that they would not like to pursue the course if given a second chance. PMID- 24476161 TI - The conundrum of prolonged delirium. AB - Withdrawal delirium in alcohol dependence usually lasts 48 to 72 hours. However, certain factors can prolong delirium. We report a 39-year-old man with long standing alcohol use who presented with delirium, which failed to resolve with treatment. On evaluation, he was found to have AIDS and limbic encephalitis due to herpes simplex virus. PMID- 24476162 TI - Oral cancer: review of current management strategies. AB - BACKGROUND: India has one of the highest incidences of oral cancer and accounts for about 30% of all new cases annually. A high prevalence of smokeless tobacco use has led to an increasing incidence, which in combination with delayed presentation has made oral cancer a major health problem in India. Limited access to cancer care, relative lack of trained healthcare providers and financial resources are some of the challenges to the management of oral cancer in India despite improvements in diagnostic techniques and management strategies. METHODS: We reviewed the literature pertaining to the epidemiology, aetiopathogenesis, pre malignancy, tumour progression, management of the primary site, mandible, neck lymph node metastases, reconstruction options and screening of oral cancer. The parameters evaluated were overall survival, disease-free survival, recurrence and loco-regional control. RESULTS: Nine studies on surgical intervention were reviewed. There were 23 studies on the management of chemotherapy and 30 trials analysing radiotherapy as an intervention. CONCLUSION: India has one of the highest incidences of oral cancer and delayed stage presentation is common. Surgery remains the treatment of choice and adjuvant treatment is recommended in high-risk patients. Elective neck dissection is warranted in clinically lymph node-negative neck for patients with thick tumours, imaging-suspected lymph nodes and those who may not have a reliable follow-up. Functional outcomes and treatment-related morbidity needs to be considered, and reconstruction with free tissue transfer provides the best results. PMID- 24476163 TI - Colon rescue therapy in acute severe ulcerative colitis. PMID- 24476164 TI - Preventing infection in the intensive care unit: targeted or universal decolonization. PMID- 24476165 TI - Oxygen saturation targets in extremely premature neonates. PMID- 24476166 TI - Teaching healthcare management to medical students: an early experience. AB - BACKGROUND: Public health services throughout the country are managed by healthcare professionals. However, our present- day medical education does not prepare students to undertake these supervisory and managerial responsibilities. Their lack of preparation results in poor quality of patient care and service and suboptimal use of valuable resources. We introduced medical graduates to concepts of healthcare management and collected their feedback to assess if they find this knowledge relevant and useful. METHOD: Concepts of healthcare management relevant to healthcare professionals such as hospital set-up, hospital support services, quality in healthcare, evidence-based care, managed healthcare, etc. were introduced in a series of lectures during the postgraduate orientation programme at our institution. Student feedback was collected through a questionnaire with items rated on the Likert scale as well as through a few open- ended questions. Data was analysed for probability of responses on a binomial scale. RESULTS: Students perceived the course material to be useful and agreed that training in leadership and management skills should be part of their medical education. Seventy per cent felt that such training should be imparted during the period of internship. CONCLUSION: Current medical education should prepare healthcare professionals to be able to deal with the intricacies of healthcare delivery systems in addition to their clinical skills. Training in healthcare management relevant to the needs of healthcare professionals should be integrated into the medical curriculum. PMID- 24476167 TI - Research-oriented medical education for graduate medical students. AB - BACKGROUND: In most parts of the world, medical education is predominantly geared to create service personnel for medical and health services. Training in research is ignored, which is a major handicap for students who are motivated to do research. The main objective of this study was to develop, for such students, a cost-effective 'in-study' research training module that could be adopted even by medical colleges, which have a modest research infrastructure, in different regions of India. METHOD: Short-duration workshops on the clinical and laboratory medicine research methods including clinical protocol development were held in different parts of India to facilitate participation of students from various regions. Nine workshops covering the entire country were conducted between July 2010 and December 2011. Participation was voluntary and by invitation only to the recipients of the Indian Council of Medical Research-Short-term Studentship programme (ICMR- STS), which was taken as an index of students' research motivation. Faculty was drawn from the medical institutions in the region. All expenses on students, including their travel, and that of the faculty were borne by the academy. Impact of the workshop was judged by the performance of the participants in pre- and post-workshop tests with multiple-choice questions (MCQs) containing the same set of questions. There was no negative marking. Anonymous student feedback was obtained using a questionnaire. RESULTS: Forty-one per cent of the 1009 invited students attended the workshops. These workshops had a positive impact on the participants. Only 20% students could pass and just 2.3% scored >80% marks in the pre-workshop test. There was a three-fold increase in the pass percentage and over 20% of the participants scored >80% marks (A grade) in the post-workshop test. The difference between the pre- and post- workshop performance was statistically significant at all the centres. In the feedback from participants, the workshop received an average rating of 8.1 on a scale of 1 to 10. CONCLUSION: This cost-effective, 'in-study' module of short-duration 'mobile' workshops can be used to educate graduate medical students in basic research procedures employed in clinical and laboratory medicine research. The module is suitable for resource-strapped developing nations. PMID- 24476169 TI - Letter from glasgow. PMID- 24476170 TI - Letter from Chennai. PMID- 24476177 TI - Atypical presentation of Henoch-Schonlein purpura. PMID- 24476178 TI - How clean are the hands of medical students? PMID- 24476179 TI - Assessing long-term motivation of trained volunteers of a psycho-oncology workshop. PMID- 24476180 TI - India's contribution to folic acid research after Lucy Willis and Subbarow. PMID- 24476181 TI - Rash associated with influenza B virus infection. PMID- 24476182 TI - Peripheral gangrene in a patient with Plasmodium vivax malaria. PMID- 24476183 TI - Gifts to doctors form over 20% of marketing expenditure of pharmaceutical companies in Washington, DC. PMID- 24476190 TI - iPhone applications for eye care professionals: a review of current capabilities and concerns. AB - PURPOSE: To quantitatively review and categorize the eye care-related iPhone((r)) (Apple((r)), Cupertino, CA) applications ("apps") currently available, evaluate qualified professional involvement in app development, and suggest future needs in this emerging area of mobile health. MATERIALS AND METHODS: The Apple iTunes((r)) store was searched for iPhone eye care-themed apps using the general terms "ophthalmology," "ophthalmologist," "optometry," "optometrist," "eye care," and "ocular," in addition to terms based on the Centers for Disease Control and Prevention's common eye conditions. Data collected from each app included publication date, target audience, category of app, estimated number of downloads, average user rating, and documented involvement of qualified professionals. RESULTS: In total, 182 apps were identified. The majority of apps lacked community user ratings and had 3,000 or fewer downloads (84% and 69%, respectively). Consistent with other medical specialties, only 37% of apps had documented qualified professional involvement in their development. When stratified by intended audience, 52% and 44% of apps designed for ophthalmologists and optometrists, respectively, had professional input, compared with 31% for non-eye care clinicians and 21% for the general public. CONCLUSIONS: Smartphone apps are likely to become of increasingly greater relevance to the modern eye care professional with tremendous versatility in daily practice. However, despite the rapid emergence of eye care apps, a low level of qualified professional involvement in app development and a lack of peer review after publishing remain. There is a clear need for evidence-based principles and standards of app development to be adopted in this emerging area. PMID- 24476191 TI - The origins of telemedicine and e-Health. PMID- 24476192 TI - A lexicon of assessment and outcome measures for telemental health. AB - BACKGROUND: The purpose of this document is to provide initial recommendations to telemental health (TMH) professionals for the selection of assessment and outcome measures that best reflect the impacts of mental health treatments delivered via live interactive videoconferencing. MATERIALS AND METHODS: The guidance provided here was created through an expert consensus process and is in the form of a lexicon focused on identified key TMH outcomes. RESULTS: Each lexical item is elucidated by a definition, recommendations for assessment/measurement, and additional commentary on important considerations. The lexicon is not intended as a current literature review of the field, but rather as a resource to foster increased dialogue, critical analysis, and the development of the science of TMH assessment and evaluation. The intent of this lexicon is to better unify the TMH field by providing a resource to researchers, program managers, funders, regulators and others for assessing outcomes. CONCLUSIONS: This document provides overall context for the key aspects of the lexicon. PMID- 24476193 TI - Telemedicine spirometry training and quality assurance program in primary care centers of a public health system. AB - BACKGROUND: Forced spirometry is essential for diagnosing respiratory diseases and is widely used across levels of care. However, several studies have shown that spirometry quality in primary care is not ideal, with risks of misdiagnosis. Our objective was to assess the feasibility and performance of a telemedicine based training and quality assurance program for forced spirometry in primary care. MATERIALS AND METHODS: The two phases included (1) a 9-month pilot study involving 15 centers, in which spirometry tests were assessed by the Basque Office for Health Technology Assessment, and (2) the introduction of the program to all centers in the Public Basque Health Service. Technicians first received 4 h of training, and, subsequently, they sent all tests to the reference laboratory using the program. Quality assessment was performed in accordance with clinical guidelines (A and B, good; C-F, poor). RESULTS: In the first phase, 1,894 spirometry tests were assessed, showing an improvement in quality: acceptable quality tests increased from 57% at the beginning to 78% after 6 months and 83% after 9 months (p<0.001). In the second phase, 7,200 spirometry tests were assessed after the inclusion of 36 additional centers, maintaining the positive trend (61%, 87%, and 84% at the same time points; p<0.001). CONCLUSIONS: (1) The quality of spirometry tests improved in all centers. (2) The program provides a tool for transferring data that allows monitoring of its quality and training of technicians who perform the tests. (3) This approach is useful for improving spirometry quality in the routine practice of a public health system. PMID- 24476194 TI - Concurrent and lagged effects of registered nurse turnover and staffing on unit acquired pressure ulcers. AB - OBJECTIVE: We examined the concurrent and lagged effects of registered nurse (RN) turnover on unit-acquired pressure ulcer rates and whether RN staffing mediated the effects. DATA SOURCES/SETTING: Quarterly unit-level data were obtained from the National Database of Nursing Quality Indicators for 2008 to 2010. A total of 10,935 unit-quarter observations (2,294 units, 465 hospitals) were analyzed. METHODS: This longitudinal study used multilevel regressions and tested time lagged effects of study variables on outcomes. FINDINGS: The lagged effect of RN turnover on unit-acquired pressure ulcers was significant, while there was no concurrent effect. For every 10 percentage-point increase in RN turnover in a quarter, the odds of a patient having a pressure ulcer increased by 4 percent in the next quarter. Higher RN turnover in a quarter was associated with lower RN staffing in the current and subsequent quarters. Higher RN staffing was associated with lower pressure ulcer rates, but it did not mediate the relationship between turnover and pressure ulcers. CONCLUSIONS: We suggest that RN turnover is an important factor that affects pressure ulcer rates and RN staffing needed for high-quality patient care. Given the high RN turnover rates, hospital and nursing administrators should prepare for its negative effect on patient outcomes. PMID- 24476195 TI - Multifunctional hybrid nanocarrier: magnetic CNTs ensheathed with mesoporous silica for drug delivery and imaging system. AB - Here we communicate the development of a novel multifunctional hybrid nanomaterial, magnetic carbon nanotubes (CNTs) ensheathed with mesoporous silica, for the simultaneous applications of drug delivery and imaging. Magnetic nanoparticles (MNPs) were first decorated onto the multiwalled CNTs, which was then layered with mesoporous silica (mSiO2) to facilitate the loading of bioactive molecules to a large quantity while exerting magnetic properties. The hybrid nanomaterial showed a high mesoporosity due to the surface-layered mSiO2, and excellent magnetic properties, including magnetic resonance imaging in vitro and in vivo. The mesoporous and magnetic hybrid nanocarriers showed high loading capacity for therapeutic molecules including drug gentamicin and protein cytochrome C. In particular, genetic molecule siRNA was effectively loaded and then released over a period of days to a week. Furthermore, the hybrid nanocarriers exhibited a high cell uptake rate through magnetism, while eliciting favorable biological efficacy within the cells. This novel hybrid multifunctional nanocarrier may be potentially applicable as drug delivery and imaging systems. PMID- 24476197 TI - Analgesics in postoperative care in hip fracture patients with dementia - reported by nurses. AB - AIMS AND OBJECTIVES: To describe the analgesic use in hip fracture patients with dementia during the first two postoperative days as reported by nurses. BACKGROUND: Nurses play a pivotal role in treating postoperative pain in patients with dementia and monitoring the effects of administered analgesics. DESIGN: Cross-sectional descriptive questionnaire study in seven university hospitals and 10 central hospitals in Finland. METHODS: The study was conducted from March until May in 2011 in Finland. For this analysis, the focus was on the sample of nurses (n = 269) who were working in orthopaedic units. Analgesics were classified according to the Anatomical Therapeutic Chemical Classification System. Nonparametric tests were applied to find out the significant differences between analgesic use and different hospitals. RESULTS: Paracetamol and strong opioids administered orally or parenterally seemed to be the most typical of postoperatively used types of analgesics in patients with dementia. Nonsteroidal anti-inflammatory analgesics and weak opioids were also commonly reported to be in use. There were no statistically significant differences between hospitals in typical daily doses. The majority of the nurses reported that the primary aim of postoperative pain management in hip fracture patients with dementia was 'slight pain, which does not prevent normal functioning' (72%). CONCLUSION: The pharmacological postoperative pain treatment in acute care was commonly based on the use of strong opioids and paracetamol in hip fracture patients with dementia. The reported use of transdermal opioids and codeine combination warrants further examination. Further studies are also needed to find out whether the pain is appropriately and adequately treated. RELEVANCE TO CLINICAL PRACTICE: Transdermal opioids and codeine combination may not be relevant analgesics for acute pain management in older adults. It is important to create a balance between sufficient pain relief and adverse effects of analgesics to allow early mobilisation and functional recovery. PMID- 24476198 TI - Toward understanding solute-solvent interaction in room-temperature mono- and dicationic ionic liquids: a combined fluorescence spectroscopy and mass spectrometry analysis. AB - Rotational relaxation dynamics of nonpolar perylene, dipolar coumarin 153, and a negatively charged probe, sodium 8-methoxypyrene-1,3,6-sulfonate (MPTS), have been investigated in a dicationic ionic liquid, 1,6-bis-(3-methylimidazolium-1 yl)hexane bis-(trifluoromethylsulfonyl)amide ([C6(MIm)2][NTf2]2), and a structurally similar monocationic ionic liquid, 1-hexyl-3-methylimidazolium bis(trifluoromethylsulfonyl)amide ([C6MIm][NTf2]), to have a comprehensive and a quantitative understanding on the solute-solvent interaction in these media. Analysis of the rotational relaxation dynamics data by Stokes-Einstein-Debye (SED) hydrodynamic theory reveals that perylene rotation is found to be the fastest compared to the other two probes and shows slip to sub-slip behavior, coumarin 153 rotation lies between the stick and slip boundary, and MPTS shows a superstick behavior in [C6MIm][NTf2]. Interestingly, MPTS exhibits a normal SED hydrodynamics in dicationic [C6(MIm)2][NTf2]2, in spite of the fact that dicationic ionic liquid contains two cationic sites bearing acidic hydrogen (C2 H) which may be available to form stronger interaction with the negatively charged MPTS. The difference in the rotational diffusion behavior of these three probes is a reflection of their location in different distinct environments of these ILs. Superstick behavior of MPTS in monocationic IL has been attributed to its specific hydrogen bonding interaction with the corresponding imidazolium cation. The relatively faster rotational behavior of MPTS in dicationic IL has been explained by resorting to mass spectrometry. Mass spectral analysis demonstrates that positively charged (imidazolium) sites in dicationic IL are strongly associated with negatively charged bis-(trifluoromethylsulfonyl)amide anion (NTf2(-)), which in turn makes it difficult for imidazolim cation to have stronger hydrogen bonding interaction with bulkier negatively charged molecule MPTS. PMID- 24476199 TI - Atomic-scale investigation on the facilitation and inhibition of guanine tautomerization at Au(111) surface. AB - Nucleobase tautomerization might induce mismatch of base pairing. Metals, involved in many important biophysical processes, have been theoretically proven to be capable of affecting tautomeric equilibria and stabilities of different nucleobase tautomers. However, direct real-space evidence on demonstrating different nucleobase tautomers and further revealing the effect of metals on their tautomerization at surfaces has not been reported to date. From the interplay of high-resolution STM imaging and DFT calculations, we show for the first time that tautomerization of guanine from G/9H to G/7H is facilitated on Au(111) by heating, whereas such tautomerization process is effectively inhibited by introducing Ni atoms due to its preferential coordination at the N7 site of G/9H. These findings may help to elucidate possible influence of metals on nucleobase tautomerization and provide from a molecular level some theoretical basis on metal-based drug design. PMID- 24476200 TI - A selection criterion for patterns in reaction-diffusion systems. AB - BACKGROUND: Alan Turing's work in Morphogenesis has received wide attention during the past 60 years. The central idea behind his theory is that two chemically interacting diffusible substances are able to generate stable spatial patterns, provided certain conditions are met. Ever since, extensive work on several kinds of pattern-generating reaction diffusion systems has been done. Nevertheless, prediction of specific patterns is far from being straightforward, and a great deal of interest in deciphering how to generate specific patterns under controlled conditions prevails. RESULTS: Techniques allowing one to predict what kind of spatial structure will emerge from reaction-diffusion systems remain unknown. In response to this need, we consider a generalized reaction diffusion system on a planar domain and provide an analytic criterion to determine whether spots or stripes will be formed. Our criterion is motivated by the existence of an associated energy function that allows bringing in the intuition provided by phase transitions phenomena. CONCLUSIONS: Our criterion is proved rigorously in some situations, generalizing well-known results for the scalar equation where the pattern selection process can be understood in terms of a potential. In more complex settings it is investigated numerically. Our work constitutes a first step towards rigorous pattern prediction in arbitrary geometries/conditions. Advances in this direction are highly applicable to the efficient design of Biotechnology and Developmental Biology experiments, as well as in simplifying the analysis of morphogenetic models. PMID- 24476201 TI - Role of vaccine manufacturers in developing countries towards global healthcare by providing quality vaccines at affordable prices. AB - Vaccines represent one of the greatest achievements of science and medicine in the fight against infectious diseases. Vaccination is one of the most cost effective public health tools to prevent infectious diseases. Significant progress has been made in expanding the coverage of vaccines globally, resulting in the prevention of more than two million deaths annually. In 2010, nearly 200 countries endorsed a shared vision to extend the benefits of vaccines to every person by 2020, known as the Decade of Vaccine Initiative (DoV). Vaccine manufacturers in developing countries, as represented by the Developing Countries Vaccine Manufacturers Network (DCVMN), make a significant contribution to DoV by supplying quality vaccines at affordable prices to the people who need them most. About 70% of the global Expanded Program on Immunization (EPI) vaccine supplies are met by DCVMN. Besides EPI vaccine supplies, DCVMN is also targeting vaccines against rotavirus, Japanese encephalitis, pneumonia, human papillomavirus, meningitis and neglected tropical diseases. This article reviews the roles and contributions of DCVMN in making the vaccines accessible and affordable to all. PMID- 24476203 TI - Testing students' competence. PMID- 24476202 TI - Impact of hypertension on various markers of subclinical atherosclerosis in early type 2 diabetes. AB - BACKGROUND: Presence of Diabetes Mellitus increases the risk of subclinical atherosclerosis. In this study was aimed to determine the influence of hypertension (HTN) on surrogate markers of atherosclerosis in a population of patients with early type 2 diabetes. METHODS: 125 diabetic subjects drawn from Dr. Shariati outpatient's clinic list and 153 non- diabetic subjects who were the relatives in law of diabetic participants were recruited. Participants with type 2 diabetes were free of clinical evidence of cardiovascular disease and renal involvement. Two groups of diabetic and control were further divided into two subgroups of hypertensive (known case of HTN or blood pressure >=140/90 mmHg) and normotensive, and anthropometric characteristics, metabolic biomarkers as well as markers of subclinical atherosclerosis including Carotid intima media thickness (CIMT), flow mediated dilation (FMD) and Ankle Brachial Index (ABI) were measured. RESULTS: Diabetic group with a mean age of 49.9 +/- 7.5 years had significantly higher CIMT (0.64 +/- 0.14 vs 0.76 +/- 0.19, p = 0.001) and lower FMD (16.5 +/- 8.1 vs 13.3 +/- 7.1, p = 0.003) and ABI (1.2 +/- 0.1 vs 1.1 +/- 0.1, p = 0.01) than control with mean age of 52.9 +/- 10.1 years. 34% of control and 59.2% of diabetic were hypertensive. Fasting blood sugar, insulin levels and calculated insulin resistance index of HOMA IR. of hypertensive subjects were higher than normotensive subjects in both groups of diabetic and non-diabetic. Similar pattern was presented for measured inflammatory mediators of hs-CRP and IL-6. Among subclinical atherosclerosis markers, only CIMT was significantly different between hypertensive and normotensive subjects in both groups. In adjusted linear regression analysis, a constant significant association existed between age and CIMT, ABI and FMD in non-diabetic, while in diabetic, age only correlated with CIMT and not the other two markers. In multiple regression model, HTN was recognized as a risk factor for increasing CIMT (OR = 2.93, 95% CI = 1.03 8.33, p = 0.04) but not attenuating FMD or ABI. CONCLUSIONS: Since FMD and CIMT may measure a different stage of subclinical atherosclerosis in diabetic patients, influence of HTN on these markers might be different. PMID- 24476204 TI - How to: Organize and Conduct Joint and Integrated Teaching. AB - Both joint and integrated teaching are concerned with how other disciplines can contribute to medical education, but teaching of behavioural and social science in medicine(1) will not be treated specifically here (see the article in this issue by B. E. Chalmers). Rather, I shall focus on what to consider when organizing and implementing joint and integrated programmes. It is not appropriate to give rigid recommendations as to how such teaching must be organized and conducted: each educator should consider how local circumstances and resources can best be used. An established Australian programme will be used to illustrate one approach, and I will suggest some factors to take into account when planning a programme for a particular setting and set of objectives. PMID- 24476205 TI - The way we teach: behavioural sciences. AB - This paper describes a new approach to teaching human behavioural science to medical students. Designed to overcome the problems of large student numbers, limited staff resources and a minimum of student-staff contact time, the course follows a group-orientated teaching approach, with students being allocated self contained work units taking approximately one week to complete and be assessed. Standards achieved by students are as high, and in some cases much higher, than would have been expected following a traditional lecture course. Student feedback has generally been favourable. PMID- 24476206 TI - Competence in medicine. AB - During the past decade, medical educators have spent time discussing and attempting to define medical competence. There appears to be some confusion as to why definitions of competence are important and how one might describe in a logical fashion the elements of competence for physicians. Here, we try to clarify what is meant by competence, to describe how definitions of competence are of value to students, educators, institutions and the public, and to provide a conceptualization of the elements of a definition of competence in medicine. PMID- 24476207 TI - The problem orientated educational record. PMID- 24476210 TI - Explanation checklist. AB - In this series we will be printing evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to use or adapt such instruments for your own purposes. The feature in this issue has been prepared by Dr George Brown, B.SC, D.PHIL, Senior Lecturer in University Teaching Methods, University of Nottingham, University Park, Nottingham NG7 2RD, England, from whom further information is available. PMID- 24476208 TI - Computer-assisted Self Assessment. PMID- 24476212 TI - Letters. PMID- 24476213 TI - Screen or not to screen for peripheral arterial disease: guidance from a decision model. AB - BACKGROUND: Asymptomatic Peripheral Arterial Disease (PAD) is associated with greater risk of acute cardiovascular events. This study aims to determine the cost-effectiveness of one time only PAD screening using Ankle Brachial Index (ABI) test and subsequent anti platelet preventive treatment (low dose aspirin or clopidogrel) in individuals at high risk for acute cardiovascular events compared to no screening and no treatment using decision analytic modelling. METHODS: A probabilistic Markov model was developed to evaluate the life time cost effectiveness of the strategy of selective PAD screening and consequent preventive treatment compared to no screening and no preventive treatment. The analysis was conducted from the Dutch societal perspective and to address decision uncertainty, probabilistic sensitivity analysis was performed. Results were based on average values of 1000 Monte Carlo simulations and using discount rates of 1.5% and 4% for effects and costs respectively. One way sensitivity analyses were performed to identify the two most influential model parameters affecting model outputs. Then, a two way sensitivity analysis was conducted for combinations of values tested for these two most influential parameters. RESULTS: For the PAD screening strategy, life years and quality adjusted life years gained were 21.79 and 15.66 respectively at a lifetime cost of 26,548 Euros. Compared to no screening and treatment (20.69 life years, 15.58 Quality Adjusted Life Years, 28,052 Euros), these results indicate that PAD screening and treatment is a dominant strategy. The cost effectiveness acceptability curves show 88% probability of PAD screening being cost effective at the Willingness To Pay (WTP) threshold of 40000 Euros. In a scenario analysis using clopidogrel as an alternative anti-platelet drug, PAD screening strategy remained dominant. CONCLUSION: This decision analysis suggests that targeted ABI screening and consequent secondary prevention of cardiovascular events using low dose aspirin or clopidogrel in the identified patients is a cost-effective strategy. Implementation of targeted PAD screening and subsequent treatment in primary care practices and in public health programs is likely to improve the societal health and to save health care costs by reducing catastrophic cardiovascular events. PMID- 24476215 TI - Phenolics and antioxidant activity of Saskatoon berry (Amelanchier alnifolia) pomace extract. AB - Saskatoon berries (Amelanchier alnifolia Nutt.) have significantly higher levels of anthocyanins (ACY) among berries with potential health benefits. The pomace is a by-product of juice extracted from berries and is a potential source of inexpensive polyphenols. The objectives of this study were to extract the maximum amount of total phenolics from saskatoon pomace, to determine the antioxidant activity, and to identify individual phenolic components. Pomace extracts showed high content of total phenolics, total ACY, and total flavonoids of 43.3, 2.8, and 10.3 g/kg of dried weight (DW) of pomace. A high oxygen radical absorbing capacity value of 119.4 MUmol Trolox equivalents/g DW and free radical scavenging activity of pomace extract (200 ppm, 86.8%) were observed. Five major ACY, two flavonols, and three chlorogenic acids were identified and quantified in pomace extracts. This study shows that saskatoon berries pomace rich in antioxidant phenolics could be extracted by "green" solvents (water and ethanol) and used as suitable food product applications. PMID- 24476214 TI - Glyceollin transport, metabolism, and effects on p-glycoprotein function in Caco 2 cells. AB - Glyceollins are phytoalexins produced in soybeans from their isoflavone precursor daidzein. Their impressive anticancer and glucose normalization effects in rodents have generated interest in their therapeutic potential. The aim of the present studies was to begin to understand glyceollin intestinal transport and metabolism, and their potential effects on P-glycoprotein (Pgp) in Caco-2 cells. At 10 and 25 MUM, glyceollin permeability was 2.4+/-0.16*10(-4) cm/sec and 2.1+/ 0.15*10(-4) cm/sec, respectively, in the absorptive direction. Basolateral to apical permeability at 25 MUM was 1.6+/-0.10*10(-4) cm/sec. Results suggest high absorption potential of glyceollin by a passive-diffusion-dominated mechanism. A sulfate conjugate at the phenolic hydroxyl position was observed following exposure to Caco-2 cells. In contrast to verapamil inhibition of the net secretory permeability of rhodamine 123 (R123) and its enhancement of calcein AM uptake into Caco-2 cells, neither glyceollin nor genistein inhibited Pgp (MDR1; ABCB1) up to 300 MUM. There was no significant change in MDR1 mRNA expression, Pgp protein expression, or R123 transport in cells exposed to glyceollin or genistein for 24 h up to 100 MUM. Collectively, these results suggest that glyceollin has the potential to be well absorbed, but that, similar to the isoflavone genistein, its absorption may be reduced substantially by intestinal metabolism; further, they indicate that glyceollin does not appear to alter Pgp function in Caco-2 cells. PMID- 24476216 TI - Curcumin reduces cytotoxicity of 5-Fluorouracil treatment in human breast cancer cells. AB - Antimetabolites have proven successful as therapeutics for advanced-stage breast cancers, but are often accompanied by severe side effects that can limit treatment regimens. 5-Fluorouracil (5-FU), an antimetabolite that inhibits cell proliferation, has served an important role in standard chemotherapy protocols for a variety of solid tumors. Although reasonable response rates have been reported for 5-FU, continued exploration is necessary to improve clinical outcomes and reduce cytotoxic side effects that are an inherent problem for chemotherapeutic interventions. Because of its diverse anticancer properties, we explored whether by combining the natural product curcumin with 5-FU, synergistic improvements in preventing breast cancer cell proliferation and/or provide protection against 5-FU-induced cytotoxicity could be achieved. Indeed both curcumin and 5-FU inhibit DNA synthesis in MDA-MB-231 cells using BrdU incorporation assays; however, combined treatment showed no synergistic improvement. We next established the cytotoxicity profile for 5-FU in MDA-MB-231 cells using a tetrazolium-based cell viability assay and obtained an LD50 value of 28 MUM. When 5-FU incubations were repeated with the addition of curcumin, the LD50 value increased to 200-300 MUM, representing a 7-10-fold protection by curcumin against 5-FU cytotoxicity. These findings suggest that the addition of curcumin as an adjuvant therapy during 5-FU treatment might enhance the chemotherapeutic effectiveness of 5-FU by protecting normal cells from reduced viability and thus permitting higher dosing or longer treatment times. This would be especially important to those individuals who are plagued with severe cytotoxicities and require frequent interruptions, or even early termination of their treatment regimens. PMID- 24476217 TI - Effects of an orabase formulation with ethanolic extract of Malva sylvestris L. in oral wound healing in rats. AB - Malva sylvestris L. is widely used in medicine for treatment of inflammatory processes. The plant has anti-inflammatory properties due to substances such as mucilage, flavonoids, and tannins. A mouthwash with leaves from the plant can be used for the treatment of wounds in the oral mucosa. The aim of this study was to assess the wound healing effect of Malva sylvestris L. on a palate mucosa wound in rats. After intraperitoneal anesthesia, a 4-mm-diameter excisional wound was made in the center of the palatal mucosa of 136 rats, using a punch-out biopsy tool. Eight animals were used as baseline wound. The remaining rats were divided into four groups: CO, control; OB, orabase vehicle; CX, 2% chlorhexidine; and MA, 20% Malva in orabase. At 24 h postoperatively, the animals were immobilized without anesthetic to apply 25 mg of each substance twice a day, totaling 50 mg daily. The wound areas were measured photographically and the reepithelialization rates were determined histologically (%) after 0, 3, 7, 15, and 21 days. The data were analyzed by ANOVA and Tukey post hoc test. Similar healing pattern was observed among the groups (P>.05; ANOVA). According to the methodology, Malva sylvestris L. extract had no effect on wound healing in the palatal mucosa of rats. PMID- 24476218 TI - D-galactose induces a mitochondrial complex I deficiency in mouse skeletal muscle: potential benefits of nutrient combination in ameliorating muscle impairment. AB - Accumulating research has shown that chronic D-galactose (D-gal) exposure induces symptoms similar to natural aging in animals. Therefore, rodents chronically exposed to D-gal are increasingly used as a model for aging and delay-of-aging pharmacological research. Mitochondrial dysfunction is thought to play a vital role in aging and age-related diseases; however, whether mitochondrial dysfunction plays a significant role in mice exposed to D-gal remains unknown. In the present study, we investigated cognitive dysfunction, locomotor activity, and mitochondrial dysfunction involved in D-gal exposure in mice. We found that D-gal exposure (125 mg/kg/day, 8 weeks) resulted in a serious impairment in grip strength in mice, whereas spatial memory and locomotor coordination remained intact. Interestingly, muscular mitochondrial complex I deficiency occurred in the skeletal muscle of mice exposed to D-gal. Mitochondrial ultrastructure abnormality was implicated as a contributing factor in D-gal-induced muscular impairment. Moreover, three combinations (A, B, and C) of nutrients applied in this study effectively reversed D-gal-induced muscular impairment. Nutrient formulas B and C were especially effective in reversing complex I dysfunction in both skeletal muscle and heart muscle. These findings suggest the following: (1) chronic exposure to D-gal first results in specific muscular impairment in mice, rather than causing general, premature aging; (2) poor skeletal muscle strength induced by D-gal might be due to the mitochondrial dysfunction caused by complex I deficiency; and (3) the nutrient complexes applied in the study attenuated the skeletal muscle impairment, most likely by improving mitochondrial function. PMID- 24476219 TI - 8-hydrocalamenene, derived from Reynoutria elliptica, suppresses constitutive STAT3 activation, inhibiting proliferation and enhancing chemosensitization of human multiple myeloma cells. AB - The identification of the active compounds of herbal medicines and the molecular targets of those compounds is an attractive therapeutic objective. Reynoutria elliptica has been used for the treatment of various inflammatory diseases as a Korean folk remedy. Based on the evidence that anti-inflammatory agents frequently exert antiproliferative activity, we tested two sesquiterpene derivatives, 8-hydrocalamenene (HC) and 8,14-dihydrocalamenene (DHC), for their ability to induce apoptosis and suppress signal transducer and activator of transcription 3 (STAT3) activation in multiple myeloma (MM) U266 cells. We found that HC inhibited cell viability in U266, but not in peripheral blood mononuclear cells. HC exerted significant cytotoxicity and induced substantial subG1-phase arrest and apoptosis as compared with DHC. HC inhibited the expression of gene products involved in antiapoptosis (Bcl-2 and Bcl-xL), proliferation (cyclin D1), and invasion (MMP-9), all of which are known to be regulated by STAT3. Furthermore, HC up-regulated cyclin-dependent kinase inhibitor p21 and induced apoptosis through the activation of caspase-8, -9, and -3 in U266 cells. Interestingly, HC blocked constitutive STAT3 activation through the inhibition of activation of upstream kinases Janus-like kinase 1 (JAK1), JAK2, and c-Src and up regulated PIAS3. Deletion of STAT3 reversed cytotoxic effects and the down regulation of cyclin D1 and c-myc by HC in MM cells. Finally, this sesquiterpene significantly synergized the cytotoxic and apoptotic effects of bortezomib in U266 cells. Taken together, these results suggest that HC is a novel blocker of STAT3 activation which may have a potential in the prevention and treatment of MM. PMID- 24476220 TI - Drinking orange juice increases total antioxidant status and decreases lipid peroxidation in adults. AB - Cardiovascular disease (CVD) is the leading cause of death in the world and is the primary cause of mortality among Americans. One of the many reasons for the pathogenesis of CVD is attributed to eating diets high in saturated fat and refined carbohydrates and low in fruits and vegetables. Epidemiological evidence has supported a strong association between eating diets rich in fruits and vegetables and cardiovascular health. An experiment was conducted utilizing 24 adults with hypercholesterolemia and hypertriglyceridemia to evaluate the impact of drinking 20 fl oz of freshly squeezed orange juice daily for 90 days on blood pressure, lipid panels, plasma antioxidant capacity, metabolic hormones, lipid peroxidation, and inflammatory markers. Except for addition of drinking orange juice, subjects did not modify their eating habits. The findings suggested that drinking orange juice does not affect (P>.1) blood pressure, lipid panels, metabolic hormones, body fat percentage, or inflammatory markers. However, total plasma antioxidant capacity was significantly increased (P<.05) and lipid peroxidation was significantly decreased (P<.05) after orange juice consumption. Drinking orange juice may protect the cardiovascular system by increasing total plasma antioxidant status and by lowering lipid peroxidation independent of other cardiovascular risk markers evaluated in this study. PMID- 24476221 TI - Anti-inflammatory and antinociceptive effects of Sterculia striata A. St.-Hil. & Naudin (Malvaceae) in rodents. AB - The present work reports the anti-inflammatory and antinociceptive activities of the ethanol extract obtained from the stem bark of Sterculia striata A. St.-Hil. & Naudin (Ss-EtOH) in the experimental models of edema induced by carrageenan, dextran, or histamin and nociception induced by chemical stimuli, such as acetic acid, formalin, capsaicin, or glutamate. The Ss-EtOH (50 mg/kg) promoted a marked inhibition on the hind paw edema induced by carrageenan or dextran (30% and 73%, respectively). Besides, Ss-EtOH (25 mg/kg) exhibited a slight activity (30%) on the hind paw edema induced by histamin. The Ss-EtOH (12.5 and 25 mg/kg) showed the antinociceptive activity on chemical stimuli induced by acetic acid (65.59% and 38.37%, respectively), formalin, in the initial (35.08% and 31.5%, respectively) and late phases (44.09% and 83.57%, respectively), capsaicin (43.77% and 51.31%, respectively), or glutamate (36.6% and 52.12%, respectively). Regarding the possible mechanism involved in the antinociceptive effect, Ss-EtOH (12.5 mg/kg) showed a decrease in the antinociceptive effect (65.8%) in the acetic acid model after pretreatment with naloxone. Thus, opioid mechanisms might be underlying this response. PMID- 24476222 TI - Resveratrol supplementation reduces aortic atherosclerosis and calcification and attenuates loss of aerobic capacity in a mouse model of uremia. AB - The polyphenolic compound resveratrol (RSV) has been studied for its protective effects on a variety of conditions, including cardiovascular disease (CVD), reduced exercise capacity, and bone disease. Individuals with chronic kidney disease suffer from a variety of these comorbid conditions, but the efficacy of RSV supplementation in this population is unknown. The objective of this study was to determine the efficacy of resveratrol feeding on factors related to CVD, aerobic capacity, and bone health in a mouse model of uremia. At 8 weeks of age, 28 female apolipoprotein E-/- mice underwent a two-step surgical procedure to induce uremia and were randomized to one of the two treatment groups for 16 weeks: 0.04% w/w resveratrol supplemented diet (group designated as RSV) (n=12) or control diet (group designated as CON) (n=16). Cardiovascular risk was determined by analysis of aortic atherosclerotic lesion area and aortic calcium, aerobic capacity was measured by maximal oxygen consumption/maximal aerobic capacity (VO(2max)) testing, and bone microarchitecture was assessed by microcomputed tomography. RSV animals had significantly fewer aortic atherosclerotic lesions at the site of the ascending aorta and lower aortic calcium at the branch of the coronary arteries compared with CON. Furthermore, there was a significant decline in VO(2max) from baseline to final testing in the CON group, but VO(2max) was preserved in the RSV group. Last, RSV had no significant effect on bone architecture. These data indicate that RSV supplementation improves vascular health and preserves aerobic capacity in a model of uremia, suggesting RSV supplementation could be examined as a therapeutic strategy for a critically ill population. PMID- 24476224 TI - The antibiofilm effect of blueberry fruit cultivars against Staphylococcus epidermidis and Pseudomonas aeruginosa. AB - The antibiofilm and antibacterial properties against Pseudomonas aeruginosa and Staphylococcus epidermidis and chemical characterization of six hydroethanolic blueberry extracts (blueberry rabbiteye-Vaccinium virgatum) from different cultivars and means of propagation were investigated. The total flavonoid, anthocyanin, and phenolic contents were determined by specific and well established methods. Among the cultivars, Briteblue showed the lowest content of all metabolites analyzed, while Bluegem showed the highest concentrations of these compounds. All the micropropagated cultivars presented the highest amounts of chlorogenic acid. The blueberry fruit extracts showed strong activity against S. epidermidis biofilm (up to 84% inhibition) without inhibiting bacterial growth. Likewise, Bluegem micropropagated extract, which had the highest anthocyanin, flavonoids, and phenolic compound content, demonstrated the highest S. epidermidis biofilm inhibitory effect. Finally, a linear correlation between the total phenolic content and the percentage of biofilm inhibition was observed. PMID- 24476223 TI - Oral administration of SSC201, a medicinal herbal formula, suppresses atopic dermatitis-like skin lesions. AB - Atopic dermatitis (AD) is a chronic inflammatory skin disease, which requires safe and effective treatment. In this study, we evaluated the effects of SSC201, a herbal formulation consisting of Stemonae Radix, Spirodelae Herba, and Cnidii Fructus, on the development of AD induced by 2,4-dinitrochlorobenzene in the NC/Nga murine model. Oral administration of SSC201 significantly reduced the severity of dermatitis and the tendency of mice to scratch their lesions. SSC201 significantly reduced the thickening of the epidermis/dermis and the infiltration of T cells, eosinophils, and mast cells into the dermis. These results were supported by findings of reduced numbers of CD4(+), CCR3(+), and CD117(+)FcERIalpha(+) cells in the skin. Furthermore, SSC201 significantly decreased the number of CD4(+), CD8(+), and CD3(+)CD69(+) T cells in lymph nodes. SSC201 not only decreased the plasma levels of immunoglobulin E (IgE) and the numbers of IgE-producing B cells (B220(+)CD23(+)), but also reduced the number of eosinophils and the levels of eotaxin as well as concentrations of thymus and activation-regulated chemokine in the periphery. Splenic levels of Th2 cytokines, including interleukin (IL)-4, IL-5, and IL-13, were reduced, whereas the levels of IL-12, a Th1 cytokine, were increased. Taken together, our data suggest that SSC201 may be an effective therapeutic agent for the treatment of AD. PMID- 24476225 TI - Analgesic and anti-inflammatory activities of the 2,8-dihydroxy-1,6 dimethoxyxanthone from Haploclathra paniculata (Mart) Benth (Guttiferae). AB - In the present study, the pharmacological effects of 2,8-dihydroxy-1,6 dimethoxyxanthone from the bark of Haploclathra paniculata were investigated in mice using in vivo inflammation and nociception models. Acetic acid-induced writhing, paw licking induced by formalin, hot plate, and carrageenan-induced paw edema tests were used to investigate the anti-inflammatory and antinociceptive activities of the xanthone compound. Xanthone, at both doses, inhibited abdominal writhing and the formalin test. At a dose of 20 mg/kg, the time of reaction to the hot plate increased, and significant effects were observed after 30, 60 and 90 min of treatment. At doses of 10 and 20 mg/kg p.o., the 2,8-dihydroxy-1,6 dimethoxyxanthone significantly reduced paw edema at 3 h after the stimulus. The tests also showed no acute toxicity of the xanthone compound in mice. 2,2 diphenyl-1-picrylhydrazyl (DPPH) radical scavenging ability was also studied and confirmed the antioxidant activity of the xanthone. To propose the mechanism of action of anti-inflammatory activity of the xanthone, a molecular docking was performed using the isoenzymes cyclooxygenase 1 and 2 and the results indicate that the molecule is capable of inhibiting both the enzymes. Therefore, it can be concluded that 2,8-dihydroxy-1,6-dimethoxyxanthone from H. paniculata demonstrates analgesic, anti-inflammatory, and antioxidant activities. PMID- 24476226 TI - Efficacy of swaddling and heel warming on pain response to heel stick in neonates: a randomised control trial. AB - AIMS AND OBJECTIVES: To determine the efficacy of swaddling and heel warming on pain response in neonates following heel stick. BACKGROUND: Swaddling has been suggested to reduce pain response in neonates during heel stick. Heel warming is also often performed for drawing blood easily before heel stick. However, the efficacy of both on pain response is unclear. DESIGN: A randomised controlled study was used. METHODS: Twenty-five neonates were randomly assigned to each of the control, swaddling and heel-warming groups. Heart rate, oxygen saturation Neonatal Infant Pain Scale and duration of crying were used to assess pain reactivity and pain recovery. A greater heart rate and Neonatal Infant Pain Scale increase, or oxygen saturation decrease, indicated higher pain reactivity. A longer duration of heart rate and oxygen saturation changes after heel stick back to baseline indicated a longer pain recovery. RESULTS: The decrease in oxygen saturation in swaddling group was significantly greater than that in heel-warming group. The increase in the Neonatal Infant Pain Scale in control group was significantly higher than that in swaddling group. The heart rate recovery time in control group and swaddling group was significantly longer than that in heel warming group. The oxygen saturation recovery time in control group was significantly longer than that in heel-warming group. The duration of crying in control group was significantly longer than those in swaddling group and heel warming group. CONCLUSION: Both swaddling and heel warming decreased the pain response of neonates during heel stick. Heel warming resulted in a lower pain response than did swaddling for neonates, particularly in terms of pain recovery. RELEVANCE TO CLINICAL PRACTICE: Heel warming could become a routine practice to decrease the pain response of neonates during heel stick. PMID- 24476227 TI - Triggered release of doxorubicin from temperature-sensitive poly(N-(2 hydroxypropyl)-methacrylamide mono/dilactate) grafted liposomes. AB - The objective of this study was to design temperature-sensitive liposomes with tunable release characteristics that release their content at an elevated temperature generated by high intensity focused ultrasound (HIFU) exposure. To this end, thermosensitive polymers of N-(2-hydroxypropyl)methacrylamide mono/dilactate of different molecular weights and composition with a cholesterol anchor (chol-pHPMAlac) were synthesized and grafted onto liposomes loaded with doxorubicin (DOX). The liposomes were incubated at different temperatures and their release kinetics were studied. A good correlation between the release-onset temperature of the liposomes and the cloud point (CP) of chol-pHPMAlac was found. However, release took place at significantly higher temperatures than the CP of chol-pHPMAlac, likely at the CP, the dehydration and thus hydrophobicity is insufficient to penetrate and permeabilize the liposomal membrane. Liposomes grafted with chol-pHPMAlac with a CP of 11.5 degrees C released 89% DOX within 5 min at 42 degrees C while for the liposomes grafted with a polymer with CP of 25.0 degrees C, a temperature of 52 degrees C was needed to obtain the same extent of DOX release. At a fixed copolymer composition, an increase in molecular weight from 6.5 to 14.5 kDa decreased the temperature at which DOX was released with a release-onset temperature from 52 to 42 degrees C. Liposomes grafted with 5% chol-pHPMAlac exhibited a rapid release to a temperature increase, while at a grafting density of 2 and 10%, the liposomes were less sensitive to an increase in temperature. Sequential release of DOX was obtained by mixing liposomes grafted with chol-pHPMAlac having different CPs. Chol-pHPMAlac grafted liposomes released DOX nearly quantitatively after pulsed wave HIFU. In conclusion, the release of DOX from liposomes grafted with thermosensitive polymers of N-(2 hydroxypropyl)methacrylamide mono/dilactate can be tuned to the characteristics and the grafting density of chol-pHPMAlac, making these liposomes attractive for local drug delivery using hyperthermia. PMID- 24476228 TI - Ion-specific long-range correlations on interfacial water driven by hydrogen bond fluctuations. AB - Some of the most important processes in nature involve interfacial water. It has long been conjectured that specific ion effects therein are associated with the unique properties of interfacial water. Here we reveal the mechanism of such association by showing that the strength of ion-specific long-range correlations tracks the amplification of fluctuations on the surface of water-alcohol mixtures at the percolation thresholds of their hydrogen-bonded water networks. We used in situ online electrospray mass spectrometry to determine chi = [I(-)]/[Br(-)] ratios in microfilms of (NaI + NaBr) solutions in water-methanol (ME) and water isopropanol (IP) mixtures as functions of x(ME) and x(IP) molar fractions, and the addition of NaClO4. We found that, beginning at 0.1 MUM, ClO4(-) has detectable effects on chi that peak at x(ME) ~ 0.40, x(IP) ~ 0.15, i.e., at water percolation thresholds where fluctuations maximize mean water cluster sizes and, hence, interionic connections. The stronger correlations between ions of similar surface propensities suggest that correlations propagate preferentially along 2-D interfacial layers. PMID- 24476229 TI - Characterizing changes in soil bacterial community structure in response to short term warming. AB - High altitude alpine meadows are experiencing considerably greater than average increases in soil surface temperature, potentially as a result of ongoing climate change. The effects of warming on plant productivity and soil edaphic variables have been established previously, but the influence of warming on soil microbial community structure has not been well characterized. Here, the impact of 15 months of soil warming (both +1 and +2 degrees C) on bacterial community structure was examined in a field experiment on a Tibetan plateau alpine meadow using bar-coded pyrosequencing. Warming significantly changed (P < 0.05) the structure of the soil bacterial community, but the alpha diversity was not dramatically affected. Changes in the abundance of the Actinobacteria and Alphaproteobacteria were found to contribute the most to differences between ambient (AT) and artificially warmed conditions. A variance partitioning analysis (VPA) showed that warming directly explained 7.15% variation in bacterial community structure, while warming-induced changes in soil edaphic and plant phenotypic properties indirectly accounted for 28.3% and 20.6% of the community variance, respectively. Interestingly, certain taxa showed an inconsistent response to the two warming treatments, for example Deltaproteobacteria showed a decreased relative abundance at +1 degrees C, but a return to AT control relative abundance at +2 degrees C. This suggests complex microbial dynamics that could result from conditional dependencies between bacterial taxa. PMID- 24476230 TI - Active immunotherapy options for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common cause of dementia and a major contributor to disability and dependency among older people. AD pathogenesis is associated with the accumulation of amyloid-beta protein (Abeta) and/or hyperphosphorylated tau protein in the brain. At present, current therapies provide temporary symptomatic benefit, but do not treat the underlying disease. Recent research has thus focused on investigating the molecular and cellular pathways and processes involved in AD pathogenesis to support the development of effective disease-modifying agents. In accordance with the existing Abeta-cascade hypothesis for AD pathogenesis, immunotherapy has been the most extensively studied approach in Abeta-targeted therapy. Both passive and active immunotherapies have been shown to effectively reduce Abeta accumulation and prevent downstream pathology in preclinical models. Following AN1792, second generation active immunotherapies have shown promising results in terms of antibody response and safety. Comparatively, tau immunotherapy is not as advanced, but preclinical data support its development into clinical trials. Results from active amyloid-based immunotherapy studies in preclinical models indicate that intervention appears to be more effective in early stages of amyloid accumulation, highlighting the importance of diagnosing AD as early as possible and undertaking clinical trials at this stage. This strategy, combined with improving our understanding of the complex AD pathogenesis, is imperative to the successful development of these disease-modifying agents. This paper will review the active immunotherapies currently in development, including the benefits and challenges associated with this approach. PMID- 24476231 TI - Transformation of Ag nanocubes into Ag-Au hollow nanostructures with enriched Ag contents to improve SERS activity and chemical stability. AB - We report a strategy to complement the galvanic replacement reaction between Ag nanocubes and HAuCl4 with co-reduction by ascorbic acid (AA) for the formation of Ag-Au hollow nanostructures with greatly enhanced SERS activity. Specifically, in the early stage of synthesis, the Ag nanocubes are sharpened at corners and edges because of the selective deposition of Au and Ag atoms at these sites. In the following steps, the pure Ag in the nanocubes is constantly converted into Ag(+) ions to generate voids owing to the galvanic reaction with HAuCl4, but these released Ag(+) ions are immediately reduced back to Ag atoms and are co-deposited with Au atoms onto the nanocube templates. We observe distinctive SERS properties for the Ag-Au hollow nanostructures at visible and near-infrared excitation wavelengths. When plasmon damping is eliminated by using an excitation wavelength of 785 nm, the SERS activity of the Ag-Au hollow nanostructures is 15- and 33 fold stronger than those of the original Ag nanocubes and the Ag-Au nanocages prepared by galvanic replacement without co-reduction, respectively. Additionally, Ag-Au hollow nanostructures embrace considerably improved stability in an oxidizing environment such as aqueous H2O2 solution. Collectively, our work suggests that the Ag-Au hollow nanostructures will find applications in SERS detection and imaging. PMID- 24476232 TI - Structure, electronic states, and anion-binding properties of cyclo[4]naphthobipyrroles. AB - Three octaalkyl-substituted cyclo[4]naphthobipyrroles, studied in solution in the form of their sulfates, reveal absorption and magnetic circular dichroism (MCD) spectra very similar to those of the parent cyclo[8]pyrrole. A unique feature of these systems is a strong absorption in the near IR region. The analysis of MCD patterns based on a perimeter model reveals a hard-chromophore character of cyclo[4]naphthobipyrroles, i.e., DeltaHOMO ? DeltaLUMO. Comparison of Raman spectra obtained for crystalline samples and solutions, combined with the analysis of absorption and MCD spectra based on quantum chemical calculations reveals that cyclo[4]naphthobipyrroles exist in solutions as undissociated sulfates of the doubly protonated forms. PMID- 24476234 TI - Universal uncertainty relations. AB - Uncertainty relations are a distinctive characteristic of quantum theory that impose intrinsic limitations on the precision with which physical properties can be simultaneously determined. The modern work on uncertainty relations employs entropic measures to quantify the lack of knowledge associated with measuring noncommuting observables. However, there is no fundamental reason for using entropies as quantifiers; any functional relation that characterizes the uncertainty of the measurement outcomes defines an uncertainty relation. Starting from a very reasonable assumption of invariance under mere relabeling of the measurement outcomes, we show that Schur-concave functions are the most general uncertainty quantifiers. We then discover a fine-grained uncertainty relation that is given in terms of the majorization order between two probability vectors, significantly extending a majorization-based uncertainty relation first introduced in M. H. Partovi, Phys. Rev. A 84, 052117 (2011). Such a vector-type uncertainty relation generates an infinite family of distinct scalar uncertainty relations via the application of arbitrary uncertainty quantifiers. Our relation is therefore universal and captures the essence of uncertainty in quantum theory. PMID- 24476233 TI - Socioeconomic inequalities in the non-use of dental care in Europe. AB - INTRODUCTION: Oral health is an important component of people's general health status. Many studies have shown that socioeconomic status is an important determinant of access to health services. In the present study, we explored the inequality and socioeconomic factors associated with people's non-use of dental care across Europe. METHODS: We obtained data from the European Union Statistics on Income and Living Conditions survey conducted by Eurostat in 2007. These cross sectional data were collected from people aged 16 years and older in 24 European countries, except those living in long-term care facilities. The variable of interest was the prevalence of non-use of dental care while needed. We used the direct method of standardisation by age and sex to eliminate confounders in the data. Socioeconomic inequalities in the non-use of dental care were measured through differences in prevalence, the relative concentration index (RCI), and the relative index of inequality (RII). We compared the results among countries and conducted standard and multilevel logistic regression analyses to examine the socioeconomic factors associated with the non-use of dental care while needed. RESULTS: The results revealed significant socio-economic inequalities in the non use of dental care across Europe, the magnitudes of which depended on the measure of inequality used. For example, inequalities in the prevalence of non-use among education levels according to the RCI ranged from 0.005 (in the United Kingdom) to -0.271 (Denmark) for men and from -0.009 (Poland) to 0.176 (Spain) for women, whereas the RII results ranged from 1.21 (Poland) to 11.50 (Slovakia) for men and from 1.62 (Poland) to 4.70 (Belgium) for women. Furthermore, the level-2 variance (random effects) was significantly different from zero, indicating the presence of heterogeneity in the probability of the non-use of needed dental care at the country level. CONCLUSION: Overall, our study revealed considerable socioeconomic inequalities in the non-use of dental care at both the individual (intra-country) and collective (inter-country) levels. Therefore, to be most effective, policies to reduce this social inequality across Europe should address both levels. PMID- 24476235 TI - Heat engine driven by purely quantum information. AB - The key question of this Letter is whether work can be extracted from a heat engine by using purely quantum mechanical information. If the answer is yes, what is its mathematical formula? First, by using a bipartite memory we show that the work extractable from a heat engine is bounded not only by the free energy change and the sum of the entropy change of an individual memory but also by the change of quantum mutual information contained inside the memory. We then find that the engine can be driven by purely quantum information, expressed as the so-called quantum discord, forming a part of the quantum mutual information. To confirm it, as a physical example we present the Szilard engine containing a diatomic molecule with a semipermeable wall. PMID- 24476236 TI - Superfluid stiffness of a driven dissipative condensate with disorder. AB - Observations of macroscopic quantum coherence in driven systems, e.g. polariton condensates, have strongly stimulated experimental as well as theoretical efforts during the last decade. We address the question of whether a driven quantum condensate is a superfluid, allowing for the effects of disorder and its nonequilibrium nature. We predict that for spatial dimensions d<4 the superfluid stiffness vanishes once the condensate exceeds a critical size, and treat in detail the case d=2. Thus a nonequilibrium condensate is not a superfluid in the thermodynamic limit, even for weak disorder, although superfluid behavior would persist in small systems. PMID- 24476237 TI - Lieb-Robinson bounds for spin-boson lattice models and trapped ions. AB - We derive a Lieb-Robinson bound for the propagation of spin correlations in a model of spins interacting through a bosonic lattice field, which satisfies a Lieb-Robinson bound in the absence of spin-boson couplings. We apply these bounds to a system of trapped ions and find that the propagation of spin correlations, as mediated by the phonons of the ion crystal, can be faster than the regimes currently explored in experiments. We propose a scheme to test the bounds by measuring retarded correlation functions via the crystal fluorescence. PMID- 24476238 TI - Efficient universal blind quantum computation. AB - We give a cheat sensitive protocol for blind universal quantum computation that is efficient in terms of computational and communication resources: it allows one party to perform an arbitrary computation on a second party's quantum computer without revealing either which computation is performed, or its input and output. The first party's computational capabilities can be extremely limited: she must only be able to create and measure single-qubit superposition states. The second party is not required to use measurement-based quantum computation. The protocol requires the (optimal) exchange of O(Jlog2(N)) single-qubit states, where J is the computational depth and N is the number of qubits needed for the computation. PMID- 24476239 TI - Optimal blind quantum computation. AB - Blind quantum computation allows a client with limited quantum capabilities to interact with a remote quantum computer to perform an arbitrary quantum computation, while keeping the description of that computation hidden from the remote quantum computer. While a number of protocols have been proposed in recent years, little is currently understood about the resources necessary to accomplish the task. Here, we present general techniques for upper and lower bounding the quantum communication necessary to perform blind quantum computation, and use these techniques to establish concrete bounds for common choices of the client's quantum capabilities. Our results show that the universal blind quantum computation protocol of Broadbent, Fitzsimons, and Kashefi, comes within a factor of 8/3 of optimal when the client is restricted to preparing single qubits. However, we describe a generalization of this protocol which requires exponentially less quantum communication when the client has a more sophisticated device. PMID- 24476240 TI - Chemical compass model for avian magnetoreception as a quantum coherent device. AB - It is known that more than 50 species use the Earth's magnetic field for orientation and navigation. Intensive studies, particularly behavior experiments with birds, provide support for a chemical compass based on magnetically sensitive free radical reactions as a source of this sense. However, the fundamental question of how quantum coherence plays an essential role in such a chemical compass model of avian magnetoreception yet remains controversial. Here, we show that the essence of the chemical compass model can be understood in analogy to a quantum interferometer exploiting global quantum coherence rather than any subsystem coherence. Within the framework of quantum metrology, we quantify global quantum coherence and correlate it with the function of chemical magnetoreception. Our results allow us to understand and predict how various factors can affect the performance of a chemical compass from the unique perspective of quantum coherence assisted metrology. This represents a crucial step to affirm a direct connection between quantum coherence and the function of a chemical compass. PMID- 24476241 TI - Experimental distribution of entanglement with separable carriers. AB - The key requirement for quantum networking is the distribution of entanglement between nodes. Surprisingly, entanglement can be generated across a network without direct transfer-or communication-of entanglement. In contrast to information gain, which cannot exceed the communicated information, the entanglement gain is bounded by the communicated quantum discord, a more general measure of quantum correlation that includes but is not limited to entanglement. Here, we experimentally entangle two communicating parties sharing three initially separable photonic qubits by exchange of a carrier photon that is unentangled with either party at all times. We show that distributing entanglement with separable carriers is resilient to noise and in some cases becomes the only way of distributing entanglement through noisy environments. PMID- 24476242 TI - Experimental entanglement distribution by separable states. AB - Distribution of entanglement between macroscopically separated parties is crucial for future quantum information networks. Surprisingly, it has been theoretically shown that two distant systems can be entangled by sending a third system that is not entangled with either of them. Here, we experimentally distribute entanglement and successfully prove that our transmitted light beam is indeed not entangled with the parties' local systems. Our work demonstrates an unexpected variant of entanglement distribution and improves the understanding necessary to engineer multipartite quantum networks. PMID- 24476243 TI - Distributing entanglement with separable states. AB - We experimentally demonstrate a protocol for entanglement distribution by a separable quantum system. In our experiment, two spatially separated modes of an electromagnetic field get entangled by local operations, classical communication, and transmission of a correlated but separable mode between them. This highlights the utility of quantum correlations beyond entanglement for the establishment of a fundamental quantum information resource and verifies that its distribution by a dual classical and separable quantum communication is possible. PMID- 24476244 TI - General scheme for the construction of a protected qubit subspace. AB - We present a new robust decoupling scheme suitable for levels with either half integer or integer angular momentum states. Through continuous dynamical decoupling techniques, we create a protected qubit subspace, utilizing a multistate qubit construction. Remarkably, the multistate system can also be composed of multiple substates within a single level. Our scheme can be realized with state-of-the-art experimental setups and thus has immediate applications for quantum information science. While the scheme is general and relevant for a multitude of solid-state and atomic systems, we analyze its performance for the case composed of trapped ions. Explicitly, we show how single qubit gates and an ensemble coupling to a cavity mode can be implemented efficiently. The scheme predicts a coherence time of ~1 s, as compared to typically a few milliseconds for the bare states. PMID- 24476245 TI - Dynamic correlators of Fermi-Pasta-Ulam chains and nonlinear fluctuating hydrodynamics. AB - We study the equilibrium time correlations for the conserved fields of classical anharmonic chains and argue that their dynamic correlator can be predicted on the basis of nonlinear fluctuating hydrodynamics. In fact, our scheme is more general and would also cover other one-dimensional Hamiltonian systems, for example, classical and quantum fluids. Fluctuating hydrodynamics is a nonlinear system of conservation laws with noise. For a single mode, it is equivalent to the noisy Burgers equation, for which explicit solutions are available. Our focus is the case of several modes. No exact solution has been found so far, and we rely on a one-loop approximation. The resulting mode-coupling equations have a quadratic memory kernel and describe the time evolving 3*3 correlator matrix of the locally conserved fields. Long time asymptotics is computed analytically, and finite time properties are obtained through a numerical simulation of the mode-coupling equations. PMID- 24476246 TI - From metadynamics to dynamics. AB - Metadynamics is a commonly used and successful enhanced sampling method. By the introduction of a history dependent bias which depends on a restricted number of collective variables it can explore complex free energy surfaces characterized by several metastable states separated by large free energy barriers. Here we extend its scope by introducing a simple yet powerful method for calculating the rates of transition between different metastable states. The method does not rely on a previous knowledge of the transition states or reaction coordinates, as long as collective variables are known that can distinguish between the various stable minima in free energy space. We demonstrate that our method recovers the correct escape rates out of these stable states and also preserves the correct sequence of state-to-state transitions, with minimal extra computational effort needed over ordinary metadynamics. We apply the formalism to three different problems and in each case find excellent agreement with the results of long unbiased molecular dynamics runs. PMID- 24476247 TI - Symmetry breaking in d-dimensional self-gravitating systems. AB - Systems with long-range interactions, such as self-gravitating clusters and magnetically confined plasmas, do not relax to the usual Boltzmann-Gibbs thermodynamic equilibrium, but become trapped in quasistationary states (QSS) the lifetime of which diverges with the number of particles. The QSS are characterized by the lack of ergodicity which can result in a symmetry broken QSS starting from a spherically symmetric particle distribution. We will present a theory which allows us to quantitatively predict the instability threshold for spontaneous symmetry breaking for a class of d-dimensional self-gravitating systems. PMID- 24476248 TI - Robust constraint on a drifting proton-to-electron mass ratio at z=0.89 from methanol observation at three radio telescopes. AB - A limit on a possible cosmological variation of the proton-to-electron mass ratio MU is derived from methanol (CH3OH) absorption lines in the benchmark PKS1830-211 lensing galaxy at redshift z=0.89 observed with the Effelsberg 100-m radio telescope, the Institute de Radio Astronomie Millimetrique 30-m telescope, and the Atacama Large Millimeter/submillimeter Array. Ten different absorption lines of CH3OH covering a wide range of sensitivity coefficients K(MU) are used to derive a purely statistical 1sigma constraint of DeltaMU/MU=(1.5+/-1.5)*10(-7) for a lookback time of 7.5 billion years. Systematic effects of chemical segregation, excitation temperature, frequency dependence, and time variability of the background source are quantified. A multidimensional linear regression analysis leads to a robust constraint of DeltaMU/MU=(-1.0+/-0.8(stat)+/ 1.0(sys))*10(-7). PMID- 24476249 TI - Magnetorotational decay instability in Keplerian disks. AB - The saturation of the magnetorotational instability (MRI) in thin Keplerian disks through three-wave resonant interactions is introduced and discussed. That mechanism is a natural generalization of the fundamental decay instability discovered five decades ago for infinite, homogeneous, and immovable plasmas. The decay instability relies on the energy transfer from the MRI to stable slow Alfven-Coriolis as well as magnetosonic waves. A second-order forced Duffing amplitude equation for the initially unstable MRI as well as two first-order equations for the other two waves are derived. The solutions of those equations exhibit bounded bursty nonlinear oscillations for the MRI as well as unbounded growth for the linearly stable slow Alfven-Coriolis and magnetosonic perturbations, thus giving rise to the magnetorotational decay instability. PMID- 24476250 TI - Neutrino and axion bounds from the globular cluster M5 (NGC 5904). AB - The red-giant branch (RGB) in globular clusters is extended to larger brightness if the degenerate helium core loses too much energy in "dark channels." Based on a large set of archival observations, we provide high-precision photometry for the Galactic globular cluster M5 (NGC 5904), allowing for a detailed comparison between the observed tip of the RGB with predictions based on contemporary stellar evolution theory. In particular, we derive 95% confidence limits of g(ae)<4.3*10(-13) on the axion-electron coupling and MU(nu)<4.5*10(-12)MU(B) (Bohr magneton MU(B)=e/2m(e)) on a neutrino dipole moment, based on a detailed analysis of statistical and systematic uncertainties. The cluster distance is the single largest source of uncertainty and can be improved in the future. PMID- 24476251 TI - Ultraviolet properties of N=4 supergravity at four loops. AB - We demonstrate that pure N=4 supergravity is ultraviolet divergent at four loops. The form of the divergence suggests that it is due to the rigid U(1) duality symmetry anomaly of the theory. This is the first known example of an ultraviolet divergence in a pure ungauged supergravity theory in four dimensions. We use the duality between color and kinematics to construct the integrand of the four-loop four-point amplitude, whose ultraviolet divergence is then extracted by standard integration techniques. PMID- 24476252 TI - Testing the self-consistency of the excursion set approach to predicting the dark matter halo mass function. AB - The excursion set approach provides a framework for predicting how the abundance of dark matter halos depends on the initial conditions. A key ingredient of this formalism is the specification of a critical overdensity threshold (barrier) which protohalos must exceed if they are to form virialized halos at a later time. However, to make its predictions, the excursion set approach explicitly averages over all positions in the initial field, rather than the special ones around which halos form, so it is not clear that the barrier has physical motivation or meaning. In this Letter we show that once the statistical assumptions which underlie the excursion set approach are considered a drifting diffusing barrier model does provide a good self-consistent description both of halo abundance as well as of the initial overdensities of the protohalo patches. PMID- 24476253 TI - Exceptional form of D=11 supergravity. AB - Eleven-dimensional supergravity reveals large exceptional symmetries upon reduction, in accordance with the U-duality groups of M theory, but their higher dimensional geometric origin has remained a mystery. In this Letter, we show that D=11 supergravity can be extended to be fully covariant under the exceptional groups E(n(n)), n=6, 7, 8. Motivated by a similar formulation of double field theory we introduce an extended "exceptional spacetime." We illustrate the construction by giving the explicit E(6(6)) covariant form: the full D=11 supergravity, in a 5+6 splitting of coordinates but without truncation, embeds into an E(6(6)) covariant 5+27 dimensional theory. We argue that this covariant form likewise comprises type IIB supergravity. PMID- 24476254 TI - Inhomogeneous thermalization in strongly coupled field theories. AB - To describe theoretically the creation and evolution of the quark-gluon plasma, one typically employs three ingredients: a model for the initial state, nonhydrodynamic early time evolution, and hydrodynamics. In this Letter we study the nonhydrodynamic early time evolution using the AdS/CFT correspondence in the presence of inhomogeneities. We find that the AdS description of the early time evolution is well matched by free streaming. Near the end of the early time interval where our analytic computations are reliable, the stress tensor agrees with the second order hydrodynamic stress tensor computed from the local energy density and fluid velocity. Our techniques may also be useful for the study of far-from-equilibrium strongly coupled systems in other areas of physics. PMID- 24476255 TI - Possible resonance effect of axionic dark matter in Josephson junctions. AB - We provide theoretical arguments that dark-matter axions from the galactic halo that pass through Earth may generate a small observable signal in resonant S/N/S Josephson junctions. The corresponding interaction process is based on the uniqueness of the gauge-invariant axion Josephson phase angle modulo 2pi and is predicted to produce a small Shapiro steplike feature without externally applied microwave radiation when the Josephson frequency resonates with the axion mass. A resonance signal of so far unknown origin observed by C. Hoffmann et al. [Phys. Rev. B 70, 180503(R) (2004)] is consistent with our theory and can be interpreted in terms of an axion mass m(a)c2=0.11 meV and a local galactic axionic dark matter density of 0.05 GeV/cm3. We discuss future experimental checks to confirm the dark-matter nature of the observed signal. PMID- 24476257 TI - Narrow structure in the excitation function of eta photoproduction off the neutron. AB - The photoproduction of eta mesons off nucleons bound in 2H and 3He has been measured in coincidence with recoil protons and recoil neutrons for incident photon energies from threshold up to 1.4 GeV. The experiments were performed at the Mainz MAMI accelerator, using the Glasgow tagged photon facility. Decay photons from the eta->2gamma and eta->3pi0 decays and the recoil nucleons were detected with an almost 4pi electromagnetic calorimeter combining the Crystal Ball and TAPS detectors. The data from both targets are of excellent statistical quality and show a narrow structure in the excitation function of gamman->neta. The results from the two measurements are consistent, taking into account the expected effects from nuclear Fermi motion. The best estimates for position and intrinsic width of the structure are W=(1670+/-5) MeV and Gamma=(30+/-15) MeV. For the first time precise results for the angular dependence of this structure have been extracted. PMID- 24476259 TI - Pressure isotropization in high energy heavy ion collisions. AB - The early stages of high energy heavy ion collisions are studied in the color glass condensate framework, with a real-time classical lattice simulation. When increasing the coupling constant, we observe a rapid increase of the ratio of longitudinal to transverse pressure. The transient regime that precedes this behavior is of the order of 1 fm/c. PMID- 24476256 TI - Observation of D0-D-0 mixing using the CDF II detector. AB - We measure the time dependence of the ratio of decay rates for D0->K(+)pi(-) to the Cabibbo-favored decay D(0)->K(-)pi(+). The charge conjugate decays are included. A signal of 3.3*10(4) D(*+)->pi(+)D(0), D(0)->K(+)pi(-) decays is obtained with D0 proper decay times between 0.75 and 10 mean D0 lifetimes. The data were recorded with the CDF II detector at the Fermilab Tevatron and correspond to an integrated luminosity of 9.6 fb(-1) for pp- collisions at ?s=1.96 TeV. Assuming CP conservation, we search for D0-D-0 mixing and measure the mixing parameters to be R(D)=(3.51+/-0.35)*10(-3), y'=(4.3+/-4.3)*10(-3), and x'2=(0.08+/-0.18)*10(-3). We report Bayesian probability intervals in the x'2-y' plane and find that the significance of excluding the no-mixing hypothesis is equivalent to 6.1 Gaussian standard deviations, providing the second observation of D0-D-0 mixing from a single experiment. PMID- 24476262 TI - Constraints on the Skyrme equations of state from properties of doubly magic nuclei. AB - I use properties of doubly magic nuclei to constrain symmetric nuclear matter and neutron matter equations of state. I conclude that these data determine the value of the neutron equation of state at a density of rho(on)=0.10 nucleons/fm3 to be 11.4(10) MeV. The slope at that point is constrained by the value of the neutron skin. Analytical equations are given that show the dependence of the Skyrme equations of state on the neutron skin. PMID- 24476261 TI - Bogomol'nyi-Prasad-Sommerfield Skyrme model and nuclear binding energies. AB - We use the classical Bogomol'nyi-Prasad-Sommerfield (BPS) soliton solutions of the BPS Skyrme model together with corrections from the collective coordinate quantization of spin and isospin, the electrostatic Coulomb energies, and a small explicit breaking of the isospin symmetry-accounting for the proton-neutron mass difference-to calculate nuclear binding energies. We find that the resulting binding energies are already in excellent agreement with their physical values for heavier nuclei, demonstrating thereby that the BPS Skyrme model is a distinguished starting point for a detailed quantitative investigation of nuclear and low-energy strong interaction physics. PMID- 24476264 TI - Low-energy enhancement of magnetic dipole radiation. AB - Magnetic dipole strength functions are deduced from averages of a large number of M1 transition strengths calculated within the shell model for the nuclides 90Zr, 94Mo, 95Mo, and 96Mo. An enhancement of M1 strength toward low transition energy is found for all nuclides considered. Large M1 strengths appear for transitions between close-lying states with configurations including proton as well as neutron high-j orbits that recouple their spins and add up their magnetic moments coherently. The M1 strength function deduced from the calculated M1 transition strengths is compatible with the low-energy enhancement found in (3He, 3He') and (d, p) experiments. The Letter presents an explanation of the experimental findings. PMID- 24476263 TI - Classical-NOVA CONTRIBUTION to the Milky Way's 26Al abundance: exit channel of the key 25Al(p,gamma) 26Si resonance. AB - Classical novae are expected to contribute to the 1809-keV Galactic gamma-ray emission by producing its precursor 26Al, but the yield depends on the thermonuclear rate of the unmeasured 25Al(p,gamma)26Si reaction. Using the beta decay of 26P to populate the key J(pi)=3(+) resonance in this reaction, we report the first evidence for the observation of its exit channel via a 1741.6+/ 0.6(stat)+/-0.3(syst) keV primary gamma ray, where the uncertainties are statistical and systematic, respectively. By combining the measured gamma-ray energy and intensity with other experimental data on 26Si, we find the center-of mass energy and strength of the resonance to be E(r)=414.9+/-0.6(stat)+/ 0.3(syst)+/-0.6(lit.) keV and omegagamma=23+/-6(stat)(-10)(+11)(lit.) meV, respectively, where the last uncertainties are from adopted literature data. We use hydrodynamic nova simulations to model 26Al production showing that these measurements effectively eliminate the dominant experimental nuclear-physics uncertainty and we estimate that novae may contribute up to 30% of the Galactic 26Al. PMID- 24476265 TI - Broadening the cloaking bandwidth with non-Foster metasurfaces. AB - We introduce the concept and practical design of broadband, ultrathin cloaks based on non-Foster, negatively capacitive metasurfaces. By using properly tailored, active frequency-selective screens conformal to an object, within the realm of a practical realization, we show that it is possible to drastically reduce the scattering over a wide frequency range in the microwave regime, orders of magnitude broader than any available passive cloaking technology. The proposed active cloak may impact not only invisibility and camouflaging, but also practical antenna and sensing applications. PMID- 24476266 TI - Coherent control of population transfer between vibrational states in an optical lattice via two-path quantum interference. AB - We demonstrate coherent control of population transfer between vibrational states in an optical lattice by using interference between a one-phonon transition at 2omega and a two-phonon transition at omega. The omega and 2omega transitions are driven by phase- and amplitude-modulation of the lattice laser beams, respectively. By varying the relative phase of these two pathways, we control the branching ratio between transitions to the first excited state and those to the higher states. Our best result shows a branching ratio of 17+/-2, which is the highest among coherent control experiments using analogous schemes. Such quantum control techniques may find broad application in suppressing leakage errors in a variety of quantum information architectures. PMID- 24476267 TI - Three-body bound states in dipole-dipole interacting Rydberg atoms. AB - We show that the dipole-dipole interaction between three identical Rydberg atoms can give rise to bound trimer states. The microscopic origin of these states is fundamentally different from Efimov physics. Two stable trimer configurations exist where the atoms form the vertices of an equilateral triangle in a plane perpendicular to a static electric field. The triangle edge length typically exceeds R~2 MUm, and each configuration is twofold degenerate due to Kramers degeneracy. The depth of the potential wells and the triangle edge length can be controlled by external parameters. We establish the Borromean nature of the trimer states, analyze the quantum dynamics in the potential wells, and describe methods for their production and detection. PMID- 24476268 TI - Vibrationally resolved decay width of interatomic Coulombic decay in HeNe. AB - We investigate the ionization of HeNe from below the He 1s3p excitation to the He ionization threshold. We observe HeNe+ ions with an enhancement by more than a factor of 60 when the He side couples resonantly to the radiation field. These ions are an experimental proof of a two-center resonant photoionization mechanism predicted by Najjari et al. [Phys. Rev. Lett. 105, 153002 (2010)]. Furthermore, our data provide electronic and vibrational state resolved decay widths of interatomic Coulombic decay in HeNe dimers. We find that the interatomic Coulombic decay lifetime strongly increases with increasing vibrational state. PMID- 24476269 TI - Strong-field many-body physics and the giant enhancement in the high-harmonic spectrum of xenon. AB - We resolve an open question about the origin of the giant enhancement in the high harmonic generation spectrum of atomic xenon around 100 eV. By solving the many body time-dependent Schrodinger equation with all 4d, 5s, and 5p orbitals active, we truly demonstrate the enhancement results from the collective many-body excitation induced by the returning photoelectron via two-body interchannel interactions. Without the many-body interactions, which promote a 4d electron into the 5p vacancy created by strong-field ionization, no collective excitation and no enhancement in the high-harmonic generation spectrum exist. PMID- 24476270 TI - Drift-induced excitable localized states. AB - Excitable localized states, spatial structures which possess both the features of temporal excitable pulses and of transverse cavity solitons, have been theoretically predicted in model systems as single pulses of light localized in space with a finite and deterministic duration. We study experimentally the nucleation of laser localized structures on a device defect and its motion along a spatial gradient. We demonstrate that in the reference frame of the drifting localized structure, the resulting dynamics presents the typical features of excitable systems. In particular, for specific parameter values, we observe that the nucleation of laser localized structures is triggered by noise, while the drift of the localized structure up to a spatial region where it vanishes provides the deterministic orbit which brings the system back to its initial rest state. The control of such structures may open the way to novel applications of localized structures beyond that of simple stationary bits. PMID- 24476271 TI - Stimulated electronic x-ray Raman scattering. AB - We demonstrate strong stimulated inelastic x-ray scattering by resonantly exciting a dense gas target of neon with femtosecond, high-intensity x-ray pulses from an x-ray free-electron laser (XFEL). A small number of lower energy XFEL seed photons drive an avalanche of stimulated resonant inelastic x-ray scattering processes that amplify the Raman scattering signal by several orders of magnitude until it reaches saturation. Despite the large overall spectral width, the internal spiky structure of the XFEL spectrum determines the energy resolution of the scattering process in a statistical sense. This is demonstrated by observing a stochastic line shift of the inelastically scattered x-ray radiation. In conjunction with statistical methods, XFELs can be used for stimulated resonant inelastic x-ray scattering, with spectral resolution smaller than the natural width of the core-excited, intermediate state. PMID- 24476272 TI - Random lasing over gap states from a quasi-one-dimensional amplifying periodic-on average random superlattice. AB - We report the experimental implementation and theoretical analysis of a random laser system that constitutes an amplifying periodic-on-average random superlattice (PARS). The stringent conditions on monodispersity required for a periodic-on-average random superlattice system are fulfilled using a linear array of spherical microresonators whose separation and size distribution can be controlled. Statistical studies of the lasing frequency reveal a frequency controlled behavior. We perform transfer matrix calculations with gain to analyze the origin of the lasing modes, their thresholds, and frequency statistics. The results confirm that the experimentally observed lasing modes arise from states introduced into the stop gap of the underlying periodic system. On virtue of the fact that these high-quality gap states are restricted to a band of frequencies, the consequent random lasing exhibits significant reduction in frequency fluctuations. PMID- 24476273 TI - Tailoring the phase and power flow of electromagnetic fields. AB - A method for arbitrarily controlling the phase progression and power flow of electromagnetic fields within a region of space is introduced. Specifically, we describe how a 2D inhomogeneous, anisotropic medium can be designed that supports desired spatial distributions of the wave vector and Poynting vector direction. Plane-wave relations in anisotropic media are used in conjunction with an impedance matching process to find the required material parameters. The developed formulation allows one to independently tailor the phase and amplitude of a field profile. The work will find application in the design of electromagnetic or optical guiding structures and radiating apertures. PMID- 24476274 TI - Quantum synchronization of quantum van der Pol oscillators with trapped ions. AB - The van der Pol oscillator is the prototypical self-sustained oscillator and has been used to model nonlinear behavior in biological and other classical processes. We investigate how quantum fluctuations affect phase locking of one or many van der Pol oscillators. We find that phase locking is much more robust in the quantum model than in the equivalent classical model. Trapped-ion experiments are ideally suited to simulate van der Pol oscillators in the quantum regime via sideband heating and cooling of motional modes. We provide realistic experimental parameters for 171Yb+ achievable with current technology. PMID- 24476275 TI - Energy balance for a sonoluminescence bubble yields a measure of ionization potential lowering. AB - Application of energy conservation between input sound and the microplasma which forms at the moment of sonoluminescence places bounds on the process, whereby the gas is ionized. Detailed pulsed Mie scattering measurements of the radius versus time for a xenon bubble in sulfuric acid provide a complete characterization of the hydrodynamics and minimum radius. For a range of emission intensities, the blackbody spectrum emitted during collapse matches the minimum bubble radius, implying opaque conditions are attained. This requires a degree of ionization >36%. Analysis reveals only 2.1+/-0.6 eV/atom of energy available during light emission. In order to unbind enough charge, collective processes must therefore reduce the ionization potential by at least 75%. We interpret this as evidence that a phase transition to a highly ionized plasma is occurring during sonoluminescence. PMID- 24476276 TI - Geophysical turbulence and the duality of the energy flow across scales. AB - The ocean and the atmosphere, and hence the climate, are governed at large scale by interactions between pressure gradient and Coriolis and buoyancy forces. This leads to a quasigeostrophic balance in which, in a two-dimensional-like fashion, the energy injected by solar radiation, winds, or tides goes to large scales in what is known as an inverse cascade. Yet, except for Ekman friction, energy dissipation and turbulent mixing occur at a small scale implying the formation of such scales associated with breaking of geostrophic dynamics through wave-eddy interactions or frontogenesis, in opposition to the inverse cascade. Can it be both at the same time? We exemplify here this dual behavior of energy with the help of three-dimensional direct numerical simulations of rotating stratified Boussinesq turbulence. We show that efficient small-scale mixing and large-scale coherence develop simultaneously in such geophysical and astrophysical flows, both with constant flux as required by theoretical arguments, thereby clearly resolving the aforementioned contradiction. PMID- 24476277 TI - Evidence for forcing-dependent steady states in a turbulent swirling flow. AB - We study the influence on steady turbulent states of the forcing in a von Karman flow, at constant impeller speed, or at constant torque. We find that the different forcing conditions change the nature of the stability of the steady states and reveal dynamical regimes that bear similarities to low-dimensional systems. We suggest that this forcing dependence may be applicable to other turbulent systems. PMID- 24476278 TI - Capillary flow of oil in a single foam microchannel. AB - When using appropriate surfactants, oil and aqueous foam can be intimately mixed without the foam being destroyed. In this Letter, we show that a foam, initially free of oil, can draw an oil drop under the action of capillary forces and stretch it through the aqueous network. We focus on the suction of oil by a single horizontal foam channel, known as a Plateau border. In such confined channels, imbibition dynamics are governed by a balance between capillarity and viscosity. Yet, the scaling law for our system differs from that of classical imbibition in porous media such as aqueous foam. This is due to the particular geometry of the liquid channels: Plateau borders filled with foaming solution are always concave whereas they can be convex or flat when filled with oil. Finally, the oil slug, confined in the Plateau border, fragments into droplets following a film breakup. PMID- 24476280 TI - Megavolt parallel potentials arising from double-layer streams in the Earth's outer radiation belt. AB - Huge numbers of double layers carrying electric fields parallel to the local magnetic field line have been observed on the Van Allen probes in connection with in situ relativistic electron acceleration in the Earth's outer radiation belt. For one case with adequate high time resolution data, 7000 double layers were observed in an interval of 1 min to produce a 230,000 V net parallel potential drop crossing the spacecraft. Lower resolution data show that this event lasted for 6 min and that more than 1,000,000 volts of net parallel potential crossed the spacecraft during this time. A double layer traverses the length of a magnetic field line in about 15 s and the orbital motion of the spacecraft perpendicular to the magnetic field was about 700 km during this 6 min interval. Thus, the instantaneous parallel potential along a single magnetic field line was the order of tens of kilovolts. Electrons on the field line might experience many such potential steps in their lifetimes to accelerate them to energies where they serve as the seed population for relativistic acceleration by coherent, large amplitude whistler mode waves. Because the double-layer speed of 3100 km/s is the order of the electron acoustic speed (and not the ion acoustic speed) of a 25 eV plasma, the double layers may result from a new electron acoustic mode. Acceleration mechanisms involving double layers may also be important in planetary radiation belts such as Jupiter, Saturn, Uranus, and Neptune, in the solar corona during flares, and in astrophysical objects. PMID- 24476279 TI - Early-time symmetry tuning in the presence of cross-beam energy transfer in ICF experiments on the National Ignition Facility. AB - On the National Ignition Facility, the hohlraum-driven implosion symmetry is tuned using cross-beam energy transfer (CBET) during peak power, which is controlled by applying a wavelength separation between cones of laser beams. In this Letter, we present early-time measurements of the instantaneous soft x-ray drive at the capsule using reemission spheres, which show that this wavelength separation also leads to significant CBET during the first shock, even though the laser intensities are 30* smaller than during the peak. We demonstrate that the resulting early drive P2/P0 asymmetry can be minimized and tuned to <1% accuracy (well within the +/-7.5% requirement for ignition) by varying the relative input powers between different cones of beams. These experiments also provide time resolved measurements of CBET during the first 2 ns of the laser drive, which are in good agreement with radiation-hydrodynamics calculations including a linear CBET model. PMID- 24476281 TI - Structure and dynamics of colliding plasma jets. AB - Monoenergetic-proton radiographs of laser-generated, high-Mach-number plasma jets colliding at various angles shed light on the structures and dynamics of these collisions. The observations compare favorably with results from 2D hydrodynamic simulations of multistream plasma jets, and also with results from an analytic treatment of electron flow and magnetic field advection. In collisions of two noncollinear jets, the observed flow structure is similar to the analytic model's prediction of a characteristic feature with a narrow structure pointing in one direction and a much thicker one pointing in the opposite direction. Spontaneous magnetic fields, largely azimuthal around the colliding jets and generated by the well-known ?T(e)*?n(e) Biermann battery effect near the periphery of the laser spots, are demonstrated to be "frozen in" the plasma (due to high magnetic Reynolds number Re(M)~5*10(4)) and advected along the jet streamlines of the electron flow. These studies provide novel insight into the interactions and dynamics of colliding plasma jets. PMID- 24476282 TI - Angular dependence of betatron x-ray spectra from a laser-wakefield accelerator. AB - We present the first measurements of the angular dependence of the betatron x-ray spectrum produced by electrons inside the cavity of a laser-wakefield accelerator. Electrons accelerated up to 300 MeV energies produce a beam of broadband, forward-directed betatron x-ray radiation extending up to 80 keV. The angular resolved spectrum from an image plate-based spectrometer with differential filtering provides data in a single laser shot. The simultaneous spectral and spatial x-ray analysis allows for a three-dimensional reconstruction of electron trajectories with micrometer resolution, and we find that the angular dependence of the x-ray spectrum is showing strong evidence of anisotropic electron trajectories. PMID- 24476283 TI - Observations of modified three-dimensional instability structure for imploding z pinch liners that are premagnetized with an axial field. AB - Novel experimental data are reported that reveal helical instability formation on imploding z-pinch liners that are premagnetized with an axial field. Such instabilities differ dramatically from the mostly azimuthally symmetric instabilities that form on unmagnetized liners. The helical structure persists at nearly constant pitch as the liner implodes. This is surprising since, at the liner surface, the azimuthal drive field presumably dwarfs the axial field for all but the earliest stages of the experiment. These fundamentally 3D results provide a unique and challenging test for 3D-magnetohydrodynamics simulations. PMID- 24476285 TI - Observations of ionospheric ELF and VLF wave generation by excitation of the thermal cubic nonlinearity. AB - Extremely-low-frequency (ELF, 3-3000 Hz) and very-low-frequency (VLF, 3-30 kHz) waves generated by the excitation of the thermal cubic nonlinearity are observed for the first time at the High-Frequency Active Auroral Research Program high frequency transmitter in Gakona, Alaska. The observed ELF and VLF field amplitudes are the strongest generated by any high frequency (HF, 3-30 MHz) heating facility using this mechanism to date. This manner of ELF and VLF generation is independent of naturally forming currents, such as the auroral electrojet current system. Time-of-arrival analysis applied to experimental observations shows that the thermal cubic ELF and VLF source region is located within the collisional D-region ionosphere. Observations are compared with the predictions of a theoretical HF heating model using perturbation theory. For the experiments performed, two X-mode HF waves were transmitted at frequencies omega1 and omega2, with |omega2-2omega1| being in the ELF and VLF frequency range. In contrast with previous work, we determine that the ELF and VLF source is dominantly produced by the interaction between collision frequency oscillations at frequency omega2-omega1 and the polarization current density associated with the lower frequency HF wave at frequency omega1. This specific interaction has been neglected in past cubic thermal nonlinearity work, and it plays a major role in the generation of ELF and VLF waves. PMID- 24476284 TI - Experimental approach to interaction physics challenges of the shock ignition scheme using short pulse lasers. AB - An experimental program was designed to study the most important issues of laser plasma interaction physics in the context of the shock ignition scheme. In the new experiments presented in this Letter, a combination of kilojoule and short laser pulses was used to study the laser-plasma coupling at high laser intensities for a large range of electron densities and plasma profiles. We find that the backscatter is dominated by stimulated Brillouin scattering with stimulated Raman scattering staying at a limited level. This is in agreement with past experiments using long pulses but laser intensities limited to 2*10(15) W/cm2, or short pulses with intensities up to 5*10(16) W/cm2 as well as with 2D particle-in-cell simulations. PMID- 24476286 TI - Photonic-band-gap traveling-wave gyrotron amplifier. AB - We report the experimental demonstration of a gyrotron traveling-wave-tube amplifier at 250 GHz that uses a photonic band gap (PBG) interaction circuit. The gyrotron amplifier achieved a peak small signal gain of 38 dB and 45 W output power at 247.7 GHz with an instantaneous -3 dB bandwidth of 0.4 GHz. The amplifier can be tuned for operation from 245-256 GHz. The widest instantaneous 3 dB bandwidth of 4.5 GHz centered at 253.25 GHz was observed with a gain of 24 dB. The PBG circuit provides stability from oscillations by supporting the propagation of transverse electric (TE) modes in a narrow range of frequencies, allowing for the confinement of the operating TE03-like mode while rejecting the excitation of oscillations at nearby frequencies. This experiment achieved the highest frequency of operation for a gyrotron amplifier; at present, there are no other amplifiers in this frequency range that are capable of producing either high gain or high output power. This result represents the highest gain observed above 94 GHz and the highest output power achieved above 140 GHz by any conventional-voltage vacuum electron device based amplifier. PMID- 24476287 TI - Characteristics of two-dimensional quantum turbulence in a compressible superfluid. AB - Fluids subjected to suitable forcing will exhibit turbulence, with characteristics strongly affected by the fluid's physical properties and dimensionality. In this work, we explore two-dimensional (2D) quantum turbulence in an oblate Bose-Einstein condensate confined to an annular trapping potential. Experimentally, we find conditions for which small-scale stirring of the condensate generates disordered 2D vortex distributions that dissipatively evolve toward persistent currents, indicating energy transport from small to large length scales. Simulations of the experiment reveal spontaneous clustering of same-circulation vortices and an incompressible energy spectrum with k(-5/3) dependence for low wave numbers k. This work links experimentally observed vortex dynamics with signatures of 2D turbulence in a compressible superfluid. PMID- 24476288 TI - Inhomogeneous topological superfluidity in one-dimensional spin-orbit-coupled Fermi gases. AB - We theoretically predict an exotic topological superfluid state with a spatially modulated pairing gap in one-dimensional spin-orbit-coupled Fermi gases. This inhomogeneous topological superfluidity is induced by applying simultaneously a perpendicular Zeeman magnetic field and an equally weighted Rashba and Dresselhaus spin-orbit coupling in one-dimensional optical lattices. Based on the self-consistent Bogoliubov-de Gennes theory, we confirm that this novel topological phase is a unique condensation of Cooper pairs, which manifests the interplay between the inhomogeneity of a superfluid and its nontrivial topological structure. The properties of the emergent Majorana bound states are investigated in detail by examining the associated Z2 topological number, the eigenenergy and density of states spectra, as well as the wave functions of the localized Majorana end modes. The experimental feasibility of observing this new topological state of matter is also discussed. PMID- 24476289 TI - Ground state phase diagram of parahydrogen in one dimension. AB - The low-temperature phase diagram of parahydrogen in one dimension is studied by quantum Monte Carlo simulations, whose results are interpreted within the framework of Luttinger liquid theory. We show that, contrary to what was claimed in a previous study [Phys. Rev. Lett. 85, 2348 (2000)], the equilibrium phase is a crystal. The phase diagram mimics that of parahydrogen in two dimensions, with a single quasicrystaline phase and no quantum phase transition; i.e., it is qualitatively different from that of 4He in one dimension. PMID- 24476290 TI - Surface-induced order parameter distortion in superfluid 3He-B measured by nonlinear NMR. AB - The B phase of superfluid 3He is a three-dimensional time-reversal invariant topological superfluid, predicted to support gapless Majorana surface states. We confine superfluid 3He into a thin nanofluidic slab geometry. In the presence of a weak symmetry-breaking magnetic field, we have observed two possible states of the confined 3He-B phase manifold, through the small tipping angle NMR response. Large tipping angle nonlinear NMR has allowed the identification of the order parameter of these states and enabled a measurement of the surface-induced gap distortion. The results for two different quasiparticle surface scattering boundary conditions are compared with the predictions of weak-coupling quasiclassical theory. We identify a textural domain wall between the two B phase states, the edge of which at the cavity surface is predicted to host gapless states, protected in the magnetic field. PMID- 24476291 TI - High energy density mixed polymeric phase from carbon monoxide and nitrogen. AB - Carbon monoxide and nitrogen are among the potentially interesting high-energy density materials. However, in spite of the physical similarities of the molecules, they behave very differently at high pressures. Using density functional theory and structural prediction methods, we examine the ability of these systems to combine their respective properties and form novel mixed crystalline phases under pressures of up to 100 GPa. Interestingly, we find that CO catalyzes the molecular dissociation of N2, which means mixed structures are favored at a relatively low pressure (below 18 GPa), and that a three-dimensional framework with Pbam symmetry becomes the most stable phase above 52 GPa, i.e., at much milder conditions than in pure solid nitrogen. This structure is dynamically stable at ambient pressure and has an energy density of approximately 2.2 kJ g( 1), making it a candidate for a high-energy density material, and one that could be achieved at less prohibitive experimental conditions. PMID- 24476292 TI - Scaling laws of structural lubricity. AB - "Structural lubricity" refers to a unique friction state in which two flat surfaces are sliding past each other with ultralow resistance due to incommensurate atomic lattice structures. In this case, theory anticipates sublinear scaling for the area dependence of friction. Here, we experimentally confirm these predictions by measuring the sliding resistance of amorphous antimony and crystalline gold nanoparticles on crystalline graphite. For the amorphous particles a square root relation between friction and contact area is observed. For crystalline gold particles we find a more complex scaling behavior related to variations in particle shape and orientation. These results allow us to link mesoscopic friction to atomic principles. PMID- 24476293 TI - Predicting how nanoconfinement changes the relaxation time of a supercooled liquid. AB - The properties of nanoconfined fluids can be strikingly different from those of bulk liquids. A basic unanswered question is whether the equilibrium and dynamic consequences of confinement are related to each other in a simple way. We study this question by simulation of a liquid comprising asymmetric dumbbell-shaped molecules, which can be deeply supercooled without crystallizing. We find that the dimensionless structural relaxation times-spanning six decades as a function of temperature, density, and degree of confinement-collapse when plotted versus excess entropy. The data also collapse when plotted versus excess isochoric heat capacity, a behavior consistent with the existence of isomorphs in the bulk and confined states. PMID- 24476294 TI - Magnetic moment and anisotropy of individual Co atoms on graphene. AB - We report on the magnetic properties of single Co atoms on graphene on Pt(111). By means of scanning tunneling microscopy spin-excitation spectroscopy, we infer a magnetic anisotropy of K=-8.1 meV with out-of-plane hard axis and a magnetic moment of 2.2MU(B). Co adsorbs on the sixfold graphene hollow site. Upon hydrogen adsorption, three differently hydrogenated species are identified. Their magnetic properties are very different from those of clean Co. Ab initio calculations support our results and reveal that the large magnetic anisotropy stems from strong ligand field effects due to the interaction between Co and graphene orbitals. PMID- 24476295 TI - Schottky-to-Ohmic crossover in carbon nanotube transistor contacts. AB - For carbon nanotube transistors, as for graphene, the electrical contacts are a key factor limiting device performance. We calculate the device characteristics as a function of nanotube diameter and metal work function. Although the on-state current varies continuously, the transfer characteristics reveal a relatively abrupt crossover from Schottky to Ohmic contacts. We find that typical high performance devices fall surprisingly close to the crossover. Therefore, tunneling plays an important role even in this regime, so that current fails to saturate with gate voltage as was expected due to "source exhaustion." PMID- 24476296 TI - Simultaneous magnetic and charge doping of topological insulators with carbon. AB - A two-step doping process, magnetic followed by charge or vice versa, is required to produce massive topological surface states (TSS) in topological insulators for many physics and device applications. Here, we demonstrate simultaneous magnetic and hole doping achieved with a single dopant, carbon, in Bi2Se3 by first principles calculations. Carbon substitution for Se (C(Se)) results in an opening of a sizable surface Dirac gap (up to 82 meV), while the Fermi level remains inside the bulk gap and close to the Dirac point at moderate doping concentrations. The strong localization of 2p states of C(Se) favors spontaneous spin polarization via a p-p interaction and formation of ordered magnetic moments mediated by surface states. Meanwhile, holes are introduced into the system by C(Se). This dual function of carbon doping suggests a simple way to realize insulating massive TSS. PMID- 24476297 TI - Stability of branched flow from a quantum point contact. AB - In classically chaotic systems, small differences in initial conditions are exponentially magnified over time. However, it was observed experimentally that the (necessarily quantum) "branched flow" pattern of electron flux from a quantum point contact (QPC) traveling over a random background potential in two dimensional electron gases remains substantially invariant to large changes in initial conditions. Since such a potential is classically chaotic and unstable to changes in initial conditions, it was conjectured that the origin of the observed stability is purely quantum mechanical, with no classical analog. In this Letter, we show that the observed stability is a result of the physics of the quantum point contact and the nature of the experiment. We show that the same stability can indeed be reproduced classically, or quantum mechanically. In addition, we explore the stability of the branched flow with regards to changes in the eigenmodes of the quantum point contact. PMID- 24476298 TI - Projected entangled-pair states can describe chiral topological states. AB - We show that projected entangled-pair states (PEPS) in two spatial dimensions can describe chiral topological states by explicitly constructing a family of such states with a nontrivial Chern number. They are ground states of two different kinds of free-fermion Hamiltonians: (i) local and gapless; (ii) gapped, but with hopping amplitudes that decay according to a power law. We derive general conditions on topological free-fermionic projected entangled-pair states that show that they cannot correspond to exact ground states of gapped, local parent Hamiltonians and provide numerical evidence demonstrating that they can nevertheless approximate well the physical properties of topological insulators with local Hamiltonians at arbitrary temperatures. PMID- 24476299 TI - Dielectric versus magnetic pairing mechanisms in high-temperature cuprate superconductors investigated using Raman scattering. AB - We suggest, and demonstrate, a systematic approach to the study of cuprate superconductors, namely, progressive change of ion size in order to systematically alter the interaction strength and other key parameters. R(Ba,Sr)2Cu3Oy (R={La,...,Lu,Y}) is such a system where potentially obscuring structural changes are minimal. We thereby systematically alter both dielectric and magnetic properties. Dielectric fluctuation is characterized by ionic polarizability while magnetic fluctuation is characterized by exchange interactions measurable by Raman scattering. The range of transition temperatures is 70-107 K, and we find that these correlate only with the dielectric properties, a behavior which persists with external pressure. The ultimate significance may remain to be proven, but it highlights the role of dielectric screening in the cuprates and adds support to a previously proposed novel pairing mechanism involving exchange of quantized waves of electronic polarization. PMID- 24476300 TI - Intrinsic electron beam emittance from metal photocathodes: the effect of the electron effective mass. AB - A theoretical development of prior analyses, together with our solenoid scan measurements on eight planar metal photocathodes (Ag, Be, Cr, Cu, Mo, Sn, Ta, and W) and previous data on Mg [X. J. Wang, M. Babzien, R. Malone, and Z. Wu, in Proceedings of LINAC2002, Gyeongju, Korea, 2002 (Pohang Accelerator Laboratory, Pohang, Korea, 2002), pp. 142-144.] indicate that the transverse momentum (and hence intrinsic emittance) of an electron beam is fundamentally dependent on the electron effective mass in the metal. PMID- 24476301 TI - Absolute and relative stability of an optical frequency reference based on spectral hole burning in Eu3+:Y2SiO5. AB - We present and analyze four frequency measurements designed to characterize the performance of an optical frequency reference based on spectral hole burning in Eu3+:Y2SiO5. The first frequency comparison, between a single unperturbed spectral hole and a hydrogen maser, demonstrates a fractional frequency drift rate of 5*10(-18) s(-1). Optical frequency comparisons between a pattern of spectral holes, a Fabry-Perot cavity, and an Al(+) optical atomic clock show a short-term fractional frequency stability of 1*10(-15)tau(-1/2) that averages down to 2.5(-0.5)(+1.1)*10(-16) at tau=540 s (with linear frequency drift removed). Finally, spectral-hole patterns in two different Eu(3+):Y2SiO(5) crystals located in the same cryogenic vessel are compared, yielding a short-term stability of 7*10(-16)tau(-1/2) that averages down to 5.5(-0.9)(+1.8)*10(-17) at tau=204 s (with quadratic frequency drift removed). PMID- 24476302 TI - Indistinguishable tunable single photons emitted by spin-flip Raman transitions in InGaAs quantum dots. AB - This Letter reports all-optically tunable and highly indistinguishable single Raman photons from a driven single quantum dot spin. The frequency, linewidth, and lifetime of the Raman photons are tunable by varying the driving field power and detuning. Under continuous-wave excitation, subnatural linewidth single photons from off-resonant Raman scattering show an indistinguishability of 0.98(3). Under pi pulse excitation, spin- and time-tagged Raman fluorescence photons show an almost vanishing multiphoton emission probability of 0.01(2) and a two-photon quantum interference visibility of 0.95(3). Lastly, Hong-Ou-Mandel interference is demonstrated between two single photons emitted from remote, independent quantum dots with an unprecedented visibility of 0.87(4). PMID- 24476303 TI - Exciting graphene surface plasmon polaritons through light and sound interplay. AB - We propose a concept that allows for efficient excitation of surface plasmon spolaritons (SPPs) on a thin graphene sheet located on a substrate by an incident electromagnetic field. Elastic vibrations of the sheet, which are generated by a flexural wave, act as a grating that enables the electromagnetic field to couple to propagating graphene SPPs. This scheme permits fast on-off switching of the SPPs and dynamic tuning of their excitation frequency by adjusting the vibration frequency (grating period). Potential applications include single molecule detection and enhanced control of SPP trajectories via surface wave patterning of graphene metasurfaces. Analytical calculations and numerical experiments demonstrate the practical applicability of the proposed concept. PMID- 24476304 TI - Coupling light into graphene plasmons through surface acoustic waves. AB - We propose a scheme for coupling laser light into graphene plasmons with the help of electrically generated surface acoustic waves. The surface acoustic wave forms a diffraction grating which allows us to excite the long lived phononlike branch of the hybridized graphene plasmon-phonon dispersion with infrared laser light. Our approach avoids patterning the graphene sheet, does not rely on complicated optical near-field techniques, and allows us to electrically switch the coupling between far-field radiation and propagating graphene plasmons. PMID- 24476305 TI - Physicochemical basis for water-actuated movement and stress generation in nonliving plant tissues. AB - Generating stresses and strains through water uptake from atmospheric humidity is a common process in nature, e.g., in seed dispersal. Actuation depends on a balance between chemical interactions and the elastic energy required to accomplish the volume change. In order to study the poorly understood chemical interactions, we combine mechanosorption experiments with theoretical calculations of the swelling behavior to estimate the mechanical energy and extract the contribution of the chemical energy per absorbed water molecule. The latter is highest in the completely dry state and stays almost constant at about 1.2 kT for higher hydrations. This suggests that water bound to the macromolecular components of the wood tissues acquires one additional hydrogen bond per eight water molecules, thus providing energy for actuation. PMID- 24476306 TI - Cooperation dilemma in finite populations under fluctuating environments. AB - We present a novel approach allowing the study of rare events like fixation under fluctuating environments, modeled as extrinsic noise, in evolutionary processes characterized by the dominance of one species. Our treatment consists of mapping the system onto an auxiliary model, exhibiting metastable species coexistence, that can be analyzed semiclassically. This approach enables us to study the interplay between extrinsic and demographic noise on the statistics of interest. We illustrate our theory by considering the paradigmatic prisoner's dilemma game, whose evolution is described by the probability that cooperators fixate the population and replace all defectors. We analytically and numerically demonstrate that extrinsic noise may drastically enhance the cooperation fixation probability and even change its functional dependence on the population size. These results, which generalize earlier works in population genetics, indicate that extrinsic noise may help sustain and promote a much higher level of cooperation than static settings. PMID- 24476307 TI - Phase-synchronized state of oriented active fluids. AB - We present a theory for self-driven fluids, such as motorized cytoskeletal extracts or microbial suspensions, that takes into account the underlying periodic duty cycle carried by the constituent active particles. We show that an orientationally ordered active fluid can undergo a transition to a state in which the particles synchronize their phases. This spontaneous breaking of time translation invariance gives rise to flow instabilities distinct from those arising in phase-incoherent active matter. Our work is of relevance to the transport of fluids in living systems and makes predictions for concentrated active-particle suspensions and optically driven colloidal arrays. PMID- 24476308 TI - Nonlocal rheology of granular flows across yield conditions. AB - The rheology of dense granular flows is studied numerically in a shear cell controlled at constant pressure and shear stress, confined between two granular shear flows. We show that a liquid state can be achieved even far below the yield stress, whose flow can be described with the same rheology as above the yield stress. A nonlocal constitutive relation is derived from dimensional analysis through a gradient expansion and calibrated using the spatial relaxation of velocity profiles observed under homogeneous stresses. Both for frictional and frictionless grains, the relaxation length is found to diverge as the inverse square root of the distance to the yield point, on both sides of that point. PMID- 24476309 TI - Forest-fire analogy to explain the b value of the Gutenberg-Richter law for earthquakes. AB - The Drossel-Schwabl model of forest fires can be interpreted in a coarse-grained sense as a model for the stress distribution in a single planar fault. Fires in the model are then translated to earthquakes. I show that when a second class of trees that propagate fire only after some finite time is introduced in the model, secondary fires (analogous to aftershocks) are generated, and the statistics of events becomes quantitatively compatible with the Gutenberg-Richter law for earthquakes, with a realistic value of the b exponent. The change in exponent is analytically demonstrated in a simplified percolation scenario. Experimental consequences of the proposed mechanism are indicated. PMID- 24476260 TI - Directed flow of charged particles at midrapidity relative to the spectator plane in Pb-Pb collisions at ?(s(NN))=2.76 TeV. AB - The directed flow of charged particles at midrapidity is measured in Pb-Pb collisions at ?(s(NN))=2.76 TeV relative to the collision symmetry plane defined by the spectator nucleons. A negative slope of the rapidity-odd directed flow component with approximately 3 times smaller magnitude than found at the highest RHIC energy is observed. This suggests a smaller longitudinal tilt of the initial system and disfavors the strong fireball rotation predicted for the LHC energies. The rapidity-even directed flow component is measured for the first time with spectators and found to be independent of pseudorapidity with a sign change at transverse momenta p(T) between 1.2 and 1.7 GeV/c. Combined with the observation of a vanishing rapidity-even p(T) shift along the spectator deflection this is strong evidence for dipolelike initial density fluctuations in the overlap zone of the nuclei. Similar trends in the rapidity-even directed flow and the estimate from two-particle correlations at midrapidity, which is larger by about a factor of 40, indicate a weak correlation between fluctuating participant and spectator symmetry planes. These observations open new possibilities for investigation of the initial conditions in heavy-ion collisions with spectator nucleons. PMID- 24476310 TI - Inhibition of Aurora B by CCT137690 sensitizes colorectal cells to radiotherapy. AB - Colorectal cancer is the third most commonly diagnosed cancer worldwide. Although surgery remains the best treatment for this disease, adjuvant chemotherapy and radiotherapy are also very important in clinical practice. However, the notorious refractory lack of responses to radiochemotherapy greatly limits the application of radiochemotherapy in the context of colorectal cancer.There is a growing interest in the role that Aurora B may play in colorectal cancer cell survival as well as other cancer subtypes. In the current study, we sought to ascertain whether blocking of Aurora B signaling machinery by a small molecule inhibitor, CCT137690, could synergize radiation-induced colorectal cancer cell death. Results showed that CCT137690 increases the sensitivity of SW620 cells to radiation. Mechanistic studies revealed that Aurora B-Survivin pathway may be involved in this synergistic effect.Taken together, our results for the first time show that Aurora B inhibition and radiation exert a synergistic effect, resulting in enhanced colorectal cancer cell death. This synergistic effect is clinically relevant as lower doses of radiation could be used for cancer treatment, and could provide significant clinical benefits in terms of colorectal cancer management, while reducing unwanted side-effects. PMID- 24476311 TI - Three amino acid derivatives of valproic acid: design, synthesis, theoretical and experimental evaluation as anticancer agents. AB - Valproic acid (VPA) is extensively used as an anticonvulsive agent and as a treatment for other neurological disorders. It has been shown that VPA exerts an anti-proliferative effect on several types of cancer cells by inhibiting the activity of histone deacetylases (HDACs), which are involved in replication and differentiation processes. However, VPA has some disadvantages, among which are poor water solubility and hepatotoxicity. Therefore, the aim of the present study was to design and synthesize three derivatives of VPA to improve its physicochemical properties and anti-proliferative effects. For this purpose, the amino acids aspartic acid, glutamic acid and proline were added to the molecular structure of VPA. Docking and molecular dynamics simulations were used to determine the mode of recognition of these three derivatives by different conformations of HDAC8. This receptor was used as the specific target because of its high affinity for this type of substrate. The results demonstrate that, compared to VPA, the test compounds bind to different sites on the enzyme and that hydrogen bonds and hydrophobic interactions play key roles in this difference. The IC50 values of the VPA derivatives, experimentally determined using HeLa cells, were in the mM range. This result indicates that the derivatives have greater antiproliferative effects than the parent compound. Hence, these results suggest that these amino acid derivatives may represent a good alternative for anticancer treatment. PMID- 24476312 TI - ent-kaurane diterpenoids from Croton tonkinensis induce apoptosis in colorectal cancer cells through the phosphorylation of JNK mediated by reactive oxygen species and dual-specificity JNK kinase MKK4. AB - To search for new chemotherapeutic agents to treat colorectal cancer, we isolated a number of natural ent-kaurane diterpenoids from the plant Croton tonkinensis. Among them, only CeKDs with the 15-oxo-16-ene moiety induced the apoptosis of colorectal cancer cell lines Caco-2 and LS180. The active CeKD induced the activation of ERK and JNK, but the inactive ones induced that of ERK, but not that of JNK. It thus appears that JNK seemed to play an important role in the apoptotic activity of the active compounds. The dualspecificity JNK kinase MKK4 was activated in both colorectal cancer cells treated with the active CeKD, but MKK7 was not activated. Further, the active CeKD, but not the inactive one, enhanced the generation of intracellular reactive oxygen species (ROS) in both cells. CeKD-induced cell apoptosis and ROS generation, as well as JNK activation, were inhibited by the antioxidant N-acetyl-L-cysteine. These findings suggest that ROS stimulated the phosphorylation of JNK mediated by MKK4 and played a critical role in CeKD-induced apoptosis in colorectal cancer cells. PMID- 24476313 TI - East-west fusion-necrosis and apoptosis acting in concert by demethylcantharidin integrated platinum complexes. AB - The different types of cell death occurring in HCT116 colorectal cancer cell after the treatment of cisplatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(demethylcantharidin:DMC) and Pt(R,R-1,2-diaminocyclohexane: DACH)(DMC) were examined. Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) are the two DMC-integrated platinum complexes:Pt(R,R-DACH)(DMC) with the same Pt moiety as oxaliplatin and Pt(NH3)2(DMC) akin to carboplatin. Using the light scattering properties of cells combined with propidium iodide (PI) red fluorescence to distinguish between early apoptotic and necrotic cells, the results confirmed that apoptosis, which triggered by cisplatin, carboplatin and oxaliplatin, was the major type of cell death, while the major DMC-induced cell death type was necrosis. The increase in the necrotic cell population was observed after Pt((NH3)2(DMC) treatment when compared with carboplatin; therefore, the DMC ligand in Pt(NH3)2(DMC) contributing to cell death was demonstrated. However, the DMC ligand in Pt(R,RDACH)( DMC) failed to elevate the necrotic cell population significantly in contrast to oxaliplatin, thus Pt(R,R-DACH) in Pt(R,RDACH)( DMC) dominantly contributed to cell death. The IC50 value (antiproliferative activity) reflects the net effect of drugs on cell proliferation resulting from inhibition of cell growth and division, and induction of cell death. The sub-G1 populations representing the sum of the amounts of late apoptotic cells and necrotic cells after the treatment of cispatin, carboplatin, oxaliplatin, DMC, Pt(NH3)2(DMC) and Pt(R,R-DACH)(DMC) were found to be not correlated with the corresponding IC50 values;therefore, the rate of cell growth and division inhibition rather than the rate of induction of cell death dictated to the IC50 values. This combined analysis of IC50 values and the sub-G1 population data also reveals that the platinum compounds containing R,R-DACH are most efficient in inhibiting cell growth and division, while carboplatin induces cell death most rapidly. When the Pt-DNA adducts are believed to be major cytotoxic species, the combined analysis of the IC50 values and the sub-G1 population data infers that the R,R-DACH-Pt-1,2 d(GpG) intrastrand cross-links caused by oxaliplatin treatment are more effective in inducing cell growth and division inhibition, while the (NH3)2Pt-1,3- d(GpXpG) intrastrand cross-links caused by carboplatin treatment can trigger cell death more rapidly. The rate of cell growth and division inhibition and the cell death rate induced by the main cisplatin-DNA adducts:(NH3)2Pt-1,2-d(GpG) intrastrand cross-links lie in between. PMID- 24476314 TI - Anti-cancer agent-induced nephrotoxicity. AB - Patients with cancer are frequently exposed to risk of renal injuries associated with disease-related or iatrogenic causes. Nephrotoxicity is a potential adverse effect of anti-cancer agents and may result in a variety of functional abnormalities, including glomerular or tubular dysfunction, hypertension and disturbance of the renal endocrine function. In this review article, we comprehensively discuss the incidence, clinical presentation, prevention and management of anti-cancer agent-induced renal dysfunction. We focus on both relatively new anti-cancer agents (bevacizumab, gefitinib, gemcitabine, imatinib, rituximab and trastuzumab) and traditional agents (cisplatin, methotrexate, ifosfamide and taxanes) to cover a selection of the most frequently used anti cancer agents. Increased understanding of the mechanism of renal injury by these agents is considered to be important for developing novel anti-cancer agents that have far fewer adverse effects on kidneys. PMID- 24476317 TI - Using room temperature current noise to characterize single molecular spectra. AB - We propose a way to use room temperature random telegraph noise to characterize single molecules adsorbed on a backgated silicon field-effect transistor. The overlap of molecule and silicon electronic wave functions generates a set of trap levels that impose their unique scattering signatures on the voltage-dependent current noise spectrum. Our results are based on numerical modeling of the current noise, obtained by coupling a density functional treatment of the trap placement within the silicon band gap, a quantum kinetic treatment of the output current, and a Monte Carlo evaluation of the trap occupancy under resonance. As an illustrative example, we show how we can extract molecule-specific "fingerprints" of four benzene-based molecules directly from a frequency-voltage colormap of the noise statistics. We argue that such a colormap carries detailed information about the trap dynamics at the Fermi energy, including the presence of correlated interactions, observed experimentally in backgated carbon nanotubes. PMID- 24476316 TI - Comparative genomics of Cylindrospermopsis raciborskii strains with differential toxicities. AB - BACKGROUND: Cylindrospermopsis raciborskii is an invasive filamentous freshwater cyanobacterium, some strains of which produce toxins. Sporadic toxicity may be the result of gene deletion events, the horizontal transfer of toxin biosynthesis gene clusters, or other genomic variables, yet the evolutionary drivers for cyanotoxin production remain a mystery. Through examining the genomes of toxic and non-toxic strains of C. raciborskii, we hoped to gain a better understanding of the degree of similarity between these strains of common geographical origin, and what the primary differences between these strains might be. Additionally, we hoped to ascertain why some cyanobacteria possess the cylindrospermopsin biosynthesis (cyr) gene cluster and produce toxin, while others do not. It has been hypothesised that toxicity or lack thereof might confer a selective advantage to cyanobacteria under certain environmental conditions. RESULTS: In order to examine the fundamental differences between toxic and non-toxic C. raciborskii strains, we sequenced the genomes of two closely related isolates, CS 506 (CYN+) and CS-509 (CYN-) sourced from different lakes in tropical Queensland, Australia. These genomes were then compared to a third (reference) genome from C. raciborskii CS-505 (CYN+). Genome sizes were similar across all three strains and their G + C contents were almost identical. At least 2,767 genes were shared among all three strains, including the taxonomically important rpoc1, ssuRNA, lsuRNA, cpcA, cpcB, nifB and nifH, which exhibited 99.8-100% nucleotide identity. Strains CS-506 and CS-509 contained at least 176 and 101 strain-specific (or non homologous) genes, respectively, most of which were associated with DNA repair and modification, nutrient uptake and transport, or adaptive measures such as osmoregulation. However, the only significant genetic difference observed between the two strains was the presence or absence of the cylindrospermopsin biosynthesis gene cluster. Interestingly, we also identified a cryptic secondary metabolite gene cluster in strain CS-509 (CYN-) and a second cryptic cluster common to CS-509 and the reference strain, CS-505 (CYN+). CONCLUSIONS: Our results confirm that the most important factor contributing to toxicity in C. raciborskii is the presence or absence of the cyr gene cluster. We did not identify any other distally encoded genes or gene clusters that correlate with CYN production. The fact that the additional genomic differences between toxic and non-toxic strains were primarily associated with stress and adaptation genes suggests that CYN production may be linked to these physiological processes. PMID- 24476315 TI - Where does a Staphylococcus aureus vaccine stand? AB - In this review, we examine the current status of Staphylococcus aureus vaccine development and the prospects for future vaccines. Examination of the clinical trials to date show that murine models have not predicted success in humans for active or passive immunization. A key factor in the failure to develop a vaccine to prevent S. aureus infections comes from our relatively limited knowledge of human protective immunity. More recent reports on the elements of the human immune response to staphylococci are analysed. In addition, there is some controversy concerning the role of antibodies for protecting humans, and these data are reviewed. From a review of the current state of understanding of staphylococcal immunity, a working model is proposed. Some new work has provided some initial candidate biomarker(s) to predict outcomes of invasive infections and to predict the efficacy of antibiotic therapy in humans. We conclude by looking to the future through the perspective of lessons gleaned from the clinical vaccine trials. PMID- 24476318 TI - Serum amyloid A induces interleukin-6 in dermal fibroblasts via Toll-like receptor 2, interleukin-1 receptor-associated kinase 4 and nuclear factor-kappaB. AB - Systemic sclerosis is an autoimmune idiopathic connective tissue disease, characterized by vasculopathy, inflammation and fibrosis. There appears to be a link between inflammation and fibrosis, although the exact nature of the relationship is unknown. Serum amyloid A (SAA) is an acute-phase protein that is elevated up to 1000-fold in times of infection or inflammation. This acute-phase reactant, as well as being a marker of inflammation, may initiate signals in a cytokine-like manner, possibly through toll-like receptors (TLRs) promoting inflammation. This study addressed the role of SAA in initiating interleukin-6 (IL-6) production in dermal fibroblasts and the role of TLR2 in this system. We show that SAA induces IL-6 secretion in healthy dermal fibroblasts and that blockade of TLR2 with a neutralizing antibody to TLR2 or specific small interfering RNA attenuated the SAA-induced IL-6 secretion and that this was also mediated through the TLR adaptor protein IL-1 receptor-associated kinase 4. The effect is nuclear factor-kappaB-mediated because blockade of nuclear factor kappaB reduced the induction. We also demonstrate that dermal fibroblasts express TLR2; this is functional and over-expressed in the fibroblasts of patients with systemic sclerosis. Taken together these data suggest that SAA is a danger signal that initiates IL-6 signalling in systemic sclerosis via enhanced TLR2 signalling. PMID- 24476319 TI - Stress and strain in medical school. PMID- 24476320 TI - Ideals are like stars. PMID- 24476321 TI - HOW TO...: Use Videodiscs in Medical Education, Part 1. AB - The videodisc system was first demonstrated 10 years ago but it was only in mid 1982 that the first commercially available system was launched in the UK. One advantage of the videodisc is that the video image is much better than with videotape players. Another is that the optical videodisc never wears out. In addition it is possible randomly to allocate, in a short space of time, any of 54,000 frames of information. The disadvantages are that the videodisc cannot be used to record video information, there is not much software available, and the disc master and copies have to be made by a commercial production house. Specific applications will be described in part 2. PMID- 24476322 TI - The politics of partnership. PMID- 24476323 TI - THE WAY WE TEACH...: Talking with Children. AB - This paper describes how medical students are helped to understand the interactions involved in their conversations with children. It shows them how they can use this understanding to make their communication more effective. For many students this will be of continuing value throughout their medical career. PMID- 24476324 TI - Letters. PMID- 24476325 TI - Teaching practical prescribing and therapeutics. AB - As noted in our editorial in the last issue, continuity in medical education was the subject of a conference organized by the Association of Medical Education, and held in London in June 1982. One of the keynote speakers was Dr Andrew Herxheimer, whose contribution on teaching practical prescribing and therapeutics is printed below. Some will claim that the approach advocated by Dr Herxheimer is already being attempted, while others will wonder how such an increase in the competence of undergraduates is to be achieved in an already overcrowded curriculum. The paper should, at least, lead to discussion. Dr Herxheimer's paper is followed by a description of the Open University course 'Topics in Drug Therapy' (P550), made for the Council for Postgraduate Medical Education in England and Wales and launched in October 1982. It is aimed at all practising doctors, especially trainees and general practitioners. PMID- 24476326 TI - Topics in drug therapy: an open university pilot course for doctors. PMID- 24476327 TI - Personal view: is there a case for less clinical training in medical education? PMID- 24476330 TI - Jottings. PMID- 24476329 TI - In brief: role of nurse instructors in the surgery clerkship. PMID- 24476334 TI - Planning in middle childhood: early predictors and later outcomes. AB - Data from 1,364 children and families who participated in the National Institute of Child Health and Human Development's Study of Early Child Care and Youth Development were analyzed to track the early correlates and later academic outcomes of planning during middle childhood. Maternal education, through its effect on parenting quality when children were 54 months old, predicts their concurrent performance on sustained attention, inhibition, and short-term verbal memory tests. This performance predicts planning in first grade, which predicts third-grade reading and mathematics attainment, but not the rate of growth in academic skills from first to fifth grades. This path was also found when the same parenting, cognitive, and academic constructs were measured at later time points. PMID- 24476335 TI - How robust are the natural history parameters used in chlamydia transmission dynamic models? A systematic review. AB - Transmission dynamic models linked to economic analyses often form part of the decision making process when introducing new chlamydia screening interventions. Outputs from these transmission dynamic models can vary depending on the values of the parameters used to describe the infection. Therefore these values can have an important influence on policy and resource allocation. The risk of progression from infection to pelvic inflammatory disease has been extensively studied but the parameters which govern the transmission dynamics are frequently neglected. We conducted a systematic review of transmission dynamic models linked to economic analyses of chlamydia screening interventions to critically assess the source and variability of the proportion of infections that are asymptomatic, the duration of infection and the transmission probability. We identified nine relevant studies in Pubmed, Embase and the Cochrane database. We found that there is a wide variation in their natural history parameters, including an absolute difference in the proportion of asymptomatic infections of 25% in women and 75% in men, a six-fold difference in the duration of asymptomatic infection and a four-fold difference in the per act transmission probability. We consider that much of this variation can be explained by a lack of consensus in the literature. We found that a significant proportion of parameter values were referenced back to the early chlamydia literature, before the introduction of nucleic acid modes of diagnosis and the widespread testing of asymptomatic individuals. In conclusion, authors should use high quality contemporary evidence to inform their parameter values, clearly document their assumptions and make appropriate use of sensitivity analysis. This will help to make models more transparent and increase their utility to policy makers. PMID- 24476337 TI - Cellular, physiological, and molecular adaptive responses of Erwinia amylovora to starvation. AB - Erwinia amylovora causes fire blight, a destructive disease of rosaceous plants distributed worldwide. This bacterium is a nonobligate pathogen able to survive outside the host under starvation conditions, allowing its spread by various means such as rainwater. We studied E. amylovora responses to starvation using water microcosms to mimic natural oligotrophy. Initially, survivability under optimal (28 degrees C) and suboptimal (20 degrees C) growth temperatures was compared. Starvation induced a loss of culturability much more pronounced at 28 degrees C than at 20 degrees C. Natural water microcosms at 20 degrees C were then used to characterize cellular, physiological, and molecular starvation responses of E. amylovora. Challenged cells developed starvation-survival and viable but nonculturable responses, reduced their size, acquired rounded shapes and developed surface vesicles. Starved cells lost motility in a few days, but a fraction retained flagella. The expression of genes related to starvation, oxidative stress, motility, pathogenicity, and virulence was detected during the entire experimental period with different regulation patterns observed during the first 24 h. Further, starved cells remained as virulent as nonstressed cells. Overall, these results provide new knowledge on the biology of E. amylovora under conditions prevailing in nature, which could contribute to a better understanding of the life cycle of this pathogen. PMID- 24476336 TI - Diiron oxidation state control of substrate access to the active site of soluble methane monooxygenase mediated by the regulatory component. AB - The regulatory component (MMOB) of soluble methane monooxygenase (sMMO) has a unique N-terminal tail not found in regulatory proteins of other bacterial multicomponent monooxygenases. This N-terminal tail is indispensable for proper function, yet its solution structure and role in catalysis remain elusive. Here, by using double electron-electron resonance (DEER) spectroscopy, we show that the oxidation state of the hydroxylase component, MMOH, modulates the conformation of the N-terminal tail in the MMOH-2MMOB complex, which in turn facilitates catalysis. The results reveal that the N-terminal tail switches from a relaxed, flexible conformational state to an ordered state upon MMOH reduction from the diiron(III) to the diiron(II) state. This observation suggests that some of the crystallographically observed allosteric effects that result in the connection of substrate ingress cavities in the MMOH-2MMOB complex may not occur in solution in the diiron(III) state. Thus, O2 may not have easy access to the active site until after reduction of the diiron center. The observed conformational change is also consistent with a higher binding affinity of MMOB to MMOH in the diiron(II) state, which may allow MMOB to displace more readily the reductase component (MMOR) from MMOH following reduction. PMID- 24476338 TI - Effect of ADAMTS-13 on cerebrovascular microthrombosis and neuronal injury after experimental subarachnoid hemorrhage. AB - BACKGROUND: Microthrombosis and reactive inflammation contribute to neuronal injury after subarachnoid hemorrhage (SAH). ADAMTS-13 cleaves von Willebrand factor multimers, and inhibits thrombus formation and, seemingly, inflammatory reactions. OBJECTIVE: To investigate the effect of ADAMTS-13 in experimental SAH. METHODS: A total of 100 male C57/BL6 mice were randomly assigned to four groups: sham (n = 15), SAH (n = 27), vehicle (n = 25), and ADAMTS-13 (n = 23; 100 MUL per 10 g of body weight of 100 MUg of ADAMTS-13 per 1 mL of 0.9% NaCl; 20 min after SAH). Neurologic performance was assessed on days 1 and 2 after SAH. Animals were killed on day 2. The amounts of subarachnoid blood, microthrombi, apoptosis and degenerative neurons were compared. The degree of neuronal inflammation and vasospasm was also compared. In five mice each (SAH and ADAMTS-13 groups), bleeding time was assessed 2 h after SAH. RESULTS: Systemic administration of ADAMTS-13 achieved significant amelioration of microthrombosis and improvement in neurologic performance. ADAMTS-13 reduced the amount of apoptotic and degenerative neurons. A tendency for decreased neuronal inflammation was observed. ADAMTS-13 did not show any significant effect on vasospasm. The degree of systemic inflammation was not changed by ADAMTS-13 administration. ADAMTS-13 neither increased the amount of subarachnoid blood nor prolonged the bleeding time. CONCLUSIONS: ADAMTS-13 may reduce neuronal injury after SAH by reducing microthrombosis formation and neuronal inflammation, thereby providing a new option for mitigating the severity of neuronal injury after SAH. PMID- 24476339 TI - Timeliness of childhood vaccine uptake among children attending a tertiary health service facility-based immunisation clinic in Ghana. AB - BACKGROUND: Childhood immunisation is a cost-effective activity in health. Immunisation of children has contributed to reducing child morbidity and mortality. In the last two decades, global deaths from vaccine-preventable illnesses have decreased significantly as a result of immunisation. Similar trends have been observed in Ghana following the introduction of the Expanded Programme on Immunisation. The administration of vaccines is based on the period of highest susceptibility among others. Ghana has long used the proportion of children receiving vaccines and the trends in vaccine preventable illness incidence as performance indicators for immunisation. The addition of timeliness of vaccine uptake as an additional performance indicator has been recommended. This study evaluated the timeliness of vaccine uptake among children immunised at the Komfo Anokye Teaching Hospital, Kumasi, Ghana. METHODS: The study was conducted at the Maternal and Child Health clinic of the hospital between February and March 2012. A representative sample of 259 respondents was selected by simple random sampling. Data collection was by a structured questionnaire and included the examination of Child Health records booklet. Data was entered into a Microsoft Office Access database and analysed using Epi Info Version 3.5.1 2008. RESULTS: The majority of mothers attended antenatal clinics during pregnancy. An overwhelming majority of babies (98.8%) were delivered in a hospital. About 85% of babies were less than 12 months of age. Mean time taken to reach the clinic was 30 minutes. Vaccine uptake was generally timely for initial vaccines. The proportion of children receiving the vaccines later increased with latter vaccines. Overall, 87.3% of babies received vaccines on time with only 5.3% receiving vaccines beyond 28 days of the scheduled date. Children receiving immunisations services in the same facility as they were born were more likely to receive the BCG vaccine on time. CONCLUSIONS: Vaccine uptake is mostly timely among respondents in the study. The BCG vaccine in particular was received on time among children born in the same facility as the immunisation clinic. There is the need to further examine the timeliness of vaccine uptake among children delivered outside health facilities in Ghana. PMID- 24476340 TI - MRI osteitis predicts cartilage damage at the wrist in RA: a three-year prospective 3T MRI study examining cartilage damage. AB - INTRODUCTION: Cartilage damage impacts on patient disability in rheumatoid arthritis (RA). The aims of this magnetic resonance imaging (MRI) study were to investigate cartilage damage over three years and determine predictive factors. METHODS: A total of 38 RA patients and 22 controls were enrolled at t = 0 (2009). After 3 years, clinical and MRI data were available in 28 patients and 15 controls. 3T MRI scans were scored for cartilage damage, bone erosion, synovitis and osteitis. A model was developed to predict cartilage damage from baseline parameters. RESULTS: Inter-reader reliability for the Auckland MRI cartilage score (AMRICS) was high for status scores; intraclass correlation coefficient (ICC), 0.90 (0.81 to 0.95) and moderate for change scores (ICC 0.58 (0.24 to 0.77)). AMRICS scores correlated with the Outcome MEasures in Rheumatoid Arthritis Clinical Trials (OMERACT) MRI joint space narrowing (jsn) and X-Ray (XR) jsn scores (r =0.96, P < 0.0001 and 0.80, P < 0.0001, respectively). AMRICS change scores were greater for RA patients than controls (P = 0.06 and P = 0.04 for the two readers). Using linear regression, baseline MRI cartilage, synovitis and osteitis scores predicted the three-year AMRICS (R2 = 0.67, 0.37 and 0.39, respectively). A multiple linear regression model predicted the three-year AMRICS (R2 = 0.78). Baseline radial osteitis predicted increased cartilage scores at the radiolunate and radioscaphoid joints, P = 0.0001 and 0.0012, respectively and synovitis at radioulnar, radiocarpal and intercarpal-carpometacarpal joints also influenced three-year cartilage scores (P-values of 0.001, 0.04 and 0.01, respectively). CONCLUSIONS: MRI cartilage damage progression is preceded by osteitis and synovitis but is most influenced by pre-existing cartilage damage suggesting primacy of the cartilage damage pathway in certain patients. PMID- 24476341 TI - Prehospital emergency care for patients with suspected hip fractures after falling - older patients' experiences. AB - AIMS AND OBJECTIVES: To describe and explain older patients' lived experiences of prehospital emergency care in cases of suspected hip fractures after falling. BACKGROUND: Falls among the elderly is an issue internationally and a public health problem that seems to be on the increase. In the emergency medical services, older people are frequent patients after having suffered a fall, but there is little information on how older patients experience prehospital emergency care in cases of suspected hip fractures after falling. DESIGN: Qualitative interview study. METHODS: Ten older patients were interviewed. These depth interviews were tape-recorded, transcribed verbatim and analysed for meanings. RESULTS: The comprehensive understanding of the phenomenon is: 'Glad to have been rescued, despite bad experiences as well as good'. The older patient is offered care in an open and friendly atmosphere concurrently with feeling anxiety about the treatment. Intervention with streamlined care and treatment can thus simultaneously be beneficial as well as doing harm. Patients experience confusion and the need to ask questions about what really happened in the ambulance. Bad experiences remain unexplained. These findings are based on three themes with relevant subthemes: efficiency, concerned encounters and suffering from care. CONCLUSIONS: Our study shows that prehospital emergency care when hip fracture is suspected - from patients' point of view - is insufficient and unsatisfying. Prehospital emergency care for these vulnerable patients could be improved through more compassion being shown towards older patients' existential needs and their increased participation. Furthermore, alternative methods of prehospital pain relief need to be developed. RELEVANCE TO CLINICAL PRACTICE: Responsibility for patients' safety regarding pain relief is emphasised. Pain relief in the emergency medical services should be individualised. This development should focus on care that is already good and gradually eradicate compassionless care. PMID- 24476343 TI - Gender differences in the use of health care in China: cross-sectional analysis. AB - INTRODUCTION: Differences between women and men in education, employment, political and economic empowerment have been well-documented in China due to the long traditional culture that male is superior to female. This study is to explore whether the similar gender differences exist in the use of health care by analyzing hospital admission, duration of hospitalization and medical expense of both genders in a Chinese hospital. METHODS: This cross-sectional study evaluated the gender differences in clinical and epidemiologic characteristics of patients who were admitted for any reason to hospital in Zhuhai Special Economic Zone, Southern China, from January 1, 2003, through December 31, 2009. Chi-square test was used to calculate differences between proportions and the t test was used to test differences between means. RESULTS: A total of 156,887 patients were recruited in the analysis, with a male/female ratio of 1.1:1.0. The average age and the duration of hospitalization were significantly greater among men (p < 0.05). A larger proportion of hospitalized female underwent surgery compared to male (p < 0.05). The total medical expense per inpatient indicated important differences between genders, with higher expenditures observed among men (p < 0.05). Furthermore, gender differences were observed in length of hospitalization and medical expense for five common conditions respectively and most differences favoring men were significant (p < 0.05) while differences favoring women were not significant (p > 0.05). Among all the self-paid patients, men were also superior in all investigating variables compared with women. CONCLUSIONS: Gender differences in the use of health care do occur in China. Despite of demographic factors, the differences between female and male can be in part explained by social power relations. China should increase attention to gender and equity in health. PMID- 24476344 TI - Induced pluripotent stem cell-derived cardiomyocytes for cardiovascular disease modeling and drug screening. AB - Human induced pluripotent stem cells (hiPSCs) have emerged as a novel tool for drug discovery and therapy in cardiovascular medicine. hiPSCs are functionally similar to human embryonic stem cells (hESCs) and can be derived autologously without the ethical challenges associated with hESCs. Given the limited regenerative capacity of the human heart following myocardial injury, cardiomyocytes derived from hiPSCs (hiPSC-CMs) have garnered significant attention from basic and translational scientists as a promising cell source for replacement therapy. However, ongoing issues such as cell immaturity, scale of production, inter-line variability, and cell purity will need to be resolved before human clinical trials can begin. Meanwhile, the use of hiPSCs to explore cellular mechanisms of cardiovascular diseases in vitro has proven to be extremely valuable. For example, hiPSC-CMs have been shown to recapitulate disease phenotypes from patients with monogenic cardiovascular disorders. Furthermore, patient-derived hiPSC-CMs are now providing new insights regarding drug efficacy and toxicity. This review will highlight recent advances in utilizing hiPSC-CMs for cardiac disease modeling in vitro and as a platform for drug validation. The advantages and disadvantages of using hiPSC-CMs for drug screening purposes will be explored as well. PMID- 24476345 TI - A multimodal intervention for patients with secondary progressive multiple sclerosis: feasibility and effect on fatigue. AB - BACKGROUND: Multiple sclerosis is an autoimmune disease influenced by environmental factors. OBJECTIVES: The feasibility of a multimodal intervention and its effect on perceived fatigue in patients with secondary progressive multiple sclerosis were assessed. DESIGN/SETTING: This was a single-arm, open label intervention study in an outpatient setting. INTERVENTIONS: A multimodal intervention including a modified paleolithic diet with supplements, stretching, strengthening exercises with electrical stimulation of trunk and lower limb muscles, meditation, and massage was used. OUTCOME MEASURES: Adherence to each component of the intervention was calculated using daily logs. Side-effects were assessed from a monthly questionnaire and blood analyses. Fatigue was assessed using the Fatigue Severity Scale (FSS). Data were collected at baseline and months 1, 2, 3, 6, 9, and 12. RESULTS: Ten (10) of 13 subjects who were enrolled in a 2-week run-in phase were eligible to continue in the 12-month main study. Of those 10 subjects, 8 completed the study and 6 subjects fully adhered to the study intervention for 12 months. Over a 12-month period, average adherence to diet exceeded 90% of days, and to exercise/muscle stimulation exceeded 75% of days. Nutritional supplements intake varied among and within subjects. Group daily average duration of meditation was 13.3 minutes and of massage was 7.2 minutes. No adverse side-effects were reported. Group average FSS scores decreased from 5.7 at baseline to 3.32 (p=0.0008) at 12 months. CONCLUSIONS: In this small, uncontrolled pilot study, there was a significant improvement in fatigue in those who completed the study. Given the small sample size and completer rate, further evaluation of this multimodal therapy is warranted. PMID- 24476346 TI - Long-term evaluation of analytical methods used in sirolimus therapeutic drug monitoring. AB - Results of therapeutic monitoring of sirolimus blood concentrations are assay and laboratory dependent. This study compared performance over time of the IMx microparticle enzyme immunoassay (MEIA), Architect chemiluminescent microparticle immunoassay (CMIA), and liquid chromatography with mass spectrometric detection (LC/MS/MS) as part of a proficiency testing scheme. Pooled samples from sirolimus treated patients and whole-blood samples spiked with known quantities of sirolimus were assayed monthly between 2004 and 2012. When results of pooled patient samples were compared with LC/MS/MS, the MEIA assay showed an overall mean percent bias of -2.3% +/- 11.2% that, although initially positive, became increasingly negative from 2007 through 2009. The CMIA, which replaced the MEIA assay, had a mean percent bias of 21.9% +/- 12.3%, remaining stable from 2007 through 2012. Similarly, for spiked samples, the MEIA showed an increasingly negative bias over time vs. LC/MS/MS, whereas CMIA maintained a stable positive bias. Based on comparison of immunoassay measurements on individual patient samples, CMIA values were more than 25% higher than MEIA values. These results highlight the importance of continued proficiency testing and regular monitoring of sirolimus assay performance. Clinicians must be aware of the methodology used and adjust target levels accordingly to avoid potential effects on efficacy and toxicity. PMID- 24476347 TI - Cobalt-releasing 1393 bioactive glass-derived scaffolds for bone tissue engineering applications. AB - Loading biomaterials with angiogenic therapeutics has emerged as a promising approach for developing superior biomaterials for engineering bone constructs. In this context, cobalt-releasing materials are of interest as Co is a known angiogenic agent. In this study, we report on cobalt-releasing three-dimensional (3D) scaffolds based on a silicate bioactive glass. Novel melt-derived "1393" glass (53 wt % SiO2, 6 wt % Na2O, 12 wt % K2O, 5 wt % MgO, 20 wt % CaO, and 4 wt % P2O5) with CoO substituted for CaO was fabricated and was used to produce a 3D porous scaffold by the foam replica technique. Glass structural and thermal properties as well as scaffold macrostructure, compressive strength, acellular bioactivity, and Co release in simulated body fluid (SBF) were investigated. In particular, detailed insights into the physicochemical reactions occurring at the scaffold-fluid interface were derived from advanced micro-particle-induced X-ray emission/Rutherford backscattering spectrometry analysis. CoO is shown to act in a concentration-dependent manner as both a network former and a network modifier. At a concentration of 5 wt % CoO, the glass transition point (Tg) of the glass was reduced because of the replacement of stronger Si-O bonds with Co-O bonds in the glass network. Compressive strengths of >2 MPa were measured for Co containing 1393-derived scaffolds, which are comparable to values of human spongy bone. SBF studies showed that all glass scaffolds form a calcium phosphate (CaP) layer, and for 1393-1Co and 1393-5Co, CaP layers with incorporated traces of Co were observed. The highest Co concentrations of ~12 ppm were released in SBF after reaction for 21 days, which are known to be within therapeutic ranges reported for Co(2+) ions. PMID- 24476348 TI - PT/NBL ratio assessment at mid-trimester in prenatal screening for Down syndrome in a Chinese population. AB - OBJECTIVE: To investigate the ratio of prenasal thickness (PT) to nasal bone length (NBL) in normal and trisomy 21 fetuses in the second and third trimester in Chinese population. METHODS: The NBL and PT were measured blindly by using 3D volumes in 143 normal fetuses and 31 trisomy 21 fetuses. RESULTS: The mean PT (r = 0.83, p = 0.004) and NBL (r = 0.87, p = 0.0062) both increased with the gestation age, while the PT/NBL ratio (r = 0.12, p > 0.10) remained stable. There was significant difference between normal and trisomy 21 fetuses (p < 0.001). If we took the 95th of the normal fetuses as the cut-off value, the detection rate was only 46%. By using ROC curve to evaluate the screening value of PT/NBL ratio, the area under receiver operating characteristic (ROC) curve was 0.88 (95% confidence interval 0.81 to 0.94, p < 0.0001). CONCLUSIONS: In Chinese population, the PT/NBL ratio is not a very strong ultrasound marker to predict trisomy 21 fetuses. However, it can be used as an ultrasound marker for Down syndrome screening during the second and third trimester of pregnancy. PMID- 24476349 TI - Live rubella virus vaccine long-term persistence as an antigenic trigger of cutaneous granulomas in patients with primary immunodeficiency. AB - Granulomas may develop as a response to a local antigenic trigger, leading to the activation of macrophages and T-lymphocytes. Primary immunodeficiency (PID) is associated with the development of extensive cutaneous granulomas, whose aetiology remains unknown. We performed high-throughput sequencing of the transcriptome of cutaneous granuloma lesions on two consecutive index cases, and RT-PCR in a third consecutive patient. The RA27/3 vaccine strain of rubella virus the core component of a universally used paediatric vaccine-was present in the cutaneous granuloma of these three consecutive PID patients. Controls included the healthy skin of two patients, non-granulomatous cutaneous lesions of patients with immunodeficiency, and skin biopsy samples of healthy individuals, and were negative. Expression of viral antigens was confirmed by immunofluorescence. Persistence of the rubella vaccine virus was also demonstrated in granuloma lesions sampled 4-5 years earlier. The persistence of the rubella virus vaccine strain in all three consecutive cutaneous granuloma patients with PID strongly suggests a causal relationship between rubella virus and granuloma in this setting. PMID- 24476350 TI - Risk reduction strategies used by urban adolescent girls in an HIV prevention trial. AB - Adolescent girls throughout the globe are particularly vulnerable to HIV infection. In the U.S., sexually-active, adolescent girls in urban settings are at elevated risk for HIV. The purpose of this study was to describe a theoreticallydriven, HIV prevention intervention tailored for adolescent girls and evaluate its effectiveness in reducing sexually-risky behaviors. Sexually active urban adolescent girls (n=738) recruited in a mid-size, northeastern U.S. city were recruited for a randomized controlled trial and participated in a theory-based, sexual risk reduction intervention or a structurallyequivalent health promotion control group. Preferred sexual risk-reduction strategies were collected using ACASI at baseline, then at 3, 6 and 12-months post-intervention. The manualized interventions included four small group sessions and two booster sessions all of which included information, motivational and behavioral skill constructs. Facilitators were trained in motivational interviewing and incorporated this technique throughout the sessions. Relative to girls in the control group, girls receiving the sexual risk-reduction intervention were more likely to increase the number of sexual-risk reduction strategies at post intervention; however, girls in the control group also increased the number of strategies used though not at the same rate. Theory-based, HIV interventions tailored to adolescent girls can help increase sexual riskreduction behaviors and provide girls with a menu of options to employ. Due to the manualized structure of this randomized controlled trial, the intervention could be modified to meet the needs of adolescent girls throughout the world. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT 00161343). PMID- 24476351 TI - Sexual risk reduction interventions for HIV prevention among South African youth: a meta-analytic review. AB - OBJECTIVES: To examine the efficacy of sexual risk reduction interventions among South African youth. METHODS: Electronic databases were searched to identify studies published between 2007 and early 2013. Studies were eligible if they (1) targeted youth age 9-26, (2) evaluated sexual risk reduction interventions and (3) reported at least one behavioral outcome. Independent raters coded study characteristics, and intervention content. Weighted mean effect sizes were calculated; positive effect sizes indicated less sexual risk behavior and incident STIs. RESULTS: Ten studies (k = 11; N = 22,788; 54% female; 79% Black African) were included. Compared to controls, interventions were successful at delaying sexual intercourse and, among sexually active youth, at increasing condom use. A single study found reductions in the incidence of herpes simplex virus-2, but not HIV. CONCLUSIONS: Implementing behavioral interventions to delay sexual debut and improve condom use can help to reduce the transmission of HIV among South African youth. PMID- 24476353 TI - Power dynamics in adolescent couple relationships and risk of sexually transmitted infections and HIV. AB - The aim of this study was to determine whether there are differences in power distribution between males and females in couple relationships, and whether these differences are associated with risky sexual behaviour in a representative sample of Spanish adolescents. The study also examined the influence of partner's age on the power dynamics that occur in a relationship. The sample comprised 1,223 adolescents attending state and private schools in the 17 autonomous regions in Spain. All adolescents included in the sample were involved in a heterosexual relationship (for at least one month) at the time of evaluation. Relationship control and decision-making dominance were evaluated using the Spanish version of the Sexual Relationship Power Scale. Two further questionnaires were administered to collect sociodemographic data, and data on sexual behaviour. Females showed greater relationship control and greater control over decision-making than males. In the female group, participants with partners five or more years older than them were found to have less control over decision-making, while greater control over decision-making was linked to less exposure to risk. In the male group, participants with partners older than them were found to have greater control over decisionmaking, while relationship control was found to be negatively related to exposure to sexual risk. These results highlight the importance of taking power distribution and gender inequalities in couple relationships into consideration for STI and HIV prevention. PMID- 24476352 TI - Young adult women and correlates of potential adoption of pre-exposure prophylaxis (PrEP): results of a national survey. AB - We examine potential use of pre-exposure prophylaxis (PrEP) among young adult women, based on nationally representative random-digit dial telephone household survey of 1,453 US African-American and white women. The hypotheses were generated based on Health Belief Model. Our analyses showed that, as compared to women of 30-45 years old, young women of 20-29 years old experienced stronger social influences on PrEP uptake. However, as compared to older women, young women did not report higher potential PrEP uptake or adherence, despite their greater risk of HIV. For PrEP to be an effective method of prevention for young adult women, interventions are needed to increase HIV risk awareness. PMID- 24476342 TI - Radical S-adenosylmethionine enzymes. PMID- 24476354 TI - State of the evidence: intimate partner violence and HIV/STI risk among adolescents. AB - This paper provides a critical narrative review of the scientific literature on intimate partner violence (IPV) and risky sexual behavior as well as sexually transmitted infections (STIs) among adolescents, aged 14-24 years. Intimate partner violence has been associated with a number of high risk sexual behavior, including inconsistent condom use, multiple sexual partners, earlier sexual debut, consuming substances while engaging in sexual behavior, and sexually transmitted infections among adolescents. An electronic search of the literature was performed using PubMed/MEDLINE, PsycINFO, and Web of Science and articles from January 2000 - June 2013 were reviewed. Search terms included a combination of keywords for IPV, HIV/STI risk, and adolescents. The findings from the review indicated that IPV was associated with inconsistent condom use, STIs, early sexual debut, multiple sexual partners, and other HIV/STI-associated risk factors among adolescents. HIV/STI interventions for female adolescents often focus on increasing behavioral and cognitive skills, specifically condom negotiation. However, within the context of an abusive relationship, it becomes challenging for adolescents to enact these skills, where this behavior could potentially place them at greater risk. Components that address violence are necessary within HIV prevention programming. Additionally, integration of IPV screening within healthcare settings is important along with a combined approach that merges resources from healthcare, social, and community-level settings. PMID- 24476355 TI - PrEP awareness and perceived barriers among single young men who have sex with men. AB - Pre-exposure prophylaxis (PrEP) has the potential to help reduce new HIV infections among young men who have sex with men (YMSM). Using a cross-sectional survey of YMSM (N=1,507; ages 18-24), we gauged YMSM's PrEP awareness and PrEP related beliefs regarding side effects, accessibility, and affordability. Overall, 27% of the sample had heard about PrEP; 1% reported ever using PrEP prior to sex. In a multivariate logistic regression, we found that YMSM were more likely to have heard about PrEP if they were older, more educated, were residentially unstable in the prior 30 days, had insurance, or reported having at least one sexually transmitted infection in their lifetime. We found no differences by race/ethnicity, history of incarceration, or recent sexual risk behavior. In multivariate linear regression models, Black and Latino YMSM were more likely than Whites to state they would not use PrEP because of side effect concerns. YMSM were more likely to indicate that they would not be able to afford PrEP if they did not have insurance or if they had a prior sexually transmitted infection, PrEP rollout may be hindered due to lack of awareness, as well as perceived barriers regarding its use. We propose strategies to maximize equity in PrEP awareness and access if it is to be scaled up among YMSM. PMID- 24476356 TI - Analysis of sexual behavior in adolescents. AB - The aim of this study was to describe some characteristics of vaginal, anal and oral sexual behavior in Spanish adolescents. It was a cross-sectional descriptive population study conducted using a probabilistic sample survey. The sample was composed of 4,612 male and female adolescents, of whom 1,686 reported having penetrative sexual experience. Sample size was established with a 97% confidence level and a 3% estimation error. Data collection took place in secondary education schools. Mean age of vaginal sex initiation was 15 years. Compared to females, males reported an earlier age of anal and oral sex initiation and a larger number of vaginal and anal sexual partners. Males also reported a higher frequency of penetrative sexual relations under the influence of alcohol or other drugs. A higher percentage of females than males reported not using a condom in their first anal sexual experience. This study provides a current overview of the sexual behavior of adolescents that can be useful for the design of future programs aimed at preventing HIV and sexually transmitted infections (STIs). PMID- 24476357 TI - Transgelins, cytoskeletal proteins implicated in different aspects of cancer development. AB - Transgelin is an abundant protein of smooth muscle cells, where its role has been primarily studied. As a protein affecting dynamics of the actin cytoskeleton via stabilization of actin filaments, transgelin is both directly and indirectly involved in many cancer-related processes such as migration, proliferation, differentiation or apoptosis. Transgelin was previously reviewed as a tumor suppressor; however, recent data based on a number of proteomics studies indicate its pro-tumorigenic role, for example, in colorectal or hepatocellular cancer. We summarize these contradictory observations in both clinical and functional proteomics projects and analyze the role of transgelin in tumors in detail. Generally, the expression and biological role of transgelin seem to differ among various types of tumor cells and stroma, and possibly change during tumor progression. We also overview the recent data on transgelin-2, a sequence homolog of transgelin, whose role in the tumor development might be contradictory to the role of transgelin. PMID- 24476358 TI - SHEAR: sample heterogeneity estimation and assembly by reference. AB - BACKGROUND: Personal genome assembly is a critical process when studying tumor genomes and other highly divergent sequences. The accuracy of downstream analyses, such as RNA-seq and ChIP-seq, can be greatly enhanced by using personal genomic sequences rather than standard references. Unfortunately, reads sequenced from these types of samples often have a heterogeneous mix of various subpopulations with different variants, making assembly extremely difficult using existing assembly tools. To address these challenges, we developed SHEAR (Sample Heterogeneity Estimation and Assembly by Reference; http://vk.cs.umn.edu/SHEAR), a tool that predicts SVs, accounts for heterogeneous variants by estimating their representative percentages, and generates personal genomic sequences to be used for downstream analysis. RESULTS: By making use of structural variant detection algorithms, SHEAR offers improved performance in the form of a stronger ability to handle difficult structural variant types and better computational efficiency. We compare against the lead competing approach using a variety of simulated scenarios as well as real tumor cell line data with known heterogeneous variants. SHEAR is shown to successfully estimate heterogeneity percentages in both cases, and demonstrates an improved efficiency and better ability to handle tandem duplications. CONCLUSION: SHEAR allows for accurate and efficient SV detection and personal genomic sequence generation. It is also able to account for heterogeneous sequencing samples, such as from tumor tissue, by estimating the subpopulation percentage for each heterogeneous variant. PMID- 24476360 TI - Impact of 5-aza-2'-deoxycytidine and epigallocatechin-3-gallate for induction of human regulatory T cells. AB - The epigenetic regulation of transcription factor genes is critical for T-cell lineage specification. A specific methylation pattern within a conserved region of the lineage specifying transcription factor gene FOXP3, the Treg-specific demethylated region (TSDR), is restricted to regulatory T (Treg) cells and is required for stable expression of FOXP3 and suppressive function. We analysed the impact of hypomethylating agents 5-aza-2'-deoxycytidine and epigallocatechin-3 gallate on human CD4(+) CD25(-) T cells for generating demethylation within FOXP3-TSDR and inducing functional Treg cells. Gene expression, including lineage specifying transcription factors of the major T-cell lineages and their leading cytokines, functional properties and global transcriptome changes were analysed. The FOXP3-TSDR methylation pattern was determined by using deep amplicon bisulphite sequencing. 5-aza-2'-deoxycytidine induced FOXP3-TSDR hypomethylation and expression of the Treg-cell-specific genes FOXP3 and LRRC32. Proliferation of 5-aza-2'-deoxycytidine-treated cells was reduced, but the cells did not show suppressive function. Hypomethylation was not restricted to FOXP3-TSDR and expression of master transcription factors and leading cytokines of T helper type 1 and type 17 cells were induced. Epigallocatechin-3-gallate induced global DNA hypomethylation to a lesser extent than 5-aza-2'-deoxycitidine, but no relevant hypomethylation within FOXP3-TSDR or expression of Treg-cell-specific genes. Neither of the DNA methyltransferase inhibitors induced fully functional human Treg cells. 5-aza-2'-deoxycitidine-treated cells resembled Treg cells, but they did not suppress proliferation of responder cells, which is an essential capability to be used for Treg cell transfer therapy. Using a recently developed targeted demethylation technology might be a more promising approach for the generation of functional Treg cells. PMID- 24476359 TI - H2B ubiquitylation modulates spliceosome assembly and function in budding yeast. AB - BACKGROUND INFORMATION: Commitment to splicing occurs co-transcriptionally, but a major unanswered question is the extent to which various modifications of chromatin, the template for transcription in vivo, contribute to the regulation of splicing. RESULTS: Here, we perform genome-wide analyses showing that inhibition of specific marks - H2B ubiquitylation, H3K4 methylation and H3K36 methylation - perturbs splicing in budding yeast, with each modification exerting gene-specific effects. Furthermore, semi-quantitative mass spectrometry on purified nuclear mRNPs and chromatin immunoprecipitation analysis on intron containing genes indicated that H2B ubiquitylation, but not Set1-, Set2- or Dot1 dependent H3 methylation, stimulates recruitment of the early splicing factors, namely U1 and U2 snRNPs, onto nascent RNAs. CONCLUSIONS: These results suggest that histone modifications impact splicing of distinct subsets of genes using distinct pathways. PMID- 24476361 TI - Transformational silicon electronics. AB - In today's traditional electronics such as in computers or in mobile phones, billions of high-performance, ultra-low-power devices are neatly integrated in extremely compact areas on rigid and brittle but low-cost bulk monocrystalline silicon (100) wafers. Ninety percent of global electronics are made up of silicon. Therefore, we have developed a generic low-cost regenerative batch fabrication process to transform such wafers full of devices into thin (5 MUm), mechanically flexible, optically semitransparent silicon fabric with devices, then recycling the remaining wafer to generate multiple silicon fabric with chips and devices, ensuring low-cost and optimal utilization of the whole substrate. We show monocrystalline, amorphous, and polycrystalline silicon and silicon dioxide fabric, all from low-cost bulk silicon (100) wafers with the semiconductor industry's most advanced high-kappa/metal gate stack based high-performance, ultra-low-power capacitors, field effect transistors, energy harvesters, and storage to emphasize the effectiveness and versatility of this process to transform traditional electronics into flexible and semitransparent ones for multipurpose applications. PMID- 24476362 TI - Multipotent (adult) and pluripotent stem cells for heart regeneration: what are the pros and cons? AB - Heart failure after myocardial infarction is the leading cause of mortality and morbidity worldwide. Existing medical and interventional therapies can only reduce the loss of cardiomyocytes during myocardial infarction but are unable to replenish the permanent loss of cardiomyocytes after the insult, which contributes to progressive pathological left ventricular remodeling and progressive heart failure. As a result, cell-based therapies using multipotent (adult) stem cells and pluripotent stem cells (embryonic stem cells or induced pluripotent stem cells) have been explored as potential therapeutic approaches to restore cardiac function in heart failure. Nevertheless, the optimal cell type with the best therapeutic efficacy and safety for heart regeneration is still unknown. In this review, the potential pros and cons of different types of multipotent (adult) stem cells and pluripotent stem cells that have been investigated in preclinical and clinical studies are reviewed, and the future perspective of stem cell-based therapy for heart regeneration is discussed. PMID- 24476363 TI - Associations between children's independent mobility and physical activity. AB - BACKGROUND: Independent mobility describes the freedom of children to travel and play in public spaces without adult supervision. The potential benefits for children are significant such as social interactions with peers, spatial and traffic safety skills and increased physical activity. Yet, the health benefits of independent mobility, particularly on physical activity accumulation, are largely unexplored. This study aimed to investigate associations of children's independent mobility with light, moderate-to-vigorous, and total physical activity accumulation. METHODS: In 2011-2012, 375 Australian children aged 8-13 years (62% girls) were recruited into a cross-sectional study. Children's independent mobility (i.e. independent travel to school and non-school destinations, independent outdoor play) and socio-demographics were assessed through child and parent surveys. Physical activity intensity was measured objectively through an Actiheart monitor worn on four consecutive days. Associations between independent mobility and physical activity variables were analysed using generalized linear models, accounting for clustered sampling, Actiheart wear time, socio-demographics, and assessing interactions by sex. RESULTS: Independent travel (walking, cycling, public transport) to school and non-school destinations were not associated with light, moderate-to-vigorous and total physical activity. However, sub-analyses revealed a positive association between independent walking and cycling (excluding public transport) to school and total physical but only in boys (b = 36.03, p < 0.05). Frequent independent outdoor play (three or more days per week) was positively associated with light and total physical activity (b = 29.76, p < 0.01 and b = 32.43, p = 0.03, respectively). No significant associations were found between independent outdoor play and moderate-to-vigorous physical activity. When assessing differences by sex, the observed significant associations of independent outdoor play with light and total physical activity remained in girls but not in boys. All other associations showed no significant differences by sex. CONCLUSIONS: Independent outdoor play may boost children's daily physical activity levels, predominantly at light intensity. Hence, facilitating independent outdoor play could be a viable intervention strategy to enhance physical activity in children, particularly in girls. Associations between independent travel and physical activity are inconsistent overall and require further investigation. PMID- 24476366 TI - Sensitive questions. PMID- 24476367 TI - Conduct a clinical viva voce examination. PMID- 24476368 TI - Primary care medicine using a pathways model. AB - The Faculty of Medicine, University of Suez Canal, Ismailia, Egypt is the newest medical school in Egypt and a member of the network of community orientated medical schools, with an emphasis on primary care medicine. The faculty is engaged in innovative approaches to curriculum content and design and to teaching methods and sites. The model presented here is an attempt to teach primary care medicine in a logical manner. PMID- 24476369 TI - Studies of student learning: implications for medical teaching. AB - This article outlines recent studies of student learning carried out in Sweden, Australia and Britain and some implications for the medical curriculum. The findings reveal the existence of deep and surface approaches to learning, and show how the organization of departments and methods of assessment influence styles of learning. The final section of the article poses a series of questions for medical teachers to consider and perhaps discuss with their colleagues. PMID- 24476365 TI - Assessing the impact of race, social factors and air pollution on birth outcomes: a population-based study. AB - BACKGROUND: Both air pollution exposure and socioeconomic status (SES) are important indicators of children's health. Using highly resolved modeled predictive surfaces, we examine the joint effects of air pollution exposure and measures of SES in a population level analysis of pregnancy outcomes in North Carolina (NC). METHODS: Daily measurements of particulate matter <2.5 MUm in aerodynamic diameter (PM2.5) and ozone (O3) were calculated through a spatial hierarchical Bayesian model which produces census-tract level point predictions. Using multilevel models and NC birth data from 2002-2006, we examine the association between pregnancy averaged PM2.5 and O3, individual and area-based SES indicators, and birth outcomes. RESULTS: Maternal race and education, and neighborhood household income were associated with adverse birth outcomes. Predicted concentrations of PM2.5 and O3 were also associated with an additional effect on reductions in birth weight and increased risks of being born low birth weight and small for gestational age. CONCLUSIONS: This paper builds on and complements previous work on the relationship between pregnancy outcomes and air pollution exposure by using 1) highly resolved air pollution exposure data; 2) a five-year population level sample of pregnancies; and 3) including personal and areal level measures of social determinants of pregnancy outcomes. Results show a stable and negative association between air pollution exposure and adverse birth outcomes. Additionally, the more socially disadvantaged populations are at a greater risk; controlling for both SES and environmental stressors provides a better understanding of the contributing factors to poor children's health outcomes. PMID- 24476370 TI - Teaching gerontology and geriatric medicine. PMID- 24476371 TI - Videodiscs in Medical Education, part 2. AB - The potential for learning with videodiscs is enormous. However, to date, their practical application had been limited, not least because of high production costs. This article provides a brief guide to current uses of videodiscs. It concludes that the only way they are likely to be successful is for someone to sponsor their production, with the disc being essentially a rapid-access visual resource, and the microcomputer carrying the intelligence for the programme. PMID- 24476372 TI - Anatomical drawing as an aid to orthopaedic teaching. PMID- 24476373 TI - House officers' perceptions of their experience and competence. AB - An earlier study reported upon graduating medical students' experience of practical procedures and acute conditions. This paper reports briefly upon the results of a pilot study assessing house officers' cumulative experience at the end of each of their pre-registration posts. Their experience of a list of conditions and procedures by the end of the pre-registration year is presented, together with house officers' estimation of their present competence to manage and undertake them. Although many gaps identified at graduation no longer exist by the end of this year, a minority of doctors still do not feel competent to take initial responsibility for managing some important conditions or to carry out some basic procedures. PMID- 24476364 TI - Filming biomolecular processes by high-speed atomic force microscopy. PMID- 24476374 TI - Meeting the need for more formalized education in paediatrics. AB - The information explosion, the plethora of continuing medical education activities, the complexities and fragmentation of graduate and postgraduate training and the need for cost containment and faculty development all contributed to the decision to create an office of paediatric medical education (OPME) at the Children's Hospital National Medical Center. To plan and prepare strategies for this office, we surveyed all 150 moderate-to-large US paediatric programmes to elicit information about the educational organization of paediatric departments, including administration, staffing, funding, responsibilities, and level of involvement; and the current needs in paediatric medical education. The results suggest that there is a trend towards formalizing education in paediatrics. Thirty-eight per cent (33) of those responding reported OPMEs, with most (86 per cent) of the OPMEs evolving within the last decade and 50 per cent within the last five years. Respondents cited as a priority the need for better organization of medical education to improve the quality of teaching and learning and thus achieve higher quality and more cost-effective health care. PMID- 24476378 TI - Restoration of endodontically treated teeth with major hard tissue loss - influence of post surface design on pull-out bond strength of fiber-reinforced composite posts. AB - AIM: The aim was to evaluate the influence of post surface design and luting system on bond strength of quartz-fiber-reinforced composite posts (QFRCPs) luted to root canal dentin. MATERIALS AND METHODS: Single-rooted bovine teeth (n = 650) were randomly assigned (13 groups, n = 50), sectioned, endodontically treated, filled, and post space (length 8 mm) prepared. Custom-made plain-surfaced fiber posts (PSXRO) and (both RTD) macroretentive Macro-Lock Post Illusion X-RO (MLXRO) were inserted into the post spaces using six luting systems: Ketac Cem (KC), Fuji Plus (FP), RelyX Unicem, Multilink Primer_Multilink, Sealbond Ultima_CoreCem, and LuxaBond_LuxaCore Z. As control, a titanium post was cemented with KC. After water storage (24 h, 37 degrees C), pull-out test was performed, followed by failure mode assessment. Bond strength was calculated in MPa and analyzed using anova, Dunnett-T3-test, and Student's t-test with Bonferroni correction. RESULTS: Post design and luting system significantly influenced the bond strength [MPa] (P < 0.05). Compared with the control 4.3 (1.5), all test groups exhibited higher bond strengths (P < 0.05), except for group PSXRO/KC 4.2 (1.0). The remaining bond strengths were PSXRO: FP 8.6 (1.5), RelyX Unicem 10.4 (3.4), Multilink Primer_Multilink 12.7 (3.0), SealBond Ultima_CoreCem 12.7 (3.0), LuxaBond_LuxaCore Z 15.7 (2.5), and MLXRO: KC 7.2 (2.2), FP 13.4 (2.5), RelyX Unicem 9.2 (2.9), Multilink Primer_Multilink 12.5 (4.5), SealBond Ultima_CoreCem 13.7 (4.6), LuxaBond_LuxaCore Z 20.6 (2.2). The bond strengths of MLXRO were higher than those of PSXRO when luted with KC, FP, and LuxaBond_LuxaCore Z (P < 0.05). CONCLUSION: The post surface design and luting system selection influenced the bond strength of conventionally and adhesively luted QFRCPs to bovine root canal dentin. PMID- 24476379 TI - MRM for the verification of cancer biomarker proteins: recent applications to human plasma and serum. AB - Accurate cancer biomarkers are needed for early detection, disease classification, prediction of therapeutic response and monitoring treatment. While there appears to be no shortage of candidate biomarker proteins, a major bottleneck in the biomarker pipeline continues to be their verification by enzyme linked immunosorbent assays. Multiple reaction monitoring (MRM), also known as selected reaction monitoring, is a targeted mass spectrometry approach to protein quantitation and is emerging to bridge the gap between biomarker discovery and clinical validation. Highly multiplexed MRM assays are readily configured and enable simultaneous verification of large numbers of candidates facilitating the development of biomarker panels which can increase specificity. This review focuses on recent applications of MRM to the analysis of plasma and serum from cancer patients for biomarker verification. The current status of this approach is discussed along with future directions for targeted mass spectrometry in clinical biomarker validation. PMID- 24476380 TI - Uterine leiomyoma: understanding the impact of symptoms on womens' lives. AB - BACKGROUND: Most women report negative experience about the symptoms of uterine leiomyoma (UL) in their lives, such as abnormal uterine bleeding and pelvic pain. Many studies have been conducted about efficacy of UL treatment, but little research has been performed about womens health related quality of life (HRQL). METHODS: This is a semi-structured, descriptive, observational, qualitative study that was performed during eight months. Focus group (FG) interviews were performed with women attending at a tertiary hospital in Brazil, who were consecutively included in the study. Seventy women with symptomatic UL were recruited to this study. FG duration was one hour with mediators with 5-6 women at each group. Collected data from discussions was processed according to thematic analysis and stored at a qualitative software. RESULTS: Women were negatively influenced by the presence of symptomatic UL. The major themes that were noticed during analysis were: beliefs and attitudes towards UL; limitation to social and professional activities; sensation of fear/unfairness/discouragement towards the symptoms and adverse effects during treatment with GnRH analogs. CONCLUSIONS: Symptomatic UL has a negative impact on womens HRQL. Health providers should consider such impact when counseling women on their treatment options, since it may have an important influence in these patients' decision-making process. While current pharmacological treatments may improve disease specific outcomes, such as bleeding intensity and tumor volume, they fail on actually improving quality of life. PMID- 24476381 TI - Nursing personnel's attitudes towards fever and antipyresis of adult patients: cross-sectional survey. AB - AIMS AND OBJECTIVES: To investigate the attitudes of nurses caring for hospitalised adult patients towards fever and antipyresis and to identify the predictors of these attitudes. BACKGROUND: Fever is a host defence mechanism, whose harmful effects are limited to specific patients. Findings about antipyretic treatment have further challenged the need for routine or aggressive fever suppression. Unfortunately, nurses continue to be fever phobic, while their attitudes towards fever and antipyresis considerably affect antipyretic practice. DESIGN: Prospective, cross-sectional, multicentre survey. METHODS: A convenience sample of registered and assistant nurses employed in surgical/medical wards and intensive care units of nine Greek hospitals was enrolled. The developed questionnaire included 10 multiple-choice, knowledge-evaluating items about fever and antipyresis, 10 Likert-type attitude-evaluating items towards fever and 10 towards antipyresis. Multiple linear regression analysis was used to identify the predictors of attitudes towards fever and antipyresis. RESULTS: The attitudes of the 458 participants were found to be relatively positive towards both fever and antipyresis. Lower fever/antipyresis knowledge score predicted both negative attitude towards fever (p = 0.001) and positive attitude towards antipyresis (p < 0.001), while longer professional experience predicted positive attitude towards antipyresis (p = 0.002). CONCLUSIONS: Advancing nurses' evidence-based knowledge about fever and antipyresis is expected to limit their tendency to overtreat fever and favour fever care based on the assessment of actual patient demands. RELEVANCE TO CLINICAL PRACTICE: These findings highlight the need for continuing education programmes to eliminate fever phobia and improve nurses' competency for individualised fever care. PMID- 24476382 TI - Representing how rabbits quack and competitors act: limits on preschoolers' efficient ability to track perspective. AB - This study investigated whether humans have two mind-reading systems whereby the efficient system, unlike the flexible system, is naturally limited. There were two experiments and the first included adults as well as children (3- to 4-year olds; total N = 128). In Experiment 1, all groups efficiently gazed in anticipation of an agent's beliefs about object location but not object identity (an ambiguous figure). In Experiment 2, children showed limits in anticipating a competitive agent's action in terms of his perspective on what is desirable. Flexibility in verbally predicting agents' actions across contexts developed with age. Convergence on signature limits across different ages and methods suggests that indirect anticipations involve minimal mind reading, whereas direct predictions tap a refined understanding of perspective. PMID- 24476383 TI - Highly correlated electronic structure calculations of the He-C3 van der Waals complex and collision-induced rotational transitions of C3. AB - An accurate 2D ab initio potential energy surface of the He-C3 collisional system is calculated using the supermolecular coupled-cluster method with up to perturbative quadruple excitations, CCSDT(Q). This interaction potential is then incorporated in full close-coupling calculations of rotational excitation/de excitation cross sections in He + C3 collisions for rotational levels j = 0, 2, ..., 10 and collision energies up to 1000 cm(-1). Corresponding rate coefficients are reported for temperature between 1 and 100 K. Results are found to be in excellent agreement with available theoretical data that were restricted to the temperature range of 5-15 K. Implications of the computed rate coefficients to astrophysical models of C3 and carbon clusters in interstellar and circumstellar environments are discussed. PMID- 24476384 TI - A multicenter study of the attitude of secondary school teachers toward solid organ donation and transplantation in the southeast of Spain. AB - BACKGROUND: Teachers play a fundamental role in providing information to adolescents and could influence their attitudes. OBJECTIVES: To analyze the attitude of teachers toward organ donation and the concept of brain death (BD); the psychosocial variables related to attitude; and the information provided to pupils. METHODS: A multicenter study was carried out using a random sample of secondary school teaching staff from 10 schools (n = 327) in the southeast of Spain. Attitude toward organ donation was assessed using a validated questionnaire that was self-administered and completed anonymously. RESULTS: The questionnaire completion rate was 88% (n = 288), with 75% (n = 215) in favor of organ donation, 23% had doubts, and 2% were not in favor. Regarding the knowledge of BD, 62% (n = 179) accepted that this meant a person's death. The variables associated with a more favorable attitude included conversations with family and friends (p < 0.05); a partner's favorable opinion (OR 3.194); knowledge of the concept of BD (p = 0.006); being a blood donor (OR 8.264); and a favorable attitude toward autopsy (OR 4.716). Teachers provided information about organ donation to pupils in 16% of cases (n = 47). CONCLUSIONS: Seventy-five percent of teachers are in favor of organ donation. Their attitude is affected by psychosocial factors. PMID- 24476385 TI - Influence of the ABCG2 gout risk 141 K allele on urate metabolism during a fructose challenge. AB - INTRODUCTION: Both genetic variation in ATP-binding cassette sub-family G member 2 (ABCG2) and intake of fructose-containing beverages are major risk factors for hyperuricemia and gout. This study aimed to test the hypothesis that the ABCG2 gout risk allele 141 K promotes the hyperuricaemic response to fructose loading. METHODS: Healthy volunteers (n = 74) provided serum and urine samples immediately before and 30, 60, 120 and 180 minutes after ingesting a 64 g fructose solution. Data were analyzed based on the presence or absence of the ABCG2 141 K gout risk allele. RESULTS: The 141 K risk allele was present in 23 participants (31%). Overall, serum urate (SU) concentrations during the fructose load were similar in those with and without the 141 K allele (PSNP = 0.15). However, the 141 K allele was associated with a smaller increase in SU following fructose intake (PSNP <0.0001). Those with the 141 K allele also had a smaller increase in serum glucose following the fructose load (PSNP = 0.002). Higher fractional excretion of uric acid (FEUA) at baseline and throughout the fructose load was observed in those with the 141 K risk allele (PSNP <0.0001). However, the change in FEUA in response to fructose was not different in those with and without the 141 K risk allele (PSNP = 0.39). The 141 K allele effects on serum urate and glucose were more pronounced in Polynesian participants and in those with a body mass index >=25 kg/m2. CONCLUSIONS: In contrast to the predicted responses for a hyperuricemia/gout risk allele, the 141 K allele is associated with smaller increases in SU and higher FEUA following a fructose load. The results suggest that ABCG2 interacts with extra-renal metabolic pathways in a complex manner to regulate SU and gout risk. CLINICAL TRIALS REGISTRATION: The study was registered by the Australian Clinical Trials Registry (ACTRN12610001036000). PMID- 24476386 TI - Epidural analgesia and severe perineal tears: a literature review and large cohort study. AB - OBJECTIVE: Our objectives were to study the association between epidural analgesia and risk of severe perineal tears (SPT), and identify additional risk factors for SPT. METHODS: We conducted a historical cohort study of women with term delivery between 2006 and 2011. Inclusion criteria were an uncomplicated singleton pregnancy, cephalic presentation and vaginal delivery. Multivariate logistic regression models were constructed to study the association between epidural analgesia and SPT, controlling for potential confounders. Additional models studied the association between prolonged second stage and instrumental labor and SPT. RESULTS: During the study period, 61,308 eligible women gave birth, 31,631 (51.6%) of whom received epidural analgesia. SPT occurred in 0.3% of births. Deliveries with epidural had significantly higher rates of primiparity, induction and augmentation of labor, prolonged second stage of labor, instrumental births and midline episiotomies. The univariate analysis showed a significant association between the use of epidural and SPT (OR: 1.78, 95% CI: 1.34-2.36); however, this association disappeared when parity was introduced (OR: 0.95, 95% CI: 0.69-1.29). Instrumental deliveries and prolonged second stage of labor were both strongly associated with SPT (ORs of 1.82 and 1.77) CONCLUSIONS: Epidural analgesia was not associated with SPT once confounding factors were controlled for. PMID- 24476387 TI - Ligand engineering of polymer nanocomposites: from the simple to the complex. AB - One key to optimizing the performance of polymer nanocomposites for high-tech applications is surface ligand engineering of the nanofiller, which has been used to either tune the nanofiller morphology or introduce additional functionalities. Ligand engineering can be relatively simple such as a single population of short molecules on the nanoparticle surface designed for matrix compatibility. It can also have complexity that includes bimodal (or multimodal) populations of ligands that enable relatively independent control of enthalpic and entropic interactions between the nanofiller and matrix as well as introduce additional functionality and dynamic control. In this Spotlight on Applications, we provide a brief review into the use of brush ligands to tune the thermodynamic interactions between nanofiller and matrix and then focus on the potential for surface ligand engineering to create exciting nanocomposites properties for optoelectronic and dielectric applications. PMID- 24476390 TI - All-cause mortality rate in patients with idiopathic pulmonary fibrosis. Implications for the design and execution of clinical trials. AB - RATIONALE: FVC has emerged as a standard primary endpoint in clinical trials evaluating novel therapies for patients with idiopathic pulmonary fibrosis (IPF). However, it has recently been proposed that all-cause mortality or a composite comprised of all-cause mortality and all-cause nonelective hospitalization be adopted as the standard primary endpoint for IPF clinical trials. OBJECTIVES: To conduct a comprehensive evaluation of mortality in three phase 3 clinical trials and evaluate the feasibility of mortality trials in patients with IPF. METHODS: The study population included 622 patients randomized to placebo in the CAPACITY studies evaluating pirfenidone (n = 347) or the INSPIRE study evaluating interferon-gamma1b (n = 275). The Kaplan-Meier estimate of 2-year survival was fit to the exponential distribution and used to calculate sample size requirements for a mortality study with 90% power to detect a 25% reduction in all-cause mortality with a two-sided alpha of 0.05. Modeling analyses were used to assess the effects of selected variables on sample size and study design. MEASUREMENTS AND MAIN RESULTS: A total of 73 deaths occurred during the period of observation (mean duration of follow-up, 80.1 wk). The all-cause mortality rate was 6.6% at 1 year and 13.7% at 2 years. Based on the observed 2-year mortality rate, a total of 508 events would be required to detect a significant treatment benefit in a two-arm trial with 90% power to detect a 25% reduction in all-cause mortality. The estimated sample size for a trial enrolled over 3 years with a maximum follow-up period of 5 years is 2,582 patients. CONCLUSIONS: The all-cause mortality rate is relatively low in patients with IPF with mild to moderate impairment in lung function. Accordingly, the necessary size, duration, and cost of all-cause mortality trials in this population are substantial and likely prohibitive. PMID- 24476391 TI - Discovery of a novel class of potent HCV NS4B inhibitors: SAR studies on piperazinone derivatives. AB - HTS screening identified compound 2a (piperazinone derivative) as a low micromolar HCV genotype 1 (GT-1) inhibitor. Resistance mapping studies suggested that this piperazinone chemotype targets the HCV nonstructural protein NS4B. Extensive SAR studies were performed around 2a and the amide function and the C 3/C-6 cis stereochemistry of the piperazinone core were essential for HCV activity. A 10-fold increase in GT-1 potency was observed when the chiral phenylcyclopropyl amide side chain of 2a was replaced with p fluorophenylisoxazole-carbonyl moiety (67). Replacing the C-6 nonpolar hydrophobic moiety of 67 with a phenyl moiety (95) did not diminish the GT-1 potency. A heterocyclic thiophene moiety (103) and an isoxazole moiety (108) were incorporated as isosteric replacements for the C-6 phenyl moiety (95), resulting in significant improvement in GT-1b and 1a potency. However, the piperazonone class of compounds lacks GT-2 activity and, consequently, were not pursued further into development. PMID- 24476388 TI - Matrix-assisted laser desorption ionization-time of flight mass spectrometry for fast and accurate identification of Pseudallescheria/Scedosporium species. AB - An increasing number of infections due to Pseudallescheria/Scedosporium species has been reported during the past decades, both in immunocompromised and immunocompetent patients. Additionally, these fungi are now recognized worldwide as common agents of fungal colonization of the airways in cystic fibrosis patients, which represents a risk factor for disseminated infections after lung transplantation. Currently six species are described within the Pseudallescheria/Scedosporium genus, including Scedosporium prolificans and species of the Pseudallescheria/Scedosporium apiospermum complex (i.e. S. apiospermum sensu stricto, Pseudallescheria boydii, Scedosporium aurantiacum, Pseudallescheria minutispora and Scedosporium dehoogii). Precise identification of clinical isolates at the species level is required because these species differ in their antifungal drug susceptibility patterns. Matrix-assisted laser desorption ionization (MALDI)-time of flight (TOF)/mass spectrometry (MS) is a powerful tool to rapidly identify moulds at the species level. We investigated the potential of this technology to discriminate Pseudallescheria/Scedosporium species. Forty-seven reference strains were used to build a reference database library. Profiles from 3-, 5- and 7-day-old cultures of each reference strain were analysed to identify species-specific discriminating profiles. The database was tested for accuracy using a set of 64 clinical or environmental isolates previously identified by multilocus sequencing. All isolates were unequivocally identified at the species level by MALDI-TOF/MS. Our results, obtained using a simple protocol, without prior protein extraction or standardization of the culture, demonstrate that MALDI-TOF/MS is a powerful tool for rapid identification of Pseudallescheria/Scedosporium species that cannot be currently identified by morphological examination in the clinical setting. PMID- 24476393 TI - The fulfilment of knowledge expectations during the perioperative period of patients undergoing knee arthroplasty -- a Nordic perspective. AB - AIMS AND OBJECTIVES: To describe the possible differences between knowledge expectations and received knowledge of patients undergoing elective knee arthroplasty in Iceland, Sweden and Finland and also to determine the relationship between such a difference and both background factors and patient satisfaction with care. BACKGROUND: Knee arthroplasty is a fast-growing and a successful treatment for patients with osteoarthritis. Patient education can improve surgery outcomes, but it remains unknown what knowledge patients expect to receive and actually acquire during the perioperative period and what factors are related to that experience. DESIGN: Descriptive, prospective survey. METHODS: In total, 290 patients answered questionnaires about their expectations (Knowledge Expectations of hospital patients - scale) before surgery and about received knowledge (Received Knowledge of hospital patients - scale) and satisfaction with hospital care (Patient Satisfaction Scale) at discharge. Sociodemographics, clinical information, accessibility to knowledge from healthcare providers (Access to Knowledge Scale), and preferences for information and behavioural control (Krantz Health Opinion Survey) were collected as background data. RESULTS: Patients' knowledge expectations were higher (mean 3.6, SD 0.4) than their perception of received knowledge (mean 3.0, SD 0.7). Multiple linear regression analysis showed that access to knowledge, information preferences and work experience within health- or social care explained 33% (R2) of the variation in the difference between received and expected knowledge. Patients reported high satisfaction with their care except regarding how their family was involved. CONCLUSION: Patients undergoing knee arthroplasty receive less knowledge than they expect, and individual factors and communication with healthcare providers during hospitalisation are related to their experience. The content of patient education and family involvement should be considered in future care. RELEVANCE TO CLINICAL PRACTICE: The results strengthen the knowledge base on the educational needs of knee arthroplasty patients and can be used to develop and test new interventions. PMID- 24476392 TI - A step closer to membrane protein multiplexed nanoarrays using biotin-doped polypyrrole. AB - Whether for fundamental biological research or for diagnostic and drug discovery applications, protein micro- and nanoarrays are attractive technologies because of their low sample consumption, high-throughput, and multiplexing capabilities. However, the arraying platforms developed so far are still not able to handle membrane proteins, and specific methods to selectively immobilize these hydrophobic and fragile molecules are needed to understand their function and structural complexity. Here we integrate two technologies, electropolymerization and amphipols, to demonstrate the electrically addressable functionalization of micro- and nanosurfaces with membrane proteins. Gold surfaces are selectively modified by electrogeneration of a polymeric film in the presence of biotin, where avidin conjugates can then be selectively immobilized. The method is successfully applied to the preparation of protein-multiplexed arrays by sequential electropolymerization and biomolecular functionalization steps. The surface density of the proteins bound to the electrodes can be easily tuned by adjusting the amount of biotin deposited during electropolymerization. Amphipols are specially designed amphipathic polymers that provide a straightforward method to stabilize and add functionalities to membrane proteins. Exploiting the strong affinity of biotin for streptavidin, we anchor distinct membrane proteins onto different electrodes via a biotin-tagged amphipol. Antibody-recognition events demonstrate that the proteins are stably immobilized and that the electrodeposition of polypyrrole films bearing biotin units is compatible with the protein-binding activity. Since polypyrrole films show good conductivity properties, the platform described here is particularly well suited to prepare electronically transduced bionanosensors. PMID- 24476394 TI - Maternal request for caesarean section: audit of a care pathway. AB - This report is based on an audit of the delivery outcome of a specific care pathway for women who had made a maternal request for caesarean section (MRCS). The study took place in a UK inner city National Health Service maternity unit with 6,000 births per year. All 31 multiparous and 16 nulliparous women on the pathway were included. All of the former group had delivered vaginally, all reported having experienced their previous birth as traumatic, and all subsequently delivered vaginally. Of the 16 nulliparous women, six delivered by planned caesarean section; four delivered vaginally; four had an instrumental delivery and two had an emergency caesarean section. A designated multidisciplinary care pathway that incorporates education and support may have the potential to help more women to achieve a normal delivery. More research is needed to assess its potential for reducing unnecessary caesarean deliveries and for improving user experience. PMID- 24476395 TI - TORCH screening in pregnancy. Where are we now? An audit of use in a tertiary level centre. AB - This audit was performed in the obstetrics and gynaecology department of a tertiary referral hospital, to investigate the use and results of TORCH screening. St Michael's Hospital delivers approximately 6,000 women from South Bristol a year and receives tertiary referrals from the South West of England and South Wales. It was found that 739 patients over a 6-year period from April 2006 to January 2012 underwent testing. The majority's indication (21%) was polyhydramnios. Three patients had evidence of primary CMV infection in pregnancy on serology, two for fetal indications (polyhydramnios and echogenic bowel) and one following a miscarriage. There were no confirmed cases of gestational toxoplasma or rubella. Routine testing for toxoplasma and rubella infection as part of the TORCH screening in cases of fetal or obstetric abnormality should thus be discontinued in our population. PMID- 24476396 TI - Disseminated peritoneal tuberculosis mimicking advanced ovarian cancer. AB - The objective was to evaluate the clinical and radiological features of peritoneal tuberculosis (PTB) that resembled advanced ovarian malignancy. A retrospective review of all patients diagnosed with PTB over a period of 10 years was made. The data included: age, presenting symptom(s), CA125 level, microbiological, histological and cytological studies of the surgical specimens. The radiological and operative findings were also reviewed. A total of 16 patients were identified. The median age was 29.5 years (range 13-65 years). The median CA125 level was 319 U/ml (range 45-1,072 U/ml). The most common symptoms were abdominal distention and pain in 13 patients. Imaging studies showed ascites in all patients. Six patients had laparotomy and 10 had laparoscopy procedure. All patients received anti-tuberculosis treatment and had complete cure. A high index of suspicion of PTB is important to avoid unnecessary extended surgery in relatively young patients with nonspecific clinical features. PMID- 24476397 TI - A case of acute aortic dissection in a woman with Marfan syndrome at 29 weeks' gestation. PMID- 24476398 TI - Analysis of follicular fluid total phospholipids in women undergoing in-vitro fertilisation. AB - Follicular fluid (FF) samples were obtained from 100 patients referred to the University Hospital. A total of 79 subjects underwent IVF and the remaining 21 underwent ICSI. The levels of apoA-I and total phospholipid were measured using turbidometric and colorimetric phosphorus assays, respectively. Correlation analysis showed a significant inverse association of total phospholipid in FF with fertilisation ratio (r = -0.24, p = 0.04). Furthermore, the ratio of phospholipid/apoA-I in patients with a percentage of fertilised oocytes <= 50% was significantly higher (> 2.5%, p < 0.05) than in those with higher percentages of fertilised oocytes. The amounts of phospholipid and phospholipid/apoA-I ratio in FF were associated negatively to the percentage of oocyte fertilisation. Therefore, the change in the phospholipid and phospholipid/apoA-I ratio of FF might be regarded as indicators of female fertility. PMID- 24476399 TI - Preoperative diagnosis of a uterine lipoleiomyoma using transvaginal ultrasound: a case report of an unusual entity. PMID- 24476400 TI - Hypoplastic uterus: the importance of gynaecological ultrasound in its diagnosis- case report and review of the literature. PMID- 24476402 TI - Health Manpower Planning-an Impossible Dream? PMID- 24476403 TI - How to: Make a Presentation at a Scientific Meeting. AB - Giving a scientific paper is an important hurdle in a young lecturer's career. The practical advice offered here should help the novice avoid some of the major pitfalls. PMID- 24476401 TI - Impact of psm-mec in the mobile genetic element on the clinical characteristics and outcome of SCCmec-II methicillin-resistant Staphylococcus aureus bacteraemia in Japan. AB - Over-expression of alpha-phenol-soluble modulins (PSMs) results in high virulence of community-associated methicillin-resistant Staphylococcus aureus (MRSA). The psm-mec gene, located in the mobile genetic element SCCmec-II, suppresses PSMalphas production. Fifty-two patients with MRSA bacteraemia were enrolled. MRSA isolates were evaluated with regard to the psm-mec gene sequence, bacterial virulence, and the minimum inhibitory concentration (MIC) of vancomycin and teicoplanin. Fifty-one MRSA isolates were classified as SCCmec-II, and 10 had one point mutation in the psm-mec promoter. We compared clinical characteristics and outcomes between mutant MRSA and wild-type MRSA. Production of PSMalpha3 in mutant MRSA was significantly increased, but biofilm formation was suppressed. Wild-type MRSA caused more catheter-related bloodstream infections (30/41 vs. 3/10, p 0.0028), whereas mutant MRSA formed more deep abscesses (4/10 vs. 3/41, p 0.035). Bacteraemia caused by mutant MRSA was associated with reduced 30-day mortality (1/10 vs. 13/41, p 0.25), although this difference was not significant. The MIC90 of teicoplanin was higher for wild-type MRSA (1.5 mg/L vs. 1 mg/L), but the MIC of vancomycin was not different between the two groups. The 30-day mortality of MRSA with a high MIC of teicoplanin (>=1.5 mg/L) was higher than that of strains with a lower MIC (<=0.75 mg/L) (6/10 vs. 6/33, p 0.017). Mutation of the psm-mec promoter contributes to virulence of SCCmec-II MRSA, and the product of psm-mec may determine the clinical characteristics of bacteraemia caused by SCCmec-II MRSA, but it does not affect mortality. PMID- 24476404 TI - How to: Produce a Good Poster. AB - 'Poster sessions' have become a widespread feature of medical meetings. Here, an experienced medical artist gives his guidelines for producing a poster that provides clear information in an attractive and easy-to-assemble format. PMID- 24476405 TI - The way we teach: physiology. AB - A vocational training course in physiology is described in which physiology and biochemistry are interrelated, and students' skills of observation, deduction, and interpretation of data are developed in practicals and problem-solving exercises. Considerable emphasis is placed on self-directed learning, with appropriate back-up in practicals and tutorials. The self-learning courses are tightly structured. Since the course was introduced, the level of student performance has been raised. PMID- 24476406 TI - The integrated curriculum: experiences, achievements and problems. AB - In this article the aims, experiences and achievements of vertical and horizontal integration in undergraduate medical education are considered and reviewed, and some problems are identified. It is concluded that a clearer definition of integration would now be helpful. PMID- 24476407 TI - A Conceptual, Practice-orientated Biometrics Course for Medical Students. AB - In many medical schools biometrics has traditionally been taught with an abstract, mathematical emphasis. Consequently, the medical student usually does not relate the course content to his future practice as a physician, learns only to a limited degree, and develops a distaste for research methods and statistics. This unfavourable early exposure often produces a physician with little or no skill in assessing the merits of his professional literature in terms of research and statistical credibility. I therefore designed a course which emphasized research and statistical concepts, avoided mathematical explanations, stressed the relationship of research and statistics to medical practice, and used effective teaching principles. The course was first offered in the autumn of 1982 to second-year medical students at the Wright State University School of Medicine. PMID- 24476411 TI - Biology and proteomics of extracellular vesicles: harnessing their clinical potential. AB - Extracellular membrane vesicles have recently emerged as versatile mediators of intercellular communication, pathogenesis, drug and gene delivery and as potentially rich reservoirs of clinical biomarkers. Channeling their properties toward patient care is dependent on technological progress in approaches used for their analysis and molecular profiling. PMID- 24476412 TI - Outcomes of Clostridium difficile infection in recipients of solid abdominal organ transplants. AB - Knowledge of outcomes of Clostridium difficile infection (CDI) in solid organ transplant (SOT) recipients is limited. To evaluate this population, we undertook a retrospective cohort study of all recipients of kidney and liver transplants diagnosed with CDI at a single center over 14 yr. Data pertaining to all episodes of CDI were collected. Multivariate analysis using logistic regression was performed to determine independent predictors of clinical cure. Overall, 170 patients developed 215 episodes of CDI. Among these patients, 162 episodes (75%) were cured, and in 103 episodes (48%), patients were cured within 14 d. In a multivariate analysis, lack of clinical cure at 14 d was predicted by recurrent episode (0.21, 95% CI 0.06-0.72, p = 0.0128), treatment with vancomycin (OR 0.27, 95% CI 0.1-0.74, p = 0.011), vasopressor support (OR 0.23, 95% CI 0.07-0.76, p = 0.0161), and CDI before the year 2004 (OR 0.44, 95% CI 0.2-0.98, p = 0.0446). The latter three factors are likely markers for severity of illness. In this cohort, 13 patients (8%) died during hospitalization, and 49 patients (29%) died within one yr. No deaths were attributed to CDI. Recurrent episode was a major predictor of treatment failure, suggesting that research into development of therapeutic options for recurrent disease is needed. PMID- 24476413 TI - Reference intervals for the echocardiographic measurements of the right heart in children and adolescents: a systematic review. AB - BACKGROUND: Transthoracic echocardiography is the primary imaging modality for the diagnosis of right ventricular (RV) involvement in congenital and acquired heart diseases. There is increasing recognition of the contribution of RV dysfunction in heart diseases affecting children and adolescents, but there is insufficient information on reference intervals for the echocardiographic measurements of the right heart in children and adolescents that represent all the continental populations of the world. OBJECTIVE: The aim of this systematic review was to collate, from published studies, normative data for echocardiographic evaluation of the right heart in children and adolescents, and to identify gaps in knowledge in this field especially with respect to sub Saharan Africans. METHODS: We performed a systematic literature search to identify studies of reference intervals for right heart measurements as determined by transthoracic echocardiography in healthy children and adolescents of school-going age. Articles were retrieved from electronic databases with a combination of search terms from the earliest date available until May 2013. RESULTS: Reference data were available for a broad range of variables. Fifty one studies out of 3096 publications were included. The sample sizes of the reference populations ranged from 13 to 2036 with ages varying from 5 to 21 years. We identified areas lacking sufficient reference data. These included reference data for determining right atrial size, tricuspid valve area, RV dimensions and areas, the RV % fractional area change, pulmonary artery pressure gradients and the right-sided haemodynamics, including the inferior vena cava dimensions and collapsibility. There were no data for sub-Saharan African children and adolescents. CONCLUSION: Reliable reference data are lacking for important echocardiographic measurements of the RV in children and adolescents, especially for sub-Saharan Africans. PMID- 24476414 TI - Time to presentation, pattern and immediate health effects of alleged child sexual abuse at two tertiary hospitals in Addis Ababa, Ethiopia. AB - BACKGROUND: Children are vulnerable to abuse and violence because their level of development makes them unable to protect themselves. Such adversities during early childhood may have a negative impact on the future lives of the victims.This study was done to determine the delay to hospital presentation, clinical manifestations and immediate health effects of child sexual abuse in two tertiary care hospitals in Ethiopia. METHODS: We reviewed records of all cases of child sexual and physical abuse between January 2011 and December 2012. Bivariate and multivariate logistic regression models were used to test the presence and strength of association between time to reporting to hospital and, age and sex of the victim, place of residence and relation of the victim to the perpetrator. Odds ratio and 95% confidence intervals were generated. Significance was taken as p-value < 0.05. RESULTS: During the study period, we identified records of 275 children who were seen for alleged physical and sexual abuse; they accounted for 0.6% of the outpatient department (OPD) visits. The majority of the victims were cases of sexual abuse (97.3%) and most of them were female (75.7%). The mean age of the victims was 9.5 years (standard deviation (SD) = 4.2 years). The majority of the abusers were known to the victim (73.0%) and male (98.8%). Neighbors (38.95%), teachers (7.9%) and relatives (13.4%) were the most commonly reported perpetrators. The median length of time taken to present to hospital after the abuse incident was 4 days (range = 2 hours to 3 years). Male victims were 2.4 times more likely to have a delay of greater than one week to present to hospital (Adjusted Odds Ratio (AOR), 2.40; 95% Confidence interval (CI), 1.34-4.31; P value = 0.002). Sexual abuse was associated with various immediate health effects, for example, hymenal tear, urinary tract infection and, perineal laceration or tear. CONCLUSION: Presentation for care was often delayed. Male sex was independently associated with a delayed presentation to care. We recommend that further studies are carried out to identify the reasons for delay to reporting and design mechanisms to address them. PMID- 24476415 TI - A 2D DNA lattice as an ultrasensitive detector for beta radiations. AB - There is growing demand for the development of efficient ultrasensitive radiation detectors to monitor the doses administered to individuals during therapeutic nuclear medicine which is often based on radiopharmaceuticals, especially those involving beta emitters. Recently biological materials are used in sensors in the nanobio disciplines due to their abilities to detect specific target materials or sites. Artificially designed two-dimensional (2D) DNA lattices grown on a substrate were analyzed after exposure to pure beta emitters, (90)Sr-(90)Y. We studied the Raman spectra and reflected intensities of DNA lattices at various distances from the source with different exposure times. Although beta particles have very low linear energy transfer values, the significant physical and chemical changes observed throughout the extremely thin, ~0.6 nm, DNA lattices suggested the feasibility of using them to develop ultrasensitive detectors of beta radiations. PMID- 24476416 TI - Good correlation between changes in objective and subjective signs of inflammation in patients with short- but not long duration of axial spondyloarthritis treated with tumor necrosis factor-blockers. AB - INTRODUCTION: The aim of this study was to investigate the influence of symptom duration on treatment response and on the correlation between improvements in patient reported outcomes (PRO) and objective inflammation in patients with axial spondylarthritis (SpA) treated with etanercept (ETA) or adalimumab (ADA). METHODS: Data from 112 patients with axial SpA originally enrolled in two randomized controlled clinical trials were pooled and analyzed after one year of treatment with ETA (n = 66) or ADA (n = 46). Patients with <4 years and >=4 years of disease were compared for improvement in Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Ankylosing Spondylitis Disease Activity Score (ASDAS), C-reactive protein (CRP) and magnetic resonance imaging (MRI) score for sacroiliac joints (SIJ). RESULTS: Patients with <4 years of disease showed a significantly better improvement than longer diseased patients in BASDAI (3.2 (95% confidence interval (CI): 2.7 to 3.7) vs. 1.7 (1.1 to 2.2)), BASFI, BASMI and ASDAS (1.6 (1.4 to 1.8) vs. 0.9 (0.7 to 1.1)). The change in BASDAI showed a significant correlation with the change in SIJ score (Spearman's rank correlation coefficient (rho) = 0.37, P = 0.01) and the change in CRP (rho = 0.45, P = 0.001) in patients with <4 years of disease. For long diseased patients this correlation was poor and did not achieve statistical significance (rho = 0.13, P = 0.46; rho = 0.22, P = 0.13 respectively). CONCLUSION: The low correlation between change of PROs and change of objective signs of inflammation seen in axial SpA patients with longer symptom duration treated with tumor necrosis factor-blocker seems to indicate that inflammation is not the only cause of the patients' symptoms, while inflammation seems to be the major cause in short diseased patients. TRIAL REGISTRATION: Clinical Trials.gov NCT00844142 (Trial 1); NCT00235105 (Trial 2). PMID- 24476417 TI - Nearly 50 years in the making: defining the catalytic mechanism of the multifunctional enzyme, pyruvate carboxylase. AB - Numerous steady-state kinetic studies have examined the complex catalytic reaction mechanism of the multifunctional enzyme, pyruvate carboxylase (PC). Through initial velocity, product inhibition, isotopic exchange and alternate substrate experiments, early investigators established that PC catalyzes the MgATP-dependent carboxylation of pyruvate by HCO3 (-) through a nonclassical sequential Bi Bi Uni Uni reaction mechanism. This review surveys previous steady state kinetic investigations of PC and evaluates the proposed hypotheses concerning the overall catalytic mechanism, nonlinear kinetics and active site coupling in the context of recent structural and mutagenic analyses of this multifunctional enzyme. The determination several PC holoenzyme structures have aided in corroborating the proposed molecular mechanisms by which catalysis occurs and established the inextricable link between the dynamic protein motions and complex kinetic mechanisms associated with PC activity. Unexpectedly, the conclusions drawn from these early steady-state kinetic investigations have consistently proven to be in fundamental agreement with our current understanding of PC catalysis, which is a testament to the overarching sophistication of the methods pioneered by Michaelis and Menten and further developed by Northrop, Cleland and others. PMID- 24476419 TI - Physical influences on stem cells. PMID- 24476418 TI - Azithromycin may antagonize inhaled tobramycin when targeting Pseudomonas aeruginosa in cystic fibrosis. AB - RATIONALE: Recent studies of inhaled tobramycin in subjects with cystic fibrosis (CF) find less clinical improvement than previously observed. Nonhuman data suggest that in some strains of Pseudomonas aeruginosa, azithromycin can antagonize tobramycin. OBJECTIVES: We tested the hypothesis that concomitant azithromycin use correlates with less improvement in key outcome measures in subjects receiving inhaled tobramycin while not affecting those receiving a comparative, nonaminoglycoside inhaled antibiotic. METHODS: We studied a cohort of 263 subjects with CF enrolled in a recent clinical trial comparing inhaled tobramycin with aztreonam lysine. We performed a secondary analysis to examine key clinical and microbiologic outcomes based on concomitant, chronic azithromycin use at enrollment. MEASUREMENTS AND MAIN RESULTS: The cohort randomized to inhaled tobramycin and reporting azithromycin use showed a significant decrease in the percent predicted FEV1 after one and three courses of inhaled tobramycin when compared with those not reporting azithromycin use (28 d: -0.51 vs. 3.43%, P < 0.01; 140 d: -1.87 vs. 6.07%, P < 0.01). Combined azithromycin and inhaled tobramycin use was also associated with earlier need for additional antibiotics, lesser improvement in disease-related quality of life, and a trend toward less reduction in sputum P. aeruginosa density. Subjects randomized to inhaled aztreonam lysine had significantly greater improvement in these outcome measures, which were unaffected by concomitant azithromycin use. Outcomes in those not using azithromycin who received inhaled tobramycin were not significantly different from subjects receiving aztreonam lysine. Azithromycin also antagonized tobramycin but not aztreonam lysine in 40% of P. aeruginosa clinical isolates tested in vitro. CONCLUSIONS: Oral azithromycin may antagonize the therapeutic benefits of inhaled tobramycin in subjects with CF with P. aeruginosa airway infection. PMID- 24476420 TI - Clinical and molecular characterization of Rubinstein-Taybi syndrome patients carrying distinct novel mutations of the EP300 gene. AB - Rubinstein-Taybi syndrome (RSTS) is a rare congenital neurodevelopmental disorder characterized by postnatal growth deficiency, skeletal abnormalities, dysmorphic features and cognitive deficit. Mutations in two genes, CREBBP and EP300, encoding two homologous transcriptional co-activators, have been identified in ~55% and ~3-5% of affected individuals, respectively. To date, only eight EP300 mutated RSTS patients have been described and 12 additional mutations are reported in the database LOVD. In this study, EP300 analysis was performed on 33 CREBBP-negative RSTS patients leading to the identification of six unreported germline EP300 alterations comprising one deletion and five point mutations. All six patients showed a convincing, albeit mild, RSTS phenotype with minor skeletal anomalies, slight cognitive impairment and few major malformations. Beyond the expansion of the RSTS-EP300-mutated cohort, this study indicates that EP300 related RSTS cases occur more frequently than previously thought (~8% vs 3-5%); furthermore, the characterization of novel EP300 mutations in RSTS patients will enhance the clinical practice and genotype-phenotype correlations. PMID- 24476421 TI - Binocular fusion, suppression and diplopia for blurred edges. AB - PURPOSE: (1) To devise a model-based method for estimating the probabilities of binocular fusion, interocular suppression and diplopia from psychophysical judgements, (2) To map out the way fusion, suppression and diplopia vary with binocular disparity and blur of single edges shown to each eye, (3) To compare the binocular interactions found for edges of the same vs opposite contrast polarity. METHODS: Test images were single, horizontal, Gaussian-blurred edges, with blur B = 1-32 min arc, and vertical disparity 0-8.B, shown for 200 ms. In the main experiment, observers reported whether they saw one central edge, one offset edge, or two edges. We argue that the relation between these three response categories and the three perceptual states (fusion, suppression, diplopia) is indirect and likely to be distorted by positional noise and criterion effects, and so we developed a descriptive, probabilistic model to estimate both the perceptual states and the noise/criterion parameters from the data. RESULTS: (1) Using simulated data, we validated the model-based method by showing that it recovered fairly accurately the disparity ranges for fusion and suppression, (2) The disparity range for fusion (Panum's limit) increased greatly with blur, in line with previous studies. The disparity range for suppression was similar to the fusion limit at large blurs, but two or three times the fusion limit at small blurs. This meant that diplopia was much more prevalent at larger blurs, (3) Diplopia was much more frequent when the two edges had opposite contrast polarity. A formal comparison of models indicated that fusion occurs for same, but not opposite, polarities. Probability of suppression was greater for unequal contrasts, and it was always the lower-contrast edge that was suppressed. CONCLUSIONS: Our model-based data analysis offers a useful tool for probing binocular fusion and suppression psychophysically. The disparity range for fusion increased with edge blur but fell short of complete scale-invariance. The disparity range for suppression also increased with blur but was not close to scale-invariance. Single vision occurs through fusion, but also beyond the fusion range, through suppression. Thus suppression can serve as a mechanism for extending single vision to larger disparities, but mainly for sharper edges where the fusion range is small (5-10 min arc). For large blurs the fusion range is so much larger that no such extension may be needed. PMID- 24476422 TI - Risk factors for perinatal death in two different levels of care: a case-control study. AB - BACKGROUND: According to the World Health Organization, there are over 6.3 million perinatal deaths (PND) a year worldwide. Identifying the factors associated with PND is very helpful in building strategies to improve the care provided to mothers and their babies. OBJECTIVE: To investigate the maternal, gestational and neonatal factors associated with PND at two different levels of care. METHODS: Case-control study including 299 PND cases and 1161 infants that survived the early neonatal period (controls) between 2001-2006 in two hospitals at different care levels (secondary and tertiary) located in southeastern Brazil. Correlations between study variables and PND were evaluated by univariate analysis. PND-related variables were included in a multiple logistic regression model, and independent estimates of PND risk were obtained. RESULTS: Although five-minute Apgar score <7, low birthweight and maternal hemorrhage were associated with PND in the secondary care center, no independent risk factors were identified at this level of care. In the tertiary hospital, PND was positively associated with primiparity, male sex, prematurity, low 5-minute Apgar score, and pregnancy complicated by arterial hypertension or intrauterine infection. CONCLUSIONS: Several risk factors positively associated with PND were indentified in the tertiary, but not in the secondary care level hospital. Since most of the risk factors herein identified are modifiable through effective antenatal and intrapartum care, greater attention should be given to preventive strategies. PMID- 24476423 TI - Solid-State NMR investigations of a MgCl2.4(CH3)2CHCH2OH molecular adduct: a peculiar case of reversible equilibrium between two phases. AB - MgCl2.xROH molecular adducts are extensively employed as a support material for Ziegler-Natta polyolefin catalysis. However, their structural properties are not well understood. Recently, we reported on the preparation of an isobutanol adduct, MgCl2.4(CH3)2CHCH2OH (MgiBuOH) ( Dalton Trans. 2012 , 41 , 11311 ), which is very sensitive to the preparation conditions, such as the temperature and refluxing time. For the present study, the structural properties of MgiBuOH adducts prepared under different conditions have been investigated thoroughly by solid-state NMR and nonambient XRD. Formation of two phases has been confirmed, and in situ variable temperature solid-state NMR measurements confirm the coexistence of two phases as well as the oscillation from one to another phase. It is expected that such molecular adducts could have a significant role in organic transformation reactions due to an oscillating structural component. An understanding of phase oscillation with the Mg(2+) ion as the central metal ion might shed some light toward understanding various biological and structural functions. PMID- 24476425 TI - Inflammatory markers in umbilical cord blood from small-for-gestational-age newborns. AB - This study investigates the role of inflammation in intrauterine growth retardation by exploring the levels of inflammatory markers in umbilical cord blood from neonates who were born small-for-gestational-age (SGA) and comparing them to neonates who were born appropriate-for-gestational-age (AGA). Interleukin 6 (IL-6), Tumor necrosis factor-alpha (TNF-alpha) and C-reactive protein (CRP) were measured by standard methods in term or near-term (gestational age >36 weeks) neonates born SGA (n = 45) and a matched group of neonates born AGA (n = 45). Infants exposed to maternal chronic diseases, diabetes or pre-eclampsia were excluded. SGA was defined as two standard derivations below the expected for term and gender. In multivariate regression analyses significant elevation in cord blood concentration of IL-6 was demonstrated in the SGA group (mean 4.56 vs. 2.38, p = 0.002). The results indicate the presence of elevated inflammatory markers in the cord blood from SGA infants compared to AGA infants, and consequently the results suggest an inflammatory component in intrauterine growth restriction (IUGR). PMID- 24476426 TI - Comparison of vapor formation of water at the solid/water interface to colloidal solutions using optically excited gold nanostructures. AB - The phase transformation properties of liquid water to vapor is characterized by optical excitation of the lithographically fabricated single gold nanowrenches and contrasted to the phase transformation properties of gold nanoparticles located and optically excited in a bulk solution system [two and three dimensions]. The 532 nm continuous wave excitation of a single gold nanowrench results in superheating of the water to the spinodal decomposition temperature of 580 +/- 20 K with bubble formation below the spinodal decomposition temperature being a rare event. Between the spinodal decomposition temperature and the boiling point liquid water is trapped into a metastable state because a barrier to vapor nucleation exists that must be overcome before the thermodynamically stable state is realized. The phase transformation for an optically heated single gold nanowrench is different from the phase transformation of optically excited colloidal gold nanoparticles solution where collective heating effects dominates and leads to the boiling of the solution exactly at the boiling point. In the solution case, the optically excited ensemble of nanoparticles collectively raises the ambient temperature of water to the boiling point where liquid is converted into vapor. The striking difference in the boiling properties of the single gold nanowrench and the nanoparticle solution system can be explained in terms of the vapor-nucleation mechanism, the volume of the overheated liquid, and the collective heating effect. The interpretation of the observed regimes of heating and vaporization is consistent with our theoretical modeling. In particular, we explain with our theory why the boiling with the collective heating in a solution requires 3 orders of magnitude less intensity compared to the case of optically driven single nanowrench. PMID- 24476427 TI - HLA restriction of carbamazepine-specific T-Cell clones from an HLA-A*31:01 positive hypersensitive patient. AB - HLA-A*31:01 is associated with carbamazepine (CBZ) hypersensitivity in Caucasian and Japanese populations. Herein, we show that HLA-A*31:01+ restricted the activation of carbamazepine-specific CD8(+) T-cells, which provides an immunological basis for the genetic association. Furthermore, CD4(+) T-cells were activated with carbamazepine in a HLA-DRB1*04:04-restricted manner, indicating that a common HLA haplotype may contribute to the multiclonal T-cell response seen in European patients with CBZ hypersensitivity. PMID- 24476428 TI - Neisseria meningitidis B vaccines: recent advances and possible immunization policies. AB - Since the development of the first-generation vaccines based on outer membrane vesicles (OMV), which were able to contain strain-specific epidemics, but were not suitable for universal use, enormous steps forward in the prevention of Neisseria meningitidis B have been made. The first multicomponent vaccine, Bexsero((r)), has recently been authorized for use; other vaccines, bivalent rLP2086 and next-generation OMV vaccines, are under development. The new vaccines may substantially contribute to reducing invasive bacterial infections as they could cover most Neisseria meningitidis B strains. Moreover, other potentially effective serogroup B vaccine candidates are being studied in preclinical settings. It is therefore appropriate to review what has recently been achieved in the prevention of disease caused by serogroup B. PMID- 24476429 TI - Assessing the clinical benefits of lipid-disorder drugs. PMID- 24476430 TI - Still delirious after all these years. PMID- 24476431 TI - Incidence of childhood obesity in the United States. AB - BACKGROUND: Although the increased prevalence of childhood obesity in the United States has been documented, little is known about its incidence. We report here on the national incidence of obesity among elementary-school children. METHODS: We evaluated data from the Early Childhood Longitudinal Study, Kindergarten Class of 1998-1999, a representative prospective cohort of 7738 participants who were in kindergarten in 1998 in the United States. Weight and height were measured seven times between 1998 and 2007. Of the 7738 participants, 6807 were not obese at baseline; these participants were followed for 50,396 person-years. We used standard thresholds from the Centers for Disease Control and Prevention to define "overweight" and "obese" categories. We estimated the annual incidence of obesity, the cumulative incidence over 9 years, and the incidence density (cases per person-years) overall and according to sex, socioeconomic status, race or ethnic group, birth weight, and kindergarten weight. RESULTS: When the children entered kindergarten (mean age, 5.6 years), 12.4% were obese and another 14.9% were overweight; in eighth grade (mean age, 14.1 years), 20.8% were obese and 17.0% were overweight. The annual incidence of obesity decreased from 5.4% during kindergarten to 1.7% between fifth and eighth grade. Overweight 5-year-olds were four times as likely as normal-weight children to become obese (9-year cumulative incidence, 31.8% vs. 7.9%), with rates of 91.5 versus 17.2 per 1000 person-years. Among children who became obese between the ages of 5 and 14 years, nearly half had been overweight and 75% had been above the 70th percentile for body-mass index at baseline. CONCLUSIONS: Incident obesity between the ages of 5 and 14 years was more likely to have occurred at younger ages, primarily among children who had entered kindergarten overweight. (Funded by the Eunice Kennedy Shriver National Institute of Child Health and Human Development.). PMID- 24476432 TI - Genetic PTX3 deficiency and aspergillosis in stem-cell transplantation. AB - BACKGROUND: The soluble pattern-recognition receptor known as long pentraxin 3 (PTX3) has a nonredundant role in antifungal immunity. The contribution of single nucleotide polymorphisms (SNPs) in PTX3 to the development of invasive aspergillosis is unknown. METHODS: We screened an initial cohort of 268 patients undergoing hematopoietic stem-cell transplantation (HSCT) and their donors for PTX3 SNPs modifying the risk of invasive aspergillosis. The analysis was also performed in a multicenter study involving 107 patients with invasive aspergillosis and 223 matched controls. The functional consequences of PTX3 SNPs were investigated in vitro and in lung specimens from transplant recipients. RESULTS: Receipt of a transplant from a donor with a homozygous haplotype (h2/h2) in PTX3 was associated with an increased risk of infection, in both the discovery study (cumulative incidence, 37% vs. 15%; adjusted hazard ratio, 3.08; P=0.003) and the confirmation study (adjusted odds ratio, 2.78; P=0.03), as well as with defective expression of PTX3. Functionally, PTX3 deficiency in h2/h2 neutrophils, presumably due to messenger RNA instability, led to impaired phagocytosis and clearance of the fungus. CONCLUSIONS: Genetic deficiency of PTX3 affects the antifungal capacity of neutrophils and may contribute to the risk of invasive aspergillosis in patients treated with HSCT. (Funded by the European Society of Clinical Microbiology and Infectious Diseases and others.). PMID- 24476258 TI - Measurement of top quark polarization in top-antitop events from proton-proton collisions at ?s=7 TeV using the ATLAS detector. AB - This Letter presents measurements of the polarization of the top quark in top antitop quark pair events, using 4.7 fb(-1) of proton-proton collision data recorded with the ATLAS detector at the Large Hadron Collider at ?s=7 TeV. Final states containing one or two isolated leptons (electrons or muons) and jets are considered. Two measurements of alpha(l)P, the product of the leptonic spin analyzing power and the top quark polarization, are performed assuming that the polarization is introduced by either a CP conserving or a maximally CP violating production process. The measurements obtained, alpha(l)P(CPC)=-0.035+/ 0.014(stat)+/-0.037(syst) and alpha(l)P(CPV)=0.020+/-0.016(stat)( 0.017)(+0.013)(syst), are in good agreement with the standard model prediction of negligible top quark polarization. PMID- 24476433 TI - Sedation and delirium in the intensive care unit. PMID- 24476435 TI - Images in clinical medicine. Occult spinal dysraphism. PMID- 24476437 TI - Who becomes obese during childhood--clues to prevention. PMID- 24476439 TI - Albumin-bound paclitaxel plus gemcitabine in pancreatic cancer. PMID- 24476436 TI - Case records of the Massachusetts General Hospital. Case 4-2014. A 39-year-old man with night sweats and abdominal pain. PMID- 24476438 TI - Albumin-bound paclitaxel plus gemcitabine in pancreatic cancer. PMID- 24476441 TI - Tiotropium and the risk of death in COPD. PMID- 24476440 TI - Albumin-bound paclitaxel plus gemcitabine in pancreatic cancer. PMID- 24476434 TI - Necroptosis. PMID- 24476442 TI - Tiotropium and the risk of death in COPD. PMID- 24476443 TI - Tiotropium and the risk of death in COPD. PMID- 24476444 TI - Saxagliptin, alogliptin, and cardiovascular outcomes. PMID- 24476445 TI - Saxagliptin, alogliptin, and cardiovascular outcomes. PMID- 24476447 TI - Preparing for responsible sharing of clinical trial data. PMID- 24476448 TI - Preparing for responsible sharing of clinical trial data. PMID- 24476449 TI - Access to patient-level trial data. PMID- 24476450 TI - Maraviroc and JC virus-associated immune reconstitution inflammatory syndrome. PMID- 24476451 TI - Health care spending by high-income countries, 1980-2011. PMID- 24476452 TI - Images in clinical medicine. Mandibular tori. PMID- 24476453 TI - The risk of acute rejection and the influence of induction agents in lower-risk African American kidney transplant recipients receiving modern immunosuppression. AB - BACKGROUND: While kidney transplant recipients of African American (AA) descent are frequently considered at increased risk of acute rejection, the value of induction therapy is not defined in settings of lower immunologic risk and modern immunosuppression. METHODS: Using the Scientific Registry of Transplant Recipients database, we identified 23,244 primary kidney transplant recipients with panel-reactive antibody (PRA) = 0% treated with TAC/MPA and prednisone from 2000 to 2008. We compared acute rejection, graft survival (GS), and patient survival rates among AA and non-AA and further stratified by induction therapy (none, IL2ra, or rATG). RESULTS: One-yr acute rejection was higher in AA than in non-AA overall (14.5% vs. 9.9%, hazard ratio [HR] for acute rejection [AR] 1.43, p < 0.0001) and was higher regardless of induction agent use. Induction therapy was associated with a reduction in AR, but no benefit in GS in AA or non-AA. In AA, rATG (adjusted relative risk [RR] 0.81, CI 0.70-0.94) and IL2ra (adjusted RR 0.80, CI 0.68-0.93) were similarly effective in reducing AR rates, but did not reach comparable outcomes as in non-AA. CONCLUSION: African Americans who are at otherwise lower immunologic risk have a higher risk of rejection despite modern immunosuppression. Depleting or non-depleting induction therapy similarly reduces but does not entirely mitigate this increased risk, with no impact on three-yr GS. PMID- 24476454 TI - Effects of two commonly used mydriatics on choroidal thickness: direct and crossover effects. AB - PURPOSE: To investigate the effect of 2 commonly used mydriatics on choroidal thickness using enhanced depth imaging optical coherence tomography (EDI-OCT). METHODS: In this prospective study, 90 healthy subjects were enrolled. The participants were randomly divided into 3 groups based on the application of drops. One eye of each subject received a drop of tropicamide 1% in the tropicamide group (n=30), a drop of phenylephrine 2.5% in the phenylephrine group (n=30), and a drop of artificial tear in the control group (n=30). Drops were given thrice at 5 min intervals. Subfoveal choroidal thickness (SFCT) was measured using EDI-OCT before and at 45 min after drop application in both the dilated eye and nondilated contralateral eye. RESULTS: The SFCT was significantly decreased after drop instillation in both the dilated eye and contralateral eye in the tropicamide group (P<0.001 and P=0.001, respectively) and in the phenylephrine group (P<0.001 and P=0.001, respectively). However, the SFCT did not significantly differ after drop instillation in either the dropped eye or contralateral eye in the control group (P=0.108 and P=0.695, respectively). CONCLUSION: The findings of the present study revealed that tropicamide and phenylephrine cause a decrease in choroidal thickness. PMID- 24476455 TI - Editorial. Molecular image-guided cancer treatment: moving towards personalized medicine--Part I. PMID- 24476457 TI - The impact of virtual admission on self-efficacy in patients with chronic obstructive pulmonary disease - a randomised clinical trial. AB - AIMS AND OBJECTIVES: To investigate how virtual admission during acute exacerbation influences self-efficacy in patients with chronic obstructive pulmonary disease, compared with conventional hospital admission. BACKGROUND: Telemedicine solutions have been highlighted as a possible way to increase self efficacy in patients with chronic diseases, such as chronic obstructive pulmonary disease. However, little is known about how telemedicine-based virtual admission as a replacement of hospital admission during acute exacerbation affects chronic obstructive pulmonary disease patients' self-efficacy. DESIGN: This study was a nonblinded, randomised clinical multicentre trial. The study was a substudy to The Virtual Hospital, investigating the feasibility and safety of telemedicine based treatment at home for patients with acute exacerbation of chronic obstructive pulmonary disease. METHODS: Participants were consecutively randomised to virtual admission or conventional hospital admission. Data from 50 patients were analysed. Self-efficacy was assessed at baseline, three days after discharge, and also six weeks and three months after discharge, using the Danish version of 'The chronic obstructive pulmonary disease self-efficacy scale'. RESULTS: Intergroup comparison showed no significant differences between the two groups at baseline, three days after discharge, six weeks after discharge or three months after discharge. Furthermore, intragroup comparison did not reveal significant differences in the chronic obstructive pulmonary disease self efficacy scale mean sum score within the two groups. CONCLUSIONS: The results of the study suggest that there is no difference between self-efficacy in chronic obstructive pulmonary disease patients undergoing virtual admission, compared with conventional hospital admission. However, the anticipated sample size could not be reached, which prompts caution regarding interpretation of the findings. RELEVANCE TO CLINICAL PRACTICE: This study provides new insight into how virtual admission affects chronic obstructive pulmonary disease patients' self-efficacy. Clinicians should consider the timing, duration and the content in the design of telemedical interventions directed at improving chronic obstructive pulmonary disease patients' self-efficacy, as telemedicine solutions alone may not be sufficient to enhance self-efficacy. PMID- 24476456 TI - Long-term hepatitis E viral load kinetics in an immunocompromised patient treated with ribavirin. AB - Hepatitis E virus (HEV) can cause chronic infections in immunocompromised hosts. Viral kinetics in plasma and stools are poorly understood, particularly during antiviral treatment. Prolonged faecal shedding may be a concern for transmission. We describe HEV kinetics in an immunocompromised patient with prolonged faecal shedding despite undetectable viraemia on ribavirin treatment. PMID- 24476458 TI - Sensitive Pb(2+) probe based on the fluorescence quenching by graphene oxide and enhancement of the leaching of gold nanoparticles. AB - A novel strategy was developed for fluorescent detection of Pb(2+) in aqueous solution based on the fact that graphene oxide (GO) could quench the fluorescence of amino pyrene (AP)-grafted gold nanoparticles (AP-AuNPs) and Pb(2+) could accelerate the leaching rate of AuNPs in the presence of S2O3(2-). In this system, fluorescence reporter AP was grafted on AuNPs through the Au-N bond. In the presence of GO, the system shows fluorescence quenching because of pi-pi stacking between AP and GO. With the addition of Pb(2+) and S2O3(2-), the system displays fluorescence recovery, which is attributed to the fact that Pb(2+) could accelerate the leaching of the AuNPs from GO surfaces and release of AP into aqueous solution. Interestingly, the concentration of GO could control the fluorescence "turn-off" or "turn-on" for Pb(2+) detection. In addition, GO is also an excellent promoter for the acceleration of the leaching of AuNPs and shortening the analytical time to ~15 min. Under the optimal conditions, the fluorescence Pb(2+) sensor shows a linear range from 2.0 * 10(-9) to 2.3 * 10(-7) mol/L, with a detection limit of 1.0 * 10(-10) mol/L. PMID- 24476459 TI - Association of weight misperception with weight loss in a diabetes prevention program. AB - BACKGROUND: Weight misperception may have an impact on perceived risk and susceptibility for chronic diseases. Little has been reported on the long term effects of this misperception in chronic disease interventions, particularly in field of diabetes prevention. The aim of this study was to investigate the relationship between weight misperception and weight loss during a diabetes prevention project conducted in south-east Australia with individuals at moderate to high risk of developing diabetes. METHODS: A total of n=251 at risk individuals provided self-reported weight during recruitment from 2004-2006. Objectively measured weight was assessed at baseline (0-21 days after recruitment), and subsequently at three months and 12 months after the intervention. Differences between self-reported and actual weight status are presented as percentages. Linear regression was used to investigate the relationship between weight misperception and weight loss, adjusting for baseline weight and BMI. RESULTS: Those who had high levels of under-reporting at baseline had greater weight loss at three and 12 months compared with those who under reported to some degree, and those over-reporting their weight. A significant association was found between weight misperception and weight loss at the three and the 12 month time points. Baseline weight was not associated with weight loss. CONCLUSIONS: Weight misperception should be acknowledged as a factor to be addressed when screening and identifying individuals at risk for diabetes. Screening and giving feedback is important in terms of awareness of participants' actual weight status and may have an effect on program outcomes. PMID- 24476460 TI - Novel mutations in PCYT1A are responsible for spondylometaphyseal dysplasia with cone-rod dystrophy. PMID- 24476461 TI - Matrix metalloproteinase-9 overexpression is closely related to poor prognosis in patients with colon cancer. AB - BACKGROUND: Matrix metalloproteinase-9 (MMP-9) is an important member of the matrix metalloproteinase family and is considered to be involved in the invasion and metastasis of cancer cells. This study analyzed the expression of MMP-9 in colon cancer patients and the relationship between this expression and clinicopathological features and survival. METHODS: We immunohistochemically investigated 68 specimens of colon cancer tissues and corresponding distal normal mucosa tissues using MMP-9 antibody. Then, the correlation between MMP-9 expression and clinicopathological features and its prognostic relevance were determined. RESULTS: The expression rate of MMP-9 in colon cancer tissues was significantly higher than that in distal normal mucosa (69.1% versus 2.9%, P < 0.001). Significant correlations were only found between high levels of MMP-9 expression and metastasis of lymph nodes and Dukes' stage. Overexpression of MMP 9 was associated with shorter survival times in univariate analysis. Multivariate analysis confirmed that MMP-9 expression was an independent prognostic factor. CONCLUSIONS: MMP-9 is correlated with the metastasis of lymph nodes, and its elevated expression may be an adverse prognostic indicator for the patients of colon cancer. PMID- 24476462 TI - Epigenetics and transcriptomics to detect adverse drug effects in model systems of human development. AB - Prenatal exposure to environmental chemicals or drugs has been associated with functional or structural deficits and the development of diseases in later life. For example, developmental neurotoxicity (DNT) is triggered by lead, and this compound may predispose to neurodegenerative diseases in later life. The molecular memory for such late consequences of early exposure is not known, but epigenetic mechanisms (modification of the chromatin structure) could take this role. Examples and underlying mechanisms have been compiled here for the field of DNT. Moreover, we addressed the question as to what readout is suitable for addressing drug memory effects. We summarize how complex developmental processes can be modelled in vitro by using the differentiation of human stem cells. Although cellular models can never replicate the final human DNT phenotype, they can model the adverse effect that a chemical has on key biological processes essential for organ formation and function. Highly information-rich transcriptomics data may inform on these changes and form the bridge from in vitro models to human prediction. We compiled data showing that transcriptome analysis can indicate toxicity patterns of drugs. A crucial question to be answered in our systems is when and how transcriptome changes indicate adversity (as opposed to transient adaptive responses), and how drug-induced changes are perpetuated over time even after washout of the drug. We present evidence for the hypothesis that changes in the histone methylation pattern could represent the persistence detector of an early insult that is transformed to an adverse effect at later time-points in life. PMID- 24476463 TI - Paracrine signaling in mammary gland development: what can we learn about intratumoral heterogeneity? AB - Paracrine signaling mechanisms play a critical role in both normal mammary gland development and breast cancer. Dissection of these mechanisms using genetically engineered mouse models has provided significant insight into our understanding of the mechanisms that guide intratumoral heterogeneity. In the following perspective, we briefly review some of the emerging concepts in this field and emphasize why elucidation of these pathways will be important for future progress in devising new and improved combinatorial therapeutic approaches for breast and other solid cancers. PMID- 24476464 TI - Exercise- and resveratrol-mediated alterations in adipose tissue metabolism. AB - Owing to its obligatory role in locomotion and the fact that it accounts for the vast majority of whole-body glucose and lipid oxidation, much work has focused on studying the biochemical adaptations that occur in skeletal muscle in response to exercise. However, over the past several years there has been a growing appreciation that adipose tissue is an important player in regulating systemic carbohydrate and lipid homeostasis. Despite this, the examination of how exercise alters adipose tissue function and metabolism is, when compared with skeletal muscle, in its infancy. The purpose of the current review is to highlight some of the recent findings from our laboratory and others that focus on the emerging area of adipose tissue exercise biochemistry. Specifically, the role of exercise on the induction of mitochondrial and glyceroneogenic enzymes will be examined and will be compared with the well-characterized effects of thiazolidinediones, which are insulin-sensitizing drugs. A particular emphasis will be placed on the role of interleukin-6 in mediating the effects of exercise. Finally, we will discuss recent data from our laboratory demonstrating beneficial effects of resveratrol supplementation on adipose tissue metabolism. PMID- 24476465 TI - Are circulating cytokine responses to exercise in the heat augmented in older men? AB - Age-related chronic low-grade inflammation may render older individuals more susceptible to heat illnesses. The purpose of this study was to examine the influence of intermittent work in the heat on the circulating cytokine responses of older workers. Fourteen young (aged 25.6 +/- 0.7 years) and older (aged 57.7 +/- 1.5 years) males, matched for body surface area, cycled for 4 * 15 min (separated by 15-min rest) at moderate to heavy intensity (400 W heat production) in warm/dry (35 degrees C, 20% relative humidity (RH)) and warm/humid (35 degrees C, 60% RH) conditions. Rectal (Tre) and mean skin (MTsk) temperatures and heart rate were measured continuously, ratings of perceived exertion and thermal sensation recorded at the end of each exercise bout, and blood samples at baseline (PRE) and following the final 60-min recovery (POST) were analyzed for interleukin (IL)-6, tumor necrosis factor (TNF)-alpha, and percent changes in blood (BV) and plasma (PV) volumes. No differences were observed between the age groups for Tre, MTsk, heart rate, perceptual strain, or percentage of changes in BV, PV, or DeltaTNF-alpha. Under both conditions, the older males had elevated IL 6 and TNF-alpha (PRE, POST) compared with the young males. DeltaIL-6 tended to be greater in the warm/humid condition (+2.53 +/- 0.49 and +1.52 +/- 0.41 pg.mL(-1)) compared with the warm/dry condition (+1.02 +/- 0.13 and +0.68 +/- 0.18 pg.mL( 1)) for older but not young males, respectively. Young and older males experienced similar thermal, cardiovascular, and perceptual strain within the warm/dry and warm/humid conditions. PMID- 24476466 TI - Repeated familiarisation with hypohydration attenuates the performance decrement caused by hypohydration during treadmill running. AB - This study examined the effect of repeated familiarisation to hypohydration on hypohydrated exercise performance. After familiarisation with the exercise protocol, 10 recreationally active males completed a euhydrated (EU-pre) and hypohydrated (HYPO-pre) trial, which involved a 45-min steady state run at 75% peak oxygen uptake (45SS) followed by a 5-km time trial (TT). Euhydration and hypohydration were induced by manipulating fluid intake in the 24-h pre-exercise and during the 45SS. Subjects then completed 4 habituation sessions that involved replication of the HYPO-pre trial, except they completed 60 min of running at 75% peak oxygen uptake and no TT. Subjects then replicated the euhydrated (EU-post) and hypohydrated (HYPO-post) trials. Body mass loss pre-TT was 0.2 (0.2)% (EU pre), 2.4 (0.3)% (HYPO-pre), 0.1 (0.1)% (EU-post), and 2.4 (0.3)% (HYPO-post). TT performance was 5.8 (2.4)% slower during the HYPO-pre trial (1459 (250) s) than during the EU-pre trial (1381 (237) s) (p < 0.01), but only 1.2 (1.6)% slower during the HYPO-post trial (1381 (200) s) than during the EU-post trial (1366 (211) s) (p = 0.064). TT performance was not different between EU-pre and EU-post trials, but was 5.1 (2.3)% faster during the HYPO-post trial than the HYPO-pre trial (p < 0.01). Heart rate was greater during HYPO trials than EU trials (p < 0.001), whilst rating of perceived exertion (RPE) response was similar to TT time and was lower in the HYPO-post trial than the HYPO-pre trial (p < 0.01). In conclusion, hypohydration impaired 5-km running performance in subjects unfamiliar with the hypohydration protocol, but 4 familiarisation sessions designed to habituate subjects with the hypohydration protocol attenuated the performance decrement, seemingly via an attenuation of RPE during hypohydrated exercise. PMID- 24476467 TI - Cytokine mRNA expression responses to resistance, aerobic, and concurrent exercise in sedentary middle-aged men. AB - Concurrent resistance and aerobic exercise (CE) is recommended to ageing populations, though is postulated to induce diminished acute molecular responses. Given that contraction-induced cytokine mRNA expression reportedly mediates remunerative postexercise molecular responses, it is necessary to determine whether cytokine mRNA expression may be diminished after CE. Eight middle-aged men (age, 53.3 +/-1.8 years; body mass index, 29.4 +/- 1.4 kg.m(-2)) randomly completed (balanced for completion order) 8 * 8 leg extensions at 70% maximal strength (RE), 40 min of cycling at 55% of peak aerobic workload (AE), or (workload-matched) 50% RE and 50% AE (CE). Muscle (vastus lateralis) was obtained pre-exercise, and at 1 h and 4 h postexercise, and analyzed for changes of glycogen concentration, tumor necrosis factor (TNF)alpha, TNF receptor-1 and -2 (TNF-R1 and TNF-R2, respectively), interleukin (IL)-6, IL-6R, IL-1beta, and IL-1 receptor-antagonist (IL-1ra). All exercise modes upregulated cytokine mRNA expression at 1 h postexercise comparably (TNFalpha, TNF-R1, TNF-R2, IL-1beta, IL 6) (p < 0.05). Expression remained elevated at 4 h after RE and AE (p < 0.05), though returned to pre-exercise levels after CE (p > 0.05). Moreover, AE and RE upregulated IL-1beta and IL-1ra expression, whereas CE upregulated IL-1beta expression only (p < 0.05). Only AE reduced muscle glycogen concentration (p < 0.05), whilst upregulating receptor expression the greatest; though, IL-6R expression remained unchanged after all modes (p > 0.05). In conclusion, in middle-aged men, all modes induced commensurate cytokine mRNA expression at 1 h postexercise; however, only CE resulted in ameliorated expression at 4 h postexercise. Whether the RE or AE components of CE are independently or cumulatively sufficient to upregulate cytokine responses, or whether they collectively inhibit cytokine mRNA expression, remains to be determined. PMID- 24476468 TI - Novel hydration assessment techniques employing thirst and a water intake challenge in healthy men. AB - Exploring novel hydration indices is important because no human biomarker has been shown to be incontrovertibly valid in all life situations. The present investigation was designed to identify inexpensive, nontechnical methods to use when self-assessing hydration status. This investigation evaluated the validity and efficacy of 2 novel techniques (i.e., thirst sensation and urine volume) to assess hydration state of 29 active men (mean +/- SD; age, 23 +/- 4 years; body mass, 76.02 +/- 11.94 kg) at rest. Eight combinations of 4 water challenges (4.8, 9.3, 11.0, or 14 mL.kg(-1)) and 2 hydration states (mildly hypohydrated (HY), 2.0%; euhydrated (EU), -0.2% body mass) were employed. First, thirst was linearly related to body water loss, and ratings of thirst distinguished HY from EU (p < 0.001) subsequent to 19 h of controlled food and fluid intake. Second, measurements of urine volume 60 min after consuming a water bolus (11.0 or 14 mL.kg(-1)) were strongly and inversely correlated with entering hydration state, assessed by urine specific gravity (r(2) = 0.76, p < 0.0001) and urine osmolality (r(2) = 0.77, p < 0.0001). We concluded that healthy men can employ simple measurements of morning thirst sensation and urine volume to identify the presence of mild hypohydration and to guide fluid replacement. These 2 techniques are relevant because HY (-2% body mass) is the approximate threshold for the onset of thirst, reduced endurance exercise performance, and decrements of working memory and mood. PMID- 24476469 TI - Effect of black tea consumption on brachial artery flow-mediated dilation and ischaemia-reperfusion in humans. AB - Tea consumption is associated with reduced cardiovascular risk. Previous studies found that tea flavonoids work through direct effects on the vasculature, leading to dose-dependent improvements in endothelial function. Cardioprotective effects of regular tea consumption may relate to the prevention of endothelial ischaemia reperfusion (IR) injury. Therefore, we examined the effect of black tea consumption on endothelial function and the ability of tea to prevent IR injury. In a randomized, crossover study, 20 healthy subjects underwent 7 days of tea consumption (3 cups per day) or abstinence from tea. We examined brachial artery (BA) endothelial function via flow-mediated dilation (FMD), using high resolution echo-Doppler, before and 90 min after tea or hot water consumption. Subsequently, we followed a 20-min ischaemia and 20-min reperfusion protocol of the BA after which we measured FMD to examine the potential of tea consumption to protect against IR injury. Tea consumption resulted in an immediate increase in FMD% (pre consumption: 5.8 +/- 2.5; post-consumption: 7.2 +/- 3.2; p < 0.01), whilst no such change occurred after ingestion of hot water. The IR protocol resulted in a significant decrease in FMD (p < 0.005), which was also present after tea consumption (p < 0.001). This decline was accompanied by an increase in the post IR baseline diameter. In conclusion, these data indicate that tea ingestion improves BA FMD. However, the impact of the IR protocol on FMD was not influenced by tea consumption. Therefore, the cardioprotective association of tea ingestion relates to a direct effect of tea on the endothelium in humans in vivo. PMID- 24476470 TI - Anti-cholelithogenic effect of dietary tender cluster beans (Cyamopsis tetragonoloba) on the formation of cholesterol gallstones in mice. AB - Providing a lithogenic diet that contains 0.5% cholesterol to experimental mice for 10 weeks resulted in cholesterol supersaturation in gallbladder bile, which induced the formation of cholesterol gallstones. In this study, to evaluate the anti-cholelithogenic potential of dietary tender cluster bean, a freeze-dried powder of the test legume was included in the lithogenic diet at 5%, 10%, and 15%. Dietary cluster beans reduced the cholesterol gallstone incidence by 43%, 46%, and 58% at the respective doses. Dietary cluster beans markedly reduced biliary cholesterol and, hence, the cholesterol saturation index. This was corroborated by the beneficial modification of the cholesterol/phospholipid ratio and the cholesterol/bile acid ratio in the bile. Dietary cluster beans countered the alterations in serum and liver cholesterol and lipid profiles caused by the lithogenic diet. Thus, dietary tender cluster beans exerted an anti cholelithogenic influence by decreasing cholesterol hypersecretion into bile and, hence, the cholesterol saturation index, decreasing the formation of lithogenic bile in experimental mice. PMID- 24476471 TI - Comparing serum responses to acute feedings of an extensively hydrolyzed whey protein concentrate versus a native whey protein concentrate in rats: a metabolomics approach. AB - We examined how gavage feeding extensively hydrolyzed whey protein (WPH) versus a native whey protein concentrate (WPC) transiently affected serum biochemical profiles in rodents. Male Wistar rats (250-300 g) were 8 h fasted and subsequently fed isonitrogenous amounts of WPH or WPC, or remained unfed (control). Animals were sacrificed 15 min, 30 min, and 60 min post-gavage for serum extraction, and serum was analyzed using untargeted global metabolic profiling via gas chromatography/mass spectrometry (MS) and liquid chromatography/MS/MS platforms. We detected 333 serum metabolites amongst the experimental and control groups. Both WPH and WPC generally increased amino acids (1.2-2.8-fold), branched-chain amino acids (1.2-1.7-fold), and serum di- and oligo-peptides (1.1-2.7-fold) over the 60 min time course compared with control (q < 0.05). However, WPH increased lysine (false discovery rate using a q-value <0.05) and tended to increase isoleucine and valine 15 min post-feeding (q < 0.10) as well as aspartylleucine 30 min post-feeding compared with WPC (q < 0.05). While both protein sources led to a dramatic increase in free fatty acids compared with control (up to 6-fold increases, q < 0.05), WPH also uniquely resulted in a 30 min post-feeding elevation in free fatty acids compared with WPC (q < 0.05), an effect which may be due to the robust 30 min postprandial increase in epinephrine in the WPH cohort. These data provide a unique postprandial time course perspective on how WPH versus WPC feedings affect circulating biochemicals and will guide future research comparing these 2 protein sources. PMID- 24476472 TI - Cardiorespiratory function associated with dietary nitrate supplementation. AB - The advent of medical nutrition therapy and nutritional physiology affords the opportunity to link diet to specific cardiovascular mechanisms, suggesting novel treatments for cardiovascular disease. This study tests the hypothesis that beetroot juice increases the plasma nitric oxide (NO) concentration, which is associated with improvements in cardiorespiratory function at rest and during submaximal aerobic exercise. The subjects were 12 healthy, young adult, normotensive African-American females, with a body mass of 61 +/- 2 kg, body fat of 28% +/- 4%, and peak oxygen consumption of 26 +/- 3 mL.kg(-1).min(-1). The subjects were studied at rest and during cycle ergometer exercise at 40%, 60%, and 80% of peak oxygen consumption. Plasma NO concentration, respiratory quotient (RQ), minute ventilation, systolic and diastolic blood pressure (SBP and DBP), heart rate, and oxygen consumption were compared between isocaloric, isovolumetric placebo control orange juice and experimental beetroot juice treatments on separate days. The beetroot juice treatment increased plasma NO concentration and decreased oxygen consumption, SBP, and the heart rate-SBP product at rest and at 40%, 60%, and 80% of peak oxygen consumption in the absence of significant effects on RQ, minute ventilation, heart rate, and DBP. These findings suggest that, in healthy subjects, beetroot juice treatments increase plasma NO concentration and decrease cardiac afterload and myocardial oxygen demand at rest and during 3 submaximal levels of aerobic exercise. Future studies should determine the cellular and molecular mechanisms responsible for the improvement in cardiorespiratory function associated with dietary nitrate supplementation and whether they translate into better cardiovascular function and exercise tolerance in individuals with a compromised cardiovascular system. PMID- 24476473 TI - The effect of acute dark chocolate consumption on carbohydrate metabolism and performance during rest and exercise. AB - Consumption of cocoa-enriched dark chocolate (DC) has been shown to alter glucose and insulin concentration during rest and exercise compared with cocoa-depleted control (CON). However, the impact of DC consumption on exercise metabolism and performance is uncertain. Therefore, we investigated carbohydrate metabolism via stable isotope tracer techniques during exercise after subjects ingested either DC or CON. Sixteen overnight-fasted male cyclists performed a single-blinded, randomized, crossover design trial, after consuming either DC or CON at 2 h prior to 2.5 h of steady-state (SS) exercise (~45% peak oxygen uptake). This was followed by an ~15-min time-trial (TT) and 60 min of recovery. [6,6-(2)H2]Glucose and [U-(13)C]glucose were infused during SS to assess glucose rate of appearance (Ra) and disappearance (Rd). After DC consumption, plasma (-)-glucose and insulin concentrations were significantly (p < 0.001) elevated throughout vs. CON. During SS, there was no difference in [6,6-(2)H2]glucose Ra between treatments, but towards the end of SS (last 60 min) there was a ~16% decrease in Rd in DC vs. CON (p < 0.05). Accordingly, after DC there was an ~18% significant decrease in plasma glucose oxidation (trial effect; p = 0.032), and an ~15% increase in tracer-derived muscle glycogen utilization (p = 0.045) late during SS exercise. The higher blood glucose concentrations during exercise and recovery after DC consumption coincided with high concentrations of epicatechin and (or) theobromine. In summary, DC consumption altered muscle carbohydrate partitioning, between muscle glucose uptake and glycogen oxidation, but did not effect cycling TT performance. PMID- 24476474 TI - Absence of leucine in an essential amino acid supplement reduces activation of mTORC1 signalling following resistance exercise in young females. AB - The purpose of the study was to investigate the specific effect of leucine on mTORC1 signalling and amino acid metabolism in connection with resistance exercise. Comparisons were made between ingestion of supplements with and without leucine. Eight young women performed leg press exercise on 2 occasions. In randomized order they received either an aqueous solution of essential amino acids with leucine (EAA) or without leucine (EAA-Leu), given as small boluses throughout the experiment. Muscle biopsies were taken after an overnight fast before exercise and 1 and 3 h postexercise and samples of blood were taken repeatedly during the experiment. Plasma and muscle concentrations of leucine rose 60%-140% (p < 0.05) with EAA and fell 35%-45% (p < 0.05) with the EAA-Leu supplement. In the EAA-trial, plasma and muscle levels of tyrosine (not present in the supplement) and the sum of the EAA were 15%-25% (p < 0.05) lower during recovery. Phosphorylation of mTOR and p70S6k was elevated to a larger extent following 1 h of recovery with leucine in the supplement (120% vs. 49% (p < 0.05) and 59- vs. 8-fold (p < 0.05) for EAA and EAA-Leu, respectively). The levels of MAFbx and MuRF-1 mRNA and of the corresponding proteins were not significantly altered after 3 h recovery from exercise. In conclusion, the presence of leucine in the supplement enhances the stimulatory effect on mTORC1 signalling and reduces the level of tyrosine and the sum of the EAA in muscle and plasma, suggesting a stimulation of protein synthesis and (or) inhibition of breakdown, leading to improvement in net protein balance. PMID- 24476475 TI - The association between food patterns and adiposity among Canadian children at risk of overweight. AB - Identifying food patterns related to obesity can provide information for health promotion in nutrition. Food patterns and their relation with obesity among Canadian children have not been reported to date. Our aim was to identify and describe food patterns associated with obesity in children at risk of overweight. Caucasian children (n = 630) with at least 1 obese biological parent recruited into the Quebec Adiposity and Lifestyle Investigation in Youth (QUALITY) cohort were studied in cross-sectional analyses. Measures of adiposity (body mass index (BMI), waist circumference, body fat mass percentage measured by dual-energy X ray absorptiometry), screen time, physical activity (accelerometer over 7 days), and dietary intake (three 24-h food recalls) were collected. Factor analysis was used to identify food patterns. The relationships between food patterns and overweight were investigated in logistic and multiple linear regression models. Three food patterns were retained for analysis: traditional food (red meats, main dishes-soups, high-fat dairy products, tomato products, dressings, etc.); healthy food (low-fat dairy products, whole grains, legumes-nuts-seeds, fruits, vegetables); and fast food (sugar-sweetened beverages, fried potatoes, fried chicken, hamburgers-hot dogs-pizza, salty snacks). Higher scores on the fast food pattern were associated with overweight (BMI >= 85th percentile), and other measures of adiposity (BMI, waist circumference, body fat mass percentage) after adjustment for age, sex, physical activity, screen time, sleep time, family income, and mother's obesity (p < 0.05). Controlling for energy intake did not change these relationships. Our results provide further evidence of a link between fast food intake and obesity in children. PMID- 24476476 TI - Positive effect of specific low-frequency electrical stimulation during short term recovery on subsequent high-intensity exercise. AB - The objective of this study was to test how low-frequency electrical stimulation (LFES; Veinoplus Sport (AdRem Technology, Paris, France)) of the calf muscles affects recovery indices compared with 2 other commonly used recovery methods (active, ACT; passive, PAS). The tests used assessed predominantly anaerobic performance after short-term (15 min) recovery, and the kinetics of blood markers. Fourteen highly trained female handball players completed 2 Yo-Yo Intermittent Recovery tests (level 2; YYIR2) separated by a 15-min recovery period. During recovery, 1 of 3 recovery methods (ACT, LFES or PAS) was randomly selected. Performance (i.e., distance run) was measured at the end of each YYIR2 test. Blood lactate, pH, bicarbonate concentrations, heart rate, respiratory gas exchange and tissue saturation index for the lateral gastrocnemius were recorded. LFES showed a very likely beneficial effect on performance during the second YYIR2 relative to PAS and a possible beneficial effect relative to ACT (distance Pre vs. Post; LFES: -1.8%; ACT: -7.6%; PAS: -15.9%). Compared with PAS recovery, LFES and ACT recovery clearly showed a faster return to baseline for blood lactate, pH and bicarbonate concentrations during the recovery period. LFES of the calf muscles and, to a lesser extent, ACT recovery appear to effectively improve short-term recovery between 2 bouts of exhausting exercises. These methods could be of benefit if applied during half-time, for sports involving successive rounds, or where only a limited recovery period is available. PMID- 24476477 TI - Effects of curcumin on brain-derived neurotrophic factor levels and oxidative damage in obesity and diabetes. AB - We evaluated the effects of curcumin treatment on protein oxidation (PO), lipid peroxidation (LP) and brain-derived neurotrophic factor (BDNF) levels in the hippocampus and frontal cortex (FC) of diabetic db/db mice (DM) and in sera of obese humans. Thus, DM were treated daily with 50 mg/kg of curcumin during an 8 week period. Obese human were treated daily with 500 and 750 mg of curcumin that was administered orally for 12 weeks; BDNF, PO and LP levels in sera were determined at in weeks 0, 2, 6 and 12 of treatment. BDNF levels decreased in hippocampus and FC of DM as compared with untreated wild-type mice. Curcumin improved or restored BDNF levels to normal levels in DM, but curcumin did not have any effect on BDNF levels in sera of obese humans. In hippocampus and FC of DM, hyperglycaemia and curcumin did not have effect on LP levels. Hyperglycaemia increased PO levels in hippocampus and FC, whereas curcumin decreased these levels in hippocampus but not in FC. In sera of obese humans, the 500-mg dose decreased LP levels in weeks 6 and 12 when compared with basal levels, but the 750-mg dose did not have any effect; both doses of curcumin decreased PO levels in weeks 2, 6 and 12 of treatment when compared with basal levels. Present results suggest a therapeutic potential of curcumin to decrease oxidation caused by obesity in humans and also show that curcumin restores BDNF levels in DM. PMID- 24476478 TI - A snapshot of nitrogen balance in endurance-trained women. AB - Indirect estimates of the mean daily protein requirement for female endurance athletes are 1.2-1.4 g.kg(-1).day(-1); however, an empirical estimate using nitrogen balance is absent. A 72-h nitrogen balance was determined during the mid follicular phase of 10 female cyclists and triathletes training for 10.8 h.week( 1) (SD 2.8) following 2 habituated protein intakes: (i) normal habitual (NH) (protein 85 g.day(-1)), and (ii) isocaloric high-protein (HP) (~2-fold increase in protein). Total 72-h nitrogen intake was determined from Leco total combustion of ingested food samples. Nitrogen loss was determined from micro-Kjeldahl analysis of 72-h total urinary nitrogen and representative resting and exercise sweat output, plus estimates for fecal and miscellaneous losses. Habituated (steady state) protein requirement was estimated from the mean regression of adapted nitrogen balance vs nitrogen intake. Mean (SD) 24-h dietary protein and energy intake was NH: 1.4 g.kg(-1).day(-1) (0.2), energy: 9078 kJ.day(-1) (1492), HP: 2.7 g.kg(-1).day(-1) (0.3) 8909 kJ.day(-1) (1411). Average 24-h urinary nitrogen and sweat urea nitrogen outputs were 13.2 g.day(-1) (2.4) and 0.33 g.day(-1) (0.08) in NH; 21.5 g.day(-1) (3.9) and 0.54 g.day(-1) (0.12) in HP, respectively. Nitrogen balance was negative in NH (-0.59 gN.day(-1) SD 1.64) but positive in HP (2.69 gN.day(-1) SD 3.09). Estimated mean protein requirement was 1.63 g.kg(-1).day(-1) (95% confidence interval: 1.1-3.8). In conclusion the snapshot of follicular phase dietary protein requirement conformed with previous estimates for men, but was higher than previous nonempirical estimates for endurance-training women; low self-selected energy and carbohydrate intakes may explain the higher than expected nitrogen turnover, and consequently protein requirement. PMID- 24476479 TI - Exercise training induced myosin heavy chain isoform alteration in the infarcted heart. AB - The myosin heavy chain isoform MHC-alpha has 3-fold higher ATPase activity than MHC-beta. After myocardial infarction (MI), MHC-alpha expression is profoundly downregulated and MHC-beta expression is reciprocally upregulated. This shift, which is attributed to low thyroid hormone (TH), contributes to myocardial systolic dysfunction. We investigated the effect of post-MI exercise training on MHC isoforms, TH, and cardiac function. MI was surgically induced in 7-week-old rats by ligation of the coronary artery. The survivors were assigned to 3 groups (n = 10/group): Sham (no MI, no exercise), MISed (MI, no exercise), and MIEx (MI, exercise). Treadmill exercise training began 1 week post-MI and lasted for 8 weeks. Echocardiogram measurements were taken on the day prior to initiation of exercise training and at the end of exercise training. Tissue and blood samples were collected at the end of the experiment. MHC isoform gene and protein expression and TH were measured. Our results illustrated that MHC-alpha gene expression was higher and MHC-beta gene expression was lower in the MIEx group than in the MISed group. Resting serum TH concentrations (T3 and T4) were similar between the 2 MI groups. The MIEx group had higher fractional shortening than the MISed group. In conclusion, post-MI exercise training beneficially altered MHC isoforms and improved cardiac function without changing TH. PMID- 24476480 TI - The effect of acute endurance exercise on lipoproteins: a comparison of the nuclear magnetic resonance technique with the conventional lipid profile in healthy men. AB - Nuclear magnetic resonance (NMR) of lipoprotein particle size and number may provide greater sensitivity to detecting cardiovascular disease risk compared with the conventional lipid profile in some individuals. The salubrious effect of cardiovascular exercise on blood lipids using the conventional profile is well documented; however, NMR analysis is lacking. The purpose of this study was to examine the effect of a 60-min bout of dynamic exercise on lipoprotein particle size and number as measured by NMR and compare it with the conventional blood lipid profile. Eight active, healthy men (26 +/- 5.17 years) ran for 60 min at 70% maximal oxygen uptake on a motor-driven treadmill. Fasting blood samples were drawn at pre-exercise and 5-10 min and 24 h postexercise. The conventional lipid profile showed a significant change in triglycerides (p = 0.019) immediately after exercise with an increase of 22% and a nonsignificant decrease of 13% from baseline after 24 h. The NMR profile showed a significant change in the large high-density lipoprotein particle concentration (p = 0.046) with an increase of 5.8% immediately after exercise, and a decrease of 6.7% at 24 h after exercise. None of the NMR profile changes were significantly different from the baseline value. These data suggest that sensitivity differences between techniques depend on the variable considered; however, they do not warrant concomitant analysis in future studies using this population. Finally, no appreciable favorable or adverse effect was observed in the overall cardiovascular disease risk profile in active, normolipidemic males. PMID- 24476482 TI - Morning-evening differences in response to exhaustive severe-intensity exercise. AB - The aim was to investigate the effect of time of day on 4 variables that are related to sport performance. Twenty healthy young men (mean +/- SD: 22 +/- 3 years, 1.78 +/- 0.08 m, 72.0 +/- 7.0 kg) performed exhaustive severe-intensity cycle ergometer tests at 278 +/- 35 W (3.8 +/- 0.4 W.kg(-1)) in the morning (between 0630 h and 0930 h) and in the evening (between 1700 h and 2000 h). Despite that gross efficiency was lower in the evening (estimated oxygen demand was 6% higher, P < 0.05), time to exhaustion was 20% greater (P < 0.01) in the evening (329 +/- 35 s) than in the morning (275 +/- 29 s). Performance in the evening was associated with a 4% higher (P < 0.01) maximal oxygen uptake (54 +/- 7 mL.kg(-1).min(-1) vs. 52 +/- 6 mL.kg(-1).min(-1), for the evening and the morning, respectively) and a 7% higher (P < 0.01) anaerobic capacity (as reflected by maximal accumulated oxygen deficit: 75 +/- 9 mL.kg(-1) vs. 70 +/- 7 mL.kg(-1), for the evening and the morning, respectively). In addition, oxygen uptake kinetics was faster in the evening, which resulted in slower utilization of the anaerobic reserves. It is concluded that modest morning-evening differences in maximal oxygen uptake, anaerobic capacity, and oxygen uptake kinetics conflate to produce a markedly longer performance in the evening than in the morning. Time of day must be considered for exercise testing and perhaps for exercise training. PMID- 24476481 TI - Effect of a high-protein diet on development of heart failure in response to pressure overload. AB - Heart failure treatment guidelines provide no recommendations regarding the intake of protein, though it has been proposed that increasing protein intake may result in clinical improvement. High-protein intake might improve protein synthesis and cell function, and prevent deterioration in mitochondrial and left ventricular function. We assessed the effects of a high-protein diet on the development of heart failure characterized by cardiac hypertrophy, impaired mitochondrial oxidative metabolism and contractile dysfunction induced by transverse aortic constriction in rats. A standard diet with 18% of energy intake from protein was compared with a high-protein diet (30% of energy intake). First, we evaluated the effects of protein intake on the development of heart failure during 14 weeks of aortic constriction, and found similar cardiac hypertrophy, contractile dysfunction, ventricular dilation, and decreased cardiac mitochondrial oxidative capacity with both 18% and 30% protein. We then assessed more advanced heart failure, with 22 weeks of aortic constriction. We again saw no difference in cardiac mass, left ventricular volume, mitochondrial oxidative capacity or resistance to permeability transition between the 18% and 30% protein diets. There was a modest but significant decrease in survival with heart failure with the 30% protein diet compared with 18% protein (p < 0.003). In conclusion, consumption of a high-protein diet did not affect cardiac mass, left ventricular volumes or ejection fraction, or myocardial mitochondrial oxidative capacity in rats with pressure overload induced heart failure, but significantly decreased survival. PMID- 24476483 TI - Wild blueberry consumption affects aortic vascular function in the obese Zucker rat. AB - This study evaluates the effect of wild blueberry (WB) consumption on the biomechanical properties of the aorta in the obese Zucker rat (OZR), a model of the metabolic syndrome. Thirty-six OZRs and 36 lean controls (lean Zucker rats) were placed either on a WB-enriched or a control (C) diet for 8 weeks. Phenylephrine (Phe)-mediated vasoconstriction and acetylcholine (Ach)-mediated vasorelaxation in the aortic vessel were investigated, as well as the contribution of the nitric oxide synthase and cyclooxygenase (COX) pathways in each of the above responses by using specific inhibitors. Obese Zucker rats exhibited a reduced vasocontstrictor response to Phe and an exaggerated vasorelaxant response to Ach. The WB diet partially restored Phe-induced constrictor responses and attenuated Ach-induced relaxant responses in OZR. Plasma nitric oxide was significantly attenuated (22.1 +/- 1.1 MUmol.L(-1), WB vs 25.6 +/- 1.4 MUmol.L(-1), C, p <= 0.05) with the WB diet. Thromboxane A2 levels in the aortic effluent were not significantly affected in the WB diet group, while PGI2 concentration significantly increased (766.5 +/- 92.2 pg.mg(-1) aorta in the WB vs 571.7 +/- 37.8 pg.g(-1) aorta in the C group, p <= 0.05). Downregulation of inducible nitric oxide synthase and COX2 expression in the OZR aorta was observed in the WB diet group. In conclusion, WB consumption altered the biomechanical properties of the OZR aorta by partially restoring the impaired Phe-induced constrictor responses and attenuating the exaggerated response to Ach induced vasorelaxation. PMID- 24476484 TI - Performing resistance exercise before versus after aerobic exercise influences growth hormone secretion in type 1 diabetes. AB - We compared growth hormone (GH) and plasma glucose (PG) levels in type 1 diabetic individuals performing aerobic before resistance exercise (AR) to when resistance exercise was performed first (RA). In AR, GH secretion declined in late exercise while it rose throughout exercise in RA, resulting in higher GH in RA versus AR at exercise completion. Higher GH during RA may support PG by increasing hepatic glucose production and lipid mobilization. PMID- 24476485 TI - Exercise-induced arterial hypoxemia is unaffected by intense physical training: a case report. AB - Exercise-induced arterial hypoxemia (EIAH) occurs in some healthy humans at sea level, whereby the most aerobically trained individuals develop the most severe hypoxemia. A female competitive runner completed 2 maximal exercise tests. Maximal oxygen consumption increased by 15% between testing days, but the degree of hypoxemia remained similar (PaO2, SaO2; 82 and 80 mm Hg; 93.8% and 92.8%; first and second test, respectively). Our case indicates that EIAH does not necessarily worsen with aerobic training. PMID- 24476486 TI - Women reduced the sex difference in open-water ultra-distance swimming [Formula: see text] La Traversee Internationale du Lac St-Jean, 1955-2012. AB - In La Traversee Internationale du Lac St-Jean, held between 1955 and 2012 in Canada, the fastest women (r(2) = 0.61, p < 0.0001) and men (r(2) = 0.66, p < 0.0001) improved swimming speed over the years but the sex difference remained unchanged at 8.8% +/- 5.6% (r(2) = 0.069, p = 0.065). Annually, for the 3 fastest swimmers, both women (r(2) = 0.53, p < 0.0001) and men (r(2) = 0.71, p < 0.0001) improved swimming speed between 1973 and 2012 and the sex difference decreased (r(2) = 0.29, p = 0.0016) from 14.4% +/- 11.0% (1973) to 3.7% +/- 1.4% (2012). PMID- 24476488 TI - Translation of ERC resuscitation guidelines into clinical practice by emergency physicians. AB - PURPOSE: Austrian out-of-hospital emergency physicians (OOHEP) undergo mandatory biannual emergency physician refresher courses to maintain their licence. The purpose of this study was to compare different reported emergency skills and knowledge, recommended by the European Resuscitation Council (ERC) guidelines, between OOHEP who work regularly at an out-of-hospital emergency service and those who do not currently work as OOHEP but are licenced. METHODS: We obtained data from 854 participants from 19 refresher courses. Demographics, questions about their practice and multiple-choice questions about ALS-knowledge were answered and analysed. We particularly explored the application of therapeutic hypothermia, intraosseous access, pocket guide use and knowledge about the participants' defibrillator in use. A multivariate logistic regression analysed differences between both groups of OOHEP. Age, gender, years of clinical experience, ERC-ALS provider course attendance and the self-reported number of resuscitations were control variables. RESULTS: Licenced OOHEP who are currently employed in emergency service are significantly more likely to initiate intraosseous access (OR = 4.013, p < 0.01), they initiate mild-therapeutic hypothermia after successful resuscitation (OR = 2.550, p < 0.01) more often, and knowledge about the used defibrillator was higher (OR = 2.292, p < 0.01). No difference was found for the use of pocket guides.OOHEP who have attended an ERC ALS provider course since 2005 have initiated more mild therapeutic hypothermia after successful resuscitation (OR = 1.670, p <0.05) as well as participants who resuscitated within the last year (OR = 2.324, p < 0.01), while older OOHEP initiated mild therapeutic hypothermia less often, measured per year of age (OR = 0.913, p <0.01). CONCLUSION: Licenced and employed OOHEP implement ERC guidelines better into clinical practice, but more training on life-saving rescue techniques needs to be done to improve knowledge and to raise these rates of application. PMID- 24476489 TI - Associations of number of teeth with risks for all-cause mortality and cause specific mortality in middle-aged and elderly men in the northern part of Japan: the Iwate-KENCO study. AB - OBJECTIVES: The objective of this study was to determine the associations of number of teeth with all-cause mortality and cause-specific mortality among middle-aged and elderly Japanese men. METHODS: A total of 7779 men aged 40-79 years who were free from cardiovascular disease (CVD) were followed up prospectively for 5.6 years. Participants were categorized into four groups (no teeth, 1-9 teeth, 10-19 teeth, and >=20 teeth) by a self-administered questionnaire. Using Cox's proportional hazard model, multivariate hazard ratios (HRs) and 95% confidence intervals (CIs) for mortality from all causes, CVD, cancer, and noncancer, non-CVD according to number of teeth were estimated with adjustments for age, body mass index, systolic blood pressure, total- and HDL cholesterol, HbA1c, current smoking, current alcohol drinking, and low level of education. RESULTS: The numbers (proportions) of participants with no teeth, 1-9 teeth, 10-19 teeth, and >=20 teeth were 1613 (20.7%), 1650 (21.2%), 1721 (22.1%), and 2795 (35.9%), respectively. During follow-up, a total of 455 deaths (including 175 deaths from cancer, 98 deaths from CVD, and 130 deaths from noncancer, non-CVD) were recorded. In total participants, an inverse relationship between number of teeth and all-cause mortality was found (P for trend = 0.049). Among men aged 40-64 years, inverse relationships were also found in risks for mortality from all causes, CVD, and cancer: multivariate-adjusted HRs (95% CI) for all-cause mortality in men with no teeth, 1-9 teeth, and 10-19 teeth relative to men with >=20 teeth were 2.75 (1.37-5.49), 1.89 (0.99-3.63), and 1.94 (1.09 3.43), respectively. However, there were no associations of number of teeth with all-cause mortality and cause-specific mortality among men aged 65-79 years. CONCLUSIONS: The number of teeth is an important predictive factor for mortality among middle-aged Japanese men. PMID- 24476490 TI - Lack of P2Y13 in mice fed a high cholesterol diet results in decreased hepatic cholesterol content, biliary lipid secretion and reverse cholesterol transport. AB - BACKGROUND: The protective effect of HDL is mostly attributed to their metabolic function in reverse cholesterol transport (RCT), a process whereby excess cellular cholesterol is taken up from peripheral cells, processed in HDL particles, and later delivered to the liver for further metabolism and biliary secretion. Mechanistically, the purinergic P2Y13 ADP-receptor is involved in hepatic HDL endocytosis (i.e., uptake of both HDL protein + lipid moieties), which is considered an important step of RCT. Accordingly, chow-fed P2Y13 knockout (P2Y13-/-) mice exhibit lower hepatic HDL uptake, which translates into a decrease of hepatic free cholesterol content and biliary cholesterol and phospholipid secretion. FINDINGS: The aim of this study was to determine the effect of high cholesterol diet (HCD) in P2Y13-/- mice, in order to mimic high dietary cholesterol intake, which is a major cause of dyslipidemia in humans. As previously reported with chow-diet, HCD did not affect plasma lipid levels in P2Y13-/- compared with control mice but decreased hepatic free and esterified cholesterol content (p < 0.05, P2Y13-/- versus control). Interestingly, biliary lipid secretion and macrophages-to-feces RCT were more dramatically impaired in P2Y13-/- mice fed a HCD than chow-diet. HCD did not enhance atherosclerosis in P2Y13-/- compared with control mice. CONCLUSION: This study demonstrates that high dietary cholesterol intake accentuated the metabolic phenotype of P2Y13-/- mice, with impaired hepatobiliary RCT. Although other animal models might be required to further evaluate the role of P2Y13 receptor in atherosclerosis, P2Y13 appears a promising target for therapeutic intervention aiming to stimulate RCT, particularly in individuals with lipid-rich diet. PMID- 24476492 TI - Anaplastic lymphoma kinase inhibitors as anticancer therapeutics: a patent review. AB - INTRODUCTION: Anaplastic lymphoma kinase (ALK), a receptor tyrosine kinase from the insulin receptor superfamily, is implicated in the oncogenesis of numerous cancers including anaplastic large-cell lymphoma, non-small-cell lung cancer, diffuse large B-cell lymphoma, inflammatory myofibroblastic tumors, glioblastoma, as well as neuroblastoma. The root cause for these specific cancers has been identified as aberrant ALK kinase activity, which has been shown to be associated with specific gene translocations, single-point mutations, gene amplification and/or overexpression. The direct inhibition of ALK with small-molecule inhibitors represents a viable therapeutic intervention that has achieved clinical proof of concept. AREAS COVERED: Small-molecule ALK inhibitors covered in the patent literature from 2010 to September 2013 are described. Relevant peer reviewed journal articles that describe discovery and development of the above identified ALK inhibitors are also discussed. Keyword-based (e.g., ALK, anaplastic lymphoma kinase) literature searches were conducted in Scifinder(r). EXPERT OPINION: Novel ALK inhibitors continued to be discovered at a fast pace over the covered period, with many distinct chemotypes emerging. Crizotinib received FDA approval in 2011, and six additional ALK inhibitors have entered clinical trials. The focus of ALK research appears to have shifted toward inhibitors that display activity against resistant mutants unearthed in clinical studies with crizotinib. PMID- 24476491 TI - The development of a guideline implementability tool (GUIDE-IT): a qualitative study of family physician perspectives. AB - BACKGROUND: The potential of clinical practice guidelines has not been realized due to inconsistent adoption in clinical practice. Optimising intrinsic characteristics of guidelines (e.g., its wording and format) that are associated with uptake (as perceived by their end users) may have potential. Using findings from a realist review on guideline uptake and consultation with experts in guideline development, we designed a conceptual version of a future tool called Guideline Implementability Tool (GUIDE-IT). The tool will aim to involve family physicians in the guideline development process by providing a process to assess draft guideline recommendations. This feedback will then be given back to developers to consider when finalizing the recommendations. As guideline characteristics are best assessed by end-users, the objectives of the current study were to explore how family physicians perceive guideline implementability, and to determine what components should comprise the final GUIDE-IT prototype. METHODS: We conducted a qualitative study with family physicians in Toronto, Ontario. Two experienced investigators conducted one-hour interviews with family physicians using a semi-structured interview guide to 1) elicit feedback on perceptions on guideline implementability; 2) to generate a discussion in response to three draft recommendations; and 3) to provide feedback on the conceptual GUIDE-IT. Sessions were audio taped and transcribed verbatim. Data collection and analysis were guided by content analyses. RESULTS: 20 family physicians participated. They perceived guideline uptake according to facilitators and barriers across 6 categories of guideline implementability (format, content, language, usability, development, and the practice environment). Participants' feedback on 3 draft guideline recommendations were grouped according to guideline perception, cognition, and agreement. When asked to comment on GUIDE-IT, most respondents believed that the tool would be useful, but urged to involve "regular" or community family physicians in the process, and suggested that an online system would be the most efficient way to deliver it. CONCLUSIONS: Our study identified facilitators and barriers of guideline implementability from the perspective of community and academic family physicians that will be used to build our GUIDE-IT prototype. Our findings build on current knowledge by showing that family physicians perceive guideline uptake mostly according to factors that are in the control of guideline developers. PMID- 24476494 TI - Electron beam nanosculpting of Kirkendall oxide nanochannels. AB - The nanomanipulation of metal nanoparticles inside oxide nanotubes, synthesized by means of the Kirkendall effect, is demonstrated. In this strategy, a focused electron beam, extracted from a transmission electron microscope source, is used to site-selectively heat the oxide material in order to generate and steer a metal ion diffusion flux inside the nanochannels. The metal ion flux generated inside the tube is a consequence of the reduction of the oxide phase occurring upon exposure to the e-beam. We further show that the directional migration of the metal ions inside the nanotubes can be achieved by locally tuning the chemistry and the morphology of the channel at the nanoscale. This allows sculpting organized metal nanoparticles inside the nanotubes with various sizes, shapes, and periodicities. This nanomanipulation technique is very promising since it enables creating unique nanostructures that, at present, cannot be produced by an alternative classical synthesis route. PMID- 24476493 TI - Study of the structural and dynamic effects in the FimH adhesin upon alpha-d heptyl mannose binding. AB - Uropathogenic Escherichia coli cause urinary tract infections by adhering to mannosylated receptors on the human urothelium via the carbohydrate-binding domain of the FimH adhesin (FimHL). Numerous alpha-d-mannopyranosides, including alpha-d-heptyl mannose (HM), inhibit this process by interacting with FimHL. To establish the molecular basis of the high-affinity HM binding, we solved the solution structure of the apo form and the crystal structure of the FimHL-HM complex. NMR relaxation analysis revealed that protein dynamics were not affected by the sugar binding, yet HM addition promoted protein dimerization, which was further confirmed by small-angle X-ray scattering. Finally, to address the role of Y48, part of the "tyrosine gate" believed to govern the affinity and specificity of mannoside binding, we characterized the FimHL Y48A mutant, whose conformational, dynamical, and HM binding properties were found to be very similar to those of the wild-type protein. PMID- 24476495 TI - Chemotherapy-induced oral mucositis: effect of LED and laser phototherapy treatment protocols. AB - BACKGROUND AND OBJECTIVE: Over the last few decades, many studies have focused on the effect of lasers on the management of oral mucositis in oncologic patients treated with chemotherapy and/or radiotherapy. However, the effect of light emitting diode (LED) has been poorly studied, and was not compared with that of laser phototherapy (LPT). For this reason, the aim of the present study was to clinically compare the effect of these two therapies on chemotherapy-induced oral mucositis (CIOM) and pain. METHODS: Forty patients with CIOM were divided into two groups: G1, patients treated with LPT; G2, patients treated with LED. The treatment was administered during 10 consecutive days, with exception of weekends. LPT was applied using an InGaAlP laser (660 nm/40 mW/6.6 J cm-(2)/0.24 J per point/0.036 cm(2) of spot size). LED phototherapy was applied using 0.24 J per point/80 mW/630 nm/1 cm(2) of spot size. CIOM was assessed during each session in accordance to the World Health Organization (WHO) score. The patient self-assessed pain was scored on a visual analog scale (VAS). RESULTS: The mean VAS and WHO scores were significantly smaller in the LED group (p<0.05). However, both groups required the same number of days to reach score zero for mucositis and pain (p>0.05). Moreover, in the group with severe mucositis (score III), there was a lower frequency of patients with complete healing and pain relief, with the exception of analgesia in G2, in which almost all patients were completely relieved from pain. CONCLUSIONS: These findings suggest that LED therapy is more effective than LPT in the treatment of COIM, with the parameters used in the present study. PMID- 24476496 TI - Light pumping energy into blood mitochondria: a new trend against depression? PMID- 24476498 TI - In vivo multiclonal transfer of bla(KPC-3) from Klebsiella pneumoniae to Escherichia coli in surgery patients. AB - During active surveillance at the Mediterranean Institute for Transplantation and Advanced Specialized Therapies (ISMETT, Palermo, Italy) with the CARBA screening medium, five pairs of Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae and Escherichia coli strains were isolated in each of five colonized patients. In each patient, lateral gene transfer was demonstrated by comparing K. pneumoniae and E. coli strains, both possessing KPC-3, Tn4401a and pKpQIL-IT elements. The isolates were found to be multiclonal by multilocus sequence typing (sequence type (ST) 512 related to ST258, and ST307 belonging to a clonal complex different from the habitual sequence clone ST258 isolated in Italy) and pulsed field gel electrophoresis. The results of our study highlight the easy transfer of KPC among Enterobacteriaceae colonizing the human intestine, and the active and careful surveillance required to identify and prevent the spread of these multidrug-resistant microorganisms. PMID- 24476499 TI - Angiogenic factors in sepsis: are we ready for the new therapeutic era? PMID- 24476500 TI - Proteome-driven elucidation of adaptive responses to combined vitamin E and C deficiency in zebrafish. AB - The purpose of this study was to determine the system-wide consequences of deficiencies in two essential micronutrients, vitamins E and C, on the proteome using zebrafish (Danio rerio) as one of the few vertebrate models that similar to humans cannot synthesize vitamin C. We describe a label-free proteomics workflow to detect changes in protein abundance estimates dependent on vitamin regimes. We used ion-mobility-enhanced data-independent tandem mass spectrometry to determine differential regulation of proteins in response to low dietary levels of vitamin C with or without vitamin E. The detection limit of the method was as low as 20 amol, and the dynamic range was five orders of magnitude for the protein-level estimates. On the basis of the quantitative changes obtained, we built a network of protein interactions that reflect the whole organism's response to vitamin C deficiency. The proteomics-driven study revealed that in vitamin-E-deficient fish, vitamin C deficiency is associated with induction of stress response, astrogliosis, and a shift from glycolysis to glutaminolysis as an alternative mechanism to satisfy cellular energy requirements. PMID- 24476501 TI - Outcome of deceased donor renal transplantation in patients with an ileal conduit. AB - Renal transplantation in recipients with an ileal conduit is uncommon and occasionally controversial as it has been associated with high morbidity and mortality rates. We report on 17 patients with an ileal conduit who received a deceased donor renal transplant at our institution between January 1986 and December 2012. We retrospectively reviewed their allograft and surgical outcome. There were four mortalities at five, five, 39, and 66 months post-transplant. Sixteen of 17 grafts functioned immediately; one patient had primary non-function secondary to vascular thrombosis. Thirteen of 17 (76.5%) grafts were functioning at a mean follow-up period of 105 months. The mean serum creatinine at follow-up was 111 MUM (+/-38.62). Five patients had seven episodes of urosepsis requiring hospital admission, and five patients received treatment for renal stone disease. We conclude that given improvements in immunosuppression, surgical technique, infection treatment, and selection criteria, we believe that renal transplantation in the patient with an ileal conduit yields excellent graft survival, although there is a high morbidity rate in this cohort of patients in the long term. PMID- 24476503 TI - Simultaneous reinforcing and toughening of polyurethane via grafting on the surface of microfibrillated cellulose. AB - In the present work, a series of thermoplastic polyurethane (TPU)/microfibrillated cellulose (MFC) nanocomposites were successfully synthesized via in situ polymerization. TPU was covalently grafted onto the MFC by particular association with the hard segments, as evidenced by Fourier transform infrared spectroscopy, X-ray photoelectron spectroscopy, and thermogravimetric analysis. The adequate dispersion and network structure of MFC in the TPU matrix and the strong interfacial interaction through covalent grafting and hydrogen bonding between MFC and TPU resulted in significantly improved mechanical properties and thermostability of the prepared nanocomposites. The tensile strength and elongation-at-break of the nanocomposite containing only 1 wt % MFC were increased by 4.5-fold and 1.8-fold compared with that of neat TPU, respectively. It was also very interesting to find that the glass transition temperature (Tg) of TPU was decreased significantly with the introduction of MFC, indicating potential for low-temperature resistance applications. Most importantly, compared with TPU nanocomposites reinforced with other nanofillers, the TPU/MFC nanocomposites prepared in this work exhibited excellent transparency and higher reinforcing efficiency. PMID- 24476502 TI - PARP-1 inhibition attenuates neuronal loss, microglia activation and neurological deficits after traumatic brain injury. AB - Traumatic brain injury (TBI) causes neuronal cell death as well as microglial activation and related neurotoxicity that contribute to subsequent neurological dysfunction. Poly (ADP-ribose) polymerase (PARP-1) induces neuronal cell death through activation of caspase-independent mechanisms, including release of apoptosis inducing factor (AIF), and microglial activation. Administration of PJ34, a selective PARP-1 inhibitor, reduced cell death of primary cortical neurons exposed to N-Methyl-N'-Nitro-N-Nitrosoguanidine (MNNG), a potent inducer of AIF-dependent cell death. PJ34 also attenuated lipopolysaccharide and interferon-gamma-induced activation of BV2 or primary microglia, limiting NF kappaB activity and iNOS expression as well as decreasing generation of reactive oxygen species and TNFalpha. Systemic administration of PJ34 starting as late as 24 h after controlled cortical impact resulted in improved motor function recovery in mice with TBI. Stereological analysis demonstrated that PJ34 treatment reduced the lesion volume, attenuated neuronal cell loss in the cortex and thalamus, and reduced microglial activation in the TBI cortex. PJ34 treatment did not improve cognitive performance in a Morris water maze test or reduce neuronal cell loss in the hippocampus. Overall, our data indicate that PJ34 has a significant, albeit selective, neuroprotective effect after experimental TBI, and its therapeutic effect may be from multipotential actions on neuronal cell death and neuroinflammatory pathways. PMID- 24476504 TI - Endocrine profile following stimulation with recombinant follicle stimulating hormone and luteinizing hormone versus highly purified human menopausal gonadotropin. AB - BACKGROUND: Luteinizing hormone (LH) activity in human menopausal gonadotropin (hMG) preparations is derived from human chorionic gonadotropin (hCG) rather than LH. Therefore, we aimed to determine whether there are similarities in the endocrine and follicular profiles of serum and follicular fluid from controlled ovarian stimulation with the recombinant gonadotropins follicle-stimulating hormone plus luteinizing hormone (rFSH + rLH) or highly purified human menopausal gonadotropin (HP-hMG). METHODS: We performed a prospective observational study with 50 oocyte donors that received either a combination of recombinant gonadotropins (rFSH + rLH) or a mixture of urinary gonadotropins (HP-hMG) plus purified urinary FSH (uFSH). Results were analyzed using Student's t-test to compare continuous variables and the chi-squared test to compare proportions. P values < 0.05 were considered statistically significant. RESULTS: Although more oocytes were retrieved after treatment with recombinant than urinary gonadotropins (16.5 vs. 11.8; P = 0.049), a higher proportion of metaphase II ova (71.2% vs. 80.6%; P = 0.003) were obtained using urinary gonadotropins. On day 6 and on the day of triggering, serum steroid hormone levels were slightly but not significantly elevated in the recombinant group compared with the urinary group. In follicular fluid, no statistical differences were observed for intra follicular levels of steroid hormones between the two protocols; ongoing pregnancy rates were similar (46.1% vs. 46.1%). CONCLUSIONS: Our data suggest that endocrinological and follicular profiles do not differ between rFSH + rLH and HP-hMG stimulation. PMID- 24476506 TI - Measurement of stiffness in patients with rheumatoid arthritis in low disease activity or remission: a systematic review. AB - BACKGROUND: Recent qualitative research has shown that stiffness is an important symptom for patients to identify remission. However, it is unclear how to measure stiffness in low disease activity. This systematic review aims to summarise the existing literature on validity of patient reported outcomes to measure stiffness in RA low disease activity states, to aid the choice for a measurement instrument. METHODS: An extensive pubmed-search was undertaken, identifying measurement instruments for patient perceived stiffness used in low disease activity. Eligible studies reported on 1) stiffness as an outcome in relation to other core set measures, 2) development of a patient reported tool to measure stiffness, or 3) comparison of two different tools to measure aspects of stiffness, all in low disease activity. RESULTS: Of 788 titles, only two studies report on validity of stiffness measures within low disease activity. Morning stiffness (MS) is reported in 44 to 80% of patients in low disease activity. A difference of 40 to 60 minutes in duration until maximum improvement is observed between active and inactive patients. Severity of MS might discriminate better between high and low disease activity compared to measurement of duration of MS. CONCLUSIONS: There is insufficient data on measurement of stiffness in the spectrum of low disease activity or remission. PMID- 24476507 TI - The neuronal cytoskeleton as a potential target in the developmental neurotoxicity of organophosphorothionate insecticides. AB - Phosphorothionates are toxicologically the most important class of organophosphorus ester (OP) insecticides. Phosphorothionates are metabolically converted in vivo to their oxon analogues. These oxon metabolites can bind and inhibit acetylcholinesterase, thus causing acute cholinergic neurotoxicity. Oxon binding to the same target may also be partly responsible for manifestation of the 'intermediate syndrome'. More recent evidence suggests that the oxons may be also capable of inducing developmental neurotoxicity. The neuronal cytoskeleton may represent a potential target for the developmental neurotoxicity of the oxons because of its vital importance in many stages of normal neurodevelopment. Data obtained in the last five years and critically reviewed here indicate that the oxon metabolites, at concentrations that can be attained in vivo, exert potent effects on the neuronal cytoskeleton disrupting all three cytoskeletal networks. This disruption is expressed at the level of cytoskeletal protein expression, intracellular distribution, post-translational modification, cytoskeletal dynamics and function and may involve effects on both neuronal and glial cells. These effects are not secondary to other changes but may constitute primary effects of the oxons, as these compounds have been shown to be capable of covalently binding to and organophosphorylating multiple sites on tubulin and actin. Analogous studies must be extended to include other neurodevelopmentally important cytoskeletal proteins, such as neurofilament heavy chain, and tau, which are known to contain unusually high numbers of phosphorylatable sites and to establish whether organophosphorylation by the oxons takes place at sites where neurodevelopmentally relevant, endogenous, reversible phosphorylation is known to occur. PMID- 24476508 TI - Editorial: Educating the good for nothing student. PMID- 24476509 TI - Gas phase production and loss of isoprene epoxydiols. AB - Isoprene epoxydiols (IEPOX) form in high yields from the OH-initiated oxidation of isoprene under low-NO conditions. These compounds contribute significantly to secondary organic aerosol formation. Their gas-phase chemistry has, however, remained largely unexplored. In this study, we characterize the formation of IEPOX isomers from the oxidation of isoprene by OH. We find that cis-beta- and trans-beta-IEPOX are the dominant isomers produced, and that they are created in an approximate ratio of 1:2 from the low-NO oxidation of isoprene. Three isomers of IEPOX, including cis-beta- and trans-beta, were synthesized and oxidized by OH in environmental chambers under high- and low-NO conditions. We find that IEPOX reacts with OH at 299 K with rate coefficients of (0.84 +/- 0.07) * 10(-11), (1.52 +/- 0.07) * 10(-11), and (0.98 +/- 0.05) * 10(-11) cm(3) molecule(-1) s(-1) for the delta1, cis-beta, and trans-beta isomers. Finally, yields of the first generation products of IEPOX + OH oxidation were measured, and a new mechanism of IEPOX oxidation is proposed here to account for the observed products. The substantial yield of glyoxal and methylglyoxal from IEPOX oxidation may help explain elevated levels of those compounds observed in low-NO environments with high isoprene emissions. PMID- 24476512 TI - Commercially available blood-group antibodies may be used to visualize blood group A antigen in paraffin-embedded tissue sections. PMID- 24476510 TI - Psychometric properties of the Late-Life Function and Disability Instrument: a systematic review. AB - BACKGROUND: The choice of measure for use as a primary outcome in geriatric research is contingent upon the construct of interest and evidence for its psychometric properties. The Late-Life Function and Disability Instrument (LLFDI) has been widely used to assess functional limitations and disability in studies with older adults. The primary aim of this systematic review was to evaluate the current available evidence for the psychometric properties of the LLFDI. METHODS: Published studies of any design reporting results based on administration of the original version of the LLFDI in community-dwelling older adults were identified after searches of 9 electronic databases. Data related to construct validity (convergent/divergent and known-groups validity), test-retest reliability and sensitivity to change were extracted. Effect sizes were calculated for within group changes and summarized graphically. RESULTS: Seventy-one studies including 17,301 older adults met inclusion criteria. Data supporting the convergent/divergent and known-groups validity for both the Function and Disability components were extracted from 30 and 18 studies, respectively. High test-retest reliability was found for the Function component, while results for the Disability component were more variable. Sensitivity to change of the LLFDI was confirmed based on findings from 25 studies. The basic lower extremity subscale and overall summary score of the Function component and limitation dimension of the Disability component were associated with the strongest relative effect sizes. CONCLUSIONS: There is extensive evidence to support the construct validity and sensitivity to change of the LLFDI among various clinical populations of community-dwelling older adults. Further work is needed on predictive validity and values for clinically important change. Findings from this review can be used to guide the selection of the most appropriate LLFDI subscale for use an outcome measure in geriatric research and practice. PMID- 24476513 TI - In reply. PMID- 24476514 TI - Screening for cervical cancer in low-resource settings in 2011. PMID- 24476515 TI - Checklists, protocols, and the "gold standard" approach. PMID- 24476516 TI - Luminal subtypes predict improved survival following central nervous system metastasis in patients with surgically managed metastatic breast carcinoma. AB - CONTEXT: Metastatic breast cancer to the central nervous system (CNS) is second only to lung cancer metastasis to the CNS in frequency. Patients with triple negative primary breast cancer and those with human epidermal growth factor receptor 2 (HER2)-positive primary breast cancer are at an increased risk for metastasis. Very little is known about predictive or prognostic variables once patients develop CNS metastases. Currently, therapeutic options are limited, with surgery generally offered primarily to those with solitary lesions. OBJECTIVES: To determine the influence of molecular subtypes of metastatic breast cancer on survival from the time of CNS metastasis and to aid in the prognostic stratification of these patients. DESIGN: We identified 59 cases of metastatic breast cancer to the CNS and analyzed them for various demographic and clinicopathologic parameters. Tumors were categorized into molecular subtypes using immunohistochemical methods: luminal A [estrogen receptor (ER+)/Ki67low], luminal B (ER+/Ki67 high), intrinsic HER2 (ER-/HER2+), and triple-negative. Survival after CNS metastasis for each group was plotted using a Kaplan-Meier curve, and multivariate analysis was performed. RESULTS: Patients with metastases from luminal tumors had a statistically significant survival advantage when compared with those of the triple-negative phenotype. Importantly, survival among patients with luminal A and luminal B tumors was not significantly different. Similarly, patient's age, histologic grade, and number of lesions did not contribute to determining outcomes. CONCLUSIONS: Estrogen receptor positivity (ie, luminal phenotype) of tumors appears to determine outcomes after development of metastases. In contrast, proliferation rate had little or no effect on the long-term survival. Understanding the biology of metastases can help stratify patients into prognostically meaningful categories and tailor treatment regimens for individual patients. PMID- 24476517 TI - Protocol for the examination of specimens from patients with pheochromocytomas and extra-adrenal paragangliomas. AB - During the last decade there have been revolutionary breakthroughs in understanding the biology of pheochromocytomas and extra-adrenal paragangliomas. Discoveries of new susceptibility genes and genotype-phenotype correlations have led to the realization that appropriate patient care requires a complete integration of clinical, genetic, biochemical, imaging, and pathology findings. Clinical practice has in many cases not kept pace with the rate of discovery, underscoring a need for updated procedures for evaluation of patient specimens and reporting of data. We therefore propose a new synoptic reporting approach for pheochromocytomas and extra-adrenal paragangliomas that will provide clear and uniform information to pathologists and clinicians, in order to advance the diagnosis of these neoplasms and optimize patient care. PMID- 24476518 TI - Evaluation of Barrett esophagus by multiphoton microscopy. AB - CONTEXT: Multiphoton microscopy (MPM) based on 2-photon excitation fluorescence and second-harmonic generation allows simultaneous visualization of cellular details and extracellular matrix components of fresh, unfixed, and unstained tissue. Portable multiphoton microscopes, which could be placed in endoscopy suites, and multiphoton endomicroscopes are in development, but their clinical utility is unknown. OBJECTIVE: To examine fresh, unfixed endoscopic biopsies obtained from the distal esophagus and gastroesophageal junction to (1) define the MPM characteristics of normal esophageal squamous mucosa and gastric columnar mucosa, and (2) evaluate whether diagnosis of intestinal metaplasia/Barrett esophagus (BE) could be made reliably with MPM. DESIGN: The study examined 35 untreated, fresh biopsy specimens from 25 patients who underwent routine upper endoscopy. A Zeiss LSM 710 Duo microscope (Carl Zeiss, Thornwood, New York) coupled to a Spectra-Physics (Mountain View, California) Tsunami Ti:sapphire laser was used to obtain a MPM image within 4 hours of fresh specimen collection. After obtaining MPM images, the biopsy specimens were placed in 10% buffered formalin and submitted for routine histopathologic examination. Then, the MPM images were compared with the findings in the hematoxylin-eosin-stained, formalin fixed, paraffin-embedded sections. The MPM characteristics of the squamous, gastric-type columnar and intestinal-type columnar epithelium were analyzed. In biopsies with discrepancy between MPM imaging and hematoxylin-eosin-stained sections, the entire tissue block was serially sectioned and reevaluated. A diagnosis of BE was made when endoscopic and histologic criteria were satisfied. RESULTS: Based on effective 2-photon excitation fluorescence of cellular reduced pyridine nucleotides and flavin adenine dinucleotide and lack of 2-photon excitation fluorescence of mucin and cellular nuclei, MPM could readily identify and distinguish among squamous epithelial cells, goblet cells, gastric foveolar type mucous cells, and parietal cells in the area of gastroesophageal junction. Based on the cell types identified, the mucosa was defined as squamous, columnar gastric type (cardia/fundic-type), and metaplastic columnar intestinal-type/BE. Various types of mucosa seen in the study of 35 biopsies included normal squamous mucosa only (n = 14; 40%), gastric cardia-type mucosa only (n = 2; 6%), gastric fundic mucosa (n = 6; 17%), and both squamous and gastric mucosa (n = 13; 37%). Intestinal metaplasia was identified by the presence of goblet cells in 10 of 25 cases (40%) leading to a diagnosis of BE on MPM imaging and only in 7 cases (28%) by histopathology. In 3 of 35 biopsies (9%), clear-cut goblet cells were seen by MPM imaging but not by histopathology, even after the entire tissue block was sectioned. Based on effective 2-photon excitation fluorescence of elastin and second-harmonic generation of collagen, connective tissue in the lamina propria and the basement membrane was also visualized with MPM. CONCLUSIONS: Multiphoton microscopy has the ability to accurately distinguish squamous epithelium and different cellular elements of the columnar mucosa obtained from biopsies around the gastroesophageal junction, including goblet cells that are important for the diagnosis of BE. Thus, use of MPM in the endoscopy suite might provide immediate microscopic images during endoscopy, improving screening and surveillance of patients with BE. PMID- 24476520 TI - Reevaluating significance of perineural invasion in gastric cancer based on double immunohistochemical staining. AB - CONTEXT: In gastric cancer, the significance of perineural invasion remains controversial. Detecting perineural invasion with hematoxylin-eosin staining often leads to misdiagnosis. Labeling nerves by immunohistochemistry greatly assists perineural invasion detection, but it might also be misdiagnosed, because scattered cancer cells are difficult to recognize. OBJECTIVE: To reevaluate the significance of perineural invasion in gastric cancer by double immunohistochemical staining that labels both nerves and cancer cells, and to examine agreements on perineural invasion detection between double immunohistochemical staining and single immunochemical staining (to label nerves) or hematoxylin-eosin staining. DESIGN: We evaluated perineural invasion in 160 cases of gastric cancer with double immunohistochemical staining, single immunochemical staining, and hematoxylin-eosin staining, respectively; then we investigated the prognostic significance of perineural invasion. RESULTS: Perineural invasion was detected in 65.0% (104 of 160), 38.1% (61 of 160), and 56.9% (91 of 160) of cases with double immunohistochemical staining, hematoxylin eosin staining, and single immunohistochemical staining, respectively. Agreement was low between double staining and hematoxylin-eosin staining (kappa = .34), and most false reports occurred in diffuse gastric cancer. Agreement between single immunochemical staining and double staining was good (kappa = .67), but it declined in diffuse gastric cancer (kappa = .28). Perineural invasion was closely associated with other clinicopathologic variables. Although perineural invasion positive patients had a worse outcome than perineural invasion-negative patients, it was not an independent prognostic factor (P = .11; hazard ratio, 0.637; 95% confidence interval, 0.366-1.110). CONCLUSIONS: Double immunohistochemical staining could improve accuracy of perineural invasion detection in gastric cancer, particularly in the diffuse type. Moreover, perineural invasion predicts a poor outcome in gastric cancer, but it cannot provide more information than traditional clinicopathologic variables. PMID- 24476519 TI - Differentiation of pancreatic ductal adenocarcinoma from chronic pancreatitis by PAM4 immunohistochemistry. AB - CONTEXT: PAM4 is a monoclonal antibody that shows high specificity for pancreatic ductal adenocarcinoma (PDAC) and its neoplastic precursor lesions. A PAM4-based serum immunoassay is able to detect 71% of early-stage patients and 91% with advanced disease. However, approximately 20% of patients diagnosed with chronic pancreatitis (CP) are also positive for circulating PAM4 antigen. The specificity of the PAM4 antibody is critical to the interpretation of the serum-based and immunohistochemical assays for detection of PDAC. OBJECTIVE: To determine whether PAM4 can differentiate PDAC from nonneoplastic lesions of the pancreas. DESIGN: Tissue microarrays of PDAC (N = 43) and surgical specimens from CP (N = 32) and benign cystic lesions (N = 19) were evaluated for expression of the PAM4 biomarker, MUC1, MUC4, CEACAM5/6, and CA19-9. RESULTS: PAM4 and monoclonal antibodies (MAbs) to MUC1, MUC4, CEACAM5/6, and CA19-9 were each reactive with the majority of PDAC cases; however, PAM4 was the only monoclonal antibody not to react with adjacent, nonneoplastic parenchyma. Although PAM4 labeled 19% (6 of 32) of CP specimens, reactivity was restricted to pancreatic intraepithelial neoplasia associated with CP; inflamed tissues were negative in all cases. In contrast, MUC1, MUC4, CEACAM5/6, and CA19-9 were detected in 90%, 78%, 97%, and 100% of CP, respectively, with reactivity also present in nonneoplastic inflamed tissue. CONCLUSIONS: PAM4 was the only monoclonal antibody able to differentiate PDAC (and pancreatic intraepithelial neoplasia precursor lesions) from benign, nonneoplastic tissues of the pancreas. These results suggest the use of PAM4 for evaluation of tissue specimens, and support its role as an immunoassay for detection of PDAC. PMID- 24476521 TI - Comparison of conventional, molecular, and immunohistochemical methods in diagnosis of typical and atypical cutaneous leishmaniasis. AB - CONTEXT: Localized cutaneous leishmaniasis (CL) typically presents as papules, crusted nodules, plaques, or noduloulcerative lesions. Atypical CL does not show these features or mimic malignant lesion. In atypical forms, CL may be overlooked because of its similarity to other dermal diseases. OBJECTIVE: To compare conventional, molecular, and immunohistochemical methods in the diagnosis of typical and atypical CL. DESIGN: The kinetoplast DNA, nested, polymerase chain reaction assay and immunohistochemical methods were compared and validated against conventional methods, including cytology and pathology, using 100 specimens of typical and atypical lesions of suspected CL. RESULTS: Compared with other methods, polymerase chain reaction of the kinetoplast DNA showed the highest sensitivity (typical positive, 100%, 67 of 67; atypical positive, 94%, 31 of 33) and specificity (100%), followed by immunohistochemistry (typical positive, 97%, 65 of 67, with 100% specificity; atypical positives, 94%, 31 of 33, with 100% specificity), and cytology (typical positive, 79%, 53 of 67, with 100% specificity; atypical positive, 58%, 19 of 33, with 100% specificity), followed by pathology (typical positive, 70%, 47 of 67, with 100% specificity; atypical positive, 42%, 14 of 33, with 100% specificity). In addition, polymerase chain reaction enabled identification of 98% (98 of 100) of the positive samples that included strains of Leishmania major (99% [99 of 100] cases) and Leishmania tropica (1% [1 of 100] cases). CONCLUSIONS: Because cytology is cheap and easy to perform with high sensitivity, it is the preferred, primary approach for typical CL, but cytology and pathology do not have sufficient sensitivity for diagnosis of atypical CL cases. Nested polymerase chain reaction and immunohistochemistry are sensitive tests for diagnosis of both typical and atypical CL and are recommended as complementary tests in suspected CL with negative conventional microscopy results. PMID- 24476522 TI - Approach to lung biopsies from patients with pneumothorax. AB - CONTEXT: Patients with pneumothorax occasionally require limited lung resections to control persistent air leaks. In some patients, especially smokers, histopathologic findings suggest that a ruptured bulla or bleb caused the pneumothorax. Other patients only exhibit histopathologic changes related to the physical trauma of acute, and likely occult recurrent, peripheral lung injury in the setting of "spontaneous," or idiopathic, lung rupture. Sometimes, pneumothorax occurs secondary to an underlying localized or diffuse parenchymal lung disease. A comprehensive description of the morphologic findings that may be seen in these specimens will help the surgical pathologist distinguish patients with more common and indolent occurrences of pneumothorax from those requiring additional workup or treatment. OBJECTIVE: To develop a diagnostic approach for surgical pathologists encountering lung specimens obtained in the context of pneumothorax repair. DATA SOURCES: Literature review and consultation experience of the authors. CONCLUSIONS: Two general categories of histopathologic changes can be identified: (1) nonspecific changes, reflecting the lung's acute and chronic response to localized injury, and (2) changes suggesting an underlying lung disease that may have played an etiologic role in the development of pneumothorax. The latter changes are important to recognize because they may require additional workup or treatment of clinically occult lung disease. Difficulty arises when nonspecific histopathologic changes overlap with those of an underlying lung disease. Awareness of these diagnostic challenges and pitfalls, together with clinicoradiographic correlation, is essential in these situations and will help guide the surgical pathologist toward an accurate diagnosis and the appropriate management of clinically occult disease. PMID- 24476523 TI - Squamoid cyst of pancreatic ducts: a case series describing novel immunohistochemistry, cytology, and quantitative cyst fluid chemistry. AB - Squamoid cyst of pancreatic ducts (SCPD) is a benign pancreatic cyst often misdiagnosed preoperatively as a mucinous cyst. The histopathologic features are well described but the cytology and quantitative fluid chemistry profiles from fine-needle aspiration have not been reported. This case series discusses the cytology and cyst fluid chemistry profiles in 2 SCPDs and describes morphologic and immunohistochemical features that have not been previously reported. Fine needle aspiration of 2 SCPDs yielded acellular debris lacking mucin or exfoliated squamous cells. Two cysts had elevated fluid carcinoembryonic antigen (CEA) and amylase levels. Positive immunohistochemical staining included cytokeratin 5/6, pCEA, synaptophysin, and chromogranin (both focal). MUC2 and MUC5AC showed negativity in all cases, while PAX8 showed negative nuclear staining. An accurate preoperative diagnosis of SCPD is potentially difficult in the setting of elevated fluid CEA levels, and acellular cytology as a mucinous cyst cannot be confidently excluded. PMID- 24476524 TI - A de novo unclassified malignant spindle cell neoplasm of liver allograft. AB - Spindle cell neoplasms are rarely reported in liver allografts; most are benign and associated with Epstein-Barr virus infection. We present a case of a malignant spindle cell neoplasm arising in a liver allograft. The patient underwent orthotopic liver transplant for cirrhosis secondary to nonalcoholic steatohepatitis. After 2 years, he presented with vague abdominal complaints. Imaging studies revealed a 10-cm right hepatic lobe mass. The patient underwent right-sided hepatectomy. The tumor displayed areas of broad, relatively hypocellular fascicles, whorls, and perivascular clustering; spindle cells with mild to moderate nuclear pleomorphism; and relatively abundant eosinophilic cytoplasm. Mitotic activity ranged from 2 to 4 mitotic figures per 20 high-power fields. Immunostaining displayed positivity for epithelial membrane antigen, vimentin, CD99, BCL2, cytokeratin, and human herpesvirus 8. Interphase fluorescence in situ hybridization findings were negative for a translocation involving the SS18 gene (18q11). We believe the tumor represents the first reported case of a novel unclassified spindle cell malignant neoplasm in a liver allograft. PMID- 24476525 TI - Factor XIII: congenital deficiency factor XIII, acquired deficiency, factor XIII A-subunit, and factor XIII B-subunit. AB - Factor XIII (FXIII) is a transglutaminase consisting of 2 catalytic A subunits and 2 noncatalytic B subunits in plasma. The noncatalytic B subunits protect the catalytic A subunits from clearance. Congenital FXIII deficiency may manifest as a lifelong bleeding tendency, abnormal wound healing, and recurrent miscarriage. Acquired FXIII deficiency, with significant reductions in FXIII levels, has been reported in several medical conditions. The routine screening tests for coagulopathies-prothrombin time, activated partial thromboplastin time, and thrombin time-do not show abnormalities in cases of FXIII deficiency. A quantitative, functional, FXIII activity assay that detects all forms of FXIII deficiency should be used as a first-line screening test. Treatment consists of recombinant FXIII or FXIII concentrate. If these are unavailable, then fresh frozen plasma and cryoprecipitates may be used. Factor XIII has a long half-life; therefore, the patients can lead near-normal lives with regular replacements. Patients with acquired FXIII deficiency with inhibitors need immunosuppressive therapy in addition to factor replacements. PMID- 24476526 TI - Adult T-cell leukemia/lymphoma. AB - Adult T-cell leukemia/lymphoma is a rare mature CD4(+) T-cell neoplasm caused by the retrovirus human T-lymphotrophic virus type 1. At present there are approximately 20 million people infected globally with this virus, and most of these individuals belong to the endemic areas in southern Japan, Africa, the Caribbean basin, and Latin America. In the United States, it is usually seen in immigrants from these endemic regions. Adult T-cell leukemia/lymphoma predominantly affects the adult population and is rare in children. Adult T-cell leukemia/lymphoma has 4 subtypes: acute, lymphomatous, chronic, and smoldering. Clinically, the first 2 variants are classified as aggressive, and the latter two are classified as indolent. Given the rare occurrence and diagnostic challenges associated with adult T-cell leukemia/lymphoma, this review will highlight its salient features to aid in recognition of this entity and perform a comprehensive diagnostic workup. PMID- 24476527 TI - Relationship between rates of attending religious services and oral health in Brazilian adolescents. AB - OBJECTIVES: To determine whether there is a relationship between rates of attending religious services and oral health and oral health-related behaviors in Brazilian adolescents. METHODS: A cross-sectional study was carried out using clinical examinations and self-applied questionnaires. Sample was 664 15-year-old schoolchildren from public and private schools in the city of Goiania-GO, Middle West Brazil. Dependent variables were dental caries (DMFT and DMFS), periodontal condition (Plaque Index and bleeding on probing), perceived importance given to the care of the teeth and oral health-related behaviors (sugar consumption, oral hygiene and pattern of dental attendance). Independent explanatory variable was frequency of attending religious services. Poisson log-linear regressions were used for statistical analysis of the data. RESULTS: Oral health status was not associated with attending religious services. Attending religious services was positively associated with oral health behaviors such as pattern of dental attendance for dental checkups and to the importance given to the care of the teeth. These associations remained statistically significant after controlling for sex and social class (P < 0.05). CONCLUSIONS: Adolescents' frequency of attending religious services is not associated with their oral health status but is positively related to pattern of dental attendance and perceived importance of care of their teeth. PMID- 24476528 TI - Clonal expansion of Verticillium dahliae in lettuce. AB - Few studies in population biology have documented how structure and diversity of pathogens evolve over time at local scales. With the historical samples of Verticillium dahliae available from lettuce, we investigated the structure and diversity of this pathogen in time and space. Three hundred twenty-nine V. dahliae isolates from lettuce fields collected over 18 years were characterized with polymorphic microsatellite markers and polymerase chain reaction tests for race and mating type. Genetic variation within and among commercial lettuce fields in a single season was also investigated using an additional 146 isolates. Sixty-two haplotypes (HTs) were observed among the 329 isolates. A single HT was frequently observed over multiple years and locations (61.40%). Genetic diversity, allelic richness, and private allelic richness suggested a relatively recent clonal expansion. Race 1 (93.63%) and MAT1-2-1 (99.69%) were overwhelmingly represented among the isolates. Linkage disequilibrium was significant (P < 0.001) for all populations, suggesting limited sexual recombination in the sampled populations from lettuce. Populations from 2006, 2009, and 2010 had higher numbers of unique HTs, implying a recent introduction of novel HTs. We conclude that V. dahliae population from lettuce evaluated in this study is expanding clonally, consistent with an asexually reproducing pathogen, and the movement of clonal genotypes locally occurs over time. PMID- 24476529 TI - The impact of workplace factors on filing of workers' compensation claims among nursing home workers. AB - BACKGROUND: Injuries reported to workers' compensation (WC) system are often used to estimate incidence of health outcomes and evaluate interventions in musculoskeletal epidemiology studies. However, WC claims represent a relatively small subset of all musculoskeletal disorders among employed individuals, and perhaps not a representative subset. This study determined the influence of workplace and individual factors on filing of workers' compensation claims by nursing home employees with back pain. METHODS: Surveys were conducted in 18 skilled nursing facilities in four U.S. states. Self-administered questionnaires obtained information on demographic characteristics, working environment, and health behaviors/status. Employees who reported low back pain at least once in four questionnaire surveys were included. WC claims from the same facilities were obtained from the employer's workers compensation insurer and matched by employee name. The dichotomous dependent variable was filing of back-related worker's compensation claim. Association with predictors of interest, including pain severity, physical job demand, job strain, social support, schedule control, and safety climate, was assessed using multivariate regression modeling. Individual characteristics were tested as potential confounders. RESULTS: Pain severity level was significantly associated with filing low-back related claims (odds ratio (OR) = 1.49, 95% CI = 1.18 - 1.87). Higher physical demands at work (OR = 1.07, 95% CI = 1.01 - 1.14) also increased the likelihood of claim filing. Higher job strain (OR = 0.83, 95% CI = 0.73 - 0.94), social support at work (OR = 0.90, 95% CI = 0.82 - 0.99), and education (OR = 0.79, 95% CI = 0.71 - 0.89) decreased the likelihood of claim filing. CONCLUSIONS: The results suggest that the WC system captured the most severe occupational injuries. Workplace factors had additional influence on workers' decision to file claims, after adjusting for low back pain severity. Education was correlated with worker's socioeconomic status; its influence on claim filing is difficult to interpret because of the possible mixed effects of working conditions, self-efficacy, and content knowledge. PMID- 24476530 TI - A rehabilitation intervention to promote physical recovery following intensive care: a detailed description of construct development, rationale and content together with proposed taxonomy to capture processes in a randomised controlled trial. AB - BACKGROUND: Increasing numbers of patients are surviving critical illness, but survival may be associated with a constellation of physical and psychological sequelae that can cause ongoing disability and reduced health-related quality of life. Limited evidence currently exists to guide the optimum structure, timing, and content of rehabilitation programmes. There is a need to both develop and evaluate interventions to support and expedite recovery during the post-ICU discharge period. This paper describes the construct development for a complex rehabilitation intervention intended to promote physical recovery following critical illness. The intervention is currently being evaluated in a randomised trial (ISRCTN09412438; funder Chief Scientists Office, Scotland). METHODS: The intervention was developed using the Medical Research Council (MRC) framework for developing complex healthcare interventions. We ensured representation from a wide variety of stakeholders including content experts from multiple specialties, methodologists, and patient representation. The intervention construct was initially based on literature review, local observational and audit work, qualitative studies with ICU survivors, and brainstorming activities. Iterative refinement was aided by the publication of a National Institute for Health and Care Excellence guideline (No. 83), publicly available patient stories (Healthtalkonline), a stakeholder event in collaboration with the James Lind Alliance, and local piloting. Modelling and further work involved a feasibility trial and development of a novel generic rehabilitation assistant (GRA) role. Several rounds of external peer review during successive funding applications also contributed to development. RESULTS: The final construct for the complex intervention involved a dedicated GRA trained to pre-defined competencies across multiple rehabilitation domains (physiotherapy, dietetics, occupational therapy, and speech/language therapy), with specific training in post-critical illness issues. The intervention was from ICU discharge to 3 months post-discharge, including inpatient and post-hospital discharge elements. Clear strategies to provide information to patients/families were included. A detailed taxonomy was developed to define and describe the processes undertaken, and capture them during the trial. The detailed process measure description, together with a range of patient, health service, and economic outcomes were successfully mapped on to the modified CONSORT recommendations for reporting non-pharmacologic trial interventions. CONCLUSIONS: The MRC complex intervention framework was an effective guide to developing a novel post-ICU rehabilitation intervention. Combining a clearly defined new healthcare role with a detailed taxonomy of process and activity enabled the intervention to be clearly described for the purpose of trial delivery and reporting. These data will be useful when interpreting the results of the randomised trial, will increase internal and external trial validity, and help others implement the intervention if the intervention proves clinically and cost effective. PMID- 24476531 TI - Ischaemic heart disease in first-degree relatives to coeliac patients. AB - OBJECTIVE: Coeliac disease (CD) has been linked to an increased risk of ischaemic heart disease (IHD). We examined the risk of IHD in first-degree relatives and spouses to coeliac patients to ascertain the genetic contribution to IHD excess risk. STUDY DESIGN AND SETTING: Coeliac disease was defined as having a biopsy verified villous atrophy (Marsh grade 3) in 1969-2008 (n = 29,096). Coeliac patients were matched to 144,522 controls. Through Swedish registers, we identified all first-degree relatives and spouses to coeliac patients and their controls, in total 87,622 unique coeliac relatives and 432,655 unique control relatives. Our main outcome measure was IHD defined according to relevant international classification of disease codes in the Swedish Inpatient Registry or in the Cause of Death Registry. Hazard ratios (HR) and confidence intervals (CI) were estimated through Cox regression adjusted for sex, age-group and calendar year at study entry of the relative. RESULT: During a median follow-up of 10.8 years, 2880 coeliac relatives and 13,817 control relatives experienced IHD. First-degree relatives of coeliac patients were at increased risk of IHD (HR = 1.05; 95% CI = 1.00-1.09, P-value = 0.04), while spouses were at no increased risk (HR = 0.99; 95% CI = 0.87-1.12). The excess risk of IHD in coeliac first degree relatives aged 40-59 years was 70/100,000 person-years. CONCLUSION: First degree relatives to coeliac patients seem to be at an increased risk of IHD but the excess risk is so small that it has little clinical relevance. PMID- 24476533 TI - Metabolomic analysis of siderophore cheater mutants reveals metabolic costs of expression in uropathogenic Escherichia coli. AB - Bacterial siderophores are a group of chemically diverse, virulence-associated secondary metabolites whose expression exerts metabolic costs. A combined bacterial genetic and metabolomic approach revealed differential metabolomic impacts associated with biosynthesis of different siderophore structural families. Despite myriad genetic differences, the metabolome of a cheater mutant lacking a single set of siderophore biosynthetic genes more closely approximate that of a non-pathogenic K12 strain than its isogenic, uropathogen parent strain. Siderophore types associated with greater metabolomic perturbations are less common among human isolates, suggesting that metabolic costs influence success in a human population. Although different siderophores share a common iron acquisition function, our analysis shows how a metabolomic approach can distinguish their relative metabolic impacts in E. coli. PMID- 24476532 TI - The RNA-binding protein hnRNPLL induces a T cell alternative splicing program delineated by differential intron retention in polyadenylated RNA. AB - BACKGROUND: Retention of a subset of introns in spliced polyadenylated mRNA is emerging as a frequent, unexplained finding from RNA deep sequencing in mammalian cells. RESULTS: Here we analyze intron retention in T lymphocytes by deep sequencing polyadenylated RNA. We show a developmentally regulated RNA-binding protein, hnRNPLL, induces retention of specific introns by sequencing RNA from T cells with an inactivating Hnrpll mutation and from B lymphocytes that physiologically downregulate Hnrpll during their differentiation. In Ptprc mRNA encoding the tyrosine phosphatase CD45, hnRNPLL induces selective retention of introns flanking exons 4 to 6; these correspond to the cassette exons containing hnRNPLL binding sites that are skipped in cells with normal, but not mutant or low, hnRNPLL. We identify similar patterns of hnRNPLL-induced differential intron retention flanking alternative exons in 14 other genes, representing novel elements of the hnRNPLL-induced splicing program in T cells. Retroviral expression of a normally spliced cDNA for one of these targets, Senp2, partially corrects the survival defect of Hnrpll-mutant T cells. We find that integrating a number of computational methods to detect genes with differentially retained introns provides a strategy to enrich for alternatively spliced exons in mammalian RNA-seq data, when complemented by RNA-seq analysis of purified cells with experimentally perturbed RNA-binding proteins. CONCLUSIONS: Our findings demonstrate that intron retention in mRNA is induced by specific RNA-binding proteins and suggest a biological significance for this process in marking exons that are poised for alternative splicing. PMID- 24476534 TI - Coping strategies among patients with newly diagnosed amyotrophic lateral sclerosis. AB - AIMS AND OBJECTIVES: To prospectively identify different coping strategies among newly diagnosed amyotrophic lateral sclerosis patients and whether they change over time and to determine whether physical function, psychological well-being, age and gender correlated with the use of different coping strategies. BACKGROUND: Amyotrophic lateral sclerosis is a fatal disease with impact on both physical function and psychological well-being. Different coping strategies are used to manage symptoms and disease progression, but knowledge about coping in newly diagnosed amyotrophic lateral sclerosis patients is scarce. DESIGN: This was a prospective study with a longitudinal and descriptive design. METHODS: A total of 33 patients were included and evaluation was made at two time points, one to three months and six months after diagnosis. Patients were asked to complete the Motor Neuron Disease Coping Scale and the Hospital Anxiety and Depression Scale. Physical function was estimated using the revised Amyotrophic Lateral Sclerosis Functional Rating Scale. RESULTS: The most commonly used strategies were support and independence. Avoidance/venting and information seeking were seldom used at both time points. The use of information seeking decreased between the two time points. Men did not differ from women, but patients <=64 years used positive action more often than older patients. Amyotrophic Lateral Sclerosis Functional Rating Scale was positively correlated with positive action at time point 1, but not at time point 2. Patients' psychological well-being was correlated with the use of different coping strategies. CONCLUSIONS: Support and independence were the most used coping strategies, and the use of different strategies changed over time. Psychological well-being was correlated with different coping strategies in newly diagnosed amyotrophic lateral sclerosis patients. RELEVANCE TO CLINICAL PRACTICE: The knowledge about coping strategies in early stage of the disease may help the nurses to improve and develop the care and support for these patients. PMID- 24476535 TI - Validation of 1-hour post-thyroidectomy parathyroid hormone level in predicting hypocalcemia. AB - BACKGROUND: Prior work by our group suggested that a single one hour post thyroidectomy parathyroid hormone (1 hr PTH) level could accurately stratify patients into high and low risk groups for the development of hypocalcemia. This study looks to validate the safety and efficacy of a protocol based on a 1 hr PTH threshold of 12 pg/ml. STUDY DESIGN: Retrospective analysis of consecutive cohort treated with standardized protocol. METHODS: One hundred and twenty five consecutive patients underwent total or completion thyroidectomy and their PTH level was drawn 1-hour post operatively. Based on our previous work, patients were stratified into either a low risk group (PTH >=12 pg/ml) or a high risk group (PTH < 12 pg/ml) [Corrected]. Patients in the high risk group were immediately started on prophylactic calcium carbonate (5-10 g/d) and calcitriol (0.5-1.0 mcg/d). The outcomes were then reviewed focusing mainly on how many low risk patients developed hypocalcemia (false negative rate), and how many high risk patients failed prophylactic therapy. RESULTS: Thirty one patients (25%) were stratified as high risk, and 94 (75%) as low risk. Five (16%) of the high risk patients became hypocalcemic despite prophylactic therapy. Two of the low risk group became hypocalcemic, (negative predictive value = 98%). None of the hypocalcemic patients had anything more than mild symptoms. CONCLUSIONS: A single 1-hour post-thyroidectomy PTH level is a very useful way to stratify thyroidectomy patients into high and low risk groups for development of hypocalcemia. Early implementation of oral prophylactic calcium and vitamin D in the high risk patients is a very effective way to prevent serious hypocalcemia. Complex protocols requiring multiple calcium and PTH measurements are not required to guide post-thyroidectomy management. PMID- 24476536 TI - Effect of intrauterine injection of human chorionic gonadotropin before embryo transfer on clinical pregnancy rates from in vitro fertilisation cycles: a prospective study. AB - BACKGROUND: The implantation process after embryo transfer depends on the embryo quality and endometrial receptivity. It is estimated that fifty to seventy-five per cent of pregnancies are lost due to a failure of implantation. There is evidence that there is an early secretion of human chorionic gonadotrophin before embryo implantation, and this secretion has been linked to an important function in angiogenesis and the inflammatory response that promotes the implantation process. Our objective was to determine the effects of intrauterine injection of human chorionic gonadotropin (hCG) before the embryo transfer in an in vitro fertilisation cycle. METHODS: A prospective randomised study was conducted in Reproductive Medicine Centre PROCREA in Mexico City. Infertile patients who had a medical indication for in vitro fertilisation were studied. Two groups were included (n 210); the intervention group received an intrauterine injection of 500 IU of hCG before the embryo transfer (n 101). The control group (n 109) did not receive hCG. Comparisons were performed using a chi-square test. RESULTS: The clinical pregnancy rate (CPR) was our principal outcome. The implantation rate was a secondary outcome. The implantation rate was significantly higher in the hCG group compared to the control group (52.4% vs 35.7%, p 0.014). The clinical pregnancy rate was also significantly higher (50.4 vs 33.0%, p 0.010). No adverse effects were observed. CONCLUSIONS: The intrauterine injection of hCG before embryo transfer showed a significant increase in the clinical pregnancy rate. More clinical trials are needed to reproduce these results on this promising intervention. The live birth rate must be included in subsequent studies. PMID- 24476537 TI - Self-cleaning properties, mechanical stability, and adhesion strength of transparent photocatalytic TiO(2)-ZnO coatings on polycarbonate. AB - Transparent layers containing TiO2 have been intensively studied because of their interesting application potential including photocatalytically active and self cleaning surfaces. In the present work, transparent TiO2-ZnO thin films on a SiO2 interlayer were successfully deposited on the surface of polycarbonate to provide polymeric sheets with a self-cleaning, superhydrophilic, and photocatalytically active surface layer. To ensure a good adhesion of the SiO2 interlayer, the polycarbonate sheets were first modified by irradiation with UV(C) light. The prepared films were characterized by UV/vis spectrophotometry, SEM, XRD, Raman spectroscopy, ellipsometry, and water contact-angle measurements. All prepared films are transparent, have thicknesses in the range between 120 and 250 nm, and possess superhydrophilic properties. Moreover, they exhibit good adhesion qualities as defined quantitatively by cross-cut tests. However, their mechanical strengths, checked by felt-abrasion tests, differ by changing the molar TiO2-ZnO ratio. The photocatalytic activity, expressed as photonic efficiency, of the coated surfaces was estimated from the kinetics of the photocatalytic degradation of methylene blue and methyl stearate. The combination between superhydrophilic properties and photocatalytic activity was determined by studying the change of water contact angle during the storage of the prepared films in the dark under an ambient atmosphere and under an atmosphere containing either acetone or isopropanol followed by UV(A) irradiation. In addition, self-cleaning properties were examined by determining the changes in the contact angle during the irradiation time after applying oleic acid to the surface. The results show that increasing the molar ratio of ZnO in TiO2 coatings up to 5% yields maximum photonic efficiency values of 0.023%, as assessed by the photocatalytic degradation of methylene blue. Moreover, the superhydrophilic coating with a molar TiO2-ZnO ratio of 1:0.05 exhibits the best self-cleaning properties combined with a good mechanical stability and a very good stability against UV irradiation. PMID- 24476538 TI - Diagnosing skin rejection in vascularized composite allotransplantation: advances and challenges. AB - Refinements in microsurgical techniques coupled with advances in immunosuppressive and immunomodulatory protocols have enabled broader clinical application of vascularized composite allotransplantation (VCA) with encouraging immunological, functional, and esthetic results. However, skin rejection remains a significant obstacle and a serious complication for VCA recipients. Clinical and histopathological features of rejection in VCA have been described in a number of studies, which led to the development of an international consensus on the classification guidelines of rejection in the context of VCA. Nevertheless, currently available diagnostic modalities still have several limitations and shortcomings that can pose a significant diagnostic challenge, particularly when signs of rejection are found to be equivocal. In this review, we provide a critical analysis of these advances and challenges in diagnosing skin rejection. Specifically, we highlight the gaps in understanding of rejection mechanisms, the shortfalls in correlating cellular, molecular, and clinicopathologic markers with rejection grades, deficiencies in defining chronic rejection, and antibody mediated rejection after VCA, as well as providing an outlook on novel concepts, such as the utilization of advanced computational analyses and cross-disciplinary diagnostic approaches. PMID- 24476540 TI - Identifying small molecules via high resolution mass spectrometry: communicating confidence. PMID- 24476541 TI - Daily smoking and 4-year caries increment in Finnish adults. AB - OBJECTIVES: Although the harmful effects of smoking on periodontal disease and oral cancer are now indisputable, its effect on dental caries is less well known. This study assessed whether daily smoking predicts caries increment in adults over 4 years. METHODS: Data from 955 adults who participated in both the Health 2000 Survey and the Follow-Up Study of Finnish Adults' Oral Health were analysed. At baseline, participants provided information on demographic characteristics, education and dental behaviours. The 4-year net increment in the numbers of decayed (DT), filled (FT) and missing (MT) teeth and the DMFT index were calculated using the data from baseline and follow-up clinical oral examinations. RESULTS: Daily smoking was not associated with net DMFT increment. In subsequent analysis by components, daily smoking was associated with net DT increment, but not with net FT or MT increments. When daily smokers were split into two groups by consumption level (1-19 and 20+ cigarettes/day) and compared to nondaily smokers, a significant dose-response relationship was additionally found between levels of tobacco consumption and net DT increment. Although daily smokers reported less favourable behaviours than nonsmokers, these associations only explained partially the effect of daily smoking on net DT increment. CONCLUSIONS: Daily smoking was independently related to caries development (net DT increment) in adults over 4 years, but not to caries treatment (net FT and MT increments) or caries experience (net DMFT increment). PMID- 24476542 TI - Impact of sentence length and phonetic complexity on intelligibility of 5-year old children with cerebral palsy. AB - Reduced speech intelligibility is a barrier to effective communication for many children with cerebral palsy (CP). Many variables may impact intelligibility, yet little research attention has sought to quantify these variables. This study examined the influence of sentence characteristics on intelligibility in two groups of children with CP (those with and without dysarthria) and typically developing children. Questions addressed effects of sentence length on transcription intelligibility among groups; effects of phonetic complexity on intelligibility; and differences in the relationship between sentence characteristics and intelligibility across individual children with dysarthria. Speech samples varying in length from 2-7 words were elicited from 16 children with CP (mean age 59.6 months) and eight typically-developing children (mean age = 59.8 months). One hundred and nineteen naive listeners made orthographic transcriptions of the children's sentence productions. Sentence length and phonetic complexity affected intelligibility for all groups of children, but had a greater impact on intelligibility for children with dysarthria than those without speech motor impairment. Variable relationships between sentence characteristics and intelligibility were found across individual children with dysarthria. Results suggest that reducing both the length and phonetic complexity of utterances may enhance intelligibility for children with dysarthria. However, there may be important individual differences in the impact of one or both types of sentence characteristics. This highlights the importance of considering individual speech motor profiles when deciding on treatment strategies. PMID- 24476543 TI - Structural factors affecting cytotoxic activity of (E)-1-(Benzo[d ][1,3]oxathiol 6-yl)-3-phenylprop-2-en-1-one derivatives. AB - Derivatives of (E)-1-(5-alkoxybenzo[d][1,3]oxathiol-6-yl)-3-phenylprop-2-en-1-one demonstrated exceptionally high in vitro cytotoxic activity, with IC50 values of the most active derivatives in the nanomolar range. To identify structural fragments necessary for the activity, several analogs deprived of selected fragments were prepared, and their cytotoxic activity was tested. It was found that the activity depends on combined effects of (i) the heterocyclic ring, (ii) the alkoxy group at position 5 of the benzoxathiole ring, and (iii) the substituents in the phenyl ring B. Replacement of the sulfur atom by oxygen does not influence the activity. None of the listed structural fragments alone assured high cytotoxic activity. PMID- 24476544 TI - Microwave spectrum and conformational properties of 4-isocyano-1-butene (H2C?CHCH2CH2N=C). AB - The microwave spectrum of 4-isocyano-1-butene (H2C?CHCH2CH2NC) has been investigated in the 35-80 GHz spectral region. Selected measurements have also been made outside this spectral range. Rotation about the -CH-CH2- and -CH2-CH2- single bonds may produce rotational isomerism resulting in five conformers. The spectra of three of them, denoted I, III, and IV, have been assigned. In conformer I, the C?C-C-C link of atoms is +anticlinal and the C-C-C-N chain is antiperiplanar. In III, the two links of atoms are +anticlinal and +synclinal, whereas in IV, the two chains are synperiplanar and antiperiplanar, respectively. Conformer I was found to have the lowest energy of the three forms by relative intensity measurements. These measurements yielded EIII - EI = 1.1(7) kJ/mol, and EIV - EI = 2.9(7) kJ/mol for the internal energy differences. The microwave study was augmented by quantum chemical calculations at the CCSD/cc-pVQZ and MP2/cc pVTZ levels of theory. Good agreement between experimental and theoretical results was seen in most cases. PMID- 24476545 TI - Aspirin enhances opsonophagocytosis and is associated to a lower risk for Klebsiella pneumoniae invasive syndrome. AB - BACKGROUND: Klebsiella pneumoniae (KP) expressing hypermucoviscosity phenotype (HV-KP) has abundant capsular polysaccharide (CPS) and is capable of causing invasive syndrome. Sodium salicylate (SAL) reduces the production of CPS. The study was aimed to investigate the relationship between aspirin usage and KP mediated invasive syndrome and the effect of SAL on HV-KP. METHODS: Patients with community-acquired KP bacteraemia were prospectively enrolled. KP-M1, a serotype K1 HV-KP clinical isolate, was used in the following experiments: CPS production, HV-KP phenotype, and the effect of SAL on neutrophils phagocytosis. The effect of oral aspirin intake on the leukocyte bactericidal activity was evaluated. RESULTS: Patients infected by HV-KP and diabetic patients with poor glycemic control were at an increased risk for invasive syndrome (p < 0.01); those who had recent use of aspirin (p = 0.02) were at a lower risk. CPS production was significantly reduced in the presence of SAL. The HV-KP phenotype and resistance to neutrophil phagocytosis were both significantly reduced in the KP-M1 after incubation with SAL (p < 0.01). Aspirin treatment significantly enhanced the killing of KP-M1 by leukocytes (p < 0.01). CONCLUSION: Treatment with SAL significantly reduces CPS production in HV-KP, thereby contributing to leukocyte phagocytosis and bactericidal activity against this pathogen. PMID- 24476546 TI - Prioritization of candidate genes for periodontitis using multiple computational tools. AB - BACKGROUND: Both genetic and environmental factors contribute to the development of periodontitis. Genetic studies identified a variety of candidate genes for periodontitis. The aim of the present study is to identify the most promising candidate genes for periodontitis using an integrative gene ranking method. METHODS: Seed genes that were confirmed to be associated with periodontitis were identified using text mining. Three types of candidate genes were then extracted from different resources (expression profiles, genome-wide association studies). Combining the seed genes, four freely available bioinformatics tools (ToppGene, DIR, Endeavour, and GPEC) were integrated for prioritization of candidate genes. Candidate genes that identified with at least three programs and ranked in the top 20 by each program were considered the most promising. RESULTS: Prioritization analysis resulted in 21 promising genes involved or potentially involved in periodontitis. Among them, IL18 (interleukin 18), CD44 (CD44 molecule), CXCL1 (chemokine [CXC motif] ligand 1), IL6ST (interleukin 6 signal transducer), MMP3 (matrix metallopeptidase 3), MMP7, CCR1 (chemokine [C-C motif] receptor 1), MMP13, and TLR9 (Toll-like receptor 9) had been associated with periodontitis. However, the roles of other genes, such as CSF3 (colony stimulating factor 3 receptor), CD40, TNFSF14 (tumor necrosis factor receptor superfamily, member 14), IFNB1 (interferon-beta1), TIRAP (toll-interleukin 1 receptor domain containing adaptor protein), IL2RA (interleukin 2 receptor alpha), ETS1 (v-ets avian erythroblastosis virus E26 oncogene homolog 1), GADD45B (growth arrest and DNA-damage-inducible 45 beta), BIRC3 (baculoviral IAP repeat containing 3), VAV1 (vav 1 guanine nucleotide exchange factor), COL5A1 (collagen, type V, alpha1), and C3 (complement component 3), have not been investigated thoroughly in the process of periodontitis. These genes are mainly involved in bacterial infection, immune response, and inflammatory reaction, suggesting that further characterizing their roles in periodontitis will be important. CONCLUSIONS: A combination of computational tools will be useful in mining candidate genes for periodontitis. These theoretical results provide new clues for experimental biologists to plan targeted experiments. PMID- 24476547 TI - Clinical outcomes of using lasers for peri-implantitis surface detoxification: a systematic review and meta-analysis. AB - The aim of this systematic review is to compare the clinical outcomes of lasers with other commonly applied detoxification methods for treating peri-implantitis. An electronic search of four databases and a hand search of peer-reviewed journals for relevant articles were conducted. Comparative human clinical trials and case series with >= 6 months of follow-up in >= 10 patients with peri implantitis treated with lasers were included. Additionally, animal studies applying lasers for treating peri-implantitis were also included. The included studies had to report probing depth (PD) reduction after the therapy. RESULTS: Seven human prospective clinical trials and two animal studies were included. In four and three human studies, lasers were accompanied with surgical and non surgical treatments, respectively. The meta-analyses showed an overall weighted mean difference of 0.00 mm (95% confidence interval = -0.18 to 0.19 mm) PD reduction between the laser and conventional treatment groups (P = 0.98) for non surgical intervention. In animal studies, laser-treated rough-surface implants had a higher percentage of bone-to-implant contact than smooth-surface implants. In a short-term follow-up, lasers resulted in similar PD reduction when compared with conventional implant surface decontamination methods. PMID- 24476548 TI - Three-dimensional defect evaluation of air polishing on extracted human roots. AB - BACKGROUND: Root surfaces experience continuous abrasive instrumentation during lifelong periodontal maintenance. Periodontists need both effective and minimally abrasive debridement techniques. Air polishing devices might, therefore, constitute a good alternative to mechanical instrumentation. Because little is known of the three-dimensional shape and volume of the abrasion caused by different powders, it is the aim of the study to investigate the three dimensional extent of these defects. METHODS: Cementum-covered roots of 20 extracted human premolars were coated with resin caps, leaving four areas with identical diameter open for instrumentation using bicarbonate powder and glycine powder. Treatment times were 5 and 10 seconds in a first interval and 10 seconds in a second interval. Maximum settings were chosen for power and lavage. The teeth were scanned using microcomputed tomography initially and after every treatment interval. Differences in volume and defect depths were calculated by superimposition of the scans and tested for significance (Wilcoxon test, P <0.001). RESULTS: Defect volumes (in mm(3)) presented in medians (interquartile ranges) for the bicarbonate powder after 5, 10, 15, and 20 seconds, respectively, were 0.16 (0.11), 0.28 (0.16), 0.32 (0.18), and 0.41 (0.28), and for glycine powder, 0.00 (0.02), 0.01 (0.05), 0.03 (0.11), and 0.06 (0.1). For each time period, abrasion caused by glycine was significantly lower (five- to 20-fold) compared to defects caused by bicarbonate. CONCLUSIONS: In patients with exposed root surfaces, cleaning with bicarbonate powder cannot be recommended. Less abrasive glycine powder, however, demonstrated non-critical substance loss. PMID- 24476549 TI - Response of human periodontal ligament cells to baicalin. AB - BACKGROUND: Periodontitis is the most common cause of tooth loss in adults. Periodontal ligament cell (PLC)-based therapy is considered one of the most promising methods in periodontal tissue regeneration. The traditional Chinese medicine baicalin has been shown to possess antimicrobial and anti-inflammatory activities and enhance cell proliferation and alkaline phosphatase activity. The aim of this study is to investigate the response of human PLCs (HPLCs) to baicalin. METHODS: The effect of baicalin on cultured HPLC proliferation was measured with a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. The effect of baicalin on the expression of osteoprotegerin (OPG), receptor activator of nuclear factor-kappaB ligand (RANKL), core binding factor alpha1 (Cbfalpha1), and osteocalcin (OC) was determined by quantitative real-time polymerase chain reaction and immunodetection. RESULTS: Baicalin at a concentration of 0.01 MUg/mL promoted HPLC proliferation, upregulated OPG messenger RNA (mRNA) and protein expression, and downregulated RANKL mRNA and protein expression. In addition to reducing the RANKL/OPG expression ratio significantly, it also increased Cbfalpha1 and OC mRNA and protein expression. CONCLUSION: Baicalin showed multifaceted regulation of genes with important roles in tissue growth and differentiation, and thus it has the potential to be a promising candidate for HPLC-based periodontal regeneration therapy. PMID- 24476550 TI - Sesquiterpenes from Neurolaena lobata and their antiproliferative and anti inflammatory activities. AB - Five new sesquiterpenes, neurolobatin A (1), neurolobatin B (2), 5beta-hydroxy 8beta-isovaleroyloxy-9alpha-hydroxycalyculatolide (3), 3-epi desacetylisovaleroylheliangine (4), and 3beta-acetoxy-8beta isovaleroyloxyreynosin (5), were isolated from the aerial parts of Neurolaena lobata. The structures were established by means of a combined spectroscopic data analysis, including ESIMS, APCI-MS, and 1D- and 2D-NMR techniques. Neurolobatin A (1) and B (2) are unusual isomeric seco-germacranolide sesquiterpenes with a bicyclic acetal moiety, compounds 3 and 4 are unsaturated epoxy-germacranolide esters, and compound 5 is the first eudesmanolide isolated from the genus Neurolaena. The isolated compounds (1-5) were shown to have noteworthy antiproliferative activities against human tumor cell lines (A2780, A431, HeLa, and MCF7). The anti-inflammatory effects of 1-5, evaluated in vitro using LPS- and TNF-alpha-induced IL-8 expression inhibitory assays, revealed that all these compounds strongly down-regulated the LPS-induced production of IL-8 protein, with neurolobatin B (2) and 3-epi-desacetylisovaleroylheliangine (4) being the most effective. PMID- 24476551 TI - New vasoactive peptides in cirrhosis: organ extraction and relation to the vasodilatory state. AB - BACKGROUND: Patients with cirrhosis have substantial circulatory imbalance between vasoconstrictive and vasodilating forces. The study of circulatory vasoactive peptides may provide important pathophysiological information. This study aimed to assess concentrations, organ extraction and relations to haemodynamic changes in the pro-peptides copeptin, proadrenomedullin and pro atrial natriuretic peptide (proANP) in patients with cirrhosis. MATERIALS AND METHODS: Fifty-four cirrhotic patients and 15 controls were characterized haemodynamically during a liver vein catheterization. Copeptin, proadrenomedullin and proANP were measured in hepatic and renal veins and the femoral artery. RESULTS: We found no differences in concentrations of copeptin and proadrenomedullin between patients and controls. ProANPs were higher in cirrhotic patients, median 138 pm (25/75 percentiles 101-194) compared with controls, median 91 pm (25/75 percentiles 82-153) P=0.02. ProANPs were higher in the femoral artery and renal vein, median 140 pm and 116 pm (25/75 percentiles 109 191 and 92-164, respectively), compared with controls, median 99 and 81 (25/75 percentiles 85-146 and 66-123) P=0.02 and P=0.007, respectively. We found no extraction of copeptin, proadrenomedullin or proANP over the liver. Copeptin correlated with portal pressure (R=0.50, P<0.001). Proadrenomedullin correlated with portal pressure (R=0.48, P<0.001) and heart rate (R=0.36, P<0.01). ProANP correlated with cardiac output (R=0.46, P<0.002) and portal pressure (R=0.32, P<0.02). All propeptides correlated with Child score (R>0.31, P<0.03). CONCLUSIONS: Pro-atrial natriuretic peptide is elevated in cirrhosis. Copeptin, proadrenomedullin and proANP are related to portal pressure and seem associated with systemic haemodynamics. These propeptides may participate in development and perpetuation of vasodilatation and hyperdynamic circulation in cirrhosis. PMID- 24476552 TI - Risk factors for acute pancreatitis in patients with severe motor and intellectual disabilities. AB - BACKGROUND: Acute pancreatitis in patients with severe motor and intellectual disability (SMID) is a rare but life-threatening condition. Possible causes of acute pancreatitis in these patients including valproic acid therapy, hypothermia and nasoduodenal tube feeding, have not yet been investigated in detail. The aim of this study was therefore to investigate the risk factors for acute pancreatitis in patients with SMID. METHODS: Five SMID patients with acute pancreatitis and 15 SMID patients without acute pancreatitis were reviewed. Age; serum total cholesterol, triglyceride, total protein, and albumin; height; bodyweight; body surface area; body mass index; daily calorie intake; daily calorie intake per unit of body mass surface area; daily calorie intake per kilogram bodyweight; and valproic acid usage were examined. RESULTS: A statistically significant difference was observed in serum albumin level between the two groups (P = 0.026). CONCLUSION: The mechanism of acute pancreatitis in these patients was considered as pancreatic morphological change, acinar damage, and elevated serum trypsinogen level caused by malnutrition. It is likely that acute pancreatitis in patients with SMID occurs due to the same mechanism as in anorexia nervosa and malnourished patients. To prevent acute pancreatitis in these patients, it is important to maintain adequate nutritional status. PMID- 24476553 TI - Detection of soft tissue foreign bodies by nurse practitioner-performed ultrasound. AB - BACKGROUND: This study aimed to evaluate the accuracy of emergency nurse practitioner (NP)-performed point-of-care ultrasound (POCUS) for the detection of soft tissue foreign bodies (FBs). METHODS: Following a 2-h training session, ten NPs were assessed on their ability to detect various FBs in an experimental model. FBs (wood, metal and plastic) were inserted randomly into eight experimental models (uncooked chicken thighs) by an independent observer. Control experimental models had no FB inserted, but all had a 1-cm incision made on their surface. NPs, blinded to the type of model, were then assessed on their ability to detect the FBs by ultrasound examination using high-frequency linear transducers (Toshiba Nemio). Models were also scanned by two experienced emergency physicians (EPs) as a further control. RESULTS: Overall, NP-performed POCUS detected 47 of the 60 foreign bodies with a sensitivity, specificity, positive predictive value and negative predictive value of 78.3%, 50%, 82% and 43%, respectively, compared with 83.3%, 75%, 90.9% and 60% for EPs. Sensitivity for detecting specific types of FB was 95%, 85% and 50% for wood, metal and plastic, respectively, for NP-performed POCUS, compared with 100%, 100% and 50% in the EP group. CONCLUSIONS: NPs with no previous ultrasound experience can detect soft tissue FBs with accuracy comparable to that of EPs in an experimental model. Test sensitivity was high for wood and metal foreign bodies. Specificity was generally low. PMID- 24476554 TI - Long-term results of radical prostatectomy with immediate adjuvant androgen deprivation therapy for pT3N0 prostate cancer. AB - BACKGROUND: Radical prostatectomy is used to treat patients with clinically localized prostate cancer, but there have been few reports of its use in locally advanced disease. We evaluated the long-term results of radical prostatectomy and immediate adjuvant androgen deprivation therapy in Japanese patients with pT3N0M0 prostate cancer. METHODS: We retrospectively reviewed 128 patients with pT3N0M0 prostate cancer who underwent radical prostatectomy at our institute from 2000 to 2006. All pT3N0 patients were treated with adjuvant androgen deprivation therapy shortly after radical prostatectomy. Immediate adjuvant androgen deprivation therapy was continued for at least 5 years. Twenty-three were excluded because of preoperative hormonal therapy, missing data, or others. Death from any cause, death from prostate cancer, clinical recurrence and hormone-refractory biochemical progression were analyzed by Kaplan-Meier graphs. Relative risks of progression were estimated using Cox proportional hazards models with 95% confidence intervals. RESULTS: The 10-year hormone-refractory biochemical progression-free survival rate was 88.3% and the cancer-specific survival rate was 96.3% after a median follow-up period of 8.2 years (range 25.6-155.6 months). Higher clinical stage (p = 0.013), higher Gleason score at biopsy (p = 0.001), seminal vesicle invasion (p = 0.003) and microlymphatic invasion (p = 0.006) were predictive factors for hormone-refractory biochemical progression by univariate analyses. Multivariate analyses identified Gleason score at biopsy (p = 0.027) and seminal vesicle invasion (p = 0.030) as independent prognostic factors for hormone-refractory biochemical progression. None of the patients with clinical T1 cancers (n = 20), negative surgical margin (n = 12), or negative perineural invasion (n = 11) experienced hormone-refractory biochemical progression. CONCLUSIONS: Radical prostatectomy with immediate adjuvant androgen deprivation therapy may be a valid treatment option for patients with pT3N0M0 prostate cancer. PMID- 24476555 TI - GET.ON Mood Enhancer: efficacy of Internet-based guided self-help compared to psychoeducation for depression: an investigator-blinded randomised controlled trial. AB - BACKGROUND: Major depressive disorder (MDD) imposes a considerable disease burden on individuals and societies. A large number of randomised controlled trials (RCTs) have shown the efficacy of Internet-based guided self-help interventions in reducing symptoms of depression. However, study quality varies considerably. The aim of this study is to evaluate the efficacy of a new Internet-based guided self-help intervention (GET.ON Mood Enhancer) compared to online-based psychoeducation in an investigator-blinded RCT. METHODS/DESIGN: A RCT will be conducted to compare the efficacy of GET.ON Mood Enhancer with an active control condition receiving online psychoeducation on depression (OPD). Both treatment groups will have full access to treatment as usual. Adults with MDD (n=128) will be recruited and randomised to one of the two conditions. Primary outcome will be observer-rated depressive symptoms (HRSD-24) by independent assessors blind to treatment conditions. Secondary outcomes include changes in self-reported depressive symptom severity, anxiety and quality of life. Additionally, potential negative effects of the treatments will systematically be evaluated on several dimensions (for example, symptom deteriorations, attitudes toward seeking psychological help, relationships and stigmatisation). Assessments will take place at baseline, 6 and 12 weeks after randomisation. DISCUSSION: This study evaluates a new Internet-based guided self-help intervention for depression using an active control condition (psychoeducation-control) and an independent, blinded outcome evaluation. This study will further enhance the evidence for Internet based guided self-help interventions for MDD. TRIAL REGISTRATION: German Clinical Trial Registration (DRKS): DRKS00005025. PMID- 24476556 TI - Activation of RANKL-induced osteoclasts and memory T lymphocytes by Porphyromonas gingivalis is serotype dependant. AB - AIM: Destructive periodontitis is associated with a Th1-Th17 immune response and activation of RANKL-induced osteoclasts. In addition, Porphyromonas gingivalis K1 and K2 serotypes induce a strong Th1-Th17 response. This study aimed to investigate whether these P. gingivalis serotypes induce higher osteoclasts activation, by increased Th17-associated RANKL production, and an antigen specific memory T-lymphocyte response. MATERIAL AND METHODS: The RANKL production and TRAP(+) osteoclast induction were quantified on naive T lymphocytes stimulated with dendritic cells primed with the P. gingivalis serotypes. The T bet, GATA-3, RORC2 and Foxp3 expression was correlated with RANKL production. The frequency of proliferating memory T lymphocytes in response to P. gingivalis serotypes was determined in both periodontitis and healthy subjects. RESULTS: T lymphocytes stimulated by K1 or K2-primed dendritic cells elicited higher levels of RANKL and TRAP(+) osteoclasts than cells stimulated with the other serotypes. RANKL positively correlated with RORC2. Whereas periodontitis patients had a higher frequency of memory T lymphocytes responding to K1 or K2, healthy subjects had a higher frequency of memory T lymphocytes responding to K4 or K(-) . CONCLUSIONS: P. gingivalis serotypes K1 and K2, but not others, are associated with an increased production of the osteoclastogenesis-related factor RANKL. This important information suggests that these serotypes could elicit a greater bone resorption in vivo and have a role in the periodontitis pathogenesis. PMID- 24476557 TI - The economic burden to medicare of stroke events in atrial fibrillation populations with and without thromboprophylaxis. AB - Some 3 million people in the United States have atrial fibrillation (AF). Without thromboprophylaxis, AF increases overall stroke risk 5-fold. Prevention is paramount as AF-related strokes tend to be severe. Thromboprophylaxis reduces the annual incidence of stroke in AF patients by 22%-62%. However, antithrombotics are prescribed for only about half of appropriate AF patients. The study team estimates the economic implications for Medicare of fewer stroke events resulting from increased thromboprophylaxis among moderate- to high-risk AF patients. The decision model used considers both reduced stroke and increased bleeding risk from thromboprophylaxis for a hypothetical cohort on no thromboprophylaxis (45%), antiplatelets (10%), and anticoagulation (45%). AF prevalence, stroke risk, and stroke risk reduction are adjusted for age, comorbidities, and anticoagulation/antiplatelet status. Health care costs are literature based. At baseline, an estimated 24,677 ischemic strokes, 9127 hemorrhagic strokes, and 9550 bleeding events generate approximately $2.63 billion in annual event-related health care costs to Medicare for every million AF patients eligible for thromboprophylaxis. A 10% increase in anticoagulant use in the untreated population would reduce stroke events by 9%, reduce stroke fatalities by 9%, increase bleed events by 5%, and reduce annual stroke/bleed-related costs to Medicare by about $187 million (7.1%) for every million eligible AF patients. A modest 10% increase in the use of thromboprophylaxis would reduce event-related costs to Medicare by 7.1%, suggesting a compelling economic motivation to improve rates of appropriate thromboprophylaxis. New oral anticoagulants offering better balance between the risks of stroke and major bleeding events may improve these clinical and economic outcomes. PMID- 24476558 TI - Making it local: Beacon Communities use health information technology to optimize care management. AB - Care management aims to provide cost-effective, coordinated, non-duplicative care to improve care quality, population health, and reduce costs. The 17 communities receiving funding from the Office of the National Coordinator for Health Information Technology through the Beacon Community Cooperative Agreement Program are leaders in building and strengthening their health information technology (health IT) infrastructure to provide more effective and efficient care management. This article profiles 6 Beacon Communities' health IT-enabled care management programs, highlighting the influence of local context on program strategy and design, and describing challenges, lessons learned, and policy implications for care delivery and payment reform. The unique needs (eg, disease burden, demographics), community partnerships, and existing resources and infrastructure all exerted significant influence on the overall priorities and design of each community's care management program. Though each Beacon Community needed to engage in a similar set of care management tasks--including patient identification, stratification, and prioritization; intervention; patient engagement; and evaluation--the contextual factors helped shape the specific strategies and tools used to carry out these tasks and achieve their objectives. Although providers across the country are striving to deliver standardized, high quality care, the diverse contexts in which this care is delivered significantly influence the priorities, strategies, and design of community-based care management interventions. Gaps and challenges in implementing effective community based care management programs include: optimizing allocation of care management services; lack of available technology tailored to care management needs; lack of standards and interoperability; integrating care management into care settings; evaluating impact; and funding and sustainability. PMID- 24476559 TI - Self-report of tobacco use status: comparison of paper-based questionnaire, online questionnaire, and direct face-to-face interview--implications for meaningful use. AB - Identifying tobacco use status is essential to address use and provide resources to help patients quit. Being able to collect this information in an electronic format will become increasingly important, as the Centers for Medicare and Medicaid Services has included the assessment of tobacco use as part of its Stage 1 Meaningful Use criteria. The objective was to compare the accuracy of online vs. paper assessment methods to ascertain cigarette smoking status using a face to-face structured interview as the gold standard. This was a retrospective analysis of a stratified opportunity sample of consecutive patients, reporting in 2010 for a periodic health evaluation, who completed either a scannable paper based form or an online questionnaire and underwent a standardized rooming interview. Compared with face-to-face structured interview, the overall observed agreement and kappa coefficient for both methods combined (paper and online) were 97.7% and 0.69 (95% confidence interval (CI) 0.51-0.86) . For the online form they were 97.4% and 0.61 (95% CI 0.33-0.90), and for the paper form they were 97.9% and 0.75 (95% CI 0.54-0.96). There was no statistically significant difference in agreement between the online and paper-based methods (P=0.76) compared with a face-to-face structured interview. Online assessment of tobacco use status is as accurate as a paper questionnaire, and both methods have greater than 97% observed agreement with a face-to-face structured interview. The use of online assessment of tobacco use status has several advantages and more widespread use should be explored. PMID- 24476560 TI - Impacts of the Primary School Free Breakfast Initiative on socio-economic inequalities in breakfast consumption among 9-11-year-old schoolchildren in Wales. AB - OBJECTIVES: Universal interventions may widen or narrow inequalities if disproportionately effective among higher or lower socio-economic groups. The present paper examines impacts of the Primary School Free Breakfast Initiative in Wales on inequalities in children's dietary behaviours and cognitive functioning. DESIGN: Cluster-randomised controlled trial. Responses were linked to free school meal (FSM) entitlement via the Secure Anonymised Information Linkage databank. Impacts on inequalities were evaluated using weighted school-level regression models with interaction terms for intervention * whole-school percentage FSM entitlement and intervention * aggregated individual FSM entitlement. Individual level regression models included interaction terms for intervention * individual FSM entitlement. SETTING: Fifty-five intervention and fifty-six wait-list control primary schools. SUBJECTS: Approximately 4500 children completed measures of dietary behaviours and cognitive tests at baseline and 12-month follow-up. RESULTS: School-level models indicated that children in intervention schools ate a greater number of healthy items for breakfast than children in control schools (b = 0.25; 95 % CI 0.07, 0.44), with larger increases observed in more deprived schools (interaction term b = 1.76; 95 % CI 0.36, 3.16). An interaction between intervention and household-level deprivation was not significant. Despite no main effects on breakfast skipping, a significant interaction was observed, indicating declines in breakfast skipping in more deprived schools (interaction term b = 0.07; 95 % CI -0.15, -0.00) and households (OR = 0.67; 95 % CI 0.46, 0.98). No significant influence on inequality was observed for the remaining outcomes. CONCLUSIONS: Universal breakfast provision may reduce socio-economic inequalities in consumption of healthy breakfast items and breakfast skipping. There was no evidence of intervention-generated inequalities in any outcomes. PMID- 24476561 TI - Biochemical and cellular mechanisms regulating Acanthamoeba castellanii adherence to host cells. AB - Free-living amoebae belonging to the genus Acanthamoeba are the causative agents of infections such as amoebic keratitis (AK), granulomatous amoebic encephalitis (GAE) and cutaneous lesions. The mechanisms involved in the establishment of infection are unknown. However, it is accepted that the initial phase of pathogenesis involves adherence to the host tissue. In this work, we analysed surface molecules with an affinity for epithelial and neuronal cells from the trophozoites of Acanthamoeba castellanii. We also investigated the cellular mechanisms that govern the process of trophozoite adhesion to the host cells. We first used confocal and epifluorescence microscopy to examine the distribution of the A. castellanii actin cytoskeleton during interaction with the host cells. The use of drugs, as cytochalasin B (CB) and latrunculin B (LB), revealed the participation of cytoskeletal filaments in the adhesion process. In addition, to identify the proteins and glycoproteins on the surface of A. castellanii, the trophozoites were labelled with biotin and biotinylated lectins. The results revealed bands of surface proteins, some of which were glycoproteins with mannose and N-acetylglucosamine residues. Interaction assays of biotinylated amoebae proteins with epithelial and neuronal cells showed that some surface proteins had affinity for both cell types. The results of this study provide insight into the biochemical and cellular mechanisms of the Acanthamoeba infection process. PMID- 24476562 TI - Improved gold chloride staining method for anatomical analysis of sensory nerve endings in the shoulder capsule and labrum as examples of loose and dense fibrous tissues. AB - Consistency in gold chloride staining is essential for anatomical analysis of sensory nerve endings. The gold chloride stain for this purpose has been modified by many investigators, but often yields inconsistent staining, which makes it difficult to differentiate structures and to determine nerve ending distribution in large tissue samples. We introduce additional steps and major changes to the modified Gairns' protocol. We controlled the temperature and mixing rate during tissue staining to achieve consistent staining and complete solution penetration. We subjected samples to sucrose dehydration to improve cutting efficiency. We then exposed samples to a solution containing lemon juice, formic acid and paraformaldehyde to produce optimal tissue transparency with minimal tissue deformity. We extended the time for gold chloride impregnation 1.5 fold. Gold chloride was reduced in the labrum using 25% formic acid in water for 18 h and in the capsule using 25% formic acid in citrate phosphate buffer for 2 h. Citrate binds gold nanoparticles, which minimizes aggregation in the tissue. We stored samples in fresh ultrapure water at 4 degrees C to slow reduction and to maintain color contrast in the tissue. Tissue samples were embedded in Tissue Tek and sectioned at 80 and 100 MUm instead of using glycerin and teasing the tissue apart as in Gairns' modified gold chloride method. We attached sections directly to gelatin subbed slides after sectioning with a cryostat. The slides then were processed and coverslipped with Permount. Staining consistency was demonstrated throughout the tissue sections and neural structures were clearly identifiable. PMID- 24476563 TI - Effects of carbon dioxide exposure on early brain development in rats. AB - The developing brain is vulnerable to environmental factors. We investigated the effects of air that contained 0.05, 0.1 and 0.3% CO2 on the hippocampus, prefrontal cortex (PFC) and amygdala. We focused on the circuitry involved in the neurobiology of anxiety, spatial learning, memory, and on insulin-like growth factor-1 (IGF-1), which is known to play a role in early brain development in rats. Spatial learning and memory were impaired by exposure to 0.3% CO2 air, while exposure to 0.1 and 0.3% CO2 air elevated blood corticosterone levels, intensified anxiety behavior, increased superoxide dismutase (SOD) enzyme activity and MDA levels in hippocampus and PFC; glutathione peroxidase (GPx) enzyme activity decreased in the PFC with no associated change in the hippocampus. IGF-1 levels were decreased in the blood, PFC and hippocampus by exposure to both 0.1 and 0.3% CO2. In addition, apoptosis was increased, while cell numbers were decreased in the CA1 regions of hippocampus and PFC after 0.3% CO2 air exposure in adolescent rats. A positive correlation was found between the blood IGF-1 level and apoptosis in the PFC. We found that chronic exposure to 0.3% CO2 air decreased IGF-1 levels in the serum, hippocampus and PFC, and increased oxidative stress. These findings were associated with increased anxiety behavior, and impaired memory and learning. PMID- 24476566 TI - Carbon dots based dual-emission silica nanoparticles as a ratiometric nanosensor for Cu(2+). AB - A simple and effective strategy for designing ratiometric fluorescent nanosensor has been described in this work. A carbon dots (CDs) based dual-emission nanosensor for Cu(2+) detection was prepared by coating CDs on the surface of Rhodamine B-doped silica nanoparticles. The fluorescent CDs were synthesized using N-(beta-aminoethyl)-gamma-aminopropyl methyldimethoxysilane (AEAPMS) as the main raw material, so that the residual ethylenediamine groups and methoxysilane groups on the surface of CDs can serve as the Cu(2+) recognition sites and the silylation reaction groups. The obtained nanosensor showed characteristic fluorescence emissions of Rhodamine B (red) and CDs (blue) under a single excitation wavelength. Upon binding to Cu(2+), only the fluorescence of CDs was quenched, resulting in the ratiometric fluorescence response of the dual-emission silica nanoparticles. This ratiometric nanosensor exhibited good selectivity to Cu(2+) over other substances, such as metal ions, amino acids, proteins, and vitamin C. The ratio of F467/F585 linearly decreased with the increasing of Cu(2+) concentration in the range of 0 to 3 * 10(-6) M, a detection limit as low as 35.2 nM was achieved. Additionally, this nanosensor was successfully applied for the ratiometric fluorescence imaging of Cu(2+) in cells and determination of Cu(2+) in real tap water. PMID- 24476564 TI - The evolutionary dynamics of sexually antagonistic mutations in pseudoautosomal regions of sex chromosomes. AB - Sex chromosomes can evolve gene contents that differ from the rest of the genome, as well as larger sex differences in gene expression compared with autosomes. This probably occurs because fully sex-linked beneficial mutations substitute at different rates from autosomal ones, especially when fitness effects are sexually antagonistic (SA). The evolutionary properties of genes located in the recombining pseudoautosomal region (PAR) of a sex chromosome have not previously been modeled in detail. Such PAR genes differ from classical sex-linked genes by having two alleles at a locus in both sexes; in contrast to autosomal genes, however, variants can become associated with gender. The evolutionary fates of PAR genes may therefore differ from those of either autosomal or fully sex-linked genes. Here, we model their evolutionary dynamics by deriving expressions for the selective advantages of PAR gene mutations under different conditions. We show that, unless selection is very strong, the probability of invasion of a population by an SA mutation is usually similar to that of an autosomal mutation, unless there is close linkage to the sex-determining region. Most PAR genes should thus evolve similarly to autosomal rather than sex-linked genes, unless recombination is very rare in the PAR. PMID- 24476567 TI - Thermolysis, nonisothermal decomposition kinetics, specific heat capacity and adiabatic time-to-explosion of [Cu(NH3)4](DNANT)2 (DNANT= dinitroacetonitrile). AB - A new energetic copper complex of dinitroacetonitrile (DNANT), [Cu(NH3)4](DNANT)2, was first synthesized through an unexpected reaction. The thermal decomposition of [Cu(NH3)4](DNANT)2 was studied with DSC and TG/DTG methods. The gas products were analyzed through a TG-FTIR-MS method. The nonisothermal kinetic equation of the exothermic process is dalpha/dT = 10(10.92)/beta4(1 - alpha)[-ln(1 - alpha)](3/4) exp(-1.298 * 10(5)/RT). The self accelerating decomposition temperature and critical temperature of thermal explosion are 217.9 and 221.0 degrees C. The specific heat capacity of [Cu(NH3)4](DNANT)2 was determined with a micro-DSC method, and the molar heat capacity is 512.6 J mol(-1) K(-1) at 25 degrees C. Adiabatic time-to-explosion of Cu(NH3)4(DNANT)2 was also calculated to be about 137 s. PMID- 24476568 TI - Identification of chromomoric acid C-I as an Nrf2 activator in Chromolaena odorata. AB - Activation of nuclear factor-erythroid 2-related factor 2 (Nrf2) contributes to several beneficial bioactivities of natural products, including induction of an increased cellular stress resistance and prevention or resolution of inflammation. In this study, the potential of a crude leaf extract of Chromolaena odorata, traditionally used against inflammation and skin lesions, was examined for Nrf2 activation. Guided by an Nrf2-dependent luciferase reporter gene assay, the phytoprostane chromomoric acid C-I (1) was identified as a potent Nrf2 activator from C. odorata with a CD (concentration doubling the response of vehicle-treated cells) of 5.2 MUM. When tested at 1-10 MUM, 1 was able to induce the endogenous Nrf2 target gene heme oxygenase 1 (HO-1) in fibroblasts. Between 2 and 5 MUM, compound 1 induced HO-1 in vascular smooth muscle cells (VSMC) and inhibited their proliferation in a HO-1-dependent manner, without eliciting signs of cytotoxicity. PMID- 24476569 TI - Intercostal administration of liposomal bupivacaine as a prognostic nerve block prior to phenol neurolysis for intractable chest wall pain. AB - Inadequate pain relief from systemic medications is common in patients with advanced malignancy. Chest wall pain secondary to tumor involvement of chest wall structures can be challenging to manage with systemic medications, and occasionally patients benefit from interventional procedures such as intercostal nerve blocks and neurolysis. In this report, the authors describe the case of a 58-year-old woman with advanced non-small cell lung cancer with tumor invasion into the third thoracic rib. After reaching maximum tolerated doses of transdermal fentanyl, oral hydromorphone, and oral ketamine, the patient elected for intercostal nerve blockade and neurolysis. Prognostic nerve blockade was performed using liposomal bupivacaine administered via intercostal approach. This formulation of bupivacaine provided an excellent prognostic blockade, which lasted for approximately 96 hours. This extended period of time allowed the patient to fully evaluate the prognostic blockade, prior to proceeding with neurolysis with phenol. This case suggests that liposomal bupivacaine may be a valuable adjunctive agent for prognostic blockade prior to neurolysis for cancer pain. PMID- 24476570 TI - Bordetella pertussis in sporadic and outbreak settings in Alberta, Canada, July 2004-December 2012. AB - BACKGROUND: ProvLab Alberta provides all laboratory testing for Bordetella pertussis including sporadic cases and outbreak investigations through collaborations with provincial public health partners. We describe B. pertussis activity in Alberta from July 2004 to December 2012. METHODS: Laboratory testing for pertussis was analyzed using interpreted laboratory data that was generated by DIAL, a secure web-based platform. Duplicate specimens from the same individual <=90 days were excluded to generate a case-based dataset. Immunization status of confirmed pertussis cases from the provincial immunization repository was reviewed. RESULTS: Overall, 7.1% of suspected pertussis cases tested positive with a higher positivity rate in outbreak as compared to sporadic setting. Annual variations in sporadic pertussis cases were observed across the province with higher positivity rates in 2005, 2008, 2009 and 2012. A significantly higher positivity rate was observed in a northern region of Alberta. While the positivity rate in sporadic setting was highest in adolescents aged 10 to <15 years old (14.8%), population-based disease burden was highest in young children <5 years old. Of the 81.6% (n = 1,348) pertussis cases with immunization records, 48.3% were up-to-date with immunization. The pertussis cases that were up-to-date with their immunization were older (median age 12.9 years) as compared to those with incomplete (median age 9.7 years) or no pertussis immunization (median age 3.8 years). CONCLUSIONS: Cyclic pattern of annual pertussis activity with geographic variation was observed in Alberta with no obvious case finding effect from outbreak investigations. The high positivity rates in adolescents suggested an underestimation of disease burden in this age group. PMID- 24476571 TI - Viral aetiology and clinico-epidemiological features of acute encephalitis syndrome in eastern India. AB - This study reports clinico-epidemiological features and viral agents causing acute encephalitis syndrome (AES) in the eastern Indian region through hospital based case enrolment during April 2011 to July 2012. Blood and CSF samples of 526 AES cases were investigated by serology and/or PCR. Viral aetiology was identified in 91 (17.2%) cases. Herpes simplex virus (HSV; types I or II) was most common (16.1%), followed by measles (2.6%), Japanese encephalitis virus (1.5%), dengue virus (0.57%), varicella zoster virus (0.38%) and enteroviruses (0.19%). Rash, paresis and cranial nerve palsies were significantly higher (P < 0.05) with viral AES. Case-fatality rates were 10.9% and 6.2% in AES cases with and without viral aetiology, respectively. Simultaneous infection of HSV I and measles was observed in seven cases. This report provides the first evidence on viral aetiology of AES viruses from eastern India showing dominance of HSV that will be useful in informing the public health system. PMID- 24476572 TI - [Abstracts - 27 degrees Congresso Nazionale - Associazione Italiana di Neuroradiologia. Coppito (AQ), Italy, 18-21 settembre 2013]. PMID- 24476573 TI - Sensitivity of Culicoides obsoletus (Meigen) (Diptera: Ceratopogonidae) to deltamethrin determined by an adapted WHO standard susceptibility test. AB - Bluetongue is a disease of major economic concern in Europe. Its causative agent, bluetongue virus (BTV), is transmitted by several Culicoides species (mainly Culicoides imicola and Culicoides obsoletus in Europe). The application of insecticides on animals may reduce transmission of BTV, however, no formulation is currently licensed specifically against Culicoides midges. The present study assesses the susceptibility of C. obsoletus to deltamethrin using an adapted World Health Organization (WHO) susceptibility test. Midges were exposed to different dosages of deltamethrin for 1 h, and mortality after 1 h and 24 h was recorded. Results indicated that deltamethrin is highly toxic to C. obsoletus since a dose of 1.33*10(-4)% was enough to kill 50% of the population (LD50) in 24 h. The deltamethrin concentration needed to kill 90% of the population (LD90) was 5.55*10(-4)%. The results obtained in the present work could help to create a system that can be used to assess insecticide resistance and susceptibility of Culicoides biting midges. PMID- 24476574 TI - A longitudinal analysis of maternal depressive symptoms and children's food consumption and weight outcomes. AB - OBJECTIVE: Maternal depressive symptoms negatively impact mothers' parenting practices and children's development, but the evidence linking these symptoms to children's obesity is mixed. DESIGN: We use a large sample to examine contemporaneous and lagged associations between maternal depressive symptoms and children's BMI, obesity and food consumption, controlling for background characteristics. SETTING: Data from the Early Childhood Longitudinal Study-Birth Cohort (ECLS-B), a longitudinal study of children from infancy through kindergarten in the USA, were collected at four waves from 2001 to 2007, when children were 9 months, 2 years, 4 years and 51/2years of age, through surveys, child assessments and observations. SUBJECTS: A sub-sample of children from the ECLS-B is used (n 6500). RESULTS: Between 17 % and 19 % of mothers reported experiencing depressive symptoms; 17 % to 20 % of children were obese. Maternal depressive symptoms were associated with a small decrease in the likelihood her child was obese (0.8 percentage points) and with lower consumption of healthy foods. The duration of maternal depressive symptoms was associated with higher BMI (0.02 sd) among children whose parents lacked college degrees. CONCLUSIONS: Results indicate that mothers' depressive symptoms have small associations with children's food consumption and obesity. Among children whose parents lack college degrees, persistent maternal depressive symptoms are associated with slightly higher child BMI. Findings highlight the need to control for depression in analyses of children's weight. Interventions that consider maternal depression early may be useful in promoting healthy weight outcomes and eating habits among children. PMID- 24476576 TI - Pathway-dependent inhibition of paclitaxel hydroxylation by kinase inhibitors and assessment of drug-drug interaction potentials. AB - Paclitaxel is often used in combination with small molecule kinase inhibitors to enhance antitumor efficacy against various malignancies. Because paclitaxel is metabolized by CYP2C8 and CYP3A4, the possibility of drug-drug interactions mediated by enzyme inhibition may exist between the combining agents. In the present study, a total of 12 kinase inhibitors were evaluated for inhibitory potency in human liver microsomes by monitoring the formation of CYP2C8 and CYP3A4 metabolites simultaneously. For reversible inhibition, nilotinib was found to be the most potent inhibitor against both CYP2C8 and CYP3A4, and the inhibition potency could be explained by strong hydrogen binding based on molecular docking simulations and type II binding based on spectral analysis. Comparison of K(i) values revealed that the CYP2C8 pathway was more sensitive toward some kinase inhibitors (such as axitinib), while the CYP3A4 pathway was preferentially inhibited by others (such as bosutinib). Pathway-dependent inactivation (time-dependent inhibition) was also observed for a number of kinase inhibitors against CYP3A4 but not CYP2C8. Further studies showed that axitinib had a K(I) of 0.93 MUM and k(inact) of 0.0137 min(-1), and the observed inactivation toward CYP3A4 was probably due to the formation of reactive intermediate(s). Using a static model, a reasonably accurate prediction of drug drug interactions was achieved by incorporating parallel pathways and hepatic extraction ratio. The present results suggest that potent and pathway-dependent inhibition of CYP2C8 and/or CYP3A4 pathways by kinase inhibitors may alter the ratio of paclitaxel metabolites in vivo, and that such changes can be clinically relevant as differential metabolism has been linked to paclitaxel-induced neurotoxicity in cancer patients. PMID- 24476575 TI - Association of methylenetetrahytrofolate reductase (MTHFR) C677T and A1298C polymorphisms with the susceptibility of childhood acute lymphoblastic leukaemia (ALL) in Chinese population. AB - BACKGROUND: The aim of this study was to investigate the relationship between the polymorphisms of the methylenetetrahytrofolate reductase (MTHFR) gene and susceptibility to childhood acute lymphoblastic leukemia (ALL). METHODS: A case control study was conducted among 98 children with ALL and 93 age- and sex- matched non-ALL controls. Genotyping of MTHFR C677T and A1298C polymorphisms was performed by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The odds ratios (ORs) of MTHFR genotypes were used to assess the associations of these polymorphisms with childhood ALL susceptibility. RESULTS: No significant differences were observed for frequencies of the 677CC, 677CT and 677TT genotypes between patients and controls. Frequencies of the 1298AA, 1298 AC and 1298CC genotypes between the two groups were significantly different. The risk of ALL with the 1298C allele carriers (AC + CC) was elevated by 1.1 times compared with the AA genotype [OR = 2.100; 95% CI (1.149; 3.837); P = 0.015]. CONCLUSIONS: The MTHFR A1298C polymorphism is associated with susceptibility to childhood ALL in the Chinese population. PMID- 24476577 TI - Long-term analysis of osseointegrated implants in non-smoker patients with a previous history of periodontitis. AB - AIM: To evaluate long-term clinical and radiographic parameters of osseointegrated implants in non-smoker patients with a previous history of chronic periodontitis. MATERIALS AND METHODS: Fifty-four screw-type implants with a moderately roughened surface and internal hexagonal implant-abutment connection were placed according to a two-phase protocol and 40 reference teeth were analysed at baseline, and after 5 and 10 years. Pocket probing depth (PPD), clinical attachment level (CAL) and bleeding on probing were analysed 6x/tooth in all teeth, implants and reference teeth. Radiographic peri-implant bone level was measured on the mesial and distal surfaces. The prevalence of peri-implantitis and the survival rate of the implants were assessed at the patient and implant levels. Data were analysed using descriptive statistics, Mann-Whitney U-test, and Wald Z-test, at alpha = 5%. RESULTS: In implants, the CAL at 5 years was 0.3 mm higher, and at 10 years 1.2 mm higher in comparison to baseline. The corresponding data for the reference teeth were 0 mm and 0.5 mm respectively. Multilevel testing showed statistical difference for PPD between implants and teeth over time. After 10 years, the mean mesial bone loss was 0.63 +/- 0.26 mm, and the mean distal bone loss was 0.56 +/- 0.25. The survival rates were 100% and 92.3% for the implants in the mandible and the implants in the maxilla respectively. CONCLUSIONS: Screw-type implants with internal hexagon placed in patients with a previous history of periodontitis attending a regular maintenance programme demonstrated stable clinical and radiographic results after 5 and 10 years. PMID- 24476579 TI - Self-disorders and the schizophrenia spectrum: a study of 100 first hospital admissions. AB - INTRODUCTION: Self-disorders (SD) have been described as a core feature of schizophrenia both in classical and recent psychopathological literature. However, the specificity of SD for the schizophrenia spectrum disorders has never been demonstrated in a diagnostically heterogeneous sample, nor has the concurrent validity of SD been examined. AIM: (1) To examine the specificity of Examination of Anomalous Self-Experiences (EASE) measured SD to the schizophrenia spectrum disorder in first contact inpatients, (2) to explore the internal consistency and factorial structure of the EASE, (3) to assess the concurrent validity of SD by exploring correlations between SD and the canonical psychopathological dimensions of schizophrenia, (4) to explore relations of SD to intelligence, sociodemographic, and extrinsic illness characteristics. METHODS: A total of 100 consecutive first admission patients underwent a comprehensive psychopathological examination and an assessment of SD with the EASE scale. The diagnostic distribution of the EASE scores was tested with ANOVA, whereas the relations between the EASE scores and other symptomatic dimensions of schizophrenia were tested with Spearman's rho. A potential factorial structure and the internal consistency of the EASE scale were also examined. RESULTS: SD aggregated significantly in the schizophrenia spectrum disorders, with no differences between schizophrenia and schizotypal disorders. EASE scores correlated moderately with canonical psychopathological dimensions of schizophrenia. Factor analysis of the EASE disclosed only one factor and the internal consistency of the EASE was excellent. CONCLUSIONS: SD aggregate selectively in the schizophrenia spectrum disorders, with similar levels in schizophrenia and schizotypy. The study lends validity to the view of SD as an experiential vulnerability phenotype of the schizophrenia spectrum disorders. PMID- 24476580 TI - Successful implementation of a laboratory iodization quality assurance system in small-scale salt production facilities in India. AB - OBJECTIVE: To establish a laboratory iodization quality assurance system to support small-scale salt production facilities in India and to assess the level of agreement for the internal quality assurance (IQA) and external quality assurance (EQA) protocols. DESIGN: Operational research. The IQA and EQA programme was established in the year 2008. Agreement between field laboratories and the reference laboratory for estimation of iodine content of salt from 2008 to 2011 was assessed. Agreement was assessed using the chi 2 test, kappa statistics and the Bland-Altman plot. SETTING: Small-scale salt producers in the states of Andhra Pradesh, Gujarat, Rajasthan, Tamil Nadu, Odisha and Karnataka; 'field laboratories' supporting the small-scale salt producers; and the 'reference laboratory' of the Regional Office (South Asia) of the International Council for the Control of Iodine Deficiency Disorders. SUBJECTS: Three hundred small-scale salt producers in the states of Andhra Pradesh, Gujarat, Rajasthan, Tamil Nadu, Odisha and Karnataka and seventeen 'field laboratories'. RESULTS: A total of 6573 salt samples for IQA and 347 salt samples for EQA were exchanged between field and reference laboratories during 2008-2012. Out of the total salt sample exchanges, 527 were from Andhra Pradesh and Odisha, 2343 from Gujarat, 2016 from Rajasthan and 1677 from Tamil Nadu and Karnataka. The overall between laboratory agreement was for 61.6 % for IQA and 64.8 % for EQA. The mean difference between iodine content estimation of field laboratories and the reference laboratory was 0.3 ppm (sd 8.2 ppm) for IQA and -0.3 ppm (sd 3.5 ppm) for EQA. CONCLUSIONS: Our study successfully documents implementation of a laboratory iodization quality assurance protocol in laboratories supporting small scale salt production facilities in India. PMID- 24476581 TI - New body scans help detect spread of myeloma. PMID- 24476582 TI - Perceptions of Giving Support and Depressive Symptoms in Late Life. AB - PURPOSE OF THE STUDY: Research shows that parents benefit psychologically from generativity--giving and caring for the next generation--but older adults' perceptions on giving support to their children are rarely if ever explored in these studies. The current study examines the association between the support that aging parents give to one of their middle-aged offspring, their perception of this support as rewarding or stressful, and their levels of depressive symptoms. DESIGN AND METHODS: The sample draws from The Family Exchanges Study and consisted of 337 older parents (mean age: 76) who were drawn from a larger study of middle-aged adults (i.e., target participants). Older parents reported tangible and nontangible forms of support given to the target middle-aged child and the extent to which they viewed providing such support as stressful and/or rewarding. RESULTS: We found significant interactions between tangible support and feelings of reward and between nontangible support and feelings of stress in explaining parental depressive symptoms. Parents who found giving support to be highly rewarding had lower levels of depressive symptoms when giving high amounts of tangible support. Conversely, parents who view giving support to be highly stressful had higher levels of depressive symptoms when they gave low amounts of nontangible support. IMPLICATIONS: Findings suggest older parents' perceptions of supporting their offspring may condition how generativity affects their mental health. PMID- 24476583 TI - Observed drug-receptor association rates are governed by membrane affinity: the importance of establishing "micro-pharmacokinetic/pharmacodynamic relationships" at the beta2-adrenoceptor. AB - Current pharmacological models for determining affinity and kinetics of drugs for membrane receptors assume the interacting molecules are homogeneously distributed in the bulk aqueous phase. The phospholipid membrane can, however, provide a second compartment into which drugs can partition, particularly lipophilic/basic compounds. In this study we measured the phospholipid affinity and receptor binding kinetics of several clinically relevant beta2-adrenoceptor agonists and antagonists and demonstrated that the degree of phospholipid interaction directly affects the observed kinetic association rate (k on) and dissociation constant (Kd), but not the dissociation rate (k off) from the target, by concentrating drug in the local environment around the receptor. When the local drug concentration was accounted for, the k on was comparable across the cohort and the corrected Kd was directly related to the k off. In conclusion, we propose a new approach to determining the pharmacology of drugs for membrane targets that accounts for differences in local drug concentration brought about by direct affinity for phospholipids, establishing "micro-pharmacokinetic/pharmacodynamic relationships" for drugs. PMID- 24476584 TI - Surgical reconstruction versus peripheral intervention in patients with critical limb ischemia - a prospective multicenter registry in Japan: the SPINACH study design and rationale. AB - Clinical evidence reflecting the recent development of treatments for patients with critical limb ischemia is mandatory to guide the decision-making process for the selection of revascularization procedures, including bypass or endovascular treatment. This paper describes the protocol for a clinical study that is designed and carried out by both vascular surgeons and interventional cardiologists collaboratively, and will investigate current treatment for critical limb ischemia in Japan. The registry aimed to recruit approximately 450 patients with critical limb ischemia, including approximately 150 patients who underwent bypass surgery and approximately 300 patients who underwent endovascular treatment in 23 institutions. The primary endpoint of this study is amputation-free survival at 36 months, and the secondary endpoints include major amputation, cardiovascular events, re-intervention, death, ulcer healing, and their composite outcomes. The SPINACH study aims to provide a suitable patient model for each revascularization procedure, bypass and endovascular treatment, and will expound on the role of each approach for critical limb ischemia treatment (Clinical trial registration UMIN000007050). PMID- 24476585 TI - The fluorescent two-hybrid assay to screen for protein-protein interaction inhibitors in live cells: targeting the interaction of p53 with Mdm2 and Mdm4. AB - Protein-protein interactions (PPIs) are attractive but challenging targets for drug discovery. To overcome numerous limitations of the currently available cell based PPI assays, we have recently established a fully reversible microscopy assisted fluorescent two-hybrid (F2H) assay. The F2H assay offers a fast and straightforward readout: an interaction-dependent co-localization of two distinguishable fluorescent signals at a defined spot in the nucleus of mammalian cells. We developed two reversible F2H assays for the interactions between the tumor suppressor p53 and its negative regulators, Mdm2 and Mdm4. We then performed a pilot F2H screen with a subset of compounds, including small molecules (such as Nutlin-3) and stapled peptides. We identified five cell penetrating compounds as potent p53-Mdm2 inhibitors. However, none exhibited intracellular activity on p53-Mdm4. Live cell data generated by the F2H assays enable the characterization of stapled peptides based on their ability to penetrate cells and disrupt p53-Mdm2 interaction as well as p53-Mdm4 interaction. Here, we show that the F2H assays enable side-by-side analysis of substances' dual Mdm2-Mdm4 activity. In addition, they are suitable for testing various types of compounds (e.g., small molecules and peptidic inhibitors) and concurrently provide initial data on cellular toxicity. Furthermore, F2H assays readily allow real-time visualization of PPI dynamics in living cells. PMID- 24476586 TI - Magnetic phase transition and clustered state in Ca-doped lanthanum cobaltite and manganite with insulator ground states. AB - The transport and magnetic properties (ac linear and nonlinear (second and third orders) susceptibilities) are presented for La0.8Ca0.2MnO3 and La0.8Ca0.2CoO3 single crystals with insulator ground states. The ferromagnetic (FM) clusters with similar magnetic characteristics originate in the paramagnetic phases of both compounds below some temperature T(*). At high temperatures the FM clusters arise at the preferable sites that can be attributed to the chemical inhomogeneities, their density being weakly T-dependent. On cooling a homogeneous nucleation of the FM clusters develops below a definite temperature T(#) that is characterized by a fast growth of their density. These two stages are observed in both compounds. At the third stage a coalescence of the FM clusters starts in the doped cobaltite, whereas in the manganite the development of matrix FM ordering occurs which changes a cluster's behavior. The indicated features support the common nature of the cluster state in the doped cobaltite and manganite. The difference in their evolution is a consequence of the different magnetic properties of the matrices in the manganite and cobaltite. PMID- 24476587 TI - Prevalence of depression, quality of life and antidepressant treatment in the Danish General Suburban Population Study. AB - BACKGROUND: The Danish General Suburban Population Study (GESUS), the objective of which is to facilitate epidemiological and genetic research, has included the Major Depression Inventory (MDI) and the WHO-Five Well-Being Index (WHO-5) among the medical health questionnaires. We were thus in a position to compare the 2 week prevalence of ICD-10 depression in the period from 2010 to 2012 with our previous Danish general population study from 2003, in which the MDI was also included. AIMS: The aim of our analysis was not only to evaluate the point prevalence of ICD-10 depression but also to describe the prevalence of antidepressants received by the respondents in the GESUS study and the correspondence to their subjective well-being on the WHO-5 questionnaire. METHODS: To evaluate the validity (scalability) of the MDI and the WHO-5 in the GESUS study we performed the non-parametric Mokken analysis. The scalability of the MDI and the WHO-5 was quite acceptable. RESULTS: In total, 14,787 respondents were available from a response rate of 50%. The 2-week prevalence of ICD-10 depression was 2.3%, which is rather similar to the 2.8% in our 2003 study. The rate of people receiving antidepressants increased consistently with increasing severity of ICD-10 depression. CONCLUSION: This study has confirmed that the use of the MDI to obtain an ICD-10 depression diagnosis gives rather conservative estimates of the 2-week prevalence of depression in the Danish general population. The prescription of antidepressants depends on the severity of the ICD-10 depression diagnosis. PMID- 24476588 TI - Fewer re-admissions and bed days following an intensive transitional post discharge aftercare programme for a mixed diagnostic group of patients. AB - BACKGROUND: The organization of aftercare is important for a successful outcome; still the optimal organization has not been fully explored. An intensive transitional post-discharge aftercare (TA) programme, for a mixed group of non psychotic patients, was recently developed. Patients with non-psychotic diagnoses are often discharged with low well-being while still symptomatic, placing high demands on aftercare. AIMS: To evaluate retrospectively the short and long-term mental healthcare service use during and after the TA programme compared with the service use of a retrospective comparison group (RC), receiving less intensive outpatient aftercare. METHODS: Number of re-admissions, bed days and emergency visits after 10 weeks, 6 months and 1 year was retrospectively collected from electronic patient registers. Descriptive statistics, independent samples T-tests and repeated-measures analysis of variance was used to compare the groups. RESULTS: The majority of patients in both groups suffered from affective disorders, followed by personality disorders and a small number of other psychiatric diagnoses. Service use in the TA group was lower than in the RC group with fewer bed days after 10 weeks (P = 0.01) and after 6 months (P = 0.003), and fewer re-admissions after 6-12 months (P = 0.04). Emergency contacts did not differ significantly between the two groups at any point. CONCLUSIONS: The present study indicates beneficial effects of intensive TA, for a mixed group of non-psychotic patients. The lower service use in the TA programme group is in line with day treatment programme research for patients with affective disorders. PMID- 24476589 TI - [Clarification of molecular targets of dioxin toxicity]. AB - Health effects associated with exposure to various chemicals have been extensively studied. However, in most cases, the molecular basis of the underlying mechanism has been elusive. Dioxin toxicity, which has raised a significant concern in society, was discovered to be mediated by a high-affinity receptor, aryl hydrocarbon receptor (AhR), more than three decades ago. This receptor has been established to be essential for the manifestation of various toxicities, such as carcinogenicity, reproductive toxicity, developmental neurotoxicity, and immunotoxicity. However, it has not been clarified how AhR mediates such a wide variety of dioxin toxicities through AhR-dependent mechanisms. In recent years, several lines of experimental evidence have provided clues for opening the "black box" that contains the molecular mechanisms of dioxin action. In this review, I focus on dioxin toxicity phenotypes for which downstream molecular targets have begun to be elucidated. The toxicity phenotypes include impaired prostate development and hydronephrosis in mouse fetuses and pups, respectively, as well as abnormality in organogenesis in zebrafish embryos and adults. As the molecular basis of the tissue-specific endpoints of dioxin toxicity, dysregulation of AhR downstream pathways, such as signaling of prostanoid synthesis, Wnt/beta-catenin signaling, and signaling by receptors for inflammatory cytokines, are discussed. The new findings on the molecular targets of dioxin may provide clues to the prospective discovery of new molecular events associated with the growth and development of organs and pathogenesis of diseases. PMID- 24476590 TI - [Application of molecular-targeting cancer prevention to tumor immunity]. AB - The development of methods of cancer prevention is a particularly important issue. We have proposed a strategy termed "combination-oriented molecular targeting prevention" of cancer. As the molecular target of our model, we focused on the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and its receptor. TRAIL is a cytokine from immune cells and is important for immune surveillance and defense mechanisms against cancer cells. First, we searched for food factors inducing the expression of death receptor 5 (DR5), one of the TRAIL receptors. DR5 is specifically expressed on the membrane of cancer cells, not on that of normal cells. We found that many food factors markedly induced DR5 expression, enhancing TRAIL sensitivity against cancer cells. We next found that lactic acid bacteria induced endogenous TRAIL production in human peripheral blood mononuclear cells (PBMCs). Importantly, lactic acid bacteria increased the NK activity of PBMCs against cancer cells. Moreover, we found that butyric acid bacterium, one of the antiflatulents, induced the release of endogenous TRAIL from polymorphonuclear neutrophils. The butyric acid bacterium was proven effective against cancer cells by inducing apoptosis in vivo as well as in vitro. Taken together, these results strongly suggest that the strategy of "combination of DR5-inducing food factors and TRAIL-inducing food factors" as molecular targeting prevention of cancer will be a practical approach. PMID- 24476591 TI - [Role of zinc in type 2 diabetes]. AB - Pancreatic beta cells contain the highest amount of zinc among cells within the human body, and hence, the relationship between zinc and diabetes has been of great interest. To date, many studies of zinc and diabetes have been reported, including studies demonstrating that diabetic patients and mice have a decreased amount of zinc in the pancreas. Zinc may counteract the deleterious effects of oxidative stress, which contributes to reduced insulin resistance, and may also protect pancreatic beta cells from glucolipotoxicity. Recently, we have shown that SLC30A8/zinc transporter 8, which is a transporter expressed on the surface of insulin granules, plays a key role in zinc transport into insulin granules and in the regulation of hepatic insulin clearance. Here, we review the role of zinc in whole-body maintenance and the latest information on the relationship between zinc and diabetes. PMID- 24476592 TI - [Psychophysiological effects of hand massage in geriatric facility residents]. AB - OBJECTIVES: Geriatric facility residents experience easy decrease of their quality of life (QOL) compared with elderly people cared for in their own homes owing to environmental changes. Because complementary and alternative medicine is useful to improve QOL, a simple manual for hand massage for inexperienced volunteers was developed, and the physical and psychological effects of this method were examined. METHODS: Thirty-six female geriatric facility residents (mean age, 84.5 years) were chosen. They were divided into two groups: the control and hand-massaged groups. In the hand-massaged group, females received 15 min hand massage from volunteers in accordance with a simple manual. No hand massage was performed in the control group. Before and after the treatment, a survey using a questionnaire (7 items; e.g., tension, fatigue) and physiological measurements (e.g., blood pressure, hand skin temperature), and measurement of cortisol and chromogranin A levels in saliva samples using enzyme-linked immunosorbent assay kits were carried out. Data were analyzed by two-way analysis of variance (ANOVA) to determine the effects of group and time on the dependent variables. RESULTS: The hand-massaged group showed greater increases in skin temperature than the control group, as shown by ANOVA (p<.05). Results showed that improvements of the scores in the questionnaire (condition and feel-good items) were greater in the hand-massaged group than in the control group (p<.05). Cortisol level increased in the control group, but was not statistically significantly different from that in the hand-massaged group, as shown by ANOVA. Chromogranin A level was also not significantly different between the two groups. CONCLUSIONS: These results confirmed the benefits of complementary and alternative medicine including touching and massage found in previous studies. Hand massage prompted relaxation in geriatric facility residents in this experiment. PMID- 24476593 TI - [Measurement of hazardous chemical constituents and mutagenic activity in fillers and mainstream smoke from Neo Cedar]. AB - OBJECTIVE: To determine constituents of fillers and mainstream smoke from Neo Cedar. METHODS: Neo Cedar is a second-class over-the-counter (OTC) drug and similar to cigarettes in a number of ways. In particular, the design and usage are very similar to those of cigarettes. For the fillers of the drug, the levels of nicotine, tobacco-specific nitrosamines (TSNA), and heavy metals, and mutagenicity were determined using the methods for cigarette products. For the mainstream smoke, the levels of tar, nicotine, carbon monoxide (CO), TSNA, polycyclic aromatic hydrocarbons (PAH), and carbonyl compounds were also determined using the methods for cigarettes. The mainstream smoke from the drug were collected with a smoking machine using two smoking protocols (ISO and Health Canada Intense methods). RESULTS: The nicotine and total TSNA levels in the fillers of the drug averaged 2.86 mg/g and 185 ng/g, respectively. The nine species of heavy metals were also detected in the fillers of the drug. The levels of nicotine, tar, CO, TSNA, PAH, and carbonyl compounds of mainstream smoke from the drug were higher when determined using the HCI regime than when using the ISO regime. The mutagenicity of the mainstream smoke determined using the HCI regime was also higher than that determined using the ISO regime. CONCLUSION: In this study, all constituents of Neo Cedar were determined by methods for cigarette products. The drug had a ventilation hole on its filter. Thus, its constituents are different from those determined by the smoking protocols. Neo Cedar users should be careful of higher exposure to the hazardous gases owing to smoking patterns. PMID- 24476594 TI - [Effect of variation of lemon intake and walking in daily life on various indicators of muscle mass and blood biochemistry in menopausal middle-aged and elderly women]. AB - OBJECTIVES: We examined the factors considered to change body composition and blood biochemistry indicators in menopausal middle-aged and elderly women. These changes result from exercise by walking as part of their daily activities and lemon consumption by women who live on the small islands of the Seto Inland Sea, Japan's largest citrus fruit (lemon)-producing region. METHODS: Between September 2011 and March 2012, we recorded the daily lemon consumption and the number of steps taken by 101 middle-aged and elderly female lemon farmers. We also measured their body dimensions, body compositions, and blood pressure pulse wave velocity and conducted blood tests before and after the survey period. The results before and after the survey period were compared by the t-test and associations were determined on the basis of Pearson's correlation coefficient. Covariance structural analysis was carried out to determine causal associations. RESULTS: From the results of covariance structure analysis, lemon intake did not have a direct impact on each item examined. The third item, i.e., "the factors related to arteriosclerosis," was affected indirectly via citric acid and fatigue, and anticoagulation was shown. The fourth item, i.e., "the factors related to maintenance of muscle mass," which is affected by menopausal years and the change in walking speed, was shown to be associated with the second item, i.e., "the factors related to lipid metabolism." Menopausal years affected the first, third and fourth items. CONCLUSIONS: Lemon intake did not have a direct impact on each item. Lemon has been shown to indirectly affect the third item through citric acid. Walking affected the second item, the level of total cholesterol, such as HDL cholesterol, through the fourth item. The importance of providing services that lead to sustained physical activity and a well-balanced metabolism between lipids and carbohydrates has been shown. PMID- 24476595 TI - [Challenges and development of a nutritional management service system home page that targets personal computer novices 65 years of age or older]. AB - OBJECTIVES: We intended to develop contents for nutritional management for elderly people using the Internet, and to consider factors relatied to the promotion of Information and Communication Technology (ICT) use. METHODS: A questionnaire survey was carried out consisting of items on diet support conditions and promoting the use of ICT by the elderly. Then, we developed a nutritional management system using a home page on a trial basis, after which n we studied the need, operability and environmental support of this system. RESULTS: Regarding the state of ICT use more than one- half of the respondents were daily users of the Internet 62.4%, and mobile phones 65.2%. On the four items on diet, such as "buy the same food, forget to buy food", 22.7%responded that "forget to buy food", which was the highest, and interest in "lunch home delivery" showed a low percentage. Among the respondents 19.6% answer "yes" to the question that memory, "have trouble remembering where you put things" and 13.4% responded that they forget to take medicine". There was a positive correlation of what with five items on operability, "What is simple and easy to use is good" and the effectiveness of personal computers and mobile phones has been shown. In addition, 32.3% responded "When the operation is difficult, the use becomes inconvenient". CONCLUSIONS: It was suggested that by setting up an opportunity to experience the effectiveness and the satisfaction of using a system that addresses elderly people's concerns, we can modify attitudes and provide motivation, reducing the sense of weakness or irrelevance that can hinder the use of a nutritional management system. It was suggested that along with the sense of effectiveness of screen displays with color instructions and simple design that match the physical characteristics of the elderly, the sense of being able to operate the system afterwards will affect the need for ICT use and utilization rate. PMID- 24476596 TI - [Present status of expanded newborn screening project for inborn errors of metabolism by tandem mass spectrometry]. AB - In Japan, screening for six diseases including four inborn errors of metabolism has been performed since 1977 for all neonates to prevent severe mental handicaps or death. A rapid screening procedure for analysis of several amino acids and acylcarnitines in blood spots by tandem mass spectrometry was developed by Millington DS et al. in the early 1990s. Although it is called expanded (or extended) newborn screening, the procedure is insufficiently sensitive to or specific for several diseases. Screening for all diseases that can be screened using this procedure is suggested to be cost-ineffective. Many European countries target only two diseases: medium-chain acyl-CoA dehydrogenase deficiency and phenylketonuria; their prevalence in Caucasian populations is very high, but some countries target more than twenty diseases and others an intermediate number. A pilot study targeting 22 diseases suggests that the combined incidence is one per 9,000 (0.01%) in Japan. This primary screening requires secondary screening to confirm the disease using urine, and either organic acids with solvent extraction or metabolome without fractionation are analyzed by gas chromatography-mass spectrometry. There is no need for primary or secondary screening tests to be performed at the same laboratory because the skills required are quite different. Understanding of the methodological problems of tandem mass screening and amelioration of variation and false positivity rate of this screening method among laboratories are critical to the success of the screening system in Japan. GC/MS-based urine metabolomics is expected to become one of the primary screening methodologies for neonates/infants who are already ill. PMID- 24476597 TI - [History of ignorance of methylmercury toxicity and intoxication in Japan in relation to Minamata disease]. AB - The first reports of methylmercury intoxication appeared in 1865 and 1866. These reports had sensational effects in European countries, and were introduced not only in journals but also in newspapers. These two reports were referable in Japan at the latest in 1927. The formation of organic mercury in the production of acetoaldehyde was also referable in 1906 in Japan. In 1931 (one year before the start of acetoaldehyde production in Minamata) these important reports cited above were referable in Kumamoto University, and there were warnings about the toxicity of organic mercury and environmental pollution prior to the start of acetoaldehyde production. However, not only the plant, authorities (Ministry of Welfare), and Kumamoto Prefectural Office, but also the scientists completely ignored these reports. Waste was dumped into the environment without any treatment. Serious pollution of the environment by organic mercury started, which resulted in the outbreak of Minamata disease (=methylmercury intoxication). PMID- 24476599 TI - Geographical spread of influenza incidence in Spain during the 2009 A(H1N1) pandemic wave and the two succeeding influenza seasons. AB - The aim of this study was to monitor the spatio-temporal spread of influenza incidence in Spain during the 2009 pandemic and the following two influenza seasons 2010-2011 and 2011-2012 using a Bayesian Poisson mixed regression model; and implement this model of geographical analysis in the Spanish Influenza Surveillance System to obtain maps of influenza incidence for every week. In the pandemic wave the maps showed influenza activity spreading from west to east. The 2010-2011 influenza epidemic wave plotted a north-west/south-east pattern of spread. During the 2011-2012 season the spread of influenza was geographically heterogeneous. The most important source of variability in the model is the temporal term. The model of spatio-temporal spread of influenza incidence is a supplementary tool of influenza surveillance in Spain. PMID- 24476600 TI - Evidence of human neurocysticercosis in Slovenia. AB - To assess the prevalence of Taenia solium cysticercosis in patients with neurological disorders in Slovenia, serum/cerebrospinal fluid (CSF) samples from 348 suspected patients were collected between the beginning of January 2001 and the end of December 2012 and analysed serologically for the presence of anti-T. solium IgG antibodies. Of 20 patients whose samples tested positive or equivocal by enzyme-linked immunosorbent assay (ELISA), samples of 7 patients were confirmed positive by Western blot (WB). The overall seroprevalence rate of T. solium infection in patients with neurological disorders included in the study was 2.0%. Serological results of positive patients corresponded to clinical and/or imaging findings concerning their brain cysts. Based on their personal data, it was ascertained that neurocysticercosis (NCC) positive patients had immigrated or came to Slovenia from the former Yugoslav republics. Since the disease is believed not to be endemic in Slovenia we assume that all of the NCC positive patients had acquired the infection before immigration to Slovenia or visiting or being visited by their relatives infected with an adult T. solium parasite. The present results represent the first insight into the prevalence of NCC in patients with neurological disorders in Slovenia. PMID- 24476601 TI - Molecular cloning and yeast expression of cinnamate 4-hydroxylase from Ornithogalum saundersiae baker. AB - OSW-1, isolated from the bulbs of Ornithogalum saundersiae Baker, is a steroidal saponin endowed with considerable antitumor properties. Biosynthesis of the 4 methoxybenzoyl group on the disaccharide moiety of OSW-1 is known to take place biochemically via the phenylpropanoid biosynthetic pathway, but molecular biological characterization of the related genes has been insufficient. Cinnamic acid 4-hydroxylase (C4H, EC 1.14.13.11), catalyzing the hydroxylation of trans cinnamic acid to p-coumaric acid, plays a key role in the ability of phenylpropanoid metabolism to channel carbon to produce the 4-methoxybenzoyl group on the disaccharide moiety of OSW-1. Molecular isolation and functional characterization of the C4H genes, therefore, is an important step for pathway characterization of 4-methoxybenzoyl group biosynthesis. In this study, a gene coding for C4H, designated as OsaC4H, was isolated according to the transcriptome sequencing results of Ornithogalum saundersiae. The full-length OsaC4H cDNA is 1,608-bp long, with a 1,518-bp open reading frame encoding a protein of 505 amino acids, a 55-bp 5' non-coding region and a 35-bp 3'-untranslated region. OsaC4H was functionally characterized by expression in Saccharomyces cerevisiae and shown to catalyze the oxidation of trans-cinnamic acid to p-coumaric acid, which was identified by high performance liquid chromatography with diode array detection (HPLC-DAD), HPLC-MS and nuclear magnetic resonance (NMR) analysis. The identification of the OsaC4H gene was expected to open the way to clarification of the biosynthetic pathway of OSW-1. PMID- 24476602 TI - 4-aminobenzoic acid-coated maghemite nanoparticles as potential anticancer drug magnetic carriers: a case study on highly cytotoxic Cisplatin-like complexes involving 7-azaindoles. AB - This study describes a one-pot synthesis of superparamagnetic maghemite-based 4 aminobenzoic acid-coated spherical core-shell nanoparticles (PABA@FeNPs) as suitable nanocomposites potentially usable as magnetic carriers for drug delivery. The PABA@FeNPs system was subsequently functionalized by the activated species (1* and 2*) of highly in vitro cytotoxic cis-[PtCl2(3Claza)2] (1; 3Claza stands for 3-chloro-7-azaindole) or cis-[PtCl2(5Braza)2] (2; 5Braza stands for 5 bromo-7-azaindole), which were prepared by a silver(I) ion assisted dechlorination of the parent dichlorido complexes. The products 1*@PABA@FeNPs and 2*@PABA@FeNPs, as well as an intermediate PABA@FeNPs, were characterized by a combination of various techniques, such as Mossbauer, FTIR and EDS spectroscopy, thermal analysis, SEM and TEM. The results showed that the products consist of well-dispersed maghemite-based nanoparticles of 13 nm average size that represent an easily obtainable system for delivery of highly cytotoxic cisplatin-like complexes in oncological practice. PMID- 24476603 TI - Simultaneous determination of fifteen constituents of jitai tablet using ultra high-performance liquid chromatography coupled with triple quadrupole electrospray tandem mass spectrometry. AB - An ultra-high-performance liquid chromatography-electrospray ionization tandem mass spectrometry (UHPLC-ESI-MS/MS) method was developed for simultaneous determination of fifteen constituents in Jitai tablet (JTT), a complex Traditional Chinese Medicine prescription (TCMP) used in treating opiate addiction. Benefitting from a small particle size (1.8 um) C18 column, accelerated analysis with satisfactory resolution, sensitivity and selectivity were achieved in a single run within 7 min with linear gradient elution of acetonitrile-0.1% (v/v) formic acid in water. The analytical signal was obtained by multiple reaction monitoring transitions via electrospray ionization source operating in both positive and negative ionization mode. The approach was validated for linearity, sensitivity, precision, repeatability, stability and recovery. All analytes showed good linearity over a wide concentration range (r > 0.99). The method limits ranged from 0.03 ng/mL to 19.35 ng/mL which are sensitive enough for quality control studies. The developed method was successfully applied to the simultaneous determination of fifteen constituents in JTT. In conclusion, our experimental results demonstrate that UHPLC-ESI-MS/MS is a useful approach for the overall quality assessment of complex TCMPs. PMID- 24476604 TI - Atypical femur fractures. AB - Osteoporosis (OP) results from an imbalance between bone production and absorption that results in decreased bone mass and microstructural deterioration of the bone trabeculae, leading to diminished bone quality and fragility fractures. It is synonymous with decreased bone strength and affects millions of people worldwide. The most commonly prescribed drugs for the treatment of OP are the bisphosphonates (BPs). Long-term BP use may be associated with stress fractures of the subtrochanteric and shaft regions of the femur known as atypical femur fractures (AFFs). Although AFFs can be devastating, BPs have decreased the number of low-energy hip fractures and the number of vertebral and nonvertebral fractures that occur each year. Many trials and population-based studies have assessed the association between AFF and BP, and several studies have attempted to establish AFF's true incidence. The authors will summarize a few of the major studies and discuss their strengths and limitations. The findings of an association between BPs and AFFs have been variable and may reflect sample selection and measurement bias. AFFs are uncommon; the increase in risk associated with BP use is very small and does not outweigh the benefit of fracture prevention in patients with OP. Evidence for the efficacy of BPs for the prevention of fractures in postmenopausal women with OP is very strong, and the current clinical practice of using BPs as first-line therapy for these patients should be continued. Further information is required to determine the appropriate duration and time of discontinuation of BP therapy. PMID- 24476605 TI - Heterogeneous reconstitution of the PQQ-dependent glucose dehydrogenase immobilized on an electrode: a sensitive strategy for PQQ detection down to picomolar levels. AB - A highly sensitive electroanalytical method for determination of PQQ in solution down to subpicomolar concentrations is proposed. It is based on the heterogeneous reconstitution of the PQQ-dependent glucose dehydrogenase (PQQ-GDH) through the specific binding of its pyrroloquinoline quinone (PQQ) cofactor to the apoenzyme anchored on an electrode surface. It is shown from kinetics analysis of both the enzyme catalytic responses and enzyme surface-reconstitution process (achieved by cyclic voltammetry under redox-mediated catalysis) that the selected immobilization strategy (i.e., through an avidin/biotin linkage) is well-suited to immobilize a nearly saturated apoenzyme monolayer on the electrode surface with an almost fully preserved PQQ binding properties and catalytic activity. From measurement of the overall rate constants controlling the steady-state catalytic current responses of the surface-reconstituted PQQ-GDH and determination of the PQQ equilibrium binding (Kb = 2.4 * 10(10) M(-1)) and association rate (kon = 2 * 10(6) M(-1) s(-1)) constants with the immobilized apoenzyme, the analytical performances of the method could be rationally evaluated, and the signal amplification for PQQ detection down to the picomolar levels is well-predicted. These performances outperform by several orders of magnitude the direct electrochemical detection of PQQ in solution and by 1 to 2 orders the detection limits previously achieved by UV-vis spectroscopic detection of the homogeneous PQQ-GDH reconstitution. PMID- 24476606 TI - Comparison of energy balance-related behaviours and measures of body composition between Turkish adolescents in Turkey and Turkish immigrant adolescents in the Netherlands. AB - OBJECTIVE: To explore the influences of migration to a Western country on obesity and related risk factors by comparing measures of body composition and energy balance-related behaviours between Turkish adolescents in Turkey (TR-TR) and adolescents from Turkish immigrant ethnicity in the Netherlands (TR-NL). DESIGN: Cross-sectional survey or baseline intervention data from six Dutch school-based studies and one Turkish study. SETTING: Primary and secondary schools. SUBJECTS: A total of 915 (49 % girls; mean age 13.1 (sd 0.8) years) TR-TR adolescents and 433 (51 % girls; mean age 11.7 (sd 1.3) years) TR-NL adolescents were included. Outcome measures were self-reported sugar-containing beverage consumption, fruit and vegetable intake, screen time, physical activity, measured body height and weight, BMI, waist and hip circumferences, and skinfold thicknesses. RESULTS: Our data showed that more TR-NL adolescents were overweight (31 % v. 26 %) and obese (9 % v. 6 %) and had significantly higher mean BMI (21.1 v. 20.0 kg/m2), waist circumference (72.2 v. 71.3 cm) and suprailiac skinfold thickness (19.8 v. 13.1 mm) than TR-TR adolescents. TR-NL adolescents reported significantly higher sugar containing beverage consumption (1173 v. 115 ml/d), less fruit and vegetable intake (295 v. 647 g/d), less screen time (253 v. 467 min/d) and higher physical activity levels (61 v. 27 min/d) than TR-TR adolescents. CONCLUSIONS: Immigrant adolescents in the Netherlands were more often overweight and had a less favourable dietary pattern than their peers in Turkey, while their physical activity and screen time patterns were more favourable. These results suggest that adolescents from Turkish immigrant ethnicity in the Netherlands have adopted lifestyles towards the host culture. PMID- 24476607 TI - Influence of hydrogencalcium salts of oxidized cellulose on MMP-2, MMP-9 and TNF alpha production and wound healing in non-healing wounds. AB - Levels of matrix metalloproteinase-2 (MMP-2), matrix metalloproteinase-9 (MMP-9) and tumor necrosis factor-alpha (TNF-alpha) may influence wound healing and wound closure in non-healing wounds. The aim of the study was to test the hypothesis that hydrogencalcium salts of oxidized cellulose change the production of matrix metalloproteinases (MMPs) and TNF-alpha, wound size and number of bacterial strains in non-healing wounds. We analyzed MMP-2, MMP-9 and TNF-alpha in the wound fluid from 20 patients by ELISA every fourteen days over six weeks. Wound size, pain, wound closure and bacterial strains in the wound were also investigated. The wound size was reduced in 14 patients and pain in 16 patients. Bacterial contamination of the wound decreased significantly after treatment. The level of MMP-2 correlated with TNF-alpha production. The level of MMP-9 was unchanged during the healing period. We conclude that hydrogencalcium salts of oxidized cellulose have a favorable effect on the reduction of bacterial contamination, wound size and pain. PMID- 24476608 TI - Cutaneous findings in patients with acromegaly. AB - Acromegaly is a systemic syndrome caused by overproduction of growth hormone. The syndrome affects cutaneous, endocrine, cardiovascular, skeletal, and respiratory systems. Cutaneous manifestations of acromegaly are various, usually being the first presenting findings of the disease. Forty-nine patients with acromegaly, followed-up at a tertiary referral hospital, underwent dermatological examination. There were 27 (55.1%) female and 22 (44.9%) male patients. The age at onset of the disease was older in females than males (P=0.045). Most patients had acral enlargements, large triangular nose, coarse face, thickened lower lip, and prognathism. Fourteen (28.6%) patients had multiple cherry angiomas, five (10.2%) had varicose veins in lower limbs, and two (4.1%) had psoriasis. In conclusion, a wide spectrum of cutaneous symptoms and features may be associated with acromegaly. Detailed dermatological examination of patients with acromegaly should be an essential component of systemic evaluation. Future prospective studies investigating the relationships between changes in skin signs, hormone levels, and response to treatments may help understand details of skin involvement in acromegaly. PMID- 24476609 TI - The frequency and causes of photoallergic contact dermatitis among dermatology outpatients. AB - Too many patients with photoallergy remain undiagnosed due to unsatisfactory knowledge among doctors and limited access to photopatch testing. The objectives of this study were to analyze the frequency of patients requiring diagnostic work up for photoallergic contact dermatitis among dermatology patients, and to identify the causative photosensitizers. This prospective study involved 1000 consecutive, first-referred dermatology outpatients. All patients with a history of dermatitis induced or aggravated by exposure to light were qualified for photopatch testing. In the study group, 36 (3.6%; 95%CI: 2.4-4.8%) persons required photopatch testing based on their clinical symptoms. As the total number of patients requiring patch tests of any kind amounted to 205, the percentage of photopatch tested patients among all patch-tested patients was 17.5% (95%CI: 12.2 22.8%). Photoallergic contact dermatitis was ultimately confirmed in 15 (1.5%; 0.7-2.3%) persons: 7 females and 8 males aged 6-60 (median 33) years. Nine patients turned out photoallergic to at least one nonsteroidal antiinflammatory drug, with ketoprofen photoallergy being most frequent (5 patients, in each case clinically relevant), followed by etofenamate (4 non-relevant reactions) and diclofenac (1 relevant reaction). Five patients were positive to at least one organic sunscreen, most frequently to benzophenone-3 (2 patients). "Classical" contact allergy to tested photohaptens was found in 15 persons, including 7 with coexisting photoallergy. In conclusion, patients requiring diagnostic work-up for photoallergy constitute a relevant group among dermatology patients, therefore, it seems advisable that all second-level dermatology referral centers be capable of photopatch testing. Due attention should also be paid to photoallergy in dermatology training. PMID- 24476610 TI - Mycoplasma genitalium: clinical significance and diagnosis. AB - Mycoplasma genitalium is considered the smallest self-replicating cell. It was first isolated in 1981, from 2 of 13 men with urethritis. Mycoplasma genitalium causes urethritis, cervicitis and pelvic inflammatory disease. Because of difficulties in cultivation, the diagnosis is based exclusively on PCR methodology. The recommended therapy for Mycoplasma genitalium infections is azithromycin or doxycycline. Development of macrolide resistance was shown to correlate with treatment failure. PMID- 24476611 TI - Fatal lower limb infection by Trichosporon asahii in an immunocompetent patient. AB - Trichosporon (T.) asahii can cause superficial skin infections and can be an opportunistic pathogen that produces potentially fatal systemic infections in immunocompromised hosts. We report a case of lower limb infection due to T. asahii in an immunocompetent patient who displayed no evidence of underlying disease. There is a strong possibility that our patient had been colonized at the infection site as part of the normal skin flora. After one-month bed rest due to an accidental fall and fracture of the right shoulder blade, a 61-year-old woman experienced severe edema and redness in the right lower limb and received topical treatment with iodine solution and antibiotics without improvement. She presented at our Outpatient Clinic with cellulitis and lymphedema. Samples collected from the affected areas revealed T. asahii and the patient was referred to a hospital for infectious diseases for appropriate therapy. The patient was treated with wound dressings until she was admitted to our intensive care unit when her general condition abruptly deteriorated. Despite in vitro susceptibility results, therapy with liposomal amphotericin and voriconazole could not change the fatal outcome. Nowadays, physicians must suspect this emerging difficult-to-treat fungal pathogen and treatment must start promptly in these infections. PMID- 24476612 TI - Palisaded neutrophilic and granulomatous dermatitis in association with subcutaneous nodular and systemic sarcoidosis. AB - Palisaded neutrophilic granulomatous dermatitis (PNGD) is a rare entity that has been clearly defined neither clinically nor histopathologically. PNGD has been associated with some immune-mediated disorders such as rheumatoid arthritis, systemic lupus erythematosus, systemic vasculitis, Behcet's disease, as well as with lymphoproliferative conditions, bacterial endocarditis, sarcoidosis, and various drugs. We present a 44-year-old Caucasian woman with roundish erythematous-livid plaque and erythematous papules on the left calf that were present for three months. Histopathology of plaque lesion showed palisading neutrophilic and granulomatous dermatitis. Subsequently, she developed a firm and tender nodule on the right calf. Histopathology of the nodule showed typical naked sarcoid granulomas in the dermis and subcutis. Additionally, the patient developed non-tender subcutaneous nodules on the cheeks, submandibular region and left breast with normal overlying skin, which were histopathologically diagnosed as sarcoid granuloma. Red eyes and lower visual acuity on the right eye were diagnosed as anterior uveitis. Therefore, systemic sarcoidosis was established. This is a case of PNGD described in an adult patient with sarcoidosis with cutaneous, breast, eye and lung involvement established by clinical, radiographic, laboratory, and histopathologic criteria. PMID- 24476613 TI - Successful use of silver impregnated hydrofiber dressing in the treatment of kerion celsi caused by Microsporum gypseum. AB - A method of treatment of tinea capitis is presented in a case of a 10-year-old boy who was referred to the pediatric surgical unit for the treatment of a skin lesion on the scalp, which had persisted for more than two months. The initial dermatologic examination led to the clinical diagnosis of inflammation of the scalp, while mycological analysis revealed an uncommon dermatophyte agent, Microsporum gypseum, in the culture. The lesion was subsequently treated with local and oral antifungal agents, but antifungal therapy was discontinued due to the resulting liver dysfunction and was replaced by treatment with a silver impregnated hydrofiber dressing. During one-month treatment, the patient's scalp lesion cleared completely. The treatment of tinea capitis is discussed. PMID- 24476614 TI - Clinical characteristics of alopecia areata in Down syndrome. AB - This study was undertaken to better understand clinical characteristics, environmental and physical events in Down syndrome (DS) and alopecia areata (AA). This cross-sectional study included 18 DS patients who were currently presenting or had presented AA. We evaluated gender, age, location and type of AA, presence of autoimmune disease or atopy, AA in first-degree relatives, and environmental, physical, and clinical intercurrences. The mean age of study subjects was 11.6 (SD +/- 5.5) years and mean age at AA onset 7.2 (2.5 to 15.2) years. The duration of alopecia episodes varied, with a mean of 2.7 (0.1 to 18.7) years. Recurrence of AA was reported in 27.7% (5/18) of subjects, with a mean number of recurrences of 3.6. Localized type AA was seen in 83.4% of individuals, with the most frequent location on the scalp (100%). Seven of the individuals presented atopy. Fourteen individuals had undergone environmental and/or clinical intercurrences. In conclusion, the most frequent presentation of AA in DS is the non-recurrent, localized form on the scalp, with a varied period of duration. Changes in the individuals' routine occurred in more than half of the study group. We suggest further studies of the psychology and immunogenetics in the etiopathology of AA in DS. PMID- 24476615 TI - Omenn syndrome: two case reports. AB - Omenn syndrome is a variant of combined severe immunodeficiency due to mutations in RAG genes. It is characterized by polymorph symptoms and lethal outcome. We report on two cases of Omenn syndrome. Infants were aged 50 and 46 days. The clinical and biological signs were typical and complete in the first case. In the second case, only the cutaneous signs were present. Diagnosis was confirmed by genetic study. The Rag1 T631 mutation was found in these two patients. Hematopoietic stem cell transplantation could not be done and the evolution was fatal in both cases because of severe infectious episodes. Prenatal diagnosis was performed in the two families and each family has currently a healthy child. In conclusion, early diagnosis of Omenn syndrome may avoid infectious complications responsible for delay in therapeutic management. Genetic study confirms the diagnosis. The treatment usually consists of hematopoietic stem cell transplantation in association with immunosuppressive drugs. Prenatal diagnosis is very important to allow parents to have healthy children. PMID- 24476616 TI - Rosacea-like tinea incognito due to Trichophyton mentagrophytes vr. mentagrophytes. PMID- 24476617 TI - Two cases of acrodermatitis continua of Hallopeau associated with generalized arthritis. AB - Acrodermatitis continua of Hallopeau (ACH), a variant of pustular psoriasis, chiefly affects distal parts of the hands and feet (1,2). Arthritis occasionally occurs in psoriasis, including pustular psoriasis, as psoriatic arthritis (3), but it is uncommon in ACH. Here, we report on two cases of ACH with arthritis that was improved by infliximab together with methotrexate as well as salazosulfapyridine. As arthritis is refractory to conventional therapies, our cases could provide a clue to clarifying therapies for ACH. PMID- 24476618 TI - Epidermal nevus in association with some uncommon manifestations. PMID- 24476619 TI - Nanotechnology in prevention and therapy of epidermal barrier disorders. PMID- 24476620 TI - Professor Emeritus Eugenija Zuskin, MD, PhD 1933-2013. PMID- 24476622 TI - Transplantable malignant melanoma in LT.B6 congenic mice resembling pigmented epithelioid melanocytoma in humans. PMID- 24476623 TI - CARD14 c.526G>C (p.Asp176His) is a significant risk factor for generalized pustular psoriasis with psoriasis vulgaris in the Japanese cohort. PMID- 24476624 TI - Overexpressed beta-catenin localizes to plasma membrane in respiratory papillomas. PMID- 24476625 TI - Validation and reproducibility of dietary assessment methods in adolescents: a systematic literature review. AB - OBJECTIVE: The aim of the present work was to determine what dietary assessment method can provide a valid and accurate estimate of nutrient intake by comparison with the gold standard. DESIGN: A MEDLINE, EMBASE, ISI Web of Science, Cochrane and related references literature review was conducted on dietary assessment methods for adolescents reporting the validity and/or reproducibility values. A study quality assessment on the retrieved FFQ was carried out according to two different scoring systems, judging respectively the quality of FFQ nutrition information and of FFQ validation and calibration. SETTING: The present review considered adolescents attending high schools and recruited in hospitals or at home. SUBJECTS: The target of the review was the healthy adolescent population in the age range 13-17 years. RESULTS: Thirty-two eligible papers were included and analysed separately as 'original articles' (n 20) and 'reviews' (n 12). The majority (n 17) assessed the validation and reproducibility of FFQ. Almost all studies found the questionnaires to be valid and reproducible (r > 0.4), except for some food groups and nutrients. Different design and validation issues were highlighted, such as portion-size estimation, number of food items and statistics used. CONCLUSIONS: The present review offers new insights in relation to the characteristics of assessment methods for dietary intake in adolescents. Further meta-analysis is required although the current review provides important indications on the development of a new FFQ, addressing the need for a valid, reproducible, user-friendly, cost-effective method of accurately assessing nutrient intakes in adolescents. PMID- 24476626 TI - RSPO2-LGR5 signaling has tumour-suppressive activity in colorectal cancer. AB - R-spondins are a family of secreted Wnt agonists. One of the family members, R spondin 2 (RSPO2), has an important role in embryonic development, bone formation and myogenic differentiation; however, its role in human cancers remains largely unknown. Here we show that RSPO2 expression is downregulated in human colorectal cancers (CRCs) due to promoter hypermethylation, and that the RSPO2 reduction correlates with tumour differentiation, size and metastasis. Overexpression of RSPO2 suppresses CRC cell proliferation and tumorigenicity, whereas the depletion of RSPO2 enhances tumour cell growth. RSPO2 has an inhibitory effect on Wnt/beta catenin signaling in the CRC cells that show suppressed cell proliferation. In human CRC cells, the RSPO2-induced inhibition of Wnt signaling depends on leucine rich repeat-containing G-protein-coupled receptor 5 (LGR5); RSPO2 interacts with LGR5 to stabilize the membrane-associated zinc and ring finger 3 (ZNRF3). Our data suggest that RSPO2 functions as a tumour suppressor in human CRCs, and these data reveal a RSPO2-induced, LGR5-dependent Wnt signaling-negative feedback loop that exerts a net growth-suppressive effect on CRC cells. PMID- 24476627 TI - (1)H-Magnetic resonance spectroscopy study of stimulant medication effect on brain metabolites in French Canadian children with attention deficit hyperactivity disorder. AB - BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is a common neurodevelopmental disorder in school aged children. Functional abnormalities have been reported in brain imaging studies in ADHD populations. Psychostimulants are considered as the first line treatment for ADHD. However, little is known of the effect of stimulants on brain metabolites in ADHD patients. OBJECTIVES: To compare the brain metabolite concentrations in children with ADHD and on stimulants with those of drug naive children with ADHD, versus typically developed children, in a homogenous genetic sample of French Canadians. METHODS: Children with ADHD on stimulants (n=57) and drug naive children with ADHD (n=45) were recruited, as well as typically developed children (n=38). The presence or absence of ADHD diagnosis (Diagnostic and Statistical Manual of Mental Disorders IV criteria) was based on clinical evaluation and The Diagnostic Interview Schedule for Children IV. All children (n=140) underwent a proton magnetic resonance spectroscopy session to measure the ratio of N-acetyl-aspartate, choline, glutamate, and glutamate-glutamine to creatine, respectively, in the left and right prefrontal and striatal regions of the brain, as well as in the left cerebellum. RESULTS: When compared with drug naive children with ADHD, children with ADHD on stimulants and children typically developed were found to have higher choline ratios in the left prefrontal region (P=0.04) and lower N acetyl-aspartate ratios in the left striatum region (P=0.01), as well as lower glutamate-glutamine ratios in the left cerebellum (P=0.05). In these three regions, there was no difference between children with ADHD on stimulants and typically developed children. CONCLUSION: Therapeutic psychostimulant effects in children with ADHD may be mediated by normalization of brain metabolite levels, particularly in the left fronto-striato-cerebellar regions. PMID- 24476628 TI - Identifying the affected hemisphere with a multimodal approach in MRI-positive or negative, unilateral or bilateral temporal lobe epilepsy. AB - Patients with non-lesional or bilateral temporal-lobe epilepsy (TLE) are often excluded from surgical treatment. This study investigated focus lateralization in TLE to understand identification of the affected hemisphere with regard to non lesional or bilateral affection and postsurgical outcome. A total of 24 TLE patients underwent presurgical evaluation with magnetic resonance imaging (MRI), proton magnetic resonance spectroscopy ((1)H-MRS), video-electroencephalogram (video-EEG), and/or intracranial EEG (icEEG), and they were classified as MRI positive or negative, unilateral or bilateral TLE cases. In patients with positive-MRI, MRI and (1)H-MRS indicated high (100%) concordant lateralization to EEG findings in unilateral TLE, and moderate (75%) concordance to icEEG findings in bilateral TLE; whereas in patients with negative-MRI, (1)H-MRS indicated moderate (60%-75%) concordance to EEG and/or icEEG in unilateral TLE, and relatively low (50%) concordance to icEEG in bilateral TLE. Ninety point nine percent of patients with unilateral TLE and 41.7% of patients with bilateral TLE (including 50% of MRI-negative bilateral TLE) became seizure-free. The MRS findings were not correlated with seizure outcome, while non-seizure-free patients had an insignificantly higher percentage of contralateral N-acetyl aspartate (NAA) reduction compared with seizure-free patients, indicating the relatively low predictive value of (1)H-MRS for surgical outcome. Further, EEG and icEEG findings were significantly correlated with seizure outcome, and for patients with positive MRI, MRI findings were also correlated with seizure outcome, indicating the predictive value of these modalities. The results suggested that a multimodal approach including neuroimaging, EEG, and/or icEEG could identify seizure focus in most cases, and provide surgical options for non lesional or bilateral TLE patients with a possible good outcome. PMID- 24476629 TI - Balance deficits and ADHD symptoms in medication-naive school-aged boys. AB - BACKGROUND AND OBJECTIVES: Functional disturbances developed early in life include balance deficits which are linked to dysfunctions of higher levels of cognitive and motor integration. According to our knowledge, there are only a few studies suggesting that balance deficits are related to behavioral disturbances in attention-deficit/hyperactivity disorder (ADHD). METHODS: We tested the extent to which balance deficits were related to ADHD symptoms in 35 medication-naive boys of school age (8-11 years) and compared the results with a control group of 30 boys of the same age. RESULTS: ADHD symptoms in medication-naive boys had specific relationships to disturbances of postural and gait balance. CONCLUSION: To our knowledge, this study provides the first evidence in the medical literature for a direct relationship between ADHD symptoms and balance deficits, that cannot be attributed to medication and the presence of any neurological disease. PMID- 24476631 TI - Giant thrombosed intracavernous carotid artery aneurysm presenting as Tolosa-Hunt syndrome in a patient harboring a new pathogenic neurofibromatosis type 1 mutation: a case report and review of the literature. AB - Neurofibromatosis type 1 (NF1) is a relatively common single-gene disorder, and is caused by heterozygous mutations in the NF1 gene that result in a loss of activity or in a nonfunctional neurofibromin protein. Despite the common association of NF1 with neurocutaneous features, its pathology can extend to numerous tissues not derived from the neural crest. Among the rare cerebrovascular abnormalities in NF1, more than 85% of cases are of purely occlusive or stenotic nature, with intracranial aneurysm being uncommon. Predominantly, the aneurysms are located in the internal carotid arteries (ICAs), being very rare bilateral aneurysms. This report describes a very unusual case of fusiform aneurysms of both ICAs in a Caucasian NF1 patient, with a new pathogenic intragenic heterozygous deletion of the NF1 gene, presenting at age 22 years with Tolosa-Hunt syndrome, because of partial thrombosis of the left giant intracavernous aneurysm. Medical treatment with anticoagulant therapy allowed a good outcome for the patient. In conclusion, early identification of cerebral arteriopathy in NF1 and close follow-up of its progression by neuroimaging may lead to early medical or surgical intervention and prevention of significant neurologic complications. PMID- 24476632 TI - A concept for routine emergency-care data-based syndromic surveillance in Europe. AB - We developed a syndromic surveillance (SyS) concept using emergency dispatch, ambulance and emergency-department data from different European countries. Based on an inventory of sub-national emergency data availability in 12 countries, we propose framework definitions for specific syndromes and a SyS system design. We tested the concept by retrospectively applying cumulative sum and spatio-temporal cluster analyses for the detection of local gastrointestinal outbreaks in four countries and comparing the results with notifiable disease reporting. Routine emergency data was available daily and electronically in 11 regions, following a common structure. We identified two gastrointestinal outbreaks in two countries; one was confirmed as a norovirus outbreak. We detected 1/147 notified outbreaks. Emergency-care data-based SyS can supplement local surveillance with near real time information on gastrointestinal patients, especially in special circumstances, e.g. foreign tourists. It most likely cannot detect the majority of local gastrointestinal outbreaks with few, mild or dispersed cases. PMID- 24476630 TI - Unmet needs in the management of schizophrenia. AB - Studies on unmet needs during the last decades have played a significant role in the development and dissemination of evidence-based community practices for persistent schizophrenia and other severe mental disorders. This review has thoroughly considered several blocks of unmet needs, which are frequently related to schizophrenic disorders. Those related to health have been the first block to be considered, in which authors have examined the frequent complications and comorbidities found in schizophrenia, such as substance abuse and dual diagnosis. A second block has been devoted to psychosocial and economic needs, especially within the field of recovery of the persistently mentally ill. Within this block, the effects of the current economic difficulties shown in recent literature have been considered as well. Because no patient is static, a third block has reviewed evolving needs according to the clinical staging model. The fourth block has been dedicated to integrated evidence-based interventions to improve the quality of life of persons with schizophrenia. Consideration of community care for those reluctant to maintain contact with mental health services has constituted the fifth block. Finally, authors have aggregated their own reflections regarding future trends. The number of psychosocial unmet needs is extensive. Vast research efforts will be needed to find appropriate ways to meet them, particularly regarding so-called existential needs, but many needs could be met only by applying existing evidence-based interventions. Reinforcing research on the implementation strategies and capacity building of professionals working in community settings might address this problem. The final aim should be based on the collaborative model of care, which rests on the performance of a case manager responsible for monitoring patient progress, providing assertive follow-up, teaching self-help strategies, and facilitating communication among the patient, family doctor, mental health specialist, and other specialists. PMID- 24476634 TI - Methods for modeling cytoskeletal and DNA filaments. AB - This review summarizes the models that researchers use to represent the conformations and dynamics of cytoskeletal and DNA filaments. It focuses on models that address individual filaments in continuous space. Conformation models include the freely jointed, Gaussian, angle-biased chain (ABC), and wormlike chain (WLC) models, of which the first three bend at discrete joints and the last bends continuously. Predictions from the WLC model generally agree well with experiment. Dynamics models include the Rouse, Zimm, stiff rod, dynamic WLC, and reptation models, of which the first four apply to isolated filaments and the last to entangled filaments. Experiments show that the dynamic WLC and reptation models are most accurate. They also show that biological filaments typically experience strong hydrodynamic coupling and/or constrained motion. Computer simulation methods that address filament dynamics typically compute filament segment velocities from local forces using the Langevin equation and then integrate these velocities with explicit or implicit methods; the former are more versatile and the latter are more efficient. Much remains to be discovered in biological filament modeling. In particular, filament dynamics in living cells are not well understood, and current computational methods are too slow and not sufficiently versatile. Although primarily a review, this paper also presents new statistical calculations for the ABC and WLC models. Additionally, it corrects several discrepancies in the literature about bending and torsional persistence length definitions, and their relations to flexural and torsional rigidities. PMID- 24476633 TI - Molecular identification of Sarcocystis spp. helped to define the origin of green pythons (Morelia viridis) confiscated in Germany. AB - Sarcocystis spp. represent apicomplexan parasites. They usually have a heteroxenous life cycle. Around 200 species have been described, affecting a wide range of animals worldwide, including reptiles. In recent years, large numbers of reptiles have been imported into Europe as pets and, as a consequence, animal welfare and species protection issues emerged. A sample of pooled feces from four confiscated green pythons (Morelia viridis) containing Sarcocystis spp. sporocysts was investigated. These snakes were imported for the pet trade and declared as being captive-bred. Full length 18S rRNA genes were amplified, cloned into plasmids and sequenced. Two different Sarcocystis spp. sequences were identified and registered as Sarcocystis sp. from M. viridis in GenBank. Both showed a 95-97% sequence identity with the 18S rRNA gene of Sarcocystis singaporensis. Phylogenetic analysis positioned these sequences together with other Sarcocystis spp. from snakes and rodents as definitive and intermediate hosts (IH), respectively. Sequence data and also the results of clinical and parasitological examinations suggest that the snakes were definitive hosts for Sarcocystis spp. that circulate in wild IH. Thus, it seems unlikely that the infected snakes had been legally bred. Our research shows that information on the infection of snakes with Sarcocystis spp. may be used to assess compliance with regulations on the trade with wildlife species. PMID- 24476635 TI - Mediation of parental educational level on fruit and vegetable intake among schoolchildren in ten European countries. AB - OBJECTIVE: To examine which factors act as mediators between parental educational level and children's fruit and vegetable (F&V) intake in ten European countries. DESIGN: Cross-sectional data were collected in ten European countries participating in the PRO GREENS project (2009). Schoolchildren completed a validated FFQ about their daily F&V intake and filled in a questionnaire about availability of F&V at home, parental facilitation of F&V intake, knowledge of recommendations about F&V intake, self-efficacy to eat F&V and liking for F&V. Parental educational level was determined from a questionnaire given to parents. The associations were examined with multilevel mediation analyses. SETTING: Schools in Bulgaria, Finland, Germany, Greece, Iceland, the Netherlands, Norway, Portugal, Slovenia and Sweden. SUBJECTS: Eleven-year-old children (n 8159, response rate 72%) and their parents. RESULTS: In five of the ten countries, children with higher educated parents were more likely to report eating fruits daily. This association was mainly mediated by knowledge but self-efficacy, liking, availability and facilitation also acted as mediators in some countries. Parents' education was positively associated with their children's daily vegetable intake in seven countries, with knowledge and availability being the strongest mediators and self-efficacy and liking acting as mediators to some degree. CONCLUSIONS: Parental educational level correlated positively with children's daily F&V intake in most countries and the pattern of mediation varied among the participating countries. Future intervention studies that endeavour to decrease the educational-level differences in F&V intake should take into account country-specific features in the relevant determinants of F&V intake. PMID- 24476636 TI - FDG PET/CT in follicular dendritic cell sarcoma with extensive peritoneal involvement. AB - Follicular dendritic cell sarcoma (FDCS) is a rare neoplasm that originates from follicular dendritic cells. A 33-year-old woman was referred because of a 2-month history of lower abdominal fullness. Enhanced T1-weighted MR images showed enhancement of the thickened pelvic peritoneum. FDG PET/CT was performed showing multiple FDG-avid lymph nodes in the parapharyngeal, bilateral supraclavicular, left axillary, mediastinal, and abdominal regions, and intense FDG uptake in the thickened mesentery and peritoneum. Pathologic findings of both the left supraclavicular lymph node and peritoneal biopsy specimens were consistent with high-grade FDCS. In this case, extensive peritoneal involvement by FDCS was unusual. PMID- 24476637 TI - Xanthogranulomatous osteomyelitis of rib mimicking malignant lesions in (18)F-FDG PET/CT imaging: a report of two cases. AB - Xanthogranulomatous osteomyelitis is a rare inflammatory process characterized histologically by collection of foamy macrophages admixed with mononuclear cells. We describe 2 cases with chest and back pain; radiography and CT scan identified expansile osteolytic rib destructive lesions with soft tissue mass. F-FDG PET/CT revealed accumulation of F-FDG similar to malignancy. Xanthogranulomatous osteomyelitis was histologically confirmed with numerous foamy histiocytes admixed with inflammatory infiltrate. PMID- 24476638 TI - Peptide ligation from alkoxyamine based radical addition. AB - Intermolecular radical 1,2-addition (IRA) of N-tert-butyl-N-(1-diethylphosphono 2,2-dimethylpropyl)aminoxyl (SG1) based alkoxyamines onto activated olefins is used as a tool for peptide ligation. This strategy relies on simple peptide pre derivatization to obtain (i) a SG1 nitroxide functionalized resin peptide at its N-terminus (SG1-peptide alkoxyamine), (ii) a vinyl functionalized peptide (either at its C-terminus or N-terminus), and does not require any coupling agents. PMID- 24476639 TI - Carotenoid biosynthetic and catabolic pathways: gene expression and carotenoid content in grains of maize landraces. AB - Plant carotenoids have been implicated in preventing several age-related diseases, and they also provide vitamin A precursors; therefore, increasing the content of carotenoids in maize grains is of great interest. It is not well understood, however, how the carotenoid biosynthetic pathway is regulated. Fortunately, the maize germplasm exhibits a high degree of genetic diversity that can be exploited for this purpose. Here, the accumulation of carotenoids and the expression of genes from carotenoid metabolic and catabolic pathways were investigated in several maize landraces. The carotenoid content in grains varied from 10.03, in the white variety MC5, to 61.50 MUg.g-1, in the yellow-to-orange variety MC3, and the major carotenoids detected were lutein and zeaxanthin. PSY1 (phythoene synthase) expression showed a positive correlation with the total carotenoid content. Additionally, the PSY1 and HYD3 (ferredoxin-dependent di-iron monooxygenase) expression levels were positively correlated with beta cryptoxanthin and zeaxanthin, while CYP97C (cytochrome P450-type monooxygenase) expression did not correlate with any of the carotenoids. In contrast, ZmCCD1 (carotenoid dioxygenase) was more highly expressed at the beginning of grain development, as well as in the white variety, and its expression was inversely correlated with the accumulation of several carotenoids, suggesting that CCD1 is also an important enzyme to be considered when attempting to improve the carotenoid content in maize. The MC27 and MC1 varieties showed the highest HYD3/CYP97C ratios, suggesting that they are promising candidates for increasing the zeaxanthin content; in contrast, MC14 and MC7 showed low HYD3/CYP97C, suggesting that they may be useful in biofortification efforts aimed at promoting the accumulation of provitamin A. The results of this study demonstrate the use of maize germplasm to provide insight into the regulation of genes involved in the carotenoid pathway, which would thus better enable us to select promising varieties for biofortification efforts. PMID- 24476640 TI - Plant anesthesia supports similarities between animals and plants: Claude Bernard's forgotten studies. AB - The French scientist Claude Bernard (1813-1878) is famous for his discoveries in physiology and for introducing rigorous experimental methods to medicine and biology. One of his major technical innovations was the use of chemicals in order to disrupt normal physiological function to test hypotheses. But less known is his conviction that the physiological functions of all living organisms rely on the same underlying principles. He hypothesized that similarly to animals, plants are also able to sense changes in their environment. He called this ability "sensitivity." In order to test his ideas, he performed anesthesia on plants and the results of these experiments were presented in 1878 in "Leconssur les phenomenes de la vie communs aux animaux et aux vegetaux." The phenomena described by Claude Bernard more than a century ago are not fully understood yet. Here, we present a short overview of anesthetic effects in animals and we discuss how anesthesia affects plant movements, seed germination, and photosynthesis. Surprisingly, these phenomena may have ecological relevance, since stressed plants generate anesthetics such as ethylene and ether. Finally, we discuss Claude Bernard's interpretations and conclusions in the perspective of modern plant sciences. PMID- 24476641 TI - Mediterranean diet and health status: an updated meta-analysis and a proposal for a literature-based adherence score. AB - OBJECTIVE: To update previous meta-analyses of cohort studies that investigated the association between the Mediterranean diet and health status and to utilize data coming from all of the cohort studies for proposing a literature-based adherence score to the Mediterranean diet. DESIGN: We conducted a comprehensive literature search through all electronic databases up to June 2013. SETTING: Cohort prospective studies investigating adherence to the Mediterranean diet and health outcomes. Cut-off values of food groups used to compute the adherence score were obtained. SUBJECTS: The updated search was performed in an overall population of 4 172 412 subjects, with eighteen recent studies that were not present in the previous meta-analyses. RESULTS: A 2-point increase in adherence score to the Mediterranean diet was reported to determine an 8 % reduction of overall mortality (relative risk = 0.92; 95 % CI 0.91, 0.93), a 10 % reduced risk of CVD (relative risk = 0.90; 95 % CI 0.87, 0.92) and a 4 % reduction of neoplastic disease (relative risk = 0.96; 95 % CI 0.95, 0.97). We utilized data coming from all cohort studies available in the literature for proposing a literature-based adherence score. Such a score ranges from 0 (minimal adherence) to 18 (maximal adherence) points and includes three different categories of consumption for each food group composing the Mediterranean diet. CONCLUSIONS: The Mediterranean diet was found to be a healthy dietary pattern in terms of morbidity and mortality. By using data from the cohort studies we proposed a literature-based adherence score that can represent an easy tool for the estimation of adherence to the Mediterranean diet also at the individual level. PMID- 24476642 TI - From the editors. PMID- 24476643 TI - Mentoring leaders in perinatal nursing. PMID- 24476644 TI - What are best practices for beginning oral feedings for high-risk infants? PMID- 24476645 TI - Ask an expert: Frequently asked questions on nursing liability issues. PMID- 24476646 TI - Internet resources. PMID- 24476647 TI - Prevention of childhood obesity risk from a pre-conceptual and pregnancy care perspective. PMID- 24476648 TI - Preventing obesity: exercise and daily activities of low-income pregnant women. AB - Low-income women are at risk for excessive gestational weight gain. Inactive lifestyle and lack of regular moderate exercise may contribute to the risk of weight gain. This study was conducted to (1) determine the rate and characteristics of low-income pregnant women who exercised regularly and met the American College of Obstetricians and Gynecologists recommendation and (2) describe how these women spent time for other physical activities compared with those who did not exercise regularly. Medicaid-recipient or uninsured pregnant women (n = 816) were asked to complete a physical activity questionnaire at rural and urban county health departments located in North Carolina. Twenty percent of low-income women met the American College of Obstetricians and Gynecologists recommendation for moderate exercise (>=10 METs-h/wk [metabolic equivalent task hours per week]). The women who met the recommendation spent 3 hours 45 minutes per week walking as exercise, whereas those who did not meet the recommendation spent 1 hour per week (P < .0001). Women who exercised regularly spent longer hours at work (4.25 vs. 1.75 hours per day; P = .019) and on household tasks (5.25 vs. 4.0 hours per day; P = .002) than women who did not exercise regularly. Time spent on domestic and occupation activities does not seem to prohibit low income women from engaging in moderate exercise on a regular basis. PMID- 24476649 TI - Pregnancy in women with glycogen storage disease Ia and Ib. AB - Over the past 9 decades since glycogen storage disease (GSD) was described, an almost universally fatal disease has become one where women are living well into adulthood and choosing to bear children. This inborn error of metabolism associated with the creation and utilization of glycogen, when untreated, manifests with unrelenting hypoglycemia. The initiation of continuous feeds has improved outcomes, and later in 1982, the administration of intermittent doses of cornstarch in water provided a continuous supply of exogenous glucose. As metabolic control has improved, morbidity has decreased. Glycogen storage disease Ib has the same severity of hypoglycemia as GSD Ia, with associated immune disturbance. Prior to the introduction of granulocyte colony-stimulating factor (G-CSF), infections caused significant mortality in GSD Ib. Pregnancy in patients with GSD Ia and Ib poses unique challenges during gestation and delivery. Good metabolic control before conception and throughout pregnancy is directly related to successful outcomes. There is no nursing literature to date addressing perinatal and neonatal care in this population. PMID- 24476650 TI - Obesity in pregnancy: addressing risks to improve outcomes. AB - The rapidly increasing rates of obesity among women of childbearing age, not only in the United States but also across the globe, contribute to increased risks during pregnancy and childbirth. Overweight and obesity are quantified by body mass index (BMI) for clinical purposes. In 2010, 31.9% of U.S. women aged 20 to 39 years met the definition of obesity, a BMI of 30 kg/m or greater. Across the life span, obesity is associated with increased risks of hypertension, cardiovascular disease, diabetes, sleep apnea, and other diseases. During pregnancy, increasing levels of prepregnancy BMI are associated with increases in both maternal and fetal/neonatal risks. This article reviews current knowledge about obesity in pregnancy and health risks related to increased maternal BMI, addresses weight stigma as a barrier to care and interventions that have evidence of benefit, and discusses the development of policies and guidelines to improve care. PMID- 24476651 TI - Preventing obesity starts with breastfeeding. AB - Preventing obesity starts with breastfeeding. An infant's nutrition at birth affects not only short-term health outcomes but also the health of that person as a child, adolescent, and adult. This article examines major findings that all conclude that any breastfeeding will help protect an infant from obesity and overweight. Research supports that the more exclusive and longer a child is breastfed, the more protection from overweight and obesity is conferred. Mechanisms of action are explored in this article. It is of paramount importance to provide evidence-based lactation support and care to families to improve the incidence, exclusivity, and duration of breastfeeding. Breastfeeding is one concrete method to address the obesity epidemic that is growing worldwide. PMID- 24476652 TI - State of the science: a contemporary review of feeding readiness in the preterm infant. AB - Oral feeding readiness has been described by researchers in the neonatal intensive care unit, and research has continued on this topic for many years. The purpose of this narrative review is to identify research and practice guidelines related to oral feeding readiness in preterm infants that have occurred during the last decade. The introduction and mastery of oral feeding is a major developmental task for the preterm infant that is often a prerequisite for discharge from the neonatal intensive care unit. Having a better understanding of the evidence supporting the development of this skill will help the practicing nurse choose appropriate interventions and the researcher to develop trajectories of research that continue to increase our knowledge in this important practice area. PMID- 24476653 TI - Setting the stage for successful oral feeding: the impact of implementing the SOFFI feeding program with medically fragile NICU infants. AB - To evaluate the impact of implementing the Supporting Oral Feeding in Fragile Infants (SOFFI) program in a tertiary-level neonatal intensive care unit (NICU) on the oral feeding, growth, and length of stay outcomes of a heterogeneous population of medically fragile infants at discharge and feeding and growth outcomes postdischarge at 3 to 5 months postterm. Data related to feeding, growth, and length of stay from a convenience sample of 81 infants recruited pre SOFFI training were compared with data for 75 infants recruited post-SOFFI training of the NICU staff. Subjects were not excluded on the basis of level of illness or medical diagnoses. To establish comparability of subject groups, infants were assigned scores using the Neonatal Medical Index. At 3 to 5 months postterm, semistructured parent phone interviews related to feeding and growth at home were conducted (n = 128). Post-SOFFI infants born at less than 37 weeks' gestation achieved full oral feedings in significantly fewer days than pre-SOFFI infants (P = .01). Time to achieve full oral feedings was not significantly different in post-SOFFI infants born at 37 or more weeks' gestation. Growth and length of stay were not significantly different at discharge. At follow-up, parents of post-SOFFI infants reported significantly fewer feeding problems overall (P = .01), less arching (P = .003), less vomiting (P = .006), and fewer infants seeing feeding specialists (P = .03). Results of the study support that NICU implementation of the SOFFI feeding program positively influences feeding outcomes before and following discharge. PMID- 24476654 TI - Efficacy of semielevated side-lying positioning during bottle-feeding of very preterm infants: a pilot study. AB - Very preterm (VP, <=30 wk gestational age) infants are at risk for impaired lung function, which significantly limits their ability to eat. A semielevated side lying (ESL) position is a feeding strategy that may improve oral feeding by supporting breathing during feeding. The study evaluated the efficacy of the ESL position compared with the semielevated supine (ESU) position on physiological stability and feeding performance of bottle-fed VP infants. Using a within subject crossover design, 6 VP infants were bottle-fed twice on 1 day, in both the ESL and ESU positions in a random order. Physiological stability (heart rate, oxygen saturation [SaO2], and respiratory characteristics) and feeding performance (percent intake, proficiency, efficiency, and duration of feeding) were measured before and/or during feeding. Very preterm infants fed in the ESL position demonstrated significantly less variation in heart rate, less severe and fewer decreases in heart rate, respiratory rate that was closer to the prefeeding state, shorter and more regular intervals between breaths, and briefer feeding related apneic events. No significant differences for SaO2 or feeding performance were found. The findings indicate that the ESL position may support better regulation of breathing during feeding, thereby allowing VP infants to better maintain physiological stability throughout feeding. PMID- 24476655 TI - Nutritional and immunological considerations relevant to infant nutrition. AB - Optimal nutrition during infancy is critical not only to support the dramatic growth and development that takes place during the first 12 months following birth but also for establishing a healthy immune response throughout childhood and across the life span. The normative standards for infant feeding and nutrition are breast-feeding and human breast milk. However, in cases in which human breast milk is not available, infant formula is substituted. Providing optimal patient care that results in the best clinical outcomes depends on understanding the unique attributes of the 3 main sources of nutrition for newborns. This state of the science review provides an update on the macronutrient and immunological content of human milk, donor milk, and infant formula and highlights the relevance of these sources of infant nutrition on the development of immune system. PMID- 24476656 TI - Infant of a diabetic mother: a preexisting disease? PMID- 24476659 TI - Investigation of increased listeriosis revealed two fishery production plants with persistent Listeria contamination in Finland in 2010. AB - In 2010, a marked increase in listeriosis incidence was observed in Finland. Listeria monocytogenes PFGE profile 96 was responsible for one-fifth of the reported cases and a cluster of PFGE profile 62 was also detected. Investigations revealed two fishery production plants with persistent Listeria contamination. It appears likely that the plants were at least partly responsible for the increase of listeriosis. Epidemiological investigation revealed that 57% (31/54) of cases with underlying immunosuppressive condition or medication reported eating gravad or cold-smoked fish. Two public notices were issued by THL and Evira informing which groups were most at risk from the effects of listeriosis and should therefore be cautious in consuming certain products. Systematic sampling of foods and adequate epidemiological investigation methods are required to identify the sources of Listeria infections. Continuous control measures at fishery production plants producing risk products are essential. PMID- 24476660 TI - Nucleated red blood cells and fetal hypoxia: a biologic marker whose 'timing' has come? PMID- 24476661 TI - Hemimelia and absence of the peroneal artery. AB - The arterial patterns of the lower extremities of three patients with congenital absence fibulae (hemimelia) were evaluated to determine whether the relationship existed between the absence of peroneal artery and hemimelia. Computerized tomograph angiography revealed the absence of peroneal artery in all the patients with dysplastic limbs and absent fibula. PMID- 24476662 TI - Neonatal neuroimaging findings in congenital myotonic dystrophy. AB - We report on a preterm neonate of 30 weeks gestational age who presented with marked muscular hypotonia and severe respiratory failure at birth and was diagnosed with congenital myotonic dystrophy. Neuroimaging at 36 gestational weeks demonstrated diffuse T2-hyperintense signal of the supratentorial white matter and a simplified gyration and sulcation pattern. Follow-up imaging showed progressive myelination, brain maturation and decrease in T2-signal of the white matter. We discuss possible pathomechanisms for white matter signal abnormalities in this neonate. PMID- 24476663 TI - Clinical experience with Leptospermum honey use for treatment of hard to heal neonatal wounds: case series. AB - Preterm, critically ill neonates represent a challenge in wound healing. Many factors predispose infants to skin injuries, including decreased epidermal-dermal cohesion, deficient stratum corneum, relatively alkaline pH of skin surface, impaired nutrition and presence of multiple devices on the skin. We present a case series describing the use of medical-grade honey-Leptospermum honey (Medihoney), for successful treatment of slowly healing neonatal wounds, specifically stage 3 pressure ulcer, dehiscent and infected sternal wound, and full-thickness wound from an extravasation injury. PMID- 24476664 TI - Crouzono-dermo-skeletal syndrome, Crouzon syndrome with acanthosis nigricans syndrome. PMID- 24476666 TI - Selenoether oxytocin analogues have analgesic properties in a mouse model of chronic abdominal pain. AB - Poor oral availability and susceptibility to reduction and protease degradation is a major hurdle in peptide drug development. However, drugable receptors in the gut present an attractive niche for peptide therapeutics. Here we demonstrate, in a mouse model of chronic abdominal pain, that oxytocin receptors are significantly upregulated in nociceptors innervating the colon. Correspondingly, we develop chemical strategies to engineer non-reducible and therefore more stable oxytocin analogues. Chemoselective selenide macrocyclization yields stabilized analogues equipotent to native oxytocin. Ultra-high-field nuclear magnetic resonance structural analysis of native oxytocin and the seleno-oxytocin derivatives reveals that oxytocin has a pre-organized structure in solution, in marked contrast to earlier X-ray crystallography studies. Finally, we show that these seleno-oxytocin analogues potently inhibit colonic nociceptors both in vitro and in vivo in mice with chronic visceral hypersensitivity. Our findings have potentially important implications for clinical use of oxytocin analogues and disulphide-rich peptides in general. PMID- 24476667 TI - Transient ischemic attacks: predictability of future ischemic stroke or transient ischemic attack events. AB - The short-term risk of an ischemic stroke after a transient ischemic attack (TIA) is estimated to be approximately 3%-10% at 2 days, 5% at 7 days, and 9%-17% at 90 days, depending on active or passive ascertainment of ischemic stroke. Various risk prediction scores are available to identify high-risk patients. We present here a pragmatic review of the literature discussing the main scoring systems. We also provide the sensitivity, specificity, positive predictive value, and negative predictive value for each scoring system. Our review shows that scoring systems including brain imaging and vascular imaging are better at risk prediction than scores that do not include this information. PMID- 24476668 TI - Subfoveal choroidal thickness after photodynamic therapy in patients with acute idiopathic central serous chorioretinopathy. AB - BACKGROUND: The purpose of this study was to evaluate changes in subfoveal choroidal thickness after photodynamic therapy in patients with acute idiopathic central serous chorioretinopathy (ICSCR). METHODS: This was a retrospective observational study conducted in 63 participants. The primary outcome measure was subfoveal choroidal thickness at baseline and 3 days, one week, 4 weeks, and 12 weeks after photodynamic therapy. The secondary outcome measure was indocyanine green angiography at baseline and 4 weeks and 12 weeks after photodynamic therapy. RESULTS: Four weeks after photodynamic therapy, 20 (64.51%) symptomatic eyes showed hypofluorescence corresponding to the area of photodynamic therapy irradiation at the posterior pole. The mean subfoveal choroidal thickness increased significantly from 422+/-132 MUm at baseline to 478+/-163 MUm at day 3 after treatment (P=0.022) and then decreased to 362+/-113 MUm at week 4 (P<0.001) and 339+/-135 MUm at week 12 (P<0.001). CONCLUSION: The subfoveal choroid in patients with acute ICSCR is thicker than in the normal population, and in symptomatic eyes is significantly thicker than in fellow eyes. Photodynamic therapy using a one third dose of verteporfin may decrease choroidal vascular hyperpermeability and choroidal thickness in patients with acute ICSCR. PMID- 24476669 TI - Eldecalcitol improves chair-rising time in postmenopausal osteoporotic women treated with bisphosphonates. AB - An open-label randomized controlled trial was conducted to clarify the effect of eldecalcitol (ED) on body balance and muscle power in postmenopausal osteoporotic women treated with bisphosphonates. A total of 106 postmenopausal women with osteoporosis (mean age 70.8 years) were randomly divided into two groups (n=53 in each group): a bisphosphonate group (control group) and a bisphosphonate plus ED group (ED group). Biochemical markers, unipedal standing time (body balance), and five-repetition chair-rising time (muscle power) were evaluated. The duration of the study was 6 months. Ninety-six women who completed the trial were included in the subsequent analyses. At baseline, the age, body mass index, bone mass indices, bone turnover markers, unipedal standing time, and chair-rising time did not differ significantly between the two groups. During the 6-month treatment period, bone turnover markers decreased significantly from the baseline values similarly in the two groups. Although no significant improvement in the unipedal standing time was seen in the ED group, compared with the control group, the chair-rising time decreased significantly in the ED group compared with the control group. The present study showed that ED improved the chair-rising time in terms of muscle power in postmenopausal osteoporotic women treated with bisphosphonates. PMID- 24476670 TI - Resurrecting surviving Neandertal lineages from modern human genomes. AB - Anatomically modern humans overlapped and mated with Neandertals such that non African humans inherit ~1 to 3% of their genomes from Neandertal ancestors. We identified Neandertal lineages that persist in the DNA of modern humans, in whole genome sequences from 379 European and 286 East Asian individuals, recovering more than 15 gigabases of introgressed sequence that spans ~20% of the Neandertal genome (false discovery rate = 5%). Analyses of surviving archaic lineages suggest that there were fitness costs to hybridization, admixture occurred both before and after divergence of non-African modern humans, and Neandertals were a source of adaptive variation for loci involved in skin phenotypes. Our results provide a new avenue for paleogenomics studies, allowing substantial amounts of population-level DNA sequence information to be obtained from extinct groups, even in the absence of fossilized remains. PMID- 24476672 TI - A brief review of spatial analysis concepts and tools used for mapping, containment and risk modelling of infectious diseases and other illnesses. AB - Fast response and decision making about containment, management, eradication and prevention of diseases, are increasingly important aspects of the work of public health officers and medical providers. Diseases and the agents causing them are spatially and temporally distributed, and effective countermeasures rely on methods that can timely locate the foci of infection, predict the distribution of illnesses and their causes, and evaluate the likelihood of epidemics. These methods require the use of large datasets from ecology, microbiology, health and environmental geography. Geodatabases integrating data from multiple sets of information are managed within the frame of geographic information systems (GIS). Many GIS software packages can be used with minimal training to query, map, analyse and interpret the data. In combination with other statistical or modelling software, predictive and spatio-temporal modelling can be carried out. This paper reviews some of the concepts and tools used in epidemiology and parasitology. The purpose of this review is to provide public health officers with the critical tools to decide about spatial analysis resources and the architecture for the prevention and surveillance systems best suited to their situations. PMID- 24476671 TI - Biparental resequencing coupled with SNP genotyping of a segregating population offers insights into the landscape of recombination and fixed genomic regions in elite soybean. AB - Identification of genes underlying agronomic traits is dependent on the segregation of quantitative trait loci (QTL). A popular hypothesis is that elite lines are becoming increasingly similar to each other, resulting in large genomic regions with fixed genes. Here, we resequenced two parental modern elite soybean lines [ZhongHuang13 (ZH) and ZhongPin03-5373 (ZP)] and discovered 794,876 SNPs with reference to the published Williams82 genome. SNPs were distributed unevenly across the chromosomes, with 87.1% of SNPs clustering in 4.9% of the soybean reference genome. Most of the regions with a high density of SNP polymorphisms were located in the chromosome arms. Moreover, seven large regions that were highly similar between parental lines were identified. A GoldenGate SNP genotyping array was designed using 384 SNPs and the 254 recombinant inbred lines (F8) derived from the cross of ZP * ZH were genotyped. We constructed a genetic linkage map using a total of 485 molecular markers, including 313 SNPs from the array, 167 simple sequence repeats (SSRs), 4 expressed sequence tag-derived SSRs, and 1 insertion/deletion marker. The total length of the genetic map was 2594.34 cM, with an average marker spacing of 5.58 cM. Comparing physical and genetic distances, we found 20 hotspot and 14 coldspot regions of recombination. Our results suggest that the technology of resequencing of parental lines coupled with high-throughput SNP genotyping could efficiently bridge the genotyping gap and provide deep insights into the landscape of recombination and fixed genomic regions in biparental segregating populations of soybean with implications for fine mapping of QTL. PMID- 24476673 TI - Screening behaviors, health beliefs, and related factors of first-degree relatives of colorectal cancer patients with ongoing treatment in Turkey. AB - BACKGROUND: Colorectal cancer (CRC) is one of the most common cancers. Family history is an important risk factor; first-degree relatives (FDRs) are most at risk. Studies are needed to determine the screening behavior of FDRs and factors affecting their health behaviors. OBJECTIVE: The purpose of this study was to investigate the screening behaviors, health beliefs, and related factors of FDRs (parent, sibling, or child) of CRC patients undergoing treatment. METHODS: A cross-sectional design was used with 400 FDRs of patients undergoing treatment at 2 hospitals in Turkey. Data were collected using the Colorectal Cancer Risk Questionnaire and the Turkish Colorectal Cancer Health Belief Model Scale. RESULTS: A slight majority of the participants were male (51.3%), with a mean of age 37.7 years. The rate of having at least 1 colonoscopy in FDRs was 22.2%. First-degree relatives reported high perceived confidence-benefits scores on average (mean, 48.4 +/- 5.2) and high perceived barrier scores on average (mean, 15.5 +/- 3.8). Health motivation of FDRs was the strongest predictor of their having a colonoscopy (odds ratio, 7.50; 95% confidence interval, 3.40-16.5). CONCLUSIONS: First-degree relatives have a low rate of having a colonoscopy but are more likely to have had this procedure if they have strong health motivation. IMPLICATIONS FOR PRACTICE: Nurses working with CRC patients must develop strategies to increase FDRs' knowledge of, awareness of, and motivation for CRC screening tests. Risk counseling of FDRs during the treatment period might increase screening rates. PMID- 24476674 TI - Making self-care a priority for women at risk of breast cancer-related lymphedema. AB - Estimates suggest that between 41% and 94% of breast cancer survivors may develop the chronic condition of secondary lymphedema at some point during their lifetimes. Self-care is critical for effective lymphedema management and risk reduction. At the same time, women in general have been characterized as engaging in self-sacrificing behaviors in which they choose other-care over self-care. This study explored the self-care experiences of women with breast cancer within the contexts of complex and demanding familial and work-related responsibilities. Participants (N=14) were enrolled in a behavioral-educational intervention aimed at lymphedema risk-reduction. This feminist family theory-informed secondary analysis of qualitative data focused on women's familial roles and the balance or lack of balance between self-sacrifice and self-care. Findings included participants' struggles with time management and prioritizing self-care over care of others as well as making a commitment to self-care. Findings have implications for patient and family-level education and research with regard to gender role based barriers to self-care and self-care within complex social contexts. PMID- 24476675 TI - "I tell my partner everything . . . (or not)": patients' perceptions of sharing heart-related information with their partner. AB - This study is grounded in theories of information management. Patients with a diagnosed heart-related condition (N=253) completed a survey regarding their perceptions of sharing/not sharing information with a partner about their health condition. Data were analyzed using descriptive and inferential statistics. Results indicated that although most patients reported sharing "everything" with their partner, others reported not sharing certain topics such as health issues and physical symptoms/ailments. In addition, patients who reported sharing everything with a partner reported significantly greater communication efficacy, and breadth, depth, and frequency of communication about a heart-related condition compared with those who reported not sharing certain topics. Finally, as hypothesized, there were no significant group differences in terms of sharing specific physical and psychological health information. We discuss the findings and implications of the study for nursing practice. PMID- 24476676 TI - Evaluating the diet of children at increased risk for type 1 diabetes: first results from the TEENDIAB study. AB - OBJECTIVE: The development of type 1 diabetes (T1D) is potentially influenced by nutrition. The aim of our study was to assess food and nutrient intakes of children at increased risk of T1D. DESIGN: Dietary intake of the last 4 weeks was assessed using a diet history interview. The daily nutrient and food intakes were compared with the German Dietary Reference Intakes, the Optimized Mixed Diet recommendations and those of a representative sample of children from the EsKiMo study. SETTING: Children included in the analysis participated in the prospective TEENDIAB study. SUBJECTS: First-degree relatives of people with T1D (n 268), aged 8-12 years. RESULTS: The TEENDIAB children consumed 52.0 % of their total energy from carbohydrates, 32.6 % from fat and 14.3 % from protein. Compared with the reference values, their intake was lowest for folate at 61.3 % of the reference, for iodine at 58.1 % and for vitamin D at 8.9 %, and exceeded the reference for vitamin K about 5-fold, for Na about 3.5-fold and for protein about 1.5-fold. Their nutrient intakes were similar to those of a control cohort without increased T1D risk. The consumption of non-desirable food groups (meat products, sweets/snacks) was above the recommendations and the consumption of desirable food groups (fruits, vegetables, carbohydrate-rich foods) was below the recommendations. CONCLUSIONS: The TEENDIAB children had intakes considerably below the recommendations for vitamin D, iodine, folate and plant-based foods, and intakes above for vitamin K, Na, protein, meat products and sweets/snacks. They showed similar dietary patterns to non-risk children. PMID- 24476677 TI - Stochastic hybrid model of spontaneous dendritic NMDA spikes. AB - Following recent advances in imaging techniques and methods of dendritic stimulation, active voltage spikes have been observed in thin dendritic branches of excitatory pyramidal neurons, where the majority of synapses occur. The generation of these dendritic spikes involves both Na(+) ion channels and M methyl-D-aspartate receptor (NMDAR) channels. During strong stimulation of a thin dendrite, the resulting high levels of glutamate, the main excitatory neurotransmitter in the central nervous system and an NMDA agonist, modify the current-voltage (I-V) characteristics of an NMDAR so that it behaves like a voltage-gated Na(+) channel. Hence, the NMDARs can fire a regenerative dendritic spike, just as Na(+) channels support the initiation of an action potential following membrane depolarization. However, the duration of the dendritic spike is of the order 100 ms rather than 1 ms, since it involves slow unbinding of glutamate from NMDARs rather than activation of hyperpolarizing K(+) channels. It has been suggested that dendritic NMDA spikes may play an important role in dendritic computations and provide a cellular substrate for short-term memory. In this paper, we consider a stochastic, conductance-based model of dendritic NMDA spikes, in which the noise originates from the stochastic opening and closing of a finite number of Na(+) and NMDA receptor ion channels. The resulting model takes the form of a stochastic hybrid system, in which membrane voltage evolves according to a piecewise deterministic dynamics that is coupled to a jump Markov process describing the opening and closing of the ion channels. We formulate the noise-induced initiation and termination of a dendritic spike in terms of a first passage time problem, under the assumption that glutamate unbinding is negligible, which we then solve using a combination of WKB methods and singular perturbation theory. Using a stochastic phase-plane analysis we then extend our analysis to take proper account of the combined effects of glutamate unbinding and noise on the termination of a spike. PMID- 24476678 TI - An initial investigation of the relationships between hoarding and smoking. AB - Cigarette smokers have increased rates of mood and anxiety-related conditions. Hoarding is another anxiety-related condition that has yet to be examined in relation to smoking behavior. The current investigation sought to examine smoking rates among a sample of individuals with hoarding disorder and individuals with non-hoarding obsessive-compulsive disorder (OCD). Additionally, we examined the relationship between hoarding symptoms and reasons for smoking. Participants in Study 1 consisted of 57 individuals with non-hoarding OCD or hoarding disorder. Participants in Study 2 consisted of 661 adult daily smokers. Results revealed that a significantly greater proportion of individuals diagnosed with hoarding were current smokers compared to the non-hoarding OCD group. Additionally, hoarding severity was associated with negative affect reduction expectancies. These results provide important information regarding smoking behaviors within hoarding disorder. Given the poor treatment outcomes and negative health risks associated with hoarding, this information could inform future research and treatment programs. PMID- 24476680 TI - Hepatitis B vaccination for healthcare personnel in American Samoa: pre implementation survey for policy decision. AB - American Samoa does not have a hepatitis B vaccination policy for healthcare personnel (HCP). Consequently, hepatitis B has remained a health threat to HCP. In this study, we performed a cross-sectional study and examined demographic and risk information and hepatitis B vaccination, testing, and serostatus in hospital employees in American Samoa. Of 604 hospital employees, 231 (38.2%) participated, and of these, 158 (68.4%) were HCP. Of HCP participants, 1.9% had chronic hepatitis B infection, 36.1% were susceptible, and 60.8% were immune. Nearly half of HCP participants reported history of needlestick injury. Overall, participants' knowledge of their hepatitis B infection and vaccination status was low. These data support the adoption of a hepatitis B vaccination policy for HCP by American Samoa, as currently recommended by the World Health Organization and the US Centers for Disease Control and Prevention. Adherence to the policy could be monitored as a way to measure protection. PMID- 24476679 TI - Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma. AB - Acquired resistance to BRAF inhibitors often involves MAPK re-activation, yet the MEK inhibitor trametinib showed minimal clinical activity in melanoma patients that had progressed on BRAF-inhibitor therapy. Selective ERK inhibitors have been proposed as alternative salvage therapies. We show that ERK inhibition is more potent than MEK inhibition at suppressing MAPK activity and inhibiting the proliferation of multiple BRAF inhibitor resistant melanoma cell models. Nevertheless, melanoma cells often failed to undergo apoptosis in response to ERK inhibition, because the relief of ERK-dependent negative feedback activated RAS and PI3K signalling. Consequently, the combination of ERK and PI3K/mTOR inhibition was effective at promoting cell death in all resistant melanoma cell models, and was substantially more potent than the MEK/PI3K/mTOR inhibitor combination. Our data indicate that a broader targeting strategy concurrently inhibiting ERK, rather than MEK, and PI3K/mTOR may circumvent BRAF inhibitor resistance, and should be considered during the clinical development of ERK inhibitors. PMID- 24476681 TI - Usual dietary fatty acid intakes and red-blood-cell membrane fatty acid composition in Inuit children attending child-care centres in Nunavik, northern Quebec, Canada. AB - OBJECTIVES: To assess dietary fatty acid intakes and to examine the relationship between dietary sources of n-3 and n-6 PUFA and red-blood-cell (RBC) n-3 and n-6 PUFA composition. DESIGN: A cross-sectional study. Dietary intakes were assessed with a 24 h dietary recall. A second recall was performed for 44 % of the children. Usual dietary intakes were estimated with the Software for Intake Distribution Estimation (SIDE). The fatty acid composition was measured in RBC membranes. Multivariate linear regression analyses were performed to explain RBC n-3 and n-6 PUFA concentrations. SETTING: Child-care centres in Nunavik, northern Quebec, Canada. SUBJECTS: One hundred and sixty-seven Inuit children aged 11-53 months. RESULTS: A high proportion of the participants had inadequate n-3 and n-6 PUFA intakes (47.9 % and 93.5 %, respectively). Breast-feeding status and consumption of traditional food during the first 24 h dietary recall were significantly associated with RBC n-3 PUFA levels. Older children also tended to have higher RBC n-3 PUFA levels (P = 0.0528), whereas sex, infant formula status and n-3 PUFA dietary intakes were not associated with RBC n-3 PUFA concentrations. RBC n-6 PUFA concentrations were positively associated with breast-feeding status and n-6 PUFA dietary intakes, whereas age, sex and infant formula status were not. CONCLUSIONS: The present findings highlight the fact that Inuit pre-school children are not consuming enough n-3 and n-6 PUFA for optimum health. These observations call for actions to increase traditional food intake among Inuit children and to help them and their parents make healthier store-bought food choices. PMID- 24476682 TI - Optimal configuration for relaxation times estimation in complex spin echo imaging. AB - Many pathologies can be identified by evaluating differences raised in the physical parameters of involved tissues. In a Magnetic Resonance Imaging (MRI) framework, spin-lattice T1 and spin-spin T2 relaxation time parameters play a major role in such an identification. In this manuscript, a theoretical study related to the evaluation of the achievable performances in the estimation of relaxation times in MRI is proposed. After a discussion about the considered acquisition model, an analysis on the ideal imaging acquisition parameters in the case of spin echo sequences, i.e., echo and repetition times, is conducted. In particular, the aim of the manuscript consists in providing an empirical rule for optimal imaging parameter identification with respect to the tissues under investigation. Theoretical results are validated on different datasets in order to show the effectiveness of the presented study and of the proposed methodology. PMID- 24476683 TI - A multimetric, map-aware routing protocol for VANETs in urban areas. AB - In recent years, the general interest in routing for vehicular ad hoc networks (VANETs) has increased notably. Many proposals have been presented to improve the behavior of the routing decisions in these very changeable networks. In this paper, we propose a new routing protocol for VANETs that uses four different metrics. which are the distance to destination, the vehicles' density, the vehicles' trajectory and the available bandwidth, making use of the information retrieved by the sensors of the vehicle, in order to make forwarding decisions, minimizing packet losses and packet delay. Through simulation, we compare our proposal to other protocols, such as AODV (Ad hoc On-Demand Distance Vector), GPSR (Greedy Perimeter Stateless Routing), I-GPSR (Improvement GPSR) and to our previous proposal, GBSR-B (Greedy Buffer Stateless Routing Building-aware). Besides, we present a performance evaluation of the individual importance of each metric to make forwarding decisions. Experimental results show that our proposed forwarding decision outperforms existing solutions in terms of packet delivery. PMID- 24476684 TI - Textured fluorapatite bonded to calcium sulphate strengthen stomatopod raptorial appendages. AB - Stomatopods are shallow-water crustaceans that employ powerful dactyl appendages to hunt their prey. Deployed at high velocities, these hammer-like clubs or spear like devices are able to inflict substantial impact forces. Here we demonstrate that dactyl impact surfaces consist of a finely-tuned mineral gradient, with fluorapatite substituting amorphous apatite towards the outer surface. Raman spectroscopy measurements show that calcium sulphate, previously not reported in mechanically active biotools, is co-localized with fluorapatite. Ab initio computations suggest that fluorapatite/calcium sulphate interfaces provide binding stability and promote the disordered-to-ordered transition of fluorapatite. Nanomechanical measurements show that fluorapatite crystalline orientation correlates with an anisotropic stiffness response and indicate significant differences in the fracture tolerance between the two types of appendages. Our findings shed new light on the crystallochemical and microstructural strategies allowing these intriguing biotools to optimize impact forces, providing physicochemical information that could be translated towards the synthesis of impact-resistant functional materials and coatings. PMID- 24476685 TI - Preparation and structure of acenaphthylene-1,2-diyldi(9-acridine) derivatives with a long C=C bond. AB - Due to purely steric effects of acridine units, acenaphthylene-1,2-diyldi(9 acridine) has a long C=C bond [1.3789(19) A] while maintaining its sp(2) hybridized nature and bond order. PMID- 24476687 TI - Use of dynamic spinal brace in the management of neuromuscular scoliosis: a preliminary report. AB - Neuromuscular scoliosis is difficult to treat with braces because the collapsing trunk with the spinal deformity cannot tolerate the hard materials used for most orthoses. The dynamic spinal brace (DSB) is a novel three-point support brace used in Japan. We present our preliminary findings of 52 pediatric patients with neuromuscular scoliosis treated using DSBs. A positive correlation was found between the Cobb angle at the initiation of bracing and the degree of scoliosis progression. We concluded that DSBs may be effective for early-stage scoliosis. We also found that DSB improved sitting stability and thereby caregiver satisfaction. PMID- 24476686 TI - The role of chemokines in severe malaria: more than meets the eye. AB - Plasmodium falciparum malaria is responsible for over 250 million clinical cases every year worldwide. Severe malaria cases might present with a range of disease syndromes including acute respiratory distress, metabolic acidosis, hypoglycaemia, renal failure, anaemia, pulmonary oedema, cerebral malaria (CM) and placental malaria (PM) in pregnant women. Two main determinants of severe malaria have been identified: sequestration of parasitized red blood cells and strong pro-inflammatory responses. Increasing evidence from human studies and malaria infection animal models revealed the presence of host leucocytes at the site of parasite sequestration in brain blood vessels as well as placental tissue in complicated malaria cases. These observations suggested that apart from secreting cytokines, leucocytes might also contribute to disease by migrating to the site of parasite sequestration thereby exacerbating organ-specific inflammation. This evidence attracted substantial interest in identifying trafficking pathways by which inflammatory leucocytes are recruited to target organs during severe malaria syndromes. Chemo-attractant cytokines or chemokines are the key regulators of leucocyte trafficking and their potential contribution to disease has recently received considerable attention. This review summarizes the main findings to date, investigating the role of chemokines in severe malaria and the implication of these responses for the induction of pathogenesis and immunity to infection. PMID- 24476688 TI - Validation of four devices: Omron M6 Comfort, Omron HEM-7420, Withings BP-800, and Polygreen KP-7670 for home blood pressure measurement according to the European Society of Hypertension International Protocol. AB - BACKGROUND: Four oscillometric devices, including the Omron M6 Comfort, Omron HEM 7420, Withings BP-800, and Polygreen KP-7670, designed for self-blood pressure measurement (SBPM) were evaluated according to the European Society of Hypertension (ESH) International Protocol Revision 2010 in four separate studies. METHODS: The four devices measure brachial blood pressure (BP) using the oscillometric method. The Withings BP-800 has to be connected to an Apple(r) iOS device such as an iPhone(r), iPad(r), or iPod(r). The ESH International Protocol Revision 2010 includes a total number of 33 subjects. The difference between observer and device BP values was calculated for each measure. Ninety-nine pairs of BP differences were classified into three categories (<=5 mmHg, <=10 mmHg, <=15 mmHg). The protocol procedures were followed precisely in each of the four studies. RESULTS: All four tested devices passed the validation process. The mean differences between the device and mercury readings were: -1.8+/-5.1 mmHg and 0.4+/-2.8 mmHg for systolic and diastolic BP, respectively, using the Omron M6 Comfort device; 2.5+/-4.6 mmHg and -1.2+/-4.3 mmHg for the Omron HEM-7420 device; -0.2+/-5.0 mmHg and 0.4+/-4.2 mmHg for the Withings BP-800 device; and 3.0+/-5.3 mmHg and 0.3+/-5.2 mmHg for the Polygreen KP-7670 device. CONCLUSION: Omron M6 Comfort, Omron HEM-7420, Withings BP-800, and Polygreen KP-7670 readings differing by less than 5 mmHg, 10 mmHg, and 15 mmHg fulfill the ESH International Protocol Revision 2010 requirements, and therefore are suitable for use by patients for SBPM, if used correctly. PMID- 24476689 TI - Dabigatran and myocardial infarction: a foggy scenario. PMID- 24476690 TI - Obesity prevalence in Colombian adults is increasing fastest in lower socio economic status groups and urban residents: results from two nationally representative surveys. AB - OBJECTIVE: Low- and middle-income countries are experiencing rises in the prevalence of adult obesity. Whether these increases disproportionately affect vulnerable subpopulations is unclear because most previous investigations were not nationally representative, were limited to women, or relied on self-reported anthropometric data which are subject to bias. The aim of the present study was to assess changes in the prevalence of obesity from 2005 to 2010 in Colombian adults; overall and by levels of sociodemographic characteristics. DESIGN: Two cross-sectional, nationally representative surveys. SETTING: Colombia. SUBJECTS: Men and women 18-64 years old (n 31 105 in 2005; n 81 115 in 2010). RESULTS: The prevalence of obesity (BMI >=30 kg/m2) was 13.9 % in 2005 and 16.4 % in 2010 (prevalence difference = 2.7 %; 95 % CI 1.9, 3.4 %). In multivariable analyses, obesity was positively associated with female sex, age, wealth, and living in the Pacific or National Territories regions in each year. In 2010, obesity was also associated with living in an urban area. The change in the prevalence of obesity from 2005 to 2010 varied significantly according to wealth; 5.0 % (95 % CI 3.3, 6.7 %) among the poorest and 0.3 % (95 % CI -1.6, 2.2 %) in the wealthiest (P, test for interaction = 0.007), after adjustment. Obesity rates also increased faster in older than younger people (P, test for interaction = 0.01), among people from urban compared with non-urban areas (P, test for interaction = 0.06) and in adults living in the Atlantic region compared with others. CONCLUSIONS: Adult obesity prevalence has increased in Colombia and its burden is shifting towards the poor and urban populations. PMID- 24476691 TI - Buffer regulation of calcium puff sequences. AB - Puffs are localized Ca(2 +) signals that arise in oocytes in response to inositol 1,4,5-trisphosphate (IP3). They are the result of the liberation of Ca(2 +) from the endoplasmic reticulum through the coordinated opening of IP3 receptor/channels clustered at a functional release site. The presence of buffers that trap Ca(2 +) provides a mechanism that enriches the spatio-temporal dynamics of cytosolic calcium. The expression of different types of buffers along the cell's life provides a tool with which Ca(2 +) signals and their responses can be modulated. In this paper we extend the stochastic model of a cluster of IP3R-Ca(2 +) channels introduced previously to elucidate the effect of buffers on sequences of puffs at the same release site. We obtain analytically the probability laws of the interpuff time and of the number of channels that participate of the puffs. Furthermore, we show that under typical experimental conditions the effect of buffers can be accounted for in terms of a simple inhibiting function. Hence, by exploring different inhibiting functions we are able to study the effect of a variety of buffers on the puff size and interpuff time distributions. We find the somewhat counter-intuitive result that the addition of a fast Ca(2 +) buffer can increase the average number of channels that participate of a puff. PMID- 24476692 TI - FSH and LH receptors are differentially expressed in cumulus cells surrounding developmentally competent and incompetent mouse fully grown antral oocytes. AB - Cumulus cells (CCs) maintain strict functional relationships with the enclosed antral oocyte and are thought to reflect its developmental competence. Several studies have described a correlation between CC gene expression and oocyte quality. Herein, we tested whether CC-specific FSH and LH receptors (FSHR and LHR, respectively) are differentially expressed in CCs enclosing developmentally competent or incompetent oocytes. To this end, mouse fully grown cumulus-oocyte complexes were isolated and their CCs and oocytes analysed separately. Based on their chromatin organisation, oocytes were classified as those with a surrounded nucleolus (SN) or a non-surrounded nucleolus (NSN), the former being developmentally competent, whereas the latter arrest at the 2-cell stage. The CCs were then analysed to compare the pattern of expression of the Fshr and Lhr genes and their proteins. Quantitative reverse transcription-polymerase chain reaction analysis revealed that only Lhr is significantly differentially expressed. Immunofluorescence analysis revealed that both FSHR and LHR proteins are significantly upregulated in CCs surrounding oocytes arrested at the 2-cell stage, reflecting their developmental incompetence. PMID- 24476693 TI - Activation of the receptor for advanced glycation end products induces nuclear inhibitor of protein phosphatase-1 suppression. AB - The activation of the receptor for advanced glycation end products (RAGE) is involved in the development of diabetic nephropathy. Analysis of protein phosphatase-1 indicated that advanced glycation end products did not affect its expression, but increased its phosphatase activity. Using differential display analysis we previously demonstrated that stimulation of RAGE in podocytes modulates the expression of numerous genes, among others nuclear inhibitor of protein phosphatase-1 (NIPP1). Here we found that silencing of NIPP1 induced podocyte hypertrophy, cell cycle arrest, and significantly increased protein phosphatase-1 activity. NIPP1 downregulation was associated with increased p27(Kip1) protein expression. Reporter assays revealed a transcriptional activation of nuclear factor-kappaB in podocytes after suppression of NIPP1. The protein level of NIPP1 was also significantly reduced in podocytes of diabetic mice. Blocking the RAGE in vivo by a soluble analog elevated the NIPP1 protein in podocytes of diabetic mice. Thus, activation of the RAGE by advanced glycation end products or other ligands suppresses NIPP1 expression in diabetic nephropathy, contributes to podocyte hypertrophy, and glomerular inflammation. PMID- 24476694 TI - The calcium-activated chloride channel Anoctamin 1 contributes to the regulation of renal function. AB - The role of calcium-activated chloride channels for renal function is unknown. By immunohistochemistry we demonstrate dominant expression of the recently identified calcium-activated chloride channels, Anoctamin 1 (Ano1, TMEM16A) in human and mouse proximal tubular epithelial (PTE) cells, with some expression in podocytes and other tubular segments. Ano1-null mice had proteinuria and numerous large reabsorption vesicles in PTE cells. Selective knockout of Ano1 in podocytes (Ano1-/-/Nphs2-Cre) did not impair renal function, whereas tubular knockout in Ano1-/-/Ksp-Cre mice increased urine protein excretion and decreased urine electrolyte concentrations. Purinergic stimulation activated calcium-dependent chloride currents in isolated proximal tubule epithelial cells from wild-type but not from Ano1-/-/Ksp-Cre mice. Ano1 currents were activated by acidic pH, suggesting parallel stimulation of Ano1 chloride secretion with activation of the proton-ATPase. Lack of calcium-dependent chloride secretion in cells from Ano1-/ /Ksp-Cre mice was paralleled by attenuated proton secretion and reduced endosomal acidification, which compromised proximal tubular albumin uptake. Tubular knockout of Ano1 enhanced serum renin and aldosterone concentrations, probably leading to enhanced compensatory distal tubular reabsorption, thus maintaining normal blood pressure levels. Thus, Ano1 has a role in proximal tubular proton secretion and protein reabsorption. The results correspond to regulation of the proton-ATPase by the Ano1-homolog Ist2 in yeast. PMID- 24476695 TI - Validation of insulin sensitivity surrogate indices and prediction of clinical outcomes in individuals with and without impaired renal function. AB - As chronic kidney disease (CKD) progresses with abnormalities in glucose and insulin metabolism, commonly used insulin sensitivity indices (ISIs) may not be applicable in individuals with CKD. Here we sought to validate surrogate ISIs against the glucose disposal rate by the gold-standard hyperinsulinemic euglycemic glucose clamp (HEGC) technique in 1074 elderly men of similar age (70 years) of whom 495 had and 579 did not have CKD (estimated glomerular filtration rate (eGFR) under 60 ml/min per 1.73 m(2) (median eGFR of 46 ml/min per 1.73 m(2))). All ISIs provided satisfactory (weighted kappa over 0.6) estimates of the glucose disposal rate in patients with CKD. ISIs derived from oral glucose tolerance tests (OGTTs) agreed better with HEGC than those from fasting samples (higher predictive accuracy). Regardless of CKD strata, all ISIs allowed satisfactory clinical discrimination between the presence and absence of insulin resistance (glucose disposal rate under 4 mg/kg/min). We also assessed the ability of both HEGC and ISIs to predict all-cause and cardiovascular mortality during a 10-year follow-up. Neither HEGC nor ISIs independently predicted mortality. Adjustment for renal function did not materially change these associations. Thus, ISIs can be applied in individuals with moderately impaired renal function for diagnostic purposes. For research matters, OGTT-derived ISIs may be preferred. Our data do not support the hypothesis of kidney function mediating insulin sensitivity (IS)-associated outcomes nor a role for IS as a predictor of mortality. PMID- 24476696 TI - Comparing the impact of two concurrent infectious disease outbreaks on The Netherlands population, 2009, using disability-adjusted life years. AB - In 2009 two notable outbreaks, Q fever and the novel influenza A(H1N1)pdm09, occurred in The Netherlands. Using a composite health measure, disability adjusted life years (DALYs), the outbreaks were quantified and compared. DALYs were calculated using standardized methodology incorporating age- and sex stratified data in a disease progression model; years lost due to disability and years of life lost were computed by outcome. Nationally, influenza A(H1N1)pdm09 caused more DALYs (24 484) than Q fever (5797). However, Q fever was 8.28 times more severe [497 DALYs/1000 symptomatic cases (DP1SC)] than A(H1N1)pdm09 (60 DP1SC). The A(H1N1)pdm09 burden is largely due to mortality while the Q fever burden is due primarily to long-term sequelae. Intervention prioritization for influenza should support patients in a critical condition while for Q fever it should target immediate containment and support for patients with long-term sequelae. Burden estimates provide guidance for focusing intervention options during outbreaks of infectious diseases. PMID- 24476697 TI - Myocardial stress perfusion-fibrosis imaging pattern in sarcoidosis, assessed by cardiovascular magnetic resonance imaging. PMID- 24476698 TI - Functional capacity in heart failure with preserved ejection fraction: looking for interactions and explanations. PMID- 24476699 TI - Histamine in atrial fibrillation (AF)--is there any connection? Results from an unselected population. PMID- 24476700 TI - Acquired/hidden noncompaction in metabolic encephalopathy with non-convulsive epileptic state. PMID- 24476701 TI - Malignant response to ajmaline challenge in SCN5A mutation carriers: experience from a large familial study. PMID- 24476702 TI - Ginger Therapy for Osteoarthritis: A Typical Case. AB - PURPOSE: To describe a treatment for osteoarthritis known as ginger therapy applied by anthroposophic nurses for a specific personality type. BACKGROUND: Ginger has been used medicinally in Asia since ancient times to bring inner warmth. Ginger therapy is part of the tradition of anthroposophic nursing, when managing chronic inflammatory conditions such as osteoarthritis. Osteoarthritis is a progressive disease of the synovial joint tissue that primarily affects those older than 65 years, causing pain on movement. DESIGN: A patient with specific characteristics suffering osteoarthritis received 7 consecutive days of ginger therapy by anthroposophic nurses at an integrative medical center. Two weeks after the therapy, education was given to enable self-treatment in the home for a further 24 weeks. Data were obtained using body physiological recordings, a case diary and pain scale, and self-report arthritis Health Assessment Questionnaire. FINDINGS: Ginger therapy activated a marked relief of osteoarthritis symptoms that progressively improved over the 24 weeks, with no negative effects reported. Ginger therapy needs to be considered by nurses caring for specific personality types with osteoarthritis. PMID- 24476703 TI - Sural flap for coverage of a soft-tissue defect of a leg with an occluded fibular artery: a case report. AB - Coverage of soft-tissue defects of the leg has improved with the discovery of new flaps. However, surgeons now have to deal with new lesions on top of previous reconstructive surgeries. We present a case of soft-tissue defect of the anterior lower third of the leg presenting 20 years after reconstructive surgery for an open fracture and its management. The anterior tibial and fibular arteries were occluded with a retrograde vascularisation of the fibular artery; this provided a perforator artery that we used as a pivot point for an atypical sural island flap with a good result at 6 months. This case challenges the classic contraindication of this flap in case of occluded arteries. PMID- 24476704 TI - Comparison of gluteal perforator flaps and gluteal fasciocutaneous rotation flaps for reconstruction of sacral pressure sores. AB - BACKGROUND AND AIM: The gluteus maximus myocutaneous flap was considered the workhorse that reconstructed sacral pressure sores, but was gradually replaced by fasciocutaneous flap because of several disadvantages. With the advent of the perforator flap technique, gluteal perforator (GP) flap has gained popularity nowadays. The aim of this study was to compare the complications and outcomes between GP flaps and gluteal fasciocutaneous rotation (FR) flaps in the treatment of sacral pressure sores. METHODS: Between April 2007 and June 2012, 63 patients underwent sacral pressure sore reconstructions, with a GP flap used in 31 cases and an FR flap used in 32 cases. Data collected on the patients included patient age, gender, co-morbidity for being bedridden and follow-up time. Surgical details collected included the defect size, operative time and estimated blood loss. Complications recorded included re-operation, dehiscence, flap necrosis, wound infection, sinus formation, donor-site morbidity and recurrence. The complications and clinical outcomes were compared between these two groups. RESULTS: We found that there was no significant difference in patient demographics, surgical complications and recurrence between these two groups. In gluteal FR flap group, all recurrent cases (five) were treated by reuse of previous flaps. CONCLUSIONS: Both methods are comparable, good and safe in treating sacral pressure sores. Gluteal FR flap can be performed without microsurgical dissection, and re-rotation is feasible in recurrent cases. The authors suggest using gluteal FR flaps in patients with a high risk of sore recurrence. PMID- 24476705 TI - One-stage reconstruction of a tracheal defect with a free radial forearm flap and free costal cartilage grafts. AB - Reconstructing the trachea is challenging because of its multilayer structure and airway function; multiple procedures are often required. We report a case of one stage reconstruction for a tracheal defect. The surgery was performed with a free radial forearm flap and free costal cartilage grafts. Air leakage occurred postoperatively but healed without additional surgery. The reconstructed trachea has retained its shape, diameter and airway function for 14 months despite the patient's history of radiotherapy. This one-stage procedure with well vascularised tissue was successfully used to reconstruct a stable, well functioning trachea. PMID- 24476706 TI - Understanding differences between high- and low-price hospitals: implications for efforts to rein in costs. AB - Private insurers pay widely varying prices for inpatient care across hospitals. Previous research indicates that certain hospitals use market clout to obtain higher payment rates, but there have been few in-depth examinations of the relationship between hospital characteristics and pricing power. This study used private insurance claims data to identify hospitals receiving inpatient prices significantly higher or lower than the median in their market. High-price hospitals, compared to other hospitals, tend to be larger; be major teaching hospitals; belong to systems with large market shares; and provide specialized services, such as heart transplants and Level I trauma care. High-price hospitals also receive significant revenues from nonpatient sources, such as state Medicaid disproportionate-share hospital funds, and they enjoy healthy total financial margins. Quality indicators for high-price hospitals were mixed: High-price hospitals fared much better than low-price hospitals did in U.S. News & World Report rankings, which are largely based on reputation, while generally scoring worse on objective measures of quality, such as postsurgical mortality rates. Thus, insurers may face resistance if they attempt to steer patients away from high-price hospitals because these facilities have good reputations and offer specialized services that may be unique in their markets. PMID- 24476708 TI - Phytotoxicity evaluation of type B trichothecenes using a Chlamydomonas reinhardtii model system. AB - Type B trichothecenes, which consist of deoxynivalenol (DON) and nivalenol (NIV) as the major end products, are produced by phytotoxic fungi, such as the Fusarium species, and pollute arable fields across the world. The DON toxicity has been investigated using various types of cell systems or animal bioassays. The evaluation of NIV toxicity, however, has been relatively restricted because of its lower level compared with DON. In this study, the Chlamydomonas reinhardtii testing system, which has been reported to have adequate NIV sensitivity, was reinvestigated under different mycotoxin concentrations and light conditions. The best concentration of DON and NIV, and their derivatives, for test conditions was found to be 25 ppm (2.5 * 10(-2) mg/mL). In all light test conditions, DON, NIV, and fusarenon-X (FusX) indicated significant growth inhibition regardless of whether a light source existed, or under differential wavelength conditions. FusX growth was also influenced by changes in photon flux density. These results suggest that C. reinhardtii is an appropriate evaluation system for type B trichothecenes. PMID- 24476707 TI - The impact of Fusarium mycotoxins on human and animal host susceptibility to infectious diseases. AB - Contamination of food and feed with mycotoxins is a worldwide problem. At present, acute mycotoxicosis caused by high doses is rare in humans and animals. Ingestion of low to moderate amounts of Fusarium mycotoxins is common and generally does not result in obvious intoxication. However, these low amounts may impair intestinal health, immune function and/or pathogen fitness, resulting in altered host pathogen interactions and thus a different outcome of infection. This review summarizes the current state of knowledge about the impact of Fusarium mycotoxin exposure on human and animal host susceptibility to infectious diseases. On the one hand, exposure to deoxynivalenol and other Fusarium mycotoxins generally exacerbates infections with parasites, bacteria and viruses across a wide range of animal host species. Well-known examples include coccidiosis in poultry, salmonellosis in pigs and mice, colibacillosis in pigs, necrotic enteritis in poultry, enteric septicemia of catfish, swine respiratory disease, aspergillosis in poultry and rabbits, reovirus infection in mice and Porcine Reproductive and Respiratory Syndrome Virus infection in pigs. However, on the other hand, T-2 toxin has been shown to markedly decrease the colonization capacity of Salmonella in the pig intestine. Although the impact of the exposure of humans to Fusarium toxins on infectious diseases is less well known, extrapolation from animal models suggests possible exacerbation of, for instance, colibacillosis and salmonellosis in humans, as well. PMID- 24476709 TI - Aedes aegypti Mos20 cells internalizes cry toxins by endocytosis, and actin has a role in the defense against Cry11Aa toxin. AB - Bacillus thuringiensis (Bt) Cry toxins are used to control Aedes aegypti, an important vector of dengue fever and yellow fever. Bt Cry toxin forms pores in the gut cells, provoking larvae death by osmotic shock. Little is known, however, about the endocytic and/or degradative cell processes that may counteract the toxin action at low doses. The purpose of this work is to describe the mechanisms of internalization and detoxification of Cry toxins, at low doses, into Mos20 cells from A. aegypti, following endocytotic and cytoskeletal markers or specific chemical inhibitors. Here, we show that both clathrin-dependent and clathrin independent endocytosis are involved in the internalization into Mos20 cells of Cry11Aa, a toxin specific for Dipteran, and Cry1Ab, a toxin specific for Lepidoptera. Cry11Aa and Cry1Ab are not directed to secretory lysosomes. Instead, Mos20 cells use the Rab5 and Rab11 pathways as a common mechanism, most probably for the expulsion of Cry11Aa and Cry1Ab toxins. In conclusion, we propose that endocytosis is a mechanism induced by Cry toxins independently of specificity, probably as part of a basal immune response. We found, however, that actin is necessary for defense-specific response to Cry11Aa, because actin-silenced Mos20 cells become more sensitive to the toxic action of Cry11A toxin. Cry toxin internalization analysis in insect cell lines may contribute to a better understanding to Cry resistance in mosquitoes. PMID- 24476710 TI - Co-occurrence of the cyanotoxins BMAA, DABA and anatoxin-a in Nebraska reservoirs, fish, and aquatic plants. AB - Several groups of microorganisms are capable of producing toxins in aquatic environments. Cyanobacteria are prevalent blue green algae in freshwater systems, and many species produce cyanotoxins which include a variety of chemical irritants, hepatotoxins and neurotoxins. Production and occurrence of potent neurotoxic cyanotoxins beta-N-methylamino-L-alanine (BMAA), 2,4-diaminobutyric acid dihydrochloride (DABA), and anatoxin-a are especially critical with environmental implications to public and animal health. Biomagnification, though not well understood in aquatic systems, is potentially relevant to both human and animal health effects. Because little is known regarding their presence in fresh water, we investigated the occurrence and potential for bioaccumulation of cyanotoxins in several Nebraska reservoirs. Collection and analysis of 387 environmental and biological samples (water, fish, and aquatic plant) provided a snapshot of their occurrence. A sensitive detection method was developed using solid phase extraction (SPE) in combination with high pressure liquid chromatography-fluorescence detection (HPLC/FD) with confirmation by liquid chromatography-tandem mass spectrometry (LC/MS/MS). HPLC/FD detection limits ranged from 5 to 7 ug/L and LC/MS/MS detection limits were <0.5 ug/L, while detection limits for biological samples were in the range of 0.8-3.2 ng/g depending on the matrix. Based on these methods, measurable levels of these neurotoxic compounds were detected in approximately 25% of the samples, with detections of BMAA in about 18.1%, DABA in 17.1%, and anatoxin-a in 11.9%. PMID- 24476711 TI - Geographical patterns in cyanobacteria distribution: climate influence at regional scale. AB - Cyanobacteria are a component of public health hazards in freshwater environments because of their potential as toxin producers. Eutrophication has long been considered the main cause of cyanobacteria outbreak and proliferation, whereas many studies emphasized the effect of abiotic parameters (mainly temperature and light) on cell growth rate or toxin production. In view of the growing concerns of global change consequences on public health parameters, this study attempts to enlighten climate influence on cyanobacteria at regional scale in Brittany (NW France). The results show that homogeneous cyanobacteria groups are associated with climatic domains related to temperature, global radiation and pluviometry, whereas microcystins (MCs) occurrences are only correlated to local cyanobacteria species composition. As the regional climatic gradient amplitude is similar to the projected climate evolution on a 30-year timespan, a comparison between the present NW and SE situations was used to extrapolate the evolution of geographical cyanobacteria distribution in Brittany. Cyanobacteria composition should shift toward species associated with more frequent Microcystins occurrences along a NW/SE axis whereas lakes situated along a SW/NE axis should transition to species (mainly Nostocales) associated with lower MCs detection frequencies. PMID- 24476712 TI - Assessment of multi-mycotoxin exposure in southern Italy by urinary multi biomarker determination. AB - Human exposure assessment to deoxynivalenol (DON), aflatoxin B1 (AFB1), fumonisin B1 (FB1), zearalenone (ZEA) and ochratoxin A (OTA) can be performed by measuring their urinary biomarkers. Suitable biomarkers of exposure for these mycotoxins are DON + de-epoxydeoxynivalenol (DOM-1), aflatoxin M1 (AFM1), FB1, ZEA + alpha zearalenol (alpha-ZOL) + beta-zearalenol (beta-ZOL) and OTA, respectively. An UPLC-MS/MS multi-biomarker method was used to detect and measure incidence and levels of these biomarkers in urine samples of 52 volunteers resident in Apulia region in Southern Italy. The presence of ZEA + ZOLs, OTA, DON, FB1 and AFM1 were detected in 100%, 100%, 96%, 56% and 6%, of samples, respectively. All samples contained biomarkers of two or more mycotoxins. The mean concentrations of biomarkers ranged from 0.055 ng/mL (FB1) to 11.89 ng/mL (DON). Urinary biomarker concentrations were used to estimate human exposure to multiple mycotoxin. For OTA and DON, 94% and 40% of volunteers, respectively exceeded the tolerable daily intake (TDI) for these mycotoxins. The estimated human exposure to FB1 and ZEA was largely below the TDI for these mycotoxins for all volunteers. PMID- 24476713 TI - Food poisonings by ingestion of cyprinid fish. AB - Raw or dried gallbladders of cyprinid fish have long been ingested as a traditional medicine in the Asian countries, particularly in China, for ameliorating visual acuity, rheumatism, and general health; however, sporadic poisoning incidences have occurred after their ingestion. The poisoning causes complex symptoms in patients, including acute renal failure, liver dysfunction, paralysis, and convulsions of limbs. The causative substance for the poisoning was isolated, and its basic properties were examined. The purified toxin revealed a minimum lethal dose of 2.6 mg/20 g in mouse, when injected intraperitoneally. The main symptoms were paralysis and convulsions of the hind legs, along with other neurological signs. Liver biopsy of the euthanized mice clearly exhibited hepatocytes necrosis and infiltration of neutrophils and lymphocytes, suggesting the acute dysfunction of the liver. Blood tests disclosed the characteristics of acute renal failure and liver injury. Infrared (IR) spectrometry, fast atom bombardment (FAB) mass spectrometry, and 1H- and 13C-nuclear magnetic resonance (NMR) analysis indicated, a molecular formula of C27H48O8S, containing a sulfate ester group for the toxin. Thus, we concluded that the structure of carp toxin to be 5alpha-cyprinol sulfate (5alpha-cholestane-3alpha, 7alpha, 12alpha, 26, 27 pentol 26-sulfate). This indicated that carp toxin is a nephro- and hepato- toxin, which could be the responsible toxin for carp bile poisoning in humans. PMID- 24476715 TI - The feasibility of implementing food-based dietary guidelines in the South African primary-school curriculum. AB - OBJECTIVE: To explore the perceptions of educators from the Western Cape Province about the feasibility of implementing South African food-based dietary guidelines (FBDG) in the national curriculum of primary schools. DESIGN: Combined quantitative and qualitative methods. We report on the quantitative component. SETTING: Twelve public primary schools of different socio-economic status in three education districts of the Western Cape: Metro Central, Metro East and Cape Winelands. SUBJECTS: Educators (n 256) participated in the self-completed questionnaire survey. RESULTS: Educators assessed that FBDG were appropriate to South African schoolchildren (94%), could be used as an education tool (97%) and fill gaps in the current curriculum about healthy dietary habits (91%). Besides Life Orientation, FBDG could be taught in other learning areas from grades 3 to 7 (9-13 years old). Important barriers to implementing FBDG in the curriculum were educators' workload (61%), insufficient time (46%), learners' disadvantaged background (43%) and educators' lack of knowledge (33%). Other approaches to teach children about FBDG included linking these to the National School Nutrition Programme (82%), school tuck shops (79%), parent meetings (75%), school nutrition policy (73%) and school assembly (57%). Educators in high-income schools perceived that learners' lifestyle was significantly worse (P < 0.001) and that tuck shops and the school assembly were the best means to teach pupils about FBDG (P < 0.001 and P < 0.05). CONCLUSIONS: Implementing FBDG in the national school curriculum is seen as important together with optimizing the school physical environment. Key factors required for successful implementation in the curriculum are sufficient educational materials, adequate time allocation and appropriate educator training. PMID- 24476714 TI - Soluble T cell receptor Vbeta domains engineered for high-affinity binding to staphylococcal or streptococcal superantigens. AB - Staphylococcus aureus and group A Streptococcus secrete a collection of toxins called superantigens (SAgs), so-called because they stimulate a large fraction of an individual's T cells. One consequence of this hyperactivity is massive cytokine release leading to severe tissue inflammation and, in some cases, systemic organ failure and death. The molecular basis of action involves the binding of the SAg to both a T cell receptor (TCR) on a T cell and a class II product of the major histocompatibility complex (MHC) on an antigen presenting cell. This cross-linking leads to aggregation of the TCR complex and signaling. A common feature of SAgs is that they bind with relatively low affinity to the variable region (V) of the beta chain of the TCR. Despite this low affinity binding, SAgs are very potent, as each T cell requires only a small fraction of their receptors to be bound in order to trigger cytokine release. To develop high affinity agents that could neutralize the activity of SAgs, and facilitate the development of detection assays, soluble forms of the Vbeta regions have been engineered to affinities that are up to 3 million-fold higher for the SAg. Over the past decade, six different Vbeta regions against SAgs from S. aureus (SEA, SEB, SEC3, TSST-1) or S. pyogenes (SpeA and SpeC) have been engineered for high affinity using yeast display and directed evolution. Here we review the engineering of these high-affinity Vbeta proteins, structural features of the six different SAgs and the Vbeta proteins, and the specific properties of the engineered Vbeta regions that confer high-affinity and specificity for their SAg ligands. PMID- 24476716 TI - Experimental realization of quantum zeno dynamics. AB - It is generally impossible to probe a quantum system without disturbing it. However, it is possible to exploit the back action of quantum measurements and strong couplings to tailor and protect the coherent evolution of a quantum system. This is a profound and counterintuitive phenomenon known as quantum Zeno dynamics. Here we demonstrate quantum Zeno dynamics with a rubidium Bose-Einstein condensate in a five-level Hilbert space. We harness measurements and strong couplings to dynamically disconnect different groups of quantum states and constrain the atoms to coherently evolve inside a two-level subregion. In parallel to the foundational importance due to the realization of a dynamical superselection rule and the theory of quantum measurements, this is an important step forward in protecting and controlling quantum dynamics and, broadly speaking, quantum information processing. PMID- 24476717 TI - Alleviation of radiation-induced genomic damage in human peripheral blood lymphocytes by active principles of Podophyllum hexandrum: an in vitro study using chromosomal and CBMN assay. AB - This study was aimed to evaluate the protection against radiation of human peripheral blood lymphocytic DNA by a formulation of three isolated active principles of Podophyllum hexandrum (G-002M). G-002M in various concentrations was administered 1h prior to irradiation in culture media containing blood. Radioprotective efficacy of G-002M to lymphocytic DNA was estimated using various parameters such as dicentrics, micronuclei (MN), nucleoplasmic bridges (NPB) and nuclear buds (NuB) in binucleated cells. Certain experiments to ascertain the G2/M arrest potential of G-002M were also conducted. It was effective in arresting the cells even at half of the concentration of colchicine used. Observations demonstrated a radiation-dose-dependent increase in dicentric chromosomes (DC), acentric fragments, MN, NPB and NuB upto 5Gy. These changes were found significantly decreased by pre-administration of G-002M. A highly significant dose modifying factor (DMF) 1.43 and 1.39 based on dicentric assay and cytokinesis block micronuclei assay, respectively, was observed against 5Gy exposure in the current experiments. G-002M alone in its effective dose did not induct any change in any of the parameters mentioned above. Observations on cell cycle arrest by G-002M showed that the formulation has potential in arresting cells at G2/M, compared with colchicine. Based on significant DMF at highest radiation dose (5Gy) studied currently and meaningful reduction in radiation induced chromosomal aberrations, we express that G-002M has a potential of minimising radiation-induced DNA (cytogenetic) damage. PMID- 24476719 TI - A seat at the table: redesigning cancer care. AB - The Institute of Medicine's ([IOM's], 2011) report, The Future of Nursing: Leading Change, Advancing Health, included the key message, "Nurses should be full partners, with physicians and other health professionals, in redesigning health care in the United States" (p. 221). That is a call for nurses to lead at every level-to have a seat at the table when critical decisions are being made. Those decisions extend from clinical care to national policy, and all require the voice of nurses. The annual Gallup (2013) Honesty/Ethics in Professions survey again listed nursing as the most ethical profession. With that trust and the IOM report, among other things, nursing is well positioned to be at many tables. Having a seat is not enough, though. Nurses must contribute to the action at the table. PMID- 24476720 TI - Challenges associated with hereditary cancer susceptibility testing. AB - Selection of letters to be published is the decision of the editor. For acceptance, letters must be signed. A letter can appear anonymously if requested by the author. All letters are subject to editing. A letter that questions, criticizes, or responds to a previously published Clinical Journal of Oncology Nursing article automatically will be sent to the author of that article for a reply. This type of collegial exchange is encouraged. Send letters to CJONEditor@ons.org. PMID- 24476718 TI - Epigenomic and transcriptomic signatures of a Klinefelter syndrome (47,XXY) karyotype in the brain. AB - Klinefelter syndrome (KS) is the most common sex-chromosome aneuploidy in humans. Most affected individuals carry one extra X-chromosome (47,XXY karyotype) and the condition presents with a heterogeneous mix of reproductive, physical and psychiatric phenotypes. Although the mechanism(s) by which the supernumerary X chromosome determines these features of KS are poorly understood, skewed X chromosome inactivation (XCI), gene-dosage dysregulation, and the parental origin of the extra X-chromosome have all been implicated, suggesting an important role for epigenetic processes. We assessed genomic, methylomic and transcriptomic variation in matched prefrontal cortex and cerebellum samples identifying an individual with a 47,XXY karyotype who was comorbid for schizophrenia and had a notably reduced cerebellum mass compared with other individuals in the study (n = 49). We examined methylomic and transcriptomic differences in this individual relative to female and male samples with 46,XX or 46,XY karyotypes, respectively, and identified numerous locus-specific differences in DNA methylation and gene expression, with many differences being autosomal and tissue-specific. Furthermore, global DNA methylation, assessed via the interrogation of LINE-1 and Alu repetitive elements, was significantly altered in the 47,XXY patient in a tissue-specific manner with extreme hypomethylation detected in the prefrontal cortex and extreme hypermethylation in the cerebellum. This study provides the first detailed molecular characterization of the prefrontal cortex and cerebellum from an individual with a 47,XXY karyotype, identifying widespread tissue specific epigenomic and transcriptomic alterations in the brain. PMID- 24476722 TI - Providing care for previvors: implications for oncology nurses. AB - Previvors are individuals who are survivors of a genetic predisposition for developing cancer. They often are confronted with difficult decisions about management of risks that might include aggressive screening and prophylactic surgery. Psychosocial challenges exist for the affected individual, their partners, and offspring. Oncology nurses need to be aware of the complex and special needs of this ever-growing population. PMID- 24476723 TI - Development of an outcome measure to monitor the effectiveness of pain management. AB - Attention to the pain that occurs during treatments and procedures for pediatric patients with cancer continues to be a priority. This article describes the development of a pain effectiveness outcome measure at an academic pediatric medical center in order to inform about the implementation of quality improvement strategies and evaluate the effect of these pain interventions within the hospital setting. PMID- 24476724 TI - Improving patient knowledge of discharge medications in an oncology setting. AB - Discharge medications for a patient with cancer typically are numerous and complex. During the transition between inpatient stays and ambulatory follow-up visits, patients commonly misunderstand medication instructions, placing them at risk for under- or overdosing. This column discusses the results of an evidence based practice change project at the Seattle Cancer Care Alliance to improve adult patient knowledge and use of discharge medications. Ensuring patient receipt of written discharge medication instructions and checking in with patients after discharge may be an approach to maximize the safety of self administered medication. PMID- 24476725 TI - Management strategy for steroid-induced malglycemia during cancer treatment. AB - Malglycemia is a temporary problem that has significant negative sequelae. This article attempts to clarify and educate oncology nurses about the impact and management of steroid-induced malglycemia on patients with cancer receiving treatment. A management algorithm is provided to aid in evaluation and treatment decisions. PMID- 24476726 TI - Cardiopulmonary arrest in the outpatient setting: enhancing patient safety through rapid response algorithms and simulation teaching. AB - Ambulatory and outpatient centers constantly are challenged with administrating cancer treatments in an efficient and safe way. With the advent of numerous novel cancer medications known to cause hypersensitivity reactions, nurses have become experts in managing these emergencies. However, patients rarely exhibit severe infusion reactions or cardiopulmonary arrest. Outpatient nurse knowledge and comfort with grade 4, life-threatening emergencies requiring cardiopulmonary resuscitative measures often is low because of infrequent occurrence. That is largely a result of nurses' ability to immediately identify the need for emergency intervention, thus preventing the sequelae of patient deterioration that could lead to cardiopulmonary arrest. This article describes how the authors' institution developed methods to improve emergency care by bridging the gap between knowledge and experience of handling life-threatening emergencies. PMID- 24476727 TI - Linking cancer and intimate partner violence: the importance of screening women in the oncology setting. AB - Millions of women in the United States experience physical abuse because of intimate partner violence (IPV) that results in injuries, social and family dysfunction, mental health disorders, chronic pain and illness, and death. Cancer causes a quarter of the deaths of women in the United States. When IPV and a cancer diagnosis intersect, a special population of women with unique needs is created. The purpose of the current study was to determine the rates of IPV and the types of cancer reported by women seeking services for IPV. Safety, community agency use, severity of violence, danger, psychological distress, post-traumatic stress disorder, self-efficacy, social support, pain, and marginality also were assessed. Three hundred abused women were interviewed in person to determine their health, safety, and functioning. Of the 300 women, eight reported receiving a cancer diagnosis, and most of those women had cervical cancer. The prevalence of cervical cancer reported by abused women was 10 times higher than the general population. Higher danger scores and risk for revictimization were reported. Increased awareness of the potential connection between IPV and cancer is needed, and evidence-based strategies that promote IPV screening in the oncology setting should be developed. PMID- 24476728 TI - Review of therapies for the treatment of oral chronic graft-versus-host disease. AB - Oral chronic graft-versus-host disease is a frequent complication of allogeneic hematopoietic stem cell transplantation, contributing to patient morbidity and mortality. Although an optimal treatment is not available, several systemic and topical or local therapies have shown efficacy in treating the disease. New therapies are being tested through clinical trials. This article examines the efficacy and safety of reported treatment modalities studied from 2006-2012. Nurses will encounter patients with oral chronic graft-versus-host disease suffering from pain, discomfort, and a decreased quality of life. Knowledge of new therapies found to be effective in managing these symptoms is imperative. Nurses play a key role in the assessment and management of this complex oral disease. PMID- 24476729 TI - Timeliness in breast cancer care as an indicator of quality. AB - The current study sought to define best practice for timeliness for a breast cancer program at each diagnostic step. The study was a retrospective review of patients newly diagnosed with invasive breast cancer who were enrolled in the breast cancer database from 2009-2011. A convenience sampling methodology was used for patient selection, and descriptive statistics for various time intervals were calculated for identified data points from abnormal imaging to surgery. No evidence-based practice standards exist for access to breast cancer care. Practice guidelines that include benchmarks for quality measures and an established process to measure patient outcomes would promote high-quality care. An understanding of how practice sites function also would help healthcare providers identify and develop resources to improve patient outcomes. In the current study, the advanced practice nurse (APN) in the practice setting was identified as a key point person in facilitating patients' timely access to healthcare services. The physician and APN practice model was instrumental in influencing the process. The results of the current study provided clinical data to identify benchmarks that a breast oncology practice can use to monitor timeliness as a quality indicator. PMID- 24476730 TI - Prediction of adverse events in patients receiving rapid rituximab infusion: validation of a predictive model. AB - Rapid rituximab infusion was approved as treatment for non-Hodgkin lymphoma by the U.S. Food and Drug Administration in 2012, but it has been administered clinically since approval of the drug rituximab in 1997. Because of the delay between the approval of the drug and the approval of the procedure, researchers sought to discover predictors for adverse events related to rapid rituximab infusion. The current study is a retrospective cohort study using medical records from a cancer center in Singapore. The purpose of the study is to validate whether high absolute lymphocyte counts can predict the occurrence of adverse events from rapid rituximab infusion over 90-minute intervals. A total of 120 patients were selected by purposive sampling, and 394 cycles of rapid rituximab infusions were available for analysis. The authors found that high absolute lymphocyte count is highly specific in identifying patients who will not experience any adverse event from rapid rituximab infusion. However, lack of sensitivity can occur when screening potential patients for adverse events. PMID- 24476732 TI - Effective iron chelation practice for patients with beta-thalassemia major. AB - Chronic blood transfusion is the only treatment for severe anemia in patients with beta-thalassemia major. However, red blood cell transfusions lead to iron overload and subsequent organ damage because of the toxic effects of iron. The heart is particularly vulnerable to iron toxicity, and heart failure is the leading cause of death among these patients. Iron chelation therapy prevents or reverses iron loading, thereby reducing the risk of complications from excess iron. Serum ferritin and liver iron concentration often are used to gauge the risk of organ iron overload, but these measurements may not correlate well with cardiac iron load. Magnetic resonance imaging (MRI) is a noninvasive diagnostic tool that can provide a more direct measure of iron concentration in both the heart and liver. Cardiac iron determined by MRI is expressed as a function of T2*, in which higher values represent lower concentrations. Changes in T2* are used to assess the effectiveness of iron chelation and to adjust therapy. Early treatment and compliance are keys to successful therapy. Nursing strategies to optimize chelation therapy include identifying patients who are at risk for developing organ damage, developing chelation plans, promoting compliance, and educating patients. The efficacy and safety of iron chelators, as well as nursing best practices, are reviewed. PMID- 24476733 TI - E-cigarettes: facts, perceptions, and marketing messages. AB - Electronic cigarettes (e-cigarettes) are perceived as an alternative to standard tobacco cigarette smoking, primarily because of the e-cigarette industry's marketing messages. However, scientific studies about e-cigarette safety and efficacy remain limited. This column presents some of the issues associated with e-cigarette use, such as potential components of regulation, perceptions that e cigarettes can help users quit smoking, and free-wheeling marketing strategies that include expanding e-cigarette use to young people. Nurses can be a reliable source of information about e-cigarettes. PMID- 24476731 TI - Resilience among patients across the cancer continuum: diverse perspectives. AB - Each phase of the cancer experience profoundly affects patients' lives. Much of the literature has focused on negative consequences of cancer; however, the study of resilience may enable providers to promote more positive psychosocial outcomes before, during, and after the cancer experience. The current review describes the ways in which elements of resilience have been defined and studied at each phase of the cancer continuum. Extensive literature searches were conducted to find studies assessing resilience during one or more stages of the adult cancer continuum. For all phases of the cancer continuum, resilience descriptions included preexisting or baseline characteristics, such as demographics and personal attributes (e.g., optimism, social support), mechanisms of adaptation, such as coping and medical experiences (e.g., positive provider communication), as well as psychosocial outcomes, such as growth and quality of life. Promoting resilience is a critical element of patient psychosocial care. Nurses may enable resilience by recognizing and promoting certain baseline characteristics and optimizing mechanisms of adaptation. PMID- 24476734 TI - Patient fears of tumor cell dissemination secondary to surgical interventions part II. AB - Patient fears are an ever-present factor of patient care, and addressing those fears is a responsibility of the healthcare provider. One such fear may be of tumor cell dissemination secondary to surgical interventions. Preparing for such discussions will allow the healthcare provider to speak with authority on the topic of tumor dissemination secondary to breast biopsy or surgery, even in a situation where a patient has underlying fears. PMID- 24476735 TI - A nursing workforce program to advance knowledge and skills for nurses implementing cancer clinical research. AB - Clinical nursing research is an emerging subspecialty that enhances nursing expertise. In an effort to provide a basic educational curriculum on cancer research and clinical trials, a major academic cancer center launched a novel program titled Clinical Research Nursing Grand Rounds that allowed nurses to receive continuing education units. The purpose of the current article is to describe the development and content of the education model, challenges encountered, and implications for oncology nursing education, practice, and research. PMID- 24476736 TI - Low-concentration topical capsaicin for chronic neuropathic pain in adults. AB - To assess the efficacy and tolerability of topically applied low-concentration (less than 1%) capsaicin for treating chronic neuropathic pain in adults. PMID- 24476737 TI - Finding the way by following the heart. PMID- 24476738 TI - Educational needs of inpatient oncology nurses in providing psychosocial care. AB - Patients with cancer have multiple psychosocial needs during inpatient admissions. However, nurses often are not sure how to best approach those psychosocial needs. Therefore, the purpose of this survey was to determine the educational needs of inpatient oncology nurses in terms of providing psychosocial care to patients and to determine the barriers that inpatient nurses experience when providing psychosocial care. Twenty-six inpatient oncology RNs participated in an online survey that assessed barriers to psychosocial care as well as educational needs. Nurses identified that time, lack of patient privacy, nurses' emotional energy, confusion about clinical guidelines, lack of experience with screening tools, not knowing how to approach sensitive topics, and poor communication between team members undermine psychosocial care. Inpatient nurses need additional training to provide excellent psychosocial care. PMID- 24476739 TI - Triple-negative breast cancer: what is known about it? AB - Triple-negative breast cancer (TNBC) is considered a rare diagnosis. This malignancy targets a specific population of women and has risk factors differing from those of other breast cancers. TNBC exhibits distinct pathologic features that result in aggressive metastasis and poor prognosis. Pathologically, TNBC cancer cells are characterized by negative receptors for progesterone and estrogen and by the lack of over-expression of human epidermal growth factor receptor 2, which limits chemotherapeutic treatment options for women with TNBC. Nurses can assist in early detection by offering patient education about the little known risk factors for TNBC. Psychosocial issues can overwhelm patients diagnosed with breast cancer. This article provides suggestions for nurses as they guide women who are experiencing an atypical breast cancer diagnosis with an uncertain prognosis and limited treatment options. PMID- 24476740 TI - Progenitor cell therapy for sacral pressure sore: a pilot study with a novel human chronic wound model. AB - INTRODUCTION: Chronic wounds are a major health-care issue, but research is limited by the complexity and heterogeneity in terms of wound etiology as well as patient-related factors. A suitable animal model that replicates the situation in humans is not available. Therefore, the aim of the present work is to present a standardized human wound model and the data of a pilot study of topically applied progenitor cells in a sacral pressure sore. METHODS: Three patients underwent cell harvest from the iliac crest at the time of the initial debridement. Forty eight hours after bone marrow harvest and debridement, the CD34+ selected cell suspension was injected into the wound. With the aid of a laser scanner, three dimensional analyses of wound morphometry were performed until the defect was reconstructed with a local flap 3 weeks after debridement. RESULTS: Decreases in volume to 60%+/-6% of baseline on the sham side and to 52%+/-3% of baseline on the cell side were measured. Histologic work-up revealed no signs of metaplastic, dysplastic, or neoplastic proliferation/differentiation after progenitor cell treatment. CD34+ cells were detected in the biopsies of day 0. CONCLUSIONS: The pressure sore wound model allows investigation of the initial 3 weeks after cell based therapy. Objective outcome analysis in terms of wound volume and histology can be performed without, or with, minimal additional morbidity, and the anatomy of the sacral area allows a control and study side in the same patient. Therefore, this model can serve as a standard for wound-healing studies. TRIAL REGISTRATION: ClinicalTrials.gov NCT00535548. PMID- 24476741 TI - India's vitamin A supplementation programme is reaching the most vulnerable districts but not all vulnerable children. New evidence from the seven states with the highest burden of mortality among under-5s. AB - OBJECTIVE: To characterize the coverage of India's national vitamin A supplementation (VAS) programme and document its performance in reaching children in the districts with higher concentration of poor households (2006-2011). DESIGN: Analysis of VAS programme coverage data collated and collected using standardized bottom-up procedures, data from India's Office of the Registrar General and Census Commissioner, and data from India's District Level Household Survey to compute exposure (poverty) and outcome (full VAS coverage) variables. SETTING: Seven Indian states with the highest burden of mortality in children (74 % of all deaths among under-5s in the country in 2006). SUBJECTS: Children 6-59 months old. RESULTS: Between 2006 and 2011, the mean full VAS coverage (two VAS doses per child per year) in these seven states increased from 44.7 % to 67.3 % while the number of districts with high (>=80 %) full VAS coverage increased from twenty-four (9.4 %) to 131 (51.4 %). The highest increases in full VAS coverage figures were recorded in the districts with the highest concentration of poor households. The estimated number of poor children (i.e. children living in households classified as poor) who did not receive two VAS doses annually decreased from 8.5 million in 2006 to 5.1 million in 2011 (40.3 % decrease); 2.5 million (49.1 %) of these children lived in the districts with the lowest proportion of poor households. CONCLUSIONS: Despite significant improvements in VAS, a large number of Indian children are not benefitting yet from this life protecting intervention, particularly among those who are potentially the most vulnerable. Future programme action needs to give priority to sub-district level units - blocks and villages - with higher concentrations of poor households. PMID- 24476742 TI - Physiological characteristics of international female soccer players. AB - The purpose of this study was to investigate the physiological characteristics of Federation Internationale de Football Association (FIFA) eligible international female soccer players aged 14-36 years and to determine if measures were significantly different for players selected (i.e., starters) to the starting line up for an FIFA tournament as compared with those not selected (i.e., nonstarters). Fifty-one (N = 18 Under 17; N = 18 Under 20; N = 15 Senior) international female soccer players participated in this study. The subjects underwent measurements of anthropometry (height and body mass), lower body strength (isokinetic testing), sprint kinetics and kinematics (nonmotorized treadmill), leg power (unilateral jumping), and maximal aerobic velocity (30:15 intermittent fitness test) during the final preparatory stage for an FIFA event. Outcomes of the age group data indicate that differences in physiological capacities are evident for the Under 17 players as compared with those for the Under 20 and Senior capped international players, suggesting a plateau in the acquisition of physical qualities as players mature. Starters tended to be faster (effect size [ES] = 0.55-1.0, p < 0.05) and have a higher maximal aerobic velocity (ES = 0.78-2.45, p < 0.05), along with greater eccentric leg strength (ES = 0.33-1.67, p < 0.05). Significant differences were detected between starters and nonstarters for isokinetic leg strength (ES = 0.54-1.24, p < 0.05) and maximal aerobic velocity (ES = 0.87, p < 0.05) for Under 17 players, where maximal aerobic velocity was the primary difference between starters and nonstarters (ES = 0.83-2.45, p < 0.05) for the Under 20 and Senior players. Coaches should emphasize the development of speed, maximal aerobic velocity, and leg strength in developing female soccer players. PMID- 24476743 TI - Methods for quantifying training in sprint kayak. AB - The aims of this study were to determine the validity of the session rating of perceived exertion (session-RPE) method by comparing 3 different scales of perceived exertion with common measures of training load (TL). A secondary aim was to verify the relationship between TLs, fitness, and performance in Sprint Kayak athletes. After laboratory assessment of maximal oxygen uptake (V[Combining Dot Above]O2peak) and lactate threshold, the athletes performed on water time trials over 200 and 1,000 m. Training load was quantified for external (distance and speed) and internal (session-RPE: 6-20, category ratio [CR]-10 and CR-100 scales, training impulse [TRIMP], and individual TRIMP). Ten (6 male, 4 female) well-trained junior Sprint Kayak athletes (age 17.1 +/- 1.2 years; V[Combining Dot Above]O2peak 4.2 +/- 0.7 L.min) were monitored over a 7-week period. There were large-to-very large within-individual correlations between the session distance and the various heart rate (HR) and RPE-based methods for quantifying TL (0.58-0.91). Correlations between the mean session speed and various HR- and RPE based methods for quantifying TL were small to large (0.12-0.50). The within individual relationships between the various objective and subjective methods of internal TL were large to very large (0.62-0.94). Moderate-to-large inverse relationships were found between mean session-RPE TL and various aerobic fitness variables (-0.58 to -0.37). Large-to-very large relationships were found between mean session-RPE TL and on water performance (0.57-0.75). In conclusion, session RPE is a valid method for monitoring TL for junior Sprint Kayak athletes, regardless of the RPE scale used. The session-RPE TL relates to fitness and performance, supporting the use of session-RPE in Sprint Kayak training. PMID- 24476744 TI - Correlation of Titleist Performance Institute (TPI) level 1 movement screens and golf swing faults. AB - Although some research in the past has examined how physical limitations in strength or flexibility affect a golfer's performance, the performance outcome most measured was driving distance. Currently, there are no data that have examined the relationship between selected strength and flexibility variables and golf swing faults. The purpose of this study was to examine the relationship between Titleist Performance Institute (TPI) level 1 movement screen variables and 14 common golf swing faults. Thirty-six male and female golfers (mean age, 25.4 +/- 9.9 years; height, 175.9 +/- 16.2 cm; mass, 76.2 +/- 14.6 kg; handicap, 14.2 +/- 10.4) participated. Twelve physical tests of strength, flexibility, and balance were assessed using the TPI level 1 golf fitness screening tool. Golfers then hit 4 golf shots (with a 5-iron) while being videoed, and those were then analyzed for 14 different golf swing faults (using V1Pro software). Three significant associations between a physical limitation and a particular golf swing fault were found: toe touch and early hip extension (p = 0.015), bridge on right side with both early hip extension (p = 0.050), and loss of posture (p = 0.028). In addition, an odds ratio showed that when a golfer could not overhead deep squat or single leg balance on left side, they were 2-3 times more likely to exhibit a early hip extension, loss of posture, or slide during the golf swing, as compared with those who could perform a correct overhead deep squat. Based on our findings, it is important for the golf fitness professional to particularly address a golfer's core strength, balance, and hamstring flexibility to help avoid common golf swing faults, which affect a golfer's ball striking ability and ultimately their performance. PMID- 24476745 TI - Session ratings of perceived exertion responses during resistance training bouts equated for total work but differing in work rate. AB - Session ratings of perceived exertion (SRPE) during resistance training may be influenced by specific exercise parameters. The purpose of this study was to examine the influence of work rate (total work per unit time) and recording time on SRPE. Participants performed 3 exercise bouts of bench press, lat pull-down, overhead press, upright row, triceps extension, and biceps curl at 60% of predetermined 1 repetition maximum according to these protocols: (a) 3 sets * 8 repetitions (reps) * 1.5 minutes of recovery, (b) 3 sets * 8 reps * 3 minutes of recovery, and (c) 2 sets * 12 reps * 3 minutes of recovery. Session ratings of perceived exertion for the 3 * 8 * 1.5-minute recovery (5.3 +/- 1.8) and 2 * 12 * 3-minute recovery trials (6.2 +/- 1.7) were significantly greater vs. 3 * 8 * 3 minute recovery trial (4.2 +/- 1.8). The difference approached significance between work rate-matched protocols (p = 0.08). No difference was observed between SRPE at 15 minutes (5.1 +/- 1.8) vs. 30 minutes (5.2 +/- 1.9) post exercise. Post-set in-task ratings of perceived exertion were higher for the 2 * 12 * 3-minute recovery trial (5.9 +/- 1.4) vs. 3 * 8 * 1.5-minute recovery trial (4.8 +/- 1.2) and 3 * 8 * 3-minute recovery trial (4.0 +/- 1.6). The difference approached significance (p = 0.07) for the 3 * 8 * 3-minute recovery trial vs. 3 * 8 * 1.5-minute recovery trial. Session ratings of perceived exertion responded to changes in work rate with no significant difference at matched work rates, indicating that SRPE is responsive to training load. Results indicated that more proximal monitoring (15 minutes post exercise) yielded reliable estimates of SRPE increasing the practical utility of the measure. PMID- 24476746 TI - Criterion-related validity of sit-and-reach and toe-touch tests as a measure of hamstring extensibility in athletes. AB - The aims of this study were (a) to determine and compare the concurrent hamstring criterion-related validity of the sit-and-reach (SR) and toe-touch (TT) tests in different athletes (tennis players, kayakers, canoeists, and cyclists); (b) to determine the criterion-related validity of the pelvic tilt assessed by the Spinal Mouse system as a measure of hamstring flexibility in athletes; and (c) to evaluate the influence of spinal posture, pelvic tilt, and hamstring muscle flexibility in the SR and TT scores. Twenty-four tennis players, 30 canoeists, 43 kayakers, and 44 cyclists were recruited. Passive straight leg raise (PSLR), SR, and TT tests were randomly performed. Spinal curvatures and pelvic tilt were evaluated with a Spinal Mouse system when the maximal trunk flexion was achieved in the SR and TT tests. Tennis players and cyclists showed moderate correlations between PSLR with respect to SR (beta = 0.78 and beta = 0.76, respectively) and TT (beta = 0.77 and beta = 0.74, respectively). Correlations were slightly lower in canoeists (SR, beta = 0.64; TT, beta = 0.75). Kayakers showed the lowest correlation values (SR, beta = 0.53; TT, beta = 0.57). Correlation values between PSLR and pelvic tilt angle in both the SR and TT tests were beta < 0.70 in all the groups of athletes. Stepwise multiple regression analysis showed a high variance explained from pelvic tilt and lumbar spine in the SR score. In conclusion, the SR and TT tests can be appropriate measures to determine spine flexibility and pelvic tilt range of motion but not to evaluate the hamstring muscle flexibility in tennis players, canoeists, kayakers, and cyclists. PMID- 24476749 TI - Collective behavior of minus-ended motors in mitotic microtubule asters gliding toward DNA. AB - Microtubules (MTs) nucleated by centrosomes form star-shaped structures referred to as asters. Aster motility and dynamics is vital for genome stability, cell division, polarization and differentiation. Asters move either toward the cell center or away from it. Here, we focus on the centering mechanism in a membrane independent system of Xenopus cytoplasmic egg extracts. Using live microscopy and single particle tracking, we find that asters move toward chromatinized DNA structures. The velocity and directionality profiles suggest a random-walk with drift directed toward DNA. We have developed a theoretical model that can explain this movement as a result of a gradient of MT length dynamics and MT gliding on immobilized dynein motors. In simulations, the antagonistic action of the motor species on the radial array of MTs leads to a tug-of-war purely due to geometric considerations and aster motility resembles a directed random-walk. Additionally, our model predicts that aster velocities do not change greatly with varying initial distance from DNA. The movement of asymmetric asters becomes increasingly super-diffusive with increasing motor density, but for symmetric asters it becomes less super-diffusive. The transition of symmetric asters from superdiffusive to diffusive mobility is the result of number fluctuations in bound motors in the tug-of-war. Overall, our model is in good agreement with experimental data in Xenopus cytoplasmic extracts and predicts novel features of the collective effects of motor-MT interactions. PMID- 24476748 TI - Targeted therapy in triple-negative metastatic breast cancer: a systematic review and meta-analysis. AB - OBJECTIVE: To perform a systematic review and meta-analysis of randomized controlled trials that compared the efficacy of targeted therapy to conventional chemotherapy (CT) in patients with metastatic triple-negative breast cancer (TNBC). METHODS: Several databases were searched, including Medline, Embase, LILACS, and CENTRAL. The primary end point was progression-free survival (PFS). We performed a meta-analysis of the published data. The results are expressed as hazard ratio (HR) or risk ratio, with their corresponding 95% confidence intervals (95% CIs). RESULTS: The final analysis included twelve trials comprising 2,054 patients with TNBC, which compared conventional CT alone against CT combined with targeted therapy (bevacizumab [Bev], sorafenib [Sor], cetuximab, lapatinib, and iniparib). PFS was superior in previously untreated patients with TNBC who received Bev plus CT compared to CT alone (fixed effect, HR 0.62, 95% CI 0.51-0.75; P<0.00001). Also, PFS was higher in one study that tested Bev plus CT combination in previously treated patients (HR 0.49, 95% CI 0.33-0.74; P=0.0006). Sor plus CT was also tested as first-line and second-line treatments. The pooled data of PFS favored the combination CT plus Sor (fixed effect, HR 0.69, 95% CI 0.49-0.98; P=0.04). Comparisons of iniparib plus CT also had a better PFS than CT alone (fixed effect, HR 0.75, 95% CI 0.62-0.90; P=0.002). CONCLUSION: Targeted therapy, when associated with conventional CT, demonstrated gains in the PFS of patients with TNBC. PMID- 24476750 TI - Epidemiology of respiratory syncytial virus in children in Cyprus during three consecutive winter seasons (2010-2013): age distribution, seasonality and association between prevalent genotypes and disease severity. AB - This study reports the epidemiology of respiratory syncytial virus (RSV) in hospitalized children in Cyprus over three successive seasons (2010-2013) and the association between prevalent genotypes and disease severity. RSV infections had a circulation pattern from December to March. Most RSV-positive children (83%) were aged <2 years. Genotyping of RSV isolates showed that during the first winter season of the study (2010-2011), the only RSV genotype circulating was GA2 (RSV-A), followed by genotype BA (RSV-B) in the next winter season with only few sporadic cases of GA2. During the last winter season of the study (2012-2013) the newly emerged RSV genotype ON1 (RSV-A) was virtually the only circulating genotype. Children infected with genotype ON1 suffered a significantly milder illness compared to infections with genotypes GA2 and BA with a higher percentage of BA-infected children requiring oxygen. Our findings are in contrast to the majority of published reports that suggest RSV-A causes more severe illness than RSV-B. Therefore, further investigation of the association between RSV genotypes and disease severity is required, as it might affect treatment strategies in the future. PMID- 24476751 TI - Asymptomatic cryptococcal antigenemia is associated with mortality among HIV positive patients in Indonesia. AB - INTRODUCTION: Previous studies, mostly from Africa, have shown that serum cryptococcal antigenemia may precede the development of cryptococcal meningitis and early death among patients with advanced HIV infection. We examined cryptococcal antigenemia as a risk factor for HIV-associated mortality in Indonesia, which is experiencing a rapidly growing HIV epidemic. METHODS: We included ART-naive HIV patients with a CD4 cell count below 100 cells/MUL and no signs of meningitis in an outpatient HIV clinic in Bandung, West Java, Indonesia. Baseline clinical data and follow-up were retrieved from a prospective database, and cryptococcal antigen was measured in stored serum samples using a semiquantitative lateral flow assay. Cox regression analysis was used to identify factors related to mortality. RESULTS: Among 810 patients (median CD4 cell count 22), 58 (7.1%) had a positive cryptococcal antigen test with a median titre of 1:80 (range: 1:1 to 1:2560). Cryptococcal antigenemia at baseline was strongly associated with the development of cryptococcal meningitis and early death and loss to follow-up. After one year, both death (22.4% vs. 11.6%; p=0.016; adjusted HR 2.19; 95% CI 1.78-4.06) and the combined endpoint of death or loss to follow up (67.2% vs. 40.4%; p<0.001; adjusted HR 1.57; 95% CI 1.12-2.20) were significantly higher among patients with a positive cryptococcal antigen test. CONCLUSIONS: Cryptococcal antigenemia is common and clinically relevant among patients with advanced HIV in this setting. Routine screening for cryptococcal antigen followed by lumbar puncture and pre-emptive antifungal treatment for those who are positive may help in reducing early mortality. PMID- 24476752 TI - Characterization of the Natural Organic Matter (NOM) in groundwater contaminated with (60)Co and (137)Cs using ultrafiltration, Solid Phase Extraction and fluorescence analysis. AB - Spot samples of shallow groundwaters have been taken between the years 2004 and 2010 near a site formerly used for the dispersal of radioactive liquid wastes. Three sampling points, one clean (upstream), and two downstream of the contamination source, were processed by ultrafiltration (5000 Da cut-off) and Solid Phase Extraction (SPE) to determine the association of selected artificial radionuclides ((60)Co, (137)Cs) with Natural Organic Matter (NOM). The last two sampling episodes (2008 and 2010) also benefited from fluorescence analysis to determine the major character of the NOM. The fluorescence signals are reported as humic-like, fulvic-like and protein-like, which are used to characterize the different NOM types. The NOM from the clean site comprised mostly fine material, whereas the colloidal content (retained by ultrafiltration) was higher (e.g., 15 40% of the Total Organic Carbon - TOC). Most of the 137Cs was present in the colloidal fraction, whereas (60)Co was found in the filtered fraction. Fluorescence analysis, on the other hand, indicated a contrasting behavior between the clean and contaminated sites, with a dominance of protein-like material, a feature usually associated with human impacts. Finally, SPE removed almost quantitatively the protein-like material (>90%), whereas it removed a much smaller fraction of the (137)Cs (<28%). This finding indicates that the (137)Cs preferential binding occurs with a fraction other than the protein-like NOM, likely the fulvic-like or humic-like portion. PMID- 24476753 TI - Human cytomegalovirus UL34 early and late proteins are essential for viral replication. AB - UL34 is one of the ~50 genes of human cytomegalovirus (HCMV) required for replication in cell culture in human fibroblasts. UL34 encodes highly related early (UL34a) and late (UL34b) proteins that are virtually identical, with the early protein containing an additional 21 amino terminal amino acids. The UL34 proteins are sequence-specific DNA-binding proteins that localize to the nucleus. The HCMV genome contains 14 to 15 UL34 binding sites; two of the UL34 binding sites contribute to transcriptional regulation of two other viral genes, US3 and US9. The roles of the remaining binding sites and the requirement for both UL34 proteins during viral infection remain unknown. We examined the contributions of the early and late UL34 proteins to viral replication by generating HCMV containing bacterial artificial chromosomes with the initiation codon for the early or the late protein mutated. Neither virus was able to replicate, demonstrating that UL34 expression is required throughout the viral replication cycle. A marked decrease in viral gene expression for each of the mutants suggests that UL34 proteins may contribute generally to transcriptional regulation. Intracellular localization studies demonstrated that UL34 colocalizes with the major immediate early protein, IE2, and the viral DNA polymerase processivity factor, UL44, to viral DNA replication centers. In conclusion, sustained UL34 protein expression is required for viral replication. The sequence specific DNA binding ability of UL34 proteins, their localization to viral DNA replication centers and their general effects on viral gene expressions suggests that UL34 proteins contribute to the establishment of a nuclear environment necessary for viral gene expression and DNA replication. PMID- 24476754 TI - Paying for outpatient care in rural China: cost escalation under China's New Co operative Medical Scheme. AB - China's New Co-operative Medical Scheme (NCMS), a government-subsidized health insurance programme, was launched in 2003 in response to deterioration in access to health services in rural areas. Initially designed to cover inpatient care, it has begun to expand its benefit package to cover outpatient care since 2007. The impacts of this initiative on outpatient care costs have raised growing concern, in particular regarding whether it has in fact reduced out-of-pocket (OOP) payments for services among rural participants. This study investigates the impacts on outpatient costs by analysing data from an individual-level longitudinal survey, the China Health and Nutrition Survey, for 2004 and 2009, years shortly before and after NCMS began coverage of outpatient services in 2007. Various health econometrics strategies were employed in the analysis of these data, including the Two-Part Model, the Heckman Selection Model and Propensity Score Matching with the Differences-in-Differences model, to estimate the effects of the 2007 NCMS initiative on per episode outpatient costs. We find that NCMS outpatient coverage starting in 2007 had little impact on reducing its participants' OOP payments for outpatient services. The new coverage may also have contributed to an observed increase in total per episode outpatient costs billed to the insured patients. This increase was more pronounced among village clinics and township health centres-the backbone of the health system for rural residents-than at county and municipal hospitals. PMID- 24476755 TI - Self-organization into quantized eigenstates of a classical wave-driven particle. AB - A growing number of dynamical situations involve the coupling of particles or singularities with physical waves. In principle these situations are very far from the wave particle duality at quantum scale where the wave is probabilistic by nature. Yet some dual characteristics were observed in a system where a macroscopic droplet is guided by a pilot wave it generates. Here we investigate the behaviour of these entities when confined in a two-dimensional harmonic potential well. A discrete set of stable orbits is observed, in the shape of successive generalized Cassinian-like curves (circles, ovals, lemniscates, trefoils and so on). Along these specific trajectories, the droplet motion is characterized by a double quantization of the orbit spatial extent and of the angular momentum. We show that these trajectories are intertwined with the dynamical build-up of central wave-field modes. These dual self-organized modes form a basis of eigenstates on which more complex motions are naturally decomposed. PMID- 24476756 TI - Correlates of victim-blaming attitudes regarding partner violence against women among the Spanish general population. AB - This article analyzes correlates of victim-blaming attitudes regarding partner violence against women (PVAW) among the Spanish general population (N = 1,006). Results showed that victim-blaming attitudes were more common among respondents who were older, less educated, and who placed themselves at the bottom of the social scale. Furthermore, the odds of expressing victim-blaming attitudes were higher among respondents who thought that PVAW was common in society, considered it more acceptable, and knew women victims of partner violence in their circle of friends and family. Implications for public education are discussed. PMID- 24476757 TI - Never innocent victims: street sex workers in Canadian print media. AB - Over the past decade, street sex workers and their families garnered considerable media attention through extensive coverage of disappeared and murdered women in Western Canada. The research presented here examines whether recent media accounts differ from past coverage given that families and friends of disappeared and unaccounted for women inserted themselves into media discussions and circulated alternative readings of their stories. We found that coverage was dominated by two discourses: Vermin-victim discourse demonstrates the tensions between historically dominant conceptualizations and more recent ideas promulgated by families; and risky lifestyle discourse is related to neo-liberal ideologies about personal choice and responsibility. PMID- 24476758 TI - Intimate partner violence in late life: a review of the empirical literature. AB - This integrated review of the empirical literature synthesizes a decade of scientific research across scholarly and professional publications addressing intimate partner violence (IPV) in late life. Deriving insights through a qualitative coding scheme and detailed analysis of 57 empirical sources, we discuss the theoretical frameworks, conceptual themes, and methodological approaches that cut across the literature. Based on these findings, we identify future research directions for improved understanding of late-life IPV as well as implications for policy development and refined community interventions. PMID- 24476759 TI - Prevalence of intimate partner violence across medical and surgical health care settings: a systematic review. AB - Intimate partner violence (IPV) is a serious health problem and a leading cause of nonfatal injury in North American females. Prevalence of IPV has ranged from less than 20% to more than 50% across primary care, emergency medicine, and family medicine. We conducted a systematic review and meta-analysis of the literature to examine best estimates of IPV prevalence as opportunities for targeted interventions in health care specialties. We included 37 articles in this study. Based on our pooled data, best estimates of the lifetime prevalence of any type of IPV were 38% in family medicine and 40% in emergency medicine. PMID- 24476760 TI - Intimate partner violence and neighborhood income: a longitudinal analysis. AB - This investigation used a longitudinal design to examine the relationship between neighborhood-level income, individual-level predictors, and police-reported intimate partner violence in 5,994 urban couples followed over 2 years. At the baseline abuse incident, intimate partner violence rates were highest in the poorest neighborhoods (13.8 per 1,000 women in the lowest income quartile, followed by 12.1, 8.2, and 5.0 in the respective higher income quartiles). However, in the longitudinal analysis, weapon use at the baseline abuse event was a much stronger predictor of repeat abuse (incident rate ratios ranging from 1.72 for physical abuse to 1.83 for non-physical abuse) than neighborhood income. PMID- 24476762 TI - Initial studies on mechanism of action and cell death of active N-oxide containing heterocycles in Trypanosoma cruzi epimastigotes in vitro. AB - Chagas disease, endemic in 21 countries across Latin America, kills more people in the region each year than any other parasite-borne disease. Therapeutic options have problems ranging from toxicity, poor efficacy, drug resistance and high cost. Thus, cheaper and less toxic treatments are necessary. From our in house chemical library of agents against Trypanosoma cruzi the most relevant N oxide-containing heterocycles were selected for mode of action and type of death studies. Also included in these studies were two active nitrofuranes. Epimastigotes of T. cruzi were used as the biological model in this study. The metabolic profile was studied by 1H NMR in association with the MTT assay. Excreted catabolites data, using 1H NMR spectroscopy, showed that most of the studied N-oxides were capable of decreasing both the release of succinate and acetate shedding, the compounds therefore possibly acting on mitochondria. Only quinoxalines and the nitrofurane Nf1 showed significant mitochondrial dehydrogenase inhibitions, but with different dose-time profiles. In the particular case of quinoxaline Qx2 the glucose uptake study revealed that the integrity of some pathways into the glycosome could be affected. Optic, fluorescence (TUNEL and propidium iodide) and transmission electron microscopy (TEM) were employed for type of death studies. These studies were complemented with 1H NMR to visualize mobile lipids. At low concentrations none of the selected compounds showed a positive TUNEL assay. However, both quinoxalines, one furoxan and one benzofuroxan showed a necrotic effect at high concentrations. Curiously, one furoxan, Fx1, one benzofuroxan, Bfx1, and one nitrofurane, Nf1, caused a particular phenotype, with a big cytoplasmatic vacuole being observed while the parasite was still alive. Studies of TEM and employing a protease inhibitor (3-methyladenine) suggested an autophagic phenotype for Bfx1 and Nf1 and a 'BigEye' phenotype for Fx1. PMID- 24476761 TI - Bisphenol A activates BK channels through effects on alpha and beta1 subunits. AB - We demonstrated previously that BK (K(Ca)1.1) channel activity (NP(o)) increases in response to bisphenol A (BPA). Moreover, BK channels containing regulatory beta1 subunits were more sensitive to the stimulatory effect of BPA. How BPA increases BK channel NPo remains mostly unknown. Estradiol activates BK channels by binding to an extracellular site, but neither the existence nor location of a BPA binding site has been demonstrated. We tested the hypothesis that an extracellular binding site is responsible for activation of BK channels by BPA. We synthesized membrane-impermeant BPA-monosulfate (BPA-MS) and used patch clamp electrophysiology to study channels composed of alpha or alpha + beta1 subunits in cell-attached (C-A), whole-cell (W-C), and inside-out (I-O) patches. In C-A patches, bath application of BPA-MS (100 MUM) had no effect on the NP(o) of BK channels, regardless of their subunit composition. Importantly, however, subsequent addition of membrane-permeant BPA (100 MUM) increased the NP(o) of both alpha and alpha + beta1 channels in C-A patches. The C-A data indicate that in order to alter BK channel NP(o), BPA must interact with the channel itself (or some closely associated partner) and diffusible messengers are not involved. In W C patches, 100 MUM BPA-MS activated current in cells expressingalpha subunits, whereas cells expressing alpha + beta1 subunits responded similarly to a log order lower concentration (10 MUM). The W-C data suggest that an extracellular activation site exists, but do not eliminate the possibility that an intracellular site may also be present. In I-O patches, where the cytoplasmic face was exposed to the bath, BPA-MS had no effect on the NP(o) of BK alpha subunits, but BPA increased it. BPA-MS increased the NP(o) of alpha + beta1 channels in I-O patches, but not as much as BPA. We conclude that BPA activates BK alpha via an extracellular site and that BPA-sensitivity is increased by the beta1 subunit, which may also constitute part of an intracellular binding site. PMID- 24476763 TI - Validation of a self-administered FFQ in adults in Argentina, Chile and Uruguay. AB - OBJECTIVE: To assess the reproducibility and validity among adults in the Southern Cone of Latin America (Argentina, Chile and Uruguay) of a self administered FFQ to be used in the CESCAS I Study, an ongoing observational prospective cohort study to detect and follow up CVD and their risk factors, as well as in other epidemiological studies. DESIGN: Relative validity of the FFQ was evaluated by comparing nutrient and selected food group intakes with those from three 24 h recalls (24HR) administered over 6 months. The FFQ was administered at baseline (FFQ1) and again after 3 months (FFQ2). SETTING: Primary care centres in Argentina, Chile and Uruguay. SUBJECTS: Adults (n 147) aged 21-74 years. RESULTS: Reproducibility (FFQ1 v. FFQ2): the intra-class correlation coefficients for nutrients ranged from 0.52 (potassium) to 0.74 (fat). Validity (FFQ1 v. the average of three 24HR): the Pearson correlations for energy-adjusted nutrients ranged from 0.39 (thiamin and cholesterol) to 0.59 (carbohydrate). Joint classification: overall, 66 % of participants in the lowest 24HR quintile were in the lowest one or two FFQ1 quintiles, and 62 % of those in the highest 24HR quintile were in the highest one or two FFQ1 quintiles. On average, only 4 % were misclassified into extreme quintiles. CONCLUSIONS: The FFQ version for the Southern Cone seems to present moderate to acceptable relative validity and reliability for its use in the CESCAS I Study to measure dietary exposure. PMID- 24476764 TI - A role for nematocytes in the cellular immune response of the drosophilid Zaprionus indianus. AB - The melanotic encapsulation response mounted by Drosophila melanogaster against macroparasites, which is based on haemocyte binding to foreign objects, is poorly characterized relative to its humoral immune response against microbes, and appears to be variable across insect lineages. The genus Zaprionus is a diverse clade of flies embedded within the genus Drosophila. Here we characterize the immune response of Zaprionus indianus against endoparasitoid wasp eggs, which elicit the melanotic encapsulation response in D. melanogaster. We find that Z. indianus is highly resistant to diverse wasp species. Although Z. indianus mounts the canonical melanotic encapsulation response against some wasps, it can also potentially fight off wasp infection using two other mechanisms: encapsulation without melanization and a non-cellular form of wasp killing. Zaprionus indianus produces a large number of haemocytes including nematocytes, which are large fusiform haemocytes absent in D. melanogaster, but which we found in several other species in the subgenus Drosophila. Several lines of evidence suggest these nematocytes are involved in anti-wasp immunity in Z. indianus and in particular in the encapsulation of wasp eggs. Altogether, our data show that the canonical anti-wasp immune response and haemocyte make-up of the model organism D. melanogaster vary across the genus Drosophila. PMID- 24476765 TI - A novel TLR-9 agonist C792 inhibits plasmacytoid dendritic cell-induced myeloma cell growth and enhance cytotoxicity of bortezomib. AB - Our prior study in multiple myeloma (MM) patients showed increased numbers of plasmacytoid dendritic cells (pDCs) in the bone marrow (BM), which both contribute to immune dysfunction as well as promote tumor cell growth, survival and drug resistance. Here we show that a novel Toll-like receptor (TLR-9) agonist C792 restores the ability of MM patient-pDCs to stimulate T-cell proliferation. Coculture of pDCs with MM cells induces MM cell growth; and importantly, C792 inhibits pDC-induced MM cell growth and triggers apoptosis. In contrast, treatment of either MM cells or pDCs alone with C792 does not affect the viability of either cell type. In agreement with our in vitro data, C792 inhibits pDC-induced MM cell growth in vivo in a murine xenograft model of human MM. Mechanistic studies show that C792 triggers maturation of pDCs, enhances interferon-alpha and interferon-lambda secretion and activates TLR-9/MyD88 signaling axis. Finally, C792 enhances the anti-MM activity of bortezomib, lenalidomide, SAHA or melphalan. Collectively, our preclinical studies provide the basis for clinical trials of C792, either alone or in combination, to both improve immune function and overcome drug resistance in MM. PMID- 24476766 TI - Low rate of calreticulin mutations in refractory anaemia with ring sideroblasts and marked thrombocytosis. PMID- 24476767 TI - CALR mutations are infrequent in WHO-defined refractory anemia with ring sideroblasts. PMID- 24476769 TI - Relationship between functional hamstring: quadriceps ratios and running economy in highly trained and recreational female runners. AB - The purpose of this study was to investigate the relationship between running economy (RE), functional hamstring:quadriceps peak torque ratios (f-H:Q), and flexibility among female runners. Seven highly trained (HT) female runners (age: 25.7 +/- 4.7 years, VO2peak of 62.0 +/- 4.8 ml.kg-1.min-1) and 11 recreational female runners (age of 28.8 +/- 5.6 years, VO2peak of 49.2 +/- 4.6 ml.kg-1.min-1) were measured for maximal aerobic power (VO2peak), RE, heart rate, respiratory exchange ratio, f-H:Q (Hecc:Qcon and Hcon:Qecc), and sit-and-reach hamstring/trunk flexibility. On 2 separate days, RE was measured on a treadmill at 1% grade at 2 velocities (160.9 and 201.2 m.min-1) for 6 minutes each, and isokinetic knee strength was measured at 3 angular velocities (60, 120, and 180 degrees .s-1) for both concentric and eccentric muscle actions. The unpaired t tests showed a consistent trend toward higher f-H:Q ratios at all angular velocities among the HT runners. Highly trained runners had significantly higher Hecc:Qcon at 120 degrees .s-1 (p <= 0.05) and 180 degrees .s-1 (p <= 0.05). Whole group correlations demonstrated a significant correlation between Hcon:Qecc at 180 degrees .s-1 and RE (ml.kg-1.km-1) at 201.2 m.min-1 (R = -0.48, p <= 0.05). No significant relationships were found between flexibility, or hamstring and quadriceps peak torque (N.m) and RE (p > 0.05). This cross-sectional analysis suggests that higher f-H:Q torque ratios, and not muscle strength per se, are associated with a lower metabolic cost of running. Therefore, runners should consider implementing hamstring exercises to improve their f-H:Q ratios. PMID- 24476768 TI - The germline sequence variant rs2736100_C in TERT associates with myeloproliferative neoplasms. PMID- 24476770 TI - The current state of NCAA Division I collegiate strength facilities: size, equipment, budget, staffing, and football status. AB - Strength and conditioning training programs are essential components of athletic performance, and the effectiveness of these programs can be linked to the strength and conditioning facilities (SCFs) used by athletes. The primary purpose of this study was to provide a statistical overview of National Collegiate Athletic Association (NCAA) Division I SCFs, equipment and maintenance budget, and the relationship between SCF budget and staffing space, and equipment. The secondary purpose was to note differences in SCFs between those schools with and without football programs. An 84-item online survey instrument, developed with expert input from certified strength professionals, was used to collect data regarding the SCFs in NCAA Division I universities. A total of 110 valid and complete surveys were returned for a response rate of 38.6%. Results of Pearson's chi2 analysis demonstrated that the larger reported annual equipment budgets were associated with larger SCFs (chi2 = 451.4, p <= 0.001), greater maximum safe capacity of athletes using the facility (chi2 = 366.9, p <= 0.001), increased numbers of full-time coaches (chi2 = 224.2, p <= 0.001), and increased number of graduate assistant or intern coaches (chi2 = 102.9, p <= 0.001). Based on these data, it can be suggested to athletic administrators and strength and conditioning professionals at the collegiate level that budgets need to be re evaluated as the number of personnel available to monitor student-athletes and the size and safe capacity of the facility are related to the ability of the strength and conditioning staff to safely and adequately perform their duties. PMID- 24476771 TI - Performance and Age of the Fastest Female and Male 100-KM Ultramarathoners Worldwide From 1960 to 2012. AB - The purpose of this cross-sectional study was to investigate the change in 100-km running performance and in the age of peak performance for 100-km ultramarathoners. Age and running speed of the annual fastest women and men in all 100-km ultramarathons held worldwide between 1960 and 2012 were analyzed in 148,017 finishes with 18,998 women and 129,019 men using single, multivariate, and nonlinear regressions. Running speed of the annual fastest men increased from 8.67 to 15.65 km.h(-1) and from 8.06 to 13.22 km.h(-1) for the annual fastest women. For the annual 10 fastest men, running speed increased from 10.23 +/- 1.22 to 15.05 +/- 0.29 km.h(-1) (p < 0.0001) and for the annual 10 fastest women from 7.18 +/- 1.54 to 13.03 +/- 0.18 km.h(-1) (p < 0.0001). The sex difference decreased from 56.1 to 16.3% for the annual fastest finishers (p < 0.0001) and from 46.7 +/- 8.7% to 14.0 +/- 1.2% for the annual 10 fastest finishers (p < 0.0001). The age of the annual fastest men increased from 29 to 40 years (p = 0.025). For the annual fastest women, the age remained unchanged at 35.0 +/- 9.7 years (p = 0.469). For the annual 10 fastest women and men, the age remained unchanged at 34.9 +/- 3.2 (p = 0.902) and 34.5 +/- 2.5 years (p = 0.064), respectively. To summarize, 100-km ultramarathoners became faster, the sex difference in performance decreased but the age of the fastest finishers remained unchanged at ~ 35 years. For athletes and coaches to plan a career as 100-km ultramarathoner, the age of the fastest female and male 100-km ultramarathoners remained unchanged at ~ 35 years between 1960 and 2012 although the runners improved their performance over time. PMID- 24476772 TI - The effect of pre-exercise galactose and glucose ingestion on high-intensity endurance cycling. AB - This study evaluated the effects of the pre-exercise (30 minutes) ingestion of galactose (Gal) or glucose (Glu) on endurance capacity as well as glycemic and insulinemic responses. Ten trained male cyclists completed 3 randomized high intensity cycling endurance tests. Thirty minutes before each trial, cyclists ingested 1 L of either 40 g of glucose, 40 g of galactose, or a placebo in a double-blind manner. The protocol comprised 20 minutes of progressive incremental exercise (70-85% maximal power output [Wmax]); ten 90-second bouts at 90% Wmax, separated by 180 seconds at 55% Wmax; and 90% Wmax until exhaustion. Blood samples were drawn throughout the protocol. Times to exhaustion were longer with Gal (68.7 +/- 10.2 minutes, p = 0.005) compared with Glu (58.5 +/- 24.9 minutes), with neither being different to placebo (63.9 +/- 16.2 minutes). Twenty-eight minutes after Glu consumption, plasma glucose and serum insulin concentrations were higher than with Gal and placebo (p < 0.001). After the initial 20 minutes of exercise, plasma glucose concentrations increased to a relative hyperglycemia during the Gal and placebo, compared with Glu condition. Higher plasma glucose concentrations during exercise, and the attenuated serum insulin response at rest, may explain the significantly longer times to exhaustion produced by Gal compared with Glu. However, neither carbohydrate treatment produced significantly longer times to exhaustion than placebo, suggesting that the pre-exercise ingestion of galactose and glucose alone is not sufficient to support this type of endurance performance. PMID- 24476773 TI - Association of fitness with life satisfaction, health risk behaviors, and adherence to the Mediterranean diet in Spanish adolescents. AB - The aim of this study was to examine the association between aerobic, musculoskeletal, and motor capacity and life satisfaction, risk behavior, and adherence to the Mediterranean diet in adolescents. A total of 1,988 Spanish adolescents (12-16 years old) participated in this cross-sectional study. Life satisfaction, risk behavior, and adherence to the Mediterranean diet were measured by validated questionnaires for these ages. Aerobic, musculoskeletal muscle, and motor capacity were evaluated objectively with the ALPHA battery tests. Adolescents with low aerobic capacity had a higher risk of showing less (vs. very happy) life satisfaction (odds ratio [OR] = 1.303, 95% confidence interval [CI] = 1,054-1,611). These adolescents were also more likely to report risk behaviors such as sometimes (vs. never) of smoking tobacco (OR = 1.752, 95% CI = 1,218-2,520), besides having a low adherence to the Mediterranean diet (vs. high) (OR = 1.410, 95% CI = 1,113-1,786). Adolescents with low upper-body musculoskeletal capacity showed a lower risk of reporting risk behaviors such as alcohol consumption or getting drunk occasionally (vs. never) (OR = 0.662, 95% CI = 520-843; OR = 0.561, 95% CI = 419-753, respectively). The results suggest that the aerobic capacity contributes significantly to greater adherence to the Mediterranean diet, greater life satisfaction, and lower tobacco consumption, whereas musculoskeletal capacity seems to be related to alcohol consumption. PMID- 24476774 TI - Effects of Psyching-Up on Sprint Performance. AB - Hammoudi-Nassib, S, Nassib, S, Chtara, M, Briki, W, Chaouachi, A, Tod, D, and Chamari, K. Effects of psyching-up on sprint performance. J Strength Cond Res 31(8): 2066-2074, 2017-The present research aimed at examining whether the psyching up (PU) strategies improve performance in 30-m sprinting. Sixteen male sprinters (age, 20.6 +/- 1.3 years; body mass, 77.5 +/- 7.1 kg; height, 180.8 +/- 5.6 cm) participated in this study. Before each experimental session, the Hooper index was used to monitor the subject's feeling for the quality of sleep of the previous night, perceived quantity of stress, delayed onset muscle soreness, and fatigue. After completing general and specific warm-up, participants had to rate their degree of self-confidence. Then, they were asked to follow 1 of these 4 conditions: Imagery (experimental PU condition), Preparatory arousal (experimental PU condition), Attention placebo (control condition), and Distraction (control condition) during the final 30 seconds of the rest period right before performing a 30-m sprint. Participants separately and randomly performed all conditions. Results showed that although the imagery and preparatory arousal strategies contributed to increase the performance in the short-distance sprints (from 0 to 10 m), the imagery strategy contributed to increase the performance in the 30-m sprints. These findings support the general view that the PU strategies could improve athletic performance. PMID- 24476775 TI - A comparison of traditional and block periodized strength training programs in trained athletes. AB - The purpose of this study was to compare 2 different periodization models in strength and power athletes. Twenty-four experienced resistance trained men were randomly assigned to either a block periodization training program (BP; age = 24.2 +/- 3.1 years, body mass = 78.5 +/- 11.0 kg, height = 177.6 +/- 4.9 cm) or to a traditional periodization program (TP; age = 26.2 +/- 6.0 years, body mass = 80.5 +/- 13.3 kg, height = 179.2 +/- 4.6). Participants in both training programs performed 4 training sessions per week. Each training program consisted of the same exercises and same volume of training (total resistance lifted per session). The difference between the groups was in the manipulation of training intensity within each training phase. Strength and power testing occurred before training (PRE) and after 15 weeks (POST) of training. Magnitude-based inferences were used to compare strength and power performance between the groups. Participants in BP were more likely (79.8%) to increase the area under the force-power curve than TP. Participants in BP also demonstrated a likely positive (92.76%) decrease in the load corresponding to maximal power at the bench press compared with TP group, and a possible improvement (~60%) in maximal strength and power in the bench press. No significant changes were noted between groups in lower-body strength or jump power performance after the 15-week training period. Results of this study indicate that BP may enhance upper-body power expression to a greater extent than TP with equal volume; however, no differences were detected for lower body performance and body composition measures. PMID- 24476776 TI - Physiological and psychological responses to outdoor vs. laboratory cycling. AB - The purpose of this study was to determine the physiological and psychological responses to laboratory vs. outdoor cycling. Twelve recreationally trained male cyclists participated in an initial descriptive testing session and 2 experimental trials consisting of 1 laboratory and 1 outdoor session, in a randomized order. Participants were given a standardized statement instructing them to give the same perceived effort for both the laboratory and outdoor 40-km trials. Variables measured include power output, heart rate (HR), core temperature, skin temperature, body weight, urine specific gravity (USG), Rating of Perceived Exertion (RPE), attentional focus, and environmental conditions. Wind speed was higher in the outdoor trial than in the laboratory trial (2.5 +/- 0.6 vs. 0.0 +/- 0.0 m.s-1, p = 0.02) whereas all other environmental conditions were similar. Power output (208.1 +/- 10.2 vs. 163.4 +/- 11.8 W, respectively, p < 0.001) and HR (152 +/- 4 and 143 +/- 6 b.min-1, respectively, p = 0.04) were higher in the outdoor trial than in the laboratory trial. Core temperature was similar, whereas skin temperature was cooler during the outdoor trial than during the laboratory trial (31.4 +/- 0.3 vs. 33.0 +/- 0.2 degrees C, respectively, p < 0.001), thus creating a larger thermal gradient between the core and skin outdoors. No significant differences in body weight, USG, RPE, or attentional focus were observed between trials. These data indicate that outdoor cycling allows cyclists to exercise at a higher intensity than in laboratory cycling, despite similar environmental conditions and perceived exertion. In light of this, cyclists may want to ride at a higher perceived exertion in indoor settings to acquire the same benefit as they would from an outdoor ride. PMID- 24476777 TI - Proximal-to-distal sequencing in vertical jumping with and without arm swing. AB - Vertical jumping performance is dependent on muscle strength and motor skill. An understanding of motor skill strategies and their influence on jumping mechanics provides insight into how to improve performance. This study aimed to determine whether kinematic sequencing strategy influenced jump height, the effect of sequencing on jumping mechanics, and whether arm swing influences sequencing strategy. Women volleyball players (n = 16) performed vertical jumps with and without arm swing on force platforms while recorded with a 6-camera motion capture system. Sequencing strategy was determined as the relative time delay between pelvis and knee extension. A long time delay indicated a proximal-to distal strategy, whereas no time delay represented a simultaneous strategy. Longer relative time delay was correlated with higher jump height in jumps with (r = 0.82, p < 0.001) and without arm swing (r = 0.58, p = 0.02). Longer relative time delay and higher jump height were associated with greater hip extensor and ankle plantar flexor net joint moments (NJM), and greater ratio of concentric to eccentric knee extensor NJM (p <= 0.05). Longer relative time delay and higher jump height were correlated with greater thigh and leg angular accelerations (p <= 0.05). These kinetic and kinematic variables, along with relative time delay and jump height were greater in jumps with arm swing than without (p <= 0.05), indicating arm swing promotes use of a proximal-to-distal strategy. Use of a proximal-to-distal strategy is associated with greater NJM and segment accelerations, which may contribute to better vertical jump performance. PMID- 24476778 TI - Chronological age vs. biological maturation: implications for exercise programming in youth. AB - Biological maturation is associated with significant change to a number of physiological and structural processes throughout childhood and, in particular, adolescence. Mismatched rapid growth in the long bones relative to muscular lengthening may disrupt structure, neuromuscular function, and physical performance. Practitioners who work with school-age youth should be aware of the age-related changes that typically take place during a child's development to ensure that their strength and conditioning programming is as safe and effective as possible for enhancing performance and reducing injury risk. Although there are several methods available to assess biological maturation, practitioners who work with youth can benefit from assessment methods that are available and feasible, and that provide utility in the quantification of the degree and stages of biological maturation that affect motor performance in children and adolescents. This article synthesizes the relevant assessment methods and provides a rationale for understanding usable biological maturation assessment tools that can aid in the development of training program design for youth. PMID- 24476779 TI - Factors that contribute to and account for strength and work capacity in a large cohort of recreationally trained adult healthy men with high- and low-strength levels. AB - The factors that best account for differences in strength across all types of exercise, body types, and training histories are not well understood. The purpose of this study was to assess the effects of strength level and body composition on upper- and lower-body work capacity in adult men. From a cohort of 295 adult men (25.6 +/- 7.5 years, 178 +/- 8 cm, 85.2 +/- 15 kg), low-strength (LS, n = 72) and high-strength (HS, n = 66) samples were selected based on 1 repetition maximum (1RM) bench press (BP) and leg strength (LP) values. Work capacity for each exercise was determined from the product of repetition weight (80% 1RM) and maximum repetitions-to-fatigue (RTF). Body composition was measured using dual energy x-ray absorptiometry. The HS group was significantly greater than the LS group in total body mass and fat-free mass but not in age, height, fat mass, or %fat. Low-strength and HS groups were not significantly different (p > 0.05) in RTF for either BP (8.7 +/- 3.1 vs. 8.3 +/- 1.9 reps, respectively) or LP (15.6 +/ 7.6 vs. 17.0 +/- 6.3 reps, respectively), making the ratio of RTF for BP vs. LP nonsignificant (LS = 2.0 +/- 1.0; HS = 2.2 +/- 0.9). The HS group produced significantly greater (p < 0.001) absolute and relative work capacities for both BP and LP compared with the LS group. Repetitions-to-fatigue had a greater influence on BP (r2 = 0.74) and LP (r2 = 0.85) work capacities in the LS group than did RepWt (r2 = 0.07 and 0.28, respectively). In the HS group, RTF (r2 = 0.79) had a greater influence than RepWt (r2 = 0.10) on BP work capacity, whereas the 2 components were more similar for LP work capacity (r2 = 0.64 and 0.47, respectively). When evaluated at the same %1RM, muscular endurance is similar across divergent strength levels meaning that work capacity (load * reps) will be greater for HS individuals. Controlling for the influence of body composition variables (e.g., fat or fat-free mass) does not eliminate the difference in work capacity between strength groups suggesting that other factors are accounting for strength expression. Prescribing repetitions against a fixed relative load is largely dependent on exercise type and must be considered by strength and conditioning professionals. PMID- 24476780 TI - Kinetic and kinematic associations between vertical jump performance and 10-m sprint time. AB - Implementing objective methods to assess physical performance has become an invaluable component of athlete or player development, monitoring, and talent identification in distinct sports. Many sports depend heavily upon muscular strength, muscle power output, and sprint performance, especially at competition level. Therefore, the aim of this study was to examine the relationships between 10-m time and several kinetic and kinematic parameters variables related to a weighted countermovement jump using a linear transducer in a large sample of trained sportsmen. A group of 32 trained sportsmen volunteered to participate in the study (mean +/- SD: age 21.4 +/- 1.5 years, body mass 67.5 +/- 4.8 kg, body height 1.74 +/- 0.02 m). The major findings of this study were the significant associations between 10-m sprint time and peak velocity during jumping (r = 0.630; p < 0.01); and also the nonsignificant associations between sprint and of force, mechanical impulse and rate of force development. These results underline the important relationship between 10-m sprint and maximal lower-body strength, as assessed by the force, power, and bar velocity displacement. It is suggested that sprinting time performance would benefit from training regimens aimed to improve these performance qualities. PMID- 24476781 TI - Recovery effects of repeated exposures to normobaric hyperoxia on local muscle fatigue. AB - Reported recovery effects of hyeroxia are conflicted. This study aimed to identify the effects and the mechanisms of normobaric hyperoxia on the recovery of local muscle fatigue, which is the most commonly encountered form of fatigue both daily and in training and competitions. Twelve male subjects performed 3 * 3 * no less than 30 seconds of isometric quadriceps exercise at 70% of maximum voluntary isometric contraction (MVIC) separated by two 15-minute recovery sessions under 1 of 2 different atmospheric oxygen concentrations, one in normoxia (NOX; 20.9% O2) and another in hyperoxia (HOX; 30.0% O2). To assess the degree of fatigue and recovery, 4 parameters were used; MVIC, endurance time to exhaustion, blood lactate, and perceived exertion measured by a visual analog scale (VAS). Maximum voluntary isometric contraction improved an average by approximately 14% in HOX compared with NOX at the conclusion of the second recovery session. However, this was not associated with changes in other parameters because changes in endurance time, blood lactate, and VAS during the trials were similar. Based on our findings, we conclude that 2 sets of 15-minute recovery session in normobaric hyperoxia are effective for restoring MVIC from local muscle fatigue induced by intermittent intense exercises. For quicker recovery, athletes are recommended to repeat 15-minute recovery process under 30.0% hyperoxia. PMID- 24476782 TI - The effects of a 7-week practical blood flow restriction program on well-trained collegiate athletes. AB - The purpose of this study was to examine the effects of a 7-week practical blood flow restriction (BFR) protocol used in conjunction with a strength training program on measures of muscular strength and size in collegiate American football players. Sixty-two participants were divided into 4 groups. Three groups completed a traditional upper- and lower-body split strength program. Two of these groups also completed supplemental lifting sessions. Of these 2, 1 completed the additional lifts with BFR. The final group completed a modified training program, followed by the supplemental lifts, with BFR. The supplemental lifting protocol consisted of bench press and squat, using 20% 1 repetition maximum (1RM) for 4 sets with 30 repetitions performed in the first set and 20 repetitions performed in the following 3 sets. Each set was separated by 45 seconds of rest. The supplemental bench press was completed at the end of upper body days and the squat at the end of lower-body days. Dependent measures were taken before the start of the program and again on conclusion the following dependent variables were measured: upper- and lower-body girths, 1RM bench, and squat. Results of a 4 * 2 mixed-model multivariate analysis of covariance revealed a significant difference for the interaction on the dependent variables. Follow-up univariate analysis of variances indicated a significant difference for 1RM squat. This suggests that a practical BFR program used in addition to a traditional strength training program can be effective at increasing 1RM squat performance. The use of elastic knee wraps makes BFR a feasible training option for coaches and athletes. PMID- 24476783 TI - The effect of 16-week plyometric training on explosive actions in early to mid puberty elite soccer players. AB - Plyometric training (PT) programs are widely used to improve explosive actions in soccer players of various ages, although there is debate about optimal training duration and time course of improvement. Twenty-two early to mid-puberty elite soccer players were assigned to a control group (CG, n = 10, regular soccer training) or a plyometric training group (PTG, n = 12, regular soccer training substituted with 2 PT sessions each week). Both groups trained for 16 weeks during the in-season period. Control group performed only tests at baseline and after intervention, whereas PTG performed additional tests after 4, 8, and 12 weeks. During each test, subjects' performances in speed (10 and 30 m; 5 and 20 m), agility, shuttle run, multiple 5 bounds (MB5), and standing long jump (LJ) were recorded. The PTG showed improved performance in 20-m sprint time (-3.2%), agility time (-6.1%), MB5 distance (+11.8%), and LJ distance (+7.3%) (all, p <= 0.05) after 16 weeks. All these improvements were higher compared with CG (all, p <= 0.05). The time course of improvement in the PT group showed that 20-m sprint time improved after 16 weeks (p = 0.012); agility after 4 (p = 0.047) and 8 weeks (p = 0.004) but stopped after 12 weeks (p = 0.007); MB5 after 8 (p = 0.039), 12 (p = 0.028), and 16 weeks (p < 0.001); and LJ improved after 4 (p = 0.045), 12 (p = 0.008), and 16 weeks (p < 0.001). Plyometric training seems to be an appropriate training tool to enhance some but not all explosive actions. The results indicate that the duration of a PT program is highly dependent on what type of explosive actions should be improved, or whether several explosive actions should be improved at the same time. PMID- 24476784 TI - Perceptions of successful cues to action and opportunities to augment behavioral triggers in diabetes self-management: qualitative analysis of a mobile intervention for low-income Latinos with diabetes. AB - BACKGROUND: The increasing prevalence of diabetes and the associated cost of managing this complicated disease have a significant impact on public health outcomes and health expenditures, especially among resource-poor Latino patients. Mobile health (mHealth) may be the solution to reaching this group and improving their health. OBJECTIVE: In this qualitative study, we examined nuances of motivation, intention, and triggers to action effected by TExT-MED (Trial to Examine Text Messaging for Emergency Department patient with Diabetes), an mHealth intervention tailored to low-income, urban Latinos with diabetes. TExT MED is a fully-automated, text message-based program designed to increase knowledge, self-efficacy, and subsequent disease management and glycemic control. METHODS: We conducted 5 focus group interviews with 24 people who participated in TExT-MED. We employed a modified grounded theory analytic approach-an iterative process of coding and immersion in the data used to recognize the patterns and links between concepts voiced by the participants. We coded data to identify themes of participant experiences, motivations, and responses to the program. We organized themes into a theory of TExT-MED's action. RESULTS: Participants enjoyed their experience with TExT-MED and believed it improved their diabetes management. Through analysis of the transcripts, we identified that the strengths of the program were messages that cued specific behaviors such as medication reminders and challenge messages. Our analysis also revealed that increasing personalization of message delivery and content could augment these cues. CONCLUSIONS: This in-depth qualitative analysis of TExT-MED shows that low-income Latino patients will accept text messages as a behavioral intervention. This mHealth intervention acts as a behavioral trigger rather than an education platform. Personalization is an opportunity to enhance these cues to action and further research should be conducted on the ideal forms of personalization. PMID- 24476789 TI - Endovascular treatment of the extracranial carotid pseudoaneurysms resulting from stab penetrating injury using overlapping bare stents. AB - Injury pertaining to the common carotid artery may result in complete or partial arterial transection, pseudoaneurysms, or arteriovenous connections. Endovascular treatment option of the pseudoaneurysm has already been established with favorable success rate and minimal morbidity. Our purpose is to report one 18 year-old male patient having 2 traumatic pseudoaneurysms as a result of penetrating stab injury in the extracranial common carotid. The patient was successfully treated using 2 overlapping bare-metal stents. The 2 common carotid pseudoaneurysms had different degree inflow angles defined as the space between the lines indicating the direction of blood flow from the parent artery and through the aneurysmal neck to the dome. Computed tomography angiography was utilized to follow the evolution of the pseudoaneurysms until total occlusion was demonstrated. The treatment modality used in this report represents an alternative approach of the endovascular treatment for the extracranial carotid pseudoaneurysm. PMID- 24476788 TI - A phase II trial of oxaliplatin, docetaxel, and bevacizumab as first-line therapy of advanced cancer of the ovary, peritoneum, and fallopian tube. AB - OBJECTIVE: To determine the safety and efficacy of the novel combination of docetaxel, oxaliplatin, and bevacizumab as first-line treatment of advanced cancer of the ovary, peritoneum or fallopian tube after initial debulking surgery. METHODS: Eligible patients (stage IB-IV) were treated with 6 cycles of oxaliplatin (85 mg/m(2)), docetaxel (75 mg/m(2)), and bevacizumab (15 mg/kg) every 3 weeks, followed by single-agent bevacizumab 15 mg/kg every 3 weeks to complete one year of therapy. The primary endpoint was 12-month progression-free survival (PFS). RESULTS: A total of 132 patients (80 with measurable disease at baseline; 52 with non-measurable, evaluable disease at baseline) enrolled and received study treatment. At diagnosis, 76.5% of patients had stage III disease and 20% had stage IV. 62.9% were optimally cytoreduced. The most common grade 3/4 adverse events were neutropenia (42.4%), leukopenia (13.6%), hypertension (8.3%), fatigue (6.1%), and nausea (6.1%). One patient (0.8%) had a fatal gastrointestinal perforation. The best overall confirmed response rate (complete response+partial response [measurable disease subgroup]) was 58.6% (95% CI 49%, 67%). CA-125 response rates for the measurable and non-measurable disease subgroups were 83.0% and 81.5%, respectively. The 12-month PFS rate for the measurable disease subgroup was 65.7% (95% CI 53.4%, 76.7%); median PFS was 16.3 (95% CI 12.6, 19.6) months. Median overall survival was 47.3 (95% CI 34.1, upper limit not applicable) months. CONCLUSIONS: This novel treatment regimen may provide a promising therapeutic approach for women with ovarian, primary peritoneal, or fallopian tube carcinoma. No unanticipated safety concerns were identified. PMID- 24476790 TI - Photonic Aharonov-Bohm effect in photon-phonon interactions. AB - The Aharonov-Bohm effect is one of the most intriguing phenomena in both classical and quantum physics, and associates with a number of important and fundamental issues in quantum mechanics. The Aharonov-Bohm effects of charged particles have been experimentally demonstrated and found applications in various fields. Recently, attention has also focused on the Aharonov-Bohm effect for neutral particles, such as photons. Here we propose to utilize the photon-phonon interactions to demonstrate that photonic Aharonov-Bohm effects do exist for photons. By introducing nonreciprocal phases for photons, we observe experimentally a gauge potential for photons in the visible range based on the photon-phonon interactions in acousto-optic crystals, and demonstrate the photonic Aharonov-Bohm effect. The results presented here point to new possibilities to control and manipulate photons by designing an effective gauge potential. PMID- 24476791 TI - Lack of in vitro-in vivo correlation of adulthood cytochrome p450 activities in low-birth-weight rats. PMID- 24476792 TI - Trichodina heterodentata (Ciliophora) infestation on Prochilodus lineatus larvae: a host-parasite relationship study. AB - Prochilodus lineatus is a freshwater fish species found in South America. It is common in aquaculture, but few studies regarding diseases of this fish have been performed. This study presents data of the occurrence of Trichodina heterodentata Duncan, 1977, as well as the pathological alterations detected by light and scanning electron microscopy (SEM). Twenty 20-day-old larvae were harvested from an earth pond and examined. Larvae showed erratic swimming on the pond edges and some had a whitish tegument. Larval smears were either impregnated with silver nitrate or stained with Giemsa stain to observe the taxonomic features of the ciliates. Five larvae were fixed in formalin solution for histopathological analysis, and another five specimens were fixed in glutaraldehyde for SEM. All larvae were diagnosed with a severe infestation by trichodinid T. heterodentata. Histological sections showed discrete hyperplasia of the gill filaments with subepithelial oedema of the secondary lamellae. In the SEM, suction areas were observed on the skin, gill and eye; corrosion and ulceration of the fins were associated with the bacterial presence of cocci on the lesions. This is the first report of T. heterodentata in P. lineatus that is responsible for an acute disease that culminates in larval mortality. PMID- 24476793 TI - Temperature sensitivity of acid-sensitive outwardly rectifying (ASOR) anion channels in cortical neurons is involved in hypothermic neuroprotection against acidotoxic necrosis. AB - The acid-sensitive outwardly rectifying (ASOR) anion channel has been found in non-neuronal cell types and was shown to be involved in acidotoxic death of epithelial cells. We have recently shown that the ASOR channel is sensitive to temperature. Here, we extend those results to show that temperature-sensitive ASOR anion channels are expressed in cortical neurons and involved in acidotoxic neuronal cell death. In cultured mouse cortical neurons, reduction of extracellular pH activated anionic currents exhibiting phenotypic properties of the ASOR anion channel. The neuronal ASOR currents recorded at pH 5.25 were augmented by warm temperature, with a threshold temperature of 26 degrees C and the Q(10) value of 5.6. After 1 h exposure to acidic solution at 37 degrees C, a large population of neurons suffered from necrotic cell death which was largely protected not only by ASOR channel blockers but also by reduction of temperature to 25 degrees C. Thus, it is suggested that high temperature sensitivity of the neuronal ASOR anion channel provides, at least in part, a basis for hypothermic neuroprotection under acidotoxic situations associated with a number of pathological brain states. PMID- 24476794 TI - Dung beetles and fecal helminth transmission: patterns, mechanisms and questions. AB - Dung beetles are detrivorous insects that feed on and reproduce in the fecal material of vertebrates. This dependency on vertebrate feces implies frequent contact between dung beetles and parasitic helminths with a fecal component to their life-cycle. Interactions between dung beetles and helminths carry both positive and negative consequences for successful parasite transmission, however to date there has been no systematic review of dung beetle-helminth interactions, their epidemiological importance, or their underlying mechanisms. Here we review the observational evidence of beetle biodiversity-helminth transmission relationships, propose five mechanisms by which dung beetles influence helminth survival and transmission, and highlight areas for future research. Efforts to understand how anthropogenic impacts on biodiversity may influence parasite transmission must include the development of detailed, mechanistic understanding of the multiple interactions between free-living and parasitic species within ecological communities. The dung beetle-helminth system may be a promising future model system with which to understand these complex relationships. PMID- 24476795 TI - Liver intake in 24-59-month-old children from an impoverished South African community provides enough vitamin A to meet requirements. AB - OBJECTIVE: To assess the contribution of liver to the vitamin A intake of 24-59 month-old children from an impoverished South African community where liver is frequently consumed and vitamin A deficiency previously shown to be absent. DESIGN: Cross-sectional. SETTING: Northern Cape Province, South Africa. SUBJECTS: Children aged 24-59 months (n 150). Vitamin A intake from liver was assessed using a single 24 h recall and a quantified liver frequency questionnaire. In addition, information on vitamin A intake via the national fortification programme was obtained from the 24 h recall and information on vitamin A supplementation from the Road-to-Health Chart. Height, weight and socio-economic data were also collected. RESULTS: Stunting, underweight and wasting were prevalent in 36.9 %, 25.5 % and 12.1 % of children. Mean daily vitamin A intake from liver was 537 and 325 MUg retinol equivalents measured by the 24 h recall and liver frequency questionnaire, respectively. Liver was consumed in 92.7 % of households and by 84.7 % of children; liver intake was inversely related to socio economic status (P < 0.05). The food fortification programme contributed 80 MUg retinol equivalents and the vitamin A supplementation programme 122 MUg retinol equivalents to daily vitamin A intake. CONCLUSIONS: The study showed that liver alone provided more than 100 % of the Estimated Average Requirement of the pre school children in this impoverished community. The results also challenge the notion generally held by international health bodies that vitamin A deficiency, poor anthropometric status and poverty go together, and reinforces the fact that South Africa is a culturally diverse society for which targeted interventions are required. PMID- 24476796 TI - Things that go bump in the day or night: the aetiology of infant head injuries presenting to a Scottish Paediatric Emergency Department. AB - The aim of this study was to describe the aetiology and severity of head injury in an infant (age<1 year) population presenting to a Scottish Paediatric Emergency Department (PED) and to discern preventable risk factors. The records of infants who presented to the PED of the Royal Aberdeen Children's Hospital between September 2010 and December 2011 with isolated head trauma were reviewed, patient demographics were extracted and information on aetiology, including nonaccidental injury (NAI), was recorded. Of 1574 attendances, 233 suffered isolated head injury. The majority (97%) were minor; six patients suffered skull fractures, three had traumatic intracranial haemorrhage and only three were considered to have sustained an NAI. The most common mode of injury was fall from a height (37%). Infants commonly present to the PED with head injury, many of which should be easily preventable. The number of cases because of NAI in our population is smaller than previously published figures. PMID- 24476797 TI - Implementation of A Better Choice Healthy Food and Drink Supply Strategy for staff and visitors in government-owned health facilities in Queensland, Australia. AB - OBJECTIVE: The present paper reports on a quality improvement activity examining implementation of A Better Choice Healthy Food and Drink Supply Strategy for Queensland Health Facilities (A Better Choice). A Better Choice is a policy to increase supply and promotion of healthy foods and drinks and decrease supply and promotion of energy-dense, nutrient-poor choices in all food supply areas including food outlets, staff dining rooms, vending machines, tea trolleys, coffee carts, leased premises, catering, fundraising, promotion and advertising. DESIGN: An online survey targeted 278 facility managers to collect self-reported quantitative and qualitative data. Telephone interviews were sought concurrently with the twenty-five A Better Choice district contact officers to gather qualitative information. SETTING: Public sector-owned and -operated health facilities in Queensland, Australia. SUBJECTS: One hundred and thirty-four facility managers and twenty-four district contact officers participated with response rates of 48.2% and 96.0%, respectively. RESULTS: Of facility managers, 78.4% reported implementation of more than half of the A Better Choice requirements including 24.6% who reported full strategy implementation. Reported implementation was highest in food outlets, staff dining rooms, tea trolleys, coffee carts, internal catering and drink vending machines. Reported implementation was more problematic in snack vending machines, external catering, leased premises and fundraising. CONCLUSIONS: Despite methodological challenges, the study suggests that policy approaches to improve the food and drink supply can be implemented successfully in public-sector health facilities, although results can be limited in some areas. A Better Choice may provide a model for improving food supply in other health and workplace settings. PMID- 24476799 TI - Therapeutic monoclonal antibodies in human breast milk: a case study. AB - Recently, therapeutic monoclonal antibodies have been introduced for the treatment of advanced melanoma and other diseases. It remains unclear whether these drugs can be safely administered to women who are breast feeding because of the potential hazardous side effects for nursing infants. One such therapy for metastatic melanoma is ipilimumab, a human monoclonal antibody that blocks cytotoxic T-lymphocyte-antigen-4, and is the preferred treatment for patients with metastatic melanoma when other molecular therapies are not viable. This study measured ipilimumab levels in the breast milk of a patient undergoing treatment that were enough to raise concerns for a nursing infant exposed to ipilimumab. PMID- 24476798 TI - Fusion of HCV nonstructural antigen to MHC class II-associated invariant chain enhances T-cell responses induced by vectored vaccines in nonhuman primates. AB - Despite viral vectors being potent inducers of antigen-specific T cells, strategies to further improve their immunogenicity are actively pursued. Of the numerous approaches investigated, fusion of the encoded antigen to major histocompatibility complex class II-associated invariant chain (Ii) has been reported to enhance CD8(+) T-cell responses. We have previously shown that adenovirus vaccine encoding nonstructural (NS) hepatitis C virus (HCV) proteins induces potent T-cell responses in humans. However, even higher T-cell responses might be required to achieve efficacy against different HCV genotypes or therapeutic effect in chronically infected HCV patients. In this study, we assessed fusion of the HCV NS antigen to murine and human Ii expressed by the chimpanzee adenovirus vector ChAd3 or recombinant modified vaccinia Ankara in mice and nonhuman primates (NHPs). A dramatic increase was observed in outbred mice in which vaccination with ChAd3 expressing the fusion antigen resulted in a 10-fold increase in interferon-gamma(+) CD8(+) T cells. In NHPs, CD8(+) T-cell responses were enhanced and accelerated with vectors encoding the Ii-fused antigen. These data show for the first time that the enhancement induced by vector vaccines encoding li-fused antigen was not species specific and can be translated from mice to NHPs, opening the way for testing in humans. PMID- 24476800 TI - The association between life course socioeconomic position and life satisfaction in different welfare states: European comparative study of individuals in early old age. AB - BACKGROUND: whether socioeconomic position over the life course influences the wellbeing of older people similarly in different societies is not known. OBJECTIVE: to investigate the magnitude of socioeconomic inequalities in life satisfaction among individuals in early old age and the influence of the welfare state regime on the associations. DESIGN: comparative study using data from Wave 2 and SHARELIFE, the retrospective Wave of the Survey of Health, Ageing, and Retirement in Europe (SHARE), collected during 2006-07 and 2008-09, respectively. SETTING: thirteen European countries representing four welfare regimes (Southern, Scandinavian, Post-communist and Bismarckian). SUBJECTS: a total of 17,697 individuals aged 50-75 years. METHODS: slope indices of inequality (SIIs) were calculated for the association between life course socioeconomic position (measured by the number of books in childhood, education level and current wealth) and life satisfaction. Single level linear regression models stratified by welfare regime and multilevel regression models, containing interaction terms between socioeconomic position and welfare regime type, were calculated. RESULTS: socioeconomic inequalities in life satisfaction were present in all welfare regimes. Educational inequalities in life satisfaction were narrowest in Scandinavian and Bismarckian regimes among both genders. Post-communist and Southern countries experienced both lower life satisfaction and larger socioeconomic inequalities in life satisfaction, using most measures of socioeconomic position. Current wealth was associated with large inequalities in life satisfaction across all regimes. CONCLUSIONS: Scandinavian and Bismarckian countries exhibited narrower socioeconomic inequalities in life satisfaction. This suggests that more generous welfare states help to produce a more equitable distribution of wellbeing among older people. PMID- 24476801 TI - Expert surgeon's quiet eye and slowing down: expertise differences in performance and quiet eye duration during identification and dissection of the recurrent laryngeal nerve. AB - BACKGROUND: Long quiet eye (QE) duration is central to expertise in sports, while cognitive "slowing down" has been identified as a perceptual skill possessed by skilled surgeons. Eye-tracking evidence is lacking about the relationship of QE duration to slowing down in surgeons. The aim of this study was to examine QE duration, hand movement time (MT), fixation location, and fixation duration in highly experienced (HE) and less experienced (LE) surgeons. METHODS: A mobile eye tracker and camera recorded coupled gaze and hand movements. Performance was quantified by blinded review. RESULTS: HE surgeons were rated higher than LE surgeons but did not differ in operating time or MT. HE and LE surgeons differed in fixation duration on the ligament of Berry during phases 1 and 2 and QE duration on the recurrent laryngeal nerve in phase 2. CONCLUSIONS: Long-duration fixation on the ligament of Berry and long-duration QE on the recurrent laryngeal nerve combined with no significant differences in MT provide empirical evidence that HE surgeons cognitively slow down more than LE surgeons during critical phases of the operation. PMID- 24476802 TI - Is high leukocyte count synonymous with the presence of endothelial dysfunction or atherosclerosis? PMID- 24476803 TI - Is high leukocyte count synonymous with the presence of endothelial dysfunction or atherosclerosis? PMID- 24476804 TI - Emergency care for acute myocardial infarction in disasters. PMID- 24476805 TI - Robot-assisted gait training improves motor performances and modifies Motor Unit firing in poststroke patients. AB - BACKGROUND: Robotics and related technologies are realizing their promise to improve the delivery of rehabilitation therapy but the mechanism by which they enhance recovery is still unknown. The electromechanical-driven gait orthosis Lokomat has demonstrated its utility for gait rehabilitation after stroke. AIM: To test the efficacy of Lokomat in gait retraining and to investigate the neurophysiological mechanisms underlying the recovery process. DESIGN: Case series study. SETTING: Unit of Neurorehabilitation of a University Hospital. POPULATION: Fifteen patients with post-stroke hemiparesis. METHODS: Patients underwent a six weeks rehabilitative treatment provided by Lokomat. The outcome measures were: Fugl-Meyer Motor Scale (FMMS), Berg Balance Scale (BBS), 10 metres Walking Test (10mWT), Timed Up and Go test (TUG), 6 Minute Walking Test (6MWT). Strength and Motor Unit firing rate of vastus medialis (VM) were analyzed during isometric knee extension through an isokinetic dynamometer and surface EMG recording. RESULTS: An increase of duration and covered distance, a decrease of body weight support and guidance force on the paretic side along the sessions were observed. The FMMS, the BBS, the TUG and the 6MWT demonstrated a significant improvement after the training. No increase of force was observed whereas a significant increase of firing rate of VM was recorded. CONCLUSION: The evidence that the improvement of walking ability observed in our study determines a significant increase of firing rate of VM not accompanied by an increase of force could suggest an effect of training on motorneuronal firing rate that thus contributes to improve motor control. CLINICAL REHABILITATION IMPACT: Given the current wide use of robotics in gait retraining after stroke, our approach can contribute to clarify the mechanisms underlying its rehabilitative impact so as to incorporate the findings of evidence-based practice into appropriate treatment plans for persons poststroke. PMID- 24476806 TI - Does reduced movement restrictions and use of assistive devices affect rehabilitation outcome after total hip replacement? A non-randomized, controlled study. AB - BACKGROUND: Improvements in surgical techniques and increase of femoral head size might have changed the rationale for movement restrictions after total hip replacement (THR). AIM: To evaluate the influence of movement restrictions and assistive devices on rehabilitation after fast track THR. DESIGN: Non-randomized, controlled study. SETTING: Inpatient. POPULATION: 365 consecutively included THR patients. METHODS: Patients included the 3 initial month of the study underwent rehabilitation with restrictions in hip movement and a standard package of assistive devices (restricted group). This group was compared to patients included the following 3 months with less restricted hip movement and use of assistive devices according to individual needs (unrestricted group). Questionnaires on function, pain, quality of life (HOOS), anxiety (HADS), working status and patient satisfaction were completed before THR, 3 and 6 weeks after. RESULTS: The HOOS function score at the 3 measurement times was (mean +/- SD); unrestricted group: 46 +/- 17 - 76 +/- 9 - 83 +/- 14 compared to restricted group: 43 +/- 16 - 81 +/- 14 - 83 +/- 13. Changes over time was significantly higher in the restricted group (P=0.004). Return to work 6 weeks after THR for the unrestricted group compared to restricted group was: 53% versus 32% (P=0.045). No significant differences between groups in pain, symptoms, quality of life, anxiety/depression, hip dislocations and patient satisfaction. CONCLUSION: This study showed slightly slower recovery in patient-reported function after reduction in movement restrictions and use of assistive devices, but the difference was eliminated after 6 weeks. Reduced movement restrictions did not affect the other patient-reported outcomes and led to earlier return to work. CLINICAL REHABILITATION IMPACT: It is possible to reduce movement restrictions and use of assistive devices considerably. More research on safety issues is needed to elucidate the effect of unrestricted rehabilitation on hip dislocation. PMID- 24476807 TI - A comparison of the University of New Brunswick Test of Prosthetic Function and the Assessment of Capacity for Myoelectric Control. AB - BACKGROUND: Valid outcome measures are required for gathering evidence on when, how and using which prosthetic components to start prosthetic fitting to children with congenital upper limb deficiencies and those following acquired upper limb amputation. We have been using the University of New Brunswick Test of Prosthetic Function (UNB, which measures skill and spontaneity of prosthetic use) in our country since 1996, and the Assessment of Capacity for Myoelectric Control (ACMC, which was developed for persons using a myoelectric prosthesis) since 2008. AIM: We wanted to explore whether the UNB and the ACMC measure the same construct (i.e., assess convergent validity), and whether the ACMC can also be used for assessing children and adolescents who use a body-powered upper-limb prosthesis. DESIGN: Observational. SETTING: Inpatient. POPULATION: All the 19 children and adolescents who were visiting the outpatient clinic for rehabilitation of children with upper limb deficiencies and amputations at our institute from January 2010 to December 2011 and had a myoelectric (15 participants) or body powered prosthesis (4 participants). METHODS: The participants were assessed by the age-appropriate UNB subtest; 60 assessments were performed in total. Two tests (moving a plastic glass half-full with water from table to the sink, and tying apron at the back) were added to obtain the ACMC scores. RESULTS: Simple and autocorrelation-adjusted correlation and regression analyses demonstrated that ACMC score is highly positively correlated with UNB spontaneity and skill score in children and adolescents who use a myoelectric prosthesis. Neither of the two associations could be observed in children and adolescents who use a body powered prosthesis. CONCLUSION: The results suggest that both tests can be used for assessing children and adolescents who use a myolectric prosthesis, but only the UNB appears to be appropriate for those who use a body-powered prosthesis. CLINICAL REHABILITATION IMPACT: This small study indicates that either the ACMC or the UNB are applicable for assessing children and adolescents who use a myolectric upper-limb prosthesis because of congenital upper limb deficiencies or acquired upper limb amputation, but only the UNB seems to be applicable for those children or adolescents who use a body-powered prosthesis. PMID- 24476808 TI - Serum aflatoxin levels of the healthy adult population living in the north and south regions of Turkey. AB - OBJECTIVE: To determine the serum concentrations of aflatoxin B1 (AFB1), aflatoxin B2 (AFB2), aflatoxin G1 (AFG1) and aflatoxin G2 (AFG2) in the healthy adult population living in both the Black Sea and Mediterranean regions of Turkey and to investigate the regional, seasonal and gender variability in aflatoxins (AF) exposure in these regions. DESIGN: Serum AFB1, AFB2, AFG1 and AFG2 concentrations were analysed by HPLC. Settings In total, four hundred and eighty four serum samples were analysed. SUBJECTS: Four hundred and eighty-four healthy adult volunteers living in rural areas of the Black Sea and Mediterranean regions of Turkey were studied. RESULTS: The mean serum concentration of total AF in the Black Sea region was 1.33 ppb (min-max 0.15-3.38 ppb) and 0.90 ppb (min-max 0.18 2.48 ppb) for summer and winter, respectively. In the Mediterranean region, the mean serum concentration of total AF was determined as 0.55 ppb (range 0.04-1.72 ppb) for summer and 0.45 ppb (range 0.12-1.43 ppb) for winter. The total AF concentrations in serum samples were statistically higher in summer compared with winter for the two regions. The differences between the regions were statistically significant concerning all samples, with higher total AF concentrations in the Black Sea region. CONCLUSIONS: The overall results suggest that the Turkish population living in these two regions is continuously exposed to AF, particularly in the summer, and that mycotoxin contamination in food should be monitored routinely for food safety and human health. PMID- 24476809 TI - Intracellular delivery of functionally active proteins using self-assembling pyridylthiourea-polyethylenimine. AB - Intracellular delivery of functionally active proteins into cells is emerging as a novel strategy for research and therapeutic applications. Here, we present the properties of a self-assembling pyridylthiourea-modified polyethylenimine (piPEI), which interacts with proteins and promotes their delivery into the cytosol of mammalian cells. In aqueous medium at pH7.4, self-association of piPEI in the presence of green fluorescent proteins (GFP) leads to supramolecular protein-entrapped assemblies. These assemblies protect GFP from losing its fluorescence upon pH variation and assist delivery/translocation into the cytosol of mammalian cells via the endocytic pathway. The scope of application of this delivery system was extended to antibodies against intracellular targets as illustrated using a monoclonal antibody directed against the HPV-16 viral E6 oncoprotein and an antibody directed against the threonine-927 phosporylation site of the EG5 kinesin spindle protein. The piPEI-mediated delivery of native anti-E6 antibodies or anti-E6 antibodies equipped with a nuclear localization signal (NLS), led to regeneration of the p53 tumor suppression protein in E6 transformed CaSki cells. Delivery of functionally active anti-EG5 antibodies, with the same polymer, reduced HeLa cell viability and appeared to perturb, as expected, chromosome segregation during mitosis. Altogether, these results provide an easy to use delivery system for extending the scope of application of antibodies for epitope recognition within living cells and may provide novel opportunities for selective interference of cell function by a steric hindrance modality. PMID- 24476810 TI - Polymorphism of dislocation core structures at the atomic scale. AB - Dislocation defects together with their associated strain fields and segregated impurities are of considerable significance in many areas of materials science. However, their atomic-scale structures have remained extremely challenging to resolve, limiting our understanding of these ubiquitous defects. Here, by developing a complex modelling approach in combination with bicrystal experiments and systematic atomic-resolution imaging, we are now able to pinpoint individual dislocation cores at the atomic scale, leading to the discovery that even simple magnesium oxide can exhibit polymorphism of core structures for a given dislocation species. These polymorphic cores are associated with local variations in strain fields, segregation of defects, and electronic states, adding a new dimension to understanding the properties of dislocations in real materials. The findings advance our fundamental understanding of basic behaviours of dislocations and demonstrate that quantitative prediction and characterization of dislocations in real materials is possible. PMID- 24476811 TI - Intergenerational differences in acculturation experiences, food beliefs and perceived health risks among refugees from the Horn of Africa in Melbourne, Australia. AB - OBJECTIVE: To investigate the differences in acculturation experiences between parent and adolescent refugees from the Horn of Africa in Melbourne, Australia and to explore food beliefs and perceived health risks from an intergenerational perspective. DESIGN: Qualitative cross-sectional study involving a combination of semi-structured one-on-one interviews and focus group discussions. SETTING: North West suburbs of Melbourne, Australia. SUBJECTS: Eritrean, Ethiopian, Somali and Sudanese refugees. RESULTS: Using a purposeful sampling technique, twelve semi structured face-to-face interviews (nine adults and three adolescents) and four in-depth focus groups (two with adolescents each containing six participants and two with adults one containing six participants and the other ten participants) were carried out. Thus overall data were obtained on fifteen adolescents and twenty-five parents. Qualitative analysis identified differences between parents and adolescents in relation to lifestyle, diet and physical activity. Views regarding health consequences of their changed diets also differed. Parental feeding practices encompassed a variety of methods and were enforced in an attempt by parents to control their children's dietary behaviours and prevent their drift away from traditional eating habits. CONCLUSIONS: These findings call for more research to contextualise dietary acculturation among refugee youth and the impact of migration on parenting styles and feeding practices in communities from the Horn of Africa. Preventive health programmes with Horn of Africa refugees need to acknowledge the effect of acculturation on diet and physical activity levels and a socio-cultural framework needs to be developed with respect to the importance and influence of the family environment. PMID- 24476812 TI - Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. AB - OBJECTIVE: In recent years, safety alerts have been made warning of the risk of serious drug-induced liver injury (DILI) caused by cardiovascular drugs. The new oral anticoagulants (NOACs) have now reached the market. However, safety concerns have been raised about their hepatic safety. Therefore we aimed to evaluate NOAC liver-related safety. METHODS: Systematic review and meta-analysis of phase III randomised controlled trials (RCTs). Medline and CENTRAL were searched to September 2013. Reviews and reference lists were also searched. Two reviewers independently searched for studies and retrieved data estimates. Primary outcome was DILI (transaminases elevations >3* upper limit of normal (ULN) with total bilirubin >2* ULN). NOACs were compared against any control group. Random-effects meta-analysis was performed, and pooled estimates were expressed as relative risk (RR) and 95% CI heterogeneity was evaluated with I(2) test. RESULTS: Twenty-nine RCTs evaluating 152 116 patients (mean follow-up of 16 months) were included. All RCTs were rated as having low risk of bias. NOAC were not associated with an increased risk of DILI (RR 0.90, 95% CI 0.72 to 1.13, I(2)=0%). Similar results were obtained for individual NOAC (rivaroxaban, apixaban, dabigatran, darexaban, edoxaban) and considering the different control groups (vitamin K antagonists, low molecular weight heparin (LMWH) and placebo). The risk of transaminases elevations (>3*ULN) was lower among NOAC-treated patients, in particular in comparison with LMWH-treated patients (RR 0.71, 95% CI 0.59 to 0.85; I(2)=27%) CONCLUSIONS: NOACs are not associated with an increased risk of DILI. The unexpected 'protective' effect of NOAC is probably due to LMWH-associated hepatotoxicity. PMID- 24476813 TI - Multi-locus sequence typing confirms the clonality of Trichomonas gallinae isolates circulating in European finches. AB - In recent years, Trichomonas gallinae emerged as the causative agent of an infectious disease of passerine birds in Europe leading to epidemic mortality of especially greenfinches Chloris chloris and chaffinches Fringilla coelebs. After the appearance of finch trichomonosis in the UK and Fennoscandia, the disease spread to Central Europe. Finch trichomonosis first reached Austria and Slovenia in 2012. In the present study the genetic heterogeneity of T. gallinae isolates from incidents in Austria and Slovenia were investigated and compared with British isolates. For this purpose comparative sequence analyses of the four genomic loci ITS1-5.8S-ITS2, 18S rRNA, rpb1 and Fe-hydrogenase were performed. The results corroborate that one clonal T. gallinae strain caused the emerging infectious disease within passerine birds and that the disease is continuing to spread in Europe. The same clonal strain was also found in a columbid bird from Austria. Additionally, the present study demonstrates clearly the importance of multi-locus sequence typing for discrimination of circulating T. gallinae strains. PMID- 24476817 TI - Ocean science: eddy effects on biogeochemistry. PMID- 24476815 TI - The genomic landscape of Neanderthal ancestry in present-day humans. AB - Genomic studies have shown that Neanderthals interbred with modern humans, and that non-Africans today are the products of this mixture. The antiquity of Neanderthal gene flow into modern humans means that genomic regions that derive from Neanderthals in any one human today are usually less than a hundred kilobases in size. However, Neanderthal haplotypes are also distinctive enough that several studies have been able to detect Neanderthal ancestry at specific loci. We systematically infer Neanderthal haplotypes in the genomes of 1,004 present-day humans. Regions that harbour a high frequency of Neanderthal alleles are enriched for genes affecting keratin filaments, suggesting that Neanderthal alleles may have helped modern humans to adapt to non-African environments. We identify multiple Neanderthal-derived alleles that confer risk for disease, suggesting that Neanderthal alleles continue to shape human biology. An unexpected finding is that regions with reduced Neanderthal ancestry are enriched in genes, implying selection to remove genetic material derived from Neanderthals. Genes that are more highly expressed in testes than in any other tissue are especially reduced in Neanderthal ancestry, and there is an approximately fivefold reduction of Neanderthal ancestry on the X chromosome, which is known from studies of diverse species to be especially dense in male hybrid sterility genes. These results suggest that part of the explanation for genomic regions of reduced Neanderthal ancestry is Neanderthal alleles that caused decreased fertility in males when moved to a modern human genetic background. PMID- 24476818 TI - Quantum error correction in a solid-state hybrid spin register. AB - Error correction is important in classical and quantum computation. Decoherence caused by the inevitable interaction of quantum bits with their environment leads to dephasing or even relaxation. Correction of the concomitant errors is therefore a fundamental requirement for scalable quantum computation. Although algorithms for error correction have been known for some time, experimental realizations are scarce. Here we show quantum error correction in a heterogeneous, solid-state spin system. We demonstrate that joint initialization, projective readout and fast local and non-local gate operations can all be achieved in diamond spin systems, even under ambient conditions. High-fidelity initialization of a whole spin register (99 per cent) and single-shot readout of multiple individual nuclear spins are achieved by using the ancillary electron spin of a nitrogen-vacancy defect. Implementation of a novel non-local gate generic to our electron-nuclear quantum register allows the preparation of entangled states of three nuclear spins, with fidelities exceeding 85 per cent. With these techniques, we demonstrate three-qubit phase-flip error correction. Using optimal control, all of the above operations achieve fidelities approaching those needed for fault-tolerant quantum operation, thus paving the way to large scale quantum computation. Besides their use with diamond spin systems, our techniques can be used to improve scaling of quantum networks relying on phosphorus in silicon, quantum dots, silicon carbide or rare-earth ions in solids. PMID- 24476819 TI - Cancer: interference identifies immune modulators. PMID- 24476820 TI - DNA interrogation by the CRISPR RNA-guided endonuclease Cas9. AB - The clustered regularly interspaced short palindromic repeats (CRISPR)-associated enzyme Cas9 is an RNA-guided endonuclease that uses RNA-DNA base-pairing to target foreign DNA in bacteria. Cas9-guide RNA complexes are also effective genome engineering agents in animals and plants. Here we use single-molecule and bulk biochemical experiments to determine how Cas9-RNA interrogates DNA to find specific cleavage sites. We show that both binding and cleavage of DNA by Cas9 RNA require recognition of a short trinucleotide protospacer adjacent motif (PAM). Non-target DNA binding affinity scales with PAM density, and sequences fully complementary to the guide RNA but lacking a nearby PAM are ignored by Cas9 RNA. Competition assays provide evidence that DNA strand separation and RNA-DNA heteroduplex formation initiate at the PAM and proceed directionally towards the distal end of the target sequence. Furthermore, PAM interactions trigger Cas9 catalytic activity. These results reveal how Cas9 uses PAM recognition to quickly identify potential target sites while scanning large DNA molecules, and to regulate scission of double-stranded DNA. PMID- 24476822 TI - Microbiology: a talented genus. PMID- 24476823 TI - An environmental bacterial taxon with a large and distinct metabolic repertoire. AB - Cultivated bacteria such as actinomycetes are a highly useful source of biomedically important natural products. However, such 'talented' producers represent only a minute fraction of the entire, mostly uncultivated, prokaryotic diversity. The uncultured majority is generally perceived as a large, untapped resource of new drug candidates, but so far it is unknown whether taxa containing talented bacteria indeed exist. Here we report the single-cell- and metagenomics based discovery of such producers. Two phylotypes of the candidate genus 'Entotheonella' with genomes of greater than 9 megabases and multiple, distinct biosynthetic gene clusters co-inhabit the chemically and microbially rich marine sponge Theonella swinhoei. Almost all bioactive polyketides and peptides known from this animal were attributed to a single phylotype. 'Entotheonella' spp. are widely distributed in sponges and belong to an environmental taxon proposed here as candidate phylum 'Tectomicrobia'. The pronounced bioactivities and chemical uniqueness of 'Entotheonella' compounds provide significant opportunities for ecological studies and drug discovery. PMID- 24476827 TI - Do you make a difference? PMID- 24476825 TI - Poly(A)-tail profiling reveals an embryonic switch in translational control. AB - Poly(A) tails enhance the stability and translation of most eukaryotic messenger RNAs, but difficulties in globally measuring poly(A)-tail lengths have impeded greater understanding of poly(A)-tail function. Here we describe poly(A)-tail length profiling by sequencing (PAL-seq) and apply it to measure tail lengths of millions of individual RNAs isolated from yeasts, cell lines, Arabidopsis thaliana leaves, mouse liver, and zebrafish and frog embryos. Poly(A)-tail lengths were conserved between orthologous mRNAs, with mRNAs encoding ribosomal proteins and other 'housekeeping' proteins tending to have shorter tails. As expected, tail lengths were coupled to translational efficiencies in early zebrafish and frog embryos. However, this strong coupling diminished at gastrulation and was absent in non-embryonic samples, indicating a rapid developmental switch in the nature of translational control. This switch complements an earlier switch to zygotic transcriptional control and explains why the predominant effect of microRNA-mediated deadenylation concurrently shifts from translational repression to mRNA destabilization. PMID- 24476824 TI - In vivo discovery of immunotherapy targets in the tumour microenvironment. AB - Recent clinical trials showed that targeting of inhibitory receptors on T cells induces durable responses in a subset of cancer patients, despite advanced disease. However, the regulatory switches controlling T-cell function in immunosuppressive tumours are not well understood. Here we show that such inhibitory mechanisms can be systematically discovered in the tumour microenvironment. We devised an in vivo pooled short hairpin RNA (shRNA) screen in which shRNAs targeting negative regulators became highly enriched in murine tumours by releasing a block on T-cell proliferation upon tumour antigen recognition. Such shRNAs were identified by deep sequencing of the shRNA cassette from T cells infiltrating tumour or control tissues. One of the target genes was Ppp2r2d, a regulatory subunit of the PP2A phosphatase family. In tumours, Ppp2r2d knockdown inhibited T-cell apoptosis and enhanced T-cell proliferation as well as cytokine production. Key regulators of immune function can therefore be discovered in relevant tissue microenvironments. PMID- 24476826 TI - Follicular pancreatitis, report of a case clinically mimicking pancreatic cancer and literature review. AB - We herein present a 71-year-old man who underwent pancreatoduodenectomy with the diagnosis of follicular pancreatitis. We could not completely deny malignancy by a preoperative imaging study. Endoscopic ultrasonography-guided fine needle aspiration biopsy demonstrated clusters of benign acinar cells and no proliferation of atypical lymphoid cells or rich plasma cells. Histologically, the prominent lymphoid follicle formation was seen in an ill-defined mass, 15 mm in size, in the pancreatic parenchyma. Duct-centered fibrotic rims were seen in the pancreatic ducts accompanied by mild fibrotic change between the follicles and obliterative phlebitis. No neoplastic epithelial cells were observed in the resected specimen, and infiltrating lymphocytes did not show any morphological atypia and monoclonal proliferation by immunohistochemical staining with B and T cell markers. In addition, we could exclude IgG4-related disease, because plasmacytic cells were rarely positive for IgG4. Although follicular pancreatitis is rare, this mass-forming inflammatory disease (pancreatitis) should be included in the preoperative differential diagnosis of pancreatic cancer. PMID- 24476828 TI - Nothing by mouth at midnight: saving or starving? A literature review. AB - Historical use of fasting at midnight before anesthesia and surgery has been based on tradition instead of evidence. Research has challenged this practice and determined consuming clear liquids (e.g., water, apple juice, black tea, black coffee) 2-3 hours before surgery does not increase gastric residual volume or risk for aspiration. Liberal fasting guidelines have been published to support this research; however, there continues to be a disparity between practice and evidence. Metabolic alterations occur in the starved state and current available evidence suggests the use of a carbohydrate-rich clear liquid beverage to stimulate the fed state. The fed state is characterized by insulin secretion that stimulates the storage of macronutrients for fuel and promotes protein synthesis. Implementing this practice may decrease insulin resistance and support immune function. Allowing the patient to consume carbohydrate-rich clear liquid beverages may reduce postoperative nausea and vomiting and improve patient reports of anxiety, hunger, and thirst. This article evaluates the evidence for providing clear liquids and carbohydrate-rich clear liquid beverages to healthy adults undergoing surgery to optimize postoperative recovery. PMID- 24476821 TI - Comprehensive molecular characterization of urothelial bladder carcinoma. AB - Urothelial carcinoma of the bladder is a common malignancy that causes approximately 150,000 deaths per year worldwide. So far, no molecularly targeted agents have been approved for treatment of the disease. As part of The Cancer Genome Atlas project, we report here an integrated analysis of 131 urothelial carcinomas to provide a comprehensive landscape of molecular alterations. There were statistically significant recurrent mutations in 32 genes, including multiple genes involved in cell-cycle regulation, chromatin regulation, and kinase signalling pathways, as well as 9 genes not previously reported as significantly mutated in any cancer. RNA sequencing revealed four expression subtypes, two of which (papillary-like and basal/squamous-like) were also evident in microRNA sequencing and protein data. Whole-genome and RNA sequencing identified recurrent in-frame activating FGFR3-TACC3 fusions and expression or integration of several viruses (including HPV16) that are associated with gene inactivation. Our analyses identified potential therapeutic targets in 69% of the tumours, including 42% with targets in the phosphatidylinositol-3-OH kinase/AKT/mTOR pathway and 45% with targets (including ERBB2) in the RTK/MAPK pathway. Chromatin regulatory genes were more frequently mutated in urothelial carcinoma than in any other common cancer studied so far, indicating the future possibility of targeted therapy for chromatin abnormalities. PMID- 24476829 TI - Anxiety, depression, and catecholamine levels after self-management intervention in irritable bowel syndrome. AB - Patients with irritable bowel syndrome (IBS) often report higher levels of psychological distress, specifically anxiety, and depression than non-IBS patients. The management of gastrointestinal symptoms and psychological distress is demonstrably amenable to cognitive-behavioral therapies in a significant number of patients with IBS. The present secondary analysis evaluates the impact of nurse-delivered self-management interventions on anxiety, depression, and urine catecholamine levels in adult IBS patients. Participants in the study were randomized to 2 intervention groups of either comprehensive self-management (CSM) intervention or usual care control. Daily diary ratings of gastrointestinal symptoms, anxiety, and depression were recorded every evening for 28 days during the baseline period and subsequently at 3, 6, and 12 months postrandomization. Catecholamine levels of epinephrine and norepinephrine were measured from 4 weekly 1st morning urine samples at baseline as well as at each follow-up time. The CSM group reported significantly lower levels of anxiety and depression at follow-up than the usual care group (p = .018 and .021, respectively). In contrast, urine catecholamine levels displayed no appreciable change. Thus, although nurse-delivered CSM interventions showed no impact on urinary catecholamine levels, daily psychological distress was measurably reduced. PMID- 24476830 TI - Acute pulmonary hypertension after transjugular intrahepatic portosystemic shunt: a potentially deadly but commonly forgotten complication. AB - Hepatitis C virus (HCV) is a common cause of chronic liver disease and is the most common indication for liver transplantation in the United States. As increasing numbers of the population experience complications from chronic liver disease, management of these complications comes into focus. One such management technique is a transjugular intrahepatic portosystemic shunt (TIPS). As the number of patients with HCV cirrhosis increases, the proportion of TIPS procedures performed will also increase. It is, therefore, paramount to understand the potential adverse effects of this increasingly used procedure. This case report focuses on a 52-year-old man with HCV cirrhosis who developed the complication of acute pulmonary hypertension after receiving a TIPS procedure. In this case report, we discuss this important but commonly missed complication of TIPS, including incidence, diagnosis, and treatment. PMID- 24476832 TI - Eosinophilic esophagitis: affecting all ages. AB - Eosinophilic esophagitis is a chronic inflammatory disorder in which elevated eosinophils are found in the esophagus, and symptoms related to esophageal dysfunction are experienced. It has been found in both children and adults. Diagnosis is based on 15 or more eosinophils per high power field in one or more esophageal biopsy specimens coupled with a lack of response to acid suppression therapy or a normal pH monitoring study. It is often associated with other allergic conditions such as eczema and asthma. The reported cases of eosinophilic esophagitis have risen in the past decade, but whether this reflects a true increase in incidence or simply an increased recognition of the disorder by providers is not clear. Patients present with a wide range of symptoms from feeding difficulties, food refusal, and vomiting in children, to dysphagia and food impaction in adults. Treatment options for patients include dietary restrictions, topical steroids, and esophageal dilation. PMID- 24476834 TI - Symptoms and distress among patients with liver cirrhosis but without hepatocellular carcinoma in Taiwan. AB - A cross-sectional study design was used to assess the items and frequency of physical symptoms and psychological distress among patients with liver cirrhosis (LC) but without hepatocellular carcinoma. Inpatients with LC were recruited from a medical center in northern Taiwan. Informants were asked to describe their frequency of symptoms and distress at 2 weeks before admission. During August 2008 and July 2009, 49 patients participated. The symptoms and distress were moderate, with a mean of 3.9 and 4.2 of 7, respectively. The mean ranking of subscales from the highest to lowest was abdominal symptoms, fatigue, fluid retention, loss of appetite, systemic symptoms, decreased attention, and bleeding. Symptoms and distress were significantly correlated (r = .59). The total scores of symptoms and distress were not associated with causes of the disease (p = .7644, p = .8548, respectively), disease severity (p = .7203, p = .3354, respectively), disease duration (p = .5820, p = .8184, respectively), or previous admission (p = .3094, p = .7365, respectively), but decreased attention was significantly associated with disease severity (p = .0317) and systemic symptoms were significantly associated with disease duration (p = .0267). The study found that physical symptoms and psychological distress are multidimensional and highly correlated. Our findings can be used to develop a symptom management program to relieve discomfort and indirectly improve the quality of life for individuals with LC. PMID- 24476835 TI - Dietary practices of Chinese patients with inflammatory bowel disease: a naturalistic inquiry. AB - Dietary factors have been linked to the development and symptoms of inflammatory bowel disease. However, little is known about the dietary practices of these patients after being diagnosed and what factors shape those practices. This article reports the findings of a naturalistic inquiry that explored the experience of dietary practices of Chinese patients with inflammatory bowel diseases. Purposive sampling was used and in-depth interviews were conducted with 17 patients with inflammatory bowel disease. Analysis of the transcribed data is presented thematically. Five themes were derived: (a) seeking dietary information, (b) testing out, (c) modifying diet, (d) barriers to diet modification, and (e) fear and stress. Understanding the dietary practice of patients with inflammatory bowel disease from the perspective of those diagnosed is a first step in attempting to assist them with diet management. Healthcare professionals should encourage patients to report diet modification and be aware of both personal and environmental barriers of diet modification. PMID- 24476836 TI - Mesalamine-induced nephrotoxicity in the treatment of Crohn disease: a case study. PMID- 24476837 TI - Inpatient care of hepatitis C patients on telaprevir treatment. PMID- 24476838 TI - Endoscopic treatment of internal concealment of illegal drugs. PMID- 24476839 TI - Whole-brain gray matter volume abnormalities in patients with generalized anxiety disorder: voxel-based morphometry. AB - Patients with generalized anxiety disorder (GAD) experience psychological distress because of excessive and uncontrollable anxiety in everyday life. Only a few morphological studies have so far focused on specific brain regions of interest as well as the gray matter volume changes in GAD patients. This study evaluated gray matter volume alterations in whole-brain areas between GAD patients and healthy controls, and sex differences between the specific brain areas with significant volume changes in GAD patients using voxel-based morphometry. Twenty-two patients with GAD (13 men and nine women), who were diagnosed using the DSM-IV-TR, and 22 age-matched healthy controls (13 men and nine women) participated in this study. The high-resolution MRI data were processed using voxel-based morphometry analysis on the basis of diffeomorphic anatomical registration through an exponentiated Lie algebra algorithm in Statistical Parametric Mapping 8. There was no significant difference in the total intracranial volume between GAD patients and controls, but a significant difference was observed between sexes (P<0.05). Patients with GAD showed significant volume reductions in the hippocampus, midbrain, thalamus, insula, and superior temporal gyrus compared with the controls. As for the sex comparison, female patients showed a significant increase in the volume of the dorsolateral prefrontal cortex relative to male patients. Also, the volume of the dorsolateral prefrontal cortex in female patients was correlated positively with the Hamilton Anxiety Rating Scale score (gamma=0.68, P=0.04). The specific morphological variations in patient with GAD will be helpful to understand the neural mechanism associated with a symptom of GAD. Furthermore, the findings would be valuable for the diagnostic accuracy of GAD using morphometric MRI analysis. PMID- 24476840 TI - Racial/ethnic and sociodemographic factors associated with micronutrient intakes and inadequacies among pregnant women in an urban US population. AB - OBJECTIVE: To assess sociodemographic correlates of micronutrient intakes from food and dietary supplements in an urban, ethnically diverse sample of pregnant women in the USA. DESIGN: Cross-sectional analyses of data collected using a validated semi-quantitative FFQ. Associations between racial, ethnic and sociodemographic factors and micronutrient intakes were examined using logistic regression controlling for pre-pregnancy BMI, maternal age and smoking status. SETTING: Prenatal clinics, Boston, MA, USA. SUBJECTS: Analyses included pregnant women (n 274) in the PRogramming of Intergenerational Stress Mechanisms (PRISM) study, an urban longitudinal cohort designed to examine how stress influences respiratory health in children when controlling for other environmental exposures (chemical stressors, nutrition). RESULTS: High frequencies of vitamin E (52 %), Mg (38 %), Fe (57 %) and vitamin D (77 %) inadequacies as well as suboptimal intakes of choline (95 %) and K (99 %) were observed. Factors associated with multiple antioxidant inadequacies included being Hispanic or African American, lower education and self-reported economic-related food insecurity. Hispanics had a higher prevalence of multiple methyl-nutrient inadequacies compared with African Americans; both had suboptimal betaine intakes and higher odds for vitamin B6 and Fe inadequacies compared with Caucasians. Nearly all women (98 %) reported Na intakes above the tolerable upper limit; excessive intakes of Mg (35 %), folate (37 %) and niacin (38 %) were also observed. Women reporting excessive intakes of these nutrients were more likely Caucasian or Hispanic, more highly educated, US-born and did not report food insecurity. CONCLUSIONS: Racial/ethnic and other sociodemographic factors should be considered when tailoring periconceptional dietary interventions for urban ethnic women in the USA. PMID- 24476842 TI - Higher level at admission and subsequent decline in hemoglobin in patients with acute pulmonary edema. AB - BACKGROUND: Acute pulmonary edema (APE) often occurs without remarkable fluid retention, and the benefits of diuretics are unclear in such patients. Although aggressive diuresis induces an increase in intravascular substances including hemoglobin (Hb), acute changes in Hb level remain to be investigated. METHODS AND RESULTS: We analyzed 237 consecutive acute heart failure patients (74+/-12 years; 60.8% men) without shock, hemodialysis, bleeding, or urgent coronary angiography. APE was defined as acute onset of dyspnea within the preceding 6h and radiographic alveolar edema requiring immediate airway intervention. At admission, Hb level was higher in APE (n=29) than non-APE patients (n=208; 13.4+/ 2.2 vs 12.2+/-2.1g/dl, P<0.01). Although diuretic therapy was performed in 232 patients (97.9%), hemoconcentration (ie, any increase in Hb) was observed in only 64 patients (27.0%) at 24h after admission. Conversely, Hb level decreased in both groups and the difference was larger in APE patients (-1.8+/-1.1 in APE and 0.5+/-1.0g/dl in non-APE patients, P<0.001). APE was significantly related to a greater decrease in Hb after adjusting for baseline Hb (beta=-1.08g/dl, SE=0.20, P<0.001, ANCOVA). CONCLUSIONS: APE patients had higher Hb level at admission and a more remarkable decline in 24h than did those without APE. Acute change in Hb might be caused by factors other than diuresis-induced hemoconcentration. The present findings may be useful in the selection of diuretic strategies. PMID- 24476841 TI - The role of ryanodine receptor type 3 in a mouse model of Alzheimer disease. AB - Dysregulated endoplasmic reticulum (ER) calcium (Ca(2+)) signaling is reported to play an important role in Alzheimer disease (AD) pathogenesis. The role of ER Ca(2+) release channels, the ryanodine receptors (RyanRs), has been extensivelys tudied in AD models and RyanR expression and activity are upregulated in the brains of various familial AD (FAD) models.The objective of this study was to utilize a genetic approach to evaluate the importance of RyanR type 3 (RyanR3) in the context of AD pathology.The expression of RyanR3 was also elevated in hippocampus of APPPS1 mice (Thy1-APPKM670/671NL, Thy1-PS1L166P).In young (<= 3 mo) APPPS1 mice, the deletion of RyanR3 increased hippocampal neuronal network excitability and accelerated AD pathology, leading to mushroom spine loss and increased amyloid accumulation. In contrast, deletion of RyanR3 in older APPPS1 mice (>= 6 mo) rescued network excitability and mushroom spine loss, reduced amyloid plaque load and reduced spontaneous seizure occurrence.Our data suggests a dual role for RyanR3 in AD pathology. In young AD neurons, RyanR3 protects AD neurons from synaptic and network dysfunction. In older AD neurons, increased RyanR3 activity contributes to pathology. These results imply that blockade of RyanR3 may be beneficial for those in the later stages of the disease, but RyanR activators may be beneficial when used prior to disease onset or in its initial stages. Caffeine is an activator of RyanRs and our results may help to explain a complex epidemiological connection between coffee consumption in mid-life and risk of AD development in old age. PMID- 24476843 TI - Estimation of right atrial pressure on inferior vena cava ultrasound in Asian patients. AB - BACKGROUND: Right atrial pressure (RAP) is commonly estimated using inferior vena cava (IVC) diameter and its respirophasic variations. Although a guideline has been provided for estimation of RAP due to variation in IVC dimensions based on studies in Western subjects, echocardiographic values in Asian subjects are unknown. METHODS AND RESULTS: We studied 369 patients who underwent IVC ultrasound within 24h of right heart catheterization (RHC). The maximum and minimum IVC diameter during a respiratory cycle and the percent collapse after a sniff test were measured. These IVC parameters were compared with mean RAP measured on RHC. Receiver operating characteristic curves were generated for each IVC parameter to determine the optimal cut-off to detect RAP >10mmHg. The IVC maximum diameter cut-off for detecting RAP >10mmHg was 19mm (sensitivity, 75%; specificity, 78%) and the percent collapse cut-off was 30% (sensitivity, 75%; specificity, 83%). Both cut-offs were smaller than those previously reported in patients from Western countries. When the cut-off values from the existing guideline were applied to the present cohort, the sensitivity and specificity for normal RAP (0-5mmHg) were 38.6% and 74.2%, respectively, and 60.0% and 92.0% for elevated RAP (>10mmHg). CONCLUSIONS: The optimal IVC maximum diameter and percent collapse cut-offs to detect elevated RAP were smaller in Asian subjects than in a previously reported Western cohort. PMID- 24476844 TI - Population-based study provides a step towards evidence-based management of thyroid nodules detected on ultrasound. PMID- 24476845 TI - Use of the parenteral antibiotic Ertapenem as short term prophylaxis in bariatric surgery: a pharmaco-kinetic-pharmacodynamic study in class III obese female patients. AB - BACKGROUND: The objective of this study was to determine the pharmacokinetics pharmacodynamics (PK/PD) of Ertapenem in extremely obese female patients (Body Mass Index [BMI] >= 40 kg/m2) undergoing bariatric surgery. METHODS: Ten patients received 1 g intravenous Ertapenem 0.5 h prior to surgery as short term prophylaxis. Serum Ertapenem concentrations were determined at baseline, at the end of infusion (30 minutes), then at 1, 2, 4, 8, 12 and 24 hours postinfusion. In patients in whom a liver biopsy was necessitated by clinical need, Ertapenem liver concentrations were determined through intraoperative biopsies at 1 and 2 h postadministration. Peritoneal Ertapenem concentrations were determined in drainage fluid samples collected during the 4-8, 8-12, and 12-24 h intervals after Ertapenem administration. A Monte Carlo simulation was performed to estimate the probability of achieving free drug levels above the minimum inhibitory concentration (fT>MIC) for at least 20% and 40% of the dosing interval as PK/PD targets. RESULTS: Peak drug concentration and 24-h area under the concentration-time curve (AUC) were found to be 191.9 +/- 37.4 mg/L and 574.3 +/- 110.5 mg.h/L, respectively. Ertapenem liver/serum concentration ratios were 6% at 1 h and 5% at 2 h. Drug concentrations in peritoneal fluid were 28.2 +/- 6.4 mg/L at 4-8h, declined to 15.2 +/- 5.9 at 8-12h and fell further to 4.79 +/- 0.2 mg/L at 12-24 h post-administration. The probability to reach the desired PK/PD targets were never reached at any MICs >0.25 ug/mL with a 90% probability. CONCLUSION: Our data suggest that in extremely obese female patients, the standard dose of 1 g i.v. Ertapenem as short term prophylaxis may not provide optimal clinical levels of free drug for prevention of surgical site infections. PMID- 24476846 TI - Neurally adjusted ventilatory assist and Guillain-Barre syndrome in a child. PMID- 24476847 TI - Atomistic insight into viscosity and density of silicate melts under pressure. AB - A defining characteristic of silicate melts is the degree of polymerization (tetrahedral connectivity), which dictates viscosity and affects compressibility. While viscosity of depolymerized silicate melts increases with pressure consistent with the free-volume theory, isothermal viscosity of polymerized melts decreases with pressure up to ~3-5 GPa, above which it turns over to normal (positive) pressure dependence. Here we show that the viscosity turnover in polymerized liquids corresponds to the tetrahedral packing limit, below which the structure is compressed through tightening of the inter-tetrahedral bond angle, resulting in high compressibility, continual breakup of tetrahedral connectivity and viscosity decrease with increasing pressure. Above the turnover pressure, silicon and aluminium coordination increases to allow further packing, with increasing viscosity and density. These structural responses prescribe the distribution of melt viscosity and density with depth and play an important role in magma transport in terrestrial planetary interiors. PMID- 24476848 TI - Accuracy of food portion size estimation from digital pictures acquired by a chest-worn camera. AB - OBJECTIVE: Accurate estimation of food portion size is of paramount importance in dietary studies. We have developed a small, chest-worn electronic device called eButton which automatically takes pictures of consumed foods for objective dietary assessment. From the acquired pictures, the food portion size can be calculated semi-automatically with the help of computer software. The aim of the present study is to evaluate the accuracy of the calculated food portion size (volumes) from eButton pictures. DESIGN: Participants wore an eButton during their lunch. The volume of food in each eButton picture was calculated using software. For comparison, three raters estimated the food volume by viewing the same picture. The actual volume was determined by physical measurement using seed displacement. SETTING: Dining room and offices in a research laboratory. SUBJECTS: Seven lab member volunteers. RESULTS: Images of 100 food samples (fifty Western and fifty Asian foods) were collected and each food volume was estimated from these images using software. The mean relative error between the estimated volume and the actual volume over all the samples was -2.8 % (95 % CI -6.8 %, 1.2 %) with sd of 20.4 %. For eighty-five samples, the food volumes determined by computer differed by no more than 30 % from the results of actual physical measurements. When the volume estimates by the computer and raters were compared, the computer estimates showed much less bias and variability. CONCLUSIONS: From the same eButton pictures, the computer-based method provides more objective and accurate estimates of food volume than the visual estimation method. PMID- 24476849 TI - Serial changes of CD4+CD25+FoxP3+ regulatory T cell in canine model of sepsis induced by endotoxin. AB - Regulatory T cells (Tregs) suppress the immune system and maintain the homeostasis of the immune system in healthy dogs. In septic patients, the percentage of circulating Tregs is increasing, which may cause the sepsis-induced immunosuppression. This study was performed to investigate the changes of the percentage of Tregs in total lymphocytes of the peripheral blood in the experimental canine endotoxemia model. The animals injected with a high dose lipopolysaccharide (LPS) induced severe leukopenia followed by leukocytosis, but the total lymphocytes number was relatively consistent. As a result of flow cytometric analysis, the percentage of Tregs in total lymphocytes of the peripheral blood was 8.45 +/- 1.30% (day 0), and it temporarily decreased 2.54 +/ 1.16% (day 1) and increased continuously until the end of the experiment (14.34 +/- 4.10% on day 3 and 25.70 +/- 7.39% on day 7), respectively. This study provides basic information in physiologic and immunologic changes in Tregs in dogs with sepsis model. PMID- 24476850 TI - Antimicrobial susceptibility of indicator bacteria isolated from chickens in Southeast Asian countries (Vietnam, Indonesia and Thailand). AB - To determine the prevalence of indicator bacteria resistant to antimicrobials among poultry in three Southeast Asian countries (Vietnam, Indonesia and Thailand), we examined the antimicrobial susceptibilities of commensal bacteria isolated from chickens. In total, 125, 117 and 180 isolates of Escherichia coli, Enterococcus faecalis and Enterococcus faecium, respectively, were used to test for antimicrobial susceptibility. Bacterial resistance to antimicrobial treatment was most frequently observed with oxytetracycline with a prevalence of 73.6% (E. coli), 69.2% (E. faecalis) and 92.2% (E. faecium). Resistance to fluoroquinolones, which are critically important medicines, was also frequently observed in E. coli (48.8%), E. faecalis (17.9%) and E. faecium (82.8%). The prevalence of indicator bacteria resistant to most of the antimicrobials tested in these countries was higher than those for developed countries. The factors underlying antimicrobial resistance may include inappropriate and/or excessive use of antimicrobials. These results highlight the need for monitoring the emergence and prevalence of antimicrobial resistance in developing countries. PMID- 24476851 TI - Studies on morphology and cytochemistry in blood cells of ayu Plecoglossus altivelis altivelis. AB - Peripheral blood cells from ayu, Plecoglossus altivelis altivelis, were separated using a density gradient. Blood cells were then smeared using Shandon Cytospin and subjected to cytochemical staining. Blood cells were categorized based on morphological and cytochemical characteristics, and the density fractionation range and nucleus area/cell area ratio were observed. Lymphocytes are distinguished from neutrophils by their basophilic cytoplasm and Golgi-like field. The features of chromatin in thrombocytes are different from those of lymphocytes or neutrophils, but some small neutrophils have similar chromatin. Therefore, it is necessary to perform peroxidase staining to distinguish small neutrophils from thrombocytes. Basophils have large basophilic granules in cytoplasm. Based on density fractionation of blood cells, thrombocytes in the low density area were separated from other blood cells. Identification of peripheral blood cells from ayu was possible with these staining methods. Monocytes/macrophages from spleen are specifically positive for esterase staining by alpha-naphthyl butyrate. As a result, thrombocytes, lymphocytes, neutrophils, basophils and monocytes/macrophages were identified in smears from peripheral blood or spleen tissue. In this paper, we confirmed that the peripheral blood corpuscles of ayu are able to be identified using the present staining methods. PMID- 24476852 TI - Quiet green revolution starts to make some noise. PMID- 24476864 TI - Whistle-blower breaks his silence. PMID- 24476865 TI - US struggles to offload telescopes. PMID- 24476867 TI - EU climate targets under fire. PMID- 24476866 TI - Acid bath offers easy path to stem cells. PMID- 24476868 TI - Synthetic-biology firms shift focus. PMID- 24476869 TI - Ukrainian scientists in forefront of protest. PMID- 24476870 TI - Molecular structures: The crystal century. PMID- 24476871 TI - Crystallography: Atomic secrets. PMID- 24476872 TI - X-ray science: The big guns. PMID- 24476877 TI - Gender: resolve bias, don't excuse it. PMID- 24476878 TI - Gender: why publish an offensive letter? PMID- 24476879 TI - Laboratory equipment: Cut costs with open-source hardware. PMID- 24476880 TI - Earth science: Plume hypothesis challenged. PMID- 24476881 TI - Crystallography: Sources of inspiration. PMID- 24476882 TI - Molecular biology: A second layer of information in RNA. PMID- 24476883 TI - Cell biology: Potency unchained. PMID- 24476884 TI - Astrophysics: Portrait of a dynamic neighbour. PMID- 24476885 TI - Atomic physics: Polar exploration. PMID- 24476886 TI - Solar System evolution from compositional mapping of the asteroid belt. AB - Advances in the discovery and characterization of asteroids over the past decade have revealed an unanticipated underlying structure that points to a dramatic early history of the inner Solar System. The asteroids in the main asteroid belt have been discovered to be more compositionally diverse with size and distance from the Sun than had previously been known. This implies substantial mixing through processes such as planetary migration and the subsequent dynamical processes. PMID- 24476887 TI - Stimulus-triggered fate conversion of somatic cells into pluripotency. AB - Here we report a unique cellular reprogramming phenomenon, called stimulus triggered acquisition of pluripotency (STAP), which requires neither nuclear transfer nor the introduction of transcription factors. In STAP, strong external stimuli such as a transient low-pH stressor reprogrammed mammalian somatic cells, resulting in the generation of pluripotent cells. Through real-time imaging of STAP cells derived from purified lymphocytes, as well as gene rearrangement analysis, we found that committed somatic cells give rise to STAP cells by reprogramming rather than selection. STAP cells showed a substantial decrease in DNA methylation in the regulatory regions of pluripotency marker genes. Blastocyst injection showed that STAP cells efficiently contribute to chimaeric embryos and to offspring via germline transmission. We also demonstrate the derivation of robustly expandable pluripotent cell lines from STAP cells. Thus, our findings indicate that epigenetic fate determination of mammalian cells can be markedly converted in a context-dependent manner by strong environmental cues. PMID- 24476888 TI - A global cloud map of the nearest known brown dwarf. AB - Brown dwarfs--substellar bodies more massive than planets but not massive enough to initiate the sustained hydrogen fusion that powers self-luminous stars--are born hot and slowly cool as they age. As they cool below about 2,300 kelvin, liquid or crystalline particles composed of calcium aluminates, silicates and iron condense into atmospheric 'dust', which disappears at still cooler temperatures (around 1,300 kelvin). Models to explain this dust dispersal include both an abrupt sinking of the entire cloud deck into the deep, unobservable atmosphere and breakup of the cloud into scattered patches (as seen on Jupiter and Saturn). However, hitherto observations of brown dwarfs have been limited to globally integrated measurements, which can reveal surface inhomogeneities but cannot unambiguously resolve surface features. Here we report a two-dimensional map of a brown dwarf's surface that allows identification of large-scale bright and dark features, indicative of patchy clouds. Monitoring suggests that the characteristic timescale for the evolution of global weather patterns is approximately one day. PMID- 24476889 TI - Observation of Dirac monopoles in a synthetic magnetic field. AB - Magnetic monopoles--particles that behave as isolated north or south magnetic poles--have been the subject of speculation since the first detailed observations of magnetism several hundred years ago. Numerous theoretical investigations and hitherto unsuccessful experimental searches have followed Dirac's 1931 development of a theory of monopoles consistent with both quantum mechanics and the gauge invariance of the electromagnetic field. The existence of even a single Dirac magnetic monopole would have far-reaching physical consequences, most famously explaining the quantization of electric charge. Although analogues of magnetic monopoles have been found in exotic spin ices and other systems, there has been no direct experimental observation of Dirac monopoles within a medium described by a quantum field, such as superfluid helium-3 (refs 10-13). Here we demonstrate the controlled creation of Dirac monopoles in the synthetic magnetic field produced by a spinor Bose-Einstein condensate. Monopoles are identified, in both experiments and matching numerical simulations, at the termini of vortex lines within the condensate. By directly imaging such a vortex line, the presence of a monopole may be discerned from the experimental data alone. These real-space images provide conclusive and long-awaited experimental evidence of the existence of Dirac monopoles. Our result provides an unprecedented opportunity to observe and manipulate these quantum mechanical entities in a controlled environment. PMID- 24476890 TI - Australian tropical cyclone activity lower than at any time over the past 550 1,500 years. AB - The assessment of changes in tropical cyclone activity within the context of anthropogenically influenced climate change has been limited by the short temporal resolution of the instrumental tropical cyclone record (less than 50 years). Furthermore, controversy exists regarding the robustness of the observational record, especially before 1990. Here we show, on the basis of a new tropical cyclone activity index (CAI), that the present low levels of storm activity on the mid west and northeast coasts of Australia are unprecedented over the past 550 to 1,500 years. The CAI allows for a direct comparison between the modern instrumental record and long-term palaeotempest (prehistoric tropical cyclone) records derived from the (18)O/(16)O ratio of seasonally accreting carbonate layers of actively growing stalagmites. Our results reveal a repeated multicentennial cycle of tropical cyclone activity, the most recent of which commenced around AD 1700. The present cycle includes a sharp decrease in activity after 1960 in Western Australia. This is in contrast to the increasing frequency and destructiveness of Northern Hemisphere tropical cyclones since 1970 in the Atlantic Ocean and the western North Pacific Ocean. Other studies project a decrease in the frequency of tropical cyclones towards the end of the twenty first century in the southwest Pacific, southern Indian and Australian regions. Our results, although based on a limited record, suggest that this may be occurring much earlier than expected. PMID- 24476891 TI - Bidirectional developmental potential in reprogrammed cells with acquired pluripotency. AB - We recently discovered an unexpected phenomenon of somatic cell reprogramming into pluripotent cells by exposure to sublethal stimuli, which we call stimulus triggered acquisition of pluripotency (STAP). This reprogramming does not require nuclear transfer or genetic manipulation. Here we report that reprogrammed STAP cells, unlike embryonic stem (ES) cells, can contribute to both embryonic and placental tissues, as seen in a blastocyst injection assay. Mouse STAP cells lose the ability to contribute to the placenta as well as trophoblast marker expression on converting into ES-like stem cells by treatment with adrenocorticotropic hormone (ACTH) and leukaemia inhibitory factor (LIF). In contrast, when cultured with Fgf4, STAP cells give rise to proliferative stem cells with enhanced trophoblastic characteristics. Notably, unlike conventional trophoblast stem cells, the Fgf4-induced stem cells from STAP cells contribute to both embryonic and placental tissues in vivo and transform into ES-like cells when cultured with LIF-containing medium. Taken together, the developmental potential of STAP cells, shown by chimaera formation and in vitro cell conversion, indicates that they represent a unique state of pluripotency. PMID- 24476892 TI - Landscape and variation of RNA secondary structure across the human transcriptome. AB - In parallel to the genetic code for protein synthesis, a second layer of information is embedded in all RNA transcripts in the form of RNA structure. RNA structure influences practically every step in the gene expression program. However, the nature of most RNA structures or effects of sequence variation on structure are not known. Here we report the initial landscape and variation of RNA secondary structures (RSSs) in a human family trio (mother, father and their child). This provides a comprehensive RSS map of human coding and non-coding RNAs. We identify unique RSS signatures that demarcate open reading frames and splicing junctions, and define authentic microRNA-binding sites. Comparison of native deproteinized RNA isolated from cells versus refolded purified RNA suggests that the majority of the RSS information is encoded within RNA sequence. Over 1,900 transcribed single nucleotide variants (approximately 15% of all transcribed single nucleotide variants) alter local RNA structure. We discover simple sequence and spacing rules that determine the ability of point mutations to impact RSSs. Selective depletion of 'riboSNitches' versus structurally synonymous variants at precise locations suggests selection for specific RNA shapes at thousands of sites, including 3' untranslated regions, binding sites of microRNAs and RNA-binding proteins genome-wide. These results highlight the potentially broad contribution of RNA structure and its variation to gene regulation. PMID- 24476895 TI - Serous ovarian cancer signaling pathways. AB - Ovarian cancer is the most lethal malignancy of the female genital tract, mainly due to the failure of early diagnosis and the limitations posed by the conventional chemotherapies. Current research has focused in the study of cascades of various cellular molecular reactions, known as signaling pathways. In this review article, authors try to describe the current knowledge regarding the signaling pathways that influence multiple cellular processes in serous ovarian cancer and especially the pathogenesis. Thorough understanding of the precise role of these pathways can lead to the development of new and more effective targeted therapies as well as novel biomarkers in ovarian cancer. PMID- 24476894 TI - ARHI overexpression induces epithelial ovarian cancer cell apoptosis and excessive autophagy. AB - OBJECTIVE: ARHI is a maternally imprinted tumor suppressor gene that is responsible for initiating programmed cell death and inhibiting cancer cell growth. However, the influence of ARHI on epithelial ovarian cancer cell death and the underlying mechanisms behind how ARHI regulates cancer cells still require further studies. METHODS: Epithelial ovarian cancer cells TOV112D and ES 2 were used in this in vitro study. Cell proliferation, apoptosis, and autophagy activities were compared in TOV112D and ES-2 cells transfected with ARHI vectors or control vectors. Bcl-2 siRNA was transfected into TOV112D cells to investigate the roles of Bcl-2 played in regulating apoptosis and autophagy. RESULTS: ARHI expression was reduced in TOV112D and ES-2 cells compared with normal epithelial ovarian cells (NOE095 and HOSEpiC). Overexpressed ARHI inhibited cancer cell proliferation, whereas induced forced cell apoptosis and excessive formation of autophagosomes inhibited promoted cell death. Furthermore, we found that Bcl-2 expression moderately declined in response to ARHI overexpressing in ES-2 and TOV112D cells; meanwhile, more apoptotic cells and higher LC3 level presented after silence of Bcl-2 in TOV112D cells. Reduced Bcl-2-Beclin 1 complex were observed in ARHI overexpressing cells. Moreover, modulation of ARHI to Bcl-2 expression could be ascribed partially to the activation of PI3k/AKT pathway. The addition of LY294002 enabled to suppress Bcl-2 expression and cell proliferation. CONCLUSIONS: The silence of ARHI expression in vitro seems to accelerate the malignant transformation of healthy ovarian cells by restraining apoptosis and autophagy. The overexpressed ARHI in TOV112D cancer cells suppresses the activation of PI3K/AKT and reduces the expression of Bcl-2, leading to enhanced cell apoptosis and autophagic cancer cell death. PMID- 24476896 TI - Does positive peritoneal cytology not affect the prognosis for stage I uterine endometrial cancer?: the remaining controversy and review of the literature. AB - OBJECTIVE: The objective of this study was to elucidate factors that affect prognosis in patients with stage I endometrial cancer. METHODS: The study group comprised 265 patients with stage I endometrial cancer treated surgically at either of our facilities between January 1998 and December 2010 (238 patients with negative peritoneal cytology and 27 patients with positive peritoneal cytology). Progression-free survivals were evaluated between the 2 groups, and multivariate analysis was conducted with correlation factors including positive peritoneal cytology, vessel permeation, lymph node dissection, histologic diagnosis, age at diagnosis, adjuvant chemotherapy, and the depth of myometrial invasion. RESULTS: Disease-free survival was significantly poorer for patients with positive peritoneal cytology than those with negative peritoneal cytology on stage I disease (P = 0.000). The stratified log-rank test with vessel permeation shows the similar results. By univariate Cox model, positive peritoneal cytology, vessel permeation, and systemic lymph node dissection at surgery are significant factors on stage I endometrial cancer. CONCLUSIONS: Although this is a small scale preliminary study with adjustment of other factors, positive peritoneal cytology can contribute to the risk of progression-free survival in patients with stage I endometrial cancer. PMID- 24476897 TI - Why routine clinical follow-up for patients with early stage endometrial cancer is not always necessary: a study on women in South Wales. AB - OBJECTIVE: This study aimed to examine the existing methods of follow-up in women who have undergone treatment of early endometrial carcinoma in South Wales and to assess if they are appropriate. DESIGN: This study used a retrospective analysis of follow-up data. SETTING: This study was performed in the Virtual Gynaecological Oncology Centre, South Wales, United Kingdom. SAMPLE: This study sample is composed of 552 women. METHODS: Data regarding follow-up were collected retrospectively from patient case notes and computerized data systems. Data were analyzed using the Pearson chi test, Cox proportional hazard regression analysis, and Kaplan-Meier curves. MAIN OUTCOME MEASURES: This study aimed to determine whether routine follow-up was beneficial in detecting disease recurrence and whether outcome was influenced by routine follow-up. RESULTS: Between January 1, 2000, and December 31, 2010, 552 women were treated for early stage endometrial carcinoma. The 5-year survival was 81%, and the 5-year progression-free survival was 77%. Of these 552 women, 81 (15%) developed a disease recurrence; the majority (61/81 [75%]) recurred within 3 years. The median survival was 35 months compared with 47 months in patients who did not develop a recurrence. Of the 81 patients, 73 (90%) were symptomatic and only 5 patients were truly asymptomatic at follow-up. The most important and significant prognostic factor was "recurrent disease" with overall survival (hazard ratio, 2.20; P < 0.001; 95% confidence interval, 1.75-2.65) and progression-free survival (hazard ratio, 2.52; P < 0.001; 95% confidence interval, 2.09-2.95). "Asymptomatic recurrence" was not an independent predictor of outcome. CONCLUSIONS: Routine follow-up for early endometrial cancer is not beneficial for patients because most were symptomatic at the time of detection. It does not significantly improve the outcome. We propose altering the follow-up time regimen and adopting alternative follow-up strategies for women in South Wales. PMID- 24476899 TI - Optimising the selection of food items for FFQs using Mixed Integer Linear Programming. AB - OBJECTIVE: To support the selection of food items for FFQs in such a way that the amount of information on all relevant nutrients is maximised while the food list is as short as possible. DESIGN: Selection of the most informative food items to be included in FFQs was modelled as a Mixed Integer Linear Programming (MILP) model. The methodology was demonstrated for an FFQ with interest in energy, total protein, total fat, saturated fat, monounsaturated fat, polyunsaturated fat, total carbohydrates, mono- and disaccharides, dietary fibre and potassium. RESULTS: The food lists generated by the MILP model have good performance in terms of length, coverage and R 2 (explained variance) of all nutrients. MILP generated food lists were 32-40 % shorter than a benchmark food list, whereas their quality in terms of R 2 was similar to that of the benchmark. CONCLUSIONS: The results suggest that the MILP model makes the selection process faster, more standardised and transparent, and is especially helpful in coping with multiple nutrients. The complexity of the method does not increase with increasing number of nutrients. The generated food lists appear either shorter or provide more information than a food list generated without the MILP model. PMID- 24476898 TI - Strategies to improve the dietary quality of Supplemental Nutrition Assistance Program (SNAP) beneficiaries: an assessment of stakeholder opinions. AB - OBJECTIVE: To examine the opinions of stakeholders on strategies to improve dietary quality of Supplemental Nutrition Assistance Program (SNAP) participants. DESIGN: Participants answered a thirty-eight-item web-based survey assessing opinions and perceptions of SNAP and programme policy changes. SETTING USA SUBJECTS: Survey of 522 individuals with stakeholder interest in SNAP, conducted in October through December 2011. RESULTS: The top three barriers to improving dietary quality identified were: (i) unhealthy foods marketed in low-income communities; (ii) the high cost of healthy foods; and (iii) lifestyle challenges faced by low-income individuals. Many respondents (70 %) also disagreed that current SNAP benefit levels were adequate to maintain a healthy diet. Stakeholders believed that vouchers, coupons or monetary incentives for purchasing healthful foods might have the greatest potential for improving the diets of SNAP participants. Many respondents (78 %) agreed that sodas should not be eligible for purchases with SNAP benefits. More than half (55 %) believed retailers could easily implement such restrictions. A majority of respondents (58 %) agreed that stores should stock a minimum quantity of healthful foods in order to be certified as a SNAP retailer, and most respondents (83 %) believed that the US Department of Agriculture should collect data on the foods purchased with SNAP benefits. CONCLUSIONS: Results suggest that there is broad stakeholder support for policies that align SNAP purchase eligibility with national public health goals of reducing food insecurity, improving nutrition and preventing obesity. PMID- 24476900 TI - Conventional PCR for molecular diagnosis of human strongyloidiasis. AB - Strongyloidiasis is frequently asymptomatic and diagnosis of latent infection is difficult due to limitations of current parasitological and serological methods. This study aimed to verify the use of conventional polymerase chain reaction (PCR) assay for molecular diagnosis of Strongyloides stercoralis infection. Fresh stool samples were obtained from 103 individuals: 33 S. stercoralis positive, 30 positive for other parasites and 40 negative for parasitological methods. These samples were examined by the Lutz, Rugai and agar plate culture methods and conventional PCR assay. Two sets of primers (S. stercoralis species-specific and genus-specific sets), located in the 18S ribosomal RNA gene, were used for PCR. Of the 33 samples positive for S. stercoralis by parasitological methods, 28 (84.8%) were also detected by PCR assay using species-specific primers and 26 (78.8%) using genus-specific primers. Among the stool samples negative by parasitological methods, seven (17.5%) were positive by PCR using species specific primers and two (5.0%) using genus-specific primers. In conclusion, the conventional PCR assay described in this study using a species-specific primer pair provided a molecular method for S. stercoralis diagnosis in human stool samples. PMID- 24476903 TI - Enhancement of the subtemporal approach by partial posterosuperior petrosectomy with hearing preservation. AB - BACKGROUND: The microsurgical management of aneurysms in the interpeduncular and ambient cisterns remains challenging. The classic subtemporal approach has several limitations. OBJECTIVE: To present a modification of this approach that allows for broader exposure with hearing preservation. METHODS: We retrospectively reviewed our clinical database between August 2007 and February 2012 for all patients who underwent a modified subtemporal partial posterosuperior petrosectomy. Clinical data, complications, and postoperative head computed tomography (CT) scans were analyzed. Improvement in the angle of view acquired by the new approach was measured using the OsiriX 3-D rendering software and was compared with that obtained from the subtemporal approach. Similar methods were used to study improvement in the angle of view in head CT scans of randomly selected control patients. RESULTS: Five patients underwent a modified subtemporal approach for posterior circulation aneurysm clipping. All patients were women with a mean age of 49.8 years. Mean aneurysm size was 5.75 mm. Mean improvement in the angle of view was 17.52 degrees in the study group (n = 5) and 11.7 degrees in the control group (n = 10). Hearing was completely preserved in 3 patients. One patient had a subclinical conductive hearing loss, and 1 patient was not assessed formally at follow-up, but had no hearing concerns. No neurological sequelae were recorded. CONCLUSION: Our modified subtemporal approach appears to be safe and provides an increased angle of view with minimal additional operative time and with low risk to hearing. This approach may expand this surgical corridor and reduce the need for temporal lobe retraction. PMID- 24476902 TI - RGK protein-mediated impairment of slow depolarization- dependent Ca2+ entry into developing myotubes. AB - Three physiological functions have been described for the skeletal muscle 1,4 dihydropyridine receptor (Ca(V)1.1):(1) voltage-sensor for excitation-contraction (EC) coupling, (2) L-type Ca(2+) channel, and (3) voltage-sensor for slow depolarization-dependent Ca(2+) entry. Members of the RGK (Rad, Rem, Rem2, Gem/Kir) family of monomeric GTP-binding proteins are potent inhibitors of the former two functions of Ca(V)1.1. However, it is not known whether the latter function that has been attributed to Ca(V)1.1 is subject to modulation by RGK proteins. Thus, the purpose of this study was to determine whether Rad, Gem and/or Rem inhibit the slowly developing, persistent Ca(2+) entry that is dependent on the voltage-sensing capability of Ca(V)1.1. As a means to investigate this question, Venus fluorescent protein-fused RGK proteins(V-Rad, V Rem and V-Gem) were overexpressed in "normal" mouse myotubes. We observed that such overexpression of V-Rad, V-Rem or V-Gem in myotubes caused marked changes in morphology of the cells. As shown previously for YFPRem,both L-type current and EC coupling were also impaired greatly in myotubes expressing either V-Rad or V Gem. There ductions in L-type current and EC coupling were paralleled by reductions in depolarization-induced Ca(2+) entry. Our observations provide the first evidence of modulation of this enigmatic Ca(2+) entry pathway peculiar to skeletal muscle. PMID- 24476904 TI - Significance of cochlear dose in the radiosurgical treatment of vestibular schwannoma: controversies and unanswered questions. AB - BACKGROUND: Cochlear dose has been identified as a potentially modifiable contributor to hearing loss after stereotactic radiosurgery (SRS) for vestibular schwannoma (VS). OBJECTIVE: To evaluate the association between computed tomography-based volumetric cochlear dose and loss of serviceable hearing after SRS, to assess intraobserver and interobserver reliability when determining modiolar point dose with the use of magnetic resonance imaging and computed tomography, and to discuss the clinical significance of the cochlear dose with regard to radiosurgical planning strategy. METHODS: Patients with serviceable pretreatment hearing who underwent SRS for sporadic VS between the use of Gamma Knife Perfexion were studied. Univariate and multivariate associations with the primary outcome of time to nonserviceable hearing were evaluated. RESULTS: A total of 105 patients underwent SRS for VS during the study period, and 59 (56%) met study criteria and were analyzed. Twenty-one subjects (36%) developed nonserviceable hearing at a mean of 2.2 years after SRS (SD, 1.0 years; median, 2.1 years; range 0.6-3.8 years). On univariate analysis, pretreatment pure tone average, speech discrimination score, American Academy of Otolaryngology-Head and Neck Surgery hearing class, marginal dose, and mean dose to the cochlear volume were statistically significantly associated with time to nonserviceable hearing. However, after adjustment for baseline differences, only pretreatment pure tone average was statistically significantly associated with time to nonserviceable hearing in a multivariable model. CONCLUSION: Cochlear dose is one of many variables associated with hearing preservation after SRS for VS. Until further studies demonstrate durable tumor arrest with reduced dose protocols, routine tumor dose planning should not be modified to limit cochlear dose at the expense of tumor control. PMID- 24476905 TI - C2 nerve root transection during C1 lateral mass screw fixation: does it affect functionality and quality of life? AB - BACKGROUND: Sectioning of the C2 nerve root allows for direct visualization of the C1-2 joint and may facilitate arthrodesis. OBJECTIVE: To determine the clinical and functional consequences of C2 nerve root sectioning during placement of C1 lateral mass screws. METHODS: All patients undergoing C1 lateral mass screw fixation were included in this prospective study. A standard questionnaire was used to determine the severity of occipital numbness/pain and its effect on quality of life (QOL). Domains of the neck disability index were used to assess the disability related to C2 symptoms. RESULTS: A total of 28 patients were included (C2 transection, 8; C2 preservation, 20). A trend of decreased blood loss and length of surgery was observed in the C2 transection cohort. Occipital numbness was reported by 4 (50.0%) patients after C2 transection. Occipital neuralgia was reported by 7 (35.0%) patients with C2 preservation. None of the patients with numbness after C2 transection reported being "bothered" by it. All patients with occipital neuralgia after C2 sparing reported being "bothered" by it, and 57.1% reported a moderate to severe effect on QOL. The use of medication was reported by 5 (71.4%) patients with neuralgia vs none with numbness. Mean disability was significantly higher with neuralgia vs numbness (P = .016). CONCLUSION: C2 nerve root transection is associated with increased occipital numbness but this has no effect on patient-reported outcomes and QOL. C2 nerve root preservation can be associated with occipital neuralgia, which has a negative impact on patient disability and QOL. C2 nerve root transection has no negative consequences during C1-2 stabilization. PMID- 24476906 TI - Technological developments and future perspectives on graphene-based metamaterials: a primer for neurosurgeons. AB - Graphene, a monolayer atomic-scale honeycomb lattice of carbon atoms, has been considered the greatest revolution in metamaterials research in the past 5 years. Its developers were awarded the Nobel Prize in Physics in 2010, and massive funding has been directed to graphene-based experimental research in the last years. For instance, an international scientific collaboration has recently received a ?1 billion grant from the European Flagship Initiative, the largest amount of financial resources ever granted for a single research project in the history of modern science. Because of graphene's unique optical, thermal, mechanical, electronic, and quantum properties, the incorporation of graphene based metamaterials to biomedical applications is expected to lead to major technological breakthroughs in the next few decades. Current frontline research in graphene technology includes the development of high-performance, lightweight, and malleable electronic devices, new optical modulators, ultracapacitors, molecular biodevices, organic photovoltaic cells, lithium-ion microbatteries, frequency multipliers, quantum dots, and integrated circuits, just to mention a few. With such advances, graphene technology is expected to significantly impact several areas of neurosurgery, including neuro-oncology, neurointensive care, neuroregeneration research, peripheral nerve surgery, functional neurosurgery, and spine surgery. In this topic review, the authors provide a basic introduction to the main electrophysical properties of graphene. Additionally, future perspectives of ongoing frontline investigations on this new metamaterial are discussed, with special emphasis on those research fields that are expected to most substantially impact experimental and clinical neurosurgery in the near future. PMID- 24476908 TI - Reflections on holism and the passing of Nelson Mandela. PMID- 24476907 TI - Development of a new compact intraoperative magnetic resonance imaging system: concept and initial experience. AB - BACKGROUND: Magnetic resonance imaging (MRI) during surgery has been shown to improve surgical outcomes, but the current intraoperative MRI systems are too large to install in standard operating suites. Although 1 compact system is available, its imaging quality is not ideal. OBJECTIVE: We developed a new compact intraoperative MRI system and evaluated its use for safety and efficacy. METHODS: This new system has a magnetic gantry: a permanent magnet of 0.23 T and an interpolar distance of 32 cm. The gantry system weighs 2.8 tons and the 5-G line is within the circle of 2.6 m. We created a new field-of-view head coil and a canopy-style radiofrequency shield for this system. A clinical trial was initiated, and the system has been used in 44 patients. RESULTS: This system is significantly smaller than previous intraoperative MRI systems. High-quality T2 images could discriminate tumor from normal brain tissue and identify anatomic landmarks for accurate surgery. The average imaging time was 45.5 minutes, and no clinical complications or MRI system failures occurred. Floating organisms or particles were minimal (1/200 L maximum). CONCLUSION: This intraoperative, compact, low-magnetic-field MRI system can be installed in standard operating suites to provide relatively high-quality images without sacrificing safety. We believe that such a system facilitates the introduction of the intraoperative MRI. PMID- 24476909 TI - Healing the healer: one step at a time. AB - Health care workers have the most challenging of professions. They are expected to work long hours while demonstrating compassion and care for the patients that they serve. Although health care practitioners are among the most disciplined of working professionals, they are often some of the unhealthiest of individuals, facing enormous amounts of stress in their lives. Healing the Healer: One Step at a Time is a 6-week health fitness program. It explores the unique challenges faced in the field of health care and teaches techniques to address those challenges head on. Healing the Healer uses Nordic walking as the exercise portion of the class. The case study examines the structure, purpose, and design of this 6-week course. Special attention is given to four basic sections: balance, pacing, joy, and discipline. The arguments presented in this article are theory based and supported by case study evidence. PMID- 24476911 TI - The omega subunit of the RNA polymerase core directs transcription efficiency in cyanobacteria. AB - The eubacterial RNA polymerase core, a transcription machinery performing DNA dependent RNA polymerization, consists of two alpha subunits and beta, beta' and omega subunits. An additional sigma subunit is recruited for promoter recognition and transcription initiation. Cyanobacteria, a group of eubacteria characterized by oxygenic photosynthesis, have a unique composition of the RNA polymerase (RNAP) core due to splitting of the beta' subunit to N-terminal gamma and C terminal beta' subunits. The physiological roles of the small omega subunit of RNAP, encoded by the rpoZ gene, are not yet completely understood in any bacteria. We found that although omega is non-essential in cyanobacteria, it has a major impact on the overall gene expression pattern. In DeltarpoZ strain, recruitment of the primary sigma factor into the RNAP holoenzyme is inefficient, which causes downregulation of highly expressed genes and upregulation of many low-expression genes. Especially, genes encoding proteins of photosynthetic carbon concentrating and carbon fixing complexes were down, and the DeltarpoZ mutant showed low light-saturated photosynthetic activity and accumulated photoprotective carotenoids and alpha-tocopherol. The results indicate that the omega subunit facilitates the association of the primary sigma factor with the RNAP core, thereby allowing efficient transcription of highly expressed genes. PMID- 24476912 TI - Physical constraints determine the logic of bacterial promoter architectures. AB - Site-specific transcription factors (TFs) bind to their target sites on the DNA, where they regulate the rate at which genes are transcribed. Bacterial TFs undergo facilitated diffusion (a combination of 3D diffusion around and 1D random walk on the DNA) when searching for their target sites. Using computer simulations of this search process, we show that the organization of the binding sites, in conjunction with TF copy number and binding site affinity, plays an important role in determining not only the steady state of promoter occupancy, but also the order at which TFs bind. These effects can be captured by facilitated diffusion-based models, but not by standard thermodynamics. We show that the spacing of binding sites encodes complex logic, which can be derived from combinations of three basic building blocks: switches, barriers and clusters, whose response alone and in higher orders of organization we characterize in detail. Effective promoter organizations are commonly found in the E. coli genome and are highly conserved between strains. This will allow studies of gene regulation at a previously unprecedented level of detail, where our framework can create testable hypothesis of promoter logic. PMID- 24476913 TI - The alpha isoform of topoisomerase II is required for hypercompaction of mitotic chromosomes in human cells. AB - As proliferating cells transit from interphase into M-phase, chromatin undergoes extensive reorganization, and topoisomerase (topo) IIalpha, the major isoform of this enzyme present in cycling vertebrate cells, plays a key role in this process. In this study, a human cell line conditional null mutant for topo IIalpha and a derivative expressing an auxin-inducible degron (AID)-tagged version of the protein have been used to distinguish real mitotic chromosome functions of topo IIalpha from its more general role in DNA metabolism and to investigate whether topo IIbeta makes any contribution to mitotic chromosome formation. We show that topo IIbeta does contribute, with endogenous levels being sufficient for the initial stages of axial shortening. However, a significant effect of topo IIalpha depletion, seen with or without the co-depletion of topo IIbeta, is the failure of chromosomes to hypercompact when delayed in M-phase. This requires much higher levels of topo II protein and is impaired by drugs or mutations that affect enzyme activity. A prolonged delay at the G2/M border results in hyperefficient axial shortening, a process that is topo IIalpha dependent. Rapid depletion of topo IIalpha has allowed us to show that its function during late G2 and M-phase is truly required for shaping mitotic chromosomes. PMID- 24476914 TI - Structural basis of sodium-potassium exchange of a human telomeric DNA quadruplex without topological conversion. AB - Understanding the mechanism of Na(+)/K(+)-dependent spectral conversion of human telomeric G-quadruplex (G4) sequences has been limited not only because of the structural polymorphism but also the lack of sufficient structural information at different stages along the conversion process for one given oligonucleotide. In this work, we have determined the topology of the Na(+) form of Tel23 G4, which is the same hybrid form as the K(+) form of Tel23 G4 despite the distinct spectral patterns in their respective nuclear magnetic resonance (NMR) and circular dichroism spectra. The spectral difference, particularly the well resolved imino proton NMR signals, allows us to monitor the structural conversion from Na(+) form to K(+) form during Na(+)/K(+) exchange. Time-resolved NMR experiments of hydrogen-deuterium exchange and hybridization clearly exclude involvement of the global unfolding for the fast Na(+)/K(+) spectral conversion. In addition, the K(+) titration monitored by NMR reveals that the Na(+)/K(+) exchange in Tel23 G4 is a two-step process. The addition of K(+) significantly stabilizes the unfolding kinetics of Tel23 G4. These results offer a possible explanation of rapid spectral conversion of Na(+)/K(+) exchange and insight into the mechanism of Na(+)/K(+) structural conversion in human telomeric G4s. PMID- 24476915 TI - A phylogenomics approach for selecting robust sets of phylogenetic markers. AB - Reconstructing the evolutionary relationships of species is a major goal in biology. Despite the increasing number of completely sequenced genomes, a large number of phylogenetic projects rely on targeted sequencing and analysis of a relatively small sample of marker genes. The selection of these phylogenetic markers should ideally be based on accurate predictions of their combined, rather than individual, potential to accurately resolve the phylogeny of interest. Here we present and validate a new phylogenomics strategy to efficiently select a minimal set of stable markers able to reconstruct the underlying species phylogeny. In contrast to previous approaches, our methodology does not only rely on the ability of individual genes to reconstruct a known phylogeny, but it also explores the combined power of sets of concatenated genes to accurately infer phylogenetic relationships of species not previously analyzed. We applied our approach to two broad sets of cyanobacterial and ascomycetous fungal species, and provide two minimal sets of six and four genes, respectively, necessary to fully resolve the target phylogenies. This approach paves the way for the informed selection of phylogenetic markers in the effort of reconstructing the tree of life. PMID- 24476916 TI - Multiplexing clonality: combining RGB marking and genetic barcoding. AB - RGB marking and DNA barcoding are two cutting-edge technologies in the field of clonal cell marking. To combine the virtues of both approaches, we equipped LeGO vectors encoding red, green or blue fluorescent proteins with complex DNA barcodes carrying color-specific signatures. For these vectors, we generated highly complex plasmid libraries that were used for the production of barcoded lentiviral vector particles. In proof-of-principle experiments, we used barcoded vectors for RGB marking of cell lines and primary murine hepatocytes. We applied single-cell polymerase chain reaction to decipher barcode signatures of individual RGB-marked cells expressing defined color hues. This enabled us to prove clonal identity of cells with one and the same RGB color. Also, we made use of barcoded vectors to investigate clonal development of leukemia induced by ectopic oncogene expression in murine hematopoietic cells. In conclusion, by combining RGB marking and DNA barcoding, we have established a novel technique for the unambiguous genetic marking of individual cells in the context of normal regeneration as well as malignant outgrowth. Moreover, the introduction of color specific signatures in barcodes will facilitate studies on the impact of different variables (e.g. vector type, transgenes, culture conditions) in the context of competitive repopulation studies. PMID- 24476917 TI - A knowledge-based scoring function for protein-RNA interactions derived from a statistical mechanics-based iterative method. AB - Protein-RNA interactions play important roles in many biological processes. Given the high cost and technique difficulties in experimental methods, computationally predicting the binding complexes from individual protein and RNA structures is pressingly needed, in which a reliable scoring function is one of the critical components. Here, we have developed a knowledge-based scoring function, referred to as ITScore-PR, for protein-RNA binding mode prediction by using a statistical mechanics-based iterative method. The pairwise distance-dependent atomic interaction potentials of ITScore-PR were derived from experimentally determined protein-RNA complex structures. For validation, we have compared ITScore-PR with 10 other scoring methods on four diverse test sets. For bound docking, ITScore-PR achieved a success rate of up to 86% if the top prediction was considered and up to 94% if the top 10 predictions were considered, respectively. For truly unbound docking, the respective success rates of ITScore-PR were up to 24 and 46%. ITScore-PR can be used stand-alone or easily implemented in other docking programs for protein-RNA recognition. PMID- 24476919 TI - Comment on "Checklist for anesthesiological process: analysis of risks". PMID- 24476918 TI - Mapping of six somatic linker histone H1 variants in human breast cancer cells uncovers specific features of H1.2. AB - Seven linker histone H1 variants are present in human somatic cells with distinct prevalence across cell types. Despite being key structural components of chromatin, it is not known whether the different variants have specific roles in the regulation of nuclear processes or are differentially distributed throughout the genome. Using variant-specific antibodies to H1 and hemagglutinin (HA)-tagged recombinant H1 variants expressed in breast cancer cells, we have investigated the distribution of six H1 variants in promoters and genome-wide. H1 is depleted at promoters depending on its transcriptional status and differs between variants. Notably, H1.2 is less abundant than other variants at the transcription start sites of inactive genes, and promoters enriched in H1.2 are different from those enriched in other variants and tend to be repressed. Additionally, H1.2 is enriched at chromosomal domains characterized by low guanine-cytosine (GC) content and is associated with lamina-associated domains. Meanwhile, other variants are associated with higher GC content, CpG islands and gene-rich domains. For instance, H1.0 and H1X are enriched at gene-rich chromosomes, whereas H1.2 is depleted. In short, histone H1 is not uniformly distributed along the genome and there are differences between variants, H1.2 being the one showing the most specific pattern and strongest correlation with low gene expression. PMID- 24476920 TI - Transversus abdominis plane catheter infusions after major abdominal surgery in morbidly obese patients: reply to comments. PMID- 24476921 TI - A selective and efficient electrocatalyst for carbon dioxide reduction. AB - Converting carbon dioxide to useful chemicals in a selective and efficient manner remains a major challenge in renewable and sustainable energy research. Silver is an interesting electrocatalyst owing to its capability of converting carbon dioxide to carbon monoxide selectively at room temperature; however, the traditional polycrystalline silver electrocatalyst requires a large overpotential. Here we report a nanoporous silver electrocatalyst that is able to electrochemically reduce carbon dioxide to carbon monoxide with approximately 92% selectivity at a rate (that is, current) over 3,000 times higher than its polycrystalline counterpart under moderate overpotentials of <0.50 V. The high activity is a result of a large electrochemical surface area (approximately 150 times larger) and intrinsically high activity (approximately 20 times higher) compared with polycrystalline silver. The intrinsically higher activity may be due to the greater stabilization of CO2 (-) intermediates on the highly curved surface, resulting in smaller overpotentials needed to overcome the thermodynamic barrier. PMID- 24476922 TI - Positive co-occurrence of flea infestation at a low biological cost in two rodent hosts in the Canary archipelago. AB - Non-random assemblages have been described as a common pattern of flea co occurrence across mainland host species. However, to date, patterns of flea co occurrence on islands are unknown. The present work investigates, on one hand, whether the decrease in the number of species on islands affects the pattern of flea co-occurrence, and on the other hand, how the cost of higher flea burdens affects host body mass. The study was carried out in the Canary Islands (Spain) using null models to analyse flea co-occurrence on Rattus rattus and Mus musculus. Results supported aggregation of flea species in Mus but not in Rattus, probably due to the relationship between abundance and both prevalence and intensity of infection of the main flea species parasitizing Mus. In addition, heavy individuals of both rodent species showed the highest flea burdens as well as higher species richness, probably due to the continued accumulation of fleas throughout life and/or immunological resistance mechanisms. Whatever the mechanisms involved, it is clear that co-occurrence and high parasite intensities do not imply a detrimental biological cost for the rodents of the Canary Islands. PMID- 24476923 TI - Prenatal and postnatal exposure to an unhealthy diet is associated with behavioural and emotional problems in children. PMID- 24476924 TI - Financial incentives improve adherence to maintenance antipsychotic treatment. PMID- 24476925 TI - Current understanding of the thrombospondin-1 interactome. AB - The multifaceted action of thrombospondin-1 (TSP-1) depends on its ability to physically interact with different ligands, including structural components of the extracellular matrix, other matricellular proteins, cell receptors, growth factors, cytokines and proteases. Through this network, TSP-1 regulates the ligand activity, availability and structure, ultimately tuning the cell response to environmental stimuli in a context-dependent manner, contributing to physiological and pathological processes. Complete mapping of the TSP-1 interactome is needed to understand its diverse functions and to lay the basis for the rational design of TSP-1-based therapeutic approaches. So far, large scale approaches to identify TSP-1 ligands have been rarely used, but many interactions have been identified in small-scale studies in defined biological systems. This review, based on information from protein interaction databases and the literature, illustrates current knowledge of the TSP-1 interactome map. PMID- 24476926 TI - Molecular determinants responsible for sedative and non-sedative properties of histamine H1-receptor antagonists. AB - There is argument whether non-sedative properties of histamine H1-receptor antagonists (antihistamines) are determined by their active extrusions from the brain via P-glycoprotein or their restricted penetration through the blood-brain barrier. We have reported that sedative and non-sedative antihistamines can be well discriminated by measuring changes in their binding to H1 receptors upon receptor internalization in intact cells, which depends on their membrane penetrating ability. In this study, molecular determinants responsible for sedative and non-sedative properties of antihistamines were evaluated by quantitative structure-activity relationship (QSAR) analyses. Multiple regression analyses were applied to construct a QSAR model, taking internalization-mediated changes in the binding of antihistamines as objective variables and their structural descriptors as explanatory variables. The multiple regression model was successfully constructed with two explanatory variables, i.e., lipophilicity of the compounds at physiological pH (logD) and mean information content on the distance degree equality (IDDE) (r(2) = 0.753). The constructed model discriminated between sedative and non-sedative antihistamines with 94% accuracy for external validation. These results suggest that logD and IDDE concerning lipophilicity and molecular shapes of compounds, respectively, predominantly determine the membrane-penetrating ability of antihistamines for their side effects on the central nervous system. PMID- 24476927 TI - Chotosan, a Kampo formula, ameliorates hippocampal LTD and cognitive deficits in juvenile-onset diabetes rats. AB - Childhood-onset type 1 diabetes is associated with modest impairments in cognition and has an elevated risk of cognitive decline. Our previous study showed that working memory and hippocampal long-term depression (LTD) were impaired in juvenile-onset diabetes mellitus (JDM) rats. In this study, we investigated the effect of chotosan (CTS), a traditional herbal formula called a Kampo medicine, which has been clinically demonstrated to be effective for the treatment of vascular dementia, on JDM rats. The repeated treatment with CTS (1 g/kg per day) for 3 - 7 days restored spatial working memory and hippocampal LTD in JDM rats. The expression level of NR2B glutamate receptor subunits, but not other glutamate receptor subunits was enhanced in the hippocampus of JDM rats, and repeated treatment with CTS reversed these changes. These results suggest that CTS improves diabetes-induced cognitive deficits by modulating NMDA-receptor subunit expression. PMID- 24476928 TI - European Forum of Rehabilitation Research. PMID- 24476930 TI - Waist-to-height ratio, inflammation and CVD risk in obese children. AB - OBJECTIVE: To evaluate the association between waist-to-height ratio (WHtR) and specific biomarkers of inflammation, CVD risk and endothelial dysfunction in prepubertal obese children. DESIGN: Prospective, multicentre case-control study matched by age and sex. SETTING: Children were recruited between May 2007 and May 2010 from primary-care centres and schools in three cities in Spain (Cordoba, Santiago de Compostela and Zaragoza). SUBJECTS: Four hundred and forty-six (223 normal weight and 223 obese) Caucasian prepubertal children aged 6-12 years. RESULTS: WHtR was higher in the obese than in the normal-weight children. Blood pressure, waist circumference, weight, height, insulin, plasma lipids, leptin, resistin, abnormal neutrophil and monocyte counts, C-reactive protein, IL-6, IL 8, TNF-alpha, myeloperoxidase, soluble intercellular adhesion molecule-1, selectin and plasminogen activator inhibitor-1 levels were higher in the obese than in the normal-weight group. Adiponectin and HDL-cholesterol were lower and glucose and metalloproteinase-9 showed no differences. Resistin, TNF-alpha and active plasminogen activator inhibitor-1 were associated with WHtR, a sensitive indicator of central obesity. CONCLUSIONS: Our results lead to the hypothesis that changes in biomarker levels of insulin resistance, inflammation and CVD risk before puberty might induce metabolic consequences of obesity in obese children before reaching adulthood. PMID- 24476931 TI - Association of vitamin D with adiposity measures and other determinants in a cross-sectional study of Cypriot adolescents. AB - OBJECTIVE: To assess vitamin D status among Cypriot adolescents and investigate potential determinants including BMI and body fat percentage (BF%). DESIGN: Participants had cross-sectional assessments of serum vitamin D, physical activity, dietary vitamin D intake and sun exposure. Linear and logistic regression models were used to explore the associations of vitamin D with potential predictors. SETTING: Hospitals, Cyprus, November 2007-May 2008. SUBJECTS: Adolescents (n 671) aged 16-18 years. RESULTS: Mean serum vitamin D was 22.90 (sd 6.41) ng/ml. Only one in ten children had sufficient levels of vitamin D (>=30 ng/ml), while the prevalence of vitamin D deficiency (12-20 ng/ml) and severe deficiency (<12 ng/ml) was 31.7 % and 4.0 %, respectively. Lower vitamin D was associated with winter and spring season, female gender, reduced sun exposure in winter and darker skin. Participants with highest BMI and BF% when compared with a middle reference group had increased adjusted odds of vitamin D insufficiency (OR = 3.00; 95 % CI 1.21, 7.45 and OR = 5.02; 95 % CI 1.80, 13.97, respectively). A similar pattern, although not as strong, was shown for vitamin D deficiency with BF% (OR = 1.81; 95 % CI 1.04, 3.16) and BMI (OR = 1.51; 95 % CI 0.85, 2.67). Participants in the lowest BMI and BF% groups also displayed compromised vitamin D status, suggesting a U-shaped association. CONCLUSIONS: Vitamin D deficiency in adolescence is very prevalent in sunny Cyprus, particularly among females, those with darker skin and those with reduced sun exposure in winter. Furthermore, vitamin D status appears to have a U-shaped association with adiposity measures. PMID- 24476932 TI - Vaccine against scabies: necessity and possibility. AB - Scabies is an infectious disease that is endemic in poorly resourced communities, and also common in industrialized countries. Although the disease, which is caused by infestation of Sarcoptes scabiei, is generally mild, the need for a vaccine against S. scabiei is proposed. The immunological mechanisms that control S. scabiei infection are discussed and the current status of scabies vaccine development reviewed. Future directions for scabies vaccine development are also addressed. PMID- 24476933 TI - A novel ATP7B gene mutation in a liver failure patient with normal ceruloplasmin and low serum alkaline phosphatase. AB - Wilson's disease (WD) is a rare disorder of copper metabolism resulting in accumulation of copper in liver and other organs. We present a liver failure patient, who was misdiagnosed for two years, with normal ceruloplasmin and low serum alkaline phosphatase. Molecular testing revealed a novel p.Ala982Thr mutation within ATP7B gene. The pathology of liver sample showed a large amount of copper deposition in the hepatocytes and confirmed the diagnosis of WD. Our data highlighted the importance of molecular testing in the early diagnosis of atypical WD. PMID- 24476935 TI - Independent associations of income and education with nutrient intakes in Brazilian adults: 2008-2009 National Dietary Survey. AB - OBJECTIVE: To verify associations of income and education with nutrient intakes in Brazilian adults. DESIGN: Data from the population-based National Dietary Survey conducted in 2008-2009. Family per capita income and education levels were categorized into quartiles. Prevalences of inadequate nutrient intakes and excessive intakes of saturated fat and Na were calculated by using the method prescribed by the National Cancer Institute. The Estimated Average Requirement was used as a reference for micronutrient intake. Linear regression models for both the independent and the mutually adjusted associations of education and income with nutrient intakes were tested. Interaction between education and income was tested. SETTING: Households (n 13 569) selected using a two-stage cluster sampling design. SUBJECTS: Food records for two non-consecutive days were obtained for 21 003 Brazilian adults (aged 20-59 years). RESULTS: For most of eleven nutrients, the prevalence of inadequate intake declined with increasing income and education levels; however, it remained high across all income and education quartiles. Excessive intake of saturated fat and low fibre intake increased with both variables. Most nutrients were independently associated with income and education in both sexes. Fe, vitamin B12 and Na intakes among women were associated only with education. There was an interaction between income and education for Na intake in men, P intake in women and Ca intake in both sexes. CONCLUSIONS: Education is one important step to improve nutrient intakes in Brazil. Emphasis should be laid on enhancing dietary knowledge and formulating economic strategies that would allow lower-income individuals to adopt a healthy diet. PMID- 24476934 TI - New functions of the chloroplast Preprotein and Amino acid Transporter (PRAT) family members in protein import. AB - Plant cells contain distinct compartments such as the nucleus, the endomembrane system comprising the endoplasmic reticulum and Golgi apparatus, peroxisomes, vacuoles, as well as mitochondria and chloroplasts. All of these compartments are surrounded by 1 or 2 limiting membranes and need to import proteins from the cytosol. Previous work led to the conclusion that mitochondria and chloroplasts use structurally different protein import machineries in their outer and inner membranes for the uptake of cytosolic precursor proteins. Our most recent data show that there is some unexpected overlap. Three members of the family of preprotein and amino acid transporters, PRAT, were identified in chloroplasts that mediate the uptake of transit sequence-less proteins into the inner plastid envelope membrane. By analogy, mitochondria contain with TIM22 a related PRAT protein that is involved in the import of transit sequence-less proteins into the inner mitochondrial membrane. Both mitochondria and chloroplasts thus make use of similar import mechanisms to deliver some of their proteins to their final place. Because single homologs of HP20- and HP30-like proteins are present in algae such as Chlamydomonas, Ostreococcus, and Volvox, which diverged from land plants approximately 1 billion years ago, it is likely that the discovered PRAT-mediated mechanism of protein translocation evolved concomitantly with the secondary endosymbiotic event that gave rise to green plants. PMID- 24476936 TI - Hypertrophic cardiomyopathy: implications for anesthesia. AB - Hypertrophic cardiomyopathy (HCM) is a genetic disorder and it is recognized as the most common cause of sudden cardiac death in the young, and an important substrate for disability at any age. Anesthetists may be confronted with clinically unrecognized HCM and must be prepared to anticipate the hemodynamic changes and cardiovascular instability that such patients may impose. When HCM patients are subjected to the stress of surgery, perioperative complications occur and can be devastating. Anesthesia providers need to be aware of the relevant pathophysiology and the mechanisms that may trigger or accentuate dynamic left ventricle outflow tract obstruction. Factors that worsen the degree of left ventricle outflow tract obstruction and hemondynamic strategies to improve cardiac outoput are described in the present review. Strategies to respond to hypotension must be promptly instituted to prevent the development of cardiovascular collapse, and subsequent complications. Therefore, a complete understanding of the pathophysiology, hemodynamic changes and anesthetic implications is needed for successful perioperative outcome. PMID- 24476937 TI - Dementia care in nursing homes: a golden opportunity. PMID- 24476938 TI - Small ruminant lentivirus-induced arthritis: clinicopathologic findings in sheep infected by a highly replicative SRLV B2 genotype. AB - We describe the clinicopathologic features of an arthritis outbreak in sheep induced by small ruminant lentivirus (SRLV), linked to the presence of a new SRLV isolate phylogenetically assigned to caprine arthritis encephalitis virus-like subgroup B2. Thirteen SRLV seropositive Rasa Aragonesa adult ewes were selected from 5 SRLV highly infected flocks (mean seroprevalence, 90.7%) for presenting uni- or bilateral chronic arthritis in the carpal joint. A complete study was performed, including symptomatology, histopathology, immunocytochemistry, immunohistochemistry, in situ hybridization, and microbiology. The carpus was the joint almost exclusively affected, with 10 sheep (76%) showing a moderate increase in carpal joint size (diameter range, 18-20 cm; normal range, 15-16 cm) without signs of locomotion problems and with 3 ewes (23%) showing severe inflammation with marked increase in diameter (21-24 cm), pain at palpation, and abnormal standing position. Grossly, chronic proliferative arthritis was observed in affected joints characterized by an increased thickness of the synovial capsule and synovial membrane proliferation. Microscopically, synovial membrane inflammation and proliferation and hyperplasia of synoviocytes were observed. More positive cases of SLRV infection were detected by immunocytochemistry of articular fluid than of bronchoalveolar lavage fluid. Immunohistochemistry and in situ hybridization also detected positive cells in the subsynovial connective tissue, lung, mediastinal lymph node, mammary gland, and mammary lymph node. All animals were negative for the presence of Mycoplasma or other bacteria in the articular space. The present outbreak likely represents an adaptation of a caprine virus to sheep. Our results underline the importance of the arthritis induced by SRLV in sheep, a clinical form that might be underestimated. PMID- 24476939 TI - Pathology of articular cartilage and synovial membrane from elbow joints with and without degenerative joint disease in domestic cats. AB - The elbow joint is one of the feline appendicular joints most commonly and severely affected by degenerative joint disease. The macroscopic and histopathological lesions of the elbow joints of 30 adult cats were evaluated immediately after euthanasia. Macroscopic evidence of degenerative joint disease was found in 22 of 30 cats (39 elbow joints) (73.33% cats; 65% elbow joints), and macroscopic cartilage erosion ranged from mild fibrillation to complete ulceration of the hyaline cartilage with exposure of the subchondral bone. Distribution of the lesions in the cartilage indicated the presence of medial compartment joint disease (most severe lesions located in the medial coronoid process of the ulna and medial humeral epicondyle). Synovitis scores were mild overall and correlated only weakly with macroscopic cartilage damage. Intra articular osteochondral fragments either free or attached to the synovium were found in 10 joints. Macroscopic or histologic evidence of a fragmented coronoid process was not found even in those cases with intra-articular osteochondral fragments. Lesions observed in these animals are most consistent with synovial osteochondromatosis secondary to degenerative joint disease. The pathogenesis for the medial compartmentalization of these lesions has not been established, but a fragmented medial coronoid process or osteochondritis dissecans does not appear to play a role. PMID- 24476940 TI - Bovine viral diarrhea virus infections: manifestations of infection and recent advances in understanding pathogenesis and control. AB - Bovine viral diarrhea virus (BVDV) continues to be of economic significance to the livestock industry in terms of acute disease and fetal loss. Many of the lesions relating to BVDV infection have been well described previously. The virus is perpetuated in herds through the presence of calves that are persistently infected. Relationships between various species and biotypes of BVDV and host defenses are increasingly understood. Understanding of the host defense mechanisms of innate immunity and adaptive immunity continues to improve, and the effects of the virus on these immune mechanisms are being used to explain how persistent infection develops. The noncytopathic biotype of BVDV plays the major role in its effects on the host defenses by inhibiting various aspects of the innate immune system and creation of immunotolerance in the fetus during early gestation. Recent advances have allowed for development of affordable test strategies to identify and remove persistently infected animals. With these improved tests and removal strategies, the livestock industry can begin more widespread effective control programs. PMID- 24476941 TI - Recent advances in understanding the pathogenesis of Lawsonia intracellularis infections. AB - Proliferative enteropathy is an infectious disease caused by an obligate intracellular bacterium, Lawsonia intracellularis, and characterized by thickening of the intestinal epithelium due to enterocyte proliferation. The disease is endemic in swine herds and has been occasionally reported in various other species. Furthermore, outbreaks among foals began to be reported on breeding farms worldwide within the past 5 years. Cell proliferation is directly associated with bacterial infection and replication in the intestinal epithelium. As a result, mild to severe diarrhea is the major clinical sign described in infected animals. The dynamics of L. intracellularis infection in vitro and in vivo have been well characterized, but little is known about the genetic basis for the pathogenesis or ecology of this organism. The present review focuses on the recent advances regarding the pathogenesis and host-pathogen interaction of L. intracellularis infections. PMID- 24476942 TI - Correct use of nomenclature. PMID- 24476943 TI - Monoacylglycerol lipase inhibition blocks chronic stress-induced depressive-like behaviors via activation of mTOR signaling. AB - The endocannabinoid (eCB) system regulates mood, emotion, and stress coping, and dysregulation of the eCB system is critically involved in pathophysiology of depression. The eCB ligand 2-arachidonoylglycerol (2-AG) is inactivated by monoacylglycerol lipase (MAGL). Using chronic unpredictable mild stress (CUS) as a mouse model of depression, we examined how 2-AG signaling in the hippocampus was altered in depressive-like states and how this alteration contributed to depressive-like behavior. We report that CUS led to impairment of depolarization induced suppression of inhibition (DSI) in mouse hippocampal CA1 pyramidal neurons, and this deficiency in 2-AG-mediated retrograde synaptic depression was rescued by MAGL inhibitor JZL184. CUS induced depressive-like behaviors and decreased mammalian target of rapamycin (mTOR) activation in the hippocampus, and these biochemical and behavioral abnormalities were ameliorated by chronic JZL184 treatments. The effects of JZL184 were mediated by cannabinoid CB1 receptors. Genetic deletion of mTOR with adeno-associated viral (AAV) vector carrying the Cre recombinase in the hippocampus of mTORf/f mice recapitulated depressive-like behaviors induced by CUS and abrogated the antidepressant-like effects of chronic JZL184 treatments. Our results suggest that CUS decreases eCB-mTOR signaling in the hippocampus, leading to depressive-like behaviors, whereas MAGL inhibitor JZL184 produces antidepressant-like effects through enhancement of eCB-mTOR signaling. PMID- 24476945 TI - Serum interleukin-23 (IL-23) is increased in Hashimoto's thyroiditis. AB - Recent studies have demonstrated that T-helper 17 lymphocytes (Th17), which produce mostly IL-17, play a major role in several autoimmune diseases commonly thought to be Th1-related, including Hashimoto's thyroiditis (HT). IL-23, a member of the IL-12 cytokine family, is known to guide T cells toward the Th17 phenotype and its serum levels are increased in several autoimmune disease. Few data are available in the literature on IL-23 in HT. Using IL-23 Quantikine ELISA Kit (lower limit of detection 2.7 pg/mL) we analyzed the serum levels of IL-23 in 81 HT patients (75 females and 6 males, aged 14-70; mean age 39+/-17 years), and an age- and sex-matched group of 80 healthy persons. Both patients and controls did not receive any treatment. The positive detection rates of serum IL-23 were significantly higher in patients with HT: 56% of HT patients had detectable IL-23 in serum compared to 36% of healthy subjects (Chi chi2 test, p=0.014). Moreover, HT patients had significantly higher serum concentrations of IL-23 (157.38 +/- 17.92 pg/mL) in comparison with healthy controls (21.46 +/- 5.4 pg/mL; p <0.0001). No significant correlation was found between serum levels of IL-23 and Tg-Ab or TPO-Ab levels, as well as with TSH values, in HT patients. In conclusion, serum IL-23 is increased in euthyroid and untreated HT patients, as compared to healthy subjects. Our data suggest that IL-23 would play a role in the pathogenesis of HT. PMID- 24476944 TI - Selective effects of D- and L-govadine in preclinical tests of positive, negative, and cognitive symptoms of schizophrenia. AB - There is a critical need to develop novel pharmacotherapeutics capable of addressing the positive, negative, and cognitive symptoms of schizophrenia. Building on recent studies with a racemic mixture of the synthetic tetrahydroprotoberberine, D,L-Govadine, we isolated the D- and L-stereoisomers and employed a battery of behavioral, neurochemical, and electrophysiological procedures to assess their individual therapeutic potential. Rodent models predictive of antipsychotic efficacy and those that model positive symptoms were employed and we found that L-Govadine, but not D-Govadine, improved these measures. Pretreatment with either stereoisomer during CS pre-exposure prevented the disruption of latent inhibition by amphetamine. Moreover, pretreatment with either stereoisomer also improved deficits in social interaction in the neonatal ventral hippocampal lesioned rat. Improved cognitive performance in two different prefrontal cortex-dependent tasks was observed with D-, but not L-Govadine, which strongly suggests that the D-steroisomer may be an effective cognitive enhancer. Alterations in dopamine efflux were also assessed and L-Govadine increased dopamine efflux in both the prefrontal cortex and nucleus accumbens. However, D Govadine only increased dopamine efflux in the prefrontal cortex and not in the nucleus accumbens. Electrophysiological studies confirmed that L-Govadine is a DA D2 antagonist, whereas D-Govadine shows no appreciable physiological effects at this receptor. Collectively these data show that L-Govadine performs well on measures predictive of antipsychotic efficacy and rodent models of positive symptoms through antagonism of DA-D2 receptors, whereas D-Govadine improves impairments in compromised memory function in delayed response tasks possibly through selective increases in DA efflux in the frontal cortex. PMID- 24476946 TI - Permanent hypoparathyroidism after completion total thyroidectomy as a second surgery: How do we avoid it? AB - A permanent hypoparathyroidism is a problematic complication of total thyroidectomy. In this study, we investigated its incidence and how to avoid it at the time of completion total thyroidectomy after hemithyroidectomy. Eight of the 154 patients who underwent completion total thyroidectomy as the second surgery (5%) after hemithyroidectomy (two-surgery group) showed a permanent hypothyroidism. Patients without parathyroid autotransplantation either at initial or second surgery were more likely to show a permanent hypoparathyroidism. In the subset of 74 patients in two-surgery group, who underwent bilateral central dissection, 6 (8%) had a permanent hypoparathyroidism. The incidence was higher than those in control group who underwent total thyroidectomy with bilateral central dissection at one time, which was 2%. However, all 6 patients showing a permanent hypoparathyroidsm underwent bilateral central dissection in initial surgery and none of the patients who underwent bilateral central dissection in twice had a permanent hypoparathyroidism. Taken together, we can conclude that 1) in initial surgery of hemithyroidectomy, we have to carefully search the parathyroid glands and if dissected, they should retrieved and autotransplanted to save the patients from a permanent hypoparathyroidism when they undergo second surgery in future, and 2) hemithyroidectomy with bilateral central dissection significantly increases the risk of permanent hypoparathyroidism and only ipsilateral dissection is better when we do not perform total thyroidectomy. PMID- 24476947 TI - Is vitamin D status associated with open-angle glaucoma? A cross-sectional study from South Korea. AB - OBJECTIVE: Open-angle glaucoma (OAG) is one of the major chronic diseases involving the optic nerve. However, little is known about the association between vitamin D and OAG. The present study was conducted to test the hypothesis that lower vitamin D status is associated with greater prevalence of OAG. DESIGN: Cross-sectional study. Multivariable logistic regression was performed to examine the relationship between serum 25-hydroxyvitamin D (25(OH)D) and OAG after adjusting for traditional potential confounders. OAG was defined by the criteria of the International Society for Geographical and Epidemiological Ophthalmology. SETTING: The Fifth Korean National Health and Nutrition Examination Survey conducted in 2010-2011. SUBJECTS: Six thousand and ninety-four adult participants randomly selected from 192 surveys in 131 locations in South Korea. RESULTS: Multivariable-adjusted odds ratios of OAG across quintiles of decreasing 25(OH)D were 1.26, 1.00 (reference), 1.31, 1.36 and 1.69 (P for quadratic trend <0.01). The odds ratio for the lowest 25(OH)D quintile was significantly higher than that for the second quintile (P < 0.01). In addition, we discovered that the predictors for worsening of OAG, such as intraocular pressure or vertical and horizontal cup-to-disc ratios, had a significant relationship with 25(OH)D level. CONCLUSIONS: There was a reverse J-shaped association between 25(OH)D levels and the risk of OAG, with significantly elevated risk at lower 25(OH)D. The findings of this research suggest that vitamin D deficiency should be considered as a potential risk factor for the development of OAG. To our knowledge, the present study is the first one that shows an association between vitamin D status and OAG. PMID- 24476948 TI - Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. AB - The genetic etiology of non-aneuploid fetal structural abnormalities is typically investigated by karyotyping and array-based detection of microscopically detectable rearrangements, and submicroscopic copy-number variants (CNVs), which collectively yield a pathogenic finding in up to 10% of cases. We propose that exome sequencing may substantially increase the identification of underlying etiologies. We performed exome sequencing on a cohort of 30 non-aneuploid fetuses and neonates (along with their parents) with diverse structural abnormalities first identified by prenatal ultrasound. We identified candidate pathogenic variants with a range of inheritance models, and evaluated these in the context of detailed phenotypic information. We identified 35 de novo single-nucleotide variants (SNVs), small indels, deletions or duplications, of which three (accounting for 10% of the cohort) are highly likely to be causative. These are de novo missense variants in FGFR3 and COL2A1, and a de novo 16.8 kb deletion that includes most of OFD1. In five further cases (17%) we identified de novo or inherited recessive or X-linked variants in plausible candidate genes, which require additional validation to determine pathogenicity. Our diagnostic yield of 10% is comparable to, and supplementary to, the diagnostic yield of existing microarray testing for large chromosomal rearrangements and targeted CNV detection. The de novo nature of these events could enable couples to be counseled as to their low recurrence risk. This study outlines the way for a substantial improvement in the diagnostic yield of prenatal genetic abnormalities through the application of next-generation sequencing. PMID- 24476950 TI - Quantum metrology with parametric amplifier-based photon correlation interferometers. AB - Conventional interferometers usually utilize beam splitters for wave splitting and recombination. These interferometers are widely used for precision measurement. Their sensitivity for phase measurement is limited by the shot noise, which can be suppressed with squeezed states of light. Here we study a new type of interferometer in which the beam splitting and recombination elements are parametric amplifiers. We observe an improvement of 4.1+/-0.3 dB in signal-to noise ratio compared with a conventional interferometer under the same operating condition, which is a 1.6-fold enhancement in rms phase measurement sensitivity beyond the shot noise limit. The improvement is due to signal enhancement. Combined with the squeezed state technique for shot noise suppression, this interferometer promises further improvement in sensitivity. Furthermore, because nonlinear processes are involved in this interferometer, we can couple a variety of different waves and form new types of hybrid interferometers, opening a door for many applications in metrology. PMID- 24476951 TI - Time for change? Food choices in the transition to cohabitation and parenthood. AB - OBJECTIVE: We compared the dietary behaviour of three different household types and explored developmental trends in food choices following a life event. DESIGN: The study is based on data from three Swiss Food Panel survey periods. A cross sectional comparison between household types was conducted by using a one-way independent ANOVA. Repeated measures were analysed with a mixed ANCOVA to examine changes in dietary behaviour following a life event. SETTING: Participants in the survey filled in a questionnaire in the years 2010, 2011 and 2012. SUBJECTS: The final sample consisted of 3559 persons with a mean age of 56 years (range 22-94 years; 46 % men). Seventy-two people moved in with their partner and sixty-five people reported the birth of their first child. RESULTS: Cross-sectional evidence confirmed that women living in households with a partner reported higher consumption frequencies for meat and processed meats compared with those living alone. Men living in cohabitation had a higher vegetable intake. The transitional effect of moving in with a partner, however, resulted in a higher intake of processed meats for both genders and a higher intake of pork and savoury items for men. Transition to motherhood was linked to an increase in vegetable consumption, while the transition to fatherhood did not change consumption patterns significantly. CONCLUSIONS: Individuals in life-stage transitions are more likely to change their nutritional strategies and life events can be a window of opportunity for changes towards better food choices. PMID- 24476953 TI - Minimally invasive segmental artery coil embolization for preconditioning of the spinal cord collateral network before one-stage descending and thoracoabdominal aneurysm repair. AB - OBJECTIVE: Paraplegia remains the most devastating complication after thoracic and thoracoabdominal aortic aneurysm (TAA/A) repair. The collateral network (CN) concept of spinal cord perfusion suggests segmental artery (SA) occlusion to mobilize redundant intraspinal and paraspinal arterial sources and ultimately trigger arteriogenesis, leading to spinal cord blood flow restoration within 96 to 120 hours. This principle is used by the two-staged approach to TAA/A-repair- which has lead to an elimination of paraplegia in an experimental model. However, the clinical implementation of a two-staged surgical procedure is challenging, particularly in the absence of an appropriate vascular segment for a "staged" open anastomosis or an appropriate endovascular landing zone. Selective, transfemoral minimally invasive SA coil embolization (MISACE) could provide the solution for one-stage repair of extensive aortic pathologies by triggering arteriogenic CN preconditioning and thereby allowing for recruitment of otherwise redundant arterial collaterals to the spinal cord. METHODS: The feasibility of MISACE was explored in a single animal using an established piglet model. A 6F sheet was introduced via the femoral artery, and a 4F standard Judkins catheter was used for selective angiography and coil insertion. All thoracic and lumbar aortic SAs (15 pairs; Th4-L5) were successfully identified by dye injection. Pediatric platinum endovascular coils (Trufill Pushable Coils, 3 * 20 mm; Cordis, Waterloo, Belgium) were deployed to serially occlude the SA mimicking a CN preconditioning procedure. RESULTS: All intercostal (thoracic) and lumbar aortic SAs (Th4-L5) were successfully identified and occluded by coil embolization. Successful SA coil embolization was verified intraoperatively by selective dye injection on angiography. No intraoperative coil dislodgement occurred. Autopsy revealed complete occlusion of all embolized SAs enhanced by early local thrombus formation. Thrombotic material was found only distally to the coils. No SA dissection was observed at the aortic SA origins. CONCLUSIONS: The MISACE technique allows for rapid serial endovascular occlusion of all thoracic and lumbar SAs. This new innovative approach bares the potential to CN preconditioning at the respective level of aortic pathology--to allow for adequate perioperative spinal cord blood supply--before conventional open or endovascular surgery. Selective, transarterial MISACE might lead to a dramatic reduction of ischemic spinal cord injury after open and endovascular TAA/A repair in the future. PMID- 24476952 TI - Successful vaccines for naturally occurring protozoal diseases of animals should guide human vaccine research. A review of protozoal vaccines and their designs. AB - Effective vaccines are available for many protozoal diseases of animals, including vaccines for zoonotic pathogens and for several species of vector transmitted apicomplexan haemoparasites. In comparison with human diseases, vaccine development for animals has practical advantages such as the ability to perform experiments in the natural host, the option to manufacture some vaccines in vivo, and lower safety requirements. Although it is proper for human vaccines to be held to higher standards, the enduring lack of vaccines for human protozoal diseases is difficult to reconcile with the comparatively immense amount of research funding. Common tactical problems of human protozoal vaccine research include reliance upon adapted rather than natural animal disease models, and an overwhelming emphasis on novel approaches that are usually attempted in replacement of rather than for improvement upon the types of designs used in effective veterinary vaccines. Currently, all effective protozoal vaccines for animals are predicated upon the ability to grow protozoal organisms. Because human protozoal vaccines need to be as effective as animal vaccines, researchers should benefit from a comparison of existing veterinary products and leading experimental vaccine designs. With this in mind, protozoal vaccines are here reviewed. PMID- 24476954 TI - Lyme borreliosis. PMID- 24476955 TI - Transmission of acute gastroenteritis and respiratory illness from children to parents. AB - BACKGROUND: Acute respiratory illness (ARI) and acute gastroenteritis (AGE) are the most common infections in children; the risk of such illness increases with daycare attendance. We estimated the risk of transmission of ARI and AGE from daycare attendees to their parents and describe measures used by families to prevent that transmission. METHODS: We performed a retrospective cohort study of parents and children 12-60 months of age attending childcare centers attended by >=60 children in the greater Quebec City area, Canada. Participants were contacted at home by phone to answer a standardized questionnaire on infections that occurred in children and parents during the winter period. RESULTS: Overall, 374 households and 608 participants were included. AGE and ARI occurred at an incidence of 8.7 and 19 episodes per 100 child-months, respectively. Transmission to parents occurred about once in every 3 episodes for both types of infections. AGE in parents caused more frequent work absenteeism than ARI (62% vs. 34%, P < 0.005) with slightly longer duration (23% vs. 15% missing >=2 days). Hand hygiene with soap was the primary household preventive measure. The 2009 pandemic may have positively influenced home hand hygiene practices overall but alcohol-based disinfection was infrequently applied. CONCLUSIONS: Parental risk and impact of AGE and ARI acquisition from their children are substantial. ARI occur more frequently overall among children, but parental work loss appears greater with AGE transmission. Our findings suggest that preventive practices to reduce the risk of secondary ARI and AGE transmission to parents warrants greater emphasis, evaluation and education. PMID- 24476956 TI - Periostin is upregulated in coronary arteriopathy in Kawasaki disease and is a potential diagnostic biomarker. AB - Periostin was upregulated 11-fold in acute and chronic Kawasaki disease coronary arteries compared with controls (P = 0.003). Kawasaki disease patients had significantly elevated serum periostin values compared with febrile controls (P = 0.0086). There was no relationship between serum periostin values and age, gender or acute phase reactants; there was a relationship between serum periostin and maximal coronary artery Z scores that did not reach significance (P = 0.08). Periostin may prove to be useful as a component of a future diagnostic biomarker panel for Kawasaki Disease. PMID- 24476959 TI - Importance of symplasmic communication in cell differentiation. AB - Symplasmic communication via plasmodesmata (PD) is part of the system of information exchange between plant cells. Molecules that pass through the PD include ions, some hormones, minerals, amino acids, and sugars but also proteins, transcription factors, and different classes of RNA, and as such PD can participate in the coordination of plant growth and development. This review summarizes the current literature on this subject and the role of PD in signal exchange, the importance of symplasmic communication and symplasmic domains in plant cell differentiation, and highlights the future prospective in the exploration of PD functions in plants. Moreover, this review also describes the potential use of barley root epidermis and non-zygotic embryogenesis in study of symplasmic communication during cell differentiation. PMID- 24476960 TI - The TORC1 effector kinase Npr1 fine tunes the inherent activity of the Mep2 ammonium transport protein. AB - The TORC1 complex controls cell growth upon integrating nutritional signals including amino-acid availability. TORC1 notably adapts the plasma membrane protein content by regulating arrestin-mediated endocytosis of amino-acid transporters. Here we demonstrate that TORC1 further fine tunes the inherent activity of the ammonium transport protein, Mep2, a yeast homologue of mammalian Rhesus factors, independently of arrestin-mediated endocytosis. The TORC1 effector kinase Npr1 and the upstream TORC1 regulator Npr2 control Mep2 transport activity by phospho-silencing a carboxy-terminal autoinhibitory domain. Under poor nitrogen supply, Npr1 enables Mep2 S457 phosphorylation and thus ammonium transport activity. Supplementation of the preferred nitrogen source glutamine leads to Mep2 inactivation and instant S457 dephosphorylation via plasma membrane Psr1 and Psr2 redundant phosphatases. This study underscores that TORC1 also adjusts nutrient permeability to regulate cell growth in a fast and flexible response to environmental perturbation, establishing a hierarchy in the transporters to be degraded, inactivated or maintained active at the plasma membrane. PMID- 24476957 TI - Advances in stem cell mobilization. AB - Use of granulocyte colony stimulating factor (G-CSF)-mobilized peripheral blood hematopoietic progenitor cells (HPCs) has largely replaced bone marrow (BM) as a source of stem cells for both autologous and allogeneic cell transplantation. With G-CSF alone, up to 35% of patients are unable to mobilize sufficient numbers of CD34 cells/kg to ensure successful and consistent multi-lineage engraftment and sustained hematopoietic recovery. To this end, research is ongoing to identify new agents or combinations which will lead to the most effective and efficient stem cell mobilization strategies, especially in those patients who are at risk for mobilization failure. We describe both established agents and novel strategies at various stages of development. The latter include but are not limited to drugs that target the SDF-1/CXCR4 axis, S1P agonists, VCAM/VLA-4 inhibitors, parathyroid hormone, proteosome inhibitors, Grobeta, and agents that stabilize HIF. While none of the novel agents have yet gained an established role in HPC mobilization in clinical practice, many early studies exploring these new pathways show promising results and warrant further investigation. PMID- 24476961 TI - In the routine HIV testing era, primary care physicians in community health centers remain unaware of HIV testing recommendations. AB - BACKGROUND: Despite the 2006 U.S. Centers for Disease Control and Prevention (CDC) recommendations for routine HIV testing in health care settings, many persons remain untested. PURPOSE: To determine physician barriers to HIV testing, we surveyed primary care physicians in community health centers in a high HIV prevalence city. METHODS: Primary care physicians were invited via e-mail to participate in a Web-based survey. One hundred and thirty-seven physicians participated (response rate: 43.9%). RESULTS: Fifty-five physicians (41.0%) were unaware of updated CDC HIV testing recommendations. Physicians were unaware that testing should be routinely offered in primary care settings caring for adolescents (62 physicians, 45.6%) and primary care settings caring for adults (33, 24.3%). Physicians were also unaware that teenage years patients aged 13 to 17 years (68, 49.6%) and adult patients aged 18 to 64 years (40, 29.2%) should be routinely HIV tested. CONCLUSION: With the new 2013 US Preventive Services Task Force recommendations to support routine HIV testing, it is critical to address ongoing physician HIV testing barriers to mitigate the HIV epidemic. PMID- 24476963 TI - Analysis of early angiographic outcome using unique large diameter coils in comparison with standard coils in the embolization of cerebral aneurysms: a retrospective review. AB - BACKGROUND: The initial experience with the large diameter Penumbra Coil 400 (PC400) system has been positive regarding safety, efficacy, improved packing density and cost effectiveness, but follow-up data are limited. METHODS: This is a single-center retrospective review of 76 aneurysms treated with PC400 coils compared with 301 aneurysms treated with a variety of different bare platinum and bioactively coated coils. Atypical and giant aneurysms were excluded as well as those that had undergone previous treatment. Occlusion classification was determined immediately after the procedure and at short-term follow-up. RESULTS: Compared with controls, in the PC400 group fewer coils were used (3.53 vs 5.44, p<0.05), procedure time was decreased (48 vs 64 min, p<0.05) and packing density was increased (31.7% vs 24.8%, p<0.05). There were more grade III aneurysms (71.1% vs 38.2%, p<0.05) and fewer grade I aneurysms (13.2% vs 30.2%, p<0.05) in the PC400 group than in the control group immediately after the procedure. At first follow-up, however, more aneurysms in the PC400 group improved (51.3% vs 28.7%, p<0.05) in angiographic grade leading to similar rates of acceptable outcome (grades I or II) at first follow-up (PC400 79.5% vs control 77.2%). The adverse event rate was similar in the two groups. CONCLUSIONS: Large diameter PC400 coils can be used to safely treat cerebral aneurysms with fewer coils, decreased procedure time and increased packing density compared with standard coils. The early angiographic outcome is similar to that achieved with standard coils. PMID- 24476962 TI - A case of primary HIV type 1 and cytomegalovirus coinfection presenting with widespread clinical disease. AB - Coinfection of HIV-1 and cytomegalovirus (CMV) may occur given the shared routes of transmission, and the clinical presentations of each process overlap. We present a case of acute HIV-1 and CMV coinfection presenting with an acute febrile illness complicated by meningitis, hepatitis, and retinopathy. This and other similar cases demonstrate the need to consider CMV coinfection in acute HIV 1 disease, particularly in situations with significant end-organ damage. PMID- 24476964 TI - Hospital-based financial analysis of endovascular therapy and intravenous thrombolysis for large vessel acute ischemic strokes: the 'bottom line'. AB - BACKGROUND: Economic viability is important to any hospital striving to be a comprehensive stroke center. An inability to recover cost can strain sustained delivery of advanced stroke care. OBJECTIVE: To carry out a comparative financial analysis of intravenous (IV) recombinant tissue plasminogen activator and endovascular (EV) therapy in treating large vessel strokes from a hospital's perspective. METHODOLOGY: Actual hospital's charges, costs, and payments were analyzed for 265 patients who received treatment for large vessel strokes. The patients were divided into an EV (n=141) and an IV group (n=124). The net gain/loss was calculated as the difference between payments received and the total cost. RESULTS: The charges, costs, and payments were significantly higher for the EV than the IV group (p<0.0001 for all). Medicare A was the main payer. Length of stay was inversely related to net gain/loss (p<0.0001). Favorable outcome was associated with a net gain of $3853 (+/-$21,155) and poor outcome with a net deficit of $2906 (+/-$15,088) (p=0.003). The hospital showed a net gain for the EV group versus a net deficit for the IV group in patients who survived the admission (p=0.04), had a favorable outcome (p=0.1), or were discharged to home (p=0.03). There was no difference in the time in hospital based on in-hospital mortality for the EV group but patients who died in the IV group had a significantly shorter length of stay than those who survived (p=0.04). The favorable outcome of 42.3% in the EV group was significantly higher than the 29.4% in the IV group (p=0.03). CONCLUSIONS: Endovascular therapy was associated with better outcomes and higher cost-recovery than IV thrombolysis in patients with large vessel strokes. PMID- 24476965 TI - Inferences about infants' visual brain mechanisms. AB - We discuss hypotheses that link the measurements we can make with infants to inferences about their developing neural mechanisms. First, we examine evidence from the sensitivity to visual stimulus properties seen in infants' responses, using both electrophysiological measures (transient and steady-state recordings of visual evoked potentials/visual event-related potentials) and behavioral measures and compare this with the sensitivity of brain processes, known from data on mammalian neurophysiology and human neuroimaging. The evidence for multiple behavioral systems with different patterns of visual sensitivity is discussed. Second, we consider the analogies which can be made between infants' behavior and that of adults with identified brain damage, and extend these links to hypothesize about the brain basis of visual deficits in infants and children with developmental disorders. Last, we consider how these lines of data might allow us to form "inverse linking hypotheses" about infants' visual experience. PMID- 24476966 TI - Linking hypotheses underlying Class A and Class B methods. AB - Class A psychophysical observations are based on the linking hypothesis that perceptually distinguishable stimuli must correspond to different brain events. Class B observations are related to the appearance of stimuli not their discriminability. There is no clear linking hypothesis underlying Class B observations, but they are necessary for studying the effects of context on appearance, including a large class of phenomena known as "illusions." Class B observations are necessarily measures of observer bias (Fechner's "constant error") as opposed to Class A measures of sensitivity (Fechner's "variable error"). It is therefore important that Class B observations distinguish between response biases, decisional biases, and perceptual biases. This review argues that the commonly used method of single stimuli fails to do this, and that multiple-alternative forced choice (mAFC) methods can do a better job, particularly if combined with a roving pedestal. PMID- 24476967 TI - Three comments on Teller's "bridge locus". AB - The notion of a set of neurons that form a "bridge locus" serving as the immediate substrate of visual perception is examined in the light of evidence on the architecture of the visual pathway, of current thinking about perceptual representations, and of the basis of perceptual awareness. The bridge locus is likely to be part of a tangled web of representations, and this complexity raises the question of whether another scheme that relies less on geography might offer a better framework. The bridge locus bears a close relationship to the neural correlate of consciousness (NCC), and like the NCC may be a concept which is no longer precise enough to provide a useful basis for reasoning about the relationship between brain activity and perceptual experience. PMID- 24476968 TI - Trichomonads in birds--a review. AB - Members of the family Trichomonadidae, mainly Trichomonas gallinae and Tetratrichomonas gallinarum, represent important parasites in birds with worldwide presence, since being reported in the 19th century. Especially Columbiformes, Falconiformes and Strigiformes can be severely affected by trichomonads, whereas the majority of infections in Galliformes and Anatiformes are subclinical although severe infections are occasionally reported. With the recent appearance of deadly infections in wild Passeriformes the protozoan parasite T. gallinae obtained greater attention which will be addressed in this review. Although light microscopy remains the method of choice to confirm the presence of trichomonads molecular studies were introduced in recent years, in order to characterize the parasites and to establish relationships between isolates. Isolation of trichomonads is a prerequisite for detailed in vitro and in vivo studies and different media are reported to obtain suitable material. The limited information about virulence factors will be reviewed in context with the pathogenicity of trichomonads which varies greatly, indicating certain strain heterogeneity of the parasites. Options for treatment characterized by the leading role of imidazoles whose activity is sometimes hampered by resistant parasites remains a challenge for the future. Introducing more standardized genetic studies and investigations concentrating on the host-pathogen interaction should be helpful to elucidate virulence factors which might lead to new concepts of treatment. PMID- 24476969 TI - Evaluation of progression prior to surgery after neoadjuvant chemoradiotherapy with computed tomography in esophageal cancer patients. AB - BACKGROUND: The risk of tumor progression during neoadjuvant chemoradiotherapy (CRT) in esophageal cancer (EC) is around 8% to 17%. We assessed the efficacy of computed tomography (CT) to identify these patients before esophagectomy. METHODS: Ninety-seven patients with locally advanced EC treated with Carboplatin/Paclitaxel and 41.4 Gy neoadjuvantly were restaged with CT. Two radiologists reviewed pre- and post-CRT CT images. The primary outcome was detection of clinically relevant progressive disease. Missed metastases were defined as metastatic disease found during surgery or within 3 months after post CRT CT. RESULTS: Progressive disease was detected in 9 patients (9%). Both radiologists detected 5 patients with distant metastases (liver, n = 4; lung metastasis, n = 1), but missed progressive disease in 4 cases. One radiologist falsely assessed 2 metastatic lesions, but after agreement progressive disease was detected with sensitivity and specificity of 56% and 100%, respectively. CONCLUSION: CT is effective in detecting clinically relevant progressive disease in EC patients, after neoadjuvant treatment. PMID- 24476970 TI - Risk factors for failure of percutaneous drainage and need for reoperation following symptomatic gastrointestinal anastomotic leak. AB - BACKGROUND: Few studies have evaluated the role of computed tomography-guided percutaneous drainage (PD) in the management of gastrointestinal (GI) anastomotic leaks. METHODS: Ten-year review of an interventional radiology database identified patients with symptomatic GI anastomotic leaks. Clinical, laboratory, radiographic, and operative characteristics following a technically successful PD which then failed and required reoperation for anastomotic leak were compared with those successfully treated with PD. RESULTS: Sixty-one patients met study inclusion criteria. Fifty patients (82%) successfully underwent therapeutic PD of a perianastomotic fluid collection, with median follow-up of 16 months. Eleven patients (18%), at a median interval of 16 days, required reoperation following PD. A forward logistic regression showed cardiopulmonary disease (P = .03) and cancer surgery (P = .01) to be factors independently associated with the need for reoperation. The level of the anastomosis, initial fecal diversion/stoma, fluid collection size, and microbiology of aspirate did not predict failure of PD. CONCLUSIONS: Cardiopulmonary disease and cancer surgery appear to be independent predictors for failure of PD and need for reoperation following a symptomatic GI anastomotic leak. PMID- 24476971 TI - Tumour microenvironment: a beta-catenin mutation in osteoblasts induces leukaemia. PMID- 24476973 TI - Distributions of new Stockholm Convention POPs in soils across South Korea. AB - In this study, we monitored the newly added Stockholm Convention persistent organic pollutants (POPs) HCHs, PeCBz, endosulfans, chlordecone, PBDEs, PBBs and PFCs in industrial, urban, and agricultural soils in South Korea, in order to evaluate their distributions and potential sources. These POPs were widely distributed throughout South Korea, and their concentrations and distributions were affected by land use, reflecting their sources. The overall concentrations of HCHs, PeCBz, endosulfans, PBDEs, and PFCs in soils were in the range of ND (non-detectable)-0.358 ng/g (average+/-standard deviation: 0.060+/-0.080 ng/g), ND-0.531 ng/g (0.083+/-0.133 ng/g), 0.058-8.42 ng/g (2.19+/-2.43 ng/g), 0.004 4.78 ng/g (0.68+/-1.06 ng/g), and ND-1.62 ng/g (0.50+/-0.46 ng/g), respectively. Agricultural soils showed the highest concentration of endosulfan, which was the most recently used pesticide monitored in this study. On the other hand, industrial soils contained the highest concentrations of PeCBz, PBDEs, and PFCs, which were mainly introduced to environment via the industrial activities. PMID- 24476974 TI - Environmental factors influencing mercury speciation in Subarctic and Boreal lakes. AB - Environmental drivers of total mercury (TotHg) concentrations, methylmercury (MeHg) concentrations, and MeHg fractions (a proxy for methylation potential, expressed as %MeHg) were assessed in a synoptic study of 51 lakes in southeast (Boreal) and northeast (Subarctic) Norway. Concentrations of TotHg and MeHg ranged between 0.5-6.6 ng/L and <0.02-0.70 ng/L, respectively. The lakes span wide ranges of explanatory environmental variables, including water chemistry, catchment characteristics, climate conditions, and atmospheric deposition of Hg, sulphur and nitrogen (N). Dissolved organic matter (DOM), measured as total organic carbon (TOC), was the variable most strongly correlated with TotHg (r(2)=0.76) and MeHg (r(2)=0.64) concentrations. Lakes in the Subarctic region had significantly lower TotHg and MeHg concentrations, and %MeHg than lakes in the Boreal region (p<0.01), implying a lower aquatic food web exposure of aqueous Hg species in Subarctic Norway than in the Boreal lakes. Statistical modelling (partial least squares) using data from the Boreal lakes produced models explaining 82%, 75% and 50% of the spatial variation of TotHg and MeHg concentrations and %MeHg, respectively. After TOC, the most significant explanatory variables were N availability, base cation status, and lake and catchment size. We conclude that a key process driving TotHg concentrations is DOM as a transport vector, while the role of DOM for MeHg and %MeHg is likely related to a combination of transport and DOM as a substrate for methylation. Also, negative correlations between MeHg, and catchment and lake size are consistent with in-lake and in-stream de-methylation processes. The statistical relationship suggests that N availability exerts a positive contribution on concentrations of MeHg and %MeHg. PMID- 24476972 TI - The association of binge eating and neighbourhood fast-food restaurant availability on diet and weight status. AB - OBJECTIVE: Fast-food restaurants (FFR) are prevalent. Binge eating is common among overweight and obese women. For women prone to binge eating, neighbourhood FFR availability (i.e. the neighbourhood around one's home) may promote poor diet and overweight/obesity. The present study tested the effects of binge eating and neighbourhood FFR availability on diet (fat and total energy intake) and BMI among African American and Hispanic/Latino women. DESIGN: All measures represent baseline data from the Health is Power randomized clinical trial. The numbers of FFR in participants' neighbourhoods were counted and dichotomized (0 or >=1 neighbourhood FFR). Participants completed measures of binge eating status and diet. Weight and height were measured and BMI calculated. 2 (binge eating status) * 2 (neighbourhood FFR availability) ANCOVA tested effects on diet and BMI while controlling for demographics. SETTING: Houston and Austin, TX, USA. SUBJECTS: African American and Hispanic/Latino women aged 25-60 years. RESULTS: Of the total sample (n 162), 48 % had 1-15 neighbourhood FFR and 29 % were binge eaters. There was an interaction effect on BMI (P = 0.05). Binge eaters with >=1 neighbourhood FFR had higher BMI than non-binge eaters or binge eaters with no neighbourhood FFR. There were no significant interactions or neighbourhood FFR main effects on total energy or fat intake (P > 0.05). A main effect of binge eating showed that binge eaters consumed more total energy (P = 0.005) and fat (P = 0.005) than non-binge eaters. CONCLUSIONS: Binge eaters represented a substantial proportion of this predominantly overweight and obese sample of African American and Hispanic/Latino women. The association between neighbourhood FFR availability and weight status is complicated by binge eating status, which is related to diet. PMID- 24476975 TI - Modelling metal speciation in the Scheldt Estuary: combining a flexible resolution transport model with empirical functions. AB - Predicting metal concentrations in surface waters is an important step in the understanding and ultimately the assessment of the ecological risk associated with metal contamination. In terms of risk an essential piece of information is the accurate knowledge of the partitioning of the metals between the dissolved and particulate phases, as the former species are generally regarded as the most bioavailable and thus harmful form. As a first step towards the understanding and prediction of metal speciation in the Scheldt Estuary (Belgium, the Netherlands), we carried out a detailed analysis of a historical dataset covering the period 1982-2011. This study reports on the results for two selected metals: Cu and Cd. Data analysis revealed that both the total metal concentration and the metal partitioning coefficient (Kd) could be predicted using relatively simple empirical functions of environmental variables such as salinity and suspended particulate matter concentration (SPM). The validity of these functions has been assessed by their application to salinity and SPM fields simulated by the hydro environmental model SLIM. The high-resolution total and dissolved metal concentrations reconstructed using this approach, compared surprisingly well with an independent set of validation measurements. These first results from the combined mechanistic-empirical model approach suggest that it may be an interesting tool for risk assessment studies, e.g. to help identify conditions associated with elevated (dissolved) metal concentrations. PMID- 24476976 TI - Unfinished business in the regulation of shale gas production in the United States. AB - With increased drilling for natural gas, toxic chemicals used to fracture wells have been introduced into the environment accompanied by allegations of injuries. This article evaluates laws and regulations governing shale gas production to disclose ideas for offering further protection to people and the environment. The aim of the study is to offer state governments ideas for addressing contractual obligations of drilling operators, discerning health risks, disclosing toxic chemicals, and reporting sufficient information to detect problems and enforce regulations. The discussion suggests opportunities for state regulators to become more supportive of public health through greater oversight of shale gas extraction. PMID- 24476977 TI - CDC grand rounds: Reducing the burden of HPV-associated cancer and disease. AB - Human papillomavirus (HPV) infection is the most common sexually transmitted infection in men and women in the United States. Most sexually active persons will acquire HPV in their lifetime. Recent data indicate that approximately 79 million persons are currently infected with HPV, and 14 million persons are newly infected each year in the United States. PMID- 24476978 TI - Rapidly building global health security capacity--Uganda demonstration project, 2013. AB - Increasingly, the need to strengthen global capacity to prevent, detect, and respond to public health threats around the globe is being recognized. CDC, in partnership with the World Health Organization (WHO), has committed to building capacity by assisting member states with strengthening their national capacity for integrated disease surveillance and response as required by International Health Regulations (IHR). CDC and other U.S. agencies have reinforced their pledge through creation of global health security (GHS) demonstration projects. One such project was conducted during March-September 2013, when the Uganda Ministry of Health (MoH) and CDC implemented upgrades in three areas: 1) strengthening the public health laboratory system by increasing the capacity of diagnostic and specimen referral networks, 2) enhancing the existing communications and information systems for outbreak response, and 3) developing a public health emergency operations center (EOC) (Figure 1). The GHS demonstration project outcomes included development of an outbreak response module that allowed reporting of suspected cases of illness caused by priority pathogens via short messaging service (SMS; i.e., text messaging) to the Uganda District Health Information System (DHIS-2) and expansion of the biologic specimen transport and laboratory reporting system supported by the President's Emergency Plan for AIDS Relief (PEPFAR). Other enhancements included strengthening laboratory management, establishing and equipping the EOC, and evaluating these enhancements during an outbreak exercise. In 6 months, the project demonstrated that targeted enhancements resulted in substantial improvements to the ability of Uganda's public health system to detect and respond to health threats. PMID- 24476979 TI - Strengthening global health security capacity--Vietnam demonstration project, 2013. AB - Over the past decade, Vietnam has successfully responded to global health security (GHS) challenges, including domestic elimination of severe acute respiratory syndrome (SARS) and rapid public health responses to human infections with influenza A(H5N1) virus. However, new threats such as Middle East respiratory syndrome coronavirus (MERS-CoV) and influenza A(H7N9) present continued challenges, reinforcing the need to improve the global capacity to prevent, detect, and respond to public health threats. In June 2012, Vietnam, along with many other nations, obtained a 2-year extension for meeting core surveillance and response requirements of the 2005 International Health Regulations (IHR). During March-September 2013, CDC and the Vietnamese Ministry of Health (MoH) collaborated on a GHS demonstration project to improve public health emergency detection and response capacity. The project aimed to demonstrate, in a short period, that enhancements to Vietnam's health system in surveillance and early detection of and response to diseases and outbreaks could contribute to meeting the IHR core capacities, consistent with the Asia Pacific Strategy for Emerging Diseases. Work focused on enhancements to three interrelated priority areas and included achievements in 1) establishing an emergency operations center (EOC) at the General Department of Preventive Medicine with training of personnel for public health emergency management; 2) improving the nationwide laboratory system, including enhanced testing capability for several priority pathogens (i.e., those in Vietnam most likely to contribute to public health emergencies of international concern); and 3) creating an emergency response information systems platform, including a demonstration of real-time reporting capability. Lessons learned included awareness that integrated functions within the health system for GHS require careful planning, stakeholder buy-in, and intradepartmental and interdepartmental coordination and communication. PMID- 24476980 TI - Notes from the field: rotavirus vaccine administration errors--United States, 2006-2013. AB - Two live rotavirus oral vaccines, RotaTeq (RV5) (Merck & Co., Inc.) and Rotarix (RV1) (GlaxoSmithKline Biologicals), are approved for prevention of rotavirus gastroenteritis and recommended at ages 2, 4 (RV5/RV1), and 6 (RV5) months by the Advisory Committee on Immunization Practices. Because most childhood vaccines are injectable, vaccination providers might have less experience administering oral vaccines. To assess that hypothesis, CDC searched for reports to the Vaccine Adverse Event Reporting System (VAERS) of rotavirus vaccine administration errors involving injection and eye splashes in the United States during the period January 1, 2006-August 1, 2013. A total of 66 reports were found. PMID- 24476981 TI - Effects of changes in adipocyte hormones and visceral adipose tissue and the reduction of obesity-related comorbidities after laparoscopic sleeve gastrectomy in Japanese patients with severe obesity. AB - The aim of this study was to evaluate the relative contribution of serum adipokines and adipokines from the patient's omentum-derived adipocytes (PODAs) and visceral adipose tissue (VAT) of Japanese patients with severe obesity. Secondarily, we analyzed patients' metabolic changes after laparoscopic sleeve gastrectomy (LSG). Twenty-three LSG patients and 23 non-obese patients undergoing elective abdominal surgery were enrolled. The levels of adipokines in the serum and the PODAs were measured. The clinical and metabolic data were evaluated at 6 months after LSG. The mean serum leptin levels and the mean serum plasminogen activator inhibitor type-1 (PAI-1) levels were significantly greater (p < 0.001) and the mean adiponectin levels were significantly lower in the LSG group (p = 0.006). In the measurements of the PODAs, the mean leptin levels (p < 0.001) were significantly greater and the mean adiponectin levels (p < 0.001) were significantly lower in the LSG group. The mean BMI (-12 kg/m2, p < 0.001) and mean VAT (-135.5 cm2, p = 0.001) were significantly decreased after LSG. In nine patients with type 2 diabetes mellitus, the reduction in VAT correlated with the change in high-sensitivity C-reactive protein (p = 0.006) and the homeostasis model of assessment of insulin resistance (p = 0.001). After 6 months, LSG markedly improved most obesity-related comorbidities. Our results suggest that LSG may contribute to VAT reduction, improved adipocyte hormone levels, and changes in gut physiology and endocrinology. PMID- 24476982 TI - Pregnancy outcomes of gestational diabetes mellitus according to pre-gestational BMI in a retrospective multi-institutional study in Japan. AB - The aim of this study was to determine the effects of pre-gestational body mass index on pregnancy outcomes of women with gestational diabetes in Japan. A multi institutional retrospective study was performed. We examined pregnant women who met the former criteria for gestational diabetes in Japan, receiving dietary intervention with self-monitoring of blood glucose with or without insulin therapy. Women with gestational diabetes were divided into three groups according to pre-gestational body mass index: body mass index <25 (control group), 25 <= body mass index <30 (overweight group), body mass index >=30 (obese group). Data from a total of 1,758 eligible women were collected from 40 institutions. Participants included 960 controls, 426 overweight women, and 372 obese women with gestational diabetes. Gestational weight gain was highest in the control and lowest in the obese group. The prevalences of chronic hypertension and pregnancy induced hypertension were higher in the overweight and obese groups than in the control group. Multiple logistic regression analysis revealed pre-gestational body mass index, gestational weight gain, chronic hypertension, and nulliparity to be associated with the onset of pregnancy induced hypertension, while the 75-g OGTT results were unrelated to pregnancy induced hypertension. The prevalence of large-for-gestational age was lower in infants born to obese women than in those born to overweight or control women. The present results suggest that medical interventions for obese women with gestational diabetes may contribute to reducing the prevalence of large-for-gestational age but would not achieve marked reductions in maternal complications. PMID- 24476983 TI - Micellar drug nanocarriers and biomembranes: how do they interact? AB - Pluronic based formulations are among the most successful nanomedicines and block copolymer micelles including drugs that are undergoing phase I/II studies as anticancer agents. Using coarse-grained models, molecular dynamics simulations of large-scale systems, modeling Pluronic micelles interacting with DPPC lipid bilayers, on the MUs timescale have been performed. Simulations show, in agreement with experiments, the release of Pluronic chains from the micelle to the bilayer. This release changes the size of the micelle. Moreover, the presence of drug molecules inside the core of the micelle has a strong influence on this process. The picture emerging from the simulations is that the micelle stability is a result of an interplay of drug-micelle core and block-copolymer-bilayer interactions. The equilibrium size of the drug vector shows a strong dependency on the hydrophobicity of the drug molecules embedded in the core of the micelle. In particular, the radius of the micelle shows an abrupt increase in a very narrow range of drug molecule hydrophobicity. PMID- 24476984 TI - Food hygiene, deprivation, types of premises and rates of gastrointestinal illnesses in the UK. AB - OBJECTIVE: To understand more about the relationship between economic deprivation, types of premises, food hygiene scores and rates of gastrointestinal illness in the UK. DESIGN: Data were extracted from the UK Food Standards Agency for about 300 000 UK premises which had hygiene scores based on visits from local authority food safety officers. These scores were analysed by type of premises, deprivation and local authority. Local authority-level average scores were mapped and compared with rates of laboratory-detected gastrointestinal illness from the Health Protection Agency. SETTING: UK. SUBJECTS: UK premises (n 311 458) from 341 local authority areas that sell or produce food. RESULTS: There was a modest but statistically significant relationship between average food hygiene score and deprivation, which was caused by deprived areas having more of the categories of premises with significantly lower hygiene scores; these were pub/club (n 40 525), restaurant/cafe/canteen (n 73 052), small retailer (n 42 932) and takeaway (n 36 708). No relationship was established between local authority average food hygiene scores and rates of laboratory-detected gastrointestinal illness; however, this result does not preclude a relationship between food hygiene and rates of gastrointestinal illnesses, as laboratory-detected illness rates make up only a small proportion of actual rates of illness in the community. CONCLUSIONS: Certain types of UK premises are more likely to have low hygiene scores, which means that they should be targeted more for enforcement. These types of premises are more prevalent in the most economically deprived areas. PMID- 24476985 TI - A synthetic, self-oscillating vocal fold model platform for studying augmentation injection. AB - OBJECTIVE: To design and evaluate a platform for studying the mechanical effects of augmentation injections using synthetic, self-oscillating vocal fold models. STUDY DESIGN: Basic science. METHODS: Life-sized, synthetic, multilayer, self oscillating vocal fold models were created that simulated bowing via volumetric reduction of the body layer relative to that of a normal, unbowed model. Material properties of the layers were unchanged. Models with varying degrees of bowing were created and paired with normal models. Following initial acquisition of data (onset pressure, vibration frequency, flow rate, and high-speed image sequences), bowed models were injected with silicone that had material properties similar to those used in augmentation procedures. Three different silicone injection quantities were tested: sufficient to close the glottal gap, insufficient to close the glottal gap, and excess silicone to create convex bowing of the bowed model. The above-mentioned metrics were again taken and compared. Pre- and post injection high-speed image sequences were acquired using a hemilarynx setup, from which medial surface dynamics were quantified. RESULTS: The models vibrated with mucosal wave-like motion and at onset pressures and frequencies typical of human phonation. The models successfully exhibited various degrees of bowing which were then mitigated by injecting filler material. The models showed general pre- to post-injection decreases in onset pressure, flow rate, and open quotient and a corresponding increase in vibration frequency. CONCLUSION: The model may be useful in further explorations of the mechanical consequences of augmentation injections. PMID- 24476986 TI - Lateral pH gradient between OXPHOS complex IV and F(0)F(1) ATP-synthase in folded mitochondrial membranes. AB - Ion-driven ATP synthesis by rotary F0F1 ATP-synthase powers aerobic life. Since Mitchell's seminal hypothesis, this synthesis has been discussed in terms of the proton-motive force between two bulk phases, each in equilibrium. In active mitochondria, a steady proton flow cycles between pumps and the distant ATP synthase. Here we determine the lateral pH profile along the p-side of cristae in situ by attaching a ratiometric fluorescent pH-sensitive GFP variant to OXPHOS complex IV, a proton pump, and the dimeric F0F1 ATP-synthase, a proton consumer. In respiring HeLa cells, we observe that the local pH at F0F1 dimers is 0.3 units less acidic than that at complex IV. This finding is consistent with the calculated pH profile for steady proton diffusion from CIV to F0F1. The observed lateral variation in the proton-motive force necessitates a modification to Peter Mitchell's chemiosmotic proposal. The experimental technique can be extended to other pH-dependent reactions in membrane microcompartments. PMID- 24476987 TI - The impact of nicotine lozenges and stimulus expectancies on cigarette craving. AB - Reduced craving associated with nicotine replacement therapy use is frequently attributed to the effects of nicotine pharmacology, however non-pharmacological factors may also play a role. This study examined the impact of nicotine pharmacology and non-pharmacological components of an acute nicotine lozenge (4 mg) on cigarette craving, mood and heart rate in 70 daily smokers (36 male). Smoking-related stimuli were used to assess cue-induced craving. Participants were randomly assigned to one of four conditions in a balanced placebo design where half the participants were provided deceptive information regarding the nicotine content of a lozenge. Subjective ratings of craving and mood were collected and heart rate was assessed before and after neutral and smoking cues. Nicotine expectancy reduced withdrawal-related craving (p = 0.006) regardless of actual nicotine administration while combined nicotine expectancy and administration reduced intentions to smoke (p = 0.046) relative to each of the other conditions. Exposure to smoking-related stimuli increased cigarette craving (p <= 0.001) and negative affect (p <= 0.001) regardless of expectancy or pharmacology. Following the smoking cue, women reported a greater increase in withdrawal-related craving than men (p = 0.027). Findings suggest that both pharmacological and non-pharmacological components of nicotine lozenge administration contribute to its acute effects on craving, yet neither appears effective in preventing craving triggered by exposure to environmental smoking stimuli. PMID- 24476988 TI - Effect of exercise on burn-induced changes in tissue-specific glucose metabolism. AB - Exercise is a component of the clinical management for burn patients, to help reduce muscle wasting associated with prolonged hospitalization. In the present study the authors examined 2-deoxy-2-[18F] fluoro-D-glucose (18FDG) uptake in mice subjected to burn injury with and without exercise. Mice had their the dorsums shaven, were placed in molds, and the exposed area was immersed in 90 degrees C water for 9 seconds followed by resuscitation with saline (2 ml) to produce a 30% full-thickness burn injury. Twenty-four hours later, the mice were subjected to treadmill exercise for 1 hour. Before exercise, mice were injected with ~50 MUCi 18FDG. Mice were killed after running and a complete biodistribution was performed. Exercise produced a stimulation of 18FDG update by skeletal muscle and heart, while reducing 18FDG accumulation in brain. Burn injury had no significant effect on 18FDG update by skeletal muscle, but did increase 18FDG accumulation in heart, while reducing 18FDG accumulation in brain. However, exercise combined with a burn injury produced a significant increase in 18FDG uptake in the skeletal muscle compared with the burned mice, as great as that produced in the sham animals subjected to exercise. The combination of burn plus exercise appeared to prevent the stimulation of 18FDG uptake by the heart produced by burn injury alone. Exercise treatment did not correct the changes in 18FDG uptake in the brain produced by burn injury. Separately, exercise and burn injury significantly increased serum interleukin-6 levels, increases that were higher when exercise was combined with the burn injury. These findings suggest that exercise may exert some therapeutic effects in burn patients by tissue specific modulation of glucose metabolism, and these changes may be related to interleukin-6. PMID- 24476990 TI - Extensive toxic epidermal necrolysis versus acute graft versus host disease after allogenic hematopoietic stem-cell transplantation: challenges in diagnosis and management. AB - Toxic epidermal necrolysis (TEN) is a rare complication after allogeneic hematopoietic stem-cell transplantation and carries high mortality rates. Graft vs-host disease (GVHD) is also a life-threatening complication, and potentially indistinguishable from TEN because of similar clinical symptoms. However, current therapeutic recommendations differ between these two conditions, thereby posing a diagnostic dilemma. The authors, herein, present a complicated postoperative course after bone marrow transplantation with concurrent gastrointestinal and hepatic GVHD, and extensive epidermolytic disease compatible with both severe cutaneous GVHD and TEN. An early consult to a specialized burn service, and prompt transfer to a burn intensive care unit with extensive supportive care and nursing are of paramount importance in the management of immunosuppressed patients with TEN. Better understanding of the pathogenesis of TEN and GVHD after hematopoietic stem-cell transplantation, further treatment strategies, and more advanced diagnostic techniques are still needed to achieve acceptable mortality rates. PMID- 24476989 TI - Commercially available topical platelet-derived growth factor as a novel agent to accelerate burn-related wound healing. AB - The authors investigated whether the application of platelet-derived growth factor (PDGF) to donor site wounds would speed healing in a porcine model. In a red duroc pig model, three wounds that were 3 inches * 3 inches were created with a dermatome (0.06-inch depth) on one side of two different animals. These wounds were digitally and laser Doppler (LDI) imaged and biopsied immediately pre- and postwound creation and every 2 days for 2 weeks. A set of identical wounds were subsequently created on the opposite side of the same animals and treated with topical PDGF (becaplermin gel 0.01%, 4 g/wound) immediately on wounding. PDGF treated wounds were imaged and biopsied as above. Digital images of wounds were assessed for epithelialization by clinicians using an ordinal scale. Perfusion units (PU) were evaluated by LDI. Wound healing was evaluated by hematoxylin and eosin histological visualization of an epithelium and intact basement membrane. First evidence of partial epithelialization was seen in control and PDGF-treated wounds within 7.7 +/- 1.4 and 6.4 +/- 1.1 days postwounding, respectively (P=.03). Completely epithelialized biopsies were seen in control and PDGF-treated wounds at 11.7 +/- 2.6 and 9.6 +/- 1.5 days, respectively (P=.02). Clinician evaluation of digital images showed that on day 9, control wounds were, on average, 48.3 +/- 18.5% epithelialized vs 57.2 +/- 20.2% epithelialized for PDGF treated wounds. At day 16, control wounds showed an average of 72.9 +/- 14.6% epithelialization and PDGF-treated wounds showed an average of 90 +/- 11.8%epithelialization. Overall, PDGF-treated wounds had statistically significantly higher scores across all timepoints (P=.02). Average perfusion units as measured by LDI were similar for control and PDGF-treated wounds at time of excision (225 +/- 81and 257 +/- 100, respectively). On day 2 postwounding, average PU for control wounds were 803 and were 764 for PDGF-treated wounds. Control wounds maintained higher PU values compared with PDGF-treated wounds at all time points and returned to excision PU values by day 12.2 +/- 1.1 postwounding. PDGF-treated wounds reached the same values by day 9.7 +/- 2.3 (P=.03). The authors conclude that topical PDGF speeds time to epithelialization of partial-thickness wounds in a porcine model as evidenced by histology, clinical appearance, and time to return to prewounding vascularity. PMID- 24476991 TI - Falling clothes irons rarely cause burns. AB - Children's Hospital of Michigan's Burn Center treats approximately three pediatric contact burns annually related to clothes irons, which involve the face, torso, and extremities. These burns leave well-demarcated burn patterns, including the steam holes from the heat plate of the iron. The average age of these children is 15 months. The history given by the parent is that the child pulled the cord of an iron that was on an ironing board or high shelf. It seemed unlikely to the investigators that a falling iron would produce such demarcated burns. A free-standing shelf unit was built with shelf heights of 36, 60, and 72 inches (the height of an ironing board and shelves at home). Three irons of different weights were put in three different positions on each shelf, with the cord dangling. A doll the approximate size of a 15-month old was positioned in front of the shelf. The dangling cord was pulled, and the falling iron was videotaped. The video was edited in freeze frame at the point at which the iron hit the doll. Two hundred seventy falls were recorded. The flat heat plate of the iron never hit the doll. The linear edge of the heat plate hit the doll on only seven falls. This study demonstrates that it is very unlikely for the flat heat plate of a falling iron to contact a toddler-sized doll. Children who allegedly sustain demarcated burns in this manner need to be investigated for nonaccidental injury. PMID- 24476992 TI - Haemogregarines from western Palaearctic freshwater turtles (genera Emys, Mauremys) are conspecific with Haemogregarina stepanowi Danilewsky, 1885. AB - The majority of Haemogregarina species have been based on the morphology of their erythrocytic stages and supposed strict host specificity. The quantity of species with a limited number of overlapping diagnostic traits has led to a considerable mess in haemogregarine taxonomy and significant synonymy. We analysed host specificity, intra- and interspecific variability, evolutionary relationships, and the distribution of the type species of the genus Haemogregarina--H. stepanowi. The morphology of blood stages and 18S rDNA sequences of this haemogregarine from four western Palaearctic hard-shelled freshwater turtles (Emys orbicularis, Mauremys caspica, Mauremys leprosa and Mauremys rivulata) were compared with Haemogregarina balli. Additional sequences of 18S rDNA of Haemogregarina-like isolates collected from three species of African hinged terrapins (genus Pelusios) were used to enlarge the dataset for phylogenetic analyses. Thirteen sequences (1085 bp) of Haemogregarina representing all four western Palaearctic turtle species were identical, corresponding to H. stepanowi, which is closely related to the Nearctic species H. balli. In our analyses, Haemogregarina spp. constituted a monophyletic clade sister to the genus Hepatozoon. Haemogregarina stepanowi possesses a wide distribution range from the Maghreb, through Europe, Turkey and the Middle East to Iran. We consider that the genus Haemogregarina has a low host specificity crossing the family level of its vertebrate hosts and that its distribution is likely to be linked to the vector and definitive host--the leech. PMID- 24476993 TI - Liposomes produced by reverse phase evaporation: in vitro and in vivo efficacy of diminazene aceturate against Trypanosoma evansi. AB - This study aimed to develop and test the in vitro and in vivo effectiveness of diminazene aceturate encapsulated into liposomes (L-DMZ) on Trypanosoma evansi. To validate the in vitro tests with L-DMZ, the efficacy of a commercial formulation of diminazene aceturate (C-DMZ) was also assessed. The tests were carried out in culture medium for T. evansi, at concentrations of 0.25, 0.5, 1, 2 and 3 MUg mL(-1) of L-DMZ and C-DMZ. A dose-dependent effect was observed for both formulations (L-DMZ and C-DMZ), with the highest dose-dependent mortality of trypomastigotes being observed at 1 and 3 h after the onset of tests with L-DMZ. The results of in vivo tests showed the same effects in the animals treated with L-DMZ and C-DMZ in single doses of 3.5 mg kg(-1) and for 5 consecutive days (3.5 mg kg(-1) day(-1)). It was possible to conclude that T. evansi showed greater in vitro susceptibility to L-DMZ when compared with C-DMZ. In vivo tests suggest that treatment with the L-DMZ and C-DMZ showed similar efficacy in vivo. The potential of the formulation developed in this study was clearly demonstrated, as it increased the efficacy of the treatment against trypanosomosis, but more studies are needed to increase the effectiveness in vivo. PMID- 24476994 TI - Acellular porcine small intestinal submucosa graft for cervicovaginal reconstruction in eight patients with malformation of the uterine cervix. AB - STUDY QUESTION: Can surgical reconstruction of the cervix and vagina in patients be achieved using an acellular porcine small intestinal submucosa (SIS) graft? SUMMARY ANSWER: Our experiences of combined laparoscopic and vaginal cervicovaginal reconstruction using an SIS graft in eight patients were positive, with successful reconstruction and no complications, cervical stenosis or vaginal stenosis. WHAT IS KNOWN ALREADY: In patients with agenesis and dysgenesis of the uterine cervix and vagina, surgical reconstruction of the internal genitalia is a challenging problem for gynecologists. Hysterectomy with the creation of an artificial vagina was the treatment of choice in the 1990s. Recently, conservative management has been gradually adopted to avoid extirpation of the uterus, including the canalization techniques, the uterovaginal anastomosis and the reconstruction of cervical and vaginal agenesis with some autologous tissues. STUDY DESIGN, SIZE, DURATION: This prospective observational study from January 2012 to March 2013 included 8 patients aged 10-18 years with malformation of the cervix (1 with cervical agenesis, 1 with a cervical body consisting of a fibrous band and 6 with obstruction of the cervical os) and vagina (4 with complete vaginal aplasia and 4 with a 1-3 cm long vaginal pouch) diagnosed by physical examination and magnetic resonance imaging. PARTICIPANTS/MATERIALS, SETTING, METHODS: Eight patients underwent combined laparoscopic and vaginal cervicovaginal reconstruction using an SIS graft during the end of menstruation. A T-shaped intrauterine device connected with a 14-French Foley catheter was inserted into the uterine cavity to keep the newly created cervix patent, and then a permanent lower uterine cerclage was placed. Patients were assessed post operatively at 1, 2, 4, 6, 12 and 15 months, and data on menstruation and the morphology of the neovagina and cervix were recorded. MAIN RESULTS AND THE ROLE OF CHANCE: The mean +/- SD age of the patients was 14.5 +/- 2.8 (10-18) years. All patients had a history of cyclic abdominal pain, and the average delay in diagnosis was 4.5 +/- 4.0 (0-12) months. One patient had a previous history of unsuccessful attempt at canalization and two post-operative hematometra drainages before referral. The mean operating time was 201 +/- 67 (120-330) min, with a mean estimated blood loss of 157 +/- 154 (30-500) ml. The first case was converted to laparotomy, and the others were successfully completed. None of the patients had a complication or required blood transfusion. All the patients showed resumption of menstruation. The patients were followed for 8 +/- 4 (4-15) months, and no cervical or vaginal stenosis occurred in any of the cases. LIMITATIONS, REASONS FOR CAUTION: The sample size of this study was small. A larger study that compared this method with previous techniques regarding the complication and success rates would increase the value of the study. WIDER IMPLICATIONS OF THE FINDINGS: A combined laparoscopic and vaginal cervicovaginal reconstruction with an SIS graft is a potential alternative to the management of congenital agenesis and dysgenesis of uterine cervix and vagina. STUDY FUNDING/COMPETING INTEREST(S): The work was supported by National Key Clinical Faculty Construction Program of China. No competing interests are declared. PMID- 24476995 TI - Insufficient autumn vitamin D intake and low vitamin D status in 7-year-old Icelandic children. AB - OBJECTIVE: The aim was to investigate autumn vitamin D intake and status in 7 year-old Icelanders, fitting BMI and cardiorespiratory fitness as predictors. DESIGN: Three-day food records and fasting blood samples were collected evenly from September to November, and cardiorespiratory fitness was measured with an ergometer bike. Food and nutrient intakes were calculated, and serum 25 hydroxyvitamin D (s-25(OH)D) and serum parathyroid hormone were analysed. Suboptimal vitamin D status was defined s-25(OH)D <50 nmol/l, and deficient status as s-25(OH)D <25 nmol/l. SETTING: School-based study in Reykjavik, Iceland in 2006. SUBJECTS: Of the 7-year-olds studied (n 265), 165 returned valid intake information (62 %), 158 gave blood samples (60 %) and 120 gave both (45 %). RESULTS: Recommended vitamin D intake (10 MUg/d) was reached by 22.4 % of the children and 65.2 % had s-25(OH)D <50 nmol/l. Median s-25(OH)D was higher for children taking vitamin D supplements (49.2 nmol/l v. 43.2 nmol/l, respectively; P < 0.0 0 1). Median s-25(OH)D was lower in November (36.7 nmol/l) than in September (59.9 nmol/l; P < 0.001). The regression model showed that week of autumn accounted for 18.9 % of the variance in s-25(OH)D (P < 0.001), vitamin D intake 5.2 % (P < 0.004) and cardiorespiratory fitness 4.6 % (P < 0.005). CONCLUSIONS: A minority of children followed the vitamin D recommendations and 65 % had suboptimal vitamin D status during the autumn. Week of autumn was more strongly associated with vitamin D status than diet or cardiorespiratory fitness, which associated with vitamin D status to a similar extent. These results demonstrate the importance of sunlight exposure during summer to prevent suboptimal vitamin D status in young schoolchildren during autumn in northern countries. An increased effort is needed for enabling adherence to the vitamin D recommendations and increasing outdoor activities for sunlight exposure. PMID- 24476996 TI - Predicting cancer's next move. PMID- 24476997 TI - Investigating MicroRNA Expression Profiles in Pancreatic Cystic Neoplasms. AB - OBJECTIVES: Current diagnostic tools for pancreatic cysts fail to reliably differentiate mucinous from nonmucinous cysts. Reliable biomarkers are needed. MicroRNAs (miRNA) may offer insights into pancreatic cysts. Our aims were to (1) identify miRNAs that distinguish benign from both premalignant cysts and malignant pancreatic lesions using formalin-fixed, paraffin-embedded (FFPE) pathology specimens; (2) identify miRNAs that distinguish mucinous cystic neoplasm (MCN) from branch duct-intraductal papillary mucinous neoplasm (BD IPMN). METHODS: A total of 69 FFPE pancreatic specimens were identified: (1) benign (20 serous cystadenoma (SCA)), (2) premalignant (10 MCN, 10 BD-IPMN, 10 main duct IPMN (MD-IPMN)), and (3) malignant (19 pancreatic ductal adenocarcinoma (PDAC)). Total nucleic acid extraction was performed followed by miRNA expression profiling of 378 miRNAs interrogated using TaqMan MicroRNA Arrays Pool A and verification of candidate miRNAs. Bioinformatics was used to generate classifiers. RESULTS: MiRNA profiling of 69 FFPE specimens yielded 35 differentially expressed miRNA candidates. Four different 4-miRNA panels differentiated among the lesions: one panel separated SCA from MCN, BD-IPMN, MD IPMN, and PDAC with sensitivity 85% (62, 97), specificity 100% (93, 100), a second panel distinguished MCN from SCA, BD-IPMN, MD-IPMN, and PDAC with sensitivity and specificity 100% (100, 100), a third panel differentiated PDAC from IPMN with sensitivity 95% (76, 100) and specificity 85% (72, 96), and the final panel diagnosed MCN from BD-IPMN with sensitivity and specificity approaching 100%. CONCLUSIONS: MiRNA profiling of surgical pathology specimens differentiates serous cystadenoma from both premalignant pancreatic cystic neoplasms and PDAC and MCN from BD-IPMN. PMID- 24476998 TI - Turning the Titanic. PMID- 24476999 TI - Right answers, wrong questions in clinical research. AB - To ensure that clinical research arrives at the "right" answers to the right questions for patients, studies should be designed to more closely approximate real-world use of therapeutics and devices. PMID- 24477001 TI - Bioengineering dermo-epidermal skin grafts with blood and lymphatic capillaries. AB - The first bioengineered, autologous, dermo-epidermal skin grafts are presently undergoing clinical trials; hence, it is reasonable to envisage the next clinical step at the forefront of plastic and burn surgery, which is the generation of autologous skin grafts that contain vascular plexuses, preformed in vitro. As the importance of the blood, and particularly the lymphatic vascular system, is increasingly recognized, it is attractive to engineer both human blood and lymphatic vessels in one tissue or organ graft. We show here that functional lymphatic capillaries can be generated using three-dimensional hydrogels. Like normal lymphatics, these capillaries branch, form lumen, and take up fluid in vitro and in vivo after transplantation onto immunocompromised rodents. Formation of lymphatic capillaries could be modulated by both lymphangiogenic and anti lymphangiogenic stimuli, demonstrating the potential usefulness of this system for in vitro testing. Blood and lymphatic endothelial cells never intermixed during vessel development, nor did blood and lymphatic capillaries anastomose under the described circumstances. After transplantation of the engineered grafts, the human lymphatic capillaries anastomosed to the nude rat's lymphatic plexus and supported fluid drainage. Successful preclinical results suggest that these skin grafts could be applied on patients suffering from severe skin defects. PMID- 24477000 TI - Intramuscular therapeutic vaccination targeting HPV16 induces T cell responses that localize in mucosal lesions. AB - About 25% of high-grade cervical intraepithelial neoplasias (CIN2/3) caused by human papillomavirus serotype 16 (HPV16) undergo complete spontaneous regression. However, to date, therapeutic vaccination strategies for HPV disease have yielded limited success when measured by their ability to induce robust peripheral blood T cell responses to vaccine antigen. We report marked immunologic changes in the target lesion microenvironment after intramuscular therapeutic vaccination targeting HPV16 E6/E7 antigens, in subjects with CIN2/3 who had modest detectable responses in circulating T lymphocytes. Histologic and molecular changes, including markedly (average threefold) increased intensity of CD8(+) T cell infiltrates in both the stromal and epithelial compartments, suggest an effector response to vaccination. Postvaccination cervical tissue immune infiltrates included organized tertiary lymphoid-like structures in the stroma subjacent to residual intraepithelial lesions and, unlike infiltrates in unvaccinated lesions, showed evidence of proliferation induced by recognition of cognate antigen. At a molecular level, these histologic changes in the stroma were characterized by increased expression of genes associated with immune activation (CXCR3) and effector function (Tbet and IFNbeta), and were also associated with an immunologic signature in the overlying dysplastic epithelium. High-throughput T cell receptor sequencing of unmanipulated specimens identified clonal expansions in the tissue that were not readily detectable in peripheral blood. Together, these findings indicate that peripheral therapeutic vaccination to HPV antigens can induce a robust tissue-localized effector immune response, and that analyses of immune responses at sites of antigen are likely to be much more informative than analyses of cells that remain in the circulation. PMID- 24477002 TI - Antioxidants accelerate lung cancer progression in mice. AB - Antioxidants are widely used to protect cells from damage induced by reactive oxygen species (ROS). The concept that antioxidants can help fight cancer is deeply rooted in the general population, promoted by the food supplement industry, and supported by some scientific studies. However, clinical trials have reported inconsistent results. We show that supplementing the diet with the antioxidants N-acetylcysteine (NAC) and vitamin E markedly increases tumor progression and reduces survival in mouse models of B-RAF- and K-RAS-induced lung cancer. RNA sequencing revealed that NAC and vitamin E, which are structurally unrelated, produce highly coordinated changes in tumor transcriptome profiles, dominated by reduced expression of endogenous antioxidant genes. NAC and vitamin E increase tumor cell proliferation by reducing ROS, DNA damage, and p53 expression in mouse and human lung tumor cells. Inactivation of p53 increases tumor growth to a similar degree as antioxidants and abolishes the antioxidant effect. Thus, antioxidants accelerate tumor growth by disrupting the ROS-p53 axis. Because somatic mutations in p53 occur late in tumor progression, antioxidants may accelerate the growth of early tumors or precancerous lesions in high-risk populations such as smokers and patients with chronic obstructive pulmonary disease who receive NAC to relieve mucus production. PMID- 24477003 TI - Structures of an intramembrane vitamin K epoxide reductase homolog reveal control mechanisms for electron transfer. AB - The intramembrane vitamin K epoxide reductase (VKOR) supports blood coagulation in humans and is the target of the anticoagulant warfarin. VKOR and its homologues generate disulphide bonds in organisms ranging from bacteria to humans. Here, to better understand the mechanism of VKOR catalysis, we report two crystal structures of a bacterial VKOR captured in different reaction states. These structures reveal a short helix at the hydrophobic active site of VKOR that alters between wound and unwound conformations. Motions of this 'horizontal helix' promote electron transfer by regulating the positions of two cysteines in an adjacent loop. Winding of the helix separates these 'loop cysteines' to prevent backward electron flow. Despite these motions, hydrophobicity at the active site is maintained to facilitate VKOR catalysis. Biochemical experiments suggest that several warfarin-resistant mutations act by changing the conformation of the horizontal helix. Taken together, these studies provide a comprehensive understanding of VKOR function. PMID- 24477004 TI - Determinants of intrathoracic adipose tissue volume and associations with cardiovascular disease risk factors in Amish. AB - BACKGROUND AND AIM: Hypothesizing that intrathoracic fat might exert local effects on the coronary vasculature, we assessed the association of intrathoracic fat volume and its two subcomponents with coronary artery calcification (CAC) in 909 relatively healthy Amish adults. METHODS AND RESULTS: Intrathoracic fat, which is comprised of fat between the surface of the heart and the visceral epicardium (epicardial fat) and fat around the heart but outside of the fibrous pericardium (pericardial fat), was measured from electron beam CT scans. We examined the association between intrathoracic fat volume and cardiovascular disease risk factors in multivariate regression model. Fat volume in the epicardial and pericardial compartments were highly correlated with each other and with body mass index. Neither CAC extent nor CAC presence (Agatston score > 0) was associated with increased intrathoracic fat volume in sex-stratified models adjusting for age (p > 0.10). Intrathoracic fat volume was significantly correlated with higher systolic/diastolic blood pressure, pulse pressure, fasting glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol in sex-stratified models adjusting for age (p < 0.05). However, associations were attenuated after further adjustment for body mass index. CONCLUSIONS: These data do not provide support for a significant role for intrathoracic fat in the development of CAC. PMID- 24477005 TI - Impact of mild to moderate reductions of glomerular filtration rate on coronary artery disease severity. AB - BACKGROUND & AIMS: The bases of the link between reduced glomerular filtration rate (GFR) and coronary artery disease (CAD) are complex and to some extent still unclear. We performed this observational, single referral center, cohort study to evaluate whether mild to moderate GFR reduction is associated with more severe CAD and/or with a worse cardiac prognosis independently of proteinuria, diabetes and traditional risk factors. METHODS AND RESULTS: In 1752 consecutive non diabetic patients without proteinuria or moderate/severe kidney disease undergoing a clinically driven coronary angiography, coronary arteries lesions, myocardial function and hypertrophy and 10-yrs incidence of cardiac events and death were evaluated in relation to classes of estimated GFR defined according the lowest eGFR value (105+, 90+, 75+, 60+, 45+). A reduced eGFR was independently associated with hypertension, myocardial hypertrophy and stress induced ischemia, while the excess coronary lesions and the worse myocardial systolic function were both largely explained by age and cardiovascular risk factors. When compared to subjects 75+, both the risk of cardiac death (1.67[1.10 2.57] and 3.06[1.85-5.10]) and non-fatal myocardial infarction (2.58[1.12-6.49] and 2.73[1.31-6.41]) adjusted for age and comorbidities were higher in eGFR 60+ and 45+ patients. CONCLUSIONS: A mild-moderate reduction of eGFR is closely associated to higher rates of stress-induced ischemia, myocardial hypertrophy and higher risk of fatal and non-fatal cardiac events. The associations of reduced eGFR with coronary atherosclerosis and myocardial systolic dysfunction are both largely explained by age and traditional risk factors. PMID- 24477007 TI - Is England's public health system still fit for purpose? PMID- 24477008 TI - The need for effective lobbying by England's public health community. PMID- 24477009 TI - Clinical guidance is not designed to replace professional judgment. PMID- 24477006 TI - Dietary intake, plasma homocysteine, and repetitive element DNA methylation in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND AND AIMS: DNA methylation of repetitive elements may explain the relations between dietary intake, hyperhomocysteinemia, and cardiovascular disease risk. We investigated associations of methyl micronutrient intake and plasma total homocysteine with LINE-1 and Alu methylation in a cross-sectional study of 987 adults aged 45-84 y who participated in the Multi-Ethnic Study of Atherosclerosis (MESA) Stress Study. METHODS AND RESULTS: DNA methylation was estimated using pyrosequencing technology. A 120-item food frequency questionnaire was used to ascertain daily intake of folate, vitamin B12, vitamin B6, zinc, and methionine. Plasma total homocysteine was quantified using a fluorescence polarization immunoassay. Associations of micronutrient intake and homocysteine with LINE-1 and Alu methylation were examined using linear regression. Adjusted differences in %5-methylated cytosines (%5 mC) were examined by categories of predictors using multivariable linear regression models. Intake of methyl-donor micronutrients was not associated with DNA methylation. After adjustment for covariates, each 3 MUmol/L increment of homocysteine corresponded with 0.06 (-0.01, 0.13) %5 mC higher LINE-1 methylation. Additionally, BMI was positively associated with LINE-1 methylation (P trend = 0.03). Participants with BMI >= 40 kg/m2 had 0.35 (0.03, 0.67) %5 mC higher LINE-1 than those with normal BMI. We also observed a 0.10 (0.02, 0.19) %5 mC difference in Alu methylation per 10 cm of height. These associations did not differ by sex. CONCLUSION: Dietary intake of methyl-donor micronutrients was not associated with measures of DNA methylation in our sample. However, higher BMI was related to higher LINE-1 methylation, and height was positively associated with Alu methylation. PMID- 24477010 TI - Replacing beta agonists with antimuscarinic drugs in patients with COPD. PMID- 24477011 TI - Major changes in practice and interpreting data from the past. PMID- 24477012 TI - Author's reply to Wolstenholme and Sanfilippo and colleagues. PMID- 24477013 TI - For a truly humanistic ethic, we need truly humanistic medicine. PMID- 24477014 TI - Use of alcohol to reduce stress. PMID- 24477015 TI - Readmission rates are a poor marker of quality. PMID- 24477016 TI - Readmission rates reflect how well whole health and social care systems function. PMID- 24477017 TI - Diabetes UK responds to comments by Asimakopoulou and colleagues. PMID- 24477018 TI - Conflicts of interest are everywhere. PMID- 24477019 TI - What about non-financial conflicts of interest? PMID- 24477020 TI - Exactly how much of evidence based medicine is corrupted? PMID- 24477021 TI - Importance of self care. PMID- 24477022 TI - Early diagnosis prevents further trouble. PMID- 24477023 TI - Treasury keeps alcohol meetings secret. PMID- 24477024 TI - Why ordinary Greeks need medical aid. PMID- 24477025 TI - When will the tobacco industry apologise for its monstrous harms? PMID- 24477026 TI - Characterization of biochemical properties of a selenium-independent glutathione peroxidase of Cryptosporidium parvum. AB - Glutathione peroxidase (GPx; EC 1.11.1.9) is an important antioxidant enzyme that catalyses the reduction of organic and inorganic hydroperoxides to water in oxygen-consuming organisms, using glutathione as an electron donor. Here, we report the characterization of a GPx of Cryptosporidium parvum (CpGPx). CpGPx contained a standard UGU codon for cysteine instead of a UGA opal codon for seleno-cysteine (SeCys) at the active site, and no SeCys insertion sequence (SECIS) motif was identified within the 3'-untranslated region (UTR) of CpGPx, which suggested its selenium-independent nature. In silico and biochemical analyses indicated that CpGPx is a cytosolic protein with a monomeric structure. Recombinant CpGPx was active over a wide pH range and was stable under physiological conditions. It showed a substrate preference against organic hydroperoxides, such as cumene hydroperoxide and t-butyl hydroperoxide, but it also showed activity against inorganic hydroperoxide, hydrogen peroxide. Recombinant CpGPx was not inhibited by potassium cyanide or by sodium azide. The enzyme effectively protected DNA and protein from oxidative damage induced by hydrogen peroxide, and was functionally expressed in various developmental stages of C. parvum. These results collectively suggest the essential role of CpGPx for the parasite's antioxidant defence system. PMID- 24477027 TI - Metabolic syndrome and early carotid atherosclerosis in the elderly. AB - AIMS: To investigate whether metabolic syndrome(MetS) can predict the new onset of carotid plaque or the progression of carotid intima-media thickness(C-IMT) and identify other associated factors in an elderly population without evidence of early carotid atherosclerosis. METHODS: B-mode carotid ultrasonography was used to assess the presence of carotid plaque and the C-IMT at baseline and follow-up. Participants with carotid plaque or an increased C-IMT(>=1.0mm) at baseline were excluded from the study. The new occurrence of carotid plaque, defined as early carotid atherosclerosis and the progression of C-IMT, was evaluated. Multiple regression analyses were used to determine predictors of these findings. RESULTS: A total of 370 participants over 60 years of age(median age=66 years, 34.1% men) were enrolled. After a median follow-up period of 25 months, 64 participants(17.3%) had newly developed carotid plaque. After adjusting for variables determined to be statistically significant in univariate analyses, a multivariable regression analysis showed that predictors of newly developed carotid plaque were metabolic syndrome(hazard ratio [HR]=1.916; 95% confidence interval [CI]: 1.059-3.466), white blood cell count(HR=1.313; 95% CI: 1.094 1.576) and vitamin B12(HR=1.001; 95% CI: 1.000-1.002) and total cholesterol(HR=1.009; 95% CI: 1.001-1.017) levels. A multiple linear regression analysis showed that the rate of change for C-IMT tended to be associated with the development of metabolic syndrome. CONCLUSIONS: Metabolic syndrome is associated with the progression of early carotid atherosclerosis in the general population, suggesting that metabolic syndrome plays an important role in initiating the atherosclerotic process. PMID- 24477029 TI - Contribution of visceral fat accumulation and adiponectin to the clustering of metabolic abnormalities in a Japanese population. AB - AIM: The clustering of metabolic abnormalities occurs not only due to abdominal obesity but also other etiologies. We investigated the contribution of visceral fat accumulation and the circulating adiponectin level to the clustering of metabolic abnormalities in a Japanese population. METHODS: We used the data for 1,989 Japanese employees to perform a structural equation modeling analysis. According to the concept of metabolic syndrome, we developed a multiple indicator multiple cause (MIMIC) model and investigated to what extent measurements of the visceral fat area (VFA) and circulating adiponectin levels explain the morbidity of clustering of metabolic abnormalities, represented as a latent variable termed "risk clustering." The following clinically measurable parameters were set as the phenotypes of the risk clustering: systolic blood pressure and glucose, high density lipoprotein cholesterol, triglyceride, uric acid and alanine aminotransferase levels. RESULTS: The mean age of the subjects was 46+/-11 years, and 72% of the participants were men. A VFA of >=100 cm(2) was observed in 32% of the subjects. The squared multiple correlation R(2) of the risk clustering was as high as 0.73, indicating that the measurements of the VFA and adiponectin levels explained 73% of the variance in the risk clustering. The R(2) between the risk clustering and metabolic parameters ranged from 0.14 to 0.54, thus indicating that these metabolic parameters reflected the development of morbidity of the risk clustering in the body within a range of 14% to 54%. CONCLUSIONS: The measurements of the VFA and adiponectin level makes a considerable contribution to the risk clustering. PMID- 24477028 TI - Effects of pioglitazone on macrovascular events in patients with type 2 diabetes mellitus at high risk of stroke: the PROFIT-J study. AB - AIM: The present study evaluated the effects of pioglitazone treatment on the incidence of primary cardiovascular events in Japanese subjects with type 2 diabetes mellitus at high risk of stroke. METHODS: A prospective, multicenter, randomized, open label, comparative study was conducted among diabetic patients recruited from 50 medical institutions nationwide. A total of 522 patients with hypertension and/or dyslipidemia who had one or more silent cerebral infarcts, advanced carotid atherosclerosis or microalbuminuria at baseline were randomly treated with (n=254) or without pioglitazone (n=268) and observed for a medium of 672 days. The hypertension and dyslipidemia were concurrently treated according to the respective treatment guidelines. The primary outcome was the time to the first occurrence of a composite of all-cause death, nonfatal cerebral infarction and nonfatal myocardial infarction. RESULTS: Treatment with pioglitazone resulted in significant reductions in the levels of HbA1c, diastolic blood pressure and LDL-cholesterol and a significant increase in the levels of HDL-cholesterol. The pioglitazone non-users exhibited a significant reduction in the LDL-cholesterol levels alone. Primary events were registered during the study period in nine patients in the pioglitazone group and 10 patients in the non-pioglitazone group. The difference in the cumulative incidence of the primary outcome was not significant between the two groups(1.8% per year). CONCLUSIONS: Pioglitazone therapy produces immediate and effective improvements in glycemic control, diastolic blood pressure and lipid profiles. While this study was too underpowered to determine the effects of pioglitazone on the incidence of cardiovascular events, the results indicated that two years of pioglitazone treatment did not produce any statistically significant reductions in the rate of primary cardiovascular events. PMID- 24477030 TI - Cross-sectional examination of physical and social contexts of episodes of eating and drinking in a national sample of US adults. AB - OBJECTIVE: The current study characterizes associations between physical and social contexts of self-reported primary episodes of eating/drinking and sociodemographic and obesity-related variables in US adults. DESIGN: Multinomial logistic regression was used to analyse a nationally representative sample of adults from the 2006-2008 American Time Use Survey. Models identifying physical (where) and social (whom) contexts of primary eating/drinking episodes at the population level, controlling for demographic characteristics, weight status and time of eating, were conducted. SETTING USA SUBJECTS: A nationally representative sample of US adults (n 21 315). RESULTS: Eating/drinking with immediate family was positively associated with age (OR = 1.15 (95 % CI 1.04, 1.27) to 1.23 (95 % CI 1.09, 1.39)), education level (OR = 1.16 (95 % CI 1.03, 1.30) to 1.36 (95 % CI 1.21, 1.54)), obesity (OR = 1.13 (95 % CI 1.04, 1.22)), children in the household (OR = 3.39 (95 % CI 3.14, 3.66)) and time of day (OR = 1.70 (95 % CI 1.39, 2.07) to 5.73 (95 % CI 4.70, 6.99)). Eating in the workplace was negatively associated with female gender (OR = 0.65 (95 % CI 0.60, 0.70)) and children in the household (OR = 0.90 (95 % CI 0.83, 0.98)), while positively associated with non-white status (OR = 1.14 (95 % CI 1.01, 1.29) to 1.47 (95 % CI 1.32, 1.65)) and time of day (OR = 0.25 (95 % CI 0.28, 0.30) to 5.65 (95 % CI 4.66, 6.85)). Women (OR = 0.80 (95 % CI 0.74, 0.86)), those aged >34 years (OR = 0.48 (95 % CI 0.43, 0.54) to 0.83 (95 % CI 0.74, 0.93)) and respondents with children (OR = 0.69 (95 % CI 0.63, 0.75)) were less likely to eat in a restaurant/bar/retail than at home. Overweight and obese respondents had a greater odds of reporting an episode of eating in social situations v. alone (e.g. immediate family and extended family; OR = 1.13 (95 % CI 1.04, 1.22)) and episodes occurring in restaurant/bar/retail locations (OR = 1.12 (95 % CI 1.03, 1.23) to 1.14 (95 % CI 1.05, 1.24)). CONCLUSIONS: Findings underscore the multidimensional nature of describing eating/drinking episodes. Social and physical contexts for eating/drinking and their demographic correlates suggest opportunities for tailoring interventions related to diet and may inform intervention targeting and scope. PMID- 24477031 TI - Laparoscopic incisionless stoma creation for patients with colorectal malignant stricture. AB - BACKGROUND: Minimally invasive techniques have been applied with increasing frequency to stoma creation. A recent focus in the field of minimally invasive surgery is laparoscopic single-site surgery. The aim of this study was to assess whether this procedure is a feasible option compared with other techniques of stoma creation. MATERIALS AND METHODS: We introduced laparoscopic surgery to fecal diversion in April 2010 at the Cancer Institute Hospital of the Japanese Foundation for Cancer Research. This technique was performed on 53 patients, including 15 laparoscopic single-site surgeries, from April 2010 to December 2011. RESULTS: Of these 15 cases, 8 ileostomies and 7 colostomies were created. The mean operative time was 65.9 minutes (range, 32 to 93 min). The estimated volume of blood loss was small in all cases. There were no intraoperative complications. All patients started an oral diet on the second postoperative day with the exception of 1 patient who suffered from prolonged paralytic ileus. CONCLUSIONS: A laparoscopic single-site approach to stoma creation may be a feasible option in fecal diversion. PMID- 24477032 TI - Cardiorespiratory effects of balancing PEEP with intra-abdominal pressures during laparoscopic cholecystectomy. AB - BACKGROUND: Applying appropriate positive end-expiratory pressure (PEEP) to corresponding intra-abdominal pressure (IAP) can improve gas exchange during capnoperitoneum without any hemodynamic effects. MATERIALS AND METHODS: A total of 75 patients were randomly allocated to group 0PEEP (n=25), group 5PEEP (n=25), and group 10PEEP (n=25) according to the level of PEEP, in whom capnoperitoneum was created with IAP of 14, 8, and 14 mm Hg, respectively. Hemodynamic and respiratory parameters were recorded up to 30 minutes after capnoperitoneum. RESULTS: In 0PEEP group, mean end-tidal carbon dioxide demonstrated significant rise 2 minutes after capnoperitoneum and plateaued at about 15 minutes but remained at high level for up to 30 minutes when compared with the 5PEEP and 10PEEP groups (P<0.05). Correspondingly, the mean PaCO2 (48.0+/-4.1 mm Hg) for the 0PEEP group was higher at 30 minutes when compared with 5PEEP (37.8+/-2.7 mm Hg) and 10PEEP (37.2+/-3.9 mm Hg) groups. The oxygenation was better preserved in 5PEEP and 10PEEP groups with significantly higher PaO2/Fio2 ratio. Heart rate, mean arterial pressure, and cardiac output remained stable throughout the study in all the 3 groups. CONCLUSIONS: Application of appropriate PEEP corresponding to the IAP helped maintain CO2 elimination and improved oxygenation without any hemodynamic disturbance in patients undergoing laparoscopic cholecystectomy. PMID- 24477033 TI - The proportion of unhealthy foodstuffs children are exposed to at the checkout of convenience supermarkets. AB - OBJECTIVE: To investigate the proportion of foods that are unhealthy to which children are exposed at the checkout of convenience supermarkets. DESIGN: We performed a cross-sectional survey of foodstuffs displayed at the checkout. Products displayed at or below children's eye-level were designated as healthy, unhealthy or unclassifiable using the Food Standards Agency's scoring criteria. SETTING: Thirteen convenience supermarkets from the three leading UK supermarket chains were selected on the basis of proximity to the town hall in Sheffield, England. SUBJECTS: Convenience supermarkets were defined as branches of supermarket chains that were identified as being other than superstores on their company's store locator website. RESULTS: In almost all of the convenience supermarkets surveyed, the main healthy product on display was sugar-free chewing gum. On average, when chewing gum was not included as a foodstuff, 89% of the products on display at the checkouts of convenience supermarkets were unhealthy using the Food Standards Agency's criteria. One store was a notable outlier, providing only fruit and nuts at its checkout. CONCLUSIONS: The overwhelming majority of products to which children are exposed at the convenience supermarket checkout are unhealthy. This is despite all the supermarket chains surveyed having signed up to the UK Government's 'responsibility deal'. PMID- 24477034 TI - Supplementing with vitamin C the diet of honeybees (Apis mellifera carnica) parasitized with Varroa destructor: effects on antioxidative status. AB - We studied a total of eight developmental stages of capped brood and newly emerged workers of Apis mellifera carnica colonies naturally parasitized with Varroa destructor. During winter and early spring four colonies were fed syrup containing 1.8 mg vitamin C kg(-1) (ascorbic acid group; group AA) while four colonies were fed syrup without the vitamin C (control group C). Selected elements of the antioxidative system were analysed including total antioxidant status (TAS), glutathione content and antioxidative enzyme activities (superoxide dismutase, catalase, peroxidase and glutathione S-transferase). Body weight, protein content and indices of infestation were also determined. The prevalence (8.11%) and intensity (1.15 parasite per bee) of the infestation were lower in group AA compared with group C (11.3% and 1.21, respectively). Changes in the indicators of antioxidative stress were evidence for the strengthening of the antioxidative system in the brood by administration of vitamin C. In freshly emerged worker bees of group AA, despite the infestation, protein content, TAS, and the activity of all antioxidative enzymes had significantly higher values in relation to group C. PMID- 24477035 TI - Corneal topographical and biomechanical variations associated with hypothyroidism. PMID- 24477036 TI - Portion sizes for children are predicted by parental characteristics and the amounts parents serve themselves. AB - BACKGROUND: Children's energy intakes are influenced by the portions they are served. Factors influencing the amounts adults offer children are not well described. OBJECTIVE: We assessed whether the amounts that were served to and consumed by children at meals were related to amounts that parents served themselves. DESIGN: In this repeated-measures, cross-sectional observational study, 145 parents and their preschoolers (82 Hispanic, 57 African American, 6 unidentified) were recruited from Head Start settings in Houston, TX. The amounts served to and consumed by children and parents during 3 at-home evening meals were measured and analyzed. We assessed children's and parents' heights and weights, and body mass indexes (BMIs) were calculated. Associations between portions served for parents and children and between amounts served to and consumed by children were evaluated. Multiple linear regression was used to determine whether maternal characteristics (race-ethnicity, sociodemographic factors, and caregivers' BMIs) predicted the amounts caregivers served to children. RESULTS: The amounts that parents served themselves were significantly associated with the amounts that they served to their children (r = 0.51, P < 0.0001). Multiple regression analysis showed that African American parents (compared with Hispanics) served more food to themselves and to their children (P < 0.01, R2 = 6.9%) and that employed (compared with unemployed) parents served more food to their children (P = 0.025, R2 = 3.3%). The amounts served to children were strongly associated with the amounts children consumed (r = 0.88, P < 0.0001). When parents served more to themselves, they also served more to their children (P < 0.001). CONCLUSIONS: These findings underscore the strong relation between portions offered by caregivers and the amounts children consume at a meal and suggest that factors unrelated to the child (such as the amount a parent serves himself or herself) are important predictors of children's consumption. Efforts aimed at improving parents' recognition of developmentally appropriate portions for young children could be useful for future obesity-prevention efforts. PMID- 24477037 TI - Physical activity in infancy: developmental aspects, measurement, and importance. AB - Relative to work on nutrient intake and growth in infancy and toddlerhood, research on physical activity (PA) from birth to age 24 mo is limited. In this review, the developmental course of PA in infancy and toddlerhood is described, and the issues that surround its measurement are addressed. Of the variety of techniques that allow for gauging PA in infancy and toddlerhood, caregiver questionnaires, direct observations, and motion sensors have been used most frequently. Although each method has shown utility, the limitations of each are also acknowledged. In addition, the relation of early PA to nutrition and overweight in infants is considered. Despite the challenges to accurately monitoring early PA, its possible contribution to early excess weight gain should be recognized. PMID- 24477038 TI - Nature and nurture in children's food preferences. AB - BACKGROUND: Health professionals identify food provision in the home as a key influence on children's food preferences. In contrast, parents often perceive children's food preferences to be inborn. One explanation for this discrepancy could be that environmental and genetic influences vary by food type. OBJECTIVE: We assessed genetic and environmental contributions to preferences for a wide variety of foods in a large pediatric twin sample. DESIGN: Data were from Gemini, which is a cohort of UK twins born in 2007. Preferences for 114 foods were assessed by parent-completed questionnaire when children were aged 3 y (n = 2686). Foods tried by >75% of respondents were grouped into protein, vegetables, fruit, dairy, starches, and snacks. Quantitative model-fitting analyses were used to assess genetic and environmental influences for each food group. RESULTS: The genetic influence was higher for vegetables (54%; 95% CI: 47%, 63%), fruit (53%; 95% CI: 45%, 61%), and protein (48%; 95% CI: 40%, 57%) but lower for starches (32%; 95% CI: 26%, 38%), snacks (29%; 95% CI: 24%, 35%), and dairy (27%; 95% CI: 20%, 35%). In contrast, shared-environment effects were higher for snacks (60%; 95% CI: 54%, 65%), starches (57%; 95% CI: 51%, 62%), and dairy (54%; 95% CI: 47%, 60%) and lower for vegetables (35%; 95% CI: 27%, 42%), fruit (35%; 95% CI: 26%, 43%), and protein (37%; 95% CI: 27%, 45%). Nonshared environment effects were small for all foods (11-19%). CONCLUSIONS: Both genetic and environmental effects were significant for all food groups, but genetic effects dominated for more nutrient-dense foods (vegetables, fruit, and protein), whereas shared environmental effects dominated for snacks, dairy, and starches. These findings endorse the view of health professionals that the home environment is the main determinant of children's liking for energy-dense foods implicated in excessive weight gain but suggest that parents are also correct by identifying innate differences in liking, particularly for nutrient-dense foods that parents and health educators try to encourage. PMID- 24477039 TI - Similar metabolic responses in pigs and humans to breads with different contents and compositions of dietary fibers: a metabolomics study. AB - BACKGROUND: In nutritional studies, pigs are often used as models for humans because of nutritional and physiologic similarities. However, evidence supporting similar metabolic responses to nutritional interventions is lacking. OBJECTIVE: The objective was to establish whether pigs and humans respond similarly to a nutritional intervention. Using metabolomics, we compared the acute metabolic response to 4 test breads between conventional pigs (growing) and adult human subjects (with the metabolic syndrome). DESIGN: Six catheterized pigs and 15 human subjects were tested in a randomized crossover design with 4 breads: white wheat bread low in dietary fiber, rye bread with whole-rye kernels, and 2 white wheat breads supplemented with either wheat arabinoxylan or oat beta-glucan. Blood samples drawn -15, 30, and 120 min postprandially were analyzed by untargeted liquid chromatography-mass spectrometry metabolomics. RESULTS: We found that the postprandial responses, as reflected in blood metabolomes, are similar in pigs and humans. Twenty-one of 26 identified metabolites that were found to be different between the species were qualitatively similar in response to the test breads, despite different basal metabolome concentrations in the plasma of pigs and humans. Humans had higher contents of phosphatidylcholines, oleic acid, and carnitine in plasma, possibly reflecting a higher intake of meats and fats. In pigs, betaine, choline, creatinine, tryptophan, and phenylalanine were higher, probably because of the higher doses of bread provided to the pigs (per kg body weight) and/or because of their growing status. Acute metabolic differences in these metabolites induced by the breads were, however, comparable between the 2 species. CONCLUSION: Our results indicate that pigs are a suitable model for human metabolic studies in food research. The human trial was registered at clinicaltrials.gov as NCT01316354. The animal experiment was conducted according to a license obtained by the Danish Animal Experiments Inspectorate, Ministry of Food, Agriculture and Fisheries, Danish Veterinary and Food Administration. PMID- 24477040 TI - WIC Infant and Toddler Feeding Practices Study: protocol design and implementation. AB - The federal Special Supplemental Nutrition Program for Women, Infants, and Children (WIC), which began in the 1970s, has undergone revisions in the past several years, including revision to contents of the supplemental food "packages" in 2009 based on recommendations provided by an Institute of Medicine (IOM) committee of The National Academies. In 2010, the IOM held a workshop to examine and recommend research priorities for the program. The overall purpose of the current (ie, second) WIC Infant and Toddler Feeding Practices Study (ITFPS-2) is to conduct a nationally representative, longitudinal study of contemporary WIC infant and toddler feeding practices. This study will update earlier studies and collect information on variations in WIC program components. The study will also assess ways in which WIC may address obesity in early childhood and examine changes in feeding practices that may stem from the 2009 food package revisions. The sample is drawn from the universe of WIC sites nationally, excluding only those with an insufficient volume of eligible participants. Eligibility for the study includes the ability to be interviewed in English or Spanish. Approximately 8000 women and infants are being sampled, and ~ 4000 are expected to participate. Eligible women are invited to participate during their WIC enrollment visit, and informed consent is sought. The design includes a core sample to be followed until the infant reaches age 2 y and a supplemental sample to be used in some cross-sectional analyses to ensure adequate representation of groups that might be underrepresented in the core sample. Participants will complete up to 11 interviews (core sample) or 4 interviews (supplemental sample) each except for the prenatal interview, which includes a quantitative 24-h recall of food intake for the infant. Eighty sites have been sampled across 26 states and 1 territory. Instruments have been developed and pretested in both English and Spanish, and interviewers have been rigorously trained. Recruitment and interviewing began in July 2013. This study will provide the only current large-sample longitudinal feeding data available on a nationally representative sample of infants in low income families, and results will be available to inform the 2020 Dietary Guidelines for Americans for the 0- to 24-mo age group. PMID- 24477041 TI - No vitamin D threshold for calcium absorption: why does this matter? PMID- 24477042 TI - Genetic variants in GCKR and PNPLA3 confer susceptibility to nonalcoholic fatty liver disease in obese individuals. AB - BACKGROUND: A genome-wide association study identified variants in or near patatin-like phospholipase domain-containing-3 (PNPLA3), neurocan (NCAN), lysophospholipase-like 1 (LYPLAL1), glucokinase regulatory protein (GCKR), and protein phosphatase 1 regulatory subunit 3b (PPP1R3B) that were strongly associated with nonalcoholic fatty liver disease (NAFLD) in adults of European ancestry. OBJECTIVE: We examined these genetic variants in obese children and tested whether their effects on NAFLD are significant in the Taiwanese Han Chinese population. DESIGN: We genotyped PNPLA3 rs738409, NCAN rs2228603, LYPLAL1 rs12137855, GCKR rs780094, and PPP1R3B rs4240624 in 797 obese children aged 7-18 y. NAFLD was identified by liver ultrasonography. We analyzed the effect of these genetic variants on NAFLD. RESULTS: NAFLD was identified in 24% of the recruited obese children. We found significant associations with NAFLD at variants in PNPLA3 and GCKR but not in NCAN, LYPLAL1, and PPP1R3B. Multiple logistic regression analysis showed that, after control for the effects of age- and sex adjusted body mass index, waist-to-hip ratio, sex, and PNPLA3 rs738409 polymorphism, the variant GCKR rs780094 TT genotype independently increased the OR of NAFLD by 1.997 (95% CI: 1.196, 3.335; P = 0.008) compared with the CC genotype. Subjects with the variant GCKR rs780094 TT genotype had a higher mean serum alanine aminotransferase concentration than did those with the CC genotype (30.8 +/- 34.7 compared with 22.2 +/- 18.6 IU/L; P = 0.01). CONCLUSIONS: By studying the genetic variants of obese Taiwanese children, we confirmed that the genetic variants in GCKR rs780094 and PNPLA3 rs738409, but not in NCAN rs2228603, LYPLAL1 rs12137855, and PPP1R3B rs4240624, are associated with an increased risk of NAFLD. GCKR and PNPLA3 variants are the common genetic factors that may confer susceptibility to NAFLD in obese individuals across multiple ethnic groups. PMID- 24477043 TI - Protein-enriched diet, with the use of lean red meat, combined with progressive resistance training enhances lean tissue mass and muscle strength and reduces circulating IL-6 concentrations in elderly women: a cluster randomized controlled trial. AB - BACKGROUND: Physical inactivity, inadequate dietary protein, and low-grade systemic inflammation contribute to age-related muscle loss, impaired function, and disability. OBJECTIVE: We assessed the effects of progressive resistance training (PRT) combined with a protein-enriched diet facilitated through lean red meat on lean tissue mass (LTM), muscle size, strength and function, circulating inflammatory markers, blood pressure, and lipids in elderly women. DESIGN: In a 4 mo cluster randomized controlled trial, 100 women aged 60-90 y who were residing in 15 retirement villages were allocated to receive PRT with lean red meat (~160 g cooked) to be consumed 6 d/wk [resistance training plus lean red meat (RT+Meat) group; n = 53] or control PRT [1 serving pasta or rice/d; control resistance training (CRT) group; n = 47)]. All women undertook PRT 2 times/wk and received 1000 IU vitamin D3/d. RESULTS: The mean (+/- SD) protein intake was greater in the RT+Meat group than in the CRT group throughout the study (1.3 +/- 0.3 compared with 1.1 +/- 0.3 g . kg-1 . d-1, respectively; P < 0.05). The RT+Meat group experienced greater gains in total body LTM (0.45 kg; 95% CI: 0.07, 0.84 kg), leg LTM (0.22 kg; 95% CI: 0.02, 0.42 kg), and muscle strength (18%; 95% CI: 0.03, 0.34) than did the CRT group (all P < 0.05). The RT+Meat group also experienced a 10% greater increase in serum insulin-like growth factor I (P < 0.05) and a 16% greater reduction in the proinflammatory marker interleukin-6 (IL 6) (P < 0.05) after 4 mo. There were no between-group differences for the change in blood lipids or blood pressure. CONCLUSION: A protein-enriched diet equivalent to ~1.3 g . kg-1 . d-1 achieved through lean red meat is safe and effective for enhancing the effects of PRT on LTM and muscle strength and reducing circulating IL-6 concentrations in elderly women. This trial was registered at the Australian Clinical Trials Registry as ACTRN12609000223235. PMID- 24477044 TI - Drp1 loss-of-function reduces cardiomyocyte oxygen dependence protecting the heart from ischemia-reperfusion injury. AB - Mitochondria are key organelles for ATP production in cardiomyocytes, which is regulated by processes of fission and fusion. We hypothesized that the mitochondria fusion protein dynamin-related protein 1 (Drp1) inhibition, attenuates ischemia-reperfusion (I/R) injury through modifications in mitochondrial metabolism. Rats were subjected to I/R through coronary artery ligation, and isolated cardiomyocytes were treated with an ischemia-mimicking solution. In vivo, cardiac function, myocardial infarction area, and mitochondrial morphology were determined, whereas in vitro, viability, mitochondrial membrane potential, intracellular ATP levels, and oxygen consumption rate (OCR) were assessed. In both models, an adenovirus expressing Drp1 dominant-negative K38A (Drp1K38A) was used to induce Drp1 loss-of-function. Our results showed that I/R stimulated mitochondrial fission. Myocardial infarction size and cell death induced by I/R were significantly reduced, whereas cardiac function after I/R was improved in Drp1K38A-treated rats compared with controls. Drp1K38A-transduced cardiomyocytes showed lower OCR with no decrease in intracellular ATP levels, and on I/R, a larger decrease in OCR with a smaller reduction in intracellular ATP level was observed. However, proton leak associated oxygen consumption was comparatively higher in Drp1K38A-treated cardiomyocytes, suggesting a protective mitochondrial uncoupling effect against I/R. Collectively, our results show that Drp1 inhibition triggers cardioprotection by reducing mitochondrial metabolism during I/R. PMID- 24477045 TI - Signaling via P2Y12 may be critical for early stabilization of platelet aggregates. AB - P2Y(12) receptor antagonism inhibits platelet aggregation by preventing adenosine diphosphate (ADP)-mediated amplification of activation pathways downstream of primary agonists, such as thrombin and collagen. However, the role of ADP signaling in maintaining aggregate stability and the effects of P2Y(12) antagonists on preestablished aggregates in vitro and arterial thrombus in vivo are not well understood. This study evaluated the impact of P2Y(12) signaling on platelet aggregate stability and early thrombotic occlusion using a reversible P2Y(12) antagonist, ticagrelor. There were 2 study objectives: (1) to determine if there was a time-dependent factor on the capacity of a P2Y(12) antagonist to affect human platelet aggregate stability in vitro using light transmission aggregometry and (2) to evaluate the extent of arterial thrombus reversal in a preclinical model upon administration of ticagrelor in vivo. Platelet aggregates were exposed to ticagrelor after ADP or collagen activation, monitored for stability by aggregometry, and visualized by microscopy. Freshly formed ADP- and collagen-induced platelet aggregates were more rapidly dispersed by a P2Y(12) antagonist than drug carrier control at clinically relevant concentrations (P < 0.05). However, stable aggregates were not noticeably affected. A murine arterial thrombosis model was used to evaluate thrombus stability in an in vivo mouse model. Thrombotic occlusion was induced by FeCl(3), followed by a bolus intravenous administration of ticagrelor or vehicle control. Doppler blood flow was monitored before injury and 30 minutes after bolus administration. Arteries were retrieved for inspection for residual thrombus. Early arterial thrombotic occlusion in vivo was partially reversed by ticagrelor administration. Blood flow through the injured artery increased, and thrombus size within the artery decreased (P < 0.05, n = 3). In conclusion, P2Y(12) antagonism disrupts the stability of newly formed platelet aggregates, promoting disaggregation, and reverses thrombotic vascular occlusion. Thus, in addition to activating platelets, signaling via P2Y(12) seems to be required for stabilizing platelet thrombi. PMID- 24477047 TI - [Abstracts - 22 degrees congresso nazionale associazione italiana di neuroradiologia - palazzo mezzanotte, milano, Italy, 4-6 october 2006]. PMID- 24477046 TI - Impact of castration on changes in left ventricular diastolic pressure-volume relations induced by chronic adrenergic stimulation in rats. AB - A reduced testosterone concentration characterizes heart failure and independently predicts outcomes. Although testosterone replacement therapy may have non cardiac-related therapeutic benefits in heart failure, whether reduced testosterone concentrations protect against adverse left ventricular remodeling (LV dilatation) is uncertain. We therefore evaluated whether surgical castration modifies LV dilatation after 6 months of daily injections of the beta-adrenergic receptor (AR) agonist, isoproterenol (ISO) (0.015 mg.kg(-1).d(-1)), to rats. The extent of LV dilatation and LV systolic chamber dysfunction were determined using both echocardiography and isolated perfused heart procedures. The extent of LV dilatation was determined from LV diastolic pressure-volume (P-V) relationships. As compared with the saline vehicle-treated group, after 6 months of beta-AR activation in sham-castrated rats, a marked right shift in the LV diastolic P-V relationship was noted with an increased LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (ISO = 0.38 +/- 0.02, saline vehicle = 0.30 +/- 0.02, P < 0.05). However, chronic beta-AR activation did not alter LV systolic chamber function either in vivo (LV endocardial fractional shortening, echocardiography) or ex vivo (LV end systolic elastance). Although castration decreased body weight, castration failed to modify the impact of ISO on the LV diastolic P-V relationships or the LV volume intercept at 0 mm Hg diastolic pressure (LV V(0) in milliliters) (castration ISO = 0.35 +/- 0.02, castration saline vehicle = 0.27 +/- 0.03, P < 0.05). In conclusion, castration does not influence the extent of LV dilatation induced by chronic adrenergic activation in an animal model, where adverse LV remodeling precedes LV systolic chamber dysfunction. PMID- 24477048 TI - Insulin treatment of streptozotocin-induced diabetes re-establishes the patterns in carbohydrate, fat and amino acid metabolisms in growing pigs. AB - The effects of streptozotocin (STZ) were studied in eight high-health herd certified Yorkshire * Swedish Landrace pigs (32.5 +/- 2.6 kg initial body weight [BW]), and an insulin treatment protocol was developed to re-establish their metabolisms. A single intravenous dose of 150 mg STZ/kg BW successfully induced hyperglycaemia and alterations in their fat and protein metabolisms. Within 13 h post-STZ treatment blood glucose concentration had fallen to a range of 1.3 to 4.7 mmol/L. Hypoglycaemia was promptly treated with 0.5 g glucose/kg BW intravenously. All the pigs became hyperglycaemic with blood glucose concentrations >23 mmol/L within 48 h post-STZ. Two days post-STZ serum C-peptide concentrations fell below 60 rhomol/L in all the pigs and remained below 96 rhomol/L for five weeks until the end of the study. The pigs were left untreated for one week after STZ injection. At the end of this week 13-fold and nine-fold increases in serum concentrations of triglycerides and non-esterified fatty acids, respectively, were observed. Also, at this time-point a three-fold increase in the concentration of branched-chain amino acids (BCAA) was observed, and alanine and taurine were decreased by approximately 70% and 40%, respectively. During the week when the pigs were untreated, a reduced weight gain was observed, but after the onset of insulin treatment the daily weight gain was at least as good as that of conventional high-health pigs. Then a subcutaneous treatment with short-acting insulin was initiated. The initial dose of 2/3 IU/kg BW daily, divided between two doses, was gradually increased to 1 IU/kg BW. Within three weeks, the insulin treatment restored the metabolic changes in carbohydrate, fat and protein metabolisms produced by the STZ. In conclusion, the results underscore the usefulness of this animal model in translational research as insulin treatment re-establishes the changes in carbohydrate, fat and amino acid metabolisms observed in STZ-diabetic pigs and resolves clinical signs of disease similar to those in humans. PMID- 24477049 TI - Mesenchymal stem cells modified with angiopoietin-1 gene promote wound healing. AB - INTRODUCTION: Treatment of chronic skin wounds is difficult and largely ineffective. Little improvement has been shown in promoting the healing of these wounds in the past few decades. Innovative treatments to enhance chronic wound healing process are therefore needed. METHODS: In this study, we examined the efficacy of angiopoietin-1 gene-modified bone marrow mesenchymal stem cells (Ang1 MSCs) on the promotion of cutaneous wound healing in rats. Excisional full thickness wounds were treated with Ang1-MSCs, a recombinant adenovirus encoding angiopoietin-1 (Ad-Ang1), unmodified bone marrow mesenchymal stem cells (MSCs), or vehicle medium (sham). RESULTS: The results showed that Ang1-MSCs significantly promoted wound healing with increased epidermal and dermal regeneration, and enhanced angiogenesis compared with MSCs, Ad-Ang1 or sham treatment. Moreover, Ang1-MSCs expressed CD31 in the wound, suggesting a direct contribution of Ang1-MSCs to angiogenesis. CONCLUSIONS: Here we show that Ang1 MSCs accelerate wound healing by promoting skin regeneration and angiogenesis, compared with MSCs or Ad-Ang1 alone. PMID- 24477050 TI - The quality of oral anticoagulation in general practice in patients with atrial fibrillation. AB - BACKGROUND: The aims of this study were to evaluate the quality of oral anticoagulation (OAC) in AF patients in the practices of general practitioners (GPs) in Germany and to investigate possible causal factors which influence OAC quality. METHODS: We conducted a multi-center, non-interventional, prospective observational cohort study among general practitioners (GPs) in Germany. To assess the quality of OAC on the basis of the prospectively documented international normalized ratio (INR) values, the time in therapeutic range (TTR) was calculated using the Rosendaal linear trend method. The causes of poor OAC quality were identified by a multivariate analysis model (logistical regression; poor OAC quality: TTR <60%). RESULTS AND CONCLUSIONS: For 525 OAC patients (66.8%; patients with at least 2 prospectively documented INR values) the average TTR (target range of 2.0-3.0) was 67.6%. About 34.7% of the patients had a TTR <60%. None of the variables representing characteristics of the medical practices were capable of explaining the occurrence of poor OAC quality. However, with regard to care provision-based variables, the existence of a brief discontinuation of medication was important. As the existence of adherence barriers increased, the probability of poor anticoagulation quality increased. In conclusion, the provision of OAC in the German health care system is to be regarded as good, but far from ideal. Our causal analysis shows that patient based factors should be addressed through the provision of improved training and that the rationale behind the interruption of OAC treatment should be critically examined. PMID- 24477051 TI - Dietary patterns and breakfast consumption in relation to insulin resistance in children. The Healthy Growth Study. AB - OBJECTIVE: Insulin resistance is a significant cross-point for the manifestation of several chronic diseases in children and adults. The aim of the present study was to investigate the possible relationship of certain dietary patterns and breakfast consumption habits with insulin resistance in children. SUBJECTS: A representative sample of 1912 schoolchildren (aged 9-13 years) participated in a cross-sectional epidemiological study, the Healthy Growth Study, which was initiated in May 2007 and completed in June 2009. SETTING: It was conducted in seventy-seven primary schools in four large regions in Greece. DESIGN: Dietary intake, breakfast consumption, anthropometric and physical examination data, biochemical indices and socio-economic information collected from parents were assessed in all children. Principal components analysis was used to identify dietary patterns. RESULTS: A dietary pattern of increased consumption of margarine, sweets (candies, lollipops, jellies, traditional fruit in heavy syrup) and savoury snacks (chips, cheese puffs and not home-made popcorn) was associated with homeostasis model assessment of insulin resistance index (HOMA-IR; beta = 0.08, P < 0.001) in multivariate models. Children in the third tertile of this dietary pattern had a 2.51 (95 % CI 1.30, 4.90) times higher risk of insulin resistance (HOMA-IR > 3.16) than those in the first tertile. Breakfast consumption had an inverse correlation with insulin resistance, but the correlation lost its significance after adjustments for waist circumference, birth weight, parental BMI and socio-economic status. CONCLUSIONS: Increased consumption of margarine, sweets and savoury snacks, which is a common dietary pattern in childhood, was positively associated with insulin resistance, while breakfast consumption had an inverse association with HOMA-IR, in schoolchildren (aged 9-13 years). Identification of dietary behaviours that might affect insulin resistance in children offers valuable advice in cardiometabolic risk prevention strategies. PMID- 24477052 TI - Formative assessment of oncology trainees' communication with cancer patients about internet information. AB - OBJECTIVE: Cancer patients and their caregivers often turn to the internet for information and support following a cancer diagnosis. Research shows a need for improvement in doctors' communication with patients about internet information. The purpose of this formative assessment was to evaluate oncology trainees' skills in talking about internet information with cancer patients. METHODS: Thirty-nine oncology trainees were evaluated in a baseline standardized patient assessment as part of their participation in the Comskil Training Program. As part of the assessment, standardized patients were instructed to raise the topic of internet information they had read. Transcriptions of the video-recorded assessments were coded for patient statements and trainee responses. RESULTS: Fifty-six percent of trainees used a probe to get more information before addressing the content of the internet search, while 18% addressed it immediately. Eighteen percent of trainees warned the patient about using the internet, and 8% warned about and also encouraged internet use. Thirteen percent of trainees praised the patient for seeking out information on the internet. SIGNIFICANCE OF RESULTS: This formative assessment indicated that the majority of trainees addressed the content of the internet search, while a minority addressed the internet as a tool and praised patients' efforts. Research in this area should examine the effectiveness of educational interventions for trainees to improve discussions about internet information. PMID- 24477053 TI - Comparison of patient and surgeon perceptions of adverse events after adult spinal deformity surgery. AB - STUDY DESIGN: Survey based on complication scenarios. OBJECTIVE: To assess and compare perceived potential impacts of various perioperative adverse events by both surgeons and patients. SUMMARY OF BACKGROUND DATA: Incidence of adverse events after adult spinal deformity surgery remains substantial. Patient-centered outcomes tools measuring the impact of these events have not been developed. An important first step is to assess the perceptions of surgeons and patients regarding the impact of these events on surgical outcome and quality of life. METHODS: Descriptions of 22 potential adverse events of surgery (heart attack, stroke, spinal cord injury, nerve root injury, cauda equina injury, blindness, dural tear, blood transfusion, deep vein thrombosis, pulmonary embolism, superficial infection, deep infection, lung failure, urinary tract infection, nonunion, adjacent segment disease, persistent deformity, implant failure, death, renal failure, gastrointestinal complications, and sexual dysfunction) were presented to 14 spinal surgeons and 16 adult patients with spinal deformity. Impact scores were assigned to each complication on the basis of perceptions of overall severity, satisfaction with surgery, and effect on quality of life. Impact scores were compared between surgeons and patients with a Wilcoxon/Kruskal Wallis test. RESULTS: Mean impact scores varied from 0.9 (blood transfusion) to 10.0 (death) among surgeons and 2.3 (urinary tract infection) to 9.2 (stroke) among patients. Patients' scores were consistently higher (P < 0.05) than surgeons in all 3 categories for 6 potential adverse events: stroke, lung failure, heart attack, pulmonary embolism, dural tear, and blood transfusion. Three additional complications (renal failure, non-union, and deep vein thrombosis) were rated higher in 1 or 2 categories by patients. CONCLUSION: There was substantial variation in how both surgeons and patients perceived impacts of various adverse events after spine surgery. Patients generally perceived the impact of adverse events to be greater than surgeons. Patient-centered descriptions of adverse events would provide a more complete description of surgical outcomes. PMID- 24477054 TI - What is the effect of surgery on the quality of life of the adolescent with adolescent idiopathic scoliosis? A review and statistical analysis of the literature. AB - STUDY DESIGN: Review and statistical analysis of studies evaluating the effect of surgery on the health-related quality of life of adolescents with adolescent idiopathic scoliosis, using Scoliosis Research Society (SRS) outcomes. OBJECTIVE: Apply published minimum clinical important differences (MCID) values for the SRS22r questionnaire to the literature to identify what areas of health-related quality of life are consistently affected by surgery and whether changes are clinically meaningful. SUMMARY OF BACKGROUND DATA: The interpretation of published studies using the SRS outcomes has been limited by the lack of MCID values for the questionnaire domains. The recent publication of these data allows the clinical importance of any changes in these studies to be examined for the first time. METHODS: A literature search was undertaken to locate suitable studies that were then analyzed. Statistically significant differences from baseline to 2 years postoperatively were ascertained by narratively reporting the analyses within included studies. When possible, clinically significant changes were assessed using 95% confidence intervals for the change in mean domain score. If the lower bound of the confidence intervals for the change exceeded the MCID for that domain, the change was considered clinically significant. RESULTS: The numbers of cohorts available for the different analyses varied (5-16). Eighty-one percent and 94% of included cohorts experienced statistically significant improvements in pain and self-image domains. In terms of clinical significance, it was only self-image that regularly improved by more than MCID, doing so in 4 of 5 included cohorts (80%) compared with 1 of 12 cohorts (8%) for pain. No clinically relevant changes occurred in mental health or activity domains. CONCLUSION: Evidence suggests that surgery can lead to clinically important improvement in patient self-image. Surgeons and patients should be aware of the limited evidence for improvements in domains other than self-image after surgery. Surgical decision-making will also be influenced by the natural history of adolescent idiopathic scoliosis. PMID- 24477055 TI - Socioeconomic and physical characteristics of individuals with degenerative lumbar spinal stenosis. AB - STUDY DESIGN: A descriptive study of the association between demographic factors, and physical characteristics, and degenerative lumbar spinal stenosis (DLSS). OBJECTIVE: To shed light on the association between socioeconomic parameters, physical characteristics, and DLSS. SUMMARY OF BACKGROUND DATA: Lumbar spinal stenosis is a prevalent and disabling condition in the aging population. DLSS is considered to be the most common type and is essentially associated with disc disease, facet joint arthrosis, ligamentum flavum thickening, and osteophyte formation. Although there is ample information regarding the association between body mass index, cardiovascular disorders, smoking habits, and disc disease, very little is known about their association with DLSS. Data on the association of body physique (e.g., height and weight) and DLSS are limited. METHODS: Two sample populations were studied. The first included 165 individuals with DLSS (mean age, 64 +/- 9.9 yr) and the second 180 individuals without spinal stenosis related symptoms (mean age, 62.5 +/- 12.6 yr). An evaluation of the cross-sectional area of the dural sac and degenerative listhesis for all participants was performed using computed tomographic lumbar spine images, obtained by Philips EBW station (Brilliance 64, Philips Medical System, Cleveland, OH). All participants were interviewed to obtain demographic, physical, and health data. Independent t test, Mann-Whitney and chi tests were used to determine the association between parametric and nonparametric variables and DLSS. Logistic regression analysis was carried out to reveal predicting variables for DLSS. RESULTS: Females with stenosis were significantly heavier and shorter than their counterparts in the control group. We also noticed that they delivered babies more often than those in the control group. Prevalence of individuals experiencing diabetes mellitus was significantly higher in the males with stenosis than control group. In the stenosis group, the frequencies of individuals engaged in heavy manual labor (males) and housekeeping (females) were significantly higher than that of their counterparts in the control group. CONCLUSION: Heavy manual labor and diabetes mellitus in males and housekeeping (females) play major roles in the genesis of DLSS. PMID- 24477058 TI - Usefulness of V3-radial artery graft-V4 bypass in bilateral fusiform aneurysms of vertebral artery: case report. AB - A 55-year-old woman with bilateral vertebral artery (VA) aneurysms was transferred to our hospital. She suffered from a minor stroke. Magnetic resonance imaging (MRI) for the stroke incidentally revealed bilateral VA aneurysms. Due to its size, more observation was recommended, and the patient was found eager to be treated. Both side surgeries were found inappropriate because of severe lower cranial nerve disturbances. The right aneurysm involved the posterior inferior cerebellar artery (PICA) and the V4 segment was deviated to the right side. Therefore, the smaller right aneurysm was treated first with an occipital artery (OA)-PICA bypass and a V3-radial artery graft (RAG)-V4 bypass followed by proximal clipping of the PICA and the right VA. The right VA was successfully remade by RAG and the right aneurysm was not revealed on postoperative examination. By doing so, the opposite aneurysm was able to be eliminated by the parent artery occlusion even by using an interventional radiology (IVR). The V3 RAG-V4 bypass is a useful method for treating bilateral VA aneurysms. This is a new bypass which has not been reported so far to the best of our knowledge. PMID- 24477059 TI - Cervical radiculopathy due to disc herniation with adjacent facet hypertrophy: case report. AB - We report a rare case of cervical radiculopathy associated with facet hypertrophy and disc herniation. The patient was a 38-year-old woman with sudden-onset left arm pain. As conservative therapy failed to alleviate her symptoms she was referred to us. On physical examination she manifested no neurological deficits except pain and dysesthesia in the left C7 territory. Computed tomography revealed hypertrophic ossified changes in the left T1 facet joint with encroachment on the spinal canal. Magnetic resonance imaging showed compression of the spinal cord at C6/7 by disc herniation at C6/7. Anterior cervical decompression and fusion by corpectomy (C7 corpectomy and C6/T1 fixation with a titanium cage) ameliorated her pain. Facet hypertrophy in a morphologically normal cervicothoracic spine is extremely rare and its etiology is unknown. We speculate the possibility that our patient harbored a congenital anomaly and that the morphologic changes were the consequence of an injury she sustained in a traffic accident. PMID- 24477060 TI - Usefulness of C-stopper coil for neurointervention. AB - C-stopper coil (CSC) which are available for 0.018-inch inner diameter microcenter have been used for neurointervention such as transarterial embolization (TAE) of feeding artery. Although various shapes of pushable microcoils have been developed, microcoils are usually short to embolize the lesion and require lots of coils. The most specific feature of CSC is the extended length of 18 cm. To evaluate the usefulness of CSC, we reviewed our experience of CSC. Neurointervention using CSC was performed for 28 patients (31 treatments). Intervention procedures were TAE for dural arteriovenous fistula (AVF)(n = 15), transvenous embolization for dural AVF (n = 4), parent artery occlusion for cerebral aneurysm, dissection and carotid-cavernous fistula (n = 8), TAE for epistaxis (n = 2), and preoperative embolization for tumor (n = 2). CSCs were deployed with push technique through microcatheter. CSCs were successfully placed into the lesion namely feeding artery, venous sinus, parent artery of aneurysm, or dissection. There were no major technical complications resulting in morbidity. Postoperative course was uneventful. No recanalization of the occluded vessel occurred during follow-up. Use of CSCs was safe and feasible for embolization of cerebrovascular lesion. PMID- 24477061 TI - A rare case of Chiari type-1 malformation accompanied by symptomatic cerebrospinal fluid hypovolemia: comparison of congenital Chiari type-1 malformation and acquired Chiari malformation secondary to cerebrospinal fluid hypovolemia: case report. AB - A 23-year-old woman was injured in a rear-end collision. She had general malaise and posterior neck pain, which were more severe when she was in an upright position. Magnetic resonance imaging (MRI) revealed the presence of cerebellar tonsil descensus and syringomyelia in the spinal cord. Radioisotope (RI) cisternography showed signs of an early accumulation of RI in the bladder, and a delayed accumulation of RI in the cerebral fornix. We considered the possibilities of cerebrospinal fluid (CSF) hypovolemia and congenital Chiari type 1 malformation as being responsible for her headache. To obtain a definitive diagnosis, we performed gadolinium (Gd)-enhanced MR cisternography and found evidence of CSF leakage. We performed an epidural blood patch (EBP), and her symptoms resolved. In 2 years since the episode, her symptoms have not recurred, and additional treatment has not been required. In addition, MRI performed 2 years after the EBP did not reveal any changes. There seems no previous report which described successful differentiation of pre-existing congenital Chiari type 1 malformation from the acquired one caused by symptomatic CSF hypovolemia. Because treatment protocols differ between these two conditions, the establishment of a correct diagnosis is important. PMID- 24477062 TI - Simultaneous discovery of cranial and spinal intradural chordomas: case report. AB - The present case illustrates the unexpected occurrence of intradural chordomas that were simultaneously discovered in cranial and spinal locations. A 63-year old female presented with weakness in the left upper extremity. The patient visited a local doctor and underwent brain computerized tomography (CT). CT revealed a brain tumor, and she was referred to our hospital. Brain magnetic resonance imaging (MRI) demonstrated a midline intradural retroclival tumor in addition to an intradural extramedullary mass lesion at the level of C1-C2. The patient developed a spastic gait disturbance that forced her to use a cane. She underwent laminectomy at C1-C2 along with total removal of the tumor and showed no remarkable symptoms after surgery. Histopathological examination confirmed the diagnosis of chordoma. One month after the cervical surgery, the intracranial tumor was subtotally removed in intracranial surgery via the right subtemporal approach. Histopathological data were identical to that of the cervical tumor. The patient consulted another hospital and underwent gamma-knife surgery. Her neurological examination is relatively unchanged 20 months after the cervical surgery. This case suggests that neuroradiological evaluation should also be performed for an intradural spinal chordoma when an intracranial chordoma is detected. Careful determination of the tumor responsible for the symptoms is necessary if an intradural spinal chordoma is simultaneously detected with an intracranial chordoma. PMID- 24477063 TI - Chronic subdural hematoma in elderly patient with EDTA-dependent pseudothrombocytopenia recently treated with aspirin and warfarin: case report. AB - A 78-year-old man who had a history of myocardial and cerebral infarction and who was treated with aspirin and warfarin, presented with left chronic subdural hematoma. Cerebral computed tomography showed severe brain compression of hematoma with midline shift, indicating the need for emergent surgery. The hematology and clotting tests upon admission revealed severe thrombocytopenia (platelet count, 1.3 * 10(4)/MUL) with normal clotting activity. Because platelet aggregation was evident in the smear, we re-examined the patient for hematology using tubes that contained heparin, showing also low platelet count (2.3 * 10(4)/MUL). The day on admission, we performed irrigation and drainage of the chronic subdural hematoma through single burr-hole craniostomy. During surgery, we used 10 units of platelet concentrates (PCs) for the reason that the patient was taking aspirin and coagulopathy derived from low platelet count could not be excluded. After surgery, we re-evaluated the hematology of the blood stored in tubes that contained ethylenediaminetetraacetic acid (EDTA) with or without kanamycin (KM). Treatment with KM dissociated EDTA-induced platelet aggregation and revealed platelet counts with highest accuracy (no KM treatment, 1.3 * 10(4)/MUL; KM treatment, 15.2 * 10(4)/MUL). This phenomenon is called EDTA Dependent Pseudothrombocytopenia (PTCP) defined as falsely low platelet counts reported by automated hematology analyzers due to platelet aggretgation. Awareness of the phenomenon will enable neurosurgeons to manage patients with PTCP appropriately and clinical laboratory especially in emergency hospital is recommended to prepare for the hematological tubes being added KM in routine analysis, resulting in preventing mistaken diagnosis. PMID- 24477064 TI - Effect of inner membrane tearing in the treatment of adult chronic subdural hematoma: a comparative study. AB - The postoperative results of chronic subdural hematoma (CSDH) procedures using catheterization and tearing of inner membrane (CTIM) technique have not previously been discussed in the literature. This article compares the effects of CTIM technique on brain re-expansion and re-accumulation with cases operated on with a burr-hole craniotomy and outer membrane incision (BCOMI) technique. The study involved operations on 144 patients (Group 1) using the CTIM technique and 108 patients (Group 2) using the BCOMI technique. In the operations using the CTIM technique in Group 1, the mean effusion measured in the subdural space (SDS) was 10.0 +/- 0.2 mm, and for Group 2, 14.3 +/- 0.6 mm in the postoperative period on the first and third days and this difference was found to be significant (p < 0.05). The means were 6.6 +/- 0.2 mm for Group 1 and 10.3 +/- 0.5 mm for Group 2 on the seventh day (p < 0.05). Recurrence rate was 8.3% in Group 2 and 0 in Group 1. This difference was statistically significant (p = 0001). The length of hospital stay was 7.0 +/- 0.1 days for the Group 1 and 8.8 +/- 0.2 days for Group 2 and this difference was significant (p < 0.05). These results indicate that the CTIM technique is preferable because it results in earlier re-expansion, lower recurrence, less subdural effusion and pneumocephalus, and shorter hospital stays. PMID- 24477065 TI - Rotational acceleration during head impact resulting from different judo throwing techniques. AB - Most severe head injuries in judo are reported as acute subdural hematoma. It is thus necessary to examine the rotational acceleration of the head to clarify the mechanism of head injuries. We determined the rotational acceleration of the head when the subject is thrown by judo techniques. One Japanese male judo expert threw an anthropomorphic test device using two throwing techniques, Osoto-gari and Ouchi-gari. Rotational and translational head accelerations were measured with and without an under-mat. For Osoto-gari, peak resultant rotational acceleration ranged from 4,284.2 rad/s(2) to 5,525.9 rad/s(2) and peak resultant translational acceleration ranged from 64.3 g to 87.2 g; for Ouchi-gari, the accelerations respectively ranged from 1,708.0 rad/s(2) to 2,104.1 rad/s(2) and from 120.2 g to 149.4 g. The resultant rotational acceleration did not decrease with installation of an under-mat for both Ouchi-gari and Osoto-gari. We found that head contact with the tatami could result in the peak values of translational and rotational accelerations, respectively. In general, because kinematics of the body strongly affects translational and rotational accelerations of the head, both accelerations should be measured to analyze the underlying mechanism of head injury. As a primary preventative measure, throwing techniques should be restricted to participants demonstrating ability in ukemi techniques to avoid head contact with the tatami. PMID- 24477066 TI - The neuroprotective effect of treatment with curcumin in acute spinal cord injury: laboratory investigation. AB - The purpose of this study was investigating the effects of curcumin on the histological changes and functional recovery following spinal cord injury (SCI) in a rat model. Following either sham operation or SCI, 36 male Sprague-Dawley rats were distributed into three groups: sham group, curcumin-treated group, and vehicle-injected group. Locomotor function was assessed according to the Basso, Beattie, and Bresnahan (BBB) scale in rats who had received daily intraperitoneal injections of 200 mg/kg curcumin or an equivalent volume of vehicle for 7 days following SCI. The injured spinal cord was then examined histologically, including quantification of cavitation. BBB scores were significantly higher in rats receiving curcumin than receiving vehicle (P < 0.05). The cavity volume was significantly reduced in the curcumin group as compared to the control group (P = 0.039). Superoxide dismutase (SOD) activity was significantly elevated in the curcumin group as compared to the vehicle group but was not significantly different from the sham group (P < 0.05, P > 0.05, respectively) at one and two weeks after SCI. Malondialdehyde (MDA) levels were significantly elevated in the vehicle group as compared to the sham group (P < 0.05 at 1 and 2 weeks). MDA activity was significantly reduced in the curcumin group at 2 weeks after SCI when compared to the vehicle group (P = 0.004). The numbers of macrophage were significantly decreased in the curcumin group (P = 0.001). This study demonstrated that curcumin enhances early functional recovery after SCI by diminishing cavitation volume, anti-inflammatory reactions, and antioxidant activity. PMID- 24477067 TI - Intra-arterial fluorescence angiography with injection of fluorescein sodium from the superficial temporal artery during aneurysm surgery: technical notes. AB - Intra-arterial fluorescence angiography from a catheter inserted into the external carotid artery (ECA) via the superficial temporal artery (STA) allowed us to satisfactorily evaluate cerebral arterial and venous blood flow. We report this novel method that allowed for repeated angiography within minutes with a low risk of complications due to catheter placement from the STA. The STA was secured at the edge of the standard skin incision during cerebral aneurysm surgery. A 3 Fr catheter was inserted approximately 5 cm to 10 cm into the STA. After manual injection of 5 ml of 20 times diluted 10% fluorescein sodium (fluorescein), fluorescein reached the intracranial internal carotid artery (ICA) through the common carotid artery or anastomoses between the ECA and ICA. Fluorescence emission from the cerebral arteries, capillaries, and veins was clearly observed through the microscope and results were recorded. Quick dye clearance makes it possible to reexamine within 1 minute. In addition, we made a graph of the fluorescence emission intensity in the arteries, capillaries, and veins using fluorescence analysis software. With intravenous fluorescence angiography, dye remains in the vessels for a long time. When repeated examinations are necessary, intervals of approximately 10 minutes are required. There were some cases we could not correctly evaluate with intravenous injection due to weak fluorescence emission. Fluorescence angiography with intra-arterial injection from a catheter inserted into the carotid artery or another major vessel, like conventional angiography, has a risk of procedure-related complications. We report our new method since it solved these problems and is useful. PMID- 24477068 TI - Magnitude of placebo response and response variance in antidepressant clinical trials using structured, taped and appraised rater interviews compared to traditional rating interviews. AB - The high failure rate of antidepressant clinical trials is due in part to a high magnitude of placebo response and considerable variance in placebo response. In some recent trials enhanced patient interview techniques consisting of Structured Interview Guide for the Montgomery-Asberg Depression Rating Scale (SIGMA) interviews, audiotaping of patient interviews and 'central' appraisal with Rater Applied Performance Scale (RAPS) criteria have been implemented in the hope of increasing reliability and thus reducing the placebo response. However, the data supporting this rationale for a change in patient interview technique are sparse. We analyzed data from depressed patients assigned to placebo in antidepressant clinical trials conducted at a single research site between 2008 and 2012. Three trials included 34 depressed patients undergoing SIGMA depression interviews with taping and RAPS appraisal and 4 trials included 128 depressed patients using traditional interview methods. Using patient level data we assessed the mean decrease in total MADRS scores and the variability of the decrease in MADRS scores in trials using SIGMA interviews versus trials using traditional interviews. Mean decrease in total MADRS score was significantly higher in the 3 trials that used SIGMA interviews compared to the 4 trials using traditional interviews (M = 13.0 versus 8.3, t(df = 160) = 2.04, p = 0.047). Furthermore, trials using SIGMA had a larger magnitude of response variance based on Levene's test for equality of variance (SD = 12.3 versus 9.4, F = 7.3, p = 0.008). The results of our study suggest that enhanced patient interview techniques such as SIGMA interviews, audiotaping and RAPS appraisal may not result in the intended effect of reducing the magnitude of placebo response and placebo variance. PMID- 24477069 TI - Noise-induced quantum coherence drives photo-carrier generation dynamics at polymeric semiconductor heterojunctions. AB - Here we report on an exciton/lattice model of the electronic dynamics of primary photo excitations in a polymeric semiconductor heterojunction that includes both polymer pi-stacking, energetic disorder and phonon relaxation. Our model indicates that that in polymer/fulerene heterojunction systems, resonant tunnelling processes brought about by environmental fluctuations couple photo excitations directly to photocurrent producing charge-transfer states on <100 fs time scales. Moreover, we find this process to be independent of the location of energetic disorder in the system, and hence we expect exciton fission via resonant tunnelling to polarons to be a ubiquitous feature of these systems. PMID- 24477070 TI - Marine parasites as biological tags in South American Atlantic waters, current status and perspectives. AB - Many marine fisheries in South American Atlantic coasts (SAAC) are threatened by overfishing and under serious risk of collapsing. The SAAC comprises a diversity of environments, possesses a complex oceanography and harbours a vast biodiversity that provide an enormous potential for using parasites as biological tags for fish stock delineation, a prerequisite for the implementation of control and management plans. Here, their use in the SAAC is reviewed. Main evidence is derived from northern Argentine waters, where fish parasite assemblages are dominated by larval helminth species that share a low specificity, long persistence and trophic transmission, parasitizing almost indiscriminately all available fish species. The advantages and constraints of such a combination of characteristics are analysed and recommendations are given for future research. Shifting the focus from fish/parasite populations to communities allows expanding the concept of biological tags from local to regional scales, providing essential information to delineate ecosystem boundaries for host communities. This new concept arose as a powerful tool to help the implementation of ecosystem-based approaches to fisheries management, the new paradigm for fisheries science. Holistic approaches, including parasites as biological tags for stock delineation will render valuable information to help insure fisheries and marine ecosystems against further depletion and collapse. PMID- 24477071 TI - Deep-gray nuclei susceptibility-weighted imaging filtered phase shift in patients with Wilson's disease. AB - BACKGROUND: Susceptibility-weighted imaging (SWI) is a useful tool for evaluating brain paramagnetic mineralization. The aim of this study was to evaluate SWI filtered phase shift in brain gray nuclei of Wilson's disease (WD). METHODS: Twenty-three WD patients and 23 age- and gender-matched healthy controls underwent SWI. Phase values of bilateral brain gray nuclei were measured on corrected phase image of all subjects. RESULTS: Compared with healthy controls, WD patients showed a trend of negative phase shift in all regions of interest, and significantly lower phase value was found in bilateral putamen (PU) (left P = 0.009, right P = 0.001), caudate (left P = 0.001, right P = 0.001), thalamus (TH) (left P < 0.001, right P < 0.001), red nucleus (left P = 0.031, right P = 0.049), and substantia nigra (left P = 0.003, right P = 0.047). The WD patients groups were divided into neurological, hepatic, and asymptomatic onset subgroups. And neurological onset patients had lower phase value than hepatic onset patients on bilateral PU (left P = 0.025, right P = 0.002) and TH (left P = 0.025, right P = 0.025). CONCLUSION: Abnormal negative phase value was significantly increased in brain gray nuclei of WD patients, giving evidence in vivo about paramagnetic mineralization accumulating in brain gray nuclei. The phase shift of SWI could be used as a potential biomarker to help in diagnosing and evaluating WD. PMID- 24477072 TI - Rare cranial nerve extension of a parotid tumor. PMID- 24477073 TI - Transplantation of photoreceptors derived from human Muller glia restore rod function in the P23H rat. AB - Muller glia possess stem cell characteristics that have been recognized to be responsible for the regeneration of injured retina in fish and amphibians. Although these cells are present in the adult human eye, they are not known to regenerate human retina in vivo. Human Muller glia with stem cell characteristics (hMSCs) can acquire phenotypic and genotypic characteristics of rod photoreceptors in vitro, suggesting that they may have potential for use in transplantation strategies to treat human photoreceptor degenerations. Much work has been undertaken in rodents using various sources of allogeneic stem cells to restore photoreceptor function, but the effect of human Muller glia-derived photoreceptors in the restoration of rod photoreceptor function has not been investigated. This study aimed to differentiate hMSCs into photoreceptor cells by stimulation with growth and differentiation factors in vitro to upregulate gene and protein expression of CRX, NR2E3, and rhodopsin and various phototransduction markers associated with rod photoreceptor development and function and to examine the effect of subretinal transplantation of these cells into the P23H rat, a model of primary photoreceptor degeneration. Following transplantation, hMSC derived photoreceptor cells migrated and integrated into the outer nuclear layer of the degenerated retinas and led to significant improvement in rod photoreceptor function as shown by an increase in a-wave amplitude and slope using scotopic flash electroretinography. These observations suggest that hMSCs can be regarded as a cell source for development of cell-replacement therapies to treat human photoreceptor degenerations and may also offer potential for the development of autologous transplantation. PMID- 24477074 TI - Astrocyte-like cells derived from human oral mucosa stem cells provide neuroprotection in vitro and in vivo. AB - Human oral mucosa stem cells (hOMSC) are a recently described neural crest derived stem cell population. Therapeutic quantities of potent hOMSC can be generated from small biopsies obtained by minimally invasive procedures. Our objective was to evaluate the potential of hOMSC to differentiate into astrocyte like cells and provide peripheral neuroprotection. We induced hOMSC differentiation into cells showing an astrocyte-like morphology that expressed characteristic astrocyte markers as glial fibrillary acidic protein, S100beta, and the excitatory amino acid transporter 1 and secreted neurotrophic factors (NTF) such as brain-derived neurotrophic factor, vascular endothelial growth factor, glial cell line-derived neurotrophic factor, and insulin-like growth factor 1. Conditioned medium of the induced cells rescued motor neurons from hypoxia or oxidative stress in vitro, suggesting a neuroprotective effect mediated by soluble factors. Given the neuronal support (NS) ability of the cells, the differentiated cells were termed hOMSC-NS. Rats subjected to sciatic nerve injury and transplanted with hOMSC-NS showed improved motor function after transplantation. At the graft site we found the transplanted cells, increased levels of NTF, and a significant preservation of functional neuromuscular junctions, as evidenced by colocalization of alpha-bungarotoxin and synaptophysin. Our findings show for the first time that hOMSC-NS generated from oral mucosa exhibit neuroprotective effects in vitro and in vivo and point to their future therapeutic use in neural disorders. PMID- 24477075 TI - Arthritic periosteal tissue from joint replacement surgery: a novel, autologous source of stem cells. AB - The overarching aim of this study is to assess the feasibility of using periosteal tissue from the femoral neck of arthritic hip joints, usually discarded in the normal course of hip replacement surgery, as an autologous source of stem cells. In addition, the study aims to characterize intrinsic differences between periosteum-derived cell (PDC) populations, isolated via either enzymatic digestion or a migration assay, including their proliferative capacity, surface marker expression, and multipotency, relative to commercially available human bone marrow-derived stromal cells (BMSCs) cultured under identical conditions. Commercial BMSCs and PDCs were characterized in vitro, using a growth assay, flow cytometry, as well as assay of Oil Red O, alizarin red, and Safranin O/Fast Green staining after respective culture in adipo-, osteo , and chondrogenic media. Based on these outcome measures, PDCs exhibited proliferation rate, morphology, surface receptor expression, and multipotency similar to those of BMSCs. No significant correlation was observed between outcome measures and donor age or diagnosis (osteoarthritis [OA] and rheumatoid arthritis [RA], respectively), a profound finding given recent rheumatological studies indicating that OA and RA share not only common biomarkers and molecular mechanisms but also common pathophysiology, ultimately resulting in the need for joint replacement. Furthermore, PDCs isolated via enzymatic digestion and migration assay showed subtle differences in surface marker expression but otherwise no significant differences in proliferation or multipotency; the observed differences in surface marker expression may indicate potential effects of isolation method on the population of cells isolated and/or the behavior of the respective isolated cell populations. This study demonstrates, for the first time to our knowledge, the feasibility of using arthritic tissue resected during hip replacement as a source of autologous stem cells. In sum, periosteum tissue that is resected with the femoral neck in replacing the hip represents an unprecedented and, to date, unstudied source of stem cells from OA and RA patients. Follow-up studies will determine the degree to which this new, autologous source of stem cells can be banked for future use. PMID- 24477076 TI - Geographical patterns of Toxoplasma gondii genetic diversity revealed by multilocus PCR-RFLP genotyping. AB - In recent years, an extensive collection of Toxoplasma gondii samples have been typed using a set of 10 PCR-RFLP genetic markers. Here we summarize the data reported until the end of 2012. A total of 1457 samples were typed into 189 genotypes. Overall, only a few genotypes dominate in the northern hemisphere, which is in stark contrast to the southern hemisphere where hundreds of genotypes coexist with none being notably dominant. PCR-RFLP genotype #1 (Type II clonal), #2 (Type III), #3 (Type II variant) and #10 (Type I) are identified globally. Genotypes #2 and #3 dominate in Africa, genotypes #9 (Chinese 1) and #10 are prevalent in Asia, genotypes #1, #2 and #3 are prevalent in Europe, genotypes #1, #2, #3, #4 and #5 dominate in North America (#4 and #5 are collectively known as Type 12). In Central and South America, there is no clear dominance of any genotype even though a few have relatively higher frequencies. Statistical analysis indicates significant differences among populations in Africa, Asia, Europe, North America, and Central and South America, with only Europe and North America exhibiting similar diversity. Collectively, the results revealed distinct population structures and geographical patterns of diversity in T. gondii. PMID- 24477077 TI - Abstracts - 23 degrees Congresso Nazionale Associazione Italiana di Neuroradiologia - Centro Congressi Giovanni XXIII, Bergamo, Italy, 20-23 June 2007. PMID- 24477078 TI - Modeling and calibration for exposure to time-varying, modifiable risk factors: the example of smoking behavior in India. AB - BACKGROUND: Risk factors increase the incidence and severity of chronic disease. To examine future trends and develop policies addressing chronic diseases, it is important to capture the relationship between exposure and disease development, which is challenging given limited data. OBJECTIVE: To develop parsimonious risk factor models embeddable in chronic disease models, which are useful when longitudinal data are unavailable. DESIGN: The model structures encode relevant features of risk factors (e.g., time-varying, modifiable) and can be embedded in chronic disease models. Calibration captures time-varying exposures for the risk factor models using available cross-sectional data. We illustrate feasibility with the policy-relevant example of smoking in India. METHODS: The model is calibrated to the prevalence of male smoking in 12 Indian regions estimated from the 2009-2010 Indian Global Adult Tobacco Survey. Nelder-Mead searches (250,000 starting locations) identify distributions of starting, quitting, and restarting rates that minimize the difference between modeled and observed age-specific prevalence. We compare modeled life expectancies to estimates in the absence of time-varying risk exposures and consider gains from hypothetical smoking cessation programs delivered for 1 to 30 years. RESULTS: Calibration achieves concordance between modeled and observed outcomes. Probabilities of starting to smoke rise and fall with age, while quitting and restarting probabilities fall with age. Accounting for time-varying smoking exposures is important, as not doing so produces smaller estimates of life expectancy losses. Estimated impacts of smoking cessation programs delivered for different periods depend on the fact that people who have been induced to abstain from smoking longer are less likely to restart. CONCLUSIONS: The approach described is feasible for important risk factors for numerous chronic diseases. Incorporating exposure-change rates can improve modeled estimates of chronic disease outcomes and of the long-term effects of interventions targeting risk factors. PMID- 24477079 TI - Growth faltering and recovery in children aged 1-8 years in four low- and middle income countries: Young Lives. AB - OBJECTIVE: We characterized post-infancy child growth patterns and determined the incidence of becoming stunted and of recovery from stunting. DESIGN: Data came from Young Lives, a longitudinal study of childhood poverty in four low- and middle-income countries. SETTING: We analysed length/height measurements for children at ages 1, 5 and 8 years. SUBJECTS: Children (n 7171) in Ethiopia, India, Peru and Vietnam. RESULTS: Mean height-for-age Z-score (HAZ) at age 1 year ranged from -1.51 (Ethiopia) to -1.08 (Vietnam). From age 1 to 5 years, mean HAZ increased by 0.27 in Ethiopia (P < 0.001) and decreased among the other cohorts (range: -0.19 (Peru) to -0.32 (India); all P < 0.001). From 5 to 8 years, mean HAZ increased in all cohorts (range: 0.19 (India) to 0.38 (Peru); all P < 0.001). Prevalence of stunting (HAZ<-2.0) at 1 year ranged from 21 % (Vietnam) to 46 % (Ethiopia). From age 1 to 5 years, stunting prevalence decreased by 15.1 percentage points in Ethiopia (P < 0.001) and increased in the other cohorts (range: 3.0 percentage points (Vietnam) to 5.3 percentage points (India); all P <= 0.001). From 5 to 8 years, stunting prevalence decreased in all cohorts (range: 5.0 percentage points (Vietnam) to 12.7 percentage points (Peru); all P < 0.001). The incidence of becoming stunted between ages 1 to 5 years ranged from 11 % (Vietnam) to 22 % (India); between ages 5 to 8 years, it ranged from 3 % (Peru) to 6 % (India and Ethiopia). The incidence of recovery from stunting between ages 1 and 5 years ranged from 27 % (Vietnam) to 53 % (Ethiopia); between ages 5 and 8 years, it ranged from 30 % (India) to 47 % (Ethiopia). CONCLUSIONS: We found substantial recovery from early stunting among children in four low- and middle-income countries. PMID- 24477080 TI - Stepwise withdrawal of inhaled corticosteroids in COPD patients receiving dual bronchodilation: WISDOM study design and rationale. AB - Long-acting bronchodilators in combination with inhaled corticosteroids (ICS) are recommended to decrease the risk of recurrent exacerbations in patients with Global initiative for chronic Obstructive Lung Disease (GOLD) stage 3-4 chronic obstructive pulmonary disease (COPD). There is increasing concern about the clinical benefit and long-term safety of ICS use in COPD patients. The WISDOM (Withdrawal of Inhaled Steroids During Optimised bronchodilator Management) study (NCT00975195) aims to evaluate the need for ICS use via stepwise withdrawal of ICS in COPD patients (GOLD 3-4 with a history of at least one exacerbation during the 12-month period prior to screening) receiving dual bronchodilation. During the 6-week run-in period, 2456 patients receive tiotropium 18 MUg once daily, salmeterol 50 MUg twice daily and fluticasone 500 MUg twice daily. In a randomized, double-blind, parallel-group, active-controlled fashion, one group of patients continues to receive tiotropium, salmeterol and fluticasone, while the second group initiates stepwise withdrawal of fluticasone. The primary end point is time to first moderate or severe exacerbation following randomized treatment over 52 weeks. Lung function, symptoms and safety are also assessed. A sub-study aims to identify sub-populations and markers of steroid need. This study will determine the benefit of continued ICS therapy in combination with dual long acting bronchodilators in COPD. PMID- 24477082 TI - Scoliosis surgery in children with congenital heart disease. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To describe preoperative evaluation, anesthetic and perioperative management, and complications in patients with congenital heart disease (CHD) who underwent surgery to correct a spine deformity. SUMMARY OF BACKGROUND DATA: Patients with surgically palliated or repaired CHD may have nearly normal circulation or may have important residual abnormalities that affect the planning and conduct of surgery to correct a spine deformity. METHODS: We examined the records of 21 patients with spine deformity who had previous surgical intervention for CHD. Three types of spine surgery and instrumentation were examined, posterior spinal fusion with instrumentation (PSFI), growing rod (GR) instrumentation, and vertical expandable prosthetic titanium rib instrumentation (VEPTR). To objectify the degree of preoperative cardiac physiological derangement, patients were classified into 3 groups: single ventricle physiology and Fontan circulation (S), two ventricles with no residual abnormal cardiac physiology condition (2N), and two ventricles with residual cardiac physiology problem (2R). RESULTS: Subjects were 8 boys and 13 girls with mean age of 11.1 +/- 5.2 years. Sixteen patients underwent surgery to correct scoliosis, 1 to correct kyphosis, and 4 did not undergo surgery. Total number of surgical procedures was 23 (16 PSFI, 5 GR, and 2 VEPTR). On the basis of cardiac physiology, 2 patients belonged 2N, 11 were 2R, and 8 were group S. Mean estimated blood loss was 1685 mL during PSFI, 515 mL during GR, and 150 mL during VEPTR. Mean volume of blood transfusion was 44 mL/kg for PSFI, 19 mL/kg for GR, whereas no transfusion was administered during VEPTR. Median intensive care unit stay was 2 days ranging from hours to 78 days. Median hospital length of stay was 7 days ranging from 3 to 93 days. There were no deaths. CONCLUSION: Given meticulous multidisciplinary planning and execution, major spine surgery can be safely and successfully performed in patients with significant residua of CHD. LEVEL OF EVIDENCE: 4. PMID- 24477081 TI - Does recombinant human bone morphogenetic protein-2 use in adult spinal deformity increase complications and are complications associated with location of rhBMP-2 use? A prospective, multicenter study of 279 consecutive patients. AB - STUDY DESIGN: Multicenter, prospective analysis of consecutive patients with adult spinal deformity (ASD). OBJECTIVE: Evaluate complications associated with recombinant human bone morphogenetic protein-2 (rhBMP-2) use in ASD. SUMMARY OF BACKGROUND DATA: Off-label rhBMP-2 use is common; however, underreporting of rhBMP-2 associated complications has been recently scrutinized. METHODS: Patients with ASD consecutively enrolled into a prospective, multicenter database were evaluated for type and timing of acute perioperative complications. INCLUSION CRITERIA: age 18 years and older, ASD, spinal arthrodesis of more than 4 levels, and 3 or more months of follow-up. Patients were divided into those receiving rhBMP-2 (BMP) or no rhBMP-2 (NOBMP). BMP divided into location of use: posterior (PBMP), interbody (IBMP), and interbody + posterior spine (I + PBMP). Correlations between acute perioperative complications and rhBMP-2 use including total dose, dose/level, and location of use were evaluated. RESULTS: A total of 279 patients (mean age: 57 yr; mean spinal levels fused: 12.0; and mean follow up: 28.8 mo) met inclusion criteria. BMP (n = 172; average posterior dose = 2.5 mg/level, average interbody dose = 5 mg/level) had similar age, smoking history, previous spine surgery, total spinal levels fused, estimated blood loss, and duration of hospital stay as NOBMP (n = 107; P > 0.05). BMP had greater Charlson Comorbidity Index (1.9 vs. 1.2), greater scoliosis (43 degrees vs. 38 degrees ), longer operative time (488.2 vs. 414.6 min), more osteotomies per patient (4.0 vs. 1.6), and greater percentage of anteroposterior fusion (APSF; 20.9% vs. 8.4%) than NOBMP, respectively (P < 0.05). BMP had more total complications per patient (1.4 vs. 0.6) and more minor complications per patient (0.9 vs. 0.2) than NOBMP, respectively (P < 0.05). NOBMP had more complications requiring surgery per patient than BMP (0.3 vs. 0.2; P < 0.05). Major, neurological, wound, and infectious complications were similar for NOBMP, BMP, PBMP, IBMP, and I + PBMP (P > 0.05). Multivariate analysis demonstrated small to nonexistent correlations between rhBMP-2 use and complications. CONCLUSION: RhBMP-2 use and location of rhBMP-2 use in ASD surgery, at reported doses, do not increase acute major, neurological, or wound complications. Research is needed for higher rhBMP-2 dosing and long-term follow-up. LEVEL OF EVIDENCE: 2. PMID- 24477083 TI - Surgical planning and neurological outcome after anterior approach to remove a disc herniation at the C7-T1 level in 19 patients. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: The purpose of this study was to report the neurological presentation, outcome and surgical planning in a series of patients with a symptomatic single-level C7-T1 disc herniation who underwent anterior surgical discectomy and fusion. SUMMARY OF BACKGROUND DATA: Disc herniations at C7-T1 are uncommon, and there are few large series in the literature describing anterior treatment of such herniations. METHODS: We performed a retrospective study of patients who underwent surgery for a C7-T1 disc herniation and reviewed the medical records, operative reports, and imaging studies. The surgeons' view line was drawn and its relation to the manubrium and the great vessels was determined on T1 sagittal magnetic resonance imaging. The location of the herniated disc in the spinal canal was determined using a T2 axial magnetic resonance imaging and classified as central, foraminal, and central/foraminal. Loss of muscle strength was evaluated preoperatively and at the last follow-up according to the classification of the Medical Research Council. The disc space was approached anteriorly by a standard cervical supramanubrial Smith-Robinson approach. RESULTS: We identified 19 patients who had undergone C7-T1 discectomy and fusion. The mean age of the sample was 54.26 +/- 8.65 years. There was a higher proportion of male patients (57.9%, 11/19). The clinical presentation was predominantly motor deficit in 15/19 cases (78.9%) in intrinsic hand muscles, and usually improved after surgery. The mean follow-up period was 27.05 +/- 15.10 months. All the patients underwent an anterior cervical supramanubrial approach with microdiscectomy and fusion. Anterior cervical plate fixation was used in 9/19 cases (47.3%). In the rest of the cases, a stand-alone intervertebral device was placed. CONCLUSION: An anterior cervical supramanubrial approach was easily accomplished in all patients. Motor deficit was the most common surgical indication. LEVEL OF EVIDENCE: 4. PMID- 24477085 TI - Energy drinks and other dietary supplement use among adolescents attending secondary schools in Trinidad and Tobago. AB - OBJECTIVE: The objective of the present study was to determine the knowledge and practices among Trinidad and Tobago school-attending adolescents towards energy drinks (ED), alcohol combined with energy drinks (AwED), weight-altering supplements (WAS) and vitamin/mineral supplements (VMS) and their experience of adverse effects associated with such use. DESIGN: A cross-sectional, proportionate, stratified sampling strategy was adopted using a self administered, de novo questionnaire. SETTING: Secondary schools throughout Trinidad and Tobago. SUBJECTS: Students aged 15-19 years. RESULTS: Five hundred and sixty-one students participated, an 84% response rate; 43.0% were male, 40.5% East Indian and 34.1% mixed race. VMS, ED, WAS and anabolic steroids were used by 52.4%, 44.0%, 8.9% and 1.4% of students, respectively, with 51.6% of ED users using AwED. Predictors of use of AwED were males and students who played sport for their school (OR = 1.9; 95% CI 1.2, 3.2 and OR = 2.6; 95% CI 1.4, 4.7, respectively). Predictors of ED use were males and attendees of government secondary schools (OR = 1.7; 95% CI 1.1, 2.4 and OR = 1.7; 95% CI 1.2, 2.4, respectively). Side-effects, mainly palpitations, headaches and sleep disturbances, were reported in 20.7% of dietary supplement users. CONCLUSIONS: Many adolescent students in Trinidad and Tobago use dietary supplements, including ED and AwED, and about one-fifth of users experience side-effects. Identification of students at risk for ED, AwED and WAS use and education of students about the dangers of using dietary supplements need to be instituted to prevent potential adverse events. PMID- 24477086 TI - The problem with p. PMID- 24477087 TI - Antibodies against interferon-beta in neuromyelitis optica patients. AB - Neuromyelitis optica (NMO) is an antibody-mediated autoimmune inflammatory disease of the CNS. A poor response to treatment with recombinant interferon beta (IFN-beta) in NMO patients has been suggested, although the precise mechanisms remain uncertain. We analyzed occurrence and clinical consequences of IFN neutralizing antibodies (NAbs) in 15 IFN-beta treated NMO-patients from a population-based retrospective case series cohort. NMO patients not treated with IFN-beta acted as a reference group. IFN-beta antibody determinations included binding antibodies (BAbs) measured by immunoassay and NAbs measured by a neutralization bioassay. Antibodies were determined 6-36 months after initiation of IFN-beta therapy and NAbs additionally 5-10 years post-therapy. BAbs were detected in 14/15 NMO patients; 6/15 were NAbs-positive (3 at 5-10 years post therapy) two of those anti-AQP4 antibody-positive; seven of the nine NAbs negative patients were anti-AQP4 antibody-positive. Eleven patients (three NAbs positive, eight NAbs-negative) developed cerebral lesions and 12 patients (four NAbs-positive, eight NAbs-negative) spinal cord lesions on magnetic resonance imaging as gadolinium positive lesions or T2-weighted lesions, at significantly higher frequencies than NMO reference group (p<0.009). Exacerbation occurred within 90 days in four and 6-36 months in eight patients. Progression of disease activity in NMO patients occurred during IFN-beta treatment, irrespective of IFN neutralizing antibody status. PMID- 24477088 TI - The provision of end-of-life care by medical-surgical nurses working in acute care: a literature review. AB - OBJECTIVE: Caring for terminally ill patients is complex, stressful, and at times distressing for nurses. Acute care hospitals continue to be the predominant place of death for terminally ill patients in most Western countries. The objective of the present literature review was to explore and gain an in-depth understanding of the experience of providing end-of-life (EOL) care by medical-surgical RNs working in acute care hospitals, to identify knowledge gaps, and to recommend future research. METHOD: A comprehensive literature review was conducted using the following electronic databases: CINAHL, MEDLINE, and PsyInfo (from 1992 to October 2012). RESULTS: The findings from the 16 reviewed studies suggest that nurses felt a strong commitment to help terminally ill patients experience a good death. Nurses reported feeling deeply rewarded and privileged to share the EOL experience with patients/families. Organizational and individual factors influenced nurses' experience. Important challenges were associated with managing the divergent needs of a mixed patient load (i.e., curative and palliative care patients) in a biomedical culture of care that is heavily oriented toward cure and recovery. In this culture, nurses' emotional work and ideals of good EOL care are often not recognized and supported. SIGNIFICANCE OF RESULTS: Managerial and organizational support that recognize the centrality of emotional work nurses provide to dying patients is needed. More research exploring ways to improve communication among nurses and medical colleagues is essential. Finally, a critical examination of the ideological assumptions guiding nurses' practice of EOL care within the context of acute care is recommended to help reveal their powerful influence in shaping nurses' overall understanding and experience of EOL care. PMID- 24477089 TI - Incorporating Target Shedding Into a Minimal PBPK-TMDD Model for Monoclonal Antibodies. AB - Shedding of a pharmacological target from cells, giving rise to a soluble target that can also bind therapeutic proteins, is a common phenomenon. In this study, a minimal physiologically based pharmacokinetic model was used to simulate the pharmacokinetics of trastuzumab and the simultaneous binding of the compound to soluble (in blood and tissue interstitial space) and membrane-bound (in the tissue interstitial space) forms of human epidermal growth factor receptor 2 (HER2). The parameter values describing binding of trastuzumab to HER2 were largely derived from in vitro data, and the effects of varying HER2 levels, the affinity difference between membrane-bound HER2 and shed antigen, and slow binding kinetics were investigated. The model simulates a sharp decrease in trough drug concentrations at concentrations of soluble target between 500 and 1,000 ng/ml in plasma. This corresponds with the clinical concentration range of soluble target wherein changes in half-life of trastuzumab have been observed.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e96; doi:10.1038/psp.2013.73; published online 29 January 2014. PMID- 24477091 TI - Cardiovascular-risk prediction and type of event. PMID- 24477090 TI - Identifying tinnitus-related genes based on a side-effect network analysis. AB - Tinnitus, phantom sound perception, is a worldwide highly prevalent disorder for which no clear underlying pathology has been established and for which no approved drug is on the market. Thus, there is an urgent need for new approaches to understand this condition. We used a network pharmacology side-effect analysis to search for genes that are involved in tinnitus generation. We analyzed a network of 1,313 drug-target pairs, based on 275 compounds that elicit tinnitus as side effect and their targets reported in databases, and used a quantitative score to identify emergent significant targets that were more common than expected at random. Cyclooxigenase 1 and 2 were significant, which validates our approach, since salicylate is a known tinnitus generator. More importantly, we predict previously unknown tinnitus-related targets. The present results have important implications toward understanding tinnitus pathophysiology and might pave the way toward the design of novel pharmacotherapies.CPT Pharmacometrics Syst. Pharmacol. (2014) 3, e97; doi:10.1038/psp.2013.75; published online 29 January 2014. PMID- 24477092 TI - Is antioxidant therapy effective for advanced hypertension and renal injury? PMID- 24477093 TI - The quest for blood pressure reference values in children. PMID- 24477094 TI - Hypertension, inflammation and atrial fibrillation. PMID- 24477095 TI - Is intensified diuretic therapy an effective new treatment strategy in obstructive sleep apnoea patients with uncontrolled hypertension? PMID- 24477096 TI - Overall cardiovascular prognosis of isolated systolic hypertension, isolated diastolic hypertension and pulse pressure defined with home measurements: the Finn-home study. AB - OBJECTIVE: The overall cardiovascular prognosis of isolated systolic hypertension, isolated diastolic hypertension and pulse pressure defined with home blood pressure (BP) measurements remains unclear. METHODS: A prospective nationwide study was initiated in 2000-2001 on 1924 randomly selected participants aged 44-74 years. We determined home and office BP at baseline and classified the individuals into four groups according to their home BP levels: normotension, isolated diastolic hypertension, isolated systolic hypertension and systolic-diastolic hypertension. The primary endpoint was incidence of a composite cardiovascular event. RESULTS: After a median follow-up of 11.2 years, 236 individuals had suffered a cardiovascular event. In multivariable Cox proportional hazard models, the relative hazards and 95% confidence intervals (CIs) for cardiovascular events were significantly higher in participants with isolated diastolic hypertension (relative hazard 1.95; 95% CI, 1.06-3.57; P=0.03), isolated systolic hypertension (relative hazard 2.08; 95% CI, 1.42-3.05; P<0.001) and systolic-diastolic hypertension (relative hazard 2.79; 95% CI, 2.02 3.86; P<0.001) than in participants with normotension. Home (relative hazard 1.21; 95% CI, 1.05-1.40; P=0.009 per 10 mmHg increase), but not office (relative hazard 1.10; 95% CI, 1.00-1.21, P=0.06) pulse pressure, adjusted for mean arterial pressure, was an independent predictor of cardiovascular risk. CONCLUSION: Isolated diastolic and systolic hypertension defined with home measurements are associated with an increased cardiovascular risk. Close follow up and possible treatment of these patients is therefore warranted. Home-measured pulse pressure is an independent predictor of cardiovascular events while office measured pulse pressure is not, which fortifies the view that home BP provides more accurate risk prediction than office BP. PMID- 24477097 TI - Association of parental blood pressure with retinal microcirculatory abnormalities indicative of endothelial dysfunction in children. AB - OBJECTIVE: Microcirculatory abnormalities precede the onset of hypertension and may explain its familial nature. We examined the relationship between parental blood pressure (BP) and offspring retinal microvasculature in Pakistani trios [father, mother, and child (aged 9-14 years)]. METHODS: This is a substudy of a population-based trial of BP reduction. Data were available on 358 normotensive, and 410 offspring of at least one hypertensive parent. Retinal vessel characteristics were measured from digital images. Multivariable linear regression models were built to assess the associations between maternal and paternal BP and offspring retinal microvasculature. RESULTS: Optimality deviation was greatest in offspring of two hypertensive parents, compared with those with one or no hypertensive parent (P=0.030 for trend). Paternal SBP and DBP were each significantly associated with optimality deviation in offspring (P=0.023 and P=0.006, respectively). This relationship persisted after accounting for offspring cardiovascular risk factors [increase in optimality deviation (95% confidence interval, CI) 0.0053 (0.0001-0.0106, P=0.047) and 0.0109 (0.0025 0.0193, P=0.011), for each 10 mmHg increase in paternal SBP and DBP, respectively]. Maternal DBP was inversely associated with offspring arteriovenous ratio -0.0102 (-0.0198 to -0.0007, P=0.035). CONCLUSION: Microvascular endothelial dysfunction in children is associated with increasing levels of parental hypertension. The association with paternal BP is independent of other cardiovascular risk factors, including the child's BP. Higher maternal DBP is associated with evidence of arteriolar narrowing in offspring. These early microcirculatory changes may help explain familial predisposition to hypertension in people of Pakistani origin at an early age. VIDEO ABSTRACT: : PMID- 24477098 TI - Resistant hypertension and central aortic pressure. PMID- 24477099 TI - Reply to 'resistant hypertension and central aortic pressure'. PMID- 24477100 TI - Nocturnal blood pressure dipping: systolic, diastolic or both? PMID- 24477101 TI - Response to: nocturnal blood pressure dipping: systolic, diastolic or both? PMID- 24477102 TI - Learning disability in 10- to 16-year-old adolescents with very low birth weight in Japan. AB - In recent years, there has been an increase in the number of infants with very low birth weight (VLBW, i.e., weight less than 1,500 g) in Japan. However, the effect of VLBW on subsequent behavioral development and mental health remains unknown. Subjects enrolled were 57 individuals (13.4 +/- 1.9 years old) with VLBW (VLBW group), including 23 small-for-gestational-age (SGA) infants (i.e., the SGA/VLBW group) and 34 appropriate-for-gestational-age (AGA) infants (the AGA/VLBW group). The control group was 29 individuals born AGA at term. We used the questionnaires, the Pupil Rating Scale Revised (PRS) to screen for learning disabilities and the Children's Depression Inventory (CDI) to examine the presence of depression. The PRS score in the VLBW group was significantly lower than that of the control group (p < 0.001). Suspected learning disabilities (LD, defined by a score below 65 points on the PRS) were found in 6 out of the 56 subjects in the VLBW group (10.7%), whereas none were found in the 29 control subjects (p = 0.074). The frequency of suspected LD children was higher in the SGA/VLBW group (4 out of 22 evaluated infants, 18.2%) than that in the AGA/VLBW group (2/34, 5.9%). The frequency of suspected LD in the non-verbal field was significantly higher (p = 0.02) in the SGA/VLBW group (18.2%) than in the AGA/VLBW group (0%). However, CDI score did not significantly differ between groups. These findings suggest that VLBW and fetal growth restriction may pose a risk for LD among adolescents with VLBW. PMID- 24477103 TI - Development of the feline lungworms Aelurostrongylus abstrusus and Troglostrongylus brevior in Helix aspersa snails. AB - Aelurostrongylus abstrusus (Strongylida, Angiostrongylidae) and Troglostrongylus brevior (Strongylida, Crenosomatidae) are regarded as important lungworm species of domestic felids, with the latter considered an emerging threat in the Mediterranean region. The present study aimed to assess their concurrent development in the mollusc Helix aspersa (Pulmonata, Helicidae). Thirty snails were infested with 100 first-stage larvae (L1) of A. abstrusus and T. brevior, isolated from a naturally infested kitten. Larval development was checked by digesting five specimens at 2, 6 and 11 days post infestation. Larvae retrieved were morphologically described and their identification was confirmed by specific PCR and sequencing. All H. aspersa snails were positive for A. abstrusus and T. brevior, whose larval stages were simultaneously detected at each time point. In addition, snails were exposed to outdoor conditions and examined after overwintering, testing positive up to 120 days post infestation. Data herein presented suggest that A. abstrusus and T. brevior develop in H. aspersa snails and may eventually co-infest cats. Data on the morphology of both parasitic species in H. aspersa provide additional information on their development and identification, to better understand the population dynamics of these lungworms in receptive snails and paratenic hosts. PMID- 24477105 TI - Does improving misery cerebral perfusion improve misery cognition? PMID- 24477104 TI - The effects of dust-haze on mortality are modified by seasons and individual characteristics in Guangzhou, China. AB - This study aimed to investigate the effects of dust-haze on mortality and to estimate the seasonal and individual-specific modification effects in Guangzhou, China. Mortality, air pollution and meteorological data were collected for 2006 2011. A dust-haze day was defined as daily visibility <10 km with relative humidity <90%. This definition was further divided into light (8-10 km), medium (5-8 km) and heavy dust-haze (<5 km). A distributed lag linear model (DLM) was employed. Light, medium and heavy dust-haze days were associated with increased mortality of 3.4%, 6.8% and 10.4% respectively, at a lag of 0-6 days. This effect was more pronounced during the cold season, for cardiovascular mortality (CVD), respiratory mortality (RESP), in males and people >=60years. These effects became insignificant after adjustment for PM10. We concluded that dust-haze significantly increased mortality risk in Guangzhou, China, and this effect appears to be dominated by particulate mass and modified by season and individual specific factors. PMID- 24477106 TI - Cerebral metabolic abnormalities in A3243G mitochondrial DNA mutation carriers. AB - OBJECTIVE: To establish cerebral metabolic features associated with the A3243G mitochondrial DNA mutation with proton magnetic resonance spectroscopic imaging ((1)H MRSI) and to assess their potential as prognostic biomarkers. METHODS: In this prospective cohort study, we investigated 135 clinically heterogeneous A3243G mutation carriers and 30 healthy volunteers (HVs) with (1)H MRSI. Mutation carriers included 45 patients with mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes (MELAS); 11 participants who would develop the MELAS syndrome during follow-up (converters); and 79 participants who would not develop the MELAS syndrome during follow-up (nonconverters). The groups were compared with respect to MRSI metabolic indices of 1) anaerobic energy metabolism (lactate), 2) neuronal integrity (N-acetyl-l-aspartate [NAA]), 3) mitochondrial function (NAA; lactate), 4) cell energetics (total creatine), and 5) membrane biosynthesis and turnover (total choline [tCho]). RESULTS: Consistent with prior studies, the patients with MELAS had higher lactate (p < 0.001) and lower NAA levels (p = 0.01) than HVs. Unexpectedly, converters showed higher NAA (p = 0.042), tCho (p = 0.004), and total creatine (p = 0.002), in addition to higher lactate levels (p = 0.032), compared with HVs. Compared with nonconverters, converters had higher tCho (p = 0.015). Clinically, converters and nonconverters did not differ at baseline. Lactate and tCho levels were reliable biomarkers for predicting the risk of individual mutation carriers to develop the MELAS phenotype. CONCLUSIONS: (1)H MRSI assessment of cerebral metabolism in A3243G mutation carriers shows promise in identifying disease biomarkers as well as individuals at risk of developing the MELAS phenotype. PMID- 24477107 TI - Clinical characteristics and outcome of brain abscess: systematic review and meta analysis. AB - OBJECTIVE: To define clinical characteristics, causative organisms, and outcome, and evaluate trends in epidemiology and outcome of brain abscesses over the past 60 years. METHODS: We performed a systematic review and meta-analysis of studies on brain abscesses published between 1970 and March 2013. Studies were included if they reported at least 10 patients with brain abscesses, included less than 50% extra-axial CNS infections (empyema) without brain abscess, and did not solely report on brain abscesses caused by a single pathogen. RESULTS: We identified 123 studies including 9,699 patients reported between 1935 and 2012. There was a male predominance of 2.4 to 1, and the mean age of patients with brain abscesses was 34 years. The most common causative microorganisms were Streptococcus and Staphylococcus species, comprising 2,000 (34%) and 1,076 (18%) of 5,894 cultured bacteria. Geographical distribution of causative microorganisms over continents was similar and did not substantially change over the past 60 years. Predisposing conditions were present in 8,134 of 9,484 patients (86%) and mostly consisted of contiguous or metastatic foci of infection. The classic triad of fever, headache, and focal neurologic deficits was present in 131 of 668 (20%) of patients. Case fatality rate decreased from 40% to 10% over the past 5 decades, while the rate of patients with full recovery increased from 33% to 70%. CONCLUSIONS: The prognosis of patients with brain abscesses has gradually improved over the past 60 years. Important changes over time were the modality of cranial imaging, neurosurgical technique, and antimicrobial regimen. PMID- 24477108 TI - Effect of pain in pediatric inherited neuropathies. AB - OBJECTIVE: Assess the prevalence and impact of pain in children with Charcot Marie-Tooth (CMT) disease. METHODS: In this prospective cross-sectional study on children with CMT disease seen at study sites of the Inherited Neuropathy Consortium, we collected standardized assessments of pain (Wong-Baker FACES Pain Rating Scale) from 176 patients (140 children aged 8-18 years, and 36 children aged 2-7 years through parent proxies), along with standardized clinical assessments and quality-of-life (QOL) outcomes. We then developed a series of multivariate regression models to determine whether standardized measures of neuropathy severity, functional impact, or structural changes to the feet explained the observed pain scores. RESULTS: The mean score on the Wong-Baker FACES Pain Rating Scale was 2 (range 0-5). Increased pain strongly correlated with worse QOL scores but not with more severe neuropathy. Independent determinants of increased pain in children with CMT disease included measures of ankle inflexibility. CONCLUSION: Pain is present in children with CMT disease and negatively affects QOL. Pain scores do not positively correlate with neuropathy severity but do correlate in limited univariate analyses with measures of ankle inflexibility. Further studies to elucidate the mechanisms of pain may help identify treatments that can reduce pain and improve QOL in patients with CMT disease. PMID- 24477110 TI - Homocysteine and progression of generalized small-vessel disease: the SMART-MR Study. AB - OBJECTIVES: Assuming the involvement of homocysteine in a generalized small vessel disease, we investigated the association of homocysteine levels with progression of white matter lesions, lacunar infarcts, and kidney disease. METHODS: Within the SMART-MR (Second Manifestations of ARTerial disease-Magnetic Resonance) Study, a prospective cohort study on brain aging in patients with symptomatic atherosclerotic disease, 663 patients (aged 57 +/- 9 years) had vascular screening and 1.5-tesla MRI at baseline and after a mean follow-up of 3.9 years. Multiple regression analysis was used to estimate the longitudinal association between total homocysteine level, defined as a continuous variable and as hyperhomocysteinemia (the highest quintile of homocysteine), and progression of white matter lesion volume, lacunar infarcts, and estimated glomerular filtration rate. RESULTS: After adjusting for age, sex, follow-up time, and vascular risk factors, hyperhomocysteinemia was significantly associated with increased risk of white matter lesion progression (odds ratio 2.4, 95% confidence interval [CI] 1.5-4.1) and lower estimated glomerular filtration rate at follow-up (B = -3.4 mL/min, 95% CI -5.9 to -0.9) and borderline significantly associated with new lacunar infarcts (odds ratio 1.8, 95% CI 0.9-3.4). CONCLUSIONS: Our findings implicate a role for homocysteine in the development of a generalized small-vessel disease in which both brain and kidney are affected. PMID- 24477109 TI - Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON) trial: main results. AB - OBJECTIVE: To determine whether extracranial-intracranial (EC-IC) bypass can improve cognition over 2 years compared to best medical therapy alone in patients with symptomatic internal carotid artery (ICA) occlusion and increased oxygen extraction fraction (OEF) on PET. METHODS: Patients underwent (15)O PET and were randomized if OEF ratio was >1.13 on the occluded side. Using blinded baseline and 2-year cognitive assessments, age-adjusted composite z scores were generated from subtests sensitive to right/left hemisphere plus global cognitive functioning. Multiple regression predicted 2-year cognitive change. RESULTS: Eighty-nine patients were enrolled; 41 had increased OEF and were randomized. Two died, 2 were lost to follow-up, and 2 refused 2-year testing. Of the 35 remaining, 6 had ipsilateral stroke or death, leaving 13 surgical and 16 medical patients. Controlling for age, education, and depression, there was no difference in 2-year cognitive change between the medical and surgical arms (95% confidence interval -0.5 to 0.5, p = 0.9). In post hoc analysis of 26 patients with no stroke in the follow-up period, cognitive improvement was associated with less impaired PET OEF at baseline (p = 0.045). CONCLUSION: Cognitive improvement following bypass surgery was not superior to medical therapy among patients with recently symptomatic carotid occlusion and increased OEF. Among those with no recurrent stroke, less hemodynamic impairment at baseline was associated with greater cognitive gain in both groups. Reversing cognitive impairment in hemodynamic failure remains an open challenge. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with symptomatic ICA occlusion and increased OEF on PET, EC-IC bypass compared to no bypass does not improve cognitive function after 2 years. PMID- 24477111 TI - High plasma estradiol interacts with diabetes on risk of dementia in older postmenopausal women. AB - OBJECTIVE: We aimed to investigate the impact of endogenous estradiol (E2) on dementia and to evaluate the contribution of vascular risk factors and inflammatory and blood coagulation markers to this association. METHODS: Using data from a French population-based prospective study (the Three-City Study) including 5,644 postmenopausal women aged 65 years or older, we investigated the association of endogenous total-E2 and bioavailable-E2 and total-testosterone with the 4-year incidence of all-cause dementia. We further focused on the role of dementia and cardiovascular risk factors as well as inflammation (C-reactive protein, fibrinogen) and hypercoagulability (fibrin d-dimers, thrombin generation) in these associations. We used a case-cohort design consisting of a random subcohort of 562 women not using hormone therapy and 132 incident dementia cases. RESULTS: Adjusted Cox proportional hazards models showed a J-shaped relationship between total-E2 and risk of dementia (p = 0.001). Total-E2 values in the lower and upper quartiles were associated with an increased dementia risk (adjusted hazard ratio [HR] [95% confidence interval] = 2.2 [1.1-4.5] and HR = 2.4 [1.2-5.2], respectively). Importantly, the risk associated with higher E2 levels was dramatically increased in women with diabetes compared with nondiabetic women (adjusted HR associated with the upper E2 quartile = 14.2 [1.60 123] and HR = 3.4 [0.1-147], respectively, p interaction <0.05). Similar results were found for bioavailable-E2. Adjustment for inflammatory and blood coagulation markers did not modify our results. No significant association was found for total-testosterone. CONCLUSION: High E2 level is an independent predictor of incident dementia, particularly in postmenopausal women with diabetes. PMID- 24477112 TI - Confidentiality in preclinical Alzheimer disease studies: when research and medical records meet. AB - Clinical trials to advance the diagnosis and treatment of Alzheimer disease (AD) may expose research subjects to discrimination risks. An individual enrolled in a research study that uses positive test results from amyloid PET imaging or CSF measures of beta-amyloid 42 as inclusion criteria has biomarkers indicative of AD pathology. If insurers and employers learn this information, it could expose subjects to discrimination. Unfortunately, current legal and regulatory mechanisms are not sufficient to protect against harms that have significant consequences for subjects. Existing law that prohibits employment and insurance discrimination based on genetic status does not apply to amyloid biomarkers or any other biomarkers for neurodegenerative diseases. Gaps in legal protections fail to protect research subjects from discrimination by long-term care and disability insurers. This risk is particularly concerning because individuals with AD dementia ultimately need long-term care services. To maximize subject protections and advance valuable research, policymakers, investigators, and research institutions must address shortcomings in the design of the electronic medical record, revise laws to limit discrimination, and develop practices that inform research participants of risks associated with loss of confidentiality. PMID- 24477113 TI - Prevalence of cortical superficial siderosis in a memory clinic population. AB - OBJECTIVE: To determine prevalence, topography, and severity of cortical superficial siderosis (SS), a recently recognized manifestation of cerebral amyloid angiopathy, and its possible association with Alzheimer disease (AD) in a memory clinic patient cohort. METHODS: We included 809 patients (56% men, aged 66 +/- 10 years) from the Amsterdam Dementia Cohort between November 2010 and November 2012 scanned on a 3-tesla MRI system. We analyzed prevalence and topography of cortical SS according to demographic, clinical, and MRI data. Agreement for SS detection between 2 neuroradiologists was calculated by using Cohen kappa. RESULTS: Agreement for detection of SS was excellent (unweighted kappa of 0.81). In 17 patients (2.1%), cortical SS was found without a known cause. The prevalence of idiopathic SS differed according to diagnostic groups (p < 0.001): nearly 5% (95% confidence interval [CI] 2.8%-8.2%) in patients with AD (n = 168) vs 2% (95% CI 0.7%-6.0%) in patients with mild cognitive impairment (n = 143) and 2.5% (95% CI 0.7%-8.7%) in other types of dementia (n = 80). By contrast, SS was not found in patients with subjective complaints (n = 168) or in those with other disorders (n = 157). Presence of SS was associated with APOE epsilon4, microbleeds, and white matter hyperintensities (all p < 0.05) independent of diagnosis. CONCLUSION: The prevalence of cortical SS in a memory clinic setting is higher than reported in the general population but lower than reported in cerebral amyloid angiopathy. The relatively high prevalence of SS in AD suggests that SS is a relevant radiologic manifestation of amyloid pathology in AD. Presence of SS does not seem to predict severity of AD. Further longitudinal research is needed to investigate clinical relevance. PMID- 24477114 TI - Probing backbone hydrogen bonding in PDZ/ligand interactions by protein amide-to ester mutations. AB - PDZ domains are scaffolding modules in protein-protein interactions that mediate numerous physiological functions by interacting canonically with the C-terminus or non-canonically with an internal motif of protein ligands. A conserved carboxylate-binding site in the PDZ domain facilitates binding via backbone hydrogen bonds; however, little is known about the role of these hydrogen bonds due to experimental challenges with backbone mutations. Here we address this interaction by generating semisynthetic PDZ domains containing backbone amide-to ester mutations and evaluating the importance of individual hydrogen bonds for ligand binding. We observe substantial and differential effects upon amide-to ester mutation in PDZ2 of postsynaptic density protein 95 and other PDZ domains, suggesting that hydrogen bonding at the carboxylate-binding site contributes to both affinity and selectivity. In particular, the hydrogen-bonding pattern is surprisingly different between the non-canonical and canonical interaction. Our data provide a detailed understanding of the role of hydrogen bonds in protein protein interactions. PMID- 24477115 TI - Guidelines for laboratory analyses for poisoned patients in the United Kingdom. AB - To enable consistency of investigation and the establishment of best practice standards, consensus guidelines were formulated previously by the UK National Poisons Information Service and the Association for Clinical Biochemistry. These joint guidelines have now been updated to reflect current best practice. The types of laboratory investigation required for poisoned patients are categorized as either (a) essential common laboratory investigations or (b) specific toxicological assays, and also as either (i) common or (ii) specialist or infrequent. Tests in categories (a) and (bi) should be available 24 hours per day, with a maximum turnaround time of 2 h. For the specialist assays, i.e. category (bii), availability and turnaround times have been specified individually. The basis for selection of these times has been clinical utility. The adoption of these guidelines, along with the use of the National Poisons Information Service (0844 8920111) and its online poisons information resource TOXBASE((r)) (www.toxbase.org) enable the poisoned patient to receive appropriate, 'best practice' investigations according to their clinical needs and will avoid unnecessary investigations. PMID- 24477116 TI - The association of soda sales tax and school nutrition laws: a concordance of policies. AB - OBJECTIVE: The current research examined the association between state disfavoured tax on soda (i.e. the difference between soda sales tax and the tax on food products generally) and a summary score representing the strength of state laws governing competitive beverages (beverages that compete with the beverages in the federally funded school lunch programme) in US schools. DESIGN: The Classification of Laws Associated with School Students (CLASS) summary score reflected the strength of a state's laws restricting competitive beverages sold in school stores, vending machines, school fundraisers and a la carte cafeteria items. Bridging the Gap (BTG) is a nationally recognized research initiative that provided state-level soda tax data. The main study outcome was the states' competitive beverage summary scores for elementary, middle and high school grade levels, as predicted by the states' disfavoured soda tax. Univariate and multivariate analyses were conducted, adjusting for year and state. SETTING: Data from BTG and CLASS were used. SUBJECTS: BTG and CLASS data from all fifty states and the District of Columbia from 2003 to 2010 were used. RESULTS: A higher disfavoured soda sales tax was generally associated with an increased likelihood of having strong school beverage laws across grade levels, and especially when disfavoured soda sales tax was >5 %. CONCLUSIONS: These data suggest a concordance between states' soda taxes and laws governing beverages sold in schools. States with high disfavoured sales tax on soda had stronger competitive beverage laws, indicating that the state sales tax environment may be associated with laws governing beverage policy in schools. PMID- 24477117 TI - Identification of a vir-orthologous immune evasion gene family from primate malaria parasites. AB - The immune evasion gene family of malaria parasites encodes variant surface proteins that are expressed at the surface of infected erythrocytes and help the parasite in evading the host immune response by means of antigenic variation. The identification of Plasmodium vivax vir orthologous immune evasion gene family from primate malaria parasites would provide new insight into the evolution of virulence and pathogenesis. Three vir subfamilies viz. vir-B, vir-D and vir-G were successfully PCR amplified from primate malaria parasites, cloned and sequenced. DNA sequence analysis confirmed orthologues of vir-D subfamily in Plasmodium cynomolgi, Plasmodium simium, Plasmodium simiovale and Plasmodium fieldi. The identified vir-D orthologues are 1-9 distinct members of the immune evasion gene family which have 68-83% sequence identity with vir-D and 71.2-98.5% sequence identity within the members identified from primate malaria parasites. The absence of other vir subfamilies among primate malaria parasites reflects the limitations in the experimental approach. This study clearly identified the presence of vir-D like sequences in four species of Plasmodium infecting primates that would be useful in understanding the evolution of virulence in malaria parasites. PMID- 24477118 TI - The PsbP and PsbQ family proteins in the photosynthetic machinery of chloroplasts. AB - The PsbP and PsbQ proteins are extrinsic subunits of the photosystem II in eukaryotic photosynthetic organisms including higher plants, green algae and euglena. It has been suggested that PsbP and PsbQ have evolved from their cyanobacterial homologs, while considerable genetic and functional modifications have occurred to generate the eukaryote-type proteins. In addition, number of PsbP and PsbQ homologs exist in the thylakoid lumen of chloroplasts. These homologs are nuclear-encoded and likely diverged by gene duplication, and recent studies have elucidated their various functions in the photosynthetic machinery. In this short review, recent findings and new idea about these components will be discussed. PMID- 24477119 TI - Vitamin D status and its relationship with metabolic syndrome risk factors among adolescent girls in Boukan, Iran. AB - OBJECTIVE: To investigate vitamin D status and its association with components of the metabolic syndrome (MetS) in adolescent girls attending high school in Boukan, Iran during winter 2012. DESIGN: A cross-sectional study. SETTING: High schools of Boukan city, Iran. SUBJECTS: A sample of 216 girls aged 14-17 years was selected by multistage random sampling from four districts of Boukan. Weight, height, waist circumference, blood pressure, daily energy intake, physical activity and serum 25-hydroxyvitamin D (25(OH)D), fasting blood glucose, TAG and HDL-cholesterol levels of all participants were evaluated. Serum 25(OH)D level <20 ng/ml was defined as vitamin D deficiency. RESULTS: Mean serum 25(OH)D was 7.26 (sd 2.81) ng/ml and 96 % of the participants had vitamin D deficiency. According to age-modified definitions of the National Cholesterol Education Program Adult Treatment Panel III, MetS was diagnosed in 10.6% of the participants. In multivariable regression analysis after adjustment for BMI, energy intake and physical activity level, serum 25(OH)D was inversely associated with fasting blood glucose (beta = -0.143, P = 0.04). No significant relationship was found between serum 25(OH)D and other components of MetS. CONCLUSIONS: The high prevalence of vitamin D deficiency warrants national polices and interventions towards improving this major health problem among adolescent girls. Low 25(OH)D level was significantly associated with increased fasting blood glucose. Prospective studies are needed to determine the effects of vitamin D deficiency on the development of MetS and related metabolic diseases in adolescent girls. PMID- 24477120 TI - Structural brain abnormalities are related to retinal nerve fiber layer thinning and disease duration in neuromyelitis optica spectrum disorders. AB - BACKGROUND: Although aquaporin-4 (AQP4) is widely expressed in the human brain cortex, lesions are rare in neuromyelitis optica (NMO) spectrum disorders (NMOSD). Recently, however, several studies have demonstrated occult structural brain atrophy in NMO. OBJECTIVE: This study aims to investigate magnetic resonance imaging (MRI) patterns of gray matter (GM) and white matter (WM) abnormalities in patients with NMOSD and to assess the visual pathway integrity during disease duration correlation of the retinal nerve fiber layer (RNFL) and pericalcarine cortex thickness. METHODS: Twenty-one patients with NMOSD and 34 matched healthy controls underwent both high-field MRI (3T) high-resolution T1 weighted and diffusion-tensor MRI. Voxel-based morphometry, cortical analyses (Freesurfer) and diffusion-tensor imaging (DTI) analyses (TBSS-FSL) were used to investigate brain abnormalities. In addition, RNFL measurement by optic-coherence tomography (OCT) was performed. RESULTS: We demonstrate that NMOSD is associated with GM and WM atrophy, encompassing more frequently the motor, sensory and visual pathways, and that the extent of GM atrophy correlates with disease duration. Furthermore, we demonstrate for the first time a correlation between RNFL and pericalcarine cortical thickness, with cortical atrophy evolving over the course of disease. CONCLUSIONS: Our findings indicate a role for retrograde and anterograde neurodegeneration in GM atrophy in NMOSD. However, the presence atrophy encompassing almost all lobes suggests that additional pathomechanisms might also be involved. PMID- 24477121 TI - In praise of Grandgarden. PMID- 24477122 TI - [Intermittent smoking--a health threat?]. PMID- 24477123 TI - [How is the quality of the diabetes care?]. PMID- 24477124 TI - [The doctor personality--does it exist?]. PMID- 24477125 TI - [The physician's role]. PMID- 24477126 TI - [Registered opiate addicts in Norway]. PMID- 24477127 TI - [Violation of the Helsinki Declaration]. PMID- 24477128 TI - [L.S. Stavseth and colleagues reply]. PMID- 24477129 TI - [Disagreement among physicians]. PMID- 24477130 TI - [Building bridges]. PMID- 24477131 TI - [E. Ulvestad replies]. PMID- 24477132 TI - [Borreliosis and embarrassment]. PMID- 24477133 TI - [Scientificity and justifiability]. PMID- 24477134 TI - [E. Ulvestad replies]. PMID- 24477135 TI - [The start of a fruitful debate?]. PMID- 24477136 TI - [Conflicts of interest in the borreliosis debate]. PMID- 24477137 TI - [Patients with unexplained illness]. PMID- 24477138 TI - [Important about microbes in the intestines]. PMID- 24477142 TI - [Valproate should be avoided in pregnancy]. PMID- 24477143 TI - [Cellular Borrelia tests]. PMID- 24477144 TI - [Consensus-based guidelines may prevent necessary research]. PMID- 24477145 TI - New consciousness scale for delirium. PMID- 24477146 TI - [Too many pinches of salt]. PMID- 24477149 TI - [Occasional smoking in Norway]. AB - BACKGROUND: In recent decades, daily smoking has become less common, while occasional smoking has stayed at the same level. The purpose of the study is to describe occasional smokers on the basis of their smoking behaviour and socio demographic characteristics. MATERIAL AND METHOD: Data from Statistics Norway's quarterly surveys of tobacco use in 2010 and 2011 were used. Information on smoking habits, smoking-related behaviour and the respondents' attitudes to their own smoking was collected in telephone interviews. RESULTS: Of the 8,700 men and women aged 16-74 (response rate 57%) who were included, altogether 1,583 were daily smokers and 907 occasional smokers. The occasional smokers were younger, more frequently lived in large cities and had a higher level of education and income than the daily smokers. Twenty-nine of 174 (17%) occasional smokers used snus on a daily basis, compared to 10 of 394 (3%) of the daily smokers. The occasional smokers had great confidence in their ability to quit: 95% responded that they would be smoke-free in five years, compared to 55% of the daily smokers (n = 2,158). Fifty-five (35%) of the occasional smokers lit up several times weekly (16 cigarettes per week on average), while the remaining (65%) smoked only once per week as a maximum (five cigarettes per week on average). Those who smoked several times each week had attitudes to their own smoking and usage pattern for tobacco that were similar to those of the daily smokers. Nearly half of the occasional smokers defined themselves as non-smokers. INTERPRETATION: Norwegian occasional smokers are a heterogeneous group in terms of their smoking pattern and frequency, and many define themselves as non-smokers. PMID- 24477151 TI - Warfarin therapy for atrial fibrillation in general practice--is bleeding risk underestimated? AB - BACKGROUND: Atrial fibrillation increases by fivefold the risk for thromboembolic stroke. Warfarin therapy reduces that risk by 64%, but increases the risk for major bleeding. We wanted to study the quality of the warfarin therapy given in a Norwegian general practice and to calculate which patients would have probable benefit of the treatment. MATERIAL AND METHOD: We retrospectively recorded the patients diagnosed with atrial fibrillation and calculated the thromboembolism risk (CHA2DS2-VASc score) and bleeding risk (HAS-BLED score) for each patient. Absolute bleeding risk was calculated using two alternative methods of calculation based on the studies Euro Heart Survey on Atrial Fibrillation (EHS) and SPORTIF. The expected net benefit of warfarin therapy was calculated thus: Reduction in thromboembolism risk (risk for thromboembolism * 0.64) - Risk for major bleeding. RESULTS: 112 patients had atrial fibrillation. Their median age was 79 years, and 60% were men. Of patients with a CHA2DS2-VASc score of >= 2, 85% used warfarin or new oral anticoagulants, while for patients with a lower risk score the corresponding percentage was 13%. 69% of the International Normalised Ratio (INR) measurements were in the target range. Of 79 patients with a CHA2DS2-VASc score of >= 3, all had expected benefit of the treatment when it was based on the EHS study and 72 patients when it was based on the SPORTIF study, but for patients with lower risk the two calculation alternatives gave differing results. Calculated on the basis of the SPORTIF study, two out of 33 patients with a CHA2DS2-VASc score of < 3 had expected benefit of the treatment. INTERPRETATION: For patients with high thromboembolism risk, we calculated a convincing benefit of warfarin therapy. Where there was lower risk the net benefit in our patients depended on which study population the calculation was based on. The EHS population forms the basis for the European guidelines for anticoagulant therapy, but appears to differ from the patients in Norwegian general practice. This may lead to an underestimation of the bleeding risk. PMID- 24477150 TI - [Diabetes in general practice--were treatment goals reached?]. AB - BACKGROUND: In Norway, most people with diabetes are treated by general practitioners. At our own general practice, we wanted to find out whether we were succeeding in following the Directorate of Health's 2009 clinical guidelines on treatment and management of diabetes. MATERIAL AND METHOD: All patients with the diagnosis diabetes mellitus in our electronic archive between November 2009 and October 2010 were registered. Those patients on our general practice lists in October 2010 were identified. The patient records were manually reviewed and relevant data recorded. RESULTS: In all, 271 patients with diabetes attended our surgery for check-ups in October 2010. 11% had type 1 diabetes and 88% had type 2 diabetes. HbA1c was measured in 99% of the diabetes patients, blood pressure in 98% and lipids in 93%. The measurements were taken at our surgery during the past year for 96% of the patients. The treatment goals for HbA1c, systolic blood pressure and LDL cholesterol were reached in, respectively, 55%, 55% and 49% of the patients. 13% reached all three treatment goals. 82% had a check-up with an ophthalmologist. Weight and smoking habits were documented in 85% and 90% respectively. 19% of the patients for whom we had documented data, smoked. Examinations of height, feet and microalbumin were documented in 57%, 35% and 28% of the patients respectively. INTERPRETATION: The guidelines are being followed on most points to a high degree, and the proportion of patients reaching the stricter treatment goals is consistent with the results of earlier Norwegian surveys. There is the potential for further improvement of these results. PMID- 24477152 TI - Ischaemic stroke with patent foramen ovale. AB - BACKGROUND: There is no sound scientific documentation of current guidelines for the treatment of cerebral infarction assumed to be due to patent foramen ovale. In this article, we present a young patient with this condition. In addition, we provide a general overview of the prevalence, recommended assessment and indications for treatment of patent foramen ovale in ischaemic stroke patients. METHOD: The article is based on a non-systematic search in PubMed. We emphasise three recently published randomised trials on the subject. RESULTS: Transoesophageal echocardiography with saline contrast is the gold standard for detecting patent foramen ovale. Just who will benefit from the diagnosis and treatment of this condition remains unclear, however. None of the three randomised studies of antithrombotic treatment versus transcatheter closure in patients who have suffered ischaemic stroke show a difference in outcomes, but subgroup analyses indicate that closure in young patients (age <50 years) with a large foramen ovale reduces the number of recurrent ischaemic events. Two other randomised studies of antithrombotic treatment alone versus closure are presently ongoing. INTERPRETATION: For stroke patients with patent foramen ovale, the choice between lifelong antithrombotic therapy alone and transcatheter closure is a difficult one. Treatment with antiplatelet agents remains the first choice in most cases. Well-designed studies are needed to identify which patients will benefit most from closure. PMID- 24477153 TI - Leak after aortic stent-graft repair. PMID- 24477154 TI - [Glucocorticoid injections in the treatment of seasonal allergies]. PMID- 24477155 TI - [A woman with long-lasting diarrhoea and fatigue]. AB - BACKGROUND: Intestinal trematodes are common parasites in man and many mammals. Infection is often asymptomatic and unrecognised. CASE PRESENTATION: A woman in her twenties presented with loose stools of variable intensity over six months. Additionally, she had experienced considerable fatigue during this period. There was no weight loss and initial blood tests were normal. Further testing at the second visit included stool microscopy, and small trematode eggs consistent with H. heterophyes infection were found. A more thorough anamnesis revealed the onset of symptoms on the day she returned from a week's holiday, and the probable exposure occurred from eating sushi twice during this holiday. After one day of treatment with praziquantel 40 mg/kg administered in three doses, the patient recovered completely within two to four weeks. Her asymptomatic partner had consumed the same food and had the same eggs in his stool sample. He was successfully treated with the same treatment dose. INTERPRETATION: A detailed travel history may provide important information relating to the diagnosis of diarrhoea and fatigue. Symptoms of H. heterophyes infection are variable. A single day's dose of 40 mg/kg of praziquantel was sufficient to eradicate infection in the two cases presented. PMID- 24477156 TI - [Local food at exotic vacation]. PMID- 24477157 TI - [Critical heart defects in newborns overlooked]. PMID- 24477158 TI - [A norwegian proverb for dying]. PMID- 24477160 TI - Desmoid-type fibromatosis and pregnancy: a multi-institutional analysis of recurrence and obstetric risk. AB - BACKGROUND: Many women who present with desmoid-type fibromatosis (DF) have had a recent pregnancy. Long-term data about disease behavior during and after pregnancy are lacking. OBJECTIVE: To investigate the possible relationship between DF and pregnancy. PATIENTS AND METHODS: A cohort of women with DF and pregnancy was identified from 4 sarcoma centers. Four groups were identified: diagnosis during pregnancy (A); diagnosis after delivery (B); DF clinically evident during pregnancy (C); and DF resected before pregnancy (D). Progression/regression rates, recurrence rates after resection, and obstetric outcomes were analyzed. RESULTS: Ninety-two women were included. Forty-four women (48%) had pregnancy-related DF (A + B), whereas 48 (52%) had a history of DF before conception (C + D). Initial treatment was resection in 52%, medical therapy in 4%, and watchful waiting in 43%. Postsurgical relapse rate in A + B was 13%, although progression during watchful waiting was 63%. Relapse/progression in C + D was 42%. After pregnancy, 46% underwent treatment of DF, whereas 54% were managed with watchful waiting. Eventually, only 17% experienced further progression after treatment. Spontaneous regression occurred in 14%. After further pregnancies, only 27% progressed. The only related obstetric event was a cesarean delivery. CONCLUSIONS: Pregnancy-related DF has good outcomes. Progression risk during pregnancy is high, but it can be safely managed. DF does not increase obstetric risk, and it should not be a contraindication to future pregnancy. PMID- 24477161 TI - Laparoscopic "Successful" Excision of Deep Endometriosis: A Fertility-enhancing Surgery. PMID- 24477162 TI - Biomaterials in Abdominal Wall Surgery: Change Your Mind! PMID- 24477165 TI - 33th European Society of Neuroradiology Annual Meeting. 17th Advanced Course "Intracranial tumors from structural to functional imaging" - Cracow, Poland, 18 21 September 2008. PMID- 24477163 TI - Intrinsic autoimmune capacities of hematopoietic cells from female New Zealand hybrid mice. AB - Most systemic autoimmune diseases occur more frequently in females than in males. This is particularly evident in Sjogren's syndrome, systemic lupus erythromatosis (SLE) and thyroid autoimmunity, where the ratio of females to males ranges from 20:1 to 8:1. Our understanding of the etiology of SLE implies important roles for genetics, environmental factors and sex hormones, but the relative significance of each remains unknown. Using the New Zealand hybrid mouse model system of SLE, we present here a new fetal liver chimera-based system in which we can segregate effects of immune system genes from that of sex hormones in vivo. We show that female hematopoietic cells express an intrinsic capacity to drive lupus-like disease in both male and female recipient mice, suggesting that this capacity is hormone independent. Particularly, only chimeric mice with a female hematopoietic system showed significantly increased numbers of germinal center B cells, memory B cells and plasma cells followed by a spontaneous loss of tolerance to nuclear components and hence elevated serum antinuclear autoantibodies. A protective effect of testosterone was noted with regard to disease onset, but not disease incidence. Thus, genetic factors encoded within the female hematopoietic system can effectively drive lupus-like disease even in male recipients. PMID- 24477164 TI - BXSB-type genome causes murine autoimmune glomerulonephritis: pathological correlation between telomeric region of chromosome 1 and Yaa. AB - The autoimmune-prone BXSB/MpJ-Yaa mouse is a model of membranous proliferative glomerulonephritis (MPGN). Severe MPGN has been reported only in male BXSB/MpJ Yaa mice because of the Y-linked autoimmune accelerator (Yaa) locus. However, we show that female BXSB/MpJ mice develop age-related MPGN without Yaa. Female BXSB/MpJ mice clearly developed MPGN characterized by increased mesangial cells, thickening of the glomerular basement membrane (GBM), double contouring and spike formation of GBM with T-cell infiltrations and podocyte injuries corresponding with increased autoantibody production and albuminuria. Analysis of the renal levels of the Fc gamma receptor (Fcgr) and interferon-activated gene 200 (Ifi200) family genes, which are MPGN candidate genes localized to the telomeric region of chromosome 1 (Chr.1), showed that Fcgr2b levels decreased, whereas Fcgr3 and Ifi202b levels increased in female BXSB/MpJ mice compared with healthy C57BL/6 mice. Furthermore, in isolated glomeruli, microarray analysis revealed that Fcgr3, Fcgr4 and Ifi202b expression was higher in male BXSB/MpJ-Yaa mice than in male BXSB/MpJ mice. These findings indicate that the BXSB/MpJ-type genome causes age-related MPGN with significant contribution from the telomeric region of Chr.1, and Yaa enhances the expression of genes localizing to this locus, thereby leading to severe MPGN in male mice. PMID- 24477166 TI - Magnetic resonance imaging using gadolinium-based contrast agents. AB - The purpose of this article was to review the basic properties of available gadolinium-based magnetic resonance contrast agents, discuss their fundamental differences, and explore common and evolving applications of gadolinium-based magnetic resonance contrast throughout the body excluding the central nervous system. A more specific aim of this article was to explore novel uses of these gadolinium-based contrast agents and applications where a particular agent has been demonstrated to behave differently or be better suited for certain applications than the other contrast agents in this class. PMID- 24477167 TI - Three more polio workers are killed in Pakistan. PMID- 24477168 TI - Use of the Mental Health Act in England shows year-on-year increase. PMID- 24477169 TI - Identifying socio-environmental factors that facilitate resilience among Canadian palliative family caregivers: a qualitative case study. AB - OBJECTIVE: In Canada, friends and family members are becoming increasingly responsible for providing palliative care in the home. This is resulting in some caregivers experiencing high levels of stress and burden that may ultimately surpass their ability to cope. Recent palliative care research has demonstrated the potential for caregiver resilience within such contexts. This research, however, is primarily focused on exploring individual-level factors that contribute to resilience, minimizing the inherent complexity of this concept, and how it is simultaneously influenced by one's social context. Therefore, our study aims to identify socio-environmental factors that contribute to palliative family caregiver resilience in the Canadian homecare context. METHODS: Drawing on ethnographic fieldnotes and semistructured interviews with family caregivers, care recipients, and homecare nurses, this secondary analysis employs an intersectionality lens and qualitative case study approach to identify socio environmental factors that facilitate family caregivers' capacity for resilience. Following a case study methodology, two cases are purposely selected for analysis. RESULTS: Findings demonstrate that family caregiver resilience is influenced not only by individual-level factors but also by the social environment, which sets the lived context from which caregiving roles are experienced. Thematic findings of the two case studies revealed six socio environmental factors that play a role in shaping resilience: access to social networks, education/knowledge/awareness, employment status, housing status, geographic location, and life-course stage. SIGNIFICANCE OF RESULTS: Findings contribute to existing research on caregiver resilience by empirically demonstrating the role of socio-environmental factors in caregiving experiences. Furthermore, utilizing an intersectional approach, these findings build on existing notions that resilience is a multidimensional and complex process influenced by numerous related variables that intersect to create either positive or negative experiences. The implications of the results for optimizing best homecare nursing practice are discussed. PMID- 24477170 TI - Contribution of Exocervical Biopsy, Endocervical Curettage, and Colposcopic Grading in Diagnosing High-Grade Cervical Intraepithelial Neoplasia. AB - OBJECTIVE: To determine the utility of random biopsy and endocervical curettage (ECC) during colposcopy among women who ultimately underwent cervical excisional biopsy. MATERIALS AND METHODS: In a retrospective observational study, the charts were reviewed of every patient who underwent cervical excisional procedure performed between June 2010 and August 2011, including the antecedent colposcopic examination and any pathological specimens. A random sample of 15% all pathologic specimens was reviewed. Practice of biopsy, use of ECC, demographic factors, referral cytology results, lesion distribution, and size were assessed for correlation with high-grade cervical intraepithelial neoplasia 2 or worse (CIN 2+). RESULTS: A total of 555 patients were included in our analysis. Of them, 333 (60%) had CIN 2+ on colposcopy or excision. CIN 2+ was most likely in younger women and those referred for high-grade cytology. Among 111 women with no visual lesion seen at colposcopy, 66 underwent ECC alone, 33 had ECC and random biopsy, 9 were referred straight to excision, and 3 underwent random biopsy alone. Of the 99 who underwent ECC, this was consistent with the highest-grade lesion in 68% of cases. Among the 36 with random biopsy, this was consistent with the highest grade lesion in 72% of cases.At the time of colposcopy, there were 326 who had CIN 2+ diagnosed with satisfactory colposcopy. Biopsy and ECC were performed in 278 cases. In 235 cases, biopsy alone showed CIN 2+; in 43, the biopsy and ECC both showed CIN 2+. In the remaining 48 cases, CIN 2+ was diagnosed with ECC alone. CONCLUSIONS: In those ultimately treated with excision, younger women and those whose referral cytology was high-grade both were at higher risk of high grade histology. Random biopsy and ECC (even among satisfactory colposcopy) were significantly associated with disclosure of high-grade pathology. PMID- 24477172 TI - mRNA expression in cervical specimens for determination of severe dysplasia or worse in HPV-16/18-positive squamous lesions. AB - OBJECTIVES: The objective of current study was to determine the p16 mRNA level in cervical cells by relative quantification (RQ) and to test viral E6 expression in human papillomavirus (HPV) -16 or -18-positive specimens by widely used methods. We targeted the pivotal mRNA level associated with severe dysplasia or worse. MATERIALS AND METHODS: Cervical specimens were taken from 134 women with cervical disease and 132 women with normal cytologic results. The presence of HPV was analyzed by sequencing. The results of p16 and E6 analyses were statistically processed in receiver operating characteristic curve analysis to predict severe dysplasia or worse. RESULTS: The HPV DNA was detected in 81.4% (109/134) of women with cervical disease and in 27.3% (36/132) of women with normal cytologic results. HPV-16 or -18 were present in 59.7% (80/134) of abnormal specimens. p16 and E6 mRNA expression was increasing with severity of cervical dysplasia. p16 mRNA expression was found 4.35-fold and 13.15-fold increased in high-grade squamous intraepithelial lesions and squamous cell carcinomas, respectively. E6 mRNA expression was significantly increased (p = .0038) in severe dysplasias or worse. The RQ method achieved better sensitivity (82.6%), and E6 mRNA got better specificity (80.6%) for the prediction of severe dysplasia or worse. CONCLUSIONS: An increasing level of p16 and E6 mRNA transcripts could mean the potential of cervical dysplasia progression to cancer, but further studies should be done to confirm this proposition. Nevertheless, we consider using both tests to improve the sensitivity and specificity for prediction of severe dysplasia or worse. PMID- 24477171 TI - Prevalence of human papillomavirus types in invasive cervical cancers from 7 US cancer registries before vaccine introduction. AB - OBJECTIVE: We conducted a baseline study of human papillomavirus (HPV) type prevalence in invasive cervical cancers (ICCs) using data from 7 cancer registries (CRs) in the United States. Cases were diagnosed between 1994 and 2005 before the implementation of the HPV vaccines. MATERIALS AND METHODS: Cancer registries from Florida, Kentucky, Louisiana, Michigan, Hawaii, Iowa, and Los Angeles, California identified eligible ICC cases and obtained sections from representative blocks of archived tumor specimens for DNA extraction. All extracts were assayed by linear array and, if inadequate or HPV negative, retested with INNO-LiPA Genotype test. Clinical and demographic factors were obtained from the CRs and merged with the HPV typing data to analyze factors associated with different types and with HPV negativity. RESULTS: A total of 777 ICCs were included in this analysis, with broad geographic, age, and race distribution. Overall, HPV was detected in 91% of cases, including 51% HPV-16, 16% HPV-18 (HPV-16-negative), and 24% other oncogenic and rare types. After HPV 16 and -18, the most common types were 45, 33, 31, 35, and 52. Older age and nonsquamous histology were associated with HPV-negative typing. CONCLUSIONS: This study provides baseline prevaccine HPV types for postvaccine ICC surveillance in the future. HPV-16 and/or -18 were found in 67% of ICCs, indicating the potential for vaccines to prevent a significant number of cervical cancers. PMID- 24477173 TI - Fluorescence in situ hybridization testing for the diagnosis of high-grade cervical abnormalities: a systematic review. AB - OBJECTIVE: We examined the diagnostic performance of fluorescence in situ hybridization (FISH) tests on cervical cytology for precancerous lesions or cancer on cervical histology. MATERIALS AND METHODS: A search was conducted in MEDLINE, the Cochrane Central Register of Controlled Trials, and Scopus through September 3, 2013. Eleven studies examined FISH tests for telomerase RNA component gene (TERC), myelocytomatosis oncogene (MYC), or human papillomavirus (HPV) type 16 or 18 in samples exhibiting atypical squamous cells of unknown significance (ASC-US) or low-grade squamous intraepithelial lesions (LSIL). None examined HPV-positive, cytologically normal samples. We extracted data on the sensitivity and specificity for high-grade cervical intraepithelial neoplasia (CIN 2+ or CIN 3+). RESULTS: Fluorescence in situ hybridization test probes and thresholds varied across studies. Included populations were convenience samples. Only 1 study testing for TERC specified HPV status. In meta-analysis, FISH for TERC in LSIL (9 studies, 1,082 cases) had a summary sensitivity of 0.76 (95% confidence interval = 0.63-0.85) and a summary specificity of 0.78 (95% confidence interval = 0.57-0.91) for CIN 2+. Fluorescence in situ hybridization for TERC in ASC-US (3 studies, 839 cases) showed sensitivities ranging from 0.75 to 1.00 and specificities from 0.87 to 0.93 for CIN 2+. For CIN 3+, sensitivity and specificity appeared similar, although a small number of studies preclude firm conclusions. For FISH tests for HPV, we found only few studies with small sample sizes. CONCLUSIONS: The evidence on FISH testing is limited given the small number of studies for each cytology subgroup and the lack of studies in well-defined screening contexts stratifying participants by HPV status. PMID- 24477174 TI - Vulvar trichoblastoma: case report and literature review. AB - OBJECTIVE: Trichoblastomas are rare and benign tumors that arise from rudimentary hair follicles. Presentation varies from superficial plaques to papular or nodular lesions. Trichoblastomas usually arise on the head or neck. A few cases of other vulvar trichoblastic tumors such as trichofibromas and trichoepitheliomas have been reported to this day, but no such report of vulvar trichoblastoma exists. MATERIALS AND METHODS: We report the case of a 61-year-old woman who presented with a vulvar trichoblastoma. The woman presented with a lump of the labium majus. She was managed surgically, first by wide excision of the mass followed by a second surgery consisting of a partial vulvectomy. Because surgical margins were positive and there is a potential for malignant transformation, a third surgery was performed. The margins came back negative. A literature review on trichoblastomas was performed, including its potential for malignant transformation, management, and immunohistochemistry to differentiate it from basal cell carcinoma. RESULTS: Trichoblastomas are benign tumors that have a potential for malignant transformation. These tumors can present aggressive characteristics. Differential diagnosis from basal cell carcinoma can be difficult but is facilitated using immunohistochemistry. CONCLUSIONS: This is the first case of vulvar trichoblastoma reported in the literature. Although it is a benign tumor, excision with negative margins is recommended because it can be difficult to distinguish from basal cell carcinoma and it has a potential for malignant transformation. PMID- 24477175 TI - How does human-induced environmental change influence host-parasite interactions? AB - Host-parasite interactions are an integral part of ecosystems that influence both ecological and evolutionary processes. Humans are currently altering environments the world over, often with drastic consequences for host-parasite interactions and the prevalence of parasites. The mechanisms behind the changes are, however, poorly known. Here, we explain how host-parasite interactions depend on two crucial steps--encounter rate and host-parasite compatibility--and how human activities are altering them and thereby host-parasite interactions. By drawing on examples from the literature, we show that changes in the two steps depend on the influence of human activities on a range of factors, such as the density and diversity of hosts and parasites, the search strategy of the parasite, and the avoidance strategy of the host. Thus, to unravel the mechanisms behind human induced changes in host-parasite interactions, we have to consider the characteristics of all three parts of the interaction: the host, the parasite and the environment. More attention should now be directed to unfold these mechanisms, focusing on effects of environmental change on the factors that determine encounter rate and compatibility. We end with identifying several areas in urgent need of more investigations. PMID- 24477176 TI - The perception and experience of gender-based discrimination related to professional advancement among Japanese physicians. AB - Previous studies from the US have found that female physicians often experience gender-based discrimination related to professional advancement. In Japan, female physicians are underrepresented in leadership positions but little is known about the prevalence of gender discrimination. We investigated the perception and prevalence of gender-based career obstacles and discrimination among Japanese physicians. The study was based on surveys of alumnae from 13 medical schools and alumni from 3 medical schools. In total, 1,684 female and 808 male physicians completed a self-administered questionnaire (response rate 83% and 58%). More women than men had the perception of gender-based career obstacles for women (77% vs. 55%; p < 0.0001). Women with part-time positions were more likely to have the perception of gender-based career obstacles than women working full-time (OR 1.32, 95% CI: 1.01-1.73). More women than men reported experience of gender discrimination related to professional advancement (21% vs. 3%; p < 0.0001). Factors associated with experience of gender discrimination included age (p < 0.0001), marital status (p < 0.0001), academic positions (p < 0.0001), subspecialty board certification (p = 0.0011), and PhD status (p < 0.0001). Women older than 40 years were more likely to experience gender discrimination compared with younger women (OR 5.77, 95% CI: 1.83-18.24 for women above 50, and OR 3.2, 95% CI: 1.48-7.28 for women between 40 and 49) and women with PhD were more likely to experience gender discrimination (OR 4.23, 95% CI: 1.81-9.89). Our study demonstrated that a significant proportion of Japanese women experienced gender-based discrimination and perceived gender-based career obstacles compared with male physicians. PMID- 24477177 TI - Dressed or undressed? How to measure children's body weight in overweight surveillance? AB - OBJECTIVE: To simplify body weight measurement and, particularly, to encourage children and their parents to participate in the Italian nutritional surveillance system OKkio alla SALUTE, children were measured with clothes and then the weight was corrected for the estimated weight of the clothes. In the present study we compared the children's weight measured in underwear, as recommended by the WHO (WWHO), with that obtained using the OKkio alla SALUTE protocol (WOK) and investigated how the latter affects the calculation of BMI and the assessment of overweight and obesity prevalence. DESIGN: Weight (twice in close sequence, with and without clothing) and height were measured. A checklist was used to describe the type of clothing worn. The estimated weight of clothing was subtracted from the WOK. BMI was calculated considering both values of weight and height; ponderal status was defined using both the International Obesity Task Force and WHO BMI cut-offs. SETTING: Thirty-seven third grade classes of thirteen primary schools in Rome and in two towns in the Lazio Region were recruited. SUBJECTS: The anthropometric measurements were taken on 524 children aged 8-9 years. RESULTS: The error in the calculation of BMI from WOK was very low, 0.005 kg/m2 (95 % CI -0.185, 0.195 kg/m2); the agreement between the percentages of overweight (not including obesity) and obese children calculated with the two methods was very close to 1 (kappa = 0.98). CONCLUSIONS: The error in BMI and in nutritional classification can be considered minor in a surveillance system for monitoring overweight/obesity, but eases the procedure for measuring children. PMID- 24477178 TI - Development of the Eating Choices Index (ECI): a four-item index to measure healthiness of diet. AB - OBJECTIVE: Current indices of diet quality generally include intakes of specific foods or nutrients. We sought to develop an index that discriminates healthy and unhealthy eating choices for use in large surveys as a short questionnaire and as a measure in existing studies with adequate dietary data. DESIGN: The Eating Choices Index (ECI) score included four components: (i) consumption of breakfast, (ii) consumption of two portions of fruit per day, (iii) type of milk consumed and (iv) type of bread consumed, each providing a score from 1 to 5. In analysis of 5 d food records, the ECI score was examined in relation to macronutrients, fibre, vitamin C, Fe, Ca and folate using Pearson correlations. Variation with sex, BMI, socio-economic status, marital status, smoking status and physical activity were also investigated. SETTING: Medical Research Council National Survey of Health and Development. SUBJECTS: Individuals (n 2256) aged 43 years. RESULTS: The ECI score (mean 12.3 (sd 3.5)) was significantly positively associated with protein, carbohydrate, fibre, vitamin C, Fe, Ca and folate (r = 0.2-0.5; P < 0.001) and significantly negatively associated with fat intake (r = 0.2; P < 0.001); ECI scores were not correlated with total energy intake. Individuals with a lower ECI score were more likely to be men (P < 0.001), overweight or obese (P < 0.001), have lower socio-economic status (P < 0.001), smoke more (P < 0.001) and be less physically active (P < 0.001). CONCLUSIONS: ECI scores correlated with nutrient profiles consistent with a healthy diet. It provides a simple method to rank diet healthiness in large observational studies. PMID- 24477180 TI - Abstracts - XXIV Congresso Nazionale Associazione Italiana di Neuroradiologia - Roma, Italy, 1-3 October 2008 - Atti del IX Congresso Nazionale di Neuroradiologia Pediatrica - Catania, Italy, 12-14 June 2008. PMID- 24477179 TI - Rivaroxaban versus warfarin in Japanese patients with non-valvular atrial fibrillation in relation to hypertension: a subgroup analysis of the J-ROCKET AF trial. AB - The majority of the patients enrolled in the rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation (J-ROCKET AF) trial had hypertension. In this subgroup analysis, we investigated differences in the safety and efficacy of rivaroxaban and warfarin in subjects with and without hypertension. The baseline blood pressure (BP) measurements of patients with hypertension in the rivaroxaban and warfarin groups were 130/77 mm Hg and 131/77 mm Hg, respectively, whereas those of patients without hypertension were 123/74 mm Hg and 124/73 mm Hg, respectively. The incidence rates of the principal safety outcomes in the rivaroxaban and warfarin groups were 18.39% per year and 16.81% per year, respectively, among patients with baseline hypertension (hazard ratio (HR): 1.10; 95% confidence interval (CI): 0.84-1.45) and 16.71% per year and 15.00% per year, respectively, among patients without hypertension at baseline (HR: 1.14; 95% CI: 0.66-1.97), indicating no significant interaction (P=0.933). The incidence rates of the primary efficacy endpoints in the rivaroxaban group and the warfarin group were 0.54% per year and 2.24% per year, respectively, in patients without baseline hypertension (HR: 0.25; 95% CI: 0.03-2.25), and 1.45% per year and 2.71% per year, respectively, in patients with baseline hypertension (HR: 0.54; 95% CI: 0.25-1.16), indicating no significant interaction (P=0.509). In conclusion, the safety and efficacy profile of rivaroxaban was similar to that of warfarin, independent of baseline hypertensive status. PMID- 24477181 TI - An implementation intervention to encourage healthy eating in centre-based child care services: impact of the Good for Kids Good for Life programme. AB - OBJECTIVE: To determine the impact of an implementation intervention designed to introduce policies and practices supportive of healthy eating in centre-based child-care services. Intervention strategies included staff training, resources, incentives, follow-up support, and performance monitoring and feedback. DESIGN: A quasi-experimental design was used to assess change over 20 months in healthy eating policy and practice in intervention and comparison child-care services. SETTING: The Hunter New England (HNE) region of New South Wales (NSW), Australia. SUBJECTS: All centre-based child-care services (n 287) in the intervention region (HNE) were invited and 240 (91% response rate) participated. Two hundred and ninety-six services in the rest of NSW were randomly selected as a comparison region and 191 participated (76% response rate). A sub-analysis was conducted on those services that provided children food (n 196 at baseline and n 190 at follow up). Ninety-six provided menus for analysis at baseline (HNE, n 36; NSW, n 50) and 102 provided menus at follow-up (HNE, n 50; NSW, n 52). RESULTS: Services in the intervention region were significantly more likely to provide only plain milk and water for children (P = 0.018) and to engage parents in nutrition policy or programmes (P = 0.002). They were also more likely (P = 0.056) to have nutrition policy on home packed food. In addition, menus of services that provided lunch were significantly more likely to comply with healthy eating guidelines for sweetened drinks (P < 0.001), fruit (P < 0.001) and vegetables (P = 0.01). CONCLUSIONS: An implementation intervention was able to modify policy and practice in a large number of child-care services so that they were more supportive of healthy eating. PMID- 24477182 TI - Characterization of production processes for tetanus and diphtheria anatoxins. AB - Tetanus and diphtheria are diseases that still cause significant morbidity and mortality. Clostridium tetani produces the tetanus toxin, a 150-kDa protein. The diphtheria toxin is synthesized by Corynebacterium diphtheriae as a protein of 58 kDa. The objective of this study was to carry out a chemical characterization of the tetanus and diphtheria toxin forms in the several production process stages, and thus to establish an affordable alternative in vitro quality control to aggregate to the classical tests. The 150 kDa band of the tetanus toxin and approximately 58 kDa band of the diphtheria toxin were observed by electrophoresis similar as that described in the literature. The same band of 58 KDa was detected in Western blotting reactions. The results obtained for diphtheria toxin showed very similar protein profiles between distinct lots. For the tetanus toxin, the profiles of the initial stage showed some variability, but the ones of the following stages were similar. The similarity of the electrophoresis results indicated reproduction and consistency of the production processes in Butantan Institute and correlated with the yield and antigenic purity classical data. The establishment of alternative in vitro quality control tests can significantly contribute to achieve the consistency approach supported by WHO. PMID- 24477183 TI - Characterization of Thrombate III(r), a pasteurized and nanofiltered therapeutic human antithrombin concentrate. AB - Thrombate III((r)) is a highly purified antithrombin concentrate that has been used by clinicians worldwide for more than two decades for the treatment of hereditary antithrombin deficiency. The manufacturing process is based on heparin affinity chromatography and pasteurization. To modernize the process and to further enhance the pathogen safety profile of the final product, despite the absence of infectious disease transmission, a nanofiltration step was added. The biochemical characterization and pathogen safety evaluation of Thrombate III((r)) manufactured using the modernized process are presented. Bioanalytical data demonstrate that the incorporation of nanofiltration has no impact on the antithrombin content, potency, and purity of the product. Scaledown models of the manufacturing process were used to assess virus and prion clearance under manufacturing setpoint conditions. Additionally, robustness of virus clearance was evaluated at or slightly outside the manufacturing operating limits. The results demonstrate that pasteurization inactivated both enveloped and non enveloped viruses. The addition of nanofiltration substantially increased clearance capacities for both enveloped and non-enveloped viruses by approximately 4-6 log10. In addition, the process achieves 6.0 log10 ID50 prion infectivity clearance. Thus, the introduction of nanofiltration increased the pathogen safety margin of the manufacturing process without impacting the key biochemical characteristics of the product. PMID- 24477184 TI - Surface-Constrained 3D Reconstruction in Cryo-EM. AB - Random spherically-constrained (RSC) reconstruction is a new form of single particle reconstruction (SPR) using cryo-EM images of membrane proteins embedded in spherical lipid vesicles to generate a 3D protein structure. The method has many advantages over conventional SPR, including a more native environment for protein particles and an initial estimate of the particle's angular orientation. These advances allow us to determine structures of membrane proteins such as ion channels and derive more reliable structure estimates. We present an algorithm that relates conventional SPR to the RSC model, and generally, to projection images of particles embedded with an axis parallel to the local normal of a general 2D manifold. We illustrate the performance of this algorithm in the spherical system using synthetic data. PMID- 24477185 TI - Frustration-induced nanometre-scale inhomogeneity in a triangular antiferromagnet. AB - Phase inhomogeneity of otherwise chemically homogenous electronic systems is an essential ingredient leading to fascinating functional properties, such as high Tc superconductivity in cuprates, colossal magnetoresistance in manganites and giant electrostriction in relaxors. In these materials distinct phases compete and can coexist owing to intertwined ordered parameters. Charge degrees of freedom play a fundamental role, although phase-separated ground states have been envisioned theoretically also for pure spin systems with geometrical frustration that serves as a source of phase competition. Here we report a paradigmatic magnetostructurally inhomogenous ground state of the geometrically frustrated alpha-NaMnO2 that stems from the system's aspiration to remove magnetic degeneracy and is possible only due to the existence of near-degenerate crystal structures. Synchrotron X-ray diffraction, nuclear magnetic resonance and muon spin relaxation show that the spin configuration of a monoclinic phase is disrupted by magnetically short-range-ordered nanoscale triclinic regions, thus revealing a novel complex state of matter. PMID- 24477186 TI - Randomized trial of three induction antibodies in kidney transplantation: long term results. AB - BACKGROUND: In searching for an optimal induction regimen, we conducted two separate randomized trials of 38 living donor and 90 deceased donor adult, primary kidney transplant recipients comparing antithymocyte globulin (Thymoglobulin) (group A, N=43) versus alemtuzumab (group B, N=43) versus daclizumab (group C, N=42), using exactly the same three treatment arms in each trial. METHODS: For the purpose of maximizing statistical power, results from the two randomized trials were combined. Groups A and C received standard maintenance dosing with tacrolimus (TAC), mycophenolate mofetil (MMF), and corticosteroids. Because of intense lymphodepletion expected with alemtuzumab use (and hoped-for achievement of a truer immunoregulatory state), group B received lower TAC and MMF dosing and corticosteroid avoidance. Long-term target TAC trough level and MMF dosing were 5 to 7 ng/mL and 1,000 mg b.i.d. in groups A and C; 4 to 6 ng/mL and 500 mg b.i.d. in group B. RESULTS: With median follow-up of 95 months, biopsy proven cute rejection incidence was similar in the three groups (8/43, 14/43, and 12/42, P=0.34), but biopsy-proven chronic allograft injury incidence was significantly higher in group B (19/43) in comparison with groups A (9/43) and C (7/42) combined (P=0.0008). Mean calculated creatinine clearance was significantly lower in group B versus the average of groups A and C means throughout 60 months posttransplant (62.9+/-4.2 vs. 83.6+/-6.9 and 79.8+/-5.9 at 60 months, P=0.01), and death-censored graft failure was significantly higher in group B (13/43) versus groups A (5/43) and C (5/42) combined (P=0.009). Total infection and new-onset diabetes after transplant rates were not significantly different. Ad hoc analysis suggested that the inferior results in group B were specifically a result of reduced dosing and greater withholding of TAC and MMF occurring in that group. CONCLUSIONS: Long-term results clearly indicate inferior clinical outcomes in group B. PMID- 24477187 TI - Chylothorax in POEMS syndrome. AB - Chylothorax results from various causes, such as malignancy, trauma, or infection. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) is a multisystemic syndrome that is associated with plasma cell disorder. Pleural effusion is a common manifestation of POEMS syndrome, but the association of POEMS syndrome with chylothorax has not been reported. We report on a 61-year-old female patient who initially presented with dyspnea and bilateral leg edema. Importantly, the patient had normal renal function. Her chest X-ray and computed tomographic imaging showed bilateral pleural effusion, and her chest drainage revealed chylothorax. Detailed examination failed to reveal the definitive cause of the chylothorax. She received several treatments for chylothorax, namely, a low-fat diet or fasting, total parenteral nutrition, a somatostatin analog (octreotide), thoracic duct ligation by video-assisted thoracic surgery, and pleurodesis. However, further examination revealed endocrinopathy, monoclonal plasma cell disorder, peripheral neuropathy, and elevation of the serum level of vascular endothelial growth factor. The patient's condition was consequently diagnosed as POEMS syndrome. Eventually, her chylothorax was controlled by pleurodesis, and she was transferred to another hospital for stem cell transplantation. Herein, we report on the apparent first case of POEMS syndrome with chylothorax. In some cases of idiopathic chylothorax, the underlying primary disease may be latent, such as in the present patient. POEMS syndrome is rare, but this syndrome should be included in the differential diagnosis of chylothorax with unexplained etiology. PMID- 24477189 TI - Latent class comparison of test accuracy when evaluating antimicrobial susceptibility using disk diffusion and broth microdilution to test Escherichia coli and Mannheimia haemolytica isolates recovered from beef feedlot cattle. AB - The study objective was to use Bayesian latent class analysis to evaluate the accuracy of susceptibility test results obtained from disk diffusion and broth microdilution using bacteria recovered from beef feedlot cattle. Isolates of Escherichia coli and Mannheimia haemolytica were tested for susceptibility to ampicillin, ceftiofur, streptomycin, sulfisoxazole, tetracycline, and trimethoprim-sulfamethoxazole. Results showed that neither testing method was always or even generally superior to the other. Specificity (ability to correctly classify non-resistant isolates) was extremely high for both testing methods, but sensitivity (ability to correctly classify resistant isolates) was lower, variable in the drugs evaluated, and variable between the two bacterial species. Predictive values estimated using Bayesian Markov chain Monte Carlo models showed that the ability to predict true susceptibility status was equivalent for test results obtained with the two testing methods for some drugs, but for others there were marked differences between results obtained from disk diffusion and broth microdilution tests. PMID- 24477188 TI - Dietary intake assessment in women with different weight and pregnancy status using a short questionnaire. AB - OBJECTIVE: First, to evaluate the ability of a short dietary questionnaire (SDQ) to estimate energy intake (EI) on group and individual levels compared with total energy expenditure (TEE) measured by the doubly labelled water method. Second, to compare the SDQ's performance in estimating energy, nutrient and food intakes with a sixty-six-item FFQ used in large-scale Swedish epidemiological research. DESIGN: Cross-sectional. SETTING: Umea, Sweden. SUBJECTS: In total, sixty-five non-pregnant women, of whom thirty-one were overweight or obese, and twenty-five pregnant, normal-weight women completed the protocol. RESULTS: On average, the SDQ captured 78 % and 79 % of absolute TEE in the non-pregnant and pregnant normal-weight women, respectively. Furthermore, the SDQ captured an average of 57 % of TEE in the overweight/obese non-pregnant women. The Spearman correlation of EI and TEE was significant in the overweight and obese women only (rho = 0.37, 95 % CI 0.02, 0.64). There was no significant difference between the SDQ and the more extensive FFQ in the ability to assess EI when compared with TEE. Intakes of most nutrients and foods were significantly higher when assessed with the SDQ compared with the FFQ. CONCLUSIONS: A new short dietary questionnaire with an alternative design underestimated EI of non-pregnant and pregnant, overweight and obese women on a group level but was able to rank the overweight/obese women according to EI. Furthermore, the short questionnaire captured as much or more of the energy, nutrient and food intakes of non-pregnant normal-weight and overweight/obese women on the group level as a traditional, more extensive FFQ. PMID- 24477190 TI - FRET-enabled biological characterization of polymeric micelles. AB - Translation of micelles from the laboratory to the clinic is limited by a poor understanding of their in vivo fate following administration. In this paper, we establish a robust approach to real-time monitoring of the in vivo stability of micelles using Forster Resonance Energy Transfer (FRET). This characterization method allows for exquisite insight into the fate of micellar constituents, affording the capabilities to rapidly and efficiently evaluate a library of synthetically derived micellar systems as new therapeutic platforms in vivo. FRET enabled biological characterization further holds potential to tailor material systems being uniquely investigated across the delivery community towards the next generation of stable therapeutics for disease management. PMID- 24477191 TI - Direct in vitro selection of titanium-binding epidermal growth factor. AB - Epidermal growth factor (EGF) with affinity to TiO2 surfaces was obtained by direct in vitro selection. A random peptide library was generated for fusion to the N-terminal of EGF, and polypeptides exhibiting affinity were selected in vitro by ribosome display. The best-performing polypeptide sequence was selected for synthesis using a solid-phase method and showed high affinity to TiO2 after refolding. Molecular dynamic simulations indicated that the interaction of the selected peptide segment with the TiO2 surface was comparable to that of a previously reported titanium-binding peptide, TBP-1. The hydroxyl groups in the selected peptide segment were found to be critical for the binding interaction. NIH3T3 cell culture for two days in the presence of the TiO2-binding EGF showed that it was able to enhance cell proliferation as much as unmodified EGF in solution. As a result, the selected EGF construct was able to induce cell proliferation on titanium surfaces. This direct in vitro selection technique should extend the possibilities for the design of other surface-binding growth factors. PMID- 24477192 TI - Treatment of chemotherapy-induced neutropenia in a rat model by using multiple daily doses of oral administration of G-CSF-containing nanoparticles. AB - Chemotherapy-induced neutropenia often increases the likelihood of life threatening infections. In this study, a nanoparticle (NP) system composed of chitosan and poly(gamma-glutamic acid) conjugated with diethylene triamine pentaacetic acid (gammaPGA-DTPA) was prepared for oral delivery of granulocyte colony-stimulating factor (G-CSF), a hematopoietic growth factor. The therapeutic potential of this NP system for daily administration of G-CSF to treat neutropenia associated with chemotherapy was evaluated in a rat model. In vitro results indicate that the procedures of NP loading and release preserved the structural integrity and bioactivity of the G-CSF molecules adequately. Those results further demonstrated the enzymatic inhibition activity of gammaPGA-DTPA towards G-CSF against intestinal proteases. Additionally, the in vivo biodistribution study clearly identified accumulations of G-CSF in the heart, liver, bone marrow, and urinary bladder, an indication of systemic absorption of G-CSF; its relative bioavailability was approximately 13.6%. Moreover, significant glucose uptake was observed in bone marrow during G-CSF treatment, suggesting increased bone marrow metabolism and neutrophil production. Consequently, neutrophil count in the blood increased in a sustained manner; this fact may help a patient's immune system recover from the side effects of chemotherapy. PMID- 24477193 TI - The mechanisms by which pardaxin, a natural cationic antimicrobial peptide, targets the endoplasmic reticulum and induces c-FOS. AB - Pardaxin is a cationic antimicrobial peptide derived from Red Sea Moses sole. Previous studies have shown that pardaxin selectively triggers the death of cancer cells, initiating the development of a pardaxin-based cancer vaccine; however, the underlying mechanism by which pardaxin kills cancer cells has not yet been elucidated. Here, we demonstrate that this mechanism involves endoplasmic reticulum (ER) targeting and c-FOS induction. Transcriptiome analysis of pardaxin-treated HT-1080 cells revealed induction of the gene encoding c-FOS, an AP-1 transcription factor. Pardaxin mediates cell death by activating c-FOS, but not other AP-1 transcription factors. Overexpression of c-FOS caused a dramatic increase in cell death, while knockdown of c-FOS induced pardaxin resistance; such effects were observed in both an in vitro cell model and an in vivo xenograft tumor model. Treatment with pardaxin also increased the level of calcium, and blockage of cellular calcium signaling disrupted pardaxin-induced cell death. Immunocytochemistry was used to demonstrate targeting of pardaxin to the endoplasmic reticulum, but not to the Golgi apparatus or mitochondria. Importantly, pardaxin treatment or c-FOS overexpression induced cell death in diverse cancer cell lines, indicating that pardaxin and c-FOS may possess therapeutic potential for use in cancer treatment. PMID- 24477194 TI - Biomaterials in search of a meniscus substitute. AB - The menisci fulfill key biomechanical functions in the tibiofemoral (knee) joint. Unfortunately meniscal injuries are quite common and most often treated by (partial) meniscectomy. However, some patients experience enduring symptoms, and, more importantly, it leads to an increased risk for symptomatic osteoarthritis. Over the past decades, researchers have put effort in developing a meniscal substitute able to prevent osteoarthritis and treat enduring clinical symptoms. Grossly, two categories of substitutes are observed: First, a resorbable scaffold mimicking biomechanical function which slowly degrades while tissue regeneration and organization is promoted. Second, a non resorbable, permanent implant which mimics the biomechanical function of the native meniscus. Numerous biomaterials with different (material) properties have been used in order to provide such a substitute. Nevertheless, a clinically applicable cartilage protecting material is not yet emerged. In the current review we provide an overview, and discuss, these different materials and extract recommendations regarding material properties for future developmental research. PMID- 24477195 TI - Perceived sex discrimination amplifies the effect of antagonism on cigarette smoking. AB - INTRODUCTION: Compared to men, the decline in smoking during the past few decades has been slower for women, and smoking-related morbidity and mortality has increased substantially. Identifying sex-specific risk factors will inform more targeted intervention/prevention efforts. The purpose of this research is to examine the interactive effect of psychological (trait antagonism) and social (perceived sex discrimination) factors on current cigarette smoking and whether these effects differ by sex. METHODS: Participants in the Healthy Aging in Neighborhoods of Diversity across the Life Span study (HANDLS; N = 454) and participants in the Health and Retirement Study (HRS; N = 8,155) completed measures of antagonism, perceived sex discrimination, and reported whether they smoked currently. Logistic regressions were used to predict smoking from antagonism, discrimination, and their interaction. RESULTS: Antagonism was associated with an increased risk of smoking. For women, there was an interaction between antagonism and discrimination: among women who perceived sex discrimination, every standard deviation increase in antagonism was associated with a 2.5 increased risk of current smoking in HANDLS (odds ratio [OR] = 2.54, 95% confidence interval [CI] = 1.46-4.39) and an almost 1.5 increased risk in HRS (OR = 1.43, 95% CI = 1.18-1.73). This interaction was not significant for men in either sample. CONCLUSION: In 2 independent samples, perceived sex discrimination amplified the effect of antagonism on cigarette smoking for women but not men. A hostile disposition and a perceived hostile social environment have a synergistic effect on current cigarette smoking for women. PMID- 24477196 TI - Genomic analysis of Chthonomonas calidirosea, the first sequenced isolate of the phylum Armatimonadetes. AB - Most of the lineages of bacteria have remained unknown beyond environmental surveys using molecular markers. Until the recent characterisation of several strains, the phylum Armatimonadetes (formerly known as 'candidate division OP10') was a dominant and globally-distributed lineage within this 'uncultured majority'. Here we report the first Armatimonadetes genome from the thermophile Chthonomonas calidirosea T49(T) and its role as a saccharide scavenger in a geothermal steam-affected soil environment. Phylogenomic analysis indicates T49(T) to be related closely to the phylum Chloroflexi. The predicted genes encoding for carbohydrate transporters (27 carbohydrate ATP-binding cassette transporter-related genes) and carbohydrate-metabolising enzymes (including at least 55 putative enzymes with glycosyl hydrolase domains) within the 3.43 Mb genome help explain its ability to utilise a wide range of carbohydrates as well as its inability to break down extracellular cellulose. The presence of only a single class of branched amino acid transporter appears to be the causative step for the requirement of isoleucine for growth. The genome lacks many commonly conserved operons (for example, lac and trp). Potential causes for this, such as dispersion of functionally related genes via horizontal gene transfer from distant taxa or recent genome recombination, were rejected. Evidence suggests T49(T) relies on the relatively abundant sigma-factors, instead of operonic organisation, as the primary means of transcriptional regulation. Examination of the genome with physiological data and environmental dynamics (including interspecific interactions) reveals ecological factors behind the apparent elusiveness of T49(T) to cultivation and, by extension, the remaining 'uncultured majority' that have so far evaded conventional microbiological techniques. PMID- 24477197 TI - Ecogenomic sensor reveals controls on N2-fixing microorganisms in the North Pacific Ocean. AB - Nitrogen-fixing microorganisms (diazotrophs) are keystone species that reduce atmospheric dinitrogen (N2) gas to fixed nitrogen (N), thereby accounting for much of N-based new production annually in the oligotrophic North Pacific. However, current approaches to study N2 fixation provide relatively limited spatiotemporal sampling resolution; hence, little is known about the ecological controls on these microorganisms or the scales over which they change. In the present study, we used a drifting robotic gene sensor to obtain high-resolution data on the distributions and abundances of N2-fixing populations over small spatiotemporal scales. The resulting measurements demonstrate that concentrations of N2 fixers can be highly variable, changing in abundance by nearly three orders of magnitude in less than 2 days and 30 km. Concurrent shipboard measurements and long-term time-series sampling uncovered a striking and previously unrecognized correlation between phosphate, which is undergoing long-term change in the region, and N2-fixing cyanobacterial abundances. These results underscore the value of high-resolution sampling and its applications for modeling the effects of global change. PMID- 24477199 TI - Chaperones for intimate examinations in family medicine: findings from a pilot study in Melbourne, Australia. AB - BACKGROUND: The use of medical chaperones during clinical examinations is important whether one practises as a specialist, nurse, medical student or generalist. Chaperone use in general practice remains largely unknown in most countries across the world and, what is known is limited to a handful of countries. Their use in Australian general practice remains unknown. OBJECTIVE: To explore the attitudes and practices of a cohort of general practitioners in urban Melbourne regarding the use of chaperones in their daily clinical practice. METHODS: Self-administered postal questionnaire to pilot group of general practitioners in urban Melbourne, Australia. MAIN OUTCOME MEASURES: Frequency of chaperone use; views on chaperone use itself; preferred choice for the role of chaperone; main reasons for using chaperones. RESULTS: The majority (95% respondents) had never or occasionally used a chaperone. The use of chaperones correlated with general practitioner gender - male general practitioners were more likely to use a chaperone. General practitioners preferred choice as chaperone was the practice nurse. There was no association found between chaperone use and the respondents' age, practice size or the availability of a practice nurse. The most highly rated influence by general practitioners for using a chaperone was because of anticipated patient embarrassment and/or distress. CONCLUSION: This is the first step in understanding attitudes and experiences of general practitioners in general practice in Australia. The results of a larger, national study would provide further insight into this important issue taking into account the realities of general practice in Australia and relationship between general practitioners and patients. PMID- 24477200 TI - Influence of Gd3+ co-doping on structural property of CaMoO4:Eu nanoparticles. AB - A facile auto-combustion route is used for the synthesis of Gd(3+) (2, 5, 7 and 10 at%) co-doped CaMoO4:Eu nanoparticles. X-ray diffraction study suggests that as-prepared samples have extra impurity phases in addition to main tetragonal phase of CaMoO4, and such extra phases decrease as the annealing temperature increases from 600 to 900 degrees C. The crystal structure has been analysed using Rietveld program. It has space group I41/a (88) and Z = 4 (number of CaMoO4 formula units per unit cell). Average crystallite sizes of as-prepared, 600 and 900 degrees C annealed samples for 2 at% Gd(3+) are found to be ~33, 48 and 61 nm, respectively. The lattice strains of 5 at% Gd(3+) co-doped CaMoO4:Eu for as prepared and 900 degrees C are 0.001 and 0.002, respectively. Fourier transform infrared spectroscopy gives the absorption bands at ~815 and 427 cm(-1), which are related to asymmetric stretching and bending vibrations of MoO4(2-) tetrahedron. Particle morphology is studied using scanning and transmission electron microscopy (SEM and TEM), and aggregation of particles is found. X-ray photoelectron spectroscopy (XPS) is utilized to examine the oxidation states of metal ions/oxygen and oxygen ion vacancies in Gd(3+) co-doped CaMoO4:Eu. With an increase in Gd(3+) concentration, peaks corresponding to the Gd(3+) (2p(3/2) and 2p(5/2)) binding energy could be detected. PMID- 24477198 TI - A microarray for assessing transcription from pelagic marine microbial taxa. AB - Metagenomic approaches have revealed unprecedented genetic diversity within microbial communities across vast expanses of the world's oceans. Linking this genetic diversity with key metabolic and cellular activities of microbial assemblages is a fundamental challenge. Here we report on a collaborative effort to design MicroTOOLs (Microbiological Targets for Ocean Observing Laboratories), a high-density oligonucleotide microarray that targets functional genes of diverse taxa in pelagic and coastal marine microbial communities. MicroTOOLs integrates nucleotide sequence information from disparate data types: genomes, PCR-amplicons, metagenomes, and metatranscriptomes. It targets 19 400 unique sequences over 145 different genes that are relevant to stress responses and microbial metabolism across the three domains of life and viruses. MicroTOOLs was used in a proof-of-concept experiment that compared the functional responses of microbial communities following Fe and P enrichments of surface water samples from the North Pacific Subtropical Gyre. We detected transcription of 68% of the gene targets across major taxonomic groups, and the pattern of transcription indicated relief from Fe limitation and transition to N limitation in some taxa. Prochlorococcus (eHLI), Synechococcus (sub-cluster 5.3) and Alphaproteobacteria SAR11 clade (HIMB59) showed the strongest responses to the Fe enrichment. In addition, members of uncharacterized lineages also responded. The MicroTOOLs microarray provides a robust tool for comprehensive characterization of major functional groups of microbes in the open ocean, and the design can be easily amended for specific environments and research questions. PMID- 24477201 TI - Additive diagnostic and prognostic value of bioelectrical impedance vector analysis (BIVA) to brain natriuretic peptide 'grey-zone' in patients with acute heart failure in the emergency department. AB - BACKGROUND: Few data are available on diagnostic and prognostic role of quantitative fluid retention evaluated by bioelectrical impedance vector analysis (BIVA) in acute heart failure (AHF) patients at the moment of emergency department presentation. METHODS AND RESULTS: Point vectors and hydration index (HI) by BIVA were obtained in 381 patients referring to an emergency department. For evaluating cardiovascular events, a 30-day follow-up was performed. Patients were divided into AHF (n=270; 70.8%) and no-AHF groups, (n=111; 29.2%). Compared with the no-AHF cohort, the HI value resulted significantly higher in the AHF group (81.2% +/- 6.7 vs. 72.9 +/- 3.6%, p<0.001). HI showed a significant diagnostic power for AHF (cut-off 73.4%, area under curve (AUC) 0.87, sensitivity 90%, specificity 54%) and also showed a significant prognostic value both by univariate (odds ratio 1.03 (1-1.07), p =0.025) and multivariate analysis (odds ratio 1.96 (1.05-3.66) p= 0.034) for cardiac events at 30 days. Although in the overall population BIVA did not increase diagnostic accuracy provided by brain natriuretic peptide (BNP), for AHF patients in BNP 'grey values' (100-400 pg/ml) HI showed a significant additive improvement for diagnosis (net reclassification improvement (NRI) 77%) and prognosis (NRI 45%). CONCLUSIONS: While in the overall population BIVA did not increase diagnostic accuracy provided by BNP, in AHF patients a quantitative evaluation of fluid congestion obtained by BIVA at the time of emergency department arrival provides significant additive diagnostic and 30-day prognostic value to BNP, particularly in the BNP 'grey-zone'. This could lead to a better management of these patients with possible improvement in reducing subsequent cardiovascular events. PMID- 24477202 TI - 34th European Society of Neuroradiology Annual Meeting. 18th Advanced Course "New insights in white matter diseases" & 2nd Interventional Advanced Course "Spine and Spinal Cord" - Athens, Greece, 17-20 September 2009. PMID- 24477203 TI - Graphene radio frequency receiver integrated circuit. AB - Graphene has attracted much interest as a future channel material in radio frequency electronics because of its superior electrical properties. Fabrication of a graphene integrated circuit without significantly degrading transistor performance has proven to be challenging, posing one of the major bottlenecks to compete with existing technologies. Here we present a fabrication method fully preserving graphene transistor quality, demonstrated with the implementation of a high-performance three-stage graphene integrated circuit. The circuit operates as a radio frequency receiver performing signal amplification, filtering and downconversion mixing. All circuit components are integrated into 0.6 mm(2) area and fabricated on 200 mm silicon wafers, showing the unprecedented graphene circuit complexity and silicon complementary metal-oxide-semiconductor process compatibility. The demonstrated circuit performance allow us to use graphene integrated circuit to perform practical wireless communication functions, receiving and restoring digital text transmitted on a 4.3-GHz carrier signal. PMID- 24477204 TI - Structure-function relationship in COPD revisited: an in vivo microscopy view. AB - BACKGROUND: Fibred confocal fluorescence microscopy (FCFM) is a novel technology that allows the in vivo assessment and quantification during bronchoscopy of the bronchial wall elastic fibre pattern, alveolar and vessel diameters and thickness of the elastic fibre in the alveolar wall. AIMS: To relate these structural characteristics with lung function parameters in healthy subjects, smokers with normal spirometry and patients with chronic obstructive pulmonary disease (COPD). METHODS: We performed FCFM in 20 never smokers, 20 smokers with normal spirometry and 23 patients with COPD who required bronchoscopy for clinical reasons. The bronchial wall elastic fibre pattern was classified as lamellar, loose and mixed pattern, and later confirmed pathologically. Airspace dimensions and extra alveolar vessel diameters were measured. Lung function measurements and pulmonary CT scans were obtained in all participants. RESULTS: Patients with COPD were characterised by a significantly higher prevalence of loose fibre bronchial deposition pattern and larger alveolar diameter which correlated inversely with several lung function parameters (forced expiratory volume in 1 s (FEV1) , FEV1/forced vital capacity ratio, maximum expiratory flow, carbon monoxide transfer factor and carbon monoxide transfer coefficient; p<0.05). Increased alveolar macrophages were demonstrated in active smokers with or without COPD. CONCLUSIONS: This is the first FCFM study to describe in vivo microscopic changes in the airways and alveoli of patients with COPD that are related to lung function impairment. These findings open the possibility of assessing the in vivo effects of therapeutic interventions for COPD in future studies. PMID- 24477205 TI - What are the new requirements for performing commercial driver medical (DOT) examinations? AB - The Occupational Medicine Forum is prepared by the ACOEM Occupational and Environmental Medical Practice Committee and does not necessarily represent an official ACOEM position. The Forum is intended for health professionals and is not intended to provide medical or legal advice, including illness prevention, diagnosis or treatment, or regulatory compliance. Such advice should be obtained directly from a physician and/or attorney. PMID- 24477206 TI - Preface. IFPA Meeting 2013. PMID- 24477207 TI - IFPA Senior Award Lecture: making sense of pre-eclampsia - two placental causes of preeclampsia? AB - Incomplete spiral artery remodelling is the first of two stages of pre-eclampsia, typically of early onset. The second stage comprises dysregulated uteroplacental perfusion and placental oxidative stress. Oxidatively stressed syncytiotrophoblast (STB) over-secretes proteins that perturb maternal angiogenic balance and are considered to be pre-eclampsia biomarkers. We propose that, in addition and more fundamentally, these STB-derived proteins are biomarkers of a cellular (STB) stress response, which typically involves up-regulation of some proteins and down-regulation of others (positive and negative stress proteins respectively). Soluble vascular growth factor receptor-1 (sVEGFR-1) and reduced growth factor (PlGF) then exemplify positive and negative STB stress response proteins in the maternal circulation. Uncomplicated term pregnancy is associated with increasing sVEGFR-1 and decreasing PlGF, which can be interpreted as evidence of increasing STB stress. STB pathology, at or after term (for example focal STB necrosis) demonstrates this stress, with or without pre-eclampsia. We review the evidence that when placental growth reaches its limits at term, terminal villi become over-crowded with diminished intervillous pore size impeding intervillous perfusion with increasing intervillous hypoxia and STB stress. This type of STB stress has no antecedent pathology, so the fetuses are well-grown, as typifies late onset pre-eclampsia, and prediction is less effective than for the early onset syndrome because STB stress is a late event. In summary, abnormal placental perfusion and STB stress contribute to the pathogenesis of early and late onset pre-eclampsia. But the former has an extrinsic cause - poor placentation, whereas the latter has an intrinsic cause, 'microvillous overcrowding', as placental growth reaches its functional limits. This model explains important features of late pre-eclampsia and raises questions of how antecedent medical risk factors such as chronic hypertension affect early and late sub-types of the syndrome. It also implies that all pregnant women may be destined to get pre-eclampsia but spontaneous or induced delivery averts this outcome in most instances. PMID- 24477209 TI - Baroreflex activation therapy in hypertension. AB - The sympathetic nervous system is an effective homeostatic mechanism for modulating hemodynamics in times of stress and illness. Unfortunately, in some patients, this mechanism escapes physiologic control and through various mechanisms leads to resistant hypertension. Antihypertensive drug therapy is successful only to a point, leaving a significant percentage of patients nationwide with blood pressure measurements above guidelines despite being treated with at least three agents at maximally tolerated doses, consistent with a diagnosis of resistant hypertension. Novel methods of modifying the activity of the sympathetic nervous system have been studied in animals, and this review discusses the data in support of one of the techniques at the forefront of non pharmacologic blood pressure therapy. PMID- 24477210 TI - Resistance markers and genetic diversity in Acinetobacter baumannii strains recovered from nosocomial bloodstream infections. AB - In this study, phenotypic and genotypic methods were used to detect metallo-beta lactamases, cephalosporinases and oxacillinases and to assess genetic diversity among 64 multiresistant Acinetobacter baumannii strains recovered from blood cultures in five different hospitals in Brazil from December 2008 to June 2009. High rates of resistance to imipenem (93.75%) and polymyxin B (39.06%) were observed using the disk diffusion (DD) method and by determining the minimum inhibitory concentration (MIC). Using the disk approximation method, thirty-nine strains (60.9%) were phenotypically positive for class D enzymes, and 51 strains (79.6%) were positive for cephalosporinase (AmpC). Using the E-test, 60 strains (93.75%) were positive for metallo-beta-lactamases (MbetaLs). All strains were positive for at least one of the 10 studied genes; 59 (92.1%) contained blaVIM-1, 79.6% contained blaAmpC, 93.7% contained blaOXA23 and 84.3% contained blaOXA51. Enterobacteria Repetitive Intergenic Consensus (ERIC)-PCR analysis revealed a predominance of certain clones that differed from each other. However, the same band pattern was observed in samples from the different hospitals studied, demonstrating correlation between the genotypic and phenotypic results. Thus, ERIC-PCR is an appropriate method for rapidly clustering genetically related isolates. These results suggest that defined clonal clusters are circulating within the studied hospitals. These results also show that the prevalence of MDR A. baumannii may vary among clones disseminated in specific hospitals, and they emphasize the importance of adhering to appropriate infection control measures. PMID- 24477211 TI - Cancer cluster investigations: review of the past and proposals for the future. AB - Residential clusters of non-communicable diseases are a source of enduring public concern, and at times, controversy. Many clusters reported to public health agencies by concerned citizens are accompanied by expectations that investigations will uncover a cause of disease. While goals, methods and conclusions of cluster studies are debated in the scientific literature and popular press, investigations of reported residential clusters rarely provide definitive answers about disease etiology. Further, it is inherently difficult to study a cluster for diseases with complex etiology and long latency (e.g., most cancers). Regardless, cluster investigations remain an important function of local, state and federal public health agencies. Challenges limiting the ability of cluster investigations to uncover causes for disease include the need to consider long latency, low statistical power of most analyses, uncertain definitions of cluster boundaries and population of interest, and in- and out migration. A multi-disciplinary Workshop was held to discuss innovative and/or under-explored approaches to investigate cancer clusters. Several potentially fruitful paths forward are described, including modern methods of reconstructing residential history, improved approaches to analyzing spatial data, improved utilization of electronic data sources, advances using biomarkers of carcinogenesis, novel concepts for grouping cases, investigations of infectious etiology of cancer, and "omics" approaches. PMID- 24477212 TI - Joint effects of smoking and sedentary lifestyle on lung function in African Americans: the Jackson Heart Study cohort. AB - This study examined: (a) differences in lung function between current and non current smokers who had sedentary lifestyles and non sedentary lifestyles and (b) the mediating effect of sedentary lifestyle on the association between smoking and lung function in African Americans. Sedentary lifestyle was defined as the lowest quartile of the total physical activity score. The results of linear and logistic regression analyses revealed that non smokers with non sedentary lifestyles had the highest level of lung function, and smokers with sedentary lifestyles had the lowest level. The female non-smokers with sedentary lifestyles had a significantly higher FEV1% predicted and FVC% predicted than smokers with non sedentary lifestyles (93.3% vs. 88.6%; p = 0.0102 and 92.1% vs. 86.9%; p = 0.0055 respectively). FEV1/FVC ratio for men was higher in non smokers with sedentary lifestyles than in smokers with non sedentary lifestyles (80.9 vs. 78.1; p = 0.0048). Though smoking is inversely associated with lung function, it seems to have a more deleterious effect than sedentary lifestyle on lung function. Physically active smokers had higher lung function than their non physically active counterparts. PMID- 24477208 TI - Infant feeding patterns in families with a diabetes history - observations from The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort study. AB - OBJECTIVE: To assess the association between diabetes family history and infant feeding patterns. DESIGN: Data on breast-feeding duration and age at first introduction of cow's milk and gluten-containing cereals were collected in 3 month intervals during the first 24 months of life. SETTING: Data from the multicentre TEDDY (The Environmental Determinants of Diabetes in the Young) study, including centres in the USA, Sweden, Finland and Germany. SUBJECTS: A total of 7026 children, including children with a mother with type 1 diabetes (T1D; n 292), gestational diabetes mellitus (GDM; n 404) or without diabetes but with a father and/or sibling with T1D (n 464) and children without diabetes family history (n 5866). RESULTS: While exclusive breast-feeding ended earlier and cow's milk was introduced earlier in offspring of mothers with T1D and GDM, offspring of non-diabetic mothers but a father and/or sibling with T1D were exclusively breast-fed longer and introduced to cow's milk later compared with infants without diabetes family history. The association between maternal diabetes and shorter exclusive breast-feeding duration was attenuated after adjusting for clinical variables (delivery mode, gestational age, Apgar score and birth weight). Country-specific analyses revealed differences in these associations, with Sweden showing the strongest and Finland showing no association between maternal diabetes and breast-feeding duration. CONCLUSIONS: Family history of diabetes is associated with infant feeding patterns; however, the associations clearly differ by country, indicating that cultural differences are important determinants of infant feeding behaviour. These findings need to be considered when developing strategies to improve feeding patterns in infants with a diabetes family history. PMID- 24477213 TI - Perceptions of heat risk to health: a qualitative study of professional bus drivers and their managers in Jinan, China. AB - Summer extreme heat threatens the health of individuals, especially persons who are involved in outdoor activities. Ensuring the normal function of a city, bus drivers are among those who participate in outdoor physical activities and are exposed to excessive heat in hot summer weather. This qualitative study was performed to explore professional bus drivers' in-depth views of extreme heat risks to their health, and ultimately develop targeted advice and policy interventions for city bus drivers. An interview-based study was performed among professional bus drivers in Jinan, China, including four focus groups with professional bus drivers (n = 37) and three interviews with their managers (n = 14). Five central themes or categories from the bus driver interviews were found: concerns about summer heat; health effects related to extreme heat; adaptive measures; barriers in implementing these adaptive measures; and suggested interventions. The beneficial role of cooling facilities (particularly air conditioning) during extreme heat are addressed. The barriers not only impede the implementation of behavioral adaptive measures but also enhance the negative attitudes of bus drivers towards their effectiveness. The responsibilities of managers in promoting preventive actions are addressed. PMID- 24477214 TI - Investigating environmental determinants of injury and trauma in the Canadian north. AB - Unintentional injury and trauma rates are disproportionately high in Inuit regions, and environmental changes are predicted to exacerbate injury rates. However, there is a major gap in our understanding of the risk factors contributing to land-based injury and trauma in the Arctic. We investigated the role of environmental and other factors in search and rescue (SAR) incidents in a remote Inuit community in northern Canada using a collaborative mixed methods approach. We analyzed SAR records from 1995 to 2010 and conducted key consultant interviews in 2010 and 2011. Data showed an estimated annual SAR incidence rate of 19 individuals per 1,000. Weather and ice conditions were the most frequent contributing factor for cases. In contrast with other studies, intoxication was the least common factor associated with SAR incidents. The incidence rate was six times higher for males than females, while land-users aged 26-35 had the highest incidence rate among age groups. Thirty-four percent of individuals sustained physical health impacts. Results demonstrate that environmental conditions are critical factors contributing to physical health risk in Inuit communities, particularly related to travel on sea ice during winter. Age and gender are important risk factors. This knowledge is vital for informing management of land based physical health risk given rapidly changing environmental conditions in the Arctic. PMID- 24477215 TI - Effects of simulated heat waves on ApoE-/- mice. AB - The effects of simulated heat waves on body weight, body temperature, and biomarkers of cardiac function in ApoE-/- mice were investigated. Heat waves were simulated in a meteorological environment simulation chamber according to data from a heat wave that occurred in July 2001 in Nanjing, China. Eighteen ApoE-/- mice were divided into control group, heat wave group, and heat wave BH4 group. Mice in the heat wave and BH4 groups were exposed to simulated heat waves in the simulation chamber. Mice in BH4 group were treated with gastric lavage with BH4 2 h prior to heat wave exposure. Results showed that the heat waves did not significantly affect body weight or ET-1 levels. However, mice in the heat wave group had significantly higher rectal temperature and NO level and lower SOD activity compared with mice in the control group (p < 0.01), indicating that heat wave had negative effects on cardiac function in ApoE-/- mice. Gastric lavage with BH4 prior to heat wave exposure significantly reduced heat wave-induced increases in rectal temperature and decreases in SOD activity. Additionally, pretreatment with BH4 further increased NO level in plasma. Collectively, these beneficial effects demonstrate that BH4 may potentially mitigate the risk of coronary heart disease in mice under heat wave exposure. These results may be useful when studying the effects of heat waves on humans. PMID- 24477216 TI - Diffusion of nitrogen and phosphorus across the sediment-water interface and in seawater at aquaculture areas of Daya Bay, China. AB - With the yearly increasing marine culture activities in floating cages in Daya Bay, China, the effects of pollution may overlap and lead to more severe water environmental problems. In order to track the impacts of the marine culture in floating cages on water environment, sediments and overlying water were sampled by cylindrical samplers at three representative aquaculture areas of Daya Bay. The water content, porosity, density of sediments as well as the vertical distributions of ammonia nitrogen and active phosphate in pore water along sediments depth were measured. The release rate and annual released quantity of the nutrients across sediment-water interface were calculated using Fick's Law. A horizontal two-dimensional mathematical model was developed to compute the spatial and temporal distributions of the nutrients in seawater after being released across the sediment-water interface. The results showed that the sediments, with a high content and a large annual released quantity of nitrogen and phosphorus, constitute a potential inner source of seawater pollution. Influenced by tide and water depth, the scope of diffusion and migration of the nutrients appears as a long belt which is about 1 km long and 50 m wide. Seawater in this area is vulnerable to eutrophication. PMID- 24477217 TI - Personality traits influencing somatization symptoms and social inhibition in the elderly. AB - PURPOSE: Somatization is a common symptom among the elderly, and even though personality disorders have been found to be associated with somatization, personality traits have not yet been explored with regard to this symptom. The aim of this study is to investigate the relationship between personality traits and somatization, and social inhibition. PATIENTS AND METHODS: As part of a cross sectional study of a community sample, 126 elderly Thais aged 60 years or over completed self-reporting questionnaires related to somatization and personality traits. Somatization was elicited from the somatization subscale when using the Symptom Checklist SCL-90 instrument. Personality traits were drawn from the 16 Personality Factor Questionnaire and social inhibition was identified when using the inventory of interpersonal problems. In addition, path analysis was used to establish the influence of personality traits on somatization and social inhibition. RESULTS: Of the 126 participants, 51% were male, 55% were married, and 25% were retired. The average number of years in education was 7.6 (standard deviation =5.2). "Emotional stability" and "dominance" were found to have a direct effect on somatization, as were age and number of years in education, but not sex. Also, 35% of the total variance could be explained by the model, with excellent fit statistics. Dominance was found to have an indirect effect, via vigilance, on social inhibition, which was also influenced by number of years in education and emotional stability. Social inhibition was not found to have any effect on somatization, although hypothetically it should. CONCLUSION: "Emotional stability", "dominance", and "vigilance", as well as age and the number of years in education, were found to have an effect on somatization. Attention should be paid to these factors in the elderly with somatization. PMID- 24477218 TI - Reducing inappropriate antibiotic prescribing in the residential care setting: current perspectives. AB - Residential aged care facilities are increasingly identified as having a high burden of infection, resulting in subsequent antibiotic use, compounded by the complexity of patient demographics and medical care. Of particular concern is the recent emergence of multidrug-resistant organisms among this vulnerable population. Accordingly, antimicrobial stewardship (AMS) programs have started to be introduced into the residential aged care facilities setting to promote judicious antimicrobial use. However, to successfully implement AMS programs, there are unique challenges pertaining to this resource-limited setting that need to be addressed. In this review, we summarize the epidemiology of infections in this population and review studies that explore antibiotic use and prescribing patterns. Specific attention is paid to issues relating to inappropriate or suboptimal antibiotic prescribing to guide future AMS interventions. PMID- 24477219 TI - The abilities of new anthropometric indices in identifying cardiometabolic abnormalities, and influence of residence area and lifestyle on these anthropometric indices in a Chinese community-dwelling population. AB - OBJECTIVE: The study aimed to investigate the prevalence of overweight, obesity, and cardiometabolic abnormalities, the influence of residence area, occupation, and lifestyle on new anthropometric indices, and the relationship between anthropometric indices and cardiometabolic abnormalities in a Chinese community dwelling population. METHODS: The study included 4,868 residents through a large health check-up program in Beijing. RESULTS: Overall obesity existed in 22.2% of men and 28.1% of women. 67.1% of men and 65.2% of women were overweight. 65.99% of men and 65.97% of women had central obesity. Residents of rural areas, manual workers, and smokers had significantly higher anthropometric indices. The power of each anthropometric index varied for identifying different cardiometabolic abnormalities, and the ability of the waist-to-height ratio to identify participants with greater than one or two cardiometabolic abnormalities was optimal. The appropriate cut-off values of all anthropometric indices for cardiometabolic abnormalities were obtained. CONCLUSION: Overweight is common for both sexes in the People's Republic of China, as are general and central obesity. Residents of rural areas, manual workers, and smokers have significantly higher anthropometric indices. Waist-to-height ratio has the ability to reflect the compound risk of different cardiometabolic abnormalities and the greatest potential to be widely applied in clinical practice. PMID- 24477220 TI - Current and emerging treatment options for the elderly patient with chronic kidney disease. AB - The objective of this article is to review the current and emerging treatments of CKD prior to dialysis in the elderly. Worldwide, there are increasing numbers of people who are aged over 65 years. In parallel, there are increasing numbers of elderly patients presenting with chronic kidney disease (CKD), particularly in the more advanced stages. The elderly have quite different health care needs related to their associated comorbidity, frailty, social isolation, poor functional status, and cognitive decline. Clinical trials assessing treatments for CKD have usually excluded patients older than 70-75 years; therefore, it is difficult to translate current therapies recommended for younger patients with CKD across to the elderly. Many elderly people with CKD progress to end-stage kidney disease and face the dilemma of whether to undertake dialysis or accept a conservative approach supported by palliative care. This places pressure on the patient, their family, and on health care resources. The clinical trajectory of elderly CKD patients has in the past been unclear, but recent evidence suggests that many patients over 75 years of age with multiple comorbidities have greatly reduced life expectancies and quality of life, even if they choose dialysis treatment. Offering a conservative pathway supported by palliative care is a reasonable option for some patients under these circumstances. The elderly person who chooses to have dialysis will frequently have different requirements than younger patients. Kidney transplantation can still result in improved life expectancy and quality of life in the elderly, in carefully selected people. There is a genuine need for the inclusion of the elderly in CKD clinical trials in the future so we can produce evidence-based therapies for this group. In addition, new therapies to treat and slow CKD progression are needed for all age groups. PMID- 24477221 TI - Sustained effect of resistance training on blood pressure and hand grip strength following a detraining period in elderly hypertensive women: a pilot study. AB - INTRODUCTION: Hypertension is the most prevalent modifiable risk factor with a high prevalence among older adults. Exercise is a nonpharmacological treatment shown to benefit all patients with hypertension. OBJECTIVE: This study examined the effects of a 14-week moderate intensity resistance training program (RT) on the maintenance of blood pressure and hand grip strength during an extended detraining period in elderly hypertensive women. METHODS: Twelve hypertensive sedentary elderly women completed 14 weeks of whole body RT at a moderate perceived exertion following a detraining period of 14 weeks. RESULTS: Following the training period, participants demonstrated an increase in absolute hand grip strength (P=0.001), relative hand grip strength (P=0.032) and a decrease of systolic (P=0.001), diastolic (P=0.008), and mean blood pressure (P=0.002) when compared to pre-exercise values. In addition, these effects were sustained after 14 weeks of detraining. CONCLUSION: Resistance training may be a valuable method to improve muscular strength and blood pressure in elderly people with benefits being maintained up to 14 weeks following training cessation. PMID- 24477222 TI - A novel H-FABP assay and a fast prognostic score for risk assessment of normotensive pulmonary embolism. AB - We tested whether heart-type fatty acid binding protein (H-FABP) measured by a fully-automated immunoturbidimetric assay in comparison to ELISA provides additive prognostic value in patients with pulmonary embolism (PE), and validated a fast prognostic score in comparison to the ESC risk prediction model and the simplified Pulmonary Embolism Severity Index (sPESI). We prospectively examined 271 normotensive patients with PE; of those, 20 (7%) had an adverse 30-day outcome. H-FABP levels determined by immunoturbidimetry were higher (median, 5.2 [IQR; 2.7-9.8] ng/ml) than those by ELISA (2.9 [1.1-5.4] ng/ml), but Bland-Altman plot demonstrated a good agreement of both assays. The area under the curve for H FABP was greater for immunoturbidimetry than for ELISA (0.82 [0.74-0.91] vs 0.78 [0.68-0.89]; P=0.039). H-FABP measured by immunoturbidimetry (but not by ELISA) provided additive prognostic information to other predictors of 30-day outcome (OR, 12.4 [95% CI, 1.6-97.6]; P=0.017). When H-FABP determined by immunoturbidimetry was integrated into a novel prognostic score (H-FABP, Syncope, and Tachycardia; FAST score), the score provided additive prognostic information by multivariable analysis (OR, 14.2 [3.9-51.4]; p<0.001; c-index, 0.86) which were superior to information obtained by the ESC model (c-index, 0.62; net reclassification improvement (NRI), 0.39 [0.21-0.56]; P<0.001) or the sPESI (c index, 0.68; NRI, 0.24 [0.05-0.43]; P=0.012). In conclusion, determination of H FABP by immunoturbidimetry provides prognostic information superior to that of ELISA and, if integrated in the FAST score, appears more suitable to identify patients with an adverse 30-day outcome compared to the ESC model and sPESI. PMID- 24477223 TI - Pharmacogenetics and clinical biomarkers for subtherapeutic plasma efavirenz concentration in HIV-1 infected Thai adults. AB - The aim of this study was to assess the influence of host genetic variations and clinical factors in relation to efavirenz level in HIV-1 infected Thai adults. A total of 100 HIV-infected subjects treated with efavirenz/lamivudine/tenofivir were prospectively enrolled. The panel of CYP2A6, CYP2B6 and CYP3A4/5 polymorphisms was genotyped. At steady state, plasma efavirenz concentrations were measured using high performance liquid chromatography. The relationship between host genetic and clinical factors in terms of efavirenz pharmacokinetics in HIV-1 infected Thai adults was analyzed. The minor allele frequency for CYP2A6 -48T>G, CYP2B6 g.18492T>C, CYP3A4*1B c.-392A>G, CYP3A4*18 c.878T>C and CYP3A5*3 c.6986A>G was 0.14, 0.27, 0.01, 0.03 and 0.38, respectively. Univariant and multivariant analysis indicated associations for CYP2B6 g.18492T>C (p < 0.001 and p = 0.001), aspartate aminotransferase (AST; p = 0.001 and p = 0.006) and blood urea nitrogen (BUN; p = 0.011 and p = 0.016) with plasma efavirenz concentration. However, CYP2A6 -48T>G, CYP3A4*1B c.-392A>G, CYP3A4*18 c.878T>C and CYP3A5*3 c.6986A>G had no significant impact on plasma efavirenz concentration in HIV-1 infected Thai adults. The CYP2B6 g.18492T>C polymorphism, AST and BUN were significantly associated with low efavirenz concentrations. The results from this study can be used to improve the prediction of efavirenz plasma concentration and to optimize its dose in antiretroviral therapy. PMID- 24477224 TI - Ring contraction of 1,3-diphenylbenzo[1,2,4]triazinyl radicals to 1,2 diphenylbenzimidazoles. AB - Reductive ring contraction of 1,3-diphenyl-1,4-dihydrobenzo[e][1,2,4]triazin-4 yls (Blatter's radicals) using zinc powder (2 equiv.) in acetic acid heated to ca. 118 degrees C gives 1,2-diphenylbenzimidazoles in high yield. 1,3 Diphenylbenzo[e][1,2,4]triazin-7(1H)-one and the zwitterionic tetraphenylhexaazaanthracene (TPHA) also undergo reductive ring contractions to give 1,2-diphenylbenzimidaz-6-ol and 1,2,6,7-tetraphenyl-1,7-dihydrobenzo[1,2 d:4,5-d']diimidazole, respectively. By using less zinc, the incomplete reduction of TPHA gave the stable organic radical 1,3,7,8-tetraphenyl-4,8-dihydro-1H imidazo[4,5-g][1,2,4]benzotriazin-1-yl. Imidazolo-, oxazolo- and thiazolo-fused 1,2,4-benzotriazinyls all undergo zinc mediated ring contractions to give imidazolo-, oxazolo- and thiazolo-fused benzimidazoles in excellent yields. PMID- 24477225 TI - Neonatal central venous catheter thrombosis: diagnosis, management and outcome. AB - Thrombotic occlusion of central venous catheters (CVCs) is a common problem in newborns. There is no guideline that systematically addresses the diagnosis, management, and prevention of this complication. The objective of this review is to establish evidence-based guidance for the management of CVC-related thrombosis. A comprehensive search of the scientific literature was conducted from 1948 to 2012. Twenty-six articles fulfilling four criteria - humans, neonates aged below 28 days, CVC insertion, and English language - were included for analysis. The incidence of thrombosis was 9.2% (308/3332). Singly inserted umbilical venous catheters (UVCs) and peripherally inserted central catheters accounted for over 80% of all CVCs. Frequently reported thrombotic sites were the hepatic vein, right atrium, and inferior vena cava. Symptoms included distal swelling of affected areas and thrombocytopenia. Increased length of catheter stay, infusion of blood products and malpositioned UVCs were identified as risk factors. The commonest diagnostic investigations to confirm thrombosis were echocardiography and ultrasonography. Spontaneous resolution may occur in UVC related thrombosis, but this warrants close monitoring. Thrombolysis with urokinase alone or combined with low-molecular-weight heparin might be effective and well tolerated as treatment strategies. Prophylactic heparin increases the duration of catheter usability (P < 0.005, 95% confidence interval 0.35-0.81), decreases catheter occlusion, but may not uniformly prevent thrombosis. CVL related thrombosis is an underreported complication because events in the majority occur silently. Currently, solid evidence-based recommendations for diagnosis and treatment are not possible. Well designed prospective studies are urgently required to establish a concrete investigational approach to CVC-related thrombosis and to institute safe therapeutic modalities. PMID- 24477226 TI - Association between thrombophilia and seated immobility venous thromboembolism. AB - Prolonged work and recreation-related seated immobility increases the risk of venous thromboembolism (VTE). Little is known about links of thrombophilia and prolonged immobility. We sought to determine factors associated with the occurrence of seated immobility venous thromboembolism (SIT). Four hundred and ninety-three consecutive outpatients with a history of first-ever VTE, aged up to 65 years were referred for evaluation of suspected thrombophilia. Exclusion criteria were provoked VTE unless family history of VTE was positive, arterial thrombosis, cancer, infection and chronic inflammatory diseases. The prolonged immobility group was defined as being seated at least 8 h daily and at least 3 h daily without getting up, or 10 h daily and 2 h daily without getting up, or 12 h daily and 1 h daily without getting up during 12 weeks prior to VTE onset. SIT was observed in 115 patients (24.5%). Inherited thrombophilia was more common among SIT patients than in the remainder [Odds ratio (OR) 3.98, 95% confidence interval (CI) 2.55-6.25], with a major impact of factor V Leiden mutation (FVL) (OR 4.86, 95% CI 2.95-8.05). In multivariate analysis, FVL (OR 5.43, 95% CI 3.23 9.15), trauma (OR 2.55, 95% CI 1.30-4.99), current smoking (OR 1.68, 95% CI 1.06 2.67) and varices (OR 2.08, 95% CI 1.27-3.40) were independent predictors of SIT. Moreover, FVL (OR 4.05, 95% CI 2.12-7.76), prothrombin G20210A variant (OR 3.84, 95% CI 1.47-10.05) and computer use (OR 2.84, 95% CI 1.43-5.63) were independent predictors of unprovoked VTE in the SIT group. Inherited thrombophilia, current smoking and varices characterize patients with SIT. PMID- 24477227 TI - Cerebral venous sinus thrombosis in the setting of combined vaginal contraception. AB - We present a case of a 27-year-old women admitted to the hospital with migraine and left upper extremity weakness. Subsequent imaging with computed tomography and magnetic resonance angiography/venography demonstrated an acute-appearing central venous sinus thrombosis. Her only risk factor for venous thromboembolism (VTE) was the use of etonogestrel/ethinyl estradiol vaginal contraceptive ring (NuvaRing). The contraceptive ring was removed and the patient was treated according to the current guidelines. She achieved full neurologic recovery at 6 months' follow-up. Here, we describe this unusual case and review the risk of VTE between combined vaginal contraception and combined oral contraception. PMID- 24477228 TI - Whether chicken or egg hatch? PMID- 24477229 TI - Mean platelet volume in patients with acute pancreatitis: insight from methodological aspect. PMID- 24477230 TI - Comment on: predictive value of elevated D-dimer in patients undergoing primary angioplasty for ST-elevation myocardial infarction. PMID- 24477231 TI - Surface-charge accumulation effects on open-circuit voltage in organic solar cells based on photoinduced impedance analysis. AB - The accumulation of dissociated charge carriers plays an important role in reducing the loss occurring in organic solar cells. We find from light-assisted capacitance measurements that the charge accumulation inevitably occurred at the electrode and photovoltaic layer interface for bulk-heterojunction ITO/PEDOT:PSS/P3HT:PCBM/Ca/Al solar cells. Our results indicate, for the first time through impedance measurements, that the charge accumulation exists at the anode side of the device, and more importantly, we successfully identify the type of charge accumulated. Further study shows that the charge accumulation can significantly affect open circuit voltage and short circuit current. As a result, our experimental results from light assisted capacitance measurements provide a new understanding of the loss in open-circuit voltage and short-circuit photocurrent based on charge accumulation. Clearly, controlling charge accumulation presents a new mechanism to improve the photovoltaic performance of organic solar cells. PMID- 24477232 TI - A novel beta-adrenergic response element regulates both basal and agonist-induced expression of cyclin-dependent kinase 1 gene in cardiac fibroblasts. AB - Cardiac fibrosis, a known risk factor for heart disease, is typically caused by uncontrolled proliferation of fibroblasts and excessive deposition of extracellular matrix proteins in the myocardium. Cyclin-dependent kinase 1 (CDK1) is involved in the control of G2/M transit phase of the cell cycle. Here, we showed that isoproterenol (ISO)-induced cardiac fibrosis is associated with increased levels of CDK1 exclusively in fibroblasts in the adult mouse heart. Treatment of primary embryonic ventricular cell cultures with ISO (a nonselective beta-adrenergic receptor agonist) increased CDK1 protein expression in fibroblasts and promoted their cell cycle activity. Quantitative PCR analysis confirmed that ISO increases CDK1 transcription in a transient manner. Further, the ISO-responsive element was mapped to the proximal -100-bp sequence of the CDK1 promoter region using various 5'-flanking sequence deletion constructs. Sequence analysis of the -100-bp CDK1 minimal promoter region revealed two putative nuclear factor-Y (NF-Y) binding elements. Overexpression of the NF-YA subunit in primary ventricular cultures significantly increased the basal activation of the -100-bp CDK1 promoter construct but not the ISO-induced transcription of the minimal promoter construct. In contrast, dominant negative NF-YA expression decreased the basal activity of the minimal promoter construct and ISO treatment fully rescued the dominant negative effects. Furthermore, site directed mutagenesis of the distal NF-Y binding site in the -100-bp CDK1 promoter region completely abolished both basal and ISO-induced promoter activation of the CDK1 gene. Collectively, our results raise an exciting possibility that targeting CDK1 or NF-Y in the diseased heart may inhibit fibrosis and subsequently confer cardioprotection. PMID- 24477233 TI - Glucose stimulates calcium-activated chloride secretion in small intestinal cells. AB - The sodium-coupled glucose transporter-1 (SGLT1)-based oral rehydration solution (ORS) used in the management of acute diarrhea does not substantially reduce stool output, despite the fact that glucose stimulates the absorption of sodium and water. To explain this phenomenon, we investigated the possibility that glucose might also stimulate anion secretion. Transepithelial electrical measurements and isotope flux measurements in Ussing chambers were used to study the effect of glucose on active chloride and fluid secretion in mouse small intestinal cells and human Caco-2 cells. Confocal fluorescence laser microscopy and immunohistochemistry measured intracellular changes in calcium, sodium glucose linked transporter, and calcium-activated chloride channel (anoctamin 1) expression. In addition to enhancing active sodium absorption, glucose increased intracellular calcium and stimulated electrogenic chloride secretion. Calcium imaging studies showed increased intracellular calcium when intestinal cells were exposed to glucose. Niflumic acid, but not glibenclamide, inhibited glucose stimulated chloride secretion in mouse small intestines and in Caco-2 cells. Glucose-stimulated chloride secretion was not seen in ileal tissues incubated with the intracellular calcium chelater BAPTA-AM and the sodium-potassium-2 chloride cotransporter 1 (NKCC1) blocker bumetanide. These observations establish that glucose not only stimulates active Na absorption, a well-established phenomenon, but also induces a Ca-activated chloride secretion. This may explain the failure of glucose-based ORS to markedly reduce stool output in acute diarrhea. These results have immediate potential to improve the treatment outcomes for acute and/or chronic diarrheal diseases by replacing glucose with compounds that do not stimulate chloride secretion. PMID- 24477234 TI - Intermittent hypoxia-induced endothelial barrier dysfunction requires ROS dependent MAP kinase activation. AB - The objective of the present study was to determine the impact of simulated apnea with intermittent hypoxia (IH) on endothelial barrier function and assess the underlying mechanism(s). Experiments were performed on human lung microvascular endothelial cells exposed to IH-consisting alternating cycles of 1.5% O2 for 30s followed by 20% O2 for 5 min. IH decreased transendothelial electrical resistance (TEER) suggesting attenuated endothelial barrier function. The effect of IH on TEER was stimulus dependent and reversible after reoxygenation. IH-exposed cells exhibited stress fiber formation and redistribution of cortactin, vascular endothelial-cadherins, and zona occludens-1 junction proteins along with increased intercellular gaps at cell-cell boundaries. Extracellular signal regulated kinase (ERK) and c-jun NH2-terminal kinase (JNK) were phosphorylated in IH-exposed cells. Inhibiting either ERK or JNK prevented the IH-induced decrease in TEER and the reorganization of the cytoskeleton and junction proteins. IH increased reactive oxygen species (ROS) levels, and manganese (III) tetrakis (1 methyl-4-pyridyl) porphyrin pentachloride, a membrane-permeable antioxidant, prevented ERK and JNK phosphorylation as well as IH-induced changes in endothelial barrier function. These results demonstrate that IH via ROS-dependent activation of MAP kinases leads to reorganization of cytoskeleton and junction proteins resulting in endothelial barrier dysfunction. PMID- 24477235 TI - Expression and function of a T-type Ca2+ conductance in interstitial cells of Cajal of the murine small intestine. AB - Interstitial cells of Cajal (ICC) generate slow waves in gastrointestinal (GI) muscles. Previous studies have suggested that slow wave generation and propagation depends on a voltage-dependent Ca(2+) entry mechanism with the signature of a T-type Ca(2+) conductance. We studied voltage-dependent inward currents in isolated ICC. ICC displayed two phases of inward current upon depolarization: a low voltage-activated inward current and a high voltage activated current. The latter was of smaller current density and blocked by nicardipine. Ni(2+) (30 MUM) or mibefradil (1 MUM) blocked the low voltage activated current. Replacement of extracellular Ca(2+) with Ba(2+) did not affect the current, suggesting that either charge carrier was equally permeable. Half activation and half-inactivation occurred at -36 and -59 mV, respectively. Temperature sensitivity of the Ca(2+) current was also characterized. Increasing temperature (20-30 degrees C) augmented peak current from -7 to -19 pA and decreased the activation time from 20.6 to 7.5 ms [temperature coefficient (Q10) = 3.0]. Molecular studies showed expression of Cacna1g (Cav3.1) and Cacna1h (Cav3.2) in ICC. The temperature dependence of slow waves in intact jejunal muscles of wild-type and Cacna1h(-/-) mice was tested. Reducing temperature decreased the upstroke velocity significantly. Upstroke velocity was also reduced in muscles of Cacna1h(-/-) mice, and Ni(2+) or reduced temperature had little effect on these muscles. Our data show that a T-type conductance is expressed and functional in ICC. With previous studies our data suggest that T-type current is required for entrainment of pacemaker activity within ICC and for active propagation of slow waves in ICC networks. PMID- 24477236 TI - The inhibitory effect of simvastatin and aspirin on histamine responsiveness in human vascular endothelial cells. AB - Statins and aspirin deliver well-established cardiovascular benefits resulting in their increased use as combined polypills to decrease risk of stroke and heart disease. However, the direct endothelial effect of combined statin/aspirin cotreatment remains unclear. Histamine is an inflammatory mediator that increases vascular permeability, and so we examined the effect of treating human umbilical vein endothelial cells (HUVECs) for 24 h with 1 MUM simvastatin and 100 MUM aspirin on histamine responsiveness. Subsequent histamine (1 MUM) challenge increased intracellular calcium (Ca(2+)i) concentration, an effect that was significantly inhibited by combined simvastatin/aspirin pretreatment but not when then the compounds were given separately, even at 10-fold higher concentrations. In contrast, the Ca(2+)i mobilization response to ATP challenge (10 MUM) was not inhibited by combined simvastatin/aspirin pretreatment. The H1 receptor antagonist pyrilamine significantly inhibited both histamine-induced Ca(2+)i mobilization and extracellular signal-regulated kinase (ERK) activation, whereas ranitidine (H2 receptor antagonist) was without effect. However, combined simvastatin/aspirin pretreatment failed to decrease H1 receptor protein expression ruling out receptor downregulation as the mechanism of action. Histamine-induced ERK activation was also inhibited by atorvastatin pretreatment, while simvastatin further inhibited histamine-induced vascular endothelial cadherin phosphorylation as well as altered HUVEC morphology and inhibited actin polymerization. Therefore, in addition to the known therapeutic benefits of statins and aspirin, here we provide initial cellular evidence that combined statin/aspirin treatment inhibits histamine responsiveness in HUVECs. PMID- 24477239 TI - Synthesis, characterisation and some chemistry of C- and B-substituted carboxylic acids of cobalt bis(dicarbollide). AB - Low temperature reactions of lithiated cobalt bis(1,2-dicarbollide)(1-) (1-) in DME with carbon dioxide leads to the substitution of 1- at the C-atoms by carboxy function(s). This results in a good yield formation of monosubstituted and disubstituted products of formulations [(1-HOOC-1,2-C2B9H10)(1',2'-C2B9H11)-3,3' Co)](-) (2-) and [(HOOC)2-(1,2-C2B9H10)2-3,3'-Co](-) (3a,b-), respectively. Indeed, the latter compound is in fact a mixture of two diastereoisomers, denoted here as 1,1'-anti (3a-) and 1,2'-syn-isomer (3b-), from which only the former major species (3a-) could be isolated in pure form. Considerations about stereochemistry of these species are supported by geometry optimizations and calculations of (11)B NMR shifts at the GIAO-DFT level. In addition, three monocarboxylic acids with three different linear spacers between the carboxy groups and the cage are reported. The first one of the formula [(1-HOOC-CH2-1,2 C2B9H10)(1',2'-C2B9H11)-3,3'-Co](-) (5-) results in a lithiation followed by reaction with BrCH2COOEt and hydrolysis of the respective ethyl ester (4-). Another one with ethylene chain [(1-HOOC-(CH2)2-1,2-C2B9H10)(1',2'-C2B9H11)-3,3' Co](-) (6-) was prepared by the oxidation of a hydroxypropyl derivative of the ion 1-. The sole representative of B-substituted species of the formulation [8 (HOOC-CH2-O-1,2-C2B9H10)(1',2'-C2B9H11)-3,3'-Co](-) (7-) is prepared by alkylation of the known 8-hydroxy derivatives of the ion 1- by BrCH2COOEt and alkaline hydrolysis. A synthetic route to active nitrofenyl esters (8-, 9- and 10 ) is described here based on the respective acids 5- to 7-. As verified, the nitrophenyl esters provide easy access to the formation of amidic bonds between the boron cage and organic primary amino functions. Examples of compounds containing butylamide or benzylamide [(1-RNHOC-(CH2)n-1,2-C2B9H10)(1',2'-C2B9H11) 3,3'-Co](-) (n = 1,2; R = Bu 11a,b-, R = Bn: 12a,b-) end group are described. Also the possibility of inter-connecting two clusters of the anion 1- via the amidic bond is shown in derivative (13-). These methods are applicable in the synthesis of a variety of functional molecules, particularly those applicable in drug design, surface modifications, and material science. PMID- 24477237 TI - Physiological contractility of cardiomyocytes in the wall of mouse and rat azygos vein. AB - We recently demonstrated the abundant presence of cardiomyocytes in the wall of thoracic veins of adult mouse and rat. The highly differentiated morphology and myofilament protein contents of the venous cardiomyocytes suggested contractile functions. Here we further investigated the contractility of mouse and rat azygos venous rings compared with that of atrial strips and ventricular papillary muscle. 5-Bromo-4-chloro-indolyl-galactopyranoside (X-gal) staining of transgenic mouse vessels expressing lacZ under a cloned cardiac troponin T promoter demonstrated that the venous cardiomyocytes are discontinuous from atrial myocardium and aligned in the wall of thoracic veins perpendicular to the vessel axis. Histological sections displayed sarcomeric striations in the venous cardiomyocytes, which indicate an encirclement orientation of myofibrils in the vessel wall. Mechanical studies found that the rings of mouse and rat azygos vein produce strong cardiac type twitch contractions when stimulated with electrical pacing in contrast to the weak and slow smooth muscle contractions induced using 90 mM KCl. The twitch contraction and relaxation of mouse azygos veins further exhibited a cardiac type of beta-adrenergic responses. Quantitative comparison showed that the contractions of venous cardiomyocytes are slightly slower than those of atrium muscle but significantly faster than those of ventricular papillary muscle. These novel findings indicate that the cardiomyocytes abundant in the wall of rodent thoracic veins possess fully differentiated cardiac muscle phenotype despite their anatomical and functional segregations from the heart. PMID- 24477238 TI - Role of c-Abl tyrosine kinase in smooth muscle cell migration. AB - c-Abl is a nonreceptor protein tyrosine kinase that has a role in regulating smooth muscle cell proliferation and contraction. The role of c-Abl in smooth muscle cell migration has not been investigated. In the present study, c-Abl was found in the leading edge of smooth muscle cells. Knockdown of c-Abl by RNA interference attenuated smooth muscle cell motility as evidenced by time-lapse microscopy. Furthermore, the actin-associated proteins cortactin and profilin-1 (Pfn-1) have been implicated in cell migration. In this study, cell adhesion induced cortactin phosphorylation at Tyr-421, an indication of cortactin activation. Phospho-cortactin and Pfn-1 were also found in the cell edge. Pfn-1 directly interacted with cortactin in vitro. Silencing of c-Abl attenuated adhesion-induced cortactin phosphorylation and Pfn-1 localization in the cell edge. To assess the role of cortactin/Pfn-1 coupling, we developed a cell permeable peptide. Treatment with the peptide inhibited the interaction of cortactin with Pfn-1 without affecting cortactin phosphorylation. Moreover, treatment with the peptide impaired the recruitment of Pfn-1 to the leading edge and cell migration. Finally, beta1-integrin was required for the recruitment of c Abl to the cell edge. Inhibition of actin dynamics impaired the spatial distribution of c-Abl. These results suggest that beta1-integrin may recruit c Abl to the leading cell edge, which may regulate cortactin phosphorylation in response to cell adhesion. Phosphorylated cortactin may facilitate the recruitment of Pfn-1 to the cell edge, which promotes localized actin polymerization, leading edge formation, and cell movement. Conversely, actin dynamics may strengthen the recruitment of c-Abl to the leading edge. PMID- 24477240 TI - Giant primary melanoma with no apparent metastases: a report of 2 cases. PMID- 24477241 TI - Implementing, adapting, and validating an evidence-based algorithm for hip fracture surgery. AB - OBJECTIVES: Reoperations are common after surgical treatment of hip fractures but may be reduced by optimal choice of implant based on fracture classification. We hypothesized that implementing a surgical treatment algorithm was possible in our hospital and would result in a reduced reoperation rate. DESIGN: Retrospective comparative study. SETTING: Provincial level III trauma center. PATIENTS: The evidence-based "Hvidovre Algorithm" for treatment of hip fractures was adopted and implemented at our provincial institution in September 2008. Three hundred eighty-six consecutive patients older than 50 years admitted with a hip fracture in the first year after implementation were prospectively included and compared with 417 retrospectively included similar patients admitted within the last year before implementation. INTERVENTION: Implementation of an evidence-based treatment algorithm for hip fracture surgery. RESULTS: Eighty-five percent (330 of 386) patients were operated according to the algorithm after implementation, compared with 67% (280 of 417) of procedures before implementation (P < 0.001). After implementation, the overall reoperation rate showed a tendency toward a reduction to 8% (32 of 386) from 12% (48 of 417) (P = 0.1). Among all the 803 included patients, the reoperation rate was lower if procedures had been performed according to the algorithm recommendations: 9% (53 of 610) versus 14% (27 of 193) (P = 0.009). CONCLUSIONS: The algorithm for hip fracture surgery was easily implemented, and our results support that using it facilitates a low reoperation rate. The reoperation rate may be further reduced with higher adherence to algorithm recommendation. LEVEL OF EVIDENCE: Therapeutic level III. See instructions for authors for a complete description of levels of evidence. PMID- 24477242 TI - GLP-1 infusion reduces IGFBP-1 serum level in humans. AB - OBJECTIVE: Glucagon-like peptide-1 (GLP-1) and the insulin-like growth factor (IGF) system are important factors in metabolic regulation and cellular growth. Interactions between the systems exist but these are vaguely explored and only in vitro, where GLP-1 has been reported to stimulate IGF-binding protein 1 (IGFBP 1). This study, therefore, aimed to elucidate the effects of GLP-1 on IGF-I and the IGFBPs, which regulate IGF-I bioactivity. DESIGN: We investigated the effects of a 2-hour intravenous GLP-1 infusion on the IGF system in 12 overnight fasted healthy humans, using a randomized, double-blinded, cross-over study design. Serum samples were assessed for immunoreactive levels of IGF-I, IGFBP-1 and -2 as well as for bioactive IGF-I, which was determined by a cell-based IGF-I kinase receptor activation assay. RESULTS: GLP-1 infusion markedly increased insulin levels (p<0.0001), reduced IGFBP-1 levels (p=0.02), and tended to increase IGF-I bioactivity (p=0.06). There were no significant changes in IGFBP-2 or immunoreactive IGF-I levels. CONCLUSION: In this short-term study, GLP-1 reduced IGFBP-1 levels in vivo and tended to increase IGF-I bioactivity. The IGFBP-1 outcome is opposite to the in vitro situation, hereby demonstrating that in vivo the ability of GLP-1 to stimulate insulin and hereby suppress IGFBP-1 outweighs any direct stimulatory effects of GLP-1 on IGFBP-1. PMID- 24477243 TI - Vitamin D deficiency and cardiovascular disease: potential mechanisms and novel perspectives. AB - Interest in contemporary vitamin D research has been sparked in recent years, stemming from the identification of vitamin D receptors in virtually all cells as well as the enzymatic machinery necessary to produce its active form. Both epidemiological and in-vitro studies have linked vitamin D deficiency to enigmatic diseases including cardiovascular disease; however, a clear mechanistic link remains missing. This review highlights conclusions of observational studies, in-vitro experiments and randomized-controlled trials that aimed to link deficiency of the sunshine vitamin to one of the leading causes of death in the world, cardiovascular disease. Furthermore, putative mechanisms viewed from a novel perspective are also discussed. PMID- 24477244 TI - Effects of ascorbic acid deficiency on protein and lipid oxidation in livers from SMP30/GNL knockout mice. AB - Ascorbic acid (AA) functions as an electron donor and scavenges reactive oxygen species such as superoxide, singlet oxygen, and hydroxyl radicals in vitro. However, little is known about the effect of an AA deficiency on protein and lipid oxidation levels in the liver. Therefore, we measured the levels of protein carbonyl and thiobarbituric acid reactive substances (TBARS) in livers from senescence marker protein-30 (SMP30)/gluconolactonase (GNL) knockout (KO) mice. These mice are deficient in AA, because they lack the SMP30/GNL gene, which is essential for the biosynthesis of AA in vivo. To track the effect of an AA deficiency, at 30 d of age, mice were divided into the following four groups: AA (-) SMP30/GNL KO, AA (+) SMP30/GNL KO, AA (-) wild type (WT), and AA (+) WT. The AA (+) groups were given water containing 1.5 g/L AA, whereas the AA (-) groups received water without AA for 57 d. All mice were fed an AA-free diet. Subsequently, protein carbonyl levels in livers from AA (-) SMP30/GNL KO mice were significantly higher than those from the other three groups; however, TBARS levels were not significantly different among the four groups. Therefore, AA must act as an anti-oxidant for proteins but might not directly protect lipid oxidation in the liver. PMID- 24477245 TI - Vitamin A and beta-carotene concentrations in adults with HIV/AIDS on highly active antiretroviral therapy. AB - Micronutrient deficiency is a common condition in HIV-infected individuals and may occur in all stages of the disease. The objective of this cross-sectional study was to compare the concentrations of vitamin A and beta-carotene, micronutrients related to immunity and oxidative stress, in 182 adults with HIV/AIDS, under different highly active antiretroviral therapy (HAART) regimens. Patients were divided into 3 groups according to their HAART regimen: combination of nucleoside analog reverse transcriptase inhibitors (NRTIs) and non-NRTIs; combination of NRTIs, protease inhibitors, and ritonavir; combination of NRTIs and other classes. Multiple linear regression analysis determined the effect of the treatment regimen, time of use, and compliance with the regimen, on vitamin A and beta-carotene concentrations, controlling for the following variables: gender, age, educational level, smoking, physical activity, body mass index, time of infection with HIV, presence of comorbidities, CD4(+) T lymphocyte count, total cholesterol and fractions, and triglyceride levels. There was no significant difference in vitamin A or beta-carotene concentrations in patients under the different HAART regimens. However, approximately 4% of the patients had deficient/low concentrations of vitamin A (<0.70 MUmol/L), and 98% showed concentrations of beta-carotene <1.0 MUmol/L. In conclusion, HIV/AIDS patients in this region will not benefit from vitamin A supplementation, independently of the HAART regimen utilized, but beta-carotene may be of importance, considering its antioxidant effect. PMID- 24477246 TI - Water-soluble vitamin deficiencies in complicated peptic ulcer patients soon after ulcer onset in Japan. AB - We investigated over time whether contemporary Japanese patients with complicated peptic ulcers have any water-soluble vitamin deficiencies soon after the onset of the complicated peptic ulcers. In this prospective cohort study, fasting serum levels of water-soluble vitamins (vitamins B1, B2, B6, B12, C, and folic acid) and homocysteine were measured at 3 time points (at admission, hospital discharge, and 3 mo after hospital discharge). Among the 20 patients who were enrolled in the study, 10 consecutive patients who completed measurements at all 3 time points were analyzed. The proportion of patients in whom any of the serum water-soluble vitamins that we examined were deficient was as high as 80% at admission, and remained at 70% at discharge. The proportion of patients with vitamin B6 deficiency was significantly higher at admission and discharge (50% and 60%, respectively, p<0.05) than at 3 mo after discharge (10%). In conclusion, most patients with complicated peptic ulcers may have a deficiency of one or more water-soluble vitamins in the early phase of the disease after the onset of ulcer complications, even in a contemporary Japanese population. PMID- 24477247 TI - Pantothenic acid deficiency may increase the urinary excretion of 2-oxo acids and nicotinamide catabolites in rats. AB - Pantothenic acid (PaA) is involved in the metabolism of amino acids as well as fatty acid. We investigated the systemic metabolism of amino acids in PaA deficient rats. For this purpose, urine samples were collected and 2-oxo acids and L-tryptophan (L-Trp) and its metabolites including nicotinamide were measured. Group 1 was freely fed a conventional chemically-defined complete diet and used as an ad lib-fed control, which group was used for showing reference values. Group 2 was freely fed the complete diet without PaA (PaA-free diet) and used as a PaA-deficient group. Group 3 was fed the complete diet, but the daily food amount was equal to the amount of the PaA-deficient group and used as a pair fed control group. All rats were orally administered 100 mg of L-Trp/kg body weight at 09:00 on day 34 of the experiment and the following 24-h urine samples were collected. The urinary excretion of the sum of pyruvic acid and oxaloacetic acid was higher in rats fed the PaA-free diets than in the rats fed pair-fed the complete diet. PaA deficiency elicited the increased urinary excretion of anthranilic acid and kynurenic acid, while the urinary excretion of xanthurenic acid decreased. The urinary excretion of L-Trp itself, 3-hydroxyanthranilic acid, and quinolinic acid revealed no differences between the rats fed the PaA-free and pair-fed the complete diets. PaA deficiency elicited the increased excretion of N(1)-methylnicotinamide, N(1)-methyl-2-pyridone-5-carboxamide, and N(1)-methyl-4 pyridone-3-carboxamide. These findings suggest that PaA deficiency disturbs the amino acid catabolism. PMID- 24477248 TI - Postprandial thermic effect of chicken involves thyroid hormones and hepatic energy metabolism in rats. AB - We investigated the postprandial thermic effect of chicken and its mechanisms in rats. A chicken diet showed a strong thermic effect after consumption, and the removal of fat induced more rapid and stronger thermogenesis. Although thermogenesis induced by a purified chicken protein diet was also strong, the thermic reaction was not so rapid and a remarkable rise of peripheral temperatures was not observed. Defatted chicken and purified chicken protein activated the thyroid hormone system and up-regulated rate-limiting enzyme genes of glucose metabolism and the tricarboxylic acid (TCA) cycle in the liver. Moreover, chicken protein up-regulated the mRNA expression of a rate-limiting enzyme of hepatic lipid metabolism. It is possible that the mechanisms by which body temperature is raised are different between chicken protein and defatted chicken. On the other hand, it is possible that chicken fat suppressed the expression of energy metabolism-related genes that was induced by the consumption of lean chicken. As a result, a rise of postprandial body temperature might not have been induced after consumption of chicken fat. These results suggest that the consumption of lean chicken activates the thyroid hormone system and hepatic energy metabolism and consequently induces the postprandial thermic effect of chicken. PMID- 24477249 TI - Circulating interleukin-1beta concentrations are independently-positively associated with gamma-glutamyltransferase activity within the normal range in middle-aged apparently healthy Japanese women. AB - We previously demonstrated that the circulating concentrations of interleukin (IL)-1beta, which is known to induce the development and progression of type 2 diabetes and its complications, were positively associated with gamma glutamyltransferase (gamma-GTP) activity in middle-aged apparently healthy Japanese men. It was still unknown if the association between IL-1beta concentrations and gamma-GTP activity is within the normal range in apparently healthy Japanese women. In this study, we conducted a cross-sectional study of 824 apparently healthy women aged 40-64 y [mean+/-standard deviation age, 53.1+/ 7.1 y; body mass index (BMI), 22.0+/-3.1 kg/m(2)] who participated in health checkups in Japan, and whose gamma-GTP activity was within the normal range (<38 U/L). Associations of gamma-GTP with IL-1beta and other clinical or lifestyle factors were determined using analysis of variance (ANOVA) and one-way analysis of covariance (ANCOVA) followed by Tukey's multiple-range test. Multivariate logistic regression analyses (MLRA) were performed with gamma-GTP activity as the dependent variable; independent variables included IL-1beta plus clinical and lifestyle factors. ANOVA and ANCOVA indicated that IL-1beta concentrations were positively associated with gamma-GTP activity. MLRA showed that gamma-GTP activity showed trends for higher IL-1beta concentrations after adjusting for age, BMI, energy intake, alcohol intake, and smoking status. Together, IL-1beta concentrations are positively associated with gamma-GTP activity within the normal range in middle-aged apparently healthy Japanese women. Our results suggest that gamma-GTP activity would be useful for assessing inflammation from the healthy state in Japanese women. PMID- 24477250 TI - The effects of glycine, L-threonine, and L-cystine supplementation to a 9% casein diet on the conversions of L-tryptophan to nicotinamide and to serotonin in rats. AB - Nicotinamide and serotonin are synthesized from L-tryptophan in mammals. It is important to know the nutritional factors affecting the synthesis of nicotinamide and serotonin. We investigated the effects of amino acid composition. Young adult rats were fed ad libitum for 21 d a low-protein (9% casein) diet([1] control), or one of the low protein diets supplemented with following amino acids: [2] glycine, L-threonine, and L-cystine, [3] L-threonine and L-cystine, [4] glycine and L-cystine, and [5] glycine and L-threonine. The amounts of glycine, L threonine and L-cystine supplementations were 2%, 0.078%, and 0.2%, respectively, and the amino acid contents of all diet were adjusted with supplementation of L glutamic acid. The body weight gain, food efficiency ratio, and the amino acid nutrition biomarker, which is the urinary excretion ratio of (N(1)-methyl-2 pyridone-5-carboxamide+N(1)-methyl-4-pyridone-3-carboxamide)/N(1) methylnicotinamide, improved by adding the amino acids glycine, L-threonine and L cystine to a 9% casein diet. The conversion percentage of L-tryptophan to nicotinamide decreased with the addition of the amino acids glycine, L-threonine and L-cystine to a 9% casein diet, while the concentrations of serotonin in the brain, stomach and small intestine were not affected at all. The effects of each amino acid on body weight gain and the conversion ratios were also investigated. Glycine did not affect these variables. L-Cystine improved the body weight gain, the food efficiency ratio and the urine ratio, and decreased the conversion percentage. L-Threonine did not affect body weight gain or food efficiency ratio; however, it improved the urine ratio and decreased the conversion percentage. PMID- 24477251 TI - Dietary supplementation with a low dose of (-)-epigallocatechin-3-gallate reduces pro-inflammatory responses in peripheral leukocytes of non-obese type 2 diabetic GK rats. AB - (-)-Epigallocatechin-3-gallate (EGCG), which is largely found in green tea, is known to eliminate reactive oxygen species and associated inflammatory responses in vitro and in cells. However, the in vivo mechanisms underlying the effects of EGCG on the amelioration of metabolic disorders are not fully understood. In this study, we examined whether dietary supplementation with EGCG reduces inflammatory responses in peripheral leukocytes of a non-obese type 2 diabetes animal model, Goto-Kakizaki (GK) rats. GK rats at 9 wk of age were fed a control high-fat diet (46 energy % from lard and corn oil) or a high-fat diet containing 0.1%, 0.2%, or 0.5% EGCG (w/w) for 25 wk. The oxidative stress markers 8-hydroxydeoxyguanosine (OHdG) and total malondialdehyde (MDA) were reduced by supplementation with EGCG at 0.1%, but not at 0.2% or more. Significant reductions in the mRNA levels of genes related to inflammatory responses (TNF-alpha, IFN-gamma, IL-1beta, IL-6, IL 18, MCP-1, CD11b, and S100a6), 8-OHdG, and total MDA were induced in peripheral leukocytes of GK rats by EGCG supplementation at 0.1%, but not at 0.2% or more, compared with rats fed the control diet. The present results suggest that supplementation with a low dose of EGCG reduces oxidative stress and the expressions of genes involved in inflammation in peripheral leukocytes of GK rats. PMID- 24477252 TI - Low pyridoxine concentrations enhance lipopolysaccharide-stimulated gene expression of cyclooxygenase-2 and inducible nitric oxide synthase in RAW264.7 cells. AB - Pyridoxal (PL) has been shown to suppress lipopolysaccharide (LPS)-induced gene expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS). Commonly used cell culture media contain extremely high concentrations of pyridoxine (PN) compared to total serum levels of vitamin B6. Therefore, we evaluated how physiological concentrations of PN influence LPS-stimulated gene expression of COX-2 and iNOS. The mouse macrophage cell line, RAW264.7, was cultured in PN-free DMEM supplemented with 10% fetal bovine serum (DMEM(-PN+FBS)) for 7 d. Although the level of pyridoxal 5'-phosphate in these cells was decreased by 65%, no change was observed in cell proliferation rate or aspartate aminotransferase activity for 7 d. LPS-induced expression of COX-2 mRNA was compared between DMEM(+FBS) and DMEM(-PN+FBS). COX-2 expression was enhanced by 2.2 or 1.9 times with a 1 or 3 d treatment, respectively; however, no difference was observed at 7 d. PN (0.032-100 MUm) added to the DMEM(-PN+FBS) and RAW264.7 cells was cultured in the medium containing each concentration of PN for 1 d. Enhancement of COX-2 and iNOS gene expression was suppressed by PN addition in a concentration-dependent manner. COX-2 and iNOS mRNA were similarly expressed in cells grown in media containing PN at 4 MUm or higher. Overall, induction of COX 2 and iNOS by LPS was transiently enhanced when RAW264.7 cells were cultured in physiological PN concentrations. PMID- 24477253 TI - Comparison of the effects of dietary protein on the sexual organ development of male mice and rats kept under constant darkness. AB - The purpose of this study was to determine whether the effects of dietary protein on sexual organ development were different in mice and rats kept under constant darkness. Four-week-old mice (ICR strain) and rats (F344 strain) were kept under constant darkness (D) or normal lighting (N; 12-h light/dark cycle) for 4 wk. The dietary protein level was 9% casein with the addition of 0.135% cystine (9PC) or without it (9P); other components of the diet were based on the AIN-93G diet. The testes and epididymides weights (g/100 g BW) of the rats given the 9P diet in the D-group were lower than those of the rats given the 9P diet in the N-group. In the mice, lighting conditions and diet did not affect testes or epididymides weights. Body weight and food intake in the rats were affected by diet, and these values were lower in the 9P diet group; however, body weight and food intake in the mice was not affected by diet. The serum albumin concentration in the rats was lower in the 9P diet group, while that of the mice was lower in the 9PC diet group. In the rats kept under constant darkness, a diet lacking in cystine accelerated the suppression of sexual organ development and decreased serum albumin concentration, but this diet had no such effects on the mice. The finding that the effects of dietary protein were different in mice and rats suggests that protein requirements of mice are different from those of rats. PMID- 24477254 TI - Magnesium deficiency induces the emergence of mast cells in the liver of rats. AB - Mast cells, multifunctional effector cells of the immune system, are implicated in the pathogenesis of hepatic steatosis and fibrosis. Magnesium (Mg) deficiency was reported to increase triglyceride concentration in the liver, and to exacerbate the collagen deposition induced by carbon tetrachloride in the liver. Although Mg deficiency increases mast cells in the small intestine, the kidney and bone marrow, the effect of Mg deficiency on mast cells has not been clarified in the liver. We examined the emergence of mast cells in the liver of Sprague Dawley rats given an Mg-deficient diet. Rats were fed a control diet or an Mg deficient diet for 4 wk. Mg deficiency increased the levels of mRNA known to be expressed by mast cells in the liver; the mRNA of alpha- and beta-chain high affinity immunoglobulin E receptor (FcepsilonR1alpha, FcepsilonR1beta), and the mRNA of mast cell protease 1 (Mcpt1), and mast cell protease 2 (Mcpt2). Histological observation showed that some mast cells were locally distributed around portal triads in the Mg-deficient group but mast cells were scarcely found in the control group. These results clearly indicate that Mg deficiency induces the emergence of mast cells around portal triads of the liver in Sprague-Dawley rats. PMID- 24477255 TI - Fermented soybean powder with rice mold in the absence of salt stimulates the cellular immune system and suppresses the humoral immune response in mice. AB - The immunomodulatory effect of fermented non-salty soybean powder (NSBP) was investigated in C3H/HeN mice. The number of splenic CD11b(+), CD49b(+), and interferon (IFN)-gamma(+)CD4(+) cells increased significantly, while that of interleukin (IL)-4(+)CD4(+) and CD19(+) cells decreased significantly in cultures containing NSBP. Similarly, in the spleen and Peyer's patches of mice fed a diet containing NSBP, the number of IL-12(+)CD11b(+), CD49b(+), and IFN-gamma(+)CD4(+) cells increased noticeably, whereas the number of splenic IL-4(+)CD4(+) and CD19b(+) cells was lower compared to mice fed an NSBP-free diet. Superoxide production by peritoneal macrophages was significantly higher in mice fed an NSBP containing diet. Both intestinal total IgA and serum total IgG levels declined in mice fed the NSBP-containing diet. Microarray analysis of mRNAs extracted from Peyer's patch cells of mice fed the NSBP-containing diet indicated an increase in the expression of several genes related to cellular immune responses, while the expression of genes related to immunoglobulin production decreased. These results indicate that NSBP stimulates the cellular immune response, but suppresses the acquired humoral immune response in C3H/HeN mice. PMID- 24477256 TI - Chemical evidence for potent xanthine oxidase inhibitory activity of Glechoma hederacea var. grandis leaves (kakidoushi-cha). AB - In this study, chemical evidence for the potent xanthine oxidase inhibitory activity of "kakidoushi-cha" (dry leaves of Glechoma hederacea var. grandis), a traditional folk tea consumed in Japan, was clarified on the basis of structure identification of the active constituents. Assay-guided fractionation and purification afforded 15 compounds from the most active chromatographic fraction of an extract of the tea. Two flavonoids, apigenin and luteolin, showed remarkable inhibitory activity against xanthine oxidase (XO). The contribution of these flavonoid constituents to the observed XO inhibitory activity of the methanol and boiling-water extracts of the tea was estimated to be ca. 35% and ca. 18%, respectively. PMID- 24477257 TI - Distribution of vitamin E intake among Japanese dietary supplement and fortified food users: a secondary analysis from the National Health and Nutrition Survey, 2003-2009. AB - This study was performed to: (1) assess the prevalence of dietary supplement and fortified food use, (2) examine the differences in vitamin E intake with and without dietary supplementation and/or fortified food use, and (3) determine whether some individuals consume vitamin E above the tolerable upper intake level (UL). Data were obtained from 64,624 individuals (age, >=1 y; 47.4% males) who completed a 1-d household dietary assessment that was part of the National Health and Nutrition Survey conducted in Japan, 2003-2009. The survey also obtained information on the brand or generic name of each dietary supplement or fortified food reported, including their ingredients, through dietary assessment. The prevalence of a potential risk of excess was estimated by the proportion of persons above the age-/sex-specific ULs provided by the Dietary Reference Intakes for Japanese 2010. Supplement use was reported by 5.8% of men and 7.7% of women, whereas fortified food consumption was reported by only 2.9% of men and 3.6% of women. Use of dietary supplements was most common among older women, whereas use of fortified foods was most common among younger women. Both dietary supplement and fortified food use accounted for maximum vitamin E intake; however, the use of dietary supplements and fortified foods had little effect on the median and 95th percentile intake values. None of the subjects consumed nutrients above the UL. The collected data confirm that the use of both dietary supplements and fortified foods contributes a small amount to nutrient intake in Japanese subjects. PMID- 24477258 TI - Dietary intake of nutrients with adequate intake values in the dietary reference intakes for Japanese. AB - The Adequate Intake (AI) values in the Dietary Reference Intakes for Japanese (DRIs-J) 2010 were mainly determined based on the median intakes from 2 y of pooled data (2005-2006) from the National Health and Nutrition Survey-Japan (NHNS J). However, it remains unclear whether 2 y of pooled data from the NHNS-J are appropriate for evaluating the intake of the population. To clarify the differences in nutrient intakes determined from 2 and 7 y of pooled data, we analyzed selected nutrient intake levels by sex and age groups using NHNS-J data. Intake data were obtained from 64,624 individuals (age: >=1 y; 47.4% men) who completed a semi-weighed 1-d household dietary record that was part of the NHNS-J conducted annually in Japan from 2003 to 2009. There were no large differences between the median intakes calculated from 2 or 7 y of pooled data for n-6 or n-3 polyunsaturated fatty acids (PUFAs), vitamin D, pantothenic acid, potassium, or phosphorus. When the AI values and median intakes were compared, there was no large difference in the values for n-6 or n-3 PUFAs, pantothenic acid, or phosphorus. Conversely, the AI values for vitamin D and potassium differed from the median intakes of these nutrients for specific sex and age groups, because values were not based on NHNS-J data. Our results indicate that 2 y of pooled data from the NHNS-J adequately reflect the population's intake, and that the current system for determination of AI values will be applicable for future revisions. PMID- 24477259 TI - Swedish nurses' perceptions of influencers on patient advocacy: a phenomenographic study. AB - BACKGROUND: A limited number of studies have shown that patient advocacy can be influenced by both facilitators and barriers which can encourage and discourage nurses to act as patient advocates. OBJECTIVE: This study's aim was to describe Swedish nurses' perceptions of influencers on patient advocacy. RESEARCH DESIGN AND CONTEXT: Interviews with 18 registered nurses from different Swedish clinical contexts were analysed using the phenomenographic method. ETHICAL CONSIDERATIONS: Ethical revisions were made in accordance with national legislation and guidelines by committees for research ethics at Karlstad University. FINDINGS: Three levels of hierarchically related influencers on patient advocacy were found in the descriptive categories. The fundamental influencer, the nurse's character traits, was described in the perceptions that advocacy is influenced by nurse's having a moral compass, having control over the care situation, being protective and feeling secure as a nurse. The second most vital influencer, the nurse's bond with the patient, was expressed in the perceptions of knowing the patient and feeling empathy for the patient. The third level of influencers, the organisational conditions, was described in the perceptions that the organisational structures and organisational culture influence patient advocacy. DISCUSSION: The results correspond with findings from earlier research but add an understanding that influencers on patient advocacy exist at three hierarchically related levels. CONCLUSION: The nurse's character traits are the fundamental influencer to patient advocacy, but in order to be comfortable and secure when advocating for patients, nurses also need to be familiar with both the patient and the situation. A supposition could be that all influencers interact, which needs to be further addressed in future studies. PMID- 24477260 TI - Nurse middle manager ethical dilemmas and moral distress. AB - BACKGROUND: Nurse managers are placed in a unique position within the healthcare system where they greatly impact upon the nursing work environment. Ethical dilemmas and moral distress have been reported for staff nurses but not for nurse middle managers. OBJECTIVE: To describe ethical dilemmas and moral distress among nurse middle managers arising from situations of ethical conflict. METHODS: The Ethical Dilemmas in Nursing-Middle Manager Questionnaire and a personal characteristics questionnaire were administered to a convenience sample of middle managers from four hospitals in Israel. RESULTS: Middle managers report low to moderate levels of frequency and intensity of ethical dilemmas and moral distress. Highest scores were for administrative dilemmas. CONCLUSION: Middle managers experience lower levels of ethical dilemmas and moral distress than staff nurses, which are irrespective of their personal characteristics. Interventions should be developed, studied, and then incorporated into institutional frameworks in order to improve this situation. PMID- 24477261 TI - Precision spectroscopy by photon-recoil signal amplification. AB - Precision spectroscopy of atomic and molecular ions offers a window to new physics, but is typically limited to species with a cycling transition for laser cooling and detection. Quantum logic spectroscopy has overcome this limitation for species with long-lived excited states. Here we extend quantum logic spectroscopy to fast, dipole-allowed transitions and apply it to perform an absolute frequency measurement. We detect the absorption of photons by the spectroscopically investigated ion through the photon recoil imparted on a co trapped ion of a different species, on which we can perform efficient quantum logic detection techniques. This amplifies the recoil signal from a few absorbed photons to thousands of fluorescence photons. We resolve the line centre of a dipole-allowed transition in (40)Ca(+) to 1/300 of its observed linewidth, rendering this measurement one of the most accurate of a broad transition. The simplicity and versatility of this approach enables spectroscopy of many previously inaccessible species. PMID- 24477262 TI - Antidiabetic activity of zinc oxide and silver nanoparticles on streptozotocin induced diabetic rats. AB - The use of nanoparticles in medicine is an attractive proposition. In the present study, zinc oxide and silver nanoparticles were evaluated for their antidiabetic activity. Fifty male albino rats with weight 120 +/- 20 and age 6 months were used. Animals were grouped as follows: control; did not receive any type of treatment, diabetic; received a single intraperitoneal dose of streptozotocin (100 mg/kg), diabetic + zinc oxide nanoparticles (ZnONPs), received single daily oral dose of 10 mg/kg ZnONPs in suspension, diabetic + silver nanoparticles (SNPs); received a single daily oral dose of SNP of 10 mg/kg in suspension and diabetic + insulin; received a single subcutaneous dose of 0.6 units/50 g body weight. Zinc oxide and silver nanoparticles induce a significant reduced blood glucose, higher serum insulin, higher glucokinase activity higher expression level of insulin, insulin receptor, GLUT-2 and glucokinase genes in diabetic rats treated with zinc oxide, silver nanoparticles and insulin. In conclusion, zinc oxide and sliver nanoparticles act as potent antidiabetic agents. PMID- 24477264 TI - A molecular genetic linkage map of Eucommia ulmoides and quantitative trait loci (QTL) analysis for growth traits. AB - Eucommia ulmoides is an economically important tree species for both herbal medicine and organic chemical industry. Effort to breed varieties with improved yield and quality is limited by the lack of knowledge on the genetic basis of the traits. A genetic linkage map of E. ulmoides was constructed from a full-sib family using sequence-related amplified polymorphism, amplified fragment length polymorphism, inter-simple sequence repeat and simple sequence repeat markers. In total, 706 markers were mapped in 25 linkage groups covering 2133 cM. The genetic linkage map covered approximately 89% of the estimated E. ulmoides genome with an average of 3.1 cM between adjacent markers. The present genetic linkage map was used to identify quantitative trait loci (QTL) affecting growth-related traits. Eighteen QTLs were found to explain 12.4%-33.3% of the phenotypic variance. This genetic linkage map provides a tool for marker-assisted selection and for studies of genome in E. ulmoides. PMID- 24477266 TI - Abstracts - XIX Symposium Neuroradiologicum. The World Congress of Diagnostic & Therapeutic Neuroradiology - Bologna, Italy, 4-9 October 2010. PMID- 24477265 TI - Cellular behavior of human adipose-derived stem cells on wettable gradient polyethylene surfaces. AB - Appropriate surface wettability and roughness of biomaterials is an important factor in cell attachment and proliferation. In this study, we investigated the correlation between surface wettability and roughness, and biological response in human adipose-derived stem cells (hADSCs). We prepared wettable and rough gradient polyethylene (PE) surfaces by increasing the power of a radio frequency corona discharge apparatus with knife-type electrodes over a moving sample bed. The PE changed gradually from hydrophobic and smooth surfaces to hydrophilic (water contact angle, 90 degrees to ~ 50 degrees ) and rough (80 to ~120 nm) surfaces as the power increased. We found that hADSCs adhered better to highly hydrophilic and rough surfaces and showed broadly stretched morphology compared with that on hydrophobic and smooth surfaces. The proliferation of hADSCs on hydrophilic and rough surfaces was also higher than that on hydrophobic and smooth surfaces. Furthermore, integrin beta 1 gene expression, an indicator of attachment, and heat shock protein 70 gene expression were high on hydrophobic and smooth surfaces. These results indicate that the cellular behavior of hADSCs on gradient surface depends on surface properties, wettability and roughness. PMID- 24477263 TI - Adenosine receptors: expression, function and regulation. AB - Adenosine receptors (ARs) comprise a group of G protein-coupled receptors (GPCR) which mediate the physiological actions of adenosine. To date, four AR subtypes have been cloned and identified in different tissues. These receptors have distinct localization, signal transduction pathways and different means of regulation upon exposure to agonists. This review will describe the biochemical characteristics and signaling cascade associated with each receptor and provide insight into how these receptors are regulated in response to agonists. A key property of some of these receptors is their ability to serve as sensors of cellular oxidative stress, which is transmitted by transcription factors, such as nuclear factor (NF)-kappaB, to regulate the expression of ARs. Recent observations of oligomerization of these receptors into homo- and heterodimers will be discussed. In addition, the importance of these receptors in the regulation of normal and pathological processes such as sleep, the development of cancers and in protection against hearing loss will be examined. PMID- 24477267 TI - Anatomic variants of arteries often coil-occluded prior to hepatic radioembolization. AB - BACKGROUND: Prior to radioembolization (RE) treatment of malignant liver lesions, many interventionalists occlude the right gastric artery (RGA), the cystic artery (CA), and the gastroduodenal artery (GDA) to prevent radioactive microspheres from entering non-target vessels. PURPOSE: To systematically analyze anatomic variants of arteries that are important to know for the interventional radiologist performing RE of the liver. MATERIAL AND METHODS: The computed tomography (CT) angiographies and conventional angiographies of 166 patients evaluated for RE were retrospectively analyzed for the presence of anatomic variants of the RGA, GDA, and CA. RESULTS: The RGA was found to arise from the left hepatic artery in 42% of cases, from the proper hepatic artery in 40%, from the GDA in 10%, from the right hepatic artery in 4%, and from the common hepatic artery in 3% of cases. The GDA originated in the common hepatic artery in 97% of cases, in the left hepatic artery in 2%, and in the celiac trunk in 1% of cases. The CA arose from the right hepatic artery in 96% of cases and from the GDA in 2% of cases; in 2% of our study population, the gallbladder was supplied by small branches from the liver parenchyma. CONCLUSION: Variant anatomy of the RGA is common, while it is quite rare for the GDA and CA. Knowledge of the variations of liver supplying arteries helps the interventionalist to embolize necessary vessels prior to RE. PMID- 24477268 TI - Estimation of proliferative potentiality of central neurocytoma: correlational analysis of minimum ADC and maximum SUV with MIB-1 labeling index. AB - BACKGROUND: Central neurocytoma was initially believed to be benign tumor type, although atypical cases with more aggressive behavior have been reported. Preoperative estimation for proliferating activity of central neurocytoma is one of the most important considerations for determining tumor management. PURPOSE: To investigate predictive values of image characteristics and quantitative measurements of minimum apparent diffusion coefficient (ADCmin) and maximum standardized uptake value (SUVmax) for proliferative activity of central neurocytoma measured by MIB-1 labeling index (LI). MATERIAL AND METHODS: Twelve cases of central neurocytoma including one recurrence from January 2001 to December 2011 were included. Preoperative scans were conducted in 11, nine, and five patients for computed tomography (CT), diffusion-weighted imaging (DWI), and fluorine-18-fluorodeoxyglucose positron emission tomography (FDG-PET), respectively, and ADCmin and SUVmax of the tumors were measured. Image characteristics were investigated using CT, T2-weighted (T2W) imaging and contrast-enhanced T1-weighted (T1W) imaging, and their differences were examined using the Fisher's exact test between cases with MIB-1 LI below and above 2%, which is recognized as typical and atypical central neurocytoma, respectively. Correlational analysis was conducted for ADCmin and SUVmax with MIB-1 LI. A P value <0.05 was considered significant. RESULTS: Morphological appearances had large variety, and there was no significant correlation with MIB-1 LI except a tendency that strong enhancement was observed in central neurocytomas with higher MIB-1 LI (P = 0.061). High linearity with MIB-1 LI was observed in ADCmin and SUVmax (r = -0.91 and 0.74, respectively), but only ADCmin was statistically significant (P = 0.0006). CONCLUSION: Central neurocytoma had a wide variety of image appearance, and assessment of proliferative potential was considered difficult only by morphological aspects. ADCmin was recognized as a potential marker for differentiation of atypical central neurocytomas from the typical ones. PMID- 24477269 TI - The association of chronic obstructive pulmonary disease, disability, engagement in social activities, and mortality among US adults aged 70 years or older, 1994 2006. AB - PURPOSE: To assess associations among chronic obstructive pulmonary disease (COPD), disability as measured by activities of daily living (ADL) and instrumental ADL (IADL), engagement in social activities, and death among elderly noninstitutionalized US residents. MATERIALS AND METHODS: A nationally representative sample of 9,415 adults who were aged >=70 years and responded to the Second Supplement on Aging survey in 1994-1996 and mortality follow-up study through 2006 were assessed. Multiple logistic regression analyses were performed to assess the risk of all-cause mortality in participants with COPD after accounting for age, sex, race/ethnicity, and smoking status. RESULTS: At baseline, approximately 9.6% of study participants reported having COPD. Compared with participants without COPD, those with COPD were significantly more likely (P<0.05) to have difficulty with at least one ADL (44.3% versus [vs] 27.5%) and with at least one IADL (59.9% vs 40.2%), significantly less likely to be engaged in social activities (32.6% vs 26.3%), and significantly more likely to die by 2006 (70.7% vs 60.4%; adjusted risk ratio 1.15, P<0.05). The association between COPD and risk for death was moderately attenuated by disability status. CONCLUSION: COPD is positively associated with disability and mortality risk among US adults aged >=70 years. The significant relationship between COPD and mortality risk was moderately attenuated, but was not completely explained by stages of ADL and IADL limitations and social activities. PMID- 24477271 TI - Time spent by people managing chronic obstructive pulmonary disease indicates biographical disruption. AB - Since Bury's 1982 proposal that chronic illness creates biographical disruption for those who are living with it, there has been no effort to quantitatively measure such disruption. "Biographical disruption" refers to the substantial and directive influence that chronic illness can have over the course of a person's life. Qualitative research and time use studies have demonstrated that people with chronic illnesses spend considerable amounts of time managing their health, and that these demands may change over time. This study was designed to measure the time that older people with chronic illnesses spend on selected health practices as one indicator of biographical disruption. We look specifically at the time use of people with chronic obstructive pulmonary disease (COPD). As part of a larger time use survey, a recall questionnaire was mailed to 3,100 members of Lung Foundation Australia in 2011. A total of 681 responses were received (22.0% response rate), 611 of which were from people with COPD. Descriptive analyses were undertaken on the amount of time spent on selected health-related activities including personal care, nonclinical health-related care, and activity relating to health services. Almost all people with COPD report spending some time each day on personal or home-based health-related tasks, with a median time of 15 minutes per day spent on these activities. At the median, people also report spending about 30 minutes per day exercising, 2.2 hours per month (the equivalent of 4.4 minutes per day) on nonclinical health-related activities, and 4.1 hours per month (equivalent to 8.2 minutes per day) on clinical activities. Excluding exercise, the median total time spent on health-related activities was 17.8 hours per month (or 35.6 minutes per day). For people in the top 10% of time use, the total amount of time was more than 64.6 hours per month (or 2.2 hours per day) excluding exercise, and 104 hours per month (or 3.5 hours per day) including exercise. The amount of time spent on health-related activity, such as engaging in personal care tasks, may be regular and predictable. The execution of these tasks generally takes relatively small amounts of time, and might be incorporated into daily life (biography) without causing significant disruption. Other activities may require large blocks of time, and they may be disruptive in a practical way that almost inevitably disrupts biography. The amount of time required does not appear to alter in relation to the time since diagnosis. The scale of time needed to manage one's health could easily be interpreted as disruptive, and for some people, even overwhelming. PMID- 24477272 TI - Factors associated with a prolonged length of stay after acute exacerbation of chronic obstructive pulmonary disease (AECOPD). AB - BACKGROUND: Early identification of patients with a prolonged stay due to acute exacerbation of chronic obstructive pulmonary disease (COPD) may reduce risk of adverse event and treatment costs. This study aimed to identify predictors of prolonged stay after acute exacerbation of COPD based on variables on admission; the study also looked to establish a prediction model for length of stay (LOS). METHODS: We extracted demographic and clinical data from the medical records of 599 patients discharged after an acute exacerbation of COPD between March 2006 and December 2008 at Oslo University Hospital, Aker. We used logistic regression analyses to assess predictors of a length of stay above the 75th percentile and assessed the area under the receiving operating characteristic curve to evaluate the model's performance. RESULTS: We included 590 patients (54% women) aged 73.2+/-10.8 years (mean +/- standard deviation) in the analyses. Median LOS was 6.0 days (interquartile range [IQR] 3.5-11.0). In multivariate analysis, admission between Thursday and Saturday (odds ratio [OR] 2.24 [95% CI 1.60-3.51], P<0.001), heart failure (OR 2.26, 95% CI 1.34-3.80), diabetes (OR 1.90, 95% CI 1.07-3.37), stroke (OR 1.83, 95% CI 1.04-3.21), high arterial PCO2 (OR 1.26 [95% CI 1.13-1.41], P<0.001), and low serum albumin level (OR 0.92 [95% CI 0.87-0.97], P=0.001) were associated with a LOS >11 days. The statistical model had an area under the receiver operating characteristic curve of 0.73. CONCLUSION: Admission between Thursday and Saturday, heart failure, diabetes, stroke, high arterial PCO2, and low serum albumin level were associated with a prolonged LOS. These findings may help physicians to identify patients that will need a prolonged LOS in the early stages of admission. However, the predictive model exhibited suboptimal performance and hence is not ready for clinical use. PMID- 24477273 TI - Sequential stereodivergent organocatalysis and programmed organocascades. AB - Asymmetric organocatalysis has attracted great interest as a synthetic strategy during the past decade. But, although the inertness of organocatalysts to moisture and oxygen offers great opportunities to tune the reaction conditions, the stereoswitchable character of organocatalysts has not been systematically studied, and most findings have been serendipitous. In this Perspective, we emphasize the importance of in situ tunability in dynamic asymmetric organocatalysis for obtaining different functional outcomes with single-flask operation. PMID- 24477274 TI - Phosphatidylserine exposure, microparticle formation and mitochondrial depolarisation in Glanzmann thrombasthenia platelets. PMID- 24477275 TI - Health-related claims on food labels in Australia: understanding environmental health officers' roles and implications for policy. AB - OBJECTIVE: Health and related claims on food labels can support consumer education initiatives that encourage purchase of healthier foods. A new food Standard on Nutrition, Health and Related Claims became law in January 2013. Implementation will need careful monitoring and enforcement to ensure that claims are truthful and have meaning. The current study explored factors that may impact on environmental health officers' food labelling policy enforcement practices. DESIGN: The study used a mixed-methods approach, using two previously validated quantitative questionnaire instruments that provided measures of the level of control that the officers exercised over their work, as well as qualitative, semi structured, in-depth interviews. SETTING: Local government; Australia. SUBJECTS: Thirty-seven officers in three Australian states participated in semi-structured in-depth interviews, as well as completing the quantitative questionnaires. Senior and junior officers, including field officers, participated in the study. RESULTS: The officers reported a high level of autonomy and control of their work, but also a heavy workload, dominated by concerns for public health and food safety, with limited time for monitoring food labels. Compliance of labels with proposed health claims regulations was not considered a priority. Lipsky's theory of street-level bureaucracy was used to enhance understanding of officers' work practices. CONCLUSIONS: Competing priorities affect environmental health officers' monitoring and enforcement of regulations. Understanding officers' work practices and their perceptions of enforcement is important to increase effectiveness of policy implementation and hence its capacity to augment education initiatives to optimize health benefits. PMID- 24477276 TI - Combined TSC1 and LMX1B mutations in a single patient. AB - Tuberous sclerosis complex (TSC) and nail-patella syndrome (NPS) are autosomal dominant pleiotropic disorders with full penetrance that can both involve kidneys. TSC1 and NPS genes are located on chromosome 9q3. In a large family with the two disorders with two novel frameshift TSC1 and LMX1B mutations, we describe the phenotypes. The father, who has both disorders, has passed on TSC to three of his children, NPS to another three, and both TSC and NPS to one child. Patients carrying both mutations appear to show an additive phenotype and no obvious epistatic effects. The segregation of two dominant disorders in this family poses a challenge for genetic counseling and indicates the importance of a careful clinical and molecular evaluation for accurate risk assessment. PMID- 24477277 TI - Long-term follow-up in Stuve-Wiedemann syndrome: a case report with articular involvement. PMID- 24477279 TI - Deciphering the infrared spectrum of the protonated water pentamer and the hybrid Eigen-Zundel cation. AB - Traditionally, infrared band assignment for the protonated water clusters, such as H(+)(H2O)5, is based on their lowest energy isomer. Recent experiments extend the observation spectral window to lower frequencies, for which such assignment appears to be inadequate. Because this hydrogen-bonded system is highly anharmonic, harmonic spectral calculations are insufficient for reliable interpretation. Consequently, we have calculated the IR spectrum of several isomers of the protonated water pentamer using an inherently anharmonic methodology, utilizing dipole and velocity autocorrelation functions computed from ab initio molecular dynamic trajectories. While the spectrum of H(+)(H2O)5 is universally assumed to represent the branched Eigen isomer, we find a better agreement for a mixture of a ring and linear isomers. The first has an Eigen core and contributes at high frequencies, whereas the latter accounts for all prominent low-frequency bands. Interestingly, its core is neither a classical Eigen nor a Zundel cation, but rather has hybrid geometry. Such an isomer may play a role in proton conductance along short proton wires. PMID- 24477278 TI - International prevalence of indoor tanning: a systematic review and meta analysis. AB - IMPORTANCE: Indoor tanning is a known carcinogen, but the scope of exposure to this hazard is not known. OBJECTIVE: To summarize the international prevalence of exposure to indoor tanning. DATA SOURCES: Studies were identified through systematic searches of PubMed (1966 to present), Scopus (1823 to present), and Web of Science (1898 to present) databases, last performed on March 16, 2013. We also hand searched reference lists to identify records missed by database searches and publicly available data not yet published in the scientific literature. STUDY SELECTION: Records reporting a prevalence of indoor tanning were eligible for inclusion. We excluded case-control studies, reports with insufficient study information, and reports of groups recruited using factors related to indoor tanning. Two independent investigators performed searches and study selection. Our search yielded 1976 unique records. After exclusions, 161 records were assessed for eligibility in full text, and 88 were included. DATA EXTRACTION AND SYNTHESIS: Two independent investigators extracted data on characteristics of study participants, inclusion/exclusion criteria, data collection format, outcomes, and statistical methods. Random-effects meta analyses were used to summarize the prevalence of indoor tanning in different age categories. We calculated the population proportional attributable risk of indoor tanning in the United States, Europe, and Australia for nonmelanoma skin cancer (NMSC) and melanoma. MAIN OUTCOMES AND MEASURES: Ever and past-year exposure to indoor tanning. RESULTS: The summary prevalence of ever exposure was 35.7% (95% CI, 27.5%-44.0%) for adults, 55.0% (33.0%-77.1%) for university students, and 19.3% (14.7%-24.0%) for adolescents. The summary prevalence of past-year exposure was 14.0% (95% CI, 11.5%-16.5%) for adults, 43.1% (21.7%-64.5%) for university students, and 18.3% (12.6%-24.0%) for adolescents. These results included data from 406 696 participants. The population proportional attributable risk were 3.0% to 21.8% for NMSC and 2.6% to 9.4% for melanoma, corresponding to more than 450 000 NMSC cases and more than 10 000 melanoma cases each year attributable to indoor tanning in the United States, Europe, and Australia. CONCLUSIONS AND RELEVANCE: Exposure to indoor tanning is common in Western countries, especially among young persons. Given the large number of skin cancer cases attributable to indoor tanning, these findings highlight a major public health issue. PMID- 24477280 TI - Optical tweezers reveal force plateau and internal friction in PEG-induced DNA condensation. AB - The simplified artificial environments in which highly complex biological systems are studied do not represent the crowded, dense, salty, and dynamic environment inside the living cell. Consequently, it is important to investigate the effect of crowding agents on DNA. We used a dual-trap optical tweezers instrument to perform force spectroscopy experiments at pull speeds ranging from 0.3 to 270 MUm/s on single dsDNA molecules in the presence of poly(ethylene glycol) (PEG) and monovalent salt. PEG of sizes 1,500 and 4,000 Da condensed DNA, and force extension data contained a force plateau at approximately 1 pN. The level of the force plateau increased with increasing pull speed. During slow pulling the dissipated work increased linearly with pull speed. The calculated friction coefficient did not depend on amount of DNA incorporated in the condensate, indicating internal friction is independent of the condensate size. PEG300 had no effect on the dsDNA force-extension curve. The force plateau implies that condensation induced by crowding agents resembles condensation induced by multivalent cations. PMID- 24477281 TI - Fundamental chemistry of iodine. The reaction of di-iodine towards thiourea and its methyl-derivative: formation of aminothiazoles and aminothiadiazoles through dicationic disulfides. AB - The reactivity of di-iodine towards thiourea (TU) and its derivative methylthiourea (MeTU) was studied. A diversity of products was obtained from these reactions. TU reacted with di-iodine in the absence or presence of hydroiodic or hydrochloric acids in a 1 : 1, 1 : 1 : 1 or 1 : 1 : 2 (TU : I2 : HX (X = I, Cl)) molar ratio to form the ionic compounds [(TU2)(2+)2(I(-)).H2O] (1), [2(TU2) (2+).(Cl(-)).2(I(-)).(I3(-))] (2) and [(TUH)(+) (I3(-))] (3). The compounds [(TU2)(2+)(Br(-))(I3(-))] (4) and [(TU2)(2+)2(Br(-)).H2O] (5) were derived from the reactions of TU with di-iodine in the presence of hydrobromic acid in a 1 : 1 : 1 or 1 : 2 : 1 (TU : I2 : HBr) molar ratio. However, when the product of the reaction between TU and di-iodine in a 2 : 1 (TU : I2) molar ratio was crystallized in acetone-ethylether media the ionic salt of formula [(DAThdH(+))(I(-))] (6) (DAThd = 3,5-diamino-1,2,4-thiadiazole) was obtained. Methylthiourea (MeTU) reacted with di-iodine in the presence of hydrobromic acid (1 : 1 : 1, MeTU : I2 : HBr) in dichloromethane to form a solid product which gives [2(MeTU2) (2+).(2Br(-))(I4(2-))] (7). Moreover, MeTU reacted with I2 in 2 : 1 (MeTU : I2) to form an intermediate powder product which was crystallized in acetone to give the 2-amino-3,4-dimethylthiazolium cation in [(DMeAThH(+))(I( ))(H2O)] (8). Upon changing the crystallization medium to ethanol, instead of acetone, the cationic 5-amino-3-methylamino-4-methyl-1,2,4-thiadiazolium (AMeAThdH)(+) in [(AMeAThdH(+))(I3(-))] (9) was formed. The compounds were characterized by m.p., FT-IR, UV-Vis, (1)H-NMR spectroscopy and mass spectrometry. The crystal structures of compounds 1-9 were determined by X-ray crystallography. PMID- 24477282 TI - Newborn screening for guanidinoacetate methyl transferase deficiency. PMID- 24477283 TI - Isolation and characterization of anti-adenoviral secondary metabolites from marine actinobacteria. AB - Adenovirus infections in immunocompromised patients are associated with high mortality rates. Currently, there are no effective anti-adenoviral therapies available. It is well known that actinobacteria can produce secondary metabolites that are attractive in drug discovery due to their structural diversity and their evolved interaction with biomolecules. Here, we have established an extract library derived from actinobacteria isolated from Vestfjorden, Norway, and performed a screening campaign to discover anti-adenoviral compounds. One extract with anti-adenoviral activity was found to contain a diastereomeric 1:1 mixture of the butenolide secondary alcohols 1a and 1b. By further cultivation and analysis, we could isolate 1a and 1b in different diastereomeric ratio. In addition, three more anti-adenoviral butenolides 2, 3 and 4 with differences in their side-chains were isolated. In this study, the anti-adenoviral activity of these compounds was characterized and substantial differences in the cytotoxic potential between the butenolide analogs were observed. The most potent butenolide analog 3 displayed an EC50 value of 91 MUM and no prominent cytotoxicity at 2 mM. Furthermore, we propose a biosynthetic pathway for these compounds based on their relative time of appearance and structure. PMID- 24477284 TI - Antibacterial and antibiofilm activities of tryptoquivalines and meroditerpenes isolated from the marine-derived fungi Neosartorya paulistensis, N. laciniosa, N. tsunodae, and the soil fungi N. fischeri and N. siamensis. AB - A new meroditerpene, sartorypyrone C (5), was isolated, together with the known tryptoquivalines L (1a), H (1b), F (1c), 3'-(4-oxoquinazolin-3-yl) spiro [1H indole-3,5']-2,2'-dione (2) and 4(3H)-quinazolinone (3), from the culture of the marine sponge-associated fungus Neosartorya paulistensis (KUFC 7897), while reexamination of the fractions remaining from a previous study of the culture of the diseased coral-derived fungus N. laciniosa (KUFC 7896) led to isolation of a new tryptoquivaline derivative tryptoquivaline T (1d). Compounds 1a-d, 2, 3, and 5, together with aszonapyrones A (4a) and B (4b), chevalones B (6) and C (7a), sartorypyrones B (7b) and A (8), were tested for their antibacterial activity against four reference strains (Staphylococcus aureus, Bacillus subtilis, Escherichia coli, and Pseudomonas aeruginosa), as well as the environmental multidrug-resistant isolates. Only aszonapyrone A (4a) and sartorypyrone A (8) exhibited significant antibacterial activity as well as synergism with antibiotics against the Gram-positive multidrug-resistant strains. Antibiofilm assays of aszonapyrone A (4a) and sartorypyrone A (8) showed that practically no biofilm was formed in the presence of their 2* MIC and MIC. However, the presence of a sub-inhibitory concentration of 1/2 MIC of 4a and 8 was found to increase the biofilm production in both reference strain and the multidrug-resistant isolates of S. aureus. PMID- 24477285 TI - Bioactive cembranoids, sarcocrassocolides P-R, from the Dongsha Atoll soft coral Sarcophyton crassocaule. AB - New cembranoids, sarcocrassocolides P-R (1-3) and four known compounds (4-7) were isolated from the soft coral Sarcophyton crassocaule. The structures of the metabolites were determined by extensive spectroscopic analysis. Compounds 3-5 and 7 were shown to exhibit cytotoxicity toward a limited panel of cancer cell lines and all compounds 1-7 displayed potent in vitro anti-inflammatory activity in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophage cells by inhibiting the expression of inducible nitric oxide synthase (iNOS) protein. Compound 7 also showed significant activity in reducing the accumulation of cyclooxygenase-2 (COX 2) protein in the same macrophage cells. PMID- 24477287 TI - An economic analysis of aseptic revision hip arthroplasty: calculation of partial hospital costs in relation to reimbursement. AB - INTRODUCTION: Aseptic loosening is one of the most common intermediate and long term complications after total hip replacement (THR). These complications cause suffering and require expensive revision surgery. Little concrete data on direct costs are available from the hospital's, moreover operating department's perspective. We here provide a detailed analysis of the costs of THR revision and relate them to reimbursement underlying the German diagnosis-related groups (DRG) system. MATERIALS AND METHODS: Major cost parameters were identified using for orientation the cost matrix of the German Institute for Hospital Reimbursement (InEK GmbH). We then retrospectively analysed the major direct costs of aseptic revision THR in terms of contribution margins I and II. The analysis included a total of 114 patients who underwent aseptic revision from 1 January 2009 to 31 March 2012. Data were retrieved from the hospital information system and patient records. All costs of surgery, diagnostic tests, and other treatments were calculated as purchase prices in EUR. The comparative analysis of direct costs and reimbursements was done for DRG I46A and I46B from the hospital's, especially treating department's rather than the society or healthcare insurance's perspective. RESULTS: The average direct cost incurred by the hospital for a THR revision was 4,380.0. The largest share was accounted for surgical costs (62.7 % of total). Implant and staff costs were identified as the most important factors that can be influenced. The proportion of the daily contribution margin that was left to cover the hospital's indirect cost decreased with the relative cost weight of the DRG to which a patient was assigned. CONCLUSION: Our study for the first time provides a detailed analysis of the major direct case costs of THR revision for aseptic loosening from the provider's perspective. Our findings suggest that these revision operations could be performed cost-beneficially by the operating unit. From an economic perspective, cases with higher cost weights are more favorable for a hospital. These results need to be confirmed in multicenter studies. PMID- 24477288 TI - Three-dimensional imaging of children with severe limitation of pronation/supination after a both-bone forearm fracture. AB - INTRODUCTION: Although both-bone forearm fractures in children may result in severe limitation of forearm rotation, finding the cause remains a diagnostic challenge. This study tries to evaluate the role of rotational malunion, bony impingement and contractures of the interosseous membrane. PATIENTS AND METHODS: Children (5-16 years) who suffered from a both-bone forearm fracture in diaphysis or distal metaphysis with a limitation of pronation/supination >=40 degrees at >=6 months after trauma were included for analysis with conventional radiographs, computed tomography (CT) and magnetic resonance imaging (MRI). RESULTS: A total of 410 children with a both-bone forearm fracture were prospectively followed in four Dutch hospitals. At a median of 205 days, 7.3 % suffered from a limitation of pronation/supination >=40 degrees . 14 children were included (median limitation of 40 degrees ) and the radiographs revealed a median maximum angular malunion of 16 degrees . CT analysis showed rotational malunion of both radius (median 19 degrees ) and ulna (median 9 degrees ). MRI analysis revealed neither bony impingement nor contractures of the interosseous membrane. CONCLUSIONS: Three-dimensional imaging of children with a severe limitation of pronation/supination after a both-bone forearm fracture revealed rotational malunions of both radius and ulna without bony impingement or soft tissue contractures. LEVEL OF EVIDENCE: Prospective multicenter study, Level 2. PMID- 24477286 TI - Fucoidan as a marine anticancer agent in preclinical development. AB - Fucoidan is a fucose-containing sulfated polysaccharide derived from brown seaweeds, crude extracts of which are commercially available as nutritional supplements. Recent studies have demonstrated antiproliferative, antiangiogenic, and anticancer properties of fucoidan in vitro. Accordingly, the anticancer effects of fucoidan have been shown to vary depending on its structure, while it can target multiple receptors or signaling molecules in various cell types, including tumor cells and immune cells. Low toxicity and the in vitro effects of fucoidan mentioned above make it a suitable agent for cancer prevention or treatment. However, preclinical development of natural marine products requires in vivo examination of purified compounds in animal tumor models. This review discusses the effects of systemic and local administration of fucoidan on tumor growth, angiogenesis, and immune reaction and whether in vivo and in vitro results are likely applicable to the development of fucoidan as a marine anticancer drug. PMID- 24477289 TI - Allograft ligament transplantation in anterior cruciate ligament reconstruction patients with meniscal tears. AB - BACKGROUND: It currently remains unclear whether the meniscal repair clinical results were affected by the graft used in anterior cruciate ligament (ACL) reconstruction. This retrospective study designed to evaluate the difference in clinical outcomes of meniscal repair using autograft and allograft for the ACL reconstruction. METHODS: The injury of the ACL and meniscus was evaluated with MRI and treated simultaneously. One hundred and eighty-nine cases were initially fulfilled the study criteria, and had the surgery in the period June 2007 and July 2010. Thirty-four patients were lost to follow-up. Seventy-five patients underwent meniscus repair with autograft reconstruction of the ACL (autograft group) and 80 patients underwent meniscus repair with allograft reconstruction of the ACL (allograft group). RESULTS: The meniscus healing rate based on the clinical examination of Barrett's criteria was 81.3 % (61/75) in the autograft group and 80.0 % (64/80) in the allograft (P > 0.05). There was no significant difference in the Lysholm scores in the allograft group compared to the allograft group (89.1 +/- 10.6 versus 88.7 +/- 11.2, P > 0.05). The values of immunoglobulin's and complements (IgG, IgA, IgM, C3 and C4) were not significantly different between the two groups (P > 0.05). CONCLUSION: The data support our assumption that patients undergoing meniscal repair associated with ACL reconstruction with allograft had good clinical outcomes. Although allograft implantation induces an immunological response on a subclinical level, there were no signs of allograft affecting the nature of meniscus healing. PMID- 24477290 TI - Low inter- and intraobserver variability allows for reliable tunnel measurement in ACL reconstruction using the quadrant method. AB - INTRODUCTION: Correct anatomic tunnel positions are essential in anterior cruciate ligament (ACL) reconstruction. To establish recommendations for tunnel positioning based on anatomical findings and to compare tunnel positions with clinical results, different radiological measurement methods as the quadrant method exist. Comparing the data of different observers requires the validation of the reliability of measurement methods. The purpose of this study therefore was to determine the reliability of the quadrant method to measure tunnel positions in ACL reconstruction. The hypothesis was, that the quadrant method shows a low inter- and intraobserver variability. MATERIALS AND METHODS: In a test/retest scenario 20 knee surgeons were asked to determine defined tunnel positions in five lateral radiographs applying the quadrant method. Rotation, angle deviation, height and depth of the quadrant as well as absolute and relative tunnel positions of each observation were measured along referenced scales. Mean sizes and angle deviations of the quadrants, tunnel positions and deviations between the test/retest positions were calculated as well as standard deviations and range. RESULTS: Interobserver variability analyses, to plan as well as to determine tunnel positions in ACL reconstruction, showed a mean variability (SD) of <1 mm, with ranges of 2.5 mm for planning and 3.7 mm for determination of tunnel positions using the quadrant method. Intraobserver analysis showed mean variability with deviations of <1 mm and maximum standard deviations of 0.7 mm and ranges of up to 2.3 mm. CONCLUSIONS: We confirmed the hypothesis that the quadrant method has a low inter- and intraobserver variability. Based on the presented validation data, the quadrant method can be recommended as reliable method to radiographically describe insertion areas of the ACL as well as to determine tunnel positions in ACL reconstruction intra and postoperatively. PMID- 24477291 TI - Second-look arthroscopy after surgical treatment of Schatzker type II plateau fractures through the lateral submeniscal approach. AB - MAIN PROBLEM: To evaluate cartilage healing using second-look arthroscopic examination in tibia plateau fracture patients who have undergone open reduction and internal fixation with a submeniscal approach technique. METHODS: Between January 2007 and January 2010, we used second-look arthroscopy during 18-24-month follow-up of 20 patients with Schatzkar type II tibial plateau fractures who had undergone open reduction and internal fixation with a submeniscal approach technique. We classified patients according to step-off, knee range of motion, and Knee Society Score, and compared the results with those obtained by arthroscopy. RESULTS: Radiologically, 16 cases (80 %) were reduced within 2 mm of step-off. In 11 of these cases, according to the Outerbridge classification, we checked for chondromalacia from grade II to III. We observed 2 mm of step-off in four cases, and each had chondromalacia of at least grade III. The Knee Society Score was associated with chondromalacia grade (p < 0.05). CONCLUSION: Even in patients with normal joint range of motion and good clinical and radiological results, the actual condition of the articular cartilage varied significantly. Therefore, more long-term and regular follow-up is needed for proximal plateau fractures. PMID- 24477293 TI - Oxenoids in organic synthesis. AB - Experimental and theoretical studies of metalated peroxides confirmed their unique properties as oxenoids (electrophilic oxidants) allowing for a highly selective and efficient oxidation processes of nucleophilic organometallic species. In this short review we present the most prominent examples of the application of this class of reagents towards organic synthesis. PMID- 24477292 TI - p85alpha recruitment by the CD300f phosphatidylserine receptor mediates apoptotic cell clearance required for autoimmunity suppression. AB - Apoptotic cell (AC) clearance is essential for immune homeostasis. Here we show that mouse CD300f (CLM-1) recognizes outer membrane-exposed phosphatidylserine, and regulates the phagocytosis of ACs. CD300f accumulates in phagocytic cups at AC contact sites. Phosphorylation within CD300f cytoplasmic tail tyrosine-based motifs initiates signals that positively or negatively regulate AC phagocytosis. Y276 phosphorylation is necessary for enhanced CD300f-mediated phagocytosis through the recruitment of the p85alpha regulatory subunit of phosphatidylinositol-3-kinase (PI3K). CD300f-PI3K association leads to activation of downstream Rac/Cdc42 GTPase and mediates changes of F-actin that drive AC engulfment. Importantly, primary macrophages from CD300f-deficient mice have impaired phagocytosis of ACs. The biological consequence of CD300f deficiency is predisposition to autoimmune disease development, as FcgammaRIIB-deficient mice develop a systemic lupus erythematosus-like disease at a markedly accelerated rate if CD300f is absent. In this report we identify the mechanism and role of CD300f in AC phagocytosis and maintenance of immune homeostasis. PMID- 24477294 TI - RGN matters: celebrating milestones. PMID- 24477295 TI - Efforts to promote physical activity must battle ageist stereotypes. PMID- 24477296 TI - Measurement of quality of life outcomes. PMID- 24477298 TI - Dietary protein distribution positively influences 24-h muscle protein synthesis in healthy adults. AB - The RDA for protein describes the quantity that should be consumed daily to meet population needs and to prevent deficiency. Protein consumption in many countries exceeds the RDA; however, intake is often skewed toward the evening meal, whereas breakfast is typically carbohydrate rich and low in protein. We examined the effects of protein distribution on 24-h skeletal muscle protein synthesis in healthy adult men and women (n = 8; age: 36.9 +/- 3.1 y; BMI: 25.7 +/- 0.8 kg/m2). By using a 7-d crossover feeding design with a 30-d washout period, we measured changes in muscle protein synthesis in response to isoenergetic and isonitrogenous diets with protein at breakfast, lunch, and dinner distributed evenly (EVEN; 31.5 +/- 1.3, 29.9 +/- 1.6, and 32.7 +/- 1.6 g protein, respectively) or skewed (SKEW; 10.7 +/- 0.8, 16.0 +/- 0.5, and 63.4 +/- 3.7 g protein, respectively). Over 24-h periods on days 1 and 7, venous blood samples and vastus lateralis muscle biopsy samples were obtained during primed (2.0 MUmol/kg) constant infusion [0.06 MUmol/(kg?min)] of l-[ring (13)C6]phenylalanine. The 24-h mixed muscle protein fractional synthesis rate was 25% higher in the EVEN (0.075 +/- 0.006%/h) vs. the SKEW (0.056 +/- 0.006%/h) protein distribution groups (P = 0.003). This pattern was maintained after 7 d of habituation to each diet (EVEN vs. SKEW: 0.077 +/- 0.006 vs. 0.056 +/- 0.006%/h; P = 0.001). The consumption of a moderate amount of protein at each meal stimulated 24-h muscle protein synthesis more effectively than skewing protein intake toward the evening meal. PMID- 24477299 TI - Urinary isoxanthohumol is a specific and accurate biomarker of beer consumption. AB - Biomarkers of food consumption are a powerful tool to obtain more objective measurements of dietary exposure and to monitor compliance in clinical trials. In this study, we evaluated the effectiveness of urinary isoxanthohumol (IX) excretion as an accurate biomarker of beer consumption. A dose-response clinical trial, a randomized, crossover clinical trial, and a cohort study were performed. In the dose-response trial, 41 young volunteers (males and females, aged 28 +/- 3 y) consumed different doses of beer at night and a spot urine sample was collected the following morning. In the clinical trial, 33 males with high cardiovascular risk (aged 61 +/- 7 y) randomly were administered 30 g of ethanol/d as gin or beer, or an equivalent amount of polyphenols as nonalcoholic beer for 4 wk. Additionally, a subsample of 46 volunteers from the PREDIMED (Prevenciomicronn con Dieta Mediterranea) study (males and females, aged 63 +/- 5 y) was also evaluated. Prenylflavonoids were quantified in urine samples by liquid chromatography coupled to mass spectrometry. IX urinary recovery increased linearly with the size of the beer dose in male volunteers. A significant increase in IX excretion (4.0 +/- 1.6 MUg/g creatinine) was found after consumption of beer and nonalcoholic beer for 4 wk (P < 0.001). Receiver operating characteristic curves showed that IX is able to discriminate between beer consumers and abstainers with a sensitivity of 67% and specificity of 100% (positive predictive value = 70%, negative predictive value = 100% in real-life conditions). IX in urine samples was found to be a specific and accurate biomarker of beer consumption and may be a powerful tool in epidemiologic studies. PMID- 24477300 TI - DNA methylation patterns are associated with n-3 fatty acid intake in Yup'ik people. AB - A large body of evidence links a high dietary intake of n-3 (omega-3) polyunsaturated fatty acids (PUFAs) with improved cardiometabolic outcomes. Recent studies suggested that the biologic processes underlying the observed associations may involve epigenetic changes, specifically DNA methylation. To evaluate changes in methylation associated with n-3 PUFA intake, we conducted an epigenome-wide methylation association study of long-chain n-3 PUFA intake and tested associations between the diabetes- and cardiovascular disease-related traits. We assessed DNA methylation at ~470,000 cytosine-phosphate-guanine (CpG) sites in a cross-sectional study of 185 Yup'ik Alaska Native individuals representing the top and bottom deciles of PUFA intake. Linear regression models were used to test for the associations of interest, adjusting for age, sex, and community group. We identified 27 differentially methylated CpG sites at biologically relevant regions that reached epigenome-wide significance (P < 1 * 10-7). Specifically, regions on chromosomes 3 (helicase-like transcription factor), 10 (actin alpha 2 smooth muscle/Fas cell surface death receptor), and 16 (protease serine 36/C16 open reading frame 67) each harbored 2 significant correlates of n-3 PUFA intake. In conclusion, we present promising evidence of association between several biologically relevant epigenetic markers and long term intake of marine-derived n-3 PUFAs. PMID- 24477302 TI - [Abstracts - 26 degrees congresso nazionale - associazione italiana di neuroradiologia. Centro congressi "a. Luciani", padova, Italy, 19-22 ottobre 2011]. PMID- 24477301 TI - Immature platelet fraction analysis demonstrates a difference in thrombopoiesis between normotensive and preeclamptic pregnancies. PMID- 24477303 TI - Vacuolar protein in apical and flower-petal cells. AB - Vegetative apices, floral apices and flower petals of five Solanaceae (potato, tomato, tobacco, petunia and nightshade) and of corn and Nigella were examined with an electron microscope for the presence of protein bodies in the cell vacuoles. Electron-dense bodies were found in vacuoles of all plants investigated but not in every tissue examined. The bodies observed in the apices are similar to the protein bodies previously found in tomato leaves where they appear to be related to the presence of chymotrypsin inhibitor I protein (Shumway et al., 1970). The bodies appeared in very young cells in small vacuoles, disappearing as the cell matured. They are apparently related to the growth and development of the new cells. The results suggest that plants may regulate specific proteins within the apical region through selective synthesis and degradation of proteins accompanied by compartmentalization in the vacuole. PMID- 24477304 TI - Auxin transport in roots : IX. Movement, export, resorption and loss of radioactivity from IAA by Zea root segments. AB - The reasons underlying the initial increase and subsequent decrease in the amount of radioactivity in the receiver block at the apical end of a Zea root segment supplied with a basal donor block containing labelled IAA have been investigated.The phenomenon was observed in segments supplied with IAA-1-(14)C, IAA-2-(14)C and IAA-5-(3)H. An acropetal polarity in the movement of radioactivity into the receiver blocks was observed using donor blocks containing IAA-5-(3)H at concentrations as low as 10(-10)M.The decrease in the amount of radioactivity in the receiver block begins after 6-8 h of transport at 25 degrees C, and is unaffected by renewal of the donor block every 2 h, or the presence of 2% sucrose in the donor and receiver blocks.The net export of radioactivity into the receiver block at the apical end of the segment virtually ceases after 6-8 h of transport at 25 degrees C, and is not prolonged by the presence of 2% sucrose in the donor and receiver blocks. At 10 degrees C, net export of radioactivity continues for at least the first 50 h of transport, and the amount of radioactivity in a continuously applied receiver block continues to increase over this period.Receiver blocks removed from the apical end of segments after 8 h of transport and placed on planchettes show little or no decrease in the amount of radioactivity they contain as a function of time, in marked contrast to those left in contact with the segment.There is a marked, and metabolically dependent, resorption of radioactivity from the receiver block at the apical end of the segment after about 8 h of transport at 25 degrees C; most of the resorbed radioactivity remains in the apical 2-4 mm of the segment.There is a loss of radioactive CO2 from segments supplied with a basal donor block containing 10( 6)M IAA-1-(14)C at 25 degrees C, the emission beginning after 6-8 h of transport. Segments similarly supplied with 10(-6)M IAA-2-(14)C did not begin to lose radioactive CO2 until after about 10-12 h of transport.The ability of the segments to transport radioactivity in a polar manner declines with time after they are excised from the root, regardless of whether their cut ends are kept in the intervening period in contact with plain agar blocks, or ones containing unlabelled IAA at 10(-6)M. By the 6th h after excision at 25 degrees C no transport of radioactivity through the segments and into the receiver blocks could be detected in either the aropetal or basipetal direction.The decrease in radioactivity in the receiver block after transport periods of 6-8 h at 25 degrees C is therefore due to (1) a cessation of net export of radioactivity into the block, and (2) the onset of a metabolically-dependent, net resorption of radioactivity. At this time substantial amounts of radioactive CO2 begin to be evolved from segments supplied with IAA-1-(14)C, whereas with IAA-2-(14)C radioactive CO2 is not evolved for a further 4-6 h. PMID- 24477305 TI - The role of phytochrome in the geotropic behavior of roots of Convolvulus arvensis. AB - Geotropic behavior in roots of Convolvulus arvensis is influenced by both gravity and light. In darkness, the roots grow horizontally; exposure to light induces a positive orthogeotropic response. The response is elicited by red light of narrow band width and is reversed by a far-red-light treatment following the red exposure. Phytochrome thus mediates this light response. Experiments with microbeam irradiation suggest that this pigment is located in the root apex, probably in the root cap. Statoliths are present and are shown to sediment upon reorientation of the root apex in both light-and dark-grown roots. PMID- 24477306 TI - Phytochrome regulation of endogenous bud development in root cultures of Convolvulus arvensis. AB - Buds produced endogenously from dark-grown Convolvulus root segments do not elongate more than a few millimeters. Red-light exposures given repeatedly during the culture period induce the buds to elongate and to develop a morphology characteristic of etiolated shoots. Far-red light exposure following each red exposure completely reverses the promotive effect of red light. The role of light in regulating both root geotropism and bud development is discussed as it relates to the developmental pattern of Convolvulus. PMID- 24477307 TI - [Light dependent carotenoid synthesis : VIII. Different action mechanisms of light and mercuribenzoate]. AB - The fungus Fusarium aquaeductuum synthesizes large amounts of carotenoids only after illumination or in the presence of mercuribenzoate (HMB) in the dark. The effect of HMB is abolished entirely by the addition of excess thiols such as cysteine or mercaptoethanol; evidently "active" HMB must be present continuously within the cell. In contrast, photoinduction needs only a short exposure to light to set off pigment production in a subsequent dark period. Illumination of mycelia preincubated with HMB in the dark induces an additional proportion of carotenoid synthesis which shows the same kinetics and quantitative yields as that observed in untreated controls. This demonstrates that HMB, though inhibiting O2-uptake by 50%, does not interfere with light-induced carotenoid production as such. The effects of light and HMB are additive under various experimental conditions tested. After addition of thiols to mycelia treated with HMB in the light, carotenoid production decreased to an extent equal to the amount mediated by HMB in the dark controls. These results provide strong evidence that the mechanisms and the action sites of light and HMB in carotenoid synthesis are different. Incubation with HMB after exposure to light reduces the agent's effectiveness, which declines gradually to about 30% during the first two hours.These findings are interpreted to mean that in Fusarium there are two isoenzyme systems at work in carotenoid production: a constitutive one showing very low net activity is subject to direct stimulation by HMB; light somehow eliminates this enzyme system and, at the same time, induces an isoenzyme set which exhibits high carotenogenic activity and is insensitive to HMB treatment. PMID- 24477308 TI - [Light-dependent carotenoid synthesis : IX. On the induction mechanism of carotenogenic enzymes in Fusarium aquaeductuum]. AB - Under anaerobic conditions Fusarium aquaeductuum is able to synthesize carotenogenic enzymes but does not produce pigments. If illumination of the mycelia in the presence of oxygen is followed by an incubation in the dark under N2 atmosphere, the strictly concurrent formation of the different carotenoids sets off as soon as aerobic conditions are restored. The paraboloidal increase of pigment production possibly indicates that synthesis of carotenogenic enzymes is also resumed. Blocking this enzyme synthesis by addition of cycloheximide leads to a simultaneous and linear increase of each carotenoid portion as soon as oxygen is replenished. This is interpreted to mean that light induces carotenogenic enzymes in a coupled group. On the other hand, our present and earlier results do not support any hypothesis on the existence of a carotenogenic multienzyme complex. The composition of the pigment after carotenoid production has ceased provides evidence for a selective inhibition of the synthesis of individual carotenogenic enzymes. Changes in pigment composition caused by an incubation of the mycelia for 12 h under anaerobic conditions are also reported. PMID- 24477309 TI - [O2- and CO2-exchange of illuminated leaves and the CO2/O 2 ratios at normal and low CO 2 partial pressure]. AB - The O2- and CO2-exchange of detached, illuminated leaves from 18 species of plants grown in the Botanical Garden at the University of Frankfurt was measured at 22 degrees C in an open gas stream (400 ppm CO2 supplied to the assimilation chamber) at both 2% O2 and 21% O2.At a low partial pressure of oxygen (2%) the ratios of CO2 uptake to O2 evolution were in all cases near unity, with a mean of 0.93+/-0.01. In normal atmosphere (21% O2) the CO2/O2 ratios were higher than those in 2% O2 and averaged 1.26+/-0.01.The results are interpreted as showing that oxygen is involved in the regulation of metabolism and may cause a shift in the direction of carbon flow in photosynthesizing tissue. PMID- 24477310 TI - Diffusible gibberellins and phototropism in Helianthus annuus. AB - Endogenous gibberellins were obtained in agar from the lower cut surface of upright sunflower shoot-tips. Exposure to unilateral light of the tips standing on agar, with the lower cut ends bisected by a vertical glass barrier at right angles to incident light, resulted in approximately 8 times the quantity of gibberellins moving into the agar below the shaded side than into the agar below the illuminated side. These results are similar to those reported earlier for gibberellins and geotropism in sunflower shoots, and suggest than the development of both light-and gravity-induced growth curvatures involve an asymmetry in gibberellin distribution across elongating internodes. PMID- 24477311 TI - Isoelectric focusing of sieve-tube protein. PMID- 24477312 TI - Implications of inconsistent anaemia policies for children and adolescents in Africa. AB - OBJECTIVE: To evaluate the quality of policies concerning the diagnosis, treatment and prevention of anaemia in children and adolescents; to determine to what extent these are evidence-based; and to use this analysis to inform the policy-making process. SUBJECTS: Children and adolescents in sub-Saharan Africa. SETTING: Almost 50 % of children and adolescents in sub-Saharan Africa are anaemic, which has profound effects on their intellectual and physical development and their chance of survival. Evidence-based policies are essential to reduce anaemia but because it is caused by an array of interdependent factors, developing policies is challenging. DESIGN: Forty-six policy documents concerning the diagnosis, treatment and prevention of anaemia in children and adolescents were identified and analysed. RESULTS: There was policy consensus on the usefulness of Fe supplements, the need to treat co-morbidities and the use of blood transfusions for severe anaemia. Information about diagnosis was scarce, and messages regarding the control of anaemia were mixed. Few of the policies were tailored for the African context and they were located on several websites hosted by different health programmes. CONCLUSIONS: The weakest aspects of the policies and consequently the priorities for better policy making were: lack of adherence to WHO recommendations for guideline development; little involvement of African practitioners/policy makers in the guideline group and as peer reviewers; and lack of harmonisation, demonstrating the need to establish a single body responsible for developing/revising anaemia policies. PMID- 24477313 TI - Designing a quality improvement program with electronic health records: New York City's Health eQuits. AB - Despite clear recommendations for identifying and intervening with smokers, clinical preventive practice is inconsistent in primary care. Use of electronic health records could facilitate improvement. Community health centers treating low-income and Medicaid recipients with greater smoking prevalence than the general population were recruited for a pilot program. Key design elements used to engage centers' participation include designating a project champion at each organization, confirming ability to transmit data for reporting and participation, and offering money to facilitate initial engagement; however, financial incentives did not motivate all organizations. Other methods to elicit participation and to motivate practice change included building on centers' previous experiences with similar programs, utilizing existing relationships with state cessation centers, and harnessing the "competitive" spirit-sharing both good news and areas for improvement to stimulate action. These experiences and observations may assist others in designing programs to improve clinical interventions with smokers. PMID- 24477314 TI - Northern Territory Heart Failure Initiative-Clinical Audit (NTHFI-CA)-a prospective database on the quality of care and outcomes for acute decompensated heart failure admission in the Northern Territory: study design and rationale. AB - INTRODUCTION: Congestive heart failure is a significant cause of morbidity and mortality in Australia. Accurate data for the Northern Territory and Indigenous Australians are not presently available. The economic burden of this chronic cardiovascular disease is felt by all funding bodies and it still remains unclear what impact current measures have on preventing the ongoing disease burden and how much of this filters down to more remote areas. Clear differentials also exist in rural areas including a larger Indigenous community, greater disease burden, differing aetiologies for heart failure as well as service and infrastructure discrepancies. It is becoming increasingly clear that urban solutions will not affect regional outcomes. To understand regional issues relevant to heart failure management, an understanding of the key performance indicators in that setting is critical. METHODS AND ANALYSIS: The Northern Territory Heart Failure Initiative-Clinical Audit (NTHFI-CA) is a prospective registry of acute heart failure admissions over a 12-month period across the two main Northern Territory tertiary hospitals. The study collects information across six domains and five dimensions of healthcare. The study aims to set in place an evidenced and reproducible audit system for heart failure and inform the developing heart failure disease management programme. The findings, is believed, will assist the development of solutions to narrow the outcomes divide between remote and urban Australia and between Indigenous and Non-Indigenous Australians, in case they exist. A combination of descriptive statistics and mixed effects modelling will be used to analyse the data. ETHICS AND DISSEMINATION: This study has been approved by respective ethics committees of both the admitting institutions. All participants will be provided a written informed consent which will be completed prior to enrolment in the study. The study results will be disseminated through local and international health conferences and peer reviewed manuscripts. PMID- 24477315 TI - The effect of community-acquired bacteraemia on return to workforce, risk of sick leave, permanent disability pension and death: a Danish population-based cohort study. AB - OBJECTIVES: Little is known about the prognosis of community-acquired bacteraemia (CAB) in workforce adults. We assessed return to workforce, risk for sick leave, disability pension and mortality within 1 year after CAB in workforce adults compared with blood culture-negative controls and population controls. DESIGN: Population-based cohort study. SETTING: North Denmark, 1996-2011. PARTICIPANTS: We used population-based healthcare registries to identify all patients aged 20 58 years who had first-time blood cultures obtained within 48 h of medical hospital admission, and who were part of the workforce (450 bacteraemia exposed patients and 6936 culture-negative control patients). For each bacteraemia patient, we included up to 10 matched population controls. PRIMARY AND SECONDARY OUTCOME MEASURES: Return to workforce, risk of sick leave, permanent disability pension and mortality within 1 year after bacteraemia. Regression analyses were used to compute adjusted relative risks (RRs) with 95% CIs. RESULTS: One year after admission, 78% of patients with CAB, 85.7% of culture-negative controls and 96.8% of population controls were alive and in the workforce, and free from sick leave or disability pension. Compared with culture-negative controls, bacteraemia was associated with an increased risk for long-term sick leave (4-week duration, 40.2% vs 23.9%, adjusted RR, 1.51; CI 1.34 to 1.70) and an increased risk for mortality (30-day mortality, 4% vs 1.4%, adjusted RR, 2.34, CI 1.22 to 4.50; 1 year mortality, 8% vs 3.9%, adjusted RR, 1.73; CI 1.18 to 2.55). Bacteraemia patients had a risk for disability pension similar to culture-negative controls (2.7% vs 2.6%, adjusted RR, 0.99, CI 0.48 to 2.02) but greater than population controls (adjusted RR, 5.20; 95% CI 2.16 to 12.50). CONCLUSIONS: CAB is associated with long duration of sick leave and considerable mortality in working age adults when compared with blood culture-negative controls, and an increased 1 year risk for disability pension when compared with population controls. PMID- 24477316 TI - Association among work exposure, alcohol intake, smoking and Dupuytren's disease in a large cohort study (GAZEL). AB - OBJECTIVES: In view of the debate of factors in Dupuytren's disease, we aimed to describe its relationship with certain occupational factors, alcohol intake and smoking. SETTING: The French GAZEL cohort (employees of Electricite de France and Gaz de France). PARTICIPANTS: Participants of the cohort who answered a questionnaire in 2012, that is, 13 587 participants (73.7% of the questionnaire sent). In 2007, self-assessed lifetime occupational biomechanical exposure was recorded (carrying loads, manipulating a vibrating tool and climbing stairs), as well as alcohol intake, smoking and diabetes mellitus. Analyses were performed on high alcohol intake, smoking and duration of relevant work exposure, stratified by gender. PRIMARY AND SECONDARY OUTCOME MEASURES: From a specific question on Dupuytren's disease assessed in 2012, the outcome measures were self-reported Dupuytren's disease (yes/no) and disabling Dupuytren's disease (including surgery). RESULTS: A total of 10 017 men and 3570 women, aged 64-73 years, were included; the mean age for men was 68 years and for women was 65 years. Among men, the following were significantly associated with Dupuytren's disease: age (OR 1.03 (1.00; 1.06)), diabetes (OR 1.31 (1.07; 1.60)), heavy drinking (OR 1.36 (1.10; 1.69)) and over 15 years of manipulating a vibrating tool at work (OR 1.52 (1.15; 2.02)); except for diabetes, the association with these factors was stronger for disabling Dupuytren's disease (or surgery), with OR 1.07 (1.03; 1.11), 1.71 (1.25; 2.33) and 1.98(1.34; 2.91), respectively, for age, heavy drinking and over 15 years of manipulating a vibrating tool at work. Among the 3570 women included, 160 reported Dupuytren's disease (4.5%). The number of cases in the group of women was too low to reach conclusions, although the findings seemed similar for age, diabetes and vibration exposure. CONCLUSIONS: In this large French cohort study, Dupuytren's disease in men was associated with high levels of alcohol consumption and exposure to hand-transmitted vibration. It is likely that the same applied to women. PMID- 24477318 TI - The accuracy of caries risk assessment in children attending South Australian School Dental Service: a longitudinal study. AB - OBJECTIVES: To determine the accuracy of the caries risk assessment system and performance of clinicians in their attempts to predict caries for children during routine practice. DESIGN: Longitudinal study. SETTING AND PARTICIPANTS: Data on caries risk assessment conducted by clinicians during routine practice while providing care for children in the South Australian School Dental Service (SA SDS) were collected from electronic patient records. Baseline data on caries experience, clinicians' ratings of caries risk status and child demographics were obtained for all SA SDS patients aged 5-15 years examined during 2002-2005. OUTCOME MEASURE: Children's caries incidence rate, calculated using examination data after a follow-up period of 6-48 months from baseline, was used as the gold standard to compute the sensitivity (Se) and specificity (Sp) of clinicians' baseline ratings of caries risk. Multivariate binomial regression models were used to evaluate effects of children's baseline characteristics on Se and Sp. RESULTS: A total of 133 clinicians rated caries risk status of 71 430 children during 2002-2005. The observed Se and Sp were 0.48 and 0.86, respectively (Se+Sp=1.34). Caries experience at baseline was the strongest factor influencing accuracy in multivariable regression model. Among children with no caries experience at baseline, overall accuracy (Se+Sp) was only 1.05, whereas it was 1.28 among children with at least one tooth surfaces with caries experience at baseline. CONCLUSIONS: Clinicians' accuracy in predicting caries risk during routine practice was similar to levels reported in research settings that simulated patient care. Accuracy was acceptable in children who had prior caries experience at the baseline examination, while it was poor among children with no caries experience. PMID- 24477317 TI - A cohort study on mental disorders, stage of cancer at diagnosis and subsequent survival. AB - OBJECTIVES: To assess the stage at cancer diagnosis and survival after cancer diagnosis among people served by secondary mental health services, compared with other local people. SETTING: Using the anonymised linkage between a regional monopoly secondary mental health service provider in southeast London of four London boroughs, Croydon, Lambeth, Lewisham and Southwark, and a population-based cancer register, a historical cohort study was constructed. PARTICIPANTS: A total of 28 477 cancer cases aged 15+ years with stage of cancer recorded at diagnosis were identified. Among these, 2206 participants had been previously assessed or treated in secondary mental healthcare before their cancer diagnosis and 125 for severe mental illness (schizophrenia, schizoaffective or bipolar disorders). PRIMARY AND SECONDARY OUTCOME MEASURES: Stage when cancer was diagnosed and all cause mortality after cancer diagnosis among cancer cases registered in the geographical area of southeast London. RESULTS: Comparisons between people with and without specific psychiatric diagnosis in the same residence area for risks of advanced stage of cancer at diagnosis and general survival after cancer diagnosed were analysed using logistic and Cox models. No associations were found between specific mental disorder diagnoses and beyond local spread of cancer at presentation. However, people with severe mental disorders, depression, dementia and substance use disorders had significantly worse survival after cancer diagnosis, independent of cancer stage at diagnosis and other potential confounders. CONCLUSIONS: Previous findings of associations between mental disorders and cancer mortality are more likely to be accounted for by differences in survival after cancer diagnosis rather than by delayed diagnosis. PMID- 24477319 TI - The administration of intermittent parathyroid hormone affects functional recovery from pertrochanteric fractured neck of femur: a protocol for a prospective mixed method pilot study with randomisation of treatment allocation and blinded assessment (FRACTT). AB - INTRODUCTION: Pertrochanteric hip fractures occur in an elderly population and cause considerable morbidity and loss of functional ability as the fracture heals. Recently, parathyroid hormone (PTH), which is licensed for the treatment of osteoporosis, has been shown to potentially accelerate bone healing in animal and human studies. If its administration could allow a faster functional recovery after pertrochanteric hip fracture, then a patient's hospital stay may be reduced and rehabilitation could be potentially accelerated. PTH can currently only be administered by subcutaneous injection. The acceptability of this intervention is unknown in this elderly population. The aim of this pilot study is to inform the design of a future powered study comparing the functional recovery after pertrochanteric hip fracture in patients undergoing standard care versus those who undergo administration of subcutaneous injection of PTH. METHODS AND ANALYSIS: The study is an open label, prospective, randomised, comparative pilot study with blinded outcomes assessment to establish feasibility of the trial design. Patients will be randomised to receive a 6-week course of PTH or usual treatment. Functional outcomes will be assessed at 6 weeks and 12 weeks. Blinded assessment will be used to minimise the effect of bias of an open label study design. A nested qualitative study will investigate the patient experience of, and expectations following, hip fracture and the patient important aspects of recovery compared with the outcome measures proposed. RESULTS: Results will be analysed to establish the potential recruitment, compliance and retention rates using 95% CIs, and trial outcomes quoted with SDs and 95% CIs for the effect size. ETHICS AND DISSEMINATION: The study has been approved by the South West 2 Research Ethics committee (reference 10/H0206/34). The findings of this study will be disseminated to the medical community via presentations to orthopaedic, orthogeriatric and osteoporosis societies, and their relevant specialist journals. TRIAL REGISTRATION: ISRCTN Register reference number: ISRCTN03362357. Eudract Number: 2010-020081-22. PMID- 24477321 TI - Lanthanide ion exchange properties of a coordination polymer consisting of di(2 ethylhexyl) phosphoric acid and trivalent metal ions (Ce3+, Fe3+, or Al3+). AB - Three kinds of coordination polymers ([M(dehp)3], M = Ce, Fe, or Al) were prepared by mixing the sodium form (Na(dehp)) of di(2-ethylhexyl) phosphoric acid and MCl3 in an ethanol-water binary mixture. They have monoclinic crystalline structure with similar lattice parameters. The lanthanide ion (Ln(3+) = La(3+), Sm(3+), Dy(3+), or Yb(3+)) exchange properties were studied in a 20 : 80 vol% ethanol-water binary mixture containing 2 mM Ln(NO3)3 at room temperature. The rate of Ln(3+) adsorption is relatively slow; it requires over 3 weeks to reach equilibrium. [M(dehp)3] has different Ln(3+) affinities depending on the kind of central metal ions: the affinity order at 3 week adsorption is Yb(3+) < La(3+) < Dy(3+) < Sm(3+) for [Ce(dehp)3], La(3+) < Sm(3+) < Dy(3+) < Yb(3+) for [Fe(dehp)3], and La(3+) < Sm(3+), Dy(3+), Yb(3+) for [Al(dehp)3]. The difference in affinity order can be explained by two factors: the coordination preference and steric strain caused by the polymeric structure. The chemical and structural analyses suggested that the Ln(3+) adsorption progresses first by the central M(3+)/Ln(3+) exchange, followed by a morphological change to a rod-like or fibrous form by a solid phase reaction. In the case of [Fe(dehp)3], the eluted Fe(3+) may be hydrolyzed and precipitated as amorphous iron hydroxide. PMID- 24477320 TI - Retreatment with omalizumab results in rapid remission in chronic spontaneous and inducible urticaria. AB - IMPORTANCE: Omalizumab has emerged as a novel and effective treatment option for patients with antihistamine-resistant chronic urticaria. It is unclear whether patients with recurrent urticaria symptoms after discontinuation of omalizumab treatment can benefit from retreatment. OBJECTIVE: To assess the response of patients with chronic urticaria who receive omalizumab retreatment. DESIGN, SETTING, AND PARTICIPANTS: Retrospective analyses were conducted of outpatients treated at an urticaria specialist center of a university hospital. Participants included 25 consecutive patients (aged 18-74 years; 18 women) with chronic spontaneous urticaria, chronic inducible urticaria, or both who showed complete response to omalizumab treatment, experienced relapse after discontinuation of treatment, and received retreatment with omalizumab. INTERVENTIONS: Subcutaneous treatment with omalizumab (150-600 mg/mo). MAIN OUTCOMES AND MEASURES: Response after retreatment was assessed by the urticaria activity score in patients with chronic spontaneous urticaria and by trigger threshold testing (in patients with cold urticaria or symptomatic dermographism) and/or a carefully determined history (in patients with cholinergic urticaria, solar urticaria, or pressure urticaria). Adverse events were documented. RESULTS: All patients experienced complete response after retreatment. None of the patients reported relevant adverse events during omalizumab treatment and retreatment. CONCLUSIONS AND RELEVANCE: Omalizumab retreatment is effective and safe in patients with chronic urticaria who have benefited from initial omalizumab treatment. PMID- 24477322 TI - Quality of life in patients with craniocervical dystonia: Italian validation of the "Cervical Dystonia Impact Profile (CDIP-58)" and the "Craniocervical Dystonia Questionnaire (CDQ-24)". AB - Dystonia is a disabling and disfiguring disorder that can often affect many aspects of patients' daily lives, and lower their self-esteem. To date, quality of life (QoL) has been assessed in dystonic patients using generic measures that do not address the specific problems of this diagnostic group. Recently, two disease-specific scales "The Cervical Dystonia Impact Profile (CDIP-58)" and the "Craniocervical Dystonia Questionnaire (CDQ-24)" were validated for measuring QoL in craniocervical dystonia patients. No disease-specific scales for QoL for dystonic patients are currently available in Italian. The aim of our study was to produce and validate the Italian version of the CDIP-58 and CDQ-24. We obtained the Italian version of CDQ-24 and CDIP-58 with a back-translation design. Both scales were applied to a population of 94 craniocervical dystonia patients along with the Short Form 36 health-survey questionnaire (SF-36), both before and 4 weeks after botulinum toxin therapy. A group of 65 controls matched for sex, age and comorbidity underwent the SF-36. Internal consistency was satisfactory for all subscales. Both the CDIP-58 and CDQ-24 showed moderate to high correlations with similar items of the SF-36. Sensitivity to change was confirmed by highly significant improvements in all CDQ-24 subscales and by moderate improvements in three out of eight CDIP-58 subscales and total score. This is the first Italian study on QoL in dystonia patients. We validated the Italian version of two disease-specific questionnaires to evaluate QoL in craniocervical dystonia patients. These scales could be useful for both clinical practice and clinical trials. PMID- 24477323 TI - COMT Val158Met and PPARgamma Pro12Ala polymorphisms and susceptibility to Alzheimer's disease: a meta-analysis. AB - The aim of this study was to explore whether the catechol-O-methyltransferase (COMT) Val158Met or the peroxisome proliferator-activated receptor-gamma (PPARgamma) Pro12Ala polymorphisms are associated with susceptibility to Alzheimer's disease (AD). We conducted a meta-analysis of the associations between the COMT Val158Met and the PPARgamma Pro12Ala polymorphisms and AD in subjects. Meta-analysis showed no association between AD and the COMT G allele in any of the study subjects [odds ratio (OR) = 0.972, 95 % confidence intervals (95 % CI) = 0.893-1.059, p = 0.515]. Stratification by ethnicity indicated an association between the COMT GG+GA genotype and AD in an Asian group (OR = 0.702, 95 % CI = 0.517-0.953, p = 0.023), but not in Europeans (OR = 1.058, 95 % CI = 0.868-1.289, p = 0.579). Homozygote contrast analysis showed the same pattern for the COMT GG+GA genotype. Meta-analysis showed no association between AD and the PPARgamma polymorphism (OR for the C allele = 0.963, 95 % CI = 0.818-1.134, p = 0.649). This meta-analysis identified an association between AD and the COMT Val158Met polymorphism in Asians but not in Europeans, but it revealed no association between AD and the PPARgamma Pro12Ala polymorphism. PMID- 24477324 TI - Isolated pons variant of posterior reversible encephalopathy syndrome complicated with ischemic stroke in a young patient: association or coincidence? PMID- 24477325 TI - How long do the effects of acupuncture on hot flashes persist in cancer patients? AB - PURPOSE: Acupuncture has been suggested as therapy for hot flashes in women with breast cancer and men with prostate cancer. In this systematic review, we sought to evaluate the long-term effects on vasomotor symptoms after the end of a defined treatment period of acupuncture in women with breast cancer and men with prostate cancer. METHODS: A literature search revealed 222 articles within the field. With defined exclusion criteria, we identified 17 studies. We also used the Jadad quality score and identified seven studies with a score of at least 3. RESULTS: Six of seven identified studies qualified for inclusion in an analysis that measured frequency of hot flashes weighted in relation to number of patients (n=172). The average reduction from baseline to end of acupuncture (ranging between 5 and 12 weeks of treatment) showed 43.2 % reduction of hot flashes. At the last follow-up (mean 5.8 months, range 3-9 months) after the end of therapy, the weighted reduction from baseline was sustained at 45.6 % in the 153 of 172 patients (89 %) who were followed up. CONCLUSIONS: Data from six prospective analyzed studies indicate at least 3-month effects after the end of acupuncture treatment for flashes in women with breast cancer and men with prostate cancer. However, larger randomized trials with long-term follow-up will be needed to confirm these preliminary findings. PMID- 24477326 TI - Awareness, concern, and communication between physicians and patients on bone health in cancer. AB - PURPOSE: This study aims to explore physician-patient communications about bone metastases and cancer treatment-induced bone loss (CTIBL). METHODS: The study utilizes online survey of patients with breast cancer, prostate cancer, and multiple myeloma, and the physicians who treat them. RESULTS: Even though 69 and 48 % of patients with nonmetastatic breast and prostate cancer aware of treatment induced bone loss, only 39 and 23 %, respectively, were concerned about bone loss. Yet, 62 and 71 % of oncologists treating breast and prostate cancer felt that their patients were concerned. Among patients with metastatic breast and prostate cancer, two thirds had not discussed treatment for bone metastases with their doctor; when discussed, 88 and 91 % of discussions were initiated by the doctor, usually prior to initiating treatment. Most myeloma patients (77 %) had discussed treatment options with their physicians; 99 % of hematologists reported discussing treatment of bone disease with patients. CONCLUSIONS: Physicians are primary sources of information to patients regarding bone health. There is a gap between what physicians assume their patients know about bone health and the patients' perceptions, presenting a need for systematic awareness and education. PMID- 24477328 TI - Contradiction between in vitro and clinical outcome: intravenous followed by oral azithromycin therapy demonstrated clinical efficacy in macrolide-resistant pneumococcal pneumonia. AB - We conducted a multicenter, unblinded, non-comparative, phase 3 trial of azithromycin-intravenous therapy followed by oral administration in Japanese adults to evaluate clinical efficacy and safety against community-acquired pneumonia in order to obtain regulatory approval for the intravenous formulation in Japan. Azithromycin (500 mg, once daily) was intravenously administered for 2 5 days followed by oral 500 mg once daily administration to complete a total of 7 10 days treatment in 102 adults with moderate-to-severe community-acquired pneumonia. The efficacy rate in the Clinical Per Protocol Set overall was 84.5% (60/71 subjects) on Day 15 (primary analysis). The most common causative pathogen was Haemophilus influenzae (17 strains), followed by Streptococcus pneumoniae (14 strains), Moraxella catarrhalis (5 strains) and Mycoplasma pneumoniae (5 strains). Eleven of 14 S. pneumoniae isolates were resistant to azithromycin (MIC >=2.0 MUg/ml), of which 5 strains with a relatively low MIC of <32 MUg/ml had only mef A gene and 6 strains with a high MIC of >64 MUg/ml had only the erm B gene except for 2 isolates having both the mef A and erm B genes. Despite dominance of macrolide-resistant strains in Japan, clinical efficacy and bacterial eradication were achieved in 10 of 11 patients (90.9%). Intravenous-to oral azithromycin therapy demonstrated excellent clinical and bacteriological effects on moderate-to-severe pneumococcal pneumonia despite a high MIC and resistance gene development. This discrepancy is referred to as the "in vivo-in vitro paradox". The current study results provide an insight into this paradox. REGISTRATION NUMBER: NCT00809328. PMID- 24477329 TI - Pathogenesis and clinical features of chronic pulmonary aspergillosis - is it possible to distinguish CNPA and CCPA clinically? AB - BACKGROUND: The pathogenesis of chronic pulmonary aspergillosis (CPA) including chronic necrotizing pulmonary aspergillosis (CNPA), chronic cavitary pulmonary aspergillosis (CCPA), and simple aspergilloma (SA) has been poorly investigated. We examined all types of CPA cases with histopathological evidence to clarify the differences in pathogenesis and clinical features. METHOD: We searched for cases diagnosed as pulmonary aspergillosis by histopathological examination in Nagasaki University Hospital between 1964 and September 2010. All available clinical information including radiological findings were collected and analyzed. RESULT: We found 7, 5, 8, and 7 cases of proven CNPA, probable CNPA, CCPA, and SA, respectively. The radiograph of proven and probable CNPA was initially infiltrates or nodules that progress to form cavities with or without aspergilloma, whereas the radiograph of CCPA showed pre-existed cavities and peri cavitary infiltrates with or without aspergilloma. The patients with proven and probable CNPA exhibited not only respiratory symptoms but also systemic symptoms and malnutrition. Aspergillus fumigatus was the most frequently isolated Aspergillus species (n = 14), however, Aspergillus niger was the predominant isolated species in proven CNPA cases (n = 4). CONCLUSION: Our data indicate that the cases with chronic infiltration, progressive cavitation, and subsequent aspergilloma formation should be diagnosed as CNPA, and the cases with pre existed cavities showing peri-cavitary infiltrates with or without aspergilloma would mean CCPA. However, it may be difficult to distinguish the two subtypes if a series of adequate radiography films are not available. We propose the term "chronic progressive pulmonary aspergillosis (CPPA)" for the clinical syndrome including both CNPA and CCPA. PMID- 24477330 TI - A case of successful hepatitis C virus eradication by 24 weeks of telaprevir based triple therapy for a hemophilia patient with hepatitis C virus/human immunodeficiency virus co-infection who previously failed pegylated interferon alpha and ribavirin therapy. AB - In Japan, the human immunodeficiency virus (HIV) and hepatitis C virus (HCV) coinfection of some patients with hemophilia was caused by the transfusion of imported blood products, such as unheated coagulation factor. With the development of antiretroviral therapy (ART) for HIV, chronic HCV infection has become a major cause of liver disease and mortality for hemophiliac patients coinfected with HCV/HIV. Data is limited regarding the efficacy and safety of antiviral therapy with the HCV protease inhibitor telaprevir (TVR) in combination with pegylated interferon-alpha (PegIFN-alpha) and ribavirin (RBV) for hemophilia patients coinfected with HCV/HIV. We report a case of a Japanese patient with hemophilia and HCV/HIV coinfection who had partial response to prior to PegIFN alpha and RBV therapy. This is the first published report of 24-week TVR-based triple therapy for a hemophilia patient coinfected with HCV/HIV. The patient had HCV genotype 1a infection with a high viral load. His single-nucleotide polymorphism of the interleukin 28B (rs8099917) gene was the TT major allele. He presented with undetectable HIV RNA and a high CD4(+) T cell counts by taking ART including tenofovir, emtricitabine and raltegravir. He was again treated for HCV with TVR plus PegIFN-alpha2b and RBV for the first 12 weeks, followed by the continuation of PegIFN-alpha2b and RBV for 12 additional weeks while continuing ART. He had rapid virological response and achieved sustained virological response with the 24-week treatment. No serious adverse events such as skin rash, severe anemia or exacerbated bleeding tendency were observed, only a mild headache. No dose adjustment was necessary when tenofovir and raltegravir were used in combined with TVR, and no HIV breakthrough was observed. TVR-based triple therapy with ART could can an effective treatment for hemophilia patients coinfected with HCV (genotype 1)/HIV regardless of prior response. TVR can be used in combination with tenofovir, emtricitabine and raltegravir for patients with hemophilia. Furthermore, patients with undetectable HCV RNA at week 4 could be successfully treated with a 24-week regimen. PMID- 24477331 TI - Bilateral symmetry of breast tissue composition by magnetic resonance in young women and adults. AB - BACKGROUND: Some reports suggest that there is a slightly higher frequency of breast cancer in the left breast compared with the right in middle-aged women. The reasons for this association are unknown. The water and fat content of both breasts was compared using magnetic resonance (MR). Breast water by MR reflects fibro-glandular tissue and is strongly positively correlated with percent mammographic density, a strong risk factor for breast cancer. METHODS: Magnetic resonance was used to measure fat and water content of the breast in 400 young women aged 15-30 years and a random sample of 100 of their mothers. All MR examinations were carried out using a 1.5T MR system, and 45 contiguous slices were obtained in the sagittal plane. One reader identified the breast tissue in the image, and subsequently, fat and water content was calculated using a three point Dixon technique. Left- and right-sided images were read independently in random order. RESULTS: In young women, mean percent water was on average 0.84 % higher in the right compared with the left breast (p < 0.001) and total breast water was on average 6.42 cm(3) greater on the right side (p < 0.001). In mothers, there were no significant differences in any breast measure between right and left sides. CONCLUSION: The small differences in breast tissue composition in young women are unlikely to be associated with large differences in breast cancer risk between sides. The reported excess of left-sided breast cancer in older women is unlikely to be explained by differences in breast tissue composition. PMID- 24477332 TI - Carbon monoxide induces chromatin remodelling to facilitate endothelial cell migration. AB - Vascular injury to vessel endothelial cells (EC), caused by either mechanical damage or chronic inflammation, is still awaiting effective therapies. In the present study we hypothesised that carbon monoxide (CO) acts on the nuclear receptor Rev-erbalpha to induce chromatin modification and endothelial cell migration. We demonstrate that administration of low, safe doses of exogenous CO enhances endothelial cell (EC) migration, which occurs in part through chromatin remodelling and histone H3 acetylation. Further, we show that the effects of CO are dependent on inhibition of phosphorylation of glycogen synthase kinase-3 beta (GSK3beta), activation of haem synthesis, and increased expression of Rev erbalpha. Rev-erbalpha is a haem-containing transcription factor which in response to CO binds to target DNA, recruits the Histone Deacetylase/nuclear Receptor Corepressor (HDAC/N-CoR) complex, and regulates transcription of genes responsible for endothelial cell migration and angiogenesis. Decreased levels of Rev-erbalpha in chimeric mice after bone marrow transplant from Rev-erbalpha following bone marrow transplantation from rev-erb+/- mice resulted in loss of protective effects of CO against neointima formation after wire injury. Collectively, CO modifies chromatin structure through enhanced acetylation of histone H3 via a GSK3beta-Rev-erbalpha-mediated pathway to increase EC migration. We propose that CO enhances vessel repair following injury in part by regulating EPC/EC motility via Rev-erbalpha. Thus, inhaled CO may be beneficial in the treatment of vascular syndromes associated with dysregulated thrombosis, wound healing, and angiogenesis. PMID- 24477333 TI - Nickel accumulation by Streptanthus polygaloides (Brassicaceae) reduces floral visitation rate. AB - Hyperaccumulation is the phenomenon whereby plants take up and sequester in high concentrations elements that generally are excluded from above-ground tissues. It largely is unknown whether the metals taken up by these plants are transferred to floral rewards (i.e., nectar and pollen) and, if so, whether floral visitation is affected. We grew Streptanthus polygaloides, a nickel (Ni) hyperaccumulator, in short-term Ni supplemented soils and control soils to determine whether Ni is accumulated in floral rewards and whether floral visitation is affected by growth in Ni-rich soils. We found that while supplementation of soils with Ni did not alter floral morphology or reward quantity (i.e., anther size or nectar volume), Ni did accumulate in the nectar and pollen-filled anthers-providing the first demonstration that Ni is accumulated in pollinator rewards. Further, S. polygaloides grown in Ni-supplemented soils received fewer visits per flower per hour from both bees and flies (both naive to Ni-rich floral resources in the study area) relative to plants grown in control soils, although the probability a plant was visited initially was unaffected by Ni treatment. Our findings show that while Ni-rich floral rewards decrease floral visitation, floral visitors are not completely deterred, so some floral visitors may collect and ingest potentially toxic resources from metal-hyperaccumulating plants. In addition to broadening our understanding of the effects of metal accumulation on ecological interactions in natural populations, these results have implications for the use of insect-pollinated plants in phytoremediation. PMID- 24477334 TI - Parry-Romberg syndrome studied by spectral-domain optical coherence tomography. AB - Parry-Romberg syndrome is a rare disorder characterized by progressive hemifacial atrophy. Ophthalmic findings are characterized by enophthalmos, strabismus, nerve palsies, anisometropia, glaucoma, and angle abnormalities. Vision loss has also been reported due to retinal changes such as venous dilatation, disc edema, retinal edema, and retinal folds. The authors describe a case of Parry-Romberg syndrome with retinal alterations but a normal macula on spectral-domain optical coherence tomography. PMID- 24477335 TI - Manganese concentrations in maternal-infant blood and birth weight. AB - Manganese (Mn) is an essential mineral nutrient in mammals. The physiological role of Mn in animal models is well documented, but little is known about the adverse effects of Mn deficiency or overexposure in humans, including pregnancy outcomes such as birth weight. We examined the relationship of the maternal and cord blood Mn levels with birth weight in a cohort of 172 mother-infant pairs born in Shanghai, China. Non-linear spline and quadratic regression models were used to test the hypothesis of an inverted U-shaped association between the Mn levels and birth weight. The median (range) levels of Mn in the maternal and cord blood were 5.38 (2.34-30.37) MUg/dL and 7.66 (2.57-34.23) MUg/dL, respectively. An inverted U-shaped relationship was observed between maternal Mn and birth weight after adjusting for potential confounders. The birth weight increased with Mn levels up to 4.18 MUg/dL, and a slight reduction in weight was observed at higher levels. The cord blood Mn levels were not found to be associated with birth weight. Both lower and higher Mn exposures are associated with lower birth weight, which may influence important developmental parameters; the association of higher Mn levels with lower weight was weak and imprecise. PMID- 24477336 TI - Seasonal and spatial variation of organic tracers for biomass burning in PM1 aerosols from highly insolated urban areas. AB - PM1 aerosol characterization on organic tracers for biomass burning (levoglucosan and its isomers and dehydroabietic acid) was conducted within the AERTRANS project. PM1 filters (N = 90) were sampled from 2010 to 2012 in busy streets in the urban centre of Madrid and Barcelona (Spain) at ground-level and at roof sites. In both urban areas, biomass burning was not expected to be an important local emission source, but regional emissions from wildfires, residential heating or biomass removal may influence the air quality in the cities. Although both areas are under influence of high solar radiation, Madrid is situated in the centre of the Iberian Peninsula, while Barcelona is located at the Mediterranean Coast and under influence of marine atmospheres. Two extraction methods were applied, i.e. Soxhlet and ASE, which showed equivalent results after GC-MS analyses. The ambient air concentrations of the organic tracers for biomass burning increased by an order of magnitude at both sites during winter compared to summer. An exception was observed during a PM event in summer 2012, when the atmosphere in Barcelona was directly affected by regional wildfire smoke and levels were four times higher as those observed in winter. Overall, there was little variation between the street and roof sites in both cities, suggesting that regional biomass burning sources influence the urban areas after atmospheric transport. Despite the different atmospheric characteristics in terms of air relative humidity, Madrid and Barcelona exhibit very similar composition and concentrations of biomass burning organic tracers. Nevertheless, levoglucosan and its isomers seem to be more suitable for source apportionment purposes than dehydroabietic acid. In both urban areas, biomass burning contributions to PM were generally low (2 %) in summer, except on the day when wildfire smoke arrive to the urban area. In the colder periods the contribution increase to around 30 %, indicating that regional biomass burning has a substantial influence on the urban air quality. PMID- 24477337 TI - Biological activity in metal-contaminated calcareous agricultural soils: the role of the organic matter composition and the particle size distribution. AB - Organic matter (OM) plays a key role in microbial response to soil metal contamination, yet little is known about how the composition of the OM affects this response in Mediterranean calcareous agricultural soils. A set of Mediterranean soils, with different contents and compositions of OM and carbonate and fine mineral fractions, was spiked with a mixture of Cd, Cu, Pb, and Zn and incubated for 12 months for aging. Microbial (Biolog Ecoplates) and enzyme activities (dehydrogenase, DHA; beta-galactosidase, BGAL; phosphatase, PHOS; and urease, URE) were assessed and related to metal availability and soil physicochemical parameters. All enzyme activities decreased significantly with metal contamination: 36-68 % (DHA), 24-85 % (BGAL), 22-72 % (PHOS), and 14-84 % (URE) inhibitions. Similarly, catabolic activity was negatively affected, especially phenol catabolism (~86 % compared to 25-55 % inhibition for the rest of the substrates). Catabolic and DHA activities were negatively correlated with ethylenediaminetetraacetic acid (EDTA)-extractable Cd and Pb, but positively with CaCl2, NaNO3, and DTPA-extractable Cu and Zn. Soluble OM (water- and hot-water soluble organic C) was positively related to enzyme and catabolic activities. Recalcitrant OM and fine mineral fractions were positively related to BGAL and PHOS. Conversely, catabolic activity was negatively related to clay and positively to silt and labile OM. Results indicate that the microbial response to metal contamination is highly affected by texture and OM composition. PMID- 24477338 TI - Red emitting [Ir(C^N)2(N^N)]+ complexes employing bidentate 2,2':6',2'' terpyridine ligands for light-emitting electrochemical cells. AB - 2,2':6',2''-Terpyridine (tpy), 4'-(4-HOC6H4)-2,2':6',2''-terpyridine (1), 4'-(4 MeOC6H4)-2,2':6',2''-terpyridine (2), 4'-(4-MeSC6H4)-2,2':6',2''-terpyridine (3), 4'-(4-H2NC6H4)-2,2':6',2''-terpyridine (4) and 4'-(4-pyridyl)-2,2':6',2'' terpyridine (4) act as N^N chelates in complexes of the type [Ir(C^N)2(N^N)][PF6] in which the cyclometallating ligand, C^N, is derived from 2-phenylpyridine (Hppy) or 3,5-dimethyl-1-phenyl-1H-pyrazole (Hdmppz). The single crystal structures of eight complexes have been determined, and in each iridium(III) complex cation, the non-coordinated pyridine ring of the tpy unit is involved in a face-to-face pi-stacking interaction with the cyclometallated ring of an adjacent ligand. Solution NMR spectra of the [Ir(ppy)2(N^N)](+) complexes are consistent with the presence of a non-classical hydrogen bond between the non coordinated N-donor of the tpy domain and a CH unit of one pyridine ring of an adjacent ppy(-) ligand; the presence of the N...HC interaction was confirmed in one of the solid-state structures. The pendant pyridine ring of the coordinated tpy undergoes hindered rotation on the NMR timescale at 295 K. In CH2Cl2, the complexes are orange or red emitters, with lambda(max)(em) in the range 580 to 642 nm; photoluminescence quantum yields (PLQY) are <10%, and lifetimes range from 54 to 136 ns. N-Methylation of the pendant 4'-(4-pyridyl) group in [Ir(dmppz)2(pytpy)][PF6] essentially quenches the emission. Light-emitting electrochemical cells (LECs) have been fabricated in a thin film configuration; the emission spectra of the LECs are red-shifted with respect to the PL spectra of the corresponding complex in thin film configuration. For the device incorporating [Ir(ppy)2(pytpy)][PF6], the PL to EL red-shift is extremely large and this is indicative of a different emitting state being involved. The most efficient devices used [Ir(ppy)2(1)][PF6], [Ir(ppy)2(2)][PF6] or [Ir(ppy)2(3)][PF6] in the emissive layer; the devices exhibited rapid turn-on times, but showed relatively low efficiencies in accordance with the solid state photoluminescence quantum yields. PMID- 24477339 TI - Systemic symptoms in the progression of cutaneous to systemic lupus erythematosus. AB - IMPORTANCE: Patients with cutaneous lupus erythematosus (CLE) who develop systemic lupus erythematosus (SLE) may have few and mild systemic symptoms. OBJECTIVE: To characterize the types and severity of systemic symptoms in a longitudinal cohort of patients with CLE. DESIGN, SETTING, AND PARTICIPANTS: Prospective, longitudinal cohort study of 77 patients with CLE who presented between January 2007 and April 2011 at a university autoimmune skin disease clinic. MAIN OUTCOMES AND MEASURES: Systemic symptoms and severity were determined from data recorded at each study visit and from medical records. RESULTS: Of 77 patients with CLE, 13 (17%) went on to meet criteria for SLE, with a mean (SD) time from CLE diagnosis to SLE of 8.03 (6.20) years. Of the 13 patients, 1 (8%) solely met the mucocutaneous American College of Rheumatology (ACR) criteria of malar rash, discoid rash, photosensitivity, and oral ulcers, and 3 (23%) met the mucocutaneous ACR criteria plus positive antinuclear and other antibody titers. After a mean (SD) follow-up time of 2.81 (1.34) years, only 5 of the 13 patients with CLE (38%) who progressed to meet SLE criteria developed moderate to severe additional systemic disease. CONCLUSIONS AND RELEVANCE: Patients with CLE who developed SLE during our study did so mostly by meeting the mucocutaneous ACR criteria, and the majority developed none to mild additional systemic disease during the study period. Thus, our study suggests that a small percentage of patients with CLE eventually develop SLE and that even if they do, most patients will have mild systemic disease. PMID- 24477340 TI - Mucosal biofilm detection in chronic otitis media: a study of middle ear biopsies from Greenlandic patients. AB - The objectives of this study were to examine middle ear biopsies from Greenlandic patients with chronic otitis media (COM) for the presence of mucosal biofilms and the bacteria within the biofilms. Thirty-five middle ear biopsies were obtained from 32 Greenlandic COM patients admitted to ear surgery. All biopsies were examined by means of peptide nucleic acid-fluorescent in situ hybridization (PNA FISH), and if possible culture and polymerase chain reaction (PCR) of the 16s rDNA and sequencing. Light microscopy and confocal laser scanning microscopy were used. Skin biopsies from 23 of the patients served as controls. PNA-FISH showed morphological signs of biofilms in 15 out of 35 (43 %) middle ear biopsies. In the control skin biopsies, there were signs of biofilms in eight out of 23 biopsies (30 %), probably representing skin flora. PCR and 16s sequencing detected bacteria in seven out of 20 (35 %) usable middle ear biopsies, and in two out of ten (20 %) usable control samples. There was no association between biofilm findings and PCR and 16s sequencing. Staphylococci were the most common bacteria in bacterial culture. We found evidence of bacterial biofilms in 43 % of middle ear biopsies from patients COM. The findings may indicate that biofilms are a part of the pathogenesis in recurrent episodes of ear discharge in COM, but further investigations are necessary. PMID- 24477341 TI - Unexpected pathologies in patients referred for endoscopic DCR. AB - The objective of this study is to describe a series of patients with different pathologies mimicking nasolacrimal duct obstruction (NLDO), diagnosed with the use of a computed tomography (CT) scan prior to a scheduled endoscopic dacryocystorhinostomy (DCR). This study is a retrospective report. We reviewed the medical records of 47 consecutive patients (57 sides) with long-standing epiphora between 2007 and 2012. All patients were referred to our tertiary Medical Center with a diagnosis of NLDO and were expected to undergo endoscopic dacryocystorhinostomy (DCR). They all underwent routine sinus CT scan prior to surgery. All scans, as well as the demographic and medical characteristics of these patients were reviewed. Of all 47 patients enrolled, in 4 patients (7 % of all sides), unexpected pathologies, other than nasolacrimal system distention, inflammation or infection were identified preoperatively. These included squamous cell carcinoma of the lacrimal sac and nasolacrimal duct, rhinoscleroma at Hasner's valve region, a compressing ethmoidal mucocele and a case of dacryocystocele. These unusual pathologies mandated a different management and surgical approach. In all four cases, a preoperative CT scan helped in identifying the pathology and in localizing the lacrimal apparatus in relation to the paranasal sinuses. Different nasal, paranasal and lacrimal pathologies may mimic primary acquired NLDO. A high index of suspicion, a thorough clinical evaluation and utilizing preoperative imaging may lead to an alteration of patient management and to a completely different surgical approach. PMID- 24477342 TI - Luteolin induces apoptosis by activating Fas signaling pathway at the receptor level in laryngeal squamous cell line Hep-2 cells. AB - Luteolin, a naturally occurring flavonoid, possesses anti-cancer activities against several human cancers, but the exact molecular and biochemical mechanisms of above findings are not very clear, and its activity against head and neck squamous cell carcinoma (HNSCC) is seldom mentioned. In this study, we investigated luteolin against human laryngeal squamous cell line Hep-2 cells, using MTT assay, flow cytometry, Western blot and reverse transcriptase polymerase chain reaction (RT-PCR) analysis. Luteolin inhibited Hep-2 cells proliferation at the inhibitive concentrations of 50% (IC50) near to 50 MUM and induced the apoptosis in Hep-2 cells through caspase-3 and caspase-8 activation. Up-regulation of Fas and down-regulation of long form cellular FLICE-like inhibitory protein (c-FLIPL) protein were also involved after luteolin treatment at both protein and mRNA levels. Luteolin could not only inhibit cell proliferation but also induce apoptosis by activating the Fas signaling pathway at the receptor level in laryngeal squamous cell line Hep-2 cells. PMID- 24477343 TI - A two-nucleotide deletion renders the mannose-binding lectin 2 (MBL2) gene nonfunctional in Danish Landrace and Duroc pigs. AB - The mannose-binding lectins (MBLs) are central components of innate immunity, facilitating phagocytosis and inducing the lectin activation pathway of the complement system. Previously, it has been found that certain single-nucleotide polymorphisms (SNPs) in porcine MBL1 and MBL2 (pMBL1, pMBL2) affect mRNA expression, serum concentration, and susceptibility to disease, but the combinatory effect of pMBL1 and pMBL2 genotypes needs further elucidation. In the present study, pMBL1 and pMBL2 alleles, combined pMBL haplotypes, and MBL-A concentration in serum were analyzed in purebred Landrace (N = 30) and Duroc (N = 10) pigs. Furthermore, the combined pMBL haplotypes of 89 Pietrain * (Large White * Landrace) crossbred pigs were studied, and the genotypes of 67 crossbreds challenged with Escherichia coli were compared to their individual disease records. In the purebred animals, three non-synonymous SNPs and a two-nucleotide deletion were detected in the coding sequence of pMBL2. The two-nucleotide deletion was present at a frequency of 0.88 in the Landrace pigs and 0.90 in the Duroc pigs, respectively. In the crossbreds, the T allele of the SNP G949T in pMBL1-previously shown to have profound effect on MBL-A concentration even in the heterozygote condition-was detected in 47 % of the animals. Finally, an association was found between low-producing MBL genotypes and low body weight on the day of weaning in the same animals. PMID- 24477344 TI - The association of Toxoplasma gondii infection with neurocognitive deficits in a population-based analysis. AB - PURPOSE: To examine the relationship between infection with Toxoplasma gondii (toxo) and cognition. METHODS: Multivariate logistic regression was used to test the association of toxo seropositivity with indices of cognitive function among over 4,200 adults in the third National Health and Nutrition Examination Survey. RESULTS: Toxo-seropositive participants were more likely than seronegative participants to score in the worst quartile of the simple reaction time test (OR 1.3, 95 % CI 1.0, 1.6), symbol-digit substitution test (SDST, OR 1.5, 95 % CI 1.2, 1.9) and the serial-digit learning test (trials to criterion) (SDLTNT, OR 1.4, 95 % CI 1.1, 1.8) in models adjusted for age, race/ethnicity, gender and foreign birth. After further adjustment for all cofactors, the association between toxo seropositivity and these outcomes was no longer significant. However, seropositivity was associated with worse scores on the SDST (OR 2.9, 95 % CI 1.8, 4.8) among those in the lowest income category and the SDLTNT (OR 1.5, 95 % CI 1.1, 2.5) among those foreign born. CONCLUSIONS: Toxo seropositivity may be associated with poor cognitive test scores in certain subgroups; however, causation cannot be established in this cross-sectional study. PMID- 24477345 TI - NO oxidation catalysis on copper doped hexagonal phase LaCoO3: a combined experimental and theoretical study. AB - Cobalt-based perovskite catalysts showed excellent performance towards NO-NO2 oxidation. We systematically investigated the influence of different levels of Cu doping on the catalytic performance of hexagonal phase LaCoO3 (LaCo1-xCuxO3 (x = 0.1, 0.2, 0.3)) for NO oxidation. The catalytic activities of the oxide catalysts followed the sequence: LaCo0.9Cu0.1O3 > LaCoO3 > LaCo0.8Cu0.2O3 > LaCo0.7Cu0.3O3 where the highest NO conversion for LaCo0.9Cu0.1O3 was 82% at 310 degrees C. The relevant structural characterizations were conducted by XRD, BET, FTIR and TEM. The interaction between Co and Cu promoted the conversion of NO to NO2. Upon increasing the Cu doping content, a decrease of the performance resulted from the generation of isolated CuO on the surface of the oxides, confirmed using H2-TPR and XPS. Combined with first-principle calculations, we explored the reaction mechanism of NO oxidation on the surface and found that Cu doping would facilitate the reaction by decreasing the energy of oxygen vacancy formation and the NO2 desorption barrier from Co- or Cu-nitrite. PMID- 24477346 TI - Sporopollenin in the cell wall of Chlorella and other algae: Ultrastructure, chemistry, and incorporation of (14)C-acetate, studied in synchronous cultures. AB - Cells of Chlorella fusca var. vacuolata (Cambridge 211/8p) resisted efforts aimed at producing naked protoplasts by enzymatic degradation of the cell wall, and a study of the development and composition of the wall was therefore undertaken. 1. After cytokinesis has produced naked autospores within the mother cell wall, cell wall formation commences outside the autospore plasma membrane with the appearance of small trilaminar plaques. These enlarge while inter-autospore granular material diminishes in quantity, and they eventually fuse to produce a complete trilaminar sheath around each autospore. 2. A microfibrillar, cellulase digestible, layer is deposited between the trilaminar component and the plasma membrane. Meanwhile the corresponding microfibrillar component of the mother cell wall is digested leaving only its resistant trilaminar component. 3. The trilaminar component includes a substance considered to be the polymerized carotenoid, sporopollenin, on the basis of its resistance to extreme extraction procedures including acetolysis, and its infra red absorption spectrum. 4. Two phases of sporopollenin biosynthesis were detected by means of pulse and pulse chase treatments with (14)C-acetate at intervals during the cell cycle in synchronous cultures. One coincides with the formation of the sporopollenin containing trilaminar wall component, and the other is 6-8 hours earlier while the cells are in karyokinesis. The former yields labelled sporopollenin directly and the latter probably represents formation of a precursor. 5. Of five other strains of Chlorella tested, only one possesses sporopollenin, and so does one Scenedesmus and two out of three strains of Prototheca. 6. Examination of the wall structure of the above algae suggest a relationship between the presence of sporopollenin and the development of an outer, trilaminar wall component. 7. A survey of the literature gives support to this hypothesis and further suggests that the ability to synthesise sporopollenin is related to the ability to produce secondary carotenoids. 8. The significance of the findings is discussed. PMID- 24477347 TI - [Investigation of photosynthetic transients in Chlorella vulgaris at different temperatures using radioactive CO2]. AB - CO2 exchange, (14)CO2 fixation and radioactive products of Chlorella vulgaris (strain 211-11f) were examined during the induction period at temperatures of +10 degrees and +35 degrees C. The algae were grown under low CO2 concentration (0.03 vol.-%) at a temperature of +27 degrees C. The formation of transients in CO2 uptake in Chlorella, measured with an infrared gas analyser, is highly dependent on the temperature used during the measurements. At higher temperatures (+15 degrees C and above) a maximum in CO2 uptake exists at the beginning of the illumination period followed by a minimum before a steady rate of photosynthesis is reached. At a temperature of +10 degrees C, on the other hand, a long lag phase without a minimum in CO2 uptake could be observed which also occurs in the time course of (14)CO2 fixation.The autoradiographic studies of the kinetics of the appearance of labelled products at a temperature of +10 degrees C showed that at the beginning of the light period nearly all of the radioactivity was incorporated into malate and aspartate. Under these conditions intermediates of the Calvin cycle were labelled after an illumination time of 2 minutes. At a temperature of +35 degrees C radioactivity appeared in 3-phosphoglycerate as well as in malate and aspartate after a photosynthetic period of 10 sec. At this temperature 3-phosphoglycerate not only appeared earlier than at +10 degrees C but it was also more strongly labelled. Moreover the intermediates of the Calvin cycle were labelled after 20 or 30 sec of photosynthesis. These results show that a carboxylation of phosphoenolpyruvate and the Calvin cycle are involved in the formation of the transients of CO2 uptake in Chlorella vulgaris. The possible role of the control of photosynthetic carbon metabolism during the induction period is discussed. PMID- 24477348 TI - Hydroxyproline: Observations on its chemical and autoradiographical localization in plant cell wall protein. AB - In sycamore suspension cells both autoradiographical and chemical techniques have confirmed the idea that most of the protein that contains hydroxyproline is located within the cell wall. Relatively more hydroxyproline is incorporated into the walls of stationary phase cells than into those of cells actively engaged in cell division. It is probable that the protein enters the wall during and after the later stages of cell plate consolidation, and this may be facilitated by means of smooth membrane. Distinctive and heavy incorporation of radioactive proline is found associated with unusual wall thickenings or 'warts'. PMID- 24477349 TI - Blue-light control of sporangiophore initiation in Phycomyces. AB - Many fungi produce spores or spore-bearing structures under the control of blue light. Sporangiophores of Phycomyces blakesleeanus are produced continuously along racing tube cultures grown in constant darkness or constant light. However, if a dark-grown culture is exposed to light for a short time on one day a narrow, dense band of sporangiophores is observed the next day at that point of the tube occupied by the mycelial tips during the light pulse. A periodic program with "short days" (e.g., 4 h light; 20 h dark), leads to periodic bands of sporangiophores spaced at intervals corresponding to one period-length (in this case 24 h) of mycelial growth. Sporangiophore initiation is inhibited by a light to dark transition and is stimulated by a dark to light transition. A partial action spectrum of the initiation response, covering the critical 480-540 nm region, strongly suggests that the same photoreceptor pigment is involved as in the phototropic response and light growth response of sporangiophores. Mutants with altered light control of sporangiophore initiation have been found among those selected for altered phototropism. This joint elimination of these two responses to blue light by a single mutation is evidence for a common early transduction system. PMID- 24477350 TI - Lipids of membranes and of the cell envelope in heterocysts of a blue-green alga. AB - Heterocysts of Anabaena cylindrica, isolated rapidly in the cold, were found-in contrast to earlier reports-to contain all of the same lipids and lipophilic pigments, and in about the same proportions, as vegetative cells. In broken filaments and in heterocysts damaged during isolation, the membrane lipids and certain pigments (myxoxanthophyll and an unidentified red pigment) break down rapidly. The glycolipids specific to heterocyst-forming blue-green algae are localized in the laminated layer of the heterocyst envelope. A possible role of the laminated layer is discussed. PMID- 24477351 TI - The biological activity of fluorogibberellins. AB - The biological activities of gibberellin A9 (GA9), gibberellin A12 (GA12) and monofluoro-analogues (F-GA9 and F-GA12), substituted in the 1 beta-methyl group, were compared in the barley endosperm, cucumber hypocotyl, lettuce hypocotyl, 'Meteor' dwarf pea, dwarf-5 maize and Rumex leaf disc assays. In most cases the fluorosubstituted compounds had a potency similar to, or less than, the relevant unmodified gibberellin but, in the lettuce assay, F-GA9 was approximately 5 times more active than GA9 up to a dose rate of 10(-1) MUg.A 27-30% mixture of fluorogibberellin A3 (F-GA3) in GA3 had a lower activity than 100% GA3 in the barley endosperm, lettuce hypocotyl and dwarf maize assays. This suggested that pure F-GA3 may be a competitive inhibitor of GA3 action. The findings are discussed in the context of the structure/activity relationships of the gibberellins. PMID- 24477352 TI - The effect of protease digestion (in situ) on the slime substance of mature sieve tubes. AB - The sieve tube slime of Tetragonia and Lycopersicum petiolar phloem was subjected to proteolytic enzymes both before and after embedding and sectioning. Subsequent electron microscopical examination confirmed that the fibrillar material is protein in nature, and provided evidence that the protein is acidic rather than basic. PMID- 24477353 TI - Local bias induced ferroelectricity in manganites with competing charge and orbital order states. AB - Perovskite-type manganites, such as Pr1-xCaxMnO3, La1-xCaxMnO3 and La1-xSrxMnO3 solid solutions, are set forth as a case study of ferroelectricity formation mechanisms associated with the appearance of site- and bond-centered orbital ordering which breaks structural inversion symmetry. Even though the observation of macroscopic ferroelectricity may be hindered by the finite conductivity of manganites, polarization can still exist in nanoscale volumes. We use Piezoresponse Force Microscopy to probe local bias induced modifications of electrical and electromechanical properties at the manganite surface. Clear bias induced piezocontrast and local hysteresis loops are observed for La0.89Sr0.11MnO3 and Pr0.60Ca0.40MnO3 compounds providing convincing evidence of the existence of locally induced polar states well above the transition temperature of the CO phase, while the reference samples without CO behavior show no ferroelectric-like response. Such coexistence of ferroelectricity and magnetism in manganites due to the charge ordering (CO) under locally applied electric field opens up a new pathway to expand the phase diagrams of such systems and to achieve spatially localized multiferroic effects with a potential to be used in a new generation of memory cells and data processing circuits. PMID- 24477354 TI - Real-world cost-effectiveness: lower cost of treating patients to glycemic goal with liraglutide versus exenatide. AB - INTRODUCTION: While the liraglutide effect and action in diabetes (LEAD-6) clinical trial compared the efficacy and safety of liraglutide once daily (LIRA) to exenatide twice daily (EXEN) in adult patients with type 2 diabetes, few studies have explored the associated per-patient costs of glycemic goal achievement of their use in a real-world clinical setting. METHODS: This retrospective cohort study used integrated medical and pharmacy claims linked with glycated hemoglobin A1C (A1C) results from the IMS Patient-Centric Integrated Data Warehouse. Patients' >=18 years and naive to incretin therapies during a 6-month pre-index period, with >=1 prescription for LIRA or EXEN between January 2010 and December 2010, were included. Patients with evidence of insulin use (pre- or post-index) were excluded. Only patients who were persistent on their index treatment during a 180-day post-index period were included. Follow-up A1C assessments were based on available laboratory data within 45 days before or after the 6-month post-index point in time. Diabetes-related pharmacy costs over the 6-month post-index period were captured and included costs for both the index drugs and concomitant diabetes medications. RESULTS: 234 LIRA and 182 EXEN patients were identified for the analysis. The adjusted predicted diabetes related pharmacy costs per patient over the 6-month post-index period were higher for LIRA compared to EXEN ($2,002 [95% confidence interval (CI): $1,981, $2,023] vs. $1,799 [95% CI: $1,778, $1,820]; P < 0.001). However, a higher adjusted predicted percentage of patients on LIRA reached A1C < 7% goal (64.4% [95% CI: 63.5, 65.3] vs. 53.6% [95% CI: 52.6, 54.6]; P < 0.05), translating into lower average diabetes-related pharmacy costs per successfully treated patient for LIRA as compared to EXEN ($3,108 vs. $3,354; P < 0.0001). CONCLUSIONS: Although predicted diabetes-related pharmacy costs were greater with LIRA vs. EXEN, a higher proportion of patients on LIRA achieved A1C < 7%, resulting in a lower per patient cost of A1C goal achievement with LIRA compared to EXEN. PMID- 24477355 TI - Combining oxime-based [Mn6] clusters with cyanometalates: 1D chains of [Mn6] SMMs from [M(CN)2]- (M = Au, Ag). AB - The linear [M(CN)2](-) (M = Au, Ag) anions can be used as metalloligands in oxime based Mn chemistry to afford 1D chains of [Mn(III)6] single-molecule magnets (SMMs). PMID- 24477356 TI - Natural inhibitors of thrombin. AB - The serine protease thrombin is the effector enzyme of blood coagulation. It has many activities critical for the formation of stable clots, including cleavage of fibrinogen to fibrin, activation of platelets and conversion of procofactors to active cofactors. Thrombin carries-out its multiple functions by utilising three special features: a deep active site cleft and two anion binding exosites (exosite I and II). Similarly, thrombin inhibitors have evolved to exploit the unique features of thrombin to achieve rapid and specific inactivation of thrombin. Exogenous thrombin inhibitors come from several different protein families and are generally found in the saliva of haematophagous animals (blood suckers) as part of an anticoagulant cocktail that allows them to feed. Crystal structures of several of these inhibitors reveal how peptides and proteins can be targeted to thrombin in different and interesting ways. Thrombin activity must also be regulated by endogenous inhibitors so that thrombi do not occlude blood flow and cause thrombosis. A single protein family, the serpins, provides all four of the endogenous thrombin inhibitors found in man. The crystal structures of these serpins bound to thrombin have been solved, revealing a similar exosite dependence on complex formation. In addition to forming the recognition complex, serpins destroy the structure of thrombin, allowing them to be released from cofactors and substrates for clearance. This review examines how the special features of thrombin have been exploited by evolution to achieve inhibition of the ultimate coagulation protease. PMID- 24477357 TI - Early diastolic strain rate predicts response to heart failure therapy in patients with dilated cardiomyopathy. AB - The aim of this prospective study was to assess the value of speckle tracking echocardiographic (2D-STE) parameters to predict response to heart failure therapy in patients with dilated cardiomyopathy (DCM). Eighty-seven patients (mean age 51 +/- 13 years) with DCM, defined as ejection fraction (EF) <45 %, left ventricular (LV) end-diastolic diameter >112 % of normal range derived from age and body surface area. Based on 2D-STE following parameters were extracted from three apical views of the LV: global longitudinal strain, systolic and diastolic strain rate (SRE). Mechanical dispersion was calculated as standard deviation of time-to-peak strain values including all LV segments. After receiving heart failure therapy (mean 39 +/- 11 months, range 3-60 months) 50 patients reached combined endpoint defined as following: death, heart transplantation, rehospitalization due to heart failure, and absence of improvement in EF. On stepwise multivariate regression analysis, SRE was independently of EF and LV volumes predictive for combined endpoint (OR 0.44, 95 %CI 0.27-0.70, p = 0.001) with an area under the ROC-curve (AUC) of 0.91. In patients with cQRS duration <=120 ms mechanical dispersion was predictive for combined endpoint with the highest AUC (OR 1.53, 95 %CI 1.08-2.16, p = 0.002; AUC = 0.94). In this study, SRE, a surrogate parameter of myocardial relaxation, was able to predict a response to heart failure therapy in patients with DCM. In patients with narrow QRS complex, mechanical dispersion yielded the highest predictive value. Parameters of 2D-STE may contribute to risk stratification in this patient population. PMID- 24477358 TI - Three-dimensional speckle tracking echocardiography for the preclinical diagnosis of hypertrophic cardiomyopathy. AB - The aim is to detect early changes in myocardial mechanics in hypertrophic cardiomyopathy (HCM) mutation carriers, three-dimensional speckle tracking echocardiography (3DSTE) was used for screening of family members in the HCM population. Eighty subjects were divided as: HCM mutation carriers (n = 23), manifest HCM patients (n = 28), and normal controls (n = 29). They prospectively underwent 3DSTE for left atrial (LA) and left ventricle (LV) strain analysis. HCM mutation carriers showed significantly higher LA minimum volume (ml/m(2)) (17 +/- 6 vs. 14 +/- 4, respectively, P = 0.03) and a significantly lower peak atrial longitudinal strain (PALS) (%), (27 +/- 5 vs. 31 +/- 7, respectively, P = 0.02) when compared to controls. However, no differences were found in global or regional LV systolic myocardial deformation between both groups. Manifest HCM patients, compared to carriers showed significantly higher LA minimum (27 +/- 10 vs. 17 +/- 6, respectively, P < 0.001) and maximum volume (42 +/- 14 vs. 32 +/- 8, respectively, P = 0.007) as well as lower LA ejection fraction (%) (35 +/- 8 vs. 47 +/- 9, respectively, P < 0.001) and PALS (17 +/- 5 vs. 27 +/- 5, respectively, P < 0.001). Comparing LV strain, HCM patients showed reduced global longitudinal (-11 +/- 4 vs. -16 +/- 3, respectively, P < 0.001) and area strain ( 35 +/- 6 vs. -40 +/- 5, respectively, P = 0.005). HCM mutation carriers may be distinguished from healthy subjects using 3DSTE through detection of LA dysfunction that may indicate LV diastolic dysfunction. Further research in a larger study population with gene-specific analysis is warranted for potential clinical usefulness of 3DSTE in family screening for HCM. PMID- 24477359 TI - [Social cognition in patients with mood disorders. Part II: bipolar disorder : a selective review of the literature]. AB - OBJECTIVE: Overview on the current knowledge regarding social cognition in patients with bipolar disorder. METHODS: Selective literature research on deficits in social cognition intrinsic to bipolar disorder, their occurrence and effects. RESULTS: Deficits in social cognition are considered to be core features of bipolar disorder. They are apparent during acute episodes of the disorder, endure when patients are in remission and have a significant negative impact on the patients' psychosocial outcomes. CONCLUSIONS: It is important to consider deficits in social cognition as an integral part of a treatment approach to achieve mental stabilization in patients with bipolar disorder. PMID- 24477360 TI - Revisiting the impact of REM sleep behavior disorder on motor progression in Parkinson's disease. AB - BACKGROUND: Estimation of progression in Parkinson's disease (PD) is useful to guide clinical decisions and to enable patients to plan and manage their life with PD. Rapid eye movement (REM) sleep behavior disorder (RBD) and REM sleep without atonia (RWA) are recognized as early harbingers of neurodegeneration and may precede motor symptoms by years. However, their impact on motor progression remains elusive. METHODS: We retrospectively analyzed polysomnographic and clinical data of 59 PD patients, grouping them into patients with RBD (n = 15), RWA (n = 22) and those with normal muscle atonia (n = 22). We compared the three groups with regard to motor progression, defined as changes in Unified Parkinson's Disease Rating Scale (UPDRS) III values per year, and selected PD specific characteristics. RESULTS: Motor disability at first visit and time interval between first and last visits were similar between groups. We observed a significantly faster motor progression in PD patients with RBD and RWA than in those with preserved REM sleep atonia. CONCLUSION: Our findings suggest that impaired muscle atonia during REM sleep might represent a marker of faster motor progression in PD. PMID- 24477362 TI - Post-polypectomy complications: high risk in the cecum. PMID- 24477363 TI - Risk factors for adverse events related to polypectomy in the English Bowel Cancer Screening Programme. AB - BACKGROUND AND STUDY AIMS: The English National Health Service Bowel Cancer Screening Programme (NHSBCSP) is one of the world's largest organized screening programs. Minimizing adverse events is essential for any screening program. Study aims were to determine rates and to examine risk factors for adverse events. PATIENTS AND METHODS: Bleeding and perforations in NHSBCSP colonoscopies between August 2006 and January 2012 were examined. Logistic regression was used to examine risk factors for adverse events, including age, gender, polyp size, morphology, and location. For accurate attribution of adverse events, procedures with resection of only one polyp ("single-polypectomy") were analyzed in detail. RESULTS: 130 831 colonoscopies (167 208 polypectomies) were analyzed, including 30 881 single-polypectomies. Overall bleeding rate was 0.65 %, rate of bleeding requiring transfusion was 0.04 % and perforation rate was 0.06 %. Polypectomy increased bleeding risk 11.14-fold and perforation risk 2.97-fold. Cecal location (but not elsewhere in the proximal colon) and increasing polyp size were the two most important risk factors for bleeding and perforation. After adjustment for polyp size, the odds ratio (OR) relative to the distal colon for bleeding requiring transfusion after cecal snare polypectomy was 13.5 (95 %CI 3.9 - 46.4) and for perforation after cecal nonpedunculated polypectomy it was 12.2 (95 %CI 1.2 - 119.5). CONCLUSION: This is the largest study focusing on polyp-specific risk factors. We have confirmed that the greatest risk factor for both post polypectomy bleeding and perforation is polyp size. This is the first demonstration of substantial and significantly increased risk for both noteworthy bleeding (requiring transfusion) and perforation from cecal polypectomy for a given polyp size, compared with elsewhere in the colon. PMID- 24477364 TI - Narrow band imaging does not reliably predict residual intestinal metaplasia after radiofrequency ablation at the neo-squamo columnar junction. AB - BACKGROUND AND STUDY AIMS: After radiofrequency ablation (RFA) of Barrett's esophagus, it may be difficult to determine whether complete eradication of intestinal metaplasia at the neosquamocolumnar junction (neo-SCJ) in the cardia has been achieved. It is claimed that narrow band imaging (NBI) may predict the presence of intestinal metaplasia, which would enable immediate treatment. The aim of the current study was to evaluate whether inspection of the neo-SCJ with NBI after RFA results in reliable detection of intestinal metaplasia. PATIENTS AND METHODS: Patients with a normal-appearing neo-SCJ who were scheduled for RFA were included in the study. Two expert endoscopists obtained images from the neo SCJ in overview (high resolution white light and NBI mode) and from four areas using NBI zoom, followed by corresponding biopsies. Four other blinded expert endoscopists evaluated the images for the presence of intestinal metaplasia and type of mucosal pattern (round, small tubular, large tubular, villous). Endpoints were sensitivity and specificity for identifying patients and areas with intestinal metaplasia. RESULTS: From 21 patients overview images from 21 neo-SCJs and NBI zoom images from 83 neo-SCJ areas were obtained. Intestinal metaplasia was present in five overview images (24 %) and nine zoom images (11 %). Using the overview images, sensitivity and specificity for identifying patients with intestinal metaplasia were 65 % (95 % confidence interval [CI] 38 - 86) and 46 % (95 %CI 33 - 60), respectively. For individual zoom images, sensitivity was 71 % (95 %CI 54 - 85) and specificity was 37 % (95 %CI 32 - 43). CONCLUSIONS: After RFA, endoscopic inspection of the neo-SCJ with NBI in overview or zoom does not reliably predict presence or absence of intestinal metaplasia. PMID- 24477366 TI - Prediction of celiac disease at endoscopy. AB - BACKGROUND AND STUDY AIMS: Celiac disease is increasingly recognized worldwide, but guidelines on how to detect the condition and diagnose patients are unclear. In this study the prevalence and predictors of celiac disease were prospectively determined in a cross-sectional sample of Lebanese patients undergoing esophagogastroduodenoscopy (EGD). PATIENTS AND METHODS: Consecutive consenting patients (n = 999) undergoing EGD answered a questionnaire and had blood taken for serologic testing. Endoscopic markers for celiac disease were documented and duodenal biopsies were obtained. The diagnosis of celiac disease was based on abnormal duodenal histology and positive serology. Risk factors were used to classify patients to either high or low risk for celiac disease. Independent predictors of celiac disease were derived via multivariate logistic regression. RESULTS: Villous atrophy (Marsh 3) and celiac disease were present in 1.8 % and 1.5 % of patients, respectively. Most were missed on clinical and endoscopic grounds. The sensitivity of tissue transglutaminase (tTG) testing for the diagnosis of villous atrophy and celiac disease was 72.2 % and 86.7 %, respectively. The positive predictive value of the deamidated gliadin peptide (DGP) test was 34.2 % and that of a strongly positive tTG was 80 %. While the strongest predictor of celiac disease was a positive tTG (odds ratio [OR] 131.7, 95 % confidence interval [CI] 29.0 - 598.6), endoscopic features of villous atrophy (OR 64.8, 95 %CI 10.7 - 391.3), history of eczema (OR 4.6, 95 %CI 0.8 - 28.8), anemia (OR 6.7, 95 %CI 1.2 - 38.4), and being Shiite (OR 5.4, 95 %CI 1.1 - 26.6) significantly predicted celiac disease. A strategy of biopsying the duodenum based on independent predictors had a sensitivity of 93 % - 100 % for the diagnosis of celiac disease, with an acceptable (22 % - 26 %) rate of performing unnecessary biopsies. A strategy that excluded pre-EGD serology produced a sensitivity of 93 % - 94 % and an unnecessary biopsy rate of 52 %. CONCLUSION: An approach based solely on standard clinical suspicion and endoscopic findings is associated with a significant miss rate for celiac disease. A strategy to biopsy based on the derived celiac disease prediction models using easily obtained information prior to or during endoscopy, maximized the diagnosis while minimizing unnecessary biopsies. PMID- 24477367 TI - Antireflux stents to reduce the risk of cholangitis in patients with malignant biliary strictures: a randomized trial. AB - BACKGROUND AND STUDY AIMS: There are limited data on the role of antireflux biliary stents. This single-center randomized trial compared the endoscopic use of partly covered antireflux metal stents (pcARMS) with that of standard uncovered self-expandable metal stents (ucSEMS) for the palliation of nonhilar malignant biliary obstruction. PATIENTS AND METHODS: Between August 2007 and February 2012, patients with nonhilar malignant biliary obstruction were randomly assigned to treatment with either pcARMS or ucSEMS. Subsequent follow-up was conducted in clinic or by phone. The primary outcome was onset of cholangitis within 12 months of stenting. Secondary outcomes included other morbidities, stent dysfunctions, and survival. RESULTS: Altogether 112 patients were included, 56 in each group. The stents were successfully deployed in all patients. Satisfactory jaundice control was achieved in 49 cases in the pcARMS group, compared with 47 in the ucSEMS group (P = 0.135). Fewer patients experienced cholangitis in the pcARMS group than in the ucSEMS group (10 vs. 21 patients; P = 0.035), and the frequency of episodes was less (P = 0.022). Respectively, 17 and 29 stent dysfunctions before death were observed in the pcARMS and ucSEMS groups (P = 0.051) and the median stent patency was 13.0 (standard deviation [SD] 3.4) and 10.0 (1.2) months, respectively (P = 0.044). At final follow-up, in January 2013, 50 /52 and 52 /55 patients had died and no difference in median survival was seen between the two groups (8.0 vs. 9.0 months, P = 0.56). CONCLUSIONS: Stenting with pcARMS compared with standard ucSEMS reduces risk of ascending cholangitis and has longer stent patency, but does not increase patient survival. Chictr.org. number, ChiCTR-TRC-11001800. PMID- 24477368 TI - Endoscopic papillectomy for early ampullary tumors: long-term results from a large multicenter prospective study. AB - BACKGROUND AND STUDY AIMS: Endoscopic papillectomy of early tumors of the ampulla of Vater is an alternative to surgery. This large prospective multicenter study was aimed at evaluating the long-term results of endoscopic papillectomy. PATIENTS AND METHODS: Between September 2003 and January 2006, 10 centers included all patients referred for endoscopic papillectomy and meeting the inclusion criteria: biopsies showing at least adenoma, a uT1N0 lesion without intraductal involvement at endoscopic ultrasound (EUS), and no previous treatment. A standardized endoscopic papillectomy was done, with endoscopic monitoring with biopsies 4 - 8 weeks later where complications were recorded and complementary resection performed when necessary. Follow-up with duodenoscopy, biopsies, and EUS was done at 6, 12, 18, 24 and 36 months. Therapeutic success was defined as complete resection (no residual tumor found at early monitoring) without duodenal submucosal invasion in the resection specimen in the case of adenocarcinoma and without relapse during follow-up. RESULTS: 93 patients were enrolled. Mortality was 0.9 % and morbidity 35 %, including pancreatitis in 20 %, bleeding 10 %, biliary complications 7 %, perforation 3.6 %, and papillary stenosis in 1.8 %. Adenoma was not confirmed in the resection specimen in 14 patients who were therefore excluded. Initial treatment was insufficient in 9 cases (8 carcinoma with submucosal invasion; 1 persistence of adenoma). During follow-up, 5 patients had tumor recurrence and 7 died from unrelated diseases without recurrence. Finally, 81.0 % of patients were cured (95 % confidence interval 72.3 % - 89.7 %). CONCLUSION: Endoscopic papillectomy of selected ampullary tumors is curative in 81.0 % of cases. It must be considered to be the first-line treatment for early tumors of the ampulla of Vater without intraductal invasion. PMID- 24477369 TI - Safety of the colonoscope magnetic imaging device (ScopeGuide) in patients with implantable cardiac devices. AB - BACKGROUND AND STUDY AIMS: Use of the colonoscope magnetic imaging device (ScopeGuide, Olympus Medical Systems, Tokyo, Japan) is currently contraindicated by the manufacturer for patients with implantable cardiac devices, a group of patients that is increasing annually along with the number of colonoscopies performed in the era of colorectal cancer screening. This is the first study to examine the safety of ScopeGuide in patients with permanent pacemakers, implantable cardioverter defibrillators, and cardiac resynchronization therapy. PATIENTS AND METHODS: Nonimplanted cardiac devices were exposed to the electromagnetic field of ScopeGuide ex vivo and assessed for evidence of interference or change in device settings. Following this, consecutive patients attending device check clinics were prospectively recruited and exposed to the ScopeGuide electromagnetic field. After an initial device check, patients underwent continuous external cardiac monitoring and device interrogation while a colonoscope was placed on the abdomen over clothing and connected to ScopeGuide to simulate colonoscopy. Patients were monitored for 2 minutes to assess for any interference. ScopeGuide was then disconnected and devices were checked for any change in settings. RESULTS: A total of 230 patients were invited to participate and 100 were recruited to the study. There was no evidence of interference on device leads or change in programming following exposure to the electromagnetic field generated by ScopeGuide. CONCLUSION: ScopeGuide does not appear to cause interference or change in settings and is therefore likely to be safe for use in patients with implantable cardiac devices. PMID- 24477370 TI - Is wire-guided selective bile duct cannulation effective for prevention of post ERCP pancreatitis by all endoscopists? PMID- 24477371 TI - Reply to Kawakami et al. PMID- 24477372 TI - Standard or ultrathin device for colonoscopy? PMID- 24477375 TI - Factors associated with a low level of physical activity in patients with chronic obstructive pulmonary disease. AB - BACKGROUND: Physical activity such as walking is strongly recommended for patients with chronic obstructive pulmonary disease (COPD). METHODS: We undertook a multicenter observational study on COPD patients, collecting the daily walking time, COPD severity score (COPDSS), functional status [London Chest Activity of Daily Living (LCADL) questionnaire], health-related quality of life (QoL) rating [five-item EuroQL (EQ-5D) and Airways Questionnaire 20 (AQ20)], and anxiety and depression rating (Hospital Anxiety and Depression Scale). Multivariate logistic regression modeling was performed to identify the independent predictors of a low walking time (<30 min/day). RESULTS: We included 4,574 patients with a mean (+/ standard deviation) age of 67.1 +/- 10.0 years, with a mean FEV1 (%) of 54.0 +/- 23.7. The mean daily walking time was 73.6 +/- 67.1 min (58.9 % at >=60 min and 13.7 % at <30 min). A strong direct relationship was observed between daily walking time and better QoL (EQ-5D and AQ20) and functional status (LCADL; p < 0.001 in all cases). The independent predictors of a low walking time were a worse score in EQ-5D [odds ratio (OR) (95 % confidence interval per one-point increase of 0.23 (0.15-0.35)], a higher COPDSS [OR per one-point increase of 1.04 (1.02-1.07)], and the presence of depression [OR 1.58 (1.25-2.01)]. CONCLUSIONS: After adjustment for age and severity of symptoms, poor health status, severity of COPD, and depression are the main factors associated with a low walking time in COPD patients. PMID- 24477376 TI - Improved ticagrelor antiplatelet effect on discontinuation of phenytoin. AB - OBJECTIVE: To report the influence of phenytoin on the antiplatelet effects of ticagrelor using a validated platelet aggregation study. CASE SUMMARY: A 71-year old man with coronary artery disease underwent percutaneous coronary intervention to revascularize several major coronary arteries. The patient was previously on phenytoin and was initiated on ticagrelor for antiplatelet therapy following stent placement. While the patient was receiving both drugs, platelet aggregation studies revealed less platelet inhibition than would be expected in a patient not taking a concomitant inducer of ticagrelor metabolism. On discontinuation of phenytoin, platelet inhibition improved. DISCUSSION: Dual antiplatelet therapy with aspirin and a P2Y12 receptor antagonist following placement of coronary stents is critical to prevent stent thrombosis and subsequent myocardial infarction. Ticagrelor is a recently approved P2Y12 receptor antagonist that is subject to drug-drug interactions involving the hepatic cytochrome P450-3A4 enzyme system because of its metabolic elimination pathway. This case demonstrates ticagrelor's drug-drug interaction with phenytoin through a platelet aggregation study and supports the manufacturer recommendation to avoid the combination of ticagrelor with any known inducers of cytochrome P450-3A4 metabolism. CONCLUSION: The combination of ticagrelor and phenytoin may represent a potentially clinically significant drug-drug interaction because of phenytoin induction of ticagrelor metabolism and reduced P2Y12 receptor inhibition in patients who have recently undergone percutaneous coronary intervention and cardiac stent placement. PMID- 24477377 TI - Shared decision-making in back pain consultations: an illusion or reality? AB - PURPOSE: Amid a political agenda for patient-centred healthcare, shared decision making is reported to substantially improve patient experience, adherence to treatment and health outcomes. However, observational studies have shown that shared decision-making is rarely implemented in practice. The purpose of this study was to measure the prevalence of shared decision-making in clinical encounters involving physiotherapists and patients with back pain. METHOD: Eighty outpatient encounters (comprising 40 h of data) were observed audio-recorded, transcribed verbatim and analysed using the 12-item OPTION scale. The higher the score, the greater is the shared decision-making competency of the clinicians. RESULTS: The mean OPTION score was 24.0% (range 10.4-43.8%). CONCLUSION: Shared decision-making was under-developed in the observed back pain consultations. Clinicians' strong desire to treat acted as a barrier to shared decision-making and further work should focus on when and how it can be implemented. PMID- 24477378 TI - Validity of a single-item measure to assess leg or back pain as the predominant symptom in patients with degenerative disorders of the lumbar spine. AB - PURPOSE: Recent studies suggest that the location of predominant pain (back or leg) can be a significant predictor of the outcome of surgery for degenerative spinal disorders. However, others challenge the notion that the predominant symptom can be reliably identified. This study examined the validity of a single item used to determine the most troublesome symptom. METHODS: A total of 2,778 patients with degenerative disorders of the lumbar spine scheduled for surgery with the goal of pain relief completed a questionnaire enquiring as to their most troublesome symptom ["main symptom"; back pain (BACK) or leg/buttock pain (LEG)]. They also completed separate 0-10 graphic rating scales for back pain (LBP) and leg/buttock pain (LP) intensity. Receiver operating characteristics (ROC) analysis was used to determine the accuracy with which the "LP minus LBP" score was able to classify patients into their declared "main symptom" group. Sub studies evaluated the test-retest reliability of the patients' self-rated pain scores (N = 45) and the agreement between the main symptom declared by the patient in the questionnaire and that documented by the surgeon after the clinical consultation (N = 118). RESULTS: Test-retest reliability of the back and leg pain scores was good (ICC2,1 of 0.8 for each), as was patient-surgeon agreement regarding the main symptom (BACK or LEG) (kappa value 0.79). In the BACK group, the mean values for pain intensity were 7.3 +/- 2.0 (LBP) and 5.2 +/- 2.9 (LP); in the LEG group, they were 4.3 +/- 2.9 (LBP) and 7.5 +/- 1.9 (LP). The area under the curve for the ROC was 0.95 (95 % CI 0.94-0.95), indicating excellent discrimination between the BACK and LEG groups based on the "LP minus LBP" scores. A cutoff score >0.0 for "LP minus LBP" score gave optimal sensitivity and specificity for indicating membership of the LEG group (sensitivity 79.1%, specificity 95.7%). CONCLUSIONS: The responses on the single item for the "main symptom" were in good agreement with the differential ratings on the 0-10 pain scales for LBP and LP intensity. The cutoff >0 for "LP minus LBP" for classifying patients as LEG pain predominant seemed appropriate and suggests good concurrent validity for the single-item measure. The single item may be of use in sub-grouping patients with the same disorder (e.g. spondylolisthesis) or as an indication in surgical decision-making. PMID- 24477379 TI - Identification of intervertebral disc regeneration with magnetic resonance imaging after a long-term follow-up in patients treated with percutaneous diode laser nucleoplasty: a retrospective clinical and radiological analysis of 14 patients. AB - PURPOSE: The aim of this study was to demonstrate regeneration of intervertebral discs undergoing laser therapy with sagittal relaxation time (T2) mapping after a long-term follow-up. MATERIALS AND METHODS: Fourteen patients (9 men, 5 women; age range 20-57 years; mean age 36.5 years) treated with percutaneous 908-nm wave length diode laser nucleoplasty for lumbar disc prolapsus at our clinic between January 2006 and June 2009 were studied. For the application of laser nucleoplasty in the past, patients who did not have central canal stenosis and/or lateral stenosis, sequestered disc fragment, operation scars and bleeding disorders were selected. The intervertebral disc levels undergoing laser therapy were L3-L4 (n = 2) or L4-L5 (n = 12). Patients were called for follow-up visits after a maximum 6-years (n = 2) or a minimum 3 years (n = 3) with a mean of 4.4 years. The patients' clinical status for leg pain was evaluated according to the visual analog scale (VAS) and subsequently, a lumbar magnetic resonance imaging was performed. Sagittal T2 mapping was performed for the intervertebral discs undergoing laser nucleoplasty. We analyzed the relationship between T2 in the regions of interest (ROIs), which is known to correlate with changes in the composition of intervertebral discs, and the degree of degeneration determined using the Pfirrmann grading system and VAS of patients. RESULTS: On the basis of the evaluation of the results of intervertebral discs in all patients, there was a significant increase in T2 in the anterior NP (ROI 2, +10.3 ms; p < 0.05). A significant increase was noted in T2 in the middle NP (ROI 3, +24.6 ms; p < 0.001). The most significant increase was recorded for the posterior NP (ROI 4, +28.6 ms; p < 0.001). No significant decrease was found in T2 in the anterior and posterior AF (ROI 1, -1.5 ms; p = 0.925; ROI 5, -0.1 ms; p = 0.683). According to the Pfirrmann grading system, disc degeneration grades before laser therapy were recorded as grade III (n = 6) and grade IV (n = 8) whereas disc degeneration grades after laser therapy were found to be grade I (n = 6) and II (n = 8). A significant decrease was noted in Pfirrmann grades of disc degeneration after laser therapy (p < 0.0005). CONCLUSIONS: In this study, there was a prolongation of T2 indicating regeneration in the nucleus pulposus after laser therapy and these results were found to be consistent with VAS measurements after a long-term follow-up. This study, which demonstrates the quantitative efficacy of laser therapy, indicates that MRG can be more effectively used in the future. PMID- 24477382 TI - Intrinsic photosensitizer fluorescence measured using multi-diameter single-fiber spectroscopy in vivo. AB - Quantification of fluorescence in vivo is complicated by the influence of tissue optical properties on the collected fluorescence signal. When tissue optical properties in the measurement volume are quantified, one can obtain the intrinsic fluorescence, which equals the product of fluorophore absorption coefficient and quantum yield. We applied this method to in vivo single-fiber fluorescence spectroscopy measurements on mouse tongue, skin, liver, and oral squamous cell carcinoma, where we detected intrinsic fluorescence spectra of the photosensitizers chlorin e6 and Bremachlorin at t=[3,4.5,6,24,48] h incubation time. We observed a tissue-dependent maximum of 35% variation in the total correction factor over the visible wavelength range. Significant differences in spectral shape over time between sensitizers were observed. Although the wavelength position of the fluorescence intensity maximum for ce6 shifted to the red, Bremachlorin showed a blue shift. Furthermore, the Bremachlorin peak appeared to be broader than the ce6 fluorescence peak. Intrinsic fluorescence intensity, which can be related to photosensitizer concentration, was decreasing for all time points but showed significantly more Bremachlorin present compared to ce6 at long incubation times. Results from this study can be used to define an optimal treatment protocol for Bremachlorin-based photodynamic therapy. PMID- 24477380 TI - Lumbar trabecular bone mineral density distribution in patients with and without vertebral fractures: a case-control study. AB - PURPOSE: The proportion of load transmitted through the lumbar neural arch increases with aging, spinal degeneration, and lordosis, effectively shielding the lumbar vertebral bodies from load. This stress shielding may contribute to bone loss in the vertebral body, leading to increased fracture risk. To test his hypothesis, we performed a study to determine if vertebral body fractures were associated with a higher neural arch/vertebral body volumetric bone mineral density (vBMD) ratio. METHODS: Trabecular vBMD was calculated by quantitative CT in the L3 vertebral body and neural arch (pars interarticularis) of 36 women with vertebral compression fractures and 39 controls. Neural arch/vertebral body vBMD ratio was calculated, and its relationship to fracture status was determined using linear regression models adjusted for age and body mass index. RESULTS: Vertebral body trabecular vBMD was lower in fracture cases as compared to controls (mean +/- SD, 49.0 +/- 36.0 vs. 87.5 +/- 36.8 mg/cm(3), respectively; P < 0.001), whereas trabecular vBMD of the neural arch was similar (96.1 +/- 57.6 in cases vs. 118.2 +/- 57.4 mg/cm(3) in controls; P = 0.182). The neural arch/vertebral body vBMD ratio was significantly greater in the fracture group than in controls (2.31 +/- 1.07 vs. 1.44 +/- 0.57, respectively; P < 0.001). CONCLUSION: These results support the hypothesis that stress shielding is a contributor to vertebral body bone loss and may increase fracture risk. Although further studies are needed, there may be a role for interventions that can shift vertebral loading in the spine to help prevent fracture. PMID- 24477383 TI - Comparative study on the production of poly(3-hydroxybutyrate) by thermophilic Chelatococcus daeguensis TAD1: a good candidate for large-scale production. AB - In spite of numerous advantages on operating fermentation at elevated temperatures, very few thermophilic bacteria with polyhydroxyalkanoates (PHAs) accumulating ability have yet been found in contrast to the tremendous mesophiles with the same ability. In this study, a thermophilic poly(3-hydroxybutyrate) (PHB)-accumulating bacteria (Chelatococcus daeguensis TAD1), isolated from the biofilm of a biotrickling filter used for NOx removal, was extensively investigated and compared to other PHB-accumulating bacteria. The results demonstrate that C. daeguensis TAD1 is a growth-associated PHB-accumulating bacterium without obvious nutrient limitation, which was capable of accumulating PHB up to 83.6 % of cell dry weight (CDW, w/w) within just 24 h at 45 degrees C from glucose. Surprisingly, the PHB production of C. daeguensis TAD1 exhibited strong tolerance to high heat stress as well as nitrogen loads compared to that of other PHB-accumulating bacterium, while the optimal PHB amount (3.44 +/- 0.3 g l(-1)) occurred at 50 degrees C and C/N = 30 (molar) with glucose as the sole carbon source. In addition, C. daeguensis TAD1 could effectively utilize various cheap substrates (starch or glycerol) for PHB production without pre-hydrolyzed, particularly the glycerol, exhibiting the highest product yield (Y P/S, 0.26 g PHB per gram substrate used) as well as PHB content (80.4 % of CDW, w/w) compared to other carbon sources. Consequently, C. daeguensis TAD1 is a viable candidate for large-scale production of PHB via utilizing starch or glycerol as the raw materials. PMID- 24477384 TI - Efficient preparation of pseudoalteromone A from marine Pseudoalteromonas rubra QD1-2 by combination of response surface methodology and high-speed counter current chromatography: a comparison with high-performance liquid chromatography. AB - Pseudoalteromone A (PA) is a cytotoxic and anti-inflammatory ubiquinone discovered recently from a marine bacterium Pseudoalteromonas sp. CGH2XX. In order to meet its sample supply for further in vivo pharmacological investigation, an efficient method was developed for the preparation of PA by combination of response surface methodology (RSM) and high-speed counter-current chromatography (HSCCC) from marine bacterium P. rubra QD1-2. First, optimization of culture conditions was studied by the RSM to enhance PA production. The results indicated that the optimal cultivation condition was peptone (2.21 g/l), yeast extract (3.125 g/l), glucose (0.125 g/l), KBr (0.02 g/l), inoculum size (6.5 %), medium volume (595 ml), initial pH value (7.0), temperature (28 degrees C). Under the optimized fermentation condition, PA production was 1.04 mg/l with 14.8-fold increase comparing to 0.07 mg/l under original standard fermentation condition. The PA production was further investigated using a 14-l jar fermenter. Compared to the flask culture, P. rubra QD1-2 offered 45 % increase of PA production at 1.51 mg/l. Then, a rapid and efficient method for the separation and purification of PA from crude culture extract was developed using HSCCC. The two-phase solvent system used for HSCCC separation was composed of n-hexane-ethyl acetate-methanol-water (5:5:9:5, v/v/v/v). The isolation was accomplished within 100 min, and the purity of PA was over 95 %. The recovery of the process was 93 %. PMID- 24477385 TI - Loop-mediated isothermal amplification (LAMP) assays for detection and identification of aquaculture pathogens: current state and perspectives. AB - Since its invention in 2000, loop-mediated isothermal amplification (LAMP) assay has been one of the most extensively used molecular diagnostic tools in bio medical fields due to the rapidity, accuracy, and cost-effectiveness of the technique. This technique has also earned popularity in aquaculture disease diagnosis. Aquaculture, as a result of its rapid intensification and expansion, experiences increased infectious disease occurrences. For maintenance of economic viability, rapid, sensitive and efficient diagnosis of disease causing agents is an important step prior to undertaking effective prevention and control measures in aquaculture. Constraints on time and expertise required for conventional biochemical, serological and polymerase chain reaction (PCR)-based techniques offer avenues in adoption of the LAMP by the aquaculturists at field conditions. This assay has been successfully applied in detection of several bacterial, viral and parasitic pathogens causing serious diseases in aquaculture. In this review, we endeavored to accommodate the LAMP methodology with its different recent improvements and an overview of its application for the detection of aquaculture associated pathogens. PMID- 24477386 TI - Transgenic protein production in silkworm silk glands requires cathepsin and chitinase of Autographa californica multicapsid nucleopolyhedrovirus. AB - The silkworm Bombyx mori represents an established in vivo system for the production of recombinant proteins. Baculoviruses have been extensively investigated and optimised for the expression of high protein levels inside the haemolymph of larvae and pupae of this lepidopteran insect. Current technology includes deletion of genes responsible for the activity of virus-borne proteases, which in wild-type viruses, cause liquefaction of the host insect and enhance horizontal transmission of newly synthesised virus particles. Besides the haemolymph, the silk gland of B. mori provides an additional expression system for recombinant proteins. In this paper, we investigated how silk gland can be efficiently infected by a Autographa californica multicapsid nuclear polyhedrosis virus (AcMNPV). We demonstrated that the viral chitinase and the cysteine protease cathepsin are necessary to permit viral entry into the silk gland cells of intrahaemocoelically infected B. mori larvae. Moreover, for the first time, we showed AcMNPV crossing the basal lamina of silk glands in B. mori larvae, and we assessed a new path of infection of silk gland cells that can be exploited for protein production. PMID- 24477387 TI - Epigenetics of sleep and chronobiology. AB - The circadian clock choreographs fundamental biological rhythms. This system is comprised of the master circadian pacemaker in the suprachiasmatic nucleus and associated pacemakers in other tissues that coordinate complex physiological processes and behaviors, such as sleep, feeding, and metabolism. The molecular circuitry that underlies these clocks and orchestrates circadian gene expression has been the focus of intensive investigation, and it is becoming clear that epigenetic factors are highly integrated into these networks. In this review, we draw attention to the fundamental roles played by epigenetic mechanisms in transcriptional and post-transcriptional regulation within the circadian clock system. We also highlight how alterations in epigenetic factors and mechanisms are being linked with sleep-wake disorders. These observations provide important insights into the pathogenesis and potential treatment of these disorders and implicate epigenetic deregulation in the significant but poorly understood interconnections now emerging between circadian processes and neurodegeneration, metabolic diseases, cancer, and aging. PMID- 24477388 TI - Dreaming and offline memory consolidation. AB - Converging evidence suggests that dreaming is influenced by the consolidation of memory during sleep. Following encoding, recently formed memory traces are gradually stabilized and reorganized into a more permanent form of long-term storage. Sleep provides an optimal neurophysiological state to facilitate this process, allowing memory networks to be repeatedly reactivated in the absence of new sensory input. The process of memory reactivation and consolidation in the sleeping brain appears to influence conscious experience during sleep, contributing to dream content recalled on awakening. This article outlines several lines of evidence in support of this hypothesis, and responds to some common objections. PMID- 24477390 TI - Socioeconomic disparities in colorectal cancer mortality in the United States, 1990-2007. AB - United States colorectal cancer mortality rates have declined; however, disparities by socioeconomic status and race/ethnicity persist. The objective of this study was to describe the temporal association between colorectal cancer mortality and socioeconomic status by sex and race/ethnicity. Cancer mortality rates in the United States from 1990 to 2007, which were generated by the National Center for Health Statistics, and county-level socioeconomic status, which was estimated as the proportion of county residents living below the national poverty line based on 1990 US Census Bureau data, were obtained from the Surveillance, Epidemiology, and End Results program. The Kunst-Mackenbach relative index of inequality, which considers data across all poverty levels when comparing risks in the poorest (>= 20%) and richest counties (<10%), was calculated as the measure of association. The study found that colorectal cancer mortality rates were significantly lower in the poorest counties than the richest counties during 1990-1992 among non-Hispanic whites, non-Hispanic black women and non-Hispanic API men. Over time though the tendency was for the poorest counties to have higher mortality rates. By 2003-2007 colorectal cancer mortality rates were significantly higher in the poorest than the richest counties among all sex race/ethnicity groups. This disparity was most noticeable and appeared to be increasing most among Hispanic men. This suggests that socioeconomic disparities in colorectal cancer mortality were apparent after stratifying by sex and race/ethnicity and reversed over time. Further studies into the causes of these disparities would provide a basis for targeted cancer control interventions and allocation of public health resources. PMID- 24477389 TI - Distal myopathies. AB - Advanced molecular genetic possibilities have made it possible to clarify and delineate an ever growing number of distinct new disease entities in the group of distal myopathies. These diseases share the clinical features of preferential muscle weakness in the feet and/or hands, and as they are genetic disorders that lead to progressive loss of muscle tissue they can also be called distal muscular dystrophies. More than 20 entities are currently identified and many are still waiting for genetic characterisation. No final diagnosis can be made on other grounds than by the molecular genetic defect. Besides the usual investigations, including electromyography and muscle biopsy, muscle imaging is very important in defining the precise pattern of muscle involvement. Based on the combination of age at onset, mode of inheritance, pathology and muscle imaging, the list of possible underlying genes can be tracked down to minimal number allowing for specific genetic testing. PMID- 24477392 TI - Low-level laser therapy with a wrist splint to treat carpal tunnel syndrome: a double-blinded randomized controlled trial. AB - The efficacy of low-level laser therapy (LLLT) was evaluated in a total of 66 patients with mild to moderate carpal tunnel syndrome (CTS) with a double-blinded randomized controlled study. The patients were randomly assigned into two groups. Group I received 15 sessions of a gallium-aluminum-arsenide laser treatment at a dosage of 18 J per session over the carpal tunnel area with neutral wrist splint. Group II received placebo laser therapy with neutral wrist splint. The patients were evaluated with the following parameters: (1) clinical parameters which consisted of visual analog scale, symptom severity scale, functional status scale, and pinch strength and grip strength before the treatment and at 5- and 12 week follow-ups and (2) electroneurophysiological parameters from nerve conduction study which were evaluated before the treatment and at 12-week follow up. Fifty nine patients (112 hands: unilateral CTS = 6 hands and bilateral CTS = 106 hands) completed the study. Both groups I and II had n = 56 hands. Improvements were significantly more pronounced in the LLLT-treated group than the placebo group especially for grip strength at 5- and 12-week follow-ups. At 12-week follow-up, distal motor latency of the median nerve was significantly improved in the LLLT group than the placebo group (p < 0.05). LLLT therapy, as an alternative for a conservative treatment, is effective for treating mild to moderate CTS patients. It can improve hand grip strength and electroneurophysiological parameter with a carry-over effect up to 3 months after treatment for grip strength of the affected hands. PMID- 24477391 TI - Effect of Er,Cr:YSGG laser application in the treatment of experimental periodontitis. AB - The purpose of this study was to evaluate the influence of an erbium, chromium:yttrium-scandium-gallium-garnet (Er,Cr:YSGG) laser in the absence or presence of manual scaling and root planning (SRP) for the treatment of induced periodontitis in rats. Ligatures were placed in the subgingival region of the maxillary first molar. After a 7-day period, the ligatures were removed, and 40 rats were randomly divided into four groups (G), as follows: (GI) no treatment, (GII) scaling and root planning (SRP) with curettes, (GIII) Er,Cr:YSGG laser irradiation and (GIV) SRP with curettes followed by Er,Cr:YSGG laser irradiation. Seven and 30 days after the treatment, the animals were sacrificed and histologic, histometric and immunohistochemistry analyses were performed. All groups showed similar histopathological characteristics during the evaluation period. The histometric analysis was confirmed using Bonferroni and paired t tests. At 7 and 30 days, groups II, III and IV exhibited greater bone formation in the furcation area when compared to group I (p < 0.0001; p < 0.05). During the 7-day period, the groups irradiated with the laser (III and IV) showed a statistically larger new bone area than the group treated with SRP (II) (p < 0.01). Immunohistochemistry analysis revealed that the control group exhibited a higher expression of tartrate-resistant acid phosphatase (TRAP) and the receptor activator of nuclear factor kappaBeta ligand (RANKL) when compared to groups II, III and IV (p < 0.05). All treatments were able to reduce the inflammatory processes, consequently enabling the repair of periodontal tissues. The results achieved with the application of the Er,Cr:YSGG laser suggest that this laser can stimulate greater bone formation, especially over a shorter period of time. PMID- 24477393 TI - Tissue-specific antioxidant responses in pale chub (Zacco platypus) exposed to copper and benzo[a]pyrene. AB - In this study, antioxidant responses including lipid peroxidation (LPO), superoxide dismutase (SOD), catalase (CAT) and glutathione S-transferase (GST), were evaluated in the liver, gill and muscle tissues of pale chub (Zacco platypus) exposed to copper (Cu) and benzo[a]pyrene (BaP). Cu exposure induced significant antioxidant responses in Z. platypus, particularly in the liver, whereas BaP exposure had a negligible effect. Following Cu exposure, both SOD and CAT activity increased in a concentration-dependent manner, showing significant correlations with malondialdehyde (MDA) levels as a measure of LPO (r = 0.646 and 0.663, respectively). SOD, CAT and GST mRNA levels were also enhanced following Cu exposure, except at 20 MUg L(-1), although significant correlations with antioxidant enzyme activities were not found. The results of this study suggest that combined information on SOD and CAT activities together with LPO levels in the liver could be a useful indicator for assessing oxidative stress in freshwater fish. PMID- 24477394 TI - Effects of arsenate and arsenite on germination and some physiological attributes of barley Hordeum vulgare L. AB - Arsenic (As) is toxic to plants and animals. We tested the effects of arsenite and arsenate (0-16 mg/L) on seed germination, and on relative root and shoot length, alpha-amylase activity, reducing sugars and soluble total protein contents, and malondialdehyde content in barley seedlings. We also measured As accumulation in barley stems and roots. The alpha-amylase activity, relative root and shoot length, and seed germination decreased with increasing concentrations of arsenate and arsenite. The reducing sugars content in barley seedlings increased after 4 days of growth on media containing As. In general, the protein content in roots and seedlings decreased with increasing doses of As. Arsenic in the tissues was quantified by hydride generation-atomic absorption spectrophotometry. To confirm the accuracy of the method, we analyzed the certified reference material WEPAL-IPE-168. The limit of detection was 1.2 MUg/L and the relative standard deviation was <2.0 %. PMID- 24477395 TI - Cytokinin control of growth of Spirodela oligorrhiza in darkness. AB - Continuous heterotrophic growth of Spirodela oligorrhiza cultures following transfer to darkness requires cytokinins, or periodic brief treatment with red light. In the absence of cytokinins or red light growth ceases after 2-3 days. However, growth resumes spontaneously after 3-4 weeks in darkness to produce etiolated plants. The growth rate of these etiolated plants is not stimulated by kinetin.Although the kinetin concentration in treated plants reaches a plateau 30 60 min after adding kinetin to "dormant" plants in darkness new fronds do not appear for 24 h. Dormant colonies treated with kinetin in darkness for only 6-12 h subsequently grow in darkness at the same rate as plants treated with kinetin for 1, 2 or 3 days. Treatments which inhibit growth in the light, for example cold, chloramphenicol or actidione, eliminate the requirement for cytokinin and allow subsequent growth in darkness. The results suggest that a growth inhibitor may be present but ineffective in Spirodela growing in the light. The inhibitor is active in darkness but slowly decays. Kinetin appears to inactivate the inhibitor in darkness. PMID- 24477396 TI - Bud formation in leaves, leaf fragments and midrib pieces of Heloniopsis orientalis (Liliaceae). AB - Isolated leaves, leaf fragments and pieces of the midrib portion devoid of lamina, of Heloniopsis orientalis were grown on an inorganic nutrient medium without organic nutrients and growth regulators in order to investigate their regenerative ability. Bud formation in intact, attached leaves occurs only at the tip, in isolated leaves at the tip and the base, whereas leaf fragments cut transversely at a distance from the tip and isolated midrib pieces form numerous shoot buds in a random distribution. Lamina fragments lacking midrib frequently fail to regenerate even after a long time of culture. It is suggested that endogeneous growth regulators in the leaf, especially the vascular tissues, play an important role in bud initiation. Very young leaves of Heloniopsis are capable forming buds and roots when isolated from the mother plants. PMID- 24477397 TI - Metabolism of trypsin-inhibitory proteins in the germinating seeds of kidney bean (Phaseolus vulgaris). AB - A number of proteins with trypsin-inhibitory activity was separated by isoelectric focusing and their amounts measured in the extracts of the seeds of kidney bean at various stages of germination up to 16 days.The total trypsin inhibitor content of the dormant seed, 2.2 mg per g bean rose to about 3.6 mg by the seventh day and declined slowly after the tenth day of germination. The individual trypsin inhibitors however, appeared to change independently of each other and some components disappeared almost completely with the progress of germination. The emergence of an inhibitor not found in the dormant seed was also observed. Some of the inhibitor proteins attained a maximum concentration by the 7-8th day of germination. This coincided with a similar maximum in the general protein and proteolytic enzyme content of the germinating bean seeds. The results obtained suggested that the main function during germination of these protein components might not be related to their trypsin-inhibitory activity. PMID- 24477398 TI - Fine structure of swarmers of Cladophora and Chaetomorpha : III. Wall synthesis and development. AB - Naked swarmers of Cladophora have been collected and wall synthesis and development have been followed using the techniques of freeze-etching and sectioning. Swarmers frozen after 9 hours liberation have lost their flagella, developed the characteristic fibrous layer and show the initial stages of wall production. Both the first formed (randomly oriented) and the later (more ordered) microfibrils appear to have a distinct granular texture. Occasionally linear arrays of granules up to 4 MUm long may be seen. After 5 days settling a thick wall composed of almost transversely oriented microfibrils is present and a rhizoid is pushed out. Also characteristic of this stage is the central localisation of cell components and peripheral vacuolar distribution. Longitudinally oriented microtubules also reappear at this stage having been absent during carlier wall formation.A possible relationship between the cortical microtubules of the motile swarmer and the development of the fibrous layer is suggested. PMID- 24477399 TI - Annulate lamellae in plant cells: Formation during microsporogenesis and pollen development in Canna generalis Bailey. AB - The occurrence of stacked annulate lamellae is documented for a plant cell system, namely for pollen mother cells and developing pollen grains of Canna generalis. Their structural subarchitecture and relationship to endoplasmic reticulum (ER) and nuclear envelope cisternae is described in detail. The results demonstrate structural homology between plant and animal annulate lamellae and are compatible with, though do not prove, the view that annulate lamellar cisternae may originate as a degenerative form of endoplasmic reticulum. PMID- 24477400 TI - Development and differentiation of haploid Lycopersicon esculentum (tomato). AB - Haploid callus cultures of selected races of Lycopersicon (tomato) species can be obtained from anther culture. This is a further demonstration of a proposed general method of haploid culture developed with Arabidopsis thaliana. Differentiation of haploid callus of Lycopersicon esculentum can be controlled both in the dark and the light by hormones added to defined minimal media. Development to plantlets is achieved only in the light. Callus cells can be induced to develop into seedless pseudo-fruits. Chromosome counts on callus cells or root-tip cells establishes haploidy (n=12).Haploidy can be maintained in culture on defined minimal media for at least one year. PMID- 24477401 TI - Pathways of auxin transport in the intact pea seedling (Pisum sativum L.). AB - When small colonies of the pea aphid [Acyrthosiphon pisum (Harris)] were established on the stem of Meteor Dwarf Pea seedlings (Pisum sativum L.), (14)C was found in the honeydew 4.5 h after applying IAA-1-(14)C to a fully-expanded foliage leaf. In contrast, no activity was found in the honeydew or aphids 4.5 h after the application of IAA-1-(14)C to the intact apical bud even though the internode upon which the aphids were feeding contained high levels of (14)C. The lack of radio-activity in aphids feeding on stems to which IAA-1-(14)C was applied via the apical bud was found not to be influenced by the internode position or by the transport interval allowed (up to 24 h).Radioactivity derived from either foliar or apical applications of IAA-1-(14)C was not transported through stem tissues killed by heat treatment. Xylem function was shown not to be impared by the heat treatment employed.It was concluded that the long-distance transport of IAA from the apical bud of intact pea seedlings does not take place in the phloem sieve tubes involved in the transport of metabolites from foliage leaves, or in the non-living tissues of the xylem. PMID- 24477402 TI - Xylem transfer cells in the rosette plant Hieracium floribundum. AB - Xylem transfer cells in the rhizome of Hieracium floribundum are described for the first time and several methods used in visualizing these cells are discussed. The most marked wall ingrowths occur in transfer cells associated with the xylem of foliar traces. PMID- 24477403 TI - Integrin/Chemokine receptor interactions in the pathogenesis of experimental autoimmune encephalomyelitis. AB - Excessive infiltration of leukocytes and the elaboration of inflammatory cytokines are believed to be responsible for the observed damage to neurons and oligodendrocytes during multiple sclerosis (MS). Blocking adhesion molecules or preventing the effects of chemotactic mediators such as chemokines can be exploited to prevent immune cell recruitment to inflamed tissues. An anti-alpha4 integrin antibody (anti-VLA-4mAb/natalizumab (Tysabri(r))) has been used as a treatment for MS and reduces leukocyte influx into the brain. In patients, anti VLA-4 reduces relapses and disability progression. However, its mechanism of action in the brain is not completely understood. The anti-VLA-4mAb was demonstrated to mobilize hematopoietic progenitor cells. Interestingly, the chemokine SDF-1/CXCL12 and its receptor CXCR4 are also key factors regulating the migration of hematopoietic stem cells. Moreover, studies have revealed a crosstalk between SDF-1/CXCR4 and VLA-4 signaling in regulating cell migration. In this study, we address the effects of anti-VLA-4 on chemokine signaling in the brain during MS. We assessed the ability of anti-VLA-4 to regulate Experimental Autoimmune Encephalomyelitis (EAE) and chemokine/receptor signaling. Preclinical administration of anti-VLA-4 delayed clinical signs of EAE. We found that anti VLA-4 treatment reduced chemokine expression. In order to further explore the interaction of anti-VLA-4 with chemokine/receptor signaling we used dual color transgenic mice. After EAE induction, the expression of both SDF-1/CXCL12 and CXCR4 receptor was upregulated, treatment with anti-VLA-4 inhibited this effect. The effects of anti-VLA-4 on chemokine signaling in the CNS may be of importance when considering its mechanism of action and understanding the pathogenesis of EAE. PMID- 24477404 TI - Clinical value of supine and upright myocardial perfusion imaging in obese patients using the D-SPECT camera. AB - PURPOSE: We have assessed whether additional upright imaging increases the confidence of interpretation of stress only supine myocardial perfusion imaging (MPI) in obese patients. METHODS AND RESULTS: Tc-MIBI stress MPI of 101 consecutive patients (M = 49, 62 +/- 12 years) with BMI >=30 scanned on the D SPECT cardiac camera were assessed. Images were interpreted as diagnostic or equivocal and the need for a rest study was recorded. Stress supine MPI was interpreted first, then gated and finally upright data were added. Defects on supine but not on upright were defined as artefacts and defects seen on both as abnormal. The total perfusion deficit (TPD) was also quantified. There were 27 normal, 22 abnormal, and 52 equivocal supine scans. The median EF was 52%, unaffecting the need for rest imaging. Upright imaging reclassified 32/52 (62%) equivocal studies as normal and 6/52 (11%) as abnormal (P < 0.001). Rest scan was deemed needed in 74/101 patients on supine vs 42/101 on supine/upright (P < 0.001). Supine TPD was normal in 53 and supine/upright TPD was normal in 70 patients (P < 0.001). CONCLUSION: Supine stress MPI is inadequate in obese patients. The addition of upright imaging significantly increases the ability to interpret scans as diagnostic and may reduce considerably the need for rest imaging. PMID- 24477405 TI - Role of multimodality imaging in the early identification of cardiac sarcoidosis. PMID- 24477406 TI - Impact of point spread function modeling and time-of-flight on myocardial blood flow and myocardial flow reserve measurements for rubidium-82 cardiac PET. AB - BACKGROUND: Myocardial flow reserve (MFR) obtained from dynamic cardiac positron emission tomography (PET) with rubidium-82 (Rb-82) has been shown to be a useful measurement in assessing coronary artery disease. Advanced PET reconstructions with point spread function modeling and time-of-flight have been shown to improve image quality but also have an impact on kinetic analysis of dynamic data. This study aims to determine the impact of these algorithms on MFR data. METHODS: Dynamic Rb-82 cardiac PET images from 37 patients were reconstructed with standard and advanced reconstructions. Area under curve (AUC) of the blood input function (BIF), myocardial blood flow (MBF) and MFR were compared with each reconstruction. RESULTS: No significant differences were seen in MFR for the two reconstructions. A relatively small mean difference in MBF data of +11.9% was observed with advanced reconstruction compared with the standard reconstruction but there was considerable variability in the degree of change (95% confidence intervals of -16.2% to +40.0%). Small systematic relative differences were seen for AUC BIF (mean difference of -6.3%; 95% CI -17.5% to +5.4%). CONCLUSION: MFR results from Rb-82 dynamic PET appear to be robust when generated by standard or advanced PET reconstructions. Considerable increases in MBF values may occur with advanced reconstructions, and further work is required to fully understand this. PMID- 24477407 TI - Directional genomic hybridization: inversions as a potential biodosimeter for retrospective radiation exposure. AB - Chromosome aberrations in blood lymphocytes provide a useful measure of past exposure to ionizing radiation. Despite the widespread and successful use of the dicentric assay for retrospective biodosimetry, the approach suffers substantial drawbacks, including the fact that dicentrics in circulating blood have a rather short half-life (roughly 1-2 years by most estimates). So-called symmetrical aberrations such as translocations are far more stable in that regard, but their high background frequency, which increases with age, also makes them less than ideal for biodosimetry. We developed a cytogenetic assay for potential use in retrospective biodosimetry that is based on the detection of chromosomal inversions, another symmetrical aberration whose transmissibility (stability) is also ostensibly high. Many of the well-known difficulties associated with inversion detection were circumvented through the use of directional genomic hybridization, a method of molecular cytogenetics that is less labor intensive and better able to detect small chromosomal inversions than other currently available approaches. Here, we report the dose-dependent induction of inversions following exposure to radiations with vastly different ionization densities [i.e., linear energy transfer (LET)]. Our results show a dramatic dose-dependent difference in the yields of inversions induced by low-LET gamma rays, as compared to more damaging high-LET charged particles similar to those encountered in deep space. PMID- 24477408 TI - The RABiT: high-throughput technology for assessing global DSB repair. AB - At the Center for High-Throughput Minimally Invasive Radiation Biodosimetry, we have developed a rapid automated biodosimetry tool (RABiT); this is a completely automated, ultra-high-throughput robotically based biodosimetry workstation designed for use following a large-scale radiological event, to perform radiation biodosimetry measurements based on a fingerstick blood sample. High throughput is achieved through purpose built robotics, sample handling in filter-bottomed multi well plates and innovations in high-speed imaging and analysis. Currently, we are adapting the RABiT technologies for use in laboratory settings, for applications in epidemiological and clinical studies. Our overall goal is to extend the RABiT system to directly measure the kinetics of DNA repair proteins. The design of the kinetic/time-dependent studies is based on repeated, automated sampling of lymphocytes from a central reservoir of cells housed in the RABiT incubator as a function of time after the irradiation challenge. In the present study, we have characterized the DNA repair kinetics of the following repair proteins: gamma H2AX, 53-BP1, ATM kinase, MDC1 at multiple times (0.5, 2, 4, 7 and 24 h) after irradiation with 4 Gy gamma rays. In order to provide a consistent dose exposure at time zero, we have developed an automated capillary irradiator to introduce DNA DSBs into fingerstick-size blood samples within the RABiT. To demonstrate the scalability of the laboratory-based RABiT system, we have initiated a population study using gamma-H2AX as a biomarker. PMID- 24477409 TI - The risk of leukaemia in young children from exposure to tritium and carbon-14 in the discharges of German nuclear power stations and in the fallout from atmospheric nuclear weapons testing. AB - Towards the end of 2007, the results were published from a case-control study (the "KiKK Study") of cancer in young children, diagnosed <5 years of age during 1980-2003 while resident near nuclear power stations in western Germany. The study found a tendency for cases of leukaemia to live closer to the nearest nuclear power station than their matched controls, producing an odds ratio that was raised to a statistically significant extent for residence within 5 km of a nuclear power station. The findings of the study received much publicity, but a detailed radiological risk assessment demonstrated that the radiation doses received by young children from discharges of radioactive material from the nuclear reactors were much lower than those received from natural background radiation and far too small to be responsible for the statistical association reported in the KiKK Study. This has led to speculation that conventional radiological risk assessments have grossly underestimated the risk of leukaemia in young children posed by exposure to man-made radionuclides, and particular attention has been drawn to the possible role of tritium and carbon-14 discharges in this supposedly severe underestimation of risk. Both (3)H and (14)C are generated naturally in the upper atmosphere, and substantial increases in these radionuclides in the environment occurred as a result of their production by atmospheric testing of nuclear weapons during the late 1950s and early 1960s. If the leukaemogenic effect of these radionuclides has been seriously underestimated to the degree necessary to explain the KiKK Study findings, then a pronounced increase in the worldwide incidence of leukaemia among young children should have followed the notably elevated exposure to (3)H and (14)C from nuclear weapons testing fallout. To investigate this hypothesis, the time series of incidence rates of leukaemia among young children <5 years of age at diagnosis has been examined from ten cancer registries from three continents and both hemispheres, which include registration data from the early 1960s or before. No evidence of a markedly increased risk of leukaemia in young children following the peak of above-ground nuclear weapons testing, or that incidence rates are related to level of exposure to fallout, is apparent from these registration rates, providing strong grounds for discounting the idea that the risk of leukaemia in young children from (3)H or (14)C (or any other radionuclide present in both nuclear weapons testing fallout and discharges from nuclear installations) has been grossly underestimated and that such exposure can account for the findings of the KiKK Study. PMID- 24477410 TI - Validation of proposed prostate cancer biomarkers with gene expression data: a long road to travel. AB - Biomarkers are important for early detection of cancer, prognosis, response prediction, and detection of residual or relapsing disease. Special attention has been given to diagnostic markers for prostate cancer since it is thought that early detection and surgery might reduce prostate cancer-specific mortality. The use of prostate-specific antigen, PSA (KLK3), has been debated on the base of cohort studies that show that its use in preventive screenings only marginally influences mortality from prostate cancer. Many groups have identified alternative or additional markers, among which PCA3, in order to detect early prostate cancer through screening, to distinguish potentially lethal from indolent prostate cancers, and to guide the treatment decision. The large number of markers proposed has led us to the present study in which we analyze these indicators for their diagnostic and prognostic potential using publicly available genomic data. We identified 380 markers from literature analysis on 20,000 articles on prostate cancer markers. The most interesting ones appeared to be claudin 3 (CLDN3) and alpha-methysacyl-CoA racemase highly expressed in prostate cancer and filamin C (FLNC) and keratin 5 with highest expression in normal prostate tissue. None of the markers proposed can compete with PSA for tissue specificity. The indicators proposed generally show a great variability of expression in normal and tumor tissue or are expressed at similar levels in other tissues. Those proposed as prognostic markers distinguish cases with marginally different risk of progression and appear to have a clinically limited use. We used data sets sampling 152 prostate tissues, data sets with 281 prostate cancers analyzed by microarray analysis and a study of integrated genomics on 218 cases to develop a multigene score. A multivariate model that combines several indicators increases the discrimination power but does not add impressively to the information obtained from Gleason scoring. This analysis of 10 years of marker research suggests that diagnostic and prognostic testing is more difficult in prostate cancer than in other neoplasms and that we must continue to search for better candidates. PMID- 24477412 TI - On the thermodynamics of carbon nanotube single-file water loading: free energy, energy and entropy calculations. AB - Single-file water chains confined in carbon nanotubes have been extensively studied using molecular dynamics simulations. Specifically, the pore loading process of periodic (6,6) and (5,5) single-walled carbon nanotubes was thermodynamically characterized by means of free-energy calculations at every loading state and compared to bulk water employing thermodynamic cycles. Long simulations of each end-state allowed for the partitioning of the free energy into its energetic and entropic components. The calculations revealed that the initial loading states are dominated by entropic (both translational and rotational) components, whereas the latter stages are energetically driven by strong dipolar interactions among the water molecules in the file. PMID- 24477411 TI - Immunotherapy for prostate cancer: recent developments and future challenges. AB - Since the approval of sipuleucel-T for men with metastatic castrate resistant prostate cancer in 2010, great strides in the development of anti-cancer immunotherapies have been made. Current drug development in this area has focused primarily on antigen-specific (i.e. cancer vaccines and antibody based therapies) or checkpoint inhibitor therapies, with the checkpoint inhibitors perhaps gaining the most attention as of late. Indeed, drugs blocking the inhibitory signal generated by the engagement of cytotoxic T-lymphocyte antigen-4 (CTLA-4) and programmed cell death-1 (PD-1) found on T-cells has emerged as potent means to combat the immunosuppressive milieu. The anti-CTLA-4 monoclonal antibody ipilimumab has already been approved in advanced melanoma and two phase III trials evaluating ipilimumab in men with metastatic castrate-resistant prostate cancer are underway. A phase III trial evaluating ProstVac-VF, a poxvirus-based therapeutic prostate cancer vaccine, is also underway. While there has been reason for encouragement over the past few years, many questions regarding the use of immunotherapies remain. Namely, it is unclear what stage of disease is most likely to benefit from these approaches, how best to incorporate said treatments with each other and into our current treatment regimens and which therapy is most appropriate for which disease. Herein we review some of the recent advances in immunotherapy as related to the treatment of prostate cancer and outline some of the challenges that lie ahead. PMID- 24477413 TI - Developments in sclerostin biology: regulation of gene expression, mechanisms of action, and physiological functions. AB - The SOST gene, which encodes the protein sclerostin, was identified through genetic linkage analysis of sclerosteosis and van Buchem's disease patients. Sclerostin is a secreted glycoprotein that binds to the low-density lipoprotein receptor-related proteins 4, 5, and 6 to inhibit Wnt signaling. Since the initial discovery of sclerostin, much understanding has been gained into the role of this protein in the regulation of skeletal biology. In this article, we discuss the latest findings in the regulation of SOST expression, sclerostin mechanisms of action, and the potential utility of targeting sclerostin in conditions of low bone mass. PMID- 24477414 TI - Regulatory mechanisms of RANKL presentation to osteoclast precursors. AB - It is important to understand the molecular mechanisms regulating osteoclast formation, as excess activation of osteoclasts is associated with various osteopenic disorders. Receptor activator of nuclear factor kappa B (RANKL) is a central player in osteoclastogenesis. Recent findings suggest that osteocytes are the major supplier of RANKL to osteoclast precursors. It has also been suggested that osteocyte cell death upregulates the RANKL/osteoprotegerin (OPG) ratio in viable osteocytes adjacent to apoptotic osteocytes in areas of bone microdamage, thus, contributing to localized osteoclast formation. Indeed, viable osteocytes can provide RANKL through direct interactions with osteoclast precursors at osteocyte dendritic processes. In addition, OPG tightly regulates RANKL cell surface presentation in osteocytes, which contributes to the inhibition of RANKL signaling, as well as the decoy receptor function of OPG. By contrast, the physiological role of RANKL in osteoblasts is yet to be clarified, although similar mechanisms of regulation are observed in both osteocytes and osteoblasts. PMID- 24477415 TI - Mesenchymal progenitors and the osteoblast lineage in bone marrow hematopoietic niches. AB - The bone marrow cavity is essential for the proper development of the hematopoietic system. In the last few decades, it has become clear that mesenchymal stem/progenitor cells as well as cells of the osteoblast lineage, besides maintaining bone homeostasis, are also fundamental regulators of bone marrow hematopoiesis. Several studies have demonstrated the direct involvement of mesenchymal and osteoblast lineage cells in the maintenance and regulation of supportive microenvironments necessary for quiescence, self-renewal and differentiation of hematopoietic stem cells. In addition, specific niches have also been identified within the bone marrow for maturing hematopoietic cells. Here we will review recent findings that have highlighted the roles of mesenchymal progenitors and cells of the osteoblast lineage in regulating distinct stages of hematopoiesis. PMID- 24477416 TI - Implications of osteoblast-osteoclast interactions in the management of osteoporosis by antiresorptive agents denosumab and odanacatib. AB - Antiresorptive agents, used in the treatment of osteoporosis, inhibit either osteoclast formation or function. However, with these approaches, osteoblast activity is also reduced because of the loss of osteoclast-derived coupling factors that serve to stimulate bone formation. This review discusses how osteoclast inhibition influences osteoblast function, comparing the actions of an inhibitor of osteoclast formation [anti-RANKL/Denosumab (DMAB)] with that of a specific inhibitor of osteoclastic cathepsin K activity [Odanacatib (ODN)]. Denosumab rapidly and profoundly, but reversibly, reduces bone formation. In contrast, preclinical studies and clinical trials of ODN showed that bone formation at some skeletal sites was preserved although resorption was reduced. This preservation of bone formation appears to be due to effects of coupling factors, secreted by osteoclasts and released from demineralized bone matrix. This indicates that bone resorptive activities of osteoclasts are separable from their coupling activities. PMID- 24477417 TI - Laparoscopic completion total gastrectomy for remnant gastric cancer: a single institution experience. AB - BACKGROUND: The aim of the present study was to evaluate the feasibility of laparoscopic completion total gastrectomy (LCTG) in patients with remnant gastric cancer. METHODS: Patients who underwent completion total gastrectomy for remnant gastric cancer between May 2003 and December 2012 were divided into two groups: an open completion total gastrectomy (OCTG) group and an LCTG group. Clinicopathological data, operative data, and patient survival rates were analyzed. RESULTS: Thirty-four remnant gastrectomies (17 OCTG and 17 LCTG) were performed. The mean time interval between the prior gastrectomy and the remnant gastrectomy was 17.2 years, and benign disease showed a longer time interval than malignancy (30.9 vs. 8.1 years; p < 0.0001). LCTG required a longer operation time than OCTG (234.4 vs. 170.0 min; p = 0.002); however, there were no significant differences in the estimated blood loss, the number of retrieved lymph nodes, the time to first flatus passage, the length of hospital stay, complication rates, and postoperative analgesia between the two groups. Eight patients (47.1%) required conversion to open surgery during LCTG. The median overall survival was 69.1 months. There was no difference in 5-year survival between the two groups (p = 0.085). CONCLUSION: LCTG was technically feasible; however, it showed no definitive clinical advantage over OCTG. PMID- 24477418 TI - A case of local recurrence and distant metastasis following curative endoscopic submucosal dissection of early gastric cancer. AB - Currently in Japan, differentiated-type gastric submucosal invasive cancers <500 MUm with negative lymphovascular involvement are included in expanded pathological criteria for curative endoscopic treatment. This categorization is based on a retrospective examination of surgical resection cases in which patients suitable for such expanded criteria were determined to have a negligible risk of lymph node metastasis. We performed endoscopic submucosal dissection on a 66-year-old man with early gastric cancer in June 2004, and pathology revealed a well-differentiated adenocarcinoma, 16 * 8 mm in size, minute submucosal invasion depth (100 MUm), and negative lymphovascular invasion or ulceration as well as tumor-free margins, so the case was diagnosed as a curative resection. In this case, however, local recurrence and distant metastasis resulted in August 2011. The patient received systemic chemotherapy but died of gastric cancer 23 months after recurrence. PMID- 24477419 TI - Is a clear benefit in survival enough to modify patient access to the surgery service? A retrospective analysis in a cohort of gastric cancer patients. AB - BACKGROUND: Surgery has become an important tool for cancer treatment, requiring many available resources and a good organization of the surgery service. The aim of this study was to provide robust data for policymakers on the impact of hospital volume on survival, taking into account different sources of information. METHODS: We performed a retrospective study in a cohort of patients with gastric cancer submitted to partial or total gastrectomy. Data for the analysis were retrieved from regional administrative databases, the regional death registry, and histological reports. The main outcome measures were operative mortality and long-term survival. The associations between hospital volume and risk of mortality were calculated using a Cox multiple regression analysis. RESULTS: The estimated relationship between operative mortality and volume was not statistically significant. Conversely, high-volume hospitals had an increased likelihood of long-term survival compared to low-volume institutions: hazard ratio 0.79 (95% confidence interval, 0.66-0.94, p = 0.01). The percentage variation between crude and adjusted HRs using only administrative data or administrative and histological data was very small. However, the combined use of administrative and clinical data provided a more accurate model for estimating risk-adjusted mortality. CONCLUSIONS: A positive association between hospital volume and survival was evident for long-term outcome after adjusting for patient and tumor confounding. Moreover, the patient's choice of hospital was not guided by specific care pathways or screening programs, and prognosis was not poorer for patients in high-volume hospitals. These findings suggest that there is leeway for improving access to surgery for gastric cancer patients. PMID- 24477420 TI - Re.: 'cloacal exstrophy: a single center experience'. PMID- 24477421 TI - Single center experience with oxybutynin transdermal system (patch) for management of symptoms related to non-neuropathic overactive bladder in children: an attractive, well tolerated alternative form of administration. AB - OBJECTIVE: Oxybutynin is the current gold standard drug for management of overactive bladder (OAB) in children, but can have significant side effects or be difficult to administer in multiple daily doses. Herein, we report our experience with transdermal oxybutynin patch (TOP) as an alternative in a selected patient population without neuropathic compromise. MATERIALS AND METHODS: Consecutive patients assessed in a pediatric urology clinic over a 1-year period, diagnosed with OAB with minimum follow-up of 3 months, were included. TOP starting dose was 3.9 mg/day based on product design (Oxytrol). Demographics and outcomes data were retrospectively collected. Symptomatic response was defined as improvement or resolution of lower urinary tract symptoms. RESULTS: 35 children met inclusion criteria (mean age 8 years, range 4-16). Overall, 97% reported good symptom response. The main side effect was skin irritation at TOP site (35%), leading to discontinuation in 20%. There were no reports of other significant side effects. Mean bladder capacity increased from 104 ml to 148 ml at follow-up. CONCLUSIONS: Our data suggest that TOP is a viable alternative for children with non neuropathic OAB who do not tolerate other formulations of oxybutynin. These findings highlight the potential benefit of transdermal drug delivery in the pediatric setting. PMID- 24477422 TI - Buffered aspirin: what is your gut feeling? PMID- 24477423 TI - Do residents in cardiology need more training to make them talk about sex? PMID- 24477424 TI - Consistency of thromboelastometry analysis under scrutiny: results of a systematic evaluation within and between analysers. AB - While the use of thromboelastometry analysis (ROTEM(r)) in evaluation of haemostasis is rapidly increasing, important validity parameters of testing remain inadequately examined. We aimed to study systematically the consistency of thromboelastometry parameters within individual tests regarding measurements between different analysers, between different channels of the same analyser, between morning and afternoon measurements (circadian variation), and if measured four weeks apart. Citrated whole blood samples from 40 healthy volunteers were analysed with two analysers in parallel. EXTEM, INTEM, FIBTEM, HEPTEM and APTEM tests were conducted. A Bland-Altman comparison was performed and homogeneity of variances was tested using the pitman test. P-value ranges were used to classify the level of homogeneity (p<0.15 - low homogeneity, p = 0.15 to 0.5 - intermediate homogeneity, p>0.5 high homogeneity). Less than half of all comparisons made showed high homogeneity of variances (p>0.5) and in about a fifth of comparisons data distributions were heterogeneous (p<0.15). There was no clear pattern for homogeneity. On average, comparisons of MCF, ML and LI30 measurements tended to be better, but none of the tests assessed outperformed another. In conclusion, systematic investigation reveals large differences in the results of some thromboelastometry parameters and lack of consistency. Clinicians and scientists should take these inconsistencies into account and focus on parameters with a higher homogeneity such as MCF. PMID- 24477425 TI - Image guided radiofrequency thermo-ablation therapy of chondroblastomas: should it replace surgery? AB - OBJECTIVE: To assess the safety and effectiveness of image-guided radiofrequency ablation (RF ablation) in the treatment of chondroblastomas as an alternative to surgery. MATERIALS AND METHODS: Twelve patients with histologically proven chondroblastoma at our institution from 2003 to date. We reviewed the indications, recurrences and complications in patients who underwent RF ablation. RESULTS: Twelve patients were diagnosed with chondroblastoma. Out of these, 8 patients (6 male, 2 female, mean age 17 years) with chondroblastoma (mean size 2.7 cm) underwent RF ablation. Multitine expandable electrodes were used in all patients. The number of probe positions needed varied from 1 to 4 and lesions were ablated at 90 degrees C for 5 min at each probe position. The tumours were successfully treated and all patients became asymptomatic. There were no recurrences. There were 2 patients with knee complications, 1 with minor asymptomatic infraction of the subchondral bone and a second patient with osteonecrosis/chondrolysis. CONCLUSION: Radiofrequency ablation appears to be a safe and effective alternative to surgical treatment with a low risk of recurrence and complications for most chondroblastomas. RF ablation is probably superior to surgery when chondroblastomas are small (less than 2.5 cm) with an intact bony margin with subchondral bone and in areas of difficult surgical access. PMID- 24477426 TI - [Shoulder dislocation in athletes. Current therapy concepts]. AB - BACKGROUND: Shoulder dislocation is a common injury in athletes participating in contact and overhead sports. Optimal treatment is still a subject of controversial debate. STUDY AIM: Presentation of current concepts for therapy of shoulder dislocation in athletes. METHODS: A selective literature search in PubMed was carried out. RESULTS: Surgical and non-surgical therapy options are described in the literature and can be successful in certain situations. A gold standard has yet to be defined. CONCLUSION: For decision-making numerous patient and sports-related factors need to be considered. There is a current trend towards early surgical stabilization in young athletes. PMID- 24477427 TI - Development and initial validation of the Observer-Rated Housing Quality Scale (OHQS) in a multisite trial of housing first. AB - Quality of housing has been shown to be related to health outcomes, including mental health and well-being, yet "objective" or observer-rated housing quality is rarely measured in housing intervention research. This may be due to a lack of standardized, reliable, and valid housing quality instruments. The objective of this research was to develop and validate the Observer-Rated Housing Quality Scale (OHQS) for use in a multisite trial of a "housing first" intervention for homeless individuals with mental illness. A list of 79 housing unit, building, and neighborhood characteristics was generated from a review of the relevant literature and three focus groups with consumers and housing service providers. The characteristics were then ranked by 47 researchers, consumers, and service providers on perceived importance, generalizability, universality of value, and evidence base. Items were then drafted, scaled (five points, half values allowed), and pretested in seven housing units and with seven raters using cognitive interviewing techniques. The draft scale was piloted in 55 housing units in Toronto and Winnipeg, Canada. Items were rated independently in each unit by two trained research assistants and a housing expert. Data were analyzed using classical psychometric approaches and intraclass correlation coefficients (ICC) for inter-rater reliability. The draft scale consisted of 34 items assessing three domains: the unit, the building, and the neighborhood. Five of 18 unit items and 3 of 7 building items displayed ceiling or floor effects and were adjusted accordingly. Internal consistency was very good (Cronbach's alpha = 0.90 for the unit items, 0.80 for the building items, and 0.92 total (unit and building)). Percent agreement ranged from 89 to 100 % within one response scale value and 67 to 91 % within one half scale value. Inter-rater reliability was also good (ICCs were 0.87 for the unit, 0.85 for the building, and 0.93 for the total scale). Three neighborhood items (e.g., distance to transit) were found to be most efficiently rated using publicly available information. The physical quality of housing can be reliably rated by trained but nonexpert raters using the OHQS. The tool has potential for improved measurement in housing-related health research, including addressing the limitations of self-report, and may also enable documenting the quality of housing that is provided by publicly funded housing programs. PMID- 24477428 TI - Rethinking medical humanities. AB - This paper questions different conceptions of Medical Humanities in order to provide a clearer understanding of what they are and why they matter. Building upon former attempts, we defend a conception of Medical Humanities as a humanistic problem-based approach to medicine aiming at influencing its nature and practice. In particular, we discuss three main conceptual issues regarding the overall nature of this discipline: (i) a problem-driven approach to Medical Humanities; (ii) the need for an integration of Medical Humanities into medicine; (iii) the methodological requirements that could render Medical Humanities an effective framework for medical decision-making. PMID- 24477429 TI - A systematic review of osteoporosis medication adherence and osteoporosis-related fracture costs in men. AB - BACKGROUND AND OBJECTIVE: Male osteoporosis is an increasingly important public health concern. Although several medications are approved for the treatment of osteoporosis, medication non-adherence and the associated consequences are not well documented in male populations. Our objective was to identify and summarize the current knowledge related to osteoporotic medication adherence, the potential implications of non-adherence to the medication, and the cost of osteoporosis related fractures and health-resource utilization in men. METHODS: Two separate systematic searches were conducted concurrently: one to identify literature reporting male-specific adherence to anti-osteoporotic medication and the clinical consequence of non-adherence in men, and the other to identify literature reporting the cost and resource burden of osteoporosis-related fractures in men. The PubMed, MEDLINE, EMBASE, and Cochrane databases were searched using a date range of 1 January 1998 to 30 June 2012, and citations were screened based on pre-defined criteria. RESULTS: The percentage of males adherent to bisphosphonates [medication possession ratio (MPR) >0.8] over a 1-year period ranged from 32% to 64%. The data imply worse clinical outcomes with treatment non adherence. Costs and resource use associated with osteoporosis-related fractures in men are high, with hip fractures generating the most cost. CONCLUSIONS: One third to two-thirds of men are not adherent to bisphosphonates. Non-adherence is associated with increased fracture risk. Estimates of direct and indirect osteoporosis-related fracture costs are also substantial in men, and may even be more costly than in women. More robust data would better inform disease management initiatives that could improve adherence to medication and outcomes in men with osteoporosis. PMID- 24477432 TI - Spontaneous versus deliberate vicarious representations: different routes to empathy in psychopathy and autism. PMID- 24477435 TI - [Risk disclosure in lymph node excision: not withholding permanent damage]. PMID- 24477431 TI - Reduced glucocerebrosidase is associated with increased alpha-synuclein in sporadic Parkinson's disease. AB - Heterozygous mutations in GBA1, the gene encoding lysosomal glucocerebrosidase, are the most frequent known genetic risk factor for Parkinson's disease. Reduced glucocerebrosidase and alpha-synuclein accumulation are directly related in cell models of Parkinson's disease. We investigated relationships between Parkinson's disease-specific glucocerebrosidase deficits, glucocerebrosidase-related pathways, and alpha-synuclein levels in brain tissue from subjects with sporadic Parkinson's disease without GBA1 mutations. Brain regions with and without a Parkinson's disease-related increase in alpha-synuclein levels were assessed in autopsy samples from subjects with sporadic Parkinson's disease (n = 19) and age- and post-mortem delay-matched controls (n = 10). Levels of glucocerebrosidase, alpha-synuclein and related lysosomal and autophagic proteins were assessed by western blotting. Glucocerebrosidase enzyme activity was measured using a fluorimetric assay, and glucocerebrosidase and alpha-synuclein messenger RNA expression determined by quantitative polymerase chain reaction. Related sphingolipids were analysed by mass spectrometry. Multivariate statistical analyses were performed to identify differences between disease groups and regions, with non-parametric correlations used to identify relationships between variables. Glucocerebrosidase protein levels and enzyme activity were selectively reduced in the early stages of Parkinson's disease in regions with increased alpha-synuclein levels although limited inclusion formation, whereas GBA1 messenger RNA expression was non-selectively reduced in Parkinson's disease. The selective loss of lysosomal glucocerebrosidase was directly related to reduced lysosomal chaperone-mediated autophagy, increased alpha-synuclein and decreased ceramide. Glucocerebrosidase deficits in sporadic Parkinson's disease are related to the abnormal accumulation of alpha-synuclein and are associated with substantial alterations in lysosomal chaperone-mediated autophagy pathways and lipid metabolism. Our data suggest that the early selective Parkinson's disease changes are likely a result of the redistribution of cellular membrane proteins leading to a chronic reduction in lysosome function in brain regions vulnerable to Parkinson's disease pathology. PMID- 24477436 TI - [Dysphagia]. AB - Difficulties in swallowing occur in every age and have a great impact on the morbidity as well as on the mortality in patients especially if also an aspiration occurs. This article reports on the one hand the anatomy and physiology in the normal process of swallowing. On the other hand the cause of dysphagia, the diagnostic possibilities and therapeutic approaches are described. PMID- 24477437 TI - [Surgical methods: safe, logical and step by step infundibulotomy (uncinectomy) with or without maxillary sinus operation]. PMID- 24477438 TI - Peripheral reticulum in chloroplasts of plants differing in CO2 fixation pathways and photorespiration. AB - The development of peripheral reticulum (PR) in chloroplasts varies in C3 and C4 plants. In general, PR is more extensive in C4 plants, but PR is also seen in the chloroplasts of some C3 plants. Within some C4 plants, PR is seen in the bundle sheath cells which predominantly use the C3 pathway. Thus, PR is not associated directly with the presence of the C4 pathway on a cellular basis. Its predominance in C4 plants must be related to some characteristic other than the method of CO2 fixation. Ultrastructural evidence suggests that PR is associated with the rapid transfer of substances into and out of chloroplasts and from mesophyll to bundle sheath cells. PMID- 24477439 TI - The role of the tapetum in the formation of sporopollenin-containing structures during microsporogenesis in Pinus banksiana. AB - In the microsporangium of Pinus the outer layer of the peritapetal membrane and the pro-orbicular cores are not only formed in a similar manner, but are composed of apparently identical materials. Precursors for this lipoidal material are produced by the tapetal protoplasts, as are the precursors of sporopollenin. Production the precursors is sequential and appears to involve different cytoplasmic structures.The sporopollenin synthesised by the tapetum condenses upon the pro-orbicular cores, the peritapetal membrane, the exine initials and, on fragmentation of the tapetum, parts of the disintegrating cytoplasm. The evident unpolarised nature of the tapetal protoplasts, and the sequential nature of the synthesis of the lipoid and the sporopollenin by them, may point to orbicule formation in gymnosperms being a necessary by-product of the development of the peritapetal membrane. PMID- 24477430 TI - Clinical, genetic and imaging findings identify new causes for corpus callosum development syndromes. AB - The corpus callosum is the largest fibre tract in the brain, connecting the two cerebral hemispheres, and thereby facilitating the integration of motor and sensory information from the two sides of the body as well as influencing higher cognition associated with executive function, social interaction and language. Agenesis of the corpus callosum is a common brain malformation that can occur either in isolation or in association with congenital syndromes. Understanding the causes of this condition will help improve our knowledge of the critical brain developmental mechanisms required for wiring the brain and provide potential avenues for therapies for callosal agenesis or related neurodevelopmental disorders. Improved genetic studies combined with mouse models and neuroimaging have rapidly expanded the diverse collection of copy number variations and single gene mutations associated with callosal agenesis. At the same time, advances in our understanding of the developmental mechanisms involved in corpus callosum formation have provided insights into the possible causes of these disorders. This review provides the first comprehensive classification of the clinical and genetic features of syndromes associated with callosal agenesis, and provides a genetic and developmental framework for the interpretation of future research that will guide the next advances in the field. PMID- 24477440 TI - Some observations on the role of ATP in sieve tube translocation. AB - Using the aphid stylet technique (14)C ATP was shown to be readily taken up into the sieve elements of willow. At the same time this compound was found to be metabolised during uptake resulting in labelled ADP and AMP appearing in the stylet exudate. Longitudinal movement of labelled ATP was also found to occur.Measurement of the levels of ATP and ADP in stylet exudate showed that both were present in high concentrations. The ratio ATP/ADP varied between 2.0 and 5.3.The effect of certain inhibitors of oxidative phosphorylation (oligomycin and DNP) and glycolysis (fluoride) on the rate of stylet exudation was studied. All three inhibitors caused a cessation of exudation but this did not occur until several hours after inhibitor application. Oligomycin and DNP had no effect on the concentration of ATP in the sap. Fluoride however, appeared in some cases to reduce the ATP concentration to a low level an hour or more before exudation finally stopped.Incorporation of (32)Pi into organic phosphate esters present in stylet exudate was found to occur within 15 minutes of the application of the tracer to a bark strip. Labelling of organic phosphates also took place, at a slower rate, when (32)P inorganic phosphate was incubated with stylet exudate. PMID- 24477441 TI - [Ultrastructure and crassulacean acid metabolism in Mesembryanthemum crystallinum leaves during normal and NaCl-induced ageing]. AB - NaCl-treated young plants of Mesembryanthemum crystallinum undergo specific cytological changes which are accompanied by distinct alterations in CO2 gas exchange reactions. Prior to salt treatment mesophyll cells are quite normal. Only lomasome-like structures extrude from the cytoplasm into the vacuole. CO2 gas exchange is that of a Calvin-plant. Later on NaCl-treated plants differ from control plants in several respects. They show the CO2 gas exchange reactions typical for CAM-plants. Electron microscopy clearly shows the formation of new vacuole-like spaces just under the chloroplasts between plasmalemma and cell wall, which are mostly filled with structures similar to "Hecht'sche Faden" of plasmolyzed cells. In many cases a large amount of vesicles and membranes can be observed in the central vacuole, at least some of which are in connection with cytoplasm and even chloroplasts. Chloroplasts themselves sometimes seem to be damaged by high concentrations of NaCl. While having a more distinct crassulacean acid metabolism, old NaCl-treated plants exhibit features of aged cells: cytoplasm becomes empty and vacuolized, stoma thylacoids are reduced.Not only the described changes in fine structure but also the altered CO2 gas exchange reactions take place when glycophytic control plants grow older, thus indicating that NaCl may accelerate the normal ageing process in Mesembryanthemum crystallinum. PMID- 24477442 TI - [Effect of verapamil on dark acidification in Bryophyllum tubiflorum]. AB - Excised phyllodia of Bryophyllum tubiflorum standing in phosphate buffer to which verapamil is added undergo specific alterations in their gaseous exchange reactions as well as in the amount of malate accumulated in the dark period. Inhibition of accumulation of malate increases with increasing concentrations of verapamil. The effects caused by verapamil are reversible. During the dark period plasmalemma under the chloroplasts detaches itself from the cell wall, forming a vacuole-like space between plasmalemma and cell wall which disappears in the following light period. In the presence of verapamil this formation of a vacuole like structure does not occur.Verapamil is thought to influence the permeability of plasma membranes, thus decreasing the capacity of the vacuole to accumulate malate in the dark. Our interpretation of the results seems to demonstrate that the occurence of crassulacean acid metabolism is dependent on the integrity of the plasma membranes. Further details are discussed. PMID- 24477443 TI - Reversal of 5-fluorodeoxyuridine-caused growth inhibition in intact and excised etiolated hypocotyls of Sinapis alba L. by thymidine. AB - The elongation growth in etiolated, intact seedlings and excised hypocotyl segments of Sinapis alba is inhibited by FdUrd in the same fashion, and in either case there is a direct correlation between FdUrd concentration and inhibition of elongation growth. Removal of the roots reduced elongation; however, the percentage inhibition by FdUrd remained the same. Therefore, the growth inhibition by FdUrd is not a consequence of root growth inhibition.The growth inhibition in excised hypocotyls cultured on synthetic media is inversely proportional to the size of the segments, and of the seedlings from which they are taken. Elongation of the smaller segments is more sensitive to FdUrd than that of the larger ones. Anatomical observations showed that the inhibition of growth elongation by FdUrd in the hypocotyl segments is due to inhibition of cell elongation, and not of cell division. Root formation is inhibited in all isolated segments.The growth inhibition by FdUrd could be reversed by dThd but not by uridine, and this reversibility depended upon the FdUrd concentration. When FdUrd inhibition is partial (up to 10(-7)M) relatively high dThd concentration (up to 100 fold) are required for complete reversal; when inhibition is maximal relatively lower dThd concentrations effect a complete or near-complete reversal. Irreversible, unspecific effects of FdUrd were not found.These experiments confirm that DNA synthesis is involved in cell elongation of the hypocotyls even when the apical meristem and roots are removed, and that the growth inhibition by FdUrd is not a nonspecific, toxic effect. PMID- 24477444 TI - On the use of morphactin and triiodobenzoic acid in apical dominance studies. AB - Application of either CFM or TIBA to bean plants caused four main effects: (i) inhibition of main shoot and leaf growth; (ii) abscission of young leaflets and internodes; (iii) limited outgrowth of lateral buds below the point of application of the substances followed by abscission of these buds; (iv) abscission of all other lateral buds. Although the chemical pruning effects of CFM and TIBA may be the result of their action in blocking auxin transport, the use of these substances for analysing auxin effects in apical dominance is questionable. PMID- 24477445 TI - Cuticular penetration of abscisic acid. AB - Penetration of 2-(14)C abscisic acid (ABA) through enzymatically isolated cuticles from tomato fruit and from the upper epidermis of apricot, pear and orange leaves was assessed. Penetration was linear with time, greater as the undissociated than the dissociated ion, and greater through dewaxed than non dewaxed cuticles. Significantly less (3-6 times) (2-(14)C)ABA penetrated the tomato fruit cuticle than NAA or 2,4-D. The leaf cuticles were less permeable than the tomato fruit cuticle. There was no evidence that the ABA was altered during transfer across the cuticle. PMID- 24477446 TI - Fine structural observations on the epidermis : I. The epidermal cell wall. AB - The organization of the wall of epidermal cells in the petiole of species of Apium, Eryngium, Rumex, and Abutilon as well as that of the epidermis of Avena coleoptile has been investigated. The outer and inner tangential walls consist of layers in which the cellulose microfibrils are oriented alternately parallel or transverse to the longitudinal cell axis. This organization resembles that previously described for collenchyma cell walls (Wardrop, 1969; Chafe, 1970). On the radial (anticlinal) walls the orientation of the microfibrils is transverse and these appear continuous with the layers of transverse orientation of the outer and inner tangential walls. Variation in thickness of the outer tangential, and radial, and inner tangential walls appears to result from the variation in thickness of those layers in which the microfibrils have a longitudinal orientation. The extent to which these observations can interpreted in terms of some type of modified "multi-net" growth is discussed. PMID- 24477447 TI - A systematic review of sensory processing interventions for children with autism spectrum disorders. AB - Children with autism spectrum disorders often exhibit co-occurring sensory processing problems and receive interventions that target self-regulation. In current practice, sensory interventions apply different theoretic constructs, focus on different goals, use a variety of sensory modalities, and involve markedly disparate procedures. Previous reviews examined the effects of sensory interventions without acknowledging these inconsistencies. This systematic review examined the research evidence (2000-2012) of two forms of sensory interventions, sensory integration therapy and sensory-based intervention, for children with autism spectrum disorders and concurrent sensory processing problems. A total of 19 studies were reviewed: 5 examined the effects of sensory integration therapy and 14 sensory-based intervention. The studies defined sensory integration therapies as clinic-based interventions that use sensory-rich, child-directed activities to improve a child's adaptive responses to sensory experiences. Two randomized controlled trials found positive effects for sensory integration therapy on child performance using Goal Attainment Scaling (effect sizes ranging from .72 to 1.62); other studies (Levels III-IV) found positive effects on reducing behaviors linked to sensory problems. Sensory-based interventions are characterized as classroom-based interventions that use single-sensory strategies, for example, weighted vests or therapy balls, to influence a child's state of arousal. Few positive effects were found in sensory-based intervention studies. Studies of sensory-based interventions suggest that they may not be effective; however, they did not follow recommended protocols or target sensory processing problems. Although small randomized controlled trials resulted in positive effects for sensory integration therapies, additional rigorous trials using manualized protocols for sensory integration therapy are needed to evaluate effects for children with autism spectrum disorders and sensory processing problems. PMID- 24477450 TI - Abdominal imaging in zinc phosphide poisoning. AB - Radiography has been proved to be a good diagnostic tool in visualization of many radiopaque xenobiotics in clinical toxicology. Zinc is a potentially radiopaque material which is a constituent of the zinc phosphide (ZN2P3) rodenticide. We report two cases of zinc phosphide poisoning with positive abdominal X-rays in whom the diagnosis was confirmed by abdominal imaging. Positive abdominal imaging was an indication for aggressive management; however, aggressive treatment was not lifesaving in one of them. We aim to emphasize the diagnostic value of abdominal X-rays in zinc phosphide-poisoned patients. We also would like to suggest that zinc phosphide (ZP)-poisoned patients with positive X-rays have more chance to become unstable even if they are symptom free on presentation and should be more aggressively managed. PMID- 24477449 TI - Cytochrome P450 1B1 contributes to increased blood pressure and cardiovascular and renal dysfunction in spontaneously hypertensive rats. AB - PURPOSE: We investigated the contribution of cytochrome P450 (CYP) 1B1 to hypertension and its pathogenesis by examining the effect of its selective inhibitor, 2,4,3',5'-tetramethoxystilbene (TMS), in spontaneously hypertensive rats (SHR). METHODS: Blood pressure (BP) was measured bi-weekly. Starting at 8 weeks, TMS (600 MUg/kg, i.p.) or its vehicle was injected daily. At 14 weeks, samples were collected for measurement. RESULTS: TMS reversed increased BP in SHR (207 +/- 7 vs. 129 +/- 2 mmHg) without altering BP in Wistar-Kyoto rats. Increased CYP1B1 activity in SHR was inhibited by TMS (RLU: aorta, 5.4 +/- 0.7 vs. 3.7 +/- 0.7; heart, 6.0 +/- 0.8 vs. 3.4 +/- 0.4; kidney, 411 +/- 45 vs. 246 +/- 10). Increased vascular reactivity, cardiovascular hypertrophy, endothelial and renal dysfunction, cardiac and renal fibrosis in SHR were minimized by TMS. Increased production of reactive oxygen species and NADPH oxidase activity in SHR, were diminished by TMS. In SHR, TMS reduced increased plasma levels of nitrite/nitrate (46.4 +/- 5.0 vs. 28.1 +/- 4.1 MUM), hydrogen-peroxide (36.0 +/- 3.7 vs. 14.1 +/- 3.8 MUM), and thiobarbituric acid reactive substances (6.9 +/- 1.0 vs. 3.4 +/- 1.5 MUM). Increased plasma levels of pro-inflammatory cytokines and catecholamines, and cardiac activity of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Src tyrosine kinase, and protein kinase B in SHR were also inhibited by TMS. CONCLUSIONS: These data suggests that increased oxidative stress generated by CYP1B1 contributes to hypertension, increased cytokine production and sympathetic activity, and associated pathophysiological changes in SHR. CYP1B1 could be a novel target for developing drugs to treat hypertension and its pathogenesis. PMID- 24477451 TI - The dosimetric importance of the number of 90Y microspheres in liver transarterial radioembolization (TARE). PMID- 24477452 TI - The analysis of pupal development period in Lucilia sericata (Diptera: Calliphoridae) forensically important insect. AB - Forensic entomology is a study that insect evidence is used for the determination of postmortem interval (PMImin). While determining PMImin, the pupal period is given as the duration between the beginning of the pupal period and the stage of adult emergence. The pupal period constitutes approximately 50 % of the immature development, and with detailed examination it would be possible to present a much more accurate PMImin. In this study, the pupal period of Lucilia sericata (Meigen, 1826), which is one of the species used in PMImin estimation in forensic entomology, was investigated. Studies about the pupal period of development are considerably limited in the forensic entomology world. Stages and duration of the pupal period of Lucilia sericata were studied at temperatures of 20 degrees C, 25 degrees C, and 30 degrees C. For all temperatures, pupae specimens were dissected and photographed hourly. According to findings based on all three temperatures, it was determined that as the temperature increases, the duration of development shortens. Also, in addition to 11 pre-determined development stages, nine new development stages were identified. PMID- 24477454 TI - Research accomplishments that are too good to be true: comment. PMID- 24477453 TI - Cerebral metabolic effects of exogenous lactate supplementation on the injured human brain. AB - PURPOSE: Experimental evidence suggests that lactate is neuroprotective after acute brain injury; however, data in humans are lacking. We examined whether exogenous lactate supplementation improves cerebral energy metabolism in humans with traumatic brain injury (TBI). METHODS: We prospectively studied 15 consecutive patients with severe TBI monitored with cerebral microdialysis (CMD), brain tissue PO2 (PbtO2), and intracranial pressure (ICP). Intervention consisted of a 3-h intravenous infusion of hypertonic sodium lactate (aiming to increase systemic lactate to ca. 5 mmol/L), administered in the early phase following TBI. We examined the effect of sodium lactate on neurochemistry (CMD lactate, pyruvate, glucose, and glutamate), PbtO2, and ICP. RESULTS: Treatment was started on average 33 +/- 16 h after TBI. A mixed-effects multilevel regression model revealed that sodium lactate therapy was associated with a significant increase in CMD concentrations of lactate [coefficient 0.47 mmol/L, 95% confidence interval (CI) 0.31-0.63 mmol/L], pyruvate [13.1 (8.78-17.4) MUmol/L], and glucose [0.1 (0.04-0.16) mmol/L; all p < 0.01]. A concomitant reduction of CMD glutamate [-0.95 (-1.94 to 0.06) mmol/L, p = 0.06] and ICP [-0.86 (-1.47 to -0.24) mmHg, p < 0.01] was also observed. CONCLUSIONS: Exogenous supplemental lactate can be utilized aerobically as a preferential energy substrate by the injured human brain, with sparing of cerebral glucose. Increased availability of cerebral extracellular pyruvate and glucose, coupled with a reduction of brain glutamate and ICP, suggests that hypertonic lactate therapy has beneficial cerebral metabolic and hemodynamic effects after TBI. PMID- 24477455 TI - A pulsatile chest wall mass: pseudoaneurysm of the ascending aorta. PMID- 24477456 TI - Energy expenditure in the critically ill performing early physical therapy. AB - PURPOSE: Resting energy expenditure (REE) determination is of high relevance to avoid both overfeeding and underfeeding. We conducted an observational study to determine the impact of early exercise on energy requirements to adjust caloric intake accordingly in critically ill patients. METHODS: This was a prospective observational study conducted in an intensive care unit in 49 hemodynamically stable critically ill patients and 15 healthy volunteers. Indirect calorimetry (IC) was performed for 15 min at baseline during resting conditions, and then continuously recorded during 30 min of cycling at 0, 3, or 6 watts (W), followed by a 15-min resting period. REE determined by IC was compared with predictive formulas and correlated with several biomarkers. The energy cost of early exercise was compared between critically ill patients and healthy volunteers. RESULTS: In patients, REE determined by IC was higher than predicted by Harris Benedict (29 +/- 31 %, p < 0.001) and Fleisch equations (23 +/- 31 %, p < 0.001) but lower than predicted by the Faisy-Fagon equation for ventilated patients (16 +/- 19 %, p < 0.05). Differences between Harris-Benedict predictions and IC determination were positively correlated with C-reactive protein (CRP) in patients with sepsis (r = 0.51, p = 0.003). During a similar exercise, VO2 increase in patients was higher when compared with healthy volunteers at 3 W, close to significant at 6 W, and not present in the passive group. CONCLUSIONS: The critically ill have increased REE according to inflammation defined by CRP. Increased energy requirement for physical activity was only present for active exercise and seems to differ from that in the healthy population. For the exercise duration and intensity tested, nutritional adjustment is not indicated. PMID- 24477457 TI - Research accomplishments that are too good to be true: reply to Ting. PMID- 24477458 TI - Transglutaminase 2 reprogramming of glucose metabolism in mammary epithelial cells via activation of inflammatory signaling pathways. AB - Aberrant glucose metabolism characterized by high levels of glycolysis, even in the presence of oxygen, is an important hallmark of cancer. This metabolic reprogramming referred to as the Warburg effect is essential to the survival of tumor cells and provides them with substrates required for biomass generation. Molecular mechanisms responsible for this shift in glucose metabolism remain elusive. As described herein, we found that aberrant expression of the proinflammatory protein transglutaminase 2 (TG2) is an important regulator of the Warburg effect in mammary epithelial cells. Mechanistically, TG2 regulated metabolic reprogramming by constitutively activating nuclear factor (NF)-kappaB, which binds to the hypoxia-inducible factor (HIF)-1alpha promoter and induces its expression even under normoxic conditions. TG2/NF-kappaB-induced increase in HIF 1alpha expression was associated with increased glucose uptake, increased lactate production and decreased oxygen consumption by mitochondria. Experimental suppression of TG2 attenuated HIF-1alpha expression and reversed downstream events in mammary epithelial cells. Moreover, downregulation of p65/RelA or HIF 1alpha expression in these cells restored normal glucose uptake, lactate production, mitochondrial respiration and glycolytic protein expression. Our results suggest that aberrant expression of TG2 is a master regulator of metabolic reprogramming and facilitates metabolic alterations in epithelial cells even under normoxic conditions. A TG2-induced shift in glucose metabolism helps breast cancer cells to survive under stressful conditions and promotes their metastatic competence. PMID- 24477459 TI - Righteousness in the land of forgetfulness. AB - The experience of dementia is raises many important questions about the nature of self and personhood. No disease is experienced in isolation and dementia embodies this. Ideas of loss of self and loss of life feature strongly in dementia and have the potential to profoundly affect a person's spirituality. The Christian faith offers the possibility of retaining and recovering the sense of personhood and connection with God and others. This allows for the possibility of hope. PMID- 24477460 TI - Forbidden therapies: Santo Daime, ayahuasca, and the prohibition of entheogens in Western society. AB - Santo Daime, a Brazilian religion organized around a potent psychoactive beverage called ayahuasca, is now being practiced across Europe and North America. Deeming ayahuasca a dangerous "hallucinogen," most Western governments prosecute people who participate in Santo Daime. On the contrary, members of Santo Daime (called "daimistas") consider ayahuasca a medicinal sacrament (or "entheogen"). Empirical studies corroborate daimistas' claim that entheogens are benign and can be beneficial when employed in controlled contexts. Following from anthropology's goal of rendering different cultural logics as mutually explicable, this article intercedes in a misunderstanding between policies of prohibition and an emergent subculture of entheogenic therapy. PMID- 24477461 TI - Religiosity and behavioral health outcomes of adolescents living in disaster vulnerable areas. AB - The influence of religiosity on behavioral health outcomes among adolescents living in disaster-prone areas has been understudied. This study utilized data from the National Survey on Drug Use and Health (2005-2010) to examine the relationship between religion, depression, marijuana use, and binge drinking. The sample included 12,500 adolescents residing in the Gulf Coast region of the USA. Results show that religious salience was directly related to depression, marijuana, and binge drinking. It was also indirectly related to both substance use outcomes through depression. Religious service attendance was unrelated to any of the outcomes. Implications of the findings are discussed. PMID- 24477462 TI - Efficacy and safety of 1 % terbinafine film-forming solution in Chinese patients with tinea pedis: a randomized, double-blind, placebo-controlled, multicenter, parallel-group study. AB - BACKGROUND AND OBJECTIVES: Superficial fungal skin infections are treated using topical antifungals. The aim of this study was to demonstrate the efficacy of a single application of 1 % terbinafine film-forming solution (FFS) versus placebo for the treatment of tinea pedis in the Chinese population. METHODS: Six centers in China randomized 290 patients in a 1:1 ratio to receive either 1 % terbinafine FFS or FFS vehicle (placebo) once on the affected foot/feet. Efficacy assessments included microscopy and mycologic culture, and assessing clinical signs and symptoms at baseline, and at weeks 1 and 6 after the topical treatment. All adverse events were recorded. RESULTS: At week 6, 1 % terbinafine FFS was superior to placebo for effective treatment rate (63 vs. 8 %); clinical cure (30 vs. 6 %); mycological cure (86 vs. 12 %); negative microscopy (90 vs. 24 %); and negative mycological culture (90 vs. 27 %): all p <= 0.001 and clinically relevant. At week 6, 1 % terbinafine FFS was clinically superior to placebo for the absence of: erythema (69 vs. 29 %); desquamation (33 vs. 8 %); and pruritus (70 vs. 30 %): all p <= 0.001 and clinically relevant. At week 6, differences in the average total signs and symptoms scores were significantly lower for 1 % terbinafine FFS versus placebo (p <= 0.001). Both 1 % terbinafine FFS and placebo were safe and well tolerated based on adverse events and investigator and patient assessments. CONCLUSIONS: This double-blind, randomized, multicenter study demonstrated one single topical application of 1 % terbinafine FFS was safe and effective in the treatment of tinea pedis in the Chinese population. PMID- 24477463 TI - [Disease modification and duration of omalizumab treatment in patients with severe allergic asthma]. AB - BACKGROUND AND METHODS: Omalizumab is a monoclonal anti-IgE-antibody that is used to treat severe allergic asthma. The aim of this review was to evaluate the available evidence in a panel of experts and to provide recommendations on therapy duration with omalizumab. RESULTS: A direct or indirect interaction between omalizumab and IgE production seems likely. Pharmacokinetic pharmakodynamic models suggest that omalizumab modulates IgE production. This hypothesis is currently investigated in clinical studies. In addition, available evidence suggests that omalizumab mitigates different factors of airway remodeling. However, based on the currently available data, no recommendations can be given in regard to reduction of dosage or discontinuation of omalizumab in long term treated patients. CONCLUSIONS: Currently, neither dose reductions nor treatment withdrawal can be recommended in patients with severe allergic asthma and long term treatment with omalizumab. Clinical studies addressing these issues are being conducted. PMID- 24477464 TI - Perioperative transesophageal echocardiography for aortic dissection. AB - PURPOSE: Aortic dissection is an infrequent but serious condition that often requires immediate operative intervention. We explore recent developments in the classification of aortic dissection and perioperative transesophageal echocardiography that assist with quantifying the severity of disease and facilitate its management. PRINCIPAL FINDINGS: We describe the pivotal role of echocardiography in relation to key surgical considerations such as cannulation, aortic root surgery, perfusion in the aortic arch vessels, stenting in hybrid arch repair, and timing of preventative surgery. CONCLUSION: Developments in the classification of aortic dissection have improved our perspective and understanding of the key presenting features that affect mortality. Improvements in patient outcome may be achieved in part by appropriately timed echocardiography-guided surgery. PMID- 24477465 TI - Keys to minimizing the risk of spinal cord trauma during a lumbar approach to thoracic epidural. PMID- 24477466 TI - The protective effect of Aloysia triphylla aqueous extracts against brain lipid peroxidation. AB - In a normal diet, the use of herbs may contribute significantly to the total intake of plant antioxidants and even be a better source of dietary antioxidants than many other food groups. Therefore, the aims of this study were to evaluate the protective effect of aqueous extracts of Aloysia triphylla (infusion and decoction) against lipid-peroxidation of brain homogenates and to determine changes in the prooxidant/antioxidant balance when the plant material is added. In order to elucidate a possible antioxidant mechanism in vitro evaluation of total antioxidant capacity, oxygen species scavenging ability and reducing power (RP) were studied. Tested extracts had shown a strong inhibition of lipid peroxidation measured as thiobarbituric acid-reactive products of lipid peroxidation (TBARS) and chemiluminescence. Furthermore, infusion and decoction exhibited free radical trapping ability, expressed by the capacity to scavenge superoxide and hydrogen peroxide. Additionally, both aqueous extracts presented antioxidant activity measured as total reactive antioxidant potential (TRAP), 1,1 diphenyl-2-picrylhydrazyl radical (DPPH) and 2,2'-azino-bis(3 ethylbenzthiazoline)-6-sulfonic acid radical (ABTS) scavenging activity and RP. These results suggest that the lipid-peroxidation inhibition mechanism proposed is that the antioxidants present in Aloysia triphylla could act as strong scavengers of reactive oxygen species not only at the initiation of the lipid peroxidation chain reaction, but also at the propagation step. Therefore, they could be used as prophylactic and therapeutic agents for those diseases where the occurrence of oxidative stress and lipid-peroxidation contributes to the progression of damage. PMID- 24477467 TI - Current and Future Status for Evaluation of Dysplasia and Carcinoma in IBD. AB - OPINION STATEMENT: Endoscopic surveillance is an important method to identify colorectal neoplasia in patients with inflammatory bowel disease. Advances in endoscopic techniques using pancolonic chromoendoscopy have improved the detection of dysplasia compared to white-light endoscopy, which has the potential to decrease the risk of colorectal cancer. Currently, pancolonic chromoendoscopy is readily available for use, and in the future, it will likely become the standard of care for endoscopic surveillance. Pancolonic chromoendoscopy followed by confocal laser endomicroscopy may further increase the yield on surveillance endoscopy, although confocal laser endomicroscopy is not readily available outside of a limited number of institutions. Other endoscopic tools such as narrow band imaging have not been shown to be beneficial over white-light endoscopy. Emerging tools such as stool DNA testing show promise as an adjunct to colonoscopy but are still in the early stages of development. For management, patients with well-demarcated circumscribed dysplastic lesions should be resected endoscopically, followed by a continued endoscopic surveillance program. Patients with lesions that cannot be resected completely or that have features suggestive of invasive carcinoma on either endoscopy or histology should undergo colectomy. Patients with flat high-grade dysplasia should undergo colectomy. Patients with flat low-grade dysplasia should have a discussion about the risks and benefits of undergoing colectomy versus continuing in an endoscopic surveillance program. If they opt for surveillance, these patients should have more frequent follow-up surveillance examinations (every 3 to 6 months) with pancolonic chromoendoscopy. PMID- 24477468 TI - Fixed low-dose ultrasound-assisted catheter-directed thrombolysis followed by routine stenting of residual stenosis for acute ilio-femoral deep-vein thrombosis. AB - Patients with ilio-femoral deep-vein thrombosis (DVT) are at high risk of developing the post-thrombotic syndrome (PTS). In comparison to anticoagulation therapy alone, extended venography-guided catheter-directed thrombolysis without routine stenting of venous stenosis in patients with ilio-femoral DVT is associated with an increased risk of bleeding and a moderate reduction of PTS. We performed a prospective single-centre study to investigate safety, patency and incidence of PTS in patients with acute ilio-femoral DVT treated with fixed-dose ultrasound-assisted catheter-directed thrombolysis (USAT; 20 mg rt-PA during 15 hours) followed by routing stenting of venous stenosis, defined as residual luminal narrowing >50%, absent antegrade flow, or presence of collateral flow at the site of suspected stenosis. A total of 87 patients (age 46 +/- 21 years, 60% women) were included. At 15 hours, thrombolysis success >=50% was achieved in 67 (77%) patients. Venous stenting (mean 1.9 +/- 1.3 stents) was performed in 70 (80%) patients, with the common iliac vein as the most frequent stenting site (83%). One major (1%; 95% CI, 0-6%) and 6 minor bleedings (7%; 95%CI, 3-14%) occurred. Primary and secondary patency rates at 1 year were 87% (95% CI, 74-94%) and 96% (95% CI, 88-99%), respectively. At three months, 88% (95% CI, 78-94%) of patients were free from PTS according to the Villalta scale, with a similar rate at one year (94%, 95% CI, 81-99%). In conclusion, a fixed-dose USAT regimen followed by routine stenting of underlying venous stenosis in patients with ilio femoral DVT was associated with a low bleeding rate, high patency rates, and a low incidence of PTS. PMID- 24477471 TI - UK veterinary schools: emphasis on end-of-life issues. PMID- 24477469 TI - Expression patterning reveals retinal inflammation as a minor factor in experimental retinopathy of ZDF rats. AB - Obese Zucker diabetic fatty (ZDF) rats are used as a type-2 diabetes model for microvascular complications. In order to study retinopathy in this model, changes in retinal vasculature were analyzed by quantitative morphometry and related to retinal expression of 46 selected genes that were analyzed by microfluidic card PCR technology. At 3 months of age, obese animals had developed stable hyperglycemia (20.7 +/- 1.3 mmol/L plasma glucose vs. 6.5 +/- 0.1 mmol/L in lean). Hyperinsulinemia initially presented in obese rats at 2 months (10.5 +/- 0.7 MUg/L plasma insulin vs. 0.2 +/- 0.04 MUg/L in lean) and decreased at 3 months (3.9 +/- 0.6 vs. 0.5 +/- 0.09 MUg/ml in lean). At 8 months of age, animals had developed microvascular complications. An increased number of acellular capillaries in obese (24 +/- 5/mm(2)) versus lean (15 +/- 4/mm(2)) and a decreased number of retinal pericytes in obese (2,270 +/- 250/mm(2)) versus lean animals (1,620 +/- 243/mm(2)) could be observed. VEGFa, MIF, and HIF-1alpha were the most abundantly expressed and inflammatory genes such as TNFalpha and IL-6 are the least abundantly expressed genes. None of these genes were differentially regulated. Surprisingly, specific growth factors such as bFGF (FGF2) and placental growth factor, and adhesion molecules such as ICAM-1 were abundantly expressed and up-regulated in diabetic versus non-diabetic ZDF rats. In summary, we observed in type-2 diabetic ZDF rats retinopathy with retinal vasoregression along with a simultaneous up-regulation of specific growth factors such as bFGF and adhesion molecules, but only minor changes in key inflammatory genes. PMID- 24477472 TI - Epidemiological study (2006-2012) on the poisoning of small animals by human and veterinary drugs. AB - A retrospective study was conducted on the exposure of dogs and cats to drugs, reported to the Poison Control Centre of Milan (Centro Antiveleni di Milano (CAV)) between January 2006 and December 2012. Calls related to drugs for human use and veterinary drugs accounted for 23.7 per cent of total inquiries (1415) received by CAV and mostly involved dogs (70 per cent of enquiries). Exposure to drugs for human use accounted for 79 per cent of cases involving dogs, whereas veterinary drugs were the main culprit (77 per cent) in the case of cats. The most common class of drugs for human use proved to be CNS drugs (26.8 per cent), followed by NSAIDs (19.6 per cent) and cardiovascular and endocrine drugs (12.9 per cent each). The majority of calls (95.2 per cent) related to veterinary drugs involved dogs and cats exposed to parasiticides. The outcome was reported in only 58.2 per cent of cases, and fatal poisoning accounted for 8.7 per cent of these cases. Epidemiological data from this Italian survey provide useful information on animal exposure to drugs. The knowledge of agents involved in poisoning episodes can help veterinarians make the correct diagnosis and institute preventive measures to possibly reduce animal exposure to drugs. PMID- 24477473 TI - Field studies on the elimination of footrot in sheep through whole flock treatments with gamithromycin. PMID- 24477474 TI - Total hip arthroplasty with acetabular reconstruction using a bulk autograft for patients with developmental dysplasia of the hip results in high loosening rates at mid-term follow-up. AB - PURPOSE: Managing a deficient acetabulum in patients with developmental dysplasia of the hip (DDH) can be challenging. The purpose of the study was to determine the mid-term results of total hip arthroplasty (THA) using a bulk structural autograft for reconstruction of the acetabular roof in patients with DDH. METHODS: Between 1982 and 1999, 112 patients underwent THA with acetabular roof plasty using a bulk structural autograft for secondary osteoarthritis related to DDH. A total of 106 patients (115 hips) met inclusion criteria and were followed for an average of 11.6 years (seven to 24 years). The mean age was 52.5 years at the index operation. Clinical and radiological evaluations were performed according to the methods of Merle d'Aubigne and Postel, Johnston et al. and DeLee and Charnley. RESULTS: The overall Merle d'Aubigne hip score significantly improved (3.7 vs 10.4, p < 0.01). The limb length discrepancy decreased from 30 to 6 mm (p < 0.01). The average distance that the hip centre was distalised was 22.3 mm (0-56 mm). However, radiolucent lines were observed in 27 % of patients at final follow-up, and the overall rate of revision for aseptic loosening was 16 %. Further, Kaplan-Meier survivorship curves predicted a rapid increase in the failure rate at 15 years. CONCLUSIONS: The mid-term functional outcome of THA with an acetabular roof-plasty using a bulk autograft is satisfactory; however, the long-term results are questionable. PMID- 24477475 TI - Can rotatory knee laxity be predicted in isolated anterior cruciate ligament surgery? AB - PURPOSE: Despite the overall success of the surgical anterior cruciate ligament (ACL) reconstruction, some patients still present with instability symptoms even after the surgery, mainly due to the presence of associated lesions. At present, the pivot shift test has been reported to be the benchmark to assess rotatory knee laxity. The purpose of this study was to quantitatively evaluate rotatory knee laxity at time-zero in order to determine whether detected post reconstruction laxity was predictable by its value measured before the reconstruction, which was hypothized to be influenced by the presence of associated lesions. METHODS: Rotatory knee laxity was retrospectively analysed in 42 patients, including two different ACL reconstructions. The maximal anterior displacement and the absolute value of the posterior acceleration reached during the reduction of the tibial lateral compartment were intra-operatively acquired by using a navigation system and identified as discriminating parameters. For each parameter, statistical linear regression analysis (line slope and intercept) was performed between pre- and post-reconstruction values. RESULTS: No statistically significant influence of the initial posterior acceleration on the post-reconstruction outcome was found (line slope, p > 0.05), although a statistically significant line intercept was indeed identified (p < 0.001). A statistically significant influence on the surgery outcome was instead found for the initial value of the anterior tibial displacement (line slope = 0.39, p = 0.004), meaning that, on average, about 40 % of the post-reconstruction lateral compartment displacement could be explained by the corresponding pre reconstruction value. Both of these findings highlighted the importance of intra operative quantification of rotatory knee laxity to identify correct indications for the surgery. CONCLUSIONS: This study provided important implications for the future possibility of defining a quantifying tool able to assess rotatory knee laxity during ACL reconstruction. This could allow detection of additional injuries to secondary restraints by easily performing rotatory knee laxity tests, which in turn could reduce post-surgical recurrence of knee instability. PMID- 24477476 TI - Novel roles for the MiTF/TFE family of transcription factors in organelle biogenesis, nutrient sensing, and energy homeostasis. AB - The MiTF/TFE family of basic helix-loop-helix leucine zipper transcription factors includes MITF, TFEB, TFE3, and TFEC. The involvement of some family members in the development and proliferation of specific cell types, such as mast cells, osteoclasts, and melanocytes, is well established. Notably, recent evidence suggests that the MiTF/TFE family plays a critical role in organelle biogenesis, nutrient sensing, and energy metabolism. The MiTF/TFE family is also implicated in human disease. Mutations or aberrant expression of most MiTF/TFE family members has been linked to different types of cancer. At the same time, they have recently emerged as novel and very promising targets for the treatment of neurological and lysosomal diseases. The characterization of this fascinating family of transcription factors is greatly expanding our understanding of how cells synchronize environmental signals, such as nutrient availability, with gene expression, energy production, and cellular homeostasis. PMID- 24477477 TI - Glutamine deprivation initiates reversible assembly of mammalian rods and rings. AB - Rods and rings (RR) are protein assemblies composed of cytidine triphosphate synthetase type 1 (CTPS1) and inosine monophosphate dehydrogenase type 2 (IMPDH2), key enzymes in CTP and GTP biosynthesis. Small-molecule inhibitors of CTPS1 or IMPDH2 induce RR assembly in various cancer cell lines within 15 min to hours. Since glutamine is an essential amide nitrogen donor in these nucleotide biosynthetic pathways, glutamine deprivation was examined to determine whether it leads to RR formation. HeLa cells cultured in normal conditions did not show RR, but after culturing in media lacking glutamine, short rods (<2 MUm) assembled after 24 h, and longer rods (>5 MUm) formed after 48 h. Upon supplementation with glutamine or guanosine, these RR underwent almost complete disassembly within 15 min. Inhibition of glutamine synthetase with methionine sulfoximine also increased RR assembly in cells deprived of glutamine. Taken together, our data support the hypothesis that CTP/GTP biosynthetic enzymes polymerize to form RR in response to a decreased intracellular level of glutamine. We speculate that rod and ring formation is an adaptive metabolic response linked to disruption of glutamine homeostasis. PMID- 24477478 TI - Individualized assessments in treatment research: an examination of parent nominated target problems in the treatment of disruptive behaviors in youth with Tourette syndrome. AB - Youth with Tourette syndrome (TS) often exhibit disruptive behaviors. Although improvement data on rating scales support the efficacy of structured psychotherapeutic interventions, there is growing interest in personalized outcome assessments. This report examined parent-nominated target problems (PTPs) as an individualized outcome measure in 48 youth with TS and disruptive behaviors, who participated in one of two randomized psychotherapy trials. At baseline, parents described two primary problems to an independent evaluator who generated a structured narrative for each problem. These narratives were reviewed and updated at endpoint. When rated by five treatment-blind judges, the PTP rating demonstrated excellent reliability and good convergent validity with the Disruptive Behavior Rating Scale (DBRS). The PTP rating exhibited comparable treatment effects to the DBRS, and accounted for additional variance in global treatment outcome. The PTP rating serves a reliable, valid, and sensitive personalized assessment in research trials that provides complementary information to standardized rating scales. PMID- 24477479 TI - Solution flow in tubular semipermeable membranes. AB - Solution flow in tubular semipermeable membranes was studied as a model for assimilate transport in sieve tubes. A mass flow of solution was demonstrated both in closed turgid tubes and in open tubes without turgor pressure. These results can be explained in terms of hydrostatic and osmotic pressure differences across the semipermeable membrane without consideration of a decrease in hydrostatic pressure along the direction of solution flow. A theoretical model based on nonequilibrium thermodynamics is developed that is in fairly good quantitative agreement with the experimental results. Munch's original experiment demonstrating solution flow is analyzed and shown not to depend on a gradient of hydrostatic pressure but rather to depend on the same driving forces operative in these experiments. On the basis of these findings a "volume-flow" mechanism of phloem transport is proposed. PMID- 24477480 TI - Fixation patterns of (14)C within developing leaves of eastern cottonwood. AB - Individual leaves of eastern cottonwood (Populus deltoides), representing an ontogenetic series from leaf plastochron index 0.0 to 8.0, were fed (14)CO2 photosynthetically and then harvested at times ranging from 15 to 1440 min. The lamina of each fed leaf was sectioned from tip to base into 5 parts, and each part was quantitatively assayed for (14)C activity. In young leaves, the percentage of the total (14)C fixed (expressed in dpm/mg of dry leaf tissue) was high in the lamina tip and decreased almost linearly toward the base. With increasing leaf age, the percentage of (14)C fixed decreased in the lamina tip and increased in the base. The relative activity in mature leaves was almost uniform throughout the lamina. No differences were detected in the (14)C distribution patterns within leaves over the time series.On the basis of the data presented and of anatomical observations of developing cottonwood leaves, the hypothesis that the precociously mature lamina tip may provide photosynthates to the still-expanding lamina base was shown to be invalid. It is concluded that bidirectional transport in a developing cottonwood leaf results from simultaneous import to the immature basal region and export from the mature tip. PMID- 24477481 TI - Uptake and metabolism of (3)H-Gibberellin A 1 by barley aleurone layers: Response to abscisic acid. AB - When barley aleurone layers were incubated with (3)H-Gibberellin A1 ((3)H-GA1), the hormone was converted to (3)H-GA-X (not identified), (3)H-GA8 and two other compounds tentatively identified as (3)H-GA1-glucoside, and (3)H-GA8-glucoside. Uptake and metabolism of the (3)H-GA1 were markedly enhanced by simultaneous treatment with abscisic acid (ABA). Uptake of (3)H-GA1 from the medium containing ABA was linear over a 24-h period, whereas in the absence of ABA, uptake of (3)H GA1 leveled off after 5 h. After 24 h, aleurones treated with (3)H-GA1 and (3)H GA1 plus ABA, had taken up 9 and 24%, respectively, of the original (3)H-GA1 provided. Metabolism of (3)H-GA1 proceeded at a linear rate in the presence of ABA. The amount of (3)H-GA1-metabolites which had accumulated by the end of a 24 h incubation appeared to be linearly correlated to the logarithm of the ABA concentration. Gibberellins A8 and-A8-glucoside did not reverse GA1-enhanced synthesis of alpha-amylase. PMID- 24477482 TI - In-vitro auxin binding to particulate cell fractions from corn coleoptiles. AB - When low concentrations (e.g. 10(-6) M) of labelled 3-indoleacetic acid ((14)C IAA) or alpha-naphthaleneacetic acid ((14)C-NAA) are added in vitro to homogenates of corn coleoptiles, radioactivity is reversibly bound to pelletable particles. From the saturation kinetics of the binding it is possible to estimate an apparent K M between 10(-6) M and 10(-5) M and a concentration of specific sites of 10(-7)-10(-6) M per tissue volume.The binding is auxin-specific. Among many compounds tested, only auxins and such auxin analogues that are known to interact directly with auxin in transport and/or growth were found to interfere with this binding. For instance, the growth-active D-dichlorophenoxyisopropionic acid at 10(-4) M inhibits (14)C-NAA binding more than the less active L isomer.The auxin-binding fractions are practically free of DNA and cytochrome-C oxidase and contain binding sites for 1-naphthylphthalamic acid. The results are discussed in context with the hyothesis-derived mainly from physiological data that auxin receptors are localized at the plasma membrane. PMID- 24477483 TI - Phytochrome decay in seedlings under continuous incandescent light. AB - Under continuous high intensity incandescent light the decay of phytochrome in Amaranthus seedlings deviates from the predicted first order rate characteristic of the P fr/P total ratio maintained. This deviation takes the form of a slower decay than would be predicted and is only observed at high intensities. Experiments are presented to test the hypothesis that this reduced rate of decay is the result of a high level of phytochrome intermediates maintained under high intensity incandescent light. Accumulation of intermediates under these conditions has been demonstrated using a quasi-continuous measuring spectrophotometer. They are weakly absorbing and their concentration increases with light intensity. Although they form P fr in darkness, it is proposed that they do not decay. The model predicts that in a sample cuvette, where a light intensity gradient exists, there is more probability of a phytochrome molecule being presnet as P fr at the back of the cuvette: the region of lowest light intensity. Under conditions which favour phytochrome decay, a preferential loss of phytochrome should result at the back of the cuvette and an increasingly higher proportion of the remaining phytochrome will consequently be measured as intermediate as the experiment progresses. The results confirm the hypothesis and in addition, after 60 min incandescent light, demonstrate an accumulation of intermediates which form P fr with a longer half-life that at the begining of the experiment. Pisum epicotyl hooks show no such intermediate accumulation or preferential decay at the back of the cuvette, which is in agreement with the observed first order phytochrome decay under high intensity incandescent light. A scheme is presented explaining the results on the basis of the decay process. PMID- 24477484 TI - Studies on the isolation and purification of chloroplasts from Euglena gracilis. AB - A method has been developed for the isolation of chloroplasts from Euglena gracilis grown under mixotrophic conditions. This method utilizes sucrose density gradient centrifugation in the AXII zonal rotor and allows the rapid preparation of large amounts of chloroplasts free from contaminating whole cells and other cytoplasmic materials. The majority of the isolated chloroplasts appear intact in phase contrast and electron micrographs. The purified chloroplast fraction contains DNA, the major species of which has a density of 1.682 g/cm(3). The species of DNA having a density of 1.707 g/cm(3) seemed to result from the presence of contaminating nuclear fragments which could be removed by isopycnic flotation. PMID- 24477485 TI - A bimodal temperature response and effect of light intensity in the photocontrol of germination of seeds in Jussiaea suffruticosa. AB - A bimodal temperature response is observed in the germination of seeds in Jussiaea suffruticosa, both under continuous and cyclic light treatments. Germination exhibits two maxima at around 25 degrees C and at 40 degrees , and a minimum in the region of 30-35 degrees . The response depends on light intensity both under continuous and intermittent light treatments. This dependence is much more noticeable in the region of minimum germination (30 degrees ). Both preincubation in darkness at 35 degrees and high light intensities (15 500 lux) tend to eliminate the bimodal temperature response. PMID- 24477486 TI - Co-registration of intra-operative brain surface photographs and pre-operative MR images. AB - PURPOSE: Brain shift, the change in configuration of the brain after opening the dura mater, is a significant problem for neuronavigation. Brain structures at intra-operative deformed positions must be matched with corresponding structures in the pre-operative 3D planning data. A method to co-register the cortical surface from intra-operative microscope images with pre-operative MRI-segmented data was developed and tested. METHODS: Automated classification of sulci on MRI extracted cortical surfaces was tested by comparison with user guided marking of prominent sulci on an intra-operative photography. A variational registration method with a fidelity energy for 3D deformations of the cortical surface in conjunction with a higher-order, linear elastic prior energy was used for the actual registration. The minimization of this energy was performed with a regularized gradient descent scheme using finite elements for spatial discretization. The sulcal classification method was tested on eight different clinical MRI data sets by comparison of the deformed MRI scans with intra operative photographs of the brain surface. RESULTS: User intervention was required for marking sulci on the photographs demonstrating the potential for incorporating an automatic classifier. The actual registration was validated first on an artificial testbed. The complete algorithm for the co-registration of actual clinical MRI data was successful for eight different patients. CONCLUSIONS: Pre-operative MRI scans can be registered to intra-operative brain surface photographs using a surface-to-surface registration method. This co registration method has potential applications in neurosurgery, particularly during functional procedures. PMID- 24477488 TI - Enhanced ionic conductivity in polycrystalline TiO2 by "one-dimensional doping". AB - The influence of line defects (dislocations) on the electrical properties of polycrystalline TiO2 was investigated. Line defects were created in TiO2 during spark plasma sintering at 1000 degrees C and 400 MPa. TEM characterisation indicates dislocations to be preferably oriented on {110} and {101} planes. The measured electrical conductivity as a function of oxygen partial pressure and temperature revealed that the dislocations play a vital role in modifying the defect chemistry of TiO2. The presence of dislocations enhanced the ionic conductivity over a wide range of oxygen partial pressures. The observed changes can be interpreted in terms of negatively charged dislocation cores and adjacent space charge accumulation layers. The present findings point towards an alternative method to tune the electrical properties of ionic solids. PMID- 24477489 TI - Cortisol levels and the severity and outcomes of acute stroke: a systematic review. AB - Studies in non-stroke patients have shown an association between dysregulation of the hypothalamic-pituitary-adrenal axis and morbidity and mortality. We conducted a systematic review to evaluate cortisol levels in acute stroke and their associations with outcome. We searched MEDLINE and EMBASE for articles up to April 2013 and PsychINFO for articles up to July 2013, using the keywords "cortisol" and "stroke" and associated terms or synonyms. We included studies published in peer-reviewed journals that recruited 10 or more participants and measured cortisol at least once in the first year following stroke. Data were extracted regarding cortisol levels, including changes over time and their relationship to stroke severity, and outcome. Of 11,240 abstracts, 101 full texts were obtained and 48 fulfilled our inclusion criteria. Cortisol levels were high in the first week after stroke in the majority of studies (26 studies, n = 1,340). Higher cortisol was associated with dependency (8/11 studies, n = 822), delirium (5/6 studies, n = 269) depression (3/5 studies n = 117) and mortality (8/10 studies, n = 856). Five studies adjusted for stroke severity; one found an association between higher cortisol and dependency, and three found an association between higher cortisol and mortality. Cortisol levels are high for at least 7 days after stroke. Elevated cortisol after stroke is associated with dependency, morbidity, and mortality; however, there is insufficient evidence to conclude that these relationships are independent of stroke severity. PMID- 24477490 TI - Long-term levodopa/carbidopa intestinal gel in advanced Parkinson's disease. AB - The short-term benefits of levodopa/carbidopa intestinal gel (LCIG) in patients with advanced Parkinson's disease (PD) are well documented, but the long-term benefits are still uncertain. The aim of this study was to investigate the motor and cognitive outcome of LCIG treatment in advanced PD after a follow-up period of at least 24 months. We assessed 29 patients with advanced PD who started LCIG infusion at our centre between 2007 and 2013. Motor fluctuations, parkinsonian symptoms, activities of daily living and impact on quality of life were evaluated. We also investigated the cognitive outcome using a battery of neuropsychological tests. All adverse events were recorded. Of the 29 PD patients who initiated LCIG, 16 patients reached the follow-up evaluation (24 months), after a mean time period of 32.2 +/- 12.4 months. Six patients did not fulfil the 24-month follow-up visit and were evaluated after a mean time period of 8.6 +/- 5.4 months. Seven patients discontinued the treatment before the scheduled visit. "Off" time and "On" dyskinesia duration were significantly reduced. LCIG improved quality of life and non motor symptoms, despite overall unchanged total levodopa doses prior to LCIG beginning. Motor and cognitive decline were detected. A relatively high number of adverse events occurred during the follow-up, above all, technical problems with the infusion device and mild problems related with gastrostomy. There were four cases of peripheral neuropathy (PN), 2 of which were considered serious. Our data confirm that LCIG is beneficial in the long-term treatment of advanced PD patients despite a decline in cognitive functions in a subgroup of patients, probably due to disease progression. PN in patients with LCIG may be more frequent than the published date suggest. PMID- 24477493 TI - POLG: a cause of intractable epilepsy. PMID- 24477492 TI - Use of selective serotonin reuptake inhibitors and risk of stroke: a systematic review and meta-analysis. AB - Since several studies have inconsistently reported the association between the use of selective serotonin reuptake inhibitors (SSRIs) and the risk of stroke, we performed a meta-analysis on this issue. We identified studies by searching three electronic databases (MEDLINE, EMBASE, and the Cochrane Library) from their inception to August, 2013. Pooled effect estimates were obtained by using random effects meta-analysis. Thirteen relevant studies (three case-control, six nested case-control, and four cohort studies) were finally included in our study. In our meta-analyses, the use of SSRIs was associated with an increased risk of all types of stroke [adjusted odds ratio (aOR), 1.40; 95 % confidence interval (CI), 1.09-1.80], ischemic stroke (aOR 1.48; 95 % CI 1.08-2.02), and hemorrhagic stroke (aOR 1.32; 95 % CI 1.02-1.71). Between the two subtypes of hemorrhagic stroke, that is, intracerebral and subarachnoid, the increased risk of intracerebral hemorrhage was associated with the use of SSRIs (aOR 1.30; 95 % CI 1.02-1.67). When the analysis was restricted to the studies in which potential confounding by depression was considered, the risks were still higher in SSRI users than in non users and the heterogeneities among studies were significantly decreased. Since there was heterogeneity among studies and a possible confounding effect from depression could not be fully excluded, further well-designed studies are needed to confirm this association. PMID- 24477491 TI - Unusual features of Creutzfeldt-Jakob disease followed-up in a memory clinic. AB - Sporadic Creutzfeldt-Jakob disease (sCJD) generally manifests itself by cognitive or rapidly progressive motor symptoms. An atypical onset or an unusual evolution may delay the diagnosis. Among patients with a confirmed diagnosis of sCJD following a post-mortem neuropathological examination at the Neuropathology Centre of Lille, France, those who had presented with atypical cognitive disorders at onset were included in the study. Four patients were included. The first patient (64-years-old) presented early language disorders, later accompanied by apathy and behavioral disorders. The prolonged course suggested a diagnosis of progressive primary aphasia. The second patient (68-years-old) presented with aphasia, apraxia, and ataxia of the right upper limb with parkinsonian syndrome, suggesting corticobasal degeneration. In the two last patients (58- and 61-years-old), the onset was marked by an anxiety-depression syndrome, falls, visual hallucinations, extra-pyramidal syndrome, and fluctuating cognitive decline. The diagnosis raised was probable Lewy body dementia. The 14.3.3 protein was found in two of the four cases. The clinical elements found may initially suggest focal atrophy or Lewy body dementia. A very rapid clinical deterioration generally suggests sCJD, but in the last case, the evolution was particularly slow. The diagnosis of sCJD must be considered in cases of rapid onset dementia, even if all of the clinical criteria are not present. The detection of the 14.3.3 protein and multifold increase in total-Tau with normal or slightly increased phosphorylated-Tau in the CSF are additional arguments to reinforce the diagnosis. The post-mortem neuropathological examination is important to confirm the diagnosis. PMID- 24477494 TI - No correction angle loss with stable plates in open-wedge high tibial osteotomy. AB - PURPOSE: The aim of this study was to compare the clinical and radiological results of the wedge plate and locking plate systems in open-wedge high tibial osteotomy. METHODS: Between 2007 and 2010, the wedge plate was used as the fixation device for osteotomy to treat a total of 67 patients; from 2009 to 2010, the locking plate was used in 19 patients. Matching for gender, age, body mass index (BMI), and articular cartilage status, 19 pairs of wedge plate and locking plate cases were enrolled in a 1:1 retrospective matched-pair analysis. Clinical data were collected and scored using the visual analogue scale and the International Knee Documentation subjective score. Additionally, pre-operative, immediate post-operative, and last follow-up radiographs were obtained to assess changes in the hip-knee-ankle (H-K-A) angle and posterior tibial slope. RESULTS: No significant differences in gender, age, BMI, follow-up period, and articular cartilage status were found between the groups. Although the initial correction of the H-K-A angles, 8.9 degrees +/- 1.9 degrees and 9.4 degrees +/- 4.2 degrees for the wedge plate and locking plate groups, respectively, was not significantly different, a significant difference (P = 0.046) in the final correction angles, 7.2 degrees +/- 2.1 degrees and 9.4 degrees +/- 4.4 degrees , respectively, was found. The increase in the posterior tibial slope, 0.5 degrees +/- 2.0 degrees and 3.2 degrees +/- 2.6 degrees , for the wedge plate and locking plate groups, respectively, was significantly different (P = 0.010). When classified according to the correction angle, we found that when the initial correction angle exceeded 10.0 degrees , an average correction loss of 2.9 degrees +/- 0.5 degrees was observed in the wedge plate group, whereas an average increase in the posterior tibial slope of 5.8 degrees +/- 1.6 degrees was evident for the locking plate group. CONCLUSIONS: At 2 years post operatively, the final correction angles of the wedge and the locking plate groups differed significantly, and the wedge plate group had a smaller increase in the posterior tibial slope than the locking plate group. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 24477495 TI - Clinical results after ultrasound-guided intratissue percutaneous electrolysis (EPI(r)) and eccentric exercise in the treatment of patellar tendinopathy. AB - PURPOSE: To investigate the outcome of ultrasound (US)-guided intratissue percutaneous electrolysis (EPI((r))) and eccentric exercise in the treatment of patellar tendinopathy during a long-term follow-up. METHODS: Forty patients with patellar tendinopathy were prospectively evaluated over a 10-year follow-up period. Pain and function were evaluated before treatment, at 3 months and at 2, 5 and 10 years using the Victorian Institute of Sport Assessment-Patella (VISA-P) score, the Tegner score and Blazina's classification. According to VISA-P score at baseline, patients were also dichotomized into Group 1 (<50 points) and Group 2 (>=50 points). There were 21 patients in Group 1 and 19 in Group 2. Patient satisfaction was measured according to the Roles and Maudsley score. RESULTS: The VISA-P score improved globally by 41.2 points (p < 0.01) after a mean 4.1 procedures. In Group 1, VISA-P score improved from 33.1 +/- 13 to 78.9 +/- 14.4 at 3-month and to 88.8 +/- 10.1 at 10-year follow-up (p < 0.001). In Group 2, VISA-P score improved from 69.3 +/- 10.5 to 84.9 +/- 9 at 3-month and to 96.0 +/- 4.3 at 10-year follow-up (p < 0.001). After 10 years, 91.2 % of the patients had a VISA-P score >80 points. The same level (80 % of patients) or the Tegner score at no more than one level lower (20 % of patients) was restored, and 97.5 % of the patients were satisfied with the procedure. CONCLUSION: Treatment with the US guided EPI((r)) technique and eccentric exercises in patellar tendinopathy resulted in a great improvement in knee function and a rapid return to the previous level of activity after few sessions. The procedure has proved to be safe with no recurrences on a long-term basis. LEVEL OF EVIDENCE: Therapeutic study, Level IV. PMID- 24477496 TI - Fibronectin-aggrecan complex as a marker for cartilage degradation in non arthritic hips. AB - PURPOSE: To report hip synovial fluid cytokine concentrations in hips with and without radiographic arthritis. METHODS: Patients with no arthritis (Tonnis grade 0) and patients with Tonnis grade 2 or greater hip osteoarthritis (OA) were identified from patients undergoing either hip arthroscopy or arthroplasty. Synovial fluid was collected at the time of portal establishment for those undergoing hip arthroscopy and prior to arthrotomy for the arthroplasty group. Analytes included fibronectin-aggrecan complex (FAC) as well as a standard 12 cytokine array. Variables recorded were Tonnis grade, centre-edge angle of Wiberg, as well as labrum and cartilage pathology for the hip arthroscopy cohort. A priori power analysis was conducted, and a Mann-Whitney U test and regression analyses were used with an alpha value of 0.05 set as significant. RESULTS: Thirty-four patients were included (17 arthroplasty, 17 arthroscopy). FAC was the only analyte to show a significant difference between those with and without OA (p < 0.001). FAC had significantly higher concentration in those without radiographic evidence of OA undergoing microfracture versus those not receiving microfracture (p < 0.05). CONCLUSION: There was a significantly higher FAC concentration in patients without radiographic OA. Additionally, those undergoing microfracture had increased levels of FAC. As FAC is a cartilage breakdown product, no significant amounts may be present in those with OA. In contrast, those undergoing microfracture have focal area(s) of cartilage breakdown. These data suggest that FAC may be useful in predicting cartilage pathology in those patients with hip pain but without radiographic evidence of arthritis. PMID- 24477497 TI - Aneurysm shape reconstruction from biplane angiograms in the ISUIA collection. AB - The International Study of Unruptured Intracranial Aneurysms (ISUIA) is an epidemiologic international study of the natural history of unruptured intracranial aneurysms that enrolled 4,060 subjects. A conventional biplane cerebral angiogram available for central review was required for enrollment resulting in a large database. Data on aneurysms that ruptured during follow-up of the 1,692 untreated subjects provides an opportunity to investigate the anatomic features that may be predictive of future rupture. The objective of the study is to develop and test a method for three-dimensional (3D) shape reconstruction of aneurysms using biplane angiographic data in the ISUIA for retrospective morphometric assessment. Beginning with the two boundaries of the biplane views, curve morphing techniques were employed to estimate a number of intermediate boundaries around the aneurysm sac resulting in the creation of a 3D sac surface. The method was tested using simulated biplane "angiograms" of pre reconstructed 3D models of patient-specific aneurysms. An algorithm to perform the image analysis was developed, and the morphometric indices of 150 intracranial aneurysms in the ISUIA database were estimated. Simultaneously, experienced neuroradiologists made manual measurements of key dimensions in the sac from the biplane angiograms for all cases. 3D reconstructions using our proposed method matched well with the original pre-reconstructed 3D geometries and were consistent with manual measurements of the neuroradiologists for the ISUIA aneurysms. A method for reconstructing the 3D geometry of the intracranial aneurysm sac from biplane angiograms in the ISUIA database with reasonable fidelity has been developed. PMID- 24477498 TI - Academic achievement in the high school years: the changing role of school engagement. AB - School engagement is an important theoretical and practical cornerstone to the promotion of academic accomplishments. This article used a tripartite-behavioral, emotional, and cognitive-model of school engagement to assess the relationship between school engagement and academic success among high school students, and to determine whether a reciprocal relationship exists between these constructs. Data were derived from 710 youth (69% female) who took part in Waves 6 through 8 (Grades 10 through 12) of the 4-H study of positive youth development. Longitudinal confirmatory factor analyses confirmed the invariance of the tripartite model of school engagement. Results of a structural equation model showed that the components of school engagement and academic achievement were mutually predictive and that these predictions varied from grade to grade. Future possibilities for evaluating the relationship between school engagement and academic achievement, as well as the implications for educational policy and practice, are discussed. PMID- 24477500 TI - Age-related injury and compensation claim rates in heavy industry. AB - BACKGROUND: Although ageing workers face specific health and safety concerns, conflicting evidence exists regarding the effects of age on workplace injury rates and workers' compensation claims. AIMS: To examine injury and workers' compensation claim rates by age and injury type in an aluminium smelter over a 9 year period. METHODS: Routinely collected data for workplace injuries and workers' compensation claims were retrieved for the period from 1997 to 2005. RESULTS: The study included a total of 709 workers who experienced 2281 at-work injuries and submitted 446 claims. In 1997, 16% of employees were aged 50 or over; by 2005 that proportion had more than doubled to 35%. Injury and claim rates in all age groups did not change significantly during this period. Workers younger than 30 years of age had the highest injury rates, with differences most significant for injuries other than sprains and strains. Claim rates were not significantly different across age groups. CONCLUSIONS: These findings do not provide evidence to support the notion that older workers sustain more injuries and are more likely to claim compensation for their injuries. Our findings demonstrate that in this workplace, older workers were able to maintain their ability to work safely. This contrasts with the finding that younger workers had the highest injury and claim rates. While adapting to the needs of an ageing workforce, employers should not lose sight of the need to nurture a strong culture of working safely among their youngest workers. PMID- 24477501 TI - Standards for 'Health for Health Professionals' services in the UK. AB - BACKGROUND: Doctors are more likely to suffer from work-related mental ill-health than other professions in the UK and internationally. Services to support doctors with health problems are emerging in the UK and have diverse models of delivery and funding. Services should be able to demonstrate agreed standards of practice for those who wish to commission, develop or access them. AIMS: To develop consensus about standards for 'Health for Health Professionals' (HHP) services in the UK through a modified Delphi study. METHODS: We conducted a two-stage Delphi study over 6 months. The questionnaire development took place during the UK Association of Physician Health (UKAPH) meeting in London in 2012, an invited meeting for clinicians with a specific interest in the area of physician health. The final questionnaire was disseminated via the UKAPH database. RESULTS: Forty four people took part in round 1 and 40 in round 2. Participants were mainly GPs, occupational physicians and psychiatrists. Consensus was reached on major criteria for HHP services, with greatest consensus (45% agreement or greater) for four statements concerning the clarity and transparency of the services offered and one statement that anyone working within the service should have received suitable training in physician health. Consensus about some statements varied among the three specialities. CONCLUSIONS: This study will assist discussion about providing and improving consistent services across the UK, while recognizing the flexibility required in view of geographical differences. PMID- 24477502 TI - Sitting time and step counts in office workers. AB - BACKGROUND: Technological advances mean that many adults are now employed in sedentary occupations. Given evidence linking prolonged sitting to chronic disease risk, understanding sitting and physical activity in and outside the workplace may usefully inform effective interventions. AIMS: To assess sitting time and physical activity during and outside working hours in full-time office workers. METHODS: Participants wore a pedometer and recorded sitting times and step counts during and outside working hours for 7 days. Participants were divided into tertiles based on the proportion of time spent sitting at work. Sitting times and step counts reported outside work were compared between groups, using one-way analysis of variance. RESULTS: There were 72 participants. Almost two-thirds (65%) of time at work was spent sitting. The sample accumulated 3742+/ 2493 steps at work and 5159+/-2474 steps outside work on workdays. Participants in the highest tertile for workplace sitting reported sitting for longer than those in the lowest tertile during transport (64+/-59 versus 21+/-16min), after work (154+/-30 versus 126+/-51min) and at weekends (382+/-133 versus 288+/ 124min, all P < 0.05). Work duration and steps reported outside work did not differ between groups. CONCLUSIONS: Office workers who sit for a large proportion of their working day also report sitting for longer outside work. They do not compensate for their sedentary behaviour at work by being more active outside work. Occupational health interventions should focus on reducing workplace and leisure-time sitting in sedentary office workers. PMID- 24477503 TI - Risk factors and prognostic impact of venous thromboembolism in Asian patients with non-small cell lung cancer. AB - Although the overall risk of venous thromboembolism (VTE) is high in patients with non-small cell lung cancer (NSCLC), risk identification is limited. The goal of this study was to estimate the incidence, risk factors and prognostic implications of VTE, and to evaluate a genetic link between oncogenes and the risk of VTE in Asian patients with NSCLC. A total of 1,998 consecutive patients with NSCLC were enrolled and analysed retrospectively. Since the effects of therapeutics on VTE development were modified by stage, stratified analyses were performed. When comparing overall survival in terms of VTE development, a propensity score-matching method was adopted to minimise potential confounding. The six-month and two-year cumulative incidences of VTE were 4.2% and 6.4%, respectively. The risk of VTE increased 2.45-fold with each advancing stage in NSCLC (p<0.001). The independent predictors of VTE were advanced age, pneumonectomy and palliative radiotherapy in localised NSCLC and ineligibility for surgery and palliative radiotherapy in locally advanced NSCLC. Adenocarcinoma histology (vs squamous cell) and former/current smoking status were significant predictors of VTE in metastatic NSCLC. A significant association between VTE and decreased survival was observed only among patients with localised NSCLC. EGFR mutations (p=0.170) and ALK rearrangements (p=0.159) were not associated with VTE development in lung adenocarcinoma. In conclusion, the two-year cumulative incidence of VTE is 6.4% in Asian patient with NSCLC. The significant predictors of VTE are different across stages of NSCLC. The prognostic impact of VTE on poor survival was limited to localised NSCLC. PMID- 24477504 TI - Dose reduction in computed tomography of the chest: image quality of iterative reconstructions at a 50% radiation dose compared to filtered back projection at a 100% radiation dose. AB - PURPOSE: The aim of this study was to evaluate the potential of iterative reconstruction (IR) in chest computed tomography (CT) to reduce radiation exposure. The qualitative and quantitative image quality of standard reconstructions with filtered back projection (FBP) and half dose (HD) chest CT data reconstructed with FBP and IR was assessed. MATERIALS AND METHODS: 52 consecutive patients underwent contrast-enhanced chest CT on a dual-source CT system at 120 kV and automatic exposure control. The tube current was equally split on both tube detector systems. For the HD datasets, only data from one tube detector system was utilized. Thus, FD and HD data was available for each patient with a single scan. Three datasets were reconstructed from the raw data: standard full dose (FD) images applying FBP which served as a reference, HD images applying FBP and IR. Objective image quality analysis was performed by measuring the image noise in tissue and air. The subjective image quality was evaluated by 2 radiologists according to European guidelines. Additional assessment of artifacts, lesion conspicuity and edge sharpness was performed. RESULTS: Image noise did not differ significantly between HD-IR and FD-FBP (p = 0.254) but increased substantially in HD-FBP (p < 0.001). No statistically significant differences were found for the reproduction of anatomical and pathological structures between HD-IR and FD-FBP, subsegmental bronchi and bronchioli. The image quality of HD-FBP was rated inferior because of increased noise. CONCLUSION: A 50 % dose reduction in contrast-enhanced chest CT is feasible without a loss of diagnostic confidence if IR is used for image data reconstruction. Iterative reconstruction is another powerful tool to reduce radiation exposure and can be combined with other dose-saving techniques. KEY POINTS: * Iterative reconstructions allow for image noise and artifact reduction.* Comparable image data can thus be attained even at 50 % radiation dose.* Diagnostic confidence remains unaffected. PMID- 24477505 TI - 3D Rotational Angiography After Non-Traumatic SAH. AB - PURPOSE: In about 15 % of patients with SAH no causative vascular lesions can be found in acute imaging with CTA and DSA. Usually, repeat DSA is mandatory and bears the usual risk of invasive angiography. The present study attempts to assess the diagnostic impact of 3 D rotational angiography in order to avoid repeat DSA. MATERIALS AND METHODS: From January 2004 to December 2012, 649 patients with an acute non-traumatic SAH were examined. 91 patients with negative initial imaging diagnostics concerning the bleeding source were included in this study. These patients underwent a second angiography scan: 61 in 4-plane technique, and 30 with 2-plane technique and additional 3 D DSA. Two cohorts were compared: patients with repeat angiography in conventional 4-plane technique from 2004 to July 2008 and 2-plane technique with additional 3 D rotational DSA from 2008 to 2012. Statistical significance was verified by means of Fisher's exact test. RESULTS: In the second DSA scan, 4 aneurysms in 4 patients (4/91; 4.4 %) were found and treated subsequently. Within the first 4.5 years of this study, 401 patients with SAH were treated and 61 of them underwent repeat angiography (15.2 %) compared to 30 of 248 patients (12.1 %) in the last 4.5 years of this study. In the first group we found 3 aneurysms during repeat angiography, and in the second group we found 1. No significance was reached (p = 0.29) but there was a tendency towards higher diagnostic security using 3D-DSA. CONCLUSION: Using 3 D rotational DSA in initial imaging workup might help to reduce false-negative results concerning the bleeding source of acute SAH. At least because of this fact, 3 D rotational DSA should be part of the diagnostic workup after acute SAH. PMID- 24477506 TI - Hand-carried and high-end ultrasound systems are equally inferior to abdominal radiography and multidetector computed tomography in the diagnosis of pneumoperitoneum. AB - PURPOSE: Pneumoperitoneum (PP) is a severe finding in emergency departments. Its quick and correct diagnosis is indispensable for the further treatment of patients. The aim of this study was to analyze the clinical value of abdominal ultrasound performed with a modern hand-carried ultrasound (HCU) device as well as with a high-end ultrasound (HUS) system in the diagnosis of PP in patients with acute abdominal pain. MATERIALS AND METHODS: 31 patients with acute abdominal pain were enrolled in this study irrespective of their underlying disease, and examination with a latest generation HCU and a newest generation HUS was performed. Diagnosis of PP was based on findings of multidetector computed tomography (MDCT) and abdominal radiography (AR) as the standard of reference. The study was carried out by two independent and experienced examiners unaware of the diagnosis made by MDCT or AR. RESULTS: In five (16 %) patients PP was identified by MDCT and AR. Examination with HCU was calculated with a sensitivity and specificity of 80 % and 81 %, respectively. Examination with HUS yielded a sensitivity and specificity of 80 % and 89 %, respectively. CONCLUSION: PP can be detected by HCU and HUS with almost equal accuracy in patients with acute abdominal pain but both methods are inferior compared to MDCT and AR. However, HCU and HUS can accelerate the triage of patients and help to make decisions regarding the necessity of further examinations without the need for radiation and while reducing economic and logistic resources. KEY POINTS: 1. Pneumoperitoneum (PP) is a severe finding in emergency departments. 2. Hand carried (HCU) and high-end (HUS) ultrasound systems can be helpful in detecting PP. 3. Abdominal radiography (AR) and multidetector computed tomography (MDCT) are superior in detecting PP. 4. HCU and HUS can accelerate the triage of patients. 5. HCU and HUS can be helpful when making decisions regarding the necessity of further examinations. PMID- 24477507 TI - Application of extracellular gadolinium-based MRI contrast agents and the risk of nephrogenic systemic fibrosis. AB - Nephrogenic systemic fibrosis (NSF) is a serious, sometimes fatal disease. Findings in recent years have shown that a causal association between gadolinium containing contrast media and NSF is most likely. Therefore, the regulatory authorities have issued guidelines on the use of gadolinium-containing contrast media which have reduced the number of new cases of NSF to almost zero. However, it is for precisely this reason that the greatest care must still be taken to ensure that these guidelines are complied with. The most important factors are renal function, the quantity of gadolinium administered and coexisting diseases such as inflammation. All of these factors crucially influence the quantity of gadolinium released from the chelat in the body. This free gadolinium is thought to be the trigger for NSF. Other important factors are the stability of the gadolinium complex and furthermore the route of its elimination from the body. Partial elimination via the liver might be an additional protective mechanism. In conclusion, despite the NSF risk, contrast-enhanced MRI is a safe diagnostic procedure which can be used reliably and safely even in patients with severe renal failure, and does not necessarily have to be replaced by other methods. PMID- 24477508 TI - [Changes of liver hemangioma under a standard therapy of breast cancer -- are there attendant doubts about the supposedly definitive diagnosis?]. PMID- 24477509 TI - [Intrathoracic perforation of bile duct stents in St.p. liver transplantation]. PMID- 24477510 TI - Factors impacting the decision to participate in and satisfaction with public/community psychiatry fellowship training. AB - During yearly meetings of the recently developed network of 15 public/community psychiatry fellowships, it has been noted that programs are having varying degrees of success with regard to recruitment. To understand factors that impact recruitment, a quality improvement survey of fellows and alumni was conducted. Respondents were asked to rate overall satisfaction with their fellowship training as well as perceived benefits and obstacles to participating in a fellowship program, and impact on their careers. A total of 155 (57%) fellows and alumni responded. Factor analysis was used to condense the variables, and a multiple regression explored factors predicting overall fellowship program satisfaction. Factors that represented perceived benefits had higher means than did factors that represent obstacles. Respondents highly valued the extent to which these fellowships enhanced their careers, with regard to job opportunities, academics, networking and leadership. PMID- 24477511 TI - Predictors of consumer satisfaction in community mental health center services. AB - Kentucky Department for Behavioral Health Developmental and Intellectual Disabilities conducted a survey to evaluate consumers' satisfaction with services delivered at the Community Mental Health Centers (CMHCs) in Kentucky. The survey was administered at outpatient clinics operated by fourteen CMHCs in 2010. The purpose of this study was to identify factors that predict whether clients will respond that they were "generally satisfied" with services received from CMHCs. A logistic regression model was developed using respondents' characteristics and their responses to survey questions. Survey questions were grouped into seven core domains: general satisfaction, access, quality, participation in treatment planning, outcomes, functioning, and social connectedness. In result, responses to domains of access, quality and participation in treatment planning significantly affected clients' perception of general satisfaction. Respondents who positively assessed those domains of services were more likely to answer that they were generally satisfied with services. Based on the analysis in this report, improvement in certain domains of services, especially access, quality and participation in treatment planning could increase the level of positive responses in general satisfaction. PMID- 24477513 TI - Serum levels of galactose-deficient immunoglobulin (Ig) A1 and related immune complex are associated with disease activity of IgA nephropathy. AB - BACKGROUND: The primary abnormal manifestation in immunoglobulin A nephropathy (IgAN) is recurring bouts of hematuria with or without proteinuria. Although immunohistochemical analysis of renal biopsy tissue remains the gold standard not only for diagnosis but also for evaluating the activity of IgAN, new sensitive and reasonably specific noninvasive tests are emerging to guide therapeutic strategy applicable to all stages of IgAN. The present study examined serum levels of galactose-deficient IgA1 (Gd-IgA1) and its immune complex (IgA/IgG-IC) as noninvasive markers for the disease activity. METHODS: We enrolled 50 IgAN patients (male 40 %, median age 37 years) showing complete or partial clinical remission after steroid pulse therapy with tonsillectomy (TSP) whose clinical data and serum could be followed up for 3-5 years. RESULTS: Cross-sectional analysis revealed that the degree of hematuria and proteinuria were significantly associated with levels of Gd-IgA1 and levels of IgA/IgG-IC. Longitudinal analysis further showed that from the group of 44 patients with heavy hematuria before TSP, 31 patients showed complete disappearance of hematuria (group A), but the remaining patients did not (group B). Although the levels of Gd-IgA1 and IgA/IgG IC in the two groups before TSP were similar, percentage decrease of Gd-IgA1 and IgA/IgG-IC levels in group A was significantly higher than in group B. CONCLUSION: Disease activity of IgAN assessed by hematuria and proteinuria correlated with serum levels and changes of Gd-IgA1 and IgA/IgG-IC. These new noninvasive disease activity markers can be useful for future activity scoring system and guiding therapeutic approaches. PMID- 24477514 TI - Baseline immune biomarkers as predictors of MBSR(BC) treatment success in off treatment breast cancer patients. AB - Researchers focused on patient-centered medicine are increasingly trying to identify baseline factors that predict treatment success. Because the quantity and function of lymphocyte subsets change during stress, we hypothesized that these subsets would serve as stress markers and therefore predict which breast cancer patients would benefit most from mindfulness-based stress reduction (MBSR) facilitated stress relief. The purpose of this study was to assess whether baseline biomarker levels predicted symptom improvement following an MBSR intervention for breast cancer survivors (MBSR[BC]). This randomized controlled trial involved 41 patients assigned to either an MBSR(BC) intervention group or a no-treatment control group. Biomarkers were assessed at baseline, and symptom change was assessed 6 weeks later. Biomarkers included common lymphocyte subsets in the peripheral blood as well as the ability of T cells to become activated and secrete cytokines in response to stimulation with mitogens. Spearman correlations were used to identify univariate relationships between baseline biomarkers and 6 week improvement of symptoms. Next, backward elimination regression models were used to identify the strongest predictors from the univariate analyses. Multiple baseline biomarkers were significantly positively related to 6-week symptom improvement. The regression models identified B-lymphocytes and interferon-gamma as the strongest predictors of gastrointestinal improvement (p < .01), +CD4+CD8 as the strongest predictor of cognitive/psychological (CP) improvement (p = .02), and lymphocytes and interleukin (IL)-4 as the strongest predictors of fatigue improvement (p < .01). These results provide preliminary evidence of the potential to use baseline biomarkers as predictors to identify the patients likely to benefit from this intervention. PMID- 24477515 TI - Real-time optogenetic control of intracellular protein concentration in microbial cell cultures. AB - Perturbations in the concentration of a specific protein are often used to study and control biological networks. The ability to "dial-in" and programmatically control the concentration of a desired protein in cultures of cells would be transformative for applications in research and biotechnology. We developed a culturing apparatus and feedback control scheme which, in combination with an optogenetic system, allows us to generate defined perturbations in the intracellular concentration of a specific protein in microbial cell culture. As light can be easily added and removed, we can control protein concentration in culture more dynamically than would be possible with long-lived chemical inducers. Control of protein concentration is achieved by sampling individual cells from the culture apparatus, imaging and quantifying protein concentration, and adjusting the inducing light appropriately. The culturing apparatus can be operated as a chemostat, allowing us to precisely control microbial growth and providing cell material for downstream assays. We illustrate the potential for this technology by generating fixed and time-varying concentrations of a specific protein in continuous steady-state cultures of the model organism Saccharomyces cerevisiae. We anticipate that this technology will allow for quantitative studies of biological networks as well as external tuning of synthetic gene circuits and bioprocesses. PMID- 24477516 TI - The globin superfamily: functions in nitric oxide formation and decay. AB - Globin proteins are ubiquitous in living organisms and carry out a variety of functions related to the ability of their prosthetic heme group to bind gaseous ligands, such as oxygen, nitric oxide (NO), and CO. Moreover, they catalyze important reactions with nitrogen oxide species, such as NO dioxygenation and nitrite reduction. The formation of NO from nitrite is a reaction catalyzed by globins that has received increasing attention due to its potential as a hypoxic NO signaling mechanism. In this review, we revisit the current knowledge about the role of globins in NO formation and its physiological implications. PMID- 24477517 TI - The extended reductive acetyl-CoA pathway: ATPases in metal cluster maturation and reductive activation. AB - The reductive acetyl-coenzyme A (acetyl-CoA) pathway, also known as the Wood Ljungdahl pathway, allows reduction and condensation of two molecules of carbon dioxide (CO2) to build the acetyl-group of acetyl-CoA. Productive utilization of CO2 relies on a set of oxygen sensitive metalloenzymes exploiting the metal organic chemistry of nickel and cobalt to synthesize acetyl-CoA from activated one-carbon compounds. In addition to the central catalysts, CO dehydrogenase and acetyl-CoA synthase, ATPases are needed in the pathway. This allows the coupling of ATP binding and hydrolysis to electron transfer against a redox potential gradient and metal incorporation to (re)activate one of the central players of the pathway. This review gives an overview about our current knowledge on how these ATPases achieve their tasks of maturation and reductive activation. PMID- 24477518 TI - Reply to the article entitled "Identification of an 18 bp deletion in the TWIST1 gene by CO-amplification at lower denaturation temperature-PCR (COLD-PCR) for non invasive prenatal diagnosis of craniosynostosis: first case report" by Galbiati et al., Clin Chem Lab Med 2014;52(4):505-9. PMID- 24477519 TI - Nipple-sparing mastectomy and immediate reconstruction in ductal carcinoma in situ: a critical assessment with 41 patients. AB - BACKGROUND: Nipple-sparing mastectomy (NSM) is increasingly popular for the treatment of select breast cancers and prophylactic mastectomy. This study aimed to analyze the authors' 11-year experience with NSM and breast reconstruction in cases of ductal carcinoma in situ (DCIS) with an emphasis on indications, complications, and cancer recurrence rate. METHODS: Between January 2000 and December 2010, 41 NSMs were performed in 41 women for DCIS. The mean age of the women was 49.7+/-8.7 years (range, 33-66 years). The indications for NSM were tumor size greater than 3 cm (18 cases), multifocal tumor (16 cases), and tumor recurrence (7 cases). In all cases, the tumor was located more than 2 cm from the nipple-areola complex (NAC), as shown by preoperative radiologic imaging. Histologic results, secondary NAC resection, complications, and cancer recurrence rates were recorded. RESULTS: The NAC was lost in seven cases (17%) due to postoperative necrosis. In another 10 patients (25%), the NAC was secondarily removed due to proximity of the tumor to the resection margin. Five patients were lost to follow-up evaluation (12%). The authors report the long-term follow-up data for the remaining 19 patients (46%). In this group, they observed one local recurrence (5.3%) and one case of ovarian cancer. CONCLUSION: Despite the low locoregional recurrence rate for DCIS, NSM remains controversial because of the nipple necrosis observed and the irradical tumor excisions. Given the ethical impossibility of conducting randomized controlled studies to compare NSM with conventional or skin-sparing mastectomy in DCIS, only long-term follow-up evaluations can demonstrate the safety of NSM. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24477520 TI - Is it possible to repair diastasis recti and shorten the aponeurosis at the same time? AB - BACKGROUND: Abdominal wall deformity secondary to pregnancy is multidirectional. Plication of the anterior rectus sheath is the most widely used technique for correction of this condition. However, it would be desirable to simultaneously perform the transverse and longitudinal repair of this deformity. The aim of this study was to assess changes in the length of the musculoaponeurotic layer after diastasis recti repair using triangular mattress sutures. METHODS: Thirty-one women with Nahas' type III/A deformity were divided into two groups: the triangular mattress suture (TS) group and the continuous suture (CS) group. All patients underwent conventional abdominoplasty and diastasis recti repair with medial longitudinal plication performed between two metal clips. The two types of suture were used in both groups. In the TS group, after a CS was performed and removed, TSs were used and maintained in place. In the CS group, the order of suture placement was reversed. The distance between clips was measured before and immediately after suturing and at 3 weeks and 6 months postoperatively using plain abdominal radiographs. Statistical analysis was conducted using Friedman's analysis of variance and Wilcoxon's test. RESULTS: The use of TSs significantly reduced the length of the aponeurosis compared with both the intraoperative situation without suture (P<0.001) and the use of CS (intraoperatively and 6 months after surgery; P<0.001). CONCLUSION: The repair of diastasis recti using TSs resulted in vertical shortening of musculoaponeurotic layer immediately after the procedure and in the long term. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24477521 TI - The capsular hammock flap for correction of breast implant ptosis. AB - A well-defined inframammary fold (IMF) is essential in providing an aesthetically pleasing and stable result in breast procedures. The position of the IMF on the chest wall determines the "footprint" of the breast, and hence the breast and chest aesthetic as a whole. Implant malposition is reported in the literature to occur in 5-8 % of primary breast augmentation patients. This occurs most commonly in a caudal direction, which is the most difficult problem to correct, as reported by Tebbett (Clin Plast Surg 28:425-434, 2001). Numerous surgical techniques to correct the malpositioned IMF have been described, including periosteal anchorage techniques as reported by Persichetti et al. (Ann Plast Surg 70:636-638, 2013), periareolar approaches that secure the IMF to the rib cage, and superiorly based capsular flaps. Here we describe a novel simple capsular flap technique using the lower anterior capsule, which is divided and formed into an inferiorly based flap and used as a "hammock" to re-establish the IMF and support the implant. As the capsule is made of a compact fibrous shell with a dense collagen network and excellent blood supply, using it as a flap to reposition and maintain the implant is ideal. Previous studies and tests have shown the reliability of capsule-based flap reconstruction due to the capsule's intrinsic strength and good vascularity, as shown by Rubino et al. (Ann Plast Surg 46:95-102, 2001). We describe our series of 12 primary breast augmentation patients with caudal implant malposition who underwent IMF reconstruction and implant repositioning with this technique. We explain our simple and repeatable technique that shows a stable and very durable result in repositioning the IMF and implant, with no recurrence of implant ptosis. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266. PMID- 24477522 TI - One-stage breast reconstruction using the inferior dermal flap, implant, and free nipple graft. AB - BACKGROUND: An inferior dermal flap with implant is a useful option for women hoping for immediate breast reconstruction. This one-stage procedure uses autologous tissue as an inferolateral local sling, avoiding the costs and potential morbidity of prosthetic mesh and reducing valuable operating time. Patient comorbidity or choice may restrict autologous reconstruction options available. Many patients will still require a second procedure for subsequent nipple reconstruction and further appointments and costs for tattooing. METHOD: A prospective database was kept of a single surgeon's experience with 16 patients (19 breasts) from 2010 to 2012. Reconstruction was performed following a Wise pattern skin incision. An inferior, deepithelialized dermal sling was sutured to the pectoralis major to form a pocket for a silicone implant or tissue expander. A free nipple graft was sited at the time of reconstruction, with biopsies taken from retroareolar tissue. RESULTS: Patient average age was 54 years (range 36 66). Six mastectomies were for ductal carcinoma in situ, 6 for invasive carcinoma, 2 for lobular carcinoma, and 5 of 19 mastectomies were prophylactic. Average operative time was 165 min. There were no immediate complications requiring reoperation. All retroareolar biopsies were benign and no locoregional recurrences have occurred. Two nipples had partial necrosis of the lower pole but healed with conservative treatment. No patients required any subsequent procedures to their reconstructed breast. CONCLUSION: The inferior dermal flap with implant and free nipple graft is an excellent single-stage reconstruction option. This method offers a potentially safe, reliable, and aesthetically acceptable outcome for women with larger, ptotic breasts. LEVEL OF EVIDENCE V: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24477523 TI - Gastroparesis after living-donor lobar lung transplantation: report of five cases. AB - Gastroparesis is a challenging gastrointestinal complication of deceased-donor lung transplantation and heart-lung transplantation, but it has not been reported after living-donor lobar lung transplantation (LDLLT). To better understand this complication after LDLLT, we reviewed our institutional experiences. Among the 32 patients who survived for at least 3 months after LDLLT, five (16 %) developed symptomatic gastroparesis. All five patients had undergone bilateral LDLLT, and gastroparesis was diagnosed within 2 months after transplantation. Neither adult patients who received single lobar LDLLT nor pediatric patients who received either bilateral or single lobar LDLLT developed gastroparesis. Although gastroparesis-related symptoms improved after medical treatment in three patients, two patients died of complications related to gastroparesis. We conclude that gastroparesis can occur after LDLLT and may cause grave complications unless carefully managed. PMID- 24477524 TI - Surgical management of acute esophageal necrosis. PMID- 24477525 TI - Successful case of pancreaticoduodenectomy with resection of the hepatic arteries preserving a single aberrant hepatic artery for a pancreatic neuroendocrine tumor: report of a case. AB - A 65-year-old male with a pancreatic neuroendocrine tumor presenting with a duodenal ulcer was referred to our department. The tumor involved the common hepatic artery, gastroduodenal artery, left hepatic artery and the right posterior hepatic artery, but not the right anterior hepatic artery originating from the superior mesenteric artery. The hepatic arteries, except the aberrant right anterior hepatic artery, were embolized using coils 18 days before the surgery. The patient underwent pancreaticoduodenectomy with resection of the tumor-encased hepatic arteries, while preserving the aberrant artery. The patient was discharged uneventfully on postoperative day 13 with no ischemic complications. A histopathological examination revealed a grade 2 pancreatic neuroendocrine tumor according to the classification of the World Health Organization, and the surgical margin was negative. The patient developed hepatic metastases 16 months after surgery; hence, hepatic resection was performed. The present surgical strategy is applicable in patients with relatively low-grade pancreatic malignancies involving major hepatic arteries. PMID- 24477526 TI - Laparoscopic diagnosis and treatment of neonates with duodenal obstruction associated with an annular pancreas: report of 11 cases. AB - PURPOSE: Laparoscopic procedures involving a neonatal annular pancreas have only been sporadically reported in the literature. We herein present our initial experience with an annular pancreas in newborns treated via a laparoscopic approach. METHODS: A retrospective review of the laparoscopic methods used for an annular pancreas in 11 neonates from September 2009 to April 2013 was performed. Among the patients, seven were male and four were female. The age of the patients ranged from 1 to 13 days (mean 4.2 days). An annular pancreas was diagnosed under laparoscopic vision. In all of the cases, the surgical procedures were performed laparoscopically. RESULTS: The operation was accomplished by a laparoscopic procedure in all cases. The length of the operation ranged from 70 to 145 min (mean, 96.6 min). Feedings started on postoperative days 4-7 (mean, day 5), and patients were discharged on postoperative days 9-15 (mean, day 10.6). Ten cases were followed up for 4-39 months (mean, 15.2 months). The case complicated with anal atresia died of pneumonia 6 months later after the procedure, but the other patients were doing well at the most recent follow-up examination. CONCLUSION: The laparoscopic approach for an annular pancreas can be securely performed in the neonatal period. Our early experience suggests the outcomes were excellent. PMID- 24477527 TI - Spinal imaging features in Japanese patients with Marfan syndrome: a case-control study. AB - PURPOSE: The purpose of our study was to evaluate the morphology of the lumbosacral spine, i.e. the dura and vertebral body shape, of Japanese patients with Marfan syndrome (MFS) by comparing it with sex- and age-matched controls. MATERIALS AND METHODS: Spinal MR or CT images of 32 MFS patients and 32 controls were retrospectively reviewed. The anteroposterior dural sac diameter (DSD), anteroposterior vertebral body diameter (VBD), and vertebral body height (VBH) were measured from L1 to S1 levels and the dural sac ratio [DSR = (DSD/VBD)] and vertebral body aspect ratio [VAR = (VBH/VBD)] were calculated. RESULTS: At each level, mean DSD and DSR were significantly higher in MFS patients; VBD was not. The cutoff values for DSR to differentiate between MFS patients and the controls were 0.59, 0.46, 0.42, 0.45, 0.47, and 0.47 from the level of L1 to S1. At a sensitivity of 93.8 % and a specificity of 84.4 % the cutoff value at S1 was most diagnostic. In MFS patients VAR was significantly higher at L3 and L4. CONCLUSION: Our cutoff value for DSR >0.47 at S1 may help to identify MFS in the Japanese population. A square-like appearance of the L3 and L4 vertebral bodies is a supplementary finding in MFS patients. PMID- 24477528 TI - Constitutive S-adenosylmethionine decarboxylase gene expression increases drought tolerance through inhibition of reactive oxygen species accumulation in Arabidopsis. AB - Using subtractive hybridization analysis, the S-adenosylmethionine decarboxylase (SAMDC) gene from Capsicum annuum was isolated and renamed CaSAMDC. We generated independent transgenic Arabidopsis (Arabidopsis thaliana) lines constitutively expressing a 35S::CaSAMDC construct. Drought tolerance was significantly enhanced in Arabidopsis T4 transgenic homozygous lines as compared to wild-type (WT) plants. The levels of main polyamines (PAs) were more significantly increased in CaSAMDC-overexpressing transgenic plants after 6 h of drought stress as compared to stressed WT plants. Basal transcription of polyamine oxidase (PAO) showed at a much higher level in unstressed-transgenic plants as compared to unstressed WT plants. However, the difference in PAO transcription level between WT and transgenic plants was reduced after drought stress. Cellular accumulation of reactive oxygen species (ROS) was significantly reduced following drought stress in transgenic Arabidopsis plants as compared to WT plants. These results were in agreement with additional observations that stress-induced ROS generation, as determined by qRT-PCR analysis of NADPH oxidase (RbohD and RbohF), was significantly suppressed while transcription of ROS-detoxifying enzymes was notably elevated in transgenic lines in response to drought stress. Further, ROS induced transcription of the metacaspase II gene was remarkably inhibited in transgenic plants. Collectively, these results suggest that drought stress tolerance due to reduction of ROS production and enhancement of ROS detoxification can be attributed to elevation of PAs. PMID- 24477530 TI - Strategic innovation in the total synthesis of complex natural products using gold catalysis. AB - Novel organic reactions drive the advance of chemical synthesis in the same way that enabling technologies drive new scientific discoveries. One area of organic methodology that has undergone significant growth during the last decade is that of homogeneous gold-catalyzed transformations. This trend has been further enhanced by the employment of gold catalysis on a routine basis to accomplish the total synthesis of natural products. In particular, the superior pi acidity of the cationic gold complex for the activation of alkynes and allenes towards nucleophilic addition has significantly enriched the toolkit of transformations available to the total synthesis community, and inspired a new era of creativity in terms of the strategic disconnection of target compounds during their retrosynthetic analysis. Instead of simply supplementing the many existing reviews of gold catalysis, this review has been organized from the perspective of synthetic target families, with particular emphasis on the use of gold-catalyzed transformations during the late stages of syntheses involving complicated substrates, and cascade reactions that significantly increase molecular complexity. PMID- 24477531 TI - Advancing evidence-based practice to improve patient care. PMID- 24477532 TI - Exploring and accounting for publication bias in mental health: a brief overview of methods. AB - OBJECTIVE Publication bias undermines the integrity of published research. The aim of this paper is to present a synopsis of methods for exploring and accounting for publication bias. METHODS We discussed the main features of the following methods to assess publication bias: funnel plot analysis; trim-and-fill methods; regression techniques and selection models. We applied these methods to a well-known example of antidepressants trials that compared trials submitted to the Food and Drug Administration (FDA) for regulatory approval. RESULTS The funnel plot-related methods (visual inspection, trim-and-fill, regression models) revealed an association between effect size and SE. Contours of statistical significance showed that asymmetry in the funnel plot is probably due to publication bias. Selection model found a significant correlation between effect size and propensity for publication. CONCLUSIONS Researchers should always consider the possible impact of publication bias. Funnel plot-related methods should be seen as a means of examining for small-study effects and not be directly equated with publication bias. Possible causes for funnel plot asymmetry should be explored. Contours of statistical significance may help disentangle whether asymmetry in a funnel plot is caused by publication bias or not. Selection models, although underused, could be useful resource when publication bias and heterogeneity are suspected because they address directly the problem of publication bias and not that of small-study effects. PMID- 24477533 TI - Antidepressants during ECT. PMID- 24477534 TI - Age may moderate response to different unguided Internet-delivered interventions for depression. PMID- 24477535 TI - How to assess publication bias: funnel plot, trim-and-fill method and selection models. PMID- 24477536 TI - The expression and significance of T helper cell subsets and regulatory T cells CD4+ CD25+ in peripheral blood of patients with human leukocyte antigen B27 positive acute anterior uveitis. AB - BACKGROUND: Human leukocyte antigen B27 (HLA-B27)-associated uveitis is the most common reason for non-infectious uveitis. This purpose of the research was to study the expression and significance of T lymphocyte subsets and CD4+ CD25+ T regulatory (Treg) cells in peripheral blood of patients with Human leukocyte antigen B27-positive acute anterior uveitis (HLA-B27-positive AAU). METHODS: The concentrations of Th1, Th2, Th17, CD4+ CD25+and CD4+ CD25+FOXP3+ Treg cells in peripheral blood were tested by flow cytometry. C-reactive protein (CRP) in peripheral blood was detected by immunoturbidimetry (ITM). Spearman's rank correlation was used to analyze the relationships between the concentration of Th1, Th2, Th17, CD4+ CD25+, and CD4+ CD25+ FOXP3(+) Treg cells in peripheral blood and disease activity score and CRP content. RESULTS: The ratio of both gamma [interferon (IFN)-gamma] (+)CD4+Th1 cells and CD4+IL-17+Th17 cells in peripheral blood of patients with HLA-B27-positive AAU (P = 0.041) was higher than that of the control group (P = 0.002). The concentration of CD4+ CD25+ FOXP3(+) T cells in peripheral blood of patients with AAU was lower than that of the control group (P = 0.026). The concentration of Th1 cells in peripheral blood of the patients had no correlation with disease activity score (P = 0.50) or CRP content (P = 0.383). This was also true of the concentration of Th2 cells (Disease activity score: R = 0.068, P = 0.817; CRP content: R = 0.439, P = 0.116). Th17 cell concentration positively correlated with disease activity score (R = 0.805, P = 0.001). The concentration of CD4+ CD25+ T cells showed no correlation with disease activity score (R =-0.209, P = 0.472) or CRP content (R =-0.169, P = 0.563), whereas the concentration of CD4+ CD25+ FOXP3+ T cells negatively correlated with disease activity score but did not correlate with CRP (R =-0.248, P = 0.392). CONCLUSIONS: The peripheral blood of patients with HLA B27-positive AAU showed a higher expression of interferon-gamma and interleukin 17 cells in CD4+T cells, whereas CD4+CD25+FOXP3+ T cells displayed a lower expression of the cytokines. The balance between Th17 cells and CD4+ CD25+ FOXP3+ T cells may contribute to the activity of HLA-B27-positive AAU. PMID- 24477537 TI - Assessment of functional and morphometric endpoints in patients with non arteritic anterior ischemic optic neuropathy (NAION). AB - BACKGROUND: The primary objective of this bi-center explorative pilot study was the quantitative assessment of visual field defects and retinal nerve fiber layer thickness (RNFT) over 6 months in patients with acute non-arteritic anterior ischemic optic neuropathy (NAION), in order to elucidate the natural course of NAION and provide a reference dataset for future treatment studies. METHODS: 16 patients (age 41-80 years, nine males, seven females) suffering from acute NAION and presenting within 7 days after onset of symptoms were included in this study. The following examinations were carried out at the initial visit (month 0) and at months 2, 4 and 6: entire (90 degrees ) visual field examination with automated static white-on-white perimetry, quantified by mean defect (MD); peripapillary retinal nerve fiber layer thickness (RNFT) measurement with spectral domain optical coherence tomography (SD-OCT); assessment of distant best correct visual acuity (D-BCVA) and a quantification of the relative afferent pupillary defect (RAPD) using the swinging flashlight test with neutral density filters. Perimetric Mean Defect (MD) and RNFT values were each compared between the consecutive visits using the non-parametric Friedman test. RESULTS: The initial MD was 6.2 dB (IQR 5.0-7.4) without significant changes further on. RNFT was 183 MUm (IQR 148-252) initially, decreased significantly at month 2 (78 MUm (IQR 71 93) and further at month 4 (64 MUm (IQR 58-74) and 6 (61 MUm (IQR 52-81), Friedman test, p < 0.001). Initially, RNFT was above normal limits (due to swelling) in 15/16 patients; at month 2 it was below normal limits in 13/16 patients, at month 4 in 12/13 patients and at month 6 in 9/10 patients. 7/16 patients exhibited segmental swelling of the optic disc, whereas the entire circumference of the optic disc showed RNFL thickening in 9/16 patients. CONCLUSION: Functional deficits were present directly after onset of NAION and did not change relevantly further on. Morphological changes comprise severe swelling after onset of NAION, which rapidly turns into atrophy. Already after 2 months more than 80 % of the patients showed a RNFT below normal limits. Progressive RNFL thinning between month 2 and month 4 suggests ongoing atrophy, whereas a stable morphologic end point is reached after month 4. PMID- 24477538 TI - EUK-134 ameliorates nNOSMU translocation and skeletal muscle fiber atrophy during short-term mechanical unloading. AB - Reduced mechanical loading during bedrest, spaceflight, and casting, causes rapid morphological changes in skeletal muscle: fiber atrophy and reduction of slow twitch fibers. An emerging signaling event in response to unloading is the translocation of neuronal nitric oxide synthase (nNOSMU) from the sarcolemma to the cytosol. We used EUK-134, a cell-permeable mimetic of superoxide dismutase and catalase, to test the role of redox signaling in nNOSMU translocation and muscle fiber atrophy as a result of short-term (54 h) hindlimb unloading. Fischer 344 rats were divided into ambulatory control, hindlimb-unloaded (HU), and hindlimb-unloaded + EUK-134 (HU-EUK) groups. EUK-134 mitigated the unloading induced phenotype, including muscle fiber atrophy and muscle fiber-type shift from slow to fast. nNOSMU immunolocalization at the sarcolemma of the soleus was reduced with HU, while nNOSMU protein content in the cytosol increased with unloading. Translocation of nNOS from the sarcolemma to cytosol was virtually abolished by EUK-134. EUK-134 also mitigated dephosphorylation at Thr-32 of FoxO3a during HU. Hindlimb unloading elevated oxidative stress (4-hydroxynonenal) and increased sarcolemmal localization of Nox2 subunits gp91phox (Nox2) and p47phox, effects normalized by EUK-134. Thus, our findings are consistent with the hypothesis that oxidative stress triggers nNOSMU translocation from the sarcolemma and FoxO3a dephosphorylation as an early event during mechanical unloading. Thus, redox signaling may serve as a biological switch for nNOS to initiate morphological changes in skeletal muscle fibers. PMID- 24477539 TI - Phase-dependent resetting of the adrenal clock by ACTH in vitro. AB - The adrenal cortex has a molecular clock that generates circadian rhythms in glucocorticoids, yet how the clock is synchronized to the external environment is unknown. Using mPER2::Luciferase (mPER2Luc) knockin mice, in which luciferase is rhythmically expressed under the control of the mouse Per2 clock gene, we hypothesized that ACTH transmits entrainment signals to the adrenal. Adrenal explants were administered ACTH at different phases of the mPER2Luc rhythm. Treatment with ACTH 1-39 produced a phase delay that was phase-dependent, with a maximum at circadian time (CT)18; ACTH did not alter the period or amplitude of the rhythm. Forskolin produced a parallel response, suggesting that the phase delay was cAMP-mediated. The response to ACTH was concentration-dependent and peptide-specific. Pulse administration (60 min) of ACTH 1-39 also produced phase delays restricted to late CTs. In contrast to ACTH 1-39, other ACTH fragments, including alpha-melanocyte-stimulating hormone, which do not activate the melanocortin 2 (MC2/ACTH) receptor, had no effect. The finding that ACTH in vitro phase delays the adrenal mPER2luc rhythm in a monophasic fashion argues for ACTH as a key resetter, but not the sole entrainer, of the adrenal clock. PMID- 24477540 TI - Exposure to rosiglitazone, a PPAR-gamma agonist, in late gestation reduces the abundance of factors regulating cardiac metabolism and cardiomyocyte size in the sheep fetus. AB - It is unknown whether cardiomyocyte hypertrophy and the transition to fatty acid oxidation as the main source of energy after birth is dependent on the maturation of the cardiomyocytes' metabolic system, or on the limitation of substrate availability before birth. This study aimed to investigate whether intrafetal administration of a peroxisome proliferator-activated receptor-gamma (PPAR-gamma) agonist, rosiglitazone, during late gestation can stimulate the expression of factors regulating cardiac growth and metabolism in preparation for birth, and the consequences of cardiac contractility in the fetal sheep at ~140 days gestation. The mRNA expression and protein abundance of key factors regulating growth and metabolism were quantified using quantitative RT-PCR and Western blot analysis, respectively. Cardiac contractility was determined by measuring the Ca(2+) sensitivity and maximum Ca(2+)-activated force of skinned cardiomyocyte bundles. Rosiglitazone-treated fetuses had a lower cardiac abundance of insulin signaling molecules, including insulin receptor-beta, insulin receptor substrate 1 (IRS-1), phospho-IRS-1 (Tyr-895), phosphatidylinositol 3-kinase (PI3K) regulatory subunit p85, PI3K catalytic subunit p110alpha, phospho-3 phosphoinositide-dependent protein kinase 1 (Ser-241), protein kinase B (Akt-1), phospho-Akt (Ser-273), PKCzeta, phospho-PKCzeta(Thr-410), Akt substrate 160 kDa (AS160), phospho-AS160 (Thr-642), and glucose transporter type-4. Additionally, cardiac abundance of regulators of fatty acid beta-oxidation, including adiponectin receptor 1, AMPKalpha, phospho-AMPKalpha (Thr-172), phospho-acetyl CoA carboxylase (Ser-79), carnitine palmitoyltransferase-1, and PGC-1alpha was lower in the rosiglitazone-treated group. Rosiglitazone administration also resulted in a decrease in cardiomyocyte size. Rosiglitazone administration in the late-gestation sheep fetus resulted in a decreased abundance of factors regulating cardiac glucose uptake, fatty acid beta-oxidation, and cardiomyocyte size. These findings suggest that activation of PPAR-gamma using rosiglitazone does not promote the maturation of cardiomyocytes; rather, it may decrease cardiac metabolism and compromise cardiac health later in life. PMID- 24477541 TI - Maternal food restriction modulates cerebrovascular structure and contractility in adult rat offspring: effects of metyrapone. AB - Although the effects of prenatal undernutrition on adult cardiovascular health have been well studied, its effects on the cerebrovascular structure and function remain unknown. We used a pair-fed rat model of 50% caloric restriction from day 11 of gestation to term, with ad libitum feeding after birth. We validated that maternal food restriction (MFR) stress is mediated by glucocorticoids by administering metyrapone, a corticosterone synthesis inhibitor, to MFR mothers at day 11 of gestation. At age 8 mo, offspring from Control, MFR, and MFR + Metyrapone groups were killed, and middle cerebral artery (MCA) segments were studied using vessel-bath myography and confocal microscopy. Colocalization of smooth muscle alpha-actin (SMalphaA) with nonmuscle (NM), SM1 and SM2 myosin heavy-chain (MHC) isoforms was used to assess smooth muscle phenotype. Our results indicate that artery stiffness and wall thickness were increased, pressure-evoked myogenic reactivity was depressed, and myofilament Ca(2+) sensitivity was decreased in offspring of MFR compared with Control rats. MCA from MFR offspring exhibited a significantly greater SMalphaA/NM colocalization, suggesting that the smooth muscle cells had been altered toward a noncontractile phenotype. MET significantly reversed the effects of MFR on stiffness but not myogenic reactivity, lowered SMalphaA/NM colocalization, and increased SMalphaA/SM2 colocalization. Together, our data suggest that MFR alters cerebrovascular contractility via both glucocorticoid-dependent and glucocorticoid-independent mechanisms. PMID- 24477542 TI - Supraoptic oxytocin and vasopressin neurons function as glucose and metabolic sensors. AB - Neurons in the supraoptic nuclei (SON) produce oxytocin and vasopressin and express insulin receptors (InsR) and glucokinase. Since oxytocin is an anorexigenic agent and glucokinase and InsR are hallmarks of cells that function as glucose and/or metabolic sensors, we evaluated the effect of glucose, insulin, and their downstream effector ATP-sensitive potassium (KATP) channels on calcium signaling in SON neurons and on oxytocin and vasopressin release from explants of the rat hypothalamo-neurohypophyseal system. We also evaluated the effect of blocking glucokinase and phosphatidylinositol 3 kinase (PI3K; mediates insulin induced mobilization of glucose transporter, GLUT4) on responses to glucose and insulin. Glucose and insulin increased intracellular calcium ([Ca(2+)]i). The responses were glucokinase and PI3K dependent, respectively. Insulin and glucose alone increased vasopressin release (P < 0.002). Oxytocin release was increased by glucose in the presence of insulin. The oxytocin (OT) and vasopressin (VP) responses to insulin+glucose were blocked by the glucokinase inhibitor alloxan (4 mM; P <= 0.002) and the PI3K inhibitor wortmannin (50 nM; OT: P = 0.03; VP: P <= 0.002). Inactivating K ATP channels with 200 nM glibenclamide increased oxytocin and vasopressin release (OT: P < 0.003; VP: P < 0.05). These results suggest that insulin activation of PI3K increases glucokinase-mediated ATP production inducing closure of K ATP channels, opening of voltage-sensitive calcium channels, and stimulation of oxytocin and vasopressin release. The findings are consistent with SON oxytocin and vasopressin neurons functioning as glucose and "metabolic" sensors to participate in appetite regulation. PMID- 24477543 TI - Biomarkers of vascular function in premenopausal and recent postmenopausal women of similar age: effect of exercise training. AB - Menopause is associated with an accelerated decline in vascular function; however, whether this is an effect of age and/or menopause and how exercise training may affect this decline remains unclear. We examined a range of molecular measures related to vascular function in matched premenopausal and postmenopausal women before and after 12 wk of exercise training. Thirteen premenopausal and 10 recently postmenopausal [1.6 +/- 0.3 (means +/- SE) years after final menstrual period] women only separated by 3 yr (48 +/- 1 vs. 51 +/- 1 yr) were included. Before training, diastolic blood pressure, soluble intercellular adhesion molecule-1 (sICAM-1), and skeletal muscle expression of thromboxane A synthase were higher in the postmenopausal women compared with the premenopausal women, all indicative of impaired vascular function. In both groups, exercise training lowered diastolic blood pressure, the levels of sICAM 1, soluble vascular adhesion molecule-1 (sVCAM-1), as well as plasma and skeletal muscle endothelin-1. The vasodilator prostacyclin tended (P = 0.061) to be higher in plasma with training in the postmenopausal women only. These findings demonstrate that already within the first years after menopause, several biomarkers of vascular function are adversely altered, indicating that these biomarker changes are more related to hormonal changes than aging. Exercise training appears to have a positive impact on vascular function, as indicated by a marked improvement in the biomarker profile, in both premenopausal and postmenopausal women. PMID- 24477544 TI - Long-term metabolic benefits of exenatide in mice are mediated solely via the known glucagon-like peptide 1 receptor. AB - Glucagon-like peptide 1 receptors (GLP-1R) are expressed in multiple tissues and activation results in metabolic benefits including enhanced insulin secretion, slowed gastric emptying, suppressed food intake, and improved hepatic steatosis. Limited and inconclusive knowledge exists regarding whether the effects of chronic exposure to a GLP-1R agonist are solely mediated via this receptor. Therefore, we examined 3-mo dosing of exenatide in mice lacking a functional GLP 1R (Glp1r(-/-)). Exenatide (30 nmol . kg(-1) . day(-1)) was infused subcutaneously for 12 wk in Glp1r(-/-) and wild-type (Glp1r(+/+)) control mice fed a high-fat diet. Glycated hemoglobin A1c (HbA1c), plasma glucose, insulin, amylase, lipase, alanine aminotransferase (ALT), aspartate aminotransferase (AST), body weight, food intake, terminal hepatic lipid content (HLC), and plasma exenatide levels were measured. At the end of the study, oral glucose tolerance test (OGTT) and rate of gastric emptying were assessed. Exenatide produced no significant changes in Glp1r(-/-) mice at study end. In contrast, exenatide decreased body weight, food intake, and glucose in Glp1r(+/+) mice. When compared with vehicle, exenatide reduced insulin, OGTT glucose AUC0-2h, ALT, and HLC in Glp1r(+/+) mice. Exenatide had no effect on plasma amylase or lipase levels. Exenatide concentrations were approximately eightfold higher in Glp1r(-/-) versus Glp1r(+/+) mice after 12 wk of infusion, whereas renal function was similar. These data support the concept that exenatide requires a functional GLP-1R to exert chronic metabolic effects in mice, and that novel "GLP-1" receptors may not substantially contribute to these changes. Differential exenatide plasma levels in Glp1r(+/+) versus Glp1r(-/-) mice suggest that GLP-1R may play an important role in plasma clearance of exenatide and potentially other GLP-1-related peptides. PMID- 24477545 TI - Treatment status and risk factors for incidence and persistence of urinary incontinence in women. AB - INTRODUCTION AND HYPOTHESIS: The objective of this analysis was to describe urinary incontinence (UI) incidence and persistence over 5 years in association with treatment status, sociodemographic, medical, and lifestyle factors, in a racially/ethnically diverse population-based female sample. METHODS: The Boston Area Community Health Survey enrolled 3,201 women aged 30-79 years of black, Hispanic, and white race/ethnicity. Five-year follow-up was completed by 2,534 women (conditional response rate 83.4 %), allowing population-weighted estimates of UI incidence and persistence rates. Predictors of UI were determined using multivariate logistic regression models. RESULTS: Incidence of UI at least monthly was 14.1 % and weekly 8.9 %. Waist circumference at baseline and increasing waist circumference over 5-year follow-up were the most robust predictors of UI incidence in multivariate models (P <= 0.01). Among 475 women with UI at baseline, persistence was associated with depression symptoms [monthly UI, odds ratio (OR) = 2.39, 95 % confidence interval (CI) 1.14-5.02] and alcohol consumption (weekly UI, OR = 3.51, 95 % CI 1.11-11.1). Among women with weekly UI at baseline, 41.7 % continued to report weekly UI at follow-up, 14.1 % reported monthly UI, and 44.2 % had complete remission. Persistence of UI was not significantly higher (58.2 % vs. 48.0 %, chi-square P = 0.3) among untreated women. Surgical or drug treatment for UI had little impact on estimates for other risk factors or for overall population rates of persistence or remission. CONCLUSIONS: Women with higher gains in waist circumference over time were more likely to develop UI, but waist circumference was not predictive of UI persistence. UI treatments did not affect associations for other risk factors. Additional research on the role of alcohol intake in UI persistence is warranted. PMID- 24477547 TI - Long-term strenuous exercise induces a hypercoagulable state through contact activation. PMID- 24477546 TI - Examining the electro-neural interface of cochlear implant users using psychophysics, CT scans, and speech understanding. AB - This study examines the relationship between focused-stimulation thresholds, electrode positions, and speech understanding in deaf subjects treated with a cochlear implant (CI). Focused stimulation is more selective than monopolar stimulation, which excites broad regions of the cochlea, so may be more sensitive as a probe of neural survival patterns. Focused thresholds are on average higher and more variable across electrodes than monopolar thresholds. We presume that relatively high focused thresholds are the result of larger distances between the electrodes and the neurons. Two factors are likely to contribute to this distance: (1) the physical position of electrodes relative to the modiolus, where the excitable auditory neurons are normally located, and (2) the pattern of neural survival along the length of the cochlea, since local holes in the neural population will increase the distance between an electrode and the nearest neurons. Electrode-to-modiolus distance was measured from high-resolution CT scans of the cochleae of CI users whose focused-stimulation thresholds were also measured. A hierarchical set of linear models of electrode-to-modiolus distance versus threshold showed a significant increase in threshold with electrode-to modiolus distance (average slope = 11 dB/mm). The residual of these models was hypothesized to reflect neural survival in each subject. Consonant-Nucleus Consonant (CNC) word scores were significantly correlated with the within-subject variance of threshold (r(2) = 0.82), but not with within-subject variance of electrode distance (r(2) = 0.03). Speech understanding also significantly correlated with how well distance explained each subject's threshold data (r(2) = 0.63). That is, subjects with focused thresholds that were well described by electrode position had better speech scores. Our results suggest that speech understanding is highly impacted by individual patterns of neural survival and that these patterns manifest themselves in how well (or poorly) electrode position predicts focused thresholds. PMID- 24477548 TI - Mutagenicity and genotoxicity of dicapthon insecticide. AB - Mutagenic and genotoxic effects of dicapthon were investigated by using the bacterial reverse mutation assay in Salmonella typhimurium TA97, TA98, TA100 and TA102 strains with or without metabolic activation system (S9 mix), and chromosome aberrations (CAs), sister chromatid exchanges (SCEs), and micronucleus (MN) tests in human peripheral blood lymphocytes in vitro. Dicapthon was dissolved in dimethyl sulfoxide for all test systems. 0.1, 1, 10 and 100 MUg/plate doses of dicapthon were found to be weakly mutagenic on S. typhimurium TA 98 without S9 mix. The human peripheral lymphocytes were treated with four experimental concentrations of dicapthon (25, 50, 100, and 200 MUg/mL) for 24 and 48 h. Dicapthon increased the frequency of SCE only at the 100 MUg/mL concentration for the 24 and 48 h applications. Dicapthon also induced abnormal cell frequency, CA/cell ratio and frequency of MN dose dependently for 24 and 48 h. Dicapthon showed a statistically significant cytotoxic effect by decreasing the mitotic index in all concentrations and a cytostatic effect by decreasing nuclear division index in 100 and 200 MUg/mL concentrations for both treatment periods when compared with both untreated and solvent controls. These values decreased also in a dose dependent manner. PMID- 24477549 TI - Effects of DNA damage and short-term spindle disruption on oocyte meiotic maturation. AB - DNA damage has recently been shown to inhibit or delay germinal vesicle breakdown (GVBD) in mouse oocytes, but once meiosis resumes, DNA-damaged oocytes are able to extrude the first polar body. In this study, using porcine oocytes, we showed that DNA damage did not affect GVBD, but inhibited the final stages of maturation, as indicated by failure of polar body emission. Unlike mitotic cells in which chromosome mis-segregation causes DNA double-strand breaks, meiotic mouse oocytes did not show increased DNA damage after disruption of chromosome attachment to spindle microtubules. Nocodazole-treated oocytes did not display increased DNA damage signals that were marked by gammaH2A.X signal strength, but reformed spindles and underwent maturation, although aneuploidy increased after extended nocodazole treatment. By using the mouse for parthenogenetic activation studies, we showed that early cleavage stage embryos derived from parthenogenetic activation of nocodazole-treated oocytes displayed normal activation rate and normal gammaH2A.X signal strength, indicating that no additional DNA damage occured. Our results suggest that DNA damage inhibits porcine oocyte maturation, while nocodazole-induced dissociation between chromosomes and microtubules does not lead to increased DNA damage either in mouse meiotic oocytes or in porcine oocytes. PMID- 24477551 TI - Fast screening of bacterial suspension culture conditions on chips. AB - Culture conditions including pH, nutrient concentration and temperature strongly influence the properties of a microbial strain by affecting many factors such as the microbial membrane and metabolism. We present a microfluidic chip for screening pH and nutrient content with a concentration gradient generator connected to eight parallel suspension culture loops and another chip for the screening of temperature with four different temperature zones under suspension culture loops. Bacteria grow much faster on chips than in test tubes, and yet interestingly, on-chip screening of culture conditions for E. coli yields results similar to those from a culture in test tubes, demonstrating the validity of the on-chip screening approach. The microfluidic chips were applied to study the growth conditions of two wild type Bacillus subtilis strains isolated from polluted water. The on-chip screening experiments show advantages of nanoliter scale screening units, high-throughput and requiring only one-fourth of the time. PMID- 24477550 TI - Differentiation of human embryonic stem cells to hepatocyte-like cells on a new developed xeno-free extracellular matrix. AB - Human embryonic stem cells (hESCs) provide a new source for hepatocyte production in translational medicine and cell replacement therapy. The reported hESC-derived hepatocyte-like cells (HLCs) were commonly generated on Matrigel, a mouse cell line-derived extracellular matrix (ECM). Here, we performed the hepatic lineage differentiation of hESCs following a stepwise application of growth factors on a newly developed serum- and xeno-free, simple and cost-benefit ECM, designated "RoGel," which generated from a modified conditioned medium of human fibroblasts. In comparison with Matrigel, the differentiated HLCs on both ECMs expressed similar levels of hepatocyte-specific genes, secreted alpha-fetoprotein, and metabolized ammonia, showed glycogen storage activity as well as low-density lipoprotein and indocyanine green uptake. The transplantation of hESC-HLCs into the carbon tetrachloride-injured liver demonstrated incorporation of the cells into the host mouse liver and the expression of albumin. The results suggest that the xeno-free and cost-benefit matrix may be applicable in bioartificial livers and also may facilitating a clinical application of human pluripotent stem cell derived hepatocytes in the future. PMID- 24477552 TI - Perceiving patagonia: an assessment of social values and perspectives regarding watershed ecosystem services and management in southern South America. AB - Research on human dimensions of ecosystems through the ecosystem services (ES) concept has proliferated over recent decades but has largely focused on monetary value of ecosystems while excluding other community-based values. We conducted 312 surveys of general community members and regional researchers and decision makers (specialists) to understand local perceptions and values of watershed ES and natural resource management in South America's southern Patagonian ecoregion. Results indicated that specialists shared many similar values of ES with community members, but at the same time their mentalities did not capture the diversity of values that existed within the broader community. The supporting services were most highly valued by both groups, but generally poorly understood by the community. Many services that are not easily captured in monetary terms, particularly cultural services, were highly valued by community members and specialists. Both groups perceived a lack of communication and access to basic scientific information in current management approaches and differed slightly in their perspective on potential threats to ES. We recommend that a community-based approach be integrated into the natural resource management framework that better embodies the diversity of values that exist in these communities, while enhancing the science-society dialog and thereby encouraging the application of multiple forms of ecological knowledge in place-based environmental management. PMID- 24477553 TI - Periostin and its emerging role in systemic carcinogenesis. PMID- 24477554 TI - An electrochemical and high-speed imaging study of micropore decontamination by acoustic bubble entrapment. AB - Electrochemical and high-speed imaging techniques are used to study the abilities of ultrasonically-activated bubbles to clean out micropores. Cylindrical pores with dimensions (diameter * depth) of 500 MUm * 400 MUm (aspect ratio 0.8), 125 MUm * 350 MUm (aspect ratio 2.8) and 50 MUm * 200 MUm (aspect ratio 4.0) are fabricated in glass substrates. Each pore is contaminated by filling it with an electrochemically inactive blocking organic material (thickened methyl salicylate) before the substrate is placed in a solution containing an electroactive species (Fe(CN)6(3-)). An electrode is fabricated at the base of each pore and the Faradaic current is used to monitor the decontamination as a function of time. For the largest pore, decontamination driven by ultrasound (generated by a horn type transducer) and bulk fluid flow are compared. It is shown that ultrasound is much more effective than flow alone, and that bulk fluid flow at the rates used cannot decontaminate the pore completely, but that ultrasound can. In the case of the 125 MUm pore, high-speed imaging is used to elucidate the cleaning mechanisms involved in ultrasonic decontamination and reveals that acoustic bubble entrapment is a key feature. The smallest pore is used to explore the limits of decontamination and it is found that ultrasound is still effective at this size under the conditions employed. PMID- 24477555 TI - Bmp 2 and bmp 7 induce odonto- and osteogenesis of human tooth germ stem cells. AB - Bone morphogenetic proteins (BMPs) initiate, promote, and maintain odontogenesis and osteogenesis. In this study, we studied the effect of bone morphogenic protein 2 (BMP 2) and bone morphogenic protein 7 (BMP 7) as differentiation inducers in tooth and bone regeneration. We compared the effect of BMP 2 and BMP 7 on odontogenic and osteogenic differentiation of human tooth germ stem cells (hTGSCs). Third molar-derived hTGSCs were characterized with mesenchymal stem cell surface markers by flow cytometry. BMP 2 and BMP 7 were transfected into hTGSCs and the cells were seeded onto six-well plates. One day after the transfection, hTGSCs were treated with odontogenic and osteogenic mediums for 14 days. For confirmation of odontogenic and osteogenic differentiation, mRNA levels of BMP2, BMP 7, collagen type 1 (COL1A), osteocalsin (OCN), and dentin sialophosphoprotein (DSPP) genes were measured by quantitative real-time PCR. In addition to this, immunocytochemistry was performed by odontogenic and osteogenic antibodies and mineralization obtained by von Kossa staining. Our results showed that the BMP 2 and BMP 7 both promoted odontogenic and osteogenic differentiation of hTGSCs. Data indicated that BMP 2 treatment and BMP 7 treatment induce odontogenic differentiation without affecting each other, whereas they induce osteogenic differentiation by triggering expression of each other. These findings provide a feasible tool for tooth and bone tissue engineering. PMID- 24477556 TI - RNAi knockdown of potent sugar sensor in cellulase-producing fungus Acremonium cellulolyticus. AB - A potent sugar sensor gene (g9105) was screened from the genomic data of the cellulase-producing fungus Acremonium cellulolyticus. The transcriptional level of g9105 in the SA49 transformant, which carried the knockdown RNA interference (RNAi) construct, was less than 10% compared with the parental YP-4 strain. The hairpin-type RNAi construct could be useful for this fungal gene knockdown. Changes in cellulase productivity and protein secretion between these two strains were not observed. The numbers of hyphal tips at subapical branching site were counted for the SA49 and YP-4 strains incubated with potato-dextrose medium at 30 degrees C for 4 days. The hyphal branching ratio of the SA49 strain was higher than that of the YP-4 strain. The present results suggest that the potent sugar sensor gene in A. cellulolyticus could be related with hyphal branch formation. PMID- 24477557 TI - Regarding paper "Somatotropic and thyroid hormones in the acute phase of subarachnoid haemorrhage". PMID- 24477558 TI - Artifacts and pitfalls in contrast-enhanced ultrasound of the liver. AB - Ultrasound technology is always connected to possible artefacts. Since introduction of ultrasound technology the knowledge of those artefacts is eminent to avoid misinterpretations. It is important to know that with the introduction of new ultrasound technology the possibility of artefacts are rising.Whereas artefacts initially were limited to B-mode sonography, every technological step (colour Doppler sonography, contrast enhanced sonography) comes with a range of new artefacts. This article is written to explain the technological basics of ultrasound artefacts and provide the reader with examples in daily practice and how to avoid them. PMID- 24477559 TI - Synthesis of tetrahydropyrimidin-2-ones via FeCl3 catalyzed one-pot domino reaction of amines, methyl propiolate, aromatic aldehydes, and urea. AB - Polysubstituted 3-arylaminoacrylate and tetrahydropyrimidin-2-one derivatives could be selectively produced from the one-pot domino reaction of arylamines, methyl propiolate, aromatic aldehydes, and urea in ethanol in the presence of FeCl3 as catalyst. Under similar reactions secondary amines such as morpholine and piperidine predominately afford tetrahydropyrimidin-2-one derivatives in good yields. PMID- 24477560 TI - Surface electromyographic analysis of the biceps brachii muscle of cricket bowlers during bowling. AB - Cricket bowling generates forces with torques on the upper limb muscles and makes the biceps brachii (BB) muscle vulnerable to overuse injury. The aim of this study was to investigate whether there are differences in the amplitude of the EMG signal of the BB muscle during fast and spin delivery, during the seven phases of both types of bowling and the kinesiological interpretation of the bowling arm for muscle contraction mechanisms during bowling. A group of 16 male amateur bowlers participated in this study, among them 8 fast bowlers (FB) and 8 spin bowlers (SB). The root mean square (EMGRMS), the average sEMG (EMGAVG), the maximum peak amplitude (EMGpeak), and the variability of the signal were calculated using the coefficient of variance (EMGCV) from the BB muscle of each bowler (FB and SB) during each bowling phase. The results demonstrate that, (i) the BB muscle is more active during FB than during SB, (ii) the point of ball release and follow-through generated higher signals than the other five movements during both bowling categories, (iii) the BB muscle variability is higher during SB compared with FB, (iv) four statistically significant differences (p<0.05) found between the bowling phases in fast bowling and three in spin bowling, and (v) several arm mechanics occurred for muscle contraction. There are possible clinical significances from the outcomes; like, recurring dynamic contractions on BB muscle can facilitate to clarify the maximum occurrence of shoulder pain as well as biceps tendonitis those are medically observed in professional cricket bowlers, and treatment methods with specific injury prevention programmes should focus on the different bowling phases with the maximum muscle effect. Finally, these considerations will be of particular importance in assessing different physical therapy on bowler's muscle which can improve the ball delivery performance and stability of cricket bowlers. PMID- 24477561 TI - Rotary bioreactor culture can discern specific behavior phenotypes in Trk-null and Trk-expressing neuroblastoma cell lines. AB - Neuroblastoma is characterized by biological and genetic heterogeneity that leads to diverse, often unpredictable, clinical behavior. Differential expression of the Trk family of neurotrophin receptors strongly correlates with clinical behavior; TrkA expression is associated with favorable outcome, whereas TrkB with unfavorable outcome. Neuroblastoma cells cultured in a microgravity rotary bioreactor spontaneously aggregate into tumor-like structures, called organoids. We wanted to determine if the clinical heterogeneity of TrkA- or TrkB-expressing neuroblastomas was reflected in aggregation kinetics and organoid morphology. Trk null SY5Y cells were stably transfected to express either TrkA or TrkB. Short term aggregation kinetics were determined by counting the number of single (non aggregated) viable cells in the supernatant over time. Organoids were harvested after 8 d of bioreactor culture, stained, and analyzed morphometrically. SY5Y TrkA cells aggregated significantly slower than SY5Y and SY5Y-TrkB cells, as quantified by several measures of aggregation. SY5Y and TrkB cell lines formed irregularly shaped organoids, featuring stellate projections. In contrast, TrkA cells formed smooth (non-stellate) organoids. SY5Y organoids were slightly smaller on average, but had significantly larger average perimeter than TrkA or TrkB organoids. TrkA expression alone is sufficient to dramatically alter the behavior of neuroblastoma cells in three-dimensional, in vitro rotary bioreactor culture. This pattern is consistent with both clinical behavior and in vivo tumorigenicity, in that SY5Y-TrkA represents a more differentiated, less aggressive phenotype. The microgravity bioreactor is a useful in vitro tool to rapidly investigate the biological characteristics of neuroblastoma and potentially to assess the effect of cytotoxic as well as biologically targeted drugs. PMID- 24477562 TI - The influence of static magnetic fields on canine and equine mesenchymal stem cells derived from adipose tissue. AB - The aim of this study was to evaluate the proliferation rate and morphological changes of adipose-derived mesenchymal stem cells of canine and equine origin (Eq and CaAdMSC). Investigated cells were exposed to a static magnetic field (MF) with the intensity of 0.5 T. Proliferation activity of cells was determined with the Alamar Blue assay. Obtained results, normalized in respect to the control culture, showed that EqAdMSC exposed to MF maintained a high proliferation status, whereas proliferation activity of CaAdMSC cultured in the presence of MF was decreased. Estimations of population doubling time (PDT) also revealed that EqAdMSCs exposed to static MF achieved a twofold increase in the total number of cells in a shorter amount of time than the control culture. The PDT value obtained for investigated CaAdMSCs indicated that MF exposure resulted in the prolongation of population doubling time. Morphology of cells and cellular composition was investigated using a light inverted microscope and a fluorescent microscope. A scanning electron microscope was used for microvesicles (MVs) imaging. Obtained results showed that both cell types maintained fibroblastic morphology and did not reveal signs of apoptosis or necrosis. However, the MF had an influence on the MVs secretion. While EqAdMSCs propagated in the presence of MF were characterized by the abundant MVs presence, CaAdMSCs revealed poor secretory activity. The approach presented provides complex analysis, which enables one to determine changes in equine and canine cytophysiology. PMID- 24477564 TI - Controllable Ag nanostructure patterning in a microfluidic channel for real-time SERS systems. AB - We present a microfluidic patterning system for fabricating nanostructured Ag thin films via a polyol method. The fabricated Ag thin films can be used immediately in a real-time SERS sensing system. The Ag thin films are formed on the inner surfaces of a microfluidic channel so that a Ag-patterned Si wafer and a Ag-patterned PDMS channel are produced by the fabrication. The optimum sensing region and fabrication duration for effective SERS detection were determined. As SERS active substrates, the patterned Ag thin films exhibit an enhancement factor (EF) of 4.25 * 10(10). The Ag-patterned polymer channel was attached to a glass substrate and used as a microfluidic sensing system for the real-time monitoring of biomolecule concentrations. This microfluidic patterning system provides a low cost process for the fabrication of materials that are useful in medical and pharmaceutical detection and can be employed in mass production. PMID- 24477563 TI - Efficient in vitro adipocyte model of long-term lipolysis: a tool to study the behavior of lipophilic compounds. AB - The triglycerides (TGs) stored in the white adipose tissue are mobilized during periods of negative energy balance. To date, there is no in vitro model of adipocytes imitating a long period of negative energy balance in which triglycerides are highly mobilized. Such model would allow studying the mobilization of TGs and lipophilic compounds trapped within the adipose tissue (e.g., pollutants and vitamins). The present study aims at developing a performing long-term in vitro lipolysis in adipocytes, resulting in a significant decrease of TG stores. Lipolysis was induced on differentiated rat adipocytes by a lipolytic medium with or without isoproterenol for 12 h. The condition with isoproterenol was duplicated, once with medium renewal every 3 h and once without medium renewal. Adding isoproterenol efficiently triggered lipolysis in a short time (3 h). However, a single stimulation by isoproterenol, without medium renewal, was not sufficient to reduce the TG content during a longer term (12 h). A reesterification of fatty acids occurred after a few hours of lipolysis, resulting in a novel increase of cellular lipids. Regular medium renewal combined with repeated isoproterenol stimulations led to almost emptied cells after 12 h. However, medium renewal without isoproterenol stimulation for 12 h was as efficient in terms of lipid mobilization. Our study demonstrates that, over a short-term period, isoproterenol is required to exert a significant lipolytic effect on adipocytes. During a long-term period, the presence of isoproterenol is no longer essential. Instead, medium renewal becomes the main factor involved in cell emptying. The efficiency of this protocol was demonstrated by visual tracking of the cells and by monitoring the dynamics of release of a lipophilic compound, PCB-153, from adipocytes during lipolysis. PMID- 24477565 TI - Downregulation of a putative tumor suppressor BMP4 by SOX2 promotes growth of lung squamous cell carcinoma. AB - SOX2 is a transcription factor essential for self-renewal and pluripotency of embryonic stem cells. Recently, SOX2 was found overexpressed in the majority of the lung squamous cell carcinoma (SQC), in which it acts as a lineage-survival oncogene. However, downstream targets/pathways of SOX2 in lung SQC cells remain to be identified. Here, we show that BMP4 is a downstream target of SOX2 in lung SQC. We found that SOX2-silencing-mediated inhibition of cell growth was accompanied by upregulation of BMP4 mRNA and its protein expression. Meta analysis with 293 samples and qRT-PCR validation with 73 clinical samples revealed an inversely correlated relationship between levels of SOX2 and BMP4 mRNA, and significantly lower mRNA levels in tumor than in adjacent normal tissues. This was corroborated by immunohistochemistry analysis of 35 lung SQC samples showing lower BMP4 protein expression in tumor tissues. Cell-based experiments including siRNA transfection, growth assay and flow cytometry assay, further combined with a xenograft tumor model in mice, revealed that reactivation of BMP4 signaling could partially account for growth inhibition and cell cycle arrest in lung SQC cells upon silencing SOX2. Finally, chromatin immunoprecipitation analysis and luciferase reporter assay revealed that SOX2 could negatively regulate BMP4 promoter activity, possibly through binding to the promoter located in the first intron region of BMP4. Collectively, our findings suggest that BMP4 could act as a tumor suppressor and its downregulation by elevated SOX2 resulting in enhanced growth of lung SQC cells. PMID- 24477566 TI - A scoring-system for angiographic findings in nonocclusive mesenteric ischemia (NOMI): correlation with clinical risk factors and its predictive value. AB - PURPOSE: This study was designed to evaluate the clinical value of a standardized angiographic scoring system in patients with nonocclusive mesenteric ischemia (NOMI). METHODS: Sixty-three consecutive patients (mean age: 73 +/- 8 years) with suspect of NOMI after cardiac or major thoracic vessel surgery underwent catheter angiography of the superior mesenteric artery. Images were assessed by two experienced radiologists on consensus basis using a scoring system consisting of five categories, namely vessel morphology, reflux of contrast medium into the aorta, contrasting and distension of the intestine, as well as the time to portal vein filling. These were correlated to previously published risk factors of NOMI and outcome data. RESULTS: The most significant correlation was found between the vessel morphology and death (p < 0.001) as well as reflux of contrast medium into the aorta and death (p = 0.005). Significant correlation was found between delayed portal vein filling and preoperative statin administration (p = 0.011), previous stroke (p = 0.033), and renal insufficiency (p = 0.043). Reflux of contrast medium correlated significantly with serum lactate >10 mmol/L (p = 0.046). The overall angiographic score correlated with death (p = 0.017) and renal insufficiency (p = 0.02). The ROC-analysis revealed that a score of >=3.5 allows for identifying patients with increased perioperative mortality with a sensitivity of 85.7 % and a specificity of 49 %. With the use of a simplified score (vessel morphology, reflux of contrast medium into the aorta, and time to portal vein filling), specificity was increased to 71.4 %. CONCLUSIONS: The applied scoring system allows standardized interpretation of angiographic findings in NOMI patients. Beyond that the score seems to correlate well with risk factors of NOMI and outcome. PMID- 24477567 TI - Comparison of microbial communities involved in souring and corrosion in offshore and onshore oil production facilities in Nigeria. AB - Samples were obtained from the Obigbo field, located onshore in the Niger delta, Nigeria, from which oil is produced by injection of low-sulfate groundwater, as well as from the offshore Bonga field from which oil is produced by injection of high-sulfate (2,200 ppm) seawater, amended with 45 ppm of calcium nitrate to limit reservoir souring. Despite low concentrations of sulfate (0-7 ppm) and nitrate (0 ppm), sulfate-reducing bacteria (SRB) and heterotrophic nitrate reducing bacteria (NRB) were present in samples from the Obigbo field. Biologically active deposits (BADs), scraped from corrosion-failed sections of a water- and of an oil-transporting pipeline (both Obigbo), had high counts of SRB and high sulfate and ferrous iron concentrations. Analysis of microbial community composition by pyrosequencing indicated anaerobic, methanogenic hydrocarbon degradation to be a dominant process in all samples from the Obigbo field, including the BADs. Samples from the Bonga field also had significant activity of SRB, as well as of heterotrophic and of sulfide-oxidizing NRB. Microbial community analysis indicated high proportions of potentially thermophilic NRB and near-absence of microbes active in methanogenic hydrocarbon degradation. Anaerobic incubation of Bonga samples with steel coupons gave moderate general corrosion rates of 0.045-0.049 mm/year, whereas near-zero general corrosion rates (0.001-0.002 mm/year) were observed with Obigbo water samples. Hence, methanogens may contribute to corrosion at Obigbo, but the low general corrosion rates cannot explain the reasons for pipeline failures in the Niger delta. A focus of future work should be on understanding the role of BADs in enhancing under-deposit pitting corrosion. PMID- 24477568 TI - In situ pH management for microbial culture in shake flasks and its application to increase plasmid yield. AB - Shake flasks are widely used to culture microorganisms, but they do not allow for pH control without additional infrastructure. In the presence of a carbon source like glucose, culture pH typically decreases due to overflow metabolism and can limit the growth of microorganisms in shake flasks. In this study, we demonstrate the use of magnesium hydroxide-loaded pH managing hydrogels (m-pHmH) for in situ base release to counter the decrease in culture pH in shake flasks using Escherichia coli as a model organism, in both complex and mineral salts medium. Base release from m-pHmH is shown to increase with decreasing pH (22-fold increase in release rate from pH 8 to 5), thus providing feedback from culture pH. The addition of m-pHmH resulted in better pH maintenance and higher biomass yields of E. coli K12 in media containing glucose as a carbon source. The use of m-pHmH with additional buffer resulted in pH being maintained above 6.9 while pH decreases below 5 without m-pHmH. We demonstrate one application of such in situ pH management to increase the volumetric plasmid yield from E. coli in shake flask culture. In situ glucose release through a hydrogel to mimic fed-batch culture along with the addition of m-pHmH resulted in a 395 % increase in volumetric plasmid yield to 38 MUg/ml in shake flask culture. PMID- 24477569 TI - Atypical antipsychotic-induced metabolic disturbances in the elderly. AB - The metabolic side effects of atypical antipsychotics (AAPs) have been widely studied in younger populations, but research investigating these sequelae in the elderly is lacking. This article reviews the available literature examining the use of AAPs in the elderly, evaluating their association with weight gain and changes in blood glucose and lipid parameters. We find a relative paucity of studies in this area; while some data highlight significant, collective changes in metabolic parameters, the majority suggests an apparent low vulnerability to these side effects. We conclude that the risk and clinical implications of unfavorable metabolic changes in the elderly being treated with AAP medications remain largely undetermined, and we caution against drawing firm conclusions based on the available data. The conflicting evidence leaves us recommending that metabolic monitoring be implemented, with regular follow-up as advocated in other populations. PMID- 24477570 TI - Influence of the world's most challenging mountain ultra-marathon on energy cost and running mechanics. AB - PURPOSE: To examine the effects of the world's most challenging mountain ultra marathon (Tor des Geants((r)) 2012) on the energy cost of three types of locomotion (cycling, level and uphill running) and running kinematics. METHODS: Before (pre-) and immediately after (post-) the competition, a group of ten male experienced ultra-marathon runners performed in random order three submaximal 4 min exercise trials: cycling at a power of 1.5 W kg(-1) body mass; level running at 9 km h(-1) and uphill running at 6 km h(-1) at an inclination of +15 % on a motorized treadmill. Two video cameras recorded running mechanics at different sampling rates. RESULTS: Between pre- and post-, the uphill-running energy cost decreased by 13.8 % (P = 0.004); no change was noted in the energy cost of level running or cycling (NS). There was an increase in contact time (+10.3 %, P = 0.019) and duty factor (+8.1 %, P = 0.001) and a decrease in swing time (-6.4 %, P = 0.008) in the uphill-running condition. CONCLUSION: After this extreme mountain ultra-marathon, the subjects modified only their uphill-running patterns for a more economical step mechanics. PMID- 24477572 TI - Ferromagnetism in MnX2 (X = S, Se) monolayers. AB - Using density functional theory combined with Monte Carlo (MC) simulations, we show that the two dimensional (2D) MnS2 and MnSe2 sheets are ideal magnetic semiconductors with long-range magnetic ordering and high magnetic moments (3 MUB per unit cell), where all the Mn atoms are ferromagnetically coupled, and the Curie temperatures (TC) estimated for MnS2 and MnSe2 by the MC simulations are 225 and 250 K, respectively, which can be further increased to 330 K and 375 K by applying 5% biaxial tensile strains. PMID- 24477571 TI - The validity of the Moxus Modular metabolic system during incremental exercise tests: impacts on detection of small changes in oxygen consumption. AB - PURPOSE: We investigated the accuracy of the Moxus Modular Metabolic System (MOXUS) against the Douglas Bag Method (DBM) during high-intensity exercise, and whether the two methods agreed when detecting small changes in [Formula: see text] between two consecutive workloads ([Formula: see text]). METHODS: Twelve trained male runners performed two maximal incremental running tests while gas exchange was analyzed simultaneously by the two systems using a serial setup for four consecutive intervals of 30 s on each test. Comparisons between methods were performed for [Formula: see text], [Formula: see text], fractions of expired O2 (FeO2) and CO2 (FeCO2) and [Formula: see text]. RESULTS: The MOXUS produced significant higher (mean +/- SD, n = 54) readings for [Formula: see text] (80 +/- 200 mL min(-1), p = 0.005) and [Formula: see text] (2.9 +/- 4.2 L min(-1), p < 0.0001), but not FeO2 (-0.01 +/- 0.09). Log-transformed 95 % limits of agreement for readings between methods were 94-110 % for [Formula: see text], 97-108 % for [Formula: see text] and 99-101 % for FeO2. [Formula: see text] for two consecutive measurements was not different between systems (120 +/- 110 vs. 90 +/ 190 mL min(-1) for MOXUS and DBM, respectively, p = 0.26), but agreement between methods was very low (r = 0.25, p = 0.12). DISCUSSION: Although it was tested during high-intensity exercise and short sampling intervals, the MOXUS performed within the acceptable range of accuracy reported for automated analyzers. Most of the differences between equipments were due to differences in [Formula: see text]. Detecting small changes in [Formula: see text] during an incremental test with small changes in workload, however, might be beyond the equipment's accuracy. PMID- 24477573 TI - Combination of a novel photosensitizer DTPP with 650 nm laser results in efficient apoptosis and cytoskeleton collapse in breast cancer MCF-7 cells. AB - Luminal A type breast cancer was suitable for Photodynamic therapy (PDT) as its strong adhesion ability, low malignancy and easily being exposed to laser. To examine the novel photosensitizer agent 5-5-(4-N, N-diacetoxylphenyl-10, 15, 20 tetraphenylporphyrin)(DTPP) mediate PDT in breast cancer cell, Luminal A type breast cancer MCF-7 cells were used in this study, various concentrations of DTPP (0, 2, 4, 6, 8, 10, 12, 15, 20, 25, 30 MUg/mL) and different time intervals (0, 0.5, 1, 2, 4, 6, 8 min) of laser exposure at 650 nm wavelength (power of 20 mW) were tested in PDT. The survival rates of MCF-7 cells were measured using a sensitive cell proliferation assay (MTT) to establish optimal semilethal dose and optimal time exposure, a further study of effects on cytoskeleton and apoptosis were also performed. Cell cycle and apoptosis variation were assayed by flow cytometry. Microtubule, microfilament, and nuclei were observed using laser scanning confocal microscopy. Oncoproteins Bcl-2, beta-tubulin, and beta-catenin were detected by means of electrophoresis. The novel DTPP showed an efficient growth inhibition of MCF-7 during PDT, effective combinations in MCF-7 cells were shown to be 4 MUg mL(-1) PS irradiated for 8 min at least or 15 MUg mL(-1) irradiated for 2 min at least. Microtubule, microfilament, and nucleus staining demonstrated that cytoskeletal collapse occurs at 0.5 h after PDT. Bcl-2 and skeleton adhesion proteins beta-catenin were reduced in the level of expression; whereas, skeleton proteins beta-tubulin and actin maintained similar levels of expression 12 h after PDT. These results provided a better understanding of DTPP PDT in MCF-7 cells. PMID- 24477574 TI - Genetic imbalances detected by multiplex ligation-dependent probe amplification in a cohort of patients with oral squamous cell carcinoma-the first step towards clinical personalized medicine. AB - Oral tumors are a growing health problem worldwide; thus, it is mandatory to establish genetic markers in order to improve diagnosis and early detection of tumors, control relapses and, ultimately, delineate individualized therapies. This study was the first to evaluate and discuss the clinical applicability of a multiplex ligation-dependent probe amplification (MLPA) probe panel directed to head and neck cancer. Thirty primary oral squamous cell tumors were analyzed using the P428 MLPA probe panel. We detected genetic imbalances in 26 patients and observed a consistent pattern of distribution of genetic alterations in terms of losses and gains for some chromosomes, particularly for chromosomes 3, 8, and 11. Regarding the latter, some specific genes were highlighted due to frequent losses of genetic material--RARB, FHIT, CSMD1, GATA4, and MTUS1--and others due to gains--MCCC1, MYC, WISP1, PTK2, CCND1, FGF4, FADD, and CTTN. We also verified that the gains of MYC and WISP1 genes seem to suggest higher propensity of tumors localized in the floor of the mouth. This study proved the value of this MLPA probe panel for a first-tier analysis of oral tumors. The probemix was developed to include target regions that have been already shown to be of diagnostic/prognostic relevance for oral tumors. Furthermore, this study emphasized several of those specific genetic targets, suggesting its importance to oral tumor development, to predict patients' outcomes, and also to guide the development of novel molecular therapies. PMID- 24477575 TI - Association of XRCC1 polymorphisms with thyroid cancer risk. AB - Due to the important role in the DNA repair pathways, numerous studies have been carried out to explore the relationship between the polymorphisms in the X-ray repair cross-complementing group 1 (XRCC1) gene and thyroid cancer risk. But previous reports have produced conflicting results. Thus, we performed an updated comprehensive meta-analysis to better investigate the association of the XRCC1 polymorphisms with thyroid cancer risk. There were a total of nine studies included with 1,621 cases and 3,669 controls examining the effects of the XRCC1 Arg280His, Arg399Gln, and Arg194Trp polymorphisms on the susceptibility of thyroid cancer. In our study, the XRCC1 Arg280His polymorphism was found to be associated with an increased thyroid cancer risk in the Caucasian population [allelic contrast: odds ratio (OR) = 1.38, 95% CI = 1.05-1.80, P(Z) = 0.02, P(Q) = 0.61; dominant model: OR = 1.43, 95% CI = 1.08-1.89, P(Z) = 0.01, P(Q) = 0.57]. The Arg399Gln polymorphism was associated with a significant decreased risk [allelic contrast: OR = 0.73, 95% CI = 0.59-0.92, P(Z) = 0.006, P(Q) = 0.31; dominant model: OR = 0.73, 95% CI = 0.55-0.97, P(Z) = 0.03, P(Q) = 0.33; recessive model: OR = 0.56, 95% CI = 0.34-0.93, P(Z) = 0.02, P(Q) = 0.59], while the Arg194Trp SNP conferred an increased risk for thyroid cancer in the mixed populations [allelic contrast: OR = 1.49, 95% CI = 1.02-2.17, P(Z) = 0.04]. To conclude, the present meta-analysis demonstrated that the polymorphisms in the XRCC1 gene may be associated with developing of thyroid cancer. PMID- 24477576 TI - Circulatory miR-628-5p is downregulated in prostate cancer patients. AB - Prostate cancer (PCa) is a major health concern for men in the USA. Aberrant expression of microRNAs (miRNAs) has been associated with the pathogenesis of various cancers, including PCa. Circulatory forms of miRNAs have been detected in serum and hold promise as minimally invasive cancer biomarkers. This study aimed to identify potential circulatory miRNAs that can provide insights into new mechanisms for clinical diagnosis of PCa and can serve as potential biomarkers and/or therapeutic targets. Candidate serum miRNAs were detected by using PCR microarray in a learning set of six African American (AA) and six Caucasian American (CA) PCa patients. Discriminating performance of candidate miRNAs was validated by qRT-PCR in serum samples from 36 AA (24 PCa patients and 12 controls) and 36 CA (16 PCa patients and 20 controls). From the miRNA profiling experiments, three differentially expressed miRNAs (miR-25, miR-101, and miR-628 5p) were selected for future validation. In the validation set, there was an overall low expression of miR-25 (p < 0.01), miR-101 (p < 0.001), and miR-628-5p (p < 0.0001) in serum of PCa patients as compared with normal individuals. Subdivision on the basis of ethnicity showed that serum expression levels of miR 628-5p were significantly downregulated in both AA and CA PCa patients when compared with their respective controls. Our results demonstrate that the three miRNAs, particularly miR-628-5p, may be further developed as a biomarker, which can serve as novel noninvasive biomarker for PCa diagnosis and prognosis. PMID- 24477577 TI - Metabolism of benzo(a)pyrene by subcellular fractions of gastrointestinal (GI) tract and liver in Apc(Min) mouse model of colon cancer. AB - Given the fact that increased dietary intake of polycyclic aromatic hydrocarbons (PAHs; a family of environmental toxicants) leads to the formation and development of colon tumors, the ability of the gastrointestinal tract to process these compounds is important from the viewpoint of toxicity/carcinogenesis. Benzo(a)pyrene (BaP), a prototypical PAH compound is released into the environment from automobile exhausts, cigarette smoke, and industrial emissions. Additionally, considerable intake of BaP is expected in people who consume barbecued foods and a diet rich in saturated fat. In exposed animals, BaP becomes activated to potent metabolites that interfere with target organ function and as a consequence cause toxicity and cancer. Therefore, knowledge of BaP metabolism in the digestive system will be of importance in the management of cancers of the digestive tract. The objective of our study was to study the metabolism of BaP by subcellular fractions (nuclear, cytosolic, mitochondrial, and microsomal) of the gastrointestinal tract and liver. Subcellular fractions were isolated by differential centrifugation from the stomach, jejunum, colon, and liver tissues of Apc(Min) mice that received a subchronic dose of 25 MUg/kg BaP. The fractions were incubated with 1 and 3 MUM BaP. Subsequent to incubation, samples were extracted with ethyl acetate and analyzed for BaP metabolites by reverse-phase HPLC equipped with fluorescence detection. Among the different fractions tested, microsomal BaP metabolism was higher than the rest of the fractions in all the samples analyzed. Additionally, a BaP exposure concentration-dependent effect on metabolite levels generated by the subcellular fractions was recorded. The BaP metabolites identified were the following: BaP-9,10-diol; BaP-4,5-diol; BaP-7,8 diol; 9(OH) BaP; 3(OH) BaP; BaP-3,6-dione; and BaP-6,12-dione. While the diol group of metabolites was frequently detected, among diones, the 3,6 and 6,12 dione metabolites were infrequently detected. Among the diol metabolites, the preponderance of BaP-7,8-dihydrodiol is interesting, since this metabolite is a precursor to the DNA-reactive BaP-7,8-dihydrodiol epoxide (BPDE) that has been linked to BaP-induced cancer. PMID- 24477578 TI - Atherosclerosis is not a risk factor for anti-platelet factor 4/heparin antibody formation after cardiopulmonary bypass surgery. PMID- 24477580 TI - Fifteen minute consultation: tremor in children. AB - Tremor is defined as a rhythmic, involuntary, oscillatory movement of body parts. Although constituting nearly 20% of presentations with paediatric movement disorders, tremor in childhood, beginning in the neonatal period, has rarely been described in the literature. Tremor may be an isolated finding or a part of associated neurological or systemic disorders. In this review we aim to discuss the classification, aetiology, clinical features and management of various tremor syndromes in childhood. PMID- 24477579 TI - Brain activation during neurocognitive testing using functional near-infrared spectroscopy in patients following concussion compared to healthy controls. AB - There is no accepted clinical imaging modality for concussion, and current imaging modalities including fMRI, DTI, and PET are expensive and inaccessible to most clinics/patients. Functional near-infrared spectroscopy (fNIRS) is a non invasive, portable, and low-cost imaging modality that can measure brain activity. The purpose of this study was to compare brain activity as measured by fNIRS in concussed and age-matched controls during the performance of cognitive tasks from a computerized neurocognitive test battery. Participants included nine currently symptomatic patients aged 18-45 years with a recent (15-45 days) sport related concussion and five age-matched healthy controls. The participants completed a computerized neurocognitive test battery while wearing the fNIRS unit. Our results demonstrated reduced brain activation in the concussed subject group during word memory, (spatial) design memory, digit-symbol substitution (symbol match), and working memory (X's and O's) tasks. Behavioral performance (percent-correct and reaction time respectively) was lower for concussed participants on the word memory, design memory, and symbol match tasks than controls. The results of this preliminary study suggest that fNIRS could be a useful, portable assessment tool to assess reduced brain activation and augment current approaches to assessment and management of patients following concussion. PMID- 24477581 TI - Development and molecular characterization of genic molecular markers for grain protein and calcium content in finger millet (Eleusine coracana (L.) Gaertn.). AB - Finger millet (Eleusine coracana (L.) Gaertn), holds immense agricultural and economic importance for its high nutraceuticals quality. Finger millets seeds are rich source of calcium and its proteins are good source of essential amino acids. In the present study, we developed 36 EST-SSR primers for the opaque2 modifiers and 20 anchored-SSR primers for calcium transporters and calmodulin for analysis of the genetic diversity of 103 finger millet genotypes for grain protein and calcium contents. Out of the 36 opaque2 modifiers primers, 15 were found polymorphic and were used for the diversity analysis. The highest PIC value was observed with the primer FMO2E33 (0.26), while the lowest was observed FMO2E27 (0.023) with an average value of 0.17. The gene diversity was highest for the primer FMO2E33 (0.33), however it was lowest for FMO2E27 (0.024) at average value of 0.29. The percentage polymorphism shown by opaque2 modifiers primers was 68.23%. The diversity analysis by calcium transporters and calmodulin based anchored SSR loci revealed that the highest PIC was observed with the primer FMCA8 (0.30) and the lowest was observed for FMCA5 (0.023) with an average value of 0.18. The highest gene diversity was observed for primer FMCA8 (0.37), while lowest for FMCA5 (0.024) at an average of 0.21. The opaque2 modifiers specific EST-SSRs could able to differentiate the finger millet genotypes into high, medium and low protein containing genotypes. However, calcium dependent candidate gene based EST-SSRs could broadly differentiate the genotypes based on the calcium content with a few exceptions. A significant negative correlation between calcium and protein content was observed. The present study resulted in identification of highly polymorphic primers (FMO2E30, FMO2E33, FMO2-18 and FMO2 14) based on the parameters such as percentage of polymorphism, PIC values, gene diversity and number of alleles. PMID- 24477582 TI - 2-Cys peroxiredoxin responds to low temperature and other cues in Caragana jubata, a plant species of cold desert of Himalaya. AB - A 2-Cys peroxiredoxin cDNA (CjPrx) was isolated and characterized from Caragana jubata, a temperate/alpine plant species of high altitude cold desert of Himalaya and Eurasia. The cDNA obtained was 1,064 bp long consisting of an open reading frame of 789 bp encoding 262 amino acids. The calculated molecular mass of the mature protein was 28.88 kDa and pI was 5.84. Deduced amino acid sequence of CjPrx shared a high degree homology with 2-CysPrx proteins from other plants. CjPrx had both the PRX_type 2-Cys domain and thioredoxin-like superfamily domains. CjPrx contained 26.72% alpha-helices, 6.87% beta-turns, 20.61% extended strands and 45.80% random coils, and was a hydrophilic protein. Expression of CjPrx was modulated by low temperature, methyl jasmonate (MJ), salicylic acid and drought stress, but no significant change was observed in response to abscisic acid treatment. Among all the treatments, a strong up-regulation of CjPrx was observed in response to MJ treatment. PMID- 24477583 TI - Conservation and function of Dazl in promoting the meiosis of goat male germline stem cells. AB - Dazl (deleted in azoospermia-like) is a conserved gene in mammalian meiosis, which encodes RNA binding protein required for spermatocyte meiosis. Up to date, the expression and function of Dazl in the goat testis are unknown. The objectives of this study were to investigate the expression pattern of Dazl in dairy goat testis and their function in male germline stem cells (mGSCs). The results first revealed that the expression level of Dazl in adult testes was significantly higher than younger and immature goats, and azoospermia and male intersex testis. The dairy goat Dazl is highly conserved analysed by several online and bioinformatics software, respectively. Over-expression of Dazl promoted the expression of meiosis-related genes in dairy goat mGSCs. The expression of Stra8 was up-regulated by over-expression of Dazl analysed by Luciferase reporter assay. Taken together, results suggest the Dazl plays an important role in dairy goat spermatogenesis and that over-expression of Dazl may promote Stra8 expression in dairy goat mGSCs. PMID- 24477584 TI - Genetic association of IDE, POU2F1, PON1, IL1alpha and IL1beta with type 2 diabetes in Pakistani population. AB - A number of genes are known to be involved in glucose homeostasis. Mutations and polymorphisms in candidate genes may effect insulin production, action or resistance. This study was designed to report the association of genetic polymorphism with the type 2 diabetes (T2D) in Pakistani population. A total of 458 subjects (case n=288, control n=170) participated in the study. Nine single nucleotide polymorphisms were investigated in genes IDE (rs6583813 C>T, rs7910977 C>T), POU2F1 (rs3767434 A>T, rs10918682 A>T, rs2146727 A>G), WFS1 (rs734312 A>G), PON1 (rs854560 T>A), IL1alpha (rs1800587 C>T) and IL1beta (rs1143634 C>T). Genotyping was performed by DNA sequencing after nested polymerase chain reaction of targeted regions. Results indicated that rs7910977 in IDE showed significant association with the development of T2D [P=0.012, OR 1.677 (95% CI 1.112-2.438)]. The rs10918682 in POU2F1 was associated with T2D [P<0.001, OR 3.606 (95% CI 2.165 6.005)]. The rs854560 in PON1 was associated with incidences of T2D and increased the risk of cardiovascular complications [P=0.031, OR 0.663 (95% CI 0.455-0.965)] in diabetics. The rs734312 from WFS1 gene was associated with diabetes at genotype level (P<0.01). Haplotype analysis of rs1800587-rs1143634 depicted CC haplotype increased the susceptibility to diabetes (P<0.05). Haplotype GAA from rs2146727-10918682-rs3767434 was protective against diabetes (P<0.01) and GGA exhibited the association with T2D (P<0.01). Haplotype CT from rs6583813 rs7910977 was protective against diabetes (P=0.02). Our study provided evidence to IDE, PON1, WFS1, POU2F1, IL1alpha and IL1beta associated with T2D in Pakistanis. PMID- 24477585 TI - Comparative de novo transcriptome analysis and metabolic pathway studies of Citrus paradisi flavedo from naive stage to ripened stage. AB - Grapefruit (Citrus pardisi) is a popular citrus fruit that is a cross between a sweet orange and pummelo. This research article focuses on an in silico approach for comparative analysis of C. paradisi green flavedo (GF) and ethylene treated flavedo (ETF) transcriptome data. Our pathway analysis provides comprehensive information of genes playing significant role in different stages of ripening in fruit. De novo assembly was carried out using six different assemblers namely GS assembler, SeqMan NGEN, Velvet/Oases, CLC, iAssembler and Cortex followed by subsequent meta-assembly, annotation and pathway analysis. We conclude that de novo transcriptome assembly using meta-assembly approach is used to increase assembly quality in comparison to single assembler. PMID- 24477586 TI - In-silico mining, type and frequency analysis of genic microsatellites of finger millet (Eleusine coracana (L.) Gaertn.): a comparative genomic analysis of NBS LRR regions of finger millet with rice. AB - In recent years, the increased availability of the DNA sequences has given the possibility to develop and explore the expressed sequence tags (ESTs) derived SSR markers. In the present study, a total of 1956 ESTs of finger millet were used to find the microsatellite type, distribution, frequency and developed a total of 545 primer pairs from the ESTs of finger millet. Thirty-two EST sequences had more than two microsatellites and 1357 sequences did not have any SSR repeats. The most frequent type of repeats was trimeric motif, however the second place was occupied by dimeric motif followed by tetra-, hexa- and penta repeat motifs. The most common dimer repeat motif was GA and in case of trimeric SSRs, it was CGG. The EST sequences of NBS-LRR region of finger millet and rice showed higher synteny and were found on nearly same positions on the rice chromosome map. A total of eight, out of 15 EST based SSR primers were polymorphic among the selected resistant and susceptible finger millet genotypes. The primer FMBLEST5 could able to differentiate them into resistant and susceptible genotypes. The alleles specific to the resistant and susceptible genotypes were sequenced using the ABI 3130XL genetic analyzer and found similarity to NBS-LRR regions of rice and finger millet and contained the characteristic kinase-2 and kinase 3a motifs of plant R-genes belonged to NBS-LRR region. The In-silico and comparative analysis showed that the genes responsible for blast resistance can be identified, mapped and further introgressed through molecular breeding approaches for enhancing the blast resistance in finger millet. PMID- 24477587 TI - Multivariate meta-analysis of the association of G-protein beta 3 gene (GNB3) haplotypes with cardiovascular phenotypes. AB - The objective of the present study was to review previous investigations on the association of haplotypes in the G-protein beta3 subunit (GNB3) gene with representative cardiovascular risk factors/phenotypes: hypertension, overweight, and variation in the systolic and diastolic blood pressures (SBP and DBP, respectively) and as well as body mass index (BMI). A comprehensive literature search was undertaken in Pubmed, Web of Science, EMBASE, Biological Abstracts, LILACS and Google Scholar to identify potentially relevant articles published up to April 2011. Six genetic association studies encompassing 16,068 participants were identified. Individual participant data were obtained for all studies. The three most investigated GNB3 polymorphisms (G-350A, C825T and C1429T) were considered. Expectation-maximization and generalized linear models were employed to estimate haplotypic effects from data with uncertain phase while adjusting for covariates. Study-specific results were combined through a random-effects multivariate meta-analysis. After carefully adjustments for relevant confounding factors, our analysis failed to support a role for GNB3 haplotypes in any of the investigated phenotypes. Sensitivity analyses excluding studies violating Hardy Weinberg expectations, considering gender-specific effects or more extreme phenotypes (e.g. obesity only) as well as a fixed-effects "pooled" analysis also did not disclose a significant influence of GNB3 haplotypes on cardiovascular phenotypes. We conclude that the previous cumulative evidence does not support the proposal that haplotypes formed by common GNB3 polymorphisms might contribute either to the development of hypertension and obesity, or to the variation in the SBP, DBP and BMI. PMID- 24477588 TI - Comparative transcripts profiling of fruit mesocarp and endocarp relevant to secondary metabolism by suppression subtractive hybridization in Azadirachta indica (neem). AB - Azadirachta indica (neem) is a medicinally important plant that is valued for its bioactive secondary metabolites. Higher levels of the bioactive phytochemicals are accumulated in fruits than in other tissues. In the present study, a total of 387 and 512 ESTs, respectively, from endocarp and mesocarp of neem fruits were isolated and analyzed. Out of them 318 ESTs (82.17%) clones from endocarp and 418 ESTs (81.64%) from mesocarp encoded putative proteins that could be classified into three major gene ontology categories: biological process, molecular function and cellular component. From the analyses of contigs, 73 unigenes from the forward subtracted library and 35 unigenes from the reverse subtracted library were obtained. The ESTs from mesocarp encoded cytochrome P450 enzymes, which indicated hydroxylation to be a major metabolic event and that biogeneration of hydroxylated neem fruit phytochemicals was differentially regulated with developmental stage-specificity of synthesis. Through this study, we present the first report of any gene expression data in neem tissues. Neem hydroxy-methyl glutaryl-coenzyme A reductase (NHMGR) gene was used as expressing control vis-a vis subtracted tissues. NHMGR was present in fruit, endocarp and mesocarp tissues, but absent in subtractive libraries, revealing that it was successfully eliminated during subtraction. Eight genes of interest from subtracted libraries were profiled for their expression in fruit, mesocarp and endocarp. Expression profiles validated the quality of the libraries and functional diversity of the tissues. The subtractive cDNA library and EST database described in this study represent a valuable transcript sequence resource for future research aimed at improving the economically important medicinal plant. PMID- 24477589 TI - Identification and characterization of nucleotide variations in the genome of Ziziphus jujuba (Rhamnaceae) by next generation sequencing. AB - In this study, single-nucleotide polymorphisms (SNPs) and insertions/deletions (InDels) in the genome of Ziziphus jujuba were identified using sequences generated by the Roche 454 GS-FLX sequencer. A total of, 573,141 reads were produced with an average read length of 360 bp. After quality control, 258,754 of the filtered reads were assembled into 23,864 contigs, and 293,458 remained as singletons. Using the contig assemblies as a reference, 17,160 SNPs and 478 InDels were identified. Among the SNPs, transitions occurred three times more frequently than transversions. In transitions, the number of C/T and G/A transitions was similar. Among the transversions, A/T was the most abundant, and C/G was much rarer than any of the other types of transversions, accounting for only about half the numbers of A/C, A/T and G/T transversions. For the InDels, mononucleotide changes amounted to 64.4% of the total number of InDels. In general, the frequency of detected InDels decreased as the length of the InDels increased. This study provides valuable marker resources for future genetic studies of Ziziphus spp. PMID- 24477590 TI - TLR3 plays significant roles against hepatitis B virus. AB - Hepatitis B virus (HBV) as the main prevalent infectious agent, play important roles in inducing severe liver diseases. Previous studies demonstrated that during prolonged forms of hepatitis B infection including chronic, asymptomatic and occult forms, patients are unable to eradicate HBV from hepatocytes completely. The main mechanisms responsible for development of the forms of hepatitis B are yet to be identified. Investigators suggested that the various genetic and immunological parameters of the patients may are responsible for resulting in the prolonged infection forms. It has been evidenced that TLRs play key roles in inducing appropriate immune responses, against viral infections. Therefore, these molecules can be considered as crucial sensors for HBV detection to induce immune responses against this virus. It has also been documented that the TLR3 detects intracellular viral dsRNA and subsequently activates NF-kappaB via the TRIF pathway. Therefore, impaired TLR3 expression may result in inappropriate immune responses against HBV which is reported in prolonged forms of hepatitis B. This review collected the recent information regarding the important roles of TLR3 in immune responses against HBV and also the status of TLR3 expression and its genetic variations in prolonged forms of HBV infections. PMID- 24477591 TI - The -930A>G polymorphism of the CYBA gene is associated with premature coronary artery disease. A case-control study and gene-risk factors interactions. AB - Reactive oxygen species (ROS) are involved in the pathogenesis of atherosclerosis and coronary artery disease (CAD). NADPH oxidases are the main source of ROS in the vasculature. p22phox is a critical component of vascular NADPH oxidases and is encoded by the CYBA (cytochrome b245 alpha) gene. The -930A>G CYBA polymorphism (rs9932581:A>G) modulates the activity of the CYBA promoter, and influences CYBA transcriptional activity. The aim of the present study was to analyze a possible association between the -930A>G polymorphism and CAD and to search for gene-traditional risk factors interactions. 480 subjects were studied: 240 patients with premature CAD, 240 age and sex matched blood donors. The 930A>G polymorphism was genotyped using the TaqMan(r) Pre-designed SNP Genotyping Assay (Applied Biosystems). The -930G allele carrier state was a risk factor for CAD (OR 2.03, 95% CI 1.21-3.44, P=0.007). A synergistic effect of the -930G allele with overweight/obesity (BMI>=25) and cigarette smoking was found. The estimated CAD risk for BMI>=25 and the -930G allele interaction was about 160% greater than that predicted by assuming additivity of the effects, and about 40% greater for interaction of cigarette smoking and the -930G allele. Overweight/obesity was a risk factor for CAD only in the -930G allele carriers (P<10(-10)) but not in the AA homozygotes (P=1.00). In conclusion the -930A>G CYBA polymorphism is associated with CAD in the Polish population. The -930G allele carriers are particularly at risk of consequences of obesity and tobacco smoke exposure. PMID- 24477592 TI - Hitching a ride on vesicles: cauliflower mosaic virus movement protein trafficking in the endomembrane system. AB - The transport of a viral genome from cell to cell is enabled by movement proteins (MPs) targeting the cell periphery to mediate the gating of plasmodesmata. Given their essential role in the development of viral infection, understanding the regulation of MPs is of great importance. Here, we show that cauliflower mosaic virus (CaMV) MP contains three tyrosine-based sorting signals that interact with an Arabidopsis (Arabidopsis thaliana) MUA-adaptin subunit. Fluorophore-tagged MP is incorporated into vesicles labeled with the endocytic tracer N-(3 triethylammoniumpropyl)-4-(6-(4-(diethylamino)phenyl)hexatrienyl)pyridinium dibromide. The presence of at least one of the three endocytosis motifs is essential for internalization of the protein from the plasma membrane to early endosomes, for tubule formation, and for CaMV infection. In addition, we show that MP colocalizes in vesicles with the Rab GTPase AtRAB-F2b, which is resident in prevacuolar late endosomal compartments that deliver proteins to the vacuole for degradation. Altogether, these results demonstrate that CaMV MP traffics in the endocytic pathway and that virus viability depends on functional host endomembranes. PMID- 24477594 TI - Evidence for maternal imprinting of 45S ribosomal RNA genes in Xenopus hybrids. AB - We discovered that gene clusters of 45S ribosomal RNA in Xenopus hybrid frogs are maternally imprinted, similar to X chromosome inactivation in marsupial females. Paternal expression was partly restored after chemical inhibition of histone deacetylation during larval stages. This provides a new spectacular example of epigenetic silencing and first evidence of genomic imprinting in amphibians. PMID- 24477595 TI - Attenuation of microRNA-126 expression that drives CD34+38- stem/progenitor cells in acute myeloid leukemia leads to tumor eradication. AB - Despite high remission rates after therapy, 60% to 70% of patients with acute myeloid leukemia (AML) do not survive 5 years after their initial diagnosis. The main cause of treatment failures may be insufficient eradication of a subpopulation of leukemic stem-like cells (LSC), which are thought to be responsible for relapse by giving rise to more differentiated leukemic progenitors (LP). To address the need for therapeutic targets in LSCs, we compared microRNA (miRNA) expression patterns in highly enriched healthy CD34(+)CD38(-) hematopoietic stem cells (HSC), CD34(+)CD38(-) LSCs, and CD34(+)CD38(+) LPs, all derived from the same patients' bone marrow (BM) specimens. In this manner, we identified multiple differentially expressed miRNAs, in particular miR-126, which was highly expressed in HSCs and increased in LSCs compared with LPs, consistent with a stem-like cell function. High miR 126 expression in AML was associated with poor survival, higher chance of relapse, and expression of genes present in LSC/HSC signatures. Notably, attenuating miR-126 expression in AML cells reduced in vitro cell growth by inducing apoptosis, but did not affect the survival of normal BM in which it instead enhanced expansion of HSCs. Furthermore, targeting miR-126 in LSCs and LPs reduced their clonogenic capacity and eliminated leukemic cells, again in the absence of similar inhibitory effects on normal BM cells. Our results define miR 126 as a therapeutic focus to specifically eradicate LSCs and improve AML outcome. PMID- 24477598 TI - Temperature variation and the incidence of cluster headache periods: A nationwide population study. AB - BACKGROUND: Cluster headache (CH) is well known to show a seasonal predilection; however, the impact of temperature and other meteorological factors on cluster periods (or bouts) has not been established. METHODS: This nationwide survey included 758 patients with episodic CH retrieved from the Taiwan National Health Insurance Research Database from 2005 to 2009. Corresponding meteorological recordings were obtained from the Central Weather Bureau. A case-crossover study design was used to investigate the association between cluster periods and meteorological factors. RESULTS: A total of 2452 episodes of cluster periods were recorded. The cluster periods were most frequent in the autumn and least frequent in the winter. Seasonal changes from winter to spring and from autumn to winter also increased the frequency of cluster periods. The risk of cluster periods increased when there was a higher mean temperature on event days (odds ratio (OR), 1.014, 95% confidence interval (CI), 1.005-1.023, p = 0.003) or within seven to 56 days. Either an increase or a decrease in temperature (0.05C/day) following a warm period (mean temperature >=26C) was associated with the onset of cluster periods. In contrast, a greater increase in temperature (0.15C/day) following a cold period (mean temperature < 21C) was needed to evoke cluster periods. No such associations were found following moderate periods (21C <=mean temperature <26C). DISCUSSION: Our study shows that temperature is associated with precipitating or priming cluster periods. The influence depends on the temperature of the preceding periods. PMID- 24477596 TI - Expression of variant isoforms of the tyrosine kinase SYK determines the prognosis of hepatocellular carcinoma. AB - The spleen tyrosine kinase (SYK) has been reported as a novel biomarker for human hepatocellular carcinoma, but the functional contributions of its two isoforms SYK(L) and SYK(S) are undefined. In this study, we investigated their biologic functions and possible prognostic values in hepatocellular carcinoma. SYK(L) was downregulated in 38% of human specimens of hepatocellular carcinoma examined, whereas SYK(S) was detectable in 40% of these specimens but not in normal liver tissue samples without cirrhosis. SYK(S) expression correlated with pathologic parameters characteristic of tumor metastasis, including multiple tumors (P = 0.003) and vascular invasion (P = 0.001). Further, SYK(S) was specifically associated with epithelial-mesenchymal transition (EMT) in hepatocellular carcinoma specimens. Functional studies showed that SYK(S) promoted tumor growth, suppressed apoptosis, and induced EMT through the extracellular signal-regulated kinase pathway, countering the opposite effects of SYK(L). Patients with SYK(L(+)/S(-)) tumors exhibited longer overall survival and time to recurrence than those with SYK(L(-)/S(-)) or SYK(L(+)/S(+)) tumors (P < 0.001). Taken together, our findings showed that SYK(S) enhances invasion, whereas SYK(L) inhibits metastasis in hepatocellular carcinoma. We suggest that SYK(L) downregulation or SYK(S) elevation are strong predictors of poor survival in patients with hepatocellular carcinoma, indicative of a need for aggressive therapeutic intervention. PMID- 24477599 TI - Validation of ICHD-3 beta diagnostic criteria for 13.7 Tolosa-Hunt syndrome: Analysis of 77 cases of painful ophthalmoplegia. AB - BACKGROUND: Three editions of International Classification of Headache Disorders (ICHD) diagnostic criteria for Tolosa-Hunt syndrome (THS) have been published in 1988, 2004 and 2013, in ICHD-3 beta, there have been considerable changes [corrected]. The validity of these new diagnostic criteria remains to be established. METHODS: We retrospectively identified 77 patients with non traumatic painful ophthalmoplegia (PO) admitted between 2003 and 2013. We reviewed patients' age at onset and gender, time courses between onset of pain and development of cranial nerve palsy, the cranial nerves involved, imaging findings, therapeutic efficacy of steroid treatment and recurrence of attacks. RESULTS: THS was the most frequent type of PO (46/77). In THS patients, the third cranial nerve was most commonly involved (76.3%). The median time interval between pain and cranial nerve palsy was two days, although in five patients (10.9%) the interval ranged from 16 to 30 days. Definitely abnormal MRI findings were found in 24 patients (52.2%). CONCLUSIONS: It is essential to rule out other causes of PO in diagnosing THS, with MRI playing a crucial role in differential diagnosis. It may be helpful to understand and master the entity of THS for researchers and clinicians to adjust the gradation and ranking of the diagnostic criteria. PMID- 24477601 TI - Graphene-nickel interfaces: a review. AB - Graphene on nickel is a prototypical example of an interface between graphene and a strongly interacting metal, as well as a special case of a lattice matched system. The chemical interaction between graphene and nickel is due to hybridization of the metal d-electrons with the pi-orbitals of graphene. This interaction causes a smaller separation between the nickel surface and graphene (0.21 nm) than the typical van der Waals gap-distance between graphitic layers (0.33 nm). Furthermore, the physical properties of graphene are significantly altered. Main differences are the opening of a band gap in the electronic structure and a shifting of the pi-band by ~2 eV below the Fermi-level. Experimental evidence suggests that the ferromagnetic nickel induces a magnetic moment in the carbon. Substrate induced geometric and electronic changes alter the phonon dispersion. As a consequence, monolayer graphene on nickel does not exhibit a Raman spectrum. In addition to reviewing these fundamental physical properties of graphene on Ni(111), we also discuss the formation and thermal stability of graphene and a surface-confined nickel-carbide. The fundamental growth mechanisms of graphene by chemical vapor deposition are also described. Different growth modes depending on the sample temperature have been identified in ultra high vacuum surface science studies. Finally, we give a brief summary for the synthesis of more complex graphene and graphitic structures using nickel as catalyst and point out some potential applications for graphene-nickel interfaces. PMID- 24477600 TI - Adenosine regulates the proinflammatory signaling function of thrombin in endothelial cells. AB - The plasma level of the regulatory metabolite adenosine increases during the activation of coagulation and inflammation. Here we investigated the effect of adenosine on modulation of thrombin-mediated proinflammatory responses in HUVECs. We found that adenosine inhibits the barrier-disruptive effect of thrombin in HUVECs by a concentration-dependent manner. Analysis of cell surface expression of adenosine receptors revealed that A2A and A2B are expressed at the highest level among the four receptor subtypes (A2B > A2A > A1 > A3 ) on HUVECs. The barrier-protective effect of adenosine in response to thrombin was recapitulated by the A2A specific agonist, CGS 21680, and abrogated both by the siRNA knockdown of the A2A receptor and by the A2A -specific antagonists, ZM-241385 and SCH 58261. The thrombin-induced RhoA activation and its membrane translocation were both inhibited by adenosine in a cAMP-dependent manner, providing a molecular mechanism through which adenosine exerts a barrier-protective function. Adenosine also inhibited thrombin-mediated activation of NF-kappaB and decreased adhesion of monocytic THP-1 cells to stimulated HUVECs via down-regulation of expression of cell surface adhesion molecules, VCAM-1, ICAM-1, and E-selectin. Moreover, adenosine inhibited thrombin-induced elevated expression of proinflammatory cytokines, IL-6 and HMGB-1; and chemokines, MCP-1, CXCL-1, and CXCL-3. Taken together, these results suggest that adenosine may inhibit thrombin-mediated proinflammatory signaling responses, thereby protecting the endothelium from injury during activation of coagulation and inflammation. PMID- 24477602 TI - Automated segmentation and volumetric analysis of renal cortex, medulla, and pelvis based on non-contrast-enhanced T1- and T2-weighted MR images. AB - OBJECT: The aim of our study was to enable automatic volumetry of the entire kidneys as well as their internal structures (cortex, medulla, and pelvis) from native magnetic resonance imaging (MRI) data sets. MATERIALS AND METHODS: Segmentation of the entire kidneys and differentiation of their internal structures were performed in 12 healthy volunteers based on non-contrast-enhanced T1- and T2-weighted MR images. Two data sets (each acquired in one breath-hold) were co-registered using a rigid registration algorithm compensating for possible breathing-related displacements. An automatic algorithm based on thresholding and shape detection segmented the kidneys into their compartments and was compared to a manual labeling procedure. RESULTS: The resulting kidney volumes of the automated segmentation correlated well with those created manually (R(2) = 0.96). Average volume errors were determined to be 4.97 +/- 4.08% (entire kidney parenchyma), 7.03 +/- 5.56% (cortex), 12.33 +/- 7.35% (medulla), and 17.57 +/- 14.47% (pelvis). The variation of the kidney volume resulting from the automatic algorithm was found to be 4.76% based on the measuring of one volunteer with three independent examinations. CONCLUSION: The results demonstrate the feasibility of an accurate and repeatable automatic segmentation of the kidneys and their internal structures from non-contrast-enhanced magnetic resonance images. PMID- 24477603 TI - An open-label, dose-escalation, safety, and pharmacokinetics phase I study of ombrabulin, a vascular disrupting agent, administered as a 30-min intravenous infusion every 3 weeks in Japanese patients with advanced solid tumors. AB - PURPOSE: To determine ombrabulin's maximum tolerated dose and dose recommended for Japanese patients with advanced solid tumors and to assess its antitumor activity and overall safety and pharmacokinetic profiles. METHODS: This was a multi-center, open-label, sequential-cohort, dose-escalation phase I study of ombrabulin, a vascular disrupting agent, administered once every 3 weeks. Patients were treated with 15.5, 25, 35, or 50 mg/m(2) ombrabulin over a 30-min intravenous infusion. The recommended dose was the highest dose at which <33 % of all evaluable patients experienced dose-limiting toxicities (DLTs) during the first treatment cycle or 50 mg/m(2) (recommended in Caucasian patients) if the previous definition was not met. RESULTS: Fifteen patients were treated. No DLT occurred with 15.5, 25, or 35 mg/m(2) ombrabulin. In the 50 mg/m(2) group, one patient had Grade 3 lymphopenia, and another experienced Grade 2 hypertension and Grade 3 diarrhea judged as DLTs. The most frequent related adverse events in this group were diarrhea, nausea, and hypertension. Two patients had Grade 3 anemia, one at the 15.5 mg/m(2) and the other at the 50 mg/m(2). No AEs necessitating dose reduction or Grade 4 AEs were observed. Overall, five patients had stable disease. Pharmacokinetic parameters were comparable to those in non-Japanese patients. CONCLUSIONS: Ombrabulin treatment once every 3 weeks was well tolerated in Japanese patients with advanced solid tumors. The dose recommended is 50 mg/m(2), as in Caucasian patients. The safety and pharmacokinetic profiles were comparable between Japanese and Caucasian patients (funded by Sanofi; ClinicalTrials.gov number, NCT00968916). PMID- 24477604 TI - Efficacy against subcutaneous or intracranial murine GL261 gliomas in relation to the concentration of the vascular-disrupting agent, 5,6-dimethylxanthenone-4 acetic acid (DMXAA), in the brain and plasma. AB - PURPOSE: Glioblastomas are amongst the most highly vascularised tumours, and the pursuit of anti-angiogenic approaches such as bevacizumab has provided short-term benefits. The purpose of this study was to determine whether the vascular disrupting agent, dimethylxanthenone-4-acetic acid (DMXAA), could provide longer lasting therapeutic benefits in a murine model of glioblastoma. METHODS: Luciferase-expressing murine GL261 glioma cells were inoculated subcutaneously or intracranially into C57Bl/6 mice. Mice with tumours were administered DMXAA, and tumours measured using callipers or by optical imager. Concentrations of DMXAA in plasma and brain were measured by LC-MS/MS. RESULTS: DMXAA (25 mg/kg) caused widespread necrosis at 24 h, a 9-day growth delay and complete regressions in 50 % of the mice with subcutaneous GL261 tumours. Co-administered lenalidomide (100 mg/kg) increased the growth delay to 20 days and the percentage of cures to 83 %. The same dose of DMXAA with or without lenalidomide had minimal effects on intracranial GL261 tumours. Concentrations of DMXAA extracted from brain tissue were approximately 25-fold lower than those measured in plasma 15 min to 4 h after DMXAA administration. The presence of intracranial GL261 tumours did not alter the concentrations of DMXAA entering the brain. CONCLUSIONS: DMXAA does not appear to cross the blood-brain barrier efficiently. Thus, whilst excellent activity was obtained against subcutaneous GL261 gliomas, minimal effects were observed against intracranial GL261 tumours. These results emphasise the need to use appropriate orthotopic models for the evaluation of new approaches for the treatment of brain cancers. PMID- 24477605 TI - Increased serum level of epidermal growth factor receptor (EGFR) is associated with poor progression-free survival in patients with epithelial ovarian cancer. AB - PURPOSE: Epidermal growth factor receptor (EGFR) plays an important role in the pathogenesis of multiple malignancies, and its expression also strongly affects the outcomes of cancer patients. The objective of this study was to determine the clinical significance of the serum levels of EGFR in epithelial ovarian cancer (EOC) patients. MATERIALS AND METHODS: A total of 50 patients with a pathologically confirmed diagnosis of EOC were enrolled into this study. Serum EGFR levels were determined by the solid-phase sandwich ELISA method. Age and sex matched 20 healthy controls were included in the analysis. RESULTS: Median age of patients was 56.5 years old, range 22-83 years. Majority of the patients had advanced disease (FIGO stage III-IV) (90 %). No significant difference in baseline serum EGFR levels between EOC patients and controls (65.9 vs. 65.4 ng/mL, p = 0.86). Patients with normal CA 125 had higher serum EGFR level compared with the higher CA 125 level (p = 0.02). No other clinical variables including histology, stage of disease, and response to chemotherapy were found to be correlated with serum EGFR assay (p > 0.05). The patients with increased serum EGFR levels had poor progression-free survival than those with lower levels (median survival 4 vs. 12 months, respectively, p = 0.01). However, serum EGFR level was found no prognostic role for overall survival (p = 0.15). CONCLUSION: Increased serum level of EGFR is associated with poor progression-free survival in EOC patients. PMID- 24477606 TI - From physiology to physics: are we recognizing the flexibility of biologging tools? AB - The remote measurement of data from free-ranging animals has been termed 'biologging' and in recent years this relatively small set of tools has been instrumental in addressing remarkably diverse questions--from 'how will tuna respond to climate change?' to 'why are whales big?'. While a single biologging dataset can have the potential to test hypotheses spanning physiology, ecology, evolution and theoretical physics, explicit illustrations of this flexibility are scarce and this has arguably hindered the full realization of the power of biologging tools. Here we present a small set of examples from studies that have collected data on two parameters widespread in biologging research (depth and acceleration), but that have interpreted their data in the context of extremely diverse phenomena: from tests of biomechanical and diving-optimality models to identifications of feeding events, Levy flight foraging strategies and expanding oxygen minimum zones. We use these examples to highlight the remarkable flexibility of biologging tools, and identify several mechanisms that may enhance the scope and dissemination of future biologging research programs. PMID- 24477607 TI - Ocean acidification slows retinal function in a damselfish through interference with GABAA receptors. AB - Vision is one of the most efficient senses used by animals to catch prey and avoid predators. Therefore, any deficiency in the visual system could have important consequences for individual performance. We examined the effect of CO2 levels projected to occur by the end of this century on retinal responses in a damselfish, by determining the threshold of its flicker electroretinogram (fERG). The maximal flicker frequency of the retina was reduced by continuous exposure to elevated CO2, potentially impairing the capacity of fish to react to fast events. This effect was rapidly counteracted by treatment with a GABA antagonist (gabazine), indicating that GABAA receptor function is disrupted by elevated CO2. In addition to demonstrating the effects of elevated CO2 on fast flicker fusion of marine fishes, our results show that the fish retina could be a model system to study the effects of high CO2 on neural processing. PMID- 24477608 TI - Unilateral range finding in diving beetle larvae. AB - One of the biggest challenges that predators, such as the larvae of the diving beetle Thermonectus marmoratus (Coleoptera: Dytiscidae), are faced with is to accurately assess the distance of their prey. Most animals derive distance information from disparities of images that are viewed from different angles, from information that is obtained from well-controlled translational movements (motion parallax) or from the image size of known objects. Using a behavioral assay we demonstrated that T. marmoratus larvae continue to accurately strike at artificial prey, even if none of these typical distance estimation cues are available to them. Specifically, we excluded bilateral binocular stereopsis by occlusion, confounded possible motion parallax cues with an artificially moving prey, and excluded the possibility that beetle larvae simply approached their targets based on known prey size by presenting different prey sizes. Despite these constraints, larvae consistently struck our artificial targets from a distance of ~4.5 mm. Based on these findings we conclude that T. marmoratus likely employ an unusual mechanism to accurately determine prey distances, possibly mediated by the object-distance-dependent activation of specific subsets of their many-tiered and peculiarly positioned photoreceptors. PMID- 24477609 TI - Equal latency contours and auditory weighting functions for the harbour porpoise (Phocoena phocoena). AB - Loudness perception by human infants and animals can be studied under the assumption that sounds of equal loudness elicit equal reaction times (RTs). Simple RTs of a harbour porpoise to narrowband frequency-modulated signals were measured using a behavioural method and an RT sensor based on infrared light. Equal latency contours, which connect equal RTs across frequencies, for reference values of 150-200 ms (10 ms intervals) were derived from median RTs to 1 s signals with sound pressure levels (SPLs) of 59-168 dB re. 1 MUPa and centre frequencies of 0.5, 1, 2, 4, 16, 31.5, 63, 80 and 125 kHz. The higher the signal level was above the hearing threshold of the harbour porpoise, the quicker the animal responded to the stimulus (median RT 98-522 ms). Equal latency contours roughly paralleled the hearing threshold at relatively low sensation levels (higher RTs). The difference in shape between the hearing threshold and the equal latency contours was more pronounced at higher levels (lower RTs); a flattening of the contours occurred for frequencies below 63 kHz. Relationships of the equal latency contour levels with the hearing threshold were used to create smoothed functions assumed to be representative of equal loudness contours. Auditory weighting functions were derived from these smoothed functions that may be used to predict perceived levels and correlated noise effects in the harbour porpoise, at least until actual equal loudness contours become available. PMID- 24477610 TI - Geared up to stretch: pennate muscle behavior during active lengthening. AB - Many locomotor activities require muscles to actively lengthen, dissipate energy and decelerate the body. These eccentric contractions can disrupt cytoskeletal structures within myofibrils and reduce force output. We examined how architectural features of pennate muscles can provide a protective mechanism against eccentric muscle damage by limiting fascicle lengthening. It has been previously shown that the angled fibers of pennate muscles change orientation when shortening. This change in fiber orientation can amplify fascicle shortening, resulting in a velocity advantage at the level of the muscle-tendon unit (MTU) that is characterized by a gear ratio (MTU velocity/fascicle velocity). A muscle's architectural gear ratio (AGR) has been shown to vary as a function of force during shortening, while AGR during lengthening remains largely unknown. We independently measured fascicle length and MTU length in vitro in the bullfrog plantaris. We characterized the muscle's force-velocity curve and AGR during both shortening and lengthening across a broad range of forces (10-190% peak isometric force). AGR was measured during the isotonic portion of each contraction, to eliminate possible contributions of series elasticity to MTU length changes. We found that gear ratio varies with force during both shortening and lengthening contractions. The highest AGR was observed during lengthening contractions, indicating that lengthening of the MTU can occur with relatively little stretch of the fascicle. As fascicle strain is considered an important determinant of muscle damage, a high gear ratio may afford pennate muscles protection against the damaging effects of active lengthening. PMID- 24477611 TI - Aerodynamics of the flying snake Chrysopelea paradisi: how a bluff body cross sectional shape contributes to gliding performance. AB - A prominent feature of gliding flight in snakes of the genus Chrysopelea is the unique cross-sectional shape of the body, which acts as the lifting surface in the absence of wings. When gliding, the flying snake Chrysopelea paradisi morphs its circular cross-section into a triangular shape by splaying its ribs and flattening its body in the dorsoventral axis, forming a geometry with fore-aft symmetry and a thick profile. Here, we aimed to understand the aerodynamic properties of the snake's cross-sectional shape to determine its contribution to gliding at low Reynolds numbers. We used a straight physical model in a water tunnel to isolate the effects of 2D shape, analogously to studying the profile of an airfoil of a more typical flyer. Force measurements and time-resolved (TR) digital particle image velocimetry (DPIV) were used to determine lift and drag coefficients, wake dynamics and vortex-shedding characteristics of the shape across a behaviorally relevant range of Reynolds numbers and angles of attack. The snake's cross-sectional shape produced a maximum lift coefficient of 1.9 and maximum lift-to-drag ratio of 2.7, maintained increases in lift up to 35 deg, and exhibited two distinctly different vortex-shedding modes. Within the measured Reynolds number regime (Re=3000-15,000), this geometry generated significantly larger maximum lift coefficients than many other shapes including bluff bodies, thick airfoils, symmetric airfoils and circular arc airfoils. In addition, the snake's shape exhibited a gentle stall region that maintained relatively high lift production even up to the highest angle of attack tested (60 deg). Overall, the cross-sectional geometry of the flying snake demonstrated robust aerodynamic behavior by maintaining significant lift production and near-maximum lift-to-drag ratios over a wide range of parameters. These aerodynamic characteristics help to explain how the snake can glide at steep angles and over a wide range of angles of attack, but more complex models that account for 3D effects and the dynamic movements of aerial undulation are required to fully understand the gliding performance of flying snakes. PMID- 24477612 TI - Visual odometry in the wolf spider Lycosa tarantula (Araneae: Lycosidae). AB - The wolf spider Lycosa tarantula homes using path integration. The angular component of the displacement is measured using a polarized-light compass associated with the functioning of the anterior median eyes. However, how L. tarantula estimates the linear component of the displacement was not known prior to this investigation. The ability of L. tarantula to gauge the distance walked after being displaced from its burrow was investigated using experimental channels placed in an indoor setup. Firstly, we manipulated the perception of visual stimuli by covering all the spider's eyes. Secondly, we changed the optic flow supplied by a black-and-white grating (lambda=2 cm) perceived either in the lateral or in the ventral field of view. Finally, the period of the lateral or ventral grating was changed from lambda=2 cm to lambda=1 cm. Our results indicate that visual information contributes to distance estimation because when the spider's eyes were covered, the spiders tended to search for the burrow at very variable distances. This visual information is created by the motion of the image as the spider walks, the motion in the lateral field of view being the most important. The preference of a lateral optic flow over the ventral flow can be explained by the difference in the resolution capacity of the posterior lateral eyes and the anterior lateral eyes. PMID- 24477614 TI - Negative effect of litter of invasive weed Lantana camara on structure and composition of vegetation in the lower Siwalik Hills, northern India. AB - Lantana camara, an aromatic shrub, native to tropical America, was introduced into India for ornamental hedging, but later escaped and became a serious invasive weed. This study assessed the quantitative and qualitative status of plant community richness and diversity in areas invaded by L. camara in the Siwalik Hills (Himachal Pradesh, India), and explored allelopathy as a possible mechanism of interference. We measured species diversity, richness and evenness of the vegetation in areas invaded and uninvaded by L. camara. Allelopathic effects of L. camara rhizosphere soil and litter were assessed against two native plants-Achyranthes aspera (a herb) and Albizia lebbeck (a tree). Density, biomass and indices of diversity, richness and evenness were reduced by L. camara, indicating a significant alteration in composition and structure of native communities. Seedling growth of the test species was reduced in L. camara rhizosphere- and litter-amended soil. The inhibitory effect was ameliorated by the addition of activated charcoal, indicating the presence of organic inhibitors (quantified as phenolics) in the soil. Lantana invasion greatly reduces the density and diversity of the vegetation in the invaded area, and chemical interference of its litter plays an important role in invasion. PMID- 24477615 TI - Spatial and seasonal characteristics of river water chemistry in the Taizi River in Northeast China. AB - Anthropogenic activities have led to water quality deterioration in many parts of the world, especially in Northeast China. The current work investigated the spatiotemporal variations of water quality in the Taizi River by multivariate statistical analysis of data from the 67 sampling sites in the mainstream and major tributaries of the river during dry and rainy seasons. One-way analysis of variance indicated that the 20 measured variables (except pH, 5-day biological oxygen demand, permanganate index, and chloride, orthophosphate, and total phosphorus concentrations) showed significant seasonal (p <= 0.05) and spatial (p < 0.05) variations among the mainstream and major tributaries of the river. Hierarchical cluster analysis of data from the different seasons classified the mainstream and tributaries of the river into three clusters, namely, less, moderately, and highly polluted clusters. Factor analysis extracted five factors from data in the different seasons, which accounted for the high percentage of the total variance and reflected the integrated characteristics of water chemistry, organic pollution, phosphorous pollution, denitrification effect, and nitrogen pollution. The results indicate that river pollution in Northeast China was mainly from natural and/or anthropogenic sources, e.g., rainfall, domestic wastewater, agricultural runoff, and industrial discharge. PMID- 24477616 TI - Selective evidence of eutrophication in the Great Barrier Reef: comment on Bell et al. (2014). PMID- 24477617 TI - Maritime transport in the Gulf of Bothnia 2030. AB - Scenarios for shipping traffic in the Gulf of Bothnia (GoB) by 2030 are described in order to identify the main factors that should be taken into account when preparing a Maritime Spatial Plan (MSP) for the area. The application of future research methodology to planning of marine areas was also assessed. The methods include applying existing large scale quantitative scenarios for maritime traffic in the GoB and using real-time Delphi in which an expert group discussed different factors contributing to future maritime traffic in the GoB to find out the probability and significance of the factors having an impact on maritime traffic. MSP was tested on transnational scale in the Bothnian sea area as a pilot project. PMID- 24477618 TI - alpha-Lipoic acid and superoxide dismutase in the management of chronic neck pain: a prospective randomized study. AB - BACKGROUND AND OBJECTIVE: Since oxidative stress plays a pathogenetic role in chronic neck pain (CNP), we investigated whether a combination of alpha-lipoic acid (ALA) and superoxide dismutase (SOD) might improve pain control and the efficacy of physiotherapy ("multimodal therapy") in patients with CNP. SETTING: This study was conducted in the Rehabilitation Unit of the Department of Surgical and Oncological Sciences at the University Policlinic in Palermo, Italy. DESIGN AND PATIENTS: This was a prospective, randomized, open study in outpatients. INTERVENTION: Patients randomly received either physiotherapy alone (group 2; n = 45) or a combination of ALA 600 mg and SOD 140 IU daily in addition to physiotherapy (group 1; n = 51), for 60 days. Pain was assessed by a visual analogue scale (VAS) and a modified Neck Pain Questionnaire (mNPQ). Treatment compliance and safety were also evaluated. RESULTS: Both groups experienced a significant reduction in the VAS and mNPQ scores after 1 month; however, while no further improvement was observed in group 2 at 60 days, group 1 showed a further VAS reduction (p < 0.001). In addition, in the mNPQ at 60 days, more patients in group 1 than in group 2 reported that their neck pain was improved (p < 0.01), and they showed greater compliance with prescribed physiotherapy (p = 0.048). No drug reaction was observed. CONCLUSION: Use of ALA/SOD in combination with physiotherapy may be a useful approach to CNP, being antioxidants that act on nerve inflammation and disease progression. CLINICAL REHABILITATION IMPACT: These preliminary observations suggest that some interesting goals (better pain control and physical wellbeing) can be achieved by multimodal therapy in CNP patients. PMID- 24477619 TI - Stimulus-specific adaptation and deviance detection in the auditory system: experiments and models. AB - Stimulus-specific adaptation (SSA) is the reduction in the response to a common stimulus that does not generalize, or only partially generalizes, to other, rare stimuli. SSA has been proposed to be a correlate of 'deviance detection', an important computational task of sensory systems. SSA is ubiquitous in the auditory system: It is found both in cortex and in subcortical stations, and it has been demonstrated in many mammalian species as well as in birds. A number of models have been suggested in the literature to account for SSA in the auditory domain. In this review, the experimental literature is critically examined in relationship to these models. While current models can all account for auditory SSA to some degree, none is fully compatible with the available findings. PMID- 24477620 TI - PRMT5 is required for human embryonic stem cell proliferation but not pluripotency. AB - Human pluripotent stem cells (PSCs) are critical in vitro tools for understanding mechanisms that regulate lineage differentiation in the human embryo as well as a potentially unlimited supply of stem cells for regenerative medicine. Pluripotent human and mouse embryonic stem cells (ESCs) derived from the inner cell mass of blastocysts share a similar transcription factor network to maintain pluripotency and self-renewal, yet there are considerable molecular differences reflecting the diverse environments in which mouse and human ESCs are derived. In the current study we evaluated the role of Protein arginine methyltransferase 5 (PRMT5) in human ESC (hESC) self-renewal and pluripotency given its critical role in safeguarding mouse ESC pluripotency. Unlike the mouse, we discovered that PRMT5 has no role in hESC pluripotency. Using microarray analysis we discovered that a significant depletion in PRMT5 RNA and protein from hESCs changed the expression of only 78 genes, with the majority being repressed. Functionally, we discovered that depletion of PRMT5 had no effect on expression of OCT4, NANOG or SOX2, and did not prevent teratoma formation. Instead, we show that PRMT5 functions in hESCs to regulate proliferation in the self-renewing state by regulating the fraction of cells in Gap 1 (G1) of the cell cycle and increasing expression of the G1 cell cycle inhibitor P57. Taken together our data unveils a distinct role for PRMT5 in hESCs and identifies P57 as new target. PMID- 24477621 TI - Personal health records as portal to the electronic medical record. AB - This topic review discusses the evolving clinical challenges associated with the implementation of electronic personal health records (PHR) that are fully integrated with electronic medical records (EMR). The benefits of facilitating patient access to the EMR through web-based, PHR-portals may be substantial; foremost is the potential to enhance the flow of information between patient and healthcare practitioner. The benefits of improved communication and transparency of care are presumed to be a reduction in clinical errors, increased quality of care, better patient-management of disease, and better disease and symptom comprehension. Yet PHR databases allow patients open access to newly-acquired clinical data without the benefit of concurrent expert clinical interpretation, and therefore may create the potential for greater patient distress and uncertainty. With specific attention to neuro-oncology patients, this review focuses on the developing conflicts and consequences associated with the use of a PHR that parallels data acquisition of the EMR in real-time. We conclude with a discussion of recommendations for implementing fully-integrated PHR for neuro oncology patients. PMID- 24477622 TI - Prognostic significance of telomere maintenance mechanisms in pediatric high grade gliomas. AB - Children with high-grade glioma, including diffuse intrinsic pontine glioma (DIPG), have a poor prognosis despite multimodal therapy. Identifying novel therapeutic targets is critical to improve their outcome. We evaluated prognostic roles of telomere maintenance mechanisms in children with HGG, including DIPG. A multi-institutional retrospective study was conducted involving 50 flash-frozen HGG (35 non-brainstem; 15 DIPG) tumors from 45 children (30 non-brainstem; 15 DIPG). Telomerase activity, expression of hTERT mRNA (encoding telomerase catalytic component) and TERC (telomerase RNA template) and alternative lengthening of telomeres (ALT) mechanism were assayed. Cox Proportional Hazard regression analyses assessed association of clinical and pathological variables, TERC and hTERT levels, telomerase activity, and ALT use with progression-free or overall survival (OS). High TERC and hTERT expression was detected in 13/28 non brainstem HGG samples as compared to non-neoplastic controls. High TERC and hTERT expression was identified in 13/15 and 11/15 DIPG samples, respectively, compared to controls. Evidence of ALT was noted in 3/11 DIPG and 10/19 non-brainstem HGG specimens. ALT and telomerase use were identified in 4/19 non-brainstem HGG and 2/11 DIPG specimens. In multivariable analyses, increased TERC and hTERT levels were associated with worse OS in patients with non-brainstem HGG, after controlling for tumor grade or resection extent. Children with HGG and DIPG, have increased hTERT and TERC expression. In children with non-brainstem HGG, increased TERC and hTERT expression levels are associated with a worse OS, making telomerase a promising potential therapeutic target in pediatric HGG. PMID- 24477624 TI - Lumbar spine neuroarthropathy (Charcot joint) caused by a myxopapillary ependymoma. PMID- 24477623 TI - Role of Akt in human malignant glioma: from oncogenesis to tumor aggressiveness. AB - Gathering evidence has revealed that Akt signaling pathway plays an important role in glioma progression and aggressiveness. Among Akt kinases the most studied, Akt1, has been involved in many cellular processes that are in favor of cell malignancy. More recently, the actions of the two other isoforms, Akt2 and Akt3 have emerged in glioma. After a description of Akt pathway activation, we will explore the role of each isoform in malignant glioma that strengthens the current preclinical and clinical studies evaluating the impact of Akt pathway targeting in glioblastomas. PMID- 24477626 TI - Efficacy of the rePON1 mutant IIG1 to prevent cyclosarin toxicity in vivo and to detoxify structurally different nerve agents in vitro. AB - The potent human toxicity of organophosphorus (OP) nerve agents calls for the development of effective antidotes. Standard treatment for nerve agent poisoning with atropine and an oxime has a limited efficacy. An alternative approach is the development of catalytic bioscavengers using OP-hydrolyzing enzymes such as paraoxonases (PON1). Recently, a chimeric PON1 mutant, IIG1, was engineered toward the hydrolysis of the toxic isomers of soman and cyclosarin with high in vitro catalytic efficiency. In order to investigate the suitability of IIG1 as a catalytic bioscavenger, an in vivo guinea pig model was established to determine the protective effect of IIG1 against the highly toxic nerve agent cyclosarin. Prophylactic i.v. injection of IIG1 (1 mg/kg) prevented systemic toxicity in cyclosarin (~2LD50)-poisoned guinea pigs, preserved brain acetylcholinesterase (AChE) activity, and protected erythrocyte AChE activity partially. A lower IIG1 dose (0.2 mg/kg) already prevented mortality and reduced systemic toxicity. IIG1 exhibited a high catalytic efficiency with a homologous series of alkylmethylfluorophosphonates but had low efficiency with the phosphoramidate tabun and was virtually ineffective with the nerve agent VX. This quantitative analysis validated the model for predicting in vivo protection by catalytic bioscavengers based on their catalytic efficiency, the level of circulating enzyme, and the dose of the intoxicating nerve agent. The in vitro and in vivo results indicate that IIG1 may be considered as a promising candidate bioscavenger to protect against the toxic effects of a range of highly toxic nerve agents. PMID- 24477627 TI - A new method for muscle fatigue assessment: Online model identification techniques. AB - INTRODUCTION: The purpose of this study was to propose a method that allows extraction of the current muscle state under electrically induced fatigue. METHODS: The triceps surae muscle of 5 subjects paralyzed by spinal cord injury was fatigued by intermittent electrical stimulation (5 * 5 trains at 30 Hz). Classical fatigue indices representing muscle contractile properties [peak twitch (Pt) and half-relaxation time (HRT)] were assessed before and after each 5-train series and were used to identify 2 relevant parameters (Fm , Ur ) of a previously developed mathematical model using the Sigma-Point Kalman Filter. RESULTS: Pt declined significantly during the protocol, whereas HRT remained unchanged. Identification of the model parameters with experimental data yielded a model based fatigue assessment that gave a more stable evaluation of fatigue than classical parameters. CONCLUSIONS: This work reinforces clinical research by providing a tool that clinicians can use to monitor fatigue development during stimulation. PMID- 24477628 TI - Patient's values and preferences for stroke prevention in atrial fibrillation: balancing stroke and bleeding risk with oral anticoagulation. PMID- 24477625 TI - Talin and kindlin: the one-two punch in integrin activation. AB - Abstract Proper cell-cell and cell-matrix contacts mediated by integrin adhesion receptors are important for development, immune response, hemostasis and wound healing. Integrins pass trans-membrane signals bidirectionally through their regulated affinities for extracellular ligands and intracellular signaling molecules. Such bidirectional signaling by integrins is enabled by the conformational changes that are often linked among extracellular, transmembrane and cytoplasmic domains. Here, we review how talin-integrin and kindlin-integrin interactions, in cooperation with talin-lipid and kindlin-lipid interactions, regulate integrin affinities and how the progress in these areas helps us understand integrin-related diseases. PMID- 24477629 TI - Gastritis staging: interobserver agreement by applying OLGA and OLGIM systems. AB - Atrophic gastritis remains a difficult histopathological diagnosis with low interobserver agreement. The aim of our study was to compare gastritis staging and interobserver agreement between general and expert gastrointestinal (GI) pathologists using Operative Link for Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM). We enrolled 835 patients undergoing upper endoscopy in the study. Two general and two expert gastrointestinal pathologists graded biopsy specimens according to the Sydney classification, and the stage of gastritis was assessed by OLGA and OLGIM system. Using OLGA, 280 (33.4 %) patients had gastritis (stage I-IV), whereas with OLGIM this was 167 (19.9 %). OLGA stage III- IV gastritis was observed in 25 patients, whereas by OLGIM stage III-IV was found in 23 patients. Interobserver agreement between expert GI pathologists for atrophy in the antrum, incisura angularis, and corpus was moderate (kappa = 0.53, 0.57 and 0.41, respectively, p < 0.0001), but almost perfect for intestinal metaplasia (kappa = 0.82, 0.80 and 0.81, respectively, p < 0.0001). However, interobserver agreement between general pathologists was poor for atrophy, but moderate for intestinal metaplasia. OLGIM staging provided the highest interobserver agreement, but a substantial proportion of potentially high-risk individuals would be missed if only OLGIM staging is applied. Therefore, we recommend to use a combination of OLGA and OLGIM for staging of chronic gastritis. PMID- 24477630 TI - Combination contraceptives: effects on weight. AB - BACKGROUND: Weight gain is often considered a side effect of combination hormonal contraceptives, and many women and clinicians believe that an association exists. Concern about weight gain can limit the use of this highly effective method of contraception by deterring the initiation of its use and causing early discontinuation among users. However, a causal relationship between combination contraceptives and weight gain has not been established. OBJECTIVES: The aim of the review was to evaluate the potential association between combination contraceptive use and changes in weight. SEARCH METHODS: In November 2013, we searched the computerized databases CENTRAL (The Cochrane Library), MEDLINE, POPLINE, EMBASE, and LILACS for studies of combination contraceptives, as well as ClinicalTrials.gov and International Clinical Trials Registry Platform (ICTRP). For the initial review, we also wrote to known investigators and manufacturers to request information about other published or unpublished trials not discovered in our search. SELECTION CRITERIA: All English-language, randomized controlled trials were eligible if they had at least three treatment cycles and compared a combination contraceptive to a placebo or to a combination contraceptive that differed in drug, dosage, regimen, or study length. DATA COLLECTION AND ANALYSIS: All titles and abstracts located in the literature searches were assessed. Data were entered and analyzed with RevMan. A second author verified the data entered. For continuous data, we calculated the mean difference and 95% confidence interval (CI) for the mean change in weight between baseline and post-treatment measurements using a fixed-effect model. For categorical data, such as the proportion of women who gained or lost more than a specified amount of weight, the Peto odds ratio with 95% CI was calculated. MAIN RESULTS: We found 49 trials that met our inclusion criteria. The trials included 85 weight change comparisons for 52 distinct contraceptive pairs (or placebos). The four trials with a placebo or no intervention group did not find evidence supporting a causal association between combination oral contraceptives or a combination skin patch and weight change. Most comparisons of different combination contraceptives showed no substantial difference in weight. In addition, discontinuation of combination contraceptives because of weight change did not differ between groups where this was studied. AUTHORS' CONCLUSIONS: Available evidence was insufficient to determine the effect of combination contraceptives on weight, but no large effect was evident. Trials to evaluate the link between combination contraceptives and weight change require a placebo or non-hormonal group to control for other factors, including changes in weight over time. PMID- 24477631 TI - Alcohol and bone. AB - Alcohol is widely consumed across the world in different cultural and social settings. Types of alcohol consumption differ between (a) light, only occasional consumption, (b) heavy chronic alcohol consumption, and (c) binge drinking as seen as a new pattern of alcohol consumption among teenagers and young adults. Heavy alcohol consumption is detrimental to many organs and tissues, including bones. Osteoporosis is regularly mentioned as a secondary consequence of alcoholism, and chronic alcohol abuse is established as an independent risk factor for osteoporosis. The review will present the different mechanisms and effects of alcohol intake on bone mass, bone metabolism, and bone strength, including alcoholism-related "life-style factors" such as malnutrition, lack of exercise, and hormonal changes as additional causative factors, which also contribute to the development of osteoporosis due to alcohol abuse. PMID- 24477632 TI - [Lung transplantation]. AB - Lung transplantation is a therapeutic option for patients with end-stage lung diseases. Selection of candidates requires careful consideration of the disease specific indications and contraindications for transplantation. Advances have been made in candidate selection via the ability to prognosticate outcomes of various lung diseases and through the implementation of the lung allocation score (LAS) with specific consideration of the degree of urgency and good postoperative survival rate, after neglecting the waiting time. This system has resulted in decreased mortality on the waiting list for lung transplantation. The availability of donor organs can possibly be increased by implementation of ex vivo lung perfusion as an alternative to conventional organ preservation. Risk factors for poor outcomes post-lung transplantation have been identified and understanding of the physiological, cellular and molecular mechanisms responsible for lung and airway damage has been extensively expanded. Primary graft dysfunction, infectious diseases, acute rejection, antibody-mediated rejection, lymphocytic bronchiolitis, obliterative bronchiolitis, restrictive allograft syndrome, and chronic lung allograft dysfunction are well defined complications and continue to be common causes of morbidity and mortality. This article provides a comprehensive update on these topics for the non-transplantation clinician. PMID- 24477633 TI - [Differential therapy in coronary heart disease]. AB - The various contemporary therapeutic options for coronary artery disease (CAD) require differentiated, individualized treatment strategies. The foundations of CAD therapy are lifestyle modifications targeted on the individual risk profile of the patients. Pharmacological therapy of CAD should prevent secondary coronary events (e.g. platelet aggregation inhibitors and statins) and reduce angina in symptomatic patients (e.g. short-acting nitrates, beta blockers, calcium channel blockers and if necessary ivabradine and ranolazine). Revascularization therapy has to be performed promptly in patients with acute coronary syndromes; however, in patients with stable CAD the decision to perform revascularization therapy has to consider symptoms, detection of ischemia and if appropriate intracoronary assessment of hemodynamic relevance of an intermediate stenosis (fractional flow reserve). The differential indications of percutaneous coronary intervention compared to coronary artery bypass grafting depend on the severity of coronary artery disease and the morphology (SYNTAX score), comorbidities and the will of the individual patient. The international guidelines emphasize the value of an interdisciplinary treatment decision in a "heart team". In summary, differential therapy of CAD has become challenging in the current clinical practice; future developments will probably further improve individualized strategies to treat patients with CAD. PMID- 24477636 TI - The strength and directionality of a halogen bond are co-determined by the magnitude and size of the sigma-hole. AB - The sigma-holes of halogen atoms on various aromatic scaffolds were described in terms of their size and magnitude. The electrostatic potential maps at the CAM B3LYP-D3(bj)/def2-QZVP level were calculated and the sigma-holes of more than 100 aromatic analogues were thoroughly analysed to relate the sigma-holes to the binding preferences of the halogenated compounds. Both the size and magnitude of the sigma-hole increase when passing from chlorinated to iodinated analogues. Also, the sigma-hole properties were studied upon chemical substitution of the aromatic ring as well as in the aromatic ring. Further, the angular variations of the interactions were investigated on a selected set of halogenbenzene complexes with argon and hydrogen fluoride (HF). In order to analyse interaction energy components, DFT-SAPT angular scans were performed. The interaction energies of bromobenzene complexes were evaluated at the CCSD(T)/complete basis set level providing the benchmark energetic data. The strength of the halogen bond between halogenbenzenes and Ar atoms and HF molecules increases while its directionality decreases when passing from chlorine to iodine. The decrease of the directionality of the halogen bond is larger for a HF-containing complex and is caused by electrostatic and exchange-repulsion energies. These findings are especially valuable for protein-halogenated ligand-binding studies, applied in the realm of rational drug development and lead optimisation. PMID- 24477634 TI - [Sleep-related breathing disorders and (resulting) cardiovascular diseases]. AB - Sleep-related breathing disorders occur in cardiology patients mostly as obstructive or central sleep apnea with Cheyne-Stokes respiration. The prevalence and incidence are clearly increased in comparison to the general population. Depending on the underlying cardiac disease up to 75% of patients can have obstructive or central sleep apnea and up to 50% have indications for therapy according to the current guidelines. Obstructive sleep apnea is considered to be an independent and well treatable risk factor for the development and deterioration of many cardiovascular diseases. This review briefly describes examples of prevalence, pathophysiology and current study situation with respect to the association between sleep-related breathing disorders and arterial hypertension, atrial fibrillation, arteriosclerosis with coronary heart disease, myocardial infarction and heart failure. Although the role of obstructive sleep apnea as a risk factor for the development of these diseases is well documented, central sleep apnea is less of a risk factor per se but is considered to mirror an underlying cardiac disease with then further negative consequences for this disease. It is not the sleep apnea per se but the subsequent cardiovascular diseases which limit the prognosis of these patients and therefore bring them into the focus of cardiology. Obstructive and central sleep apnea can be successfully and sustainably treated by various forms of nocturnal positive airway pressure therapy. Furthermore, there are several therapeutic procedures which are currently being tested and the significance will be investigated in the coming years. PMID- 24477637 TI - Dynamic optimization of chemotherapy outpatient scheduling with uncertainty. AB - Chemotherapy outpatient scheduling is a complex, dynamic, uncertain problem. Chemotherapy centres are facing increasing demands and they need to increase their efficiency; however there are very few studies looking at using optimization technology on the chemotherapy scheduling problem. We address dynamic uncertainty that arises from requests for appointments that arrive in real time and uncertainty due to last minute scheduling changes. We propose dynamic template scheduling, a novel technique that combines proactive and online optimization and we apply it to the chemotherapy outpatient scheduling problem. We create a proactive template of an expected day in the chemotherapy centre using a deterministic optimization model and a sample of appointments. As requests for appointments arrive, we use the template to schedule them. When a request arrives that does not fit the template, we update the template online using the optimization model and a revised set of appointments. To accommodate last minute additions and cancellations to the schedule, we propose a shuffling algorithm that moves appointment start times within a predefined time limit. We test the use of dynamic template scheduling against the optimal offline solution and the actual performance of the cancer centre. We find improvements in makespan of up to 20 % when using dynamic template scheduling compared to current practice. PMID- 24477638 TI - Intraoperative adverse events during laparoscopic colorectal resection--better laparoscopic treatment but unchanged incidence. Lessons learnt from a Swiss multi institutional analysis of 3,928 patients. AB - PURPOSE: Intraoperative adverse events significantly influence morbidity and mortality of laparoscopic colorectal resections. Over an 11-year period, the changes of occurrence of such intraoperative adverse events were assessed in this study. METHODS: Analysis of 3,928 patients undergoing elective laparoscopic colorectal resection based on the prospective database of the Swiss Association of Laparoscopic and Thoracoscopic Surgery was performed. RESULTS: Overall, 377 intraoperative adverse events occurred in 329 patients (overall incidence of 8.4 %). Of 377 events, 163 (43 %) were surgical complications and 214 (57 %) were nonsurgical adverse events. Surgical complications were iatrogenic injury to solid organs (n = 63; incidence of 1.6 %), bleeding (n = 62; 1.6 %), lesion by puncture (n = 25; 0.6 %), and intraoperative anastomotic leakage (n = 13; 0.3 %). Of note, 11 % of intraoperative organ/puncture lesions requiring re-intervention were missed intraoperatively. Nonsurgical adverse events were problems with equipment (n = 127; 3.2 %), anesthetic problems (n = 30; 0.8 %), and various (n = 57; 1.5 %). Over time, the rate of intraoperative adverse events decreased, but not significantly. Bleeding complications significantly decreased (p = 0.015), and equipment problems increased (p = 0.036). However, the rate of adverse events requiring conversion significantly decreased with time (p < 0.001). Patients with an intraoperative adverse event had a significantly higher rate of postoperative local and general morbidity (41.2 and 32.9 % vs. 18.0 and 17.2 %, p < 0.001 and p < 0.001, respectively). CONCLUSIONS: Intraoperative surgical complications and adverse events in laparoscopic colorectal resections did not change significantly over time and are associated with an increased postoperative morbidity. PMID- 24477639 TI - Letter to the editor: 'Local tissue ischemia is not necessary for suture-induced adhesion formation' by Dr. Rajab. PMID- 24477640 TI - Long-term in vitro culture of grape berries and its application to assess the effects of sugar supply on anthocyanin accumulation. AB - Grape berry development and ripening are under complex regulation by the nutrients, hormones, and environment cues sensed by the berry. However, the biochemical and molecular mechanisms underlying these types of regulation are poorly understood. A simplified but realistic model system that enables fruit growth conditions to be modulated easily will facilitate the deciphering of these mechanisms. Here, an in vitro culture system of intact detached grape berries was developed by coupling the production of greenhouse fruiting-cuttings and in vitro organ culture techniques. (13)C and (15)N labelling experiments showed that this system enables the intact detached berries actively to absorb and utilize carbon and nitrogen from the culture medium. It was further used to study the effects of sugars on anthocyanin accumulation. A sucrose concentration >2% could induce anthocyanin synthesis in the absence of additional exogenous abscisic acid. The higher the sucrose concentration, the earlier was the induction of anthocyanin accumulation. Glucose, fructose, and sucrose increased anthocyanin accumulation, with glucose and fructose being more effective than sucrose. This increase was not due to an increase in its precursor level, since the phenylalanine content was decreased by a high sugar supply. Instead, genome-wide transcriptome analysis suggests that the sugar-induced enhancement of anthocyanin accumulation results from altered expression of regulatory and structural genes (especially UDP glucose:anthocyanidin 3-O-glucosyltransferase), together with massive reprogramming in signalling transduction pathways. This in vitro system may serve to study the response of berry composition to nutrient factors and hormones, and their interaction with environmental factors (e.g. light and temperature), which can all be finely tuned and controlled. PMID- 24477641 TI - Phosphorylation-regulated degradation of the tumor-suppressor form of PED by chaperone-mediated autophagy in lung cancer cells. AB - PED/PEA-15 is a death effector domain (DED) family member with a variety of effects on cell growth and metabolism. To get further insight into the role of PED in cancer, we aimed to find new PED interactors. Using tandem affinity purification, we identified HSC70 (Heat Shock Cognate Protein of 70 kDa)-which, among other processes, is involved in chaperone-mediated autophagy (CMA)-as a PED interacting protein. We found that PED has two CMA-like motifs (i.e., KFERQ), one of which is located within a phosphorylation site, and demonstrate that PED is a bona fide CMA substrate and the first example in which phosphorylation modifies the ability of HSC70 to access KFERQ-like motifs and target the protein for lysosomal degradation. Phosphorylation of PED switches its function from tumor suppression to tumor promotion, and we show that HSC70 preferentially targets the unphosphorylated form of PED to CMA. Therefore, we propose that the up-regulated CMA activity characteristic of most types of cancer cell enhances oncogenesis by shifting the balance of PED function toward tumor promotion. This mechanism is consistent with the notion of a therapeutic potential for targeting CMA in cancer, as inhibition of this autophagic pathway may help restore a physiological ratio of PED forms. PMID- 24477643 TI - Inhibitors of suppressive histone modification promote direct reprogramming of fibroblasts to cardiomyocyte-like cells. PMID- 24477644 TI - Patient safety and quality in healthcare: nursing ethics for ethics quality. PMID- 24477642 TI - Signalling between microvascular endothelium and cardiomyocytes through neuregulin. AB - Heterocellular communication in the heart is an important mechanism for matching circulatory demands with cardiac structure and function, and neuregulins (Nrgs) play an important role in transducing this signal between the hearts' vasculature and musculature. Here, we review the current knowledge regarding Nrgs, explaining their roles in transducing signals between the heart's microvasculature and cardiomyocytes. We highlight intriguing areas being investigated for developing new, Nrg-mediated strategies to heal the heart in acquired and congenital heart diseases, and note avenues for future research. PMID- 24477647 TI - A clinical study of metastasized rectal cancer treatment: assessing a multimodal approach. AB - Metastasized rectal cancer has long been considered incurable. During recent years, the treatment of rectal cancer patients has been improved, and nowadays, a subgroup of patients might even be cured. The aim of this study was to investigate the optimal timing of treatment in a multimodal therapy schedule in order to see whether the addition of bevacizumab (Avastin) to conventional chemotherapy was effective. The study included 39 patients with metastatic rectal cancer between 2009 and 2011, and three were excluded due to the lack of metastases or lack of follow-up information. The remaining 36 patients were divided into groups by treatment intention. The group with curative intention received mainly oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) with or without bevacizumab (Avastin) for 2 months followed by preoperative radiotherapy (RT) and surgery. Palliative patients had very different treatments depending on their needs of palliation. The median survival time for patients with curative intention was 31 months and for the palliative patients 12 months. Four of the patients (11%) with curative intention were considered cured at the end of follow-up. The response to chemotherapy after 2-month treatment is a good prognostic sign for which patients can be cured. Long-lasting palliation can be obtained with this treatment schedule. The main side effects were gastrointestinal events, including bowel perforation, neuropathy, thrombo-embolic disease and reduced general condition. All side effects are known, and the treatment is considered tolerable. We conclude that a good treatment schedule would be oxaliplatin (Eloxatin) in combination with capecitabine (Xeloda) with or without bevacizumab (Avastin) for 2 months, followed by preoperative RT and surgery. PMID- 24477648 TI - Prognostic significance of serum albumin in patients with metastatic renal cell carcinoma. AB - Systemic inflammation has been suggested to impact on the prognosis of metastatic renal cell carcinoma (mRCC). We undertook a retrospective analysis of patients with mRCC treated at Akademiska University Hospital in Sweden during the years 2005-2012 to assess the possible prognostic significance of inflammation-related factors including serum albumin, platelet count, weight loss and C-reactive protein (CRP). The Memorial Sloan-Kettering Cancer Center (MSKCC) criteria for prognosis of mRCC and ECOG performance status were assessed for all patients. Overall survival (OS) and progression-free survival (PFS) were calculated according to Kaplan-Meier, and Cox proportional hazards regression was used for uni- and multivariate analyses. The median OS of all patients (n=84) was 20 months. Univariate analysis identified low serum albumin (HR=4.17, p<0.001), elevated platelet count (HR=2.98, p<0.001) and patient-reported weight loss prior to diagnosis of mRCC (HR=2.73, p<0.001), in addition to MSKCC (HR=3.35, p=0.0088) to be associated with shorter OS. CRP did not significantly affect OS. Serum albumin retained prognostic significance for OS in multivariate analysis (HR=2.72, p=0.015). In patients treated with an angiogenesis-targeted agent (n=47), low serum albumin level (HR=4.63, p<0.001) and elevated platelet count (HR=2.11, p=0.022) were associated with shorter PFS. In contrast, CRP, weight loss and MSKCC risk group did not significantly affect PFS. In multivariate analysis serum albumin remained associated with PFS (HR=3.92, p=0.0035). Our findings identify serum albumin as an independent prognostic factor for patients with mRCC treated with angiogenesis-targeted therapy. PMID- 24477649 TI - The neutrophil-to-lymphocyte ratio as a predictor for recurrence of colorectal liver metastases following radiofrequency ablation. AB - The purpose of this study was to assess the value of the neutrophil-to-lymphocyte ratio (NLR) as a predictive factor for recurrence of colorectal liver metastases following radiofrequency ablation (RFA) treatment. We retrospectively analyzed clinical data from 98 patients who received routine RFA treatment for colorectal liver metastases. Univariate analyses were conducted to evaluate the effects of preoperative maximum tumor diameter, number of tumors, colon cancer staging, carcinoembryonic antigen levels, and preoperative and postoperative NLRs on disease-free survival (DFS). Statistically significant factors were further analyzed using multivariate Cox regression models to identify independent factors that were predictive of tumor recurrence. The one-, three-, and five-year DFS rates for patient were 66.3, 28.6, and 17.3%, respectively. Univariate analysis showed that preoperative NLR>=2.5 and postoperative increase in NLR were associated with decreased DFS rates. One-, three-, and five-year DFS rates for patients with preoperative NLR>=2.5 were 53.3, 20.0, and 11.1%, whereas patients with preoperative NLR<2.5 had DFS rates of 77.4, 35.8, and 22.6%, respectively (P=0.044). One-, three- and five-year DFS rates for patients with NLRs increased 1 month after RFA treatment were 52.3, 17.1, and 8.6%, while patients with no increased postoperative NLRs had DFS rates of 73.0, 34.9, and 22.2%, respectively (P=0.022). Cox regression analysis showed that postoperative NLR increase was an independent risk factor (P=0.029) for recurrence after RFA treatment in patients with colorectal liver metastases. The present study suggests that patients with preoperative NLRs>=2.5 or increased postoperative NLR are at an increased risk for recurrence after RFA treatment for colorectal liver metastases. PMID- 24477650 TI - Interstitial pneumonia during bevacizumab-based chemotherapy for colorectal cancer. AB - Bevacizumab is a widely used agent for treatment for colorectal cancer. Though it relates to several adverse events, a few cases have been reported of drug-induced interstitial lung damage in bevacizumab-based chemotherapy for advanced colorectal cancer. In this study, we retrospectively reviewed a consecutive series of 72 patients with advanced colorectal cancer who received bevacizumab based chemotherapy and identified five cases (6.9%) who developed interstitial pneumonia (IP). The median age was 68 years, all five were male, and four of five patients were smokers. Three cases were asymptomatic, and they immediately recovered by withdrawal of chemotherapeutic drugs. On the other hand, two severe cases were required high-dose infusion of corticosteroid. It is suggested that early diagnosis of IP contributes to prevent exacerbation of the event and results in better outcomes. IP may have been associated with systemic chemotherapy, suggesting that a caution should be raised for pulmonary damage by bevacizumab-based chemotherapy. PMID- 24477651 TI - Prostate-specific membrane antigen as a marker of pancreatic cancer cells. AB - The aim of this study was to identify the expression of prostate-specific membrane antigen (PSMA) and analyze the correlation between PSMA with clinical characteristics in patients with pancreatic cancer. The expression of PSMA protein and mRNA was detected by immunohistochemistry and real-time quantitative polymerase chain reaction in pancreatic cancer tissues, pancreatic intraepithelial neoplasia or normal pancreatic tissues, respectively. And clinical characteristics and prognosis of patients were investigated. PSMA was expressed in pancreatic cancer cells, both in protein and mRNA levels. Moreover, the PSMA levels were associated with the prognosis of patients with pancreatic ductal adenocarcinoma. The overall survival time of pancreatic cancer patients with high expression of PSMA was significantly shorter than that of the low ones. Moreover, the PSMA levels were correlated with clinicopathological features including the histological grade and pathological tumor-node-metastasis stage. PSMA is involved in the carcinogenesis of pancreatic cancer, and it might serve as a potential therapeutic target for pancreatic cancer. PMID- 24477652 TI - Association between gastric cardia adenocarcinoma risk and alcohol flushing response, but not alcohol consumption. AB - The relationship between the development of gastric cardia cancer (GCA) and alcohol consumption remains unclear. Alcohol flushing response reflects an accumulation of the carcinogenic acetaldehyde and has been proved to be a risk factor for many cancers. The main objective of the present study was to assess the impact of alcohol flushing response on GCA risk in a Chinese population in conjunction with lifetime alcohol consumption. The study subjects consist of 281 male patients [130 with GCA and 151 with esophageal squamous cell carcinoma (ESCC)] and 160 non-cancer male controls, matched with respect to age. Conditional logistic regression was used to calculate odds ratios (ORs) and 95% confidence intervals (95% CI). There is no significant association between GCA risk and alcohol consumption. However, the adjusted ORs for flushing response of GCA and ESCC was 2.03 (95% CI 1.15-3.56, p=0.014) and 2.32 (95% CI 1.34-4.03, p=0.003), respectively, compared with those reporting no flushing response. Furthermore, compared with non-drinkers, the heavy drinkers and moderate drinkers with current/former flushing response experienced significant GCA risk (heavy drinkers: OR 2.59, 95% CI 1.06-6.31, p=0.037; moderate drinkers: OR 3.11, 95% CI 1.17-8.26, p=0.023), while drinkers without flushing response did not have increased risk. The drinkers with flushing response also had a higher ESCC risk than those without flushing response. In conclusion, alcohol flushing response is a clinically useful biomarker of susceptibility to GCA and ESCC risk from alcohol. PMID- 24477654 TI - Synergistically enhanced activity of graphene quantum dot/multi-walled carbon nanotube composites as metal-free catalysts for oxygen reduction reaction. AB - Graphene quantum dots (GQDs), as metal-free carbon nanomaterials, have potential applications in electrochemical fields due to their strong chemical inertness, oxygen-rich functional groups and remarkable quantum confinement and edge effects. Herein, we demonstrate that a novel metal-free electrode composed of GQDs and multi-walled carbon nanotubes (MWCNTs) exhibits a significant synergistic effect on enhanced catalytic activity for oxygen reduction reaction (ORR). Compared to commercially available Pt/C catalysts, enhanced electrocatalytic activity, improved long-term stability and excellent resistance to crossover effect were observed for the novel composite electrode. Interestingly, the amount of GQDs introduced is found to have an apparent effect on the positions of the reduction peaks of the electrodes. PMID- 24477653 TI - miR-200b as a prognostic factor targets multiple members of RAB family in glioma. AB - miR-200b is a tumor suppressor in multiple tumors including gastric cancer, breast cancer, ovarian cancer and glioma. In this study, we detected the expression of miR-200b and analyzed its correlation with clinicopathological parameters in glioma tissues. miR-200b was downregulated in glioma tissues. And its downexpression was correlated with poor prognosis in gliomas. Members of RAB family, RAB21, RAB23, RAB18 and RAB3B were predicted to be novel targets of miR 200b. The direct suppression of RAB21, RAB23, RAB18 and RAB3B expressions by miR 200b was revealed by luciferase reporter assay, quantitative RT-PCR analysis and Western blot. Furthermore, the overall survival of patients with different expression of RABs was analyzed. The expression of RAB21, RAB23, RAB18 and RAB3B was related to the prognosis and histopathology of glioma. The patients who had the upregulation of all the four RABs had the worst outcome; those who had the downregulation of all RABs had the best outcome (p<0.001). miR-200b was a potential biomarker for glioma prognosis. PMID- 24477655 TI - Integrating a palliative approach in a transcatheter heart valve program: bridging innovations in the management of severe aortic stenosis and best end-of life practice. AB - Severe aortic stenosis (AS) is the most prevalent structural heart disease and affects primarily older adults in their last decade of life. If the risk for surgery is high, transcatheter aortic valve implantation (TAVI) is the treatment of choice for many patients with suitable anatomy who are likely to derive significant benefit from this innovative and minimally invasive approach. In a large transcatheter heart valve (THV) centre that offers TAVI as one of the treatment options, of 565 consecutive referrals for the assessment of eligibility for TAVI over 18 months, 78 (14%) were deemed unsuitable candidates for TAVI or higher risk surgery by the interdisciplinary Heart Team because of their advanced disease, excessive frailty or comorbid burden. Concerns were raised for patients for whom TAVI is not an option. The integration of a palliative approach in a THV program offers opportunities to adopt best end-of-life practices while promoting innovative approaches for treatment. An integrated palliative approach to care focuses on meeting a patient's full range of physical, psychosocial and spiritual needs at all stages of a life-limiting illness, and is well suited for the severe AS and TAVI population. A series of interventions that reflect best practices and current evidence were adopted in collaboration with the Palliative Care Team and are currently under evaluation in a large TAVI centre. Changes include the introduction of a palliative approach in patient assessment and education, the measurement of symptoms, improved clarity about responsibility for communication and follow-up, and triggering referrals to palliative care services. PMID- 24477656 TI - Do inequalities in end of life care matter? PMID- 24477657 TI - MicroRNAs in neuroblastoma: small-sized players with a large impact. AB - Neuroblastoma, a malignant embryonal tumor of the sympathetic nervous system, is the most common solid extracranial malignancy of childhood and accounts for 15 % of all childhood cancer deaths. The biological behavior of neuroblastoma is extensively heterogeneous, ranging from spontaneous regression to rapid progression despite multimodal aggressive therapy. Although the molecular basis of neuroblastoma has received considerable attention over the past decade, elucidating the mechanisms for the aggressive progression of neuroblastoma is needed for improving the efficacy of treatment. miRNAs (microRNAs) are small non coding RNA molecules generally 19-22 nucleotides in length. miRNAs regulate 60 % of human gene expression at the post-transcriptional level by targeting regions of sequence complementarity on the 3'-untranslated regions (3'-UTRs) of specific mRNAs. miRNAs can either cause degradation of mRNAs or can inhibit their translation and therefore play major roles in normal growth and development. miRNA dysregulation has oncogenic or tumor-suppressive functions in virtually all forms of cancer, including neuroblastoma. The present review highlights the current insights on dysregulated miRNAs in neuroblastoma and on their roles in the diagnosis, prognosis, and treatment of this malignancy. As a rapidly evolving field of basic and biomedical sciences, miRNA research holds a great potential to impact on the management of neuroblastoma. PMID- 24477658 TI - Outcome of supportive talks in a hospital setting: insights from cancer patients and their relatives. AB - BACKGROUND: In psychosocial cancer rehabilitation, relatives are often central to patients' experiences and management of their cancer disease, and they need to be actively involved in rehabilitation. To address this need we developed a psychosocial rehabilitation intervention. As part of the intervention, lung or gynecological cancer patients and a relative as a pair were offered three supportive talks initiated on the date of admission and completed within 2 months. OBJECTIVE: The objective of this study was to qualitatively assess the outcome of supportive talks from the pairs' perspectives and to provide a nuanced understanding of psychosocial support offered to pairs in a hospital setting in Denmark. METHODS: Using a qualitative approach, we conducted semi-structured interviews with pairs receiving supportive talks and pairs receiving usual care. The interviews focused on the pairs' experiences of psychosocial supportive talks in a hospital setting. A constant comparative analysis was applied to identify themes related to the ways the pairs experienced the talks. RESULTS: The analysis revealed two main themes: 'appreciation of the supportive talks' and 'the influence of the hospital setting'. The majority of pairs valued the focus on relationship and interpersonal communication, although they appreciated various aspects of the talks. The hospital setting provided valuable resources (trained nurses and medical expertise), but existing clinical routines challenged the implementation of the supportive talks. CONCLUSIONS: The supportive talks were appreciated as psychosocial support in line with the objective, or as information on cancer treatment and routine care. The implementation of a new rehabilitation practice was challenged by the influence of the hospital setting. PMID- 24477659 TI - Actual insights into the clinical management of febrile seizures. AB - Febrile seizures (FS) are a benign epileptic manifestation of infancy occurring between 3 months and 5 years of age and affecting an estimated 2-5 % of children. They have usually no important negative effects on motor and cognitive development. Simple FS (generalized seizures, lasting less than 10 min and single episodes during the same febrile event) have a benign prognosis in almost all cases and do not require an extensive diagnostic workup. In complex FS (focal semiology and lasting more than 10 min, more than one episode during the same febrile event), a more detailed clinical, electroencephalographic, laboratory, and neuroimaging evaluation is necessary because of a higher percentage of underlying detectable causes and a mildly higher risk for later development of epilepsy. Febrile status epilepticus is the most severe type of complex FS even if its morbidity and mortality is extremely low. Simple FS plus (more than one convulsive episode in 24 h) have the same benign prognosis of simple FS. Neither intermittent nor continuous prophylaxis is actually recommended both in simple and complex FS because its side effects outweigh its possible benefits. CONCLUSION: This review summarizes recent developments into the clinical management of FS including a suggested algorithm for simple and complex FS, the concept of simple FS plus, the controversies about the relationships between FS and hippocampal sclerosis, the relationships between FS and complex syndrome such as Dravet syndrome, genetic epilepsy with FS plus or febrile infection-related epilepsy syndrome, and the results of recent epidemiologic studies on febrile status epilepticus. PMID- 24477661 TI - Immunohistochemical localization of Pax6 in the developing tooth germ of mice. AB - Recent studies have reported that supernumerary teeth were observed in the maxillary incisor area in several Pax6 homozygous mutant mouse and rat strains. To date, it remains unknown whether Pax6 is expressed during tooth development in any species. The study aimed to analyze the expression of Pax6 during mouse incisor and molar development. C57BL/6J mouse embryos on days E12.5, E13.5, E14.5, E16.5 and E18.5 were produced. Heads from these embryos, as well as from P1.5 mice, were processed for paraffin wax embedding (N >= 3 for each stage) and prepared for immunohistochemistry. Pax6 immunostaining was found in all tooth germs examined. At the E12.5 dental placode, E13.5 bud stage, E14.5 cap stage and E16.5 early bell stage, Pax6 was expressed in ectodermally derived tissues of tooth germs and oral epithelia adjacent to the tooth germs. Cells in the underlying dental ectomesenchyme that showed Pax9 expression were Pax6 negative. At E18.5 and P1.5, Pax6 was expressed in more differentiated ameloblasts and cells of the stratum intermedium and stellate reticulum that were derived from the oral epithelium, as well as in mesenchyme-derived differentiated odontoblasts. Pax6 expression was also observed in the submandibular gland, tongue filiform papilla and hair follicle at E16.5 and P1.5. The present study demonstrated that Pax6 was expressed in incisor and molar germs during mouse tooth development. The results provide a basis for exploring the function of Pax6 during tooth development. PMID- 24477663 TI - Effects of architecture on the stability of thermosensitive unimolecular micelles. AB - The influence of architecture on polymer interactions is investigated and differences between branched and linear copolymers are found. A comprehensive picture is drawn with the help of a fluorescence approach (using pyrene and 4HP as probe molecules) together with IR or NMR spectroscopy and X-ray/light scattering measurements. Five key aspects are addressed: (1) synergistic intramolecular complexation within miktoarm stars. The proximity of thermoresponsive poly(propylene oxide) (PPO) and poly(dimethylaminoethyl methacrylate) (PDMAEMA) within a miktoarm star leads to complexation between these weakly interacting partners. Consequently, the original properties of the constituents are lost, showing hydrophobic domains even at low temperatures, at which all homopolymers are water soluble. (2) Unimolecular micelles for miktoarm stars. The star does not exhibit intermolecular self-assembly in a large temperature range, showing unimers up to 55 degrees C. This behavior was traced back to a reduced interfacial tension between the PPO-PDMAEMA complex and water (PDMAEMA acts as a "microsurfactant"). (3) Unimolecular to multimolecular micelle transition for stars. The otherwise stable unimolecular micelles self-assemble above 55 degrees C. This aggregation is not driven by PPO segregation, but by collapse of residual PDMAEMA. This leads to micrometer-sized multilamellar vesicles stabilized by poly(ethylene oxide) (PEO). (4) Prevention of pronounced complexation within diblock copolymers. In contrast to the star copolymers, PPO and PDMAEMA adapt rather their homopolymer behavior within the diblock copolymers. Then they show their immanent LCST properties, as PDMAEMA turns insoluble at elevated temperatures, whereas PPO becomes hydrophobic below room temperature. (5) Two-step micellization for diblock copolymers. Upon heating of linear copolymers, the dehydration of PPO is followed by self-assembly into spherical micelles. An intermediate prevalence of unimolecular micelles is revealed in a small temperature window between PPO collapse and self-assembly of PEO-b-PPO. Also for PPO-b-PDMAEMA, PPO segregation prevails after initial weak complexation, leading to micelles with a PPO core. Considerable amounts of water are entrapped within the collapsed PDMAEMA domains above 55 degrees C (skin effect), preventing PPO-PDMAEMA complexation within precipitating PPO-b-PDMAEMA. Further, collapsed PDMAEMA is rather polar as sensed by pyrene and 4HP. In summary, advanced macromolecular architectures can lead to an unprecedented intramolecular self-assembly behavior, where internal complexation prevents intermolecular aggregation. PMID- 24477662 TI - Overexpression of leucine aminopeptidase 3 contributes to malignant development of human esophageal squamous cell carcinoma. AB - Leucine aminopeptidases (LAPs) were associated with tumor cell proliferation, invasion and/or angiogenesis. We aimed to examine the biological function of LAP3 in esophageal squamous cell carcinoma (ESCC). LAP3 expressions were examined in human ESCC tissue and cell lines ECA109 and TE1 cells. Recombinant pSilencer4.1 LAP3-shRNA was transfected into ECA109 cells to silence LAP3 expression. The effects of LAP3 silencing on ECA109 cell proliferation in vitro were evaluated. Flow cytometry profiling was used to detect the differentiate cell cycle distribution in LAP3-silenced ECA109 cells. Wound-healing assay and transwell assay were used to examine the activities of migration and invasion in LAP3 silenced ECA109 cells. We overexpressed LAP3 in TE1 cells to find out the corresponding results. LAP3 expression level was abundance in ESCC tissue. LAP3 silencing significantly reduced ECA109 cell proliferation and colony formation. The knockdown of LAP3 resulted in cell cycle arrest at G1-phase. Moreover, over expression of LAP3 favors TE1 cell proliferation and invasiveness which also confirms its contribution in malignant development. We came to the conclusion that LAP3 contributed to ESCC progression by overcoming cell cycle arrest. The proliferative and migration effects of LAP3 might contribute to malignant development of human ESCC. PMID- 24477664 TI - Temporal evolution of intraparenchymal hyperdensity after intra-arterial therapy in patients with ischemic stroke: optimal discrimination between hemorrhage and iodinated contrast. AB - PURPOSE: CT hyperattenuation arising from iodinated contrast has a different temporal evolution than that arising due to hemorrhage. This paper presents a method for optimal discrimination between hemorrhage and iodinated contrast in a postintervention CT in stroke patients. METHODS: We analyzed the brain computed tomography (CT) scans of consecutive patients with intraparenchymal hyperattenuation due to hemorrhage (n=41), those due to iodinated contrast alone (n=24), and those due to contrast mixed with hemorrhage after reperfusion therapy (n=14) in stroke patients. The difference between the maximum enhancement in hyperattenuation in the affected area and the corresponding contralateral area, dubbed Relative Maximum Enhancement (RME), was tracked over time. We fitted regression models to the RME changes due to hemorrhage and contrast to describe their temporal decay, and then derived the optimal discriminant curve that distinguishes the two. A computer algorithm coregistered the baseline and follow up CT scans and performed pixel-by-pixel comparison to determine hemorrhage and iodinated contrast based on the RME changes with respect to the discriminant curve. RESULTS: For both hemorrhage (k= -0.004, R (2) =0.7) and iodinated contrast (k= -0.064, R (2) =0.9), the temporal evolution of RMEs were best fitted by exponential decay curves, with respective half-lives of 192.3 and 10.7 h. An exponential decay model (k= -0.026) for optimal discrimination of hemorrhage vs. contrast was fitted. The computer algorithm implementing this model was successful in predicting the presence of hemorrhage in a hyperdense lesion with sensitivity =93% and specificity =91%. CONCLUSION: Intraparenchymal hemorrhage and contrast have markedly different decay half-lives that can be used to assess hemorrhage in a hyperdense lesion on a CT scan after intra-arterial therapy. PMID- 24477665 TI - Radiological image features of the atypical teratoid/rhabdoid tumor in adults: a systematic review. AB - PURPOSE: Atypical teratoid/rhabdoid tumor (AT/RT) occurs in children less than 3 years old, and has a very poor prognosis. AT/RT seldom occurs in adult. We have experienced four cases of AT/RT at our institute. The purpose of this study is to evaluate the radiological image findings of adult-onset AT/RT and to conduct a systematic review. METHODS: Image findings of four AT/RTs in our institute were retrospectively evaluated by an experienced neuroradiologist. If the images were unavailable, image findings were evaluated from the former image interpretation report. We assembled papers of adult-onset AT/RT (n = 38) and evaluated the image findings. RESULTS: AT/RT occurs in a variety of sites (spinal region, pineal region, suprasellar region, jugular foramen, and so on). High density on computed tomography (CT) was seen in 10 of 11 cases; mixed intensity in T2-weighted image was seen in 13 of 18 cases; and high intensity on diffusion-weighted image (DWI) was seen in 3 of 3 cases. Contrast enhancement was observed in all cases in which images were available. CONCLUSIONS: We have experienced four adult-onset AT/RT cases at our institute and have evaluated image findings through systematic review. The image findings of high density on CT, high intensity on DWI, with low apparent diffusion coefficient, and a heterogenous component should lead to an inclusion of AT/RT in the differential diagnosis of a tumor; these findings may be able to suggest AT/RT; however, they cannot make the diagnosis. PMID- 24477666 TI - Improved visual outcome with early treatment in macular edema secondary to retinal vein occlusions: 6-month results of a Korean RVO study. AB - PURPOSE: To determine the correlation between the duration of macular edema (ME) and visual outcomes among Korean patients with retinal vein occlusion (RVO). METHODS: Multicenter, interventional case series. Treatment-naive patients (n = 249) with branch or central RVO (BRVO/CRVO) and ME for <6 months were included. We assessed the correlation between the duration of ME and treatment outcomes including the mean logarithm of the minimum angle of resolution best-corrected visual acuity (logMAR BCVA) improvement, the proportion of patients achieving at least a 3-line gain in BCVA, and the mean reduction in central retinal thickness (CRT) at 6 months. RESULTS: One hundred and fifty-six patients with BRVO and 93 patients with CRVO were divided into five groups based on the duration of ME (<2, 2-4 weeks, 1-2, 2-3, 3-6 months); the mean baseline BCVA and CRT among the groups did not differ significantly. In BRVO, the mean logarithm of the minimum angle of resolution (logMAR) BCVA improvements in the groups were 0.51, 0.32, 0.17, 0.19, and 0.13, respectively (P = 0.002). The respective percentages of at least 3-line gains were 64, 53, 39, 38, and 21 % (P < 0.001). The BCVA didn't significantly improve in CRVO. The decrease in CRT was not correlated significantly with the duration of ME in either disease. CONCLUSIONS: Treatment of BRVO as early as 2 weeks after onset of ME enhanced the visual outcome; there was no correlation in the patients with CRVO. This finding supports the current trend favoring early treatment to obtain better visual outcomes in patients with BRVO. PMID- 24477668 TI - Photovoltaic enhancement due to surface-plasmon assisted visible-light absorption at the inartificial surface of lead zirconate-titanate film. AB - PZT film of 300 nm thickness was deposited on tin indium oxide (ITO) coated quartz by a sol-gel method. Four metal electrodes, such as Pt, Au, Cu and Ag, were used as top electrodes deposited on the same PZT film by sputtering at room temperature. In ITO-PZT-Ag and ITO-PZT-Au structures, the visible light (400-700 nm) can be absorbed partially by a PZT film, and the maximum efficiency of photoelectric conversion of the ITO-PZT-Ag structure was enhanced to 0.42% (100 mW cm(-2), AM 1.5G), which is about 15 times higher than that of the ITO-PZT-Pt structure. Numerical simulations show that the natural random roughness of polycrystalline-PZT-metal interface can offer a possibility of coupling between the incident photons and SPs at the metal surface. The coincidence between the calculated SP properties and the measured EQE spectra reveals the SP origin of the photovoltaic enhancement in these ITO-PZT-metal structures, and the improved photocurrent output is caused by the enhanced optical absorption in the PZT region near the metal surface, rather than by the direct charge-transfer process between two materials. PMID- 24477667 TI - Midbrain cues dictate differentiation of human dental pulp stem cells towards functional dopaminergic neurons. AB - Dental pulp originating from the neural crest is considered a better source of postnatal stem cells for cell-based therapies in neurodegenerative diseases. Dental Pulp Stem Cells (DPSCs) have been shown to differentiate into cell-types of cranial neural crest ontology; however, their ability to differentiate to functional neurons of the central nervous system remains to be studied. We hypothesized that midbrain cues might commit DPSCs to differentiate to functional dopaminergic cell-type. As expected, DPSCs in their naive state spontaneously expressed early and mature neuronal markers like nestin, musashi12, beta tubulin III, and Map2ab. On exposure to midbrain cues (sonic hedgehog, fibroblast growth factor 8 and basic fibroblast growth factor), DPSCs showed upregulation of dopaminergic neuron-specific transcription factors Nuclear Receptor related protein 1 (Nurr1), Engrailed 1 (En1) and paired-like homeodomain transcription factor 3 (Pitx3) as revealed by real-time RT-PCR. Immunofluorescence and flow cytometry analysis showed enhanced expression of mature neuronal marker Map2ab and dopaminergic-neuronal markers [tyrosine hydroxylase (TH), En1, Nurr1, and Pitx3], with nearly 77% of the induced DPSCs positive for TH. Functional studies indicated that the induced DPSCs could secrete dopamine constitutively and upon stimulation with potassium chloride (KCl) and adenosine triphosphate (ATP), as measured by dopamine ELISA. Additionally, the induced DPSCs showed intracellular Ca(2+) influx in the presence of KCl, unlike control DPSCs. ATP-stimulated Ca(2+) influx was observed in control and induced DPSCs, but only the induced cells secreted dopamine. Our data clearly demonstrate for the first time that DPSCs in the presence of embryonic midbrain cues show efficient propensity towards functional dopaminergic cell-type. PMID- 24477669 TI - Safety, tolerability, and efficacy of insulin aspart in people with type 2 diabetes, as biphasic insulin aspart or with Basal insulin: findings from the multinational, non-interventional a1chieve study. AB - INTRODUCTION: The aim of the study was to investigate the clinical safety and effectiveness of starting insulin aspart (aspart) therapy in people with type 2 diabetes mellitus (T2DM) as a sub-analysis of the multinational, non interventional A1chieve study. METHODS: Insulin-naive and insulin-experienced people with T2DM in routine clinical care starting aspart alone at baseline and continuing aspart alone, changing to biphasic insulin aspart 30 (aspart premix) or adding a basal insulin by study end, were included. Safety, tolerability, and efficacy were evaluated over 24 weeks. RESULTS: Overall, 3,898 people started aspart at baseline. Of the 3,313 with 24-week data, 1,545 (46.6%) continued with aspart, 1,379 (41.6%) switched to aspart premix, and 214 (6.5%) added basal insulin, while the remainder switched to other regimens. No serious adverse drug reactions were reported. The proportion of participants reporting hypoglycemia decreased from baseline to week 24 in the aspart alone group (11.2% versus 4.1%, p < 0.001) and in the aspart + basal insulin group (13.1% versus 7.5%, p = 0.040), and was 3.7% at week 24 in the aspart premix group. The mean HbA1c decreased from baseline to week 24 (aspart: -2.1 +/- 2.0% [-23 +/- 22 mmol/mol], aspart premix: -2.3 +/- 1.7% [-25 +/- 19 mmol/mol], aspart + basal insulin: -2.0 +/- 2.1% [-22 +/- 23 mmol/mol]; p < 0.001). CONCLUSION: Insulin aspart therapy was well tolerated and was associated with improved glucose control over 24 weeks in people with T2DM. PMID- 24477670 TI - Type 2 diabetes mellitus management and body mass index: experiences with initiating insulin detemir in the a1chieve study. AB - INTRODUCTION: This sub-analysis of the A1chieve study aimed to examine the safety and efficacy of insulin detemir (IDet) initiation over 24 weeks in relation to baseline body mass index (BMI) in people with type 2 diabetes mellitus (T2DM). METHODS: A1chieve was a 24-week non-interventional study to assess the safety and efficacy of insulin analogs in routine practice. This sub-analysis included insulin-naive patients who initiated IDet therapy based on their physicians' decision. Patients were stratified according to baseline BMI (Group I, <25.0 kg/m(2); Group II, 25.0 to <30.0 kg/m(2); Group III, 30.0 to <35.0 kg/m(2); Group IV >=35.0 kg/m(2)). Safety and efficacy variables were assessed over 24 weeks. RESULTS: Overall, 10,650 insulin-naive patients were included (3,045 patients in Group I, 4,186 patients in Group II, 2,365 patients in Group III, and 1,054 patients in Group IV). Four serious adverse drug reactions (SADRs) were reported. From baseline to Week 24, there was no statistically significant difference in the proportion of patients reporting overall hypoglycemia in Group I (4.0% vs. 4.4%), while a significant decrease in Group II (4.8% vs. 4.0%, p = 0.0335) and significant increases in Groups III and IV (3.3% vs. 5.4% and 3.4% vs. 7.0%, respectively, p < 0.001) were noted. The mean body weight increased from baseline to Week 24 in Group I (60.7 +/- 8.4 vs. 61.8 +/- 8.5 kg) and reduced in Groups II, III, and IV (74.5 +/- 9.2 vs. 74.2 +/- 9.2 kg, 87.4 +/- 10.3 vs. 86.0 +/- 9.8 kg, and 102.2 +/- 14.3 vs. 100.1 +/- 14.2 kg, respectively; all p < 0.001). Significant improvements were noted in glycemic parameters, systolic blood pressure, and lipids over 24 weeks, irrespective of baseline BMI status. CONCLUSION: IDet therapy was associated with improved glycemic control and a low number of SADRs. Greater weight loss was observed with higher BMI. PMID- 24477671 TI - Phospho-GlcNAc modulation of slow MLC2 during soleus atrophy through a multienzymatic and sarcomeric complex. AB - Although calcium is the major regulator of excitation-contraction coupling, myofilament function can also be modulated through post-translational modifications. In particular, phosphorylation and O-GlcNAcylation are key modulators of calcium activation parameters. Among the regulatory proteins of skeletal muscle contraction, the myosin light chain 2 (MLC2) can undergo both types of post-translational modification. During aging or physical inactivity, the phosphorylation status of the slow isoform of MLC2 (sMLC2) does not correlate with calcium sensitivity, suggesting that the O-GlcNAcylation might modulate sMLC2 activity. To increase understanding of the contractile dysfunction associated with muscle atrophy, we studied the phosphorylation/O-GlcNAcylation interplay on the sMLC2. We demonstrate a two-fold decrease of O-GlcNAcylation level on sMLC2 in a rat model of skeletal muscle atrophy (hindlimb unloading), while phosphorylation increased. Both post-translational modifications were mutually exclusive. Their interplay reversed during reloading. The expression of enzymes involved in the phosphorylation and O-GlcNAcylation interplay on sMLC2 was modified on whole protein pattern as well as on myofilament, and was load dependent. All enzymes were colocalized on the contractile apparatus. Finally, we describe a multienzymatic complex which might finely modulate the phosphorylation/dephosphorylation and O-GlcNAcylation/de-O-GlcNAcylation of sMLC2 that could be involved in the contractile dysfunction of atrophied muscle. Importantly, this complex was localized at the Z-disk, a nodal point of signalling in skeletal muscle. PMID- 24477672 TI - Interventions for preventing critical illness polyneuropathy and critical illness myopathy. AB - BACKGROUND: Critical illness polyneuropathy or myopathy (CIP/CIM) is a frequent complication in the intensive care unit (ICU) and is associated with prolonged mechanical ventilation, longer ICU stay and increased mortality. This is an interim update of a review first published in 2009 (Hermans 2009). It has been updated to October 2011, with further potentially eligible studies from a December 2013 search characterised as awaiting assessment. OBJECTIVES: To systematically review the evidence from RCTs concerning the ability of any intervention to reduce the incidence of CIP or CIM in critically ill individuals. SEARCH METHODS: On 4 October 2011, we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE, and EMBASE. We checked the bibliographies of identified trials and contacted trial authors and experts in the field. We carried out an additional search of these databases on 6 December 2013 to identify recent studies. SELECTION CRITERIA: All randomised controlled trials (RCTs), examining the effect of any intervention on the incidence of CIP/CIM in people admitted to adult medical or surgical ICUs. The primary outcome was the incidence of CIP/CIM in ICU, based on electrophysiological or clinical examination. Secondary outcomes included duration of mechanical ventilation, duration of ICU stay, death at 30 and 180 days after ICU admission and serious adverse events from the treatment regimens. DATA COLLECTION AND ANALYSIS: Two authors independently extracted the data and assessed the risk of bias in included studies. MAIN RESULTS: We identified five trials that met our inclusion criteria. Two trials compared intensive insulin therapy (IIT) to conventional insulin therapy (CIT). IIT significantly reduced CIP/CIM in the screened (n = 825; risk ratio (RR) 0.65, 95% confidence interval (CI) 0.55 to 0.77) and total (n = 2748; RR 0.70, 95% CI 0.60 to 0.82) population randomised. IIT reduced duration of mechanical ventilation, ICU stay and 180-day mortality, but not 30 day mortality compared with CIT. Hypoglycaemia increased with IIT but did not cause early deaths.One trial compared corticosteroids with placebo (n = 180). The trial found no effect of treatment on CIP/CIM (RR 1.27, 95% CI 0.77 to 2.08), 180 day mortality, new infections, glycaemia at day seven, or episodes of pneumonia, but did show a reduction of new shock events.In the fourth trial, early physical therapy reduced CIP/CIM in 82/104 evaluable participants in ICU (RR 0.62. 95% CI 0.39 to 0.96). Statistical significance was lost when we performed a full intention-to-treat analysis (RR 0.81, 95% CI 0.60 to 1.08). Duration of mechanical ventilation but not ICU stay was significantly shorter in the intervention group. Hospital mortality was not affected but 30- and 180-day mortality results were not available. No adverse effects were noticed.The last trial found a reduced incidence of CIP/CIM in 52 evaluable participants out of a total of 140 who were randomised to electrical muscle stimulation (EMS) versus no stimulation (RR 0.32, 95% CI 0.10 to 1.01). These data were prone to bias due to imbalances between treatment groups in this subgroup of participants. After we imputed missing data and performed an intention-to-treat analysis, there was still no significant effect (RR 0.94, 95% CI 0.78 to 1.15). The investigators found no effect on duration of mechanical ventilation and noted no difference in ICU mortality, but did not report 30- and 180-day mortality.We updated the searches in December 2013 and identified nine potentially eligible studies that will be assessed for inclusion in the next update of the review. AUTHORS' CONCLUSIONS: There is moderate quality evidence from two large trials that intensive insulin therapy reduces CIP/CIM, and high quality evidence that it reduces duration of mechanical ventilation, ICU stay and 180-day mortality, at the expense of hypoglycaemia. Consequences and prevention of hypoglycaemia need further study. There is moderate quality evidence which suggests no effect of corticosteroids on CIP/CIM and high quality evidence that steroids do not affect secondary outcomes, except for fewer new shock episodes. Moderate quality evidence suggests a potential benefit of early rehabilitation on CIP/CIM which is accompanied by a shorter duration of mechanical ventilation but without an effect on ICU stay. Very low quality evidence suggests no effect of EMS, although data are prone to bias. Strict diagnostic criteria for CIP/CIM are urgently needed for research purposes. Large RCTs need to be conducted to further explore the role of early rehabilitation and EMS and to develop new preventive strategies. PMID- 24477673 TI - Determination of vagal baroreflex sensitivity in normal subjects. AB - INTRODUCTION: The Valsalva maneuver (VM) is used widely to quantify the sensitivity of the vagal baroreflex loop (vagal baroreflex sensitivity, BRS_v), but most studies have focused on the heart rate (HR) response to blood pressure (BP) decrement (BRS_v?), even though the subsequent response to an increment in BP after the VM (BRS_v?) is important and different. METHODS: We evaluated recordings of HR and BP in 187 normal subjects during the VM and determined both BRS_v?, as determined by relating HR to the BP increase after phase III and BRS_v?. RESULTS: BRS_v? was related inversely to age. In addition, BRS_v?, age, and magnitude of phase IV were independent predictors of BRS_v? in a multivariate model, accounting for 47% of the variance of BRS_v?. CONCLUSIONS: The results indicate that both BRS_v? and BRS_v? become blunted with increasing age and that these indices relate to each other. PMID- 24477674 TI - A role for H/ACA and C/D small nucleolar RNAs in viral replication. AB - We have employed gene-trap insertional mutagenesis to identify candidate genes whose disruption confer phenotypic resistance to lytic infection, in independent studies using 12 distinct viruses and several different cell lines. Analysis of >2,000 virus-resistant clones revealed >1,000 candidate host genes, approximately 20 % of which were disrupted in clones surviving separate infections with 2-6 viruses. Interestingly, there were 83 instances in which the insertional mutagenesis vector disrupted transcripts encoding H/ACA-class and C/D-class small nucleolar RNAs (SNORAs and SNORDs, respectively). Of these, 79 SNORAs and SNORDs reside within introns of 29 genes (predominantly protein-coding), while 4 appear to be independent transcription units. siRNA studies targeting candidate SNORA/Ds provided independent confirmation of their roles in infection when tested against cowpox virus, Dengue Fever virus, influenza A virus, human rhinovirus 16, herpes simplex virus 2, or respiratory syncytial virus. Significantly, eight of the nine SNORA/Ds targeted with siRNAs enhanced cellular resistance to multiple viruses suggesting widespread involvement of SNORA/Ds in virus-host interactions and/or virus-induced cell death. PMID- 24477675 TI - Molecular phylogeny and SNP variation of polar bears (Ursus maritimus), brown bears (U. arctos), and black bears (U. americanus) derived from genome sequences. AB - We assessed the relationships of polar bears (Ursus maritimus), brown bears (U. arctos), and black bears (U. americanus) with high throughput genomic sequencing data with an average coverage of 25* for each species. A total of 1.4 billion 100 bp paired-end reads were assembled using the polar bear and annotated giant panda (Ailuropoda melanoleuca) genome sequences as references. We identified 13.8 million single nucleotide polymorphisms (SNP) in the 3 species aligned to the polar bear genome. These data indicate that polar bears and brown bears share more SNP with each other than either does with black bears. Concatenation and coalescence-based analysis of consensus sequences of approximately 1 million base pairs of ultraconserved elements in the nuclear genome resulted in a phylogeny with black bears as the sister group to brown and polar bears, and all brown bears are in a separate clade from polar bears. Genotypes for 162 SNP loci of 336 bears from Alaska and Montana showed that the species are genetically differentiated and there is geographic population structure of brown and black bears but not polar bears. PMID- 24477676 TI - Non-linear increases in danazol exposure with dose in older vs. younger beagle dogs: the potential role of differences in bile salt concentration, thermodynamic activity, and formulation digestion. AB - PURPOSE: To explore the possibility that age-related changes in physiology may result in differences in drug bioavailability after oral administration of lipid based formulations of danazol. METHODS: Danazol absorption from lipid formulations with increasing drug load was examined in younger (9 months) and older (8 years) beagles. Age related changes to hepatic function were assessed via changes to systemic clearance and serum bile acid concentrations. Changes to lipolytic enzyme activity and intestinal bile salt concentration were evaluated using in vitro lipolysis. RESULTS: Drug exposure increased linearly with dose in younger animals. In older animals, bioavailability increased with increasing dose to a tipping point, beyond which bioavailability reduced (consistent with initiation of precipitation). No differences in hepatic function were apparent across cohorts. Changes to enzyme concentrations in lipolysis studies had little impact on drug precipitation/solubilisation. In contrast, higher bile salt concentrations better supported supersaturation at higher drug loads. CONCLUSIONS: Differences in animal cohort can have a significant impact on drug absorption from lipid based formulation. For danazol, bioavailability was enhanced under some circumstances in older animals. In vitro experiments suggest that this was unlikely to reflect changes to metabolism or lipolysis, but might be explained by increases in luminal bile salt/phospholipid concentrations in older animals. PMID- 24477677 TI - Marked differences in the effect of antiepileptic and cytostatic drugs on the functionality of P-glycoprotein in human and rat brain capillary endothelial cell lines. AB - PURPOSE: The expression of P-glycoprotein (Pgp) is increased in brain capillary endothelial cells (BCECs) of patients with pharmacoresistant epilepsy. This may restrict the penetration of antiepileptic drugs (AEDs) into the brain. However, the mechanisms underlying increased Pgp expression in epilepsy patients are not known. One possibility is that AEDs induce the expression and functionality of Pgp in BCECs. Several older AEDs that induce human cytochrome P450 enzymes also induce Pgp in hepatocytes and enterocytes, but whether this extends to Pgp at the human BBB and to newer AEDs is not known. METHODS: This prompted us to study the effects of various old and new AEDs on Pgp functionality in the human BCEC line, hCMEC/D3, using the rhodamine 123 (Rho123) efflux assay. For comparison, experiments were performed in two rat BCEC lines, RBE4 and GPNT, and primary cultures of rat and pig BCECs. Furthermore, known Pgp inducers, such as dexamethasone and several cytostatic drugs, were included in our experiments. RESULTS: Under control conditions, GPNT cells exhibited the highest and RBE4 the lowest Pgp expression and Rho123 efflux, while intermediate values were determined in hCMEC/D3. Known Pgp inducers increased Rho123 efflux in all cell lines, but marked inter-cell line differences in effect size were observed. Of the various AEDs examined, only carbamazepine (100 MUM) moderately increased Pgp functionality in hCMEC/D3, while valproate (300 MUM) inhibited Pgp. CONCLUSIONS: These data do not indicate that treatment with AEDs causes a clinically relevant induction in Pgp functionality in BCECs that form the BBB. PMID- 24477679 TI - Estimating QALY gains in applied studies: a review of cost-utility analyses published in 2010. AB - Reimbursement agencies in several countries now require health outcomes to be measured in terms of quality-adjusted life-years (QALYs), leading to an immense increase in publications reporting QALY gains. However, there is a growing concern that the various 'multi-attribute utility' (MAU) instruments designed to measure the Q in the QALY yield disparate values, implying that results from different instruments are incommensurable. By reviewing cost-utility analyses published in 2010, we aim to contribute to improved knowledge on how QALYs are currently calculated in applied analyses; how transparently QALY measurement is presented; and how large the expected incremental QALY gains are. We searched Embase, MEDLINE and NHS EED for all cost-utility analyses published in 2010. All analyses that had estimated QALYs gained from health interventions were included. Of the 370 studies included in this review, 48% were pharmacoeconomic evaluations. Active comparators were used in 71% of studies. The median incremental QALY gain was 0.06, which translates to 3 weeks in best imaginable health. The EQ-5D-3L is the dominant instrument used. However, reporting of how QALY gains are estimated is generally inadequate. In 55% of the studies there was no reference to which MAU instrument or direct valuation method QALY data came from. The methods used for estimating expected QALY gains are not transparently reported in published papers. Given the wide variation in utility scores that different methodologies may assign to an identical health state, it is important for journal editors to require a more transparent way of reporting the estimation of incremental QALY gains. PMID- 24477678 TI - Conditional knockout of the RNA-binding protein HuR in CD4+ T cells reveals a gene dosage effect on cytokine production. AB - The posttranscriptional mechanisms by which RNA binding proteins (RBPs) regulate T-cell differentiation and cytokine production in vivo remain unclear. The RBP HuR binds to labile mRNAs, usually leading to increases in mRNA stability and/or translation. Previous work demonstrated that HuR binds to the mRNAs encoding the Th2 transcription factor trans-acting T-cell-specific transcription factor (GATA 3) and Th2 cytokines interleukin (IL)-4 and IL-13, thereby regulating their expression. By using a novel conditional HuR knockout (KO) mouse in which HuR is deleted in activated T cells, we show that Th2-polarized cells from heterozygous HuR conditional (OX40-Cre HuR(fl/+)) KO mice had decreased steady-state levels of Gata3, Il4 and Il13 mRNAs with little changes at the protein level. Surprisingly, Th2-polarized cells from homozygous HuR conditional (OX40-Cre HuR(fl/fl)) KO mice showed increased Il2, Il4 and Il13 mRNA and protein via different mechanisms. Specifically, Il4 was transcriptionally upregulated in HuR KO T cells, whereas Il2 and Il13 mRNA stabilities increased. Additionally, when using the standard ovalbumin model of allergic airway inflammation, HuR conditional KO mice mounted a robust inflammatory response similar to mice with wild-type HuR levels. These results reveal a complex differential posttranscriptional regulation of cytokines by HuR in which gene dosage plays an important role. These findings may have significant implications in allergies and asthma, as well as autoimmune diseases and infection. PMID- 24477680 TI - Identifying Homogeneous Subgroups in Neurological Disorders: Unbiased Recursive Partitioning in Cervical Complete Spinal Cord Injury. AB - Background The reliable stratification of homogeneous subgroups and the prediction of future clinical outcomes within heterogeneous neurological disorders is a particularly challenging task. Nonetheless, it is essential for the implementation of targeted care and effective therapeutic interventions. Objective This study was designed to assess the value of a recently developed regression tool from the family of unbiased recursive partitioning methods in comparison to established statistical approaches (eg, linear and logistic regression) for predicting clinical endpoints and for prospective patients' stratification for clinical trials. Methods A retrospective, longitudinal analysis of prospectively collected neurological data from the European Multicenter study about Spinal Cord Injury (EMSCI) network was undertaken on C4 C6 cervical sensorimotor complete subjects. Predictors were based on a broad set of early (<2 weeks) clinical assessments. Endpoints were based on later clinical examinations of upper extremity motor scores and recovery of motor levels, at 6 and 12 months, respectively. Prediction accuracy for each statistical analysis was quantified by resampling techniques. Results For all settings, overlapping confidence intervals indicated similar prediction accuracy of unbiased recursive partitioning to established statistical approaches. In addition, unbiased recursive partitioning provided a direct way of identification of more homogeneous subgroups. The partitioning is carried out in a data-driven manner, independently from a priori decisions or predefined thresholds. Conclusion Unbiased recursive partitioning techniques may improve prediction of future clinical endpoints and the planning of future SCI clinical trials by providing easily implementable, data-driven rationales for early patient stratification based on simple decision rules and clinical read-outs. PMID- 24477681 TI - NBCe1A dimer assemble visualized by bimolecular fluorescence complementation. AB - Mutations in the electrogenic Na(+)/HCO3(-) cotransporter (NBCe1) that cause proximal renal tubular acidosis (pRTA), glaucoma, and cataracts in patients are recessive. Parents and siblings of these affected individuals seem asymptomatic although their tissues should make some mutant NBCe1 protein. Biochemical studies with AE1 and NBCe1 indicate that both, and probably all, Slc4 members form dimers. However, the physiologic implications of dimerization have not yet been fully explored. Here, human NBCe1A dimerization is demonstrated by biomolecular fluorescence complementation (BiFC). An enhanced yellow fluorescent protein (EYFP) fragment (1-158, EYFP(N)) or (159-238, EYFP(C)) was fused to the NH2 or COOH terminus of NBCe1A and mix-and-matched expressed in Xenopus oocyte. The EYFP fluorescent signal was observed only when both EYFP fragments are fused to the NH2 terminus of NBCe1A (EYFP(N)-N-NBCe1A w/ EYFP(C)-N-NBCe1A), and the electrophysiology data demonstrated this EYFP-NBCe1A coexpressed pair have wild type transport function. These data suggest NBCe1A forms dimers and that NH2 termini from the two monomers are in close proximity, likely pair up, to form a functional unit. To explore the physiologic significance of NBCe1 dimerization, we chose two severe NBCe1 mutations (6.6 and 20% wild-type function individually): S427L (naturally occurring) and E91R (for NH2-terminal structure studies). When we coexpressed S427L and E91R, we measured 50% wild-type function, which can only occur if the S427L-E91R heterodimer is the functional unit. We hypothesize that the dominant negative effect of heterozygous NBCe1 carrier should be obvious if the mutated residues are structurally crucial to the dimer formation. The S427L-E91R heterodimer complex allows the monomers to structurally complement each other resulting in a dimer with wild-type like function. PMID- 24477682 TI - Clopidogrel preserves whole kidney autoregulatory behavior in ANG II-induced hypertension. AB - This study tested the hypothesis that P2Y12 receptor blockade with clopidogrel preserves renal autoregulatory ability during ANG II-induced hypertension. Clopidogrel was administered orally to male Sprague-Dawley rats chronically infused with ANG II. After 14 days of treatment, whole kidney autoregulation of renal blood flow was assessed in vivo in pentobarbital-anesthetized rats using an ultrasonic flow probe placed around the left renal artery. In ANG II-vehicle treated rats, decreasing arterial pressure over a range from 160 to 100 mmHg resulted in a 25 +/- 5% decrease in renal blood flow, demonstrating a significant loss of autoregulation with an autoregulatory index of 0.66 +/- 0.15. However, clopidogrel treatment preserved autoregulatory behavior in ANG II-treated rats to levels indistinguishable from normotensive sham-operated (sham) rats (autoregulatory index: 0.04 +/- 0.14). Compared with normotensive sham-vehicle treated rats, ANG II infusion increased renal CD3-positive T cell infiltration by 66 +/- 6%, induced significant thickening of the preglomerular vessels and glomerular basement membrane and increased glomerular collagen I deposition, tubulointerstitial fibrosis, damage to the proximal tubular brush border, and protein excretion. Clopidogrel significantly reduced renal infiltration of T cells by 39 +/- 9% and prevented interstitial artery thickening, ANG II-induced damage to the glomerular basement membrane, deposition of collagen type I, and tubulointerstitial fibrosis, despite the maintenance of hypertension. These data demonstrate that systemic P2Y12 receptor blockade with clopidogrel protects against impairment of autoregulatory behavior and renal vascular injury in ANG II induced hypertension, possibly by reducing renal T cell infiltration. PMID- 24477684 TI - Angiotensin-converting enzyme 2 mediates hyperfiltration associated with diabetes. AB - The degradation of ANG II by angiotensin-converting enzyme 2 (ACE2), leading to the formation of ANG(1-7), is an important step in the regulation of the renin angiotensin-aldosterone system (RAAS), and one that is significantly altered in the diabetic kidney. This study examined the role of ACE2 in the hyperfiltration associated with diabetes. Streptozotocin diabetes was induced in male C57BL6 mice and ACE2 knockout (KO) mice. C57BL6 mice were further randomized to receive the selective ACE2 inhibitor MLN-4760. After 2 wk of study, animals were subjected to micropuncture experiments. The renal reserve was further assessed in C57BL6 mice and ACE2 KO mice after exposure to a high-protein diet. The induction of diabetes in wild-type mice was associated with increased renal ACE2 activity, hyperfiltration, and renal hypertrophy. On micropuncture, diabetes was associated with increased tubular free flow and stop-flow pressure, enhanced tubuloglomerular feedback reactivity, and an increased maximal response indicative of increased glomerular hydrostatic capillary pressure. Each of these increases were prevented in diabetic ACE2 KO mice and diabetic mice treated with a selective ACE2 inhibitor for 2 wk. However, unlike chronically treated animals, ACE2 inhibition with MLN-4760 had no acute effect on stop-flow pressure or tubuloglomerular feedback reactivity. ACE2 KO mice also failed to increase their creatinine clearance in response to a high-protein diet. The results of our study suggest that ACE2 plays a key role in the recruitment of the renal reserve and hyperfiltration associated with diabetes. PMID- 24477683 TI - Regulation of nephron water and electrolyte transport by adenylyl cyclases. AB - Adenylyl cyclases (AC) catalyze formation of cAMP, a critical component of G protein-coupled receptor signaling. So far, nine distinct membrane-bound AC isoforms (AC1-9) and one soluble AC (sAC) have been identified and, except for AC8, all of them are expressed in the kidney. While the role of ACs in renal cAMP formation is well established, we are just beginning to understand the function of individual AC isoforms, particularly with regard to hormonal regulation of transporter and channel phosphorylation, membrane abundance, and trafficking. This review focuses on the role of different AC isoforms in regulating renal water and electrolyte transport in health as well as potential pathological implications of disordered AC isoform function. In particular, we focus on modulation of transporter and channel abundance, activity, and phosphorylation, with an emphasis on studies employing genetically modified animals. As will be described, it is now evident that specific AC isoforms can exert unique effects in the kidney that may have important implications in our understanding of normal physiology as well as disease pathogenesis. PMID- 24477686 TI - Three-dimensional reconstruction of the rat nephron. AB - This study gives a three-dimensional (3D) structural analysis of rat nephrons and their connections to collecting ducts. Approximately 4,500 2.5-MUm-thick serial sections from the renal surface to the papillary tip were obtained from each of 3 kidneys of Wistar rats. Digital images were recorded and aligned into three image stacks and traced from image to image. Short-loop nephrons (SLNs), long-loop nephrons (LLNs), and collecting ducts (CDs) were reconstructed in 3D. We identified a well-defined boundary between the outer stripe and the inner stripe of the outer medulla corresponding to the transition of descending thick limbs to descending thin limbs and between the inner stripe and the inner medulla, i.e., the transition of ascending thin limbs into ascending thick limbs of LLNs. In all nephrons, a mosaic pattern of proximal tubule (PT) cells and descending thin limb (DTL) cells was observed at the transition between the PT and the DTL. The course of the LLNs revealed tortuous proximal "straight" tubules and winding of the DTLs within the outer half of the inner stripe. The localization of loop bends of SLNs in the inner stripe of the outer medulla and the bends of LLNs in the inner medulla reflected the localization of their glomeruli; i.e., the deeper the glomerulus, the deeper the bend. Each CD drained approximately three to six nephrons with a different pattern than previously established in mice. This information will provide a basis for evaluation of structural changes within nephrons as a result of physiological or pharmaceutical intervention. PMID- 24477685 TI - Functional consequences of NKCC2 splice isoforms: insights from a Xenopus oocyte model. AB - The Na(+)-K(+)-2Cl(-) cotransporter NKCC2 is exclusively expressed in the renal thick ascending limb (TAL), where it exists as three main splice isoforms, NKCC2B, NKCC2A, and NKCC2F, with the latter two predominating. NKCC2A is expressed in both medullary and cortical TAL, but NKCC2F localizes to the medullary TAL. The biochemical characteristics of the isoforms have been extensively studied by ion uptake studies in Xenopus oocytes, but the functional consequences of alternative splicing remain unclear. We developed a charge difference model of an NKCC2-transfected oocyte. The model closely recapitulated existing data from ion-uptake experiments. This allowed the reconciliation of different apparent Km values reported by various groups, which have hitherto either been attributed to species differences or remained unexplained. Instead, simulations showed that apparent Na(+) and Cl(-) dependencies are influenced by the ambient K(+) or Rb(+) bath concentrations, which differed between experimental protocols. At steady state, under bath conditions similar to the outer medulla, NKCC2F mediated greater Na(+) reabsorption than NKCC2A. Furthermore, Na(+) reabsorption by the NKCC2F-transfected oocyte was more energy efficient, as quantified by J NKCC/J Pump. Both the increased Na(+) reabsorption and the increased efficiency were eroded as osmolarity decreased toward levels observed in the cortical TAL. This supports the hypothesis that the NKCC2F is a medullary specialization of NKCC2 and demonstrates the utility of modeling in analyzing the functional implications of ion uptake data at physiologically relevant steady states. PMID- 24477687 TI - Promotion of cell proliferation by clusterin in the renal tissue repair phase after ischemia-reperfusion injury. AB - Renal repair begins soon after the kidney suffers ischemia-reperfusion injury (IRI); however, its molecular pathways are not fully understood. Clusterin (Clu) is a chaperone protein with cytoprotective functions in renal IRI. The aim of this study was to investigate the role of Clu in renal repair after IRI. IRI was induced in the left kidneys of wild-type (WT) C57BL/6J (B6) vs. Clu knockout (KO) B6 mice by clamping the renal pedicles for 28-45 min at the body temperature of 32 degrees C. The renal repair was assessed by histology and confirmed by renal function. Gene expression was examined using PCR array. Here, we show that following IRI, renal tubular damage and Clu expression in WT kidneys were induced at day 1, reached the maximum at day 3, and significantly diminished at day 7 along with normal function, whereas the tubular damage in Clu KO kidneys steadily increased from initiation of insult to the end of the experiment, when renal failure occurred. Renal repair in WT kidneys was positively correlated with an increase in Ki67(+) proliferative tubular cells and survival from IRI. The functions of Clu in renal repair and renal tubular cell proliferation in cultures were associated with upregulation of a panel of genes that could positively regulate cell cycle progression and DNA damage repair, which might promote cell proliferation but not involve cell migration. In conclusion, these data suggest that Clu is required for renal tissue regeneration in the kidney repair phase after IRI, which is associated with promotion of tubular cell proliferation. PMID- 24477688 TI - Galectin-9 ameliorates anti-GBM glomerulonephritis by inhibiting Th1 and Th17 immune responses in mice. AB - Antiglomerular basement membrane glomerulonephritis (anti-GBM GN) is a Th1- and Th17-predominant autoimmune disease. Galectin-9 (Gal-9), identified as the ligand of Tim-3, functions in diverse biological processes and leads to the apoptosis of CD4(+)Tim-3(+) T cells. It is still unclear how Gal-9 regulates the functions of Th1 and Th17 cells and prevents renal injury in anti-GBM GN. In this study, Gal-9 was administered to anti-GBM GN mice for 7 days. We found that Gal-9 retarded the increase of Scr, ameliorated renal tubular injury, and reduced the formation of crescents. The infiltration of Th1 and Th17 cells into the spleen and kidneys significantly decreased in Gal-9-treated nephritic mice. The reduced infiltration of Th1 and Th17 cells might be associated with the downregulation of CCL-20, CXCL 9, and CXCL-10 mRNAs in the kidney. In parallel, the blood levels of IFN-gamma and IL-17A declined in Gal-9-treated nephritic mice at days 21 and 28. In addition, an enhanced Th2 cell-mediated immune response was observed in the kidneys of nephritic mice after a 7-day injection of Gal-9. In conclusion, the protective role of Gal-9 in anti-GBM GN is associated with the inhibition of Th1 and Th17 cell-mediated immune responses and enhanced Th2 immunity in the kidney. PMID- 24477689 TI - Endovascular treatment of infrapopliteal arteries: angioplasty vs stent in the drug-eluting era. AB - To analyse data comparing drug-eluting devices versus non-coated devices in the treatment of vascular disease in the infrapopliteal region. All data available in the literature (16 studies were included) comparing drug-eluting stents (DESs) and drug-eluting balloons (DEBs) versus bare-metal stents (BMSs) and conventional balloons were analysed. For each single study, primary and secondary endpoints were reported. As comparative studies between DEBs and DESs were not available, a technical evaluation of the advantages and disadvantages of both were also included. Besides the limitations of the published studies, all of them were reporting interesting results for the new generation devices (DEB and DES). DES: primary patency at 1 year comprised between 75.0 % and 86 %; target lesion revascularisation between 8.7 % and 13.8 %. DEB: primary patency comprised between 71 % and 84.6 % at 12 months; target lesion revascularisation between 15.3 % and 17.6 %. However, limb salvage rates were not always higher using a DEB rather than a standard percutaneous transluminal angioplasty (PTA); a clinical improvement for patients treated with DEB was demonstrated only in the Leipzig registry. On the basis of the results available, the drug-eluting devices produced better results. DEB can be considered the leading approach in below-the knee disease. A comparative evaluation with DES is mandatory in the future. KEY POINTS: *We present data about advanced endovascular treatment of peripheral artery disease. *This provides an update on drug-eluting devices in infrapopliteal vascular disease. *Drug-eluting devices (DEB/DES) show promising results compared with traditional ones. PMID- 24477690 TI - Myosin-binding protein C displaces tropomyosin to activate cardiac thin filaments and governs their speed by an independent mechanism. AB - Myosin-binding protein C (MyBP-C) is an accessory protein of striated muscle thick filaments and a modulator of cardiac muscle contraction. Defects in the cardiac isoform, cMyBP-C, cause heart disease. cMyBP-C includes 11 Ig- and fibronectin-like domains and a cMyBP-C-specific motif. In vitro studies show that in addition to binding to the thick filament via its C-terminal region, cMyBP-C can also interact with actin via its N-terminal domains, modulating thin filament motility. Structural observations of F-actin decorated with N-terminal fragments of cMyBP-C suggest that cMyBP-C binds to actin close to the low Ca(2+) binding site of tropomyosin. This suggests that cMyBP-C might modulate thin filament activity by interfering with tropomyosin regulatory movements on actin. To determine directly whether cMyBP-C binding affects tropomyosin position, we have used electron microscopy and in vitro motility assays to study the structural and functional effects of N-terminal fragments binding to thin filaments. 3D reconstructions suggest that under low Ca(2+) conditions, cMyBP-C displaces tropomyosin toward its high Ca(2+) position, and that this movement corresponds to thin filament activation in the motility assay. At high Ca(2+), cMyBP-C had little effect on tropomyosin position and caused slowing of thin filament sliding. Unexpectedly, a shorter N-terminal fragment did not displace tropomyosin or activate the thin filament at low Ca(2+) but slowed thin filament sliding as much as the larger fragments. These results suggest that cMyBP-C may both modulate thin filament activity, by physically displacing tropomyosin from its low Ca(2+) position on actin, and govern contractile speed by an independent molecular mechanism. PMID- 24477691 TI - DNA-binding specificities of plant transcription factors and their potential to define target genes. AB - Transcription factors (TFs) regulate gene expression through binding to cis regulatory specific sequences in the promoters of their target genes. In contrast to the genetic code, the transcriptional regulatory code is far from being deciphered and is determined by sequence specificity of TFs, combinatorial cooperation between TFs and chromatin competence. Here we addressed one of these determinants by characterizing the target sequence specificity of 63 plant TFs representing 25 families, using protein-binding microarrays. Remarkably, almost half of these TFs recognized secondary motifs, which in some cases were completely unrelated to the primary element. Analyses of coregulated genes and transcriptomic data from TFs mutants showed the functional significance of over 80% of all identified sequences and of at least one target sequence per TF. Moreover, combining the target sequence information with coexpression analysis we could predict the function of a TF as activator or repressor through a particular DNA sequence. Our data support the correlation between cis-regulatory elements and the sequence determined in vitro using the protein-binding microarray and provides a framework to explore regulatory networks in plants. PMID- 24477692 TI - Astronomical reach of fundamental physics. AB - Using basic physical arguments, we derive by dimensional and physical analysis the characteristic masses and sizes of important objects in the universe in terms of just a few fundamental constants. This exercise illustrates the unifying power of physics and the profound connections between the small and the large in the cosmos we inhabit. We focus on the minimum and maximum masses of normal stars, the corresponding quantities for neutron stars, the maximum mass of a rocky planet, the maximum mass of a white dwarf, and the mass of a typical galaxy. To zeroth order, we show that all these masses can be expressed in terms of either the Planck mass or the Chandrasekar mass, in combination with various dimensionless quantities. With these examples, we expose the deep interrelationships imposed by nature between disparate realms of the universe and the amazing consequences of the unifying character of physical law. PMID- 24477693 TI - On the mis-presentation and misinterpretation of gender-related data: the case of Ingalhalikar's human connectome study. PMID- 24477694 TI - Hypoxia-inducible factor (HIF)-independent expression mechanism and novel function of HIF prolyl hydroxylase-3 in renal cell carcinoma. AB - PURPOSE: We previously found that hypoxia-inducible factor (HIF) prolyl hydroxylase-3 (PHD3) was frequently overexpressed in renal cell carcinomas (RCCs), unlike in normal tissues, and therefore, we studied the mechanism and role of PHD3 expression in RCC. METHODS: The von Hippel-Lindau (VHL)-gene-mutant RCC cell lines SMKT-R2 and SMKT-R3 and wild-type VHL cell lines Caki-1 and ACHN were used. Associations of the expression of PHD3 with HIF-alpha proteins and signal transduction pathways were evaluated under normoxic conditions. The effect of PHD3 on cell proliferation was also examined by small interference RNA and cDNA transfection. Moreover, the prognostic impact of PHD3 expression in clear cell RCC (CCRCC) was evaluated using primary cancer tissues. RESULTS: In SMKT-R2 and SMKT-R3, HIF-alpha proteins were expressed and PHD3 was highly expressed. On the other hand, ACHN had low expression of HIF-alpha proteins and PHD3. However, Caki-1 had high expression of PHD3 even though there was no distinct expression of HIF-alpha proteins. PHD3 expression was inhibited by blockade of Akt and mammalian target of rapamycin (mTOR), but not by HIF-1alpha and HIF-2alpha double knockdown. In addition, PHD3 knockdown resulted in the promotion of cell proliferation in SMKT-R2, SMKT-R3 and Caki-1. On the other hand, forced expression of PHD3 reduced cell proliferation in ACHN. In immunohistochemistry, PHD3 expression was a significant factor for better recurrence-free survival in patients with CCRCC. CONCLUSIONS: PHD3 expression can be induced by the phosphatidylinositol-3 kinase/Akt/mTOR pathway in RCC independently of HIF proteins. Furthermore, PHD3 has an antiproliferative function independent of HIF protein status in RCC, indicating a novel expression mechanism and function of PHD3. PMID- 24477696 TI - Hierarchical nanostructures of polypyrrole@MnO2 composite electrodes for high performance solid-state asymmetric supercapacitors. AB - A solid-state high performance flexible asymmetric supercapacitor (ASC) was fabricated. Its anode is based on organic-inorganic materials, where polypyrrole (PPy) is uniformly wrapped on MnO2 nanoflowers grown on carbon cloth (CC), and its cathode is made of activated carbon (AC) on CC. The ASC has an areal capacitance of 1.41 F cm(-2) and an energy density of 0.63 mW h cm(-2) at a power density of 0.9 mW cm(-2). An energy storage unit fabricated using multiple ASCs can drive a light-emitting diode (LED) segment display, a mini motor and even a toy car after full charging. The high-performance ASCs have significant potential applications in flexible electronics and electrical vehicles. PMID- 24477695 TI - Role of IL-10 -819(t/c) promoter polymorphism in preeclampsia. AB - Preeclampsia is a severe complication of pregnancy characterized by an excessive maternal systemic inflammatory response with activation of both the innate and adaptive immune system. Interleukin-10 affects maternal intravascular inflammation, as well as endothelial dysfunction. The aim of the study was to investigate the association between IL-10 T-819 C polymorphism and preeclampsia. A total of 120 pregnant women with preeclampsia and 120 women with normal pregnancy attending the Gynecological Unit of Government Maternity Hospital, Petlaburz, Hyderabad, India, were considered for the present study. A standard amplification refractory mutation system (ARMS) PCR was carried out for genotyping of IL-10 T-819 C promoter polymorphism in all the participants. Genotypic distribution of the control and patient groups was compared with values predicted by the Hardy-Weinberg equilibrium using chi2 test. Odds ratios (OR) and their respective 95 % confidence intervals were used to measure the strength of association between IL-10 gene polymorphism and preeclampsia. The frequencies of IL-10 T-819 C genotypes, CC, CT, and TT, were 47.5, 28.3, and 24.2 % in women with preeclampsia and 20.8, 48.3, and 30.8 % in the controls, respectively. There is a significant difference in the distribution of genotypes and alleles of IL-10 T-819 C between the two groups (test power = 0.66). The present study suggests that the IL-10 T-819 C gene promoter polymorphism can be a major genetic regulator in the etiology of preeclampsia. PMID- 24477697 TI - Structure and function in the euglenoid eyespot apparatus: The fine structure, and response to environmental changes. AB - The microanatomy of the eyespot apparatus of Euglena gracilis Z was examined with the electron microscope. The stigma was found to be a membrane-bounded organelle showing no close homology with the chloroplast or any other organelle. The structure and pigment content of the stigma both diminish with extended hetrotrophic growth, and quickly regain normal dimensions upon exposure to light. Synthesis of the red pigment is particularly sensitive to inhibition by chloramphenicol, whereas construction of the structure itself is specifically inhibited by cycloheximide.The paraflagellar body appears to consist of two sets of parallel 80 A striations intersecting at 60 degrees . It is within the flagellar membrane, but separated from the axoneme by another structure, the paraflagellar rod. This elongated structure has an ordered substructure which appears as intersecting sets of parallel striations; part of its basal portion projects as a circular flange which makes contact with the paraflagellar body. PMID- 24477698 TI - The effect of the source of inorganic nitrogen on growth and enzymes of nitrogen assimilation in soybean and wheat cells in suspension cultures. AB - Soybean (Glycine max L. cv. Mandarin) and wheat (Triticum monococcum L.) cells were grown in media with NO3 (-) plus NH4 (+) (B5) and NO3 (-) without NH4 (+) (B5-NH4) as nitrogen sources. Changes in pH, [NO3 (-)] and [NH4 (+)] in media, and dry weight, protein content, nitrate reductase (NR) and glutamate dehydrogenase (GDH) in the cells were followed for about 170 h. With both NH4 (+) and NO3 (-) in the medium, NH4 (+) was utilized very quickly. Soybean cells grew poorly in the absence of NH4 (+) while wheat cells grew equally well on media with or without NH4 (+). When soybean cells were grown in medium with NO3 (-) plus NH4 (+), dry weight and NR activity remained relatively low for several hours after which both increased rapidly. This coincided with the time NH4 (+) was depleted from the medium. In the absence of NH4 (+), soybean cell growth and NR activity remained low. NR activity in wheat cells, and GDH activity in soybean and wheat cells, did not vary significantly in the presence or absence of NH4 (+). PMID- 24477699 TI - The ability of amino compounds and conditioned medium to alleviate the reduced nitrogen requirement of soybean cells grown in suspension cultures. AB - Various nitrogen compounds were tested for their ability to alleviate the reduced nitrogen requirement of soybean cells growing in defined liquid medium containing nitrate as the alternative nitrogen source. Either L-glutamine, L-alanine, putrescine or NH4 (+) satisfied this requirement. Addition of L-glutamate resulted in poor growth. Where growth was stimulated, nitrate reductase (NR) activity increased whereas glutamate dehydrogenase activity in the cells showed no such correlation. In all fresh media which supported rapid growth, NR activity first decreased rapidly to a low value. Subsequent dry weight increases occurred concommitantly with an increase in NR activity. When 2,4-dichlorophenoxyacetic acid was omitted from the medium the growth was slow and the NR activity did not increase. During the first 40 h of incubation in medium containing NH4 (+) plus NO3 (-) the cells produced a growth-enhancing factor(s). This factor(s) was present in the cells and in the medium and eliminated the requirement for reduced nitrogen. PMID- 24477701 TI - Effects of plant hormones on the stomata of barley: A study of the interaction between abscisic acid and kinetin. AB - It is known that kinetin and abscisic acid affect stomatal aperture. A statistically significant interaction between kinetin and abscisic acid at concentrations of abscisic acid between 10(-5) and 10(-6)M is demonstrated for barley. It is suggested from this and other work that the results obtained may only be true for graminaceous species and not for other monocotyledons or for dicotyledons. PMID- 24477700 TI - The role of roots, cytokinins and apical dominance in the control of lateral shoot form in Solanum andigena. AB - The lateral bud of Solanum andigena has the potentiality to develop as a stolon or as a leafy, orthotropic shoot. Natural stolons are normally only produced from underground nodes, but aerial stolons can be induced to form by the application of a combination of indole-3-acetic acid and gibberellic acid (IAA/GA3) paste to the cut surface; under some conditions both natural or induced stolons are converted to upright, leafy shoots. The presence of roots was found to be necessary for the conversion of a natural stolon to a leafy shoot, but this root effect could be replaced by the synthetic cytokinin, 6-benzylaminopurine (BAP). By using alpha-(14)C-BAP it was demonstrated that cytokinin accumulates in the tip of an induced stolon, prior to its conversion to a leafy shoot caused by withdrawal of the IAA/GA3 paste. The application of IAA/GA3 to decapitated plants was shown to influence both the distribution and metabolism of the cytokinin. The possibility that the role of auxin in apical dominance, at least in part, is to control the distribution and metabolism of cytokinins is discussed. PMID- 24477702 TI - [Evidence for catalase activity in peroxisomes of Micrasterias fimbriata (Ralfs)]. AB - By ultrastructural methods, cytology, and cytochemistry it is shown that peroxysomes are present during all stages of the life cycle of the green unicellular alga Micrasterias fimbriata, cultivated on mineral medium. These organelles, surrounded by a single membrane, are in connection with endoplasmic reticulum. In full-grown cells, they are preferentially situated near chloroplasts and cell walls. The number of peroxisomes increase before cellular division and the organelles flow into the young bulge in front of the chloroplast.Application of a modified Graham and Karnosky's medium using DAB at pH 9 shows that an important activity of catalase is present not only at the level of peroxisomes but also at the level of the cell walls and certain Golgi vesicles.The topographic relations of peroxisomes with different cellular organelles and their possible functions in cell wall or mucus synthesis are discussed. PMID- 24477703 TI - The characterisation of vicilin during seed development in Vicia faba (L.). AB - Vicilin and legumin were extracted from developing seeds at different stages using the classical method of repeated isoelectric precipitations. The subunits of these two protein fractions were separated by SDS gel electrophoresis, and it was shown that the sub-unit structure of vicilin changed during development whereas that of legumin did not. Thus vicilin is not a single protein.Vicilin was formed prior to legumin during seed development although the rate of synthesis of the latter was faster, so that in the mature seed the ratio of legumin to vicilin was about 4:1 by weight. PMID- 24477704 TI - Uptake of maleic hydrazide and related compounds into willow. A comparison between molecular structure and biological activity. AB - A study has been made of a range of maleic hydrazide (MH) derivatives to compare their molecular structures with what has already been found concerning MH behaviour in willow (Salix viminalis L.). Use was made of two properties of MH, one of which was the ability to become concentrated into root apices of young willow roots (Coupland and Peel, 1971); the other was the ability of MH to inhibit the uptake of uracil into the sieve elements in bark strip material (Coupland and Peel, 1972). As a result of the present investigations it appears that an unsaturated heterocyclic ring system, including the grouping-CH=CH-CO-NH- is essential to retain the characteristics of the MH molecule. PMID- 24477705 TI - Studies of the mechanism of action of fusicoccin, the fungal toxin that induces wilting, and its interaction with abscisic acid. AB - Effects of fusicoccin alone and together with abscisic acid were observed on the stomatal complex of Commelina communis. The experimental material consisted of isolated epidermal strips incubated in a medium containing the ions required for stomatal opening. Fusicoccin stimulated opening and this was accompanied by potassium entry into the guard cells, and hydrolysis of the starch in their chloroplasts. Abscisic acid alone inhibited potassium entry and starch hydrolysis, but these effects could be almost entirely overcome by fusicoccin.Attempts were made to measure the solute potential of the guard cells under the various treatments. Abscisic acid clearly increased their solute potential, but no absolute measurements could be made in the presence of fusicoccin owing to a failure of plasmolysis even with mannitol solutions of solute potential as low as -35 bars. Experiments using isotopically labelled mannitol indicated a massive uptake into the epidermis in the presence of fusicoccin.The mechanism of stimulation of stomatal opening by fusicoccin probably depends in part on a stimulation of the normal processes associated with opening in the guard cells, but may also involve release of pressure due to destruction of the surrounding cells. The effectiveness of this toxin under natural conditions may depend on its ability to counteract effects of abscisic acid, the stress hormone that induces stomatal closure. PMID- 24477706 TI - Further characterization of the alkali-stable material from the scales of Pleurochrysis scherffelii: A cellulosic glycoprotein. AB - Crude and alkali-purified fractions of scales isolated from the haptophycean alga Pleurochrysis scherffelii Pringsheim were analyzed. The predominantly cellulosic nature of the fibrillar, alkali-resistent polysaccharide component has been confirmed by gas chromatography of the hydrolysate, by X-ray diffraction and by viscosimetric studies using the nitrified product. Peptide material is covalently linked to this cellulosic structural polysaccharide and remains associated with it through the harsh purification treatments. The amino acid composition of this peptide moiety is given. The relationship of this cellulosic "glycoprotein" to other cell wall glycoproteins is discussed and possible functions during the formation and secretion of wall materials are hypothesized. PMID- 24477707 TI - Systematic analysis of neuronal wiring of the rodent deep cerebellar nuclei reveals differences reflecting adaptations at the neuronal circuit and internuclear levels. AB - A common view of the architecture of different brain regions is that, despite their heterogeneity, they have optimized their wiring schemes to make maximal use of space. Based on experimental findings, computational models have delineated how about two-thirds of the neuropil is filled out with dendrites and axons optimizing cable costs and conduction time while keeping the connectivity at the highest level. However, whether this assumption can be generalized to all brain regions has not yet been tested. Here we quantified and charted the components of the neuropil in the four deep cerebellar nuclei (DCN) of the rat's brain. We segmented and traced the neuropil stained with one of two antibodies, one antibody against dendritic microtubule-associated proteins (MAP2a,b) and the second against the Purkinje cell axons (PCP2). We compared fiber length density, average fiber diameter, and volume fraction within different components of the DCN in a random, systematic fashion. We observed differences in dendritic and axonal fiber length density, average fiber diameters, and volume fraction within the four different nuclei that make up the DCN. We observe a relative increase in the length density of dendrites and Purkinje cell axons in two of the DCN, namely, the posterior interposed nucleus and the lateral nucleus. Furthermore, the DCN have a surprisingly low volume fraction of their dendritic length density, which we propose is related to their special circuitry. In summary, our results show previously unappreciated functional adaptations among these nuclei. PMID- 24477708 TI - Four amino acid residues influence the substrate chain-length and regioselectivity of Siganus canaliculatus Delta4 and Delta5/6 desaturases. AB - Although omega3- and omega6- desaturases have been well studied in terms of substrate preference and regiospecificity, relatively little is known about the membrane-bound, "front-end" long chain fatty acid desaturases, such as ?4, Delta5 or Delta6 desaturases. The first vertebrate ?4 desaturase was recently identified in the marine teleost fish Siganus canaliculatus (S. canaliculatus), which also possesses a bifunctional Delta5/6 desaturase. These two long chain polyunsaturated fatty acid desaturases are very different in terms of regiospecificity and substrate chain-length, but share an unusually high degree of amino acid identity (83 %). We took advantage of this similarity by constructing a series of chimeric enzymes, replacing regions of one enzyme with the corresponding sequence of the other. Heterologous expression of the chimeric series of enzymes in yeast indicated that the substitution of a four amino acid region was sufficient to convert a ?4 desaturase to an enzyme with ?6 desaturase activity, and convert a ?5/6 desaturase to an enzyme with a low level of ?4 desaturase activity. In addition, enzymes having both ?4 and ?6 desaturase activities were produced by single or double amino acid substitutions within this four-amino acid region. PMID- 24477709 TI - Cardiopulmonary exercise testing for preoperative risk assessment before pancreaticoduodenectomy for cancer. AB - OBJECTIVE: Pancreaticoduodenectomy is the standard of care for tumors confined to the head of pancreas and can be undertaken with low operative mortality. The procedure has a high morbidity, particularly in older patient populations with preexisting comorbidities. This study evaluated the role of cardiopulmonary exercise testing to predict postoperative morbidity and outcome in high-risk patients undergoing pancreaticoduodenectomy. METHODS: In a prospective cohort of consecutive patients undergoing pancreaticoduodenectomy, those aged over 65 years (or younger with comorbidity) were categorized as high risk and underwent preoperative assessment by cardiopulmonary exercise testing (CPET) according to a predefined protocol. Data were collected on functional status, postoperative complications, and survival. RESULTS: A total of 143 patients underwent preoperative assessment, 50 of whom were deemed to be at low risk for surgery per study protocol. Of 93 high-risk patients, 64 proceeded to surgery after preoperative CPET. Neither anaerobic threshold (AT) nor maximal oxygen consumption ([Formula: see text] O 2 MAX) predicted patient mortality or morbidity. However, ventilatory equivalent of carbon dioxide ([Formula: see text] E/[Formula: see text] CO 2) at AT was a predictive marker of postoperative mortality, with an area under the curve (AUC) of 0.84 (95 % confidence interval [CI] 0.63-1.00, p = 0.020); a threshold of 41 was 75 % sensitive and 95 % specific (positive predictive value 50 %, negative predictive value 98 %). Above this threshold, raised [Formula: see text] E/[Formula: see text] CO 2 predicted poor long-term survival (hazard ratio 2.05, 95 % CI 1.09-3.86, p = 0.026). CONCLUSIONS: CPET is a useful adjunctive test for predicting postoperative outcome in patients being assessed for pancreaticoduodenectomy. Raised CPET derived [Formula: see text] E/[Formula: see text] CO 2 predicts early postoperative death and poor long-term survival. PMID- 24477710 TI - Length of hospitalisation for people with severe mental illness. AB - BACKGROUND: In high-income countries, over the last three decades, the length of hospital stays for people with serious mental illness has reduced drastically although considerable variation remains. In lower-income countries this variation may be greater. Some argue that reduction in hospital stay leads to 'revolving door admissions' and worsening mental health outcomes despite apparent cost savings, whilst others suggest longer stays may be more harmful by institutionalising people to hospital care. OBJECTIVES: To evaluate the effect of short stay/brief admission hospital care with long stay/standard in-patient care in people with serious mental illness. SEARCH METHODS: We searched the Cochrane Schizophrenia Group's register of trials, July 2007 and updated this search in May 2012. SELECTION CRITERIA: We included all randomised controlled trials comparing planned short/brief with long/standard hospital stays for people with serious mental illnesses. DATA COLLECTION AND ANALYSIS: We extracted data independently. For dichotomous data we calculated risk ratios (RR) and their 95% confidence intervals (CI) on an intention-to-treat basis based using a fixed effect model. For continuous data, had we identified such data, we planned to calculate fixed-effect mean differences (MD). We assessed risk of bias for included studies and rated quality of evidence using GRADE. MAIN RESULTS: We included six relevant trials undertaken between 1969 and 1980. We found no significant difference in death (n = 175, 1 RCT, RR in the longer term 0.42, CI 0.10 to 1.83, very low quality evidence). In the long term, there was no difference in improvement of mental state (n = 61, 1 RCT, RR 3.39, CI 0.76 to 15.02, very low quality evidence). There was no difference in readmission to hospital (n = 651, 4 RCTs, RR by the long term 1.26, CI 1.00 to 1.57, low quality evidence). Data for leaving the study prematurely by the longer term showed no difference (n = 229, 2 RCTs, (RR 0.77, CI 0.34 to 1.77, low quality evidence). There was a significant difference favouring short stay (P = 0.01) in numbers of participants with delayed discharge from hospital exceeding the time planned in study (n = 404, 3 RCTs, RR in the longer term 0.54, CI 0.33 to 0.88, low quality evidence). There was no difference in numbers of participants lost to follow-up (n = 404, 3 RCTs, RR by the longer term 1.07, CI 0.70 to 1.62, low quality evidence). Finally, there was a significant difference favouring short-stay hospitalisation for social functioning, including unemployment, unable to housekeep, or unknown employment status (n = 330, 2 RCTs, RR by longer term 0.61, CI 0.50 to 0.76, very low quality evidence). AUTHORS' CONCLUSIONS: The effects of hospital care and the length of stay is important for mental health policy. We found limited low and very low quality data which were all over 30 years old. Outcomes from these studies do suggest that a planned short-stay policy does not encourage a 'revolving door' pattern of admission and disjointed care for people with serious mental illness. More large, well-designed and reported trials are justified especially where a short-stay policy is not routine care. PMID- 24477711 TI - Chronic treatment with 17-DMAG improves balance and coordination in a new mouse model of Machado-Joseph disease. AB - Machado-Joseph disease (MJD) or spinocerebellar ataxia type 3 (SCA3) is a neurodegenerative disease currently with no treatment. We describe a novel mouse model of MJD which expresses mutant human ataxin-3 at near endogenous levels and manifests MJD-like motor symptoms that appear gradually and progress over time. CMVMJD135 mice show ataxin-3 intranuclear inclusions in the CNS and neurodegenerative changes in key disease regions, such as the pontine and dentate nuclei. Hsp90 inhibition has shown promising outcomes in some neurodegenerative diseases, but nothing is known about its effects in MJD. Chronic treatment of CMVMJD mice with Hsp90 inhibitor 17-DMAG resulted in a delay in the progression of their motor coordination deficits and, at 22 and 24 weeks of age, was able to rescue the uncoordination phenotype to wild-type levels; in parallel, a reduction in neuropathology was observed in treated animals. We observed limited induction of heat-shock proteins with treatment, but found evidence that 17-DMAG may be acting through autophagy, as LC3-II (both at mRNA and protein levels) and beclin 1 were induced in the brain of treated animals. This resulted in decreased levels of the mutant ataxin-3 and reduced intranuclear aggregation of this protein. Our data validate this novel mouse model as a relevant tool for the study of MJD pathogenesis and for pre-clinical studies, and show that Hsp90 inhibition is a promising therapeutic strategy for MJD. PMID- 24477712 TI - Enhancement of pediatric ophthalmologic diagnosis with a handheld polarized dermatoscope. AB - OBJECTIVE: In pediatric primary care, an adjunct for ophthalmology diagnosis and monitoring of treatment could be of great advantage. The portable polarized dermatoscope can readily fit the purpose as an alternative to the classic slit lamp device. METHODS: We describe and demonstrate our clinical experience using the dermatoscope for diverse ocular conditions. MAIN MESSAGE: Beyond its effective primary role as an examination tool for detecting dermatopathology, the dermatoscope proves its worth in a variety of separate ophthalmologic clinical states where intricate details need recognition. From corneal or subtarsal foreign body identification, to tear gutter assessment, this instrument can facilitate our work whenever magnification and illumination is beneficial. CONCLUSION: The technique described raises the option of using a substitute for usually lacking, cumbersome equipment for many therapeutic situations, rural clinics and home visits, easily available for the busy pediatrician, demanding little training, and at a reasonable cost. PMID- 24477714 TI - Virtual histology assessment of coronary atheroma influences treatment strategy in the young acute coronary syndrome patient. AB - A 43-year-old woman having significant risk factors for ischaemic heart disease was admitted with an acute coronary syndrome (ACS). Coronary angiography revealed a non-flow limiting lesion in her right coronary artery with the rest of her arteries unremarkable. Risk stratification of the culprit lesion in the right coronary artery through intravascular ultrasound virtual histology demonstrated that the rupture plaque had less than 5% necrotic core with low vulnerability indices. This important finding suggested that the re-rupture risk was low so aggressive pharmacological treatment that can influence the plaque characteristics was instigated in preference to mechanical plaque sealing with a coronary stent. At a year of follow-up the patient was well and had no further events. PMID- 24477713 TI - Clinical features of pediatric nonalcoholic fatty liver disease: a need for increased awareness and a consensus for screening. PMID- 24477715 TI - Breast malignancy masquerading under the cloak of acute urticaria. AB - Urticaria is a common disorder characterised by well-demarcated and intensely pruritic erythematous skin swellings. Common triggers include infection, allergic reactions or medications. While often idiopathic, the presence of urticaria can be associated with underlying systemic disease. We report a case of a patient who presented with diffuse and refractory urticaria. A thorough workup was conducted to determine the aetiology including routine age-appropriate cancer screening. Mammography revealed four lesions in the patient's left breast with biopsy consistent with invasive ductal carcinoma. Disappearance of the urticarial lesions with mastectomy suggests an association between breast malignancy and urticaria. Thus, refractory urticaria with unknown cause should prompt a thorough history, physical examination and review of age-appropriate cancer screening. PMID- 24477716 TI - Spin-dependent ballistic transport properties and electronic structures of pristine and edge-doped zigzag silicene nanoribbons: large magnetoresistance. AB - The electronic structure and conductance of substitutionally edge-doped zigzag silicene nanoribbons (ZSiNRs) are investigated using the nonequilibrium Green's function method combined with the density functional theory. Two-probe systems of ZSiNRs in both ferromagnetic and antiferromagnetic states are considered. Doping effects of elements from groups III and V, in a parallel or antiparallel magnetic configuration of the two electrodes, are discussed. By switching on and off the external magnetic field, we may convert the metallic ferromagnetic ZSiNRs into insulating antiferromagnetic ZSiNRs. In the ferromagnetic state, even- or odd width ZSiNRs exhibit a drastically different magnetoresistance. In an odd-width edge-doped ZSiNR a large magnetoresistance occurs compared to that in a pristine ZSiNR. The situation is reversed in even-width ZSiNRs. These phenomena result from the drastic change in the conductance in the antiparallel configuration. PMID- 24477717 TI - Quantification of cyclic dipeptides from cultures of Lactobacillus brevis R2Delta by HRGC/MS using stable isotope dilution assay. AB - Lactic acid bacteria (LAB) play an important role as natural preservatives in fermented food and beverage systems, reducing the application of chemical additives. Thus, investigating their antifungal compounds, such as cyclic dipeptides, has gained prominence. Previous research has primarily focussed on isolation of these compounds. However, their precise quantification will provide further information regarding their antifungal performance in a complex system. To address this, deuterated labelled standards of the cyclic dipeptides cyclo(Leu Pro), cyclo(Pro-Pro), cyclo(Met-Pro) and cyclo(Phe-Pro) were synthesized, and stable isotope dilution assays were developed, enabling an accurate quantification of cyclo(Leu-Pro), cyclo(Pro-Pro), cyclo(Met-Pro) and cyclo(Phe Pro) in MRS-broth and wort. Quantitative results showed that, in the Lactobacillus brevis R2Delta fermented MRS-broth, the concentrations of cyclo(Leu Pro), cyclo(Pro-Pro) and cyclo(Phe-Pro) were significantly higher (P < 0.05), than in wort for cyclo (Leu-Pro) when compared with their controls. This indicates that the formation of these three cyclic dipeptides is related to L. brevis R2Delta metabolism. Furthermore, this represents the first report of cyclic dipeptides quantification using stable isotope dilution assays in LAB cultures both in vitro and in a food system. PMID- 24477718 TI - Acute and chronic ataxic neuropathies with disialosyl antibodies: a continuous clinical spectrum and a common pathophysiological mechanism. AB - Acute ataxic neuropathies with disialosyl antibodies include Fisher syndrome, ataxic Guillain-Barre syndrome (GBS), and acute sensory ataxic neuropathy. Fisher syndrome and ataxic GBS are more strongly associated with IgG anti-GQ1b and anti GT1a than with anti-GD1b antibodies, whereas the association is reversed in the case of acute sensory ataxic neuropathy. Chronic ataxic neuropathy with disialosyl antibodies is associated with IgM paraprotein to GD1b and GQ1b, which occasionally reacts with GT1a. The clinical, electrophysiological, and pathological features, along with experimental findings, suggest that acute and chronic ataxic neuropathies with disialosyl antibodies form a continuous clinical and pathophysiological spectrum characterized by a complement-mediated disruption at the nodal region and are better classified in the new category of nodo paranodopathies. PMID- 24477720 TI - Influence of pharmaceutical care on the delayed emesis associated with chemotherapy. AB - BACKGROUND: Complete control of emesis during chemotherapy remains to be achieved. This could be improved by increasing adherence to medicines and recommendations. OBJECTIVE: The aim of this study was to analyse the effects of pharmaceutical care on the incidence of delayed chemotherapy-induced nausea and vomiting (CINV) in adult cancer outpatients. METHOD: This is a longitudinal prospective intervention study. Patients included were those who received a new cancer intravenous treatment. We compared complete response (no vomiting and no rescue treatment) and the incidence of nausea in the control group (CG) and in the intervention group (IG), as well as patients' adherence. Pharmaceutical intervention consisted of: reviewing the antiemetic protocol and giving some recommendations to the patients. RESULTS: 102 patients were studied. In the delayed phase complete response was achieved in 84.8 % of the patients in the IG, compared with 69.6 % in the control group [absolute risk reduction (ARR), 15.2 %; p = 0.144]. Regarding absence of vomiting, the difference was higher (71.0 CG vs 97.0 % IG, ARR, 26.0%; p = 0.002). Absence of delayed nausea were also better in the IG (61 vs. 52 %). Compliant patients increased from 59 to 76 %. CONCLUSION: The intervention of a pharmacist reduced the incidence of delayed CINV and improved medication adherence. PMID- 24477722 TI - Enteropathic arthritis in Brazil: data from the Brazilian Registry of Spondyloarthritis. AB - Inflammatory bowel diseases (Crohn's disease and ulcerative rectocolitis) have extraintestinal manifestations 25% of the patients, with the most common one being the enteropathic arthritis. METHODS: Prospective, observational, multicenter study with patients from 29 reference centers participating in the Brazilian Registry of Spondyloarthritis (RBE), which incorporates the RESPONDIA (Ibero-American Registry of Spondyloarthritis) group. Demographic and clinical data were collected from 1472 patients and standardized questionnaires for the assessment of axial mobility, quality of life, enthesitic involvement, disease activity and functional capacity were applied. Laboratory and radiographic examinations were performed. The aim of this study is to compare the clinical, epidemiological, genetic, imaging, treatment and prognosis characteristics of patients with enteropathic arthritis with other types of spondyloarthritis in a large Brazilian cohort. RESULTS: A total of 3.2% of patients were classified as having enteroarthritis, 2.5% had spondylitis and 0.7%, arthritis (peripheral predominance). The subgroup of individuals with enteroarthritis had a higher prevalence in women (P < 0.001), lower incidence of inflammatory axial pain (P < 0.001) and enthesitis (P = 0.004). HLA-B27 was less frequent in the group with enteroarthritis (P = 0.001), even when considering only those with the pure axial form. There was a lower prevalence of radiographic sacroiliitis (P = 0.009) and lower radiographic score (BASRI) (P = 0.006) when compared to patients with other types of spondyloarthritis. They also used more corticosteroids (P < 0.001) and sulfasalazine (P < 0.001) and less non-steroidal anti-inflammatory drugs (P < 0.001) and methotrexate (P = 0.001). CONCLUSION: There were differences between patients with enteroarthritis and other types of spondyloarthritis, especially higher prevalence of females, lower frequency of HLA-B27, associated with less severe axial involvement. PMID- 24477723 TI - Correlation between demographic and clinical variables and fibromyalgia severity. AB - INTRODUCTION: Fibromyalgia (FM) is a rheumatic condition characterized by a picture of generalized chronic pain, hyperalgesia and allodynia. Symptoms such as fatigue, sleep disorders, morning stiffness, headache and paresthesia can also be present. It is also associated with other comorbidities, such as depression, anxiety, irritable bowel syndrome, myofascial pain syndrome and nonspecific urethral syndrome. Few studies have addressed the evolution of FM, especially regarding medium and long-term evolution, such as why some patients do better than others, despite the fact of being submitted to the same treatment. OBJECTIVE: To determine whether there is a correlation between demographic and clinical variables and FM severity. MATERIAL AND METHODS: Sixty women who met the classification criteria for FM of the American College of Rheumatology of 1990 were divided into three groups, according to the severity established by the Fibromyalgia Impact Questionnaire (FIQ): severe (70-100), moderate (50 to 70) and mild (0 to 50). RESULTS: Nine demographic and clinical variables were assessed, with a significant difference (P <0.05) being observed only in the groups showing higher FIQ scores with the presence of depression and workers' compensation interests. CONCLUSION: The impact of FM measured by the FIQ is directly correlated with the severity of depression and the presence of workers' compensation interests. PMID- 24477724 TI - Serum homocysteine levels in children and adolescents with impaired bone health. AB - INTRODUCTION: Association between high serum homocysteine (S-Hcy) levels and low bone mineral density (BMD) and increased fracture risk in postmenopausal women has been documented. Data concerning S-Hcy and bone health in children are scarce. OBJECTIVE: Our aim was to evaluate S-Hcy in children and adolescents with impaired bone health and look for correlations with clinical and laboratory data. PATIENTS AND METHODS: We assessed S-Hcy levels in 37 children and adolescents (22 boys and 15 girls; mean age 13.9 +/- 3.5 years) with prevalent low-energy trauma fractures (mean 3.3 +/- 2.3 per patient) and/or low spinal L1-L4 BMD (below -2SD Z-score; DXA Lunar GE). We also evaluated S-ALP, serum CrossLaps, osteocalcin (S OC), body height, weight, body mass index (BMI) and serum levels of folate and vitamin B12. At the time of assessment, the children were not taking any drugs known to influence bone metabolism. The age-dependent parameters were expressed as Z-scores +/- SD. RESULTS: S-Hcy Z-score was significantly higher (1.3 +/- 1.5; P < 0.0001) and L1-L4 BMD Z-score was significantly lower (-1.7 +/- 1.3; P < 0.0001), respectively, in comparison with reference values. S-ALP did not differ from reference values (P = 0.88), while S-CrossLaps and S-osteocalcin were higher (1.2 +/- 1.8 and 0.4 +/- 0.5; P = 0.0001 and P = 0.001, respectively). S-Hcy was inversely correlated to L1-L4 BMD (r = -0.33; P = 0.05) and S-ALP (r = -0.36; P = 0.04) and not related to number of prevalent fractures (r = 0.01), S-osteocalcin (r = -0.22) or S-CrossLaps (r = 0.003). CONCLUSION: These results suggest increased bone turnover and negative influence of elevated S-Hcy on bone formation and BMD in children and adolescents with recurrent fractures. PMID- 24477725 TI - Evaluation of sub-clinical atherosclerosis and plasma levels of minimally modified LDL in patients with ankylosing spondylitis and its correlation with disease activity. AB - INTRODUCTION: Accelerated atherosclerosis has been shown in some autoimmune diseases, mainly in Systemic Lupus Erythematosus and Rheumatoid Arthritis. Although high prevalence of corticosteroids use may be a confounding factor due to their detrimental effects on several risk factors, systemic inflammation per se is supposed to play an important role in atherogenesis in these patients. METHODS: We have evaluated sub-clinical atherosclerosis and plasma levels of circulating electronegative LDL, which represents the fraction of LDL that is minimally modified, in patients with ankylosing spondylitis (AS). Fourteen patients who fulfilled the modified New York criteria for AS were compared with 13 paired controls. Carotid intimal-media thickness (IMT) was assessed by ultrasonography bilaterally in common carotid artery, internal carotid artery and in the bifurcation. Groups were homogeneous regarding cardiovascular risk factors. Only a single patient in AS group was in use of corticosteroid. RESULTS: The presence of active inflammation was demonstrated by elevated BASDAI and higher CRP levels and in patients versus controls (12.36 vs. 3.45 mg/dl, P = 0.002). No difference was found in carotid IMT between both groups, in any site of artery. Averaged IMT (6 measurements, at 3 pre-specified sites bilaterally) was 0.72 +/- 0.28 in AS group and 0.70 +/- 0.45 mm in controls (P = 0.91). Minimally modified LDL did not differ significantly either between patients and controls (14.03 +/- 17.40 vs. 13.21 +/- 10.21; P = 0.88). CONCLUSIONS: Patients with AS did not show increased carotid IMT in comparison to controls. In the same way, circulating plasma levels of LDL (-), did not differ significantly in both groups. PMID- 24477726 TI - Effectiveness of imaging-guided intra-articular injection: a comparison study between fluoroscopy and ultrasound. AB - OBJECTIVE: Compare the effectiveness of ultrasound and fluoroscopy to guide intra articular injections (IAI) in selected cases. MATERIAL AND METHODS: A prospective study in our outpatient clinics at the Rheumatology Division at Universidade Federal de Sao Paulo (UNIFESP), Brazil, was conducted to compare the short-term (4 weeks) effectiveness of ultrasound and fluoroscopy-guided IAI in patients with rheumatic diseases. Inclusion criteria were: adults with refractory synovitis undergoing IAI with glucocorticoid. All patients had IAI performed with triamcinolone hexacetonide (20mg/ml) with varying doses according to the joint injected. RESULTS: A total of 71 rheumatic patients were evaluated (52 women, 44 whites). Mean age was 51.9 +/- 13 years and 47 of them (66.2%) were on regular DMARD use. Analysis of the whole sample (71 patients) and hip sub-analysis (23 patients) showed that significant improvement was observed for both groups in terms of pain (P < 0.001). Global analysis also demonstrated better outcomes for patients in the FCG in terms of joint flexion (P < 0.001) and percentage change in joint flexion as compared to the USG. Likert scale score analyses demonstrated better results for the patients in the USG as compared to the FCG at the end of the study (P < 0.05). No statistically significant difference between groups was observed for any other study variable. DISCUSSION AND CONCLUSION: Imaging-guided IAI improves regional pain in patients with various types of synovitis in the short term. For the vast majority of variables, no significant difference in terms of effectiveness was observed between fluoroscopy and ultrasound guided IAI. PMID- 24477727 TI - Transcultural adaptation of the "EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI)" into Brazilian Portuguese. AB - INTRODUCTION: The EULAR Sjogren's Syndrome Disease Activity Index (ESSDAI) is an index of primary Sjogren's syndrome (PSS) systemic activity. OBJECTIVE: To perform the ESSDAI transcultural adaptation into Brazilian Portuguese. METHOD: This was a cross-sectional study with 62 patients with PSS according to the criteria of the 2002 American-European Consensus. Six stages were conducted: conceptual, item, semantic, operational, functional, and measurement equivalences (interobserver reproducibility and construct validity). For the validity assessment, the ESSDAI was compared with the Physician's Global Assessment (PhGA), the Sjogren's Syndrome Disease Activity Index (SSDAI), and the Sjogren's Systemic Clinical Activity Index (SCAI). Patients were classified by a specialist physician into two groups according to disease activity (active and inactive), and according to the intention-to-treat (increase in therapy and no increase in therapy). The ESSDAI was tested in these groups. The following statistical tests were used: intraclass correlation coefficient (ICC), Bland-Altman plot for reproducibility, and Spearman's correlation coefficient (r s) and Mann-Whitney's test for validity (P < 0.05 and 95% CI). RESULTS: The mean ESSDAI score was 4.95 +/- 6.73. The reproducibility obtained a strong ICC of 0.89 and good agreement. When compared with other indices, it showed a strong r s with PhGA (0.83; P < 0.000), a moderate r s with SSDAI (0.658; P < 0.000) and a weak r s with the SCAI (0.411; P = 0.001). The group "active" and the group " increase in therapy" had higher ESSDAI values (P = 0.000). CONCLUSION: The Brazilian Portuguese version of ESSDAI was shown to be adaptable, reproducible, and valid for this language. PMID- 24477728 TI - Pain, quality of life, self perception of health and depression in patients with fibromyalgia, submited to hydrokinesiotherapy. AB - OBJECTIVES: The aim of this study was to analyze the effects of treatment by hydrotherapy on quality of life, perception of pain and the severity of depression in a group of patients with fibromyalgia. MATERIALS AND METHODS: We evaluated 64 females divided into two groups: hydrocinesiotherapy (n = 33, 58.2 +/- 10.6 years) and control group (n = 31 with 59.6 +/- 9.4 years) with clinical diagnosis of fibromyalgia. Individuals were assessed by Visual Analog Scale of Pain (VAS), the Fibromyalgia Impact Questionnaire (FIQ) and the Beck Depression Inventory. Participants underwent a treatment in a hydrotherapy pool heated to 33oC over a period of 15 weeks, two sessions per week of 45 minutes, a total of 30 sessions. The exercises were underwater: cardiovascular conditioning, strength training, mobility, coordination, balance and still, stretching exercises and muscle relaxation. The ANOVA 2 * 2 and Kruskall-Wallis was used for statistical analysis RESULTS: There were statistically significant improvements in the perception of pain intensity (Delta% = -28.2%, p < 0, 01), quality of life (Delta% = -32.4%, p < 0, 05) and depression symptoms (Delta% = -35.4%, p < 0, 05) in favor of the Hydrotherapy group compared to the control group. CONCLUSIONS: The study suggests that hydrocinesiotherapy was effective as an alternative therapy for fibromyalgia, however further studies are recommended to test the associations between the variables and intervention programs and using the water activities, and the modifiability of the parameters of physical and mental health when these individuals undergo programs of short, medium and long duration. PMID- 24477729 TI - A systematic review of the influence of anti-TNF on infection rates in patients with rheumatoid arthritis. AB - OBJECTIVE: The present article aims to provide a systematic review of the influence of antitumor necrosis factor (TNF) on infection rates in patients with rheumatoid arthritis (RA). METHOD: Medline was searched to obtain quality control information on infection rates in RA patients treated with anti-TNF. RESULTS: A high proportion of RA patients are now established users of anti-TNF agents. Data from national registries in European countries of patients with RA treated with anti-TNF suggest that biological therapies are closely linked to sepsis. Although previous studies reported a higher risk of infections, there are now emerging data with longer duration of follow-up that suggested an adjusted hazard risk of 1.2. Elderly patients and those with longstanding disease may have a higher rate of serious infections compared to their counterparts who were younger with early disease. There are now emerging data to suggest that anti-TNF therapy is associated with the development of neutropenia shortly after the commencement of treatment. The biologic registries found that RA patients treated with monoclonal antibodies are at increased risk of tuberculosis (TB) compared to those on TNF receptor blockers. This risk of infection needs to be weighed against the established benefits of TNF blockers. CONCLUSION: Current evidence suggests that anti-TNF treatment in RA is closely linked to infection. Patients need to be aware of the risk of infection together with the established benefits of TNF blockers in order to give informed consent for treatment. PMID- 24477730 TI - Update on etiopathogenesis of systemic sclerosis. AB - Systemic Sclerosis (SSc) is an autoimmune disease of multifactorial etiology, triggered by a combination of genetic and environmental factors. Its varied clinical expression results from the complex physiopathogenic interaction of three main elements: proliferative vasculopathy, immune dysregulation and abnormal deposition and remodeling of the extracellular matrix (ECM), of which the characteristic disease fibrosis is the result. Early physiopathogenic events appear to be endothelial injury and imbalance in vascular repair with the activation of endothelial cells, the immune system and platelets, with the release of multiple mediators such as TH2 proinflammatory cytokines and growth factors, triggering a sequence of simultaneous or cascading events that involve several intracellular signaling pathways. The most important result of these events is the hyperactivation of fibroblasts, the main effector cells of fibrosis, which will then produce large amounts of ECM constituents and secrete multiple growth factors and cytokines that perpetuate the process. In this article we review the main factors potentially involved in the etiology of SSc and reexamine the current knowledge about the most important mechanisms involved in the development of lesions that are characteristic of the disease. A better understanding of these physiopathogenic mechanisms will help identify potential therapeutic targets, which may result in advances in the management of this complex and debilitating disease. PMID- 24477731 TI - Sialometry: aspects of clinical interest. AB - Whole saliva is a multiglandular secretion complex consisting of gingival fluid, desquamated epithelial cells, microorganisms, products of bacterial metabolism, food debris, leukocytes mucus from the nasal cavity and the pharynx. Saliva has many functions, including tissue repair, tamponage, protection, digestion, taste, antimicrobial action, maintaining tooth integrity and antioxidant defense system. A decrease in salivary flow (hyposalivation) is a common disorder and it is estimated that approximately 20% of the general population have this alteration. Hyposalivation may be due to diabetes mellitus, hypothyroidism, dehydration, impaired glandular parenchyma by infectious processes, granulomatous diseases or autoimmune and inflammatory conditions (such as Sjogren's syndrome and rheumatoid arthritis), radiotherapy of head and/or neck region, or it may be associated with mood disorders, adverse effects caused by the use of some medications or even be idiopathic. Conventional therapies for the treatment of reduced saliva flow with the use of chemical and gustatory secretagogues are still limited. However, new alternatives have shown great perspective in the treatment of this disorder. To diagnose a patient as having chronic hyposalivation is a challenge in clinical practice and methods of salivary flow assessment are little known by rheumatologists. The serial evaluation of salivary flow is important for the diagnosis and prognosis of certain oral and systemic conditions. This review addresses some aspects related to the role of saliva, the consequences of hyposalivation and methods of salivary flow rate measurement, useful concepts in the daily practice of rheumatology. PMID- 24477732 TI - Adult Still's disease associated with ovarian cancer: case report. AB - We report a case of adult-onset Still's disease in a female patient with fever, myalgia, vanishing rash and bilateral inguinal lymphadenopathy, diagnosed after extensive workup to exclude other rheumatic, infectious and neoplastic diseases. The patient initially responded to corticosteroid therapy, but progressed to increased lymph nodes size that when biopsied, revealed serous ovarian adenocarcinoma. To our knowledge, this is the first report of ovarian neoplasm associated with adult-onset Still's disease. PMID- 24477733 TI - Association between juvenile idiopathic arthritis and osteogenesis imperfecta: case report. AB - The authors report a rare association case of juvenile idiopathic arthritis (JIA) and osteogenesis imperfecta (OI) in a 53 years-old female patient, present a literature review and discuss the radiological aspects of the temporo-mandibular joint involvement. To our knowledge, this is the first case report of JIA an OI association. PMID- 24477734 TI - Effects of physical exercise on serum levels of serotonin and its metabolite in fibromyalgia: a randomized pilot study. AB - To evaluate the effects of aerobic training and stretching on serum levels of serotonin (5HT) and its main metabolite 5-hydroxindolacetic acid (5HIAA). Twenty two women with FM were randomized into one of two exercise modalities (aerobic walking exercise or stretching exercise) to be accomplished three times a week for 20 weeks. The serum levels of 5HT and 5HIAA were evaluated before and after the exercise program by high performance liquid chromatography (HPLC) with colorimetric detection. Within group analysis (pre-post) showed that serum levels of both 5HT and 5HIAA changed significantly in the aerobic group during the 20 week course of therapy (5HT: P = 0,03; 5HIAA: P = 0,003). In the stretching group, however, no statistically significant change was observed (5HT: P=0,491; 5HIAA: P=0,549). Between group statistical comparisons of laboratory measures disclosed that aerobic training was superior to stretching in that it significantly increased the levels of 5HIAA (F test = 6.61; P = 0.01), but the average difference between groups on the levels of 5HT did not meet significance criteria (F test = 3.42; P = 0.08). Aerobic training increases the 5HIAA and 5HT levels and it could explain why aerobic exercise can improve symptoms in fibromyalgia syndrome patient more than stretching exercise. PMID- 24477735 TI - Prevalence of juvenile idiopathic arthritis in children aged 6 to 12 years in Embu das Artes, state of Sao Paulo, Brazil. AB - The aim of the study was to study the prevalence of juvenile idiopathic arthritis (JIA) in school children in the city of Embu das Artes in Sao Paulo State. 2880 school children from seven public schools, aged between 6 and 12 years, were evaluated (clinical findings) by a pediatric rheumatologist. A board certified Pediatric Rheumatologist evaluated the subjects with suspected inflammatory arthropathy. Children with higher suspicion were referred to a specialized service. One hundred and forty-one children have presented abnormalities on examination of musculoskeletal system, with isolated pain on palpation the most common finding in the first evaluation (60.9%), with improvement in almost all cases in the second examination. Most of the abnormalities were related to recent injuries or congenital malformations. Six children have clinical findings suggestive of chronic arthropathy and were referred to a specialized pediatric rheumatology clinic. Of these, a 12 year-old girl fulfilled the criteria for JIA. The other diagnoses were aseptic necrosis of the hip (P = 1) of and post-trauma synovitis (P = 4). The prevalence of JIA in children aged between 6 and 12 years was 1/2.880 (or 0.34/1.000). PMID- 24477737 TI - Disease-associated mutations of TDP-43 promote turnover of the protein through the proteasomal pathway. AB - TAR DNA-binding protein (TDP-43) is a major component of most ubiquitin-positive neuronal and glial inclusions of amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD). A number of missense mutations in the TARDBP gene have been identified in patients with familial and sporadic ALS, as well as familial FTLD with ALS. In the diseased states, TDP-43 proteins exhibit characteristic alterations, including truncation, abnormal phosphorylation, and altered subcellular distribution. However, the mechanisms by which TDP-43 mutations induce neurodegeneration remain unclear at present. In the current study, we analyzed protein turnover and subcellular distribution of wild-type TDP 43 and two disease-associated mutants (G298S and A382T) in human neuroblastoma SH SY5Y cells stably expressing TDP-43 with a C-terminal tag. Cycloheximide chase experiments revealed more rapid turnover of TDP-43 mutant proteins than their wild-type counterpart. The decrease in the TDP-43 level after cycloheximide treatment was partially recovered upon co-treatment with the proteasome inhibitor, epoxomicin, but not the lysosomotropic agent, chloroquine, suggesting involvement of the proteasomal pathway in TDP-43 degradation. Analysis of the subcellular distribution of TDP-43 revealed predominant localization in the nuclear fraction, whereas the relative level in the cytoplasm remained unaltered in cells expressing either mutant protein, compared with wild-type protein. Our results suggest that higher turnover of disease-associated mutant TDP-43 proteins through the ubiquitin proteasome system is pathogenetically relevant and highlight the significance of proteolysis in the pathogenetic mechanism of TDP-43 proteinopathy. PMID- 24477738 TI - Endovascular therapy in patients with genetically triggered thoracic aortic disease: applications and short- and mid-term outcomes. AB - OBJECTIVES: For patients with genetically triggered thoracic aortic disease, the morbidity and mortality associated with reoperation are high, making endovascular treatment an appealing option. We evaluated the short- and mid-term outcomes of different applications of endovascular intervention in such patients. METHODS: Between January 2003 and April 2013, 60 patients received endovascular or hybrid treatment for genetically triggered thoracic aortic disease. The inclusion criteria were based on those devised by the National Registry of Genetically Triggered Thoracic Aortic Aneurysms and Cardiovascular Conditions. We included patients with thoracic aneurysm or dissection not due to trauma in a patient aged <=50 years (n = 30), bicuspid aortic valve (BAV) and coarctation (n = 11), Marfan syndrome (n = 10), BAV with thoracic aneurysm (n = 4), Loeys-Dietz syndrome (n = 3), familial thoracic aneurysm or dissection (n = 3) and genetic mutations (n = 2). Some patients met more than one inclusion criterion. Forty-one (68.3%) patients were treated with only endovascular stent grafting. Nineteen (31.7%) patients underwent a hybrid procedure with open proximal or total arch replacement and concomitant endovascular stenting of the aortic arch or the descending thoracic aorta. Twenty-nine (48.3%) had previous cardiovascular operations (mean +/- SD, 1.9 +/- 1.4) before undergoing hybrid or endovascular therapy. The median follow-up was 2.3 years (interquartile interval 25-75%, 1.4 4.6 years). RESULTS: The technical success rate was 100%. In-hospital mortality was 3.3% (n = 2) and neurological events occurred in 2 patients; 1 (1.6%) had a stroke and 1 (1.6%) suffered paraparesis with partial recovery. Fifteen repeat open or endovascular interventions were required in 10 surviving patients (17.2%). Overall survival during follow-up was 94.8% (55/58). CONCLUSIONS: Endovascular technology can be helpful in treating selected young patients with genetically triggered thoracic aortic disease. Long-term studies and further evolution of endovascular technology will be necessary for it to be incorporated into the armamentarium of surgical options for this challenging patient population. PMID- 24477739 TI - Long-term outcomes of tricuspid valve replacement after previous left-side heart surgery. AB - OBJECTIVES: To assess long-term outcomes of tricuspid valve replacement (TVR) after previous left-side heart surgery. METHODS: We reviewed reoperative TVR after left-side heart surgery performed at our institution between March 1997 and June 2012. In-hospital data were retrieved from our institutional database or medical records; follow-up was performed through telephone call, surviving patients being asked to provide a recent (<=6 months) echocardiogram. RESULTS: Reoperative TVR was performed in 117 patients. Preoperative characteristics included: mean age 63.7 years, median logistic EuroSCORE (LES) 11.8, New York Heart Association (NYHA) class >2 in 79.5% of patients, right ventricle (RV) dysfunction >mild in 23.9% of patients and mean systolic pulmonary artery pressure (sPAP) 48.4 mmHg. A mechanical prosthesis was implanted in 5.1% of patients. A right thoracotomy was preferred to median sternotomy in 8.6% of cases. Isolated-TVR (I-TVR) was performed in 52.1% of patients, a beating-heart approach being used in 85.2% of I-TVR cases. Postoperative RV failure occurred in 46.1% of patients. Median length-of-stay was 11.5 days. Thirty-day mortality was 6.0% overall and 8.2% in the I-TVR group. Higher preoperative LES (P = 0.002), ascites (P = 0.004), RV dysfunction (P = 0.033) and sPAP (P = 0.046) were associated with acute mortality. No significant difference in acute outcomes was observed between beating and arrested-heart I-TVR, except for postoperative median length-of-stay (9 vs 28 days, respectively, P = 0.007). Among survivors median follow-up time was 5.1 years. Five-year and 10-year freedom from cardiac death were 79.4 and 61.0%, freedom from tricuspid reoperation were 97.3 and 87.5%, freedom from bioprosthesis degeneration were 92.8 and 74.3%, respectively. Five-year and 10-year survival in the I-TVR subgroup were respectively 74.4 and 61.6%. Higher preoperative sPAP was associated with increased follow-up mortality (P = 0.048). At the last follow-up, NYHA class I-II was found in 86.1% of surviving patients. CONCLUSIONS: In selected cases, TVR is currently feasible with low acute mortality, especially if performed in the absence of ascites, significant RV dysfunction and pulmonary hypertension. Long-term mortality remains more difficult to predict, although it appeared to be also associated with higher preoperative pulmonary pressure. The global high-complexity profile of these patients is likely to impair long-term outcomes. PMID- 24477740 TI - Segmentectomy for clinical stage IA lung adenocarcinoma showing solid dominance on radiology. AB - OBJECTIVES: This study aimed to compare prognosis after segmentectomy and after lobectomy for radiologically determined solid-dominant clinical stage IA lung adenocarcinoma. METHODS: From a multicentre database of 610 consecutive patients with clinical stage IA lung adenocarcinoma who underwent complete resection after preoperative high-resolution computed tomography (HRCT) and F-18 fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT), 327 patients with a radiologically determined solid-dominant tumour (solid component on HRCT >=50%) who underwent lobectomy (n = 286) or segmentectomy (n = 41) were included. RESULTS: No significant difference existed in recurrence-free survival (RFS) between the lobectomy and segmentectomy groups (3-year RFS, 84.4 vs 84.8%, respectively; P = 0.69). There was no significant difference in recurrence pattern between these two groups (local, 5.6 vs 7.3%, P = 0.72; distant, 9.1 vs 4.9%, P = 0.55, respectively). Even in patients with pure solid tumours, no significant difference was observed in RFS between lobectomy and segmentectomy groups (3-year RFS, 76.8 vs 84.7%, respectively; P = 0.48), as well as in those with a mixed ground-glass opacity tumour (3-year RFS, 91.0 vs 85.0%, respectively; P = 0.60). Multivariate Cox analysis demonstrated that solid tumour size on HRCT (P = 0.048) and maximum standardized uptake value (SUVmax) on FDG PET/CT (P < 0.001), not the surgical procedure (P = 0.40), were independent prognostic factors for RFS. CONCLUSIONS: RFS depends on solid tumour size on HRCT and SUVmax on FDG-PET/CT, rather than on the surgical procedure, in patients with radiologically detected solid-dominant clinical stage IA lung adenocarcinoma. Patient prognosis is similar after lobectomy and after segmentectomy for solid dominant tumour. PMID- 24477741 TI - Failed valve-in-valve transcatheter mitral valve implantation. PMID- 24477742 TI - Syncope caused by pulmonary artery intima sarcoma: a cardiac magnetic resonance imaging-based differentiating diagnosis. PMID- 24477743 TI - Can extracapsular lymph node involvement be a tool to fine-tune pN1 for adenocarcinoma of the oesophagus and gastro-oesophageal junction in the Union Internationale contre le Cancer (UICC) TNM 7th edition??. AB - OBJECTIVES: The current (7th) International Union Against Cancer (UICC) pN staging system is based on the number of positive lymph nodes but does not take into consideration the characteristics of the metastatic lymph nodes itself. In particular, it has been suggested that tumour penetration beyond the lymph node capsule in metastatic lymph nodes, which is also called extracapsular lymph node involvement, has a prognostic impact. The aim of the current study was to assess the prognostic value of extracapsular (EC) and intracapsular (IC) lymph node involvement (LNI) in adenocarcinoma of the oesophagus and gastro-oesophageal junction (GOJ) and to assess its potential impact on the 7th edition of the UICC TNM manual. METHODS: From 2000 to 2010, all consecutive adenocarcinoma patients with primary R0-resection (n = 499) were prospectively included for analysis. The number of resected lymph nodes, number of positive lymph nodes and number of EC LNI/IC-LNI were determined. Extracapsular spread was defined as infiltration of cancer cells beyond the capsule of the positive lymph node. RESULTS: Two hundred and eighteen (43%) patients had positive lymph nodes. Cancer-specific 5-year survival in lymph node-positive patients was significantly (P < 0.0001) worse compared with lymph node-negative patients, being 88.3 vs 28.7%, respectively. In 128 (58.7%) cases EC-LNI was detected. EC-LNI showed significantly worse cancer specific 5-year survival compared with IC-LNI, 19.6 vs 44.0% (P < 0.0001). In the pN1 category (1 or 2 positive LN's-UICC stages IIB and IIIA), this was 30.4% vs 58%; (P = 0.029). In higher pN categories, this effect was no longer noticed. Integrating these findings into an adapted TNM classification resulted in improved homogeneity, monotonicity of gradients and discriminatory ability indicating an improved performance of the staging system. CONCLUSIONS: EC-LNI is associated with worse survival compared with IC-LNI. EC-LNI patients show survival rates that are more closely associated with the current TNM stage IIIB, while IC-LNI patients have a survival more similar to TNM stage IIB. Incorporating the EC-IC factor in the TNM classification results in an increased performance of the TNM model. Further confirmation from other centres is required within the context of future adaptations of the UICC/AJCC (American Joint Committee on Cancer) staging system for oesophageal cancer. PMID- 24477744 TI - Massive anterior chamber involvement after intra-arterial chemotherapy for retinoblastoma: ultrasound biomicroscopy and histopathology. AB - This case report highlights the usefulness of Ultrasound Biomicroscopy (UBM) in a case of retinoblastoma which showed massive anterior chamber involvement after treatment with intra-arterial chemotherapy. UBM was used to document tumour pseudohypopion, cells in the aqueous humor, implanted clusters of cells on the corneal endothelium, iris nodules, lens capsule deposits and ciliary body invasion. The UBM data, compared with the histopathologic analysis, performed on eye tissue, after enucleation of the affected eye, revealed a significant concordance. UBM may represent an important diagnostic tool in retinoblastoma, when the decision about enucleation of the eye must be made in the absence of histopathologic data. PMID- 24477745 TI - (18)Fluorine-fluorodeoxyglucose positron emission tomography/computed tomography total glycolytic volume in thymic epithelial neoplasms evaluation: a reproducible image biomarker. AB - INTRODUCTION: (18)Fluorine-fluorodeoxyglucose positron emission tomography/computed tomography is not yet accepted as a standard pretreatment evaluation of thymic epithelial neoplasm (TEN). Statistical correlation between standardized uptake value of tumor/mediastinum ratio and patients' WHO risk class has been reported. PET metabolic tumor volume (MTV) and total glycolytic volume (TGV) have been reported as additional prognostic imaging biomarkers in several human tumors. Purpose of study was to establish whether MTV and TGV add prognostic information in TEN. MATERIALS AND METHODS: A retrospective dynamic cohort study of prospectively collected data (2006-2012) on 23 consecutive patients with pathologically proven TEN (no thymic carcinoma) was conducted. All patients underwent chest CT, and PET for staging. SUV T/M ratio, semi quantitative and volumetric analyses of TEN were calculated. Patients were categorized according to WHO classification (low-risk and high-risk thymomas). Statistical analysis was performed with bootstrap method. Multi-collinearity was established using Pearson correlation coefficient. Cut-off point for TGV was compared using Mantel Cox log rank test. RESULTS: SUV T/M ratio, MTV, and TGV correlate with low- and high-risk TEN. However, the statistical correlation between TGV and WHO classification (rho = 0.897) was higher than SUV T/M ratio (rho = 0.873). Since sample distributions were not uniformly smooth, only one cut off value was identified: a TGV of 383 served as a cut-off value between low-risk and high-risk TEN. CONCLUSION: TGV is a PET reproducible imaging marker in patients with TEN, provides prognostic information, and could be useful in pretreatment stratification of patients. Nevertheless, it needs validation in larger cohort studies. PMID- 24477746 TI - Repeated occurrence of slow flow phenomenon during and late after sirolimus eluting stent implantation. AB - A 78-year-old man with unstable angina showed 90% stenosis in the proximal left anterior descending artery. Pre-procedural intravascular ultrasound revealed ruptured plaque and attenuated plaque in the lesion. Under these conditions, two overlapping sirolimus-eluting stent (SES) implantation in this lesion resulted in slow flow which was recovered by intracoronary nitrates, nicorandil, and nitroprusside without further complications. When the patient showed up again 5 years later with recurrence of angina pectoris, angiography revealed a hazy ulcerated in-stent restenosis (ISR) at the site of the SES. Pre-procedural optical coherence tomography (OCT) imaging revealed multiple intimal ruptures, cavity formation behind the stent struts, a thin-cap fibroatheroma containing neointima surrounded by signal-poor, lipid-rich area in the proximal SES, suggesting the progression of neoatherosclerosis within SES. Importantly, there occurred slow flow again after balloon angioplasty for this lesion. We would suggest careful OCT examination is warranted to confirm development of neoatherosclerosis within the stent, and distal protection device should be considered to prevent slow flow phenomenon even in a patient with very late ISR. PMID- 24477747 TI - Gastrointestinal parasites of free-living Indo-Pacific bottlenose dolphins (Tursiops aduncus) in the Northern Red Sea, Egypt. AB - The present study represents the first report on the gastrointestinal parasite fauna infecting the free-living and alive Indo-Pacific bottlenose dolphins (Tursiops aduncus) inhabiting waters of the Red Sea at Hurghada, Egypt. A total of 94 individual faecal samples of the examined bottlenose dolphins were collected during several diving expeditions within their natural habitats. Using classical parasitological techniques, such as sodium acetate acetic acid formalin method, carbol fuchsin-stained faecal smears, coproantigen ELISA, PCR and macroscopical analyses, the study revealed infections with 21 different parasite species belonging to protozoans and metazoans with some of them bearing zoonotic and/or pathogenic potential. Four identified parasite species are potential zoonotic species (Giardia spp., Cryptosporidium spp., Diphyllobothrium spp., Ascaridida indet.); three of them are known to have high pathogenic potential for the examined dolphin species (Nasitrema attenuata, Zalophotrema spp. and Pholeter gastrophilus) and some appear to be directly associated with stranding events. In detail, the study indicates stages of ten protozoan species (Giardia spp., Sarcocystis spp., Isospora (like) spp., Cystoisospora (like) spp., Ciliata indet. I and II, Holotricha indet., Dinoflagellata indet., Hexamita (like) spp., Cryptosporidium spp.), seven trematode species (N. attenuata, Nasitrema spp. I and II, Zalophotrema curilensis, Zalophotrema spp., Pholeter gastrophilus, Trematoda indet.), one cestode species (Diphyllobothrium spp.), two nematode species (Ascaridida indet, Capillaria spp.) and one crustacean parasite (Cymothoidae indet.). Additionally, we molecularly identified adult worms of Anisakis typica in individual dolphin vomitus samples by molecular analyses. A. typica is a common parasite of various dolphin species of warmer temperate and tropical waters and has not been attributed as food-borne parasitic zoonoses so far. Overall, these parasitological findings include ten new host records for T. aduncus (i.e. in case of Giardia spp., Sarcocystis spp., Cryptosporidium spp., Nasitrema spp., Zalophotrema spp., Pholeter gastrophilus, A. typica, Capillaria spp., Diphyllobothrium spp. and Cymothoidae indet.). The present results may be used as a baseline for future monitoring studies targeting the impact of climate or other environmental changes on dolphin's health conditions and therefore contribute to the protection of these fascinating marine mammals. PMID- 24477748 TI - Trends in alcohol and other drugs detected in fatally injured drivers in the United States, 1999-2010. AB - Drugged driving is a safety issue of increasing public concern. Using data from the Fatality Analysis Reporting System for 1999-2010, we assessed trends in alcohol and other drugs detected in drivers who were killed within 1 hour of a motor vehicle crash in 6 US states (California, Hawaii, Illinois, New Hampshire, Rhode Island, and West Virginia) that routinely performed toxicological testing on drivers involved in such crashes. Of the 23,591 drivers studied, 39.7% tested positive for alcohol and 24.8% for other drugs. During the study period, the prevalence of positive results for nonalcohol drugs rose from 16.6% in 1999 to 28.3% in 2010 (Z = -10.19, P < 0.0001), whereas the prevalence of positive results for alcohol remained stable. The most commonly detected nonalcohol drug was cannabinol, the prevalence of which increased from 4.2% in 1999 to 12.2% in 2010 (Z = -13.63, P < 0.0001). The increase in the prevalence of nonalcohol drugs was observed in all age groups and both sexes. These results indicate that nonalcohol drugs, particularly marijuana, are increasingly detected in fatally injured drivers. PMID- 24477750 TI - Deep UV generation and direct DNA photo-interaction by harmonic nanoparticles in labelled samples. AB - A biophotonics approach based on the nonlinear optical process of second harmonic generation is presented and demonstrated on malignant human cell lines labelled by harmonic nanoparticles. The method enables independent imaging and therapeutic action, selecting each modality by simply tuning the excitation laser wavelength from infrared to visible. In particular, the generation of deep ultraviolet radiation at 270 nm allows direct interaction with nuclear DNA in the absence of photosensitizing molecules. PMID- 24477751 TI - Auxin transport in roots : VII. Uptake and movement of radioactivity from IAA (14)C by Zea roots. AB - The net uptake and movement of radioactivity by 12-mm root segments of Zea mays have been studied as a function of time at 5, 15 and 25 degrees C. Segments were supplied with an agar donor block containing 1 MUM IAA-1-(14)C or IAA-2-(14)C continuously or for a limited period of time (pulse-labelling). In the latter case the original donor block was replaced either by a plain agar block or by one containing 1 MUM unlabelled IAA. Receiver blocks were placed at the other end of the segments.The net uptake of radioactivity from the donor block at 15 degrees C was greater at the basal end than at the apical end of the segment. At 5 and 15 degrees C, the net uptake from a basal donor was virtually linear with time but at 25 degrees C the rate of net accumulation decreased after about 10 h. Decarboxylation of IAA undoubtedly occurred at 15 and 25 degrees C when the concentration in the tissue attained a high value.An acropetally polarised movement of radioactivity into the receiver blocks occurred regardless of whether the results were based on the actual amounts of radioactivity in the receiver block, or on the amounts in the receiver block expressed as a percentage of the net total radioactivity accumulated from the donor block. Only one radioactive substance was present in the receiver block and it ran to the same Rf as IAA in the isopropanol: ammonium: water solvent system.The amounts of radioactivity moving into that part of the root segment at least 6 mm distant from the end in contact with either an apical or a basal donor block were assessed. An acropetal polarity in the movement of radioactivity was observed on the basis of the actual amounts of radioactivity in these distal parts of the segments, but no such polarity was evident when the amounts of radioactivity were expressed as a percentage of the net total accumulated from the donor block. At least 3 radioactive substances were present in the tissue in addition to the substance running to the same Rf as IAA. The distribution of radioactivity in the segment cannot therefore be used to assess the distribution of IAA.Acropetal movement of radioactivity into an apical receiver block is not dependent upon the continued uptake of IAA at the basal end of the segment. No distinct pulses of radioactivity were detected moving through the root segments.Only a small part of the radioactivity in the root segment appears to be located in the polar transport system, while the bulk is not. The polarity found in the movement of the bulk radioactivity within the segment seems to be related to the polarity in IAA uptake from the donor blocks. PMID- 24477752 TI - The occurrence of microbodies and peroxisomal enzymes in achlorophyllous leaves. AB - Several types of leaves of leaf parts lacking chlorophyll were fixed and embedded according to conventional procedures and examined electron-microscopically for microbodies. Comparisons of relative abundance of microbodies, plastids and mitochondria were made by computing the average numbers of organelle profiles per cell section. Similar leaves were homogenized and assayed for three enzymes characteristic of leaf peroxisomes. The localization of these enzymes in microbodies was indicated for the achlorophyllous tissues by the positive result obtained when 3,3'-diaminobenzidine was used as an electron cytochemical stain for catalase activity.Microbodies were present in all non-photosynthetic leaves or leaf parts examined, including yellowish-white segments of variegated leaves, albino leaves, and etiolated leaves of two species. In several cases, the numbers of microbody profiles per cell section were as great in the achlorophyllous leaves as in the chlorophyllous. The levels of peroxisomal enzyme activity in the yellowish-white leaves were substantial, although often not as high as in the green leaves. It was concluded that enzymatically these microbodies are probably similar to the peroxisomes characterized from chlorophyllous leaves. In the absence of the photosynthetic product, glycolate, however, it seems unlikely that the organelle is performing the same functions as in green leaves. It is also apparent that the initial formation of peroxisomes in leaves can occur when neither light nor a photosynthate such as glycolate is present as an inducer. PMID- 24477753 TI - Transport of indoleacetic acid in intact roots of Phaseolus coccineus. AB - Indoleacetic acid (IAA)-5-(3)H (2*10(-9)) was applied to intact roots of Phaseolus coccineus seedlings at the apex or 2 cm above the apex, and the movement of IAA-(3)H and its metabolites traced by sectioning and chromatography. Basipetal movement of label occurred for 2 cm or less, declining exponentially, and the amount increased with time. Acropetal transport from above the apex showed quantitatively less movement of radioactivity. After a 6h treatment period a decline of label occurred in the first 0.5cm, below which there was a long distance movement of small amounts of label, mainly in IAA, towards the apex where the label concentrated by a factor of approximately 2. Short-distance basipetal movement consisted of about equal amounts of IAA and metabolites, and only metabolites were found in areas more basipetal than 2cm. Label from solutions of sucrose-(14)C and (3)H2O followed the same general pattern of movement as label from IAA-(3)H, except that acropetal movement of water showed a steady decrease in the amount of label as the distance from the area of application increased. The short distance basipetal transport of label with the breakdown of IAA-(3)H indicates that the extent of basipetal movement was limited by catabolic processes. The acropetal pattern of IAA-(3)H movement with the concentration of the transported material close to the apex, is possibly the result of transport in the phloem. PMID- 24477754 TI - The influence of the origin of the mother plant on yield and germination of their caryopses in Aegilops ovata. AB - Dispersal units of Aegilops ovata contain in their spikelets caryopses differing in morphology, weight and germinability according to their position in the spikelets. Plants originating from caryopses of the diverse orders were grown under various photo- and thermoperiodic conditions, and the caryopses harvested germinated under uniform conditions. Under all conditions tested, the relative difference in weight between the caryopses of the various orders was not affected. But plants grown under long days and/or low temperatures produced heavier caryopses than plants grown under short days and/or high temperatures respectively. There was a positive correlation between weight and germinability in caryopses of the various orders derived from one mother plant, and a reverse correlation in caryopses formed on mother plants grown under low and high temperatures. When mother plants arising from various orders of caryopses were grown under long days and low temperatures, they produced caryopses of different germinability, showing that the origin of the mother plant may affect the germination qualities of its offspring. The implications of these results are discussed. PMID- 24477755 TI - Ethylene biosynthesis: Methionine as an in-vivo precursor of ethylene in auxin treated mungbean hypocotyl segments. AB - Ethylene production was induced in excised hypocotyl segments of etiolated mungbean seedlings in response to exogenous auxin. 1,2,3,4-(14)C-Methionine was efficiently incorporated into C2H4, although cold methionine added at substrate level did not enhance C2H4 production. Incorporation of labeled glucose into C2H4 was reduced when hypocotyl segments were incubated with cold methionine and homoserine, but the rate of labeling of CO2 was not affected. Feeding of labeled glucose to segments resulted in production of labeled methionine both in the presence and the absence of auxin, and auxin did not affect rate of methionine synthesis from glucose. The decrease in the amount of endogenous methionine during auxin treatment approximated the amount of C2H4 produced. The timecourse pattern of incorporation of radioactivity from labeled methionine into C2H4 during removal or re-addition of auxin was very similar to that of C2H4 production. The role of endogenous methionine as a C2H4 precursor is discussed. PMID- 24477756 TI - [The fine structure of lamellar inclusions in the nuclei of nectary gland cells in Catalpa bungei]. AB - In the nectary of Catalpa bungei the gland cells contain nuclear inclusions consisting of stacks of lamellae 12.7 nm thick. Each lamella is composed of globular particles with a diameter of approximately 12.7 nm. The particles are arranged in a monolayer, revealing a regular square pattern in face view. In adjacent lamellae the globular subunits are almost exactly superimposed; each of them is probably built up of smaller subunits having a diameter of 0.4 nm. PMID- 24477757 TI - [The ability of Agrobacterium to induce tumors and to produce phage PS8]. AB - Twenty strains of the genus Agrobacterium do not show any correlation between tumor-initiating ability and the ability to produce the bacteriophage PS8. Only some virulent strains produce the phage at temperatures permissive and non permissive for tumor induction. PMID- 24477758 TI - Cu(I)-based delafossite compounds as photocathodes in p-type dye-sensitized solar cells. AB - The research of p-type dye-sensitized solar cells (p-DSSCs) has attracted growing attention because of the potential for integration with conventional n-type DSSCs (n-DSSCs) into the more efficient tandem-DSSCs. However, to date the performance of p-DSSCs is lagging behind that of n-DSSCs. One main reason is the lack of optimal photocathode materials. This article reviews the most recent progress in utilizing Cu(I)-based delafossite compounds, CuMO2 (M = Al, Ga or Cr), as photocathodes in p-DSSCs. As alternative materials to the commonly used NiO, the CuMO2 compounds have their intrinsic advantages such as lower valence band edge, larger optical bandgap and higher conductivity. By providing an insight into these materials and their applications in p-DSSCs, this perspective aims to stimulate more exciting research in the development of p-DSSCs as well as of tandem-DSSCs. PMID- 24477760 TI - Statistical analysis of quiet stance sway in 2-D. AB - Subjects exposed to a rotating environment that perturbs their postural sway show adaptive changes in their voluntary spatially directed postural motion to restore accurate movement paths but do not exhibit any obvious learning during passive stance. We have found, however, that a variable known to characterize the degree of stochasticity in quiet stance can also reveal subtle learning phenomena in passive stance. We extended Chow and Collins (Phys Rev E 52(1):909-912, 1995) one dimensional pinned-polymer model (PPM) to two dimensions (2-D) and then evaluated the model's ability to make analytical predictions for 2-D quiet stance. To test the model, we tracked center of mass and centers of foot pressures, and compared and contrasted stance sway for the anterior-posterior versus medio-lateral directions before, during, and after exposure to rotation at 10 rpm. Sway of the body during rotation generated Coriolis forces that acted perpendicular to the direction of sway. We found significant adaptive changes for three characteristic features of the mean square displacement (MSD) function: the exponent of the power law defined at short time scales, the proportionality constant of the power law, and the saturation plateau value defined at longer time scales. The exponent of the power law of MSD at a short time scale lies within the bounds predicted by the 2-D PPM. The change in MSD during exposure to rotation also had a power-law exponent in the range predicted by the theoretical model. We discuss the Coriolis force paradigm for studying postural and movement control and the applicability of the PPM model in 2-D for studying postural adaptation. PMID- 24477761 TI - Torque response to external perturbation during unconstrained goal-directed arm movements. AB - It is unclear to what extent control strategies of 2D reaching movements of the upper limbs also apply to movements with the full seven degrees of freedom (DoFs) including rotation of the forearm. An increase in DoFs may result in increased movement complexity and instability. This study investigates the trajectories of unconstrained reaching movements and their stability against perturbations of the upper arm. Reaching movements were measured using an ultrasound marker system, and the method of inverse dynamics was applied to compute the time courses of joint torques. In full DoF reaching movements, the velocity of some joint angles showed multiple peaks, while the bell-shaped profile of the tangential hand velocity was preserved. This result supports previous evidence that tangential hand velocity is an essential part of the movement plan. Further, torque responses elicited by external perturbation started shortly after perturbation, almost simultaneously with the perturbation-induced displacement of the arm, and were mainly observed in the same joint angles as the perturbation torques, with similar shapes but opposite signs. These results indicate that these torque responses were compensatory and contributed to system stabilization. PMID- 24477762 TI - Factors affecting grip force: anatomy, mechanics, and referent configurations. AB - The extrinsic digit muscles naturally couple wrist action and grip force in prehensile tasks. We explored the effects of wrist position on the steady-state grip force and grip-force change during imposed changes in the grip aperture [apparent stiffness (AS)]. Subjects held an instrumented handle steady using a prismatic five-digit grip. The grip aperture was changed slowly, while the subjects were instructed not to react voluntarily to these changes. An increase in the aperture resulted in an increase in grip force, and its contraction resulted in a proportional drop in grip force. The AS values (between 4 and 6 N/cm) were consistent across a wide range of wrist positions. These values were larger when the subjects performed the task with eyes open as compared to eyes closed trials. They were also larger for trials that started from a larger initial aperture. After a sequence of aperture increase and decrease to the initial width, grip force dropped by about 25% without the subjects being aware of this. We interpret the findings within the referent configuration hypothesis of grip-force production. The results support the idea of back-coupling between the referent and actual digit coordinates. According to this idea, the central nervous system defines referent coordinates for the digit tips, and the difference between the referent and actual coordinates leads to force production. If actual coordinates are not allowed to move to referent ones, referent coordinates show a relatively slow drift toward the actual ones. PMID- 24477763 TI - Effects of probability bias in response readiness and response inhibition on reaching movements. AB - It is solidly established that unequal stimulus frequencies lead to faster responses to the more likely stimulus; however, the effect of this probability bias on response inhibition is still debated. To tackle this issue, we administered two versions of the stop-signal task to 18 right-handed healthy subjects. In one version, we manipulated the frequency of right and left targets appearance when subjects were required to produce speeded responses (no-stop trials) with the right arm, whereas stop signals occurred with equal frequencies after right or left targets (no-stop signal bias). In the other version, we manipulated the frequency of appearance of stop signals after right or left targets, whereas no-stop trials toward right or left targets had the same frequency (stop-signal bias). Surprisingly, we found a very modest, if any, increase in response readiness toward the more frequent stimulus. However, the no stop signal bias had an effect on the speed of inhibitory control, as subjects were always faster to suppress a movement toward the side where targets were less likely to occur. Differently, the stop-signal bias had a much more powerful effect. In fact, subjects were faster to withhold movements toward the side where targets were more frequent, while they exhibited longer reaction times for reaches toward the more likely targets. Overall, these results suggest that action preparation and action inhibition are independent competing processes, but subjects tend to place automatically greater importance on the stop task. PMID- 24477764 TI - Consistent interindividual increases or decreases in muscle sympathetic nerve activity during experimental muscle pain. AB - We recently showed that long-lasting muscle pain, induced by intramuscular infusion of hypertonic saline, evoked two patterns of cardiovascular responses across subjects: one group showed parallel increases in muscle sympathetic nerve activity (MSNA), blood pressure, and heart rate, while the other group showed parallel decreases. Given that MSNA is consistent day to day, we tested the hypothesis that individuals who show increases in MSNA during experimental muscle pain will show consistent responses over time. MSNA was recorded from the peroneal nerve, together with blood pressure and heart rate, during an intramuscular infusion of hypertonic saline causing pain for an hour in 15 subjects on two occasions, 2-27 weeks apart. Pain intensity ratings were not significantly different between the first (5.8 +/- 0.4/10) and second (6.1 +/- 0.2) recording sessions. While four subjects showed significant decreases in the first session (46.6 +/- 9.2% of baseline) and significant increases in the second (159.6 +/- 8.9%), in 11 subjects, there was consistency in the changes in MSNA over time: either a sustained decrease (55.6 +/- 6.8%, n = 6) or a sustained increase (143.5 +/- 6.1%, n = 5) occurred in both recording sessions. There were no differences in pain ratings between sessions for any subjects. We conclude that the changes in MSNA during long-lasting muscle pain are consistent over time in the majority of individuals, reflecting the importance of studying interindividual differences in physiology. PMID- 24477765 TI - Response speed advantage for vision does not extend to touch in early deaf adults. AB - Early deaf adults typically respond faster than hearing controls when performing a speeded simple detection on visual targets. Whether this response time advantage can generalise to another intact modality (touch) or it is instead specific to visual processing remained unexplored. We tested eight early deaf adults and twelve hearing controls in a simple detection task, with visual or tactile targets delivered on the arms and occupying the same locations in external space. Catch trials were included in the experimental paradigm. Results revealed a response time advantage in deaf adults compared to hearing controls, selectively for visual targets. This advantage did not extend to touch. The number of anticipation errors was negligible and comparable in both groups. The present findings strengthen the notion that response time advantage in deaf adults emerges as a consequence of changes specific to visual processing. They also exclude the involvement of sensory-unspecific cognitive mechanisms in this improvement (e.g. increased impulsivity in initiation of response, longer-lasting sustained attention or higher motivation to perform the task). Finally, they provide initial evidence that the intact sensory modalities can reorganise independently from each other following early auditory deprivation. PMID- 24477767 TI - Towards a facile and convenient synthesis of highly functionalized indole derivatives based on multi-component reactions. AB - A library of potentially bioactive compounds through the novel 1H-indole-methyl isocyanide and MCRs has been described. A flexible and efficient synthesis affording great complexity and diversity is achieved with moderate to good yields with no need for protection and deprotection steps. PMID- 24477768 TI - Designing randomized clinical trials in surgery. PMID- 24477769 TI - Understanding the relationships among HIV/AIDS-related stigma, health service utilization, and HIV prevalence and incidence in Sub-Saharan Africa: a multi level theoretical perspective. AB - HIV-positive individuals often face community-wide discrimination or public shame and humiliation as a result of their HIV-status. In Sub-Saharan Africa, high HIV incidence coupled with unique cultural contexts make HIV-positive individuals particularly likely to experience this kind of HIV/AIDS-related (HAR) stigma. To date, there is a relatively small amount of high-quality empirical literature specific to HAR stigma in this context, supporting the notion that a better understanding of this phenomenon is needed to inform potential interventions. This paper provides a thorough review of the literature specific to HAR stigma in Sub-Saharan Africa, finding (a) qualitative support for the existence of important relationships between HAR stigma and health service utilization and barriers; (b) a need for more quantitative study of stigma and its relationships both to health service utilization and to HIV outcomes directly; and (c) a disconnect between methodological techniques used in this context-specific literature and well-known theories about stigma as a general phenomenon. This paper then draws from its empirical literature review, as well as from well-known theoretical frameworks from multiple disciplines, to propose a theoretical framework for the ecological and multilevel relationships among HAR stigma, health service utilization, and HIV outcomes in this context. PMID- 24477766 TI - Harnessing system models of cell death signalling for cytotoxic chemotherapy: towards personalised medicine approaches? AB - Most cytotoxic chemotherapeutics are believed to kill cancer cells by inducing apoptosis. Understanding the factors that contribute to impairment of apoptosis in cancer cells is therefore critical for the development of novel therapies that circumvent the widespread chemoresistance. Apoptosis, however, is a complex and tightly controlled process that can be induced by different classes of chemotherapeutics targeting different signalling nodes and pathways. Moreover, apoptosis initiation and apoptosis execution strongly depend on patient-specific, genomic and proteomic signatures. Here, we will review recent translational studies that suggest a critical link between the sensitivity of cancer cells to initiate apoptosis and clinical outcome. Next we will discuss recent advances in the field of system modelling of apoptosis pathways for the prediction of treatment responses. We propose that initiation of mitochondrial apoptosis, defined as the process of mitochondrial outer membrane permeabilisation (MOMP), is a dose-dependent decision process that allows for a prediction of individual therapy responses and therapeutic windows. We provide evidence in contrast that apoptosis execution post-MOMP may be a binary decision that dictates whether apoptosis is executed or not. We will discuss the implications of this concept for the future use of novel adjuvant therapeutics that specifically target apoptosis signalling pathways or which may be used to reduce the impact of cell to-cell heterogeneity on therapy responses. Finally, we will discuss the technical and regulatory requirements surrounding the use and implications of system-based patient stratification tools for the future of personalised oncology. PMID- 24477771 TI - Coordination of end-of-life care for patients with lung cancer and those with advanced COPD: are there transferable lessons? A longitudinal qualitative study. AB - BACKGROUND: Care coordination is defined as good communication between professionals to enable access to services based on need. AIMS: To explore patients' experience of care coordination in order to inform current debates on how best to coordinate care and deliver services in end-of-life for patients with lung cancer and those with chronic obstructive pulmonary disease (COPD). METHODS: A qualitative study involving serial interviews was performed in 18 patients recruited from three hospital outpatient clinics situated in a hospital. Interviews were transcribed verbatim and data were analysed thematically. RESULTS: Data comprised 38 interviews. Patients experiencing services related to lung cancer reported good access enabled by the involvement of a keyworker. This contrasted with COPD patients' experiences of services. The keyworker coordinated care between and within clinical settings, referred patients to community palliative care services, helped them with financial issues, and provided support. CONCLUSIONS: For patients with lung cancer, the keyworker's role augmented access to various services and enabled care based on their needs. The experiences of patients with COPD highlight the importance of providing a keyworker for this group of patients in both secondary and primary care. PMID- 24477770 TI - Restoration of quinine-stimulated Fos-immunoreactive neurons in the central nucleus of the amygdala and gustatory cortex following reinnervation or cross reinnervation of the lingual taste nerves in rats. AB - Remarkably, when lingual gustatory nerves are surgically rerouted to inappropriate taste fields in the tongue, some taste functions recover. We previously demonstrated that quinine-stimulated oromotor rejection reflexes and neural activity (assessed by Fos immunoreactivity) in subregions of hindbrain gustatory nuclei were restored if the posterior tongue, which contains receptor cells that respond strongly to bitter compounds, was cross-reinnervated by the chorda tympani nerve. Such functional recovery was not seen if instead, the anterior tongue, where receptor cells are less responsive to bitter compounds, was cross-reinnervated by the glossopharyngeal nerve, even though this nerve typically responds robustly to bitter substances. Thus, recovery depended more on the taste field being reinnervated than on the nerve itself. Here, the distribution of quinine-stimulated Fos-immunoreactive neurons in two taste associated forebrain areas was examined in these same rats. In the central nucleus of the amygdala (CeA), a rostrocaudal gradient characterized the normal quinine-stimulated Fos response, with the greatest number of labeled cells situated rostrally. Quinine-stimulated neurons were found throughout the gustatory cortex, but a "hot spot" was observed in its anterior-posterior center in subregions approximating the dysgranular/agranular layers. Fos neurons here and in the rostral CeA were highly correlated with quinine-elicited gapes. Denervation of the posterior tongue eliminated, and its reinnervation by either nerve restored, numbers of quinine-stimulated labeled cells in the rostralmost CeA and in the subregion approximating the dysgranular gustatory cortex. These results underscore the remarkable plasticity of the gustatory system and also help clarify the functional anatomy of neural circuits activated by bitter taste stimulation. PMID- 24477772 TI - Accuracy of diagnosis and classification of COPD in primary and specialist nurse led respiratory care in Rotherham, UK: a cross-sectional study. AB - BACKGROUND: Studies have suggested that chronic obstructive pulmonary disease (COPD) is commonly misdiagnosed and misclassified in primary care, but less is known about the quality of diagnosis in specialist respiratory care. AIMS: To measure the accuracy of COPD diagnosis and classification of airway obstruction in primary care and at a specialist respiratory centre, and to explore associations between misdiagnosis and misclassification and a range of explanatory factors. METHODS: Data were obtained for 1,205 referrals to a specialist respiratory centre between 2007 and 2010. Standard analysis methods were used. RESULTS: The majority of patients were referred for pulmonary rehabilitation (676/1,205, 56%). Of 1,044 patients with a primary care diagnosis of COPD, 211 (20%) had spirometry inconsistent with COPD. In comparison, of 993 specialist centre diagnoses, 65 (6.5%) had inconsistent spirometry. There was poor agreement between the airflow obstruction grade recorded on the referral and that based on spirometry (kappa=0.26, n=448), whereas agreement between the respiratory centre assessment of airflow obstruction and spirometry was good (kappa=0.88, n=1,016). Referral by practice nurse was associated with accuracy of airflow obstruction classification in primary care (OR 1.85, 95% CI 1.33 to 2.57). Males were more likely than females to have an accurate specialist care classification of airway obstruction (OR 1.40, 95% CI 1.01 to 1.93). Grade of airway obstruction changed between referral and assessment in 56% of cases. CONCLUSIONS: In primary care, a proportion of patients diagnosed with COPD do not have COPD, and misclassification of grade of airflow obstruction is common. Misdiagnosis and misclassification is less common in the specialist care setting of BreathingSpace. PMID- 24477773 TI - Losing face: impaired discrimination of featural and configural information in the mouth region of an inverted face. AB - Given that all faces share the same set of features-two eyes, a nose, and a mouth that are arranged in similar configuration, recognition of a specific face must depend on our ability to discern subtle differences in its featural and configural properties. An enduring question in the face-processing literature is whether featural or configural information plays a larger role in the recognition process. To address this question, the face dimensions task was designed, in which the featural and configural properties in the upper (eye) and lower (mouth) regions of a face were parametrically and independently manipulated. In a same different task, two faces were sequentially presented and tested in their upright or in their inverted orientation. Inversion disrupted the perception of featural size (Exp. 1), featural shape (Exp. 2), and configural changes in the mouth region, but it had relatively little effect on the discrimination of featural size and shape and configural differences in the eye region. Inversion had little effect on the perception of information in the top and bottom halves of houses (Exp. 3), suggesting that the lower-half impairment was specific to faces. Spatial cueing to the mouth region eliminated the inversion effect (Exp. 4), suggesting that participants have a bias to attend to the eye region of an inverted face. The collective findings from these experiments suggest that inversion does not differentially impair featural or configural face perceptions, but rather impairs the perception of information in the mouth region of the face. PMID- 24477774 TI - Impact of outpatient interventions made at an ambulatory cancer centre oncology pharmacy in Singapore. AB - OBJECTIVES: To evaluate the clinical significance of interventions made by pharmacists in an oncology pharmacy in Singapore and their acceptance rate and to identify common drug-related problems and workflow-related interventions. METHODS: A two-month prospective intervention study was conducted at National Cancer Centre Singapore. During the study, pharmacists documented the reason for intervening and its related drug(s). Each intervention was evaluated for its clinical significance by an expert panel: two oncologists and a pharmacist using a five-point scale. The Kendall's test of concordance and Cohen's weighted kappa were employed for analysis of agreement among the respondents. Other variables were analysed using descriptive statistics. RESULTS: A total of 331 interventions were recorded: 147 cases were due to missing chemotherapy orders while 184 cases had potential drug-related problems. Among the 184 cases, 60 cases were related to clarification of orders, while the others had drug-related problems. The Kendall's concordance coefficient was calculated to be 0.612 (p < 0.001) while weighted kappa test results showed fair agreement across the evaluators. Acceptance rate of interventions was 93%. Most commonly documented drugs requiring interventions were carboplatin, trastuzumab and capecitabine. CONCLUSIONS: About half of the documented interventions by pharmacists were evaluated as clinically 'significant' or 'very significant'. PMID- 24477775 TI - Turner syndrome revisited: review of new data supports the hypothesis that all viable 45,X cases are cryptic mosaics with a rescue cell line, implying an origin by mitotic loss. AB - We review the data pertinent to the hypothesis we proposed three decades ago, that all embryos that survive gestation as women with Turner syndrome and have an ostensibly non-mosaic 45,X karyotype, actually are cryptic mosaics for a "rescue line" that includes a viable karyotype. Reanalysis of the prevalence and frequency of 45,X in available data on spontaneous abortuses, and livebirths, confirms prior estimates that 1 % to 1.5 % of all recognizable pregnancies start as an apparent non-mosaic 45,X but about 99 % do not survive gestation. From the rates of 45,X in early embryos, which are notably higher than the inferred rate of gametes hypohaploid for a sex chromosome, as well as the negative maternal age association with 45,X of maternal origin we deduce, in agreement with but on independent grounds from Hall et al. (2006), that a very large proportion of 45,X embryos acquired their 45,X line after fertilization. Results of a search for mosaic cell lines in patients with "Turner syndrome" in several reports indicate that not only does the detection rate of a mosaic line depend upon the number and sensitivity of the markers used, and the number of different tissues examined, but also upon the severity of the phenotype of those cases studied, and the number of cells karyotyped initially. Such factors may explain variation in the extent of detected "cryptic" mosaicism in 45,X individuals (currently at least 50 %). We note a report by Urbach and Benvenitsy (2009) of a gene necessary for placental function, PSF2RA, which lies in the pseudoautosomal-one region of the X and Y chromosomes. Deletion of such a gene could account for the high embryonic lethality in 45,X conceptions, and a rescue line in the placenta could account for embryonic and fetal survival of those cases in which a cryptic mosaic line cannot be found in the usual studies of blood and other tissues from affected individuals. Our primary conclusions are 1) all 45,X individuals with Turner syndrome are cryptic mosaics, 2) absence of the X chromosome in 45,X embryos is caused primarily by mitotic factors, and 3) the placenta is a strong candidate for the location of the rescue line in apparently non-mosaic 45,X individuals. PMID- 24477776 TI - Addressing the variation of post-surgical inpatient census with computer simulation. AB - OBJECTIVE: This study describes the development of a Discrete Event Simulation (DES) of a large pediatric perioperative department, and its use to compare the effectiveness of increasing the number of post-surgical inpatient beds vs. implementing a new discharge strategy on the proportion of patients admitted to the surgical unit to recover. MATERIALS AND METHODS: A DES of the system was developed and simulated data were compared with 1 year of inpatient data to establish baseline validity. Ten years of simulated data generated by the baseline simulation (control) was compared to 10 years of simulated data generated by the simulation for the experimental scenarios. Outcome and validation measures include percentage of patients recovering in post-surgical beds vs. "off floor" in medical beds, and daily census of inpatient volumes. RESULTS: The proportion of patients admitted to the surgical inpatient unit rose from 79.0% (95% CI, 77.9-80.1%) to 89.4% (95% CI, 88.7-90.0%) in the discharge strategy scenario, and to 94.2% (95% CI, 93.5-95.0%) in the additional bed scenario. The daily mean number of patients admitted to medical beds fell from 9.3 +/- 5.9 (mean +/- SD) to 4.9 +/- 4.5 in the discharge scenario, and to 2.4 +/ 3.2 in the additional bed scenario. DISCUSSION: Every hospital is tasked with placing the right patient in the right bed at the right time. Appropriately validated DES models can provide important insight into system dynamics. No significant variation was found between the baseline simulation and real-world data. This allows us to draw conclusions about the ramifications of changes to system capacity or discharge policy, thus meeting desired system performance measures. PMID- 24477777 TI - Laparoscopic resection of adrenal neuroblastoma without image-defined risk factors: a prospective study on 21 consecutive pediatric patients. AB - BACKGROUND: Over the last 20 years MIS has progressively gained popularity in children with cancer. We therefore aimed at evaluating the safety of Minimally Invasive Surgery (MIS) resection in a series of children affected by adrenal neuroblastoma (NB) presenting without Image-Defined Risk Factors (IDRFs). METHODS: An Institutional protocol for MIS resection of adrenal NB in pediatric patients without IDRFs has been applied since 2008. Absence of IDRFs represented the main indication for MIS in NB, regardless of tumor size. All pediatric patients who underwent MIS for NB between January 2008 and May 2013 were included. Specific technical considerations, demographic data, and outcome have been recorded. RESULTS: Twenty-one patients underwent MIS resection for IDRFs negative adrenal NB. Nine of these patients experienced preoperative downgrading of IDRFs after chemotherapy. Radiological median diameter of the mass was 30 mm (range 10-83 mm). Median operative time was 90 min. Median hospital stay was 4 days. All patients were treated successfully, without serious intraoperative complications. One mild intraoperative hemorrhage occurred and was treated without the need for conversion to open surgery nor blood transfusion was required. No postoperative complications, including port-site or peritoneal metastases were experienced. CONCLUSIONS: This study demonstrated the safety and effectiveness of MIS for the resection of adrenal NB without IDRFs in children. Pediatric surgeons dedicated to oncology should be aware of this alternative approach to open resection. PMID- 24477778 TI - Design and rationale of the GAUSS-2 study trial: a double-blind, ezetimibe controlled phase 3 study of the efficacy and tolerability of evolocumab (AMG 145) in subjects with hypercholesterolemia who are intolerant of statin therapy. AB - Statins effectively lower low-density lipoprotein cholesterol (LDL-C), reducing cardiovascular morbidity and mortality. Most patients tolerate statins well, but approximately 10% to 20% experience side effects (primarily muscle-related) contributing to diminished compliance or discontinuation of statin therapy and subsequent increase in cardiovascular risk. Statin-intolerant patients require more effective therapies for lowering LDL-C. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a compelling target for LDL-C-lowering therapy. Evolocumab (AMG 145) is a fully human monoclonal antibody that binds PCSK9, inhibiting its interaction with the LDL receptor to preserve LDL-receptor recycling and reduce LDL-C. Phase 2 studies have demonstrated the safety, tolerability, and preliminary efficacy of subcutaneous evolocumab in diverse populations, including statin-intolerant patients. This article describes the rationale and design of the Goal Achievement After Utilizing an anti-PCSK9 Antibody in Statin-Intolerant Subjects 2 (GAUSS-2) trial, a randomized, double blind, ezetimibe-controlled, multicenter phase 3 study to evaluate the effects of 12 weeks of evolocumab 140 mg every 2 weeks or 420 mg every month in statin intolerant patients with hypercholesterolemia. Eligible subjects were unable to tolerate effective doses of >=2 statins because of myalgia, myopathy, myositis, or rhabdomyolysis that resolved with statin discontinuation. The primary objective of the study is to assess the effects of evolocumab on percentage change from baseline in LDL-C. Secondary objectives include evaluation of safety and tolerability, comparison of the effects of evolocumab vs ezetimibe on absolute change from baseline in LDL-C, and percentage changes from baseline in other lipids. Recruitment of approximately 300 subjects was completed in August 2013. PMID- 24477779 TI - Comparing the impact of psoriasis and atopic dermatitis on quality of life: co calibration of the PSORIQoL and QoLIAD. AB - BACKGROUND: Disease-specific patient-reported outcome (PRO) measures are designed to be highly relevant to one disease. It is widely believed that comparisons of outcomes between patients with different diseases are only possible using generic measures. The present study employs a novel method of using Rasch analysis to co calibrate scores from different disease-specific PRO measures, allowing scores to be compared across diseases. METHODS: Psoriasis patients (n = 146, mean age = 44.4, males = 50 %) completed the Psoriasis Quality of Life scale (PSORIQoL) and atopic dermatitis patients (n = 146, mean age = 45.5, males = 50 %) the Quality of Life in Atopic Dermatitis scale (QoLIAD). Both measures employ the needs-based model of QoL, and they share five common items-providing a link between assessments. The groups were analysed separately, and then combined to test fit to the Rasch model. RESULTS: Both scales showed good fit to the Rasch model after minor adjustments (PSORIQoL: chi (2) p = 0.25; QoLIAD: chi (2) p = 0.51). For the combined dataset, one common item showing differential item functioning by disease was removed and fit to the Rasch model was achieved (chi (2) p = 0.08). The co-calibrated scale successfully distinguished between perceived severity groups (p < 0.001). CONCLUSIONS: It is possible to co-calibrate scores on the PSORIQoL and QoLIAD. This is one of the first studies in health research to demonstrate how Rasch analysis can be used to make comparisons across diseases using different disease-specific measures. Such an approach maintains the greater relevance and, consequently, accuracy associated with disease-specific measurement. PMID- 24477780 TI - The ethics of providing a balanced presentation of facts: comment on the article: quality of life, human insecurity, and distress among Palestinians in the Gaza strip before and after the winter 2008-2009 Israeli war. PMID- 24477782 TI - A signal-on electrochemical aptasensor for ultrasensitive detection of endotoxin using three-way DNA junction-aided enzymatic recycling and graphene nanohybrid for amplification. AB - Endotoxin, also known as lipopolysaccharide (LPS), is able to induce a strong immune response on its internalization into mammalian cells. To date, aptamer based biosensors for LPS detection have been rarely reported. This work describes a new signal-on electrochemical aptasensor for the ultrasensitive detection of LPS by combining the three-way DNA hybridization process and nanotechnology-based amplification. With the help of DNA1 (associated with the concentration of target LPS), the capture probe hybridizes with DNA1 and the assistant probe to open its hairpin structure and form a ternary "Y" junction structure. The DNA1 can be released from the structure in the presence of nicking endonuclease to initiate the next hybridization process. Then a great deal of cleaved capture probe produced in the cyclic process can bind with DNA2-nanocomposite, which contains the electroactive toluidine blue (Tb) with the amplification materials graphene (Gra) and gold nanoparticles (AuNPs). Thus, an enhanced electrochemical signal can be easily read out. With the cascade signal amplification, this newly designed protocol provides an ultrasensitive electrochemical detection of LPS down to the femtogram level (8.7 fg mL(-1)) with a linear range of 6 orders of magnitude (from 10 fg mL(-1) to 50 ng mL(-1)). Moreover, the high sensitivity and specificity make this method versatile for the detection of other biomolecules by changing the corresponding sequences of the capture probe and the assistant probe. PMID- 24477781 TI - Oocyte vitrification: advances, progress and future goals. AB - BACKGROUND: Recent advances in vitrification technology have markedly improved the efficacy of oocyte cryopreservation in terms of oocyte survival and pregnancy, as well as live birth rates. However, there still remains room for improvement in terms of vitrification techniques. OBJECTIVE: The remaining challenges include the development of a less cytotoxic vitrification solution and of a safe vitrification device in order to have vitrification techniques considered as a standard clinical laboratory procedure. METHODS: A systematic electronic literature search strategy has been conducted using PubMed (Medline) databases with the use of the following key words: oocyte, vitrification, cryoprotectant, preservation, pregnancy, and live birth. A list of published papers focused on the improvement of vitrification techniques to have the vitrification protocol standardized have been evaluated in full text for this review. Only key references were cited. CONCLUSIONS: Vitrification technology has made significant advancements and holds great promise, but many issues remains to be addressed before it becomes a standardized procedure in clinical laboratories such as the fact that oocyte vitrification may not require a high concentration of cryoprotectant in the vitrification solution when it has a suitable cooling and warming rate. There is also no consistent evidence that indicates the absence of risk to the vitrified oocytes when they are stored for a prolonged period of time in direct-contact with liquid nitrogen. The long-term development of infants born as a result of this technology equally remains to be evaluated. PMID- 24477783 TI - Zinc sulfide nanoparticles selectively induce cytotoxic and genotoxic effects on leukemic cells: involvement of reactive oxygen species and tumor necrosis factor alpha. AB - The aim of the present study was to develop zinc sulfide nanoparticles (ZnS NPs) and to study their cytotoxicity against the KG-1A (human acute myeloid leukemia) cell line. ZnS NPs were synthesized using the pyrolytic method and characterized by X-ray diffraction, dynamic light scattering, surface zeta potential, scanning electron microscopy and atomic force microscopy. Cell viability study and flow cytometric analysis confirmed the potent cytotoxic effects of ZnS NPs on cancer cells in a dose-dependent fashion. Successful uptakes of ZnS NPs by leukemic cells were confirmed by phase contrast fluorescence microscopy. pH-dependent dissolution of ZnS NPs was done using atomic absorption microscopy to understand the cell-specific internalization of Zn(+) . This internalization of NPs facilitated the generation of excess reactive oxygen species (ROS), followed by tumor necrosis factor alpha (TNF-alpha) secretion which caused severe DNA damage as observed in the comet assay and altered the mitochondrial membrane potential (MMP) in leukemic cells. Surprisingly ZnS NPs had no toxic effects on normal lymphocytes at doses up to 50 ug ml(-1) . Pre-treatment with ROS and TNF-alpha inhibitor confirmed that these nanoparticles were able to kill leukemic cells by generating an excess amount of ROS and thereby initiated TNF-alpha mediated apoptosis pathway. These findings clarify the mechanism with which ZnS NPs induced anticancer activities in vitro. To elicit its utilities and its application to cancer treatment in vivo is under investigation. PMID- 24477784 TI - Prognostic value of Rb-82 positron emission tomography myocardial perfusion imaging in coronary artery bypass patients. AB - AIMS: We sought to determine the prognostic value of positron emission tomography (PET) myocardial perfusion imaging (MPI) in patients with prior coronary artery bypass graft (CABG) surgery. PET MPI has recently been shown to provide incremental risk stratification for patients with suspected coronary artery disease (CAD), but the prognostic utility of PET MPI in CABG patients has not been well studied. METHODS AND RESULTS: A multi-centre PET registry of 7061 patients who underwent Rb-82 PET MPI from four participating centres was screened. Nine hundred and fifty-three CABG patients were identified and their images were analysed. Outcomes of all-cause mortality and cardiac death were collected. With a mean follow-up of 2.4 +/- 1.4 years, 128 (13.4%) all-cause deaths and 44 (4.6%) cardiac deaths were observed. Multivariable analyses, adjusted for clinical variables, demonstrated that the summed stress score (SSS) was a significant independent predictor of both all-cause mortality [HR: 1.60 (per 1 category increase in SSS); 95% CI: 1.34-1.92; P < 0.001] and cardiac death (HR: 1.80; 95% CI: 1.33, 2.44; P < 0.001). The receiver-operator characteristic (ROC) curves showed that the addition of SSS increased the area under the curve (AUC) from 0.645 to 0.693 (P = 0.014) for all-cause mortality, and from 0.612 to 0.704 (P = 0.027) for cardiac death. SSS also improved the net reclassification improvement (NRI) for all-cause mortality (category-free NRI = 0.422; 95% CI: 0.240-0.603; P < 0.001) and cardiac death (category-free NRI = 0.552; 95% CI: 0.268-0.836; P < 0.001). CONCLUSIONS: PET MPI provides independent and incremental prognostic value to clinical variables in predicting all-cause mortality and cardiac death in CABG patients. PMID- 24477785 TI - Mutations in the FPIV motif of Newcastle disease virus matrix protein attenuate virus replication and reduce virus budding. AB - The FPIV-like late domains identified in the matrix (M) proteins of parainfluenza virus 5 and mumps virus have been demonstrated to be critical for virus budding. In this study, we found that the same FPIV sequence motif is present in the N terminus of the Newcastle disease virus (NDV) M protein. Mutagenesis experiments demonstrated that mutation of either phenylalanine (F) or proline (P) to alanine led to a more obvious decrease in viral virulence and replication and resulted in poor budding of the mutant viruses. Additionally, evidence for the involvement of cellular multivesicular body (MVB) proteins was obtained, since NDV production was inhibited upon expression of dominant-negative versions of the VPS4A-E228Q protein. Together, these results demonstrate that the FPIV motif, especially the residues F and P, within the NDV M protein, plays a critical role in NDV replication and budding, and this budding process likely involves the cellular MVB pathway. PMID- 24477786 TI - Interaction of phospholipase A of the E. coli outer membrane with the inhibitors of eucaryotic phospholipases A2 and their effect on the Ca2+-induced permeabilization of the bacterial membrane. AB - Phospholipase A of the bacterial outer membrane (OMPLA) is a beta-barrel membrane protein which is activated under various stress conditions. The current study examines interaction of inhibitors of eucaryotic phospholipases A2--palmitoyl trifluoromethyl ketone (PACOCF3) and aristolochic acid (AA)--with OMPLA and considers a possible involvement of the enzyme in the Ca2+-dependent permeabilization of the outer membrane of Escherichia coli. Using the method of molecular docking, it has been predicted that PACOCF3 and AA bind to OMPLA at the same site and with the same affinity as the OMPLA inhibitors, hexadecanesulfonylfluoride and bromophenacyl bromide, and the substrate of the enzyme palmitoyl oleoyl phosphatidylethanolamine. It has also been shown that PACOCF3, AA, and bromophenacyl bromide inhibit the Ca2+-induced temperature dependent changes in the permeability of the bacterial membrane for the fluorescent probe propidium iodide and suppressed the transformation of E. coli cells with plasmid DNA induced by Ca2+ and heat shock. The cell viability was not affected by the eucaryotic phospholipases A2 inhibitors. The study discusses a possible involvement of OMPLA in the mechanisms of bacterial transmembrane transport based on the permeabilization of the bacterial outer membrane. PMID- 24477787 TI - Estimation of the impact of warfarin's time-in-therapeutic range on stroke and major bleeding rates and its influence on the medical cost avoidance associated with novel oral anticoagulant use-learnings from ARISTOTLE, ROCKET-AF, and RE-LY trials. AB - Warfarin's time-in-therapeutic range (TTR) is highly variable among patients with nonvalvular atrial fibrillation (NVAF). The objective of this study was to estimate the impact of variations in wafarin's TTR on rates of stroke/systemic embolism (SSE) and major bleedings among NVAF patients in the ARISTOTLE, ROCKET AF, and RE-LY trials. Additionally, differences in medical costs for clinical endpoints when novel oral anticoagulants (NOACs) were used instead of warfarin at different TTR values were estimated. Quartile ranges of TTR values and corresponding event rates (%/patient - year = %/py) of SSE and major bleedings among NVAF patients treated with warfarin were estimated from published literature and FDA documents. The associations of SSE and major bleeding rates with TTR values were evaluated by regression analysis and then the calculated regression coefficients were used in analysis of medical cost differences associated with use of each NOAC versus warfarin (2010 costs; US payer perspective) at different TTRs. Each 10 % increase in warfarin's TTR correlated with a -0.32%/py decrease in SSE rate (R(2) = 0.61; p < 0.001). Although, the rate of major bleedings decreased as TTR increased, it was not significant ( 0.035%/py, p = 0.63). As warfarin's TTR increased from 30 to 90% the estimated medical cost decreased from -$902 to -$83 for apixaban, from -$506 to +$314 for rivaroxaban, and from -$596 to +$223 for dabigatran. Among NVAF patients there is a significant negative correlation between warfarin's TTR and SSE rate, but not major bleedings. The variations in warfarin's TTR impacted the economic comparison of use of individual NOACs versus warfarin. PMID- 24477789 TI - Severe intra-abdominal bleeding leading to hemorrhagic shock, rectal perforation, and bilateral hydrothorax after stapling procedure for prolapsed hemorrhoids (PPH): is the transanal drainage feasible in this situation? : report of a case and a successful experience. PMID- 24477790 TI - Does anastomotic leakage impair functional results and quality of life after laparoscopic sphincter-saving total mesorectal excision for rectal cancer? A case matched study. AB - PURPOSE: Anastomotic leakage (AL) after total mesorectal excision (TME) for rectal cancer is suspected to alter function. However, very few reports have been devoted to this problem. The aim of this study was to assess the influence of AL on function and quality of life (QoL) after laparoscopic TME for cancer. METHODS: A total of 170 patients who underwent laparoscopic TME and sphincter-saving surgery for mid and low rectal cancer were included (67 % after neoadjuvant chemoradiotherapy). Twenty-one patients with AL were assessed for function and QoL (Short Form 36 (SF-36), Fecal Incontinence Quality of Life (FIQL), CR-29, and Wexner's score) at the most recent follow-up. These patients were matched to 42 patients without AL according to sex, body mass index, ypTNM, radiotherapy, and type of anastomosis. RESULTS: After a median follow-up of 30 months, AL significantly impaired physical activity (SF-36) (p = 0.004), self-respect (FIQL) (p = 0.029), wear pad's score (Wexner's score) (p = 0.043), and blood and mucus in stool score (CR-29) (p = 0.001). Overall Wexner's score did not show any significant difference in the two groups, 8.9 in AL patients vs. 11.6 in patients without AL (p = 0.1). CONCLUSION: AL significantly impairs both functional results and quality of life after laparoscopic sphincter-saving TME for rectal cancer. However, the observed difference was only limited, leading to similar outcomes on most of the tested scores. Patients with AL should be warned that if they initially experience severely impaired results, outcomes tend with time to become similar to those observed in noncomplicated patients. PMID- 24477788 TI - The rationale behind complete mesocolic excision (CME) and a central vascular ligation for colon cancer in open and laparoscopic surgery : proceedings of a consensus conference. AB - BACKGROUND: It has been evident for a while that the result after resection for colon cancer may not have been optimal. Several years ago, this was showed by some leading surgeons in the USA but a concept of improving results was not consistently pursued. Later, surgeons in Europe and Japan have increasingly adopted the more radical principle of complete mesocolic excision (CME) as the optimal approach for colon cancer. The concept of CME is a similar philosophy to that of total mesorectal excision for rectal cancer and precise terminology and optimal surgery are key factors. METHOD: There are three essential components to CME. The main component involves a dissection between the mesenteric plane and the parietal fascia and removal of the mesentery within a complete envelope of mesenteric fascia and visceral peritoneum that contains all lymph nodes draining the tumour area (Hohenberger et al., Colorectal Disease 11:354-365, 2009; West et al., J Clin Oncol 28:272-278, 2009). The second component is a central vascular tie to completely remove all lymph nodes in the central (vertical) direction. The third component is resection of an adequate length of bowel to remove involved pericolic lymph nodes in the longitudinal direction. RESULT: The oncological rationale for CME and various technical aspects of the surgical management will be explored. CONCLUSION: The consensus conference agreed that there are sound oncological hypotheses for a more radical approach than has been common up to now. However, this may not necessarily apply in early stages of the tumour stage. Laparoscopic resection appears to be equally well suited for resection as open surgery. PMID- 24477791 TI - Manganese hexacyanoferrate derived Mn3O4 nanocubes-reduced graphene oxide nanocomposites and their charge storage characteristics in supercapacitors. AB - Mn3O4-reduced graphene oxide (RGO) nanocomposites were prepared by chemical decomposition of the manganese hexacyanoferrate (MnHCF) complex directly on the graphene surface. XRD studies revealed the formation of crystalline hausmannite Mn3O4 nanocubes in the as-prepared nanocomposites without any heat treatment. The FE-SEM images showed the formation of Mn3O4 nanocubes on the graphene surface in the as-prepared nanocomposites. HR-TEM studies confirmed the homogeneous dispersion of ~25 nm Mn3O4 nanocubes on graphene nanosheets. The amount of Mn3O4 nanocubes and graphene in the nanocomposites was estimated using TGA analysis from room temperature to 800 degrees C in air. The FT-IR and Raman spectroscopic analysis confirmed the functional groups in the nanocomposites and defects in graphene nanosheets in the nanocomposites. Cyclic voltammetry and galvanostatic charge-discharge experiments demonstrated a high specific capacitance of 131 F g( 1) in 1 M Na2SO4 electrolyte at a current density of 0.5 A g(-1) for the RGM-0.5 nanocomposite. A capacitance retention of 99% was observed for 500 charge discharge cycles at a current density of 5 A g(-1), which conformed the excellent stability of the RGM electrodes. The prepared Mn3O4-RGO nanocomposites are promising for electrochemical energy storage. PMID- 24477792 TI - Introduction to the special issue in honor of Edward E. Smith. PMID- 24477793 TI - Intracystic concentrations of tumour markers for the diagnosis of cystic liver lesions. AB - BACKGROUND: Imaging occasionally fails to differentiate hepatic simple cysts from malignant or premalignant mucinous cystic lesions such as biliary cystadenomas. Hepatic simple cysts can be treated conservatively, whereas malignant or premalignant cysts require complete resection. This study assessed the ability of intracystic tumour marker concentrations to differentiate these disease entities. METHODS: Intracystic fluid was sampled in patients undergoing partial or complete resection of a cystic lesion of the liver. The indication for surgery in hepatic simple cysts was symptoms or suspicion of a biliary cystadenoma. Intracystic concentrations of carcinoembryonic antigen (CEA), carbohydrate antigen (CA) 19-9 and tumour-associated glycoprotein (TAG) 72 were measured to assess the diagnostic accuracy of these tumour markers. Cut-off values were defined by receiver operating characteristic (ROC) curves. RESULTS: The study population comprised 118 patients (94 women) with a median age of 59 years. There were 75 patients with hepatic simple cysts, 27 with mucinous cysts (19 biliary cystadenomas, 4 biliary cystadenocarcinomas, 4 intraductal papillary mucinous neoplasms of the bile duct) and 16 with miscellaneous cysts. Unlike CEA and CA19 9, a TAG-72 concentration of more than 25 units/ml differentiated hepatic simple cysts from mucinous cysts with a sensitivity and a specificity of 0.79 and 0.97 respectively. The area under the ROC curve was 0.98 for mucinous versus hepatic simple cysts. CONCLUSION: The concentration of TAG-72 in cyst fluid accurately identified hepatic cysts that required complete resection. PMID- 24477794 TI - Hypertension in pregnancy. AB - Hypertensive disorders of pregnancy represent the second commonest cause of direct maternal death and complicate an estimated 5-10 % of pregnancies. Classification systems aim to separate hypertension similar to that seen outside pregnancy (chronic and gestational hypertension) from the potentially fatal pregnancy-specific conditions. Preeclampsia, HELLP syndrome, and eclampsia represent increasing severities of this disease spectrum. The American College of Obstetricians and Gynecologists' 2013 guidelines no longer require proteinuria as a diagnostic criterion, because of its variable appearance in the disease spectrum. The cause involves inadequate cytotrophoblastic invasion of the myometrium, resulting in placental hypoperfusion and diffuse maternal endothelial dysfunction. Changes in angiogenic and antiangiogentic peptide profiles precede the onset of clinical preeclampsia. Women with preeclampsia should be closely monitored and receive magnesium sulfate intravenously if severe features, HELLP syndrome, or eclampsia occur. Definitive therapy is delivery of the fetus. Hypertension in pregnancy increases future maternal risk of hypertension and cardiovascular disorders. PMID- 24477795 TI - New insights into the vulnerable plaque from imaging studies. AB - The concept of the vulnerable atherosclerotic plaque first developed through histological evaluation of post-mortem coronary arteries has been significantly advanced in recent years by new imaging modalities. Imaging has: 1) verified histological findings, 2) identified features that are associated with unstable plaque, 3) followed plaques over time to study the dynamic nature of vulnerable plaque, 4) predicted clinical events based on imaging features, 5) tested the impact of medical interventions on plaque morphology. This review will summarize the major findings of imaging studies with a focus on how the knowledge base of vulnerable plaque has been advanced. PMID- 24477796 TI - Cloning of corticotropin-releasing hormone (CRH) precursor cDNA and immunohistochemical detection of CRH peptide in the brain of the Japanese eel, paying special attention to gonadotropin-releasing hormone. AB - The stress-related corticotropin-releasing hormone (CRH) was first identified by isolation of its cDNA from the brain of the Japanese eel Anguilla japonica. CRH cDNA encodes a signal peptide, a cryptic peptide and CRH (41 amino acids). The sequence homology to mammalian CRH is high. Next, the distribution of CRH immunoreactive (ir) cell bodies and fibers in the brain and pituitary were examined by immunohistochemistry. CRH-ir cell bodies were detected in several brain regions, e.g., nucleus preopticus pars magnocellularis, nucleus preopticus pars gigantocellularis and formatio reticularis superius. In the brain, CRH-ir fibers were distributed not only in the hypothalamus but also in various regions. Some CRH-ir fibers projected to adrenocorticotropic hormone (ACTH) cells in the rostral pars distalis of the pituitary and also the alpha-melanocyte-stimulating hormone (alpha-MSH) cells in the pars intermedia of the pituitary. Finally, the neuroanatomical relationship between the CRH neurons and gonadotropin-releasing hormone (GnRH) neurons was examined by dual-label immunohistochemistry. CRH-ir fibers were found to be in close contact with GnRH-ir cell bodies in the hypothalamus and in the midbrain tegmentum and GnRH-ir fibers were in close contact with CRH-ir cell bodies in the nucleus preopticus pars magnocellularis. These results suggest that CRH has some physiological functions other than the stimulation of ACTH and alpha-MSH secretion and that reciprocal connections may exist between the CRH neurons and GnRH neurons in the brain of the Japanese eel. PMID- 24477797 TI - The distribution and ultrastructure of the forming blood capillaries and the effect of apoptosis on vascularization in mouse embryonic molar mesenchyme. AB - Vascularization is essential for organ and tissue development. Teeth develop through interactions between epithelium and mesenchyme. The developing capillaries in the enamel organ, the dental epithelial structure, occur simultaneously by mechanisms of vasculogenesis and angiogenesis at the onset of dentinogenesis. The vascular neoformation in the dental mesenchyme has been reported to start from the cap stage. However, the mechanisms of vascularization in the dental mesenchyme remain unknown. In the hope of understanding the mechanisms of the formation of dental mesenchymal vasculature, mouse lower molar germs from embryonic day (E) 13.5 to E16.5 were processed for immunostaining of CD31 and CD34, terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling (TUNEL) and transmission electron microscopy (TEM). In addition, the role of apoptosis for the vascularization in dental mesenchyme was examined by in vitro culture of E14.0 lower molars in the presence of the apoptosis inhibitor (z VAD-fmk) and a subsequent subrenal culture. Our results showed that CD31- and CD34-positive cells progressively entered the central part of the dental papilla from the peridental mesenchyme. For TEM, angioblasts, young capillaries with thick endothelium and endothelial cells containing vacuoles were observed in peripheral dental mesenchyme, suggesting vasculogenesis was taking place. The presence of lateral sprouting, cytoplasmic filopodia and transluminal bridges in the dental papilla suggested angiogenesis was also occurring. Inhibition of apoptosis delayed the angiogenic vascularization of the dental papilla. Therefore, these data demonstrated that molar mesenchyme is progressively vascularized by mechanisms of both vasculogenesis and angiogenesis and apoptosis partially contributes to the vascularization of the dental papilla. PMID- 24477798 TI - Serious transport accidents in adults with attention-deficit/hyperactivity disorder and the effect of medication: a population-based study. AB - IMPORTANCE: Studies have shown that attention-deficit/hyperactivity disorder (ADHD) is associated with transport accidents, but the magnitude of the association remains unclear. Most important, it is also unclear whether ADHD medication reduces this risk. OBJECTIVES: To estimate the association between ADHD and the risk of serious transport accidents and to explore the extent to which ADHD medication influences this risk among patients with ADHD. DESIGN, SETTING, AND PARTICIPANTS: In total, 17,408 patients with a diagnosis of ADHD were observed from January 1, 2006, through December 31, 2009, for serious transport accidents documented in Swedish national registers. The association between ADHD and accidents was estimated with Cox proportional hazards regression. To study the effect of ADHD medication, we used stratified Cox regression to compare the risk of accidents during the medication period with the risk during the nonmedication period within the same patients. MAIN OUTCOMES AND MEASURES: Serious transport accident, identified as an emergency hospital visit or death due to transport accident. RESULTS: Compared with individuals without ADHD, male patients with ADHD (adjusted hazard ratio, 1.47; 95% CI, 1.32-1.63) and female patients with ADHD (1.45; 1.24-1.71) had an increased risk of serious transport accidents. In male patients with ADHD, medication was associated with a 58% risk reduction (hazard ratio, 0.42; 95% CI, 0.23-0.75), but there was no statistically significant association in female patients. Estimates of the population-attributable fractions suggested that 41% to 49% of the accidents in male patients with ADHD could have been avoided if they had been receiving treatment during the entire follow-up. CONCLUSIONS AND RELEVANCE: Attention deficit/hyperactivity disorder is associated with an increased risk of serious transport accidents, and this risk seems to be possibly reduced by ADHD medication, at least among male patients. This should lead to increased awareness among clinicians and patients of the association between serious transport accidents and ADHD medication. PMID- 24477799 TI - Testing and validation of the Automated Topology Builder (ATB) version 2.0: prediction of hydration free enthalpies. AB - To test and validate the Automated force field Topology Builder and Repository (ATB; http://compbio.biosci.uq.edu.au/atb/ ) the hydration free enthalpies for a set of 214 drug-like molecules, including 47 molecules that form part of the SAMPL4 challenge have been estimated using thermodynamic integration and compared to experiment. The calculations were performed using a fully automated protocol that incorporated a dynamic analysis of the convergence and integration error in the selection of intermediate points. The system has been designed and implemented such that hydration free enthalpies can be obtained without manual intervention following the submission of a molecule to the ATB. The overall average unsigned error (AUE) using ATB 2.0 topologies for the complete set of 214 molecules was 6.7 kJ/mol and for molecules within the SAMPL4 7.5 kJ/mol. The root mean square error (RMSE) was 9.5 and 10.0 kJ/mol respectively. However, for molecules containing functional groups that form part of the main GROMOS force field the AUE was 3.4 kJ/mol and the RMSE was 4.0 kJ/mol. This suggests it will be possible to further refine the parameters provided by the ATB based on hydration free enthalpies. PMID- 24477800 TI - The SAMPL4 hydration challenge: evaluation of partial charge sets with explicit water molecular dynamics simulations. AB - We used blind predictions of the 47 hydration free energies in the SAMPL4 challenge to test multiple partial charge models in the context of explicit solvent free energy simulations with the general AMBER force field. One of the partial charge models, IPolQ-Mod, is a fast continuum solvent-based implementation of the IPolQ approach. The AM1-BCC, restrained electrostatic potential (RESP) and IpolQ-Mod approaches all perform reasonably well (R(2) > 0.8), while VCharge, though faster, gives less accurate results (R(2) of 0.5). The AM1-BCC results are more accurate than those of RESP for tertiary amines and nitrates, but the overall difference in accuracy between these methods is not statistically significant. Interestingly, the IPolQ-Mod method is found to yield partial charges in very close agreement with RESP. This observation suggests that the success of RESP may be attributed to its fortuitously approximating the arguably more rigorous IPolQ approach. PMID- 24477802 TI - [Prehospital resuscitation of patients with multiple injuries]. AB - INTRODUCTION: Polytrauma is the leading cause of morbidity and mortality in young adults (aged 35-45 years). At 30-40%, traumatic hemorrhage is the most frequent preventable cause of death. Approximately every fourth patient with multiple injuries suffers from trauma-induced coagulopathy. METHODS: The current knowledge of prehospital resuscitation of patients with multiple injuries based on a selective literature research and experience in a level I trauma center are presented. RESULTS: Hemorrhagic shock is a clinical diagnosis and the recognition by the first responding emergency physician requires rapid evaluation of the accident situation, injury pattern and patient's hemodynamic status. In the future, tools will help to reliably estimate shock. Development of trauma-induced coagulopathy is multifactorial and is characterized by interaction of tissue damage, shock, hypothermia, acidosis and dilution. Preclinical therapy follows the concept of damage control resuscitation and involves bleeding hemostasis, permissive hypotension with a target systolic blood pressure between 80 and 90 mmHg (>=80 mmHg in presence of traumatic brain injury) by modest infusion of primarily crystalloid solutions, avoiding hypothermia and acidosis. CONCLUSION: The current knowledge and therapy recommendations are presented. PMID- 24477803 TI - [Trauma-induced coagulopathy]. AB - The main cause of death in the patient group less than 45 years is trauma. Beside severe traumatic brain injury, bleeding remains a leading cause of death in this group. For a causal therapy, it is necessary to understand the pathophysiology of trauma-induced coagulopathy (TIC). Beside the well-known lethal triad of trauma (hypothermia, acidosis, and coagulopathy), dilution and hypoperfusion with activation of the protein C pathway play a crucial role. TIC is a complex independent syndrome which may be present without initial hypercoagulopathy. A rapid and differentiated diagnosis and goal-directed therapy is crucial for causal therapy. PMID- 24477801 TI - The role of voltage-gated calcium channels in neurotransmitter phenotype specification: Coexpression and functional analysis in Xenopus laevis. AB - Calcium activity has been implicated in many neurodevelopmental events, including the specification of neurotransmitter phenotypes. Higher levels of calcium activity lead to an increased number of inhibitory neural phenotypes, whereas lower levels of calcium activity lead to excitatory neural phenotypes. Voltage gated calcium channels (VGCCs) allow for rapid calcium entry and are expressed during early neural stages, making them likely regulators of activity-dependent neurotransmitter phenotype specification. To test this hypothesis, multiplex fluorescent in situ hybridization was used to characterize the coexpression of eight VGCC alpha1 subunits with the excitatory and inhibitory neural markers xVGlut1 and xVIAAT in Xenopus laevis embryos. VGCC coexpression was higher with xVGlut1 than xVIAAT, especially in the hindbrain, spinal cord, and cranial nerves. Calcium activity was also analyzed on a single-cell level, and spike frequency was correlated with the expression of VGCC alpha1 subunits in cell culture. Cells expressing Cav 2.1 and Cav 2.2 displayed increased calcium spiking compared with cells not expressing this marker. The VGCC antagonist diltiazem and agonist (-)BayK 8644 were used to manipulate calcium activity. Diltiazem exposure increased the number of glutamatergic cells and decreased the number of gamma aminobutyric acid (GABA)ergic cells, whereas (-)BayK 8644 exposure decreased the number of glutamatergic cells without having an effect on the number of GABAergic cells. Given that the expression and functional manipulation of VGCCs are correlated with neurotransmitter phenotype in some, but not all, experiments, VGCCs likely act in combination with a variety of other signaling factors to determine neuronal phenotype specification. PMID- 24477805 TI - Morphogenesis in the red alga, Griffithsia pacifica: Regeneration from single cells. AB - The regeneration of plants of the red alga Griffithsia pacifica from single, isolated cells is described. Regeneration can start from any cell and is triggered by the removal of an abutting cell. An isolated, single shoot cell forms a shoot and a rhizoidal cell within one day. The shoot then adds new cells by apical division at the rate of 1-2 cells/day; branches are formed at predictable but not fixed locations by budding of subapical cells. Each shoot cell enlarges for 6-8 days. The resulting plant consists of uniseriate, pseudodichotomously-branched shoot filaments with multicellular rhizoidal filaments at their base. The predictability and rapidity of this development combined with the large size of these cells (1.0*0.2 mm) facilitate developmental studies on this organism. PMID- 24477804 TI - Ethylene reverses photosynthetic inhibition by nickel and zinc in mustard through changes in PS II activity, photosynthetic nitrogen use efficiency, and antioxidant metabolism. AB - We investigated the influence of exogenously sourced ethylene (200 MUL L(-1) ethephon) in the protection of photosynthesis against 200 mg kg(-1) soil each of nickel (Ni)- and zinc (Zn)-accrued stress in mustard (Brassica juncea L.). Plants grown with Ni or Zn but without ethephon exhibited increased activity of 1 aminocyclopropane carboxylic acid synthase, and ethylene with increased oxidative stress measured as H2O2 content and lipid peroxidation compared with control plants. The oxidative stress in Ni-grown plants was higher than Zn-grown plants. Under metal stress, ethylene protected photosynthetic potential by efficient PS II activity and through increased activity of ribulose-1,5-bisphosphate carboxylase and photosynthetic nitrogen use efficiency (P-NUE). Application of 200 MUL L(-1) ethephon to Ni- or Zn-grown plants significantly alleviated toxicity and reduced the oxidative stress to a greater extent together with the improved net photosynthesis due to induced activity of ascorbate peroxidase and glutathione (GSH) reductase, resulting in increased production of reduced GSH. Ethylene formation resulting from ethephon application alleviated Ni and Zn stress by reducing oxidative stress caused by stress ethylene production and maintained increased GSH pool. The involvement of ethylene in reversal of photosynthetic inhibition by Ni and Zn stress was related to the changes in PS II activity, P-NUE, and antioxidant capacity was confirmed using ethylene action inhibitor, norbornadiene. PMID- 24477806 TI - Development in the red alga, Griffithsia pacifica: Control by internal and external factors. AB - Development in the red alga Griffithsia pacifica is affected by both external and internal factors. Under 16:8 photoperiods, both cell division and cell elongation show a diurnal rhythm. The rhythm of division persists for at least 7 cycles in continuous light, and can be reset; this indicates that the timing of cell division is controlled by an endogenous rhythm. Both cell division and elongation require light, but the rate of division of apical cells and the rate of cell elongation are both relatively insensitive to either light intensity or photoperiod. In contrast. division in nodal cells, which leads to branch formation, is strongly promoted by high light intensity or long photoperiods. By manipulating the conditions of illumination, one can obtain Griffithsia plants varying from unbranched to highly branched. PMID- 24477807 TI - Flowering of Chrysanthemum under non-inductive long days by gibberellins and N(6) benzyladenine. AB - The flowering and inflorescence development of Chrysanthemum morifolium cv. Pink Champagne under non-inductive long days was promoted by exogenous application of GA5, GA3, GA4+GA7 or GA9 in combination with the cytokinin, BA. The combination of BA and GA5 was highly effective, BA and GA3 moderately effective. Applications of the GAs alone or BA alone also resulted in some flowering, with GA3 and GA5 being most effective. In general, the effects of GA and BA were synergistic, and the concentration of both growth substances was a limiting factor with regard to the number of plants flowering under long days. Only the concentration of GA was a limiting factor for inflorescence development, however. Simultaneous application of indole-3-acetic acid reduced inflorescence development in most treatments. Development to the stage of anthesis was in no case effected. PMID- 24477808 TI - The effects of abscisic acid on senescence in leaf discs of radish, Raphanus sativus L. AB - After a 6 day incubation period, abscisic acid (ABA) at 10(-4) M retarded the decline in pigment levels and promoted the decline in protein levels of radish leaf discs. ABA treatment also retarded the rise in the specific activity of the RNA fraction (calculated by counts per minute incorporated of (14)C-8-adenine as a fraction of optical density at 260 nm) observed in water-treated control discs. The results indicated that ABA was primarily effective in enhancing senescence in the early stages following leaf excision. Thus the increase in RNA specific activity during an initial 24 h incubation period was especially pronounced with ABA treatment although there was no effect of the hormone on RNA level. Moreover, in contrast to control discs, the pigment levels declined markedly in ABA-treated discs in this period. When the discs had been incubated in water ("preaged") for 3 or 5 days prior to ABA treatment, however, the hormone then had little effect on RNA metabolism and protein and pigment levels relative to the water control.Data are collated from different experiments to show the changes in RNA, pigment and protein with ABA treatment during a 6 day senescence period.It is considered that ABA is speeding up the natural changes in RNA metabolism possibly by affecting both RNA synthesis and degradation. PMID- 24477809 TI - The role of light in nitrite reduction; Studies with leaf discs. AB - The reduction of nitrite by leaf discs has been studied. In short term experiments the reduction is markedly stimulated by light, but is not affected by the absence of oxygen or carbon dioxide from the gas phase. Carbon dioxide assimilation is more sensitive than nitrite reduction to 3-(3',4'-dichloro-)-1,1 dimethyl urea (DCMU) inhibition. Uncouplers such as carbonyl cyanide m chlorophenyl-hydrazone (CCCP) do not inhibit nitrite reduction although dinitrophenol (DNP) has a small effect.Although nitrite stimulates oxygen evolution in the light in the absence of CO2 the stoichiometry of nitrite reduction to oxygen evolution is much less than would be predicted if nitrite is simply acting as a classical Hill reagent. PMID- 24477810 TI - Endogenous gibberellin transport and biosynthesis in relation to geotropic induction of excised sunflower shoot-tips. AB - Surgical experiments on Helianthus annuus and Phaseolus multiflorus seedlings involving the application of auxin and gibberellin to decapitated plants, suggested that internode extension growth occurs under the controlling influence of apically synthesised gibberellin rather than auxin. Studies were made of diffusible gibberellins from sunflower apical buds in relation to geotropic stimulation. Approximately ten times as much gibberellin was obtained from lower than from upper tissues of horizontal shoot-tips, whereas approximately equal quantities were obtained from the two halves of upright tips. Evidence was obtained suggesting both lateral transport of gibberellin in the young internode, and also enhanced gibberellin synthesis in buds maintained in a horizontal position during the collection of diffusible gibberellins into agar. The results are discussed in relation to current concepts of the role of auxin in geotropism. PMID- 24477811 TI - The development of protein and oil bodies in the seed of Sinapis alba L. AB - The cotyledons of Sinapis alba L. seed are the storage organs and first photosynthetic organs. The development of the cotyledon cell contents was studied using electron and light microscopy. From the heart shaped embryo (11 days from petal fall) to the mature seed, nine stages were examined.Both types of protein grains (designated aleurone grains and myrosin grains) were found to form within vacuoles, but the mode of protein accumulation differed with each type of grain.Oil bodies were apparent with the EM from 18 days onwards, but could not be seen to arise from the ER. They were granular in appearance at early stages, but later became electron transparent. PMID- 24477812 TI - Induction of male flowers on female plants of Cannabis sativa by gibberellins and its inhibition by abscisic acid. AB - Gibberellins (GA3, GA4+7, GA7 and GA9) induce male flowers on female plants of Cannabis sativa. This is, depending on concentration, partially or fully inhibited by abscisic acid (ABA). The ABA effect can in turn be partially overcome by increasing the concentration of GA3. PMID- 24477813 TI - Accumulation of protochlorophyll and chlorophyll a as controlled by photomorphogenically effective light. AB - Data are presented which indicate that the rate of synthesis and the pool size of photoconvertible protochlorophyll(ide) in the cotyledons of the mustard seedling are controlled by the active form of phytochrome (Pfr). Inductionreversion experiments show that formation of chlorophyll a through photoconversion of the protochlorophyll(ide) by repeated red pulses (5 min each) has no effect on synthesis of carotenoids and galactolipids. Since the protochlorophyll(ide) converting activity of the standard far-red light used in this laboratory is very low, chlorophyll-a accumulation is very slow under continuous standard far-red light. It is concluded that photosynthesis (or photosynthetic phosphorylation) does not participate in the "high irradiance reaction" of photomorphogenesis. PMID- 24477814 TI - Pseudoxanthomonas gei sp. nov., a novel endophytic bacterium isolated from the stem of Geum aleppicum. AB - A Gram stain-negative, strictly aerobic, rod-shaped, non-motile and deep-yellow coloured bacterial strain, designated ZFJR-3(T), was isolated from the stem of Geum aleppicum Jacq. collected from Taibai Mountain in Shaanxi Province, north west China, and characterized by using a polyphasic approach. The novel isolate grew optimally at 25-28 degrees C and in the absence of NaCl. Flexirubin-type pigments were produced. The predominant respiratory quinone was ubiquinone-8 (Q 8) and the major cellular fatty acids were iso-C15:0 (29.2 %), iso-C16:0 (18.5 %), summed feature 9 (comprising iso-C17:1 omega9c and/or C16:0 10-methyl; 8.8 %), C16:1 omega7c alcohol (8.8 %), iso-C11:0 3-OH (6.9 %) and iso-C11:0 (6.8 %). The DNA G+C content was 66.1 mol %. The only polyamine was spermidine and the major polar lipids were diphosphatidylglycerol, phosphatidylethanolamine and phosphatidylglycerol. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain ZFJR-3(T) belongs to the genus Pseudoxanthomonas and was most closely related to Pseudoxanthomonas yeongjuensis KCTC 22757(T) (16S rRNA gene sequence similarity, 99.0 %) and Pseudoxanthomonas sacheonensis KCTC 22080(T) (98.0 %). The levels of 16S rRNA gene sequence similarity with respect to other Pseudoxanthomonas species with validly published names were less than 96.5 %. DNA DNA relatedness values for strain ZFJR-3(T) with respect to its closely related neighbours P. yeongjuensis KCTC 22757(T) and P. sacheonensis KCTC 22080(T) were 48.7 and 36.3 %, respectively. Based on the phenotypic, phylogenetic and genotypic data, strain ZFJR-3(T) is considered to represent a novel species of the genus Pseudoxanthomonas, for which the name Pseudoxanthomonas gei sp. nov. is proposed. The type strain is ZFJR-3(T) (=CCTCC AB 2013020(T) =KCTC 32298(T)). PMID- 24477815 TI - Employment of telemedicine in emergency medicine. Clinical requirement analysis, system development and first test results. AB - OBJECTIVES: Demographic change, rising co-morbidity and an increasing number of emergencies are the main challenges that emergency medical services (EMS) in several countries worldwide are facing. In order to improve quality in EMS, highly trained personnel and well-equipped ambulances are essential. However several studies have shown a deficiency in qualified EMS physicians. Telemedicine emerges as a complementary system in EMS that may provide expertise and improve quality of medical treatment on the scene. Hence our aim is to develop and test a specific teleconsultation system. METHODS: During the development process several use cases were defined and technically specified by medical experts and engineers in the areas of: system administration, start-up of EMS assistance systems, audio communication, data transfer, routine tele-EMS physician activities and research capabilities. Upon completion, technical field tests were performed under realistic conditions to test system properties such as robustness, feasibility and usability, providing end-to-end measurements. RESULTS: Six ambulances were equipped with telemedical facilities based on the results of the requirement analysis and 55 scenarios were tested under realistic conditions in one month. The results indicate that the developed system performed well in terms of usability and robustness. The major challenges were, as expected, mobile communication and data network availability. Third generation networks were only available in 76.4% of the cases. Although 3G (third generation), such as Universal Mobile Telecommunications System (UMTS), provides beneficial conditions for higher bandwidth, system performance for most features was also acceptable under adequate 2G (second generation) test conditions. CONCLUSIONS: An innovative concept for the use of telemedicine for medical consultations in EMS was developed. Organisational and technical aspects were considered and practical requirements specified. Since technical feasibility was demonstrated in these technical field tests, the next step would be to prove medical usefulness and technical robustness under real conditions in a clinical trial. PMID- 24477816 TI - Loading of an anti-cancer drug onto graphene oxide and subsequent release to DNA/RNA: a direct optical detection. AB - Graphene oxide based molecular switching of ellipticine (E) has been utilized to probe its efficient loading onto graphene oxide (GO) and subsequent release to intra-cellular biomolecules like DNA/RNA. The green fluorescence of E switches to blue in GO and switches back to green with polynucleotides. The intensified blue emission of the ellipticine-GO (E-GO) complex with human serum albumin (HSA), switches to a bluish green upon addition of dsDNA. Electron microscopy reveals the formation of distinctive 3D assemblies involving GO and biomolecule(s) probably through non-covalent interactions and this is primarily responsible for the biomolcule(s) assisted fluorescence-switching of E. To our knowledge, such morphological patterning of a GO-DNA complex is very unusual, reported here the first time and could find applications in the fabrication of biomedical devices. Moreover, our approach of direct optical detection of drug loading and releasing is very cheap, appealing and will be useful for clinical trial experiments once the cytotoxicity of GO is duly taken care. PMID- 24477817 TI - Oxidative status, inflammation, and postoperative atrial fibrillation with metoprolol vs carvedilol or carvedilol plus N-acetyl cysteine treatment. AB - BACKGROUND: Atrial fibrillation is associated with inflammation and oxidative stress. HYPOTHESIS: Carvedilol and N-acetyl cysteine (NAC) combination decreases inflammation, oxidative stress, and postoperative atrial fibrillation (POAF) rates more than metoprolol or carvedilol. METHODS: Preoperative and postoperative total oxidative stress (TOS), total antioxidant capacity (TAC), and white blood cells (WBC) were measured in metoprolol, carvedilol, or carvedilol plus NAC groups, and association with POAF was evaluated. RESULTS: Preoperative TAC, TOS, and WBC levels were similar among the groups. Postoperative TAC levels were lower in the metoprolol group compared with the carvedilol group (1.0 vs 1.4) or the carvedilol plus NAC group (1.0 vs 1.9) and were also lower in the carvedilol group compared with the carvedilol plus NAC group (all P < 0.0001). Postoperative TOS levels were higher in the metoprolol group as compared with the carvedilol (29.6 vs 24.2; P < 0.0001) or the carvedilol plus NAC groups (P < 0.0001), and were also higher in the carvedilol group as compared with the carvedilol plus NAC group (24.2 vs 19.3; P < 0.0001). Postoperative WBC counts were lower in the carvedilol plus NAC group compared with the metoprolol group (12.9 vs 14.8; P = 0.004), were similar between the carvedilol and the metoprolol groups (13 vs 14.8) and between the carvedilol plus NAC group and the carvedilol group (both P > 0.05). Postoperative TAC, TOS, and WBC were associated with POAF. CONCLUSIONS: Carvedilol plus NAC reduced oxidative stress and inflammation compared with metoprolol and decreased oxidative stress compared with carvedilol. Postoperative TAC, TOS, and WBC were associated with POAF. PMID- 24477818 TI - Refreshing memories. AB - The exchange of CaMKII enzymes between larger structures called holoenzymes may provide the molecular mechanism underlying the long-term stability of memories. PMID- 24477819 TI - Analysis of irradiation on the clinical effectiveness of allogenic tissue when used for primary anterior cruciate ligament reconstruction. AB - BACKGROUND: It is unclear whether the use of low-dose irradiation or other tissue processing methods, such as preservation by fresh-frozen (FF), freeze-drying (FD), or cryopreservation (CP) methods, affects the clinical outcomes of primary anterior cruciate ligament reconstruction (ACLR) using allograft. HYPOTHESIS: Low dose gamma irradiation (<2.5 Mrad) and method of allograft preservation do not affect subjective and objective clinical outcomes after primary ACLR in studies reviewed between November 2010 and September 2012. STUDY DESIGN: Systematic review; Level of evidence, 3. METHODS: A computerized search of multiple electronic databases was conducted from November 2010 to September 2012 for prospective and retrospective studies involving primary allograft ACLR. Inclusion criteria were English-language publications with a minimum average of 2 years' follow-up. Studies were excluded if they involved revision surgery, open surgery, multiple ligament procedures, autograft, xenograft, meniscal allograft, skeletally immature patients, or grafts treated with ethylene oxide, Tutoplast, or irradiation>2.5 Mrad or if the tissue-processing methods were not specified. Clinical outcomes were evaluated using the Lysholm score, Tegner score, International Knee Documentation Committee (IKDC) score, KT-1000/2000 arthrometer score, Lachman test, and pivot-shift test, as well as by assessing complications related to graft rupture, revision surgery, and infections. RESULTS: A total of 21 publications met the criteria, involving a total of 1453 patients, with 415 irradiated and 1038 nonirradiated allografts. Mean follow-up was 49.8 months (range, 12-170 months). Mean age of the patients was 32.2 years. Knees with nonirradiated allografts had higher mean Lysholm scores (89.8 vs 84.4; P<.05), and a higher proportion of <5-mm difference on KT-1000/2000 arthrometer (0.97 vs 0.84; P<.0001), grade 0 and 1 pivot-shift (0.99 vs 0.94; P<.0001), and grade 0 and 1 Lachman (0.94 vs 0.89; P<.01) than those with irradiated grafts. Knees with irradiated allografts had a higher proportion of grade A and B IKDC outcomes (0.91 vs 0.86; P<.05) and revision surgery (0.0250 vs 0.0022; P<.001) compared with those with nonirradiated allografts. The lack of data for FD and CP allografts meant no statistical analysis could be made comparing FF versus FD versus CP allografts. The effect of irradiation was similar within FF allografts. The effect of graft type and surgical technique could not be determined because of insufficient data. CONCLUSION: These results suggest that primary ACLRs using nonirradiated allografts may provide superior clinical outcomes than those using low-dose (<2.5 Mrad) irradiated grafts. PMID- 24477820 TI - 20 years of pediatric anterior cruciate ligament reconstruction in New York State. AB - BACKGROUND: There have been no population-based studies to evaluate the rate of pediatric anterior cruciate ligament (ACL) reconstruction. PURPOSE: The primary aim of the current study was to determine the yearly rate of ACL reconstruction over the past 20 years in New York State. Secondary aims were to determine the age distribution for ACL reconstruction and determine whether patient demographic and socioeconomic factors were associated with ACL reconstruction. STUDY DESIGN: Descriptive epidemiology study. METHODS: The Statewide Planning and Research Cooperative System (SPARCS) database contains a census of all hospital admissions and ambulatory surgery in New York State. This database was used to identify pediatric ACL reconstructions between 1990 and 2009; ICD-9-CM (International Classification of Diseases, 9 Revision, Clinical Modification) and CPT-4 (Current Procedural Terminology, 4th Revision) codes were used to identify reconstructions. Patient sex, age, race, family income, education, and insurance status were assessed. RESULTS: The rate of ACL reconstruction per 100,000 population aged 3 to 20 years has been increasing steadily over the past 20 years, from 17.6 (95% confidence interval [CI], 16.4-18.9) in 1990 to 50.9 (95% CI, 48.8-53.0) in 2009. The peak age for ACL reconstruction in 2009 was 17 years, at a rate of 176.7 (95% CI, 160.9-192.5). In 2009, the youngest age at which ACL reconstruction was performed was 9 years. The rate of ACL reconstruction in male patients was about 15% higher than in females, and ACL reconstruction was 6-fold more common in patients with private health insurance compared with those enrolled in Medicaid. CONCLUSION: This study is the first to quantify the increasing rate of ACL reconstructions in the skeletally immature. Only ACL reconstructions were assessed, and it is possible that some ACL tears in children are not diagnosed or are treated nonoperatively. The rate of ACL tears in New York State is likely higher than the rate of reconstructions reported in this study. SIGNIFICANCE: This study quantifies the increasing rate of ACL reconstruction in the skeletally immature and suggests that there may be some disparities in care based on insurance status. PMID- 24477821 TI - Mevalonate deprivation mediates the impact of lovastatin on the differentiation of murine 3T3-F442A preadipocytes. AB - The statins competitively inhibit 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase activity and consequently the synthesis of mevalonate. The use of statins is associated with insulin resistance, presumably due to the impaired differentiation and diminished glucose utilization of adipocytes. We hypothesize that mevalonate is essential to adipocyte differentiation and adipogenic gene expression. Adipo-Red assay and Oil Red O staining showed that an eight-day incubation with 0-2.5 umol/L lovastatin dose-dependently reduced the intracellular triglyceride content of murine 3T3-F442A adipocytes. Concomitantly, lovastatin downregulated the expression of peroxisome proliferator-activated receptor gamma (Ppargamma), leptin (Lep), fatty acid binding protein 4 (Fabp4), and adiponectin (AdipoQ) as measured by quantitative real-time polymerase chain reaction (real-time qPCR). The expression of sterol regulatory element binding protein 1 (Srebp-1), a transcriptional regulator of Ppargamma and Lep genes, was also suppressed by lovastatin. Western-blot showed that lovastatin reduced the level of CCAAT/enhancer binding protein alpha (C/EBPalpha) while inducing a compensatory over-expression of HMG CoA reductase. The impact of lovastatin on intracellular triglyceride content and expression of the adipogenic genes was reversed by supplemental mevalonate. Mevalonate-derived metabolites have essential roles in promoting adipogenic gene expression and adipocyte differentiation. PMID- 24477822 TI - Sparstolonin B attenuates hypoxia-reoxygenation-induced cardiomyocyte inflammation. AB - Myocardial ischemia-reperfusion (MIR) injury is characterized by a rapid increase in cytokines and chemokines and an infiltration of inflammatory cells. Toll-like receptors (TLRs) 2 and 4 mediate these inflammatory responses. Herein we investigated the ability of Sparstolonin B (SsnB), a new selective TLR2/4 antagonist, to inhibit the TLR2/4-mediated inflammatory responses during cardiomyocyte hypoxia-reoxygenation injury as well as the responsible mechanisms. Lactate dehydrogenase (LDH) assay was performed to measure the cytotoxicity of SsnB on H9c2 cardiomyocytes. Quantitative real-time PCR (qRT-PCR) confirmed that TLR2 and TLR4 expression was elevated during hypoxia-reoxygenation, and that their up-regulation in cardiomyocytes was significantly inhibited by SsnB (P < 0.05). Both the mRNA and protein levels of monocyte chemotactic protein-1 and high mobility group box 1 were up-regulated during hypoxia-reoxygenation and were significantly attenuated by SsnB (P < 0.05). Next we found that extracellular signal-regulated kinase 1 or 2 (ERK1/2) and c-Jun NH2-terminal kinase (JNK) signaling pathways were activated during hypoxia-reoxygenation and SsnB significantly inhibited their activation (P < 0.05). Moreover, transwell migration assays revealed that the migration of mouse macrophages to hypoxia reoxygenation injured cardiomyocytes was significantly reduced by SsnB (P < 0.05). In conclusion, our data indicate that the new selective TLR2 and TLR4 antagonist, SsnB, can substantially attenuate hypoxia-reoxygenation-induced inflammation of cardiomyocytes via inhibiting ERK1/2 and JNK signaling pathways. Accordingly, SsnB has the potential to serve as a therapeutic agent for the prevention of MIR injury. PMID- 24477823 TI - Transplantation of mesenchymal stem cells carrying the human receptor activity modifying protein 1 gene improves cardiac function and inhibits neointimal proliferation in the carotid angioplasty and myocardial infarction rabbit model. AB - Although transplanting mesenchymal stem cells (MSCs) can improve cardiac function and contribute to endothelial recovery in a damaged artery, natural MSCs may induce neointimal hyperplasia by directly or indirectly acting on vascular smooth muscle cells (VSMCs). Receptor activity-modifying protein 1 (RAMP1) is the component and the determinant of ligand specificity of calcitonin gene-related peptide (CGRP). It is recently reported that CGRP and its receptor involve the proliferation and the apoptosis in vivo and in vitro, and the exogenous RAMP1 enhances the antiproliferation effect of CGRP in VSMCs. Here, we investigated the effects of MSCs overexpressing the human receptor activity-modifying protein 1 (hRAMP1) on heart function and artery repair in rabbit models of myocardial infarction (MI) reperfusion and carotid artery injury. MSCs transfected with a recombinant adenovirus containing the hRAMP1 gene (EGFP-hRAMP1-MSCs) were injected into the rabbit models via the ear vein at 24 h after carotid artery injury and MI 7 days post-EGFP-hRAMP1-MSC transplantation. The cells that expressed both enhance green fluorescent protein (EGFP) and CD31 were detected in the neointima of the damaged artery via immunofluorescence. EGFP-hRAMP1 expression was observed in the injured artery and infarcted myocardium by western blot analysis, confirming that the engineered MSCs targeted the injured artery and infarcted myocardium and expressed hRAMP1 protein. Compared with the EGFP MSCs group, the EGFP-hRAMP1-MSCs group had a significantly smaller infarcted area and improved cardiac function by 28 days after cell transplantation, as detected by triphenyltetrazolium chloride staining and echocardiography. Additionally, arterial hematoxylin-eosin staining revealed that the area of the neointima and the area ratio of intima/media were significantly decreased in the EGFP-hRAMP1 MSCs group. An immunohistological study showed that the expression of alpha smooth muscle antigen and proliferating cell nuclear antigen in the neointima cells of the carotid artery of the EGFP-hRAMP1-MSCs group was approximately 50% lower than that of the EGFP-MSCs group, suggesting that hRAMP1 expression may inhibit VSMCs proliferation within the neointima. Therefore, compared with natural MSCs, EGFP-hRAMP1-engineered MSCs improved infarcted heart function and endothelial recovery from artery injury more efficiently, which will provide valuable information for the development of MSC-based therapy. PMID- 24477824 TI - Benchmark dose of cadmium concentration in rice for renal effects in a cadmium polluted area in Japan. AB - The aim of this study was to estimate the reference level of cadmium in rice as the benchmark doses (BMD) and their 95% lower confidence limits (BMDL) for various renal effects by applying an updated hybrid approach. The participants were 1120 men and 1274 women aged 50 years or older who lived in the environmentally exposed Kakehashi river basin for at least 30 years. As indicators of renal dysfunction, glucose, protein, aminonitrogen, metallothionein and beta(2) -microgrobulin in urine were measured. Cadmium concentration was determined for rice samples stored in warehouses of the farmers in all of the polluted hamlets. The BMD and BMDL that corresponded to an additional risk of 5% were calculated with background risk at a zero exposure set at 5%. The obtained BMDLs were 0.39 (aminonitrogen), 0.26 (metallothionein), 0.25 (beta(2) microgrobulin) mg kg(-1) in men and 0.44 (glucose), 0.32 (protein), 0.33 (aminonitrogen), 0.28 (metallothionein) and 0.24 (beta(2) -microgrobulin) mg kg( 1) in women. The lowest BMDL was 0.25 and 0.24 mg kg(-1) (beta(2) -microgrobulin) in men and women respectively. These values were lower than the maximum level (0.4 mg kg(-1)) determined by the Codex Alimentarius Commission, indicating that these BMDLs may contribute to further discussion on the health risk assessment of cadmium exposure. PMID- 24477825 TI - Difficult airway management for novice physicians: a randomized trial comparing direct and video-assisted laryngoscopy. AB - OBJECTIVES: To detect a difference in (1) intubation success and (2) successful intubation times between novice physicians using a Macintosh-style or video assisted laryngoscope on a difficult airway manikin. STUDY DESIGN: Prospective randomized trial. SETTING: Academic, tertiary medical center. METHODS: Forty first-year residents across a variety of disciplines with fewer than 5 total live intubations were recruited for the study. Testing took place during orientation prior to commencement of clinical duties. The entire group was provided training by faculty otolaryngologists and anesthesiologists using both laryngoscope types on a manikin airway simulator in a standard intubating scenario. Subjects were then randomized into 2 testing groups, using either a Macintosh laryngoscope or video-assisted laryngoscope in a difficult intubation scenario. The difficult airway simulation entailed oral cavity/oropharyngeal obstruction using inflation of the tongue, as well as cervical spine immobilization with a rigid collar preventing extension and elevation of the head and limiting oral cavity opening. Success was defined as a confirmed endotracheal intubation by the testing instructor in 120 seconds or less. RESULTS: The Macintosh laryngoscope group (n = 19) had an intubation success rate of 47.4% with a mean intubation time of 69.0 seconds (95% confidence interval [CI]: 52.7, 85.2). The video-assisted group (n = 21) demonstrated a significantly higher success rate of 100% (P < .0001) and a decreased mean intubation time of 23.1 seconds (95% CI: 18.4, 27.8; P < .0001). The mean difference in success rate between groups was 52.6% (95% CI: 30.0%, 75.3%). CONCLUSIONS: Novice physicians with little to no prior intubation experience showed significantly higher intubation success with lower intubation times using a video-assisted laryngoscope in a difficult airway manikin simulator. PMID- 24477826 TI - Intratympanic gentamicin for Meniere's disease: short- and long-term follow-up of two regimens of treatment. AB - OBJECTIVES: (1) To compare the results of the 2 regimens of treatment at 2-year follow-up and (2) to evaluate the need and the efficacy of retreatment after the recurrence of vertigo attacks in a longer period of follow-up (using the Kaplan Meier method of analysis). STUDY DESIGN: Retrospective chart review. SETTING: Tertiary referral center. SUBJECTS AND METHODS: We analyzed 77 patients treated with intratympanic gentamicin (ITG). Thirty-five patients were treated with high dose (HD) ITG (in total 6 injections, twice a day, repeated every 3 days) and 42 with low-dose (LD) ITG (1-2 injections). The results of treatment were evaluated in terms of functional level scale, control of vertigo, and hearing impairment. RESULTS: At 2-year follow-up, a similar percentage of vertigo control was obtained in the 2 groups; the incidence of hearing loss and posttreatment disequilibrium was significantly higher in patients treated with HD-ITG. The long term follow-up showed a control of vertigo attacks with a single round of treatment in 71.4% of patients treated with HD-ITG and in 55% of those treated with LD-ITG. With repeated rounds, an effective control of vertigo could be achieved in 88.5% using a HD-ITG protocol and 97.7% using a LD-ITG protocol. CONCLUSIONS: LD-ITG allows obtaining good results in term of vertigo attacks associated with a limited occurrence of side effects. The long-term follow-up showed that LD-ITG needed repeated rounds more frequently than the HD-protocol. HD-ITG ran less risk of needing repeated rounds, but retreatment was ineffective in 40% of the cases requiring surgical therapy. PMID- 24477827 TI - Erratum to: An elemental model of retrospective revaluation without within compound associations. PMID- 24477828 TI - On an early gene for membrane-integral inorganic pyrophosphatase in the genome of an apparently pre-luca extremophile, the archaeon Candidatus Korarchaeum cryptofilum. AB - A gene for membrane-integral inorganic pyrophosphatase (miPPase) was found in the composite genome of the extremophile archaeon Candidatus Korarchaeum cryptofilum (CKc). This korarchaeal genome shows unusual partial similarity to both major archaeal phyla Crenarchaeota and Euryarchaeota. Thus this Korarchaeote might have retained features that represent an ancestral archaeal form, existing before the occurrence of the evolutionary bifurcation into Crenarchaeota and Euryarchaeota. In addition, CKc lacks five genes that are common to early genomes at the LUCA border. These two properties independently suggest a pre-LUCA evolutionary position of this extremophile. Our finding of the miPPase gene in the CKc genome points to a role for the enzyme in the energy conversion of this very early archaeon. The structural features of its miPPase indicate that it can pump protons through membranes. An miPPase from the extremophile bacterium Caldicellulosiruptor saccharolyticus also has a sequence indicating a proton pump. Recent analysis of the three-dimensional structure of the miPPase from Vigna radiata has resulted in the recognition of a strongly acidic substrate (orthophosphate: Pi, pyrophosphate: PPi) binding pocket, containing 11 Asp and one Glu residues. Asp (aspartic acid) is an evolutionarily very early proteinaceous amino acid as compared to the later appearing Glu (glutamic acid). All the Asp residues are conserved in the miPPase of CKc, V. radiata and other miPPases. The high proportion of Asp, as compared to Glu, seems to strengthen our argument that biological energy conversion with binding and activities of orthophosphate (Pi) and energy-rich pyrophosphate (PPi) in connection with the origin and early evolution of life may have started with similar or even more primitive acidic peptide funnels and/or pockets. PMID- 24477829 TI - [Research with participants suffering from dementia. Ethical and legal considerations in research involving human subjects]. AB - Using case reports from the health services research project Action Alliance Pain Free City Muenster, fundamental issues of research ethics, data protection and legal guardianship are shown and explained. A plan of important aspects to be considered while planning, conducting and recruiting for research with nursing home inhabitants suffering from dementia in a legally correct and safe manner is presented. PMID- 24477830 TI - Effectiveness of diabetes interventions in the patient-centered medical home. AB - The patient-centered medical home (PCMH) is an innovative care model for the provision of primary care that is being rapidly adopted in the U.S. with the support of federal agencies and professional organizations. Its goal is to provide comprehensive, patient-centered care with increased access, quality, and efficiency. Diabetes, as a common, costly, chronic disease that requires ongoing management by patients and providers, is a condition that is frequently monitored as a test case in PCMH implementations. While in theory a PCMH care model that supports patient engagement and between-visit care may help improve diabetes care delivery and outcomes, the success of this approach may depend largely upon the specific strategies used and implementation approach. The cost-effectiveness of diabetes care in the PCMH model is not yet clear. Interventions have been most effective and most cost-effective for those with the poorest diabetes management at baseline. PMID- 24477831 TI - Prognostic subdivision of ypT3 rectal tumours according to extension beyond the muscularis propria. AB - BACKGROUND: The subdivision of T3 in rectal carcinoma according to the depth of invasion into perirectal fat has been recommended in the TNM Supplement since 1993. This study assessed the prognostic impact of this pathological staging in tumours removed after neoadjuvant chemoradiotherapy (ypT3). METHODS: Data from patients with ypT3 rectal carcinoma (less than 12 cm from the anal verge) treated with neoadjuvant chemoradiation and total mesorectal excision were analysed. Tumour category ypT3 was subdivided into ypT3a (5 mm or less) and ypT3b (more than 5 mm), based on histological measurements of maximal tumour invasion beyond the outer border of the muscularis propria. RESULTS: Important differences between ypT3a (81 patients) and ypT3b (43) were found in 5-year rates of locoregional recurrence (7 versus 18 per cent; P = 0.049), distant metastasis (20 versus 41 per cent; P = 0.002), disease-free survival (73 versus 47 per cent; P = 0.001), overall survival (79 versus 74 per cent; P = 0.036) and cancer-related survival (81 versus 74 per cent; P = 0.007). In Cox regression analyses, the ypT3 subclassification was identified as an independent prognostic factor for disease free (ypT3b: hazard ratio (HR) 2.13, 95 per cent confidence interval 1.16 to 3.89; P = 0.014), observed (ypT3b: HR 2.02, 1.05 to 3.87; P = 0.035) and cancer related (ypT3b: HR 2.46, 1.20 to 5.04; P = 0.014) survival. Extramural venous invasion was found to be an additional prognostic factor, but the pathological node category after chemoradiotherapy (ypN) did not influence survival. CONCLUSION: In ypT3 rectal carcinomas, the proposed subclassification is superior to ypN in predicting prognosis. PMID- 24477832 TI - Moisture status during a strong El Nino explains a tropical montane cloud forest's upper limit. AB - Growing evidence suggests short-duration climate events may drive community structure and composition more directly than long-term climate means, particularly at ecotones where taxa are close to their physiological limits. Here we use an empirical habitat model to evaluate the role of microclimate during a strong El Nino in structuring a tropical montane cloud forest's upper limit and composition in Hawai'i. We interpolate climate surfaces, derived from a high density network of climate stations, to permanent vegetation plots. Climatic predictor variables include (1) total rainfall, (2) mean relative humidity, and (3) mean temperature representing non-El Nino periods and a strong El Nino drought. Habitat models explained species composition within the cloud forest with non-El Nino rainfall; however, the ecotone at the cloud forest's upper limit was modeled with relative humidity during a strong El Nino drought and secondarily with non-El Nino rainfall. This forest ecotone may be particularly responsive to strong, short-duration climate variability because taxa here, particularly the isohydric dominant Metrosideros polymorpha, are near their physiological limits. Overall, this study demonstrates moisture's overarching influence on a tropical montane ecosystem, and suggests that short-term climate events affecting moisture status are particularly relevant at tropical ecotones. This study further suggests that predicting the consequences of climate change here, and perhaps in other tropical montane settings, will rely on the skill and certainty around future climate models of regional rainfall, relative humidity, and El Nino. PMID- 24477833 TI - A combined DFT + U and Monte Carlo study on rare earth doped ceria. AB - We investigate the dopant distribution and its influence on the oxygen ion conductivity of ceria doped with rare earth oxides by combining density functional theory and Monte Carlo simulations. We calculate the association energies of dopant pairs, oxygen vacancy pairs and between dopant ions and oxygen vacancies by means of DFT + U including finite size corrections. The cation coordination numbers from ensuing Metropolis Monte Carlo simulations show remarkable agreement with experimental data. Combining Metropolis and Kinetic Monte Carlo simulations we find a distinct dependence of the ionic conductivity on the dopant distribution and predict long term degradation of electrolytes based on doped ceria. PMID- 24477834 TI - L-methionine supplementation maintains the integrity and barrier function of the small-intestinal mucosa in post-weaning piglets. AB - This study was conducted to test the hypothesis that different dietary Met levels affect small-intestinal mucosal integrity in post-weaning piglets. Two groups of piglets (n = 6/group) were weaned at 28 days of age and randomly allotted to a basal diet (without extra Met supplementation) or a Met-supplemented diet (with 0.12% L-Met) for 14 days. The standardized ileal digestible (SID) Met levels were 0.24 and 0.35%, respectively. At days 7 and 14 of the trial, venous blood samples were obtained from piglets, followed by their euthanasia for tissue collection. Piglets fed the diet supplemented with L-Met had a higher average daily gain during days 7-14 and improved feed efficiency during the entire period. Concentrations of sulfur amino acids (SAA), glutamate acid (Glu), glutamine (Gln), and taurine in the plasma and tissues were higher for the piglets in the Met-supplemented group. Met supplementation increased cysteine (Cys) and glutathione (GSH) concentrations in the plasma and tissues, leading to reductions in plasma Cys/CySS redox potential and tissue GSH/GSSH redox potential. The small intestinal mucosa of Met-supplemented piglets exhibited improved villus architecture, compared with control piglets. Met supplementation increased transepithelial electrical resistance of the jejunal mucosa. Transport of Met, Gln and Cys across the jejunal mucosa did not differ between control and Met supplemented piglets. The abundance occludin was higher, whereas the abundance of active caspase-3 was lower, in the jejunum of the Met-supplemented piglets. Collectively, adequate dietary Met is required for optimal protein synthesis and mucosal integrity in the small intestine of post-weaning piglets. PMID- 24477835 TI - A 7-day oral supplementation with branched-chain amino acids was ineffective to prevent muscle damage during a marathon. AB - The aim of this study was to determine the effectiveness of a 7-day oral supplementation with branched-chain amino acids (BCAA) to prevent muscle damage during a marathon. Forty-six experienced runners were randomly divided into two groups, one with BCAA supplementation (n = 25, supplemented with 5 g day(-1) of powdered 1:0.5:0.5 leucine:isoleucine:valine, during the 7 days prior to the competition) and the other as a control group (n = 21, supplemented with an isocaloric placebo). Before the marathon race and within 3 min of finishing, leg muscle power was measured with a maximal countermovement jump and a urine sample was obtained. During the race, running pace was measured by means of a time-chip. Myoglobin concentration was determined in the urine samples as an indirect marker of muscle damage. A visual analog scale (0-10 points) was used to assess leg muscle pain during the race. In the BCAA group, the mean running pace during the marathon was similar to the control group (3.3 +/- 0.4 vs. 3.3 +/- 0.5 m s(-1), respectively, 0.98). The pre- to post-race reduction in muscle power was similar in both BCAA and control groups (-23.0 +/- 16.1 vs. -17.3 +/- 13.8 %, P = 0.13). Post-race urine myoglobin concentration was similar in both BCAA and control groups (5.4 +/- 7.5 vs. 4.5 +/- 8.6 MUg mL(-1), P = 0.70). Finally, there were no differences between groups in the perceived muscle pain during the race (6 +/- 1 vs. 5 +/- 1 points, P = 0.80). A 7-day supplementation of BCAA (5 g day(-1)) did not increase the running performance during a marathon. Furthermore, BCAA supplementation was ineffective to prevent muscle power loss, muscle damage or perceived muscle pain during a marathon race. PMID- 24477837 TI - Naturalistic follow-up of youths treated for pediatric anxiety disorders. AB - IMPORTANCE: Pediatric anxiety disorders are highly prevalent and impairing and are considered gateway disorders in that they predict adult psychiatric problems. Although they can be effectively treated in the short term, data are limited on the long-term outcomes in treated children and adolescents, particularly those treated with medication. OBJECTIVE: To determine whether acute clinical improvement and treatment type (i.e., cognitive behavioral therapy, medication, or their combination) predicted remission of anxiety and improvement in global functioning at a mean of 6 years after randomization and to examine predictors of outcomes at follow-up. DESIGN, SETTING, AND PARTICIPANTS: This naturalistic follow-up study, as part of the Child/Adolescent Anxiety Multimodal Extended Long term Study (CAMELS), was conducted at 6 academic sites in the United States and included 288 youths (age range, 11-26 years; mean age, 17 years). Youths were randomized to 1 of 4 interventions (cognitive behavioral therapy, medication, combination, or pill placebo) in the Child/Adolescent Anxiety Multimodal Study (CAMS) and were evaluated a mean of 6 years after randomization. Participants in this study constituted 59.0% of the original CAMS sample. EXPOSURES: Participants were assessed by independent evaluators using a semistructured diagnostic interview to determine the presence of anxiety disorders, the severity of anxiety, and global functioning. Participants and their parents completed questionnaires about mental health symptoms, family functioning, life events, and mental health service use. MAIN OUTCOMES AND MEASURES: Remission, defined as the absence of all study entry anxiety disorders. RESULTS Almost half of the sample (46.5%) were in remission a mean of 6 years after randomization. Responders to acute treatment were significantly more likely to be in remission (odds ratio, 1.83; 95% CI, 1.08-3.09) and had less severe anxiety symptoms and higher functioning; the assigned treatment arm was unrelated to outcomes. Several predictors of remission and functioning were identified. CONCLUSIONS AND RELEVANCE: Youths rated as responders during the acute treatment phase of CAMS were more likely to be in remission a mean of 6 years after randomization, although the effect size was small. Relapse occurred in almost half (48%) of acute responders, suggesting the need for more intensive or continued treatment for a sizable proportion of youths with anxiety disorders. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00052078. PMID- 24477836 TI - Localization of tyrosine hydroxylase-like immunoreactivity in the nervous systems of Biomphalaria glabrata and Biomphalaria alexandrina, intermediate hosts for schistosomiasis. AB - Planorbid snails of the genus Biomphalaria are major intermediate hosts for the digenetic trematode parasite Schistosoma mansoni. Evidence suggests that levels of the neurotransmitter dopamine (DA) are reduced during the course of S. mansoni multiplication and transformation within the snail. This investigation used immunohistochemical methods to localize tyrosine hydroxylase (TH), the rate limiting enzyme in the biosynthesis of catecholamines, in the nervous system of Biomphalaria. The two species examined, Biomphalaria glabrata and Biomphalaria alexandrina, are the major intermediate hosts for S. mansoni in sub-Saharan Africa, where more than 90% of global cases of human intestinal schistosomiasis occur. TH-like immunoreactive (THli) neurons were distributed throughout the central nervous system (CNS) and labeled fibers were present in all commissures, connectives, and nerves. Some asymmetries were observed, including a large distinctive neuron (LPeD1) in the pedal ganglion described previously in several pulmonates. The majority of TH-like immunoreactive neurons were detected in the peripheral nervous system (PNS), especially in lip and foot regions of the anterior integument. Independent observations supporting the dopaminergic phenotype of THli neurons included 1) block of LPeD1 synaptic signaling by the D2/3 antagonist sulpiride, and 2) the similar localization of aqueous aldehyde (FaGlu)-induced fluorescence. The distribution of THli neurons indicates that, as in other gastropods, dopamine functions as a sensory neurotransmitter and in the regulation of feeding and reproductive behaviors in Biomphalaria. It is hypothesized that infection could stimulate transmitter release from dopaminergic sensory neurons and that dopaminergic signaling could contribute to modifications of both host and parasite behavior. PMID- 24477838 TI - Examination of important life experiences of the oldest-old: cross-cultural comparisons of U.S. and Japanese centenarians. AB - The purpose of this study was to compare the most important life events reported by U.S. and Japanese centenarians. This study included a population-based sample of 239 U.S. centenarians from the Georgia Centenarian Study and 304 Japanese centenarians from the Tokyo Centenarian Study. Two open-ended life events questions were categorized and grouped into different life event domains. Several cross-tabulations were computed to investigate culture and gender differences in most important life event domains. Next, four configural frequency analyses were conducted using Neuroticism, Extraversion, and the first most often mentioned life event domain for each sample (i.e., marriage and historical life events). Results suggest that events related to marriage were the most frequent important event domains mentioned by U.S. centenarians. The Japanese sample was more likely to report historical events. Men from the U.S. were more likely to report events related to work and retirement compared to U.S. women, and U.S. women reported events related to family as the most important life events when compared to U.S. men. Japanese women considered events related to marriage, death and grief as the most important life events when compared to Japanese men. In addition, Japanese men reported events related to work and retirement as the most important life events. A cross-cultural difference was found in life events: U.S. centenarians were more likely to mention positive experiences related to marriage and children, whereas Japanese centenarians reported mostly negative and traumatic experiences such as historical, death/grief, and work/retirement events. PMID- 24477839 TI - [Recurrent atrial fibrillation after pulmonary vein isolation. Myocardial extracellular volume as prognosis marker]. PMID- 24477840 TI - Evaluation of the effectiveness of Duddingtonia flagrans and Monacrosporium thaumasium in the biological control of gastrointestinal nematodes in female bovines bred in the semiarid region. AB - Brazil has a herd of 212 million cattle and 171 million hectares of pastures that produce approximately 96 % of Brazilian beef. The Brazilian production system enables animal infection by endoparasites, which are considered one of the main obstacles for the development of this industry and are responsible for considerable economic losses. The control of parasitic diseases is performed via the administration of antiparasitic drugs, but they leave residues of the products in the treated animal, affect non-target organisms and select resistant strains of the parasites. The species D. flagrans and M. thaumasium are promising and sustainable alternatives for controlling gastrointestinal helminths of ruminants and other herbivores. In this study, we evaluated the efficacy of isolates of these species, formulated in a sodium alginate matrix and administered twice a week, to reduce the number of environmental infective larvae of gastrointestinal nematodes that affect prepubescent zebu females. The treated animals presented fewer eggs and a lower number of infective larvae per gram of faeces (p < 0.05). The pastures occupied by treated animals showed a statistically significant reduction (p < 0.05) of the number of L3 and, furthermore, the genera Cooperia sp., Haemonchus sp., and Oesophagostomum sp. were the most prevalent. The average weight of the animals did not differ statistically (p > 0.05) among the treated and control groups. The use of sodium alginate pellets as vehicle for delivery of the fungus mycelia D. flagrans (isolate AC001) and M. thaumasium (isolate NF34A) proved effective in controlling trichostrongylids in prepubescent cows bred in the semi-arid region, with an effective reduction in the number of infective larvae in the pastures. PMID- 24477841 TI - Effect of Edwardsiella tarda immunization on systemic immune response, mucosal immune response and protection in catla (Catla catla). AB - The effect of immunization on systemic and cutaneous mucosal immune responses of fish and their possible relation with protection has not been fully assessed. In this study, healthy catla (Catla catla) were immunized against Edwardsiella tarda using two antigenic preparations namely, whole cell bacterin (B) and bacterin mixed with Freund's complete adjuvant in a 1:1 (v/v) ratio (B+A) followed by a booster dose after 3 weeks of first injection. Different systemic and cutaneous mucosal immune responses were measured at weekly interval upto 8th week post vaccination (pv). Fish were challenged 8 weeks pv with live E. tarda to study vaccine induced protection. The result showed that although there were strong systemic as well as mucosal immune responses, particularly after booster dose, the challenge produced low to moderate protection in terms of relative percent survival (RPS). The maximum RPS (50 %) was recorded in the adjuvanted bacterin group after 8 weeks pv. Low to moderate protection after challenge, which may be attributed to the intracellular nature of E. tarda and/or use of crude antigenic preparation, accounts for new strategy to be developed for immunization programme against such intracellular pathogen. The results collectively suggest possible involvement of systemic as well as mucosal immune responses in inducing protective immunity in catla. PMID- 24477843 TI - Auxin transport in roots : VIII. The distribution of radioactivity in the tissues of Zea root segments. AB - Experiments involving soluble-compound microautoradiography and girdling procedures have been carried out in an attempt to identify the tissues responsible for the acropetally polarised transport of indole-3-acetic acid through segments of Zea mays roots. The results strongly suggest that acropetal movement of IAA takes place in both the stele and the cortex, but with a much greater efficiency in the former tissue than in the latter. Basipetal movement of IAA is much less than acropetal movement and appears to take place with equel efficiency in the cortex and stele. PMID- 24477842 TI - The protective effect of SnF2 containing toothpastes and solution on enamel surfaces subjected to erosion and abrasion in situ. AB - BACKGROUND: Stannous fluoride solutions have shown promising protective effect against erosion/abrasion, but the effect of SnF2 toothpastes is uncertain. AIM: The aim of the study was to test the inhibiting effect of two SnF2 toothpastes and a SnF2 solution against erosive/abrasive wear in a single-blind, randomised in situ study, using a white light interferometer. METHODS: Sixteen human molars were each divided into four specimens, mounted on mouth appliances and worn by 8 volunteers for 9 days. Specimens were brushed with toothpaste twice each day for 30 s either with fluoride-free toothpaste or toothpastes including SnF2. Toothpaste was left on the surface for 90 additional seconds. Group 1, fluoride free toothpaste; Group 2, toothpaste A (0.4% SnF2, Solidox); Group 3, toothpaste B (0.454 % SnF2, Oral-B((r))); Group 4, brushed with fluoride-free toothpaste (30 s) and treated for 2 min with a 0.4 % SnF2 solution (1,000 ppm F). To mimic gastric reflux/vomit, specimens were etched for 2 min twice a day (0.01 M HCl). Procedures were performed extra-orally. RESULTS: The mean enamel wear (in MUm) for the control specimens was: -29.2 +/- SD 10.5; for group 2 -14.5 SD +/- 9.3; for group 3 -33.3 SD +/- 7.4, and for group 4 +0.4 SD +/- 1.3. The specimens treated with SnF2 solution and toothpaste A showed significantly lower enamel wear than the control group. Toothpaste B gave no significant reduction in enamel wear. CONCLUSIONS: The SnF2 solution fully protected the enamel surface against erosive and abrasive challenges. The SnF2 toothpaste A (Solidox) showed less, but significant protection of the enamel, while no statistically significant protection was demonstrated by SnF2 toothpaste B (Oral-B((r)) Pro-Expert). PMID- 24477844 TI - Embryogenesis and germination in rye (Secale cereale L.) : II. Biochemical and fine structural changes during germination. AB - When rye embryos imbibe water they rapidly return to a condition of biochemical and structural complexity. Three stages of imbibition can be recognised: Phase I a short period (10 min) of physical wetting; Phase II a longer period (1 h) when little further imbibition occurs, followed by Phase III a continuous phase of active water uptake. The latter coincides with an increase in respiration rate and an increase both in the number of mitochondria and of cristae within them. Changes in fine structure become evident in all organelles in Phase III, after 2 h of imbibition. In the unimbibed embryo endoplasmic reticulum is present only as short crescents associated with electron lucent bodies, but in Phase III the endoplasmic reticulum proliferates to form many surrounding cirlets. After 6 h these circlets become fewer and instead the endoplasmic reticulum is seen in close association with the nuclear membrane. Concurrently incorporation of radioactive uridine and thymidine is first detectible. This suggests that the large increase in protein synthesis occurs on new ribosomes present on the reticulum associated with the nuclear membrane. For the first 6 h protein synthesis must occur either on polysomes within the dense packing of ribosomes or on these circlets of endoplasmic reticulum associated with electron lucent bodies. PMID- 24477845 TI - [An in vivo study of phytochrome in seeds of Pinus nigra Arn by differential spectrophotometry]. AB - Phytochrome photoconversions Pr->Pfr and Pfr->Pr can be measured by differential spectrophotometry in "dry" seeds (6% water content) of Pinus nigra Arn. A red light irradiation given before imbibition induces germination when the seeds are subsequently wetted and kept in darkness.In continuous darkness the phytochrome content shows a drastic increase at the beginning of moistening.The detectable pigment is entirely in the Pr form. The normal Pfr->Pr dark reversion is observed. Pfr destruction does not take place. PMID- 24477846 TI - Tubular and filamentous structures in pollen tubes: Possible involvement as guide elements in protoplasmic streaming and vectorial migration of secretory vesicles. AB - An ultrastructural study of the pollen tubes of Lilium and Clivia has demonstrated three different classes of longitudinal structures which could influence patterns of protoplasmic streaming and/or serve as "guide elements" in the vectorial migration of secretory vesicles: (a), cortical and noncortical microtubules; (b), microfilaments; and (c), subcortical tubules and cisternae of the endoplasmic reticulum ("subsurface cisternae"). Morphological details of these structures are described. Colchicine concentrations which lead to the complete disappearance of the microtubules affect neither germination of the pollen nor cytoplasmic streaming and tip growth of the elongating pollen tubes. Tip growth is initially uninhibited by cycloheximide, and cytoplasmic streaming is insensitive to this inhibitor. However, both of these processes are sensitive to cytochalasin B and vinblastine. Our results suggest that neither microtubules nor subsurface cisternae are essential for cytoplasmic streaming and directional secretion of cell surface materials in the pollen tube but would be consistent with an involvement of microfilamentous structures in these processes. Additionally, the possible importance of the lateral cross-link elements interconnecting all three types of structures is discussed. PMID- 24477847 TI - [On demethylation and decarboxylation of benzoic acids in plant cell suspension cultures]. AB - Various benzoic acids (14)C-labelled in para and meta methoxyl groups as well as (O-methyl-(14)C) p-methoxy cinnamic acid were tested for O-demethylation in cell suspension cultures of Phaseolus aureus Roxb. and Glycine max Merr. On the basis of (14)CO2-formation and product analyses the O-demethylation reactions were shown to be specific for para methoxyl groups. A vanillate-O-demethylase known from microbial sources seemed to be absent in the plant cell cultures.In this and in an earlier publication (Berlin et al., 1971) some twenty (14)C-labelled aromatic compounds were tested for catabolic reactions in the cell cultures, and here we report on the product analyses and the general pattern of distribution of radioactivity. Finally, some indications for compartmentalisation in connection with catabolic studies of aromatic compounds in plant cell cultures are discussed.Decarboxylation of substituted benzoic acids in the cell cultures is restricted to aromatic acids possessing a hydroxyl group in the para position. Only trace amounts of labelled CO2 were released from (carboxyl-(14)C)-anisic acid. This acid, however, was nearly quantitatively demethylated to p hydroxybenzoic acid, which itself was decarboxylated to a considerable extent after being fed to cell suspension cultures. Similar differences in respect to decarboxylation were observed with syringic acid produced by demethylation of trimethoxybenzoic acid and syringic acid applied directly to the cell cultures. PMID- 24477848 TI - [The effect of monochromatic light on the extracellular excretion of glycolate and the photorespiration in the blue-green alga Anacystis nidulans]. AB - The algae were grown under normal air conditions in a low light intensity (400 lux) and measured in the normal CO2-concentration (0.03 Vol. %). After an illumination period we observed a CO2 gush which is dependent on the temperature and wavelength used during the measurements. At +20 degrees C a CO2 gush occurs only in the blue and far red regions. At +35 degrees C, on the other hand, a CO2 outburst appears over the whole spectrum. The magnitude of the CO2 gush varies with the wavelength used during the light period. On this basis we have measured an action spectrum of photorespiration which is identical with the action spectrum of photosynthetic CO2 uptake.Only at a low temperature (+20 degrees C) and illumination with red light (550 to 651 nm; 10(-s) einsteins/cm(2).sec) did we find a light induced release of glycolate; in blue (432 and 473 nm; 10(-s) einsteins/cm(2).sec) and far red light (681 and 703 nm; 10(-8) einsteins/cm(2).sec) no glycolate excretion occurred. But after addition of alpha hydroxy-2-pyridylmethane sulfonate (10(-3)M) glycolate was excreted during illumination with all used wavelengths. The magnitude of glycolate production was nearly the same in all cases. No glycolate excretion occurred at +35 degrees C in the whole region of the spectrum. Here, too, the addition of alpha-HPMS forced release of glycolate in all wavelengths, indicating that glycolate biosynthesis was occurring.The results are discussed with reference to the physiological behaviour of the algae and activation of photorespiration in blue light. The obtained action spectrum of photorespiration is explained on the basis of a close relationship to photosynthesis. PMID- 24477849 TI - The promotive effect of gibberellic acid on the production of adventitious roots on stem cuttings of Ipomoea fistulosa. AB - Treatment with gibberellic acid (GA3) enhances the number of adventitious roots and the number and length of sprouted buds on stem cuttings of Ipomoea fistulosa. Such simultaneous promotion of both rooting and sprouting is in contrast to most earlier reports on the effect of GA3 on these processes. PMID- 24477850 TI - Psychophysiological activation during preparation, performance, and recovery in high- and low-anxious music students. AB - The present study provides a comprehensive view of (a) the time dynamics of the psychophysiological responding in performing music students (n = 66) before, during, and after a private and a public performance and (b) the moderating effect of music performance anxiety (MPA). Heart rate (HR), minute ventilation (VE), and all affective and somatic self-report variables increased in the public session compared to the private session. Furthermore, the activation of all variables was stronger during the performances than before or after. Differences between phases were larger in the public than in the private session for HR, VE, total breath duration, anxiety, and trembling. Furthermore, while higher MPA scores were associated with higher scores and with larger changes between sessions and phases for self-reports, this association was less coherent for physiological variables. Finally, self-reported intra-individual performance improvements or deteriorations were not associated with MPA. This study makes a novel contribution by showing how the presence of an audience influences low- and high-anxious musicians' psychophysiological responding before, during and after performing. Overall, the findings are more consistent with models of anxiety that emphasize the importance of cognitive rather than physiological factors in MPA. PMID- 24477851 TI - Home-centered health-enabling technologies and regional health information systems. An integration approach based on international standards. AB - INTRODUCTION: This article is part of the Focus Theme of Methods of Information in Medicine on "Using Data from Ambient Assisted Living and Smart Homes in Electronic Health Records". OBJECTIVES: In this paper, we present a prototype of a Home-Centered Health-Enabling Technology (HET-HC), which is able to capture, store, merge and process data from various sensor systems at people's home. In addition, we present an architecture designed to integrate HET-HC into an exemplary regional Health Information System (rHIS). METHODS: rHIS are traditionally document-based to fit to the needs in a clinical context. However, HET-HC are producing continuous data streams for which documents might be an inappropriate representation. Therefore, the HET-HC could register placeholder documents at rHIS. These placeholder-documents are assembled upon user authenticated request by the HET-HC and are always up-to-date. Moreover, it is not trivial to find a clinical coding system for continuous sensor data and to make the data machine-readable in order to enhance the interoperability of such systems. Therefore, we propose the use of SNOCAP-HET, which is a nomenclature to describe the context of sensor-based measurements in health-enabling technologies. RESULTS: We present an architectural approach to integrate HET-HC into rHIS. Our solution is the centralized registration of placeholder-documents with rHIS and the decentralized data storage at people's home. CONCLUSIONS: We concluded that the presented architecture of integrating HET-HC into rHIS might fit well to the traditional approach of document-based data storage. Data security and privacy issues are also duly considered. PMID- 24477852 TI - Colonic immunopathogenesis of Clostridium difficile infections. AB - There are major gaps in our understanding of the immunopathogenesis of Clostridium difficile infections (CDIs). In this study, 36 different biomarkers were examined in the stools of CDI and non-CDI patients using the Proteome Profiler human cytokine array assay and quantitative enzyme-linked immunosorbent assay. Diarrheal stools from patients with CDI (CDI-positive diarrheal stools) showed higher relative amounts of the following inflammatory markers than the diarrheal stools from CDI-negative patients (CDI-negative diarrheal stools): C5a, CD40L, granulocyte colony-stimulating factor, I-309, interleukin-13 (IL-13), IL 16, IL-27, monocyte chemoattractant protein 1, tumor necrosis factor alpha, and IL-8. IL-8 and IL-23 were present in a larger number of CDI-positive diarrheal stools than CDI-negative diarrheal stools. Th1 and Th2 cytokines were not significantly different between the CDI-positive and CDI-negative diarrheal stools. Lactoferrin and calprotectin concentrations were also higher in the CDI positive diarrheal stools. Our results demonstrate that CDI elicits a proinflammatory host response, and we report for the first time that IL-23 is a major marker in CDI-positive diarrheal stools. IL-23 may explain the lack of a robust immunological response exhibited by a proportion of CDI patients and may relate to recurrence; the IL-23 levels induced during CDI in these patients may be inadequate to sustain the cellular immunity conferred by this cytokine in promoting the induction and proliferation of effector memory T cells. PMID- 24477853 TI - Performance of the BioPlex 2200 flow immunoassay in critical cases of serodiagnosis of toxoplasmosis. AB - The BioPlex 2200 automated analyzer (Bio-Rad Laboratories, Hercules, CA) is a recently developed multiplex analyzer that enables the detection of anti Toxoplasma, -rubella, and -cytomegalovirus antibodies in the same assay. The aim of this study was to compare this new technology (using the BioPlex 2200 ToRC IgG/IgM kit) in critical cases of serodiagnosis of toxoplasmosis (acute, chronic, or congenital infections and cases with discrepant results) to the technologies used in our routine practice, i.e., the Platelia IgG/IgM enzyme-linked immunosorbent assays (ELISAs) (Bio-Rad Laboratories) and the Toxo-Screen direct agglutination assay (bioMerieux, Lyon, France). Overall, most cases of false positive/negative results obtained with the Platelia IgG or Toxo-Screen assay were corrected by the BioPlex 2200 ToRC IgG (87.5%). Furthermore, the analysis of 35 sequences of sera showed a trend toward a more rapid decrease of IgM titers by BioPlex 2200 than by Platelia. These results for IgM detection can be explained by a weaker detection of residual IgM. Indeed, among 23 serum samples from patients with probable past infection with long-lasting IgM (Platelia M positive and IgG avidity index, >=0.5), the BioPlex 2200 Toxoplasma IgM assay was positive for only 11 serum samples. In our panel of critical cases comprising 156 serum and 6 cord blood samples from 103 patients with acute, chronic, or congenital infection, the BioPlex 2200 IgG assay was a sensitive (97.8%) and specific (91.3%) method for IgG detection. The high specificity (97.4%) of IgM detection combined with the shorter kinetics of IgM titers may considerably reduce the number of residual IgM detections, thus yielding more precise diagnoses of acute infections. PMID- 24477854 TI - Miniaturized and high-throughput assays for analysis of T-cell immunity specific for opportunistic pathogens and HIV. AB - Monitoring of antigen-specific T-cell responses is valuable in numerous conditions that include infectious diseases, vaccinations, and opportunistic infections associated with acquired or congenital immune defects. A variety of assays that make use of peripheral lymphocytes to test activation markers, T-cell receptor expression, or functional responses are currently available. The last group of assays calls for large numbers of functional lymphocytes. The number of cells increases with the number of antigens to be tested. Consequently, cells may be the limiting factor, particularly in lymphopenic subjects and in children, the groups that more often require immune monitoring. We have developed immunochemical assays that measure secreted cytokines in the same wells in which peripheral blood mononuclear cells (PBMC) are cultured. This procedure lent itself to miniaturization and automation. Lymphoproliferation and the enzyme linked immunosorbent spot (ELISPOT) assay have been adapted to a miniaturized format. Here we provide examples of immune profiles and describe a comparison between miniaturized assays based on cytokine secretion or proliferation. We also demonstrate that these assays are convenient for use in testing antigen specificity in established T-cell lines, in addition to analysis of PBMC. In summary, the applicabilities of miniaturization to save cells and reagents and of automation to save time and increase accuracy were demonstrated in this study using different methodological approaches valuable in the clinical immunology laboratory. PMID- 24477855 TI - Comparative analysis of Bacillus subtilis spores and monophosphoryl lipid A as adjuvants of protein-based mycobacterium tuberculosis-based vaccines: partial requirement for interleukin-17a for induction of protective immunity. AB - The development of adjuvants for vaccines has become an important area of research as the number of protein-based vaccines against infectious pathogens increases. Currently, there are a number of adjuvant-based Mycobacterium tuberculosis vaccines in clinical trials that have shown efficacy in animal models. Despite these novel adjuvants, there is still a need to design new and more versatile adjuvants that have minimal adverse side effects but produce robust long-lasting adaptive immune responses. To this end, we hypothesized that Bacillus subtilis spores may provide the appropriate innate signals that are required to generate such vaccine-mediated responses, which would be sufficient to reduce the mycobacterial burden after infection with M. tuberculosis. In addition, we compared the response generated by B. subtilis spores to that generated by monophosphoryl lipid A (MPL), which has been used extensively to test tuberculosis vaccines. The well-characterized, 6-kDa early secretory antigenic target of M. tuberculosis (ESAT-6; Rv3875) was used as a test antigen to determine the T cell activation potential of each adjuvant. Inoculated into mice, B. subtilis spores induced a strong proinflammatory response and Th1 immunity, similar to MPL; however, unlike MPL formulated with dimethyldioctadecylammonium (DDA) bromide, it failed to induce significant levels of interleukin-17A (IL-17A) and was unable to significantly reduce the mycobacterial burden after pulmonary infection with M. tuberculosis. Further analysis of the activity of MPL-DDA suggested that IL-17A was required for protective immunity. Taken together, the data emphasize the requirement for a network of cytokines that are essential for protective immunity. PMID- 24477856 TI - Correlations between peripheral blood Coxiella burnetii DNA load, interleukin-6 levels, and C-reactive protein levels in patients with acute Q fever. AB - From 2007 to 2010, the Netherlands experienced the largest reported Q fever outbreak, with >4,000 notified cases. We showed previously that C-reactive protein is the only traditional infection marker reflecting disease activity in acute Q fever. Interleukin-6 is the principal inducer of C-reactive protein. We questioned whether increased C-reactive protein levels in acute Q fever patients coincide with increased interleukin-6 levels and if these levels correlate with the Coxiella burnetii DNA load in serum. In addition, we studied their correlation with disease severity, expressed by hospital admission and the development of fatigue. Interleukin-6 and C-reactive protein levels were analyzed in sera from 102 patients diagnosed with seronegative PCR-positive acute Q fever. Significant but weak negative correlations were observed between bacterial DNA loads expressed as cycle threshold values and interleukin-6 and C-reactive protein levels, while a significant moderate-strong positive correlation was present between interleukin-6 and C-reactive protein levels. Furthermore, significantly higher interleukin-6 and C-reactive protein levels were observed in hospitalized acute Q fever patients in comparison to those in nonhospitalized patients, while bacterial DNA loads were the same in the two groups. No marker was prognostic for the development of fatigue. In conclusion, the correlation between interleukin-6 and C-reactive protein levels in acute Q fever patients points to an immune activation pathway in which interleukin-6 induces the production of C-reactive protein. Significant differences in interleukin-6 and C reactive protein levels between hospitalized and nonhospitalized patients despite identical bacterial DNA loads suggest an important role for host factors in disease presentation. Higher interleukin-6 and C-reactive protein levels seem predictive of more severe disease. PMID- 24477857 TI - Prevalence and interannual changes in multiple chemical sensitivity in Japanese workers. AB - OBJECTIVE: We aimed to evaluate the prevalence rates and interannual fluctuations in multiple chemical sensitivity (MCS) in Japanese workers. METHODS: We assessed MCS using the Quick Environmental Exposure and Sensitivity Inventory, employing both Miller and Japanese criteria. Workers of two manufacturing companies located in Kyushu, Japan, were assessed, with company A surveyed in 2003, 2006 and 2011, and company B in 2003 and 2011. RESULTS: In company A, the Miller criteria-based MCS prevalence rate was higher in 2011 than in 2003, and according to the Japanese criteria, it was higher in 2011 than 2006. In company B, the Miller criteria-based MCS prevalence rate was lower in 2011 than in 2003. CONCLUSION: The results indicated that MCS exists among industrial workers in Japan. We found no statistically significant interannual changes in MCS rates. PMID- 24477858 TI - Association between sleep quality and cardiovascular health: a door-to-door survey in rural Ecuador. AB - OBJECTIVES: Cardiovascular correlates of sleep disorders have not been well investigated in underserved populations. The aim of this door-to-door survey was to evaluate the association between sleep quality and cardiovascular health status in persons aged >=40 years living in a village that is representative of rural Ecuador. METHODS: All stroke-free Atahualpa residents aged >=40 years were screened with a validated Spanish version of the Pittsburgh Sleep Quality Index and the seven cardiovascular health (CVH) metrics proposed by the American Heart Association to assess the CVH status. RESULTS: A total of 635 persons (mean age 59 +/- 13 years; 58 % women) were identified. A poor sleep quality was present in 27 % of the subjects (95 % CI 24-31 %) and a poor cardiovascular health in 69 % (95 % CI 63-71 %). In a multivariate logistic regression model, a poor sleep quality was associated with some CVH metrics in the poor range, including smoking status (p = 0.026), physical activity (p = 0.01) and blood glucose levels (p = 0.036). CONCLUSIONS: A poor sleep quality may be linked to individual cardiovascular risk factors in this underserved Latin American population. This finding provides useful insights for the implementation of regional prevention priorities. PMID- 24477859 TI - Error bars in within-subject designs: a comment on Baguley (2012). AB - The problem of calculating error bars in within-subject designs has proven to be a difficult problem and has received much attention in recent years. Baguley (Behavior Research Methods, 44, 158-175, 2012) recommended what he called the Cousineau-Morey method. This method requires two steps: first, centering the data set in a certain way to remove between-subject differences and, second, integrating a correction factor to debias the standard errors obtained from the normalized data set. However, within some statistical packages, it can be difficult to integrate this correction factor. Baguley (2012) proposed a solution that works well in most statistical packages in which the alpha level is altered to incorporate the correction factor. However, with this solution, it is possible to plot confidence intervals, but not standard errors. Here, we propose a second solution that can return confidence intervals or standard error bars in a mean plot. PMID- 24477860 TI - A methodological framework for capturing relative eyetracking coordinate data to determine gaze patterns and fixations from two or more observers. AB - Few studies have published methodologies that can be used to analyze simultaneous gaze behaviors and recurrent fixations while multiple observers are viewing dynamic scenes and moving their heads. In this study, we aimed to develop a methodological framework to assess simultaneous gaze behaviors and recurrent fixations in predetermined areas of interest, while accounting for head movement and nonstandard observer positioning. Gaze coordinates were recorded during six trials in which a single participant focused on the center of a video image and moved his head in six degrees of freedom. Markers were positioned at the image corners. Eyetracking equipment recorded the video image and gaze behaviors (crosshair), which were then uploaded to SIMI Motion Analysis software. The corner markers were digitized in order to determine image position as the head moved, and were used to calculate new gaze coordinates relative to this head movement. Calculations accounted for the perspective error due to nonstandard participant positioning. Across all trials, the error between the measured and calculated coordinates was acceptable (<3.5%CV). The frequencies and durations of fixations (>=100 ms within 1 degrees of visual angle) within six areas of interest are reported, and they compared well to manual calculations. This methodology was then assessed using participant dyads (N = 5), each simultaneously observing the same images. Recurrent fixations were determined using a hierarchical model, and these also compared well to manual analysis. This article presents a valid and reliable methodological framework for determining fixation frequency, duration, and location from multiple observers, while accounting for head movement and nonstandard positioning. This framework facilitates the analysis of simultaneous oculomotor variables, improving ecological validity and reducing environmental constraints. PMID- 24477861 TI - Local structural investigation of Eu(3+)-doped BaTiO3 nanocrystals. AB - A structural investigation of sub-15 nm xEu:BaTiO3 nanocrystals (x = 0-5 mol%) was conducted to determine the distribution of the Eu(3+) ion in the BaTiO3 lattice. Pair distribution function analysis of X-ray total scattering data (PDF), steady-state photoluminescence, and X-ray absorption spectroscopy (XANES/EXAFS) were employed to interrogate the crystal structure of the nanocrystals and the local atomic environment of the Eu(3+) ion. The solubility limit of the Eu(3+) ion in the nanocrystalline BaTiO3 host synthesized via the vapor diffusion sol-gel method was estimated to be ~4 mol%. A contraction of the perovskite unit cell volume was observed upon incorporation of 1 mol% of europium, while an expansion was observed for nominal concentrations between 1 and 3 mol%. The average Eu-O distance and europium coordination number decreased from 2.46 A and 9.9 to 2.42 A and 8.6 for europium concentrations of 1 and 5 mol%, respectively. Structural trends were found to be consistent with the substitution of Eu(3+) for Ba(2+)via creation of a Ti(4+) vacancy at low europium concentrations (<1 mol%), and with the substitution of Eu(3+) for both Ba(2+) and Ti(4+) at high europium concentrations (1-3 mol%). The significance of accounting for local structural distortions to rationalize the distribution of lanthanide ions in the perovskite host is highlighted. PMID- 24477862 TI - Silver and zinc oxide nanostructures loaded on activated carbon as new adsorbents for removal of methylene green: a comparative study. AB - In this study, the removal of methylene green (MG) from aqueous solution based on two new adsorbents including silver nanoparticles and zinc oxide nanorods loaded on activated carbon (Ag-NP-AC and ZnO-NR-AC, respectively) has been carried out. The dependency of removal process to variables such as contact time, pH, amount of adsorbents, and initial MG concentration were examined and optimized. It was found that the maximum MG removal percentage was achieved at pH = 7.0 following stirring at 400 r min(-1) for 7 and 6 min for Ag-NP-AC and ZnO-NR-AC, respectively. Equilibrium data were well fitted with the Langmuir model having maximum adsorption capacity of 166.7 and 200 mg g(-1) for Ag-NP-AC and ZnO-NR-AC, respectively. Thermodynamic parameters of MG adsorption on Ag-NP-AC such as enthalpy and entropy changes, activation energy, sticking probability, and Gibbs free energy changes show the spontaneous and endothermic nature of the removal process. Among different conventional kinetic models, the pseudo second-order kinetics in addition to particle diffusion mechanism is the best and efficient model for the prediction and explanation of experimental data of MG adsorption onto both adsorbents. PMID- 24477863 TI - Regional variation across the United States in management and outcomes of ST elevation myocardial infarction: analysis of the 2003 to 2010 nationwide inpatient sample database. AB - BACKGROUND: Regional differences in the treatment and outcomes of patients with ST-elevation myocardial infarction (STEMI) within the United States remain poorly understood. HYPOTHESIS: Treatment choice and outcomes in patients with STEMI differ between regions within the United States. METHODS: We used the 2003 to 2010 Nationwide Inpatient Sample databases to identify all patients age >= 40 years hospitalized with STEMI. Patients were divided into 4 groups according to region: Northeast, Midwest, South, and West. Multivariable logistic regression was used to identify differences in treatment choice and outcomes (in-hospital mortality, acute stroke, and cardiogenic shock) among the 4 regions. RESULTS: Of 1,990,486 patients age >= 40 years with STEMI, 350,073 (17.6%) were hospitalized in the Northeast, 483,323 (24.3%) in the Midwest, 784,869 (39.4%) in the South, and 372,222 (18.7%) in the West. Compared with the Northeast, patients in the Midwest, South, and West were less likely to receive medical therapy alone and more likely to receive percutaneous coronary intervention and coronary artery bypass grafting. Risk-adjusted in-hospital mortality was higher in the Midwest (odds ratio [OR]: 1.07, 95% confidence interval [CI]: 1.05-1.09, P <0.001), South (OR: 1.03, 95% CI: 1.01-1.05, P = 0.001), and West (OR: 1.06, 95% CI: 1.04-1.08, P <0.001), as compared with the Northeast. When adjusted further for regional variation in treatment selection, risk-adjusted in-hospital mortality was even higher in the Midwest, West, and South. CONCLUSIONS: Despite higher reperfusion and revascularization rates, STEMI patients in the Midwest, West, and South have paradoxically higher risk-adjusted in-hospital mortality as compared with patients in the Northeast. PMID- 24477864 TI - Acute hepatitis C: management in the rapidly evolving world of HCV. AB - The acute phase of hepatitis C (HCV) infection is typically defined as the initial 6 months following exposure to the virus; however, in some individuals, the acute phase of the infection can last much longer (Orland et al. Hepatology 33:321-27, 2001). Although some patients have symptoms of acute hepatitis, most infected individuals are entirely asymptomatic. As a result, many patients are unaware of the infection until it progresses to chronic infection, and may not develop symptoms until decades later with the onset of decompensated cirrhosis or hepatocellular carcinoma (HCC). A substantial proportion (20-40%) of infected patients clear the virus during the acute phase. Interferon-based treatment is also much more likely to be successful in the acute phase of infection but is relatively poorly tolerated. Therefore, recognition of acute HCV infection is critical to prioritize those patients who do not spontaneously clear the infection for immediate therapy. However, the promise of highly effective well tolerated all-oral therapies in development may alter the management approach. This review will focus on the epidemiology, natural history, diagnosis, and treatment of acute HCV infection. PMID- 24477865 TI - Cardiac magnetic resonance imaging in patients undergoing percutaneous mitral valve repair with the MitraClip system. AB - BACKGROUND: Percutaneous mitral valve repair (MVR) with the MitraClip((r)) system in patients with mitral regurgitation (MR) is known to reduce symptoms and to improve cardiac morphology and function. MitraClip has been approved for cardiac magnetic resonance imaging (MRI). To date, however, no systematic analysis exists on cardiac MRI in patients undergoing the MitraClip procedure. OBJECTIVE: The aim of this study was to (1) prove feasibility and robustness of cardiac MRI and (2) visualize effects of the procedure on cardiac morphology and function by cardiac MRI. METHODS: 27 consecutive patients (age 77.5 +/- 7.6 years) with symptomatic moderate to severe MR undergoing the MitraClip((r)) procedure were prospectively included. Cardiac MRI at 1.5 T was performed before and at 3 months after intervention. Cardiac morphology and function were evaluated using steady-state free precession (SSFP) cine sequences by assessment of left ventricular enddiastolic and endsystolic diameters (LVEDD, LVESD) and volumes (EDV, ESV), ejection fraction (LVEF) and stroke volume (SV), diameter of mitral annulus, and myocardial mass (MM). Planimetry of the left atrium (LA) was performed in identical slices in a four-chamber view. RESULTS: Around the clip an extinction artifact was observed which did not disturb the evaluation of cardiac morphology and function. At follow-up, we observed significant decreases of LVEDD (58.0 to 53.3 mm, p < 0.0001), EDV (167 to 159 mL, p = 0.0006) and ESV (101 to 89 mL, p < 0.0001), diameter of mitral annulus (41.4 to 37.9 mm, p < 0.0001), myocardial mass (148.4 to 144.5 g, p = 0.0004) and LA size (40.2 to 37.6 cm(2), p < 0.0001). LVEF improved (43.3 to 46.7 %, p = 0.0041). CONCLUSIONS: Cardiac MRI is feasible and robust in patients with MitraClips. The clinical benefit of a successful MitraClip intervention is paralleled by significant improvements of cardiac morphology and function which can be monitored and validated using MRI in clinical follow-up examinations. PMID- 24477867 TI - Study by electrical conductivity measurements of semiconductive and redox properties of M-doped NiO (M = Li, Mg, Al, Ga, Ti, Nb) catalysts for the oxidative dehydrogenation of ethane. AB - Pure and M-doped nickel oxides with M = Li, Mg, Al, Ga, Ti, Nb, catalysts for the oxidative dehydrogenation of ethane into ethylene, were characterized by in situ electrical conductivity measurements. Their electrical conductivity was studied as a function of temperature and oxygen partial pressure and was followed with time during sequential exposures to air, an ethane-air mixture (reaction mixture) and pure ethane under conditions similar to those of catalysis. All the materials appeared to be p-type semiconductors under air with positive holes as the main charge carriers and their electrical conductivity decreased in the following order: Li-NiO > NiO > Mg-NiO > Nb-NiO > Ga-NiO > Al-NiO > Ti-NiO. All the catalysts remained p-type semiconductors in the reaction mixture at 400 degrees C. Correlations between the p-type semiconductivity and the catalytic properties have been evidenced. The reaction mechanism involves surface lattice O(-) species and can be assimilated to a Mars and van Krevelen mechanism. PMID- 24477868 TI - Phytoremediation of water polluted by thallium, cadmium, zinc, and lead with the use of macrophyte Callitriche cophocarpa. AB - The objective of the present work was to study the phytoremediation capacity of Callitriche cophocarpa concerning water contaminated with thallium (Tl), cadmium (Cd), zinc (Zn), and lead (Pb) derived from the natural environment. We found that after a 10-day incubation period, shoots of C. cophocarpa effectively biofiltrated the water so that it met (for Cd, Zn, and Pb) appropriate quality standards. The order of accumulation of the investigated elements by shoots (mg kg(-1) dry weight) were as follows: Zn (1120) < Tl (251) < Cd (71) < Pb (35). The order of bioconcentration factors were as follows: Cd (1177) < Tl (1043) < Zn (718) < Pb (597). According to Microtox bioassay, C. cophocarpa significantly eradicated polluted water toxicity. During the experiment, the physiological status of plants was monitored by taking measurements of photosystem II activity (maximum efficiency of PSII, photochemical fluorescence quenching, nonphotochemical fluorescence quenching, and quantum efficiency of PSII), photosynthetic pigment contents, and shoot morphology. Plants exposed to metallic pollution did not exhibit significant changes in their physiological status compared with the control. This work is potentially applicable to the future use of C. cophocarpa in the phytoremediation of polluted, natural watercourses. PMID- 24477866 TI - Delayed transplantation of precursor cell-derived astrocytes provides multiple benefits in a rat model of Parkinsons. AB - In addition to dopaminergic neuron loss, it is clear that Parkinson disease includes other pathological changes, including loss of additional neuronal populations. As a means of addressing multiple pathological changes with a single therapeutically-relevant approach, we employed delayed transplantation of a unique class of astrocytes, GDAs(BMP), that are generated in vitro by directed differentiation of glial precursors. GDAs(BMP) produce multiple agents of interest as treatments for PD and other neurodegenerative disorders, including BDNF, GDNF, neurturin and IGF1. GDAs(BMP) also exhibit increased levels of antioxidant pathway components, including levels of NADPH and glutathione. Delayed GDA(BMP) transplantation into the 6-hydroxydopamine lesioned rat striatum restored tyrosine hydroxylase expression and promoted behavioral recovery. GDA(BMP) transplantation also rescued pathological changes not prevented in other studies, such as the rescue of parvalbumin(+) GABAergic interneurons. Consistent with expression of the synaptic modulatory proteins thrombospondin-1 and 2 by GDAs(BMP), increased expression of the synaptic protein synaptophysin was also observed. Thus, GDAs(BMP) offer a multimodal support cell therapy that provides multiple benefits without requiring prior genetic manipulation. PMID- 24477869 TI - Changes in hematological parameters of Cichlasoma dimerus (Teleostei, Perciformes) exposed to sublethal concentrations of 4-tert-octylphenol. AB - Stress response involves various physiological changes, including alteration in hematological parameters closely related to the response of fish to the environment. 4-tert-octylphenol (OP) is one of the worldwide-used surfactants and can pollute the aquatic environment, both marine and freshwater. Previous studies have already shown estrogenic effects of this compound in various wildlife species, e.g., it can disrupt the reproductive system of males organisms including fish. The purpose of this study was to evaluate the effects caused by sublethal concentrations of OP on hematological parameters as biomarkers to assess environmental stress. Adult males and females of Cichlasoma dimerus were exposed to waterborne OP during 60 days under semistatic conditions. Experimental groups consisted of control (ethanol 0.005 %), OP 150, and OP 300 MUg/L. OP caused hemodynamic stress in C. dimerus, which lead to normochromic and normocytic anemia, as well as erythrocytic pathologies such as a significant increase in erythroblasts and amitotic erythrocytes. All of the studied parameters can be used as biomarkers for the presence of xenobiotics in water. PMID- 24477870 TI - The effects of humic acid on the uptake and depuration of fullerene aqueous suspensions in two aquatic organisms. AB - The authors investigated the uptake and depuration of fullerene aqueous suspensions (nC(60)) in 2 aquatic organisms: Daphnia magna and zebrafish. The effects of humic acid were examined to elucidate its possible mechanisms in the aquatic environment. The uptake was concentration-dependent in both organisms, and the maximum uptake concentration of nC(60) in Daphnia (2268 +/- 158 mg/kg) was approximately 1 order of magnitude higher than that in zebrafish (222 +/- 30 mg/kg) because of the larger gut volume ratio to the mass of Daphnia or its high uptake efficiency. Humic acid reduced the uptake of nC(60) in Daphnia and zebrafish as a result of the size effect and the polarity alternation of nC(60). The depuration patterns were rapid for Daphnia and slow for zebrafish, and the differences were most likely the result of different water exchange frequencies between organisms. The remaining nC(60) percentages were approximately 20% for Daphnia and 30% for zebrafish after 48-h depuration, suggesting that a large nC(60) burden still existed for both aquatic organisms and that there is a need for further studies on the potential for trophic transfer. PMID- 24477871 TI - Distribution of neurotransmitter receptors and zinc in the pigeon (Columba livia) hippocampal formation: A basis for further comparison with the mammalian hippocampus. AB - The avian hippocampal formation (HF) and mammalian hippocampus share a similar functional role in spatial cognition, but the underlying neuronal mechanisms allowing the functional similarity are incompletely understood. To understand better the organization of the avian HF and its transmitter receptors, we analyzed binding site densities for glutamatergic AMPA, NMDA, and kainate receptors; GABAA receptors; muscarinic M1 , M2 and nicotinic (nACh) acetylcholine receptors; noradrenergic alpha1 and alpha2 receptors; serotonergic 5-HT1A receptors; dopaminergic D1/5 receptors by using quantitative in vitro receptor autoradiography. Additionally, we performed a modified Timm staining procedure to label zinc. The regionally different receptor densities mapped well onto seven HF subdivisions previously described. Several differences in receptor expression highlighted distinct HF subdivisions. Notable examples include 1) high GABAA and alpha1 receptor expression, which rendered distinctive ventral subdivisions; 2) high alpha2 receptor expression, which rendered distinctive a dorsomedial subdivision; 3) distinct kainate, alpha2 , and muscarinic receptor densities that rendered distinctive the two dorsolateral subdivisions; and 4) a dorsomedial region characterized by high kainate receptor density. We further observed similarities in receptor binding densities between subdivisions of the avian and mammalian HF. Despite the similarities, we propose that 300 hundred million years of independent evolution has led to a mosaic of similarities and differences in the organization of the avian HF and mammalian hippocampus and that thinking about the avian HF in terms of the strict organization of the mammalian hippocampus is likely insufficient to understand the HF of birds. PMID- 24477872 TI - A novel injectable borate bioactive glass cement for local delivery of vancomycin to cure osteomyelitis and regenerate bone. AB - Osteomyelitis (bone infection) is often difficult to cure. The commonly-used treatment of surgical debridement to remove the infected bone combined with prolonged systemic and local antibiotic treatment has limitations. In the present study, an injectable borate bioactive glass cement was developed as a carrier for the antibiotic vancomycin, characterized in vitro, and evaluated for its capacity to cure osteomyelitis in a rabbit tibial model. The cement (initial setting time = 5.8 +/- 0.6 min; compressive strength = 25.6 +/- 0.3 MPa) released vancomycin over ~25 days in phosphate-buffered saline, during which time the borate glass converted to hydroxyapatite (HA). When implanted in rabbit tibial defects infected with methicillin-resistant Staphylococcus aureus (MRSA)-induced osteomyelitis, the vancomycin-loaded cement converted to HA and supported new bone formation in the defects within 8 weeks. Osteomyelitis was cured in 87 % of the defects implanted with the vancomycin-loaded borate glass cement, compared to 71 % for the defects implanted with vancomycin-loaded calcium sulfate cement. The injectable borate bioactive glass cement developed in this study is a promising treatment for curing osteomyelitis and for regenerating bone in the defects following cure of the infection. PMID- 24477873 TI - Pre-incubation of chemically crosslinked hyaluronan-based hydrogels, loaded with BMP-2 and hydroxyapatite, and its effect on ectopic bone formation. AB - The effects of pre-incubation of hyaluronan hydrogels, for different lengths of time after the initiation of chemical crosslinking and prior to injection, were explored both by investigating the in vitro BMP-2 release kinetics from the hydrogel and by studying the ectopic bone formation in rats. From the curing profile, obtained from rheological analysis, appropriate pre-incubation times (1 min, 5 h and 3 days) were selected, to prepare slightly, moderately and fully cured hydrogels. Comparable release profiles were observed for all three test groups in vitro. Furthermore, radiography, pQCT and histology of the explanted grafts showed cancellous bone formation in all groups after 5 weeks in vivo. However, longer pre-incubation times gave rise to an increase in bone volume, but a decrease in bone density. Moreover, the 5 h and the 3 days grafts appeared to be more ordered and resistant to deformation from the surrounding tissue than the 1 min grafts. The observed variations in mechanical and biological properties could potentially be used to adapt the treatment for a specific indication. PMID- 24477874 TI - Smart magnetic poly(N-isopropylacrylamide) to control the release of bio-active molecules. AB - Thermo switchable magnetic hydrogels undoubtedly have a great potential for medical applications since they can behave as smart carriers able to transport bioactive molecules to a chosen part of the body and release them on demand via magneto-thermal activation. We report on the ability to modify the lower critical solution temperature (LCST) of poly(N-isopropylacrylamide) (PNIPAM) on demand from 32 degrees C to LCST >= 37 degrees C. This was achieved by the absorption of controlled amounts of magnetite nanoparticles on the polymer chains. We show, through the effect on cell viability, that the resulting magnetic PNIPAM is able to trap and to release bio-active molecules, such as cell growth factors. The activities of the released bio molecule are tested on human umbilical vein endothelial cells culture. We demonstrate that the LCST of the magnetic PNIPAM can be reached remotely via inductive heating with an alternating magnetic field. This approach on magnetic PNIPAM clearly supports appealing applications in safe biomedicine. PMID- 24477875 TI - Flexor tendon healing within the tendon sheath using bioabsorbable poly-L/D lactide 96/4 suture. A histological in vivo study with rabbits. AB - The bioabsorbable poly-L/D-lactide (PLDLA) 96/4 suture has good biomechanical and knot properties, and sufficient tensile strength half-life for flexor tendon repair. In the present study, the biocompatibility of PLDLA suture was compared with that of coated braided polyester suture in the rabbit flexor digitorum profundus tendon repaired within the tendon sheath. Postoperative unrestricted active mobilization was allowed. The tendons were studied histologically after 1 , 3-, 6-, 12-, 26-, and 52-week follow-ups. No differences were found in the biocompatibility between the suture materials, with only scattered multinuclear giant cells near the sutures in both groups from 6 weeks onwards. At 52 weeks, most of the PLDLA material was absorbed and the histological structure of the tendon appeared normal, whereas in the polyester repairs the suture knots filled the repair site, causing bulking of the tendon surface, and the collagen alignment appeared disoriented. The results suggest that the PLDLA 96/4 is a suitable suture material for flexor tendon repair. PMID- 24477876 TI - Electrochemical characteristics of calcium-phosphatized AZ31 magnesium alloy in 0.9 % NaCl solution. AB - Magnesium alloys suffer from their high reactivity in common environments. Protective layers are widely created on the surface of magnesium alloys to improve their corrosion resistance. This article evaluates the influence of a calcium-phosphate layer on the electrochemical characteristics of AZ31 magnesium alloy in 0.9 % NaCl solution. The calcium phosphate (CaP) layer was electrochemically deposited in a solution containing 0.1 M Ca(NO3)2, 0.06 M NH4H2PO4 and 10 ml l(-1) of H2O2. The formed surface layer was composed mainly of brushite [(dicalcium phosphate dihidrate (DCPD)] as proved by energy-dispersive X ray analysis. The surface morphology was observed by scanning electron microscopy. Immersion test was performed in order to observe degradation of the calcium phosphatized surfaces. The influence of the phosphate layer on the electrochemical characteristics of AZ31, in 0.9 % NaCl solution, was evaluated by potentiodynamic measurements and electrochemical impedance spectroscopy. The obtained results were analysed by the Tafel-extrapolation method and equivalent circuits method. The results showed that the polarization resistance of the DCPD coated surface is about 25 times higher than that of non-coated surface. The CaP electro-deposition process increased the activation energy of corrosion process. PMID- 24477877 TI - Evaluation of plasma Epstein-Barr virus DNA load to distinguish nasopharyngeal carcinoma patients from healthy high-risk populations in Southern China. AB - BACKGROUND: The utility of circulating Epstein-Barr Virus (EBV) DNA as a tumor marker for nasopharyngeal carcinoma (NPC) detection suggests that it might improve the diagnostic performance of anti-EBV antibody markers in NPC screening. In this study, the authors evaluated whether circulating EBV DNA load is capable of distinguishing NPC patients from high-risk individuals who have positive anti EBV antibodies. METHODS: In a population-based NPC screening trial in Sihui City and Zhongshan City, Guangdong Province, China, the authors previously identified 862 high-risk participants with 2 screening markers, immunoglobulin A (IgA) antibodies to EBV capsid antigen (VCA/IgA) and nuclear antigen-1 (EBNA1/IgA). In the current study, real-time polymerase chain reaction was used to measure the baseline plasma EBV DNA load among 825 participants (97%). Follow-up was extended to the end of 2011 to evaluate the diagnostic and predictive values of plasma EBV DNA load. RESULTS: By using 0 copies/mL as the cutoff value, plasma EBV DNA had a sensitivity of 86.8% (33 of 38 patients) for NPC detected within the first year of follow-up, yielding a positive predictive value of 30% (33 of 110 participants) and a negative predictive value of 99.3% (696 of 701 participants). The patients who had early stage NPC had lower sensitivity (81.5%; 22 of 27 patients) than those who had advanced NPC (100%; 11 of 11 patients). For the 14 patients who had NPC detected after 1 year of follow-up, only 50% (7 of 14 patients) tested positive for EBV DNA at baseline. CONCLUSIONS: The plasma EBV DNA load may improve the accuracy of diagnosing NPC in high-risk individuals, but it appears to have limited value in screening patients who have early stage NPC and predicting NPC development. PMID- 24477878 TI - The effect of diesel exhaust exposure on blood-brain barrier integrity and function in a murine model. AB - Epidemiological studies indicate that exposure to diesel exhaust (DE) is associated with vascular-based disorders. To investigate the effect of DE on blood-brain barrier (BBB) function and integrity, 8-week-old BALB/c mice were randomized to DE in a cyclical treatment regimen over a 2-week period. Functional integrity of BBB was determined by considering brain parenchymal abundance of IgG within the hippocampal formation and cortex at 6 h and 24 h intervals following final exposure treatment. Neurovascular inflammation was expressed as the abundance of glial fibrillar acidic protein. Two doses of DE were studied and compared to air-only treated mice. Mice exposed to DE had substantially greater abundance of parenchymal IgG compared to control mice not exposed to DE. Increased parenchymal glial fibrillar acidic protein at 24 h post-DE exposure suggested heightened neurovascular inflammation. Our findings are proof-of concept that inhalation of DE can compromise BBB function and support the broader contention that DE exposure may contribute to neurovascular disease risk. PMID- 24477879 TI - [Consultation hours for adolescent males: because men's health begins in adolescence]. AB - BACKGROUND: Young men are underrepresented in terms of offers concerning primary and secondary prevention in medicine. As a consequence, urologists often only see boys and young men from the perspective of missed prevention. AIM: What should an offer for boys and young men look like in a urologist's practice that focuses on the physical, social and sexual health of boys and young men? The author draws analogies for the establishment of consultation hours for young men in a urologist's practice based on her successful establishment of consultation hours for girls in a gynecologist's practice. RESULTS: Due to acceleration, boys also enter puberty early today. Because of their lack of knowledge about the changes in their body, they can be described as overnewsed and underinformed, despite their intense media consumption. This mixture of half-knowledge, coolness, sexual curiosity and lack of ability for predictive planning and action prevents boys and young men from having the knowledge they need to adequately and responsibly deal with their physical, social and sexual health care. CONCLUSION: If boys and young men had the opportunity to learn, appreciate, and protect their bodies at an early stage through competent preventive offers in the urologist's practice, then they would also experience less stress and powerlessness. In addition, it is almost certain that solid, fundamental understanding concerning their health will also lead to specific effects in male health competence. Only in this manner can young men be made aware of the preventive services in a urological practice and can be a partner in other medically necessary decision-making processes. PMID- 24477881 TI - Continuous microalgal cultivation in a laboratory-scale photobioreactor under seasonal day-night irradiation: experiments and simulation. AB - In this work, the production of Scenedesmus obliquus in a continuous flat-plate laboratory-scale photobioreactor (PBR) under alternated day-night cycles was tested both experimentally and theoretically. Variation of light intensity according to the four seasons of the year were simulated experimentally by a tunable LED lamp, and effects on microalgal growth and productivity were measured to evaluate the conversion efficiency of light energy into biomass during the different seasons. These results were used to validate a mathematical model for algae growth that can be applied to simulate a large-scale production unit, carried out in a flat-plate PBR of similar geometry. The cellular concentration in the PBR was calculated in both steady-state and transient conditions, and the value of the maintenance kinetic term was correlated to experimental profiles. The relevance of this parameter was finally outlined. PMID- 24477880 TI - [Follow-up care - consequences of urinary diversion after bladder cancer]. AB - Radical cystectomy is the standard of care for muscle-invasive bladder cancer. Continent urinary diversions utilizing both small and large bowel are becoming more prominent: therefore, the postoperative follow-up has to focus on different aspects. In the first instance after radical cystectomy functional issues with respect to potential stenosis, post-void residual urine and micturition disorders are important. In the early phase the oncological follow-up aims to detect local, urethral and systemic recurrences and new data show the importance of the first 3 years after surgery. Long-term follow-up focuses on metabolic aspects, such as cobalamin or bile acid deficits, acidosis and disorders of calcium and bone metabolism. Follow-up care should consider specific complications of different types of urinary diversions; however to date standardized follow-up guidelines are lacking. PMID- 24477882 TI - Enhancement of riboflavin production by deregulating gluconeogenesis in Bacillus subtilis. AB - The regulation of metabolic flux through glycolytic versus the gluconeogenic pathway plays an important role in central carbon metabolism. In this study, we made an attempt to enhance riboflavin production by deregulating gluconeogenesis in Bacillus subtilis. To this end, gapB (code for NADPH-dependent glyceraldehyde 3-phosphate dehydrogenase), fbp (code for fructose-1,6-bisphosphatase) and pckA (code for phosphoenolpyruvate carboxykinase) were overexpressed in parental strain B. subtilis RH33. Compared with RH33, overexpression of fbp and gapB resulted in approximately 18.0 and 14.2 % increased riboflavin production, respectively, while overexpression of pckA obtained the opposite result. Significant enhancement of riboflavin titers up to 4.89 g/l was obtained in shake flask cultures when gapB and fbp were co-overexpressed, nevertheless the specific growth rate decreased slightly and the specific glucose uptake rate remained almost unchanged. An improvement by 21.9 and 27.8 % of the riboflavin production was achieved by co-overexpression of gapB and fbp in shake flask and fed-batch fermentation, respectively. These results imply that deregulation of gluconeogenesis is an effective strategy for production of metabolites directly stemming from the pentose phosphate pathway as well as other NADPH-demanding compounds with glucose as carbon source in B. subtilis. PMID- 24477883 TI - A novel functionalized silver nanoparticles solid chemosensor for detection of Hg(II) in aqueous media. AB - We report a simple strategy for the fabrication of a highly selective and sensitive Hg(II) chemosensor based on HMS-Ag composite functionalized rhodamine derivative (R). The prepared chemosensor HMS-Ag-R was characterized by transmission electron microscopy (TEM), X-ray powder diffraction (XRD), UV-vis spectrum and Fourier transform infrared spectroscopy (FT-IR). HMS-Ag-R has both fluorescence and colorimetry performance, and it can realize onsite and real-time detection of Hg(II) with a high sensitivity (0.7 ppb) in aqueous solution. In high concentration of mercury ions, the fluorescence intensity of HMS-Ag-R against Hg(II) sufficiently showed a typical sigmoidal shape. Moreover, HMS-Ag-R presents excellent anti-disturbance ability when exposed to a series of competitive cations such as Ag(I), K(I), Li(I), Na(I), Ba(II), Ca(II), Cd(II), Co(II), Cu(II), Mg(II), Mn(II), Ni(II), Pb(II) and Zn(II). It can be applied to the determination of Hg(II) in aqueous media. The interaction between HMS-Ag-R and Hg(II) could occur in a short time (90 s). Importantly, HMS-Ag-R could be regenerated with tetrapropyl ammonium hydroxide (TPAOH) solution. PMID- 24477884 TI - Enlarging breast mass in a 55-year-old woman. PMID- 24477885 TI - An economic evaluation of the parent-child assistance program for preventing fetal alcohol spectrum disorder in Alberta, Canada. AB - Parent-Child Assistance Program (P-CAP) is a 3-year home visitation/harm reduction intervention to prevent alcohol exposed births, thereby births with fetal alcohol spectrum disorder, among high-risk women. This article used a decision analytic modeling technique to estimate the incremental cost effectiveness ratio and the net monetary benefit of the P-CAP within the Alberta Fetal Alcohol Spectrum Disorder Service Networks in Canada. The results indicate that the P-CAP is cost-effective and support placing a high priority not only on reducing alcohol use during pregnancy, but also on providing effective contraceptive measures when a program is launched. PMID- 24477886 TI - First documented outbreak of KPC-2-producing Klebsiella pneumoniae in Switzerland: infection control measures and clinical management. AB - We report the epidemiological and clinical features of the first outbreak of Klebsiella pneumoniae carbapenemase-producing K. pneumoniae (KPC-KP) type 2 in Switzerland. The outbreak took place in the medical intensive care unit (MICU) of our tertiary care hospital and affected three severely ill patients. After the implementation of strict infection control measures, no further patients colonised with KPC-KP could be detected by the screening of exposed patients. Successful treatment of patients infected with KPC-KP consisted of a combination therapy of meropenem, colistin and tigecycline. PMID- 24477887 TI - IGRA-positive patients and interferon-gamma/interleukin-2 signatures: can the Fluorospot assay provide further information? AB - A goal of testing for latent tuberculosis (TB) infection is to identify individuals who are at increased risk for the development of active TB. No laboratory tool is currently available to distinguish between individuals in the process of progressing from latent TB infection towards active disease and those who are not. Determination of the interferon-gamma and interleukin-2 T cell signature might provide an additional and rapid tool to evaluate treatment necessity and clinical management of a patient. Here, we present three cases of interferon-gamma release assay-positive patients with differing interferon-gamma and interleukin-2 signatures when analyzed by the Fluorospot assay. PMID- 24477888 TI - The influence of kinematic conditions and design on the wear of patella-femoral replacements. AB - The success rate of patella-femoral arthroplasty varies between 44% and 90% in 17 years of follow-up. Several studies have been performed previously for assessing the surface wear in the patella-femoral joint. However, they have not included all six degrees of freedom. The aim of this study was to develop a six-axis patella-femoral joint simulator to assess the wear rate for two patellae designs (round and oval dome) at different kinematic conditions. An increase in patellar rotation from 1 degrees to 4 degrees led to a significantly (p<0.049) increased wear rate of round dome from 8.6 mm(3)/million cycles to 12.3 mm(3)/million cycles. The wear rate for oval dome increased from 6.3 mm(3)/million cycles to 14.5 mm(3)/million cycles. However, the increase was nonsignificant (p>0.08). The increase in wear rate was likely due to the higher cross shear. A decrease in patellar medial lateral displacement from passive to constrained resulted in a nonsignificant reduction in wear (p>0.06). There was no significant difference in wear rate between the two patellae designs (p>0.28). The volumetric wear under all conditions was positively correlated with the level of passive patellar tilt (rho>0.8). This is the first report of preclinical wear simulation of patella femoral joint in a six-axis simulator under different kinematic conditions. PMID- 24477889 TI - Heterotopic ossification in cervical total disk replacement: a finite element analysis. AB - Heterotopic ossification is one of the possible complications following cervical total disk replacement. Although there are numerous hypotheses regarding the etiology of heterotopic ossification, the main causes of heterotopic ossification remain unknown. In this study, we hypothesize that heterotopic ossification formation is related to external loading in the cervical vertebrae after total disk replacement. A two-dimensional finite element model of a cervical vertebra treated by total disk replacement in the sagittal plane was developed. The bone adaptation process of heterotopic ossification was simulated based on strain energy density under both compressive and shear forces. Different types of heterotopic ossification formation were analyzed according to the directions of forces. Two distinct types of heterotopic ossification following cervical total disk replacement were predicted, which was consistent with previous clinical studies. Type 1 heterotopic ossification was observed in the posterior upper part of the vertebra under compressive forces, while type 2 heterotopic ossification was detected mostly in the anterior upper part under shear forces. In addition, heterotopic ossification formation enhanced the strain energy distribution, which is known to be related to bone remodeling. This article presents the effects of different mechanical loading conditions on the occurrence of heterotopic ossification following cervical total disk replacement, and the results may be useful for the design of artificial disks that minimize heterotopic ossification. PMID- 24477890 TI - Increased oxidative stress tolerance results in general stress tolerance in Candida albicans independently of stress-elicited morphological transitions. AB - A selection of tert-butylhydroperoxide (tBOOH)-tolerant Candida albicans mutants showed increased tolerances to 19 different stress conditions. These mutants are characterized by a constitutively upregulated antioxidative defense system and, therefore, adaptation to oxidative stress may play an important role in gaining general stress tolerance in C. albicans. Although C. albicans cells may undergo morphological transitions under various stress treatments, this ability shows considerable stress-specific and strain-specific variability and, hence, it is independent of mounting stress cross protections. PMID- 24477891 TI - Comment on comparison of powder dustiness methods. PMID- 24477892 TI - Assessment of occupational exposure to chemicals by air sampling for comparison with limit values: the influence of sampling strategy. AB - This study was aimed at quantifying the impact of sampling duration and the number of measurements taken on the quality of assessing occupational exposure to toluene. To this end, a measurement database was built, based on four campaigns carried out in an industrial printing facility. Five homogeneous exposure groups (HEGs) were set up and between 120 and 290 individual measurements lasting from 2 to 8 h were collected for each of them. These measurements were performed with the objective of comparing them to the 8-h Occupational Exposure Limit (8-h OEL). The resulting data were used to define a reference exposure profile per HEG: the 'gold standard'. This exposure profile corresponds to a log-normal distribution of measurements from which compliance/non-compliance with the 8-h OEL decision is derived. To simulate the possible sampling strategies used by industrial hygienists, six scenarios were defined, each containing a different number of measurements: 2, 3, 4, 6, 9, and 12 measurements performed per HEG, over different working days and different seasons of the year. The measurement values per scenario were simulated by sampling from the real measurement per HEG. For each scenario, 1000 simulated exposure profiles and corresponding simulated compliance decisions were computed. They were compared to the gold standard compliance decision using statistical indicators. Three methods were used for computing the simulated compliance decision: (i) the 95th percentile must be lower than the 8-h OEL, (ii) the exceedance fraction with respect to the 8-h OEL must be <0.1% (as defined by standard CEN 689, Appendix D), and (iii) the 70% upper confidence limit of the exceedance fraction with respect to the 8-h OEL must be <5% (as defined by French regulations). The results show that exposure assessment quality increases with both the number of measurements and sampling duration when using the 95th percentile and exposure assessment based on French regulations, whereas it decreases when using the standard. Moreover, guidelines for the efficient evaluation of chemical exposure in the workplace can be drawn up to help professional occupational hygienists. Indeed, boundaries can be recommended regarding the number of measurements and sampling duration necessary to obtain a reliable exposure assessment while minimizing effort devoted to sampling and analysis. PMID- 24477893 TI - Actinomycin D and the hormonal induction of amylase synthesis in barley aleurone layers. AB - The induction of amylase synthesis in barley aleurone layers by gibberellic acid is most sensitive to Actinomycin D (AM) over a short interval late in the lag phase. The duration of the lag phase may be extended as much as 3 fold by lower temperatures over the range 30 degrees to 15 degrees C. At each temperature the AM sensitive period remains close to the end of the lag phase, the period we have previously determined as the stage less sensitive to temperature.Lack of sensitivity to the inhibitor at other periods is not due to failure to penetrate, or to degradation. AM has no effect on tissue respiration, leucine, uridine or uracil uptake, leucine incorporation, or leucine pool size. At all stages it inhibits uracil and uridine incorporation into RNA. Thus AM probably acts by inhibiting RNA synthesis. PMID- 24477894 TI - Endogenous abscisic acid in relation to photoperiodically induced bud dormancy. AB - The abscisic acid contents of birch, maple and sycamore plants growing under long and short photoperiods were measured by gas-liquid chromatography. No increase was observed in the abscisic acid content of extracts when plants were transferred to dormancy-inducing conditions. PMID- 24477895 TI - Nuclear DNA contents of Pisum genotypes grown in vivo and in vitro. AB - The nuclear DNA content of prophase nuclei in root tips of two cultivars and two primitive lines of Pisum sativum and of Pisum fulvum have been determined, using a scanning microdensitometer. The nuclear DNA contents differed significantly between the genotypes investigated but there was no correlation with their supposed phylogenetic positions.A loss of 73% of the DNA from cells of aseptically cultured excised pea roots has been recently reported (Abbott, 1971). In marked contrast to this claim, our measurements of the nuclear 4C DNA content of root tip meristematic cells have shown that there is no significant loss in excised roots compared with attached roots. PMID- 24477896 TI - [An in vivo study of detectable phytochrome in seeds of Cucurbita pepo L. in the course of different phases of germination]. AB - In dry gourd seeds all the phytochrome is in the Pfr form. The increase of phytochrome content from the beginning of hydration involves two phases, A and B, in the embryonic axis as well as in the cotyledons. Cycloheximide does not prevent the appearance of Pr during phase A. We assume that Pr is gradually released from an inactive complex. On the other hand phase B is inhibited by cycloheximide; this could mean that a de novo synthesis of Pr occurs.Some experiments indicate that the phytochrome which is localized in the embryonic axis may be involved only in the germinating process.The phytochrome which is synthesized during phase B disappears when the seeds are irradiated with red light, while the original phytochrome does not.According to our data it seems necessary to lay down a new and precise definition of the germination process. PMID- 24477897 TI - The function of the aleurone layer during galactomannan mobilisation in germinating seeds of fenugreek (Trigonella foenum-graecum L.), crimson clover (Trifolium incarnatum L.) and lucerne (Medicago sativa L.): A correlative biochemical and ultrastructural study. AB - The reserve endosperm galactomannans of fenugreek (Trigonella foenum-graecum L.), crimson clover (Trifolium incarnatum L.) and lucerne (Medicago sativa L.) are broken down to free galactose and mannose in dry-isolated endosperms (devoid of embryo) incubated under germination conditions. Breakdown is prevented by inhibition of protein synthesis or of oxidative phosphorylation in the aleurone layer. Resting aleurone cells contain inter alia a large number of ribosomes more or less regularly distributed in the ground plasma. At the onset of germination, before galactomannan breakdown begins, polysomes are formed and seem, at least partly, to become associated with vesicles and flat cisternae both probably newly formed and derived from ER. Concurrently with galactomannan breakdown in the reserve cells, wall corrosion occurs in the aleurone layer, the contents of the aleurone grains disappear and the rough vesicles and cisternae proliferate. Later a large central vacuole is formed which incorporates smaller vacuoles emerging from the cytoplasm, and at the same time the rough ER vesicles and cisternae become highly distended.It is concluded that the cells of the aleurone layer are responsible for the synthesis and secretion into the storage cells of the enzymes necessary for galactomannan degradation. The physiology of galactomannan breakdown is compared and contrasted with that of starch mobilisation in the endosperm of germinating cereal grains. PMID- 24477898 TI - Absence of auxin-induced stored growth in Avena coleoptiles and its implication concerning the mechanism of wall extension. AB - We have reinvestigated the ability of Avena coleoptiles to undergo auxin-induced stored growth (stored growth is defined as the ability of a cell to store up a potential for extension during periods of reduced turgor which can be converted into extra extension upon restoration of normal turgor). We could detect little or no stored growth, with either moderate (1-2 bar) or more severe (3-5 bar) reductions in turgor, and with varying periods (10-100 min) of reduced turgor. Earlier reports of a stored growth potential (e.g., Cleland and Bonner, 1956) are shown to be in error, in that the apparent growth potential is probably an artifact of the use of argon or nitrogen as an inhibitor of auxin action. The absence of stored growth reported here is not due to a direct inhibitory effect of the osmoticum itself on auxin action, since coleoptiles can extend in response to auxin even in the presence of mannitol if an external force is applied to the section to replace the normal turgor. These results show that the two components of cell-wall extension, wall loosening and wall extension, usually are inseparable. Two possible explanations are considered; the walls may be extending by the process of chemical creep, or the wall loosening may only occur when the load-bearing bonds are under tension. PMID- 24477899 TI - [Effect of K(+) on Na (+) fluxes and transport in barley roots: K(+)-stimulated Na (+) efflux in the root cortex]. AB - Barley roots grown on a nutrient solution containing 1 mM Na(+) but no K(+) are capable of a considerable Na(+) transport via the symplasm of the root and the xylem vessels. K(+) added to the medium surrounding the root cortex severely inhibits this transport after a lag period at a high rate constant (Fig. 3).It is likely that the fluxes of Na(+) are changed drastically during this transition from low to high K(+) status. Although originally limited to steady state fluxes, the extended method of efflux analysis for excised roots (Pitman, 1971) has been applied to the non-steady fluxes which occur upon the addition of K(+) to the roots. It is shown that besides other changes the efflux of (22)Na(+) through the cortex of barley roots is stimulated instantaneously (Fig. 5) by the addition of K(+) and presumably by an influx of K(+) ions. From this a transient, K(+) stimulated Na(+) efflux at the plasmalemma of the cortical cells can be estimated. It amounts to 10.9 MU moles/g fw . h compared to the control efflux of 3.3 MU moles/g fw . h without K(+).The stimulated efflux is attributed to a Na(+) efflux pump at the plasmalemma and is thus related to the K-Na-selectivity of barley plants. The inhibition of the Na(+) transport by K(+) is probably a consequence of this increased efflux of Na(+) from the symplasm through the root cortex. PMID- 24477900 TI - Editors and authors: two halves of a whole. PMID- 24477901 TI - Telepsychiatry education and curriculum development in residency training. PMID- 24477902 TI - Philosophy in medical education: a means of protecting mental health. AB - OBJECTIVE: This study sought to identify and examine less commonly discussed challenges to positive mental health faced by medical students, residents, and physicians with hopes of improving current efforts to protect the mental health of these groups. Additionally, this work aimed to suggest an innovative means of preventing poor mental health during medical education. METHODS: Literature on medical student, resident, and physician mental health was carefully reviewed and a number of psychiatrists who treat physician-patients were interviewed. RESULTS: The culture of medicine, medical training, common physician psychology and identity, and conflicting professional expectations all seem to contribute to poor mental health among medical students, residents, and physicians. Many current efforts may be more successful by better addressing the negative effects of these characteristics of modern medicine. CONCLUSIONS: Programs aimed at promoting healthy mental lifestyles during medical education should continue to be developed and supported to mitigate the deleterious effects of the challenging environment of modern medicine. To improve these efforts, educators may consider incorporating philosophical discussions on meaning and fulfillment in life between medical students and faculty. Through medical school faculty members sharing and living out their own healthy outlooks on life, students may emulate these habits and the culture of medicine may become less challenging for positive mental health. PMID- 24477903 TI - Interleukin-6 signaling, soluble glycoprotein 130, and inflammation in heart failure. AB - Both experimental and clinical evidence accumulated over the last couple of decades has linked inflammatory activation to the initiation and progression of chronic heart failure (HF). Circulating levels of inflammatory mediators are associated with cardiac function and inform risk prediction in patients, but the effect of anti-inflammatory therapy in HF remains uncertain. Interleukin (IL)-6 type cytokines are central to the inflammatory response, and convey their signals through the ubiquitously expressed glycoprotein (gp) 130 receptor subunit. IL-6 type/gp130 signaling therefore represents an inflammatory nexus, with inherent potential for disease modification. This review focuses on the current knowledge of IL-6/gp130 signaling in relation to HF, with a particular emphasis on the role of soluble gp130 (sgp130), a signaling pathway modulator. Biological aspects of sgp130 and IL-6 signaling are discussed, as are potential novel therapeutic approaches to modulate this central inflammatory signaling pathway. PMID- 24477904 TI - The importance of assessing nutritional status in elderly patients with heart failure. AB - Heart failure (HF) is a syndrome characterized by high morbidity and mortality, despite advances in medical and device therapy that have significantly improved survival. The outcome of HF in elderly patients results from a combination of biological, functional, psychological, and environmental factors, one of which is nutritional status. Malnutrition, as well as HF, is frequently present with aging. Early detection might lead to earlier intervention. It is our goal to review the importance of nutritional status in elderly patients with HF, as well as tools for assessing it. We also propose a simple decision algorithm for the nutritional assessment of elderly patients with HF. PMID- 24477905 TI - Determinants of survival following hospitalization for acute heart failure. AB - Heart failure constitutes a major public health concern in the United States and is one of the leading causes of hospitalization, readmission, and death. Due to an aging U.S. population, it is estimated that the prevalence of heart failure will increase by 25% over the coming decades, affecting approximately 3.5% of the population by the year 2030. The ability to discriminate patients admitted with acute heart failure syndromes who are at increased risk for poor post hospitalization outcomes is thus critical to guide therapeutic decision making for healthcare providers. This review paper will discuss clinical, hemodynamic, as well as biochemical markers that have been demonstrated to predict post discharge outcomes among patients hospitalized with acute heart failure. PMID- 24477907 TI - NK cells are required for dendritic cell-based immunotherapy at the time of tumor challenge. AB - Increasing evidence suggests that NK cells act to promote effective T cell-based antitumor responses. Using the B16-OVA melanoma model and an optimized Gram positive bacteria-dendritic cell (DC) vaccination strategy, we determined that in vivo depletion of NK cells at time of tumor challenge abolished the benefit of DC immunotherapy. The contribution of NK cells to DC immunotherapy was dependent on tumor Ag presentation by DC, suggesting that NK cells act as helper cells to prime or reactivate tumor-specific T cells. The absence of NK cells at tumor challenge resulted in greater attenuation of tumor immunity than observed with selective depletion of either CD4 or CD8 T cell subsets. Although successful DC immunotherapy required IFN-gamma, perforin expression was dispensable. Closer examination of the role of NK cells as helper cells in enhancing antitumor responses will reveal new strategies for clinical interventions using DC-based immunotherapy. PMID- 24477906 TI - Epigenetic silencing of the human NOS2 gene: rethinking the role of nitric oxide in human macrophage inflammatory responses. AB - Macrophages, including alveolar macrophages, are primary phagocytic cells of the innate immune system. Many studies of macrophages and inflammation have been done in mouse models, in which inducible NO synthase (NOS2) and NO are important components of the inflammatory response. Human macrophages, in contrast to mouse macrophages, express little detectable NOS2 and generate little NO in response to potent inflammatory stimuli. The human NOS2 gene is highly methylated around the NOS2 transcription start site. In contrast, mouse macrophages contain unmethylated cytosine-phosphate-guanine (CpG) dinucleotides proximal to the NOS2 transcription start site. Further analysis of chromatin accessibility and histone modifications demonstrated a closed conformation at the human NOS2 locus and an open conformation at the murine NOS2 locus. In examining the potential for CpG demethylation at the NOS2 locus, we found that the human NOS2 gene was resistant to the effects of demethylation agents both in vitro and in vivo. Our data demonstrate that epigenetic modifications in human macrophages are associated with CpG methylation, chromatin compaction, and histone modifications that effectively silence the NOS2 gene. Taken together, our findings suggest there are significant and underappreciated differences in how murine and human macrophages respond to inflammatory stimuli. PMID- 24477908 TI - Smad and NFAT pathways cooperate to induce CD103 expression in human CD8 T lymphocytes. AB - The interaction of integrin alphaE(CD103)beta7, often expressed on tumor infiltrating T lymphocytes, with its cognate ligand, the epithelial cell marker E cadherin on tumor cells, plays a major role in antitumor CTL responses. CD103 is induced on CD8 T cells upon TCR engagement and exposure to TGF-beta1, abundant within the tumor microenvironment. However, the transcriptional mechanisms underlying the cooperative role of these two signaling pathways in inducing CD103 expression in CD8 T lymphocytes remain unknown. Using a human CTL system model based on a CD8(+)/CD103(-) T cell clone specific of a lung tumor-associated Ag, we demonstrated that the transcription factors Smad2/3 and NFAT-1 are two critical regulators of this process. We also identified promoter and enhancer elements of the human ITGAE gene, encoding CD103, involved in its induction by these transcriptional regulators. Overall, our results explain how TGF-beta1 can participate in CD103 expression on locally TCR-engaged Ag-specific CD8 T cells, thus contributing to antitumor CTL responses and cancer cell destruction. PMID- 24477909 TI - Adult thymic epithelium contains nonsenescent label-retaining cells. AB - Progress in our understanding of thymic epithelial cell (TEC) renewal and homeostasis is hindered by the lack of markers for TEC progenitors. Stem and progenitor cell populations display remarkable diversity in their proliferative behavior. In some but not all tissues, stemness is associated with quiescence. The primary goal of our study was to discover whether quiescent cells were present in neonatal and adult TECs. To this end, we used a transgenic label retaining cell (LRC) assay in which a histone H2B-GFP fusion protein is expressed under the control of the reverse tetracycline-controlled transactivator and the tetracycline operator minimal promoter. In adult mice, we found that both cortical and medullary TECs (cTECs and mTECs) proliferated more actively in females than males. Moreover, we observed three main differences between neonatal and adult TECs: 1) neonatal TECs proliferated more actively than adult TECs; 2) whereas cTECs and mTECs had similar turnover rates in young mice, the turnover of mTECs was more rapid than that of cTECs in adults; and 3) although no LRCs could be detected in young mice, LRCs were detectable after a 16-wk chase in adults. In female mice, LRCs were found almost exclusively among cTECs and expressed relatively low levels of p16INK4a, p19ARF, and Serpine1, and high levels of Bmi1, Foxn1, Trp63, and Wnt4. We conclude that LRCs in adult TECs are not senescent postmitotic cells and may represent the elusive progenitors responsible for TEC maintenance in the adult thymus. PMID- 24477910 TI - Upregulation of GRAIL is associated with impaired CD4 T cell proliferation in sepsis. AB - The loss of numbers and functionality of CD4 T cells is observed in sepsis; however, the mechanism remains elusive. Gene related to anergy in lymphocytes (GRAIL) is critical for the impairment of CD4 T cell proliferation. We therefore sought to examine the role of GRAIL in CD4 T cell proliferation during sepsis. Sepsis was induced in 10-wk-old male C57BL/6 mice by cecal ligation and puncture. Splenocytes were isolated and subjected to flow cytometry to determine CD4 T cell contents. CD4 T cell proliferation was assessed by CFSE staining, and the expression of GRAIL in splenocytes was measured by immunohistochemistry, real time PCR, and flow cytometry. The expressions of IL-2 and early growth response-2 were determined by real-time PCR. As compared with shams, the numbers of CD4 T cells were significantly reduced in spleens. Septic CD4 T cells were less efficient in proliferation than shams. The IL-2 expression was significantly reduced, whereas the GRAIL expression was significantly increased in septic mice splenocytes as compared with shams. The small interfering RNA-mediated knockdown of GRAIL expression re-established the CD4 T cell proliferation ability ex vivo. Similarly, the treatment with recombinant murine IL-2 to the septic CD4 T cells restored their proliferation ability by downregulating GRAIL expression. Our findings reveal a novel association of the increased GRAIL expression with impaired CD4 T cell proliferation, implicating an emerging therapeutic tool in sepsis. PMID- 24477911 TI - B-1a cell diversity: nontemplated addition in B-1a cell Ig is determined by progenitor population and developmental location. AB - Natural Abs produced by B-1a cells are required for immediate protection against infection. The protective capacity of natural Abs is attributed to germline-like structure, which includes the relative absence of N-region addition. Previous studies have shown B-1a cell Ig from aged mice contains abundant nontemplated (N) additions. B-1a cells have been shown to derive from a specific lineage-negative (Lin(-))CD45R(low/-)CD19(+) progenitor found both in fetal liver and adult bone marrow. In this study, we report identification of a fetal liver population characterized phenotypically as Lin(-)CD45R(-)CD19(-), which gives rise to IgM(+)IgD(low)CD45R(low)CD5(+)Mac-1(+)CD19(high)CD43(+)CD23(low) B-1a cells upon adoptive transfer to SCID recipients. These B-1a cells derived from the Lin( )CD45R(-)CD19(-) fetal liver population produce natural Ab that binds pneumococcal Ags, but this Ig contains substantial N-addition despite initial absence of TdT. Furthermore, we show extensive N-addition is also present in B-1a cells derived from the Lin(-)CD45R(low/-)CD19(+) B-1 progenitor found in the bone marrow. Together these results demonstrate B-1a cell N-addition depends on the type of progenitor and the location of the progenitor during its development. These findings have implications for how regulation of different progenitors from fetal liver and bone marrow may play a role in the age-related increase in N region addition by B-1a cells in normal animals. PMID- 24477912 TI - Leukotriene B4 enhances the generation of proinflammatory microRNAs to promote MyD88-dependent macrophage activation. AB - MicroRNAs are known to control TLR activation in phagocytes. We have shown that leukotriene (LT) B4 (LTB4) positively regulates macrophage MyD88 expression by decreasing suppressor of cytokine signaling-1 (SOCS-1) mRNA stability. In this study, we investigated the possibility that LTB4 control of MyD88 expression involves the generation of microRNAs. Our data show that LTB4, via its receptor B leukotriene receptor 1 (BLT1) and Galphai signaling, increased macrophage expression of inflammatory microRNAs, including miR-155, miR-146b, and miR-125b. LTB4-mediated miR-155 generation was attributable to activating protein-1 activation. Furthermore, macrophage transfection with antagomirs against miR-155 and miR-146b prevented both the LTB4-mediated decrease in SOCS-1 and increase in MyD88. Transfection with miR-155 and miR-146b mimics decreased SOCS-1 levels, increased MyD88 expression, and restored TLR4 responsiveness in both wild type and LT-deficient macrophages. To our knowledge, our data unveil a heretofore unrecognized role for the GPCR BLT1 in controlling expression of microRNAs that regulate MyD88-dependent activation of macrophages. PMID- 24477913 TI - Galectin-9 signaling through TIM-3 is involved in neutrophil-mediated Gram negative bacterial killing: an effect abrogated within the cystic fibrosis lung. AB - The T cell Ig and mucin domain-containing molecule (TIM) family of receptors have emerged as potential therapeutic targets to correct abnormal immune function in chronic inflammatory conditions. TIM-3 serves as a functional receptor in structural cells of the airways and via the ligand galectin-9 (Gal-9) can modulate the inflammatory response. The aim of this study was to investigate TIM 3 expression and function in neutrophils, focusing on its potential role in cystic fibrosis (CF) lung disease. Results revealed that TIM-3 mRNA and protein expression values of circulating neutrophils were equal between healthy controls (n = 20) and people with CF (n = 26). TIM-3 was detected on resting neutrophil membranes by FACS analysis, and expression levels significantly increased post IL 8 or TNF-alpha exposure (p < 0.05). Our data suggest a novel role for TIM-3/Gal-9 signaling involving modulation of cytosolic calcium levels. Via TIM-3 interaction, Gal-9 induced neutrophil degranulation and primed the cell for enhanced NADPH oxidase activity. Killing of Pseudomonas aeruginosa was significantly increased upon bacterial opsonization with Gal-9 (p < 0.05), an effect abrogated by blockade of TIM-3 receptors. This mechanism appeared to be Gram-negative bacteria specific and mediated via Gal-9/ LPS binding. Additionally, we have demonstrated that neutrophil TIM-3/Gal-9 signaling is perturbed in the CF airways due to proteolytic degradation of the receptor. In conclusion, results suggest a novel neutrophil defect potentially contributing to the defective bacterial clearance observed in the CF airways and suggest that manipulation of the TIM-3 signaling pathway may be of therapeutic value in CF, preferably in conjunction with antiprotease treatment. PMID- 24477915 TI - Modification and preliminary use of the five-minute speech sample in the postpartum: associations with postnatal depression and posttraumatic stress. AB - Little is known about what constitutes key components of partner support during the childbirth experience. This study modified the five minute speech sample, a measure of expressed emotion (EE), for use with new parents in the immediate postpartum. A coding framework was developed to rate the speech samples on dimensions of couple support. Associations were explored between these codes and subsequent symptoms of postnatal depression and posttraumatic stress. 372 couples were recruited in the early postpartum and individually provided short speech samples. Posttraumatic stress and postnatal depression symptoms were assessed via questionnaire measures at six and thirteen weeks. Two hundred and twelve couples completed all time-points. Key elements of supportive interactions were identified and reliably categorised. Mothers' posttraumatic stress was associated with criticisms of the partner during childbirth, general relationship criticisms and men's perception of helplessness. Postnatal depression was associated with absence of partner empathy and any positive comments regarding the partner's support. The content of new parents' descriptions of labour and childbirth, their partner during labour and birth and their relationship within the immediate postpartum may have significant implications for later psychological functioning. Interventions to enhance specific supportive elements between couples during the antenatal period merit development and evaluation. PMID- 24477914 TI - The transcriptional repressor BLIMP1 curbs host defenses by suppressing expression of the chemokine CCL8. AB - The transcriptional repressor B lymphocyte-induced maturation protein 1 (BLIMP1) is a master regulator of B and T cell differentiation. To examine the role of BLIMP1 in innate immunity, we used a conditional knockout (CKO) of Blimp1 in myeloid cells and found that Blimp1 CKO mice were protected from lethal infection induced by Listeria monocytogenes. Transcriptome analysis of Blimp1 CKO macrophages identified the murine chemokine (C-C motif) ligand 8, CCL8, as a direct target of Blimp1-mediated transcriptional repression in these cells. BLIMP1-deficient macrophages expressed elevated levels of Ccl8, and consequently Blimp1 CKO mice had higher levels of circulating CCL8, resulting in increased neutrophils in the peripheral blood, promoting a more aggressive antibacterial response. Mice lacking the Ccl8 gene were more susceptible to L. monocytogenes infection than were wild-type mice. Although CCL8 failed to recruit neutrophils directly, it was chemotactic for gamma/delta T cells, and CCL8-responsive gamma/delta T cells were enriched for IL-17F. Finally, CCL8-mediated enhanced clearance of L. monocytogenes was dependent on gamma/delta T cells. Collectively, these data reveal an important role for BLIMP1 in modulating host defenses by suppressing expression of the chemokine CCL8. PMID- 24477916 TI - Natriuretic peptides modulate ATP-sensitive K(+) channels in rat ventricular cardiomyocytes. AB - B-type natriuretic peptide (BNP) and C-type natriuretic peptide (CNP), and (Cys 18)-atrial natriuretic factor (4-23) amide (C-ANF), are cytoprotective under conditions of ischemia-reperfusion, limiting infarct size. ATP-sensitive K(+) channel (KATP) opening is also cardioprotective, and although the KATP activation is implicated in the regulation of cardiac natriuretic peptide release, no studies have directly examined the effects of natriuretic peptides on cardiac KATP activity. Normoxic cardiomyocytes were patch clamped in the cell-attached configuration to examine sarcolemmal KATP (sKATP) activity. The KATP opener pinacidil (200 MUM) increased the open probability of the patch (NPo; values normalized to control) at least twofold above basal value, and this effect was abolished by HMR1098 10 MUM, a selective KATP blocker (5.23 +/- 1.20 versus 0.89 +/- 0.18; P < 0.001). We then examined the effects of BNP, CNP, C-ANF and 8Br cGMP on the sKATP current. Bath application of BNP (>=10 nM) or CNP (>=0.01 nM) suppressed basal NPo (BNP: 1.00 versus 0.56 +/- 0.09 at 10 nM, P < 0.001; CNP: 1.0 versus 0.45 +/- 0.16, at 0.01 nM, P < 0.05) and also abolished the pinacidil activated current at concentrations >=10 nM. C-ANF (>=10 nM) enhanced KATP activity (1.00 versus 3.85 +/- 1.13, at 100 nM, P < 0.05). The cGMP analog 8Br cGMP 10 nM dampened the pinacidil-activated current (2.92 +/- 0.60 versus 1.53 +/ 0.32; P < 0.05). Natriuretic peptides modulate sKATP current in ventricular cardiomyocytes. This may be at least partially associated with their ability to augment intracellular cGMP concentrations via NPR-A/B, or their ability to bind NPR-C with high affinity. Although the mechanism of modulation requires elucidation, these preliminary data give new insights into the relationship between natriuretic peptide signaling and sKATP in the myocardium. PMID- 24477917 TI - Lessons learned from a health record bank start-up. AB - INTRODUCTION: This article is part of a Focus Theme of METHODS of Information in Medicine on Health Record Banking. BACKGROUND: In late summer 2010, an organization was formed in greater Phoenix, Arizona (USA), to introduce a health record bank (HRB) in that community. The effort was initiated after market research and was aimed at engaging 200,000 individuals as members in the first year (5% of the population). It was also intended to evaluate a business model that was based on early adoption by consumers and physicians followed by additional revenue streams related to incremental services and secondary uses of clinical data, always with specific permission from individual members, each of whom controlled all access to his or her own data. OBJECTIVES: To report on the details of the HRB experience in Phoenix, to describe the sources of problems that were experienced, and to identify lessons that need to be considered in future HRB ventures. METHODS: We describe staffing for the HRB effort, the computational platform that was developed, the approach to marketing, the engagement of practicing physicians, and the governance model that was developed to guide the HRB design and implementation. RESULTS: Despite efforts to engage the physician community, limited consumer advertising, and a carefully considered financial strategy, the experiment failed due to insufficient enrollment of individual members. It was discontinued in April 2011. CONCLUSIONS: Although the major problem with this HRB project was undercapitalization, we believe this effort demonstrated that basic HRB accounts should be free for members and that physician engagement and participation are key elements in constructing an effective marketing channel. Local community governance is essential for trust, and the included population must be large enough to provide sufficient revenues to sustain the resource in the long term. PMID- 24477918 TI - Ketones as electrophiles in two component Baylis-Hillman reaction: a facile one pot synthesis of substituted indolizines. AB - 2-Alkanoyl(aroyl)-pyridines have been successfully used for coupling with alkyl vinyl ketones under the influence of TMSOTf providing a facile protocol for the synthesis of substituted indolizines, thus demonstrating the application of ketones as electrophiles in a two component Baylis-Hillman reaction. PMID- 24477919 TI - New opportunities for tensor-free calculations of residual dipolar couplings for the study of protein dynamics. AB - Residual dipolar couplings (RDCs) can provide exquisitely detailed information about the structure and dynamics of proteins. It is challenging, however, to extract such information from RDC measurements in conformationally heterogeneous states of proteins because of the complex relationship between RDCs and protein structures. To obtain new insights into this problem, we discuss methods of calculating the RDCs that do not require the definition of an alignment tensor. These methods can help in particular in the search of effective ways to use RDCs to characterise disordered or partially disordered states of proteins. PMID- 24477920 TI - Feasibility of central meditation and imagery therapy for dementia caregivers. AB - OBJECTIVES: Family dementia caregivers are at high risk of depression and burnout. We assessed the feasibility of Central Meditation and Imagery Therapy for Caregivers (CMIT-C), a novel 8-week group meditation and guided imagery group therapy program, for dementia caregivers reporting stress because of caregiving responsibilities. METHODS: Twelve family dementia caregivers enrolled in CMIT-C. Primary outcomes included depression and anxiety, and secondary outcomes included insomnia, quality of life, and mindfulness. Changes over the study and 3 month follow-up were analyzed with non-parametric related samples tests. Correlations of feeling state changes from meditation diaries at 1 week were made with symptom changes post meditation training. RESULTS: Ten participants completed the study. Completers came to an average of 7 +/- 1 sessions out of a possible 8 sessions, and turned in home practice logs of 90 +/- 10% of the time. Anxiety, depression, and insomnia symptoms decreased, and mindfulness ratings improved with large effects (all p < 0.05 and Cohen's d >= 0.7). Gains were stable at 3 months. Early response during the first week of meditation practice was associated with subsequent home meditation practice, anxiety change at 8 weeks, and endpoint satisfaction with CMIT-C. CONCLUSIONS: Central Meditation and Imagery Therapy for Caregivers is a feasible intervention for dementia caregivers. Results suggest that this therapeutic technique can reduce symptoms of anxiety, depression, and insomnia, and increase levels of mindfulness. Early response to meditation practice predicted those with the greatest short-term benefits, and this may inform future studies of meditation. Larger controlled efficacy studies of CMIT-C for dementia caregivers are warranted. PMID- 24477922 TI - Viewing marine bacteria, their activity and response to environmental drivers from orbit: satellite remote sensing of bacteria. AB - Satellite-based remote sensing of marine microorganisms has become a useful tool in predicting human health risks associated with these microscopic targets. Early applications were focused on harmful algal blooms, but more recently methods have been developed to interrogate the ocean for bacteria. As satellite-based sensors have become more sophisticated and our ability to interpret information derived from these sensors has advanced, we have progressed from merely making fascinating pictures from space to developing process models with predictive capability. Our understanding of the role of marine microorganisms in primary production and global elemental cycles has been vastly improved as has our ability to use the combination of remote sensing data and models to provide early warning systems for disease outbreaks. This manuscript will discuss current approaches to monitoring cyanobacteria and vibrios, their activity and response to environmental drivers, and will also suggest future directions. PMID- 24477921 TI - Variability in microbial community composition and function between different niches within a coral reef. AB - To explore how microbial community composition and function varies within a coral reef ecosystem, we performed metagenomic sequencing of seawater from four niches across Heron Island Reef, within the Great Barrier Reef. Metagenomes were sequenced from seawater samples associated with (1) the surface of the coral species Acropora palifera, (2) the surface of the coral species Acropora aspera, (3) the sandy substrate within the reef lagoon and (4) open water, outside of the reef crest. Microbial composition and metabolic function differed substantially between the four niches. The taxonomic profile showed a clear shift from an oligotroph-dominated community (e.g. SAR11, Prochlorococcus, Synechococcus) in the open water and sandy substrate niches, to a community characterised by an increased frequency of copiotrophic bacteria (e.g. Vibrio, Pseudoalteromonas, Alteromonas) in the coral seawater niches. The metabolic potential of the four microbial assemblages also displayed significant differences, with the open water and sandy substrate niches dominated by genes associated with core house-keeping processes such as amino acid, carbohydrate and protein metabolism as well as DNA and RNA synthesis and metabolism. In contrast, the coral surface seawater metagenomes had an enhanced frequency of genes associated with dynamic processes including motility and chemotaxis, regulation and cell signalling. These findings demonstrate that the composition and function of microbial communities are highly variable between niches within coral reef ecosystems and that coral reefs host heterogeneous microbial communities that are likely shaped by habitat structure, presence of animal hosts and local biogeochemical conditions. PMID- 24477924 TI - Longitudinal photosynthetic gradient in crust lichens' thalli. AB - In order to evaluate the self-shading protection for inner photobionts, the photosynthetic activities of three crust lichens were detected using Microscope Imaging-PAM. The false color images showed that longitudinal photosynthetic gradient was found in both the green algal lichen Placidium sp. and the cyanolichen Peltula sp. In longitudinal direction, all the four chlorophyll fluorescence parameters Fv/Fm, Yield, qP, and rETR gradually decreased with depth in the thalli of both of these two lichens. In Placidium sp., qN values decreased with depth, whereas an opposite trend was found in Peltula sp. However, no such photosynthetic heterogeneity was found in the thalli of Collema sp. in longitudinal direction. Microscope observation showed that photobiont cells are compactly arranged in Placidium sp. and Peltula sp. while loosely distributed in Collema sp. It was considered that the longitudinal photosynthetic heterogeneity was ascribed to the result of gradual decrease of incidence caused by the compact arrangement of photobiont cells in the thalli. The results indicate a good protection from the self-shading for the inner photobionts against high radiation in crust lichens. PMID- 24477923 TI - Composition of Archaea in seawater, sediment, and sponges in the Kepulauan Seribu reef system, Indonesia. AB - Coral reefs are among the most diverse and productive ecosystems in the world. Most research has, however, focused on eukaryotes such as corals and fishes. Recently, there has been increasing interest in the composition of prokaryotes, particularly those inhabiting corals and sponges, but these have mainly focused on bacteria. There have been very few studies of coral reef Archaea, despite the fact that Archaea have been shown to play crucial roles in nutrient dynamics, including nitrification and methanogenesis, of oligotrophic environments such as coral reefs. Here, we present the first study to assess Archaea in four different coral reef biotopes (seawater, sediment, and two sponge species, Stylissa massa and Xestospongia testudinaria). The archaeal community of both sponge species and sediment was dominated by Crenarchaeota, while the seawater community was dominated by Euryarchaeota. The biotope explained more than 72% of the variation in archaeal composition. The number of operational taxonomic units (OTUs) was highest in sediment and seawater biotopes and substantially lower in both sponge hosts. No "sponge-specific" archaeal OTUs were found, i.e., OTUs found in both sponge species but absent from nonhost biotopes. Despite both sponge species hosting phylogenetically distinct microbial assemblages, there were only minor differences in Kyoto Encyclopedia of Genes and Genomes (KEGG) functional pathways. In contrast, most functional pathways differed significantly between microbiomes from sponges and nonhost biotopes including all energy metabolic pathways. With the exception of the methane and nitrogen metabolic pathway, all energy metabolic pathways were enriched in sponges when compared to nonhost biotopes. PMID- 24477925 TI - Characterization of bacterial communities in sediments receiving various wastewater effluents with high-throughput sequencing analysis. AB - 454 Pyrosequencing was applied to examine bacterial communities in sediment samples collected from a river receiving effluent discharge from rural domestic sewage (RDS) and various factories, including a tannery (TNS), clothing plant (CTS), and button factory (BTS), respectively. For each sample, 4,510 effective sequences were selected and utilized to do the bacterial diversity and abundance analysis, respectively. In total, 1,288, 2,036, 1,800, and 2,150 operational taxonomic units were obtained at 3% distance cutoff in TNS, CTS, BTS, and RDS, respectively. Bacterial phylotype richness in RDS was higher than the other samples, and TNS had the least richness. The most predominant class in the TNS, CTS, and BTS samples is Betaproteobacteria. Cyanobacteria (no_rank) is the most predominant one in the RDS sample. Circa 31% sequences in TNS were affiliated with the Rhodocyclales order. In the four samples, Aeromonas, Arcobacter, Clostridium, Legionella, Leptospira, Mycobacterium, Pseudomonas, and Treponema genera containing pathogenic bacteria were detected. Characterization of bacterial communities in sediments from various downstream branches indicated that distinct wastewater effluents have similar potential to reduce the natural variability in river ecosystems and contribute to the river biotic homogenization. PMID- 24477926 TI - Topography and architecture of visual and somatosensory areas of the agouti. AB - We analyzed the organization of the somatosensory and visual cortices of the agouti, a diurnal rodent with a relatively big brain, using a combination of multiunit microelectrode recordings and histological techniques including myelin and cytochrome oxidase staining. We found multiple representations of the sensory periphery in the parietal, temporal, and occipital lobes. While the agouti's primary (V1) and secondary visual areas seemed to lack any obvious modular arrangement, such as blobs or stripes, which are found in some primates and carnivores, the primary somatosensory area (S1) was internally subdivided in discrete regions, isomorphically associated with peripheral structures. Our results confirm and extend previous reports on this species, and provide additional data to understand how variations in lifestyle can influence brain organization in rodents. PMID- 24477927 TI - Bioaccumulation of fullerene (C60) and corresponding catalase elevation in Lumbriculus variegatus. AB - Fullerene (C(60)), with its unique physical properties and nanometer size, has been mass-produced for many applications in recent decades. The increased likelihood of direct release into the environment has raised interest in understanding both the environmental fate and corresponding biological effects of fullerenes to living organisms. Because few studies have emphasized fullerene uptake and resulting biochemical responses by living organisms, a toxicity screening test and a 28-d bioaccumulation test for Lumbriculus variegatus were performed. No mortality was observed in the range of 0.05 mg C(60) /kg dry sediment to 11.33 mg C(60) /kg dry sediment. A biota-sediment accumulation factor of micron-sized fullerene agglomerates (u-C(60)) was 0.032 +/- 0.008 at day 28, which is relatively low compared with pyrene (1.62 +/- 0.22). Catalase (CAT) activity, an oxidative stress indicator, was elevated significantly on day 14 for L. variegatus exposed to u-C(60) (p = 0.034). This peak CAT activity corresponded to the highest body residues observed in the present study, 199 +/- 80 ug C(60) /kg dry weight sediment. Additionally, smaller C(60) agglomerate size increased bioaccumulation potential in L. variegatus. The relationship between C(60) body residue and the increased CAT activity followed a linear regression. All results suggest that C(60) has a lower bioaccumulation potential than pyrene but a higher potential to induce oxidative stress in L. variegatus. PMID- 24477928 TI - GATA3 mutations define a unique subtype of luminal-like breast cancer with improved survival. AB - BACKGROUND: The GATA3 gene (GATA-binding protein 3) is one of the most frequently mutated genes in breast cancer. The objective of the current study was to determine the clinicopathologic characteristics of patients with breast cancer harboring GATA3 mutations. METHODS: The authors examined the somatic mutation status of GATA3 and performed survival analysis in The Cancer Genome Atlas (TCGA) cohort (n=934) and the Fudan University Shanghai Cancer Center (FUSCC) cohort (n=308). Patient characteristics, including age; menopausal status; tumor laterality; tumor size; lymph node status; tumor grade; molecular subtypes; adjuvant radiotherapy, chemotherapy, and endocrine therapy; and prognosis, together with PIK3CA (phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha) and TP53 (tumor protein p53) mutation status, were collected. RESULTS: GATA3 mutations were detected in 8.8% of patients (82 of 934 patients) in the TCGA cohort and 14.9% of patients (46 of 308 patients) in the FUSCC cohort. GATA3 mutations were found to be significantly associated with luminal like breast cancer (P=.002 in the TCGA cohort and P<.001 in the FUSCC cohort), and were highly mutually exclusive to PIK3CA mutations (P=.001 in the TCGA cohort and P=.003 in the FUSCC cohort) and TP53 mutations (P<.001 in both cohorts). Furthermore, GATA3 mutations were correlated with improved overall survival in the entire population (P=.025 in the TCGA cohort and P = .043 in the FUSCC cohort) as well as in patients with luminal-like disease who received adjuvant endocrine therapy. CONCLUSIONS: GATA3 mutations mainly occur in patients with luminal-like breast cancer and have identifiable clinicopathologic and genetic characteristics, highlighting a subgroup of patients with breast cancer in whom limited therapy may be appropriate. PMID- 24477929 TI - Palliative surgery for malignant bowel obstruction from carcinomatosis: a systematic review. AB - IMPORTANCE: Care of patients with malignant bowel obstruction caused by peritoneal metastases may present an ethical dilemma for surgeons when nonoperative management fails. OBJECTIVE: To characterize outcomes of palliative surgery for malignant bowel obstruction from peritoneal carcinomatosis to guide decision making about surgery and postoperative interventions for patients with terminal illness. EVIDENCE REVIEW: We searched PubMed, EMBASE, Cochrane Library, Web of Knowledge, Cumulative Index to Nursing and Allied Health Literature Plus, and Google Scholar and performed manual searches of selected journals from inception to August 30, 2012, with no filters, limits, or language restrictions. We used database-specific combinations of the terms intestinal obstruction, malignant, surgery or surgical, and palliat*. We included studies reporting outcomes after palliative surgery for malignant bowel obstruction from peritoneal carcinomatosis from any primary malignant neoplasm and excluded case studies, curative surgery, isolated percutaneous procedures, stenting for intraluminal lesions, and studies in which benign and malignant obstructions could not be distinguished. We assessed quality with the Newcastle-Ottawa Scale. FINDINGS: We screened 2347 unique articles, selected 108 articles for full-text review, and included 17 studies. Surgery was able to palliate obstructive symptoms for 32% to 100% of patients, enable resumption of a diet for 45% to 75% of patients, and facilitate discharge to home in 34% to 87% of patients. Mortality was high (6% 32%), and serious complications were common (7%-44%). Frequent reobstructions (6% 47%), readmissions (38%-74%), and reoperations (2%-15%) occurred. Survival was limited (median, 26-273 days), and hospitalization for surgery consumed a substantial portion of the patient's remaining life (11%-61%). CONCLUSIONS AND RELEVANCE: Although palliative surgery can benefit patients, it comes at the cost of high mortality and substantial hospitalization relative to the patient's remaining survival time. Preoperatively, surgeons should present realistic goals and limitations of surgery. For patients choosing surgery, clarifying preferences for aggressive postoperative interventions preoperatively is critical given the high complication rate and limited survival after surgery for malignant bowel obstruction. PMID- 24477930 TI - Development of single vial kits for preparation of (68)Ga-labelled peptides for PET imaging of neuroendocrine tumours. AB - PURPOSE: The present work was aimed at the formulation and evaluation of freeze dried kits of 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) peptides for the preparation of (68)Ga-labelled peptides for PET imaging of neuroendocrine tumours. The (68)GaCl3 was obtained from the locally produced nanoceria-PAN, composite-sorbent-based (68)Ge/(68)Ga generator. PROCEDURES: Single vial kits of somatostatin analogues DOTA-[Tyr(3)]-octreotide (DOTA-TOC), DOTA-[NaI(3)]-octreotide (DOTA-NOC) and DOTA-Tyr(3)-Thre(8)-octreotide (DOTA TATE) were formulated. Optimization of radiolabelling with (68)Ga from the in house generator, characterization, long term evaluation of stability of kits and bioevaluation studies in animals was carried out. RESULTS: DOTA-TOC, DOTA-NOC and DOTA-TATE kits could be successfully formulated. Consistently high radiochemical yields (>95 %) were obtained on radiolabelling with (68)Ga. The radiolabelled peptides exhibited excellent in vitro stability. Biodistribution studies in normal non-tumour bearing Swiss mice revealed fast clearance of activity via renal route as reported for the respective peptides. CONCLUSION: Availability of ready to use DOTA-peptide kits in conjunction with (68)Ge/(68)Ga generators would pave way for the establishment of (68)Ga radiopharmacy, a long-felt need of the nuclear medicine community. PMID- 24477931 TI - People who inject drugs in intimate relationships: it takes two to combat HIV. AB - We reviewed papers published during the past 18 months (2012-2013) focusing on micro-social contexts of gender and power inequalities as drivers of HIV risks among people who inject drugs (PWID) in intimate heterosexual relationships. Although there has been a proliferation of social and behavioral research on the micro-social contexts of drug injection in heterosexual intimate relationships, there is still a gap in knowledge of these issues, particularly in low- and middle-income countries. Research has identified couple-based approaches for PWID in intimate relationships as an effective HIV prevention strategy to address micro-social contexts driving HIV risks. While HIV incidence has declined in many countries, prevalence remains at troubling levels among PWID and transmission from PWID to their sex partners is increasing in many parts of the world. HIV prevention among drug-using couples must address the importance of the relationship dyad and micro-social contexts. PMID- 24477932 TI - Latent classiness and other mixtures. AB - The aim of this article is to laud Lindon Eaves' role in the development of mixture modeling in genetic studies. The specification of models for mixture distributions was very much in its infancy when Professor Eaves implemented it in his own FORTRAN programs, and extended it to data collected from relatives such as twins. It was his collaboration with the author of this article which led to the first implementation of mixture distribution modeling in a general-purpose structural equation modeling program, Mx, resulting in a 1996 article on linkage analysis in Behavior Genetics. Today, the popularity of these methods continues to grow, encompassing methods for genetic association, latent class analysis, growth curve mixture modeling, factor mixture modeling, regime switching, marginal maximum likelihood, genotype by environment interaction, variance component twin modeling in the absence of zygosity information, and many others. This primarily historical article concludes with some consideration of some possible future developments. PMID- 24477933 TI - A direct role of Mad1 in the spindle assembly checkpoint beyond Mad2 kinetochore recruitment. AB - The spindle assembly checkpoint (SAC) ensures accurate chromosome segregation by delaying entry into anaphase until all sister chromatids have become bi-oriented. A key component of the SAC is the Mad2 protein, which can adopt either an inactive open (O-Mad2) or active closed (C-Mad2) conformation. The conversion of O-Mad2 into C-Mad2 at unattached kinetochores is thought to be a key step in activating the SAC. The "template model" proposes that this is achieved by the recruitment of soluble O-Mad2 to C-Mad2 bound at kinetochores through its interaction with Mad1. Whether Mad1 has additional roles in the SAC beyond recruitment of C-Mad2 to kinetochores has not yet been addressed. Here, we show that Mad1 is required for mitotic arrest even when C-Mad2 is artificially recruited to kinetochores, indicating that it has indeed an additional function in promoting the checkpoint. The C-terminal globular domain of Mad1 and conserved residues in this region are required for this unexpected function of Mad1. PMID- 24477934 TI - Mad1 contribution to spindle assembly checkpoint signalling goes beyond presenting Mad2 at kinetochores. AB - The spindle assembly checkpoint inhibits anaphase until all chromosomes have become attached to the mitotic spindle. A complex between the checkpoint proteins Mad1 and Mad2 provides a platform for Mad2:Mad2 dimerization at unattached kinetochores, which enables Mad2 to delay anaphase. Here, we show that mutations in Bub1 and within the Mad1 C-terminal domain impair the kinetochore localization of Mad1:Mad2 and abrogate checkpoint activity. Artificial kinetochore recruitment of Mad1 in these mutants co-recruits Mad2; however, the checkpoint remains non functional. We identify specific mutations within the C-terminal head of Mad1 that impair checkpoint activity without affecting the kinetochore localization of Bub1, Mad1 or Mad2. Hence, Mad1 potentially in conjunction with Bub1 has a crucial role in checkpoint signalling in addition to presenting Mad2. PMID- 24477935 TI - Differences in colonoscopy technique impact quality. AB - BACKGROUND: Colonoscopists differ in skill, technique, and attitude in relation to the examination. These differences have a potential impact on the quality of the examination and the risk of complications. This study aimed to document differences in technique between individual colonoscopists and to explore some possible consequences to the patient and the examination. METHODS: This prospective, comparative study analyzed 10 individual endoscopists practicing in outpatient endoscopy clinics at a major medical center. Consecutive patients presenting for elective outpatient colonoscopy were included in the study. Examinations were observed, and techniques used during scope insertion and withdrawal were recorded. The type and dose of medication, the pain score recorded by the endoscopy nurses (scale of 1-10), and the incidence of hypotension and hypoxia were noted. RESULTS: The study involved 245 patients (129 men and 116 women) with a mean age of 59.5 years. The number of colonoscopies per examiner ranged from 12 to 31, with nine tenths of the examiners performing more than 20 colonoscopies. Completion rates ranged from 82.6 to 100 %; the withdrawal time averages ranged from 3.5 to 21.7 min; and the average number of techniques used ranged from one per four exams to three per exam. The average pain score per endoscopist ranged from 2.1 to 4.3, and the percentage of patients with either hypoxia or hypotension ranged from 11.5 to 85.0 %. A sedation/analgesia product (SAP) was derived by multiplying the mean dose of versed by the mean dose of meperidine. Regression analysis showed significant relationships between the number of techniques used and the levels of pain (R (2) = 0.395) and hypoxia/hypotension (R (2) = 0.513). The findings showed that SAP was significantly associated with hypoxia/hypotension (R (2) = 0.826) but not pain (R (2) = 0.01). CONCLUSIONS: Use of ancillary techniques for colonoscope insertion minimizes pain, narcotic use, and hypoxia/hypotension. The product of benzodiazepine dose and narcotic dose is a good way of assessing sedative effect. PMID- 24477936 TI - Long-term follow-up evaluation of endoscopic sclerotherapy for dilated gastrojejunostomy after gastric bypass. AB - BACKGROUND: Endoscopic sclerotherapy using sodium morrhuate has been used to treat patients with weight regain after Roux-en-Y gastric bypass whose presumed etiology is loss of restriction due to gastrojejunostomy dilation. Weight loss and stability have been demonstrated in several studies with short-term follow-up evaluation. METHODS: This retrospective review evaluated all the patients who underwent sclerotherapy for a dilated gastrojejunostomy between 2007 and 2012. RESULTS: The study identified 48 patients with a mean follow-up period of 22 months (range 12-60 months). The mean age of these patients was 47.5 +/- 10.5 years, and 92 % were women. The average weight loss from the primary procedure was 132.5 +/- 54.82 lb, and the average weight regain from the lowest weight to the maximum weight before sclerotherapy was 46 +/- 40.32 lb. The median number of sclerotherapy sessions was two (range 1-4). The pre-procedure mean gastrojejunostomy diameter was 20 +/- 3.6 mm, and the mean volume of sodium morrhuate injected per session was 12.8 +/- 3.7 ml. The average weight loss from sclerotherapy to the final documented weight was 3.17 +/- 19.70 lb, which was not statistically significant. The following variables in the multivariate analysis were not associated with statistically significant weight loss: volume of sodium morrhuate, patient age, gastrojejunostomy diameter, number of sclerotherapy sessions, decrease in gastrojejunostomy diameter between the first and second sessions, and number of follow-up years. Weight stabilization or loss was achieved by 58 % of our cohort, with a mean weight loss of 15.9 +/- 14.6 lb in this subgroup. CONCLUSION: The long-term follow-up evaluation of patients undergoing sclerotherapy of the gastrojejunostomy for weight regain after gastric bypass showed only a marginal weight loss, which was not statistically significant in our study population, although more than 50 % of the patients achieved weight loss or stabilization. PMID- 24477938 TI - Amputation neuroma growing intravascularly into a thrombus. AB - An adult man underwent arm amputation for a sarcoma. Pain and three masses observed radiologically prompted surgical exploration five years later. Microscopically, the masses represented amputation neuromas. One of them was located in the lumen of an artery, in a remote organized thrombus. Intravascular growth of an amputation neuroma has not been described previously. PMID- 24477937 TI - Should laterally spreading tumors granular type be resected en bloc in endoscopic resections? AB - BACKGROUND: Currently, granular-type laterally spreading tumors (LST-G) have been classified into uniform [LST-G (UNI)] and nodular mixed [LST-G (MIX)] subtypes. However, the progression pattern of each subtype has not been evaluated in detail. The present study was designed to assign adequate treatment strategies to each LST-G subtype, based on the progression pattern. METHODS: This retrospective study included 457 consecutive patients with 482 LST-Gs that had been removed endoscopically or surgically in a tertiary cancer center between September 2002 and December 2011. We classified the tumors as LST-G (UNI) or LST-G (MIX) subtypes. We analyzed clinicopathological characteristics and submucosal invasion rates for both subtypes, and we determined the incidence of submucosal invasions associated with the largest nodules for each subtype. RESULTS: We evaluated the histopathological data from 136 LST-G (UNI) and 316 LST-G (MIX) lesions with diameters of 10-19 mm (14%), 20-29 mm (26%), 30-39 mm (25%), or >40 mm (35%). Submucosal invasions were observed in 3 (1.8%) LST-G (UNI) and 49 (15.5%) LST-G (MIX) lesions. In LST-G (MIX) lesions, the submucosal invasion incidences (within a tumor-size category) were as follows: 5.8% (10-19 mm), 11.1% (20-29 mm), 14.7% (30-39 mm), and 19.1% (>40 mm), respectively. In LST-G (MIX) lesions that showed submucosal invasions, the invasive cancers were located under the largest nodule (69%; 34/49), outside the largest nodule (25%; 12/49), or in both sites (6%; 3/49). CONCLUSIONS: Our results indicated that, for LST-G (UNI) lesions, piecemeal resections would be acceptable due to the low risk of submucosal invasion. For LST-G (MIX) lesions, particularly those with diameters >=20 mm, en bloc removal in an endoscopic resection is preferable for sufficient histological evaluation. PMID- 24477939 TI - Interobserver reproducibility study of the histological patterns of primary lung adenocarcinoma with emphasis on a more complex glandular pattern distinct from the typical acinar pattern. AB - The newly proposed International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society (IASLC/ATS/ERS) classification of lung adenocarcinoma has emphasized the prognostic significance of histological subtyping. In this study, 2 surgical pathologists reevaluated 49 consecutive cases of invasive primary pulmonary adenocarcinomas; histological subtyping was performed according to the IASLC/ATS/ERS classification. The 2 reviewers agreed on the predominant pattern in 23 out of 32 independently reviewed cases (71.9%, k = 0.628, 95% confidence interval = 0.442-0.815). Postconsensus, a complex glandular pattern consisting of fused, closely packed glands and cribriform architecture was identified in 9 of 49 (18%) cases. This pattern has a strong association with lymphovascular invasion (78%; P = .0091), high mitotic activity (89%), and higher tumor stage (78%). Frequent association of complex glandular pattern with poor prognostic factors and its overlap with acinar pattern warrant a more detailed description of this pattern in the classification system and a large-scale study to evaluate its prognostic significance. PMID- 24477940 TI - Establishment of a short-term, in vivo screening method for detecting chemicals with juvenile hormone activity using adult Daphnia magna. AB - Juvenile hormone (JH) and JH agonists have been shown to induce male offspring production in various daphnids, including Daphnia magna using OECD TG211. The critical period (about 1h) for JH action on ova in the parent's ovary to induce male offspring is existing at 7-8h later from ovulation. Therefore, we considered that adult D. magna could be used to produce a short-term screening method for detecting JH analogs. Using this method, we successfully demonstrated male offspring induction in the second broods after exposure to JH or JH agonists. After investigating the exposure time, the number of repetitions and the exposure concentration, we established a short-term, in vivo screening method for detecting JH analogs using adult D. magna. We examined positive and negative control chemicals using a previously developed method and verified the validity of our new testing method. PMID- 24477941 TI - Formation of activity cliffs is accompanied by systematic increases in ligand efficiency from lowly to highly potent compounds. AB - Activity cliffs (ACs) are defined as pairs of structurally similar compounds sharing the same biological activity but having a large difference in potency. Therefore, ACs are often studied to rationalize structure-activity relationships (SARs) and aid in lead optimization. Hence, the AC concept plays an important role in compound development. For compound optimization, ligand efficiency (LE) represents another key concept. LE accounts for the relation between compound potency and mass. A major goal of lead optimization is to increase potency and also LE. Despite their high relevance for drug development, the AC and LE concepts have thus far not been considered in combination. It is currently unknown how compounds forming ACs might be related in terms of LE. To explore this question, ACs were systematically identified on the basis of high-confidence activity data and LE values for cliff partners were determined. Surprisingly, a significant increase in LE was generally detected for highly potent cliff partners compared to their lowly potent counterparts, regardless of the compound classes and their targets. Hence, ACs reveal chemical modifications that determine SARs and improve LE. These findings further increase the attractiveness of AC information for compound optimization and development. PMID- 24477942 TI - Neuro-fuzzy models as an IVIVR tool and their applicability in generic drug development. AB - The usefulness of neuro-fuzzy (NF) models as an alternative in vitro-in vivo relationship (IVIVR) tool and as a support to quality by design (QbD) in generic drug development is presented. For drugs with complicated pharmacokinetics, immediate release drugs or nasal sprays, suggested level A correlations are not capable to satisfactorily describe the IVIVR. NF systems were recognized as a reasonable method in comparison to the published approaches for development of IVIVR. Consequently, NF models were built to predict 144 pharmacokinetic (PK) parameter ratios required for demonstration of bioequivalence (BE) for 88 pivotal BE studies. Input parameters of models included dissolution data and their combinations in different media, presence of food, formulation strength, technology type, particle size, and spray pattern for nasal sprays. Ratios of PK parameters Cmax or AUC were used as output variables. The prediction performance of models resulted in the following values: 79% of models have acceptable external prediction error (PE) below 10%, 13% of models have inconclusive PE between 10 and 20%, and remaining 8% of models show inadequate PE above 20%. Average internal predictability (LE) is 0.3%, and average external predictability of all models results in 7.7%. In average, models have acceptable internal and external predictabilities with PE lower than 10% and are therefore useful for IVIVR needs during formulation development, as a support to QbD and for the prediction of BE study outcome. PMID- 24477943 TI - Community engagement: outcomes for occupational therapy students, faculty and clients. AB - Students in health care professions, including occupational therapy, are required to develop knowledge, skills and attitudes in mental health and research. Persons diagnosed with a mental illness, a learning disability or an autism-spectrum disorder desire to achieve goals in higher education and employment. Faculty in health care programmes strives to meet professional goals and accreditation and institution requirements for teaching, service and scholarship. The Bridge Program, a programme based on principles of community engagement, was developed to meet the needs of these three stakeholders. The objective of this paper is to provide programme description and outcomes of the effectiveness of the Bridge Program for all three stakeholders. This uses mixed methods research design including descriptive and quantitative and qualitative one-group pre-test-post test designs. Instruments consisted of the Occupational Therapy Student and Mental Health Population Scale and the Canadian Occupational Performance Measure. Quantitative results support that graduate occupational therapy students gained research and clinical skills (n = 100; p = .000); clients increased performance and satisfaction toward goals (n = 113; p = .000) and faculty (n = 1) achieved goals related to teaching, service and scholarship. Programmes based on principles of community engagement can address the needs of the community, can provide outcomes that advance knowledge about community practice and can result in benefits for all stakeholders. This paper is limited to generalization and instrumentation and recommends an ongoing evaluation of other community engagement programmes involving all stakeholders in the future research. PMID- 24477945 TI - Mo-Cu metal cluster formation and binding in an orange protein isolated from Desulfovibrio gigas. AB - The orange protein (ORP) isolated from the sulfate-reducing bacterium Desulfovibrio gigas (11.8 kDa) contains a mixed-metal sulfide cluster of the type [S2MoS2CuS2MoS2](3-) noncovalently bound to the polypeptide chain. The D. gigas ORP was heterologously produced in Escherichia coli in the apo form. Different strategies were used to reconstitute the metal cluster into apo-ORP and obtain insights into the metal cluster synthesis: (1) incorporation of a synthesized inorganic analogue of the native metal cluster and (2) the in situ synthesis of the metal cluster on the addition to apo-ORP of copper chloride and tetrathiomolybdate or tetrathiotungstate. This latter procedure was successful, and the visible spectrum of the Mo-Cu reconstituted ORP is identical to the one reported for the native protein with absorption maxima at 340 and 480 nm. The (1)H-(15)N heteronuclear single quantum coherence spectra of the reconstituted ORP obtained by strategy 2, in contrast to strategy 1, exhibited large changes, which required sequential assignment in order to identify, by chemical shift differences, the residues affected by the incorporation of the cluster, which is stabilized inside the protein by both electrostatic and hydrophobic interactions. PMID- 24477944 TI - High-frequency and high-field electron paramagnetic resonance (HFEPR): a new spectroscopic tool for bioinorganic chemistry. AB - This minireview describes high-frequency and high-field electron paramagnetic resonance (HFEPR) spectroscopy in the context of its application to bioinorganic chemistry, specifically to metalloproteins and model compounds. HFEPR is defined as frequencies above ~100 GHz (i.e., above W-band) and a resonant field reaching 25 T and above. The ability of HFEPR to provide high-resolution determination of g values of S = 1/2 is shown; however, the main aim of the minireview is to demonstrate how HFEPR can extract spin Hamiltonian parameters [zero-field splitting (zfs) and g values] for species with S > 1/2 with an accuracy and precision unrivalled by other physical methods. Background theory on the nature of zfs in S = 1, 3/2, 2, and 5/2 systems is presented, along with selected examples of HFEPR spectroscopy of each that are relevant to bioinorganic chemistry. The minireview also provides some suggestions of specific systems in bioinorganic chemistry where HFEPR could be rewardingly applied, in the hope of inspiring workers in this area. PMID- 24477946 TI - Molecular dynamics simulations of apocupredoxins: insights into the formation and stabilization of copper sites under entatic control. AB - Cupredoxins perform copper-mediated long-range electron transfer (ET) in biological systems. Their copper-binding sites have evolved to force copper ions into ET-competent systems with decreased reorganization energy, increased reduction potential, and a distinct electronic structure compared with those of non-ET-competent copper complexes. The entatic or rack-induced state hypothesis explains these special properties in terms of the strain that the protein matrix exerts on the metal ions. This idea is supported by X-ray structures of apocupredoxins displaying "closed" arrangements of the copper ligands like those observed in the holoproteins; however, it implies completely buried copper binding atoms, conflicting with the notion that they must be exposed for copper loading. On the other hand, a recent work based on NMR showed that the copper binding regions of apocupredoxins are flexible in solution. We have explored five cupredoxins in their "closed" apo forms through molecular dynamics simulations. We observed that prearranged ligand conformations are not stable as the X-ray data suggest, although they do form part of the dynamic landscape of the apoproteins. This translates into variable flexibility of the copper-binding regions within a rigid fold, accompanied by fluctuations of the hydrogen bonds around the copper ligands. Major conformations with solvent-exposed copper binding atoms could allow initial binding of the copper ions. An eventual subsequent incursion to the closed state would result in binding of the remaining ligands, trapping the closed conformation thanks to the additional binding energy and the fastening of noncovalent interactions that make up the rack. PMID- 24477947 TI - Relationship of body composition with bone mineral density in northern Chinese men by body mass index levels. AB - Osteoporosis and obesity are severe public health problems in an aging society, and as we all know, bone mineral density (BMD) is closely related to fat mass (FM) and fat distribution. However, studies have long focused on pre- or post menopausal women, and its presence in men has been underestimated. To investigate the differential impact of fat on BMD, we characterized body composition of northern Chinese men and examined the relationship with BMD according to body mass index (BMI) levels. METHODS: A cross-sectional study was conducted on 502 healthy northern Chinese men aged 20-89 screened from the participants in a community-based osteoporosis prevention study conducted by the Research Center of Qianfoshan Hospital of Shandong University from 2009 to 2010. The qualified subjects were stratified according to BMI levels as normal weight (18.5 <= BMI < 24 kg/m(2), n = 137), overweight (24 <= BMI < 28 kg/m(2), n = 225), and obesity (BMI >= 28 kg/m(2), n = 140). Total body, left femur, lumbar spine BMD and lean mass (LM), FM, percent body fat (%BF) were measured by dual-energy X-ray absorptiometry. Pearson correlation and age-adjusted partial correlation analyses between body composition-related parameters and BMD were performed. Multiple regression analysis was performed to examine the relationship of BMD with LM, FM and %BF. RESULTS: Height and weight had positive associations with BMD at all sites, although age had negative associations. Of all subjects, LM and FM were positively correlated with BMD at almost sites (P < 0.01). However, when the subjects were divided into normal weight, overweight and obesity, no relations were reflected between FM and BMD. %BF showed negative correlations with BMD at arm and leg (P < 0.01) in overweight, and with BMD at total body, arm, leg, hip (P < 0.01) in obesity. In regression models, both FM and LM showed statistically positively significant relations with total body and regional BMD in all subjects (all P < 0.05). LM was positively correlated with BMD at almost site (all P < 0.05) in groups, while FM had no association. Interestingly, percent body fat (%BF) had negative associations with BMD at total body, arm, leg and total femur in overweight and obesity. CONCLUSIONS: The relationship between LM and BMD was certain in northern Chinese men while fat-bone relationship was complicated. %BF had a significantly negative association with total body and regional BMD in overweight and obese men. PMID- 24477948 TI - Management of craniopharyngiomas. AB - Craniopharyngiomas are rare epithelial tumours arising along the path of the craniopharyngeal duct. Their pathogenesis remains uncertain and they can present with a variety of manifestations attributed to pressure effects to surrounding structures. The optimal management of craniopharyngiomas remains challenging mainly due to their sharp, irregular borders and their tendency to adhere to vital neurovascular structures making surgical manipulations potentially hazardous to vital brain areas. Non-aggressive surgery followed by radiotherapy is currently the most widely used option possibly achieving the most optimal long term outcome. Other treatment modalities including intracystic irradiation, intracystic instillation of antineoplasmatic agents and stereotactic radiotherapy are also available in our armamentarium. The long-term morbidities related with the craniopharyngiomas and their treatment remain significant, with hypothalamic damage playing the protagonist role and requiring further studies to identify measures that will improve the prognosis of the patients. PMID- 24477949 TI - X-Linked agammaglobulinemia in a child with Klinefelter's syndrome. AB - Bruton's agammaglobulinemia is a rare X-linked humoral immunodeficiency manifesting with recurrent bacterial infections early in life. Klinefelter's syndrome caused by an additional X chromosome is the most common sex chromosome disorder. A previously unreported association of these two conditions is described here. PMID- 24477950 TI - Emerging Paradigm of Primary Immunodeficiency Disease: Individualizing Immunoglobulin Dose and Delivery to Enhance Outcomes. AB - An emerging paradigm for the treatment of primary immunodeficiency disease (PIDD) with immunoglobulin (IgG) replacement therapy emphasizes the tailoring of treatments to each patient with the goal of preventing infections and minimizing side effects. Increasing evidence shows that the IgG dose needed to prevent infection varies with each patient, and both intravenous immunoglobulin (IGIV) and subcutaneous immunoglobulin (IGSC) have emerged as feasible modes of delivery. Although IGIV is currently the routine treatment, IGSC is increasingly being chosen as the preferred route of delivery due to greater flexibility and reduced side effects. PMID- 24477951 TI - The mechanism of hydrogen photoproduction by several algae : I. The effect of inhibitors of photophosphorylation. AB - In order to come to a more firmly based conclusion on the mechanism of hydrogen photoproduction in green algae, we have compared two additional genera of green algae, i.e., Ankistrodesmus and Chlorella, with the previously tested Chlamydomonas and Scenedesmus. None of the algae tested required photosystem II for H2 photoproduction, since this reaction still occurred in the presence of 10( 5)M DCMU. Photophosphorylation was also not required since two potent inhibitors of this process, Cl-CCP and SAL, almost always stimulated H2 photoproduction. However, the effect of the inhibitors was found to vary with the species of alga and also with the age and growth conditions of the culture. The highest concentration of SAL tested (10(-2)M) always stimulated H2 photoproduction by photoheterotrophically grown cells, but often inhibited this reaction in autotrophically grown cells. When present, this inhibition by SAL was associated with gross pigment damage. The variation in the effect of Cl-CCP upon H2 photoproduction due to different growth conditions was particularly striking for Chlorella vulgaris.Cl-CCP gave very little if any stimulation of this reaction in autotrophically grown cells of this alga, but stimulated H2 photoproduction by photoheterotrophically grown cells approximately 450%. Chlamydomonas cells were found to be about ten times as sensitive as the other cells to both poisons. We conclude that all of the algae tested are able to photoproduce H2 via non-cyclic electron flow through photosystem I to hydrogenase. PMID- 24477952 TI - The mechanism of hydrogen photoproduction by several algae : II. The contribution of photosystem II. AB - The contribution of PS II to H2 photoproduction by several unicellular green algae was measured both when O2 evolution and photophosphorylation were unimpaired and also when these processes had been eliminated by Cl-CCP. As judged by the effects of DCMU, a PS II contribution was found under both sets of experimental conditions for several strains of Chlorella, Ankistrodesmus and Scenedesmus. However, H2 photoproduction by Chlamydomonas moewusii was insensitive to DCMU and thus was entirely due to PS I. With cells treated with Cl CCP, the relative amount of PS II contribution varied from zero in autotrophically grown Chlamydomonas reinhardii, to ~ 20% in photoheterotrophically grown and ~ 50% in autotrophically grown cells of Ankistrodesmus braunii, Chlorella fusca, Chlorella vulgaris and Scenedesmus obliquus. The dehydrogenation of reduced H-donors by PS II of Scenedesmus treated with Cl-CCP showed the same biphasic kinetics previously described for H2 photoproduction by PS I of this alga. PMID- 24477953 TI - Genetic control of beta-diketone and hydroxy-beta-diketone synthesis in epicuticular waxes of barley. AB - Five eceriferum, (cer) mutants in barley which influence beta-diketone and hydroxy-beta-diketone synthesis in spike and internode epicuticular waxes have been characterized. The mutation cer-u (69) blocks the synthesis of hydroxy-beta diketones and leads to a compensatory increase in the amount of beta-diketones, indicating that beta-diketones are precursors of the hydroxy-beta-diketones. Furthermore, highly lobed wax plates were observed for the first time on barley lemmas, in addition to the characteristic wax tubes. Both diketone classes are selectively and proportionally reduced in the spike wax of cer-i (16), which has shorter wax tubes. The three mutants cer-c (36), -q (42), and -c,u (108) synthesize neither diketone class and form no wax tubes. In contrast to the variable composition of most individual barley wax classes, only a single beta diketone was identified, namely hentriacontan-14,16-dione. PMID- 24477954 TI - The chemical composition of Ricinus phloem exudate. AB - The chemical composition of exudate obtained from incisions made in the bark of the stem of actively growing Ricinus plants has been determined. The exudate had a high dry matter content (100-125 mg/ml), a high sugar content (80-106 mg/ml) which was solely sucrose, reducing sugars being absent. The amino acid composition was mainly glutamic and aspartic acids and threonine with a total amino acid concentration of 35.2 mM. The exudate had a pH of 8.0-8.2. Potassium was the major cation (60-112 mM) with sodium present at a lower concentration (2 12 mM). Of the divalent cations, calcium was at a low concentration (0.5-2.3 mM) and magnesium relatively higher (4.5-5.4 mM). Chloride was the major inorganic anion (10-19 mM). Phosphate concentration was relatively high (3.7-5.7 mM) and low concentrations of sulphate (0.3-0.5 mM) and bicarbonate (1.7 mM) were also present. Nitrate was absent. The ionic balance was maintained by the presence of relatively large quantities (30-47 meq/l) of organic anions, mainly malate. Bioassays revealed auxin, gibberellin and cytokinin activities in chromatographed exudate. Adenosine triphosphate was found in the exudate (0.40-0.60 mM). The analysis is dicussed with respect to the composition of phloem sap reported for other plant species. PMID- 24477955 TI - [Transport of newly synthesized rRNA from the nucleus to the cytoplasm in freely suspended cells of parsley (Petroselinum sativum)]. AB - A rapidly labelled rRNA precursor can be detected in callus cells of Petroselinum sativum grown on a liquid synthetic medium. Its molecular weight has been calculated to be 2.3*10(6). This value agrees with that of the rRNA precursor from other plant material. In order to follow the synthesis and processing of rRNA in time and to correlate single steps in this process with cell organelles it was necessary to obtain pure fractions of nuclei and ribosomes. The isolation method for nuclei is given in detail. The nucleic acids are separated on polyacrylamide gels of low acrylamide concentration. Pulse-chase experiments show that the rRNA precursor is split into two fragments within the nucleus: an 18S and a 25S component. The 18S RNA leaves the nucleus rapidly. It is already found quantitatively in the ribosomal fraction after 30-60 min chase. At that time the 25S RNA is still within the nucleus; it appears much later in the ribosomes. Since the increase in ribosomal label occurs simultaneously with the decrease in nuclear label, it is concluded that there is no degradation of 18S RNA within the nucleus. Apparently there are two distinct transport mechanisms with different kinetics for the two RNA components. PMID- 24477956 TI - An investigation of the contractile protein hypothesis of phloem translocation. AB - Experiments are reported which were designed to test the hypothesis that the movement of the translocation stream is driven by the contractile activity of P protein filaments. The different types of filament found after negative staining of phloem exudates from Ricinus communis and Cucurbita pepo are described. An approximate model is proposed for the quaternary structure of a 20 nm component in the R. communis exudate. None of the filaments showed any ability to bind heavy meromyosin subfragment one. In experiments with cytochalasin B, no evidence of effects on the movement of (14)C-assimilates or on the ultrastructure of the sieve elements of Lepidium sativum was found. It is concluded that the available evidence is unfavourable to the view that P-protein resembles known contractile proteins elsewhere. PMID- 24477957 TI - [Effects of Na-fluorescein on the ultrastructure of root hairs in Lepidium sativum]. AB - Cytoplasmic disarrangements in the root hairs of Lepidium sativum caused by the vital stain Na-fluorescein (Uranine) after applications of different duration were analyzed by electron microscopy. After an application time of eight min there appear microbody-like structures and vacuoles in the cytoplasm. After a 16 min application severe disorganizations of membranes are brought about. There are distortions and dissolutions of the internal mitochondrial structures. The long cisternae of the ER are fragmented. Vesicle-like structures with a twofold border appear, which probably arise from Golgi cisternae transformed into "rings". Between the cell wall and the plasmalemma, which is masked by a substance of high contrast, vacuole-like structures are formed. As these processes coincide with the extrusion of the dye from the cytoplasm, which may be observed in the light microscope, a connection between the two phenomena is assumed, the possibility of which is discussed under the aspect of decompartimentation. PMID- 24477958 TI - Root cap and root growth. AB - The caps of the roots of Zea mays (var. Kelvedon 33) are the source of a growth inhibitor system which also acts on the root elongation of Lens culinaris. PMID- 24477959 TI - Minimal organic medium for suspension cultures of Paul's scarlet rose. AB - Maximum growth of suspension cultures of Paul's Scarlet rose has been demonstrated in a minimal organic medium possessing only 4 organic compounds: napthaleneacetic acid, kinetin, myo-inositol, and sucrose. Myo-inositol was not essential for growth, but sustained growth was reduced by 90% when it was omitted. Maximum growth required nitrate plus a supplemental amount of either NH 4 (+) or glutamine. PMID- 24477960 TI - Production of Gibberellin-like substances by an autotrophically grown Thiobacillus. AB - Gibberellin-like substances were present in cell-free culture medium of autotrophically grown Thiobacillus novellus. Dwarf-pea and cucumber-hypocotyl bioassays indicate presence of two gibberellin-like compounds. PMID- 24477961 TI - The action of nitrite on NADP reduction by intact spinach chloroplasts. AB - Isolated, intact spinach chloroplasts incubated in light in the presence of HCO 3 (-) and NO 2 (-) have the greater proportion of their NADP present in the reduced form. The steady state concentration of NADPH in light in these chloroplasts is significantly higher in the presence of NO2 than in its absence. These results invalidate earlier conclusions (Grant and Canvin, 1970) that NO 2 (-) inhibits photosynthesis by preventing NADP reduction. PMID- 24477963 TI - Antidepressant treatment patterns in younger and older adults from the general population in a real-life setting. AB - OBJECTIVE: The treatment of depression in real-life settings appears to be influenced by health care systems. Antidepressant drugs have been found to be underused in the older population relative to younger adults when refunding of such drugs is poor. No study assessed the pattern of antidepressant use according to age in a universal health care system. The objective is to assess whether the pattern of antidepressant drug use differs between younger and older adults with respect to treatment duration, adherence to treatment, coprescription of other psychotropic drugs, switch, or combination of antidepressant drugs. METHODS: A historical cohort study included 7747 older (65+ years) and 27,306 younger (younger than 65 years) adults representative of the beneficiaries of the French national health care insurance system who initiated a new antidepressant treatment. Follow-up after treatment initiation was at least 6 months. RESULTS: Older patients had a significantly longer duration of treatment than younger adults (hazard ratio = 0.90; 95%CI[0.88-0.93]). Adherence was more often good in older than in younger adults when the treatment was initiated by a general practitioner (23.4% vs. 16.7%; Odds ratio (OR) = 1.35[1.25-1.46]), a hospital practitioner (OR = 1.68[1.40-2.03]) or another specialist (OR = 1.60[1.19-2.17]). The coprescription of psychotropic drugs decreased with older age in men (OR = 0.77[0.70-0.85]) and increased with older age in women (OR = 1.14[1.07-1.22]). Switches and combinations of antidepressants were not associated with age. CONCLUSION: In a universal health care system, with similar reimbursement of drugs regardless of age, treatment duration, and adherence were better in the older patients than in the younger ones. PMID- 24477962 TI - A unique ion channel clustering domain on the axon initial segment of mammalian neurons. AB - The axon initial segment (AIS) plays a key role in initiation of action potentials and neuronal output. The plasma membrane of the AIS contains high densities of voltage-gated ion channels required for these electrical events, and much recent work has focused on defining the mechanisms for generating and maintaining this unique neuronal plasma membrane domain. The Kv2.1 voltage-gated potassium channel is abundantly present in large clusters on the soma and proximal dendrites of mammalian brain neurons. Kv2.1 is also a component of the ion channel repertoire at the AIS. Here we show that Kv2.1 clusters on the AIS of brain neurons across diverse mammalian species including humans define a noncanonical ion channel clustering domain deficient in Ankyrin-G. The sites of Kv2.1 clustering on the AIS are sites where cisternal organelles, specialized intracellular calcium release membranes, come into close apposition with the plasma membrane, and are also sites of clustering of gamma-aminobutyric acid (GABA)ergic synapses. Using an antibody specific for a single Kv2.1 phosphorylation site, we find that the phosphorylation state differs between Kv2.1 clusters on the proximal and distal portions of the AIS. Together, these studies show that the sites of Kv2.1 clustering on the AIS represent specialized domains containing components of diverse neuronal signaling pathways that may contribute to local regulation of Kv2.1 function and AIS membrane excitability. PMID- 24477964 TI - Understanding how cutaneous lupus erythematosus progresses to systemic lupus erythematosus. PMID- 24477965 TI - Selective social learning of plant edibility in 6- and 18-month-old infants. AB - Recent research underscores the importance of social learning to the development of food preferences. Here, we explore whether social information about edibility- an adult placing something in his or her mouth--can be selectively tied to certain types of entities. Given that humans have relied on gathered plant resources across evolutionary time, and given the costs of trial-and-error learning, we predicted that human infants may possess selective social learning strategies that rapidly identify edible plants. Evidence from studies with 6- and 18-month-olds demonstrated that infants selectively identify plants, over artifacts, as food sources after seeing the same food-relevant social information applied to both object types. These findings are the first evidence for content specific social learning mechanisms that facilitate the identification of edible plant resources. Evolved learning mechanisms such as these have enabled humans to survive and thrive in varied and changing environments. PMID- 24477966 TI - Geographical differences in subjective well-being predict extraordinary altruism. AB - Altruistic kidney donation is a form of extraordinary altruism, the antecedents of which are poorly understood. Although well-being is known to increase the incidence of prosocial behaviors and there is significant geographical variation in both well-being and altruistic kidney donation in the United States, it is unknown whether geographical variation in well-being predicts the prevalence of this form of extraordinary altruism. We calculated per capita rates of altruistic kidney donation across the United States and found that an index of subjective well-being predicted altruistic donation, even after we controlled for relevant sociodemographic variables. This relationship persisted at the state level and at the larger geographic regional level. Consistent with hypotheses about the relationship between objective and subjective well-being, results showed that subjective well-being mediated the relationship between increases in objective well-being metrics, such as income, and altruism. These results suggest that extraordinary altruism may be promoted by societal factors that increase subjective well-being. PMID- 24477967 TI - Platelet degranulation and glycoprotein IIbIIIa opening are not related to bleeding phenotype in severe haemophilia A patients. AB - Recently we reported data suggesting that platelets could compensate for the bleeding phenotype in severe haemophilia A (HA). The aim of this study was to confirm these results in a larger population with a detailed characterisation of clinical phenotype. Patients with diagnostic severe HA (FVIII:C <1%) were scored for clinical phenotype by integrating data on age at first joint bleed, joint damage, bleeding frequency and FVIII consumption. Phenotype was defined as onset of joint bleeding-score + arthropathy-score + joint bleeding-score + (2* treatment intensity-score). After a washout period of three days, blood was collected for measurement of basal level of platelet activation, platelet reactivity, endothelial cell activation and presence of procoagulant phospholipids in plasma. Thirty-three patients with severe HA were included, 13 patients with a mild, 12 patients with an average and eight patients with a severe clinical phenotype. No relevant differences in basal level of platelet activation, platelet reactivity, endothelial cell activation and procoagulant phospholipids between all three groups were observed. The mean annual FVIII consumption per kg did not correlate with the platelet P-selectin expression and glycoprotein (GP)IIbIIIa activation on platelets. In conclusion, variability in clinical phenotype in patients with diagnostic severe HA is not related to platelet activation or reactivity, measured as platelet degranulation and platelet GPIIbIIIa opening. PMID- 24477968 TI - Sharpening the focus on causes and timing of readmission after radical cystectomy for bladder cancer. AB - BACKGROUND: Readmissions after radical cystectomy are common, burdensome, and poorly understood. For these reasons, the authors conducted a population-based study that focused on the causes of and time to readmission after radical cystectomy. METHODS: Using Surveillance, Epidemiology, and End Results-Medicare data, at total of 1782 patients who underwent radical cystectomy from 2003 through 2009 were identified. A piecewise exponential model was used to examine reasons for readmission as well as patient and clinical factors associated with the timing of readmission. RESULTS: One in 4 patients (25.5%) were readmitted within 30 days of discharge after radical cystectomy. Compared with patients without readmission, those readmitted were similar with regard to age, sex, and race. Readmitted patients had more complications (33.8% vs 13.9%; P< .001) and were more likely to have been discharged to skilled nursing facilities from their index admission (P< .001). The average time to readmission and subsequent length of stay were 11.5 days and 6.7 days, respectively. The majority of readmissions (67.4%) occurred within 2 weeks of discharge, 66.8% had emergency department charges, and 25.9% involved intensive care unit use. Although the spectrum of reasons for readmission varied over the 4 weeks after discharge, the most common included infection (51.4%), failure to thrive (36.3%), and urinary (33.2%) and gastrointestinal (23.1%) etiologies; 95.8% of patients had >= 1 of these diagnosis groups present at the time of readmission. CONCLUSIONS: Readmissions after radical cystectomy are common and time-dependent. Interventions to prevent and reduce the readmission burden after cystectomy likely need to focus on the first 2 weeks after discharge, take into consideration the spectrum of reasons for readmission, and target high-risk individuals. PMID- 24477969 TI - Fathead minnow (Pimephales promelas Rafinesque) exposure to three novel brominated flame retardants in outdoor mesocosms: bioaccumulation and biotransformation. AB - The phaseout of polybrominated diphenyl ethers (PBDEs) has prompted the search for appropriate substitutes. These substitutes, referred to as novel brominated flame retardants (NBFRs), are poorly characterized in terms of their persistence, bioaccumulation, and toxicity. The authors assessed the bioaccumulation potential of 3 non-PBDE brominated flame retardants: 1,2-bis(2,4,6-tribromophenoxy)ethane (BTBPE), tetrabromobisphenol A bis(2,3-dibromopropylether) (TBBPA-BDBPE), and BZ 54, a mixture of bis(2-ethylhexyl)tetrabromophthalate) (BEH-TEBP) and 2 ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB). Replicate outdoor aquatic mesocosms were treated individually at concentrations designed to give a maximum load of 500 ng/g of flame retardant in the upper 5 cm of the sediment. Caged fathead minnows (Pimephales promelas, 24 fish per replicate) were introduced to each mesocosm and acclimated for 10 d prior to exposure. The exposure period was 42 d, followed by 28 d of depuration after transfer to a control mesocosm, during which physical, reproductive, and biochemical end points were examined. Tissue samples were taken to measure the accumulation, depuration, and biotransformation of NBFRs. Fathead minnows were observed to accumulate, after growth adjustment, BTBPE (16-4203 ng/g lipid) and TBBPA-BDBPE (>1000 ng/g lipid) but with a lack of consistent accumulation observed for EH-TBB and BEH-TEBP. However, limited biologically meaningful or consistent responses were observed in the monitored physical, reproductive, and biochemical parameters. Fathead minnows from each treatment exhibited several brominated transformation products. The authors conclude that these NBFRs have the potential to be bioaccumulative and persistent in vivo and, therefore, warrant further study of physiological effects linked to chronic, sublethal responses. PMID- 24477970 TI - MOOCs and SMOCs: changing the face of medical education? PMID- 24477971 TI - A blended design in acute care training: similar learning results, less training costs compared with a traditional format. AB - Introduction There is a demand for more attractive and efficient training programmes in postgraduate health care training. This retrospective study aims to show the effectiveness of a blended versus traditional face-to-face training design. For nurses in postgraduate Acute and Intensive Care training, the effectiveness of a blended course design was compared with a traditional design. Methods In a first pilot study 57 students took a traditional course (2-h lecture and 2-h workshop) and 46 students took a blended course (2-h lecture and 2-h online self-study material). Test results were compared for both groups. After positive results in the pilot study, the design was replicated for the complete programme in Acute and Intensive Care. Now 16 students followed the traditional programme (11 days face-to-face education) and 31 students did the blended programme (7 days face-to-face and 40 h online self-study). An evaluation was done after the pilot and course costs were calculated. Results Results show that the traditional and blended groups were similar regarding the main characteristics and did not differ in learning results for both the pilot and the complete programme. Student evaluations of both designs were positive; however, the blended group were more confident that they had achieved the learning objectives. Training costs were reduced substantially. Conclusion The blended training design offers an effective and attractive training solution, leading to a significant reduction in costs. PMID- 24477972 TI - Highly efficient electrocatalysts for oxygen reduction based on 2D covalent organic polymers complexed with non-precious metals. AB - A class of 2D covalent organic polymers (COPs) incorporating a metal (such as Fe, Co, Mn) with precisely controlled locations of nitrogen heteroatoms and holes were synthesized from various N-containing metal-organic complexes (for example, metal-porphyrin complexes) by a nickel-catalyzed Yamamoto reaction. Subsequent carbonization of the metal-incorporated COPs led to the formation of COP-derived graphene analogues, which acted as efficient electrocatalysts for oxygen reduction in both alkaline and acid media with a good stability and free from any methanol-crossover/CO-poisoning effects. PMID- 24477974 TI - Dyrk1a haploinsufficiency induces diabetes in mice through decreased pancreatic beta cell mass. AB - AIMS/HYPOTHESIS: Growth factors and nutrients are important regulators of pancreatic beta cell mass and function. However, the signalling pathways by which these factors modulate these processes have not yet been fully elucidated. DYRK1A (also named minibrain/MNB) is a member of the dual-specificity tyrosine phosphorylation-regulated kinase (DYRK) family that has been conserved across evolution. A significant amount of data implicates DYRK1A in brain growth and function, as well as in neurodegenerative processes in Alzheimer's disease and Down's syndrome. We investigated here whether DYRK1A would be an attractive candidate for beta cell growth modulation. METHODS: To study the role of DYRK1A in beta cell growth, we used Dyrk1a-deficient mice. RESULTS: We show that DYRK1A is expressed in pancreatic islets and provide evidence that changes in Dyrk1a gene dosage in mice strongly modulate glycaemia and circulating insulin levels. Specifically, Dyrk1a-haploinsufficient mice show severe glucose intolerance, reduced beta cell mass and decreased beta cell proliferation. CONCLUSIONS/INTERPRETATION: Taken together, our data indicate that DYRK1A is a critical kinase for beta cell growth as Dyrk1a-haploinsufficient mice show a diabetic profile. PMID- 24477975 TI - Association between variants of 5-hydroxytryptamine receptor 3C (HTR3C) and chemotherapy-induced symptoms in women receiving adjuvant treatment for breast cancer. AB - Administration of chemotherapy is associated with a wide array of symptoms affecting quality of life. Genetic risk factors for severity of chemotherapy induced symptoms have not been determined. The present study aimed to explore the associations between polymorphisms in candidate genes and chemotherapy-induced symptoms. Women treated with at least two cycles of adjuvant doxorubicin and cyclophosphamide, with or without paclitaxel for early breast cancer (n = 105) completed the memorial symptom assessment scale and provided blood for genotyping. DNA was extracted from peripheral blood leukocytes and assayed for single nucleotide polymorphisms (SNPs) in GTP cyclohydrolase 1 (GCH1, rs10483639, rs3783641, and rs8007267), catecholamine-o-methyltransferase (COMT, rs4818), and 5-hydroxytryptamine (serotonin) receptor 3C (HTR3C, rs6766410, and rs6807362). Genotyping of HTR3C revealed a significant association between the presence of rs6766410 and rs6807362 SNPs (K163 and G405 variants) and increased severity of symptoms (p = 0.0001 and p = 0.007, respectively). Multiple regressions revealed that rs6766410 and rs6807362, but not age or stage at diagnosis, predicted severity of symptoms (p = 0.001 and p = 0.006, respectively) and explained 12 % of the variance in each regression model. No association was found between the genetic variants of CGH1 or COMT and symptom score. Our study indicates, for the first time, an association between variants of HTR3C and severity of chemotherapy induced symptoms. Analyzing these genetic variants may identify patients at increased risk for the development of chemotherapy-induced symptoms and targeting the serotonin pathway may serve as a novel treatment strategy for these patients. PMID- 24477973 TI - Molecular mechanisms of diabetic cardiomyopathy. AB - In recent years, diabetes mellitus has become an epidemic and now represents one of the most prevalent disorders. Cardiovascular complications are the major cause of mortality and morbidity in diabetic patients. While ischaemic events dominate the cardiac complications of diabetes, it is widely recognised that the risk for developing heart failure is also increased in the absence of overt myocardial ischaemia and hypertension or is accelerated in the presence of these comorbidities. These diabetes-associated changes in myocardial structure and function have been called diabetic cardiomyopathy. Numerous molecular mechanisms have been proposed to contribute to the development of diabetic cardiomyopathy following analysis of various animal models of type 1 or type 2 diabetes and in genetically modified mouse models. The steady increase in reports presenting novel mechanistic data on this subject expands the list of potential underlying mechanisms. The current review provides an update on molecular alterations that may contribute to the structural and functional alterations in the diabetic heart. PMID- 24477976 TI - Long-term prognosis of early-onset breast cancer in a population-based cohort with a known BRCA1/2 mutation status. AB - All women in the South Sweden Health Care Region with breast cancer diagnosed aged less than 41 during the period between 1990 and 1995 were contacted in 1996 and offered germline mutation analysis of the BRCA1 and BRCA2 genes. Mutation carriers (n = 20) were compared with noncarriers (n = 201) for overall survival (OS) and risk of contralateral breast cancer (CBC). Mutation carriers were younger at diagnosis and more likely to have ER-negative, PgR-negative and grade III tumors. Median follow-up was 19 years. The 5-, 10-, 15-, and 20-year OS were 60, 45, 39, and 39 % for mutation carriers and 82, 70, 59, and 53 % for noncarriers, respectively (5-year log-rank P = 0.013; 10-year P = 0.008; 15-year P = 0.020; and 20-year P = 0.046). In univariable analysis, there was a trend for an inferior OS for mutation carriers (HR 1.8; 95 % CI 1.0-3.3). When stratified for use of (neo)adjuvant chemotherapy, an inferior OS was significant only for the subgroup of patients who did not receive chemotherapy (HR 3.0; 95 % CI 1.2 7.7). In multivarible analysis, BRCA1/2 mutation status was a significant predictor of OS when adjusting for tumor stage, age, and use of chemotherapy, but not when ER status was also included in the model. The 15-year cumulative risk of CBC was 53 % for mutation carriers and 10 % for noncarriers (HR 5.9; 95 % CI 1.9 18.6); among the noncarriers the risks were 5, 22, and 30 % for patients without close relatives having breast cancer, with second-degree relatives having breast cancer, and with firstdegree relatives with breast cancer, respectively. In conclusion, the poor prognosis of young BRCA1/2 mutation carriers with breast cancer is mainly explained by the prevalent occurrence of negative prognostic factors rather than mutation status per se, and can to at least some extent be abrogated by the use of chemotherapy. PMID- 24477977 TI - Reproductive risk factors and breast cancer subtypes: a review of the literature. AB - Aside from age, sex, and family history, risk of developing breast cancer is largely linked to reproductive factors, which characterize exposure to sex hormones. Given that, molecular testing at the tumor level is currently possible, clinical characterization of tumor subtypes is routinely conducted to guide treatment decisions. However, despite the vast amount of published data from observational studies on reproductive factor associations and breast cancer risk, relatively fewer reports have been published on associations specific to breast tumor subtypes. We conducted a review of the literature and summarized the results of associations between reproductive factors and risk or odds of three distinct tumor subtypes: estrogen receptor/progesterone receptor positive (hormone receptor positive, HR+ tumors), tumors overexpressing the human epidermal receptor 2 protein (HER2+), and triple negative breast cancer (TNBC), which lacks the three markers. Results show that the most consistent evidence for associations with reproductive risk factors exists for HR+ breast cancers, with nulliparity, current use of menopausal hormone therapy, and prolonged interval between menarche and age at first birth being the strongest risk factors; increased age at first birth and decreased age at menarche were fairly consistently associated with HR+ cancers; and though less consistent, older age at menopause was also positively associated, while lactation was inversely associated with HR+ tumors. Fewer consistent associations have been reported for TNBC. The single protective factor most consistently associated with TNBC was longer duration of breastfeeding. Increased parity, younger age at first birth, older age at menarche, and oral contraceptive use were less consistently shown to be associated with TNBC. No remarkable associations for HER2+ breast cancers were evident, although this was based on relatively scarce data. Findings suggest heterogeneity in reproductive risk factors for the distinct subtypes of breast tumors, which may have implications for recommended prevention strategies. PMID- 24477978 TI - Fetal renin-angiotensin-system blockade syndrome: renal lesions. AB - BACKGROUND: Fetuses exposed to angiotensin-converting enzyme inhibitors or angiotensin receptor antagonists during the second and/or third trimesters of gestation are at high risk of developing severe complications. They consist in fetal hypotension, and anuria/oligohydramnios leading to Potter sequence, frequently associated with hypocalvaria. Most fetuses die during the pre- or postnatal period, whereas others recover normal or subnormal renal function. However, the secondary occurrence of renal failure or hypertension has been reported in children after apparent complete recovery. METHODS: In this context, we analyzed renal lesions in 14 fetus/neonates who died soon after exposure to renin-angiotensin-system (RAS) blockers. Our objective was to determine the causes for the persistence or the secondary occurrence of renal complications reported in some of the survivors. RESULTS: As previously described, renal tubular dysgenesis is usually observed. Additional lesions, such as thickening of the muscular wall of arterioles and interlobular arteries, glomerular cysts, and interstitial fibrosis, develop early during fetal life. CONCLUSION: We suggest that renal lesions that develop before birth may persist after withdrawal of the causative drugs and normalization of blood and renal perfusion pressure. Their persistence could explain the severe long-term outcome of some of these patients. Long-term study of children exposed to RAS blockers during fetal life is strongly recommended. PMID- 24477979 TI - Desmopressin alone versus desmopressin and an anticholinergic in the first-line treatment of primary monosymptomatic nocturnal enuresis: a multicenter study. AB - BACKGROUND: The aim of this study was to compare the efficacy of combination therapy with desmopressin and an anticholinergic to desmopressin monotherapy for the first-line treatment of children with primary monosymptomatic nocturnal enuresis (PMNE). METHODS: A total of 98 children with PMNE (male:female 71:27) aged 5-16 (mean age 7.18 +/- 1.8) years were retrospectively analyzed. The patients were divided into two groups: the monotherapy group (n = 49) was given oral desmopressin alone, and the combination therapy group (n = 49) was given desmopressin plus an anticholinergic (propiverine 10 mg) as a first-line treatment. The two groups were matched according to the following criteria: age, gender, and baseline frequency of nocturnal enuresis. The efficacy was evaluated by International Children's Continence Society criteria at 1 and 3 months after treatment initiation. RESULTS: The combination therapy group showed a higher rate of complete response than the monotherapy group (20.4 vs. 6.1% at 1 month of treatment; 46.9 vs. 22.4% at 3 months of treatment). In terms of success (response and complete response), there was a significant difference between the two groups after 3 months of treatment (P = 0.002). CONCLUSIONS: Our results indicate that combination therapy with desmopressin plus an anticholinergic is quicker and more effective than desmopressin monotherapy in reducing PMNE. PMID- 24477981 TI - Nutritional status of patients on maintenance hemodialysis in urban sub-Saharan Africa: evidence from Cameroon. AB - BACKGROUND: Malnutrition is an important predictive factor for morbidity and mortality in patients on maintenance dialysis. The evidence on the magnitude of the problem in sub-Saharan Africa is scanty. We assessed the nutritional status of patients on maintenance hemodialysis in the renal unit of the Douala General Hospital (Cameroon). METHODS: Patients on maintenance hemodialysis for >=3 months were enrolled between March and June 2012. Nutritional status was assessed via dietary recalls, anthropometric, and biochemical measurements including body mass index (BMI), triceps skinfold thickness, mid-arm circumference, mid-arm muscle circumference (MAMC), serum albumin, C-reactive protein (CRP) and hemoglobin, calcium, phosphorus, and vitamin D. RESULTS: A total of 113 patients (75 men) were included. They were aged 49.4 years, and had been on dialysis for a median of 25 months. The mean BMI, MAMC and serum albumin was 22.4 kg/m(2), 23.7 cm and 42.4 g/l respectively. We observed that 28.3 % of patients were underweight (BMI <=20 kg/m(2)), 23.9 % had muscle wasting (MAMC < adequacy to 50th percentile), and 31.6 % had low serum albumin (<=40 g/dl), while 21 % of patients had a combination of the three abnormalities. Prevalence rates for other indicators of under-nutrition were 26.3 % (low plasma cholesterol), 28 % (positive CRP) and 82.7 % (anemia). Female gender, younger age, less meals/day and frequent vegetable intake were associated with malnutrition risk. CONCLUSIONS: Patients on maintenance hemodialysis in this setting have rates of malnutrition similar to those reported elsewhere. However, the high prevalence of malnutrition among women and young patients deserves further consideration. PMID- 24477982 TI - SN-38-cyclodextrin complexation and its influence on the solubility, stability, and in vitro anticancer activity against ovarian cancer. AB - SN-38, an active metabolite of irinotecan, is up to 1,000-fold more potent than irinotecan. But the clinical use of SN-38 is limited by its extreme hydrophobicity and instability at physiological pH. To enhance solubility and stability, SN-38 was complexed with different cyclodextrins (CDs), namely, sodium sulfobutylether beta-cyclodextrin (SBEbetaCD), hydroxypropyl beta-cyclodextrin, randomly methylated beta-cyclodextrin, and methyl beta-cyclodextrin, and their influence on SN-38 solubility, stability, and in vitro cytotoxicity was studied against ovarian cancer cell lines (A2780 and 2008). Phase solubility studies were conducted to understand the pattern of SN-38 solubilization. SN-38-betaCD complexes were characterized by differential scanning calorimetry (DSC), X-ray powder diffraction analysis (XRPD), and Fourier transform infrared (FTIR). Stability of SN-38-SBEbetaCD complex in pH 7.4 phosphate-buffered saline was evaluated and compared against free SN-38. Phase solubility studies revealed that SN-38 solubility increased linearly as a function of CD concentration and the linearity was characteristic of an AP-type system. Aqueous solubility of SN-38 was enhanced by about 30-1,400 times by CD complexation. DSC, XRPD, and FTIR studies confirmed the formation of inclusion complexes, and stability studies revealed that cyclodextrin complexation significantly increased the hydrolytic stability of SN-38 at physiological pH 7.4. Cytotoxicity of SN-38-SBEbetaCD complex was significantly higher than SN-38 and irinotecan in both A2780 and 2008 cell lines. Results suggest that SBEbetaCD encapsulated SN-38 deep into the cavity forming stable inclusion complex and as a result increased the solubility, stability, and cytotoxicity of SN-38. It may be concluded that preparation of inclusion complexes with SBEbetaCD is a suitable approach to overcome the solubility and stability problems of SN-38 for future clinical applications. PMID- 24477983 TI - Effects of cylindrospermopsin on a common carp leucocyte cell line. AB - Cylindrospermopsin (CYN) is a cytotoxin produced by different cyanobacterial species, increasingly detected in water reservoirs worldwide. There is very little information available concerning the effects of the toxin on fish immune cells. The aim of the study was to elucidate the potential impact of cylindrospermopsin on the selected parameters of a common carp (Cyprinus carpio L.) leucocyte cell line (CLC). The cells were incubated with the cyanotoxin at concentrations of 10, 1 or 0.1 ug ml(-1) for up to 48 h. Cell viability and proliferation, apoptosis/necrosis induction, cell morphology and phagocytic activity were determined. The two higher toxin concentrations occurred to be evidently cytotoxic in a time-dependent manner and influenced all studied parameters. The lowest used concentration had no effects on cell viability and cell number; however, a strong reduction of bacteria uptake after 24-h exposure was detected. The obtained results indicate that cylindrospermopsin may interfere with the basic functions of fish phagocytic cells and as a consequence influence the fish immunity. PMID- 24477984 TI - Designing injectable, covalently cross-linked hydrogels for biomedical applications. AB - Hydrogels that can form spontaneously via covalent bond formation upon injection in vivo have recently attracted significant attention for their potential to address a variety of biomedical challenges. This review discusses the design rules for the effective engineering of such materials, and the major chemistries used to form injectable, in situ gelling hydrogels in the context of these design guidelines are outlined (with examples). Directions for future research in the area are addressed, noting the outstanding challenges associated with the use of this class of hydrogels in vivo. PMID- 24477986 TI - Statin therapy is associated with the development of new-onset diabetes after transplantation in liver recipients with high fasting plasma glucose levels. AB - New-onset diabetes after transplantation (NODAT) and dyslipidemia are important metabolic complications after liver transplantation (LT) that can adversely affect both allograft and patient survival. Statins are used as first-line therapies for dyslipidemia because of their effectiveness and safety profile. However, it has recently been reported that statin therapy is associated with new onset diabetes in the nontransplant population. The aim of this study was to investigate the association between statin therapy and the development of NODAT in LT recipients. Three hundred sixty-four LT recipients who underwent transplantation between the ages of 20 and 75 years without a previous history of diabetes were enrolled in this study. We evaluated the incidence of NODAT with respect to statin use as well as other risk factors. The incidence of NODAT was significantly higher in the statin group (31.7%) versus the control group (17.6%, P = 0.03). The mean follow-up period was 37.8 +/- 19.0 months for the statin group and 42.7 +/- 16.0 months for the control group (P = 0.07). Statin use was significantly associated with NODAT development after adjustments for other risk factors [hazard ratio (HR) = 2.32, 95% confidence interval (CI) = 1.23-4.39, P = 0.01]. Impaired fasting glucose before transplantation was also a risk factor for NODAT development (HR = 2.21, 95% CI = 1.36-3.62, P = 0.001). There were no significant differences in age, body mass index, cumulative corticosteroid dose, or fasting plasma glucose (FPG) levels between the groups. Patients with high FPG levels were more likely to develop NODAT when they were placed on statins after LT (P = 0.002). In conclusion, statin treatment could contribute to the development of NODAT in LT recipients, especially if they have high baseline FPG levels. PMID- 24477987 TI - Parental smoking and allergic rhinitis in children. AB - BACKGROUND: Parental smoking is one of the controversial risk factors associated with allergic rhinitis. The aim of this study was to investigate the relationship between parental smoking and allergic rhinitis; considering confounding factors. METHODS: A cross-sectional study was conducted on 671 children aged 2 to 7 years. Random cluster sampling was used to select the participants. The signs and symptoms of allergic rhinitis in children were assessed through standard questionnaires and physical examinations. RESULTS: In the multivariate analysis, parental smoking (odds ratio [OR] 1.07; 95% confidence interval [CI], 0.48-2.41) was not a significant risk factor for allergic rhinitis; positive family history of allergy was the only significant factor among other factors (OR 23.64; 95% CI, 11.63-48.04). Sex (OR 1.16; 95% CI, 0.60-2.24), family size (OR 1.06; 95% CI, 0.22-5.05), family income (OR 0.60; 95% CI, 0.24-1.47), and parents' education (OR 1.79; 95% CI, 0.61-5.20) were not statistically significant. CONCLUSION: The findings suggest that there is no significant relationship between parental smoking and allergic rhinitis. PMID- 24477985 TI - DSCAM localization and function at the mouse cone synapse. AB - The Down syndrome cell adhesion molecule (DSCAM) is required for regulation of cell number, soma spacing, and cell type-specific dendrite avoidance in many types of retinal ganglion and amacrine cells. In this study we assay the organization of cells making up the outer plexiform layer of the retina in the absence of Dscam. Some types of OFF bipolar cells, type 3b and type 4 bipolar cells, had defects in dendrite arborization in the Dscam mutant retina, whereas other cell types appeared similar to wild type. The cone synapses that these cells project their dendrites to were intact, as visualized by electron microscopy, and had a distribution and density that was not significantly different from that of wild type. The spacing of type 3b bipolar cell dendrites was further analyzed by Voronoi domain analysis, density recovery profiling (DRP) analysis, and nearest neighbor analysis. Spacing was found to be significantly different when wild-type and mutant type 3b bipolar cell dendrites were compared. Defects in arborization of these bipolar cells could not be attributed to the disorganization of inner plexiform layer cells that occurs in the Dscam mutant retina or an increase in cell number, as they arborized when Dscam was targeted in retinal ganglion cells only or in the bax null retina. Localization of DSCAM was assayed and the protein was localized near to cone synapses in mouse, macaque, and ground squirrel retinas. DSCAM protein was detected in several types of bipolar cells, including type 3b and type 4 bipolar cells. PMID- 24477989 TI - A miniaturized solid contact test with Arthrobacter globiformis for the assessment of the environmental impact of silver nanoparticles. AB - Silver nanoparticles (AgNPs) are widely applied for their antibacterial activity. Their increasing use in consumer products implies that they will find their way into the environment via wastewater-treatment plants. The aim of the present study was to compare the ecotoxicological impact of 2 differently designed AgNPs using the solid contact test for the bacterial strain Arthrobacter globiformis. In addition, a miniaturized version of this test system was established, which requires only small-sized samples because AgNPs are produced in small quantities during the design level. The results demonstrate that the solid contact test can be performed in 24-well microplates and that the miniaturized test system fulfills the validity criterion. Soils spiked with AgNPs showed a concentration dependent reduction of Arthrobacter dehydrogenase activity for both AgNPs and Ag ions (Ag(+)). The toxic effect of the investigated AgNPs on the bacterial viability differed by 1 order of magnitude and can be related to the release of dissolved Ag(+). The release of dissolved Ag(+) can be attributed to particle size and surface area or to the fact that AgNPs are in either metallic or oxide form. Environ PMID- 24477988 TI - Immigration factors and prostate cancer survival among Hispanic men in California: does neighborhood matter? AB - BACKGROUND: Hispanics are more likely than other racial/ethnic groups in the United States to be diagnosed with later stage of prostate cancer, yet they have lower prostate cancer mortality rates. The authors evaluated the impact of nativity and neighborhood-level Hispanic ethnic enclave on prostate cancer survival among Hispanics. METHODS: A total of 35,427 Hispanic men diagnosed with invasive prostate cancer from 1995 through 2008 in the California Cancer Registry were studied; vital status data were available through 2010. Block group-level neighborhood measures were developed from US Census data. Stage-stratified Cox proportional hazards models were used to assess the effect of nativity and ethnic enclave on prostate cancer survival. RESULTS: In models adjusted for neighborhood socioeconomic status and other individual factors, foreign-born Hispanics were found to have a significantly lower risk of prostate cancer survival (hazards ratio [HR], 0.81; 95% confidence interval [95% CI], 0.75-0.87). Living in an ethnic enclave appeared to modify this effect, with the survival advantage slightly more pronounced in the high ethnic enclave neighborhoods (HR, 0.78; 95% CI, 0.71-0.86) compared with low ethnic enclave neighborhoods (HR, 0.86; 95% CI, 0.76-0.98). CONCLUSIONS: Despite lower socioeconomic status, Hispanic immigrants have better survival after prostate cancer than US-born Hispanics and this pattern was more striking among those living in ethnic enclaves. Identifying the modifiable individual and neighborhood-level factors that facilitate this survival advantage in Hispanic immigrants may help to inform specific interventions to improve survival among all patients. PMID- 24477990 TI - Awareness is essential for differential delay eyeblink conditioning with soft tone but not loud-tone conditioned stimuli. AB - The role of awareness in differential delay eyeblink conditioning (DEC) remains controversial. Here, we investigated the involvement of awareness in differential DEC with a soft or a loud tone as the conditioned stimulus (CS). In the experiment, 36 participants were trained in differential DEC with a soft tone (60 dB) or a loud tone (85 dB) as the CS, paired with a corneal air-puff as the unconditioned stimulus (US). After conditioning, awareness of the relationship between the CS and the US was assessed with a 17-item true/false questionnaire. Interestingly, during differential DEC with a soft-tone CS, a higher proportion of differential conditioned responses (CRs) was evident in participants who were aware than those who were unaware. In contrast, when a loud tone was used as the CS, the proportion of differential CRs of the aware participants did not differ significantly from those who were unaware over any of the blocks of 20 trials. In unaware participants, the percentage of differential CRs with a loud-tone CS was significantly higher than that with a soft-tone CS; however in participants classified as aware, the percentage of differential CRs with a loud-tone CS did not differ significantly from that with a soft-tone CS. The present findings suggest that awareness is critical for differential DEC when the delay task is rendered more difficult. PMID- 24477991 TI - Ephrin-B2/EphA4 forward signaling is required for regulation of radial migration of cortical neurons in the mouse. AB - Postmitotic neurons in the neocortex migrate to appropriate positions and form layered structures of nascent cortex during brain development. The migration of these neurons requires precise control and coordination of a large number of molecules such as axon guidance cues. The Eph-ephrin signaling pathway plays important roles in the development of the nervous system in a wide variety of ways, including cell segregation, axon pathfinding, and neuron migration. However, the role of ephrin-B2/EphA4 signaling in cortical neuron migration remains elusive. Here we demonstrated that ephrin-B2 and its receptor EphA4 were expressed in complementary and overlapping patterns in the developing neocortex. Deletion of the EphA4 gene in the embryonic cerebral cortex resulted in faster migration of cortical neurons, whereas knockdown or overexpression of ephrin-B2 did not alter the normal process of migration. These results suggest that ephrin B2 forward signaling through EphA4 is required for the precise control of cortical neuron migration. PMID- 24477992 TI - Oscillations in stomatal conductance and plant functioning associated with stomatal conductance: Observations and a model. AB - Measurements of transpiration, leaf water content, and flux of water in a cotton plant exhibiting sustained oscillations, in stomatal conductance are presented, and a model of the mechanism causing this behaviour is developed. The dynamic elements, of the model are capacitors-representing the change of water content with water potential in mesophyll, subsidiary and guard cells-interconnected by resistances representing flow paths in the plant. Increase of water potential in guard cells causes an increase in stomatal conductance. Increase of water potential in the subsidiary cells has the opposite effect and provides the positive feed-back which can cause stomatal conductance to oscillate. The oscillations are shown to have many of the characteristics of free-running oscillations in real plants. The behaviour of the model has been examined, using an analogue computer, with constraints and perturbations representing some of those which could be applied to real plants in physiological experiments. Aspects of behaviour which have been simulated are (a) opening and closing of stomata under the influence of changes in illumination, (b) transient responses due to step changes in potential transpiration, root permeability and potential of water surrounding the roots, (c) the influence of these factors on the occurrence and shape of spontaneous oscillations, and (d) modulation of sustained oscillations due to a circadian rhythm in the permeability of roots. PMID- 24477993 TI - An electrical analogue of evaporation from, and flow of water in plants. AB - The currents generated in the analogue circuit represent vapour loss from leaves, heat loss from leaves, and liquid flow in plant and soil. The plant and soil resistances are defined in such a way that they are consistent with the resistances to transport of vapour in the atmosphere and there is continuity of potential at the analogue liquid: air interface in the leaves. The action of the environment on plant water movement is treated as an application of Thevenin's theorem of electric circuits. PMID- 24477994 TI - Cytoplasmic particles in Tropaeolum majus. AB - Solitary (S) bodies were present in the cytoplasm of the cells of many cultivars of Tropaeolum majus. However, cultivars have also been found which completely lack these S bodies. The S bodies occur in all cells of all kinds of tissues and organs of the plant. In the anthers they occur in the cells of the endothecium tissue as well as in the tapetum layer, and even in the pollen cells. The shape of the S bodies is nearly spherical (diameter ca. 60 nm) with a tail-like appendage with a length of ca. 90-150 nm and a diameter of ca. 16 nm. The nature of the S bodies is unknown. Transmission studies by mechanical inoculation and by grafting gave no indications of a virus nature of these bodies. Reciprocal crosses between plants containing and lacking these S bodies showed that the bodies were transmitted to the progeny only if they occur in the mother plant, that is, indicated a cytoplasmic inheritance. PMID- 24477995 TI - Adventive plants from ovules and nucelli in Citrus. AB - 1- to 8-week-old ovules and nucelli from three Citrus cultivars-Shamouti and Valencia (Citrus sinensis) oranges and Marsh Seedless (C. paradisi) grapefruit were cultured in vitro. No embryo differentiation was observed in the explants prior to culture. The Shamouti ovules had degenerated and were apparently unfertilized. Embryoids formed on Murashige and Tucker nutrient medium supplemented with 500 mg/l malt extract. Whole plants developed on the same basal medium supplemented with kinetin and indole-3-acetic acid (IAA), coconut milk or gibberellic acid (GA3). A higher kinetin/IAA ratio or the addition of coconut milk favoured stem elongation more than root formation while a lower kinetin/IAA ratio favoured root formation and inhibited stem elongation. The addition of GA3 to the basal medium stimulated rooting and stem elongation. These results can be of aid in mutation research, allowing irradiation at stages prior to embryonic development. PMID- 24477996 TI - An action spectrum in the blue for inhibition of germination of lettuce seed. AB - Using a 2-h irradiation period at constant quantum irradiance, a complete action spectrum for inhibition of germination of lettuce seed has been obtained. Action maxima were near 470 and 720 nm, the latter being the most active wavelength. It was also shown, under conditions where light inhibition cannot occur, that phytochrome potentiation of germination is maximal at all wavelengths below 700 nm, including the highly active blue region. Evidence was presented for promotion of germination by a 2-h irradiation in the red which cannot be explained on the basis of conversion of phytochrome to the active form. PMID- 24477997 TI - Phytochrome-mediated induction of ascorbate oxidase in different organs of a dicotyledonous seedling (Sinapis alba L.). AB - The time courses of the level of ascorbate oxidase (AO; EC 1.10.3.3.) were followed in the different organs (cotyledons, hypocotyl, taproot) of the developing mustard seedling. Phytochrome (operationally, far-red light, cf. [20]) rapidly and strongly enhances the rate of apparent ascorbate oxidase (AO)(1) synthesis in cotyledons and hypocotyl, while in the taproot the detectable amount of AO is only small. However, the relative increase of AO as mediated by continuous far-red light is the same in all organs. Far-red -> dark kinetics indicate that the phytochrome-induced enzyme is much less stable in the hypocotyl than in the cotyledons, at least during the experimental period. It is concluded that the effect of phytochrome on enzyme induction is precisely the same in cotyledons and hypocotyl, while the processes of enzyme degradation are specific for the organ. Thus the time courses of enzyme levels can be determined by the "nature" of the particular organ, even if no isoenzymes are involved and the "mechanism" of the inductive process is the same in the different organs. PMID- 24477998 TI - Phytohemagglutinin: Transitory enhancement of growth in Phaseolus and Allium. AB - Phytohemagglutinin (Difco) stimulates germination and early seedling growth in Phaseolus coccineus, but not in Ph. vulgaris, the species from which the compound is extracted. The differences to the controls reach a maximum at day 8, then they disappear. Root growth in Allium cepa is enhanced by phytohemagglutinin during the first 12 days of treatment, but only at temperatures below 20 degrees C. PMID- 24477999 TI - Dithiothreitol: An inhibitor of glucose-6-phosphate-dehydrogenase activity in leaf extracts and isolated chloroplasts. AB - The activity of glucose-6-phosphate dehydrogenase (G-6-P-DH; D-glucose 6 phosphate: NADP oxidoreductase, EC 1.1.1.49) in leaf extracts of barley and spinach can be decreased 20-35% by incubation of the leaf extracts with dithiothreitol (DTT). This inhibition is complete within 2 min at 0 degrees C and is reversible. The DTT-inhibited portion of G-6-P-DH activity in leaf extracts is probably that portion of leaf enzyme inhibited during illumination, and evidence has been obtained that this activity is located in the chloroplasts. PMID- 24478000 TI - Outdoor thermal comfort characteristics in the hot and humid region from a gender perspective. AB - Thermal comfort is a subjective psychological perception of people based also on physiological thermoregulation mechanisms when the human body is exposed to a combination of various environmental factors including air temperature, air humidity, wind speed, and radiation conditions. Due to the importance of gender in the issue of outdoor thermal comfort, this study compared and examined the thermal comfort-related differences between male and female subjects using previous data from Taiwanese questionnaire survey. Compared with males, the results indicated that females in Taiwan are less tolerant to hot conditions and intensely protect themselves from sun exposure. Our analytical results are inconsistent with the findings of previous physiological studies concerning thermal comfort indicating that females have superior thermal physiological tolerance than males. On the contrary, our findings can be interpreted on psychological level. Environmental behavioral learning theory was adopted in this study to elucidate this observed contradiction between the autonomic thermal physiological and psychological-behavioral aspects. Women might desire for a light skin tone through social learning processes, such as observation and education, which is subsequently reflected in their psychological perceptions (fears of heat and sun exposure) and behavioral adjustments (carrying umbrellas or searching for shade). Hence, these unique psychological and behavioral phenomena cannot be directly explained by autonomic physiological thermoregulation mechanisms. The findings of this study serve as a reference for designing spaces that accommodates gender-specific thermal comfort characteristics. Recommendations include providing additional suitable sheltered areas in open areas, such as city squares and parks, to satisfy the thermal comfort needs of females. PMID- 24478001 TI - Concordant localization of functional urotensin II and urotensin II-related peptide binding sites in the rat brain: Atypical occurrence close to the fourth ventricle. AB - Urotensin II (UII) and Urotensin II-related peptide (URP) are structurally related paralog peptides that exert peripheral and central effects. UII binding sites have been partly described in brain, and those of URP have never been reported. We exhaustively compared [(125)I]-UII and -URP binding site distributions in the adult rat brain, and found that they fully overlapped at the regional level. We observed UII/URP binding sites in structures lining ventricles, comprising the sphenoid nucleus and cell rafts scattered on a line joining the fourth ventricle and its lateral recess. After injection of UII and URP in the lateral ventricle, we observed c-Fos-positive cell nuclei in areas close to the fourth ventricle, indicating that these receptors are functional. Different c-Fos-containing cell populations were activated. They were all positive for vimentin and glial fibrillary acidic protein (GFAP), excluding the possibility of an ependymal nature. In conclusion, this study demonstrated that UII and URP binding sites are totally overlapping and that these sites were functional in regions bordering the fourth ventricle. These data support a role for UII/URP at the interface between brain parenchyma and cerebrospinal fluid. PMID- 24478004 TI - Landscaping plant epigenetics. AB - The understanding of epigenetic mechanisms is necessary for assessing the potential impacts of epigenetics on plant growth, development and reproduction, and ultimately for the response of these factors to evolutionary pressures and crop breeding programs. This volume highlights the latest in laboratory and bioinformatic techniques used for the investigation of epigenetic phenomena in plants. Such techniques now allow genome-wide analyses of epigenetic regulation and help to advance our understanding of how epigenetic regulatory mechanisms affect cellular and genome function. To set the scene, we begin with a short background of how the field of epigenetics has evolved, with a particular focus on plant epigenetics. We consider what has historically been understood by the term "epigenetics" before turning to the advances in biochemistry, molecular biology, and genetics which have led to current-day definitions of the term. Following this, we pay attention to key discoveries in the field of epigenetics that have emerged from the study of unusual and enigmatic phenomena in plants. Many of these phenomena have involved cases of non-Mendelian inheritance and have often been dismissed as mere curiosities prior to the elucidation of their molecular mechanisms. In the penultimate section, consideration is given to how advances in molecular techniques are opening the doors to a more comprehensive understanding of epigenetic phenomena in plants. We conclude by assessing some opportunities, challenges, and techniques for epigenetic research in both model and non-model plants, in particular for advancing understanding of the regulation of genome function by epigenetic mechanisms. PMID- 24478002 TI - Sclerocornea in a patient with van den Ende-Gupta syndrome homozygous for a SCARF2 microdeletion. AB - Van den Ende-Gupta Syndrome (VDEGS) is an autosomal recessive disorder characterized by blepharophimosis, distinctive nose, hypoplastic maxilla, and skeletal abnormalities. Using homozygosity mapping in four VDEGS patients from three consanguineous families, Anastacio et al. [Anastacio et al. (2010); Am J Hum Genet 87:553-559] identified homozygous mutations in SCARF2, located at 22q11.2. Bedeschi et al. [2010] described a VDEGS patient with sclerocornea and cataracts with compound heterozygosity for the common 22q11.2 microdeletion and a hemizygous SCARF2 mutation. Because sclerocornea had been described in DiGeorge velo-cardio-facial syndrome but not in VDEGS, they suggested that the ocular abnormalities were caused by the 22q11.2 microdeletion. We report on a 23-year old male who presented with bilateral sclerocornea and the VDGEGS phenotype who was subsequently found to be homozygous for a 17 bp deletion in exon 4 of SCARF2. The occurrence of bilateral sclerocornea in our patient together with that of Bedeschi et al., suggests that the full VDEGS phenotype may include sclerocornea resulting from homozygosity or compound heterozygosity for loss of function variants in SCARF2. PMID- 24478005 TI - The Gene Balance Hypothesis: dosage effects in plants. AB - The concept of genomic balance traces to the early days of genetics. In recent years, studies of gene expression have found parallels to the classical phenotypic studies in that aneuploid changes have greater effects than whole genome changes. This has an explanation in terms of potential stoichiometric imbalances of the gene products encoded in the aneuploid regions. Studies of transcriptional factor mutations indicated that they tend to be haplo insufficient as heterozygotes. Molecular evolution studies found that genes encoding members of macromolecular complexes were preferentially retained following polyploidy and underrepresented in copy number variants. In this review chapter, we synthesize these observations under the rubric of the Gene Balance Hypothesis. PMID- 24478006 TI - High-throughput RNA-seq for allelic or locus-specific expression analysis in Arabidopsis-related species, hybrids, and allotetraploids. AB - With the next generation sequencing technology, RNA-Seq (RNA sequencing) becomes one of the most powerful tools in quantification of global transcriptomes, discovery of new transcripts and alternative isoforms, as well as detection of single nucleotide polymorphisms (SNPs). RNA-Seq is advantageous over hybridization-based gene quantification methods: (1) it does not require prior information about genomic sequences, (2) it avoids high background problem caused by cross-hybridization, and (3) it is highly sensitive and avoids background and saturation of signals; and finally it is capable of detecting allelic expression differences in hybrids and allopolyploids. We used the RNA-Seq method to determine the genome-wide transcriptome changes in Arabidopsis allotetraploids and their parents, A. thaliana and A. arenosa. The use of this approach allows us to quantify transcriptome from these species and more importantly, to identify allelic or homoeologous-specific gene expression that plays a role in morphological evolution of allopolyploids. The computational pipelines developed are also applicable to the analysis of chromatin immunoprecipitation sequencing (ChIP-seq) data in Arabidopsis-related species, hybrids, and allopolyploids. Comparative analysis of RNA-Seq and ChIP-Seq data will allow us to determine the effects of chromatin modifications on nonadditive gene expression in hybrids and allopolyploids. PMID- 24478007 TI - Inference of allele-specific expression from RNA-seq data. AB - The differential abundance of transcripts from alternative alleles of a gene, for example in a hybrid plant or an outbred natural population, can provide information about the nature of interindividual or interstrain variation in gene expression. Allele-specific expression (ASE) can result from epigenetic phenomena, such as imprinting (when the overexpressed allele is inherited consistently from one parent) or allele-specific chromatin modifications. Alternatively, DNA sequence variants in the promoter or within the transcribed region of a gene can affect the rate of transcription or the rate of decay of the transcript, respectively. The existence of this allelic variation and the insights it provides into the nature of the gene regulation are of significant interest. With the recent widespread availability of sequencing based transcriptomics, the power to detect ASE has increased; however, inference of ASE from transcriptome sequencing data is subject to several caveats and potential biases and the results need to be interpreted with care. PMID- 24478008 TI - Screening for imprinted genes using high-resolution melting analysis of PCR amplicons. AB - High-resolution melting (HRM) analysis is a technique that enables researchers to detect polymorphisms in DNA molecules based on different melting profiles and is becoming widely used as a method for detecting SNPs in genomic DNA. In this chapter, we describe how HRM analysis can be used to detect allelic imbalances typical of imprinted genes, where alleles are differentially expressed based on their parent of origin. This involves first producing hybrid seed using parental plants that have sufficient genetic differences to distinguish the parental origin of each allele of the candidate genes. RNA is then isolated from the hybrid seed and converted to cDNA. PCR amplicons are produced using primers designed to span a polymorphic sequence within the transcript of the candidate gene. By using a real-time PCR machine with HRM analysis capability, the PCR amplicons can be analyzed without further manipulations directly after amplification to detect instances of strong allelic imbalance and parent-of origin-dependent expression. PMID- 24478009 TI - Analysis of genomic imprinting by quantitative allele-specific expression by Pyrosequencing((r)). AB - Genomic imprinting is a parent-of-origin phenomenon whereby gene expression is restricted to the allele inherited from either the maternal or paternal parent. It has been described from flowering plants and eutherian mammals and may have evolved due to parental conflicts over resource allocation. In mammals, imprinted genes are responsible for ensuring correct rates of embryo development and for preventing parthenogenesis. The molecular basis of imprinting depends upon the presence of differential epigenetic marks on the alleles inherited from each parent, although in plants the exact mechanisms that control imprinting are still unclear in many cases. Recent studies have identified large numbers of candidate imprinted genes from Arabidopsis thaliana and other plants (see Chap. 7 by Kohler and colleagues elsewhere in this volume) providing the tools for more thorough investigation into how imprinted gene networks (IGNs) are regulated. Analysis of genomic imprinting in animals has revealed important information on how IGNs are regulated during development, which often involves intermediate levels of imprinting. In some instances, small but significant changes in the degree of parental bias in gene expression have been linked to developmental traits, livestock phenotypes, and human disease. As some of the imprinted genes recently reported from plants show differential rather than complete (binary) imprinting, there is a clear need for tools that can quantify the degree of allelic expression bias occurring at a transcribed locus. In this chapter, we describe the use of Quantification of Allele-Specific Expression by Pyrosequencing((r)) (QUASEP) as a tool suitable for this challenge. We describe in detail the factors which ensure that a Pyrosequencing((r)) assay will be suitable for giving robust QUASEP and the problems which may be encountered during the study of imprinted genes by Pyrosequencing((r)), with particular reference to our work in A. thaliana and in cattle. We also discuss some considerations with respect to the statistical analysis of the resulting data. Finally, we provide a brief overview of the future possibility of adapting Pyrosequencing((r)) for analyzing other aspects of imprinting including the analysis of methylated regions. PMID- 24478010 TI - Endosperm-specific chromatin profiling by fluorescence-activated nuclei sorting and ChIP-on-chip. AB - Cell-type-specific analysis of gene expression and chromatin profiling requires the isolation of discrete cell populations from complex pools. However, until now this most critical step has been labor intensive and technical challenging. Here, we describe a rapid protocol based on fluorescence-activated cell sorting (FACS) for cell-type-specific RNA and chromatin profiling. We detail how to isolate nuclei from Arabidopsis inflorescence and silique homogenates and how to purify endosperm nuclei labeled by nuclear-targeted green fluorescent protein using FACS. The purified fluorescent endosperm nuclei can be further used for chromatin immunoprecipitation (ChIP) followed by hybridization to high-resolution whole genome tiling microarrays (ChIP-on-chip) or transcriptional profiling. PMID- 24478011 TI - Imaging sexual reproduction in Arabidopsis using fluorescent markers. AB - Sexual reproduction in higher plants is a stealth process as most events occur within tissues protected by multiple surrounding cell layers. Female gametes are produced inside the embryo sac surrounded by layers of ovule integument cells. Upon double fertilization, two male gametes are released at one end of the embryo sac and migrate towards their respective female partner to generate the embryo and its feeding tissue, the endosperm, within a seed. Since the early discovery of plant reproduction, advances in microscopy have contributed enormously to our understanding of this process (Faure and Dumas, Plant Physiol 125:102-104, 2001). Recently, live imaging of double fertilization has been possible using a set of fluorescent markers for gametes in Arabidopsis. The following chapter will detail protocols to study male and female gametogenesis and double fertilization in living tissues using fluorescent markers. PMID- 24478012 TI - Genome-wide analysis of DNA methylation in Arabidopsis using MeDIP-chip. AB - DNA methylation is an epigenetic mark that is essential for preserving genome integrity and normal development in plants and mammals. Although this modification may serve a variety of purposes, it is best known for its role in stable transcriptional silencing of transposable elements and epigenetic regulation of some genes. In addition, it is increasingly recognized that alterations in DNA methylation patterns can sometimes be inherited across multiple generations and thus are a source of heritable phenotypic variation that is independent of any DNA sequence changes. With the advent of genomics, it is now possible to analyze DNA methylation genome-wide with high precision, which is a prerequisite for understanding fully the various functions and phenotypic impact of this modification. Indeed, several so-called epigenomic mapping methods have been developed for the analysis of DNA methylation. Among these, immunoprecipitation of methylated DNA followed by hybridization to genome tiling arrays (MeDIP-chip) arguably offers a reasonable compromise between cost, ease of implementation, and sensitivity to date. Here we describe the application of this method, from DNA extraction to data analysis, to the study of DNA methylation genome-wide in Arabidopsis. PMID- 24478013 TI - Methylation-sensitive amplified polymorphism (MSAP) marker to investigate drought stress response in Montepulciano and Sangiovese grape cultivars. AB - Methylation-sensitive amplified polymorphism (MSAP) is a technique developed for assessing the extent and pattern of cytosine methylation and has been applied to genomes of several species (Arabidopsis, grape, maize, tomato, and pepper). The technique relies on the use of isoschizomers that differ in their sensitivity to methylation. PMID- 24478014 TI - Detecting histone modifications in plants. AB - Histone modifications play an essential role in chromatin-associated processes including gene regulation and epigenetic inheritance. It is therefore very important to quantitatively analyze histone modifications at both the single gene and whole genome level. Here, we describe a robust chromatin immunoprecipitation (ChIP) method for Arabidopsis, which could be adapted for other plant species. This method is compatible with multiple downstream applications including qPCR, tilling arrays, and high-throughput sequencing. PMID- 24478015 TI - Quantitatively profiling genome-wide patterns of histone modifications in Arabidopsis thaliana using ChIP-seq. AB - Genome-wide quantitative profiling of chromatin modifications is a critical experimental approach to study epigenetic and transcriptional control mechanisms. Since first being reported in 2007, chromatin immunoprecipitation followed by high-throughput sequencing (ChIP-seq) has soon became a popular method-of-choice for profiling chromatin modifications and transcription factor-binding sites in eukaryote genomes. ChIP-seq has the advantage over the earlier ChIP-chip approach in multiple aspects including the lower amount of input DNA required, an expanded dynamic range and compatibility with sample multiplexing. Here we describe a detailed protocol for profiling histone modification in the Arabidopsis thaliana genome with ChIP-seq using the SOLiDTM 2.0 high-throughput sequencing platform. As read length and sequencing depth are two critical factors determining data quality and cost, we have developed bioinformatics approach to evaluate the effect of read length and sequencing depth on the alignment accuracy and the generated chromatin profile, respectively. Our analyses suggest that 2-3 million high quality sequencing tags with a read length of 35 nucleotides would be sufficient to profile the majority of histone modifications in this popular model plant species. PMID- 24478016 TI - Analysis of retrotransposon activity in plants. AB - Retrotransposons are transposable elements that duplicate themselves by converting their transcribed RNA genome into cDNA, which is then integrated back into the genome. Retrotransposons can be divided into two major classes based on their mechanism of transposition and the presence or absence of long terminal repeats (LTRs). In contrast to mammalian genomes, in which non-LTR retrotransposons have proliferated, plant genomes show evolutionary evidence of an explosion in LTR retrotransposon copy number. These retrotransposons can comprise a large fraction of the genome (75 % in maize). Although often viewed as molecular parasites, retrotransposons have been shown to influence neighboring gene expression and play a structural and potential regulatory role in the centromere. To prevent retrotransposon activity, eukaryotic cells have evolved overlapping mechanisms to repress transposition. Plants are an excellent system for studying the mechanisms of LTR retrotransposon inhibition such as DNA methylation and small RNA-mediated degradation of retrotransposon transcripts. However, analysis of these multi-copy, mobile elements is considerably more difficult than analysis of single-copy genes located in stable regions of the genome. In this chapter we outline methods for analyzing the progress of LTR retrotransposons through their replication cycle in plants. We describe a mixture of traditional molecular biology experiments, such as Southern, Northern, and Western blotting, in addition to nontraditional techniques designed to take advantage of the specific mechanism of LTR retrotransposition. PMID- 24478017 TI - Detecting epigenetic effects of transposable elements in plants. AB - Transposable elements (TE) represent a major fraction of eukaryotic genomes and play many roles in plant epigenetics. In this chapter, we describe the use of Sequence-Specific Amplified Polymorphism (SSAP) as a reliable Transposon Display technique applicable for use in many plant species. We also discuss the interpretation of SSAP data and associated risks. This technique has potential to allow rapid screening of plant populations, especially in nonmodel or wild species. PMID- 24478018 TI - Detection and investigation of transitive gene silencing in plants. AB - RNA-induced post-transcriptional silencing is a common tool in functional gene analysis and its application in crop improvement is widely investigated. However, its specificity might be impaired by off-target silencing as a result of transitivity. Generally transitivity is investigated by the detection of secondary siRNAs; however, these tests fail to demonstrate the siRNA's bioactivity. Here, we describe protocols to detect the occurrence of transitive silencing across an endogene by using a reporter GUS gene. In addition, we provide a setup to test the influence of a sequence of interest present in the primary target on the progression of transitivity. PMID- 24478019 TI - Clinical implications of preoperative and intraoperative liver biopsies for evaluating donor steatosis in living related liver transplantation. AB - The role of liver biopsy in selecting optimal donors is an area of continuing controversy in living donor liver transplantation (LDLT). Our aim was to assess the potential implications of preoperative and intraoperative biopsies for evaluating donor liver fat content. Three thousand eight hundred fifty-nine consecutive subjects underwent predonation needle biopsy of the right lobe, and 1766 of these subjects actually donated their livers for LDLT and underwent intraoperative wedge biopsies of paired right and left lobes. The preoperative workup protocol also included abdominal ultrasonography (USG) and computed tomography (CT). Intersample agreement on steatosis grades (<5%, 5% to <15%, 15% to <30%, and >=30%) was calculated, and clinicometabolic factors related to sampling variability were evaluated. For detecting >=30% steatosis in the 3859 potential donors, USG and CT had sensitivities of 84.9% and 57.3%, specificities of 76.3% and 92.7%, positive predictive values of 29.6% and 48.0%, and negative predictive values of 97.7% and 94.8%, respectively. Analyses of the 1766 actual donors showed that with respect to the total steatosis grades of intraoperative right and left biopsies versus preoperative biopsy, 36.7% and 36.0% of the pairs, respectively, differed from the weighted kappa values of 0.44 and 0.40. Similar agreement levels existed for macrovesicular and microvesicular steatosis subtypes. The per-subject agreement rate for the total steatosis grade between intraoperative right and left biopsies was 83.6%. According to a multivariate analysis, independent factors affecting the variability of the total steatosis results from preoperative and intraoperative biopsies (major features) were higher systolic blood pressure, body mass index, and alanine aminotransferase values and lower high-density lipoprotein cholesterol values. In conclusion, imaging may be insufficiently sensitive for evaluating donor hepatic steatosis. Preoperative and selective intraoperative liver biopsies are mandatory for assessing donor steatosis in LDLT unless preoperative imaging demonstrates no fat. PMID- 24478020 TI - Cholera outbreaks in South-East Asia. AB - This chapter highlights the cholera situation in South Asia and the Bay of Bengal region, the original 'homeland' of cholera. A detailed discussion of cholera outbreaks in individual countries in South-East Asia follows. The countries of the World Health Organization (WHO) SEARO (South-East Asia Region) region are discussed first, followed by discussions about the other countries in South-East Asia that do not fall within the purview of the WHO SEARO classification of the member countries of the region. Therefore, the chapter attempts to provide a comprehensive yet precise outline of the major cholera outbreaks that have occurred in the region over the years. PMID- 24478021 TI - Hierarchical diagnostic classification models: a family of models for estimating and testing attribute hierarchies. AB - Although latent attributes that follow a hierarchical structure are anticipated in many areas of educational and psychological assessment, current psychometric models are limited in their capacity to objectively evaluate the presence of such attribute hierarchies. This paper introduces the Hierarchical Diagnostic Classification Model (HDCM), which adapts the Log-linear Cognitive Diagnosis Model to cases where attribute hierarchies are present. The utility of the HDCM is demonstrated through simulation and by an empirical example. Simulation study results show the HDCM is efficiently estimated and can accurately test for the presence of an attribute hierarchy statistically, a feature not possible when using more commonly used DCMs. Empirically, the HDCM is used to test for the presence of a suspected attribute hierarchy in a test of English grammar, confirming the data is more adequately represented by hierarchical attribute structure when compared to a crossed, or nonhierarchical structure. PMID- 24478022 TI - Hierarchical diagnostic classification models morphing into unidimensional 'diagnostic' classification models-a commentary. AB - This commentary addresses the modeling and final analytical path taken, as well as the terminology used, in the paper "Hierarchical diagnostic classification models: a family of models for estimating and testing attribute hierarchies" by Templin and Bradshaw (Psychometrika, doi: 10.1007/s11336-013-9362-0, 2013). It raises several issues concerning use of cognitive diagnostic models that either assume attribute hierarchies or assume a certain form of attribute interactions. The issues raised are illustrated with examples, and references are provided for further examination. PMID- 24478023 TI - The use and misuse of psychometric models. PMID- 24478024 TI - Gene-dosage dependent overexpression at the 13q amplicon identifies DIS3 as candidate oncogene in colorectal cancer progression. AB - Colorectal cancer (CRC) development is in most cases marked by the accumulation of genomic alterations including gain of the entire q-arm of chromosome 13. This aberration occurs in 40%-60% of all CRC and is associated with progression from adenoma to carcinoma. To date, little is known about the effect of the 13q amplicon on the expression of the therein located genes and their functional relevance. We therefore aimed to identify candidate genes at the 13q amplicon that contribute to colorectal adenoma to carcinoma progression in a gene dosage dependent manner. Integrative analysis of whole genome expression and DNA copy number signatures resulted in the identification of 36 genes on 13q of which significant overexpression in carcinomas compared with adenomas was linked to a copy number gain. Five genes showing high levels of overexpression in carcinomas versus adenomas were further tested by quantitative reverse transcription-PCR in two independent sample sets of colorectal tumors (n = 40 and n = 47). DIS3 and LRCH1 revealed significant overexpression in carcinomas compared with adenomas in a 13q gain dependent manner. Silencing of DIS3 affected important tumorigenic characteristics such as viability, migration, and invasion. In conclusion, significant overexpression of DIS3 and LRCH1 associated with adenoma to carcinoma progression is linked to the CRC specific gain of 13q. The functional relevance of this copy number aberration was corroborated for DIS3, thereby identifying this gene as novel candidate oncogene contributing to the 13q-driven adenoma to carcinoma progression. PMID- 24478025 TI - Crystal structure of metallo DNA duplex containing consecutive Watson-Crick-like T-Hg(II)-T base pairs. AB - The metallo DNA duplex containing mercury-mediated T-T base pairs is an attractive biomacromolecular nanomaterial which can be applied to nanodevices such as ion sensors. Reported herein is the first crystal structure of a B-form DNA duplex containing two consecutive T-Hg(II)-T base pairs. The Hg(II) ion occupies the center between two T residues. The N3-Hg(II) bond distance is 2.0 A. The relatively short Hg(II)-Hg(II) distance (3.3 A) observed in consecutive T Hg(II)-T base pairs suggests that the metallophilic attraction could exist between them and may stabilize the B-form double helix. To support this, the DNA duplex is largely distorted and adopts an unusual nonhelical conformation in the absence of Hg(II). The structure of the metallo DNA duplex itself and the Hg(II) induced structural switching from the nonhelical form to the B-form provide the basis for structure-based design of metal-conjugated nucleic acid nanomaterials. PMID- 24478026 TI - The effects of suicide prevention measures reported through a psychoeducational video: a practice in Japan. AB - BACKGROUND: As the suicide rate in Japan has remained high since 1998, various suicide prevention measures have been implemented in Japanese local communities. AIMS: To report our findings on the effect of a psychoeducational video as a suicide prevention measure in a Japanese rural town. METHODS: Questionnaires were randomly mailed to 2,000 residents aged between 30 and 79 years. Within 4 weeks, volunteers in the town visited the residents individually and collected the questionnaires. The variables reported in this study are demographics, awareness of suicide prevention measures available in the town, whether the residents watched the video, help-seeking from advisers regarding suicidal ideation and financial problems and attitudes towards suicide. RESULTS: We analysed data collected from 1,118 people who reported their demographics (i.e. sex, age, and job) and whether they had watched the video. By conducting a series of logistic regression and multiple regression analyses and controlling for demographic variables, we found that watching the video had substantial psychoeducational effects. CONCLUSION: Despite conducting a cross-sectional study, our new suicide prevention measures were considered effective for psychoeducation. However, further studies using a longitudinal design are needed. PMID- 24478027 TI - Reversible hepatic decompensation following cessation of antiretroviral therapy in a patient with HIV and hepatitis C co-infection. AB - We report the case of 47-year-old man with HIV and hepatitis C virus-associated cirrhosis who, following discontinuation of his antiretroviral therapy (ART), rapidly developed hepatic decompensation. On restarting his ART there was a noticeable improvement in his liver function, which was attributed to regaining good HIV virus control. Further data on the effects of restarting ART after ART cessation-associated hepatic decompensation are needed. PMID- 24478028 TI - Tension pneumoperitoneum. PMID- 24478029 TI - A rare cause for a shortened tingly finger. PMID- 24478030 TI - Paternal exposure to testis cancer chemotherapeutics alters sperm fertilizing capacity and affects gene expression in the eight-cell stage rat embryo. AB - Treatment of testicular cancer includes the coadministration of bleomycin, etoposide and cis-platinum (BEP); however, along with its therapeutic benefit, BEP exposure results in extensive reproductive chemotoxic effects, including alterations to sperm chromatin integrity. As an intact paternal genome is essential for successful fertilization and embryogenesis, we assessed the effect of paternal exposure to BEP on sperm fertilization capacity and the resulting consequences on early embryonic gene expression. Adult male Brown Norway rats received a 9-week treatment with BEP or saline and then were sacrificed immediately or subject to a 9-week recovery period. HSP90AA1, HSP90B1 and PDIA3, involved in spermatozoa-egg interactions, were overexpressed in BEP-exposed spermatozoa after the 9-week treatment period; overexpression was also observed in spermatozoa from BEP-treated rats after 9 weeks of recovery. These proteins were localized to the plasma membrane of the sperm head; this localization may facilitate their role in spermatozoa-egg interactions as the highest staining intensities were observed in capacitated spermatozoa. The fertilization potential of spermatozoa was determined by in vitro fertilization with oocytes from unexposed naturally cycling female rats. Interestingly, the fertilization potential of spermatozoa following a 9-week recovery period from BEP treatment was significantly enhanced compared with controls. Moreover, stem cell transcription factors, involved in the regulation of a plethora of early embryonic events, were upregulated by more than twofold in eight-cell stage embryos sired by BEP recovery males compared with controls; this suggests that there are potential deleterious effects on embryo development well after termination of BEP exposure. PMID- 24478031 TI - New generation lipid emulsions prevent PNALD in chronic parenterally fed preterm pigs. AB - Total parenteral nutrition (TPN) is associated with the development of parenteral nutrition-associated liver disease (PNALD) in infants. Fish oil-based lipid emulsions can reverse PNALD, yet it is unknown if they can prevent PNALD. We studied preterm pigs administered TPN for 14 days with either 100% soybean oil (IL), 100% fish oil (OV), or a mixture of soybean oil, medium chain triglycerides (MCTs), olive oil, and fish oil (SL); a group was fed formula enterally (ENT). In TPN-fed pigs, serum direct bilirubin, gamma glutamyl transferase (GGT), and plasma bile acids increased after the 14 day treatment but were highest in IL pigs. All TPN pigs had suppressed hepatic expression of farnesoid X receptor (FXR), cholesterol 7-hydroxylase (CYP7A1), and plasma 7alpha-hydroxy-4-cholesten 3-one (C4) concentrations, yet hepatic CYP7A1 protein abundance was increased only in the IL versus ENT group. Organic solute transporter alpha (OSTalpha) gene expression was the highest in the IL group and paralleled plasma bile acid levels. In cultured hepatocytes, bile acid-induced bile salt export pump (BSEP) expression was inhibited by phytosterol treatment. We show that TPN-fed pigs given soybean oil developed cholestasis and steatosis that was prevented with both OV and SL emulsions. Due to the presence of phytosterols in the SL emulsion, the differences in cholestasis and liver injury among lipid emulsion groups in vivo were weakly correlated with plasma and hepatic phytosterol content. PMID- 24478032 TI - TG-interacting factor 1 acts as a transcriptional repressor of sterol O acyltransferase 2. AB - Acat2 [gene name: sterol O-acyltransferase 2 (SOAT2)] esterifies cholesterol in enterocytes and hepatocytes. This study aims to identify repressor elements in the human SOAT2 promoter and evaluate their in vivo relevance. We identified TG interacting factor 1 (Tgif1) to function as an important repressor of SOAT2. Tgif1 could also block the induction of the SOAT2 promoter activity by hepatocyte nuclear factor 1alpha and 4alpha. Women have ~ 30% higher hepatic TGIF1 mRNA compared with men. Depletion of Tgif1 in mice increased the hepatic Soat2 expression and resulted in higher hepatic lipid accumulation and plasma cholesterol levels. Tgif1 is a new player in human cholesterol metabolism. PMID- 24478034 TI - Correlating habenular subnuclei in rat and mouse by using topographic, morphological, and cytochemical criteria. AB - The mammalian habenulae consist of medial (MHb) and lateral (LHb) nuclear complexes. Especially the LHb has received much interest because it has been recognized as the potential center of an "anti-reward system." Subnuclear organization and connectivity of the LHb are well known. In contrast, criteria to classify habenular neurons into distinct groups with potentially different biological functions are missing, most likely as a result of the lack of appropriate marker proteins. Actually, a huge amount of data concerning the localization of more than 20,000 mouse protein genes is provided in the Allen Brain Atlas. Unfortunately, the immediate use of this information is prohibited by the fact that the subnuclear organization of the habenular complexes in mouse is not known so far. The present report, therefore, uses topographic, structural, and cytochemical information from the rat to recognize corresponding areas within the mouse habenulae. Taking advantage of the fact that the Kluver-Barrera technique allows simultaneous observation of neuronal cell bodies and myelinated fibers, we were able to correlate subnuclear areas in the mouse habenula to subnuclei, which had been rigorously identified by several criteria in the rat. Our data suggest that the topographic localization of habenular subnuclei is rather similar between mouse and rat and that they may be homologous in these two species. Consequently, our data may allow using the Allen Brain Atlas as a source of basal information, which should be helpful to select candidate molecular markers for functionally different neurons in the mouse and potentially in higher mammalian species. PMID- 24478033 TI - Inhibition of plasminogen activation by apo(a): role of carboxyl-terminal lysines and identification of inhibitory domains in apo(a). AB - Apo(a), the distinguishing protein component of lipoprotein(a) [Lp(a)], exhibits sequence similarity to plasminogen and can inhibit binding of plasminogen to cell surfaces. Plasmin generated on the surface of vascular cells plays a role in cell migration and proliferation, two of the fibroproliferative inflammatory events that underlie atherosclerosis. The ability of apo(a) to inhibit pericellular plasminogen activation on vascular cells was therefore evaluated. Two isoforms of apo(a), 12K and 17K, were found to significantly decrease tissue-type plasminogen activator-mediated plasminogen activation on human umbilical vein endothelial cells (HUVECs) and THP-1 monocytes and macrophages. Lp(a) purified from human plasma decreased plasminogen activation on THP-1 monocytes and HUVECs but not on THP-1 macrophages. Removal of kringle V or the strong lysine binding site in kringle IV10 completely abolished the inhibitory effect of apo(a). Treatment with carboxypeptidase B to assess the roles of carboxyl-terminal lysines in cellular receptors leads in most cases to decreases in plasminogen activation as well as plasminogen and apo(a) binding; however, inhibition of plasminogen activation by apo(a) was unaffected. Our findings directly demonstrate that apo(a) inhibits pericellular plasminogen activation in all three cell types, although binding of apo(a) to cell-surface receptors containing carboxyl-terminal lysines does not appear to play a major role in the inhibition mechanism. PMID- 24478035 TI - Clinical utility of serum cystatin C in predicting coronary artery disease in patients without chronic kidney disease. AB - BACKGROUND: Cystatin C has been proposed as a novel marker of renal function and predictor of cardiovascular risk. The aim of this study was to investigate the role of cystatin C level as a predictor of cardiovascular events in patients with coronary artery disease (CAD). METHODS: Three hundred and five coronary artery patients were included in this study. Serum cystatin C levels, high-sensitive C reactive protein (hs-CRP), and oxidative stress were measured. Estimated glomerular filtration rate (eGFR) and the CAD severity score were calculated. RESULTS: Cystatin C was correlated with the CAD severity score (r = 0.631, P < 0.0001) and was significantly elevated in the CAD severity score >50. Every 0.1 mg/l increase in cystatin C, 2 mg/l increase in hs-CRP, 0.2 mmol/l decrease in high-density lipoprotein cholesterol, 13.7 ml/min decrease in eGFR, and 1.51 MUmol/l increase in homocysteine caused a 34, 12, 5, and 22% increase in the risk of having CAD, respectively. CONCLUSION: Cystatin C could be a useful laboratory biochemical marker in predicting the severity of CAD. Cystatin C is associated with biochemical atherosclerosis markers such as CRP and homocysteine. PMID- 24478036 TI - PDP1 regulates energy metabolism through the IIS-TOR pathway in the red flour beetle, Tribolium castaneum. AB - The PAR-domain protein 1 (PDP1) is essential for locomotor activity of insects. However, its functions in insect growth and development have not been studied extensively, which prompted our hypothesis that PDP1 acts in energy metabolism. Here we report identification of TcPDP1 in the red flour beetle, Tribolium castaneum, and its functional analysis by RNAi. Treating larvae with dsTcPDP1 induced pupae developmental arrestment, accompanied by accelerated fat body degradation. dsTcPDP1 treatments in adults resulted in reduced female fecundity. Disruption of TcPDP1 expression affected the transcription of genes involved in insulin signaling transduction and mechanistic target of rapamycin (mTOR) pathway. These results support our hypothesis that TcPDP1 acts in energy metabolism in T. castaneum. PMID- 24478038 TI - Adult hippocampal neurogenesis in depression: behavioral implications and regulation by the stress system. AB - Adult hippocampal neurogenesis, the birth of new neurons in the dentate gyrus of the adult brain, can be regulated by stress and antidepressant treatment, and has consistently been implicated in the behavioral neurobiology of stress-related disorders, especially depression and anxiety. A reciprocal relationship between hippocampal neurogenesis and the hypothalamus-pituitary-adrenal (HPA) axis has recently been suggested, which may play a crucial role in the development and in the resolution of depressive symptoms. This chapter will review some of the existing evidence for stress- and antidepressant-induced changes in adult hippocampal neurogenesis, and critically evaluate the behavioral effects of these changes for depression and anxiety. The potential role of neurogenesis as a neurobiological mechanism for sustained remission from depressive symptoms will be discussed, integrating existing data from clinical studies, animal work, and cellular models. The effect of glucocorticoid hormones and the glucocorticoid receptor (GR) will thereby be evaluated as a central mechanism by which stress and antidepressant may exert their opposing effects on neurogenesis, and ultimately, on mood and behavior. PMID- 24478037 TI - Basophil activation test in the diagnosis and monitoring of mastocytosis patients with wasp venom allergy on immunotherapy. AB - BACKGROUND: There is need for an accurate diagnostic test in mastocytosis patients with wasp venom allergy (WVA) and monitoring of these patients during immunotherapy (IT). In this study, we aimed to evaluate sensitivity and specificity of the Basophil Activation Test (BAT) as a diagnostic and monitoring test in patients with mastocytosis and WVA. METHODS: Seventeen patients with mastocytosis and WVA and six mastocytosis patients without WVA were included. BAT was performed before the start of IT (first visit) and at 6 weeks (second visit) and 1 year (third visit), after reaching the maintenance dose. Of 17 patients included, 11 completed the third visit. In mastocytosis patients with WVA, dose dependent wasp-venom induced upregulation of CD63 and CD203c expression on basophils was observed compared with mastocytosis patients without WVA. Serum specific IgE, IgG4, and tryptase levels were measured in all patients. RESULTS: BAT had a sensitivity of 87% and specificity of 100% in diagnosing WVA in mastocytosis patients. Basophil allergen threshold sensitivity with respect to CD63 and CD203c was significantly decreased in the second visit compared with the first visit and increased significantly in the third visit compared with the second visit. Specific IgE levels increased significantly in the second visit compared with first and decreased significantly in the third visit compared with the second. Specific IgG4 levels rose significantly in the second visit compared with the first and on the third visit compared with the second. Tryptase levels did not change significantly during the study. CONCLUSIONS: BAT represents a diagnostic test with 100% specificity in allergic patients with mastocytosis and these patients are better to be monitored for a longer period during IT. PMID- 24478039 TI - Total synthesis of (18S)- and (18R)-homolargazole by rhodium-catalyzed hydrocarboxylation. AB - Homolargazole derivatives, in which the macrocycle of natural largazole is extended by one methylene group, were prepared by the recently developed rhodium catalyzed hydrocarboxylation reaction onto allenes. This strategy gives access to both the (18S)- and (18R)-stereoisomers in high stereoselectivity under ligand control. PMID- 24478040 TI - A nano-LC/UV method for the analysis of principal phenolic compounds in commercial citrus juices and evaluation of antioxidant potential. AB - In this study, a simple and rapid methodology to analyze and quantify principal flavanones in citrus fruit juices through the use of a nano-LC/UV-Vis apparatus, employing a 75 MUm id capillary column packed with sub-2 MUm particles C18 stationary phase for 10 cm, was developed. All compounds were baseline resolved working with a step gradient elution mode in 10 min. The developed analytical method was validated and the resulting RSD% for intra- and interday repeatability, related to retention time and peak area, were <4.7 and 5.5%, respectively. LOD and LOQ values corresponded to 0.40 and 1.56 MUg/mL for didymin, hesperitin, and narinegenin, while for the other flavanones were 0.78 and 3 MUg/mL, respectively. Good linearity with acceptable determination coefficients R(2) was obtained in the range between LOQ concentration and 200 MUg/mL (500 MUg/mL naringin and hesperidin). Good recovery values were also obtained. Then, the method was applied to the analysis of selected hand-squeezed and commercial citrus juices. Further, the nano-LC system was coupled to a mass spectrometer to confirm analyte identification. Antioxidant capacity of selected samples was also evaluated measured by Folin-Ciocalteu assay and Trolox equivalent antioxidant capacity assay. Results were compared to determine total flavanones concentrations. PMID- 24478041 TI - Protection of MES23.5 dopaminergic cells by obestatin is mediated by proliferative rather than anti-apoptotic action. AB - Obestatin is an endogenous peptide sharing a precursor with ghrelin. This study aims to investigate whether and how obestatin protects MES23.5 dopaminergic cells against 1-methyl-4-phenylpyridinium (MPP(+))-induced neurotoxicity. MES23.5 cells were pretreated with obestatin (10(-13)-10(-6) mol/L) for 20 min prior to incubation with 200 MUmol/L MPP(+) for 12 or 24 h, or treated with obestatin alone (10(-13) to 10(-6) mol/L) for 0, 6, 12, and 24 h. The methyl thiazolyl tetrazolium (MTT) assay was used to measure cell viability. Flow cytometry was used to measure the caspase-3 activity and the mitochondrial transmembrane potential. Proliferating cell nuclear antigen (PCNA) protein levels were determined by Western blotting. Obestatin (10(-13) to 10(-7) mol/L) pretreatment blocked or even reversed the MPP(+)-induced reduction of viability in MES23.5 cells, but had no effect on MPP(+)-induced mitochondrial transmembrane potential collapse and caspase-3 activation. When applied alone, obestatin increased viability. Elevated PCNA levels occurred with 10(-7), 10(-9), 10(-11) and 10(-13) mol/L obestatin treatment for 12 h. The results suggest that the protective effects of obestatin against MPP(+) in MES23.5 cells are due to its proliferation promoting rather than anti-apoptotic effects. PMID- 24478042 TI - Liver transplantation for alcoholic cirrhosis in Japan. PMID- 24478043 TI - Exploration of the binding mode between (-)-zampanolide and tubulin using docking and molecular dynamics simulation. AB - The binding mode of (-)-zampanolide (ZMP) to tubulin was investigated using docking, molecular dynamics (MD) simulation, and binding free-energy calculations. The docking studies validated the experimental results indicating that the paclitaxel site is the binding site for (-)-ZMP. The 18 ns MD simulation shows the docking mode has changed a lot, whereas it offers more reliable binding data. MM-PBSA binding free-energy calculations further confirmed the results of the MD simulation. The study revealed that hydrophobic interactions play an important role in stabilizing the binding, and the strong hydrogen bond formed with Asp224 enhances the affinity for tubulin. Meanwhile, the results support the assumption that (-)-ZMP can be attacked by His227, leading to a nucleophilic reaction and covalent binding. These theoretical results lead to a greater understanding of the mechanism of action of binding to tubulin, and will therefore aid the design of new compounds with higher affinities for tubulin. PMID- 24478044 TI - A regio- and stereoselective omega-transaminase/monoamine oxidase cascade for the synthesis of chiral 2,5-disubstituted pyrrolidines. AB - Biocatalytic approaches to the synthesis of optically pure chiral amines, starting from simple achiral building blocks, are highly desirable because such motifs are present in a wide variety of important natural products and pharmaceutical compounds. Herein, a novel one-pot omega-transaminase (TA)/monoamine oxidase (MAO-N) cascade process for the synthesis of chiral 2,5 disubstituted pyrrolidines is reported. The reactions proceeded with excellent enantio- and diastereoselectivity (>94 % ee; >98 % de) and can be performed on a preparative scale. This methodology exploits the complementary regio- and stereoselectivity displayed by both enzymes, which ensures that the stereogenic center established by the transaminase is not affected by the monoamine oxidase, and highlights the potential of this multienzyme cascade for the efficient synthesis of chiral building blocks. PMID- 24478045 TI - Choroid plexus carcinomas are characterized by complex chromosomal alterations related to patient age and prognosis. AB - Choroid plexus carcinoma is a malignant brain tumor predominantly occurring in young children. Only limited data are available regarding the underlying molecular genetic alterations. Therefore, molecular inversion probe single nucleotide polymorphism (MIP SNP) arrays were performed on a series of 26 neuropathologically well-characterized choroid plexus carcinomas. Recurrent copy number losses of chromosomes 5, 6, 16, 18, 19, and 22 as well as gains of chromosomes 1, 2, 4, 12, and 20 were identified. Furthermore, GISTIC analysis identified significant recurrent gains of 17 genes in 9 regions, and recurrent losses of 96 genes in 14 regions. Clustering analysis separated choroid plexus carcinomas into two groups: one characterized by marked losses and the other characterized by gains across the chromosomes. Chromosomal losses of 9, 19p, and 22q were significantly more frequent in younger children (<36 months), whereas gains on chromosomes 7 and 19, and chromosome arms 8q, 14q, and 21q prevailed in older patients. Multivariate analysis revealed that loss of 12q was associated with shorter survival [12 +/- 5 months vs. 86 +/- 8 months; (mean +/- SD; P = 0.001)] and, in addition, 45 smaller chromosomal regions showing genetic alterations significantly associated with survival could be identified. The MIP SNP array profiles also contributed to the diagnosis of two difficult SMARCB1 negative tumors as choroid plexus carcinoma and cribriform neuroepithelial tumor (CRINET), respectively. In conclusion, choroid plexus carcinomas are characterized by complex genetic alterations, which are related to patient age and may have prognostic and diagnostic value. PMID- 24478046 TI - Reversal of Mycobacterium tuberculosis phenotypic drug resistance by 2 aminoimidazole-based small molecules. AB - The expression of phenotypic drug resistance or drug tolerance serves as a strategy for Mycobacterium tuberculosis to survive in vivo antimicrobial drug treatment; however, the mechanisms are poorly understood. Progress toward a more in depth understanding of in vivo drug tolerance and the discovery of new therapeutic strategies designed specifically to treat drug-tolerant M. tuberculosis are hampered by the lack of appropriate in vitro assays. A library of 2-aminoimidazole-based small molecules combined with the antituberculosis drug isoniazid was screened against M. tuberculosis expressing in vitro drug tolerance as microbial communities attached to an extracellular matrix derived from lysed leukocytes. Based on the ability of nine of ten 2-aminoimidazole compounds to inhibit Mycobacterium smegmatis biofilm formation and three of ten molecules capable of dispersing established biofilms, two active candidates and one inactive control were tested against drug-tolerant M. tuberculosis. The two active compounds restored isoniazid susceptibility as well as reduced the in vitro minimum inhibitory concentrations of isoniazid in a dose-dependent manner. The dispersion of drug-tolerant M. tuberculosis with 2-aminoimidazole-based small molecules as an adjunct to antimicrobial treatment has the potential to be an effective antituberculosis treatment strategy designed specifically to eradicate drug-tolerant M. tuberculosis. PMID- 24478048 TI - Comparison between screening and confirmatory serological assays in blood donors in a region of South Italy. AB - BACKGROUND: Screening assays are needed in order to guarantee safety of donated blood, but a significant number of safe donations are removed from blood supply because of reactive screening results. It is important to evaluate the positive predictive value (PPV) of screening assays in order to modulate confirmatory algorithm and implement an adequate counseling. METHODS: An analysis of 17,912 blood donations has been conducted at Transfusion Medicine at Second University Naples, Italy, in 2009-2012. Serological screening for syphilis, hepatitis B virus (HBV), hepatitis C virus (HCV), and human immunodeficiency virus (HIV) was performed by ARCHITECT (Abbott Diagnostics, Wiesbaden, Germany); repeatedly reactive (RR) samples were checked by respective confirmatory tests. The relationship between sample/cutoff and confirmed seropositivity were analyzed. RESULTS: RR rates were low as expected in blood donors: 0.47% for syphilis, 0.42% for HBV, 0.50% for HCV, and 0.15% for HIV. The specificity on RR + gray zone (GZ) was 99.67%, 99.79%, 99.77%, and 99.88%, respectively; due to the low prevalence, PPV value was 30.6% for syphilis, 50.7% for HBV, 42.2% for HCV, and 18.5% for HIV. These values increased substantially reaching a plateau of 89.3% for syphilis, 94.6% for HBV, 85.7% for HCV, and 100% for HIV at the threshold established by receiver operating characteristics curve analysis. CONCLUSIONS: Supplemental testing on samples with high signal by screening assays seems to add little information. GZ settings and confirmatory testing for positive screening results should be designed taking in account several factors, including difference in the natural history among blood-borne infections, the characteristics of first- and second-level tests, and, when available, the results of nucleic acid amplification testing. PMID- 24478047 TI - Enhancing diabetes self-care among rural African Americans with diabetes: results of a two-year culturally tailored intervention. AB - PURPOSE: The purpose of this study is to test the feasibility of conducting a community-based randomized controlled trial evaluating a culturally tailored community-based group diabetes self-management education (DSME) program among rural African Americans. METHODS: Thirty-two African American rural adults with type 2 diabetes were recruited and 25 adults were retained and participated in an interventional study designed to test the effectiveness of the "Taking Care of Sugar" DSME program for the 2-year follow-up. Participants were selected from rural central Virginia. Primary outcomes variables included average blood sugar levels, cardiovascular risk factors, and general physical and mental health. These outcomes were assessed at baseline, 3 months, 6 months, and 12 months post baseline. RESULTS: From baseline to 3-month follow-up assessment, participants exhibited significant improvement on several physiological and behavioral measures. Given the small sample size, hypothesis testing was limited. Results show change from baseline over time, illustrating that the primary outcome of A1C decreased, although not significant. Additionally, participants reported more knowledge about diabetes self-management and personal care skills (ie, exercise and foot care) that persisted over time. The feasibility of the culturally tailored DSME was established, and participation with the program was high. CONCLUSIONS: A community-based group DSME program using storytelling is feasible. This research will help to inform clinicians and health policymakers as to the types of interventions that are feasible in a larger rural population. If such a program is carried out, we can improve knowledge, reduce complications, and improve quality of life among rural African Americans. PMID- 24478049 TI - Biotype expression and insecticide response of Bemisia tabaci chemosensory protein-1. AB - Chemosensory proteins (CSPs) are a group of small soluble proteins found so far exclusively in arthropod species. These proteins act in chemical communication and perception. In this study, a gene encoding the Type 1 CSP (BtabCSP1) from the agricultural pest Bemisia tabaci (whitefly) was analyzed to understand sequence variation and expression specificity in different biotypes. Sequence analysis of BtabCSP1 showed significant differences between the two genetically characterized biotypes, B and Q. The B-biotype had a larger number of BtabCSP1 mutations than the Q-biotype. Similar to most other CSPs, BtabCSP1 was more expressed in the head than in the rest of the body. One-step RT-PCR and qPCR analysis on total messenger RNA showed that biotype-Q had higher BtabCSP1 expression levels than biotype-B. Females from a mixed field-population had high levels of BtabCSP1 expression. The interaction of BtabCSP1 with the insecticide thiamethoxam was investigated by analyzing the BtabCSP1 expression levels following exposure to the neonicotinoid, thiamethoxam, in a time/dose-response study. Insecticide exposure increased BtabCSP1 expression (up to tenfold) at 4 and 24 h following 50 or 100 g/ml treatments. PMID- 24478050 TI - Whole-grain intake favorably affects markers of systemic inflammation in obese children: a randomized controlled crossover clinical trial. AB - SCOPE: Whole-grain foods have been reported to affect serum levels of inflammatory cytokines. However, we are aware of no study examining the effect of whole-grain intake on inflammatory biomarkers among children. The present study aimed to determine the effect of whole-grain intake on serum levels of inflammatory biomarkers in overweight or obese children. METHODS AND RESULTS: In this randomized crossover clinical trial, 44 overweight or obese girls aged 8-15 years participated. After a 2-week run-in period, subjects were randomly assigned to either whole-grain or control groups. Subjects in the whole-grain group were given a list of whole-grain foods and were asked to obtain half of their needed servings of grains from whole-grain foods each day for 6 weeks. Individuals in the control group were also given a list of whole-grain foods and were asked not to consume any of these foods during the intervention phase of the study. A 4 week washout period was applied following which subjects were crossed over to the alternate arm for an additional 6 weeks. Fasting blood samples were taken before and after each phase of the study to quantify markers of systemic inflammation. Mean age, weight, and BMI of study participants were 11.2 +/- 1.49 years, 51.2 +/ 10.2 kg, and 23.5 +/- 2.5 kg/m(2) , respectively. No significant effect of whole grain intake on weight and BMI was seen compared with the control group. We found a significant effect of whole-grain intake on serum levels of high-sensitive C reactive protein (-21.8 versus +12.1%, p = 0.03), soluble intercellular adhesion molecule-1 (-28.4 versus +6.3%, p = 0.02), serum amyloid A (-17.4 versus +9.9%, p = 0.02), and leptin (-9.7 versus +39.2%, p = 0.02) after 6 weeks. A trend toward the significant effect of whole-grain intake on serum levels of soluble vascular cell adhesion molecule-1 (-36.2% versus -7.8%, p = 0.07) was also observed. CONCLUSION: This study provides evidence supporting the beneficial effects of whole-grain foods on biomarkers of systemic inflammation in obese children. PMID- 24478051 TI - [Importance and evidence of regular physical activity for prevention and treatment of diseases]. PMID- 24478052 TI - [Importance and evidence of regular physical activity for prevention and treatment of diseases]. PMID- 24478053 TI - The human anti-HIV antibodies 2F5, 2G12, and PG9 differ in their susceptibility to proteolytic degradation: down-regulation of endogenous serine and cysteine proteinase activities could improve antibody production in plant-based expression platforms. AB - The tobacco-related species Nicotiana benthamiana has recently emerged as a promising host for the manufacturing of protein therapeutics. However, the production of recombinant proteins in N. benthamiana is frequently hampered by undesired proteolysis. Here, we show that the expression of the human anti-HIV antibodies 2F5, 2G12, and PG9 in N. benthamiana leaves leads to the accumulation of discrete heavy chain-derived degradation products of 30-40 kDa. Incubation of purified 2F5 with N. benthamiana intercellular fluid resulted in rapid conversion into the 40-kDa fragment, whereas 2G12 proved largely resistant to degradation. Such a differential susceptibility to proteolytic attack was also observed when these two antibodies were exposed to various types of proteinases in vitro. While serine and cysteine proteinases are both capable of generating the 40-kDa 2F5 fragment, the 30-kDa polypeptide is most readily obtained by treatment with the latter class of enzymes. The principal cleavage sites reside within the antigen binding domain, the VH -CH 1 linker segment and the hinge region of the antibodies. Collectively, these results indicate that down-regulation of endogenous serine and cysteine proteinase activities could be used to improve the performance of plant-based expression platforms destined for the production of biopharmaceuticals. PMID- 24478055 TI - Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies. AB - Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment. PMID- 24478054 TI - RANK- and c-Met-mediated signal network promotes prostate cancer metastatic colonization. AB - Prostate cancer (PCa) metastasis to bone is lethal and there is no adequate animal model for studying the mechanisms underlying the metastatic process. Here, we report that receptor activator of NF-kappaB ligand (RANKL) expressed by PCa cells consistently induced colonization or metastasis to bone in animal models. RANK-mediated signaling established a premetastatic niche through a feed-forward loop, involving the induction of RANKL and c-Met, but repression of androgen receptor (AR) expression and AR signaling pathways. Site-directed mutagenesis and transcription factor (TF) deletion/interference assays identified common TF complexes, c-Myc/Max, and AP4 as critical regulatory nodes. RANKL-RANK signaling activated a number of master regulator TFs that control the epithelial-to mesenchymal transition (Twist1, Slug, Zeb1, and Zeb2), stem cell properties (Sox2, Myc, Oct3/4, and Nanog), neuroendocrine differentiation (Sox9, HIF1alpha, and FoxA2), and osteomimicry (c-Myc/Max, Sox2, Sox9, HIF1alpha, and Runx2). Abrogating RANK or its downstream c-Myc/Max or c-Met signaling network minimized or abolished skeletal metastasis in mice. RANKL-expressing LNCaP cells recruited and induced neighboring non metastatic LNCaP cells to express RANKL, c Met/activated c-Met, while downregulating AR expression. These initially non metastatic cells, once retrieved from the tumors, acquired the potential to colonize and grow in bone. These findings identify a novel mechanism of tumor growth in bone that involves tumor cell reprogramming via RANK-RANKL signaling, as well as a form of signal amplification that mediates recruitment and stable transformation of non-metastatic bystander dormant cells. PMID- 24478056 TI - Polycatenation-driven self-assembly of nanoporous frameworks based on a 1D ribbon of rings: regular structural evolution, interpenetration transformation, and photochemical modification. AB - A series of nanoporous frameworks constructed by a polycatenated isoreticular 1D ribbon of rings have been developed. The orientation of catenated ribbons can be fine tuned by varying counter anions, which allows both pore size and shape to be systematically adjusted in a pre-synthetic process. Distinct from conventional pore construction modes in which the organic linkers are alternately connected by metal nodes into a 3D periodic arrangement, the present polycatenation approach represents an alternative for constructing soft porous materials with tunable pore metrics and functions. Furthermore, these porous structures can interconvert into each other based on an anion-exchange process, accompanied by the transformation of the interpenetrating structures in different dimensional networks, which is unusual in porous frameworks. In addition, such a porous framework can be post-synthetically modified by a photoinduced [2+2] cycloaddition reaction, which not only achieves the surface modification (from conjugated to non-conjugated inner surface), but also triggers the structural transformation from low dimension to high dimension. Such a post-modification process reinforces the pore architecture through a covalent locking effect and has a great impact on the adsorption properties. PMID- 24478057 TI - Alteration of protein profile in rat liver of animals exposed to subacute diazinon: a proteomic approach. AB - Diazinon, an organophosphorus insecticide, is employed to control pests in agriculture. Diazinon may contaminate the environment during the manufacturing process or agricultural application. Previous studies have revealed that diazinon may induce alteration in the protein profile of the liver. Here, a proteomics approach was used to investigate the effects on the protein profile in the liver of rats of subacute oral exposures at 15 mg/kg of diazinon. Liver proteins were separated using 2D-PAGE, and stained by MS-compatible silver staining and/or the fluorescent SYPRO(r) Ruby protein gel stain. Gels were scanned and analyzed using the Image Master software. Differentially displayed protein species were identified using MALDI-TOF/TOF and MASCOT software. Significantly altered protein species were identified to be involved in apoptosis, cell metabolism, transport, and antioxidant systems. Exposure to diazinon decreased levels of some species of catalase, peroxiredoxin-6, 3-ketoacyl-CoA thiolase, and glucose regulated protein78, whereas the level of protein disulfide-isomerase A3 increased. Our results suggested that diazinon may induce hepatotoxicity through oxidative stress, apoptosis, and metabolic disorders in rat liver. PMID- 24478058 TI - Reply: To PMID 23197388. PMID- 24478059 TI - Development and validation of the Diagnostic Interview Adjustment Disorder (DIAD). AB - Adjustment disorders (ADs) are under-researched due to the absence of a reliable and valid diagnostic tool. This paper describes the development and content/construct validation of a fully structured interview for the diagnosis of AD, the Diagnostic Interview Adjustment Disorder (DIAD). We developed the DIAD by partly adjusting and operationalizing DSM-IV criteria. Eleven experts were consulted on the content of the DIAD. In addition, the DIAD was administered by trained lay interviewers to a representative sample of disability claimants (n = 323). To assess construct validity of the DIAD, we explored the associations between the AD classification by the DIAD and summary scores of the Kessler Psychological Distress 10-item Scale (K10) and the World Health Organization Disability Assessment Schedule (WHODAS) by linear regression. Expert agreement on content of the DIAD was moderate to good. The prevalence of AD using the DIAD with revised criteria for the diagnosis AD was 7.4%. The associations of AD by the DIAD with average sum scores on the K10 and the WHODAS supported construct validity of the DIAD. The results provide a first indication that the DIAD is a valid instrument to diagnose AD. Further studies on reliability and on other aspects of validity are needed. PMID- 24478061 TI - Powerful fluoroalkoxy molybdenum(V) reagent for selective oxidative arene coupling reaction. AB - We introduce the novel fluoroalkoxy molybdenum(V) reagent 1 which has superior reactivity and selectivity in comparison to MoCl5 or the MoCl5 /TiCl4 reagent mixture in the oxidative coupling reactions of aryls. Common side reactions, such as chlorination and/or oligomer formation, are drastically diminished creating a powerful and useful reagent for oxidative coupling. Theoretical treatment of the reagent interaction with 1,2-dimethoxybenzene-type substrates indicates an inner sphere electron transfer followed by a radical cationic reaction pathway for the oxidative-coupling process. EPR spectroscopic and electrochemical studies, X-ray analyses, computational investigations, and the experimental scope provide a highly consistent picture. The substitution of chlorido ligands by hexafluoroisopropoxido moieties seems to boost both the reactivity and selectivity of the metal center which might be applied to other reagents as well. PMID- 24478060 TI - Expression of antimicrobial drug tolerance by attached communities of Mycobacterium tuberculosis. AB - There is an urgent need to improve methods used to screen antituberculosis drugs. An in vitro assay was developed to test drug treatment strategies that specifically target drug-tolerant Mycobacterium tuberculosis. The H37Rv strain of M. tuberculosis survived antimicrobial treatment as attached microbial communities when maintained in tissue culture media (RPMI-1640) with or without lysed human peripheral blood leukocytes. When cultured planktonically in the presence of Tween-80, bacilli failed to form microbial communities or reach logarithmic phase growth yet remained highly susceptible to antimicrobial drugs. In the absence of Tween, bacilli tolerated drug therapy by forming complex microbial communities attached to untreated well surfaces or to the extracellular matrix derived from lysed human leukocytes. Treatment of microbial communities with DNase I or Tween effectively dispersed bacilli and restored drug susceptibility. These data demonstrate that in vitro expression of drug tolerance by M. tuberculosis is linked to the establishment of attached microbial communities and that dispersion of bacilli targeting the extracellular matrix including DNA restores drug susceptibility. Modifications of this in vitro assay may prove beneficial in a high-throughput platform to screen new antituberculosis drugs especially those that target drug-tolerant bacilli. PMID- 24478062 TI - The diagnostic value and performance evaluation of five serological tests for the detection of Treponema pallidum. AB - BACKGROUND: Syphilis is caused by the bacterium Treponema pallidum (TP). The aim of this study was to establish a clinical approach for serodiagnosis of syphilis by evaluating the performance and diagnostic value of five serological tests for the detection of TP. METHODS: Five tests were used to test the serum from syphilis patients and control patients, namely rapid plasma reagin (RPR) test, toluidine red unheated serum test (TRUST), TP passive particle agglutination assay (TPPA), TP-specific enzyme-linked immunosorbent assay (TP-ELISA), and TP specific chemiluminescent immunoassay (TP-CMIA). RESULTS: The sensitivity and diagnostic efficiency of TPPA (96.25%/98.38%), TP-ELISA (100%/95.41%), and TP CMIA (100%/94.86%) were significantly higher than that of RPR (73.13%/86.22%) and TRUST (73.75%/86.49%) (P < 0.05). The minimum detectable concentrations for the five tests were 30 mIU/ml, 20 mIU/ml, 15 mIU/ml, 150 mIU/ml, and 150 mIU/ml, respectively. According to receiver operating characteristic (ROC) curve, the optimal cut-off values for syphilis diagnosis by TP-CMIA and TP-ELISA were 2.2 and 2.0 S/CO (where S/CO = Sample/calibrator cut off), and the area under the ROC curve (AUC) were 0.998 for TP-CMIA and 0.999 for TP-ELISA. The titers/positive rates for RPR and TRUST dropped from 1:4 (100%) to 1:1 (23.3%) (both P < 0.05) after treatment. However, there were no significant differences when we compared the positive rate of syphilis patients before and after treatment by TPPA, TP ELISA, and TP-CMIA. CONCLUSIONS: Treponemal tests, such as TPPA, TP-ELISA, and TP CMIA, are recommended for clinical routine screening of syphilis. However, nontreponemal tests, for example, RPR and TRUST, perform better in therapy response assessment. Serological test should be tailored to respective facilities and clinical demands. PMID- 24478063 TI - Mycobacteria and the greasy macrophage: getting fat and frustrated. AB - In the current issue of Infection and Immunity, Caire-Brandli and coworkers (Infect. Immun. 82:476-490, 2014, doi:10.1128/IAI.01196-13) describe a novel cell system for studying mycobacterial interactions with foamy macrophages and provide a magnificent series of electron microscopy-based observations providing major insight into the microbiology and cell biology of these interactions. PMID- 24478064 TI - Reversible lipid accumulation and associated division arrest of Mycobacterium avium in lipoprotein-induced foamy macrophages may resemble key events during latency and reactivation of tuberculosis. AB - During the dormant phase of tuberculosis, Mycobacterium tuberculosis persists in lung granulomas by residing in foamy macrophages (FM) that contain abundant lipid bodies (LB) in their cytoplasm, allowing bacilli to accumulate lipids as intracytoplasmic lipid inclusions (ILI). An experimental model of FM is presented where bone marrow-derived mouse macrophages are infected with M. avium and exposed to very-low-density lipoprotein (VLDL) as a lipid source. Quantitative analysis of detailed electron microscope observations showed the following results. (i) Macrophages became foamy, and mycobacteria formed ILI, for which host triacylglycerides, rather than cholesterol, was essential. (ii) Lipid transfer occurred via mycobacterium-induced fusion between LB and phagosomes. (iii) Mycobacteria showed a thinned cell wall and became elongated but did not divide. (iv) Upon removal of VLDL, LB and ILI declined within hours, and simultaneous resumption of mycobacterial division restored the number of mycobacteria to the same level as that found in untreated control macrophages. This showed that the presence of ILI resulted in a reversible block of division without causing a change in the mycobacterial replication rate. Fluctuation between ILI either partially or fully extending throughout the mycobacterial cytoplasm was suggestive of bacterial cell cycle events. We propose that VLDL driven FM constitute a well-defined cellular system in which to study changed metabolic states of intracellular mycobacteria that may relate to persistence and reactivation of tuberculosis. PMID- 24478065 TI - Enzymatic modification of lipid A by ArnT protects Bordetella bronchiseptica against cationic peptides and is required for transmission. AB - Pathogen transmission cycles require many steps: initial colonization, growth and persistence, shedding, and transmission to new hosts. Alterations in the membrane components of the bacteria, including lipid A, the membrane anchor of lipopolysaccharide, could affect any of these steps via its structural role protecting bacteria from host innate immune defenses, including antimicrobial peptides and signaling through Toll-like receptor 4 (TLR4). To date, lipid A has been shown to affect only the within-host dynamics of infection, not the between host dynamics of transmission. Here, we investigate the effects of lipid A modification in a mouse infection and transmission model. Disruption of the Bordetella bronchiseptica locus (BB4268) revealed that ArnT is required for addition of glucosamine (GlcN) to B. bronchiseptica lipid A. ArnT modification of lipid A did not change its TLR4 agonist activity in J774 cells, but deleting arnT decreased resistance to killing by cationic antimicrobial peptides, such as polymyxin B and beta-defensins. In the standard infection model, mutation of arnT did not affect B. bronchiseptica colonization, growth, persistence throughout the respiratory tract, recruitment of neutrophils to the nasal cavity, or shedding of the pathogen. However, the number of bacteria necessary to colonize a host (50% infective dose [ID50]) was 5-fold higher for the arnT mutant. Furthermore, the arnT mutant was defective in transmission between hosts. These results reveal novel functions of the ArnT lipid A modification and highlight the sensitivity of low-dose infections and transmission experiments for illuminating aspects of infectious diseases between hosts. Factors such as ArnT can have important effects on the burden of disease and are potential targets for interventions that can interrupt transmission. PMID- 24478066 TI - EatA, an immunogenic protective antigen of enterotoxigenic Escherichia coli, degrades intestinal mucin. AB - Enterotoxigenic Escherichia coli (ETEC) is a major cause of morbidity and mortality due to infectious diarrhea in developing countries for which there is presently no effective vaccine. A central challenge in ETEC vaccinology has been the identification of conserved surface antigens to formulate a broadly protective vaccine. Here, we demonstrate that EatA, an immunogenic secreted serine protease of ETEC, contributes to virulence by degrading MUC2, the major protein present in the small intestinal mucous layer, and that removal of this barrier in vitro accelerates toxin access to the enterocyte surface. In addition, we demonstrate that vaccination with the recombinant secreted passenger domain of EatA (rEatAp) elicits high titers of antibody and is protective against intestinal infection with ETEC. These findings may have significant implications for development of both subunit and live-attenuated vaccines against ETEC and other enteric pathogens, including Shigella flexneri, that express similar proteins. PMID- 24478067 TI - Enterotoxigenic Escherichia coli secretes a highly conserved mucin-degrading metalloprotease to effectively engage intestinal epithelial cells. AB - Enterotoxigenic Escherichia coli (ETEC) is a leading cause of death due to diarrheal illness among young children in developing countries, and there is currently no effective vaccine. Many elements of ETEC pathogenesis are still poorly defined. Here we demonstrate that YghJ, a secreted ETEC antigen identified in immunoproteomic studies using convalescent patient sera, is required for efficient access to small intestinal enterocytes and for the optimal delivery of heat-labile toxin (LT). Furthermore, YghJ is a highly conserved metalloprotease that influences intestinal colonization of ETEC by degrading the major mucins in the small intestine, MUC2 and MUC3. Genes encoding YghJ and its cognate type II secretion system (T2SS), which also secretes LT, are highly conserved in ETEC and exist in other enteric pathogens, including other diarrheagenic E. coli and Vibrio cholerae bacteria, suggesting that this mucin-degrading enzyme may represent a shared virulence feature of these important pathogens. PMID- 24478068 TI - Protection from Clostridium difficile infection in CD4 T Cell- and polymeric immunoglobulin receptor-deficient mice. AB - Clostridium difficile rivals methicillin-resistant Staphylococcus aureus as the primary hospital-acquired infection. C. difficile infection (CDI) caused by toxins A and/or B can manifest as mild diarrhea to life-threatening pseudomembranous colitis. Although most patients recover fully from CDI, ~20% undergo recurrent disease. Several studies have demonstrated a correlation between anti-toxin antibody (Ab) and decreased recurrence; however, the contributions of the systemic and mucosal Ab responses remain unclear. Our goal was to use the CDI mouse model to characterize the protective immune response to C. difficile. C57BL/6 mice infected with epidemic C. difficile strain BI17 developed protective immunity against CDI and did not develop CDI upon rechallenge; they generated systemic IgG and IgA as well as mucosal IgA Ab to toxin. To determine if protective immunity to C. difficile could be generated in immunodeficient individuals, we infected CD4(-/-) mice and found that they generated both mucosal and serum IgA anti-toxin Abs and were protected from CDI upon rechallenge, with protection dependent on major histocompatibility complex class II (MHCII) expression; no IgG anti-toxin Ab was found. We found that protection was likely due to neutralizing mucosal IgA Ab. In contrast, pIgR(-/-) mice, which lack the receptor to transcytose polymeric Ab across the epithelium, were also protected from CDI, suggesting that although mucosal anti-toxin Ab may contribute to protection, it is not required. We conclude that protection from CDI can occur by several mechanisms and that the mechanism of protection is determined by the state of immunocompetence of the host. PMID- 24478069 TI - Fungal morphogenetic pathways are required for the hallmark inflammatory response during Candida albicans vaginitis. AB - Vulvovaginal candidiasis, caused primarily by Candida albicans, presents significant health issues for women of childbearing age. As a polymorphic fungus, the ability of C. albicans to switch between yeast and hyphal morphologies is considered its central virulence attribute. Armed with new criteria for defining vaginitis immunopathology, the purpose of this study was to determine whether the yeast-to-hypha transition is required for the hallmark inflammatory responses previously characterized during murine vaginitis. Kinetic analyses of vaginal infection with C. albicans in C57BL/6 mice demonstrated that fungal burdens remained constant throughout the observation period, while polymorphonuclear leukocyte (PMN), S100A8, and interleukin-1beta levels obtained from vaginal lavage fluid increased by day 3 onward. Lactate dehydrogenase activity was also positively correlated with increased effectors of innate immunity. Additionally, immunodepletion of neutrophils in infected mice confirmed a nonprotective role for PMNs during vaginitis. Determination of the importance of fungal morphogenesis during vaginitis was addressed with a two-pronged approach. Intravaginal inoculation of mice with C. albicans strains deleted for key transcriptional regulators (bcr1Delta/Delta, efg1Delta/Delta, cph1Delta/Delta, and efg1Delta/Delta cph1Delta/Delta) controlling the yeast-to-hypha switch revealed a crucial role for morphogenetic signaling through the Efg1 and, to a lesser extent, the Bcr1 pathways in contributing to vaginitis immunopathology. Furthermore, overexpression of transcription factors NRG1 and UME6, to maintain yeast and hyphal morphologies, respectively, confirmed the importance of morphogenesis in generating innate immune responses in vivo. These results highlight the yeast-to-hypha switch and the associated morphogenetic response as important virulence components for the immunopathogenesis of Candida vaginitis, with implications for transition from benign colonization to symptomatic infection. PMID- 24478071 TI - Fbp1-mediated ubiquitin-proteasome pathway controls Cryptococcus neoformans virulence by regulating fungal intracellular growth in macrophages. AB - Cryptococcus neoformans is a human fungal pathogen that often causes lung and brain infections in immunocompromised patients, with a high fatality rate. Our previous results showed that an F-box protein, Fbp1, is essential for Cryptococcus virulence independent of the classical virulence factors, suggesting a novel virulence control mechanism. In this study, we show that Fbp1 is part of the ubiquitin-proteasome system, and we further investigated the mechanism of Fbp1 function during infection. Time course studies revealed that the fbp1Delta mutant causes little damage in the infected lung and that the fungal burden in the lung remains at a low but persistent level throughout infection. The fbp1Delta mutant cannot disseminate to other organs following pulmonary infection in the murine inhalation model of cryptococcosis but still causes brain infection in a murine intravenous injection model, suggesting that the block of dissemination of the fbp1Delta mutant is due to its inability to leave the lung. The fbp1Delta mutant showed a defect in intracellular proliferation after phagocytosis in a Cryptococcus-macrophage interaction assay, which likely contributes to its virulence attenuation. To elucidate the molecular basis of the SCF(Fbp1) E3 ligase function, we analyzed potential Fbp1 substrates based on proteomic approaches combined with phenotypic analysis. One substrate, the inositol phosphosphingolipid-phospholipase C1 (Isc1), is required for fungal survival inside macrophage cells, which is consistent with the role of Fbp1 in regulating Cryptococcus-macrophage interaction and fungal virulence. Our results thus reveal a new determinant of fungal virulence that involves the posttranslational regulation of inositol sphingolipid biosynthesis. PMID- 24478070 TI - Loss of sigma factor RpoN increases intestinal colonization of Vibrio parahaemolyticus in an adult mouse model. AB - Vibrio parahaemolyticus is the leading cause of bacterial seafood-borne gastroenteritis worldwide, yet little is known about how this pathogen colonizes the human intestine. The alternative sigma factor RpoN/sigma-54 is a global regulator that controls flagellar synthesis, as well as a wide range of nonflagellar genes. We constructed an in-frame deletion mutation in rpoN (VP2670) in V. parahaemolyticus RIMD2210633, a clinical serogroup O3:K6 isolate, and examined the effects in vivo using a streptomycin-treated mouse model of colonization. We confirmed that deletion of rpoN rendered V. parahaemolyticus nonmotile, and it caused reduced biofilm formation and an apparent defect in glutamine synthetase production. In in vivo competition assays between the rpoN mutant and a wild-type RIMD2210633 strain marked with the beta-galactosidase gene lacZ (WBWlacZ), the mutant colonized significantly more proficiently. Intestinal persistence competition assays also demonstrated that the rpoN mutant had enhanced fitness and outcompeted WBWlacZ. Mutants defective in the polar flagellum biosynthesis FliAP sigma factor also outcompeted WBWlacZ but not to the same level as the rpoN mutant, which suggested that lack of motility is not the sole cause of the fitness effect. In an in vitro growth competition assay in mouse intestinal mucus, the rpoN mutant also outcompeted the wild type and exhibited faster doubling times when grown in mucus and on individual components of mucus. Genes in the pathways for the catabolism of mucus sugars also had significantly higher expression levels in a DeltarpoN mutant than in the wild type. These data suggest that in V. parahaemolyticus, RpoN plays an important role in carbon utilization regulation, which may significantly affect host colonization. PMID- 24478072 TI - IscR is a global regulator essential for pathogenesis of Vibrio vulnificus and induced by host cells. AB - A mutant that exhibited less cytotoxic activity toward INT-407 human intestinal epithelial cells than the wild type was screened from a random transposon mutant library of Vibrio vulnificus, and an open reading frame encoding an Fe-S cluster regulator, IscR, was identified using a transposon-tagging method. A mutational analysis demonstrated that IscR contributes to mouse mortality as well as cytotoxicity toward the INT-407 cells, indicating that IscR is essential for the pathogenesis of V. vulnificus. A whole-genome microarray analysis revealed that IscR influenced the expression of 67 genes, of which 52 were upregulated and 15 were downregulated. Among these, 12 genes most likely involved in motility and adhesion to host cells, hemolytic activity, and survival under oxidative stress of the pathogen during infection were selected and experimentally verified to be upregulated by IscR. Accordingly, the disruption of iscR resulted in a significant reduction in motility and adhesion to INT-407 cells, in hemolytic activity, and in resistance to reactive oxygen species (ROS) such as H2O2 and tert-butyl hydroperoxide (t-BOOH). Furthermore, the present study demonstrated that iscR expression was induced by exposure of V. vulnificus to the INT-407 cells, and the induction appeared to be mediated by ROS generated by the host cells during infection. Consequently, the combined results indicated that IscR is a global regulator that contributes to the overall success in the pathogenesis of V. vulnificus by regulating the expression of various virulence and survival genes in addition to Fe-S cluster genes. PMID- 24478073 TI - In vitro spatial and temporal analysis of Mycoplasma pneumoniae colonization of human airway epithelium. AB - Mycoplasma pneumoniae is an important cause of respiratory disease, especially in school-age children and young adults. We employed normal human bronchial epithelial (NHBE) cells in air-liquid interface culture to study the interaction of M. pneumoniae with differentiated airway epithelium. These airway cells, when grown in air-liquid interface culture, polarize, form tight junctions, produce mucus, and develop ciliary function. We examined both qualitatively and quantitatively the role of mycoplasma gliding motility in the colonization pattern of developing airway cells, comparing wild-type M. pneumoniae and mutants thereof with moderate to severe defects in gliding motility. Adherence assays with radiolabeled mycoplasmas demonstrated a dramatic reduction in binding for all strains with airway cell polarization, independent of acquisition of mucociliary function. Adherence levels dropped further once NHBE cells achieved terminal differentiation, with mucociliary activity strongly selecting for full gliding competence. Analysis over time by confocal microscopy demonstrated a distinct colonization pattern that appeared to originate primarily with ciliated cells, but lateral spread from the base of the cilia was slower than expected. The data support a model in which the mucociliary apparatus impairs colonization yet cilia provide a conduit for mycoplasma access to the host cell surface and suggest acquisition of a barrier function, perhaps associated with tethered mucin levels, with NHBE cell polarization. PMID- 24478074 TI - Prevotella intermedia induces severe bacteremic pneumococcal pneumonia in mice with upregulated platelet-activating factor receptor expression. AB - Streptococcus pneumoniae is the leading cause of respiratory infection worldwide. Although oral hygiene has been considered a risk factor for developing pneumonia, the relationship between oral bacteria and pneumococcal infection is unknown. In this study, we examined the synergic effects of Prevotella intermedia, a major periodontopathic bacterium, on pneumococcal pneumonia. The synergic effects of the supernatant of P. intermedia (PiSup) on pneumococcal pneumonia were investigated in mice, and the stimulation of pneumococcal adhesion to human alveolar (A549) cells by PiSup was assessed. The effects of PiSup on platelet activating factor receptor (PAFR) transcript levels in vitro and in vivo were analyzed by quantitative real-time PCR, and the differences between the effects of pneumococcal infection induced by various periodontopathic bacterial species were verified in mice. Mice inoculated with S. pneumoniae plus PiSup exhibited a significantly lower survival rate, higher bacterial loads in the lungs, spleen, and blood, and higher inflammatory cytokine levels in the bronchoalveolar lavage fluid (macrophage inflammatory protein 2 and tumor necrosis factor alpha) than those infected without PiSup. In A549 cells, PiSup increased pneumococcal adhesion and PAFR transcript levels. PiSup also increased lung PAFR transcript levels in mice. Similar effects were not observed in the supernatants of Porphyromonas gingivalis or Fusobacterium nucleatum. Thus, P. intermedia has the potential to induce severe bacteremic pneumococcal pneumonia with enhanced pneumococcal adhesion to lower airway cells. PMID- 24478075 TI - Large-scale investigation of Leishmania interaction networks with host extracellular matrix by surface plasmon resonance imaging. AB - We have set up an assay to study the interactions of live pathogens with their hosts by using protein and glycosaminoglycan arrays probed by surface plasmon resonance imaging. We have used this assay to characterize the interactions of Leishmania promastigotes with ~70 mammalian host biomolecules (extracellular proteins, glycosaminoglycans, growth factors, cell surface receptors). We have identified, in total, 27 new partners (23 proteins, 4 glycosaminoglycans) of procyclic promastigotes of six Leishmania species and 18 partners (15 proteins, 3 glycosaminoglycans) of three species of stationary-phase promastigotes for all the strains tested. The diversity of the interaction repertoires of Leishmania parasites reflects their dynamic and complex interplay with their mammalian hosts, which depends mostly on the species and strains of Leishmania. Stationary phase Leishmania parasites target extracellular matrix proteins and glycosaminoglycans, which are highly connected in the extracellular interaction network. Heparin and heparan sulfate bind to most Leishmania strains tested, and 6-O-sulfate groups play a crucial role in these interactions. Numerous Leishmania strains bind to tropoelastin, and some strains are even able to degrade it. Several strains interact with collagen VI, which is expressed by macrophages. Most Leishmania promastigotes interact with several regulators of angiogenesis, including antiangiogenic factors (endostatin, anastellin) and proangiogenic factors (ECM-1, VEGF, and TEM8 [also known as anthrax toxin receptor 1]), which are regulated by hypoxia. Since hypoxia modulates the infection of macrophages by the parasites, these interactions might influence the infection of host cells by Leishmania. PMID- 24478076 TI - Liposomal cholesterol delivery activates the macrophage innate immune arm to facilitate intracellular Leishmania donovani killing. AB - Leishmania donovani causes visceral leishmaniasis (VL) by infecting the monocyte/macrophage lineage and residing inside specialized structures known as parasitophorous vacuoles. The protozoan parasite has adopted several means of escaping the host immune response, with one of the major methods being deactivation of host macrophages. Previous reports highlight dampened macrophage signaling, defective antigen presentation due to increased membrane fluidity, and the downregulation of several genes associated with L. donovani infection. We have reported previously that the defective antigen presentation in infected hamsters could be corrected by a single injection of a cholesterol-containing liposome. Here we show that cholesterol in the form of a liposomal formulation can stimulate the innate immune arm and reactivate macrophage function. Augmented levels of reactive oxygen species (ROS) and reactive nitrogen intermediates (RNI), along with proinflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) and interleukin 6 (IL-6), corroborate intracellular parasite killing. Cholesterol incorporation kinetics is favored in infected macrophages more than in normal macrophages. Such an enhanced cholesterol uptake is associated with preferential apoptosis of infected macrophages in an endoplasmic reticulum (ER) stress-dependent manner. All these events are coupled with mitogen-activated protein (MAP) kinase activation, while inhibition of such pathways resulted in increased parasite loads. Hence, liposomal cholesterol is a potential facilitator of the macrophage effector function in favor of the host, independently of the T cell arm. PMID- 24478077 TI - A toxoplasma patatin-like protein changes localization and alters the cytokine response during toxoplasmic encephalitis. AB - Toxoplasma gondii is an obligate intracellular parasite that forms a lifelong infection within the central nervous system of its host. The T. gondii genome encodes six members of the patatin-like phospholipase family; related proteins are associated with host-microbe interactions in bacteria. T. gondii patatin-like protein 1 (TgPL1) was previously determined to be necessary for parasites to suppress nitric oxide and prevent degradation in activated macrophages. Here, we show that in the rapidly replicating tachyzoite stage, TgPL1 is localized within vesicles inside the parasite that are distinct from the dense granules; however, in the encysted bradyzoite stage, TgPL1 localizes to the parasitophorous vacuole (PV) and cyst wall. While we had not previously seen a defect of the TgPL1 deletion mutant (DeltaTgPL1) during acute and early chronic infection, the localization change of TgPL1 in bradyzoites caused us to reevaluate the DeltaTgPL1 mutant during late chronic infection and in a toxoplasmic encephalitis (TE) mouse model. Mice infected with DeltaTgPL1 are more resistant to TE and have fewer inflammatory lesions than mice infected with the wild type and DeltaTgPL1 genetically complemented with TgPL1. This increased resistance to TE could result from several contributing factors. First, we found that DeltaTgPL1 bradyzoites did not convert back to tachyzoites readily in tissue culture. Second, a subset of cytokine levels were higher in DeltaTgPL1-infected mice, including gamma interferon (IFN-gamma), tumor necrosis factor alpha (TNF-alpha), interleukin 6 (IL-6), and monocyte chemotactic protein 1 (MCP-1). These studies suggest that TgPL1 plays a role in the maintenance of chronic T. gondii infection. PMID- 24478078 TI - Key role of Toll-like receptor 2 in the inflammatory response and major histocompatibility complex class ii downregulation in Brucella abortus-infected alveolar macrophages. AB - Alveolar macrophages (AM) seem to constitute the main cellular target of inhaled brucellae. Here, we show that Brucella abortus invades and replicates in murine AM without inducing cytotoxicity. B. abortus infection induced a statistically significant increase of tumor necrosis factor alpha (TNF-alpha), CXCL1 or keratinocyte chemoattractant (KC), interleukin-1beta (IL-1beta), IL-6, and IL-12 in AM from C57BL/6 mice and BALB/c mice, but these responses were generally weaker and/or delayed compared to those elicited in peritoneal macrophages. Studies using knockout mice for TLR2, TLR4, and TLR9 revealed that TNF-alpha and KC responses were mediated by TLR2 recognition. Brucella infection reduced in a multiplicity of infection-dependent manner the expression of major histocompatibility complex class II (MHC-II) molecules induced by gamma interferon (IFN-gamma) in AM. The same phenomenon was induced by incubation with heat-killed B. abortus (HKBA) or the lipidated form of the 19-kDa outer membrane protein of Brucella (L-Omp19), and it was shown to be mediated by TLR2 recognition. In contrast, no significant downregulation of MHC-II was induced by either unlipidated Omp19 or Brucella LPS. In a functional assay, treatment of AM with either L-Omp19 or HKBA reduced the MHC-II-restricted presentation of OVA peptides to specific T cells. One week after intratracheal infection, viable B. abortus was detected in AM from both wild-type and TLR2 KO mice, but CFU counts were higher in the latter. These results suggest that B. abortus survives in AM after inhalatory infection in spite of a certain degree of immune control exerted by the TLR2-mediated inflammatory response. Both the modest nature of the latter and the modulation of MHC-II expression by the bacterium may contribute to such survival. PMID- 24478080 TI - Porphyromonas gingivalis lipid A phosphatase activity is critical for colonization and increasing the commensal load in the rabbit ligature model. AB - Periodontitis is a disease of polymicrobial etiology characterized by inflammation, degradation of host tissue, and bone that irreversibly destroys the supporting apparatus of teeth. Porphyromonas gingivalis contains lipid A with structural heterogeneity that has been postulated to contribute to the initiation of dysbiosis in oral communities by modulating the host response, thereby creating a permissive environment for its growth. We examined two P. gingivalis lipid A phosphatase mutants which contain different "locked" lipid A structures that induce different host cellular responses for their ability to induce dysbiosis and periodontitis in rabbits. Lipopolysaccharide (LPS) preparations obtained from these strains were also examined. After repeated applications of all strains and their respective LPS preparations, P. gingivalis wild type, but not the lipid A mutants, had a significant impact on both the oral commensal microbial load and composition. In contrast, in rabbits exposed to the mutant strains or the LPS preparations, the microbial load did not increase, and yet significant changes in the oral microbial composition were observed. All strains and their respective LPS preparations induced periodontitis. Therefore, the ability to alter the lipid A composition in response to environmental conditions by lipid A phosphatases is required for both colonization of the rabbit and increases in the microbial load. Furthermore, the data demonstrate that multiple dysbiotic oral microbial communities can elicit periodontitis. PMID- 24478079 TI - Outer membrane protein P5 is required for resistance of nontypeable Haemophilus influenzae to both the classical and alternative complement pathways. AB - The complement system is an important first line of defense against the human pathogen Haemophilus influenzae. To survive and propagate in vivo, H. influenzae has evolved mechanisms for subverting this host defense, most of which have been shown to involve outer surface structures, including lipooligosaccharide glycans and outer surface proteins. Bacterial defense against complement acts at multiple steps in the pathway by mechanisms that are not fully understood. Here we identify outer membrane protein P5 as an essential factor in serum resistance of both H. influenzae strain Rd and nontypeable H. influenzae (NTHi) clinical isolate NT127. P5 was essential for resistance of Rd and NT127 to complement in pooled human serum. Further investigation determined that P5 expression decreased cell surface binding of IgM, a potent activator of the classical pathway of complement, to both Rd and NT127. Additionally, P5 expression was required for NT127 to bind factor H (fH), an important inhibitor of alternative pathway (AP) activation. Collectively, the results obtained in this work highlight the ability of H. influenzae to utilize a single protein to perform multiple protective functions for evading host immunity. PMID- 24478081 TI - The Vps/VacJ ABC transporter is required for intercellular spread of Shigella flexneri. AB - The Vps/VacJ ABC transporter system is proposed to function in maintaining the lipid asymmetry of the outer membrane. Mutations in vps or vacJ in Shigella flexneri resulted in increased sensitivity to lysis by the detergent sodium dodecyl sulfate (SDS), and the vpsC mutant showed minor differences in its phospholipid profile compared to the wild type. vpsC mutants were unable to form plaques in cultured epithelial cells, but this was not due to a failure to invade, to replicate intracellularly, or to polymerize actin via IcsA for movement within epithelial cells. The addition of the outer membrane phospholipase gene pldA on a multicopy plasmid in a vpsC or vacJ mutant restored its resistance to SDS, suggesting a restoration of lipid asymmetry to the outer membrane. However, the pldA plasmid did not restore the mutant's ability to form plaques in tissue culture cells. Increased PldA levels also failed to restore the mutant's phospholipid profile to that of the wild type. We propose a dual function of the Vps/VacJ ABC transporter system in S. flexneri in both the maintenance of lipid asymmetry in the outer membrane and the intercellular spread of the bacteria between adjacent epithelial cells. PMID- 24478082 TI - An Escherichia coli Nissle 1917 missense mutant colonizes the streptomycin treated mouse intestine better than the wild type but is not a better probiotic. AB - Previously we reported that the streptomycin-treated mouse intestine selected for two different Escherichia coli MG1655 mutants with improved colonizing ability: nonmotile E. coli MG1655 flhDC deletion mutants that grew 15% faster in vitro in mouse cecal mucus and motile E. coli MG1655 envZ missense mutants that grew slower in vitro in mouse cecal mucus yet were able to cocolonize with the faster growing flhDC mutants. The E. coli MG1655 envZ gene encodes a histidine kinase that is a member of the envZ-ompR two-component signal transduction system, which regulates outer membrane protein profiles. In the present investigation, the envZP41L gene was transferred from the intestinally selected E. coli MG1655 mutant to E. coli Nissle 1917, a human probiotic strain used to treat gastrointestinal infections. Both the E. coli MG1655 and E. coli Nissle 1917 strains containing envZP41L produced more phosphorylated OmpR than their parents. The E. coli Nissle 1917 strain containing envZP41L also became more resistant to bile salts and colicin V and grew 50% slower in vitro in mucus and 15% to 30% slower on several sugars present in mucus, yet it was a 10-fold better colonizer than E. coli Nissle 1917. However, E. coli Nissle 1917 envZP41L was not better at preventing colonization by enterohemorrhagic E. coli EDL933. The data can be explained according to our "restaurant" hypothesis for commensal E. coli strains, i.e., that they colonize the intestine as sessile members of mixed biofilms, obtaining the sugars they need for growth locally, but compete for sugars with invading E. coli pathogens planktonically. PMID- 24478083 TI - Impact of surfactant protein D, interleukin-5, and eosinophilia on Cryptococcosis. AB - Cryptococcus neoformans is an opportunistic fungal pathogen that initiates infection following inhalation. As a result, the pulmonary immune response provides a first line of defense against C. neoformans. Surfactant protein D (SP D) is an important regulator of pulmonary immune responses and is typically host protective against bacterial and viral respiratory infections. However, SP-D is not protective against C. neoformans. This is evidenced by previous work from our laboratory demonstrating that SP-D-deficient mice infected with C. neoformans have a lower fungal burden and live longer than wild-type (WT) control animals. We hypothesized that SP-D alters susceptibility to C. neoformans by dysregulating the innate pulmonary immune response following infection. Thus, inflammatory cells and cytokines were compared in the bronchoalveolar lavage fluid from WT and SP-D(-/-) mice after C. neoformans infection. Postinfection, mice lacking SP-D have reduced eosinophil infiltration and interleukin-5 (IL-5) in lung lavage fluid. To further explore the interplay of SP-D, eosinophils, and IL-5, mice expressing altered levels of eosinophils and/or IL-5 were infected with C. neoformans to assess the role of these innate immune mediators. IL-5 overexpressing mice have increased pulmonary eosinophilia and are more susceptible to C. neoformans infection than WT mice. Furthermore, susceptibility of SP-D(-/-) mice to C. neoformans infection could be restored to the level of WT mice by increasing IL-5 and eosinophils by crossing the IL-5-overexpressing mice with SP-D(-/-) mice. Together, these studies support the conclusion that SP-D increases susceptibility to C. neoformans infection by promoting C. neoformans driven pulmonary IL-5 and eosinophil infiltration. PMID- 24478084 TI - The core promoter of the capsule operon of Streptococcus pneumoniae is necessary for colonization and invasive disease. AB - Streptococcus pneumoniae is a commensal of the human nasopharynx but can cause invasive diseases, including otitis media, pneumonia, sepsis, and meningitis. The capsular polysaccharide (capsule) is a critical virulence factor required for both asymptomatic colonization and invasive disease, yet the expression level is different in each anatomical site. During colonization, reduced levels of capsule promote binding to the host epithelium and biofilm formation, while during systemic infection, increased capsule is required to evade opsonophagocytosis. How this regulation of capsule expression occurs is incompletely understood. To investigate the contribution of transcriptional regulation on capsule level in the serotype 4 strain TIGR4, we constructed two mutants harboring a constitutive promoter that was either comparably weaker (Pcat) or stronger (PtRNAGlu) than the wild-type (WT) capsule promoter, Pcps. Mild reductions in cpsA and cpsE transcript levels in the Pcat promoter mutant resulted in a 2-fold reduction in total amounts of capsule and in avirulence in murine models of lung and blood infection. Additionally, the PtRNAGlu mutant revealed that, despite expressing enhanced levels of cpsA and cpsE and possessing levels of capsule comparable to those of WT TIGR4, it was still significantly attenuated in all tested in vivo niches. Further analysis using chimeric promoter mutants revealed that the WT -10 and -35 boxes are required for optimal nasopharyngeal colonization and virulence. These data support the hypothesis that dynamic transcriptional regulation of the capsule operon is required and that the core promoter region plays a central role in fine-tuning levels of capsule to promote colonization and invasive disease. PMID- 24478085 TI - Toxoplasma gondii Inhibits gamma interferon (IFN-gamma)- and IFN-beta-induced host cell STAT1 transcriptional activity by increasing the association of STAT1 with DNA. AB - The gamma interferon (IFN-gamma) response, mediated by the STAT1 transcription factor, is crucial for host defense against the intracellular pathogen Toxoplasma gondii, but prior infection with Toxoplasma can inhibit this response. Recently, it was reported that the Toxoplasma type II NTE strain prevents the recruitment of chromatin remodeling complexes containing Brahma-related gene 1 (BRG-1) to promoters of IFN-gamma-induced secondary response genes such as Ciita and major histocompatibility complex class II genes in murine macrophages, thereby inhibiting their expression. We report here that a type I strain of Toxoplasma inhibits the expression of primary IFN-gamma response genes such as IRF1 through a distinct mechanism not dependent on the activity of histone deacetylases. Instead, infection with a type I, II, or III strain of Toxoplasma inhibits the dissociation of STAT1 from DNA, preventing its recycling and further rounds of STAT1-mediated transcriptional activation. This leads to increased IFN-gamma induced binding of STAT1 at the IRF1 promoter in host cells and increased global IFN-gamma-induced association of STAT1 with chromatin. Toxoplasma type I infection also inhibits IFN-beta-induced interferon-stimulated gene factor 3 mediated gene expression, and this inhibition is also linked to increased association of STAT1 with chromatin. The secretion of proteins into the host cell by a type I strain of Toxoplasma without complete parasite invasion is not sufficient to block STAT1-mediated expression, suggesting that the effector protein responsible for this inhibition is not derived from the rhoptries. PMID- 24478086 TI - The phtC-phtD locus equips Legionella pneumophila for thymidine salvage and replication in macrophages. AB - The phagosomal transporter (Pht) family of the major facilitator superfamily (MFS) is encoded by phylogenetically related intracellular gammaproteobacteria, including the opportunistic pathogen Legionella pneumophila. The location of the pht genes between the putative thymidine kinase (tdk) and phosphopentomutase (deoB) genes suggested that the phtC and phtD loci contribute to thymidine salvage in L. pneumophila. Indeed, a phtC(+) allele in trans restored pyrimidine uptake to an Escherichia coli mutant that lacked all known nucleoside transporters, whereas a phtD(+) allele did not. The results of phenotypic analyses of L. pneumophila strains lacking phtC or phtD strongly indicate that L. pneumophila requires PhtC and PhtD function under conditions where sustained dTMP synthesis is compromised. First, in broth cultures that mimicked thymidine limitation or starvation, L. pneumophila exhibited a marked requirement for PhtC function. Conversely, mutation of phtD conferred a survival advantage. Second, in medium that lacked thymidine, multicopy phtC(+) or phtD(+) alleles enhanced the survival of L. pneumophila thymidylate synthase (thyA)-deficient strains, which cannot synthesize dTMP endogenously. Third, under conditions in which transport of the pyrimidine nucleoside analog 5-fluorodeoxyuridine (FUdR) would inhibit growth, PhtC and PhtD conferred a growth advantage to L. pneumophila thyA(+) strains. Finally, when cultured in macrophages, L. pneumophila required the phtC phtD locus to replicate. Accordingly, we propose that PhtC and PhtD contribute to protect L. pneumophila from dTMP starvation during its intracellular life cycle. PMID- 24478087 TI - Host-nonspecific iron acquisition systems and virulence in the zoonotic serovar of Vibrio vulnificus. AB - The zoonotic serovar of Vibrio vulnificus (known as biotype 2 serovar E) is the etiological agent of human and fish vibriosis. The aim of the present work was to discover the role of the vulnibactin- and hemin-dependent iron acquisition systems in the pathogenicity of this zoonotic serovar under the hypothesis that both are host-nonspecific virulence factors. To this end, we selected three genes for three outer membrane receptors (vuuA, a receptor for ferric vulnibactin, and hupA and hutR, two hemin receptors), obtained single and multiple mutants as well as complemented strains, and tested them in a series of in vitro and in vivo assays, using eels and mice as animal models. The overall results confirm that hupA and vuuA, but not hutR, are host-nonspecific virulence genes and suggest that a third undescribed host-specific plasmid-encoded system could also be used by the zoonotic serovar in fish. hupA and vuuA were expressed in the internal organs of the animals in the first 24 h of infection, suggesting that they may be needed to achieve the population size required to trigger fatal septicemia. vuuA and hupA were sequenced in strains representative of the genetic diversity of this species, and their phylogenies were reconstructed by multilocus sequence analysis of selected housekeeping and virulence genes as a reference. Given the overall results, we suggest that both genes might form part of the core genes essential not only for disease development but also for the survival of this species in its natural reservoir, the aquatic environment. PMID- 24478088 TI - Hepcidin induction by pathogens and pathogen-derived molecules is strongly dependent on interleukin-6. AB - Hepcidin, the iron-regulatory hormone, is increased during infection or inflammation, causing hypoferremia. This response is thought to be a host defense mechanism that restricts iron availability to invading pathogens. It is not known if hepcidin is differentially induced by bacterial versus viral infections, whether the stimulation of pattern recognition receptors directly regulates hepcidin transcription, or which of the proposed signaling pathways are essential for hepcidin increase during infection. We analyzed hepcidin induction and its dependence on interleukin-6 (IL-6) in response to common bacterial or viral infections in mice or in response to a panel of pathogen-derived molecules (PAMPs) in mice and human primary hepatocytes. In wild-type (WT) mice, hepcidin mRNA was induced several hundred-fold both by a bacterial (Streptococcus pneumoniae) and a viral infection (influenza virus PR8) within 2 to 5 days. Treatment of mice and human primary hepatocytes with most Toll-like receptor ligands increased hepcidin mRNA within 6 h. Hepcidin induction by microbial stimuli was IL-6 dependent. IL-6 knockout mice failed to increase hepcidin in response to S. pneumoniae or influenza infection and had greatly diminished hepcidin response to PAMPs. In vitro, hepcidin induction by PAMPs in primary human hepatocytes was abolished by the addition of neutralizing IL-6 antibodies. Our results support the key role of IL-6 in hepcidin regulation in response to a variety of infectious and inflammatory stimuli. PMID- 24478089 TI - Susceptibility to acute rheumatic fever based on differential expression of genes involved in cytotoxicity, chemotaxis, and apoptosis. AB - It is unknown why only some individuals are susceptible to acute rheumatic fever (ARF). We investigated whether there are differences in the immune response, detectable by gene expression, between individuals who are susceptible to ARF and those who are not. Peripheral blood mononuclear cells (PBMCs) from 15 ARF susceptible and 10 nonsusceptible (control) adults were stimulated with rheumatogenic (Rh+) group A streptococci (GAS) or nonrheumatogenic (Rh-) GAS. RNA from stimulated PBMCs from each subject was cohybridized with RNA from unstimulated PBMCs on oligonucleotide arrays to compare gene expression. Thirty four genes were significantly differentially expressed between ARF-susceptible and control groups after stimulation with Rh+ GAS. A total of 982 genes were differentially expressed between Rh+ GAS- and Rh- GAS-stimulated samples from ARF susceptible individuals. Thirteen genes were differentially expressed in the same direction (predominantly decreased) between the two study groups and between the two stimulation conditions, giving a strong indication of their involvement. Seven of these were immune response genes involved in cytotoxicity, chemotaxis, and apoptosis. There was variability in the degree of expression change between individuals. The high proportion of differentially expressed apoptotic and immune response genes supports the current model of autoimmune and cytokine dysregulation in ARF. This study also raises the possibility that a "failed" immune response, involving decreased expression of cytotoxic and apoptotic genes, contributes to the immunopathogenesis of ARF. PMID- 24478090 TI - Murine neonates infected with Yersinia enterocolitica develop rapid and robust proinflammatory responses in intestinal lymphoid tissues. AB - Neonatal animals are generally very susceptible to infection with bacterial pathogens. However, we recently reported that neonatal mice are highly resistant to orogastric infection with Yersinia enterocolitica. Here, we show that proinflammatory responses greatly exceeding those in adults arise very rapidly in the mesenteric lymph nodes (MLN) of neonates. High-level induction of proinflammatory gene expression occurred in the neonatal MLN as early as 18 h postinfection. Marked innate phagocyte recruitment was subsequently detected at 24 h postinfection. Enzyme-linked immunosorbent spot assay (ELISPOT) analyses indicated that enhanced inflammation in neonatal MLN is contributed to, in part, by an increased frequency of proinflammatory cytokine-secreting cells. Moreover, both CD11b(+) and CD11b(-) cell populations appeared to play a role in proinflammatory gene expression. The level of inflammation in neonatal MLN was also dependent on key bacterial components. Y. enterocolitica lacking the virulence plasmid failed to induce innate phagocyte recruitment. In contrast, tumor necrosis factor alpha (TNF-alpha) protein expression and neutrophil recruitment were strikingly higher in neonatal MLN after infection with a yopP deficient strain than with wild-type Y. enterocolitica, whereas only modest increases occurred in adults. This hyperinflammatory response was associated with greater colonization of the spleen and higher mortality in neonates, while there was no difference in mortality among adults. This model highlights the dynamic levels of inflammation in the intestinal lymphoid tissues and reveals the protective (wild-type strain) versus harmful (yopP-deficient strain) consequences of inflammation in neonates. Moreover, these results reveal that the neonatal intestinal lymphoid tissues have great potential to rapidly mobilize innate components in response to infection with bacterial enteropathogens. PMID- 24478091 TI - G proteins Galphai1/3 are critical targets for Bordetella pertussis toxin-induced vasoactive amine sensitization. AB - Pertussis toxin (PTX) is an AB5-type exotoxin produced by the bacterium Bordetella pertussis, the causative agent of whooping cough. In vivo intoxication with PTX elicits a variety of immunologic and inflammatory responses, including vasoactive amine sensitization (VAAS) to histamine (HA), serotonin (5-HT), and bradykinin (BDK). Previously, by using a forward genetic approach, we identified the HA H1 receptor (Hrh1/H1R) as the gene in mice that controls differential susceptibility to B. pertussis PTX-induced HA sensitization (Bphs). Here we show, by using inbred strains of mice, F1 hybrids, and segregating populations, that, unlike Bphs, PTX-induced 5-HT sensitivity (Bpss) and BDK sensitivity (Bpbs) are recessive traits and are separately controlled by multiple loci unlinked to 5-HT and BDK receptors, respectively. Furthermore, we found that PTX sensitizes mice to HA independently of Toll-like receptor 4, a purported receptor for PTX, and that the VAAS properties of PTX are not dependent upon endothelial caveolae or endothelial nitric oxide synthase. Finally, by using mice deficient in individual Galphai/o G-protein subunits, we demonstrate that Galphai1 and Galphai3 are the critical in vivo targets of ADP-ribosylation underlying VAAS elicited by PTX exposure. PMID- 24478092 TI - Vaginal epithelial cell-derived S100 alarmins induced by Candida albicans via pattern recognition receptor interactions are sufficient but not necessary for the acute neutrophil response during experimental vaginal candidiasis. AB - Vulvovaginal candidiasis (VVC), caused by Candida albicans, affects women worldwide. Animal and clinical studies suggest that the immunopathogenic inflammatory condition of VVC is initiated by S100 alarmins in response to C. albicans, which stimulate polymorphonuclear neutrophil (PMN) migration to the vagina. The purpose of this study was to extend previous in vitro data and determine the requirement for the alarmin S100A8 in the PMN response and to evaluate pattern recognition receptors (PRRs) that initiate the response. For the former, PMN migration was evaluated in vitro or in vivo in the presence or absence of S100 alarmins initiated by several approaches. For the latter, vaginal epithelial cells were evaluated for PRR expression and C. albicans-induced S100A8 and S100A9 mRNAs, followed by evaluation of the PMN response in inoculated PRR deficient mice. Results revealed that, consistent with previously reported in vitro data, eukaryote-derived S100A8, but not prokaryote-derived recombinant S100A8, induced significant PMN chemotaxis in vivo. Conversely, a lack of biologically active S100A8 alarmin, achieved by antibody neutralization or by using S100A9(-/-) mice, had no effect on the PMN response in vivo. In PRR analyses, whereas Toll-like receptor 4 (TLR4)- and SIGNR1-deficient vaginal epithelial cells showed a dramatic reduction in C. albicans-induced S100A8/S100A9 mRNAs in vitro, inoculated mice deficient in these PRRs showed PMN migration similar to that in wild-type controls. These results suggest that S100A8 alarmin is sufficient, but not necessary, to induce PMN migration during VVC and that the vaginal PMN response to C. albicans involves PRRs in addition to SIGNR1 and TLR4, or other induction pathways. PMID- 24478093 TI - Immunogenicity of a prime-boost vaccine containing the circumsporozoite proteins of Plasmodium vivax in rodents. AB - Plasmodium vivax is the most widespread and the second most prevalent malaria causing species in the world. Current measures used to control the transmission of this disease would benefit from the development of an efficacious vaccine. In the case of the deadly parasite P. falciparum, the recombinant RTS,S vaccine containing the circumsporozoite antigen (CSP) consistently protects 30 to 50% of human volunteers against infection and is undergoing phase III clinical trials in Africa with similar efficacy. These findings encouraged us to develop a P. vivax vaccine containing the three circulating allelic forms of P. vivax CSP. Toward this goal, we generated three recombinant bacterial proteins representing the CSP alleles, as well as a hybrid polypeptide called PvCSP-All-CSP-epitopes. This hybrid contains the conserved N and C termini of P. vivax CSP and the three variant repeat domains in tandem. We also generated simian and human recombinant replication-defective adenovirus vectors expressing PvCSP-All-CSP-epitopes. Mice immunized with the mixture of recombinant proteins in a formulation containing the adjuvant poly(I.C) developed high and long-lasting serum IgG titers comparable to those elicited by proteins emulsified in complete Freund's adjuvant. Antibody titers were similar in mice immunized with homologous (protein protein) and heterologous (adenovirus-protein) vaccine regimens. The antibodies recognized the three allelic forms of CSP, reacted to the repeated and nonrepeated regions of CSP, and recognized sporozoites expressing the alleles VK210 and VK247. The vaccine formulations described in this work should be useful for the further development of an anti-P. vivax vaccine. PMID- 24478094 TI - Model for in vivo assessment of humoral protection against malaria sporozoite challenge by passive transfer of monoclonal antibodies and immune serum. AB - Evidence from clinical trials of malaria vaccine candidates suggests that both cell-mediated and humoral immunity to pre-erythrocytic parasite stages can provide protection against infection. Novel pre-erythrocytic antibody (Ab) targets could be key to improving vaccine formulations, which are currently based on targeting antigens such as the circumsporozoite protein (CSP). However, methods to assess the effects of sporozoite-specific Abs on pre-erythrocytic infection in vivo remain underdeveloped. Here, we combined passive transfer of monoclonal Abs (MAbs) or immune serum with a luciferase-expressing Plasmodium yoelii sporozoite challenge to assess Ab-mediated inhibition of liver infection in mice. Passive transfer of a P. yoelii CSP MAb showed inhibition of liver infection when mice were challenged with sporozoites either intravenously or by infectious mosquito bite. However, inhibition was most potent for the mosquito bite challenge, leading to a more significant reduction of liver-stage burden and even a lack of progression to blood-stage parasitemia. This suggests that Abs provide effective protection against a natural infection. Inhibition of liver infection was also achieved by passive transfer of immune serum from whole parasite-immunized mice. Furthermore, we demonstrated that passive transfer of a MAb against P. falciparum CSP inhibited liver-stage infection in a humanized mouse/P. falciparum challenge model. Together, these models constitute unique and sensitive in vivo methods to assess serum-transferable protection against Plasmodium sporozoite challenge. PMID- 24478096 TI - MyD88 signaling is directly involved in the development of murine placental malaria. AB - Malaria is a widespread infectious disease caused by the parasite Plasmodium. During pregnancy, malaria infection leads to a range of complications that can affect both the mother and fetus, including stillbirth, infant mortality, and low birth weight. In this study, we utilized a mouse model of placental malaria (PM) infection to determine the importance of the protein MyD88 in the host immune response to Plasmodium during pregnancy. Initially, we demonstrated that Plasmodium berghei NK65GFP adhered to placental tissue via chondroitin sulfate A and induced PM in mice with a C57BL/6 genetic background. To evaluate the involvement of MyD88 in the pathology of PM, we performed a histopathological analysis of placentas obtained from MyD88(-/-) and wild-type (WT) mice following infection on the 19th gestational day. Our data demonstrated that the detrimental placental alterations observed in the infected mice were correlated with the expression of MyD88. Moreover, in the absence of this protein, production of interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) was significantly reduced in the infected mice. More importantly, in contrast to fetuses from infected WT mice, which exhibited a reduction in body weight, the fetuses from infected MyD88(-/-) mice did not display significant weight loss compared to their noninfected littermates. In addition, we observed a decrement of maternal care associated with malaria infection, which was attenuated in the MyD88-deficient mice. Collectively, the results of this study illustrate the pivotal importance of the MyD88 signaling pathway in the pathogenesis of placental malaria, thus presenting new possibilities for targeting MyD88 in therapeutic interventions. PMID- 24478095 TI - Antibodies to a single, conserved epitope in Anopheles APN1 inhibit universal transmission of Plasmodium falciparum and Plasmodium vivax malaria. AB - Malaria transmission-blocking vaccines (TBVs) represent a promising approach for the elimination and eradication of this disease. AnAPN1 is a lead TBV candidate that targets a surface antigen on the midgut of the obligate vector of the Plasmodium parasite, the Anopheles mosquito. In this study, we demonstrated that antibodies targeting AnAPN1 block transmission of Plasmodium falciparum and Plasmodium vivax across distantly related anopheline species in countries to which malaria is endemic. Using a biochemical and immunological approach, we determined that the mechanism of action for this phenomenon stems from antibody recognition of a single protective epitope on AnAPN1, which we found to be immunogenic in murine and nonhuman primate models and highly conserved among anophelines. These data indicate that AnAPN1 meets the established target product profile for TBVs and suggest a potential key role for an AnAPN1-based panmalaria TBV in the effort to eradicate malaria. PMID- 24478097 TI - Role of ferric reductases in iron acquisition and virulence in the fungal pathogen Cryptococcus neoformans. AB - Iron acquisition is critical for the ability of the pathogenic yeast Cryptococcus neoformans to cause disease in vertebrate hosts. In particular, iron overload exacerbates cryptococcal disease in an animal model, defects in iron acquisition attenuate virulence, and iron availability influences the expression of major virulence factors. C. neoformans acquires iron by multiple mechanisms, including a ferroxidase-permease high-affinity system, siderophore uptake, and utilization of both heme and transferrin. In this study, we examined the expression of eight candidate ferric reductase genes and their contributions to iron acquisition as well as to ferric and cupric reductase activities. We found that loss of the FRE4 gene resulted in a defect in production of the virulence factor melanin and increased susceptibility to azole antifungal drugs. In addition, the FRE2 gene was important for growth on the iron sources heme and transferrin, which are relevant for proliferation in the host. Fre2 may participate with the ferroxidase Cfo1 of the high-affinity uptake system for growth on heme, because a mutant lacking both genes showed a more pronounced growth defect than the fre2 single mutant. A role for Fre2 in iron acquisition is consistent with the attenuation of virulence observed for the fre2 mutant. This mutant also was defective in accumulation in the brains of infected mice, a phenotype previously observed for mutants with defects in high-affinity iron uptake (e.g., the cfo1 mutant). Overall, this study provides a more detailed view of the iron acquisition components required for C. neoformans to cause cryptococcosis. PMID- 24478098 TI - Klebsiella pneumoniae induces an inflammatory response in an in vitro model of blood-retinal barrier. AB - Klebsiella pneumoniae has become an important pathogen in recent years. Although most cases of K. pneumoniae endogenous endophthalmitis occur via hematogenous spread, it is not yet clear which microbial and host factors are responsible for the ability of K. pneumoniae to cross the blood-retinal barrier (BRB). In the present study, we show that in an in vitro model of BRB based on coculturing primary bovine retinal endothelial cells (BREC) and primary bovine retinal pericytes (BRPC), K. pneumoniae infection determines changes of transendothelial electrical resistance (TEER) and permeability to sodium fluorescein. In the coculture model, bacteria are able to stimulate the enzyme activities of endothelial cytosolic and Ca(2+)-independent phospholipase A2s (cPLA2 and iPLA2). These results were confirmed by the incremental expression of cPLA2, iPLA2, cyclo oxygenase-1 (COX1), and COX2 in BREC, as well as by cPLA2 phosphorylation. In supernatants of K. pneumoniae-stimulated cocultures, increases in prostaglandin E2 (PGE2), interleukin-6 (IL-6), IL-8, and vascular endothelial growth factor (VEGF) production were found. Incubation with K. pneumoniae in the presence of arachidonoyl trifluoromethyl ketone (AACOCF3) or bromoenol lactone (BEL) caused decreased PGE2 and VEGF release. Scanning electron microscopy and transmission electron microscopy images of BREC and BRPC showed adhesion of K. pneumoniae to the cells, but no invasion occurred. K. pneumoniae infection also produced reductions in pericyte numbers; transfection of BREC cocultured with BRPC and of human retinal endothelial cells (HREC) cocultured with human retinal pericytes (HRPC) with small interfering RNAs (siRNAs) targeted to cPLA2 and iPLA2 restored the pericyte numbers and the TEER and permeability values. Our results show the proinflammatory effect of K. pneumoniae on BREC, suggest a possible mechanism by which BREC and BRPC react to the K. pneumoniae infection, and may provide physicians and patients with new ways of fighting blinding diseases. PMID- 24478099 TI - Two-photon intravital imaging of lungs during anthrax infection reveals long lasting macrophage-dendritic cell contacts. AB - The dynamics of the lung immune system at the microscopic level are largely unknown because of inefficient methods of restraining chest motion during image acquisition. In this study, we developed an improved intravital method for two photon lung imaging uniquely based on a posteriori parenchymal tissue motion correction. We took advantage of the alveolar collagen pattern given by the second harmonic generation signal as a reference for frame registration. We describe here for the first time a detailed dynamic account of two major lung immune cell populations, alveolar macrophages and CD11b-positive dendritic cells, during homeostasis and infection by spores of Bacillus anthracis, the agent of anthrax. We show that after alveolar macrophages capture spores, CD11b-positive dendritic cells come in prolonged contact with infected macrophages. Dendritic cells are known to carry spores to the draining lymph nodes and elicit the immune response in pulmonary anthrax. The intimate and long-lasting contacts between these two lines of defense may therefore coordinate immune responses in the lung through an immunological synapse-like process. PMID- 24478100 TI - Entry of a recombinant, full-length, atoxic tetanus neurotoxin into Neuro-2a cells. AB - Tetanus neurotoxin (TeNT) and botulinum neurotoxin (BoNT) are clostridial neurotoxins (CNTs) responsible for the paralytic diseases tetanus and botulism, respectively. CNTs are AB toxins with an N-terminal zinc-metalloprotease light chain that is linked by a disulfide bond to a C-terminal heavy chain that includes a translocation domain and a receptor-binding domain (HCR). Current models predict that the HCR defines how CNTs enter and traffic in neurons. Recent studies implicate that domains outside the HCR contribute to CNT trafficking in neurons. In the current study, a recombinant, full-length TeNT derivative, TeNT(RY), was engineered to analyze TeNT cell entry. TeNT(RY) was atoxic in a mouse challenge model. Using Neuro-2a cells, a mouse neuroblastoma cell line, TeNT HCR (HCR/T) and TeNT(RY) were found to bind gangliosides with similar affinities and specificities, consistent with the HCR domain containing receptor binding function. Temporal studies showed that HCR/T and TeNT(RY) entered Neuro 2a cells slower than the HCR of BoNT/A (HCR/A), transferrin, and cholera toxin B. Intracellular localization showed that neither HCR/T nor TeNT(RY) localized with HCR/A or synaptic vesicle protein 2, the protein receptor for HCR/A. HCR/T and TeNT(RY) exhibited only partial intracellular colocalization, indicating that regions outside the HCR contribute to the intracellular TeNT trafficking. TeNT may require this complex functional entry organization to target neurons in the central nervous system. PMID- 24478101 TI - Pathogenic fungus Microsporum canis activates the NLRP3 inflammasome. AB - Microsporum canis is a pathogenic fungus with worldwide distribution that causes tinea capitis in animals and humans. M. canis also causes invasive infection in immunocompromised patients. To defy pathogenic fungal infection, the host innate immune system is the first line of defense. As an important arm of innate immunity, the inflammasomes are intracellular multiprotein complexes that control the activation of caspase-1, which cleaves proinflammatory cytokine pro interleukin-1beta (IL-1beta) into its mature form. To determine whether the inflammasome is involved in the host defense against M. canis infection, we challenged human monocytic THP-1 cells and mouse dendritic cells with a clinical strain of M. canis isolated from patients with tinea capitis. We found that M. canis infection triggered rapid secretion of IL-1beta from both THP-1 cells and mouse dendritic cells. Moreover, by using gene-specific shRNA and competitive inhibitors, we determined that M. canis-induced IL-1beta secretion was dependent on NLRP3. The pathways proposed for NLRP3 inflammasome activation, namely, cathepsin B activity, K(+) efflux, and reactive oxygen species production, were all required for the inflammasome activation triggered by M. canis. Meanwhile, Syk, Dectin-1, and Card9 were found to be involved in M. canis-induced IL-1beta secretion via regulation of pro-IL-1beta transcription. More importantly, our data revealed that M. canis-induced production of IL-1beta was dependent on the NLRP3 inflammasome in vivo. Together, this study unveils that the NLRP3 inflammasome exerts a critical role in host innate immune responses against M. canis infection, and our data suggest that diseases that result from M. canis infection might be controlled by regulating the activation of inflammasomes. PMID- 24478102 TI - Oral immunization with Escherichia coli expressing a lipidated form of LigA protects hamsters against challenge with Leptospira interrogans serovar Copenhageni. AB - Leptospirosis is a potentially fatal zoonosis transmitted by reservoir host animals that harbor leptospires in their renal tubules and shed the bacteria in their urine. Leptospira interrogans serovar Copenhageni transmitted from Rattus norvegicus to humans is the most prevalent cause of urban leptospirosis. We examined L. interrogans LigA, domains 7 to 13 (LigA7-13), as an oral vaccine delivered by Escherichia coli as a lipidated, membrane-associated protein. The efficacy of the vaccine was evaluated in a susceptible hamster model in terms of the humoral immune response and survival from leptospiral challenge. Four weeks of oral administration of live E. coli expressing LigA7-13 improved survival from intraperitoneal (i.p.) and intradermal (i.d.) challenge by L. interrogans serovar Copenhageni strain Fiocruz L1-130 in Golden Syrian hamsters. Immunization with E. coli expressing LigA7-13 resulted in a systemic antibody response, and a significant LigA7-13 IgG level after the first 2 weeks of immunization was completely predictive of survival 28 days after challenge. As in previous LigA vaccine studies, all immunized hamsters that survived infection had renal leptospiral colonization and histopathological changes. In summary, an oral LigA based vaccine improved survival from leptospiral challenge by either the i.p. or i.d. route. PMID- 24478106 TI - Comparison of sampling strategies and sparsifying transforms to improve compressed sensing diffusion spectrum imaging. AB - PURPOSE: Diffusion Spectrum Imaging enables to reconstruct the ensemble average propagator (EAP) at the expense of having to acquire a large number of measurements. Compressive sensing offers an efficient way to decrease the required number of measurements. The purpose of this work is to perform a thorough experimental comparison of three sampling strategies and six sparsifying transforms to show their impact when applied to accelerate compressive sensing diffusion spectrum imaging. METHODS: We propose a novel sampling scheme that assures uniform angular and random radial q-space samples. We also compare and implement six discrete sparse representations of the EAP and thoroughly evaluate them on synthetic and real data using metrics from the full EAP, kurtosis, and orientation distribution function. RESULTS: The discrete wavelet transform with Cohen-Daubechies-Feauveau 9/7 wavelets and uniform angular sampling in combination with random radial sampling showed to be better than other tested techniques to accurately reconstruct the EAP and its features. CONCLUSION: It is important to jointly optimize the sampling scheme and the sparsifying transform to obtain accelerated compressive sensing-diffusion spectrum imaging. Experiments on synthetic and real human brain data show that one can robustly recover both radial and angular EAP features while undersampling the acquisition to 64 measurements (undersampling factor of 4). PMID- 24478103 TI - Vaccinated C57BL/6 mice develop protective and memory T cell responses to Coccidioides posadasii infection in the absence of interleukin-10. AB - High concentrations of lung tissue-associated interleukin-10 (IL-10), an anti inflammatory and immunosuppressive cytokine, correlate with susceptibility of mice to Coccidioides spp. infection. In this study, we found that macrophages, dendritic cells, neutrophils, and both CD8(+) and CD4(+) T cells recruited to Coccidioides posadasii-infected lungs of nonvaccinated and vaccinated mice contributed to the production of IL-10. The major IL-10-producing leukocytes were CD8(+) T cells, neutrophils, and macrophages in lungs of nonvaccinated mice, while both Foxp3(+) and Foxp3(-) subsets of IL-10(+) CD4(+) T cells were significantly elevated in vaccinated mice. Profiles of the recruited leukocytes in lungs revealed that only CD4(+) T cells were significantly increased in IL-10( /-) knockout mice compared to their wild-type counterparts. Furthermore, ex vivo recall assays showed that CD4(+) T cells isolated from vaccinated IL-10(-/-) mice compared to vaccinated wild-type mice produced significantly higher amounts of IL 2, gamma interferon (IFN-gamma), IL-4, IL-6, and IL-17A in the presence of a coccidioidal antigen, indicating that IL-10 suppresses Th1, Th2, and Th17 immunity to Coccidioides infection. Analysis of absolute numbers of CD44(+) CD62L(-) CD4(+) T effector memory T cells (TEM) and IFN-gamma- and IL-17A producing CD4(+) T cells in the lungs of Coccidioides-infected mice correlated with better fungal clearance in nonvaccinated IL-10(-/-) mice than in nonvaccinated wild-type mice. Our results suggest that IL-10 suppresses CD4(+) T cell immunity in nonvaccinated mice during Coccidioides infection but does not impede the development of a memory response nor exacerbate immunopathology of vaccinated mice over at least a 4-month period after the last immunization. PMID- 24478107 TI - Resistant starch type 4-enriched diet lowered blood cholesterols and improved body composition in a double blind controlled cross-over intervention. AB - A metabolic health crisis is evident as cardiovascular diseases (CVD) remain the leading cause of mortality in the United States. Effects of resistant starch type 4 (RS4), a prebiotic fiber, in comprehensive management of metabolic syndrome (MetS) remain unknown. This study examined the effects of a blinded exchange of RS4-enriched flour (30% v/v) with regular/control flour (CF) diet on multiple MetS comorbidities. In a double blind (participants-investigators), placebo controlled, cluster cross-over intervention (n = 86, age>=18, 2-12 week interventions, 2-week washout) in the United States, individuals were classified as having MetS (With-MetS) or not (No-MetS) following International Diabetes Federation (IDF)-criteria. RS4 consumption compared with CF resulted in 7.2% (p = 0.002) lower mean total cholesterol, 5.5% (p = 0.04) lower non-HDL, and a 12.8% (p < 0.001) lower HDL cholesterol in the With-MetS group. No-MetS individuals had a 2.6% (p = 0.02) smaller waist circumference and 1.5% (p = 0.03) lower percent body fat following RS4 intervention compared to CF. A small but significant 1% increase in fat-free mass was observed in all participants combined (p = 0.02). No significant effect of RS4 was observed for glycemic variables and blood pressures. RS4 consumption improved dyslipidemia and body composition. Incorporation of RS4 in routine diets could offer an effective strategy for public cardio-metabolic health promotion. PMID- 24478108 TI - A novel homozygous splicing mutation in PSAP gene causes metachromatic leukodystrophy in two Moroccan brothers. AB - Prosaposin (PSAP) gene mutations, affecting saposin B (Sap-B) domain, cause a rare metachromatic leukodystrophy (MLD) variant in which arylsulfatase A (ARSA) activity is normal. To date, only 10 different PSAP mutations have been associated with a total of 18 unrelated MLD patients worldwide. In this study, we report for the first time a family with Moroccan origins in which the proband, presenting with a late-infantile onset of neurological involvement and a brain MRI with the typical tigroid MLD pattern, showed normal values of ARSA activity in the presence of an abnormal pattern of urinary sulfatides. In view of these findings, PSAP gene was analyzed, identifying the newly genomic homozygous c.909 + 1G > A mutation occurring within the invariant GT dinucleotide of the intron 8 donor splice site. Reverse transcriptase-polymerase chain reaction (RT-PCR), showing the direct junction of exon 7 to exon 9, confirmed the skipping of the entire exon 8 (p.Gln260_Lys303) which normally contains two cysteine residues (Cys271 and Cys265) involved in disulfide bridges. Our report provides further evidence that phenotypes of patients with Sap-B deficiency vary widely depending on age of onset, type, and severity of symptoms. Awareness of this rare MLD variant is crucial to prevent delayed diagnosis or misdiagnosis and to promptly provide an accurate genetic counseling, including prenatal diagnosis, to families. PMID- 24478109 TI - Operative outcomes of adult living donor liver transplantation and deceased donor liver transplantation: a systematic review and meta-analysis. AB - Living donor liver transplantation (LDLT) has emerged as an alternative to deceased donor liver transplantation (DDLT) because of the increasing number of patients waiting for liver transplantation (LT). However, whether it can achieve operative outcomes similar to those achieved with DDLT for adult patients remains controversial. We conducted this meta-analysis to compare the operative outcomes of LDLT and DDLT recipients. A literature search was performed to identify clinical controlled studies comparing LDLT and DDLT that were published before October 2013. Four perioperative outcomes [duration of the recipient operation (DRO), red blood cell (RBC) transfusion requirement, length of the hospital stay, and cold ischemia time (CIT)] and 5 postoperative complication outcomes (biliary complications, vascular complications, intra-abdominal bleeding, perioperative death, and retransplantation) were the main outcomes assessed. Nineteen studies with a total of 5450 patients were included in the meta-analysis. In comparison with DDLT, LDLT was associated with a significantly longer DRO and a shorter CIT. We found that biliary complications [odds ratio (OR) = 3.08, 95% confidence interval (CI) = 1.97-4.81, P < 0.001], vascular complications (OR = 2.16, 95% CI = 1.32-3.54, P = 0.002), and retransplantation (OR = 1.76, 95% CI = 1.09-2.83, P = 0.02) occurred more frequently for LDLT recipients, and the subgroup analysis indicated that the biliary complication rate decreased dramatically with greater LDLT experience. No significant difference was observed in RBC transfusion requirements, the lengths of hospital stays, intra-abdominal bleeding rates, or perioperative mortality between LDLT and DDLT recipients. In conclusion, LDLT is associated with a higher rate of surgical complications after transplantation. A reduction of postoperative complication rates can be achieved as centers gain greater experience with LDLT. However, LDLT is still an excellent alternative to DDLT because it facilitates access to LT. PMID- 24478110 TI - Assessing the environmental sustainability of ethanol from integrated biorefineries. AB - This paper considers the life cycle environmental sustainability of ethanol produced in integrated biorefineries together with chemicals and energy. Four types of second-generation feedstocks are considered: wheat straw, forest residue, poplar, and miscanthus. Seven out of 11 environmental impacts from ethanol are negative, including greenhouse gas (GHG) emissions, when the system is credited for the co-products, indicating environmental savings. Ethanol from poplar is the best and straw the worst option for most impacts. Land use change from forest to miscanthus increases the GHG emissions several-fold. For poplar, the effect is opposite: converting grassland to forest reduces the emissions by three-fold. Compared to fossil and first-generation ethanol, ethanol from integrated biorefineries is more sustainable for most impacts, with the exception of wheat straw. Pure ethanol saves up to 87% of GHG emissions compared to petrol per MJ of fuel. However, for the current 5% ethanol-petrol blends, the savings are much smaller (<3%). Therefore, unless much higher blends become widespread, the contribution of ethanol from integrated biorefineries to the reduction of GHG emissions will be insignificant. Yet, higher ethanol blends would lead to an increase in some impacts, notably terrestrial and freshwater toxicity as well as eutrophication for some feedstocks. PMID- 24478111 TI - Metal-ion-regulated miniature DNA-binding proteins based on GCN4 and non-native regulation sites. AB - The design of artificial peptide dimers containing polypyridine switching domains, for which metal-ion coordination is shown to regulate DNA binding, is reported. Short peptides, based on the basic domain of the GCN4 transcription factor (GCN4bd), dimerised with either 2,2'-bipyridine (bipy(GCN4bd)2 ) or 2,2':6',2''-terpyridine (terpy(GCN4bd)2 ) linker units, undergo a conformational rearrangement on Cu(II) and Zn(II) coordination. Depending on the linker substitution pattern, this is proposed to alter the relative alignment of the two peptide moieties, and in turn regulate DNA binding. Circular dichroism and UV visible spectroscopy reveal that Cu(II) and Zn(II) coordination promotes binding to DNA containing the CRE target site, but to a differing and opposite degree for the two linkers, and that the metal-ion affinity for terpy(GCN4bd)2 is enhanced in the presence of CRE DNA. Binding to DNA containing the shorter AP1 target site, which lacks a single nucleobase pair compared to CRE, as well as half-CRE, which contains only half of the CRE target site, was also investigated. Cu(II) and Zn(II) coordination to terpy(GCN4bd)2 promotes binding to AP1 DNA, and to a lesser extent half-CRE DNA. Whereas, bipy(GCN4bd)2 , for which interpeptide distances are largely independent of metal-ion coordination and less suitable for binding to these shorter sites, displays allosteric ineffective behaviour in these cases. These findings for the first time demonstrate that biomolecular recognition, and specifically sequence-selective DNA binding, can be controlled by metal-ion coordination to designed switching units, non-native regulation sites, in artificial biomolecules. We believe that in the future these could find a wide range of applications in biotechnology. PMID- 24478112 TI - Toxin-Antitoxin systems: their role in persistence, biofilm formation, and pathogenicity. AB - One of the most pertinent recent outcomes of molecular microbiology efforts to understand bacterial behavior is the discovery of a wide range of toxin-antitoxin (TA) systems that are tightly controlling bacterial persistence. While TA systems were originally linked to control over the genetic material, for example plasmid maintenance, it is now clear that they are involved in essential cellular processes like replication, gene expression, and cell wall synthesis. Toxin activity is induced stochastically or after environmental stimuli, resulting in silencing of the above-mentioned biological processes and entry in a dormant state. In this minireview, we highlight the recent developments in research on these intriguing systems with a focus on their role in biofilms and in bacterial virulence. We discuss their potential as targets in antimicrobial drug discovery. PMID- 24478114 TI - Metal-free aminosulfonylation of aryldiazonium tetrafluoroborates with DABCO?(SO2)2 and hydrazines. AB - The coupling of aryldiazonium tetrafluoroborates, DABCO?(SO2)2, and hydrazines under metal-free conditions leads to the formation of aryl N-aminosulfonamides. The reaction proceeds smoothly at room temperature and shows broad functional group tolerance. A radical process is proposed for this transformation. PMID- 24478113 TI - Developing an African youth psychosocial assessment: an application of item response theory. AB - This study aimed to refine a dimensional scale for measuring psychosocial adjustment in African youth using item response theory (IRT). A 60-item scale derived from qualitative data was administered to 667 war-affected adolescents (55% female). Exploratory factor analysis (EFA) determined the dimensionality of items based on goodness-of-fit indices. Items with loadings less than 0.4 were dropped. Confirmatory factor analysis (CFA) was used to confirm the scale's dimensionality found under the EFA. Item discrimination and difficulty were estimated using a graded response model for each subscale using weighted least squares means and variances. Predictive validity was examined through correlations between IRT scores (theta) for each subscale and ratings of functional impairment. All models were assessed using goodness-of-fit and comparative fit indices. Fisher's Information curves examined item precision at different underlying ranges of each trait. Original scale items were optimized and reconfigured into an empirically-robust 41-item scale, the African Youth Psychosocial Assessment (AYPA). Refined subscales assess internalizing and externalizing problems, prosocial attitudes/behaviors and somatic complaints without medical cause. The AYPA is a refined dimensional assessment of emotional and behavioral problems in African youth with good psychometric properties. Validation studies in other cultures are recommended. PMID- 24478115 TI - Iron metabolism: from health to disease. AB - BACKGROUND: Iron is vital for almost all living organisms by participating in a wide range of metabolic processes. However, iron concentration in body tissues must be tightly regulated since excessive iron may lead to microbial infections or cause tissue damage. Disorders of iron metabolism are among the most common human diseases and cover several conditions with varied clinical manifestations. METHODS: An extensive literature review on the basic aspects of iron metabolism was performed, and the most recent findings on this field were highlighted as well. RESULTS: New insights on iron metabolism have shed light into its real complexity, and its role in both healthy and pathological states has been recognized. Important discoveries about the iron regulatory machine and imbalances in its regulation have been made, which may lead in a near future to the development of new therapeutic strategies against iron disorders. Besides, the toxicity of free iron and its association with several pathologies has been addressed, although it requires further investigations. CONCLUSION: This review will provide students in the fields of biochemistry and health sciences a brief and clear overview of iron physiology and toxicity, as well as imbalances in the iron homeostasis and associated pathological conditions. PMID- 24478116 TI - Second-generation cryoballoon ablation for paroxysmal atrial fibrillation: 1-year follow-up. AB - BACKGROUND: The novel cryoballoon Advance (CB-A) has proven to achieve significantly lower temperatures and faster pulmonary vein isolation (PVI) times in comparison with the first-generation device. Although acutely very effective, to the best of our knowledge, data on mid-term clinical follow-up is lacking. AIMS: The aim of the study was to analyse the freedom from recurrence of atrial fibrillation (AF) on a 1-year follow-up period, in a series of consecutive patients having undergone PVI with the CB-A for paroxysmal AF (PAF). METHODS AND RESULTS: Forty-two patients [30 male (71%); mean age: 57.9 +/- 21.1 years] were included. All patients underwent a procedure with the large 28 mm CB-A. A total 168 PVs were depicted on the pre-procedural computed tomography scan. All PVs (100%) could be isolated with the CB only. The freedom from AF off-antiarrhythmic drug treatment after a single procedure was 78% of patients at a mean 11.6 +/- 2.0 months follow-up. If considering a blanking period (BP) of 3 months, success rate was 83%. Phrenic nerve palsy (PNP) was the most frequent complication occurring in 19% of individuals. CONCLUSION: The CB-A is very effective in producing PVI and affords freedom from AF at 12 months follow-up in 83% of patients affected by drug-resistant PAF following a 3-month BP. The most frequent complication observed was PNP which occurred in 19% of patients. All PNP reverted during follow-up. PMID- 24478117 TI - Endoluminal MR-guided ultrasonic applicator embedding cylindrical phased-array transducers and opposed-solenoid detection coil. AB - PURPOSE: MR-guided high-intensity contact ultrasound (HICU) was suggested as an alternative therapy for esophageal and rectal cancer. To offer high-quality MR guidance, two prototypes of receive-only opposed-solenoid coil were integrated with 64-element cylindrical phased-array ultrasound transducers (rectal/esophageal). METHODS: The design of integrated coils took into account the transducer geometry (360 degrees acoustic window within endoluminal space). The rectal coil was sealed on a plastic support and placed reversibly on the transducer head. The esophageal coil was fully embedded within the transducer head, resulting in one indivisible device. Comparison of integrated versus external coils was performed on a clinical 1.5T scanner. RESULTS: The integrated coils showed higher sensitivity compared with the standard extracorporeal coil with factors of up to 7.5 (rectal applicator) and 3.3 (esophageal applicator). High-resolution MR images for both anatomy (voxel 0.4 * 0.4 * 5 mm(3)) and thermometry (voxel 0.75 * 0.75 * 8 mm(3), 2 s/image) were acquired in vivo with the rectal endoscopic device. The temperature feedback loop accurately controlled multiple control points over the region of interest. CONCLUSION: This study showed significant improvement of MR data quality using endoluminal integrated coils versus standard external coil. Inframillimeter spatial resolution and accurate feedback control of MR-guided HICU thermotherapy were achieved. PMID- 24478119 TI - Generic chromatography-based purification strategies accelerate the development of downstream processes for biopharmaceutical proteins produced in plants. AB - Plants offer a valuable alternative to cultured mammalian cells for the production of recombinant biopharmaceutical proteins. However, the target protein typically represents only a minor fraction of the total protein in the initial plant extract, which means that the development of product-specific chromatography-based purification strategies is often laborious and expensive. To address this challenge, we designed a generic downstream process that is suitable for the purification of recombinant proteins with diverse properties from plant production platforms. This was achieved by focusing on the binding behavior of tobacco host cell proteins (HCPs) to a broad set of chromatography resins under different pH and conductivity conditions. Strong cation exchanger and salt tolerant anion exchanger resins exhibited the best resolution of tobacco HCPs among the 13 tested resins, and their selectivity was easy to manipulate through the adjustment of pH and conductivity. The advantages, such as direct capture of a target protein from leaf extract, and limitations, such as low binding capacity, of various chromatography ligands and resins are discussed. We also address the most useful applications of the chromatography ligands, namely recovery of proteins with a certain pI, in a downstream process that aims to purify diverse plant-derived biopharmaceutical proteins. Based on these results, we describe generic purification schemes that are suitable for acidic, neutral, and basic target proteins, as a first step toward the development of industrial platform processes. PMID- 24478120 TI - Response to Tarone and McLaughlin: RE: Mortality from solid tumors in the updated NCI formaldehyde worker cohort. PMID- 24478121 TI - Iron 10-thiacorroles: bioinspired iron(III) complexes with an intermediate spin (S=3/2) ground state. AB - A first systematic study upon the preparation and exploration of a series of iron 10-thiacorroles with simple halogenido (F, Cl, Br, I), pseudo-halogenido (N3 , I3 ) and solvent-derived axial ligands (DMSO, pyridine) is reported. The compounds were prepared from the free-base octaethyl-10-thiacorrole by iron insertion and subsequent ligand-exchange reactions. The small N4 cavity of the ring-contracted porphyrinoid results in an intermediate spin (i.s., S=3/2) state as the ground state for the iron(III) ion. In most of the investigated cases, the i.s. state is found unperturbed and independent of temperature, as determined by a combination of X-ray crystallography and magnetometry with (1) H NMR-, EPR-, and Mossbauer spectroscopy. Two exceptions were found. The fluorido iron(III) complex is inhomogenous in the solid and contains a thermal i.s. (S=3/2)->high spin (h.s., S=5/2) crossover fraction. On the other side, the cationic bis(pyridine) complex resides in the expected low spin (l.s., S=1/2) state. Chemically, the iron 10 thiacorroles differ from the iron porphyrins mainly by weaker axial ligand binding and by a cathodic shift of the redox potentials. These features make the 10-thiacorroles interesting ligands for future research on biomimetic catalysts and model systems for unusual heme protein active sites. PMID- 24478122 TI - Characterization of the biochemical effects of naphthalene on the mouse respiratory system using NMR-based metabolomics. AB - Naphthalene is a ubiquitous environmental pollutant to which humans are exposed. Previous studies have demonstrated that naphthalene causes bronchiolar epithelial necrosis in the mouse distal airway, after parenteral administration. In this study, metabolic variations in the bronchoalveolar lavage fluid (BALF) and the lung tissues of naphthalene-treated mice and controls were examined using nuclear magnetic resonance (NMR)-based metabolomics to identify the toxic mechanism. Male ICR mice were treated with naphthalene [0, 50, 100 and 200 mg kg(-1), intraperitoneally (i.p.)]. After 24 h, BALF and lung tissues were collected and prepared for (1)H and J-resolved (JRES) NMR analysis after principal component analysis (PCA). PCA modeling of p-JRES spectra from the BALF, as well as hydrophilic and hydrophobic lung metabolites, enabled the high-dose group to be discriminated from the control group; increased levels of isopropanol, ethane, and acetone and lower levels of ethanol, acetate, formate, and glycerophosphocholine were detected in the BALF of mice treated with higher doses of naphthalene. Furthermore, increased isopropanol and phosphorylcholine containing lipid levels and decreased succinate and glutamine levels were discovered in the lungs of naphthalene-exposed mice. These metabolic changes may be related to lipid peroxidation, disruptions of membrane components and imbalanced energy supply, and these results may partially explain the loss of cell membrane integrity in the airway epithelial cells of naphthalene-treated mice. We conclude that NMR-based metabolomic studies on BALF and lung tissues are a powerful tool to understand the mechanisms underlying respiratory toxicity. PMID- 24478123 TI - Pregnancy outcomes after living donor liver transplantation: results from a Japanese survey. AB - A national survey of pregnancy outcomes after living donor liver transplantation (LDLT) was performed in Japan. Thirty-eight pregnancies in 30 recipients resulted in 31 live births (25 recipients), 3 artificial abortions in the first trimester (3 recipients), 1 spontaneous abortion (1 recipient), and 3 fetal deaths (3 recipients). After the exclusion of the 3 artificial abortions, there were 35 pregnancies in 27 recipients: pregnancy-induced hypertension developed during 6 pregnancies (5 recipients), fetal growth restriction developed during 7 pregnancies (6 recipients), acute rejection developed during 2 pregnancies (2 recipients), and ileus developed during 1 pregnancy (1 recipient). Preterm delivery (<37 weeks) occurred for 10 pregnancies (10 recipients), and cesarean delivery was performed for 12 pregnancies (12 recipients). After delivery, acute rejection developed in 3 recipients. Twelve neonates were born with low birth weights (<2500 g), and 4 of these 12 neonates had extremely low birth weights (<1500 g). Two neonates had congenital malformations. The pregnancy outcomes after LDLT were similar to those reported for cadaveric liver transplantation (LT). The incidence of pregnancy-induced hypertension in recipients who were 33 years old or older at the diagnosis of pregnancy was significantly higher than the incidence in recipients who were less than 33 years old at the diagnosis of pregnancy. The incidences of fetal growth restriction, pregnancy-induced hypertension, and extremely low birth weight were significantly higher in the early group (<3 years after transplantation) versus the late group (>=3 years after transplantation). In conclusion, it is necessary to pay careful attention to complications during pregnancy in recipients who become pregnant within 3 years of LT, particularly if the age at the diagnosis of pregnancy is >=33 years. PMID- 24478124 TI - Minimum information about a biofilm experiment (MIABiE): standards for reporting experiments and data on sessile microbial communities living at interfaces. AB - The minimum information about a biofilm experiment (MIABiE) initiative has arisen from the need to find an adequate and scientifically sound way to control the quality of the documentation accompanying the public deposition of biofilm related data, particularly those obtained using high-throughput devices and techniques. Thereby, the MIABiE consortium has initiated the identification and organization of a set of modules containing the minimum information that needs to be reported to guarantee the interpretability and independent verification of experimental results and their integration with knowledge coming from other fields. MIABiE does not intend to propose specific standards on how biofilms experiments should be performed, because it is acknowledged that specific research questions require specific conditions which may deviate from any standardization. Instead, MIABiE presents guidelines about the data to be recorded and published in order for the procedure and results to be easily and unequivocally interpreted and reproduced. Overall, MIABiE opens up the discussion about a number of particular areas of interest and attempts to achieve a broad consensus about which biofilm data and metadata should be reported in scientific journals in a systematic, rigorous and understandable manner. PMID- 24478125 TI - Ultrasonography is useful to detect subclinical synovitis in SLE patients without musculoskeletal involvement before symptoms appear. AB - The purpose of this study is to investigate the frequency of the subclinical synovitis in hand or wrist joints of the SLE patients using ultrasonography (US) and to correlate them with clinical parameters. Forty-eight systemic lupus erythematosus (SLE) patients without musculoskeletal (MS) involvement were enrolled and underwent clinical and laboratory examinations. Gray-scale and power Doppler (PD) US was performed for imaging the wrist, second and third metacarpophalangeal (MCP) joints, and flexor tendons on non-dominant sides of the individuals. US synovitis index (USSI) and PD index were calculated as sum of the synovitis and PD semiquantitative scores, respectively, obtained from each joint. Subclinical synovitis was found by US in 28 (58.3%) out of 48 patients. US revealed synovitis of the wrist in 16 (33.3%) patients, of the second MCP joint in 14 (29.2%) and of the third MCP joint in 15 (31.3%). PD signals in three (6.3%) patients and tenosynovitis in two (4.2%) were also detected. USSI scores showed significant positive correlation with erythrocyte sedimentation rate (ESR) levels (r = 0.30, p < 0.05) or anti-dsDNA Ab titers (r = 0.34, p < 0.05). Within 6 months after US examination, new MS symptoms were developed in 11 (22.9%) patients. Older age at diagnosis (OR 1.283, 95% CI 1.029-1.601, p = 0.027) or higher USSI scores (OR 12.93, 95% CI 1.023-163.503, p = 0.048) were independently associated with development of new MS symptoms. Subclinical synovitis is common in SLE patients who do not suffer from MS symptoms. US is useful to detect joint abnormalities before symptoms appear in SLE patients. PMID- 24478126 TI - Two Takayasu arteritis patients successfully treated with rituximab. AB - Takayasu arteritis (TA) is a rare form of chronic large vessel vasculitis of unknown origin involving the aorta and its major branches. Recently, the involvement of B lymphocytes in TA has been suggested, and active refractory TA patients were successfully treated with B cell depletion therapy (BCDT). We report two cases of patients with TA successfully treated with anti-CD20 monoclonal antibody (rituximab). The favorable outcome of rituximab treatment in our patients also support the view that BCDT can be a useful option for refractory TA, and its potential should be evaluated in controlled trials. PMID- 24478127 TI - Mesenchymal-mode migration assay and antimetastatic drug screening with high throughput microfluidic channel networks. AB - Increasing evidence shows that activated mesenchymal migration is a key process of the metastatic cascade. Cancer cells usually gain such migratory capability through an epithelial-to-mesenchymal transition. Herein we present a high throughput microfluidic device with 3120 microchambers to specifically monitor mesenchymal migration. Through imaging of the whole chip and statistical analysis, we can evaluate the two key factors of velocity and percentage related to cell migratory capacity at different cell densities in culture. We also used the device to screen antimetastatic drugs for their inhibition of mesenchymal migration and prevention of metastatic malignancy. This device will provide an excellent platform for biologists to gain a better understanding of cancer metastasis. PMID- 24478128 TI - Cross-cultural factorial validation of the Clinical Interview Schedule--Revised (CIS-R); findings from a nationally representative survey (EMPIRIC). AB - The Clinical Interview Schedule - Revised (CIS-R) has been widely adopted across cultures to assess common mental disorders. We assessed the factorial validity of the CIS-R across ethnic minority groups, using data from a nationally representative survey conducted in England in 2000. The sample comprised White British (n = 837), Irish (n = 733), Black Caribbean (n = 694), Bangladeshi (n = 650), Indian (n = 643) and Pakistani (n = 724) respondents. Ordered logistic regression determined the reporting of CIS-R symptoms. Principal components analysis (PCA) determined the underlying construct of the CIS-R in White British participants. These factor solutions were then assessed for "best fit" using confirmatory factor analyses (CFAs) across all ethnic groups. In ordered logistic regression analyses, there was heterogeneity in the reporting of worries, phobias, panic and somatic symptoms across ethnic minority groups relative to the White British group. "Best" fit solutions confirmed through CFA were models where all symptoms were allowed to vary across ethnic groups, or models where an underlying "depression-anxiety" construct was held invariant while "somatic symptoms" were permitted to vary across groups, although differences between models assessed were slight. In conclusion, there may be benefits in assessing the functioning of certain CIS-R items within specific cultural contexts to ensure adequate face validity of the CIS-R. PMID- 24478129 TI - Association of neutrophil to lymphocyte ratio with presence and severity of gastritis due to Helicobacter pylori infection. AB - OBJECTIVE: Infection with the bacterial pathogen Helicobacter pylori (HP) clearly results in chronic mucosal inflammation in the stomach and duodenum, which, in turn, might lead to abnormalities in gastroduodenal motility and sensitivity and is the most frequent cause of dyspepsia and peptic disease. Some studies have shown that there was a correlation between low-grade inflammation as C-reactive protein (CRP) and HP infection. The aim of this study was to investigate the relationship between the presence of gastritis due to HP infection and neutrophil/lymphocyte ratio (NLR), a simple and reliable indicator of inflammation. DESIGN: Fifty patients met the HP criteria and half of them have had severe symptoms and upper endoscopy showed atrophic gastritis, and fifty age- and sex-matched control subjects with gastritis without HP infection were included in this randomized controlled trial. Patients were diagnosed to have HP according to the use of urea breath testing (UBT) and multiple biopsies. NLR was calculated from complete blood count at the time of diagnosis and before initiating the treatment to all groups. RESULTS: Patients with HP infection had significantly higher NLR compared to those without HP. Moreover, the patients with symptomatic HP and grade 4 gastritis had higher NLR than those asymptomatic with past history of peptic disease (P 0.007 and P 0.068, respectively). Although NLR increased as the severity of gastritis and HP symptoms increased (r = 0.564, P < 0.001), Receiver operating characteristic (ROC) Curve analysis was performed. The cut-off level for NLR with optimal sensitivity and specificity was calculated as 1.82 (area under curve [AUC] = 0.825 [0.753-0.884], P < 0.001). CONCLUSION: The present study indicated, for the first time, a significant correlation between HP infection and inflammation on the basis of NLR, a simple and reliable indicator of inflammation. Furthermore, there is an increase in NLR as the severity of gastritis with HP increases. This elevated ratio gets normalized with treatment. PMID- 24478131 TI - Thieno[3,4-c]pyrrole-4,6-dione-based small molecules for highly efficient solution-processed organic solar cells. AB - Two small molecules named BT-TPD and TBDT-TTPD with a thieno[3,4-c]pyrrole-4,6 dione (TPD) unit were designed and synthesized for solution-processed bulk heterojunction solar cells. Their thermal, electrochemical, optical, charge transport, and photovoltaic characteristics were investigated. These compounds exhibit strong absorption at 460-560 nm and low highest occupied molecular orbital levels (-5.36 eV). Field-effect hole mobilities of these compounds are 1.7-7.7*10(-3) cm(2) V(-1) s(-1). Small-molecule organic solar cells based on blends of these donor molecules and a acceptor display power conversion efficiencies as high as 4.62% under the illumination of AM 1.5G, 100 mW cm(-2). PMID- 24478130 TI - Gradient rotating outer volume excitation (GROOVE): A novel method for single shot two-dimensional outer volume suppression. AB - PURPOSE: To introduce a new outer volume suppression (OVS) technique that uses a single pulse and rotating gradients to accomplish frequency-swept excitation. This new technique, which is called gradient rotating outer volume excitation (GROOVE), produces a circular or elliptical suppression band rather than suppressing the entire outer volume. METHODS: Theoretical and k-space descriptions of GROOVE are provided. The properties of GROOVE were investigated with simulations, phantom, and human experiments performed using a 4T horizontal bore magnet equipped with a TEM coil. RESULTS: Similar suppression performance was obtained in phantom and human brain using GROOVE with circular and elliptical shapes. Simulations indicate that GROOVE requires less SAR and time than traditional OVS schemes, but traditional schemes provide a sharper transition zone and less residual signal. CONCLUSION: GROOVE represents a new way of performing OVS in which spins are excited temporally in space on a trajectory that can be tailored to fit the shape of the suppression region. In addition, GROOVE is capable of suppressing tailored regions of space with more flexibility and in a shorter period of time than conventional methods. GROOVE provides a fast, low SAR alternative to conventional OVS methods in some applications (e.g., scalp suppression). PMID- 24478132 TI - Light-regulated tetracycline binding to the Tet repressor. AB - Elucidation of the signal-transmission pathways between distant sites within proteins is of great importance in medical and bioengineering sciences. The use of optical methods to redesign protein functions is emerging as a general approach for the control of biological systems with high spatiotemporal precision. Here we report the detailed thermodynamic and kinetic characterization of novel chimeric light-regulated Tet repressor (TetR) switches in which light modulates the TetR function. Light absorbed by flavin mononucleotide (FMN) generates a signal that is transmitted to As-LOV and YtvA-LOV fused TetR proteins (LOV=light-oxygen-voltage), in which it alters the binding to tetracycline, the TetR ligand. The engineering of light-sensing protein modules with TetR is a valuable tool that deepens our understanding of the mechanism of signal transmission within proteins. In addition, the light-regulated changes of drug binding that we describe here suggest that engineered light-sensitive proteins may be used for the development of novel therapeutic strategies. PMID- 24478133 TI - Application of the SOS/umu test and high-content in vitro micronucleus test to determine genotoxicity and cytotoxicity of nine benzothiazoles. AB - Benzothiazole and benzothiazole derivatives (BTs) have been detected in various environmental matrices as well as in human beings, but little is currently available regarding their toxicities. In our study, genotoxicities of nine BTs (benzothiazole [BT], 2-chlorobenzothiazole [CBT], 2-bromobenzothiazole [BrBT], 2 fluorobenzothiazole [FBT], 2-methylbenzothiazole [MeBT], 2-mercaptobenzothiazole [MBT], 2-aminobenzothiazole [ABT], 2-hydroxy-benzothiazole [OHBT] and 2 methythiobenzothiazole [MTBT]) are comprehensively evaluated by the SOS/umu test using the bacterial Salmonella typhimurium TA1535/pSK1002 for DNA-damaging effect and the high content in vitro micronucleus test using two human carcinoma cells (MGC-803 and A549) for chromosome-damaging effect. The cytotoxicity of BTs on both bacteria and two human cells was also evaluated. Except for the cytotoxic effect of MBT on MGC-803 and A549, the other tested BTs showed more than 50% cytotoxicity at their highest concentrations in a dose-dependent manner, and their LC50s ranged from 19 (MBT in bacteria) to 270 mg l(-1) (CBT in A549). Activation and inactivation were observed for specific BTs after metabolism. On the other hand, no evidence of genotoxicity was obtained for BT, FBT and MBT, and DNA damage was induced by ABT, OHBT, BrBT and MTBT in MGC-803, by MeBT in A549 and by CBT in both cells. Through quantitative structure-activity relationship analysis, two structure alerts for chemical genotoxicity, including heterocyclic amine and hacceptor-path3-hacceptor are present in ABT and OHBT respectively; however, the underlying mechanisms still need further evaluation. PMID- 24478134 TI - Probability estimation with machine learning methods for dichotomous and multicategory outcome: theory. AB - Probability estimation for binary and multicategory outcome using logistic and multinomial logistic regression has a long-standing tradition in biostatistics. However, biases may occur if the model is misspecified. In contrast, outcome probabilities for individuals can be estimated consistently with machine learning approaches, including k-nearest neighbors (k-NN), bagged nearest neighbors (b NN), random forests (RF), and support vector machines (SVM). Because machine learning methods are rarely used by applied biostatisticians, the primary goal of this paper is to explain the concept of probability estimation with these methods and to summarize recent theoretical findings. Probability estimation in k-NN, b NN, and RF can be embedded into the class of nonparametric regression learning machines; therefore, we start with the construction of nonparametric regression estimates and review results on consistency and rates of convergence. In SVMs, outcome probabilities for individuals are estimated consistently by repeatedly solving classification problems. For SVMs we review classification problem and then dichotomous probability estimation. Next we extend the algorithms for estimating probabilities using k-NN, b-NN, and RF to multicategory outcomes and discuss approaches for the multicategory probability estimation problem using SVM. In simulation studies for dichotomous and multicategory dependent variables we demonstrate the general validity of the machine learning methods and compare it with logistic regression. However, each method fails in at least one simulation scenario. We conclude with a discussion of the failures and give recommendations for selecting and tuning the methods. Applications to real data and example code are provided in a companion article (doi:10.1002/bimj.201300077). PMID- 24478135 TI - Effects of air embolism size and location on porcine hepatic microcirculation in machine perfusion. AB - The handling of donor organs frequently introduces air into the microvasculature, but little is known about the extent of the damage caused as a function of the embolism size and distribution. Here we introduced embolisms of different sizes into the portal vein, the hepatic artery, or both during the flushing stage of porcine liver procurement. The outcomes were evaluated during 3 hours of machine perfusion and were compared to the outcomes of livers with no embolisms. Dynamic contrast-enhanced ultrasound (DCEUS) was used to assess the perfusion quality, and it demonstrated that embolisms tended to flow mostly into the left lobe, occasionally into the right lobe, and rarely into the caudate lobe. Major embolisms could disrupt the flow entirely, whereas minor embolisms resulted in reduced or heterogeneous flow. Embolisms occasionally migrated to different regions of the same lobe and, regardless of their size, caused a general deterioration in the flow over time. Histological damage resulted primarily when both vessels of the liver were compromised, whereas bile production was diminished in livers that had arterial embolisms. Air embolisms produced a dose dependent increase in vascular resistance and a decline in oxygen consumption. This is the first article to quantify the impact of air embolisms on microcirculation in an experimental model, and it demonstrates that air embolisms have the capacity to degrade the integrity of donor organs. The extent of organ damage is strongly dependent on the size and distribution of air embolisms. The diagnosis of embolism severity can be safely and easily made with DCEUS. PMID- 24478136 TI - Quantitative analysis of location- and sequence-dependent deamination by APOBEC3G using real-time NMR spectroscopy. AB - The human antiretroviral factor APOBEC3G (A3G) deaminates the newly synthesized minus strand of the human immunodeficiency virus 1 (HIV-1), which results in the abolition of the infectivity of virus-infectivity-factor (Vif)-deficient HIV-1 strains.1-6 A unique property of A3G is that it deaminates a CCC hot spot that is located close to the 5' end more effectively than one that is less close to the 5' end. However, the mechanism of this process is elusive as it includes nonspecific binding of A3G to DNA and sliding of A3G along the DNA strand. Therefore, this process cannot be analyzed by existing methods using the Michaelis-Menten theory. A new real-time NMR method has been developed to examine the nonspecific binding and the sliding processes explicitly, and it was applied to the analysis of the deamination by A3G. As a result, the location-dependent deamination can be explained by a difference in the catalytic rates that depend on the direction of the approach of A3G to the target cytidine. Real-time NMR experiments also showed that A3G deaminates CCCC tandem hotspots with little redundancy, which suggests that A3G efficiently mutates many CCC hotspots that are scattered throughout the HIV-1 genome. PMID- 24478137 TI - MRI at 7 Tesla and above: demonstrated and potential capabilities. AB - With more than 40 installed MR systems worldwide operating at 7 Tesla or higher, ultra-high-field (UHF) imaging has been established as a platform for clinically oriented research in recent years. Along with technical developments that, in part, have also been successfully transferred to lower field strengths, MR imaging and spectroscopy at UHF have demonstrated capabilities and potentials for clinical diagnostics in a variety of studies. In terms of applications, this overview article focuses on already achieved advantages for in vivo imaging, i.e., in imaging the brain and joints of the musculoskeletal system, but also considers developments in body imaging, which is particularly challenging. Furthermore, new applications for clinical diagnostics such as X-nuclei imaging and spectroscopy, which only really become feasible at ultra-high magnetic fields, will be presented. PMID- 24478138 TI - Hepatitis C virus genotyping methods: evaluation of AmpliSens((r)) HCV-1/2/3-FRT compared to sequencing method. AB - BACKGROUND: Hepatitis C virus (HCV) genotyping is important for treatment and epidemiological purposes. The objective of this study was to evaluate the performance of AmpliSens((r)) HCV-1/2/3-FRT kit in comparison to sequencing method for genotyping. METHODS: A total of 17 samples collected from December 2009 to January 2011 were analyzed. Reverse transcriptase polymerase chain reaction (PCR) was performed, followed by sequencing technique. Results were analyzed based on sequence information in GenBank. A second genotyping method (AmpliSens((r)) HCV-1/2/3-FRT) was done, which differentiates HCV genotypes by means of real-time hybridization-fluorescence detection. RESULTS: From 17 samples, four were untypeable by AmpliSens((r)) HCV-1/2/3-FRT. Eleven of 13 (84.6%) results showed concordant genotypes. A specimen that was determined as genotype 3a by sequencing was genotype 1 by the AmpliSens((r)) HCV-1/2/3-FRT. Another specimen that was genotype 1 by sequencing was identified as genotype 3 by AmpliSens((r)) HCV-1/2/3-FRT. CONCLUSION: HCV genotyping with AmpliSens((r)) HCV-1/2/3-FRT using real-time PCR method provides a much simpler and more feasible workflow with shorter time compared to sequencing method. There was good concordance compared to sequencing method. However, more evaluation studies would be required to show statistical significance, and to troubleshoot discordant results. AmpliSens((r)) HCV-1/2/3-FRT does differentiate between genotype but not until subtype level. PMID- 24478139 TI - Direct fermentation of raw starch using a Kluyveromyces marxianus strain that expresses glucoamylase and alpha-amylase to produce ethanol. AB - Raw starch and raw cassava tuber powder were directly and efficiently fermented at elevated temperatures to produce ethanol using the thermotolerant yeast Kluyveromyces marxianus that expresses alpha-amylase from Aspergillus oryzae as well as alpha-amylase and glucoamylase from Debaryomyces occidentalis. Among the constructed K. marxianus strains, YRL 009 had the highest efficiency in direct starch fermentation. Raw starch from corn, potato, cassava, or wheat can be fermented at temperatures higher than 40 degrees C. At the optimal fermentation temperature 42 degrees C, YRL 009 produced 66.52 g/L ethanol from 200 g/L cassava starch, which was the highest production among the selected raw starches. This production increased to 79.75 g/L ethanol with a 78.3% theoretical yield (with all cassava starch were consumed) from raw cassava starch at higher initial cell densities. Fermentation was also carried out at 45 and 48 degrees C. By using 200 g/L raw cassava starch, 137.11 and 87.71 g/L sugar were consumed with 55.36 and 32.16 g/L ethanol produced, respectively. Furthermore, this strain could directly ferment 200 g/L nonsterile raw cassava tuber powder (containing 178.52 g/L cassava starch) without additional nutritional supplements to produce 69.73 g/L ethanol by consuming 166.07 g/L sugar at 42 degrees C. YRL 009, which has consolidated bioprocessing ability, is the best strain for fermenting starches at elevated temperatures that has been reported to date. PMID- 24478140 TI - Intercalation-controlled cyclodehydration of sorbitol in water over layered niobium-molybdate solid acid. AB - Layered niobium molybdate (HNbMoO6 ) was used in the aqueous-phase dehydration of sorbitol and was found to exhibit remarkable selectivity toward its monomolecular dehydrated intermediate 1,4-sorbitan. This was attributed to the selective intercalation of sorbitol within the interlayers with strong Bronsted acid sites. PMID- 24478141 TI - Tandem Pd/Au-catalyzed route to alpha-sulfenylated carbonyl compounds from terminal propargylic alcohols and thiols. AB - An efficient and highly atom-economical tandem Pd/Au-catalyzed route to alpha sulfenylated carbonyl compounds from terminal propargylic alcohols and thiols has been developed. This one-step procedure has a wide substrate scope with respect to substituents at the alpha-position of the alcohol. Both aromatic and aliphatic thiols generated the alpha-sulfenylated carbonyl products in good to excellent yields. A mechanism is proposed in which the reaction proceeds through a Pd catalyzed regioselective hydrothiolation at the terminal triple bond of the propargyl alcohol followed by an Au-catalyzed 1,2-hydride migration. PMID- 24478142 TI - High-resolution respiratory self-gated golden angle cardiac MRI: Comparison of self-gating methods in combination with k-t SPARSE SENSE. AB - PURPOSE: To compare the applicability of different self-gating (SG) strategies for respiratory SG in cardiac MRI in combination with iteratively reconstructed (k-t SPARSE SENSE) cine data with low and high temporal resolution. METHODS: Eleven SG variants were compared in five volunteers by assessment of the resulting image sharpness compared with nongated reconstructions. Promising SG techniques were applied for high temporal resolution reconstructions of the heart function. RESULTS: SG was successful in all volunteers with image-based SG and the ?||p|| technique. These approaches were also superior to gating from the respiratory bellows signal on average. Combination with k-t SPARSE SENSE enabled high temporally resolved visualization of the heart motion with free breathing. CONCLUSION: Respiratory SG can be applied for improving image sharpness. Combining SG with iterative reconstruction allows generation of high temporal resolution cine data, which reveal more details of cardiac motion. PMID- 24478143 TI - Absence of mature microRNAs inactivates the response of gene expression to carcinogenesis induced by N-ethyl-N-nitrosourea in mouse liver. AB - This study aims to evaluate the role of microRNAs (miRNAs) in chemical tumorigenesis by evaluating genomic gene expression in miRNA knockout mice. Previous studies showed that mice without mature miRNAs due to hepatocyte specific Dicer1 knockout (KO) had a much higher liver tumor incidence than wild type mice. In this study, Dicer1 KO or the wild-type mice were treated intraperitoneally with genotoxic carcinogen N-ethyl-N-nitrosourea (ENU) at a single dose (150 mg kg(-1) that resulted in liver tumorigenesis) or the vehicle at 3 weeks of age. The animals were killed 2 weeks after treatment and the liver samples were collected for the gene expression study. Principal components analysis and hierarchical cluster analysis showed that gene expression was globally altered by the Dicer1 KO and ENU exposure. There were 5621, 3286 and 2565 differentially expressed genes for Dicer1 disruption, ENU treatment in wild type mice and ENU treatment in Dicer1 KO mice, respectively. Functional analysis of the differentially expressed genes suggests that the Dicer1 KO mouse liver lost their capability to suppress the carcinogenesis induced by ENU exposure in genomic level. In addition, the miRNA-mediated BRCA1 and P53 signaling pathways were identified as the main pathways responsible for the tumorigenesis. We conclude that the mouse livers in the absence of mature miRNAs could not appropriately respond to carcinogenic insults from ENU treatment, indicating that miRNAs play a critical role in chemical carcinogenesis. PMID- 24478144 TI - Summarizing EC50 estimates from multiple dose-response experiments: a comparison of a meta-analysis strategy to a mixed-effects model approach. AB - Dose-response studies are performed to investigate the potency of a compound. EC50 is the concentration of the compound that gives half-maximal response. Dose response data are typically evaluated by using a log-logistic model that includes EC50 as one of the model parameters. Often, more than one experiment is carried out to determine the EC50 value for a compound, requiring summarization of EC50 estimates from a series of experiments. In this context, mixed-effects models are designed to estimate the average behavior of EC50 values over all experiments by considering the variabilities within and among experiments simultaneously. However, fitting nonlinear mixed-effects models is more complicated than in a linear situation, and convergence problems are often encountered. An alternative strategy is the application of a meta-analysis approach, which combines EC50 estimates obtained from separate log-logistic model fitting. These two proposed strategies to summarize EC50 estimates from multiple experiments are compared in a simulation study and real data example. We conclude that the meta-analysis strategy is a simple and robust method to summarize EC50 estimates from multiple experiments, especially suited in the case of a small number of experiments. PMID- 24478145 TI - The analytical performance evaluation of FreeliteTM Human Kappa Free and Human Lambda Free on the SPAPLUSTM immunoturbidimetric analyzer. AB - BACKGROUND: SPAPLUSTM is a turbidimetric immunoassay analyzer for detection of excess free light chain (FLC) antigens in serum. Here, we evaluated the analytical performance of FreeliteTM Human Kappa Free and Lambda Free on a SPAPLUSTM instrument. METHODS: We evaluated the precision, linearity, sample carryover, and drift of the SPAPLUSTM instrument and compared it with Hitachi 7600 and BNTM II instruments. We evaluated the detection of antigen excess for 12 specimens from patients with monoclonal gammopathy. RESULTS: The coefficients of variations of kappaFLC and lambdaFLC were below 5.0%. Linearity was shown in the range of 9.68-152.25 mg/l for kappaFLC and 4.96-171.09 mg/l for lambdaFLC, and no drift was observed. The kappaFLC sample carryover was statistically significant, but much smaller than the optimum allowable bias. Agreement rates with the two comparative methods were 87.1, 87.1, and 97.1% or higher for kappaFLC, lambdaFLC, and the kappa/lambda ratio, respectively. Antigen excess signals were observed for all 12 antigen excess specimens. CONCLUSIONS: The FreeliteTM on the SPAPLUSTM exhibited appropriate precision, linearity, and relative comparability to the reagents on the other instruments. It was good at detecting specimens that had previously demonstrated the hook effect due to antigen excess. PMID- 24478146 TI - Substrate-directed hydroacylation: rhodium-catalyzed coupling of vinylphenols and nonchelating aldehydes. AB - We report a protocol for the hydroacylation of vinylphenols with aryl, alkenyl, and alkyl aldehydes to form branched products with high selectivity. This cross coupling yields alpha-aryl ketones that can be cyclized to benzofurans, and it enables access to eupomatenoid natural products in four steps or less from eugenol. Excellent reactivity and high levels of regioselectivity for the formation of the branched products were observed. We propose that aldehyde decarbonylation is avoided by the use of an anionic directing group on the alkene and a diphosphine ligand with a small bite angle. PMID- 24478147 TI - Motion-compensated real-time MR thermometry augmented by tracking coils. AB - PURPOSE: To develop and evaluate a real-time proton resonant frequency (PRF) based MR thermometry method with a novel motion compensation technique, using linear phase model and active tracking coils. MATERIALS AND METHODS: A 6F catheter with multiple tracking coils and radiofrequency (RF) ablation tip was built for ex vivo experiments using excised bovine liver on a 1.5 Tesla scanner. A real-time MR acquisition scheme with interleaved active catheter tracking and multislice imaging was implemented. To evaluate the proposed method, in-plane periodic linear motion and through-plane irregular motion were induced by the rocker capability of the scanner and hand, respectively. Real-time temperature maps of the tissue undergoing a 2-min RF ablation cycle were obtained and used to compare the performance of the proposed method with that of the multi-baseline method. RESULTS: The temporal window achieved per acquisition of one slice and catheter tracking is ~380 ms. The standard deviations of tracking errors are less than 1 mm for both irregular and periodic motions in x-y plane. The measurements at the heated and unheated regions demonstrate that the proposed thermometry method perform equally well for both in-plane and through-plane motion while maintaining a similar accuracy (sigma = 1.10 versus 1.04 degrees C) compared with the conventional multi-baseline method. CONCLUSION: The new MR thermometry method using catheter-based tracking coils and linear phase model for motion compensation and phase correction is promising and may offer reliable MR thermometry for real-time MRI-guided thermal therapies. PMID- 24478148 TI - Proteomic analysis of uterine fluid during the pre-implantation period of pregnancy in cattle. AB - The aims of this study were (i) to characterize the global changes in the composition of the uterine luminal fluid (ULF) from pregnant heifers during pregnancy recognition (day 16) using nano-LC MS/MS; (ii) to describe quantitative changes in selected proteins in the ULF from days 10, 13, 16 and 19 by Isobaric tags for Relative and Absolute Quantification (iTRAQ) analysis; and (iii) to determine whether these proteins are of endometrial or conceptus origin, by examining the expression profiles of the associated transcripts by RNA sequencing. On day 16, 1652 peptides were identified in the ULF by nano-LC MS/MS. Of the most abundant proteins present, iTRAQ analysis revealed that RPB4, TIMP2 and GC had the same expression pattern as IFNT, while the abundance of IDH1, CST6 and GDI2 decreased on either day 16 or 19. ALDOA, CO3, GSN, HSP90A1, SERPINA31 and VCN proteins decreased on day 13 compared with day 10 but subsequently increased on day 16 (P<0.05). Purine nucleoside phosphorylase (PNP) and HSPA8 decreased on day 13, increased on day 16 and decreased and increased on day 19 (P<0.05). The abundance of CATD, CO3, CST6, GDA, GELS, IDHC, PNPH and TIMP2 mRNAs was greater (P<0.001) in the endometrium than in the conceptus. By contrast, the abundance of ACTB, ALDOA, ALDR, CAP1, CATB, CATG, GD1B, HSP7C, HSP90A, RET4 and TERA was greater (P<0.05) in the conceptus than in the endometrium. In conclusion, significant changes in the protein content of the ULF occur during the pre-implantation period of pregnancy reflecting the morphological changes that occur in the conceptus. PMID- 24478149 TI - Effect of the sol-gel route on the textural characteristics of silica imprinted with Rhodamine B. AB - A series of silica xerogels that support Rhodamine B as a template were synthesized using distinct sol-gel routes, namely, acid-catalyzed routes, a base catalyzed route, acid-catalyzed with base-catalyzed (two steps) hydrolytic routes, and a FeCl3 -catalyzed nonhydrolytic route. The extraction methods (thermal, Soxhlet, water washing, and ultrasound) were also evaluated. The resulting xerogels were characterized through porosimetry using nitrogen adsorption/desorption. The samples were further analyzed through small-angle X ray scattering, Fourier transform infrared spectroscopy, and SEM. The preparation route affected the materials' textural properties. Extraction was optimized using acid and two-step routes. The acid route from Rhodamine B to Rhodamine 6G generated the highest selectivity factor (2.5). The nonhydrolytic route produced the best imprinting factor. Competitive adsorption was also used, from which the approximate imprinting factor was 2. The cavity shape generated during the production of the imprinted silica dictates the adsorption behavior, not the magnitude of the surface area. PMID- 24478150 TI - Ferrocene-modified carbon nitride for direct oxidation of benzene to phenol with visible light. AB - Ferrocene moieties were heterogenized onto carbon nitride polymers by a covalent C=N- linkage bridging the two conjugation systems, enabling the merging of the redox function of ferrocene with carbon nitride photocatalysis to construct a heterogeneous Photo-Fenton system for green organocatalysis at neutral conditions. The synergistic donor-acceptor interaction between the carbon nitride matrix and ferrocene group, improved exciton splitting, and coupled photocatalytic performance allowed the direct synthesis of phenol from benzene in the presence of H2 O2 under visible light irradiation. This innovative modification method will offer an avenue to construct functionalized two dimensional polymers useful also for other green synthesis processes using solar irradiation. PMID- 24478151 TI - Diagnostic evaluation of sentinel lymph node biopsy in early head and neck squamous cell carcinoma: a meta-analysis. AB - BACKGROUND: The purpose of this study was to evaluate the efficacy of sentinel lymph node biopsy (SLNB) in early head and neck squamous cell carcinoma (HNSCC). METHODS: The PubMed database was searched for studies published before October 31, 2012. Pooled values for the sentinel lymph node identification rate, sensitivity, false-negative rate, negative predictive value, and accuracy were calculated. RESULTS: A total of 16 studies (987 patients) was included. The pooled identification rate, sensitivity, false-negative rate, negative predictive value, and accuracy were 95.2%, 86.3%, 13.7%, 94.2%, and 95.0%, respectively. The subgroup with high methodological quality showed a mean identification rate of 95.4% for SLNB validation trials and 94.2% for SLNB alone trials, and mean sensitivity of 91.0% for SLNB validation trials and 84.2% for SLNB alone trials. CONCLUSION: The SLNB procedure has shown a high sensitivity rate, but the pooled sensitivity and false-negative rate were worse in SLNB alone trials than in SLNB validation trials. PMID- 24478152 TI - Intracardiac echocardiography-guided transcatheter aortic valve replacement. AB - Echocardiographic imaging is an essential component of successful transcatheter aortic valve replacement (TAVR). Currently, transesophageal echocardiography (TEE) is the imaging modality of choice for TAVR. However, a limitation of TEE is the need for general anesthesia and endotracheal intubation in most centers. Additionally, the TEE probe can obscure fluoroscopic views during valve positioning and deployment. Intracardiac echocardiography (ICE) has been used for imaging guidance for structural and valvular intervention, though its use has rarely been reported for primary imaging guidance during TAVR. Recently, a new volumetric three-dimensional intracardiac ultrasound (volume ICE) system has become available with the potential for improved visualization of intracardiac structures. We describe a recent TAVR case that was successfully performed with the use of volume ICE exclusively for imaging guidance. We found that assessment of valve positioning and aortic insufficiency were comparable to that provided by conventional TEE imaging, though there were several important limitations. ICE guided TAVR may represent an important alternative to TEE for TAVR imaging guidance and possibly allow for less-intensive sedation or anesthesia. PMID- 24478154 TI - Spatiotemporal stimulus properties modulate responses to trajectory changes in a locust looming-sensitive pathway. AB - The lobula giant movement detector (LGMD) and descending contralateral movement detector (DCMD) constitute one motion-sensitive pathway in the locust visual system that is implicated in collision-avoidance behaviors. While this pathway is thought to respond preferentially to objects approaching on a direct collision course, emerging studies suggest the firing rate is able to monitor more complicated movements that would occur under natural conditions. While previous studies have compared the response of the DCMD to objects on collision courses that travel at different speeds, velocity has not been manipulated for other simple or compound trajectories. Here we test the possibility that the LGMD/DCMD pathway is capable of responding uniquely to complex aspects of object motion, including translation and trajectory changes at different velocities. We found that the response of the DCMD to translational motion initiated in the caudal visual field was a low-amplitude peak in firing rate that occurred before the object crossed 90 degrees azimuth that was invariant to different object velocities. Direct looms at different velocities resulted in peak firing rates that occurred later in time and with greater amplitude for higher velocities. In response to transitions from translational motion to a collision course, the firing rate change depended on both the location within the visual field and the velocity. These results suggest that this pathway is capable of conveying information about multiple properties of a moving object's trajectory. PMID- 24478153 TI - Impact of subthreshold membrane potential on synaptic responses at dendritic spines of layer 5 pyramidal neurons in the prefrontal cortex. AB - Glutamatergic inputs onto cortical pyramidal neurons are received and initially processed at dendritic spines. AMPA and NMDA receptors generate both synaptic potentials and calcium (Ca) signals in the spine head. These responses can in turn activate a variety of Ca, sodium (Na), and potassium (K) channels at spines. In principle, the roles of these receptors and channels can be strongly regulated by the subthreshold membrane potential. However, the impact of different receptors and channels has usually been studied at the level of dendrites. Much less is known about their influence at spines, where synaptic transmission and plasticity primarily occur. Here we examine single-spine responses in the basal dendrites of layer 5 pyramidal neurons in the mouse prefrontal cortex. Using two photon microscopy and two-photon uncaging, we first show that synaptic potentials and Ca signals differ at resting and near-threshold potentials. We then determine how subthreshold depolarizations alter the contributions of AMPA and NMDA receptors to synaptic responses. We show that voltage-sensitive Ca channels enhance synaptic Ca signals but fail to engage small-conductance Ca-activated K (SK) channels, which require greater numbers of inputs. Finally, we establish how the subthreshold membrane potential controls the ability of voltage-sensitive Na channels and K channels to influence synaptic responses. Our findings reveal how subthreshold depolarizations promote electrical and biochemical signaling at dendritic spines by regulating the contributions of multiple glutamate receptors and ion channels. PMID- 24478155 TI - Muscle activation patterns are bilaterally linked during split-belt treadmill walking in humans. AB - There is growing evidence that human locomotion is controlled by flexibly combining a set of basic muscle activity patterns. To explore how these patterns are modified to cope with environmental constraints, 10 healthy young adults 1st walked on a split-belt treadmill at symmetric speeds of 4 and 6 km/h for 2 min. An asymmetric condition was then performed for 10 min in which treadmill speeds for the dominant (fast) and nondominant (slow) sides were 6 and 4 km/h, respectively. This was immediately followed by a symmetric speed condition of 4 km/h for 5 min. Gait kinematics and ground reaction forces were recorded. Electromyography (EMG) was collected from 12 lower limb muscles on each side of the body. Nonnegative matrix factorization was applied to the EMG signals bilaterally and unilaterally to obtain basic activation patterns. A cross correlation analysis was then used to quantify temporal changes in the activation patterns. During the early (1st 10 strides) and late (final 10 strides) phases of the asymmetric condition, the patterns related to ankle plantar flexor (push-off) of the fast limb and quadriceps muscle (contralateral heel contact) of the slow limb occurred earlier in the gait cycle compared with the symmetric conditions. Moreover, a bilateral temporal alignment of basic patterns between limbs was still maintained in the split-belt condition since a similar shift was observed in the unilateral patterns. The results suggest that the temporal structure of these locomotor patterns is shaped by sensory feedback and that the patterns are bilaterally linked. PMID- 24478157 TI - Fast feedback control involves two independent processes utilizing knowledge of limb dynamics. AB - Corrective muscle responses occurring 50-100 ms after a mechanical perturbation are tailored to the mechanical features of the limb and its environment. For example, the evoked response by the shoulder's extensor muscle counters an imposed shoulder torque, rather than local shoulder motion, by integrating motion information from the shoulder and elbow appropriate for their dynamic interaction. Previous studies suggest that arm muscle activity within this epoch, alternately termed the R2/3 response, or long-latency reflex, reflects the summed result of two distinct components: an activity-dependent component which scales with the background muscle activity, and a task-dependent component which scales with the required vigor of the behavioral task. Here we examine how the knowledge of limb dynamics expressed during the shoulder muscle's R2/3 epoch is related to these two functional components. Subjects countered torque steps applied to their shoulder and/or elbow under different conditions of background torque and target size to recruit the activity-dependent and task-dependent component in varying degrees. Experiment 1 involved four torque perturbations, two levels of background torques and two target sizes; this design revealed that both background torque and target size impacted the shoulder's R2/3 activity, indicative of knowledge of limb dynamics. Experiment 2 involved two perturbation torques, five levels of background torque and two target sizes; this design demonstrated that the two factors had an independent impact on the R2/3 activity indicative of knowledge of limb dynamics. We conclude that a sophisticated feature of upper limb feedback control reflects the summation of two processes having a common capability. PMID- 24478156 TI - Characterization of pruriceptive trigeminothalamic tract neurons in rats. AB - Rodent models of facial itch and pain provide a valuable tool for distinguishing between behaviors related to each sensation. In rats, pruritogens applied to the face elicit scratching using the hindlimb while algogens elicit wiping using the forelimb. We wished to determine the role of trigeminothalamic tract (VTT) neurons in carrying information regarding facial itch and pain to the forebrain. We have characterized responses to facially applied pruritogens (serotonin, BAM8 22, chloroquine, histamine, capsaicin, and cowhage) and noxious stimuli in 104 VTT neurons recorded from anesthetized rats. Each VTT neuron had a mechanically sensitive cutaneous receptive field on the ipsilateral face. All pruriceptive VTT neurons also responded to noxious mechanical and/or thermal stimulation. Over half of VTT neurons responsive to noxious stimuli also responded to at least one pruritogen. Each tested pruritogen, with the exception of cowhage, produced an increase in discharge rate in a subset of VTT neurons. The response to each pruritogen was characterized, including maximum discharge rate, response duration, and spike timing dynamics. Pruriceptive VTT neurons were recorded from throughout superficial and deep layers of the spinal trigeminal nucleus and were shown to project via antidromic mapping to the ventroposterior medial nucleus or posterior thalamic nuclei. These results indicate that pruriceptive VTT neurons are a subset of polymodal nociceptive VTT neurons and characterize a system conducive to future experiments regarding the similarities and differences between facial itch and pain. PMID- 24478158 TI - Cerebellar fastigial nucleus influence on ipsilateral abducens activity during saccades. AB - To characterize the cerebellar influence on neurons in the abducens (ABD) nucleus, we recorded ABD neurons before and after we inactivated the caudal part of the ipsilateral cerebellar fastigial nucleus (cFN) with muscimol injection. cFN activity influences the horizontal component of saccades. cFN inactivation increased the activity of most ipsilateral ABD neurons (19/22 in 2 monkeys) during ipsiversive (hypermetric) saccades, primarily by increasing burst duration. During contraversive (hypometric) saccades, the off-direction pause of most (10/15) ABD neurons was shorter than normal because of the early resumption of ABD activity. Early ABD firing caused the early contraction of antagonist muscles that reduced eye rotation and made contraversive saccades hypometric. Thus the cerebellum controls ipsilateral ABD activity by truncating on-direction bursts during ipsiversive saccades and extending off-direction pauses during contraversive saccades. We conclude that cFN output keeps saccades accurate by controlling when ABD on-direction bursts and off-direction pauses end. PMID- 24478160 TI - Large-scale identification of proteins involved in the development of a sexually dimorphic behavior. AB - Sexually dimorphic behaviors develop under the influence of sex steroids, which induce reversible changes in the underlying neural network of the brain. However, little is known about the proteins that mediate these activational effects of sex steroids. Here, we used a proteomics approach for large-scale identification of proteins involved in the development of a sexually dimorphic behavior, the electric organ discharge of brown ghost knifefish, Apteronotus leptorhynchus. In this weakly electric fish, the discharge frequency is controlled by the medullary pacemaker nucleus and is higher in males than in females. After lowering the discharge frequency by chronic administration of beta-estradiol, 2-dimensional difference gel electrophoresis revealed 62 proteins spots in tissue samples from the pacemaker nucleus that exhibited significant changes in abundance of >1.5 fold. The 20 identified protein spots indicated, among others, a potential involvement of astrocytes in the establishment of the behavioral dimorphism. Indeed, immunohistochemical analysis demonstrated higher expression of the astrocytic marker protein GFAP and increased gap-junction coupling between astrocytes in females compared with males. We hypothesize that changes in the size of the glial syncytium, glial coupling, and/or number of glia-specific potassium channels lead to alterations in the firing frequency of the pacemaker nucleus via a mechanism mediating the uptake of extracellular potassium ions from the extracellular space. PMID- 24478159 TI - Theta phase shift in spike timing and modulation of gamma oscillation: a dynamic code for spatial alternation during fixation in rat hippocampal area CA1. AB - Although hippocampus is thought to perform various memory-related functions, little is known about the underlying dynamics of neural activity during a preparatory stage before a spatial choice. Here we focus on neural activity that reflects a memory-based code for spatial alternation, independent of current sensory and motor parameters. We recorded multiple single units and local field potentials in the stratum pyramidale of dorsal hippocampal area CA1 while rats performed a delayed spatial-alternation task. This task includes a 1-s fixation in a nose-poke port between selecting alternating reward sites and so provides time-locked enter-and-leave events. At the single-unit level, we concentrated on neurons that were specifically active during the 1-s fixation period, when the rat was ready and waiting for a cue to pursue the task. These neurons showed selective activity as a function of the alternation sequence. We observed a marked shift in the phase timing of the neuronal spikes relative to the theta oscillation, from the theta peak at the beginning of fixation to the theta trough at the end of fixation. The gamma-band local field potential also changed during the fixation period: the high-gamma power (60-90 Hz) decreased and the low-gamma power (30-45 Hz) increased toward the end. These two gamma components were observed at different phases of the ongoing theta oscillation. Taken together, our data suggest a switch in the type of information processing through the fixation period, from externally cued to internally generated. PMID- 24478161 TI - Footprints of inhibition in the response of cortical delay-tuned neurons of bats. AB - Responses of echo-delay-tuned neurons that encode target distance were investigated in the dorsal auditory cortex of anesthetized short-tailed fruit bats (Carollia perspicillata). This species echolocates using short downward frequency-modulated (FM) biosonar signals. In response to FM sweeps of increasing level, 60 out of 131 studied neurons (47%) displayed a "paradoxical latency shift," i.e., longer response latency to loud sounds and shorter latency to faint sounds. In addition, a disproportionately large number of neurons (80%) displayed nonmonotonic responses, i.e., weaker responses to loud sounds and stronger responses to faint sounds. We speculate that the observed paradoxical latency shift and nonmonotonic responses are extracellular footprints of inhibitory processes evoked by loud sounds and that they could represent a specialization for the processing of the emitted loud biosonar pulse. Supporting this idea is the fact that all studied neurons displayed strong response suppression when an artificial loud pulse and a faint echo were presented together at a nonoptimal delay. In 24 neurons, iontophoresis of bicuculline (an antagonist of A-type gamma aminobutyric acid receptors) did not remove inhibitory footprints but did increase the overall spike output, and in some cases it also modified the response bandwidth and shifted the neuron's "best delay." We suggest that inhibition could play a dual role in shaping delay tuning in different auditory stations. Below the cortex it participates in delay-tuning implementation and leaves a footprint that is measurable in cortical responses, while in the cortex it provides a substrate for an in situ control of neuronal selectivity. PMID- 24478162 TI - Neonatal infraorbital nerve crush-induced CNS synaptic plasticity and functional recovery. AB - Infraorbital nerve (ION) transection in neonatal rats leads to disruption of whisker-specific neural patterns (barrelettes), conversion of functional synapses into silent synapses, and reactive gliosis in the brain stem trigeminal principal nucleus (PrV). Here we tested the hypothesis that neonatal peripheral nerve crush injuries permit better functional recovery of associated central nervous system (CNS) synaptic circuitry compared with nerve transection. We developed an in vitro whisker pad-trigeminal ganglion (TG)-brain stem preparation in neonatal rats and tested functional recovery in the PrV following ION crush. Intracellular recordings revealed that 68% of TG cells innervate the whisker pad. We used the proportion of whisker pad-innervating TG cells as an index of ION function. The ION function was blocked by ~64%, immediately after mechanical crush, then it recovered beginning after 3 days postinjury and was complete by 7 days. We used this reversible nerve-injury model to study peripheral nerve injury-induced CNS synaptic plasticity. In the PrV, the incidence of silent synapses increased to ~3.5 times of control value by 2-3 days postinjury and decreased to control levels by 5-7 days postinjury. Peripheral nerve injury-induced reaction of astrocytes and microglia in the PrV was also reversible. Neonatal ION crush disrupted barrelette formation, and functional recovery was not accompanied by de novo barrelette formation, most likely due to occurrence of recovery postcritical period (P3) for pattern formation. Our results suggest that nerve crush is more permissive for successful regeneration and reconnection (collectively referred to as "recovery" here) of the sensory inputs between the periphery and the brain stem. PMID- 24478163 TI - Propensity score balance measures in pharmacoepidemiology: a simulation study. AB - BACKGROUND: Conditional on the propensity score (PS), treated and untreated subjects have similar distribution of observed baseline characteristics when the PS model is appropriately specified. The performance of several PS balance measures in assessing the balance of covariates achieved by a specific PS model and selecting the optimal PS model was evaluated in simulation studies. However, these studies involved only normally distributed covariates. Comparisons in binary or mixed covariate distributions with rare outcomes, typical of pharmacoepidemiologic settings, are scarce. METHODS: Monte Carlo simulations were performed to examine the performance of different balance measures in terms of selecting an optimal PS model, thus reduction in bias. The balance of covariates between treatment groups was assessed using the absolute standardized difference, the Kolmogorov-Smirnov distance, the Levy distance, and the overlapping coefficient. Spearman's correlation coefficient (r) between each of these balance measures and bias were calculated. RESULTS: In large sample sizes (n >= 1000), all balance measures were similarly correlated with bias (r ranging between 0.50 and 0.68) irrespective of the treatment effect's strength and frequency of the outcome. In smaller sample sizes with mixed binary and continuous covariate distributions, these correlations were low for all balance measures (r ranging between 0.11 and 0.43), except for the absolute standardized difference (r = 0.51). CONCLUSIONS: The absolute standardized difference, which is an easy-to calculate balance measure, displayed consistently better performance across different simulation scenarios. Therefore, it should be the balance measure of choice for measuring and reporting the amount of balance reached, and for selecting the final PS model. PMID- 24478164 TI - Approximate Fourier domain expression for Bloch-Siegert shift. AB - PURPOSE: In this study, a new simple Fourier domain-based analytical expression for the Bloch-Siegert (BS) shift-based B1 mapping method is proposed to obtain |B1+| more accurately while using short BS pulse durations and small off resonance frequencies. THEORY AND METHODS: A new simple analytical expression for the BS shift is derived by simplifying the Bloch equations. In this expression, the phase is calculated in terms of the Fourier transform of the radiofrequency pulse envelope, and thus making the off- and on-resonance effects more easily understandable. To verify the accuracy of the proposed expression, Bloch simulations and MR experiments are performed for the hard, Fermi, and Shinner-Le Roux pulse shapes. RESULTS: Analyses of the BS phase shift-based B1 mapping method in terms of radiofrequency pulse shape, pulse duration, and off-resonance frequency show that |B1+| can be obtained more accurately with the aid of this new expression. CONCLUSIONS: In this study, a new simple frequency domain analytical expression is proposed for the BS shift. Using this expression, |B1+| values can be predicted from the phase data using the frequency spectrum of the radiofrequency pulse. This method works well even for short pulse durations and small offset frequencies. PMID- 24478165 TI - A core-expanded subphthalocyanine analogue with a significantly distorted conjugated surface and unprecedented properties. AB - The introduction of a seven-membered-ring unit in the place of a five-membered ring unit in the structure of subphthalocyanine resulted in significant distortion of the bowl-shaped structure of the conjugated molecule as well as the following unprecedented properties: the preferential formation of the axially fluoro substituted species, the fluttering-dynamic-motion-induced rapid exchange of P and M enantiomers, markedly split Q-band absorption, and a clear difference in the ring-current effects arising from the convex and concave surfaces. PMID- 24478167 TI - Cyclic peptides as inhibitors of amyloid fibrillation. AB - Many neurodegenerative diseases, like Parkinson's, Alzheimer's, or Huntington's disease, occur as a result of amyloid protein fibril formation and cell death induced by this process. Cyclic peptides (CPs) and their derivatives form a new class of powerful inhibitors that prevent amyloid fibrillation and decrease the cytotoxicity of aggregates. The strategies for designing CPs are described, with respect to their amino acid sequence and/or conformational similarity to amyloid fibrils. The implications of CPs for the study and possible treatment of amyloid related diseases are discussed. PMID- 24478166 TI - Factors associated with survival in a contemporary adult sickle cell disease cohort. AB - In this study, the relationship of clinical differences among patients with sickle cell disease (SCD) was examined to understand the major contributors to early mortality in a contemporary cohort. Survival data were obtained for 542 adult subjects who were enrolled since 2002 at three university hospitals in the southeast United States. Subjects were followed up for a median of 9.3 years. At enrollment, clinical parameters were collected, including hemoglobin (Hb) genotype, baseline laboratory values, comorbidities, and medication usage. Levels of soluble adhesion molecules were measured for a subset of 87 subjects. The relationship of clinical characteristics to survival was determined using regression analysis. Median age at enrollment was 32 years. Median survival was 61 years for all subjects. Median survival for Hb SS and Sbeta(0) was 58 years and for Hb SC and Sbeta(+) was 66 years. Elevated white blood count, lower estimated glomerular filtration rate, proteinuria, frequency of pain crises, pulmonary hypertension, cerebrovascular events, seizures, stroke, sVCAM-1, and short-acting narcotics use were significantly associated with decreased survival. Forty-two percent of subjects were on hydroxyurea therapy, which was not associated with survival. SCD continues to reduce life expectancy for affected individuals, particularly those with Hb Sbeta(0) and SS. Not only were comorbidities individually associated with decreased survival but also an additive effect was observed, thus, those with a greater number of negative endpoints had worse survival (P < 0.0001). The association of higher sVCAM-1 levels with decreased survival suggests that targeted therapies to reduce endothelial damage and inflammation may also be beneficial. PMID- 24478168 TI - Role of VEGF-C gene polymorphisms in susceptibility to hepatocellular carcinoma and its pathological development. AB - BACKGROUND: Vascular endothelial growth factor C (VEGF-C), an angiogenic/lymphangiogenic factor with high expression levels in tumor tissues, plays important roles in the development of several malignancies including hepatocellular carcinoma (HCC). The purpose of this study was to examine whether VEGF-C gene polymorphisms are associated with susceptibility to HCC and its clinicopathological development. METHODS: Genetic polymorphisms of VEGF-C of 135 patients with HCC and 520 noncancer controls were analyzed by a real-time polymerase chain reaction (PCR). RESULTS: We found that a significantly (P = 0.021) higher risk for HCC was shown in individuals with the VEGF-C rs1485766 A/A genotype compared to those with wild-type homozygotes; a high frequency of an advanced stage and a low frequency of being positive for cirrhosis were respectively shown in HCC patients with the VEGF-C rs7664413 CT/TT and rs3775194 GC/CC genotypes. Moreover, we found that the GGACA, GACTG, CGATG, and GGCTG haplotypes of five VEGF-C single-nucleotide polymorphisms (SNPs) combined were also related to the risk of HCC. CONCLUSIONS: Our results suggest that the VEGF-C rs1485766 SNP and either of five haplotypes combined might contribute to a prediction of susceptibility to HCC. The genetic polymorphism of VEGF-C rs7664413 might be a predictive factor for advanced-stage HCC. PMID- 24478169 TI - The role of osteoclasts in bone tissue engineering. AB - The success of scaffold-based bone regeneration approaches strongly depends on the performance of the biomaterial utilized. Within the efforts of regenerative medicine towards a restitutio ad integrum (i.e. complete reconstruction of a diseased tissue), scaffolds should be completely degraded within an adequate period of time. The degradation of synthetic bone substitute materials involves both chemical dissolution (physicochemical degradation) and resorption (cellular degradation by osteoclasts). Responsible for bone resorption are osteoclasts, cells of haematopoietic origin. Osteoclasts play also a crucial role in bone remodelling, which is essential for the regeneration of bone defects. There is, however, surprisingly limited knowledge about the detailed effects of osteoclasts on biomaterials degradation behaviour. This review covers the relevant fundamental knowledge and progress made in the field of osteoclast activity related to biomaterials used for bone regeneration. In vitro studies with osteoclastic precursor cells on synthetic bone substitute materials show that there are specific parameters that inhibit or enhance resorption. Moreover, analyses of the bone-material interface reveal that biomaterials composition has a significant influence on their degradation in contact with osteoclasts. Crystallinity, grain size, surface bioactivity and density of the surface seem to have a less significant effect on osteoclastic activity. In addition, the topography of the scaffold surface can be tailored to affect the development and spreading of osteoclast cells. The present review also highlights possible areas on which future research is needed and which are relevant to enhance our understanding of the complex role of osteoclasts in bone tissue engineering. PMID- 24478170 TI - Electrochemical fabrication of a novel polycarbazole coating for the headspace solid-phase microextraction and GC determination of some chlorobenzenes. AB - A novel polycarbazole coating was prepared by cyclic voltammetry on a platinum wire. The solution for electropolymerization contained N,N-dimethylformamide, propylene carbonate (v/v = 1:9), 0.10 M carbazole and 0.10 M tetrabutylammonium perchlorate; the cyclic scan potential range was 0.8-2.0 V (versus Ag/AgCl). The resulting polycarbazole coating showed a porous structure and had a large specific surface area. When it was used for the headspace solid-phase microextraction of chlorobenzenes (i.e. chlorobenzene, 2-chlorotoluene, 1,2 dichlorobenzene, 1,3-dichlorobenzene, 1,2,4-trichlorobenzene) followed by GC analysis, it presented excellent analytical performance. Under the optimized conditions the linear ranges were 0.25-250 MUg/L with correlation coefficients >0.985, and the low detection limits were 15-61 ng/L (S/N = 3) for different chlorobenzenes. The RSDs were 2.4-4.9% for five successive measurements with a single fiber, and for fiber-to-fiber they were 6.3-13.1% (n = 5). Furthermore, the polycarbazole coating displayed good thermal stability (>350 degrees C) and durability (more than 250 times). The proposed method was successfully applied to the extraction and determination of chlorobenzenes in waste water and lake water, and the recoveries for standards added were 86-114% for different analytes. PMID- 24478171 TI - Warfarin: Impact on hemostasis after radial catheterization. AB - OBJECTIVES: This study explores bleeding risk of warfarin patients undergoing radial catheterization. BACKGROUND: Traditionally warfarin has been held prior to catheterization due to bleeding risk; however, this practice is being reconsidered with radial access. This study examined if radial patients receiving warfarin have similar hemostasis times to those not taking warfarin. METHODS: A convenience sample of patients undergoing radial catheterization was analyzed. Demographics, procedure characteristics, and pharmacologic therapies were reviewed. Hemostasis times, defined as compression band times, were compared. To exclude confounding effects of aspirin and clopidogrel, a separate analysis of band times for each medication was performed. Specifically, analysis of variance models and exact logistic regression models were used to assess means between usage or nonusage of medications (warfarin, aspirin, clopidogrel) while adjusting for other medications. RESULTS: Of 208 patients, 60 (29%) were taking warfarin. The breakdown of warfarin, aspirin, and clopidogrel use was as follows: 6 (3%) not taking medications; 14 (7%) warfarin alone; 88 (42%) aspirin alone; 2 (1%) clopidogrel alone; 39 (19%) both warfarin and aspirin; 52 (25%) clopidogrel and aspirin; and 7 (3%) warfarin, aspirin, and clopidogrel. No major complications occurred. Mean hemostasis times for warfarin and nonwarfarin patients were not different (118 vs. 116 min; P = 0.25). Likewise, there was no difference for aspirin (117 vs. 114 min; P = 0.70). There was a nonsignificant trend toward clopidogrel prolonging hemostasis (123 vs. 114 min; P = 0.09). CONCLUSION: There were no apparent differences in adequacy of hemostasis or duration of compression time between patients taking warfarin or not taking warfarin after controlling for antiplatelet therapy. (c) 2014 Wiley Periodicals, Inc. PMID- 24478172 TI - Fgfr signaling is required as the early eye field forms to promote later patterning and morphogenesis of the eye. AB - BACKGROUND: A major step in eye morphogenesis is the transition from optic vesicle to optic cup, which occurs as a ventral groove forms along the base of the optic vesicle. A ventral gap in the eye, or coloboma, results when this groove fails to close. Extrinsic signals, such as fibroblast growth factors (Fgfs), play a critical role in the development and morphogenesis of the vertebrate eye. Whether these extrinsic signals are required throughout eye development, or within a defined critical period remains an unanswered question. RESULTS: Here we show that an early Fgf signal, required as the eye field is first emerging, drives eye morphogenesis. In addition to triggering coloboma, inhibition of this early Fgf signal results in defects in dorsal-ventral patterning of the neural retina, particularly in the nasal retina, and development of the periocular mesenchyme (POM). These processes are unaffected by inhibition of Fgfr signaling at later time points. CONCLUSIONS: We propose that Fgfs act within an early critical period as the eye field forms to promote development of the neural retina and POM, which subsequently drive eye morphogenesis. PMID- 24478173 TI - A 1D/2D helical CdS/ZnIn2 S4 nano-heterostructure. AB - Multidimensional nano-heterostructures (NHSs) that have unique dimensionality dependent integrative and synergic effects are intriguing but still underdeveloped. Here, we report the first helical 1D/2D epitaxial NHS between CdS and ZnIn2S4. Experimental and theoretical studies reveal that the mismatches in lattice and dangling bonds between 1D and 2D units govern the growth procedure. The resulting well-defined interface induces the delocalized interface states, thus facilitate the charge transfer and enhance the performance in the photoelectrochemical cells. We foresee that the mechanistic insights gained and the electronic structures revealed would inspire the design of more complex 1D/2D NHSs with outstanding functionalities. PMID- 24478174 TI - Silver-catalyzed cross-coupling of propargylic alcohols with isocyanides: an atom economical synthesis of 2,3-allenamides. AB - Cross-coupling reactions between propargylic alcohols and isocyanides, by means of silver catalysis, have been described. This new reaction is both atom and step efficient and is applicable to a broad scope of substrates, allowing the synthesis of a range of synthetically valuable 2,3-allenamides in moderate to excellent yields. PMID- 24478175 TI - The effect of low b-values on the intravoxel incoherent motion derived pseudodiffusion parameter in liver. AB - PURPOSE: To examine the effect of low b-values (0 < b < 50 s/mm(2)) on the calculation of the intravoxel incoherent motion (IVIM) derived pseudodiffusion parameter in the normal liver. METHODS: Simulations were performed to examine the effects of adding low b-values on the pseudodiffusion parameter. Low b-values were cumulatively added to the distribution and the IVIM signal was generated with varying pseudodiffusion values. The signal was fit with the IVIM model after the addition of Gaussian noise, and the simulated values were compared with the true values. In addition, the livers of eight control subjects were imaged using respiratory-triggered DWI. Pseudodiffusion was calculated with and without low b values and compared. RESULTS: Pseudodiffusion tended to be underestimated when low b-values were not included in the b-value distribution as predicted by simulations and confirmed with in vivo imaging. The number of outlier values was also reduced as more low b-values were added. CONCLUSION: In conclusion, this study showed pseudodiffusion in the liver tended to be underestimated when too few low b-values (0 < b < 50 s/mm(2)) were included in the distribution. Therefore, it is recommended to include at least two low b-values when performing liver IVIM studies. PMID- 24478177 TI - Changes in platelet count and mean platelet volume during infectious and inflammatory disease and their correlation with ESR and CRP. AB - BACKGROUND: The measurements of platelet count and mean platelet volume (MPV) are routinely available nowadays. The aim of this study was to evaluate the platelet count and MPV trend in infectious and inflammatory processes. We also investigated whether these parameters were associated with the known markers of disease activity, erythrocyte sedimentation rate (ESR) and C- reactive protein (CRP). METHODS: This cross-sectional study was conducted on 100 children with diagnosis of infectious and inflammatory diseases. Platelet count, MPV, ESR, and CRP were measured at the time of hospitalization and thereafter in the recovery phase. RESULTS: Mean platelet count increased in the patients at the time of admission in the hospital compared to the recovery and discharge time (mean 430,820 +/- 134,643/MUl vs. 350,970 +/- 99,374/MUl, P < 0.001). However, MPV decreased significantly during the same period (8.2 +/- 1.1 fl vs. 8.7 +/- 0.9, P < 0.001). Platelet count was directly correlated with CRP (mean 6.4 +/- 0.3 mg/l), (r = 0.49, P < 0.001) and ESR (mean 10.9 +/- 1.1 mm/hr), (r = 0.32, P = 0.003). On the other hand, MPV was inversely correlated with CRP (r = 0.39, P < 0.001) and ESR (r = -0.24, P = 0.034). CONCLUSIONS: This study demonstrated a higher level of platelet count and lower MPV in the patients with active disease compared to the recovered patients. These parameters were well correlated with the known disease activity markers. We propose that platelet parameters can be considered as reliable markers for assessment of disease activity and response to treatment. PMID- 24478176 TI - A novel mutation (g.106737G>T) in zone of polarizing activity regulatory sequence (ZRS) causes variable limb phenotypes in Werner mesomelia. AB - Werner mesomelia is characterized by a sequence variation in the specific region (position 404) of the enhancer ZRS of SHH. The phenotype comprises variable mesomelia, abnormalities of the thumb and great toe and supernumerary digits. We describe extensive variation in limb phenotype in a large family and report on a novel sequence variation NG_009240.1: g.106737G>T (traditional nomenclature: ZRS404G>T) in the ZRS within the LMBR1 gene. The newly recognized clinical features in this family include small thenar eminence, sandal gap, broad first metatarsals, mesoaxial polydactyly, and postaxial polydactyly. We provide information on 12 affected family members. We review the literature on how a sequence variation in ZRS may cause such diverse phenotypes. PMID- 24478178 TI - Controlled tubulogenesis from dispersed ureteric bud-derived cells using a micropatterned gel. AB - Developmental engineering is a potential option for neo-organogenesis of complex organs such as the kidney. The application of this principle requires the ability to construct a tubular structure from dispersed renal progenitor cells with defined size and geometry. In this present study we report the generation of tubular structures from dispersed ureteric bud cells in vitro by using a micropatterned gel. Dispersed CMUB-1 cells, a mouse ureteric bud-derived cell line, or mIMCD cells, a mouse collecting duct-derived cell line, were suspended in collagen I and seeded into an agarose-based micropatterned gel. We found that within 24-36 h of incubation, the cells developed a tubular structure that conformed to the geometry of the micropattern of the gel. The lumen formation of the tubular structure was confirmed by immunohistochemical staining and observed by confocal microscopy. We found that higher concentrations of collagen I negatively influenced the efficiency of tubular formation. Tubule formation in CMUB-1, but not mIMCD, cells was positively influenced by the addition of aldosterone (10, 50 and 200 ug/ml), FGF (50 and 100 ug/ml) and fibronectin (10 and 50 ug/ml) to the growth medium. We further demonstrated the functionality of the generated tubes by in vitro budding, which was induced by growth factors, such as glial cell-derived neurotrophic factor (GDNF) or fibroblast growth factor 7 (FGF7), in the presence of beads soaked with the activin A inhibitor follistatin. Our current study thus demonstrates the possibility of constructing a functional tubular structure from dispersed ureteric bud cells in vitro in a controlled manner. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24478179 TI - Prognostic factors in squamous cell lip carcinoma treated with high-dose-rate brachytherapy. AB - BACKGROUND: The purpose of this study was for us to present our analysis of the results and prognostic factors in squamous lip carcinoma treated with high-dose rate (HDR) brachytherapy. METHODS: From 1999 to 2010, 102 patients were treated with HDR-brachytherapy, 54 with T1, 33 with T2, and 15 with T4. Eight cases were N+. Twenty-one patients were treated with surgery plus brachytherapy because of close/positive margins. Nine fractions of 5 Gy were given over 5 days in 67% of the patients. Elective neck treatment was performed in 23 cases. RESULTS: The 10 year actuarial local control was 94.6%, nodal regional control was 88.6%, disease free survival was 84.6%, and cause-specific survival was 93.2%. In the univariate analysis, T4 tumors had higher risk of local failure and T2 of regional relapse. In the multivariate analysis, skin involvement was the only significant factor for tumor progression. CONCLUSION: HDR-brachytherapy yields excellent local control rates. Skin involvement increases the risk of local and cervical recurrence. Elective neck treatment should be done in T2 to T4 tumors or with skin or commissure involvement. PMID- 24478181 TI - Separation of electrical and optical energy gaps: selectively adjusting the electrical and optical properties for a highly efficient blue emitter. AB - The design concept of separation of optical and electrical bandgap for wide bandgap materials is further developed in DCzSiPI. The HOMO/LUMO levels can be tuned by incorporation of PI and DCz substituents. The tetraphenylsilane core avoids the intramolecular charge transfer from DCz to PI (DCz = dimer carbazole, PI = phenanthro[9,10-d]imidazole). The allowed transitions are found to be from HOMO-1 to LUMO providing DCzSiPI with sufficient bandgap. PMID- 24478182 TI - Prevalence and anatomical features of acute longitudinal stent deformation: An intravascular ultrasound study. AB - OBJECTIVES: We report the prevalence and anatomical features of longitudinal stent deformation as detected by intravascular ultrasound (IVUS) BACKGROUND: Angiographic studies have recently reported longitudinal stent deformation as a mechanical complication occurring during percutaneous coronary intervention; however, there are no IVUS studies on this phenomenon METHODS: We retrospectively analyzed 1,489 consecutive stent-treated lesions in 1,057 patients who underwent IVUS post-stent implantation RESULTS: Seventeen longitudinal stent deformations in 17 lesions (1.1% per lesion) in 17 patients (1.6% per patient) were identified by IVUS. Of the 17 IVUS-detected deformations, only three deformations (17.6%) were detectable by angiography. By IVUS, there were three patterns of longitudinal stent deformation: (1) Deformation with intra-stent wrinkling and overlapping of the proximal and distal stent fragments within a single stent (n = 14), (2) deformation with elongation (n = 2), and (3) deformation with shortening (n = 1). Most of the deformations were located near to the proximal stent edge (88%), consistent with the finding that they were observed in 11 ostial (65%) and eight left main lesions (47%), and 8.3% of 96 left main stented lesions had evidence of deformation CONCLUSIONS: By IVUS, longitudinal stent deformation during percutaneous coronary intervention was seen more frequently than in previous studies; however, it is still uncommon (1.1%) except in the left main location. The most frequent pattern was intrastent wrinkling and overlapping of the proximal and distal stent fragments. PMID- 24478183 TI - Locus-specific databases in cancer: what future in a post-genomic era? The TP53 LSDB paradigm. AB - Locus-specific databases (LSDBs) are curated compilations of sequence variants in genes associated with disease and have been invaluable tools for both basic and clinical research. These databases contain extensive information provided by the literature and benefit from manual curation by experts. Cancer genome sequencing projects have generated an explosion of data that are stored directly in centralized databases, thus possibly alleviating the need to develop independent LSDBs. A single cancer genome contains several thousand somatic mutations. However, only a handful of these mutations are truly oncogenic and identifying them remains a challenge. However, we can expect that this increase in data and the development of novel biocuration algorithms will ultimately result in more accurate curation and the release of stable sets of data. Using the evolution and content of the TP53 LSDB as a paradigm, it is possible to draw a model of gene mutation analysis covering initial descriptions, the accumulation and organization of knowledge in databases, and the use of this knowledge in clinical practice. It is also possible to make several assumptions on the future of LSDBs and how centralized databases could change the accessibility of data, with interfaces optimized for different types of users and adapted to the specificity of each region of the genome, coding or noncoding, associated with tumor development. PMID- 24478184 TI - Radical cyclization/ipso-1,4-aryl migration cascade: asymmetric synthesis of 3,3 difluoro-2-propanoylbicyclo[3.3.0]octanes. AB - A novel method for the asymmetric synthesis of 3,3-difluoro-2-propanoylbicyclo [3.3.0]octanes involves an unprecedented intramolecular radical cyclization/ipso 1,4-aryl migration cascade. PMID- 24478185 TI - Simultaneous determination of dyes in wines by HPLC coupled to quadrupole orbitrap mass spectrometry. AB - A new method combining the QuEChERS (quick, easy, cheap, effective, rugged, and safe) method with ultra high performance liquid chromatography and ESI quadrupole Orbitrap high-resolution MS was developed for the highly accurate and sensitive screening of 69 dyes in wines. Response surface methodology was employed to optimize the QuEChERS sample preparation method for the determination of 69 different analytes in wines for the first time. After optimization, the maximum predicted recovery was 99.48% rate for canacert indigo carmine under the optimized conditions of 10 mL acetonitrile, 1.45 g sodium acetate, 107 mg primary secondary amine, and 96 mg C18 . For the matrices studied, the recovery rates of the other 68 compounds ranged from 87.2-107.4%, with coefficient of variation < 6.4%. The mass accuracy typically obtained is routinely better than 1.6 ppm and only needed to be calibrated once a week. The LODs for the analytes are in the range 1-1000 MUg/kg. This method has been successfully applied on screening of dyes in commercial wines, and it is very useful for the fast screening of different food additives. PMID- 24478186 TI - Distribution of lymphocyte subpopulations in thyroid glands of human autoimmune thyroid disease. AB - BACKGROUND: The autoimmune thyroid disease (AITD) is an organ-specific autoimmune disease characterized by the breakdown of self-tolerance to thyroid antigens. Some lymphocytes have been identified to be related notably to the pathogenesis of AITD. This article evaluated the distribution of the lymphocytic subpopulation in thyroid glands in order to develop the immunospecific forms of therapy for AITD. METHODS: Damaged thyroid specimens were obtained from 18 Graves' disease (GD) and 17 Hashimoto's thyroiditis (HT) patients. Normal thyroid specimens were obtained from unaffected glands of 17 patients who underwent parathyroidectomy. We evaluated the distribution of lymphocytic subpopulation by analyzing the expression difference and correlationship among CD4+ T lymphocyte, CD8+ T lymphocyte, CD20+ B lymphocyte as well as regulatory T cells(Tregs)' marker FoxP3 in the thyroid tissues via immunohistochemistry. RESULTS: Our research uncovered that no distinct lymphocyte infiltrated in the normal thyroid specimens. Scarcely any lymphocyte infiltration could be found in half of the totally 18 GD thyroid specimens. For the rest 9 GD specimens, CD8+ T cells and CD20+ B cells were expressed more or less in all of them, FoxP3+ Tregs were detected in 7 of them and CD4+ T cells were weakly expressed in only 2 of them. For the 17 HT thyroid specimens, CD20+ B cells were stained strongly in all of them, CD4+, CD8+ T cells were expressed more or less in most of them and FoxP3+ Tregs could be detected in 9 of them. CONCLUSION: Based on CD20+ B cells predominantly infiltrating in all HT thyroid tissues we suggested CD20 antibody might be of help for HT treatment. Furthermore based on FoxP3+ Tregs abundantly infiltrating in some of the AITD thyroid specimens, we considered that activating the Tregs' function in comparison to increasing the Tregs' number only, may be a more effective approach to the treatment of AITD in some cases. PMID- 24478187 TI - Dynamically phase-cycled radial balanced SSFP imaging for efficient banding removal. AB - PURPOSE: Balanced steady-state free precession (bSSFP) imaging suffers from banding artifacts due to its inherent sensitivity to inhomogeneities in the main magnetic field. These artifacts can be removed by the acquisition of multiple images at different frequency offsets. However, conventional phase-cycling is hindered by a long scan time. The purpose of this work is to present a novel approach for efficient banding removal in bSSFP imaging. THEORY AND METHODS: To this end, the phase-cycle during a single-shot radial acquisition of an image was dynamically changed. Thus, each projection is acquired with a different frequency offset. Using conventional radial gridding, an artifact-free image can be reconstructed out of this dataset. RESULTS: The approach is validated at clinical field strength [3.0 Tesla (T)] as well as at ultrahigh field (9.4T). Robust elimination of banding artifacts was obtained for different imaging regions, including brain imaging at ultrahigh field with an in-plane resolution of 0.25 * 0.25 mm(2). Besides banding artifact-free imaging, the applicability of the proposed technique for fat-water separation is demonstrated. CONCLUSION: Dynamically phase-cycled radial bSSFP has the potential for banding-free bSSFP imaging in a short scan time, in the presence of severe field inhomogeneities and at high resolution. PMID- 24478188 TI - Clinical characterization and identification of duplication breakpoints in a Japanese family with Xq28 duplication syndrome including MECP2. AB - Xq28 duplication syndrome including MECP2 is a neurodevelopmental disorder characterized by axial hypotonia at infancy, severe intellectual disability, developmental delay, mild characteristic facial appearance, epilepsy, regression, and recurrent infections in males. We identified a Japanese family of Xq28 duplications, in which the patients presented with cerebellar ataxia, severe constipation, and small feet, in addition to the common clinical features. The 488-kb duplication spanned from L1CAM to EMD and contained 17 genes, two pseudo genes, and three microRNA-coding genes. FISH and nucleotide sequence analyses demonstrated that the duplication was tandem and in a forward orientation, and the duplication breakpoints were located in AluSc at the EMD side, with a 32-bp deletion, and LTR50 at the L1CAM side, with "tc" and "gc" microhomologies at the duplication breakpoints, respectively. The duplicated segment was completely segregated from the grandmother to the patients. These results suggest that the duplication was generated by fork-stalling and template-switching at the AluSc and LTR50 sites. This is the first report to determine the size and nucleotide sequences of the duplicated segments at Xq28 of three generations of a family and provides the genotype-phenotype correlation of the patients harboring the specific duplicated segment. PMID- 24478189 TI - Rhodium-catalyzed [2+2+2] cycloaddition of diynes with carbodiimides and carbon dioxide under ambient conditions. AB - It has been established that a cationic rhodium(I)/H8-binap complex is able to catalyze the [2+2+2] cycloaddition of diynes with carbodiimides and carbon dioxide under ambient conditions. Enantio- and/or regioselective variants of these reactions are also disclosed. PMID- 24478190 TI - Discomfort assessment in peripheral angiography: randomized clinical trial of Iodixanol 270 versus Ioversol 320 in diabetics with critical limb ischemia. AB - OBJECTIVES: To assess and compare the intra-arterial injection-associated discomfort of iodinated contrast media (CM) and the impact on diagnostic efficacy in diabetics with critical limb ischemia (CLI). BACKGROUND: Arterial revascularization is a mainstay in patients with CLI. Previous diagnostic angiography is a crucial step that can be affected by CM injection discomfort compromising the revascularization results, and it could vary related to the CM agents. METHODS: One hundred forty-eight patients received Iodixanol 270 mg iodine pro ml or Ioversol 320 mg iodine pro ml in a prospective, double-blind, randomized, parallel-group clinical trial. Injection-associated discomfort was assessed by Visual Analogic Scale (VAS). Diagnostic efficacy and safety up to 1 week were evaluated. RESULTS: The incidence of pain has been around 50% of the all population in study, with lesser incidence of pain (25.7% vs 74.3%; P < 0.0001) and of heat sensation (55.4% vs 85.1%; P < 0.0001), after Iodixanol than after Ioversol injection. Discomfort mean score, according to VAS assessment, was less in the Iodixanol group (8.1 +/- 15.3) than in the Ioversol group (36.0 +/- 29.7), after first injection (P < 0.001) and for all injections (P < 0.001). A significant difference was also observed in favor of Iodixanol (P < 0.001), respect to mean score of discomfort and heat sensation, assessed by the operators after all the CM injections. CONCLUSIONS: Iodixanol caused less frequent and severe discomfort, characterized as pain and heat during intra-arterial administration compared with Ioversol. The pain severity is tightly related to image and diagnosis quality with an impact on the patients for additional injections and larger CM volumes. PMID- 24478191 TI - Primary immunodeficiency caused by an exonized retroposed gene copy inserted in the CYBB gene. AB - Retrotransposon-mediated insertion of a long interspersed nuclear element (LINE) 1 or an Alu element into a human gene is a well-known pathogenic mechanism. We report a novel LINE-1-mediated insertion of a transcript from the TMF1 gene on chromosome 3 into the CYBB gene on the X-chromosome. In a Dutch male patient with chronic granulomatous disease, a 5.8-kb, incomplete and partly exonized TMF1 transcript was identified in intron 1 of CYBB, in opposite orientation to the host gene. The sequence of the insertion showed the hallmarks of a retrotransposition event, with an antisense poly(A) tail, target site duplication, and a consensus LINE-1 endonuclease cleavage site. This insertion induced aberrant CYBB mRNA splicing, with inclusion of an extra 117-bp exon between exons 1 and 2 of CYBB. This extra exon contained a premature stop codon. The retrotransposition took place in an early stage of fetal development in the mother of the patient, because she showed a somatic mosaicism for the mutation that was not present in the DNA of her parents. However, the mutated allele was not expressed in the patient's mother because the insertion was found only in the methylated fraction of her DNA. PMID- 24478192 TI - Effect of straw leachates from Cry1Ca-expressing transgenic rice on the growth of Chlorella pyrenoidosa. AB - Because of the prevalence of algae in rice paddy fields, they will be exposed to Bacillus thurigiensis (Bt) proteins released from Bt protein-expressing genetically engineered rice. To assess the effects of leachates extracted from Cry1Ca-expressing transgenic rice (T1C-19) straw on the microalga Chlorella pyrenoidosa, the authors added purified Cry1Ca (10 ug/L, 100 ug/L, and 1000 ug/L) and 5 concentrations of diluted extracts (5%, 10%, 20%, 40%, and 80%) from T1C-19 and the nontransformed control strain Minghui 63 (MH63) to the medium of C. pyrenoidosa. The authors found that the growth curves of C. pyrenoidosa treated with purified Cry1Ca overlapped with the medium control; that the order of C. pyrenoidosa growth rates for the T1C-19 leachate concentrations was 5% > 10% > 20% > control > 40% > 80%, and for the MH63 concentrations the order was 5% > 10% > control > 20% > 40% > 80%, but there were no statistical differences between the 20% T1C-19 or 20% MH63 leachate treatment and the medium control on day 8; and that after 7 d of culture, Cry1Ca could be detected in C. pyrenoidosa treated with different concentrations of T1C-19 leachate. The results demonstrated that Cry1Ca protein released from T1C-19 rice can be absorbed into C. pyrenoidosa but that purified Cry1Ca and leachates from T1C-19 rice have no obvious adverse effects on the growth of C. pyrenoidosa. PMID- 24478193 TI - Active efflux influences the potency of quorum sensing inhibitors in Pseudomonas aeruginosa. AB - Many bacteria regulate gene expression through a cell-cell signaling process called quorum sensing (QS). In proteobacteria, QS is largely mediated by signaling molecules known as N-acylated L-homoserine lactones (AHLs) and their associated intracellular LuxR-type receptors. The design of non-native small molecules capable of inhibiting LuxR-type receptors (and thereby QS) in proteobacteria is an active area of research, and numerous lead compounds are AHL derivatives that mimic native AHL molecules. Much of this previous work has focused on the pathogen Pseudomonas aeruginosa, which controls an arsenal of virulence factors and biofilm formation through QS. The MexAB-OprM efflux pump has been shown to play a role in the secretion of the major AHL signal in P. aeruginosa, N-(3-oxododecanoyl) L-homoserine lactone. In the current study, we show that a variety of non-native AHLs and related derivatives capable of inhibiting LuxR-type receptors in P. aeruginosa display significantly higher potency in a P. aeruginosa Delta(mexAB-oprM) mutant, suggesting that MexAB-OprM also recognizes these compounds as substrates. We also demonstrate that the potency of 5,6-dimethyl-2-aminobenzimidazole, recently shown to be a QS and biofilm inhibitor in P. aeruginosa, is not affected by the presence/absence of the MexAB-OprM pump. These results have implications for the use of non-native AHLs and related derivatives as QS modulators in P. aeruginosa and other bacteria, and provide a potential design strategy for the development of new QS modulators that are resistant to active efflux. PMID- 24478194 TI - Combining perfluorocarbon and superparamagnetic iron-oxide cell labeling for improved and expanded applications of cellular MRI. AB - PURPOSE: The ability to detect the migration of cells in living organisms is fundamental in understanding biological processes and important for the development of novel cell-based therapies to treat disease. MRI can be used to detect the migration of cells labeled with superparamagnetic iron-oxide (SPIO) or perfluorocarbon (PFC) agents. In this study, we explored combining these two cell labeling approaches to overcome current limitations and enable new applications for cellular MRI. METHODS: We characterized (19)F-NMR relaxation properties of PFC-labeled cells in the presence of SPIO and imaged cells both ex vivo and in vivo in a rodent inflammation model to demonstrate selective visualization of cell populations. RESULTS: We show that with UTE3D, RARE, and FLASH (19) F images one can uniquely identify PFC-labeled cells, colocalized PFC- and SPIO-labeled cells, and PFC/SPIO-colabeled cells. CONCLUSION: This new methodology has the ability to improve and expand applications of MRI cell tracking. Combining PFC and SPIO strategies can potentially provide a method to quench PFC signal transferred from dead cells to macrophages, thereby eliminating false positives. In addition, combining these techniques could also be used to track two cell types simultaneously and probe cell-cell proximity in vivo with MRI. PMID- 24478195 TI - Two mutations in IFITM5 causing distinct forms of osteogenesis imperfecta. AB - The IFITM5 gene has recently been found to be mutated in patients with autosomal dominant osteogenesis imperfecta (OI) type V. This form of OI is characterized by distinctive clinical manifestations, including hyperplastic callus formation at the site of fractures, calcification of the interosseous membrane of the forearm, and dislocation of the head of the radius. Notably, in spite of the fact that a considerable number of patients with IFITM5 mutations have been identified, to date all of them have been shown to have the same heterozygous mutation (c. 14C>T). Herein, we describe one patient with a de novo c.119C>T heterozygous mutation in IFITM5, which predicts p.Ser40Leu, and another with the recurrent c. 14C>T transition that was also apparently de novo. While the patient with the p.Ser40Leu mutation had none of the typical signs of OI type V and was diagnosed with limb shortening at prenatal stages, the patient with the c.-14C>T mutation developed hyperplastic calluses and had calcification of the forearm interosseous membrane. This study challenges the lack of allelic and clinical heterogeneity in IFITM5 mutations. PMID- 24478196 TI - Silver-coated monolithic columns for separation in radiopharmaceutical applications. AB - In this study, we demonstrate the preparation of a macroporous monolithic column containing anchored silver nanoparticles and its use for the elimination of excess radioiodine from the radiolabeled pharmaceutical. The poly(glycidyl methacrylate-co-ethylene dimethacrylate) monolith was first functionalized with cystamine and the free thiol groups liberated by reaction with borohydride. In house-prepared silver nanoparticles were then attached by interaction with the surface thiols. The deiodization process was demonstrated with the commonly used radiopharmaceutical m-iodobenzylguanidine labeled with radionuclide iodine-125. PMID- 24478197 TI - Do circumstances of the death matter? Identifying socioenvironmental risks for grief-related psychopathology in bereaved youth. AB - We examined bereaved children's and surviving caregivers' psychological responses following the death of the other caregiver as a function of the stated cause of death. Participants included 63 parentally bereaved children and 38 surviving caregivers who were assessed using self-report instruments and in-person interviews. Surviving caregivers reported the causes of death as resulting from sudden natural death (34.9%), illness (33.3%), accident (17.5%), and suicide (14.3%). Results revealed differences between caregiver-reported versus child reported cause of death, particularly in cases of suicide. Children who lost a caregiver due to a prolonged illness exhibited higher levels of both maladaptive grief (d = 3.13) and posttraumatic stress symptoms (PTSS; d = 3.33) when compared to children who lost a caregiver due to sudden natural death (e.g., heart attack). In contrast, surviving caregivers did not differ in their levels of maladaptive grief and PTSS as a function of the cause of death; however, caregivers bereaved by sudden natural death reported higher levels of depression than those bereaved by prolonged illness (d = 1.36). Limited sample size prevented analysis of outcomes among those bereaved by suicide or accident. These findings suggest that anticipated deaths may contain etiologic risk factors for maladaptive grief and PTSS in children. PMID- 24478198 TI - Hidden altruism in a real-world setting. AB - Concerns for reputation can promote cooperative behaviour. Individuals that behave cooperatively stand to benefit if they gain in influence, status or are more likely to be chosen as interaction partners by others. Most theoretical and empirical models of cooperation predict that image score will increase with cooperative contributions. Individuals are therefore expected to make higher contributions when observed by others and should opt to make contributions publicly rather than privately, particularly when contributions are higher than average. Here, however, I find the opposite effect. Using data from an online fundraising website, I show that donors are more likely to opt for anonymity when making extremely low and extremely high donations. Mid-range donations, on the other hand, are typically publicized. Recent work has shown that extremely generous individuals may be ostracized or punished by group members. The data presented here suggest that individuals may hide high donations to avoid these repercussions. PMID- 24478199 TI - Salmon lice increase the age of returning Atlantic salmon. AB - The global increase in the production of domestic farmed fish in open net pens has created concerns about the resilience of wild populations owing to shifts in host-parasite systems in coastal ecosystems. However, little is known about the effects of increased parasite abundance on life-history traits in wild fish populations. Here, we report the results of two separate studies in which 379 779 hatchery-reared Atlantic salmon smolts were treated (or not) against salmon lice, marked and released. Adults were later recaptured, and we specifically tested whether the age distribution of the returning spawners was affected by the treatment. The estimates of parasite-induced mortality were 31.9% and 0.6% in the River Vosso and River Dale stock experiments, respectively. Age of returning salmon was on average higher in untreated [corrected] versus untreated fish. The percentages of fish returning after one winter at sea were 37.5% and 29.9% for the treated and untreated groups, respectively. We conclude that salmon lice increase the age of returning salmon, either by affecting their age at maturity or by disproportionately increasing mortality in fish that mature early. PMID- 24478200 TI - Rewards and the evolution of cooperation in public good games. AB - Properly coordinating cooperation is relevant for resolving public good problems, such as clean energy and environmental protection. However, little is known about how individuals can coordinate themselves for a certain level of cooperation in large populations of strangers. In a typical situation, a consensus-building process rarely succeeds, owing to a lack of face and standing. The evolution of cooperation in this type of situation is studied here using threshold public good games, in which cooperation prevails when it is initially sufficient, or otherwise it perishes. While punishment is a powerful tool for shaping human behaviours, institutional punishment is often too costly to start with only a few contributors, which is another coordination problem. Here, we show that whatever the initial conditions, reward funds based on voluntary contribution can evolve. The voluntary reward paves the way for effectively overcoming the coordination problem and efficiently transforms freeloaders into cooperators with a perceived small risk of collective failure. PMID- 24478201 TI - No universal scale-dependent impacts of invasive species on native plant species richness. AB - A growing number of studies seeking generalizations about the impact of plant invasions compare heavily invaded sites to uninvaded sites. But does this approach warrant any generalizations? Using two large datasets from forests, grasslands and desert ecosystems across the conterminous United States, we show that (i) a continuum of invasion impacts exists in many biomes and (ii) many possible species-area relationships may emerge reflecting a wide range of patterns of co-occurrence of native and alien plant species. Our results contradict a smaller recent study by Powell et al. 2013 (Science 339, 316-318. (doi:10.1126/science.1226817)), who compared heavily invaded and uninvaded sites in three biomes and concluded that plant communities invaded by non-native plant species generally have lower local richness (intercepts of log species richness log area regression lines) but steeper species accumulation with increasing area (slopes of the regression lines) than do uninvaded communities. We conclude that the impacts of plant invasions on plant species richness are not universal. PMID- 24478202 TI - Ubx promotes corbicular development in Apis mellifera. AB - The key morphological feature that distinguishes corbiculate bees from other members of the Apidae family is the presence of the corbicula (pollen basket) on the tibial segment of hind legs. Here, we show that in the honeybee (Apis mellifera), the depletion of the gene Ultrabithorax (Ubx) by RNAi transforms the corbicula from a smooth, bristle-free concave structure to one covered with bristles. This is accompanied by a reduction of the pollen press, which is located on the basitarsus and used for packing the pollen pellet as well as a loss of the orderly arrangement of the rows of bristles that form the pollen comb. All these changes make the overall identity of workers' T3 legs assume that of the queen. Furthermore, in a corbiculate bee of a different genus, Bombus impatiens, Ubx expression is also localized in T3 tibia and basitarsus. These observations suggest that the evolution of the pollen gathering apparatus in corbiculate bees may have a shared origin and could be traced to the acquisition of novel functions by Ubx, which in Apis were instrumental for subsequent castes and behavioural differentiation. PMID- 24478203 TI - Favoring trienamine activation through unconjugated dienals: organocatalytic enantioselective remote functionalization of alkenes. AB - Unconjugated 2,5-dienals are more reactive substrates than the corresponding fully conjugated alpha,beta,gamma,delta-unsaturated aldehydes towards organocatalytic activation through trienamine intermediates. This difference in reactivity has been demonstrated in the Diels-Alder reaction with nitroalkenes, a reaction that proceeds with clean beta,epsilon-selectivity to afford the final products in high yields and stereoselectivities, the related polyconjugated 2,4 dienals being completely unreactive. PMID- 24478204 TI - Simultaneous stenting of tightly stenosed patent ductus arteriosus and pulmonary artery bifurcation using two stents (Y stenting): an innovative technique. AB - Stenting of patent ductus arteriosus (PDA) is a palliative technique that is evolving as an alternative to shunt surgery. Patients with duct-dependant pulmonary circulation and branch pulmonary artery stenosis are often palliated by shunt surgery with repair of branch pulmonary arteries under cardiopulmonary bypass. We present here an 8-month-old male child with duct-dependant pulmonary circulation with bifurcation stenosis who was palliated successfully by transcatheter means. He had stenosed PDA with tight pulmonary artery bifurcation stenosis and underwent successful "Y" stenting of PDA with simultaneous deployment of two stents. He successfully underwent bidirectional Glenn surgery 8 months after the procedure. Simultaneous stenting of bifurcation stenosis of branch pulmonary arteries with two stents has not been described in the literature. PMID- 24478205 TI - Salegentibacter chungangensis sp. nov., isolated from a sea sand and emended description of the genus Salegentibacter. AB - A Gram-stain-negative, non-motile, rod-shaped, strictly aerobic bacterial strain, designated CAU 1289T, was isolated from a marine sand and its taxonomic position was investigated using a polyphasic approach. It grew optimally at pH 6.5 and 30 degrees C and in the presence of 3% (w/v) NaCl. Phylogenetic analysis based on 16S rRNA gene sequences showed that strain CAU 1289T belonged to the genus Salegentibacter, exhibiting sequence similarity values of 93.6-96.3% to members of this genus, and was related most closely to Salegentibacter mishustinae KMM 6049T (96.3% similarity). Strain CAU 1289T contained MK-6 as the predominant menaquinone. The major fatty acid was iso-C15:0. The cell-wall peptidoglycan of strain CAU 1289T contained meso-diaminopimelic acid. The polar lipids were composed of phosphatidylethanolamine, phosphatidylmethylethanolamine, phosphatidylcholine, an unidentified phospholipid, an unidentified aminolipid, an unidentified aminophospholipid, an unidentified glycolipid and ten unidentified lipids. The DNA G+C content was 38.7 mol%. On the basis of phenotypic, chemotaxonomic and phylogenetic inference, strain CAU 1289T is considered to represent a novel species of the genus Salegentibacter, for which the name Salegentibacter chungangensis sp. nov. is proposed. The type strain is CAU 1289T (KCTC 24000T=CCUG 64793T). An emended description of the genus Salegentibacter is also proposed. PMID- 24478206 TI - Photorhabdus heterorhabditis sp. nov., a symbiont of the entomopathogenic nematode Heterorhabditis zealandica. AB - The bacterial symbionts SF41T and SF783 were isolated from populations of the insect pathogenic nematode Heterorhabditis zealandica collected in South Africa. Both strains were closely related to strain Q614 isolated from a population of Heterorhabditis sp. collected from soil in Australia in the 1980s. Sequence analysis based on a multigene approach, DNA-DNA hybridization data and phenotypic traits showed that strains SF41T, SF783 and Q614 belong to the same species of the genus Photorhabdus with Photorhabdus temperata subsp. cinerea as the most closely related taxon (DNA-DNA hybridization value of 68%). Moreover, the phylogenetic position of Photorhabdus temperata subsp. cinerea DSM 19724T initially determined using the gyrB sequences, was reconsidered in the light of the data obtained by our multigene approach and DNA-DNA hybridization experiments. Strains SF41T, SF783 and Q614 represent a novel species of the genus Photorhabdus, for which the name Photorhabdus heterorhabditis sp. nov. is proposed (type strain SF41T=ATCC BAA-2479T=DSM 25263T). PMID- 24478207 TI - Paenibacillus relictisesami sp. nov., isolated from sesame oil cake. AB - A facultatively anaerobic, Gram-stain-positive, rod-shaped bacterium, designated strain KB0549T, was isolated from sesame oil cake. Cells were motile, round-ended rods, and produced central or terminal spores. The cell wall peptidoglycan contained meso-diaminopimelic acid as the diamino acid. The major fatty acids were anteiso-C15:0 and anteiso-C17:0. The DNA G+C content of strain KB0549T was 51.9 mol%. On the basis of 16S rRNA gene sequence phylogeny, strain KB0549T was affiliated with the genus Paenibacillus in the phylum Firmicutes and was most closely related to Paenibacillus cookii with 97.4% sequence similarity. Strain KB0549T was physiologically differentiated from P. cookii by the high content of anteiso-C17:0, inability to grow at 50 degrees C, spore position, and negative Voges-Proskauer reaction. Based on these unique physiological and phylogenetic characteristics, it is proposed that the isolate represents a novel species, Paenibacillus relictisesami sp. nov.; the type strain is KB0549T (=JCM 18068T=DSM 25385T). PMID- 24478208 TI - Rhizobium azibense sp. nov., a nitrogen fixing bacterium isolated from root nodules of Phaseolus vulgaris. AB - Three microbial strains isolated from common beans, 23C2T (Tunisia), Gr42 (Spain) and IE4868 (Mexico), which have been identified previously as representing a genomic group closely related to Rhizobium gallicum, are further studied here. Their 16S rRNA genes showed 98.5-99% similarity with Rhizobium loessense CCBAU 7190BT, R. gallicum R602spT, Rhizobium mongolense USDA 1844T and Rhizobium yanglingense CCBAU 71623T. Phylogenetic analysis based on recA, atpD, dnaK and thrC sequences showed that the novel strains were closely related and could be distinguished from the four type strains of the closely related species. Strains 23C2T, Gr42 and IE4868 could be also differentiated from their closest phylogenetic neighbours by their phenotypic and physiological properties and their fatty acid contents. All three strains harboured symbiotic genes specific to biovar gallicum. Levels of DNA-DNA relatedness between strain 23C2T and the type strains of R. loessense, R. mongolense, R. gallicum and R. yanglingense ranged from 58.1 to 61.5%. The DNA G+C content of the genomic DNA of strain 23C2T was 59.52%. On the basis of these data, strains 23C2T, Gr42 and IE4868 were considered to represent a novel species of the genus Rhizobium for which the name Rhizobium azibense is proposed. Strain 23C2T (=CCBAU 101087T=HAMBI3541T) was designated as the type strain. PMID- 24478209 TI - Winogradskyella wandonensis sp. nov., isolated from a tidal flat. AB - A Gram-stain-negative, non-flagellated, non-gliding, aerobic, rod-shaped bacterium, designated WD-2-2T, was isolated from a tidal flat of Wando, an island of South Korea, and subjected to a polyphasic taxonomic analysis. Strain WD-2-2T grew optimally at 30 degrees C, at pH 7.0-8.0 and in the presence of 2.0% (w/v) NaCl. Phylogenetic analyses based on 16S rRNA gene sequences showed that strain WD-2-2T belonged to the genus Winogradskyella, clustering coherently with the type strain of Winogradskyella litorisediminis. Strain WD-2-2T exhibited 16S rRNA gene sequence similarity of 97.4% to W. litorisediminis DPS-8T and 94.5-96.6% to the type strains of the other species of the genus Winogradskyella. Strain WD-2 2T contained MK-6 as the predominant menaquinone and iso-C15:1 G, iso-C17:0 3-OH and iso-C15:0 as the major fatty acids. The major polar lipids detected in strain WD-2-2T were phosphatidylethanolamine, one unidentified lipid and one unidentified aminolipid. The DNA G+C content was 36.4 mol%, and DNA-DNA relatedness with W. litorisediminis DPS-8T was 13%. Differential phenotypic properties, together with its phylogenetic and genetic distinctiveness, revealed that strain WD-2-2T is separate from recognized species of the genus Winogradskyella. On the basis of the data presented, strain WD-2-2T is considered to represent a novel species of the genus Winogradskyella, for which the name Winogradskyella wandonensis sp. nov. is proposed. The type strain is WD-2-2T (=KCTC 32579T=CECT 8445T). PMID- 24478210 TI - Noviherbaspirillum suwonense sp. nov., isolated from an air sample. AB - A Gram-stain-negative bacterium, strain 5410S-62T, was isolated from an air sample collected in Suwon, Republic of Korea. It was aerobic, motile, mesophilic and formed rod-shaped cells. Colonies on R2A agar were convex, circular and pale orange with entire margins. Growth occurred at pH 5-9 (optimally at pH 7) and at 10-40 degrees C (optimally at 28 degrees C). It did not grow in the presence of 1% NaCl. Comparative analyses of 16S rRNA gene sequences demonstrated that the novel strain was closely related to members of the genus Noviherbaspirillum. Strain 5410S-62T showed the highest sequence similarity (98.2%) to Glaciimonas singularis A2-57T. It also showed high 16S rRNA gene sequence similarity (98.1 95.6%) to members of the genus Noviherbaspirillum (98.1% to Noviherbaspirillum aurantiacum SUEMI08T, 97.8% to Noviherbaspirillum soli SUEMI10T and Noviherbaspirillum canariense SUEMI03T, 97.6% to Noviherbaspirillum psychrotolerans PB1T and 95.6% to Noviherbaspirillum malthae CC-AFH3T). The strain contained summed feature 3 (C16:1omega6c and/or C16:1omega7c), C16:0 and summed feature 8 (C18:1omega6c and/or C18:1omega7c) as major fatty acids, Q-8 as the only ubiquinone and large amounts of phosphatidylethanolamine, diphosphatidylglycerol and phosphatidylglycerol. Strain 5410S-62T revealed less than 70% DNA-DNA relatedness with the type strains of closely related species of the genera Noviherbaspirillum and Herbaspirillum and Glaciimonas singularis. Based on the physiological, biochemical and chemotaxonomic data obtained in this study, it is proposed that strain 5410S-62T represents a novel species, Noviherbaspirillum suwonense sp. nov., with 5410S-62T (=KACC 16657T= NBRC 108944T) as the type strain. PMID- 24478211 TI - Puniceibacterium antarcticum gen. nov., sp. nov., isolated from seawater. AB - A Gram-reaction-negative, aerobic, non-flagellated, rod-shaped bacterium, designated strain SM1211T, was isolated from Antarctic seawater. The isolate grew at 4-35 degrees C and with 0-10% (w/v) NaCl. It could produce bacteriochlorophyll a, but did not reduce nitrate to nitrite or hydrolyse DNA. Phylogenetic analysis of 16S rRNA gene sequences revealed that strain SM1211T constituted a distinct phylogenetic line within the family Rhodobacteraceae and was closely related to species in the genera Litorimicrobium, Leisingera, Seohaeicola and Phaeobacter with 95.1-96.0% similarities. The predominant cellular fatty acid was C18:1omega7c. The major polar lipids were phosphatidylethanolamine, phosphatidylglycerol, phosphatidylcholine, an unidentified aminolipid and two unidentified phospholipids. The genomic DNA G+C content of strain SM1211T was 60.7 mol%. Based on the phylogenetic, chemotaxonomic and phenotypic data obtained in this study, strain SM1211T is considered to represent a novel species in a new genus within the family Rhodobacteraceae, for which the name Puniceibacterium antarcticum gen. nov., sp. nov. is proposed. The type strain of Puniceibacterium antarcticum is SM1211T (=CCTCC AB 2013147T=KACC 16875T). PMID- 24478212 TI - Bacillus luteus sp. nov., isolated from soil. AB - Two bacterial strains (JC167T and JC168) were isolated from a soil sample collected from Mandpam, Tamilnadu, India. Colonies of both strains were orange and cells Gram-stain-positive. Cells were small rods, and formed terminal endospores of ellipsoidal to oval shape. Both strains were positive for catalase, oxidase and hydrolysis of starch/gelatin, and negative for chitin hydrolysis, H2S production, indole production and nitrate reduction activity. Major fatty acids of both strains (>5%) were anteiso-C15:0, iso-C16:0, iso-C15:0, anteiso-C17:0, iso-C14:0 and C16:0 with minor (<5 but >1%) amounts of iso-C17:0, anteiso-C17:0 B/iso-C17:0 I and C16:1omega11c. Diphosphatydilglycerol, phosphatidylethanolamine and phosphatidylglycerol were the major polar lipids of both strains. Cell wall amino acids were L-alanine, D-alanine, D-glutamic acid and meso-diaminopimelic acid. beta-Carotene and five unidentified carotenoids were present in both strains. Mean genomic DNA G+C content was 53.4+/-1 mol% and the two strains were closely related (mean DNA-DNA hybridization>90%). 16S rRNA gene sequence comparisons of both strains indicated that they represent species of the genus Bacillus within the family Bacillaceae of the phylum Firmicutes. Both strains had a sequence similarity of 97.6% with Bacillus saliphilus 6AGT and <96.8% with other members of the genus Bacillus. Sequence similarity between strain JC167T and 168 was 100%. Strain JC167T showed 25.8+/-1% reassociation (based on DNA-DNA hybridization) with B. saliphilus DSM 15402T (=6AGT). Distinct morphological, physiological and genotypic differences from previously described taxa support the classification of strain JC167T as a representative of a novel species of the genus Bacillus, for which the name Bacillus luteus sp. nov. is proposed. The type strain is JC167T (=KCTC 33100T=LMG 27257T). PMID- 24478213 TI - Streptomyces graminisoli sp. nov. and Streptomyces rhizophilus sp. nov., isolated from bamboo (Sasa borealis) rhizosphere soil. AB - Four strains of actinomycete, designated strains JR-19T, JR-12, JR-29 and JR-41T were isolated from bamboo (Sasa borealis) rhizosphere soil. Phylogenetic, morphological, chemotaxonomic and phenotypic analysis demonstrated that the four strains belong to the genus Streptomyces. Microscopic observation revealed that the four strains produced spirales spore chains with spiny surfaces. The cell wall peptidoglycan of the four strains contained ll-diaminopimelic acid, glutamic acid, alanine and glycine. Whole-cell hydrolysates mainly contained glucose and ribose. The predominant menaquinones were MK-9 (H6) and MK-9 (H8). Phylogenetic analysis based on 16S rRNA gene sequence comparisons revealed that these strains and the members of the genus Streptomyces exhibited moderately high 16S rRNA gene sequence similarities of 98.3-99.3%, with the most closely related strains being Streptomyces shenzhenensis 172115T and Streptomyces gramineus JR-43T. Based on the phenotypic and genotypic data, the four strains are considered to represent two novel species of the genus Streptomyces, for which the names Streptomyces graminisoli sp. nov. [to accommodate strains JR-19T (type strain; =KACC 16472T=NBRC 108883T), JR-12 (=KACC 16471) and JR-29 (=KACC 16473)] and Streptomyces rhizophilus sp. nov. [for strain JR-41T (=KACC 16580T=NBRC 108885T)] are proposed. PMID- 24478214 TI - Lactobacillus rodentium sp. nov., from the digestive tract of wild rodents. AB - Three strains of regular, long, Gram-stain-positive bacterial rods were isolated using TPY, M.R.S. and Rogosa agar under anaerobic conditions from the digestive tract of wild mice (Mus musculus). All 16S rRNA gene sequences of these isolates were most similar to sequences of Lactobacillus gasseri ATCC 33323T and Lactobacillus johnsonii ATCC 33200T (97.3% and 97.2% sequence similarities, respectively). The novel strains shared 99.2-99.6% 16S rRNA gene sequence similarities. Type strains of L. gasseri and L. johnsonii were also most related to the newly isolated strains according to rpoA (83.9-84.0% similarities), pheS (84.6-87.8%), atpA (86.2-87.7%), hsp60 (89.4-90.4%) and tuf (92.7-93.6%) gene sequence similarities. Phylogenetic studies based on 16S rRNA, hsp60, rpoA, atpA and pheS gene sequences, other genotypic and many phenotypic characteristics (results of API 50 CHL, Rapid ID 32A and API ZYM biochemical tests; cellular fatty acid profiles; cellular polar lipid profiles; end products of glucose fermentation) showed that these bacterial strains represent a novel species within the genus Lactobacillus. The name Lactobacillus rodentium sp. nov. is proposed to accommodate this group of new isolates. The type strain is MYMRS/TLU1T (=DSM 24759T=CCM 7945T). PMID- 24478215 TI - Acinetobacter harbinensis sp. nov., isolated from river water. AB - A bacterial strain, HITLi 7T, with nitrifying ability was isolated from the surface water of the Songhua River in China. Cells were Gram-stain-negative, strictly aerobic, oxidase-negative, non-motile coccobacilli, capable of growth in mineral media with acetate as the sole carbon source and ammonia as the sole source of nitrogen. The cells did not grow at 37 degrees C, but did grow at 2 degrees C. The DNA G+C content was 45.5 mol%. Results of 16S rRNA gene sequence analysis indicated a close relationship between this isolate and Acinetobacter lwoffii (98.4% similarity for strain DSM 2403T). rpoB and gyrB gene sequences did not show significant similarity with those from other species of the genus Acinetobacter. Predominant cellular fatty acids were 9-octadecenoic acid (C18 : 1omega9c) and summed feature 4 (iso-C15:0 2-OH and/or C16:1omega7c). Acid was not produced from d-glucose, and gelatin was not hydrolysed by the isolate. Genotypic, phenotypic and chemotaxonomic data from this study indicate that the isolate should be classified as a representative of a novel species of the genus Acinetobacter. The name Acinetobacter harbinensis sp. nov. is proposed for the novel species, with HITLi 7T (=CGMCC 1.12528T=KCTC 32411T) as the type strain. PMID- 24478216 TI - Anatomical variations in the aortic bifurcation in new zealand white rabbits on arteriography. AB - The radiologic anatomy of the aortic bifurcation in the rabbit has received little study but it is important as this anatomical area is widely used in atherosclerosis research. Thirty rabbits were used to study the aortic bifurcation and subsequent branching patterns on arteriography. Fifteen different arteries were identified. Mean arterial diameters of 2.88 +/- 0.7 and 2.27 +/- 0.55 mm were obtained for the aorta and external iliac arteries, respectively. The cranial and middle aspects at the seventh lumbar vertebra (L7) were the most frequent anatomical landmarks (53.3% of the cases) for aortic and common iliac bifurcations, respectively. The caudal aspect of L6 was the most frequent origin (50% of the cases) for the median sacral artery. Deep circumflex iliac arteries originated from common iliac arteries and not the abdominal aorta in the rabbit, showing anatomical asymmetry in 73.3% of the cases. No gender disparity was found in the anatomical location of any of the arteries of the study. Knowledge of normal vascular landmarks for the aortic bifurcation as well as anatomical variations should be helpful to future experimental studies. PMID- 24478217 TI - Maximum mouth opening and trismus in 143 patients treated for oral cancer: a 1 year prospective study. AB - BACKGROUND: Patients with oral cancer can develop restricted mouth opening (trismus) because of the oncologic treatment. METHODS: Maximum mouth opening (MMO) was measured in 143 patients shortly before treatment and 0, 6, and 12 months posttreatment, and the results were analyzed using a linear mixed-effects model. RESULTS: In every patient, MMO decreased after treatment. The patients who underwent surgery, recovered partially by 6 and 12 months after treatment, whereas the patients who received both surgery and radiotherapy or primary radiotherapy did not recover. Tumor location, tumor size, and alcohol consumption had independent effects on MMO. Having trismus (MMO <35 mm) 1 year after treatment was associated most strongly with pretreatment MMO, receiving both surgery and radiotherapy, and maxillary or mandibular tumor involvement. CONCLUSION: Postoperative radiotherapy and maxillary or mandibular tumor involvement are the highest contributing risk factors to decreasing MMO and the subsequent development of trismus after oral cancer treatment. PMID- 24478218 TI - Identification of pyrroloformamide as a cytokinesis modulator. AB - Discovered in the late 1940s, the pyrrolinonodithioles represent a family of potent disulfide-containing natural products. Although they are understood in a synthetic and biosynthetic context, the biological role of these materials remains unresolved. To date, their activity has been suggested to arise through regulating RNA metabolism, and more recently they have been suggested to function as backup thiols for detoxification. Using materials identified through a natural products program, we now identify the biological function of one member of this family, pyrroloformamide, as an antimitotic agent acting, in part, by disrupting cytokinesis. PMID- 24478220 TI - Degradation rate of sodium fluoroacetate in three New Zealand soils. AB - The degradation rate of sodium fluoroacetate (SFA) was assessed in a laboratory microcosm study incorporating 3 New Zealand soil types under different temperature (5 degrees C, 10 degrees C, or 20 degrees C) and soil moisture (35% or 60% water holding capacity) conditions using guideline 307 from the Organisation for Economic Co-operation and Development. A combination of nonlabeled and radiolabeled (14) C-SFA was added to soil microcosms, with sampling and analysis protocols for soil, soil extracts, and evolved CO(2) established using liquid scintillation counting and liquid chromatography-mass spectrometry. Degradation products of SFA and their rates of formation were similar in the 3 soil types. The major degradation pathway for SFA was through microbial degradation to the hydroxyl metabolite, hydroxyacetic acid, and microbial mineralization to CO(2), which constituted the major transformation product. Temperature, rather than soil type or moisture content, was the dominant factor affecting the rate of degradation. Soil treatments incubated at 20 degrees C displayed a more rapid loss of (14)C-SFA residues than lower temperature treatments. The transformation half-life (DT50) of SFA in the 3 soils increased with decreasing temperature, varying from 6 d to 8 d at 20 degrees C, 10 d to 21 d at 10 degrees C, and 22 d to 43 d at 5 degrees C. PMID- 24478219 TI - Prioritizing disease-linked variants, genes, and pathways with an interactive whole-genome analysis pipeline. AB - Whole-genome sequencing (WGS) studies are uncovering disease-associated variants in both rare and nonrare diseases. Utilizing the next-generation sequencing for WGS requires a series of computational methods for alignment, variant detection, and annotation, and the accuracy and reproducibility of annotation results are essential for clinical implementation. However, annotating WGS with up to date genomic information is still challenging for biomedical researchers. Here, we present one of the fastest and highly scalable annotation, filtering, and analysis pipeline-gNOME-to prioritize phenotype-associated variants while minimizing false-positive findings. Intuitive graphical user interface of gNOME facilitates the selection of phenotype-associated variants, and the result summaries are provided at variant, gene, and genome levels. Moreover, the enrichment results of specific variants, genes, and gene sets between two groups or compared with population scale WGS datasets that is already integrated in the pipeline can help the interpretation. We found a small number of discordant results between annotation software tools in part due to different reporting strategies for the variants with complex impacts. Using two published whole-exome datasets of uveal melanoma and bladder cancer, we demonstrated gNOME's accuracy of variant annotation and the enrichment of loss-of-function variants in known cancer pathways. gNOME Web server and source codes are freely available to the academic community (http://gnome.tchlab.org). PMID- 24478221 TI - Adaptive online self-gating (ADIOS) for free-breathing noncontrast renal MR angiography. AB - PURPOSE: To develop a respiratory self-gating method, adaptive online self-gating (ADIOS), for noncontrast MR angiography (NC MRA) of renal arteries to overcome some limitations of current free-breathing methods. METHODS: A NC MRA pulse sequence for online respiratory self-gating was developed based on three dimensional balanced steady-state free precession (bSSFP) and slab-selective inversion-recovery. Motion information was derived directly from the slab being imaged for online gating. Scan efficiency was maintained by an automatic adaptive online algorithm. Qualitative and quantitative assessments of image quality were performed and results were compared with conventional diaphragm navigator (NAV). RESULTS: NC MRA imaging was successfully completed in all subjects (n = 15). Similarly good image quality was observed in the proximal-middle renal arteries with ADIOS compared with NAV. Superior image quality was observed in the middle distal renal arteries in the right kidneys with no NAV-induced artifacts. Maximal visible artery length was significantly longer with ADIOS versus NAV in the right kidneys. NAV setup was completely eliminated and scan time was significantly shorter with ADIOS on average compared with NAV. CONCLUSION: The proposed ADIOS technique for noncontrast MRA provides high-quality visualization of renal arteries with no diaphragm navigator-induced artifacts, simplified setup, and shorter scan time. PMID- 24478222 TI - Recurrent proximal 18p monosomy and 18q trisomy in a family due to a pericentric inversion. AB - Here, we report on a family with pericentric inversion of chromosome 18 [inv(18)(p11.2q21)] and two recombinants with a duplication of q21 -> qter and a deletion of p11.2 -> pter regions in a four-generation family. This chromosomal abnormality was inherited in our first patient from the father, while it was transmitted to the second patient from the mother. Array-CGH analysis were used to better characterize duplicated and deleted chromosomal regions and showed no genomic copy number variation (CNV) differences between these two relatives. We discussed genotype-phenotype correlations including previously reported. PMID- 24478223 TI - Validation of the Fear of Sleep Inventory (FOSI) in an urban young adult African American sample. AB - The Fear of Sleep Inventory (FOSI) was developed to identify factors that contribute to sleep disturbances in individuals exposed to trauma. This investigation examined the psychometric properties of the FOSI in a sample of African American young adults residing in urban areas. A 5-factor structure was derived from an exploratory factor analysis and then verified by confirmatory factor analysis. FOSI factors were positively correlated with the severity of PTSD (rs = .30 to .58, all ps < .001) and insomnia symptoms (rs = .36 to .64, all ps < .001). Individuals with probable PTSD or insomnia had higher scores on the total FOSI and each of the factors compared to those without probable PTSD (all ps < .001; effect sizes: r = .32 to .62) or insomnia (all ps < .001; effect sizes: r = .42 to .70). These data expand the evidence that the FOSI identifies factors contributing to sleep disturbances in trauma-exposed individuals. PMID- 24478224 TI - Automatic calibration of trigger delay time for cardiac MRI. AB - This study aimed to automatically identify the cardiac rest period using a rapid free-breathing (FB) calibration scanning procedure, and to determine the optimal trigger delay for cardiac imaging. A standard deviation (SD) method was used to rapidly identify cardiac quiescent phases employing multiphase cine cardiac images. The accuracy of this method was investigated using 46 datasets acquired from 22 healthy volunteers. The possibility of using a low-resolution FB method to rapidly acquire cine images was also evaluated. The reproducibility and accuracy of the trigger delay obtained using the rapid calibration scanning process were assessed before its application to a real-time feedback system. The real-time trigger delay calibration system was then used to perform T1 -weighted, short-axis imaging at the end of the cardiac systolic period. Linear regression analysis of the trigger times obtained using the SD method and a reference method indicated that the SD algorithm accurately identified the cardiac rest period (linear regression: slope = 0.94-1, R(2) = 0.68-0.84). Group analysis showed that the number of pixels in the left ventricular blood pool in images acquired at the end-systolic time calculated in real time was significantly lower than in those acquired 50 ms in advance or later (p < 0.01, paired t-test). The low resolution FB imaging method was reproducible for the calibration scanning of an image in a vertical long-axis slice position (average SD of trigger times, 16-39 ms). Combined with rapid FB calibration scanning, the real-time feedback system accurately adjusted the trigger delay for T1 -weighted short-axis imaging. The real-time feedback method is rapid and reliable for trigger time calibration, and could facilitate cardiac imaging during routine examination. PMID- 24478225 TI - Determination of naproxen in human plasma by GC-MS. AB - This paper describes a GC-MS method for the determination of naproxen in human plasma. Naproxen and internal standard ibuprofen were extracted from plasma using a liquid-liquid extraction method. Derivatization was carried out using N-methyl N-(trimethylsilyl)trifluoroacetamide. The calibration curve was linear between the concentration range of 0.10-5.0 MUg/mL. Intra- and interday precision values for naproxen in plasma were <5.14, and accuracy (relative error) was better than 4.67%. The extraction recoveries of naproxen from human plasma were between 93.0 and 98.9%. The LOD and LOQ of naproxen were 0.03 and 0.10 MUg/mL, respectively. Also, this assay was applied to determine the pharmacokinetic parameters of naproxen in six healthy Turkish volunteers who had been given 220 mg naproxen. PMID- 24478226 TI - Baseline and 9 months IVUS analysis of the bifurcation-dedicated biolimus A9 eluting Axxess stent system: the DIVERGE IVUS substudy. AB - BACKGROUND: Percutaneous treatment of complex coronary bifurcation lesions remains challenging, even in the drug-eluting stent era. We sought to evaluate the baseline and 9 months intravascular ultrasound (IVUS) analysis of the AxxessTM stent, a self-expanding, Biolimus A9TM-eluting, and dedicated bifurcation stent. METHODS AND RESULTS: We enrolled the first 76 patients from selected sites of the 302 patients large DIVERGE trial (a prospective, single arm, multicenter trial evaluating the safety and efficacy of the Axxess stent). Both baseline and 9 months IVUS images were collected for serial two-dimensional (2D) and 3D analysis. A minimal amount and a low percentage of neointimal volume index were seen in the Axxess stent at 9 months (0.4 +/- 0.6 mm(3) /mm and 4.3 +/ 5.2%, respectively). Vessel, lumen, and stent volume indices increased significantly (respectively, 17.0 +/- 3.6 to 18.9 +/- 3.7 mm(3) /mm, P < 0.0001; 7.3 +/- 2.0 to 9.2 +/- 2.5 mm(3) /mm, P < 0.0001; and 7.4 +/- 2.0 to 9.6 +/- 2.6 mm(3) /mm, P < 0.0001). This resulted in minimum lumen area (MLA) enlargement (6.1 +/- 1.9 to 7.2 +/- 2.3 mm(2) , P < 0.0001), whereas peristent plaque area decreased (8.7 +/- 2.5 to 8.5 +/- 2.1 mm(3) /mm, P = 0.016). At 9 months, 16 (26%) incomplete stent apposition (ISA) persisted from baseline, while six resolved (9.7%). Only one (2%) ISA was late acquired. In the additional distal sirolimus-eluting stents, MLA decreased from 4.3 +/- 1.1 to 4.1 +/- 1.2 mm(2) (P = 0.04) at 9 months for the main branch, and from 3.4 +/- 1.2 to 3.2 +/- 1.2 mm(2) (P = 0.09) for the side branch. CONCLUSIONS: The dedicated bifurcation Axxess stent system demonstrates significant stent volume increase with minimal neointimal formation and a low incidence of late-acquired ISA at 9 months. PMID- 24478227 TI - Feeding tube use in patients with head and neck cancer. AB - BACKGROUND: Use of a prophylactic feeding tube before concurrent chemotherapy and radiotherapy (CRT) for patients with head and neck cancer is often debated. METHODS: A retrospective, exploratory study of 109 veterans with stage III/IV head and neck cancer who completed standard CRT was conducted. Relationships among 3 feeding tube status groups: prophylactic feeding tube (PFT), reactive feeding tube (RFT), and no feeding tube (no-FT) were compared for clinical outcomes. RESULTS: Patients with a PFT had significantly less weight loss during CRT, fewer nutrition-related emergency department visits or hospitalizations, and higher proportions of chemotherapy cycles completed compared to those with an RFT or no-FT. At 12 months post-CRT, there was no relationship between the use of a PFT and 100% feeding tube dependency. CONCLUSION: Use of a PFT in this veteran population with stage III/IV head and neck cancer produced better outcomes when compared to both an RFT or no feeding tube without higher rates of long-term dysphagia. PMID- 24478228 TI - Simultaneous inhibition assay for human and microbial kinases via MALDI-MS/MS. AB - Selective inhibition of one kinase over another is a critical issue in drug development. For antimicrobial development, it is particularly important to selectively inhibit bacterial kinases, which can phosphorylate antimicrobial compounds such as aminoglycosides, without affecting human kinases. Previous work from our group showed the development of a MALDI-MS/MS assay for the detection of small molecule modulators of the bacterial aminoglycoside kinase APH3'IIIa. Herein, we demonstrate the development of an enhanced kinase MALDI-MS/MS assay involving simultaneous assaying of two kinase reactions, one for APH3'IIIa, and the other for human protein kinase A (PKA), which leads to an output that provides direct information on selectivity and mechanism of action. Specificity of the respective enzyme substrates were verified, and the assay was validated through generation of Z'-factors of 0.55 for APH3'IIIa with kanamycin and 0.60 for PKA with kemptide. The assay was used to simultaneously screen a kinase directed library of mixtures of ten compounds each against both enzymes, leading to the identification of selective inhibitors for each enzyme as well as one non selective inhibitor following mixture deconvolution. PMID- 24478229 TI - Functional mutation analysis provides evidence for a role of REEP1 in lipid droplet biology. AB - Hereditary axonopathies are frequently caused by mutations in proteins that reside in the endoplasmic reticulum (ER). Which of the many ER functions are pathologically relevant, however, remains to be determined. REEP1 is an ER protein mutated in hereditary spastic paraplegia (HSP) and hereditary motor neuropathy (HMN). We found that HSP-associated missense variants at the N terminus of REEP1 abolish ER targeting, whereas two more central variants are either rare benign SNPs or confer pathogenicity via a different mechanism. The mis-targeted variants accumulate at lipid droplets (LDs). N-terminal tagging, deletion of the N-terminus, and expression of a minor REEP1 isoform had the same effect. We also confirmed an increase in LD size upon cooverexpression of atlastins and REEP1. Neither wild-type REEP1, LD-targeted HSP variants, nor a non LD-targeted HMN variant reproduced this effect when expressed alone. We conclude that the N-terminus of REEP1 is necessary for proper targeting to and/or retention in the ER. The protein's potential to also associate with LDs corroborates a synergistic effect with atlastins on LD size. Interestingly, LD size is also altered upon knockdown of seipin, mutations of which also cause HSP and HMN. Regulation of LDs may thus be an ER function critical for long-term axonal maintenance. PMID- 24478230 TI - Work-related road traffic injury: a multilevel systems protocol. AB - BACKGROUND: Although road traffic injury is reported as the leading cause of work related death in Australia, it is not clear, due to limitations in previous methods used, just how large a burden it is. Many organisations are unaware of the extent of work-related road traffic injury and, importantly, what can be done to reduce the burden. The proposed research will (i) estimate the prevalence of work-related road traffic injury and (ii) identify the organisational determinants associated with work-related road traffic injury. METHODS AND DESIGN: The current study is designed to enumerate the problem and identify the individual driver-level, the supervisor-level and organisational-level factors associated with work-related road traffic injury. The multilevel systems protocol will involve a series of cross-sectional surveys administered to drivers of fleet vehicles (n=1200), supervisors of the drivers (n=1200) and senior managers (n=300) within the same organisation. DISCUSSION: The novel use of the multilevel systems protocol is critical to be able to accurately assess the specific determinants of driving safety within each context of an organisation. RESULTS: The results are expected to highlight that reducing injury in the workplace requires more than just individual compliance with safety procedures. It will also establish, for the first time, an occupational translation taskforce to ensure that the research findings are adopted into work-place practice and thereby directly contribute to reductions in work-related road traffic injury. PMID- 24478231 TI - Isotropic reconstruction of a 4-D MRI thoracic sequence using super-resolution. AB - PURPOSE: Four-dimensional (4D) thoracic magnetic resonance imaging (MRI) sequences have been shown to successfully monitor both tumor and lungs anatomy. However, a high temporal resolution is required to avoid motion artifacts, which leads to volumes with poor spatial resolution. This article proposes to reconstruct an isotropic 4D MRI thoracic sequence with minimum modifications to the acquisition protocols. This could be an important step toward the use of 4D MRI for thoracic radiotherapy applications. METHODS: In a postacquisition step, three orthogonal 4D anisotropic acquisitions are combined using super-resolution to reconstruct a series of isotropic volumes. A new phantom that simulates lung tumor motion is developed to evaluate the performance of the algorithm. The proposed framework is also applied to real data of a lung cancer patient. RESULTS: Subjective and objective evaluations show clear resolution enhancement and partial volume effect diminution. The isotropic reconstruction of patient data significantly improves both the visualization and segmentation of thoracic structures. CONCLUSIONS: The results presented here are encouraging and suggest that super-resolution can be regarded as an efficient method to improve the resolution of 4D MRI sequences. It produces an isotropic 4D sequence that would be impossible to acquire in practice. Further investigations will be required to evaluate its reproducibility in various clinical applications. PMID- 24478232 TI - The appositional articular morphology of the talo-crural joint: the influence of substrate use on joint shape. AB - The appositional articular morphology of the talo-crural joint is the third component of the joint complex. It is a site of internal integration of this highly stable functional evolutionary unit. Prior studies of the other two components, tibia and talus, demonstrated that substrate preference influenced their articular shape. This effect was unrelated to physical attributes (size and mass) and phylogeny (superfamily). The effect of this behavioral factor, substrate preference, on shape and integration of the appositional articular morphology was investigated. Two hundred forty-five matched distal tibial and proximal talar landmarked surfaces from 12 diverse Catarrhine taxa were studied. Shape effects due to the same factors previously studied were examined in the tibial and talar subsets and were highly significant (P < 0.0001). These were assessed using Multivariate Regression and Relative Warps analysis, and Permutation tests, with results consistent with prior unmatched cohorts. Substrate preference influenced shape and was unrelated to the other factors across taxa. Singular Warp analysis of the cross-covariance matrix revealed sorting of taxa by substrate use, unrelated to physical attributes and phylogeny. Finally, the sorting demonstrated a signal of convergent evolution among distantly related taxa and divergent evolution among closely related taxa reflecting substrate use. Results were consistent with a behavioral influence, substrate use, affecting articular shape and integration in this highly stable functional evolutionary unit, and signals with evolutionary implications. PMID- 24478233 TI - Autosomal recessive cutis laxa type 2A (ARCL2A) mimicking Ehlers-Danlos syndrome by its dermatological manifestations: report of three affected patients. AB - Through a survey of more than 20 patients with a specific subgroup of autosomal recessive congenital cutis laxa (ARCL), namely ATP6V0A2-related cutis laxa, we noted that the clinical findings on three patients included pretibial pseudo ecchymotic skin lesions very similar to those found in classical Ehlers-Danlos syndrome. The finding is apparently age-related, occurring during the second decade in two of the three patients. PMID- 24478234 TI - Laboratory algal bioassays using PAM fluorometry: effects of test conditions on the determination of herbicide and field sample toxicity. AB - Pulse Amplitude Modulation (PAM) fluorometry, based on chlorophyll a fluorescence, is a frequently used technique in algal bioassays to assess toxicity of single compounds or complex field samples. Several test conditions can influence the test results, and because a standardized test protocol is currently lacking, linking the results of different studies is difficult. Therefore, the aim of the present study was to gain insight into the effects of test conditions of laboratory algal bioassays using PAM fluorometry on the outcome of toxicity tests. To this purpose, we described the results from several pilot studies on test development in which information is provided on the effects of the main test factors during the pretest phase, the test preparation, the exposure period, and the actual measurement. The experiments were focused on individual herbicides and complex field samples and included the effects of culturing conditions, cell density, solvent concentration, exposure time, and the presence of actinic light. Several of these test conditions were found to influence the outcome of the toxicity test, and the presented information provides important background information for the interpretation of toxicity results and describes which test conditions should be taken into account when using an algal bioassay with PAM fluorometry. Finally, the application of PAM fluorometry in algal toxicity testing is discussed. PMID- 24478236 TI - Predictors of treatment engagement in ethnically diverse, urban children receiving treatment for trauma exposure. AB - Keeping traditionally underrepresented children and their families engaged in treatment until completion is a major challenge for many community-based mental health clinics. The current study used data collected as part of the National Child Traumatic Stress Network Core Data Set to examine whether racial/ethnic disparities exist in treatment duration and completion in children seeking treatment for trauma exposure. We then explored whether disparities persist after accounting for other variables associated with children's social contexts and the treatment setting. The sample included 562 ethnically diverse children receiving services from a child abuse prevention and treatment agency in Southern California. The results indicated that African American children had significantly shorter trauma-informed treatment duration and higher rates of premature termination than Spanish-speaking Latino children. These disparities persisted even with other variables associated with treatment duration and completion (e.g., child's age, level of functional impairment, and receipt of group and field services) in the model. Implications and future directions for research and practice are discussed. PMID- 24478235 TI - Caffeine alters resting-state functional connectivity measured by blood oxygenation level-dependent MRI. AB - This study aimed to investigate the pharmacological effect of caffeine on functional connectivity measured by resting-state blood oxygenation level dependent (BOLD) MRI in the motor cortex, visual cortex and default mode network (DMN). The protocols and procedures of the study were reviewed and approved by the Institutional Review Board of our institution. On a 3-T clinical MR system, 20 healthy volunteers underwent imaging before and after oral ingestion of a 200 mg over-the-counter caffeine pill (data from three individuals were excluded from further analysis because of excessive motion). The demographics of the remaining participants were as follows: female/male, 8/9; age, 21-35 years; non-habitual caffeine consumers over the past 6 months. Functional connectivity was calculated using the general linear model, assessed in terms of connected area (voxels) and statistical significance (Student t-values), and correlated with changes in regional cerebral blood flow as measured by arterial spin labeling MRI. Per subject data analysis showed that caffeine decreased functional connectivity in the motor/visual cortices, but its effects on DMN varied among subjects. Correlation analysis of the changes in functional connectivity and regional blood flow suggested that the effect of caffeine on BOLD functional connectivity was predominantly neural (motor/visual cortices) and partly vascular (DMN). Group analysis showed that, after caffeine ingestion, DMN involved more attentional networks, and more extrastriate areas were integrated into the functional connectivity of the visual cortex, which may be associated with the known pharmacological effect of caffeine in elevating alertness. Caffeine consumption should thus be considered in the experimental design and data interpretation of functional connectivity studies using resting-state BOLD MRI. PMID- 24478237 TI - Transapical JenaValve in a patient with mechanical mitral valve prosthesis. AB - We report the first case of transcatheter aortic valve replacement implantation using JenaValveTM in a patient with mechanical mitral valve prosthesis. We believe that the design features of this valve may be particularly suited for use in this setting. PMID- 24478238 TI - Use of prototyping in preoperative planning for patients with head and neck tumors. AB - BACKGROUND: Prototyping technologies for reconstructions consist of obtaining a 3 dimensional model of the object of interest. Solid models are constructed by the deposition of materials in successive layers. The purpose of this study was to perform a double-blind, randomized, prospective study to evaluate the efficacy of prototype use in head and neck surgeries. METHODS: Thirty-seven cases were randomized into prototype and nonprototype groups. The following factors were recorded: the time of plate and locking screw apposition, flap size, time for reconstruction, and an aesthetic evaluation. RESULTS: The prototype group exhibited a reduced surgical time (43.7 minutes vs 127.7 minutes, respectively; p = .001), a tendency to reduce the size of the bone flap taken for reconstruction, and better aesthetic results than the group that was not prototyped. CONCLUSION: The use of prototyping demonstrated a trend toward a reduced surgical time, smaller bone flaps, and better aesthetic results. PMID- 24478239 TI - Thorough investigation of the oxygen heterocyclic fraction of lime (Citrus aurantifolia (Christm.) Swingle) juice. AB - Reversed-phase-HPLC analysis by means of superficially porous silica particle columns (fused-core) was applied to the investigation of flavonoids, coumarins, and psoralens in lime juice samples. Hesperidin (367.0 +/- 16.0 ppm) and eriocitrin (148.0 +/- 7.9 ppm) were the most abundant flavonoids. Fifteen coumarins and furocoumarins were determined, including bergamottin (29.6 +/- 1.1 ppm), 5-geranyloxy-7-methoxycoumarin (16.5 +/- 0.6 ppm), and oxypeucedanin hydrate (9.9 +/- 0.5 ppm) as predominant compounds. These molecules are today well known for their beneficial effects on human health. As a consequence, the present study, beyond investigating for the first time the chemical composition of lime juice, highlights also its health-promoting qualities, due to its content of flavonoids and coumarins. PMID- 24478240 TI - Magnetic Resonance in Medicine at 30. PMID- 24478241 TI - Single-molecule metal-induced energy transfer (smMIET): resolving nanometer distances at the single-molecule level. AB - We present a new concept for measuring distance values of single molecules from a surface with nanometer accuracy using the energy transfer from the excited molecule to surface plasmons of a metal film. We measure the fluorescence lifetime of individual dye molecules deposited on a dielectric spacer as a function of a spacer thickness. By using our theoretical model, we convert the lifetime values into the axial distance of individual molecules. Similar to Forster resonance energy transfer (FRET), this allows emitters to be localized with nanometer accuracy, but in contrast to FRET the distance range at which efficient energy transfer takes place is an order of magnitude larger. Our technique can be potentially used as a tool for measuring intramolecular distances of biomolecules and complexes. PMID- 24478242 TI - Microarray delineation of familial chromosomal imbalance with deletion 5q35 and duplication 10q25 in a child showing multiple anomalies and dysmorphism. AB - We describe a 6-month-old female with developmental delay, hypotonia, supernumerary nipples, and distinct craniofacial features. Postnatal chromosome analysis revealed an unbalanced karyotype involving a der (5) and array-CGH defined two unbalanced regions with partial 2.3 Mb deletion of 5q35.3 in combination with a large 19.5 Mb duplication of chromosome 10 from q25.3 to q26.3. Parental karyotyping analysis showed that the father was carrier of a balanced t(5;10)(q35;q25). Two cousins of the proband with similar facial features had the same unbalanced karyotype with presence of the der (5) inherited from the malsegregation of the familial translocation. Additionally, three siblings (two deceased and one abortion) manifested a more severe phenotype including congenital heart defect, cleft palate, and agenesis of the corpus callosum and were diagnosed with unbalanced karyotypes inherited from the familial balanced translocation. PMID- 24478243 TI - Contrasting histopathology and crystal deposits in kidneys of idiopathic stone formers who produce hydroxy apatite, brushite, or calcium oxalate stones. AB - Our previous work has shown that stone formers who form calcium phosphate (CaP) stones that contain any brushite (BRSF) have a distinctive renal histopathology and surgical anatomy when compared with idiopathic calcium oxalate stone formers (ICSF). Here we report on another group of idiopathic CaP stone formers, those forming stone containing primarily hydroxyapatite, in order to clarify in what ways their pathology differs from BRSF and ICSF. Eleven hydroxyapatite stone formers (HASF) (2 males, 9 females) were studied using intra-operative digital photography and biopsy of papillary and cortical regions to measure tissue changes associated with stone formation. Our main finding is that HASF and BRSF differ significantly from each other and that both differ greatly from ICSF. Both BRSF and ICSF patients have significant levels of Randall's plaque compared with HASF. Intra-tubular deposit number is greater in HASF than BRSF and nonexistent in ICSF while deposit size is smaller in HASF than BRSF. Cortical pathology is distinctly greater in BRSF than HASF. Four attached stones were observed in HASF, three in 25 BRSF and 5-10 per ICSF patient. HASF and BRSF differ clinically in that both have higher average urine pH, supersaturation of CaP, and calcium excretion than ICSF. Our work suggests that HASF and BRSF are two distinct and separate diseases and both differ greatly from ICSF. PMID- 24478244 TI - Soil genotoxicity induced by successive applications of chlorothalonil under greenhouse conditions. AB - Greenhouse production of vegetables has been developed rapidly in China. High temperature and humidity inside the greenhouse make this environment more suitable for fast reproduction of fungal diseases. Fungicides are among the chemicals used extensively in the greenhouse to prevent crops from invasive infections by phytopathogens; however, little is known about the accumulation of fungicides in soil and their effect on soil quality under greenhouse conditions. In the present study, the accumulation of the fungicide chlorothalonil (CT) and its toxic metabolite hydroxy-chlorothalonil (HCT) in soil as well as their related soil genotoxicity under greenhouse conditions was investigated. The results indicated that both CT and HCT accumulated in soil with repeated applications of CT, and the accumulation level was strongly correlated to application dosage and its frequency. In addition, soil genotoxicity, which was measured by Vicia faba, also increased with the accumulation of CT and HCT, and the main contributor to this phenomenon was CT rather than HCT. The data demonstrated that successive applications of fungicides may result in their accumulation in soil and thus a decline in soil quality. PMID- 24478245 TI - Assessment of fetal midbrain and hindbrain in mid-sagittal cranial plane by three dimensional multiplanar sonography. Part 2: application of nomograms to fetuses with posterior fossa malformations. AB - OBJECTIVES: To apply fetal midbrain (MB) and hindbrain (HB) nomograms, developed using three-dimensional multiplanar sonographic reconstruction (3D-MPR) in the mid-sagittal cranial plane, to fetuses with known posterior fossa malformations. METHODS: In this retrospective study we examined sonographic volumes obtained by sagittal acquisition in 43 fetuses diagnosed with posterior fossa abnormalities and evaluated in the mid-sagittal cranial plane, using 3D-MPR, the following: MB parameters tectal length (TL) and anteroposterior midbrain diameter (APMD), and HB parameters anteroposterior pons diameter (APPD), superoinferior vermian diameter (SIVD) and anteroposterior vermian diameter (APVD). Fetuses were grouped, according to malformation, into eight categories: cobblestone malformation complex (CMC, n = 3), Chiari-II malformation (C-II, n = 7), pontocerebellar hypoplasia (PCH, n = 2), rhombencephalosynapsis (RES, n = 4), Dandy-Walker malformation (n = 8), vermian dysgenesis (VD, n = 7), persistent Blake's pouch cyst (n = 6) and megacisterna magna (n = 6). In each case and for each subgroup, the MB-HB biometric parameters and their z-scores were evaluated with reference to our new nomograms. RESULTS: The new MB-HB nomograms were able to identify the brainstem and vermian anomalies and differentiate fetuses with MB HB malformations from those with isolated enlarged posterior fossa cerebrospinal fluid spaces. Use of the nomograms enabled detection of an elongated tectum in fetuses with CMC, C-II and RES, and a flattened pontine belly in cases of CMC, PCH and VD. In the fetuses with VD, the nomograms enabled division into three distinctive groups: (1) those with small SIVD and APVD, (2) those with normal SIVD but small APVD, and (3) those with small SIVD but normal APVD. CONCLUSIONS: Application of our new reference data, that for the first time include the MB, enables accurate diagnosis of brain malformations affecting the MB and HB and makes possible novel characterization of previously described features of posterior fossa anomalies. PMID- 24478246 TI - The hidden effects of child maltreatment in a war region: correlates of psychopathology in two generations living in Northern Uganda. AB - Adverse life experiences are a major risk factor for psychopathology. Studies from industrialized countries have consistently shown the detrimental effects of child maltreatment on the mental health of the victims. Research in war-affected populations, however, has mostly been restricted to the psychological damage caused by the war. Both war trauma and child maltreatment have rarely been studied simultaneously. In a comparative study of 2 generations living in severely war-affected regions in Northern Uganda, we determined the relationship between both trauma types and posttraumatic stress disorder (PTSD), anxiety, depression, and suicide ideation. A total of 100 adolescents, 50 with and 50 without a history of abduction by the rebel army with both their parents (100 mothers and 100 fathers) living in camps in northern Uganda were interviewed. The study showed that both generations were severely affected by war and child maltreatment. Both trauma types were independently correlated with psychological disorders in the adolescent group. Only child maltreatment, however, not war violence, accounted for PTSD symptoms in the parent group (beta = .253, p = .002). We conclude that, even in the context of severe war, the impact of child maltreatment on psychological disorders surpasses the damage of war trauma. PMID- 24478247 TI - Meta-analysis of bioabsorbable versus durable polymer drug-eluting stents in 20,005 patients with coronary artery disease: an update. AB - OBJECTIVES: To perform an updated meta-analysis comparing biodegradable polymer drug eluting stents (BP-DES) and durable polymer drug eluting stents (DP-DES). BACKGROUND: BP-DES have been suggested to reduce late stent thrombosis (LST) rates as compared to first generation DP-DES. Recently, second generation DP-DES have replaced older DES, but comparison of these stents with BP-DES has not yielded consistent results. METHODS: Medline/Web databases were searched for studies comparing BP-DES and DP-DES, and reporting rates of overall/cardiac mortality, myocardial infarction (MI), LST, target lesion revascularization (TLR) and target vessel revascularization (TVR) and late lumen loss (LLL), with a follow-up >=6 months. RESULTS: Twenty studies (20,005 patients) were included in the meta-analysis. Median follow-up time was 1 year. Compared with DP-DES, BP-DES showed lower LLL (in stent: weighted mean difference WMD -0.45 mm, 95% CI -0.66 to -0.24 mm, P = 0.00001; in segment: WMD -0.15 mm, 95% CI = -0.24 to -0.06 mm, P = 0.001) and lower rates of LST (OR 0.51, 95% CI = 0.30 to 0.86, P = 0.01), although they did not improve mortality, MI, TLR, and TVR rates. BP-DES coated with sirolimus or novolimus, in comparison with biolimus or paclitaxel, were associated with reduced LLL (P < 0.0001 for subgroups). CONCLUSIONS: In comparison with DP-DES, BP-DES significantly reduce LLL and LST rates, without clear benefits on harder endpoints. The efficacy of BP-DES in preserving lumen patency seems larger for sirolimus and novolimus DES. PMID- 24478248 TI - Silole-infiltrated photonic crystal films as effective fluorescence sensor for Fe3+ and Hg2+. AB - We develop a highly effective silole-infiltrated photonic crystal (PC) film fluorescence sensor with high sensitivity, good selectivity and excellent reproducibility for Fe(3+) and Hg(2+) ions. Hexaphenylsilole (HPS) infiltrated PCs show amplified fluorescence due to the slow photon effect of PC because the emission wavelength of HPS is at the blue band edge of the selected PC's stopband. The fluorescence can be quenched significantly by Fe(3+)/Hg(2+) ions owing to electron transfer between HPS and metal ions. The amplified fluorescence enhances the sensitivity of detection, with a detection limit of 5 nM for Fe(3+)/Hg(2+) ions. The sensor is negligibly responsive to other metal ions and can easily be reproduced by rinsing with pure water due to the special surface wettability of PC. As a result, a highly effective Fe(3+)/Hg(2+) ions sensor based on HPS-infiltrated PC film has been achieved, which will be important for effective and practical detection of heavy metal ions. PMID- 24478249 TI - Top-down protein identification of proteasome proteins with nanoLC-FT-ICR-MS employing data-independent fragmentation methods. AB - A comparison of different data-independent fragmentation methods combined with LC coupled to high-resolution FT-ICR-MS/MS is presented for top-down MS of protein mixtures. Proteins composing the 20S and 19S proteasome complexes and their PTMs were identified using a 15 T FT-ICR mass spectrometer. The data-independent fragmentation modes with LC timescales allowed for higher duty-cycle measurements that better suit online LC-FT-ICR-MS. Protein top-down dissociation was effected by funnel-skimmer collisionally activated dissociation (FS-CAD) and CASI (continuous accumulation of selected ions)-CAD. The N-termini for 9 of the 14 20S proteasome proteins were found to be modified, and the alpha3 protein was found to be phosphorylated; these results are consistent with previous reports. Mass measurement accuracy with the LC-FT-ICR system for the 20- to 30-kDa 20S proteasome proteins was 1 ppm. The intact mass of the 100-kDa Rpn1 subunit from the 19S proteasome complex regulatory particle was measured with a deviation of 17 ppm. The CASI-CAD technique is a complementary tool for intact-protein fragmentation and is an effective addition to the growing inventory of dissociation methods that are compatible with online protein separation coupled to FT-ICR-MS. PMID- 24478251 TI - Klippel-Trenaunay syndrome in a boy with concomitant ipsilateral overgrowth and undergrowth. AB - Klippel-Trenaunay syndrome comprises congenital vascular malformations of the capillary (nevus flammeus), venous (varicosities) or lymphatic systems and disturbed (usually over-) growth of one or more extremities and adjacent parts of the trunk. In some individuals the affected body area may show reduced rather than increased growth. Such patients have been described inverse Klippel Trenaunay syndrome and included within the spectrum of the syndrome. We report on a 3-year-old boy with vascular malformation of the nevus flammeus type extending from the right buttock to the sole of the right foot with clinical and radiological evidence of leg varicosities and underlying deficiency of the soft tissues and bone. In addition, he had macrodactyly of the first, second, and third toes with small nails, and cutaneous syndactyly of the second and third toes of the ipsilateral foot. Cranial magnetic resonance imaging showed high signal lesions in the peritrigonal areas with normal spinal images. This mosaic phenotype demonstrates that decreased and increased growth can coexist in the same body area of an individual with Klippel-Trenaunay syndrome. PMID- 24478250 TI - Accounting for population stratification in DNA methylation studies. AB - DNA methylation is an important epigenetic mechanism that has been linked to complex diseases and is of great interest to researchers as a potential link between genome, environment, and disease. As the scale of DNA methylation association studies approaches that of genome-wide association studies, issues such as population stratification will need to be addressed. It is well documented that failure to adjust for population stratification can lead to false positives in genetic association studies, but population stratification is often unaccounted for in DNA methylation studies. Here, we propose several approaches to correct for population stratification using principal components (PCs) from different subsets of genome-wide methylation data. We first illustrate the potential for confounding due to population stratification by demonstrating widespread associations between DNA methylation and race in 388 individuals (365 African American and 23 Caucasian). We subsequently evaluate the performance of our PC-based approaches and other methods in adjusting for confounding due to population stratification. Our simulations show that (1) all of the methods considered are effective at removing inflation due to population stratification, and (2) maximum power can be obtained with single-nucleotide polymorphism (SNP) based PCs, followed by methylation-based PCs, which outperform both surrogate variable analysis and genomic control. Among our different approaches to computing methylation-based PCs, we find that PCs based on CpG sites chosen for their potential to proxy nearby SNPs can provide a powerful and computationally efficient approach to adjust for population stratification in DNA methylation studies when genome-wide SNP data are unavailable. PMID- 24478252 TI - A case of brachymetatarsia from medieval Sardinia (Italy). AB - Archaeological excavations carried out in the Medieval village of Geridu (Sardinia) uncovered several burials dating to the late 13th or the first half of 14th century. Among these individuals, the skeleton of an adult female showing a bilateral abnormal shortness of the fourth metatarsal bone was identified. Bilaterality and absence of other skeletal anomalies allow to rule out an acquired aetiology of the disease and to support a diagnosis of congenital brachymetatarsia. Such a rare deformity has a clinical incidence of 0.02% to 0.05%, with strong predominance of the female gender. To our knowledge, no other cases of brachymetatarsia have been reported in paleopathology so far. PMID- 24478253 TI - Screening and identification of a specific peptide binding to hepatocellular carcinoma cells from a phage display peptide library. AB - To screen and identify the novel probe markers binding hepatocellular carcinoma specifically and sensitively, a phage-displayed 12-mer peptide library was used to make biopanning with the modified protocols on HepG2 cells. After four rounds of panning, the consensus sequences were obtained, and the PC28, a phage clone with most specific and sensitive binding to HepG2 cells, was identified as the best positive clone. The peptide probe HCSP4 (sequence SLDSTHTHAPWP) was synthesized based on the sequencing result of PC28. The specificity and sensitivity of HCSP4 were primarily analyzed using immunofluorescence, flow cytometry, and other methods. The results show that HCSP4 can bind to hepatocellular carcinoma cells with satisfactory specificity and sensitivity. It may be a promising lead candidate for molecular imaging and targeted drug delivery in the diagnosis and therapy of hepatocellular carcinoma. PMID- 24478254 TI - Natural products for pest control: an analysis of their role, value and future. AB - Natural products (NPs) have long been used as pesticides and have broadly served as a source of inspiration for a great many commercial synthetic organic fungicides, herbicides and insecticides that are in the market today. In light of the continuing need for new tools to address an ever-changing array of fungal, weed and insect pests, NPs continue to be a source of models and templates for the development of new pest control agents. Interestingly, an examination of the literature suggests that NP models exist for many of the pest control agents that were discovered by other means, suggesting that, had circumstances been different, these NPs could have served as inspiration for the discovery of a great many more of today's pest control agents. Here, an attempt is made to answer questions regarding the existence of an NP model for existing classes of pesticides and what is needed for the discovery of new NPs and NP models for pest control agents. PMID- 24478255 TI - High-resolution observation of nucleation and growth behavior of nanomaterials using a graphene template. AB - By using graphene as an electron beam-transparent substrate for both nanomaterial growth and transmission electron microscopy (TEM) measurements, we investigate initial growth behavior of nanomaterials. The direct growth and imaging method using graphene facilitate atomic-resolution imaging of nanomaterials at the very early stage of growth. This enables the observation of the transition in crystal structure of ZnO nuclei and the formation of various defects during nanomaterial growth. PMID- 24478256 TI - Predictive value of ophthalmic artery Doppler velocimetry in relation to development of pre-eclampsia. AB - OBJECTIVE: To test the hypothesis that ophthalmic artery Doppler velocimetry is predictive of the development of pre-eclampsia (PE). METHODS: This was a prospective cohort study that included pregnant women in the second trimester who had risk factors for PE. Seven ophthalmic artery Doppler parameters, in addition to uterine artery (UtA) Doppler and clinical variables, were investigated for their prognostic value with respect to PE. RESULTS: A total of 347 women were recruited, of whom 40 developed PE. A comparison of the mean ophthalmic artery Doppler parameter values between women with and those without PE showed statistically significant differences in several parameters: peak systolic velocity, end-diastolic velocity, mean velocity, peak mesodiastolic velocity (PMDV) and peak ratio. After adjusting for confounding variables, only PMDV remained statistically significant (P < 0.001), with an area under the receiver operating characteristics curve (AUC) of 0.73. The best cut-off for predicting PE was a PMDV of > 22.11 cm/s, with sensitivity of 70%, specificity of 75%, positive likelihood ratio of 2.8, negative likelihood ratio of 0.4, positive predictive value of 28% and negative predictive value of 95%. The AUC increased from 0.72 to 0.78 when the PMDV was incorporated into a prediction model based on clinical variables, demonstrating that this marker increased the discriminatory capability of the model. The performance of ophthalmic artery Doppler was similar to that of UtA Doppler for predicting PE. Additionally, the AUC increased significantly from 0.82 to 0.88 when the PMDV was incorporated into the model containing clinical variables and UtA Doppler indices. CONCLUSION: A high ophthalmic artery PMDV in the second trimester of pregnancy is an independent predictor of PE that increases the discriminatory ability of clinical markers, as well as of models that include clinical variables and UtA Doppler indices. PMID- 24478257 TI - The origin of the "snap-in" in the force curve between AFM probe and the water/gas interface of nanobubbles. AB - The long-range attractive force or "snap-in" is an important phenomenon usually occurring when a solid particle interacts with a water/gas interface. By using PeakForce quantitative nanomechanics the origin of snap-in in the force curve between the atomic force microscopy (AFM) probe and the water/gas interface of nanobubbles has been investigated. The snap-in frequently happened when the probe was preserved for a certain time or after being used for imaging solid surfaces under atmospheric conditions. In contrast, imaging in liquids rarely induced a snap-in. After a series of control experiments, it was found that the snap-in can be attributed to hydrophobic interactions between the water/gas interface and the AFM probe, which was either modified or contaminated with hydrophobic material. The hydrophobic contamination could be efficiently removed by a conventional plasma-cleaning treatment, which prevents the occurring of the snap-in. In addition, the adsorption of sodium dodecyl sulfate onto the nanobubble surface changed the water/gas interface into hydrophilic, which also eliminated the snap in phenomenon. PMID- 24478258 TI - Younger age of dementia diagnosis in a Hispanic population in southern California. AB - OBJECTIVE: Prior studies of US Hispanics, largely performed on the East Coast, have found a younger age of dementia onset than in White non-Hispanics. We performed a cross-sectional study to examine clinical and sociodemographic variables associated with age of dementia diagnosis in older Hispanics and White, non-Hispanics in southern California. METHODS: Two hundred ninety (110 Hispanic and 180 White non-Hispanic) community dwelling, cognitively symptomatic subjects, aged 50 years and older, were assessed and diagnosed with probable Alzheimer's disease or probable vascular dementia. Apolipoprotein E (APOE) genotype was assessed in a subset of cases. Analysis of variance and multiple stepwise linear regression were used to assess main effects and interactions of ethnicity with dementia severity (indexed by mini mental state examination scores) and other sociodemographic and clinical variables on age of dementia diagnosis. RESULTS: Hispanics were younger by an average of 4 years at the time of diagnosis, regardless of dementia subtype, despite a similar prevalence of the APOE epsilon4 genotype. The earlier age at diagnosis for Hispanics was not explained by gender, dementia severity, years of education, history of hypercholesterolemia, hypertension, or diabetes. Only ethnicity was significantly associated with age of onset. CONCLUSIONS: These findings confirm that US Hispanics living in the southwestern USA tend to be younger at the time of dementia diagnosis than their White non-Hispanic counterparts. As this is not explained by the presence of the APOE epsilon4 genotype, further studies should explore other cultural, medical, or genetic risk factors influencing the age of dementia onset in this population. PMID- 24478259 TI - Growing indication for FNA to study and analyze tumor heterogeneity at metastatic sites. AB - In routine practice, suspected metastases in patients with cancer are only occasionally biopsied, primarily because of the cost and invasiveness of the procedure. However, biopsies of metastatic lesions can be valuable, not only in confirming the presence of metastatic disease, but also in revealing unsuspected benign disease or secondary malignancies. In addition, such biopsies also allow the assessment of biomarkers that might differ from those on primary tumor cells, and can thereby facilitate selection of the optimal treatment. Because of the increasing recognition of clonal and phenotypic heterogeneity of tumors, we anticipate that in the near future, biopsying of metastatic lesions will constitute a standard-of-care practice, allowing assessment of molecular differences between the primary tumor and metastatic lesions. In our opinion, fine-needle aspiration is currently the best method for making repeated biopsies to monitor the tumor: it is minimally invasive, safe, and cost effective and can be coupled with modern ancillary techniques. Here we provide an up-to-date review of the clinical implications of tumor heterogeneity in metastatic disease and the ancillary molecular techniques used in cytology; we also discuss the role of modern cytology in contemporary diagnosis and management of metastatic cancer. PMID- 24478260 TI - Queries of MALDI-imaging global datasets identifying ion mass signatures associated with tissue compartments. AB - Scanning MS by MALDI MS imaging (MALDI-MSI) creates large volumetric global datasets that describe the location and identity of ions registered at each sampling location. While thousands of ion peaks are recorded in a typical whole tissue analysis, only a fraction of these measured molecules are purposefully scrutinized within a given experimental design. To address this need, we recently reported new methods to query the full volume of MALDI-MSI data that correlate all ion masses to one another. As an example of this utility, we demonstrate that specific ion peak m/z signatures can be used to localize similar histological structures within tissue samples. In this study, we use the example of ion peak masses that are associated with tissue spaces occupied by airway bronchioles in rat lung samples. The volume of raw data was preprocessed into structures of 0.1 mass unit bins containing metadata collected at each sampling position. Interactive visualization in ParaView identified ion peaks that especially showed strong association with airway bronchioles but not vascular or parenchymal tissue compartments. Further iterative statistical correlation queries provided ranked indices of all m/z values in the global dataset regarding coincident distributions at any given X, Y position in the histological spaces occupied by bronchioles The study further provides methods for extracting important information contained in global datasets that previously was unseen or inaccessible. PMID- 24478261 TI - Nanostructures from the self-assembly of alpha-helical peptide amphiphiles. AB - Self-assembly of PAs composed of palmitic acid and several repeated heptad peptide sequences, C15H31CO-(IEEYTKK)(n)-NH2 (n = 1-4, represented by PA1-PA4), was investigated systematically. The secondary structures of the PAs were characterized by CD. PA3 and PA4 (n = 3 and 4, respectively) showed an alpha helical structure, whereas PA1 and PA2 (n = 1 and 2, respectively) did not display an alpha-helical conformations under the tested conditions. The morphology of the self-assembled peptides in aqueous medium was studied by transmission electron microscopy. As the number of heptad repeats in the PAs increased, the nanostructure of the self-assembled peptides changed from nanofibers to nanovesicles. Changes of the secondary structures and the self assembly morphologies of PA3 and PA4 in aqueous medium with various cations were also studied. The critical micelle concentrations were determined using a pyrene fluorescence probe. In conclusion, this method may be used to design new peptide nanomaterials. PMID- 24478262 TI - Congenital nasal pyriform aperture stenosis and ocular albinism co-occurring in a sibship with a maternally-inherited 97 kb Xp22.2 microdeletion. AB - Congenital Nasal Pyriform Aperture Stenosis (CNPAS) is a rare congenital malformation caused by overgrowth of the maxillary bone. We report on two patients, brothers born 3 and 11/2 years apart, both presented at birth with radiographically diagnosed CNPAS. Both siblings also were born with ocular albinism, which is known to have X-linked inheritance. Subsequent genetic testing demonstrated a 97 kb deletion in the p arm of the X chromosome in both siblings and their mother. This deletion encompasses a gene known to cause ocular albinism (GPR143), as well as partial deletion of two other genes, TBL1X and SHROOM2. This is the first reported case of CNPAS in siblings, both males, sharing a maternally inherited Xp22.2 deletion. PMID- 24478263 TI - On the benefits of rubbing salt in the cut: self-healing of saloplastic PAA/PAH compact polyelectrolyte complexes. AB - The inherent room temperature mending and self-healing properties of saloplastic PAA/PAH CoPECs are studied. After ultracentrifugation of PAA/PAH polyelectrolyte complexes, tough, elastic materials are obtained that undergo self-healing facilitated by salt. At intermediate salt concentrations the CoPECs remain elastic enough to recover their original shape while the chains are mobile enough to repair the cut, thus leading to actual self-healing behavior. PMID- 24478264 TI - Asymmetric neural development in the Caenorhabditis elegans olfactory system. AB - Asymmetries in the nervous system have been observed throughout the animal kingdom. Deviations of brain asymmetries are associated with a variety of neurodevelopmental disorders; however, there has been limited progress in determining how normal asymmetry is established in vertebrates. In the Caenorhabditis elegans chemosensory system, two pairs of morphologically symmetrical neurons exhibit molecular and functional asymmetries. This review focuses on the development of antisymmetry of the pair of amphid wing "C" (AWC) olfactory neurons, from transcriptional regulation of general cell identity, establishment of asymmetry through neural network formation and calcium signaling, to the maintenance of asymmetry throughout the life of the animal. Many of the factors that are involved in AWC development have homologs in vertebrates, which may potentially function in the development of vertebrate brain asymmetry. PMID- 24478265 TI - Isthmic-vaginal smear cytology in the follow-up after radical vaginal trachelectomy for early stage cervical cancer: is it safe? AB - BACKGROUND: Isthmic-vaginal cytology is a follow-up method in patients who have undergone radical vaginal trachelectomy (RVT) for early cervical cancer. However, to the authors' knowledge, little is known regarding its ability to monitor patients and diagnose disease recurrence. Herein, the authors report their experience with cytology after RVT compared with cytology in patients after cone biopsy and women undergoing screening. METHODS: A database of 563 specimens from 303 patients was analyzed retrospectively (RVT in 361 specimens, conization in 102 specimens, and screening in 100 specimens). The following criteria were applied: Bethesda system, the presence of endocervical and metaplasia cells, regeneration criteria, vaginal flora, and morphological signs of human papillomavirus. The analysis was performed by 2 cytopathologists. Differences between the groups and correlation between the cytopathologists were analyzed. RESULTS: Smears without endocervical and metaplasia cells were significantly less frequent among the patients who underwent RVT. There was no difference in regeneration signs, vaginal flora, and morphologic signs of human papillomavirus between the groups. After RVT, 26/23 smears (cytopathologist 1/cytopathologist 2) smears were diagnosed as abnormal. Biopsies revealed 7 cases of dysplasia and 1 case of disease recurrence. After conization, 1 patient was diagnosed with a low grade lesion on cytology; follow-up cytology was normal. In the screening, 10/13 smears were diagnosed with lesions on cytology; biopsy revealed dysplasia in 2 cases. The correlation between both cytopathologists was high. CONCLUSIONS: After RVT, histological verification of cytology is frequently needed. The reasons might include alterations of anatomy, regeneration, and inflammation process after RVT. Cytopathologists should become familiar with the spectrum of changes in post-RVT cytology and communication between cytopathologists and clinicians should be improved. This might reduce false-positive results. PMID- 24478267 TI - Frequency of FMR1 gene mutation and CGG repeat polymorphism in intellectually disabled children in Pakistan. AB - Fragile X syndrome is considered the most common heritable form of X-linked intellectual disability (ID). The syndrome is caused by silencing of the fragile X mental retardation 1 gene (Xq27.3) due to hypermethylation. This mutation results in absence or deficit of its protein product, the fragile X mental retardation protein (FMRP) that affects synaptic plasticity in neurons, hence leads to brain dysfunction. The syndrome is widely distributed throughout the world. This study reported for the first time the frequency of the fragile X mental retardation 1 gene mutations in intellectually disabled children in Pakistan. We recruited 333 intellectually disabled children and 250 normal children with age ranging from 5 to 18 years for this study. Genomic DNA was extracted from peripheral blood and full mutations were identified by methylation sensitive PCR using primers corresponding to modified methylated and unmethylated DNA. Southern blot was used for confirmation of the results. The frequency of fragile X syndrome with full mutation was found as 4.8%. It was 6.5% in males as opposed to 0.9% in females; 29 CGG repeats were found as the most common allele; 31.5% in the intellectually disabled and 34% in control subjects. In Pakistan intellectual disability is considered as a social stigma for the individuals and their families. Due to lack of knowledge and cultural background people make such patients and families isolated. This study will increase public awareness about the intellectual disability and importance of prenatal screening and genetic counseling for vulnerable families. PMID- 24478266 TI - National assessment of early biliary complications following liver transplantation: incidence and outcomes. AB - Despite improved overall liver transplant outcomes, biliary complications remain a significant cause of morbidity. A national data set linking transplant registry and Medicare claims data for 17,012 liver transplant recipients was used to identify all recipients with a posttransplant biliary diagnosis code within the first 6 months after transplantation. Patients were further categorized as follows: a diagnosis without a procedure, a diagnosis and an associated radiological or endoscopic procedure, or a diagnosis treated with surgery. Overall, 15.0% had a biliary diagnosis, 11.2% required a procedure, and 2.2% had a surgical revision. Factors independently associated with biliary complications included donation after cardiac death (DCD), donor age, recipient age, split grafts, and long cold ischemia times. Graft loss was significantly more common for patients with biliary diagnoses [adjusted hazard ratio (aHR) = 1.89, confidence interval (CI) = 1.63-2.19], interventions (aHR = 2.08, CI = 1.77 2.44), and surgical procedures (aHR = 1.80, CI = 1.31-2.49). Mortality after transplantation was also markedly increased for patients with biliary diagnoses (aHR = 2.18, CI = 1.97-2.40), procedures (aHR = 2.21, CI = 1.99-2.46), and surgeries (aHR = 1.77, CI = 1.41-2.23). In stratified analyses, the impact of early biliary complications was greater for DCD liver recipients, but they remained highly significant for recipients of allografts from brain-dead donors as well. Reducing biliary complications should improve posttransplant survival and reduce graft loss. PMID- 24478268 TI - The experiences of intimate relationships by people with intellectual disabilities: a qualitative study. AB - BACKGROUND: People with intellectual disabilities face attitudinal and service barriers when attempting to form intimate relationships. To date, their experiences and views are under-represented in the existing evidence base. METHOD: The aim of this study was to carry out an interpretative phenomenological analysis exploring the experience of intimate relationships for nine adults with intellectual disabilities. RESULTS: Four main themes were identified: desiring relationships; expressing sexuality; having relationships; and who has control? Together these themes demonstrated that intimate relationships were desired and important to all participants, fulfilling a variety of their needs. In addition, participants faced a number of challenges related to intimate relationships. CONCLUSION: The findings raise questions about how best to support people with intellectual disabilities with sexuality and intimate relationships. Implications for caregivers and services are discussed. PMID- 24478269 TI - Sensorineural hearing loss in patients with head and neck cancer after chemoradiotherapy and radiotherapy: a systematic review of the literature. AB - BACKGROUND: Both radiotherapy (RT) and cisplatin-based chemoradiotherapy (CRT) in patients with head and neck cancer may cause sensorineural hearing loss (SNHL). The purpose of this review was to provide more insight into SNHL because of CRT compared to RT. METHODS: Comprehensive search of Medline and Embase with the terms "radiotherapy" combined with "ototoxicity," "head and neck squamous cell carcinoma," and synonyms. RESULTS: Of the 2507 studies found, 21 were included in this study. Pooled analysis could not be committed because of heterogeneity. Incidence rates of SNHL after RT and CRT varied considerably, with percentages ranging from 0% to 43% and 17% to 88%, respectively. Factors that influenced the risk of SNHL were radiation dose to the cochlea, follow-up time, age, baseline hearing level, and cisplatin dose. CONCLUSION: The wide range of SNHL incidence rates makes it impossible to draw any conclusions on the severity of RT- and CRT induced ototoxicity. To allow for future comparison of study outcomes, development of uniform criteria is of utmost importance. PMID- 24478270 TI - Clinical and angiographic outcomes of patients undergoing entrapped guidewire retrieval in stent-jailed side branch using a balloon catheter. AB - OBJECTIVE: The purpose of this study was to examine the efficacy and safety of method for retrieval of entrapped guidewire in stent-jailed side branch using a balloon catheter. BACKGROUND: Guidewire entrapment in the side branch after main vessel stenting is an infrequent but potentially serious complication of bifurcation lesion treatment. Entrapped wire retrieval with device advancement over the wire is a previously reported bail-out method, but its efficacy and impact on the proximal edge of the stent are unknown. METHODS: We conducted a single-center, prospective study to evaluate the outcome of 28 consecutive patients who developed guidewire entrapment in a stent-jailed side branch after drug-eluting stent implantation, and underwent retrieval of entrapped wire using a balloon catheter. The primary objective was cumulative 12-month major adverse cardiac events including death, non-fatal myocardial infarction, target lesion revascularization, and stent thrombosis. Secondary objectives included binary restenosis and late lumen loss, evaluated in-stent, 5-mm proximal edge, and 5-mm distal edge sites at 9-month angiographic follow-up. RESULTS: Entrapped guidewire retrieval was successfully achieved in all patients. Cumulative 12-month major adverse cardiac events were not observed in any patient. At angiographic follow up, no significant differences were observed in late lumen loss between in-stent, 5-mm proximal edge, and 5-mm distal edge sites (0.12 +/- 0.38 mm vs. 0.09 +/- 0.27 mm vs. 0.03 +/- 0.3 mm, P = 0.57). None of the patients had binary in-stent or in-segment restenosis. CONCLUSION: Although the decision to apply the present method for entrapped guidewire retrieval should be made with careful consideration, it appears effective for bail-out. (c) 2013 Wiley Periodicals, Inc. PMID- 24478271 TI - Synthetic biology of avermectin for production improvement and structure diversification. AB - Natural products are still key sources of current clinical drugs and innovative therapeutic agents. Since wild-type microorganisms only produce natural products in very small quantities, yields of production strains need to be improved by breaking down the precise genetic and biochemical circuitry. Herein, we use avermectins as an example of production improvement and chemical structure diversification by synthetic biology. Avermectins are macrocyclic lactones produced by Streptomyces avermitilis and are well known and widely used for antiparasitic therapy. Given the importance of this molecule and its derivatives, many efforts and strategies were employed to improve avermectin production and generate new active analogues. This review describes the current status of synthetic strategies successfully applied for developing natural-product producing strains and discusses future prospects for the application of enhanced avermectin production. PMID- 24478272 TI - Autism treatment research. PMID- 24478273 TI - Mucopolysaccharidosis type IVA: evidence of primary and secondary central nervous system involvement. AB - Mucopolysaccharidosis type IVA is a rare lysosomal storage disease caused by a deficiency of N-acetylgalactosamine 6-sulfatase. Studies usually focus on skeletal abnormalities and their consequences. This study explores the neurological manifestations in a cohort of mucopolysaccharidosis type IVA patients, with a detailed focus on brain and spinal magnetic resonance imaging (MRI) findings. We performed a cross-sectional study involving nine patients with a biochemical confirmation of mucopolysaccharidosis type IVA. The protocol consists of a comprehensive clinical examination and brain and spinal cord MRI analysis for all subjects. The mean age was 16.4 years (+/-5.7) and the mean onset of symptoms was 11.5 months (+/-6.3). Overall, cognition was spared in all but one patient and motor weakness was a constant finding in all patients. Deep sensation impairment was found in six patients. The brain MRIs showed non specific white matter changes in two patients. Other abnormalities such as clival hypoplasia, basilar invagination, and arachnoid cists appeared in seven of the nine patients. Eight patients presented spinal cord compression, and in three of them, two spinal levels were compromised. Odontoid hypoplasia and degenerative features in the neuroaxis were present in all patients. Our experience with mucopolysaccharidosis type IVA patients supports the evidence of central nervous system involvement. We emphasize the importance of regular clinical assessments with complete MRI studies, as an attempt to detect the early signs of spinal cord compression. This evaluation may be especially important before surgical interventions, as occult lesions may become symptomatic and promote postoperative unfavorable outcomes. PMID- 24478274 TI - Long-term outcomes after liver transplantation for deoxyguanosine kinase deficiency: a single-center experience and a review of the literature. AB - Deoxyguanosine kinase (DGUOK) deficiency is a well-known cause of hepatocerebral mitochondrial DNA depletion syndromes, which include a broad spectrum of clinical presentations. Affected patients often develop life-threatening liver failure, but the benefits of liver transplantation (LT) are controversial because of the frequently severe neurological involvement due to the underlying mitochondrial disease. We describe the long-term clinical course of 2 patients from our institution and provide an update on their outcomes after LT with this condition. Another 12 pediatric patients were identified through a systematic search of the literature. All 14 reported patients underwent transplantation in infancy despite mild to moderate neurological impairment in some cases. The 2 DGUOK-deficient patients from our center displayed liver failure and mild to moderate neurological involvement. At the time of this writing, they had been followed for 5 and 8 years after LT, both patients were alive, and they had only mild neurological symptoms. Three of the 12 patients identified through the literature review survived for a long time (17, 12, and 23 years); 8 died during early follow-up; and for 1 patient, no follow-up information was available. The 1-year survival rate was 64%; 36% survived for more than 5 years. The long-term survivors had good quality of life. In conclusion, although survival after LT for DGUOK deficiency is lower than survival after LT for other indications, a significant proportion of patients benefit from LT with long-term survival and a stable neurological situation despite initial neurological abnormalities. Nevertheless, a decision to carry out LT for patients with DGUOK deficiency remains difficult because neurological symptoms may occur and worsen after LT despite their absence before transplantation. PMID- 24478276 TI - Decoding spatial and temporal features of neuronal cAMP/PKA signaling with FRET biosensors. AB - Cyclic adenosine monophosphate (cAMP) and the cyclic-AMP-dependent protein kinase (PKA) regulate a plethora of cellular functions in virtually all eukaryotic cells. In neurons, the cAMP/PKA signaling cascade controls a number of biological properties such as axonal growth, pathfinding, efficacy of synaptic transmission, regulation of excitability, or long term changes. Genetically encoded optical biosensors for cAMP or PKA are considerably improving our understanding of these processes by providing a real-time measurement in living neurons. In this review, we describe the recent progress made in the creation of biosensors for cAMP or PKA activity. These biosensors revealed profound differences in the amplitude of the cAMP signal evoked by neuromodulators between various neuronal preparations. These responses can be resolved at the level of individual neurons, also revealing differences related to the neuronal type. At the sub-cellular level, biosensors reported different signal dynamics in domains like dendrites, cell body, nucleus, and axon. Combining this imaging approach with pharmacology or genetic models points at phosphodiesterases and phosphatases as critical regulatory proteins. Biosensor imaging will certainly emerge as a forefront tool to decipher the subtle mechanics of intracellular signaling. This will certainly help us to understand the mechanism of action of current drugs and foster the development of novel molecules for neuropsychiatric diseases. PMID- 24478275 TI - Stereospecific nickel-catalyzed cross-coupling reactions of alkyl Grignard reagents and identification of selective anti-breast-cancer agents. AB - Alkyl Grignard reagents that contain beta-hydrogen atoms were used in a stereospecific nickel-catalyzed cross-coupling reaction to form C(sp(3))-C(sp(3)) bonds. Aryl Grignard reagents were also utilized to synthesize 1,1-diarylalkanes. Several compounds synthesized by this method exhibited selective inhibition of proliferation of MCF-7 breast cancer cells. PMID- 24478277 TI - New psychoactive substances legislation in Ireland - Perspectives from academia. AB - The emergence of 'legal highs' or 'new psychoactive substances' (NPS) on the Irish market is reflective of their appearance in many countries, with some notable exceptions. The official response to the situation is examined here by looking at Irish controlled drugs legislation and drug enforcement policies as enacted in recent years and their effects on academic research on NPS. The philosophy and practice of outright bans of scheduled substances has not been effective in delivering the stated aims of illicit drug control, namely harm reduction. With these legislative changes, we have witnessed the removal of the 'legitimate' sale and open marketing of a number of NPS to the general public in commercial retail premises. However, as legislation was enacted, suppliers and vendors rapidly changed the contents of their legal high products from now controlled to non-controlled substances. We have found that it is administratively challenging to perform scientific research on controlled substances at academic institutions. It is desirable to gather analytical, pharmacological, and toxicological data on these substances as they emerge on the market but due to the restrictive nature of licensing requirements, once a substance or generic class of substances is controlled, this becomes more difficult. The facts that any quantity of substance, no matter how small, is controlled, the nomenclature used to describe compounds is not consistent within the enacted legislation and the use of catch-all classes of compounds with the intention of controlling many similar molecular structures, all create problematic issues for academic researchers. PMID- 24478278 TI - Nonlinear light-sheet fluorescence microscopy by photobleaching imprinting. AB - We present a nonlinear light-sheet fluorescence microscopy (LSFM) scheme based on photobleaching imprinting. By measuring photobleaching-induced fluorescence decay, our method simultaneously achieves a large imaging field of view and a thin optical section. Furthermore, the scattered-light-induced background is significantly reduced, considerably improving image contrast. Our method is expected to expand the application field of LSFM into the optical quasi-ballistic regime, enabling studies on non-transparent biological samples. PMID- 24478279 TI - Growth, homeostatic regulation and stem cell dynamics in tissues. AB - The regulation of cell growth in animal tissues is a question of critical importance: most tissues contain different types of cells in interconversion and the fraction of each type has to be controlled in a precise way, by mechanisms that remain unclear. Here, we provide a theoretical framework for the homeostasis of stem-cell-containing epithelial tissues using mechanical equations, which describe the size of the tissue and kinetic equations, which describe the interconversions of the cell populations. We show that several features, such as the evolution of stem cell fractions during intestinal development, the shape of a developing intestinal wall, as well as the increase in the proliferative compartment in cancer initiation, can be studied and understood from generic modelling which does not rely on a particular regulatory mechanism. Finally, inspired by recent experiments, we propose a model where cell division rates are regulated by the mechanical stresses in the epithelial sheet. We show that pressure-controlled growth can, in addition to the previous features, also explain with few parameters the formation of stem cell compartments as well as the morphologies observed when a colonic crypt becomes cancerous. We also discuss optimal strategies of wound healing, in connection with experiments on the cornea. PMID- 24478280 TI - The structure-function relationships of a natural nanoscale photonic device in cuttlefish chromatophores. AB - Cuttlefish, Sepia officinalis, possess neurally controlled, pigmented chromatophore organs that allow rapid changes in skin patterning and coloration in response to visual cues. This process of adaptive coloration is enabled by the 500% change in chromatophore surface area during actuation. We report two adaptations that help to explain how colour intensity is maintained in a fully expanded chromatophore when the pigment granules are distributed maximally: (i) pigment layers as thin as three granules that maintain optical effectiveness and (ii) the presence of high-refractive-index proteins-reflectin and crystallin-in granules. The latter discovery, combined with our finding that isolated chromatophore pigment granules fluoresce between 650 and 720 nm, refutes the prevailing hypothesis that cephalopod chromatophores are exclusively pigmentary organs composed solely of ommochromes. Perturbations to granular architecture alter optical properties, illustrating a role for nanostructure in the agile, optical responses of chromatophores. Our results suggest that cephalopod chromatophore pigment granules are more complex than homogeneous clusters of chromogenic pigments. They are luminescent protein nanostructures that facilitate the rapid and sophisticated changes exhibited in dermal pigmentation. PMID- 24478282 TI - Radiative energy budget reveals high photosynthetic efficiency in symbiont bearing corals. AB - The light field on coral reefs varies in intensity and spectral composition, and is the key regulating factor for phototrophic reef organisms, for example scleractinian corals harbouring microalgal symbionts. However, the actual efficiency of light utilization in corals and the mechanisms affecting the radiative energy budget of corals are underexplored. We present the first balanced light energy budget for a symbiont-bearing coral based on a fine-scale study of the microenvironmental photobiology of the massive coral Montastrea curta. The majority (more than 96%) of the absorbed light energy was dissipated as heat, whereas the proportion of the absorbed light energy used in photosynthesis was approximately 4.0% under an irradiance of 640 umol photons m( 2) s(-1). With increasing irradiance, the proportion of heat dissipation increased at the expense of photosynthesis. Despite such low energy efficiency, we found a high photosynthetic efficiency of the microalgal symbionts showing high gross photosynthesis rates and quantum efficiencies (QEs) of approximately 0.1 O2 photon(-1) approaching theoretical limits under moderate irradiance levels. Corals thus appear as highly efficient light collectors with optical properties enabling light distribution over the corallite/tissue microstructural canopy that enables a high photosynthetic QE of their photosynthetic microalgae in hospite. PMID- 24478283 TI - Corruption drives the emergence of civil society. AB - Centralized sanctioning institutions have been shown to emerge naturally through social learning, displace all other forms of punishment and lead to stable cooperation. However, this result provokes a number of questions. If centralized sanctioning is so successful, then why do many highly authoritarian states suffer from low levels of cooperation? Why do states with high levels of public good provision tend to rely more on citizen-driven peer punishment? Here, we consider how corruption influences the evolution of cooperation and punishment. Our model shows that the effectiveness of centralized punishment in promoting cooperation breaks down when some actors in the model are allowed to bribe centralized authorities. Counterintuitively, a weaker centralized authority is actually more effective because it allows peer punishment to restore cooperation in the presence of corruption. Our results provide an evolutionary rationale for why public goods provision rarely flourishes in polities that rely only on strong centralized institutions. Instead, cooperation requires both decentralized and centralized enforcement. These results help to explain why citizen participation is a fundamental necessity for policing the commons. PMID- 24478281 TI - Novel biological strategies for treatment of wear particle-induced periprosthetic osteolysis of orthopaedic implants for joint replacement. AB - Wear particles and by-products from joint replacements and other orthopaedic implants may result in a local chronic inflammatory and foreign body reaction. This may lead to persistent synovitis resulting in joint pain and swelling, periprosthetic osteolysis, implant loosening and pathologic fracture. Strategies to modulate the adverse effects of wear debris may improve the function and longevity of joint replacements and other orthopaedic implants, potentially delaying or avoiding complex revision surgical procedures. Three novel biological strategies to mitigate the chronic inflammatory reaction to orthopaedic wear particles are reported. These include (i) interference with systemic macrophage trafficking to the local implant site, (ii) modulation of macrophages from an M1 (pro-inflammatory) to an M2 (anti-inflammatory, pro-tissue healing) phenotype in the periprosthetic tissues, and (iii) local inhibition of the transcription factor nuclear factor kappa B (NF-kappaB) by delivery of an NF-kappaB decoy oligodeoxynucleotide, thereby interfering with the production of pro-inflammatory mediators. These three approaches have been shown to be viable strategies for mitigating the undesirable effects of wear particles in preclinical studies. Targeted local delivery of specific biologics may potentially extend the lifetime of orthopaedic implants. PMID- 24478284 TI - Training an asymmetric signal perceptron through reinforcement in an artificial chemistry. AB - State-of-the-art biochemical systems for medical applications and chemical computing are application-specific and cannot be reprogrammed or trained once fabricated. The implementation of adaptive biochemical systems that would offer flexibility through programmability and autonomous adaptation faces major challenges because of the large number of required chemical species as well as the timing-sensitive feedback loops required for learning. In this paper, we begin addressing these challenges with a novel chemical perceptron that can solve all 14 linearly separable logic functions. The system performs asymmetric chemical arithmetic, learns through reinforcement and supports both Michaelis Menten as well as mass-action kinetics. To enable cascading of the chemical perceptrons, we introduce thresholds that amplify the outputs. The simplicity of our model makes an actual wet implementation, in particular by DNA-strand displacement, possible. PMID- 24478285 TI - Optimal feedback correction in string quartet synchronization. AB - Control of relative timing is critical in ensemble music performance. We hypothesize that players respond to and correct asynchronies in tone onsets that arise from fluctuations in their individual tempos. We propose a first-order linear phase correction model and demonstrate that optimal performance that minimizes asynchrony variance predicts a specific value for the correction gain. In two separate case studies, two internationally recognized string quartets repeatedly performed a short excerpt from the fourth movement of Haydn's quartet Op. 74 no. 1, with intentional, but unrehearsed, expressive variations in timing. Time series analysis of successive tone onset asynchronies was used to estimate correction gains for all pairs of players. On average, both quartets exhibited near-optimal gain. However, individual gains revealed contrasting patterns of adjustment between some pairs of players. In one quartet, the first violinist exhibited less adjustment to the others compared with their adjustment to her. In the second quartet, the levels of correction by the first violinist matched those exhibited by the others. These correction patterns may be seen as reflecting contrasting strategies of first-violin-led autocracy versus democracy. The time series approach we propose affords a sensitive method for investigating subtle contrasts in music ensemble synchronization. PMID- 24478286 TI - Unlocking the secrets of multi-flagellated propulsion: drawing insights from Tritrichomonas foetus. AB - In this work, a high-speed imaging platform and a resistive force theory (RFT) based model were applied to investigate multi-flagellated propulsion, using Tritrichomonas foetus as an example. We discovered that T. foetus has distinct flagellar beating motions for linear swimming and turning, similar to the 'run and tumble' strategies observed in bacteria and Chlamydomonas. Quantitative analysis of the motion of each flagellum was achieved by determining the average flagella beat motion for both linear swimming and turning, and using the velocity of the flagella as inputs into the RFT model. The experimental approach was used to calculate the curvature along the length of the flagella throughout each stroke. It was found that the curvatures of the anterior flagella do not decrease monotonically along their lengths, confirming the ciliary waveform of these flagella. Further, the stiffness of the flagella was experimentally measured using nanoindentation, allowing for calculation of the flexural rigidity of T. foetus's flagella, 1.55*10(-21) N m(2). Finally, using the RFT model, it was discovered that the propulsive force of T. foetus was similar to that of sperm and Chlamydomonas, indicating that multi-flagellated propulsion does not necessarily contribute to greater thrust generation, and may have evolved for greater manoeuvrability or sensing. The results from this study have demonstrated the highly coordinated nature of multi-flagellated propulsion and have provided significant insights into the biology of T. foetus. PMID- 24478287 TI - Intrinsic foot muscles have the capacity to control deformation of the longitudinal arch. AB - The human foot is characterized by a pronounced longitudinal arch (LA) that compresses and recoils in response to external load during locomotion, allowing for storage and return of elastic energy within the passive structures of the arch and contributing to metabolic energy savings. Here, we examine the potential for active muscular contribution to the biomechanics of arch deformation and recoil. We test the hypotheses that activation of the three largest plantar intrinsic foot muscles, abductor hallucis, flexor digitorum and quadratus plantae is associated with muscle stretch in response to external load on the foot and that activation of these muscles (via electrical stimulation) will generate sufficient force to counter the deformation of LA caused by the external load. We found that recruitment of the intrinsic foot muscles increased with increasing load, beyond specific load thresholds. Interestingly, LA deformation and muscle stretch plateaued towards the maximum load of 150% body weight, when muscle activity was greatest. Electrical stimulation of the plantar intrinsic muscles countered the deformation that occurred owing to the application of external load by reducing the length and increasing the height of the LA. These findings demonstrate that these muscles have the capacity to control foot posture and LA stiffness and may provide a buttressing effect during foot loading. This active arch stiffening mechanism may have important implications for how forces are transmitted during locomotion and postural activities as well as consequences for metabolic energy saving. PMID- 24478288 TI - Nanohydroxyapatite shape and its potential role in bone formation: an analytical study. AB - Bone cells (osteoblasts) produce a collagen-rich matrix called osteoid, which is mineralized extracellularly by nanosized calcium phosphate (CaP). Synthetically produced CaP nanoparticles (NPs) have great potential for clinical application. However few studies have compared the effect of CaP NPs with different properties, such as shape and aspect ratio, on the survival and behaviour of active bone-producing cells, such as primary human osteoblasts (HOBs). This study aimed to investigate the biocompatibility and ultrastructural effects of two differently shaped hydroxyapatite [Ca10(PO4)6(OH)2] nanoparticles (HA NPs), round (aspect ratio 2.12, AR2) and rice-shaped (aspect ratio 3.79, AR4). The ultrastructural response and initial extracellular matrix (ECM) formation of HOBs to HA NPs were observed, as well as matrix vesicle release. A transmission electron microscopy (TEM)-based X-ray microanalytical technique was used to measure cytoplasmic ion levels, including calcium (Ca), phosphorus (P), sodium (Na) and potassium (K). K/Na ratios were used as a measure of cell viability. Following HA NP stimulation, all measured cytoplasmic ion levels increased. AR2 NPs had a greater osteogenic effect on osteoblasts compared with AR4 NPs, including alkaline phosphatase activity and matrix vesicle release. However, they produced only a moderate increase in intracellular Ca and P levels compared with AR4. This suggests that particular Ca and P concentrations may be required for, or indicative of, optimal osteoblast activity. Cell viability, as measured by Na and K microanalysis, was best maintained in AR2. Initial formation of osteoblast ECM was altered in the presence of either HA NP, and immuno-TEM identified fibronectin and matrilin-3 as two ECM proteins affected. Matrilin-3 is here described for the first time as being expressed by cultured osteoblasts. In summary, this novel and in-depth study has demonstrated that HA NP shape can influence a range of different parameters related to osteoblast viability and activity. PMID- 24478289 TI - Dronedarone: an alternate choice to sotalol and amiodarone in the treatment of atrial fibrillation/flutter in patients who have coronary heart disease. PMID- 24478290 TI - Successful ablation of an incessant ventricular tachycardia in a 3.5 kg infant. PMID- 24478291 TI - Management of acute coronary syndrome in patients with non-valvular atrial fibrillation: results of the European Heart Rhythm Association Survey. AB - Management of patients with non-valvular atrial fibrillation (AF) presenting with an acute coronary syndrome (ACS) may be particularly challenging. Given the lack of sound evidence-based recommendations for the management of such patients, the aim of this European Heart Rhythm Association survey was to provide an insight into current practice in Europe regarding management of these patients. Overall, 41 centres submitted a valid response. The majority of respondents were university hospitals (85%). The survey has shown that the principal aspects of the European Society of Cardiology guidelines on the management of AF, and those on ACS, have been adopted. The survey highlights two important areas of uncertainty regarding the optimal composition and duration of antithrombotic therapy with multiple drugs and the optimal regimen(s) of novel oral anticoagulants in patients with AF and ACS. PMID- 24478292 TI - Females allocate differentially to offspring size and number in response to male effects on female and offspring fitness. AB - Female investment in offspring size and number has been observed to vary with the phenotype of their mate across diverse taxa. Recent theory motivated by these intriguing empirical patterns predicted both positive (differential allocation) and negative (reproductive compensation) effects of mating with a preferred male on female investment. These predictions, however, focused on total reproductive effort and did not distinguish between a response in offspring size and clutch size. Here, we model how specific paternal effects on fitness affect maternal allocation to offspring size and number. The specific mechanism by which males affect the fitness of females or their offspring determines whether and how females allocated differentially. Offspring size is predicted to increase when males benefit offspring survival, but decrease when males increase offspring growth rate. Clutch size is predicted to increase when males contribute to female resources (e.g. with a nuptial gift) and when males increase offspring growth rate. The predicted direction and magnitude of female responses vary with female age, but only when per-offspring paternal benefits decline with clutch size. We conclude that considering specific paternal effects on fitness in the context of maternal life-history trade-offs can help explain mixed empirical patterns of differential allocation and reproductive compensation. PMID- 24478293 TI - Testing optimal foraging theory in a penguin-krill system. AB - Food is heterogeneously distributed in nature, and understanding how animals search for and exploit food patches is a fundamental challenge in ecology. The classic marginal value theorem (MVT) formulates optimal patch residence time in response to patch quality. The MVT was generally proved in controlled animal experiments; however, owing to the technical difficulties in recording foraging behaviour in the wild, it has been inadequately examined in natural predator-prey systems, especially those in the three-dimensional marine environment. Using animal-borne accelerometers and video cameras, we collected a rare dataset in which the behaviour of a marine predator (penguin) was recorded simultaneously with the capture timings of mobile, patchily distributed prey (krill). We provide qualitative support for the MVT by showing that (i) krill capture rate diminished with time in each dive, as assumed in the MVT, and (ii) dive duration (or patch residence time, controlled for dive depth) increased with short-term, dive-scale krill capture rate, but decreased with long-term, bout-scale krill capture rate, as predicted from the MVT. Our results demonstrate that a single environmental factor (i.e. patch quality) can have opposite effects on animal behaviour depending on the time scale, emphasizing the importance of multi-scale approaches in understanding complex foraging strategies. PMID- 24478294 TI - Correlations in fertility across generations: can low fertility persist? AB - Correlations in family size across generations could have a major influence on human population size in the future. Empirical studies have shown that the associations between the fertility of parents and the fertility of children are substantial and growing over time. Despite their potential long-term consequences, intergenerational fertility correlations have largely been ignored by researchers. We present a model of the fertility transition as a cultural process acting on new lifestyles associated with fertility. Differences in parental and social influences on the acquisition of these lifestyles result in intergenerational correlations in fertility. We show different scenarios for future population size based on models that disregard intergenerational correlations in fertility, models with fertility correlations and a single lifestyle, and models with fertility correlations and multiple lifestyles. We show that intergenerational fertility correlations will result in an increase in fertility over time. However, present low-fertility levels may persist if the rapid introduction of new cultural lifestyles continues into the future. PMID- 24478295 TI - Heritable variation in host tolerance and resistance inferred from a wild host parasite system. AB - Hosts have evolved two distinct defence strategies against parasites: resistance (which prevents infection or limit parasite growth) and tolerance (which alleviates the fitness consequences of infection). However, heritable variation in resistance and tolerance and the genetic correlation between these two traits have rarely been characterized in wild host populations. Here, we estimate these parameters for both traits in Leuciscus burdigalensis, a freshwater fish parasitized by Tracheliastes polycolpus. We used a genetic database to construct a full-sib pedigree in a wild L. burdigalensis population. We then used univariate animal models to estimate inclusive heritability (i.e. all forms of genetic and non-genetic inheritance) in resistance and tolerance. Finally, we assessed the genetic correlation between these two traits using a bivariate animal model. We found significant heritability for resistance (H = 17.6%; 95% CI: 7.2-32.2%) and tolerance (H = 18.8%; 95% CI: 4.4-36.1%), whereas we found no evidence for the existence of a genetic correlation between these traits. Furthermore, we confirm that resistance and tolerance are strongly affected by environmental effects. Our results demonstrate that (i) heritable variation exists for parasite resistance and tolerance in wild host populations, and (ii) these traits can evolve independently in populations. PMID- 24478296 TI - Increased temperature variation poses a greater risk to species than climate warming. AB - Increases in the frequency, severity and duration of temperature extremes are anticipated in the near future. Although recent work suggests that changes in temperature variation will have disproportionately greater effects on species than changes to the mean, much of climate change research in ecology has focused on the impacts of mean temperature change. Here, we couple fine-grained climate projections (2050-2059) to thermal performance data from 38 ectothermic invertebrate species and contrast projections with those of a simple model. We show that projections based on mean temperature change alone differ substantially from those incorporating changes to the variation, and to the mean and variation in concert. Although most species show increases in performance at greater mean temperatures, the effect of mean and variance change together yields a range of responses, with temperate species at greatest risk of performance declines. Our work highlights the importance of using fine-grained temporal data to incorporate the full extent of temperature variation when assessing and projecting performance. PMID- 24478297 TI - Interactions between fungi and bacteria influence microbial community structure in the Megachile rotundata larval gut. AB - Recent declines in bee populations coupled with advances in DNA-sequencing technology have sparked a renaissance in studies of bee-associated microbes. Megachile rotundata is an important field crop pollinator, but is stricken by chalkbrood, a disease caused by the fungus Ascosphaera aggregata. To test the hypothesis that some gut microbes directly or indirectly affect the growth of others, we applied four treatments to the pollen provisions of M. rotundata eggs and young larvae: antibacterials, antifungals, A. aggregata spores and a no treatment control. We allowed the larvae to develop, and then used 454 pyrosequencing and quantitative PCR (for A. aggregata) to investigate fungal and bacterial communities in the larval gut. Antifungals lowered A. aggregata abundance but increased the diversity of surviving fungi. This suggests that A. aggregata inhibits the growth of other fungi in the gut through chemical or competitive interaction. Bacterial richness decreased under the antifungal treatment, suggesting that changes in the fungal community caused changes in the bacterial community. We found no evidence that bacteria affect fungal communities. Lactobacillus kunkeei clade bacteria were common members of the larval gut microbiota and exhibited antibiotic resistance. Further research is needed to determine the effect of gut microbes on M. rotundata health. PMID- 24478298 TI - Temperature-responsive release of thyroxine and its environmental adaptation in Australians. AB - The hormone thyroxine that regulates mammalian metabolism is carried and stored in the blood by thyroxine-binding globulin (TBG). We demonstrate here that the release of thyroxine from TBG occurs by a temperature-sensitive mechanism and show how this will provide a homoeostatic adjustment of the concentration of thyroxine to match metabolic needs, as with the hypothermia and torpor of small animals. In humans, a rise in temperature, as in infections, will trigger an accelerated release of thyroxine, resulting in a predictable 23% increase in the concentration of free thyroxine at 39 degrees C. The in vivo relevance of this fever-response is affirmed in an environmental adaptation in aboriginal Australians. We show how two mutations incorporated in their TBG interact in a way that will halve the surge in thyroxine release, and hence the boost in metabolic rate that would otherwise occur as body temperatures exceed 37 degrees C. The overall findings open insights into physiological changes that accompany variations in body temperature, as notably in fevers. PMID- 24478299 TI - Metabolic 'engines' of flight drive genome size reduction in birds. AB - The tendency for flying organisms to possess small genomes has been interpreted as evidence of natural selection acting on the physical size of the genome. Nonetheless, the flight-genome link and its mechanistic basis have yet to be well established by comparative studies within a volant clade. Is there a particular functional aspect of flight such as brisk metabolism, lift production or maneuverability that impinges on the physical genome? We measured genome sizes, wing dimensions and heart, flight muscle and body masses from a phylogenetically diverse set of bird species. In phylogenetically controlled analyses, we found that genome size was negatively correlated with relative flight muscle size and heart index (i.e. ratio of heart to body mass), but positively correlated with body mass and wing loading. The proportional masses of the flight muscles and heart were the most important parameters explaining variation in genome size in multivariate models. Hence, the metabolic intensity of powered flight appears to have driven genome size reduction in birds. PMID- 24478300 TI - Specific non-monotonous interactions increase persistence of ecological networks. AB - The relationship between stability and biodiversity has long been debated in ecology due to opposing empirical observations and theoretical predictions. Species interaction strength is often assumed to be monotonically related to population density, but the effects on stability of ecological networks of non monotonous interactions that change signs have not been investigated previously. We demonstrate that for four kinds of non-monotonous interactions, shifting signs to negative or neutral interactions at high population density increases persistence (a measure of stability) of ecological networks, while for the other two kinds of non-monotonous interactions shifting signs to positive interactions at high population density decreases persistence of networks. Our results reveal a novel mechanism of network stabilization caused by specific non-monotonous interaction types through either increasing stable equilibrium points or reducing unstable equilibrium points (or both). These specific non-monotonous interactions may be important in maintaining stable and complex ecological networks, as well as other networks such as genes, neurons, the internet and human societies. PMID- 24478301 TI - Evolution of a unique anatomical precision in angiosperm leaf venation lifts constraints on vascular plant ecology. AB - The main role of leaf venation is to supply water across the photosynthetic surface to keep stomata open and allow access to atmospheric CO2 despite evaporative demand. The optimal uniform delivery of water occurs when the distance between veins equals the depth of vein placement within the leaf away from the evaporative surface. As presented here, only angiosperms maintain this anatomical optimum across all leaf thicknesses and different habitats, including sheltered environments where this optimization need not be required. Intriguingly, basal angiosperm lineages tend to be underinvested hydraulically; uniformly high optimization is derived independently in the magnoliids, monocots and core eudicots. Gymnosperms and ferns, including available fossils, are limited by their inability to produce high vein densities. The common association of ferns with shaded humid environments may, in part, be a direct evolutionary consequence of their inability to produce hydraulically optimized leaves. Some gymnosperms do approach optimal vein placement, but only by virtue of their ability to produce thick leaves most appropriate in environments requiring water conservation. Thus, this simple anatomical metric presents an important perspective on the evolution and phylogenetic distribution of plant ecologies and further evidence that the vegetative biology of flowering plants-not just their reproductive biology-is unique. PMID- 24478302 TI - Costs of deception and learned resistance in deceptive interactions. AB - The costs that species suffer when deceived are expected to drive learned resistance, although this relationship has seldom been studied experimentally. Flowers that elicit mating behaviour from male insects by mimicking conspecific females provide an ideal system for such investigation. Here, we explore interactions between a sexually deceptive daisy with multiple floral forms that vary in deceptiveness, and the male flies that pollinate it. We show that male pollinators are negatively impacted by the interaction, suffering potential mating costs in terms of their ability and time taken to locate genuine females within deceptive inflorescences. The severity of these costs is determined by the amount of mating behaviour elicited by deceptive inflorescences. However, inexperienced male flies exhibit the ability to learn to discriminate the most deceptive inflorescences as female mimics and subsequently reduce the amount of mating behaviour they exhibit on them with increased exposure. Experienced males, which interact with sexually deceptive forms naturally, exhibit similar patterns of reduced mating behaviour on deceptive inflorescences in multiple populations, indicating that pollinator learning is widespread. As sexually deceptive plants are typically dependent on the elicitation of mating behaviour from male pollinators for pollination, this may result in antagonistic coevolution within these systems. PMID- 24478303 TI - Common-garden studies on adaptive radiation of photosynthetic physiology among Hawaiian lobeliads. AB - Species in an adaptive radiation often occupy different habitats so that individuals of each species develop under different conditions. Showing that a radiation is adaptive thus requires evidence that taxa have diverged genetically and that each has an ecological advantage in using particular habitats or resources, taking into account both phenotypic plasticity and phylogenetic relationships among species. Here, we use a common-garden experiment to show that representative species of Hawaiian lobeliads have diverged adaptively in their leaf-level photosynthetic light responses. Across species, plants genetically shifted their photosynthetic physiology with native light regime in accord with theoretical predictions and exhibited adaptive crossover in net carbon gain-that is, species native to a given light regime outperformed others only under conditions similar to those they occupy in the field, with the rank order of species based on photosynthesis per unit leaf mass changing with light level. These findings make a powerful case for adaptation of photosynthetic light responses to native light regimes and, combined with our earlier field studies, provide the strongest demonstration to date for the evolution of divergent adaptations for energy capture in any group of closely related plants. PMID- 24478304 TI - Links between plant species' spatial and temporal responses to a warming climate. AB - To generate realistic projections of species' responses to climate change, we need to understand the factors that limit their ability to respond. Although climatic niche conservatism, the maintenance of a species's climatic niche over time, is a critical assumption in niche-based species distribution models, little is known about how universal it is and how it operates. In particular, few studies have tested the role of climatic niche conservatism via phenological changes in explaining the reported wide variance in the extent of range shifts among species. Using historical records of the phenology and spatial distribution of British plants under a warming climate, we revealed that: (i) perennial species, as well as those with weaker or lagged phenological responses to temperature, experienced a greater increase in temperature during flowering (i.e. failed to maintain climatic niche via phenological changes); (ii) species that failed to maintain climatic niche via phenological changes showed greater northward range shifts; and (iii) there was a complementary relationship between the levels of climatic niche conservatism via phenological changes and range shifts. These results indicate that even species with high climatic niche conservatism might not show range shifts as instead they track warming temperatures during flowering by advancing their phenology. PMID- 24478305 TI - Rapid increase in southern elephant seal genetic diversity after a founder event. AB - Genetic diversity provides the raw material for populations to respond to changing environmental conditions. The evolution of diversity within populations is based on the accumulation of mutations and their retention or loss through selection and genetic drift, while migration can also introduce new variation. However, the extent to which population growth and sustained large population size can lead to rapid and significant increases in diversity has not been widely investigated. Here, we assess this empirically by applying approximate Bayesian computation to a novel ancient DNA dataset that spans the life of a southern elephant seal (Mirounga leonina) population, from initial founding approximately 7000 years ago to eventual extinction within the past millennium. We find that rapid population growth and sustained large population size can explain substantial increases in population genetic diversity over a period of several hundred generations, subsequently lost when the population went to extinction. Results suggest that the impact of diversity introduced through migration was relatively minor. We thus demonstrate, by examining genetic diversity across the life of a population, that environmental change could generate the raw material for adaptive evolution over a very short evolutionary time scale through rapid establishment of a large, stable population. PMID- 24478306 TI - Design and verification of the shielding around the new Neutron Standards Laboratory (LPN) at CIEMAT. AB - The construction of the new Neutron Standards Laboratory at CIEMAT (Laboratorio de Patrones Neutronicos) has been finalised and is ready to provide service. The facility is an ~8 m*8 m*8 m irradiation vault, following the International Organization for Standardization 8529 recommendations. It relies on several neutron sources: a 5-GBq (5.8* 10(8) s(-1)) (252)Cf source and two (241)Am-Be neutron sources (185 and 11.1 GBq). The irradiation point is located 4 m over the ground level and in the geometrical centre of the room. Each neutron source can be moved remotely from its storage position inside a water pool to the irradiation point. Prior to this, an important task to design the neutron shielding and to choose the most appropriate materials has been developed by the Radiological Security Unit and the Ionizing Radiations Metrology Laboratory. MCNPX was chosen to simulate the irradiation facility. With this information the walls were built with a thickness of 125 cm. Special attention was put on the weak points (main door, air conditioning system, etc.) so that the ambient dose outside the facility was below the regulatory limits. Finally, the Radiation Protection Unit carried out a set of measurements in specific points around the installation with an LB6411 neutron monitor and a Reuter-Stokes high-pressure ion chamber to verify experimentally the results of the simulation. PMID- 24478307 TI - Area dose rate values derived from NaI or LaBr3 spectra. AB - More and more spectrometric systems are being installed in environmental radiation monitoring stations instead of or in addition to dosimetric detectors, because novel spectrometric systems have been developed which do not need any cooling and because the necessary electronics, especially digital multichannel analysers, have become more manageable and more affordable. The advantage of obtaining information about nuclide vectors can justify the operation of a more complex spectroscopic measuring system, but if spectrometers are also used for dose rate measurements in the natural environment, ambient dose equivalent rate values have to be calculated from measured spectra. Different approaches to achieve this goal will be presented in this article. Some practical recommendations will also be presented to avoid known errors. PMID- 24478308 TI - Global and gene-specific DNA methylation across multiple tissues in early infancy: implications for children's health research. AB - An increasing number of population studies are assessing epigenetic variation in relation to early-life outcomes in tissues accessible to epidemiologic researchers. Epigenetic mechanisms are highly tissue specific, however, and it is unclear whether the variation observed in one of the tissue types is representative of other sources or whether the variation in DNA methylation is distinct, reflecting potential functional differences across tissues. To assess relations between DNA methylation in various samples from newborns and children in early infancy, we measured promoter or gene-body DNA methylation in matched term placenta, cord blood, and 3-6 mo saliva samples from 27 unrelated infants enrolled in the Rhode Island Child Health Study. We investigated 7 gene loci (KLF15, NR3C1, LEP, DEPTOR, DDIT4, HSD11B2, and CEBPB) and global methylation, using repetitive region LINE-1 and ALUYb8 sequences. We observed a great degree of interlocus, intertissue, and interindividual epigenetic variation in most of the analyzed loci. In correlation analyses, only cord blood NR3C1 promoter methylation correlated negatively with methylation in saliva. We conclude that placenta, cord blood, and saliva cannot be used as a substitute for one another to evaluate DNA methylation at these loci during infancy. Each tissue has a unique epigenetic signature that likely reflects their differential functions. Future studies should consider the uniqueness of these features, to improve epigenetic biomarker discovery and translation. PMID- 24478309 TI - Functional swapping between transmembrane proteins TMEM16A and TMEM16F. AB - The transmembrane proteins TMEM16A and -16F each carry eight transmembrane regions with cytoplasmic N and C termini. TMEM16A carries out Ca(2+)-dependent Cl(-) ion transport, and TMEM16F is responsible for Ca(2+)-dependent phospholipid scrambling. Here we established assay systems for the Ca(2+)-dependent Cl(-) channel activity using 293T cells and for the phospholipid scramblase activity using TMEM16F(-/-) immortalized fetal thymocytes. Chemical cross-linking analysis showed that TMEM16A and -16F form homodimers in both 293T cells and immortalized fetal thymocytes. Successive deletion from the N or C terminus of both proteins and the swapping of regions between TMEM16A and -16F indicated that their cytoplasmic N-terminal (147 amino acids for TMEM16A and 95 for 16F) and C terminal (88 amino acids for TMEM16A and 68 for 16F) regions were essential for their localization at plasma membranes and protein stability, respectively, and could be exchanged. Analyses of TMEM16A and -16F mutants with point mutations in the pore region (located between the fifth and sixth transmembrane regions) indicated that the pore region is essential for both the Cl(-) channel activity of TMEM16A and the phospholipid scramblase activity of TMEM16F. Some chemicals such as epigallocatechin-3-gallate and digallic acid inhibited the Cl(-) channel activity of TMEM16A and the scramblase activity of TMEM16F with an opposite preference. These results indicate that TMEM16A and -16F use a similar mechanism for sorting to plasma membrane and protein stabilization, but their functional domains significantly differ. PMID- 24478310 TI - Claudin-3 and claudin-5 protein folding and assembly into the tight junction are controlled by non-conserved residues in the transmembrane 3 (TM3) and extracellular loop 2 (ECL2) segments. AB - The mechanism of tight junction (TJ) assembly and the structure of claudins (Cldn) that form the TJ strands are unclear. This limits the molecular understanding of paracellular barriers and strategies for drug delivery across tissue barriers. Cldn3 and Cldn5 are both common in the blood-brain barrier but form TJ strands with different ultrastructures. To identify the molecular determinants of folding and assembly of these classic claudins, Cldn3/Cldn5 chimeric mutants were generated and analyzed by cellular reconstitution of TJ strands, live cell confocal imaging, and freeze-fracture electron microscopy. A comprehensive screening was performed on the basis of the rescue of mutants deficient for strand formation. Cldn3/Cldn5 residues in transmembrane segment 3, TM3 (Ala-127/Cys-128, Ser-136/Cys-137, Ser-138/Phe-139), and the transition of TM3 to extracellular loop 2, ECL2 (Thr-141/Ile-142) and ECL2 (Asn-148/Asp-149, Leu-150/Thr-151, Arg-157/Tyr-158), were identified to be involved in claudin folding and/or assembly. Blue native PAGE and FRET assays revealed 1% n-dodecyl beta-d-maltoside-resistant cis-dimerization for Cldn5 but not for Cldn3. This homophilic interaction was found to be stabilized by residues in TM3. The resulting subtype-specific cis-dimer is suggested to be a subunit of polymeric TJ strands and contributes to the specific ultrastructure of the TJ detected by freeze-fracture electron microscopy. In particular, the Cldn5-like exoplasmic face-associated and particle-type strands were found to be related to cis dimerization. These results provide new insight into the mechanisms of paracellular barrier formation by demonstrating that defined non-conserved residues in TM3 and ECL2 of classic claudins contribute to the formation of TJ strands with differing ultrastructures. PMID- 24478311 TI - Determinants of RNA binding and translational repression by the Bicaudal-C regulatory protein. AB - Bicaudal-C (Bic-C) RNA binding proteins function as important translational repressors in multiple biological contexts within metazoans. However, their RNA binding sites are unknown. We recently demonstrated that Bic-C functions in spatially regulated translational repression of the xCR1 mRNA during Xenopus development. This repression contributes to normal development by confining the xCR1 protein, a regulator of key signaling pathways, to specific cells of the embryo. In this report, we combined biochemical approaches with in vivo mRNA reporter assays to define the minimal Bic-C target site within the xCR1 mRNA. This 32-nucleotide Bic-C target site is predicted to fold into a stem-loop secondary structure. Mutational analyses provided evidence that this stem-loop structure is important for Bic-C binding. The Bic-C target site was sufficient for Bic-C mediated repression in vivo. Thus, we describe the first RNA binding site for a Bic-C protein. This identification provides an important step toward understanding the mechanisms by which evolutionarily conserved Bic-C proteins control cellular function in metazoans. PMID- 24478312 TI - Structure of a PL17 family alginate lyase demonstrates functional similarities among exotype depolymerases. AB - Brown macroalgae represent an ideal source for complex polysaccharides that can be utilized as precursors for cellulosic biofuels. The lack of recalcitrant lignin components in macroalgae polysaccharide reserves provides a facile route for depolymerization of constituent polysaccharides into simple monosaccharides. The most abundant sugars in macroalgae are alginate, mannitol, and glucan, and although several classes of enzymes that can catabolize the latter two have been characterized, studies of alginate-depolymerizing enzymes have lagged. Here, we present several crystal structures of Alg17c from marine bacterium Saccharophagus degradans along with structure-function characterization of active site residues that are suggested to be involved in the exolytic mechanism of alginate depolymerization. This represents the first structural and biochemical characterization of a family 17 polysaccharide lyase enzyme. Despite the lack of appreciable sequence conservation, the structure and beta-elimination mechanism for glycolytic bond cleavage by Alg17c are similar to those observed for family 15 polysaccharide lyases and other lyases. This work illuminates the evolutionary relationships among enzymes within this unexplored class of polysaccharide lyases and reinforces the notion of a structure-based hierarchy in the classification of these enzymes. PMID- 24478313 TI - Proteolytic histone modification by mast cell tryptase, a serglycin proteoglycan dependent secretory granule protease. AB - A hallmark feature of mast cells is their high content of cytoplasmic secretory granules filled with various preformed compounds, including proteases of tryptase , chymase-, and carboxypeptidase A3 type that are electrostatically bound to serglycin proteoglycan. Apart from participating in extracellular processes, serglycin proteoglycan and one of its associated proteases, tryptase, are known to regulate cell death by promoting apoptosis over necrosis. Here we sought to outline the underlying mechanism and identify core histones as primary proteolytic targets for the serglycin-tryptase axis. During the cell death process, tryptase was found to relocalize from granules into the cytosol and nucleus, and it was found that the absence of tryptase was associated with a pronounced accumulation of core histones both in the cytosol and in the nucleus. Intriguingly, tryptase deficiency resulted in defective proteolytic modification of core histones even at baseline conditions, i.e. in the absence of cytotoxic agent, suggesting that tryptase has a homeostatic impact on nuclear events. Indeed, tryptase was found in the nucleus of viable cells and was shown to cleave core histones in their N-terminal tail. Moreover, it was shown that the absence of the serglycin-tryptase axis resulted in altered chromatin composition. Together, these findings implicate histone proteolysis through a secretory granule-derived serglycin-tryptase axis as a novel principle for histone modification, during both cell homeostasis and cell death. PMID- 24478314 TI - A remodeled protein arginine methyltransferase 1 (PRMT1) generates symmetric dimethylarginine. AB - Protein arginine methylation is emerging as a significant post-translational modification involved in various cell processes and human diseases. As the major arginine methylation enzyme, protein arginine methyltransferase 1 (PRMT1) strictly generates monomethylarginine and asymmetric dimethylarginine (ADMA), but not symmetric dimethylarginine (SDMA). The two types of dimethylarginines can lead to distinct biological outputs, as highlighted in the PRMT-dependent epigenetic control of transcription. However, it remains unclear how PRMT1 product specificity is regulated. We discovered that a single amino acid mutation (Met-48 to Phe) in the PRMT1 active site enables PRMT1 to generate both ADMA and SDMA. Due to the limited amount of SDMA formed, we carried out quantum mechanical calculations to determine the free energies of activation of ADMA and SDMA synthesis. Our results indicate that the higher energy barrier of SDMA formation (DeltaDeltaG(?) = 3.2 kcal/mol as compared with ADMA) may explain the small amount of SDMA generated by M48F-PRMT1. Our study reveals unique energetic challenges for SDMA-forming methyltransferases and highlights the exquisite control of product formation by active site residues in the PRMTs. PMID- 24478315 TI - Sterol regulatory element-binding protein (SREBP) cleavage regulates Golgi-to endoplasmic reticulum recycling of SREBP cleavage-activating protein (SCAP). AB - Sterol regulatory element-binding protein (SREBP) transcription factors are central regulators of cellular lipogenesis. Release of membrane-bound SREBP requires SREBP cleavage-activating protein (SCAP) to escort SREBP from the endoplasmic reticulum (ER) to the Golgi for cleavage by site-1 and site-2 proteases. SCAP then recycles to the ER for additional rounds of SREBP binding and transport. Mechanisms regulating ER-to-Golgi transport of SCAP-SREBP are understood in molecular detail, but little is known about SCAP recycling. Here, we have demonstrated that SCAP Golgi-to-ER transport requires cleavage of SREBP at site-1. Reductions in SREBP cleavage lead to SCAP degradation in lysosomes, providing additional negative feedback control to the SREBP pathway. Current models suggest that SREBP plays a passive role prior to cleavage. However, we show that SREBP actively prevents premature recycling of SCAP-SREBP until initiation of SREBP cleavage. SREBP regulates SCAP in human cells and yeast, indicating that this is an ancient regulatory mechanism. PMID- 24478316 TI - Calcium regulates molecular interactions of otoferlin with soluble NSF attachment protein receptor (SNARE) proteins required for hair cell exocytosis. AB - Mutations in otoferlin, a C2 domain-containing ferlin family protein, cause non syndromic hearing loss in humans (DFNB9 deafness). Furthermore, transmitter secretion of cochlear inner hair cells is compromised in mice lacking otoferlin. In the present study, we show that the C2F domain of otoferlin directly binds calcium (KD = 267 MUM) with diminished binding in a pachanga (D1767G) C2F mouse mutation. Calcium was found to differentially regulate binding of otoferlin C2 domains to target SNARE (t-SNARE) proteins and phospholipids. C2D-F domains interact with the syntaxin-1 t-SNARE motif with maximum binding within the range of 20-50 MUM Ca(2+). At 20 MUM Ca(2+), the dissociation rate was substantially lower, indicating increased binding (KD = ~10(-9)) compared with 0 MUM Ca(2+) (KD = ~10(-8)), suggesting a calcium-mediated stabilization of the C2 domain.t-SNARE complex. C2A and C2B interactions with t-SNAREs were insensitive to calcium. The C2F domain directly binds the t-SNARE SNAP-25 maximally at 100 MUM and with reduction at 0 MUM Ca(2+), a pattern repeated for C2F domain interactions with phosphatidylinositol 4,5-bisphosphate. In contrast, C2F did not bind the vesicle SNARE protein synaptobrevin-1 (VAMP-1). Moreover, an antibody targeting otoferlin immunoprecipitated syntaxin-1 and SNAP-25 but not synaptobrevin-1. As opposed to an increase in binding with increased calcium, interactions between otoferlin C2F domain and intramolecular C2 domains occurred in the absence of calcium, consistent with intra-C2 domain interactions forming a "closed" tertiary structure at low calcium that "opens" as calcium increases. These results suggest a direct role for otoferlin in exocytosis and modulation of calcium-dependent membrane fusion. PMID- 24478317 TI - Platelet-activating factor contributes to Bacillus anthracis lethal toxin associated damage. AB - The lethal toxin (LeTx) of Bacillus anthracis plays a central role in the pathogenesis of anthrax-associated shock. Platelet-activating factor (PAF) is a potent lipid mediator that has been implicated in endotoxin-associated shock. In this study, we examined the contribution of PAF to the manifestations of lethal toxin challenge in WT mice. LeTx challenge resulted in transient increase in serum PAF levels and a concurrent decrease in PAF acetylhydrolase activity. Inhibition of PAF activity using PAF antagonists or toxin challenge of PAF receptor negative mice reversed or ameliorated many of the pathologic features of LeTx-induced damage, including changes in vascular permeability, hepatic necrosis, and cellular apoptosis. In contrast, PAF inhibition had minimal effects on cytokine levels. Findings from these studies support the continued study of PAF antagonists as potential adjunctive agents in the treatment of anthrax associated shock. PMID- 24478318 TI - Clinical benefit of continuing ALK inhibition with crizotinib beyond initial disease progression in patients with advanced ALK-positive NSCLC. AB - BACKGROUND: Crizotinib is approved to treat advanced ALK-positive non-small-cell lung cancer (NSCLC), but most patients ultimately develop progressive disease (PD). We investigated whether continuing ALK inhibition with crizotinib beyond PD (CBPD) is clinically beneficial and attempted to identify clinicopathologic characteristics associated with patients who experience clinical benefit. PATIENTS AND METHODS: Patients with advanced ALK-positive NSCLC enrolled in two ongoing multicenter, single-arm trials who developed RECIST-defined PD were allowed to continue crizotinib if they were deriving ongoing clinical benefit. In the present retrospective analysis, continuation of CBPD was defined as >3 weeks of crizotinib treatment after PD documentation. Patients who had PD as best response to initial crizotinib treatment were excluded. Baseline and post progression characteristics, sites of PD, and overall survival (OS) were compared in patients who continued CBPD versus those who did not. The impact of continuing CBPD on OS after adjusting for potential confounding factors was assessed. RESULTS: Among 194 crizotinib-treated patients with RECIST-defined PD, 120 (62%) continued CBPD. A significantly higher proportion of patients who continued CBPD than patients who did not had an ECOG performance status (PS) of 0/1 at PD (96% versus 82%; P=0.02). CBPD patients had significantly longer OS from the time of PD [median 16.4 versus 3.9 months; hazards ratio (HR) 0.27, 95% confidence interval (CI): 0.17-0.42; P<0.0001] and from the time of initial crizotinib treatment (median 29.6 versus 10.8 months; HR 0.30, 95% CI: 0.19-0.46; P<0.0001). The multiple-covariate Cox regression analysis revealed that CBPD remained significantly associated with improved OS after adjusting for relevant factors. CONCLUSIONS: Patients who continued CBPD were more likely to have good ECOG PS (0/1) at the time of PD. Continuing ALK inhibition with crizotinib after PD may provide survival benefit to patients with advanced ALK-positive NSCLC. PMID- 24478319 TI - Poor response to erlotinib in patients with tumors containing baseline EGFR T790M mutations found by routine clinical molecular testing. AB - BACKGROUND: EGFR T790M is the most common mutation associated with acquired resistance to EGFR tyrosine kinase inhibitors (TKIs). Baseline EGFR T790M mutations in EGFR TKI-naive patients have been reported, but the frequency and their association with response to EGFR TKIs remain unclear. PATIENTS AND METHODS: The frequency of baseline EGFR T790M as detected by routine molecular genotyping was determined by reviewing clinical results obtained at our institution from 2009 to 2013. We also collected outcome data for treatment with EGFR TKIs. RESULTS: To define the incidence of EGFR T790M, we reviewed 2774 sequentially tested patients with lung cancer who underwent molecular testing using a mass spectrometry-based assay, and 11 (0.5%) had baseline EGFR T790M. Compiling results from several molecular techniques, we observed EGFR T790M in tumors from 20 patients who had not previously been treated with an EGFR TKI. In all cases, EGFR T790M occurred concurrently with another EGFR mutation, L858R (80%, 16/20), or exon 19 deletion (20%, 4/20). Two percent of all pre-treatment EGFR-mutant lung cancers harbored an EGFR T790M mutation. Thirteen patients received erlotinib monotherapy as treatment for metastatic disease. The response rate was 8% (1/13, 95% confidence interval 0%-35%). For the patients who received erlotinib, the median progression-free survival was 2 months and the median overall survival was 16 months. CONCLUSIONS: De novo EGFR T790M mutations are rare (<1%) when identified by standard sensitivity methods. TKI therapy for patients with baseline EGFR T790M detected by standard molecular analysis has limited benefit. PMID- 24478320 TI - Improved outcomes in elderly patients with metastatic castration-resistant prostate cancer treated with the androgen receptor inhibitor enzalutamide: results from the phase III AFFIRM trial. AB - BACKGROUND: The randomized, double-blind phase III AFFIRM trial demonstrated that enzalutamide, an oral androgen receptor inhibitor, significantly prolonged overall survival (OS) [median 18.4 versus 13.6 months (hazard ratio, HR) 0.63 (95% confidence interval, CI, 0.53-0.75); P<0.001] compared with placebo in patients with metastatic castration-resistant prostate cancer who received prior docetaxel chemotherapy. PATIENTS AND METHODS: A post hoc analysis was carried out to assess the efficacy and safety of enzalutamide on outcomes in younger (<75 years) and elderly (>=75 years) patients in the AFFIRM population. Statistics are presented by age group (<75 years, >=75 years) for efficacy outcomes of OS, radiographic progression-free survival (rPFS), time to prostate-specific antigen (PSA) progression, PSA response, and safety. RESULTS: OS was significantly improved with enzalutamide over placebo in patients<75 years [median not yet reached versus 13.6 months; HR 0.63 (95% CI 0.52-0.78), P<0.001] and in patients >=75 years [median 18.2 versus 13.3 months; HR 0.61 (95% CI 0.43-0.86), P=0.004], respectively. rPFS was similarly improved in both the younger [HR 0.45 (95% CI 0.38-0.53), P<0.001] and elderly patient cohorts [HR 0.27 (95% CI 0.20-0.37), P<0.001] relative to placebo, as were time to PSA progression and PSA response. Adverse events (AEs) were similar between the two enzalutamide age groups, with the exception of an increase in patients>=75 years in the rates of all grade peripheral edema (22.1% versus 12.5%), fatigue (39.7% versus 31.6%), and diarrhea (26.6% versus 19.6%). The overall grade>=3 AE rates were low with no major difference in frequency or severity between age groups or treatment arms. Five patients were reported with seizure events; three patients<75 years and two patients >=75 years. CONCLUSIONS: Enzalutamide significantly improves outcomes in both younger (<75 years) and elderly patients (>=75 years), with comparable safety and tolerability. PMID- 24478321 TI - Preference for involvement in treatment decisions and request for prognostic information in newly diagnosed patients with higher-risk myelodysplastic syndromes. AB - BACKGROUND: The main objective of this study was to assess preferences for involvement in treatment decisions and requests for prognostic information in newly diagnosed higher-risk myelodysplastic syndrome (MDS) patients. PATIENT AND METHODS: This was a prospective cohort observational study that consecutively enrolled MDS patients with an international prognostic scoring system (IPSS) risk category of intermediate-2 or high risk (summarized as 'higher risk'). The control preference scale was used to assess patient preferences for involvement in treatment decisions, and whether a request by patients for prognostic information during consultation was made, was also recorded. All of the patients were surveyed at the time of diagnosis before receiving treatment. Univariate and multivariate analyses were carried out to assess how sociodemographic, clinical and laboratory data related to decision-making preferences and requests for prognostic information. Relationship with the health-related quality of life (HRQOL) profile was also examined. RESULTS: A total of 280 patients were enrolled, 74% with intermediate-2 and 26% with high-risk IPSS. The mean age of patients was 70-year old (range: 32-89 years). One hundred thirty-two patients (47%) favored a passive role in treatment decision-making, whereas only 14% favored an active role. The remaining 39% of patients favored a shared decision making approach. Patients with lower hemoglobin levels were more likely to prefer a passive role (P=0.037). HRQOL was generally better in patients preferring an active role versus those preferring a passive one. Overall, 61% (N=171) of patients requested prognostic information on survival during consultation. The likelihood of not requesting prognostic information was higher for older patients (P = 0.003) and for those with lower education (P=0.010). CONCLUSION: Decision making preferences vary among patients with newly diagnosed higher-risk MDS. Current findings suggest that patients with worse underlying health conditions are more likely to prefer less involvement in treatment decisions. PMID- 24478322 TI - Effect of adding gemtuzumab ozogamicin to induction chemotherapy for newly diagnosed acute myeloid leukemia: a meta-analysis of prospective randomized phase III trials. AB - BACKGROUND: Gemtuzumab ozogamicin (GO) is a targeted antineoplastic agent comprised of a recombinant anti-CD33 humanized antibody linked to calicheamicin. Previous trials have showed conflicting results concerning the efficacy and toxicity of adding GO to induction chemotherapy for newly diagnosed acute myeloid leukemia (AML). A systematic review and meta-analysis was conducted to resolve this controversial issue. PATIENTS AND METHODS: Summary data from five randomized phase III trials compared adding GO to induction chemotherapy with induction chemotherapy alone for newly diagnosed AML were meta-analyzed. Pooled hazard ratios (HRs) and 95% confidence intervals (CIs) for overall survival (OS) and relapse-free survival (RFS), and pooled odds ratios (ORs) and 95% CIs for complete remission (CR) rate, incidences of resistance disease, relapse and toxicity were calculated. RESULTS: Data of 3596 patients (1798 GO and 1798 controls) from five randomized phase III trials were analyzed. Compared with induction chemotherapy alone, adding GO significantly prolonged OS (HR 0.93, 95% CI 0.86-1.00, P=0.05) and RFS (HR 0.87, 95% CI 0.79-0.95, P=0.003), decreased the incidences of resistant disease (OR 0.71, 95% CI 0.55-0.93, P=0.01) and relapse (OR 0.75, 95% CI 0.63-0.90, P=0.002), but had no effect on CR rate (OR 1.15, 95% CI 0.91-1.46, P=0.24). Sensitivity analysis yielded similar results. Subgroup analysis identified that cytogenetics might be an influencing factor for the effect of adding GO. In addition, the risks of grade 3-4 nausea/vomiting, diarrhea and liver aspartate transaminase (AST) elevation were increased in GO arm. CONCLUSIONS: Adding GO to induction chemotherapy for newly diagnosed AML can significantly prolong OS and RFS, decrease incidences of resistant disease and relapse, but may increase risks of grade 3-4 nausea/vomiting, diarrhea and liver AST elevation. PMID- 24478323 TI - Exercise program improves therapy-related side-effects and quality of life in lymphoma patients undergoing therapy. AB - BACKGROUND: Lymphoma patients undergoing therapy must cope with the side-effects of the disease itself, therapy and associated immobility. Peripheral neuropathy (PNP), loss of balance control and weakness not only diminishes patients' quality of life (QOL), it can also affect planning and the dosage of therapy. Exercise may enable patients to reverse these declines, improving their performance level and QOL. PATIENTS AND METHODS: We carried out a randomized, controlled trial, assigning 61 lymphoma patients either to a control group (CG; N=31) or to a 36 week intervention (IG; N=30), consisting of sensorimotor-, endurance- and strength training twice a week. Primary end point was QOL; secondary end points included movement coordination, endurance, strength and therapy-induced side effects. RESULTS: Intergroup comparison revealed improved QOL- (DeltaT1-T0; P=0.03) and PNP-related deep sensitivity in the IG: 87.5% were able to reduce the symptom, compared with 0% in the CG (P<0.001). Significant differences in the change of balance control could be found between the groups, with the IG improving while the CG steadily declined (monopedal static DeltaT3-T0; P=0.03; dynamic DeltaT3-T0; P=0.007; perturbed mono-DeltaT3-T0; P=0.009 and bipedal DeltaT3-T0; P=0.006), failed attempts (monopedal static DeltaT3-T0; P=0.02, dynamic DeltaT3-T0; P<0.001and perturbed DeltaT3-T0; P=0.006) and improved time to regain balance (DeltaT3-T0; P=0.04). Moreover, the change in the aerobic performance level (DeltaT3-T0; P=0.05) and additional amount of exercise carried out per week [metabolic equivalent (MET); P=0.02] differed significantly across groups. CONCLUSIONS: Exercise, especially sensorimotor training, is a feasible and promising method to support cancer patients during therapy. It improves patients QOL, reduces restrictions from side-effects such as PNP and improves patients' balance control, physical performance level and mobility. GERMAN CLINICAL TRIALS REGISTER NUMBER: DRKS00003894. PMID- 24478324 TI - Not only chemotherapy in the second-line treatment of metastatic gastric cancer. PMID- 24478327 TI - An exophytic mass on the mandible of an immunocompromised man. PMID- 24478326 TI - Early life stress modulates oxytocin effects on limbic system during acute psychosocial stress. AB - Early life stress (ELS) is associated with altered stress responsivity, structural and functional brain changes and an increased risk for the development of psychopathological conditions in later life. Due to its behavioral and physiological effects, the neuropeptide oxytocin (OXT) is a useful tool to investigate stress responsivity, even though the neurobiological underpinnings of its effects are still unknown. Here we investigate the effects of OXT on cortisol stress response and neural activity during psychosocial stress. Using functional magnetic resonance imaging in healthy subjects with and without a history of ELS, we found attenuated hormonal reactivity and significantly reduced limbic deactivation after OXT administration in subjects without a history of ELS. Subjects who experienced ELS showed both blunted stress reactivity and limbic deactivation during stress. Furthermore, in these subjects OXT had opposite effects with increased hormonal reactivity and increased limbic deactivation. Our results might implicate that reduced limbic deactivation and hypothalamic pituitary-adrenal axis responsivity during psychosocial stress are markers for biological resilience after ELS. Effects of OXT in subjects with a history of maltreatment could therefore be considered detrimental and suggest careful consideration of OXT administration in such individuals. PMID- 24478330 TI - 3' end formation of pre-mRNA and phosphorylation of Ser2 on the RNA polymerase II CTD are reciprocally coupled in human cells. AB - 3' end formation of pre-mRNAs is coupled to their transcription via the C terminal domain (CTD) of RNA polymerase II (Pol II). Nearly all protein-coding transcripts are matured by cleavage and polyadenylation (CPA), which is frequently misregulated in disease. Understanding how transcription is coordinated with CPA in human cells is therefore very important. We found that the CTD is heavily phosphorylated on Ser2 (Ser2p) at poly(A) (pA) signals coincident with recruitment of the CstF77 CPA factor. Depletion of the Ser2 kinase Cdk12 impairs Ser2p, CstF77 recruitment, and CPA, strongly suggesting that the processes are linked, as they are in budding yeast. Importantly, we additionally show that the high Ser2p signals at the 3' end depend on pA signal function. Down-regulation of CPA results in the loss of a 3' Ser2p peak, whereas a new peak is formed when CPA is induced de novo. Finally, high Ser2p signals are generated by Pol II pausing, which is a well-known feature of pA site recognition. Thus, a reciprocal relationship between early steps in pA site processing and Ser2p ensures efficient 3' end formation. PMID- 24478332 TI - Response to: 'Paying attention to arbitrary causality and the preciseness of conclusion' by Lei et al. PMID- 24478331 TI - Restricted expression of cdc25a in the tailbud is essential for formation of the zebrafish posterior body. AB - The vertebrate body forms from a multipotent stem cell-like progenitor population that progressively contributes newly differentiated cells to the most posterior end of the embryo. How the progenitor population balances proliferation and other cellular functions is unknown due to the difficulty of analyzing cell division in vivo. Here, we show that proliferation is compartmentalized at the posterior end of the embryo during early zebrafish development by the regulated expression of cdc25a, a key controller of mitotic entry. Through the use of a transgenic line that misexpresses cdc25a, we show that this compartmentalization is critical for the formation of the posterior body. Upon misexpression of cdc25a, several essential T-box transcription factors are abnormally expressed, including Spadetail/Tbx16, which specifically prevents the normal onset of myoD transcription, leading to aberrant muscle formation. Our results demonstrate that compartmentalization of proliferation during early embryogenesis is critical for both extension of the vertebrate body and differentiation of the multipotent posterior progenitor cells to the muscle cell fate. PMID- 24478333 TI - Sildenafil improves exercise hemodynamics in Fontan patients. AB - BACKGROUND: Patients with Fontan circulation have reduced exercise capacity. The absence of a presystemic pump may limit flow through the pulmonary circulation, restricting ventricular filling and cardiac output. We evaluated exercise hemodynamics and the effect of sildenafil on exercise hemodynamics in Fontan patients. METHODS AND RESULTS: Ten Fontan patients (6 men, 20+/-4 years) underwent cardiac magnetic resonance imaging at rest and during supine bicycle exercise before and after sildenafil. Systemic ventricular volumes were obtained at rest and during low- (34+/-15 W), moderate- (69+/-29 W), and high-intensity (97+/-36 W) exercise using an ungated, free-breathing cardiac magnetic resonance sequence and analyzed correcting for cardiac phase and respiratory translation. Radial and pulmonary artery pressures and cGMP were measured. Before sildenafil, cardiac index increased throughout exercise (4.0+/-0.9, 5.9+/-1.1, 7.0+/-1.6, 7.4+/-1.7 L/(min.m(2)); P<0.0001) with 106+/-49% increase in heart rate. Stroke volume index (P=0.015) and end-diastolic volume index (P=0.001) decreased during exercise. End-systolic volume index remained unchanged (P=0.8). Total pulmonary resistance index (P=0.005) increased, whereas systemic vascular resistance index decreased during exercise (P<0.0001). Sildenafil increased cardiac index (P<0.0001) and stroke volume index (P=0.003), especially at high-intensity exercise (interaction P=0.004 and P=0.003, respectively). Systemic vascular resistance index was reduced (P<0.0001-interaction P=0.1), whereas total pulmonary resistance index was reduced at rest and reduced further during exercise (P=0.008-interaction P=0.029). cGMP remained unchanged before sildenafil (P=0.9), whereas it increased significantly after sildenafil (P=0.019). CONCLUSIONS: In Fontan patients, sildenafil improved cardiac index during exercise with a decrease in total pulmonary resistance index and an increase in stroke volume index. This implies that pulmonary vasculature represents a physiological limitation, which can be attenuated by sildenafil, the clinical significance of which warrants further study. PMID- 24478334 TI - Deletion of yes-associated protein (YAP) specifically in cardiac and vascular smooth muscle cells reveals a crucial role for YAP in mouse cardiovascular development. AB - RATIONALE: Our previous study has shown that yes-associated protein (YAP) plays a crucial role in the phenotypic modulation of vascular smooth muscle cells (SMCs) in response to arterial injury. However, the role of YAP in vascular SMC development is unknown. OBJECTIVE: The goal of this study was to investigate the functional role of YAP in cardiovascular development in mice and determine the mechanisms underlying YAP's actions. METHODS AND RESULTS: YAP was deleted in cardiomyocytes and vascular SMCs by crossing YAP flox mice with SM22alpha-Cre transgenic mice. Cardiac/SMC-specific deletion of YAP directed by SM22alpha-Cre resulted in perinatal lethality in mice because of profound cardiac defects including hypoplastic myocardium, membranous ventricular septal defect, and double outlet right ventricle. The cardiac/SMC-specific YAP knockout mice also displayed severe vascular abnormalities including hypoplastic arterial wall, short/absent brachiocephalic artery, and retroesophageal right subclavian artery. Deletion of YAP in mouse vascular SMCs induced expression of a subset of cell cycle arrest genes including G-protein-coupled receptor 132 (Gpr132). Silencing Gpr132 promoted SMC proliferation, whereas overexpression of Gpr132 attenuated SMC growth by arresting cell cycle in G0/G1 phase, suggesting that ablation of YAP-induced impairment of SMC proliferation was mediated, at least in part, by induction of Gpr132 expression. Mechanistically, YAP recruited the epigenetic repressor histone deacetylase-4 to suppress Gpr132 gene expression via a muscle CAT element in the Gpr132 gene. CONCLUSIONS: YAP plays a critical role in cardiac/SMC proliferation during cardiovascular development by epigenetically regulating expression of a set of cell cycle suppressors. PMID- 24478335 TI - Highly specific and efficient CRISPR/Cas9-catalyzed homology-directed repair in Drosophila. AB - We and others recently demonstrated that the readily programmable CRISPR/Cas9 system can be used to edit the Drosophila genome. However, most applications to date have relied on aberrant DNA repair to stochastically generate frameshifting indels and adoption has been limited by a lack of tools for efficient identification of targeted events. Here we report optimized tools and techniques for expanded application of the CRISPR/Cas9 system in Drosophila through homology directed repair (HDR) with double-stranded DNA (dsDNA) donor templates that facilitate complex genome engineering through the precise incorporation of large DNA sequences, including screenable markers. Using these donors, we demonstrate the replacement of a gene with exogenous sequences and the generation of a conditional allele. To optimize efficiency and specificity, we generated transgenic flies that express Cas9 in the germline and directly compared HDR and off-target cleavage rates of different approaches for delivering CRISPR components. We also investigated HDR efficiency in a mutant background previously demonstrated to bias DNA repair toward HDR. Finally, we developed a web-based tool that identifies CRISPR target sites and evaluates their potential for off target cleavage using empirically rooted rules. Overall, we have found that injection of a dsDNA donor and guide RNA-encoding plasmids into vasa-Cas9 flies yields the highest efficiency HDR and that target sites can be selected to avoid off-target mutations. Efficient and specific CRISPR/Cas9-mediated HDR opens the door to a broad array of complex genome modifications and greatly expands the utility of CRISPR technology for Drosophila research. PMID- 24478336 TI - Discovery of supernumerary B chromosomes in Drosophila melanogaster. AB - B chromosomes are small, heterochromatic chromosomes that are transmitted in a non-Mendelian manner. We have identified a stock of Drosophila melanogaster that recently (within the last decade) acquired an average of 10 B chromosomes per fly. These B chromosomes are transmitted by both males and females and can be maintained for multiple generations in a wild-type genetic background despite the fact that they cause high levels of 4(th) chromosome meiotic nondisjunction in females. Most curiously, these B chromosomes are mitotically unstable, suggesting either the absence of critical chromosomal sites or the inability of the meiotic or mitotic systems to cope with many additional chromosomes. These B chromosomes also contain centromeres and are primarily composed of the heterochromatic AATAT satellite sequence. Although the AATAT sequence comprises the majority of the 4(th) chromosome heterochromatin, the B chromosomes lack most, if not all, 4(th) chromosome euchromatin. Presumably as a consequence of their heterochromatic content, these B chromosomes significantly modify position-effect variegation in two separate reporter systems, acting as enhancers of variegation in one case and suppressors in the other. The identification of B chromosomes in a genetically tractable organism like D. melanogaster will facilitate studies of chromosome evolution and the analysis of the mechanisms by which meiotic and mitotic processes cope with additional chromosomes. PMID- 24478337 TI - Heterochromatin position effects on circularized sex chromosomes cause filicidal embryonic lethality in Drosophila melanogaster. AB - Some circularized X-Y chromosomes in Drosophila melanogaster are mitotically unstable and induce early embryonic lethality, but the genetic basis is unknown. Our experiments suggest that a large region of X-linked satellite DNA causes anaphase bridges and lethality when placed into a new heterochromatic environment within certain circularized X-Y chromosomes. These results reveal that repetitive sequences can be incompatible with one another in cis. The lethal phenotype also bears a remarkable resemblance to a case of interspecific hybrid lethality. PMID- 24478338 TI - PUmPER: phylogenies updated perpetually. AB - SUMMARY: New sequence data useful for phylogenetic and evolutionary analyses continues to be added to public databases. The construction of multiple sequence alignments and inference of huge phylogenies comprising large taxonomic groups are expensive tasks, both in terms of man hours and computational resources. Therefore, maintaining comprehensive phylogenies, based on representative and up to-date molecular sequences, is challenging. PUmPER is a framework that can perpetually construct multi-gene alignments (with PHLAWD) and phylogenetic trees (with ExaML or RAxML-Light) for a given NCBI taxonomic group. When sufficient numbers of new gene sequences for the selected taxonomic group have accumulated in GenBank, PUmPER automatically extends the alignment and infers extended phylogenetic trees by using previously inferred smaller trees as starting topologies. Using our framework, large phylogenetic trees can be perpetually updated without human intervention. Importantly, resulting phylogenies are not statistically significantly worse than trees inferred from scratch. AVAILABILITY AND IMPLEMENTATION: PUmPER can run in stand-alone mode on a single server, or offload the computationally expensive phylogenetic searches to a parallel computing cluster. Source code, documentation, and tutorials are available at https://github.com/fizquierdo/perpetually-updated-trees. CONTACT: Fernando.Izquierdo@h-its.org SUPPLEMENTARY INFORMATION: Supplementary Material is available at Bioinformatics online. PMID- 24478339 TI - Minfi: a flexible and comprehensive Bioconductor package for the analysis of Infinium DNA methylation microarrays. AB - MOTIVATION: The recently released Infinium HumanMethylation450 array (the '450k' array) provides a high-throughput assay to quantify DNA methylation (DNAm) at ~450 000 loci across a range of genomic features. Although less comprehensive than high-throughput sequencing-based techniques, this product is more cost effective and promises to be the most widely used DNAm high-throughput measurement technology over the next several years. RESULTS: Here we describe a suite of computational tools that incorporate state-of-the-art statistical techniques for the analysis of DNAm data. The software is structured to easily adapt to future versions of the technology. We include methods for preprocessing, quality assessment and detection of differentially methylated regions from the kilobase to the megabase scale. We show how our software provides a powerful and flexible development platform for future methods. We also illustrate how our methods empower the technology to make discoveries previously thought to be possible only with sequencing-based methods. AVAILABILITY AND IMPLEMENTATION: http://bioconductor.org/packages/release/bioc/html/minfi.html. CONTACT: khansen@jhsph.edu; rafa@jimmy.harvard.edu SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24478340 TI - Basic mechanisms of numerical processing: cross-modal number comparisons and symbolic versus nonsymbolic numerosity in the intraparietal sulcus. PMID- 24478341 TI - M1-muscarinic receptors promote fear memory consolidation via phospholipase C and the M-current. AB - Neuromodulators released during and after a fearful experience promote the consolidation of long-term memory for that experience. Because overconsolidation may contribute to the recurrent and intrusive memories of post-traumatic stress disorder, neuromodulatory receptors provide a potential pharmacological target for prevention. Stimulation of muscarinic receptors promotes memory consolidation in several conditioning paradigms, an effect primarily associated with the M1 receptor (M1R). However, neither inhibiting nor genetically disrupting M1R impairs the consolidation of cued fear memory. Using the M1R agonist cevimeline and antagonist telenzepine, as well as M1R knock-out mice, we show here that M1R, along with beta2-adrenergic (beta2AR) and D5-dopaminergic (D5R) receptors, regulates the consolidation of cued fear memory by redundantly activating phospholipase C (PLC) in the basolateral amygdala (BLA). We also demonstrate that fear memory consolidation in the BLA is mediated in part by neuromodulatory inhibition of the M-current, which is conducted by KCNQ channels and is known to be inhibited by muscarinic receptors. Manipulating the M-current by administering the KCNQ channel blocker XE991 or the KCNQ channel opener retigabine reverses the effects on consolidation caused by manipulating beta2AR, D5R, M1R, and PLC. Finally, we show that cAMP and protein kinase A (cAMP/PKA) signaling relevant to this stage of consolidation is upstream of these neuromodulators and PLC, suggesting an important presynaptic role for cAMP/PKA in consolidation. These results support the idea that neuromodulatory regulation of ion channel activity and neuronal excitability is a critical mechanism for promoting consolidation well after acquisition has occurred. PMID- 24478342 TI - Distributed effects of biological sex define sex-typical motor behavior in Caenorhabditis elegans. AB - Sex differences in shared behaviors (for example, locomotion and feeding) are a nearly universal feature of animal biology. Though these behaviors may share underlying neural programs, their kinematics can exhibit robust differences between males and females. The neural underpinnings of these differences are poorly understood because of the often-untested assumption that they are determined by sex-specific body morphology. Here, we address this issue in the nematode Caenorhabditis elegans, which features two sexes with distinct body morphologies but similar locomotor circuitry and body muscle. Quantitative behavioral analysis shows that C. elegans and related nematodes exhibit significant sex differences in the dynamics and geometry of locomotor body waves, such that the male is generally faster. Using a recently proposed model of locomotor wave propagation, we show that sex differences in both body mechanics and the intrinsic dynamics of the motor system can contribute to kinematic differences in distinct mechanical contexts. By genetically sex-reversing the properties of specific tissues and cells, however, we find that sex-specific locomotor frequency in C. elegans is determined primarily by the functional modification of shared sensory neurons. Further, we find that sexual modification of body wall muscle together with the nervous system is required to alter body wave speed. Thus, rather than relying on a single focus of modification, sex differences in motor dynamics require independent modifications to multiple tissue types. Our results suggest shared motor behaviors may be sex-specifically optimized though distributed modifications to several aspects of morphology and physiology. PMID- 24478343 TI - Structural maturation and brain activity predict future working memory capacity during childhood development. AB - Human working memory capacity develops during childhood and is a strong predictor of future academic performance, in particular, achievements in mathematics and reading. Predicting working memory development is important for the early identification of children at risk for poor cognitive and academic development. Here we show that structural and functional magnetic resonance imaging data explain variance in children's working memory capacity 2 years later, which was unique variance in addition to that predicted using cognitive tests. While current working memory capacity correlated with frontoparietal cortical activity, the future capacity could be inferred from structure and activity in basal ganglia and thalamus. This gives a novel insight into the neural mechanisms of childhood development and supports the idea that neuroimaging can have a unique role in predicting children's cognitive development. PMID- 24478344 TI - HSF1 protects neurons through a novel trimerization- and HSP-independent mechanism. AB - Heat shock factor 1 (HSF1) protects neurons from death caused by the accumulation of misfolded proteins. It is believed that this protective effect is mediated by the transcriptional stimulation of genes encoding heat shock proteins (HSPs), a family of chaperones that refold or degrade misfolded proteins. Whether HSF1 is protective when neuronal death is not caused by protein misfolding has not been studied. Here, we report that HSF1 expression is necessary for the survival of rat neurons and that HSF1 mRNA and protein expression is reduced in neurons primed to die. Knock-down of HSF1 induces death of otherwise healthy neurons, whereas reestablishment of elevated levels of HSF1 protects neurons even when death is not due to accumulation of misfolded proteins. Neuroprotection by HSF1 does not require its trimerization, an event obligatory for the binding of HSF1 to heat shock elements within HSP gene promoters. Moreover, knock-down of HSP70 or blockade of HSP90 signaling does not reduce neuroprotection by HSF1. Although several neuroprotective molecules and signaling pathways, including CaMK, PKA, Casein kinase-II, and the Raf-MEK-ERK and PI-3K-Akt pathways, are not required for HSF1-mediated neuroprotection, protection is abrogated by inhibition of classical histone deacetylases (HDACs). We report that the novel mechanism of neuroprotection by HSF1 involves cooperation with SIRT1, an HDAC with well documented neuroprotective effects. Using a cell culture model of Huntington's disease, we show that HSF1 trimerization is not required for protection against mutant huntingtin-induced neurotoxicity, suggesting that HSF1 can protect neurons against both proteinopathic and nonproteinopathic death through a noncanonical pathway. PMID- 24478345 TI - Neuronal activity and glutamate uptake decrease mitochondrial mobility in astrocytes and position mitochondria near glutamate transporters. AB - Within neurons, mitochondria are nonuniformly distributed and are retained at sites of high activity and metabolic demand. Glutamate transport and the concomitant activation of the Na(+)/K(+)-ATPase represent a substantial energetic demand on astrocytes. We hypothesized that mitochondrial mobility within astrocytic processes might be regulated by neuronal activity and glutamate transport. We imaged organotypic hippocampal slice cultures of rat, in which astrocytes maintain their highly branched morphologies and express glutamate transporters. Using time-lapse confocal microscopy, the mobility of mitochondria within individual astrocytic processes and neuronal dendrites was tracked. Within neurons, a greater percentage of mitochondria were mobile than in astrocytes. Furthermore, they moved faster and farther than in astrocytes. Inhibiting neuronal activity with tetrodotoxin (TTX) increased the percentage of mobile mitochondria in astrocytes. Mitochondrial movement in astrocytes was inhibited by vinblastine and cytochalasin D, demonstrating that this mobility depends on both the microtubule and actin cytoskeletons. Inhibition of glutamate transport tripled the percentage of mobile mitochondria in astrocytes. Conversely, application of the transporter substrate d-aspartate reversed the TTX-induced increase in the percentage of mobile mitochondria. Inhibition of reversed Na(+)/Ca(2+) exchange also increased the percentage of mitochondria that were mobile. Last, we demonstrated that neuronal activity increases the probability that mitochondria appose GLT-1 particles within astrocyte processes, without changing the proximity of GLT-1 particles to VGLUT1. These results imply that neuronal activity and the resulting clearance of glutamate by astrocytes regulate the movement of astrocytic mitochondria and suggest a mechanism by which glutamate transporters might retain mitochondria at sites of glutamate uptake. PMID- 24478346 TI - Large-scale axonal reorganization of inhibitory neurons following retinal lesions. AB - The functional properties of adult cortical neurons are subject to alterations in sensory experience. Retinal lesions lead to remapping of cortical topography in the region of primary visual cortex representing the lesioned part of the retina, the lesion projection zone (LPZ), with receptive fields shifting to the intact parts of the retina. Neurons within the LPZ receive strengthened input from the surrounding region by growth of the plexus of excitatory long-range horizontal connections. Here, by combining cell type-specific labeling with a genetically engineered recombinant adeno-associated virus and in vivo two-photon microscopy in adult macaques, we showed that the remapping was also associated with alterations in the axonal arbors of inhibitory neurons, which underwent a parallel process of pruning and growth. The axons of inhibitory neurons located within the LPZ extended across the LPZ border, suggesting a mechanism by which new excitatory input arising from the peri-LPZ is balanced by reciprocal inhibition arising from the LPZ. PMID- 24478347 TI - Nogo receptor homolog NgR2 expressed in sensory DRG neurons controls epidermal innervation by interaction with Versican. AB - Primary sensory afferents of the dorsal root ganglion (DRG) that innervate the skin detect a wide range of stimuli, such as touch, temperature, pain, and itch. Different functional classes of nociceptors project their axons to distinct target zones within the developing skin, but the molecular mechanisms that regulate target innervation are less clear. Here we report that the Nogo66 receptor homolog NgR2 is essential for proper cutaneous innervation. NgR2(-/-) mice display increased density of nonpeptidergic nociceptors in the footpad and exhibit enhanced sensitivity to mechanical force and innocuous cold temperatures. These sensory deficits are not associated with any abnormality in morphology or density of DRG neurons. However, deletion of NgR2 renders nociceptive nonpeptidergic sensory neurons insensitive to the outgrowth repulsive activity of skin-derived Versican. Biochemical evidence shows that NgR2 specifically interacts with the G3 domain of Versican. The data suggest that Versican/NgR2 signaling at the dermo-epidermal junction acts in vivo as a local suppressor of axonal plasticity to control proper density of epidermal sensory fiber innervation. Our findings not only reveal the existence of a novel and unsuspected mechanism regulating epidermal target innervation, but also provide the first evidence for a physiological role of NgR2 in the peripheral nervous system. PMID- 24478348 TI - EMG activation patterns associated with high frequency, long-duration intracortical microstimulation of primary motor cortex. AB - The delivery of high-frequency, long-duration intracortical microstimulation (HFLD-ICMS) to primary motor cortex (M1) in primates produces hand movements to a common final end-point regardless of the starting hand position (Graziano et al., 2002). We have confirmed this general conclusion. We further investigated the extent to which the (1) temporal pattern, (2) magnitude, and (3) latency of electromyographic (EMG) activation associated with HFLD-ICMS-evoked movements are dependent on task conditions, including limb posture. HFLD-ICMS was applied to layer V sites in M1 cortex. EMG activation with HFLD-ICMS was evaluated while two male rhesus macaques performed a number of tasks in which the starting position of the hand could be varied throughout the workspace. HFLD-ICMS-evoked EMG activity was largely stable across all parameters tested independent of starting hand position. The most common temporal pattern of HFLD-ICMS-evoked EMG activity (58% of responses) was a sharp rise to a plateau. The plateau level was maintained essentially constant for the entire duration of the stimulus train. The plateau pattern is qualitatively different from the largely bell-shaped patterns typical of EMG activity associated with natural goal directed movements (Brown and Cooke, 1990; Hoffman and Strick, 1999). HFLD-ICMS produces relatively fixed parameters of muscle activation independent of limb position. We conclude that joint movement associated with HFLD-ICMS occurs as a function of the length tension properties of stimulus-activated muscles until an equilibrium between agonist and antagonist muscle force is achieved. PMID- 24478350 TI - Local pruning of dendrites and spines by caspase-3-dependent and proteasome limited mechanisms. AB - Synapse loss occurs normally during development and pathologically during neurodegenerative disease. Long-term depression, a proposed physiological correlate of synapse elimination, requires caspase-3 and the mitochondrial pathway of apoptosis. Here, we show that caspase-3 activity is essential--and can act locally within neurons--for regulation of spine density and dendrite morphology. By photostimulation of Mito-KillerRed, we induced caspase-3 activity in defined dendritic regions of cultured neurons. Within the photostimulated region, local elimination of dendritic spines and dendrite retraction occurred in a caspase-3-dependent manner without inducing cell death. However, pharmacological inhibition of inhibitor of apoptosis proteins or proteasome function led to neuronal death, suggesting that caspase activation is spatially restricted by these "molecular brakes" on apoptosis. Caspase-3 knock-out mice have increased spine density and altered miniature EPSCs, confirming a physiological involvement of caspase-3 in the regulation of spines in vivo. PMID- 24478349 TI - Performance monitoring in monkey frontal eye field. AB - The frontal eye fields (FEF) are thought to mediate response selection during oculomotor decision tasks. In addition, many FEF neurons have robust postsaccadic responses, but their role in postchoice evaluative processes (online performance monitoring) is only beginning to become apparent. Here we report error-related neural activity in FEF while monkeys performed a biased speed-categorization task that enticed the animals to make impulsive errors. Twenty-three percent of cells in macaque FEF coded an internally generated error-related signal, and many of the same cells also coded task difficulty. The observed responses are primarily consistent with three related concepts that have been associated with performance monitoring: (1) response conflict; (2) uncertainty; and (3) reward prediction. Overall, our findings suggest a novel role for the FEF as part of the neural network that evaluates the preceding choice to optimize behavior in the future. PMID- 24478351 TI - Novel roles for osteopontin and clusterin in peripheral motor and sensory axon regeneration. AB - Previous studies demonstrated that Schwann cells (SCs) express distinct motor and sensory phenotypes, which impact the ability of these pathways to selectively support regenerating neurons. In the present study, unbiased microarray analysis was used to examine differential gene expression in denervated motor and sensory pathways in rats. Several genes that were significantly upregulated in either denervated sensory or motor pathways were identified and two secreted factors were selected for further analysis: osteopontin (OPN) and clusterin (CLU) which were upregulated in denervated motor and sensory pathways, respectively. Sciatic nerve transection induced upregulation of OPN and CLU and expression of both returned to baseline levels with ensuing regeneration. In vitro analysis using exogenously applied OPN induced outgrowth of motor but not sensory neurons. CLU, however, induced outgrowth of sensory neurons, but not motor neurons. To assess the functional importance of OPN and CLU, peripheral nerve regeneration was examined in OPN and CLU(-/-) mice. When compared with OPN(+/+) mice, motor neuron regeneration was reduced in OPN(-/-) mice. Impaired regeneration through OPN(-/-) peripheral nerves grafted into OPN(+/+) mice indicated that loss of OPN in SCs was responsible for reduced motor regeneration. Sensory neuron regeneration was impaired in CLU(-/-) mice following sciatic nerve crush and impaired regeneration nerve fibers through CLU(-/-) nerve grafts transplanted into CLU(+/+) mice indicated that reduced sensory regeneration is likely due to SC-derived CLU. Together, these studies suggest unique roles for SC-derived OPN and CLU in regeneration of peripheral motor and sensory axons. PMID- 24478352 TI - Trans-spinal direct current stimulation alters muscle tone in mice with and without spinal cord injury with spasticity. AB - Muscle tone abnormalities are associated with many CNS pathologies and severely limit recovery of motor control. Muscle tone depends on the level of excitability of spinal motoneurons and interneurons. The present study investigated the following hypotheses: (1) direct current flowing from spinal cord to sciatic nerve [spinal-to-sciatic direct current stimulation (DCS)] would inhibit spinal motor neurons and interneurons, hence reducing muscle tone; and (2) direct current flowing in the opposite direction (sciatic-to-spinal DCS) would excite spinal motor neurons and interneurons, hence increasing muscle tone. Current intensity was biased to be ~170 times greater at the spinal column than at the sciatic nerve. The results showed marked effects of DCS on muscle tone. In controls and mice with spinal cord injuries with spasticity, spinal-to-sciatic DCS reduced transit and steady stretch-induced nerve and muscle responses. Sciatic-to-spinal DCS caused opposite effects. These findings provide the first direct evidence that trans-spinal DCS can alter muscle tone and suggest that this approach could be used to reduce both hypotonia and hypertonia. PMID- 24478353 TI - JIP1 mediates anterograde transport of Rab10 cargos during neuronal polarization. AB - Axon development and elongation require strictly controlled new membrane addition. Previously, we have shown the involvement of Rab10 in directional membrane insertion of plasmalemmal precursor vesicles (PPVs) during neuronal polarization and axonal growth. However, the mechanism responsible for PPV transportation remains unclear. Here we show that c-Jun N-terminal kinase interacting protein 1 (JIP1) interacts with GTP-locked active form of Rab10 and directly connects Rab10 to kinesin-1 light chain (KLC). The kinesin-1/JIP1/Rab10 complex is required for anterograde transport of PPVs during axonal growth. Downregulation of JIP1 or KLC or disrupting the formation of this complex reduces anterograde transport of PPVs in developing axons and causes neuronal polarity defect. Furthermore, this complex plays an important role in neocortical neuronal polarization of rats in vivo. Thus, this study has demonstrated a mechanism underlying directional membrane trafficking involved in axon development. PMID- 24478354 TI - Intrinsic fluctuations in sustained attention and distractor processing. AB - Although sustaining a moderate level of attention is critical in daily life, evidence suggests that attention is not deployed consistently, but rather fluctuates from moment to moment between optimal and suboptimal states. To better characterize these states in humans, the present study uses a gradual-onset continuous performance task with irrelevant background distractors to explore the relationship among behavioral fluctuations, brain activity, and, in particular, the processing of visual distractors. Using fMRI, we found that reaction time variability, a continuous measure of attentional instability, was positively correlated with activity in task-positive networks and negatively correlated with activity in the task-negative default mode network. We also observed greater processing of distractor images during more stable and less error prone "in the zone" epochs compared with suboptimal "out of the zone" epochs of the task. Overall, the data suggest that optimal states of attention are accomplished with more efficient and potentially less effortful recruitment of task-relevant resources, freeing remaining resources to process task irrelevant features of the environment. PMID- 24478355 TI - Bidirectional plasticity of Purkinje cells matches temporal features of learning. AB - Many forms of learning require temporally ordered stimuli. In Pavlovian eyeblink conditioning, a conditioned stimulus (CS) must precede the unconditioned stimulus (US) by at least about 100 ms for learning to occur. Conditioned responses are learned and generated by the cerebellum. Recordings from the cerebellar cortex during conditioning have revealed CS-triggered pauses in the firing of Purkinje cells that likely drive the conditioned blinks. The predominant view of the learning mechanism in conditioning is that long-term depression (LTD) at parallel fiber (PF)-Purkinje cell synapses underlies the Purkinje cell pauses. This raises a serious conceptual challenge because LTD is most effectively induced at short CS-US intervals, which do not support acquisition of eyeblinks. To resolve this discrepancy, we recorded Purkinje cells during conditioning with short or long CS US intervals. Decerebrated ferrets trained with CS-US intervals >=150 ms reliably developed Purkinje cell pauses, but training with an interval of 50 ms unexpectedly induced increases in CS-evoked spiking. This bidirectional modulation of Purkinje cell activity offers a basis for the requirement of a minimum CS-US interval for conditioning, but we argue that it cannot be fully explained by LTD, even when previous in vitro studies of stimulus-timing dependent LTD are taken into account. PMID- 24478356 TI - Binocular rivalry: frontal activity relates to introspection and action but not to perception. AB - When two dissimilar stimuli are presented to the eyes, perception alternates between multiple interpretations, a phenomenon dubbed binocular rivalry. Numerous recent imaging studies have attempted to unveil neural substrates underlying multistable perception. However, these studies had a conceptual constraint: access to observers' perceptual state relied on their introspection and active report. Here, we investigated to what extent neural correlates of binocular rivalry in healthy humans are confounded by this subjective measure and by action. We used the optokinetic nystagmus and pupil size to objectively and continuously map perceptual alternations for binocular-rivalry stimuli. Combining these two measures with fMRI allowed us to assess the neural correlates of binocular rivalry time locked to the perceptual alternations in the absence of active report. When observers were asked to actively report their percept, our objective measures matched the report. In this active condition, objective measures and subjective reporting revealed that occipital, parietal, and frontal areas underlie the processing of binocular rivalry, replicating earlier findings. Furthermore, objective measures provided additional statistical power due to their continuous nature. Importantly, when observers passively experienced rivalry without reporting perceptual alternations, a different picture emerged: differential neural activity in frontal areas was absent, whereas activation in occipital and parietal regions persisted. Our results question the popular view of a driving role of frontal areas in the initiation of perceptual alternations during binocular rivalry. Instead, we conclude that frontal areas are associated with active report and introspection rather than with rivalry per se. PMID- 24478357 TI - Activity of the principal cells of the olfactory bulb promotes a structural dynamic on the distal dendrites of immature adult-born granule cells via activation of NMDA receptors. AB - The adult olfactory bulb is continuously supplied with neuronal precursors that differentiate into granule and periglomerular cells. Little is known about the structural dynamic of adult-born granule cells (GCs) at their different maturational stages, the mechanisms controlling the integration of new neurons into the pre-existing neuronal circuitry, or the role of principal cell activity in these processes. We used two-photon time-lapse imaging to reveal a high level of filopodia formation and retraction on the distal dendrites of adult-born GCs at their early maturational stages. This dynamic decreased as the adult-born interneurons matured. Filopodia formation/retraction on the dendrites of adult born GCs at the early maturational stages depended on the activation of NMDA receptors (NMDARs). The stimulation of mitral cells using a pattern that mimics activity of these principal neurons to odor presentation promotes the NMDAR dependent filopodia dynamic of adult-born GCs during their early but not late maturational stages. Moreover, NMDA iontophoresis was sufficient to induce the formation of new filopodia on the distal dendrites of immature adult-born GCs. The maturation of adult-born interneurons was accompanied by a progressive hyperpolarization of the membrane potential and an increased Mg(2+) block of NMDARs. Decreasing the extracellular Mg(2+) concentration led to filopodia formation on the dendrites of mature adult-born GCs following NMDA iontophoresis. Our findings reveal an increased structural dynamic of adult-born GCs during the early stages of their integration into the mouse bulbar circuitry and highlight a critical period during which the principal cells' activity influences filopodia formation/retraction on the dendrites of interneurons. PMID- 24478359 TI - Rapid online selection between multiple motor plans. AB - Recent theories of voluntary control predict that multiple motor strategies can be precomputed and expressed throughout movement. We examined online decisional processing in humans by asking them to make reaching movements with obstacles located just to the sides of a direct path between start and end targets. On random trials, the limb was perturbed with one of four mechanical loads that varied in direction and amplitude. Notably, we observed two different strategies when we applied a perturbation (left medium-sized) that deviated the participants' hand directly toward an obstacle. In some trials, subjects directed their hand between the obstacles and in other trials to the left of the obstacles. Importantly, changes in the muscle stretch response between these two strategies were observed in <60 ms after perturbation, during the R2 long-latency epoch (~45-75 ms). As predicted, the selected strategy depended on the estimated position of the limb when it was perturbed. In our second experiment, we presented either one or three potential goal targets. Movements initially directed to the closest target could be quickly redirected to other potential targets after a perturbation. Differences in muscle stretch responses for redirected movements were observed ~75 ms after perturbation during the R3 long latency epoch (~75-105 ms). The results show that decisional processes are rapidly implemented during movement execution. In addition, our data suggest a hierarchical process with corrective responses on "how" to attain a behavioral goal expressed during the R2 epoch and responses on "what" goal to attain during the R3 epoch. PMID- 24478358 TI - Three distinct blue-green color pathways in a mammalian retina. AB - In mammalian retinae, the first steps in the process of discrimination of color are mediated by color-opponent neurons that respond with opposite polarity to signals from short (S, blue) and longer wavelength (M, green or L, red) cones. Primates also contain a second system that is different from M and L cones. Although pathways responding to the onset of S-cone stimulation (S-ON) are well known, the existence of bipolar cells and retinal ganglion cells that respond to the offset of S-cone stimulation (S-OFF) has been controversial. We have recorded from and stained three different types of S/M color-opponent ganglion cells in the rabbit retina that are distinguished by the polarity of their responses to S cone stimulation, the stratification pattern of their dendrites, and the distinct mechanisms underlying their color-opponent responses. We describe an S-ON and an S-OFF pathway formed by amacrine cells inverting the S-ON signal. Most importantly, we also provide both anatomical and physiological evidence for a direct S-OFF pathway dependent on an S-OFF cone bipolar cell. The results indicate a greater diversity of pathways for processing of signals from S-cones than previously suspected. PMID- 24478360 TI - Incubation of cocaine seeking following brief cocaine experience in mice is enhanced by mGluR1 blockade. AB - The incubation of cocaine craving describes the time-dependent augmentation of cue-induced cocaine seeking during withdrawal from prolonged cocaine self administration and requires time-dependent changes in neuroplasticity at the level of glutamatergic synapses in the nucleus accumbens (NAc). In contrast to most studies that use multiple cocaine-cue conditioning sessions, the present study tested mice with limited cocaine experience (i.e., a single conditioning session) in the incubation of cue-mediated cocaine seeking and its associated changes in the glutamate system. Mice that self-administered cocaine during a single session exhibited a time-dependent increase in their response for the drug associated cue as compared to mice that self-administered saline. This behavior was associated with changes in AMPA and NMDA receptor binding characteristics. Furthermore, Group I metabotropic glutamate receptor (mGluR1) mRNA levels were altered in several brain regions, including the NAc. Because of the pivotal role of mGluR1 in the control of cocaine-induced plasticity, we investigated the role of mGluR1 in the formation of drug cue-mediated cocaine seeking. After prolonged withdrawal, mice in which an mGluR1 antagonist was administered following cocaine self-administration displayed increased cocaine seeking compared to vehicle treated mice. These results suggest that limited cocaine experience is sufficient to induce neurobiological changes that enable an initially neutral cue to acquire motivational value that increases over time, an effect that likely involves glutamate signaling through mGluR1. PMID- 24478361 TI - Analysis of local and global topographic order in mouse retinocollicular maps. AB - We introduce the Lattice Method for the quantitative assessment of the topographic order within the pattern of connections between two structures. We apply this method to published visuocollicular mapping data obtained by Fourier based intrinsic imaging of mouse colliculus. We find that, in maps from wild types and beta2 knock-outs, at least 150 points on the colliculus are represented in the visual field in the correct relative order. In maps from animals with knock-out of the three ephrinA ligands (TKO), thought to specify the rostrocaudal axis of the map, the projection on the colliculus of each small circular area of visual field is elongated approximately rostrocaudally. Of these projections, 9% are made up of two distinct regions lying along the direction of ingrowth of retinal fibers. These are similar to the ectopic projections found in other ephrinA knock-out data. Coexisting with the ectopic projections, each TKO map contains a submap where neighbor-neighbor relations are preserved, which is ordered along both rostrocaudal and mediolateral axes, in the orientation found in wild-type maps. The submaps vary in size with order well above chance level, which can approach the order in wild-type maps. Knock-out of both beta2 and two of the three ephrinAs yields maps with some order. The ordered TKO maps cannot be produced by correlated neural activity acting alone, as this mechanism is unable to specify map orientation. These results invite reassessment of the role of molecular signaling, particularly that of ephrinAs, in the formation of ordered nerve connections. PMID- 24478362 TI - Motor costs and the coordination of the two arms. AB - We have two arms, many muscles in each arm, and numerous neurons that contribute to their control. How does the brain assign responsibility to each of these potential actors? We considered a bimanual task in which people chose how much force to produce with each arm so that the sum would equal a target. We found that the dominant arm made a greater contribution, but only for specific directions. This was not because the dominant arm was stronger. Rather, it was less noisy. A cost that included unimanual noise and strength accounted for both direction- and handedness-dependent choices that young people made. To test whether there was a causal relationship between unimanual noise and bimanual control, we considered elderly people, whose unimanual noise is comparable in the two arms. We found that, in bimanual control, the elderly showed no preference for their dominant arm. We noninvasively stimulated the motor cortex to produce a change in unimanual strength and noise, and found a corresponding change in bimanual control. Using the noise measurements, we built a neuronal model. The model explained the anisotropic distribution of preferred directions of neurons in the monkey motor cortex and predicted that, in humans, there are changes in the number of these cortical neurons with handedness and aging. Therefore, we found that coordination can be explained by the noise and strength of each effector, where noise may be a reflection of the number of task-related neurons available for control of that effector in the motor cortex. PMID- 24478363 TI - Differential associative training enhances olfactory acuity in Drosophila melanogaster. AB - Training can improve the ability to discriminate between similar, confusable stimuli, including odors. One possibility of enhancing behaviorally expressed discrimination (i.e., sensory acuity) relies on differential associative learning, during which animals are forced to detect the differences between similar stimuli. Drosophila represents a key model organism for analyzing neuronal mechanisms underlying both odor processing and olfactory learning. However, the ability of flies to enhance fine discrimination between similar odors through differential associative learning has not been analyzed in detail. We performed associative conditioning experiments using chemically similar odorants that we show to evoke overlapping neuronal activity in the fly's antennal lobes and highly correlated activity in mushroom body lobes. We compared the animals' performance in discriminating between these odors after subjecting them to one of two types of training: either absolute conditioning, in which only one odor is reinforced, or differential conditioning, in which one odor is reinforced and a second odor is explicitly not reinforced. First, we show that differential conditioning decreases behavioral generalization of similar odorants in a choice situation. Second, we demonstrate that this learned enhancement in olfactory acuity relies on both conditioned excitation and conditioned inhibition. Third, inhibitory local interneurons in the antennal lobes are shown to be required for behavioral fine discrimination between the two similar odors. Fourth, differential, but not absolute, training causes decorrelation of odor representations in the mushroom body. In conclusion, differential training with similar odors ultimately induces a behaviorally expressed contrast enhancement between the two similar stimuli that facilitates fine discrimination. PMID- 24478364 TI - Combination of engineered Schwann cell grafts to secrete neurotrophin and chondroitinase promotes axonal regeneration and locomotion after spinal cord injury. AB - Transplantation of Schwann cells (SCs) is a promising therapeutic strategy for spinal cord repair. SCs introduced into lesions support axon regeneration, but because these axons do not exit the transplant, additional approaches with SCs are needed. Here, we transplanted SCs genetically modified to secrete a bifunctional neurotrophin (D15A) and chondroitinase ABC (ChABC) into a subacute contusion injury in rats. We examined the effects of these modifications on graft volume, SC number, degradation of chondroitin sulfate proteoglycans (CSPGs), astrogliosis, SC myelination of axons, propriospinal and supraspinal axon numbers, locomotor outcome (BBB scoring, CatWalk gait analysis), and mechanical and thermal sensitivity on the hind paws. D15A secreted from transplanted SCs increased graft volume and SC number and myelinated axon number. SCs secreting ChABC significantly decreased CSPGs, led to some egress of SCs from the graft, and increased propriospinal and 5-HT-positive axons in the graft. SCs secreting both D15A and ChABC yielded the best responses: (1) the largest number of SC myelinated axons, (2) more propriospinal axons in the graft and host tissue around and caudal to it, (3) more corticospinal axons closer to the graft and around and caudal to it, (4) more brainstem neurons projecting caudal to the transplant, (5) increased 5-HT-positive axons in the graft and caudal to it, (6) significant improvement in aspects of locomotion, and (7) improvement in mechanical and thermal allodynia. This is the first evidence that the combination of SC transplants engineered to secrete neurotrophin and chondroitinase further improves axonal regeneration and locomotor and sensory function. PMID- 24478365 TI - Pathogenic mutation of spastin has gain-of-function effects on microtubule dynamics. AB - Mutations to the SPG4 gene encoding the microtubule-severing protein spastin are the most common cause of hereditary spastic paraplegia. Haploinsufficiency, the prevalent model for the disease, cannot readily explain many of its key aspects, such as its adult onset or its specificity for the corticospinal tracts. Treatment strategies based solely on haploinsufficiency are therefore likely to fail. Toward developing effective therapies, here we investigated potential gain of-function effects of mutant spastins. The full-length human spastin isoform called M1 or a slightly shorter isoform called M87, both carrying the same pathogenic mutation C448Y, were expressed in three model systems: primary rat cortical neurons, fibroblasts, and transgenic Drosophila. Although both isoforms had ill effects on motor function in transgenic flies and decreased neurite outgrowth from primary cortical neurons, mutant M1 was notably more toxic than mutant M87. The observed phenotypes did not result from dominant-negative effects of mutated spastins. Studies in cultured cells revealed that microtubules can be heavily decorated by mutant M1 but not mutant M87. Microtubule-bound mutant M1 decreased microtubule dynamics, whereas unbound M1 or M87 mutant spastins increased microtubule dynamics. The alterations in microtubule dynamics observed in the presence of mutated spastins are not consistent with haploinsufficiency and are better explained by a gain-of-function mechanism. Our results fortify a model wherein toxicity of mutant spastin proteins, especially mutant M1, contributes to axonal degeneration in the corticospinal tracts. Furthermore, our results provide details on the mechanism of the toxicity that may chart a course toward more effective treatment regimens. PMID- 24478366 TI - The hormone prolactin is a novel, endogenous trophic factor able to regulate reactive glia and to limit retinal degeneration. AB - Retinal degeneration is characterized by the progressive destruction of retinal cells, causing the deterioration and eventual loss of vision. We explored whether the hormone prolactin provides trophic support to retinal cells, thus protecting the retina from degenerative pressure. Inducing hyperprolactinemia limited photoreceptor apoptosis, gliosis, and changes in neurotrophin expression, and it preserved the photoresponse in the phototoxicity model of retinal degeneration, in which continuous exposure of rats to bright light leads to retinal cell death and retinal dysfunction. In this model, the expression levels of prolactin receptors in the retina were upregulated. Moreover, retinas from prolactin receptor-deficient mice exhibited photoresponsive dysfunction and gliosis that correlated with decreased levels of retinal bFGF, GDNF, and BDNF. Collectively, these data unveiled prolactin as a retinal trophic factor that may regulate glial neuronal cell interactions and is a potential therapeutic molecule against retinal degeneration. PMID- 24478367 TI - Chronic sleep restriction disrupts sleep homeostasis and behavioral sensitivity to alcohol by reducing the extracellular accumulation of adenosine. AB - Sleep impairments are comorbid with a variety of neurological and psychiatric disorders including depression, epilepsy, and alcohol abuse. Despite the prevalence of these disorders, the cellular mechanisms underlying the interaction between sleep disruption and behavior remain poorly understood. In this study, the impact of chronic sleep loss on sleep homeostasis was examined in C57BL/6J mice following 3 d of sleep restriction. The electroencephalographic power of slow-wave activity (SWA; 0.5-4 Hz) in nonrapid eye movement (NREM) sleep and adenosine tone were measured during and after sleep restriction, and following subsequent acute sleep deprivation. During the first day of sleep restriction, SWA and adenosine tone increased, indicating a homeostatic response to sleep loss. On subsequent days, SWA declined, and this was accompanied by a corresponding reduction in adenosine tone caused by a loss of one source of extracellular adenosine. Furthermore, the response to acute sleep deprivation (6 h) was significantly attenuated in sleep-restricted mice. These effects were long lasting with reduced SWA and adenosine tone persisting for at least 2 weeks. To investigate the behavioral consequences of chronic sleep restriction, sensitivity to the motor-impairing effects of alcohol was also examined. Sleep-restricted mice were significantly less sensitive to alcohol when tested 24 h after sleep restriction, an effect that persisted for 4 weeks. Intracerebroventricular infusion of an adenosine A1 receptor antagonist produced a similar decrease in sensitivity to alcohol. These results suggest that chronic sleep restriction induces a sustained impairment in adenosine-regulated sleep homeostasis and consequentially impacts the response to alcohol. PMID- 24478368 TI - A spiking neural integrator model of the adaptive control of action by the medial prefrontal cortex. AB - Subjects performing simple reaction-time tasks can improve reaction times by learning the expected timing of action-imperative stimuli and preparing movements in advance. Success or failure on the previous trial is often an important factor for determining whether a subject will attempt to time the stimulus or wait for it to occur before initiating action. The medial prefrontal cortex (mPFC) has been implicated in enabling the top-down control of action depending on the outcome of the previous trial. Analysis of spike activity from the rat mPFC suggests that neural integration is a key mechanism for adaptive control in precisely timed tasks. We show through simulation that a spiking neural network consisting of coupled neural integrators captures the neural dynamics of the experimentally recorded mPFC. Errors lead to deviations in the normal dynamics of the system, a process that could enable learning from past mistakes. We expand on this coupled integrator network to construct a spiking neural network that performs a reaction-time task by following either a cue-response or timing strategy, and show that it performs the task with similar reaction times as experimental subjects while maintaining the same spiking dynamics as the experimentally recorded mPFC. PMID- 24478369 TI - Omega-3 fatty acids protect the brain against ischemic injury by activating Nrf2 and upregulating heme oxygenase 1. AB - Ischemic stroke is a debilitating clinical disorder that affects millions of people, yet lacks effective neuroprotective treatments. Fish oil is known to exert beneficial effects against cerebral ischemia. However, the underlying protective mechanisms are not fully understood. The present study tests the hypothesis that omega-3 polyunsaturated fatty acids (n-3 PUFAs) attenuate ischemic neuronal injury by activating nuclear factor E2-related factor 2 (Nrf2) and upregulating heme oxygenase-1 (HO-1) in both in vitro and in vivo models. We observed that pretreatment of rat primary neurons with docosahexaenoic acid (DHA) significantly reduced neuronal death following oxygen-glucose deprivation. This protection was associated with increased Nrf2 activation and HO-1 upregulation. Inhibition of HO-1 activity with tin protoporphyrin IX attenuated the protective effects of DHA. Further studies showed that 4-hydroxy-2E-hexenal (4-HHE), an end product of peroxidation of n-3 PUFAs, was a more potent Nrf2 inducer than 4 hydroxy-2E-nonenal derived from n-6 PUFAs. In an in vivo setting, transgenic mice overexpressing fatty acid metabolism-1, an enzyme that converts n-6 PUFAs to n-3 PUFAs, were remarkably resistant to focal cerebral ischemia compared with their wild-type littermates. Regular mice fed with a fish oil-enhanced diet also demonstrated significant resistance to ischemia compared with mice fed with a regular diet. As expected, the protection was associated with HO-1 upregulation, Nrf2 activation, and 4-HHE generation. Together, our data demonstrate that n-3 PUFAs are highly effective in protecting the brain, and that the protective mechanisms involve Nrf2 activation and HO-1 upregulation by 4-HHE. Further investigation of n-3 PUFA neuroprotective mechanisms may accelerate the development of stroke therapies. PMID- 24478370 TI - Tissue plasminogen activator contributes to alterations of neuronal migration and activity-dependent responses in fragile X mice. AB - Fragile X syndrome (FXS) is the most common inherited neurodevelopmental disorder with intellectual disability. Here, we show that the expression of tissue plasminogen activator (tPA) is increased in glial cells differentiated from neural progenitors of Fmr1 knock-out mice, a mouse model for FXS, and that tPA is involved in the altered migration and differentiation of these progenitors lacking FMR1 protein (FMRP). When tPA function is blocked with an antibody, enhanced migration of doublecortin-immunoreactive neurons in 1 d differentiated FMRP-deficient neurospheres is normalized. In time-lapse imaging, blocking the tPA function promotes early glial differentiation and reduces the velocity of nuclear movement of FMRP-deficient radial glia. In addition, we show that enhanced intracellular Ca(2+) responses to depolarization with potassium are prevented by the treatment with the tPA-neutralizing antibody in FMRP-deficient cells during early neural progenitor differentiation. Alterations of the tPA expression in the embryonic, postnatal, and adult brain of Fmr1 knock-out mice suggest an important role for tPA in the abnormal neuronal differentiation and plasticity in FXS. Altogether, the results indicate that tPA may prove to be an interesting potential target for pharmacological intervention in FXS. PMID- 24478371 TI - Dscam1 is required for normal dendrite growth and branching but not for dendritic spacing in Drosophila motoneurons. AB - Down syndrome cell adhesion molecule, Dscam, serves diverse neurodevelopmental functions, including axon guidance and synaptic adhesion, as well as self recognition and self-avoidance, depending on the neuron type, brain region, or species under investigation. In Drosophila, the extensive molecular diversity that results from alternative splicing of Dscam1 into >38,000 isoforms provides neurons with a unique molecular code for self-recognition in the nervous system. Each neuron produces only a small subset of Dscam1 isoforms, and distinct Dscam1 isoforms mediate homophilic interactions, which in turn, result in repulsion and even spacing of self-processes, while allowing contact with neighboring cells. While these mechanisms have been shown to underlie mushroom body development and spacing of mechanosensory neuron dendrites, here we report that Dscam1 plays no role in adult Drosophila motoneuron dendrite spacing, but is required for motoneuron dendritic growth. Targeted expression of Dscam-RNAi in an identified flight motoneuron did not impact dendrite spacing, but instead produced overgrowth. Increasing the knockdown strength severely reduced dendritic growth and branching. Similarly, Dscam mutant motoneurons in an otherwise control background (MARCM) were completely devoid of mature dendrites. These data suggest that Dscam1 is required cell autonomously for normal adult motoneuron dendrite growth in Drosophila. This demonstrates a previously unreported role of Drosophila Dscam1 in central neuron development, and expands the current understanding that Dscam1 operates as a cell adhesion molecule that mediates homophilic repulsion. PMID- 24478372 TI - Activity-dependent modulation of layer 1 inhibitory neocortical circuits by acetylcholine. AB - Layer 1 neocortical GABAergic interneurons control the excitability of pyramidal neurons through cell-class-specific direct inhibitory and disynaptic disinhibitory circuitry. The engagement of layer 1 inhibitory circuits during behavior is powerfully controlled by the cholinergic neuromodulatory system. Here we report that acetylcholine (ACh) influences the excitability of layer 1 interneurons in a cell-class and activity-dependent manner. Whole-cell recordings from identified layer 1 interneurons of the rat somatosensory neocortex revealed that brief perisomatic application of ACh excited both neurogliaform cells (NGFCs) and classical-accommodating cells (c-ACs) at rest by the activation of nicotinic receptors. In contrast, under active, action potential firing states, ACh excited c-ACs, but inhibited NGFCs through muscarinic receptor-mediated, IP3 receptor-dependent elevations of intracellular calcium that gated surface membrane calcium-activated potassium channels. These excitatory and inhibitory actions of ACh could be switched between by brief periods of NGFC action potential firing. Paired recordings demonstrated that cholinergic inhibition of NGFCs disinhibited the apical dendrites of layer 2/3 pyramidal neurons by silencing widespread, GABA(B) receptor-mediated, monosynaptic inhibition. Together, these data suggest that the cholinergic system modulates layer 1 inhibitory circuits in an activity-dependent manner to dynamically control dendritic synaptic inhibition of pyramidal neurons. PMID- 24478373 TI - Developmental changes in NMDA receptor subunit composition at ON and OFF bipolar cell synapses onto direction-selective retinal ganglion cells. AB - In the developing mouse retina, spontaneous and light-driven activity shapes bipolar->ganglion cell glutamatergic synapse formation, beginning around the time of eye-opening (P12-P14) and extending through the first postnatal month. During this time, glutamate release can spill outside the synaptic cleft and possibly stimulate extrasynaptic NMDA-type glutamate receptors (NMDARs) on ganglion cells. Furthermore, the role of NMDARs during development may differ between ON and OFF bipolar synapses as in mature retina, where ON synapses reportedly include extrasynaptic NMDARs with GluN2B subunits. To better understand the function of glutamatergic synapses during development, we made whole-cell recordings of NMDAR mediated responses, in vitro, from two types of genetically identified direction selective ganglion cells (dsGCs): TRHR (thyrotropin-releasing hormone receptor) and Drd4 (dopamine receptor 4). Both dsGC types responded to puffed NMDA between P7 and P28; and both types exhibited robust light-evoked NMDAR-mediated responses at P14 and P28 that were quantified by conductance analysis during nicotinic and GABA(A) receptor blockade. For a given cell type and at a given age, ON and OFF bipolar cell inputs evoked similar NMDAR-mediated responses, suggesting that ON versus-OFF differences in mature retina do not apply to the cell types or ages studied here. At P14, puff- and light-evoked NMDAR-mediated responses in both dsGCs were partially blocked by the GluN2B antagonist ifenprodil, whereas at P28 only TRHR cells remained ifenprodil-sensitive. NMDARs contribute at both ON and OFF bipolar cell synapses during a period of robust activity-dependent synaptic development, with declining GluN2B involvement over time in specific ganglion cell types. PMID- 24478374 TI - Cerebellar potentiation and learning a whisker-based object localization task with a time response window. AB - Whisker-based object localization requires activation and plasticity of somatosensory and motor cortex. These parts of the cerebral cortex receive strong projections from the cerebellum via the thalamus, but it is unclear whether and to what extent cerebellar processing may contribute to such a sensorimotor task. Here, we subjected knock-out mice, which suffer from impaired intrinsic plasticity in their Purkinje cells and long-term potentiation at their parallel fiber-to-Purkinje cell synapses (L7-PP2B), to an object localization task with a time response window (RW). Water-deprived animals had to learn to localize an object with their whiskers, and based upon this location they were trained to lick within a particular period ("go" trial) or refrain from licking ("no-go" trial). L7-PP2B mice were not ataxic and showed proper basic motor performance during whisking and licking, but were severely impaired in learning this task compared with wild-type littermates. Significantly fewer L7-PP2B mice were able to learn the task at long RWs. Those L7-PP2B mice that eventually learned the task made unstable progress, were significantly slower in learning, and showed deficiencies in temporal tuning. These differences became greater as the RW became narrower. Trained wild-type mice, but not L7-PP2B mice, showed a net increase in simple spikes and complex spikes of their Purkinje cells during the task. We conclude that cerebellar processing, and potentiation in particular, can contribute to learning a whisker-based object localization task when timing is relevant. This study points toward a relevant role of cerebellum-cerebrum interaction in a sophisticated cognitive task requiring strict temporal processing. PMID- 24478375 TI - Selective adaptation to "oddball" sounds by the human auditory system. AB - Adaptation to both common and rare sounds has been independently reported in neurophysiological studies using probabilistic stimulus paradigms in small mammals. However, the apparent sensitivity of the mammalian auditory system to the statistics of incoming sound has not yet been generalized to task-related human auditory perception. Here, we show that human listeners selectively adapt to novel sounds within scenes unfolding over minutes. Listeners' performance in an auditory discrimination task remains steady for the most common elements within the scene but, after the first minute, performance improves for distinct and rare (oddball) sound elements, at the expense of rare sounds that are relatively less distinct. Our data provide the first evidence of enhanced coding of oddball sounds in a human auditory discrimination task and suggest the existence of an adaptive mechanism that tracks the long-term statistics of sounds and deploys coding resources accordingly. PMID- 24478377 TI - A common cortical metric for spatial, temporal, and social distance. AB - Distance describes more than physical space: we speak of close friends and distant relatives, and of the near future and distant past. Did these ubiquitous spatial metaphors arise in language coincidentally or did they arise because they are rooted in a common neural computation? To address this question, we used statistical pattern recognition techniques to analyze human fMRI data. First, a machine learning algorithm was trained to discriminate patterns of fMRI responses based on relative egocentric distance within trials from one distance domain (e.g., photographs of objects relatively close to or far away from the viewer in spatial distance trials). Next, we tested whether the decision boundary generated from this training could distinguish brain responses according to relative egocentric distance within each of two separate distance domains (e.g., phrases referring to the immediate or more remote future within temporal distance trials; photographs of participants' friends or acquaintances within social distance trials). This procedure was repeated using all possible combinations of distance domains for training and testing the classifier. In all cases, above-chance decoding across distance domains was possible in the right inferior parietal lobule (IPL). Furthermore, the representational similarity structure within this brain area reflected participants' own judgments of spatial distance, temporal soon-ness, and social familiarity. Thus, the right IPL may contain a parsimonious encoding of proximity to self in spatial, temporal, and social frames of reference. PMID- 24478376 TI - Autonomous encoding of irrelevant goals and outcomes by prefrontal cortex neurons. AB - Two rhesus monkeys performed a distance discrimination task in which they reported whether a red square or a blue circle had appeared farther from a fixed reference point. Because a new pair of distances was chosen randomly on each trial, and because the monkeys had no opportunity to correct errors, no information from the previous trial was relevant to a current one. Nevertheless, many prefrontal cortex neurons encoded the outcome of the previous trial on current trials. A smaller, intermingled population of cells encoded the spatial goal on the previous trial or the features of the chosen stimuli, such as color or shape. The coding of previous outcomes and goals began at various times during a current trial, and it was selective in that prefrontal cells did not encode other information from the previous trial. The monitoring of previous goals and outcomes often contributes to problem solving, and it can support exploratory behavior. The present results show that such monitoring occurs autonomously and selectively, even when irrelevant to the task at hand. PMID- 24478378 TI - Dissociable memory traces within the macaque medial temporal lobe predict subsequent recognition performance. AB - Functional magnetic resonance imaging (fMRI) studies have revealed that activity in the medial temporal lobe (MTL) predicts subsequent memory performance in humans. Because of limited knowledge on cytoarchitecture and axonal projections of the human MTL, precise localization and characterization of the areas that can predict subsequent memory performance are benefited by the use of nonhuman primates in which integrated approach of the MRI- and cytoarchiture-based boundary delineation is available. However, neural correlates of this subsequent memory effect have not yet been identified in monkeys. Here, we used fMRI to examine activity in the MTL during memory encoding of events that monkeys later remembered or forgot. Application of both multivoxel pattern analysis and conventional univariate analysis to high-resolution fMRI data allowed us to identify memory traces within the caudal entorhinal cortex (cERC) and perirhinal cortex (PRC), as well as within the hippocampus proper. Furthermore, activity in the cERC and the hippocampus, which are directly connected, was responsible for encoding the initial items of sequentially presented pictures, which may reflect recollection-like recognition, whereas activity in the PRC was not. These results suggest that two qualitatively distinct encoding processes work in the monkey MTL and that recollection-based memory is formed by the interplay of the hippocampus with the cERC, a focal cortical area anatomically closer to the hippocampus and hierarchically higher than previously believed. These findings will advance the understanding of common memory system between humans and monkeys and accelerate fine electrophysiological characterization of these dissociable memory traces in the monkey MTL. PMID- 24478379 TI - Responses to cell loss become restricted as the supporting cells in mammalian vestibular organs grow thick junctional actin bands that develop high stability. AB - Sensory hair cell (HC) loss is a major cause of permanent hearing and balance impairments for humans and other mammals. Yet, fish, amphibians, reptiles, and birds readily replace HCs and recover from such sensory deficits. It is unknown what prevents replacement in mammals, but cell replacement capacity declines contemporaneously with massive postnatal thickening of F-actin bands at the junctions between vestibular supporting cells (SCs). In non-mammals, SCs can give rise to regenerated HCs, and the bands remain thin even in adults. Here we investigated the stability of the F-actin bands between SCs in ears from chickens and mice and Madin-Darby canine kidney cells. Pharmacological experiments and fluorescence recovery after photobleaching (FRAP) of SC junctions in utricles from mice that express a gamma-actin-GFP fusion protein showed that the thickening F-actin bands develop increased resistance to depolymerization and exceptional stability that parallels a sharp decline in the cell replacement capacity of the maturing mammalian ear. The FRAP recovery rate and the mobile fraction of gamma-actin-GFP both decreased as the bands thickened with age and became highly stabilized. In utricles from neonatal mice, time-lapse recordings in the vicinity of dying HCs showed that numerous SCs change shape and organize multicellular actin purse strings that reseal the epithelium. In contrast, adult SCs appeared resistant to deformation, with resealing responses limited to just a few neighboring SCs that did not form purse strings. The exceptional stability of the uniquely thick F-actin bands at the junctions of mature SCs may play an important role in restricting dynamic repair responses in mammalian vestibular epithelia. PMID- 24478381 TI - AMPK-derived peptides reduce blood glucose levels but lead to fat retention in the liver of obese mice. AB - AMP-activated protein kinase (AMPK) is a regulator of energy balance at both the cellular and the whole-body levels. Direct activation of AMPK has been highlighted as a potential novel, and possibly safer, alternative to treat type II diabetes and obesity. In this study, we aimed to design and characterize novel peptides that mimic the alphaG region of the alpha2 AMPK catalytic domain to modulate its activity by inhibiting interactions between AMPK domains or other interacting proteins. The derived peptides were tested in vivo and in tissue culture. The computationally predicted structure of the free peptide with the addition of the myristoyl (Myr) or acetyl (Ac) moiety closely resembled the protein structure that it was designed to mimic. Myr-peptide and Ac-peptide activated AMPK in muscle cells and led to reduced adipose tissue weight, body weight, blood glucose levels, insulin levels, and insulin resistance index, as expected from AMPK activation. In addition, triglyceride, cholesterol, leptin, and adiponectin levels were also lower, suggesting increased adipose tissue breakdown, a result of AMPK activation. On the other hand, liver weight and liver lipid content increased due to fat retention. We could not find an elevated pAMPK:AMPK ratio in the liver in vivo or in hepatocytes ex vivo, suggesting that the peptide does not lead to AMPK activation in hepatocytes. The finding that an AMPK-derived peptide leads to the activation of AMPK in muscle cells and in adipose tissue and leads to reduced glucose levels in obese mice, but to fat accumulation in the liver, demonstrates the differential effect of AMPK modulation in various tissues. PMID- 24478380 TI - Circulating oncometabolite 2-hydroxyglutarate is a potential surrogate biomarker in patients with isocitrate dehydrogenase-mutant intrahepatic cholangiocarcinoma. AB - PURPOSE: Mutations in the IDH1 and IDH2 (IDH1/2) genes occur in approximately 20% of intrahepatic cholangiocarcinoma and lead to accumulation of 2-hydroxyglutarate (2HG) in the tumor tissue. However, it remains unknown whether IDH1/2 mutations can lead to high levels of 2HG circulating in the blood and whether serum 2HG can be used as a biomarker for IDH1/2 mutational status and tumor burden in intrahepatic cholangiocarcinoma. EXPERIMENTAL DESIGN: We initially measured serum 2HG concentration in blood samples collected from 31 patients with intrahepatic cholangiocarcinoma in a screening cohort. Findings were validated across 38 resected patients with intrahepatic cholangiocarcinoma from a second cohort with tumor volume measures. Circulating levels of 2HG were evaluated relative to IDH1/2 mutational status, tumor burden, and a number of clinical variables. RESULTS: Circulating levels of 2HG in the screening cohort were significantly elevated in patients with IDH1/2-mutant (median, 478 ng/mL) versus IDH1/2-wild type (median, 118 ng/mL) tumors (P < 0.001). This significance was maintained in the validation cohort (343 ng/mL vs. 55 ng/mL, P < 0.0001) and levels of 2HG directly correlated with tumor burden in IDH1/2-mutant cases (P < 0.05). Serum 2HG levels >=170 ng/mL could predict the presence of an IDH1/2 mutation with a sensitivity of 83% and a specificity of 90%. No differences were noted between the allelic variants IDH1 or IDH2 in regard to the levels of circulating 2HG. CONCLUSIONS: This study indicates that circulating 2HG may be a surrogate biomarker of IDH1 or IDH2 mutation status in intrahepatic cholangiocarcinoma and that circulating 2HG levels may correlate directly with tumor burden. Clin Cancer Res; 20(7); 1884-90. (c)2014 AACR. PMID- 24478382 TI - Patterns of ALK expression in different human cancer types. AB - AIMS: Oncogenic gene fusions involving the anaplastic lymphoma kinase (ALK) tyrosine kinase have been identified in several haematopoietic and sporadically also in solid tumour types. Preliminary results from clinical trials suggest that patients with ALK fusion positive cancers might optimally benefit from the tyrosine kinase inhibitor crizotinib, but a comprehensive analysis of solid tumour types for ALK fusion and fusion associated expression is lacking. METHODS: In order to identify human solid cancers carrying ALK alterations, we performed real-time PCR screening of 1000 tumour samples representing 29 different tumour entities. ALK-positive samples were then transferred into a tissue microarray format and subjected to ALK break-apart fluorescence in situ hybridisation (FISH) analysis and ALK immunohistochemistry (IHC) analysis. RESULTS: ALK expression was detected by real-time PCR in 260 of 896 (29%) interpretable tumour samples. FISH analysis was successful in 189 of 260 arrayed cancers but did not detect ALK rearrangement. There was also no ALK expression detectable by IHC. CONCLUSIONS: Different levels of ALK expression can be found in various cancer types using sensitive methods like real-time PCR. However, such low-level expression is independent from oncogenic ALK fusions and cannot be detected with less-sensitive methods like IHC. ALK fusion is a rare event in human solid cancers. PMID- 24478383 TI - Tie2 and Eph receptor tyrosine kinase activation and signaling. AB - The Eph and Tie cell surface receptors mediate a variety of signaling events during development and in the adult organism. As other receptor tyrosine kinases, they are activated on binding of extracellular ligands and their catalytic activity is tightly regulated on multiple levels. The Eph and Tie receptors display some unique characteristics, including the requirement of ligand-induced receptor clustering for efficient signaling. Interestingly, both Ephs and Ties can mediate different, even opposite, biological effects depending on the specific ligand eliciting the response and on the cellular context. Here we discuss the structural features of these receptors, their interactions with various ligands, as well as functional implications for downstream signaling initiation. The Eph/ephrin structures are already well reviewed and we only provide a brief overview on the initial binding events. We go into more detail discussing the Tie-angiopoietin structures and recognition. PMID- 24478385 TI - For debate: the Operational Patient Care Pathway. AB - This paper introduces the Operational Patient Care Pathway which is a unified approach for clinical care to all operational patients arising from the Defence population at risk (PAR) exposed to the 'all-hazards environment' while deployed on military operations. It comprises three organisational models: the Healthcare Cycle, the Chain of Care and the Operational Patient Care Pathway. It is supported by a number key definitions including: the 'All-Hazards Environment', the Defence PAR, and the seven Capabilities of Operational Healthcare. Key new clinical concepts include: Tactical Field Care, Care under Fire, Enhanced Field Care, Prolonged Field Care, Progressive Resuscitation and Enhanced Diagnostics. The Operational Patient Care Pathway has been introduced to embed the medical lessons from the last decade of military operations into concepts and doctrine for the Defence Medical Services of the future. Readers of this journal are encouraged to debate the Operational Patient Care Pathway paper in order to enable a final version to be published in the next revision of Joint Medical Doctrine. PMID- 24478384 TI - The cell biology of the endocytic system from an evolutionary perspective. AB - Evolutionary cell biology can afford an interdisciplinary comparative view that gives insights into both the functioning of modern cells and the origins of cellular systems, including the endocytic organelles. Here, we explore several recent evolutionary cell biology studies, highlighting investigations into the origin and diversity of endocytic systems in eukaryotes. Beginning with a brief overview of the eukaryote tree of life, we show how understanding the endocytic machinery in a select, but diverse, array of organisms provides insights into endocytic system origins and predicts the likely configuration in the last eukaryotic common ancestor (LECA). Next, we consider three examples in which a comparative approach yielded insight into the function of modern cellular systems. First, using ESCRT-0 as an example, we show how comparative cell biology can discover both lineage-specific novelties (ESCRT-0) as well as previously ignored ancient proteins (Tom1), likely of both evolutionary and functional importance. Second, we highlight the power of comparative cell biology for discovery of previously ignored but potentially ancient complexes (AP5). Finally, using examples from ciliates and trypanosomes, we show that not all organisms possess canonical endocytic pathways, but instead likely evolved lineage-specific mechanisms. Drawing from these case studies, we conclude that a comparative approach is a powerful strategy for advancing knowledge about the general mechanisms and functions of endocytic systems. PMID- 24478386 TI - Bioethics of organ transplantation. AB - As the ability to transplant organs and tissues has grown, the demand for these procedures has increased as well--to the point at which it far exceeds the available supply creating the core ethical challenge for transplantation- rationing. The gap between supply and demand, although large, is worse than it appears to be. There are two key steps to gaining access to a transplant. First, one must gain access to a transplant center. Then, those waiting need to be selected for a transplant. Many potential recipients do not get admitted to a program. They are deemed too old, not of the right nationality, not appropriate for transplant as a result of severe mental impairment, criminal history, drug abuse, or simply because they do not have access to a competent primary care physician who can refer them to a transplant program. There are also financial obstacles to access to transplant waiting lists in the United States and other nations. In many poor nations, those needing transplants simply die because there is no capacity or a very limited capacity to perform transplants. Although the demand for organs now exceeds the supply, resulting in rationing, the size of waiting lists would quickly expand were there to suddenly be an equally large expansion in the number of organs available for transplantation. Still, even with the reality of unavoidable rationing, saving more lives by increasing organ supply is a moral good. Current public policies for obtaining organs from cadavers are not adequate in that they do not produce the number of organs that public polls of persons in the United States indicate people are willing to donate. PMID- 24478387 TI - Facial and hand allotransplantation. AB - Vascularized composite allotransplantation (VCA) is a novel therapeutic option for treatment of patients suffering from limb loss or severe facial disfigurement. To date, 72 hand and 19 facial transplantations have been performed worldwide. VCA in hand and facial transplantation is a complex procedure requiring a multidisciplinary team approach and extensive surgical planning. Despite good functional outcome, courses after hand and facial transplantation have been complicated by skin rejection. Long-term immunosuppression remains a necessity in VCA for allograft survival. To widen the scope of these quality-of-life-improving procedures, minimization of immunosuppression to limit risks and side effects is needed. PMID- 24478388 TI - Mouse Sertoli cells sustain de novo generation of regulatory T cells by triggering the notch pathway through soluble JAGGED1. AB - FOXP3(+) regulatory T cells (Tregs) are central to the maintenance of immunological homeostasis and tolerance. It has long been known that Sertoli cells are endowed with immune suppressive properties; however, the underlying mechanisms as well as the effective nature and role of soluble factors secreted by Sertoli cells have not been fully elucidated as yet. We hypothesized that conditioned medium from primary mouse Sertoli cells (SCCM) may be able and sufficient to induce Tregs. By culturing CD4(+)CD25(-)EGFP(-) T splenocytes purified from FOXP3-EGFP knock-in mice in SCCM, here we show, by flow cytometry and suppression assay, the conversion of peripheral CD4(+)FOXP3(-) T cells into functional CD4(+)FOXP3(+) Tregs. We also demonstrate that the Notch/Jagged1 axis is involved in regulating the de novo generation of Tregs although this process is transforming growth factor-beta1 (TGF-B) dependent. In particular, we identified by Western blot analysis a soluble form of JAGGED1 (JAG1) in SCCM that significantly influences the induction of Tregs, as demonstrated by performing the conversion assay in presence of a JAG1-specific neutralizing antibody. In addition, we show that SCCM modulates the Notch pathway in converted Tregs by triggering the recruitment of the Notch-specific transcription factor CSL/RBP-Jk to the Foxp3 promoter and by inducing the Notch target gene Hey1, as shown by chromatin immunoprecipitation assay and by real time-RT-PCR experiments, respectively. Overall, these results contribute to a better understanding of the molecular mechanisms involved in Sertoli cell-mediated immune tolerance and provide a novel approach to generate ex vivo functional Tregs for therapeutic purpose. PMID- 24478390 TI - A man for all seasons: celebrating the scientific career of Yves Clermont. PMID- 24478389 TI - RNA-seq transcriptome profiling of equine inner cell mass and trophectoderm. AB - Formation of the inner cell mass (ICM) and trophectoderm (TE) marks the first differentiation event in mammalian development. These two cell types have completely divergent fates for the remainder of the developmental process. The molecular mechanisms that regulate ICM and TE formation are poorly characterized in horses. The objective of this study was to establish the transcriptome profiles of ICM and TE cells from horse blastocysts using RNA sequencing (RNA seq). A total of 12 270 genes were found to be expressed in either lineage. Global analysis of the transcriptome profiles by unsupervised clustering indicated that ICM and TE samples presented different gene expression patterns. Statistical analysis indicated that 1662 genes were differentially expressed (adjusted P < 0.05 and fold change > 2) between ICM and TE. Genes known to be specific to the ICM and TE were expressed primarily in their respective tissue. Transcript abundance for genes related to biological processes important for horse blastocyst formation and function is presented and discussed. Collectively, our data and analysis serve as a valuable resource for gene discovery and unraveling the fundamental mechanisms of early horse development. PMID- 24478391 TI - Maternal obesity impairs specific regulatory pathways in human myometrial arteries. AB - Obese women (body mass index >=30 kg/m(2)) are at greater risk than normal weight women of pregnancy complications associated with maternal and infant morbidity, particularly the development of cardiovascular disease and metabolic disorders in later life; why this occurs is unknown. Nonpregnant, obese individuals exhibit systemic vascular endothelial dysfunction. We tested the hypothesis that obese pregnant women have altered myometrial arterial function compared to pregnant women of normal (18-24 kg/m(2)) and overweight (25-29 kg/m(2)) body mass index. Responses to vasoconstrictors, U46619 (thromboxane mimetic) and arginine vasopressin, and vasodilators, bradykinin and the nitric oxide donor sodium nitroprusside, were assessed by wire myography in myometrial arteries from normal weight (n = 18), overweight (n = 18), and obese (n = 20) women with uncomplicated pregnancies. Thromboxane-prostanoid receptor expression was assessed using immunostaining in myometrial arteries of normal weight and obese women. Vasoconstriction and vasodilatation were impaired in myometrial arteries from obese women with otherwise uncomplicated pregnancies. Disparate agonist responses suggest that vascular function in obese women is not globally dysregulated but may be specific to thromboxane and nitric oxide pathways. Because obesity rates are escalating, it is important to identify the mechanisms underlying impaired vascular function and establish why some obese women compensate for vascular dysfunction and some do not. Future studies are needed to determine whether central adiposity results in an altered endocrine milieu that may promote vascular dysfunction by altering the function of perivascular adipose tissue. PMID- 24478392 TI - Synergistic effect of interferon-gamma and tumor necrosis factor-alpha on coxsackievirus and adenovirus receptor expression: an explanation of cell sloughing during testicular inflammation in mice. AB - Coxsackievirus and adenovirus receptor (CAR) is a junction molecule that expresses on Sertoli and germ cells. It mediates Sertoli-germ cell adhesion and facilitates migration of preleptotene/leptotene spermatocytes across the blood testis barrier, suggesting that CAR-based cell adhesion and migration are crucial for spermatogenesis. Interferon-gamma (IFNG) and tumor necrosis factor alpha (TNF) are two major cytokines that are elevated during testicular inflammation and cause reduced fertility. We investigated the mechanism by which IFNG and TNF exert their disruptive effects on testicular cell adhesion. We have demonstrated that combined treatment with IFNG and TNF (IFNG+TNF) exerts a synergistic effect by downregulating CAR mRNA and protein levels. Immunofluorescence staining revealed that IFNG+TNF treatment effectively removes CAR from the site of cell cell contact. Using inhibitor and co-immunoprecipitation, we confirmed that IFNG+TNF mediates CAR protein degradation via ubiquitin-proteasome and NFKB pathways. Blockage of ubiquitin-proteasome pathway significantly inhibits CAR degradation, as indicated by the reappearance of CAR at the site of cell-cell contact. Additionally, IFNG+TNF reduces CAR mRNA via transcriptional regulation. Mutational studies have shown that IFNG+TNF-induced CAR repression is achieved by suppression of the basal transcription. Electrophoretic mobility shift assay and chromatin immunoprecipitation assays further confirmed that IFNG+TNF treament not only inhibits binding of the basal transcription factors but also promotes binding of NFKB subunits and Sp1 (negative regulators) to the CAR promoter region. Taken together, IFNG+TNF treatment significantly downregulates CAR expression, which provides an explanation of how cell sloughing in the epithelium mediates, by loss of CAR-based cell adhesion, during testicular inflammation. PMID- 24478393 TI - Retinoic acid induces multiple hallmarks of the prospermatogonia-to-spermatogonia transition in the neonatal mouse. AB - In mammals, most neonatal male germ cells (prospermatogonia) are quiescent and located in the center of the testis cords. In response to an unknown signal, prospermatogonia transition into spermatogonia, reenter the cell cycle, divide, and move to the periphery of the testis cords. In mice, these events occur by 3-4 days postpartum (dpp), which temporally coincides with the onset of retinoic acid (RA) signaling in the neonatal testis. RA has a pivotal role in initiating germ cell entry into meiosis in both sexes, yet little is known about the mechanisms and about cellular changes downstream of RA signaling. We examined the role of RA in mediating the prospermatogonia-to-spermatogonia transition in vivo and found 24 h of precocious RA exposure-induced germ cell changes mimicking those that occur during the endogenous transition at 3-4 dpp. These changes included: 1) spermatogonia proliferation; 2) maturation of cellular organelles; and 3), expression of markers characteristic of differentiating spermatogonia. We found that germ cell exposure to RA did not lead to cellular loss from apoptosis but rather resulted in a delay of ~2 days in their entry into meiosis. Taken together, our results indicate that exogenous RA induces multiple hallmarks of the transition of prospermatogonia to spermatogonia prior to their entry into meiosis. PMID- 24478394 TI - Differential endometrial cell sensitivity to a cholesterol-dependent cytolysin links Trueperella pyogenes to uterine disease in cattle. AB - Purulent disease of the uterus develops in 40% of dairy cows after parturition, when the epithelium of the endometrium is disrupted to expose the underlying stroma to bacteria. The severity of endometrial pathology is associated with isolation of Trueperella pyogenes. In the present study, T. pyogenes alone caused uterine disease when infused into the uterus of cattle where the endometrial epithelium was disrupted. The bacterium secretes a cholesterol-dependent cytolysin, pyolysin (PLO), and the plo gene was identical and the plo gene promoter was highly similar amongst 12 clinical isolates of T. pyogenes. Bacteria free filtrates of the T. pyogenes cultures caused hemolysis and endometrial cytolysis, and PLO was the main cytolytic agent, because addition of anti-PLO antibody prevented cytolysis. Similarly, a plo-deletion T. pyogenes mutant did not cause hemolysis or endometrial cytolysis. Endometrial stromal cells were notably more sensitive to PLO-mediated cytolysis than epithelial or immune cells. Stromal cells also contained more cholesterol than epithelial cells, and reducing stromal cell cholesterol content using cyclodextrins protected against PLO. Although T. pyogenes or plo-deletion T. pyogenes stimulated accumulation of inflammatory mediators, such as IL-1beta, IL-6, and IL-8, from endometrium, PLO did not stimulate inflammatory responses by endometrial or hematopoietic cells, or in vitro organ cultures of endometrium. The marked sensitivity of stromal cells to PLO-mediated cytolysis provides an explanation for how T. pyogenes acts as an opportunistic pathogen to cause pathology of the endometrium once the protective epithelium is lost after parturition. PMID- 24478395 TI - Parametric modeling of whole-genome sequencing data for CNV identification. AB - Copy number variants (CNVs) constitute an important class of genetic variants in human genome and are shown to be associated with complex diseases. Whole-genome sequencing provides an unbiased way of identifying all the CNVs that an individual carries. In this paper, we consider parametric modeling of the read depth (RD) data from whole-genome sequencing with the aim of identifying the CNVs, including both Poisson and negative-binomial modeling of such count data. We propose a unified approach of using a mean-matching variance stabilizing transformation to turn the relatively complicated problem of sparse segment identification for count data into a sparse segment identification problem for a sequence of Gaussian data. We apply the optimal sparse segment identification procedure to the transformed data in order to identify the CNV segments. This provides a computationally efficient approach for RD-based CNV identification. Simulation results show that this approach often results in a small number of false identifications of the CNVs and has similar or better performances in identifying the true CNVs when compared with other RD-based approaches. We demonstrate the methods using the trio data from the 1000 Genomes Project. PMID- 24478396 TI - A humanized mouse model of autoimmune insulitis. AB - Many mechanisms of and treatments for type 1 diabetes studied in the NOD mouse model have not been replicated in human disease models. Thus, the field of diabetes research remains hindered by the lack of an in vivo system in which to study the development and onset of autoimmune diabetes. To this end, we characterized a system using human CD4(+) T cells pulsed with autoantigen-derived peptides. Six weeks after injection of as few as 0.5 * 10(6) antigen-pulsed cells into the NOD-Scid Il2rg(-/-) mouse expressing the human HLA-DR4 transgene, infiltration of mouse islets by human T cells was seen. Although islet infiltration occurred with both healthy and diabetic donor antigen-pulsed CD4(+) T cells, diabetic donor injections yielded significantly greater levels of insulitis. Additionally, significantly reduced insulin staining was observed in mice injected with CD4(+) T-cell lines from diabetic donors. Increased levels of demethylated beta-cell-derived DNA in the bloodstream accompanied this loss of insulin staining. Together, these data show that injection of small numbers of autoantigen-reactive CD4(+) T cells can cause a targeted, destructive infiltration of pancreatic beta-cells. This model may be valuable for understanding mechanisms of induction of human diabetes. PMID- 24478397 TI - LECT2 functions as a hepatokine that links obesity to skeletal muscle insulin resistance. AB - Recent articles have reported an association between fatty liver disease and systemic insulin resistance in humans, but the causal relationship remains unclear. The liver may contribute to muscle insulin resistance by releasing secretory proteins called hepatokines. Here we demonstrate that leukocyte cell derived chemotaxin 2 (LECT2), an energy-sensing hepatokine, is a link between obesity and skeletal muscle insulin resistance. Circulating LECT2 positively correlated with the severity of both obesity and insulin resistance in humans. LECT2 expression was negatively regulated by starvation-sensing kinase adenosine monophosphate-activated protein kinase in H4IIEC hepatocytes. Genetic deletion of LECT2 in mice increased insulin sensitivity in the skeletal muscle. Treatment with recombinant LECT2 protein impaired insulin signaling via phosphorylation of Jun NH2-terminal kinase in C2C12 myocytes. These results demonstrate the involvement of LECT2 in glucose metabolism and suggest that LECT2 may be a therapeutic target for obesity-associated insulin resistance. PMID- 24478398 TI - Hypothalamic nesfatin-1/NUCB2 knockdown augments hepatic gluconeogenesis that is correlated with inhibition of mTOR-STAT3 signaling pathway in rats. AB - Nesfatin-1, an 82-amino acid neuropeptide, has recently been characterized as a potent metabolic regulator. However, the metabolic mechanisms and signaling steps directly associated with the action of nesfatin-1 have not been well delineated. We established a loss-of-function model of hypothalamic nesfatin-1/NUCB2 signaling in rats through an adenoviral-mediated RNA interference. With this model, we found that inhibition of central nesfatin-1/NUCB2 activity markedly increased food intake and hepatic glucose flux and decreased glucose uptake in peripheral tissue in rats fed either a normal chow diet (NCD) or a high-fat diet (HFD). The change of hepatic glucose fluxes in the hypothalamic nesfatin-1/NUCB2 knockdown rats was accompanied by increased hepatic levels of glucose-6 phosphatase and PEPCK and decreased insulin receptor, insulin receptor substrate 1, and AKT kinase phosphorylation. Furthermore, knockdown of hypothalamic nesfatin-1 led to decreased phosphorylation of mammalian target of rapamycin (mTOR) and signal transducer and activator of transcription 3 (STAT3) and the subsequent suppressor of cytokine signaling 3 levels. These results demonstrate that hypothalamic nesfatin-1/NUCB2 plays an important role in glucose homeostasis and hepatic insulin sensitivity, which is, at least in part, associated with the activation of the mTOR-STAT3 signaling pathway. PMID- 24478399 TI - Profiling of circulating microRNAs reveals common microRNAs linked to type 2 diabetes that change with insulin sensitization. AB - OBJECTIVE: This study sought to identify the profile of circulating microRNAs (miRNAs) in type 2 diabetes (T2D) and its response to changes in insulin sensitivity. RESEARCH DESIGN AND METHODS: The circulating miRNA profile was assessed in a pilot study of 12 men: 6 with normal glucose tolerance (NGT) and 6 T2D patients. The association of 10 circulating miRNAs with T2D was cross sectionally validated in an extended sample of 45 NGT vs. 48 T2D subjects (65 nonobese and 28 obese men) and longitudinally in 35 T2D patients who were recruited in a randomized, double-blinded, and placebo-controlled 3-month trial of metformin treatment. Circulating miRNAs were also measured in seven healthy volunteers before and after a 6-h hyperinsulinemic-euglycemic clamp and insulin plus intralipid/heparin infusion. RESULTS: Cross-sectional studies disclosed a marked increase of miR-140-5p, miR-142-3p, and miR-222 and decreased miR-423-5p, miR-125b, miR-192, miR-195, miR-130b, miR-532-5p, and miR-126 in T2D patients. Multiple linear regression analyses revealed that miR-140-5p and miR-423-5p contributed independently to explain 49.5% (P < 0.0001) of fasting glucose variance after controlling for confounders. A discriminant function of four miRNAs (miR-140-5p, miR-423-5p, miR-195, and miR-126) was specific for T2D with an accuracy of 89.2% (P < 0.0001). Metformin (but not placebo) led to significant changes in circulating miR-192 (49.5%; P = 0.022), miR-140-5p (-15.8%; P = 0.004), and miR-222 (-47.2%; P = 0.03), in parallel to decreased fasting glucose and HbA1c. Furthermore, while insulin infusion during clamp decreased miR-222 ( 62%; P = 0.002), the intralipid/heparin mixture increased circulating miR-222 (163%; P = 0.015) and miR-140-5p (67.5%; P = 0.05). CONCLUSIONS: This study depicts the close association between variations in circulating miRNAs and T2D and their potential relevance in insulin sensitivity. PMID- 24478400 TI - Clonal evolution and clinical correlates of somatic mutations in myeloproliferative neoplasms. AB - Myeloproliferative neoplasms (MPNs) are a group of clonal disorders characterized by aberrant hematopoietic proliferation and an increased tendency toward leukemic transformation. We used targeted next-generation sequencing (NGS) of 104 genes to detect somatic mutations in a cohort of 197 MPN patients and followed clonal evolution and the impact on clinical outcome. Mutations in calreticulin (CALR) were detected using a sensitive allele-specific polymerase chain reaction. We observed somatic mutations in 90% of patients, and 37% carried somatic mutations other than JAK2 V617F and CALR. The presence of 2 or more somatic mutations significantly reduced overall survival and increased the risk of transformation into acute myeloid leukemia. In particular, somatic mutations with loss of heterozygosity in TP53 were strongly associated with leukemic transformation. We used NGS to follow and quantitate somatic mutations in serial samples from MPN patients. Surprisingly, the number of mutations between early and late patient samples did not significantly change, and during a total follow-up of 133 patient years, only 2 new mutations appeared, suggesting that the mutation rate in MPN is rather low. Our data show that comprehensive mutational screening at diagnosis and during follow-up has considerable potential to identify patients at high risk of disease progression. PMID- 24478402 TI - Essential role of BRG, the ATPase subunit of BAF chromatin remodeling complexes, in leukemia maintenance. AB - In mammals, combinatorial assembly of alternative families of subunits confers functional specificity to adenosine triphosphate (ATP)-dependent SWI/SNF-like Brg/Brm-associated factor (BAF) chromatin remodeling complexes by creating distinct polymorphic surfaces for interaction with regulatory elements and DNA binding factors. Although redundant in terms of biochemical activity, the core ATPase subunits, BRG/SMARCA4 and BRM/SMARCA2, are functionally distinct and may contribute to complex specificity. Here we show using quantitative proteomics that BAF complexes expressed in leukemia are specifically assembled around the BRG ATPase. Moreover, using a mouse model of acute myeloid leukemia, we demonstrate that BRG is essential for leukemia maintenance, as leukemic cells lacking BRG rapidly undergo cell-cycle arrest and apoptosis. Most importantly, we show that BRG is dispensable for the maintenance of immunophenotypic long-term repopulating hematopoietic stem cells, suggesting that adroit targeting of BRG in leukemia may have potent and specific therapeutic effects. PMID- 24478401 TI - Epistasis between the haptoglobin common variant and alpha+thalassemia influences risk of severe malaria in Kenyan children. AB - Haptoglobin (Hp) scavenges free hemoglobin following malaria-induced hemolysis. Few studies have investigated the relationship between the common Hp variants and the risk of severe malaria, and their results are inconclusive. We conducted a case-control study of 996 children with severe Plasmodium falciparum malaria and 1220 community controls and genotyped for Hp, hemoglobin (Hb) S heterozygotes, and alpha(+)thalassemia. Hb S heterozygotes and alpha(+)thalassemia homozygotes were protected from severe malaria (odds ratio [OR], 0.12; 95% confidence interval [CI], 0.07-0.18 and OR, 0.69; 95% CI, 0.53-0.91, respectively). The risk of severe malaria also varied by Hp genotype: Hp2-1 was associated with the greatest protection against severe malaria and Hp2-2 with the greatest risk. Meta analysis of the current and published studies suggests that Hp2-2 is associated with increased risk of severe malaria compared with Hp2-1. We found a significant interaction between Hp genotype and alpha(+)thalassemia in predicting risk of severe malaria: Hp2-1 in combination with heterozygous or homozygous alpha(+)thalassemia was associated with protection from severe malaria (OR, 0.73; 95% CI, 0.54-0.99 and OR, 0.48; 95% CI, 0.32-0.73, respectively), but alpha(+)thalassemia in combination with Hp2-2 was not protective. This epistatic interaction together with varying frequencies of alpha(+)thalassemia across Africa may explain the inconsistent relationship between Hp genotype and malaria reported in previous studies. PMID- 24478403 TI - Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. AB - Therapy-related acute myeloid leukemia and myelodysplastic syndromes (t-AML/MDS) represent severe late effects in patients treated for Hodgkin lymphoma (HL). Because more recent data are scarce, we retrospectively analyzed incidence, outcome, and risk factors for the development of t-AML/MDS after HL. A total of 11,952 patients treated for newly diagnosed HL within German Hodgkin Study Group trials between 1993 and 2009 were considered. At a median follow-up of 72 months, t-AML/MDS was diagnosed in 106/11,952 patients (0.9%). Median time from HL treatment to t-AML/MDS was 31 months. The median age of patients with t-AML/MDS was higher than in the whole patient group (43 vs 34 years, P < .0001). Patients who received 4 or more cycles of BEACOPP(escalated) had an increased risk to develop t-AML/MDS when compared with patients treated with less than 4 cycles of BEACOPP(escalated) or no BEACOPP chemotherapy (1.7% vs 0.7% vs 0.3%, P < .0001). The median overall survival (OS) for all t-AML/MDS patients was 7.2 months. However, t-AML/MDS patients proceeding to allogeneic stem cell transplantation had a significantly better outcome with a median OS not reached after a median follow-up of 41 months (P < .001). PMID- 24478404 TI - Comparison of two assays for molecular determination of rifampin resistance in clinical samples from patients with Buruli ulcer disease. AB - This study evaluates a novel assay for detecting rifampin resistance in clinical Mycobacterium ulcerans isolates. Although highly susceptible for PCR inhibitors in 50% of the samples tested, the assay was 100% M. ulcerans specific and yielded >98% analyzable sequences with a lower limit of detection of 100 to 200 copies of the target sequence. PMID- 24478405 TI - Potential impact of a microarray-based nucleic acid assay for rapid detection of Gram-negative bacteria and resistance markers in positive blood cultures. AB - We evaluated the Verigene Gram-negative blood culture (BC-GN) test, a microarray that detects Gram-negative bacteria and several resistance genes. A total of 102 positive blood cultures were tested, and the BC-GN test correctly identified 97.9% of the isolates within its panel. Resistance genes (CTX-M, KPC, VIM, and OXA genes) were detected in 29.8% of the isolates, with positive predictive values of 95.8% (95% confidence interval [CI], 87.7% to 98.9%) in Enterobacteriaceae and 100% (95% CI, 75.9% to 100%) in Pseudomonas aeruginosa and negative predictive values of 100% (95% CI, 93.9% to 100%) and 78.6% (95% CI, 51.0% to 93.6%), respectively. PMID- 24478406 TI - Abdominal abscess caused by Mycobacterium llatzerense. AB - Mycobacterium llatzerense was cultured from a subdiaphragmatic abscess. To our knowledge, this is the first report of isolation of this rapidly growing mycobacterium from a human. Growth characteristics and antimicrobial susceptibilities different from those previously reported for environmental isolates were observed. PMID- 24478407 TI - Evaluation of a short, on-plate formic acid extraction method for matrix-assisted laser desorption ionization-time of flight mass spectrometry-based identification of clinically relevant yeast isolates. AB - This report describes a short, on-plate formic acid (FA) extraction method for the identification of clinical yeast isolates using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). A total of 41.1% (78/190) and 63.7% (121/190) of yeasts were identified using species log score thresholds of >2.0 and >1.9, respectively. Overall, 97.4% (185/190) of yeasts were identified in combination with conventional FA extraction. PMID- 24478408 TI - Prevalence of mupirocin resistance in Staphylococcus pseudintermedius. AB - In the United States, veterinary use of mupirocin is primarily limited to the treatment of canine pyoderma caused by methicillin-resistant Staphylococcus pseudintermedius (MRSP). In this study, only 1 of 581 S. pseudintermedius isolates tested was resistant to mupirocin and carried the high-level mupirocin resistance gene, ileS2, on a plasmid. PMID- 24478410 TI - Molecular characterization of methicillin-resistant Staphylococcus aureus strains isolated from patients with hospital readmissions. AB - It is unclear whether patients colonized with methicillin-resistant Staphylococcus aureus (MRSA) continue to harbor the same genotype during hospital readmissions. We characterized 140 MRSA strains isolated from 33 persistent MRSA carriers with hospital readmissions. Nearly half of the patients continued to harbor the same genotype, and the rest acquired different genotypes. Among 25 patients who received eradication therapy, 16 (64%) were colonized with MRSA strains exhibiting different genotypes from the preexisting one. PMID- 24478409 TI - A multiplex real-time PCR assay for identification of Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans/Cryptococcus gattii in samples from AIDS patients with opportunistic pneumonia. AB - A molecular diagnostic technique based on real-time PCR was developed for the simultaneous detection of three of the most frequent causative agents of fungal opportunistic pneumonia in AIDS patients: Pneumocystis jirovecii, Histoplasma capsulatum, and Cryptococcus neoformans/Cryptococcus gattii. This technique was tested in cultured strains and in clinical samples from HIV-positive patients. The methodology used involved species-specific molecular beacon probes targeted to the internal transcribed spacer regions of the rDNA. An internal control was also included in each assay. The multiplex real-time PCR assay was tested in 24 clinical strains and 43 clinical samples from AIDS patients with proven fungal infection. The technique developed showed high reproducibility (r(2) of >0.98) and specificity (100%). For H. capsulatum and Cryptococcus spp., the detection limits of the method were 20 and 2 fg of genomic DNA/20 MUl reaction mixture, respectively, while for P. jirovecii the detection limit was 2.92 log10 copies/20 MUl reaction mixture. The sensitivity in vitro was 100% for clinical strains and 90.7% for clinical samples. The assay was positive for 92.5% of the patients. For one of the patients with proven histoplasmosis, P. jirovecii was also detected in a bronchoalveolar lavage sample. No PCR inhibition was detected. This multiplex real-time PCR technique is fast, sensitive, and specific and may have clinical applications. PMID- 24478411 TI - Real-time PCR assay for detection of blaZ genes in Staphylococcus aureus clinical isolates. AB - The Clinical and Laboratory Standards Institute recommends consideration of blaZ gene testing for cases of serious Staphylococcus aureus infection. Conventional PCR methods have demonstrated superior sensitivity and specificity to phenotypic tests. To our knowledge, this is the first description of real-time PCR detection of the blaZ gene. PMID- 24478412 TI - Tools for detection of Mycoplasma amphoriforme: a primary respiratory pathogen? AB - Mycoplasma amphoriforme is a recently described organism isolated from the respiratory tracts of patients with immunodeficiency and evidence of chronic infection. Novel assays for the molecular detection of the organism by real-time quantitative PCRs (qPCRs) targeting the uracil DNA glycosylase gene (udg) or the 23S rRNA gene are described here. The analytical sensitivities are similar to the existing conventional M. amphoriforme 16S rRNA gene PCR, with the advantage of being species specific, rapid, and quantitative. By using these techniques, we demonstrate the presence of this organism in 17 (19.3%) primary antibody deficient (PAD) patients, 4 (5%) adults with lower respiratory tract infection, 1 (2.6%) sputum sample from a patient attending a chest clinic, and 23 (0.21%) samples submitted for viral diagnosis of respiratory infection, but not in normal adult control subjects. These data show the presence of this microorganism in respiratory patients and suggest that M. amphoriforme may infect both immunocompetent and immunocompromised people. Further studies to characterize this organism are required, and this report provides the tools that may be used by other research groups to investigate its pathogenic potential. PMID- 24478413 TI - Specific noninvasive detection of Leishmania donovani in desquamated buccal cell swab samples from human visceral Leishmaniasis-HIV coinfected patients. AB - Diagnosis of human immunodeficiency virus (HIV) infection with visceral leishmaniasis (VL) coinfection is challenging. Specific diagnosis of VL in HIV coinfected patients was evaluated by molecular methods in desquamated buccal swab samples, demonstrating 86.3% sensitivity and 98.3% specificity in controls. This test holds significant potential for development as a noninvasive diagnostic tool for VL in HIV-coinfected patients. PMID- 24478414 TI - Multiplex high-resolution melting analysis as a diagnostic tool for detection of plasmid-mediated AmpC beta-lactamase genes. AB - High-resolution melting (HRM) analysis can be a diagnostic tool to evaluate the presence of resistance genes with the added bonus of discriminating sequence modifications. A real-time, multiplex PCR assay using HRM was designed for the detection of plasmid-mediated ampC genes. The specificity and sensitivity of this assay were 96% and 100%, respectively. PMID- 24478415 TI - Bacterial lymphadenitis at a major referral hospital in France from 2008 to 2012. AB - Lymph node enlargement is a common medical problem, and in a large number of patients, the causes of lymphadenopathy remain undiagnosed. We report a thorough microbiological analysis of 1,688 lymph node biopsy specimens collected in our bartonellosis reference center. We studied lymph node biopsy samples from patients with suspected regional infectious lymph node enlargement from January 2008 to December 2012. To evaluate a useful strategy for the diagnosis of infectious lymphadenitis, specimens were cultured and subjected to molecular assays. Histologic analysis was done when possible. A total of 642 (38%) biopsy specimens were infected with a bacterial agent, and quantitative PCR (qPCR) was significantly better than 16S rRNA gene PCR (rrs) for the detection of Bartonella henselae (P = 0.05), Mycobacterium tuberculosis (P = 0.05), and Mycobacterium avium (P = 0.007). Molecular assays were significantly better than bacterial cultures for the diagnosis of Francisella tularensis (P = 0.017) but were less effective for detecting M. tuberculosis (P = 0.004) and M. avium (P = 0.001). Histologic analysis was done for 412 lymph nodes, and 20% of these were compatible with an infectious lymphadenitis, whereas a neoplasm was found in 29% of these lymph nodes. M. tuberculosis was detected significantly more in female than in male patients (P = 0.01), and patients with cat scratch disease (CSD) were younger than patients with M. tuberculosis, Tropheryma whipplei, and F. tularensis. Negative rrs PCR does not exclude the diagnosis of infectious lymphadenitis. Histologic analysis of lymph node biopsy specimens is critical, as a diagnosis of infectious lymphadenitis does not preclude other concurrent diseases. PMID- 24478416 TI - Fatal fulminant hepatitis E associated with autoimmune hepatitis and excessive paracetamol intake in Southeastern France. AB - We present, to our knowledge, the first case of fatal fulminant liver failure associated with hepatitis E virus infection, autoimmune hepatitis, and excessive paracetamol intake, which occurred in a 77-year-old woman. Hepatitis E testing should be performed in severe acute liver failure cases, even when another cause has been identified. PMID- 24478417 TI - De Novo meningitis caused by Propionibacterium acnes in a patient with metastatic melanoma. AB - Propionibacterium acnes is a known cause of postneurosurgical meningitis; however, it is rarely implicated in de novo meningitis. Herein we report a case of a 49-year-old male with de novo meningitis caused by P. acnes with metastatic melanoma as the only identified risk factor for his infection. PMID- 24478418 TI - Simultaneous detection of five enteric viruses associated with gastroenteritis by use of a PCR assay: a single real-time multiplex reaction and its clinical application. AB - We developed a highly sensitive reverse transcription and multiplex real-time PCR (rtPCR) assay that can identify five viruses, including six genogroups, in a single reaction: norovirus genogroups I and II; sapovirus genogroups I, II, IV, and V; human rotavirus A; adenovirus serotypes 40 and 41; and human astrovirus. In comparison to monoplex rtPCR assays, the sensitivities and specificities of the multiplex rtPCR ranged from 75% to 100% and from 99% to 100%, respectively, evaluated on 812 clinical stool specimens. PMID- 24478419 TI - Transcriptional derepression of the ERVWE1 locus following influenza A virus infection. AB - Syncytin-1, a fusogenic protein encoded by a human endogenous retrovirus of the W family (HERV-W) element (ERVWE1), is expressed in the syncytiotrophoblast layer of the placenta. This locus is transcriptionally repressed in adult tissues through promoter CpG methylation and suppressive histone modifications. Whereas syncytin-1 appears to be crucial for the development and functioning of the human placenta, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. We previously reported on the transactivation of HERV-W elements, including ERVWE1, during influenza A/WSN/33 virus infection in a range of human cell lines. Here we report the results of quantitative PCR analyses of transcripts encoding syncytin-1 in both cell lines and primary fibroblast cells. We observed that spliced ERVWE1 transcripts and those encoding the transcription factor glial cells missing 1 (GCM1), acting as an enhancer element upstream of ERVWE1, are prominently upregulated in response to influenza A/WSN/33 virus infection in nonplacental cells. Knockdown of GCM1 by small interfering RNA followed by infection suppressed the transactivation of ERVWE1. While the infection had no influence on CpG methylation in the ERVWE1 promoter, chromatin immunoprecipitation assays detected decreased H3K9 trimethylation (H3K9me3) and histone methyltransferase SETDB1 levels along with influenza virus proteins associated with ERVWE1 and other HERV-W loci in infected CCF-STTG1 cells. The present findings suggest that an exogenous influenza virus infection can transactivate ERVWE1 by increasing transcription of GCM1 and reducing H3K9me3 in this region and in other regions harboring HERV-W elements. IMPORTANCE: Syncytin-1, a protein encoded by the env gene in the HERV-W locus ERVWE1, appears to be crucial for the development and functioning of the human placenta and is transcriptionally repressed in nonplacental tissues. Nevertheless, its ectopic expression has been associated with pathological conditions, such as multiple sclerosis and schizophrenia. In the present paper, we report findings suggesting that an exogenous influenza A virus infection can transactivate ERVWE1 by increasing the transcription of GCM1 and reducing the repressive histone mark H3K9me3 in this region and in other regions harboring HERV-W elements. These observations have implications of potential relevance for viral pathogenesis and for conditions associated with the aberrant transcription of HERV-W loci. PMID- 24478420 TI - TRIM5alpha and TRIM22 are differentially regulated according to HIV-1 infection phase and compartment. AB - The antiviral role of TRIM E3 ligases in vivo is not fully understood. To test the hypothesis that TRIM5alpha and TRIM22 have differential transcriptional regulation and distinct anti-HIV roles according to infection phase and compartment, we measured TRIM5alpha, TRIM22, and type I interferon (IFN-I) inducible myxovirus resistance protein A (MxA) levels in peripheral blood mononuclear cells (PBMCs) during primary and chronic HIV-1 infection, with chronic infection samples being matched PBMCs and central nervous system (CNS) derived cells. Associations with biomarkers of disease progression were explored. The impact of IFN-I, select proinflammatory cytokines, and HIV on TRIM E3 ligase specific expression was investigated. PBMCs from individuals with primary and chronic HIV-1 infection had significantly higher levels of MxA and TRIM22 than did PBMCs from HIV-1-negative individuals (P < 0.05 for all comparisons). PBMCs from chronic infection had lower levels of TRIM5alpha than did PBMCs from primary infection or HIV-1-uninfected PBMCs (P = 0.0001 for both). In matched CNS-derived samples and PBMCs, higher levels of MxA (P = 0.001) and TRIM5alpha (P = 0.0001) in the CNS were noted. There was a negative correlation between TRIM22 levels in PBMCs and plasma viral load (r = -0.40; P = 0.04). In vitro, IFN-I and, rarely, proinflammatory cytokines induced TRIM5alpha and TRIM22 in a cell type-dependent manner, and the knockdown of either protein in CD4(+) lymphocytes resulted in increased HIV-1 infection. These data suggest that there are infection-phase specific and anatomically compartmentalized differences in TRIM5alpha and TRIM22 regulation involving primarily IFN-I and specific cell types and indicate subtle differences in the antiviral roles and transcriptional regulation of TRIM E3 ligases in vivo. IMPORTANCE: Type I interferon-inducible TRIM E3 ligases are a family of intracellular proteins with potent antiviral activities mediated through diverse mechanisms. However, little is known about the contribution of these proteins to antiviral immunity in vivo and how their expression is regulated. We show here that TRIM5alpha and TRIM22, two prominent members of the family, have different expression patterns in vivo and that the expression pattern depends on HIV-1 infection status and phase. Furthermore, expression differs in peripheral blood versus central nervous system anatomical sites of infection. Only TRIM22 expression correlated negatively with HIV-1 viral load, but gene silencing of both proteins enhances HIV-1 infection of target cells. We report subtle differences in TRIM5alpha and TRIM22 gene induction by IFN-I and proinflammatory cytokines in CD4(+) lymphocytes, monocytes, and neuronal cells. This study enhances our understanding of antiviral immunity by intrinsic antiviral factors and how their expression is determined. PMID- 24478421 TI - Development of continuous cell culture of brown planthopper to trace the early infection process of oryzaviruses in insect vector cells. AB - Rice ragged stunt virus (RRSV), an oryzavirus in the family Reoviridae, is transmitted by the brown planthopper, Nilaparvata lugens, in a persistent propagative manner. Here, we established a continuous cell line of brown planthopper to investigate the mechanism underlying the formation of the viroplasm, the putative site for viral replication and assembly, during infection of RRSV in its insect vector cells. Within 24 h of viral infection of cultured cells, the viroplasm had formed and contained the viral nonstructural proteins Pns6 and Pns10, known to be constituents of viroplasm. Core capsid protein P3, core particles, and newly synthesized viral RNAs were accumulated inside the viroplasm, while outer capsid protein P8 and virions were accumulated at the periphery of the viroplasm, confirming that the viroplasm induced by RRSV infection was the site for viral replication and assembly. Pns10 formed viroplasm like inclusions in the absence of viral infection, suggesting that the viroplasm matrix was largely composed of Pns10. Pns6 was recruited in the viroplasm by direct interaction with Pns10. Core capsid protein P3 was recruited to the viroplasm through specific association with Pns6. Knockdown of Pns6 and Pns10 expression using RNA interference inhibited viroplasm formation, virion assembly, viral protein expression, and viral double-stranded RNA synthesis. Thus, the present study shows that both Pns6 and Pns10 of RRSV play important roles in the early stages of viral life cycle in its insect vector cells, by recruiting or retaining components necessary for viral replication and assembly. IMPORTANCE: The brown planthopper, a commonly distributed pest of rice in Asia, is the host of numerous insect endosymbionts, and the major vector of two rice viruses (RRSV and rice grassy stunt virus). For the first time, we successfully established the continuous cell line of brown planthopper. The unique uniformity of brown planthopper cells in the monolayer can support a consistent, synchronous infection by endosymbionts or viral pathogens, improving our understanding of molecular insect-microbe interactions. PMID- 24478422 TI - Inhibition of hepatitis C virus in chimeric mice by short synthetic hairpin RNAs: sequence analysis of surviving virus shows added selective pressure of combination therapy. AB - We have recently shown that a cocktail of two short synthetic hairpin RNAs (sshRNAs), targeting the internal ribosome entry site of hepatitis C virus (HCV) formulated with lipid nanoparticles, was able to suppress viral replication in chimeric mice infected with HCV GT1a by up to 2.5 log10 (H. Ma et al., Gastroenterology 146:63-66.e5, http://dx.doi.org/10.1053/j.gastro.2013.09.049) Viral load remained about 1 log10 below pretreatment levels 21 days after the end of dosing. We have now sequenced the HCV viral RNA amplified from serum of treated mice after the 21-day follow-up period. Viral RNA from the HCV sshRNA treated groups was altered in sequences complementary to the sshRNAs and nowhere else in the 500-nucleotide sequenced region, while the viruses from the control group that received an irrelevant sshRNA had no mutations in that region. The ability of the most commonly selected mutations to confer resistance to the sshRNAs was confirmed in vitro by introducing those mutations into HCV-luciferase reporters. The mutations most frequently selected by sshRNA treatment within the sshRNA target sequence occurred at the most polymorphic residues, as identified from an analysis of available clinical isolates. These results demonstrate a direct antiviral activity with effective HCV suppression, demonstrate the added selective pressure of combination therapy, and confirm an RNA interference (RNAi) mechanism of action. IMPORTANCE: This study presents a detailed analysis of the impact of treating a hepatitis C virus (HCV)-infected animal with synthetic hairpin-shaped RNAs that can degrade the virus's RNA genome. These RNAs can reduce the viral load in these animals by over 99% after 1 to 2 injections. The study results confirm that the viral rebound that often occurred a few weeks after treatment is due to emergence of a virus whose genome is mutated in the sequences targeted by the RNAs. The use of two RNA inhibitors, which is more effective than use of either one by itself, requires that any resistant virus have mutations in the targets sites of both agents, a higher hurdle, if the virus is to retain the ability to replicate efficiently. These results demonstrate a direct antiviral activity with effective HCV suppression, demonstrate the added selective pressure of combination therapy, and confirm an RNAi mechanism of action. PMID- 24478423 TI - Roles of the putative integrin-binding motif of the human metapneumovirus fusion (f) protein in cell-cell fusion, viral infectivity, and pathogenesis. AB - Human metapneumovirus (hMPV) is a relatively recently identified paramyxovirus that causes acute upper and lower respiratory tract infection. Entry of hMPV is unusual among the paramyxoviruses, in that fusion is accomplished by the fusion (F) protein without the attachment glycoprotein (G protein). It has been suggested that hMPV F protein utilizes integrin alphavbeta1 as a cellular receptor. Consistent with this, the F proteins of all known hMPV strains possess an integrin-binding motif ((329)RGD(331)). The role of this motif in viral entry, infectivity, and pathogenesis is poorly understood. Here, we show that alpha5beta1 and alphav integrins are essential for cell-cell fusion and hMPV infection. Mutational analysis found that residues R329 and G330 in the (329)RGD(331) motif are essential for cell-cell fusion, whereas mutations at D331 did not significantly impact fusion activity. Furthermore, fusion-defective RGD mutations were either lethal to the virus or resulted in recombinant hMPVs that had defects in viral replication in cell culture. In cotton rats, recombinant hMPV with the R329K mutation in the F protein (rhMPV-R329K) and rhMPV-D331A exhibited significant defects in viral replication in nasal turbinates and lungs. Importantly, inoculation of cotton rats with these mutants triggered a high level of neutralizing antibodies and protected against hMPV challenge. Taken together, our data indicate that (i) alpha5beta1 and alphav integrins are essential for cell-cell fusion and viral replication, (ii) the first two residues in the RGD motif are essential for fusion activity, and (iii) inhibition of the interaction of the integrin-RGD motif may serve as a new target to rationally attenuate hMPV for the development of live attenuated vaccines. IMPORTANCE: Human metapneumovirus (hMPV) is one of the major causative agents of acute respiratory disease in humans. Currently, there is no vaccine or antiviral drug for hMPV. hMPV enters host cells via a unique mechanism, in that viral fusion (F) protein mediates both attachment and fusion activity. Recently, it was suggested that hMPV F protein utilizes integrins as receptors for entry via a poorly understood mechanism. Here, we show that alpha5beta1 and alphav integrins are essential for hMPV infectivity and F protein-mediated cell-cell fusion and that the integrin binding motif in the F protein plays a crucial role in these functions. Our results also identify the integrin-binding motif to be a new, attenuating target for the development of a live vaccine for hMPV. These findings not only will facilitate the development of antiviral drugs targeting viral entry steps but also will lead to the development new live attenuated vaccine candidates for hMPV. PMID- 24478424 TI - Chimeric bovine/human parainfluenza virus type 3 expressing respiratory syncytial virus (RSV) F glycoprotein: effect of insert position on expression, replication, immunogenicity, stability, and protection against RSV infection. AB - A recombinant chimeric bovine/human parainfluenza type 3 virus (rB/HPIV3) vector expressing the respiratory syncytial virus (RSV) fusion F glycoprotein previously exhibited disappointing levels of RSV F immunogenicity and genetic stability in children (D. Bernstein et al., Pediatr. Infect. Dis. J. 31:109-114, 2012; C.-F. Yang et al., Vaccine 31:2822-2827, 2013). To investigate parameters that might affect vaccine performance and stability, we constructed and characterized rB/HPIV3 viruses expressing RSV F from the first (pre-N), second (N-P), third (P M), and sixth (HN-L) genome positions. There was a 30- to 69-fold gradient in RSV F expression from the first to the sixth position. The inserts moderately attenuated vector replication in vitro and in the upper and lower respiratory tracts of hamsters: this was not influenced by the level of RSV F expression and syncytium formation. Surprisingly, inserts in the second, third, and sixth positions conferred increased temperature sensitivity: this was greatest for the third position and was the most attenuating in vivo. Each rB/HPIV3 vector induced a high titer of neutralizing antibodies in hamsters against RSV and HPIV3. Protection against RSV challenge was greater for position 2 than for position 6. Evaluation of insert stability suggested that RSV F is under selective pressure to be silenced during vector replication in vivo, but this was not exacerbated by a high level of RSV F expression and generally involved a small percentage of recovered vector. Vector passaged in vitro accumulated mutations in the HN open reading frame, causing a dramatic increase in plaque size that may have implications for vaccine production and immunogenicity. IMPORTANCE: The research findings presented here will be instrumental for improving the design of a bivalent pediatric vaccine for respiratory syncytial virus and parainfluenza virus type 3, two major causes of severe respiratory tract infection in infants and young children. Moreover, this knowledge has general application to the development and clinical evaluation of other mononegavirus vectors and vaccines. PMID- 24478425 TI - Novel avian-origin influenza A (H7N9) virus attachment to the respiratory tract of five animal models. AB - We determined the pattern of attachment of the avian-origin H7N9 influenza viruses A/Anhui/1/2013 and A/Shanghai/1/2013 to the respiratory tract in ferrets, macaques, mice, pigs, and guinea pigs and compared it to that in humans. The H7N9 attachment pattern in macaques, mice, and to a lesser extent pigs and guinea pigs resembled that in humans more closely than the attachment pattern in ferrets. This information contributes to our knowledge of the different animal models for influenza. PMID- 24478426 TI - Reversible and efficient activation of HIV-1 cell entry by a tyrosine-sulfated peptide dissects endocytic entry and inhibitor mechanisms. AB - HIV-1 membranes contain gp120-gp41 trimers. Binding of gp120 to CD4 and a coreceptor (CCR5 or CXCR4) reduces the constraint on metastable gp41, enabling a series of conformational changes that cause membrane fusion. An analytic difficulty occurs because these steps occur slowly and asynchronously within cohorts of adsorbed virions. We previously isolated HIV-1JRCSF variants that efficiently use CCR5 mutants severely damaged in the tyrosine-sulfated amino terminus or extracellular loop 2. Surprisingly, both independent adaptations included gp120 mutations S298N, F313L, and N403S, supporting other evidence that they function by weakening gp120's grip on gp41 rather than by altering gp120 binding to specific CCR5 sites. Although several natural HIV-1 isolates reportedly use CCR5(Delta18) (CCR5 with a deletion of 18 N-terminal amino acids, including the tyrosine-sulfated region) when the soluble tyrosine-sulfated peptide is present, we show that HIV-1JRCSF with the adaptive mutations [HIV 1JRCSF(Ad)] functions approximately 100 times more efficiently and that coreceptor activation is reversible, enabling synchronous efficient entry control under physiological conditions. This system revealed that three-stranded gp41 folding intermediates susceptible to the inhibitor enfuvirtide form slowly and asynchronously on cell surface virions but resolve rapidly, with virions generally forming only one target. Adsorbed virions asynchronously and transiently become competent for entry at 37 degrees C but are inactivated if the CCR5 peptide is absent during their window of opportunity. This competency is conferred by endocytosis, which results in inactivation if the peptide is absent. For both wild-type and adapted HIV-1 isolates, early gp41 refolding steps obligatorily occur on cell surfaces, whereas the final step(s) is endosomal. This system powerfully dissects HIV-1 entry and inhibitor mechanisms. IMPORTANCE: We present a powerful means to reversibly and efficiently activate or terminate HIV 1 entry by adding or removing a tyrosine-sulfated CCR5 peptide from the culture medium. This system uses stable cell clones and a variant of HIV-1JRCSF with three adaptive mutations. It enabled us to show that CCR5 coreceptor activation is rapidly reversible and to dissect aspects of entry that had previously been relatively intractable. Our analyses elucidate enfuvirtide (T-20) function and suggest that HIV-1 virions form only one nonredundant membrane fusion complex on cell surfaces. Additionally, we obtained novel and conclusive evidence that HIV-1 entry occurs in an assembly line manner, with some steps obligatorily occurring on cell surfaces and with final membrane fusion occurring in endosomes. Our results were confirmed for wild-type HIV-1. Thus, our paper provides major methodological and mechanistic insights about HIV-1 infection. PMID- 24478427 TI - Specific sequence of a Beta turn in human la protein may contribute to species specificity of hepatitis C virus. AB - Human La protein is known to be an essential host factor for translation and replication of hepatitis C virus (HCV) RNA. Previously, we have demonstrated that residues responsible for interaction of human La protein with the HCV internal ribosomal entry site (IRES) around the initiator AUG within stem-loop IV form a beta-turn in the RNA recognition motif (RRM) structure. In this study, sequence alignment and mutagenesis suggest that the HCV RNA-interacting beta-turn is conserved only in humans and chimpanzees, the species primarily known to be infected by HCV. A 7-mer peptide corresponding to the HCV RNA-interacting region of human La inhibits HCV translation, whereas another peptide corresponding to the mouse La sequence was unable to do so. Furthermore, IRES-mediated translation was found to be significantly high in the presence of recombinant human La protein in vitro in rabbit reticulocyte lysate. We observed enhanced replication with HCV subgenomic and full-length replicons upon overexpression of either human La protein or a chimeric mouse La protein harboring a human La beta-turn sequence in mouse cells. Taken together, our results raise the possibility of creating an immunocompetent HCV mouse model using human-specific cell entry factors and a humanized form of La protein. IMPORTANCE: Hepatitis C virus is known to infect only humans and chimpanzees under natural conditions. This has prevented the development of a small-animal model, which is important for development of new antiviral drugs. Although a number of human-specific proteins are responsible for this species selectivity and some of these proteins--mostly entry factors--have been identified, full multiplication of the virus in mouse cells is still not possible. In this study, we show that a turn in the human La protein that is responsible for the interaction with the viral RNA is highly specific for the human sequence. Replacement of the corresponding mouse sequence with the human sequence allows the mouse La to behave like its human counterpart and support viral growth in the mouse cell efficiently. This observation, in combination with previously identified cell entry factors, should open up the possibility of creating a mouse model of hepatitis C. PMID- 24478428 TI - Role of phosphatidylserine receptors in enveloped virus infection. AB - We recently demonstrated that a soluble protein, Gas6, can facilitate viral entry by bridging viral envelope phosphatidylserine to Axl, a receptor tyrosine kinase expressed on target cells. The interaction between phosphatidylserine, Gas6, and Axl was originally shown to be a molecular mechanism through which phagocytes recognize phosphatidylserine exposed on dead cells. Since our initial report, several groups have confirmed that Axl/Gas6, as well as other phosphatidylserine receptors, facilitate entry of dengue, West Nile, and Ebola viruses. Virus binding by viral envelope phosphatidylserine is now a viral entry mechanism generalized to many families of viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most of the known human phosphatidylserine-recognizing molecules, including MFG-E8, TIM-1, -3, and -4, CD300a, BAI1, and stabilin-1 and -2, for their abilities to facilitate virus binding and infection. Using pseudotyped lentiviral vectors, we found that a soluble phosphatidylserine-binding protein, MFG-E8, enhances transduction. Cell surface receptors TIM-1 and -4 also enhance virus binding/transduction. The extent of enhancement by these molecules varies, depending on the type of pseudotyping envelope proteins. Mutated MFG-E8, which binds viral envelope phosphatidylserine without bridging virus to cells, but, surprisingly, not annexin V, which has been used to block phagocytosis of dead cells by concealing phosphatidylserine, efficiently blocks these phosphatidylserine-dependent viral entry mechanisms. These results provide insight into understanding the role of viral envelope phosphatidylserine in viral infection. IMPORTANCE: Envelope phosphatidylserine has previously been shown to be important for replication of various envelope viruses, but details of this mechanism(s) were unclear. We were the first to report that a bifunctional serum protein, Gas6, bridges envelope phosphatidylserine to a cell surface receptor, Axl. Recent studies demonstrated that many envelope viruses, including vaccinia, dengue, West Nile, and Ebola viruses, utilize Axl/Gas6 to facilitate their entry, suggesting that the phosphatidylserine-mediated viral entry mechanism can be shared by various enveloped viruses. In addition to Axl/Gas6, various molecules are known to recognize phosphatidylserine; however, the effects of these molecules on virus binding and entry have not been comprehensively evaluated and compared. In this study, we examined most human phosphatidylserine-recognizing molecules for their abilities to facilitate viral infection. The results provide insights into the role(s) of envelope phosphatidylserine in viral infection, which can be applicable to the development of novel antiviral reagents that block phosphatidylserine-mediated viral entry. PMID- 24478429 TI - Functional implications of the binding mode of a human conformation-dependent V2 monoclonal antibody against HIV. AB - Data from the RV144 HIV vaccine trial indicated that gp120 V2 antibodies were associated with a lower risk of infection; thus, the mapping of V2 epitopes can contribute to the design of an effective HIV vaccine. We solved the crystal structure of human monoclonal antibody (MAb) 2158, which targets a conformational V2 epitope overlapping the alpha4beta7 integrin binding site, and constructed a full-length model of V1V2. Comparison of computational energy stability to experimental enzyme-linked immunosorbent assay (ELISA) results identified a hydrophobic core that stabilizes the V2 region for optimal 2158 binding, as well as residues that directly mediate side chain interactions with MAb 2158. These data define the binding surface recognized by MAb 2158 and offer a structural explanation for why a mismatched mutation at position 181 (I181X) in the V2 loop was associated with a higher vaccine efficiency in the RV144 clinical vaccine trial. IMPORTANCE: Correlate analysis of the RV144 HIV-1 vaccine trial suggested that the presence of antibodies to the second variable region (V2) of HIV-1 gp120 was responsible for the modest protection observed in the trial. V2 is a highly variable and immunogenic region, and structural information on its antigenic landscape will be important for rational design of an effective HIV-1 vaccine. Using X-ray crystallography, computational design tools, and mutagenesis assays, we carried out a detailed and systematic investigation of the epitope recognition of human V2 MAb 2158 and demonstrated that its epitope region overlaps the integrin binding site within V2. In addition, we propose a structure-based mechanism for mismatching of the isoleucine at position 181 and the increased vaccine efficacy seen in the RV144 vaccine trial. PMID- 24478430 TI - Resveratrol inhibits the TRIF-dependent pathway by upregulating sterile alpha and armadillo motif protein, contributing to anti-inflammatory effects after respiratory syncytial virus infection. AB - Respiratory syncytial virus (RSV) is the most important cause of lower respiratory tract infection in young children and the leading cause of infant hospitalization worldwide. Uncontrolled response to RSV is mediated by a toll like receptor (TLR)-mediated immune response. Resveratrol possesses anti-RSV activity and is an inhibitor of the TRIF/TBK1/IRF-3 complex. We hypothesize that resveratrol inhibits the TRIF-dependent pathway through upregulation of SARM post RSV infection. BALB/c mice were infected with RSV and were injected with resveratrol 1 h postinoculation. SARM short interfering RNA was administered to RSV-infected and resveratrol-treated mice. Lung function was measured by whole body plethysmography, lung histopathology was examined, and lymphocytes in bronchoalveolar lavage fluid were quantified. SARM and TRIF protein expression were detected in the lung by Western blot analyses. The expression of gamma interferon in bronchoalveolar lavage fluid (BALF) was evaluated by enzyme-linked immunosorbent assay (ELISA). SARM expression was reduced and TRIF expression was increased after infection with RSV. Resveratrol increased SARM expression and decreased TRIF expression after RSV infection. SARM knockdown in resveratrol treated mice enhanced gamma interferon production, RSV-induced airway inflammation, and airway hyperresponsiveness (AHR). Resveratrol decreased TRIF expression and prevented the RSV-mediated reduction of SARM expression. Resveratrol-mediated inhibition of the TRIF-dependent pathway may be dependent on SARM expression. IMPORTANCE: Our study provides insights into the regulation of innate immunity in response to RSV infection. The results suggest that resveratrol-mediated alterations in SARM have therapeutic potential against RSV immunopathology caused by deregulation of the TLR-mediated immune response. Ultimately, improved insight into the complex interplay between TLR adaptor proteins and the occurrence of severe RSV infection might lead to novel therapeutic treatment strategies, such as TLR adjuvants. PMID- 24478431 TI - Hijacking of RIG-I signaling proteins into virus-induced cytoplasmic structures correlates with the inhibition of type I interferon responses. AB - Recognition of viral pathogens by the retinoic acid-inducible gene I (RIG-I)-like receptor (RLR) family results in the activation of type I interferon (IFN) responses. To avoid this response, most viruses have evolved strategies that target different essential steps in the activation of host innate immunity. In this study, we report that the nonstructural protein NSs of the newly described severe fever with thrombocytopenia syndrome virus (SFTSV) is a potent inhibitor of IFN responses. The SFTSV NSs protein was found to inhibit the activation of the beta interferon (IFN-beta) promoter induced by viral infection and by a RIG-I ligand. Astonishingly, we found that SFTSV NSs interacts with and relocalizes RIG I, the E3 ubiquitin ligase TRIM25, and TANK-binding kinase 1 (TBK1) into SFTSV NSs-induced cytoplasmic structures. Interestingly, formation of these SFTSV NSs induced structures occurred in the absence of the Atg7 gene, a gene essential for autophagy. Furthermore, confocal microscopy studies revealed that these SFTSV NSs induced structures colocalize with Rab5 but not with Golgi apparatus or endoplasmic reticulum markers. Altogether, the data suggest that sequestration of RIG-I signaling molecules into endosome-like structures may be the mechanism used by SFTSV to inhibit IFN responses and point toward a novel mechanism for the suppression of IFN responses. IMPORTANCE: The mechanism by which the newly described SFTSV inhibits host antiviral responses has not yet been fully characterized. In this study, we describe the redistribution of RIG-I signaling components into virus-induced cytoplasmic structures in cells infected with SFTSV. This redistribution correlates with the inhibition of host antiviral responses. Further characterization of the interplay between the viral protein and components of the IFN responses could potentially provide targets for the rational development of therapeutic interventions. PMID- 24478432 TI - Natural single-nucleotide polymorphisms in the 3' region of the HIV-1 pol gene modulate viral replication ability. AB - We previously showed that prototype macaque-tropic human immunodeficiency virus type 1 (HIV-1) acquired nonsynonymous growth-enhancing mutations within a narrow genomic region during the adaptation process in macaque cells. These adaptive mutations were clustered in the 3' region of the pol gene, encoding a small portion of the C-terminal domain of integrase (IN). Mutations in HIV-1 IN have been reported to have pleiotropic effects on both the early and late phases in viral replication. cis-acting functions in the IN-coding sequence for viral gene expression have also been reported. We here demonstrated that the adaptive mutations promoted viral growth by increasing virion production with no positive effects on the early replication phase. Synonymous codon alterations in one of the adaptive mutations influenced virion production levels, which suggested nucleotide-dependent regulation. Indeed, when the single-nucleotide natural polymorphisms observed in the 3' regions of 196 HIV-1/simian immunodeficiency virus (SIVcpz) pol genes (nucleotides [nt] 4895 to 4929 for HIV-1 NL4-3) were introduced into macaque- and human-tropic HIV-1 clones, more than half exhibited altered replication potentials. Moreover, single-nucleotide mutations caused parallel increases or decreases in the expression levels of viral late proteins and viral replication potentials. We also showed that the overall expression profiles of viral mRNAs were markedly changed by single-nucleotide mutations. These results demonstrate that the 3' region of the HIV-1 pol gene (nt 4895 to 4929) can alter viral replication potential by modulating the expression pattern of viral mRNAs in a nucleotide-dependent manner. IMPORTANCE: Viruses have the plasticity to adapt themselves under various constraints. HIV-1 can mutate and evolve in growth-restrictive cells by acquiring adaptive changes in its genome. We have previously identified some growth-enhancing mutations in a narrow region of the IN-coding sequence, in which a number of cis-acting elements are located. We now focus on the virological significance of this pol gene region and the mechanistic basis underlying its effects on viral replication. We have found several naturally occurring synonymous mutations within this region that alter viral replication potentials. The effects caused by these natural single nucleotide polymorphisms are linked to the definite expression patterns of viral mRNAs. We show here that the nucleotide sequence of the pol gene (nucleotides 4895 to 4929 for HIV-1 NL4-3) plays an important role in HIV-1 replication by modulating viral gene expression. PMID- 24478433 TI - Kaposi's sarcoma-associated herpesvirus-encoded LANA contributes to viral latent replication by activating phosphorylation of survivin. AB - Kaposi's sarcoma-associated herpesvirus (KSHV) is a human gammaherpesvirus casually linked to Kaposi's sarcoma (KS), multicentric Castleman's disease (MCD), and primary effusion lymphoma (PEL). Previously, we showed that LANA encoded by KSHV upregulates expression of survivin, a member of the inhibitor of apoptosis (IAP) family. This leads to an increase in the rate of cell proliferation of KSHV infected B cells. LANA is required for tethering of the KSHV episome to the host chromosomes and efficiently segregates the viral genomes into dividing tumor cells. Here we show that LANA interacts with Aurora kinase B (AK-B) and induces phosphorylation of survivin at residue T34. Phosphorylation of survivin specifically on residue T34 enhances the activity of p300 and inhibits the activity of histone deacetylase 1 (HDAC-1), which then leads to an increase in acetylation of histone H3 on the viral genome. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases, which then leads to an increase in viral copy number in KSHV-infected B cells. This results in a boost of KSHV replication in latently infected B-lymphoma cells. The studies showed that LANA can also function to regulate viral replication prior to mitosis of the latently infected cells, suggesting that LANA possesses a novel role in regulating KSHV replication in infected B cells. IMPORTANCE: This work represents a report of KSHV latent protein LANA and its interactions with AK-B leading to induction of phosphorylation of the oncoprotein survivin at residue T34. Phosphorylation of survivin specifically on residue T34 upregulates the activities of histone acetyltransferases and deacetylases. This leads to an increase in viral copy number in KSHV-infected B cells. These studies support a role for LANA in regulating KSHV replication through posttranslation modification in KSHV-infected B cells. PMID- 24478435 TI - Surfactant-modified nanoclay exhibits an antiviral activity with high potency and broad spectrum. AB - Nanomaterials have the characteristics associated with high surface-to-volume ratios and have been explored for their antiviral activity. Despite some success, cytotoxicity has been an issue in nanomaterial-based antiviral strategies. We previously developed a novel method to fully exfoliate montmorillonite clay to generate the most fundamental units of nanoscale silicate platelet (NSP). We further modified NSP by capping with various surfactants and found that the surfactant-modified NSP (NSQ) was less cytotoxic. In this study, we tested the antiviral potentials of a series of natural-clay-derived nanomaterials. Among the derivatives, NSP modified with anionic sodium dodecyl sulfate (NSQc), but not the pristine clay, unmodified NSP, a silver nanoparticle-NSP hybrid, NSP modified with cationic n-octadecanylamine hydrochloride salt, or NSP modified with nonionic Triton X-100, significantly suppressed the plaque-forming ability of Japanese encephalitis virus (JEV) at noncytotoxic concentrations. NSQc also blocked infection with dengue virus (DEN) and influenza A virus. Regarding the antiviral mechanism, NSQc interfered with viral binding through electrostatic interaction, since its antiviral activity can be neutralized by Polybrene, a cationic polymer. Furthermore, NSQc reduced the lethality of JEV and DEN infection in mouse challenge models. Thus, the surfactant-modified exfoliated nanoclay NSQc may be a novel nanomaterial with broad and potent antiviral activity. IMPORTANCE: Nanomaterials have being investigated as antimicrobial agents, yet their antiviral potential is overshadowed by their cytotoxicity. By using a novel method, we fully exfoliated montmorillonite clay to generate the most fundamental units of nanoscale silicate platelet (NSP). Here, we show that the surfactant-modified NSP (NSQ) is less cytotoxic and that NSQc (NSP modified with sodium dodecyl sulfate) could potently block infection by dengue virus (DEN), Japanese encephalitis virus (JEV), and influenza A virus at noncytotoxic concentrations. For the antiviral mechanism, we find that the electrostatic interaction between the negatively charged NSQc and the positively charged virus particles blocks viral binding. Furthermore, we used mouse challenge models of JEV and DEN to demonstrate the in vivo antiviral potential of NSQc. Thus, NSQc may function as a potent and safe antiviral nanohybrid against several viruses, and our success in synthesizing surfactant-modified NSP with antiviral activity may shed some light on future antiviral development. PMID- 24478434 TI - Human papillomavirus E7 oncoprotein increases production of the anti-inflammatory interleukin-18 binding protein in keratinocytes. AB - Human papillomavirus (HPV) can successfully evade the host immune response to establish a persistent infection. We show here that expression of the E7 oncoprotein in primary human keratinocytes results in increased production of interleukin-18 (IL-18) binding protein (IL-18BP). This anti-inflammatory cytokine binding protein is a natural antagonist of IL-18 and is necessary for skin homeostasis. We map increased IL-18BP production to the CR3 region of E7 and demonstrate that this ability is shared among E7 proteins from different HPV types. Furthermore, mutagenesis shows that increased IL-18BP production is mediated by a gamma-activated sequence (GAS) in the IL-18BP promoter. Importantly, the increased IL-18BP levels seen in E7-expressing keratinocytes are capable of diminishing IL-18-mediated CD4 lymphocyte activation. This study provides the first evidence for a virus protein that targets IL-18BP and further validates E7 as a key component of the HPV immune evasion armor. IMPORTANCE: Infection with human papillomavirus is a leading cause of morbidity and mortality worldwide. This study demonstrates that the E7 protein increases production of the anti-inflammatory IL-18BP, a major regulator of epithelial homeostasis. A number of E7 proteins can increase IL-18BP production, and a region within the CR3 of E7 is necessary for mediating the increase. A consequence of increased IL 18BP production is a reduction in CD4-positive lymphocyte activation in response to IL-18 costimulation. These findings may shed light on the immune evasion abilities of HPV. PMID- 24478437 TI - Activation of the interferon induction cascade by influenza a viruses requires viral RNA synthesis and nuclear export. AB - We have examined the requirements for virus transcription and replication and thus the roles of input and progeny genomes in the generation of interferon (IFN) inducing pathogen-associated molecular patterns (PAMPs) by influenza A viruses using inhibitors of these processes. Using IFN regulatory factor 3 (IRF3) phosphorylation as a marker of activation of the IFN induction cascade that occurs upstream of the IFN-beta promoter, we demonstrate strong activation of the IFN induction cascade in A549 cells infected with a variety of influenza A viruses in the presence of cycloheximide or nucleoprotein (NP) small interfering RNA (siRNA), which inhibits viral protein synthesis and thus complementary ribonucleoprotein (cRNP) and progeny viral RNP (vRNP) synthesis. In contrast, activation of the IFN induction cascade by influenza viruses was very effectively abrogated by treatment with actinomycin D and other transcription inhibitors, which correlated with the inhibition of the synthesis of all viral RNA species. Furthermore, 5,6-dichloro-1-beta-d-ribofuranosyl-benzimidazole, an inhibitor that prevents viral RNA export from the nucleus, was also a potent inhibitor of IRF3 activation; thus, both viral RNA synthesis and nuclear export are required for IFN induction by influenza A viruses. While the exact nature of the viral PAMPs remains to be determined, our data suggest that in this experimental system the major influenza A virus PAMPs are distinct from those of incoming genomes or progeny vRNPs. IMPORTANCE: The host interferon system exerts an extremely potent antiviral response that efficiently restricts virus replication and spread; the interferon response can thus dictate the outcome of a virus infection, and it is therefore important to understand how viruses induce interferon. Both input and progeny genomes have been linked to interferon induction by influenza viruses. However, our experiments in tissue culture cells show that viral RNA synthesis and nuclear export are required to activate this response. Furthermore, the interferon induction cascade is activated under conditions in which the synthesis of progeny genomes is inhibited. Therefore, in tissue culture cells, input and progeny genomes are not the predominant inducers of interferon generated by influenza A viruses; the major viral interferon inducer(s) still remains to be identified. PMID- 24478436 TI - Recombinant adeno-associated virus utilizes host cell nuclear import machinery to enter the nucleus. AB - Recombinant adeno-associated viral (rAAV) vectors have garnered much promise in gene therapy applications. However, widespread clinical use has been limited by transduction efficiency. Previous studies suggested that the majority of rAAV accumulates in the perinuclear region of cells, presumably unable to traffic into the nucleus. rAAV nuclear translocation remains ill-defined; therefore, we performed microscopy, genetic, and biochemical analyses in vitro in order to understand this mechanism. Lectin blockade of the nuclear pore complex (NPC) resulted in inhibition of nuclear rAAV2. Visualization of fluorescently labeled particles revealed that rAAV2 localized to importin-beta-dense regions of cells in late trafficking steps. Additionally, small interfering RNA (siRNA) knockdown of importin-beta partially inhibited rAAV2 nuclear translocation and inhibited transduction by 50 to 70%. Furthermore, coimmunopreciptation (co-IP) analysis revealed that capsid proteins from rAAV2 could interact with importin-beta and that this interaction was sensitive to the small GTPase Ran. More importantly, mutations to key basic regions in the rAAV2 capsid severely inhibited interactions with importin-beta. We tested several other serotypes and found that the extent of importin-beta interaction varied, suggesting that different serotypes may utilize alternative import proteins for nuclear translocation. Co IP and siRNA analyses were used to investigate the role of other karyopherins, and the results suggested that rAAV2 may utilize multiple import proteins for nuclear entry. Taken together, our results suggest that rAAV2 interacts with importin-beta alone or in complex with other karyopherins and enters the nucleus via the NPC. These results may lend insight into the design of novel AAV vectors that have an enhanced nuclear entry capability and transduction potential. IMPORTANCE: Use of recombinant adeno-associated viral (rAAV) vectors for gene therapy applications is limited by relatively low transduction efficiency, in part due to cellular barriers that hinder successful subcellular trafficking to the nucleus, where uncoating and subsequent gene expression occur. Nuclear translocation of rAAV has been regarded as a limiting step for successful transduction but it remains ill-defined. We explored potential nuclear entry mechanisms for rAAV2 and found that rAAV2 can utilize the classical nuclear import pathway, involving the nuclear pore complex, the small GTPase Ran, and cellular karyopherins. These results could lend insight into the rational design of novel rAAV vectors that can more efficiently translocate to the nucleus, which may lead to more efficient transduction. PMID- 24478438 TI - Forkhead box transcription factor regulation and lipid accumulation by hepatitis C virus. AB - We have previously shown that hepatitis C virus (HCV) infection modulates the expression of forkhead box transcription factors, including FoxO1 and FoxA2, which play key roles in gluconeogenesis and beta-oxidation of fatty acid, respectively. The aim of the present study was to determine the role of forkhead box transcription factors in modulating lipid metabolism. HCV infection or core protein expression alone in transfected Huh7.5 cells increased expression of sterol regulatory element binding protein 1c (SREBP-1c) and its downstream target, fatty acid synthase (FASN), which are key proteins involved in lipid synthesis. Knockdown of FoxO1 by small interfering RNA in HCV-infected cells significantly decreased SREBP-1c and FASN expression. Further, HCV infection or core protein expression in Huh7.5 cells significantly decreased the expression of medium-chain acyl coenzyme A dehydrogenase (MCAD) and short-chain acyl coenzyme A dehydrogenase (SCAD), involved in the regulation of beta-oxidation of fatty acids. Ectopic expression of FoxA2 in HCV-infected cells rescued the expression of MCAD and SCAD. Oil red O and neutral lipid staining indicated that HCV infection significantly increases lipid accumulation compared to that in the mock infected control. This was further verified by the increased expression of perilipin-2 and decreased activity of hormone-sensitive lipase (HSL) in HCV infected hepatocytes, implying increased accumulation of neutral lipids. Knockdown of FoxO1 and ectopic expression of FoxA2 significantly decreased HCV replication. Taken together, these results suggest that HCV modulates forkhead box transcription factors which together increase lipid accumulation and promote viral replication. IMPORTANCE: Hepatic steatosis is a frequent complication associated with chronic HCV infection. Its presence is a key prognostic indicator associated with the progression to hepatic fibrosis and hepatocellular carcinoma. Several mechanisms have been proposed to account for the development of steatosis and fatty liver during HCV infection. We observed that HCV infection increases expression of both SREBP-1c and FASN. Further investigation suggested that the expression of SREBP-1c and FASN is controlled by the transcription factor FoxO1 during HCV infection. In addition, HCV infection significantly decreased both MCAD and SCAD expression, which is controlled by FoxA2. HCV infection also increased lipid droplet accumulation, increased perilipin-2 expression, and decreased HSL activity. Thus, knockdown of FoxO1 (decreased lipogenesis) and overexpression of FoxA2 (increased beta-oxidation) resulted in a significant disruption of the platform and, hence, a decrease in HCV genome replication. Thus, targeting of FoxO1 and FoxA2 might be useful in developing a therapeutic approach against HCV infection. PMID- 24478439 TI - The influenza A virus protein NS1 displays structural polymorphism. AB - NS1 of influenza A virus is a potent antagonist of host antiviral interferon responses. This multifunctional protein with two distinctive domains, an RNA binding domain (RBD) and an effector domain (ED) separated by a linker region (LR), is implicated in replication, pathogenesis, and host range. Although the structures of individual domains of NS1 from different strains of influenza viruses have been reported, the only structure of full-length NS1 available to date is from an H5N1 strain (A/Vietnam/1203/2004). By carrying out crystallographic analyses of full-length H6N6-NS1 (A/blue-winged teal/MN/993/1980) and an LR deletion mutant, combined with mutational analysis, we show here that these full-length NS1 structures provide an exquisite structural sampling of various conformational states of NS1 that based on the orientation of the ED with respect to RBD can be summarized as "open," "semi open," and "closed" conformations. Our studies show that preference for these states is clearly dictated by determinants such as linker length, residue composition at position 71, and a mechanical hinge, providing a structural basis for strain-dependent functional variations in NS1. Because of the flexibility inherent in the LR, any particular NS1 could sample the conformational space around these states to engage ED in different quaternary interactions so that it may participate in specific protein-protein or protein-RNA interactions to allow for the known multifunctionality of NS1. We propose that such conformational plasticity provides a mechanism for autoregulating NS1 functions, depending on its temporal distribution, posttranslational modifications, and nuclear or cellular localization, during the course of virus infection. IMPORTANCE: NS1 of influenza A virus is a multifunctional protein associated with numerous strain specific regulatory functions during viral infection, including conferring resistance to antiviral interferon induction, replication, pathogenesis, virulence, and host range. NS1 has two domains, an RNA-binding domain and an effector domain separated by a linker. To date, the only full-length NS1 structure available is that from an H5N1 strain (A/Vietnam/1203/2004). Here, we determined crystal structures of the wild type and a linker region mutant of the H6N6 NS1 (A/blue-winged teal/MN/993/1980), which together with the previously determined H5N1 NS1 structure show that NS1 exhibits significant strain-dependent structural polymorphism due to variations in linker length, residue composition at position 71, and a mechanical hinge. Such a structural polymorphism may be the basis for strain-specific functions associated with NS1. PMID- 24478440 TI - Murine leukemia virus uses NXF1 for nuclear export of spliced and unspliced viral transcripts. AB - Intron-containing mRNAs are subject to restricted nuclear export in higher eukaryotes. Retroviral replication requires the nucleocytoplasmic transport of both spliced and unspliced RNA transcripts, and RNA export mechanisms of gammaretroviruses are poorly characterized. Here, we report the involvement of the nuclear export receptor NXF1/TAP in the nuclear export of gammaretroviral RNA transcripts. We identified a conserved cis-acting element in the pol gene of gammaretroviruses, including murine leukemia virus (MLV) and xenotropic murine leukemia virus (XMRV), named the CAE (cytoplasmic accumulation element). The CAE enhanced the cytoplasmic accumulation of viral RNA transcripts and the expression of viral proteins without significantly affecting the stability, splicing, or translation efficiency of the transcripts. Insertion of the CAE sequence also facilitated Rev-independent HIV Gag expression. We found that the CAE sequence interacted with NXF1, whereas disruption of NXF1 ablated CAE function. Thus, the CAE sequence mediates the cytoplasmic accumulation of gammaretroviral transcripts in an NXF1-dependent manner. Disruption of NXF1 expression impaired cytoplasmic accumulations of both spliced and unspliced RNA transcripts of XMRV and MLV, resulting in their nuclear retention or degradation. Thus, our results demonstrate that gammaretroviruses use NXF1 for the cytoplasmic accumulation of both spliced and nonspliced viral RNA transcripts. IMPORTANCE: Murine leukemia virus (MLV) has been studied as one of the classic models of retrovirology. Although unspliced host messenger RNAs are rarely exported from the nucleus, MLV actively exports unspliced viral RNAs to the cytoplasm. Despite extensive studies, how MLV achieves this difficult task has remained a mystery. Here, we have studied the RNA export mechanism of MLV and found that (i) the genome contains a sequence which supports the efficient nuclear export of viral RNAs, (ii) the cellular factor NXF1 is involved in the nuclear export of both spliced and unspliced viral RNAs, and, finally, (iii) depletion of NXF1 results in nuclear retention or degradation of viral RNAs. Our study provides a novel insight into MLV nuclear export. PMID- 24478441 TI - Large-scale nucleotide optimization of simian immunodeficiency virus reduces its capacity to stimulate type I interferon in vitro. AB - Lentiviral RNA genomes present a strong bias in their nucleotide composition with extremely high frequencies of A nucleotide in human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency virus (SIV). Based on the observation that human optimization of RNA virus gene fragments may abolish their ability to stimulate the type I interferon (IFN-I) response, we identified the most biased sequences along the SIV genome and showed that they are the most potent IFN-I stimulators. With the aim of designing an attenuated SIV genome based on a reduced capacity to activate the IFN-I response, we synthesized artificial SIV genomes whose biased sequences were optimized toward macaque average nucleotide composition without altering their regulatory elements or amino acid sequences. A synthetic SIV optimized with 169 synonymous mutations in gag and pol genes showed a 100-fold decrease in replicative capacity. Interestingly, a synthetic SIV optimized with 70 synonymous mutations in pol had a normal replicative capacity. Its ability to stimulate IFN-I was reduced when infected cells were cocultured with reporter cells. IFN regulatory factor 3 (IRF3) transcription factor was required for IFN-I stimulation, implicating cytosolic sensors in the detection of SIV-biased RNA in infected cells. No reversion of introduced mutations was observed for either of the optimized viruses after 10 serial passages. In conclusion, we have designed large-scale nucleotide-modified SIVs that may display attenuated pathogenic potential. IMPORTANCE: In this study, we synthesized artificial SIV genomes in which the most hyperbiased sequences were optimized to bring them closer to the nucleotide composition of the macaque SIV host. Interestingly, we generated a stable synthetic SIV optimized with 70 synonymous mutations in pol gene, which had a normal replicative capacity but a reduced ability to stimulate type I IFN. This demonstrates the possibility to rationally change viral nucleotide composition to design replicative and genetically stable lentiviruses with attenuated pathogenic potentials. PMID- 24478442 TI - Effects of aging on influenza virus infection dynamics. AB - The consequences of influenza virus infection are generally more severe in individuals over 65 years of age (the elderly). Immunosenescence enhances the susceptibility to viral infections and renders vaccination less effective. Understanding age-related changes in the immune system is crucial in order to design prophylactic and immunomodulatory strategies to reduce morbidity and mortality in the elderly. Here, we propose different mathematical models to provide a quantitative understanding of the immune strategies in the course of influenza virus infection using experimental data from young and aged mice. Simulation results suggested a central role of CD8(+) T cells for adequate viral clearance kinetics in young and aged mice. Adding the removal of infected cells by natural killer cells did not improve the model fit in either young or aged animals. We separately examined the infection-resistant state of cells promoted by the cytokines alpha/beta interferon (IFN-alpha/beta), IFN-gamma, and tumor necrosis factor alpha (TNF-alpha). The combination of activated CD8(+) T cells with any of the cytokines provided the best fits in young and aged animals. During the first 3 days after infection, the basic reproductive number for aged mice was 1.5-fold lower than that for young mice (P < 0.05). IMPORTANCE: The fits of our models to the experimental data suggest that the increased levels of IFN alpha/beta, IFN-gamma, and TNF-alpha (the "inflammaging" state) promote slower viral growth in aged mice, which consequently limits the stimulation of immune cells and contributes to the reported impaired responses in the elderly. A quantitative understanding of influenza virus pathogenesis and its shift in the elderly is the key contribution of this work. PMID- 24478443 TI - Inhibition of dengue and chikungunya virus infections by RIG-I-mediated type I interferon-independent stimulation of the innate antiviral response. AB - RIG-I is a cytosolic sensor critically involved in the activation of the innate immune response to RNA virus infection. In the present study, we evaluated the inhibitory effect of a RIG-I agonist on the replication of two emerging arthropod borne viral pathogens, dengue virus (DENV) and chikungunya virus (CHIKV), for which no therapeutic options currently exist. We demonstrate that when a low, noncytotoxic dose of an optimized 5'triphosphorylated RNA (5'pppRNA) molecule was administered, RIG-I stimulation generated a robust antiviral response against these two viruses. Strikingly, 5'pppRNA treatment before or after challenge with DENV or CHIKV provided protection against infection. In primary human monocytes and monocyte-derived dendritic cells, the RIG-I agonist blocked both primary infection and antibody-dependent enhancement of DENV infection. The protective response against DENV and CHIKV induced by 5'pppRNA was dependent on an intact RIG-I/MAVS/TBK1/IRF3 axis and was largely independent of the type I IFN response. Altogether, this in vitro analysis of the antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV. IMPORTANCE: DENV and CHIKV are two reemerging mosquito borne viruses for which no therapeutic options currently exist. Both viruses overlap geographically in tropical regions of the world, produce similar fever like symptoms, and are difficult to diagnose. This study investigated the inhibitory effect of a RIG-I agonist on the replication of these two viruses. RIG I stimulation using 5'pppRNA before or after DENV or CHIKV infection generated a protective antiviral response against both pathogens in immune and nonimmune cells; interestingly, the protective response against the viruses was largely independent of the classical type I interferon response. The antiviral efficacy of 5'pppRNA highlights the therapeutic potential of RIG-I agonists against emerging viruses such as DENV and CHIKV. PMID- 24478444 TI - Attenuation and restoration of severe acute respiratory syndrome coronavirus mutant lacking 2'-o-methyltransferase activity. AB - The sudden emergence of severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 and, more recently, Middle Eastern respiratory syndrome CoV (MERS-CoV) underscores the importance of understanding critical aspects of CoV infection and pathogenesis. Despite significant insights into CoV cross-species transmission, replication, and virus-host interactions, successful therapeutic options for CoVs do not yet exist. Recent identification of SARS-CoV NSP16 as a viral 2'-O methyltransferase (2'-O-MTase) led to the possibility of utilizing this pathway to both attenuate SARS-CoV infection and develop novel therapeutic treatment options. Mutations were introduced into SARS-CoV NSP16 within the conserved KDKE motif and effectively attenuated the resulting SARS-CoV mutant viruses both in vitro and in vivo. While viruses lacking 2'-O-MTase activity had enhanced sensitivity to type I interferon (IFN), they were not completely restored in their absence in vivo. However, the absence of either MDA5 or IFIT1, IFN responsive genes that recognize unmethylated 2'-O RNA, resulted in restored replication and virulence of the dNSP16 mutant virus. Finally, using the mutant as a live-attenuated vaccine showed significant promise for possible therapeutic development against SARS-CoV. Together, the data underscore the necessity of 2'-O MTase activity for SARS-CoV pathogenesis and identify host immune pathways that mediate this attenuation. In addition, we describe novel treatment avenues that exploit this pathway and could potentially be used against a diverse range of viral pathogens that utilize 2'-O-MTase activity to subvert the immune system. IMPORTANCE: Preventing recognition by the host immune response represents a critical aspect necessary for successful viral infection. Several viruses, including SARS-CoV, utilize virally encoded 2'-O-MTases to camouflage and obscure their viral RNA from host cell sensing machinery, thus preventing recognition and activation of cell intrinsic defense pathways. For SARS-CoV, the absence of this 2'-O-MTase activity results in significant attenuation characterized by decreased viral replication, reduced weight loss, and limited breathing dysfunction in mice. The results indicate that both MDA5, a recognition molecule, and the IFIT family play an important role in mediating this attenuation with restored virulence observed in their absence. Understanding this virus-host interaction provided an opportunity to design a successful live-attenuated vaccine for SARS CoV and opens avenues for treatment and prevention of emerging CoVs and other RNA virus infections. PMID- 24478445 TI - Combined proteomic and transcriptomic interrogation of the venom gland of Conus geographus uncovers novel components and functional compartmentalization. AB - Cone snails are highly successful marine predators that use complex venoms to capture prey. At any given time, hundreds of toxins (conotoxins) are synthesized in the secretory epithelial cells of the venom gland, a long and convoluted organ that can measure 4 times the length of the snail's body. In recent years a number of studies have begun to unveil the transcriptomic, proteomic and peptidomic complexity of the venom and venom glands of a number of cone snail species. By using a combination of DIGE, bottom-up proteomics and next-generation transcriptome sequencing the present study identifies proteins involved in envenomation and conotoxin maturation, significantly extending the repertoire of known (poly)peptides expressed in the venom gland of these remarkable animals. We interrogate the molecular and proteomic composition of different sections of the venom glands of 3 specimens of the fish hunter Conus geographus and demonstrate regional variations in gene expression and protein abundance. DIGE analysis identified 1204 gel spots of which 157 showed significant regional differences in abundance as determined by biological variation analysis. Proteomic interrogation identified 342 unique proteins including those that exhibited greatest fold change. The majority of these proteins also exhibited significant changes in their mRNA expression levels validating the reliability of the experimental approach. Transcriptome sequencing further revealed a yet unknown genetic diversity of several venom gland components. Interestingly, abundant proteins that potentially form part of the injected venom mixture, such as echotoxins, phospholipase A2 and con-ikots-ikots, classified into distinct expression clusters with expression peaking in different parts of the gland. Our findings significantly enhance the known repertoire of venom gland polypeptides and provide molecular and biochemical evidence for the compartmentalization of this organ into distinct functional entities. PMID- 24478446 TI - Of paradox and plausibility: the dynamic of change in medical law. AB - This article develops a model of change in medical law. Drawing on systems theory, it argues that medical law participates in a dynamic of 'deparadoxification' and 'reparadoxification' whereby the underlying contingency of the law is variously concealed through plausible argumentation, or revealed by critical challenge. Medical law is, thus, thoroughly rhetorical. An examination of the development of the law on abortion and on the sterilization of incompetent adults shows that plausibility is achieved through the deployment of substantive common sense and formal stylistic devices. It is undermined where these elements are shown to be arbitrary and constructed. In conclusion, it is argued that the politics of medical law are constituted by this antagonistic process of establishing and challenging provisionally stable normative regimes. PMID- 24478447 TI - Numerical limits in donor conception regimes: genetic links and 'extended family' in the era of identity disclosure. AB - This article critically examines the setting of limits on the number of children or family groups that may be formed with a single donor in assisted conception regimes. Originally, under conditions of anonymity, numerical limits were said to contain the risk of inadvertent consanguinity between offspring who would not know, and could not know, that they were genetic half siblings, and also between donor and offspring. The increasing embrace of identity disclosure regimes has led to calls for stricter numerical limits based on the purported harm of being exposed to 'too many' genetic relatives in the future. This article asks: how many is too many? And how do we know? The UK and Australian positions are examined, and placed alongside a discussion of qualitative research involving interviews with twenty parents of donor conceived children. PMID- 24478448 TI - Existential suffering and the extent of the right to physician-assisted suicide in Switzerland: Gross v Switzerland [2013] ECHR 67810/10. AB - In Gross v Switzerland, the European Court of Human Rights held by 4-3 majority that Switzerland had violated the right to decide when and how to die included in the right to respect for private and family life under Article 8 of the European Convention on Human Rights. To comply with the ruling, Switzerland must issue guidance detailing the circumstances (if any) under which physicians may lawfully prescribe lethal medication to competent individuals who have a voluntary and settled wish to die, yet whose suffering is not the product of a medical condition likely to result in death in the near future. PMID- 24478449 TI - Evaluation of the Clinical and Laboratory Standards Institute phenotypic confirmatory test to detect the presence of extended-spectrum beta-lactamases from 4005 Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae and Proteus mirabilis isolates. AB - A subset of Escherichia coli, Klebsiella oxytoca, Klebsiella pneumoniae and Proteus mirabilis isolates collected for the Study for Monitoring Antimicrobial Resistance Trends that were positive for the Clinical and Laboratory Standards Institute (CLSI) extended-spectrum beta-lactamase (ESBL) phenotypic confirmatory test (n = 3245) or had an ertapenem MIC of >=0.5 ug ml(-1) (n = 293), or both (n = 467), were analysed for ESBL genes. Most ESBL phenotype E. coli or K. pneumoniae possessed an ESBL gene (95.8 and 88.4 %, respectively), and this was 93.1 % if carbapenem-non-susceptible K. pneumoniae were removed. This rate was lower for P. mirabilis (73.4 %) and K. oxytoca (62.5 %). Virtually all ESBL positive isolates (99.5 %) were cefotaxime non-susceptible [CLSI or European Committee on Antimicrobial Susceptibility Testing (EUCAST) breakpoints)]. Fewer isolates (82 %) were ceftazidime non-susceptible (CLSI breakpoints). In addition, 21.1 % of E. coli, 25 % of K. oxytoca and 78.7 % of P. mirabilis isolates were ceftazidime susceptible but ESBL positive. This suggests that CLSI breakpoints for ceftazidime are too high to detect ESBLs. The lower EUCAST breakpoints detected ESBLs in E. coli and K. oxytoca better, but 59.6 % of ESBL-positive isolates of P. mirabilis were ceftazidime susceptible. For isolates with ertapenem MICs >=0.5 ug ml(-1), more accurate ESBL phenotype analysis was observed for E. coli and K. pneumoniae (sensitivity >95 % for both, specificity 94.4 and 54.1 %, respectively). If carbapenemase-positive K. pneumoniae were excluded, the specificity increased to 78 %. The positive predictive values for the ESBL phenotypic test with E. coli and K. pneumoniae were 97.6 and 81.8 %, respectively, and negative predictive values were 75.9 and 95.2 %, respectively. We therefore suggest that it would be prudent to confirm phenotypic ESBL-positive P. mirabilis, K. pneumoniae and K. oxytoca with molecular analysis. PMID- 24478450 TI - The Cox3p assembly module of yeast cytochrome oxidase. AB - Yeast cytochrome oxidase (COX) was previously inferred to assemble from three modules, each containing one of the three mitochondrially encoded subunits and a different subset of the eight nuclear gene products that make up this respiratory complex. Pull-down assays of pulse-labeled mitochondria enabled us to characterize Cox3p subassemblies that behave as COX precursors and contain Cox4p, Cox7p, and Cox13p. Surprisingly, Cox4p is a constituent of two other complexes, one of which was previously proposed to be an intermediate of Cox1p biogenesis. This suggests that Cox4p, which contacts Cox1p and Cox3p in the holoenzyme, can be incorporated into COX by two alternative pathways. In addition to subunits of COX, some Cox3p intermediates contain Rcf1p, a protein associated with the supercomplex that stabilizes the interaction of COX with the bc1 (ubiquinol cytochrome c reductase) complex. Finally, our results indicate that although assembly of the Cox1p module is not contingent on the presence of Cox3p, the converse is not true, as none of the Cox3p subassemblies were detected in a mutant blocked in translation of Cox1p. These studies support our proposal that Cox3p and Cox1p are separate assembly modules with unique compositions of ancillary factors and subunits derived from the nuclear genome. PMID- 24478451 TI - Roles for PI(3,5)P2 in nutrient sensing through TORC1. AB - TORC1, a conserved protein kinase, regulates cell growth in response to nutrients. Localization of mammalian TORC1 to lysosomes is essential for TORC1 activation. Phosphatidylinositol 3,5-bisphosphate (PI(3,5)P(2)), an endosomal signaling lipid, is implicated in insulin-dependent stimulation of TORC1 activity in adipocytes. This raises the question of whether PI(3,5)P(2) is an essential general regulator of TORC1. Moreover, the subcellular location where PI(3,5)P(2) regulates TORC1 was not known. Here we report that PI(3,5)P(2) is required for TORC1 activity in yeast and regulates TORC1 on the vacuole (lysosome). Furthermore, we show that the TORC1 substrate, Sch9 (a homologue of mammalian S6K), is recruited to the vacuole by direct interaction with PI(3,5)P(2), where it is phosphorylated by TORC1. Of importance, we find that PI(3,5)P(2) is required for multiple downstream pathways via TORC1-dependent phosphorylation of additional targets, including Atg13, the modification of which inhibits autophagy, and phosphorylation of Npr1, which releases its inhibitory function and allows nutrient-dependent endocytosis. These findings reveal PI(3,5)P(2) as a general regulator of TORC1 and suggest that PI(3,5)P(2) provides a platform for TORC1 signaling from lysosomes. PMID- 24478452 TI - Peptide aptamers define distinct EB1- and EB3-binding motifs and interfere with microtubule dynamics. AB - EB1 is a conserved protein that plays a central role in regulating microtubule dynamics and organization. It binds directly to microtubule plus ends and recruits other plus end-localizing proteins. Most EB1-binding proteins contain a Ser-any residue-Ile-Pro (SxIP) motif. Here we describe the isolation of peptide aptamers with optimized versions of this motif by screening for interaction with the Drosophila EB1 protein. The use of small peptide aptamers to competitively inhibit protein interaction and function is becoming increasingly recognized as a powerful technique. We show that SxIP aptamers can bind microtubule plus ends in cells and functionally act to displace interacting proteins by competitive binding. Their expression in developing flies can interfere with microtubules, altering their dynamics. We also identify aptamers binding to human EB1 and EB3, which have sequence requirements similar to but distinct from each other and from Drosophila EB1. This suggests that EB1 paralogues within one species may interact with overlapping but distinct sets of proteins in cells. PMID- 24478453 TI - Herp coordinates compartmentalization and recruitment of HRD1 and misfolded proteins for ERAD. AB - A functional unfolded protein response (UPR) is essential for endoplasmic reticulum (ER)-associated degradation (ERAD) of misfolded secretory proteins, reflecting the fact that some level of UPR activation must exist under normal physiological conditions. A coordinator of the UPR and ERAD processes has long been sought. We previously showed that the PKR-like, ER-localized eukaryotic translation initiation factor 2alpha kinase branch of the UPR is required for the recruitment of misfolded proteins and the ubiquitin ligase HRD1 to the ER-derived quality control compartment (ERQC), a staging ground for ERAD. Here we show that homocysteine-induced ER protein (Herp), a protein highly upregulated by this UPR branch, is responsible for this compartmentalization. Herp localizes to the ERQC, and our results suggest that it recruits HRD1, which targets to ERAD the substrate presented by the OS-9 lectin at the ERQC. Predicted overall structural similarity of Herp to the ubiquitin-proteasome shuttle hHR23, but including a transmembrane hairpin, suggests that Herp may function as a hub for membrane association of ERAD machinery components, a key organizer of the ERAD complex. PMID- 24478455 TI - Microtubule segment stabilization by RASSF1A is required for proper microtubule dynamics and Golgi integrity. AB - The tumor suppressor and microtubule-associated protein Ras association domain family 1A (RASSF1A) has a major effect on many cellular processes, such as cell cycle progression and apoptosis. RASSF1A expression is frequently silenced in cancer and is associated with increased metastasis. Therefore we tested the hypothesis that RASSF1A regulates microtubule organization and dynamics in interphase cells, as well as its effect on Golgi integrity and cell polarity. Our results show that RASSF1A uses a unique microtubule-binding pattern to promote site-specific microtubule rescues, and loss of RASSF1A leads to decreased microtubule stability. Furthermore, RASSF1A-associated stable microtubule segments are necessary to prevent Golgi fragmentation and dispersal in cancer cells and maintain a polarized cell front. These results indicate that RASSF1A is a key regulator in the fine tuning of microtubule dynamics in interphase cells and proper Golgi organization and cell polarity. PMID- 24478454 TI - A central role for vimentin in regulating repair function during healing of the lens epithelium. AB - Mock cataract surgery provides a unique ex vivo model for studying wound repair in a clinically relevant setting. Here wound healing involves a classical collective migration of the lens epithelium, directed at the leading edge by an innate mesenchymal subpopulation of vimentin-rich repair cells. We report that vimentin is essential to the function of repair cells as the directors of the wound-healing process. Vimentin and not actin filaments are the predominant cytoskeletal elements in the lamellipodial extensions of the repair cells at the wound edge. These vimentin filaments link to paxillin-containing focal adhesions at the lamellipodial tips. Microtubules are involved in the extension of vimentin filaments in repair cells, the elaboration of vimentin-rich protrusions, and wound closure. The requirement for vimentin in repair cell function is revealed by both small interfering RNA vimentin knockdown and exposure to the vimentin targeted drug withaferin A. Perturbation of vimentin impairs repair cell function and wound closure. Coimmunoprecipitation analysis reveals for the first time that myosin IIB is associated with vimentin, linking vimentin function in cell migration to myosin II motor proteins. These studies reveal a critical role for vimentin in repair cell function in regulating the collective movement of the epithelium in response to wounding. PMID- 24478456 TI - Damnacanthal, an effective inhibitor of LIM-kinase, inhibits cell migration and invasion. AB - LIM-kinases (LIMKs) play crucial roles in various cell activities, including migration, division, and morphogenesis, by phosphorylating and inactivating cofilin. Using a bimolecular fluorescence complementation assay to detect the actin-cofilin interaction, we screened LIMK1 inhibitors and identified two effective inhibitors, damnacanthal (Dam) and MO-26 (a pyrazolopyrimidine derivative). These compounds have already been shown to inhibit Lck, a Src family tyrosine kinase. However, in vitro kinase assays revealed that Dam inhibited LIMK1 more effectively than Lck. Dam suppressed LIMK1-induced cofilin phosphorylation and deceleration of actin retrograde flow in lamellipodia in N1E 115 cells. Dam impaired CXCL12-induced chemotactic migration of Jurkat T lymphocytes and Jurkat-derived, Lck-deficient JCaM1.6 cells and also inhibited serum-induced migration and invasion of MDA-MB-231 breast carcinoma cells. These results suggest that Dam has the potential to suppress cell migration and invasion primarily through the inhibition of LIMK kinase activity. Topical application of Dam also suppressed hapten-induced migration of epidermal Langerhans cells in mouse ears. Dam provides a useful tool for investigating cellular and physiological functions of LIMKs and holds promise for the development of agents against LIMK-related diseases. The bimolecular fluorescence complementation assay system used in this study will provide a useful method to screen for inhibitors of various protein kinases. PMID- 24478457 TI - Myosin Va mediates Rab8A-regulated GLUT4 vesicle exocytosis in insulin-stimulated muscle cells. AB - Rab-GTPases are important molecular switches regulating intracellular vesicle traffic, and we recently showed that Rab8A and Rab13 are activated by insulin in muscle to mobilize GLUT4-containing vesicles to the muscle cell surface. Here we show that the unconventional motor protein myosin Va (MyoVa) is an effector of Rab8A in this process. In CHO-IR cell lysates, a glutathione S-transferase chimera of the cargo-binding COOH tail (CT) of MyoVa binds Rab8A and the related Rab10, but not Rab13. Binding to Rab8A is stimulated by insulin in a phosphatidylinositol 3-kinase-dependent manner, whereas Rab10 binding is insulin insensitive. MyoVa-CT preferentially binds GTP-locked Rab8A. Full-length green fluorescent protein (GFP)-MyoVa colocalizes with mCherry-Rab8A in perinuclear small puncta, whereas GFP-MyoVa-CT collapses the GTPase into enlarged perinuclear depots. Further, GFP-MyoVa-CT blocks insulin-stimulated translocation of exofacially myc-tagged GLUT4 to the surface of muscle cells. Mutation of amino acids in MyoVa-CT predicted to bind Rab8A abrogates both interaction with Rab8A (not Rab10) and inhibition of insulin-stimulated GLUT4myc translocation. Of importance, small interfering RNA-mediated MyoVa silencing reduces insulin stimulated GLUT4myc translocation. Rab8A colocalizes with GLUT4 in perinuclear but not submembrane regions visualized by confocal total internal reflection fluorescence microscopy. Hence insulin signaling to the molecular switch Rab8A connects with the motor protein MyoVa to mobilize GLUT4 vesicles toward the muscle cell plasma membrane. PMID- 24478458 TI - The checkpoint-dependent nuclear accumulation of Rho1p exchange factor Rgf1p is important for tolerance to chronic replication stress. AB - Guanine nucleotide exchange factors control many aspects of cell morphogenesis by turning on Rho-GTPases. The fission yeast exchange factor Rgf1p (Rho gef1) specifically regulates Rho1p during polarized growth and localizes to cortical sites. Here we report that Rgf1p is relocalized to the cell nucleus during the stalled replication caused by hydroxyurea (HU). Import to the nucleus is mediated by a nuclear localization sequence at the N-terminus of Rgf1p, whereas release into the cytoplasm requires two leucine-rich nuclear export sequences at the C terminus. Moreover, Rgf1p nuclear accumulation during replication arrest depends on the 14-3-3 chaperone Rad24p and the DNA replication checkpoint kinase Cds1p. Both proteins control the nuclear accumulation of Rgf1p by inhibition of its nuclear export. A mutant, Rgf1p-9A, that substitutes nine serine potential phosphorylation Cds1p sites for alanine fails to accumulate in the nucleus in response to replication stress, and this correlates with a severe defect in survival in the presence of HU. In conclusion, we propose that the regulation of Rgf1p could be part of the mechanism by which Cds1p and Rad24p promote survival in the presence of chronic replication stress. It will be of general interest to understand whether the same is true for homologues of Rgf1p in budding yeast and higher eukaryotes. PMID- 24478459 TI - Alternate pleckstrin homology domain orientations regulate dynamin-catalyzed membrane fission. AB - The self-assembling GTPase dynamin catalyzes endocytic vesicle scission via membrane insertion of its pleckstrin homology (PH) domain. However, the molecular mechanisms underlying PH domain-dependent membrane fission remain obscure. Membrane-curvature-sensing and membrane-curvature-generating properties have been attributed, but it remains to be seen whether the PH domain is involved in either process independent of dynamin self-assembly. Here, using multiple fluorescence spectroscopic and microscopic techniques, we demonstrate that the isolated PH domain does not act to bend membranes but instead senses high membrane curvature through hydrophobic insertion into the membrane bilayer. Furthermore, we use a complementary set of short- and long-distance Forster resonance energy transfer approaches to distinguish PH-domain orientation from proximity at the membrane surface in full-length dynamin. We reveal, in addition to the GTP-sensitive "hydrophobic mode," the presence of an alternate, GTP-insensitive "electrostatic mode" of PH domain-membrane interactions that retains dynamin on the membrane surface during the GTP hydrolysis cycle. Stabilization of this alternate orientation produces dramatic variations in the morphology of membrane-bound dynamin spirals, indicating that the PH domain regulates membrane fission through the control of dynamin polymer dynamics. PMID- 24478461 TI - Mutational landscape of the essential autophagy gene BECN1 in human cancers. AB - Evidence suggests that the catabolic process of macroautophagy (autophagy hereafter) can either suppress or promote cancer. The essential autophagy gene ATG6/BECN1 encoding the Beclin1 protein has been implicated as a haploinsufficient tumor suppressor in breast, ovarian, and prostate cancers. The proximity of BECN1 to the known breast and ovarian tumor suppressor breast cancer 1, early onset, BRCA1, on chromosome 17q21, has made this determination equivocal. Here, the mutational status of BECN1 was assessed in human tumor sequencing data from The Cancer Genome Atlas (TCGA) and other databases. Large deletions encompassing both BRCA1 and BECN1, and deletions of only BRCA1 but not BECN1, were found in breast and ovarian cancers, consistent with BRCA1 loss being a primary driver mutation in these cancers. Furthermore, there was no evidence for BECN1 mutation or loss in any other cancer, casting doubt on whether BECN1 is a tumor suppressor in most human cancers. IMPLICATIONS: Contrary to previous reports, BECN1 is not significantly mutated in human cancer and not a tumor suppressor gene, as originally thought. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/01/1541-7786.MCR-13 0614/F1.large.jpg. PMID- 24478460 TI - Transportin acts to regulate mitotic assembly events by target binding rather than Ran sequestration. AB - The nuclear import receptors importin beta and transportin play a different role in mitosis: both act phenotypically as spatial regulators to ensure that mitotic spindle, nuclear membrane, and nuclear pore assembly occur exclusively around chromatin. Importin beta is known to act by repressing assembly factors in regions distant from chromatin, whereas RanGTP produced on chromatin frees factors from importin beta for localized assembly. The mechanism of transportin regulation was unknown. Diametrically opposed models for transportin action are as follows: 1) indirect action by RanGTP sequestration, thus down-regulating release of assembly factors from importin beta, and 2) direct action by transportin binding and inhibiting assembly factors. Experiments in Xenopus assembly extracts with M9M, a superaffinity nuclear localization sequence that displaces cargoes bound by transportin, or TLB, a mutant transportin that can bind cargo and RanGTP simultaneously, support direct inhibition. Consistently, simple addition of M9M to mitotic cytosol induces microtubule aster assembly. ELYS and the nucleoporin 107-160 complex, components of mitotic kinetochores and nuclear pores, are blocked from binding to kinetochores in vitro by transportin, a block reversible by M9M. In vivo, 30% of M9M-transfected cells have spindle/cytokinesis defects. We conclude that the cell contains importin beta and transportin "global positioning system"or "GPS" pathways that are mechanistically parallel. PMID- 24478462 TI - Human PLCzeta exhibits superior fertilization potency over mouse PLCzeta in triggering the Ca(2+) oscillations required for mammalian oocyte activation. AB - A sperm-specific phospholipase C-zeta (PLCzeta) is believed to play an essential role in oocyte activation during mammalian fertilization. Sperm PLCzeta has been shown to trigger a prolonged series of repetitive Ca(2+) transients or oscillations in oocytes that precede activation. This remarkable intracellular Ca(2+) signalling phenomenon is a distinctive characteristic observed during in vitro fertilization by sperm. Previous studies have notably observed an apparent differential ability of PLCzeta from disparate mammalian species to trigger Ca(2+) oscillations in mouse oocytes. However, the molecular basis and confirmation of the apparent PLCzeta species difference in activity remains to be provided. In the present study, we provide direct evidence for the superior effectiveness of human PLCzeta relative to mouse PLCzeta in generating Ca(2+) oscillations in mouse oocytes. In addition, we have designed and constructed a series of human/mouse PLCzeta chimeras to enable study of the potential role of discrete PLCzeta domains in conferring the enhanced Ca(2+) signalling potency of human PLCzeta. Functional analysis of these human/mouse PLCzeta domain chimeras suggests a novel role of the EF-hand domain in the species-specific differences in PLCzeta activity. Our empirical observations are compatible with a basic mathematical model for the Ca(2+) dependence of generating cytoplasmic Ca(2+) oscillations in mammalian oocytes by sperm PLCzeta. PMID- 24478463 TI - Syndecan-1 knockdown in endometrial epithelial cells alters their apoptotic protein profile and enhances the inducibility of apoptosis. AB - Endometrial epithelial cells are known to undergo apoptosis during trophoblast invasion. We postulate that the cell surface molecule Syndecan-1 which is expressed on endometrial cells and syncytiotrophoblast is important for implantation in general and especially for induction of maternal cell apoptosis during trophoblast invasion because Syndecan-1's influence on apoptotic susceptibility of cancer cells is already described in the literature. Using the human endometrial epithelial cell line RL95-2, a new stable cell line with Syndecan-1 knockdown was generated. Via antibody array analysis, a significant decrease in the expression of anti-apoptotic proteins like inhibitors of apoptosis, Clusterin, heme oxygenase (HO-2), heat shock protein (HSP)27 and -70 and Survivin due to the Syndecan-1 knockdown was discovered. Correspondingly, active Caspase-3 as an indicator for apoptosis was increased more severely in these cells compared with unmodified RL95-2 after treatment with implantation related stimuli, which are the cytokines interleukin-1beta, interferon-gamma, tumor necrosis factor-alpha and transforming growth factor-beta1 and an anti-Fas antibody. Furthermore, a treatment with a combination of all factors caused a higher Caspase-3 induction compared with each single treatment. These results demonstrate that Syndecan-1 is involved in the control of apoptosis in RL95-2 cells and therefore may affect the fine tuning of apoptosis in endometrial epithelium regulating the embryo's invasion depth as a crucial step for regular implantation followed by successful pregnancy. PMID- 24478464 TI - Photo quiz: a man with chest pain and a history of eating sashimi. PMID- 24478465 TI - Biographical feature: Silas G. Farmer, Ph.D. PMID- 24478466 TI - Recent advances in detection of Plasmodium ovale: implications of separation into the two species Plasmodium ovale wallikeri and Plasmodium ovale curtisi. AB - Recent molecular studies indicate that Plasmodium ovale malaria is caused by two closely related species of protozoan parasites, thereby imposing new challenges for detection and species differentiation. This minireview explores the potential value of innovative methods for the molecular diagnosis of malaria with a strong emphasis on the discrimination and genotyping of P. ovale wallikeri and P. ovale curtisi as well as tools for the simultaneous detection of P. ovale sp. An update for the widely used NP-1993 to NP-2005 (SSU rRNA) protocols for all human malaria parasites is discussed. PMID- 24478467 TI - Performance of Vitek 2 for antimicrobial susceptibility testing of Staphylococcus spp. and Enterococcus spp. AB - Vitek 2 (bioMerieux, Inc., Durham, NC) is a widely used commercial antimicrobial susceptibility testing system. We compared MIC results obtained by Vitek 2 to those obtained by the Clinical and Laboratory Standards Institute (CLSI) broth microdilution (BMD) reference method for 134 staphylococcal and 84 enterococcal clinical isolates. Nineteen agents were evaluated, including all those available on Vitek 2 for testing staphylococci and enterococci. The resistance phenotypes tested included methicillin-resistant Staphylococcus aureus (MRSA) (n = 58), S. aureus with inducible clindamycin resistance (ICR) (n = 30), trimethoprim sulfamethoxazole-resistant MRSA (n = 10), vancomycin-resistant Enterococcus (n = 37), high-level gentamicin-resistant Enterococcus (n = 15), linezolid-resistant Enterococcus (n = 5), and daptomycin-nonsusceptible Enterococcus faecalis (n = 6). For the staphylococci, there was 98.9% categorical agreement (CA). There was one very major error (VME) for gentamicin in a Staphylococcus hominis isolate, six VMEs for inducible clindamycin in S. aureus isolates, and two major errors (ME) for daptomycin in an S. aureus and a Staphylococcus epidermidis isolate. For enterococci, there was 97.3% CA. Two VMEs were observed for daptomycin in isolates of E. faecalis and 2 ME, 1 for high-level gentamicin resistance and 1 for nitrofurantoin, in E. faecium isolates. Overall, there was 98.3% CA and 99% essential agreement for the testing of staphylococci and enterococci by the Vitek 2. With the exception of detecting ICR in S. aureus, Vitek 2 performed reliably for antimicrobial susceptibility testing of staphylococci and enterococci. PMID- 24478468 TI - Increased proportions of Bifidobacterium and the Lactobacillus group and loss of butyrate-producing bacteria in inflammatory bowel disease. AB - Dysbiosis in the intestinal microbiota of persons with inflammatory bowel disease (IBD) has been described, but there are still varied reports on changes in the abundance of Bifidobacterium and Lactobacillus organisms in patients with IBD. The aim of this investigation was to compare the compositions of mucosa associated and fecal bacteria in patients with IBD and in healthy controls (HCs). Fecal and biopsy samples from 21 HCs, 21 and 15 Crohn's disease (CD) patients, and 34 and 29 ulcerative colitis (UC) patients, respectively, were analyzed by quantitative real-time PCR targeting the 16S rRNA gene. The bacterial numbers were transformed into relative percentages for statistical analysis. The proportions of bacteria were uniformly distributed along the colon regardless of the disease state. Bifidobacterium was significantly increased in the biopsy specimens of active UC patients compared to those in the HCs (4.6% versus 2.1%, P = 0.001), and the proportion of Bifidobacterium was significantly higher in the biopsy specimens than in the fecal samples in active CD patients (2.7% versus 2.0%, P = 0.012). The Lactobacillus group was significantly increased in the biopsy specimens of active CD patients compared to those in the HCs (3.4% versus 2.3%, P = 0.036). Compared to the HCs, Faecalibacterium prausnitzii was sharply decreased in both the fecal and biopsy specimens of the active CD patients (0.3% versus 14.0%, P < 0.0001 for fecal samples; 0.8% versus 11.4%, P < 0.0001 for biopsy specimens) and the active UC patients (4.3% versus 14.0%, P = 0.001 for fecal samples; 2.8% versus 11.4%, P < 0.0001 for biopsy specimens). In conclusion, Bifidobacterium and the Lactobacillus group were increased in active IBD patients and should be used more cautiously as probiotics during the active phase of IBD. Butyrate-producing bacteria might be important to gut homeostasis. PMID- 24478470 TI - Copy numbers of telomeric repeat sequences of human herpesvirus 6B in clinical isolates: possibility of mixed infections. AB - In order to determine whether mixed infections of human herpesvirus 6B (HHV-6B) occur in immunocompetent and immunocompromised individuals, we examined the copy numbers of telomeric repeat sequences (TRS) of clinical isolates. In clinical isolates obtained from patients with exanthem subitum caused by primary HHV-6B infection, PCR products with HHV-6B TRS ranging between 400 and 800 bp were amplified. PCR products of various sizes were amplified in four clinical isolates from drug-induced hypersensitivity syndrome (DIHS) patients and 15 isolates from hematopoietic stem cell transplant (HSCT) recipients with HHV-6B reactivation. Based on the sequence analysis of the PCR products, the copy numbers of TRS in DIHS and HSCT patients were between 42 and 82 and 22 and >90, respectively. For two of the HSCT recipients, HHV-6B TRS PCR products of different sizes were detected in several isolates from each patient, which suggests mixed HHV-6B infections. In two of the posttransplant HHV-6B encephalitis patients, the sizes of the TRS nested PCR products amplified from the reactivated virus detected in the central nervous system differed from those of the virus detected in initial isolates from peripheral blood mononuclear cells. Taken together, these results suggest that PCR analysis of TRS copy number is a reliable tool for the discrimination of HHV-6B clinical isolates. Additionally, mixed HHV-6B infections occurred in HSCT recipients, and in some cases, compartmentalization of the HHV 6B strains to the central nervous system versus the blood compartment occurred in posttransplant HHV-6B encephalitis patients. PMID- 24478469 TI - Characterization of Escherichia coli isolates from hospital inpatients or outpatients with urinary tract infection. AB - Uropathogenic Escherichia coli (UPEC) is the most common cause of community- and hospital-acquired urinary tract infections (UTIs). Isolates from uncomplicated community-acquired UTIs express a variety of virulence traits that promote the efficient colonization of the urinary tract. In contrast, nosocomial UTIs can be caused by E. coli strains that differ in their virulence traits from the community-acquired UTI isolates. UPEC virulence markers are used to distinguish these facultative extraintestinal pathogens, which belong to the intestinal flora of many healthy individuals, from intestinal pathogenic E. coli (IPEC). IPEC is a diarrheagenic pathogen with a characteristic virulence gene set that is absent in UPEC. Here, we characterized 265 isolates from patients with UTIs during inpatient or outpatient treatment at a hospital regarding their phylogenies and IPEC or UPEC virulence traits. Interestingly, 28 of these isolates (10.6%) carried typical IPEC virulence genes that are characteristic of enteroaggregative E. coli (EAEC), Shiga toxin-producing E. coli (STEC), and atypical enteropathogenic E. coli (aEPEC), although IPEC is not considered a uropathogen. Twenty-three isolates harbored the astA gene coding for the EAEC heat-stable enterotoxin 1 (EAST1), and most of them carried virulence genes that are characteristic of UPEC and/or EAEC. Our results indicate that UPEC isolates from hospital patients differ from archetypal community-acquired isolates from uncomplicated UTIs by their spectrum of virulence traits. They represent a diverse group, including EAEC, as well as other IPEC pathotypes, which in addition contain typical UPEC virulence genes. The combination of typical extraintestinal pathogenic E. coli (ExPEC) and IPEC virulence determinants in some isolates demonstrates the marked genome plasticity of E. coli and calls for a reevaluation of the strict pathotype classification of EAEC. PMID- 24478471 TI - Clinical insights from metagenomic analysis of sputum samples from patients with cystic fibrosis. AB - As DNA sequencing becomes faster and cheaper, genomics-based approaches are being explored for their use in personalized diagnoses and treatments. Here, we provide a proof of principle for disease monitoring using personal metagenomic sequencing and traditional clinical microbiology by focusing on three adults with cystic fibrosis (CF). The CF lung is a dynamic environment that hosts a complex ecosystem composed of bacteria, viruses, and fungi that can vary in space and time. Not surprisingly, the microbiome data from the induced sputum samples we collected revealed a significant amount of species diversity not seen in routine clinical laboratory cultures. The relative abundances of several species changed as clinical treatment was altered, enabling the identification of the climax and attack communities that were proposed in an earlier work. All patient microbiomes encoded a diversity of mechanisms to resist antibiotics, consistent with the characteristics of multidrug-resistant microbial communities that are commonly observed in CF patients. The metabolic potentials of these communities differed by the health status and recovery route of each patient. Thus, this pilot study provides an example of how metagenomic data might be used with clinical assessments for the development of treatments tailored to individual patients. PMID- 24478472 TI - Pathogens of bovine respiratory disease in North American feedlots conferring multidrug resistance via integrative conjugative elements. AB - In this study, we determined the prevalence of bovine respiratory disease (BRD) associated viral and bacterial pathogens in cattle and characterized the genetic profiles, antimicrobial susceptibilities, and nature of antimicrobial resistance determinants in collected bacteria. Nasopharyngeal swab and lung tissue samples from 68 BRD mortalities in Alberta, Canada (n = 42), Texas (n = 6), and Nebraska (n = 20) were screened using PCR for bovine viral diarrhea virus (BVDV), bovine respiratory syncytial virus, bovine herpesvirus 1, parainfluenza type 3 virus, Mycoplasma bovis, Mannheimia haemolytica, Pasteurella multocida, and Histophilus somni. Excepting bovine herpesvirus 1, all agents were detected. M. haemolytica (91%) and BVDV (69%) were the most prevalent, with cooccurrence in 63% of the cattle. Isolates of M. haemolytica (n = 55), P. multocida (n = 8), and H. somni (n = 10) from lungs were also collected. Among M. haemolytica isolates, a clonal subpopulation (n = 8) was obtained from a Nebraskan feedlot. All three bacterial pathogens exhibited a high rate of antimicrobial resistance, with 45% exhibiting resistance to three or more antimicrobials. M. haemolytica (n = 18), P. multocida (n = 3), and H. somni (n = 3) from Texas and Nebraska possessed integrative conjugative elements (ICE) that conferred resistance for up to seven different antimicrobial classes. ICE were shown to be transferred via conjugation from P. multocida to Escherichia coli and from M. haemolytica and H. somni to P. multocida. ICE-mediated multidrug-resistant profiles of bacterial BRD pathogens could be a major detriment to many of the therapeutic antimicrobial strategies currently used to control BRD. PMID- 24478473 TI - Global improvement in genotyping of human papillomavirus DNA: the 2011 HPV LabNet International Proficiency Study. AB - Accurate and internationally comparable human papillomavirus (HPV) DNA genotyping is essential for HPV vaccine research and for HPV surveillance. The HPV Laboratory Network (LabNet) has designed international proficiency studies that can be issued regularly and in a reproducible manner. The 2011 HPV genotyping proficiency panel contained 43 coded samples composed of purified plasmids of 16 HPV types (HPV6, -11, -16, -18, -31, -33, -35, -39, -45, -51, -52, -56, -58, -59, -66, -68a, and -68b) and 3 extraction controls. Tests that detected 50 IU of HPV16 and HPV18 and 500 genome equivalents for the other 14 HPV types in both single and multiple infections were considered proficient. Ninety-six laboratories worldwide submitted 134 data sets. Twenty-five different HPV genotyping assay methods were used, including the Linear Array, line blot/INNO LiPA, PapilloCheck, and PCR Luminex assays. The major oncogenic HPV types, HPV16 and HPV18, were proficiently detected in 97.0% (113/116) and 87.0% (103/118) of the data sets, respectively. In 2011, 51 data sets (39%) were 100% proficient for the detection of at least one HPV type, and 37 data sets (28%) were proficient for all 16 HPV types; this was an improvement over the panel results from the 2008 and 2010 studies, when <25 data sets (23% and 19% for 2008 and 2010, respectively) were fully proficient. The improvement was also evident for the 54 laboratories that had also participated in the previous proficiency studies. In conclusion, a continuing global proficiency program has documented worldwide improvement in the comparability and reliability of HPV genotyping assay performances. PMID- 24478474 TI - Rapid detection of hepatitis B virus variants associated with lamivudine and adefovir resistance by multiplex ligation-dependent probe amplification combined with real-time PCR. AB - Drug-resistant mutations of hepatitis B virus (HBV) are the major obstacles to successful therapy for chronic hepatitis B infection. Although there are many methods for detecting the antiviral drug-resistant mutations of HBV, their applications are restricted because of their shortcomings, such as low sensitivity, the time required, and the high cost. For this study, a multiplex ligation-dependent probe real-time PCR (MLP-RT-PCR) method was developed to simultaneously detect lamivudine (LAM)- and adefovir (ADV)-resistant HBV mutants (those with the mutations rtM204V/I, rtA181V/T, and rtN236T). The new method combined the high-throughput nature of multiplex ligation-dependent probe amplification (MLPA) with the rapid and sensitive detection of real-time PCR. In this report, MLP-RT-PCR was evaluated by detecting drug-resistant mutants in 116 patients with chronic hepatitis B infection. By MLP-RT-PCR analysis, LAM resistant mutations were detected in 41 patients (35.3%), ADV-resistant mutations were detected in 17 patients (14.7%), and LAM- and-ADV-resistant mutations were detected in 5 patients (4.3%). Based on the results of MLP-RT-PCR, the mutations rtM204V, rtM204I, rtA181T, rtA181V, and rtN236T were 95.7% (111/116 patients), 98.3% (114/116 patients), 99.1% (115/116 patients), 98.3% (114/116 patients), and 99.1% (115/116 patients) concordant, respectively, with those of direct sequencing. The MLP-RT-PCR assay was more sensitive than direct sequencing for detecting mutations with low frequencies. Four samples containing the low frequency (<10%) mutants were identified by MLP-RT-PCR and further confirmed by clonal sequencing. MLP-RT-PCR is a rapid and sensitive method that enables the detection of multidrug-resistant HBV mutations in clinical practice. PMID- 24478475 TI - Characterization of Streptococcus tigurinus small-colony variants causing prosthetic joint infection by comparative whole-genome analyses. AB - Small-colony variants (SCVs) of bacteria are associated with recurrent and persistent infections. We describe for the first time SCVs of Streptococcus tigurinus in a patient with a prosthetic joint infection. S. tigurinus is a novel pathogen of the Streptococcus mitis group and causes invasive infections. We sought to characterize S. tigurinus SCVs using experimental methods and find possible genetic explanations for their phenotypes. The S. tigurinus SCVs were compared with the wild-type (WT) isolate using phenotypic methods, including growth under different conditions, autolysis, and visualization of the cell ultrastructure by use of transmission electron microscopy (TEM). Furthermore, comparative genome analyses were performed. The S. tigurinus SCVs displayed reduced growth compared to the WT and showed either a very stable or a fluctuating SCV phenotype. TEM analyses revealed major alterations in cell separation and morphological abnormalities, which were partially explained by impaired autolytic behavior. Intriguingly, the SCVs were more resistant to induced autolysis. Whole-genome sequencing revealed mutations in the genes involved in general cell metabolism, cell division, stringent response, and virulence. Clinically, the patient recovered after a 2-stage exchange of the prosthesis. Comparative whole-genome sequencing in clinical strains is a useful tool for identifying novel genetic signatures leading to the most persistent bacterial forms. The detection of viridans streptococcal SCVs is challenging in a clinical laboratory due to the small colony size. Thus, it is of major clinical importance for microbiologists and clinicians to be aware of viridans streptococcal SCVs, such as those of S. tigurinus, which lead to difficult-to treat infections. PMID- 24478476 TI - Pyrosequencing for rapid detection of extensively drug-resistant Mycobacterium tuberculosis in clinical isolates and clinical specimens. AB - Treating extensively drug-resistant (XDR) tuberculosis (TB) is a serious challenge. Culture-based drug susceptibility testing (DST) may take 4 weeks or longer from specimen collection to the availability of results. We developed a pyrosequencing (PSQ) assay including eight subassays for the rapid identification of Mycobacterium tuberculosis complex (MTBC) and concurrent detection of mutations associated with resistance to drugs defining XDR TB. The entire procedure, from DNA extraction to the availability of results, was accomplished within 6 h. The assay was validated for testing clinical isolates and clinical specimens, which improves the turnaround time for molecular DST and maximizes the benefit of using molecular testing. A total of 130 clinical isolates and 129 clinical specimens were studied. The correlations between the PSQ results and the phenotypic DST results were 94.3% for isoniazid, 98.7% for rifampin, 97.6% for quinolones (ofloxacin, levofloxacin, or moxifloxacin), 99.2% for amikacin, 99.2% for capreomycin, and 96.4% for kanamycin. For testing clinical specimens, the PSQ assay yielded a 98.4% sensitivity for detecting MTBC and a 95.8% sensitivity for generating complete sequencing results from all subassays. The PSQ assay was able to rapidly and accurately detect drug resistance mutations with the sequence information provided, which allows further study of the association of drug resistance or susceptibility with each mutation and the accumulation of such knowledge for future interpretation of results. Thus, reporting of false resistance for mutations known not to confer resistance can be prevented, which is a significant benefit of the assay over existing molecular diagnostic methods endorsed by the World Health Organization. PMID- 24478477 TI - Development of a loop-mediated isothermal amplification method for detection of Histoplasma capsulatum DNA in clinical samples. AB - Improved methods for the detection of Histoplasma capsulatum are needed in regions with limited resources in which the organism is endemic, where delayed diagnosis of progressive disseminated histoplasmosis (PDH) results in high mortality rates. We have investigated the use of a loop-mediated isothermal amplification (LAMP) assay to facilitate rapid inexpensive molecular diagnosis of this disease. Primers for LAMP were designed to amplify the Hcp100 locus of H. capsulatum. The sensitivity and limit of detection were evaluated using DNA extracted from 91 clinical isolates of known geographic subspecies, while the assay specificity was determined using DNA extracted from 50 other fungi and Mycobacterium tuberculosis. Urine specimens (n = 6) collected from HIV-positive individuals with culture- and antigen-proven histoplasmosis were evaluated using the LAMP assay. Specimens from healthy persons (n = 10) without evidence of histoplasmosis were used as assay controls. The Hcp100 LAMP assay was 100% sensitive and specific when tested with DNA extracted from culture isolates. The median limit of detection was <=6 genomes (range, 1 to 300 genomes) for all except one geographic subspecies. The LAMP assay detected Hcp100 in 67% of antigen-positive urine specimens (4/6 specimens), and results were negative for Hcp100 in all healthy control urine specimens. We have shown that the Hcp100 LAMP assay is a rapid affordable assay that can be used to expedite culture confirmation of H. capsulatum in regions in which PDH is endemic. Further, our results indicate proof of the concept that the assay can be used to detect Histoplasma DNA in urine. Further evaluation of this assay using body fluid samples from a larger patient population is warranted. PMID- 24478478 TI - Economic evaluation of laboratory testing strategies for hospital-associated Clostridium difficile infection. AB - Clostridium difficile infection (CDI) is the most common cause of infectious diarrhea in health care settings, and for patients presumed to have CDI, their isolation while awaiting laboratory results is costly. Newer rapid tests for CDI may reduce this burden, but the economic consequences of different testing algorithms remain unexplored. We used decision analysis from the hospital perspective to compare multiple CDI testing algorithms for adult inpatients with suspected CDI, assuming patient management according to laboratory results. CDI testing strategies included combinations of on-demand PCR (odPCR), batch PCR, lateral-flow diagnostics, plate-reader enzyme immunoassay, and direct tissue culture cytotoxicity. In the reference scenario, algorithms incorporating rapid testing were cost-effective relative to nonrapid algorithms. For every 10,000 symptomatic adults, relative to a strategy of treating nobody, lateral-flow glutamate dehydrogenase (GDH)/odPCR generated 831 true-positive results and cost $1,600 per additional true-positive case treated. Stand-alone odPCR was more effective and more expensive, identifying 174 additional true-positive cases at $6,900 per additional case treated. All other testing strategies were dominated by (i.e., more costly and less effective than) stand-alone odPCR or odPCR preceded by lateral-flow screening. A cost-benefit analysis (including estimated costs of missed cases) favored stand-alone odPCR in most settings but favored odPCR preceded by lateral-flow testing if a missed CDI case resulted in less than $5,000 of extended hospital stay costs and <2 transmissions, if lateral-flow GDH diagnostic sensitivity was >93%, or if the symptomatic carrier proportion among the toxigenic culture-positive cases was >80%. These results can aid guideline developers and laboratory directors who are considering rapid testing algorithms for diagnosing CDI. PMID- 24478479 TI - Clinical and virologic factors associated with reduced sensitivity of rapid influenza diagnostic tests in hospitalized elderly patients and young children. AB - Rapid influenza diagnostic tests (RIDTs) are commonly used by clinicians to guide patient management. Data on sensitivities among hospitalized patients are limited. Here, we evaluated the clinical and virologic factors affecting the sensitivities of 2 commercially available RIDTs (BinaxNOW Influenza A&B and QuickVue Influenza A+B) on nasopharyngeal aspirate (NPA) specimens collected from elderly patients and young children hospitalized for influenza. Influenza cases and age-matched negative controls were prospectively enrolled during the 2011 2012 influenza season in Hong Kong. NPA specimens were collected at presentation before antiviral treatment. Real-time reverse transcription-PCR (RT-PCR) results were used as references for the sensitivity analyses. One hundred patients (57 influenza cases and 43 controls) were studied. Both RIDTs had 100% specificities. The sensitivities of the BinaxNOW Influenza A&B and QuickVue Influenza A+B tests were 70% and 82%, respectively. For both tests, the sensitivities were lower in cases with presentation times beyond 2 days of illness onset than for those within this time (50 to 71% versus 85 to 91%, respectively). There were trends toward lower sensitivities for influenza B than for influenza A (66 to 81% versus 76 to 84%, respectively), among young children than among the elderly patients (63 to 78% versus 80 to 88%, respectively), and among cases with pneumonia than those without pneumonia (75% versus 82 to 94%, respectively). The sensitivities of the RIDTs decreased with reduced NPA viral RNA levels (5.6 to 15.0% reduction per 1-log decrease), which declined progressively after illness onset (Spearman's rho, -0.47 [P < 0.05] and -0.66 [P < 0.001] for influenza A and B, respectively). Collectively, late presentation, a low NPA viral load, and probably lower respiratory manifestation are factors associated with reduced sensitivities of RIDTs for diagnosing influenza in hospitalized patients. A negative RIDT result should be interpreted with caution. PMID- 24478480 TI - Point-of-care system for detection of Mycobacterium tuberculosis and rifampin resistance in sputum samples. AB - Early detection of Mycobacterium tuberculosis complex (MTBC) and markers conveying drug resistance can have a beneficial impact on preventive public health actions. We describe here a new molecular point-of-care (POC) system, the Genedrive, which is based on simple sample preparation combined with PCR to detect MTBC and simultaneously detect mutation markers in the rpoB gene directly from raw sputum sample. Hybridization probes were used to detect the presence of the key mutations in codons 516, 526, and 531 of the rpoB gene. The sensitivities for MTBC and rpoB detection from sputum samples were assessed using model samples spiked with known numbers of bacteria prepared from liquid cultures of M. tuberculosis. The overall sensitivities were 90.8% (95% confidence interval [CI], 81, 96.5) for MTBC detection and 72.3% (95% CI, 59.8, 82.7) for rpoB detection. For samples containing >=1,000 CFU/ml, the sensitivities were 100% for MTBC and 85.7% for rpoB detection, while for samples containing <=100 CFU/ml, the sensitivities were 86.4% and 65.9% for MTBC and rpoB detection, respectively. The specificity was shown to be 100% (95% CI, 83.2, 100) for MTBC and rpoB. The clinical sputum samples were processed using the same protocol and showed good concordance with the data generated from the model. Tuberculosis-infected subjects with smear samples assessed as scanty or negative were detectable by the Genedrive system. In these paucibacillary patients, the performance of the Genedrive system was comparable to that of the GeneXpert assay. The characteristics of the Genedrive platform make it particularly useful for detecting MTBC and rifampin resistance in low-resource settings and for reducing the burden of tuberculosis disease. PMID- 24478481 TI - Epidemiology and molecular characterization of macrolide-resistant Streptococcus pyogenes in Taiwan. AB - Our multicenter nationwide surveillance data indicated that erythromycin (ERY) resistance among group A Streptococcus (GAS) isolates in Taiwan declined from 53.1% in 1998 and 2000 to 14.6% in 2002 and 2004 and 10.7% in 2006 to 2010 (P < 0.01). The present study aimed to assess the epidemiology of GAS in Taiwan and identify factors associated with ERY resistance. All 127 ERY-resistant (ERY(r)) isolates and 128 randomly selected ERY-susceptible (ERY(s)) isolates recovered from 1998 to 2010 were emm typed. ERY(r) isolates were also characterized by ERY resistance phenotype and mechanisms and pulsed-field gel electrophoresis (PFGE). Multilocus sequence typing was performed on selected ERY(r) isolates. The predominant emm types in ERY(r) isolates were emm22 (n = 33, 26.0%), emm12 (n = 24, 18.9%), emm4 (n = 21, 16.5%), and emm106 (n = 15, 11.8%). In ERY(s) isolates, emm12 (n = 27, 21.9%), emm1 (n = 18, 14.1%), emm106 (n = 16, 12.5%), and emm11 (n = 9, 7.1%) predominated. The most common ERY resistance phenotype was the M phenotype (resistant to macrolides) (70.9%), with all but one isolate carrying mef(A), followed by the constitutive macrolide-lincosamide-streptogramin B resistance (cMLSB) phenotype (26.8%), with isolates carrying erm(B) or erm(TR). ERY(r) isolates of the emm12-sequence type 36 (ST36) lineage with the cMLSB phenotype were mostly present before 2004, while those of the emm22-ST46 lineage with the M phenotype predominated in later years. Recovery from respiratory (throat swab) specimens was an independent factor associated with ERY resistance. emm1 and emm11 GAS isolates were significantly associated with ERY(s), while emm22 was detected only in ERY(r) GAS. In addition, emm106 isolates were prevalent among the abscess/pus isolates, whereas emm12 isolates were strongly associated with a respiratory (throat) origin. In addition to identifying factors associated with ERY resistance in GAS, our study provides helpful information on the changing GAS epidemiology in Taiwan. PMID- 24478482 TI - Comparative performances of HIV-1 RNA load assays at low viral load levels: results of an international collaboration. AB - Low-level viremia during antiretroviral therapy and its accurate measurement are increasingly relevant. Here, we present an international collaboration of 4,221 paired blood plasma viral load (pVL) results from four commercial assays, emphasizing the data with low pVL. The assays compared were the Abbott RealTime assay, the Roche Amplicor assay, and the Roche TaqMan version 1 and version 2 assays. The correlation between the assays was 0.90 to 0.97. However, at a low pVL, the correlation fell to 0.45 to 0.85. The observed interassay concordance was higher when detectability was defined as 200 copies/ml than when it was defined as 50 copies/ml. A pVL of ~100 to 125 copies/ml by the TaqMan version 1 and version 2 assays corresponded best to a 50-copies/ml threshold with the Amplicor assay. Correlation and concordance between the viral load assays were lower at a low pVL. Clear guidelines are needed on the clinical significance of low-level viremia. PMID- 24478483 TI - Multilocus sequence typing of an emerging Cryptosporidium hominis subtype in the United States. AB - The United States has experienced a substantial increase in the reported incidence of cryptosporidiosis since 2005. Accompanying this is the emergence of a new subtype of Cryptosporidium hominis based on variation at the 60-kDa glycoprotein (gp60) locus, IaA28R4, which has become a frequently identified subtype in both sporadic and outbreak-related cases. In this study, using multilocus sequence typing (MLST) at eight genetic loci, we characterized 62 specimens of IaA28R4 and 33 specimens of three other gp60 subtypes of C. hominis from four U.S. states with increased cryptosporidiosis incidences during the summer of 2008. Extensive genetic heterogeneity was seen within the gp60 subtype IaA28R4, but specimens from Ohio and southwestern states formed two distinct subpopulations, suggesting that there were at least two origins of IaA28R4 within the United States. Discordance in typing results was observed between gp60 and other genetic markers, especially DZ-HRGP, and this discordance was largely the result of genetic recombination within the gp60 subtype IaA28R4. The results of population genetic analyses supported the presence of two subpopulations of IaA28R4 and the occurrence of genetic recombination within this gp60 subtype. Thus, the IaA28R4 subtype at gp60 is likely a fitness marker for C. hominis, and genetic recombination is potentially a driving force in the emergence of the virulent IaA28R4 subtype in the United States. A rapid evolution of IaA28R4 was indicated by the observation of multiple MLST subtypes of IaA28R4 within two large outbreaks that lasted for extended periods and involved multiple swimming pools. PMID- 24478484 TI - Detection of new bunyavirus RNA by reverse transcription-loop-mediated isothermal amplification. AB - Severe fever with thrombocytopenia syndrome (SFTS) is a newly emerging and epidemic infectious disease in central and northeast China. It is caused by New Bunyavirus and carries an average 12% case fatality rate. Early and rapid detection is critical for prevention and control of New Bunyavirus infection, since no vaccine or antiviral drugs are currently available, and prevention requires careful attention to control of the suspected tick vector. In this study, a simple and sensitive reverse transcription-loop-mediated isothermal amplification (RT-LAMP) assay was developed for rapid detection of New Bunyavirus. The detection limit of the RT-LAMP assay was approximately 10(3) 50% tissue culture infective doses/ml of New Bunyavirus in culture supernatants, and no cross-reactive amplification of other viruses known to cause similar clinical manifestations was observed. The assay was further evaluated using 138 specimens from clinically suspected SFTS and 40 laboratory-proven hantavirus infection with fever and renal syndrome patients, and the assay exhibited 97% agreement compared to real-time RT-PCR and conventional RT-PCR. Using real-time RT-PCR as the diagnostic gold standard, RT-LAMP was 99% sensitive and 100% specific. The RT LAMP assay could become a useful alternative in clinical diagnosis of SFTS caused by New Bunyavirus, especially in resource-limited hospitals or rural clinics of China. PMID- 24478486 TI - Necessity for reassessment of patients with serogroup 2 hepatitis C virus (HCV) and undetectable serum HCV RNA. AB - We encountered a patient positive for anti-hepatitis C virus (HCV) whose serum HCV RNA was undetectable with the Roche AmpliPrep/Cobas TaqMan HCV assay (CAP/CTM) version 1 but showed a high viral load with the Abbott RealTime HCV assay (ART). Discrepancies in the detectability of serum HCV RNA were investigated among 891 consecutive patients who were positive for anti-HCV. Specific nucleotide variations causing the undetectability of HCV RNA were determined and confirmed by synthesizing RNA coding those variations. Serum samples with the discrepancies were also reassessed by CAP/CTM version 2. Among the 891 anti-HCV-positive patients, 4 patients had serum HCV RNA levels that were undetectable by CAP/CTM version 1 despite having levels of >5 log IU/ml that were detected by ART. All four patients had HCV genotype 2a and high titers of anti HCV. Sequencing of the HCV 5' noncoding regions revealed 2 common variations, A at nucleotide (nt) 145 and T at nt 151. Synthesized RNAs of the HCV 5' noncoding region with standard (NCR145G151C) and variant nucleotides at nt 145 and nt 151 were quantified with CAP/CTM. RNAs of NCR145G151C and NCR145G151T were quantifiable with CAP/CTM version 1, while those of NCR145A151T and NCR145A151C went undetected. The substitution from G to A at nt 145 specifically conferred this undetectability, while this undetectability was reverted in synthesized HCV RNA with correction of this variation. Reassessment of these samples by CAP/CTM version 2 resulted in similar levels of HCV RNA being detected by ART. We conclude that HCV patients with undetectable HCV RNA by CAP/CTM version 1 should be reassessed for viral quantification. PMID- 24478485 TI - Circulating Mycobacterium bovis peptides and host response proteins as biomarkers for unambiguous detection of subclinical infection. AB - Bovine tuberculosis remains one of the most damaging diseases to agriculture, and there is also a concern for human spillover. A critical need exists for rapid, thorough, and inexpensive diagnostic methods capable of detecting and differentiating Mycobacterium bovis infection from other pathogenic and environmental mycobacteria at multiple surveillance levels. In a previous study, Seth et al. (PLoS One 4:e5478, 2009, doi:10.1371/journal.pone.0005478) identified 32 host peptides that specifically increased in the blood serum of M. bovis infected animals). In the current study, 16 M. bovis proteins were discovered in the blood serum proteomics data sets. A large-scale validation analysis was undertaken for selected host and M. bovis proteins using a cattle serum repository containing M. bovis (n = 128), Mycobacterium kansasii (n = 10), and Mycobacterium avium subsp. paratuberculosis (n = 10), cases exposed to M. bovis (n = 424), and negative controls (n = 38). Of the host biomarkers, vitamin D binding protein (VDBP) showed the greatest sensitivity and specificity for M. bovis detection. Circulating M. bovis proteins, specifically polyketide synthetase 5, detected M. bovis-infected cattle with little to no seroreactivity against M. kansasii- and M. avium subsp. paratuberculosis-infected animals. These data indicate that host and pathogen serum proteins can serve as reliable biomarkers for tracking M. bovis infection in animal populations. PMID- 24478487 TI - The majority of a collection of U.S. endocarditis Enterococcus faecalis isolates obtained from 1974 to 2004 lack capsular genes and belong to diverse, non hospital-associated lineages. AB - Eighty-one endocarditis-derived Enterococcus faecalis isolates that were collected from individual patients in the United States between 1974 and 2004 were sequence typed and analyzed for the presence of various genes, including some previously associated with virulence. Overall, using our previously described trilocus sequence typing (TLST), 44 different sequence types (STs) were found within this collection; 26 isolates were singletons (a unique TLST sequence type [ST(T)]), some ST(T)s contained multiple isolates (up to 6 isolates), and 16% of the isolates (13 isolates) could be grouped by additional sequence typing into clonal cluster 21 (CC21). Of note, only four isolates (7%) of the 56 whose multilocus sequence types were determined were found to belong to one of the previously described hospital-associated clonal clusters CC2 and CC9, and only 15% and 37% of all isolates had high-level resistance to gentamicin and streptomycin, respectively, including 10% that were resistant to both. We also found that 64% of the isolates lacked the genes for production of capsule polysaccharide, which has been proposed to enhance the pathogenic potential of the hospital-associated clonal clusters. In summary, while our collection is not a random sample of cases of E. faecalis endocarditis, these results indicate that nonencapsulated strains belonging to non-hospital-associated lineages were predominant among endocarditis E. faecalis isolates recovered during this time period. PMID- 24478488 TI - Comparison of conventional PCR, multiplex PCR, and loop-mediated isothermal amplification assays for rapid detection of Arcobacter species. AB - This study aimed to develop a loop-mediated isothermal amplification (LAMP) method for the rapid detection of Arcobacter species. Specific primers targeting the 23S ribosomal RNA gene were used to detect Arcobacter butzleri, Arcobacter cryaerophilus, and Arcobacter skirrowii. The specificity of the LAMP primer set was assessed using DNA samples from a panel of Arcobacter and Campylobacter species, and the sensitivity was determined using serial dilutions of Arcobacter species cultures. LAMP showed a 10- to 1,000-fold-higher sensitivity than multiplex PCR, with a detection limit of 2 to 20 CFU per reaction in vitro. Whereas multiplex PCR showed cross-reactivity with Campylobacter species, the LAMP method developed in this study was more sensitive and reliable than conventional PCR or multiplex PCR for the detection of Arcobacter species. PMID- 24478489 TI - High-resolution typing of Leptospira interrogans strains by multispacer sequence typing. AB - Leptospirosis is a worldwide zoonosis which is responsible for the typical form of Weil's disease. The epidemiological surveillance of the Leptospira species agent is important for host prevalence control. Although the genotyping methods have progressed, the identification of some serovars remains ambiguous. We investigated the multispacer sequence typing (MST) method for genotyping strains belonging to the species Leptospira interrogans, which is the main agent of leptospirosis worldwide. A total of 33 DNA samples isolated from the reference strains of L. interrogans serogroups Icterohaemorrhagiae, Australis, Canicola, and Grippotyphosa, which are the most prevalent serogroups in France, were analyzed by both the variable-number tandem-repeat (VNTR) and MST methods. An MST database has been constructed from the DNA of these reference strains to define the MST profiles. The MST profiles corroborated with the VNTR results. Moreover, the MST analysis allowed the identification at the serovar level or potentially to the isolate level for strains belonging to L. interrogans serovar Icterohaemorrhagiae, which then results in a higher resolution than VNTR (Hunter Gaston index of 0.94 versus 0.68). Regarding L. interrogans serogroups Australis, Canicola, and Grippotyphosa, the MST and VNTR methods similarly identified the genotype. The MST method enabled the acquisition of simple and robust results that were based on the nucleotide sequences. The MST identified clinical isolates in correlation with the reference serovar profiles, thus permitting an epidemiological surveillance of circulating L. interrogans strains, especially for the Icterohaemorrhagiae serogroup, which includes the most prevalent strains of public health interest. PMID- 24478490 TI - Yeast identification algorithm based on use of the Vitek MS system selectively supplemented with ribosomal DNA sequencing: proposal of a reference assay for invasive fungal surveillance programs in China. AB - Sequence analysis of the internal transcribed spacer (ITS) region was employed as the gold standard method for yeast identification in the China Hospital Invasive Fungal Surveillance Net (CHIF-NET). It has subsequently been found that matrix assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF MS) is potentially a more practical approach for this purpose. In the present study, the performance of the Vitek MS v2.0 system for the identification of yeast isolates collected from patients with invasive fungal infections in the 2011 CHIF-NET was evaluated. A total of 1,243 isolates representing 31 yeast species were analyzed, and the identification results by the Vitek MS v2.0 system were compared to those obtained by ITS sequence analysis. By the Vitek MS v2.0 system, 96.7% (n = 1,202) of the isolates were correctly assigned to the species level and 0.2% (n = 2) of the isolates were identified to the genus level, while 2.4% (n = 30) and 0.7% (n = 9) of the isolates were unidentified and misidentified, respectively. After retesting of the unidentified and misidentified strains, 97.3% (n = 1,209) of the isolates were correctly identified to the species level. Based on these results, a testing algorithm that combines the use of the Vitek MS system with selected supplementary ribosomal DNA (rDNA) sequencing was developed and validated for yeast identification purposes. By employing this algorithm, 99.7% (1,240/1,243) of the study isolates were accurately identified with the exception of two isolates of Candida fermentati and one isolate of Cryptococcus gattii. In conclusion, the proposed identification algorithm could be practically implemented in strategic programs of fungal infection surveillance. PMID- 24478492 TI - Pathogenicity and phenotypic characterization of enterotoxigenic Escherichia coli isolates from a birth cohort of children in rural Egypt. AB - Enterotoxigenic Escherichia coli (ETEC) has consistently been the predominant bacterial cause of diarrhea in many birth cohort- and hospital-based studies conducted in Egypt. We evaluated the pathogenicity of ETEC isolates in a birth cohort of children living in a rural community in Egypt. Between 2004 and 2007, we enrolled and followed 348 children starting at birth until their second year of life. A stool sample and two rectal swabs were collected from children during twice-weekly visits when they presented with diarrhea and were collected every 2 weeks if no diarrhea was reported. From routine stool cultures, five E. coli-like colonies were screened for ETEC enterotoxins using a GM1 enzyme-linked immunosorbent assay (ELISA). The isolates were screened against a panel of 12 colonization factor antigens (CFAs) by a dot blot assay. A nested case-control study evaluated the association between initial or repeat excretion of ETEC and the occurrences of diarrhea. The pathogenicity of ETEC was estimated in symptomatic children compared to that in asymptomatic controls. ETEC was significantly associated with diarrhea (crude odds ratio, 1.37; 95% confidence interval [CI], 1.24 to 1.52). The distribution of ETEC enterotoxins varied between the symptomatic children (44.2% heat-labile toxin [LT], 38.5% heat-stable toxin [ST], and 17.3% LT/ST) and asymptomatic children (55.5% LT, 34.6% ST, and 9.9% LT/ST) (P < 0.001). The CFAs CFA/I (n = 61), CS3 (n = 8), CS1 plus CS3 (n = 24), CS2 plus CS3 (n = 18), CS6 (n = 45), CS5 plus CS6 (n = 11), CS7 (n = 25), and CS14 (n = 32) were frequently detected in symptomatic children, while CS6 (n = 66), CS12 (n = 51), CFA/I (n = 43), and CS14 (n = 20) were detected at higher frequencies among asymptomatic children. While all toxin phenotypes were associated with diarrheal disease after the initial exposure, only ST and LT/ST expressing ETEC isolates (P < 0.0001) were associated with disease in repeat infections. The role of enterotoxins and pathogenicity during repeat ETEC infections appears to be variable and dependent on the coexpression of specific CFAs. PMID- 24478491 TI - Field evaluation of dried blood spots for routine HIV-1 viral load and drug resistance monitoring in patients receiving antiretroviral therapy in Africa and Asia. AB - Dried blood spots (DBS) can be used in developing countries to alleviate the logistic constraints of using blood plasma specimens for viral load (VL) and HIV drug resistance (HIVDR) testing, but they should be assessed under field conditions. Between 2009 and 2011, we collected paired plasma-DBS samples from treatment-experienced HIV-1-infected adults in Burkina Faso, Cameroon, Senegal, Togo, Thailand, and Vietnam. The DBS were stored at an ambient temperature for 2 to 4 weeks and subsequently at -20 degrees C before testing. VL testing was performed on the plasma samples and DBS using locally available methods: the Abbott m2000rt HIV-1 test, generic G2 real-time PCR, or the NucliSENS EasyQ version 1.2 test. In the case of virological failure (VF), i.e., a plasma VL of >=1,000 copies/ml, HIVDR genotyping was performed on paired plasma-DBS samples. Overall, we compared 382 plasma-DBS sample pairs for DBS VL testing accuracy. The sensitivities of the different assays in different laboratories for detecting VF using DBS varied from 75% to 100% for the m2000rt test in labs B, C, and D, 91% to 93% for generic G2 real-time PCR in labs A and F, and 85% for the NucliSENS test in lab E. The specificities varied from 82% to 97% for the m2000rt and NucliSENS tests and reached only 60% for the generic G2 test. The NucliSENS test showed good agreement between plasma and DBS VL but underestimated the DBS VL. The lowest agreement was observed for the generic G2 test. Genotyping was successful for 96/124 (77%) DBS tested, and 75/96 (78%) plasma-DBS pairs had identical HIVDR mutations. Significant discrepancies in resistance interpretations were observed in 9 cases, 6 of which were from the same laboratory. DBS can be successfully used as an alternative to blood plasma samples for routine VL and HIVDR monitoring in African and Asian settings. However, the selection of an adequate VL measurement method and the definition of the VF threshold should be considered, and laboratory performance should be monitored. PMID- 24478494 TI - High-resolution melt PCR analysis for genotyping of Ureaplasma parvum isolates directly from clinical samples. AB - Ureaplasma sp. infection in neonates and adults underlies a variety of disease pathologies. Of the two human Ureaplasma spp., Ureaplasma parvum is clinically the most common. We have developed a high-resolution melt (HRM) PCR assay for the differentiation of the four serovars of U. parvum in a single step. Currently U. parvum strains are separated into four serovars by sequencing the promoter and coding region of the multiple-banded antigen (MBA) gene. We designed primers to conserved sequences within this region for PCR amplification and HRM analysis to generate reproducible and distinct melt profiles that distinguish clonal representatives of serovars 1, 3, 6, and 14. Furthermore, our HRM PCR assay could classify DNA extracted from 74 known (MBA-sequenced) test strains with 100% accuracy. Importantly, HRM PCR was also able to identify U. parvum serovars directly from 16 clinical swabs. HRM PCR performed with DNA consisting of mixtures of combined known serovars yielded profiles that were easily distinguished from those for single-serovar controls. These profiles mirrored clinical samples that contained mixed serovars. Unfortunately, melt curve analysis software is not yet robust enough to identify the composition of mixed serovar samples, only that more than one serovar is present. HRM PCR provides a single-step, rapid, cost-effective means to differentiate the four serovars of U. parvum that did not amplify any of the known 10 serovars of Ureaplasma urealyticum tested in parallel. Choice of reaction reagents was found to be crucial to allow sufficient sensitivity to differentiate U. parvum serovars directly from clinical swabs rather than requiring cell enrichment using microbial culture techniques. PMID- 24478493 TI - Colorimetric sensor array allows fast detection and simultaneous identification of sepsis-causing bacteria in spiked blood culture. AB - Sepsis is a medical emergency demanding early diagnosis and tailored antimicrobial therapy. Every hour of delay in initiating effective therapy measurably increases patient mortality. Blood culture is currently the reference standard for detecting bloodstream infection, a multistep process which may take one to several days. Here, we report a novel paradigm for earlier detection and the simultaneous identification of pathogens in spiked blood cultures by means of a metabolomic "fingerprint" of the volatile mixture outgassed by the organisms. The colorimetric sensor array provided significantly faster detection of positive blood cultures than a conventional blood culture system (12.1 h versus 14.9 h, P < 0.001) while allowing for the identification of 18 bacterial species with 91.9% overall accuracy within 2 h of growth detection. The colorimetric sensor array also allowed for discrimination between unrelated strains of methicillin resistant Staphylococcus aureus, indicating that the metabolomic fingerprint has the potential to track nosocomial transmissions. Altogether, the colorimetric sensor array is a promising tool that offers a new paradigm for diagnosing bloodstream infections. PMID- 24478495 TI - Comparison of Seegene Anyplex II HPV28 with the PGMY-CHUV assay for human papillomavirus genotyping. AB - The Anyplex II HPV28 (H28; Seegene) is a new semiquantitative real-time multiplex PCR assay for screening and genotyping 28 human papillomaviruses (HPV) in only 2 reaction wells. H28 was compared to the PGMY-CHUV assay (PG) with 309 archival DNA samples from cervical smears collected over 8 years in our laboratory. H28 and PG were fully concordant at the genotypic level on 228 (73.8%) out of 309 samples: 27 HPV negative and 201 HPV positive. The 201 fully concordant positive samples corresponded to single infections (n = 145) and to multiple infections (2 genotypes, n = 38; 3 to 5 genotypes, n = 18). The remaining 81 samples (26.2%) were either partially concordant (n = 64, 20.7%) or fully discordant (n = 17, 5.5%). While genotype-specific agreement was nearly perfect (kappa = 0.877), HPV51 was significantly less well detected by H28 and the converse was observed for HPV40, -42, -54, and -68. Sequencing of PG amplicons confirmed HPV51 discordants and suggested the involvement of a possibly local HPV51 subtype. Mismatches in the PGMY09 primers to HPV68a explained most of the HPV68 discordants, confirming the specificity of H28 toward HPV68. With PG as a reference, the sensitivity and specificity of H28 were 93.4% and 99.0%, respectively. Considering H28 as a reference, the sensitivity and specificity of PG were 83.8% and 99.6%, respectively. H28 is a very sensitive and specific HPV genotyping assay suitable for research and clinical use as an adjunct to a clinically validated test. H28 semiquantitative readout ought to be evaluated for primary cervical cancer screening. PMID- 24478496 TI - Rapid quantitative serological test for detection of infection with Mycobacterium leprae, the causative agent of leprosy. AB - Leprosy remains an important health problem in a number of regions. Early detection of infection, followed by effective treatment, is critical to reduce disease progression. New sensitive and specific tools for early detection of infection will be a critical component of an effective leprosy elimination campaign. Diagnosis is made by recognizing clinical signs and symptoms, but few clinicians are able to confidently identify these. Simple tests to facilitate referral to leprosy experts are not widely available, and the correct diagnosis of leprosy is often delayed. In this report, we evaluate the performance of a new leprosy serological test (NDO-LID). As expected, the test readily detected clinically confirmed samples from patients with multibacillary (MB) leprosy, and the rate of positive results declined with bacterial burden. NDO-LID detected larger proportions of MB and paucibacillary (PB) leprosy than the alternative, the Standard Diagnostics leprosy test (87.0% versus 81.7% and 32.3% versus 6.5%, respectively), while also demonstrating improved specificity (97.4% versus 90.4%). Coupled with a new cell phone-based test reader platform (Smart Reader), the NDO-LID test provided consistent, objective test interpretation that could facilitate wider use in nonspecialized settings. In addition, results obtained from sera at the time of diagnosis, versus at the end of treatment, indicated that the quantifiable nature of this system can also be used to monitor treatment efficacy. Taken together, these data indicate that the NDO-LID/Smart Reader system can assist in the diagnosis and monitoring of MB leprosy and can detect a significant number of earlier-stage infections. PMID- 24478497 TI - Toll-like receptor 2 in serum: a potential diagnostic marker of prosthetic joint infection? AB - Prosthetic joint infection (PJI) is a severe complication of arthroplasty and is still lacking diagnostic gold standards. PJI patients display high Toll-like receptor 2 (TLR2) serum levels, correlating with canonical inflammatory markers (C-reactive protein [CRP], interleukin 6 [IL-6], tumor necrosis factor alpha [TNF alpha], and IL-1). Therefore, TLR2 serum levels could be considered a new potential diagnostic tool in the early detection of PJI. PMID- 24478498 TI - Seven hours to adequate antimicrobial therapy in urosepsis using isothermal microcalorimetry. AB - Urosepsis can progress toward severe sepsis, septic shock, and, ultimately, death. Rapid antimicrobial susceptibility testing is crucial to decrease mortality and morbidity. This report shows that isothermal microcalorimetry can provide an antibiogram within 7 h with a sensitivity of 95% and specificity of 91% using Vitek-2 system as a reference. PMID- 24478499 TI - Nosocomial outbreak of Salmonella enterica serovar Typhimurium primarily affecting a pediatric ward in South Africa in 2012. AB - We describe a nosocomial outbreak of diarrheal disease caused by extended spectrum beta-lactamase-producing multidrug-resistant Salmonella enterica serovar Typhimurium, focused on a pediatric ward in South Africa. The outbreak peaked between May 2012 and July 2012. Person-to-person transmission was the most likely mechanism of spread of the infection, expedited due to a breakdown in hand washing and hygiene, suboptimal infection control practices, overcrowding of hospital wards, and an undesirable nurse-to-patient ratio. PMID- 24478500 TI - Impact of changes in Clostridium difficile testing practices on stool rejection policies and C. difficile positivity rates across multiple laboratories in the United States. AB - We describe the adoption of nucleic acid amplification tests (NAAT) for Clostridium difficile diagnosis and their impact on stool rejection policies and C. difficile positivity rates. Of the laboratories with complete surveys, 51 (43%) reported using NAAT in 2011. Laboratories using NAAT had stricter rejection policies and increased positivity rates. PMID- 24478501 TI - GeneXpert MTB/RIF version G4 for identification of rifampin-resistant tuberculosis in a programmatic setting. AB - A recent Cochrane review estimated GeneXpert MTB/RIF specificity for rifampin resistance as 98% (95% confidence interval [CI], 97 to 99), based on results from earlier test versions. The measured positive predictive value of the new generation test from programmatic implementation in Cape Town, South Africa, was 99.5% (95% CI, 98.5 to 100), confirming excellent specificity. PMID- 24478502 TI - Ethambutol resistance as determined by broth dilution method correlates better than sequencing results with embB mutations in multidrug-resistant Mycobacterium tuberculosis isolates. AB - We evaluated the correlation of phenotypic ethambutol (EMB) susceptibility as determined by two drug susceptibility methods with embB mutations in multidrug resistant (MDR) Mycobacterium tuberculosis strains. The concordance rate for EMB resistance between broth dilution method and sequencing results (83.6%) was significantly higher than between the proportion method and sequencing results (61.7%) (P = 0.004). Of the embB mutants, 75.4% (46/61) possessed a mutation at embB306. Our results demonstrated that ethambutol resistance determined by broth dilution method reveals better correlation with embB mutations than the proportion method in MDR isolates. PMID- 24478504 TI - Recurrent melioidosis in the Darwin Prospective Melioidosis Study: improving therapies mean that relapse cases are now rare. AB - The Darwin Prospective Melioidosis Study has documented 785 melioidosis cases over 23 years. Recurrent melioidosis occurred in 39/679 (5.7%) patients surviving initial infection; 29 patients suffered relapse of the original infection, and 10 presented with a new Burkholderia pseudomallei infection. With improved therapy, relapse has become rare in recent years. PMID- 24478503 TI - Diagnosis of prosthetic joint infection by use of PCR-electrospray ionization mass spectrometry. AB - We compared PCR-electrospray ionization mass spectrometry (PCR-ESI/MS) to culture using sonicate fluid from 431 subjects with explanted knee (n = 270) or hip (n = 161) prostheses. Of these, 152 and 279 subjects had prosthetic joint infection (PJI) and aseptic failure, respectively. The sensitivities for detecting PJI were 77.6% for PCR-ESI/MS and 69.7% for culture (P = 0.0105). The specificities were 93.5 and 99.3%, respectively (P = 0.0002). PMID- 24478505 TI - Early kinetics of plasma cytomegalovirus DNA load in allogeneic stem cell transplant recipients in the era of highly sensitive real-time PCR assays: does it have any clinical value? AB - We report that in a population of allogeneic stem cell transplant recipients, determination of the viral doubling time (dt) of the cytomegalovirus (CMV) DNA plasma load predicted the eventual need for inception of preemptive antiviral therapy, whereas the level of the initial plasma CMV DNA load did not. The data thus indicated that determination of the dt of CMV DNA may be useful in the therapeutic management of CMV infection in this clinical setting. PMID- 24478506 TI - Xpert GBS assay for rapid detection of group B streptococcus in gastric fluid samples from newborns. AB - The Xpert GBS real-time PCR assay was applied to gastric fluid samples from 143 newborns, and it detected group B streptococcus (GBS) within 1 h for 16 (11.2%) cases, while microscopic examination detected only 2 cases. The sensitivity and specificity of the Xpert GBS were 80% and 100%, respectively, with regard to 20 cases of GBS colonization or infection. Concordance of Xpert GBS results versus culture was 92.3%. This test detects in a timely manner newborns at risk for invasive GBS disease. PMID- 24478507 TI - Association of inconclusive sera for human immunodeficiency virus infection with malaria and Epstein-Barr virus infection in Central Africa. AB - Among 464 sera from adults in Cameroon, 56 (12.1%) gave inconclusive HIV serology. All were negative for HIV-1 DNA; 44.6% (n = 25) were significantly associated with Plasmodium (42.8%) or Epstein-Barr virus (EBV) (17.8%) infections. In Central Africa, sera giving inconclusive results for HIV are frequently associated with malaria, EBV infection, or both. PMID- 24478508 TI - A PCR-high-resolution melt assay for rapid differentiation of nontypeable Haemophilus influenzae and Haemophilus haemolyticus. AB - We have developed a PCR-high-resolution melt (PCR-HRM) assay to discriminate nontypeable Haemophilus influenzae (NTHi) colonies from Haemophilus haemolyticus. This method is rapid and robust, with 96% sensitivity and 92% specificity compared to the hpd#3 assay. PCR-HRM is ideal for high-throughput screening for NTHi surveillance and clinical trials. PMID- 24478509 TI - Ease and comfort of cervical and vaginal sampling for Chlamydia trachomatis and Trichomonas vaginalis with a new Aptima specimen collection and transportation kit. AB - Use of a new collection kit for vaginal and cervical sampling was reported as easy by the majority of 692 women and not uncomfortable (by 87.4% of those >= 25 years old and 78.8% of those <25 years old). By Aptima testing, patient- and physician-collected samples agreed strongly for Chlamydia trachomatis (99.6% to 99.3%; kappa = 0.93 to 0.89) and T. vaginalis (99.6% to 98.9%; kappa = 0.97 to 0.78). PMID- 24478510 TI - A cost-effective approach for detection of toxigenic Clostridium difficile: toxigenic culture using ChromID Clostridium difficile agar. AB - We evaluated the performance and the cost of toxigenic culture using a commercial chromogenic medium (CDIF) for 538 stool specimens. Compared with real-time PCR, this method was found to detect an additional 9% of positive specimens and result in 61% reduction in material costs, with a trade-off increase in turnaround time of 1 day. PMID- 24478511 TI - A simplified sequence-based identification scheme for Bordetella reveals several putative novel species. AB - The differentiation of Bordetella species, particularly those causing human infection, is problematic. We found that sequence analysis of an internal fragment of nrdA allowed differentiation of the currently named Bordetella species. Analysis of 107 "Bordetella" isolates recovered almost exclusively from human respiratory tract specimens identified several putative novel species. PMID- 24478512 TI - Evaluation of a chromogenic biplate medium (ChromID MRSA/ChromID S. aureus) for the simultaneous detection of methicillin-resistant and methicillin-susceptible Staphylococcus aureus in preoperative screening samples from the anterior nares. AB - We evaluated the performance of the ChromID MRSA/ChromID S. aureus biplate for the simultaneous detection of Staphylococcus aureus and methicillin-resistant S. aureus (MRSA) in preoperative screening samples. The sensitivity and specificity were 94.2% and 93.6%, respectively, for the S. aureus compartment and 92.9% and 99.7% for the MRSA compartment after 48 h incubation. PMID- 24478513 TI - A fishy tale: a man with empyema caused by Streptococcus halichoeri. AB - In 2004, veterinary laboratories in the United Kingdom reported a novel Lancefield group B streptococcus, Streptococcus halichoeri, in seals. We report a case of Streptococcus halichoeri causing postoperative empyema in a patient. A search of the literature revealed that this is the first case of S. halichoeri ever reported in humans. PMID- 24478514 TI - Fatal empyema thoracis caused by Schizophyllum commune with cross-reactive cryptococcal antigenemia. AB - We report a fatal case of Schizophyllum commune empyema thoracis with cross reactive cryptococcal antigenemia. In vitro testing confirmed the ability of the fungus to cause a positive cryptococcal antigen latex agglutination system (CALAS) test result. Such a result may lead to delay in diagnosis and treatment, as most strains of S. commune are resistant to fluconazole. PMID- 24478515 TI - Illustration of the difficulty of identifying Streptococcus equi strains at the subspecies level through a case of endocarditis in an immunocompetent man. AB - We report a case of endocarditis caused by Streptococcus equi in an immunocompetent patient who was subsequently cured after appropriate antibiotherapy and cardiac surgery. However, it was challenging to identify the strain to the subspecies level, which highlights the necessity of developing reliable molecular tools to discriminate between the subspecies. PMID- 24478516 TI - Primary cerebral alveolar echinococcosis: mycology to the rescue. AB - A case of primary cerebral alveolar echinococcosis with a favorable outcome is reported. A universal fungal PCR enabled this diagnosis, while the initial serological analysis remained noncontributive. PMID- 24478518 TI - Free-living amoebae recovered from human stool samples in Strongyloides agar culture. PMID- 24478517 TI - Brain abscess caused by Ureaplasma urealyticum in an adult patient. AB - Ureaplasma urealyticum is a fastidious bacterium usually residing in the female genitourinary tract. We present an exceedingly complicated case of a brain abscess secondary to mastoiditis by U. urealyticum in an adult hypogammaglobulinemic patient after rituximab treatment 3 years earlier. PMID- 24478519 TI - False positives and negatives obtained with PCR-based identification of Staphylococcus aureus clonal complex 398. PMID- 24478520 TI - Appearance of multidrug-resistant virulent Rhodococcus equi clinical isolates obtained in China. PMID- 24478521 TI - Described diagnostic inconsistencies were observed with an obsolete version of the Xpert MTB/RIF assay and are unlikely to recur in the current version of the assay. PMID- 24478522 TI - Reply to "described diagnostic inconsistencies were observed with an obsolete version of the Xpert MTB/RIF assay and are unlikely to recur in the current version of the assay". PMID- 24478523 TI - Performance of the Xpert MTB/RIF assay on nonrespiratory specimens and accuracy of this assay for detection of rifampin resistance in a low-prevalence setting. PMID- 24478524 TI - Reply to "performance of the Xpert MTB/RIF assay on nonrespiratory specimens and accuracy of this assay for detection of rifampin resistance in a low-prevalence setting". PMID- 24478529 TI - Side-Chain Supramolecular Polymers Employing Conformer Independent Triple Hydrogen Bonding Arrays. AB - Derivatives of thymine have been extensively used to promote supramolecular materials assembly. Such derivatives can be synthetically challenging to access and may be susceptible to degradation. The current article uses a conformer independent acceptor-donor-acceptor array (ureidopyrimidine) which forms moderate affinity interactions with diamidopyridine derivatives to effect supramolecular blend formation between polystyrene and poly(methyl methacrylate) polymers obtained by RAFT which have been functionalized with the hydrogen bonding motifs. PMID- 24478530 TI - Post-1500 Population Flows and the Long Run Determinants of Economic Growth and Inequality. AB - We construct a matrix showing the share of the year 2000 population in every country that is descended from people in different source countries in the year 1500. Using the matrix to adjust indicators of early development so they reflect the history of a population's ancestors rather than the history of the place they live today greatly improves the ability of those indicators to predict current GDP. The variance of early development history of a country's inhabitants is a good predictor for current inequality, with ethnic groups originating in regions having longer histories of organized states tending to be at the upper end of a country's income distribution. PMID- 24478531 TI - Uncertainty in dual permeability model parameters for structured soils. AB - Successful application of dual permeability models (DPM) to predict contaminant transport is contingent upon measured or inversely estimated soil hydraulic and solute transport parameters. The difficulty in unique identification of parameters for the additional macropore- and matrix-macropore interface regions, and knowledge about requisite experimental data for DPM has not been resolved to date. Therefore, this study quantifies uncertainty in dual permeability model parameters of experimental soil columns with different macropore distributions (single macropore, and low- and high-density multiple macropores). Uncertainty evaluation is conducted using adaptive Markov chain Monte Carlo (AMCMC) and conventional Metropolis-Hastings (MH) algorithms while assuming 10 out of 17 parameters to be uncertain or random. Results indicate that AMCMC resolves parameter correlations and exhibits fast convergence for all DPM parameters while MH displays large posterior correlations for various parameters. This study demonstrates that the choice of parameter sampling algorithms is paramount in obtaining unique DPM parameters when information on covariance structure is lacking, or else additional information on parameter correlations must be supplied to resolve the problem of equifinality of DPM parameters. This study also highlights the placement and significance of matrix-macropore interface in flow experiments of soil columns with different macropore densities. Histograms for certain soil hydraulic parameters display tri-modal characteristics implying that macropores are drained first followed by the interface region and then by pores of the matrix domain in drainage experiments. Results indicate that hydraulic properties and behavior of the matrix-macropore interface is not only a function of saturated hydraulic conductivity of the macroporematrix interface (Ksa ) and macropore tortuosity (lf ) but also of other parameters of the matrix and macropore domains. PMID- 24478532 TI - More than A to B: the role of free bus travel for the mobility and wellbeing of older citizens in London. AB - This study contributes to the literature on mobility and wellbeing at older ages through an empirical exploration of the meanings of free bus travel for older citizens, addressing the meanings this holds for older people in urban settings, which have been under-researched. Taking London as a case study, where older citizens have free access to a relatively extensive public transport network through a Freedom Pass, we explore from a public health perspective the mechanisms that link this travel benefit to determinants of wellbeing. In addition to the ways in which the Freedom Pass enabled access to health-related goods and services, it provided less tangible benefits. Travelling by bus provided opportunities for meaningful social interaction; travelling as part of the 'general public' provided a sense of belonging and visibility in the public arena - a socially acceptable way of tackling chronic loneliness. The Freedom Pass was described not only as providing access to essential goods and services but also as a widely prized mechanism for participation in life in the city. We argue that the mechanisms linking mobility and wellbeing are culturally, materially and politically specific. Our data suggest that in contexts where good public transport is available as a right, and bus travel not stigmatised, it is experienced as a major contributor to wellbeing, rather than a transport choice of last resort. This has implications for other jurisdictions working on accessible transport for older citizens and, more broadly, improving the sustainability of cities. PMID- 24478533 TI - Best Practices: How to Evaluate Psychological Science for Use by Organizations. AB - We discuss how organizations can evaluate psychological science for its potential usefulness to their own purposes. Common sense is often the default but inadequate alternative, and bench-marking supplies only collective hunches instead of validated principles. External validity is an empirical process of identifying moderator variables, not a simple yes-no judgment about whether lab results replicate in the field. Hence, convincing criteria must specify what constitutes high-quality empirical evidence for organizational use. First, we illustrate some theories and science that have potential use. Then we describe generally accepted criteria for scientific quality and consensus, starting with peer review for quality, and scientific agreement in forms ranging from surveys of experts to meta-analyses to National Research Council consensus reports. Linkages of basic science to organizations entail communicating expert scientific consensus, motivating managerial interest, and translating broad principles to specific contexts. We close with parting advice to both sides of the researcher practitioner divide. PMID- 24478534 TI - Role of Activated Glia and of Glial Cytokines in Alzheimer's Disease: A Review. AB - We review the role of activated microglia and activated astrocytes, and of glia derived cytokines and other molecules, in the pathogenesis and pathophysiology of Alzheimer's disease. Activated microglia overexpressing the potent immune response cytokine interleukin-1, and activated astrocytes over-expressing the neurotrophic cytokine S100beta, are near-constant components of neuritic plaques in Alzheimer's disease, and are frequent components of early, non-neuritic, amyloid deposits. The known biological activities of these two cytokines suggest an orchestrating effect on the complex cellular and molecular interactions that drive plaque progression. Furthermore, findings in brains of patients dying with conditions known to predispose to Alzheimer's disease suggest that activation of glia and overexpression of glial cytokines are early events in Alzheimer pathogenesis. These results suggest that therapeutic intervention directed toward interrupting the driving immunological processes in Alzheimer's disease might slow or arrest progression of clinical disease. PMID- 24478535 TI - A Longitudinal Study of Social Capital and Acculturation-Related Stress Among Recent Latino Immigrants in South Florida. AB - This study uses social capital to assess the effects of social support on acculturation-related stress among recently immigrated Hispanics in South Florida before and after immigration. At baseline (N = 527), first 12 months in the United States, acculturative stress was negatively related to support from friends (p < .044) and positively related to support from parents (p < .023). At first follow-up (n = 415), 24 months in the United States, emotional/informational support was negatively associated with acculturation related stress (p < .028). In the second follow-up (n = 478), 36 months in the United States, support from children was negatively associated with acculturation related stress (p < .016). Limited English proficiency was found to be negatively associated with acculturation stress at all three points (p < .001, p < .025, and p < .001, respectively). Implications of this study can be used in the design of culturally appropriate and family-oriented interventions for recent immigrants to ease the acculturation process. PMID- 24478536 TI - Identification of Affine Linear Parameter Varying Models for Adaptive Interventions in Fibromyalgia Treatment. AB - There is good evidence that naltrexone, an opioid antagonist, has a strong neuroprotective role and may be a potential drug for the treatment of fibromyalgia. In previous work, some of the authors used experimental clinical data to identify input-output linear time invariant models that were used to extract useful information about the effect of this drug on fibromyalgia symptoms. Additional factors such as anxiety, stress, mood, and headache, were considered as additive disturbances. However, it seems reasonable to think that these factors do not affect the drug actuation, but only the way in which a participant perceives how the drug actuates on herself. Under this hypothesis the linear time invariant models can be replaced by State-Space Affine Linear Parameter Varying models where the disturbances are seen as a scheduling signal signal only acting at the parameters of the output equation. In this paper a new algorithm for identifying such a model is proposed. This algorithm minimizes a quadratic criterion of the output error. Since the output error is a linear function of some parameters, the Affine Linear Parameter Varying system identification is formulated as a separable nonlinear least squares problem. Likewise other identification algorithms using gradient optimization methods several parameter derivatives are dynamical systems that must be simulated. In order to increase time efficiency a canonical parametrization that minimizes the number of systems to be simulated is chosen. The effectiveness of the algorithm is assessed in a case study where an Affine Parameter Varying Model is identified from the experimental data used in the previous study and compared with the time invariant model. PMID- 24478537 TI - Adapting Data Processing To Compare Model and Experiment Accurately: A Discrete Element Model and Magnetic Resonance Measurements of a 3D Cylindrical Fluidized Bed. AB - Discrete element modeling is being used increasingly to simulate flow in fluidized beds. These models require complex measurement techniques to provide validation for the approximations inherent in the model. This paper introduces the idea of modeling the experiment to ensure that the validation is accurate. Specifically, a 3D, cylindrical gas-fluidized bed was simulated using a discrete element model (DEM) for particle motion coupled with computational fluid dynamics (CFD) to describe the flow of gas. The results for time-averaged, axial velocity during bubbling fluidization were compared with those from magnetic resonance (MR) experiments made on the bed. The DEM-CFD data were postprocessed with various methods to produce time-averaged velocity maps for comparison with the MR results, including a method which closely matched the pulse sequence and data processing procedure used in the MR experiments. The DEM-CFD results processed with the MR-type time-averaging closely matched experimental MR results, validating the DEM-CFD model. Analysis of different averaging procedures confirmed that MR time-averages of dynamic systems correspond to particle weighted averaging, rather than frame-weighted averaging, and also demonstrated that the use of Gaussian slices in MR imaging of dynamic systems is valid. PMID- 24478538 TI - Citizens in the commons: blood and genetics in the making of the civic. AB - This essay is based on ethnographic fieldwork conducted with the Indian community in Houston, as part of a NIH/NHGRI-sponsored ethics study and sample collection initiative entitled 'Indian and Hindu Perspectives on Genetic Variation Research.' Taking a cue from my Indian interlocutors who largely support and readily respond to such initiatives on the grounds that they will undoubtedly serve 'humanity' and the common good, I explore notions of the commons that are created in the process of soliciting blood for genetic research. How does blood become the stuff of which a civic discourse is made? How do idealistic individual appeals to donate blood, ethics research protocols, open-source databases, debates on approaches to genetic research, patents and Intellectual Property regulations, markets and the nation-state itself variously engage, limit or further ideas of the common good? Moving much as my interlocutors do, between India and the United States, I explore the nature of the commons that is both imagined and pragmatically reckoned in both local and global diasporic contexts. PMID- 24478539 TI - Metacognition in Later Adulthood: Spared Monitoring Can Benefit Older Adults' Self-regulation. AB - Metacognition includes two key concepts: monitoring of internal states, and adaptive use of control strategies based on that monitoring. We review studies that indicate that aging does not materially affect the accuracy of elementary forms of monitoring encoding and retrieval states in episodic memory tasks, even though it does influence episodic memory itself. Spared monitoring accuracy can therefore serve as a basis for older adults' use of compensatory strategies to achieve learning goals, despite the influence of aging on mechanisms of learning. Metacognitive intervention studies based on this premise show greater effects on learning than traditional strategy-training approaches. Use of strategies for self-regulation, informed by monitoring, may be an important tool for older adults' effective cognitive functioning in everyday life. PMID- 24478541 TI - A quest for better understanding of biochemical changes in fibromyalgia syndrome. PMID- 24478540 TI - Beyond Brain Mapping: Using Neural Measures to Predict Real-World Outcomes. AB - One goal of social science in general, and of psychology in particular, is to understand and predict human behavior. Psychologists have traditionally used self report measures and performance on laboratory tasks to achieve this end. However, these measures are limited in their ability to predict behavior in certain contexts. We argue that current neuroscientific knowledge has reached a point where it can complement other existing psychological measures in predicting behavior and other important outcomes. This brain-as-predictor approach integrates traditional neuroimaging methods with measures of behavioral outcomes that extend beyond the immediate experimental session. Previously, most neuroimaging experiments focused on understanding basic psychological processes that could be directly observed in the laboratory. However, recent experiments have demonstrated that brain measures can predict outcomes (e.g., purchasing decisions, clinical outcomes) over longer timescales in ways that go beyond what was previously possible with self-report data alone. This approach can be used to reveal the connections between neural activity in laboratory contexts and longer term, ecologically valid outcomes. We describe this approach and discuss its potential theoretical implications. We also review recent examples of studies that have used this approach, discuss methodological considerations, and provide specific guidelines for using it in future research. PMID- 24478542 TI - "P53 codon 72 single base substitution in viral hepatitis C and hepatocarcinoma incidences". AB - Viral infection with hepatitis C virus (HCV) has a high propensity in becoming chronic and it is the major cause of hepatocellular carcinoma (HCC) worldwide. This review was basically established to illustrate the putative role of the P53 gene Arg72Pro polymorphism on various cancer models and viral infections, focusing on HCV and HCC incidences. Authors studied the 72 G/C single base substitution of P53 gene at codon 72 using various polymorphic techniques. Intriguingly, authors investigated that the P53 codon 72 plays a crucial role as risk factor in several cancer models. Others found that there is no association between codon 72 genotypes and HCV disease severity or liver cancer. Moreover, the lack of a significant relationship between this polymorphism and risk of HCC shows that it does not predispose towards hepatocarcinogenesis and the frequent loss of the proline allele in HCV-associated carcinogenesis of the liver plays some critical role in hepatocarcinogenesis. Amazingly, there is a significant correlation between male homozygotes for P53 72Pro with HCV type 1b infection. However, there was no significant difference between the P53 polymorphism and HCV genotypes 2a and 2b. It was concluded that the P53 gene polymorphism at codon 72 has been investigated as potential risk factor in several cancer models and HCV infections. PMID- 24478543 TI - The Roles of Fibroblast Growth Factor (FGF)-23, alpha-Klotho and Furin Protease in Calcium and Phosphate Homeostasis : A Mini-Review. AB - The roles of calcitonin, parathormone and calcitriol in the regulation of plasma calcium and phosphate are well-established. However, in autosomal-dominant hypophosphatemic rickety patients, studies have revealed normal plasma levels of calcium, associated with normal thyroid and parathyroid functions, but decreased levels of phosphate and calcitriol despite adequate reserves of vitamin D. Also, in tumoral calcinosis, persistent hyperphosphatemia with increased levels of 1,25(OH)2D3 have been observed. These studies indicate the involvement of factors other than the ones already known. The first decade of this century/millennium has led to the discovery of the involvement of fibroblast growth factor-23, furin protease and alpha-klotho in the homeostasis of calcium and phosphate, which is the subject of this mini-review. PMID- 24478544 TI - Antioxidant and anticancer activities of selected persian gulf algae. AB - In the present study, the effect of red (Gracillaria corticata), green (Ulva fasciata) and brown (Sargassum ilicifolium) seaweeds alcoholic extract, against five important human cancer cell lines (MCF-7, MDA-MB-231, HeLa, HepG2, and HT 29) proliferation, apoptosis and cell cycle arrest were evaluated. The reducing activity and total polyphenol content were also investigated. MTT assay was used for cytotoxicity test. Morphological alterations were examined using phase contrast, fluorescent and electron microscopy. All the extracts were antiproliferative against all the cancer cell lines, dose-dependently, with G. corticata methanol extract (GCME) having the greatest inhibition activity against MCF-7 cell line. The percentage of apoptosis increased from 18 to 78 %. The cell cycle analysis also showed that GCME can induce apoptosis which confirm by TEM. Algal extract reducing activities were as follows: G. corticata > S. ilicifolium > U. fasciata. The GCME is a good source of potential complementary and alternative functional food for prevention and treatment of cancer. PMID- 24478545 TI - Prevalence of +405G>C,-1154G>A Vascular Endothelial Growth Factor Polymorphism in Breast Cancer. AB - Vascular endothelial growth factor (VEGF) plays an important role in the development of Breast Cancer. The aim of this study was to investigate the association of polymorphisms in the VEGF gene on prognosis of Breast Cancer patients. This study comprised 200 patients with histologically confirmed cases of Breast cancer and 200 controls. Genotyping of the VEGF gene polymorphisms at +405G>C,-1154G>A, were performed by PCR-RFLP analysis. Preoperative plasma VEGF levels were determined by ELISA. Amongst both cases and controls, the genotypic distribution of the individual SNPs were all in Hardy-Weinberg equilibrium. Mean VEGF level was significantly elevated in cases compared to controls (t = 8.248; P < 0.001). No significant association was found between +405G>C,-1154G>A VEGF polymorphism and Breast Cancer. Logistic regression analysis revealed that 405GG & 1154GG were associated with higher levels of VEGF. PMID- 24478546 TI - Arsenic-Induced Hepatic Toxicity and Its Attenuation by Fruit Extract of Emblica officinalis (Amla) in Mice. AB - Arsenic a metalloid and environmental contaminated has been found to be associated with public health problems in the affected areas. It is naturally occurred in groundwater and its accumulation in plant and animals leads to toxicity in several tissues most notably hepatic organ. Arsenic exposures (3 mg/kg body weight/day for 30 days) in mice exhibited increased arsenic and Zn levels in hepatocytes associated with enhanced oxidative stress in hepatocytes while there were no significantly changes were observed in Cu level. An increase in the lipid peroxidation and decrease in the levels of reduced glutathione and activity of superoxide dismutase, catalase, and glutathione peroxidase were observed in arsenic treated mice as compared to controls. Arsenic exposure in mice also caused a significant change in serum biomarkers in the SGOT, SGPT and creatinine as compared to the controls. There were no significant changes in the serum levels of total protein in these mice. Co-administration of arsenic and fruit extract of amla (500 mg/kg body weight/day for 30 days) caused a significant reduction of arsenic transference associated with significantly decreases hepatic arsenic levels and balanced the antioxidant enzyme and levels of serum hepatic enzymes like SGOT and SGPT. The results of the present study clearly demonstrate the antioxidant property of amla that could be responsible for its protective efficacy in arsenic induced hepatic toxicity. PMID- 24478547 TI - Impairment of mitochondrial-nuclear cross talk in neutrophils of patients with type 2 diabetes mellitus. AB - Increased leukocyte apoptosis is intrinsically linked to disease patho physiology, susceptibility to and severity of infections in type 2 diabetes mellitus (T2DM) patients. A consistent defect in neutrophil function is considered central to this increased risk for infections. Although redox imbalance is considered a potential mediator of these associated complications, detailed molecular evidence in clinical samples remains largely undetected. The study consisted of three groups (n = 50 each) of Asian Indians: early diagnosed diabetic patients, cases with late-onset diabetic complications and age and gender-matched healthy controls. We evaluated mitochondrial oxidative stress, levels of nuclear DNA damage and apoptosis in peripheral blood neutrophils isolated from T2DM patients. We observed that in both early and late diabetic subjects, the HbA1c levels in neutrophils were altered considerably with respect to healthy controls. Increased oxidative stress observed in both early and late diabetics imply the disentanglement of fine equilibrium of mitochondria-nuclear cross talk which eventually effected the augmentation of downstream nuclear gammaH2AX activation and caspase-3 expression. It would be overly naive to refute the fact that mitochondrial deregulation in neutrophils perturbs immunological balance in type 2 diabetic conditions. By virtue of our data, we posit that maneuvering mitochondrial function might offer a prospective and viable method to modulate neutrophil function in T2DM. Nevertheless, similar investigations from other ethnic groups in conjunction with experimental evidences would be a preeminent need. Obviously, our study might aid to comprehend this complex interplay between mitochondrial dysfunction and neutrophil homeostasis in T2DM. PMID- 24478548 TI - A Study to Evaluate Lipid Profile in Treatment Naive HIV Positive Patients. AB - HIV infection is associated with lipid abnormalities in treatment naive patients. CD4 count is used for monitoring the HIV infection. Primary objective was to evaluate and correlate lipid profile and CD4 counts in HIV infection. Secondary objective was to evaluate the feasibility of using Lipid profile to monitor the HIV infected treatment naive patients instead of CD4 counts. 112 patients were selected based on a criteria from ART center in tertiary care center. CD4 counts were assessed and Lipid profile was evaluated enzymatically. A correlation study was done between the lipid profile and the CD4 count and clinical stages of infection. Cholesterol showed no significant correlation in any stage. HDL-C showed significant correlation (p < 0.05) with stage 2 and 4 disease. LDL-C showed no significant correlation in any stage. TGL showed significant correlation (p < 0.05) at stage 4 disease. Hence, HDL-C and TGL can be used as indicators of lipid status and for infection progression in treatment naive HIV patients, while Cholesterol and LDL-C has no role to play. PMID- 24478549 TI - Assessment of insulin resistance and metabolic syndrome in drug naive patients of bipolar disorder. AB - The levels of fasting glucose, fasting insulin, insulin resistance (IR) and the prevalence of metabolic syndrome (MS) in a sample population of bipolar disorder (BPD) patients who were newly diagnosed and psychotropically naive were assessed and compared with an age, sex and racially matched control population. 55 BPD-I patients (15-65 years) who were non-diabetic, nonpregnant, and drug naive for a period of at least 6 months were included in the study. Diagnosis was made using the structured clinical interview for DSM-IV axis I disorders (SCID IV). IR was assessed using homeostasis model of insulin resistance (HOMA-IR); MS was defined according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP-ATP III). Data were compared with 25 healthy controls. BPD patients had significantly higher mean levels of fasting plasma insulin (13.2 +/- 9.2 vs. 4.68 +/- 3.1 MUIU/ml, p < 0.05), postprandial plasma insulin (27.2 +/- 14.5 vs. 18.1 +/- 9.3 MUIU/ml, p < 0.05) and a higher value of HOMA-IR (3.16 +/- 2.2 vs. 1.19 +/- 0.8, p < 0.05) when compared to the controls. A significantly higher proportion of patients of BPD compared to controls were manifesting levels of fasting plasma glucose, serum triglyceride and blood pressure higher than the cut off while waist circumference and serum HDL cholesterol failed to show any significant difference in the proportion. There was a significantly higher proportion of prevalence of IR between BPD cases and controls (26/55 vs. 2/25, z value 9.97, p < 0.05) while there was no significant difference in proportion of prevalence of MS between these two groups. Within BPD patients, logistic regression analysis showed that age, sex or current mood status (depressed/manic) were not significantly predictive of presence or absence of MS or increased IR. PMID- 24478550 TI - Determination of Acid beta-Galactosidase Activity: Methodology and Perspectives. AB - Early, accurate diagnosis of lysosomal storage disorders is a major challenge, even for trained specialists. Finding innovative, accurate diagnostic methods, and high throughput, cost-effective tools are crucial to medical progress and will contribute to improved quality of life. The goal of this work was to improve currently used protocols to determine activity of acid beta-galactosidase, and discuss the possibility analysing lysosomal enzymes with microfluidic systems. A principle of the determination of beta-galactosidase activity was fluorometric measurement of a deprotonated form of 4-methylumbelliferone released in the enzymatic reaction. Measurements were performed using Jurkat T cells as a source of the enzyme. We observed the temperature-dependent substrate inhibition effect and determined the substrate (4-MU-beta-d-galactopyranoside) concentration which should be used to determine acid beta-galactosidase activity at 37 degrees C (0.8 mM) and at room temperature (0.6 mM). We proved that the sample incubation time may be significantly reduced to only a few minutes. We also showed that the amount of alkaline buffer used to stop the enzymatic reaction may be minimized and even, in some cases, eliminated. The presented results show how the sensitivity of the available methods to diagnose patients suffer from gangliosidosis GM1 or Morquio B disease can be improved. The proposed method may be easily implemented with microfluidic systems, which currently are promising tools for point-of-care applications. PMID- 24478551 TI - Characterization of human serum immunoglobulin g modified with singlet oxygen. AB - Reactive oxygen species, as singlet oxygen ((1)O2), is continuously being generated by aerobic organisms, and react actively with biomolecules. At excessive amounts, (1)O2 induces oxidative stress and shows carcinogenic and toxic effects due to oxidation of lipids, proteins and nucleic acids. In our study, immunoglobulin G (IgG) was modified by (1)O2 generated by the ultraviolet (UV) irradiation of methylene blue. The modified IgG was characterized by UV spectroscopy, carbonyl content determination, thermal denaturation and electrophoretic study. Oxidation induced by modification of IgG by (1)O2 also analyzed by scavenging studies. It was found that ultraviolet absorption spectra of modified IgG shows marked hyperchromicity. The carbonyl content was found to be high in modified IgG as compared to native IgG which confirms its oxidation. Thermal denaturation of modified protein sample shows decrease in Tm value by 3 degrees C and less intensity banding pattern on polyacrylamide gel electrophoresis. The quenching effect of sodium azide provides clue for modification of IgG by methylene blue, as it is known (1)O2 scavenger. Hence, the IgG modified with (1)O2 may be one of the etiological pathogenic factors for rheumatoid arthritis and diabetes. PMID- 24478552 TI - Effect of Resveratrol and Nicotine on PON1 Gene Expression: In Vitro Study. AB - Dietary and lifestyle factors have been shown to have a profound effect on paraoxonase-1 (PON1) activity. Cigarette smoke has been shown to inhibit its mass and activity where as resveratrol has been shown to enhance it. We exposed hepatoma derived cell line (HepG2) to resveratrol and nicotine in varying doses and measured PON1 enzymatic activity and PON1 gene expression. In addition, total protein content of HepG2 cells was also measured. Resveratrol in a dose of 15 MUmol/l or above significantly increased the PON1 enzyme activity (p > 0.001) where as nicotine in a dose of 1 MUmol/l or higher significantly reduced it (p < 0.05). The resveratrol in this dose also enhanced the PON1 gene expression whereas nicotine decreased it as compared to controls. However, the protein conent of cells was not changed suggesting that they were not cytotoxic in the doses used. Till date the antioxidant vitamins have shown disappointing results against LDL oxidation and cardiovascular protection. However, the effect of resveratrol on PON1 gene expression and activity was significant, suggesting increase in PON1 activity and enhanced gene expression may be its alternative mechanism for offering protection against cardiovascular disease and may be an potential pharmacological agent which can be used for this. PMID- 24478553 TI - Reference interval determination of total plasma homocysteine in an Indian population. AB - Hyperhomocysteinemia has been shown to be an independent risk factor for cardiovascular disease as well as retinal vascular occlusion. Because of the epidemiological, dietary, genetic and environmental diversity among the different countries, each country should establish the reference interval of homocysteine of their own population for recommending appropriate medical decision limits. Hence a total of 1,288 apparently healthy subjects including 636 male and 652 female were enrolled in the present study to determine the reference intervals of homocysteine in an Indian population. Results of the study were presented as mean, standard deviation, median and 2.5th and 97.5th percentile with the 0.90 confidence interval of each percentile values of homocysteine along with decade wise changes. PMID- 24478554 TI - Biochemical Evaluation of Patients of Alcoholic Liver Disease and Non-alcoholic Liver Disease. AB - Alcoholic liver disease (ALD) is due to excessive alcohol intake for long duration. Distinguishing ALD from non-ALD (non-alcoholic steatohepatitis, hepatitis of viral origin) is difficult as patient may deny alcohol abuse. Clinical examination, histology and serology may not differentiate these conditions. Accurate diagnosis is important as management of ALD differs from non ALD patients. The aim of our study was (1) To evaluate the patients of ALD and non-ALD by biochemical parameters compared to controls, (2) To assess whether these parameters can differentiate ALD from non-ALD. Study was carried out on 50 patients of ALD in group I and 35 patients of NASH (non-alcoholic steatohepatitis) and acute viral hepatitis each in group II. Age matched healthy controls n = 50. Selection criteria-history of alcohol intake (amount and duration), clinical examination, sonography of abdomen, serum alanine transaminase (ALT) and bilirubin levels. Blood samples were analyzed for bilirubin, aspartate transaminase (AST), ALT, alkaline phosphatase (ALP), gamma glutamyl transferase (GGT) by kinetic method. Statistical analysis was done by Student unpaired 't' test. Patients of ALD have raised AST/ALT ratio (De Ritis ratio) (>2), ALP and GGT compared to controls (P < 0.01).There is significant difference in AST/ALT ratio, serum GGT and ALP in ALD group compared to that in NASH and acute viral hepatitis (P < 0.05). This study suggests that De Ritis ratio >2 in ALD patients may be due to alcohol induced hepatic mitochondrial injury and pyridoxine deficiency. High GGT and ALP values may indicate enzyme induction by alcohol and mild cholestasis. Thus ALD patients have severe hepatic damage. De Ritis ratio <1 and normal to mild elevation in GGT level in NASH and acute viral hepatitis suggest mild hepatic injury of non-alcoholic origin. Our study concludes that ALD patients can be differentiated from NASH and acute viral hepatitis with certainty by measuring serum AST/ALT ratio, GGT and ALP. These biochemical parameters may help clinicians to support the diagnosis of ALD and non-ALD. PMID- 24478555 TI - In vitro evaluation of the efficacy of liposomal and pegylated liposomal hydroxyurea. AB - Breast cancer is one of the most frequent cancer types within women population. Hydroxyurea (HU) is a chemotherapy compound for treatment of patients with cancer diagnosis, including breast cancer associated with several adverse effects. In this study, we applied nanotechnology to decreased drug side effects along with improvement of therapeutic index. Liposomation is widely used in modern pharmacological developments in order to enhance the effects of the drugs. To achieve this, in this study a mixture of phosphatidylcholine and cholesterol was made up and HU was added to the resultant mixture, was then pegylated using Polyethylene Glycol 2000 to increase resistance, applicability and solubility. The mean diameters of nanoliposomal and pegylated nanoliposomal HU were measured by Zeta sizer device and obtained about 402.5 and 338.2 nm. The efficiency of non pegylated and pegylated liposomal HU was 70.8 and 64.2, respectively. Releasing HU in both formulations was estimated about 25.8 and 21.7 %. Also, this study investigated the cytotoxicity effect of nanoliposomal and pegylated nanoliposomal HU using MTT assay. Results of this investigation showed that the cytotoxic properties of pegylated HU was 3.6 % more than those non-pegylated form, while was 38.93 % more than ordinary from of HU. This study showed that the stability, releasing pattern and cytotoxicity of the pegylated nanoliposomal HU is better than that of nanoliposomal HU. PMID- 24478556 TI - Chronic exposure to lead: a cause of oxidative stress and altered liver function in plastic industry workers in kolkata, India. AB - It is well known that chronic exposure of lead leads to adverse health effects. Workers for plastic industry are generally exposed to high concentration of lead as fume, dust, and additive that protect PVC. This study was done on them to find out the detrimental effects of chronic lead exposure on hepatic and hematological toxicity. Blood and 24 h urine sample was collected from 47 plastic industry workers and matched against 42 controls for various parameters. The study group shows significant increase in blood (p < 0.0001) and urinary level of lead (p < 0.0001). Hemoglobin levels were significantly decreased (p < 0.0001), and the liver enzymes like ALP, ALT, AST and y-GT were significantly increased (p < 0.0001) in all cases exposed for >10 years. Serum lipid peroxide by quantitative assay of thiobarbituric acid reactive substances was also found increased in the study group (p < 0.0001). The observations point towards the acute health risk faced by plastic industry workers, in whom chronic exposure to lead increases the absorption and accumulation, over a period of time, of this highly toxic element in their body. This increases oxidative stress, causes metabolic damage to RBC and cell membranes, and also suggests necrosis of liver cell, hepatocellular injury and presence of space occupying lesions. Considering the data immediate health and hygiene monitoring and proper rehabilitation for the suffering population seem to be of paramount need in plastic industry to minimize occupational hazards. PMID- 24478557 TI - Interrelationship between procalcitonin and organ failure in sepsis. AB - Sepsis suffers from lack of specific clinical symptoms which contribute to one of the major causes of mortality. In the present study, our aim was to evaluate the role of a recent biomarker Procalcitonin (PCT) in predicting organ dysfunction. 71 patients admitted with sepsis were included in the study. PCT levels were measured at 0, 24, 72 h and 7th day and sequential organ failure assessment score (SOFA) scores were calculated. PCT levels significantly decreased (p < 0.001) in 89.3 % of surviving patients, whereas, in 60 % non surviving patients the PCT level increased significantly (p < 0.001). A significant positive correlation between PCT and SOFA score was observed in survivors at each hour. These observations indicate that PCT concentration is significantly associated with severity of multi organ dysfunction and also helps in determining the prognosis of septic patients. PMID- 24478558 TI - Serum urea:albumin ratio as a prognostic marker in critical patients with non chronic kidney disease. AB - Routine laboratory investigations play an important role in estimating the risk of mortality in intensive care unit (ICU) patients. The significance of urea:albumin ratio (UAR) in predicting the stay and mortality of ICU patients is not known. It is a retrospective study of patients admitted to ICU (n = 412) with non-chronic kidney disease (non-CKD). Receiver-operating characteristics (ROC) analysis for predicting mortality was carried out to find area under curve (AUC) and threshold levels. Analysis of survival probability was carried out by Kaplan Meier method and Log-rank test. The AUC to predict mortality were 0.695, 0.767 and 0.791 for serum albumin, urea and UAR, respectively. The threshold levels for albumin, urea and UAR were 2.8 g/dL, 53 mg/dL, and 23.44 mg/g, respectively. The highest odds ratio (OR) of 9.75 to predict mortality at threshold level was observed for UAR, while OR were 7.0 and 3.62 for serum urea and albumin, respectively. The serum urea above and albumin below threshold level were associated with increase in ICU stay of >3 days but the highest OR of 4.73 to predict stay of >3 days was observed for UAR. Kaplan-Meier survival analysis shows significant (p < 0.001) difference at the threshold value of UAR. Serum urea and albumin are found to be an independent predictor for the mortality and stay; however an increased UAR value is the best parameter in predicting mortality and stay in ICU patients with non-CKD illness. PMID- 24478559 TI - A rare case of mucopolysaccharidosis. AB - Mucopolysaccharidosis are a group of rare metabolic disorders of the lysosomal storage disease family caused by the absence or malfunctioning of lysosomal enzymes responsible for their breakdown. It encompasses disorders in which undegraded or partly degraded glycosaminoglycans accumulate in the lysosomes of many tissues owing to a deficiency of specific lysosomal enzymes. Here we report a case of a 7 years old child displaying the symptoms of Morquio's disease (Mucopolysaccharidosis type IV). Urine screening tests were performed which gave contrasting results. PMID- 24478560 TI - PCT as a Prognostic Marker in Cardiac Patients with Neutropenic Sepsis: Two Case Reports. AB - Procalcitonin (PCT) is an innovative and highly specific marker for diagnosis of clinically relevant bacterial infection and sepsis. PCT supports early diagnosis and Clinical decision making. A retrospective study of two classical cases of neutropenic sepsis with elevated PCT levels in cardiac ICU was done. PCT was analyzed using Elecsys Brahms PCT kit. Serum PCT levels <0.5 ng/ml and ANC <1,000/mm(3) was taken as cutoff. The first patient had initial high levels of PCT 100 ng/ml, TLC 13,600/mm(3) and ANC 12,250/mm(3). It was followed by drop with subsequent rise in PCT levels and drop in TLC 1,000/mm(3) and ANC 70/mm(3). The second patient had normal PCT 0.116 ng/ml, TLC 5,600/mm(3) and ANC 4,420/mm(3) levels followed with sharp increase in all the values with subsequent drop in TLC 2,000/mm(3) and ANC 880 cells/mm(3). Both the patients died of neutropenic sepsis with multiorgan failure. The case reports showed the correlation of PCT with TLC and ANC levels in predicting the mortality of patients with neutropenic sepsis in cardiac ICU. PMID- 24478561 TI - Ochronosis of the hip joint: differential diagnosis of inflammatory arthropathy with lytic lesion. AB - Alkaptonuria or ochronosis is a rare inborn disorder of metabolism which is characterized by deficiency of homogentisic acid oxidase. There is accumulation of homogentisic acid in the connective tissues causing brownish black pigmentation and skeletal damage. The most serious complication of this disease is crippling degenerative arthropathy which presents in late years of life. There is no definitive treatment for the condition. Symptomatic management is the main stay. Surgical management such as arthroplasty is done for severe cases of ochronosis. We report a case of ochronosis of the hip joint presenting with inflammation and lytic lesion which can create confusion and lead to error in diagnosis. PMID- 24478562 TI - Methodological concerns comparing buzzy to transilluminator device. PMID- 24478563 TI - MULTIVARIATE KERNEL PARTITION PROCESS MIXTURES. AB - Mixtures provide a useful approach for relaxing parametric assumptions. Discrete mixture models induce clusters, typically with the same cluster allocation for each parameter in multivariate cases. As a more flexible approach that facilitates sparse nonparametric modeling of multivariate random effects distributions, this article proposes a kernel partition process (KPP) in which the cluster allocation varies for different parameters. The KPP is shown to be the driving measure for a multivariate ordered Chinese restaurant process that induces a highly-flexible dependence structure in local clustering. This structure allows the relative locations of the random effects to inform the clustering process, with spatially-proximal random effects likely to be assigned the same cluster index. An exact block Gibbs sampler is developed for posterior computation, avoiding truncation of the infinite measure. The methods are applied to hormone curve data, and a dependent KPP is proposed for classification from functional predictors. PMID- 24478564 TI - VARIABLE SELECTION AND ESTIMATION IN HIGH-DIMENSIONAL VARYING-COEFFICIENT MODELS. AB - Nonparametric varying coefficient models are useful for studying the time dependent effects of variables. Many procedures have been developed for estimation and variable selection in such models. However, existing work has focused on the case when the number of variables is fixed or smaller than the sample size. In this paper, we consider the problem of variable selection and estimation in varying coefficient models in sparse, high-dimensional settings when the number of variables can be larger than the sample size. We apply the group Lasso and basis function expansion to simultaneously select the important variables and estimate the nonzero varying coefficient functions. Under appropriate conditions, we show that the group Lasso selects a model of the right order of dimensionality, selects all variables with the norms of the corresponding coefficient functions greater than certain threshold level, and is estimation consistent. However, the group Lasso is in general not selection consistent and tends to select variables that are not important in the model. In order to improve the selection results, we apply the adaptive group Lasso. We show that, under suitable conditions, the adaptive group Lasso has the oracle selection property in the sense that it correctly selects important variables with probability converging to one. In contrast, the group Lasso does not possess such oracle property. Both approaches are evaluated using simulation and demonstrated on a data example. PMID- 24478565 TI - ANALYSIS ON CENSORED QUANTILE RESIDUAL LIFE MODEL VIA SPLINE SMOOTHING. AB - We propose a general class of quantile residual life models, where a specific quantile of the residual life time, conditional on an individual has survived up to time t, is a function of certain covariates with their coefficients varying over time. The varying coefficients are assumed to be smooth unspecified functions of t. We propose to estimate the coefficient functions using spline approximation. Incorporating the spline representation directly into a set of unbiased estimating equations, we obtain a one-step estimation procedure, and we show that this leads to a uniformly consistent estimator. To obtain further computational simplification, we propose a two-step estimation approach in which we estimate the coefficients on a series of time points first, and follow this with spline smoothing. We compare the two methods in terms of their asymptotic efficiency and computational complexity. We further develop inference tools to test the significance of the covariate effect on residual life. The finite sample performance of the estimation and testing procedures are further illustrated through numerical experiments. We also apply the methods to a data set from a neurological study. PMID- 24478566 TI - Functional Linear Model with Zero-value Coefficient Function at Sub-regions. AB - We propose a shrinkage method to estimate the coefficient function in a functional linear regression model when the value of the coefficient function is zero within certain sub-regions. Besides identifying the null region in which the coefficient function is zero, we also aim to perform estimation and inferences for the nonparametrically estimated coefficient function without over-shrinking the values. Our proposal consists of two stages. In stage one, the Dantzig selector is employed to provide initial location of the null region. In stage two, we propose a group SCAD approach to refine the estimated location of the null region and to provide the estimation and inference procedures for the coefficient function. Our considerations have certain advantages in this functional setup. One goal is to reduce the number of parameters employed in the model. With a one-stage procedure, it is needed to use a large number of knots in order to precisely identify the zero-coefficient region; however, the variation and estimation difficulties increase with the number of parameters. Owing to the additional refinement stage, we avoid this necessity and our estimator achieves superior numerical performance in practice. We show that our estimator enjoys the Oracle property; it identifies the null region with probability tending to 1, and it achieves the same asymptotic normality for the estimated coefficient function on the non-null region as the functional linear model estimator when the non-null region is known. Numerically, our refined estimator overcomes the shortcomings of the initial Dantzig estimator which tends to under-estimate the absolute scale of non-zero coefficients. The performance of the proposed method is illustrated in simulation studies. We apply the method in an analysis of data collected by the Johns Hopkins Precursors Study, where the primary interests are in estimating the strength of association between body mass index in midlife and the quality of life in physical functioning at old age, and in identifying the effective age ranges where such associations exist. PMID- 24478567 TI - GENERALIZED DOUBLE PARETO SHRINKAGE. AB - We propose a generalized double Pareto prior for Bayesian shrinkage estimation and inferences in linear models. The prior can be obtained via a scale mixture of Laplace or normal distributions, forming a bridge between the Laplace and Normal Jeffreys' priors. While it has a spike at zero like the Laplace density, it also has a Student's t-like tail behavior. Bayesian computation is straightforward via a simple Gibbs sampling algorithm. We investigate the properties of the maximum a posteriori estimator, as sparse estimation plays an important role in many problems, reveal connections with some well-established regularization procedures, and show some asymptotic results. The performance of the prior is tested through simulations and an application. PMID- 24478568 TI - Power and Sample Size Calculations for Generalized Estimating Equations via Local Asymptotics. AB - We consider the problem of calculating power and sample size for tests based on generalized estimating equations (GEE), that arise in studies involving clustered or correlated data (e.g., longitudinal studies and sibling studies). Previous approaches approximate the power of such tests using the asymptotic behavior of the test statistics under fixed alternatives. We develop a more accurate approach in which the asymptotic behavior is studied under a sequence of local alternatives that converge to the null hypothesis at root-m rate, where m is the number of clusters. Based on this approach, explicit sample size formulae are derived for Wald and quasi-score test statistics in a variety of GEE settings. Simulation results show that in the important special case of logistic regression with exchangeable correlation structure, previous approaches can inflate the projected sample size (to obtain nominal 90% power using the Wald statistic) by over 10%, whereas the proposed approach provides an accuracy of around 2%. PMID- 24478569 TI - The Dantzig Selector for Censored Linear Regression Models. AB - The Dantzig variable selector has recently emerged as a powerful tool for fitting regularized regression models. To our knowledge, most work involving the Dantzig selector has been performed with fully-observed response variables. This paper proposes a new class of adaptive Dantzig variable selectors for linear regression models when the response variable is subject to right censoring. This is motivated by a clinical study to identify genes predictive of event-free survival in newly diagnosed multiple myeloma patients. Under some mild conditions, we establish the theoretical properties of our procedures, including consistency in model selection (i.e. the right subset model will be identified with a probability tending to 1) and the optimal efficiency of estimation (i.e. the asymptotic distribution of the estimates is the same as that when the true subset model is known a priori). The practical utility of the proposed adaptive Dantzig selectors is verified via extensive simulations. We apply our new methods to the aforementioned myeloma clinical trial and identify important predictive genes. PMID- 24478570 TI - Semiparametric Accelerated Failure Time Model for Length-biased Data with Application to Dementia Study. AB - A semiparametric accelerated failure time (AFT) model is proposed to evaluate the effects of risk factors on the unbiased failure times for the target population given the observed length-biased data. The analysis of length-biased data is complicated by informative right censoring due to the biased sampling mechanism, and consequently the techniques for conventional survival analysis are not applicable. We propose estimating equation methods for estimation and show the asymptotic properties of the proposed estimators. The small sample performance of the estimating methods are investigated and compared with that of existing methods under various underlying distributions and censoring mechanisms. We apply the proposed model and estimating methods to a prevalent cohort study, the Canadian Study of Health and Aging (CSHA), to evaluate the survival duration according to diagnosis of subtype of dementia. PMID- 24478571 TI - Learning of perceptual grouping for object segmentation on RGB-D data. AB - Object segmentation of unknown objects with arbitrary shape in cluttered scenes is an ambitious goal in computer vision and became a great impulse with the introduction of cheap and powerful RGB-D sensors. We introduce a framework for segmenting RGB-D images where data is processed in a hierarchical fashion. After pre-clustering on pixel level parametric surface patches are estimated. Different relations between patch-pairs are calculated, which we derive from perceptual grouping principles, and support vector machine classification is employed to learn Perceptual Grouping. Finally, we show that object hypotheses generation with Graph-Cut finds a globally optimal solution and prevents wrong grouping. Our framework is able to segment objects, even if they are stacked or jumbled in cluttered scenes. We also tackle the problem of segmenting objects when they are partially occluded. The work is evaluated on publicly available object segmentation databases and also compared with state-of-the-art work of object segmentation. PMID- 24478574 TI - A new species of Amphictene (Annelida, Pectinariidae) from the Gulf of Mexico, with a redescription of Amphictene guatemalensis (Nilsson, 1928). AB - The genus Amphictene is reported for the first time from Mexico. Previous records for America are restricted to Brazil (Amphictene catharinensis) (Grube, 1870), and Guatemala (Amphictene guatemalensis) (Nilsson, 1928). In this paper we describe a new species, Amphictene helenae sp. n., characterized by the presence of three pairs of tentacular cirri, while other species have only two pairs. The new species is closely similar to Amphictene catharinensis, and can be distinguished by the presence of a circular group of glandular papillae inserted between the lines of glandular cirri present from the second segment. Amphictene guatemalensis is redescribed based on type material; it differs from the new species in the presence of two pairs of tentacular cirri on segments 1 and 2, six pairs of glandular cirri on the third segment, and four glandular lobes fused in pairs on the fourth segment. PMID- 24478572 TI - Lensfree On-Chip Microscopy and Tomography for Bio-Medical Applications. AB - Lensfree on-chip holographic microscopy is an emerging technique that offers imaging of biological specimens over a large field-of-view without using any lenses or bulky optical components. Lending itself to a compact, cost-effective and mechanically robust architecture, lensfree on-chip holographic microscopy can offer an alternative toolset addressing some of the emerging needs of microscopic analysis and diagnostics in low-resource settings, especially for telemedicine applications. In this review, we summarize the latest achievements in lensfree optical microscopy based on partially coherent on-chip holography, including portable telemedicine microscopy, cell-phone based microscopy and field-portable optical tomographic microscopy. We also discuss some of the future directions for telemedicine microscopy and its prospects to help combat various global health challenges. PMID- 24478573 TI - CORRELATION BETWEEN MICRO-CT SECTIONS AND HISTOLOGICAL SECTIONS OF MOUSE SKULL DEFECTS IMPLANTED WITH ENGINEERED CARTILAGE. AB - One advantage of using cartilage to replace/repair bone is that the implant disappears as bone is formed by endochondral ossification. Previously, we showed that cartilage spheroids, grown in a rotating bioreactor (Synthecon, Inc.) and implanted into a 2 mm skull defect, contributed to healing of the defect. Skulls with or without implants were subjected to microCT scans. Mineralized regions from microCT sections correlated with regions of bone in histological sections of the defect region of demineralized skulls. Recently, sections from microCT scans of live mice were compared to histological sections from the same mice. The area of the defect staining for bone in histological sections of demineralized skulls was the same region shown as mineralized in microCT sections. Defects without implants were not healed. This study demonstrates that microCT scans are an important corollary to histological studies evaluating the use of implants in healing of bony defects. PMID- 24478575 TI - A new species of Phymatodes Mulsant (Coleoptera, Cerambycidae) from China. AB - A new species Phymatodes (Poecilium) latefasciatus sp. n. (Coleoptera, Cerambycidae, Cerambycinae, Callidiini) from China is described and illustrated. Features distinguishing the new species from its congeners are presented. PMID- 24478576 TI - Taxonomic note on the genus Taiwanocantharis Wittmer: synonym, new species and additional faunistic records from China (Coleoptera, Cantharidae). AB - Taiwanocantharis thibetanomima (Wittmer, 1997) is redefined and its type series is clarified. Three new speciesare described and illustrated, Taiwanocantharis wittmeri sp. n. (CHINA: Yunnan), Taiwanocantharis adentata sp. n. (CHINA: Gansu, Sichuan) and Taiwanocantharis parasatoi sp. n. (CHINA: Guangxi). Taiwanocantharis gansosichuana (Kazantsev, 2010) is synonymized with Taiwanocantharis drahuska (Svihla, 2004). Taiwanocantharis dedicata (Svihla, 2005) and Taiwanocantharis malaisei (Wittmer, 1989) are recorded to China for the first time. A key to the species of the Taiwanocantharis thibetana species-group is provided. PMID- 24478577 TI - Spatial distribution of fifty ornamental fish species on coral reefs in the Red Sea and Gulf of Aden. AB - The spatial distribution of 50 ornamental fish species from shallow water habitats on coral reefs were investigated using visual census techniques, between latitudes 11-29 degrees N in the Red Sea, in Jordan, Egypt, Saudi Arabia, and Yemen, and in the adjacent Gulf of Aden in Djibouti. One hundred eighteen transects (each 100*5 m) were examined in 29 sites (3-8 sites per country). A total of 522,523 fish individuals were counted during this survey, with mean abundance of 4428.2 +/- 87.26 individual per 500 m2 transect. In terms of relative abundance (RA), the most abundant species were Blue green damselfish, Chromis viridis (RA=54.4%),followed bySea goldie, Pseudanthias squamipinnis (RA= 34.7), Whitetail dascyllus, Dascyllus aruanus (RA= 2.6%), Marginate dascyllus, Dascyllus marginatus (RA= 2.0),Red Sea eightline flasher Paracheilinus octotaenia (RA=1.0),andKlunzinger's wrasse, Thalassoma rueppellii (0.7%). The highest number of species (S) per 500 m2 transect was found on reefs at the latitude 20 degrees in Saudi Arabia (S=21.8), and the lowest number of species was found at the latitude 15 degrees in Djibouti (S=11.11). The highest mean abundance (8565.8) was found on reefs at latitude 20 degrees in Saudi Arabia and the lowest mean abundance (230) was found on reefs at latitude 22 degrees , also in Saudi Arabia. Whereas, the highest Shannon-Wiener Diversity Index was found in reefs at the latitude 22 degrees (H'=2.4) and the lowest was found in reefs at the latitude 20 degrees (H'=0.6). This study revealed marked differences in the structure of ornamental fish assemblages with latitudinal distribution. The data support the presence of two major biogeographic groups of fishes in the Red Sea and Gulf of Aden: the southern Red Sea and Gulf of Aden group and the group in the northern and central Red Sea. Strong correlations were found between live coral cover and the number of fish species, abundance and Shannon-Wiener Diversity indices, and the strength of these correlations varied among the reefs. A conclusion was done that environmental differences among the reefs and the habitats investigated were important components of abundance variations and species diversity of ornamental fish along latitudinal gradients in the Red Sea and the Gulf of Aden. PMID- 24478579 TI - Cyphoderus (Cyphoderidae) as a major component of collembolan cave fauna in Thailand, with description of two new species. AB - Distinguishing features of Cyphoderus Collembola of the bidenticulati group are described. Taxonomic problems in the bidenticulati group of Cyphoderus are emphasized, and new characters of taxonomic value are introduced and discussed. Two new species are described from caves of Thailand, differing mainly in claw morphology. PMID- 24478578 TI - CLIMBER: Climatic niche characteristics of the butterflies in Europe. AB - Detailed information on species' ecological niche characteristics that can be related to declines and extinctions is indispensable for a better understanding of the relationship between the occurrence and performance of wild species and their environment and, moreover, for an improved assessment of the impacts of global change. Knowledge on species characteristics such as habitat requirements is already available in the ecological literature for butterflies, but information about their climatic requirements is still lacking. Here we present a unique dataset on the climatic niche characteristics of 397 European butterflies representing 91% of the European species (see Appendix). These characteristics were obtained by combining detailed information on butterfly distributions in Europe (which also led to the 'Distribution Atlas of Butterflies in Europe') and the corresponding climatic conditions. The presented dataset comprises information for the position and breadth of the following climatic niche characteristics: mean annual temperature, range in annual temperature, growing degree days, annual precipitation sum, range in annual precipitation and soil water content. The climatic niche position is indicated by the median and mean value for each climate variable across a species' range, accompanied by the 95% confidence interval for the mean and the number of grid cells used for calculations. Climatic niche breadth is indicated by the standard deviation and the minimum and maximum values for each climatic variable across a species' range. Database compilation was based on high quality standards and the data are ready to use for a broad range of applications. It is already evident that the information provided in this dataset is of great relevance for basic and applied ecology. Based on the species temperature index (STI, i.e. the mean temperature value per species), the community temperature index (CTI, i.e. the average STI value across the species in a community) was recently adopted as an indicator of climate change impact on biodiversity by the pan-European framework supporting the Convention on Biological Diversity (Streamlining European Biodiversity Indicators 2010) and has already been used in several scientific publications. The application potential of this database ranges from theoretical aspects such as assessments of past niche evolution or analyses of trait interdependencies to the very applied aspects of measuring, monitoring and projecting historical, ongoing and potential future responses to climate change using butterflies as an indicator. PMID- 24478580 TI - A new species of Tamarixia Mercet (Hymenoptera, Eulophidae), parasitoid of Trioza aguacate Hollis & Martin (Hemiptera, Triozidae) in Mexico. AB - Tamarixia aguacatensis Yefremova, sp. n. (Hymenoptera: Eulophidae: Tetrastichinae) is described from Mexico as a parasitoid of the avocado psyllid, Trioza aguacate Hollis & Martin (Hemiptera: Triozidae). Trioza aguacate is a serious pest of avocado, Persea americana Miller. A key to the species of Tamarixia Mercet in Mexico is given. PMID- 24478581 TI - Genus Indiopius Fischer, 1966 (Hymenoptera, Braconidae, Opiinae) in Iran with a key to the world species. AB - The Iranian species belonging to the genus Indiopius Fischer are reviewed. A description of the first recorded female of I. cretensis Fischer, 1966 is provided. A key to the world species of the genus Indiopius is given. PMID- 24478582 TI - Distribution and nests of paper wasps of Polistes (Polistella) in northeastern Vietnam, with description of a new species (Hymenoptera, Vespidae, Polistinae). AB - Seven species of the subgenus Polistella Ashmead of the genus Polistes Latreille including a new species, P. brunetus Nguyen & Kojima, sp. n. described here, are recognized to occur in northeastern Vietnam, the easternmost part of the eastern slope of the Himalayas. A key to these species is provided. Their distributional records are remarked. Nests of P. delhiensis Das & Gupta, P. mandarinus de Saussure and P. brunetus are also described. PMID- 24478583 TI - Temnothorax pilagens sp. n. - a new slave-making species of the tribe Formicoxenini from North America (Hymenoptera, Formicidae). AB - A new species of the ant genus Temnothorax Forel, 1890 - Temnothorax pilagens sp. n. is described from eastern North America. T. pilagens sp. n. is an obligate slave-making ant with two known hosts: T. longispinosus (Roger, 1863) and T. ambiguus (Emery, 1895). A differential diagnosis against Temnothorax duloticus (Wesson, 1937), the other dulotic congener from the Nearctic, is presented and a biological characteristics of the new species is given. PMID- 24478584 TI - Modern analyses on an historical data set: skull morphology of Italian red squirrel populations. AB - Recent molecular evidence suggests that Sciurus vulgaris populations from Calabria (southern Italy) are distinct from those occurring in northern and central Italy. Here, we re-analyzed using multivariate and univariate techniques an historical dataset provided by Cavazza (1913), who documented measurements for the now extinct squirrel population from Campania. Both univariate and multivariate analyses confirmed that the sample from Calabria was homogenous and relatively distinct compared to the rest of the squirrel samples. PMID- 24478585 TI - First song descriptions of some Anatolian species of Tettigoniidae Krauss, 1902 (Orthoptera, Ensifera). AB - Fourteen endemic and two sub-endemic species belonging to three subfamilies of Tettigoniidae (Tettigoniinae, Bradyporinae and Saginae) were sampled during field trips throughout the different ranges of Anatolia between the years of 2004 and 2013. Acoustic parameters of these 16 species affiliated to 8 genera (Anterastes, Apholidoptera, Gampsocleis, Parapholidoptera, Pezodrymadusa, Psorodonotus, Bradyporus and Saga) have been described for the first time in this study. Acoustical analysis showed that song characters are species-specific in the genera Saga and Psorodonotus. On the other hand, we could not find big differences among species of the genus Pezodrymadusa and Parapholidoptera castaneoviridis species-group. PMID- 24478586 TI - On cicadas of Hyalessa maculaticollis complex (Hemiptera, Cicadidae) of China. AB - The genus Hyalessa China is reviewed based on the discovery of male of the type species H. ronshana China as well as the description of one new species (H. batangensis sp. n.). The species formerly included in the genus Sonata Lee are removed to Hyalessa as new combinations. Intraspecific variations of H. maculaticollis are enumerated based on materials collected from various locations from China. The identity of Sonata and the systematic placement of Hyalessa are discussed. A key to all species of Hyalessa is provided. PMID- 24478587 TI - The leafhopper genus Multiproductus Xing, Dai & Li in China (Hemiptera, Cicadellidae, Deltocephalinae, Paralimnini), with description of one new species. AB - General characteristics of Multiproductus and a new species Multiproductus complantus sp. n. are described and illustrated. A key is given to distinguish all species of the genus. PMID- 24478588 TI - Two new species of Archaeohelorus (Hymenoptera, Proctotrupoidea, Heloridae) from the Middle Jurassic of China. AB - Two new fossil species, Archaeohelorus polyneurus sp. n. and A. tensus sp. n., assigned to the genus Archaeohelorus Shih, Feng & Ren, 2011 of Heloridae (Hymenoptera), are reported from the late Middle Jurassic, Jiulongshan Formation of Inner Mongolia, China. Based on the well-preserved forewings and hind wings of these specimens, the diagnosis of the Archaeohelorus is emended: forewing 2cu-a intersecting Cu and Rs+M at the same point or postfurcal, and hind wing may have tubular veins C, Sc+R, R, Rs, M+Cu, M and Cu distinct, or simplified venation. The new findings also elucidate the evolutionary trend of forewing and hind wing venation and body size for the Heloridae from the late Middle Jurassic to now. PMID- 24478589 TI - Revision of the genus Parasapyga Turner (Hymenoptera, Sapygidae), with the description of two new species. AB - Two new species, Parasapyga boschi sp. n. from Vietnam and P. yvonnae sp. n. from Indonesia are described. Parasapyga walshae van der Vecht, 1940, is treated as a valid species instead of a subspecies of P. moelleri Turner, 1910. A key to the species of the genus is added and all species are illustrated. PMID- 24478590 TI - Description and biology of two new species of Neotropical Liriomyza Mik (Diptera, Agromyzidae), mining leaves of Bocconia (Papaveraceae). AB - Liriomyza mystica Boucher & Nishida, sp. n., and Liriomyza prompta Boucher & Nishida, sp. n. are described from Costa Rica. Both species were reared from leaves of Bocconia frutescens L. (Papaveraceae). The latter species was also reared from B. arborea S. Watson. Larvae of L. mystica mine primary veins of large, relatively old, mature leaves, and L. prompta mine blades of small to large, mature leaves. These represent the first record of agromyzids feeding on Bocconia. Biological information is also given and illustrated. PMID- 24478591 TI - Systematics of treefrogs of the Hypsiboas calcaratus and Hypsiboas fasciatus species complex (Anura, Hylidae) with the description of four new species. AB - We review the systematics of the Hypsiboas calcaratus species complex, a group of widely distributed Amazonian hylid frogs. A comprehensive analysis of genetic, morphological, and bioacoustic datasets uncovered the existence of eleven candidate species, six of which are confirmed. Two of them correspond to Hypsiboas fasciatus and Hypsiboas calcaratus and the remaining four are new species that we describe here. Hypsiboas fasciatus sensu stricto has a geographic range restricted to the eastern Andean foothills of southern Ecuador while Hypsiboas calcaratus sensu stricto has a wide distribution in the Amazon basin. Hypsiboas almendarizae sp. n. occurs at elevations between 500 and 1950 m in central and northern Ecuador; the other new species (H. maculateralis sp. n., H. alfaroi sp. n., and H. tetete sp. n.) occur at elevations below 500 m in Amazonian Ecuador and Peru. The new species differ from H. calcaratus and H. fasciatus in morphology, advertisement calls, and mitochondrial and nuclear DNA sequences. Five candidate species from the Guianan region, Peru, and Bolivia are left as unconfirmed. Examination of the type material of Hyla steinbachi, from Bolivia, shows that it is not conspecific with H. fasciatus and thus is removed from its synonymy. PMID- 24478592 TI - The Trend of Vibrio parahaemolyticus Infections in Southern Thailand from 2006 to 2010. AB - The bacterium, Vibrio parahaemolyticus was isolated from 776 patients at Hat Yai Hospital in Southern Thailand from 2006 to 2010. 51.3-73.6% of the isolates were tdh (+) trh (-) and Group-specific PCR positive pandemic strains. A comparison of the number of V. parahaemolyticus isolates in this study and that from the same hospital in 2000-2005 indicates that this region of Thailandis endemic for V. parahaemolyticus. PMID- 24478593 TI - Distribution of mosquito larvae on kosrae island, kosrae state, the federated States of micronesia. AB - Surveys of mosquito larvae were carried out in six areas of Kosrae Island, Kosrae State, the Federated States of Micronesia in December 2009 and June 2012. A total of 962 larvae of six species were collected from 106 natural and artificial habitats. They were identified as Aedes aegypti, Ae. albopictus, Ae. marshallensis, Culex quinquefasciatus, Cx. annulirostris, and Cx. kusaiensis. This is the first report from Kosrae Island for three of these species-Ae. marshallensis, Cx. quinquefasciatus, and Cx. annulirostris. The most abundant species was Ae. albopictus, followed by Ae. marshallensis, and these two species were found in all areas. Relatively large numbers of Cx. quinquefasciatus and Cx. kusaiensis were found in five areas. Fewer Cx. annulirostris were found, and only in three areas. Aedes aegypti larvae were collected from a single habitat at Tafunsak in 2009. To prevent the outbreak of dengue fever, environmental management should focus on the destruction, alteration, disposal and recycling of containers that produce larger numbers of adult Aedes mosquitoes. PMID- 24478594 TI - Estimating spatial inequalities of urban child mortality. AB - BACKGROUND: Recent studies indicate that the traditional rural-urban dichotomy pointing to cities as places of better health in the developing world can be complicated by poverty differentials. Knowledge of spatial patterns is essential to understanding the processes that link individual demographic outcomes to characteristics of a place. A significant limitation, however, is the lack of spatial data and methods that offer flexibility in data inputs. OBJECTIVE: This paper tackles some of the issues in calculating intra-urban child mortality by combining multiple data sets in Accra, Ghana and applying a new method developed by Rajaratnam et al. (2010) that efficiently uses summary birth histories for creating local-level measures of under-five child mortality (5q0). Intra-urban 5q0 rates are then compared with characteristics of the environment that may be linked to child mortality. METHODS: Rates of child mortality are calculated for 16 urban zones within Accra for birth cohorts from 1987 to 2006. Estimates are compared to calculated 5q0 rates from full birth histories. 5q0 estimates are then related to zone measures of slum characteristics, housing quality, health facilities, and vegetation using a simple trendline R2 analysis. RESULTS: Results suggest the potential value of the Rajaratnam et al. method at the micro-spatial scale. Estimated rates indicate that there is variability in child mortality between zones, with a spread of up to 50 deaths per 1,000 births. Furthermore, there is evidence that child mortality is connected to environmental factors such as housing quality, slum-like conditions, and neighborhood levels of vegetation. PMID- 24478596 TI - The last issue of the year, a retrospective and a new perspective for the Revista Brasileira de Hematologia e Hemoterapia. PMID- 24478595 TI - Exercise and Bone Macro-architecture: Is Childhood a Window of Opportunity for Osteoporosis Prevention? PMID- 24478597 TI - Comment on: Relationship between splenomegaly and hematologic findings in patients with hepatosplenic schistosomiasis. PMID- 24478598 TI - Successful treatment of chronic myeloid leukemia with tyrosine kinase inhibitors goes beyond access to drugs. PMID- 24478599 TI - Comment on: Blood discard rate and the prevalence of infectious and contagious diseases in blood donors from provincial towns of the state of Parana, Brazil. PMID- 24478600 TI - Genetic diversity of the human blood group systems. PMID- 24478601 TI - Comment on: oxidative stress and antioxidant status in beta-thalassemia heterozygotes. PMID- 24478602 TI - The severity of illness and inflammatory markers cannot predict red blood cell alloimmunization in cancer patients. PMID- 24478603 TI - Chronic myeloid leukemia: an overview of the determinants of effectiveness and therapeutic response in the first decade of treatment with imatinib mesylate in a Brazilian hospital. AB - BACKGROUND: In the last decade, there has been a revolution in chronic myeloid leukemia treatment with the introduction of tyrosine kinase inhibitors with imatinib mesylate becoming the frontline therapy. OBJECTIVE: To evaluate the therapeutic efficacy of imatinib mesylate in treating chronic myeloid leukemia patients and to identify factors related to therapeutic efficacy. METHODS: This retrospective study was based on information obtained from patients' records in the Hematology Service of Hospital Universitario Walter Cantidio of the Universidade Federal do Ceara (HUWC / UFC). All patients diagnosed with chronic myeloid leukemia that took imatinib mesylate for a minimum of 12 months in the period from January 2001 to January 2011 were included. From a population of 160 patients, 100 were eligible for analysis. RESULTS: The study population consisted of 100 patients who were mostly male (51%) with ages ranging between 21 and 40 years (42%), from the countryside (59%), in the chronic phase (95%), with high risk prognostic factors (40%); the prognosis of high risk was not associated with complete hematologic response or complete cytogenetic response, but correlated to complete molecular response or major molecular response. Reticulin condensation was associated with complete hematologic response and complete cytogenetic response. It was found that 53% of patients had greater than 90% adherence to treatment. The high adherence was correlated to attaining complete cytogenetic response in less than 12 months. Moreover,20% of patients had good response. CONCLUSION: Significant changes are indispensable in the monitoring of patients with chronic myeloid leukemia. Thus, the multidisciplinary team is important as it provides access to the full treatment and not just to medications. PMID- 24478604 TI - Blood discard rate and the prevalence of infectious and contagious diseases in blood donors from provincial towns of the state of Parana, Brazil. AB - BACKGROUND: So that an improvement in the selection of donors can be achieved and the risk to the recipient of transfused blood can be reduced, prospective donors are submitted to clinical and serological screening. OBJECTIVE: This study investigated the blood discard rate and the rate of infectious and contagious diseases in blood donors from provincial towns of the state of Parana, Brazil. METHODS: This study was an exploratory cross-sectional descriptive investigation with a quantitative approach of donations between January and December 2011. RESULTS: In the study period the Regional Blood center in Maringa, Brazil received 8337 blood donations from people living in the city and neighboring towns. However, 278 (3.33%) donations were discarded during serological screening owing to one or more positive serological markers. A total of 46.4% of the discarded blood units were confirmed positive by serology with anti-HBc being the most common (66.7%), followed by syphilis (22.5%), HBsAg (4.7%), anti-hepatitis C virus (3.1%), human immunodeficiency virus (1.5%) and Chagas' disease (1.5%). The rate of infectious-contagious diseases that can be transmitted by blood transfusions was 1.55% (129/8337) of the donor population with a frequency of 1.03% for anti-HBc and 0.35% for syphilis. CONCLUSION: This study demonstrates a high prevalence of the anti-HBc marker in prospective blood donors from provincial towns in the state of Parana, Brazil. PMID- 24478605 TI - Dombrock genotyping in Brazilian blood donors reveals different regional frequencies of the HY allele. AB - BACKGROUND: Dombrock blood group system genotyping has revealed various rearrangements of the Dombrock gene and identified new variant alleles in Brazil (i.e., DO*A-SH, DO*A-WL and DO*B-WL). Because of the high heterogeneity of the Brazilian population, interregional differences are expected during the investigation of Dombrock genotypes. OBJECTIVE: The present study aims to determine the frequencies of Dombrock genotypes in blood donors from Minas Gerais and compare the frequencies of the HY and JO alleles to those of another population in Brazil. METHODS: The frequencies of the DO alleles in Minas Gerais, a southeastern state of Brazil, were determined from the genotyping of 270 blood donors. Genotyping involved polymerase chain reaction and restriction fragment length polymorphism analysis to identify the 323G>T, 350C>T, 793A>G, and 898C>G mutations, which are related to the HY, JO, DO*A/DO*B, and DO*A-WL/DO*B-WL alleles, respectively. Moreover, the frequencies of rare HY and JO alleles were statistically compared using the chi-square test with data from another Brazilian region. RESULTS: The HY allele frequency in Minas Gerais (2.4%) was almost twice that of the JO allele (1.5%). The frequency of the HY allele was significantly higher (p-value = 0.001) than that in another Brazilian population and includes a rare homozygous donor with the Hy- phenotype. In addition, the DO*A-WL and DO*B WL alleles, which were first identified in Brazil, were found in the state of Minas Gerais. CONCLUSIONS: The data confirm that the frequencies of DO alleles differ between regions in Brazil. The population of Minas Gerais could be targeted in a screening strategy to identify the Hy- phenotype in order to develop a rare blood bank. PMID- 24478606 TI - Validation of the Sysmex sp-1000i automated slide preparer-stainer in a clinical laboratory. AB - BACKGROUND: The speed and quality of information have become essential items in the release of laboratory reports. The Sysmex((r))SP1000-I device has been developed to prepare and stain smear slides. However, for a device to be cleared for use in the laboratory routine it must pass through a validation process. OBJECTIVE: To evaluate the performance and reliability of the Sysmex((r)) SP 1000i slide preparer-stainer incorporated into the routine of a hospital laboratory in Porto Alegre. METHODS: Peripheral blood samples of patients attending the laboratory for ambulatory exams with leukocyte counts between 7000/ degrees L and 12,000/ degrees L were evaluated, independent of gender and age. Two slides were prepared for each sample using the Sysmex((r)) SP-1000i equipment; one of the slides was used to perform quality control tests using the CellaVision((r)) DM96 device, and the other slide was used to compare pre classification by the same device and the classification performed by a pharmacist-biochemist. RESULTS: The results of all the slides used as controls were acceptable according to the quality control test as established by the manufacturer of the device. In the comparison between the automated pre classification and the classification made by the professional, there was an acceptable variation in the differential counts of leukocytes for 90% of the analyzed slides. Pearson correlation coefficient showed a strong correlation for band neutrophils (r = 0.802; p-value < 0.001), segmented neutrophils (r = 0.963; p-value < 0.001), eosinophils (r = 0.958; p-value < 0.001), lymphocytes (r = 0.985; p-value < 0.001) and atypical lymphocytes (r = 0.866; p-value < 0.001) using both methods. The red blood cell analysis was adequate for all slides analyzed by the equipment and by the professional. CONCLUSION: The new Sysmex((r))SP1000-i methodology was found to be reliable, fast and safe for the routines of medium and large laboratories, improving the quality of microscopic analysis in complete blood counts. PMID- 24478607 TI - Oxidative stress and antioxidant status in beta-thalassemia heterozygotes. AB - BACKGROUND: Several studies have evaluated the oxidant and antioxidant status of thalassemia patients but most focused mainly on the severe and intermediate states of the disease. Moreover, the oxidative status has not been evaluated for the different beta-thalassemia mutations. OBJECTIVE: To evaluate lipid peroxidation and Trolox equivalent antioxidant capacity in relation to serum iron and ferritin in beta thalassemia resulting from two different mutations (CD39 and IVS-I-110) compared to individuals without beta-thalassemia. METHODS: One hundred and thirty subjects were studied, including 49 who were heterozygous for beta thalassemia and 81 controls. Blood samples were subjected to screening tests for hemoglobin. Allele-specific polymerase chain reaction was used to confirm mutations for beta-thalassemia, an analysis of thiobarbituric acid reactive species was used to determine lipid peroxidation, and Trolox equivalent antioxidant capacity evaluations were performed. The heterozygous beta thalassemia group was also evaluated for serum iron and ferritin status. RESULTS: Thiobarbituric acid reactive species (486.24 +/- 119.64 ng/mL) and Trolox equivalent antioxidant capacity values (2.23 +/- 0.11 mM/L) were higher in beta thalassemia heterozygotes compared to controls (260.86 +/- 92.40 ng/mL and 2.12 +/- 0.10 mM/L, respectively; p-value < 0.01). Increased thiobarbituric acid reactive species values were observed in subjects with the CD39 mutation compared with those with the IVS-I-110 mutation (529.94 +/- 115.60 ng/mL and 453.39 +/- 121.10 ng/mL, respectively; p-value = 0.04). However, average Trolox equivalent antioxidant capacity values were similar for both mutations (2.20 +/- 0.08 mM/L and 2.23 +/- 0.12 mM/L, respectively; p-value = 0.39). There was no influence of serum iron and ferritin levels on thiobarbituric acid reactive species and Trolox equivalent antioxidant capacity values. CONCLUSION: This study shows an increase of oxidative stress and antioxidant capacity in beta-thalassemia heterozygotes, mainly in carriers of the CD39 mutation. PMID- 24478608 TI - Study of possible clinical and laboratory predictors of alloimmunization against red blood cell antigens in cancer patients. AB - BACKGROUND: The inflammatory background of patients influences the process of alloimmunization against red blood cell antigens. Proof of this statement to clinical practice is still lacking. OBJECTIVE: The aim of this study was to verify whether factors related to disease severity and inflammatory status of cancer patients can predict alloimmunization. METHODS: This was a case-control study in which alloimmunized oncologic patients treated between 2009 and 2012 were compared with a non-alloimmunized control group regarding the severity of the disease (metastasis/performance status/body mass index) and C-reactive protein levels. RESULTS: The groups did not differ significantly in terms of C reactive protein, Eastern Cooperative Oncology Group (ECOG)/Karnofsky performance status, presence of metastasis and body mass index. CONCLUSION: It is not possible to predict alloimmunization in cancer patients based on severity of illness and inflammatory markers. Strategies of screening patients by phenotyping blood based on these criteria are not justified. PMID- 24478609 TI - Guidelines on the treatment of primary immune thrombocytopenia in children and adolescents: Associacao Brasileira de Hematologia, Hemoterapia e Terapia Celular Guidelines Project: Associacao Medica Brasileira - 2012. PMID- 24478610 TI - Brazilian Thalassemia Association protocol for iron chelation therapy in patients under regular transfusion. AB - In the absence of an iron chelating agent, patients with beta-thalassemia on regular transfusions present complications of transfusion-related iron overload. Without iron chelation therapy, heart disease is the major cause of death; however, hepatic and endocrine complications also occur. Currently there are three iron chelating agents available for continuous use in patients with thalassemia on regular transfusions (desferrioxamine, deferiprone, and deferasirox) providing good results in reducing cardiac, hepatic and endocrine toxicity. These practice guidelines, prepared by the Scientific Committee of Associacao Brasileira de Thalassemia (ABRASTA), presents a review of the literature regarding iron overload assessment (by imaging and laboratory exams) and the role of T2* magnetic resonance imaging (MRI) to control iron overload and iron chelation therapy, with evidence-based recommendations for each clinical situation. Based on this review, the authors propose an iron chelation protocol for patients with thalassemia under regular transfusions. PMID- 24478611 TI - Late cytomegalovirus infection after hematopoietic stem cell transplantation: case reports. AB - Cytomegalovirus is related to high rates of morbidity and mortality after hematopoietic stem cell transplantation. This report highlights the importance of adequate monitoring and management of this infection. We report on two cases of patients with late subclinical cytomegalovirus infection. These patients were monitored for antigenemia by indirect immunofluorescence assay. Active cytomegalovirus infection is most common in the first three months after transplantation however the cases reported herein show the importance of monitoring for active infection after Day +100 post-transplantation. Early detection of active infection enables quick preemptive therapy. In conclusion, we emphasize that patients with risk factors for developing severe or late cytomegalovirus disease should be monitored for more than 100 post-transplant days as late active infection is a reality. PMID- 24478612 TI - Myelodysplastic syndrome versus idiopathic cytopenia of undetermined significance: the role of morphology in distinguishing between these entities. PMID- 24478613 TI - Early Screening for Risk of Reading Disabilities: Recommendations for a Four-Step Screening System. AB - Response-to-intervention (RTI) models incorporate a screening process to identify students who appear to be at risk for learning disabilities (LDs). The purpose of this position article is to incorporate what is known about screening into a flexible, yet comprehensive screening system to help school psychologists and other school administrators in establishing school-specific screening procedures. The authors begin by discussing past. research on screening for reading disabilities (RDs) within the RTI framework. Then, they propose a four-step screening system advocating a short screener (Step I), progress monitoring (Step 2), follow-up testing (Step 3), and ongoing revision of procedures and cut scores (Step 4). Their goal is to improve screening within RTI systems with practical procedures to permit schools to implement state-of-the-art screening batteries that accurately and efficiently distinguish students who are at high risk for RD. PMID- 24478614 TI - Implementation process and challenges for the community-based integrated care system in Japan. AB - BACKGROUND: Since 10 years ago, Japan has been creating a long-term vision to face its peak in the number of older people that will be reached in 2025 when baby boomers will turn 75 years of age. In 2003, the government set up a study group called "Caring for older people in 2015" which led to a first reform of the Long-Term Care Insurance System in 2006. This study group was the first to suggest the creation of a community-based integrated care system. REFORMS: Three measures were taken in 2006: 'Building an active ageing society: implementation of preventive care services', 'Improve sustainability: revision of the remuneration of facilities providing care' and 'Integration: establishment of a new service system'. These reforms are at the core of the community-based integrated care system. DISCUSSION: The socialization of long-term care that came along with the ageing of the population, and the second shift in Japan towards an increased reliance on the community can provide useful information for other ageing societies. As a super ageing society, the attempts from Japan to develop a rather unique system based on the widely spread concept of integrated care should also become an increasing focus of attention. PMID- 24478615 TI - Community Context of Sober Living Houses. AB - The success or failure of programs designed to address alcohol and drug problems can be profoundly influenced by the communities where they are located. Support from the community is vital for long term stability and conflict with the community can harm a program's reputation or even result in closure. This study examined the community context of sober living houses (SLHs) in one Northern California community by interviewing key stakeholder groups. SLHs are alcohol and drug free living environments for individuals attempting to abstain from substance use. Previous research on residents of SLHs showed they make long-term improvements on measures of substance use, psychiatric symptoms, arrests, and employment. Interviews were completed with house managers, neighbors, and key informants from local government and community organizations. Overall, stakeholders felt SLHs were necessary and had a positive impact on the community. It was emphasized that SLHs needed to practice a "good neighbor" policy that prohibited substance use and encouraged community service. Size and density of SLHs appeared to influence neighbor perceptions. For small (six residents or less), sparsely populated houses, a strategy of blending in with the neighborhood seemed to work. However, it was clear that larger, densely populated houses need to actively manage relationships with community stakeholders. Strategies for improving relationships with immediate neighbors, decreasing stigma, and broadening the leadership structure are discussed. Implications for a broad array of community based programs are discussed. PMID- 24478616 TI - The hermit crab's nose-antennal transcriptomics. AB - In the course of evolution, crustaceans adapted to a large variety of habitats. Probably the most extreme habitat shift was the transition from water to land, which occurred independently in at least five crustacean lineages. This substantial change in life style required adaptations in sensory organs, as the medium conveying stimuli changed in both chemical and physical properties. One important sensory organ in crustaceans is the first pair of antennae, housing their sense of smell. Previous studies on the crustacean transition from water to land focused on morphological, behavioral, and physiological aspects but did not analyze gene expression. Our goal was to scrutinize the molecular makeup of the crustacean antennulae, comparing the terrestrial Coenobita clypeatus and the marine Pagurus bernhardus. We sequenced and analyzed the antennal transcriptomes of two hermit crab species. Comparison to previously published datasets of similar tissues revealed a comparable quality and GO annotation confirmed a highly similar set of expressed genes in both datasets. The chemosensory gene repertoire of both species displayed a similar set of ionotropic receptors (IRs), most of them belonging to the divergent IR subtype. No binding proteins, gustatory receptors (GRs) or insect-like olfactory receptors (ORs) were present. Additionally to their olfactory function, the antennules were equipped with a variety of pathogen defense mechanisms, producing relevant substances on site. The overall similarity of both transcriptomes is high and does not indicate a general shift in genetic makeup connected to the change in habitat. IRs seem to perform the task of olfactory detection in both hermit crab species studied. PMID- 24478617 TI - Surgical manipulation compromises leukocyte mobilization responses and inflammation after experimental cerebral ischemia in mice. AB - Acute brain injury results in peripheral inflammatory changes, although the impact of these processes on neuronal death and neuroinflammation is currently unclear. To facilitate the translation of experimental studies to clinical benefit, it is vital to characterize the mechanisms by which acute brain injury induces peripheral inflammatory changes, and how these are affected by surgical manipulation in experimental models. Here we show that in mice, even mild surgical manipulation of extracranial tissues induced marked granulocyte mobilization (300%) and systemic induction of cytokines. However, intracranial changes induced by craniotomy, or subsequent induction of focal cerebral ischemia were required to induce egress of CXCR2-positive granulocytes from the bone marrow. CXCR2 blockade resulted in reduced mobilization of granulocytes from the bone marrow, caused an unexpected increase in circulating granulocytes, but failed to affect brain injury induced by cerebral ischemia. We also demonstrate that isoflurane anaesthesia interferes with circulating leukocyte responses, which could contribute to the reported vascular and neuroprotective effects of isoflurane. In addition, no immunosuppression develops in the bone marrow after experimental stroke. Thus, experimental models of cerebral ischemia are compromised by surgery and anaesthesia in proportion to the severity of surgical intervention and overall tissue injury. Understanding the inherent confounding effects of surgical manipulation and development of new models of cerebral ischemia with minimal surgical intervention could facilitate better understanding of interactions between inflammation and brain injury. PMID- 24478619 TI - Adaptive pulsed laser line extraction for terrain reconstruction using a dynamic vision sensor. AB - Mobile robots need to know the terrain in which they are moving for path planning and obstacle avoidance. This paper proposes the combination of a bio-inspired, redundancy-suppressing dynamic vision sensor (DVS) with a pulsed line laser to allow fast terrain reconstruction. A stable laser stripe extraction is achieved by exploiting the sensor's ability to capture the temporal dynamics in a scene. An adaptive temporal filter for the sensor output allows a reliable reconstruction of 3D terrain surfaces. Laser stripe extractions up to pulsing frequencies of 500 Hz were achieved using a line laser of 3 mW at a distance of 45 cm using an event-based algorithm that exploits the sparseness of the sensor output. As a proof of concept, unstructured rapid prototype terrain samples have been successfully reconstructed with an accuracy of 2 mm. PMID- 24478618 TI - Are non-human primates capable of rhythmic entrainment? Evidence for the gradual audiomotor evolution hypothesis. AB - We propose a decomposition of the neurocognitive mechanisms that might underlie interval-based timing and rhythmic entrainment. Next to reviewing the concepts central to the definition of rhythmic entrainment, we discuss recent studies that suggest rhythmic entrainment to be specific to humans and a selected group of bird species, but, surprisingly, is not obvious in non-human primates. On the basis of these studies we propose the gradual audiomotor evolution hypothesis that suggests that humans fully share interval-based timing with other primates, but only partially share the ability of rhythmic entrainment (or beat-based timing). This hypothesis accommodates the fact that non-human primates (i.e., macaques) performance is comparable to humans in single interval tasks (such as interval reproduction, categorization, and interception), but show differences in multiple interval tasks (such as rhythmic entrainment, synchronization, and continuation). Furthermore, it is in line with the observation that macaques can, apparently, synchronize in the visual domain, but show less sensitivity in the auditory domain. And finally, while macaques are sensitive to interval-based timing and rhythmic grouping, the absence of a strong coupling between the auditory and motor system of non-human primates might be the reason why macaques cannot rhythmically entrain in the way humans do. PMID- 24478620 TI - Dynamic neural fields as a step toward cognitive neuromorphic architectures. AB - Dynamic Field Theory (DFT) is an established framework for modeling embodied cognition. In DFT, elementary cognitive functions such as memory formation, formation of grounded representations, attentional processes, decision making, adaptation, and learning emerge from neuronal dynamics. The basic computational element of this framework is a Dynamic Neural Field (DNF). Under constraints on the time-scale of the dynamics, the DNF is computationally equivalent to a soft winner-take-all (WTA) network, which is considered one of the basic computational units in neuronal processing. Recently, it has been shown how a WTA network may be implemented in neuromorphic hardware, such as analog Very Large Scale Integration (VLSI) device. This paper leverages the relationship between DFT and soft WTA networks to systematically revise and integrate established DFT mechanisms that have previously been spread among different architectures. In addition, I also identify some novel computational and architectural mechanisms of DFT which may be implemented in neuromorphic VLSI devices using WTA networks as an intermediate computational layer. These specific mechanisms include the stabilization of working memory, the coupling of sensory systems to motor dynamics, intentionality, and autonomous learning. I further demonstrate how all these elements may be integrated into a unified architecture to generate behavior and autonomous learning. PMID- 24478621 TI - A robust sound perception model suitable for neuromorphic implementation. AB - We have recently demonstrated the emergence of dynamic feature sensitivity through exposure to formative stimuli in a real-time neuromorphic system implementing a hybrid analog/digital network of spiking neurons. This network, inspired by models of auditory processing in mammals, includes several mutually connected layers with distance-dependent transmission delays and learning in the form of spike timing dependent plasticity, which effects stimulus-driven changes in the network connectivity. Here we present results that demonstrate that the network is robust to a range of variations in the stimulus pattern, such as are found in naturalistic stimuli and neural responses. This robustness is a property critical to the development of realistic, electronic neuromorphic systems. We analyze the variability of the response of the network to "noisy" stimuli which allows us to characterize the acuity in information-theoretic terms. This provides an objective basis for the quantitative comparison of networks, their connectivity patterns, and learning strategies, which can inform future design decisions. We also show, using stimuli derived from speech samples, that the principles are robust to other challenges, such as variable presentation rate, that would have to be met by systems deployed in the real world. Finally we demonstrate the potential applicability of the approach to real sounds. PMID- 24478622 TI - Misconceptions in the use of the General Linear Model applied to functional MRI: a tutorial for junior neuro-imagers. AB - This tutorial presents several misconceptions related to the use the General Linear Model (GLM) in functional Magnetic Resonance Imaging (fMRI). The goal is not to present mathematical proofs but to educate using examples and computer code (in Matlab). In particular, I address issues related to (1) model parameterization (modeling baseline or null events) and scaling of the design matrix; (2) hemodynamic modeling using basis functions, and (3) computing percentage signal change. Using a simple controlled block design and an alternating block design, I first show why "baseline" should not be modeled (model over-parameterization), and how this affects effect sizes. I also show that, depending on what is tested; over-parameterization does not necessarily impact upon statistical results. Next, using a simple periodic vs. random event related design, I show how the hemodynamic model (hemodynamic function only or using derivatives) can affects parameter estimates, as well as detail the role of orthogonalization. I then relate the above results to the computation of percentage signal change. Finally, I discuss how these issues affect group analyses and give some recommendations. PMID- 24478623 TI - Vobi One: a data processing software package for functional optical imaging. AB - Optical imaging is the only technique that allows to record the activity of a neuronal population at the mesoscopic scale. A large region of the cortex (10-20 mm diameter) is directly imaged with a CCD camera while the animal performs a behavioral task, producing spatio-temporal data with an unprecedented combination of spatial and temporal resolutions (respectively, tens of micrometers and milliseconds). However, researchers who have developed and used this technique have relied on heterogeneous software and methods to analyze their data. In this paper, we introduce Vobi One, a software package entirely dedicated to the processing of functional optical imaging data. It has been designed to facilitate the processing of data and the comparison of different analysis methods. Moreover, it should help bring good analysis practices to the community because it relies on a database and a standard format for data handling and it provides tools that allow producing reproducible research. Vobi One is an extension of the BrainVISA software platform, entirely written with the Python programming language, open source and freely available for download at https://trac.int.univ amu.fr/vobi_one. PMID- 24478624 TI - A kinder, gentler dopamine... highlighting dopamine's role in behavioral flexibility. PMID- 24478625 TI - LSN2424100: a novel, potent orexin-2 receptor antagonist with selectivity over orexin-1 receptors and activity in an animal model predictive of antidepressant like efficacy. AB - We describe a novel, potent and selective orexin-2 (OX2)/hypocretin-2 receptor antagonist with in vivo activity in an animal model predictive of antidepressant like efficacy. N-biphenyl-2-yl-4-fluoro-N-(1H-imidazol-2-ylmethyl) benzenesulfonamide HCl (LSN2424100) binds with high affinity to recombinant human OX2 receptors (Ki = 4.5 nM), and selectivity over OX1 receptors (Ki = 393 nM). LSN2424100 inhibited OXA-stimulated intracellular calcium release in HEK293 cells expressing human and rat OX2 receptors (Kb = 0.44 and 0.83 nM, respectively) preferentially over cells expressing human and rat OX1 (Kb = 90 and 175 nM, respectively). LSN2424100 exhibits good exposure in Sprague-Dawley rats after IP, but not PO, administration of a 30 mg/kg dose (AUC0-6 h = 1300 and 269 ng(*)h/mL, respectively). After IP administration in rats and mice, LSN2424100 produces dose dependent antidepressant-like activity in the delayed-reinforcement of low-rate (DRL) assay, a model predictive of antidepressant-like efficacy. Efficacy in the DRL model was lost in mice lacking OX2, but not OX1 receptors, confirming OX2 specific activity. Importantly, antidepressant-like efficacy of the tricyclic antidepressant, imipramine, was maintained in both OX1 and OX2 receptor knock-out mice. In conclusion, the novel OX2 receptor antagonist, LSN2424100, is a valuable tool compound that can be used to explore the role of OX2 receptor-mediated signaling in mood disorders. PMID- 24478626 TI - Pin1, a new player in the fate of HIF-1alpha degradation: an hypothetical mechanism inside vascular damage as Alzheimer's disease risk factor. AB - Aetiology of neurodegenerative mechanisms underlying Alzheimer's disease (AD) are still under elucidation. The contribution of cerebrovascular deficiencies (such as cerebral ischemia/stroke) has been strongly endorsed in recent years. Reduction of blood supply leading to hypoxic condition is known to activate cellular responses mainly controlled by hypoxia-inducible transcription factor-1 (HIF-1). Thus alterations of oxygen responsive HIF-1alpha subunit in the central nervous system may contribute to the cognitive decline, especially influencing mechanisms associated to amyloid precursor protein (APP) amyloidogenic metabolism. Although HIF-1alpha protein level is known to be regulated by von Hippel-Lindau (VHL) ubiquitin-proteasome system, it has been recently suggested that glycogen synthase kinase-3beta (Gsk-3beta) promotes a VHL-independent HIF 1alpha degradation. Here we provide evidences that in rat primary hippocampal cell cultures, HIF-1alpha degradation might be mediated by a synergic action of Gsk-3beta and peptidyl-prolyl cis/trans isomerase (Pin1). In post-ischemic conditions, such as those mimicked with oxygen glucose deprivation (OGD), HIF 1alpha protein level increases remaining unexpectedly high for long time after normal condition restoration jointly with the increase of lactate dehydrogenase (LDH) and beta-secretase 1 (BACE1) protein expression (70 and 140% respectively). Interestingly the Pin1 activity decreases about 40-60% and Pin1(S16) inhibitory phosphorylation significantly increases, indicating that Pin1 binding to its substrate and enzymatic activity are reduced by treatment. Co-immunoprecipitation experiments demonstrate that HIF-1alpha/Pin1 in normoxia are associated, and that in presence of specific Pin1 and Gsk-3beta inhibitors their interaction is reduced in parallel to an increase of HIF-1alpha protein level. Thus we suggest that in post-OGD neurons the high level of HIF-1alpha might be due to Pin1 binding ability and activity reduction which affects HIF-1alpha degradation: an event that may highlight the relevance of ischemia/HIF-1alpha as a risk factor in AD pathogenesis. PMID- 24478627 TI - Optogenetic evocation of field inhibitory postsynaptic potentials in hippocampal slices: a simple and reliable approach for studying pharmacological effects on GABAA and GABAB receptor-mediated neurotransmission. AB - The GABAergic system is the main source of inhibition in the mammalian brain. Consequently, much effort is still made to develop new modulators of GABAergic synaptic transmission. In contrast to glutamatergic postsynaptic potentials (PSPs), accurate monitoring of GABA receptor-mediated PSPs (GABAR-PSPs) and their pharmacological modulation in brain tissue invariably requires the use of intracellular recording techniques. However, these techniques are expensive, time and labor-consuming, and, in case of the frequently employed whole-cell patch clamp configuration, impact on intracellular ion concentrations, signaling cascades, and pH buffering systems. Here, we describe a novel approach to circumvent these drawbacks. In particular, we demonstrate in mouse hippocampal slices that selective optogenetic activation of interneurons leads to prominent field inhibitory GABAAR- and GABABR-PSPs in area CA1 which are easily and reliably detectable by a single extracellular recording electrode. The field PSPs exhibit typical temporal and pharmacological characteristics, display pronounced paired-pulse depression, and remain stable over many consecutive evocations. Additionally validating the methodological value of this approach, we further show that the neuroactive steroid 5alpha-THDOC (5 MUM) shifts the inhibitory GABAAR-PSPs towards excitatory ones. PMID- 24478628 TI - Cryoloading: introducing large molecules into live synaptosomes. AB - Neurons communicate with their target cells primarily by the release of chemical transmitters from presynaptic nerve terminals. The study of CNS presynaptic nerve terminals, isolated as synaptosomes (SSMs) has, however, been hampered by the typical small size of these structures that precludes the introduction of non membrane permeable test substances such as peptides and drugs. We have developed a method to introduce large alien compounds of at least 150 kDa into functional synaptosomes. Purified synaptosomes are frozen in cryo-preserving buffer containing the alien compound. Upon defrosting, many of the SSMs contain the alien compound presumably admitted by bulk buffer-transfer through the surface membranes that crack and reseal during the freeze/thaw cycle. ~80% of the cryoloaded synaptosomes were functional and recycled synaptic vesicles (SVs), as assessed by a standard styryl dye uptake assay. Access of the cryoloaded compound into the cytoplasm and biological activity were confirmed by block of depolarization-induced SV recycling with membrane-impermeant BAPTA (a rapid Ca(2+)-scavenger), or botulinum A light chain (which cleaves the soluble NSF attachment protein receptor (SNARE) protein SNAP25). A major advantage of the method is that loaded frozen synaptosomes can be stored virtually indefinitely for later experimentation. We also demonstrate that individual synaptosome types can be identified by immunostaining of receptors associated with its scab of attached postsynaptic membrane. Thus, cryoloading and scab-staining permits the examination of SV recycling in identified individual CNS presynaptic nerve terminals. PMID- 24478629 TI - Schizophrenia: susceptibility genes and oligodendroglial and myelin related abnormalities. AB - Given that the genetic risk for schizophrenia is highly polygenic and the effect sizes, even for rare or de novo events, are modest at best, it has been suggested that multiple biological pathways are likely to be involved in the etiopathogenesis of the disease. Most efforts in understanding the cellular basis of schizophrenia have followed a "neuron-centric" approach, focusing on alterations in neurotransmitter systems and synapse cytoarchitecture. However, multiple lines of evidence coming from genetics and systems biology approaches suggest that apart from neurons, oligodendrocytes and potentially other glia are affected from schizophrenia risk loci. Neurobiological abnormalities linked with genetic association signal could identify abnormalities that are more likely to be primary, versus environmentally induced changes or downstream events. Here, we summarize genetic data that support the involvement of oligodendrocytes in schizophrenia, providing additional evidence for a causal role with the disease. Given the undeniable evidence of both neuronal and glial abnormalities in schizophrenia, we propose a neuro-glial model that invokes abnormalities at the node of Ranvier as a functional unit in the etiopathogenesis of the disease. PMID- 24478630 TI - Differential effects on KCC2 expression and spasticity of ALS and traumatic injuries to motoneurons. AB - Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease manifested by progressive muscle atrophy and paralysis due to the loss of upper and lower motoneurons (MN). Spasticity appears in ALS patients leading to further disabling consequences. Loss of the inhibitory tone induced by downregulation of the potassium chloride cotransporter 2 (KCC2) in MN has been proposed to importantly contribute to the spastic behavior after spinal cord injury (SCI). The aim of the present study was to test whether the alterations in the expression of KCC2 are linked to the appearance of spasticity in the SOD(G93A) ALS murine model. We compared SOD(G93A) mice to wild type mice subjected to SCI to mimic the spinal MN disconnection from motor descending pathways, and to sciatic nerve lesion to mimic the loss of MN connectivity to muscle. Electrophysiological results show that loss of motor function is observed at presymptomatic stage (8 weeks) in SOD(G93A) mice but hyperreflexia and spasticity do not appear until a late stage (16 weeks). However, KCC2 was not downregulated despite MN suffered disconnection both from muscles and upper MNs. Further experiments revealed decreased gephyrin expression, as a general marker of inhibitory systems, accompanied by a reduction in the number of Renshaw interneurons. Moreover, 5-HT fibers were increased in the ventral horn of the lumbar spinal cord at late stage of disease progression in SOD1(G93A) mice. Taken together, the present results indicate that spasticity appears late in the ALS model, and may be mediated by a decrease in inhibitory interneurons and an increase of 5-HT transmission, while the absence of down regulation of KCC2 could rather indicate an inability of MNs to respond to insults. PMID- 24478632 TI - GABAergic striatal neurons project dendrites and axons into the postnatal subventricular zone leading to calcium activity. AB - GABA regulates the behavior of neuroblasts and neural progenitor cells in the postnatal neurogenic subventricular zone (SVZ) through GABAA receptor (GABAAR) mediated calcium increases. However, the source of GABA necessary for sufficient GABAAR-mediated depolarization and calcium increase has remained speculative. Here, we explored whether GABAergic striatal neurons functionally connect with SVZ cells. Using patch clamp recordings or single cell electroporation, striatal neurons along the SVZ were filled with a fluorescent dye revealing that they send both dendrites and axons into the SVZ. About 93% of the recorded neurons were medium spiny or aspiny GABAergic neurons and each neuron sent 3-4 processes into the SVZ covering ~56 MUm. Using calcium imaging, we found that depolarization of striatal neurons led to increased calcium activity in SVZ cells that were mediated by GABAAR activation. Collectively, these findings undercover a novel mode of signaling in the SVZ providing a mechanism of brain activity-mediated regulation of postnatal neurogenesis through GABAergic striatal activity. PMID- 24478633 TI - The endogenous peptide antisecretory factor promotes tonic GABAergic signaling in CA1 stratum radiatum interneurons. AB - Tonic GABAergic inhibition regulates neuronal excitability and has been implicated to be involved in both neurological and psychiatric diseases. We have previously shown that the endogenous peptide antisecretory factor (AF) decreases phasic GABAergic inhibition onto pyramidal CA1 neurons. In the present study, using whole-cell patch-clamp recordings, we investigated the mechanisms behind this disinhibition of CA1 pyramidal neurons by AF. We found that application of AF to acute rat hippocampal slices resulted in a reduction of the frequency, but not of the amplitude, of spontaneous inhibitory postsynaptic currents (sIPSCs) in CA1 pyramidal neurons. Miniature inhibitory postsynaptic currents (mIPSCs), recorded in the presence of tetrodotoxin (TTX), were however not affected by AF, neither in CA1 pyramidal cells, nor in stratum radiatum interneurons. Instead, AF caused an increase of the tonic GABAA current in stratum radiatum interneurons, leaving the tonic GABAergic transmission in CA1 pyramidal cells unaffected. These results show that the endogenous peptide AF enhances tonic, but not phasic, GABAergic signaling in CA1 stratum radiatum interneurons, without affecting tonic GABAergic signaling in CA1 pyramidal neurons. We suggest that this increased tonic GABAergic signaling in GABAergic interneurons could be a mechanism for the AF-mediated disinhibition of pyramidal neurons. PMID- 24478631 TI - Genetic dissection of GABAergic neural circuits in mouse neocortex. AB - Diverse and flexible cortical functions rely on the ability of neural circuits to perform multiple types of neuronal computations. GABAergic inhibitory interneurons significantly contribute to this task by regulating the balance of activity, synaptic integration, spiking, synchrony, and oscillation in a neural ensemble. GABAergic interneurons display a high degree of cellular diversity in morphology, physiology, connectivity, and gene expression. A considerable number of subtypes of GABAergic interneurons diversify modes of cortical inhibition, enabling various types of information processing in the cortex. Thus, comprehensively understanding fate specification, circuit assembly, and physiological function of GABAergic interneurons is a key to elucidate the principles of cortical wiring and function. Recent advances in genetically encoded molecular tools have made a breakthrough to systematically study cortical circuitry at the molecular, cellular, circuit, and whole animal levels. However, the biggest obstacle to fully applying the power of these to analysis of GABAergic circuits was that there were no efficient and reliable methods to express them in subtypes of GABAergic interneurons. Here, I first summarize cortical interneuron diversity and current understanding of mechanisms, by which distinct classes of GABAergic interneurons are generated. I then review recent development in genetically encoded molecular tools for neural circuit research, and genetic targeting of GABAergic interneuron subtypes, particularly focusing on our recent effort to develop and characterize Cre/CreER knockin lines. Finally, I highlight recent success in genetic targeting of chandelier cells, the most unique and distinct GABAergic interneuron subtype, and discuss what kind of questions need to be addressed to understand development and function of cortical inhibitory circuits. PMID- 24478635 TI - N2A: a computational tool for modeling from neurons to algorithms. AB - The exponential increase in available neural data has combined with the exponential growth in computing ("Moore's law") to create new opportunities to understand neural systems at large scale and high detail. The ability to produce large and sophisticated simulations has introduced unique challenges to neuroscientists. Computational models in neuroscience are increasingly broad efforts, often involving the collaboration of experts in different domains. Furthermore, the size and detail of models have grown to levels for which understanding the implications of variability and assumptions is no longer trivial. Here, we introduce the model design platform N2A which aims to facilitate the design and validation of biologically realistic models. N2A uses a hierarchical representation of neural information to enable the integration of models from different users. N2A streamlines computational validation of a model by natively implementing standard tools in sensitivity analysis and uncertainty quantification. The part-relationship representation allows both network-level analysis and dynamical simulations. We will demonstrate how N2A can be used in a range of examples, including a simple Hodgkin-Huxley cable model, basic parameter sensitivity of an 80/20 network, and the expression of the structural plasticity of a growing dendrite and stem cell proliferation and differentiation. PMID- 24478634 TI - The olivo-cerebellar system: a key to understanding the functional significance of intrinsic oscillatory brain properties. AB - The reflexological view of brain function (Sherrington, 1906) has played a crucial role in defining both the nature of connectivity and the role of the synaptic interactions among neuronal circuits. One implicit assumption of this view, however, has been that CNS function is fundamentally driven by sensory input. This view was questioned as early as the beginning of the last century when a possible role for intrinsic activity in CNS function was proposed by Thomas Graham Brow (Brown, 1911, 1914). However, little progress was made in addressing intrinsic neuronal properties in vertebrates until the discovery of calcium conductances in vertebrate central neurons leading dendritic electroresponsiveness (Llinas and Hess, 1976; Llinas and Sugimori, 1980a,b) and subthreshold neuronal oscillation in mammalian inferior olive (IO) neurons (Llinas and Yarom, 1981a,b). This happened in parallel with a similar set of findings concerning invertebrate neuronal system (Marder and Bucher, 2001). The generalization into a more global view of intrinsic rhythmicity, at forebrain level, occurred initially with the demonstration that the thalamus has similar oscillatory properties (Llinas and Jahnsen, 1982) and the ionic properties responsible for some oscillatory activity were, in fact, similar to those in the IO (Jahnsen and Llinas, 1984; Llinas, 1988). Thus, lending support to the view that not only motricity, but cognitive properties, are organized as coherent oscillatory states (Pare et al., 1992; Singer, 1993; Hardcastle, 1997; Llinas et al., 1998; Varela et al., 2001). PMID- 24478636 TI - Genesis of interictal spikes in the CA1: a computational investigation. AB - Interictal spikes (IISs) are spontaneous high amplitude, short time duration <400 ms events often observed in electroencephalographs (EEG) of epileptic patients. In vitro analysis of resected mesial temporal lobe tissue from patients with refractory temporal lobe epilepsy has revealed the presence of IIS in the CA1 subfield. In this paper, we develop a biophysically relevant network model of the CA1 subfield and investigate how changes in the network properties influence the susceptibility of CA1 to exhibit an IIS. We present a novel template based approach to identify conditions under which synchronization of paroxysmal depolarization shift (PDS) events evoked in CA1 pyramidal (Py) cells can trigger an IIS. The results from this analysis are used to identify the synaptic parameters of a minimal network model that is capable of generating PDS in response to afferent synaptic input. The minimal network model parameters are then incorporated into a detailed network model of the CA1 subfield in order to address the following questions: (1) How does the formation of an IIS in the CA1 depend on the degree of sprouting (recurrent connections) between the CA1 Py cells and the fraction of CA3 Shaffer collateral (SC) connections onto the CA1 Py cells? and (2) Is synchronous afferent input from the SC essential for the CA1 to exhibit IIS? Our results suggest that the CA1 subfield with low recurrent connectivity (absence of sprouting), mimicking the topology of a normal brain, has a very low probability of producing an IIS except when a large fraction of CA1 neurons (>80%) receives a barrage of quasi-synchronous afferent input (input occurring within a temporal window of <=24 ms) via the SC. However, as we increase the recurrent connectivity of the CA1 (P sprout > 40); mimicking sprouting in a pathological CA1 network, the CA1 can exhibit IIS even in the absence of a barrage of quasi-synchronous afferents from the SC (input occurring within temporal window >80 ms) and a low fraction of CA1 Py cells (~30%) receiving SC input. Furthermore, we find that in the presence of Poisson distributed random input via SC, the CA1 network is able to generate spontaneous periodic IISs (~3 Hz) for high degrees of recurrent Py connectivity (P sprout > 70). We investigate the conditions necessary for this phenomenon and find that spontaneous IISs closely depend on the degree of the network's intrinsic excitability. PMID- 24478637 TI - Compensatory changes in cortical resource allocation in adults with hearing loss. AB - Hearing loss has been linked to many types of cognitive decline in adults, including an association between hearing loss severity and dementia. However, it remains unclear whether cortical re-organization associated with hearing loss occurs in early stages of hearing decline and in early stages of auditory processing. In this study, we examined compensatory plasticity in adults with mild-moderate hearing loss using obligatory, passively-elicited, cortical auditory evoked potentials (CAEP). High-density EEG elicited by speech stimuli was recorded in adults with hearing loss and age-matched normal hearing controls. Latency, amplitude and source localization of the P1, N1, P2 components of the CAEP were analyzed. Adults with mild-moderate hearing loss showed increases in latency and amplitude of the P2 CAEP relative to control subjects. Current density reconstructions revealed decreased activation in temporal cortex and increased activation in frontal cortical areas for hearing-impaired listeners relative to normal hearing listeners. Participants' behavioral performance on a clinical test of speech perception in noise was significantly correlated with the increases in P2 latency. Our results indicate that changes in cortical resource allocation are apparent in early stages of adult hearing loss, and that these passively-elicited cortical changes are related to behavioral speech perception outcome. PMID- 24478638 TI - What is a melody? On the relationship between pitch and brightness of timbre. AB - Previous studies showed that the perceptual processing of sound sequences is more efficient when the sounds vary in pitch than when they vary in loudness. We show here that sequences of sounds varying in brightness of timbre are processed with the same efficiency as pitch sequences. The sounds used consisted of two simultaneous pure tones one octave apart, and the listeners' task was to make same/different judgments on pairs of sequences varying in length (one, two, or four sounds). In one condition, brightness of timbre was varied within the sequences by changing the relative level of the two pure tones. In other conditions, pitch was varied by changing fundamental frequency, or loudness was varied by changing the overall level. In all conditions, only two possible sounds could be used in a given sequence, and these two sounds were equally discriminable. When sequence length increased from one to four, discrimination performance decreased substantially for loudness sequences, but to a smaller extent for brightness sequences and pitch sequences. In the latter two conditions, sequence length had a similar effect on performance. These results suggest that the processes dedicated to pitch and brightness analysis, when probed with a sequence-discrimination task, share unexpected similarities. PMID- 24478639 TI - DC-shifts in amplitude in-field generated by an oscillatory interference model of grid cell firing. AB - Oscillatory interference models propose a mechanism by which the spatial firing pattern of grid cells can arise from the interaction of multiple oscillators that shift in relative phase. These models produce aspects of the physiological data such as the phase precession dynamics observed in grid cells. However, existing oscillatory interference models did not predict the in-field DC shifts in the membrane potential of grid cells that have been observed during intracellular recordings in navigating animals. Here, we demonstrate that DC shifts can be generated in an oscillatory interference model when half-wave rectified oscillatory inputs are summed by a leaky integrate-and-fire neuron with a long membrane decay constant (100 ms). The non-linear mean of the half-wave rectified input signal is reproduced in the grid cell's membrane potential trace producing the DC shift within field. For shorter values of the decay constant integration is more effective if the input signal, comprising input from 6 head direction selective populations, is temporally spread during in-field epochs; this requires that the head direction selective populations act as velocity controlled oscillators with baseline oscillations that are phase offset from one another. The resulting simulated membrane potential matches several properties of the empirical intracellular recordings, including: in-field DC-shifts, theta-band oscillations, phase precession of both membrane potential oscillations and grid cell spiking activity relative to network theta and a stronger correlation between DC-shift amplitude and firing-rate than between theta-band oscillation amplitude and firing-rate. This work serves to demonstrate that oscillatory interference models can account for the DC shifts in the membrane potential observed during intracellular recordings of grid cells without the need to appeal to attractor dynamics. PMID- 24478640 TI - Transcranial direct current stimulation: five important issues we aren't discussing (but probably should be). AB - Transcranial Direct Current Stimulation (tDCS) is a neuromodulatory device often publicized for its ability to enhance cognitive and behavioral performance. These enhancement claims, however, are predicated upon electrophysiological evidence and descriptions which are far from conclusive. In fact, a review of the literature reveals a number of important experimental and technical issues inherent with this device that are simply not being discussed in any meaningful manner. In this paper, we will consider five of these topics. The first, inter subject variability, explores the extensive between- and within-group differences found within the tDCS literature and highlights the need to properly examine stimulatory response at the individual level. The second, intra-subject reliability, reviews the lack of data concerning tDCS response reliability over time and emphasizes the importance of this knowledge for appropriate stimulatory application. The third, sham stimulation and blinding, draws attention to the importance (yet relative lack) of proper control and blinding practices in the tDCS literature. The fourth, motor and cognitive interference, highlights the often overlooked body of research that suggests typical behaviors and cognitions undertaken during or following tDCS can impair or abolish the effects of stimulation. Finally, the fifth, electric current influences, underscores several largely ignored variables (such as hair thickness and electrode attachments methods) influential to tDCS electric current density and flow. Through this paper, we hope to increase awareness and start an ongoing dialog of these important issues which speak to the efficacy, reliability, and mechanistic foundations of tDCS. PMID- 24478641 TI - Neural signal for counteracting pre-action bias in the centromedian thalamic nucleus. AB - Most of our daily actions are selected and executed involuntarily under familiar situations by the guidance of internal drives, such as motivation. The behavioral tendency or biasing towards one over others reflects the action-selection process in advance of action execution (i.e., pre-action bias). Facing unexpected situations, however, pre-action bias should be withdrawn and replaced by an alternative that is suitable for the situation (i.e., counteracting bias). To understand the neural mechanism for the counteracting process, we studied the neural activity of the thalamic centromedian (CM) nucleus in monkeys performing GO-NOGO task with asymmetrical or symmetrical reward conditions. The monkeys reacted to GO signal faster in large-reward condition, indicating behavioral bias toward large reward. In contrast, they responded slowly in small-reward condition, suggesting a conflict between internal drive and external demand. We found that neurons in the CM nucleus exhibited phasic burst discharges after GO and NOGO instructions especially when they were associated with small reward. The small-reward preference was positively correlated with the strength of behavioral bias toward large reward. The small-reward preference disappeared when only NOGO action was requested. The timing of activation predicted the timing of action opposed to bias. These results suggest that CM signals the discrepancy between internal pre-action bias and external demand, and mediates the counteracting process-resetting behavioral bias and leading to execution of opposing action. PMID- 24478642 TI - Hormonal influences on neuroimmune responses in the CNS of females. AB - Particular reproductive stages such as lactation impose demands on the female. To cope with these demands, her physiology goes through numerous adaptations, for example, attenuation of immune and stress responses. Hormonal fluctuation during lactation exerts a strong influence, inducing neuroplasticity in the hypothalamus and extrahypothalamic regions, and diminishing the stress and inflammatory responses. Thus, hormones confer decreased vulnerability to the female brain. This mini-review focuses on the adaptations of the immune and stress response during maternity, and on the neuroprotective actions of progesterone and prolactin and their effects on inflammation. The importance of pregnancy and lactation as experimental models to study immune responses and disease is also highlighted. PMID- 24478643 TI - Age at spinal cord injury determines muscle strength. AB - As individuals with spinal cord injury (SCI) age they report noticeable deficits in muscle strength, endurance and functional capacity when performing everyday tasks. These changes begin at ~45 years. Here we present a cross-sectional analysis of paralyzed thenar muscle and motor unit contractile properties in two datasets obtained from different subjects who sustained a cervical SCI at different ages (<=46 years) in relation to data from uninjured age-matched individuals. First, completely paralyzed thenar muscles were weaker when C6 SCI occurred at an older age. Muscles were also significantly weaker if the injury was closer to the thenar motor pools (C6 vs. C4). More muscles were strong (>50% uninjured) in those injured at a younger (<=25 years) vs. young age (>25 years), irrespective of SCI level. There was a reduction in motor unit numbers in all muscles tested. In each C6 SCI, only ~30 units survived vs. 144 units in uninjured subjects. Since intact axons only sprout 4-6 fold, the limits for muscle reinnervation have largely been met in these young individuals. Thus, any further reduction in motor unit numbers with time after these injuries will likely result in chronic denervation, and may explain the late-onset muscle weakness routinely described by people with SCI. In a second dataset, paralyzed thenar motor units were more fatigable than uninjured units. This gap widened with age and will reduce functional reserve. Force declines were not due to electromyographic decrements in either group so the site of failure was beyond excitation of the muscle membrane. Together, these results suggest that age at SCI is an important determinant of long-term muscle strength, and fatigability, both of which influence functional capacity. PMID- 24478644 TI - Isolating the delay component of impulsive choice in adolescent rats. AB - Impulsive choice-the preference for small immediate rewards over larger delayed rewards-has been linked to various psychological conditions ranging from behavioral disorders to addiction. These links highlight the critical need to dissect the various components of this multifaceted behavioral trait. Delay discounting tasks allow researchers to study an important factor of this behavior: how the subjective value of a rewards changes over a delay period. However, existing methods of delay discounting include a confound of different reward sizes within the procedure. Here we present a new approach of using a single constant reward size to assess delay discounting. A complementary approach could hold delay constant and assess the utility of changing quantities of a reward. Isolating these behavioral components can advance our ability to explore the behavioral complexity of impulsive choice. We present in detail the methods for isolating delay, and further capitalize on this method by pairing it with a standard peak interval task to test whether individual variation in delay discounting can be explained by differences in perception of time in male and female adolescent rats. We find that rats that were more precise in discriminating time intervals were also less impulsive in their choice. Our data suggest that differences in timing and delay discounting are not causally related, but instead are more likely influenced by a common factor. Further, the mean-level change in our measure between post-natal day 28 and 42 suggests this test may be capturing a developmental change in this factor. In summary, this new method of isolating individual components of impulsive choice (delay or quantity) can be efficiently applied in either adolescent or adult animal models and may help elucidate the mechanisms underlying impulsivity and its links to psychological disorders. PMID- 24478646 TI - An evolutionary perspective on the behavioral consequences of exogenous oxytocin application. AB - Oxytocin (OT) is released in response to social signals, particularly positive ones like eye contact, social touch, sexual behavior, and affiliative vocalizations. Conversely, exogenous delivery of OT has diverse behavioral effects, sometimes promoting affiliative and prosocial behaviors, but sometimes suppressing them. Here, we argue that one unifying interpretation of these diverse effects is to view OT as an evolutionarily conserved physiological signal indicating affiliative interactions and predicting their behavioral consequences. In this model, OT regulates the way information about the social environment accesses the neural circuitry responsible for social behavior, thereby shaping it in sometimes counter intuitive but adaptive ways. Notably, prosociality is not always the most adaptive response to an affiliative signal from another individual. In many circumstances, an asocial or even antisocial response may confer greater fitness benefits. We argue that the behavioral effects of exogenous OT delivery not only parallel the behavioral effects of affiliative interactions, but are themselves adaptive responses to affiliative interactions. In support of this idea, we review recent evidence that OT does not unilaterally enhance social attention, as previously thought, but rather can reduce the typical prioritization of social information at the expense of other information or goals. Such diminished social vigilance may be an adaptive response to affiliative social interactions because it frees attentional resources for the pursuit of other goals. Finally, we predict that OT may mediate other behavioral consequences of social interactions, such as reduced predator vigilance, and argue that this is a rich avenue for future behavioral and neurobiological study. PMID- 24478645 TI - Sleep and protein synthesis-dependent synaptic plasticity: impacts of sleep loss and stress. AB - Sleep has been ascribed a critical role in cognitive functioning. Several lines of evidence implicate sleep in the consolidation of synaptic plasticity and long term memory. Stress disrupts sleep while impairing synaptic plasticity and cognitive performance. Here, we discuss evidence linking sleep to mechanisms of protein synthesis-dependent synaptic plasticity and synaptic scaling. We then consider how disruption of sleep by acute and chronic stress may impair these mechanisms and degrade sleep function. PMID- 24478647 TI - Identification and optogenetic manipulation of memory engrams in the hippocampus. AB - With the accumulation of our knowledge about how memories are formed, consolidated, retrieved, and updated, neuroscience is now reaching a point where discrete memories can be identified and manipulated at rapid timescales. Here, we start with historical studies that lead to the modern memory engram theory. Then, we will review recent advances in memory engram research that combine transgenic and optogenetic approaches to reveal the underlying neuronal substrates sufficient for activating mnemonic processes. We will focus on three concepts: (1) isolating memory engrams at the level of single cells to tag them for subsequent manipulation; (2) testing the sufficiency of these engrams for memory recall by artificially activating them; and (3) presenting new stimuli during the artificial activation of these engrams to induce an association between the two to form a false memory. We propose that hippocampal cells that show activity dependent changes during learning construct a cellular basis for contextual memory engrams. PMID- 24478648 TI - Water associated zero maze: a novel rat test for long term traumatic re experiencing. AB - Often, freezing and startle behaviors in the context of a previously experienced stress are taken as an indication of post-traumatic stress disorder (PTSD)-like symptoms in rats. However, PTSD is characterized by large individual variations of symptoms. In order to take into consideration the complex and long term distinctive variations in effects of trauma exposure additional behavioral measures are required. The current study used a novel behavioral test, the water associated zero maze (WAZM). This test was planned to enable a formation of an association between the context of the maze and an underwater trauma (UWT) or swim stress in order to examine the impact of exposure to the context which immediately precedes a stressful or a traumatic experience on rat's complex behavior. Rats were exposed to the WAZM and immediately after to an UWT or short swim. One month later rats were re-exposed to the context of the WAZM while their behavior was video recorded. Furthermore, c-Fos expression in the amygdala was measured 90 min after this exposure. The results of the current study indicate that the WAZM can be used to discern behavioral changes measured a long time after the actual traumatic or stressful events. Furthermore, the behavioral changes detected were accompanied by changes of c-Fos expression in the amygdala of exposed rats. We suggest that the WAZM can be used to model traumatic memories re-experiencing in rodent models of human stress-related pathologies such as PTSD. PMID- 24478649 TI - The neural correlates of risk propensity in males and females using resting-state fMRI. AB - Men are more risk prone than women, but the underlying basis remains unclear. To investigate this question, we developed a trait-like measure of risk propensity which we correlated with resting-state functional connectivity to identify sex differences. Specifically, we used short- and long-range functional connectivity densities to identify associated brain regions and examined their functional connectivities in resting-state functional magnetic resonance imaging (fMRI) data collected from a large sample of healthy young volunteers. We found that men had a higher level of general risk propensity (GRP) than women. At the neural level, although they shared a common neural correlate of GRP in a network centered at the right inferior frontal gyrus, men and women differed in a network centered at the right secondary somatosensory cortex, which included the bilateral dorsal anterior/middle insular cortices and the dorsal anterior cingulate cortex. In addition, men and women differed in a local network centered at the left inferior orbitofrontal cortex. Most of the regions identified by this resting-state fMRI study have been previously implicated in risk processing when people make risky decisions. This study provides a new perspective on the brain-behavioral relationships in risky decision making and contributes to our understanding of sex differences in risk propensity. PMID- 24478650 TI - Amygdala activation and GABAergic gene expression in hippocampal sub-regions at the interplay of stress and spatial learning. AB - Molecular processes in GABAergic local circuit neurons critically contribute to information processing in the hippocampus and to stress-induced activation of the amygdala. In the current study, we determined expression changes in GABA-related factors induced in subregions of the dorsal hippocampus as well as in the BLA of rats 5 h after spatial learning in a Morris water maze (MWM), using laser microdissection and quantitative real-time PCR. Spatial learning resulted in highly selective pattern of changes in hippocampal subregions: gene expression levels of neuropeptide Y (NPY) were reduced in the hilus of the dentate gyrus (DG), whereas somatostatin (SST) was increased in the stratum oriens (SO) of CA3. The GABA-synthesizing enzymes GAD65 and GAD67 as well as the neuropeptide cholecystokinin (CCK) were reduced in SO of CA1. In the BLA, expression of GAD65 and GAD67 were reduced compared to a handled Control group. These expression patterns were further compared to alterations in a group of rats that have been exposed to the water maze but were not provided with an invisible escape platform. In this Water Exposure group, no expression changes were observed in any of the hippocampal subregions, but a differential regulation of all selected target genes was evident in the BLA. These findings suggest that expression changes of GABAergic factors in the hippocampus are associated with spatial learning, while additional stress effects modulate expression alterations in the BLA. Indeed, while in both experimental groups plasma corticosterone (CORT) levels were enhanced, only Water Exposure stress activated the basolateral amygdala (BLA), as indicated by increased levels of phosphorylated ERK 1/2. Altered GABAergic function in the BLA may thus contribute to memory consolidation in the hippocampus, in relation to levels of stress and emotionality associated with the experience. PMID- 24478651 TI - Neurosonological Examination: A Non-Invasive Approach for the Detection of Cerebrovascular Impairment in AD. AB - There has been a growing interest in vascular impairment associated with Alzheimer's disease (AD). This interest was stimulated by the findings of higher incidence of vascular risk factors in AD. Signs of vascular impairment were investigated notably in the field of imaging methods. Our aim was to explore ultrasonographic studies of extra- and intracranial vessels in patients with AD and mild cognitive impairment (MCI) and define implications for diagnosis, treatment, and prevention of the disease. The most frequently studied parameters with extracranial ultrasound are intima-media thickness in common carotid artery, carotid atherosclerosis, and total cerebral blood flow. The transcranial ultrasound concentrates mostly on flow velocities, pulsatility indices, cerebrovascular reserve capacity, and cerebral microembolization. Studies suggest that there is morphological and functional impairment of cerebral circulation in AD compared to healthy subjects. Ultrasound as a non-invasive method could be potentially useful in identifying individuals in a higher risk of progression of cognitive decline. PMID- 24478652 TI - Stress leads to prosocial action in immediate need situations. AB - Stress clearly influences decision making, but the effects are complex. This review focuses on the potential for stress to promote prosocial decisions, serving others at a temporary cost to the self. Recent work has shown altruistic responses under stress, particularly when the target's need is salient. We discuss potential mechanisms for these effects, including emotional contagion and offspring care mechanisms. These neurobiological mechanisms may promote prosocial even heroic-action, particularly when an observer knows the appropriate response and can respond to a target in need. The effects of stress on behavior are not only negative, they can be adaptive and altruistic under conditions that promote survival and well-being at the individual and group level. PMID- 24478653 TI - The neuronal and molecular basis of quinine-dependent bitter taste signaling in Drosophila larvae. AB - The sensation of bitter substances can alert an animal that a specific type of food is harmful and should not be consumed. However, not all bitter compounds are equally toxic and some may even be beneficial in certain contexts. Thus, taste systems in general may have a broader range of functions than just in alerting the animal. In this study we investigate bitter sensing and processing in Drosophila larvae using quinine, a substance perceived by humans as bitter. We show that behavioral choice, feeding, survival, and associative olfactory learning are all directly affected by quinine. On the cellular level, we show that 12 gustatory sensory receptor neurons that express both GR66a and GR33a are required for quinine-dependent choice and feeding behavior. Interestingly, these neurons are not necessary for quinine-dependent survival or associative learning. On the molecular receptor gene level, the GR33a receptor, but not GR66a, is required for quinine-dependent choice behavior. A screen for gustatory sensory receptor neurons that trigger quinine-dependent choice behavior revealed that a single GR97a receptor gene expressing neuron located in the peripheral terminal sense organ is partially necessary and sufficient. For the first time, we show that the elementary chemosensory system of the Drosophila larva can serve as a simple model to understand the neuronal basis of taste information processing on the single cell level with respect to different behavioral outputs. PMID- 24478654 TI - In your eyes only: deficits in executive functioning after frontal TMS reflect in eye movements. AB - This study investigated the roles of the right and left dorsolateral prefrontal (rDLPFC, lDLPFC) and the medial frontal cortex (MFC) in executive functioning using a theta burst transcranial magnetic stimulation (TMS) approach. Healthy subjects solved two visual search tasks: a number search task with low cognitive demands, and a number and letter search task with high cognitive demands. To observe how subjects solved the tasks, we assessed their behavior with and without TMS using eye movements when subjects were confronted with specific executive demands. To observe executive functions, we were particularly interested in TMS-induced changes in visual exploration strategies found to be associated with good or bad performance in a control condition without TMS stimulation. TMS left processing time unchanged in both tasks. Inhibition of the rDLPFC resulted in a decrease in anticipatory fixations in the number search task, i.e., a decrease in a good strategy in this low demand task. This was paired with a decrease in stimulus fixations. Together, these results point to a role of the rDLPFC in planning and response selection. Inhibition of the lDLPFC and the MFC resulted in an increase in anticipatory fixations in the number and letter search task, i.e., an increase in the application of a good strategy in this task. We interpret these results as a compensatory strategy to account for TMS-induced deficits in attentional switching when faced with high switching demands. After inhibition of the lDLPFC, an increase in regressive fixations was found in the number and letter search task. In the context of high working memory demands, this strategy appears to support TMS-induced working memory deficits. Combining an experimental TMS approach with the recording of eye movements proved sensitive to discrete decrements of executive functions and allows pinpointing the functional organization of the frontal lobes. PMID- 24478655 TI - VTA GABA neurons modulate specific learning behaviors through the control of dopamine and cholinergic systems. AB - The mesolimbic reward system is primarily comprised of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) as well as their afferent and efferent connections. This circuitry is essential for learning about stimuli associated with motivationally-relevant outcomes. Moreover, addictive drugs affect and remodel this system, which may underlie their addictive properties. In addition to dopamine (DA) neurons, the VTA also contains approximately 30% gamma aminobutyric acid (GABA) neurons. The task of signaling both rewarding and aversive events from the VTA to the NAc has mostly been ascribed to DA neurons and the role of GABA neurons has been largely neglected until recently. GABA neurons provide local inhibition of DA neurons and also long-range inhibition of projection regions, including the NAc. Here we review studies using a combination of in vivo and ex vivo electrophysiology, pharmacogenetic and optogenetic manipulations that have characterized the functional neuroanatomy of inhibitory circuits in the mesolimbic system, and describe how GABA neurons of the VTA regulate reward and aversion-related learning. We also discuss pharmacogenetic manipulation of this system with benzodiazepines (BDZs), a class of addictive drugs, which act directly on GABAA receptors located on GABA neurons of the VTA. The results gathered with each of these approaches suggest that VTA GABA neurons bi-directionally modulate activity of local DA neurons, underlying reward or aversion at the behavioral level. Conversely, long-range GABA projections from the VTA to the NAc selectively target cholinergic interneurons (CINs) to pause their firing and temporarily reduce cholinergic tone in the NAc, which modulates associative learning. Further characterization of inhibitory circuit function within and beyond the VTA is needed in order to fully understand the function of the mesolimbic system under normal and pathological conditions. PMID- 24478656 TI - Detecting analogies unconsciously. AB - Analogies may arise from the conscious detection of similarities between a present and a past situation. In this functional magnetic resonance imaging study, we tested whether young volunteers would detect analogies unconsciously between a current supraliminal (visible) and a past subliminal (invisible) situation. The subliminal encoding of the past situation precludes awareness of analogy detection in the current situation. First, participants encoded subliminal pairs of unrelated words in either one or nine encoding trials. Later, they judged the semantic fit of supraliminally presented new words that either retained a previously encoded semantic relation ("analog") or not ("broken analog"). Words in analogs versus broken analogs were judged closer semantically, which indicates unconscious analogy detection. Hippocampal activity associated with subliminal encoding correlated with the behavioral measure of unconscious analogy detection. Analogs versus broken analogs were processed with reduced prefrontal but enhanced medial temporal activity. We conclude that analogous episodes can be detected even unconsciously drawing on the episodic memory network. PMID- 24478657 TI - Reduced expression of nogo-a leads to motivational deficits in rats. AB - Nogo-A is an important neurite growth-regulatory protein in the adult and developing nervous system. Mice lacking Nogo-A, or rats with neuronal Nogo-A deficiency, exhibit behavioral abnormalities such as impaired short-term memory, decreased pre-pulse inhibition, and behavioral inflexibility. In the current study, we extended the behavioral profile of the Nogo-A deficient rat line with respect to reward sensitivity and motivation, and determined the concentrations of the monoamines dopamine and serotonin in the prefrontal cortex (PFC), dorsal striatum (dSTR), and nucleus accumbens (NAcc). Using a limited access consumption task, we found similar intake of a sweet condensed milk solution following ad libitum or restricted feeding in wild-type and Nogo-A deficient rats, indicating normal reward sensitivity and translation of hunger into feeding behavior. When tested for motivation in a spontaneous progressive ratio task, Nogo-A deficient rats exhibited lower break points and tended to have lower "highest completed ratios." Further, under extinction conditions responding ceased substantially earlier in these rats. Finally, in the PFC we found increased tissue levels of serotonin, while dopamine was unaltered. Dopamine and serotonin levels were also unaltered in the dSTR and the NAcc. In summary, these results suggest a role for Nogo-A regulated processes in motivated behavior and related neurochemistry. The behavioral pattern observed resembles aspects of the negative symptomatology of schizophrenia. PMID- 24478658 TI - Composition of agarose substrate affects behavioral output of Drosophila larvae. AB - In the last decade the Drosophila larva has evolved into a simple model organism offering the opportunity to integrate molecular genetics with systems neuroscience. This led to a detailed understanding of the neuronal networks for a number of sensory functions and behaviors including olfaction, vision, gustation and learning and memory. Typically, behavioral assays in use exploit simple Petri dish setups with either agarose or agar as a substrate. However, neither the quality nor the concentration of the substrate is generally standardized across these experiments and there is no data available on how larval behavior is affected by such different substrates. Here, we have investigated the effects of different agarose concentrations on several larval behaviors. We demonstrate that agarose concentration is an important parameter, which affects all behaviors tested: preference, feeding, learning and locomotion. Larvae can discriminate between different agarose concentrations, they feed differently on them, they can learn to associate an agarose concentration with an odor stimulus and change locomotion on a substrate of higher agarose concentration. Additionally, we have investigated the effect of agarose concentration on three quinine based behaviors: preference, feeding and learning. We show that in all cases examined the behavioral output changes in an agarose concentration-dependent manner. Our results suggest that comparisons between experiments performed on substrates differing in agarose concentration should be done with caution. It should be taken into consideration that the agarose concentration can affect the behavioral output and thereby the experimental outcomes per se potentially due to the initiation of an escape response or changes in foraging behavior on more rigid substrates. PMID- 24478659 TI - Not all effort is equal: the role of the anterior cingulate cortex in different forms of effort-reward decisions. AB - The rat anterior cingulate cortex (ACC) mediates effort-based decision making when the task requires the physical effort of climbing a ramp. Normal rats will readily climb a barrier leading to high reward whereas rats with ACC lesions will opt instead for an easily obtained small reward. The present study explored whether the role of ACC in cost-benefit decisions extends beyond climbing by testing its role in ramp climbing as well as two novel cost-benefit decision tasks, one involving the physical effort of lifting weights and the other the emotional cost of overcoming fear (i.e., "courage"). As expected, rats with extensive ACC lesions tested on a ramp-climbing task were less likely to choose a high-reward/high-effort arm than sham controls. However, during the first few trials, lesioned rats were as likely as controls to initially turn into the high reward arm (HRA) but far less likely to actually climb the barrier, suggesting that the role of the ACC is not in deciding which course of action to pursue, but rather in maintaining a course of action in the face of countervailing forces. In the effort-reward decision task involving weight lifting, some lesion animals behaved like controls while others avoided the HRA. However, the results were not statistically significant and a follow-up study using incremental increasing effort failed to show any difference between lesion and control groups. The results suggest that the ACC is not needed for effort-reward decisions involving weight lifting but may affect motor abilities. Finally, a courage task explored the willingness of rats to overcome the fear of crossing an open, exposed arm to obtain a high reward. Both sham and ACC-lesioned animals exhibited equal tendencies to enter the open arm. However, whereas sham animals gradually improved on the task, ACC-lesioned rats did not. Taken together, the results suggest that the role of the ACC in effort-reward decisions may be limited to certain tasks. PMID- 24478660 TI - Peritraumatic startle response predicts the vulnerability to develop PTSD-like behaviors in rats: a model for peritraumatic dissociation. AB - Peritraumatic dissociation, a state characterized by alteration in perception and reduced awareness of surroundings, is considered to be a risk factor for the development of post-traumatic stress disorder (PTSD). However, the predictive ability of peritraumatic dissociation is questioned for the inconsistent results in different time points of assessment. The startle reflex is an objective behavioral measurement of defensive response to abrupt and intense sensory stimulus of surroundings, with potential to be used as an assessment on the dissociative status in both humans and rodents. The present study examined the predictive effect of acoustic startle response (ASR) in different time points around the traumatic event in an animal model of PTSD. The PTSD-like symptoms, including hyperarousal, avoidance, and contextual fear, were assessed 2-3 weeks post-trauma. The results showed that (1) the startle amplitude attenuated immediate after intense footshock in almost half of the stress animals, and (2) the attenuated startle responses at 1 h but not 24 h after stress predicted the development of severe PTSD-like symptoms. These data indicate that the startle alteration at the immediate period after trauma, including 1 h, is more important in PTSD prediction than 24 h after trauma. Our study also suggests that the startle attenuation immediate after intense stress may serve as an objective measurement of peritraumatic dissociation in rats. PMID- 24478661 TI - Effects of caffeine or RX821002 in rats with a neonatal ventral hippocampal lesion. AB - Rats with a neonatal ventral hippocampal lesion (NVHL) are used to model schizophrenia. They show enhanced locomotion and difficulties in learning after puberty. Such behavioral modifications are strengthened by dopaminergic psychostimulant drugs, which is also relevant for schizophrenia because illustrating its dopaminergic facet. But it remains questionable that only dopaminergic drugs elicit such effects. The behavioral effects could simply represent a non specific arousal, in which case NVHL rats should also be hyper responsive to other vigilance enhancing drugs. We administered an adenosine (caffeine) or an adrenaline receptor antagonist, (RX821002) at doses documented to modify alertness of rats, respectively 5 mg/kg and 1 mg/kg. Rats were selected prior to the experiments using magnetic resonance imaging (MRI). Each group contained typical and similar NVHL lesions. They were compared to sham lesioned rats. We evaluated locomotion in a new environment and the capacity to remember a visual or acoustic cue that announced the occurrence of food. Both caffeine and RX82100 enhanced locomotion in the novel environment, particularly in NVHL rats. But, RX82100 had a biphasic effect on locomotion, consisting of an initial reduction preceding the enhancement. It was independent of the lesion. Caffeine did not modify the learning performance of NVHL rats. But, RX821002 was found to facilitate learning. Patients tend to intake much more caffeine than healthy people, which has been interpreted as a means to counter some cognitive deficits. This idea was not validated with the present results. But adrenergic drugs could be helpful for attenuating some of their cognitive deficits. PMID- 24478662 TI - Left-right compatibility in the processing of trading verbs. AB - The research investigating the nature of cognitive processes involved in the representation of economical outcomes is growing. Within this research, the mental accounting model proposes that individuals may well use cognitive operations to organize, evaluate, and keep track of their financial activities (Thaler, 1999). Here we wanted to test this hypothesis by asking to a group of participants to detect a syntax mistake of verbs indicating incoming and going out activities related to economical profit (trading verbs), swapping (swapping verbs) and thinking (thinking verbs). We reported a left-right compatibility for trading verbs (i.e., participants were faster with their right hand while detecting verb referring to a monetary gain with respect to a monetary loss; and faster with their left hand while detecting a monetary loss with respect to a monetary gain). However, this pattern of result was not reported while detecting swapping verbs. Results are discussed taking into account the mental accounting theory as well as to the spatial mapping of valence hypothesis. PMID- 24478663 TI - Effect of meditation on cognitive functions in context of aging and neurodegenerative diseases. AB - Effect of different meditation practices on various aspects of mental and physical health is receiving growing attention. The present paper reviews evidence on the effects of several mediation practices on cognitive functions in the context of aging and neurodegenerative diseases. The effect of meditation in this area is still poorly explored. Seven studies were detected through the databases search, which explores the effect of meditation on attention, memory, executive functions, and other miscellaneous measures of cognition in a sample of older people and people suffering from neurodegenerative diseases. Overall, reviewed studies suggested a positive effect of meditation techniques, particularly in the area of attention, as well as memory, verbal fluency, and cognitive flexibility. These findings are discussed in the context of MRI studies suggesting structural correlates of the effects. Meditation can be a potentially suitable non-pharmacological intervention aimed at the prevention of cognitive decline in the elderly. However, the conclusions of these studies are limited by their methodological flaws and differences of various types of meditation techniques. Further research in this direction could help to verify the validity of the findings and clarify the problematic aspects. PMID- 24478664 TI - Frontopolar cortex and decision-making efficiency: comparing brain activity of experts with different professional background during an exploration-exploitation task. AB - An optimal balance between efficient exploitation of available resources and creative exploration of alternatives is critical for adaptation and survival. Previous studies associated these behavioral drives with, respectively, the dopaminergic mesocorticolimbic system and frontopolar-intraparietal networks. We study the activation of these systems in two age and gender-matched groups of experienced decision-makers differing in prior professional background, with the aim to understand the neural bases of individual differences in decision-making efficiency (performance divided by response time). We compare brain activity of entrepreneurs (who currently manage the organization they founded based on their venture idea) and managers (who are constantly involved in making strategic decisions but have no venture experience) engaged in a gambling-task assessing exploitative vs. explorative decision-making. Compared with managers, entrepreneurs showed higher decision-making efficiency, and a stronger activation in regions of frontopolar cortex (FPC) previously associated with explorative choice. Moreover, activity across a network of regions previously linked to explore/exploit tradeoffs explained individual differences in choice efficiency. These results suggest new avenues for the study of individual differences in the neural antecedents of efficient decision-making. PMID- 24478665 TI - Insular dysfunction within the salience network is associated with severity of symptoms and aberrant inter-network connectivity in major depressive disorder. AB - Major depressive disorder (MDD) is characterized by altered intrinsic functional connectivity within (intra-iFC) intrinsic connectivity networks (ICNs), such as the Default Mode- (DMN), Salience- (SN) and Central Executive Network (CEN). It has been proposed that aberrant switching between DMN-mediated self-referential and CEN-mediated goal-directed cognitive processes might contribute to MDD, possibly explaining patients' difficulties to disengage the processing of self focused, often negatively biased thoughts. Recently, it has been shown that the right anterior insula (rAI) within the SN is modulating DMN/CEN interactions. Since structural and functional alterations within the AI have been frequently reported in MDD, we hypothesized that aberrant intra-iFC in the SN's rAI is associated with both aberrant iFC between DMN and CEN (inter-iFC) and severity of symptoms in MDD. Twenty-five patients with MDD and 25 healthy controls were assessed using resting-state fMRI (rs-fMRI) and psychometric examination. High model-order independent component analysis (ICA) of rs-fMRI data was performed to identify ICNs including DMN, SN, and CEN. Intra-iFC within and inter-iFC between distinct subsystems of the DMN, SN, and CEN were calculated, compared between groups and correlated with the severity of symptoms. Patients with MDD showed (1) decreased intra-iFC within the SN's rAI, (2) decreased inter-iFC between the DMN and CEN, and (3) increased inter-iFC between the SN and DMN. Moreover, decreased intra-iFC in the SN's rAI was associated with severity of symptoms and aberrant DMN/CEN interactions, with the latter losing significance after correction for multiple comparisons. Our results provide evidence for a relationship between aberrant intra-iFC in the salience network's rAI, aberrant DMN/CEN interactions and severity of symptoms, suggesting a link between aberrant salience mapping, abnormal coordination of DMN/CEN based cognitive processes and psychopathology in MDD. PMID- 24478666 TI - The medial habenula: still neglected. AB - The habenula is a small, bilateral brain structure located at the dorsal end of the diencephalon. This structure sends projections to the dopaminergic striatum and receives inputs from the limbic forebrain, making the habenula a unique modulator of cross-talk between these brain regions. Despite strong interest in the habenula during the seventies and eighties (Herkenham and Nauta, 1977; Beckstead, 1979; Beckstead et al., 1979; Herkenham and Nauta, 1979; Caldecott Hazard et al., 1988), interest waned due to lack of a clearly identifiable functional role. Following Matsumoto and Hikosaka's seminal work on the lateral habenula as a predictor of negative reward in monkeys, the habenula has undergone a resurgence of scientific interest. Matsumoto and Hikosaka demonstrated an increase in habenular neuron firing when monkeys did not receive an expected juice reward (Matsumoto and Hikosaka, 2007). Studies have shown that increased habenular activity inactivates dopaminergic cells in the Rostromedial Tegmental Nucleus (RMTg) through GABAergic mechanisms (Jhou et al., 2009a,b). Additional studies link habenular activity to the regulation of serotonin and norepinephrine, suggesting the habenula modulates multiple brain systems (Strecker and Rosengren, 1989; Amat et al., 2001). These discoveries ushered in a series of new studies that have refocused attention on the lateral habenula and the importance of this small brain structure (Bianco and Wilson, 2009; Jhou et al., 2009a; Matsumoto and Hikosaka, 2009; Sartorius et al., 2010; Savitz et al., 2011). Recently, Geisler and Trimble reviewed this renewed interest in: The Lateral Habenula: No Longer Neglected (Geisler and Trimble, 2008). While the lateral habenula (LHb) has been extensively studied, the anatomically and histochemically distinct medial habenula (MHb) remains largely understudied. This short review argues that the MHb is functionally important and should be studied more aggressively. PMID- 24478667 TI - Fear of negative evaluation modulates electrocortical and behavioral responses when anticipating social evaluative feedback. AB - Cognitive models posit that the fear of negative evaluation (FNE) is a hallmark feature of social anxiety. As such, individuals with high FNE may show biased information processing when faced with social evaluation. The aim of the current study was to examine the neural underpinnings of anticipating and processing social-evaluative feedback, and its correlates with FNE. We used a social judgment paradigm in which female participants (N = 31) were asked to indicate whether they believed to be socially accepted or rejected by their peers. Anticipatory attention was indexed by the stimulus preceding negativity (SPN), while the feedback-related negativity and P3 were used to index the processing of social-evaluative feedback. Results provided evidence of an optimism bias in social peer evaluation, as participants more often predicted to be socially accepted than rejected. Participants with high levels of FNE needed more time to provide their judgments about the social-evaluative outcome. While anticipating social-evaluative feedback, SPN amplitudes were larger for anticipated social acceptance than for social rejection feedback. Interestingly, the SPN during anticipated social acceptance was larger in participants with high levels of FNE. None of the feedback-related brain potentials correlated with the FNE. Together, the results provided evidence of biased information processing in individuals with high levels of FNE when anticipating (rather than processing) social evaluative feedback. The delayed response times in high FNE individuals were interpreted to reflect augmented vigilance imposed by the upcoming social evaluative threat. Possibly, the SPN constitutes a neural marker of this vigilance in females with higher FNE levels, particularly when anticipating social acceptance feedback. PMID- 24478668 TI - Broca's area processes the hierarchical organization of observed action. AB - Broca's area has been suggested as the area responsible for the domain-general hierarchical processing of language and music. Although meaningful action shares a common hierarchical structure with language and music, the role of Broca's area in this domain remains controversial. To address the involvement of Broca's area in the processing action hierarchy, the activation of Broca's area was measured using near-infrared spectroscopy. Measurements were taken while participants watched silent movies that featured hand movements playing familiar and unfamiliar melodies. The unfamiliar melodies were reversed versions of the familiar melodies. Additionally, to investigate the effect of a motor experience on the activation of Broca's area, the participants were divided into well trained and less-trained groups. The results showed that Broca's area in the well trained participants demonstrated a significantly larger activation in response to the hand motion when an unfamiliar melody was played than when a familiar melody was played. However, Broca's area in the less-trained participants did not show a contrast between conditions despite identical abilities of the two participant groups to identify the melodies by watching key pressing actions. These results are consistent with previous findings that Broca's area exhibits increased activation in response to grammatically violated sentences and musically deviated chord progressions as well as the finding that this region does not represent the processing of grammatical structure in less-proficient foreign language speakers. Thus, the current study suggests that Broca's area represents action hierarchy and that sufficiently long motor training is necessary for it to become sensitive to motor syntax. Therefore, the notion that hierarchical processing in Broca's area is a common function shared between language and music may help to explain the role of Broca's area in action perception. PMID- 24478669 TI - Distinct neural systems underlying reduced emotional enhancement for positive and negative stimuli in early Alzheimer's disease. AB - Emotional information is typically better remembered than neutral content, and previous studies suggest that this effect is subserved particularly by the amygdala together with its interactions with the hippocampus. However, it is not known whether amygdala damage affects emotional memory performance at immediate and delayed recall, and whether its involvement is modulated by stimulus valence. Moreover, it is unclear to what extent more distributed neocortical regions involved in e.g., autobiographical memory, also contribute to emotional processing. We investigated these questions in a group of patients with Alzheimer's disease (AD), which affects the amygdala, hippocampus and neocortical regions. Healthy controls (n = 14), patients with AD (n = 15) and its putative prodrome amnestic mild cognitive impairment (n = 11) completed a memory task consisting of immediate and delayed free recall of a list of positive, negative and neutral words. Memory performance was related to brain integrity in region of interest and whole-brain voxel-based morphometry analyses. In the brain behavioral analyses, the left amygdala volume predicted the immediate recall of both positive and negative material, whereas at delay, left and right amygdala volumes were associated with performance with positive and negative words, respectively. Whole-brain analyses revealed additional associations between left angular gyrus integrity and the immediate recall of positive words as well as between the orbitofrontal cortex and the delayed recall of negative words. These results indicate that emotional memory impairments in AD may be underpinned by damage to regions implicated in emotional processing as well as frontoparietal regions, which may exert their influence via autobiographical memories and organizational strategies. PMID- 24478670 TI - The perception of peripersonal space in right and left brain damage hemiplegic patients. AB - Peripersonal space, as opposed to extrapersonal space, is the space that contains reachable objects and in which multisensory and sensorimotor integration is enhanced. Thus, the perception of peripersonal space requires combining information on the spatial properties of the environment with information on the current capacity to act. In support of this, recent studies have provided converging evidences that perceiving objects in peripersonal space activates a neural network overlapping with that subtending voluntary motor action and motor imagery. Other studies have also underlined the dominant role of the right hemisphere (RH) in motor planning and of the left hemisphere (LH) in on-line motor guiding, respectively. In the present study, we investigated the effect of a right or left hemiplegia in the perception of peripersonal space. 16 hemiplegic patients with brain damage to the left (LH) or right (RH) hemisphere and eight matched healthy controls performed a color discrimination, a motor imagery and a reachability judgment task. Analyses of response times and accuracy revealed no variation among the three groups in the color discrimination task, suggesting the absence of any specific perceptual or decisional deficits in the patient groups. In contrast, the patient groups revealed longer response times in the motor imagery task when performed in reference to the hemiplegic arm (RH and LH) or to the healthy arm (RH). Moreover, RH group showed longer response times in the reachability judgment task, but only for stimuli located at the boundary of peripersonal space, which was furthermore significantly reduced in size. Considered together, these results confirm the crucial role of the motor system in motor imagery task and the perception of peripersonal space. They also revealed that RH damage has a more detrimental effect on reachability estimates, suggesting that motor planning processes contribute specifically to the perception of peripersonal space. PMID- 24478671 TI - Multiple neural states of representation in short-term memory? It's a matter of attention. AB - Short-term memory (STM) refers to the capacity-limited retention of information over a brief period of time, and working memory (WM) refers to the manipulation and use of that information to guide behavior. In recent years it has become apparent that STM and WM interact and overlap with other cognitive processes, including attention (the selection of a subset of information for further processing) and long-term memory (LTM-the encoding and retention of an effectively unlimited amount of information for a much longer period of time). Broadly speaking, there have been two classes of memory models: systems models, which posit distinct stores for STM and LTM (Atkinson and Shiffrin, 1968; Baddeley and Hitch, 1974); and state-based models, which posit a common store with different activation states corresponding to STM and LTM (Cowan, 1995; McElree, 1996; Oberauer, 2002). In this paper, we will focus on state-based accounts of STM. First, we will consider several theoretical models that postulate, based on considerable behavioral evidence, that information in STM can exist in multiple representational states. We will then consider how neural data from recent studies of STM can inform and constrain these theoretical models. In the process we will highlight the inferential advantage of multivariate, information-based analyses of neuroimaging data (fMRI and electroencephalography (EEG)) over conventional activation-based analysis approaches (Postle, in press). We will conclude by addressing lingering questions regarding the fractionation of STM, highlighting differences between the attention to information vs. the retention of information during brief memory delays. PMID- 24478672 TI - Primacy and recency effects as indices of the focus of attention. AB - Ongoing debate surrounds the capacity and characteristics of the focus of attention. The present study investigates whether a pattern of larger recency effects and smaller primacy effects reported in previous working memory studies is specific to task conditions used in those studies, or generalizes across manipulations of task-demand. Two experiments varied task-demands by requiring participants to remember lists of letters and to then respond to a subsequent two item probe by indicating either the item that was presented later in the list (judgment of recency) or the item was presented earlier (judgment of primacy). Analyses tested the prediction that a WM task emphasizing later items in a list (judgment of recency) would encourage exaggerated recency effects and attenuated primacy effects, while a task emphasizing earlier items (judgment of primacy) would encourage exaggerated primacy effects and attenuated recency effects. Behavioral results from two experiments confirmed this prediction. In contrast to past studies, fMRI contrasts revealed no brain regions where activity was significantly altered by the presence of recency items in the probe, for either task condition. However, presence of the primacy item in the probe significantly influenced activity in frontal lobe brain regions linked to active maintenance, but the location and direction of activation changes varied as a function of task instructions. In sum, two experiments demonstrate that the behavioral and neural signatures of WM, specifically related to primacy and recency effects, are dependent on task-demands. Findings are discussed as they inform models of the structure and capacity of WM. PMID- 24478673 TI - Reduced frontal brain volume in non-treatment-seeking cocaine-dependent individuals: exploring the role of impulsivity, depression, and smoking. AB - In cocaine-dependent patients, gray matter (GM) volume reductions have been observed in the frontal lobes that are associated with the duration of cocaine use. Studies are mostly restricted to treatment-seekers and studies in non treatment-seeking cocaine abusers are sparse. Here, we assessed GM volume differences between 30 non-treatment-seeking cocaine-dependent individuals and 33 non-drug using controls using voxel-based morphometry. Additionally, within the group of non-treatment-seeking cocaine-dependent individuals, we explored the role of frequently co-occurring features such as trait impulsivity (Barratt Impulsivity Scale, BIS), smoking, and depressive symptoms (Beck Depression Inventory), as well as the role of cocaine use duration, on frontal GM volume. Smaller GM volumes in non-treatment-seeking cocaine-dependent individuals were observed in the left middle frontal gyrus. Moreover, within the group of cocaine users, trait impulsivity was associated with reduced GM volume in the right orbitofrontal cortex, the left precentral gyrus, and the right superior frontal gyrus, whereas no effect of smoking severity, depressive symptoms, or duration of cocaine use was observed on regional GM volumes. Our data show an important association between trait impulsivity and frontal GM volumes in cocaine-dependent individuals. In contrast to previous studies with treatment-seeking cocaine dependent patients, no significant effects of smoking severity, depressive symptoms, or duration of cocaine use on frontal GM volume were observed. Reduced frontal GM volumes in non-treatment-seeking cocaine-dependent subjects are associated with trait impulsivity and are not associated with co-occurring nicotine dependence or depression. PMID- 24478674 TI - Hyperschematia after right brain damage: a meaningful entity? AB - In recent years we reported three right-brain-damaged patients, who exhibited a left-sided disprortionate expansion of drawings, both by copying and from memory, contralateral to the side of the hemispheric lesion (Neurology, 67: 1801, 2006, Neurocase 14: 369, 2008). We proposed the term "hyperschematia" for such an expansion, with reference to an interpretation in terms of a lateral leftward distortion of the representation of extra-personal space, with a leftward anisometric expansion (relaxation) of the spatial medium. The symptom-complex shown by right-brain-damaged patients with "hyperschematia" includes: (1) a disproportionate leftward expansion of drawings (with possible addition of details), by copy and from memory (also in clay modeling, in one patient); (2) an overestimation of left lateral extent, when a leftward movement is required, associated in some patients with a perceptual underestimation; (3) unawareness of the disorder; (4) no unilateral spatial neglect. In most right-brain-damaged patients, left "hyperschematia" involves extra-personal space. In one patient the deficit was confined to a body part (left half-face: personal "hyperschematia"). The neural underpinnings of the disorder include damage to the fronto-temporo parietal cortices, and subcortical structures in the right cerebral hemisphere, in the vascular territory of the middle cerebral artery. Here, four novel additional patients are reported. Finally, "hypeschematia" is reconsidered, in its clinical components, the underlying pathological mechanisms, as well as its neural underpinnings. PMID- 24478675 TI - Lexical selection in the semantically blocked cyclic naming task: the role of cognitive control and learning. AB - Studies of semantic interference in language production have provided evidence for a role of cognitive control mechanisms in regulating the activation of semantic competitors during naming. The present study investigated the relationship between individual differences in cognitive control abilities, for both younger and older adults, and the degree of semantic interference in a blocked cyclic naming task. We predicted that individuals with lower working memory capacity (as measured by word span), lesser ability to inhibit distracting responses (as measured by Stroop interference), and a lesser ability to resolve proactive interference (as measured by a recent negatives task) would show a greater increase in semantic interference in naming, with effects being larger for older adults. Instead, measures of cognitive control were found to relate to specific indices of semantic interference in the naming task, rather than overall degree of semantic interference, and few interactions with age were found, with younger and older adults performing similarly. The increase in naming latencies across naming trials within a cycle were negatively correlated with word span for both related and unrelated conditions, suggesting a strategy of narrowing response alternatives based upon memory for the set of item names. Evidence for a role of inhibition in response selection was obtained, as Stroop interference correlated positively with the change in naming latencies across cycles for the related, but not unrelated, condition. In contrast, recent negatives interference correlated negatively with the change in naming latencies across unrelated cycles, suggesting that individual differences in this tap the degree of strengthening of links in a lexical network based upon prior exposure. Results are discussed in terms of current models of lexical selection and consequences for word retrieval in more naturalistic production. PMID- 24478676 TI - Visual Evoked Potential and Magnetic Resonance Imaging are More Effective Markers of Multiple Sclerosis Progression than Laser Polarimetry with Variable Corneal Compensation. AB - BACKGROUND: The aim of our study was to assess the role of laser polarimetry and visual evoked potentials (VEP) as potential biomarkers of disease progression in multiple sclerosis (MS). PARTICIPANTS: A total of 41 patients with MS (82 eyes) and 22 age-related healthy volunteers (44 eyes) completed the study. MS patients were divided into two groups, one (ON) with a history of optic neuritis (17 patients, 34 eyes) and another group (NON) without it (24 patients, 48 eyes). The MS patients and controls underwent laser polarimetry (GDx) examination of the retinal nerve fiber layer (RNFL). In the MS group, we also examined: Kurtzke "expanded disability status scale" (EDSS), the duration of the disorder, VEP - latency and amplitude, and conventional brain magnetic resonance imaging (MRI). Our results were statistically analyzed using ANOVA, Mann-Whitney, and Spearman correlation analyses. RESULTS: In the MS group, brain atrophy and new T2 brain lesions in MRI correlated with both VEP latencies and amplitudes. Separate comparisons revealed VEP latency testing to be less sensitive in ON than in NON patients. In ON patients, VEP amplitudes correlated mildly with brain atrophy (r = -0.15) and strongly with brain new MRI lesions (r = -0.8). In NON-patients, highly significant correlation of new MRI brain lesions with VEP latencies (r = 0.63, r = 0.6) and amplitudes (r = -0.3, r = -4.2) was found. EDSS also correlated with brain atrophy in this group (r = 0.5). Our study did not find a correlation of GDx measures with MRI tests. The GDx method was not able to detect whole brain demyelinization and the degeneration process, but was only able to reveal the involvement of optic nerves in ON and NON-patients. CONCLUSION: In our study, we found that both methods (VEP and GDx) can be used for the detection of optic nerve damage, but VEP was found to be superior in evaluating whole brain demyelinization and axonal degeneration. Both VEP and MRI, but not GDx, have an important role in monitoring disease progression in MS patients, independent of the ON history. PMID- 24478677 TI - Brain and intersubjectivity: a Hegelian hypothesis on the self-other neurodynamics. PMID- 24478678 TI - Habenular expression of rare missense variants of the beta4 nicotinic receptor subunit alters nicotine consumption. AB - The CHRNA5-CHRNA3-CHRNB4 gene cluster, encoding the alpha5, alpha3, and beta4 nicotinic acetylcholine receptor (nAChR) subunits, has been linked to nicotine dependence. The habenulo-interpeduncular (Hb-IPN) tract is particularly enriched in alpha3beta4 nAChRs. We recently showed that modulation of these receptors in the medial habenula (MHb) in mice altered nicotine consumption. Given that beta4 is rate-limiting for receptor activity and that single nucleotide polymorphisms (SNPs) in CHRNB4 have been linked to altered risk of nicotine dependence in humans, we were interested in determining the contribution of allelic variants of beta4 to nicotine receptor activity in the MHb. We screened for missense SNPs that had allele frequencies >0.0005 and introduced the corresponding substitutions in Chrnb4. Fourteen variants were analyzed by co-expression with alpha3. We found that beta4A90I and beta4T374I variants, previously shown to associate with reduced risk of smoking, and an additional variant beta4D447Y, significantly increased nicotine-evoked current amplitudes, while beta4R348C, the mutation most frequently encountered in sporadic amyotrophic lateral sclerosis (sALS), showed reduced nicotine currents. We employed lentiviruses to express beta4 or beta4 variants in the MHb. Immunoprecipitation studies confirmed that beta4 lentiviral-mediated expression leads to specific upregulation of alpha3beta4 but not beta2 nAChRs in the Mhb. Mice injected with the beta4 containing virus showed pronounced aversion to nicotine as previously observed in transgenic Tabac mice overexpressing Chrnb4 at endogenous sites including the MHb. Habenular expression of the beta4 gain-of-function allele T374I also resulted in strong aversion, while transduction with the beta4 loss-of function allele R348C failed to induce nicotine aversion. Altogether, these data confirm the critical role of habenular beta4 in nicotine consumption, and identify specific SNPs in CHRNB4 that modify nicotine-elicited currents and alter nicotine consumption in mice. PMID- 24478679 TI - Tai chi training reduces self-report of inattention in healthy young adults. AB - It is important to identify effective non-pharmacological alternatives to stimulant medications that reduce symptoms of attention deficit hyperactivity disorder (ADHD). In this study of healthy young adults, we measured the effects of training in tai chi, which involves mindful attention to the body during movement. Using a non-randomized, controlled, parallel design, students in a 15 week introductory tai chi course (n = 28) and control participants (n = 44) were tested for ADHD indicators and cognitive function at three points over the course of the 15-weeks. The tai chi students' self-report of attention, but not hyperactivity-impulsivity, improved compared to controls. At baseline, inattention correlated positively with reaction time variability in an affective go/no-go task across all participants, and improvements in attention correlated with reductions in reaction time variability across the tai chi students. Affective bias changed in the tai chi students, as reaction times to positive- and negative-valenced words equalized over time. These results converge to suggest that tai chi training may help improve attention in healthy young adults. Further studies are needed to confirm these results and to evaluate tai chi as therapy for individuals with ADHD. PMID- 24478680 TI - Linking neuroscientific research on decision making to the educational context of novice students assigned to a multiple-choice scientific task involving common misconceptions about electrical circuits. AB - Functional magnetic resonance imaging was used to identify the brain-based mechanisms of uncertainty and certainty associated with answers to multiple choice questions involving common misconceptions about electric circuits. Twenty two scientifically novice participants (humanities and arts college students) were asked, in an fMRI study, whether or not they thought the light bulbs in images presenting electric circuits were lighted up correctly, and if they were certain or uncertain of their answers. When participants reported that they were unsure of their responses, analyses revealed significant activations in brain areas typically involved in uncertainty (anterior cingulate cortex, anterior insula cortex, and superior/dorsomedial frontal cortex) and in the left middle/superior temporal lobe. Certainty was associated with large bilateral activations in the occipital and parietal regions usually involved in visuospatial processing. Correct-and-certain answers were associated with activations that suggest a stronger mobilization of visual attention resources when compared to incorrect-and-certain answers. These findings provide insights into brain-based mechanisms of uncertainty that are activated when common misconceptions, identified as such by science education research literature, interfere in decision making in a school-like task. We also discuss the implications of these results from an educational perspective. PMID- 24478682 TI - A call for an open, informed study of all aspects of consciousness. PMID- 24478681 TI - Short-term retention of relational memory in amnesia revisited: accurate performance depends on hippocampal integrity. AB - Traditionally, it has been proposed that the hippocampus and adjacent medial temporal lobe cortical structures are selectively critical for long-term declarative memory, which entails memory for inter-item and item-context relationships. Whether the hippocampus might also contribute to short-term retention of relational memory representations has remained controversial. In two experiments, we revisit this question by testing memory for relationships among items embedded in scenes using a standard working memory trial structure in which a sample stimulus is followed by a brief delay and the corresponding test stimulus. In each experimental block, eight trials using different exemplars of the same scene were presented. The exemplars contained the same items but with different spatial relationships among them. By repeating the pictures across trials, any potential contributions of item or scene memory to performance were minimized, and relational memory could be assessed more directly than has been done previously. When test displays were presented, participants indicated whether any of the item-location relationships had changed. Then, regardless of their responses (and whether any item did change its location), participants indicated on a forced-choice test, which item might have moved, guessing if necessary. Amnesic patients were impaired on the change detection test, and were frequently unable to specify the change after having reported correctly that a change had taken place. Comparison participants, by contrast, frequently identified the change even when they failed to report the mismatch, an outcome that speaks to the sensitivity of the change specification measure. These results confirm past reports of hippocampal contributions to short-term retention of relational memory representations, and suggest that the role of the hippocampus in memory has more to do with relational memory requirements than the length of a retention interval. PMID- 24478683 TI - Visual evoked potentials to change in coloration of a moving bar. AB - In our previous study we found that it takes less time to detect coloration change in a moving object compared to coloration change in a stationary one (Kreegipuu etal., 2006). Here, we replicated the experiment, but in addition to reaction times (RTs) we measured visual evoked potentials (VEPs), to see whether this effect of motion is revealed at the cortical level of information processing. We asked our subjects to detect changes in coloration of stationary (0( degrees )/s) and moving bars (4.4 and 17.6( degrees )/s). Psychophysical results replicate the findings from the previous study showing decreased RTs to coloration changes with increase of velocity of the color changing stimulus. The effect of velocity on VEPs was opposite to the one found on RTs. Except for component N1, the amplitudes of VEPs elicited by the coloration change of faster moving objects were reduced than those elicited by the coloration change of slower moving or stationary objects. The only significant effect of velocity on latency of peaks was found for P2 in frontal region. The results are discussed in the light of change-to-change interval and the two methods reflecting different processing mechanisms. PMID- 24478684 TI - Transient and steady-state selection in the striatal microcircuit. AB - Although the basal ganglia have been widely studied and implicated in signal processing and action selection, little information is known about the active role the striatal microcircuit plays in action selection in the basal ganglia thalamo-cortical loops. To address this knowledge gap we use a large scale three dimensional spiking model of the striatum, combined with a rate coded model of the basal ganglia-thalamo-cortical loop, to asses the computational role the striatum plays in action selection. We identify a robust transient phenomena generated by the striatal microcircuit, which temporarily enhances the difference between two competing cortical inputs. We show that this transient is sufficient to modulate decision making in the basal ganglia-thalamo-cortical circuit. We also find that the transient selection originates from a novel adaptation effect in single striatal projection neurons, which is amenable to experimental testing. Finally, we compared transient selection with models implementing classical steady-state selection. We challenged both forms of model to account for recent reports of paradoxically enhanced response selection in Huntington's disease patients. We found that steady-state selection was uniformly impaired under all simulated Huntington's conditions, but transient selection was enhanced given a sufficient Huntington's-like increase in NMDA receptor sensitivity. Thus our models provide an intriguing hypothesis for the mechanisms underlying the paradoxical cognitive improvements in manifest Huntington's patients. PMID- 24478685 TI - Phase synchrony facilitates binding and segmentation of natural images in a coupled neural oscillator network. AB - Synchronization has been suggested as a mechanism of binding distributed feature representations facilitating segmentation of visual stimuli. Here we investigate this concept based on unsupervised learning using natural visual stimuli. We simulate dual-variable neural oscillators with separate activation and phase variables. The binding of a set of neurons is coded by synchronized phase variables. The network of tangential synchronizing connections learned from the induced activations exhibits small-world properties and allows binding even over larger distances. We evaluate the resulting dynamic phase maps using segmentation masks labeled by human experts. Our simulation results show a continuously increasing phase synchrony between neurons within the labeled segmentation masks. The evaluation of the network dynamics shows that the synchrony between network nodes establishes a relational coding of the natural image inputs. This demonstrates that the concept of binding by synchrony is applicable in the context of unsupervised learning using natural visual stimuli. PMID- 24478686 TI - Data and model tango to aid the understanding of astrocyte-neuron signaling. PMID- 24478687 TI - The dendritic location of the L-type current and its deactivation by the somatic AHP current both contribute to firing bistability in motoneurons. AB - Spinal motoneurons may display a variety of firing patterns including bistability between repetitive firing and quiescence and, more rarely, bistability between two firing states of different frequencies. It was suggested in the past that firing bistability required that the persistent L-type calcium current be segregated in distal dendrites, far away from the spike generating currents. However, this is not supported by more recent data. Using a two compartment model of motoneuron, we show that the different firing patterns may also result from the competition between the more proximal dendritic component of the dendritic L type conductance and the calcium sensitive potassium conductance responsible for afterhypolarization (AHP). Further emphasizing this point, firing bistability may be also achieved when the L-type current is put in the somatic compartment. However, this requires that the calcium-sensitive potassium conductance be triggered solely by the high threshold calcium currents activated during spikes and not by calcium influx through the L-type current. This prediction was validated by dynamic clamp experiments in vivo in lumbar motoneurons of deeply anesthetized cats in which an artificial L-type current was added at the soma. Altogether, our results suggest that the dynamical interaction between the L-type and afterhyperpolarization currents is as fundamental as the segregation of the calcium L-type current in dendrites for controlling the discharge of motoneurons. PMID- 24478688 TI - Spike-timing computation properties of a feed-forward neural network model. AB - Brain function is characterized by dynamical interactions among networks of neurons. These interactions are mediated by network topology at many scales ranging from microcircuits to brain areas. Understanding how networks operate can be aided by understanding how the transformation of inputs depends upon network connectivity patterns, e.g., serial and parallel pathways. To tractably determine how single synapses or groups of synapses in such pathways shape these transformations, we modeled feed-forward networks of 7-22 neurons in which synaptic strength changed according to a spike-timing dependent plasticity (STDP) rule. We investigated how activity varied when dynamics were perturbed by an activity-dependent electrical stimulation protocol (spike-triggered stimulation; STS) in networks of different topologies and background input correlations. STS can successfully reorganize functional brain networks in vivo, but with a variability in effectiveness that may derive partially from the underlying network topology. In a simulated network with a single disynaptic pathway driven by uncorrelated background activity, structured spike-timing relationships between polysynaptically connected neurons were not observed. When background activity was correlated or parallel disynaptic pathways were added, however, robust polysynaptic spike timing relationships were observed, and application of STS yielded predictable changes in synaptic strengths and spike-timing relationships. These observations suggest that precise input-related or topologically induced temporal relationships in network activity are necessary for polysynaptic signal propagation. Such constraints for polysynaptic computation suggest potential roles for higher-order topological structure in network organization, such as maintaining polysynaptic correlation in the face of relatively weak synapses. PMID- 24478689 TI - Freezing of gait and response conflict in Parkinson's disease: computational directions. PMID- 24478690 TI - morphforge: a toolbox for simulating small networks of biologically detailed neurons in Python. AB - The broad structure of a modeling study can often be explained over a cup of coffee, but converting this high-level conceptual idea into graphs of the final simulation results may require many weeks of sitting at a computer. Although models themselves can be complex, often many mental resources are wasted working around complexities of the software ecosystem such as fighting to manage files, interfacing between tools and data formats, finding mistakes in code or working out the units of variables. morphforge is a high-level, Python toolbox for building and managing simulations of small populations of multicompartmental biophysical model neurons. An entire in silico experiment, including the definition of neuronal morphologies, channel descriptions, stimuli, visualization and analysis of results can be written within a single short Python script using high-level objects. Multiple independent simulations can be created and run from a single script, allowing parameter spaces to be investigated. Consideration has been given to the reuse of both algorithmic and parameterizable components to allow both specific and stochastic parameter variations. Some other features of the toolbox include: the automatic generation of human-readable documentation (e.g., PDF files) about a simulation; the transparent handling of different biophysical units; a novel mechanism for plotting simulation results based on a system of tags; and an architecture that supports both the use of established formats for defining channels and synapses (e.g., MODL files), and the possibility to support other libraries and standards easily. We hope that this toolbox will allow scientists to quickly build simulations of multicompartmental model neurons for research and serve as a platform for further tool development. PMID- 24478691 TI - A framework for streamlining research workflow in neuroscience and psychology. AB - Successful accumulation of knowledge is critically dependent on the ability to verify and replicate every part of scientific conduct. However, such principles are difficult to enact when researchers continue to resort on ad-hoc workflows and with poorly maintained code base. In this paper I examine the needs of neuroscience and psychology community, and introduce psychopy_ext, a unifying framework that seamlessly integrates popular experiment building, analysis and manuscript preparation tools by choosing reasonable defaults and implementing relatively rigid patterns of workflow. This structure allows for automation of multiple tasks, such as generated user interfaces, unit testing, control analyses of stimuli, single-command access to descriptive statistics, and publication quality plotting. Taken together, psychopy_ext opens an exciting possibility for a faster, more robust code development and collaboration for researchers. PMID- 24478692 TI - Mutual information spectrum for selection of event-related spatial components. Application to eloquent motor cortex mapping. AB - Spatial component analysis is often used to explore multidimensional time series data whose sources cannot be measured directly. Several methods may be used to decompose the data into a set of spatial components with temporal loadings. Component selection is of crucial importance, and should be supported by objective criteria. In some applications, the use of a well defined component selection criterion may provide for automation of the analysis. In this paper we describe a novel approach for ranking of spatial components calculated from the EEG or MEG data recorded within evoked response paradigm. Our method is called Mutual Information (MI) Spectrum and is based on gauging the amount of MI of spatial component temporal loadings with a synthetically created reference signal. We also describe the appropriate randomization based statistical assessment scheme that can be used for selection of components with statistically significant amount of MI. Using simulated data with realistic trial to trial variations and SNR corresponding to the real recordings we demonstrate the superior performance characteristics of the described MI based measure as compared to a more conventionally used power driven gauge. We also demonstrate the application of the MI Spectrum for the selection of task-related independent components from real MEG data. We show that the MI spectrum allows to identify task-related components reliably in a consistent fashion, yielding stable results even from a small number of trials. We conclude that the proposed method fits naturally the information driven nature of ICA and can be used for routine and automatic ranking of independent components calculated from the functional neuroimaging data collected within event-related paradigms. PMID- 24478693 TI - A psychology based approach for longitudinal development in cognitive robotics. AB - A major challenge in robotics is the ability to learn, from novel experiences, new behavior that is useful for achieving new goals and skills. Autonomous systems must be able to learn solely through the environment, thus ruling out a priori task knowledge, tuning, extensive training, or other forms of pre programming. Learning must also be cumulative and incremental, as complex skills are built on top of primitive skills. Additionally, it must be driven by intrinsic motivation because formative experience is gained through autonomous activity, even in the absence of extrinsic goals or tasks. This paper presents an approach to these issues through robotic implementations inspired by the learning behavior of human infants. We describe an approach to developmental learning and present results from a demonstration of longitudinal development on an iCub humanoid robot. The results cover the rapid emergence of staged behavior, the role of constraints in development, the effect of bootstrapping between stages, and the use of a schema memory of experiential fragments in learning new skills. The context is a longitudinal experiment in which the robot advanced from uncontrolled motor babbling to skilled hand/eye integrated reaching and basic manipulation of objects. This approach offers promise for further fast and effective sensory-motor learning techniques for robotic learning. PMID- 24478695 TI - Low-latency multi-threaded processing of neuronal signals for brain-computer interfaces. AB - Brain-computer interfaces (BCIs) require demanding numerical computations to transfer brain signals into control signals driving an external actuator. Increasing the computational performance of the BCI algorithms carrying out these calculations enables faster reaction to user inputs and allows using more demanding decoding algorithms. Here we introduce a modular and extensible software architecture with a multi-threaded signal processing pipeline suitable for BCI applications. The computational load and latency (the time that the system needs to react to user input) are measured for different pipeline implementations in typical BCI applications with realistic parameter settings. We show that BCIs can benefit substantially from the proposed parallelization: firstly, by reducing the latency and secondly, by increasing the amount of recording channels and signal features that can be used for decoding beyond the amount which can be handled by a single thread. The proposed software architecture provides a simple, yet flexible solution for BCI applications. PMID- 24478694 TI - How long did it last? You would better ask a human. AB - In the future, human-like robots will live among people to provide company and help carrying out tasks in cooperation with humans. These interactions require that robots understand not only human actions, but also the way in which we perceive the world. Human perception heavily relies on the time dimension, especially when it comes to processing visual motion. Critically, human time perception for dynamic events is often inaccurate. Robots interacting with humans may want to see the world and tell time the way humans do: if so, they must incorporate human-like fallacy. Observers asked to judge the duration of brief scenes are prone to errors: perceived duration often does not match the physical duration of the event. Several kinds of temporal distortions have been described in the specialized literature. Here we review the topic with a special emphasis on our work dealing with time perception of animate actors versus inanimate actors. This work shows the existence of specialized time bases for different categories of targets. The time base used by the human brain to process visual motion appears to be calibrated against the specific predictions regarding the motion of human figures in case of animate motion, while it can be calibrated against the predictions of motion of passive objects in case of inanimate motion. Human perception of time appears to be strictly linked with the mechanisms used to control movements. Thus, neural time can be entrained by external cues in a similar manner for both perceptual judgments of elapsed time and in motor control tasks. One possible strategy could be to implement in humanoids a unique architecture for dealing with time, which would apply the same specialized mechanisms to both perception and action, similarly to humans. This shared implementation might render the humanoids more acceptable to humans, thus facilitating reciprocal interactions. PMID- 24478696 TI - Juvenile methylphenidate reduces prefrontal cortex plasticity via D3 receptor and BDNF in adulthood. AB - BACKGROUND: Early drug intervention in childhood disorders aims to maximize individual potential in the short- and long-term. Consistently, juvenile exposure to psychostimulants, such as methylphenidate (MPH), reduces risk for substance use in animals and sub-populations of individuals with attention deficit hyperactivity disorder (ADHD). We investigated the effects of MPH on brain plasticity via dopamine receptor D3 (D3R) and brain-derived neurotrophic factor (BDNF) expression in developing rats. METHODS: Between postnatal days 20-35, rat pups were administered saline vehicle (Veh) or MPH (2 mg/kg), the D3R-preferring agonist +/-7-OHDPAT, or the antagonist nafadotride (0.05 mg/kg) alone, or in combination with MPH twice a day. In adulthood, subjects were challenged to Veh or cocaine (10 mg/kg for two days). The prefrontal cortex was analyzed for protein and mRNA levels of total BDNF, its splice variants I, IIc, III/IV, and IV/VI, and D3 receptors. A separate group of subjects was assessed for splice variants at 20, 35, 40, and 60 days of age. RESULTS: Across age strong correlations were evident between Drd3 and Bdnf mRNA levels (r = 0.65) and a negative relationship between Drd3 and exon IIc after MPH treatment (r = -0.73). BDNF protein levels did not differ between Veh- and MPH subjects at baseline, but were significantly lower in MPH-treated and cocaine challenged subjects (30.3 +/- 9.7%). Bdnf mRNA was significantly higher in MPH-treated subjects, and reversed upon exposure to cocaine. This effect was blocked by nafadotride. Furthermore, Bdnf total and Bdnf splice variants I, IIc, III/IV, and IV/VI changed across the transitions between juvenility and late adolescence. CONCLUSIONS: These data suggest a sensitive window of vulnerability to modulation of BDNF expression around adolescence, and that compared to normal animals, juvenile exposure to MPH permanently reduces prefrontal BDNF transcription and translation upon cocaine exposure in adulthood by a D3R-mediated mechanism. PMID- 24478697 TI - Environmental enrichment strengthens corticocortical interactions and reduces amyloid-beta oligomers in aged mice. AB - Brain aging is characterized by global changes which are thought to underlie age related cognitive decline. These include variations in brain activity and the progressive increase in the concentration of soluble amyloid-beta (Abeta) oligomers, directly impairing synaptic function and plasticity even in the absence of any neurodegenerative disorder. Considering the high social impact of the decline in brain performance associated to aging, there is an urgent need to better understand how it can be prevented or contrasted. Lifestyle components, such as social interaction, motor exercise and cognitive activity, are thought to modulate brain physiology and its susceptibility to age-related pathologies. However, the precise functional and molecular factors that respond to environmental stimuli and might mediate their protective action again pathological aging still need to be clearly identified. To address this issue, we exploited environmental enrichment (EE), a reliable model for studying the effect of experience on the brain based on the enhancement of cognitive, social and motor experience, in aged wild-type mice. We analyzed the functional consequences of EE on aged brain physiology by performing in vivo local field potential (LFP) recordings with chronic implants. In addition, we also investigated changes induced by EE on molecular markers of neural plasticity and on the levels of soluble Abeta oligomers. We report that EE induced profound changes in the activity of the primary visual and auditory cortices and in their functional interaction. At the molecular level, EE enhanced plasticity by an upward shift of the cortical excitation/inhibition balance. In addition, EE reduced brain Abeta oligomers and increased synthesis of the Abeta-degrading enzyme neprilysin. Our findings strengthen the potential of EE procedures as a non-invasive paradigm for counteracting brain aging processes. PMID- 24478698 TI - Assessing the emergence and reliability of cognitive decline over the life span in Fisher 344 rats using the spatial water maze. AB - The spatial water maze is routinely used to investigate hippocampal-dependent spatial memory and the biological mechanisms that underlie variability in cognitive decline during aging. The utility of the task for repeated testing in order to examine the trajectory of cognitive decline and to prescreen animals prior to therapeutic interventions maybe limited due to carryover effects of repeated training. The current study examines the role of carryover effects, as well as the reliability of individual differences, in determining age-related impairment on episodic and reference memory versions of the water maze task. Results indicate that impaired acquisition of episodic spatial information emerges in middle-age and the propensity for impairment increases with advancing age. While learning was variable across animals, acquisition deficits for episodic information were reliable across training sessions in middle-age and aged rats. A significant impairment in the 24~h retention of episodic spatial information was observed in aged animals. When animals were trained to the same location (i.e., reference memory), an impairment was limited to the rate of acquisition in aged animals. However, with continued training, all aged animals were able to acquire a reference memory and no age differences were observed in the 24~h retention of a spatial reference memory. Together, the results point to a progressive impairment in episodic spatial memory with advancing age and suggest that tests of episodic spatial memory are reliable and more sensitive than reference memory for detecting cognitive decline. PMID- 24478699 TI - Increased bilateral interactions in middle-aged subjects. AB - A hallmark of the age-related neural reorganization is that old versus young adults execute typical motor tasks by a more diffuse neural activation pattern including stronger ipsilateral activation during unilateral tasks. Whether such changes in neural activation are present already at middle age and affect bimanual interactions is unknown. We compared the amount of associated activity, i.e., muscle activity and force produced by the non-task hand and motor evoked potentials (MEPs) produced by magnetic brain stimulation between young (mean 24 years, n = 10) and middle-aged (mean 50 years, n = 10) subjects during brief unilateral (seven levels of % maximal voluntary contractions, MVCs) and bilateral contractions (4 * 7 levels of % MVC combinations), and during a 120-s-long MVC of sustained unilateral index finger abduction. During the force production, the excitability of the ipsilateral (iM1) or contralateral primary motor cortex (cM1) was assessed. The associated activity in the "resting" hand was ~2-fold higher in middle-aged (28% of MVC) versus young adults (11% of MVC) during brief unilateral MVCs. After controlling for the background muscle activity, MEPs in iM1 were similar in the two groups during brief unilateral contractions. Only at low (bilateral) forces, MEPs evoked in cM1 were 30% higher in the middle-aged versus young adults. At the start of the sustained contraction, the associated activity was higher in the middle-aged versus young subjects and increased progressively in both groups (30 versus 15% MVC at 120 s, respectively). MEPs were greater at the start of the sustained contraction in middle-aged subjects but increased further during the contraction only in young adults. Under these experimental conditions, the data provide evidence for the reorganization of neural control of unilateral force production as early as age 50. Future studies will determine if the altered neural control of such inter-manual interactions are of functional significance. PMID- 24478700 TI - Aspirin promotes oligodendrocyte precursor cell proliferation and differentiation after white matter lesion. AB - Cerebral white matter lesion (WML) is one of the main causes for cognitive impairment and is often caused by chronic cerebral hypoperfusion. A line of evidence has shown that aspirin has neuroprotective effects and produces some benefits in long-term outcome and survival for ischemic stroke patients. However, whether aspirin exerts a protective effect against WML is still largely unknown. Here, we showed that aspirin could promote oligodendrocyte precursor cell (OPC) proliferation and differentiation into oligodendrocytes after WML. Male Sprague Dawley rats were subjected to permanent bilateral common carotid artery occlusion, a well-established model for WML. Four weeks later, Morris water maze test showed an impairment of learning and memory ability of rat while aspirin treatment improved behavioral performance. Low dose of aspirin (25 mg/kg) was found to elevate the number of OPCs while relatively high doses (100-200 mg/kg) increased that of oligodendrocytes, and ameliorated WML-induced the thinning of myelin, as revealed by the electron microscope. Similarly, our in vitro study also showed that relatively low and high doses of aspirin enhanced OPC proliferation and differentiation into oligodendrocytes, respectively. Furthermore, we revealed that aspirin enhanced extracellular signal-related kinase (ERK) but inhibited RhoA activities. In summary, we provided the first evidence that aspirin can promote oligodendrogenesis and oligodendrocyte myelination after WML, which may involve ERK and RhoA pathways. PMID- 24478701 TI - Are mast cells instrumental for fibrotic diseases? AB - Idiopathic pulmonary fibrosis (IPF) is a fatal lung disorder of unknown etiology characterized by accumulation of lung fibroblasts and extracellular matrix deposition, ultimately leading to compromised tissue architecture and lung function capacity. IPF has a heterogeneous clinical course; however the median survival after diagnosis is only 3-5 years. The pharmaceutical and biotechnology industry has made many attempts to find effective treatments for IPF, but the disease has so far defied all attempts at therapeutic intervention. Clinical trial failures may arise for many reasons, including disease heterogeneity, lack of readily measurable clinical end points other than overall survival, and, perhaps most of all, a lack of understanding of the underlying molecular mechanisms of the progression of IPF. The precise link between inflammation and fibrosis remains unclear, but it appears that immune cells can promote fibrosis by releasing fibrogenic factors. So far, however, therapeutic approaches targeting macrophages, neutrophils, or lymphocytes have failed to alter disease pathogenesis. A new cell to garner research interest in fibrosis is the mast cell. Increased numbers of mast cells have long been known to be present in pulmonary fibrosis and clinically correlations between mast cells and fibrosis have been reported. More recent data suggests that mast cells may contribute to the fibrotic process by stimulating fibroblasts resident in the lung, thus driving the pathogenesis of the disease. In this review, we will discuss the mast cell and its physiological role in tissue repair and remodeling, as well as its pathological role in fibrotic diseases such as IPF, where the process of tissue repair and remodeling is thought to be dysregulated. PMID- 24478703 TI - Heterogeneity in fibroblast proliferation and survival in idiopathic pulmonary fibrosis. AB - Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease characterized by the persistence of activated myofibroblasts resulting in excessive deposition of extracellular matrix proteins and profound tissue remodeling. Myofibroblasts have been shown to arise from interstitial fibroblasts, epithelial to mesenchymal transition of type II alveolar epithelial cells, and the differentiation of recruited fibrocytes. There are many mechanisms that are utilized by these cells for survival, proliferation, and persistent activation including up-regulation of cytokines [i.e., Interleukin 6 (IL-6) and C C motif chemokine ligand 21 (CCL21)], cytokine receptors [i.e., Interleukin 6Receptor 1 (IL-6R1), Glycoprotein 130 (gp130) and C-C Chemokine Receptor type 7 (CCR7)], and innate pattern recognition receptors [(PRRs; i.e., Toll Like Receptor 9 (TLR9)]. In this review, we will discuss the role of the cytokines IL 6 and CCL21, their receptors and the PRR, TLR9, in fibroblast recruitment, activation, survival, and differentiation into myofibroblasts in IPF. PMID- 24478702 TI - Apoptotic cell: linkage of inflammation and wound healing. AB - We consider that from the wound to the healing process, the physiology point key to linkage of the process is still unclear. The process from inflammation to the wound healing is divided into three phases: (1) inflammation process, (2) tissue formation, and (3) tissue remodeling. The inflammation program includes cell produced related factors and immune cells infiltration. We thought the inflammation factors that may be also involved in the followed healing process. But the question is "what kind of factor is the major key involved in the end of the inflammation then to initiate the healing." We suspect that the apoptosis of immune cell may be the major key to end of inflammation and to initiate the healing. PMID- 24478704 TI - Advances in targeting the vacuolar proton-translocating ATPase (V-ATPase) for anti-fungal therapy. AB - Vacuolar proton-translocating ATPase (V-ATPase) is a membrane-bound, multi subunit enzyme that uses the energy of ATP hydrolysis to pump protons across membranes. V-ATPase activity is critical for pH homeostasis and organelle acidification as well as for generation of the membrane potential that drives secondary transporters and cellular metabolism. V-ATPase is highly conserved across species and is best characterized in the model fungus Saccharomyces cerevisiae. However, recent studies in mammals have identified significant alterations from fungi, particularly in the isoform composition of the 14 subunits and in the regulation of complex disassembly. These differences could be exploited for selectivity between fungi and humans and highlight the potential for V-ATPase as an anti-fungal drug target. Candida albicans is a major human fungal pathogen and causes fatality in 35% of systemic infections, even with anti fungal treatment. The pathogenicity of C. albicans correlates with environmental, vacuolar, and cytoplasmic pH regulation, and V-ATPase appears to play a fundamental role in each of these processes. Genetic loss of V-ATPase in pathogenic fungi leads to defective virulence, and a comprehensive picture of the mechanisms involved is emerging. Recent studies have explored the practical utility of V-ATPase as an anti-fungal drug target in C. albicans, including pharmacological inhibition, azole therapy, and targeting of downstream pathways. This overview will discuss these studies as well as hypothetical ways to target V ATPase and novel high-throughput methods for use in future drug discovery screens. PMID- 24478705 TI - Vitamin D supplements: a novel therapeutic approach for Alzheimer patients. PMID- 24478707 TI - Independent signaling by Drosophila insulin receptor for axon guidance and growth. AB - The Drosophila insulin receptor (DInR) regulates a diverse array of biological processes including growth, axon guidance, and sugar homeostasis. Growth regulation by DInR is mediated by Chico, the Drosophila homolog of vertebrate insulin receptor substrate proteins IRS1-4. In contrast, DInR regulation of photoreceptor axon guidance in the developing visual system is mediated by the SH2-SH3 domain adaptor protein Dreadlocks (Dock). In vitro studies by others identified five NPXY motifs, one in the juxtamembrane region and four in the signaling C-terminal tail (C-tail), important for interaction with Chico. Here we used yeast two-hybrid assays to identify regions in the DInR C-tail that interact with Dock. These Dock binding sites were in separate portions of the C-tail from the previously identified Chico binding sites. To test whether these sites are required for growth or axon guidance in whole animals, a panel of DInR proteins, in which the putative Chico and Dock interaction sites had been mutated individually or in combination, were tested for their ability to rescue viability, growth and axon guidance defects of dinr mutant flies. Sites required for viability were identified. Unexpectedly, mutation of both putative Dock binding sites, either individually or in combination, did not lead to defects in photoreceptor axon guidance. Thus, either sites also required for viability are necessary for DInR function in axon guidance and/or there is redundancy built into the DInR/Dock interaction such that Dock is able to interact with multiple regions of DInR. We also found that simultaneous mutation of all five NPXY motifs implicated in Chico interaction drastically decreased growth in both male and female adult flies. These animals resembled chico mutants, supporting the notion that DInR interacts directly with Chico in vivo to control body size. Mutation of these five NPXY motifs did not affect photoreceptor axon guidance, segregating the roles of DInR in the processes of growth and axon guidance. PMID- 24478706 TI - A comparative study of Whi5 and retinoblastoma proteins: from sequence and structure analysis to intracellular networks. AB - Cell growth and proliferation require a complex series of tight-regulated and well-orchestrated events. Accordingly, proteins governing such events are evolutionary conserved, even among distant organisms. By contrast, it is more singular the case of "core functions" exerted by functional analogous proteins that are not homologous and do not share any kind of structural similarity. This is the case of proteins regulating the G1/S transition in higher eukaryotes-i.e., the retinoblastoma (Rb) tumor suppressor Rb-and budding yeast, i.e., Whi5. The interaction landscape of Rb and Whi5 is quite large, with more than one hundred proteins interacting either genetically or physically with each protein. The Whi5 interactome has been used to construct a concept map of Whi5 function and regulation. Comparison of physical and genetic interactors of Rb and Whi5 allows highlighting a significant core of conserved, common functionalities associated with the interactors indicating that structure and function of the network-rather than individual proteins-are conserved during evolution. A combined bioinformatics and biochemical approach has shown that the whole Whi5 protein is highly disordered, except for a small region containing the protein family signature. The comparison with Whi5 homologs from Saccharomycetales has prompted the hypothesis of a modular organization of structural disorder, with most evolutionary conserved regions alternating with highly variable ones. The finding of a consensus sequence points to the conservation of a specific phosphorylation rhythm along with two disordered sequence motifs, probably acting as phosphorylation-dependent seeds in Whi5 folding/unfolding. Thus, the widely disordered Whi5 appears to act as a hierarchical, "date hub" that has evolutionary assayed an original way of modular organization before being supplanted by the globular, multi-domain structured Rb, more suitable to cover the role of a "party hub". PMID- 24478708 TI - Muscle specific miRNAs are induced by testosterone and independently upregulated by age. AB - Age dependent decline in skeletal muscle function leads to impaired metabolic flexibility in elderly individuals. Physical activity and testosterone treatment have proven efficient strategies for delaying this condition. However, a common molecular pathway has not been identified. Muscle specific miRNAs (myomiRs) regulate metabolic pathways in skeletal muscle, are regulated by physical activity, and have response elements for testosterone in their promoter region. We therefore hypothesized that myomiRs would be regulated in skeletal muscle during aging. We further investigated any potential gender-dependent regulation of these miRNAs. We found that the myomiRs miR-1, miR-133a, and miR-133b were increased in skeletal muscle of elderly men compared to younger men. In addition, miR-133a/133b expression was markedly higher in women compared to men. Elimination of circulating testosterone in men was associated with lower levels of miR-133a and miR-133b. A positive regulatory effect of testosterone on miR 133a/133b expression was confirmed in castrated male C57BL/6J mice and in a model of primary human myocytes. Yet, an improvement of fitness level in the testosterone depleted men resulted in a down-regulation of miR133a/b. In conclusion, alterations in fitness level and circulating testosterone seem to represent two independent regulatory events where testosterone is a specific regulator of miR-133a/b expression. PMID- 24478709 TI - A note on arterial to venous oxygen saturation as reference for NIRS-determined frontal lobe oxygen saturation in healthy humans. PMID- 24478710 TI - Kras as a key oncogene and therapeutic target in pancreatic cancer. AB - Pancreatic cancer is one of the deadliest human malignancies and little progress has been achieved in its treatment over the past decades. Advances in our understanding of the biology of this disease provide new potential opportunities for treatment. Pancreatic cancer is preceded by precursor lesions, the most common of which are known as Pancreatic Intraepithelial Neoplasia (PanIN). PanIN lesions, which are the focus of this review, have a high incidence of Kras mutations, and Kras mutations are a hallmark of the late-stage disease. We now know from genetically engineered mouse models that oncogenic Kras is not only driving the formation of pancreatic cancer precursor lesions, but it is also required for their progression, and for the maintenance of invasive and metastatic disease. Thus, an enormous effort is being placed in generating Kras inhibitors for clinical use. Additionally, alternative approaches, including understanding the role of Kras effector pathways at different stages of the disease progression, are being devised to target Kras effector pathways therapeutically. In particular, efforts have focused on the MAPK pathway and the PI3K pathway, for which inhibitors are widely available. Finally, recent studies have highlighted the need for oncogenic Kras to establish feedback mechanisms that maintain its levels of activity; the latter might constitute alternative ways to target Kras in pancreatic cancer. Here, we will review recent basic research and discuss potential therapeutic applications. PMID- 24478711 TI - Possible contribution of chronobiology to cardiovascular health. AB - The daily variations found in many aspects of physiology are collectively known as circadian rhythm (from "circa" meaning "about" and "dien" meaning "day"). Circadian oscillation in clock gene expression can generate quantitative or functional variations of the molecules directly involved in many physiological functions. This paper reviews the molecular mechanisms of the circadian clock, the transmission of circadian effects to cardiovascular functions, and the effects of circadian dysfunction on cardiovascular diseases. An evaluation of the operation of the internal clock is needed in clinical settings and will be an effective tool in the diagnosis of circadian rhythm disorders. Toward this end, we introduce a novel non-invasive method for assessing circadian time-regulation in human beings through the utilization of hair follicle cells. PMID- 24478712 TI - Modulation of the cardiac sodium/bicarbonate cotransporter by the renin angiotensin aldosterone system: pathophysiological consequences. AB - The sodium/bicarbonate cotransporter (NBC) is one of the major alkalinizing mechanisms in the cardiomyocytes. It has been demonstrated the existence of at least two functional isoforms, one that promotes the co-influx of 1 molecule of Na(+) per 1 molecule of HCO(-) 3 (electroneutral isoform; NBCn1) and the other one that generates the co-influx of 1 molecule of Na(+) per 2 molecules of HCO(-) 3 (electrogenic isoform; NBCe1). Both isoforms are important to maintain intracellular pH (pH i ) and sodium concentration ([Na(+)] i ). In addition, NBCe1 generates an anionic repolarizing current that modulates the action potential duration (APD). The renin-angiotensin-aldosterone system (RAAS) is implicated in the modulation of almost all physiological cardiac functions and is also involved in the development and progression of cardiac diseases. It was reported that angiotensin II (Ang II) exhibits an opposite effect on NBC isoforms: it activates NBCn1 and inhibits NBCe1. The activation of NBCn1 leads to an increase in pH i and [Na(+)] i , which indirectly, due to the stimulation of reverse mode of the Na(+)/Ca(2+) exchanger (NCX), conduces to an increase in the intracellular Ca(2+) concentration. On the other hand, the inhibition of NBCe1 generates an APD prolongation, potentially representing a risk of arrhythmias. In the last years, the potentially altered NBC function in pathological scenarios, as cardiac hypertrophy and ischemia-reperfusion, has raised increasing interest among investigators. This review attempts to draw the attention on the relevant regulation of NBC activity by RAAS, since it modulates pH i and [Na(+)] i , which are involved in the development of cardiac hypertrophy, the damage produced by ischemia-reperfusion and the generation of arrhythmic events, suggesting a potential role of NBC in cardiac diseases. PMID- 24478713 TI - Role of AE2 for pHi regulation in biliary epithelial cells. AB - The Cl(-)/HCO(-) 3anion exchanger 2 (AE2) is known to be involved in intracellular pH (pHi) regulation and transepithelial acid-base transport. Early studies showed that AE2 gene expression is reduced in liver biopsies and blood mononuclear cells from patients with primary biliary cirrhosis (PBC), a disease characterized by chronic non-suppurative cholangitis associated with antimitochondrial antibodies (AMA) and other autoimmune phenomena. Microfluorimetric analysis of the Cl(-)/HCO(-) 3 anion exchange (AE) in isolated cholangiocytes showed that the cAMP-stimulated AE activity is diminished in PBC compared to both healthy and diseased controls. More recently, it was found that miR-506 is upregulated in cholangiocytes of PBC patients and that AE2 may be a target of miR-506. Additional evidence for a pathogenic role of AE2 dysregulation in PBC was obtained with Ae2 (-/-) a,b mice, which develop biochemical, histological, and immunologic alterations that resemble PBC (including development of serum AMA). Analysis of HCO(-) 3 transport systems and pHi regulation in cholangiocytes from normal and Ae2 (-/-) a,b mice confirmed that AE2 is the transporter responsible for the Cl(-)/HCO(-) 3exchange in these cells. On the other hand, both Ae2 (+/+) a,b and Ae2 (-/-) a,b mouse cholangiocytes exhibited a Cl(-)-independent bicarbonate transport system, essentially a Na(+) bicarbonate cotransport (NBC) system, which could contribute to pHi regulation in the absence of AE2. PMID- 24478714 TI - Aphid polyphenisms: trans-generational developmental regulation through viviparity. AB - Polyphenism, in which multiple discrete phenotypes develop from a single genotype, is considered to have contributed to the evolutionary success of aphids. Of the various polyphenisms observed in the complex life cycle of aphids, the reproductive and wing polyphenisms seen in most aphid species are conspicuous. In reproductive polyphenism, the reproductive modes can change between viviparous parthenogenesis and sexual reproduction in response to the photoperiod. Under short-day conditions in autumn, sexual morphs (males and oviparous females) are produced parthenogenetically. Winged polyphenism is observed in viviparous generations during summer, when winged or wingless (flightless) aphids are produced depending on a variety of environmental conditions (e.g., density, predators). Here, we review the physiological mechanisms underlying reproductive and wing polyphenism in aphids. In reproductive polyphenism, morph determination (male, oviparous or viviparous female) within mother aphids is regulated by juvenile hormone (JH) titers in the mothers. In wing polyphenism, although JH is considered to play an important role in phenotype determination (winged or wingless), the role is still controversial. In both cases, the acquisition of viviparity in Aphididae is considered to be the basis for maternal regulation of these polyphenisms, and through which environmental cues can be transferred to developing embryos through the physiological state of the mother. Although the mechanisms by which mothers alter the developmental programs of their progeny have not yet been clarified, continued developments in molecular biology will likely unravel these questions. PMID- 24478715 TI - Potential applications of nanotechnology for the diagnosis and treatment of pancreatic cancer. AB - Despite improvements in our understanding of pancreatic cancer and the emerging concept of personalized medicine for the treatment of this disease, it is still the fourth most common cause of cancer death in the western world. It is established that pancreatic cancer is a highly heterogeneous disease with a complex tumor microenvironment. Indeed the extensive stroma surrounding the cancer cells has been shown to be important in promoting tumor growth and metastases, as well as sequestering chemotherapeutic agents consequently decreasing delivery to the tumor cells. Nanotechnology has come to the forefront in the areas of medical diagnostics, imaging, and therapeutic drug delivery. This review will focus on the potential applications of nanotechnology for diagnosis, imaging, and delivery of therapeutic agents for the treatment of pancreatic cancer. PMID- 24478716 TI - Primitive and definitive erythropoiesis in mammals. AB - Red blood cells (RBCs), which constitute the most abundant cell type in the body, come in two distinct flavors- primitive and definitive. Definitive RBCs in mammals circulate as smaller, anucleate cells during fetal and postnatal life, while primitive RBCs circulate transiently in the early embryo as large, nucleated cells before ultimately enucleating. Both cell types are formed from lineage-committed progenitors that generate a series of morphologically identifiable precursors that enucleate to form mature RBCs. While definitive erythroid precursors mature extravascularly in the fetal liver and postnatal marrow in association with macrophage cells, primitive erythroid precursors mature as a semi-synchronous cohort in the embryonic bloodstream. While the cytoskeletal network is critical for the maintenance of cell shape and the deformability of definitive RBCs, little is known about the components and function of the cytoskeleton in primitive erythroblasts. Erythropoietin (EPO) is a critical regulator of late-stage definitive, but not primitive, erythroid progenitor survival. However, recent studies indicate that EPO regulates multiple aspects of terminal maturation of primitive murine and human erythroid precursors, including cell survival, proliferation, and the rate of terminal maturation. Primitive and definitive erythropoiesis share central transcriptional regulators, including Gata1 and Klf1, but are also characterized by the differential expression and function of other regulators, including myb, Sox6, and Bcl11A. Flow cytometry-based methodologies, developed to purify murine and human stage-specific erythroid precursors, have enabled comparative global gene expression studies and are providing new insights into the biology of erythroid maturation. PMID- 24478717 TI - Polyubiquitin chain assembly and organization determine the dynamics of protein activation and degradation. AB - Protein degradation via ubiquitination is a major proteolytic mechanism in cells. Once a protein is destined for degradation, it is tagged by multiple ubiquitin (Ub) molecules. The synthesized polyubiquitin chains can be recognized by the 26S proteosome where proteins are degraded. These chains form through multiple ubiquitination cycles that are similar to multi-site phosphorylation cycles. As kinases and phosphatases, two opposing enzymes (E3 ligases and deubiquitinases DUBs) catalyze (de)ubiquitination cycles. Although multi-ubiquitination cycles are fundamental mechanisms of controlling protein concentrations within a cell, their dynamics have never been explored. Here, we fill this knowledge gap. We show that under permissive physiological conditions, the formation of polyubiquitin chain of length greater than two and subsequent degradation of the ubiquitinated protein, which is balanced by protein synthesis, can display bistable, switch-like responses. Interestingly, the occurrence of bistability becomes pronounced, as the chain grows, giving rise to "all-or-none" regulation at the protein levels. We give predictions of protein distributions under bistable regime awaiting experimental verification. Importantly, we show for the first time that sustained oscillations can robustly arise in the process of formation of ubiquitin chain, largely due to the degradation of the target protein. This new feature is opposite to the properties of multi-site phosphorylation cycles, which are incapable of generating oscillation if the total abundance of interconverted protein forms is conserved. We derive structural and kinetic constraints for the emergence of oscillations, indicating that a competition between different substrate forms and the E3 and DUB is critical for oscillation. Our work provides the first detailed elucidation of the dynamical features brought about by different molecular setups of the polyubiquitin chain assembly process responsible for protein degradation. PMID- 24478718 TI - Exercise economy in skiing and running. AB - Substantial inter-individual variations in exercise economy exist even in highly trained endurance athletes. The variation is believed to be determined partly by intrinsic factors. Therefore, in the present study, we compared exercise economy in V2-skating, double poling, and uphill running. Ten highly trained male cross country skiers (23 +/- 3 years, 180 +/- 6 cm, 75 +/- 8 kg, VO2peak running: 76.3 +/- 5.6 mL.kg(-1).min(-1)) participated in the study. Exercise economy and VO2peak during treadmill running, ski skating (V2 technique) and double poling were compared based on correlation analysis. There was a very large correlation in exercise economy between V2-skating and double poling (r = 0.81) and large correlations between V2-skating and running (r = 0.53) and double poling and running (r = 0.58). There were trivial to moderate correlations between exercise economy and the intrinsic factors VO2peak (r = 0.00-0.23), cycle rate (r = 0.03 0.46), body mass (r = -0.09-0.46) and body height (r = 0.11-0.36). In conclusion, the inter-individual variation in exercise economy could be explained only moderately by differences in VO2peak, body mass and body height. Apparently other intrinsic factors contribute to the variation in exercise economy between highly trained subjects. PMID- 24478719 TI - Cerebral hemodynamics of the aging brain: risk of Alzheimer disease and benefit of aerobic exercise. AB - Alzheimer disease (AD) and cerebrovascular disease often coexist with advanced age. Mounting evidence indicates that the presence of vascular disease and its risk factors increase the risk of AD, suggesting a potential overlap of the underlying pathophysiological mechanisms. In particular, atherosclerosis, endothelial dysfunction, and stiffening of central elastic arteries have been shown to associate with AD. Currently, there are no effective treatments for the cure and prevention of AD. Vascular risk factors are modifiable via either pharmacological or lifestyle intervention. In this regard, habitual aerobic exercise is increasingly recognized for its benefits on brain structure and cognitive function. Considering the well-established benefits of regular aerobic exercise on vascular health, exercise-related improvements in brain structure and cognitive function may be mediated by vascular adaptations. In this review, we will present the current evidence for the physiological mechanisms by which vascular health alters the structural and functional integrity of the aging brain and how improvements in vascular health, via regular aerobic exercise, potentially benefits cognitive function. PMID- 24478720 TI - Genetic evidence for conserved non-coding element function across species-the ears have it. AB - Comparison of genomic sequences from diverse vertebrate species has revealed numerous highly conserved regions that do not appear to encode proteins or functional RNAs. Often these "conserved non-coding elements," or CNEs, can direct gene expression to specific tissues in transgenic models, demonstrating they have regulatory function. CNEs are frequently found near "developmental" genes, particularly transcription factors, implying that these elements have essential regulatory roles in development. However, actual examples demonstrating CNE regulatory functions across species have been few, and recent loss-of-function studies of several CNEs in mice have shown relatively minor effects. In this Perspectives article, we discuss new findings in "fancy" rats and Highland cattle demonstrating that function of a CNE near the Hmx1 gene is crucial for normal external ear development and when disrupted can mimic loss-of function Hmx1 coding mutations in mice and humans. These findings provide important support for conserved developmental roles of CNEs in divergent species, and reinforce the concept that CNEs should be examined systematically in the ongoing search for genetic causes of human developmental disorders in the era of genome-scale sequencing. PMID- 24478721 TI - Parasympathetic preganglionic cardiac motoneurons labeled after voluntary diving. AB - A dramatic bradycardia is induced by underwater submersion in vertebrates. The location of parasympathetic preganglionic cardiac motor neurons driving this aspect of the diving response was investigated using cFos immunohistochemistry combined with retrograde transport of cholera toxin subunit B (CTB) to double label neurons. After pericardial injections of CTB, trained rats voluntarily dove underwater, and their heart rates (HR) dropped immediately to 95 +/- 2 bpm, an 80% reduction. After immunohistochemical processing, the vast majority of CTB labeled neurons were located in the reticular formation from the rostral cervical spinal cord to the facial motor nucleus, confirming previous studies. Labeled neurons caudal to the rostral ventrolateral medulla were usually spindle-shaped aligned along an oblique line running from the dorsal vagal nucleus to the ventrolateral reticular formation, while those more rostrally were multipolar with extended dendrites. Nine percent of retrogradely-labeled neurons were positive for both cFos and CTB after diving and 74% of these were found rostral to the obex. CTB also was transported transganglionically in primary afferent fibers, resulting in large granular deposits in dorsolateral, ventrolateral, and commissural subnuclei of the nucleus tractus solitarii (NTS) and finer deposits in lamina I and IV-V of the trigeminocervical complex. The overlap of parasympathetic preganglionic cardiac motor neurons activated by diving with those activated by baro- and chemoreceptors in the rostral ventrolateral medulla is discussed. Thus, the profound bradycardia seen with underwater submersion reinforces the notion that the mammalian diving response is the most powerful autonomic reflex known. PMID- 24478722 TI - Proliferation versus regeneration: the good, the bad and the ugly. PMID- 24478723 TI - The unusual stoichiometry of ADP activation of the KATP channel. AB - KATP channels, oligomers of 4 pore-forming Kir6.2 proteins and 4 sulfonylurea receptors (SUR), sense metabolism by monitoring both cytosolic ATP, which closes the channel by interacting with Kir6.2, and ADP, which opens it via SUR. SUR mutations that alter activation by ADP are a major cause of KATP channelopathies. We examined the mechanism of ADP activation by analysis of single-channel and macropatch recordings from Xenopus oocytes expressing various mixtures of wild type SUR2A and an ADP-activation-defective mutant. Evaluation of the data by a binomial distribution model suggests that wild-type and mutant SURs freely co assemble and that channel activation results from interaction of ADP with only 2 of 4 SURs. This finding explains the heterozygous nature of most KATP channelopathies linked to mutations altering ADP activation. It also suggests that the channel deviates from circular symmetry and could function as a dimer-of dimers. PMID- 24478724 TI - How man-made interference might cause gas bubble emboli in deep diving whales. AB - Recent cetacean mass strandings in close temporal and spatial association with sonar activity has raised the concern that anthropogenic sound may harm breath hold diving marine mammals. Necropsy results of the stranded whales have shown evidence of bubbles in the tissues, similar to those in human divers suffering from decompression sickness (DCS). It has been proposed that changes in behavior or physiological responses during diving could increase tissue and blood N2 levels, thereby increasing DCS risk. Dive data recorded from sperm, killer, long finned pilot, Blainville's beaked and Cuvier's beaked whales before and during exposure to low- (1-2 kHz) and mid- (2-7 kHz) frequency active sonar were used to estimate the changes in blood and tissue N2 tension (PN2 ). Our objectives were to determine if differences in (1) dive behavior or (2) physiological responses to sonar are plausible risk factors for bubble formation. The theoretical estimates indicate that all species may experience high N2 levels. However, unexpectedly, deep diving generally result in higher end-dive PN2 as compared with shallow diving. In this focused review we focus on three possible explanations: (1) We revisit an old hypothesis that CO2, because of its much higher diffusivity, forms bubble precursors that continue to grow in N2 supersaturated tissues. Such a mechanism would be less dependent on the alveolar collapse depth but affected by elevated levels of CO2 following a burst of activity during sonar exposure. (2) During deep dives, a greater duration of time might be spent at depths where gas exchange continues as compared with shallow dives. The resulting elevated levels of N2 in deep diving whales might also make them more susceptible to anthropogenic disturbances. (3) Extended duration of dives even at depths beyond where the alveoli collapse could result in slow continuous accumulation of N2 in the adipose tissues that eventually becomes a liability. PMID- 24478725 TI - Membrane-myofibril cross-talk in myofibrillogenesis and in muscular dystrophy pathogenesis: lessons from the zebrafish. AB - Striated muscle has a highly ordered structure in which specialized domains of the cell membrane involved in force transmission (costameres) and excitation contraction coupling (T tubules) as well as the internal membranes of the sarcoplasmic reticulum are organized over specific regions of the sarcomere. Optimal muscle function is dependent on this high level of organization but how it established and maintained is not well understood. Due to its ex utero development and transparency, the zebrafish embryo is an excellent vertebrate model for the study of dynamic relationships both within and between cells during development. Transgenic models have allowed the delineation of cellular migration and complex morphogenic rearrangements during the differentiation of skeletal myocytes and the assembly and organization of new myofibrils. Molecular targeting of genes and transcripts has allowed the identification of key requirements for myofibril assembly and organization. With the recent advances in gene editing approaches, the zebrafish will become an increasingly important model for the study of human myopathies and muscular dystrophies. Its high fecundity and small size make it well suited to high-throughput screenings to identify novel pharmacologic and molecular therapies for the treatment of a broad range of neuromuscular conditions. In this review, we examine the lessons learned from the zebrafish model regarding the complex interactions between the sarcomere and the sarcolemma that pattern the developing myocyte and discuss the potential for zebrafish as a model system to examine the pathophysiology of, and identify new treatments for, human myopathies and muscular dystrophies. PMID- 24478726 TI - Atrial fibrillation and microRNAs. AB - Atrial fibrillation (AF) is the most common sustained arrhythmia, especially in the elderly, and has a significant genetic component. Recently, several independent investigators have demonstrated a functional role for small non coding RNAs (microRNAs) in the pathophysiology of this cardiac arrhythmia. This report represents a systematic and updated appraisal of the main studies that established a mechanistic association between specific microRNAs and AF, focusing both on the regulation of electrical and structural remodeling of cardiac tissue. PMID- 24478728 TI - Why model? AB - Next generation sequencing technologies are bringing about a renaissance of mining approaches. A comprehensive picture of the genetic landscape of an individual patient will be useful, for example, to identify groups of patients that do or do not respond to certain therapies. The high expectations may however not be satisfied if the number of patient groups with similar characteristics is going to be very large. I therefore doubt that mining sequence data will give us an understanding of why and when therapies work. For understanding the mechanisms underlying diseases, an alternative approach is to model small networks in quantitative mechanistic detail, to elucidate the role of gene and proteins in dynamically changing the functioning of cells. Here an obvious critique is that these models consider too few components, compared to what might be relevant for any particular cell function. I show here that mining approaches and dynamical systems theory are two ends of a spectrum of methodologies to choose from. Drawing upon personal experience in numerous interdisciplinary collaborations, I provide guidance on how to model by discussing the question "Why model?" PMID- 24478727 TI - Calcium homeostasis in red blood cells of dialysis patients in dependence of erythropoietin treatment. PMID- 24478729 TI - An FMRI study of the influence of a history of substance abuse on working memory related brain activation in schizophrenia. AB - There has been little investigation of the effects of past substance abuse (SA) on working memory (WM) impairments in schizophrenia. This study examined the behavioral and neurobiological impact of past SA (6 months or longer abstinence period) on WM in schizophrenia. Thirty-seven schizophrenia patients (17 with past SA and 20 without) and 32 controls (12 with past SA and 20 without) completed two versions of a two-back WM task during fMRI scanning on separate days. Analyses focused on regions whose patterns of activation replicated across both n-back tasks. Schizophrenia patients were significantly less accurate than controls on both n-back tasks. No main effects or interactions with past SA on WM performance were observed. However, several fronto-parietal-thalamic regions showed an interaction between diagnostic group and past SA. These regions were significantly more active in controls with past SA compared to controls without past SA. Schizophrenia patients with or without past SA either showed no significant differences, or patients with past SA showed somewhat less activation compared to patients without past SA during WM. These results suggest robust effects of past SA on WM brain functioning in controls, but less impact of past SA in schizophrenia. This is consistent with previous literature indicating less impaired neurocognition in schizophrenia with SA. PMID- 24478730 TI - Early Life Stress in Depressive Patients: HPA Axis Response to GR and MR Agonist. AB - BACKGROUND: Evidence indicates that early life stress (ELS) can induce persistent changes in the hypothalamic-pituitary-adrenal (HPA) axis to respond to stress in the adult life that leads to depression. These appear to be related to the impairment of HPA hormones through binding to glucocorticoid (GR) and mineralocorticoid receptors (MR). The aim of this study was to evaluate the impact of ELS in HPA axis response to challenges with GR and MR agonists in depressed patients. METHODS: We included 30 subjects, 20 patients with current major depression (HAM-D21 >= 17). Patients were recruited into two groups according to ELS history assessed by the Childhood Trauma Questionnaire (CTQ). The cortisol measures in the saliva and plasma were evaluated after using (at 10:00 p.m.) placebo, fludrocortisone (MR agonist), or dexamethasone (GR agonist). RESULTS: Depressed patients showed a significantly lower salivary cortisol upon waking after placebo compared with controls. Moreover, cortisol awakening responses (CAR) after MR agonist were found to be lower in depressed patients than in controls. With CTQ scores, HAM-D21, body mass index and CAR after placebo, GR agonist, MR agonist we found in a Linear Regression model that depressive patients with ELS (p = 0.028) show differences between placebo vs. MR agonist (R = 0.51; p < 0.05) but not after GR agonist; in depressive patients, without ELS the data show differences between placebo vs. MR agonist (R = 0.69; p < 0.05); but now as well placebo vs. GR agonist (R = 0.53; p < 0.05). CONCLUSION: Our findings indicate that MR activity is impaired in depressed patients compared with controls. Furthermore, in spite of the previous limitations described, in depressed patients with ELS, there was suppression by MR agonist, indicating that patients with ELS are sensitive to MR agonists. In contrast with depressed patients without ELS, we find suppression after both MR and GR agonist. These data suggested that in ELS an imbalance exists between MR and GR with MR dysfunction. PMID- 24478732 TI - Major depressive disorder alters perception of emotional body movements. AB - Much recent research has shown an association between mood disorders and an altered emotion perception. However, these studies were conducted mainly with stimuli such as faces. This is the first study to examine possible differences in how people with major depressive disorder (MDD) and healthy controls perceive emotions expressed via body movements. Thirty patients with MDD and thirty healthy controls observed the video scenes of human interactions conveyed by point-light displays (PLDs). They rated the depicted emotions and judged their confidence in their rating. Results showed that patients with MDD rated the depicted interactions more negatively than healthy controls. They also rated interactions with negative emotionality as being more intense and were more confident in their ratings. It is concluded that patients with MDD exhibit an altered emotion perception compared to healthy controls when rating emotions expressed via body movements depicted in PLDs. PMID- 24478733 TI - Making memories of stressful events: a journey along epigenetic, gene transcription, and signaling pathways. AB - Strong psychologically stressful events are known to have a long-lasting impact on behavior. The consolidation of such, largely adaptive, behavioral responses to stressful events involves changes in gene expression in limbic brain regions such as the hippocampus and amygdala. However, the underlying molecular mechanisms were until recently unresolved. More than a decade ago, we started to investigate the role of these hormones in signaling and epigenetic mechanisms participating in the effects of stress on gene transcription in hippocampal neurons. We discovered a novel, rapid non-genomic mechanism in which glucocorticoids via glucocorticoid receptors facilitate signaling of the ERK-MAPK signaling pathway to the downstream nuclear kinases MSK1 and Elk-1 in dentate gyrus granule neurons. Activation of this signaling pathway results in serine10 (S10) phosphorylation and lysine14 (K14) acetylation at histone H3 (H3S10p-K14ac), leading to the induction of the immediate-early genes c-Fos and Egr-1. In addition, we found a role of the DNA methylation status of gene promoters. A series of studies showed that these molecular mechanisms play a critical role in the long-lasting consolidation of behavioral responses in the forced swim test and Morris water maze. Furthermore, an important role of GABA was found in controlling the epigenetic and gene transcriptional responses to psychological stress. Thus, psychologically stressful events evoke a long-term impact on behavior through changes in hippocampal function brought about by distinct glutamatergic and glucocorticoid-driven changes in epigenetic regulation of gene transcription, which are modulated by (local) GABAergic interneurons and limbic afferent inputs. These epigenetic processes may play an important role in the etiology of stress-related mental disorders such as major depressive and anxiety disorders like post-traumatic stress disorder. PMID- 24478734 TI - Unbounding the mental number line-new evidence on children's spatial representation of numbers. AB - Number line estimation (i.e., indicating the position of a given number on a physical line) is a standard assessment of children's spatial representation of number magnitude. Importantly, there is an ongoing debate on the question in how far the bounded task version with start and endpoint given (e.g., 0 and 100) might induce specific estimation strategies and thus may not allow for unbiased inferences on the underlying representation. Recently, a new unbounded version of the task was suggested with only the start point and a unit fixed (e.g., the distance from 0 to 1). In adults this task provided a less biased index of the spatial representation of number magnitude. Yet, so far there are no children data available for the unbounded number line estimation task. Therefore, we conducted a cross-sectional study on primary school children performing both, the bounded and the unbounded version of the task. We observed clear evidence for systematic strategic influences (i.e., the consideration of reference points) in the bounded number line estimation task for children older than grade two whereas there were no such indications for the unbounded version for any one of the age groups. In summary, the current data corroborate the unbounded number line estimation task to be a valuable tool for assessing children's spatial representation of number magnitude in a systematic and unbiased manner. Yet, similar results for the bounded and the unbounded version of the task for first- and second-graders may indicate that both versions of the task might assess the same underlying representation for relatively younger children-at least in number ranges familiar to the children assessed. This is of particular importance for inferences about the nature and development of children's magnitude representation. PMID- 24478731 TI - Effects of nicotine on the neurophysiological and behavioral effects of ketamine in humans. AB - BACKGROUND: N-methyl-d-aspartate (NMDA) receptor hypofunction has been implicated in the pathophysiology of schizophrenia and its associated neurocognitive impairments. The high rate of cigarette smoking in schizophrenia raises questions about how nicotine modulates putative NMDA receptor hypofunction in the illness. Accordingly, we examined the modulatory effects of brain nicotinic acetylcholine receptor (nAChR) stimulation on NMDA receptor hypofunction by examining the interactive effects of nicotine, a nAChR agonist, and ketamine, a non-competitive NMDA receptor antagonist, on behavioral and neurophysiological measures in healthy human volunteers. METHODS: From an initial sample of 17 subjects (age range 18-55 years), 8 subjects successfully completed 4 test sessions, each separated by at least 3 days, during which they received ketamine or placebo and two injections of nicotine or placebo in a double-blind, counterbalanced manner. Schizophrenia-like effects Positive and Negative Syndrome Scale, perceptual alterations Clinician Administered Dissociative Symptoms Scale, subjective effects Visual Analog Scale and auditory event-related brain potentials (mismatch negativity, MMN; P300) were assessed during each test session. RESULTS: Consistent with existing studies, ketamine induced transient schizophrenia-like behavioral effects. P300 was reduced and delayed by ketamine regardless of whether it was elicited by a target (P3b) or novel (P3a) stimulus, while nicotine only reduced the amplitude of P3a. Nicotine did not rescue P300 from the effects of ketamine; the interactions of ketamine and nicotine were not significant. While nicotine significantly reduced MMN amplitude, ketamine did not. CONCLUSION: Nicotine failed to modulate ketamine-induced neurophysiological and behavioral effects in this preliminary study. Interestingly, ketamine reduced P3b amplitude and nicotine reduced P3a amplitude, suggesting independent roles of NMDA receptor and nAChR in the generation of P3b and P3a, respectively. PMID- 24478735 TI - Analysis of cursive letters, syllables, and words handwriting in a French second grade child with Developmental Coordination Disorder and comparison with typically developing children. AB - Poor handwriting is a core deficit in Developmental Coordination Disorder (DCD). In a previous study, we compared the evolution of cursive letters handwriting in a girl with DCD throughout her second-grade year with that of typically developing (TD) children. We found that her handwriting evolved much less than that of TD children and remained similar to that of pre-schoolers at all stages, suggesting that her handwriting skills have reached a steady state level. We present here a continuation of this work, in which we focused on the velocity aspects of handwriting in another French child with DCD. Indeed, different velocity patterns have been observed in Chinese and English children with DCD. In the French cursive style of writing, consecutive letters are joined, a major difference with the English script style of writing. We thus analyzed the handwriting of a second-grade French girl with DCD, not only for isolated letters but also for syllables and words, in comparison to that of TD first-graders (6-7 years old; N = 85) and second-graders (7-8 years old; N = 88). Each written track was digitized, and nine kinematic parameters were measured to evaluate writing fluency. Results showed that the productions of the child with DCD were more similar to those of first-graders than to those of second-graders. In line with our previous study, the most discriminative parameters between the child with DCD and TD children were size and mean speed. Moreover, her handwriting was less fluent than that of TD children. In contrast to previous observations, we observed a higher writing velocity of the child with DCD when compared to TD children, whatever the complexity of the item, and no significant difference with TD children in the pausing time during writing. These differences may reflect linguistic specificities. For syllables and words, each letter was treated separately as a single unit, thus reflecting a problem in anticipation and automation. PMID- 24478736 TI - Recall and recognition of in-game advertising: the role of game control. AB - Digital gaming has become one of the largest entertainment sectors worldwide, increasingly turning the medium into a promising vehicle for advertisers. As a result, the inclusion of advertising messages in digital games or in-game advertising (IGA) is expected to grow steadily over the course of the following years. However, much work is still needed to maximize the effectiveness of IGA. The aim of the study was to contribute to IGA effectiveness research by analyzing the impact of two factors on the processing of IGA in terms of brand awareness. The primary objective was to investigate the effect of a person's sense of involvement related to the control and movement mechanisms in a game (i.e., kinesthetic involvement). A within-subjects experiment was conducted in which control over a racing game was varied by manipulating game controller type, resulting in two experimental conditions (symbolic versus mimetic controller). Results show that the variation in game controller has a significant effect on the recall and recognition of the brands integrated into the game, and that this effect can be partially brought back to players' perceived control over the game: when a game is easier to control, the control mechanisms require less conscious attention, freeing attentional resources that can be subsequently spent on other elements of the game such as IGA. A second factor that was taken into account in the study was brand prominence. The influence of both the size and spatial position of in-game advertisements was examined. Findings demonstrate that there are significant changes in effectiveness between different types of placements. Spatial position seems to be the most important placement characteristic, with central brand placements obtaining the highest recall and recognition scores. The effect of ad size is much smaller, with the effectiveness of the large placements not differing significantly from the effectiveness of their smaller counterparts. PMID- 24478737 TI - The nature of holistic processing in face and object recognition: current opinions. PMID- 24478738 TI - Reflectance, illumination, and appearance in color constancy. AB - We studied color constancy using a pair of identical 3-D Color Mondrian displays. We viewed one 3-D Mondrian in nearly uniform illumination, and the other in directional, nonuniform illumination. We used the three dimensional structures to modulate the light falling on the painted surfaces. The 3-D structures in the displays were a matching set of wooden blocks. Across Mondrian displays, each corresponding facet had the same paint on its surface. We used only 6 chromatic, and 5 achromatic paints applied to 104 block facets. The 3-D blocks add shadows and multiple reflections not found in flat Mondrians. Both 3-D Mondrians were viewed simultaneously, side-by-side. We used two techniques to measure correlation of appearance with surface reflectance. First, observers made magnitude estimates of changes in the appearances of identical reflectances. Second, an author painted a watercolor of the 3-D Mondrians. The watercolor's reflectances quantified the changes in appearances. While constancy generalizations about illumination and reflectance hold for flat Mondrians, they do not for 3-D Mondrians. A constant paint does not exhibit perfect color constancy, but rather shows significant shifts in lightness, hue and chroma in response to the structure in the nonuniform illumination. Color appearance depends on the spatial information in both the illumination and the reflectances of objects. The spatial information of the quanta catch from the array of retinal receptors generates sensations that have variable correlation with surface reflectance. Models of appearance in humans need to calculate the departures from perfect constancy measured here. This article provides a dataset of measurements of color appearances for computational models of sensation. PMID- 24478739 TI - The ABC of moral development: an attachment approach to moral judgment. AB - As with other cognitive faculties, the etiology of moral judgment and its connection to early development is complex. Because research is limited, the causative and contributory factors to the development of moral judgment in preverbal infants are unclear. However, evidence is emerging from studies within both infant research and moral psychology that may contribute to our understanding of the early development of moral judgments. Though its finding are preliminary, this proposed paradigm synthesizes these findings to generate an overarching, model of the process that appears to contribute to the development of moral judgment in the first year of life. I will propose that through early interactions with the caregiver, the child acquires an internal representation of a system of rules that determine how right/wrong judgments are to be construed, used, and understood. By breaking moral situations down into their defining features, the attachment model of moral judgment outlines a framework for a universal moral faculty based on a universal, innate, deep structure that appears uniformly in the structure of almost all moral judgments regardless of their content. The implications of the model for our understanding of innateness, universal morality, and the representations of moral situations are discussed. PMID- 24478740 TI - An evolutionary perspective on gradual formation of superego in the primal horde. AB - Freud proposed that the processes which occurred in the primal horde are essential for understanding superego formation and therefore, the successful dissolution of the Oedipus complex. However, Freud theorized superego formation in the primal horde as if it is an instant, all-or-none achievement. The present paper proposes an alternative model aiming to explain gradual development of superego in the primitive man. The proposed model is built on knowledge from evolutionary and neural sciences as well as anthropology, and it particularly focuses on the evolutionary significance of the acquisition of fire by hominids in the Pleistocene period in the light of up-to-date archaeological findings. Acquisition of fire is discussed as a form of sublimation which might have helped Prehistoric man to maximize the utility of limited evolutionary biological resources, potentially contributing to the rate and extent of bodily evolution. The limitations of both Freud's original conceptualization and the present model are discussed accordingly in an interdisciplinary framework. PMID- 24478741 TI - Narrative or self-feeling? A historical note on the biological foundation of the "depressive situation". PMID- 24478742 TI - An overview of human handedness in twins. AB - There has been a long-standing debate on the complex correlation between the development of human hand preference and brain lateralization. Handedness, used as a proxy for cerebral lateralization, is a topic of considerable importance because of its potential to reveal the mechanisms of the underlying pathophysiology of problems related to brain development or cognitive systems. Twin studies, which represent an important method of research in human genetics, would provide valuable suggestions to the studies on the relationship between lateralization and cognitive systems. Many studies have been performed using twin subjects; however, the results are inconsistent, partly because of sample size, background assumptions, data limits or inaccuracies, incorrect zygosity classification, and/or lack of birth histories. In summary, within the long history and large number of twin studies performed on handedness, a surprisingly large number of controversial findings have been reported, suggesting the complicated nature of this phenotype. In this mini review, the wide variety of twin studies on human handedness performed to date are introduced. PMID- 24478743 TI - Hedonic appreciation and verbal description of pleasant and unpleasant odors in untrained, trainee cooks, flavorists, and perfumers. AB - Olfaction is characterized by a salient hedonic dimension. Previous studies have shown that these affective responses to odors are modulated by physicochemical, physiological, and cognitive factors. The present study examined expertise influenced processing of pleasant and unpleasant odors on both perceptual and verbal levels. For this, performance on two olfactory tasks was compared between novices, trainee cooks, and experts (perfumers and flavorists): Members of all groups rated the intensity and pleasantness of pleasant and unpleasant odors (perceptual tasks). They were also asked to describe each of the 20 odorants as precisely as possible (verbal description task). On a perceptual level, results revealed that there were no group-related differences in hedonic ratings for unpleasant and pleasant odors. On a verbal level, descriptions of smells were richer (e.g., chemical, olfactory qualities, and olfactory sources terms) and did not refer to pleasantness in experts compared to untrained subjects who used terms referring to odor sources (e.g., candy) accompanied by terms referring to odor hedonics. In conclusion, the present study suggests that as novices, experts are able to perceptually discriminate odors on the basis of their pleasantness. However, on a semantic level, they conceptualize odors differently, being inclined to avoid any reference to odor hedonics. PMID- 24478744 TI - Phonemic awareness as a pathway to number transcoding. AB - Although verbal and numerical abilities have a well-established interaction, the impact of phonological processing on numeric abilities remains elusive. The aim of this study is to investigate the role of phonemic awareness in number processing and to explore its association with other functions such as working memory and magnitude processing. One hundred seventy-two children in 2nd grade to 4th grade were evaluated in terms of their intelligence, number transcoding, phonemic awareness, verbal and visuospatial working memory and number sense (non symbolic magnitude comparison) performance. All of the children had normal intelligence. Among these measurements of magnitude processing, working memory and phonemic awareness, only the last was retained in regression and path models predicting transcoding ability. Phonemic awareness mediated the influence of verbal working memory on number transcoding. The evidence suggests that phonemic awareness significantly affects number transcoding. Such an association is robust and should be considered in cognitive models of both dyslexia and dyscalculia. PMID- 24478745 TI - Erratum: Navigating comics: an empirical and theoretical approach to strategies of reading comic page layouts. PMID- 24478746 TI - Action feedback affects the perception of action-related objects beyond actual action success. AB - Successful object-oriented action typically increases the perceived size of aimed target objects. This phenomenon has been assumed to reflect an impact of an actor's current action ability on visual perception. The actual action ability and the explicit knowledge of action outcome, however, were confounded in previous studies. The present experiments aimed at disentangling these two factors. Participants repeatedly tried to hit a circular target varying in size with a stylus movement under restricted feedback conditions. After each movement they were explicitly informed about the success in hitting the target and were then asked to judge target size. The explicit feedback regarding movement success was manipulated orthogonally to actual movement success. The results of three experiments indicated the participants' bias to judge relatively small targets as larger and relatively large targets as smaller after explicit feedback of failure than after explicit feedback of success. This pattern was independent of the actual motor performance, suggesting that the actors' evaluations of motor actions may bias perception of target objects in itself. PMID- 24478747 TI - Not all numbers are equal: preferences and biases among children and adults when generating random sequences. AB - We investigate the number preferences of children and adults when generating random digit sequences. Previous research has shown convincingly that adults prefer smaller numbers when randomly choosing between responses 1-6. We analyze randomization choices made by both children and adults, considering a range of experimental studies and task configurations. Children - most of whom are between 8 and 11~years - show a preference for relatively large numbers when choosing numbers 1-10. Adults show a preference for small numbers with the same response set. We report a modest association between children's age and numerical bias. However, children also exhibit a small number bias with a smaller response set available, and they show a preference specifically for the numbers 1-3 across many datasets. We argue that number space demonstrates both continuities (numbers 1-3 have a distinct status) and change (a developmentally emerging bias toward the left side of representational space or lower numbers). PMID- 24478748 TI - How accurate are we at assessing others' well-being? The example of welfare assessment in horses. AB - Healthcare practitioners such as physicians or nurses often underestimate patients' well-being impairment (e.g., pain, anxiety) which may lead to undesirable consequences on treatment decisions. Lack of recognition/identification of signals and over-exposure are two reasons invoked, but a combination of factors may be involved. Studying human decoding of animals' expressions of emotions showed that "identification" to the subject was necessary to decode the other's internal state. In the present study we wanted to compare caretakers' reports on the prevalence of stereotypic or abnormal repetitive behaviors, to ethological observations performed by an experienced observer on the same horses in order to test the impact of these different factors. On the first hand, a questionnaire was given hand to hand to the caretakers. On the other hand, the experienced observer spent 18 h observing the horses in each stable. Here we show that caretakers strongly underestimate horses' expressions of well-being impairment. The caretakers who had a strong concern about their horses' well-being were also those who reported the more accurately SB/ARB's prevalence, showing that "identification" to the subject is a primary factor of bad-being signal's detection. Over-exposure also appeared to be involved as no SB/ARB was reported in stables where most of the horses were performing these abnormal behaviors. Being surrounded by a large population of individuals expressing clear signals of bad-being may change professionals' perceptions of what are behaviors or expressions of well being. These findings are of primary importance as (1) they illustrate the interest of using human-animal relationships to evaluate humans' abilities to decode others' states; (2) they put limitations on questionnaire-based studies of welfare. PMID- 24478750 TI - Use of MRI for Risk Stratification in Anticoagulation Decision Making in Atrial Fibrillation: Promising, but More Data are Needed for a Robust Algorithm. PMID- 24478749 TI - A novel closed-head model of mild traumatic brain injury caused by primary overpressure blast to the cranium produces sustained emotional deficits in mice. AB - Emotional disorders are a common outcome from mild traumatic brain injury (TBI) in humans, but their pathophysiological basis is poorly understood. We have developed a mouse model of closed-head blast injury using an air pressure wave delivered to a small area on one side of the cranium, to create mild TBI. We found that 20-psi blasts in 3-month-old C57BL/6 male mice yielded no obvious behavioral or histological evidence of brain injury, while 25-40 psi blasts produced transient anxiety in an open field arena but little histological evidence of brain damage. By contrast, 50-60 psi blasts resulted in anxiety-like behavior in an open field arena that became more evident with time after blast. In additional behavioral tests conducted 2-8 weeks after blast, 50-60 psi mice also demonstrated increased acoustic startle, perseverance of learned fear, and enhanced contextual fear, as well as depression-like behavior and diminished prepulse inhibition. We found no evident cerebral pathology, but did observe scattered axonal degeneration in brain sections from 50 to 60 psi mice 3-8 weeks after blast. Thus, the TBI caused by single 50-60 psi blasts in mice exhibits the minimal neuronal loss coupled to "diffuse" axonal injury characteristic of human mild TBI. A reduction in the abundance of a subpopulation of excitatory projection neurons in basolateral amygdala enriched in Thy1 was, however, observed. The reported link of this neuronal population to fear suppression suggests their damage by mild TBI may contribute to the heightened anxiety and fearfulness observed after blast in our mice. Our overpressure air blast model of concussion in mice will enable further studies of the mechanisms underlying the diverse emotional deficits seen after mild TBI. PMID- 24478752 TI - Traumatic brain injury and olfaction: a systematic review. AB - Traumatic brain injury (TBI) is a common condition that is often complicated by neuropsychiatric sequelae that can have major impacts on function and quality of life. An alteration in the sense of smell is recognized as a relatively common complication of TBI; however in clinical practice, this complication may not be sought or adequately characterized. We conducted a systematic review of studies concerned with olfactory functioning following TBI. Our predetermined criteria led to the identification of 25 studies published in English, which we examined in detail. We have tabulated the data from these studies in eight separate tables, beginning with Table 1, which highlights each study's key findings, and we provide a summary/synthesis of the findings in the accompanying results and discussion sections. Despite widely differing methodologies, the studies attest to a high frequency of post-TBI olfactory dysfunction and indicate that its presence can serve as a potential marker of additional structural or functional morbidities. PMID- 24478751 TI - "Left neglected," but only in far space: spatial biases in healthy participants revealed in a visually guided grasping task. AB - Hemispatial neglect is a common outcome of stroke that is characterized by the inability to orient toward, and attend to stimuli in contralesional space. It is established that hemispatial neglect has a perceptual component, however, the presence and severity of motor impairments is controversial. Establishing the nature of space use and spatial biases during visually guided actions amongst healthy individuals is critical to understanding the presence of visuomotor deficits in patients with neglect. Accordingly, three experiments were conducted to investigate the effect of object spatial location on patterns of grasping. Experiment 1 required right-handed participants to reach and grasp for blocks in order to construct 3D models. The blocks were scattered on a tabletop divided into equal size quadrants: left near, left far, right near, and right far. Identical sets of building blocks were available in each quadrant. Space use was dynamic, with participants initially grasping blocks from right near space and tending to "neglect" left far space until the final stages of the task. Experiment 2 repeated the protocol with left-handed participants. Remarkably, left-handed participants displayed a similar pattern of space use to right-handed participants. In Experiment 3 eye movements were examined to investigate whether "neglect" for grasping in left far reachable space had its origins in attentional biases. It was found that patterns of eye movements mirrored patterns of reach-to grasp movements. We conclude that there are spatial biases during visually guided grasping, specifically, a tendency to neglect left far reachable space, and that this "neglect" is attentional in origin. The results raise the possibility that visuomotor impairments reported among patients with right hemisphere lesions when working in contralesional space may result in part from this inherent tendency to "neglect" left far space irrespective of the presence of unilateral visuospatial neglect. PMID- 24478753 TI - Reaching and grasping in autism spectrum disorder: a review of recent literature. AB - Impairments in motor functioning, which, until recently, have rarely been a primary focus in autism spectrum disorder (ASD) research, may play a key role in the early expression of biological vulnerability and be associated with key social-communication deficits. This review summarizes current knowledge of motor behavior in ASD, focusing specifically on reaching and grasping. Convergent data across the lifespan indicate that impairments to reaching and grasping emerge early in life, affect the planning and execution of motor programs, and may be impacted by additional impairments to sensory control of motor behavior. The relationship between motor impairments and diagnostic outcomes will be discussed. PMID- 24478754 TI - Melodic intonation therapy: back to basics for future research. AB - We present a critical review of the literature on melodic intonation therapy (MIT), one of the most formalized treatments used by speech-language therapist in Broca's aphasia. We suggest basic clarifications to enhance the scientific support of this promising treatment. First, therapeutic protocols using singing as a speech facilitation technique are not necessarily MIT. The goal of MIT is to restore propositional speech. The rationale is that patients can learn a new way to speak through singing by using language-capable regions of the right cerebral hemisphere. Eventually, patients are supposed to use this way of speaking permanently but not to sing overtly. We argue that many treatment programs covered in systematic reviews on MIT's efficacy do not match MIT's therapeutic goal and rationale. Critically, we identified two main variations of MIT: the French therapie melodique et rythmee (TMR) that trains patients to use singing overtly as a facilitation technique in case of speech struggle and palliative versions of MIT that help patients with the most severe expressive deficits produce a limited set of useful, readymade phrases. Second, we distinguish between the immediate effect of singing on speech production and the long-term effect of the entire program on language recovery. Many results in the MIT literature can be explained by this temporal perspective. Finally, we propose that MIT can be viewed as a treatment of apraxia of speech more than aphasia. This issue should be explored in future experimental studies. PMID- 24478755 TI - Comparing the Predictive Ability of Prognostic Models in Ischemic Stroke; Derivation, Validation, and Discrimination Beyond the ROC Curve. PMID- 24478756 TI - Central circadian control of female reproductive function. AB - Over the past two decades, it has become clear just how much of our physiology is under the control of the suprachiasmatic nucleus (SCN) and the cell-intrinsic molecular clock that ticks with a periodicity of approximately 24 h. The SCN prepares our digestive system for meals, our adrenal axis for the stress of waking up in the morning, and the genes expressed in our muscles when we prepare to exercise. Long before molecular studies of genes such as Clock, Bmal1, and the Per homologs were possible, it was obvious that female reproductive function was under strict circadian control at every level of the hypothalamic-pituitary gonadal axis, and in the establishment and successful maintenance of pregnancy. This review highlights our current understanding of the role that the SCN plays in regulating female reproductive physiology, with a special emphasis on the advances made possible through the use of circadian mutant mice. PMID- 24478757 TI - Comment on "The Use of BRET to Study Receptor-Protein Interactions". PMID- 24478758 TI - Angiopoietin-like proteins: a comprehensive look. AB - Angiopoietin-like proteins (ANGPTLs) are a family of proteins structurally similar to the angiopoietins. To date, eight ANGPTLs have been discovered, namely ANGPTL1 to ANGPTL8. Emerging evidence implies a key role for ANGPTLs in the regulation of a plethora of physiological and pathophysiological processes. Most of the ANGPTLs exhibit multibiological properties, including established functional roles in lipid and glucose metabolism, inflammation, hematopoiesis, and cancer. This report represents a systematic and updated appraisal of this class of proteins, focusing on the main features of each ANGPTL. PMID- 24478759 TI - Insulin-Like Factor 3 and the HPG Axis in the Male. AB - The hypothalamic-pituitary-gonadal (HPG) axis comprises pulsatile GnRH from the hypothalamus impacting on the anterior pituitary to induce expression and release of both LH and FSH into the circulation. These in turn stimulate receptors on testicular Leydig and Sertoli cells, respectively, to promote steroidogenesis and spermatogenesis. Both Leydig and Sertoli cells exhibit negative feedback to the pituitary and/or hypothalamus via their products testosterone and inhibin B, respectively, thereby allowing tight regulation of the HPG axis. In particular, LH exerts both acute control on Leydig cells by influencing steroidogenic enzyme activity, as well as chronic control by impacting on Leydig cell differentiation and gene expression. Insulin-like peptide 3 (INSL3) represents an additional and different endpoint of the HPG axis. This Leydig cell hormone interacts with specific receptors, called RXFP2, on Leydig cells themselves to modulate steroidogenesis, and on male germ cells, probably to synergize with androgen dependent Sertoli cell products to support spermatogenesis. Unlike testosterone, INSL3 is not acutely regulated by the HPG axis, but is a constitutive product of Leydig cells, which reflects their number and/or differentiation status and their ability therefore to produce various factors including steroids, together this is referred to as Leydig cell functional capacity. Because INSL3 is not subject to the acute episodic fluctuations inherent in the HPG axis itself, it serves as an excellent marker for Leydig cell differentiation and functional capacity, as in puberty, or in monitoring the treatment of hypogonadal patients, and at the same time buffering the HPG output. PMID- 24478761 TI - Widespread dissemination of class 1 integron components in soils and related ecosystems as revealed by cultivation-independent analysis. AB - Class 1 integrons contribute to the emerging problem of antibiotic resistance in human medicine by acquisition, exchange, and expression of resistance genes embedded within gene cassettes. Besides the clinical setting they were recently reported from environmental habitats and often located on plasmids and transposons, facilitating their transfer and spread within bacterial communities. In this study we aimed to provide insights into the occurrence of genes typically associated with the class 1 integrons in previously not studied environments with or without human impact and their association with IncP-1 plasmids. Total community DNA was extracted from manure-treated and untreated soils, lettuce and potato rhizosphere, digestates, and an on-farm biopurification system and screened by PCR with subsequent Southern blot hybridization for the presence of the class 1 integrase gene intI1 as well as qacE and qacEDelta 1 resistance genes. The results revealed a widespread dissemination of class 1 integrons in the environments analyzed, mainly related to the presence of qacEDelta 1 genes. All 28 IncP-1epsilon plasmids carrying class 1 integrons, which were captured exogenously in a recent study from piggery manure and soils treated with manure, carried qacEDelta 1 genes. Based on the strong hybridization signals in the rhizosphere of lettuce compared to the potato rhizosphere, the abundances of intI1, qacE/qacEDelta 1, and sul1 genes were quantified relative to the 16S rRNA gene abundance by real-time PCR in the rhizosphere of lettuce planted in three different soils and in the corresponding bulk soil. A significant enrichment of intI1 and qacE/qacEDelta 1 genes was confirmed in the rhizosphere of lettuce compared to bulk soil. Additionally, the relative abundance of korB genes specific for IncP-1 plasmids was enriched in the rhizosphere and correlated to the intI1 gene abundance indicating that IncP-1 plasmids might have contributed to the spread of class 1 integrons in the analyzed soils. PMID- 24478760 TI - Central and direct regulation of testicular activity by gonadotropin-inhibitory hormone and its receptor. AB - Gonadotropin-inhibitory hormone (GnIH) was first identified in Japanese quail to be an inhibitor of gonadotropin synthesis and release. GnIH peptides have since been identified in all vertebrates, and all share an LPXRFamide (X = L or Q) motif at their C-termini. The receptor for GnIH is the G protein-coupled receptor 147 (GPR147), which inhibits cAMP signaling. Cell bodies of GnIH neurons are located in the paraventricular nucleus (PVN) in birds and the dorsomedial hypothalamic area (DMH) in most mammals. GnIH neurons in the PVN or DMH project to the median eminence to control anterior pituitary function via GPR147 expressed in gonadotropes. Further, GnIH inhibits gonadotropin-releasing hormone (GnRH)-induced gonadotropin subunit gene transcription by inhibiting the adenylate cyclase/cAMP/PKA-dependent ERK pathway in an immortalized mouse gonadotrope cell line (LbetaT2 cells). GnIH neurons also project to GnRH neurons that express GPR147 in the preoptic area (POA) in birds and mammals. Accordingly, GnIH can inhibit gonadotropin synthesis and release by decreasing the activity of GnRH neurons as well as by directly inhibiting pituitary gonadotrope activity. GnIH and GPR147 can thus centrally suppress testosterone secretion and spermatogenesis by acting in the hypothalamic-pituitary-gonadal axis. GnIH and GPR147 are also expressed in the testis of birds and mammals, possibly acting in an autocrine/paracrine manner to suppress testosterone secretion and spermatogenesis. GnIH expression is also regulated by melatonin, stress, and social environment in birds and mammals. Accordingly, the GnIH-GPR147 system may play a role in transducing physical and social environmental information to regulate optimal testicular activity in birds and mammals. This review discusses central and direct inhibitory effects of GnIH and GPR147 on testosterone secretion and spermatogenesis in birds and mammals. PMID- 24478762 TI - Interaction of Mason-Pfizer monkey virus matrix protein with plasma membrane. AB - Budding is the final step of the late phase of retroviral life cycle. It begins with the interaction of Gag precursor with plasma membrane (PM) through its N terminal domain, the matrix protein (MA). However, single genera of Retroviridae family differ in the way how they interact with PM. While in case of Lentiviruses (e.g., human immunodeficiency virus) the structural polyprotein precursor Gag interacts with cellular membrane prior to the assembly, Betaretroviruses [Mason Pfizer monkey virus (M-PMV)] first assemble their virus-like particles (VLPs) in the pericentriolar region of the infected cell and therefore, already assembled particles interact with the membrane. Although both these types of retroviruses use similar mechanism of the interaction of Gag with the membrane, the difference in the site of assembly leads to some differences in the mechanism of the interaction. Here we describe the interaction of M-PMV MA with PM with emphasis on the structural aspects of the interaction with single phospholipids. PMID- 24478763 TI - Molecular characterization of vulnibactin biosynthesis in Vibrio vulnificus indicates the existence of an alternative siderophore. AB - Vibrio vulnificus is a halophilic estuarine bacterium that causes fatal septicemia and necrotizing wound infections in humans. Virulent V. vulnificus isolates produce a catechol siderophore called vulnibactin, made up of one residue of 2, 3-dihydroxybenzoic acid (2, 3-DHBA) and two residues of salicylic acid (SA). Vulnibactin biosynthetic genes (VV2_0828 to VV2_0844) are clustered at one locus of chromosome 2, expression of which is significantly up-regulated in vivo. In the present study, we decipher the biosynthetic network of vulnibactin, focusing specifically on genes around SA and 2, 3-DHBA biosynthetic steps. Deletion mutant of isochorismate pyruvate lyase (VV2_0839) or 2, 3 dihydroxybenzoate-2, 3-dehydrogenase (VV2_0834) showed retarded growth under iron limited conditions though the latter showed more significant growth defect than the former, suggesting a dominant role of 2, 3-DHBA in the vulnibactin biosynthesis. A double deletion mutant of VV2_0839 and VV2_0834 manifested additional growth defect under iron limitation. Though the growth defect of respective single deletion mutants could be restored by exogenous SA or 2, 3 DHBA, only 2, 3-DHBA could rescue the double mutant when supplied alone. However, double mutant could be rescued with SA only when hydrogen peroxide was supplied exogenously, suggesting a chemical conversion of SA to 2, 3-DHBA. Assembly of two SA and one 2, 3-DHBA into vulnibactin was mediated by two AMP ligase genes (VV2_0836 and VV2_0840). VV2_0836 deletion mutant showed more significant growth defect under iron limitation, suggesting its dominant function. In conclusion, using molecular genetic analytical tools, we confirm that vulnibactin is assembled of both 2, 3-DHBA and SA. However, conversion of SA to 2, 3-DHBA in presence of hydrogen peroxide and growth profile of AMP ligase mutants suggest a plausible existence of yet unidentified alternative siderophore that may be composed solely of 2, 3-DHBA. PMID- 24478764 TI - Root exudation and root development of lettuce (Lactuca sativa L. cv. Tizian) as affected by different soils. AB - Development and activity of plant roots exhibit high adaptive variability. Although it is well-documented, that physicochemical soil properties can strongly influence root morphology and root exudation, particularly under field conditions, a comparative assessment is complicated by the impact of additional factors, such as climate and cropping history. To overcome these limitations, in this study, field soils originating from an unique experimental plot system with three different soil types, which were stored at the same field site for 10 years and exposed to the same agricultural management practice, were used for an investigation on effects of soil type on root development and root exudation. Lettuce (Lactuca sativa L. cv. Tizian) was grown as a model plant under controlled environmental conditions in a minirhizotrone system equipped with root observation windows (rhizoboxes). Root exudates were collected by placing sorption filters onto the root surface followed by subsequent extraction and GC MS profiling of the trapped compounds. Surprisingly, even in absence of external stress factors with known impact on root exudation, such as pH extremes, water and nutrient limitations/toxicities or soil structure effects (use of sieved soils), root growth characteristics (root length, fine root development) as well as profiles of root exudates were strongly influenced by the soil type used for plant cultivation. The results coincided well with differences in rhizosphere bacterial communities, detected in field-grown lettuce plants cultivated on the same soils (Schreiter et al., this issue). The findings suggest that the observed differences may be the result of plant interactions with the soil-specific microbiomes. PMID- 24478765 TI - Potential of known and short prokaryotic protein motifs as a basis for novel peptide-based antibacterial therapeutics: a computational survey. AB - Short linear motifs (SLiMs) are functional stretches of protein sequence that are of crucial importance for numerous biological processes by mediating protein protein interactions. These motifs often comprise peptides of less than 10 amino acids that modulate protein-protein interactions. While well-characterized in eukaryotic intracellular signaling, their role in prokaryotic signaling is less well-understood. We surveyed the distribution of known motifs in prokaryotic extracellular and virulence proteins across a range of bacterial species and conducted searches for novel motifs in virulence proteins. Many known motifs in virulence effector proteins mimic eukaryotic motifs and enable the pathogen to control the intracellular processes of their hosts. Novel motifs were detected by finding those that had evolved independently in three or more unrelated virulence proteins. The search returned several significantly over-represented linear motifs of which some were known motifs and others are novel candidates with potential roles in bacterial pathogenesis. A putative C-terminal G[AG].$ motif found in type IV secretion system proteins was among the most significant detected. A KK$ motif that has been previously identified in a plasminogen binding protein, was demonstrated to be enriched across a number of adhesion and lipoproteins. While there is some potential to develop peptide drugs against bacterial infection based on bacterial peptides that mimic host components, this could have unwanted effects on host signaling. Thus, novel SLiMs in virulence factors that do not mimic host components but are crucial for bacterial pathogenesis, such as the type IV secretion system, may be more useful to develop as leads for anti-microbial peptides or drugs. PMID- 24478767 TI - Current taxonomy of phages infecting lactic acid bacteria. AB - Phages infecting lactic acid bacteria have been the focus of significant research attention over the past three decades. Through the isolation and characterization of hundreds of phage isolates, it has been possible to classify phages of the dairy starter and adjunct bacteria Lactococus lactis, Streptococcus thermophilus, Leuconostoc spp., and Lactobacillus spp. Among these, phages of L. lactis have been most thoroughly scrutinized and serve as an excellent model system to address issues that arise when attempting taxonomic classification of phages infecting other LAB species. Here, we present an overview of the current taxonomy of phages infecting LAB genera of industrial significance, the methods employed in these taxonomic efforts and how these may be employed for the taxonomy of phages of currently underrepresented and emerging phage species. PMID- 24478768 TI - Localized electron transfer rates and microelectrode-based enrichment of microbial communities within a phototrophic microbial mat. AB - Phototrophic microbial mats frequently exhibit sharp, light-dependent redox gradients that regulate microbial respiration on specific electron acceptors as a function of depth. In this work, a benthic phototrophic microbial mat from Hot Lake, a hypersaline, epsomitic lake located near Oroville in north-central Washington, was used to develop a microscale electrochemical method to study local electron transfer processes within the mat. To characterize the physicochemical variables influencing electron transfer, we initially quantified redox potential, pH, and dissolved oxygen gradients by depth in the mat under photic and aphotic conditions. We further demonstrated that power output of a mat fuel cell was light-dependent. To study local electron transfer processes, we deployed a microscale electrode (microelectrode) with tip size ~20 MUm. To enrich a subset of microorganisms capable of interacting with the microelectrode, we anodically polarized the microelectrode at depth in the mat. Subsequently, to characterize the microelectrode-associated community and compare it to the neighboring mat community, we performed amplicon sequencing of the V1-V3 region of the 16S gene. Differences in Bray-Curtis beta diversity, illustrated by large changes in relative abundance at the phylum level, suggested successful enrichment of specific mat community members on the microelectrode surface. The microelectrode-associated community exhibited substantially reduced alpha diversity and elevated relative abundances of Prosthecochloris, Loktanella, Catellibacterium, other unclassified members of Rhodobacteraceae, Thiomicrospira, and Limnobacter, compared with the community at an equivalent depth in the mat. Our results suggest that local electron transfer to an anodically polarized microelectrode selected for a specific microbial population, with substantially more abundance and diversity of sulfur-oxidizing phylotypes compared with the neighboring mat community. PMID- 24478769 TI - Lack of efflux mediated quinolone resistance in Salmonella enterica serovars Typhi and Paratyphi A. AB - Salmonella enterica serovars Typhi and Paratyphi A isolates from human patients in France displaying different levels of resistance to quinolones or fluoroquinolones were studied for resistance mechanisms to these antimicrobial agents. All resistant isolates carried either single or multiple target gene mutations (i.e., in gyrA, gyrB, or parC) correlating with the resistance levels observed. Active efflux, through upregulation of multipartite efflux systems, has also been previously reported as contributing mechanism for other serovars. Therefore, we investigated also the occurrence of non-target gene mutations in regulatory regions affecting efflux pump expression. However, no mutation was detected in these regions in both Typhi and Paratyphi isolates of this study. Besides, no overexpression of the major efflux systems was observed for these isolates. Nevertheless, a large deletion of 2334 bp was identified in the acrS acrE region of all S. Typhi strains but which did not affect the resistance phenotype. As being specific to S. Typhi, this deletion could be used for specific molecular detection purposes. In conclusion, the different levels of quinolone or FQ resistance in both S. Typhi and S. Paratyphi A seem to rely only on target modifications. PMID- 24478766 TI - Blood dendritic cells: "canary in the coal mine" to predict chronic inflammatory disease? AB - The majority of risk factors for chronic inflammatory diseases are unknown. This makes personalized medicine for assessment, prognosis, and choice of therapy very difficult. It is becoming increasingly clear, however, that low-grade subclinical infections may be an underlying cause of many chronic inflammatory diseases and thus may contribute to secondary outcomes (e.g., cancer). Many diseases are now categorized as inflammatory-mediated diseases that stem from a dysregulation in host immunity. There is a growing need to study the links between low-grade infections, the immune responses they elicit, and how this impacts overall health. One such link explored in detail here is the extreme sensitivity of myeloid dendritic cells (mDCs) in peripheral blood to chronic low-grade infections and the role that these mDCs play in arbitrating the resulting immune responses. We find that emerging evidence supports a role for pathogen-induced mDCs in chronic inflammation leading to increased risk of secondary clinical disease. The mDCs that are elevated in the blood as a result of low-grade bacteremia often do not trigger a productive immune response, but can disseminate the pathogen throughout the host. This aberrant trafficking of mDCs can accelerate systemic inflammatory disease progression. Conversely, restoration of dendritic cell homeostasis may aid in pathogen elimination and minimize dissemination. Thus it would seem prudent when assessing chronic inflammatory disease risk to consider blood mDC numbers, and the microbial content (microbiome) and activation state of these mDCs. These may provide important clues ("the canary in the coal mine") of high inflammatory disease risk. This will facilitate development of novel immunotherapies to eliminate such smoldering infections in atherosclerosis, cancer, rheumatoid arthritis, and pre-eclampsia. PMID- 24478770 TI - Role of poly-proline motif in HIV-2 Vpx expression. PMID- 24478772 TI - TWEAK/Fn14 Axis: A Promising Target for the Treatment of Cardiovascular Diseases. AB - Cardiovascular diseases (CVD) are the first cause of mortality in Western countries. CVD include several pathologies such as coronary heart disease, stroke or cerebrovascular accident, congestive heart failure, peripheral arterial disease, and aortic aneurysm, among others. Interaction between members of the tumor necrosis factor (TNF) superfamily and their receptors elicits several biological actions that could participate in CVD. TNF-like weak inducer of apoptosis (TWEAK) and its functional receptor and fibroblast growth factor inducible molecule 14 (Fn14) are two proteins belonging to the TNF superfamily that activate NF-kappaB by both canonical and non-canonical pathways and regulate several cell functions such as proliferation, migration, differentiation, cell death, inflammation, and angiogenesis. TWEAK/Fn14 axis plays a beneficial role in tissue repair after acute injury. However, persistent TWEAK/Fn14 activation mediated by blocking experiments or overexpression experiments in animal models has shown an important role of this axis in the pathological remodeling underlying CVD. In this review, we summarize the role of TWEAK/Fn14 pathway in the development of CVD, focusing on atherosclerosis and stroke and the molecular mechanisms by which TWEAK/Fn14 interaction participates in these pathologies. We also review the role of the soluble form of TWEAK as a biomarker for the diagnosis and prognosis of CVD. Finally, we highlight the results obtained with other members of the TNF superfamily that also activate canonical and non canonical NF-kappaB pathway. PMID- 24478773 TI - The role of natural cytotoxicity receptors in various pathologies: emphasis on type I diabetes. AB - Natural killer (NK) cells are innate immune lymphocytes that function mainly as immune sentinels against viral infection and tumorigenesis. NK cell function is governed by inhibitory and activating signals arising from corresponding receptors. A prominent group of activating NK receptors is the natural cytotoxicity receptors (NCRs), which includes NKp30, NKp44, and NKp46. These receptors bind various diverse ligands of pathogenic, tumor, and even self origin. Type 1 diabetes mellitus (T1D) is a multifactorial autoimmune disease, in which insulin-producing beta (beta) cells are ablated by the immune system. This killing of beta cells is carried out mainly by T cells, but many other immune cells have been implicated in the pathogenesis of this disease. Importantly, NK cells were shown to be key participants in the initial autoimmune attack. It was shown that all beta cells from humans and mice, healthy or sick, express an unknown ligand for the activating NKp46 receptor. In this review, we describe the role played by the NCRs in various pathologies with an emphasis on Type I diabetes. PMID- 24478771 TI - Human immunodeficiency syndromes affecting human natural killer cell cytolytic activity. AB - Natural killer (NK) cells are lymphocytes of the innate immune system that secrete cytokines upon activation and mediate the killing of tumor cells and virus-infected cells, especially those that escape the adaptive T cell response caused by the down regulation of MHC-I. The induction of cytotoxicity requires that NK cells contact target cells through adhesion receptors, and initiate activation signaling leading to increased adhesion and accumulation of F-actin at the NK cell cytotoxic synapse. Concurrently, lytic granules undergo minus-end directed movement and accumulate at the microtubule-organizing center through the interaction with microtubule motor proteins, followed by polarization of the lethal cargo toward the target cell. Ultimately, myosin-dependent movement of the lytic granules toward the NK cell plasma membrane through F-actin channels, along with soluble N-ethylmaleimide-sensitive factor attachment protein receptor dependent fusion, promotes the release of the lytic granule contents into the cleft between the NK cell and target cell resulting in target cell killing. Herein, we will discuss several disease-causing mutations in primary immunodeficiency syndromes and how they impact NK cell-mediated killing by disrupting distinct steps of this tightly regulated process. PMID- 24478774 TI - AAV Vectors Vaccines Against Infectious Diseases. AB - Since their discovery as a tool for gene transfer, vectors derived from the adeno associated virus (AAV) have been used for gene therapy applications and attracted scientist to this field for their exceptional properties of efficiency of in vivo gene transfer and the level and duration of transgene expression. For many years, AAVs have been considered as low immunogenic vectors due to their ability to induce long-term expression of non-self-proteins in contrast to what has been observed with other viral vectors, such as adenovirus, for which strong immune responses against the same transgene products were documented. The perceived low immunogenicity likely explains why the use of AAV vectors for vaccination was not seriously considered before the early 2000s. Indeed, while analyses conducted using a variety of transgenes and animal species slowly changed the vision of immunological properties of AAVs, an increasing number of studies were also performed in the field of vaccination. Even if the comparison with other modes of vaccination was not systemically performed, the analyses conducted so far in the field of active immunotherapy strongly suggest that AAVs possess some interesting features to be used as tools to produce an efficient and sustained antibody response. In addition, recent studies also highlighted the potential of AAVs for passive immunotherapy. This review summarizes the main studies conducted to evaluate the potential of AAV vectors for vaccination against infectious agents and discusses their advantages and drawbacks. Altogether, the variety of studies conducted in this field contributes to the understanding of the immunological properties of this versatile virus and to the definition of its possible future applications. PMID- 24478775 TI - B-1a B cells regulate T cell differentiation associated with pregnancy disturbances. AB - DURING PREGNANCY, THE MATERNAL IMMUNE SYSTEM FACES A DOUBLE DILEMMA: tolerate the growing semi-allogeneic fetus and at the same time protect the mother and the progeny against pathogens. This requires a fine and extremely regulated equilibrium between immune activation and tolerance. As professional antigen presenting cells, B cells and in particular B-1a B cells, can activate or tolerize T cells and thus participate in the generation or regulation of the immune response. B-1a B cells were involved in the humoral immune response leading to pre-eclampsia, one of the main medical complications during pregnancy. Here we demonstrated that B-1a B cells are additionally involved in cellular immune mechanisms associated with pregnancy complications. Using a mouse model of pregnancy disturbances, we showed that B-1a B cells from animals suffering pregnancy disturbances but not from those developing normal pregnancies induce the differentiation of naive T cells into Th17 and Th1 cells. This differential role of B-1a B cells during pregnancy seems to be associated with the co stimulatory molecule CD86 as normal pregnant mice showed lower percentages of CD86 expressing B-1a B cells as compared to pregnant mice developing pregnancy disturbances or to non-pregnant animals. Our data bring to light a new and not explored role of B-1a B cells in the context of pregnancy. PMID- 24478776 TI - Regulatory B cells: an exciting target for future therapeutics in transplantation. AB - Transplantation is the preferred treatment for most end-stage solid organ diseases. Despite potent immunosuppressive agents, chronic rejection remains a real problem in transplantation. For many years, the predominant immunological focus of research into transplant rejection has been T cells. The pillar of immunotherapy in clinical practice is T cell-directed, which efficiently prevents acute T cell-mediated allograft rejection. However, the root of late allograft failure is chronic rejection and the humoral arm of the immune response now emerges as an important factor in transplantation. Thus, the potential effects of Abs and B cell infiltrate on transplants have cast B cells as major actors in late graft rejection. Consequently, a number of recent drugs target either B cells or plasma cells. However, immunotherapies, such as the anti-CD20 B cell depleting antibody, can generate deleterious effects on the transplant, likely due to the deletion of beneficial population. The positive contribution of regulatory B (Breg) cells or B10 cells has been reported in the case of transplantation, mainly in mice models and highlights the primordial role that some populations of B cells can play in graft tolerance. Yet, this regulatory aspect remains poorly characterized in clinical transplantation. Thus, total B cell depletion treatments should be avoided and novel approaches should be considered that manipulate the different B cell subsets. This article provides an overview of the current knowledge on the link between Breg cells and grafts, and reports a number of data advising Breg cells as a new target for future therapeutic approaches. PMID- 24478777 TI - Designing vaccines for the twenty-first century society. AB - The history of vaccination clearly demonstrates that vaccines have been highly successful in preventing infectious diseases, reducing significantly the incidence of childhood diseases and mortality. However, many infections are still not preventable with the currently available vaccines and they represent a major cause of mortality worldwide. In the twenty-first century, the innovation brought by novel technologies in antigen discovery and formulation together with a deeper knowledge of the human immune responses are paving the way for the development of new vaccines. Final goal will be to rationally design effective vaccines where conventional approaches have failed. PMID- 24478778 TI - Thymus-Derived, Peripherally Derived, and in vitro-Induced T Regulatory Cells. PMID- 24478779 TI - TWEAK/Fn14 Signaling Axis Mediates Skeletal Muscle Atrophy and Metabolic Dysfunction. AB - Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through binding to its receptor fibroblast growth factor inducible 14 (Fn14) has been shown to regulate many cellular responses including proliferation, differentiation, apoptosis, inflammation, and fibrosis, under both physiological and pathological conditions. Emerging evidence suggests that TWEAK is also a major muscle wasting cytokine. TWEAK activates nuclear factor-kappaB signaling and proteolytic pathways such as ubiquitin-proteasome system, autophagy, and caspases to induce muscle proteolysis in cultured myotubes. Fn14 is dormant or expressed in minimal amounts in normal healthy muscle. However, specific atrophic conditions, such as denervation, immobilization, and starvation stimulate the expression of Fn14 leading to activation of TWEAK/Fn14 signaling and eventually skeletal muscle atrophy. TWEAK also causes slow- to fast-type fiber transition in skeletal muscle. Furthermore, recent studies suggest that TWEAK diminishes mitochondrial content and represses skeletal muscle oxidative phosphorylation capacity. TWEAK mediates these effects through affecting the expression of a number of genes and microRNAs. In this review article, we have discussed the recent advancements toward understanding the role and mechanisms of action of TWEAK/Fn14 signaling in skeletal muscle with particular reference to different models of atrophy and oxidative metabolism. PMID- 24478781 TI - Coarse-grained computer simulation of dynamics in thylakoid membranes: methods and opportunities. AB - Coarse-grained simulation is a powerful and well-established suite of computational methods for studying structure and dynamics in nanoscale biophysical systems. As our understanding of the plant photosynthetic apparatus has become increasingly nuanced, opportunities have arisen for coarse-grained simulation to complement experiment by testing hypotheses and making predictions. Here, we give an overview of best practices in coarse-grained simulation, with a focus on techniques and results that are applicable to the plant thylakoid membrane-protein system. We also discuss current research topics for which coarse grained simulation has the potential to play a key role in advancing the field. PMID- 24478780 TI - Analysis of the Lotus japonicus nuclear pore NUP107-160 subcomplex reveals pronounced structural plasticity and functional redundancy. AB - Mutations in the Lotus japonicus nucleoporin genes, NUP85, NUP133, and NENA (SEH1), lead to defects in plant-microbe symbiotic signaling. The homologous proteins in yeast and vertebrates are part of the conserved NUP84/NUP107-160 subcomplex, which is an essential component of the nuclear pore scaffold and has a pivotal role in nuclear pore complex (NPC) assembly. Loss and down-regulation of NUP84/NUP107-160 members has previously been correlated with a variety of growth and molecular defects, however, in L. japonicus only surprisingly specific phenotypes have been reported. We investigated whether Lotus nup85, nup133, and nena mutants exhibit general defects in NPC composition and distribution. Whole mount immunolocalization confirmed a typical nucleoporin-like localization for NUP133, which was unchanged in the nup85-1 mutant. Severe NPC clustering and aberrations in the nuclear envelope have been reported for Saccharomyces cerevisiae nup85 and nup133 mutants. However, upon transmission electron microscopy analysis of L. japonicus nup85, nup133 and nena, we detected only a slight reduction in the average distances between neighboring NPCs in nup133. Using quantitative immunodetection on protein-blots we observed that loss of individual nucleoporins affected the protein levels of other NUP107-160 complex members. Unlike the single mutants, nup85/nup133 double mutants exhibited severe temperature dependent growth and developmental defects, suggesting that the loss of more than one NUP107-160 member affects basal functions of the NPC. PMID- 24478782 TI - The effects of foliar fertilization with iron sulfate in chlorotic leaves are limited to the treated area. A study with peach trees (Prunus persica L. Batsch) grown in the field and sugar beet (Beta vulgaris L.) grown in hydroponics. AB - Crop Fe deficiency is a worldwide problem. The aim of this study was to assess the effects of foliar Fe applications in two species grown in different environments: peach (Prunus persica L. Batsch) trees grown in the field and sugar beet (Beta vulgaris L. cv. "Orbis") grown in hydroponics. The distal half of Fe deficient, chlorotic leaves was treated with Fe sulfate by dipping and using a brush in peach trees and sugar beet plants, respectively. The re-greening of the distal (Fe-treated) and basal (untreated) leaf areas was monitored, and the nutrient and photosynthetic pigment composition of the two areas were also determined. Leaves were also studied using chlorophyll fluorescence imaging, low temperature-scanning electron microscopy microanalysis, scanning transmission ion microscopy-particle induced X-ray emission and Perls Fe staining. The distal, Fe treated leaf parts of both species showed a significant increase in Fe concentrations (across the whole leaf volume) and marked re-greening, with significant increases in the concentrations of all photosynthetic pigments, as well as decreases in de-epoxidation of xanthophyll cycle carotenoids and increases in photochemical efficiency. In the basal, untreated leaf parts, Fe concentrations increased slightly, but little re-greening occurred. No changes in the concentrations of other nutrients were found. Foliar Fe fertilization was effective in re-greening treated leaf areas both in peach trees and sugar beet plants. Results indicate that the effects of foliar Fe-sulfate fertilization in Fe-deficient, chlorotic leaves were minor outside the leaf surface treated, indicating that Fe mobility within the leaf is a major constraint for full fertilizer effectiveness in crops where Fe-deficiency is established and leaf chlorosis occurs. PMID- 24478783 TI - Arabidopsis mutants in sphingolipid synthesis as tools to understand the structure and function of membrane microdomains in plasmodesmata. AB - Plasmodesmata-intercellular channels that communicate adjacent cells-possess complex membranous structures. Recent evidences indicate that plasmodesmata contain membrane microdomains. In order to understand how these submembrane regions collaborate to plasmodesmata function, it is necessary to characterize their size, composition and dynamics. An approach that can shed light on these microdomain features is based on the use of Arabidopsis mutants in sphingolipid synthesis. Sphingolipids are canonical components of microdomains together with sterols and some glycerolipids. Moreover, sphingolipids are transducers in pathways that display programmed cell death as a defense mechanism against pathogens. The study of Arabidopsis mutants would allow determining which structural features of the sphingolipids are important for the formation and stability of microdomains, and if defense signaling networks using sphingoid bases as second messengers are associated to plasmodesmata operation. Such studies need to be complemented by analysis of the ultrastructure and the use of protein probes for plasmodesmata microdomains and may constitute a very valuable source of information to analyze these membrane structures. PMID- 24478784 TI - Regulation of water, salinity, and cold stress responses by salicylic acid. AB - Salicylic acid (SA) is a naturally occurring phenolic compound. SA plays an important role in the regulation of plant growth, development, ripening, and defense responses. The role of SA in the plant-pathogen relationship has been extensively investigated. In addition to defense responses, SA plays an important role in the response to abiotic stresses, including drought, low temperature, and salinity stresses. It has been suggested that SA has great agronomic potential to improve the stress tolerance of agriculturally important crops. However, the utility of SA is dependent on the concentration of the applied SA, the mode of application, and the state of the plants (e.g., developmental stage and acclimation). Generally, low concentrations of applied SA alleviate the sensitivity to abiotic stresses, and high concentrations of applied induce high levels of oxidative stress, leading to a decreased tolerance to abiotic stresses. In this article, the effects of SA on the water stress responses and regulation of stomatal closure are reviewed. PMID- 24478785 TI - When fat is not bad: the regulation of actin dynamics by phospholipid signaling molecules. AB - The actin cytoskeleton plays a key role in the plant morphogenesis and is involved in polar cell growth, movement of subcellular organelles, cell division, and plant defense. Organization of actin cytoskeleton undergoes dynamic remodeling in response to internal developmental cues and diverse environmental signals. This dynamic behavior is regulated by numerous actin-binding proteins (ABPs) that integrate various signaling pathways. Production of the signaling lipids phosphatidylinositol 4,5-bisphosphate and phosphatidic acid affects the activity and subcellular distribution of several ABPs, and typically correlates with increased actin polymerization. Here we review current knowledge of the inter-regulatory dynamics between signaling phospholipids and the actin cytoskeleton in plant cells. PMID- 24478787 TI - Electron transport and light-harvesting switches in cyanobacteria. AB - Cyanobacteria possess multiple mechanisms for regulating the pathways of photosynthetic and respiratory electron transport. Electron transport may be regulated indirectly by controlling the transfer of excitation energy from the light-harvesting complexes, or it may be more directly regulated by controlling the stoichiometry, localization, and interactions of photosynthetic and respiratory electron transport complexes. Regulation of the extent of linear vs. cyclic electron transport is particularly important for controlling the redox balance of the cell. This review discusses what is known of the regulatory mechanisms and the timescales on which they occur, with particular regard to the structural reorganization needed and the constraints imposed by the limited mobility of membrane-integral proteins in the crowded thylakoid membrane. Switching mechanisms requiring substantial movement of integral thylakoid membrane proteins occur on slower timescales than those that require the movement only of cytoplasmic or extrinsic membrane proteins. This difference is probably due to the restricted diffusion of membrane-integral proteins. Multiple switching mechanisms may be needed to regulate electron transport on different timescales. PMID- 24478786 TI - Abiotic stress responses in plant roots: a proteomics perspective. AB - Abiotic stress conditions adversely affect plant growth, resulting in significant decline in crop productivity. To mitigate and recover from the damaging effects of such adverse environmental conditions, plants have evolved various adaptive strategies at cellular and metabolic levels. Most of these strategies involve dynamic changes in protein abundance that can be best explored through proteomics. This review summarizes comparative proteomic studies conducted with roots of various plant species subjected to different abiotic stresses especially drought, salinity, flood, and cold. The main purpose of this article is to highlight and classify the protein level changes in abiotic stress response pathways specifically in plant roots. Shared as well as stressor-specific proteome signatures and adaptive mechanism(s) are simultaneously described. Such a comprehensive account will facilitate the design of genetic engineering strategies that enable the development of broad-spectrum abiotic stress-tolerant crops. PMID- 24478788 TI - Zinc allocation and re-allocation in rice. AB - AIMS: Agronomy and breeding actively search for options to enhance cereal grain Zn density. Quantifying internal (re-)allocation of Zn as affected by soil and crop management or genotype is crucial. We present experiments supporting the development of a conceptual model of whole plant Zn allocation and re-allocation in rice. METHODS: Two solution culture experiments using (70)Zn applications at different times during crop development and an experiment on within-grain distribution of Zn are reported. In addition, results from two earlier published experiments are re-analyzed and re-interpreted. RESULTS: A budget analysis showed that plant zinc accumulation during grain filling was larger than zinc allocation to the grains. Isotope data showed that zinc taken up during grain filling was only partly transported directly to the grains and partly allocated to the leaves. Zinc taken up during grain filling and allocated to the leaves replaced zinc re-allocated from leaves to grains. Within the grains, no major transport barrier was observed between vascular tissue and endosperm. At low tissue Zn concentrations, rice plants maintained concentrations of about 20 mg Zn kg(-1) dry matter in leaf blades and reproductive tissues, but let Zn concentrations in stems, sheath, and roots drop below this level. When plant zinc concentrations increased, Zn levels in leaf blades and reproductive tissues only showed a moderate increase while Zn levels in stems, roots, and sheaths increased much more and in that order. CONCLUSIONS: In rice, the major barrier to enhanced zinc allocation towards grains is between stem and reproductive tissues. Enhancing root to shoot transfer will not contribute proportionally to grain zinc enhancement. PMID- 24478789 TI - Autophagy as a possible mechanism for micronutrient remobilization from leaves to seeds. AB - Seed formation is an important step of plant development which depends on nutrient allocation. Uptake from soil is an obvious source of nutrients which mainly occurs during vegetative stage. Because seed filling and leaf senescence are synchronized, subsequent mobilization of nutrients from vegetative organs also play an essential role in nutrient use efficiency, providing source-sink relationships. However, nutrient accumulation during the formation of seeds may be limited by their availability in source tissues. While several mechanisms contributing to make leaf macronutrients available were already described, little is known regarding micronutrients such as metals. Autophagy, which is involved in nutrient recycling, was already shown to play a critical role in nitrogen remobilization to seeds during leaf senescence. Because it is a non-specific mechanism, it could also control remobilization of metals. This article reviews actors and processes involved in metal remobilization with emphasis on autophagy and methodology to study metal fluxes inside the plant. A better understanding of metal remobilization is needed to improve metal use efficiency in the context of biofortification. PMID- 24478790 TI - Genome wide association and linkage analyses identified three loci-4q25, 17q23.2, and 10q11.21-associated with variation in leukocyte telomere length: the Long Life Family Study. AB - Leukocyte telomere length is believed to measure cellular aging in humans, and short leukocyte telomere length is associated with increased risks of late onset diseases, including cardiovascular disease, dementia, etc. Many studies have shown that leukocyte telomere length is a heritable trait, and several candidate genes have been identified, including TERT, TERC, OBFC1, and CTC1. Unlike most studies that have focused on genetic causes of chronic diseases such as heart disease and diabetes in relation to leukocyte telomere length, the present study examined the genome to identify variants that may contribute to variation in leukocyte telomere length among families with exceptional longevity. From the genome wide association analysis in 4,289 LLFS participants, we identified a novel intergenic SNP rs7680468 located near PAPSS1 and DKK2 on 4q25 (p = 4.7E-8). From our linkage analysis, we identified two additional novel loci with HLOD scores exceeding three, including 4.77 for 17q23.2, and 4.36 for 10q11.21. These two loci harbor a number of novel candidate genes with SNPs, and our gene-wise association analysis identified multiple genes, including DCAF7, POLG2, CEP95, and SMURF2 at 17q23.2; and RASGEF1A, HNRNPF, ANF487, CSTF2T, and PRKG1 at 10q11.21. Among these genes, multiple SNPs were associated with leukocyte telomere length, but the strongest association was observed with one contiguous haplotype in CEP95 and SMURF2. We also show that three previously reported genes TERC, MYNN, and OBFC1-were significantly associated with leukocyte telomere length at p empirical < 0.05. PMID- 24478791 TI - Characterizing the Retinoblastoma 1 locus: putative elements for Rb1 regulation by in silico analysis. AB - Limited understanding of the Rb1 locus hinders genetic and epigenetic analyses of Retinoblastoma, a childhood cancer of the nervous systems. In this study, we used in silico tools to investigate and review putative genetic and epigenetic elements of the Rb1 gene. We report transcription start sites, CpG islands, and regulatory moieties that are likely to influence transcriptional states of this gene. These might contribute genetic and epigenetic information modulating tissue specific transcripts and expression levels of Rb1. The elements we identified include tandem repeats that reside within or next to CpG islands near Rb1's transcriptional start site, and that are likely to be polymorphic among individuals. Our analyses highlight the complexity of this gene and suggest opportunities and limitations for future studies of retinoblastoma, genetic counseling, and the accurate identification of patients at greater risk of developing the malignancy. PMID- 24478793 TI - From observational to dynamic genetics. AB - Twin and family studies have shown that most traits are at least moderately heritable. But what are the implications of finding genetic influence for the design of intervention and prevention programs? For complex traits, heritability does not mean immutability, and research has shown that genetic influences can change with age, context, and in response to behavioral and drug interventions. The most significant implications for intervention will come when we move from observational genetics to investigating dynamic genetics, including genetically sensitive interventions. Future interventions should be designed to overcome genetic risk and draw upon genetic strengths by changing the environment. PMID- 24478792 TI - Arrhythmogenic KCNE gene variants: current knowledge and future challenges. AB - There are twenty-five known inherited cardiac arrhythmia susceptibility genes, all of which encode either ion channel pore-forming subunits or proteins that regulate aspects of ion channel biology such as function, trafficking, and localization. The human KCNE gene family comprises five potassium channel regulatory subunits, sequence variants in each of which are associated with cardiac arrhythmias. KCNE gene products exhibit promiscuous partnering and in some cases ubiquitous expression, hampering efforts to unequivocally correlate each gene to specific native potassium currents. Likewise, deducing the molecular etiology of cardiac arrhythmias in individuals harboring rare KCNE gene variants, or more common KCNE polymorphisms, can be challenging. In this review we provide an update on putative arrhythmia-causing KCNE gene variants, and discuss current thinking and future challenges in the study of molecular mechanisms of KCNE associated cardiac rhythm disturbances. PMID- 24478794 TI - Estimating severity of illness and disability in Frontotemporal Dementia: Preliminary analysis of the Dementia Disability Rating (DDR). AB - BACKGROUND: Current measures of severity and disability do not stage or track the progression of disability in frontotemporal dementia (FTD) well. We investigated the reliability of the newly developed Dementia Disability Rating (DDR) in the measurement and staging of illness severity in FTD and dementia of the Alzheimer type (DAT). MATERIAL/ METHODS: We studied 48 consecutive patients of the Johns Hopkins FTD and Young-Onset Dementias Clinic, with diagnoses of DAT, FTD, vascular dementia and "other" cognitive disorder (CDNOS). Cases were scored on the CDR and DDR by three trained raters, based on neuropsychiatric examinations performed at first visit and other assessments performed within the preceding year. Consensus ratings were assigned in conference. RESULTS: Inter-rater correlations of DDR sum of ranks scores for DAT ranged from 0.88 to 0.91, for FTD 0.89-0.96 and for CDNOS 0.85-0.97. Similar correlations were observed of the CDR sum of rank scores for DAT and FTD. Correlations of DDR summary scores for DAT were 0.67-0.91 and for FTD 0.79-0.91, as compared to CDR data: 0.87-0.92 (p<0.0001) and 0.80-0.93 (p<0.0001) for DAT and FTD respectively. In DAT patients the correlation between CDR and DDR summary scores was higher than in FTD patients, whereas correlations based on sum of ranks scores were high in both groups. CONCLUSIONS: These preliminary data indicate the DDR measures disability in DAT and FTD, with reliability comparable to the CDR. Convergent validity was demonstrated for the DDR. PMID- 24478795 TI - Phenotypic and genetic divergence within a single whitefish form - detecting the potential for future divergence. AB - Human-induced nutrient input can change the selection regime and lead to the loss of biodiversity. For example, eutrophication caused speciation reversal in polymorphic whitefish populations through a flattening of littoral-pelagic selection gradients. We investigated the current state of phenotypic and genetic diversity in whitefish (Coregonus macrophthalmus) in a newly restored lake whose nutrient load has returned to pre-eutrophication levels and found that whitefish spawning at different depths varied phenotypically and genetically: individuals spawning at shallower depth had fewer gill rakers, faster growth, and a morphology adapted to benthic feeding, and they showed higher degrees of diet specialization than deeper spawning individuals. Microsatellite analyses complemented the phenotype analyses by demonstrating reproductive isolation along different spawning depths. Our results indicate that whitefish still retain or currently regain phenotypic and genetic diversity, which was lost during eutrophication. Hence, the population documented here has a potential for future divergence because natural selection can target phenotypes specialized along re established littoral-pelagic selection gradients. The biodiversity, however, will have better chances to return if managers acknowledge the evolutionary potential within the local whitefish and adapt fishing and stocking measures. PMID- 24478796 TI - Population genetic structure in a social landscape: barley in a traditional Ethiopian agricultural system. AB - Conservation strategies are increasingly driven by our understanding of the processes and patterns of gene flow across complex landscapes. The expansion of population genetic approaches into traditional agricultural systems requires understanding how social factors contribute to that landscape, and thus to gene flow. This study incorporates extensive farmer interviews and population genetic analysis of barley landraces (Hordeum vulgare) to build a holistic picture of farmer-mediated geneflow in an ancient, traditional agricultural system in the highlands of Ethiopia. We analyze barley samples at 14 microsatellite loci across sites at varying elevations and locations across a contiguous mountain range, and across farmer-identified barley types and management strategies. Genetic structure is analyzed using population-based and individual-based methods, including measures of population differentiation and genetic distance, multivariate Principal Coordinate Analysis, and Bayesian assignment tests. Phenotypic analysis links genetic patterns to traits identified by farmers. We find that differential farmer management strategies lead to markedly different patterns of population structure across elevation classes and barley types. The extent to which farmer seed management appears as a stronger determinant of spatial structure than the physical landscape highlights the need for incorporation of social, landscape, and genetic data for the design of conservation strategies in human-influenced landscapes. PMID- 24478797 TI - Dynamics of growth factor production in monolayers of cancer cells and evolution of resistance to anticancer therapies. AB - Tumor heterogeneity is well documented for many characters, including the production of growth factors, which improve tumor proliferation and promote resistance against apoptosis and against immune reaction. What maintains heterogeneity remains an open question that has implications for diagnosis and treatment. While it has been suggested that therapies targeting growth factors are robust against evolved resistance, current therapies against growth factors, like antiangiogenic drugs, are not effective in the long term, as resistant mutants can evolve and lead to relapse. We use evolutionary game theory to study the dynamics of the production of growth factors by monolayers of cancer cells and to understand the effect of therapies that target growth factors. The dynamics depend on the production cost of the growth factor, on its diffusion range and on the type of benefit it confers to the cells. Stable heterogeneity is a typical outcome of the dynamics, while a pure equilibrium of nonproducer cells is possible under certain conditions. Such pure equilibrium can be the goal of new anticancer therapies. We show that current therapies, instead, can be effective only if growth factors are almost completely eliminated and if the reduction is almost immediate. PMID- 24478798 TI - The effects of synthetic estrogen exposure on premating and postmating episodes of selection in sex-role-reversed Gulf pipefish. AB - Environmental estrogens have been shown to affect populations of aquatic organisms in devastating ways, including feminization of males, alterations in mating behaviors, and disruption of sexual selection. Studies have shown 17alpha ethinylestradiol (EE2) exposure to induce female-like secondary sexual traits in male Gulf pipefish, changing how females perceive affected males. We aimed to understand the effects of EE2 exposure on the sex-role-reversed mating system and the strength of selection in Gulf pipefish. We used artificial Gulf pipefish breeding aggregations and microsatellite-based parentage analysis to determine maternity. We then calculated the opportunity for selection and selection differentials on body size for both sexes during three consecutive episodes of selection. Exposure to EE2 did not affect the strength of selection, likely due to the unusual sex-role-reversed mating system found in this species. With respect to multiply mated females, EE2-exposed females produced more eggs with higher embryo survivorship than nonexposed females. Thus, short-term exposure to low concentrations (2.0 ng/L) of EE2 in Gulf pipefish enhanced female reproductive success. However, higher EE2 concentrations (5.0 ng/L) caused complete reproductive failure in Gulf pipefish males. These results call for more work on the long-term effects of EE2 exposure in Gulf pipefish in artificial and natural populations. PMID- 24478800 TI - Adaptive genetic markers discriminate migratory runs of Chinook salmon (Oncorhynchus tshawytscha) amid continued gene flow. AB - Neutral genetic markers are routinely used to define distinct units within species that warrant discrete management. Human-induced changes to gene flow however may reduce the power of such an approach. We tested the efficiency of adaptive versus neutral genetic markers in differentiating temporally divergent migratory runs of Chinook salmon (Oncorhynchus tshawytscha) amid high gene flow owing to artificial propagation and habitat alteration. We compared seven putative migration timing genes to ten microsatellite loci in delineating three migratory groups of Chinook in the Feather River, CA: offspring of fall-run hatchery broodstock that returned as adults to freshwater in fall (fall run), spring-run offspring that returned in spring (spring run), and fall-run offspring that returned in spring (FRS). We found evidence for significant differentiation between the fall and federally listed threatened spring groups based on divergence at three circadian clock genes (OtsClock1b, OmyFbxw11, and Omy1009UW), but not neutral markers. We thus demonstrate the importance of genetic marker choice in resolving complex life history types. These findings directly impact conservation management strategies and add to previous evidence from Pacific and Atlantic salmon indicating that circadian clock genes influence migration timing. PMID- 24478799 TI - Large fluctuations in the effective population size of the malaria mosquito Anopheles gambiae s.s. during vector control cycle. AB - On Bioko Island, Equatorial Guinea, indoor residual spraying (IRS) has been part of the Bioko Island Malaria Control Project since early 2004. Despite success in reducing childhood infections, areas of high transmission remain on the island. We therefore examined fluctuations in the effective population size (N e ) of the malaria vector Anopheles gambiae in an area of persistent high transmission over two spray rounds. We analyzed data for 13 microsatellite loci from 791 An. gambiae specimens collected at six time points in 2009 and 2010 and reconstructed the demographic history of the population during this period using approximate Bayesian computation (ABC). Our analysis shows that IRS rounds have a large impact on N e , reducing it by 65%-92% from prespray round N e . More importantly, our analysis shows that after 3-5 months, the An. gambiae population rebounded by 2818% compared shortly following the spray round. Our study underscores the importance of adequate spray round frequency to provide continuous suppression of mosquito populations and that increased spray round frequency should substantially improve the efficacy of IRS campaigns. It also demonstrates the ability of ABC to reconstruct a detailed demographic history across only a few tens of generations in a large population. PMID- 24478801 TI - Species limits, quarantine risk and the intrigue of a polyphagous invasive pest with highly restricted host relationships in its area of invasion. AB - Scirtothrips aurantii is a generalist horticultural pest in its native African range and recently established quite widely in Australia on the invasive succulent weed Bryophyllum delagoense. Paradoxically, this thrips is not polyphagous in its incursive range. The issue is principally one of quarantine. Will the thrips in Australia shift, perhaps adaptively, to citrus, and should the primary focus be on containment around Australian citrus, or does the real quarantine risk exist offshore with thrips present on citrus in Africa? We examined the phylogenetic relationships between Bryophyllum-associated thrips populations in Australia and populations sampled from various host plant species in South Africa (including Bryophyllum) using both CO1 and 28s markers. Eight variable microsatellite markers were developed to assess the extent of gene flow between the thrips on different hosts in South Africa. The COI phylogeny resolved S. aurantii into three distinct clades with samples collected from B. delagoense in South Africa and Australia representing a single clade, a second clade associated with Gloriosa lilies and the third with horticultural hosts. The microsatellite analysis confirmed that the populations associated with citrus and Bryophyllum do not hybridize with one another in sympatry. We conclude that the citrus-damaging thrips are not currently present in Australia and remain a serious quarantine concern in relation to Australian horticulture. PMID- 24478802 TI - Implications of sex-specific selection for the genetic basis of disease. AB - Mutation and selection are thought to shape the underlying genetic basis of many common human diseases. However, both processes depend on the context in which they occur, such as environment, genetic background, or sex. Sex has widely known effects on phenotypic expression of genotype, but an analysis of how it influences the evolutionary dynamics of disease-causing variants has not yet been explored. We develop a simple population genetic model of disease susceptibility and evaluate it using a biologically plausible empirically based distribution of fitness effects among contributing mutations. The model predicts that alleles under sex-differential selection, including sexually antagonistic alleles, will disproportionately contribute to genetic variation for disease predisposition, thereby generating substantial sexual dimorphism in the genetic architecture of complex (polygenic) diseases. This is because such alleles evolve into higher population frequencies for a given effect size, relative to alleles experiencing equally strong purifying selection in both sexes. Our results provide a theoretical justification for expecting a sexually dimorphic genetic basis for variation in complex traits such as disease. Moreover, they suggest that such dimorphism is interesting - not merely something to control for - because it reflects the action of natural selection in molding the evolution of common disease phenotypes. PMID- 24478803 TI - Herbicide-resistant weeds: from research and knowledge to future needs. AB - Synthetic herbicides have been used globally to control weeds in major field crops. This has imposed a strong selection for any trait that enables plant populations to survive and reproduce in the presence of the herbicide. Herbicide resistance in weeds must be minimized because it is a major limiting factor to food security in global agriculture. This represents a huge challenge that will require great research efforts to develop control strategies as alternatives to the dominant and almost exclusive practice of weed control by herbicides. Weed scientists, plant ecologists and evolutionary biologists should join forces and work towards an improved and more integrated understanding of resistance across all scales. This approach will likely facilitate the design of innovative solutions to the global herbicide resistance challenge. PMID- 24478804 TI - Dominant resistance to Bt cotton and minor cross-resistance to Bt toxin Cry2Ab in cotton bollworm from China. AB - Evolution of resistance by insect pests threatens the long-term benefits of transgenic crops that produce insecticidal proteins from Bacillus thuringiensis (Bt). Previous work has detected increases in the frequency of resistance to Bt toxin Cry1Ac in populations of cotton bollworm, Helicoverpa armigera, from northern China where Bt cotton producing Cry1Ac has been grown extensively for more than a decade. Confirming that trend, we report evidence from 2011 showing that the percentage of individuals resistant to a diagnostic concentration of Cry1Ac was significantly higher in two populations from different provinces of northern China (1.4% and 2.3%) compared with previously tested susceptible field populations (0%). We isolated two resistant strains: one from each of the two field-selected populations. Relative to a susceptible strain, the two strains had 460- and 1200-fold resistance to Cry1Ac, respectively. Both strains had dominant resistance to a diagnostic concentration of Cry1Ac in diet and to Bt cotton leaves containing Cry1Ac. Both strains had low, but significant cross-resistance to Cry2Ab (4.2- and 5.9-fold), which is used widely as the second toxin in two toxin Bt cotton. Compared with resistance in other strains of H. armigera, the resistance in the two strains characterized here may be especially difficult to suppress. PMID- 24478806 TI - Treatment plan for breast cancer with sentinel node metastasis. AB - Lymph node involvement is considered to be one of the most important independent prognostic factors in breast cancer. In patients without palpable lymphadenopathies, the method of choice for determining this involvement is the sentinel lymph node biopsy. In the presence of macrometastases, the current standard is to perform axillary lymph node dissection in spite of the knowledge that the involvement of non-sentinel lymph nodes is approximately 50%. When lymph node involvement is micrometastasic, the decision as to whether or not to proceed with lymphadenectomy remains in dispute. We set out, on the basis of the current scientific evidence and our own experience, to create guidelines that allow us to individualise each case and decide whether or not to perform a lymphadenectomy. We will discuss the arguments that support our position. PMID- 24478807 TI - Enzymatic detachment of therapeutic mesenchymal stromal cells grown on glass carriers in a bioreactor. AB - Cell therapies require the in vitro expansion of adherent cells such as mesenchymal stromal cells (hMSCs) in bioreactor systems or other culture environments, followed by cell harvest. As hMSCs are strictly adherent cells, cell harvest requires cell detachment. The use of hMSCs for cell therapy requires GMP production in accordance with the guidelines for advanced therapeutic medical products. Therefore, several GMP-conform available proteolytic enzymes were investigated for their ability to promote hMSC detachment. An allogeneic hMSC cell line (hMSC-TERT) that is used in clinical trials in the form of alginate cell capsules was chosen as a model. This study investigated the influence of several factors on the outcome of proteolytic hMSC-TERT detachment. Therefore, hMSC-TERT detachment was analyzed in different cultivation systems (static, dynamic) and in combination with further cell processing including encapsulation. Only two of the commercially available enzymes (AccutaseTM, TrypZeanTM) that fulfill all process requirements (commercial availability, cost, GMP conditions during manufacturing and non-animal origin) are found to be generally suitable for detaching hMSC-TERT. Combining cell detachment with encapsulation demonstrated a high impact of the experimental set up on cell damage. It was preferable to reduce the temperature during detachment and limit the detachment time to a maximum of 20 minutes. Cell detachment in static systems was not comparable with detachment in dynamic systems. Detachment yields in dynamic systems were lower and cell damage was higher for the same experimental conditions. Finally, only TrypZeanTM seemed to be suitable for the detachment of hMSC-TERT from dynamic reactor systems. PMID- 24478808 TI - Recombinant Salmonella Bacteria Vectoring HIV/AIDS Vaccines. AB - HIV/AIDS is an important public health problem globally. An affordable, easy-to deliver and protective HIV vaccine is therefore required to curb the pandemic from spreading further. Recombinant Salmonella bacteria can be harnessed to vector HIV antigens or DNA vaccines to the immune system for induction of specific protective immunity. These are capable of activating the innate, humoral and cellular immune responses at both mucosal and systemic compartments. Several studies have already demonstrated the utility of live recombinant Salmonella in delivering expressed foreign antigens as well as DNA vaccines to the host immune system. This review gives an overview of the studies in which recombinant Salmonella bacteria were used to vector HIV/AIDS antigens and DNA vaccines. Most of the recombinant Salmonella-based HIV/AIDS vaccines developed so far have only been tested in animals (mainly mice) and are yet to reach human trials. PMID- 24478809 TI - Characterisation of cancer support and rehabilitation programmes: a Swedish multiple case study. AB - Cancer support and rehabilitation are suggested to be an integral part of cancer care strategies. This study focuses on comparativeness of cancer support and rehabilitation programmes. The aim of this study was to analyse available cancer support and rehabilitation programmes in Sweden presented as complementary to cancer rehabilitation at cancer clinics. A multiple case study design was chosen in order to inquire the small number of existing supportive and rehabilitative cancer programmes. Based on the structures, processes and outcomes of the nine included programmes, three types of cancer support and rehabilitation programmes were identified: multimodal rehabilitation, comprehensive cancer support and art therapy. Cancer support and rehabilitation programmes offer a variety of activities and therapies which are highly valuable and relevant for people with cancer. The typology of cancer support and rehabilitation programmes and comparability between programmes need further inquiry. PMID- 24478810 TI - Benign Notochordal Cell Tumor of the Sacrum with Atypical Imaging Features: The Value of CT Guided Biopsy for Diagnosis. AB - We report a case of a benign notochordal cell tumor (BNCT) of the sacrum with atypical imaging features, which was incidentally discovered in a 74-year-old man undergoing evaluation for progressively worsening hip and back pain. It is important for radiologists, pathologists and orthopedic surgeons to be aware of the diagnosis of BNCT and be familiar with its radiographic features to avoid unnecessary treatment. This case illustrates the advantage of percutaneous computed tomography (CT)-guided biopsy as a minimally invasive technique for definitive diagnosis of a BNCT with atypical imaging features. PMID- 24478811 TI - Neural substrates underlying learning-related changes of the unconditioned fear response. AB - The ability to predict an impending threat during Pavlovian conditioning diminishes the emotional response that is produced once the threat is encountered. Diminution of the threat response appears to be mediated by somewhat independent associative learning and expectancy-related processes. Therefore, the present study was designed to better understand the neural mechanisms that support associative learning processes, independent of expectancy, that influence the emotional response to a threat. Healthy volunteers took part in a Pavlovian conditioning procedure during which trait anxiety, expectation of the unconditioned stimulus (UCS), skin conductance response (SCR), and functional magnetic resonance imaging (fMRI) signal were assessed. The results showed no evidence for associative learning that was independent of expectation. Threat related SCR expression was diminished on predictable trials vs. unpredictable trials of the UCS (i.e. conditioned UCR diminution). Similar to SCR, conditioned UCR diminution was observed within the left dorsolateral PFC, dorsomedial PFC, ventromedial PFC, and left anterior insula. In contrast, potentiation of the threat-related fMRI signal response was observed within left dorsolateral PFC, inferior parietal lobule (IPL), and posterior insula. A negative relationship was observed between UCS expectancy and UCR expression within the dorsomedial PFC, ventromedial PFC, and anterior insula. Finally, the anticipatory fMRI signal responses within the PFC, posterior cingulate, and amygdala showed an inverse relationship with threat-related activation within the brain regions that showed UCR diminution. The current findings suggest that the PFC and amygdala support learning-related processes that impact the magnitude of the emotional response to a threat. PMID- 24478812 TI - Bilateral temporal bone langerhans cell histiocytosis: radiologic pearls. AB - Langerhans cell histiocytosis (LCH) is a rare histiocytic disorder with an unpredictable clinical course and highly varied clinical presentation ranging from single system to multisystem involvement. Although head and neck involvement is common in LCH, isolated bilateral temporal bone involvement is exceedingly rare. Furthermore, LCH is commonly misinterpreted as mastoiditis, otitis media and otitis externa, delaying diagnosis and appropriate therapeutic management. To improve detection and time to treatment, it is imperative to have LCH in the differential diagnosis for unusual presentations of the aforementioned infectious head and neck etiologies. Any lytic lesion of the temporal bone identified by radiology should raise suspicion for LCH. We hereby describe the radiologic findings of a case of bilateral temporal bone LCH, originally misdiagnosed as mastoiditis. PMID- 24478813 TI - Bottom-up Retinotopic Organization Supports Top-down Mental Imagery. AB - Finding a path between locations is a routine task in daily life. Mental navigation is often used to plan a route to a destination that is not visible from the current location. We first used functional magnetic resonance imaging (fMRI) and surface-based averaging methods to find high-level brain regions involved in imagined navigation between locations in a building very familiar to each participant. This revealed a mental navigation network that includes the precuneus, retrosplenial cortex (RSC), parahippocampal place area (PPA), occipital place area (OPA), supplementary motor area (SMA), premotor cortex, and areas along the medial and anterior intraparietal sulcus. We then visualized retinotopic maps in the entire cortex using wide-field, natural scene stimuli in a separate set of fMRI experiments. This revealed five distinct visual streams or 'fingers' that extend anteriorly into middle temporal, superior parietal, medial parietal, retrosplenial and ventral occipitotemporal cortex. By using spherical morphing to overlap these two data sets, we showed that the mental navigation network primarily occupies areas that also contain retinotopic maps. Specifically, scene-selective regions RSC, PPA and OPA have a common emphasis on the far periphery of the upper visual field. These results suggest that bottom-up retinotopic organization may help to efficiently encode scene and location information in an eye-centered reference frame for top-down, internally generated mental navigation. This study pushes the border of visual cortex further anterior than was initially expected. PMID- 24478814 TI - Pyelolymphatic backflow demonstrated by an abdominal CT: A case report. AB - BACKGROUND: Pyelolymphatic backflow phenomenon, which is a subtype of pyelorenal backflow, is a rare condition that occurs during the acute phase of urinary obstruction. Pyelorenal backflow has already been described in humans with retrograde pyelography. Our report presents a rare case of pyelolyphatic backflow demonstrated by a computed tomography. CASE REPORT: A 67-year-old man with a history of bladder carcinoma was admitted to the emergency department due to right-sided flank pain and hematuria. Hematuria resolved after insertion of a 3 way urinary catheter, but flank pain persisted. As a result, an abdominopelvic CT was performed. CT revealed numerous tiny, serpiginous tubular structures connected with each other and filled with urine. They began intrarenally and extended caudally surrounding the ureter in the retroperitoneum. Subsequently, the patient underwent an ultrasound-guided nephrostomy to decompress the collecting system of the right kidney. Antegrade pyelography revealed minimal hydroneprosis. However, no leakage from the ureter to the retroperitoneum was observed, proving that the changes demonstrated by a CT were due to pyelolymphatic reflux caused by increased pressure in the collecting tubules filling the lymphatics with opaque urine. CONCLUSIONS: This report presents a very rare case of pyelolymphatic reflux demonstrated by a CT. We present this case report as a reminder that although rare, pyelolymphatic reflux can occur as a result of obstruction without manifestations of hydronephrosis and it can be confused with leakage from the ureter. PMID- 24478815 TI - KU HAPLOINSUFFIENCY CAUSES A LYMPHOPROLIFERATIVE DISORDER OF IMMATURE T-CELL PRECURSORS DUE TO IKAROS MALFUNCTION. AB - Ikaros (IK) malfunction has been implicated in the pathogenesis of acute lymphoblastic leukemia (ALL), the most common form of childhood cancer. Therefore, a stringent regulation of IK activity is very important. Here we provide unique genetic and biochemical evidence that the Ku protein components Ku70 and Ku80 act as positive regulators of IK function via formation of IK-Ku70 and IK-Ku80 heterodimers with augmented sequence-specific DNA binding activity. siRNA-mediated depletion of Ku70 or Ku80 reduced the sequence-specific DNA binding activity of IK in EMSA as well as the RT-PCR measured IK target gene expression levels in human cells. The interaction of Ku components with IK likely contributes to the anti-leukemic effects of IK as a tumor suppressor, because Ku70 as well as Ku80 haploinsuffiency in mice caused development of a lymphoproliferative disorder (LPD) involving CD2+CD4+CD8+CD1+IL7R+ thymic T-cell precursors with functional IK deficiency. PMID- 24478816 TI - Absence of Genomic Ikaros/IKZF1 Deletions in Pediatric B-Precursor Acute Lymphoblastic Leukemia. AB - Here we report the results of gene expression analyses using multiple probesets aimed at determining the incidence of Ikaros/IKZF1 deletions in pediatric B precursor acute lymphoblastic leukemia (BPL). Primary leukemia cells from 122 Philadelphia chromosome (Ph)+ BPL patients and 237 Ph- BPL patients as well as normal hematopoietic cells from 74 normal non-leukemic bone marrow specimens were organized according to expression levels of IKZF1 transcripts utilizing two-way hierarchical clustering technique to identify specimens with low IKZF1 expression for the 10 probesets interrogating Exons 1 through 4 and Exon 8. Our analysis demonstrated no changes in expression that would be expected from homozygous or heterozygous deletions of IKZF1 in primary leukemic cells. Similar results were obtained in gene expression analysis of primary leukemic cells from 20 Ph+ positive and 155 Ph- BPL patients in a validation dataset. Taken together, our gene expression analyses in 534 pediatric BPL cases, including 142 cases with Ph+ BPL, contradict previous reports that were based on SNP array data and suggested that Ph+ pediatric BPL is characterized by a high frequency of homozygous or heterozygous IKZF1 deletions. Further, exon-specific genomic PCR analysis of primary leukemia cells from 21 high-risk pediatric BPL patients and 11 standard risk pediatric BPL patients, and 8 patients with infant BPL did not show any evidence for homozygous IKZF1 locus deletions. Nor was there any evidence for homozygous or heterozygous intragenic IKZF1 deletions. PMID- 24478817 TI - Mesalazine-induced renal calculi. AB - PATIENT: Female, 32 FINAL DIAGNOSIS: Renal colic Symptoms: Acute colic pain * macrohematuria MEDICATION: Mesalazine Clinical Procedure: CT scan of urinary tract * cystoscopy * gynecological consultation * stone analysis Specialty: Gastroenterology and Hepatology * Clinical Pharmacology. OBJECTIVE: Unexpected drug reaction. BACKGROUND: Mesalazine, a 5-aminosalicylic acid compound, is one of the cornerstones in modern treatment regimens of ulcerative colitis. It is generally well tolerated, although adverse reactions such as nephrotoxicity, perimyocarditis, and pancreatitis have been reported. CASE REPORT: We report the case of a 32-year-old woman with colitis who developed recurrent episodes of renal colic after introduction of mesalazine to her treatment. Biochemical analysis of the stones showed that they were composed of crystalized drug material. CONCLUSIONS: To our knowledge this is the first report of mesalazine precipitation in the urinary tract. We believe that it is vital for physicians to recognize this potentially severe adverse effect in the use of this treatment. PMID- 24478818 TI - ANCA-positive vasculitis induced by levamisole-adulterated cocaine and nephrotic syndrome: The kidney as an unusual target. AB - PATIENT: Male, 36 FINAL DIAGNOSIS: Levamisole-induced vasculopathy Symptoms: Purpuric skin lesions Medication: Levamisole Clinical Procedure: - Specialty: Internal Medicine. OBJECTIVE: Unusual clinical course. BACKGROUND: Levamisole has been detected in seized cocaine samples and a levamisole-induced vasculopathy (LIV) has been described, mainly focused on skin. CASE REPORT: A 36-year-old Caucasian man with history of antibodies to hepatitis C infection (negative hepatitis C virus RNA and negative HIV serology), smoking, and intravenous use of cocaine and brown heroin, presented to the hospital with purpuric skin lesions on extremities and earlobes. One month before the current presentation, a skin punch biopsy of one of these lesions was performed, showing histopathologic findings suggestive of mixed cryoglobulinemia. Laboratory testing revealed leukopenia, renal failure, and nephrotic syndrome. Antimyeloperoxidase antineutrophil cytoplasmic antibodies (MPO-ANCA) were positive. The previous skin punch biopsy was revised and demonstrated pathologic findings consistent with leukocytoclastic vasculitis. An analysis of a cocaine sample for personal use, provided by the patient, was performed using mass spectrometry-gas chromatography and levamisole was detected. Three boluses of intravenous methylprednisolone were administered, followed by oral prednisone 1 mg/Kg per day. Skin lesions and renal function improved. CONCLUSIONS: To our knowledge, this is the first report of nephrotic syndrome induced by levamisole-adulterated cocaine, proven by cocaine sample toxicology. Lack of renal biopsy is a limitation of this report. PMID- 24478819 TI - Phenotype-genotype discordance in congenital malformations with communication disorders resembling trisomy 18 (Edwards syndrome). AB - PATIENT: Female, 6 FINAL DIAGNOSIS: Phenotype-genotype discordance in congenital malformations with communication disorders resembling trisomy 18 (Edwards syndrome) Symptoms: - MEDICATION: - Clinical Procedure: - Specialty: Otolaryngology. OBJECTIVE: Congenital defects. BACKGROUND: Communication process disorders are very frequent in rare cases of chromosomal aberrations (deletions, insertions, and trisomies) such as Down syndrome (trisomy 21), Turner syndrome, Edwards syndrome (trisomy 18), or Patau syndrome (trisomy 13). Sometimes phenotype may delusively correspond to the characteristic features of a given syndrome, but genotype tests do not confirm its presence. CASE REPORT: We present the case of a 6-year-old girl admitted to the Clinic of Phoniatrics and Audiology for the assessment of communication in the course of congenital malformations with phenotype characteristic for trisomy 18 (Edwards syndrome). Immediately upon birth, dysmorphic changes suggesting trisomy 18 (Edwards syndrome) were observed, but trisomy 18 was excluded after karyotype test results were normal (46, XX). CONCLUSIONS: DISTURBED ARTICULATION WAS DIAGNOSED: deformed linguo-dental and palatal sounds, interdental realization with flat tongue of the /s/, /z/, /c/, /dz/, /s/, /z/, /c/, /dz/ sounds (sigmatismus interdentalis). Hearing loss was confirmed. PMID- 24478820 TI - Metabolomics Reveal d-Alanine:d-Alanine Ligase As the Target of d-Cycloserine in Mycobacterium tuberculosis. AB - Stable isotope-mass spectrometry (MS)-based metabolomic profiling is a powerful technique for following changes in specific metabolite pool sizes and metabolic flux under various experimental conditions in a test organism or cell type. Here, we use a metabolomics approach to interrogate the mechanism of antibiotic action of d-cycloserine (DCS), a second line antibiotic used in the treatment of multidrug resistant Mycobacterium tuberculosis infections. We use doubly labeled 13C alpha-carbon-2H l-alanine to allow tracking of both alanine racemase and d alanine:d-alanine ligase activity in M. tuberculosis challenged with DCS and reveal that d-alanine:d-alanine ligase is more strongly inhibited than alanine racemase at equivalent DCS concentrations. We also shed light on mechanisms surrounding d-Ala-mediated antagonism of DCS growth inhibition and provide evidence for a postantibiotic effect for this drug. Our results illustrate the potential of metabolomics in cellular drug-target engagement studies and consequently have broad implications in future drug development and target validation ventures. PMID- 24478821 TI - Energy Transfer Observed in Live Cells Using Two-Dimensional Electronic Spectroscopy. AB - Two-dimensional electronic spectroscopy (2DES) elucidates electronic structure and dynamics on a femtosecond time scale and has proven to be an incisive tool for probing congested linear spectra of biological systems. However, samples that scatter light intensely frustrate 2DES analysis, necessitating the use of isolated protein chromophore complexes when studying photosynthetic energy transfer processes. We present a method for conducting 2DES experiments that takes only seconds to acquire thousands of 2DES spectra and permits analysis of highly scattering samples, specifically whole cells of the purple bacterium Rhodobacter sphaeroides. These in vivo 2DES experiments reveal similar timescales for energy transfer within the antennae complex (light harvesting complex 2, LH2) both in the native photosynthetic membrane environment and in isolated detergent micelles. PMID- 24478823 TI - The Stereotype Content Model: The Role Played by Competence in Inferring Group Status. AB - In the context of the Stereotype Content Model, we investigate the "backward" inferential process that leads from the competence stereotype to the structural attribute of status. Three hypotheses were tested: (1) Perceived competence affects attributions of status; (2) the less competent group is perceived as warmer (compensation effect); (3) membership leads to ingroup status enhancement. Two minimal groups were created; groups' competence and membership were manipulated. Findings supported the hypotheses: Group status was rated higher when the target group was described as competent; groups were rated warmer when lower in competence; group status was rated higher by members than non-members. PMID- 24478822 TI - Diphenylhydantoin promotes proliferation in the subventricular zone and dentate gyrus. AB - PROBLEM STATEMENT: Diphenylhydantoin (phenytoin) is an antiepileptic drug that generates hyperplasia in some tissue by stimulating Epidermal Growth Factor (EGFR) and Platelet-Derived Growth Factor beta (PDGFR-beta) receptors and by increasing serum levels of basic fibroblast growth factor (bFGF, FGF2 or FGF beta). Neural stem cells in the adult brain have been isolated from three regions: the Subventricular Zone (SVZ) lining the lateral wall of the lateral ventricles, the Subgranular Zone (SGZ) in the dentate gyrus at the hippocampus and the Subgranular Zone (SZC) lining between the hippocampus and the corpus callosum. Neural stem cells actively respond to bFGF, PDGFR-beta or EGF by increasing their proliferation, survival and differentiation. The aim of this study was to evaluate the effect of phenytoin on proliferation and apoptosis in the three neurogenic niches in the adult brain. APPROACH: We orally administrated phenytoin with an oropharyngeal cannula for 30 days: 0 mg kg-1 (controls), 1, 5, 10, 50 and 100 mg kg-1. To label proliferative cells, three injections of 100 mg kg-1 of BrdU was administrated every 12 h. Immunohistochemistry against BrdU or Caspase-3 active were performed to determine the number of proliferative or apoptotic cells. RESULTS: Our results showed that phenytoin induces proliferation in the SVZ and the SGZ in a dose-dependent manner. No statistically significant effects on cell proliferation in the SCZ neither in the apoptosis rate at the SVZ, SGZ and SCZ were found. CONCLUSION: These data indicate that phenytoin promotes a dose-dependent proliferation in the SVZ and SGZ of the adult brain. The clinical relevance of these findings remain to be elucidated. PMID- 24478824 TI - Development of a microfluidic system for measuring HIV-1 viral load. AB - The World Health Organization (WHO) is rapidly expanding antiretroviral treatment (ART) in sub-Saharan countries. However, virological failure of ART is rarely monitored due to the lack of affordable and sustainable viral load assays suitable for resource-limited settings. Here, we report a prototype of a rapid virus detection method based on microfluidic technologies. In this method, HIV-1 particles from 10 uL whole blood were captured by anti-gp120 antibody coated on the microchannel surface and detected by dual fluorescence signals under microscopy. Next, captured HIV-1 particles were counted using the free software, ImageJ (http://rsbweb.nih.gov/ij/). This rapid HIV-1 detection method has potential to be further developed for viral load monitoring at resource-limited settings. PMID- 24478825 TI - In vivo biodistribution of iron oxide nanoparticles: an overview. AB - Iron oxide nanoparticles present a promising alternative to conventional energy deposition-based tissue therapies. The success of such nanoparticles as a therapeutic for diseases like cancer, however, depends heavily on the particles' ability to localize to tumor tissue as well as provide minimal toxicity to surrounding tissues and key organs such as those involved in the reticuloendothelial system (RES). We present here the results of a long term clearance study where mice injected intravenously with 2 mg Fe of 100 nm dextran coated iron oxide nanoparticles were sacrificed at 14 and 580 days post injection. Histological analysis showed accumulation of the nanoparticles in some RES organs by the 14 day time point and clearance of the nanoparticles by the 580 day time point with no obvious toxicity to organs. An additional study reported herein employs 20 nm and 110 nm starch-coated iron oxide nanoparticles at 80 mg Fe/kg mouse in a size/biodistribution study with endpoints at 4, 24 and 72 hours. Preliminary results show nanoparticle accumulation in the liver and spleen with some elevated iron accumulation in tumoral tissues with differences between the 20 nm and the 110 nm nanoparticle depositions. PMID- 24478826 TI - Robust Non-Local Multi-Atlas Segmentation of the Optic Nerve. AB - Labeling or segmentation of structures of interest on medical images plays an essential role in both clinical and scientific understanding of the biological etiology, progression, and recurrence of pathological disorders. Here, we focus on the optic nerve, a structure that plays a critical role in many devastating pathological conditions - including glaucoma, ischemic neuropathy, optic neuritis and multiple-sclerosis. Ideally, existing fully automated procedures would result in accurate and robust segmentation of the optic nerve anatomy. However, current segmentation procedures often require manual intervention due to anatomical and imaging variability. Herein, we propose a framework for robust and fully automated segmentation of the optic nerve anatomy. First, we provide a robust registration procedure that results in consistent registrations, despite highly varying data in terms of voxel resolution and image field-of-view. Additionally, we demonstrate the efficacy of a recently proposed non-local label fusion algorithm that accounts for small scale errors in registration correspondence. On a dataset consisting of 31 highly varying computed tomography (CT) images of the human brain, we demonstrate that the proposed framework consistently results in accurate segmentations. In particular, we show (1) that the proposed registration procedure results in robust registrations of the optic nerve anatomy, and (2) that the non-local statistical fusion algorithm significantly outperforms several of the state-of-the-art label fusion algorithms. PMID- 24478827 TI - Quantitative Anatomical Labeling of the Anterior Abdominal Wall. AB - Ventral hernias (VHs) are abnormal openings in the anterior abdominal wall that are common side effects of surgical intervention. Repair of VHs is the most commonly performed procedure by general surgeons worldwide, but VH repair outcomes are not particularly encouraging (with recurrence rates up to 43%). A variety of open and laparoscopic techniques are available for hernia repair, and the specific technique used is ultimately driven by surgeon preference and experience. Despite routine acquisition of computed tomography (CT) for VH patients, little quantitative information is available on which to guide selection of a particular approach and/or optimize patient-specific treatment. From anecdotal interviews, the success of VH repair procedures correlates with hernia size, location, and involvement of secondary structures. Herein, we propose an image labeling protocol to segment the anterior abdominal area to provide a geometric basis with which to derive biomarkers and evaluate treatment efficacy. Based on routine clinical CT data, we are able to identify inner and outer surfaces of the abdominal walls and the herniated volume. This is the first formal presentation of a protocol to quantify these structures on abdominal CT. The intra- and inter rater reproducibilities of this protocol are evaluated on 4 patients with suspected VH (3 patients were ultimately diagnosed with VH while 1 was not). Mean surfaces distances of less than 2mm were achieved for all structures. PMID- 24478828 TI - Butyrylcholinesterase deficiency identified by preoperative patient interview. PMID- 24478829 TI - Ventricular tachycardia-like electrocardiographic artifact on total thyroidectomy. PMID- 24478830 TI - Day surgery in Korea, a single center experience for 15 years. PMID- 24478831 TI - Subcutaneous emphysema, pneumomediastinum, pneumoretroperitoneum, and pneumoperitoneum secondary to colonic perforation during colonoscopy. PMID- 24478832 TI - Adequate time of initiation of continuous infusion of nitroglycerin for controlling pulmonary arterial pressure during ethanol embolotherapy of congenital arteriovenous malformation of the extremities. PMID- 24478833 TI - Rotational thromboelastometry for diagnosing sudden hyperfibrinolysis immediately after cardiopulmonary bypass during cardiac surgery. PMID- 24478834 TI - A brief cardiac arrest due to saline irrigation during surgery for infratentorial cerebellar tumor. PMID- 24478835 TI - Delayed emergence from anesthesia resulting from posterior cerebral artery infarction after Guglielmi detachable coil embolization. PMID- 24478836 TI - Postoperative delayed hypercapnia and respiratory failure after robot-assisted lower anterior resection. PMID- 24478837 TI - Airway management of patients undergoing laparoscopic gastric bypass surgery: a single center analysis. PMID- 24478838 TI - Airway obstruction following palatoplasty of a patient with sleep disturbance. PMID- 24478839 TI - Iatrogenic catheter sheath shearing during radial artery cannulation. PMID- 24478840 TI - Airway compression after arthroscopic shoulder surgery under general anesthesia. PMID- 24478841 TI - Conversion of supraventricular tachycardia to normal sinus rhythm by dexmedetomidine treatment. PMID- 24478842 TI - Acute exacerbation of cold agglutinin disease during operation. PMID- 24478843 TI - Management of bronchopleural fistula using a modified single lumen tube. PMID- 24478844 TI - Comparison of analgesic effects of programmed intermittent epidural bolus and continuous epidural infusion after total knee arthroplasty. PMID- 24478845 TI - Comparison of dexmedetomidine and ketamine for the analgesic effect using intravenous patient-controlled analgesia after gynecological abdominal surgery. PMID- 24478846 TI - Sympathetically mediated upper back pain after coronary artery bypass graft surgery. PMID- 24478847 TI - Thoracic spondylitis induced myelopathy combined with herpetic neuralgia. PMID- 24478848 TI - Analysis of dispersion of lumbar interlaminar epidural injectates. PMID- 24478849 TI - Aspiration of a sponge during conscious sedation. PMID- 24478850 TI - Two cases of opioid rotation applied to patients with chronic pain. PMID- 24478851 TI - Abdominal distention and constipation followed by herpes zoster infection. PMID- 24478852 TI - Massive pleural effusion in ovarian tumor patient during laparoscopic surgery. PMID- 24478853 TI - Endotracheal intubation-related vocal cord ulcer following general anesthesia. PMID- 24478854 TI - Two cases report of brachial plexus injury in laparoscopic colorectal surgery. PMID- 24478855 TI - Antioxidant effects and mechanism of thiopental and propofol on the rabbit abdominal aortic endothelial dependent vasorelaxation against reactive oxygen species. PMID- 24478856 TI - Delayed recovery from paralysis by succinylcholine in patient with preoperatively unrecognized and inherited pseudocholinesterase deficiency. PMID- 24478857 TI - Use of light wand as an adjunct during intubation of patient with large epiglottic cyst. PMID- 24478858 TI - Plain endotracheal tube insertion carries greater risk for malpositioning than does reinforced endotracheal tube insertion in females. PMID- 24478859 TI - Pentax-AWS video laryngoscope for tracheal intubation in a patient with Klippel Feil syndrome. PMID- 24478860 TI - Occurrence bilateral bronchospasm consequently after unilateral bronchospasm. PMID- 24478861 TI - Bilateral vocal cord paralysis detected incidentally during direct laryngoscopy on general anesthesia. PMID- 24478862 TI - Successful use of i-gelTM in a patient with tracheal stenosis undergoing Montgomery t-tube insertion. PMID- 24478863 TI - Awake Glidescope(r) intubation in patients with severe arytenoid swelling after laryngeal surgery with radiation therapy. PMID- 24478864 TI - Bilateral recurrent laryngeal nerve palsy in a patient undergoing consecutive thyroid operations. PMID- 24478865 TI - Tracheal granuloma after thyroidectomy with difficult intubation. PMID- 24478866 TI - Characteristics and effectiveness of preoperative consultations in a tertiary hospital. PMID- 24478867 TI - The effect of induced hypotension on the perioperative bleeding and transfusion in the bipolar hemiarthroplasty of hip: retrospective study for four years. PMID- 24478868 TI - Operative hysteroscopy intravascular absorption syndrome caused by massive absorption of 0.9% saline as the distention/irrigation medium. PMID- 24478869 TI - Shearing of an intrathecal catheter during insertion for cerebrospinal fluid drainage. PMID- 24478870 TI - A cardiovascular collapse following vigorous cough during spinal anesthesia. PMID- 24478871 TI - The intravenously administered palonosetron does not affect the spinal anesthesia. PMID- 24478872 TI - Cervical nucleoplasty as an effective treatment method of cervical degenerative disc disease. PMID- 24478873 TI - Contralateral complete L5 palsy following ipsilateral L4 selective transforaminal epidural block. PMID- 24478874 TI - Hypopigmentation and subcutaneous fat, muscle atrophy after local corticosteroid injection. PMID- 24478875 TI - Cephalad malposition after central venous catheterization through right internal jugular vein. PMID- 24478876 TI - Unilateral laryngeal hematoma after combined carotid endarterectomy and off-pump coronary artery bypass grafting surgery. PMID- 24478877 TI - A case of Brugada syndrome patient undertaken total intravenous anesthesia with remifentanil. PMID- 24478878 TI - Large left atrial myxoma causing mitral annular dilation, functional mitral stenosis with concealed atrial septal defects. PMID- 24478879 TI - Anesthetic experiences of severe mitral regurgitation and atrial septal defect newly appeared during the operation after myxoma removal surgery. PMID- 24478880 TI - Anesthetic management of a patient with hypertrophic cardiomyopathy and patent ductus arteriosus. PMID- 24478881 TI - Recurrent paroxysmal supraventricular tachycardia in the beach chair position for shoulder surgery under general anesthesia. PMID- 24478882 TI - Fatal pulmonary thromboembolism during total hip replacement under spinal anesthesia. PMID- 24478883 TI - Inverted stress cardiomyopathy during monitored anesthesia care for endoscopic sinus surgery. PMID- 24478884 TI - Bispectral index decreased to zero for a patient undergoing orthotopic liver transplantation. PMID- 24478885 TI - Postoperative pulmonary edema in a patient with POEMS syndrome. PMID- 24478886 TI - Severe bronchospasm in a premature infant during induction of anesthesia caused ventilation failure. PMID- 24478887 TI - Anesthetic management for transfusion-free Rastelli's procedure in a pediatric Jehovah's Witness patient. PMID- 24478888 TI - Anesthetic experience in a child with femoral hypoplasia-unusual facies syndrome. PMID- 24478889 TI - Spinal anesthesia for emergency cesarean section in a preeclampsia patient diagnosed with type 1 neurofibromatosis. PMID- 24478890 TI - Pneumocephalus during labor analgesia using the combined spinal-epidural technique. PMID- 24478891 TI - Labor analgesia and anesthetic management during emergency cesarean section of parturient with spinal cord injury (SCI). PMID- 24478892 TI - Anesthetic management of a patient with narcolepsy for emergency caesarean section. PMID- 24478893 TI - Sudden persistent fetal bradycardia after spinal analgesia for labor pain. PMID- 24478894 TI - Medications in treatment of postherpetic neuralgia. PMID- 24478895 TI - Epidural lysis of adhesions. AB - As our population ages and the rate of spine surgery continues to rise, the use epidural lysis of adhesions (LOA) has emerged as a popular treatment to treat spinal stenosis and failed back surgery syndrome. There is moderate evidence that percutaneous LOA is more effective than conventional ESI for both failed back surgery syndrome, spinal stenosis, and lumbar radiculopathy. For cervical HNP, cervical stenosis and mechanical pain not associated with nerve root involvement, the evidence is anecdotal. The benefits of LOA stem from a combination of factors to include the high volumes administered and the use of hypertonic saline. Hyaluronidase has been shown in most, but not all studies to improve treatment outcomes. Although infrequent, complications are more likely to occur after epidural LOA than after conventional epidural steroid injections. PMID- 24478896 TI - The psychosomatic disorders pertaining to dental practice with revised working type classification. AB - Psychosomatic disorders are defined as disorders characterized by physiological changes that originate partially from emotional factors. This article aims to discuss the psychosomatic disorders of the oral cavity with a revised working type classification. The author has added one more subset to the existing classification, i.e., disorders caused by altered perception of dentofacial form and function, which include body dysmorphic disorder. The author has also inserted delusional halitosis under the miscellaneous disorders classification of psychosomatic disorders and revised the already existing classification proposed for the psychosomatic disorders pertaining to dental practice. After the inclusion of the subset (disorders caused by altered perception of dentofacial form and function), the terminology "psychosomatic disorders of the oral cavity" is modified to "psychosomatic disorders pertaining to dental practice". PMID- 24478897 TI - Spinal noradrenergic modulation and the role of the alpha-2 receptor in the antinociceptive effect of intrathecal nefopam in the formalin test. AB - BACKGROUND: Nefopam has shown an analgesic effect on acute pain including postoperative pain. The reuptake of monoamines including serotonin and noradrenaline has been proposed as the mechanism of the analgesic action of nefopam, but it remains unclear. Although alpha-adrenergic agents are being widely used in the perioperative period, the role of noradrenergic modulation in the analgesic effect of nefopam has not been fully addressed. METHODS: Changes in the antinociceptive effect of intrathecal (i.t.) nefopam against formalin elicited flinching responses were explored in Sprague-Dawley rats pretreated with i.t. 6-hydroxydopamine (6-OHDA), which depletes spinal noradrenaline. In addition, antagonism to the effect of nefopam by prazosin and yohimbine was evaluated to further elucidate the antinociceptive mechanism of i.t. nefopam. RESULTS: Pretreatment with i.t. 6-OHDA alone did not alter the flinching responses in either phase of the formalin test, while it attenuated the antinociceptive effect of i.t. nefopam significantly during phase 1, but not phase 2. The antagonist of the alpha-2 receptor, but not the alpha-1 receptor, reduced partially, but significantly, the antinociceptive effect of i.t. nefopam during phase 1, but not during phase 2. CONCLUSIONS: This study demonstrates that spinal noradrenergic modulation plays an important role in the antinociceptive effect of i.t. nefopam against formalin-elicited acute initial pain, but not facilitated pain, and this action involves the spinal alpha-2 but not the alpha-1 receptor. PMID- 24478898 TI - Evaluation of salivary cortisol and anxiety levels in myofascial pain dysfunction syndrome. AB - BACKGROUND: Myofascial pain dysfunction syndrome (MPDS), otherwise called myofascial pain is one of the most common temporomandibular disorders, which in turn is the most common cause of orofacial pain of non-dental origin. Its etiology is multifactorial and still poorly understood. Psychological factors have been shown to play a role in the etiology. The aim of the study was to evaluate the association between anxiety and salivary cortisol levels in patients with myofascial pain. METHODS: Twenty patients suffering from myofascial pain were recruited as the study group. The same number of age and sex matched healthy individuals were taken as the control group. The salivary samples collected between 9-9:15 am from both groups were analyzed for cortisol levels with the competitive enzyme-linked immunosorbent assay method. Anxiety levels of 40 patients were measured using Hamilton's anxiety scale. RESULTS: The mean serum cortisol level of the MPDS group showed a highly significant difference (p < 0.001) from the controls. The mean anxiety scores of the MPDS group showed a highly significant difference (p < 0.001) from the controls. A positive correlation was found between anxiety and the salivary cortisol levels in MPDS patients. CONCLUSIONS: These findings suggest that anxiety plays a vital role in the etio-pathogenesis of MPDS; thus, besides pharmacological treatment, psychological support is also needed. PMID- 24478899 TI - Epidural steroid injection in korean pain physicians: a national survey. AB - BACKGROUND: Epidural steroid injection (ESI) is one of the most common procedures for patients presenting low back pain and radiculopathy. However, there is no clear consensus on what constitutes appropriate steroid use for ESIs. To investigate optimal steroid injection methods for ESIs, surveys were sent to all academic pain centers and selected private practices in Korea via e-mail. METHODS: Among 173 pain centers which requested the public health insurance reimbursements for their ESIs and were enrolled in the Korean Pain Society, 122 completed questionnaires were returned, for a rate of 70.5%; also returned were surveys from 39 academic programs and 85 private practices with response rates of 83.0% and 65.9%, respectively. RESULTS: More than half (55%) of Korean pain physicians used dexamethasone for ESIs. The minimum interval of subsequent ESIs at the academic institutions (3.1 weeks) and the private practices (2.1 weeks) were statistically different (P = 0.01). CONCLUSIONS: Although there was a wide range of variation, there were no significant differences between the academic institutions and the private practices in terms of the types and single doses of steroids for ESIs, the annual dose of steroids, or the limitations of doses in the event of diabetes, with the exception of the minimum interval before the subsequent ESI. PMID- 24478900 TI - Bipolar Intra-articular Radiofrequency Thermocoagulation of the Thoracic Facet Joints: A Case Series of a New Technique. AB - BACKGROUND: This study tests the hypothesis that of bipolar radiofrequency thermocoagulation of the thoracic facet joint capsule may provide a safe and effect method of pain control from thoracic facet origin. METHODS: Among patients suffering from localized mid back pain, nine patients with thoracic facet disease confirmed by magnetic resonance image and diagnostic thoracic facet block were enrolled. Bipolar radiofrequency ablation in the inferior aspect of the thoracic facet joint was done. Visual Analog Scale (VAS) was measured pre-intervention and 1 month post-intervention. Any complications and changes in amount of pain medication were recorded. RESULTS: Significant 47.6% reduction in VAS was noted at 1 month. There were no serious complications. CONCLUSIONS: Intra-articular bipolarradiofrequency thermocoagulation of the thoracic facet joint may be a technically easier and valid method of treating mid back pain of thoracic facet origin. PMID- 24478901 TI - Intradermal therapy (mesotherapy) for the treatment of acute pain in carpal tunnel syndrome: a preliminary study. AB - BACKGROUND: The carpal tunnel syndrome (CTS) is the most common cause of severe hand pain. In this study we treated acute pain in CTS patients by means of local intradermal injections of anti-inflammatory drugs (mesotherapy). METHODS: In twenty-five patients (forty-five hands), CTS diagnosis was confirmed by clinical and neurophysiological examination prior to mesotherapy. A mixture containing lidocaine 10 mg, ketoprophen lysine-acetylsalycilate 80 mg, xantinol nicotinate 100 mg, cyanocobalamine 1,000 mcg plus injectable water was used. Sites of injection were three parallel lines above the transverse carpal ligament and two v-shaped lines, one at the base of the thenar eminence, and the other at the base of the hypothenar eminence. RESULTS: The day after the treatment, all but four patients reported a significant reduction in pain and paresthesias. After 12 months, 17 patients had a complete pain relief, eight patients reported recurrence of pain and sensory symptoms and four out of them underwent surgical treatment. CONCLUSIONS: With the obvious limits of a small-size open-label study, our results suggest that mesotherapy can temporary relieve pain and paresthesias in most CTS patients and in some cases its effect seems to be long-lasting. Further controlled studies are needed to confirm our preliminary findings and to compare mesotherapy to conventional approaches for the treatment of CTS. PMID- 24478903 TI - The Comparison of the Result of Epiduroscopic Laser Neural Decompression between FBSS or Not. AB - BACKGROUND: Epiduroscopic laser neural decompression (ELND) has been performed as a treatment tool for chronic refractory low back pain and/or radicular pain. There are some studies about the usefulness of epiduroscopy for post lumbar surgery syndrome, however, few studies about the effectiveness of epiduroscopy for patients without back surgery. We compared the satisfaction of patients who underwent ELND for chronic low back pain and/or radicular pain after back surgery and for the same symptoms without surgery. METHODS: We compared the degree of satisfaction of patients after ELND between who had underwent the lumbar spine surgery and who had not retrospectively by chart reviewing. We divided 39 patients who had received ELND into two groups, one is the group of patients who got the lumbar surgery (group 1), and the other is the group of patients who did not (group 2). Their medical records including age, sex, previous treatment, duration of illness, degree of symptom relief were investigated. We compared each items between two groups. RESULTS: The number of patients in group 1 was 17, and group 2 was 22. In group 1, 16 patients (94.1%) showed more than 'Acceptable', and 19 patients (86.4%) showed more than 'Acceptable' in group 2. There is no significant differences statistically in percentage of patients who showed more than 'Acceptable' in the satisfaction after ELND between two groups. CONCLUSIONS: ELND provided satisfaction (more than 85%) for patients with chronic low back pain and/or leg pain regardless of previous back surgery history. PMID- 24478902 TI - Intravenous Nefopam Reduces Postherpetic Neuralgia during the Titration of Oral Medications. AB - BACKGROUND: The recently known analgesic action mechanisms of nefopam (NFP) are similar to those of anticonvulsants and antidepressants in neuropathic pain treatment. It is difficult to prescribe high doses of oral neuropathic drugs without titration due to adverse effects. Unfortunately, there are few available intravenous analgesics for the immediate management of acute flare-ups of the chronic neuropathic pain. The aim of this study was to determine the additional analgesic effects for neuropathic pain of NFP and its adverse effects during the titration of oral medications for neuropathic pain among inpatients with postherpetic neuralgia (PHN). METHODS: Eighty inpatients with PHN were randomly divided into either the NFP or normal saline (NS) groups. Each patient received a 3-day intravenous continuous infusion of either NFP with a consecutive dose reduction of 60, 40, and 20 mg/d, or NS simultaneously while dose titrations of oral medications for neuropathic pain gradually increased every 3 days. The efficacy of additional NFP was evaluated by using the neuropathic pain symptom inventory (NPSI) score for 12 days. Adverse effects were also recorded. RESULTS: The median NPSI score was significantly lower in the NFP group from days 1 to 6 of hospitalization. The representative alleviating symptoms of pain after using NFP were both spontaneous and evoked neuropathic pain. Reported common adverse effects were nausea, dizziness, and somnolence, in order of frequency. CONCLUSIONS: An intravenous continuous infusion of NFP reduces spontaneous and evoked neuropathic pain with tolerable adverse effects during the titration of oral medications in inpatients with PHN. PMID- 24478904 TI - Development of complex regional pain syndrome after a snake bite: a case report. AB - The occurrence of CRPS after a snake bite was very rare, only two cases were reported worldwide. Here we report a case that the 44-year-old female patient bitten by snakes CRPS type 1 was treated consecutive intravenous regional block, lumbar sympathectomy and antiepileptic drug therapy, also discuss the possible pathophysiology. PMID- 24478905 TI - Radiofrequency thermal ablation in painful myeloma of the clavicle. AB - A 57-year-old male patient had myeloma. He had severe pain in the left clavicle that did not respond to radiotherapy; therefore, it was treated with radiofrequency thermal ablation (RFTA). Under fluoroscopic guidance, two RF needles at a distance of 1.5 cm from each other were inserted into the mass and conventional radiofrequency (90C and 60 seconds) at two different depths (1 cm apart) was applied. Then, 2 ml of 0.5% ropivacaine along with triamcinolone 40 mg was injected in each needle. The visual analogue pain score (VAS from 0 to 10) was decreased from 8 to 0. In the next 3 months of follow-up, the patient was very satisfied with the procedure and the mass gradually became smaller. There were no complications. This study shows that RFTA could be a useful method for pain management in painful osteolytic myeloma lesions in the clavicle. PMID- 24478906 TI - A case of neuromyelitis optica misdiagnosed as cervicogenic headache. AB - Neuromyelitis optica (NMO) is an inflammatory demyelinating disease of the central nervous system associated with longitudinally extensive myelitis and optic neuritis. It is characterized by relapses that lead to blindness and paralysis sequelaes. But, this is rare disease; therefore high clinical suspicion for a correct diagnosis and proper examinations are not easy. However, early diagnosis is essential to prevent sequelae. We report the case of NMO with headache. A 30-year male patient who suffered headache visited our pain clinic because of aggravated pain despite treatment. The cause of the pain was revealed as NMO by more detailed previous history and examination. PMID- 24478907 TI - Ultrasound-assisted mental nerve block and pulsed radiofrequency treatment for intractable postherpetic neuralgia: three case studies. AB - Postherpetic neuralgia (PHN) is one of the most difficult pain syndromes to treat. Invasive treatments may be considered when patients fail to obtain adequate pain relief from noninvasive treatment approaches. Here, we present three cases of PHN in the mandibular branch treated with ultrasound-assisted mental nerve block and pulsed radiofrequency treatment. None of the patients had adequate pain relief from the medical therapy, so we performed the mental nerve block on the affected side under ultrasound assistance. Two patients showed satisfactory pain relief continuously over 12 months without any further interventions, whereas one patient only had short-term pain relief. For the patient had short-term pain relief we performed pulsed radiofrequency treatment (PRFT) on the left mental nerve under ultrasound assistance. After PRFT, the patient had adequate pain relief for 6 months and there was no need for further management. PMID- 24478908 TI - Radiculopathy caused by discal cyst. AB - Discal cyst is an intraspinal cyst with a distinct communication with the corresponding intervertebral disc. It is a rare condition and could present with radiculopathy similar to that caused by lumbar disc herniation. We present a patient with a large discal cyst in the ventrolateral epidural space of the 5(th) lumbar vertebral (L5) level that communicated with the adjacent 4(th) lumbar and 5(th) lumbar intervertebral disc, causing L5 radiculopathy. We alleviated the radiating pain with selective transforaminal epidural blocks. PMID- 24478909 TI - Comments on "The Effect of Low-dose Ketamine on Post-caesarean Delivery Analgesia after Spinal Anesthesia". PMID- 24478910 TI - Herpes zoster and diabetes mellitus. PMID- 24478911 TI - Systematic review on the incidence of bisphosphonate related osteonecrosis of the jaw in children diagnosed with osteogenesis imperfecta. AB - OBJECTIVES: To conduct a systematic review of epidemiological literature to determine the incidence of bisphosphonate related osteonecrosis of the jaw occurring either spontaneously or after dental surgery, in children and adolescents diagnosed with osteogenesis imperfecta. MATERIAL AND METHODS: MEDLINE, HMIC and EMBASE were used to search for English-language articles published from 1946 - 2013. Inclusion criteria consisted of population based studies of children and adolescents (24 years and younger) diagnosed with osteogenesis imperfecta, only studies which included a dental examination, and patients treated with intravenous bisphosphonates were included. Articles were excluded if patients had any other co-morbidity which could affect osteonecrosis of the jaw, and those which treated patients with oral bisphosphonates only. RESULTS: Five studies consisting of four retrospective cohort studies and one case series were identified. Study populations ranged from 15 to 278 patients and number of subjects with osteogenesis imperfecta ranged from 15 to 221. Mean duration of intravenous bisphosphonate use ranged from 4.5 to 6.8 years. All patients were clinically examined and no patients were found to have osteonecrosis of the jaw. CONCLUSIONS: There is no evidence to support hypothesis of causal relationship between bisphosphonates and osteonecrosis of the jaw in children and adolescents with osteogenesis imperfecta. More prospective studies on bisphosphonate use in osteogenesis imperfecta needs to be carried out. PMID- 24478912 TI - Anatomical relationship of lingual nerve to the region of mandibular third molar. AB - OBJECTIVES: This study evaluated the relationship of the lingual nerve with the adjacent anatomical structures of the mandibular third molar region, influencing the dentist to be aware of the variability of these relationships. MATERIAL AND METHODS: Samples of 24 human corpse half-heads were selected and divided according with the presence or absence of the mandibular third molars. The lingual nerve (LN) was explored, showing its run from the oblique line until its crossing with the submandibular gland duct. The measurements along the LN and the adjacent anatomical structures were taken at the retromolar, molar and sublingual region with the use of a digital caliper. RESULTS: The distance from the LN and the third molar socket, which represents the horizontal distance of the lingual plate to the nerve, on average, was 4.4 mm (SD 2.4 mm). The distance from the LN and the lingual alveolar rim, which represents the vertical relationship between the nerve and the lingual alveolar rim of the third molar socket, on average, was 16.8 mm (SD 5.7 mm). The LN has a varied topography that leaves it very vulnerable during any procedure executed in this region. CONCLUSIONS: Unless adequate protection of the lingual nerve is acquired by following an adequate surgical technique, the lingual nerve will always be vulnerable to damage during surgical intervention or manipulation in this region. PMID- 24478913 TI - Frictional resistance of three types of ceramic brackets. AB - OBJECTIVES: To investigate the static frictional resistance at the bracket/archwire interface in two recently introduced bracket systems and compare them to conventional ceramic and conventional metal bracket systems. Three variables were considered including the bracket system, archwire type and archwire angulation. MATERIAL AND METHODS: Four bracket systems were tested in vitro: Self ligating ceramic, ceramic with metal slot and module, conventional ceramic with module and conventional metal with module. A specially constructed jig and an Instron testing machine were used to measure the static frictional resistance for 0.014 inches round and 0.018 x 0.025 inches rectangular stainless steel wires at 0 degrees and 7 degrees angulations. MAIN OUTCOME MEASURES: static frictional force at the bracket/archwire interface; recorded and measured in units of force (Newtons). RESULTS: Self ligating ceramic and metal slot ceramic bracket systems generated significantly less static frictional resistance than conventional ceramic bracket systems with the wire at both angulations (P < 0.05). Changing the wire from 0.014 round to 0.018 x 0.025 rectangular wire significantly increased frictional forces for metal slot ceramic and conventional metal bracket systems (P < 0.01). Increasing wire angulation significantly increased frictional resistance at the bracket/archwire interface for all four types of bracket systems tested (P < 0.001). CONCLUSIONS: Compared to conventional ceramic, self ligating ceramic and metal slot ceramic bracket systems should give improved clinical performance, matching that of conventional metal brackets. PMID- 24478914 TI - Findings of florid cemento-osseous dysplasia: a report of three cases. AB - BACKGROUND: Florid cemento-osseous dysplasia (FCOD) is a benign jaw lesion originating from periodontal ligament tissues usually asymptomatic and diagnosed accidentally at routine dental radiographic examination. The purpose of this paper is to report three cases diagnosed as FCOD with their clinical, radiographic and histological findings. METHODS: Radiologic and clinical symptoms of three cases diagnosed as FCOD are presented. Serum alkaline phosphatase test and biopsy taken from two of the patients are discussed to eliminate the Paget's disease. RESULTS: Three patients diagnosed as FCOD and called for routine follow up. Because of no sign of infection or osteomyelitis, conservative treatment was applied. CONCLUSIONS: Radiographic examination is significant for the diagnosis of florid cemento-osseous dysplasia, especially in the asymptomatic cases. The roles of the dentist are to ensure the follow-up of the diagnosed patients and to take the necessary measures for preventing from the infections. PMID- 24478915 TI - Making Chemistry Fun to Learn. AB - The major challenge that confronts undergraduate chemical education in US is the gap between the high demands that learning requires and the low efforts that students make partially due to the lack of motivation. This paper reports strategies to ameliorate student learning in the following areas: application of friendly presentation, utilization of analogies and correlation with everyday life. The novelty lies in the attempt to incorporate new meanings into the existing platforms on publisher provided teaching resources by utilizing commercially available software tools. The paper aims to point out ways to effective knowledge delivery that can be implemented by other chemistry instructors. The goal is to make chemistry vivid and easy to understand in order to stimulate students' intellectual curiosity, which in turn leads to learning enhancement regardless of their career choices. PMID- 24478916 TI - Efficient use of social media during the avian influenza A(H7N9) emergency response. PMID- 24478917 TI - Invasive meningococcal disease in elderly people, New South Wales, Australia, 1993 to 2012. AB - Little information is available publicly on invasive meningococcal disease (IMD) in elderly people in Australia. This study analysed IMD notifications data from New South Wales between 1993 and 2012 to determine the distribution of IMD among people aged 65 years and older and to describe the characteristics of IMD in this age group compared to younger age groups with respect to notification trends, serogroup distribution and mortality rates. Following introduction of a childhood vaccination programme against meningococcal type C in 2003, notification rates in all age groups decreased, but the proportion of IMD notifications in people aged 65 years and over rose significantly (from 4% to 6%, P = 0.01). Mortality rates from IMD in those aged 65 years and older were significantly higher than overall rates (32% compared to 5%, P < 0.01). Serogroup Y accounted for 23% of infections in the elderly compared to 3% in people aged under 65 years (P < 0.01). As the population ages, the elderly may account for a higher number of IMD cases in Australia. Protocols at the state and national level should be updated to provide guidance on the clinical and public health management of elderly people with IMD. PMID- 24478918 TI - Surveillance of avian influenza viruses in Papua New Guinean poultry, June 2011 to April 2012. AB - We investigated the circulation of avian influenza viruses in poultry populations throughout Papua New Guinea to assess the risk to the poultry industry and human health. Oropharyngeal swabs, cloacal swabs and serum were collected from 537 poultry from 14 provinces of Papua New Guinea over an 11-month period (June 2011 through April 2012). Virological and serological investigations were undertaken to determine the prevalence of avian influenza viruses. Neither influenza A viruses nor antibodies were detected in any of the samples. This study demonstrated that avian influenza viruses were not circulating at detectable levels in poultry populations in Papua New Guinea during the sampling period. However, avian influenza remains a significant risk to Papua New Guinea due to the close proximity of countries having previously reported highly pathogenic avian influenza viruses and the low biosecurity precautions associated with the rearing of most poultry populations in the country. PMID- 24478919 TI - Surveillance for arboviral zoonoses in New Zealand birds. AB - INTRODUCTION: Given the significant burden that emerging infectious diseases place on global economies and public health, the monitoring and mitigation of, and early response to, potential infectious diseases are of the highest priority. The objective of this study was to survey for known and other potential arboviral zoonoses in multiple bird species at four locations in New Zealand. METHODS: Common bird species were targeted for blood sampling during two southern hemisphere summers. Sera from each period (n = 185 and n = 693) were screened in an epitope blocking enzyme immunoassay for flavivirus antibody detection. In the first season, testing for antibodies to specific alphaviruses was conducted on samples with sufficient sera (n = 22). In the second season, blood clots (n = 544) were screened for viral presence by polymerase chain reaction (PCR) for alphaviral and flaviviral RNA, and virus isolation (n = 146) was conducted. RESULTS: Flavivirus antibodies were detected in 13 species, and one Australasian gannet (Morus serrator) from one site was positive for antibodies to Ross River virus. PCR tests and virus isolation were all negative. DISCUSSION: Evidence for flavivirus exposure in seabirds at Kaikoura Peninsula and Cape Kidnappers suggests that viruses isolated from seabirds and associated ticks in New Zealand in the late 1970s are still present. Evidence for flavivirus exposure in passerines at Kaikoura Peninsula, Cape Kidnappers and Mokoia Island is novel. The Ross River virus finding is also new and supports the hypothesis that migratory seabirds are an import pathway for such agents into New Zealand. PMID- 24478920 TI - Letter to the editor: Human infections with avian influenza A(H7N9): preliminary assessments of the age and sex distribution. PMID- 24478921 TI - A new biophysical metric for interrogating the information content in human genome sequence variation: Proof of concept. AB - The 21st century emergence of genomic medicine is shifting the paradigm in biomedical science from the population phenotype to the individual genotype. In characterizing the biology of disease and health disparities in population genetics, human populations are often defined by the most common alleles in the group. This definition poses difficulties when categorizing individuals in the population who do not have the most common allele(s). Various epidemiological studies have shown an association between common genomic variation, such as single nucleotide polymorphisms (SNPs), and common diseases. We hypothesize that information encoded in the structure of SNP haploblock variation in the human leukocyte antigen-disease related (HLA-DR) region of the genome illumines molecular pathways and cellular mechanisms involved in the regulation of host adaptation to the environment. In this paper we describe the development and application of the normalized information content (NIC) as a novel metric based on SNP haploblock variation. The NIC facilitates translation of biochemical DNA sequence variation into a biophysical quantity derived from Boltzmann's canonical ensemble in statistical physics and used widely in information theory. Our normalization of this information metric allows for comparisons of unlike, or even unrelated, regions of the genome. We report here NIC values calculated for HLA-DR SNP haploblocks constructed by Haploview, a product of the International Haplotype Map Project. These haploblocks were scanned for potential regulatory elements using ConSite and miRBase, publicly available bioinformatics tools. We found that all of the haploblocks with statistically low NIC values contained putative transcription factor binding sites and microRNA motifs, suggesting correlation with genomic regulation. Thus, we were able to relate a mathematical measure of information content in HLA-DR SNP haploblocks to biologically relevant functional knowledge embedded in the structure of DNA sequence variation. We submit that NIC may be useful in analyzing the regulation of molecular pathways involved in host adaptation to environmental pathogens and in decoding the functional significance of common variation in the human genome. PMID- 24478934 TI - Multiple Sclerosis and Experimental Allergic Encephalomyelitis. PMID- 24478933 TI - A Protection Motivation Theory-Based Scale for Tobacco Research among Chinese Youth. AB - Rates of tobacco use among adolescents in China and other lower and middle-income countries remain high despite notable prevention and intervention programs. One reason for this may be the lack of theory-based research in tobacco use prevention in these countries. In the current study, a culturally appropriate 21 item measurement scale for cigarette smoking was developed based on the core constructs of Protection Motivation Theory (PMT). The scale was assessed among a sample of 553 Chinese vocational high school students. Results from correlational and measurement modeling analysis indicated adequate measurement reliability for the proposed PMT scale structure. The two PMT Pathways and the seven PMT constructs were significantly correlated with adolescent intention to smoke and actual smoking behavior. This study is the first to evaluate a PMT scale for cigarette smoking among Chinese adolescents. The scale provides a potential tool for assessing social cognitive processes underlying tobacco use. This is essential for understanding smoking behavior among Chinese youth and to support more effective tobacco use prevention efforts. Additional studies are needed to assess its utility for use with Chinese youth in other settings. PMID- 24478935 TI - Manipulating In-House Designed Drug Databases For The Prediction of pH-Dependent Aqueous Drug Solubility. AB - Chemical, pharmacokinetic, and pharmacodynamics properties are available in the package inserts of every Food and Drug Administration (FDA) approved prescription drug, including all available chemotherapy drugs. These inserts follow a specific format imposed by the FDA. Whether chemotherapy drugs are administered via the parenteral route or alimentary tract, a significant factor affecting their bioavailability, elimination and consequently the drug's effectiveness and potency, is its state of aqueous solubility. Water solubility has always lent itself poorly to the different predictive and experimental measures employed in the determination of a useful quantitative assessment. In this project, we first built a chemical structure based searchable database for 85 FDA approved chemotherapy drugs and then used Bio-Rad's KnowItAll(r) Informatics suite to focus on the drugs pH-dependent water solubility prediction. We compared the predicted values for water solubility to the available values reported in the drug inserts, testing the practical utility and the predictive ability of our model in reporting such a clinically relevant, underreported pharmacokinetic parameter. A relational cancer drug database (MySQL) was created to further facilitate analysis and/or prediction of a chemotherapy compound's missing pharmacokinetic properties. PMID- 24478936 TI - MuB gives a new twist to target DNA selection. AB - Transposition target immunity is a phenomenon observed in some DNA transposons that are able to distinguish the host chromosome from their own DNA sequence, thus avoiding self-destructive insertions. The first molecular insight into target selection and immunity mechanisms came from the study of phage Mu transposition, which uses the protein MuB as a barrier to self-insertion. MuB is an ATP-dependent non-specific DNA binding protein that regulates the activity of the MuA transposase and captures target DNA for transposition. However, a detailed mechanistic understanding of MuB functioning was hindered by the poor solubility of the MuB-ATP complexes. Here we comment on the recent discovery that MuB is an AAA+ ATPase that upon ATP binding assembles into helical filaments that coat the DNA. Remarkably, the helical parameters of the MuB filament do not match those of the bound DNA. This intriguing mismatch symmetry led us to propose a model on how MuB targets DNA for transposition, favoring DNA bending and recognition by the transposase at the filament edge. We also speculate on a different protective role of MuB during immunity, where filament stickiness could favor the condensation of the DNA into a compact state that occludes it from the transposase. PMID- 24478937 TI - Life in Science: William C Summers. PMID- 24478938 TI - Bacteriophage as instructional organisms in introductory biology labs. AB - Designing lab exercises for introductory biology classes requires balancing the need for students to obtain results with a desire to provide unpredictable outcomes to better approximate actual research. Bacteriophage are particularly well suited for this as many species are well-understood but, with their hosts, represent a relatively complex interacting system. I have designed a seven week series of lab exercises that allow students to select bacteriophage resistant mutant hosts, isolate and sequence the corresponding receptor gene to identify the specific bacterial mutation from a large number of potential mutations. I also examined the possibility of collecting useful mutant strains for other studies. After two semesters, the lab series is working well with over 90% of students successfully isolating mutant bacteria and about half identifying the specific mutation. Here I discuss the advantages of using bacteriophage in an introductory class, the specific labs in this series and future plans. PMID- 24478940 TI - TPS1 drug design for rice blast disease in magnaporthe oryzae. AB - Magnaporthe oryzae (M. oryzae) is a fungal pathogen and the causal agent of rice blast disease. Previous lipidomics analysis of M. oryzae demonstrated that trehalose, a carbohydrate common to various fungi and algae, is thought to be involved in the possible conversion of glycogen into triacylglycerides for energy, an important step in the pathogenesis of M. oryzae. A key enzyme responsible for trehalose synthesis is trehalose-6-phosphate synthase 1 (Tps1). Therefore, we modeled the structure of Tps1 and sought to screen a chemical database in silico for possible inhibitors of the enzyme. Based on homologous alignment and sequence analysis, we first modeled the structure of Tps1 to determine the potential active site of the enzyme and its conformation. Using this model, we then undertook a docking study to determine the potential interaction that would manifest between Tsp1 and potential chemical inhibitors. Of the 400,000 chemicals screened in the Molecular Libraries Small Molecule Repository, we identified 45 potential candidates. The best candidate (Compound 24789937) was chosen and subjected to various structural optimization techniques to improve the suitability of the potential chemical inhibitors at the docking site of Tps1. From these modified versions of Compound 24789937, one lead compound (Lead 25) was shown to have the best binding affinity to Tps1 and good water solubility as compared with the ideal template compound and the other 44 potential candidates. Molecular dynamics simulation further confirmed the strength of the Tps1-Lead 25 complex and indicated the potential for Lead 25 to be used as an inhibitor of Tps1 in the control of M. oryzae-mediated rice blast disease. PMID- 24478941 TI - Prospective evaluation of fluorescence-guided cystoscopy to detect bladder cancer in a high-risk population: results from the UroScreen-Study. AB - OBJECTIVE: To prospectively evaluate the role of fluorescence-guided cystoscopy in a high-risk bladder cancer population undergoing screening based on a multi marker panel of urine-tests (UroScreen-study). PATIENTS AND METHODS: UroScreen was conducted as a validation study for tumor markers within the frame of a health surveillance program of workers with occupational exposure to aromatic amines. Voluntary annual screens were done in 1,609 men. Cytology, quantitative NMP22(r) assay, and UroVysion (FISH) were applied to 7091 urine samples. Subjects with at least one positive urine-based tumor marker and/or persisting microscopic hematuria were offered fluorescence-guided (PDD) instead of white light cystoscopy. In case of suspicious findings histopathological evaluation by transurethral biopsy was performed. Data were statistically summarized and compared to tumors found by the standard algorithm of the screening study. RESULTS: Twenty-two subjects with a mean age of 58 years (39-72) underwent PDD cystoscopy. Of those 3 had positive NMP22 tests, 14 positive FISH tests and 9 suspicious cytologies. Two had persisting microscopic hematuria only. PDD cystoscopy revealed enhanced unifocal fluorescence in 14. All had subsequent transurethral biopsy or resection. In total, 1 urothelial carcinoma (pTaG1, low grade) was diagnosed. In the other participants urothelial cancer of the bladder was ruled out. Chronic cystitis was revealed in 8 of 14 biopsies. No higher detection rate was found using PDD than with the standard algorithm of the UroScreen study in which 17 tumors were detected by white light cystoscopy. CONCLUSION: The use of PDD does not lead to a higher cancer detection rate in a high-risk screening population. Larger sample sizes may be needed to ultimately asses the value of PDD for bladder cancer screening. PMID- 24478939 TI - Claudins in intestines: Distribution and functional significance in health and diseases. AB - Intestines are organs that not only digest food and absorb nutrients, but also provide a defense barrier against pathogens and noxious agents ingested. Tight junctions (TJs) are the most apical component of the junctional complex, providing one form of cell-cell adhesion in enterocytes and playing a critical role in regulating paracellular barrier permeability. Alteration of TJs leads to a number of pathophysiological diseases causing malabsorption of nutrition and intestinal structure disruption, which may even contribute to systemic organ failure. Claudins are the major structural and functional components of TJs with at least 24 members in mammals. Claudins have distinct charge-selectivity, either by tightening the paracellular pathway or functioning as paracellular channels, regulating ions and small molecules passing through the paracellular pathway. In this review, we have discussed the functions of claudin family members, their distribution and localization in the intestinal tract of mammals, their alterations in intestine-related diseases and chemicals/agents that regulate the expression and localization of claudins as well as the intestinal permeability, which provide a therapeutic view for treating intestinal diseases. PMID- 24478942 TI - Central nervous system involvement in mycosis fungoides: relevance of tcr gene testing in cerebrospinal fluid. AB - INTRODUCTION: Mycosis Fungoides (MF) is a rare malignant T-cell lymphoma, involving mainly the skin. In 50%-75% of cases, it can involve organs other than skin, with a 11%-14% Central Nervous System involvement (CNS). CASE REPORT: A 82 year-old woman presented to our Department with a 15-years history of MF with skin lesions. Neurological examination showed dysarthria and a left facio brachial-crural hemiparesis. A CT scan showed a right fronto-rolandic lesion. A MRI, including DWI, confirmed the presence of the "neoplastic" lesion with slight hemorrhagic component and leptomeningeal contrast enhancement. Molecular TCR rearrangement test by PCR analysis was performed on skin biopsy, showed the presence of a single peak which fits with a monoclonal TCRG gene rearrangement (size 67). Molecular TCR test was also performed on the cerebrospinal fluid (CSF), which confirmed the presence of lymphocyte clone T g/ more expressed with the same size of that observed in the skin biopsy A total body CT scan did not show any lymphnodal or extranodal disease. The patient died after ten days. CONCLUSION: MF usually occurs in the context of advanced and often histologically transformed cutaneous disease. Isolated CNS involvement is remarkably rare. This case highlights the need for regular neurologic follow-up after the diagnosis of MF, in particular when features that suggest risk of disease progression are present. Furthermore, the analysis of the skin biopsy and above all of CSF by PCR technique, based on our experience, should always be executed in MF patients with signs or symptoms suggesting CNS involvement. PMID- 24478943 TI - Pcf1, a large subunit of CAF-1, required for maintenance of checkpoint kinase Cds1 activity. AB - Highly conserved chromatin assembly factor 1 (CAF-1) is required for histone deposition onto newly synthesized DNA to maintain genome stability. This study shows that the fission yeast Pcf1, the large subunit in CAF-1, is crucial for maintaining checkpoint kinase Cds1. Chromatin recruitment of Cds1 is enhanced by Pcf1 overproduction but is attenuated by the Deltapcf1 mutation. Mutation of acetylation sites in the histone H4 tail abrogates the chromatin recruitment of Pcf1, which resembles that of Cds1 as reported previously. The present results provide evidence that chromatin recruitment of Pcf1, moderated by Clr6-HDAC activity, is essential for inactivating Cds1. PMID- 24478944 TI - Development of clinical pharmacy services for intensive care units in Korea. AB - OBJECTIVE: To be utilized for the development of pharmacists' intervention service by determining factors which affect pharmacists' prescription interventions. SETTING: Patients who were admitted to intensive care units (ICUs) in internal medicine departments in Korea. METHODS: Data including age, gender, clinical departments, length of hospital stay, status of organ dysfunction, intervention status, frequently intervened drugs, and health care providers' questions were prospectively collected in ICUs in the department of internal medicine in a tertiary teaching hospital from January to December, 2012. MAIN OUTCOME MEASURE: Primary outcome was factors which affect pharmacists' prescription interventions. Secondary outcomes included frequencies of the intervention, intervention acceptance rates, intervention issues, and frequently intervened drugs. RESULTS: A total of 1,213 prescription interventions were made for 445 patients (33.1%) of the 1,344 patients that were analyzed. Length of hospital stay was significantly longer for the group that needed pharmacists' interventions (p < 0.001). Pharmacists' intervention requirements were significantly higher in patients with kidney dysfunction (p < 0.001). The percentage of intervention accepted was 96.8%, and interventions that were common were as follows (in order): clinical pharmacokinetic service, dosage or dosing interval changes, dosing time changes or dose changes, and total parenteral nutrition consultation. The five medications with the highest intervened frequency were (in order) vancomycin, famotidine, ranitidine, meropenem, and theophylline. CONCLUSION: The need for pharmacists' prescription interventions was highest among patients with longer length of stay and patients with kidney dysfunction. Based on these findings, prescription intervention activities could be initiated with severely ill patients. The results could be utilized in countries which are planning to develop pharmacists' intervention service. PMID- 24478945 TI - Effect of polyols on thermostability of xylanase from a tropical isolate of Aureobasidium pullulans and its application in prebleaching of rice straw pulp. AB - In an attempt to find a thermostable xylanase enzyme for potential application in the pretreatment prior to H2O2 bleaching of paper pulp for industry, an extracellular xylanase from Aureobasidium pullulans CBS 135684 was purified 17.3 fold to apparent homogeneity with a recovery yield of 13.7%. Its molecular mass was approximately 72 kDa as determined by SDS-PAGE. The optimal pH and temperature for activity of the purified enzyme were pH 6.0 and 70 degrees C, respectively. The enzyme was relatively stable at 50 degrees C, retaining more than half of its original activity after 3-h incubation. The thermostability of the enzyme was improved by the addition of 0.75 mM sorbitol prolonging the enzyme's activity up to 10-fold at 70 degrees C. When the potential of using the enzyme in pretreatment of rice straw pulp prior to bleaching was evaluated, the greatest efficiency was obtained in a mixture containing xylanase and sorbitol. Treatment of the rice straw pulp with xylanase prior to treatment with 10% (v/v) H2O2 and production of hand sheets increased the ISO sheet brightness by 13.5% and increased the tensile and tear strengths of the pulp by up to 1.16 and 1.71 fold, respectively, compared with pulps treated with H2O2 alone. The results suggested the potential application of the enzyme before the bleaching process of paper pulp when the maintenance of high temperature and enzyme stability are desirable. PMID- 24478946 TI - Practical problems in use of sugar substitutes in preventive dentistry. AB - Sugar (sucrose) being most acceptable sweetening agent in use by mankind is considered as the "Arch Criminal" in dental caries initiation. Search for suitable sweetening agent which will satisfy all the characteristics of sugar along with being non-cariogenic is going on since decades. At this given point of time, there is no such substitute which will replace sugar in all aspects, but, cariogenic potential can certainly be reduced by using sugar substitutes. Recently, few sugar substitutes are even considered to have antimicrobial property against caries producing microbes in oral cavity. Although sweetening agents and sugar substitutes are available in market in various forms, how acceptable are they?, what are the public perceptions regarding their use?, and their use in caries prevention are few areas still very much unclear. PMID- 24478947 TI - Halitosis: A frequently ignored social condition. AB - Halitosis is a common complaint of one third of the population. It is commonly known as 'bad breath'. The causes of halitosis can both be intraoral (90%) as well as extraoral (10%). Malodor of oral etiology results from the oral cavity itself. Non oral etiology may include various systemic diseases and use of certain drugs. Halitosis can act as a biomarker for various systemic diseases. Organoleptic examination, gas chromatography and portable sulfide monitors are the common methods of measurement of halitosis. Brushing twice daily with tongue cleaning can sufficiently manage halitosis in majority of the population while antimicrobial oral rinses can be prescribed to the non respondents. Necessary investigations and treatment should follow for those having extra oral cause of halitosis. PMID- 24478948 TI - Professional practice among woman dentist. AB - OBJECTIVE: This review aims to give an inside view of professional career of a women dentist, addresses the unique demands of being a woman dentist, and highlight ways to address these issues. MATERIALS AND METHODS: The Medline database, scholarly literature, and informal literature were considered for this review. RESULTS: Working hours of female dentists do not differ significantly from the working hours of their male counterparts, until they have children. The female dentists' working hours showed a distinct drop as soon as they started a family. It was also found that women dentists are more likely to take career break. It is clear that childrearing and family responsibilities have a great impact on women's working life. Significant differences between males and females in work title and specialization were evident in an academic institution. Due to the societal orientation which regards women as primarily home makers, the responsibilities for family caretaking continues to fall disproportionately on women, and this fact could explain why women abandon their careers in the advanced stages. CONCLUSIONS: Efforts should be made to identify and reduce barriers to women's advancement in dentistry. PMID- 24478949 TI - Comparative evaluation of ultraviolet and microwave sanitization techniques for toothbrush decontamination. AB - BACKGROUND: Toothbrushes are rapidly contaminated with different microorganisms representing a possible cause of infection or reinfection especially in the periodontal patients under therapy. The purpose of this study was to evaluate the sanitization of toothbrushes previously contaminated by various oral microorganisms using a domestic microwave oven and commercial ultraviolet (UV) light toothbrush sanitizer. MATERIALS AND METHODS: Thirty male dental graduates were randomly assigned to control or experimental groups and received standardized toothbrushes for home use. Each subject was instructed to use it with the standardized modified Bass technique for 1 week and submit it to the investigator after use. Collected toothbrushes were cultured and analyzed for the number of colony-forming units (CFUs). In the next phase, once again a new set of toothbrush was given to each subject and instructed to use it for one more week and follow the same instructions as given earlier. Subsequently, the used toothbrushes were again collected and were sanitized by microwave irradiation, UV radiation, or were not sanitized (control group). After the sanitization procedure, toothbrushes were again cultured for the number of CFUs. The collected data of the presanitized and postsanitized CFU count were log transformed to normalize their distributions prior to analysis. Furthermore, log CFU data were compared and analyzed by one-way ANOVA, Tukey's post hoc procedure, and paired t test for the difference in the mean at P<0.05. RESULTS: Result showed that after the sanitization procedure, there was a significant (P<0.001) reduction in microbial contamination in both microwave and UV group toothbrushes compared to control group toothbrushes whereas the microbial count in the microwave group was significantly less (P<0.001) compared to the UV group. CONCLUSIONS: The evidence presented in this study suggests that microwave irradiation is an effective disinfectant agent for bacteria and fungi on toothbrushes. PMID- 24478950 TI - Prevalence of early childhood caries among preschool children of low socioeconomic status in Bangalore city, India. AB - AIM: To assess the prevalence of Early Childhood Caries (ECC) among preschool children of low socio- economic status in Bangalore city, India. MATERIALS AND METHODS: A cross-sectional study was carried out among 566, 24-59 months old children attending various Anganwadi centers in Bangalore city, India, selected via cluster sampling. Caries experience was recorded using deft index (Greubbell, 1944). t Test, ANOVA, and Chi-square tests were used to find significant differences. P < 0.05 was considered as statistically significant. RESULTS: Prevalence of Early Childhood Caries (ECC) was 37.3% with a mean deft of 1.90 +/- 3.38 ranging from 0 to 17 teeth. Out of 211 children with ECC, 94.3% had severe Early Childhood Caries (s-ECC) with a mean deft score of 5.35 +/- 3.77. All of the deft was due to untreated caries. Mean caries experience of 36-47 months age group was significantly higher than other groups (P = 0.024). CONCLUSIONS: The present study showed a 37.3% prevalence of ECC. There is a need for preventive and curative oral health programs in this section of the society. PMID- 24478951 TI - The efficacy of antiseptic mouth rinses in comparison with dental floss in controlling interproximal gingivitis. AB - OBJECTIVES: Maintaining good oral hygiene is important to combat periodontal diseases. The use of tooth brush alone does not serve the purpose, especially in inaccessible areas like proximal embrasures, which demand the use of some adjuncts like proximal cleaning aids. Hence, the objective of this study was to compare the clinical efficacy of two antimicrobial mouth rinses (Cool mint Listerine and 0.2% Chlorhexidine gluconate) with dental floss in reducing interproximal gingivitis and dental plaque in an unsupervised condition. MATERIALS AND METHODS: A randomized, controlled, single-blind (observer), parallel-group clinical trial in accordance with the ADA guidelines was conducted for a period of 6 months. Four index age groups (12, 15, 35-44, and 65-74 years) were divided into four groups, i.e., brushing, brushing and flossing, brushing and rinsing with Listerine, and brushing and rinsing with Chlorhexidine, so that each group comprised 40 subjects. Interproximal gingivitis and dental plaque were assessed using Modified Gingival Index, Turesky-Gilmore-Glickman modified Quigley Hein Plaque Index and Gingival Bleeding Index. Analysis of variance (ANOVA) was used for multiple group comparisons, followed by Tukey's post hoc for group-wise comparisons. RESULTS: Chlorhexidine and Listerine showed significant reduction in plaque and gingivitis level compared to others, the activity of Chlorhexidine being more significant. CONCLUSIONS: The level of interproximal gingivitis control efficacy provided by the Listerine and Chlorhexidine was "at least as good as" that provided by the dental floss. Hence, they can be recommended for the patients with gingivitis as an adjunctive to the usual home care routine. PMID- 24478952 TI - Applications of teledentistry: A literature review and update. AB - Teledentistry is a combination of telecommunications and dentistry involving the exchange of clinical information and images over remote distances for dental consultation and treatment planning. Teledentistry has the ability to improve access to oral healthcare, improve the delivery of oral healthcare, and lower its costs. It also has the potential to eliminate the disparities in oral health care between rural and urban communities. This article reviews the origin, rationale, scope, basis, and requirements for teledentistry, along with the current evidence that exists in the literature. This article also reviews the ethical and legal issues related to the practice of teledentistry and the future of this alternative and innovative method of delivering dental care. PMID- 24478953 TI - Dental caries experience and salivary Streptococcus mutans, lactobacilli scores, salivary flow rate, and salivary buffering capacity among 6-year-old Indian school children. AB - CONTEXT: Dental caries is a disease of multifactorial etiology. A variety of potential predictors have been examined for the association with caries increments in longitudinal and cross-sectional studies. AIMS: The aim of this study was to assess the possible relationship among salivary cariogenic microflora, buffer capacity, secretion rate, and caries experience among 6-year old school-going children in Davangere city, India. SETTINGS AND DESIGN: A total of 196 6-year-old school children were selected by a two-stage random sampling method. MATERIALS AND METHODS: Parents were interrogated regarding sociodemographic details. Clinical examination of children was conducted to assess dental caries experience, and stimulated saliva was collected to assess S. mutans levels, lactobacilli, salivary flow, and buffering capacity of saliva. STATISTICAL ANALYSIS: The difference in proportions was tested using Kruskal Wallis analysis of variance (ANOVA) followed by the Mann-Whitney U-test for intragroup comparison, and the difference in mean was tested using ANOVA and independent sample t-test as necessary. Caries experience was correlated with salivary factors using Spearman's correlation coefficient. RESULTS: Out of 196 children, 96 were boys and 100 were girls. Overall, 97 (49.49%) children were caries free (dmft, DMFT = 0) and 99 (50.51%) children presented with caries (dmft, DMFT>0). The mean dmft and dmfs score for the overall group was 3.20 and 5.43, respectively. The mean DMFT and DMFS score was 0.23 and 0.25, respectively. A highly significant correlation was seen between mean the caries score and salivary variables. CONCLUSIONS: High levels of salivary microbiological counts in correlation with the caries data stress the importance of these factors and urge the necessity of elective preventive programs in this region. PMID- 24478954 TI - Dental prosthetic status, prosthetic needs in relation to socioeconomic status of the state government employees in Shimla city (Himachal Pradesh) - A cross sectional study. AB - OBJECTIVE: To know the dental prosthetic status, prosthetic needs in relation to socioeconomic status (SES) of the state government employees in Shimla city, Himachal Pradesh. MATERIALS AND METHODS: The study was carried on 1008 (705 males and 303 females) state government employees in Shimla city between February 25, 2009 and April 10, 2009. Type III examination was conducted and the prosthetic status and prosthetic needs were recorded on W.H.O. format 1997. Modified Kuppuswamy scale, with readjustment of the per capita income to suit the present levels, was used for SES classification. RESULTS: 10.3% of the subjects in the study had prosthesis of some kind. The prosthetic status was better in the upper middle and upper SES category as compared with the other categories and the findings were statistically significant. Prosthetic need in the study population was 33.2%, which was maximum for the subjects in the lower SES category and minimum for the higher SES category. Awareness on the provision of reimbursement for dental care was highest among the upper class and negligible in the lower SES category. CONCLUSIONS: Present study shows a direct relationship between SES and percentage of the subjects having prosthesis of some kind. SES shows an inverse relationship with prosthetic need and awareness on the provision of reimbursement of dental care. PMID- 24478955 TI - Change in dental caries status over 2 years in children of Panchkula, Haryana: A longitudinal study. AB - BACKGROUND: Despite credible scientific advances and the fact that it is preventable, dental caries continues to be a major public health problem in developing countries like India. The first step toward disease prevention at community level is assessment of the disease activity. AIM: Hence this study was conducted to evaluate the change in dental caries status over 2 years in children of Panchkula, Haryana. MATERIALS AND METHODS: 207 school children having mixed dentition (age 7-8 years) and 103 children (age 12-13 years) were assessed for change in their dmf/DMF status over 2 years. RESULTS AND CONCLUSION: Results revealed that 81% of 7-8-year-old children and 83 % 12-13-year-olds had caries. There was a statistically significant increase in DMFT score of children over 2 years; thus necessitating implementation of rigorous preventive strategies at community level. PMID- 24478956 TI - Prevalence of torus palatinus and torus mandibularis among Malay population. AB - The aims of this study were to determine the prevalence, size, shape, and location of torus palatinus (TP) and torus mandibularis (TM), and to assess their sex-related and age-related differences in the Malay population. Sixty-five subjects were assessed for the presence of both tori at the School of Dental Sciences University Sains Malaysia. The prevalence of TP was 38-63% and that of TM was 1-10%. TP was frequently more common in females than males (90.9% versus 9.1%; P < 0.05) and was frequently found in medium sizes, spindle shaped, and was often located at the combined premolar to molar areas. The prevalence of TM was not significantly different in males and females (33.3% versus 66.7%; P = 0.523), occurred most commonly in bilateral multiple form, and was often located at the canine to premolar area. PMID- 24478957 TI - Oral health related quality of life among dental students in a private dental institution in India. AB - BACKGROUND: The compartmentalization involved in viewing the mouth separately from the rest of the body must cease. This is because oral health affects general health by causing considerable pain and suffering; and, by changing what people eat and their speech, can bring about a change in their quality of life and well being. There are several instruments for measuring oral health related quality of life, and, OIDP (Oral Impact on Daily Performance) is one among them. AIM: The aim of this study is to assess the OIDP among dental students and to know whether students in different stages of the dental course had any difference in impact on their daily performance. MATERIALS AND METHODS: 372 students of Bachelor of Dental Sciences' (BDS) course at Manipal College of Dental Sciences, Manipal, Karnataka, India, from the first to final year, and interns answered a structured questionnaire recording their demographic characteristics, behavioral characteristics and eight items of OIDP. RESULTS: The mean OIDP Additive scores (ADD) and OIDP Simple count scores (SC) scores were 7.02 (sd = 3.3, range 8 - 40) and 2.16 (sd = 1.55, range 0 - 8), repectively. A total of 36.6%, 12.9% and 12.9% of the dental students confirmed difficulties with eating, enjoying contact with other people and carrying out major college work, respectively. Logistic regression analysis revealed that compared with the first BDS dental students, the Odds ratio (OR) for the second, third, fourth year and intern dental students for being without oral impacts, despite reporting poor oral health, were 0.21 (95% CI: 0.24 - 1.9), 0.61 (95% CI: 0.06 - 6.2), 0.70 (95% CI: 0.61 - 8.2) and 0.54 (95% CI: 0.3 - 9.3), respectively. CONCLUSION: The study reported the OIPD among dental students and provided evidence of importance of social and behavioral characteristics in shaping the response by dental students. PMID- 24478958 TI - A peer group approach model of oral health promotion among orphans at Puduchery, South India. AB - BACKGROUND: Interactions between oral and systemic health are bi-directional and complex, involving many pathways. The orphans have been sympathized with, ignored, vitrified or even hidden away in the community. Hence, providing health care services for orphans remains a challenge. Oral health education has a positive impact in lowering plaque and gingivitis scores in health educational programs. OBJECTIVE: The objective of this study is to assess the effectiveness of peer group health promotion model among 11 to 16 year old orphans at Puduchery, South India. MATERIALS AND METHODS: A clinical trial of 6 months duration was carried out among 72 orphans with age ranging from 11 to 16 years residing in Cluny Padmini Sneha Illam, at Puduchery, India. The baseline data regarding oral health and oral hygiene practices were obtained using a pre-tested close-ended questionnaire. Oral health education was provided to 4 randomly picked children who in turn provided the same to their peer group orphans, supervised by the investigator. Tooth brushes and fluoridated tooth pastes were provided to all the participants throughout the study period. Oral hygiene of the participants was assessed using Modified Plaque Index by Loe H and Gingival Index by Loe H and Silness at baseline, 3(rd) and 6(th) month interval. Paired Student t test was used to analyze the categorical data. RESULTS: Majority of the respondents felt consuming sugar was not harmful for dental health, while 15 respondents were not sure about the outcome. When asked if oral hygiene was important for general health, 45.8% were not aware of its association. Although all the participants brushed their teeth daily, none of them reported the use of dental floss. The findings of this study indicated a statisticallysignificant lower mean plaque score of 0.54 +/- 0.20 at 6(th) month when compared to the baseline score of 1.76 +/- 0.24. Similarly, statistically significant lower gingival index score of 0.65 +/- 0.11 at 6(th) month was observed when compared to the baseline score of 1.76 +/- 0.24. CONCLUSIONS: The results of this study indicate that oral hygiene of orphans was improved using a peer group approach model of oral health promotion. PMID- 24478959 TI - Uranium: A Dentist's perspective. AB - Uranium is a naturally occurring radionuclide found in granite and other mineral deposits. In its natural state, it consists of three isotopes (U-234, U-235 and U 238). On an average, 1% - 2% of ingested uranium is absorbed in the gastrointestinal tract in adults. The absorbed uranium rapidly enters the bloodstream and forms a diffusible ionic uranyl hydrogen carbonate complex (UO2HCO3+) which is in equilibrium with a nondiffusible uranyl albumin complex. In the skeleton, the uranyl ion replaces calcium in the hydroxyapatite complex of the bone crystal. Although in North India, there is a risk of radiological toxicity from orally ingested natural uranium, the principal health effects are chemical toxicity. The skeleton and kidney are the primary sites of uranium accumulation. Acute high dose of uranyl nitrate delays tooth eruption, and mandibular growth and development, probably due to its effect on target cells. Based on all previous research and recommendations, the role of a dentist is to educate the masses about the adverse effects of uranium on the overall as well as the dental health. The authors recommended that apart from the discontinuation of the addition of uranium to porcelain, the Public community water supplies must also comply with the Environmental Protection Agency (EPA) standards of uranium levels being not more than 30 ppb (parts per billion). PMID- 24478960 TI - Dental home: Patient centered dentistry. AB - Early childhood dental caries occurs in all racial and socioeconomic groups; however, it tends to be more prevalent in children in families belonging to the low-income group, where it is seen in epidemic proportions. Dental caries results from an overgrowth of specific organisms that are a part of normally occurring human flora. Human dental flora is site specific, and an infant is not colonized until the eruption of the primary dentition at approximately 6 to 30 months of age. The most likely source of inoculation of an infant's dental flora is the mother, or another intimate care provider, shared utensils, etc. Decreasing the level of cariogenic organisms in the mother's dental flora at the time of colonization can significantly impact the child's redisposition to caries. To prevent caries in children, high-risk individuals must be identified at an early age (preferably high-risk mothers during prenatal care), and aggressive strategies should be adopted, including anticipatory guidance, behavior modifications (oral hygiene and feeding practices), and establishment of a dental home by 1 year of age for children deemed at risk. PMID- 24478961 TI - Effectiveness of pictorial warnings on tobacco packs: Hospital-based study findings from Vikarabad. AB - BACKGROUND: Recently, the Indian government introduced pictorial warnings that occupy an important position among different tobacco control initiatives. A study was done to evaluate the opinion of tobacco consumers on the implementation of pictorial warnings on tobacco packs and to compare the effectiveness of these warnings among individuals of varying socioeconomic status. MATERIALS AND METHODS: This was a hospital-based study carried out among the tobacco-using patients attending the Outpatient Department of Sri Sai College of Dental Surgery, Vikarabad, Andhra Pradesh. The number of participants in the survey was 111. Questionnaire method was used for collecting the data. RESULTS: Among the 111 participants, maximum number of study participants using any form of tobacco products were in the age group of 15-24 years, and higher consumption was seen among the lower socioeconomic strata. 88.3% of the participants strongly agreed on strengthening the warnings while 73.2% of them felt that pictures on tobacco packs should occupy 100% of the display area to make them more effective. CONCLUSION: These results suggest that policy makers should not be reluctant to introduce stronger and vivid pictures. PMID- 24478962 TI - Comparison of intraoral distribution of two commercially available chlorhexidine mouthrinses with and without alcohol at three different rinsing periods. AB - OBJECTIVES: This study compared the intraoral distribution of 0.1% chlorhexidine with alcohol (CHX+Alc) and 0.2% chlorhexidine without alcohol (CHX-Alc) with shorter rinsing times (10s,20s,30s) following a 72h non brushing period. MATERIALS AND METHODS: This study was designed as a single blind, randomized two group parallel experiment with a total of 30(15male,15 female) dental students. To disclose the plaque, erythrosine-containing disclosing agent was added to both the mouthrinses. Group I (0.1% CHX+Alc) & Group II (0.2% CHX-Alc) were asked to rinse with respective mouthrinse for cumulative periods of 10,20 and 30s, following which plaque was scored. RESULTS: In Group I, comparison between 10&20, 10&30s was statistically significant but no significance was observed between 20&30s, whereas in Group II, comparison between all the time points were statistically significant. On comparison of plaque scores, plaque scores of both the groups at 10 & 30s sec, show no statistical significance but at 20 seconds was significant (P<0.001). The mean plaque scores of lingual surfaces were lesser in group II whereas in group I lingual surfaces recorded more plaque than the vestibular surfaces. CONCLUSIONS: Within the limitations of this study, it can be concluded that rinsing for 30 seconds with 0.2% CHX-Alc (Rexidin) is enough for intraoral spread of the mouthrinse whereas rinsing with 0.1% CHX+Alc(Eludril) for achieves the same in 20 seconds, for effective plaque inhibition, both of which will have a positive influence on patient compliance. PMID- 24478963 TI - Tobacco use, its influences, triggers, and associated oral lesions among the patients attending a dental institution in rural Maharashtra, India. AB - BACKGROUND: World Health Organization (WHO) predicts that tobacco deaths in India may exceed 1.5 million annually by 2020. OBJECTIVES: The aim of this study was to estimate the prevalence of tobacco use, its influences, triggers, and associated oral lesions among the patients of Rural Dental College and Hospital of Loni, Maharashtra. MATERIALS AND METHODS: A hospital based cross-sectional study was conducted from June - December 2010. All the patients from the outpatient department and with tobacco habits were included in the study. Patients were interviewed through a pre-tested structured questionnaire in relation to their tobacco habits, its influences and triggers. Also clinical examination was carried out to check for any tobacco related oral lesions. For the data analysis, Microsoft Excel and chi-square test was used. RESULTS: The overall prevalence of tobacco use was 16.38%. Smokeless form of tobacco was more prevalent in both males (81.84%) and females (100%). Majority of the patients (males - 68.22%, females- 90.62%) were light tobacco users. About 76.09% males and 31.25% females admitted that they developed the habit due to initial influence of friends. The most common oral mucosal lesion in both the males (42.20%) and females (11.07%) was tobacco hyperkeratosis. Most common trigger for tobacco use was "work related" (69.14%) in males and "after meals" (53.13%) in females. CONCLUSION: Since the number of tobacco users visiting the dental hospital is reasonably high; dentists can contribute to restrain the hazard through community educational activities such as de-addiction counseling of tobacco users to quit the habit. PMID- 24478964 TI - Maiden morsel - feeding in cleft lip and palate infants. AB - Cleft lip and cleft palate are the most common craniofacial anomalies that have an incidence of 0.28 to 3.74 per 1000 live births globally. Due to the great advancements in the field of medical science, these anomalies can today be corrected. However, it cannot be ignored that the parents of these patients may face psychological stress due to the cleft defects in the baby. Also, these conditions may cause financial difficulties to the parents and cause anxiety to the mother about the proper feeding of their infant. Feeding problems can range from excessive air intake to failure to thrive. As the management of such cases is lengthy and includes a multi-disciplinary team approach, it is the role of the Pediatrician/Pedodontist to educate the mother about the proper feeding techniques. In this article, we have reviewed and highlighted the various traditional and advanced devices and techniques which help in the successful management of these individuals. PMID- 24478965 TI - Smoking and dental implants. AB - Smoking is a prevalent behaviour in the population. The aim of this review is to bring to light the effects of smoking on dental implants. These facts will assist dental professionals when implants are planned in tobacco users. A search of "PubMed" was made with the key words "dental implant," "nicotine," "smoking," "tobacco," and "osseointegration." Also, publications on tobacco control by the Government of India were considered. For review, only those articles published from 1988 onward in English language were selected. Smoking has its influence on general as well as oral health of an individual. Tobacco negatively affects the outcome of almost all therapeutic procedures performed in the oral cavity. The failure rate of implant osseointegration is considerably higher among smokers, and maintenance of oral hygiene around the implants and the risk of peri implantitis are adversely affected by smoking. To increase implant survival in smokers, various protocols have been recommended. Although osseointegrated dental implants have become the state of the art for tooth replacement, they are not without limitations or complications. In this litigious era, it is extremely important that the practitioner clearly understands and is able and willing to convey the spectrum of possible complications and their frequency to the patients. PMID- 24478966 TI - Clinical evaluation of a new art material: Nanoparticulated resin-modified glass ionomer cement. AB - CONTEXT: The success of atraumatic restorative treatment (ART) technique depends on the restorative material; hence, clinical studies with various materials are necessary. AIM: The aim of the present study was to clinically evaluate and compare the nanoionomer and high-viscosity glass ionomer using United States Public Health Services (USPHS) Modified Cvar/Ryge Criteria with ART approach. MATERIALS AND METHODS: Two primary molars in 50 healthy children aged between 5 and 8 years were selected for the study. The teeth were treated with ART and divided into two groups. The group 1 teeth were restored with nanoionomer (Ketac Nano 100 3M ESPE) and group 2 with high-viscosity glass ionomer cement (HVGIC), (Fuji IX GC). Each restoration was evaluated using the USPHS Modified Cvar/Ryge Criteria at baseline and 6 months' and 12 months' time interval. STATISTICAL ANALYSIS USED: Chi-squared (chi(2)) test. RESULTS: Nanoionomer was significantly better than HVGIC with respect to color match at baseline, 6 months, and 12 months (P<0.001). Nanoionomers were also significantly better than HVGIC in case of cavosurface marginal discoloration and marginal adaptation (P<0.001) at 6 months and 12 months. There was no significant difference between the two materials with respect to secondary caries at 6 months (P>0.05), but at 12 months, nanoionomer was statistically better than HVGIC (P<0.05). There was no statistical significant difference with respect to anatomical form and postoperative sensitivity (P>0.05). CONCLUSION: The results indicate that nanoionomer can be a successful alternative restorative material for use with ART technique. PMID- 24478968 TI - Evaluating dental awareness and periodontal health status in different socioeconomic groups in the population of Sundernagar, Himachal Pradesh, India. AB - CONTEXT: Survey. AIMS: To evaluate dental awareness and periodontal health status in different socioeconomic groups in the population of Sundernagar, Himachal Pradesh, India. SETTINGS AND DESIGN: Cross-sectional study. MALERIALS AND METHODS: This cross-sectional study was conducted in 300 patients with different socioeconomic status who visited Himachal Dental College, Sundernagar, and Dental OPD of the Civil Hospital, Sundernagar. Mouth mirror, CPI probe, and illuminated light source were used for examination. Periodontal health status was recorded using CPI index. Information about their lifestyle, education level, and socioeconomic status was recorded using a questionnaire and correlated with the periodontal status. STATISTICAL ANALYSIS USED: Chi-square test. RESULTS: Majority of the subjects used toothbrush and toothpaste to clean their teeth once daily. Lower socioeconomic groups exhibited higher CPI scores characterized by bleeding gums and calculus deposition. The differences were statistically significant across various social strata (P < 0.01). CONCLUSIONS: The utilization of the questionnaire on dental awareness facilitates the inclusion of multiple aspects of patient information. The study revealed that oral hygiene awareness and periodontal condition were significantly associated with socioeconomic status. The socioeconomic status and oral hygiene practices were significantly associated with CPI (P < 0.01). PMID- 24478967 TI - Do the more caries in early primary dentition indicate the more caries in permanent dentition? Results of a 5-years follow-up study in rural-district. AB - AIM: In the deprived communities with high caries incidence, determination of high-risk children in early age is a valuable tool to apply the individual and/or community-level preventive measures. The purpose of this 5-years follow-up study was to examine the relationship between early caries occurrence on primary incisors and the future caries occurrence on both first permanent molars and all permanent dentition in the children living in rural Turkey. MATERIALS AND METHODS: Total 34 children living in rural-districts of southeastern Anatolia were included, and divided in both test (caries positive for maxillary primary incisors) and control groups (caries free on the same teeth). During the 5-years they were examined annually regarding new caries occurrence in either first permanent molars for the Decayed, Missing, Filled Tooth Index [(DMF(T)[6])] or all permanent dentition (DMF(T)). RESULTS: At the beginning of the study, the age range of the children was 3 to 5 (mean +/- St dv; 4.03 1.24), and d(t)[max 1,2] and df(t) indices for the deciduous dentition of test and control groups were 2.65 +/- 0.78; 4.29 +/- 2.08 and 0; 0.24 +/- 0.43, respectively. After 5-years mean DMF(T)[6] and total DMF(T) for test and control groups were 1.88 +/- 0.66; 3.12 +/- 0.69 and 0.47 +/- 0.62; 0.65 +/- 0.93, respectively (for each parameters the difference was statistically significant P < 0.01). For test group the number of caries on primary-incisors (d(t)[max 1,2]) was correlated with the DMF(T)[6] (r = 0.80) and DMF(T) (r = 0.59). CONCLUSION: The caries-information including the early primary incisors could be helpful in identifying children with increased risk so that preventive measures could be directed at those who fit the high-risk-caries profile. PMID- 24478969 TI - Comparative evaluation of oral hygiene practices and oral health status in autistic and normal individuals. AB - AIM: The present study attempts to explore the oral hygiene practices and oral health status in autistic patients as compared to nonaffected, same aged healthy individuals. MATERIALS AND METHODS: The oral hygiene practices, prevalence of caries and periodontal status were evaluated in 117 autistic patients and 126 healthy individuals. The test and control groups were divided into three categories, based on the type of dentition as Primary dentition (Category 1), Mixed dentition (Category 2) and Permanent dentition (Category 3). Plaque and gingival status was recorded by plaque index (Loe, 1967) and gingival index (Loe, 1967), periodontal status by community periodontal index of treatment needs and dental caries by DMFT/DEF index. Statistical analysis was done using descriptive statistics, independent sample t-test, contingency coefficient test and one-way ANOVA test by SPSS 14 software. RESULTS: There was no statistically significant difference in the brushing habits between autistics and controls (P = 0.573); however, Autistics required assistance in brushing. Prevalence of caries was significantly lower in autistic patients (P = 0.000). Plaque and gingival scores were significantly higher in autistic patients (P = 0.000) and prevalence of periodontal disease was significantly higher in autistic patients (P = 0.000). Greater number of autistic patients required professional scaling and root planing (P = 0.000). CONCLUSION: The present study suggests that autistic patients have a higher rate of periodontal disease and lower caries compared to controls. Attempts should be made by parents, general dentists and periodontists to teach oral hygiene methods to these patients by constant repetition and patience, as autistic individuals can develop skills over a period of time and lead a more productive and independent life. PMID- 24478970 TI - Estimation of fluoride concentration in tea infusions, prepared from different forms of tea, commercially available in Mathura city. AB - CONTEXT: Tea is a rich source of fluoride (F(-)) and its consumption has become a cultural habit. F(-) available from tea might play important role in increasing total F(-) intake leading to dental fluorosis. AIMS: To estimate F(-) concentration in different varieties of commercially available tea, in Mathura city, and to determine the change in concentration of F(-) in different forms of tea infusion, prepared by different methods. SETTING AND DESIGN: Mathura city and Clinical study. MATERIALS AND METHODS: 16 brands of tea were collected from the local market, out of which 3 were dip tea, 2 were leafy tea, and 11 were tea granules. Tea infusions were prepared from three forms of tea by three different methods, i.e., without boiling with water; after boiling with water; and after addition of milk and sugar to boiling water. F(-) concentration of those tea infusions was measured using a F(-) ion selective electrode method. STATISTICAL ANALYSIS USED: One-way ANOVA was used to compare mean F(-) concentration in tea infusions prepared by three different methods, irrespective of the form of tea and mean F(-) concentration between tea infusions prepared from three different forms of tea, by three different methods. RESULTS: The mean F(-) concentration in tea infusions prepared by three different methods irrespective of the form of tea were 1.437, 3.375, and 3.437, respectively, and tea infusion prepared from tea granules irrespective of method of preparation showed a statistical significance. CONCLUSIONS: F(-) in tea can be an additional dietary source of F(-) which can be beneficial in preventing dental caries or deleterious for occurrence of fluorosis. PMID- 24478972 TI - Oral health related quality of life. AB - Diseases and disorders that damage the mouth and face can disturb well-being and his self-esteem. Oral health-related quality of life (OHRQOL) is a relatively new but rapidly growing notion. The concept of OHRQOL can become a tool to understand and shape not only the state of clinical practice, dental research and dental education but also that of community at large. There are different approaches to measure OHRQOL; the most popular one is multiple item questionnaires. OHRQOL should be the basis for any oral health programme development. Moreover, research at the conceptual level is needed in countries where OHRQOL has not been previously assessed, including India. PMID- 24478971 TI - Epidemiology of gingival recession and risk indicators in dental hospital population of Bhimavaram. AB - OBJECTIVE: Gingival recession (GR) is a common manifestation in most populations, and is considered as an early sign of periodontal disease. GR is an intriguing condition where various factors play an important role in its etiology. Only few studies have been undertaken to assess the prevalence and risk factors for GR in patients visiting dental hospitals. The aim of this study is not only to estimate prevalence, severity, and extent of GR in hospital population, of Vishnu Dental College, Bhimavaram, Andhra Pradesh, India, but also to assess the potential risk factors for the same. MATERIALS AND METHODS: In this study, 2837 patients were examined of which 627 were included into the study. The age range was 16-80 years. Subjects were interviewed using a structural questionnaire, and full mouth clinical examination was done to assess recession. RESULTS: Of all subjects examined 45.6%, 16.2% of individuals and 13%, 4.8% of teeth per individual showed GR >3 mm. Prevalence and severity of recession was correlated with age. Recession was present but recession threshold >=3 and >=5 mm affected only small percentage of teeth in subjects younger than 45 years. Mandibular incisors showed the highest prevalence of GR >=1 mm with 61% of teeth being affected. Smoking and presence of supragingival calculus were most significantly associated localized and generalized recession. CONCLUSION: Prevalence of periodontal disease is high among this population based on the presence of gingival recession in most the individuals. High prevalence of GR is significantly associated with supragingival calculus and smoking habits. This suggests a need to improve their periodontal condition through education, motivation, and improving their periodontal health. PMID- 24478973 TI - A substantive review on tobacco use among school-going adolescents in India. AB - Tobacco use among the adolescents in india is believed to be on an increase. Therefore, a systematic review was carried out to summarize these studies. Several electronic databases were searched, supplemented by screening reference lists, smoking-related websites, and contacting experts. Selection, extraction, and quality assessments were carried out by one or two independent reviewers. The focus was on studies conducted on the school-going children in india and discussed in a global perspective. A narrative review was carried out. Many of the studies lacked sufficient power to estimate precise risks associated with the study subjects, as it mainly involved questionnaire studies. Studies were often designed to investigate tobacco use, but many had major methodological limitations including poor control and imprecise measurements of exposure. Studies in india showed a high risk of major health-related illness and several forms of cancers such as oro-pharyngeal cancers associated with the chewing form of tobacco. Studies from other regions and of other cancer types were not consistent. Tobacco use is increasing among the adolescents and has become an persistent issue that is usually carried over to their adulthood. In india, there is a stringent need for awareness creating oral health education programs in the school and college premises. PMID- 24478974 TI - Tobacco: Its historical, cultural, oral, and periodontal health association. AB - This article provides information on the origin of tobacco and its subsequent spread throughout the world. In the era of the migration of communities, tobacco use gradually gained access and subsequently migrated along with the migrants, establishing in different locations. Probably at that time people were unaware of the health hazards and were using tobacco in treating certain ailments. Much has been known and written about tobacco in the context of oral and general health hazards but little has been explored and is known to many about where from and how this plant, which is now used in various forms, and speading widely. In what form, where, and how it had been served in religious rituals and considered for treatment or remedy of certain ailments in those days could not certainly be known. In the 21(st) century, people are considering hazardous tobacco as beneficial for their teeth, good for concentration of mind, and something which keeps them engaged. Even many professionals, though knowing the deleterious effects, are still using tobacco and gutkha in one or the other form. This article has been designed to revive the awareness for health hazards of tobacco and similar products. A pilot project questionnaire survey comprising this subject involving the educated mass has already been started and will be produced after analysis of data in part II of this paper. PMID- 24478975 TI - A comparative evaluation of oral hygiene practices, oral health status, and behavior between graduate and post-graduate dentists of North India: An epidemiological survey. AB - OBJECTIVES: The present study was carried out to compare oral hygiene practices, oral health status and behavior of graduate and postgraduate dentists of North India. MATERIALS AND METHODS: The study was carried out among 727 dentists (446 graduate i.e., Group A and 281 post graduate i.e., Group B) through an online questionnaire. The questionnaire covered oral hygiene regimen, adverse oral habits, information regarding dental visits and dental treatment. RESULTS: Results showed less than adequate oral hygiene practices among both the groups with more so in the graduate group (P <= 0.05). Very few dentists in both the groups reported any adverse oral habit. A more positive (P <= 0.05) attitude towards regular dental check up and dental treatment was seen in post-graduate dentists when compared to graduates. CONCLUSION: Very few dentists in both the groups followed ideal dental hygiene regimen. Dentists are the role models for the society as far as oral health is concerned; hence they need to be more responsible and lay more stress on their daily regimen and improve the scenario. PMID- 24478976 TI - Comparative evaluation of a herbal mouthwash (Freshol) with chlorhexidine on plaque accumulation, gingival inflammation, and salivary Streptococcus mutans growth. AB - INTRODUCTION: Plaque accumulation and oral microorganisms are the main predisposing factors to various orodental infections and targeting these, therefore, can prove to be an effective way of combating these diseases. Herbal extracts have been of particular interest these days owing to various side effects associated with conventional modes of treatment. AIMS AND OBJECTIVES: The present study was conducted to compare the efficacy of a commercially available homeopathic mouthwash with chlorhexidine on plaque status, gingival status, and salivary Streptococcus mutans count. MATERIALS AND METHODS: Total sample of 55 children, aged 8-14 years, were randomly divided into two groups. Group A (35) and Group B (20) were given 10 mL of test mouthwash "Freshol" and chlorhexidine respectively during phases 1 and 3 of the clinical trial which was of 10 days each. Phase 2 of 14 days in between was the washout period during which no mouthwash was given. RESULT: Freshol was found to be better than chlorhexidine in reducing the salivary mutans streptococci count and equieffective to chlorhexidine in altering plaque and gingival scores. CONCLUSION: Herbal alternatives can prove to be an effective and safe alternative to conventional modes of treatment. PMID- 24478977 TI - Evaluation of the use of a peppermint mouth rinse for halitosis by girls studying in Tehran high schools. AB - BACKGROUND AND AIM: Oral malodor is one of the most common complaints among dental patients. It often creates serious personal and social embarrassment for the afflicted individual. Therefore, a dentist must be able to diagnose the etiology of halitosis and treat it or refer an individual to a specialist. The aim of this study was to evaluate the prevalence of halitosis and the effect of a peppermint mouth rinse on it. MATERIALS AND METHODS: This study was performed in two steps. At the first step, in a cross-sectional study, 504 students who were 14-18 years old were examined to define the students who suffered from halitosis, and then at the second step, the selected 84 students with halitosis were divided into two groups randomly. A total of 43 students in group 1 received a peppermint mouth rinse and 41 students in another group were given placebo. The students in two groups washed their mouth with 15-20 ml of the given solutions three times in a 1-week period (after breakfast, after lunch or on returning to home, before sleeping) and didn't eat anything for 30 min after rinsing. After 1 week, the students were examined again. RESULTS: The prevalence of halitosis was 24.4% totally. In the mouth rinse group, after 1 week 23 students didn't exhibit halitosis, and 11 students in the placebo group were halitosis positive. A chi square test showed that this difference was significant. CONCLUSION: Based on the results of this study, it can be said that a peppermint mouth rinse can reduce halitosis. PMID- 24478978 TI - A study of malocclusion and orthodontic treatment needs according to dental aesthetic index among school children of a hilly state of India. AB - BACKGROUND: The documentation of magnitude of malocclusion in terms of prevalence and severity has not been done till date in Himachal Pradesh, India. AIMS: To assess the prevalence of malocclusion and orthodontic treatment needs (OTNs) among 9-and 12-year-old school children by using the Dental Aesthetic Index (DAI) in the state. MATERIALS AND METHODS: A cross-sectional study was conducted among 1188 children from randomly selected schools. The survey was done according to the Oral Health Assessment Form (modified). DAI was used to assess the severity of malocclusion, along with collection of demographic data. RESULTS: The overall prevalence of malocclusion was 12.5% and required orthodontic treatment, whereas 87.5% did not require treatment. A severe malocclusion for which treatment was highly desirable was recorded in 3.1%; 8% had a definite malocclusion for which treatment was elective. Only about 1.3% had a handicapping malocclusion that needed mandatory treatment. Almost equal proportions of males and females were affected with malocclusion with the means 20 +/- 4.6 and 19.9 +/- 4.9, respectively (P < 0.641). The prevalence and severity of malocclusion was more in 12-year age group than in 9-year age group (P = 0.002**). There was an increase in the proportion of malocclusion among older children: In 12-year age group, 15.7% with mean 20.5 +/- 5.1 and in 9-year-old children, 8.9% with the mean 19.3 +/- 4.1 were in the need of orthodontic treatment. CONCLUSION: Severity and treatment needs, both are important factors in public health planning. PMID- 24478979 TI - Correlating dental caries with oral bacteria and the buffering capacity of saliva in children in Madinah, Saudi Arabia. AB - INTRODUCTION: Caries is associated with high counts of mutans streptococci (MS), lactobacillus (LB), and a low saliva buffering capacity (BC). No study using odds ratios (OR) has correlated caries and these factors and no similar study has been done in Saudi Arabia before. OBJECTIVES: To determine: The prevalence of caries, the number of colony forming units (CFUs) of MS and LB, the saliva buffering capacity (BC) and the relationship between these factors. MATERIALS AND METHODS: This was an analytical cross sectional study on children from Madinah. Caries was recorded using dmft/DMFT (decayed, missing, filled teeth). The scores for MS and LB and the BC of saliva was calculated using the Caries Risk Test (CRT)((r)). RESULTS: A total of 316 students were examined; two-thirds (62%) were female and 25% were caries free. Saliva was collected from 235 participants and the majority had high MS and LB scores (66 and 71%, respectively) while 25% had a low saliva BC. The odds for those who had high LB and MS CFUs, were 9 and 4 times more at risk to developing dental caries and those with a low BC had significantly more caries (P = 0.03). The likelihood for those having severe caries and high counts of LB and MS was 25 (P < 0.01) and 6 (P = 0.042) times greater, respectively, compared to those with no or mild caries. Those with multiple risk factors were more likely to have caries compared to those with single or no risk factors present. CONCLUSIONS: The prevalence of caries was relatively high and many respondents had greater than 10(5) CFUs/ml of MS and LB. Almost all with a low BC had severe caries. There was a strong correlation between high MS, high LB, and low BC and the high prevalence of caries; hence the combination of these factors could be confidently used to predict caries in this population. PMID- 24478980 TI - Oral health status and treatment needs among 12- and 15-year-old government and private school children in Shimla city, Himachal Pradesh, India. AB - OBJECTIVES: To assess the dental caries, periodontal health, and malocclusion of school children aged 12 and 15 years in Shimla city and to compare them in government and private schools. MATERIALS AND METHODS: A cross-sectional study of 12- and 15-year-old children in government and private schools was conducted in Shimla city, Himachal Pradesh, India. A sample of 1011 school children (both males and females) was selected by a two-stage cluster sampling method. Clinical recordings of dental caries and malocclusion were done according to World Health Organization diagnostic criteria 1997. Periodontal health was assessed by Community Periodontal Index of Treatment Needs index. The data collected was analyzed by SPSS package 13. The statistical tests used were t-test and Chi square tests. RESULTS: The prevalence of dental caries was 32.6% and 42.2% at 12 and 15 years, respectively. At the12 years of age, the mean decayed, missing, filled teeth was 0.62 +/- 1.42 and it was 1.06 +/- 2.93 at 15 years of age. Females had higher level of caries than males at both the ages. At both ages, mean of decayed teeth was statistically higher in government schools as compared with private schools. Children in government schools had significantly less number of mean filled teeth at both ages as compared with private schools. The healthy component of gingiva was present in higher percentage of children in private schools as compared with government schools at both the age groups. The prevalence of malocclusion among the 12- year-old (58.1%) was more as compared with that among the 15-year-old (53.5%). CONCLUSION: The caries experience of 12- and 15-year-old children was low but the prevalence of gingivitis and malocclusion was quite high. Effective oral health promotion strategies need to be implemented to improve the oral health of school children further in Shimla city. PMID- 24478981 TI - High-Throughput Screening to Identify Plant Derived Human LDH-A Inhibitors. AB - AIMS: Lactate dehydrogenase (LDH)-A is highly expressed in diverse human malignant tumors, parallel to aggressive metastatic disease, resistance to radiation/chemotherapy and clinically poor outcome. Although this enzyme constitutes a plausible target in treatment of advanced cancer, there are few known LDH-A inhibitors. STUDY DESIGN: In this work, we utilized a high-throughput enzyme micro-array format to screen and evaluate > 900 commonly used medicinal plant extracts (0.00001-.5 mg/ml) for capacity to inhibit activity of recombinant full length human LDHA; EC .1.1.1.27. METHODOLOGY: The protein sequence of purified enzyme was confirmed using 1D gel electrophoresis- MALDI-TOF-MS/MS, enzyme activity was validated by oxidation of NADH (500MUM) and kinetic inhibition established in the presence of a known inhibitor (Oxalic Acid). RESULTS: Of the natural extracts tested, the lowest IC50s [<0.001 mg/ml] were obtained by: Chinese Gallnut (Melaphis chinensis gallnut), Bladderwrack (Fucus vesiculosus), Kelp (Laminaria Japonica) and Babul (Acacia Arabica). Forty-six additional herbs contained significant LDH-A inhibitory properties with IC50s [<0.07 mg/ml], some of which have common names of Arjun, Pipsissewa, Cinnamon, Pink Rose Buds/Petals, Wintergreen, Cat's Claw, Witch Hazel Root and Rhodiola Root. CONCLUSION: These findings reflect relative potency by rank of commonly used herbs and plants that contain human LDH-A inhibitory properties. Future research will be required to isolate chemical constituents within these plants responsible for LDH-A inhibition and investigate potential therapeutic application. PMID- 24478983 TI - Small and Innovative Molecules as New Strategy to Revert MDR. AB - Multidrug resistance (MDR) is a complex phenomenon principally due to the overexpression of some transmembrane proteins belonging to the ATP binding cassette (ABC) transporter family. Among these transporters, P-glycoprotein (P gp) is mostly involved in MDR and its overexpression is the major cause of cancer therapy failure. The classical approach used to overcome MDR is the co administration of a P-gp inhibitor and the classic antineoplastic drugs, although the results were often unsatisfactory. Different classes of P-gp ligands have been developed and, among them, Tariquidar has been extensively studied both in vitro and in vivo. Although Tariquidar has been considered for several years as the lead compound for the development of P-gp inhibitors, recent studies demonstrated it to be a substrate and inhibitor, in a dose-dependent manner. Moreover, Tariquidar structure-activity relationship studies were difficult to carry out because of the complexity of the structure that does not allow establishing the role of each moiety for P-gp activity. For this purpose, SMALL molecules bearing different scaffolds such as tetralin, biphenyl, arylthiazole, furoxane, furazan have been developed. Many of these ligands have been tested both in in vitro assays and in in vivo PET studies. These preliminary evaluations lead to obtain a library of P-gp interacting agents useful to conjugate chemotherapeutic agents displaying reduced pharmacological activity and appropriate small molecules. These molecules could get over the limits due to the antineoplastic-P-gp inhibitor co-administration since pharmacokinetic and pharmacodynamic profiles are related to a dual innovative drug. PMID- 24478984 TI - Inhibitor of apoptosis proteins in pediatric leukemia: molecular pathways and novel approaches to therapy. AB - Inhibitor of Apoptosis (IAP) proteins are a family of proteins with antiapoptotic functions that contribute to the evasion of apoptosis, a form of programed cell death. IAP proteins are expressed at high levels in a variety of human cancers including childhood acute leukemia. This elevated expression has been associated with unfavorable prognosis and poor outcome. Therefore, IAP proteins are currently exploited as therapeutic targets for cancer drug discovery. Consequently, small-molecule inhibitors or antisense oligonucleotides directed against IAP proteins have been developed over the last years. Indeed, IAP antagonists proved to exhibit in vitro and in vivo antitumor activities against childhood pediatric leukemia in several preclinical studies. Thus, targeting IAP proteins represents a promising molecular targeted strategy to overcome apoptosis resistance in childhood leukemia, which warrants further exploitation. PMID- 24478982 TI - Radiotherapy and the tumor stroma: the importance of dose and fractionation. AB - Ionizing radiation is a non-specific but highly effective way to kill malignant cells. However, tumor recurrence sustained by a minor fraction of surviving tumor cells is a commonplace phenomenon caused by the activation of both cancer cell intrinsic resistance mechanisms, and also extrinsic intermediaries of therapy resistance, represented by non-malignant cells and structural components of the tumor stroma. The improved accuracy offered by advanced radiotherapy (RT) technology permits reduced volume of healthy tissue in the irradiated field, and has been triggering an increase in the prescription of high-dose oligo fractionated regimens in the clinics. Given the remarkable clinical success of high-dose RT and the current therapeutic shift occurring in the field, in this review we revise the existing knowledge on the effects that different radiation regimens exert on the different compartments of the tumor microenvironment, and highlight the importance of anti-tumor immunity and other tumor cell extrinsic mechanisms influencing therapeutic responses to high-dose radiation. PMID- 24478985 TI - BRCA and Early Events in the Development of Serous Ovarian Cancer. AB - Women who have an inherited mutation in the BRCA1 or BRCA2 genes have a substantial increased lifetime risk of developing epithelial ovarian cancer (EOC), and epidemiological factors related to parity, ovulation, and hormone regulation have a dramatic effect on the risk in both BRCA mutation carriers and non-carriers. The most common and most aggressive histotype of EOC, high-grade serous carcinoma (HGSC), is also the histotype associated with germline BRCA mutations. In recent years, evidence has emerged indicating that the likely tissue of origin of HGSC is the fallopian tube. We have reviewed, what is known about the fallopian tube in BRCA mutation carriers at both the transcriptional and translational aspect of their biology. We propose that changes of the transcriptome in BRCA heterozygotes reflect an altered response to the ovulatory stresses from the microenvironment, which may include the post-ovulation inflammatory response and altered reproductive hormone physiology. PMID- 24478986 TI - Gene expression analysis in ovarian cancer - faults and hints from DNA microarray study. AB - The introduction of microarray techniques to cancer research brought great expectations for finding biomarkers that would improve patients' treatment; however, the results of such studies are poorly reproducible and critical analyses of these methods are rare. In this study, we examined global gene expression in 97 ovarian cancer samples. Also, validation of results by quantitative RT-PCR was performed on 30 additional ovarian cancer samples. We carried out a number of systematic analyses in relation to several defined clinicopathological features. The main goal of our study was to delineate the molecular background of ovarian cancer chemoresistance and find biomarkers suitable for prediction of patients' prognosis. We found that histological tumor type was the major source of variability in genes expression, except for serous and undifferentiated tumors that showed nearly identical profiles. Analysis of clinical endpoints [tumor response to chemotherapy, overall survival, disease free survival (DFS)] brought results that were not confirmed by validation either on the same group or on the independent group of patients. CLASP1 was the only gene that was found to be important for DFS in the independent group, whereas in the preceding experiments it showed associations with other clinical endpoints and with BRCA1 gene mutation; thus, it may be worthy of further testing. Our results confirm that histological tumor type may be a strong confounding factor and we conclude that gene expression studies of ovarian carcinomas should be performed on histologically homogeneous groups. Among the reasons of poor reproducibility of statistical results may be the fact that despite relatively large patients' group, in some analyses one has to compare small and unequal classes of samples. In addition, arbitrarily performed division of samples into classes compared may not always reflect their true biological diversity. And finally, we think that clinical endpoints of the tumor probably depend on subtle changes in many and, possibly, alternative molecular pathways, and such changes may be difficult to demonstrate. PMID- 24478988 TI - Prostate-specific antigen bounce following stereotactic body radiation therapy for prostate cancer. AB - INTRODUCTION: Prostate-specific antigen (PSA) bounce after brachytherapy has been well-documented. This phenomenon has also been identified in patients undergoing stereotactic body radiation therapy (SBRT). While the parameters that predict PSA bounce have been extensively studied in prostate brachytherapy patients, this study is the first to analyze the clinical and pathologic predictors of PSA bounce in prostate SBRT patients. MATERIALS AND METHODS: Our institution has maintained a prospective database of patients undergoing SBRT for prostate cancer since 2006. Our study population includes patients between May 2006 and November 2011 who have at least 18 months of follow-up. All patients were treated using the CyberKnife treatment system. The prescription dose was 35-36.25 Gy in five fractions. RESULTS: One hundred twenty patients were included in our study. Median PSA follow-up was 24 months (range 18-78 months). Thirty-four (28%) patients had a PSA bounce. The median time to PSA bounce was 9 months, and the median bounce size was 0.50 ng/mL. On univariate analysis, only younger age (p = 0.011) was shown to be associated with an increased incidence of PSA bounce. Other patient factors, including race, prostate size, prior treatment by hormones, and family history of prostate cancer, did not predict PSA bounces. None of the tumor characteristics studied, including Gleason score, pre-treatment PSA, T-stage, or risk classification by NCCN guidelines, were associated with increased incidence of PSA bounces. Younger age was the only statistically significant predictor of PSA bounce on multivariate analysis (OR = 0.937, p = 0.009). CONCLUSION: PSA bounce, which has been reported after prostate brachytherapy, is also seen in a significant percentage of patients after CyberKnife SBRT. Close observation rather than biopsy can be considered for these patients. Younger age was the only factor that predicted PSA bounce. PMID- 24478987 TI - Current challenges in the bioinformatics of single cell genomics. AB - Single cell genomics is a rapidly growing field with many new techniques emerging in the past few years. However, few bioinformatics tools specific for single cell genomics analysis are available. Single cell DNA/RNA sequencing data usually have low genome coverage and high amplification bias, which makes bioinformatics analysis challenging. Many current bioinformatics tools developed for bulk cell sequencing do not work well with single cell sequencing data. Here, we summarize current challenges in the bioinformatics analysis of single cell genomic DNA sequencing and single cell transcriptomes. These challenges include calling copy number variations, identifying mutated genes in tumor samples, reconstructing cell lineages, recovering low abundant transcripts, and improving the accuracy of quantitative analysis of transcripts. Development in single cell genomics bioinformatics analysis will promote the application of this technology to basic biology and medical research. PMID- 24478991 TI - Empowering primary care physicians in India. PMID- 24478989 TI - Transcriptome analysis of Vibrio parahaemolyticus in type III secretion system 1 inducing conditions. AB - Vibrio parahaemolyticus is an emerging bacterial pathogen capable of causing inflammatory gastroenteritis, wound infections, and septicemia. As a food-borne illness, infection is most frequently associated with the consumption of raw or undercooked seafood, particularly shellfish. It is the primary cause of Vibrio associated food-borne illness in the United States and the leading cause of food borne illness in Japan. The larger of its two chromosomes harbors a set of genes encoding type III section system 1 (T3SS1), a virulence factor present in all V. parahaemolyticus strains that is similar to the Yersinia ysc T3SS. T3SS1 translocates effector proteins into eukaryotic cells where they induce changes to cellular physiology and modulate host-pathogen interactions. T3SS1 is also responsible for cytotoxicity toward several different cultured cell lines as well as mortality in a mouse model. Herein we used RNA-seq to obtain global transcriptome patterns of V. parahaemolyticus under conditions that either induce [growth in Dulbecco's Modified Eagle Medium (DMEM) media, in trans expression of transcriptional regulator exsA] or repress T3SS1 expression (growth in LB-S media, in trans exsD expression) and during infection of HeLa cells over time. Comparative transcriptomic analysis demonstrated notable differences in the expression patterns under inducing conditions and was also used to generate an expression profile of V. parahaemolyticus during infection of HeLa cells. In addition, we identified several new genes that are associated with T3SS1 expression and may warrant further study. PMID- 24478992 TI - "The Refer Less Resolve More" Initiative: A Five-year Experience from CMC Vellore, India. AB - India's one billion plus strong population presents huge health care needs. Presently, approximately 250,000 general practitioners and 30,000 Government doctors are a part of the Indian healthcare workforce, but 80% of them are based in urban India. Problems which plague healthcare delivery and attributed to physician practice may be enumerated as - physicians (1) lack competencies, (2) lack updating, (3) prescribe irrationally (pressures from pharmaceutical companies and patients), (4) practice unethically, (5) refer excessively to specialists and other clinical professionals, and (6) investigate for diseases without justification. A multi-competent Family Physician who could provide a single-window, ethical, and holistic healthcare to patients and families is the need of the hour. Therefore, training, equipping, and empowering these 250,000 doctors to become such physicians will reduce health costs considerably. Distance medical education using all the andragogic methods can be used to train large number of individuals without displacing them from their work-places. Distance learning provides a useful interface for rapidly developing a specialized pool of doctors practicing and advocating family medicine as most-needed discipline. This motivated CMC Vellore, a premier institution for medical education in India, to start a the "refer less resolve more initiative" by offering "two year family medicine diploma course" by distance mode. This is an innovatively-written program consisting of problem-based self-learning modules, video-lectures, video conferencing, and face-to-face contact programs. Ten secondary level hospitals, across the country, under the supervision of national and international family medicine faculty form the pillars of this program. This distance learning program offered by CMC Vellore has become the platform for change as there is special focus is on ethics, rational prescribing, consultation skills, application of family medicine principles; and practical demonstration of compassionate, cost effective and high-quality care. The change in attitude has resulted in transformation in three major aspects of practice: professional, ethical, and patient care. So far, 942 private practitioners and 177 government doctors have been enrolled. PMID- 24478993 TI - The Rise of E-learning and Opportunities for Indian Family Physicians. AB - The IT (information technology) revolution is sweeping across the globe. Distance, location and costs have become irrelevant. With availability of newer communication tools, medical education and practice are bound to be transformed. Rapid advancement of science requires medical professionals to update their knowledge constantly. Online interface for CME (Continued Medical Education) presents an exciting opportunity as an E learning tool. PMID- 24478994 TI - Academic institutionalization of community health services: way ahead in medical education reforms. AB - Policy on medical education has a major bearing on the outcome of health care delivery system. Countries plan and execute development of human resource in health, based on the realistic assessments of health system needs. A closer observation of medical education and its impact on the delivery system in India reveals disturbing trends. Primary care forms backbone of any system for health care delivery. One of the major challenges in India has been chronic deficiency of trained human resource eager to work in primary care setting. Attracting talent and employing skilled workforce seems a distant dream. Talking specifically of the medical education, there are large regional variations, urban - rural divide and issues with financing of the infrastructure. The existing design of medical education is not compatible with the health care delivery system of India. Impact is visible at both qualitative as well as quantitative levels. Medical education and the delivery system are working independent of each other, leading outcomes which are inequitable and unjust. Decades of negligence of medical education regulatory mechanism has allowed cropping of multiple monopolies governed by complex set of conflict of interest. Primary care physicians, supposed to be the community based team leaders stand disfranchised academically and professionally. To undo the distorted trajectory, a paradigm shift is required. In this paper, we propose expansion of ownership in medical education with academic institutionalization of community health services. PMID- 24478995 TI - Access to health services among slum dwellers in an industrial township and surrounding rural areas: a rapid epidemiological assessment. AB - CONTEXT: The biggest challenge in implementing the primary health care principles is of equitable distribution of health care to all. The rural masses and urban slum dwellers are most vulnerable to lack of access to health care. AIM: To study access to health services among slum dwellers and rural population. SETTING AND DESIGN: A cross-sectional survey in an urban slum and surrounding rural areas in field practice area of a medical college. MATERIALS AND METHODS: Structured instrument along with qualitative techniques such as focus group discussions, were used to collect information on access and utilization of health services from 865 individuals of both sexes and all ages selected from urban slums, villages, and indoor and outdoor patients. Access to basic determinants of good health such as housing, water, and sanitation was also elicited. Besides, health needs based on self-reported disease conditions were compiled. RESULTS: More than 50% of respondents were living in poor housing and insanitary conditions. Besides the burden of communicable diseases and malnutrition (especially in children), risk of lifestyle diseases as evidenced by high Body mass index in 25% of adults surveyed was found. Private medical practitioners were more accessible than government facilities. More than 60% sought treatment from private medical facilities for their own ailments (for sickness in children this proportion was 74%). People who visited government facilities were more dissatisfied with the services (30.88%) than those who visited private facilities (18.31%). This difference was significant (OR=1.99, 95% confidence interval 1.40 to 2.88; chi(2) =15.95, df=1, P=0.007). The main barriers to health care identified were waiting time long, affordability, poor quality of care, distance, and attitude of health workers. CONCLUSION: The underprivileged in India continue to have poor access to basic determinants of good health as well as to curative services from government sources during illness. PMID- 24478990 TI - Transition metal ions at the crossroads of mucosal immunity and microbial pathogenesis. AB - Transition metal ions are essential micronutrients for all living organisms. In mammals, these ions are often protein-bound and sequestered within cells, limiting their availability to microbes. Moreover, in response to infection, mammalian hosts further reduce the availability of metal nutrients by activating epithelial cells and recruiting neutrophils, both of which release metal-binding proteins with antimicrobial function. Microorganisms, in turn, have evolved sophisticated systems to overcome these limitations and acquire the metal ions essential for their growth. Here we review some of the mechanisms employed by the host and by pathogenic microorganisms to compete for transition metal ions, with a discussion of how evading "nutritional immunity" benefits pathogens. Furthermore, we provide new insights on the mechanisms of host-microbe competition for metal ions in the mucosa, particularly in the inflamed gut. PMID- 24478996 TI - Determinants of Prelacteal Feeding Among Infants of RS Pura Block of Jammu and Kashmir, India. AB - OBJECTIVE: To assess the role of various factors in determining prelacteal feeding in block R.S. Pura of district Jammu. MATERIALS AND METHODS: A stratified two-stage design with villages as the primary sampling unit and lactating mothers as the secondary sampling unit. Villages were divided into different clusters on the basis of population and sampling units were selected by a simple random technique. RESULTS: Giving prelacteal feed is almost universal with 88% of mothers feeding their children with prelacteal feeds. Income seemed to have significant effect on the preference of prelacteal feeds with low income groups showing lower preference for giving prelacteal feeds. CONCLUSION: The study showed, interalia, that a poor knowledge regarding infant feeding practice was prevalent among mothers. PMID- 24478997 TI - Knowledge and practices of paracetamol administration among caregivers of pediatric age group patients. AB - INTRODUCTION: Paracetamol is a widely used over the counter drug for pyrexia and mild to moderate pain in all age groups. OBJECTIVE: To assess the knowledge and practices of paracetamol administration among caregivers of the pediatric age group patients attending the university family practice. MATERIALS AND METHODS: A clinic-based descriptive cross-sectional survey was carried out among clients attending the family practice of the Faculty of Medicine, University of Kelaniya, Sri Lanka using pretested interviewer administrated questionnaire. RESULTS: Ninety eight caregivers Participated. Majority were females (97%) with a mean age of 32 years. Age of the patients ranged from 1 to 132 (mean: 48 months). The commonest indication for paracetamol was fever (98%) and in 99% of the patients, mother was the administrator. Forty three percent of the children received a supra-therapeutic dose (>15 mg/kg/dose). None exceeded 20 mg/kg/dose. 16% exceeded the recommended dosing frequency. Children above 3 years were at an increased risk of receiving incorrect paracetamol dose (chi(2) =19.55, df=1, P>0.001) A majority (75%) said they followed doctors' advice on paracetamol dose. There was no association between level of education of care giver, deciding dose as directed by doctor and product information leaflet and dosing accuracy. Only one caregiver was able to calculate the paracetamol dose according to weight. A majority (85%) knew about paracetamol poisoning but it was not associated with dosing accuracy. CONCLUSION AND RECOMMENDATIONS: Administration of supratheraputic doses of paracetamol is common and risk increased with child's age. Knowledge on calculating the weight appropriate paracetamol dose is poor. Physicians should educate care givers on judicious use of paracetamol. PMID- 24478998 TI - The Delivery of Sexuality-related Patient Education to Adolescent Patients: A Preliminary Study of Family Practice Resident Physicians. AB - BACKGROUND: Risky sexual behavior among adolescents is one of the leading health behaviors most associated with mortality, morbidity, and social problems. Adolescents need reliable sources of information to help them promote healthy sexual behaviors. Physicians in the United States are often seen by adolescents as a reliable and trustworthy source of accurate sexual information. However, many physicians feel uncomfortable or ill-prepared to deal with sexuality issues among their adolescent patients. PURPOSE: This study examined the impact of family resident physicians' sexual attitudes, knowledge, and comfort, on the delivery of sexuality-related patient education to their adolescent patients. MATERIALS AND METHODS: Pre-post-test scales were administered to 21 physicians. Data were also collected for patient (n=644) charts. Factors that determined the delivery of sexuality-related patient education were analyzed. RESULTS: Results indicate that sexuality-related patient education was rarely provided to adolescent patients. CONCLUSIONS: Adolescent sexuality education is not a high priority for physicians. Professional medical organizations should play a leadership role in training physicians on delivering sexuality education to adolescent patients. PMID- 24478999 TI - Urinary estrogen levels in women on contraceptives in enugu, South-East Nigeria. AB - BACKGROUND: Substantial evidence supports a causal relationship between the risk of human breast cancer and levels of endogenous estrogens. AIM: To evaluate the urinary estrogen of women on contraceptives and also compare the levels in two different classes of contraceptives; hence, the possible predisposition of such women to the risk of breast cancer. SETTING AND DESIGN: Urinary estrogen level was evaluated in 84 women attending family planning clinic in University of Nigeria Teaching Hospital Enugu, Nigeria, who have been on contraceptive device for 10 years or less (<=10 years). They were aged between 21 and 50 years and were divide into three groups (21-30 years, 31-40 years, and >40 years). The control group consisted of 30 age-matched apparently-healthy women who were not on any contraceptive device. MATERIALS AND METHODS: Estrogen was analyzed using Ecologenia(;) Estrogen (E1/E2/E3) microplate enzyme-linked immunosorbent assay (ELISA) kit, Batch No. T2GR4, from Japan Envirochemicals Ltd, Japan. STATISTICAL ANALYSIS USED: Significant differences between means were determined by two tailed Student's t-test using graph pad prism computer software program. RESULT: There was a statistically significant increase (P=0.0462), in the mean urinary estrogen level of women on contraceptives when compared with the control. The highest amount of estrogen was excreted by the women in the 21-30 years age group. When the contraceptive devices were divided into two classes of intra uterine device and oral/injectables, there was no statistical difference (P=0.8112) in the mean urinary estrogen output of the women. CONCLUSION: The synthetic estrogen content of contraceptive device most probably contributed to the level excreted in the urine. The increased estrogen output observed in women on contraceptive device was not dependent on the class of contraceptive device used. PMID- 24479000 TI - Socio demographic determinants and knowledge, attitude, practice: survey of family planning. AB - BACKGROUND: Understanding of family planning scenario among different societies and communities, which by and large reside in urban slum and rural areas, might prove useful in increasing family planning acceptance by them and decreasing population growth. OBJECTIVE: To assess the sociodemographic determinants and KAP of family planning among urban slum and rural areas of Lucknow. STUDY DESIGN: Cross sectional. SETTING: Bal Mahila Chikitsalaya, Aliganj, in urban and Primary Health Centre, Bakshi Ka Talaab, in rural area of Lucknow. STUDY PERIOD: October 2008 to April 2009. MATERIALS AND METHODS: Six hundred and eightytwo postpartum women (within 42 days of delivery) who came to these health facilities for their child's vaccination were interviewed, by a preformed and pretested schedule. RESULTS: Maximum utilization of family methods were seen among Hindu women, women of age group 30 or more, parity four and more, educational level upto high school and above and those of higher socioeconomic class. Although overall residential area (urban or rural) of women had no influence on the practice of family planning by them and all of them were willing to adopt family planning methods in future, urban women were found to have a higher level of knowledge and attitude toward modern methods of family planning. Only 2.8% were unsure of preferred method for future use. CONCLUSION: Family planning programs which effectively promotes the use of family planning methods, so that the trend toward increase in population could be arrested is the need of hour. PMID- 24479001 TI - Seroprevalence of transfusion transmissible infections among voluntary blood donors at a tertiary care teaching hospital in rural area of India. AB - BACKGROUND: Blood transfusion is a life-saving measure in various medical and surgical emergencies. Transfusion medicine, apart from being important for the medical treatment of each patient, also has great public health importance. OBJECTIVES: The present study was conducted to estimate the prevalence of transfusion transmitted infections in voluntary blood donors at a rural tertiary care teaching hospital in western Maharashtra, India. MATERIALS AND METHODS: All voluntary donors reporting to the blood bank were screened for HBsAg, Hepatitis C Virus (HCV), HIV and Syphilis by using the appropriate enzyme-linked immunosorbent assay. HIV infection was confirmed using a standard immunoblotting technique. Hepatitis B Virus (HBV) was tested for surface antigen (HBsAg) and HCV by the immunechromatographic method. The Venereal Disease Reference Laboratory (VDRL) test was used for estimation of syphilis infection. The study was designed for a duration of two years between January 2009 to December 2010. Medical reports of the donors were accessed from the hospital records and analyzed. RESULTS: A total of 5661 voluntary blood donors were screened, of which 5394 (95.28%) were males and 267 (4.72%) were females. The overall seroprevalence of HBV and HCV were 1.09% and 0.74% respectively; for HIV and syphilis the seroprevalence was estimated to be 0.07% for each. CONCLUSION: Blood is still one of the main sources of transmission of infections. HIV, hepatitis B, hepatitis C viruses and syphilis are prevalent among voluntary donors in rural India. PMID- 24479002 TI - A crusade against scorpion sting: life and works of dr. Himmatrao bawaskar. AB - In the times of rapid advancement of science and technology, advance medical equipment and hi tech hospitals represent the face of medical science. The aspirations and ambitions of medical professionals are also shifting, with growing concerns of deterioration of doctor patient relationship as well as disconnect between services and the community needs. The life of Dr Himmatrao Bawaskar defies several conventions of today's medical practice. His outstanding dedication towards patients and commitment to provide high quality care in resource poor setting makes him an ideal role model for younger generation of physicians in India. PMID- 24479003 TI - The management of sickle cell disease in a primary care setting. AB - With increasing burdens placed on Primary Care Physicians in the prevention and management of Sickle Cell Disease (SCD), it is imperative that there is some basic understanding of the same. Needless to say, its management is a multifocal, multidisciplinary approach which includes a collaborative effort between patients, family members and the healthcare team. Primary Care Physicians must be familiar with the pathophysiological processes, diagnostic evaluation, and current standard of care, new treatment options, clinical research advances and medical management of sickle hemoglobinopathies and their complications. The guidelines should include new born screening and assessment, accessible medical records for those diagnosed with SCD, system support and prevention, management of complication and crisis periods and home management (dietary and lifestyle modifications). PMID- 24479004 TI - Family Medicine: A Resident's Perspective. AB - Though family medicine has existed as a qualification for more than a decade in India, structured residency based training is a recent phenomenon. A growing number of young physicians are opting for this challenging and exciting new speciality as post graduate qualification through NBE (National Board of Examination) affiliated three year DNB (Diplomate of National Board) training program. MD family medicine is also in offing as Medical Council of India (MCI) has recently notified curriculum for this post graduate program. In this article, a resident shares his experience and excitement through the less travelled journey of family medicine residency training in India. PMID- 24479005 TI - Spice route movement: forum for young and future family physicians / primary care physicians of South Asia. AB - The past 6 years have seen the worldwide emergence of movements lead by New and Future Family/General Practitioners. The main aim of these movements is the promotion of excellence in the field of family medicine/general practice to respond the challenges pertaining to Global Health. This article will discuss some of the work being done worldwide, and in particularly in South Asia, in the context of The Spice Route movement. At the end of the article, details of the next steps to be taken and of ways in which interested parties can get involved are given. PMID- 24479006 TI - Osteoporosis - An Emerging Disease of the 21(st) Century, Part 1: An Overview. AB - Osteoporosis is a condition where bones are fragile with a poor bone mineral density. This increases the risk of fracture especially of the hip, vertebrae, and wrist. These fractures are usually termed "fragility fractures." In this article, we aim to provide a broad overview of osteoporosis-investigation, management, and prevention. PMID- 24479007 TI - Disability and rehabilitation services in India: issues and challenges. AB - Disability is an important public health problem especially in developing countries like India. The problem will increase in future because of increase in trend of non-communicable diseases and change in age structure with an increase in life expectancy. The issues are different in developed and developing countries, and rehabilitation measures should be targeted according the needs of the disabled with community participation. In India, a majority of the disabled resides in rural areas where accessibility, availability, and utilization of rehabilitation services and its cost-effectiveness are the major issues to be considered. Research on disability burden, appropriate intervention strategies and their implementation to the present context in India is a big challenge. Recent data was collected from Medline and various other sources and analyzed. The paper discusses various issues and challenges related to disability and rehabilitation services in India and emphasize to strengthen health care and service delivery to disabled in the community. PMID- 24479008 TI - Hyperglycemia: an unusual cause for hemichorea. AB - Hemichoreais a rare neurologic disorder due to oxidative stress leading to neurodegenerationof the dentate nuclei and striata. It is rarely observed in diabetes. One such case occurring in an adult female diabetic is described here. PMID- 24479009 TI - Revisiting endosulfan. AB - Endosulfan toxicity could precipitate gargantuan jeopardy and may result in irreversible and fatal damage. The spectrum of involvement may range from mild nausea, vomiting, and anxiety to intractable seizures and multiorgan damage resulting in death. We report a case of endosulfan poisoning complicated by multi organ dysfunction, cardiac arrest, and death. PMID- 24479010 TI - Recent developments in cardiovascular diseases control and prevention in India. PMID- 24479011 TI - Family Medicine at AIIMS (All India Institute of Medical Sciences) Like Institutes. PMID- 24479012 TI - Polio eradication: Current status and challenges. AB - For more than two decades mankind has been dreaming of a "polio-free world." However the dream is yet to be realized owing to various problems related to transmission of wild polio virus transmission as well as vaccine-derived polio virus. These problems are as much scientific as human. The article briefly discusses the current status of polio control across the globe, and various challenges associated with it in a nation-wise manner. PMID- 24479013 TI - Morbidity profile and seasonal variation of diseases in a primary health center in kanpur district: a tool for the health planners. AB - OBJECTIVE: The objective of this study was to determine the morbidity profile of patients being treated at the Primary Health Center, their distribution according to gender, and the seasonal trend of diseases. MATERIALS AND METHODS: The study was done retrospectively using secondary data, over a period of 1 year from June 2007 to July 2008, at the OPD of the Primary Health Center at Patara in Kanpur District, India. The study was aimed to study the pattern of diseases according to the classification provided by the Government of India. The data were collected from the OPD registers of the consultant medical officer, and the diagnosis was classified into communicable diseases, nutritional and metabolic disorders, infectious diseases, obstetric complications, and other diseases including injuries. RESULTS: A total of 6838 patients had been treated at the OPD, which included 2707 males and 4131 females. It was observed that, while communicable diseases constituted about half of the total burden of the diseases with skin infections being the commonest; the non-communicable diseases constituted about one-fifth of the total disease burden. Significant gender differences were evident in the prevalence of certain diseases such as worm infestation, acute respiratory tract infection, urinary tract infection, reproductive tract infection, chronic obstructive pulmonary disease, gastritis, arthritis/gout, falls/injuries/fractures, anemia, pyrexia of unknown origin, and snake bite. Most of the diseases were observed to have a seasonal variation, with the communicable and infectious diseases peaking in the monsoon months. Surprisingly, the non-communicable diseases such as gastritis and falls and injuries also showed a seasonal variation. CONCLUSION: Many diseases have a seasonal variation and the burden of these diseases could be reduced if we devise measures to detect the changes in their trend through the implementation of surveillance programs in this part of the world, as has been carried out in other countries. The knowledge of the burden of the diseases would also assist the health administrators in judicious allocation of the resources. PMID- 24479014 TI - A Case Control Study on School Dropouts in Children of Alcohol-Dependent Males Versus that in Abstainers/Social Drinkers' Children. AB - OBJECTIVE: To study and compare in the children of alcohol-dependent males versus those in a socio-demographically similar control group, the occurrence of school dropouts, and to examine the link between certain factors like parental education and socioeconomic status on school dropout. MATERIALS AND METHODS: This was a community-based case control study. The participants were 107 family units in both study group (alcohol-dependent male, wife, at least one child less than 14 years of age) and control group (abstainer/social drinker, wife, at least one child less than 14 years of age). It was conducted in an urban slum community in Mumbai. Interview technique was used for data collection. The study was conducted for a period of 1 year. STATISTICAL ANALYSIS: Using software SPSS version 17.0, percentages, Chi-square test. RESULTS AND CONCLUSION: The number of school dropouts was significantly higher (45.31%, P < 0.001) in the children of alcohol dependent males as compared to 22.47% in the abstainers/social drinkers' children. In the study group, there was higher number of school dropouts among boys (52.73%, P < 0.05) as compared to girls (35.37%). There was a statistically significant association between parental illiteracy and school dropout in children in both the groups. In the control group, significantly higher number of school dropouts of socioeconomic class IV and V had dropped out as compared to those of socioeconomic class III and II. PMID- 24479015 TI - Healthcare technician delivered screening of adults with diabetes to improve primary care provider recognition of depression. AB - PURPOSE: The purpose of this study was to implement a continuous quality improvement project aimed at improving primary care provider recognition of depression. MATERIALS AND METHODS: A randomized, blinded, pre- and post-test design was implemented with 92 adults attending an academic internal medicine clinic. Subjects were assigned to an intervention where healthcare technicians (HCT) trained in the fundamentals of diabetes education delivered brief probing questions about self-care behavior and tailored talking points to encourage patients to talk to their primary care physician about their emotional health. The control group received a sham intervention that included only information on standards of diabetes care. Measures included both a paper-and-pencil screening of depression and the Primary Healthcare Questionnaire-8 (PHQ-8). Outcomes were evaluated for antidepressant and/or counseling treatment modalities once the possibility of depression was identified. RESULTS: Both the control and intervention groups improved from pre-test to 3-month post-test scores on the PHQ 8 in clinically significant ways, but continued to have moderate to severe depression symptoms. There was a significant likelihood of receiving antidepressant therapy and/or counseling in those who scored high on the PHQ-8. CONCLUSION: HCT can be trained to talk to patients about emotional health issues during routine primary care visits. Depression screening measures can be administered as part of the triage routine at the start of a primary care visit, along with tasks such as vital signs. Answering a screening measure can help create awareness of symptoms and feelings that can prompt discussion during the patient-provider encounter that can result in the diagnosis and treatment of depression. PMID- 24479016 TI - Attitudes of nepalese medical students toward telling patients a diagnosis of cancer. AB - OBJECTIVES: Patient-centered communication teaching generally encourages doctors to inform patients of cancer diagnoses. In many countries, including Nepal, it is usually the patient's family that is informed. Much of the evidence about patient preferences is from western studies. The objectives of this study are: To discover the attitudes of medical students and patients in Nepal toward disclosing a cancer diagnosis; and to identify the reasons for these attitudes. MATERIALS AND METHODS: A cross-sectional survey was administered to medical students and patients in a teaching hospital in Nepal. The participants were asked about their attitudes toward and reasons for informing patients of a cancer diagnosis. The data were analyzed to compare students' and patients' attitudes and to look for differences between the first and fourth year students. RESULTS: Fifty-four percent of the students would inform a patient even if the cancer was incurable, 6% would inform only if curable, and 40% would inform the family instead. Sixty-nine percent of the students and 51% of the patients wanted a close relative informed, even if the relative was incurable (P = 0.0016). There was no significant difference between students (83%) and patients (78%) wanting to be informed of their own diagnosis. The most important reasons for students not informing the patients were fears of loss of hope and of causing depression. CONCLUSION: The results confirmed the diverse attitudes about informing a cancer diagnosis to patients, in Nepal. Students wanted more information for themselves than they felt patients should be given. This information could enlighten the practice of doctors in Nepal and other similar cultures, as well as guide the communication training of future doctors. PMID- 24479017 TI - Behavior of personality type toward stress and job performance: a study of healthcare professionals. AB - BACKGROUND: The present paper has examined the sources of stress among the healthcare professionals and the difference between responses of personality type A and type B healthcare professionals toward stressful situations. Further, the difference in the performance of both the personality types has been studied. The relationship between stress and performance among the healthcare professionals in general and with respect to personality type A and type B healthcare professionals in particular has also been investigated. METHODS: A total of 160 healthcare professionals of Post Graduate Institute (PGI), Chandigarh, were subjects of this study. RESULTS: Identification with patients, deterioration and complication in the patient condition, and job criticism emerged to be the sources of stress. Significant difference between personality type A and personality type B professionals' response pertaining to identification with the patients only has been reported. However, type A individuals showed slightly higher inclination as compared to type B individuals on majority of stressful situations. It was further noted that type A individuals had scored higher on almost all the performance indicators as compared to personality type B individuals. The mean difference between the personality types was found to be significant for two performance dimensions, i.e., relationship with colleagues, and teaching and training. CONCLUSIONS: The stressful situation relationship with patients was found to have significantly negative impact on the performance factors such as good clinical care and rapport with patients. Daily work was also found to be negatively related to good medical practice. PMID- 24479018 TI - Screening of vision and hearing in primary school children. AB - BACKGROUND: Hearing and sight are two basic senses in terms of education and profession. The World Health Organization (WHO) estimates that 15 million children worldwide suffer from uncorrected refractive disorders and another 275 million people are handicapped due to compromised hearing. In Indonesia, screening primary school children for hearing and vision is not part of the free public health-care system. Knowledge of the status of a child's hearing and vision may help secure the child's education and future profession. MATERIALS AND METHODS: In five primary schools in a poor urban neighborhood in Yogyakarta, Indonesia, we screened pupils from class 1 to 6, for vision and hearing handicaps, following the WHO's definitions of handicap. On location in the primary schools, we screened vision using a Snellen chart and hearing using distortion product otoacoustic emission (DPOAE). Those with vision below 6/18 were referred to an ophthalmologist and pupils with hearing below 30 decibels at 0.5, 1, 2, and 4 kilohertz were referred to an ear nose and throat (ENT) specialist for final testing. RESULTS: Totally, 775 pupils were vision screened and 777 pupils were hearing screened. We found that 2% were disabled by sight and 6% by hearing. CONCLUSION: Lost without proper education, these pupils can, with simple recommendations, have access to education. We recommend that Indonesia start screening its primary school pupils for hearing and vision to secure the country's future productivity and socioeconomic development. PMID- 24479019 TI - Study of clinical profile and antibiotic sensitivity in paratyphoid Fever cases admitted at teaching hospital in South India. AB - CONTEXT: Globally, there has been an increase in incidence of paratyphoid fever, including paratyphoid fever caused by antimicrobial-resistant strains. Studying the clinical profile and antimicrobial sensitivity of paratyphoid fever would help in early diagnosis, appropriate treatment, rational use of antibiotics and prevent drug resistance. AIM: The aim of the study was to evaluate the clinical profile and sensitivity patterns of antibiotics used in the treatment of paratyphoid fever. SETTINGS AND DESIGN: A record-based study was done in tertiary care hospital, South India. MATERIALS AND METHODS: A retrospective analysis of culture-proven cases of paratyphoid fever was done in a tertiary care hospital. The socio-demographic characteristics, mode of presentation and the sensitivity pattern of isolates from blood culture were recorded. One hundred and ten case files of Salmonella paratyphi were reviewed from the medical records section and the required data (data regarding the clinical profile and antibiotic sensitivity) was collected and analyzed using SPSS version 11.5. RESULTS: Fever was present in all patients. All the cases were sensitive for third-generation cephalosporins, and only 31.8% of the cases were sensitive for quinolones. Sensitivity towards other antibiotics in descending order was as follows: ampicillin 93.6%, chloramphenicol 91.8%, aminoglycosides 90.4% and sulphonamides 76.4%. CONCLUSIONS: Research shows that there is increasing resistance to fluoroquinolones and sensitivity to chloramphenicol. Considering the changing trend in the sensitivity pattern, the recommendations of treatment for enteric fever need to be rationalized and re-considered. PMID- 24479020 TI - Patients' attitudes towards medical students in a teaching family practice: a sri lankan experience. AB - BACKGROUND: Faculty of Medicine, University of Kelaniya, Sri Lanka conducts a one month under graduate training programme during their fourth year at the University family practice centre. Students get training in history taking, clinical examination, patient management and practice management during this attachment. This study was conducted to look at the patients' attitude towards student participation during consultation. MATERIALS AND METHODS: This was a descriptive cross sectional study. All the patients who were 16 years and above during a 2 month period were included in the study. Structured questionnaire was administered by demonstrators following a consultation where students were present. Their demographic data, number of consultations with student participation and questions related to presence of students at various stages of the consultation were asked. RESULTS: Total of 85 patients took part in the study and 81.3% of them were females. 88.8% were of the opinion that they benefited by the interaction with medical students while 93.8% thought students understood their problems. 26.3% patients preferred a medical student of the same sex during consultation while 71.3 had not expressed any opinion in this regard. Only 3.8% and 5% wanted the doctor alone during history taking and examination respectively. Almost every patient was happy that they could help the undergraduate training. DISCUSSION: As expected results of the study showed that patients were willing to take part in undergraduate training without any reservation. These results are compatible with the previous studies done in the western world and data is not available form either Sri Lanka or other Asian countries. PMID- 24479021 TI - Strengthening primary level health service delivery: lessons from a state in India. AB - The main aim of the study was to assess primary health centers (PHCs) in terms of availability of assured services, facility of primary management of selected cases, surgeries, maternal and newborn health care services, and child health care services with respect to Indian Public Health Standards (IPHS). Data were collected from service providers (medical officerin-charge) at PHCs through well structured questionnaire developed by referring the IPHS for PHCs prescribed by the Directorate General of Health Services, Ministry of Health and Family Welfare, Government of India. The study was conducted at five districts (i.e. Bundi, SawaiMadhopur, Kota, Tonk, and Karauli) of Rajasthan state of India. All 148 PHCs of these five districts were included in the study. Findings depict that more than 90% of the study PHCs showed availability of services such as outpatient department (OPD), antenatal check up (ANC), postnatal check up (PNC), management of reproductive tract infections/sexual transmitted infection (RTI/STI), immunization, and treatment of diarrhea. However, services such as emergency services (24 h), primary management of fractures, surgery of cataract, medical termination of pregnancy (MTP) services, management of low-birth-weight babies, facility for tubectomy and vasectomy, and facility for internal examination for gynecological conditions were poor at PHCs of the study districts, which need to be addressed for further strengthening of primary health centers. PMID- 24479022 TI - Age and BMI Adjusted Comparison of Reproductive Hormones in PCOS. AB - OBJECTIVE AND BACKGROUND: Polycystic ovary syndrome (PCOS) is a complex condition and has been described in women who have polycystic ovaries as the underlying cause of hirsutism and chronic anovulation. Studies on PCOS in the Saudi population are very few. The aim of this study was to investigate the reproductive hormones levels in patients with PCOS. Effect of age and body mass index (BMI) on the hormonal findings was eliminated through a multivariate analysis. MATERIALS AND METHODS: A comparative study was conducted on Saudi subjects attending the outpatient clinic of National Guard Hospital in Riyadh. A total of 62 cases with PCOS and 40 healthy Saudi women were included in this study. Physical evaluation and laboratory investigations were carried out. Blood luteinizing hormone (LH), follicle stimulating hormone (FSH), estradiol (E2), dehydroepiandrosterone sulfate (DHEA-SO4), sex hormone-binding globulin (SHBG), total testosterone, prolactin, and progesterone were determined. To adjust for the potentially confounding effect of age and BMI, we carried out multivariate linear regression analyses for the association between each of the reproductive hormones and PCOS. RESULTS: Serum levels of FSH, SHBG, and progesterone were significantly lower in PCOS compared to controls (respective P values 0.001, 0.001, and 0.002), while LH/FSH and testosterone levels were higher in PCOS cases than in controls (P = 0.008 and 0.003, respectively). When multivariate linear regression analyses were carried out, LH/FSH and total testosterone were positively correlated with the disease [95% confidence interval (CI) = 0.02-0.35 and 0.02-0.17, respectively], whereas FSH, SHBG, and progesterone were negatively correlated with the disease (95% CI = -0.06 to 0.001, -0.01 to 0.001, and -0.17 to -0.03, respectively), independent of age and BMI. CONCLUSION: Our study suggests that regardless of the age and weight factors, Saudi patients with PCOS have higher levels of LH/FSH and total testosterone; but have lower levels of FSH, SHBG, and progesterone compared to controls. PMID- 24479023 TI - Birth order and psychopathology. AB - CONTEXT: Ordinal position the child holds within the sibling ranking of a family is related to intellectual functioning, personality, behavior, and development of psychopathology. AIM: To study the association between birth order and development of psychopathology in patients attending psychiatry services in a teaching hospital. SETTINGS AND DESIGN: Hospital-based cross-sectional study. MATERIALS AND METHODS: Retrospective file review of three groups of patients was carried out. Patient-related variables like age of onset, birth order, family type, and family history of mental illness were compared with psychiatry diagnosis (ICD-10) generated. STATISTICAL ANALYSIS: SPSS 13; descriptive statistics and one-way analysis of variance (ANOVA) were used. RESULTS: Mean age of onset of mental illness among the adult general psychiatry patients (group I, n = 527) was found to be 33.01 +/- 15.073, while it was 11.68 +/- 4.764 among the child cases (group II, n = 47) and 26.74 +/- 7.529 among substance abuse cases (group III, n = 110). Among group I patients, commonest diagnosis was depression followed by anxiety and somatoform disorders irrespective of birth order. Dissociative disorders were most prevalent in the first born child (36.7%) among group II patients. Among group III patients, alcohol dependence was maximum diagnosis in all birth orders. CONCLUSIONS: Depression and alcohol dependence was the commonest diagnosis in adult group irrespective of birth order. PMID- 24479024 TI - Overwork Among Residents in India: A Medical Resident's Perspective. AB - This paper argues that medical residents who do most of the hard work in big hospitals and medical colleges are overworked. A hierarchical organizational structure, staffing patterns, and fear of failure in examinations leads to overwork among residents going unreported. This can lead to poor academic performance and research work. Gaps in communication have serious implications on patient health. Undesirable practices like LAMA (leave against medical advice) also result from overwork. Issues of pay and contracts including mandatory service need to be looked into carefully. National and international recommendations on work hours have consistently been ignored. The solutions suggested are simple and easy to implement. PMID- 24479025 TI - A public health perspective of road traffic accidents. AB - Road traffic accidents (RTAs) have emerged as an important public health issue which needs to be tackled by a multi-disciplinary approach. The trend in RTA injuries and death is becoming alarming in countries like India. The number of fatal and disabling road accident happening is increasing day by day and is a real public health challenge for all the concerned agencies to prevent it. The approach to implement the rules and regulations available to prevent road accidents is often ineffective and half-hearted. Awareness creation, strict implementation of traffic rules, and scientific engineering measures are the need of the hour to prevent this public health catastrophe. This article is intended to create awareness among the health professionals about the various modalities available to prevent road accidents and also to inculcate a sense of responsibility toward spreading the message of road safety as a good citizen of our country. PMID- 24479026 TI - Dopa-responsive dystonia in a ten-year-old girl. AB - Children with recent onset dystonia and gait abnormalities may pose a diagnostic challenge. A ten-year-old, developmentally normal girl, presented with a six month history of gait abnormality and dystonia. Her complaint worsened as the day progressed. In view of typical diurnal variation of dystonia, a therapeutic challenge with levodopa/carbidopa was given and there was a dramatic response. Hence, a diagnosis of dopa-responsive dystonia (DRD) was made. DRD is an inherited disorder characterized by dystonia with diurnal variation and favorable response to levodopa/carbidopa. The inheritance is usually autosomal dominant, however, in some cases, autosomal-recessive inheritance is also seen. PMID- 24479027 TI - Poly-resistant Tuberculosis in an HIV-infected Child. AB - Drug-resistant tuberculosis (DR-TB) has been reported in India, but has been rarely documented in children. HIV co-infection has led to resurgence of tuberculosis (TB), making treatment even more difficult due to complex drug interactions. Poly-resistant TB is rare in children, especially in HIV-infected children. We report an HIV-infected child who developed poly-resistant TB (resistance to Streptomycin and Isoniazid) after 3 years of completion of anti tuberculosis treatment (ATT). His mother had also received ATT 3 years back. We conclude that DR-TB in HIV-infected children should be considered if the child had been treated with ATT in the past or there is contact with adults on second line ATT therapy. PMID- 24479028 TI - A case of pulmonary tuberculosis presenting as multiple nodular opacities on a chest x-ray. AB - Tuberculosis is widely prevalent in India. The presentation of pulmonary tuberculosis as multiple nodular opacities on a chest X-ray is very infrequent. We report such a case in a 30-year-old man, who presented with the complaints of dyspnea and responded to anti-tuberculosis treatment. PMID- 24479029 TI - Diabetes, Fever and Flank Pain: Is it Emphysematous Pyelonephritis? AB - Fever and flank pain in a diabetic patient should raise the suspicion of emphysematous pyelonephritis (EPN). The clinical course of EPN can be severe and life threatening, if not recognized and treated promptly. Gas shadows in the renal or perirenal region on plain X-ray, ultrasound, or computed tomography (CT) scan of the abdomen are the radiological features of EPN. However, CT scan of the abdomen is sine qua non for classification, treatment options, and prognosis. PMID- 24479030 TI - Salmonella hepatitis: an uncommon complication of a common disease. AB - Typhoid fever is a very common infectious disease of tropics, associated with high morbidity and mortality. Typhoid fever is often associated with hepatomegaly and mildly deranged liver functions; a clinical picture of acute hepatitis is a rare complication. We report a young patient who presented with fever and jaundice and was found to have acute hepatitis secondary to typhoid fever. Recognition of Salmonella hepatitis is of clinical importance as it can mimic acute viral hepatitis. Early institution of specific therapy can improve the prognosis in these patients. Typhoid fever is a very common infectious disease of tropics, associated with high morbidity and mortality. Typhoid fever is often associated with hepatomegaly and mildly deranged liver functions; a clinical picture of acute hepatitis is a rare complication. We report a young patient who presented with fever and jaundice and was found to have acute hepatitis secondary to typhoid fever. Recognition of Salmonella hepatitis is of clinical importance as it can mimic acute viral hepatitis. Early institution of specific therapy can improve the prognosis in these patients. PMID- 24479031 TI - Prazosin, scorpion sting and dr. Bawaskar. PMID- 24479032 TI - Common geriatrics cases seen by a general practitioner in an urban area of jharkhand state, India. PMID- 24479033 TI - Quality of water distribution system in a rural area of puducherry, India. PMID- 24479034 TI - The politics of medical practice license and its impact on primary care workforce: international developments and Indian perspective. AB - As a country India has to her credit the largest number of medical colleges in the world. More than 40,000 seats of MBBS (Bachelor of Medicine and Bachelor of Surgery) are available annually but only a fraction would enter into primary health care vocation. It is a matter of common perception and also of great concern that a large majority of young Indian doctors are not willing to serve the rural, remote and underserved population. An observation on human resource policies of several developed countries reveals interesting patterns. Beyond willingness and interest of the medical students and young doctors, there are real factors which prohibit their engagement with the health care delivery system in India, especially in the area of primary health care. PMID- 24479035 TI - Right to healthcare: the way forward. AB - From the Bhore Committee Report of 1946 to the present Universal Health Coverage (UHC) 2011, nothing much has changed in terms of health status in India. The overall health status continues to be dismal and disappointing. One factor that is mainly responsible for this state of affairs is that healthcare has not been realized as a right. If healthcare becomes a right, the state will become responsible and accountable to the people, for enhancing their health. If people are invoked into a sense of belonging to the health system and made to look at healthcare as their right, there is a strong possibility of a positive change in the overall health status of the people. The article looks at healthcare from the rights perspective and explores the methods in which it can be translated into reality. It tries to look at the moral basis of the right to healthcare. For healthcare to be achieved as a right, the state can no longer be a mute spectator of the predominant market forces dictating the healthcare delivery system. The article argues that translation of healthcare as a right is only possible if the state takes full responsibility to improve the health status of the people. PMID- 24479036 TI - Systematic Reviews and Meta-analysis: Understanding the Best Evidence in Primary Healthcare. AB - Healthcare decisions for individual patients and for public health policies should be informed by the best available research evidence. The practice of evidence-based medicine is the integration of individual clinical expertise with the best available external clinical evidence from systematic research and patient's values and expectations. Primary care physicians need evidence for both clinical practice and for public health decision making. The evidence comes from good reviews which is a state-of-the-art synthesis of current evidence on a given research question. Given the explosion of medical literature, and the fact that time is always scarce, review articles play a vital role in decision making in evidence-based medical practice. Given that most clinicians and public health professionals do not have the time to track down all the original articles, critically read them, and obtain the evidence they need for their questions, systematic reviews and clinical practice guidelines may be their best source of evidence. Systematic reviews aim to identify, evaluate, and summarize the findings of all relevant individual studies over a health-related issue, thereby making the available evidence more accessible to decision makers. The objective of this article is to introduce the primary care physicians about the concept of systematic reviews and meta-analysis, outlining why they are important, describing their methods and terminologies used, and thereby helping them with the skills to recognize and understand a reliable review which will be helpful for their day-to-day clinical practice and research activities. PMID- 24479037 TI - Differences between rural and urban primary care units in Turkey: implications on residents' training. AB - CONTEXT: Family practice training takes place at primary care based training centers linked to Education and Research State Hospitals in Turkey. There is a discussion if these units are adequate to train primary care staff and if the patients of these units reflect the applicants of primary care. AIMS: THE AIM OF OUR STUDY IS TO INVESTIGATE THE DEMOGRAPHIC CHARACTERISTICS, THE EFFECT OF DISTANCE ON PRIMARY CARE UTILIZATION, AND MOST COMMON DIAGNOSIS OF THE PATIENTS WHO APPLIED TO TWO DIFFERENT OUTPATIENT CLINICS: One urban and one rural. SETTINGS AND DESIGN: Study was conducted from the electronic health records of the patients applied to outpatient clinics of Ankara Diskapi Yildirim Beyazit Training and Research Hospital Department of Family Medicine between 1 January and 31 December 2009. RESULTS: Total number of patients applied to both of the outpatient clinics was 34,632 [urban clinic: 16.506 (47.7%), rural clinic: 18.126 (52.3%)]. Leading three diagnoses were upper respiratory tract infection (URTI), general medical examination (GME), and hypertension (HT) in the most common 10 diagnosis. CONCLUSION: In our study, the rural outpatient clinic is regarded as a primary care unit in the neighborhood of living area and the urban clinic as close to working environment. We found statistically meaningful differences in most common diagnosis, gender, age, and consultation time between the rural and urban clinics. According to our results, family practitioners' field training should take place at different primary care units according to sociodemographic characteristics of each country. PMID- 24479038 TI - Obesity and Its Cardio-metabolic Co-morbidities Among Adult Nigerians in a Primary Care Clinic of a Tertiary Hospital in South-Eastern, Nigeria. AB - BACKGROUND: Obesity once thought the medical problem of affluent countries now exist in Nigeria and has been described as a time bomb for the future explosion in the frequency of cardio-metabolic diseases. The most deleterious health consequences of obesity are on the cardiovascular system and associated disorder of lipid and glucose homeostasis. AIM: This study was designed to determine the magnitude of obesity and its cardio-metabolic co-morbidities among adult Nigerians in a primary care clinic of a tertiary hospital South-Eastern, Nigeria. MATERIALS AND METHODS: A cross-sectional study carried out on 2391 adult Nigerians who were assessed for obesity using body mass index (BMI) criterion. 206 patients who had BMI >=30kg/m(2) were screened for cardio-metabolic co morbidities. The data collected included basic demographic variables, weight, height, blood pressure; fasting plasma glucose and lipid profile. RESULTS: The prevalence of obesity was 8.6%. Grade I obesity (67.5%) was the most common pattern; others included grade II obesity (23.3%) and grade III obesity (9.2%). Hypertension (42.7%) was the most common cardio-metabolic morbidity. Others included low HDL-cholesterol (22.8%), diabetes mellitus (15.1%), high triglyceride (12.6%), high total cholesterol (9.2%), and high LDL-cholesterol (6.8%). CONCLUSION: Obesity and its cardio-metabolic morbidities exist among the study population. Anthropometric determination of obesity and screening for its associated cardio-metabolic co-morbidities should constitute clinical targets for intervention in primary care clinics. PMID- 24479039 TI - Foot care knowledge and practices and the prevalence of peripheral neuropathy among people with diabetes attending a secondary care rural hospital in southern India. AB - BACKGROUND: Diabetes mellitus is a multifaceted disease and foot ulceration is one of its most common complications. Poor foot care knowledge and practices are important risk factors for foot problems among people with diabetes. AIMS: To assess the knowledge and practices regarding foot care and to estimate the proportion of people with peripheral neuropathy among people with diabetes. SETTINGS AND DESIGN: The cross-sectional study was conducted in 212 consecutive diabetes patients attending the out-patient department of a rural secondary care hospital. MATERIALS AND METHODS: A questionnaire which included demographic details, knowledge questionnaire, and Nottingham assessment of functional foot care was administered. The Michigan Neuropathy Screening Instrument was used to identify peripheral neuropathy. STATISTICAL ANALYSIS USED: Descriptive analysis with frequency distribution for knowledge and practice scores, univariate analysis, and multiple logistic regressions to find significant variables associated with good knowledge and practice scores. RESULTS: About 75% had good knowledge score and 67% had good foot care practice score. Male gender (OR 2.36, 95% CI 1.16-4.79), poor education status (OR 2.40, 95% CI 1.19-4.28), and lesser duration of diabetes (OR 2.24, 95% CI 1.15-4.41) were significantly associated with poor knowledge on foot care. Poor knowledge was associated with poor foot care practices (OR 3.43, 95% CI 1.75-6.72). The prevalence of neuropathy was 47% (95% CI 40.14-53.85) and it was associated with longer duration of the disease (OR 2.18, 95% CI 1.18-4.04). CONCLUSION: There exist deficiencies in knowledge and practices regarding foot care. Male gender, low education, and lesser duration of diabetes are associated with poor knowledge scores. The prevalence of diabetic peripheral neuropathy is high. PMID- 24479040 TI - Seroprevalence of chikungunya in southern odisha. AB - BACKGROUND: The emergence of chikungunya (CHIK) infection was observed in Odisha, India in 2006. Thereafter many cases with symptoms suggestive of CHIK were reported from different districts of Southern-Odisha. This study was aimed to know the seroprevalence, clinical presentations and seasonal trends of CHIK infection in this region. MATERIALS AND METHODS: This study was conducted in a tertiary hospital of this region. Serum samples received in the Department of Microbiology from various districts of Southern-Odisha from April 2011 to March 2012 were included in the study. The samples were tested for CHIK and dengue Immunoglobin M (IgM) antibodies by enzyme-linked immunosorbent assay and malaria parasite by immunochromatographic test (ICT) method. RESULTS: Out of the 678 serum samples tested, 174 were positive for CHIK, 15 for dengue and two samples were positive for both CHIK and dengue IgM antibodies. The most affected age group was 16-45 years. Females were more affected than males. CONCLUSION: The seroprevalence of CHIK among the suspected cases was 25.7%. Co-infection with CHIK and dengue was found to be 1.15%. The infection had spread to new areas during this outbreak. PMID- 24479041 TI - Infant rearing practices in South India: a longitudinal study. AB - BACKGROUND: Rearing practices are a major determinant of nutritional and health status of infants. Therefore these practices need to be better understood. OBJECTIVES: To find out infant rearing practices in the study area. MATERIALS AND METHODS: A longitudinal study was conducted on a birth cohort of 194 infants. Information on rearing practices and anthropometric measurements were recorded every month for a period of 1 year. RESULTS: Only 67 (34.5%) newborns were breast fed within half an hour of delivery. Prelacteal feeds was given to 65 (33.5%) newborns and this was seen more among home deliveries (P=0.018). Demand feeding was practiced by 169 (87.1%) mothers. Exclusive breast feeding (EBF) for 6 months was practiced by 81 (41.7%) mothers. Bottle feeding was seen in 7 (3.6%) cases. Weight gain during infancy was found to be maximum when infants were EBF for 6 months (P<0.001) and weaned with semi-solid and solid diet alone in the following 6 months (P=0.002). Gain in all anthropometric measurements was more in the initial 6 months of infancy compared to latter. Four (2.1%) infants were malnourished. Oil massage before bath was practiced by 189 (97.4%) mothers. Over 50% mothers practiced oil application to eyes or ears of infants. Delayed initiation of bath (beyond 1week) was seen in 15 (7.7%) cases. CONCLUSION: Faulty rearing practices need to be corrected in order to improve the health status of infants. PMID- 24479042 TI - Seroprevalance of rubella in women with bad obstetric history. AB - Rubella is a common cause of rash and fever during childhood. However, its public health importance relates to the teratogenic effects of primary rubella infection occurring in pregnant women, which can lead to fetal death with spontaneous abortion or to congenital defects in surviving infants. Most of the cases are asymptomatic and difficult to diagnose on clinical grounds. Detection of specific IgM antibodies by the enzyme-linked immunosorbent assay (ELISA) technique is a useful method for diagnosis. The present study was conducted on 180 pregnant women attending antenatal clinics at Government Maternity Hospital, Tirupati. All the serum samples were tested for Rubella-specific IgM antibodies. A seropositivity of 12.67% was observed among cases with bad obstetric history and 6.67% in normal pregnant women. Within the test group, high sero-positivity (13.33%) was observed in women with repeated abortions followed by in cases of intrauterine death (12.73%). The results indicate high prevalence of rubella in our population. All antenatal cases should be routinely screened for rubella, so that early diagnosis will help in proper management and fetal outcome. PMID- 24479043 TI - Evaluation of paperless partogram as a bedside tool in the management of labor. AB - INTRODUCTION: The partogram has been heralded as one of the most important advances in modern obstetric care. However, some healthcare practitioners, especially in high-income countries, have questioned its effectiveness. The purpose of this study is to evaluate prospectively the use of a paperless partogram as a bedside tool in the management of labor. MATERIALS AND METHODS: Women were invited to participate in the trial if they were at 36 to 42 weeks of gestation, and carrying a singleton pregnancy, with a cephalic presentation. All women who met the criteria and gave informed consent were included in the study till the required sample size of 91 was obtained. Progress of labor was monitored on the basis of Alert estimated time of delivery (ETD) and Action ETD. At the time of the Action ETD, if woman had not yet delivered, a diagnosis of abnormal labor was made and arrangements were made for emergency obstetric care. RESULTS: Out of 91 women who participated in the study 55 (60%) were primigravida and 36 (40%) were multipara. The mean age of the participants was 25.36 years and the mean duration gestation was 281.9 days. The mean duration for delivery after Alert ETD was 4.3 hours. In our study, out of 91 participants, labor was induced only in 13% of the cases. The mean duration for delivery after Alert ETD was 4.7 +/- 1.9 hours in the primigravida and 3.7 +/- 1.8 hours in multipara, but these differences were not statistically significant. CONCLUSION: In our study, the paperless partogram was found to be convenient and effective in the management of labor. The mean duration for delivery after Alert ETD was 4.3 hours in our study, which was similar to the World Health Organization's (WHO) recommendation for partograms, with a four-hour action line, denoting the timing of intervention for prolonged labor. PMID- 24479044 TI - Evaluation of immunization coverage in the rural area of pune, maharashtra, using the 30 cluster sampling technique. AB - BACKGROUND: Infectious diseases are a major cause of morbidity and mortality in children. One of the most cost-effective and easy methods for child survival is immunization. Despite all the efforts put in by governmental and nongovernmental institutes for 100% immunization coverage, there are still pockets of low coverage areas. In India, immunization services are offered free in public health facilities, but, despite rapid increases, the immunization rate remains low in some areas. The Millennium Development Goals (MDG) indicators also give importance to immunization. OBJECTIVE: To assess the immunization coverage in the rural area of Pune. MATERIALS AND METHODS: A cross-sectional study was conducted in the field practice area of the Rural Health Training Center (RHTC) using the WHO's 30 cluster sampling method for evaluation of immunization coverage. RESULTS: A total of 1913 houses were surveyed. A total of 210 children aged 12-23 months were included in the study. It was found that 86.67% of the children were fully immunized against all the six vaccine-preventable diseases. The proportion of fully immunized children was marginally higher in males (87.61%) than in females (85.57%), and the immunization card was available with 60.95% of the subjects. The most common cause for partial immunization was that the time of immunization was inconvenient (36%). CONCLUSION: Sustained efforts are required to achieve universal coverage of immunization in the rural area of Pune district. PMID- 24479045 TI - Determinants of utilization of antenatal care services in rural lucknow, India. AB - BACKGROUND: Antenatal care services are the first steps towards ensuring the health of mothers and the newborn. This is the key component for achieving Millennium Development Goals by 2015. But India's performance continues to be poor in providing antenatal care services to its huge population, particularly in the rural areas. OBJECTIVE: To assess the determinants of utilization of antenatal services by rural beneficiaries in Lucknow, a district of north India. MATERIALS AND METHODS: The study, cross-sectional in design, was conducted from August 2009 to July 2010. Multistage random sampling was used for selecting villages. A total of 352 recently delivered women were selected following systematic random sampling. Logistic regression was used to find out the determinants of three antenatal care services. RESULTS: Overall, 85.5% of the beneficiaries surveyed were found to receive at least three antenatal care services from any health facility. Community health centre was the most common source for such care. Significant difference was found between beneficiaries who took three antenatal care visits and who did not in terms of age, socio economic status, and timing of registration. On multiple regression, only age (OR = 2.107, 95% CI = 1.132 - 3.923) and timing of registration (OR = 2.817, 95% CI = 1.487 - 5.338) were found to be the predictors for three antenatal care visits. CONCLUSION: Intervention should be focused on young and late registered women for ensuring sufficient care during pregnancy. PMID- 24479046 TI - Experiences of junior public health nurses in delivery of maternal healthcare services to tribal women in kerala. AB - BACKGROUND: The maternal health care indicators are better in Kerala even in the tribal districts than the national averages. The tribal population scattered in hilly areas or other difficult terrains heavily constraints the MPHW female (Junior Public Health Nurse in Kerala) from providing services. The study was intended to describe the experiences of the Junior Public Health Nurses (JPHN) in delivery of maternal health care services to tribal women in Kerala. MATERIALS AND METHODS: JPHNs posted in Thariode panchayat under the sub centers of CHC Thariode in Wayanad district of Kerala. This is a Qualitative study with in-depth interview of the JPHNs using an interview guide. RESULTS AND INFERENCES: The various difficulties experienced by JPHNs in delivering the services in tribal areas were lack of sufficient time for field work, travel difficulties faced due to the hilly terrain and lack of public transport facilities, more time spent on travel than actual time spent for field work, cultural and language barriers and extra inputs put up in service delivery to tribal women. CONCLUSION AND RECOMMENDATIONS: The JPHNs serving in tribal areas overcame various constraints in service delivery like hilly terrain, limited public transport facilities, long hours spent in travelling, cultural and language barriers by putting in extra effort, time and personal money to fulfill their responsibilities. It is suggested that the JPHNs be given compensatory off to complete records and extra remuneration to cover their out of pocket expenditure on travelling to difficult areas. PMID- 24479047 TI - Socio-demographic and Racial Differences in Acute Coronary Syndrome: Comparison between Saudi and South Asian Patients. AB - INTRODUCTION: Acute coronary syndrome (ACS) is the leading cause of death in Saudi Arabia as elsewhere. Although, many studies found that South Asians had increased rates of ACS, others did not. The aim of the study is to explore the extent of difference between South Asians and Saudi presentation and risk factors of ACS patients. MATERIALS AND METHODS: All patients who were diagnosed as having acute myocardial infarction (AMI) based on World Health Organization (WHO) criteria in 6 month period were included in the study. RESULTS: A total of 190 patients confirmed ACS were included; 121 (63.70%) were Saudi, 50 (26.3%) were South Asians, and 19 (10.0%) were other Arab nationalities. The mean age was 53.9 (SD 14.6). Out of the total South Asians 82% had normal body mass index (BMI) (P = 0.000). Saudi patients were the lowest of the three groups who smoked cigarette and/or shisha (26.6%; P = 0.000). 52.9% of Saudi patients were diabetics and 41.3% were hypertensive (P = 0.004). More South Asians were presented with chest pain (94% vs 76%). DISCUSSION: South Asians had a double rate of ACS incidence; they were younger, lower socio-economic status, more cigarette smokers, and less diabetics and hypertensive than other patients. An association between the apolipoprotein E (apoE) genotype with the incidence of ACS in young South Asian is proposed. CONCLUSION: South Asians had double rate of ACS incidence; they were younger, lower socio-economic status, more cigarette smokers, and less diabetics and hypertensive than other patients. PMID- 24479048 TI - An exploratory study on socio economic status scales in a rural and urban setting. AB - BACKGROUND: There are many different scales to measure socioeconomic status (SES). The present study was conducted with the objective to compare the most commonly used SES in rural and urban setting. MATERIALS AND METHODS: This exploratory study was conducted in the rural and urban field practice area of a medical college situated in Bangalore for a period of 3 months between January and April 2010. STATISTICAL ANALYSIS USED: To measure the agreement between the scales spearman's rank correlations was applied. RESULTS: A total of 120 families were included in the study. Among the 60 families surveyed at rural setting, it was observed that, majority 40 (67%) belonged to high class when the Standard of Living Index (SLI) scale was applied. Among the 60 families surveyed at urban setting, majority 30 (50%) belonged to high class when the SLI scale was applied. CONCLUSIONS: The SLI scale gives a more accurate and realistic picture of the SES of the family and hence should be the scale recommended for classification of SES in urban and rural setting. PMID- 24479049 TI - Health impact of supplying safe drinking water on patients having various clinical manifestations of fluorosis in an endemic village of west bengal. AB - BACKGROUND: Excessive fluoride in drinking water causes dental, skeletal and non skeletal fluorosis which is encountered in endemic proportions in several parts of the world. The World Health Organization (WHO) guideline value and the permissible limit of fluoride as per the Bureau of Indian Standards (BIS) is 1.5 mg/L. Studies showed that withdrawal of sources identified for fluoride, often leads to reduction of fluoride in the body fluids (re-testing urine and serum after a week or ten days) and results in the disappearance of non-skeletal fluorosis within a short duration of 10-15 days. OBJECTIVE: To determine the prevalence of signs and symptoms of suspected dental, skeletal and non-skeletal fluorosis along with food habits, addictions and use of fluoride-containing toothpaste among participants taking water with fluoride concentration above permissible limit and to assess the changes in clinical manifestations of the above participants after consumption of safe drinking water with fluoride concentration below permissible limit. MATERIALS AND METHODS: A longitudinal intervention study was conducted from October 2010 to December 2011 in a village selected randomly in Purulia District of West Bengal which is endemic for fluorosis. Thirty-six families with 104 family members in the above village having history of taking unsafe water containing high level of fluoride were selected for the study. The occurrence of various dental, skeletal and non skeletal manifestations of fluorosis along with food habits, addictions and use of fluoride-containing toothpaste among the study population was assessed; the impact of taking safe water with fluoride concentration below permissible limit from a supplied community filter on these clinical manifestations was studied by follow-up examination of the above participants for six months. The data obtained is compared with the collected data from the baseline survey. RESULTS: The prevalence of signs and symptoms of dental, skeletal and non-skeletal fluorosis was (18.26%), (18.26-43.26%) and (12.49-38.46%) among the study population. Withdrawal of source(s) identified for fluoride by providing community filters supplying safe water along with nutritional interventions lead to 1.92% decrease of manifestation of dental fluorosis, 2.88-18.26% decrease of manifestations of skeletal fluorosis and 3.8-5.77% decrease in manifestations of non-skeletal fluorosis within six months. Following repeated motivation of participants during visit there was also 2.88% decrease in the usage of fluoride-containing toothpaste, 4.81% decrease in consumption of black lemon tea, supari and tobacco which are known sources of fluoride ingestion in our body. CONCLUSION: Increased prevalence of dental, skeletal and non-skeletal fluorosis was found among the study population. Withdrawal of sources(s) identified for fluoride by supplying community filter, dietary restriction and other nutritional interventions led to decrease of manifestations of the three types of fluorosis within six months. The government should play a vital role in ensuring drinking water safety at the household and community level by supplying domestic filters at affordable costs and community filter along with nutritional intervention to the fluorosis affected villages on a priority basis to mitigate the problem. PMID- 24479050 TI - A day in the life of a british general practitioner. AB - General Practitioners are key providers of patient related services in National Health Service (NHS) in United Kingdom. The general practitioner have enjoyed enormous trust from the general public. Author shares his day today work giving an interesting insight into the model of care general practitioners engage with in UK. PMID- 24479051 TI - Drug Rash with Eosinophilia and Systemic Symptoms Syndrome Due to Anti-TB Medication. AB - Drug rash with eosinophilia and systemic symptoms (DRESS) syndrome is a severe, idiosyncratic, multi-system reaction characterized by the clinical triad of fever, rash, and internal organ involvement. The mortality rate is estimated to be 8%, especially among patients with liver involvement, so early recognition is imperative. Drugs commonly associated with the development of DRESS syndrome include anticonvulsants, long-acting sulfonamides, and anti-inflammatory medications; however, there are no reported cases implicating anti-tuberculosis (anti-TB) medications. We report a case of DRESS syndrome from anti-TB therapy. A 68-year-old male with pulmonary TB presented with pruritic skin eruption and sore throat, 8 weeks after starting Rifampin, Isoniazid, Pyrazinamide, and Ethambutol (RIPE) therapy. He takes metformin and glyburide for diabetes. Physical exam was significant for diffuse, exfoliative erythematous macules with target lesions involving the entire skin surface, without mucosal involvement. Laboratory data was significant for mild transaminitis and new onset eosinophilia. Given suspicion of drug eruption, RIPE therapy was discontinued. Skin biopsy confirmed erythema multiforme. Despite discontinuation of the implicated medications, eosinophilia and transaminitis continued to worsen, and so systemic corticosteroids were started. After 4 weeks of discontinuation of RIPE therapy, the cutaneous eruption resolved and laboratory data returned to normal. The patient is finishing course of anti-TB with cycloserine and moxifloxacin. Upon follow up as outpatient, the rash was resolving and disappeared in 1 month. DRESS syndrome is always considered when there is high eosinophil counts and multisystem involvement with skin eruptions. It can be potentially life threatening with certain drugs and infectious agents in predisposed individuals. It is imperative to discontinue the causative medication and avoid re-exposure. PMID- 24479052 TI - Acute renal failure due to rhabdomyolysis following a seizure. AB - Acute renal failure, oliguric or nonoliguric, is the most common complication of rhabdomyolysis. Rhabdomyolysis should be suspected in patients presenting with states of increased muscular activity, such as seizures, agitation, strenuous muscle exercise, or dystonia. We report an adult who developed acute renal failure associated with rhabdomyolysis following a seizure. The patient made complete recovery with hemodialysis. This report illustrates importance of early recognition of rhabdomyolysis following a seizure episode to prevent the risk of acute renal failure. PMID- 24479053 TI - Early diagnosis of a large vesical calculus complicating pregnancy. AB - Vesical calculus-complicating pregnancy is rare. This is a case report of a large vesical calculus-complicating pregnancy. The early diagnosis and appropriate surgical management of the large vesical calculus prevented complications like recurrent urinary tract infections and obstructed labor. It enabled the mother to have an uneventful vaginal delivery. PMID- 24479054 TI - Guillain-barre syndrome in pregnancy: an unusual case. AB - Guillain-Barre syndrome (GBS) is rare in pregnancy with an estimated incidence between 1.2 and 1.9 cases per 100,000 people annually, and it carries a high maternal risk. We report a 29-year-old primigravida who had pain and progressive heaviness of both lower limbs in her third trimester of pregnancy. The attending gynecologist ascribed these symptoms to ongoing pregnancy. The intrapartum period (lower segment caesarian section) passed uneventfully. On third postpartum day, the patient developed weakness of all the four limbs. A detailed history and physical examination pointed toward GBS although there was no antecedent infective episode. Subsequent nerve conduction velocity studies and cerebrospinal fluid analysis confirmed GBS. All other investigations including electrolytes were normal. The patient improved without the introduction of immunomodulating therapy. PMID- 24479055 TI - Oculoauriculovertebral spectrum with radial anomaly in child. AB - Oculoauriculovertebral spectrum (OAVS) or Goldenhar syndrome is a wide spectrum of congenital anomalies that involves structures arising from the first and second branchial arches. It is characterized by a wide spectrum of symptoms and physical features. These abnormalities mainly involve the cheekbones, jaws, mouth, ears, eyes, or vertebrae. Other conditions with ear and/or radial involvement, such as, the Nager syndrome, Holt-Oram syndrome, Radial-renal syndrome, facioauriculoradial dysplasia, Fanconi anemia, and Vertebral, Anal atresia, Cardiac, Trachea, Esophageal, Renal, and Limb (VACTERL) association should be considered for differential diagnosis. Here we report a child who had facial asymmetry, microsomia, microtia, congenital facial nerve palsy, conductive hearing loss, skin tags, iris coloboma, and preaxial polydactyly. PMID- 24479056 TI - Inadvertent Intramuscular Administration of High Dose Bacillus Calmette Guerin Vaccine in a Pre-term Infant. AB - This case report examined the natural course of reaction after accidental intramuscular administration of high dose Bacille Calmette-Guiotarin (BCG) vaccine into the anterolateral aspect of thigh of a pre-term infant as a part of routine vaccination instead of intra-dermal injection into the arm. There is no consensus on the best management of this complication, although in this case healing was prolonged but was spontaneous without anti-tubercular chemotherapy. PMID- 24479057 TI - Atypical Presentation of Allergic Bronchopulmonary Aspergillosis: An Unusual Cause of Difficult-to-Treat Asthma. AB - Allergic Bronchopulmonary aspergillosis (ABPA) commonly presents with persistently uncontrolled asthma, despite of the therapy with highest possible anti-asthma medications. Most common cause of ABPA is Aspergillus fumigates. Hence, ABPA is one of the important differential diagnoses of difficult-to-treat asthma. Atypical presentation of ABPA misleads the diagnosis and asthma remains uncontrolled. Here we present such a case of 28-year-old non-smoker, normotensive male office worker who presented with persistent cough with scanty white, mucoid expectoration and gradually progressive breathlessness with bilateral crackles for last two years. Diagnosis of asthma was made based on clinical evidences and spirometry. Anti-asthma treatment was started and gradually stepped up. Further evaluation was done due to lack of clinical improvement, and diagnosis of ABPA was made from bilateral reticulonodular lesions on HRCT thorax, increased levels of serum IgE and Aspergillus fumigates specific IgE, and positive aspergillin skin test. Oral prednisolone and itraconazole were started with anti-asthma medications. PMID- 24479058 TI - Nocturnal frontal lobe epilepsy presenting as excessive daytime sleepiness. AB - Excessive daytime sleepiness (EDS) is common in the general population. Etiologies include insufficient sleep and primary sleep disorders. Due to its high prevalence, physicians often overlook EDS as a significant problem. However, EDS may also be the presenting symptom of seizures, in particular Nocturnal Frontal Lobe Epilepsy (NFLE). Due to the clinical similarity between the nocturnal behaviors of NFLE and parasomnias, and poor patient-related history, NFLE remains a challenging diagnosis. We report the case of a patient with NFLE who presented with a primary complaint of EDS, and discuss the differential diagnosis and evaluation of patients with EDS associated with nocturnal behaviors. In the context of a patient presenting with EDS and stereotyped nocturnal events, clinical suspicion should be high for NFLE. PMID- 24479059 TI - Purple urine bag syndrome. AB - Purple urine bag syndrome (PUBS) is rare disease entity, occurs predominantly in constipated women, chronically catheterized and associated with bacterial urinary infections that produce sulphatase/phosphatase. The etiology is due to indigo (blue) and indirubin (red) or to their mixture that becomes purple. We present a case report of this rare phenomenon occurring in an 86-year-old woman. PMID- 24479060 TI - Meckel gruber syndrome: report of two cases with review of literature. AB - Meckel Gruber syndrome (MKS) is a lethal, autosomal, recessive, multisystemic disorder, associated with mutations affecting ciliogenesis. Since the time it was first reported; only 200 cases have been reported. From January 2004 to December 2010, we evaluated 268 fetal autopsies in our institute, in the Department of Pathology; two of these fetuses were diagnosed as MKS. MKS is characterized by occipital meningoencephalocele, cystic kidneys, postaxial polydactyly, and fibrosis in the liver. MKS cases show genetic heterogeneity. MKS results in 100% fetal or neonatal mortality. As MKS has a high risk (25%) of recurrence; parents should be counseled for future pregnancies. PMID- 24479061 TI - Recurrent hydrocoele. AB - Hydrocele is a common cause of scrotal swelling in general practice and is caused by a patent space in the tunica vaginalis. Treatment is often conservative unless the hydrocele grows to a critical size that leads to discomfort or difficulty in walking, in which case drainage is necessary. Depending on the communication of the tunica vaginalis with the peritoneal cavity and other coexistent morbidities, hydrocoele may recur despite repeated drainage posing a problem to management in general practice. We hereby presented a 72-year male with a huge hydrocoele that recurred despite repeated drainage and hernia sac repair, arousing thoughts on this subject and discussions as to the most appropriate management. PMID- 24479062 TI - Two case reports indicating the dilemma in diagnosing lupus cerebritis. AB - Systemic Lupus Erythematosus (SLE) is a connective-tissue disorder commonly affecting females of reproductive age group. Lupus Cerebritis is a serious neurological complication encountered in a good percentage of SLE cases. In this report, we discuss two Lupus Cerebritis patients, who were successfully diagnosed and treated. The first case, presented with generalized seizure, severe metabolic acidosis, and shock, with a history of fever of one-month duration. The second case manifested with an attack of generalized seizure after suffering from low grade intermittent fever and joint pains for a duration of one-and-a-half months. Central Nervous System (CNS) involvement in SLE is caused by an inflammatory response of the autoimmune system, precipitated by an increased concentration of cytokines. Prompt identification of Lupus Cerebritis is extremely difficult, mainly because there is no single laboratory or radiological confirmatory test. Assessment of the clinical features and neurological signs, along with detection of antibodies in the serum and cerebrospinal fluid are necessary to arrive at a diagnosis. Lupus Cerebritis should be included in the provisional diagnosis of a female patient of reproductive age group, who presents with complicated neurological manifestations and with no clear-cut clinical, pathological, or image finding. PMID- 24479063 TI - Healthcare and medical education reforms in India: What lies ahead? AB - Since India became a republic in 1951, there has been steady progress on all fronts of human and economic development. India has matured as the largest democracy in the world and and also earned the reputation of being one of the fastest growing economies during last two decades. However, the country remains challenged with several pressing issues which includes maintaining good health for second largest population in world. As a signatory of Alma Ata declaration, provision of primary health care has remained a priority area in the planning process. Although the targets of "Health for all by 2000" were missed, several programs are under implementation targeted towards achieving MDGs (Millennium Development Goals). Recent years shall be marked as very eventful from the perspective of health care reforms in India. For the first time a basic framework for Universal Health Coverage (UHC) has been proposed. A brief review of the programs and policies rolled out recently, provides us an insight into the future direction of the dynamic health system of India. PMID- 24479064 TI - Open access: the changing face of scientific publishing. AB - The debate on open access to scientific literature that has been raging in scholarly circles for quite some time now has been fueled further by the recent developments in the realm of the open access movement. This article is a short commentary on the current scenario, challenges, and the future of the open access movement. PMID- 24479065 TI - Historical evolution and present status of family medicine in sri lanka. AB - Sri Lankan health system consists of Allopathic, Ayurvedic, Unani, and several other systems of medicine and allopathic medicine is catering to the majority of the health needs of the people. As in many other countries, Sri Lankan health system consists of both the state and the private sector General practitioners, MOs in OPDs of hospitals and MOs of central dispensaries, provide primary medical care in Sri Lanka. Most of the general practices are solo practices. One does not need postgraduate qualification or training in general practice to start a general practice. There is no registered population for any particular health care institution in the state sector or in the private sector and there is no strict referral procedure from primary care to secondary or tertiary care. Family doctors have been practicing in Sri Lanka for well over 150 years. The first national organization of general practitioners was Independent Medical Practitioner (IMPA)'s organization which was founded in 1929 and the College of General Practitioners of Sri Lanka was founded in 1974. College conducts its own Membership Course and Examination (MCGP) since 1999. Family Medicine was introduced to undergraduate curriculum in Sri Lanka in early 1980s and now almost all the medical faculties in the country have included Family Medicine in their curricula. In 1979, General Practice/Family Medicine was recognized as a specialty in Sri Lanka by the postgraduate institute of Medicine. Diploma in Family Medicine (DFM) and MD Family Medicine are the pathways for postgraduate training in Sri Lanka. At present 50 to 60 doctors enroll for DFM every year and the country has about 20 specialists (with MD) in Family Medicine. The author's vision for the future is that all the primary care doctors to have a postgraduate qualification in Family Medicine either DFM, MD, or MCGP which is a far cry from the present status. PMID- 24479066 TI - Family medicine specialty in singapore. AB - Family Medicine in Singapore has its roots in a generalist ethos and found its origin as a counter culture movement to the increasing sub-specialisation of medicine which resulted in a complex healthcare system where that patients are often cared for by multiple specialists potentially resulting in fragmentation of care. The aim of the discipline of Family Medicine was to train and develop more generalist physicians so as to promote holistic care. Family physicians are the largest pool of generalists who are trained to provide general medical care to patients in the context of the person, the family and the community that they live in. PMID- 24479067 TI - Hyfrecation for recalcitrant nongenital warts. AB - BACKGROUND: Verruca vulgaris is a common skin condition in general practice, which often resolves without treatment. For lesions needing treatment, they often persist despite repeated treatment and become recalcitrant warts. Hyfrecation is a form of electrosurgery which has been used in treating common and recalcitrant warts. OBJECTIVES: This article describes the history and mechanisms of hyfrecation and also reviews available evidence on the effectiveness of hyfrecation for recalcitrant nongenital warts. DISCUSSION: Hyfrecation provides controlled tissue destruction with carbonized desiccated wounds which are ideal for eradicating recalcitrant warts. A systematic literature search revealed very minimal, if any, good-quality clinical studies that compare the efficacy of hyfrecation against other treatments (i.e., liquid nitrogen) in treating recalcitrant nongenital warts. Other studies reported the benefits of hyfrecation for genital warts. The author illustrates with a case scenario, the benefits of hyfrecation in treating nongenital warts, and thereby, advocates its wider use in general practice. PMID- 24479068 TI - Structured printed referral letter (form letter); saves time and improves communication. AB - Referral of patients to hospitals, specialists and other institutions is an essential part of primary health care. Patients are referred to specialists when investigation or therapeutic options are exhausted in primary care or when opinion or advice is needed from them. Referral has considerable implications for patients, health care system and health care costs. Good communication between primary and secondary care is essential for the smooth running of any health care system. Referral and reply letters are the sole means of communication between doctors most of the time and breakdown in communication could lead to poor continuity of care, delayed diagnoses, polypharmacy, increased litigation risk and unnecessary testing. A referral letter also helps to avoid patient dissatisfaction and loss of confidence in family physician. Studies of referral letters have reported that specialists are dissatisfied with their quality and content. Inclusion of letter writing skills in the medical curriculum, peer assessment and feedback have shown to improve the quality of referral letters. Form letters have shown to enhance information content and communication in referral process. In Sri Lanka referral letters are usually hand written and frequent complaints are that these letters do not contain adequate information and retrieval of information is a problem due to poor legibility and clarity. Sometimes Primary care doctors refer patients to hospitals and specialists with only verbal instructions. To address these short comings this form letter was introduced. Based on the guidelines and systematic review of published articles, items of information to be included were decided. Printed forms of the letter are kept in the practice and the doctor has to just fill up relevant information under each heading. The objectives of introducing this structured referral letter was to improve the quality and standard of referral letters and save time for both general practitioners and specialists. PMID- 24479069 TI - HIV in Females: A Clinico-epidemiological Study. AB - BACKGROUND: Human Immunodeficiency Virusinfected women account for almost half the number of cases of HIV worldwide. Despite reduction in HIV prevalence among the population, the percentage of Indian women contracting the disease seems to have increased. The social implications are also different in females. MATERIALS AND METHODS: This prospective observational study was conducted from September 2009 to July 2011 at tertiary care hospitals attached to the Kasturba Medical College Mangalore, on a group of 200 HIV-positive patients. Patients above 18 years of age diagnosed with HIV as per National AIDS Control Organisation guidelines were included in the study. Clinical profile among women and men was compared with respect to clinical presentation, disease detection, CD4 count and response of family and society. RESULTS: Clinical presentation was similar among both men and women. Eighty-one percent men had promiscual sexual exposure, 19% of women had so. Males were identified to be HIV-positive earlier than their spouse (tested later), time lag being 27.6 weeks. After detection of positivity 77% of females felt being less cared for by the in-laws. CD4 count less than 50 was detected in more number of females as compared to men (11% females and 1% males). Death of spouse was seen more often in females (among 35% of women and 11% of men). CONCLUSION: Most of the females were likely to acquire infection from their spouse. Females tend to seek and get medical attention at the late stage of disease as compared to men. HIV in females has different social implications which includes discrimination within the family. PMID- 24479070 TI - Comparison of cold water sponging and acetaminophen in control of Fever among children attending a tertiary hospital in South Nigeria. AB - BACKGROUND: A wide range of childhood illnesses are accompanied by fever, leading to varied attempts at treatment by caregivers at home before coming to a hospital. Common modalities of treatment include use of antipyretics and physical methods such as cold water sponging, fanning and removal of clothing. These treatment modalities have been received with varied attitudes among physicians and the scientific community. This study was to assess the efficacy of both modalities in first-line management of fever in our area. OBJECTIVES: The main aim of the study is to compare the effectiveness of cold water sponging with that of oral paracetamol in the treatment of fever in children attending the University of Calabar Teaching Hospital, Calabar. SUBJECTS AND METHODS: This is a randomized clinical trial. Eighty-eight children aged 12-120 months who presented to the Children Outpatient Clinic (CHOP) and the Children Emergency Room (CHER) of University of Calabar Teaching Hospital, Calabar, with acute febrile illness and axillary temperatures spanning >= 38.0-40.0 degrees C. All children within the age limit whose caregivers gave consent were recruited into the study and were randomized to receive either cold water sponging or oral paracetamol. Axillary temperature, pulse rate, respiratory rate and assessment of discomforts (crying, shivering, goose pimples and convulsions) were recorded every 30 min for 2 h. The results were analyzed using the SPSS statistical software and have been presented in the tables. RESULTS: Cold water sponging was very effective in temperature reduction within the first 30 min, with 29 (70.73%) having their temperature reduced to within normal limits. This declined to 12 (29.26%) at 60 min and 4 (10.53%) at 120 min, with the mean temperature differences from the baseline value following the same trends (1.63 degrees C by 30 min, 0.91 degrees C by 60 min and 0.39 degrees C by 120 min). When compared with paracetamol, cold water sponging was more effective in temperature reduction within the first 30 min (P = 0.000), with the difference in effect at 60 min less significant between these two groups (P = 0.229). Paracetamol demonstrated a gradual and sustained reduction in temperature with the proportions of afebrile children in this group increasing from 7 (16.27%) at 30 min to 33 (78.57%) at 120 min. The mean temperature differences from the baseline value also showed the same trend. Children who received cold water sponging had more discomforts compared with those who received only oral paracetamol. CONCLUSIONS: It is concluded that cold water sponging, although producing rapid reduction in temperature compared with paracetamol, has effects that last only for a short time. Paracetamol on the other hand produces a gradual but sustained effect. The discomforts experienced should not be a limiting factor to the use of cold water sponging in reducing the body temperature of febrile children. Cold water sponging is safe and its use by mothers and primary caregivers should be encouraged while preparing to take the child to the nearest health facility for definitive treatment of the underlying cause of the fever. PMID- 24479071 TI - Knowledge, attitude and practice of family physicians regarding smoking cessation counseling in family practice centers, suez canal university, egypt. AB - INTRODUCTION: Family physicians are the first point of medical contact for most patients, and they come into contact with a large number of smokers. Also, they are well suited to offer effective counseling to people, because family physicians already have some knowledge of patients and their social environments. AIMS: The present study was conducted to assess family physicians' knowledge, attitude and practice of smoking cessation counseling aiming to improve quality of smoking cessation counseling among family physicians. MATERIALS AND METHODS: The study was descriptive analytic cross sectional study. It was conducted within family medicine centers. Sample was comprehensive. it included 75 family physicians. They were asked to fill previously validated anonymous questionnaire to collect data about their personal characteristics, knowledge, attitude and practice of smoking cessation counseling, barriers and recommendations of physicians. Equal or above the mean scores were used as cut off point of the best scores for knowledge, attitude and practice. STATISTICAL ANALYSIS: SPSS version 18 was used for data entry and statistical analysis. RESULTS: The best knowledge, attitude and practice scores among family physicians in the study sample were (45.3 %, 93.3% and 44% respectively). Age (P = 0.039) and qualification of family physicians (P = 0.04) were significant variables regarding knowledge scores while no statistically significance between personal characteristics of family physicians and their attitude or practice scores regarding smoking cessation counseling. More than half of the family physicians recommended training to improve their smoking cessation counseling. CONCLUSIONS: Favorable attitude scores of family physicians exceed passing knowledge scores or practice scores. Need for knowledge and training are stimulus to design an educational intervention to improve quality of smoking cessation counseling. PMID- 24479072 TI - A Cross-sectional Study of Common Psychiatric Morbidity in Children Aged 5 to 14 Years in an Urban Slum. AB - AIM: Study of the prevalence of common psychiatric disorders in children aged 5 to 14 years in a health post area of an urban slum. OBJECTIVES: (1) To study frequency of specific psychiatric disorders in the study population, (2) To study the relationship between sociodemographic variables and psychiatric morbidity. SETTINGS AND DESIGN: The present study was conducted in one of the five health posts of an urban slum, which is a field practice area of the teaching medical institute. It was a cross-sectional study. MATERIALS AND METHODS: Sample size was estimated by using 20% as a prevalence of psychiatric morbidity which was obtained from previous studies done in developing countries. Household was used as a sampling unit and systematic random sampling method was used for selecting household. Total 257 children aged 5 to 14 years were included in the study. A pre-designed, semi-structured diagnostic interview schedule based on DSM-IV criteria was used for data collection. STATISTICAL ANALYSIS USED: The tests of significance used were Chi-square and Logistic regression analysis. RESULTS: The prevalence of psychiatric morbidity in this study was 14.8%. Non-organic enuresis, Attention deficit hyperactivity disorder, Conduct disorder, and Mental retardation were identified as the common mental health problems. CONCLUSIONS: Factors like nuclear family, parents not living together, large family size, and positive family history of psychiatric disorder were associated with psychiatric morbidity in children. PMID- 24479073 TI - Third Angle of RSBY: Service Providers' Perspective to RSBY-operational Issues in Gujarat. AB - CONTEXT: Government of India in 2008, launched its flagship health insurance scheme for the poor. The Rashtriya Swasthya Bima Yojana (RSBY) combines cutting edge technology with an unusual reliance on incentives to provide inpatient insurance coverage. The scheme allows for cashless hospitalization services at any of the empaneled hospitals. Stakeholders in RSBY include members of the community, Insurance Company and the service provider. AIM: The study manuscript is an attempt to get an insight to understand the bottle necks in faced by the service providers with an overall goal to understand issues in complete roll out of RSBY and its successful implementation across country. It was conducted to undertake the stakeholder analysis and understand the service providers' perspective to RSBY. SETTING AND DESIGN: The present study was conducted in the Patan district of Gujarat state. Qualitative tool mainly in-depth interview of service providers of RSBY in Patan district of Gujarat state was utilized for the data collection. RESULTS AND CONCLUSION: Service providers opined an ineffective IEC around the utility of the RSBY service in the community. In spite of the claim that scheme relies heavily on technology to ensure paperless cashless services, on field, it was observed in the present study that the claim settlements are done through physical documents. The service providers had a perceived threat of being suspended from the list/de-empanelment of the provider by the insurance company. There is an urgent need for improved and effective IEC for the service and possibilities of an arrangement for to settle the case of grievances around suspensions ao that genuine hospitals can have fair deal as well. There definitely remains a greater and more serious role of government, which ranges from ownership to larger issue of governance. PMID- 24479074 TI - Assessment of Validity and Reliability of IMNCI Algorithm in Comparison to Provisional Diagnosis of Senior Pediatricians in a Tertiary Hospital of Kolkata. AB - BACKGROUND: Integrated management of childhood illness (IMNCI) is already operational in many states of India, but there are only limited studies in Indian scenario comparing its validity and reliability with the decisions of pediatricians. Aims and. OBJECTIVES: To assess the validity and reliability of the IMNCI algorithm with provisional diagnosis of senior pediatricians for each IMNCI classifications. MATERIALS AND METHODS: The present study is done with all the young infants between 0-2 months presented during the study period with a fresh episode of illness to test the validity and reliability of the algorithm in comparison to provisional diagnoses of senior pediatricians. The study was done in a tertiary care hospital. Validity characteristics such as sensitivity, specificity, positive predictive value, negative predictive value, and reliability characteristics such as percent agreement and Kappa were assessed for individual IMNCI classifications. RESULTS: The sensitivity of possible serious bacterial infection, local bacterial infection, jaundice, no dehydration and possible serious bacterial infection, not able to feed were 88.89, 14.29, 66.67, 25 and 44.44% respectively. The specificities for the same conditions were 71.72, 99.09, 99.07, 94.50 and 86.87%. Percent agreements for similar conditions were 74, 94, 97, 90 and 80% respectively and the Kappa ratios were 0.38, 0.20, 0.73, 0.19 and 0.29 respectively. CONCLUSION: It could be concluded that IMNCI is quite a sensitive strategy and could identify severe illnesses of young infants requiring referral to higher facility. Further studies, particularly in primary health care setting, are required. PMID- 24479075 TI - An evaluation of mass drug administration compliance against filariasis of tikamgarh district of madhya pradesh-a household-based community study. AB - BACKGROUND: Mass drug administration (MDA) means once-in-a-year administration of diethyl carbamazine (DEC) tablet to all people (excluding children under 2 years, pregnant women and severely ill persons) in identified endemic areas. It aims at cessation of transmission of lymphatic filariasis. OBJECTIVE: To study the coverage and compliance of MDA in Tikamgarh district during the campaign in April 2010. MATERIALS AND METHODS: The activities under MDA involved administration of DEC tablets to eligible population from endemic area by health staff and Integrated Child Development Scheme (ICDS) functionaries referred as drug distributors (DD) make house-to-house visits on select dates in 2010. DEC was administered to all people (excluding children under 2 years, pregnant women and severely ill persons) with the instruction to ingest the tablet preferably on the spot. STUDY DESIGN: Cross-sectional population based house-to-house visit. SETTING: Urban and rural areas in Tikamgarh district identified as endemic for filariasis where MDA 2010 was undertaken. STUDY VARIABLES: Exploratory - Rural and urban clusters of Tikamgarh district; Outcome - coverage, compliance, actual coverage, side effects. ANALYSIS: Percentage and proportions. RESULTS: Four clusters, each comprising 30 households from Tikamgarh endemic district, yielded an eligible population of 641. The coverage rate was 607 (94.6% of eligible) with variation across different areas. The compliance with drug ingestion was 89.9% with a gap of 10.1% to be targeted by intensive IEC. The effective coverage (85.2%) was just above the target (85%). Side effects of DEC were minimum, transient and drug-specific. Overall coverage was marginally better in rural areas. The causes of poor coverage and compliance have been discussed and relevant suggestions have been made. PMID- 24479076 TI - Characteristics of Hospitalized Patients with Severe and Non-Severe Pandemic Influenza A (H1N1) in Saurashtra Region, India (Two Waves Analysis). AB - BACKGROUND: In India, the first case of 2009 pandemic influenza A (H1N1) virus infection was reported in May 2009 and the same in Saurashtra region in August 2009. We describe the epidemiology and factors associated with severe and non severe cases of 2009 influenza A (H1N1) infection reported in the Saurashtra region. MATERIALS AND METHODS: From September 2009 to January 2011, we reported 511 patients who were infected with 2009 influenza A (H1N1) virus and admitted in different hospitals of Rajkot city. Real-time reverse transcriptase polymerase chain reaction (RT-PCR) testing was used to confirm infection. Factors associated with severe cases were determined by comparing with non-severe cases. RESULTS: Out of 511 patients, 140 had severe disease (requiring intensive care or died) and 371 non-severe diseases (admitted in wards and survived). Median age of 30 years; median time of 5 days from onset of illness to diagnosis, and 4 days median time was reported for hospital stay among severe disease patients. More than half (60.7%) were females. Out of the patients with severe disease, 52.1% patients residing in urban area (OR = 1.68, CI = 1.13-2.49). Significant association was reported among severe disease patients for delayed referral from general practitioner/physician after initial treatment. All patients received antiviral drug, however, only 27.1% received within 2 days of illness. Presence of coexisting condition (pregnancy (OR = 0.19, CI = 0.08-0.48) was strongly associated with severe disease. CONCLUSION: Delayed referral from general practitioner/physician, duration of antiviral treatment, presence of coexisting condition (i.e., pregnancy) were responsible for intensive care or mortality among severe influenza A (H1N1) illness. PMID- 24479077 TI - Morbidity Pattern and Health-seeking Behavior of Aged Population residing in Shimla Hills of North India: A Cross-Sectional Study. AB - BACKGROUND: Population aging is a global phenomenon. In India, the size of the elderly population is growing fast. Many older adults have multiple medical conditions. Understanding elderly health problems and health-seeking behavior is prerequisite for proving comprehensive geriatric care to them. OBJECTIVES: To assess the morbidity pattern and study the health-seeking behavior of the elderly people of Shimla district in Himachal Pradesh. MATERIALS AND METHODS: A total of 400 elderly people aged 60 years and above were selected from urban and rural areas of Shimla hills in North India by simple random sampling. Statistical software Epi info software version 3.2 was used for analyzing data. Descriptive statistics were used to describe sociodemographic and morbidity variables. RESULTS: The most common morbidity identified among them were musculoskeletal problems (55.0%) followed by hypertension (40.5%). Two third were seeking treatment for their health problems. Among older persons not seeking treatment for their medical condition, most considered these morbidities as an age-related phenomenon. Many perceived that the health services were too far. CONCLUSION: The high morbidity load among elderly in the present study stresses for efforts to provide better health care to them and thus ensure that they remain active members of our society. Residence emerged out to be most significant determinant of healthcare-seeking behavior. Policy makers must focus on rural elderly and their beliefs which prevent them from seeking healthcare. PMID- 24479078 TI - Polypharmacy and potentially inappropriate medication use as the precipitating factor in readmissions to the hospital. AB - BACKGROUND AND AIM: Readmission to the hospital within 30 days of discharge from the hospital is a common occurrence. Congestive heart failure is the most common cause of readmissions in the hospital. We hypothesized that irrespective of the admission diagnosis polypharmacy and potentially inappropriate use of medications (PIM) leads to readmissions within 30 days of discharge from the hospital. MATERIALS AND METHODS: A retrospective study was carried out by reviewing the hospital records of 414 patients who were readmitted to the hospital within 30 days of discharge from the hospital between January 2008 and December 2009. The data was stratified to see which patients were on polypharmacy and/or on PIM. Polypharmacy was defined as use of more than 5 medications. PIM was defined as per the modified Beers criteria. Day 0 was defined as the day of discharge and day1 was defined as the day-after Admission to the hospital. Statistical analysis was carried out using a two-way analysis of variance (ANOVA) on the data to see if polypharmacy and/or PIM was related to readmission within 30 days of discharge irrespective of admission diagnosis. RESULTS: Polypharmacy was related to hospital readmission at day 1 and day 0, however inappropriate drug use was found to be not related at any day. Polypharmacy and PIM combined had a positive correlation to readmission only on days 1 and 0 and it was statistically significant. The use of minimal and appropriate use of drugs was statistically significant compared to polypharmacy and PIM use. CONCLUSIONS: Polypharmacy and PIM are under recognized cause of readmissions to the hospital. PMID- 24479079 TI - Gender Difference in Blood pressure, Blood Sugar, and Cholesterol in Young Adults with Comparable Routine Physical Exertion. AB - CONTEXT: Gender differences in the risk of developing non-communicable diseases (NCD) are a matter of debate. The susceptibility of a woman to NCD should be evaluated taking into consideration the social factors that limit the physical activity among women. It will be interesting to note what will happen if women are allowed to take part in physical exercise to the extent of men. AIMS: To find out the gender difference in the pattern of the clinical and biochemical indices related to NCD in young adults with comparable daily physical activity. SETTINGS AND DESIGN: This is an institution-based cross-sectional study and the setting was Lekshmibhai National College for Physical Education (LNCPE), Thiruvananthapuram, Kerala, India. MATERIALS AND METHODS: The study participants were students who were regularly involved in more than three hours of physical exercise daily at least for the previous one year. The information on socio demography, anthropometry, and blood pressure was recorded. Blood samples were taken for laboratory examination. RESULTS: Out of 150 students registered, 126 (84%) in the age group of 17 to 25 years who fulfilled the eligibility criteria were studied. Fifty-five (43.7%) of them were women. Systolic blood pressure, fasting blood sugar, and low-density lipoprotein were found significantly lower in women. No significant difference was noted in the case of diastolic blood pressure and total cholesterol. CONCLUSION: Gender differences exist for NCD risk factors among young adults with comparable physical activity and physical exertion seems to be more protective for females. PMID- 24479080 TI - Influenza a infection unmasking an underlying mitral valve stenosis in a 19-year old boy. AB - Infection with Influenza virus is uncommon in the present times, though a number of cases were reported during pandemics in 1918 in various regions of America. We report a case where a young male patient presented to the hospital with a clinical picture of acute respiratory distress syndrome that turned out to be a viral pneumonia caused by Influenza A virus and it aggravated an underlying yet undiagnosed mitral valve stenosis. PMID- 24479081 TI - Liver Abscesses and Hyper IgM Syndrome. AB - Hyper IgM (HIGM) syndrome is an immunodeficiency that can lead to liver disease in more than 80% of affected males by an age of 20 years. Hepatitis, sclerosing cholangitis, and hepatocellular malignancies are common among them. We encountered two cases in children of less than 12 years who presented with typical manifestations of liver abscess and were later detected to have a concomitant underlying HIGM syndrome. PMID- 24479082 TI - Patient education: boon or bane? PMID- 24479083 TI - Healthcare technician delivered screening of adults with diabetes to improve primary care provider recognition of depression. PMID- 24479084 TI - Challenges for Healthcare in the 21(st) Century: How Family Medicine Can Help. PMID- 24479085 TI - Family Medicine: A Solution for Career Inequalities among Doctors in India. AB - Career in medicine is challenging. Medical education system is a ever evolving entity. Due to certain bottle necks in the medical education system, young medical graduates in India are facing difficulties in career progression. Author draws from the experience of Britain and explores how family medicine could be answer to many question which the Indian health system is challenged with. PMID- 24479086 TI - Primary care in a rural set up in Nepal: perspectives of a generalist. AB - This article deals with the author's personal perspectives while having to serve as a generalist in a rural hospital in one of the most underdeveloped and far away regions of Nepal. Having been deputed in Kalikot District Hospital (KDH) through Nick Simons Institute's (NSI) Rural Staff Support Program (RSSP), the author mentions the technical hardships and resource constraints of the government hospital. Highlighting the improvement in the hospital profile after the arrival of the RSSP, the article cursorily mentions the modalities of primary care spanning the common clinical presentations. Particularly, the difficulties related to the provision of Comprehensive Emergency Obstetric Care (CEOC) services are highlighted. Also, a brief introduction as to the NSI, Kathmandu is provided. PMID- 24479087 TI - Comparison of body mass index on children with functional constipation and healthy controls. AB - BACKGROUND: Constipation is one of the most common pediatric disorders, especially in developed population, which categorized to organic or functional (non-organic) constipation. Furthermore, obesity is a growing chronic pediatric problem that could cause any compromise in weight and height. The aim of this study is the evaluation of probable relation between obesity and pediatric functional constipation. METHODS: This study was conducted as a case-control investigation on 2-14-years-old children those referred to Baqiyatallah University clinic during 2009-2011. The constipated children with organic causes were excluded. The control group of children was those who had not any disorders affecting on height and weight. Quantitative variables were expressed by mean and standard deviation and the correlation was tested with chi2 through SPSS version 17. RESULTS: A total of 259 children (male 51.7%) consisting 124 cases and 135 controls were enrolled. The mean age in constipated and normal children was 69.47 +/- 35.03 and 74.15 +/- 39.68, respectively. BMI over 95% in the control group was 11.9% and in the constipated group was 17.7% that the difference was not statistically significant either (P = 0.188). The only significant association was found between obesity and the duration of constipation and also age (P = 0.008, 0.042, respectively). CONCLUSION: Although we found a significant relationship between duration of constipation and obesity, there was not a clear association between obesity and presence of constipation. Furthermore, we suggest extended cohort or clinical trial study regarding to the regional nutritional and growth patterns to confirm weight decrease or increase the effect on defecation. PMID- 24479088 TI - Job satisfaction of primary health-care providers (public sector) in urban setting. AB - INTRODUCTION: Job satisfaction is determined by a discrepancy between what one wants in a job and what one has in a job. The core components of information necessary for what satisfies and motivates the health work force in our country are missing at policy level. Therefore present study will help us to know the factors for job satisfaction among primary health care providers in public sector. MATERIALS AND METHODS: Present study is descriptive in nature conducted in public sector dispensaries/primary urban health centers in Delhi among health care providers. Pretested structured questionnaire was administered to 227 health care providers. Data was analyzed using SPSS and relevant statistical test were applied. RESULTS: Analysis of study reveals that ANMs are more satisfied than MOs, Pharmacist and Lab assistants/Lab technicians; and the difference is significant (P < 0.01). Age and education level of health care providers don't show any significant difference in job satisfaction. All the health care providers are dissatisfied from the training policies and practices, salaries and opportunities for career growth in the organization. Majority of variables studied for job satisfaction have low scores. Five factor were identified concerned with job satisfaction in factor analysis. CONCLUSION: Job satisfaction is poor for all the four groups of health care providers in dispensaries/primary urban health centers and it is not possible to assign a single factor as a sole determinant of dissatisfaction in the job. Therefore it is recommended that appropriate changes are required at the policy as well as at the dispensary/PUHC level to keep the health work force motivated under public sector in Delhi. PMID- 24479089 TI - Early birth registration at a center in rural India. AB - BACKGROUND: Registration of birth is mandatory in India however due to various issues compliance for timely birth registration has been poor. OBJECTIVE: The objective of this study was to determine time elapsed between birth and registration and describe the socio-demographic profile of registered births at a rural center. MATERIALS AND METHODS: A cross-sectional descriptive study was undertaken and all births registered at a primary health center of a block during the period 2010 and 2011 were retrieved and data collection carried using structured proforma based on birth formats under civil registration system (CRS). House to house visit was undertaken to identify births without registration. RESULTS: A total of 340 and 276 births were registered during 2010 and 2011 respectively. Time elapsed between birth and registration was computed to be lower, i.e., 9.38 days (+/-7.46) during 2011 in-comparison with 10.52 days (+/ 8.73) in 2010. On a positive note, higher level of education and marriage of women beyond legal age of 18 years was noticed in 2011 in comparison with 2010. Overall, institutional birth stood at a very encouraging note (66.2%). All (100%) births during the study period were registered at this (rural) or higher center (urban) depending on the place of delivery. An omission/commission of birth format is highlighted that needs urgent attention of the authorities. DISCUSSION: Majority (>92%) of birth registration occurred with-in the stipulated period of 21 days as prescribed under CRS and our study indicates early birth registration in a rural area of Haryana, India. PMID- 24479090 TI - Factors associated with psychosocial services in ogun state, Nigeria. AB - BACKGROUND: Belonging to a social network group may influence a person's decisions to engage in desired behavior. AIM: The objective of our study was to determine factors associated with utilization of psychosocial group services among people living with human immunodeficiency virus acquired immunodeficiency syndrome (PLWHAs) in a Teaching Hospital in Sagamu, Southwestern Nigeria. SETTINGS AND DESIGN: This was an analytical cross-sectional study. All consenting PLHAs who attended the anti-retroviral clinic (ART) clinic during the study period were recruited into the study. MATERIALS AND METHODS: A structured self administered questionnaire was used to collect relevant information and a total of 205 PLWHAs were interviewed. STATISTICAL ANALYSIS USED: The data analysis focused on univariate frequency table and bivariate cross tabulations that identify important relationships between the variables. Odds ratio (OR) at 95% confidence level (CI) and Chi-squared and t-tests were also computed. RESULTS: The overall point utilization of psychosocial services among the PLWHAs was 23.4%. Utilization of psychosocial services was statistically significantly associated with religion (chi(2) = 11.74, P = 0.003), disclosure of human immunodeficiency virus status (chi(2) = 9.18, P = 0.01) and satisfactory self reported health-related quality-of-life (HRQOL) (chi(2) = 5.67, P = 0.017) while sex (chi(2) = 0.02, P = 0.96), education (chi(2) = 4.67, P = 0.32) tribe (chi(2) = 1.46, P = 0.48) adherence to ART drugs (chi(2) = 0.44, P = 0.51), mental health status (chi(2) = 0.64, P = 0.42) and occupation (chi(2) = 3.61, P = 0.61) were not. The only predictor of utilization of psychosocial group services was religion (OR = 0.44, CI = 0.23-0.84). CONCLUSION: This study shows the effectiveness of the psychosocial networks group in improving the overall HRQOL of the PLWHAs. PMID- 24479092 TI - Surveillance data analysis of Revised National Tuberculosis Control Program of Kangra, Himachal Pradesh. AB - BACKGROUND: The annual risk of tuberculosis infection is 1.9% in Himachal Pradesh against a national average of 1%. Revised national tuberculosis control program (RNTCP) in Kangra was introduced in October, 1998. We analyzed the 5-year (2001 2005) RNTCP secondary data from Kangra to evaluate the performance of the program. MATERIALS AND METHODS: We collected data from all the five tuberculosis units the district. We calculated the following indicators-case detection rate, tuberculosis cases by category-new smear positive (or smear negative but seriously ill) defaulters, relapses and failures, extra-pulmonary, and new smear negative cases. We compared the results with Himachal Pradesh and India. We employed the standardized program indicators-sputum positivity, cure, death, failure and default rates. RESULTS: Extra pulmonary cases ranged in between 56% and 73%, normal being 15-20%. The highest category-1 varies from 42% to 48%. New smear positive case detection rates (78-90%) and cure rates (88-91%) were the highest as compared to figures of the state and country. Failure rate was maximum in Kangra Tuberculosis Units (TU)-6.5% and the default rate was 7.2% in TU Palampur. The tuberculosis cases have fallen down from 6,462/100, 000 in 1999 to 2,195/100, 000 in 2005 following the introduction of RNTCP in 1999. Age specific (15-55 years) and sex-wise males were more affected than the females (59-64%). CONCLUSIONS: Continue investment in the program to sustain progress achieved. Investigate the cause of high proportion of extra-pulmonary tuberculosis. Investigate Kangra TU unit with a high default rate. PMID- 24479093 TI - Proximate Family Biosocial Variables Associated with Severe Malaria Disease among Under-Five Children in Resource-Poor Setting of a Rural Hospital in Eastern Nigeria. AB - BACKGROUND: Malaria threatens the life of under-five in rural Nigerian families. Although, factors that influence malaria in under-five are manifold. However, family biosocial factors may contribute to the variability of the clinical picture. AIM: To determine proximate family biosocial variable associated with severe malaria among under-five children in a resource-poor setting of a rural hospital in Eastern Nigeria. MATERIALS AND METHODS: A cross-sectional study carried out on the families of under-five managed for malaria. Data extracted included family biosocial variables and diagnosis. An under-five child was defined to have malaria if the mother gave complaints of fever, vomiting, and other symptoms suggestive of malaria, had body temperature exceeding 37.5 degrees C with the asexual forms of Plasmodium falciparum detected on the peripheral blood film. Severe malaria is the malaria that presents with life-threatening features like severe anemia and cerebral malaria. RESULTS: The prevalence of severe malaria was 31.8% The family biosocial variables significantly associated with severe malaria were maternal low level of education (P = 0.031), family size >4 (P = 0.044), low social class of the family (P = 0.025), nonliving together of parents (P = 0.011), and poor access to health facilities (P = 0.038). The most significant predictor of severe malaria was nonliving together of parents (P = 0.000, odds ratio = 3.08, confidence interval = 1.64-5.10). CONCLUSION: This study has demonstrated that some family biosocial variables are associated with severe malaria. These families should constitute at risk families that could be targeted for malaria interventional programs. PMID- 24479091 TI - Etiology and Anti-microbial Sensitivity of Organisms Causing Community Acquired Pneumonia: A Single Hospital Study. AB - OBJECTIVE: The objective of this study was to identify the common etiological pathogens causing community acquired pneumonia (CAP) in our hospital and sensitivity patterns to the common antibiotics used. MATERIALS AND METHODS: This study was undertaken in a 750 bedded multi-specialty referral hospital in Kerala catering to both urban and semi-urban populations. It is a prospective study of patients who attended the medical out-patient department and those admitted with a clinical diagnosis of CAP, during the year 2009. Data were collected based on detailed patient interview, clinical examination and laboratory investigations. The latter included sputum culture and sensitivity pattern. These were tabulated and percentage incidence of etiological pathogens calculated. The antimicrobial sensitivity pattern was also classified by percentage and expressed as bar diagram. RESULTS: The study showed Streptococcus pneumoniae to be the most common etiological agent for CAP, in our hospital setting. The other organisms isolated in order of frequency were Klebsiella pneumoniae, Pseudomonas aeruginosa, Alpha hemolytic streptococci, Escherichia coli, Beta hemolytic streptococci and atypical coli. S. pneumoniae was most sensitive to linezolid, followed by amoxicillin-clavulanate (augmentin), cloxacillin and ceftriaxone. Overall, the common pathogens causing CAP showed highest sensitivity to amikacin, followed by ofloxacin, gentamycin, amoxicillin-clavulanate (augmentin), ceftriaxone and linezolid. The least sensitivity rates were shown to amoxicillin and cefoperazone. CONCLUSION: In a hospital setting, empirical management for cases of CAP is not advisable. The present study has shown S. pneumoniae as the most likely pathogen and either linezolid or amikacin as the most likely effective antimicrobial in cases of CAP, in our setting. PMID- 24479094 TI - End of life discussion in an academic family health team in kingston, ontario, Canada. AB - BACKGROUND: End-of-life (EOL) discussions remain difficult in non-terminal patients as death is often perceived as a taboo and uncertainty. However, the call for proper EOL discussions has recently received public attention and media coverage. Evidence also reveals that non-terminal patients are more satisfied with health-care encounters when EOL has been discussed. OBJECTIVES AND METHODS: The objective of this study was to explore the prevalence of EOL discussions in non-terminal adult patients, the perceived barriers to such discussions and suggested methods for improvement. A study mixed-methods study was performed by a group of PGY1 family medicine residents in an academic health team in Kingston, Ontario. RESULTS: EOL discussion was performed in a very small proportion of non terminal patient encounters. Compared with attending physicians, residents were less likely to discuss EOL issues and reported more perceived barriers. CONCLUSION: Our findings reflect the need for an early and open approach in conducting EOL discussion for non-terminal healthy patients. PMID- 24479095 TI - Morbidity pattern and personal hygiene in children among private primary school in urban area: are the trends changing? AB - INTRODUCTION: School health is an important intervention as a great deal of research tells us that schools can have a major effect on children's health, by teaching them about health and promoting healthy behaviors. AIMS: The aim of this study is to determine common health problems and assess personal hygiene status among primary school children. SETTINGS AND DESIGN: A cross-sectional study was conducted in academic years 2009-2010 and 2010-2011, with three health check-up camps organized in private primary school of Pune city. MATERIALS AND METHODS: A total of 450 students were assessed for health problems and composite score of personal hygiene status was calculated ranging from 0 to 5 by examination of hairs, nails, skin and clothes. STATISTICAL ANALYSIS USED: Proportions calculated with application of Chi-square test and Pearson co-efficient applied to observe the relation between two quantitative variables. RESULTS: Out of 450 students examined, 56.2% were boys and 43.8% were girls with age ranging from 5 to 10 years. The major morbidities observed were dental caries (65.1%), upper respiratory tract infections (38.2%), ear wax (29.9%) and myopia (10.0%). Mean hygiene score was significantly higher in girls (4.32) than boys (3.95) and poor hygiene observed in older boys. CONCLUSION: Increasing myopia and poor dental hygiene denotes a changing morbidity pattern in private primary school of the urban area. The hygiene status of the girls is significantly better than boys. PMID- 24479096 TI - Quality-of-Life among Elderly with Untreated Fracture of Neck of Femur: A Community Based Study from Southern India. AB - BACKGROUND AND OBJECTIVES: Owing to the high prevalence of osteoporosis and falls, elderly people are at risk of developing hip fractures. The objective of the current study is to assess the quality-of-life (QOL) of elderly (>60 years) with untreated hip fractures in a rural developmental block in Southern India. METHODOLOGY: Twenty-one elderly with an untreated fracture neck of femur were identified with the help of community level health workers. EuroQol (EQ-5D) was administered to assess the QOL before and after the event. QOL was also assessed among a comparison group, matched for age and sex among neighborhood people. Wilcoxon signed rank test and Mann-Whitney U test were used to compare EQ-5D mean scores with before the event scores and the comparison group scores respectively. RESULTS: Of people with hip fracture, 57.1% (12/21), 76.2% (16/21), 81% (17/21), 52.6% (11/21) and 85.7% (18/21) reported severe problems with mobility, pain, usual activity, self-care and anxiety respectively. The EQ-5D mean score among the elderly with fracture neck of the femur was 0.08 (SD 0.27). It was low when compared with the same subjects before the occurrence of the event (Z -4.05, P < 0.001) and as compared with the comparison group (Z -5.77 P < 0.001). CONCLUSION: The QOL scores assessed using EQ-5D index scores was poor among people with untreated fracture neck of the femur as compared with the comparison group and also as compared to their status before the occurrence of the event. A vast majority of study participants reported severe problems with mobility, pain, usual activity and self-care and anxiety domains of EQ-5D questionnaire. PMID- 24479097 TI - Utility of Consensus Statement in Assessment of Obesity: A Study among Undergraduate Medical Students from Rural Northwest India. AB - INTRODUCTION: In India, obesity is emerging as an important health problem particularly in the urban areas, paradoxically coexisting with under nutrition. Almost 30-65% of adult Indians are either overweight or obese or have abdominal obesity. MATERIALS AND METHODS: A cross-sectional study design was used to assess the prevalence of obesity among undergraduate medical using consensus statement for obesity in India. RESULTS: The results of the body mass index (BMI) calculations show 26 females and 4 males (29.79% of total students) with a BMI of <18 kg/m(2) as underweight, whereas 13 boys and 4 girls (15.54% of total students) as obese with a BMI of 25 kg/m(2) and above. A total of 18 boys and 6 girls (21.26% of total students) were overweight with a BMI between 23 and 24.9 kg/m(2). DISCUSSION: It is estimated that by application of these guidelines, additional 10-15% of Indian population would be labeled as obese or overweight. We see this very clearly in our study, where we see an increase of 14.53% of students classified as obese and 5.93% students as overweight on using the guidelines of the consensus statement. PMID- 24479099 TI - Role and Influence of the Patient's Companion in Family Medicine Consultations: "The Patient's Perspective". AB - BACKGROUND: Companions often accompany the patient in family medicine clinics and may influence the consultation. This study aims to determine the patients' perspective regarding the role and influence of the companion in the consultation process. MATERIALS AND METHODS: A cross-sectional study was conducted at the family medicine clinics of a university hospital. Adult patients accompanied by companions during the consultation were interviewed through a structured questionnaire. Attributes with respect to role and influence of companion on the consultation were assessed. Data was entered and analyzed through IBM Statistical Product and Service Solutions (SPSS) software version 18 using the Chi-square test. RESULTS: A total of 100 patients accompanied by companions participated in the study. Majority of companions were present to either provide company (90%) and/or emotional support (90%). Immediate relatives had a role in mobility (P = 0.016) and decision making (P = 0.006). Most companions remained passive and did not contribute to the doctor patient relationship (P = 0.058). Male companions were relatively helpful (54% vs. 25%, P = 0.008) in achieving the expectations from the visit. The companion played a supportive role in 62% of the consultations. CONCLUSION: This study signifies a supportive role of companion in a consultation which emphasizes the need of consultation models to include the "companion." PMID- 24479098 TI - Diagnosing Chronic Fatigue Syndrome in South Asians: Lessons from a Secondary Analysis of a UK Qualitative Study. AB - BACKGROUND: Chronic fatigue syndrome/myalgic encephalitis (CFS/ME) is rarely diagnosed in South Asia (SA), although the symptoms of this condition are seen in the population. Lessons from UK based South Asian, Black and Minority Ethnic (BME) communities may be of value in identifying barriers to diagnosis of CFS/ME in SA. OBJECTIVES: To explore why CFS/ME may not be commonly diagnosed in SA. SETTINGS AND DESIGN: A secondary analysis of qualitative data on the diagnosis and management of CFS/ME in BME people of predominantly South Asian origin in the UK using 27 semi-structured qualitative interviews with people with CFE/ME, carers, general practitioners (GPs), and community leaders. RESULTS: CFS/ME is seen among the BME communities in the UK. People from BME communities in the UK can present to healthcare practitioners with vague physical complaints and they can hold a biomedical model of illness. Patients found it useful to have a label of CFS/ME although some GPs felt it to be a negative label. Access to healthcare can be limited by GPs reluctance to diagnose CFS/ME, their lack of knowledge and patients negative experiences. Cultural aspects among BME patients in the UK also act as a barrier to the diagnosis of CFS/ME. CONCLUSION: Cultural values and practices influence the diagnosis of CFS/ME in BME communities. The variations in the perceptions around CFS/ME among patients, carers, and health professionals may pose challenges in diagnosing CFS/ME in SA as well. Raising awareness of CFS/ME would improve the diagnosis and management of patients with CFS/ME in SA. PMID- 24479100 TI - Seat belt sign and its significance. AB - Safety belts are the most important safety system in motor vehicles and when worn intend to prevent serious injuries. However, in unusual circumstances (high velocity motor vehicle collisions) these safety measures (seat belts) can be the source and cause of serious injuries. The seat belt syndrome was first described as early by Garrett and Braunste in but the term "seat belt sign" was discussed by Doersch and Dozier. Medical personnel's involved in emergency care of trauma patients should be aware of seat belt sign and there should a higher index of suspicion to rule out underlying organ injuries. PMID- 24479101 TI - Rhodococcus equi: a pathogen in immunocompetent patients. AB - Rhodococcus equi is an uncommon human pathogen known to cause lung infections in immunocompromised patients. We report two cases of Rhodococcus infections in immunocompetent individuals, who were treated successfully. PMID- 24479102 TI - Pulmonary tuberculosis presenting acutely as paraplegia: an unusual presentation. AB - Extrapulmonary tuberculosis most commonly involves the bones and the spine. The present case is that of a young boy who presented with acute onset paraplegia without any pre-existant complaints of cough with sputum, fever, night sweats or weight loss. PMID- 24479103 TI - Hemichorea-hemiballism in a nonketotic diabetic patient. AB - Hemichorea-hemiballism can be the solely presentation of a wide range of non neurological clinical pictures, such as metabolic or hydro-electrolyte derange ments. Hemichorea-hemiballism as the first presentation of type 2 diabetes mellitus has been described. The case depicted herein reinforces this association highlighting that especially in elder patients with new-ly diagnosed hemichorea hemiballism, non-ketotic hyperglycemia should promptly be recognized. PMID- 24479104 TI - Diabetic neuropathy: rare presentation as a painful pseudoabdominal mass. AB - Diabetic neuropathy has varied clinical presentations. As clinicians we should be aware of the common as well as rare manifestations of this syndrome. Diabetic truncal neuropathy presenting as a painful pseudoabdominal mass can easily mislead clinicians who are unaware of this problem. Subsequently, this can lead to unnecessary investigations and discomfort to the patient. A good blood sugar control and judicious use of drugs for neuropathic pain along with physiotherapy usually gives good relief. It is mostly a self-limiting condition. PMID- 24479105 TI - Neuro-ocular cysticercosis causing total retinal detachment and cataract. PMID- 24479106 TI - Yoga in promotion of health: translating evidence into practice at primary healthcare level in India. PMID- 24479107 TI - Assessment of outcome in hypospadias surgery - a review. AB - Hypospadias is a challenging field of urogenital reconstructive surgery with different techniques being currently used. Modern surgery claims that it is possible to create a functionally and cosmetically normal penis. Continuous re evaluation and assessment of outcome may have a major impact on future clinical practice. Assessment of outcome includes: complication rate, cosmetic appearance of the penis, functional outcome (micturition, sexuality), and psychological factors such as quality of life and psychosexual life. This article briefly reviews current strategies of outcome assessment. Somehow in the future, we will be able to give an accurate estimation of the long-term consequences of being born with hypospadias. PMID- 24479108 TI - Non-Specific Gastric Inflammation in Children is Associated with Proton Pump Inhibitor Treatment for More than 6 Weeks. AB - BACKGROUND AND AIMS: Non-specific gastric inflammation (NSGI) is a commonly reported pathological finding. We investigated if it is associated with the use of proton pump inhibitors (PPIs) in children at a single tertiary center. METHODS: We performed an IRB-approved chart review of all endoscopy and biopsy reports of patients who underwent esophagogastroduodenoscopy between July 2009 and July 2010 (n = 310). Demographic data, dose, duration of exposure to PPI, and biopsy results were collected and analyzed. All esophageal, gastric, and duodenal biopsies were independently reviewed by a pathologist. Patients with acute gastritis, moderate/severe chronic gastric inflammation, or Helicobacter pylori infection were excluded. The presence of NSGI was compared between patients exposed and not exposed to PPI as well as between patients with different doses and durations of PPI exposure to assess for potential associations. RESULTS: A total of 193 patients were included: 88 (46%) had a history of PPI use and 48 (25%) were found to have NSGI. Compared to patients not exposed to PPI, the odds ratio of NSGI in patients exposed to PPIs was 2.81 (95% CI: 1.36-5.93). The odds ratio of NSGI in patients exposed to PPI for >3 months was 4.53 (95% CI: 1.69 11.97). Gender, ethnicity, and age were not associated with NSGI. No histological differences were found in the esophagus and duodenum between patients exposed and not exposed to PPI. CONCLUSION: This study found that PPI exposure is associated with NSGI with a higher risk for those exposed for >3 months. As the clinical implications of NSGI are not known, judicious use of PPIs is needed. Prospective studies are required to confirm and to determine the etiologic factors (i.e., alteration of the gastric pH, serum gastrin) that may be related with the presence of NGSI. PMID- 24479109 TI - On preventing the extinction of the physician-scientist in pediatric pulmonology. AB - While the founders of Pediatric Pulmonology recognized the necessity of research as a vital part of the developing sub specialty, the field has struggled to develop and maintain physician-scientists and investigators. The clinical growth in Pediatric Pulmonology has resulted in significant challenges in career development faced by physician-scientists who aim to establish or maintain independent investigative programs. Such challenges may only be overcome with changes in how both trainees and established physician-scientists in Pediatric Pulmonology are supported. PMID- 24479110 TI - Bone-Anchored Hearing Aid vs. Reconstruction of the External Auditory Canal in Children and Adolescents with Congenital Aural Atresia: A Comparison Study of Outcomes. AB - OBJECTIVES/HYPOTHESIS: Congenital aural atresia is a rare condition affecting 1 in 10,000-20,000 children a year. Surgery is required to restore hearing to facilitate normal development. The objective of this study was to compare outcomes in hearing, complications, and quality of life of surgical reconstruction of the external auditory canal reconstruction (EACR) and bone anchored hearing aid (BAHA) in a pediatric population with congenital aural atresia. STUDY DESIGN: Subjects were children who had a diagnosis of congenital aural atresia or stenosis and who received either BAHA or EACR. METHODS: The medical records of 68 children were reviewed for operative complications and audiometric results. A quality of life questionnaire was prospectively administered to a subset of subjects. RESULTS: Pre-operatively, air conduction threshold was not significantly different between groups at 500, 1000, 2000, and 4000 Hz (p > 0.05). Post-operatively, the BAHA group (44.3 +/- 14.3 and 44.5 +/- 11.3) demonstrated a significantly larger hearing gain than the EACR group (20.0 +/- 18.9 and 15.3 +/- 19.9) in both the short and long-term periods (p < 0.001). Overall, the incidence of complications and need for revision surgery were comparable between groups (p > 0.05). Quality of life assessment revealed no statistical significance between the two groups (p > 0.05). CONCLUSION: Although the quality of life and incidence of surgical complications between the two interventions was not significantly different, BAHA implantation appears to provide a better, more reliable audiologic outcome than EACR. PMID- 24479112 TI - Oxytocin in pregnancy and the postpartum: relations to labor and its management. AB - The purpose of this study was to examine variations in endogenous oxytocin levels in pregnancy and postpartum state. We also explored the associations between delivery variables and oxytocin levels. A final sample of 272 mothers in their first trimester of pregnancy was included for the study. Blood samples were drawn during the first trimester and third trimester of pregnancy and at 8 weeks postpartum. Socio-demographic data were collected at each time point and medical files were consulted for delivery details. In most women, levels of circulating oxytocin increased from the first to third trimester of pregnancy followed by a decrease in the postpartum period. Oxytocin levels varied considerably between individuals, ranging from 50 pg/mL to over 2000 pg/mL. Parity was the main predictor of oxytocin levels in the third trimester of pregnancy and of oxytocin level changes from the first to the third trimester of pregnancy. Oxytocin levels in the third trimester of pregnancy predicted a self-reported negative labor experience and increased the chances of having an epidural. Intrapartum exogenous oxytocin was positively associated with levels of oxytocin during the postpartum period. Our exploratory results suggest that circulating oxytocin levels during the third trimester of pregnancy may predict the type of labor a woman will experience. More importantly, the quantity of intrapartum exogenous oxytocin administered during labor predicted plasma oxytocin levels 2 months postpartum, suggesting a possible long-term effect of this routine intervention, the consequences of which are largely unknown. PMID- 24479113 TI - Emerging technologies for assessing physical activity behaviors in space and time. AB - Precise measurement of physical activity is important for health research, providing a better understanding of activity location, type, duration, and intensity. This article describes a novel suite of tools to measure and analyze physical activity behaviors in spatial epidemiology research. We use individual level, high-resolution, objective data collected in a space-time framework to investigate built and social environment influences on activity. First, we collect data with accelerometers, global positioning system units, and smartphone based digital travel and photo diaries to overcome many limitations inherent in self-reported data. Behaviors are measured continuously over the full spectrum of environmental exposures in daily life, instead of focusing exclusively on the home neighborhood. Second, data streams are integrated using common timestamps into a single data structure, the "LifeLog." A graphic interface tool, "LifeLog View," enables simultaneous visualization of all LifeLog data streams. Finally, we use geographic information system SmartMap rasters to measure spatially continuous environmental variables to capture exposures at the same spatial and temporal scale as in the LifeLog. These technologies enable precise measurement of behaviors in their spatial and temporal settings but also generate very large datasets; we discuss current limitations and promising methods for processing and analyzing such large datasets. Finally, we provide applications of these methods in spatially oriented research, including a natural experiment to evaluate the effects of new transportation infrastructure on activity levels, and a study of neighborhood environmental effects on activity using twins as quasi-causal controls to overcome self-selection and reverse causation problems. In summary, the integrative characteristics of large datasets contained in LifeLogs and SmartMaps hold great promise for advancing spatial epidemiologic research to promote healthy behaviors. PMID- 24479111 TI - Fecal biomarkers of intestinal health and disease in children. AB - The identification of various fecal biomarkers has provided insight into the intestinal milieu. Most of these markers are associated with the innate immune system of the gut, apart from the more novel M2-pyruvate kinase. The innate immunity of the gut plays a role in maintaining a fine balance between tolerance to commensal bacteria and immune response to potential pathogens. It is a complex system, which comprises of multiple elements, including antimicrobial peptides (e.g., defensins, cathelicidins, lactoferrin, and osteoprotegerin), inflammatory proteins (e.g., calprotectin and S100A12), and microbial products (e.g., short chain fatty acids). Dysfunction of any component can lead to the development of intestinal disease, and different diseases have been associated with different fecal levels of these biomarkers. Each fecal biomarker provides information on specific biological and disease processes. Therefore, stool quantification of these biomarkers provides a non-invasive method to define potential pathways behind the pathogenesis of diseases and can assist in the assessment and diagnosis of various gastrointestinal conditions. The abovementioned fecal biomarkers and their role in intestinal health and disease will be reviewed in this paper with a pediatric focus. PMID- 24479114 TI - Consanguineous Marriage and Intellectual and Developmental Disabilities among Arab Bedouins Children of the Negev Region in Southern Israel: A Pilot Study. PMID- 24479116 TI - Antimicrobial resistance in the Netherlands: a natural experiment? PMID- 24479115 TI - Probabilistic perception, empathy, and dynamic homeostasis: insights in autism spectrum disorders and conduct disorders. AB - Homeostasis is not a permanent and stable state but instead results from conflicting forces. Therefore, infants have to engage in dynamic exchanges with their environment, in biological, cognitive, and affective domains. Empathy is an adaptive response to these environmental challenges, which contributes to reaching proper dynamic homeostasis and development. Empathy relies on implicit interactive processes, namely probabilistic perception and synchrony, which will be reviewed in the article. If typically-developed neonates are fully equipped to automatically and synchronously interact with their human environment, conduct disorders (CD) and autism spectrum disorders (ASD) present with impairments in empathetic communication, e.g., emotional arousal and facial emotion processing. In addition sensorimotor resonance is lacking in ASD, and emotional concern and semantic empathy are impaired in CD with Callous-Unemotional traits. PMID- 24479117 TI - Pesticides and asthma: challenges for epidemiology. PMID- 24479118 TI - PFMFind: a system for discovery of peptide homology and function. AB - Protein Fragment Motif Finder (PFMFind) is a system that enables e cient discovery of relationships between short fragments of protein sequences using similarity search. It supports queries based on amino acid similarity matrices and position specific score matrices (PSSMs) obtained through an iterative procedure. PSSM construction is customisable through plugins written in Python. PFMFind consists of a GUI client, an index for fast similarity search and a relational database for storing search results and sequence annotations. It is written mostly in Python. The components of PFMFind communicate through TCP/IP sockets and can be located on different physical machines. PFMFind is freely available for download (under a GPL licence) from http://pfmfind.stojmirovic.org. PMID- 24479119 TI - A comparison of the shear bond strength and failure mode to metals of unsupported and supported luting cement specimens. AB - PURPOSE: To compare the mean shear bond strength (SBS) and failure mode of a resin-modified glass-ionomer luting cement (RM-GIC) to five different metals using unsupported and supported cement specimens with different placement of the shear load. MATERIALS AND METHODS: A RM-GIC was bonded to five metals using "unsupported" and "supported" techniques at a SBS-specimen diameter of 2.36 mm. The bond was stressed to failure using shear knife and wire loop debonding protocols. For the shear knife method, the distance of the shear force from the interface was 0 mm or 0.3 mm. Failure analysis was assessed by stereomicroscope and SEM. RESULTS: Two-way ANOVA and post-hoc Tukey's test revealed a significant difference between the unsupported and supported mean SBS. The SBS of supported specimens, where the shear force was applied to the mold that enclosed the specimens, were in most cases statistically significantly higher (p < 0.05) than specimens that were not supported. The mean bond strengths of RM-GIC ranged from 4.5 +/- 2.3 MPa to 27.4 +/- 3.7 MPa. Analysis of the failure mode showed significant differences (p < 0.001) for the test methods except for adhesion to gold-based metal. The adhesive failure mode was between 91% and 97% for supported specimens and between 47% and 63% for unsupported specimens. CONCLUSION: Within the limits of this study, supported specimens exhibited higher mean SBS than unsupported specimens. The method of debonding had a significant effect on the mean SBS for RM-GIC bonded to metal. Mold-supported specimens had a higher incidence of adhesive failure than unsupported cement specimens. PMID- 24479124 TI - Submicron silica spheres decorated with silver nanoparticles as a new effective sorbent for inorganic mercury in surface waters. AB - An analytical method using silica supported silver nanoparticles as a novel sorbent for the enrichment and determination of inorganic mercury (iHg) in surface water samples has been developed. Silver nanoparticles (AgNPs) were synthesized by a completely green procedure and were deposited onto the amine functionalized surface of silica submicrospheres (SiO2-NH2). The prepared nanocomposite material (SiO2/AgNPs) was characterized by transmission electron microscopy, UV-vis spectroscopy, X-ray diffraction and atomic force microscopy. The sorption and desorption characteristics of the nanosorbent SiO2/AgNPs toward Hg species were investigated by a batch method. An excellent separation of iHg and methylHg was achieved in 20 minutes at pH 2. The high selectivity of the SiO2/AgNPs toward iHg was explained by Hg(ii) reduction and subsequent silver mercury amalgam formation. The analytical procedure for the enrichment and determination of inorganic mercury in surface waters was developed based on solid phase extraction and ICP-MS measurements. The total Hg content was determined after water sample mineralization. The recoveries reached for iHg in different surface waters e.g. river and Black sea water samples varied from 96-101%. The limits of quantification are 0.002 MUg L(-1) and 0.004 MUg L(-1) for iHg and total Hg, respectively; the relative standard deviations varied in the ranges of 5-9% and 6-11% for iHg and total Hg, respectively, for Hg content from 0.005 to 0.2 MUg L(-1). The accuracy of the procedure developed for total Hg determination was confirmed by a comparative analysis of surface river (ICP-MS) and sea (CV AFS) waters. PMID- 24479125 TI - A critical comparison of protein microarray fabrication technologies. AB - Of the diverse analytical tools used in proteomics, protein microarrays possess the greatest potential for providing fundamental information on protein, ligand, analyte, receptor, and antibody affinity-based interactions, binding partners and high-throughput analysis. Microarrays have been used to develop tools for drug screening, disease diagnosis, biochemical pathway mapping, protein-protein interaction analysis, vaccine development, enzyme-substrate profiling, and immuno profiling. While the promise of the technology is intriguing, it is yet to be realized. Many challenges remain to be addressed to allow these methods to meet technical and research expectations, provide reliable assay answers, and to reliably diversify their capabilities. Critical issues include: (1) inconsistent printed microspot morphologies and uniformities, (2) low signal-to-noise ratios due to factors such as complex surface capture protocols, contamination, and static or no-flow mass transport conditions, (3) inconsistent quantification of captured signal due to spot uniformity issues, (4) non-optimal protocol conditions such as pH, temperature, drying that promote variability in assay kinetics, and lastly (5) poor protein (e.g., antibody) printing, storage, or shelf-life compatibility with common microarray assay fabrication methods, directly related to microarray protocols. Conventional printing approaches, including contact (e.g., quill and solid pin), non-contact (e.g., piezo and inkjet), microfluidics-based, microstamping, lithography, and cell-free protein expression microarrays, have all been used with varying degrees of success with figures of merit often defined arbitrarily without comparisons to standards, or analytical or fiduciary controls. Many microarray performance reports use bench top analyte preparations lacking real-world relevance, akin to "fishing in a barrel", for proof of concept and determinations of figures of merit. This review critiques current protein-based microarray preparation techniques commonly used for analytical and function-based proteomics and their effects on array-based assay performance. PMID- 24479126 TI - A hydrodynamically optimized nano-electrospray ionization source and vacuum interface. AB - The coupling of atmospheric pressure ionization (API) sources like electrospray ionization (ESI) to vacuum based applications like mass spectrometry (MS) or ion beam deposition (IBD) is done by differential pumping, starting with a capillary or pinhole inlet. Because of its low ion transfer efficiency the inlet represents a major bottleneck for these applications. Here we present a nano-ESI vacuum interface optimized to exploit the hydrodynamic drag of the background gas for collimation and the reduction of space charge repulsion. Up to a space charge limit of 40 nA we observe 100% current transmission through a capillary with an inlet and show by MS and IBD experiments that the transmitted ion beams are well defined and free of additional contamination compared to a conventional interface. Based on computational fluid dynamics modelling and ion transport simulations, we show how the specific shape enhances the collimation of the ion cloud. Mass selected ion currents in the nanoampere range available further downstream in high vacuum open many perspectives for the efficient use of electrospray ion beam deposition (ES-IBD) as a surface coating method. PMID- 24479127 TI - Electrochemical thrombin detection based on the direct interaction of target proteins and graphene oxide as an indicator. AB - Target protein-directed adsorption of graphene oxide (GO) as an electroactive indicator was employed for electrochemical detection of thrombin. The method was highly sensitive and the detection limit was as low as 9.7 pg ml(-1). PMID- 24479129 TI - Poly(3-alkylthiophene)s show unexpected second-order nonlinear optical response. AB - Regioregular poly(3-hexylthiophene)s with chain lengths varying from 5 to 100 monomers are synthesized. Poly(3-hexylthiophene)s show in solution an unexpectedly significant second-order nonlinear optical response. The increase in transition dipole moment upon oligomerisation causes the significant second-order nonlinear optical response. PMID- 24479128 TI - Probing hypoxia-induced staurosporine resistance in prostate cancer cells with a microfluidic culture system. AB - A microfluidic system for cell culture and drug response studies was developed to elucidate the effects of hypoxia on drug susceptibility. Drug response studies were performed in prostate cancer cells and Ramos B cells under normoxic and hypoxic conditions. A vacuum actuated microfluidic culture device was used for cell culture and PC3 cells were cultured in the chip up to 16 hours. Cells were treated with several concentrations of staurosporine and apoptosis was assayed using the fluorescent probes MitoTracker Deep Red and Annexin-V. For hypoxic samples, the chip was placed in a hypoxia chamber and pre-conditioned at <1% oxygen before inducing the cells with staurosporine. Cells exposed to 2 MUM staurosporine were 32% +/- 10% apoptotic under normoxic conditions but only 1.5% +/- 12% apoptotic under hypoxic conditions. As little as 1 hour of hypoxic preconditioning increased drug resistance. Cell apoptosis correlated with drug dose, although in each case hypoxia reduced the apoptotic fraction significantly. Given the rapid nature of cell adaptation to hypoxia, this chip and analysis approach can be used to identify compounds that can induce cell death in hypoxic tumor cells rapidly. PMID- 24479130 TI - Surfactant-free exfoliation of graphite in aqueous solutions. AB - We report an ultrasound exfoliation of graphite in a weakly basic solution to produce multi-layer graphene dispersion. A unique feature of this process is that no surfactant was added to stabilize the exfoliated graphene in water. The concentration of the graphene dispersion prepared by this approach can be up to 0.02 mg mL(-1) and it was stable at room temperature for several months. PMID- 24479131 TI - Julian Hermon Chick. PMID- 24479132 TI - Invasive neighbors. PMID- 24479133 TI - Peripheral smear clues for Bordetella pertussis. PMID- 24479134 TI - The level of hepatic ABCC6 expression determines the severity of calcification after cardiac injury. AB - Because vascular or cardiac mineralization is inversely correlated with morbidity and long-term survival, we investigated the role of ABCC6 in the calcification response to cardiac injury in mice. By using two models of infarction, nonischemic cryoinjury and the pathologically relevant coronary artery ligation, we confirmed a large propensity to acute cardiac mineralization in Abcc6-/- mice. Furthermore, when the expression of ABCC6 was reduced to approximately 38% of wild-type levels in Abcc6+/- mice, no calcium deposits in injured cardiac tissue were observed. In addition, we used a gene therapy approach to deliver a functional human ABCC6 via hydrodynamic tail vein injection to approximately 13% of mouse hepatocytes, significantly reducing the calcification response to cardiac cryoinjury. We observed that the level and distribution of known regulators of mineralization, such as osteopontin and matrix Gla protein, but not osteocalcin, were concomitant to the level of hepatic expression of human and mouse ABCC6. We notably found that undercarboxylated matrix Gla protein precisely colocalized within areas of mineralization, whereas osteopontin was more diffusely distributed in the area of injury, suggesting a prominent association for matrix Gla protein and osteopontin in ABCC6-related dystrophic cardiac calcification. This study showed that the expression of ABCC6 in liver is an important determinant of calcification in cardiac tissues in response to injuries and is associated with changes in the expression patterns of regulators of mineralization. PMID- 24479136 TI - Arrhythmias white book contains first European data on removal of device leads. PMID- 24479135 TI - Prospects for flavonoid and related phytochemicals as nature-inspired treatments for Clostridium difficile infection. AB - AIMS: There is a need for novel treatments for Clostridium difficile infection(CDI). Antibacterial flavonoids are part of a large family of polyphenol phytochemicals with a long history of use in ethnomedicine, but are unexamined against Cl. difficile. We explored their anti-difficile properties. METHODS AND RESULTS: Anti-difficile activities were determined for several naturally occurring flavonoids, olympicin A and synthetic 4-chromanone and chalcone analogues. With the exception of olympicin A, most naturally occurring phytochemicals tested were poorly active. Diversified synthetic flavonoids resembling olympicin A retained anti-difficile activity, suggesting olympicin A could act as a pharmacophore to obtain novel agents. They also demonstrated concentration-dependent killing of logarithmic and stationary phase cultures and reduced sporulation and toxin production. Olympicin A and some synthetic flavonoids dissipated the bacterial transmembrane potential. Interestingly, mutants could only be selected with the analogue 207 at a frequency of 10(-9). CONCLUSIONS: Based on the potent anti-difficile properties of olympicin A and modified flavonoids, further exploration of this class of phytochemicals is warranted. SIGNIFICANCE AND IMPACT OF THE STUDY: Clostridium difficile infection is a major problem in developed countries. These studies point to there being an avenue for optimizing plant-derived flavonoids, and related antibacterial phytochemicals, as nature-inspired approaches to treat CDI. PMID- 24479137 TI - Heart failure in infective endocarditis. PMID- 24479138 TI - The FIFA(r) 11 Steps to prevent sudden cardiac death during football games. PMID- 24479139 TI - John Vetch and his trachoma battles. PMID- 24479140 TI - Critically ill elderly adults with infection: analysis of the extended prevalence of infection in intensive care study. AB - OBJECTIVES: To determine the effect of age on patterns of infection and on outcomes in individuals with infection. DESIGN: Analysis of data from an international, observational, point-prevalence study: Extended Prevalence of Infection in Intensive Care (EPIC II). SETTING: Intensive care units (ICUs; N=1,265) in 75 countries. PARTICIPANTS: All adults present in a participating ICU on May 8, 2007. Individuals with an infection were included and classified according to age (18-44, 45-64, 65-74, 75-84, >=85). MEASUREMENTS: Demographic, physiological, bacteriological, and therapeutic data were collected on the day of the study. Outcome data were collected until hospital discharge or for 60 days. RESULTS: Of the 13,796 adults enrolled in EPIC II, 7,087 (51.4%) had an infection. Of these, 330 (4.7%) were aged 85 and older, 1,405 (19.8%) were 75 to 84, 1,713 (24.2%) were 65 to 74, 2,358 (33.3%) were 45 to 64, and 1,281 (18.1%) were 18 to 44. Severity of illness did not differ between groups. Those aged 85 and older had fewer bloodstream infections than those younger than 75, fewer central nervous system infections than those who were younger than 65, and more abdominal infections than those who were younger than 45. A microbiological diagnosis was established less frequently in participants aged 85 and older than in younger participants. Gram-negative microorganisms were more frequently isolated in those aged 85 and older than in other groups. ICU and hospital mortality were significantly higher in participants aged 85 and older than in those who were younger than 65. CONCLUSION: A large proportion of individuals in the ICU with infection are aged 65 and older. Patterns of infection, including site and type of microorganism, vary according to age. Being aged 85 and older was an independent risk factor for mortality in individuals in the ICU with infection. PMID- 24479141 TI - Unmet needs of community-residing persons with dementia and their informal caregivers: findings from the maximizing independence at home study. AB - OBJECTIVES: To determine the prevalence and correlates of unmet needs in a sample of community-residing persons with dementia (PWD) and their informal caregivers. DESIGN: Analysis of cross-sectional, baseline participant characteristics before randomization in a care coordination intervention trial. SETTING: Baltimore, Maryland. PARTICIPANTS: Community-residing PWD (n=254) and their informal caregivers (n=246). MEASUREMENTS: In-home assessments of dementia-related needs based on the Johns Hopkins Dementia Care Needs Assessment. Bivariate and multivariate regression analyses were conducted to identify demographic, socioeconomic, clinical, functional, and quality-of-life correlates of unmet needs. RESULTS: The mean number of unmet needs was 7.7+/-4.8 in PWD and 4.6+/-2.3 in caregivers, with almost all PWD (99%) and caregivers (97%) having one or more unmet needs. Unmet needs in PWD were significantly greater in those with higher cognitive function. Ninety percent of PWD had unmet safety needs, more than half had unmet needs for meaningful activities, and almost one-third had not received a prior evaluation or diagnosis. Higher unmet needs in PWD was significantly associated with nonwhite race, lower income, less impairment in activities of daily living, and more symptoms of depression. For caregivers, more than 85% had unmet needs for resource referrals and caregiver education. Higher unmet caregiver needs was significantly associated with nonwhite race, less education, and more symptoms of depression. CONCLUSION: Many community-residing PWD and their caregivers have unmet dementia-related needs for care, services, and support. Providers should be aware that unmet needs may be higher in minority and low-income community residents, caregivers with lower education, and individuals with early-stage dementia. Identifying and treating symptoms of depression in PWD and caregivers may enable them to address their other unmet needs. PMID- 24479142 TI - Burden of sliding scale insulin use in elderly long-term care residents with type 2 diabetes mellitus. AB - OBJECTIVES: To examine prevalence, practice patterns, and associated burden of sliding scale insulin (SSI) therapy in elderly adults with type 2 diabetes (T2DM). DESIGN: A retrospective cross-sectional study assessing merged medical chart data and the Minimum Data Set. SETTING: One hundred seventeen long-term care (LTC) facilities in seven U.S. states. PARTICIPANTS: Elderly adults with insulin-treated T2DM (N=2,096) admitted to a LTC facility after January 1, 2009, who had been in the facility for at least 3 months before chart abstraction and had received treatment with non-SSI or SSI regimens. The latter were categorized into SSI-only, basal-SSI, prandial-SSI, basal-prandial-SSI, and multiple regimens with SSI. Data were collected from September 2010 through September 2011. MEASUREMENTS: Demographic and clinical characteristics were recorded. Fingerstick burden was assessed as the average number of fingersticks per week and average number without subsequent insulin administration. Other measures included glycosylated hemoglobin (HbA1c) and hypoglycemia events. RESULTS: Overall, 73.8% of participants received SSI therapy. SSI-treated participants were more likely to be younger (P=.01), non-white (P=.002), and receiving sulfonylurea (P=.004) than non-SSI treated participants. SSI therapy was associated with a mean+/ standard deviation of 19.9+/-7.9 fingersticks per week, of which 12.5+/-7.6 were not followed by insulin administration. Fewer SSI-treated participants than non SSI treated participants had one or more HbA1c measurements of 7.0% or less (48.8% vs 57.2%) or 8.5% or less (85.2% vs 87.6%, respectively). Rates of hypoglycemia were similar in both groups (15.0% vs 14.9%). CONCLUSION: SSI therapy is widely used in LTC facilities and is associated with a high fingerstick burden. SSI regimens are associated with poorer glycemic control but a rate of hypoglycemia similar to that of non-SSI regimens. PMID- 24479143 TI - Prevalence of and potential risk factors for mild cognitive impairment in community-dwelling residents of Beijing. AB - OBJECTIVES: To estimate the prevalence of mild cognitive impairment (MCI) in Beijing, China, and to explore the potential protective and risk factors for MCI. DESIGN: Population-based survey. SETTING: The Beijing Ageing Brain Rejuvenation Initiative (BABRI). PARTICIPANTS: Participants randomly recruited from BABRI (N=1,211). MEASUREMENTS: Participants underwent a battery of neuropsychological examinations to determine cognitive function and answered a series of personal questions. The prevalence of MCI and its subtypes were computed using Petersen's criteria. Influencing factors for MCI were estimated based on participant medical history, lifestyle, diet, and leisure activities. RESULTS: One thousand twenty (aged>55, mean 63.9+/-6.6; 36.7% male) subjects completed the neuropsychological tests. The overall prevalence of MCI was 15.7%, with single-domain amnestic, multiple-domain amnestic, and nonamnestic subtype prevalences of 6.4%, 3.7%, and 5.6%, respectively. Eight hundred sixty-four subjects were used for the case control analysis. Hypertension, diabetes mellitus, and cerebrovascular disease were found to be associated with MCI. Healthy diet and greater involvement in physical, intellectual, and social activities were associated with a lower risk of MCI. CONCLUSION: The prevalence of MCI was compatible with that found in previous published reports, and the information on the epidemiology of MCI, especially risk factors, may help to explore therapeutic strategies and preventive approaches to delay conversion to dementia. PMID- 24479144 TI - Executive function and mortality in homebound elderly adults. AB - OBJECTIVES: To determine the association between executive function and mortality in homebound elderly adults. DESIGN: Longitudinal study. SETTING: Four home care agencies in the Boston area. PARTICIPANTS: Homebound adults aged 60 and older with 8-year follow-up for mortality (N=1,172). MEASUREMENTS: Cognitive domains including executive, memory, and language functions were evaluated at baseline. Executive function was measured using the Trail-Making Test Part B (TMT B), and subjects were divided into four subgroups from lowest to highest TMT B score. The second cross-group analyses were used to compare those who were alive and those who had died. Multivariate logistic regression analysis was used to determine whether there was an association between TMT B scores and mortality. RESULTS: At baseline, 436 (37.2%) homebound elderly adults had the highest TMT B scores (>=300), which indicated the slowest performance. At 8-year follow-up, 381 (32.5%) participants had died. Participants with the highest TMT B scores were more than twice as likely to have died as those with the lowest scores (0-99) (odds ratio=2.39, 95% confidence interval=1.27-4.52, P=.003) after adjusting for confounders including medical comorbidities related to death. The other cognitive domains, including memory and language, were not associated with mortality in the same model. CONCLUSION: Many homebound elderly adults have multiple medical conditions, and executive function may be critical in their ability to manage their medical conditions and may affect the outcome of death. PMID- 24479145 TI - Prevalence, awareness, treatment, and control of hypertension in elderly adults with chronic kidney disease: results from the survey of Prevalence, Awareness, and Treatment Rates in Chronic Kidney Disease Patients with Hypertension in China. AB - OBJECTIVES: Data regarding hypertension in elderly adults with chronic kidney disease (CKD) remains limited. This study aimed to assess the epidemiological characteristics of hypertension in elderly adults with CKD using data from a nationwide survey. DESIGN: A nationwide, multicenter, cross-sectional study with a large sample. SETTING: The Survey of Prevalence, Awareness, and Treatment Rates in Chronic Kidney Disease Patients with Hypertension in China (PATRIOTIC). PARTICIPANTS: Participants in PATRIOTIC (aged>=60; n=2,414). MEASUREMENTS: Trained physicians measured blood pressure (BP) using a standard protocol with a mercury sphygmomanometer at the time of admission. RESULTS: The prevalence, awareness, and treatment of hypertension in elderly adults with CKD were 82.0%, 90.7%, and 87.3%, respectively. The control of hypertension at BP less than 140/90 mmHg was 29.6% and at BP less than 130/80 mmHg it was 12.1%. No significant differences were noted in the prevalence, awareness, treatment, or control of hypertension in individuals with CKD divided into the age groups of 60 to 69, 70 to 79, and 80 and older (P>.05). With increasing age, the proportion of isolated systolic hypertension in elderly adults with CKD with uncontrolled hypertension increased (P=.02). Obesity (P=.01), CKD Stages 4 and 5 (P<.001), and concomitant diabetes mellitus (P=.002) were significantly associated with uncontrolled hypertension in elderly adults with CKD, using the goal of BP less than 140/90 mmHg. CONCLUSION: The prevalence of hypertension in elderly adults in China with CKD is high, and its control is poor. Most elderly adults with CKD with uncontrolled hypertension have systolic hypertension. Obesity, CKD Stages 4 and 5, and diabetes mellitus were adversely associated with greater uncontrolled hypertension in elderly adults with CKD. PMID- 24479146 TI - Cognitive dysfunction and greater visit-to-visit systolic blood pressure variability. AB - OBJECTIVES: To determine whether variability in blood pressure (BP) is negatively associated with performance on cognitive testing. DESIGN: Multinational, longitudinal, observational cohort study. SETTING: The Alzheimer's Disease Neuroimaging Initiative study. PARTICIPANTS: Individuals with a screening diagnosis of mild cognitive impairment or normal cognition (N=626). MEASUREMENTS: Mean, variance, and maximum BP were calculated based on measures collected from screening to 36 months. Analysis of covariance models were used to determine the association between BP measures and cognitive scores at 36 months after adjusting for covariates. RESULTS: Greater variability in systolic (P<.05) but not diastolic (P>.18) BP was associated with worse global (Modified Alzheimer's Disease Assessment Scale Cognitive Component and Clinical Dementia Rating sum of boxes) and executive (Trail-Making Test Part B, Animal Fluency, and Vegetable Fluency) function and episodic memory (Rey Auditory Verbal Learning Test Total Score). CONCLUSION: There is a clinically significant association between greater systolic BP variability and greater cognitive dysfunction. These results should be verified in other well-characterized cohorts, and the neuroanatomical pathophysiology underlying the observed greater cognitive impairment should be further explored. PMID- 24479147 TI - Racial and sex differences in associations between activities of daily living and cognition in community-dwelling older adults. AB - OBJECTIVES: To examine the association between function measured according to activities of daily living (ADLs), instrumental activ1ities of daily living (IADLs), and cognition assessed according to Mini-Mental State Examination (MMSE) scores of older African-American and non-Hispanic white community-dwelling men and women. DESIGN: Cross-sectional study assessing associations between self reported ADL and IADL difficulty and MMSE scores for race- and sex-specific groups. SETTING: Homes of community-dwelling older adults. PARTICIPANTS: A random sample of 974 African-American and non-Hispanic white Medicare beneficiaries aged 65 and older living in west-central Alabama and participating in the University of Alabama at Birmingham Study of Aging, excluding those with reported diagnoses of dementia or with missing data. MEASUREMENTS: Function, based on self-reported difficulty in performing ADLs and IADLs, and cognition, using the MMSE. Multivariable linear regression models were used to test the association between function and cognition in race- and sex-specific groups after adjusting for covariates. RESULTS: Mini-Mental State Examination scores were modestly correlated with ADL and IADL difficulty in all four race- and sex-specific groups, with Pearson correlation coefficients ranging from -0.189 for non Hispanic white women to -0.429 for African-American men. Correlations between MMSE and ADL or IADL difficulty in any of the race- and sex-specific groups were no longer significant after controlling for sociodemographic factors and comorbidities. CONCLUSION: Mini-Mental State Examination was not significantly associated with functional difficulty in older African-American and non-Hispanic white men and women after adjusting for sociodemographic factors and comorbidities, suggesting a mediating role in the relationship between cognition and function. PMID- 24479148 TI - Predicting on-road assessment pass and fail outcomes in older drivers with cognitive impairment using a battery of computerized sensory-motor and cognitive tests. AB - OBJECTIVES: To generate a robust model of computerized sensory-motor and cognitive test performance to predict on-road driving assessment outcomes in older persons with diagnosed or suspected cognitive impairment. DESIGN: A logistic regression model classified pass-fail outcomes of a blinded on-road driving assessment. Generalizability of the model was tested using leave-one-out cross-validation. SETTING: Three specialist clinics in New Zealand. PARTICIPANTS: Drivers (n=279; mean age 78.4, 65% male) with diagnosed or suspected dementia, mild cognitive impairment, unspecified cognitive impairment, or memory problems referred for a medical driving assessment. MEASUREMENTS: A computerized battery of sensory-motor and cognitive tests and an on-road medical driving assessment. RESULTS: One hundred fifty-five participants (55.5%) received an on-road fail score. Binary logistic regression correctly classified 75.6% of the sample into on-road pass and fail groups. The cross-validation indicated accuracy of the model of 72.0% with sensitivity for detecting on-road fails of 73.5%, specificity of 70.2%, positive predictive value of 75.5%, and negative predictive value of 68%. CONCLUSION: The off-road assessment prediction model resulted in a substantial number of people who were assessed as likely to fail despite passing an on-road assessment and vice versa. Thus, despite a large multicenter sample, the use of off-road tests previously found to be useful in other older populations, and a carefully constructed and tested prediction model, off-road measures have yet to be found that are sufficiently accurate to allow acceptable determination of on-road driving safety of cognitively impaired older drivers. PMID- 24479149 TI - Review: two online curricula on transitions of care. AB - Transitional care is an important part of geriatric medicine that has not traditionally been taught to residents through formal curricula. This article reviews two online curricula available through the Portal of Geriatric Online Education. The two products reviewed here, appropriate for resident training, focus on care transitions from hospital to other care settings. PMID- 24479151 TI - The role of parental alcohol use, parental discipline and antisocial behaviour on adolescent drinking trajectories. AB - BACKGROUNDS: Parental drinking, harsh parental discipline and adolescent antisocial behaviour have been independently implicated in adolescent alcohol use. Robust prospective studies are required to examine developmental relationships between these factors and their effect on trajectories of alcohol use across adolescence. METHODS: Data were ascertained at three consecutive adolescent waves (13.5, 15.5 and 17.5 years) from the Australian Temperament Project, a 15-wave (30 year) general population birth cohort in Victoria, Australia. Adolescent alcohol trajectories, adjusted for time-varying measures of parenting and antisocial behaviour, were regressed on time-stable measures of parental alcohol use. The full case analysis comprised 751 individuals with complete data. RESULTS: Two distinct alcohol trajectories were identified across the three adolescent waves after adjusting for time-varying factors: a higher and lower drinking group. Both trajectories increased linearly over the study period. Antisocial behaviour was positively associated with both trajectories while harsh parental discipline was positively associated with alcohol use in the lower-use group only. Increased maternal and paternal drinking at 13.5 years placed teenagers at a greater risk of being included in the high-risk trajectory. CONCLUSION: Parental drinking was the strongest predictor of different drinking trajectories in adolescence. This finding underscores the importance of comprehensive public heath approaches that target both parental and adolescent drinking attitudes and behaviour. PMID- 24479150 TI - Sensor monitoring to measure and support daily functioning for independently living older people: a systematic review and road map for further development. AB - OBJECTIVES: To study sensor monitoring (use of a sensor network placed in the home environment to observe individuals' daily functioning (activities of daily living and instrumental activities of daily living)) as a method to measure and support daily functioning for older people living independently at home. DESIGN: Systematic review. SETTING: Participants' homes. PARTICIPANTS: Community-dwelling individuals aged 65 and older. MEASUREMENTS: A systematic search in PubMed, Embase, PsycINFO, INSPEC, and The Cochrane Library was performed for articles published between 2000 and October 2012. All study designs, studies that described the use of wireless sensor monitoring to measure or support daily functioning for independently living older people, studies that included community-dwelling individuals aged 65 and older, and studies that focused on daily functioning as a primary outcome measure were included. RESULTS: Seventeen articles met the inclusion criteria. Nine studies used sensor monitoring solely as a method for measuring daily functioning and detecting changes in daily functioning. These studies focused on the technical investigation of the sensor monitoring method used. The other studies investigated clinical applications in daily practice. The sensor data could enable healthcare professionals to detect alert conditions and periods of decline and could enable earlier intervention, although limited evidence of the effect of interventions was found in these studies because of a lack of high methodological quality. CONCLUSION: Studies on the effectiveness of sensor monitoring to support people in daily functioning remain scarce. A road map for further development is proposed. PMID- 24479152 TI - Mauritius: Fight against tobacco manufacturing plant. PMID- 24479153 TI - Australia: 'Village approach' to prison smoking ban. PMID- 24479155 TI - Japan: Japan Tobacco International again moves towards full privatisation. PMID- 24479154 TI - Malaysia: Standing firm on trade and tobacco. PMID- 24479157 TI - Michael Neuberger (1953-2013). PMID- 24479156 TI - Knowledge of the health consequences of obesity among overweight/obese Black and Hispanic adults. AB - OBJECTIVE: To measure knowledge of the health consequences of obesity among overweight/obese Black and Hispanic adults and examine the relationship to prior weight loss. METHODS: Knowledge of the health consequences of obesity was assessed among 410 Black and Hispanic adults with BMI >= 25 kg/m2 enrolled in a behavior change weight loss study. The relationship between obesity risk knowledge and previous weight loss was also examined. RESULTS: The majority of participants were knowledgeable of the risk of hypertension (94%), diabetes (96%), high cholesterol (91%), joint pains/arthritis (89%) and sleep apnea (89%) associated with obesity. Among post-menopausal age women, 53% were aware of the increased risk of breast cancer. There was no significant relationship between obesity risk knowledge and previous weight loss of 10 pounds or more (OR = 1.075, 95% CI: [0.808, 1.430]). CONCLUSIONS: We found that knowledge of the health consequences of obesity was high, except for knowledge of the risk of breast cancer. Obesity risk knowledge was not associated with past weight loss. PRACTICE IMPLICATIONS: Further health education is needed regarding the increased risk of breast cancer associated with obesity. Our data suggest that knowledge of the health consequences of obesity is not associated with weight loss success. PMID- 24479158 TI - Leonard Herzenberg (1931-2013): the life of FACS. PMID- 24479160 TI - Reply: To PMID 23237857. PMID- 24479161 TI - Authors' response. PMID- 24479159 TI - Dkk1 in the peri-cloaca mesenchyme regulates formation of anorectal and genitourinary tracts. AB - Anorectal malformation (ARM) is a common birth defect but the developmental history and the underlying molecular mechanism are poorly understood. Using murine genetic models, we report here that a signaling molecule Dickkopf-1 (Dkk1) is a critical regulator. The anorectal and genitourinary tracts are major derivatives of caudal hindgut, or the cloaca.Dkk1 is highly expressed in the dorsal peri-cloacal mesenchymal (dPCM) progenitors. We show that the deletion of Dkk1 causes the imperforate anus with rectourinary fistula. Mutant genital tubercles exhibit a preputial hypospadias phenotype and premature urethral canalization.Dkk1 mutants have an ectopic expansion of the dPCM tissue, which correlates with an aberrant increase of cell proliferation and survival. This ectopic tissue is detectable before the earliest sign of the anus formation, suggesting that it is most likely the primary or early cause of the defect. Deletion of Dkk1 results in an elevation of the Wnt/beta-catenin activity. Signaling molecules Shh, Fgf8 and Bmp4 are also upregulated. Furthermore, genetic hyperactivation of Wnt/beta-catenin signal pathway in the cloacal mesenchyme partially recapitulates Dkk1 mutant phenotypes. Together, these findings underscore the importance ofDKK1 in regulating behavior of dPCM progenitors, and suggest that formation of anus and urethral depends on Dkk1-mediated dynamic inhibition of the canonical Wnt/beta-catenin signal pathway. PMID- 24479162 TI - The spectrum of haemodynamic support in cardiogenic shock: how to choose and use. PMID- 24479163 TI - Evaluation of the relations between the presence of the metabolic syndrome and the degree of visceral obesity and the severity of coronary artery disease by coronary angiography. AB - BACKGROUND: The prevalence of the metabolic syndrome (MetSy) steadily increases worldwide. AIM: To evaluate the relation between the presence of MetSy and visceral obesity and the presence of coronary lesions, and to assess correlations between waist circumference and body mass index (BMI) and coronary lesions. METHODS: We studied 105 patients who underwent elective coronary angiography. The study population was divided into four groups depending on the presence of MetSy and visceral obesity. Coronary angiographic evaluation was performed by an invasive cardiologist. For ultimate objective evaluation of the degree of coronary stenoses, quantitative coronary angiography was performed. Based upon coronary angiography results, patients were divided into four groups depending on the severity of coronary artery disease (CAD): with no coronary lesions, with haemodynamically insignificant lesions (1-69% stenosis), with haemodynamically significant lesions (> 70%) in 1 or 2 vessels, and with multivessel disease (> 70% stenoses in 3 vessels or a > 50% stenosis in the left main coronary artery). RESULTS: Normal coronary arteries were significantly more commonly found in patients without obesity and MetSy (50% of patients). Haemodynamically significant lesions were most frequently found among obese patients with MetSy (40% of patients) and among obese patients without MetSy (38.1% of patients). Concomitant presence of obesity among patients with MetSy (i.e., MetSy with obesity as compared to MetSy without obesity) was not found to be significantly related to the severity of CAD. In addition, advanced CAD was significantly more frequent in obese patients with MetSy compared to the other groups. Isolated visceral obesity in patients without MetSy (i.e., obese patients without MetSy as compared to non-obese patients without MetSy) was found to correlate with haemodynamically significant coronary lesions. When we evaluated nonparametric correlations between waist circumference, BMI; and the severity of CAD, BMI did not correlate with coronary lesions (r = 0.08, p = 0.37). In contrast, a significant correlation was found between waist circumference and the severity of CAD (r = 0.55, p < 0.001). Haemodynamically significant lesions were more significantly more frequent in patients with MetSy compared to patients without MetSy (76% vs. 24%, p < 0.001). Haemodynamically significant lesions were found in 67.7% of patients with isolated visceral obesity compared to 23.2% of non obese patients without MetSy. In multivariate analysis, CAD was significantly more likely among patients with MetSy regardless of the analysed model (OR 5.3, 95% CI 1.1-25.8, p < 0.05). CONCLUSIONS: 1. The presence of MetSy significantly correlates with haemodynamically significant coronary lesions. 2. The degree of visceral obesity significantly correlates with the severity of CAD. 3. BMI does not correlate with the severity of CAD. 4. Isolated visceral obesity is a weaker determinant of haemodynamically significant coronary lesions compared to MetSy with associated obesity. 5. MetSy is associated with significantly more advanced coronary lesions, i.e. multivessel disease. PMID- 24479164 TI - [Prevalence and main methods of treatment of advanced stages of Parkinson's disease]. PMID- 24479165 TI - [A method of electrocraniostimulation in medical practice]. PMID- 24479166 TI - [Experimental and clinical evidence for anticonvulsant activity of melatonin]. PMID- 24479167 TI - [The XXI European congress of psychiatry]. PMID- 24479168 TI - [International round-table discussion << I build my life myself >>: an experience exchange on psychosocial rehabilitation]. PMID- 24479170 TI - [Korsakoff's conception on psychopathic constitution and predisposition to mental disorders]. PMID- 24479171 TI - Estradiol associated with lower thrombotic risk than conjugated equine estrogens when used as oral HRT. PMID- 24479172 TI - Vitamin D supplements for the prevention of osteoporosis judged 'inappropriate'. PMID- 24479173 TI - Continuing bonds, risk factors for complicated grief, and adjustment to bereavement. AB - This study examined type of continuing bonds (CB) expression in relation to risk factors for complicated grief and measures of bereavement-related adjustment. Externalized CB expressions involving illusions and hallucinations with the deceased were distinguished from internalized CB expressions involving use of the deceased as an autonomy promoting secure base. 502 bereaved participants completed over the internet a CB measure assessing externalized and internalized CB along with various known risk-factor measures that included cause of death (i.e., violent vs. non-violent death), responsibility for the death, and attachment style as well as measures of psychological adjustment that included complicated grief symptoms, perceived physical health, and personal growth. As predicted, externalized CB was positively associated with violent death and responsibility for the death, whereas internalized CB was negatively associated with these risk factors as well as uniquely positively linked to personal growth. The implications of the findings for the role of CB in adjustment are discussed. PMID- 24479174 TI - Acts of resistance: breaking the silence of grief following traffic crash fatalities. AB - Theoretical arguments and empirical evidence demonstrate the limited utility of a narrow construction of "normal" grief. Sudden and violent death, the young age of the deceased, and perceptions of death preventability are associated with grief reactions that extend beyond an expected grief response. Interviews were conducted with 21 adults bereaved through the death of a family member in a traffic crash. We present their attempts to resist notions of "working through" grief and "recovery" from it and consider how the participants' constructions of an alternative discourse, or normative narrative, possess the potential to challenge a prevailing grief discourse. PMID- 24479175 TI - The reasons for suicide: an analysis of the diary of Arthur Inman. AB - Previous analyses of the diary of Arthur Inman, who committed suicide in 1963, portrayed him as psychiatrically disturbed, warped, corrupt, and weak. In contrast, the present article argues that he was an eccentric individual whose diary writing enabled him to live a full life by giving his life a purpose and by enabling him to ventilate at length. PMID- 24479176 TI - Athletes, doctors, and lawyers with first names beginning with "D" die sooner. AB - For many people, names have symbolic power that extends to their timing of death. This study examined the relationship between the symbolic significance of the first letters in the names of professional athletes (baseball, football, hockey, and basketball) and their longevity. A similar analysis was performed for doctors (radiologists, dermatologists, obstetricians/gynecologists) and lawyers for comparison purposes. There was a progressive decrease in longevity associated with names beginning with A to D when all athletes were combined. In each sport, athletes whose first names began with the letter D lived fewer years than those whose names collectively began with E to Z. Doctors and lawyers whose first names began with D also died earlier than those whose names began with E to Z but differences were not statistically significant. A Cox-regression survival analysis for athletes comparing those with names beginning with A, B, C and D vs. E to Z indicated that only those whose names began with D (median survival = 68.1 years) differed significantly from those with E to Z names (median survival = 69.9 years). PMID- 24479177 TI - A meta-analysis of interventions for bereaved children and adolescents. AB - The main objective of this review was to provide a quantitative and methodologically sound evaluation of existing treatments for bereavement and grief reactions in children and adolescents. Two meta-analyses were conducted: 1 on controlled studies and 1 on uncontrolled studies. The 2 meta-analyses were based on a total of 27 treatment studies published before June 2006. Hedges's g and Cohen's d were used as measures of effect size and a random-effects model was applied. Results yielded small to moderate effect sizes. Interventions for symptomatic or impaired participants tended to show larger effect sizes than interventions for bereaved children and adolescents without symptoms. Promising treatment models were music therapy and trauma/grief-focused school based brief psychotherapy. PMID- 24479178 TI - Predictors of complicated grief after a natural disaster: a population study two years after the 2004 South-East Asian tsunami. AB - The authors examined predictors of complicated grief (CG) in Norwegians 2 years after bereavement in the 2004 South-East Asian tsunami. A cross-sectional postal survey retrospectively covering disaster experiences and assessing CG according to the Inventory of Complicated Grief yielded 130 respondents (35 directly disaster-exposed and 95 not directly exposed), with 47.7% screening CG positive. They identified positive associations between CG and being female, losing a child or spouse, and time to death confirmation, and negative associations with previous losses, being employed, and receiving social support. Direct exposure did not increase CG risk. Support service providers should be aware of this high prevalence of severe, persistent grief. PMID- 24479179 TI - Validation of the Perinatal Grief Scale for use in Chinese women who have experienced recent reproductive loss. AB - The primary objective of this research was to validate the short version of the Perinatal Grief Scale (SVPGS) in the Chinese population. The Chinese SVPGS was administered to a sample of Chinese women who had experienced recent reproductive loss (N = 314). The results of the confirmatory factor analysis rejected the original 3-factor model delineated by Potvin (1989). A follow-up exploratory factor analysis suggested an alternative 3-factor model, consisting of a 12-item Sense of Worthlessness subscale, a 7-item Social Detachment subscale, and a 7 item Painful Recollection subscale. Further analysis showed that both the original and Chinese SVPGS demonstrated good internal consistency. Cronbach's alpha equaled .86, .83, .90, and .95, respectively, for the three subscales of Active Grief, Difficulty Coping, and Despair, and the total original SVPGS, and .85, .93, .91, and .95, respectively, for the new subscales of Sense of Worthlessness, Social Detachment, and Painful Recollection, and the total Chinese SVPGS. Both versions demonstrated satisfactory correlations with the participants' psychological distress and spousal emotional support. The authors suggest that both versions are useful in measuring the responses of Chinese women to reproductive loss; the original SVPGS should be used for cross-cultural studies, whereas the Chinese SVPGS should be used for local studies. PMID- 24479180 TI - Exploring donation decisions: beliefs and preferences for organ donation in Australia. AB - The authors explored common beliefs and preferences for posthumous and living organ donation in Australia where organ donation rates are low and little research exists. Content analysis of discussions revealed the advantage of prolonging/saving life whereas disadvantages differed according to donation context. A range of people/groups perceived to approve and disapprove of donation were identified. Barriers for posthumous donation included a family's objection, with the type of organ needed important for living donation. Motivators included knowledge about potential organ recipients. Donation preferences favored loved ones, with weaker preferences for recipients who were perceived as morally questionable or responsible for their illness. PMID- 24479181 TI - Risk factors for bereavement outcome: a multivariate approach. AB - Bereavement increases the risk of ill health, but only a minority of bereaved suffers lasting health impairment. Because only this group is likely to profit from bereavement intervention, early identification is important. Previous research is limited, because of cross sectional designs, small numbers of risk factors, and use of a single measure of bereavement outcome. Our longitudinal study avoids these pitfalls by examining the impact of a large set of potential risk factors on grief depressive symptoms, emotional loneliness, and positive mood following recent bereavement (3 years maximum). Participants provided information 3 times over 6 months. A multivariate approach was chosen to avoid reporting spurious results due to confounding. As expected, risk factors were differentially related to different outcome measures. For example, being high in anxious attachment and having lost a partner were related to more intense feelings of emotional loneliness, whereas these variables did not predict any of the other outcome variables. By contrast, social support did not influence emotional loneliness but did predict grief depressive symptoms and positive mood. Implications of these findings are discussed. PMID- 24479182 TI - Of broken bonds and bondage: an analysis of loss in the Slave Narrative Collection. AB - Relatively few scholars have made use of the Slave Narrative Collection, a collection of more than 2,300 autobiographical narratives detailing the lives of people who had been born into slavery. Housed at the Library of Congress, the Collection was gathered during the 1930s under the direction of the Federal Writers Project. Research derived from the Collection thus far has dealt primarily with the experience of slavery as a whole. The present study focuses on loss as it was experienced by former slaves. This qualitative study used a grounded theory approach to analyze 48 narratives. Results culminated in a core category or central theme that for former slaves loss was both a cause and a consequence of dehumanization. Findings also suggested that people experienced loss as a result of witnessing or experiencing violence and of living in deprivation and fear. Other losses included losses of hope and identity. Losses associated with the pain and suffering of family members were hardest to bear. PMID- 24479183 TI - Giving birth to life--again!: bereaved parents' experiences with children born following the death of an adult son. AB - This article is based on a qualitative study examining the experiences of parents that lost a son during military service in Israel and consequently choose to give birth to another child. Seven couples and 3 mothers were interviewed for the study, and their interviews were analyzed using a phenomenological-hermeneutic approach. Three main themes were extracted from parents' descriptions of their experiences: (a) "From the place where pain and sadness was sown, a new smile was grown," relating to transforming the experience of loss into a new meaning for life; (b) "No to a child memorial," focusing on parents' awareness of the burden placed on the child who was born; and (c) "Different parenting," dealing with participant's parenting following their loss. The study's findings are discussed in the context of literature dealing with reconstructing meaning through coping and bereavement. PMID- 24479184 TI - Separation from loved ones in the fear of death. AB - Individuals' death anxiety or fear of death has been extensively investigated, and there are numerous conceptualizations used in the literature, including a distinction between the dimensions of death and dying of self and death and dying of others. This article addresses a gap in the literature and re-examines the relationship between these two dimensions, which are assumed to be positively, linearly related. Using both quantitative and qualitative data, this study indicates that regardless of the degree to which individuals fear their own death, most individuals fear the death and dying of others. Specifically, the leaving, or loss of loved ones, was a central theme in people's fear of death, and this is discussed in relation to current trends in the literature. PMID- 24479185 TI - Suicide notes from India and the United States: a thematic comparison. AB - Suicide is a global concern, hence, cross-cultural research ought to be important; yet, there is a paucity of cross-cultural study in suicidology. This study sought to investigate suicide notes drawn from India and the United States, as these countries have similar suicide rates but markedly different cultures. A thematic or theoretical-conceptual analysis of 72 suicide notes drawn from these countries, matched for age and gender, was undertaken, based on Leenaars' (1996) multidimensional model of suicide. The results suggested that there were more commonalities than differences; yet, not consistent with previous cross-cultural studies of suicide notes, Indian notes expressed more indirect expression including veiled aggression, or aggression turned inward, and unconscious dynamics. It was concluded that the model may be applicable to suicide in both countries, but also much greater study in India is warranted on collectivism and dissembling as a suicide risk factor. PMID- 24479186 TI - The role of grief, anxiety, and depressive symptoms in the use of bereavement services. AB - This study examined the role of psychological distress in the use of bereavement services at six months post-loss by 250 bereaved spouses in the Changing Lives of Older Couples study. Approximately 52% (129) used services, commonly provided by physicians and clergy. Hierarchical logistic regression analyses indicated that Black race, higher educational level, elevated depressive symptoms, anxiety, and grief were related to greater service use. Other predisposing, enabling, and need variables were not related to service use. Findings suggest the need for outreach and education with physicians and clergy and the importance of an accessible, comprehensive range of community-based bereavement services. PMID- 24479187 TI - Prevalence and severity of college student bereavement examined in a randomly selected sample. AB - The authors used stratified random sampling to assess the prevalence and severity of bereavement in college undergraduates, providing an advance over findings that emerge from convenience sampling methods or from anecdotal observations. Prior research using convenience sampling indicated that 22% to 30% of college students are within 12 months of having experienced the death of a family member or friend. Using an ethnically diverse sample from a private, Midwestern university, 118 randomly selected students answered demographic and life experience questions and indicated whether a family member or friend had died within the last 24 months. Those who reported experiencing such a loss also completed the PG-13, a questionnaire used to assess prolonged grief disorder. Results indicated that 30% of the sample was within 12 months of experiencing a loss and 39% was within 24 months of experiencing a loss. Two of the students bereaved at 12 months (1.7% of the sample) were classified as having prolonged grief disorder. A limiting factor in this study is the homogeneity of the sample in terms of geographic location and religious preference. The authors concluded that a significant portion of college students are bereaved at any given time, confirmed previous estimates of the prevalence rate, and noted university assistance may be needed to prevent academic decline. PMID- 24479188 TI - The debreather: a report on euthanasia and suicide assistance using adapted scuba technology. AB - In response to the general prohibition of euthanasia and assisted suicide, some right-to-die activists have developed non-medical methods to covertly hasten death. One such method is a "debreather," a closed system breathing device that laypersons can use to induce hypoxia for persons seeking euthanasia or assisted suicide. This article presents data from nine cases where the debreather was used on humans, resulting in eight deaths. The covert properties of the debreather make it almost impossible for medical examiners and law enforcers to detect its use. Clandestine behavior circumvents legal forms of social control and challenges models for regulated, medicalized euthanasia and assisted suicide. The debreather compromises the ability of forensic investigators to assign an accurate cause and manner of death, and this raises implications for law enforcement, vital statistics, and research into the causes of death. The involvement of lay organizations in euthanasia and assisted suicide means that effective social policy on right-to-die issues must take into account their activities as well as those of other health professionals. PMID- 24479189 TI - Psychological and ethical considerations concerning the debreather and assisted suicide: a commentary on Ogden. AB - This article offers a commentary on the report by Russel Ogden (2010/this issue) on the use of the "debreather" for suicide assistance by the NuTech (or New Technologies for Self-Deliverance) program. The emergence of NuTech is set within its historical and political context. Nu Tech is criticized for its anarchic and extreme advocacy of self-determination to the neglect of other psychological and ethical considerations (e.g., the individual's emotional state, the mutability of his or her quality of life, and his or her decision-making capacity). Some of the risks of covert, unregulated, assisted death are noted as is a potential shift in healthcare that might diminish interest in the undignified NuTech methods of dying. PMID- 24479190 TI - The debreather and NuTech: a reply to Kleespies. AB - This article responds to Phillip Kleespies's (2010/this issue) commentary on NuTech fieldworkers and their use of the debreather. Non-medical assistance with suicide raises legitimate concerns about accountability, public safety, and care for those who are suffering. Given that suicide is not a crime, an outcome of the NuTech movement may be that suicide techniques will become refined to a point where covert assistance is unnecessary. Assuming that the internal social controls of NuTech fieldworkers will permit greater transparency, it is foreseeable that fieldworkers will eventually report suicides to the authorities, similar to the Swiss model for assisted suicide. PMID- 24479191 TI - The role of hope in bereavement for Chinese people in Hong Kong. AB - This study examined the relationships between hope and the emotional reactions of bereaved Chinese people in Hong Kong. Three groups--a clinical bereaved sample (n = 140), a general bereaved sample (n = 152), and a non-bereaved comparison sample (n = 144)--were included. Significant differences in 3 hope measures, hope (pathway), hope (agency) and hope (total), were found between the 3 groups. Moderately strong correlations were found between hope measures and emotional reactions. A mediating effect for hope (agency), but not for hope (pathway) and hope (total), was found in the relationship between bereavement. Possibilities for working with Chinese bereaved people and implications for research and training were discussed. PMID- 24479192 TI - Death and dying anxiety among elderly Arab Muslims in Israel. AB - Death and dying anxiety were examined among elderly Arab Muslims in Israel. A total of 145 people aged 60 and over were interviewed using a standardized questionnaire. Nursing home residents reported higher death anxiety than others; women and uneducated participants reported greater levels of fear of death and dying than others. There were no differences based on religiosity. Death anxiety was related to gender and education for elderly living in the community, but social support and self-esteem were additional correlates for those living in nursing homes. The results of this study indicate that fostering a sense that one has a supportive social and familial network is important in decreasing death and dying anxiety among elderly Arab people. It would also be beneficial to provide information and knowledge that might relieve some of the anxiety they experience. PMID- 24479206 TI - [Effect of urokinase on cerebral perfusion in rabbits after cardiopulmonary resuscitation]. AB - OBJECTIVE: To investigate the effect of urokinase on cerebral microcirculatory perfusion after cardiopulmonary resuscitation (CPR) in rabbits after cardiac arrest (CA). METHODS: Twenty New Zealand rabbits were assorted into drug thrombolysis group and routine CPR group by randomized digital method with 10 in each group. Potassium chloride injection combined with asphyxia was employed to establish the CA model, CPR and basic life-support were performed in routine CPR group. Following the above treatments, 20 kU/kg urokinase was given in thrombolysis group. The relative cerebral blood flow (rCBF), cerebral blood volume (rCBV) and top teep time (rTTP) were observed by dual-slice spiral CT cerebral perfusion imaging in order to investigate the effect of urokinase on cerebral microcirculatory perfusion in rabbits. RESULTS: rCBF and rCBV in thrombolysis group were significantly higher than those in routine CPR group (rCBF: 1.248+/-0.139 vs 0.900+/-0.070, t=6.870, P=0.000; rCBV: 1.206+/-0.117 vs. 0.969+/-0.067, t=6.156, P=0.000), and rTTP in thrombolysis group was significantly shorter than that in routine CPR group (0.950+/-0.037 vs. 1.015+/ 0.026, t=3.777, P=0.004). The cerebral perfusion in thrombolysis group was obviously better than routine CPR group. There were no significant differences in the time for restoration of spontaneous circulation (ROSC), the time for restoration of spontaneous breathing or mean arterial pressure (MAP between routine CPR group and thrombolysis group [ time of ROSC (s): 307.9+/-96.4 vs. 242.0+/-71.0, t=-1.741, P=0.099; time of restoration of spontaneous breathing (minutes): 20.6+/-12.5 vs. 19.3+/-10.1, t= -0.256, P=0.801; MAP (mm Hg, 1 mm Hg=0.133 kPa): 65.5 = 6.2 vs 69.0+/-6.7, t=1.217, P=0.239]. CONCLUSION: Thrombolytic therapy with urokinase in CPR could improve the cerebral microcirculatory perfusion in CA rabbits. PMID- 24479207 TI - Incontinence nursing practice: is it evidence-based? PMID- 24479208 TI - Genome duplication is fundamental to life and health. PMID- 24479209 TI - Dr Coetzee responds. PMID- 24479210 TI - Flexural strength,water sorption and solubility of a methylmethacrylate-free denture base polymer reinforced with glass fibre reinforcement. AB - A methylmethacrylate-free denture base polymer (Eclipse) in comparison to a conventional denture base polymer (Palapress vario) was evaluated after water saturation and Stick glass fibre reinforcement. The data were analysed with ANOVA at a = 0.05. Water-storage caused a decrease in the flexural strength and stiffness of the materials (p > 0.05). Conventional denture base material with fibre reinforcement gave highest flexural strength (201.1 MPa) compared to fibre reinforced Eclipse (79.1 MPa) (p < 0.05). Water sorption after 76 days was 2.08% (Palapress vario) and 1.55% (Eclipse). Fibre-reinforcement of methylmethacrylate free material was not as successful as conventional denture base and needs to be further optimized. PMID- 24479211 TI - Effect of maleic acid and ethylenediaminetetraacetic acid on the shear bond strength of RealSeal SE sealer to root canal dentin. AB - Aim of this study was to evaluate the effect of 7% maleic acid and 17% ethylenediaminetetraacetic acid (EDTA) on the shear bond strength of RealSeal SE sealer to root canal dentin. Twenty incisors were split into coronal, middle and apical third and were treated in the following manner: Group 1: 5 ml of saline (1 minute). Group 2: 2.5% sodium hypochlorite (5 ml/min) followed by 79% maleic acid (5 ml/min). Group 3: 2.5% sodium hypochlorite (5 ml/min) followed by 17% EDTA (5 ml/min). Sealer was the placed on the root dentin and samples were subjected to bond strength measurement. There was no significant difference in bond strength between maleic acid and 17% EDTA in coronal & middle third. However, in apical third, 7% maleic acid showed higher bond strength. Least bond strength was observed with saline. Bond strength was maximum in apical third for both 7% maleic acid and 17% EDTA. PMID- 24479213 TI - Effects of radiotherapy to the jaws. I: The scale of the problem. AB - Cancer care has become one of the main targets of the National Health Service in England and with cancer patients surviving longer, it is likely that head and neck cancer patients will make up a large proportion of patients seen within secondary care settings in the future. The management of these patients can be very difficult for a number of reasons. Part one of this paper attempts to highlight the major oral health problems encountered by these patients during and after their cancer treatment and supported by the current literature. Part two of this series will address the dental management of head and neck oncology patients undergoing radiotherapy with particular attention of possible improvement to current management strategies for these patients. PMID- 24479212 TI - Markers for implant placement in CBCT: a technical overview. AB - Cone beam computer tomography (CBCT) is becoming a more accessible modality of imaging within dentistry. It has particular application in the diagnostic treatment planning for dental implant placement. The use of radiographic surgical stents with CBCT can help to provide important information about bone position and therefore placement of implants and final restorations. This article looks at a novel technique, which allows a variety of different marker positions that can be quickly and easily placed and removed. It allows the use of a current prosthesis that can be adapted to act as a surgical stent during CBCT. PMID- 24479214 TI - Effects of radiotherapy to the jaws. 2: Potential solutions. AB - Dental maintenance and rehabilitation of head and neck cancer care is becoming more important as the outcome of cancer treatment improves. The management of these patients can be very difficult for a number of reasons as discussed in part one of this two-part series. This second part attempts to suggest possible solutions for the management of the major oral health problems encountered by these patients during and after their cancer treatment. PMID- 24479215 TI - Influence of high expansion dental stone on the changes in the occlusal vertical dimension of complete dentures. AB - Although many factors that generate changes in OVD of complete dentures are known, no information is available in the dental literature regarding the effect of using high expansion dental stone (type V) on changes in OVD. This study therefore investigated the effect of a high expansion dental stone on the changes in OVD of complete dentures. A compression moulding technique was used to process twenty sets of simulated upper and lower dentures. Sample was equally divided into two groups: group of type III dental stone (DST III), and group of type V dental stone (DST V). In DST III, the lower, middle and upper parts of flask were filled with type III dental stone; In DST V, the procedure was the same as DST III except for the middle layer that was made of type V high expansion dental stone. Changes in OVD were measured before and after denture processing. A Shapiro-Wilk Normality Test was applied, and then collected data were analysed with t-test statistics for statistically significant differences at the 95% confidence level. The two groups revealed small but statistically significant increase in OVD as a result of processing. The increase in OVD was significantly less in DST V than in DST III. The use of high expansion dental stone can be recommended as investing material to reduce the increase in OVD that occurs after processing complete dentures. PMID- 24479216 TI - Colour stability of temporary restorations with different thicknesses submitted to artificial accelerated aging. AB - This study evaluated the colour stability of temporary prosthetic restorations with different thicknesses submitted to artificial accelerated aging. The occlusal surfaces of 40 molars were grinded to obtain flat enamel surfaces. Twenty acrylic resin specimens [Polymethyl methacrylate (Duralay) and Bis-methyl acrylate (Luxatemp)] were made with two different thicknesses, 0.5 mm and 1.0 mm. Temporary restorations were fixed on enamel and CIE L*a*b* colour parameters of each specimen were assessed before and after artificial accelerated aging. All groups showed colour alterations above the clinically acceptable limit. Luxatemp showed the lowest colour alteration regardless its thickness and Duralay showed the greatest alteration with 0.5 mm. PMID- 24479217 TI - [Death as liberation]. PMID- 24479218 TI - [No one has the right to judge others]. PMID- 24479219 TI - [It takes a heart and a lot of time]. PMID- 24479220 TI - [Incision into the body and soul]. PMID- 24479221 TI - [As advanced practice nurse at eye level with the physician (interview by Stephanie Gehlen)]. PMID- 24479222 TI - [Patient protection in research projects]. PMID- 24479223 TI - [A rendezvous in the art gallery]. PMID- 24479224 TI - [Learning and teaching was the elixir of her life]. PMID- 24479225 TI - [More direct care competence in general practice]. PMID- 24479226 TI - [Ventilator weaning requires interprofessional management]. PMID- 24479227 TI - ["It takes heart and time"]. PMID- 24479228 TI - [After the birth, everything is not always rosy!]. PMID- 24479229 TI - [A difficult confrontation for some]. PMID- 24479230 TI - [Feelings of revulsion in nursing]. PMID- 24479231 TI - [Maya poisoned]. PMID- 24479232 TI - [Consultant for organizing the indoors space]. PMID- 24479233 TI - [Dying with dignity]. PMID- 24479234 TI - ["How can I help you?"]. PMID- 24479235 TI - Marketing nutrition & health-related benefits of food & beverage products: enforcement, litigation & liability issues. AB - Over the past decade, the liability risks associated with food and beverage product marketing have increased significantly, particularly with respect to nutrition and health-related product benefit claims. FDA and FTC enforcement priorities appear to have contributed to the increasing liability trends that are associated with these nutrition and health-related claims. This article examines key enforcement and litigation developments involving conventional food and beverage product marketing claims during the first 18 months of President Obama's administration: Part I considers FDA enforcement priorities and recent warning letters; Part II considers FTC enforcement priorities, warning letters, and consent orders; and Part III considers the relationship between FDA and FTC enforcement priorities and recent false advertising cases brought by private parties challenging nutrition and health-related marketing claims for food and beverage products. The article makes recommendations concerning ways in which food and beverage companies can help minimize liability risks associated with health-related marketing claims. In addition, the article suggests that federal policy reforms may be required to counter the perverse chilling effects current food liability trends appear to be having on health-related marketing claims for food and beverage products, and proposes a number of specific reforms that would help encourage the responsible use of well-substantiated marketing claims that can help foster healthy dietary practices. In view of the obesity prevention and other diet-related public health priorities of the Obama administration, the article suggests that this is an opportune time to address the apparent chilling effects increasing food liability risks are having on nutrition and health related marketing claims for healthy food and beverage products, and potential adverse consequences for public health. PMID- 24479236 TI - Data quality and transparency in the dietary supplement industry. AB - Reliable and defensible data quality underpins the value and validity of decisions made by dietary supplement manufacturers, consumers, and regulatory investigators. Over the past few years, the dietary supplement industry has been pummeled by the news media about the quality, reliability, and utility of the products it sells. Sometimes the charges are justified, but often the claims are biased, inaccurate, or misinterpreted, and often the data used by investigators are not validated or transparent. This paper will initially provide a primer into the elements of a quality assurance program that provide sound scientific data, then will review regulatory requirements for testing conducted by manufacturers, critique third-party investigations of OTC dietary supplement products, and, finally, provide suggestions to investigators about how to structure a testing program that will produce defensible results, that should, if needed, be admissible in court. PMID- 24479237 TI - Heparin crisis 2008: a tipping point for increased FDA enforcement in the pharma sector? AB - Against a backdrop of steady deregulation, the pharmaceutical industry is increasingly outsourcing manufacturing, resulting in decentralized control of the global supply chain. Established products such as heparin have been held to outdated analytical standards. Ten million Americans receive heparin every year; Baxter International accounts for half of this market. In 2008, contamination of Baxter's heparin--sourced in China--resulted in about 350 adverse events and 150 deaths in the United States. In future, increasingly stringent FDA inspections and enforcement are expected for imported drugs and ingredients. More regional FDA offices will be set up overseas. FDA funding will likely be supplemented in future by user fees charged to importers. For newer products, companies will face pressure to adopt Quality by Design, with solid control of the global supply chain and a proactive focus on GMP. Older products will be held to modern standards. Long-term, imports of drugs and ingredients from developing markets will continue. This makes sense to companies from an economic standpoint, but protections will be essential to ensure that it is also justifiable from a public health perspective. PMID- 24479238 TI - Guidance for improving the federal response to foodborne illness outbreaks associated with fresh produce. AB - Today, our nation's food supply flows through a complicated chain of farmers, processors, and distributors before reaching consumers. At some point during this process, food can become contaminated with pathogens and it can make people sick. The Food and Drug Administration, along with the Centers for Disease Control, are in charge of fighting an outbreak once it occurs. The CDC first identifies a specific food that is making people ill, and then the FDA steps in to find the source of that contaminated food. This process, however, does not always run smoothly. Historically, these federal agencies have been underfunded and have had few staff dedicated to fighting foodborne illness outbreaks. This means that an outbreak is not always handled effectively or efficiently, which can have devastating effects on innocent industry actors. This Note gives practical guidance to the FDA and CDC for improving its responses to foodborne illness outbreaks so that consumers, as well as innocent industry actors, are protected. PMID- 24479239 TI - Onus of responsibility: the changing responsible corporate officer doctrine. AB - The responsible corporate officer ("RCO") doctrine permits convictions of corporate officers for violations of the Federal Food, Drug, and Cosmetic Act ("FDCA"), even in instances in which the corporate officer was not personally involved and lacked knowledge of the wrongdoing. Prosecutors have seldom prosecuted RCO FDCA cases since the doctrine was first described in 1943, but recent indications point to an imminent revival. Cases and statements from government officials indicate that this second wave of the RCO doctrine may sweep more broadly than did the first. For example, prosecutors appear ready to employ the RCO doctrine in strict liability cases, even though most past RCO FDCA cases involved knowledge on the part of the corporate officer. Moreover, the current environment promises stiffer penalties, less centralized case selection, and fewer jury trials than did the era in which the RCO doctrine was established. This article concludes with a call for the Department of Justice to issue guidelines for RCO prosecutions to ensure that this most unusual form of criminal liability is imposed fairly and consistently. PMID- 24479240 TI - Protecting the public's health through the application integrity policy. AB - FDA's recent use of the Application Integrity Policy (AIP), most notably in the ongoing Ranbaxy matter, has created interest in the policy. The article discusses actions CDER's Office of Compliance is currently undertaking to raise awareness of the AIP and establish the Office of Compliance as CDER's clearing-house for integrity issues. The article reviews a current AIP case and discusses how the use of the AIP can protect public health. PMID- 24479241 TI - Prohibited acts and enforcement tools. PMID- 24479242 TI - Off-label promotion: government theories of prosecution and facts that drive them. PMID- 24479243 TI - The FTC's regulation of advertising. PMID- 24479244 TI - DEA regulation of controlled substances and listed chemicals. PMID- 24479245 TI - Codex--what's all the fuss? AB - The internet is saturated with misinformation about The Codex Alimentarius Commission (Codex). A brief review of recent Codex actions indicates that Codex is not at all like the organization being portrayed on the web. Is the United States receiving commensurate value for the resources that it is devoting to Codex? By examining the cost of US participation in Codex activities for one year (2009-2010), the author concludes that the United States could achieve the same levels of success with significantly less expenditure. Toward that end, three proposals are put forward: 1) Reduce the size of US delegations to Codex meetings; 2) Give up the host country role for three of the four committees that the US currently hosts and 3) Reduce the US contribution to the Codex Trust Fund. A casual search of the internet, using the search term "Codex Alimentarius," will yield almost a million hits, the vast majority of which are anti-Codex screeds, filled with misinterpretations and misinformation. Many allege that Codex will deny access, or already has, to dietary supplements and that common foods such as garlic will be classified as drugs, available only by prescription. These alleged actions are seen as the work of a vast international conspiracy of the multinational pharmaceutical companies. Many see Codex as one component of a "new world order," whose primary agenda is population control. There are several organizations whose primary purpose appears to be opposition to Codex by spreading misinformation across the web. These include groups in the United States, such as Health Freedom USA and the Natural Solutions Foundation, the National Health Federation and the International Advocates for Health Freedom; as well as organizations in Europe--the Alliance for Natural Health-Europe, Ian Crane in the United Kingdom and Dr. Rath Health Foundation in Germany. Anyone coming to Codex from the internet only is bound to be confused and probably misinformed. PMID- 24479246 TI - EU orphan regulation--ten years of application. AB - In April 2000, European Regulation (EC) No 141/2000 on Orphan Medicinal Products, which, following the U.S. example, had been adopted to boost the research, development, and marketing of medicinal products for rare diseases, became effective. Ten years later, figures prove that, with an average of more than 70 orphan designations per year, the European orphan regulation is a success. To date, the key issue is no longer research and development but effective market access. Less than 10% of the orphan designated products are approved for marketing and even less products are actually placed on the European national markets due to pricing and reimbursement obstacles. The article examines the European orphan regime, focusing on its two cornerstones--orphan designation and exclusivity--and highlighting the concepts that are still unclear and the issues that have not yet been addressed. The European Orphan Regulation has been proved to work well, but it would be even more successful if orphan designation was easier and orphan incentives were more attractive. The article concludes on the changes to be made to the European orphan legal regime that would encourage even more the research and development of orphan products. PMID- 24479247 TI - An unofficial legislative history of the Biologics Price Competition and Innovation Act of 2009. AB - In March 2010, Congress passed the Biologics Price Competition and Innovation Act of 2009 (BPCIA). This law established a statutory pathway for approval of "biosimilars," follow-on versions of innovative biological products. This article traces the history of the BPCIA, beginning with a discussion of the origins of federal regulation of drugs and biologics, including passage of the Hatch-Waxman amendments, in Section I. Section I also describes the development of the European approval framework for biosimilars in the mid-2000s and how this increased interest in creation of a pathway in the United States. The article then provides, in Section II, an overview of early stakeholder discussions in the United States regarding legal and scientific issues relating to biosimilars, spanning the years 1998-2006. The legislative debate began in earnest in late 2006, when the first biosimilars bill was introduced. Section III of the article examines introduced bills, other legislative proposals, and related stakeholder discussion in detail, leading up to enactment of the BPCIA. Section IV describes the BPCIA as enacted, and the paper ends with the authors' concluding observations about the legislative negotiations and their implications for interpretation of the Act. PMID- 24479248 TI - Global regulatory standards for the approval of biosimilars. AB - On March 23, 2010, President Barack Obama signed into law the Patient Protection and Affordable Care Act, which contains the Biologics Price Competition and Innovation Act. Biosimilars have an important role in the United States health care system, and this new law creates an abbreviated approval pathway for biosimilar products in the U.S. A biosimilar is a biologic product demonstrated to be highly similar to an approved innovator biologic product ("reference product"). While the law provides general information on the standards to demonstrate biosimilarity, Congress has authorized the FDA to define the scientific standards and content of biosimilar applications. There is an increasing global interest in the development of biosimilar products, and several regulatory authorities around the world, as well as the World Health Organization (WHO), have established regulatory guidelines for the approval of biosimilars. The scientific standards and requirements in the biosimilar guidelines of the WHO and other health authorities, including the European Union, Canada, Japan, and South Africa, are reviewed in this paper. The similarities as well as the differences among the policies adopted by these regulatory authorities may provide the FDA valuable information as the agency develops its standards and approaches for the approval of biosimilars in the U.S. At the same time, while establishing such approaches, the FDA has the opportunity to demonstrate leadership in addressing significant safety and other issues related to multi source biologics and biosimilars that remain a global challenge. PMID- 24479249 TI - The history and impact of the New York City menu labeling law. AB - As a result of the recent federal health care legislation, all restaurants in the United States that are part of a chain with twenty or more locations serving substantially the same menu items will be required to post the calorie information of the food they serve directly on menus and menu boards. This development represents the culmination of a regulatory initiative to combat the growth of obesity that only began in 2006 with the decision by the New York City Board of Health to require calorie posting in New York City chain restaurants. That initiative, Regulation 81.50, was the first of its kind in the United States; and yet, less than four years later, the idea has become a national standard. This paper tracks the history of New York City's landmark regulation, detailing the drafting of the law, the initial legal victory for the restaurant association challenging it, and the ultimate triumph of the City in winning legal validation of its calorie posting mandate. In doing so, this paper will also use the New York City regulation as a launching point to discuss the rationale behind menu labeling, to examine the potential legal pitfalls of menu labeling laws, to track the development of the initiative from New York City to a national standard, and finally, to evaluate the preliminary data on whether or not menu labeling is actually effective in achieving its ultimate goal: changing consumer eating habits and reducing obesity. PMID- 24479250 TI - The Family Smoking Prevention and Tobacco Control Act and the First Amendment: why a substantial interest in protecting public health won't save some new restrictions on tobacco advertising. AB - Congress passed the Family Smoking Prevention and Tobacco Control Act in 2009 with the aim of reducing tobacco-related illnesses and deaths by curbing tobacco's appeal to and use by children and adolescents. Legislators considered provisions of the FSPTCA restricting tobacco advertising and labeling key to realizing the law's intended health benefits. But a lawsuit now before the U.S. Court of Appeals for the Sixth Circuit challenges the tobacco marketing restrictions as impermissible restraints on tobacco companies' commercial speech rights under the First Amendment. This article analyzes the constitutionality of each FSPTCA tobacco advertising and labeling restriction in light of U.S. Supreme Court decisions defining the extent of First Amendment protection for commercial speech, prior efforts to restrict tobacco marketing, and the outcomes of legal challenges to some of the prior marketing restrictions. Several of the FSPTCA tobacco advertising and labeling restrictions were drafted with insufficient accommodations for tobacco companies' First Amendment right to convey and consumers' First Amendment right to receive truthful information about lawful tobacco products and are therefore unconstitutional as currently written. PMID- 24479251 TI - I saw the sign: the new federal menu-labeling law and lessons from local experience. AB - Following the lead of several state and local governments, Congress recently imposed menu-labeling requirements on chain restaurants as part of the federal health care reform bill signed into law in March 2010. Section 4205 of the Patient Protection and Affordable Care Act requires restaurant chains with 20 or more locations nationwide to display calorie information for standard menu items on menus, menu boards, and drive-thru displays. This paper examines the new federal law in light of existing state and local regulations and considers the arguments for and against mandatory calorie labeling at restaurants as a federal tool for preventing obesity. Specifically, this paper examines the provisions of the new federal law, highlights how it differs from the municipal and state menu labeling laws already in effect, reviews early studies of the effectiveness of these state and local laws, and considers the propriety of requiring restaurants to disclose calorie information on menus by discussing arguments for and against menu labeling generally and calorie labeling in particular. This paper finds that based on initial studies of state and local menu-labeling regulations, the efficacy of compulsory menu labeling as a tool to combat obesity remains uncertain. Finally, this paper raises practical considerations associated with the new federal law, including implementation issues, potential collateral effects of the law, a survey of legal challenges that may arise, and a discussion of the Food and Drug Administration's competence to enforce a menu-labeling requirement against restaurants. PMID- 24479252 TI - Doppler ultrasound of the central retinal artery in microgravity. AB - BACKGROUND: Ocular changes have been noted during long-duration spaceflight; we studied central retinal artery (CRA) blood flow using Doppler before, during, and after long-term microgravity exposure in astronauts compared with data from a control group of nonastronauts subjected to head-down tilt (HDT). METHODS: Available Doppler spectra of International Space Station (ISS) crewmembers were obtained from the NASA Lifetime Surveillance of Astronaut Health database, along with 2D ultrasound-derived measurements of the optic nerve sheath diameter (ONSD). CRA Doppler spectra and optic nerve sheath images were also obtained from healthy test subjects in an acute HDT experiment at 20 min of exposure (the ground-based analogue). RESULTS: HDT CRA peak systolic velocity in the ground based analogue group increased by an average of 3 cm -s(-1) (33%) relative to seated values. ONSD at 300 of HDT increased by 0.5 mm relative to supine values. CRA Doppler spectra obtained on orbit were of excellent quality and demonstrated in-flight changes of +5 cm x s(-1) (50%) compared to preflight. ONSD increased in ISS crewmembers during flight relative to before flight, with some reversal postflight. DISCUSSION: A significant ONSD response to acute postural change and to spaceflight was demonstrated in this preliminary study. Increases in Doppler peak flow velocities correlated with increases in ONSD. Further investigations are warranted to corroborate the relationship between ONSD, intracranial pressure, and central retinal blood flow for occupational surveillance and research purposes. PMID- 24479253 TI - Individual susceptibility to high altitude and immersion pulmonary edema and pulmonary lymphatics. AB - BACKGROUND: High-altitude pulmonary edema (HAPE) and immersion pulmonary edema (IPE) are potentially life-threatening conditions that affect athletes, including high-altitude climbers, long-distance swimmers, and underwater divers. The objectives of this study were to measure lung density (before and after exercise) and quantify the pulmonary lymphatic network in individuals susceptible and resistant to HAPE/IPE. METHODS: Eighteen male (N = 10) and female (N = 8) subjects were recruited. Based on medical histories, nine subjects were susceptible to HAPE/IPE, and nine were resistant. Subjects were matched for gender, age, height, weight, and cold-water diving or high-altitude trekking experiences. Lung mass and density (at three slice locations) were determined using computed tomography at rest and after intense exercise. Lung mass and density were calculated from X-ray attenuation values. Two blinded investigators counted interlobular septal lines according to criteria established by the research group. RESULTS: At rest, susceptible subjects had a lower lung density [Susceptible: 0.192 (0.035 SD) g ml 1'; Resistant: 0.22 (0.029 SD) g ml(-1))], a significantly lower lung mass [Susceptible: 132.1 (24.16 SD) g; Resistant: 156.1 (19.19 SD) g], and significantly fewer interlobular septa [Susceptible: 17 (4.5 SD); Resistant: 23 (7.1 SD)] compared to resistant subjects. The differences in density and mass were not affected by intense exercise. DISCUSSION: Subjects susceptible to HAPE/IPE had lower lung density, significantly lower lung mass, and fewer interlobular septa than subjects resistant to HAPE/IPE, suggesting a smaller pulmonary lymphatic network. The observed differences in lymphatics could represent either predisposing factors to, or sequelae of, these potentially lethal conditions. PMID- 24479254 TI - Electrogastrographic and autonomic responses during oculovestibular recoupling in flight simulation. AB - INTRODUCTION: Simulator sickness causes vestibulo-autonomic responses that increase sympathetic activity and decrease parasympathetic activity. The purpose of the study was to quantify these responses through electrogastrography and cardiac interbeat intervals during flight simulation. METHODS: There were 29 subjects that were randomly assigned to 2 parallel arms: (1) oculovestibular recoupling, where galvanic vestibular stimulation was synchronous with the visual field; and (2) control. Electrogastrography and interbeat interval data were collected during baseline, simulation, and post-simulation periods. A simulator sickness questionnaire was administered. RESULTS: Statistically significant differences were observed in percentage of recording time with the dominant frequency of electrogastrography in normogastric and bradygastric domains between the oculovestibular recoupling and control groups. Normogastria was dominant during simulation in the oculovestibular recoupling group. In the control group, the percentage of recording time with the dominant frequency decreased by 22% in normogastria and increased by 20% in bradygastria. The percentage change of the dominant power instability coefficient from baseline to simulation was 26% in the oculovestibular recoupling group vs. 108% in the control group. The power of high frequency components for interbeat intervals did not change significantly in the oculovestibular recoupling group and was decreased during simulation in the control group. DISCUSSION: Electrogastrography and interbeat intervals are sensitive indices of autonomic changes in subjects undergoing flight simulation. These data demonstrate the potential of oculovestibular recoupling to stabilize gastric activity and cardiac autonomic changes altered during simulator and motion sickness. PMID- 24479255 TI - Photorefractive keratectomy in young Asian aviators with low-moderate myopia. AB - INTRODUCTION: The high prevalence of myopia among Asians led the Republic of Singapore Air Force (RSAF) to introduce photorefractive keratectomy (PRK) as a means of enlarging its pilot recruitment pool at the end of 2005. This study aims to address the efficacy and safety of PRK performed on young Asian patients with low-moderate myopia, as well as audit the RSAF's corneal refractive surgery (CRS) program. METHODS: This is a retrospective case series of 149 eyes of 76 consecutive patients that underwent PRK as part of the RSAF CRS program over the 5-yr period from 1 January 2006 to 31 December 2010. RESULTS: The median patient age was 21 yr (range, 18-26 yr) and the mean preoperative spherical equivalent (SE) refraction was -3.39 - 1.19 D. Of the patients, 96.1% were men and all were of Asian origin. At the 12-mo follow-up, 98.5% of eyes had an uncorrected distance visual acuity (UDVA) of < or = 0.00 LogMAR, 100.0% of eyes had an SE refraction of within + 0.50 D of intended correction, and 2.300% of eyes had a loss of corrected distance visual acuity (CDVA) of 0.20 LogMAR. The cumulative incidence of retreatments was 6.7% and cumulative incidence of grade II or worse corneal haze requiring retreatment was 6.0%. Refractive stability was achieved at 3 mo postsurgery. CONCLUSION: The results of this study suggest that PRK performed within the context of a stringent and structured CRS program on young Asian eyes with low-moderate myopia is both efficacious and safe, with refractive stability achieved by 3 mo. PMID- 24479256 TI - Risk of incident mental health conditions among critical care air transport team members. AB - BACKGROUND: This study investigated whether Critical Care Air Transport Team (CCATT) members are at increased risk for incident post-deployment mental health conditions. METHODS: We conducted a retrospective cohort study of 604 U.S. Air Force medical personnel without preexisting mental health conditions who had at least one deployment as a CCATT member during 2003-2012 as compared to a control group of 604 medical personnel, frequency matched based on job role, with at least one deployment during the same period, but without CCATT experience. Electronic health record data were used to ascertain the diagnosis of a mental health condition. RESULTS: The incidence of post-deployment mental health conditions was 2.1 per 1000 mo for the CCATT group versus 2.2 per 1000 mo for the control group. The six most frequent diagnoses were the same in both groups: adjustment reaction not including posttraumatic stress disorder (PTSD), anxiety, major depressive disorder, specific disorders of sleep of nonorganic origin, PTSD, and depressive disorder not elsewhere classified. Women were at marginally increased risk and nurses and technicians were at twice the risk of physicians. The distribution of the time interval from end of the most recent deployment to diagnosis of incident mental health condition was positively skewed with a median greater than 6 mo. CONCLUSIONS: CCATT members were at no increased risk for incident post-deployment mental health conditions as compared to non-CCATT medical service members. Nearly two-thirds of incident post-deployment mental health conditions were diagnosed outside the standard 6-mo medical surveillance period, a finding warranting further study. PMID- 24479257 TI - Cadets' swimming and running performance with and without a combat uniform. AB - INTRODUCTION: The aim was to examine whether a combat uniform (CU) influences the cadet's exercise performance in and out of the water. METHODS: Fourteen male Army Officer cadets performed on 6 separate days: (1) a maximal 400-m freestyle swimming trial; (2) a 4 x 50-m all-out freestyle swimming trial with 10 s rest in between; (3) a 50-m swim obstacle course with a CU (CUs); (4) a 50-m swim obstacle course without a CU (NUs); (5) a 1000-m track run with a CU (CU(R)); and (6) a 1000-m track run without a CU (NUR). In each trial, performance time, oxygen uptake (Vo2), lactate concentration ([La]), and capillary oxygen saturation (SpO2) were recorded. RESULTS: The mean performance time was 44.3 +/- 3.1 s and 33.4 +/- 1.8 s in CUs and NUs trials, respectively. Peak VO2 was similar in CUs, NUs, and 400 m (CUs: 59.1 +/- 1.1 ml x kg(-1) x min(-1), NUs: 57.3 +/- 2.1 ml kg(-1) x min(-1), 400 m: 58.2 +/- 1.6 ml x kg(-1) min(-1)). [La] was higher in CUs than in NUs (CUs: 10.0 +/- 2.0 mmol x L(-1), NUs: 8.5 +/- 1.8 mmol x L(-1)), but it was lower in CUs and NUs than during the 400 m and 4 x 50 m. SpO2 was lower (approximately 4.5%) in CUs than NUs. No differences were observed between running trials. CONCLUSIONS: The results suggest that the use of CU during swimming tasks induces high demands for energy and, thus, leads to a significant impairment of the swimming performance of the cadets. However, the influence of the CU seems to be less crucial during dry land running performance. PMID- 24479258 TI - Motion sickness: an evolutionary and genetic basis for the negative reinforcement model. AB - It has been theorized that motion sickness evolved as a negative reinforcement system which terminates motion involving postural instability and/or sensory conflict. A hypothetical example is provided by a "thought experiment" whereby protohominids are in a tree looking for food. Selection pressure results when the organisms that have an aversion to motion-producing sensory conflict do not venture out too far on the tree limbs and therefore tend to survive. In order to support an evolutionary model for motion sickness there must be evidence for genetic and/or heritable predisposition. The present study involves a retrospective literature review which reveals abundant evidence for genetic/heritable factors in motion sickness. Examples include genetic polymorphism of the alpha-2-adrenergic receptor, which has been shown to increase susceptibility to motion sickness, examination of family trees revealing heritable motion sickness susceptibility, evidence indicating that Asians are hyper-susceptible to motion sickness, and twin studies, just to mention a few. Thus, the theory of heritable negative reinforcement as a basis for motion sickness is supported by extensive evidence in the medical literature. This theory is compared and contrasted with other theories. Further areas for research are suggested. PMID- 24479259 TI - Optic nerve sheath diameter measurement techniques: examination using a novel ex vivo porcine model. AB - BACKGROUND: Ultrasound (U/S) and MRI measurements of the optic nerve sheath diameter (ONSD) have been proposed as intracranial pressure measurement surrogates, but these methods have not been fully evaluated or standardized. The purpose of this study was to develop an ex-vivo model for evaluating ONSD measurement techniques by comparing U/S and MRI measurements to physical measurements. METHODS: The left eye of post mortem juvenile pigs (N = 3) was excised and the subdural space of the optic nerve cannulated. Caliper measurements and U/S imaging measurements of the ONSD were acquired at baseline and following 1 cc saline infusion into the sheath. The samples were then embedded in 0.5% agarose and imaged in a 7 Tesla (7T) MRI. The ONSD was subsequently measured with digital calipers at locations and directions matching the U/S and direct measurements. RESULTS: Both MRI and sonographic measurements were in agreement with direct measurements. U/S data, especially axial images, exhibited a positive bias and more variance (bias: 1.318, 95% limit of agreement: 8.609) compared to MRI (bias: 0.3156, 95% limit of agreement: 2.773). In addition, U/S images were much more dependent on probe placement, distance between probe and target, and imaging plane. CONCLUSIONS: This model appears to be a valid test-bed for continued scrutiny of ONSD measurement techniques. In this model, 7T MRI was accurate and potentially useful for in-vivo measurements where direct measurements are not available. Current limitations with ultrasound imaging for ONSD measurement associated with image acquisition technique and equipment necessitate further standardization to improve its clinical utility. PMID- 24479260 TI - Personality traits of people attracted by parabolic flight. AB - BACKGROUND: Studies have shown that members of expeditions in extreme environments differed on the basis of personality factors (e.g., they were highly competitive, higher on Extraversion and Conscientiousness) compared to the control population. In order to identify individuals who are likely to participate in extreme environments, the aim of the present study using parabolic flights was to compare the personality traits of voluntary participants (VP) in a weightlessness experiment with those of the general population (GP) (French norms). METHODS: The personalities of 57 voluntary participants in a parabolic flights experiment were assessed using NEO-PI-R and Trait-Anxiety. RESULTS: Our results show significant differences with the general population: (1) in Trait Anxiety (GP = 42.25 +/- 11.44 vs. VP = 34.56 +/- 6.24) and in 3 out of 5 personality domains (Neuroticism GP = 90.04 +/- 22.68 vs. VP = 78.70 +/- 17.44, +/- 18.87 vs. VP = 123.81 +/- 15.41, and Conscientiousness GP = 109.23 +/- 22.30 vs. VP = 124.47 + 19.03); and (2) in 14 out of 30 NEO-PI-R facets. DISCUSSION: These findings indicate a specific personality profile for voluntary participants in parabolic flights and confirm that participants attracted to extreme environments differ compared to the normative population. PMID- 24479261 TI - Visual function at altitude under night vision assisted conditions. AB - INTRODUCTION: Hypoxia, even mild, is known to produce negative effects on visual function, including decreased visual acuity and sensitivity to contrast, mostly in low light. This is of special concern when night vision devices (NVDs) are used during flight because they also provide poor images in terms of resolution and contrast. METHODS: While wearing NVDs in low light conditions, 16 healthy male aviators were exposed to a simulated altitude of 12,500 ft in a hypobaric chamber. RESULTS: Snellen visual acuity decreased in normal light from 28.5 +/- 4.2/20 (normoxia) to 37.2 +/- 7.4/20 (hypoxia) and, in low light, from 33.8 +/- 6.1/20 (normoxia) to 42.2 +/- 8.4/20 (hypoxia), both at a significant level. An association was found between blood oxygen saturation and visual acuity without significance. No changes occurred in terms of sensitivity to contrast. DISCUSSION: Our data demonstrate that mild hypoxia is capable of affecting visual acuity and the photopic/high mesopic range of NVD-aided vision. This may be due to several reasons, including the sensitivity to hypoxia of photoreceptors and other retinal cells. Contrast sensitivity is possibly preserved under NVD-aided vision due to its dependency on the goggles' gain. PMID- 24479262 TI - Spine injuries related to high-performance aircraft ejections: a 9-year retrospective study. AB - BACKGROUND: During an aircraft ejection, the pilot is exposed to accelerations to the point of human tolerance, which may cause spinal injuries. Many nations have reported a spinal trauma rate of about 20-30%, with plain radiography as the first-line exam. Insofar as ejection seats and diagnostic imaging have improved, the objectives of this study are to describe the spine injuries among recently ejected French aircrew, to analyze the spinal imaging used, and, if necessary, to propose a better standardized radiological procedure. METHODS: A retrospective cohort study included all aircrews of the French forces who ejected from 2000 to 2008, with an authorized access to the technical reports of the investigations. RESULTS: There were 36 ejections collected, 75% with an MK-10 seat and an arrival on dry land. All pilots were alive, but 42% of them sustained 24 spinal fractures, most of the time with a simple compression of the thoracic segment, but also 4 ligamentous or discal lesions. Computed tomography or RMI was used in 64% of cases and four fractures were missed or underestimated on X-ray. One complex fracture required surgical treatment. A return to flying duties was frequently possible within a period of 6 mo. CONCLUSIONS: New generation ejection seats remain highly traumatic for the spine. It is recommended that all ejected aircrews be assessed with computed tomography to improve the sensitivity of the screening for fractures. The risk of asymptomatic lesions makes necessary the systematic use of a stretcher for initial evacuation when possible. PMID- 24479263 TI - Managing acute coronary syndrome during medical air evacuation from a remote location at sea. AB - BACKGROUND: Coronary emergencies at sea requiring air evacuation are not uncommon. On board a Nimitz-class aircraft carrier while in a remote location, an active duty sailor suffered a myocardial infarction. A medical evacuation by helicopter was necessary. Transfer proved difficult due to the ship's location, poor flying conditions, and the patient's deteriorating condition. This case stresses the importance of expeditious diagnosis, treatment, and air transfer to shore-based facilities capable of providing definitive coronary care. CASE REPORT: A 33-yr-old man recently started on trazodone due to depression complained of chest pain. The patient was hemodynamically unstable and electrocardiogram showed ST segment elevation and Q waves in the anterior, inferior, and lateral leads. He was air-lifted to the nearest accepting facility with cardiac catheterization capabilities, which was over 300 miles away. Poor weather conditions hindered the pilot's ability to fly the original course. The patient remained critical and medication choices were limited. Even with all of these obstacles, everyone involved performed his or her duties admirably. The patient's condition improved by the time the helicopter landed. He was then rushed by ambulance to the hospital's coronary care unit, where he was successfully treated. DISCUSSION: This case highlights the need to keep a high index of suspicion when patients complain of chest pain, regardless of age. It is of the utmost importance that individuals capable of thinking and acting quickly are assigned to medical evacuation teams, and that they continue to train regularly, as coronary events at sea are not uncommon. PMID- 24479264 TI - Air travel with known pneumocephalus following outpatient sinus surgery. AB - BACKGROUND: Intracranial air is a common finding after many neurosurgical procedures and trauma to the head. In patients requiring transport via air to reach a destination there is risk of expansion of the intracranial air and development of neurological complications. Though relatively uncommon after functional endoscopic sinus surgery (FESS), pneumocephalus may be encountered. CASE REPORT: We describe one of our patients in whom intracranial air was introduced during FESS. Following the procedure she required commercial air transportation from our center to her home. A 45-min commercial flight to the destination was safely completed without the patient experiencing any neurological sequellae. DISCUSSION: This case highlights the controversy surrounding air travel with pneumocephalus and provides an example of safe commercial air travel after diagnosis of post-FESS pneumocephalus. PMID- 24479265 TI - Intraocular/Intracranial pressure mismatch hypothesis for visual impairment syndrome in space. AB - Visual impairment intracranial pressure syndrome (VIIP) is considered a major risk for future human spaceflight. Loss of hydrostatic pressure gradients in vascular and cerebrospinal fluid systems due to the removal of gravity associated with subsequent intracranial and intraocular fluid shifts and the resulting intraocular/intracranial pressure mismatch might be important etiology factors causingVIIP syndrome. Acclimation changes in the ocular and cerebral circulation and the two fluid systems during chronic microgravity exposure and their underlying mechanisms need further elucidation. Relevant findings may help to validate the pressure differential hypothesis for VlIP syndrome and to evaluate whether a gravity based countermeasure is needed. PMID- 24479266 TI - AsMA journal covers, a history. AB - The cover of our journal has changed quite often over the years. As we look forward to changing the name and design of the journal, it seems appropriate to reflect on the previous journal titles and covers. A brief history follows. PMID- 24479267 TI - Doppler bubble grades after diving and relevance of body fat. PMID- 24479268 TI - In response. PMID- 24479269 TI - Computer modeling tools for aerospace medical research. PMID- 24479270 TI - You're the flight surgeon: tinea incognito. PMID- 24479271 TI - You're the flight surgeon: mumps. PMID- 24479272 TI - This month in aerospace medicine history. PMID- 24479273 TI - Effects of combined exogenous dextranase and sodium fluoride on Streptococcus mutans 25175 monospecies biofilms. AB - PURPOSE: To investigate the effects of exogenous dextranase and sodium fluoride on a S. mutans monospecies biofilm. METHODS: S. mutans 25175 was grown in tryptone soya broth medium, and biofilm was formed on glass slides with 1.0% sucrose. Exogenous dextranase and sodium fluoride were added alone or together. The biofilm morphology was analyzed by confocal laser scanning microscopy. The effects of the drug on the adhesion and exopolysaccharide production by the biofilms were evaluated by scintillation counting and the anthrone method, respectively. RESULTS: In this study, we found that the structure of initial biofilm and mature biofilm were partly altered by dextranase and high concentrations of sodium fluoride separately. However, dextranase combined with a low concentration of sodium fluoride could clearly destroy the typical tree-like structure of the biofilm, and led to less bacterial adhesion than when the dextranase or fluoride were used alone (P < 0.05). The amounts of soluble and insoluble exopolysaccharide were significantly reduced by combining dextranase with a low concentration of sodium fluoride, much more than when they were used alone (P < 0.05). These data indicate that dextranase and a low concentration of sodium fluoride may have synergistic effects against S. mutans biofilm and suggest the application of a low concentration of sodium fluoride in anticaries treatment. PMID- 24479275 TI - Oral biofilms, oral and periodontal infections, and systemic disease. AB - PURPOSE: Oral biofilms harbor several hundreds of species of bacteria as well as spirochetes, protozoa, fungi and viruses. The composition of the oral biofilm varies from health to disease. It is the source of microorganisms that cause dental and periodontal infections. Oral infections and periodontal disease have been implicated in the etiopathogenesis of several important chronic systemic diseases. PMID- 24479274 TI - Site specific properties of carious dentin matrices biomodified with collagen cross-linkers. AB - PURPOSE: To assess in non-cavitated carious teeth the mechanical properties of dentin matrix by measuring its reduced modulus of elasticity and the effect of dentin biomodification strategies on three dentin matrix zones: caries-affected, apparently normal dentin below caries-affected zone and sound dentin far from carious site. METHODS: Nano-indentations were performed on dentin matrices of carious molars before and after surface modification using known cross-linking agents (glutaraldehyde, proanthocyanidins from grape seed extract and carbodiimide). RESULTS: Statistically significant differences were observed between dentin zones of demineralized dentin prior to surface biomodification (P < 0.05). Following surface modification, there were no statistically significant differences between dentin zones (P < 0.05). An average increase of 30-fold, 2 fold and 2.2-fold of the reduced modulus of elasticity was observed following treatments of the three dentin zones with proanthocyanidin, carbodiimide and glutaraldehyde, respectively. PMID- 24479276 TI - Flexural resistance of Cerec CAD/CAM system ceramic blocks. Part 1: Chairside materials. AB - PURPOSE: This study tested the materials available on the market for Cerec CAD/CAM, comparing the mean flexural strength in an ISO standardized set-up, since the ISO standard for testing such materials was issued later than the marketing of the materials tested. METHODS: Following the recent Standard ISO 6872:2008, eight types of ceramic blocks were tested: Paradigm C, IPS Empress CAD LT, IPS Empress CAD Multi, Cerec Blocs, Cerec Blocs PC, Triluxe, Triluxe Forte, Mark II. Specimens were cut out from ceramic blocks, finished, polished, and tested in a three-point bending test apparatus until failure. Flexural strength, Weibull characteristic strength, and Weibull modulus, were calculated. RESULTS: The results obtained from the materials for flexural strength were IPS Empress CAD (125.10 +/- 13.05), Cerec Blocs (112.68 +/- 7.97), Paradigm C (109.14 +/- 10.10), Cerec Blocs PC (105.40 +/- 5.39), Triluxe Forte (105.06 +/- 4.93), Mark II (102.77 +/- 3.60), Triluxe (101.95 +/- 7.28) and IPS Empress CAD Multi (100.86 +/- 15.82). All the tested materials had a flexural strength greater than 100 MPa, thereby satisfying the requirements of the ISO standard for the clinical indications of the materials tested. In all tested materials the Weibull characteristic strength was greater than 100 MPa. PMID- 24479277 TI - Influence of curing light power and energy on shrinkage force and acoustic emission characteristics of a dental composite restoration. AB - PURPOSE: To evaluate the density effects of light power and energy on the volumetric polymerization shrinkage and acoustic emission (AE) characteristics of a dental resin composite in the cavities of human teeth. METHODS: Two experiments were performed at different power levels (1,000 and 4,000 mW/cm2) using a light curing unit: (1) cylindrical cavities with diameters of 4 mm and depths of 2 mm were constructed using two symmetric steel molds. The cavities were filled with resin, and the shrinkage force during polymerization was measured using a load cell attached to the mold. Polymerization shrinkage forces were measured under four conditions (1,000 mW/cm2 x 10 seconds, 1,000 mW/cm2 x 20 seconds, 4,000 mW/cm2 x 3 seconds, and 4,000 mW/cm2 x 5 seconds); (2) tooth specimens with cavity diameters of 6 mm and depths of 2 mm were made from human molars. AE signals during polymerization shrinkage were monitored in real time for 10 minutes after irradiation and two AE factors (amplitude for defect size and hit number for defect number) were assessed in the examination of defects. Two levels of light energy (20 J/cm2 = 1,000 mW/cm2 x 20 seconds and 12 J/cm2 = 4,000 mW/cm2 x 3 seconds) were used. RESULTS: Shrinkage occurred more quickly at 4,000 mW/cm2 than at 1,000 mW/cm2 during the initial phase. The shrinkage force became almost the same for equivalent light energy as time increased. Higher light energy (20 J/cm2) under low-power conditions (1,000 mW/cm2) caused larger cumulative numbers of AE hits than did lower light energy (12 J/cm2) under high-power conditions (4,000 mW/cm2). At 4,000 mW/cm2 and 12 J/cm2 (i.e., high power, low energy), the average amplitude of the AE signals was larger than at 1,000 mW/cm2 and 20 J/cm2 (low power, high energy). PMID- 24479278 TI - Mechanical properties and color stability of provisional restoration resins. AB - PURPOSE: To evaluate the mechanical strength and color stability of provisional restoration materials. METHODS: For mechanical testing, four groups [Trim (PEMA), Alike (PMMA), Versatemp (bis-acrylic resin composite, BARC) and Perfectemp II (bis-acrylic fluoride enriched resin, BAFC)] of resin disks were prepared for fracture toughness and shear punch strength testing, respectively. Five samples were fabricated for each group; therefore, a total of 20 resin disks for each testing method was prepared. The load at fracture and shear punch values of each specimen were recorded after 24-hour storage in distilled water. The stress intensity factors (K(Ic)) were calculated by the formula reported by Atkinson et al. For shear strength, the following formula was used: Shear strength = Force (N)/section thickness (mm) x punch circumference (mm). Values of each group in both tests were analyzed using one-way-ANOVA and Tukey multiple comparison test. For color stability testing, provisional resin disk specimens of the above mentioned materials were fabricated. Five samples were prepared for each subgroup (with and without a surface coating agent - Permaseal) and three different solutions (distilled water, red wine and curry); a total of 120 disk specimens were fabricated. Color values of each group were measured using a spectrophotometer after 24 hours and 2 weeks of aging in the aforementioned solutions. The color differences (deltaE*ab) between before and after aging were calculated by CIE Lab color-difference formula. The interaction of deltaE*ab values were analyzed by two-way analysis of variance followed by Newman-Keuls Multiple comparison test. RESULTS: The highest fracture toughness value [(MPa (m)1/2)] was obtained by PMMA (0.89) followed by BARC (0.67), PEMA (0.54) and BAFC (0.42). Significant differences were observed among all test groups (P < 0.05). The highest shear punch strength (MPa) was obtained by BARC (160), followed by PMMA (141) and PEMA (132). The lowest value was obtained by BAFC (106). BARC showed a significantly higher mean value than the other groups (P < 0.05). PEMA and PMMA demonstrated better color stability than the two bis-acrylic resin composites. Wine and curry showed higher stainability than water, recording higher deltaE*ab values than the clinically perceptible difference level of deltaE*ab 3.3. The surface coating agent groups demonstrated more staining than the non-coated groups. All groups, except for BARC, demonstrated significant differences dependent upon surface coating and solutions (P < 0.05). PMID- 24479279 TI - Microleakage of Class II restorations and microtensile bond strength to dentin of low-shrinkage composites. AB - PURPOSE: To evaluate the microleakage of Class II cavities restored with experimental low-shrinking resin composites proposed for bulk filling and to measure their microtensile bond strength (microTBS) to dentin and compare to those of previously marketed low-shrinkage composites. METHODS: Class II cavities (7 mm occluso-gingival height, 2 mm mesio-distal depth of the box, 4 mm occlusal depth, 4 mm bucco-lingual width) were prepared in 50 molars and randomly divided into five groups (n = 10), according to the material: SureFil SDR flow (SDR), Filtek Silorane (FS) and experimental materials (G-aenial Flo bulk fill, GF; G aenial Universal Flo bulk fill, GUF; GC Kalore bulk fill, GK). Microleakage was separately assessed at enamel and dentin margins by scoring the depth of silver nitrate penetration. Twenty teeth divided into five groups (n = 4) were selected for microTBS testing. The same materials as for microleakage assessment were placed in bulk to mid-coronal dentin. Microtensile beams were loaded in tension, and microTBS at failure was calculated in MPa. Microleakage and microTBS data were analyzed by ANOVA on ranks, followed Dunn's post hoc test (P< 0.05). RESULTS: Microleakage was not observed at the enamel interface in any of the groups. At the dentin interface, SDR recorded significantly higher microleakage than the other materials. microTBS of GF, GUF and GK did not differ among each other (33 +/- 12 MPa, 31 +/- 11 MPa, 30 +/- 9 MPa, respectively), while SDR (63 +/- 17 MPa) and FS (55 +/- 17MPa) achieved significantly higher microTBS values. No direct association between the sealing properties and the bond strength values was observed. PMID- 24479280 TI - Erosive potentials of brewed teas. AB - PURPOSE: To measure the pH, titratable acidity, fluoride concentration and erosive potential of brewed teas. METHODS: Bag teas were purchased to represent black, green, citrus, fruity, and floral tea flavors from Tulsi, Bigelow, HyVee, Tazo, and Yogi brands and brewed (1 bag/240 ml) in boiling water for 3 minutes. The pH, titratable acidity, and fluoride concentrations were measured. Following these measurements, a representative tea from each flavor was selected for investigation of erosion potential. Six extracted human molars were randomly assigned to each tea. Teeth were painted with fingernail polish to expose a 1 x 4 mm window and then soaked in tea for a total of 25 hours with teas refreshed every 5 hours. Teeth were then sectioned using a microtome and photographed using a polarized light microscope. Lesion depths (i.e., eroded surfaces) were measured using Image Pro Plus software. Differences in physiochemical properties and lesion depths between beverages were investigated using one-way ANOVA with post hoc Tukey's HSD test. Relationships among lesion depths and physiochemical properties were evaluated using the Pearson correlation test. RESULTS: pH, titratable acidity and fluoride concentrations differed between tea flavors (P < 0.05) and between brands (P < 0.05). Lesion depths produced by the citrus tea (83.1 +/- 10.3 microm) were greater than those produced by the fruity tea (56.5 +/- 6.1 microm); both teas produced greater depths than black (30.1 +/- 7.4 microm), floral (25.0 +/- 3.2 microm) or green (22.3 +/- 6.3 microm) teas (P < 0.05). pH (r = -0.96; P = 0.009) was inversely and titratable acidity (r = 0.97; P = 0.006) was positively associated with lesion depths. PMID- 24479281 TI - Low toxic effects of a whitening strip to cultured pulp cells. AB - PURPOSE: To assess the trans-enamel and trans-dentin toxicity of a 10% hydrogen peroxide (HP) whitening strip to odontoblast-like cells (MDPC-23). METHODS: Enamel surfaces of enamel/dentin discs adapted to artificial pulp chambers were subjected to two 30-minute whitening strip applications to obtain indirect extracts (DMEM + bleaching components that diffused across enamel and dentin). The extracts were applied for 1 hour to the cells for 1 or 5 days. A bleaching gel with 35% HP was used as the positive control. Cell viability (MTT assay) and morphology (SEM) as well as the quantity of HP in the extracts were assessed. RESULTS: Discrete cell viability reduction (21.9%) associated with slight alterations in cell morphology occurred after application of the extracts for 5 days to the MDPC-23 cells (Tukey's test; P < 0.05). Lower enamel/dentin diffusion of HP was observed after the use of the whitening strip compared with the bleaching gel (Mann-Whitney; P < 0.05). PMID- 24479282 TI - Ability of barrier coat S-PRG coating to arrest artificial enamel lesions in primary teeth. AB - PURPOSE: To evaluate the effects of a surface pre-reacted glass-ionomer (S-PRG) filled coating material to arrest artificial enamel lesions in primary teeth. METHODS: Buccal and lingual enamel was demineralized in 0.1 M lactic acid buffer solution (pH 4.75) for 5 days and then divided in the PRG-applied and non-PRG areas. Proximal surfaces were used as a control area without demineralization and coating application. Teeth were divided into three groups (n = 4) according to the 1-week immersion in different solutions: Group 1 (distilled water), Group 2 (demineralizing solution) and Group 3 (artificial saliva). Hardness and Young's modulus by nano-indentation test, and elemental contents and ultrastructure by SEM/EDX analysis were obtained. Data were statistically analyzed using ANOVA and Fisher's PLSD at alpha = 0.05. RESULTS: Only for the non-PRG area in Group 1, the hardness and Young's modulus of the demineralized surface enamel were significantly lower than those of the enamel 30-60 microm beneath the surface. Demineralized enamel of non-PRG and PRG-applied areas showed similar SEM views. Only for the non-PRG area in Group 2 and control area in Group 3, the Ca/P of the surface enamel was significantly higher than that of the enamel 5-10 microm beneath the surface. There was no significant difference of the Ca/P among the measuring points from the surface to 10 microm depth of enamel for the PRG applied area in Group 2. PMID- 24479283 TI - Remineralization efficacy of a toothpaste containing 8% arginine and calcium carbonate on enamel surface. AB - PURPOSE: To investigate the remineralization efficacy of different types of toothpastes on initial enamel lesions in vitro. METHODS: Artificial initial lesions were created on 150 enamel discs from freshly extracted bovine incisors. These enamel discs were divided into five groups. The test treatment consisted of undiluted Colgate Sensitive Pro-Relief Toothpaste containing 8.0% arginine, calcium carbonate and 1,450 ppm fluoride that was applied on the enamel surface under a pH-cycling including 4 x 3-minute application daily for 12 days and soaked in remineralizing solution during the untreated periods. The two other test products were commercial products: Crest Cavity Protection Toothpaste, containing 0.11% fluoride and GC Tooth Mousse, a professional remineralizing treatment paste (the active ingredients: casein phosphopeptide - amorphous calcium phosphate, fluoride). NaF solution (0.14% fluoride) was used as the positive control, while double distilled water (ddH2O) was used as the negative control. The remineralization of enamel discs was evaluated using Knoop hardness test, confocal laser scanning microscopy (CLSM) and polarized light microscopy (PLM), and the caries lesion depth was quantified using an image analyzer. The data were analyzed by ANOVA. RESULTS: All test products showed a recovery of the Knoop Hardness Number (KHN) after remineralization cycling treatment. The recovery of enamel KHN for Colgate Sensitive Pro-Relief, GC Mousse, Crest toothpasteand NaF groups were 44.53 +/- 6.72%, 35.00 +/- 7.83%, 24.56 +/- 5.95% and 42.51 +/- 6.74% respectively, while the recovery of negative control group was 18.99 +/- 4.98%. PLM results indicated the lesion depth recovery of 49.63 +/- 8.06%, 35.08 +/- 2.19%, 22.60 +/- 7.30% and 53.20 +/- 1.48% respectively, which were also significantly greater than that of the negative group (20.51 +/- 4.80%). CLSM analysis showed a reduction of average area, and total and average dye fluorescence of the lesions after treatment. The Colgate Sensitive Pro-Relief group presented significantly greater remineralization than the other toothpaste groups, while the Crest toothpaste group showed the lowest remineralization ability. PMID- 24479284 TI - Tooth bleaching induces changes in the vascular permeability of rat incisor pulps. AB - PURPOSE: To evaluate the inflammatory response in dental pulps of rat incisors subjected to tooth bleaching protocols with different HP concentrations and application times. METHODS: 42 incisors from Wistar rats were submitted to tooth bleaching using concentrations of 25% or 35% HP for treatment times of 15, 30 or 45 minutes. Four non-bleached teeth were used as controls. The animals received an intravenous injection of India ink immediately after the bleaching procedure and were sacrificed 1 hour later. Six bleached teeth from each group and three controls were made transparent, and one sample from each group was processed for histological analysis. The data were statistically analyzed using Kruskal Wallis and Dunn's tests (P < 0.05). RESULTS: The amount of dental pulp ink content was significantly higher in the samples that were bleached with 35% HP for 30 minutes and with both HP concentrations (25 and 35%) for 45 minutes than in the controls. For the samples bleached with the same HP concentration, the ink content was higher in samples that were bleached for 45 minutes. These results indicate that HP tooth bleaching can induce an increase in vascular permeability in rat incisors. Importantly, this increase is more dependent on the length of the bleaching procedure than on the concentration of the bleaching agent. PMID- 24479285 TI - Radiology and hemoptysis: key points. PMID- 24479286 TI - Sonographic evaluation of transjugular intrahepatic portosystemic shunt. AB - The purpose of this article is to review the role of sonography before, during and after transjugular intrahepatic portosystemic shunt placement. A sonographic assessment of the liver and abdomen is recommended before the procedure. We illustrate several important sonographic findings for the echographist, which may alter the procedure approach or even preclude transjugular intrahepatic portosystemic shunt placement. The most challenging step during the procedure is the puncture of the right portal vein. Sonography can be a helpful tool in reducing the number of needle passes, thereby reducing the risk of hemorrhagic complications. Because of its non-invasive and cost-benefit nature, sonography is useful for transjugular intrahepatic portosystemic shunt follow-up. A baseline study at 24 to 48 hours is recommended to discover procedure-related complications. Long-term follow-up is important to detect malfunction of the shunt. Doppler ultrasound is very accurate in detecting shunt thrombosis. However, no consensus exists on the optimal sonographic screening protocol for detecting stenosis. We describe three sonographic parameters to detect transjugular intrahepatic portosystemic shunt stenosis with high sensitivity. Finally, additional sonographic parameters and potential pitfalls are provided in order to improve sensitivity. PMID- 24479287 TI - Selective arterial embolization for control of haematuria secondary to advanced or recurrent transitional cell carcinoma of the bladder. AB - AIM: Haematuria is a common symptom in patients with advanced transitional cell carcinoma of the bladder. We report our experience of selective pelvic embolization using gelfoam as an embolic agent to treat intractable haematuria in these patients. METHODS: Three male patients aged 66-79 (mean 73.6 years) with inoperable or recurrent transitional cell carcinoma of the bladder underwent selective embolization to treat haematuria over a 9 month period. Initial pathological tumour stages were T2, T3, and T3a. Gelfoam was used as the embolic agent. RESULTS: In all patients extensive vesical neovascularisation was identified without a single focus of active extravasation. Following embolization all patients experienced cessation of haematuria. Mean transfusion requirements were 8.6 units pre-embolization and 0.3 units post-embolization. At follow up of between 6-13 months (mean 10 months) no further episodes of bleeding had been reported. No patient experienced procedure-related complications. CONCLUSION: Radiologically guided embolization is a safe and effective method for palliating haematuria in patients with transitional cell carcinoma. On the basis of our experience we would recommend gelfoam as the embolic agent of choice. PMID- 24479288 TI - Radiologic findings and percutaneous treatment of a rare giant soft tissue hydatid cyst. AB - The aim of this report is to present the radiologic findings and discuss the percutaneous treatment of an extremely rare giant soft tissue hydatid cyst located in the left thigh in a 44-year-old woman. Ultrasound showed a well circumscribed giant soft tissue cyst, and computed tomography revealed a well defined unilocular hypodense cystic mass originating from the adductor muscles and extending through the subcutaneous tissue without bony relations. On magnetic resonance imaging, the cystic mass was hypointense on T1 and hyperintense on T2 weighted images. Percutaneous treatment was performed successfully by catheterization technique with hypertonic saline and alcohol. No complications and recurrence were observed during the procedure, in the postprocedure or in the follow up period. PMID- 24479289 TI - Giant cell arteritis. AB - We report the case of a giant cell arteritis (GCA) in an 81-year-old man who presented with headaches and a decreased general condition associated with an important inflammatory syndrome in laboratory analysis responding to corticotherapy. Color-duplex ultrasonography (CDU) features of temporal arteries obtained with a high frequency probe permits us to underline the typical radiological presentation of this disease. PMID- 24479290 TI - Ureteral obstruction caused by schistosomiasis. AB - We report a unusual case of hydro-ureteronephrosis caused by schistosomiasis in a 66-year-old female. Computed tomography (CT) and biochemistry initially suggested a transitional cell carcinoma of the left proximal ureter. The patient was referred for reno-ureterectomy, but histopathological examination of the resection specimen demonstrated deposits of Schistosoma haematobium eggs. Although schistosomiasis is rare in Western Europe, this case illustrates the importance of considering infectious disease in patients with obstructive uropathy, particularly in the context of travelling or immigration from endemic areas. PMID- 24479291 TI - Subpubic cartilaginous cyst: a rare cause of dysuria. AB - A subpubic cartilaginous cyst is a rare lesion that may present as a vulvar mass or rarely with dysuria. This condition occurs predominantly in multiparous postmenopausal women and is believed to be secondary to degenerative changes in the fibrocartilaginous disc of the symphysis pubis. The midline location, close relationship with the undersurface of the symphysis pubis and the cystic nature are the clues to the correct diagnosis. PMID- 24479292 TI - Bilateral mucoid degeneration of the posterior cruciate ligaments. AB - Mucoid (myxoid) degeneration of the anterior cruciate ligament (ACL) is well documented and well known. Mucoid degeneration of the posterior cruciate ligament (PCL) has been reported, but is rare in comparison. The changes may be subtle and may be missed if one is not aware of the diagnosis. As in the ACL, degeneration may cause pain and discomfort. Recognition of the pathology and correct diagnosis is important for the patient and referring physician, as this may have an impact on the therapeutic strategy. We present a case of mucoid degeneration of both PCLs, which to the best of our knowledge has not been published before in the medical literature, as a probable cause of knee pain due to habitual kneeling. PMID- 24479293 TI - Aggressive fibromatosis: is PET-CT useful in lesion characterization? AB - Deep extra-abdominal fibromatoses (desmoids) are rare benign fibrous mesenchymal tumours occurring in adults, which may mimic primary malignancy on imaging. We present a case of a 64-year-old man with a hard painless lump in his left calf. The solid and partially hypervascular appearance on ultrasound, the infiltrative appearance, lesion heterogeneity and heterogeneous enhancement pattern on Magnetic Resonance Imaging (MRI) were suspicious for a soft tissue sarcoma. Moreover, PET-CT demonstrated FDG-avidity. Despite these aggressive imaging features, histopathology revealed a benign but locally aggressive desmoid tumour. The radiologist should be aware that PET-CT is not always helpful as an additional tool for differentiation between malignant and benign soft tissue lesions. Intralesional bandlike areas of low signal intensity on all pulse MR sequences and intimate relationship with the muscle fascia are more useful clues to the diagnosis of this soft tissue lesion. PMID- 24479295 TI - Contrast-enhanced ct and angiographic findings in hepatic perivascular epithelioid cell tumor. AB - We report a case of hepatic perivascular epithelioid cell tumor (PEComa) in a woman who was not a carrier of viral hepatitis and had a normal alpha-fetoprotein (AFP) level. CT scan showed a well-enhanced mass in the arterial-phase followed by early washout in the portal venous-phase in the lateral segment of the liver. Angiography revealed a hypervascular tumor in the liver with rapid washout of the contrast. If a hepatic tumor is found in a female patient with normal AFP level who is not a carrier of hepatitis and is free of alcoholic liver cirrhosis, tissue biopsy should precede treatment to avoid misdiagnosis of liver PEComa as hepatocellular carcinoma. PMID- 24479294 TI - A case of massive transient reduction of attenuation of iodine contrast bolus during computed tomography pulmonary angiography: why and how to avoid it. AB - We report an incidental case of combined disproportionate deep inspiration and breath-old artifacts producing during computed tomography pulmonary angiography performed to exclude pulmonary embolism in a 69-year-old patient. These known but unwelcome cumulated artifacts may cause transient major attenuation or interruption of the contrast bolus which may occasionally obscure or mimic an embolus. We shortly review the mechanisms of these classical artifacts and the adequate breathing instructions to avoid them are remembered. PMID- 24479296 TI - Hand measurements in the follow-up of acromegaly. AB - Acromegaly is a chronic progressive disease that originates from the increased secretion of the insulin-like growth-hormone (IGF-1) secondary to the hypersecretion of the growth hormone (GH). The enlargement of the minor hand and foot bones represents an early finding in this disease. Kleinberg et al. used the sesamoid index (SI) values for diagnosing the disease. The present trial was designed to investigate whether there was a difference between the control patients and the treated acromegalic patients in the SI, the terminal tuft width, the joint space and the metacarpal thickness. 34 patients were diagnosed and treated for acromegaly at the Rheumatology and Endocrinology Outpatient Clinics and 26 control patients presenting to the Rheumatology Outpatient Clinic, who were not detected to have an inflammatory rheumatologic pathology were enrolled. The hand radiographs of the patients that followed up for acromegaly and the control group were retrospectively evaluated. The SI, the tuft width, the joint space and the metacarpal thickness were measured. There was a statistically significant difference in the other parameters between the acromegalic patients and the control patients except the mean metacarpal thickness. PMID- 24479297 TI - Oleothorax. PMID- 24479298 TI - Amyloid arthropathy in a dialysis patient. PMID- 24479299 TI - Emphysematous cholecystitis in a non-diabetic patient. PMID- 24479300 TI - Aplasia of the left external iliac artery and persistant sciatic artery. PMID- 24479301 TI - Distal intestinal obstruction syndrome. PMID- 24479302 TI - Pulmonary fat embolism. PMID- 24479303 TI - Congenital absence of long head of the biceps tendon. PMID- 24479304 TI - Susac's syndrome. PMID- 24479305 TI - Pathologies of the thymus. PMID- 24479306 TI - An unusual complication after renal biopsy. PMID- 24479307 TI - [Identification and biological properties of intestinal lactic acid bacteria isolated from aged women]. AB - The strains of lactic acid bacteria have been isolated from the intestine of older women. These strains were identified and their biological activity was studied. It has been established that Lactobacillus acidophilus, L. plantarum, L. salivarius var. salivarius and Enterococcus faecium had the highest antagonistic activity against opportunistic microorganisms. It has been revealed, that the adhesive properties and antibiotic resistance of the tested cultures had strain specificity. Most of the isolates were highly adhesive and did not produce hemolysins. PMID- 24479308 TI - [The ability of actinobacteria to assimilate n-alkanes under nitrate-reducing conditions]. AB - It has been established that the oil-oxidizing strains of actinobacteria- components of the preparation "Ekolan-M" are able to assimilate n-alkanes during microaerobic cultivation in nitrate-reducing conditions. After 7 days of growth in these conditions, the level of biodegradation of n-hexadecane of the investigated strains was 52.0%, which is 1.5 times less than for the same period in the aerobic cultivation. n-Hexadecane utilized by cells was completely mineralized to carbon dioxide, the amount of which in the gas phase reached 1.6% on the 9th day of growth. PMID- 24479309 TI - [Effect of growth factors and some microelements on biosurfactant synthesis of Acinetobacter calcoaceticus IMV B-7241]. AB - The effect of yeast autolysate and microelements on synthesis of surface-active substances (SAS, biosurfactants) was investigated under cultivation of Acinetobacter calcoaceticus IMV B-7241 on various carbon substrates (n hexadecane, ethanol, glycerol). The authors have shown a possibility to substitute the yeast autolysate and microelement mixture in the composition of ethanol- and n-hexadecane-containing media by copper sulfate (0.16 micromol/l) and iron sulfate (3.6 micromol/l), and in the medium with glycerol by 0.21 mmol/l of KCl, 38 micromol/l of zinc sulfate and 0.16 micromol/l of copper sulfate. Under such conditions of cultivation of the strain IMV B-7241 the SAS concentration exceeded that on the initial media, which contained the yeast autolysate and microelements, 1.2-1.6 times. The authors have also established the activating effect of low (0.01 mM) concentrations of Fe2+ on activity of the enzymes of biosynthesis of surface-active amino- (NADP-dependent glutamate dehydrogenase) and glycolipids (phosphoenolpyruvate(PhEP)-synthetase, PhEP carboxykinase), as well as of anaplerotic reaction(PhEP-carboxylase). A necessity to introduce zinc cations into glycerol-containing medium is determined by their stimulating effect on activity of 4-dinitroso-N,N-dimethylaniline-dependent alcohol dehydrogenase--one of the enzymes of this substrate catabolism in A. calcoaceticus IMV B-7241. PMID- 24479310 TI - [Kinetic characteristics of alpha-L-rhamnosidase of Eupenicillium erubescens]. AB - It was established, as a result of investigations of the alpha-L-rhamnosidase of Eupenicillium erubescens kinetic properties, that K(m) and V(max) for the corresponding synthetic substrate were 1.0 mM and 120 micromol/min/mg of protein, respectively. alpha-L-Rhamnosidase was also competitively inhibited by the reaction product- L-rhamnose, the inhibition constant was 5.2 x 10(-2) M. One could also observe the inhibition of alpha-L-rhamnosidase reaction in the presence of 10(-3) M of glucose. It was shown that the rate of enzymatic hydrolysis of nitrophenyl substrate was directly proportional to the concentration of enzyme, and the increase of the substrate concentration leads to the increase of hydrolysis rate. The substrate concentration being increased above the optimal one (5.0 mg/ml), the reaction rate decreases due to the formation of inactive enzyme-substrate complex FS2. PMID- 24479311 TI - [Standardization of cryopreservation process of Saccharomyces boulardii yeasts for usage in collections and banks of industrial microorganism strains]. AB - New implementation principle of freeze-thawing during cryopreservation of microorganisms, initiation of the process of crystal formation at cooling and thawing stage with the controlled rate of heating was experimentally substantiated. This allows increasing the cell viability, guaranteeing their equal number in each preparation, decreasing the contamination risk of the samples at thawing stage. PMID- 24479312 TI - [Genetic variability of synthesis feature of carotenoids in Streptomyces globisporus 1912]. AB - Seventeen spontaneous and induced mutants, that acquired a new characteristic- the synthesis of beta-carotene and lycopene, were obtained from strain Streptomyces globisporus 1912. It was found that spontaneous mutants inherited more stably the acquired carotenogenesis as compared to induced ones. Synthesis of carotenoids by all isolated Crt+ Lcp+ cultures is a constitutive feature. It was shown that Crt(+)-mutants (4Crt, 6Crt, 7Crt, RVCrt and R3Crt) synthesized beta-carotene and lycopene, while Lcp(+)-mutants (TpS16-1, TpS16-2, 4Lcp and R3Lcp)--only lycopene. The obtained mutants and transformants of S. globisporus 1912, synthesizing carotene were characterized by a simultaneous change of two or three phenotypic characteristics: synthesis of the antibiotic landomycin E. sporullation and carotenogenesis. It can be assumed that the high instability of this characteristic (carotenogenesis) in strain S. globisporus 1912 was caused by localization of the crt-genes cluster close to a TIR-element in a chromosome terminal region, frequent structural reorganization of DNA here were reported in the literature. PMID- 24479313 TI - [Growth characteristics of Fusarium poae (Peck) Wollenw. and Penicillium funiculosum Thom strains]. AB - A comparative study of growth characteristics and peculiarities of glucose utilization by Fusarium poae and Penicillium funiculosum strains isolated from different habitats was conducted. It was found that F. poae and P. funiculosum strains differ as to their growth characteristics. Specific growth rate of endophytic strain F. poae was maximal (0.38 h(-1)), lower for plant pathogenic one (0.30 h(-1)) and the lowest for soil strain (0.18 hr(-1)). In contrast, the level of biomass accumulation was the highest for soil strain F. poae and minimal for plant pathogenic strain, endophytic strain took up an intermediate position. High economic coefficient was characteristic of soil strain and minimal of endophyte at medium biomass level and specific growth rate. In contrast to the strains of F. poae, the specific growth rate of soil strain of P. funiculosum was higher than that of endophyte one (0.35 and 0.24 h(-1), respectively). Biomass level of endophytic strain was significantly higher than that of the soil strain, and economic coefficient was 2.3 times higher for endophyte in comparison with soil strain. PMID- 24479314 TI - [Antibiotic activity of some fungi]. AB - Biological activity of pure extracts of cultural filtrates of Aspergillus niveus 2411, Myrothecium cinctum 910, Ulocladium consortiale 960, Penicillium sp. 10-51 concerning wide spectrum of test-organisms was investigated. It was shown that the extracts had high levels of antibacterial activity against Gram-positive microorganisms, especially against Bacillus genus. But their activity against Gram-negative bacteria was a bit lower. On the other hand, metabolites of M. cinctum 910 and Penicillium sp. 10-51 did show the activity concerning phytopathogenic bacteria. Extracts of fungi showed fungistatic activity against yeasts, but they were not so active concerning fungal test-cultures. Extracts of A. niveus 2411, Penicillium sp. 10-51 suppressed the growth of Phoma betae. The highest level of fungistatic activity was shown by metabolites of M. cinctum 910. They showed activity against Aspergillus genus strains and phytopathogenic isolates of Fusarium lactis, Rhizoctonia solani and Botrytis cinerea. PMID- 24479315 TI - [Bacillus subtilis and streptomycin resistant mutant growth in the medium with saponite]. AB - The influence of dispersed saponite on growth activity of Bacillus subtilis IMV B 7023 and its streptomycin resistant mutant has been shown. The effectiveness of this process depends on the content of dispersed material and phosphate in the medium. It has been found that when B. subtilis is cultured in the medium containing 0.6 g/l PO4(3-) stimulation of bacteria growth is observed, but at a lower concentration (0.1 g/l PO4(3-)) there is a decline in the culture growth activity. At the same time streptomycin resistant mutant is shown to increase growth activity in the growth medium which contains up to 1.0 g/l saponite, regardless of the concentration of phosphate. It is shown that this effect is a consequence of uniformity of surface properties of streptomycin resistant strain of bacteria and similar parent strain at a concentration of 0.6 g/l PO4(3-). PMID- 24479316 TI - [Electron microscopy and restriction analysis of bacteriophages isolated from quince and pear with symptoms of fire blight]. AB - Phage populations of isolates from quince and pear affected with fire blight disease were studied using electron microscopy, restriction analysis and both agarose gel electrophoresis of particles and host range scoping method. The isolate from quince (pMA1) comprises at least three phage populations and two phage variants that can be detected on different bacterial indicators. After titration of this isolate on Erwinia amylovora the bacteriophage KEY of B1 morphotype with the genome size of 82.4 kb was identified. The isolate pMA1 also includes a unique phage population 4*, which can be identified on the test bacteria Pantoea agglomerans (Pag) g150. Two analogous populations being also present in the isolate pMA1 that appeared to be close phage variants with almost identical Hpal-restriction patterns can be identified using Pag g157 and 9/7-1. The situation is similar in the case of phage isolates from pear, pMG. Three phage populations identified in it using three different indicators represent the same phage of C1 morphotype (TT10-27) with a genome size of 71.4 kb. At least two other phage populations were also detected in the same isolate using P. agglomerans 9/7-2 as an indicator. A model system allowing the most efficient analysis of the isolates for the presence of different phage populations and phage variants in plants infected by fire blight disease has been developed. It provides for using three indicator enterobacterial species closely associated with the plants: E. amylovora, Erwinia "horticola" and Pagglomerans and ignoring of the phage cloning procedure. PMID- 24479317 TI - [Computational genome analysis of three marine algoviruses]. AB - Computational analysis of genomic sequences of three new marine algoviruses: Tetraselmis viridis virus (TvV-S20 and TvV-SI1 strains) and Dunaliella viridis virus (DvV-SI2 strain) was conducted. Both considerable similarity and essential distinctions between studied strains and the most studied marine algoviruses of Phycodnaviridae family were revealed. Our data show that the tested strains are new viruses with the following features: only they were isolated from marine eukaryotic microalgae T. viridis and D. viridis, coding sequences (CDSs) of their genomes are localized mainly on one of the DNA strands and form several clusters with short intergenic spaces; there are considerable variations in genome structure within viruses and their strains; viral genomic DNA has a high GC content (55.5 - 67.4%); their genes contain no well-known optimal contexts of translation start codones, and the contexts of terminal codons read-through; the vast majority of viral genes and proteins do not have any matches in gene banks. PMID- 24479318 TI - [Endoplasmic reticulum stress, its sensor and signalling systems and the role in regulation of gene expression at malignant tumor growth and hypoxia]. AB - Hypoxia is one of the inductors of the expression of a large group of genes, which control glycolysis and proliferation processes in low oxygen conditions or as a result of low oxygen consumption. Moreover, hypoxia is one of the factors which induce the endoplasmic reticulum stress which, like hypoxia, is an obligatory component of malignant tumor growth and is connected with cytoplasm and nuclei through three sensor and signalling systems: PERK, ATF6 (Ta) ERN1. The suppression of ERNI, the main sensing and signalling enzyme of endoplasmic reticulum stress, leads to a decrease of tumor growth and changes the character of hypoxic regulation of many genes responsible for the control of proliferation and glycolysis. ERN1 sensing and signalling system controls the expression of a large set of genes, which are dependent on endoplasmic reticulum stress as well as hypoxia. Moreover, this signalling pathway is an important factor of malignant tumor growth. PMID- 24479319 TI - [Substrate specificity of Cryptococcus albidus and Eupenicillium erubescens alpha L-rhamnosidases]. AB - The substrate specificity of Cryptococcus albidus and Eupenicillium erubescens alpha-L-rhamnosidases has been investigated. It is shown that the enzymes are able to act on synthetic and natural substrates, such as naringin, neohesperidin. alpha-L-Rhamnosidases hydrolysed the latter ones very efficiently, in this case E. erubescens enzyme was characterized by higher values of V(max) in comparison with the enzyme of C. albidus. However the C. albidus alpha-L-rhamnosidase showed greater affinity for naringin and neohesperidin than the enzyme of E. erubescens (K(m) 0.77 and 3.3 mM and 5.0 and 3.0 mM, respectively). As regards the synthetic derivatives of monosaccharides, both enzymes exhibited narrow specificity for glycon: E. erubescens alpha-L-rhamnosidase--only to the p-nitrophenyl-alpha-L rhamnopiranoside (K(m) 1.0 mM, V(max) 120 micromol/min/mg protein), and C. albidus--to p-nitrophenyl-alpha-D-glucopyranoside (K(m) 10 mM, V(max) 5 micromol/min/mg protein). Thus, it was found that the enzyme preparations of E. erubescens and C. albidus are differed by their substrate specificity. The ability of E. erubescens and C. albidus alpha-L-rhamnosidases to hydrolyse natural substrates: naringin and neohesperidin, evidences for their specificity for alpha-1,2-linked L-rhamnose. Based on these data, we can predict the use of E. erubescens and C. albidus alpha-L-rhamnosidases in various industries, food industry in particular. This is also confirmed by the fact that the investigated alpha-L-rhamnosidases were stable at 20% concentration of ethanol and 500 mM glucose in the reaction mixture. PMID- 24479320 TI - [IP3-sensitive Ca(2+)-channels of endoplasmic reticulum in secretory cells of the rat exorbital lacrimal gland]. AB - The role of inositol-1,4,5-trisphosphate of (IP3)-sensitive Ca2+ channels in Ca2+ homeostasis maintenance under activation of M-cholinergic receptors and P2Y receptors in the secretory cells of the rat lacrimal gland was investigated. The study was carried out on intact and permeabilized secretory cells of exorbital lacrimal glands of rats. The cells were isolated using the modified Herzog, Sides, Miller method (1976) and permeabilized with digitonin (50 mg per 0.5 million cells). The functioning of the Ca(2+)-transport systems was estimated by changes of Ca2+ content in the studied cells, which was determined by the spectrophotometric method using arsenazo III. It was shown that IP3-sensitive Ca2+ channels (IP3Rs) of investigated cells are directly inhibited by 2-APB (10 microM/l). On the other hand, the channels are activated by IP3, cholinomimetic (carbacholine) and purine receptor agonist (ATP). When both M-cholinergic receptors and P2Y receptors were activated Ca2+ was released from the same IP3 sensitive store because the effects of ATP and carbacholine at high concentrations (1mM/l and 10 microM/l, respectively) on the Ca2+ content were non additive. The presence of the store-operated Ca(2+)-channels in secretory cells of the lacrimal gland is confirmed by the observed increase of cellular Ca2+ content as a result of Ca2+ mobilization from the store by carbacholine or thapsigargin and following restoration of Ca2+ concentration in the extracellular solution. PMID- 24479321 TI - [The effect of Ca(2+)-induced opening of cyclosporine-sensitive pore on the oxygen consumption and functional state of rat liver mitochondria]. AB - The effect of Ca(2+)-induced opening of cyclosporine-sensitive pore (mitochondrial permeability transition pore, MPTP) on the oxygen consumption and mitochondrial functional state was studied in the rat liver mitochondria. It was shown that, with the use of glutamate as oxidation substrate, in the absence of depolarization MPTP opening results in the increase of steady state respiration rate because of the activation of cyclosporine-sensitive Ca2+/H(+)-exchange and Ca2+ cycling, which was supported by the simultaneous work of MPTP and Ca(2+) uniporter. With the aid of selective blockers, cyclosporine A and ruthenium red, it was shown that MPTP and Ca(2+)-uniporter contribute equally to the Ca(2+) cycling and mitochondrial respiration. It was shown that bioenergetic effects of MPTP opening under steady state conditions (increase in the oxygen consumption rate under substrate oxidation without ADP, decrease in respiratory control ratio as well as the effectiveness of ATP synthesis, P/O) are close to the functional alterations, which result from the increase of endogenous proton conductance of mitochondrial membrane. Uncoupling effect of MPTP opening, by itself, had no effect on phosphorylation rate, which remains relatively stable because the fall of P/O is compensated by the activation of respiratory chain and the increase in the rate of state 3 respiration. It was concluded that under physiologically normal conditions MPTP might function as the endogenous mechanism of mild uncoupling of respiratory chain. PMID- 24479322 TI - [Defects in antioxidant defence enhance glyoxal toxicity in the yeast Saccharomyces cerevisiae]. AB - Glyoxal being either exogenous or endogenous compound belongs to reactive carbonyl species. In particular, its level increases under disturbance of the balance of glucose intracellular metabolism as well as of other reductive carbohydrates. Having two carbonyl reactive groups, glyoxal readily enters glycation reaction that results in carbonyl stress development. Investigations of different model systems demonstrate a strong relationship between carbonyl and oxidative stress. However, a possible role of antioxidant system in the organisms' defence against carbonyl stress is poor understood. In addition, the influence of glyoxal on living organisms is less studied than the effect of such carbonyl reactive species as malonic aldehyde or methylglyoxal. To study a potential role of antioxidant system in organisms' defence against carbonyl stress induced by glyoxal, the baker's yeast Saccharomyces cerevisiae was used. It has been found that strains with different defects in the antioxidant defence were more sensitive to glyoxal as compared with parental wild strain. Therefore, the data obtained in the present study confirm the relationship between carbonyl and oxidative stress and reveal the important role of antioxidant system in baker's yeast defence against carbonyl stress induced by glyoxal. PMID- 24479323 TI - [Carbohydrate restriction in the larval diet causes oxidative stress in adult insects of Drosophila melanogaster]. AB - The influence of 20 and 1% glucose and fructose, which were components of larval diet, on the level of oxidized proteins and lipids, low molecular mass antioxidant content as well as activities of antioxidant and associated enzymes in adult fruit fly Drosophila melanogaster were investigated. The restriction of carbohydrates in larval diet leads to oxidative stress in adult insects. It is supported by 40-50% increased content of protein carbonyl groups and by 60-70% decreased level of protein thiol groups as well as by a 4-fold increase of lipid peroxide content in 2-day-old flies of both sexes, developed on the diet with 1% carbohydrates. Oxidative stress, induced by carbohydrate restriction of the larval diet, caused the activation of antioxidant defence, differently exhibited in male and female fruit flies. Caloric restriction increased activity of superoxide dismutase and thioredoxin reductase associating only in males with 2 fold higher activity of NADPH-producing enzymes--glucose-6-phosphate dehydrogenase and isocitrate dehydrogenase. Carbohydrate restriction in the larval diet caused the increase of uric acid content, but the decrease in catalase activity in males. In females the values of these parameters were changed in opposite direction compared with males. The obtained results let us conclude the different involvement of low molecular mass antioxidants, glutathione and uric acid, and antioxidant enzyme catalase in the protection of male and female fruit fly macromolecules against oxidative damages, caused by calorie restriction of larval diet. PMID- 24479324 TI - Analysis of conformational flexibility of loop 110-120 of protein tyrosine phosphatase 1B. AB - Conformations of the catalytic center of protein tyrosine phosphatase 1B (PTP1B) and surrounding loops are known to be important in catalysis and inhibition of the enzyme. There were 98 conformations from 88 PDB files representing PTP1B with different ligands which were analyzed to investigate the details of loop 110-120 movement and mobility of separate residues. The differences were identified by a special software tool which performs multiple comparisons of selected parts of PDB files. The conformations were divided into 6 clusters. It was found that the loop formed by residues 110-120 can be characterized by four main conformations. Predominantly, the loop 110-120 adopts the main conformation and keeps it during WPD loop movement. Three other conformations appear to be stabilized in case of closed WPD loop and seem to be favorable for PTP1B with subunit structure. PMID- 24479325 TI - [Isolation and characterization of new monoclonal antibodies against human IgE]. AB - The original set of 12 clones of hybridomas, producers of monoclonal antibodies (mAbs) against human IgE, has been obtained. The study of biological properties of antibodies has been conducted: their specificity, affinity constant and titer in a cultural medium have been established. The obtained mAbs are directed to the two epitope regions on IgE molecule. The first group of mAbs relates to epitope region, represented by three epitopes (two of them overlap and one that does not overlap with others). The second epitope region is represented by only one epitope. PMID- 24479326 TI - [The effect of N-stearoylethanolamine on the activity of antioxidant enzymes, content of lipid peroxidation products and nitric oxide in the blood plasma and liver of rats with induced insulin-resistance]. AB - The influence of N-stearoylethanolamine (NSE) on the content of lipid peroxidation products, activity of antioxidant enzymes and the nitric oxide level in the liver and blood plasma of rats with insulin-resistance (IR) state was investigated. IR state was induced in rats by prolonged high-fat diet (58% of energy derived from fat) for 6 months combined with one injection of streptozotocin (15 mg/kg of body weight). The existence of IR state was estimated by results of glucoso-tolerance test and blood plasma insulin content. The level of lipid peroxides products was shown to be higher in the liver of insulin resistant animals as a result of reduced superoxide dismutase and catalase activity, however, glutathione peroxidase activity was increased. The increase of nitric-oxide content in the liver and blood plasma of high-fat diet rats compared with healthy control animals was also observed. The administration of the NSE suspension per os in a dose of 50 mg/kg during 2 weeks to the rats with induced insulin-resistance state contributed to the increase of superoxide dismutase, catalase and glutathione peroxidase activity. In consequence of antioxidant enzymes activation the intensity of POL process was decreased. The NSE administration caused normalization of nitric oxide level, restoring pro /antioxidant balance in the liver and blood plasma of rats with IR state. In conclusion, the NSE administration to the rats with insulin-resistance state restored pro-/antioxidant balance and enhanced the content of nitric oxide, therefore, improving insulin sensitivity. PMID- 24479327 TI - [Antitoxic and antioxidant effects of N-stearoylethanolamin in the content of nanocomposite complex with doxorubicin in organs of mice with Lewis carcinoma]. AB - The aim of the study was to evaluate the possibility to reduce the doxorubicin toxic effects by its immobilization with N-stearoylethanolamine (NSE) on nanocarier polyethylene glycol. The studied parameters of the doxorubicin toxicity were: the level of creatinine in the mice blood plasma and activity of alanine aminotransferase and aspartate aminotransferase in the blood plasma of mice. The activity of catalase superoxide dismutase, glutathione peroxidase and intensity of lipid peroxidation was determined in the tissues of the heart, kidneys and liver. Doxorubicin in the content of nanocarrier alone caused an increase of serum creatinine and aspartateaminotrasferase activity in plasma of experimental animals with carcinoma. Nanocomposite which contained doxorubicin and NSE, did not cause an increase of these parameters. It has been shown that the administration of a carrier containing doxorubicin to mice with Lewis lung carcinoma caused the decrease of catalase activity in mice with carcinoma. The combination of NSE and doxorubicin on the carrier led to the normalization of this parameter to the level of intact animals. NSE immobilized on a carrier together with doxorubicin caused a decrease in the activity of superoxide dismutase in the kidney tissue of mice with tumor. The tumor growth caused the increase of the of superoxide dismutase in mice. The administration of a carrier which contained doxorubicin and NSE normalized superoxide dismutase in heart tissue contrary of kidney. The obtained results show the antitoxic and antioxidant effects of N-stearoylethanolamine immobilized in the nanocarrier complex together with doxorubicin. PMID- 24479328 TI - [Arginase and NO-synthase pathways of L-arginine metabolism in peripheral blood lymphocytes of patients with ovarian cancer]. AB - The peculiarities ofarginase and NO-synthase pathways of L-arginine metabolism in peripheral blood lymphocytes of patients with ovarian cancer were studied. It was shown that the development of cancer pathology is associated with an imbalance in the NO synthesis in blood lymphocytes. The reason for such imbalance is the activation of arginase and inducible isoform of NO-synthase (iNOS) and significant inhibition of its constitutive isoform. The analysis of the kinetic properties of NOS of blood lymphocytes of patients with ovarian cancer was carried out. It was shown that the affinity constant of iNOS affinity for L arginine is 5.4-fold lower than for eNOS of blood lymphocytes of persons in the control group. The inhibition of eNOS occurs via non-competitive type and is related to the reduction of maximum reaction rate. PMID- 24479329 TI - [Influence of oxidative stress on the level of genes expression Tgfb1 and Hgf in rat liver upon long-term gastric hypochlorhydria and administration of multiprobiotic Symbiter]. AB - Free-radical processes upon long-term omeprazole-induced gastric hypochlorhydria in the rat liver were researched. Intensification of oxidative processes in the liver tissue upon gastric hypoacid state was established: overproduction of superoxide anion, hydrogen peroxide, the quantitative changes of lipid functional groups, increased level of lipid peroxidation products, and augmentation of xanthine oxidase activity. The expression of Tgfb1 gene increased, while the expression of Hgf gene was not detected upon long-term suppression of gastric acid secretion of hydrochloric acid by omeprazole that indicated possible development of liver fibrosis. Abovementioned parameters were only partially restored to control values in the case of simultaneous administration of multiprobiotic "Symbiter acidophilic" concentrated with omeprazole, thus indicating the ability of this preparation to counteract the development of oxidative damages in liver tissues upon long-term gastric hypoacidic conditions. PMID- 24479330 TI - [Oxidative stress in blood leukocytes, pro/antioxidant status and fatty acids composition of pancreas lipids at experimental acute pancreatitis in rats]. AB - In an experimental model of acute pancreatitis (AP) in rats no alteration in leukocyte's viability was found by flow cytometry as compared to control. After 1 day of AP production of reactive oxygen forms in granulocytes was increased more than 5 times, but after 3 days their level was decreased. Alterations of pro/antioxidant status and specific changes in the fatty acid composition in the pancreas were established. With the development of AP, the processes of lipids peroxidation were intensified while antioxidant system was altered, that was evidenced by inflammation in the pancreas. In these conditions, the increase of phospholipase A2 activity was accompanied by significant changes of fatty acid composition of the total lipids in the pancreas. This increased relative total content of saturated fatty acids, in particular myristic, palmitic and stearic acid increased, while the total content of polyunsaturated essential fatty acids omega-3 (linolenic, eicosapentaenoic, dokozapentayenoic, docosahexaenoic) decreased. The preparation containing omega-3 polyunsaturated fatty acids partially normalized the lipid and fatty acids composition as well as prooxidant antioxidant system. PMID- 24479332 TI - [Kinetic pattern of folic acid release from polyurethane matrices of varied structures]. AB - The development of new bioactive polymeric materials is very topical. The goal of the present work was to use an optimized reversed-phase HPLC method to determine the release of folic acid (FA) from polyurethane carriers of different structures in vitro. Two types of polymeric samples were studied as FA carriers: linear (covalent bonds between FA and the carrier; 13 mass % and 26 mass % FA--samples 1 and 2) and cross-linked (hydrogen bonds between FA and the carrier; 1 mass % FA and 6 mass % FA--samples 3 and 4). The rate and pattern of the FA release was shown to depend on the way of FA immobilization on the polymeric carrier and the polymer structure. The cumulative amount of FA released from the linear samples (1 and 2) into model medium on the 28th day was 1.20 mg/ml and 2.17 mg/ml, respectively. The cumulative amount of FA released from the cross-linked samples (3 and 4) on the 28th day was 0.16 mg/ml and 0.38 mg/ml, respectively. PMID- 24479331 TI - [Use of vitamins for correction of the functional state of cytochrome P450 systems in experimental allergic encephalomyelitis]. AB - It is known that inflammatory cytokines, which level is significantly increased in the pathogenesis of multiple sclerosis (MS), as well as interferon-beta, which is used to treat autoimmune diseases, can inhibit cytochrome P450-dependent processes of detoxification and biotransformation. The uncontrolled decrease of the activity of these processes may have a negative affect on the state of patients, so it is urgent to study the functional state of the cytochrome P450 system and to develop effective means for its regulation in these conditions. The effect of vitamin D3 and efficiency of its composition with vitamins B1, B2, B6, PP, E, alpha-lipoic, alpha-linolenoic acid and mineral substances (Mg, Zn, Se) in prevention of a functional state changes of cytochrome P450- and b5-dependent systems of the rat brain and liver endoplasmic reticulum at EAE are investigated. It has been shown that the essential decrease of the level of these cytochromes is observed both in the brain and liver. In addition the level of activity of NADH- and NADPH-oxidoreductases, which are part of microsomal electron transport chain components and coupled with monooxigenases, was reduced. These changes confirm the disturbances of a redox state and functional activity of detoxication and biotransformation systems in the studied animal tissues. Supplement of vitamin D3 as well as the composition of biologically active substances, which we developed earlier, effectively eliminated the decrease of the level of cytochromes and activities of NADH-oxidoreductase in immunised rat tissues. Normalization of these disturbances can be explained by antioxidant and membrane stabilizing properties of applied substances, and also by the ability to reduce the activity of inflammatory reactions by regulation of the level of inflammatory cytokines in rat organism at EAE. Thus the studied vitamin-mineral composition appeared to be more effective to normalize the found disturbances and it can be useful for prevention of exacerbations and for improvement of a status of patients with multiple sclerosis and other diseases, which are accompanied with hyperactivation of immune system. PMID- 24479333 TI - [Alterations of prooxidant-antioxidant system of rat liver at ethanol and tetracycline action]. AB - The state of antioxidant system and fatty acid composition of lipids in the liver tissues of rats of different sex at the ethanol and tetracycline action and at the influence of biologically active additives (BAA) "Alpha + Omega" at a dose of 0.5 mg/kg b.w. per os was investigated. It was found that the contet of lipid peroxidation products in the liver was increased at the action of 40% ethanol at a dose of 7 ml/kg b.w. per os and tetracycline--500 mg/kg and more profound at their joint using. However, the content of diene conjugates was stronger increased in the liver of females at the action of ethanol, while in the liver of males at the action of tetracycline (P < 0.05). It was shown that the application of the investigated compounds led to the reduction of an antioxidant defense system activity of males and females liver, as evidenced by the decrease of superoxide dismutase activity by 46 and 43% and reduction of glutathione content by 39 and 38% (P < 0.05). The activity of alanineaminotransferase, aspartateaminotransferase and alkalinephosphatase was increased in the liver of males and females under the influence of ethanol and tetracycline and more profound at their joint usage (P < 0.05). It was established that ethanol and tetracycline unidirectionally changed fatty acid composition of total lipids of rat liver, but at the ethanol action the changes were more expressed in females while at the tetracycline action in males. The application during 14 days of BAA "Alpha + Omega" to male and female rats with an acute tetracycline damage at subacute ethanol action led to partial normalization of prooxidant-antioxidant system and the relative content of total lipids fatty acids of the liver of both sexes animals. PMID- 24479334 TI - Seasonal dynamics of products of lipid peroxidation in liver of bank vole (Myodes glareolus) under conditions of environmental pollution by heavy metals. AB - The presented research involves the integral assessment of biochemistry indexes of natural populations of voles under conditions of environmental pollution by heavy metals. The raised content of mobile forms of Pb, Cd, Cr, Ni and Co in soils was revealed for a distance of 500 m to the south-west of Tripillya Thermal Power Plant (TPP) (Kyiv region, Ukraine). It considerably (up to 3-5 times) exceeds the levels in the territory of Kaniv Nature Reserve (Cherkassy region, Ukraine). The territory of National Nature Park "Holosiivsky" (Kyiv, Ukraine) is characterized by rather increased content of active form of investigated heavy metals, especially Pb. The increase of the concentration of diene conjugates (up to 7-10 times) and thiobarbituric acid (TBA) active compounds (up to 2-3 times) in the liver of bank vole (Myodes glareolus) polluted by heavy metals has been found. The insignificant increase of the content of Schiff bases in liver homogenate of voles in the region of impact of the Tripillya TPP (2 times in spring and summer, 3 times - in autumn) was detected. Seasonal dynamics of the maintenance of lipid peroxidation products has been revealed. The registered changes of biochemical indicators evidence for availability of biochemical stress in the bank vole organism in the region of influence of the Tripillya TPP. PMID- 24479335 TI - [Identification of components of the milky juice of Lactarius pergamenus (Fr.)Fr fungi by gas-liquid chromatography/mass spectrometry]. AB - The authors have proposed method of separation of methanol extract of Lactarius pergamenus basidiomes and investigation of fractions extracted with hexane which, according to our previous studies, possess the highest antiproliferative and antifungal activity. Main attention was given to fractionation and analysis by gas-liquid chromatography-mass spectrometry (GLC/MS) of the fraction 1.4 extracted with hexane. The key role in separation of this fraction was played by the use of dioxane which mixes well with both polar and nonpolar solvents (hexane, chloroform, methanol, water). Chemical composition of hexanoic fraction of methanol extract of dried basidomes Lactarius pergamenus fungi were completely characterized. It was found that this fraction consisted of 38% of fatty acids and their derivatives, 29%--of the phthalates, 13%--of the sesquiterpene, 2%--of aldehydes and 18%--of other compounds (hydrocarbons, alcohols, hydrazine derivatives and unidentified substances). Such combination of constituents allows forming a stable emulsion of milky juice which protects the mushroom fruit body from the bacterial and fungal infections and from eating by the mammalians and insects. PMID- 24479336 TI - [Mathematical modeling of calcium homeostasis in smooth muscle cells while activity of plasma membrane calcium pump is modulated]. AB - A mathematical model of intracellular calcium homeostasis in smooth muscle cells has been investigated by computer modelling method. The results of calculations showed that for the plasma membrane calcium pump (PMCA) the limiting rate (V(mPM)) increasing or the Michaelis constant (K(mPM)) decreasing result in a lowering of the Ca2+ concentration in cytosol and sarcoplasmic reticulum (SR); the slight V(mPM) decreasing or K(mPM) increasing result in fluent cytosolic Ca2+ strengthening due to slow basal influx (SBI) since a massive release of Ca2+ from SR does not occur. The further V(mPM) decreasing or K(mPM) increasing stimulate the Ca(2+)-induced Ca2+ release from SR and the system passes into oscillation mode; when the certain low V(mPM) or high K(mPM) level is reached the oscillations of Ca2+ concentration in cytosol are stopped, there is only first oscillation after which a new level of cytosolic Ca2+ concentration is formed fluently: this level is higher than in the initial basal condition (IBC). Sensitivity of myocytes with the lowering of V(mPM) or increasing K(mPM) to agonist action is rising but sensitivity of myocytes with increasing V(mPM) or decreasing K(mPM) to agonist action is reducing. If the PMCA parameters (V(mPM) or K(mPM)) are changed then passive influx of Ca2+ in cytosol from extracellular space remains virtually invariable and it is equal to SBI value during the whole process. Initial rate of PMCA in a new equilibrium condition (NEC) is equal virtually to initial rate in IBC: it allows to calculate a new value V(mPM) or K(mPM) from cytosolic Ca2+ concentration in NEC. PMID- 24479337 TI - Self-organization and fractality in a metabolic processes of the Krebs cycle. AB - The metabolic processes of the Krebs cycle is studied with the help of a mathematical model. The autocatalytic processes resulting in both the formation of the self-organization in the Krebs cycle and the appearance of a cyclicity of its dynamics are determined. Some structural-functional connections creating the synchronism of an autoperiodic functioning at the transport in the respiratory chain and the oxidative phosphorylation are investigated. The conditions for breaking the synchronization of processes, increasing the multiplicity of cyclicity, and for the appearance of chaotic modes are analyzed. The phase parametric diagram of a cascade of bifurcations showing the transition to a chaotic mode by the Feigenbaum scenario is obtained. The fractal nature of the revealed cascade of bifurcations is demonstrated. The strange attractors formed as a result of the folding are obtained. The results obtained give the idea of structural-functional connections, due to which the self-organization appears in the metabolism running in a cell. The constructed mathematical model can be applied to the study of the toxic and allergic effects of drugs and various substances on cell metabolism. PMID- 24479338 TI - [Purine nucleoside phosphorylase]. AB - Purine nucleoside phosphorylase (PNP) is one of the most important enzymes of the purine metabolism, wich promotes the recycling of purine bases. Nowadays is the actual to search for effective inhibitors of this enzyme which is necessary for creation T-cell immunodeficient status of the organism in the organs and tissues transplantation, and chemotherapy of a number pathologies as well. For their successful practical application necessary to conduct in-depth and comprehensive study of the enzyme, namely a structure, functions, and an affinity of the reaction mechanism. In the review the contemporary achievements in the study of PNP from various biological objects are presented. New data describing the structure of PNP are summarised and analysed. The physiological role of the enzyme is discussed. The enzyme basic reaction mechanisms and actions are considered. The studies on enzyme physicochemical, kinetic, and catalytic research are presented. PMID- 24479339 TI - [Antitumor activity of L-asparaginase from Erwinia carotovora from against different leukemic and solid tumours cell lines]. AB - We have studied dose- and time-dependent antitumor and cytotoxic effects of Erwinia carotovora L-asparaginase (ECAR LANS) and Escherichia coli L-asparaginase (MEDAC) on human leukemic cells and human and animal solid tumor cells. We determined the sensitivity of tumor cells to L-asparaginases, as well the effect L-asparaginases on cell growth rate, protein and DNA synthesis per se and with addition of different cytostatics. The data obtained demonstrated that ECAR LANS L-asparaginase suppressed growth of all tested solid tumor cells. Evaluation of leukemic cell number after treatment with L-asparaginases for 24, 48 and 72 h demonstrated that asparagine deficiency did not kill cells but stopped normal cell division and had no effect on protein and DNA synthesis. Cytofluorometric study of solid and leukemic cells demonstrated that the treatment with L asparaginase for 72 h did not change cell cycle phase distribution and did not increase the number of apoptotic cells. The HL-60 cell line was only exemption. At the same time, cells treatment with L-asparaginase and doxorubicin combination leaded to increase of apoptotypical cell number to 60% for MCF7 cells, to 40% for Jurkat cells and to 99% for HL-60 cells. We have excluded apoptosis as main reason for tumor cell death after asparaginase treatment because multi resistant Jurkat/A4 cells have been asparaginase sensitive. We have not found ECAR LANS L asparaginase effect on normal human fibroblasts growth ability and we had come to conclusion that enzyme cytotoxcisity related only with asparagine deficiency. PMID- 24479340 TI - [Modified HPLC method of determination of the valproic acid in biological fluids]. AB - Proposed modified HPLC method for determination of valproic acid in biological fluids. Created solid-phase extraction of valproic and heptanoic acids (internal standard, IS) on the cartridges packed hyper cross-linked polystyrene which maintain some tens extractions without losses of efficiency. Carboxylic acids are derivative with 1-(bromoacetyl)pyrene in acetone at presence of triethylamine. Chromatographic separation of derivatives is performed on Chromolith Perfonnance RP-18e columns, which packed unique monolithic sorbent. UV detection at 360 nm. Mobile phase acetonitrile - water (90:10, v/v) plus 1% isopropanol, speed flow 2000 microL/min, pressure 21 bar. Complete chromatographic cycle less than 3 minutes. Yield of IS and valproic acid (extraction plus derivatization) was 101 106%. Sensitivity (limit detection) was near 1 ng for valproic and near 0.6 ng for heptanoic acid during signal/noise ratio = 3. PMID- 24479341 TI - [Study of surface-active properties antivirials compound 1-boraadamantane for model monomoleculars phosphlipids layers]. AB - The surface-active properties of 1-boraadamantane have been studied using model phospholipid monolayers. Results suggest that the increase in 1-boraadamantane concentrations from 10(-7) to 10(-6) M is accompanied by the increase of the area per phospholipid molecule. This decreases to frequency of lateral diffusion of phospholipids molecules, the potential difference and the angle of the phospholipid monolayer arrangement. These phenomena may lead to impossibility of interaction between the virus and cell membranes. PMID- 24479342 TI - [Carbohydrates metabolism disturbances when simulating prenatal alcohol intoxication]. AB - The influence of prenatal alcohol intoxication on carbohydrate metabolism markers has been investigated at different terms of postnatal offspring development (15, 30 and 60 days). Plasma glucose decreased as compared with the same in control group was detected. In the liver homogenates an increase of phosphorylase activity and a decrease of glucose-6-phosphatase, aldolase and glucose-6 phosphate dehydrogenase activities were found. These changes were accompanied by the incease in the lactate/pyruvate index attributed to increased lactate content in the liver tissue. The obtained data indicate essential disturbances of carbohydrate metabolism markers in prenatal alcoholized offspring, which include stable hypoglycemia, suppression of glycolytic and pentosephosphate pathways of glucose metabolism and lactate accumulation in the liver. PMID- 24479344 TI - [The activity of glutathione antioxidant system at melaksen and valdoxan action under experimental hyperthyroidism in rats]. AB - Investigation of glutathione antioxidant system activity and diene conjugates content in rats liver and blood serum at the influence of melaksen and valdoxan under experimental hyperthyroidism (EG) has been revealed. It has been established that the activities of glutathione reductase (GR), glutathione peroxidase (GP) and glutathione transferase (GT), growing at pathological conditions, change to the side of control value at these substunces introduction. Reduced glutathione content (GSH) at melaxen and valdoxan action increased compared with values under the pathology, that, obviously, could be associated with a reduction of its spending on the detoxication of free radical oxidation (FRO) toxic products. Diene conjugates level in rats liver and blood serum, increasing at experimental hyperthyroidism conditions, under introduction of melatonin level correcting drugs, also approached to the control meaning. Results of the study indicate on positive effect of melaxen and valdoxan on free radical homeostasis, that appears to be accompanied by decrease of load on the glutathione antioxidant system in comparison with the pathology. PMID- 24479343 TI - [Matrix metalloproteinases (MMP)--MMP-1,-2,-9 and its endogenous activity regulators in transformed by E7 oncogene HPV16 and HPV18 cervical carcinoma cell lines]. AB - Matrix metalloproteinases (MMP) play a key role in development of tumor invasion and metestasis. The purpose of the work is the elucidation of peculiarities of expression of MMP-1, MMP-2, MMP-9 and their activity regulators: plasminogen activator uPA and tissue inhibitors of MMPs - TIMP-1 and TIMP-2 in human cell lines of squoamous cell carcinoma (SCC). Comparative study of MMPs' expression was carried out on cell lines SCC which differed in HPV types (HPV-16 and HPV 18): SiHa, Caski - HPV16, Hela, C4-1 - HPV18). As a control, the C33A line was used where HPV copies were absent. The human papilloma viruses (HPV) of high risk -HPV-16, HPV-18, as etiological factors of initiation of cervical cancer, are most widespread and most aggressive among oncogenic HPVs. Study of MMP expression involved estimation of expression of mRNA using the RT-PCR method and determination of collagenolytic activity by hydrolysis of fluorogenic type 1 collagen and also by the zymography method. It was shown that: 1. In both types of cell lines, the MMP-1 expression was essentially increased (2 to 8 times), and in HPV18 lines it was most expressed. The exception was made by the SiHa line in which the decrease of expression of this enzyme was observed. MMP-2 expression was at the control level in both types of cell lines. 2. Expression of inhibitors generally was at the control level. The only exception was the C4-1 line where the expression of TIMP-1 and TIMP-2 was increased in 1,7 and 2,6 times accordingly. Expression of uPA was increased 2 to 4, 5 times in all cell lines except Siha where was lowered to 20%. 3. Collagenolytic activity in the Caski and Hela cell line was 2-3 times higher that it was in control, while the activity in the SiHa cell line was compatible with that in the control. Research of gelatinolytic activity also as well as the data on an expression MPHK has revealed only presence MMFP-2, but not MMP-9 in all cervical carcinoma cell lines. The data obtained provide evidence for a significant disturbance in transformed cells of enzyme/inhibitor/activator ratio--which occurs, for the most part, at the cost of elevated expression of MMP-1 and its activator whereas the expression of MMP-2 and inhibitors remains virtually unchanged, which leads to the increase of the destructive potential of transformed cells. PMID- 24479345 TI - [Selenium and oxidative stress in cancer patients]. AB - In order to identify the features of violations of free-radical processes in blood serum of 94 untreated cancer patients with different localization of the tumor (cancer of the stomach, colon, breast, ovarian, hemoblastoses) were determined selenium levels and indicators of oxidative stress (sum of metabolites of nitrogen--NOx, the level of superoxide dismutase--Cu/ZnSOD and malondiialdehyde-MDA, and the activity of catalase). In addition, 40 patients with malignant liver disease and clinical signs of liver failure in the early postoperative period was carried out a comparative evaluation of the efficacy of selenium-containing drug "Selenaze" (sodium selenite pentahydrate). It was found that selenium levels in cancer patients by 25-30% below the norm of 110-120 mg/l at a rate of 73.0 +/- 2.6 mg/l. Low levels of NOx was detected in patients with all tumor localizations (22.1 +/- 1.1 microM, with normal range 28.4 +/- 0.9 microM). The exceptions were patients with extensive malignant process in the liver, in which the NOx levels were significantly higher than normal (p < 0.001). The high level of NOx has a toxic effect on the hepatocyte, causing metabolic disorders and inflammatory-necrotic changes in the liver. Elevated levels of SOD and MDA in normal values of catalase activity was detected in all patients. The use of "Selenaze" in postoperative patients with tumors of the liver increased selenium levels by 10-12%, which was accompanied by a decrease in the content of SOD and NOx, and contributed to earlier recovery of detoxic and synthetic liver function. These findings point to an intensification of oxidative stress and metabolic disorders in the malignant process, which is the basis for metabolic correction. PMID- 24479346 TI - [The proinsulin level in the blood of children with type 1 diabetes mellitus of various duration]. AB - Proinsulin content was measured in the serum of 82 children (aged from 3 to 14 years) with type 1 diabetes mellitus of various duration. Three groups of patients characterized by low (54%), normal (42%) and high (4%) levels of this prohormone were recognized. No dependence the proinsulin level on the disease term was found. The serum proinsulin level may be used as a parameter specifying the pathogenesis of type 1 diabetes mellitus. PMID- 24479347 TI - [Arginine and lysine as products of basic carboxypeptidase activity associated with fibrinolysis]. AB - Blood carboxypeptidases play an important role in the regulation of fibrinolysis. We have proposed here the method for the assay of blood carboxypeptidase activity associated with coagulation/fibrinolysis using the natural substrate fibrin and the detection of basic amino acids arginine and lysine as products in the conditions close to those in vivo. Plasma samples from 15 patients with arterial hypertension were investigated. The coagulation and subsequent fibrinolysis were initiated by addition of standard doses of thrombin and tissue plasminogen activator, respectively. Arginine and lysine concentrations before, during, and after completion of fibrinolysis were determined using HPLC. The parameters of fibrinolysis were evaluated by clot turbidity assay. Fibrinolysis led to a large and significant increase in concentrations of arginine and lysine in the incubation mixture by 101 and 81%, respectively. The duration of fibrinolysis initiation significantly correlated to the degree of increase of these amino acids: r(s) = -0.733 and -0.761 for arginine and lysine, respectively (p < 0.05). The rates of amino acids liberation during fibrinolysis demonstrate different pattern: arginine generation had two maximums: at the beginning of clot lysis and at his end, whereas the liberation of lysine occurred mainly at the middle of fibrinolysis. Thus, the carboxypeptidase activity associated with fibrinolysis can be considered as a local source of the essential aminoacids. PMID- 24479348 TI - [Activity of matrix metalloproteinases MMP-2 and MMP-9 in bone marrow plasma of patients with acute myeloid leukemia]. AB - Prognostic significance of the ratio of MMP-2 and MMP-9 activities (MMP-2/MMP-9) have been investigated in bone marrow plasma (BMP) of 53 patients with acute myeloid leukemia (AML) using the method of zymography. During BMP collection 33 patients were diagnosed with complete remission (CR) and 22 patients without CR. The ratio MMP-2/MMP-9 was approximately 1.00 (the upper limit was equal 1.77) in the 75% of patients. At the same time the ratio was more than 3 times higher in 13 patients (25%): their minimal value was 1.80 (p < 0.001). In the group with high ratio MMP-2/MMP-9 only 3 patients were with CR, and 10 patients with resistant variant of AML. The median of the overall survival (OS) of these 10 patients was significantly lower than OS of other investigated AML patients (7.0 vs 33.5 months p < 0.001). Thus the high MMP-2/MMP-9 ratio (> or = 1.8) may be associated with unfavorable course of AML. PMID- 24479349 TI - [Drug delivery system on the base of phospholipid nanoparticles for rifampicin]. AB - Low bioavailability of rifampicin, one of the main antituberculous drug, stimulates searches of its new optimized formulations. The present study has showen possibility of rifampicin embedding into nanoparticles from plant phosphatidylcholine (diameter of 20-30 nm). Addition of sodium oleate to the phospholipid system caused a 2-fold increase of the percent of rifampicin incorporation. After oral administration to rats, the maximal drug observed in plasma one hour after was 0.5 and 4.2 mkg/ml for free rifampicin for rifampicin in phospholipids-oleate nanoparticles, respectively. These levels were maintained for more than two hours of the experiment. High rifampicin bioavailability in the oleate containing phospholipid nanosystem suggests prospectivity of its pharmaceutical elaboration. PMID- 24479350 TI - [Mode of action prediction of ligands of steroid hormone receptors]. AB - The several predictive models based on two well-known methods PASS and SIMCA were created. These models predict a type of physiological response of steroid compounds binding to nuclear receptors of steroid hormones. We considered 10 variants: the agonists and the antagonists of estrogen, progesterone, androgen, glucocorticoid and mineralocorticoid receptors respectively. Two different sets of descriptors were used during SIMCA (the Dragon descriptors and indices of similarity). The results of discriminant analysis are good enough with average accuracy of 80-85%. PMID- 24479351 TI - [Association analysis of sIgE, IgE, EOS and the occurrence of chronic rhinosinusitis with nasal polyps]. AB - OBJECTIVE: To discuss the relation between total IgE, special IgE and Eosinophils of serum in blood and the occurrence of nasal polyps (NP) of chronic rhinosinusitis (CRS) patients, and then to get the best clinic index. METHOD: One hundred and fifty two cases of CRS patients were divided into two groups (CRSsNP, CRSwNP). Allergen in vitro were screened, and then. the acidophilic granulocyte percentage and the total IgE of serum in blood were determined. RESULT: (1) The IgE concentration of CRSsNP was mainly at one level while the IgE concentration of (CRSwNP was mainly at two or three levels (Z = 0.906, P > 0.05). There was no significant difference of sIgE serum between the two groups. (2) The EOS percentage of CRSwNP was distinctly higher than that of CRSsNP(F = 4.337, P = 0.039 t = 3.315, P < 0.01). The 95% confidential interval (CI) of EOS of CRSwNP was 3.90%-5.260, 5% TM value was 4.3, which were higher than the concentration of CRSsNP and normal val ue. There was no significant difference between different groups (classes) if the CRSwNP group were classified by sIgE concentration (P > 0.05). (3) CRSwNP patients were mainly mixed-type allergen allergy and the proportion of patients with this mixed-type allergen would increase in accordance with the increasing of allergen concentration gradient (chi2 = 8.595, P < 0.05). CONCLUSION: The occurrence of CRSwNP is related to the increase of EOS and mixed allergens. When the concentration of EOS range from 3.90% to 5.26%, CRSwNP is more likely to occur. The concentration of total IgE and sIgE are not the risk factors singly. Allergen screening result combined with the clinical symptoms can help to get knowledge of and keep away from allergen, and also is beneficial to make treatment plan of perioperative period of CRS. PMID- 24479352 TI - [Nasal mucosa remodeling in chronic rhinosinusitis without nasal polyps]. AB - OBJECTIVE: To explore the feature of nasal mucosa remodeling in chronic rhinosinusitis without nasal polyps (CRSsNP). METHOD: Histological specimens from 30 selected patients with CRSsNP who underwent endoscopic sinus surgery and 10 control subjects were studied. The paraffin sections were stained with hematoxylin-eosin(HE), alcian blue-periodic acid-Schiff (AB-PAS), Masson trichrome (MT) and Picric acid-Sirius red. The damage of epithelium, goblet cells and gland hyperplasia, deposition of collagen in extracellular matrix, the thickness of basement membrane and the type of collagen were observed respectively. RESULT: Grade 0, Grade 1, Grade 2 and Grade 3 of epithelial damage were significantly different in the CRSsNP group when compared with the control group (P < 0.01 or P < 0.05). Evident mucus gland hyperplasia and collagen deposition in extracellular matrix were observed in CRSsNP group (P < 0.01). The number of goblet cells and the thickness of basement membrane were increased obviously in CRSsNP group (P < 0.01). The collagen deposited in extracellular matrix was mainly composed of collagen type I. Collagen type III and collagen type IV was much less than collagen type I. CONCLUSION: The nasal mucosa remodeling was observed in CRSsNP group and was characterized by epithelial damage, basement membrane thickening, deposition of collagen in extracellular matrix, goblet cells and mucus gland hyperplasia. PMID- 24479353 TI - [Expression and significance of osteopontin and muscle segment homeobox gene Msx2 in sinonasal inverted papilloma]. AB - OBJECTIVE: To investigate the expression level and significance of osteopontin (OPN) and muscle segment homeobox2 (Msx2) in sinonasal inverted papilloma (SNIP), and the relationship with the process of SNIP malignant transfomation. METHOD: Immunohistochemical method was used to detect the expression of osteopontin and Msx2 in 32 cases of sinonasal inverted papilloma (SNIP), 30 cases of inflammatory nasal polyp paraffin tissue (INP) and 30 cases of sinonasal inverted papilloma with carcinoma. According to the pathology results SNIP were divided into mild dysplasia, moderate dysplasia, severe dysplasia. All the datas were analyzed by SPSS13.0. RESULT: The positive expression of OPN and Msx2 in the SNIP with carcinoma were all 100% (30/30), were significantly higher than the SNIP and INP, and the pairwise comparisons were all statistically significant (P < 0.05). The expression of OPN and Msx2 in the SNIP were divided according to pathological. There was significant difference between mild dysplasia and severe dysplasia group (P < 0.05), while there were not significant difference between light degree of dysplasia and moderate dysplasia group, moderate dysplasia and severe dysplasia group. And the expression of OPN and Msx2 was positively correlated in SNIP (P < 0.01). CONCLUSION: OPN and Msx2 may play an important role in the pathway of progression of SNIP, which may be identified as the new therapeutic targets. PMID- 24479354 TI - [Role of Nods like receptors in the patients with nasal polyps]. AB - OBJECTIVE: To investigate the expression and role of a new pattern-recognition receptors (PRR), nucleotide binding oligomerization domain (Nod) like receptors (NLRs), in the patients with nasal polyps and nasal septum normal control group. METHOD: The expressions of Nod1, Nod2 and Nalp3 mRNA and protein were explored with real-time RT-PCR, Western-Blot and immunohistochemistry respectively. RESULT: The protein levels of Nod1, Nod2 and Nalp3 were expressed in nasal polyp and the control, but the expression of Nod1 and Nalp3 in nasal polyps were higher than those in control. No significant difference of Nod2 was seen between the two groups. And then, there was no significant difference of Nod1, Nod2, Nalp3 mRNA between two groups with Real-time RT-PCR. CONCLUSION: The expression of Nod1 and Nalp3 are increased in nasal polyp tissues and maybe a etiological factors in the formation of nasal polyps. PMID- 24479355 TI - [Correlation of VEGF expression with microvessel and microlymphatic density in sinonasal squamous cell carcinoma]. AB - OBJECTIVE: To study the expression of VEGF in sinonasal squamous cell carcinoma and its correlations with microvessel density (MVD), microlymphatic vessel density (MLVD). METHOD: The expression of VEGF, MVD and MLVD in 41 cases of sinonasal squamous cell carcinoma were detected by immunohistochemical technique. RESULT: In the sinonasal squamous cell carcinoma, the positive rate of VEGF was 82.9% (34/41). The over expression of VEGF was related with tumor invasion, histological grading and lymphatic metastasis (P < 0.05). The MVD of cases with positive VEGF expression was significantly higher than those without VEGF expression (P < 0.05), but was not statistical difference in MLVD (P > 0.05). CONCLUSION: VEGF may participate in the metastasis of sinonasal squamous cell carcinoma through promoting vascularization in the tumors, but not promoting MLVD. PMID- 24479356 TI - [Effect and safety analysis of Allergovit standardized mite allergen immunotherapy in patients with allergic rhinitis]. AB - OBJECTIVE: To evaluate the effect and safety analysis of Allergovit standardized dust mite subcutaneous immunotherapy in patients with allergic rhinitis. METHOD: From Jan 2006 to Jan 2009,425 patients with persistent were treated with Allergovit standardized dust mite allergen in 3 years, which data were retrospectively analyzed. The scores of the rhinoconjunctivitis quality of life were collected per-treatment and three years treatment. VAS (visual analogue scale) of all nasal symptoms and drug use scores were evaluated before treatment and every 6 weeks. The frequency of local and systemic reactions were recorded in the duration of dose escalation and maintenance. RESULT: The Overall QOL were significantly improved after 3 years treatment [pre-treatment: 3.8 (2.9; 4.5); post-treatment: 1.1 (1.0; 2.0), P < 0.01]. VAS of all nasal symptoms and drug used scores decreased dramatically after escalation period [pro-treatment: 23. 7 (20.5; 27.8), 3.9 (3.2; 4.7); post-treatment: 2.1 (1.6; 2.2), 0(0;0), P < 0.01]. Local reaction's rate was 3.15%, the frequency systemic reaction's rate was 0.90%. CONCLUSION: The standardized specific allergen immunotherapy for allergic rhinitis is safe and effective. PMID- 24479357 TI - [Clinical analysis of surgical approaches and efficacy of benign occupying lesion of unilateral maxillary sinus]. AB - OBJECTIVE: To investigate the therapeutic methods and efficacy of benign occupying lesion of unilateral maxillary sinus. METHOD: The clinical data of 84 patients treated with endoscopic surgery from June 2005 to June 2012 were retrospectively analyzed. Among these patients, 39 cases were treated by endoscopic surgery only, 18 cases were treated by endoscopic plus modified Caldwell-Luc technique, 15 cases were treated by endoscopic plus inferior meatus antrostomy approach, and 12 cases were treated by endoscopic anterior lacrimal recess approach. All patients were followed up postoperatively. RESULT: All cases were followed up from 4 months to 7 years. Among them,81 cases had no recurrence,whereas three cases recurred during the follow-up period. All cases were preoperatively diagnosed by CT, MRI or intranasal endoscopy,which were confirmed by pathological examination postoperatively. CONCLUSION: Maxillary cyst and fungal maxillary sinusitis are the major types of benign occupying lesions of maxillary sinus. According to different clinical features of benign occupying lesions of maxillary sinus,different surgical approaches should be adopted. It can not only effectively cure maxillary sinus lesions, but aslo minimize the operation trauma. Endoscopic sinus surgery is the preferred technique for treating benign occupying lesions of maxillary sinus. PMID- 24479358 TI - [Treatment and prognosis of sinonasal mucosal melanoma]. AB - OBJECTIVE: To evaluate the treatment and prognosis of sinonasal mucosal melanoma (SMM). METHOD: Clinicopathological data of SMM patients from January 1976 to December 2005 were analyzed retrospectively. Survival analysis was performed and Kaplan-Meier analysis was used to compare the effect of clinicopathological factors on survival using SPSS 18.0 software. A Cox model was applied for multivariate analysis. RESULT: The 3-year and 5-year overall survival (OS) rates of 68 cases of SMM were 36.1% and 29.4%, respectively. The 3-year and 5-year OS of patients who underwent surgery or biotherapy were significantly higher than that of patients who underwent other therapeutic regimens without surgery or without biotherapy, respectively. Multivariate analysis showed the patients with distant metastasis at first present or residual/recurrence had a worse prognosis than that without distant metastasis or residual/recurrence, respectively. Surgery and biotherapy were effective treatments for SMM. CONCLUSION: SMM has a poor prognosis, especially in the patients with distant metastasis or residual/recurrence. Surgery or biotherapy may improve the prognosis of patients with SMM. PMID- 24479359 TI - [Extrapleural solitary fibrous tumor in nose: 2 cases report and review of literature]. AB - OBJECTIVE: To analyze the clinical characteristics, imaging features, pathological findings, treatment and prognosis of the extrapleural solitary fibrous tumor (EPSFT) in nose, and then to improve the quality of diagnosis and treatment of EPSFT. METHOD: Clinical data of two patients with EPSFT were collected in recent 2 years. All the information, including clinical symptoms, imaging characteristics, blood routine, serum biochemical, treatment options, pathological immunohistochemical findings, and following-up results were reported and analyzed, and the clinical features of EPSFT in the nose were summarized with review of the literature. RESULT: (1) The main clinical characteristics were nasal obstructive and epistaxis. (2)There were no imaging differences essentially between EPSFT and other tumors in nasal cavity. In terms of enhancement CT scanning, the image manifestations of EPSET were similar to that of hemangioma to a certain degree in nasal cavity. (3) Routine blood and serum biochemical test were normal in the patients with EPSFT in the nose. (4)Confirmed diagnosis mainly depended on pathological and immunohistochemical findings. (5) These two patients underwent surgical treatment, and the tumors were en bloc resected, and were in full recovery. Follow-up time is 2 years in one case and the other one is 1 year. No recurrence or metastasis were found in these two patients. CONCLUSION: DSA and vascular embolism is recommended before surgical treatment in some patients. En bloc resection is the preferred treatment option with definite curative effect for the patients with EPSFT in nose, and the prognosis is favorable. PMID- 24479360 TI - [Clinical analysis on 18 cases of adenoid cystic carcinoma of nasal cavity and sinuses]. AB - OBJECTIVE: To explore the clinical characteristics and treatment effect of adenoid cystic carcinoma in nasal cavity and sinuses. METHOD: Sixteen of all 18 cases of adenoid cystic carcinoma of nasal cavity and sinuses were performed operation and radiotherapy. Other 2 cases were performed radiotherapy. RESULT: Eighteen cases of patients were followed up for 5 years. Eight patients with early stage had no death. Five in 10 cases of advanced patients died, one case was out of following-up. In 11 of high differentiation group, 1 case died. In 7 of lower differentiation group, 4 cases died, 1 case lost. CONCLUSION: Adenoid cystic carcinomas of nasal cavity and sinuses are distinct clinicopathological category and the clinical symptoms are noncharacteristic. Paying attention to the differential diagnosis and promoting related knowledge can help to avoid misdiagnosis. The prognosis is related to pathological category and clinical stage. High stage and high invasion of adenoid cystic carcinoma lead to poor prognosis. PMID- 24479361 TI - [Clinical study of analgesic effect of lornoxicam in nasal packing]. AB - OBJECTIVE: To explore the pain control effect of lornoxicam on patients after nasal packing. METHOD: A total of 56 patients undergoing nasal packing between January 2011 and August 2011 were randomly divided into the treatment group and control group. (1) Treatment group: routinely given lornoxicam for injection 8 mg(2 ml), intravenous injection, twice a day; (2) CONTROL GROUP: given saline 2 ml, intravenous injection, twice a day, other treatments are the same with the treatment group. Visual analog scale was used to record the painful severity of nose and head at 3, 6, 12, 24 and 48 h,and record the sleep quality score at 24 and 48 h. RESULT: The pain in nose and head and night sleeping in treatment group were all significantly better than that in control group. CONCLUSION: The analgesic effect of lornoxicam in nasal packing is good, with no evident adverse reactions. PMID- 24479362 TI - [Allergen analysis of patients with allergic rhinitis in Quanzhou]. AB - OBJECTIVE: To understand the distribution of allergens in patients with allergic rhinitis (AR) in Quanzhou, for the diagnosis, prevention and treatment. METHOD: Twenty standardized allergen underwent skin prick testing (skin prick test, SPT) were used for 1236 patients with suspected AR patients in Quanzhou, and the different age, gender and severity in patients with allergen distribution differences of positive rate were analyzed. RESULT: The top 5 allergens with positive skin tests were D. pteronyssinus (66.7%), D. farinae (65.5%), Blattodea (32.8%), Sea crab (18.2%), and Sea lobster (16.8%). The positive rate of SPT in the minor groups and adult groups had significant difference (P < 0.05). Gender difference between the positive rate of SPT had no significant difference (P > 0.05). There was significant difference between the positive rate in patients with a family history and history of asthma and patients without above two history (P < 0.05). CONCLUSION: Dust Mite, Blattodea, Sea crab. Sea lobster are the most important allergens in quanzhou. Different ages of the patients with SPT positive rates vary, a family history, history of asthma patients with positive rate is higher than patients without a family history of asthma history, high positive rate. PMID- 24479363 TI - [Clinical treatment of sinus mucoceles invaded in orbit under endoscope]. PMID- 24479364 TI - [Transnasal endoscopic repair of cerebrospinal fluid rhinorrhea]. PMID- 24479365 TI - [Clinical report of endoscope-assisted treatment for epistaxis]. PMID- 24479366 TI - [Endoscopic inferior nasal meatal fenestration with mucosal flap for treatment of maxillary cysts]. PMID- 24479367 TI - [Familial nasal bottom supernumerary tooth dentigerous cyst: report of 1 case and review of literatures]. AB - Nasal supernumerary teeth and additional dental cyst is a common disease in Department of ENT and Department of Stomatology. In reported diseases, patients with a variety of additional teeth appeared in differ ent parts have varied clinical manifestations. Because of no obvious early symptoms, it is more difficult to diagnose, but CT examination in corresponding site can make it easy to diagnose the maxillary sinus and dentigerous cyst diagnosis. Operation is an effective method to cure the disease. Operation is simple, but the defect and tooth cavity after operation is one unavoidable problem for ENT doctor. In relevant literature it can be seen that the disease has a genetic tendency. PMID- 24479368 TI - [Refractory chronic rhinosinusitis and bacterial biofilm]. AB - Chronic rhinosinusitis (CRS) is a common disease in otolaryngology, and with the development of the therapy technology, most of the cases have reached a cure. But there are still some intractable cases in clinic, signs and symptoms of chronic rhinosinusitis of which still persist after the standardized drugs and technically adequate endoscopic sinus surgery, and this part is clinically named refractory chronic rhinosinusitis (RCRS). In recent studies of the pathogenesis of RCRS, bacterial biofilm (BBF) is attracting more attention. The main emphasis of this review will be to highlight the biological characteristics of BBF, the relationship of BBF and CRS and treatment strategies of BBF positive CRS. PMID- 24479369 TI - Precise control of quantum dot location within the P3HT-b-P2VP/QD nanowires formed by crystallization-driven 1D growth of hybrid dimeric seeds. AB - Herein, we report a simple fabrication of hybrid nanowires (NWs) composed of a p type conjugated polymer (CP) and n-type inorganic quantum dots (QDs) by exploiting the crystallization-driven solution assembly of poly(3-hexylthiophene) b-poly(2-vinylpyridine) (P3HT-b-P2VP) rod-coil amphiphiles. The visualization of the crystallization-driven growth evolution of hybrid NWs through systematic transmission electron microscopy experiments showed that discrete dimeric CdSe QDs bridged by P3HT-b-P2VP polymers were generated during the initial state of crystallization. These, in turn, assemble into elongated fibrils, forming the coaxial P3HT-b-P2VP/QDs hybrid NWs. In particular, the location of the QD arrays within the single strand of P3HT-b-P2VP can be controlled precisely by manipulating the regioregularity (RR) values of P3HT block and the relative lengths of P2VP block. The degree of coaxiality of the QD arrays was shown to depend on the coplanarity of the thiophene rings of P3HT block, which can be controlled by the RR value of P3HT block. In addition, the location of QDs could be regulated at the specific-local site of P3HT-b-P2VP NW according to the surface characteristics of QDs. As an example, the comparison of two different QDs coated with hydrophobic alkyl-terminated and hydroxyl-terminated molecules, respectively, is used to elucidate the effect of the surface properties of QDs on their nanolocation in the NW. PMID- 24479370 TI - An investigation into breast support and sports bra use in female runners of the 2012 London Marathon. AB - Although it is acknowledged that appropriate breast support during exercise is important, no published literature has assessed breast support usage in a cohort of female marathon runners. This study aimed to identify sport bra use and perceived importance of sports bra use in female marathon runners. Bra satisfaction, incidence of bra related issues and factors that influence the appropriateness of sports bras were also investigated. A 4-part, 30-question survey was administered to 1397 female runners at the 2012 London marathon registration and via an online survey. In total 1285 surveys were completed. Sports bra use and its perceived importance was high, however was lower in moderate compared to vigorous activity, and lower in participants with smaller breasts. Seventy-five per cent of participants reported bra fit issues. The most common issues were chaffing and shoulder straps digging in, with a higher incidence of issues reported by participants with larger breasts. Use of professional bra fitting was low, and perceived knowledge of breast health was poor. Engagement with sports bra use is high although sports bra design could be improved to alleviate bra fit issues experienced by female runners. Educational initiatives are needed to ensure females are informed regarding the importance of breast support and appropriate bra fit during activity. PMID- 24479371 TI - Small molecular antibacterial peptoid mimics: the simpler the better! AB - The emergence of multidrug resistant bacteria compounded by the depleting arsenal of antibiotics has accelerated efforts toward development of antibiotics with novel mechanisms of action. In this report, we present a series of small molecular antibacterial peptoid mimics which exhibit high in vitro potency against a variety of Gram-positive and Gram-negative bacteria, including drug resistant species such as methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium. The highlight of these compounds is their superior activity against the major nosocomial pathogen Pseudomonas aeruginosa. Nontoxic toward mammalian cells, these rapidly bactericidal compounds primarily act by permeabilization and depolarization of bacterial membrane. Synthetically simple and selectively antibacterial, these compounds can be developed into a newer class of therapeutic agents against multidrug resistant bacterial species. PMID- 24479372 TI - The link between MHC class I abnormalities of tumors, oncogenes, tumor suppressor genes, and transcription factors. AB - MHC class I abnormalities, frequently detected in tumors of distinct origins, are often associated with disease progression and/or poor patient survival. The underlying molecular mechanisms of these defects are either mediated by structural alterations of MHC class I antigens and/or components of the antigen processing machinery (APM) or by their deregulation, which could occur at the transcriptional, post-transcriptional, and/or epigenetic level. Recently, it has been identified that signal transduction pathways, oncogenes, and putative tumor suppressor genes play an important role in controlling the expression of MHC class I APM components in tumor cells. In addition, their expression could be modulated by various factors of the tumor microenvironment, like changes in the pH level, in the metabolism, as well as due to hypoxic conditions. The increased knowledge of MHC class I defects could be employed for (i) the selection of patients undergoing immunotherapies and for (ii) the design of novel therapeutic approaches leading to an induction of MHC class I surface expression, which might enhance the anti-tumor immune response. PMID- 24479373 TI - Aerobic dehydrogenative alpha-diarylation of benzyl ketones with aromatics through carbon-carbon bond cleavage. AB - Substituted benzyl ketones reacted with aromatics in the presence of K2S2O8 in CF3COOH at room temperature, yielding alpha-diaryl benzyl ketones through a carbon-carbon bond cleavage. In the reaction, two new carbon-carbon bonds were formed and one carbon-carbon bond was cleaved. It is very interesting that two different nucleophiles such as benzyl ketones and aromatics were coupled together without metal, which is unusual in organic synthesis. PMID- 24479374 TI - Electrokinetic measurements of thin Nafion films. AB - We perform an electrokinetic characterization of ~300 nm Nafion films deposited on glass slides over a relatively unexplored region of ionic strength and pH. Owing to the small pore size of the Nafion, we probe the Nafion-fluid interface with the streaming potential measurement, and we probe ionic transport through the entire thickness of the Nafion film with the conductivity measurements. By applying a transport model for each of these measurements, we show that the inferred fixed charge density and characteristic fluid resistance length is different in each case. Analyzing our results with data from the literature, we suggest that our result is consistent with a thin Nafion film that is both nonuniform and weakly hydrated. Our regimen of experimentation and analysis may be generalized to characterize other porous and charged layers. PMID- 24479375 TI - Endogenous alpha-calcitonin-gene-related peptide promotes exercise-induced, physiological heart hypertrophy in mice. AB - AIM: It is unknown how the heart distinguishes various overloads, such as exercise or hypertension, causing either physiological or pathological hypertrophy. We hypothesize that alpha-calcitonin-gene-related peptide (alphaCGRP), known to be released from contracting skeletal muscles, is key at this remodelling. METHODS: The hypertrophic effect of alphaCGRP was measured in vitro (cultured cardiac myocytes) and in vivo (magnetic resonance imaging) in mice. Exercise performance was assessed by determination of maximum oxygen consumption and time to exhaustion. Cardiac phenotype was defined by transcriptional analysis, cardiac histology and morphometry. Finally, we measured spontaneous activity, body fat content, blood volume, haemoglobin mass and skeletal muscle capillarization and fibre composition. RESULTS: While alphaCGRP exposure yielded larger cultured cardiac myocytes, exercise-induced heart hypertrophy was completely abrogated by treatment with the peptide antagonist CGRP(8-37). Exercise performance was attenuated in alphaCGRP(-/-) mice or CGRP(8 37) treated wild-type mice but improved in animals with higher density of cardiac CGRP receptors (CLR-tg). Spontaneous activity, body fat content, blood volume, haemoglobin mass, muscle capillarization and fibre composition were unaffected, whereas heart index and ventricular myocyte volume were reduced in alphaCGRP(-/-) mice and elevated in CLR-tg. Transcriptional changes seen in alphaCGRP(-/-) (but not CLR-tg) hearts resembled maladaptive cardiac phenotype. CONCLUSIONS: Alpha calcitonin-gene-related peptide released by skeletal muscles during exercise is a hitherto unrecognized effector directing the strained heart into physiological instead of pathological adaptation. Thus, alphaCGRP agonists might be beneficial in heart failure patients. PMID- 24479376 TI - Influence of magnetic nanoparticle size on the particle dispersion and phase separation in an ABA triblock copolymer. AB - Oleic acid modified iron oxide nanoparticles (IONs) with different sizes were synthesized and mixed with styrene-butadiene-styrene block copolymer (SBS) with a lamellar structure. The octadecene segments on the oleic acid molecules have chemical affinity with the polybutadiene (PB) blocks, which makes IONs tend to be selectively confined in the microphase-separated PB domains. However, the dispersion state strongly depends on the ratio of the particle diameter (d) to the lamellar thickness (l) of the PB domains, which further changes the phase separation of SBS. When d/l ~0.5, most of IONs are concentrated in the middle of the PB layers at low particle loading. Upon increasing the particle loading, part of IONs contact each other to form long strings due to their strong magnetic interactions. Away from the strings, IONs are either selectively dispersed in the middle and at the interfaces of the PB domains, or randomly distributed at some regions in which the phase separation of SBS is suppressed. The phase separation of SBS transforms from the lamellar structure to a cylinder structure when the IONs loading is higher than 16.7 wt %. As d is comparable to l, IONs aggregate to form clusters of 100 to 300 nm in size, but within the clusters IONs are still selectively dispersed in the PB domains instead of forming macroscopic phase separation. It is interpreted in terms of the relatively small conformational entropy of the middle blocks of SBS; thus, incorporation of nanoparticles does not lead to much loss of conformational entropy. Although incorporation of IONs with d/l ~1 significantly increases the interfacial curvature and roughness, it has less influence on the phase separation structure of SBS due to the inhomogeneous dispersion. When d is larger than l, IONs are macroscopically separated from the SBS matrix to form clusters of hundreds of nanometers to several micrometers. More interestingly, the phase separation of SBS transforms from the lamellar structure to a two-phase co-continuous structure, probably due to the rearrangement of SBS molecules to cover the clusters with PB segments and the strong magnetic interaction exerting additional force on the SBS matrix during the evaporation of the solvent and the subsequent thermal annealing process. PMID- 24479377 TI - Chemical etching of nitinol stents. AB - At present the main cause of death originates from cardiovascular diseases. Primarily the most frequent cause is vessel closing thus resulting in tissue damage. The stent can help to avoid this. It expands the narrowed vessel section and allows free blood flow. The good surface quality of stents is important. It also must have adequate mechanical characteristics or else it can be damaged which can easily lead to the fracture of the implant. Thus, we have to consider the importance of the surface treatment of these implants. In our experiments the appropriate design was cut from a 1.041 mm inner diameter and 0.100 mm wall thickness nitinol tube by using Nd:YAG laser device. Then, the stent was subjected to chemical etching. By doing so, the burr created during the laser cutting process can be removed and the surface quality refined. In our research, we changed the time of chemical etching and monitored the effects of this parameter. The differently etched stents were subjected to microscopic analysis, mass measurement and in vivo environment tests. The etching times that gave suitable surface and mechanical features were identified. PMID- 24479378 TI - The communication of secondary variants: interviews with parents whose children have undergone array-CGH testing. AB - Children with unexplained developmental disabilities or congenital anomalies are increasingly being referred for genetic diagnostic testing using array comparative genomic hybridisation (array-CGH) and next-generation sequencing (NGS) technologies. Their parents will have to deal with the secondary variants that will inevitably arise. We conducted 16 prospective semi-structured interviews with native Dutch-speaking parents whose children had undergone clinical array-CGH testing. The interviews explored the parents' experiences, expectations and opinions, specifically regarding the communication of results. Concrete examples of 'unexpected results' were provided to help guide the discussion, differing in severity, treatability, time of onset, level of risk, and carrier status. Data was analysed using content and narrative analysis methodologies. Parental motivations for and against the disclosure of unexpected results cluster around four main themes: actionability; knowledge; context; and characteristics of the result. Most parents wished to know all types of results. Disclosure was framed within a holistic, contextual, family-wide view. Genetic counselling should aim to integrate explorations of the motivations of parents surrounding the disclosure of results with good clinical care. PMID- 24479380 TI - Comparison of halide impacts on the efficiency of contaminant degradation by sulfate and hydroxyl radical-based advanced oxidation processes (AOPs). AB - The effect of halides on organic contaminant destruction efficiency was compared for UV/H2O2 and UV/S2O8(2-) AOP treatments of saline waters; benzoic acid, 3 cyclohexene-1-carboxylic acid, and cyclohexanecarboxylic acid were used as models for aromatic, alkene, and alkane constituents of naphthenic acids in oil-field waters. In model freshwater, contaminant degradation was higher by UV/S2O8(2-) because of the higher quantum efficiency for S2O8(2-) than H2O2 photolysis. The conversion of (*)OH and SO4(*-) radicals to less reactive halogen radicals in the presence of seawater halides reduced the degradation efficiency of benzoic acid and cyclohexanecarboxylic acid. The UV/S2O8(2-) AOP was more affected by Cl(-) than the UV/H2O2 AOP because oxidation of Cl(-) is more favorable by SO4(*-) than (*)OH at pH 7. Degradation of 3-cyclohexene-1-carboxylic acid, was not affected by halides, likely because of the high reactivity of halogen radicals with alkenes. Despite its relatively low concentration in saline waters compared to Cl(-), Br(-) was particularly important. Br(-) promoted halogen radical formation for both AOPs resulting in ClBr(*-), Br2(*-), and CO3(*-) concentrations orders of magnitude higher than (*)OH and SO4(*-) concentrations and reducing differences in halide impacts between the two AOPs. Kinetic modeling of the UV/H2O2 AOP indicated a synergism between Br(-) and Cl(-), with Br(-) scavenging of (*)OH leading to BrOH(*-), and further reactions of Cl(-) with this and other brominated radicals promoting halogen radical concentrations. In contaminant mixtures, the conversion of (*)OH and SO4(*-) radicals to more selective CO3(*-) and halogen radicals favored attack on highly reactive reaction centers represented by the alkene group of 3-cyclohexene-1-carboxylic acid and the aromatic group of the model compound, 2,4-dihydroxybenzoic acid, at the expense of less reactive reaction centers such as aromatic rings and alkane groups represented in benzoic acid and cyclohexanecarboxylic acid. This effect was more pronounced for the UV/S2O8(2-) AOP. PMID- 24479379 TI - Systematic review and meta-analysis: prevalence of alcohol use among young people in eastern Africa. AB - OBJECTIVE: Systematic review and meta-analysis of published studies of alcohol use among young people (age 15-24 years) in eastern Africa to estimate prevalence of alcohol use and determine the extent of use of standardised screening questionnaires in alcohol studies. METHODS: Five databases (MEDLINE, EMBASE, Global Health, Africa-wide, and PsycINFO) were searched for publications until 30th June 2013. Results were summarised using the guidelines on preferred reporting items for systematic reviews and meta-analyses (PRISMA) and on quality assessment using the modified quality assessment tool for systematic reviews of observational studies (QATSO). Heterogeneity was assessed using the I(2) statistic (DerSimonian-Laird). RESULTS: We identified 2785 potentially relevant studies, of which 56 were eligible for inclusion. Only two studies (4%) used the standardised Alcohol Use Disorder Identification Test (AUDIT) questionnaire, and six studies (13%) used the Cut down, Annoyed, Guilt, Eye opener (CAGE) questionnaire. The reported median prevalence of alcohol use was ever-use 52% [interquartile range (IQR): 20-58%], use in the last month 28% (IQR: 17-37%), use in the last year 26% (IQR: 22-32%), and problem drinking as defined by CAGE or AUDIT 15% (IQR: 3-36%). We observed high heterogeneity between studies, with the highest prevalence of ever use of alcohol among university students (82%; 95%CI: 79-85%) and female sex workers (66%; 95%CI: 58-74%). Current use was most prevalent among male sex workers (69%; 95%CI: 63-75%). CONCLUSIONS: Reported alcohol use and problem drinking were common among diverse groups of young people in eastern Africa, indicating the urgent need for alcohol-focused interventions in this population. Few studies have used standardised alcohol screening questionnaires. Epidemiological research to investigate alcohol-focused interventions in young people should aim to apply such questionnaires that should be validated for use in this population. PMID- 24479381 TI - 'Safety by DEFAULT': introduction and impact of a paediatric ward round checklist. AB - INTRODUCTION: Poor communication is a source of risk. This can be particularly significant in areas of high clinical acuity such as intensive care. Ward rounds are points where large amounts of information must be communicated in a time limited environment with many competing interests. This has the potential to reduce effective communication and risk patient safety. Checklists have been used in many industries to improve communication and mitigate risk. We describe the introduction of a ward round safety checklist 'DEFAULT' on a paediatric intensive care unit. METHODS: A non-blinded, pre- and post-intervention observational study was undertaken in a 12-bedded Level 3 tertiary PICU between July 2009 and December 2011. RESULTS: Ward round stakeholders subjectively liked the checklist and felt it improved communication. Introduction of the ward round checklist was associated with an increase in median days between accidental extubations from 14 (range 2 to 86) to 150 (56 to 365) (Mann-Whitney P <0.0001). The ward round checklist was also associated with an increase in the proportion of invasively ventilated patients with target tidal volumes of <8 ml/kg, which increased from 35 of 71 patients at 08.00 representing a proportion of 0.49 (95% CI 0.38 to 0.60) to 23 of 38 (0.61, 0.45 to 0.74). This represented a trend towards an increased proportion of cases in the target range (z = 1.68, P = 0.09). CONCLUSIONS: The introduction of a ward round safety checklist was associated with improved communication and patient safety. PMID- 24479382 TI - Bosutinib : a review of preclinical and clinical studies in chronic myelogenous leukemia. AB - INTRODUCTION: Chronic myeloid leukemia (CML) is a hematopoietic stem cell disease. It is characterized by a Bcr-Abl (breakpoint cluster region-Abelson leukemia virus) tyrosine kinase fusion protein produced from the Philadelphia (Ph) chromosome. The tyrosine kinase inhibitor (TKI) imatinib was the first targeted therapy licensed for patients with chronic-phase CML. In recent years, many other TKIs have been approved for the treatment of patients with CML. For this reason, the choice of the best strategy treatment has become increasingly complex. AREAS COVERED: Bosutinib , a dual Src/Abl kinase inhibitor, has shown potent activity against CML and it has been approved by the US FDA for the treatment of chronic, accelerated or blast-phase Ph+ CML. This review was conducted to describe the preclinical and clinical activity of bosutinib and the safety and tolerability of the drug in the treatment of CML. Included studies were identified through a search of electronic databases in July 2013 and relevant conference proceedings. EXPERT OPINION: Imatinib continues to represent the treatment of choice for CML. However, some patients develop resistance or intolerance to imatinib or to other second-generation TKIs. Bosutinib shows a good therapeutic activity with a benign safety profile, no cardiovascular toxicity, and offers an important therapeutic addition to the armamentarium that physicians can use against resistant CML. PMID- 24479383 TI - Hypoglycemia, its implications in clinical practice, and possible ways to prevent it. PMID- 24479384 TI - Post-herpetic vitiligo in an 8-year-old boy with immunosuppression. PMID- 24479385 TI - Epigenetic studies of suicidal behavior. AB - Recent studies have shown an association between gene alterations by epigenetic mechanisms and suicidal behavior. These epigenetic mechanisms are mitotically, and in some cases meiotically, heritable changes in the genome through non-DNA sequence coding processes that alter gene expression as a result of variable changes in environmental stimuli. Genome-wide association studies have been inconsistent in elucidating the association between genes and suicidal behavior, thereby making the heritability of suicidal behavior is unclear. However, recent epigenetic studies have provided evidence that epigenetic mechanisms could deliver the missing link between the heritability of suicidal behavior and the interaction between environment and the genome. The present review provides an in depth discussion of epigenetic mechanisms that may regulate gene expression in suicidal behavior. The findings of current epigenetic studies on suicidal behavior will also be discussed considering future epigenome-wide association studies on elucidating the contributions of environment and genome on suicidal behavior. PMID- 24479386 TI - Udder health in beef cows and its association with calf growth. AB - BACKGROUND: Studies outside the Nordic countries have indicated that subclinical mastitis (measured by milk somatic cell count or the California Mastitis Test), intramammary infections (IMI), or blind quarters in beef cows may have negative effects on beef calf growth. Knowledge on prevalence of such udder health problems in Swedish beef cows is scarce. Therefore, the main aim of this study was to investigate subclinical mastitis, IMI and udder conformation in a number of beef cow herds. Production of beta-lactamase in staphylococci was also investigated. Associations between certain cow factors and subclinical mastitis and IMI, and associations between cow and calf factors and 200 day calf weaning weight were also studied. The herds were visited once within a month after calving and once at weaning. Udder examination and quarter milk sampling, for somatic cell count and bacteriology, were performed in 8 to 12 cows per herd and occasion. RESULTS: Approximately 50%, 40% and 10% of the cows had subclinical mastitis, IMI, and at least one blind quarter, respectively, but the prevalence varied markedly between herds. Intramammary infections (mainly due to staphylococci) were identified in 13-16% of the milk samples. Less than 5% of the staphylococcal isolates produced beta-lactamase. Approximately 11% of the cows sampled twice had the same IMI (mostly Staphylococcus aureus) at both samplings. Cow factors of importance for subclinical mastitis and/or IMI were teat and udder shape, breed, parity, presence of blind quarters, and cow hygiene. No significant associations were found between udder health parameters studied and calf weaning weights. CONCLUSIONS: Subclinical mastitis and IMI, but not blind quarters, were common in beef cows, but the prevalence varied markedly between herds. Most IMI were caused by staphylococci and more than 95% of those were sensitive to penicillin. Cows with large funnel-shaped teats or pendulous udder after calving, and cows with blind quarters were at risk of having subclinical mastitis and/or IMI. Poor hygiene was also a risk factor for udder health problems. No significant associations were found between udder health and calf weaning weight. More studies on risk factors are warranted to improve advisory services on awareness and prevention of mastitis in beef cows. PMID- 24479388 TI - Positive effect of protein-supplemented hospital food on protein intake in patients at nutritional risk: a randomised controlled trial. AB - BACKGROUND: New evidence indicates that increased dietary protein ingestion promotes health and recovery from illness, and also maintains functionality in older adults. The present study aimed to investigate whether a novel food service concept with protein-supplementation would increase protein and energy intake in hospitalised patients at nutritional risk. METHODS: A single-blinded randomised controlled trial was conducted. Eighty-four participants at nutritional risk, recruited from the departments of Oncology, Orthopaedics and Urology, were included. The intervention group (IG) received the protein-supplemented food service concept. The control group (CG) received the standard hospital menu. Primary outcome comprised the number of patients achieving >=75% of energy and protein requirements. Secondary outcomes comprised mean energy and protein intake, body weight, handgrip strength and length of hospital stay. RESULTS: In IG, 76% versus 70% CG patients reached >=75% of their energy requirements (P = 0.57); 66% IG versus 30% CG patients reached >=75% of their protein requirements (P = 0.001). The risk ratio for achieving >=75% of protein requirements: 2.2 (95% confidence interval = 1.3-3.7); number needed to treat = 3 (95% confidence interval = 2-6). IG had a higher mean intake of energy and protein when adjusted for body weight (CG: 82 kJ kg(-1) versus IG: 103 kJ kg(-1) , P = 0.013; CG: 0.7 g protein kg(-1) versus 0.9 g protein kg(-1) , P = 0.003). Body weight, handgrip strength and length of hospital stay did not differ between groups. CONCLUSIONS: The novel food service concept had a significant positive impact on overall protein intake and on weight-adjusted energy intake in hospitalised patients at nutritional risk. PMID- 24479391 TI - WHO Has Got it Right: A New 16mm film M&B May&Baker Aspects of anaerobic infection. AB - Hilaire Belloc wrote "They answered as they took their fees 'There is no cure for this disease.'" The profession to which he was referring is probably transparent, but what may be a little more opaque is that his comment could apply to those individuals who claim to run courses suitable for medical educators, including those who come from developing countries. However, for those who read the paper Progress of the WHO Global Teaching Training Programme 1969-1979 (WHO/EDUC/79.178), the truth of Belloc's words is as painful as Mark Twain's plea to "Always tell the truth because it will gratify the few and astonish the many." PMID- 24479389 TI - Radioprotective effect of the Barbados Cherry (Malpighia glabra L.) against radiopharmaceutical iodine-131 in Wistar rats in vivo. AB - BACKGROUND: The increasing consumption of fruits and vegetables has contributed to the improvement of populational health, due in part, to the abundance of antioxidants in these foods. Antioxidants reduce the level of oxidative damage to DNA caused by free radicals and ionizing radiation, including the radioisotope iodine-131 (131I). This isotope is used for the diagnosis and treatment of thyroid injuries, such as hyperthyroidism and cancer. METHODS: This study aimed to evaluate the radioprotective and cytotoxic activity of acute and subchronic treatments with Barbados Cherry (BC) (Malpighia glabra L.) fruit juice (5 mg), which is rich in potent antioxidants such as vitamin C, phenols, carotenoids, anthocyanins and yellow flavonoids and its activity against the mutagenic activity of the therapeutic dose of 25 MUCi of radioiodine for hyperthyroidism. The test system used was the bone marrow cells of Wistar rats (Rattus norvegicus) that were treated in vivo by gavage. RESULTS: BC showed radioprotective activity in acute treatments, which is most likely due to the joint action of its antioxidant components. In subchronic treatments, the continuous treatment presented an effective radioprotective activity, which was significantly different from treatment with the radiopharmaceutical only. Treatment with BC prior to (PRE) and simultaneous with (SIM) ionizing radiation decreased the number of induced chromosomal alterations, while post-treatment produced no protective effect. In addition, BC exhibited no cytotoxic activity. CONCLUSIONS: These data serve as evidence that BC can be used as a preventive health measure to improve public health quality by countering the action of inevitable exposure to mutagens, such as 131I. PMID- 24479392 TI - The way we teach... general practice. AB - In the new medical school at Leicester, general practice contributes to the student's curriculum in each of the five years. Most of the clinical teachers are practising general practitioners in the city and county, whose enthusiasm is a major pillar of the course. Teaching methods include role play and small-group teaching involving case presentation. All students are given, in advance of the clinical course, a workbook elaborating the educational objectives and explaining both the content of the course and the reason for the methods used. At present, Leicester is unique in having a separate examination in general practice as a component of finals. PMID- 24479393 TI - Assessment of problem-solving skills, 1. AB - Assessment of problem-solving skills is best done by placing an individual in a problematical situation and observing his performance. This article examines the nature of medical problem-solving, and suggests ways of categorizing the various types of problems with which physicians must be competent. A process for constructing appropriate types of text exercises is described and techniques of assessing various components of problem solving skills are illustrated. PMID- 24479394 TI - How to...: use small groups in medical education. AB - This is the first of a number of articles on the use of small-group methods in medical education. The aim of this contribution is to introduce teachers to the underlying issues they must consider before embarking on a particular technique. The advantages of small-group learning are described and practical suggestions for facilitating effective small-group discussion are offered. Teachers are advised that the use of small groups for learning requires meticulous course planning. Specific examples of how small-group teaching methods can be used to advantage in preclinical and clinical courses will be published in future issues. PMID- 24479395 TI - The eec directives: implications for nurse educators. AB - The Nursing Qualifications (EEC Recognition) Order 1979 became law on 1 January 1980. The theoretical content of the training programme in the Nursing Directives should not cause any difficulty in the UK. It is the organization of practical experience for learners that is producing problems. Learners must now obtain clinical experience in maternity care, community care, mental health care and psychiatry, and care of the old as well as in medicine, surgery and paediatrics. Clinical teachers will have to be reallocated from acute areas to these specialist areas, with appropriate retraining. More attention will have to be paid to the basic teaching course for nurse teachers and to continuing education. PMID- 24479396 TI - The Way They Do it...: Accident and Emergency Teaching in UK Medical Schools. AB - This is the second in an occasional series of surveys of topical aspects of medical educational practice in the UK and elsewhere. It reports the results of an inquiry into the place in medical school curricula of practical work in accident and emergency medicine-'casualty'-and describes teaching practices in A & E departments. The article demonstrates considerable differences in the arrangements made in the various medical schools, and also in the place of the subject within the final examination. PMID- 24479397 TI - Letters: towards more effective meetings. PMID- 24479399 TI - Courses and conferences. PMID- 24479398 TI - Controversy: the case for the medical grand round. AB - The medical grand round is under attack-not least by Dr Jack Gilbert (Medical Teacher, 1979, 1, 314-315). The round forms a convenient symbol for the academic medical centre, for it fills a role as the showpiece of such institutions. It is impossible not to suspect that the assault on the round is a vicarious exercise: the real target is the academic centre itself, which must be exposed as an overprivileged, overspecialized ivory tower, lacking relevance to the community at large and diverting the medical student from the problems of primary health care. PMID- 24479403 TI - Exploring the impact of elevated depressive symptoms on the ability of a tailored asthma intervention to improve medication adherence among urban adolescents with asthma. AB - BACKGROUND: In patients with asthma, medication adherence is a voluntary behavior that can be affected by numerous factors. Depression is an important co-morbidity in adolescents with asthma that may significantly impact their controller medication adherence and other asthma-related outcomes. The modifying effect of depressive symptoms on an asthma intervention's ability to improve asthma controller medication adherence among urban adolescents with asthma has not yet been reported. OBJECTIVE: To assess self-reported symptoms of depression as an effect modifier of the relationship between randomization group and controller medication adherence at 6-month follow-up. METHODS: These analyses use data from a randomized controlled trial (RCT) conducted in Detroit high schools to evaluate a tailored asthma management program. The intervention included referrals to school or community resources for students reporting symptoms of depression and other issues. "Elevated depressive symptoms" was defined as a positive answer to >= 5 of 7 questions from a validated tool included on the baseline questionnaire. Self-reported adherence to controller medication was collected at intervention onset (session 1) and at 6-month follow up. Analyses were restricted to students with report of a controller medication at baseline. Logistic regression was used to assess elevated depressive symptoms as an effect modifier of the relationship between randomization group and 6-month adherence. RESULTS: Of the 422 students enrolled in the RCT, a controller medication was reported at intervention onset by n = 123 adolescents (29%). Analyzing this group, we observed an interaction between elevated depressive symptoms and adherence (p = 0.073). Stratified analysis showed better adherence in treatment group adolescents meeting criteria for elevated depressive symptoms at baseline as compared to the control group (adjusted Odds Ratio [aOR] = 9.50; p = 0.024). For adolescents without elevated depressive symptoms at baseline, differences in adherence by group assignment did not reach statistical significance (aOR 1.40, p = 0.49). CONCLUSIONS: In this sample of students reporting controller medications at baseline, report of elevated depressive symptoms at baseline and randomization to the intervention group was associated with significantly better adherence at 6-month follow up when compared to that of a control group. Larger studies are needed to evaluate the impact of depression on the relationship between adherence and asthma intervention effectiveness. PMID- 24479404 TI - Biomechanics assessment of long term consequences of talocrural joint sprain in conservatively treated males. AB - The aim of the study was an assessment of isometric torque (IT) values under static conditions and relative torque (RT) for the plantar flexion muscles (PFM) and dorsal flexion muscles (DFM) and their mutual relations in males 5 years after talocrural joint sprain. IT measurements in PFM and DFM were performed using Biodex System 3. Group I consisted of 20 males on average 5 years after the sprain of the talocrural joint. Group II comprised 23 males with no history of talocrural joint injuries. The angles of measurement were: -15 degrees of dorsiflexion (DF) and 0 degrees , 15 degrees , 30 degrees and 45 degrees for plantar flexion (PF) of the foot. In group I, the IT and RT obtained from PFM of involved leg were statistically significantly lower for most of the measured values of foot angle as compared to the contralateral joint and the results of the control group. The increase in the PF angle resulted in the decrease in IT values obtained from PFM, in favour of DFM. The IT values for PFM and DFM depend on the angle of foot and are represented by two different curves. PMID- 24479405 TI - Cultural competency of health-care providers in a Swiss University Hospital: self assessed cross-cultural skillfulness in a cross-sectional study. AB - BACKGROUND: As the diversity of the European population evolves, measuring providers' skillfulness in cross-cultural care and understanding what contextual factors may influence this is increasingly necessary. Given limited information about differences in cultural competency by provider role, we compared cross cultural skillfulness between physicians and nurses working at a Swiss university hospital. METHODS: A survey on cross-cultural care was mailed in November 2010 to front-line providers in Lausanne, Switzerland. This questionnaire included some questions from the previously validated Cross-Cultural Care Survey. We compared physicians' and nurses' mean composite scores and proportion of "3-good/4-very good" responses, for nine perceived skillfulness items (4-point Likert-scale) using the validated tool. We used linear regression to examine how provider role (physician vs. nurse) was associated with composite skillfulness scores, adjusting for demographics (gender, non-French dominant language), workplace (time at institution, work-unit "sensitized" to cultural-care), reported cultural competence training, and cross-cultural care problem-awareness. RESULTS: Of 885 questionnaires, 368 (41.2%) returned the survey: 124 (33.6%) physicians and 244 (66.4%) nurses, reflecting institutional distribution of providers. Physicians had better mean composite scores for perceived skillfulness than nurses (2.7 vs. 2.5, p < 0.005), and significantly higher proportion of "good/very good" responses for 4/9 items. After adjusting for explanatory variables, physicians remained more likely to have higher skillfulness (beta = 0.13, p = 0.05). Among all, higher skillfulness was associated with perception/awareness of problems in the following areas: inadequate cross-cultural training (beta = 0.14, p = 0.01) and lack of practical experience caring for diverse populations (beta = 0.11, p = 0.04). In stratified analyses among physicians alone, having French as a dominant language (beta = -0.34, p < 0.005) was negatively correlated with skillfulness. CONCLUSIONS: Overall, there is much room for cultural competency improvement among providers. These results support the need for cross-cultural skills training with an inter-professional focus on nurses, education that attunes provider awareness to the local issues in cross-cultural care, and increased diversity efforts in the work force, particularly among physicians. PMID- 24479406 TI - Discovery and characterization of ionic liquid-tolerant thermophilic cellulases from a switchgrass-adapted microbial community. AB - BACKGROUND: The development of advanced biofuels from lignocellulosic biomass will require the use of both efficient pretreatment methods and new biomass deconstructing enzyme cocktails to generate sugars from lignocellulosic substrates. Certain ionic liquids (ILs) have emerged as a promising class of compounds for biomass pretreatment and have been demonstrated to reduce the recalcitrance of biomass for enzymatic hydrolysis. However, current commercial cellulase cocktails are strongly inhibited by most of the ILs that are effective biomass pretreatment solvents. Fortunately, recent research has shown that IL tolerant cocktails can be formulated and are functional on lignocellulosic biomass. This study sought to expand the list of known IL-tolerant cellulases to further enable IL-tolerant cocktail development by developing a combined in vitro/in vivo screening pipeline for metagenome-derived genes. RESULTS: Thirty seven predicted cellulases derived from a thermophilic switchgrass-adapted microbial community were screened in this study. Eighteen of the twenty-one enzymes that expressed well in E. coli were active in the presence of the IL 1 ethyl-3-methylimidazolium acetate ([C2mim][OAc]) concentrations of at least 10% (v/v), with several retaining activity in the presence of 40% (v/v), which is currently the highest reported tolerance to [C2mim][OAc] for any cellulase. In addition, the optimum temperatures of the enzymes ranged from 45 to 95 degrees C and the pH optimum ranged from 5.5 to 7.5, indicating these enzymes can be used to construct cellulase cocktails that function under a broad range of temperature, pH and IL concentrations. CONCLUSIONS: This study characterized in detail twenty-one cellulose-degrading enzymes derived from a thermophilic microbial community and found that 70% of them were [C2mim][OAc]-tolerant. A comparison of optimum temperature and [C2mim][OAc]-tolerance demonstrates that a positive correlation exists between these properties for those enzymes with a optimum temperature >70 degrees C, further strengthening the link between thermotolerance and IL-tolerance for lignocelluolytic glycoside hydrolases. PMID- 24479408 TI - Influence of upper extremity position on EMG signal measures calculated in time, frequency and time-frequency domains. AB - The aim of this study was to investigate the relationship between time-frequency, time and frequency measures when considering various upper extremity positions below the level of the shoulder and in trapezius as well as deltoideus muscles. During the experiment, 15 subjects performed a task that involved screwing and unscrewing a screw cap on a board in six different locations, i.e., there were six upper extremity positions. Variables were calculated in the time, frequency and time-frequency domains on a recorded EMG signal. The results showed that parameters analyzed in the time-frequency domain were more sensitive to changes in position than parameters analyzed in the frequency domain. PMID- 24479407 TI - Prenatal risk factors for Tourette Syndrome: a systematic review. AB - BACKGROUND: Tourette Syndrome (TS) appears to be an inherited disorder, although genetic abnormalities have been identified in less than 1% of patients, and the mode of inheritance is uncertain. Many studies have investigated environmental factors that might contribute to the onset and severity of tics and associated comorbidities such as obsessive compulsive disorder (OCD) and attention deficit hyperactive disorder (ADHD). A systematic review and qualitative analysis were performed to provide a broad view of the association between pre- and perinatal factors and TS. METHODS: The Medline, Embase and PsycINFO databases were searched using terms specific to Tourette's syndrome and keywords such as "pregnancy", "prenatal", "perinatal", "birth" and "neonatal". Studies were limited to studies on human subjects published in English or French through October 2012. RESULTS: 22 studies were included. Studies were of limited methodological quality, with most samples derived from specialty clinics, and most exposures ascertained retrospectively. The majority of the results for demographic factors of parents, including age, education, socioeconomic status, and marital status, revealed no significant association with the onset of TS, or the presence of comorbidity. Many factors were reported to be significantly associated with the onset of TS, the presence of comorbidity and symptom severity, but the most consistently reported factors were maternal smoking and low birth weight. CONCLUSIONS: There are few studies evaluating the relationship between pre and perinatal events and TS, and existing studies have major limitations, including the use of clinic rather than epidemiologically derived samples, retrospective data collection on pre and perinatal events and multiple hypothesis testing without appropriate statistical correction. The mechanism by which prenatal and perinatal adversities could lead to TS onset or symptom severity is unknown, but may be related to changes in the dopaminergic system as a result of early brain injury. PMID- 24479409 TI - Selective intra-arterial infusion of rAd-p53 with chemotherapy for advanced oral cancer: a randomized clinical trial. AB - BACKGROUND: In this study, a combination of recombinant adenoviral p53 (rAd-p53) gene therapy and intra-arterial delivery of chemotherapeutic agents for treatment of oral squamous cell carcinoma was evaluated. METHODS: In total, 99 patients with stage III or IV oral carcinoma who had refused or were ineligible for surgery were enrolled in a randomized, placebo-controlled, double-blind, phase III clinical trial. They were randomly assigned to group I (n = 35; intra arterial infusion of rAd-p53 plus chemotherapy), group II (n = 33; intra-arterial infusion of rAd-p53 plus placebo chemotherapy), or group III (n = 31; intra arterial infusion of placebo rAd-p53 plus chemotherapy). RESULTS: The median length of follow-up was 36 months (range, 3 to 86 months). During follow-up, 16 patients in group I, 20 in group II, and 22 in group III died. Group I (48.5%) had a higher complete response rate than groups II (16.7%) and III (17.2%) (P = 0.006). The rate of non-responders in group I was significantly lower than that in groups II and III (P < 0.020). A log-rank test for survival rate indicated that group I had a significantly higher survival rate than group III (P = 0.019). The survival rate of patients with stage III but not stage IV oral cancer was significantly higher in group I than in group III (P = 0.015, P = 0.200, respectively). The survival rate of patients with stage IV did not differ significantly among the three groups. Or the 99 patients, 63 patients experienced adverse events of either transient flu-like symptoms or bone marrow suppression, while 13 patients had both these conditions together. No replication-deficient virus was detected in patient serum, urine, or sputum. rAd-p53 treatment increased Bax expression in the primary tumor of 80% of patients, as shown by immunohistochemical staining. CONCLUSIONS: Intra-arterial infusion of combined rAd-p53 and chemotherapy significantly increased the survival rate of patients with stage III but not stage IV oral cancer, compared with intra-arterial chemotherapy. Intra-arterial infusion of combined rAd-p53 and chemotherapy may represent a promising alternative treatment for oral squamous cell carcinoma. TRIAL REGISTRATION: ChiCTR-TRC-09000392 (Date of registration: 2009-05-18). PMID- 24479410 TI - Patients' preferences for osteoporosis drug treatment: a discrete-choice experiment. AB - INTRODUCTION: The patient's perspective is becoming increasingly important in clinical and policy decisions. In this study, we aimed to evaluate the preferences of patients with, or at risk of, osteoporosis for medication attributes, and to establish how patients trade between these attributes. METHODS: A discrete choice experiment survey was designed and patients were asked to choose between two hypothetical unlabelled drug treatments (and an opt-out option) that vary in five attributes: efficacy in reducing the risk of fracture, type of potential common side-effects, mode and frequency of administration and out-of-pocket costs. An efficient experimental design was used to construct the treatment option choice sets and a mixed logit panel data model was used to estimate patients' preferences and trade-offs between attributes. RESULTS: A total of 257 patients with, or at risk of, osteoporosis completed the experiment. As expected, patients preferred treatment with higher effectiveness and lower cost. They also preferred either an oral monthly tablet or 6-month subcutaneous injection above weekly oral tablets, 3-month subcutaneous, 3-month intravenous or yearly intravenous injections. Patients disliked being at risk of gastro intestinal disorders more than being at risk of skin reactions and flu-like symptoms. There was significant variation in preferences across the sample for all attributes except subcutaneous injection. CONCLUSIONS: This study revealed that osteoporotic patients preferred 6-month subcutaneous injection and oral monthly tablet, and disliked gastro-intestinal disorders. Moreover, patients were willing to pay a personal contribution or to trade treatment efficacy for better levels of other attributes. Preferences for treatment attributes varied across patients and this highlights the importance of clinical decision-making taking individual preferences into account to improve osteoporosis care. PMID- 24479412 TI - Evaluation of the effectiveness of training on a machine with a variable-cam. AB - The aim of the study was to assess the effectiveness of the training of elbow flexors through the use of 2 machines, one of which was equipped with a disc plate of constant radius, the other one with a variable-cam having a radius adjustable to muscle strength. The experiment included 45 men divided into 3 equal groups: training group A (variable-cam), training group B (circle), and control group C. The training lasted for 8 weeks, 3 times a week. In order to control the effects, the values of peak torque and power of the flexor muscles of the elbow were isokinetically measured for the angular velocities of 30 degrees /s and 60 degrees /s. Also taken were anthropometric measurements of the arm and the creatine kinase (CK) activity in the blood plasma. As a result of the training, significant increases of biomechanical values were noted only in group A: power increased over 20%, the peak torque over 14%. After the training, significant increases of arm circumference in the relaxed position were noted in group A (17 mm), as well as in group B (11 mm). Also, some changes in CK activity were observed between Monday and Friday in a training week. On the basis of the experimental measurements, it may be ascertained that training elbow flexor muscles on a machine with a variable-cam is more efficient for increases in strength and power, as well as for some anthropometric parameters, than training on a machine with a disc plate. PMID- 24479411 TI - High-resolution CT scoring system-based grading scale predicts the clinical outcomes in patients with idiopathic pulmonary fibrosis. AB - BACKGROUND: The 2011 idiopathic pulmonary fibrosis (IPF) guidelines are based on the diagnosis of IPF using only high-resolution computed tomography (HRCT). However, few studies have thus far reviewed the usefulness of the HRCT scoring system based on the grading scale provided in the guidelines. We retrospectively studied 98 patients with respect to assess the prognostic value of changes in HRCT findings using a new HRCT scoring system based on the grading scale published in the guidelines. METHODS: Consecutive patients with IPF who were diagnosed using HRCT alone between January 2008 and January 2012 were evaluated. HRCT examinations and pulmonary function tests were performed at six-month intervals for the first year after diagnosis. The HRCT findings were evaluated using the new HRCT scoring system (HRCT fibrosis score) over time. The findings and survival rates were analyzed using a Kaplan-Meier analysis. RESULTS: The HRCT fibrosis scores at six and 12 months after diagnosis were significantly increased compared to those observed at the initial diagnosis (p < 0.001). The patients with an elevated HRCT fibrosis score at six months based on a receiver operating characteristic (ROC) curves analysis had a poor prognosis (log-rank, hazard ratio [HR] 2.435, 95% CI 1.196-4.962; p = 0.0142). Furthermore, among the patients without marked changes in %FVC, those with an elevated score above the cut-off value had a poor prognosis (HR 2.192, 95% CI 1.003-4.791; p = 0.0491). CONCLUSIONS: Our data demonstrate that the HRCT scoring system based on the grading scale is useful for predicting the clinical outcomes of IPF and identifying patients with an adverse prognosis when used in combination with spirometry. PMID- 24479413 TI - Lipid accumulation and biosynthesis genes response of the oleaginous Chlorella pyrenoidosa under three nutrition stressors. AB - BACKGROUND: Microalgae can accumulate considerable amounts of lipids under different nutrient-deficient conditions, making them as one of the most promising sustainable sources for biofuel production. These inducible processes provide a powerful experimental basis for fully understanding the mechanisms of physiological acclimation, lipid hyperaccumulation and gene expression in algae. In this study, three nutrient-deficiency strategies, viz nitrogen-, phosphorus- and iron-deficiency were applied to trigger the lipid hyperaccumulation in an oleaginous Chlorella pyrenoidosa. Regular patterns of growth characteristics, lipid accumulation, physiological parameters, as well as the expression patterns of lipid biosynthesis-related genes were fully analyzed and compared. RESULTS: Our results showed that all the nutrient stress conditions could enhance the lipid content considerably compared with the control. The total lipid and neutral lipid contents exhibit the most marked increment under nitrogen deficiency, achieving 50.32% and 34.29% of dry cell weight at the end of cultivation, respectively. Both photosynthesis indicators and reactive oxygen species parameters reveal that physiological stress turned up when exposed to nutrient depletions. Time-course transcript patterns of lipid biosynthesis-related genes showed that diverse expression dynamics probably contributes to the different lipidic phenotypes under stress conditions. By analyzing the correlation between lipid content and gene expression level, we pinpoint several genes viz. rbsL, me g6562, accA, accD, dgat g2354, dgat g3280 and dgat g7063, which encode corresponding enzymes or subunits of malic enzyme, ACCase and diacylglycerol acyltransferase in the de novo TAG biosynthesis pathway, are highly related to lipid accumulation and might be exploited as target genes for genetic modification. CONCLUSION: This study provided us not only a comprehensive picture of adaptive mechanisms from physiological perspective, but also a number of targeted genes that can be used for a systematic metabolic engineering. Besides, our results also represented the feasibility of lipid production through trophic transition cultivation modes, throwing light on a two-stage microalgal lipid production strategy with which heterotrophy stage provides sufficient robust seed and nitrogen-starvation photoautotrophy stage enhances the overall lipid productivity. PMID- 24479414 TI - Teaching clinical reasoning by making thinking visible: an action research project with allied health clinical educators. AB - BACKGROUND: Clinical reasoning is fundamental to all forms of professional health practice, however it is also difficult to teach and learn because it is complex, tacit, and effectively invisible for students. In this paper we present an approach for teaching clinical reasoning based on making expert thinking visible and accessible to students. METHODS: Twenty-one experienced allied health clinical educators from three tertiary Australian hospitals attended up to seven action research discussion sessions, where they developed a tentative heuristic of their own clinical reasoning, trialled it with students, evaluated if it helped their students to reason clinically, and then refined it so the heuristic was targeted to developing each student's reasoning skills. Data included participants' written descriptions of the thinking routines they developed and trialed with their students and the transcribed action research discussion sessions. Content analysis was used to summarise this data and categorise themes about teaching and learning clinical reasoning. RESULTS: Two overriding themes emerged from participants' reports about using the 'making thinking visible approach'. The first was a specific focus by participating educators on students' understanding of the reasoning process and the second was heightened awareness of personal teaching styles and approaches to teaching clinical reasoning. CONCLUSIONS: We suggest that the making thinking visible approach has potential to assist educators to become more reflective about their clinical reasoning teaching and acts as a scaffold to assist them to articulate their own expert reasoning and for students to access and use. PMID- 24479415 TI - Varicella zoster-associated retinal and central nervous system vasculitis in a patient with multiple sclerosis treated with natalizumab. AB - We report the first case of combined retinal and CNS varicella zoster-associated vasculitis in a 49-year-old patient with multiple sclerosis who had been treated with natalizumab. He presented with a progressive bilateral visual loss. The diagnosis of a vasculitis was based on the fundoscopic examination and MRI findings. We confirmed the varicella zoster virus (VZV) infection of the CNS by PCR and increased intrathecal antibody indices in the cerebrospinal fluid. The patient was stabilized with antiviral treatment, methylprednisolone, plasmapheresis and cycophosphamide. Natalizumab was discontinued. This case illustrates the neuroimmunological and neuroinfectiological consequences of treatments with biologicals that influence the immune system. PMID- 24479416 TI - Authentic bosutinib inhibits triiodothyronine transport by monocarboxylate transporter 8. PMID- 24479417 TI - The influence of risk perception on biosafety level-2 laboratory workers' hand-to face contact behaviors. AB - Pathogen transmission in the laboratory is thought to occur primarily through inhalation of infectious aerosols or by direct contact with mucous membranes on the face. While significant research has focused on controlling inhalation exposures, little has been written about hand contamination and subsequent hand to-face contact (HFC) transmission. HFC may present a significant risk to workers in biosafety level-2 (BSL-2) laboratories where there is typically no barrier between the workers' hands and face. The purpose of this study was to measure the frequency and location of HFC among BSL-2 workers, and to identify psychosocial factors that influence the behavior. Research workers (N = 93) from 21 BSL-2 laboratories consented to participate in the study. Two study personnel measured workers' HFC behaviors by direct observation during activities related to cell culture maintenance, cell infection, virus harvesting, reagent and media preparation, and tissue processing. Following observations, a survey measuring 11 psychosocial predictors of HFC was administered to participants. Study personnel recorded 396 touches to the face over the course of the study (mean = 2.6 HFCs/hr). Of the 93 subjects, 67 (72%) touched their face at least once, ranging from 0.2-16.0 HFCs/hr. Among those who touched their face, contact with the nose was most common (44.9%), followed by contact with the forehead (36.9%), cheek/chin (12.5%), mouth (4.0%), and eye (1.7%). HFC rates were significantly different across laboratories F(20, 72) = 1.85, p = 0.03. Perceived severity of infection predicted lower rates of HFC (p = 0.03). For every one-point increase in the severity scale, workers had 0.41 fewer HFCs/hr (r = -.27, P < 0.05). This study suggests HFC is common among BSL-2 laboratory workers, but largely overlooked as a major route of exposure. Workers' risk perceptions had a modest impact on their HFC behaviors, but other factors not considered in this study, including social modeling and work intensity, may play a stronger role in predicting the behavior. Mucous membrane protection should be considered as part of the BSL-2 PPE ensemble to prevent HFC. PMID- 24479418 TI - Cytotoxic and protein kinase inhibiting nakijiquinones and nakijiquinols from the sponge Dactylospongia metachromia. AB - Chemical investigation of the sponge Dactylospongia metachromia afforded five new sesquiterpene aminoquinones (1-5), two new sesquiterpene benzoxazoles (6 and 7), the known analogue 18-hydroxy-5-epi-hyrtiophenol (8), and a known glycerolipid. The structures of all compounds were unambiguously elucidated by one- and two dimensional NMR and by MS analyses, as well as by comparison with the literature. Compounds 1-5 showed potent cytotoxicity against the mouse lymphoma cell line L5178Y with IC50 values ranging from 1.1 to 3.7 MUM. When tested in vitro for their inhibitory potential against 16 different protein kinases, compounds 5, 6, and 8 exhibited the strongest inhibitory activity against ALK, FAK, IGF1-R, SRC, VEGF-R2, Aurora-B, MET wt, and NEK6 kinases (IC50 0.97-8.62 MUM). PMID- 24479419 TI - QTrim: a novel tool for the quality trimming of sequence reads generated using the Roche/454 sequencing platform. AB - BACKGROUND: Many high throughput sequencing (HTS) approaches, such as the Roche/454 platform, produce sequences in which the quality of the sequence (as measured by a Phred-like quality scores) decreases linearly across a sequence read. Undertaking quality trimming of this data is essential to enable confidence in the results of subsequent downstream analysis. Here, we have developed a novel, highly sensitive and accurate approach (QTrim) for the quality trimming of sequence reads generated using the Roche/454 sequencing platform (or any platform with long reads that outputs Phred-like quality scores). RESULTS: The performance of QTrim was evaluated against all other available quality trimming approaches on both poor and high quality 454 sequence data. In all cases, QTrim appears to perform equally as well as the best other approach (PRINSEQ) with these two methods significantly outperforming all other methods. Further analysis of the trimmed data revealed that the novel trimming approach implemented in QTrim ensures that the prevalence of low quality bases in the resulting trimmed data is substantially lower than PRINSEQ or any of the other approaches tested. CONCLUSIONS: QTrim is a novel, highly sensitive and accurate algorithm for the quality trimming of Roche/454 sequence reads. It is implemented both as an executable program that can be integrated with standalone sequence analysis pipelines and as a web-based application to enable individuals with little or no bioinformatics experience to quality trim their sequence data. PMID- 24479420 TI - Influence of regression model and initial intensity of an incremental test on the relationship between the lactate threshold estimated by the maximal-deviation method and running performance. AB - This study investigated the influence of the regression model and initial intensity during an incremental test on the relationship between the lactate threshold estimated by the maximal-deviation method and performance in elite standard runners. Twenty-three well-trained runners completed a discontinuous incremental running test on a treadmill. Speed started at 9 km . h(-1) and increased by 1.5 km . h(-1) every 4 min until exhaustion, with a minute of recovery for blood collection. Lactate-speed data were fitted by exponential and polynomial models. The lactate threshold was determined for both models, using all the co-ordinates, excluding the first and excluding the first and second points. The exponential lactate threshold was greater than the polynomial equivalent in any co-ordinate condition (P < 0.001). For both models, the lactate threshold was lower when all co-ordinates were used than when the first and the first and second points were excluded (P < 0.001). 10-km race pace was correlated with both the exponential and polynomial lactate thresholds for all the co ordinate conditions (r >= 0.75, P < 0.001 and r >= 0.56, P < 0.05, respectively). The results suggest that the exponential lactate threshold should be used instead of the polynomial equivalent since it is more strongly associated with performance and is independent of the initial intensity of the test. PMID- 24479421 TI - Male involvement during pregnancy and childbirth: men's perceptions, practices and experiences during the care for women who developed childbirth complications in Mulago Hospital, Uganda. AB - BACKGROUND: Development of appropriate interventions to increase male involvement in pregnancy and childbirth is vital to strategies for improving health outcomes of women with obstetric complications. The objective was to gain a deeper understanding of their experiences of male involvement in their partners' healthcare during pregnancy and childbirth. The findings might inform interventions for increasing men's involvement in reproductive health issues. METHODS: We conducted 16 in-depth interviews with men who came to the hospital to attend to their spouses/partners admitted to Mulago National Referral Hospital. All the spouses/partners had developed severe obstetric complications and were admitted in the high dependency unit. We sought to obtain detailed descriptions of men's experiences, their perception of an ideal "father" and the challenges in achieving this ideal status. We also assessed perceived strategies for increasing male participation in their partners' healthcare during pregnancy and childbirth. Data was analyzed by content analysis. RESULTS: The identified themes were: Men have different descriptions of their relationships; responsibility was an obligation; ideal fathers provide support to mothers during childbirth; the health system limits male involvement in childbirth; men have no clear roles during childbirth, and exclusion and alienation in the hospital environment. The men described qualities of the ideal father as one who was available, easily reached, accessible and considerate. Most men were willing to learn about their expected roles during childbirth and were eager to support their partners/wives/spouses during this time. However, they identified personal, relationship, family and community factors as barriers to their involvement. They found the health system unwelcoming, intimidating and unsupportive. Suggestions to improve men's involvement include creating more awareness for fathers, male targeted antenatal education and support, and changing provider attitudes. CONCLUSIONS: This study generates information on perceived roles, expectations, experiences and challenges faced by men who wish to be involved in maternal health issues, particularly during pregnancy and childbirth. There is discord between the policy and practice on male involvement in pregnancy and childbirth. Health system factors that are critical to promoting male involvement in women's health issues during pregnancy and childbirth need to be addressed. PMID- 24479422 TI - Prefilled devices for parenteral applications. AB - Current parenteral administration of drugs suffers from several drawbacks including the requirement of healthcare personnel to administer the drug, the risk of needle stick injuries that may result in the transmission of blood borne pathogens, and patient discomfort. Prefilled devices have emerged as powerful tools to improve parenteral administration of drugs. There are a number of clinical conditions including treatment of endocrine diseases, neurological disorders, autoimmune diseases and emergency medicine where prefilled devices have made major improvements to patient care. Prefilled devices have become an important set of tools for the medical practitioner due to their ease of use and safety, cost effectiveness and patient convenience. This review provides a comprehensive summary of existing prefilled devices, their current clinical uses and corresponding regulatory processes. PMID- 24479423 TI - Prenatal molybdenum exposure and infant neurodevelopment in Mexican children. AB - OBJECTIVE: To evaluate the association between prenatal exposure to molybdenum (Mo) and infant neurodevelopment during the first 30 months of life. METHODS: We selected a random sample of 147 children who participated in a prospective cohort study in four municipalities in the State of Morelos, Mexico. The children were the products of uncomplicated pregnancies with no perinatal asphyxia, with a weight of >=2 kg at birth, and whose mothers had no history of chronic illnesses. These women were monitored before, during, and after the pregnancy. For each of these children a maternal urine sample was available for at least one trimester of pregnancy, and urine Mo levels were determined by electrothermal atomic absorption spectrometry. Neurodevelopment was evaluated using the psychomotor (PDI) and mental development indices (MDI) of the Bayley scale. Association between prenatal exposure to Mo and infant neurodevelopment was estimated using generalized mixed effect models. RESULTS: The average urinary concentrations of Mo adjusted for creatinine varied between 45.6 and 54.0 ug/g of creatinine at first and third trimester, respectively. For each doubling increase of Mo (MUg/g creatinine) during the third trimester of pregnancy, we observed a significant reduction on PDI (beta = -0.57 points; P = 0.03), and no effect on MDI (beta = 0.07 points; P = 0.66). DISCUSSION: As this is the first study that suggests a potential negative association between prenatal Mo exposure and infant neurodevelopment, these results require further confirmation. PMID- 24479424 TI - Psychosocial and contextual determinants of health among infertile women: a cross cultural study. AB - The purpose of this study was to assess the impact of emotional intelligence, social support and contextual factors on the general health of infertile women. A sample of involuntarily childless women aged 25-45 living in the UK (n = 148) and Pakistan (n = 164) completed a self-administered questionnaire. Although there were no significant differences in total scores on the General Health Questionnaire (GHQ), British women reported greater anxiety, insomnia and social dysfunction, and Pakistani women reported greater depression and somatic symptoms. Important differences in putative correlates of GHQ scores were found between the samples. British women reported significantly greater emotional satisfaction, greater satisfaction with medical information, greater satisfaction with medical care, and greater actual received support Pakistani women reported greater emotional intelligence. Regression analysis to identify correlates of higher GHQ scores revealed that greater received social support was a common correlate of better GHQ scores among British and Pakistani women. Additional correlates of better GHQ scores among British women were greater emotional intelligence and more emotional satisfaction in their relationships (overall R(2) = 0.41). Additional correlates among Pakistani women were greater education, greater perceived available social support and a nuclear family system rather than an extended family (overall R(2) =0. 40). Results suggest that psychological facets of infertility should be addressed as part of a holistic approach to the care of infertile women. They highlight a need to improve social support and to incorporate emotional intelligence training in therapeutic interventions to improve the psychological well-being of infertile women. PMID- 24479425 TI - Synthesis of a photoresponsive cryptand and its complexations with paraquat and 2,7-diazapyrenium. AB - A McMurry coupling reaction was used for the efficient synthesis of a bis(m phenylene)-32-crown-10 based cryptand Z-3 with high yield. This photoresponsive cryptand formed host-guest complexes with paraquat derivative 4 and 2,7 diazapyrenium derivative 5. Z-3, and E-3 exhibited similar binding affinity to the small guest 4, while dramatic changes were observed in the binding affinity to the large guest 5. PMID- 24479427 TI - Further landmarks in teaching primary care. PMID- 24479426 TI - Low-density lipoprotein receptor-related protein 5 governs Wnt-mediated osteoarthritic cartilage destruction. AB - INTRODUCTION: Wnt ligands bind to low-density lipoprotein receptor-related protein (LRP) 5 or 6, triggering a cascade of downstream events that include beta catenin signaling. Here we explored the roles of LRP5 in interleukin 1beta (IL 1beta)- or Wnt-mediated osteoarthritic (OA) cartilage destruction in mice. METHODS: The expression levels of LRP5, type II collagen, and catabolic factors were determined in mouse articular chondrocytes, human OA cartilage, and mouse experimental OA cartilage. Experimental OA in wild-type, Lrp5 total knockout (Lrp5-/-) and chondrocyte-specific knockout (Lrp5fl/fl;Col2a1-cre) mice was caused by aging, destabilization of the medial meniscus (DMM), or intra-articular injection of collagenase. The role of LRP5 was confirmed in vitro by small interfering RNA-mediated knockdown of Lrp5 or in Lrp5-/- cells treated with IL 1beta or Wnt proteins. RESULTS: IL-1beta treatment increased the expression of LRP5 (but not LRP6) via JNK and NF-kappaB signaling. LRP5 was upregulated in human and mouse OA cartilage, and Lrp5 deficiency in mice inhibited cartilage destruction. Treatment with IL-1beta or Wnt decreased the level of Col2a1 and increased those of Mmp3 or Mmp13, whereas Lrp5 knockdown ameliorated these effects. In addition, we found that the functions of LRP5 in arthritic cartilage were subject to transcriptional activation by beta-catenin. Moreover, Lrp5-/- and Lrp5fl/fl;Col2a1-cre mice exhibited decreased cartilage destruction (and related changes in gene expression) in response to experimental OA. CONCLUSIONS: Our findings indicate that LRP5 (but not LRP6) plays an essential role in Wnt/beta catenin-signaling-mediated OA cartilage destruction in part by regulating the expression levels of type II collagen, MMP3, and MMP13. PMID- 24479428 TI - The way we teach: reproductive biology. AB - At the University of Nottingham, students are taught aspects of reproductive biology throughout the Part I Basic Medical Science Course. Teachers from the Departments of Physiology and Pharmacology, Human Morphology, Biochemistry, Obstetrics and Gynaecology, and Psychiatry are involved, and an obstetrician in training (the author) has been appointed full-time lecturer in Physiology and Pharmacology to provide an additional link between the basic science and clinical content of the course. The Part II course includes an Honours Year, to give students an opportunity to explore further the application of scientific method in clinical practice. One project, in which students were involved in physiological measurement used in current obstetric practice, is described here. In addition to carrying out practical tasks, students were required to submit written reports and to prepare a learning resource on fetal acid-base balance for use by their junior colleagues. Supervision was provided by obstetric and paediatric registrars and senior house officers, and senior midwives, while staff in the Department of Physiology and Pharmacology assisted students with data analysis. Each project task was assessed by a supervisor and an independent observer. The project proved acceptable to students, supervisors and hospital staff, and avoided interfering with the other responsibilities of a busy obstetric unit. It is intended to repeat the exercise with minor modifications. PMID- 24479429 TI - How to: Plan An Assessment of Student Attitudes. AB - This paper outlines a planning process for teachers to follow when designing an assessment of student attitudes. The guidelines presented are drawn from the literature on attitudinal measurement and from the authors' instructional experience. They are stated in terms which are general enough to encompass attitudinal measurement in a wide range of instructional settings. PMID- 24479430 TI - Return to 'basics' in medical education: a commentary. PMID- 24479431 TI - Preferred Styles of Clinical Teaching: Measuring Physician Control over Students in Patient Care Encounters. AB - An educational instrument, the Clinical Teaching Techniques Self-assessment Inventory, was designed and administered to determine how clinical instructors react to difficult aspects of medical student instruction such as involving, facilitating, serving as a resource, problem solving, role modelling and clinical supervision. It confirmed the hypothesis that in such situations, teachers choose instructional techniques which limit active student involvement in patient care. That is, they selected the techniques of role modelling and providing feedback more frequently than those of facilitating and involving. This contrasts with students' views on what they consider to be important factors contributing to learning clinical medicine, namely assuming responsibility for their own learning and becoming involved in patient care. Requests for the instrument, together with feedback material for teachers, have been received from 18 medical schools. PMID- 24479432 TI - Medical education in the outpatient department. AB - Many disease processes are described by doctors in terms which make no sense to the layman. Here, I describe the methods I use to educate patients about the nature, management, treatment and outcome of their disease processes using teaching methods that were first applied in the undergraduate medical school. In my approach I have been influenced by the old Chinese proverb "the palest ink is stronger than the most powerful memory". PMID- 24479436 TI - Electronic, redox, and photophysical consequences of metal-for-carbon substitution in oligo-phenylene-ethynylenes. AB - The electronic structures, redox chemistry, and excited-state properties of tungsten-containing oligo-phenylene-ethynylenes (OPEs) of the form W[C(p-C6H4CC)n 1Ph](dppe)2Cl (n = 1-5; dppe =1,2-bis(diphenylphosphino)ethane) are reported and compared with those of organic analogues in order to elucidate the effects of metal-for-carbon substitution on OPE bonding and electronic properties. Key similarities between the metallo- and organic OPEs that bear on materials-related functions include their nearly identical effective conjugation lengths, reduction potentials, and pi* orbital energies and delocalization. In addition to these conserved properties, the tungsten centers endow OPEs with reversible one electron oxidation chemistry and long-lived emissive triplet excited states that are not accessible to organic OPEs. The electronic similarities and differences between metallo- and organic OPEs can be understood largely on the basis of pi/pi* orbital energy matching between tungsten and organic PE fragments and the introduction of an orthogonal mid-pi/pi*-gap d orbital in metallo-OPEs. These orbital energies can be tuned by varying the supporting ligands; this provides a means to rationally implement and control the emergent properties of metallo-OPE materials. PMID- 24479434 TI - Posterior segment eye disease in sub-Saharan Africa: review of recent population based studies. AB - OBJECTIVE: To assess the burden of posterior segment eye diseases (PSEDs) in sub Saharan Africa (SSA). METHODS: We reviewed published population-based data from SSA and other relevant populations on the leading PSED, specifically glaucoma, diabetic retinopathy and age-related macular degeneration, as causes of blindness and visual impairment in adults. Data were extracted from population-based studies conducted in SSA and elsewhere where relevant. RESULTS: PSEDs, when grouped or as individual diseases, are a major contributor to blindness and visual impairment in SSA. PSED, grouped together, was usually the second leading cause of blindness after cataract, ranging as a proportion of blindness from 13 to 37%. CONCLUSIONS: PSEDs are likely to grow in importance as causes of visual impairment and blindness in SSA in the coming years as populations grow, age and become more urban in lifestyle. African-based cohort studies are required to help estimate present and future needs and plan services to prevent avoidable blindness. PMID- 24479435 TI - DNA barcode-based delineation of putative species: efficient start for taxonomic workflows. AB - The analysis of DNA barcode sequences with varying techniques for cluster recognition provides an efficient approach for recognizing putative species (operational taxonomic units, OTUs). This approach accelerates and improves taxonomic workflows by exposing cryptic species and decreasing the risk of synonymy. This study tested the congruence of OTUs resulting from the application of three analytical methods (ABGD, BIN, GMYC) to sequence data for Australian hypertrophine moths. OTUs supported by all three approaches were viewed as robust, but 20% of the OTUs were only recognized by one or two of the methods. These OTUs were examined for three criteria to clarify their status. Monophyly and diagnostic nucleotides were both uninformative, but information on ranges was useful as sympatric sister OTUs were viewed as distinct, while allopatric OTUs were merged. This approach revealed 124 OTUs of Hypertrophinae, a more than twofold increase from the currently recognized 51 species. Because this analytical protocol is both fast and repeatable, it provides a valuable tool for establishing a basic understanding of species boundaries that can be validated with subsequent studies. PMID- 24479437 TI - Vertical and horizontal smooth pursuit eye movements in children with developmental coordination disorder. AB - AIM: Our aim was to study horizontal and vertical smooth pursuit eye movements in children with developmental coordination disorder (DCD). METHOD: Horizontal and vertical smooth pursuit eye movements of 91 children were studied using electro oculography: 27 children with DCD (23 males, four females), according to the DSM IV-TR criteria, and 64 comparison children (26 males, 38 females). All children were 7 to 12 years old (mean 9y, SD 1.5y). Among the group of children with DCD, eight had received intervention. Intervention exercised static and dynamic fixation, saccades, visual strategies, visuospatial abilities, and eye-hand coordination. A smooth pursuit gain index was calculated and statistical comparisons were made between the two groups of children. RESULTS: Horizontal pursuit gain was similar in both populations, but vertical pursuit gain was significantly impaired (p<0.001, after adjusting for age as covariate), i.e. more saccadic in children with DCD (18-99%; n=27, mean 51.6%, median 48.5%, SD 23.2%) than in comparison participants (35-97%; n=63, mean 66.4%, median 65.0%, SD 15.4%). Among the DCD group, the vertical pursuit index was also significantly higher (p=0.009) in the intervention subgroup (29-99%; n=8, mean 69.4%, median 75.5%, SD 28.7%) than in the non-intervention subgroup (18-74%; n=19, mean 44.1%, median 42.5%, SD 15.9%). INTERPRETATION: These results suggest a delay in the maturation of the pursuit system in children with DCD. PMID- 24479438 TI - Appearance of perfect amorphous linear bulk polyethylene under applied electric field and the analysis by radial distribution function and direct tunneling effect. AB - Without melting flow, linear ultrahigh molecular weight polyethylene (UHMWPE) provided X-ray intensity curve from only amorphous halo at 129.0 degrees C (surface temperature, Ts arisen by Joule heat) lower than the conventionally known melting point 145.5 degrees C on applying electric field to UHMWPE-nickel coated carbon fiber (NiCF) composite. Such surprising phenomenon was analyzed by simultaneous measurements of X-ray intensity, electric current, and Ts as a function of time. The calculated radial distribution function revealed the amorphous structure with disordered chain arrangement. The appearance of such amorphous phase was arisen by the phenomenon that the transferring electrons between overlapped adjacent NiCFs by tunneling effect struck together with X-ray photons and some of the transferring electron flown out from the gap to UHMWPE matrix collided against carbon atoms of UHMWPE. The impact by the collision caused disordering chain arrangement in crystal grains. PMID- 24479439 TI - Evaluation of selected biomechanical parameters in female team sports players. AB - The aim of this research was to evaluate the biomechanical parameters of lower limbs and their influence on height of vertical jump. The research was conducted on a group of females practicing basketball and volleyball. The following equipment was used during the experiment: a force plate by Kistler, a Biometrics electrogoniometer and a specially designed chair to measure static torque by OPIW Opole. The results indicated that the jumping abilities of the examined athletes were poor. No statistically significant correlations were observed between knee static torque and heights of vertical jumps: CMJ and DJ. The authors suggest modification of the McClymont index (RSI) to evaluate the selection of platform height during plyometric training. Such modification would enable better choice of loads and better training control of the subject. PMID- 24479440 TI - Persistent prurigo nodularis in HIV-infected patient responsive to antiretroviral therapy with raltegravir. PMID- 24479443 TI - Efficient sequential and parallel algorithms for planted motif search. AB - BACKGROUND: Motif searching is an important step in the detection of rare events occurring in a set of DNA or protein sequences. One formulation of the problem is known as (l,d)-motif search or Planted Motif Search (PMS). In PMS we are given two integers l and d and n biological sequences. We want to find all sequences of length l that appear in each of the input sequences with at most d mismatches. The PMS problem is NP-complete. PMS algorithms are typically evaluated on certain instances considered challenging. Despite ample research in the area, a considerable performance gap exists because many state of the art algorithms have large runtimes even for moderately challenging instances. RESULTS: This paper presents a fast exact parallel PMS algorithm called PMS8. PMS8 is the first algorithm to solve the challenging (l,d) instances (25,10) and (26,11). PMS8 is also efficient on instances with larger l and d such as (50,21). We include a comparison of PMS8 with several state of the art algorithms on multiple problem instances. This paper also presents necessary and sufficient conditions for 3 l mers to have a common d-neighbor. The program is freely available at http://engr.uconn.edu/~man09004/PMS8/. CONCLUSIONS: We present PMS8, an efficient exact algorithm for Planted Motif Search. PMS8 introduces novel ideas for generating common neighborhoods. We have also implemented a parallel version for this algorithm. PMS8 can solve instances not solved by any previous algorithms. PMID- 24479442 TI - Defense against HSV-1 in a murine model is mediated by iNOS and orchestrated by the activation of TLR2 and TLR9 in trigeminal ganglia. AB - BACKGROUND: Herpes simplex 1 (HSV-1) causes various human clinical manifestations, ranging from simple cold sores to encephalitis. Innate immune cells recognize pathogens through Toll-like receptors (TLRs), thus initiating the immune response. Previously, we demonstrated that the immune response against HSV 1 is dependent on TLR2 and TLR9 expression and on IFN gamma production in the trigeminal ganglia (TG) of infected mice. In this work, we further investigated the cells, molecules, and mechanisms of HSV-1 infection control, especially those that are TLR-dependent. METHODS: C57BL/6 wild-type (WT), TLR2-/-, TLR9-/-, and TLR2/9-/- mice were intranasally infected with HSV-1. On the viral peak day, the TG and brains were collected from mice and TLR expression was measured in the TG and brain and inducible nitric oxide synthase (iNOS) expression was measured in the TG by real-time PCR. Immunofluorescence assays were performed in mice TG to detect iNOS production by F4/80+ cells. Intraperitoneal macrophages nitric oxide (NO) production was evaluated by the Griess assay. WT, CD8-/-, RAG-/-, and iNOS-/ mice were intranasally infected in a survival assay, and their cytokine expression was measured in the TG by real-time PCR. RESULTS: Infected WT mice exhibited significantly increased TLR expression, compared with their respective controls, in the TG but not in the brain. TLR-deficient mice had moderately increased TLR expression in the TG and brain in compare with the non-infected animals. iNOS expression in the WT infected mice TG was higher than in the other groups with increased production by macrophages in the WT infected mice, which did not occur in the TLR2/9-/- mice. Additionally, the intraperitoneal macrophages of the WT mice had a higher production of NO compared with those of the TLR-deficient mice. The CD8-/-, RAG-/-, and iNOS-/- mice had 100% mortality after the HSV-1 infection compared with 10% of the WT mice. Cytokines were overexpressed in the iNOS-/- infected mice, while the RAG-/- mice were nearly unresponsive to the virus. CONCLUSION: TLRs efficiently orchestrate the innate immune cells, eliciting macrophage response (with NO production by the macrophages), thereby controlling the HSV-1 infection through the immune response in the TG of mice. PMID- 24479444 TI - Direct vitamin K antagonist anticoagulant treatment health care costs in patients with non-valvular atrial fibrillation. AB - BACKGROUND: There is evidence suggesting that most thromboembolic complications could be prevented with adequate pharmacological anticoagulation. We estimated the direct health care costs of anticoagulant treatment with oral vitamin K antagonists in patients diagnosed with non-valvular atrial fibrillation. METHODS: This observational study examined the clinical records of patients diagnosed with non-valvular atrial fibrillation who received anticoagulant treatment with oral vitamin K antagonists. Data from clinical records were used in the study: international normalized ratio, number of monitoring visits, type of anticoagulant, hospital admissions from complications, and concomitant medication. Drug cost was calculated based on the official Spanish Ministry of Health price list. Monitoring expenses were included the cost of the medical supplies used in the procedures. Hospitalization costs were calculated using the Diagnosis Related Group price for each case. Hospital visits costs were calculated by one of four different scenarios, using either the invoice rates for the regional health care authority or cost per visit as established by analytical accounting methods. RESULTS: We collected data from 1,257 patients diagnosed with non-valvular atrial fibrillation who were receiving oral anticoagulant therapy. Depending on the scheme used, the direct health care costs for these patients ranged from ?423,695 - ?1,436,038 per annum. The average cost per patient varied between ?392 - ?1,341, depending on the approach used. Patients with international normalized ratio values within the therapeutic range on 25% of their visits represented an average cost between ?441.70 - ?1,592. Those within the therapeutic range on 25%-50% of visits had associated costs of ?512.37 - ?1,703.91. When international normalized ratio values were within the therapeutic range on 50% - 75% of the visits, the costs ranged between ?400.80- ?1,375.74. The average cost was ?305.23 - ?1,049.84 when the values were within the therapeutic range for over 75% of visits. CONCLUSIONS: Most direct health care costs associated with the sampled patients arise from the specialist-care monitoring required for the treatment. Good monitoring is inversely related to direct health care costs. PMID- 24479445 TI - The value of robotic systems in stroke rehabilitation. AB - In this paper, we discuss robot-mediated neurorehabilitation as a significant emerging field in clinical medicine. Stroke rehabilitation is advancing toward more integrated processes, using robotics to facilitate this integration. Rehabilitation approaches have tremendous value in reducing long-term impairments in stroke patients during hospitalization and after discharge, of which robotic systems are a new modality that can provide more effective rehabilitation. The function of robotics in rehabilitative interventions has been examined extensively, generating positive yet not completely satisfactory clinical results. This article presents state-of-the-art robotic systems and their prospective function in poststroke rehabilitation of the upper and lower limbs. PMID- 24479447 TI - Surveillance for the prevention of chronic diseases through information association. AB - BACKGROUND: Research on Genomic medicine has suggested that the exposure of patients to early life risk factors may induce the development of chronic diseases in adulthood, as the presence of premature risk factors can influence gene expression. The large number of scientific papers published in this research area makes it difficult for the healthcare professional to keep up with individual results and to establish association between them. Therefore, in our work we aim at building a computational system that will offer an innovative approach that alerts health professionals about human development problems such as cardiovascular disease, obesity and type 2 diabetes. METHODS: We built a computational system called Chronic Illness Surveillance System (CISS), which retrieves scientific studies that establish associations (conceptual relationships) between chronic diseases (cardiovascular diseases, diabetes and obesity) and the risk factors described on clinical records. To evaluate our approach, we submitted ten queries to CISS as well as to three other search engines (GoogleTM, Google ScholarTM and Pubmed(r);) - the queries were composed of terms and expressions from a list of risk factors provided by specialists. RESULTS: CISS retrieved a higher number of closely related (+) and somewhat related (+/-) documents, and a smaller number of unrelated (-) and almost unrelated (-/+) documents, in comparison with the three other systems. The results from the Friedman's test carried out with the post-hoc Holm procedure (95% confidence) for our system (control) versus the results for the three other engines indicate that our system had the best performance in three of the categories (+), (-) and (+/-). This is an important result, since these are the most relevant categories for our users. CONCLUSION: Our system should be able to assist researchers and health professionals in finding out relationships between potential risk factors and chronic diseases in scientific papers. PMID- 24479446 TI - Decreased expression of key tumour suppressor microRNAs is associated with lymph node metastases in triple negative breast cancer. AB - BACKGROUND: Breast cancer is the most common malignancy that develops in women, responsible for the highest cancer-associated death rates. Triple negative breast cancers represent an important subtype that have an aggressive clinical phenotype, are associated with a higher likelihood of metastasis and are not responsive to current targeted therapies. miRNAs have emerged as an attractive candidate for molecular biomarkers and treatment targets in breast cancer, but their role in the progression of triple negative breast cancer remains largely unexplored. METHODS: This study has investigated miRNA expression profiles in 31 primary triple negative breast cancer cases and in 13 matched lymph node metastases compared with 23 matched normal breast tissues to determine miRNAs associated with the initiation of this disease subtype and those associated with its metastasis. RESULTS: 71 miRNAs were differentially expressed in triple negative breast cancer, the majority of which have previously been associated with breast cancer, including members of the miR-200 family and the miR-17-92 oncogenic cluster, suggesting that the majority of miRNAs involved in the initiation of triple negative breast cancer are not subtype specific. However, the repertoire of miRNAs expressed in lymph node negative and lymph node positive triple negative breast cancers were largely distinct from one another. In particular, miRNA profiles associated with lymph node negative disease tended to be up-regulated, while those associated with lymph node positive disease were down-regulated and largely overlapped with the profiles of their matched lymph node metastases. From this, 27 miRNAs were identified that are associated with metastatic capability in the triple negative breast cancer subtype. CONCLUSIONS: These results provide novel insight into the repertoire of miRNAs that contribute to the initiation of and progression to lymph node metastasis in triple negative breast cancer and have important implications for the treatment of this breast cancer subtype. PMID- 24479448 TI - Nutritional quality of the school-day diet in Irish children (5-12 years). AB - BACKGROUND: The European Commission has identified schools as a priority setting for health promotion, including nutrition education and intervention. The present study examined the school-day diet of Irish primary-school children with the aim of identifying opportunities for dietary improvement. METHODS: Data from The National Children's Food Survey (2003-2004) were used to establish a dataset of school-days. Dietary intake data were collected from 594 children (5-12 years) using a 7-day weighed food-record. The nutritional quality of the diet was examined for the total school-day and for food eaten 'before school', 'at school' and 'after school'. RESULTS: Examination of dietary intake on school-days has highlighted nutritional imbalances for intakes of fat, saturated fat, added sugars, sodium and dietary fibre (DF). Mean energy (E) intake for the overall school-day was 7.1 MJ, with 16% of energy provided from food eaten 'before school', 33%E from food eaten 'at school' and 53% of energy from food eaten 'after school'. Relative to the overall school-day, food eaten 'before school' was lower in saturated fat and sodium, and higher in DF and many micronutrients. Food eaten 'at school' was relatively high in added sugars and sodium; lower in DF and micronutrients; and similar in saturated fat compared to the overall school-day. Food eaten 'after school' was relatively high in DF and vitamin A; similar in saturated fat, magnesium and sodium; and lower in added sugars and other micronutrients compared to the overall school-day. CONCLUSIONS: To improve the overall nutritional quality of the school-day diet, food eaten at school should be targeted. PMID- 24479450 TI - Uniform horse-racing rules gaining momentum: 10 jurisdictions have signed on to national reforms. PMID- 24479451 TI - Processed pet foods. PMID- 24479452 TI - Writing diagnostic laboratory requisition form histories. PMID- 24479453 TI - What is your diagnosis? Prepubic hernia. PMID- 24479454 TI - Pathology in practice. Compound odontoma in a horse. PMID- 24479455 TI - Pathology in practice. Primary ciliary dyskinesia (PCD) with associated bronchopneumonia, bronchiectasis, and hydrocephalus in a dog. PMID- 24479456 TI - Evaluation of blood cardiac troponin I concentrations obtained with a cage-side analyzer to differentiate cats with cardiac and noncardiac causes of dyspnea. AB - OBJECTIVE: To determine whether measurement of blood cardiac troponin I (cTnI) concentrations with a cage-side analyzer could be used to differentiate cardiac from noncardiac causes of dyspnea in cats. DESIGN: Prospective, multicenter study. ANIMALS: 44 client-owned cats with dyspnea and 37 healthy staff-owned cats. PROCEDURES: Affected cats were examined because of dyspnea; treatment was administered in accordance with the attending clinician's discretion. Cats were judged to have a cardiac or noncardiac cause of dyspnea on the basis of results of physical examination, thoracic radiography, and echocardiography. Blood cTnI concentrations were determined with a cage-side analyzer on samples collected within 12 hours after admission of affected cats. Concentrations for healthy cats were obtained for comparison. RESULTS: 5 enrolled cats were excluded from the study because of concurrent cardiac and respiratory disease. Of the remaining 39 cats with dyspnea, 25 had a cardiac cause and 14 had a noncardiac cause. The 25 cats with a cardiac cause of dyspnea had a significantly higher blood cTnI concentration than did the 37 healthy cats or the 14 cats with a noncardiac cause of dyspnea. CONCLUSIONS AND CLINICAL RELEVANCE: Measurement of cTnI concentrations with a cage-side assay in emergency settings may be useful for differentiating cardiac from noncardiac causes of dyspnea in cats. PMID- 24479457 TI - Risk factors for transfusion-associated complications and nonsurvival in dogs receiving packed red blood cell transfusions: 211 cases (2008-2011). AB - OBJECTIVE: To determine whether the number, volume, or age of transfused packed RBC units; volume of other blood products; or pretransfusion PCV was a risk factor for transfusion-associated complications or nonsurvival in dogs. DESIGN: Retrospective case series. ANIMALS: 211 client-owned dogs receiving stored packed RBC transfusions. PROCEDURES: Information collected or calculated from the medical record of each dog included the total number, volume, and dose of packed RBC units; mean age of packed RBC units; number of packed RBC units > 14 days old; age of oldest packed RBC unit; volume and dose of other blood products used; pretransfusion PCV; acute patient physiologic and laboratory evaluation score; transfusion-associated complications; and outcome. RESULTS: The dose (mL/kg) of other blood products transfused was a risk factor for transfusion-associated complications (OR, 1.03; 95% confidence interval [CI], 1.01 to 1.05). The pretransfusion PCV (OR, 1.13; 95% CI, 1.06 to 1.21) and dose of packed RBCs administered (OR, 1.04; 95% CI, 1.02 to 1.07) were risk factors for nonsurvival. Age of transfused packed RBC units was not identified as a risk factor for transfusion-associated complications or nonsurvival, but the study was statistically underpowered to detect this finding. CONCLUSIONS AND CLINICAL RELEVANCE: Administration of larger doses of other non-packed RBC blood products was a risk factor for transfusion-associated complications, and a higher pretransfusion PCV and larger dose of packed RBCs administered were risk factors for nonsurvival. Prospective randomized studies are needed to determine whether conservative transfusion strategies will reduce transfusion-associated complications and improve outcome in dogs. PMID- 24479458 TI - Evaluation of application of a carpal brace as a treatment for carpal ligament instability in dogs: 14 cases (2008-2011). AB - OBJECTIVE: To determine whether carpal brace application is a viable treatment for dogs with unilateral carpal ligament instability. DESIGN: Retrospective case series. ANIMALS: 14 client-owned athletic dogs. PROCEDURES: Medical records were reviewed to identify dogs treated with a brace for unilateral carpal valgus or varus instability between August 2008 and August 2011. Treatment included passive motion and isometric strengthening exercises during brace application. RESULTS: Of the 14 dogs, 11 were considered to have returned to normal function; 11 of 12 dogs returned to agility competition. Carpal measurements before treatment indicated the affected limb had significantly greater valgus measurements (median, 30 degrees ; range, 30 degrees to 35 degrees ), significantly greater varus measurements (median, 15 degrees ; range, 15 degrees to 25 degrees ), and significantly less flexion (median, 37.5 degrees ; range, 30 degrees to 45 degrees ), compared with results for the contralateral carpus. Long-term monitoring revealed no differences in measurements between affected and contralateral limbs. Valgus measurements of the affected carpus at brace removal (median, 15 degrees ; range, 15 degrees to 20 degrees ) and at the end of long term monitoring (median, 15 degrees ; range, 15 degrees to 20 degrees ) were significantly lower than measurements before treatment (median, 30 degrees ; range, 30 degrees to 35 degrees ). Dogs had significantly lower lameness scores (assessed on a scale of 0 to 5) at brace removal (median, 0; range, 0) and at the end of monitoring (median, 0; range, 0 to 2), compared with scores before treatment (median, 3; range, 1 to 3). CONCLUSIONS AND CLINICAL RELEVANCE: Application of a carpal brace resulted in improved stability and resolution or reduction in lameness in dogs with carpal ligament instability. PMID- 24479459 TI - Complications after corrective surgery for lateral patellar luxation in dogs: 36 cases (2000-2011). AB - OBJECTIVE: To determine the frequency and severity of complications after corrective surgery in dogs with lateral patellar luxation (LPL) and identify risk factors for reluxation. DESIGN: Retrospective case series. ANIMALS: 36 client owned dogs with 47 affected stifle joints. PROCEDURES: Medical records of dogs that underwent surgical correction of LPL at 1 of 2 veterinary teaching hospitals between 2000 and 2011 were reviewed. Data analyzed included signalment, grade of luxation, orthopedic comorbidities, surgical procedures performed, frequency and type of complications, and whether a second surgery was performed. RESULTS: A total of 36 dogs with 47 affected stifle joints met the inclusion criteria. Complications were recorded for 24 of 47 (51.1%) stifle joints; there were major complications for 18 of 47 (38.3%) stifle joints. All complications were confirmed through examination by a veterinarian. The most frequent complication was reluxation, which was detected in 10 of 47 (21.3%) stifle joints. Dogs that underwent bilateral surgical repair during a single anesthetic episode had odds of reluxation that were 12.5 times the odds of reluxation for dogs that underwent unilateral surgical repair. CONCLUSIONS AND CLINICAL RELEVANCE: Complication rate after corrective surgery for LPL was high, with reluxation being the most common complication in this population of dogs. Performing staged bilateral surgeries may decrease the risk of reluxation. PMID- 24479460 TI - Vital pulp therapy in dogs: 190 cases (2001-2011). AB - OBJECTIVE: To evaluate factors associated with the outcome of vital pulp therapy (VPT) in dogs. DESIGN: Retrospective study. SAMPLE: 190 teeth in 138 dogs. PROCEDURES: Medical records were reviewed; radiographs obtained before, immediately after, and during the last available follow-up examination for VPT were evaluated. Treatment was categorized as successful (with radiographic evidence of continued secondary dentin production, continued root formation in immature teeth, and absence of clinical and radiographic signs of apical periodontitis and internal or external inflammatory root resorption), having no evidence of failure (with signs for success fulfilled except the width of the apical periodontal ligament space, which could be wider than but no more than double the width of the periodontal ligament space in other areas), or failed (with radiographic evidence of pulp necrosis, apical periodontitis, or inflammatory root resorption). Associations between diagnostic or treatment related variables and outcome were assessed with multinomial logistic regression. RESULTS: Overall, treatment was classified as successful for 162 of 190 (85%) teeth, including 23 (12%) teeth with no evidence of failure, and as having failed for 28 (15%) teeth. The overall success rate was 137 of 149 (92%) for teeth treated with mineral trioxide aggregate alone and 21 of 36 (58%) for teeth treated with Ca(OH)2 alone. Use of Ca(OH)2 and deep penetration of dressing material into the vital pulp were each significantly associated with increased odds of treatment failure. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated that VPT with mineral trioxide aggregate was an effective option for use in crown reduction to treat malocclusion and for treatment of recent crown fractures in immature or mature permanent teeth. PMID- 24479461 TI - Presumed solitary intraocular or conjunctival lymphoma in dogs and cats: 9 cases (1985-2013). AB - OBJECTIVE: To determine prevalence, reason for evaluation, treatment, and outcome for dogs and cats with presumed solitary ocular lymphoma (PSOL). DESIGN: Retrospective case series. ANIMALS: 7 dogs and 2 cats with PSOL. PROCEDURES: Medical records were reviewed. Progression-free survival time (PFST) and overall survival time (OST) were determined. RESULTS: Animals with intraocular (4 dogs and 1 cat) or conjunctival (3 dogs and 1 cat) lymphoma represented 0.1% and 0.08% of patients with lymphoma evaluated at the hospital during the study period, respectively. Animals with intraocular lymphoma represented 0.19% of all patients with uveitis; animals with conjunctival lymphoma represented 0.16% of all patients with conjunctivitis. Tumors included B-cell (2 intraocular and 1 conjunctival), non-B-cell, non-T-cell (1 intraocular), and T-cell (3 conjunctival) neoplasms; immunophenotype of 2 uveal lymphomas was not determined. Treatments included enucleation (4 intraocular) and chemotherapy (3 intraocular and 2 conjunctival). All dogs with intraocular lymphoma developed neurologic signs. Lymph node metastasis was detected in 2 patients with conjunctival lymphoma. Median PFST and OST were 178 days for all animals with PSOL, dogs with PSOL, and animals with intraocular lymphoma. Median PFST and OST for animals with conjunctival lymphoma were 221 and 549 days, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Results indicated PSOL was uncommon, but should be considered a differential diagnosis for animals with uveitis or conjunctivitis. Performance of MRI and cytologic analysis of CSF and regional lymph node aspirate samples may be beneficial for such patients. Prognosis seemed to be better for animals with conjunctival lymphoma than it was for those with intraocular lymphoma. PMID- 24479462 TI - Iron deficiency anemia in a ring-tailed lemur (Lemur catta) with concurrent chronic renal failure. AB - CASE DESCRIPTION: A 16-year-old vasectomized male ring-tailed lemur (Lemur catta) with a history of suspected chronic renal failure was evaluated because of extreme lethargy, hyperpnea, and abscess of the right pectoral scent gland. CLINICAL FINDINGS: Examination of the anesthetized patient revealed an impacted right pectoral scent gland with serosanguineous exudate. A CBC and serum biochemical analysis revealed severe anemia, marked azotemia, hyperphosphatemia, and hypocalcemia. TREATMENT AND OUTCOME: Supportive care (including fluid therapy and phosphorus binder administration) was initiated for renal failure; the affected gland was cleaned, and antimicrobials were administered. The patient received 1 blood transfusion, and darbepoetin alfa was administered weekly to stimulate RBC production. Anemia and azotemia persisted. Three months after treatment started, serum iron analysis revealed that iron deficiency was the probable cause for the lack of a consistent regenerative response to darbepoetin injections. Iron dextran injections resulted in a marked regenerative response; however, serum biochemical analysis results after the second injection were consistent with hepatic injury. Hepatic enzyme activities normalized following discontinuation of iron dextran treatment, but the lemur's Hct declined rapidly despite supplementary iron administration PO. The patient developed severe mandibular osteomyelitis and was euthanized because of poor prognosis. Postmortem evaluation of hepatic iron concentration confirmed iron deficiency. CLINICAL RELEVANCE: The family Lemuridae is considered prone to hemosiderosis and hemochromatosis, which delayed rapid diagnosis and treatment of the lemur's disease. Apparent hepatic injury following iron dextran injections further complicated treatment. Findings for this lemur support the use of species specific total iron binding capacity and total serum iron and ferritin concentrations in evaluation of an animal with suspected iron deficiency. PMID- 24479463 TI - Use of hydropulsion for the treatment of superficial corneal foreign bodies: 15 cases (1999-2013). AB - OBJECTIVE: To describe the use of hydropulsion with sterile isotonic buffered ophthalmic solution (ie, eyewash) for the treatment of superficial corneal foreign bodies in veterinary patients and evaluate signalment, clinical findings, and outcomes following the procedure. DESIGN: Retrospective case series. ANIMALS: 11 dogs, 2 cats, and 2 horses. PROCEDURES: Medical records were retrospectively reviewed to identify patients that underwent hydropulsion treatment for a superficial, nonpenetrating corneal foreign body confirmed by ophthalmic examination. Data regarding signalment, reason for evaluation, ocular diagnoses, and treatment were recorded. Hydropulsion was performed with a 6-mL syringe filled with eyewash solution and a 25-gauge needle with the needle tip removed. Owners and referring veterinarians of patients that did not have a recheck examination recorded were contacted by telephone for follow-up information. RESULTS: The corneal foreign body was an incidental finding in 3 of 15 patients. The most common clinical signs included blepharospasm, conjunctival hyperemia, and corneal vascularization. Hydropulsion was successful for foreign body removal in all 15 cases. No complications were observed during or following the procedure. In the 9 patients that had a follow-up examination, the cornea tested negative for retention of topically applied fluorescein (with a mean of 6.3 days from treatment to follow-up). At the time of last follow-up examination or telephone follow-up, no patients were reported to have clinical signs of ocular discomfort or corneal opacity associated with the affected site. CONCLUSIONS AND CLINICAL RELEVANCE: In these patients, hydropulsion was easily performed with readily available materials and was successful for the removal of superficial corneal foreign bodies with no adverse effects. PMID- 24479464 TI - The microcycle of inflammation and performance changes after a basketball match. AB - Basketball incorporates intense eccentric muscle activity that induces muscle microtrauma and an inflammatory response. This study investigated time-dependent inflammatory and performance responses during a weekly microcycle after a basketball match. Twenty elite-standard players underwent a trial that comprised a match followed by a 6-day simulated in-season microcycle. The trial was preceded by a control condition that did not have a match. Blood sampling and tests of maximal-intensity exercise performance and muscle damage occurred before each condition, immediately after the match and daily thereafter for 6 consecutive days. The match induced marked increases in heart rate, lactate, ammonia, glucose, non-esterified fatty acids and triglycerides. Performance deteriorated for 24-48 h after the match, whereas knee flexor and extensor soreness increased for 48 and 24 h post-match, respectively. Inflammatory (leukocytes, C-reactive protein, creatine kinase activity, adhesion molecules, cortisol, uric acid and cytokines) and oxidative stress (malondialdehyde, protein carbonyls, oxidised glutathione, antioxidant capacity, catalase and glutathione peroxidase) markers increased for ~24 h and subsided thereafter. Reduced glutathione declined for 24 h after exercise. These results suggest that a basketball match elicits moderate and relatively brief (~24-48 h) inflammatory responses, is associated with marked but short-lived performance deterioration, but is less stressful than other intermittent-type sports. PMID- 24479465 TI - Occupational exposure to crystalline silica at Alberta work sites. AB - Although crystalline silica has been recognized as a health hazard for many years, it is still encountered in many work environments. Numerous studies have revealed an association between exposure to respirable crystalline silica and the development of silicosis and other lung diseases including lung cancer. Alberta Jobs, Skills, Training and Labour conducted a project to evaluate exposure to crystalline silica at a total of 40 work sites across 13 industries. Total airborne respirable dust and respirable crystalline silica concentrations were quite variable, but there was a potential to exceed the Alberta Occupational Exposure Limit (OEL) of 0.025 mg/m(3) for respirable crystalline silica at many of the work sites evaluated. The industries with the highest potentials for overexposure occurred in sand and mineral processing (GM 0.090 mg/m(3)), followed by new commercial building construction (GM 0.055 mg/m(3)), aggregate mining and crushing (GM 0.048 mg/m(3)), abrasive blasting (GM 0.027 mg/m(3)), and demolition (GM 0.027 mg/m(3)). For worker occupations, geometric mean exposure ranged from 0.105 mg/m(3) (brick layer/mason/concrete cutting) to 0.008 mg/m(3) (dispatcher/shipping, administration). Potential for GM exposure exceeding the OEL was identified in a number of occupations where it was not expected, such as electricians, carpenters and painters. These exposures were generally related to the specific task the worker was doing, or arose from incidental exposure from other activities at the work site. The results indicate that where there is a potential for activities producing airborne respirable crystalline silica, it is critical that the employer include all worker occupations at the work site in their hazard assessment. There appears to be a relationship between airborne total respirable dust concentration and total respirable dust concentrations, but further study is require to fully characterize this relationship. If this relationship holds true, it may provide a useful hazard assessment tool for employers by which the potential for exposure to airborne respirable silica at the work site can be more easily estimated. PMID- 24479466 TI - The role of transplant-related stressors and social support in the development of anxiety among renal transplant recipients: the direct and buffering effects. AB - Several studies have shown a relevant presence of anxiety feelings among renal transplant patients. This study examines the impact of transplant-related stress and social support on anxiety. Two hypotheses were examined: H1: High transplant related stressors and low social support are related to high anxiety (additive hypothesis); H2: Social support moderates the detrimental impact of transplant related stressors on anxiety (buffer hypothesis). One hundred and four kidney transplant recipients (54% male), with a mean age of 50.8 (SD = 12.6), volunteered to participate in a cross-sectional study that included a face-to face interview and several self-administered scales. Hierarchical regression analyses indicated that higher transplant-related stressors are associated with higher levels of anxiety (F change (2, 92) = 17.4, p < .001, ?R(2) = 24%), but, contrary to our prediction, social support was not directly related with anxiety. However, social support has a moderating effect on the relationship between high transplant-related stressors and anxiety (F change (1, 91) = 5.2, p < .05, ?R(2) = 3%). The results are consistent with the hypothesis that social support has a buffering role on the patients' distress following renal transplantation and suggest that their psychological well-being could benefit from enhancing the perception of social support in post-operative care. PMID- 24479467 TI - Highly diastereoselective preparation of aldol products using new functionalized allylic aluminum reagents. AB - Chloro-substituted triethylsilyl enol ethers derived from cyclohexanone and related ketones are converted with aluminum powder in the presence of indium trichloride to functionalized allylic aluminum reagents which represent a new type of synthetic equivalent of metal enolates. These allylic organometallics undergo highly diastereoselective additions to aldehydes and methyl aryl ketones, giving aldol products with a beta-quaternary center. PMID- 24479468 TI - Pyrano-isoflavans from Glycyrrhiza uralensis with antibacterial activity against Streptococcus mutans and Porphyromonas gingivalis. AB - Continuing investigation of fractions from a supercritical fluid extract of Chinese licorice (Glycyrrhiza uralensis) roots has led to the isolation of 12 phenolic compounds, of which seven were described previously from this extract. In addition to these seven metabolites, four known components, 1 methoxyerythrabyssin II (4), 6,8-diprenylgenistein, gancaonin G (5), and isoglycyrol (6), and one new isoflavan, licorisoflavan C (7), were characterized from this material for the first time. Treatment of licoricidin (1) with palladium chloride afforded larger amounts of 7 and also yielded two new isoflavans, licorisoflavan D (8), which was subsequently detected in the licorice extract, and licorisoflavan E (9). Compounds 1-9 were evaluated for their antibacterial activities against the cariogenic Streptococcus mutans and the periodontopathogenic Porphyromonas gingivalis. Licoricidin (1), licorisoflavan A (2), and 7-9 showed antibacterial activity against P. gingivalis (MICs of 1.56 12.5 MUg/mL). The most potent activity against S. mutans was obtained with 7 (MIC of 6.25 MUg/mL), followed by 1 and 9 (MIC of 12.5 MUg/mL). This study provides further evidence for the therapeutic potential of licorice extracts for the treatment and prevention of oral infections. PMID- 24479470 TI - Relevant medical education. PMID- 24479471 TI - Biochemistry: retrospect and prospect. AB - At The Middlesex, efforts are made to tailor basic biochemical material so that it fits naturally into the clinical context. In the past, lectures and tutorials have been enlivened using simulations and a problem-solving 'information game', but traditional methods, especially if modernized, still have an important part to play. PMID- 24479469 TI - PCR-based isolation of multigene families: lessons from the avian MHC class IIB. AB - The amount of sequence data available today highly facilitates the access to genes from many gene families. Primers amplifying the desired genes over a range of species are readily obtained by aligning conserved gene regions, and laborious gene isolation procedures can often be replaced by quicker PCR-based approaches. However, in the case of multigene families, PCR-based approaches bear the often ignored risk of incomplete isolation of family members. This problem is most prominent in gene families with highly variable and thus unpredictable number of gene copies among species, such as in the major histocompatibility complex (MHC). In this study, we (i) report new primers for the isolation of the MHC class IIB (MHCIIB) gene family in birds and (ii) share our experience with isolating MHCIIB genes from an unprecedented number of avian species from all over the avian phylogeny. We report important and usually underappreciated problems encountered during PCR-based multigene family isolation and provide a collection of measures to help significantly improving the chance of successfully isolating complete multigene families using PCR-based approaches. PMID- 24479472 TI - Review a Curriculum using a Pathway Analysis of Learning Difficulties. AB - This paper describes a simple and logical method for reviewing the medical curriculum by detecting and analysing deficiencies in learning. While designed for a conventional medical curriculum it could easily be adopted for different situations. PMID- 24479473 TI - Use of Simulation Techniques in an Intermediate Course Linking up Preclinical and Clinical Studies. PMID- 24479474 TI - Jottings. PMID- 24479475 TI - Radical versus Traditional Schools: Are the Graduates Different? AB - Role models and the hidden curriculum are a much more powerful learning force than is the formal curriculum. A comparison of the radical versus the traditional medical schools suggests that both educational models may be avoiding questions about the strongest educational influence on their students. PMID- 24479476 TI - Learning preference inventory. AB - In this series we print evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to adapt such instruments for your own purposes. The feature this issue was developed by Professor A. G. Rezler, PH.D, Center for Educational Development, University of Illinois in Chicago, 808 South Wood, Chicago, Illinois 60612, USA, from whom the inventory can be obtained, together with a set of answer sheets (not shown here). PMID- 24479477 TI - A Clinical Guide to Coping When the Film Projector Won't Work. PMID- 24479479 TI - Instructional objectives in child health. PMID- 24479483 TI - Kinematic determinants of weapon velocity during the fencing lunge in experienced epee fencers. AB - The lunge is the most common attack in fencing, however there is currently a paucity of published research investigating the kinematics of this movement. The aim of this study was to investigate if kinematics measured during the epee fencing lunge had a significant effect on sword velocity at touch and whether there were any key movement tactics that produced the maximum velocity. Lower extremity kinematic data were obtained from fourteen right handed club epee fencers using a 3D motion capture system as they completed simulated lunges. A forward stepwise multiple linear regression was performed on the data. The overall regression model yielded an Adj R2 of 0.74, p <= 0.01. The results show that the rear lower extremity's knee range of motion, peak hip flexion and the fore lower extremity's peak hip flexion all in the sagittal plane were significant predictors of sword velocity. The results indicate that flexion of the rear extremity's knee is an important predictor, suggesting that the fencer sits low in their stance to produce power during the lunge. Furthermore it would appear that the magnitude of peak flexion of the fore extremity's hip was a significant indicator of sword velocity suggesting movement of fore limbs should also be considered in lunge performance. PMID- 24479481 TI - Expression and function of visfatin (Nampt), an adipokine-enzyme involved in inflammatory pathways of osteoarthritis. AB - INTRODUCTION: Visfatin is an adipokine that may be involved in intertissular joint communication in osteoarthritis (OA). With a homodimeric conformation, it exerts nicotinamide phosphoribosyltransferase (Nampt) enzymatic activity, essential for nicotinamide adenine dinucleotide biosynthesis. We examined the tissular origin and conformation of visfatin/Nampt in human OA joints and investigated the role of visfatin/Nampt in chondrocytes and osteoblasts by studying Nampt enzymatic activity. METHODS: Synovium, cartilage and subchondral bone from human OA joints were used for protein extraction or incubated for 24 hours in serum-free media (conditioned media), and synovial fluid was obtained from OA patients. Visfatin/Nampt expression in tissular extracts and conditioned media was evaluated by western blot and enzyme-linked immunosorbent assay (ELISA), respectively. Nampt activity was assessed in OA synovium by colorimetric assay. Primary cultures of murine chondrocytes and osteoblasts were stimulated with visfatin/Nampt and pretreated or not with APO866, a pharmacologic inhibitor of Nampt activity. The effect on cytokines, chemokines, growth factors and hypertrophic markers expression was examined by quantitative reverse transcriptase polymerase chain reaction and/or ELISA. RESULTS: In tissular explants, conditioned media and synovial fluid, visfatin/Nampt was found as a homodimer, corresponding to the enzymatically active conformation. All human OA joint tissues released visfatin/Nampt (synovium: 628 +/- 106 ng/g tissue; subchondral bone: 195 +/- 26 ng/g tissue; cartilage: 152 +/- 46 ng/g tissue), with significantly higher level for synovium (P <0.0005). Nampt activity was identified ex vivo in synovium. In vitro, visfatin/Nampt significantly induced the expression of interleukin 6, keratinocyte chemoattractant and monocyte chemoattractant protein 1 in chondrocytes and osteoblasts. APO866 decreased the mRNA and protein levels of these pro-inflammatory cytokines in the two cell types (up to 94% and 63% inhibition, respectively). Levels of growth factors (vascular endothelial growth factor, transforming growth factor beta) and hypertrophic genes were unchanged with treatment. CONCLUSION: Visfatin/Nampt is released by all human OA tissues in a dimeric enzymatically active conformation and mostly by the synovium, which displays Nampt activity. The Nampt activity of visfatin is involved in chondrocyte and osteoblast activation, so targeting this enzymatic activity to disrupt joint tissue interactions may be novel in OA therapy. PMID- 24479484 TI - Exploring the conformational space of cysteine by matrix isolation spectroscopy combined with near-infrared laser induced conformational change. AB - Six conformers of alpha-cysteine were identified by matrix isolation IR spectroscopy combined with NIR laser irradiation. Five of these conformers are identical with the five out of six conformers that have recently been identified by microwave spectroscopy. The sixth conformer observed in the present study is a short-lived conformer, which decays by H-atom tunneling; its half-life in a 12 K N2 matrix is (1.1 +/- 0.5) * 10(3) s. This study proves that matrix isolation IR spectroscopy combined with NIR laser irradiation is a suitable method to identify conformers of a complex system for which computations predict several dozens of conformers, and that the reliability of this method for conformational assignment is comparable to that of microwave spectroscopy. PMID- 24479485 TI - Association between chilli food habits with iron status and insulin resistance in a Chinese population. AB - Some studies have indicated that the consumption of chilli-containing foods can influence iron absorption and affect serum insulin and glucose concentrations, which may help to alleviate diabetes or prediabetes. The objective of this study was to explore the relationship between chilli food habits with iron status and insulin resistance in the Chinese population. Fasting blood samples, anthropometric data, and chilli food habit data collected from 8433 adults (aged 18 to 99), in 2009, as part of the China Health and Nutrition Survey, a large scale longitudinal, household-based survey in China. Chilli food habits were assessed using chilli food eating frequencies (no eating, sometimes eating, often eating, and usually eating) and chilli food types (a little bit hot, moderately hot, and very hot). Fasting serum ferritin, insulin, and fasting plasma glucose were also measured. The homeostasis model assessment of insulin resistance (HOMA IR) was used to estimate insulin resistance. Compared with the chilli-eating group, the no eating group had higher HOMA-IR levels for both men and women (P<.05). There were significant differences in HOMA-IR (P<.05) for both men and women and in ferritin (P<.001) for women according to different chilli food types. However, there was no significant difference in the ferritin level and HOMA-IR components for different chilli food eating frequencies in both sex groups. Chilli food habits, especially the different hotness levels of chilli food, were associated with iron status and insulin resistance in the Chinese population. Additional studies are needed to elucidate mechanisms of action and to establish causal inference. PMID- 24479486 TI - beta2-adrenergic agonists modulate TNF-alpha induced astrocytic inflammatory gene expression and brain inflammatory cell populations. AB - BACKGROUND: The NF-kappaB signaling pathway orchestrates many of the intricate aspects of neuroinflammation. Astrocytic beta2-adrenergic receptors have emerged as potential regulators in central nervous system inflammation and are potential targets for pharmacological modulation. The aim of this study was to elucidate the crosstalk between astrocytic beta2-adrenergic receptors and the TNF-alpha induced inflammatory gene program. METHODS: Proinflammatory conditions were generated by the administration of TNF-alpha. Genes that are susceptible to astrocytic crosstalk between beta2-adrenergic receptors (stimulated by clenbuterol) and TNF-alpha were identified by qPCR-macroarray-based gene expression analysis in a human 1321 N1 astrocytoma cell line. Transcriptional patterns of the identified genes in vitro were validated by RT-PCR on the 1321 N1 cell line as well as on primary rat astrocytes. In vivo expression patterns were examined by intracerebroventricular administration of clenbuterol and/or TNF alpha in rats. To examine the impact on the inflammatory cell content of the brain we performed extensive FACS analysis of rat brain immune cells after intracerebroventricular clenbuterol and/or TNF-alpha administration. RESULTS: Parallel transcriptional patterns in vivo and in vitro confirmed the relevance of astrocytic beta2-adrenergic receptors as modulators of brain inflammatory responses. Importantly, we observed pronounced effects of beta2-adrenergic receptor agonists and TNF-alpha on IL-6, CXCL2, CXCL3, VCAM1, and ICAM1 expression, suggesting a role in inflammatory brain cell homeostasis. Extensive FACS-analysis of inflammatory cell content in the brain demonstrated that clenbuterol/TNF-alpha co-administration skewed the T cell population towards a double negative phenotype and induced a shift in the myeloid brain cell population towards a neutrophilic predominance. CONCLUSIONS: Our results show that astrocytic beta2-adrenergic receptors are potent regulators of astrocytic TNF-alpha-activated genes in vitro and in vivo, and ultimately modulate the molecular network involved in the homeostasis of inflammatory cells in the central nervous system. Astrocytic beta2-adrenergic receptors and their downstream signaling pathway may serve as potential targets to modulate neuroinflammatory responses. PMID- 24479487 TI - The natural insect peptide Neb-colloostatin induces ovarian atresia and apoptosis in the mealworm Tenebrio molitor. AB - BACKGROUND: The injection of Neb-colloostatin into T. molitor females causes gonadoinhibitory effects on ovarian development. This peptide inhibits intercellular space formation (patency) in follicular epithelium and results in slowed vitellogenesis, delayed ovulation, reduced number of eggs laid and presumably cell death in the terminal follicles. However, as does the form of cell death in the terminal follicle, the mode of action of Neb-colloostatin remains unknown. RESULTS: We tested Neb-colloostatin for a sterilizing effect on females of Tenebrio molitor. We report that injection of nanomolar doses of Neb colloostatin induce ovarian follicle atresia in 4-day old females during their first gonadotropic cycle. Light microscope observations revealed morphological changes in the ovary: after Neb-colloostatin injection the terminal oocytes are significantly smaller and elicit massive follicle resorption, but the control terminal follicles possess translucent ooplasm in oocytes at different stages of vitellogenesis. A patency is visible in follicular epithelium of the control vitellogenic oocytes, whereas peptide injection inhibits intercellular space formation and, in consequence, inhibits vitellogenesis. Confocal and electron microscope examination showed that peptide injection causes changes in the morphology indicating death of follicular cells. We observed F-actin cytoskeleton disorganization, induction of caspase activity, changes in chromatin organization and autophagic vacuole formation. Moreover, the apical cytoplasm of follicular cells is filled with numerous free ribosomes, probably indicating a higher demand for protein biosynthesis, especially in preparation for autophagic vacuole formation. On the other hand, the process of polyribosomes formation is inhibited, indicating the contributing effect of this hormone. CONCLUSION: Neb colloostatin induces atresia in the mealworm ovary. Degeneration of T. molitor follicles includes changes in morphology and viability of follicular cells, and oosorption as a consequence of these changes. PMID- 24479490 TI - Nutrition in early life and the programming of adult disease: a review. AB - Foetal development and infancy are life stages that are characterised by rapid growth, development and maturation of organs and systems. Variation in the quality or quantity of nutrients consumed by mothers during pregnancy, or infants during the first year of life, can exert permanent and powerful effects upon developing tissues. These effects are termed 'programming' and represent an important risk factor for noncommunicable diseases of adulthood, including the metabolic syndrome and coronary heart disease. This narrative review provides an overview of the evidence-base showing that indicators of nutritional deficit in pregnancy are associated with a greater risk of type-2 diabetes and cardiovascular mortality. There is also a limited evidence-base that suggests some relationship between breastfeeding and the timing and type of foods used in weaning, and disease in later life. Many of the associations reported between indicators of early growth and adult disease appear to interact with specific genotypes. This supports the idea that programming is one of several cumulative influences upon health and disease acting across the lifespan. Experimental studies have provided important clues to the mechanisms that link nutritional challenges in early life to disease in adulthood. It is suggested that nutritional programming is a product of the altered expression of genes that regulate the cell cycle, resulting in effective remodelling of tissue structure and functionality. The observation that traits programmed by nutritional exposures in foetal life can be transmitted to further generations adds weight the argument that heritable epigenetic modifications play a critical role in nutritional programming. PMID- 24479488 TI - Integrative genomic analysis identifies epigenetic marks that mediate genetic risk for epithelial ovarian cancer. AB - BACKGROUND: Both genetic and epigenetic factors influence the development and progression of epithelial ovarian cancer (EOC). However, there is an incomplete understanding of the interrelationship between these factors and the extent to which they interact to impact disease risk. In the present study, we aimed to gain insight into this relationship by identifying DNA methylation marks that are candidate mediators of ovarian cancer genetic risk. METHODS: We used 214 cases and 214 age-matched controls from the Mayo Clinic Ovarian Cancer Study. Pretreatment, blood-derived DNA was profiled for genome-wide methylation (Illumina Infinium HumanMethylation27 BeadArray) and single nucleotide polymorphisms (SNPs, Illumina Infinium HD Human610-Quad BeadArray). The Causal Inference Test (CIT) was implemented to distinguish CpG sites that mediate genetic risk, from those that are consequential or independently acted on by genotype. RESULTS: Controlling for the estimated distribution of immune cells and other key covariates, our initial epigenome-wide association analysis revealed 1,993 significantly differentially methylated CpGs that between cases and controls (FDR, q < 0.05). The relationship between methylation and case-control status for these 1,993 CpGs was found to be highly consistent with the results of previously published, independent study that consisted of peripheral blood DNA methylation signatures in 131 pretreatment cases and 274 controls. Implementation of the CIT test revealed 17 CpG/SNP pairs, comprising 13 unique CpGs and 17 unique SNPs, which represent potential methylation-mediated relationships between genotype and EOC risk. Of these 13 CpGs, several are associated with immune related genes and genes that have been previously shown to exhibit altered expression in the context of cancer. CONCLUSIONS: These findings provide additional insight into EOC etiology and may serve as novel biomarkers for EOC susceptibility. PMID- 24479491 TI - Annexin A4 is a promising therapeutic target for the treatment of platinum resistant cancers. AB - INTRODUCTION: Platinum drugs are widely used for the treatment of testicular, bladder, ovarian, colorectal, lung and prostate cancers. With regard to ovarian cancer in particular, the prognosis is poor for tumours that are (or have become) platinum-resistant. Determining the mechanism underlying platinum resistance may aid in the identification of therapeutic targets for the treatment of platinum resistant tumours. AREAS COVERED: This review gives an overview of the characteristics and functions of Annexin (Anx) A4, the mechanism of Anx A4 induced platinum resistance, the association between platinum resistance and platinum transporters, recent reports that Anx A4 overexpression promotes the efflux of platinum drugs via platinum transporters and the association between other Anxs and chemoresistance. The reader will gain an understanding of recent studies on the mechanism of Anx A4-induced chemoresistance. Anx A4 represents a therapeutic target for the treatment of Anx A4-overexpressing platinum-resistant tumours. EXPERT OPINION: Anx A4 is overexpressed in ovarian clear cell carcinoma (CCC), and enhanced Anx A4 expression induces platinum resistance. Recent studies showed that Anx A4 is also associated with platinum resistance in cancers other than ovarian CCC. Furthermore, other Anxs are reportedly associated with chemoresistance, suggesting a relationship between the Anx family and chemoresistance. PMID- 24479492 TI - Biomarkers in the field of obesity and its related comorbidities. AB - INTRODUCTION: The prevalence of obesity has increased dramatically in the last decades both in children and adults and is now considered a major health problem. It is associated with numerous comorbidities such as hypertension, dyslipidemia, diabetes and subsequent cardiovascular disease (CVD). One of the mechanisms that connect obesity with these comorbidities is the secretion of so-called adipocytokines or adipokines by the adipose tissue itself. Most adipokines with pro-inflammatory properties are overproduced with increasing adiposity, whereas some adipokines with anti-inflammatory or insulin-sensitizing properties, like adiponectin, are decreased. This dysregulation of adipokines production may promote obesity-linked metabolic disorders and CVD. Except adipokines a wide complex network of chemicals balances pro-inflammatory and anti-inflammatory effects. AREAS COVERED: In this review, we summarize the role of various adipokines and other chemicals associated with obesity and its related cardiometabolic comorbidities, with a special focus on recent evidence showing their potential role as biomarkers whose expression are indicative of obesity and its complications. EXPERT OPINION: Biomarkers associated with obesity, type 2 diabetes (T2D) and CVD could prove beneficial for early identification, proper treatment and good life assurance. Unfortunately, the complexity of biological pathways interactions is such that further research is necessary before any of these markers could reach an accurate diagnostic value. PMID- 24479493 TI - Can IFN-gamma be a therapeutic target in Guillain-Barre syndrome? AB - INTRODUCTION: Guillain-Barre syndrome (GBS) is an immune-mediated acute inflammatory disorder of the PNS in humans characterized by inflammatory infiltration and damage to myelin and axon. Experimental autoimmune neuritis (EAN) is a useful animal model for studying the pathogenesis and treatment of GBS. Immunocompetent cells together with cytokines produced by various cells contribute to the inflammatory process of GBS and EAN by acting as mediators or effectors. AREAS COVERED: Both GBS and EAN have long been attributed to T helper (Th) 1 cell-mediated autoimmune disorders. IFN-gamma acts as a central mediator of Th1-mediated autoimmune disorders by deflecting the immune response toward a Th1 phenotype by inducing the differentiation of T cells to a Th1 phenotype and inhibiting the development of Th2 cells in autoimmune disorders such as GBS. In this review, we present an overview of current knowledge on the inflammatory and immunoregulatory role of IFN-gamma in GBS and EAN, which is important for evaluating whether IFN-gamma can become a potential therapeutic target in GBS. EXPERT OPINION: Analysis of immunopathogenesis of GBS and EAN revealed the significance of IFN-gamma in both diseases, even though the complex mechanism of the delicate modulation of the cytokine is still under debate. More work needs to be done to rule out its potential in immunoregulatory function and pave the way for new therapeutic strategies for GBS. PMID- 24479494 TI - HMGB1 as a therapeutic target for sepsis: it's all in the timing! AB - Morbidity and mortality from severe sepsis remain high, despite decades of research and improvements in intensive care unit (ICU) care. There have been over 100 failed clinical trials of biological response modifiers aimed at single therapeutic targets, mostly to suppress the early pro-inflammatory responses. In the last decade, extracellular HMGB1 has emerged as a late mediator of sepsis in murine sepsis models, whose blockade improves mortality and has a wider therapeutic window than previous efforts. Although this review promulgates the use of HMGB1 inhibitor as a therapeutic target, it should be recognized that it may not be an optimal approach to the early systemic inflammatory response syndrome (SIRS) response and cytokine storm, but rather for those patients who survive their cytokine storm and present with a persistent inflammatory, immunosuppressive and catabolism response (PICS). With earlier implementation of evidence-based best care principles for treating sepsis, fewer patients are dying from early septic shock, and there is an endemic increase in sepsis survivors with dismal long-term outcomes. These patients have ongoing inflammatory processes that may well be driven by the late and continued release of HMGB1 and other damage-associated molecular patterns receptors (DAMPRs). HMGB1 therapeutics, whether antibodies or natural herbal approaches, may be one novel approach for targeting not the early, but the late persistent inflammation of sepsis survivors. PMID- 24479495 TI - Perception of effort in morning-type cyclists is lower when exercising in the morning. AB - A recent study found that South African endurance athletes are likely to be morning-types and carry the PER3(5) allele, which has been associated with a preference for mornings. The aim of this study was to measure the response of morning-type cyclists to a standardised bout of exercise performed at different times of the day. Participants ncluded 20 trained male cyclists (age: 39.8 +/- 7.7 years, VO2max: 51.0 +/- 7.0 ml . kg(-1) . min(-1), training: 166 +/- 98 km . wk(-1)), categorised as morning-types (mean Horne-Ostberg score: 68.3 +/- 5.5) and carrying the PER3(5) allele. They completed a 17-min sub-maximal cycling test at 60%, 80% and 90% of maximum heart rate (HRmax) at 06h00, 10h00, 14h00, 18h00 and 22h00. These morning-type cyclists reported higher ratings of perceived exertion when cycling at 60% (P = 0.044), 80% (P < 0.001) and 90% (P < 0.001) of HRmax during the evening (18h00 and 22h00) compared to the other sessions (0600, 10h00 and 14h00). This was despite absolute power output, speed and cadence displaying no time-of-day differences. Thus, morning-type cyclists perceive the same relative intensity workload to be harder in the evening compared to the morning. This may have implications for both training and competition scheduling, and highlights the importance of considering individual chronotype in sports in which diurnal variation may be relevant to training and competition. PMID- 24479497 TI - Editorials. PMID- 24479496 TI - Compositing polyetherimide with polyfluorene wrapped carbon nanotubes for enhanced interfacial interaction and conductivity. AB - A novel approach to chemically functionalize multiwalled carbon nanotubes (MWCNTs) for making superior polyetherimide (PEI) nanocomposites with polyfluorene polymer is presented. In this approach, MWCNTs are non-covalently functionalized with poly(9,9-dioctyfluorenyl-2,7-diyl) (PFO) through pi-pi stacking as confirmed by UV-vis, fluorescence, and Raman spectra. Atomic force microscopy as well as scanning and transmission electron microscopy shows the PFO coated MWCNTs, which provides excellent dispersion of the latter in both solvent and PEI matrix. The strong interaction of PFO with PEI chains, as evidenced from fluorescence spectra, supports the good adhesion of dispersed MWCNTs to PEI leading to stronger interfacial interactions. As a result, the addition of as little as 0.25 wt % of modified MWCNTs to PEI matrix can strongly improve the mechanical properties of the composite (increase of 46% in storage modulus). Increasing the amount of MWCNTs to 2.0 wt % (0.5 wt % PFO loading) affords a great increase of 119% in storage modulus. Furthermore, a sharp decrease of 12 orders of magnitude in volume resistivity of PEI composite is obtained with only 0.5 wt % of PFO modified MWCNT. PMID- 24479498 TI - Plan and conduct programme evaluation. AB - This article describes the aim of programme evaluation and the steps involved in its implementation. Various methods of evaluation are summarized and their relevance in different situations addressed. Advice is offered on the analysis and presentation of data. PMID- 24479499 TI - Teaching gerontology in australia. AB - This article describes some general objectives and strategies for teaching health care of the elderly in medical schools in Australia. Advice is offered on the approaches most likely to be successful, and the very limited role of lectures is underlined. PMID- 24479500 TI - Community medicine. AB - It has become increasingly apparent that traditional medical education serves badly the need of many developing countries to provide effective health care for widely dispersed and often poor communities. This article describes a training programme developed in Iraq to provide final-year medical students with stimulating practical experience in community health care. PMID- 24479501 TI - The Effect of Introducing Role-play in a Practical on Communicating with Terminal Cancer Patients. AB - A practical on communicating with terminal cancer patients had been previously evaluated and found to be a useful and efficient teaching method. This exercise evaluates the introduction of a role-playing aspect. The role-playing model elicited greater changes in students' views and more students felt that they learned something from it than from the standard presentation. PMID- 24479502 TI - Role of grammatical clues in multiple choice questions: an empirical study. AB - Some dangers of the use of multiple choice questions are described. In particular, carefully selected questions drawn from published sources contain grammatical clues which enable examinees with a particular sort of linguistic knowledge to gain extra marks. PMID- 24479503 TI - The nordic Federation for medical education. PMID- 24479507 TI - How to conduct a clinical viva voce examination. PMID- 24479506 TI - The politics of partnership. PMID- 24479508 TI - Factors influencing the airborne capture of respirable charged particles by surfactants in water sprays. AB - This research measured the effects of particle diameter, surfactant-containing spray solution, and particle charge on the capture of respirable particles by surfactant-containing water spray droplets. Polystyrene latex particles with diameters of 0.6, 1.0, or 2.1 MUm were generated in a wind tunnel. Particles were given either a neutralized, unneutralized, net positive, or net negative charge, and then were captured as they passed through sprays containing anionic, cationic, or nonionic surfactant. The remaining particles were sampled, charge separated, and counted with the sprays on and off at varying voltage levels to assess collection efficiency. Overall efficiencies were measured for particles with all charge levels, as well as efficiencies for particles with specific charge levels. The overall collection efficiency significantly increased with increasing particle diameter. Collection efficiencies of 21.5% +/- 9.0%, 58.8% +/ 12.5%, and 86.6% +/- 43.5% (Mean +/- SD) were observed for particles 0.6, 1.0, and 2.1 MUm in diameter, respectively. The combination of surfactant classification and concentration also significantly affected both overall spray collection efficiency and collection efficiency for particles with specific charge levels. Ionic surfactant-containing sprays had the best performance for charged particles with the opposite sign of charge but the worst performance for charged particles with the same sign of charge, while nonionic surfactant containing spray efficiently removed particles carrying relatively few charges. Particle charge level impacted the spray collection efficiency. Highly charged particles were removed more efficiently than weakly charged particles. PMID- 24479509 TI - Dinuclear metallacycles with single M-O(H)-M bridges [M = Fe(II), Co(II), Ni(II), Cu(II)]: effects of large bridging angles on structure and antiferromagnetic superexchange interactions. AB - The reactions of M(ClO4)2.xH2O and the ditopic ligands m-bis[bis(1 pyrazolyl)methyl]benzene (Lm) or m-bis[bis(3,5-dimethyl-1 pyrazolyl)methyl]benzene (Lm*) in the presence of triethylamine lead to the formation of monohydroxide-bridged, dinuclear metallacycles of the formula [M2(MU OH)(MU-Lm)2](ClO4)3 (M = Fe(II), Co(II), Cu(II)) or [M2(MU-OH)(MU-Lm*)2](ClO4)3 (M = Co(II), Ni(II), Cu(II)). With the exception of the complexes where the ligand is Lm and the metal is copper(II), all of these complexes have distorted trigonal bipyramidal geometry around the metal centers and unusual linear (Lm*) or nearly linear (Lm) M-O-M angles. For the two solvates of [Cu2(MU-OH)(MU Lm)2](ClO4)3, the Cu-O-Cu angles are significantly bent and the geometry about the metal is distorted square pyramidal. All of the copper(II) complexes have structural distortions expected for the pseudo-Jahn-Teller effect. The two cobalt(II) complexes show moderate antiferromagnetic coupling, -J = 48-56 cm(-1), whereas the copper(II) complexes show very strong antiferromagnetic coupling, -J = 555-808 cm(-1). The largest coupling is observed for [Cu2(MU-OH)(MU Lm*)2](ClO4)3, the complex with a Cu-O-Cu angle of 180 degrees , such that the exchange interaction is transmitted through the dz(2) and the oxygen s and px orbitals. The interaction decreases, but it is still significant, as the Cu-O-Cu angle decreases and the character of the metal orbital becomes increasingly d(x(2)-y(2)). These intermediate geometries and magnetic interactions lead to spin Hamiltonian parameters for the copper(II) complexes in the EPR spectra that have large E/D ratios and one g matrix component very close to 2. Density functional theory calculations were performed using the hybrid B3LYP functional in association with the TZVPP basis set, resulting in reasonable agreement with the experiments. PMID- 24479510 TI - VIP Barcoding: composition vector-based software for rapid species identification based on DNA barcoding. AB - Species identification based on short sequences of DNA markers, that is, DNA barcoding, has emerged as an integral part of modern taxonomy. However, software for the analysis of large and multilocus barcoding data sets is scarce. The Basic Local Alignment Search Tool (BLAST) is currently the fastest tool capable of handling large databases (e.g. >5000 sequences), but its accuracy is a concern and has been criticized for its local optimization. However, current more accurate software requires sequence alignment or complex calculations, which are time-consuming when dealing with large data sets during data preprocessing or during the search stage. Therefore, it is imperative to develop a practical program for both accurate and scalable species identification for DNA barcoding. In this context, we present VIP Barcoding: a user-friendly software in graphical user interface for rapid DNA barcoding. It adopts a hybrid, two-stage algorithm. First, an alignment-free composition vector (CV) method is utilized to reduce searching space by screening a reference database. The alignment-based K2P distance nearest-neighbour method is then employed to analyse the smaller data set generated in the first stage. In comparison with other software, we demonstrate that VIP Barcoding has (i) higher accuracy than Blastn and several alignment-free methods and (ii) higher scalability than alignment-based distance methods and character-based methods. These results suggest that this platform is able to deal with both large-scale and multilocus barcoding data with accuracy and can contribute to DNA barcoding for modern taxonomy. VIP Barcoding is free and available at http://msl.sls.cuhk.edu.hk/vipbarcoding/. PMID- 24479511 TI - [Positive sentinel node in breast cancer - when and why also opt for axillary dissection?]. AB - One of the central concerns of contemporary mammary surgery is to verify the actual need for axillary dissection (AD) in patients with early breast cancer and positive sentinel lymph node biopsy. Several studies have addressed this issue (ASOCOG Z0011, IBCSG 23-01, MIRROR, EORTC AMAROS). So far, the preliminary results of the ASOCOG Z0011 trial with a median follow-up of 6.3 years and the results of the IBCSG 23-01 trial with a median follow-up of 5 years have been published. The conclusions of both randomized studies have implied that under specific circumstances, there is no significant difference in the local or regional recurrence between patients who had undergone completion AD compared to the patients in whom AD had been omitted. This article summarizes the current knowledge regarding indications for AD in patients with positive sentinel nodes. Key words: breast cancer - sentinel lymph node biopsy - axillary lymph node dissection - ACOSOG Z0011 trial. PMID- 24479512 TI - [Overall survival: is it an objective endpoint for assessing the quality of surgical treatment for colorectal cancer?]. AB - The monitoring of the quality of surgical treatment is the basic condition for improving the results of medical care. There are various endpoints available to assess the quality of surgical care. Survival time traditionally represents the key parameter for patients with colorectal cancer. Overall survival should not, however, be the only standard accepted measure of surgical care quality. Disease free survival in the early stages, neoadjuvant or adjuvant settings has been validated as a better option. Progression free survival, alone or aggregated with the quality of life, provides a useful, more sensitive parameter for advanced or metastatic colorectal cancer. The selection of appropriate, valid end-points is the basic prerequisite for improving the quality of surgical care for patients with colorectal cancer. PMID- 24479513 TI - [Repeated resection for recurrent pulmonary metastases]. AB - INTRODUCTION: Repeated pulmonary resections are predominantly used in sarcomas, colorectal cancer, Grawitz tumours, and at a young age in general. Patients with the recurrence of pulmonary metastases within a period of six months have a poor prognosis. MATERIAL AND METHODS: During the period from I/1997 to XII/2011, a total of 165 operations were performed in 149 patients. 11patients had multiple pulmonary resections. According to histological origin, sarcomas were found in 6 cases, Grawitz tumours in 2 cases, Schwannoma malignum in 1 case and laryngeal carcinoma in 1 case. There was synovialosarcoma, osteosarcoma, rhabdomyosarcoma, alveolar sarcoma and uterine sarcoma in the group of sarcomas. RESULTS: In our retrospective study, the most commonly used approach was muscle-sparing vertical thoracotomy in 14 patients, posterolateral thoracotomy in 8 patients, VATS in 3 patients and clamshell thoracotomy in 3 patients. We performed 22 extraanatomic resections - of which 3 times VATS, 6 times lobectomy (of which 1 completion pneumonectomy). We observed complications in 6 cases (small air leak in 3 patients, wound infection in 3 patients) in the postoperative period. No rethoracotomy for complications was needed, lethality was 0. The overall 5-year survival that we observed was 45.4%. CONCLUSION: Surgery is an integral part of complex oncological care. What is extremely important is strict selection of patients eligible for surgery for repeated resections and, of course, an experienced team of thoracic surgeons, but also other physicians. When performed by experienced specialists, surgical treatment of lung metastases is a safe and very useful procedure. PMID- 24479514 TI - [Minimally invasive video-assisted parathyroidectomy (MIVAP) using primary hyperparathyroidism therapy (pHPT)]. AB - INTRODUCTION: Primary hyperparathyroidism (pHPT) is a general calcium, phosphate and bone metabolism malfunction due to increased secretion of the parathyroid hormone over a substantial period of time. Causal treatment is a surgical procedure - parathyroidectomy. MATERIAL AND METHODS: A retrospective study of patients who underwent surgery was conducted in the department of surgery at the Atlas Hospital in Zlin between 2005 and 2011. In this period, 2555 patients were operated on for thyroid and parathyroid gland disease. 182 of these patients (7.1%) had hyperparathyroidism. There were 80 standard parathyroidectomies, 82 MIVAPs and 20 MIRPs (minimally invasive radio-guided parathyroidectomy). RESULTS: In the study, 82 patients were operated on using the MIVAP technique. 78 (95.1%) had a parathyroid adenoma, 2 (2.4%) had hyperplasia, 2 (2.4%) had a standard body. Using the MIVAP technique, 75 parathyroid gland adenomas were found in 72 patients, 3 patients (3.6%) had a double adenoma. Conversion was performed in 10 patients (12.2%). During standard revision, an adenoma was found intraparenchymatously in 4 cases (4.9%), in 2 cases the adenoma was removed during standard revision. There was no permanent NRL paresis. 4 patients (4.9%) experienced temporary NLR paresis, MIVAP was successful in 72 patients (87.8%), 6 adenomas were removed during conversion; currently, all these patients have normal levels of calcium and parathyroid hormone. No parathyroid gland adenoma was found in 2 patients (2.4%), nor was it removed using persistent pHPT. 2 patients (2.4%) with hyperplasia are being monitored for their borderline calcium and parathyroid hormone levels. CONCLUSION: MIVAP is a complex endoscopic technique which can achieve 90% success rate in patients with the location of a parathyroid gland adenoma confirmed both by ultrasound and MIBI scanning. PMID- 24479515 TI - [Improving the quality of histopathological examination of colorectal cancer specimens through standard protocol implementation]. AB - INTRODUCTION: Detailed, high-quality histopathological examination of colorectal carcinoma is an essential component of accurate disease staging. The aim of this study was to evaluate the influence of standard pathological protocol implementation on the quality of colorectal cancer specimen evaluation. MATERIAL AND METHODS: The standard protocol for colorectal cancer specimens evaluation was created on the basis of the NCCN guidelines for colorectal carcinoma and in accordance with the American Joint Committee on Cancer (AJCC) recommendations. The protocol has been implemented into the practice of University Hospital Ostrava since 1 January 2013. All patients who underwent resection for colorectal cancer in University Hospital Ostrava between 1 January 2011 and 30 June 2013 were included into the study. Histopathological reports (before and after protocol implementation) were analysed with a focus on the presence of the parameters being monitored; the differences underwent statistical analysis. RESULTS: In total, 235 patients who underwent resection of colorectal cancer (184 patients before and 51 patients after protocol implementation) were included into the study. The mean number of investigated lymph nodes was 12.5+/-6.3 (colon) and 12.6+/-6.2 (rectum) before protocol implementation. The mean number of lymph nodes was 15.0+/-4.6 (colon) and 16.8+/-6.7 (rectum) after protocol implementation; the differences are statistically significant. Before protocol implementation, the limit of 12 investigated lymph nodes was not reached in 49 patients with colon carcinoma (43.8%) and in 32 patients with rectal carcinoma (44.4%). Statistically significant improvement was noted after protocol implementation - the limit of 12 lymph nodes was not reached in 5 patients (18.5%) with colon and 4 patients (16.7%) with rectal carcinoma. There were also differences in the number of macroscopic mesorectal excision quality evaluation, circumferential resection margin reports and signs of microscopic tumour aggressiveness, in favour of histopathological reports after standard protocol implementation. CONCLUSIONS: Our retrospective study proved that the implementation of the standard protocol for colorectal cancer resection specimens leads to an improved quality of definitive histopathological reports. PMID- 24479516 TI - [Is accurate preoperative assessment of pancreatic cystic lesions possible?]. AB - INTRODUCTION: Cystic lesions of the pancreas (CLP) are of different origin and behaviour. Mucinous lesions with the risk of invasive cancer represent an important subgroup. The key point in differential diagnosis of CLP is to distinguish malignant and benign lesions and also correct indication for surgery in order to minimize the impact of serious complications after resection. Different and unsatisfying predictive values of each of the examinations make proper diagnosis challenging. We focused on overall diagnostic accuracy of preoperative imaging and analytic studies. We studied the accuracy of distinguishing between non-neoplastic vs. neoplastic and bening vs. malignant lesions. MATERIAL AND METHODS: We retrospectively analyzed all of the patients (N=72) with CLP (median of age 58 years, range 22-79) recommended for surgery. CT, EUS, ERCP, MRCP findings, cytology and aspirate analysis were used to establish preoperative diagnosis. Finally, preoperative diagnoses were compared with postoperative pathological findings to establish overall accuracy of preoperative assessment. RESULTS: During 5 years, 72 patients underwent resection for CLP. We performed 66 (92%) resection and 6 (8%) palliative procedures with 32% morbidity and 7% of one hospital stay mortality. All the patients were examined by CT and EUS. FNA was performed in 44 (61%) patients. Cytology was evaluable in 39 (88%) cases. ERCP was done in 40 (55%) patients. Pathology revealed non-neoplastic CLP in 25 (35%) and neoplastic lesions in 47 (65%) specimens. Mucinous lesions accounted for 25%. Malignant or potentially malignant CLP were found in 37 (51%) patients. Sensitivity, specificity and diagnostic accuracy of preoperative diagnosis for distinguishing between inflammatory and neoplastic, and benign and malignant was 100%, 46%, 85% and 61%, 61%, 44%, respectively. CONCLUSION: Correct and accurate preoperative assessment of CLP remains challenging. Despite the wide range of diagnostic modalities, the definitive preoperative identification of malignant or high-risk CLP is inaccurate. Because of this, a significant portion of the patients undergo pancreatic resection for benign or inflammatory lesions that are not potentially life-threatening. Possible serious complications after pancreatic surgery are the main reason for precise selection of patients with cystic affections recommended for surgery. PMID- 24479517 TI - [Retrospective analysis of short-term and mid-term results of percutaneous endovascular repair in patients with abdominal aortic aneurysm]. AB - INTRODUCTION: Endovascular abdominal aortic aneurysm repair (EVAR) is a modern and, compared to conventional open surgery, less invasive therapeutic strategy with short-term lower morbidity and mortality. The aim of our retrospective analysis was the assessment of safety, technical success, short-term and mid-term results of elective patients scheduled for total percutaneous EVAR implantation (PEVAR). MATERIAL AND METHODS: One hundred and sixteen consecutive patients (M:F 104:12, age 71+/-9 years, maximum AAA diameter 60+/-14mm) underwent elective PEVAR between January 2009 and August 2012. All the patients were treated under local anaesthesia by total percutaneous approach via femoral access. The immediate technical success of stentgraft implantation as well as the presence of 30-day and 1-year complications and the need of reintervention rate were assessed. RESULTS: In 115/116 patients (99.1%),immediate technical success of the procedure was recorded, with no need of conversion to open surgery; in 1 patient (0.9%) the performance technically failed due to unfavourable arterial anatomy. The mortality in 30-day follow-up was 2.6% (3 patients), during 1-year follow-up it amounted to 8.6% (10 patients), without causal relationship with stentgraft implantation. Overall event-free survival was 85% (98/116) without serious complications (mortality, MI, stroke, reintervention, severe ischemic complication) in the one-year follow-up period. CONCLUSION: Endovascular AAA repair is a safe and feasible method with low mortality and acceptable complication rate in patients scheduled for EVAR implantation. Percutaneous approach allows for the extension of indications also for the highest-risk group of polymorbid patients. Technical feasibility and adequate periprocedural management are essential for further reduction in adverse events after PEVAR. PMID- 24479518 TI - [Duplication of the gallbladder and cystic duct as a rare finding during cholecystectomy - a case report]. AB - Congenital anomalies of the gallbladder, the biliary tract and their vasculature are relatively common. They usually represent only anatomical variations that may not manifest clinically, but in some cases they are of fundamental importance for the surgeon as they can cause diagnostic confusion or lead to problems during surgery. Their ignorance may result in many errors, injury during surgery and subsequent serious consequences. Genuine duplication of the gallbladder with the cystic duct and its artery is extremely rare and is therefore still only a subject of case reports. Gallbladder duplication itself is not an indication for surgery. If it contains stones or if inflammation occurs, however, both gallbladders may not be affected equally and if this variety is not recognized, only one of them may be removed and the other one can escape attention. The case report describes the rare case of gallbladder duplication including the cystic duct during elective cholecystectomy in a middle-aged man who was operated on after birth for omphalocele. Preoperative diagnostic examination described malrotation of the intestine and a cystic lesion next to the gallbladder, considered to be rather a liver cyst. Although it was indeed possible to assume various other abnormalities in the anatomical arrangement of the organs with regard to the patients history, the finding of double gallbladder including cystic duct was still surprising. PMID- 24479519 TI - [Epithelial cyst in an intrapancreatic accessory spleen -a case report]. AB - INTRODUCTION: Accessory spleen is a relatively common congenital defect with a 10% incidence in the population. Intrapancreatic accessory spleens are rare and cystic formation may mimic a hypervascular pancreatic tumour. CASE REPORT: We present the case of a 27-year-old woman who underwent abdominal ultrasonography (USG) because of chronic abdominal discomfort. USG findings revealed a 20 mm cystic mass in the tail of the pancreas. Additional preoperative investigations showed a tumour in the tail of the pancreas suspected of being a non-active neuroendocrine tumour. The intraoperative finding was a hard mass in the tail of the pancreas and neither peritoneal dissemination nor metastasis was detected. Distal pancreatectomy was performed. Pathological examination described an epithelial cyst in an intrapancreatic accessory spleen. DISCUSSION: Cyst formation in an intrapancreatic accessory spleen is extremely rare. Most patients with this condition have no clinical symptoms and it is often detected incidentally by imaging studies. It is difficult to differentiate an epithelial splenic cyst in the pancreas from a primary pancreatic neoplasm because it lacks particular characteristics on radiological examination; epithelial splenic cysts should be considered in the differential diagnosis of a cystic lesion in the tail of the pancreas. Key words: spleen - epithelial cyst - intrapancreatic accessory spleen. PMID- 24479520 TI - Biomechanical parameters of the cornea measured with the Ocular Response Analyzer in normal eyes. AB - BACKGROUND: To evaluate the relationships between Reichert Ocular Response Analyzer (ORA) parameters corneal hysteresis (CH) and corneal response factor (CRF) and ocular dimensions, age and intraocular pressure. METHODS: Two hundred and twelve eyes of 212 participants with no ocular pathology had CH and CRF measured with the ORA. Intraocular pressure (IOP) was measured with the Dynamic Contour tonometer and central corneal thickness (CCT) was also evaluated. Partial least squares linear regression (PLSLR) analyses were performed to examine the relationships between each response variable, CH and CRF, and the predictor variables age, corneal curvature (CC), axial length (AL), CCT and IOP. RESULTS: CH was positively associated with CCT and negatively associated with age (scaled coefficients: CCT 0.62, p < 0.0001; age -0.55, p <0.0001; r2 = 0.25). CRF was positively associated with CCT and DCT IOP and negatively associated with age and AL (scaled coefficients: CCT 0.89, p < 0.0001; DCT IOP 0.46, p < 0.01; age - 0.60, p < 0.0001; AL -0.37, p < 0.01; r2 = 0.43). There was no significant association between CC and CH or CRF. CONCLUSIONS: The study suggests that age and CCT are strongly associated with CH and CRF, and that the latter is also influenced by AL and IOP. However, the variables studied could explain only 25% and 43% of the measured variation in CH and CRF, respectively, suggesting other factors also affect the values of these measurements. PMID- 24479522 TI - Peptidoglycan in combination with muramyldipeptide synergistically induces an interleukin-10-dependent T helper 2-dominant immune response. AB - In this study, peptidoglycan (PEG) from Staphylococcus aureus-stimulated, but not muramyldipeptide (MDP)-stimulated, Langerhans cells (LCs) induced a dose dependent Th2-prone immune response. However, when LCs were stimulated with PEG in combination with MDP, the strength of Th2 immune responses was synergistically augmented by MDP. Furthermore, it was found that production of IL-10, but not of IL-12 p40, by PEG-stimulated LCs was also enhanced in the presence of MDP. These results suggest that MDP enhances Th2 cell development through up-regulation of IL-10 production from PEG-stimulated LCs, increase the importance of S. aureus colonization in patients with atopic dermatitis. PMID- 24479521 TI - Runx2 activates PI3K/Akt signaling via mTORC2 regulation in invasive breast cancer cells. AB - INTRODUCTION: The Runt-related transcription factor Runx2 is critical for skeletal development but is also aberrantly expressed in breast cancers, and promotes cell growth and invasion. A de-regulated serine/threonine kinase Akt signaling pathway is implicated in mammary carcinogenesis and cell survival; however, the mechanisms underlying Runx2 role in survival of invasive breast cancer cells are still unclear. METHODS: The phenotypic analysis of Runx2 function in cell survival was performed by gene silencing and flow cytometric analysis in highly invasive MDA-MB-231 and SUM-159-PT mammary epithelial cell lines. The expression analysis of Runx2 and pAkt (serine 473) proteins in metastatic breast cancer specimens was performed by immunohistochemistry. The mRNA and protein levels of kinases and phosphatases functional in Akt signaling were determined by real-time PCR and Western blotting, while DNA-protein interaction was studied by chromatin immunoprecipitation assays. RESULTS: The high Runx2 levels in invasive mammary epithelial cell lines promoted cell survival in Akt phosphorylation (pAkt-serine 473) dependent manner. The analysis of kinases and phosphatases associated with pAkt regulation revealed that Runx2 promotes pAkt levels via mammalian target of rapamycin complex-2 (mTORC2). The recruitment of Runx2 on mTOR promoter coupled with Runx2-dependent expression of mTORC2 component Rictor defined Runx2 function in pAkt-mediated survival of invasive breast cancer cells. CONCLUSIONS: Our results identified a novel mechanism of Runx2 regulatory crosstalk in Akt signaling that could have important consequences in targeting invasive breast cancer-associated cell survival. PMID- 24479525 TI - Factors determining swimming efficiency observed in less skilled swimmers. AB - The dynamics of performance in professional sport requires a systematic improvement of the training process. Such activities should also include optimizing the children and youth training in these disciplines, where an early specialization operates. The main aim of this paper was to search for the relationship between swimmer's segmental kinematics (segmental velocities, stroke rate, stroke length, stroke index); the relationship between swimmer's technical skill level (in four competitive swimming techniques) and training overloads taking into consideration gender and age effect. The study group consisted of 121 swimmers (69 female and 52 male), of the Polish 12-15 age group swim team, volunteered to serve as subjects. Video-based methods and video equipment are being applied to assist qualitative and simple quantitative analysis for immediate feedback and research in swimming. Both technical skill level preparation and segmental kinematics of 12-15 year old swimmers proved to be highly conditioned by implemented training intensity (p < 0.001), as well as the volume of training (high and average trade at a level of significance p < 0.001). Implemented training overloads expressed by both volume and intensity of training showed high and very high correlation with the swimming efficiency, presented segmental kinematics and technical skill level, however, there appeared particularly pronounced relationship with the size of kinematic parameters taken into account in four competitive swimming techniques, components of the 100 m individual medley. PMID- 24479524 TI - Idiopathic acute myocarditis during treatment for controlled human malaria infection: a case report. AB - A 23-year-old healthy male volunteer took part in a clinical trial in which the volunteer took chloroquine chemoprophylaxis and received three intradermal doses at four-week intervals of aseptic, purified Plasmodium falciparum sporozoites to induce protective immunity against malaria. Fifty-nine days after the last administration of sporozoites and 32 days after the last dose of chloroquine the volunteer underwent controlled human malaria infection (CHMI) by the bites of five P. falciparum-infected mosquitoes. Eleven days post-CHMI a thick blood smear was positive (6 P. falciparum/MUL blood) and treatment was initiated with atovaquone/proguanil (Malarone(r)). On the second day of treatment, day 12 post CHMI, troponin T, a marker for cardiac tissue damage, began to rise above normal, and reached a maximum of 1,115 ng/L (upper range of normal = 14 ng/L) on day 16 post-CHMI. The volunteer had one ~20 minute episode of retrosternal chest pain and heavy feeling in his left arm on day 14 post-CHMI. ECG at the time revealed minor repolarization disturbances, and cardiac MRI demonstrated focal areas of subepicardial and midwall delayed enhancement of the left ventricle with some oedema and hypokinesia. A diagnosis of myocarditis was made. Troponin T levels were normal within 16 days and the volunteer recovered without clinical sequelae. Follow-up cardiac MRI at almost five months showed normal function of both ventricles and disappearance of oedema. Delayed enhancement of subepicardial and midwall regions decreased, but was still present. With the exception of a throat swab that was positive for rhinovirus on day 14 post-CHMI, no other tests for potential aetiologies of the myocarditis were positive. A number of possible aetiological factors may explain or have contributed to this case of myocarditis including, i) P. falciparum infection, ii) rhinovirus infection, iii) unidentified pathogens, iv) hyper-immunization (the volunteer received six travel vaccines between the last immunization and the CHMI), v) atovaquone/proguanil treatment, or vi) a combination of these factors. Definitive aetiology and pathophysiological mechanism for the myocarditis have not been established. PMID- 24479527 TI - Can "the voices in the car" persuade drivers to go green?: effects of benefit appeals from in-vehicle voice agents and the role of drivers' affective states on eco-driving. AB - The present research investigated the possibility of using an in-vehicle voice agent to promote eco-driving. Considering that both types of benefit appeals- egoistic (emphasizing benefits to the self) and altruistic (emphasizing benefits to others)--could be employed to promote eco-driving behavior, we explored the effects of benefit appeals delivered by an in-vehicle voice agent on driving performance. In particular, we tested whether and how the valence (positive vs. negative) of drivers' affective states moderates the effects, drawing on the functionalist affect-cognition framework, which has theorized that positive affect leads people to focus more on self-interest, whereas negative affect leads people to become more sensitive to social norms. An experiment was conducted in which participants, after undergoing affect (happy vs. sad) elicitation, received messages (egoistic vs. altruistic) promoting eco-driving from an in-vehicle voice agent while performing a simulated driving task. Results were partially consistent with the functionalist affect-cognition framework. Happy participants performed better on eco-driving when they were exposed to egoistic appeals than to altruistic appeals. On the other hand, the driving performance data from sad participants did not yield a significant difference between the egoistic condition and the altruistic condition. Participants' driving performance data further revealed that the joint effects of benefit appeals and affective states on safe driving performance mirrored the joint effects on eco-driving performance, confirming a close relationship between the two driving behaviors. Theoretical and practical implications for the use of in-vehicle voice agents and benefit appeals in promoting eco-driving and safe driving are discussed. PMID- 24479528 TI - The more friends, the less political talk? Predictors of Facebook discussions among college students. AB - Although previous research has indicated that Facebook users, especially young adults, can cultivate their civic values by talking about public matters with their Facebook friends, little research has examined the predictors of political discussion on Facebook. Using survey data from 442 college students in the United States, this study finds that individual characteristics and network size influence college students' expressive behavior on Facebook related to two controversial topics: gay rights issues and politics. In line with previous studies about offline political discussion, the results show that conflict avoidance and ambivalence about target issues are negatively associated with Facebook discussions. Perhaps the most interesting finding is that users who have a large number of Facebook friends are less likely to talk about politics and gay rights issues on Facebook despite having access to increasing human and information resources. Theoretical implications of these findings and future directions are addressed. PMID- 24479526 TI - IL-33 stimulates CXCL8/IL-8 secretion in goblet cells but not normally differentiated airway cells. AB - BACKGROUND: IL-13, a helper T cell type 2 (Th2) cytokine, transforms cultured airway epithelial cells to goblet cells, and this is not inhibited by corticosteroids. IL-33 stimulates Th2 cytokines and is highly expressed in airways of persons with asthma. The effect of IL-33 on goblet cell differentiation and cytokine secretion has not been described. OBJECTIVE: We examined the effect of IL-33 on CXCL8/IL-8 secretion from goblet or normally differentiated human bronchial epithelial (NHBE) cells and signalling pathways associated with IL-33 activation in these cells. METHODS: Normal human bronchial epithelial cells were grown to goblet or normally differentiated ciliated cell phenotype at air-liquid interface in the presence or absence of IL-13. After 14 days, differentiated cells were exposed to IL-33 for 24 h. RESULTS: CXCL8/IL-8 secretion into the apical (air) side of the goblet cells was greater than from normally differentiated cells (P < 0.01), and IL-33 stimulated apical CXCL8/IL-8 release from goblet cells, but not from normally differentiated cells (P < 0.01). IL-33 increased ERK 1/2 phosphorylation in goblet cells (P < 0.05), and PD98059, a MAPK/ERK kinase inhibitor, attenuated IL-33-stimulated CXCL8/IL-8 secretion from goblet cells (P < 0.001). IL-13 induced ST2 mRNA (P < 0.02) and membrane bound ST2 protein expression on the apical side surface of goblet cells compared with normally differentiated cells, and neutralization with anti-ST2R antibody attenuated IL-33-induced apical CXCL8/IL-8 secretion from goblet cells (P < 0.02). CONCLUSIONS AND CLINICAL RELEVANCE: Goblet cells secrete CXCL8/IL-8, and this is increased by IL-33 through ST2R-ERK pathway, suggesting a mechanism for enhanced airway inflammation in the asthmatic airway with goblet cell metaplasia. PMID- 24479529 TI - Does the mask govern the mind?: effects of arbitrary gender representation on quantitative task performance in avatar-represented virtual groups. AB - Virtual environments employing avatars for self-representation-including the opportunity to represent or misrepresent social categories-raise interesting and intriguing questions as to how one's avatar-based social category shapes social identity dynamics, particularly when stereotypes prevalent in the offline world apply to the social categories visually represented by avatars. The present experiment investigated how social category representation via avatars (i.e., graphical representations of people in computer-mediated environments) affects stereotype-relevant task performance. In particular, building on and extending the Proteus effect model, we explored whether and how stereotype lift (i.e., a performance boost caused by the awareness of a domain-specific negative stereotype associated with outgroup members) occurred in virtual group settings in which avatar-based gender representation was arbitrary. Female and male participants (N=120) were randomly assigned either a female avatar or a male avatar through a process masked as a random drawing. They were then placed in a numerical minority status with respect to virtual gender-as the only virtual female (male) in a computer-mediated triad with two opposite-gendered avatars-and performed a mental arithmetic task either competitively or cooperatively. The data revealed that participants who were arbitrarily represented by a male avatar and competed against two ostensible female avatars showed strongest performance compared to others on the arithmetic task. This pattern occurred regardless of participants' actual gender, pointing to a virtual stereotype lift effect. Additional mediation tests showed that task motivation partially mediated the effect. Theoretical and practical implications for social identity dynamics in avatar-based virtual environments are discussed. PMID- 24479531 TI - Determination of structural characteristics of all-organic radical liquid crystals based on analysis of the dipole-dipole broadened EPR spectra. AB - The angular dependences of g-value and line width of EPR spectra of paramagnetic all-organic liquid crystalline (LC) materials were measured for the quantitative characterization of the nematic, cholesteric, and smectic C phases. The detailed molecular alignment in mesophases was determined by means of numerical spectra simulation focusing on spin exchange and dipole-dipole magnetic interactions of neighboring molecules. The obtained structural data indicate that the spin polarization mechanism between neighboring molecules rather than the direct through-space interactions between paramagnetic centers is responsible for the specific magnetic properties of the studied LC materials. PMID- 24479530 TI - The effect of host social system on parasite population genetic structure: comparative population genetics of two ectoparasitic mites and their bat hosts. AB - BACKGROUND: The population genetic structure of a parasite, and consequently its ability to adapt to a given host, is strongly linked to its own life history as well as the life history of its host. While the effects of parasite life history on their population genetic structure have received some attention, the effect of host social system has remained largely unstudied. In this study, we investigated the population genetic structure of two closely related parasitic mite species (Spinturnix myoti and Spinturnix bechsteini) with very similar life histories. Their respective hosts, the greater mouse-eared bat (Myotis myotis) and the Bechstein's bat (Myotis bechsteinii) have social systems that differ in several substantial features, such as group size, mating system and dispersal patterns. RESULTS: We found that the two mite species have strongly differing population genetic structures. In S. myoti we found high levels of genetic diversity and very little pairwise differentiation, whereas in S. bechsteini we observed much less diversity, strongly differentiated populations and strong temporal turnover. These differences are likely to be the result of the differences in genetic drift and dispersal opportunities afforded to the two parasites by the different social systems of their hosts. CONCLUSIONS: Our results suggest that host social system can strongly influence parasite population structure. As a result, the evolutionary potential of these two parasites with very similar life histories also differs, thereby affecting the risk and evolutionary pressure exerted by each parasite on its host. PMID- 24479532 TI - Predicting depression outcome in mental health treatment: a recursive partitioning analysis. AB - OBJECTIVE: Recursive partitioning was applied to a longitudinal dataset of outpatient mental health clinic patients to identify empirically factors and interactions among factors that best predicted clinical improvement and deterioration in symptoms of depression across treatment. METHOD: Sixty-two variables drawn from an initial patient survey and from chart review were included as covariates in the analysis, representing nearly all of the demographic, treatment, symptom, diagnostic, and social history information obtained from patients at their initial evaluations. Trees estimated the probability of participants' having depression at their last assessment, improving to a clinically significant degree during treatment, or developing a new onset of significant depressive symptoms during treatment. RESULTS: Initial pain, the presence of anxiety, and a history of multiple types of abuse were risk factors for poorer outcome, even among patients who did not initially have significant depressive symptoms. CONCLUSIONS: By examining multiple-related outcomes, we were able to create a series of overlapping models that revealed important predictors across trees. Limitations of the study included the lack of cross-validation of the trees and the exploratory nature of the analysis. PMID- 24479533 TI - Self-learning materials and continuing education. PMID- 24479534 TI - How to: Plan an Off-Campus Clinical Teaching Programme. AB - Teaching in non-university hospitals not only supplements university-based educational resources but also provides students with greater opportunities to be involved with cases frequently encountered in actual practice. It also strengthens continuing education of doctors in the community, and can lead to a better understanding of the realities and problems of community health care. Success is partially dependent upon initial planning, which should include setting objectives, adapting them to the educational environment, and choosing an environment in which they are likely to succeed. Acceptance within the community is dependent upon prior knowledge of the political structure and the involvement of those people who command the respect of the community at large. Teaching should be shared between the university and the community, not just delegated either to the community or assumed totally by the university. Faculty development is crucial initially and on a continuing basis. This article is based on the American system, but is relevant to other situations. PMID- 24479535 TI - Development and implementation of a diagnostic evaluation technique. PMID- 24479536 TI - The way we teach: anatomy of the coronary artery system. AB - A simple model to enhance understanding of the three-dimensional anatomy of the human epicardial coronary artery circulation is discussed and potential instructive applications reviewed. The chambers of the heart are visualized as being related to one another as in a pair of opposed hands, which can be rotated to demonstrate the various structures as viewed in different angles of obliquity. PMID- 24479537 TI - Literature searches by computer. AB - Computers can make a useful contribution to the time-consuming task of literature searching. This article offers advice on when to search by computer and spells out the advantages. PMID- 24479538 TI - Improving CME Lectures. PMID- 24479539 TI - Assessment of independent learning. AB - In this series, we print evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to adapt such instruments for your own purposes. The feature in this issue has been prepared by Grahame I. Feletti, Nicholas A. Saunders, Anthony J. Smith and Charles E. Engel. Further information is available from Charles E. Engel. PMID- 24479540 TI - A clinical guide to coping with an overhead projector. PMID- 24479542 TI - Parameterized runtime analyses of evolutionary algorithms for the planar euclidean traveling salesperson problem. AB - Parameterized runtime analysis seeks to understand the influence of problem structure on algorithmic runtime. In this paper, we contribute to the theoretical understanding of evolutionary algorithms and carry out a parameterized analysis of evolutionary algorithms for the Euclidean traveling salesperson problem (Euclidean TSP). We investigate the structural properties in TSP instances that influence the optimization process of evolutionary algorithms and use this information to bound their runtime. We analyze the runtime in dependence of the number of inner points k. In the first part of the paper, we study a [Formula: see text] EA in a strictly black box setting and show that it can solve the Euclidean TSP in expected time [Formula: see text] where A is a function of the minimum angle [Formula: see text] between any three points. Based on insights provided by the analysis, we improve this upper bound by introducing a mixed mutation strategy that incorporates both 2-opt moves and permutation jumps. This strategy improves the upper bound to [Formula: see text]. In the second part of the paper, we use the information gained in the analysis to incorporate domain knowledge to design two fixed-parameter tractable (FPT) evolutionary algorithms for the planar Euclidean TSP. We first develop a [Formula: see text] EA based on an analysis by M. Theile, 2009, "Exact solutions to the traveling salesperson problem by a population-based evolutionary algorithm," Lecture notes in computer science, Vol. 5482 (pp. 145-155), that solves the TSP with k inner points in [Formula: see text] generations with probability [Formula: see text]. We then design a [Formula: see text] EA that incorporates a dynamic programming step into the fitness evaluation. We prove that a variant of this evolutionary algorithm using 2-opt mutation solves the problem after [Formula: see text] steps in expectation with a cost of [Formula: see text] for each fitness evaluation. PMID- 24479543 TI - A note on bound constraints handling for the IEEE CEC'05 benchmark function suite. AB - The benchmark functions and some of the algorithms proposed for the special session on real parameter optimization of the 2005 IEEE Congress on Evolutionary Computation (CEC'05) have played and still play an important role in the assessment of the state of the art in continuous optimization. In this article, we show that if bound constraints are not enforced for the final reported solutions, state-of-the-art algorithms produce infeasible best candidate solutions for the majority of functions of the IEEE CEC'05 benchmark function suite. This occurs even though the optima of the CEC'05 functions are within the specified bounds. This phenomenon has important implications on algorithm comparisons, and therefore on algorithm designs. This article's goal is to draw the attention of the community to the fact that some authors might have drawn wrong conclusions from experiments using the CEC'05 problems. PMID- 24479544 TI - Beat over the old ground with new strategy: engineering As...As interaction in arsenite-based Dawson cluster beta-[W18O54(AsO3)2(6-. AB - By reaction of [As2W19O67(H2O)](14-), NiCl2.6H2O, and phen under hydrothermal conditions, a new organic-inorganic tungstoarsenate hybrid [Ni(phen)3]4[As2W18O60]{[Ni(phen)2][H2As2W18O60]}.12H2O (where phen = 1,10 phenanthroline) (1) was obtained via self-assembly and characterized by elemental analysis, infrared (IR) spectroscopy, solid UV-vis absorption spectrum, and single-crystal X-ray diffraction (XRD). An unprecedented 18-tungstoarsenate Dawson cluster, beta-[W18O54(AsO3)2](6-), encapsulating two pyramidal arsenite AsO3(3-) anions as templates and exhibiting interesting intramolecular As...As interaction is first achieved. 1 displays a one-dimensional (1D) chain architecture constructed by alternating beta-[W18O54(AsO3)2](6-) and nickel(II) complexes [Ni(phen)2)](2+). The resulting hybrid can act as a photocatalyst to prompt the degradation of Rhodamine B (RhB) with excellent efficiency. PMID- 24479545 TI - Cyclophilin A promotes HIV-1 reverse transcription but its effect on transduction correlates best with its effect on nuclear entry of viral cDNA. AB - BACKGROUND: The human peptidyl-prolyl isomerase Cyclophilin A (CypA) binds HIV-1 capsid (CA) and influences early steps in the HIV-1 replication cycle. The mechanism by which CypA regulates HIV-1 transduction efficiency is unknown. Disruption of CypA binding to CA, either by genetic means or by the competitive inhibitor cyclosporine A (CsA), reduces the efficiency of HIV-1 transduction in some cells but not in others. Transduction of certain cell types increases significantly when CypA binding to particular HIV-1 CA mutants, i.e., A92E, is prevented. Previous studies have suggested that this cell type-specific effect is due to a dominant-acting, CypA-dependent restriction factor. RESULTS: Here we investigated the mechanism by which CypA regulates HIV-1 transduction efficiency using 27 different human cell lines, 32 HeLa subclones, and several previously characterized HIV-1 CA mutants. Disruption of CypA binding to wild-type CA, or to any of the mutant CAs, caused a decrease in HIV-1 reverse transcription in all the cell lines analyzed here. This block to reverse transcription, though, did not correlate with cell type-specific effects on transduction efficiency. The level of 2-LTR circles, a marker for nuclear transport of the viral cDNA that results from reverse transcription, correlated closely with effects on infectivity. No correlation was observed between the cell type-specific effects on infectivity and the steady-state CypA protein levels in these cells. Instead, as indicated by a fate-of-capsid assay, CsA released the HIV-1 CA core from an apparent state of hyperstabilization, in a cell type-specific manner. CONCLUSION: These data demonstrate that, while CypA promotes reverse transcription under all conditions tested here, its effect on HIV-1 infectivity correlates more closely with effects on nuclear entry of the viral cDNA. The data also support the hypothesis that a cell-type specific CypA-dependent restriction factor blocks HIV 1 replication by delaying CA core uncoating and hindering nuclear entry. PMID- 24479546 TI - RNA profiling reveals familial aggregation of molecular subtypes in non-BRCA1/2 breast cancer families. AB - BACKGROUND: In more than 70% of families with a strong history of breast and ovarian cancers, pathogenic mutation in BRCA1 or BRCA2 cannot be identified, even though hereditary factors are expected to be involved. It has been proposed that tumors with similar molecular phenotypes also share similar underlying pathophysiological mechanisms. In the current study, the aim was to investigate if global RNA profiling can be used to identify functional subgroups within breast tumors from families tested negative for BRCA1/2 germline mutations and how these subgroupings relate to different breast cancer patients within the same family. METHODS: In the current study we analyzed a collection of 70 frozen breast tumor biopsies from a total of 58 families by global RNA profiling and promoter methylation analysis. RESULTS: We show that distinct functional subgroupings, similar to the intrinsic molecular breast cancer subtypes, exist among non-BRCA1/2 breast cancers. The distribution of subtypes was markedly different from the distribution found among BRCA1/2 mutation carriers. From 11 breast cancer families, breast tumor biopsies from more than one affected family member were included in the study. Notably, in 8 of these families we found that patients from the same family shared the same tumor subtype, showing a tendency of familial aggregation of tumor subtypes (p-value = 1.7e-3). Using our previously developed BRCA1/2-signatures, we identified 7 non-BRCA1/2 tumors with a BRCA1-like molecular phenotype and provide evidence for epigenetic inactivation of BRCA1 in three of the tumors. In addition, 7 BRCA2-like tumors were found. CONCLUSIONS: Our finding indicates involvement of hereditary factors in non BRCA1/2 breast cancer families in which family members may carry genetic susceptibility not just to breast cancer but to a particular subtype of breast cancer. This is the first study to provide a biological link between breast cancers from family members of high-risk non-BRCA1/2 families in a systematic manner, suggesting that future genetic analysis may benefit from subgrouping families into molecularly homogeneous subtypes in order to search for new high penetrance susceptibility genes. PMID- 24479548 TI - Perceived environmental characteristics and psychosocial factors associated with physical activity levels in adolescents from Northeast Brazil: structural equation modelling analysis. AB - This study aimed to investigate the direct and indirect associations between perceived environmental characteristics and psychosocial factors and physical activity levels in adolescents from Northeast Brazil. The sample was composed of 2,361 adolescents aged 14-19 years (56.6% female). Physical activity was measured using a questionnaire and environmental (perceived environmental characteristics) and psychosocial (self-efficacy, social support from parents and friends for physical activity) factors with previously validated scales. Perceived environmental characteristics were not directly associated with the levels of physical activity, but exhibited significant indirect associations, mediated by self-efficacy in males. Self-efficacy and social support were positively and directly associated with physical activity levels, and part of the associations between social support and physical activity was mediated by self-efficacy. Perception of self-efficacy and social support, important factors associated with physical activity levels in adolescents, should be the target of interventions aimed at increasing physical activity. Favorable environments for physical activity also need to be considered, since they have a positive influence on the self-efficacy of adolescents. PMID- 24479547 TI - On the ocular findings in ochronosis: a systematic review of literature. AB - BACKGROUND: Ochronosis/Alkaptonuria is a tyrosine metabolism disorder where accumulation of homogentisic acid, in eye, skin, cartilage and several other connective tissues leads to a black pigmentation of the affected tissues. It is autosomal-recessive inherited in men with a frequency of 1-9/1,000,000. While it is clear that pigment deposits lead to joint destruction, renal stone formation and cardiac valvulopathy respectively, the significance of ocular findings is still unclear. We therefore aim to evaluate the frequency and clinical significance of ocular findings in ochronosis and discuss possible therapeutic options. METHODS: Systematic review of literature via Medline and Web of Science. Only case reports in English, German, French, Spanish or Italian documenting detailed ophthalmologic examination were included. RESULTS: Our search revealed 36 case reports including 40 patients. Average age at the onset of ocular signs was 40.6 years. The most frequent sign was symmetric brown sclera pigmentation present in 82.5 percent of the patients. "Oil-drops", brown pigment spots in the limbus are generally considered pathognomonic but were a little less frequent (75 percent). Vermiform pigment deposits at the level of the conjunctiva or increased conjunctival vessel diameter is also frequent. We found an increased incidence of central vein occlusion and elevated intraocular pressure going along with chamber angle hyperpigmentation. Another condition observed twice is rapid progressive astigmatism attributable to corneoscleral pigment accumulation. CONCLUSION: Our observations suggest that ocular findings are of double relevance. First, characteristic ocular findings can anticipate the time of diagnosis and second, ocular findings may complicate to various conditions putting sight at risk. Opthalmologists and general physicians should be aware of both. Therapeutic options include protein restriction, administration of high dose vitamin C or nitisonone. Evidence for all of them is limited. PMID- 24479549 TI - Structure binding relationship of galactosylated Glycoclusters toward Pseudomonas aeruginosa lectin LecA using a DNA-based carbohydrate microarray. AB - Pseudomonas aeruginosa (PA) is a major public health issue due to its impact on nosocomial infections as well as its impact on cystic fibrosis patient mortality. One of the main concerns is its ability to develop antibiotic resistance. Therefore, inhibition of PA virulence has been proposed as an alternative strategy to tackle PA based infections. LecA (or PA-IL), a galactose binding lectin from PA, is involved in its virulence. Herein, we aimed at designing high affinity synthetic ligands toward LecA for its inhibition and at understanding the key parameters governing the binding of multivalent galactosylated clusters. Twenty-five glycoclusters were synthesized and their bindings were studied on a carbohydrate microarray. Monosaccharide centered clusters and linear comb-like clusters were synthesized with different linkers separating the core and the galactosyl residues. Their length, flexibility, and aromaticity were varied. Our results showed that the binding profile of LecA to galactosylated clusters was dependent on both the core and the linker and also that the optimal linker was different for each core. Nevertheless, an aryl group in the linker structure drastically improved the binding to LecA. Our results also suggest that optimal distances are preferred between the core and the aromatic group and the core and the galactose. PMID- 24479550 TI - Queering education in response to the needs of LGBTQQIA students in P-12 schools. PMID- 24479551 TI - Is there an emotional cost of completing high school? Ecological factors and psychological distress among LGBT homeless youth. AB - This study explored the nexus of home and school climate on the psychological distress of lesbian, gay, bisexual, and transgender (LGBT) homeless youth, as well as their experiences during high school. Of the LGBT homeless youth (N = 89) surveyed, 39.3% reported not completing high school. Most participants did not seek support from school staff nor did they report attending a school with a Gay Straight Alliance. Significantly higher levels of psychological distress were found among high school graduates and those reporting LGBT harassment at home; however, harassment experienced at school was not statistically related to psychological distress. Findings are discussed. PMID- 24479552 TI - Easing the transition for queer student teachers from program to field: implications for teacher education. AB - Tensions exist between what some queer student teachers experience in the university setting, their lives in schools during field placements, and upon graduation. We describe a series of workshops designed for queer student teachers and their allies that were conducted prior to field placement. Participants revealed high degrees of satisfaction with the program and increased feelings of personal and professional self-efficacy. Participants reported high levels of experienced homophobia in their academic programs; as such, the workshops were a valuable "safe space." These workshops appear to fill a significant gap for queer students and their allies in teacher preparation programs. PMID- 24479553 TI - Salience, valence, context, and integration: conceptualizing the needs of sexually and gender diverse youth in P-12 schools. AB - A framework for conceptualizing the needs of lesbian, gay male, bisexual, transgender, questioning, and other sexually and gender diverse youth is essential for guiding service delivery throughout educational settings. Review and synthesis of the literature reveals that integrating assessment of the salience, valence, and context of issues related to sexual and gender diversity facilitates affirmative practice at the individual student, group, and school wide levels. The authors describe the components of the salience, valence, context, and integration (SVCI) model with emphasis on practical application. The theoretical and empirical support for each component of the model is also discussed. PMID- 24479554 TI - Fecundity in ALS. PMID- 24479555 TI - Declining malaria in Africa: improving the measurement of progress. AB - The dramatic escalation of malaria control activities in Africa since the year 2000 has increased the importance of accurate measurements of impact on malaria epidemiology and burden. This study presents a systematic review of the emerging published evidence base on trends in malaria risk in Africa and argues that more systematic, timely, and empirically-based approaches are urgently needed to track the rapidly evolving landscape of transmission. PMID- 24479556 TI - Modelling of the pathological bile flow in the duct with a calculus. AB - The aim of the present paper is to develop an analytical model for description of the pathological bile flow in the major duodenal papilla duct with a calculus. The problem is separated into two parts. The first part deals with determination of bile behaviour and constitutive relation parameters of the pathological bile. The viscosity vs. shear rate, the viscosity vs. time, and shear stress vs. shear rate dependences are obtained for different types of bile taken from patients of different age and sex. As a result, the approximation of curves described by the Casson equation was obtained. It was shown that the pathological bile is a thixotropic non-Newtonian fluid. The second part is directly related to modelling of the bile flow in the duct with a calculus. As a result of solving the problem, the bile velocity profile, flow rate vs. time, and bile pressure vs. calculus radius were obtained. The dependences obtained may play an important role in the assessment of an indication to operation. PMID- 24479557 TI - Serum butyrylcholinesterase predicts survival after extracorporeal membrane oxygenation after cardiovascular surgery. AB - INTRODUCTION: Risk stratification in patients undergoing extracorporeal membrane oxygenation (ECMO) support after cardiovascular surgery remains challenging, because data on specific outcome predictors are limited. Serum butyrylcholinesterase demonstrated a strong inverse association with all-cause and cardiovascular mortality in non-critically ill patients. We therefore evaluated the predictive value of preoperative serum butyrylcholinesterase levels in patients undergoing venoarterial ECMO support after cardiovascular surgery. METHODS: We prospectively included 191 patients undergoing venoarterial ECMO therapy after cardiovascular surgery at a university-affiliated tertiary care center in our registry. RESULTS: All-cause and cardiovascular mortality were defined as primary study end points. During a median follow-up time of 51 months (IQR, 34 to 71) corresponding to 4,197 overall months of follow-up, 65% of patients died. Cox proportional hazard regression analysis revealed a significant and independent inverse association between higher butyrylcholinesterase levels and all-cause mortality with an adjusted hazard ratio (HR) of 0.44 (95% CI, 0.25 to 0.78; P = 0.005), as well as cardiovascular mortality, with an adjusted HR of 0.38 (95% CI, 0.21 to 0.70; P = 0.002), comparing the third with the first tertile. Survival rates were higher in patients within the third tertile of butyrylcholinesterase compared with patients within the first tertile at 30 days (68% versus 44%) as well as at 6 years (47% versus 21%). CONCLUSIONS: The current study revealed serum butyrylcholinesterase as a strong and independent inverse predictor of all-cause and cardiovascular mortality in patients undergoing venoarterial ECMO therapy after cardiovascular surgery. These findings advance the limited knowledge on risk stratification in patients undergoing ECMO support and represent a valuable addition for a comprehensive decision making before ECMO implantation. PMID- 24479558 TI - Enhanced cytotoxic and genotoxic effects of gadolinium following ELF-EMF irradiation in human lymphocytes. AB - There are many studies of Gd nephrotoxicity and neurotoxicity, whereas research on cyto- and genotoxicity in normal human lymphocytes is scarce. It is important to investigate the effect of extremely low-frequency electromagnetic fields (ELF EMF) on Gd toxicity, as patients are co-exposed to Gd and ELF-EMF generated by MRI scanners. We investigated the cytotoxicity and genotoixcity of Gd and the possible enhancing effect of ELF-EMF on Gd toxicity in cultured human lymphocytes by performing a micronuclei (MN) assay, trypan blue dye exclusion, single cell gel electrophoresis, and apoptosis analyses using flow cytometry. Isolated lymphocytes were exposed to 0.2-1.2 mM of Gd only or in combination with a 60-Hz ELF-EMF of 0.8-mT field strength. Exposing human lymphocytes to Gd resulted in a concentration- and time-dependent decrease in cell viability and an increase in MN frequency, single strand DNA breakage, apoptotic cell death, and ROS production. ELF-EMF (0.8 mT) exposure also increased cell death, MN frequency, olive tail moment, and apoptosis induced by Gd treatment alone. These results suggest that Gd induces DNA damage and apoptotic cell death in human lymphocytes and that ELF-EMF enhances the cytotoxicity and genotoxicity of Gd. PMID- 24479559 TI - Tooth loss and cognitive functions among older adults. AB - OBJECTIVE: To evaluate the association between the number of teeth and cognitive functions adjusted for age and education level in a cohort of older adults living in Sweden. MATERIALS AND METHODS: The study employed a cross-sectional design in which 1147 individuals between 60-96 years underwent a clinical oral examination. The cognitive functions were assessed using Mini-Mental State Examination (MMSE) and Clock-test. The level of education was obtained from a questionnaire. Data were subjected to Chi-square tests and multivariate logistic regression analyses were employed, grouping the different variables into pre-determined categories. RESULTS: The co-variables age and education were significantly associated with the number of teeth (p < 0.05). The multivariate logistic regression analysis revealed that the association between the number of teeth and the cognitive functions persisted even after adjusting for age and level of education. CONCLUSIONS: The findings suggest that the presence of teeth may be of importance for cognitive abilities in older adults. PMID- 24479560 TI - Positive reactions to placebo in children undergoing double-blind, placebo controlled food challenge. AB - BACKGROUND: The gold standard in the diagnosis of food allergy is the double blind, placebo-controlled oral food challenge (DBPCFC). During this challenge, patients receive the allergenic food and placebo on separate randomized days, while being monitored for clinical reactions. Interestingly, some reactions are assessed as positive although the patients had received placebo. The aim of our study was to analyze incidence and characteristics of positive placebo reactions during DBPCFCs. METHODS: In food-allergic children, we retrospectively analyzed positive placebo reactions in DBPCFCs in 740 placebo challenges in our department. Individual characteristics were compared, such as age or IgE levels, as well as clinical symptoms. RESULTS: Of all placebo challenges, 2.8% (21 of 740) were assessed as positive. Young children (age <= 1.5 years) had more (P = 0.047) positive placebo challenges (4.0%) compared to older children (age > 1.5 years; 1.5%). Children with positive placebo challenges had higher levels of total IgE (median 201 kU/L) compared to negatively classified children (median 110 kU/L). In children with positive placebo reactions, skin symptoms were observed significantly more often, with a worsening of atopic eczema (AE) as the most reported symptom. CONCLUSION: Placebo reactions in DBPCFC are not common. Worsening of AE is the most frequent clinical reaction associated with positive placebo challenges, and young children (age <= 1.5 years) seem to be affected more often. Therefore - contrary to current recommendations - DBPCFC tests should be considered in infants and young children, especially those with a history of AE. PMID- 24479561 TI - Elucidating molecular motion through structural and dynamic filters of energy minimized conformer ensembles. AB - Complex RNA structures are constructed from helical segments connected by flexible loops that move spontaneously and in response to binding of small molecule ligands and proteins. Understanding the conformational variability of RNA requires the characterization of the coupled time evolution of interconnected flexible domains. To elucidate the collective molecular motions and explore the conformational landscape of the HIV-1 TAR RNA, we describe a new methodology that utilizes energy-minimized structures generated by the program "Fragment Assembly of RNA with Full-Atom Refinement (FARFAR)". We apply structural filters in the form of experimental residual dipolar couplings (RDCs) to select a subset of discrete energy-minimized conformers and carry out principal component analyses (PCA) to corroborate the choice of the filtered subset. We use this subset of structures to calculate solution T1 and T(1rho) relaxation times for (13)C spins in multiple residues in different domains of the molecule using two simulation protocols that we previously published. We match the experimental T1 times to within 2% and the T(1rho) times to within less than 10% for helical residues. These results introduce a protocol to construct viable dynamic trajectories for RNA molecules that accord well with experimental NMR data and support the notion that the motions of the helical portions of this small RNA can be described by a relatively small number of discrete conformations exchanging over time scales longer than 1 MUs. PMID- 24479563 TI - Epitope recognition of antibodies against a Yersinia pestis lipopolysaccharide trisaccharide component. AB - Today, the process of selecting carbohydrate antigens as a basis for active vaccination and the generation of antibodies for therapeutic and diagnostic purposes is based on intuition combined with trial and error experiments. In efforts to establish a rational process for glycan epitope selection, we employed glycan array screening, surface plasmon resonance, and saturation transfer difference (STD)-NMR to elucidate the interactions between antibodies and glycans representing the Yersinia pestis lipopolysaccharide (LPS). A trisaccharide epitope of the LPS inner core glycan and different LPS-derived oligosaccharides from various Gram-negative bacteria were analyzed using this combination of techniques. The antibody-glycan interaction with a heptose substructure was determined at atomic-level detail. Antibodies specifically recognize the Y. pestis trisaccharide and some substructures with high affinity and specificity. No significant binding to LPS glycans from other bacteria was observed, which suggests that the epitopes for just one particular bacterial species can be identified. On the basis of these results we are beginning to understand the rules for structure-based design and selection of carbohydrate antigens. PMID- 24479562 TI - Variant calling in low-coverage whole genome sequencing of a Native American population sample. AB - BACKGROUND: The reduction in the cost of sequencing a human genome has led to the use of genotype sampling strategies in order to impute and infer the presence of sequence variants that can then be tested for associations with traits of interest. Low-coverage Whole Genome Sequencing (WGS) is a sampling strategy that overcomes some of the deficiencies seen in fixed content SNP array studies. Linkage-disequilibrium (LD) aware variant callers, such as the program Thunder, may provide a calling rate and accuracy that makes a low-coverage sequencing strategy viable. RESULTS: We examined the performance of an LD-aware variant calling strategy in a population of 708 low-coverage whole genome sequences from a community sample of Native Americans. We assessed variant calling through a comparison of the sequencing results to genotypes measured in 641 of the same subjects using a fixed content first generation exome array. The comparison was made using the variant calling routines GATK Unified Genotyper program and the LD aware variant caller Thunder. Thunder was found to improve concordance in a coverage dependent fashion, while correctly calling nearly all of the common variants as well as a high percentage of the rare variants present in the sample. CONCLUSIONS: Low-coverage WGS is a strategy that appears to collect genetic information intermediate in scope between fixed content genotyping arrays and deep-coverage WGS. Our data suggests that low-coverage WGS is a viable strategy with a greater chance of discovering novel variants and associations than fixed content arrays for large sample association analyses. PMID- 24479564 TI - Effect of dalteparin, a low-molecular-weight heparin, as adjunctive therapy in patients with Kawasaki disease: a retrospective study. AB - BACKGROUND: Dalteparin, a low-molecular-weight heparin, has anticoagulant and anti-angiogenic activity. This study investigated whether dalteparin reduced coronary artery lesion (CAL) prevalence, and resistance to intravenous immunoglobulin (IVIG) therapy in Kawasaki disease (KD). METHODS: This retrospective study comprised two parts. In the first cohort, 126 patients with KD (68 male, 58 female; median age: 22 months, range: 1-67 months) admitted to Nihon University Nerima-Hikarigaoka Hospital from January 2004 to June 2008, received either dalteparin 75 IU/kg/day, IVIG 400 mg/kg/day for 5 consecutive days, and aspirin 30 mg/kg/day, or dalteparin 75 IU/kg/day and aspirin 30 mg/kg/day, until clinical improvement. Control data came from the 2005-6 Nationwide KD survey. In the second cohort, 112 patients with KD (59 male, 53 female; median age: 19 months, range: 1-66 months) admitted from June 2010 to February 2012, received either dalteparin 75 IU/kg/day, IVIG 2.0 g/kg over 12 h, and aspirin 30 mg/kg/day, or dalteparin 75 IU/kg/day and aspirin 30 mg/kg/day. Control data came from the 2009-10 Nationwide KD survey. No patients enrolled in the nationwide surveys received dalteparin. All patients at our institution were given dalteparin in their combination therapy. RESULTS: A comparison of the first cohort with controls in the nationwide survey showed that the prevalence of initial administration of IVIG was 80.2% versus 86.0%; the rate of additional IVIG administration was 7.1% versus 14.0% (p = 0.03); CAL prevalence in the acute period was 4.8% versus 11.9% (p < 0.01); and the prevalence of cardiovascular sequelae was 0% versus 3.8% (p < 0.05). A comparison of the second cohort with controls in the nationwide survey showed that the rate of initial administration of IVIG was 92.9% versus 89.5%; the rate of additional IVIG administration was 8.9% versus 17.1% (p = 0.02); the prevalence of resistance to IVIG was 3.6% versus 14.9% (p < 0.001); and CAL prevalence in the acute period was 2.7% versus 8.6% (p = 0.03). CONCLUSIONS: This study found that adjunctive dalteparin was associated with a lower prevalence of IVIG resistance and CAL in young children with KD. TRIAL REGISTRATION UMIN-CTR: UMIN000010349. PMID- 24479565 TI - Haptic perception accuracy depending on self-produced movement. AB - This study measured whether self-produced movement influences haptic perception ability (experiment 1) as well as the factors associated with levels of influence (experiment 2) in racket sports. For experiment 1, the haptic perception accuracy levels of five male table tennis experts and five male novices were examined under two different conditions (no movement vs. movement). For experiment 2, the haptic afferent subsystems of five male table tennis experts and five male novices were investigated in only the self-produced movement-coupled condition. Inferential statistics (ANOVA, t-test) and custom-made devices (shock & vibration sensor, Qualisys Track Manager) of the data were used to determine the haptic perception accuracy (experiment 1, experiment 2) and its association with expertise. The results of this research show that expert-level players acquire higher accuracy with less variability (racket vibration and angle) than novice level players, especially in their self-produced movement coupled performances. The important finding from this result is that, in terms of accuracy, the skill associated differences were enlarged during self-produced movement. To explain the origin of this difference between experts and novices, the functional variability of haptic afferent subsystems can serve as a reference. These two factors (self-produced accuracy and the variability of haptic features) as investigated in this study would be useful criteria for educators in racket sports and suggest a broader hypothesis for further research into the effects of the haptic accuracy related to variability. PMID- 24479566 TI - Molecular mechanisms associated with the strength of the anti-CMV response in nonagenarians. AB - BACKGROUND: Infection with human cytomegalovirus (CMV) affects the function and composition of the immune system during ageing. In addition to the presence of the pathogen, the strength of the immune response, as measured by the anti-CMV IgG titre, has a significant effect on age-related pathogenesis. High anti-CMV IgG titres have been associated with increased mortality and functional impairment in the elderly. In this study, we were interested in identifying the molecular mechanisms that are associated with the strength of the anti-CMV response by examining the gene expression profiles that are associated with the level of the anti-CMV IgG titre. RESULTS: The level of the anti-CMV IgG titre is associated with the expression level of 663 transcripts in nonagenarians. These transcripts and their corresponding pathways are, for the most part, associated with metabolic functions, cell development and proliferation and other basic cellular functions. However, no prominent associations with the immune system were found, and no associated transcripts were found in young controls. CONCLUSIONS: The lack of defence pathways associated with the strength of the anti-CMV response can indicate that the compromised immune system can no longer defend itself against the CMV infection. Our data imply that the association between high anti-CMV IgG titres and increased mortality and frailty is mediated by basic cellular processes. PMID- 24479567 TI - Teaching communication skills. PMID- 24479568 TI - How to... Design and Use a Questionnaire in Evaluation and Educational Research. AB - Questionnaires are a valuable way of collecting information and there is no doubt that a good design will help provide accurate and relevant data. This article discusses the points that contribute to a well-designed questionnaire and the steps that need to be taken in its preparation. PMID- 24479569 TI - The Way we Teach... Interviewing Skills. AB - Being able to interview well-eliciting elearly the information required whilst establishing and maintaining a rapport with the patient-is one of the doctor's greatest assets. Yet very little attention is paid to the teaching of interviewing skills. In this article Dr Maguire describes a short, successful course in interviewing skills which he and his colleagues at Manchester teach to medical students during their psychiatric attachment. Students receive feedback on their taped interviews with patients and are required to complete an interview rating scale. Role play is introduced where students have particular difficulty covering a given area, e.g. recent bereavement, or mastering a particular technique. PMID- 24479570 TI - The way we teach... haematology to postgraduates. AB - In this article, the author describes the levels of competence that residents in the postgraduate haematology programme at McMaster University are required to reach. He also discusses the rotations and elective programmes, designed to give postgraduate students experience in the clinical and laboratory setting. An account of the undergraduate haematology programme at McMaster's was published in the last issue of Medical Teacher. PMID- 24479571 TI - Improving the effectiveness of small-group learning with strategic intervention. AB - In this article, incidents that developed during small-group learning exercises have been analysed and systematized in order to provide a framework for the application of leadership intervention principles. The latter have been derived from those used in encounter and growth groups. Part of a small-group discussion on glomerulonephritis has been used to illustrate the practical application of these principles. PMID- 24479572 TI - A model for teaching respiratory medicine. PMID- 24479573 TI - Practical tips: videophobia-a practical guide for sufferers. PMID- 24479575 TI - Genetic lineages, antimicrobial resistance, and virulence in Staphylococcus aureus of meat samples in Spain: analysis of immune evasion cluster (IEC) genes. AB - The objective of this study was to determine the rate of contamination by Staphylococcus aureus in 100 meat samples obtained during 2011-2012 in La Rioja (Northern Spain), to analyze their content in antimicrobial resistance and virulence genes, as well as in immune evasion cluster (IEC) genes, and to type recovered isolates. Seven of 100 samples (7%) contained S. aureus: 6 samples harbored methicillin-susceptible S. aureus (MSSA) and 1 pork sample harbored methicillin-resistant S. aureus (MRSA). The MRSA isolate corresponded to the ST398 genetic lineage with a multidrug resistance profile and the absence of human IEC genes, which pointed to a typical livestock-associated MRSA profile. MRSA isolate was ascribed to the spa-type t011, agr-type I, and SCCmec-V and showed resistance to erythromycin, clindamycin, tetracycline, and streptomycin, in addition to beta-lactams. The remaining six MSSA strains belonged to different sequence types and clonal complexes (three isolates ST45/CC45, one ST617/CC45, one ST5/CC5, and one ST109/CC9), being susceptible to most antibiotics tested but showing a wide virulence gene profile. Five of the six MSSA strains (except ST617/CC45) contained the enterotoxin egc-cluster or egc-like-cluster genes, and strain ST109/CC9 contained eta gene (encoding exfoliatin A). The presence of human IEC genes in MSSA strains (types B and D) points to a possible contamination of meat samples from an undefined human source. The presence of S. aureus with enterotoxin genes and MRSA in food samples might have implications in public health. The IEC system could be a good marker to follow the S. aureus contamination source in meat food products. PMID- 24479576 TI - Narrative therapy vs. cognitive-behavioral therapy for moderate depression: empirical evidence from a controlled clinical trial. AB - BACKGROUND: Systematic studies of the efficacy of Narrative Therapy (NT) for depression are sparse. OBJECTIVE: To evaluate the efficacy of individual NT for moderate depression in adults compared to Cognitive-Behavioral Therapy (CBT). METHOD: Sixty-three depressed clients were assigned to either NT or CBT. The Beck Depression Inventory-II (BDI-II) and Outcome Questionnaire-45.2 (OQ-45.2) were used as outcome measures. RESULTS: We found a significant symptomatic reduction in both treatments. Group differences favoring CBT were found on the BDI-II, but not on the OQ-45.2. CONCLUSIONS: Pre- to post-treatment effect sizes for completers in both groups were superior to benchmarked waiting-list control groups. PMID- 24479577 TI - Increased prevalence of bladder and intestinal dysfunction in amyotrophic lateral sclerosis. AB - Amyotrophic lateral sclerosis (ALS) is predominantly characterized by a progressive loss of motor function. While autonomic dysfunction has been described in ALS, little is known about the prevalence of lower urinary tract symptoms (LUTS) and intestinal dysfunction. We investigated disease severity, LUTS and intestinal dysfunction in 43 patients with ALS attending our outpatient department applying the ALS functional rating scale, the International Consultation on Incontinence Modular Questionnaire, the Urinary Distress Inventory and the Cleveland Clinic Incontinence Score. Results were compared to the German population of a cross-sectional study assessing LUTS in the healthy population, the EPIC study. Results showed that urinary incontinence was increased in patients with ALS aged >= 60 years compared to the EPIC cohort (female: 50%/19% (ALS/EPIC), p = 0.026; male: 36%/11% (ALS/EPIC), p = 0.002). No difference was seen at 40-59 years of age. Urge incontinence was the predominant presentation (73% of symptoms). A high symptom burden was stated (ICIQ-SF quality of life subscore 5.5/10). Intake of muscle relaxants and anticholinergics was associated with both urinary incontinence and severity of symptoms. Furthermore, a high prevalence of constipation (46%), but not stool incontinence (9%), was noted. In conclusion, the increased prevalence of urge incontinence and high symptom burden imply that in patients with ALS, LUTS should be increasingly investigated for. PMID- 24479578 TI - The relationship between sleep habits and academic performance in dental students in Croatia. AB - INTRODUCTION: It is well accepted that sleep and lifestyle habits affect academic success in students. However, sleep patterns and sleep problems amongst dental students have been insufficiently addressed in the literature. The purpose of this study was to evaluate sleep habits of dental students and the relationship between sleep habits and academic performance. MATERIALS AND METHODS: A self administered questionnaire on sleep habits, academic performance and lifestyle was administered. The participants were 447 dental students from Split University Dental Medicine School and Zagreb University Dental Medicine School from the six academic years. The subjects were classified into two groups based on academic success (high-performing vs. low-performing students) for comparison of sleep and lifestyle habits. RESULTS: Amongst the whole group of students, average bedtime and wake time during weekday was significantly earlier compared with weekend. Main findings indicate that students with high academic performance had earlier bedtimes during weekdays and weekends, earlier wake times during weekends and shorter sleep latency compared with low academic performing students. CONCLUSION: Self-reported academic performance of dental students in Croatia is associated with timing of sleep and wakefulness, rather than with total sleep time duration. PMID- 24479579 TI - Influence of surgical drills wear on thermal process generated in bones. AB - The influence of the wear rate of drills used in bone surgery on the temperature distribution in the femur models (Sawbones) is presented in the paper. Surgical drills of diameter d = 4.5 mm and diverse edge geometry (90 degrees and 120 degrees ) were selected for the study. In order to carry out thermal analysis with the use of finite element, experimental studies of wear process were necessary. These studies, among others, consisted in determination of average values of axial forces and cutting torques as a function of the number of drilled holes. The study showed an impact of the drill geometry on values that describe cutting process. It was found that the greatest values of torques and axial cutting forces occur in drills of point angle of 120 degrees . Next, in order to determine the effect of wear rate on the generation of temperature in the cutting zone, thermal analysis of the drilling process using the finite element method was carried out. It was found that higher temperatures in the bone are observed for drilling with the use of the drill of point angle equal to 120 degrees , as in the experimental study. For the tools of such edge geometry the wear of cutting edge is more intensive and the generated temperature in femur for the wear land VBB = 0.32 mm has reached the critical value associated with the process of thermal necrosis. PMID- 24479580 TI - Atomic structure of defects in anion-deficient perovskite-based ferrites with a crystallographic shear structure. AB - Crystallographic shear (CS) planes provide a new structure-generation mechanism in the anion-deficient perovskites containing lone-pair cations. Pb2Sr2Bi2Fe6O16, a new n = 6 representative of the A(n)B(n)O(3n-2) homologous series of the perovskite-based ferrites with the CS structure, has been synthesized using the solid-state technique. The structure is built of perovskite blocks with a thickness of four FeO6 octahedra spaced by double columns of FeO5 edge-sharing distorted tetragonal pyramids, forming 1/2[110](101)p CS planes (space group Pnma, a = 5.6690(2) A, b = 3.9108(1) A, c = 32.643(1) A). Pb2Sr2Bi2Fe6O16 features a wealth of microstructural phenomena caused by the flexibility of the CS planes due to the variable ratio and length of the constituting fragments with {101}p and {001}p orientation. This leads to the formation of "waves", "hairpins", "Gamma-shaped" defects, and inclusions of the hitherto unknown layered anion-deficient perovskites Bi2(Sr,Pb)Fe3O8.5 and Bi3(Sr,Pb)Fe4O11.5. Using a combination of diffraction, imaging, and spectroscopic transmission electron microscopy techniques this complex microstructure was fully characterized, including direct determination of positions, chemical composition, and coordination number of individual atomic species. The complex defect structure makes these perovskites particularly similar to the CS structures in ReO3-type oxides. The flexibility of the CS planes appears to be a specific feature of the Sr-based system, related to the geometric match between the SrO perovskite layers and the {100}p segments of the CS planes. PMID- 24479582 TI - ACS Select on nanotechnology in food and agriculture: a perspective on implications and applications. PMID- 24479581 TI - Inequities in access to health care in different health systems: a study in municipalities of central Colombia and north-eastern Brazil. AB - INTRODUCTION: Health system reforms are undertaken with the aim of improving equity of access to health care. Their impact is generally analyzed based on health care utilization, without distinguishing between levels of care. This study aims to analyze inequities in access to the continuum of care in municipalities of Brazil and Colombia. METHODS: A cross-sectional study was conducted based on a survey of a multistage probability sample of people who had had at least one health problem in the prior three months (2,163 in Colombia and 2,167 in Brazil). The outcome variables were dichotomous variables on the utilization of curative and preventive services. The main independent variables were income, being the holder of a private health plan and, in Colombia, type of insurance scheme of the General System of Social Security in Health (SGSSS). For each country, the prevalence of the outcome variables was calculated overall and stratified by levels of per capita income, SGSSS insurance schemes and private health plan. Prevalence ratios were computed by means of Poisson regression models with robust variance, controlling for health care need. RESULTS: There are inequities in favor of individuals of a higher socioeconomic status: in Colombia, in the three different care levels (primary, outpatient secondary and emergency care) and preventive activities; and in Brazil, in the use of outpatient secondary care services and preventive activities, whilst lower-income individuals make greater use of the primary care services. In both countries, inequity in the use of outpatient secondary care is more pronounced than in the other care levels. Income in both countries, insurance scheme enrollment in Colombia and holding a private health plan in Brazil all contribute to the presence of inequities in utilization. CONCLUSIONS: Twenty years after the introduction of reforms implemented to improve equity in access to health care, inequities, defined in terms of unequal use for equal need, are still present in both countries. The design of the health systems appears to determine access to the health services: two insurance schemes in Colombia with different benefits packages and a segmented system in Brazil, with a significant private component. PMID- 24479583 TI - Missing link or not, mobilise against delirium. AB - Delirium is known to be a predictor of adverse outcomes. In a prospective study Abelha and colleagues showed that postoperative delirium was an independent risk factor for deterioration in functional capacity following discharge. While evidence for causality remains elusive, there is no doubt that patients who develop delirium are left with new functional and cognitive impairment. Finding a pharmacological treatment for the prevention and treatment of delirium is a priority in delirium research and the results of ongoing trials are awaited. Early mobilisation of ICU patients has been demonstrated to decrease delirium and improve functional outcomes. Resources should be directed to appropriate, progressive mobilisation of all critically ill patients as a priority. PMID- 24479584 TI - Metabolism and disposition of ABT-894, a novel alpha4beta2 neuronal acetylcholine receptor agonist, in mice and monkeys. AB - 1. Metabolism and disposition of ABT-894 was investigated in hepatocytes, in mice and monkeys receiving [(14)C]ABT-894. 2. In hepatocytes, turnover rate of ABT-894 was slow in all species with more than 90% of parent remaining. M3 (carbamoyl glucuronide) and M6 (mono-oxidation) were detected across species. 3. ABT-894 showed species-specific disposition profiles. ABT-894 was primarily eliminated by renal secretion in mice. Whereas, monkey mainly cleared ABT-894 metabolically. 4. ABT-894 underwent two primary routes of metabolism in monkeys: N-carbamoyl glucuronidation to form M3 and oxidation product M1. M3 was the major metabolite in monkey excreta. M3 was observed in mice urine. Circulating levels of M3 in terms of M3/ABT-894 ratios were essentially absent in mice, but were high in monkeys. 5. Understanding the species difference in the clearance mechanism is the key to the accurate projection of the human clearance and preclinical safety assessment. Lack of species difference in the metabolism of ABT-894 in hepatocytes certainly creates a challenge in predicting its metabolism and pharmacokinetics in human. Based on available metabolism and pharmacokinetic data of ABT-894 in human, monkey is the preferred species in predicting human clearance since it presents a similar clearance mechanism from that observed in human. PMID- 24479590 TI - Diabetes technology and therapy in the pediatric age group. PMID- 24479586 TI - Inhibitory effects of imatinib mesylate on human epidermal melanocytes. AB - BACKGROUND: In recent years, increasing attention has been focused on the skin hypopigmentation that develops after the initiation of imatinib mesylate therapy in patients with chronic myeloid leukaemia (CML). AIM: To understand the underlying mechanism of this hypopigmentation effect, and to explore the possibility of using imatinib in the treatment of pigmentation disorders. METHODS: We examined the effects of imatinib on the proliferation, apoptosis, melanin content and melanogenic activity of human primary epidermal melanocytes. The responsible molecular events were also investigated in a mechanism study. RESULTS: We found that imatinib led to a dramatic decrease in total melanin content in cultured melanocytes, by affecting melanocyte number and/or melanogenesis in a dose-dependent manner. This inhibition of melanogenesis was due to suppressed expression of tyrosinase and microphthalmia-associated transcription factor (MiTF). Furthermore, stem cell factor (SCF)-stimulated c-Kit activation and melanocyte proliferation were completely abrogated by imatinib. CONCLUSIONS: Inactivation of c-Kit signalling by imatinib has inhibitory effects on melanocyte survival, proliferation and melanogenesis, which explains the clinical hypopigmentation seen in patients with CML. These results also support using imatinib as a clinical depigmentation agent when dosage being carefully determined. PMID- 24479585 TI - Water dynamics in protein hydration shells: the molecular origins of the dynamical perturbation. AB - Protein hydration shell dynamics play an important role in biochemical processes including protein folding, enzyme function, and molecular recognition. We present here a comparison of the reorientation dynamics of individual water molecules within the hydration shell of a series of globular proteins: acetylcholinesterase, subtilisin Carlsberg, lysozyme, and ubiquitin. Molecular dynamics simulations and analytical models are used to access site-resolved information on hydration shell dynamics and to elucidate the molecular origins of the dynamical perturbation of hydration shell water relative to bulk water. We show that all four proteins have very similar hydration shell dynamics, despite their wide range of sizes and functions, and differing secondary structures. We demonstrate that this arises from the similar local surface topology and surface chemical composition of the four proteins, and that such local factors alone are sufficient to rationalize the hydration shell dynamics. We propose that these conclusions can be generalized to a wide range of globular proteins. We also show that protein conformational fluctuations induce a dynamical heterogeneity within the hydration layer. We finally address the effect of confinement on hydration shell dynamics via a site-resolved analysis and connect our results to experiments via the calculation of two-dimensional infrared spectra. PMID- 24479591 TI - Continuous glucose monitoring in 2013. PMID- 24479592 TI - Diabetes technology and the human factor. PMID- 24479593 TI - Newer therapies for diabetes management. PMID- 24479594 TI - Insulin pumps. PMID- 24479595 TI - Technologies in diabetes--the fifth ATTD yearbook. PMID- 24479596 TI - Closing the loop. PMID- 24479597 TI - Self-monitoring of blood glucose--an overview. PMID- 24479598 TI - New insulins and insulin therapy. PMID- 24479599 TI - Insulin pens and new ways of insulin delivery. PMID- 24479600 TI - Using health information technology to prevent and treat diabetes. PMID- 24479601 TI - Technology and pregnancy. PMID- 24479602 TI - Metabolic surgery is no longer just bariatric surgery. PMID- 24479603 TI - Immune intervention for type 1 diabetes, 2012-2013. PMID- 24479604 TI - Physical activity and exercise. PMID- 24479605 TI - Integration of primary health services: being put together does not mean they will work together. AB - BACKGROUND: This paper reports on an Australian experience of co-locating a range of different primary health services into one building, with the aim of providing integrated services. It discusses some of the early challenges involved with moving services together and reasons why collaborative and integrated working relationships to improve the clients' journey, may remain elusive. METHODS: Ethnographic observational data was collected within a GP plus site as part of day-to-day interactions between the research officer and health professionals. This involved observations of team processes within and across teams at the site. Observations were thematically analysed using a social anthropological approach. RESULTS: Three main themes arose from the analysis: Infrastructural impediments to collaboration; Territorialism; and Interprofessional practice (IPP) simply not on the agenda. The experience of this setting demonstrates that dedicated staff and resources are needed to keep IPP on the agenda of health service organisations. This is especially important where organisations are attempting to implement new models of collaborative and co-located services. Furthermore, it shows that establishing IPP within newly co-located services is a process that needs time to develop, as part of teams building trust with each other in new circumstances, in order to eventually build a new cultural identity for the co located services. CONCLUSIONS: Co-located health service systems can be complex, with competing priorities and differing strategic plans and performance indicators to meet. This, coupled with the tendency for policy makers to move on to their next issue of focus, and to shift resources in the process, means that adequate time and resources for IPP are often overlooked. Shared interprofessional student placements may be one way forward. PMID- 24479606 TI - Red blood cell antigen portrait of self-identified black donors in Quebec. AB - OBJECTIVES: The goal of this study was to establish a red blood cell antigen portrait of self-identified Black donors for the province of Quebec, Canada. BACKGROUND: The demand for extensively phenotyped red blood cells is on the rise. A good example is the sickle cell patient cohort. To better answer their transfusion needs, Hema-Quebec put forward great efforts to increase the recruitment of donors among cultural communities. MATERIALS AND METHODS: In October 2009, an optional question was added on the record of donation to indicate the donor's ethnicity. Self-identified Black donors were extensively phenotyped by the Immunohematology Laboratory, whereas the Research and Development team genotyped red blood cell antigens to complete the picture. RESULTS: Approximately 1500 self-identified Black donors have donated blood at least once since the beginning of the programme. Genotyping results predicted rare phenotypes: 18 S-s- (3 U-, 15 U+(w) ), 15 Js(a+b-), 5 Hy-, 3 Jo(a-), 34 hr(B) +(w) /- and 15 hr(B)-. CONCLUSION: These Black donors, with or without a rare phenotype, are precious to the patient cohort depending on blood transfusions and to our organisation as the blood provider for the whole province of Quebec. PMID- 24479607 TI - Inulavosin and its benzo-derivatives, melanogenesis inhibitors, target the copper loading mechanism to the active site of tyrosinase. AB - Tyrosinase, a melanosomal membrane protein containing copper, is a key enzyme for melanin synthesis in melanocytes. Inulavosin inhibits melanogenesis by enhancing a degradation of tyrosinase in lysosomes. However, the mechanism by which inulavosin redirects tyrosinase to lysosomes is yet unknown. The analyses of structure-activity relationship of inulavosin and its benzo-derivatives reveal that the hydroxyl and the methyl groups play a critical role in their inhibitory activity. Intriguingly, the docking studies to tyrosinase suggest that the compounds showing inhibitory activity bind through hydrophobic interactions to the cavity of tyrosinase below which the copper-binding sites are located. This cavity is proposed to be required for the association with a chaperon that assists in copper loading to tyrosinase in Streptomyces antibioticus. Inulavosin and its benzo-derivatives may compete with the copper chaperon and result in a lysosomal mistargeting of apo-tyrosinase that has a conformational defect. PMID- 24479609 TI - Palladium-catalyzed cyclization reactions of allenes in the presence of unsaturated carbon-carbon bonds. AB - Modern synthetic chemists have looked for rapid and efficient ways to construct complex molecules while minimizing synthetic manipulation and maximizing atom economy. Over the last few decades, researchers have made considerable progress toward these goals by taking full advantage of transition metal catalysis and the diverse reactivities of allenes, functional groups which include two cumulative carbon-carbon double bonds. This Account describes our efforts toward the development of Pd-catalyzed cyclization reactions of allenes in the presence of compounds that contain unsaturated carbon-carbon bonds such as alkenyl halides, simple alkenes, allenes, electron-deficient alkynes, or propargylic carbonates. First, we discuss the coupling-cyclization reactions of allenes bearing a nucleophilic functionality in the presence of alkenyl halides, simple alkenes, functionalized and nonfunctionalized allenes, or electron-deficient alkynes. These processes generally involve a Pd(II)-catalyzed sequence: cyclic nucleopalladation, insertion or nucleopalladation, and beta-elimination, reductive elimination, cyclic allylation or protonation. We then focus on Pd(0) catalyzed cyclization reactions of allenes in the presence of propargylic carbonates. In these transformations, oxidative addition of propargylic carbonates with Pd(0) affords allenylpalladium(II) species, which then react with allenes via insertion or nucleopalladation. These transformations provide easy access to a variety of synthetically versatile monocyclic, dumbbell-type bicyclic, and fused multicyclic compounds. We have also prepared a series of highly enantioenriched products using an axial-to-central chirality transfer strategy. A range of allenes are now readily available, including optically active ones with central and/or axial chirality. Expansion of these reactions to include other types of functionalized allenes, such as allenyl thiols, allenyl hydroxyl amines, and other structures with differing steric and electronic character, could allow access to cyclic skeletons that previously were difficult to prepare. We anticipate that other studies will continue to explore this promising area of synthetic organic chemistry. PMID- 24479608 TI - Early caffeine therapy for prevention of bronchopulmonary dysplasia in preterm infants. AB - OBJECTIVE: To determine if an early commencement of caffeine is associated with improved survival without bronchopulmonary dysplasia (BPD) in preterm infants. METHODS: Retrospective data analysis from the Alere Neonatal Database for infants weighing <=1250 g, and treated with caffeine within the first 10 days of life. The neonatal outcomes were compared between the infants who received early caffeine (0-2 days) with the infants who received delayed caffeine (3-10 days). RESULTS: A total of 2951 infants met the inclusion criteria (early caffeine 1986, late caffeine 965). The early use of caffeine was associated with reduction in BPD (OR 0.69, 95% CI 0.58-0.82, p < 0.001) and BPD or death (OR 0.77, 95% CI 0.63 0.94, p = 0.01). Other respiratory outcomes also improved with the early commencement of caffeine. The frequency of severe intraventricular hemorrhage and patent ductus arteriosus was lower and the length of hospitalization was shorter in infants receiving early caffeine therapy. However, early use of caffeine was associated with an increase in the risk of nectrotizing enterocolits (NEC) (OR 1.41, 95% CI 1.04-1.91, p = 0.027). CONCLUSION: Early commencement of caffeine was associated with improvement in survival without BPD in preterm infants. The risk of NEC with early caffeine use requires further investigation. PMID- 24479610 TI - Emergence of atrial repolarization alternans at late stages of remodeling: the "second factor" in atrial fibrillation progression? PMID- 24479611 TI - Landing ground reaction forces in figure skaters and non-skaters. AB - Researchers and clinicians have suggested that overuse injuries to the lower back and lower extremities of figure skaters may be associated with the repeated high impact forces sustained during jump landings. Our primary aim was to compare the vertical ground reaction forces (GRFs) in freestyle figure skaters (n = 26) and non-skaters (n = 18) for the same barefoot single leg landing on a force plate from a 20 cm platform. Compared with non-skaters, skaters exhibited a significantly greater normalised peak GRF (3.50 +/- 0.47 * body weight for skaters vs. 3.13 +/- 0.45 * body weight for non-skaters), significantly shorter time to peak GRF (81.21 +/- 14.01 ms for skaters vs. 93.81 +/- 16.49 ms for non skaters), and significantly longer time to stabilisation (TTS) of the GRF (2.38 +/- 0.07 s for skaters vs. 2.22 +/- 0.07 s for non-skaters). Skaters also confined their centre of pressure (CoP) to a significantly smaller mediolateral (M-L) (25%) and anterior-posterior (A-P) (40%) range during the landing phase, with the position of the CoP located in the mid to forefoot region. The narrower and more forward position of the CoP in skaters may at least partially explain the greater peak GRF, shorter time to peak, and longer TTS. Training and/or equipment modification serve as potential targets to decrease peak GRF by distributing it over a longer time period. More comprehensive studies including electromyography and motion capture are needed to fully characterise the unique figure skater landing strategy. PMID- 24479612 TI - Coparenting experiences in African American families: an examination of single mothers and their nonmarital coparents. AB - African American youth from single-mother homes continue to be overrepresented in statistics on risk behavior and delinquency, a trend that many be attributed to father-absence, socioeconomic disadvantage, and compromises in parenting more typical of single than two-parent families. Yet, this risk-focused perspective ignores a long-standing strength of the African American community, the involvement and potential protective impact of extended family members in childrearing. This study describes the experiences of 95 African American single mothers and their nonmarital coparents who participated in a study of African American single-mother families with an 11-16-year-old child. Specifically, the study examines: (a) the extent to which nonmarital coparents are involved in childrearing; (b) the relative levels of risk (i.e., depression, mother-coparent conflict) and protective (i.e., parenting) associated with maternal and coparent involvement; and (c) how similarly and/or differently coparent and mother variables operate with regard to youth externalizing problems. Findings reveal that a range of family members and other adults actively participate in childrearing in African American single-mother families, coparents do not differ from mothers on certain study variables (i.e., depression and mother-coparent conflict) but do for others (parenting), and coparent involvement is associated with youth adjustment in ways that are similar to our more established understanding of maternal involvement. The potential clinical implications of the findings are discussed and future research directions are highlighted. PMID- 24479614 TI - Public knowledge and preventive behavior during a large-scale Salmonella outbreak: results from an online survey in the Netherlands. AB - BACKGROUND: Food-borne Salmonella infections are a worldwide concern. During a large-scale outbreak, it is important that the public follows preventive advice. To increase compliance, insight in how the public gathers its knowledge and which factors determine whether or not an individual complies with preventive advice is crucial. METHODS: In 2012, contaminated salmon caused a large Salmonella Thompson outbreak in the Netherlands. During the outbreak, we conducted an online survey (n = 1,057) to assess the general public's perceptions, knowledge, preventive behavior and sources of information. RESULTS: Respondents perceived Salmonella infections and the 2012 outbreak as severe (m = 4.21; five-point scale with 5 as severe). Their knowledge regarding common food sources, the incubation period and regular treatment of Salmonella (gastro-enteritis) was relatively low (e.g., only 28.7% knew that Salmonella is not normally treated with antibiotics). Preventive behavior differed widely, and the majority (64.7%) did not check for contaminated salmon at home. Most information about the outbreak was gathered through traditional media and news and newspaper websites. This was mostly determined by time spent on the medium. Social media played a marginal role. Wikipedia seemed a potentially important source of information. CONCLUSIONS: To persuade the public to take preventive actions, public health organizations should deliver their message primarily through mass media. Wikipedia seems a promising instrument for educating the public about food-borne Salmonella. PMID- 24479613 TI - Finding the missing honey bee genes: lessons learned from a genome upgrade. AB - BACKGROUND: The first generation of genome sequence assemblies and annotations have had a significant impact upon our understanding of the biology of the sequenced species, the phylogenetic relationships among species, the study of populations within and across species, and have informed the biology of humans. As only a few Metazoan genomes are approaching finished quality (human, mouse, fly and worm), there is room for improvement of most genome assemblies. The honey bee (Apis mellifera) genome, published in 2006, was noted for its bimodal GC content distribution that affected the quality of the assembly in some regions and for fewer genes in the initial gene set (OGSv1.0) compared to what would be expected based on other sequenced insect genomes. RESULTS: Here, we report an improved honey bee genome assembly (Amel_4.5) with a new gene annotation set (OGSv3.2), and show that the honey bee genome contains a number of genes similar to that of other insect genomes, contrary to what was suggested in OGSv1.0. The new genome assembly is more contiguous and complete and the new gene set includes ~5000 more protein-coding genes, 50% more than previously reported. About 1/6 of the additional genes were due to improvements to the assembly, and the remaining were inferred based on new RNAseq and protein data. CONCLUSIONS: Lessons learned from this genome upgrade have important implications for future genome sequencing projects. Furthermore, the improvements significantly enhance genomic resources for the honey bee, a key model for social behavior and essential to global ecology through pollination. PMID- 24479615 TI - Tracking translocation of industrially relevant engineered nanomaterials (ENMs) across alveolar epithelial monolayers in vitro. AB - Abstract Relatively little is known about the fate of industrially relevant engineered nanomaterials (ENMs) in the lungs that can be used to convert administered doses to delivered doses. Inhalation exposure and subsequent translocation of ENMs across the epithelial lining layer of the lung might contribute to clearance, toxic effects or both. To allow precise quantitation of translocation across lung epithelial cells, we developed a method for tracking industrially relevant metal oxide ENMs in vitro using neutron activation. The versatility and sensitivity of the proposed in vitro epithelial translocation (INVET) system was demonstrated using a variety of industry relevant ENMs including CeO2 of various primary particle diameter, ZnO, and SiO2-coated CeO2 and ZnO particles. ENMs were neutron activated, forming gamma emitting isotopes (141)Ce and (65)Zn, respectively. Calu-3 lung epithelial cells cultured to confluency on transwell inserts were exposed to neutron-activated ENM dispersions at sub-lethal doses to investigate the link between ENM properties and translocation potential. The effects of ENM exposure on monolayer integrity was monitored by various methods. ENM translocation across the cellular monolayer was assessed by gamma spectrometry following 2, 4 and 24 h of exposure. Our results demonstrate that ENMs translocated in small amounts (e.g. <0.01% of the delivered dose at 24 h), predominantly via transcellular pathways without compromising monolayer integrity or disrupting tight junctions. It was also demonstrated that the delivery of particles in suspension to cells in culture is proportional to translocation, emphasizing the importance of accurate dosimetry when comparing ENM-cellular interactions for large panels of materials. The reported INVET system for tracking industrially relevant ENMs while accounting for dosimetry can be a valuable tool for investigating nano-bio interactions in the future. PMID- 24479617 TI - Relating individual differences in internalizing symptoms to emotional attention set-shifting in children. AB - A growing body of evidence points to links between internalizing symptoms and various executive functioning deficits, and especially to inhibition and set shifting difficulties. However, there is limited developmental research regarding the impact of internalizing symptoms on the shifting function, particularly during middle childhood. The current study investigated attention shifting in a sample of 108 early school age children (7-11 years) using a task-switching paradigm which required participants to alternate between emotional and nonemotional judgments. Results indicated that higher levels of internalizing symptoms (anxiety and depression) had a detrimental effect on performance efficiency (measured by response times) but not on response accuracy. This effect was only observed on emotional (and not on nonemotional) repetition trials and did not affect switching trials; moreover, it was only present when feedback was presented to participants. The findings partially support the predictions of the Attentional Control Theory in a developmental sample and suggest that individual differences in internalizing symptoms play a role in children's ability to flexibly alternate between emotional judgments. PMID- 24479616 TI - Beneficial effects of the nutritional supplements on the development of diabetic retinopathy. AB - PURPOSE: Increased oxidative stress and inflammatory mediators are implicated in the development of diabetic retinopathy, and in rats, its development can be prevented by antioxidants. Carotenoids are some of the powerful antioxidants, and diabetes decreases lutein and zeaxanthin levels in the serum and retina. The aim of this study is to investigate the effect of carotenoid containing nutritional supplements (Nutr), which is in clinical trials for 'Diabetes Vision Function', on diabetic retinopathy. METHODS: Streptozotocin-induced diabetic rats (Wistar, male) were fed Purina 5001 supplemented with nutritional supplements containing zeaxanthin, lutein, lipoic acid, omega-3 fatty acids and other nutrients, or without any supplementation. Retinal function was analyzed at ~4 months of diabetes by electroretinography. After 11 months of diabetes, capillary cell apoptosis (TUNEL-staining) and histopathology (degenerative capillaries) were quantified in trypsin-digested retinal vasculature. Retina was also analyzed for mitochondrial damage (by quantifying gene expressions of mtDNA-encoded proteins of the electron transport chain), VEGF and inflammatory mediators, interleukin 1beta and NF-kB. RESULTS: Diabetes impaired retinal function decreasing the amplitudes of both a- and b-waves. In the same animals, retinal capillary cell apoptosis and degenerative capillaries were increased by 3-4 fold. Gene expressions of mtDNA encoded proteins were decreased, and VEGF, interleukin-1beta and NF-kB levels were elevated. Supplementation with the nutrients prevented increased capillary cell apoptosis and vascular pathology, and ameliorated these diabetes-induced retinal abnormalities. CONCLUSIONS: Nutritional supplementation prevents diabetic retinopathy, and also maintains normal retinal function, mitochondrial homeostasis and inflammatory mediators. Thus, this supplementation could represent an achievable and inexpensive adjunct therapy to also inhibit retinopathy, a slow progressing disease feared most by diabetic patients. PMID- 24479618 TI - Additional diagnostic value of SPECT/CT to planar Iodine-123 labeled serum amyloid P component scintigraphy in a patient with pulmonary nodular amyloidosis. PMID- 24479619 TI - Regulated oligomerization induces uptake of a membrane protein into COPII vesicles independent of its cytosolic tail. AB - Export of transmembrane proteins from the endoplasmic reticulum (ER) is driven by directed incorporation into coat protein complex II (COPII)-coated vesicles. The sorting of some cargo proteins into COPII vesicles was shown to be mediated by specific interactions between transmembrane and COPII-coat-forming proteins. But even though some signals for ER exit have been identified on the cytosolic domains of membrane proteins, the general signaling and sorting mechanisms of ER export are still poorly understood. To investigate the role of cargo protein oligomer formation in the export process, we have created a transmembrane fusion protein that - owing to its FK506-binding protein domains - can be oligomerized in isolated membranes by addition of a small-molecule dimerizer. Packaging of the fusion protein into COPII vesicles is strongly enhanced in the presence of the dimerizer, demonstrating that the oligomeric state is an ER export signal for this membrane protein. Surprisingly, the cytosolic tail is not required for this oligomerization-dependent effect on protein sorting. Thus, an alternative mechanism, such as membrane bending, must account for ER export of the fusion protein. PMID- 24479620 TI - Sequence of the Essex-Lopresti lesion--a high-speed video documentation and kinematic analysis. AB - BACKGROUND AND PURPOSE: The pathomechanics of the Essex-Lopresti lesion are not fully understood. We used human cadavers and documented the genesis of the injury with high-speed cameras. METHODS: 4 formalin-fixed cadaveric specimens of human upper extremities were tested in a prototype, custom-made, drop-weight test bench. An axial high-energy impulse was applied and the development of the lesion was documented with 3 high-speed cameras. RESULTS: The high-speed images showed a transversal movement of the radius and ulna, which moved away from each other in the transversal plane during the impact. This resulted into a transversal rupture of the interosseous membrane, starting in its central portion, and only then did the radius migrate proximally and fracture. The lesion proceeded to the dislocation of the distal radio-ulnar joint and then to a full-blown Essex Lopresti lesion. INTERPRETATION: Our findings indicate that fracture of the radial head may be preceded by at least partial lesions of the interosseous membrane in the course of high-energy axial trauma. PMID- 24479621 TI - Bone transport of the tibia with a motorized intramedullary lengthening nail - a case report. PMID- 24479622 TI - A simple visual analog scale for pain is as responsive as the WOMAC, the SF-36, and the EQ-5D in measuring outcomes of revision hip arthroplasty. AB - BACKGROUND AND PURPOSE: Little is known about the comparative performance of patient-reported outcome measures in revision hip arthroplasty. We compared the performance of the WOMAC, the SF-36, the EQ-5D, and a pain-related visual analog scale (VAS) in revision hip arthroplasty. METHODS: 45 patients with aseptic prosthetic loosening following primary hip arthroplasty completed the WOMAC, the SF-36, the EQ-5D, and a VAS for pain-at baseline and 2 years after revision. Responsiveness of the measures was compared with the effect size (with >= 0.8 being considered large). Agreement between scales measuring the same type of outcome (pain or physical function) was assessed with the Bland-Altman method. RESULTS: The mean preoperative scores for the pain and physical function scales of WOMAC and SF-36, EQ-5D index, and VAS for pain improved statistically significantly 2 years after revision. The effect size for the WOMAC pain was 1.7, that for SF-36 pain was 1.4, that for WOMAC physical function was 1.6, that for SF-36 physical function was 0.8, and that for EQ-5D index was 1.2. The VAS for pain had an effect size of 2.1, which was larger than that for SF-36 pain and for the EQ-5D index (p <= 0.03) but not for WOMAC pain (p = 0.2). The limits of agreement between WOMAC pain, SF-36 pain, and the VAS scale measuring pain-and between the WOMAC and SF-36 scales measuring physical function-were wide. Internal-consistency reliability was high for the WOMAC and SF-36 scales but low for the EQ-5D. INTERPRETATION: In patients with first-time revision hip arthroplasty done for aseptic loosening, the WOMAC, SF-36, and EQ-5D showed high responsiveness in measuring patient-reported outcomes and the simple VAS for pain performed equally well. PMID- 24479623 TI - Effects of various drilling parameters on bone during implantology: An in vitro experimental study. AB - Due to temperature increase during bone drilling, bone necrosis is likely to occur. To minimize bone tissue damage during drilling, a detailed in vitro experimental study by using fresh calf cortical bones has been performed with various combined drilling parameters, such as: drilling environment, drill diameter, drill speed, drill force, feed-rate and drill coating. Bone temperatures at the drilling sites were recorded with high accuracy using multi thermocouples mounted around the tibial diaphyseal cortex. It was shown that temperatures increased with increased drill speeds. It also decreased with a higher feed-rate and drill force. It was also observed that TiBN coated drills caused higher temperatures in the bone than the uncoated drills and the temperatures increased with larger drill diameters. Although the influence of Simulated Body Fluid (SBF) on rising temperatures during drilling was higher for the TiBN coated drills, it was observed that these drills caused more damage to the bone structure. In order to minimize or avoid bone defects and necrosis, orthopaedic surgeons should consider the optimum drilling parameters. PMID- 24479624 TI - Effect of environment and genotype on commercial maize hybrids using LC/MS-based metabolomics. AB - We recently applied gas chromatography coupled to time-of-flight mass spectrometry (GC/TOF-MS) and multivariate statistical analysis to measure biological variation of many metabolites due to environment and genotype in forage and grain samples collected from 50 genetically diverse nongenetically modified (non-GM) DuPont Pioneer commercial maize hybrids grown at six North American locations. In the present study, the metabolome coverage was extended using a core subset of these grain and forage samples employing ultra high pressure liquid chromatography (uHPLC) mass spectrometry (LC/MS). A total of 286 and 857 metabolites were detected in grain and forage samples, respectively, using LC/MS. Multivariate statistical analysis was utilized to compare and correlate the metabolite profiles. Environment had a greater effect on the metabolome than genetic background. The results of this study support and extend previously published insights into the environmental and genetic associated perturbations to the metabolome that are not associated with transgenic modification. PMID- 24479625 TI - The protonation state of catalytic residues in the resting state of KasA revisited: detailed mechanism for the activation of KasA by its own substrate. AB - Mycobacterium tuberculosis is the causative pathogen of tuberculosis, the second leading cause of death from an infectious disease globally. beta-Ketoacyl ACP synthase I (KasA) is essential for the survival of M. tuberculosis, because it is one of the key enzymes in the biosynthetic pathway of mycolic acid, the building block of the cell wall in M. tuberculosis. To distinguish among the various suggested mechanisms of KasA that are based on different protonation states of the active site, we characterize its resting state by various theoretical approaches ranging from first-principle-based quantum mechanical/molecular mechanical molecular dynamics simulations (QM/MM MD) with large QM parts to force field-based MD and free energy perturbation computations. In contrast to a previous study that used less reliable semiempirical approaches in combination with smaller QM parts, our improved computations predict that the most important active site residues, Cys171 and His311, are neutral. Because the neutral catalytic residues are too unreactive to attack the substrate, the question of how their activation is achieved arises. Combining our computed results with structural information about the malonyl binding pocket, we devised a detailed model about the activation mechanism. A conformational change of Phe404 possibly triggered by the substrate is central for the activation because it switches KasA to the sufficiently reactive zwitterionic state. PMID- 24479626 TI - iPOP and its role in participatory medicine. AB - Michael Snyder shares his thoughts on participatory medicine and how omics profiling could fit into this new model of healthcare where patients are at the center of medicine. PMID- 24479627 TI - An atypical distribution of erythema elevatum diutinum. PMID- 24479628 TI - Computation of standard binding free energies of polar and charged ligands to the glutamate receptor GluA2. AB - Accurate calculation of the binding affinity of small molecules to proteins has the potential to become an important tool in rational drug design. In this study, we use the free energy perturbation (FEP) method with restraints to calculate the standard binding free energy of five ligands (ACPA, AMPA, CNQX, DNQX, and glutamate) to the glutamate receptor GluA2, which plays an essential role in synaptic transmission. To deal with the convergence problem in FEP calculations with charged ligands, we use a protocol where the ligand is coupled in the binding site while it is decoupled in bulk solution simultaneously. The contributions from the conformational, rotational, and translational entropies to the standard binding free energy are determined by applying/releasing respective restraints to the ligand in bulk/binding site. We also employ the confine-and release approach, which helps to resolve convergence problems in FEP calculations. Our results are in good agreement with the experimental values for all five ligands, including the charged ones which are often problematic in FEP calculations. We also analyze the different contributions to the binding free energy of each ligand to GluA2 and discuss the nature of these interactions. PMID- 24479629 TI - Isolation and characterisation of acetylcholinesterase inhibitors from Aquilaria subintegra for the treatment of Alzheimer's disease (AD). AB - Aquilaria subintegra, locally known as "Gaharu", belongs to the Thymelaeceae family. This plant's leaves have been claimed to be effective for the treatment of Alzheimer's disease (AD) by Malay traditional practitioner in Malaysia. In this research, the chloroform extracts of the leaves and stem of A. subintegra were tested for acetylcholinesterase (AChE) inhibitory activity. The Thin Layer Chromatography (TLC) results indicated the presence of phenols, flavonoids, terpenoids, and alkaloids compounds in the extracts. Analysis of the stem chloroform extracts with LCMS/MS displayed that it contains kaempferol 3,4,7 trimethyl ether. The AChE inhibitory activity of leaves and stem chloroform extracts and kaempferol were 80%, 93% and 85.8%, respectively. The Brine Shrimp Lethality Assay (BSLA) exhibited low to moderate toxicity of the chloroform extract from leaves (LC50=531.18 +/- 49.53 MUg/ml), the stem chloroform extract (LC50=407.34 +/- 68.05 MUg/ml) and kaempferol (LC50=762.41 +/- 45.09 MUg/ml). The extracts and kaempferol were not cytotoxic to human umbilical vein endothelial cells (HUVEC), human normal gastric epithelial cell line (GES-1) and human normal hepatic cell line (WRL-68). The effect of leaf and stem chloroform extracts and kaempferol were determined in the Radial Arm Maze (RAM) after administration by oral gavage to ICR male and female mice with valium-impaired memory. Administration of kaempferol to the mice significantly reduced the number of repeated entries into the arms of maze in males and females. In conclusion, the inhibition of AChE by leaf and stem chloroform extracts of A. subintegra could be due to the presence of kaempferol. This extract is safe for use as a natural AChE inhibitor as an alternative to berberine for the treatment of AD. PMID- 24479631 TI - Butyrylcholinesterase K and apolipoprotein epsilon4 affect cortical thickness and neuropsychiatric symptoms in Alzheimer's disease. AB - Two major genotypes are known to affect the development and progression of Alzheimer's disease (AD) and its response to cholinesterase inhibitors: the apolipoprotein E (ApoE) and butyrylcholinesterase genes (BChE). This study analyzed the effects of the BChE and ApoE genotypes on the cortical thickness of patients with AD and examined how these genotypes affect the neuropsychiatric symptoms of AD. AD-drug-naive patients who met the probable AD criteria proposed by the National Institute of Neurological and Communicative Disorders and Stroke Alzheimer's Disease and Related Disorders Association were recruited. Of 96 patients with AD, 65 were eligible for cortical thickness analysis. 3D T1 weighted images were acquired, and the cortical regions were segmented using the constrained Laplacian-based automated segmentation with proximities (CLASP) algorithm. Neuropsychiatric symptoms were measured by Neuropsychiatric Inventory (NPI) scores. BChE wild-type carriers (BChE-W) showed more thinning in the left dorsolateral prefrontal cortex, including the lateral premotor regions and anterior cingulate cortex, than did BChE-K variant carriers (BChE-K). ApoE epsilon4 carriers had a thinner left medial prefrontal cortex, left superior frontal cortex, and left posterior cingulate cortex than did ApoE-epsilon4 non carriers. Statistical analyses revealed that BChE-K carriers showed significantly less severe aberrant motor behavioral symptoms and that epsilon4 non-carriers showed less severe anxiety and indifference symptoms. The current findings show that, similar to ApoE-epsilon4 non-carriers, BChE-K carriers are protected from the pathological detriments of AD that affect frontal cortical thickness and neuropsychiatric symptoms. This study visually demonstrated the effects of the BChE-K and ApoE genotypes on the structural degeneration and complex aspects of the symptoms of AD. PMID- 24479630 TI - Identification of human ABAD inhibitors for rescuing Abeta-mediated mitochondrial dysfunction. AB - Amyloid beta (Abeta) binding alcohol dehydrogenase (ABAD) is a cellular cofactor for promoting (Abeta)-mediated mitochondrial and neuronal dysfunction, and cognitive decline in transgenic Alzheimer's disease (AD) mouse models. Targeting mitochondrial ABAD may represent a novel therapeutic strategy against AD. Here, we report the biological activity of small molecule ABAD inhibitors. Using in vitro surface plasmon resonance (SPR) studies, we synthesized compounds with strong binding affinities for ABAD. Further, these ABAD inhibitors (ABAD-4a and 4b) reduced ABAD enzyme activity and administration of phosphonate derivatives of ABAD inhibitors antagonized calcium-mediated mitochondrial swelling. Importantly, these compounds also abolished Abeta-induced mitochondrial dysfunction as shown by increased cytochrome c oxidase activity and adenosine-5'-triphosphate levels, suggesting protective mitochondrial function effects of these synthesized compounds. Thus, these compounds are potential candidates for further pharmacologic development to target ABAD to improve mitochondrial function. PMID- 24479632 TI - Shortened radiation therapy schedules for early-stage breast cancer: a review of hypofractionated whole-breast irradiation and accelerated partial breast irradiation. AB - Breast-conserving therapy consisting of segmental mastectomy followed by whole breast irradiation (WBI) has become widely accepted as an alternative to mastectomy as a treatment for women with early-stage breast cancer. WBI is typically delivered over the course of 5-6 weeks to the whole breast. Hypofractionated whole-breast irradiation and accelerated partial breast irradiation have developed as alternative radiation techniques for select patients with favorable early-stage breast cancer. These radiation regimens allow for greater patient convenience and the potential for decreased health care costs. We review here the scientific rationale behind delivering a shorter course of radiation therapy using these distinct treatment regimens in this setting as well as an overview of the published data and pending trials comparing these alternative treatment regimens to WBI. PMID- 24479633 TI - An observational study of socioeconomic and clinical gradients among diabetes patients hospitalized for avoidable causes: evidence of underlying health disparities in China? AB - INTRODUCTION: Diabetes is an ambulatory care sensitive condition that can generally be managed in outpatient settings with little or no need for inpatient care. As a preliminary step to investigate whether health disparities can be detected in the inpatient setting in China, we study how diabetic patients hospitalized without prior primary care contact or with greater severity of illness differ from other diabetic inpatients along socioeconomic and clinical dimensions. METHODS: We conduct an observational study using three years of clinical data for more than 1,800 adult patients with diabetes at two tertiary hospitals in East China. Univariate analysis and probit regression are used to characterize the differences in socioeconomic and clinical factors between patients hospitalized for diabetes with no prior primary care contact and those hospitalized with previous treatment experience. Secondarily, we use ordinary least squares regression to estimate the socioeconomic and clinical differences associated with poor serum glucose control at admission. RESULTS: We find that compared with patients hospitalized after prior treatment experience, inpatients with no previous primary care contact for diabetes have worse clinical laboratory values, are more likely to be young and male, to have lower education attainment, and to have poorer blood sugar control. Insurance, urban residence, and previous use of diabetic medication are in turn negatively correlated with HbA1c levels upon admission. CONCLUSION: Among hospitalized diabetic patients, socioeconomic factors such as lower education attainment, rural residence and lack of full insurance are associated with avoidable hospitalizations or worse indicators of health. Although we cannot definitively rule out selection bias, these findings are consistent with health disparities observable even at the inpatient level. Future studies should study the underlying mechanism by which traditionally vulnerable groups are more likely to be hospitalized for avoidable causes and with greater severity of illness. PMID- 24479634 TI - A pair of receptor-like kinases is responsible for natural variation in shoot growth response to mannitol treatment in Arabidopsis thaliana. AB - Growth is a complex trait that adapts to the prevailing conditions by integrating many internal and external signals. Understanding the molecular origin of this variation remains a challenging issue. In this study, natural variation of shoot growth under mannitol-induced stress was analyzed by standard quantitative trait locus mapping methods in a recombinant inbred line population derived from a cross between the Col-0 and Cvi-0 Arabidopsis thaliana accessions. Cloning of a major QTL specific to mannitol-induced stress condition led to identification of EGM1 and EGM2, a pair of tandem-duplicated genes encoding receptor-like kinases that are potentially involved in signaling of mannitol-associated stress responses. Using various genetic approaches, we identified two non-synonymous mutations in the EGM2[Cvi] allele that are shared by at least ten accessions from various origins and are probably responsible for a specific tolerance to mannitol. We have shown that the enhanced shoot growth phenotype contributed by the Cvi allele is not linked to generic osmotic properties but instead to a specific chemical property of mannitol itself. This result raises the question of the function of such a gene in A. thaliana, a species that does not synthesize mannitol. Our findings suggest that the receptor-like kinases encoded by EGM genes may be activated by mannitol produced by pathogens such as fungi, and may contribute to plant defense responses whenever mannitol is present. PMID- 24479635 TI - Commentary: bacteria play a critical role in the etiology of periodontal disease. PMID- 24479636 TI - A novel one-base insertion mutation in the retinitis pigmentosa 2 gene in a large X-linked Taiwanese family. PMID- 24479637 TI - Toward lead-oriented synthesis: one-pot version of Castagnoli condensation with nonactivated alicyclic anhydrides. AB - One-pot variation of Castagnoli condensation, that is, reaction of cyclic anhydrides, amines, and aldehydes, has been developed as a combinatorial approach to 1,2-disubstituted 5-oxopyrrolidine- and 6-oxopiperidine-3-carboxylic acids, as well as their benzo-analogues. Utility of the method to multigram preparation of building blocks and synthetic intermediates was also demonstrated. The final products are obtained in high yields and diastereoselectivity. The method fits well in the concept of lead-oriented synthesis; in particular, it can be used for the design of lead-like compound libraries, even if the strictest cut-offs are applied to the physicochemical properties of their members. PMID- 24479638 TI - Influence of patients' disease knowledge and beliefs about medicines on medication adherence: findings from a cross-sectional survey among patients with type 2 diabetes mellitus in Palestine. AB - BACKGROUND: Diabetes mellitus (DM) is a common serious health problem. Medication adherence is a key determinant of therapeutic success in patients with diabetes mellitus. The purpose of this study was to assess medication adherence and its potential association with beliefs and diabetes - related knowledge in patients with type II DM. METHODS: This study was carried out at Al-Makhfia governmental diabetes primary healthcare clinic in Nablus, Palestine. Main outcome of interest in the study was medication adherence. The Beliefs about Medicines Questionnaire (BMQ) was used to assess beliefs. Morisky Medication Adherence Scale (MMSA-8(c)) was used to assess medication adherence. The Michigan diabetes knowledge test (MDKT) was used to assess diabetes - related knowledge. Univariate and multivariate analysis were carried out using Statistical Package for Social Sciences (SPSS 20). RESULTS: Four hundred and five patients were interviewed. The mean +/- SD age of the participants was 58.3 +/- 10.4 (range = 28 - 90) years. More than half (53.3%) of the participants were females. Approximately 42.7% of the study sample were considered non-adherent (MMAS-8(c) score of < 6). Multivariate analysis showed that the following variables were significantly associated with non-adherence: disease-related knowledge, beliefs about necessity of anti-diabetic medications, concerns about adverse consequences of anti diabetic medications and beliefs that medicines in general are essentially harmful. Diabetic patients with high knowledge score and those with strong beliefs in the necessity of their anti-diabetic medications were less likely to be non-adherent ([O.R = 0.87, 95% CI of 0.78 - 0.97] and [O.R = 0.93, 95% of 0.88 - 0.99] respectively). However, diabetic patients with high concerns about adverse consequences of anti-diabetic medications and those with high belief that all medicines are harmful were more likely to be non-adherent ([O.R = 1.09; 95% C.I of 1.04 - 1.16] and [O.R = 1.09, 95% C.I of 1.02 - 1.16] respectively). CONCLUSIONS: Beliefs and knowledge are important factors in understanding variations in medication adherence among diabetic patients. The BMQ can be used as a tool to identify people at higher risk of non-adherence. Improving knowledge of patients about their illness might positively influence their medication adherence. PMID- 24479639 TI - Common variants explain a large fraction of the variability in the liability to psoriasis in a Han Chinese population. AB - BACKGROUND: Psoriasis is a common inflammatory skin disease with a known genetic component. Our previously published psoriasis genome-wide association study identified dozens of novel susceptibility loci in Han Chinese. However, these markers explained only a small fraction of the estimated heritable component of psoriasis. To better understand the unknown yet likely polygenic architecture in psoriasis, we applied a linear mixed model to quantify the variation in the liability to psoriasis explained by common genetic markers (minor allele frequency > 0.01) in a Han Chinese population. RESULTS: We explored the polygenic genetic architecture of psoriasis using genome-wide association data from 2,271 Han Chinese individuals. We estimated that 34.9% (s.e. = 6.0%, P = 9 * 10-9) of the variation in the liability to psoriasis is captured by common genotyped and imputed variants. We discuss these results in the context of the strong association between HLA variants and psoriasis. We also show that the variance explained by each chromosome is linearly correlated to its length (R2 = 0.27, P=0.01), and quantify the impact of a polygenic effect on the prediction and diagnosis of psoriasis. CONCLUSIONS: Our results suggest that psoriasis has a substantial polygenic component, which not only has implications for the development of genetic diagnostics and prognostics for psoriasis, but also suggests that more individual variants contributing to psoriasis may be detected if sample sizes in future association studies are increased. PMID- 24479640 TI - Self-reported impulsivity and inhibitory control in problem gamblers. AB - Impulsivity is considered a core feature of problem gambling; however, self reported impulsivity and inhibitory control may reflect disparate constructs. We examined self-reported impulsivity and inhibitory control in 39 treatment-seeking problem gamblers and 41 matched controls using a range of self-report questionnaires and laboratory inhibitory control tasks. We also investigated differences between treatment-seeking problem gamblers who prefer strategic (e.g., sports betting) and nonstrategic (e.g., electronic gaming machines) gambling activities. Treatment-seeking problem gamblers demonstrated elevated self-reported impulsivity, more go errors on the Stop Signal Task, and a lower gap score on the Random Number Generation task than matched controls. However, overall we did not find strong evidence that treatment-seeking problem gamblers are more impulsive on laboratory inhibitory control measures. Furthermore, strategic and nonstrategic problem gamblers did not differ from their respective controls on either self-reported impulsivity questionnaires or laboratory inhibitory control measures. Contrary to expectations, our results suggest that inhibitory dyscontrol may not be a key component for some treatment-seeking problem gamblers. PMID- 24479641 TI - Sustainable yield in theory and practice: bridging scientific and mainstream vernacular. AB - Groundwater is a vital resource in California, and the concept of "sustainable yield" is an attempt to determine a metric that can ensure the long-term resilience of groundwater systems. However, its meaning is ambiguous and quantification is challenging. To provide insight into developing a working definition that encompasses the inherent uncertainty and complexity of the term, this paper examines how sustainable yield in groundwater is interpreted by (1) scientists, (2) the courts in groundwater adjudications, (3) state agencies, and (4) local water practitioners. Through qualitative interviews, this paper identifies problems that local water agencies in the state encounter in engaging with sustainable yield as they incorporate the term in groundwater management practices. The authors recommend that any definitions make explicit the human dimensions of, and assumptions embedded in, the use of these terms in groundwater management practices, and they point to the value of participation in this process. PMID- 24479642 TI - Whole body vibration: unsupervised training or combined with a supervised multi purpose exercise for fitness? AB - The aim of the study was to compare the effect of an unsupervised whole body vibration (WBV) training and two different supervised multi-purpose exercise programmes, with and without WBV, on body composition, functional fitness and self-reported well-being in middle-aged adults. Fifty-four healthy participants (age 48.6 +/- 6.7 years) were randomly assigned to a vibration group (VG), a multi-purpose exercise group (MG) and a multi-purpose exercise with vibration group (VMG) and trained 3 days a week for 4 months. VG performed a standardised unsupervised WBV protocol, MG a supervised multi-purpose exercise and VMG a multi purpose exercise including vibration. After training, drop out was significantly higher in VG group (P = 0.016) when compared to VMG group. In both MG and VMG, body composition, sit-up, push-up, sit and reach, agility test, hopping test and self-reported general health significantly improved (P < 0.05). No additive effects were generated by the vibration stimulus. Percentage of body fat and agility test in VG had a significant opposite trend compared to VMG group (P < 0.05). In summary, an unsupervised WBV training should not be chosen for training protocol. However, positive effects on physical fitness and the best results in adherence could be achieved integrating WBV practice into a multi-purpose exercise training. PMID- 24479643 TI - Hydroxytyrosol and its potential therapeutic effects. AB - As olive oil is the main source of calories in the Mediterranean diet, a large number of studies have been carried out to characterize its role in various diseases and exploitation for the prevention and treatment of hypertension, carcinogenesis, diabetes, atherosclerosis, and other diseases. As one of the major polyphenols present in virgin olive oil, hydroxytyrosol shows a variety of pharmacological activities such as antioxidant properties, anticancer, anti inflammatory, and neuroprotective activities, and beneficial effects on the cardiovascular system, which show its potentiality for the development of dietary supplements. In the future, more attention should be paid to its action mechanism in vivo and synergistic effect. Further research will be performed to provide the theoretical basis for hydroxytyrosol and its derivatives use as health supplements. PMID- 24479644 TI - Living with the unexplained: coping, distress, and depression among women with chronic fatigue syndrome and/or fibromyalgia compared to an autoimmune disorder. AB - Chronic fatigue syndrome (CFS) and fibromyalgia are disabling conditions without objective diagnostic tests, clear-cut treatments, or established etiologies. Those with the disorders are viewed suspiciously, and claims of malingering are common, thus promoting further distress. It was hypothesized in the current study that levels of unsupportive social interactions and the coping styles used among those with CFS/fibromyalgia would be associated with perceived distress and depressive symptoms. Women with CFS/fibromyalgia (n=39), in fact, reported higher depression scores, greater perceived distress and more frequent unsupportive relationships than healthy women (n=55), whereas those with a chronic, but medically accepted illness comprising an autoimmune disorder (lupus erythematosus, multiple sclerosis, rheumatoid arthritis; n=28), displayed intermediate scores. High problem-focused coping was associated with low levels of depression and perceived distress in those with an autoimmune condition. In contrast, although CFS/fibromyalgia was also accompanied by higher depression scores and higher perceived distress, this occurred irrespective of problem focused coping. It is suggested that because the veracity of ambiguous illnesses is often questioned, this might represent a potent stressor in women with such illnesses, and even coping methods typically thought to be useful in other conditions, are not associated with diminished distress among those with CFS/fibromyalgia. PMID- 24479645 TI - Linguistic validation of the Alberta Context Tool and two measures of research use, for German residential long term care. AB - BACKGROUND: To study the association between organizational context and research utilization in German residential long term care (LTC), we translated three Canadian assessment instruments: the Alberta Context Tool (ACT), Estabrooks' Kinds of Research Utilization (RU) items and the Conceptual Research Utilization Scale. Target groups for the tools were health care aides (HCAs), registered nurses (RNs), allied health professionals (AHPs), clinical specialists and care managers. Through a cognitive debriefing process, we assessed response processes validity-an initial stage of validity, necessary before more advanced validity assessment. METHODS: We included 39 participants (16 HCAs, 5 RNs, 7 AHPs, 5 specialists and 6 managers) from five residential LTC facilities. We created lists of questionnaire items containing problematic items plus items randomly selected from the pool of remaining items. After participants completed the questionnaires, we conducted individual semi-structured cognitive interviews using verbal probing. We asked participants to reflect on their answers for list items in detail. Participants' answers were compared to concept maps defining the instrument concepts in detail. If at least two participants gave answers not matching concept map definitions, items were revised and re-tested with new target group participants. RESULTS: Cognitive debriefings started with HCAs. Based on the first round, we modified 4 of 58 ACT items, 1 ACT item stem and all 8 items of the RU tools. All items were understood by participants after another two rounds. We included revised HCA ACT items in the questionnaires for the other provider groups. In the RU tools for the other provider groups, we used different wording than the HCA version, as was done in the original English instruments. Only one cognitive debriefing round was needed with each of the other provider groups. CONCLUSION: Cognitive debriefing is essential to detect and respond to problematic instrument items, particularly when translating instruments for heterogeneous, less well educated provider groups such as HCAs. Cognitive debriefing is an important step in research tool development and a vital component of establishing response process validity evidence. Publishing cognitive debriefing results helps researchers to determine potentially critical elements of the translated tools and assists with interpreting scores. PMID- 24479646 TI - A tensomeric and planimetric evaluation of the durability of the bond between an orthodontic bracket and enamel. AB - The development of orthodontics has improved thanks to the introduction of adhesives which are physically and chemically akin to tooth enamel and brackets. These materials often fall short of the required durability standards. The objective was to evaluate the real strength of the adhesives and to introduce a proprietary device, generating multiple vectors of strength between dental brackets and the surface of enamel. 11 types of adhesive materials have been studied. 990 applications have been made using removed teeth, followed by a randomised creation of 11 groups containing 90 samples each. The threshold values of the strength needed to break the brackets off were determined in torsional, shear and tension strength tests. A comparison between tensometric and planimetric methods was made by means based on ARI index. Resistance was highest for torsional stress, weaker for shear stress and the weakest for tension stress. A correlation was found between tensometric results. The study attempted to systematise the methodology of direct tests. PMID- 24479648 TI - Transplastomic Nicotiana benthamiana plants expressing multiple defence genes encoding protease inhibitors and chitinase display broad-spectrum resistance against insects, pathogens and abiotic stresses. AB - Plastid engineering provides several advantages for the next generation of transgenic technology, including the convenient use of transgene stacking and the generation of high expression levels of foreign proteins. With the goal of generating transplastomic plants with multiresistance against both phytopathogens and insects, a construct containing a monocistronic patterned gene stack was transformed into Nicotiana benthamiana plastids harbouring sweet potato sporamin, taro cystatin and chitinase from Paecilomyces javanicus. Transplastomic lines were screened and characterized by Southern/Northern/Western blot analysis for the confirmation of transgene integration and respective expression level. Immunogold localization analyses confirmed the high level of accumulation proteins that were specifically expressed in leaf and root plastids. Subsequent functional bioassays confirmed that the gene stacks conferred a high level of resistance against both insects and phytopathogens. Specifically, larva of Spodoptera litura and Spodoptera exigua either died or exhibited growth retardation after ingesting transplastomic plant leaves. In addition, the inhibitory effects on both leaf spot diseases caused by Alternaria alternata and soft rot disease caused by Pectobacterium carotovorum subsp. carotovorum were markedly observed. Moreover, tolerance to abiotic stresses such as salt/osmotic stress was highly enhanced. The results confirmed that the simultaneous expression of sporamin, cystatin and chitinase conferred a broad spectrum of resistance. Conversely, the expression of single transgenes was not capable of conferring such resistance. To the best of our knowledge, this is the first study to demonstrate an efficacious stacked combination of plastid-expressed defence genes which resulted in an engineered tolerance to various abiotic and biotic stresses. PMID- 24479647 TI - Genotoxicity of multi-walled carbon nanotubes at occupationally relevant doses. AB - Carbon nanotubes are commercially-important products of nanotechnology; however, their low density and small size makes carbon nanotube respiratory exposures likely during their production or processing. We have previously shown mitotic spindle aberrations in cultured primary and immortalized human airway epithelial cells exposed to single-walled carbon nanotubes (SWCNT). In this study, we examined whether multi-walled carbon nanotubes (MWCNT) cause mitotic spindle damage in cultured cells at doses equivalent to 34 years of exposure at the NIOSH Recommended Exposure Limit (REL). MWCNT induced a dose responsive increase in disrupted centrosomes, abnormal mitotic spindles and aneuploid chromosome number 24 hours after exposure to 0.024, 0.24, 2.4 and 24 MUg/cm2 MWCNT. Monopolar mitotic spindles comprised 95% of disrupted mitoses. Three-dimensional reconstructions of 0.1 MUm optical sections showed carbon nanotubes integrated with microtubules, DNA and within the centrosome structure. Cell cycle analysis demonstrated a greater number of cells in S-phase and fewer cells in the G2 phase in MWCNT-treated compared to diluent control, indicating a G1/S block in the cell cycle. The monopolar phenotype of the disrupted mitotic spindles and the G1/S block in the cell cycle is in sharp contrast to the multi-polar spindle and G2 block in the cell cycle previously observed following exposure to SWCNT. One month following exposure to MWCNT there was a dramatic increase in both size and number of colonies compared to diluent control cultures, indicating a potential to pass the genetic damage to daughter cells. Our results demonstrate significant disruption of the mitotic spindle by MWCNT at occupationally relevant exposure levels. PMID- 24479649 TI - Genetic encoding of photocaged cysteine allows photoactivation of TEV protease in live mammalian cells. AB - We demonstrate the evolution of the PylRS/tRNA(CUA) pair for genetically encoding photocaged cysteine. By characterizing the incorporation in Escherichia coli and mammalian cells, and the photodeprotection process in vitro and in mammalian cells, we establish conditions for rapid efficient photodeprotection to reveal native proteins in live cells. We demonstrate the utility of this approach by rapidly activating TEV protease following illumination of single cells. PMID- 24479650 TI - Systemic AL amyloidosis with unusual cutaneous presentation unmasked by carotenoderma. AB - We present a case study of an elderly woman with systemic lambda-type AL amyloidosis that featured unusually extensive cutaneous involvement. The case initially presented with a sudden hyper beta-carotenemia with carotenoderma that instigated the clinical examination including skin biopsy. A diagnosis of systemic amyloidosis was made. Immunohistochemistry and Western-blot analysis indicated the presence of lambda light chain proteins in skin amyloid deposits. However, notable co-deposition of wild-type apoA-I and transthyretin was observed which caused initial diagnostic confusion. Proteomic analysis of microdissected skin amyloid deposits by mass spectrometry confirmed lambda light chain proteins in amyloid deposits and co-deposition of apolipoprotein A-IV and serum amyloid P component. The patient died from renal failure caused by amyloid nephropathy combined with analgesic nephropathy. The autopsy disclosed vascular, cardiac, renal and pulmonary amyloid deposition. While all amyloid deposits were positive for lambda light chain proteins, the immunodetection of apoA-I and transthyretin varied significantly among the visceral amyloid deposits. Although the patient exhibited a 1000-fold increase in serum beta-carotene levels, only a mild increase in retinol and lutein concentrations was observed. Increased beta carotene values were also found in the liver and the skin. The mechanisms underlying this hyper beta-carotenemia remain undetermined. PMID- 24479652 TI - Lung cancer patient advocacy and participatory medicine. AB - Kim Norris answers questions on the role of the patient advocate within a participatory medicine system. PMID- 24479651 TI - Early impact of mammographic screening in Western Siberia. PMID- 24479653 TI - Preparation and characterization of betulin nanoparticles for oral hypoglycemic drug by antisolvent precipitation. AB - Abstract Betulin, a kind of small molecular compound, was reported that has hypoglycemic effect. Due to its low aqueous solubility and high permeability, betulin has low and variable oral bioavailability. In this work, betulin nanoparticles were thus prepared by antisolvent precipitation for accelerating dissolution of this kind of poorly water-soluble drugs. Ethanol was used as solvent and deionized water was used as antisolvent. The effects of various experimental parameters on the mean particle size (MPS) of nanocrystallization betulin were investigated. The MPS of betulin nanoparticles suspension basically remain unchanged when precipitation time was within 60 min and then increased from 304 nm to 505 nm later. However, the MPS of betulin nanoparticles suspension decreased with increased betulin solution concentration. On the contrary, the MPS of betulin nanoparticles suspension decreased along with the increase of temperature. Stirring intensity and the speed ratio of solvent adding into antisolvent had no significant influences on the MPS of betulin nanoparticles suspension. Betulin nanoparticles suspension with a MPS of approximately 110 nm was achieved under the optimal precipitation conditions. FTIR, Liquid chromatography coupled with tandem mass spectrometry (LC-MS), X-ray diffraction (XRD), differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA) were used to analyze the characteristic of betulin nanoparticles powder. These results show that betulin nanoparticles powder has the same chemical structure as raw drug, but a smaller size and lower crystallinity. The dissolution rate and solubility of betulin nanoparticles powder were separately 3.12 and 1.54 times of raw drug. The bioavailability of betulin nanoparticles powder increased 1.21 times compared with raw betulin. The result of in vivo evaluation on diabetic animals demonstrates that the betulin nanoparticles powder show an excellent hypoglycemic effect compared with raw betulin. In addition, the residual ethanol is less than the ICH (International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human) limit for class 3 solvents of 5000 ppm or 0.5% for solvents. PMID- 24479654 TI - The vacuolar calcium sensors CBL2 and CBL3 affect seed size and embryonic development in Arabidopsis thaliana. AB - Stimulus-specific calcium (Ca(2+) ) signals have crucial functions in developmental processes in many organisms, and are deciphered by various Ca(2+) binding proteins. In Arabidopsis thaliana, a signaling network consisting of calcineurin B-like (CBL) protein calcium sensors and CBL-interacting protein kinases (CIPKs) has been shown to fulfil pivotal functions at the plasma membrane in regulating ion fluxes and abiotic stress responses. However, the role of tonoplast-localized CBL proteins and especially their function in regulating developmental programs remains largely unknown. In this study, we analyzed single and double mutants of the closely related tonoplast-localized calcium sensors CBL2 and CBL3, which show either reduction of function (rf) or complete loss of function (lf). While single cbl2 or cbl3 mutants did not display discernable phenotypes, cbl2/cbl3 mutants exhibited defects in vegetative growth and were severely impaired in seed development and morphology. Seeds of the cbl2/3rf mutant were smaller in size and exhibited reduced weight and fatty acid content compared to wild-type, but accumulation of sucrose was not altered. Moreover, accumulation of inositol hexakisphosphate (InsP6 ), the major storage form of phosphorus in seeds, was significantly reduced in mutant seeds. In addition, complete loss of CBL2 and CBL3 function in cbl2/3lf resulted in a high frequency of severe defects in embryonic development. Together, our findings reveal a crucial function of Ca(2+) -controlled processes at the vacuolar membrane as determinants of seed yield and size, and demonstrate the importance of vacuolar CBL calcium sensors for plant embryogenesis. PMID- 24479655 TI - Sacroiliitis secondary to catheter-related bacteremia due to Mycobacterium abscessus (sensu stricto). AB - We describe a case of sacroiliitis secondary to catheter-related bacteremia due to Mycobacterium abscessus (sensu stricto). This case confirms that MultiLocus sequence typing and variable-number tandem-repeat methods are very robust techniques to identify the pathogen species and to validate molecular epidemiological links among complex M. abscessus isolates. PMID- 24479656 TI - Pregnancy and cognition: deficits in inhibition are unrelated to changes in fitness. AB - This study investigated the relationship between changes in fitness and cognition that take place during pregnancy and the possibility that diminished fitness could be responsible for pregnancy-related cognitive deficits. Fifty-two pregnant women were compared to 15 nonpregnant controls on the Eriksen flanker task as well as a fitness test, both performed in a real-life setting to avoid laboratory related biases. Results show diminished inhibition in the third trimester unrelated to fitness level. This is the first study to report the impact of pregnancy on inhibitory control. PMID- 24479658 TI - Emotional suppression explains the link between early life stress and plasma oxytocin. AB - Early life stress (ELS) has been found to be associated with lower concentrations of plasma oxytocin (OT) in adulthood. It is not yet clear, however, what mechanisms underlie this association. The goal of the present study was to test the role of emotional suppression as an intervening variable between ELS in childhood and plasma OT. In a nonclinical sample of 90 men, ELS, emotional suppression, and plasma OT were assessed. Emotional suppression was positively associated with ELS (r = 0.37, p < 0.001) and negatively associated with plasma OT concentrations (r = -0.30, p < 0.01). In contrast, cognitive reappraisal - an alternative emotion regulation strategy - was not correlated with ELS or plasma OT concentrations. Cross-sectional regression analyses revealed that the ELS explained variance in plasma OT via emotional suppression. Moderation analyses revealed that the combination of high ELS and high emotional suppression was associated with the lowest concentrations of plasma oxytocin. These findings are consistent with the view that emotional suppression may be one pathway linking ELS and OT. PMID- 24479657 TI - Expression and activity of collagenases in the digital laminae of horses with carbohydrate overload-induced acute laminitis. AB - BACKGROUND: Matrix metalloproteinases (MMP) are hypothesized to degrade structurally important components of the laminar extracellular matrix (ECM) in horses with laminitis. OBJECTIVE: To compare levels of expression of stromelysin 1 (MMP-3), collagenases (MMP-1, -13), and membrane type-MMPs (MMP-14, -15, -16), and the distribution of their ECM substrates, in laminae of healthy horses and horses with carbohydrate overload laminitis. ANIMALS: Twenty-five adult horses. METHODS: Gene and protein expression were determined in extracts of laminae using real-time quantitative polymerase chain reaction and Western blotting after sodium dodecylsulfate polyacrylamide gel electrophoresis. Distribution of MMP-13 and ECM components was determined using indirect immunofluorescent microscopy of nonfixed frozen sections. ECM morphology was assessed by hematoxylin and eosin staining. RESULTS: Of the genes studied, only those encoding MMP-1 and -13 were upregulated in CHO-induced laminitis; MMP-1 at Obel grade (OG)1 lameness and MMP 13 at OG3 lameness. Laminar MMP-1 was present as 52 kDa proenzyme only. MMP-13 was present as pro- (61 kDa) and processed (48 kDa) enzyme. MMP-13 localized to the basal epithelium of the secondary epidermal laminae and its increased expression were accompanied by the appearance in secondary dermal laminae (SDL) of multiple foci that were devoid of collagen I, fibronectin, chondroitin and keratan sulfate glycosaminoglycans, and eosin-staining material. CONCLUSIONS AND CLINICAL RELEVANCE: MMP-13 is upregulated in laminae of horses with CHO-induced OG3 lameness and, by degrading components of the ECM, may contribute to the formation of ECM-free lesions (gaps or tears) that appear in the SDL with OG3 lameness. PMID- 24479659 TI - Modern therapeutic antibody drug discovery technologies. PMID- 24479660 TI - Detailed balance analysis and enhancement of open-circuit voltage in single nanowire solar cells. AB - We present a detailed balance analysis of current density-voltage modeling of a single-nanowire solar cell. Our analysis takes into account intrinsic material nonidealities in order to determine the theoretical efficiency limit of the single-nanowire solar cell. The analysis only requires the nanowire's absorption cross-section over all angles, which can be readily calculated analytically. We show that the behavior of both the current and voltage is due to coherent effects that arise from resonances of the nanowire. In addition, we elucidate the physics of open-circuit voltage enhancement over bulk cells in nanowires, by showing that the enhancement is related to the removal of resonances in the immediate spectral vicinity above the bandgap. PMID- 24479661 TI - The A55T and K153R polymorphisms of MSTN gene are associated with the strength training-induced muscle hypertrophy among Han Chinese men. AB - Myostatin, encoded by the MSTN gene, is a strong regulator of skeletal muscle growth. The present study aimed to investigate whether the A55T and K153R polymorphisms of MSTN were associated with the strength training-induced muscle hypertrophy among Han Chinese men. A total of 94 healthy, untrained men were recruited for an 8-week strength training programme. The thicknesses of biceps and quadriceps, along with anthropometric measurements of the participants, were assessed before and after the programme. The MSTN polymorphisms were subsequently genotyped employing polymerase chain reaction-restriction fragment length polymorphism technique and confirmed by DNA sequencing. One-way analysis of variance was used to compare the pre- and post-training measurements between carriers of different polymorphic genotypes. Our results indicated that individuals with AT + TT genotype of the A55T polymorphism showed a significant increase in the thickness of biceps (0.292 +/- 0.210 cm, P = 0.03), but not quadriceps (0.254 +/- 0.198 cm, P = 0.07), compared to carriers of AA genotype. For the K153R polymorphism, the increases in the thicknesses of both biceps (0.300 +/- 0.131 cm) and quadriceps (0.421 +/- 0.281 cm) were significantly higher among individuals with KR than those with KK genotypes (P < 0.01 for both muscles). The results obtained therefore suggested a possible association between the two polymorphisms and the strength training-induced muscle hypertrophy among men of Han Chinese ethnicity. PMID- 24479662 TI - Antiobese effects of capsaicin-chitosan microsphere (CCMS) in obese rats induced by high fat diet. AB - Chitosan (CTS) and capsaicin (CAP) are two kinds of effective ingredients for antiobesity, which are extracted from crab shells and Capsicum annuum. However, the strong taste of CAP makes it difficult to consume, and the antiobesity ability of CTS is limited. In this study, we prepared capsaicin-chitosan microspheres (CCMSs) by ion-cross-linking and spray drying and examined the antiobesity ability of CCMSs in obese rats. The effects of CCMSs on body weight, Lee's index, body fat, and serum lipids were investigated. The mRNA expression of PPARalpha, PPARgamma, leptin, UCP2, GPR120, FTO, and adiponectin in the liver was determined by quantitative real-time PCR, and the protein expression of adiponectin, leptin, PPARalpha, UCP2, and hepatic lipase in serum was evaluated by enzyme-linked immunosorbent assay. CCMSs were prepared with 85.17% entrapment efficiency and 8.87% mean drug loading. Compared with chitosan microspheres, CAP, and Orlistat, the CCMSs showed better ability to control body weight, body mass index, organ index, body fat, proportion of fat to body weight, and serum lipids. The CCMSs upregulated the expressions of PPARalpha, PPARgamma, UCP2, and adiponectin and downregulated the expression of leptin. CCMSs may thus be considered novel, safe, effective, and natural weight loss substances, and there is an additive effect between CTMS and capsaicin. PMID- 24479663 TI - Light smoking at base-line predicts a higher mortality risk to women than to men; evidence from a cohort with long follow-up. AB - BACKGROUND: There is conflicting evidence as to whether smoking is more harmful to women than to men. The UK Cotton Workers' Cohort was recruited in the 1960s and contained a high proportion of men and women smokers who were well matched in terms of age, job and length of time in job. The cohort has been followed up for 42 years. METHODS: Mortality in the cohort was analysed using an individual relative survival method and Cox regression. Whether smoking, ascertained at baseline in the 1960s, was more hazardous to women than to men was examined by estimating the relative risk ratio women to men, smokers to never smoked, for light (1-14), medium (15-24), heavy (25+ cigarettes per day) and former smoking. RESULTS: For all-cause mortality relative risk ratios were 1.35 for light smoking at baseline (95% CI 1.07-1.70), 1.15 for medium smoking (95% CI 0.89-1.49) and 1.00 for heavy smoking (95% CI 0.63-1.61). Relative risk ratios for light smoking at baseline for circulatory system disease was 1.42 (95% CI 1.01 to 1.98) and for respiratory disease was 1.89 (95% CI 0.99 to 3.63). Heights of participants provided no explanation for the gender difference. CONCLUSIONS: Light smoking at baseline was shown to be significantly more hazardous to women than to men but the effect decreased as consumption increased indicating a dose response relationship. Heavy smoking was equally hazardous to both genders. This result may help explain the conflicting evidence seen elsewhere. However gender differences in smoking cessation may provide an alternative explanation. PMID- 24479664 TI - Effect of the mild temperature and traditional treatments on residual peroxidase activity, color, and chlorophyll content on storage of mate (Ilex paraguariensis) tea. AB - The green coloring is the first characteristic in mate tea (chimarrao). Mate producers perform the sapeco process by rapidly passing the leaves through flames. It has been proven that this procedure leads to high energy consumption and also to excessive exposure of the raw material to heat. In this present work, the effect of sapeco on the inactivation of peroxidase, the color, and degradation of the chlorophyll in mate was evaluated by performing the sapeco procedure in a conveyor oven, without any direct contact with the flames. The mate processed in a conveyor oven was compared with mate processed in mate factories. Inactivation of peroxidase showed that sapeco performed in a conveyor oven at 255 oC for 20 s can replace the traditional process of the industrial sapeco. This time/temperature binomial is significantly important for the green coloring and the minimization of chlorophyll degradation, besides representing a significant reduction in the temperature traditionally applied in the industrial sapeco of mate. PMID- 24479665 TI - Simulating a population genomics data set using FlowSim. AB - BACKGROUND: The field of population genetics use the genetic composition of populations to study the effects of ecological and evolutionary factors, including selection, genetic drift, mating structure, and migration. Until recently, these studies were usually based upon the analysis of relatively few (typically 10-20) DNA markers on samples from multiple populations. In contrast, high-throughput sequencing provides large amounts of data and consequently very high resolution genetic information. Recent technological developments are rapidly making this a cost-effective alternative. In addition, sequencing allows both the direct study of genomic differences between population, and the discovery of single nucleotide polymorphism marker that can be subsequently used in high-throughput genotyping. Much of the analysis in population genetics was developed before large scale sequencing became feasible. Methods often do not take into account the characteristics of the different sequencing technologies, and consequently, may not always be well suited to this kind of data. RESULTS: Although the FlowSim suite of tools originally targeted simulation of de novo 454 genomics data, recent developments and enhancements makes it suitable also for simulating other kinds of data. We examine its application to population genomics, and provide examples and supplementary scripts and utilities to aid in this task. CONCLUSIONS: Simulation is an important tool to study and develop methods in many fields, and here we demonstrate how to simulate a high-throughput sequencing dataset for population genomics. PMID- 24479667 TI - The role of friction in the mechanism of retaining the partial removable dentures with double crown system. AB - Cylindrical telescopic crowns belong to bolt dentures, because their adhesion strength is based on the friction force. The magnitude of static and slide friction forces depends on the strain within the contact area and properties of materials employed. Friction force value between telescope elements declines in the first phase of wearing period and, subsequently, maintains particular constant value of 8 to 10 N. In the telescopic technique, homo and heterogenic joints are used. The following prosthodontic materials have been examined: goldbase alloys (Degudent Kiss, Degulor M), cobalt-base alloy (Brealloy 270), ceramics (Zircon Oxide, Zirconia) during tribological investigations on FGP composite resin. The cooperating surfaces were moistened with synthetic saliva. The research confirmed the dependence of the static friction coefficient on the contact pressure for the analyzed pairs of materials used in prosthodontics. The biggest effect of the contact pressure on the coefficient of friction value occurs when the ceramic rubs on FGP composite resin. The most stable friction coefficient in the context of contact pressure changes as well as life has been found in the case of the cobalt alloy Brealloy 270. An interesting material is a gold alloy Degulor M, for which the coefficient of friction varies only slightly with pressure in the range of 0.6 to 0.9 MPa. PMID- 24479666 TI - MicroRNA-34c is associated with emphysema severity and modulates SERPINE1 expression. AB - BACKGROUND: MicroRNAs (MiRNA) are small non-coding RNAs that regulate gene expression. The aim of this study was to identify miRNAs differentially expressed between mild and moderately emphysematous lung, as well as their functional target mRNAs. Resected lung from patients with COPD undergoing lung cancer surgery was profiled using miRNA (Agilent Human miRNA profiler G4470 V1.01) and mRNA (OperonV2.0) microarrays. Cells of lung origin (BEAS-2B and HFL1) were profiled using mRNA microarrays (Illumina HumanHT-12 V3) after in vitro manipulation. RESULTS: COPD patients had mean (SD) age 68 (6) years, FEV1 72 (17)% predicted and gas transfer (KCO) 70 (10)% predicted. Five miRNAs (miR-34c, miR-34b, miR-149, miR-133a and miR-133b) were significantly down-regulated in lung from patients with moderate compared to mild emphysema as defined by gas transfer (p < 0.01). In vitro upregulation of miR-34c in respiratory cells led to down-regulation of predicted target mRNAs, including SERPINE1, MAP4K4, ZNF3, ALDOA and HNF4A. The fold change in ex-vivo expression of all five predicted target genes inversely correlated with that of miR-34c in emphysematous lung, but this relationship was strongest for SERPINE1 (p = 0.05). CONCLUSION: Differences in miRNA expression are associated with emphysema severity in COPD patients. MiR 34c modulates expression of its putative target gene, SERPINE1, in vitro in respiratory cell lines and ex vivo in emphysematous lung tissue. PMID- 24479668 TI - Effect of an aspheric intraocular lens on the ocular wave-front adjusted for pupil size and capsulorhexis size. AB - PURPOSE: To compare the ocular wave-front of eyes with silicone Intraocular lens (IOLs) with aspheric and spherical optics after cataract surgery, taking into account the patient's pupil size under reading conditions and after pupil dilatation. METHODS: In this institutional prospective, randomized, controlled, patient and examiner masked, bilateral trial with intra-individual comparison, 60 eyes of 30 patients with bilateral age-related cataract were included. Each patient received a spherical IOL (CeeOn Edge, 911A, AMO, Santa Ana, CA, USA) in one eye and an aspheric IOL (Tecnis, Z9000, AMO) in the contra-lateral eye. Exclusion criteria were other ocular pathologies, capsular changes or zonular weakness. The main outcome variable was spherical aberration of the ocular wave front under mesopic pupil conditions measured 2 years after surgery. Additional outcome variables were visual acuity and photopic and mesopic contrast sensitivity. RESULTS: There was no significant difference in visual acuity between the two IOL types under physiological pupil conditions and also not after pupil dilation. However, spherical aberrations were significantly lower with the aspheric IOL (SA: spherical 0.38 MUm, SD: 0.11 MUm; aspheric 0.10 MUm, SD: 0.13 MUm; p < 0.01), and there was a significant difference in contrast sensitivity at 12 cycles/degree. CONCLUSIONS: This is the first randomized and masked trial on visual function and ocular wave-front after implantation with this silicone aspheric IOL, taking the patients' own pupil size into account. The effect on visual function was detectable for mesopic contrast sensitivity, but there was no difference in visual acuity. The SA was found to be significantly lower under physiological pupil conditions as well as when recalculated for the rhexis size and under pharmacological dilatation. PMID- 24479669 TI - Identification of nitrated immunoglobulin variable regions in the HIV-infected human brain: implications in HIV infection and immune response. AB - HIV can infiltrate the brain and lead to HIV-associated neurocognitive disorders (HAND). The pathophysiology of HAND is poorly understood, and there are no diagnostic biomarkers for it. Previously, an increase in inducible nitric oxide synthase levels and protein tyrosine nitration in the brain were found to correlate with the severity of HAND.1,2 In this study, we analyzed human brains from individuals who had HIV infection without encephalitis and with encephalitis/HAND and compared them to the brains of healthy individuals. We identified the nitrated proteins and determined the sites of modification using affinity enrichment followed by high-resolution and high-mass-accuracy nanoLC MS/MS. We found that nitrated proteins were predominantly present in the HIV infected individuals with encephalitis, and, interestingly, the modifications were predominantly located on immunoglobulin variable regions. Our molecular model indicated potential interactions with HIV envelope proteins and changes on the heavy and light chain interface upon the nitration and nitrohydroxylation of these residues. Therefore, our findings suggest a role for these modifications in the immune response, which may have implications in disease pathogenesis. PMID- 24479670 TI - Development and validation of a national data registry for midwife-led births: the Midwives Alliance of North America Statistics Project 2.0 dataset. AB - INTRODUCTION: In 2004, the Midwives Alliance of North America's (MANA's) Division of Research developed a Web-based data collection system to gather information on the practices and outcomes associated with midwife-led births in the United States. This system, called the MANA Statistics Project (MANA Stats), grew out of a widely acknowledged need for more reliable data on outcomes by intended place of birth. This article describes the history and development of the MANA Stats birth registry and provides an analysis of the 2.0 dataset's content, strengths, and limitations. METHODS: Data collection and review procedures for the MANA Stats 2.0 dataset are described, along with methods for the assessment of data accuracy. We calculated descriptive statistics for client demographics and contributing midwife credentials, and assessed the quality of data by calculating point estimates, 95% confidence intervals, and kappa statistics for key outcomes on pre- and postreview samples of records. RESULTS: The MANA Stats 2.0 dataset (2004-2009) contains 24,848 courses of care, 20,893 of which are for women who planned a home or birth center birth at the onset of labor. The majority of these records were planned home births (81%). Births were attended primarily by certified professional midwives (73%), and clients were largely white (92%), married (87%), and college-educated (49%). Data quality analyses of 9932 records revealed no differences between pre- and postreviewed samples for 7 key benchmarking variables (kappa, 0.98-1.00). DISCUSSION: The MANA Stats 2.0 data were accurately entered by participants; any errors in this dataset are likely random and not systematic. The primary limitation of the 2.0 dataset is that the sample was captured through voluntary participation; thus, it may not accurately reflect population-based outcomes. The dataset's primary strength is that it will allow for the examination of research questions on normal physiologic birth and midwife-led birth outcomes by intended place of birth. PMID- 24479673 TI - Gaze-fixation and pupil dilation in the processing of emotional faces: the role of rumination. AB - Sustained attentional processing of negative information plays a significant role in the development and maintenance of depression. The present study examines the relationships between rumination, a relevant factor in information processing in depression, and the attentional mechanisms activated in individuals with different levels of depression severity when attending to emotional information (i.e., sad, angry and happy faces). Behavioural and physiological indicators of sustained processing were assessed in 126 participants (39 dysphoric and 87 non dysphoric) using eye-tracking technology. Pupil dilation and total time attending to negative faces were correlated with a global ruminative style in the total sample once depression severity was controlled. Furthermore, in dysphoric participants the brooding component of rumination was specifically associated with the total time attending to sad faces. Finally, bootstrapping analyses showed that the relationships between global rumination and pupil diameter to emotional faces were accounted by total time attending to emotional faces, specifically for participants reporting lower levels of depression severity. The results support the idea that sustained processing of negative information is associated with a higher ruminative style and indicate differential associations between these factors at different levels of depressive symptomatology. PMID- 24479672 TI - Identifying driver mutations in sequenced cancer genomes: computational approaches to enable precision medicine. AB - High-throughput DNA sequencing is revolutionizing the study of cancer and enabling the measurement of the somatic mutations that drive cancer development. However, the resulting sequencing datasets are large and complex, obscuring the clinically important mutations in a background of errors, noise, and random mutations. Here, we review computational approaches to identify somatic mutations in cancer genome sequences and to distinguish the driver mutations that are responsible for cancer from random, passenger mutations. First, we describe approaches to detect somatic mutations from high-throughput DNA sequencing data, particularly for tumor samples that comprise heterogeneous populations of cells. Next, we review computational approaches that aim to predict driver mutations according to their frequency of occurrence in a cohort of samples, or according to their predicted functional impact on protein sequence or structure. Finally, we review techniques to identify recurrent combinations of somatic mutations, including approaches that examine mutations in known pathways or protein interaction networks, as well as de novo approaches that identify combinations of mutations according to statistical patterns of mutual exclusivity. These techniques, coupled with advances in high-throughput DNA sequencing, are enabling precision medicine approaches to the diagnosis and treatment of cancer. PMID- 24479674 TI - Accelerated long-term forgetting of verbal information in unilateral temporal lobe epilepsy: Is it related to structural hippocampal abnormalities and/or incomplete learning? AB - The factors contributing to accelerated long-term forgetting (ALF) are not yet clear. In this study, a 12-item word list was presented repeatedly to 23 patients with temporal lobe epilepsy (TLE) and 27 control participants (NC) until it was recalled completely on two consecutive trials or until 12 trials were undertaken. Compared to NCs, patients with hippocampal lesions and those who failed to learn the list showed ALF by one day post learning, but the alternative patient groups also showed ALF when tested after seven days. Overall, our findings suggest that in patients with TLE neither a preserved hippocampus nor intact learning protects against ALF. PMID- 24479675 TI - The premaxillary space: a location for filler injection? AB - BACKGROUND: A four-layer fat structure is found in the anterior cheek region. The deepest of these fat layers is the premaxillary fat. OBJECTIVE: To determine whether the premaxillary fat is located in a closed compartment and whether injection of substances affects the appearance of the face. METHODS & MATERIALS: Filler or arterial mass (0.5-0.8 mL) after Thiel were injected, and gross dissections, horizontal and sagittal sections, and three-dimensional reconstructions with computed tomography were performed. RESULTS: The premaxillary fat is located in a semiopen space, the premaxillary space, with mainly bony and muscular borders. The injected substances spread in lateral and superficial located tissues. CONCLUSION: Injection of substances into this space leads to discrete improvements in the appearance of the nasolabial groove. PMID- 24479676 TI - How does it really feel to be in my shoes? Patients' experiences of compassion within nursing care and their perceptions of developing compassionate nurses. AB - AIMS AND OBJECTIVES: To understand how patients experience compassion within nursing care and explore their perceptions of developing compassionate nurses. BACKGROUND: Compassion is a fundamental part of nursing care. Individually, nurses have a duty of care to show compassion; an absence can lead to patients feeling devalued and lacking in emotional support. Despite recent media attention, primary research around patients' experiences and perceptions of compassion in practice and its development in nursing care remains in short supply. DESIGN: A qualitative exploratory descriptive approach. METHODS: In depth, semi-structured interviews were conducted with a purposive sample of 10 patients in a large teaching hospital in the United Kingdom. Interviews were digitally recorded and transcribed verbatim. Thematic networks were used in analysis. RESULTS: Three overarching themes emerged from the data: (1) what is compassion: knowing me and giving me your time, (2) understanding the impact of compassion: how it feels in my shoes and (3) being more compassionate: communication and the essence of nursing. CONCLUSION: Compassion from nursing staff is broadly aligned with actions of care, which can often take time. However, for some, this element of time needs only be fleeting to establish a compassionate connection. Despite recent calls for the increased focus compassion at all levels in nurse education and training, patient opinion was divided on whether it can be taught or remains a moral virtue. Gaining understanding of the impact of uncompassionate actions presents an opportunity to change both individual and cultural behaviours. RELEVANCE TO CLINICAL PRACTICE: It comes as a timely reminder that the smallest of nursing actions can convey compassion. Introducing vignettes of real-life situations from the lens of the patient to engage practitioners in collaborative learning in the context of compassionate nursing could offer opportunities for valuable and legitimate professional development. PMID- 24479677 TI - Formulation development and evaluation of the anti-malaria properties of sustained release artesunate-loaded solid lipid microparticles based on phytolipids. AB - CONTEXTS: Artemisinins and its derivatives are considered the basis in the treatment of Plasmodium falciparum malaria due to their high potency and rapid action. However, they have short half life, low solubility, and poor oral bioavailability, hence the need to formulate sustained release lipid particulate dosage form of these drugs. OBJECTIVES: To formulate and evaluate artesunate loaded solid lipid microparticles (SLMs) based on structured lipid matrices consisting of soybean oil and dika wax. MATERIALS AND METHODS: The lipid matrices were characterized by differential scanning calorimetry (DSC), small-angle X-ray diffraction (SAXD), and wide-angle X-ray diffraction (WAXD). The SLMs were prepared by hot melt-homogenization. Time-dependent particle size analysis, time dependent pH stability studies, encapsulation efficiency (EE%), and in vitro drug release were carried out on the SLMs. In vivo anti-malarial studies were performed using a modified Peter's 4-day suppressive protocol using Plasmodium berghei infected mice. RESULTS AND DISCUSSION: Thermograms of the lipid matrices showed modifications in the microstructure of dika wax as a result of inclusion of soybean oil. SAXD and WAXD diffractograms showed that the lipid matrices were found to be non-lamellar. Particle size of SLM increased with time, while the pH was almost constant. The SLMs had maximum EE% of 80.6% and sustained the release of artesunate more than the reference tablet. In vivo pharmacodynamic studies showed that the SLMs had significant (p < 0.05) reduction in parasitaemia compared with reference tablet. CONCLUSION: Artesunate-loaded SLMs could be used once daily in the treatment of malaria. PMID- 24479678 TI - Social support and social undermining as explanatory factors for health-related quality of life in people living with HIV/AIDS. AB - This study aimed to examine the influence of social support (from personal networks and health care providers) and social undermining (from personal networks) on health-related quality of life (HRQOL; general health perceptions, physical functioning, and depression). Specifically, the authors aimed to identify the nature of the effects (direct, mediating, or moderating) of social support and social undermining on HRQOL. A total of 344 people living with HIV/AIDS and who were patients in a federally funded clinic in New Mexico completed a self-report survey questionnaire. The major findings of this study are the following: (a) social support and social undermining had direct and indirect effects on HRQOL-there was no evidence of a moderating effect of social support and social undermining; (b) for direct effects, social undermining was a stronger predictor of HRQOL than social support with social support variables having positive relations and social undermining variables having negative relations with HRQOL; and (c) for indirect effects, providers' social support partially mediated the influence of unstable employment/unemployment and social undermining on HRQOL. PMID- 24479679 TI - Emotional pictures impact repetitive sprint ability test on cycle ergometre. AB - This study investigated the interaction between emotion-eliciting pictures and power output during a repetitive supra-maximal task on a cycle ergometre. Twelve male participants (mean (+/-SD) age, height and weight: 28.58 +/- 3.23 years, 1.78 +/- 0.05 m and 82.41 +/- 13.29 kg) performed 5 repeated sprint tests on a cycle ergometre in front of neutral, pleasant or unpleasant pictures. For each sprint, mechanical (peak power and work), physiological (heart rate) and perceptual (affective load) indices were analysed. Affective load was calculated from the ratings of perceived exertion, which reflected the amount of pleasant and unpleasant responses experienced during exercise. The results showed that peak power, work and heart rate values were significantly lower (P < 0.05) for unpleasant pictures (9.18 +/- 0.20 W ? kg(-1); 47.69 +/- 1.08 J ? kg(-1); 152 +/- 4 bpm) when compared with pleasant ones (9.50 +/- 0.20 W ? kg(-1); 50.11 +/- 0.11 J ? kg(-1); 156 +/- 3 bpm). Furthermore, the affective load was found to be similar for the pleasant and unpleasant sessions. All together, these results suggested that the ability to produce maximal power output depended on whether the emotional context was pleasant or unpleasant. The fact that the power output was lower in the unpleasant versus pleasant session could reflect a regulatory process aimed at maintaining a similar level of affective load for both sessions. PMID- 24479680 TI - Micafungin as antifungal prophylaxis in recipients of allogeneic hematopoietic stem cell transplantation: results of different dosage levels in clinical practice. AB - Micafungin has been approved for the prophylaxis of Candida infections in patients undergoing allogeneic hematopoietic stem cell transplantation (allo HSCT). Here, we report a single-center experience of three different dose levels regarding efficacy, toxicity, and colonization with Candida ssp. in clinical practice. In total, 150 consecutive adult patients who underwent allo-HSCT received micafungin at a dosage of 50, 100, or 150 mg once daily for primary antifungal prophylaxis. Of those patients receiving more than six d of micafungin prophylaxis, 12/46 (26%), 6/44 (14%), and 9/46 (20%) were switched to empiric antifungal treatment. The frequency of invasive fungal infections (IFIs) according to EORTC criteria did not differ significantly (7/46; 15% vs. 5/44; 11% vs. 5/46; 11%) across the different dosage groups. In the 50-mg group, there was one case of candidemia with C. parapsilosis after 12 d of micafungin prophylaxis. In all three groups, micafungin prophylaxis was well tolerated without any case of toxicity-related treatment discontinuation. Renal function was not significantly altered, while increase of bilirubin was mainly due to concomitant ATG application. The incidence of IFIs is similar irrespective of the micafungin dosage while there was a trend toward more frequent change to empiric antifungal treatment as well as oropharyngeal colonization with candida in the lowest dosage group. PMID- 24479681 TI - IL-1beta-induced activation of p38 promotes metastasis in gastric adenocarcinoma via upregulation of AP-1/c-fos, MMP2 and MMP9. AB - BACKGROUND: Interleukin-1beta (IL-1beta) has been implicated in the progression of gastric adenocarcinoma (GA); however, the molecular mechanisms of action of IL 1beta in GA are poorly characterized. P38 and JNK are the major MAPK family members that regulate IL-1beta signaling pathways. Here, we investigated the role of both p38 and JNK in IL-1beta-induced GA cell migration, invasion and metastatic potential. METHODS: The effects of IL-1beta-induced p38 and JNK activation in GA cells were determined using in vitro Transwell migration and invasion assays of MKN-45 and AGS cells, or an in vivo metastasis assay in nude mice. The IL-1beta-induced p38 signaling pathway was further characterized in GA cells. Activation of the IL-1beta/p38 signaling pathway was also assessed in human primary GA tissues by immunohistochemistry. RESULTS: IL-1beta-induced activation of p38 increased GA cell migration and invasion in vitro and promoted the metastatic potential of GA cells in vivo; these effects were attenuated by p38 siRNA or the p38 inhibitor SB202190. MMP2 or MMP9 siRNAs and the MMP2/9 inhibitor BiPS also inhibited IL-1beta-induced GA cell migration and invasion in vitro. IL-1beta-induced p38 activation significantly increased MMP2 and MMP9 mRNA and protein expression and activity. Luciferase reporter assays demonstrated that the activator protein-1 (AP-1) and the AP-1 binding sites of the MMP9 promoter ( 670/MMP9) were activated by IL-1beta-induced p38 activation. Phospho-p38 was significantly upregulated in human GA tissues (compared to matched non-neoplastic tissues), and significantly associated with lymph node metastasis, and invasion beyond the serosa. Expression of phospho-p38 significantly correlated with IL 1beta, MMP2, MMP9, and c-fos expression in both human GA tissues and GA cell metastases in the lungs of nude mice. IL-1beta was also capable of activating JNK in GA cells, but activation of JNK was not associated with GA cell migration and invasion. Therefore, IL-1beta-induced the migration and invasion in GA cells were regulated by p38, but not by JNK. CONCLUSIONS: IL-1beta-induced p38 activation and the IL-1beta/p38/AP-1(c-fos)/MMP2 & MMP9 pathway play an important role in metastasis in GA; this pathway may provide a novel therapeutic target for GA. PMID- 24479682 TI - Ultrafast and nanoscale plasmonic phenomena in exfoliated graphene revealed by infrared pump-probe nanoscopy. AB - Pump-probe spectroscopy is central for exploring ultrafast dynamics of fundamental excitations, collective modes, and energy transfer processes. Typically carried out using conventional diffraction-limited optics, pump-probe experiments inherently average over local chemical, compositional, and electronic inhomogeneities. Here, we circumvent this deficiency and introduce pump-probe infrared spectroscopy with ~ 20 nm spatial resolution, far below the diffraction limit, which is accomplished using a scattering scanning near-field optical microscope (s-SNOM). This technique allows us to investigate exfoliated graphene single-layers on SiO2 at technologically significant mid-infrared (MIR) frequencies where the local optical conductivity becomes experimentally accessible through the excitation of surface plasmons via the s-SNOM tip. Optical pumping at near-infrared (NIR) frequencies prompts distinct changes in the plasmonic behavior on 200 fs time scales. The origin of the pump-induced, enhanced plasmonic response is identified as an increase in the effective electron temperature up to several thousand Kelvin, as deduced directly from the Drude weight associated with the plasmonic resonances. PMID- 24479683 TI - Efficacy and non-target impact of spinosad, Bti and temephos larvicides for control of Anopheles spp. in an endemic malaria region of southern Mexico. AB - BACKGROUND: The larvicidal efficacy of the naturally derived insecticide spinosad, for control of immature stages of Anopheles albimanus and associated culicids, was compared to that of synthetic and biological larvicides. Effects on non-target insects were also determined. METHODS: A field trial was performed in replicated temporary pools during the rainy season, in southern Mexico. Pools were treated with 10 ppm a.i. spinosad (Tracer 480SC), Bti granules applied at 2 kg/ha (VectoBac WDG, ABG-6511), and 100 ml/ha temephos (50 EC), or an untreated control. Numbers of immature mosquitoes, and aquatic insects in pools were monitored for 20 weeks. RESULTS: Samples of immature mosquitoes comprised approximately 10% An. albimanus, 70% Culex spp. (mostly Cx. melanoconion and Cx. coronator) and 20% Uranotaenia lowii. The most effective larvicides were spinosad and temephos that eliminated An. albimanus in 16 out of 20 post-treatment samples, or 9 weeks of continuous control of immature stages, respectively. These larvicides resulted in 15 and 5 weeks of elimination of Culex spp., respectively, or 20 and 4 weeks of continuous elimination of U. lowii, respectively. Bti treatment provided little consistent control. Aquatic insects were recorded comprising 3 orders, 20 families, 40 genera and 44 species. Shannon diversity index values (H') for aquatic insects were highest in the control (0.997) and Bti (0.974) treatments, intermediate in the spinosad treatment (0.638) and lowest in the temephos treatment (0.520). Severely affected non-target insects in the spinosad and temephos treated pools were predatory Coleoptera, Hemiptera and Odonata, which in the case of spinosad was likely due to the high concentration applied. Bti had little effect on aquatic insects. CONCLUSIONS: The spinosad treatment retained larvicidal activity for markedly longer than expected. Spinosad is likely to be an effective tool for control of anopheline and other pool-breeding mosquitoes in tropical regions. Non-target effects of spinosad on aquatic insects merit further study, but were likely related to the concentration of the product used. PMID- 24479684 TI - Quantum mechanical/molecular mechanical study of catalytic mechanism and role of key residues in methylation reactions catalyzed by dimethylxanthine methyltransferase in caffeine biosynthesis. AB - The caffeine biosynthetic pathway is of considerable importance for the beverage and pharmaceutical industries which produces two blockbuster products: theobromine and caffeine. The major biochemistry in caffeine biosynthesis starts from the initial substrate of xanthosine and ends with the final product caffeine, with theobromine serving as an intermediate. The key enzyme, S-adenosyl l-methionine (SAM) dependent 3,7-dimethyl-xanthine methyltransferase (DXMT), catalyzes two important methyl transfer steps in caffeine biosynthesis: (1) methylation of N3 of 7-methylxanthine (7mX) to form theobromine (Tb); (2) methylation of N1 of theobromine to form caffeine (Cf). Although DXMT has been structurally characterized recently, our understanding of the detailed catalytic mechanism and role of key catalytic residues is still lacking. In this work, the quantum mechanical/molecular mechanical (QM/MM) MD and free energy simulations are performed to elucidate the catalytic mechanism of the enzyme-catalyzed reactions and to explain experimental observations concerning the activity of this enzyme. The roles of certain active-site residues are studied, and the results of computer simulation seem to suggest that a histidine residue (His160) at the active site of DXMT may act as a general base/acid catalyst during the methyl transfer process. PMID- 24479685 TI - Interferon-gamma induces leucine-rich repeat kinase LRRK2 via extracellular signal-regulated kinase ERK5 in macrophages. AB - The gene encoding leucine-rich repeat kinase 2 (LRRK2) comprises a major risk factor for Parkinson's disease. Recently, it has emerged that LRRK2 plays important roles in the immune system. LRRK2 is induced by interferon-gamma (IFN gamma) in monocytes, but the signaling pathway is not known. Here, we show that IFN-gamma-mediated induction of LRRK2 was suppressed by pharmacological inhibition and RNA interference of the extracellular signal-regulated kinase 5 (ERK5). This was confirmed by LRRK2 immunostaining, which also revealed that the morphological responses to IFN-gamma were suppressed by ERK5 inhibitor treatment. Both human acute monocytic leukemia THP-1 cells and human peripheral blood monocytes stimulated the ERK5-LRRK2 pathway after differentiation into macrophages. Thus, LRRK2 is induced via a novel, ERK5-dependent IFN-gamma signal transduction pathway, pointing to new functions of ERK5 and LRRK2 in human macrophages. Leucine-rich repeat kinase 2 (LRRK2) is a major risk factor for the development of Parkinson's disease (PD). However, the role of LRRK2 in the affected neurons remains enigmatic. Recently, LRRK2 has been reported to be strongly expressed in the immune system. Here, we demonstrate that LRRK2 is induced by Interferon gamma via extracellular signal-regulated kinase 5 (ERK5) in macrophages, thus providing new insights in LRRK2 and ERK5 biology. PMID- 24479686 TI - Influence of glycation of plasma proteins in diabetes on the binding interaction with polyphenols. AB - Diabetes mellitus is one of the most serious diseases in the world. The degree of glycated plasma proteins is increased in diabetics compared to non-diabetic subjects. This mini-review focuses on the influence of glycation of human serum albumin (HSA) in diabetes on the binding interaction with dietary polyphenols. The non-enzymatic glycation of HSA leads to a conformational change in HSA, which in turn influences the ligand binding properties. HSA glycation is believed to reduce the binding affinities for acidic drugs such as dietary polyphenols and phenolic acids. PMID- 24479688 TI - Advances in the pharmacokinetics of natural bioactive polyphenols. PMID- 24479687 TI - Incorporation of pharmacogenomics into routine clinical practice: the Clinical Pharmacogenetics Implementation Consortium (CPIC) guideline development process. AB - The Clinical Pharmacogenetics Implementation Consortium (CPIC) publishes genotype based drug guidelines to help clinicians understand how available genetic test results could be used to optimize drug therapy. CPIC has focused initially on well-known examples of pharmacogenomic associations that have been implemented in selected clinical settings, publishing nine to date. Each CPIC guideline adheres to a standardized format and includes a standard system for grading levels of evidence linking genotypes to phenotypes and assigning a level of strength to each prescribing recommendation. CPIC guidelines contain the necessary information to help clinicians translate patient-specific diplotypes for each gene into clinical phenotypes or drug dosing groups. This paper reviews the development process of the CPIC guidelines and compares this process to the Institute of Medicine's Standards for Developing Trustworthy Clinical Practice Guidelines. PMID- 24479689 TI - Advances in methods for predicting phase I metabolism of polyphenols. AB - Flavonoids are natural polyphenols that can be found in many vegetables, citric fruits and dietary supplements and are widely consumed worldwide in the human diet. Over the past 30 years, studies have demonstrated that these compounds present significant biological activities, and their antioxidant properties may be responsible for the prevention of many diseases such as neurodegeneration, atherosclerosis, tumor generation, and microbial infections. Moreover, studies have shown that flavonoids may be substrates of cytochrome P450 enzymes and undergo bioactivation to metabolites that inhibit tumor cell growth. Therefore, it is important to understand the CYP450-mediated metabolic profiles of polyphenolic compounds during drug discovery and development processes. This review highlights ligand-based and structure-based methods to predict the Phase I metabolism of polyphenols. Moreover, an integrated in silico approach for the prediction of Phase I metabolism of the flavonoids quercetin, rutin, naringenin and naringin, which provided useful information about the most likely metabolites of these flavonoids and their interactions with amino acid residues of CYP2C9, is described. PMID- 24479690 TI - Outcomes of care for 16,924 planned home births in the United States: the Midwives Alliance of North America Statistics Project, 2004 to 2009. AB - INTRODUCTION: Between 2004 and 2010, the number of home births in the United States rose by 41%, increasing the need for accurate assessment of the safety of planned home birth. This study examines outcomes of planned home births in the United States between 2004 and 2009. METHODS: We calculated descriptive statistics for maternal demographics, antenatal risk profiles, procedures, and outcomes of planned home births in the Midwives Alliance of North American Statistics Project (MANA Stats) 2.0 data registry. Data were analyzed according to intended and actual place of birth. RESULTS: Among 16,924 women who planned home births at the onset of labor, 89.1% gave birth at home. The majority of intrapartum transfers were for failure to progress, and only 4.5% of the total sample required oxytocin augmentation and/or epidural analgesia. The rates of spontaneous vaginal birth, assisted vaginal birth, and cesarean were 93.6%, 1.2%, and 5.2%, respectively. Of the 1054 women who attempted a vaginal birth after cesarean, 87% were successful. Low Apgar scores (< 7) occurred in 1.5% of newborns. Postpartum maternal (1.5%) and neonatal (0.9%) transfers were infrequent. The majority (86%) of newborns were exclusively breastfeeding at 6 weeks of age. Excluding lethal anomalies, the intrapartum, early neonatal, and late neonatal mortality rates were 1.30, 0.41, and 0.35 per 1000, respectively. DISCUSSION: For this large cohort of women who planned midwife-led home births in the United States, outcomes are congruent with the best available data from population-based, observational studies that evaluated outcomes by intended place of birth and perinatal risk factors. Low-risk women in this cohort experienced high rates of physiologic birth and low rates of intervention without an increase in adverse outcomes. PMID- 24479691 TI - Rosiglitazone and fenofibrate exacerbate liver steatosis in a mouse model of obesity and hyperlipidemia. A transcriptomic and metabolomic study. AB - Peroxisome proliferator-activated receptors (PPAR) play an important role in the regulation of lipid and glucose metabolism, inflammatory, and vascular responses. We show the effect of treatment with two PPAR agonists, fenofibrate (FF) and rosiglitazone (RSG), on ob/ob and LDLR-double deficient mice, by combined gene expression and metabolomic analyses. Male mice were daily treated for 12 weeks with RSG (10 mg.kg(1-).day(-1) per os (p.o.), n = 8) and FF (50 mg.kg(1-).day(-1) p.o., n = 8). Twelve untreated ob/ob and LDLR-double deficient mice were used as controls. To integrate the transcriptomic and metabolomic results, we designed a hierarchical algorithm, based on the average linkage method in clustering. Data were also interpreted with the Ingenuity Pathway Analysis program. FF and RSG treatments significantly increased the hepatic triglyceride content in the liver when compared with the control group, and the treatments induced an increase in the number and size of hepatic lipid droplets. Both drugs simultaneously activate pro-steatotic and antisteatotic metabolic pathways with a well-ordered result of aggravation of the hepatic lipid accumulation. The present study is a cautionary note not only to researchers on the basic mechanism of the action of PPAR activators but also to the use of these compounds in clinical practice. PMID- 24479692 TI - Tuberculous uveitis in China. AB - PURPOSE: To assess tuberculous uveitis in Chinese patients. METHODS: The hospital based observational case series study included patients who attended a third referral hospital and presented with chronic and recurrent uveitis without primarily detected aetiology. The patients underwent the tuberculin skin test (TST) and/or interferon gamma release test (IGRA). Patients with positive test results received standard antituberculous therapy. Patients who responded to the therapy and did not show recurrence of uveitis in the follow-up period were diagnosed as tuberculous uveitis and formed the study group. The remaining patients were diagnosed as non-tuberculous uveitis and formed the control group. The clinical characteristics were compared between both groups. RESULTS: The study group with tuberculous uveitis included 46 patients and the non-tuberculous group 38 patients. Multifocal choroiditis [n = 9 (20%) versus n = 1(3%); p = 0.04] and retinal vasculitis [n = 25(54%) versus 8 = (21.1%); p = 0.002] were significantly more common in the study group. Of 25 patients with retinal vasculitis in the study group, 11 patients (44%) additionally showed choroiditis lesions, compared with only one (13%) of eight patients in the control group (p = 0.01). In multivariate regression analysis, multifocal choroiditis [odds ratio (OR): 32.1], choroidal granuloma (OR: 21.4) and retinal vasculitis (OR: 11.2) were independent predictors of tubercular uveitis. CONCLUSIONS: About 50% of a group of 84 patients with primarily unexplained chronic posterior uveitis had tuberculosis and showed multifocal choroiditis, choroidal granuloma and retinal vasculitis. These features had a high predictive value for the diagnosis of tuberculous uveitis. Tuberculosis is an important part in the differential diagnosis of unexplained uveitis. PMID- 24479693 TI - Disentangling public participation in science and biomedicine. AB - BACKGROUND: This article provides a framework for disentangling the concept of participation, with emphasis on participation in genomic medicine. We have derived seven 'dimensions' of participation that are most frequently invoked in the extensive, heterogeneous literature on participation. To exemplify these dimensions, we use material from a database of 102 contemporary cases of participation, and focus here on cases specific to science and medicine. We describe the stakes of public participation in biomedical research, with a focus on genomic medicine and lay out the seven dimensions. DISCUSSION: We single out five cases of participation that have particular relevance to the field of genomic medicine, we apply the seven dimensions to show how we can differentiate among forms of participation within this domain. SUMMARY: We conclude with some provocations to researchers and some recommendations for taking variation in participation more seriously. PMID- 24479695 TI - Disturbing effect of different dental materials on the MRI results: preliminary study. AB - The influence of different dental materials used for conserving reconstruction of teeth on the magnetic resonance imaging assessed on the basis of changes in NMR proton relaxation T1 of the physiological environment represented by the physiological salt solution has been studied. The dental materials studied varied in a wide range of chemical compositions: composites (Silux Plus made by 3M Dental, Tetric Cream made by Ivoclar-Vivadent), pH controlling composite (Ariston pHc made by Vivadent), hybrid glass ionomer (Vitremer made by 3M Dental), compomer (Hytac made by ESPE), amalgamate without the gamma phase (Septalloy made by Septodont), chemocured phosphate cement (Agatos made by Chema-Elektromet), phosphate cement with addition of silver (Argil made by Spora-Dental). The reference standard was a 0.9% physiological solution of NaCl. The relative deviations of the spin-lattice relaxation time vary from -18.5% to +24.0%. From the point of view of magnetic resonance imaging, the materials significantly disturbing the tomographic images are the amalgamate Septalloy-Septodont and glass ionomer Vitremer-3M Dental, while the composite Tetric Cream-Vivadent has insignificant effect. PMID- 24479694 TI - Repeated mapping of cortical language sites by preoperative navigated transcranial magnetic stimulation compared to repeated intraoperative DCS mapping in awake craniotomy. AB - BACKGROUND: Repetitive navigated transcranial magnetic stimulation (rTMS) was recently described for mapping of human language areas. However, its capability of detecting language plasticity in brain tumor patients was not proven up to now. Thus, this study was designed to evaluate such data in order to compare rTMS language mapping to language mapping during repeated awake surgery during follow up in patients suffering from language-eloquent gliomas. METHODS: Three right handed patients with left-sided gliomas (2 opercular glioblastomas, 1 astrocytoma WHO grade III of the angular gyrus) underwent preoperative language mapping by rTMS as well as intraoperative language mapping provided via direct cortical stimulation (DCS) for initial as well as for repeated Resection 7, 10, and 15 months later. RESULTS: Overall, preoperative rTMS was able to elicit clear language errors in all mappings. A good correlation between initial rTMS and DCS results was observed. As a consequence of brain plasticity, initial DCS and rTMS findings only corresponded with the results obtained during the second examination in one out of three patients thus suggesting changes of language organization in two of our three patients. CONCLUSIONS: This report points out the usefulness but also the limitations of preoperative rTMS language mapping to detect plastic changes in language function or for long-term follow-up prior to DCS even in recurrent gliomas. However, DCS still has to be regarded as gold standard. PMID- 24479697 TI - An exploration of the effects of introducing a telemonitoring system for continence assessment in a nursing home. AB - AIMS AND OBJECTIVES: To explore the effects of introducing a telemonitoring and care planning system for urinary continence assessment in a nursing home and adherence by care staff to urinary continence care plans. BACKGROUND: Only a few studies have explored the effect of introducing telemonitoring system on urinary continence care, none for older people in nursing homes. DESIGN: Pre- and postintervention repeated measures design. METHODS: Data for the study were collected from August-October 2011. Care staff were trained in the use of a telemonitoring system for continence assessment. Voiding events for each older person were recorded using the system during a 72-hour urinary continence assessment, and the data were used to prepare an individualised care plan. After two weeks of using the new care plan, a second assessment was carried out for each older person, using the telemonitoring system. RESULTS: The participants were on average 81 years old and assessed as having high care needs. The statistically significant outcomes were as follows: reduced volume of urine voided into continence aids, reduced number of prescribed toileting visits, increased number of actual toilet visits, increased number of successful toileting events and increased adherence to urinary continence care plans by staff. CONCLUSIONS: During a 12-week trial, urinary continence assessment and management of older people were improved. This suggests that the introduction of a suitably designed telemonitoring system combined with staff training can improve urinary continence care. RELEVANCE TO CLINICAL PRACTICE: The results suggest that nursing homes can improve continence assessment and management practices by adopting an appropriately designed mobile, wireless telemonitoring system for continence assessment and providing the associated staff training programmes. PMID- 24479696 TI - Hand hygiene compliance and associated factors among health care providers in Gondar University Hospital, Gondar, North West Ethiopia. AB - BACKGROUND: Health care associated infections are more predominant in developing countries where Hand hygiene compliance is associated with so many factors. However, these factors have not been studied so far in the study area. This study sought to determine Hand hygiene compliance and associated factors among health care providers. METHODS: Institution based cross-sectional study was conducted from April to May, 2013 in Gondar University Hospital. Stratified sampling technique was used to select 405 health care providers. Standardized questionnaire and world health organization observational checklist was used to collect the data. Data was entered and analyzed by using SPSS version 20. Descriptive statistics and binary logistic regression model was used to summarize the result. RESULTS: A total of 405 study participants were interviewed and observed with a response rate of 96.4%. Good Hand hygiene compliance of healthcare providers was found to be 16.5%. Having knowledge about hand hygiene compliance, (AOR = 3.80, 95% CI 1.60, 8.97), getting training (AOR = 2.60, 95% Cl 1.21, 5.62), the presence of individual towel/tissue paper (AOR = 1.91, 95% CI 1.03, 3.56) presence of alcohol based hand rub for Hand hygiene compliance (AOR = 6.58, 95% CI 2.67, 16.22) and knew the presence of infection prevention committees (AOR = 2.6, 95% CI 1.23, 5.37) were significantly associated with hand hygiene compliance. CONCLUSIONS: Hand hygiene compliance among health care providers in Gondar University Hospital was found to be low. It is better to give training on Hand hygiene compliance and provide Alcohol based hand rub and individual towel or tissue paper for hand hygiene compliance. PMID- 24479698 TI - A twin-case study of developmental number sense impairment. AB - The current study reports on 9-year-old monozygotic twin girls who fail to make any progress in learning basic mathematics in primary education. We tested the hypothesis that the twins' core maths problems were deficits in number sense that manifested as impairments in approximate and small number systems, resulting in impairment in nonsymbolic as well as in symbolic processing. While age-matched controls (eight typically developing girls) scored highly, the twins scored at chance on all number sense tasks. More specifically, on a nonsymbolic comparison task, even in the simplest ratio condition of 1:2, and on a subitizing task including only numbers under 4, the twins performed at chance and significantly below the same age control group. Responsiveness to an intervention promoting number sense is discussed. As differences between verbal and performance IQ suggest, there seems to be a high degree of specificity in the twins' developmental number sense delays. The concomitant impairments for visual-spatial processing and working memory in the twins might explain the failure to develop number sense. PMID- 24479699 TI - Math anxiety and exposure to statistics in messages about genetically modified foods: effects of numeracy, math self-efficacy, and form of presentation. AB - Health risks are often communicated to the lay public in statistical formats even though low math skills, or innumeracy, have been found to be prevalent among lay individuals. Although numeracy has been a topic of much research investigation, the role of math self-efficacy and math anxiety on health and risk communication processing has received scant attention from health communication researchers. To advance theoretical and applied understanding regarding health message processing, the authors consider the role of math anxiety, including the effects of math self-efficacy, numeracy, and form of presenting statistics on math anxiety, and the potential effects for comprehension, yielding, and behavioral intentions. The authors also examine math anxiety in a health risk context through an evaluation of the effects of exposure to a message about genetically modified foods on levels of math anxiety. Participants (N = 323) were randomly assigned to read a message that varied the presentation of statistical evidence about potential risks associated with genetically modified foods. Findings reveal that exposure increased levels of math anxiety, with increases in math anxiety limiting yielding. Moreover, math anxiety impaired comprehension but was mediated by perceivers' math confidence and skills. Last, math anxiety facilitated behavioral intentions. Participants who received a text-based message with percentages were more likely to yield than participants who received either a bar graph with percentages or a combined form. Implications are discussed as they relate to math competence and its role in processing health and risk messages. PMID- 24479700 TI - Long term stability of nanowire nanoelectronics in physiological environments. AB - Nanowire nanoelectronic devices have been exploited as highly sensitive subcellular resolution detectors for recording extracellular and intracellular signals from cells, as well as from natural and engineered/cyborg tissues, and in this capacity open many opportunities for fundamental biological research and biomedical applications. Here we demonstrate the capability to take full advantage of the attractive capabilities of nanowire nanoelectronic devices for long term physiological studies by passivating the nanowire elements with ultrathin metal oxide shells. Studies of Si and Si/aluminum oxide (Al2O3) core/shell nanowires in physiological solutions at 37 degrees C demonstrate long term stability extending for at least 100 days in samples coated with 10 nm thick Al2O3 shells. In addition, investigations of nanowires configured as field-effect transistors (FETs) demonstrate that the Si/Al2O3 core/shell nanowire FETs exhibit good device performance for at least 4 months in physiological model solutions at 37 degrees C. The generality of this approach was also tested with in studies of Ge/Si and InAs nanowires, where Ge/Si/Al2O3 and InAs/Al2O3 core/shell materials exhibited stability for at least 100 days in physiological model solutions at 37 degrees C. In addition, investigations of hafnium oxide-Al2O3 nanolaminated shells indicate the potential to extend nanowire stability well beyond 1 year time scale in vivo. These studies demonstrate that straightforward core/shell nanowire nanoelectronic devices can exhibit the long term stability needed for a range of chronic in vivo studies in animals as well as powerful biomedical implants that could improve monitoring and treatment of disease. PMID- 24479701 TI - In vitro assembly of the outer core of the lipopolysaccharide from Escherichia coli K-12 and Salmonella typhimurium. AB - There are five distinct core structures in the lipopolysaccharides of Escherichia coli and at least two in Salmonella isolates, which vary principally in the outer core oligosaccharide. Six outer core glycosyltransferases, E. coli K-12 WaaG, WaaB, and WaaO and Salmonella typhimurium WaaI, WaaJ, and WaaK, were cloned, overexpressed, and purified. A novel substrate for WaaG was isolated from DeltawaaG E. coli overexpressing the lipid A phosphatase lpxE and the lipid A late acyltransferase lpxM. The action of lpxE and lpxM in the DeltawaaG background yielded heptose2-1-dephospho Kdo2-lipid A, a 1-dephosphorylated hexa acylated lipid A with the inner core sugars that is easily isolated by organic extraction. Using this structurally defined acceptor and commercially available sugar nucleotides, each outer core glycosyltransferases was assayed in vitro. We show that WaaG and WaaB add a glucose and galactose sequentially to heptose2-1 dephospho Kdo2-lipid A. E. coli K-12 WaaO and S. typhimurium WaaI add a galactose to the WaaG/WaaB product but can also add a galactose to the WaaG product directly without the branched core sugar added by WaaB. Both WaaI and WaaO require divalent metal ions for optimal activity; however, WaaO, unlike WaaI, can add several glucose residues to its lipid acceptor. Using the product of WaaG, WaaB, and WaaI, we show that S. typhimurium WaaJ and WaaK transfer a glucose and N-acetylglucosamine, respectively, to yield the full outer core. This is the first demonstration of the in vitro assembly of the outer core of the lipopolysaccharide using defined lipid A-oligosaccharide acceptors and sugar donors. PMID- 24479703 TI - Pain in naive and non-naive subjects undergoing nonablative skin tightening dermatologic procedures: a nested randomized control trial. AB - BACKGROUND: Pain is expected during noninvasive skin tightening and can be anxiety provoking, especially for those who have not had prior treatments. OBJECTIVE: To compare pain reported by patients naive to nonablative skin tightening energy devices with those who were not naive. METHODS AND MATERIALS: The non-naive group at least three nonablative laser procedures or one nonablative skin tightening procedure, and the naive group no previous treatments. Four sites at each of two anatomic locations (periorbital and midface or cheek) were treated in each subject with needle prick, pulsed dye laser, radiofrequency, and ultrasound with the order of the interventions randomized. All interventions except ultrasound were also applied to three abdominal sites. The difference in mean pain scores between naive and nonnaive subjects were averaged over the anatomic sites. RESULTS: Ten naive and 10 non-naive subjects completed study procedures. Mean pain scores ranged from 1.3 to 4.9. The mean for all naive conditions was 2.3 +/- 1.0, vs 2.2 +/- 1.4 for non-naive conditions. There was no overall difference according to group, device, or anatomic area. CONCLUSIONS: There was no significant difference in pain between naive and non naive subjects undergoing cutaneous energy treatments. Individual devices may elicit more pain at specific anatomic locations. PMID- 24479702 TI - CANABIC: CANnabis and Adolescents: effect of a Brief Intervention on their Consumption--study protocol for a randomized controlled trial. AB - BACKGROUND: Cannabis is the most consumed illegal substance in France. General practitioners (GPs) are the health professionals who are most consulted by adolescents. Brief intervention (BI) is a promising care initiative for the consumption of cannabis, and could be a tool for GPs in caring for adolescents who consume cannabis. The aim of the CANABIC study is to measure the impact of a BI carried out by a GP on the consumption of cannabis by adolescents of 15 to 25 years of age. METHODS: A randomized clustered controlled trial, stratified over three areas (Auvergne, Languedoc-Roussillon, and Rhone - Alpes), comparing an intervention group, which carries out the BI in consultation, and a control group, which ensures routine medical care. The main assessment criterion is the consumption of cannabis by amount of joints per month, at 12 months. The amount necessary to highlight a significant difference between the two groups of 30% of consumption at 12 months is 250 patients (50 GPs, 5 patients per GP; risk alpha = 5%; power = 90%; intra-cluster correlation coefficient rho = 0.2; Hawthorne effect = 15%; lost to follow-up rates for GPs = 10% and for patients = 20%). This plan is replicated for the three areas, and therefore a total of 750 patients are expected.The secondary criteria for judgment are the associated consumption of tobacco and alcohol, the perception of the consequences of consumption, and the driving of a vehicle following consumption. DISCUSSION: Research about BI for young cannabis users is underway. The aim of the CANABIC study is to validate a BI suited to adolescents who consume cannabis, which may be performed in the general practice. This would provide a tool for their treatment by a GP, which could be widely distributed during initial or further medical training. TRIAL REGISTRATION: CANABIC is a randomized clustered trial (NCT01433692, registered 2011 Sept 12), PHRC funded: Clinical Research Hospital Program (Governmental Fund, Health Ministry). Date first patient randomized: March 2012. PMID- 24479704 TI - Attitudes to intracranial pressure monitoring of traumatic intracerebral haemorrhage. AB - INTRODUCTION: Recent research has been equivocal regarding the usefulness of intracranial pressure (ICP) monitoring for traumatic intracerebral haemorrhage (ICH). We aimed to investigate attitudes of clinicians from as wide an international audience as possible. MATERIALS AND METHODS: A SurveyMonkey((r)) questionnaire was distributed to individuals, including members of the Society of British Neurological Surgeons, the European Brain Injury Consortium, the neurotrauma committee of the Euroacademia Multidisciplinaria Neurotraumatologica and the World Federation of Neurosurgical Societies. RESULTS: N = 98 completed the survey (surgeons n = 86) from at least 25 different countries. ICP was routinely monitored by 76% and would be monitored by 5% more if they had equipment. ICP monitoring was valued (0 = not at all important, 10 = critically important) as 10 by 21% (median = 8, Q1 = 7, Q3 = 9). Triggers to begin ICP monitoring included midline shift (n = 48), contusion (n = 47), ICH (n = 46), subdural haemorrhage (n = 42), Glasgow coma scale reduction of median 2 for eye, verbal or motor, and one reactive pupil (30%). Responders stated that intervention would begin for adults with an ICP median of 25 mmHg and for children 20 mmHg. Most favourable treatments of raised ICP included Mannitol and ventriculostomy, which were ranked as most favourable (out of 10) by n = 31 each. Responders claimed to be aware of 16 different trials that investigated the value of ICP monitoring in neurotrauma, including BEST TRIP (n = 35), Rescue ICP (n = 13) and DECRA (n = 8). CONCLUSION: ICP monitoring continues to be a highly valued and clinically desirable technique for managing traumatic ICH patients. PMID- 24479705 TI - Nanocurcumin: a novel antifilarial agent with DNA topoisomerase II inhibitory activity. AB - OBJECTIVE: The aim of this study is to evaluate the antifilarial, antiwolbachial and DNA topoisomerase II inhibitory activity of nanocurcumin (nano-CUR). METHODS: Nano-CUR formulations (F1-F6) were prepared using free radical polymerization and were characterized by particle size, morphology, encapsulation efficiency and in vitro release kinetics. Antifilarial potential was evaluated in vivo against Brugian filariasis in an experimental rodent model, Mastomys coucha, by selecting the formulation that maximized parasite elimination characteristics. Wolbachial status was determined by PCR and a relaxation assay was used to estimate DNA topoisomerase II inhibitory activity. RESULTS: Nano-CUR (F3) having a 60 nm diameter and 89.78% entrapment efficiency showed the most favorable characteristics for the elimination of filarial parasites. In vivo pharmacokinetic and organ distribution studies demonstrate significantly greater C(max) (86.6 +/- 2.56 ng ml(-1)), AUC0-infinity (796 +/- 89.8 ng d ml(-1)), MRT (19.5 +/- 7.82 days) and bioavailability of CUR (70.02%) in the organs from which the adult parasites were recovered. The optimized nano-CUR (F3) (5 * 5 mg/kg, orally) significantly augmented the microfilariciadal and adulticidal action of CUR over free CUR (5 * 50 mg/kg, orally) or Diethylcarbamizine (50 mg/kg, orally) against the Brugia malayi Mastomys coucha rodent model. The PCR results showed complete elimination of wolbachia from the recovered female parasites. Interestingly, nano-CUR was also found to be a novel inhibitor of filarial worm DNA topoisomerase II, Setaria Cervi in vitro. CONCLUSION: This study recognizes the beforehand antimicrofilarial, antimacrofilarial, anti-wolbachial activity of nano-CUR (F3) over free forms and additionally its strong inhibitory action against the major target filarial parasite enzyme DNA topoisomerase II in vitro. PMID- 24479706 TI - Effect of ivabradine-induced heart rate reduction on flow-mediated dilation measured with high-sensitivity ultrasound in patients with stable coronary heart disease. AB - BACKGROUND: Experimental data suggests that exclusive heart rate reduction with ivabradine is associated with the amelioration of the endothelial function. Since it is presently unknown whether this also applies to humans, the aim of this pilot study was to investigate whether heart rate reduction with ivabradine modulates the endothelial function in humans with an established coronary heart disease. METHODS: Using high-sensitivity ultrasound, we analysed the flow mediated (FMD) and nitro-mediated dilation (NMD) of the brachial artery in 25 patients (62.9 +/- 8.4 years) with a stable coronary heart disease and a resting heart rate of >=70 beats per minute (bpm). To assess acute effects, measurements were performed before and 4 hours after the first intake of ivabradine 7.5 mg. Sustained effects of an ivabradine therapy (5 mg to 7.5 mg twice daily) were investigated after 4 weeks. RESULTS: We found a significant decrease in heart rate, both 4 hours after the intake of 7.5 mg of ivabradine (median -8 [interquartile range (IQR) -14 to -4] bpm) and after 4 weeks of twice daily intake (median -10 [IQR-17 to -5] bpm) (p < 0.05). However, the FMD did not change significantly: neither after first dose of ivabradine nor after sustained therapy (baseline FMD: median 5.0 [IQR 2.4 to 7.9]%; FMD 4 hours after 7.5 mg of ivabradine: median 4.9 [IQR 2.7 to 9.8]%; FMD after 4 weeks of ivabradine therapy: median 6.1 [IQR 4.3 to 8.2]%). No significant changes of the NMD were observed. In regression analysis, the heart rate and FMD did not correlated, irrespective of the ivabradine intake (r2 = 0.086). CONCLUSION: In conclusion, in our study heart rate reduction through ivabradine does not improve the endothelial function in patients with a stable coronary heart disease. Moreover, we found no correlation between the heart rate and the endothelial function. PMID- 24479707 TI - The use of the Rey 15-Item Test and recognition trial to evaluate noncredible effort after pediatric mild traumatic brain injury. AB - The Rey 15-Item Test (FIT) is a performance validity test commonly used in adult neuropsychological assessment. FIT classification statistics across studies have been variable, so a recognition trial was created to enhance the measure (Boone, K. B., Salazar, X., Lu, P., Warner-Chacon, K., & Razani, J. (2002). The Rey 15 Item recognition trial: A technique to enhance sensitivity of the Rey 15-Item Memorization Test. Journal of Clinical and Experimental Neuropsychology, 24(5), 561-573.). The current study assessed the utility of the FIT and recognition trial in a pediatric mild traumatic brain injury sample (N = 319, M = 14.57 years). All participants were administered the FIT and recognition trial as part of an abbreviated clinical neuropsychological evaluation. Failure on the Medical Symptom Validity Test was used as the criterion for noncredible effort. Fifteen percent of the sample met the criterion. The traditional adult cutoff score of <9 on the FIT recall trial yielded excellent specificity (98%), but very poor sensitivity (12%). When the recognition trial was utilized, a total score of <26 resulted in the best combined cutoff score (sensitivity = 55%, specificity = 91%). Results indicate that the FIT with recognition trial may be useful in the assessment of noncredible effort with children and adolescents, at least among relatively high-functioning populations. PMID- 24479708 TI - Isoflavonoids in the Amaryllidaceae family. AB - Plants of the Amaryllidaceae family are known as producers of biologically active alkaloids. Besides these a variety of flavonoids, including flavones, chalcones and chromones, have been detected in the Amaryllidaceous plants. In this study, we have analysed 16 representatives of the family for the presence of isoflavonoids. The water/ethanolic extracts were analysed with HPLC-ESI-MS both without any pre-treatment and after immunoaffinity chromatography as a clean-up step. Four individual immunosorbents specific for biochanin A, daidzein and genistein were used. In addition, five enzyme-linked immunosorbent assays specific for the above-mentioned isoflavonoids and their derivatives have been used for the analysis of the extracts after fractionation by semi-preparative HPLC. Fifteen selected isoflavonoids were detected in the studied samples, and the amount of individual compounds ranged between ca. 0.8 and 400 ng/g of dry weight. This study extends the number of known isoflavonoid-producing families within the monocotyledonous plants. PMID- 24479709 TI - Acanthamoeba and bacteria produce antimicrobials to target their counterpart. AB - BACKGROUND: In the microbial ecosystem, microbes compete for space and nutrients. Consequently, some have developed the ability to kill or inhibit the growth of other competing microbes by producing antimicrobial substances. As the 'producer' species are generally immune to these substances, their compounds act on the competing microbial species and give the producer more space and access to nutrients for growth. Many currently used antibiotics were developed by exploiting this potential of certain microbes. FINDINGS: Here, the free-living amoeba, Acanthamoeba castellanii, was investigated for its antibacterial activity against representative Gram positive and Gram negative bacteria, while bacterial isolates were tested for their anti-amoebic properties. Conditioned medium from A. castellanii showed remarkable bactericidal properties against methicillin resistant Staphylococcus aureus (MRSA) exhibiting almost 100% kill rate, but had limited effect against Acinetobacter sp., Pseudomonas aeruginosa and vancomycin resistant Enterococcus faecalis (VRE). Similarly, the conditioned medium of E. coli K1 and Enterobacter sp., exhibited potent anti-Acanthamoebic effects in a concentration-dependent manner. Conditioned media of Acanthamoeba, E. coli K1 and Enterobacter sp. showed no cytotoxicity in vitro when tested against human brain microvascular endothelial cells. Active molecule/s in aforementioned amoebic and two bacterial conditioned media were 5 - 10 kDa, and <5 kDa respectively. CONCLUSIONS: A. castellanii conditioned medium showed potent bactericidal properties against MRSA. The active molecule(s) are heat- and pronase-resistant, and in the 5 to 10 kDa molecular mass range. Contrary to this, E. coli K1 and Enterobacter sp., conditioned medium showed anti-amoebic effects that are <5 kDa in molecular mass, suggestive of active metabolites. PMID- 24479710 TI - Napsin A is a useful marker for metastatic adenocarcinomas of pulmonary origin. AB - AIMS: To address whether napsin A is useful for identifying metastatic adenocarcinomas of pulmonary origin. METHODS AND RESULTS: Fifty-four cases of adenocarcinoma that metastasized from the lungs to various sites and 1762 cases of carcinoma from various organs were immunostained for napsin A, TTF-1, CK7, CK20 and CDX2 using tissue microarray. The expression patterns of napsin A and TTF-1 in metastatic pulmonary adenocarcinomas were compared with matched primary lung tumours. Napsin A and TTF-1 were expressed in 87.0% and 81.5% of the metastatic pulmonary adenocarcinomas, respectively. Although there was no significant difference in the positivity of napsin A and TTF-1 as a single marker in metastatic pulmonary adenocarcinomas, the expression scores for napsin A were much higher than those for TTF-1 (P < 0.001). Moreover, the positivity and expression scores of napsin A in primary pulmonary adenocarcinomas were maintained in metastatic adenocarcinomas better than TTF-1. Most non-pulmonary adenocarcinomas were negative for napsin A, except for renal cell carcinomas (13.4%), ovarian adenocarcinomas (7.1%) and uterine endometrial adenocarcinomas (14.5%). In particular, clear cell adenocarcinomas of ovary (68.8%) and uterus (66.7%) frequently expressed napsin A. CONCLUSIONS: These data suggest that napsin A may be a useful marker for identifying metastatic adenocarcinomas of pulmonary origin in combination with TTF-1. PMID- 24479711 TI - Tertiary structure prediction of RNA-RNA complexes using a secondary structure and fragment-based method. AB - A method has been developed for predicting the tertiary structures of RNA-RNA complex structures using secondary structure information and a fragment assembly algorithm. The linker base pair and secondary structure potential derived from the secondary structure information are particularly useful for prediction. Application of this method to several kinds of RNA-RNA complex structures, including kissing loops, hammerhead ribozymes, and other functional RNAs, produced promising results. Use of the secondary structure potential effectively restrained the conformational search space, leading to successful prediction of kissing loop structures, which mainly consist of common structural elements. The failure to predict more difficult targets had various causes but should be overcome through such measures as tuning the balance of the energy contributions from the Watson-Crick and non- Watson-Crick base pairs, by obtaining knowledge about a wider variety of RNA structures. PMID- 24479712 TI - Reliability and validity of the Yo-Yo intermittent recovery test level 1 in young soccer players. AB - The present study investigated the test-retest reliability from the Yo-Yo IR1 (distance and heart rate responses), and the ability of the Yo-Yo IR1 to differentiate between elite and non-elite youth soccer players. A total of 228 youth soccer players (11-17 years) participated: 78 non-elite players to examine the test-retest reliability within 1 week, added with 150 elite players to investigate the construct validity. The main finding was that the distance covered was adequately reproducible in the youngest age groups (U13 and U15) and highly reproducible in the oldest age group (U17). Also, the physiological responses were highly reproducible in all age groups. Moreover, the Yo-Yo IR1 test had a high-discriminative ability to distinguish between elite and non-elite young soccer players. Furthermore, age-related standards for the Yo-Yo IR1 established for elite and non-elite groups in this study may be used for comparison of other young soccer players. PMID- 24479713 TI - Inhibitory effects of polypeptides derived from a snake venom C-type lectin, aggretin, on tumor cell-induced platelet aggregation. AB - BACKGROUND AND OBJECTIVES: Podoplanin, a transmembrane sialoglycoprotein, is expressed by lymphatic endothelial cells and many tumor cells, and is involved in tumor cell-induced platelet aggregation and tumor metastasis. A recent study found that C-type lectin-like receptor 2 (CLEC-2) is a physiologic receptor for podoplanin. Previous studies showed that aggretin, a snake venom-derived protein, activates platelets by targeting platelet CLEC-2. We hypothesized that the C terminal fragment of aggretin may bind to platelet CLEC-2 and displace podoplanin, in turn exerting antitumor metastatic effects. METHODS AND RESULTS: Aggretin alpha-chain C-terminus (residues 106-136; AACT) prolonged the lag phase of platelet aggregation induced by aggretin in human washed platelets, indicating that AACT may target the binding site of CLEC-2. HepG2 cells, which are podoplanin-expressing hepatoma cells, induced platelet aggregation with a lag phase. Pretreatment with AACT inhibited platelet aggregation and prolonged the lag phase induced by HepG2 cells. This inhibitory effect was also found with another hepatocarcinoma cell line, HuH-7. AACT inhibited the interaction between HuH-7 cells and platelets, and a specific binding assay demonstrated that CLEC-2 was the binding site for AACT on platelets. In addition, the invasive ability of HepG2 cells was abolished by AACT in a chick embryo chorioallantoic membrane model. Furthermore, formation of lung metastases after intravenous administration of HuH-7 cells was significantly reduced when mice were treated with AACT. CONCLUSIONS: AACT interacts with CLEC-2 of platelets, leading to interference with platelet aggregation and the subsequent metastatic potential of tumor cells. These results suggest that aggretin AACT is a potential candidate for the treatment of tumor metastasis through CLEC-2 blockade. PMID- 24479714 TI - How to estimate understanding: professionals' assessment of loved ones' insight into a patient's fatal disease. AB - BACKGROUND: Loved ones of a patient with an incurable disease will accompany the patient to the end of life. Health care professionals must discuss difficult matters with loved ones and be sure that they really understand the seriousness of the patient's disease. The study explore how the professionals do when they explore the grounds on which they make their assessment of loved ones' insight into a patient's fatal disease. METHOD: A qualitative design was chosen to gain deeper knowledge of professionals' perception of loved ones' understanding. The transcribed interviews were analysed using content analysis giving a richer understanding of the meaning of the content. RESULT: The participants assessed loved ones' insight into the fatal disease based on the course and content of the conversations they had with the loved ones. The professionals' assessments were based on how the loved ones talked and expressed themselves in words and behavior and on the type of questions posed by the loved ones. The loved ones' observations and hope as denial or a strategy also contributed to their assessment. CONCLUSION: Ways to communicate with loved ones are crucial when making an assessment. The different ways loved ones use hope and other strategies made it problematic for the professionals to use these as indicators of state of mind in this matter. Training in conversation skills could be one way to support professionals when discussing and managing these difficult situations. PMID- 24479716 TI - Quasiclassical trajectory study of the atmospheric reaction N((2)D) + NO(X (2)Pi) -> O((1)D) + N(2)(X (1)Sigma(g)(+)). AB - Quasiclassical trajectories have been run for the title atmospheric reaction over the range of temperatures 5 <= T/K <= 3000 on a recently proposed single-sheeted double many-body expansion (DMBE) potential energy surface for ground-state N2O((1)A'). As typical in a capture-like reaction, the rate constant decreases with temperature for 50 <= T/K <= 800 K, while showing a small dependence at higher temperature regimes. At room temperature, it is predicted to have a value of (20.1 +/- 0.2) * 10(-12) cm(3) s(-1). The calculated cross sections show a monotonic decay with temperature and translational energy. Good agreement with the experimental data has been observed, providing more realistic rate constants and hence support of enhanced accuracy for the DMBE potential energy surface with respect to other available forms. PMID- 24479715 TI - A novel ethylene-responsive factor from Tamarix hispida, ThERF1, is a GCC-box- and DRE-motif binding protein that negatively modulates abiotic stress tolerance in Arabidopsis. AB - Ethylene-responsive factor (ERF) family is one of the largest families of plant specific transcription factor that can positively or negatively regulate abiotic stress tolerance. However, their functions in regulating abiotic stress tolerance are still not fully understood. In this study, we characterized the functions of an ERF gene from Tamarix hispida, ThERF1, which can negatively regulate abiotic stress tolerance. The expression of ThERF1 was induced by salinity, PEG-simulated drought and abscisic acid (ABA) treatments. ThERF1 can specifically bind to GCC box and DRE motifs. Overexpression of ThERF1 in transgenic Arabidopsis plants showed inhibited seed germination, and decreased fresh weight gain and root growth compared with wild-type (WT) plants. In addition, the transcript levels of several superoxide dismutase (SOD) and peroxidase (POD) genes in transgenic plants were significantly inhibited compared with in WT plants, resulting in decreased SOD and POD activities in transgenic plants under salt and drought stress conditions. Furthermore, the reactive oxygen species (ROS) levels, malondialdehyde (MDA) contents and cell membrane damage in ThERF1-transformed plants were all highly increased relative to WT plants. Our results suggest that ThERF1 negatively regulates abiotic stress tolerance by strongly inhibiting the expression of SOD and POD genes, leading to decreased ROS-scavenging ability. PMID- 24479717 TI - Antiplatelet therapies: aspirin at the heart of new directions. AB - When introduced over 100 years ago, aspirin was prescribed as an analgesic drug to arthritic patients for pain relief. The prevalence of users grew quite rapidly and to this day, aspirin remains widely used in clinical practice. The popularity of aspirin resulted not only from its analgesic properties but also from a second benefit recognized later as an anti-platelet effect. It was this important activity of aspirin that made it one of the most recommended drugs for the treatment and prevention of cardiovascular diseases. The anti-platelet effect of aspirin emerged from the first few case reports published in the early 1900s and was described as a mild bleeding. The molecular mechanisms involved were described in 1971 and constituted the irreversible inhibition of cyclooxygenase-1 enzyme and prevention of platelet aggregation. Today, the contribution of aspirin to our understanding of cardiovascular health persists and remains considerable. Observations from large cohorts of aspirin users generate massive amount of valuable information used in the identification of factors influencing the potential risk for cardiovascular diseases, including sex, age and genetic predisposition. Aspirin and the path of discovery leading to its anti-platelet activity has taken a hundred years was based on manifestations of effects observed in its users, and it remains a successful strategy for the identification of new avenues to treat cardiovascular diseases associated with hyper-platelet activity. The contribution of aspirin to the understanding of cardiovascular diseases and to the design of effective treatment and prevention strategies, remains of high importance in our society. PMID- 24479719 TI - Role of alpha- and beta-adrenergic mechanisms in the pathogenesis of pulmonary injuries characterized by edema, inflammation and fibrosis. AB - Adrenergic mechanisms are involved in the formation of several types of pulmonary edema (PE) such as neurogenic pulmonary edema (NPE) or PE in patients with pheochromocytoma, but also in the development of pulmonary fibrosis and pulmonary hypertension. In severe cases of PE such as in the adult respiratory distress syndrome (ARDS), PE is typically accompanied by inflammation and followed by pulmonary vascular hypertrophy and pulmonary fibrosis. Norepinephrine and other adrenoceptor agonists are known to provoke activation of proinflammatory cytokines such as interleukin (IL)-1 and IL-6. These cytokines are involved both in the pathogenesis of PE and of pulmonary fibrosis. We therefore assume that adrenergic mechanisms may have an important role in the pathogenesis of pulmonary injuries characterized by edema, inflammation and fibrosis. The contribution of adrenoceptor stimulation, particularly the distinct role of alpha- and beta adrenergic mechanisms, to the development of PE and pulmonary fibrosis is reviewed in this paper. PMID- 24479718 TI - Contemporary risk assessment and cardiovascular outcomes in peripheral arterial disease. AB - The term peripheral arterial disease (PAD) is often used to describe atherosclerosis involving the arteries supplying the lower extremities. Risk factors that predispose to the development and progression of both symptomatic and asymptomatic PAD include age, ethnicity, smoking, diabetes mellitus, hyperlipidemia, and hypertension. In addition, emerging biomarkers of inflammation, oxidative stress, thrombosis and metabolism have also been discovered to be predictive of future PAD events. Since traditional risk factors for PAD predispose to the development of systemic atherosclerosis, identification of PAD increases the likelihood of coexistent coronary heart and cerebrovascular disease. Even after adjustment for risk factors, PAD appears to increase the risk for ischemic manifestations involving these other vascular territories with about a 2-fold increase in myocardial infarction and perhaps stroke. The most dramatic consequence of PAD is impaired survival with a 2- to 3-fold increased risk of 5- to 10-year mortality. Not only is the risk of adverse cardiovascular and cerebrovascular complications elevated in patients with severe PAD, but it is also markedly elevated in those with asymptomatic disease. The focus in the management of PAD should be on early diagnosis and efforts to reduce the risk of adverse events by risk factor modification and antiplatelet therapy. PMID- 24479720 TI - Iron supplementation therapy in end-stage renal disease patients on maintenance hemodialysis. AB - Iron supplementation therapy seems almost indispensable in adequate management of the patients with end - stage renal disease on maintenance hemodialysis, since at least one and a half grams iron is considered to be required per year to keep sufficient erythropoiesis. Iron supplementation in conjunction with erythropoietic-stimulating agents is widely carried out as a standard therapy. However, definite diagnosis of iron deficiency in hemodialysis patients is often difficult since serum ferritin levels increase frequently by various reasons including inflammation and malignancy. Although several guidelines to treat anemia of the hemodialysis patients have been proposed, they seem still insufficient and careful clinical observation is required in individual patient to avoid possible complications of iron overload. We, here, reassess the adequate iron supplementation therapy in those patients, and the necessity of new guideline employing recent advances including magnetic resonance imaging - based method (FerriScan) and hemoglobin content per each reticulocyte is also discussed. PMID- 24479721 TI - Pre-hospital fibrinolysis in the management of patients with ST elevation acute coronary syndrome: review of the evidence, implementation and future directions. AB - Time to reperfusion is among the strongest predictors of clinical outcome in patients who present with ST elevation acute myocardial infarction. When time to access is equivalent, primary percutaneous coronary intervention has demonstrated superior outcomes to fibrinolysis. However, where significant delays exist in accessing percutaneous intervention, fibrinolysis has an important role. The potential for fibrinolysis delivery in the pre-hospital setting means that delays to primary percutaneous intervention need to be considered from the time that the patient becomes eligible for fibrinolysis in the field. This can be particularly challenging in patients with symptom duration ofless than two hours, as some evidence suggests fibrinolysis may be particularly beneficial in this early phase. Additionally, access to primary percutaneous intervention provided by an experienced operator, in a timely manner at any time of the day or night, is not an available option in many healthcare settings. This review focuses on the current evidence and practice of pre-hospital fibrinolysis and assesses potential roles for this therapy in the future. PMID- 24479722 TI - Comparison of peroperative subconjunctival injection of methylprednisolone and standard postoperative steroid drops after uneventful cataract surgery. AB - PURPOSE: To compare the safety and efficacy of a single subconjunctival injection of methylprednisolone and a standard postoperative steroid regimen in terms of intraocular inflammation and intraocular pressure (IOP) after uncomplicated phacoemulsification surgery. METHODS: Two groups of 25 patients each were included in this prospective randomized controlled trial. Patients in the injection group were given a subconjunctival injection of 20 mg methylprednisolone and the topical group received the conventional postoperative care with steroid eye drops (dexamethasone 1 mg/ml). The patients were examined 1 week and 1 month after surgery. Slit-lamp evaluation of anterior chamber inflammation and IOP were performed. Changes in IOP of >=2.4 mmHg were considered clinically relevant. RESULTS: In the injection group, mean IOP decreased from 15.4 +/- 2.2 mmHg (baseline) to 14.1 +/- 3.2 mmHg at 1 week (p = 0.03). The topical group had a stable IOP at 1 week (16.3 +/- 2.6 mmHg) compared to baseline (16.1 +/- 2.7 mmHg; p = 0.74). At 1 month, mean IOP was 14.3 +/- 2.6 mmHg (p = 0.03) in the injection group and 15.6 +/- 2.3 mmHg (p = 0.2) in the topical group. The intragroup changes were neither statistically significant nor clinically relevant at any postoperative visit. Both groups had the highest values of intraocular inflammation at the 1-week postoperative visit, followed by a decline to barely traceable levels at 1 month. The difference was not clinically relevant at any postoperative visit. CONCLUSIONS: The subconjunctival injection of methylprednisolone appears to be as safe and effective as the conventional treatment, and it might therefore be considered for treatment of individuals with compliance issues. PMID- 24479723 TI - Biomechanics of distal femoral fracture fixed with an angular stable LISS plate. AB - Fractures of the distal end of the femur are infrequent and constitute less than 1% of all fractures. Only 3% to 6% of femoral fractures occur at the distal end. The two groups most at risk of the said fractures are young men and older women. The aim of treatment of fractures of the distal femur is to restore normal function of the knee joint. The authors asked themselves whether, following fixation of a 33-C2 fracture (according to the AO classification) with a LISS plate, a rehabilitation program can be undertaken immediately after surgery with the implementation of active movements in the knee joint of the operated limb. In order to answer this question, we created a digital model of a fractured femur fixed with the LISS method. The model was subjected to loads corresponding to the loads generated during active lifting of a limb extended in the knee joint and during flexing of a limb in the knee joint to the 90 degrees angle. Interfragmentary movement (IFM) is one of the key parameters taken into account in the treatment of bone fractures. It allows classification of the treatment in terms of its quality both from the mechanical and histological points of view. We analyzed interfragmentary movement in all fracture gaps. The largest recorded displacement reached in our model was 243 MUm, which, in the light of the literature data, should not interfere with bone consolidation, and thus implementation of active movement in the operated knee joint (keeping in mind the simplifications of the experimental method used) is possible in the early postoperative period. PMID- 24479724 TI - Latent variables may be useful in pain's assessment. AB - BACKGROUND: Unobserved "latent" variables have the potential to minimize "measurement error" inherent to any single clinical assessment or categorical diagnosis. OBJECTIVES: To demonstrate the potential utility of latent variable constructs in pain's assessment. DESIGN: We created two latent variables representing depressive symptom-related pain (Pd) and its residual, "somatic" pain (Ps), from survey questions. SETTING: The Hispanic Established Population for Epidemiological Studies in the Elderly (H-EPESE) project, a longitudinal population-based cohort study. PARTICIPANTS: Community dwelling elderly Mexican Americans in five Southwestern U.S. states. The data were collected in the 7th HEPESE wave in 2010 (N = 1,078). MEASUREMENTS: Self-reported pain, Center for Epidemiological Studies Depression Scale (CES-D) scores, bedside cognitive performance measures, and informant-rated measures of basic and instrumental Activities of Daily Living. RESULTS: The model showed excellent fit [chi2 = 20.37, DF = 12; p = 0.06; Comparative fit index (CFI) = 0.998; Root mean statistical error assessment (RMSEA) = 0.025]. Ps was most strongly indicated by self-reported pain-related physician visits (r = 0.48, p <=0.001). Pd was most strongly indicated by self-reported pain-related sleep disturbances (r = 0.65, p <0.001). Both Pd and Ps were significantly independently associated with chronic pain (> one month), regional pain and pain summed across selected regions. Pd alone was significantly independently associated with self-rated health, life satisfaction, self-reported falls, Life-space, nursing home placement, the use of opiates, and a variety of sleep related disturbances. Ps was associated with the use of NSAIDS. Neither construct was associated with declaration of a resuscitation preference, mode of resuscitation preference declaration, or with opting for a "Do Not Resuscitate" (DNR) order. CONCLUSION: This analysis illustrates the potential of latent variables to parse observed data into "unbiased" constructs with unique predictive profiles. The latent constructs, by definition, are devoid of measurement error that affects any subset of their indicators. Future studies could use such phenotypes as outcome measures in clinical pain management trials or associate them with potential biomarkers using powerful parametric statistical methods. PMID- 24479725 TI - Diabetes mellitus in North West Ethiopia: a community based study. AB - BACKGROUND: Diabetes mellitus is recognized as one of the emerging public health problems in developing countries. However, its magnitude has not been studied at community levels, making the provision of appropriate services difficult in such countries. Hence, this study aimed to compare the magnitude and associated risks of diabetes mellitus among urban and rural adults in northwest Ethiopia. METHODS: A cross-sectional population based survey was performed using the WHO STEPwise method on adults aged 35 years and above. A multistage cluster random sampling strategy was used to select study participants from urban and rural locations. Fasting blood glucose levels were determined using peripheral blood samples by finger puncture. Prevalence was computed with a 95% confidence interval for each residential area. Selected risk factors were assessed using logistic regression. RESULTS: The prevalence of diabetes mellitus among adults aged 35 years and above was 5.1% [95% CI: 3.8, 6.4] for urban and 2.1% [95% CI: 1.2, 2.9] for rural dwellers. The majority (69%) of the identified diabetic cases were not diagnosed prior to the survey. The highest proportion (82.6%) of the undiagnosed cases was noted among the rural population and 63% among the urban population. Family history of diabetes (AOR = 5.05; 2.43, 10.51), older age (AOR = 4.86; 1.99, 11.9) and physical inactivity (AOR = 1.92; 1.06, 3.45) were significantly associated with diabetes mellitus among the urban population. Alcohol consumption (AOR = 0 .24, 0 .06, 0.99) was inversely associated with diabetes mellitus in rural areas. CONCLUSION: The prevalence of diabetes mellitus is considerably high among the urban compared to the rural population. Diabetes is largely undiagnosed and untreated, especially in rural settings. Appropriate actions need to be taken to provide access to early diagnosis and treatment in order to reduce associated complications. PMID- 24479726 TI - Use of the i2b2 research query tool to conduct a matched case-control clinical research study: advantages, disadvantages and methodological considerations. AB - BACKGROUND: A major aim of the i2b2 (informatics for integrating biology and the bedside) clinical data informatics framework aims to create an efficient structure within which patients can be identified for clinical and translational research projects.Our objective was to describe the respective roles of the i2b2 research query tool and the electronic medical record (EMR) in conducting a case controlled clinical study at our institution. METHODS: We analyzed the process of using i2b2 and the EMR together to generate a complete research database for a case-control study that sought to examine risk factors for kidney stones among gastrostomy tube (G-tube) fed children. RESULTS: Our final case cohort consisted of 41/177 (23%) of potential cases initially identified by i2b2, who were matched with 80/486 (17%) of potential controls. Cases were 10 times more likely to be excluded for inaccurate coding regarding stones vs. inaccurate coding regarding G tubes. A majority (67%) of cases were excluded due to not meeting clinical inclusion criteria, whereas a majority of control exclusions (72%) occurred due to inadequate clinical data necessary for study completion. Full dataset assembly required complementary information from i2b2 and the EMR. CONCLUSIONS: i2b2 was critical as a query analysis tool for patient identification in our case-control study. Patient identification via procedural coding appeared more accurate compared with diagnosis coding. Completion of our investigation required iterative interplay of i2b2 and the EMR to assemble the study cohort. PMID- 24479727 TI - Symptom Checklist 90-Revised in neurological outpatients. AB - The Symptom Checklist 90-Revised (SCL-90-R) is an international, widely used, self-report questionnaire of multidimensional complaints with normative data for healthy control subjects and psychiatric patients. The questionnaire is also often used in neurological patients. Little is known about the amount and pattern of complaints in this group, and normative data are lacking. We therefore analyzed self-reported symptoms on the SCL-90-R of a neurological population (N = 600). Moreover, we compared the answer patterns of five subgroups: neurodegenerative disease, cerebrovascular disease, epilepsy, brain tumor, and traumatic brain injury. Neurological outpatients scored significantly higher in comparison with normative data from healthy control subjects, with most pronounced scores on Inadequacy of Thinking and Acting, Depression, and Somatization (p < .01, effect sizes 1.69, 0.83, and 0.83). No differences between the various pathologies were found. Although it is difficult to determine whether the complaints arise directly from the neurological disease or more indirectly from psychiatric disturbances accompanying the disease, simply comparing a neurological patient to normative data for healthy control subjects can lead to inappropriate classifications. Complaints of our patients should not be directly interpreted as psychopathology. A two-step procedure in which scores on the SCL 90-R are first compared to healthy control subjects and secondly to neurological patients can be helpful in the interpretation. PMID- 24479728 TI - Micropunch blepharopeeling of the upper eyelids: a combination approach for periorbital rejuvenation--a pilot study. AB - BACKGROUND: Upper eyelid skin excess is commonly treated using a surgical excision that is then sutured, resulting in a linear scar. Deep chemical peeling of the upper eyelids using the Baker Gordon formula has been described as a nonsurgical alternative to tighten upper eyelid skin with the advantage of lessening periorbital rhytides, although prolonged healing and hypopigmentation are risks. The goal of this study was to show the benefits of a less-invasive approach to periorbital rejuvenation that combines 89% phenol peeling with small, nonlinear excisions that heal by secondary intention. METHODS: Eight patients were chosen (mean age 59.6). All patients had thin to medium-thick skin, diffuse periorbital rhytides, and mild to moderate upper eyelid skin excess. Their eyelids were peeled using 89% phenol. Immediately after peeling, a scissor was used to make multiple small nonlinear excisions of upper eyelid skin that healed by secondary intention. RESULTS: Patients were satisfied with the results, and no complications or scarring occurred. CONCLUSIONS: Eighty-nine percent phenol peeling combined with multiple small upper eyelid skin excisions effectively tightens upper eyelid skin excess and lessens periorbital rhytides. The procedure has the advantage of not creating a linear scar and decreases the risk of prolonged healing and hypopigmentation, which is more likely with deeper peels. PMID- 24479730 TI - Manipulating nanoscale contact electrification by an applied electric field. AB - Contact electrification is about the charge transfer between the surfaces of two materials in a contact-separation process. This effect has been widely utilized in particle separation and energy harvesting, where the charge transfer is preferred to be maximized. However, this effect is always undesirable in some areas such as electronic circuit systems due to the damage from the accumulated electrostatic charges. Herein, we introduced an approach to purposely manipulate the contact electrification process both in polarity and magnitude of the charge transfer through an applied electric field between two materials. Theoretical modeling and the corresponding experiments for controlling the charge transfer between a Pt coated atomic force microscopy tip and Parylene film have been demonstrated. The modulation effect of the electric field on contact electrification is enhanced for a thinner dielectric layer. This work can potentially be utilized to enhance the output performance of energy harvesting devices or nullify contact electric charge transfer in applications where this effect is undesirable. PMID- 24479729 TI - Health services changes: is a run-in period necessary before evaluation in randomised clinical trials? AB - BACKGROUND: Most randomised clinical trials (RCTs) testing a new health service do not allow a run-in period of consolidation before evaluating the new approach. Consequently, health professionals involved may feel insufficiently familiar or confident, or that new processes or systems that are integral to the service are insufficiently embedded in routine care prior to definitive evaluation in a RCT. This study aimed to determine the optimal run-in period for a new physiotherapy led telephone assessment and treatment service known as PhysioDirect and whether a run-in was needed prior to evaluating outcomes in an RCT. METHODS: The PhysioDirect trial assessed whether PhysioDirect was as effective as usual care. Prior to the main trial, a run-in of up to 12 weeks was permitted to facilitate physiotherapists to become confident in delivering the new service. Outcomes collected from the run-in and main trial were length of telephone calls within the PhysioDirect service and patients' physical function (SF-36v2 questionnaire) and Measure Yourself Medical Outcome Profile v2 collected at baseline and six months. Joinpoint regression determined how long it had taken call times to stabilise. Analysis of covariance determined whether patients' physical function at six months changed from the run-in to the main trial. RESULTS: Mean PhysioDirect call times (minutes) were higher in the run-in (31 (SD: 12.6)) than in the main trial (25 (SD: 11.6)). Each physiotherapist needed to answer 42 (95% CI: 20,56) calls for their mean call time to stabilise at 25 minutes per call; this took a minimum of seven weeks. For patients' physical function, PhysioDirect was equally clinically effective as usual care during both the run-in (0.17 (95% CI: -0.91,1.24)) and main trial (-0.01 (95% CI: -0.80,0.79)). CONCLUSIONS: A run in was not needed in a large trial testing PhysioDirect services in terms of patient outcomes. A learning curve was evident in the process measure of telephone call length. This decreased during the run-in and stabilised prior to commencement of the main trial. Future trials should build in a run-in if it is anticipated that learning would have an effect on patient outcome. TRIAL REGISTRATION: Current Controlled Trials, ISRCTN55666618. PMID- 24479732 TI - Older diabetic patients' attitudes and beliefs about health and illness. AB - AIMS AND OBJECTIVES: To determine older diabetic patients' attitudes and beliefs about illness and health. BACKGROUND: Prevention of metabolic complications and treatment for cardiovascular risk factors are the main aims of the care and treatment of older diabetic patients. For the effective management of diabetes, it is crucial to recognise patients' beliefs and attitudes about and behaviours towards their health and illness. DESIGN: A descriptive study. METHODS: The sample included 70 diabetic patients aged 65 and older. Data were collected using a socio-demographic form and the Health Belief Model Scale. The data were analysed using descriptive statistics, Mann-Whitney U-test, t-test, Kruskal Wallis test, Welch variance analysis and Spearman correlation. RESULTS: Results showed that older diabetic patients' attitudes about illness and health were negative. Among individuals aged 65-70 years with more than secondary education and previous employment, mean perceived severity scores were found to be significantly higher than in other groups. The mean perceived barriers scores were found to be higher than in other groups, and this difference was statistically significant for older participants who declared a good economic status, who exhibited good/very good adherence to nutritional therapy and who were exercising and checking their blood sugar regularly. The perceived benefits and recommended activities scores of patients needing more education were significantly higher. CONCLUSIONS: Patients who were female, aged 70 and older, and of low educational and economic statuses; who showed poor adherence to treatment and medical nutrition therapy; and who needed diabetes-related training had negative health beliefs and were particularly at risk. RELEVANCE TO CLINICAL PRACTICE: Determining the personal factors that influence health behaviours can support the development of educational activities for diabetes management, complication prevention and treatment adherence improvement. PMID- 24479733 TI - Impact of cetuximab in current treatment of metastatic colorectal cancer. AB - INTRODUCTION: Cetuximab is a chimeric monoclonal antibody targeting the EGFR, which has proven effective in patients with metastatic colorectal cancer (mCRC), wild-type Kirsten rat sarcoma viral oncogene homolog (KRAS). AREAS COVERED: The aim of this manuscript is to discuss the current impact of cetuximab in the most important scenarios of mCRC. We review the currently available data regarding the role of other biomarkers, such as the mutational status of neuroblastoma RAS viral (v-ras) oncogene homolog in identifying patients who could benefit most from anti-EGFR. In addition, a review is included of the most relevant clinical trials that have assessed the effectiveness of cetuximab in the management of patients with potentially resectable metastatic disease and in the first-line treatment of wild-type KRAS mCRC, as well as the impact of this anti-EGFR agent on patient quality of life. EXPERT OPINION: Cetuximab has had a progressive clinical development from the earliest to the later stages of the evolution of mCRC and has been consolidated as a therapeutic option for all scenarios of unresectable disease. Patient selection by analysis of KRAS mutations has been a fundamental event to increase efficiency, being a dynamic process that continues in assessment. There are few comparative data with other biological agents in combination with chemotherapy, although data from a recent study are promising. PMID- 24479731 TI - Signaling pathways in the development of infantile hemangioma. AB - Infantile hemangioma (IH), which is the most common tumor in infants, is a benign vascular neoplasm resulting from the abnormal proliferation of endothelial cells and pericytes. For nearly a century, researchers have noted that IH exhibits diverse and often dramatic clinical behaviors. On the one hand, most lesions pose no threat or potential for complication and resolve spontaneously without concern in most children with IH. On the other hand, approximately 10% of IHs are destructive, disfiguring and even vision- or life-threatening. Recent studies have provided some insight into the pathogenesis of these vascular tumors, leading to a better understanding of the biological features of IH and, in particular, indicating that during hemangioma neovascularization, two main pathogenic mechanisms prevail, angiogenesis and vasculogenesis. Both mechanisms have been linked to alterations in several important cellular signaling pathways. These pathways are of interest from a therapeutic perspective because targeting them may help to reverse, delay or prevent hemangioma neovascularization. In this review, we explore some of the major pathways implicated in IH, including the VEGF/VEGFR, Notch, beta-adrenergic, Tie2/angiopoietins, PI3K/AKT/mTOR, HIF-alpha mediated and PDGF/PDGF-R-beta pathways. We focus on the role of these pathways in the pathogenesis of IH, how they are altered and the consequences of these abnormalities. In addition, we review the latest preclinical and clinical data on the rationally designed targeted agents that are now being directed against some of these pathways. PMID- 24479734 TI - The human microbiome and bile acid metabolism: dysbiosis, dysmetabolism, disease and intervention. AB - INTRODUCTION: Recent evidence indicates that the human gut microbiome plays a significant role in health and disease. Dysbiosis, defined as a pathological imbalance in a microbial community, is becoming increasingly appreciated as a 'central environmental factor' that is both associated with complex phenotypes and affected by host genetics, diet and antibiotic use. More recently, a link has been established between the dysmetabolism of bile acids (BAs) in the gut to dysbiosis. AREAS COVERED: BAs, which are transformed by the gut microbiota, have been shown to regulate intestinal homeostasis and are recognized as signaling molecules in a wide range of metabolic processes. This review will examine the connection between BA metabolism as it relates to the gut microbiome and its implication in health and disease. EXPERT OPINION: A disrupted gut microbiome, including a reduction of bile salt hydrolase (BSH)-active bacteria, can significantly impair the metabolism of BAs and may result in an inability to maintain glucose homeostasis as well as normal cholesterol breakdown and excretion. To better understand the link between dysbiosis, BA dysmetabolism and chronic degenerative disease, large-scale metagenomic sequencing studies, metatranscriptomics, metaproteomics and metabolomics should continue to catalog functional diversity in the gastrointestinal tract of both healthy and diseased populations. Further, BSH-active probiotics should continue to be explored as treatment options to help restore metabolic levels. PMID- 24479735 TI - Chemical composition of the essential oil of Lippia gracilis Schauer leaves and its potential as modulator of bacterial resistance. AB - Lippia gracilis Schauer (Verbenaceae) is an aromatic plant widely used in folk medicine in the Brazilian semi-arid region. This work aims at evaluating the anti microbial activity of essential oils from the leaves of L. gracilis (EOLG) when associated with commercial antibiotics against bacterial resistance. The essential oil obtained by hydrodistillation has 38 chemical constituents with thymol (44.4%), carvacrol (22.2%), p-cymene (6.2%) and alpha-pinene (5.6%) as major constituents. Microbiological assays were conducted by direct and gaseous contacts. We demonstrated that EOLG has significant synergism with all antibiotics tested. EOLG decreased the minimal inhibitory concentration of the aminoglycosides and improved their zone of inhibition more than 300% against Staphylococcus aureus and 270% against Pseudomonas aeruginosa. These results demonstrate that natural substances present in EOLG have the capacity to modulate bacterial resistance and can be used as an adjuvant therapy against multi resistant microorganisms such as S. aureus, Escherichia coli and P. aeruginosa. PMID- 24479736 TI - Ambiguous idiom processing in Parkinson's disease patients. AB - Patients affected by Parkinson's disease (PD) can provide crucial information about the involvement of the motor system and prefrontal cortex in processing idioms including action verbs, since dopamine modulates the activity of these structures, and, consequently, different levels of this neurotransmitter can induce different cognitive impairments. In order to investigate the ability to process ambiguous idioms containing an action verb in patients, we asked 15 PD patients, in both OFF- and ON-phases, and 15 healthy matched participants to judge the plausibility of literal and idiomatic sentences, each presented at a self-paced rate. Patients in OFF-phase were faster in reading idiomatic than literal sentences, supporting the view that the motor system is not involved in online idiom processing. However, patients during OFF-phase were impaired in judging the plausibility of idiomatic ambiguous sentences, possibly due to the reduction of dopamine in prefrontal regions. The involvement of the motor system was evident in the ON-phase for literal sentences, suggesting that motor activation is strictly dependent on the context. PMID- 24479737 TI - Monitoring of immunological parameters in adolescent basketball athletes during and after a sports season. AB - The objective of the present study was to monitor the immunological and hormonal responses and the occurrence of upper respiratory symptoms in adolescent basketball athletes during the different stages of a sports season. Anthropometric measures, biochemical analyses (interleukin-6, interleukin-10, tumour necrosis factor-alpha, C-reactive protein, testosterone and cortisol), neuromuscular evaluations (standing vertical jumping ability, agility and estimated VO2max) and leukocyte counts were performed at four moments: 72 h before the season (-72 h); before the season (Pre-season); after six weeks, at the end of the preparatory period (Preparatory); and after 20 weeks, at the end of the competitive period (Competitive). Also, the occurrence of upper respiratory symptoms was collected weekly during all stages of the season. There were significant increases in monocytes, cortisol, tumour necrosis factor-alpha and C-reactive protein at the Competitive moment as compared to the Pre-season. In addition, interleukin-10 decreased at the Competitive moment as compared to the Pre-season. Occurrence of upper respiratory symptoms demonstrated increases (38%) during the competitive period as compared to the preparatory. These results suggest that periods of training and competition could increase the occurrence of upper respiratory symptoms in adolescent athletes and this may be due to the unwanted effects of an inflammatory process in response to the excessive stress of training and competition. PMID- 24479738 TI - Evaluation of histological staging systems for primary biliary cirrhosis: correlation with clinical and biochemical factors and significance of pathological parameters in prognostication. AB - AIMS: A new Japanese histological staging system for primary biliary cirrhosis (PBC) has been proposed. We aimed to evaluate the efficacies of the Scheuer, Ludwig and Japanese staging systems, with emphasis on their clinical and biochemical correlations and prognostic significances. METHODS AND RESULTS: We conducted a retrospective review of a cohort of 58 Chinese PBC patients, with follow-up of up to 16.9 years. All three systems correlated well with prognostically significant parameters, namely serum bilirubin, Mayo scores and model for end-stage liver disease (MELD) score. Only the Japanese staging system was associated with Child-Pugh score, which was the single independent prognostic factor for liver-related events (log-rank P < 0.001; Cox proportional hazard ratio (HR) 6.723, P < 0.001). The Japanese system (log-rank P = 0.007; Cox proportional HR 10.400, P = 0.025) predicted liver-related events, while Scheuer (log-rank P = 0.112) and Ludwig (log-rank P = 0.147) systems did not. The copper associated protein (CAP) deposition score, a component of the Japanese system, was the most powerful histological prognostic parameter (log-rank P < 0.001; Cox proportional HR 99.534, P = 0.049) and provided extra prognostic values in additional to serum albumin, serum bilirubin, Child-Pugh score, Mayo scores and MELD score. CONCLUSION: The Japanese staging system is more effective than classical systems. The degree of CAP deposition is an essential prognostic histological parameter. PMID- 24479739 TI - Risk of ischaemic stroke associated with intravitreal bevacizumab -- a hospital based case-crossover study. PMID- 24479740 TI - Cognitive-behavioral therapy for anxious children: from evidence to practice. AB - BACKGROUND: Anxiety is the most common mental health problem in children, yet less than one third of children with anxiety disorders seek treatment. Cognitive behavioral therapy (CBT) is recommended as a first-line treatment for childhood anxiety. However, current practice generally does not include CBT due to issues of feasibility, affordability, and transportability. AIMS: The primary purpose of this review was to appraise current literature regarding the effectiveness of individual CBT for childhood anxiety. Secondary purposes were to identify reasons for the discrepancy between current evidence and practice as well as to offer suggestions to overcome this dilemma. METHODS: A systematic review of the literature published between 2007 and 2012 was conducted, searching four databases--Cochrane, PubMed, CINAHL, and PsycINFO. FINDINGS: In all 10 studies reviewed, individual CBT significantly reduced rates of anxiety diagnoses when compared with controls, and was equally effective or superior to comparison therapies. The only exception was when CBT was compared to a combination of CBT and pharmacological management, in which case the latter was more effective. LINKING EVIDENCE TO ACTION: Each study included in this review employed hour-long sessions over a minimum of 12 visits. In order to meet clinical demands and patient preferences, affordability, and feasibility of CBT interventions must be addressed. A brief, manualized CBT program that can be supported to be clinically effective is proposed as an evidence-based solution for anxious children in outpatient mental health and primary care settings. PMID- 24479741 TI - Pharmacokinetics of doxycycline in tilapia (Oreochromis aureus * Oreochromis niloticus) after intravenous and oral administration. AB - The pharmacokinetics of doxycycline was studied in plasma after a single dose (20 mg/kg) of intravenous or oral administration to tilapia (Oreochromis aureus * Oreochromis niloticus) reared in fresh water at 24 degrees C. Plasma samples were collected from six fish per sampling point. Doxycycline concentrations were determined by high-performance liquid chromatography with a 0.005 MUg/mL limit of detection, then were subjected to noncompartmental analysis. Following oral administration, the double-peak phenomenon was observed, and the first (Cmax1 ) and second (Cmax2) peaks were 1.99 +/- 0.43 MUg/mL at 2.0 h and 2.27 +/- 0.38 MUg/mL at 24.0 h, respectively. After the intravenous injection, a Cmax2 (12.12 +/- 1.97 MUg/mL) was also observed, and initial concentration of 45.76 MUg/mL, apparent elimination rate constant (lambdaz) of 0.018 per h, apparent elimination half-life (t1/2lambdaz) of 39.0 h, systemic total body clearance (Cl) of 41.28 mL/h/kg, volume of distribution (Vz) of 2323.21 mL/kg, and volume of distribution at steady-state (Vss) of 1356.69 mL/kg were determined, respectively. While after oral administration, the lambdaz, t1/2lambdaz, and bioavailability of doxycycline were 0.009 per h, 77.2 h, and 23.41%, respectively. It was shown that doxycycline was relatively slowly and incompletely absorbed, extensively distributed, and slowly eliminated in tilapia, in addition, doxycycline might undergo enterohepatic recycling in tilapia. PMID- 24479742 TI - Stress distribution comparisons of foot bones in patient with tibia vara: a finite element study. AB - Blount's disease, or tibia vara, is the most common cause of pathologic genu varum in children and adolescents. Changes in the loading of knee structures such as tibial articular cartilage, menisci and subcondral bone are well documented in case of genu varum. But the mechanical effects of this condition on foot bones are still questionable. In this study, the authors hypothesized that stress distributions on foot bones might increase in patients with tibia vara when compared with patients who had normal lower extremity mechanical axis. Three dimensional (3D) finite element analyses of human lower limb were used to investigate and compare the loading on foot bones in normal population and patient with tibia vara. The segmentation software, MIMICS was used to generate the 3D images of the bony structures of normal and varus malalignment lower extremity. Except the spaces between the adjacent surface of the phalanges fused, metatarsals, cuneiforms, cuboid, navicular, talus and calcaneus bones were independently developed to form foot and ankle complex. Also femur, tibia and fibula were modeled utilizing mechanical axis. ANSYS version 14 was used for mechanical tests and maximum equivalent stresses (MES) were examined. As a result of the loading conditions, in varus model MES on talus, calcaneus and cuboid were found higher than in normal model. And stress distributions changed through laterally on middle and fore foot in varus deformity model. PMID- 24479744 TI - Evaluation of activation parameters of molecular mobility of parylene C using differential scanning calorimetry, dielectric spectroscopy, and thermally stimulated depolarization currents. AB - The molecular kinetics of alpha-relaxation were studied by dielectric spectroscopy (DS) and thermally stimulated depolarization currents (TSDC) for the thermoplastic semicrystalline parylene C (-H2C-C6H3Cl-CH2-)n thin film. Activation energy of the alpha-relaxation process brings very close values with both methods (155 +/- 2 kJ mol(-1)). Dielectric spectroscopy carried out in a wide temperature range allowed one to determine the alpha-relaxation time against the temperature and then to estimate the Kauzmann and Angell temperatures for parylene C. From these temperatures and the determination of kinetics and thermodynamics parameters from DSC analysis, it was possible to investigate the cooperative rearranging region (CRR) in parylene C. CRR is quantified in terms of characteristic length (zetaCRR), volume (VCRR), number z of rearranging units, and height barrier DeltaMU of the rearranging unit. Moreover, the fragility index m, calculated from these three methods, is discussed. A value of m = 94 is obtained by DSC confirming a "strong" character of parylene C. A lowest value of 35 +/- 4 obtained from electric analyses (DS and TSDC) must be considered with caution because these methods of characterizations bring into play only dipolar relaxations. Last, the kinetic and thermodynamic parameters for parylene C highlighted in this work are positioned in comparison with other organic and inorganic materials. PMID- 24479743 TI - Depression severity is associated with increased risk behaviors and decreased CD4 cell counts. AB - Depression is a common comorbidity among HIV-infected individuals. We studied the relationship between depressive symptoms, risk behaviors (risky-sexual behavior, tobacco, alcohol, and illicit drug use) and HIV outcomes. This cross-sectional study conducted in 2009 at the Washington University HIV Clinic included screening for depression with patient health questionnaire, survey of sexual behavior, illicit drug, alcohol, and tobacco use within 30 days. Sociodemographics, plasma HIV RNA levels, CD4 cell counts, and sexually transmitted disease test results were obtained from medical records. Multivariate logistic and linear regression models were used to assess the association between depressive symptoms severity and risk behaviors, HIV outcomes and combination antiretroviral therapy (cART) adherence. A total of 624 persons completed the assessment of whom 432 (69%) were male and 426 (68%) African-American. The median CD4 cell count was 410 cells/mm(3) and 479 persons (77%) were on cART of whom 112 (23%) had HIV RNA level > 400 copies/mL. Overall, 96 (15%) had symptoms of major depressive disorder. Depressive symptom severity was associated with increased likelihood of high-risk drinking (odds ratio [OR], 2.4; 95% confidence interval [CI], 1.1-5.1), current tobacco use (OR, 1.8; 95% CI, 1.1-2.9), illicit drug use (OR, 1.7; 95% CI, 1.0-2.8), and risky-sexual behavior (OR, 1.5; 95% CI, 0.8-2.7). Suboptimal cART adherence (visual analog scale < 95%) was also associated with depressive symptoms severity (p < 0.05). After adjustment for age, sex, race, receipt of cART, and cART adherence, depressive symptoms severity was independently associated with lower CD4 cell count (p < 0.05) but not with higher HIV RNA level (p = 0.39). Depression adversely affects HIV-infected individuals, requiring greater effort at utilizing multidisciplinary interventions. PMID- 24479745 TI - Role of inflammation in HIV-1 disease progression and prognosis. AB - Inflammation and immune activation have been thrust to center stage in the understanding of HIV-1 disease pathogenesis and progression. Early work demonstrated that heightened levels of immune activation correlated with the extent of CD4 + T cell death in lymphoid tissue; however, this concept was not incorporated into the general view of disease pathogenesis. Since these early studies, the extension of life for patients on combination antiretroviral therapies (cART) has heralded a new era of non-AIDS-related diseases and incomplete restoration of immune function. The common link appears to be ongoing inflammation and immune activation. Thus, despite good control of viral loads, persons living with HIV (PLWH) remain at increased risk of inflammatory associated complications such as cardiovascular disease and certain cancers. HIV specific mechanisms as well as non-specific generalized responses to infection contribute to ongoing activation of the immune system. An early loss of gastrointestinal (GI) tract mucosal integrity, the pro-inflammatory cytokine milieu, co-infections and marked destruction of lymph node architecture are all factors contributing to the ongoing activation of the immune system as well as impaired immune recovery. It is becoming increasingly evident that the CD4 count and viral load do not provide a complete picture of the underlying state of the immune system. Heightened levels of inflammatory markers have been shown to predict increased mortality and other adverse events. Therefore, it will be important to incorporate these markers into management algorithms as soon as possible. This is particularly relevant in resource-poor countries where difficulties in cART roll-out and access are still encountered and, therefore, a mechanism for prioritizing individuals for therapy would be of value. This review will focus on the closely inter-related concepts of immune activation and inflammation. Both are broad concepts involving the interaction of various key players in the immune system. Importantly, immune activation promotes inflammation and thrombosis and similarly, inflammation and thrombosis induce immune activation. These concepts are thus intricately linked. Studies highlighting the potentially harmful effects of ongoing inflammation/immune activation are reviewed and the contributions of the GI tract "damage" and other co-infections such as CMV are explored. The complications resulting from persistent immune activation include enhanced CD4 + T cell death, lymphoid tissue destruction, and various pathologies related to chronic inflammation. Ultimately, we envision that the long-term management of the disease will incorporate both the identification and the amelioration of the potentially harmful effects of ongoing immune activation and inflammation. PMID- 24479746 TI - An alcohol message beneath the surface of ER: how implicit memory influences viewers' health attitudes and intentions using entertainment-education. AB - While previous research on entertainment-education has assessed its effectiveness, primarily at the conscious level (e.g., free recall and self reported change in knowledge), few studies have explored its effect on viewers' implicit knowledge. To fill this gap, this study examined the mechanism through which viewers form implicit memory of short health messages inserted in a primetime TV show and its preconscious effects on viewers' health attitudes and intentions. An experiment was conducted using a 3-group (health message: present vs. absent vs. control), posttest-only design with additional planned analyses of differences by subject variables (past experience and involvement). Overall, findings supported the hypothesized effects of implicit memory of a brief antialcohol message embedded in an ER episode on college students' attitudes and intentions against binge drinking. Results showed that participants who were exposed to the health message reported less positive attitudes toward binge drinking and lower intentions to binge drink, compared with those who were not exposed; the causal relations among viewers' implicit memory, attitudes, and intentions were also validated. Results also showed that individuals' past experience and involvement moderated the effects of the health message on attitudes and intentions. Theoretical explanations and practical implications are discussed. PMID- 24479747 TI - Vasospastic angina and Ca channel blockers. AB - Coronary artery spasm is one of the causes of angina pectoris,acute myocardial infarction and ventricular fibrillation-related sudden death. It has been established that Ca channel blockers are protective against vasospastic angina (VSA) and treatment with Ca channel blockers provides a better prognosis of VSA. However, it is not still clarified what kinds of Ca channel blockers shows the best prognosis of VSA. We performed a meta-analysis in which 4Ca channel blockers amlodipine, nifedipine, benidipine and diltiazem were used for the treatment of VSA patients and found that among 4 Ca channel blockers, benidipine showed a statistically significant better prognostic effect on MACE than amlodipine, nifedipine or diltiazem. PMID- 24479748 TI - Types of voltage-gated calcium channels: molecular and electrophysiological views. AB - Voltage-gated calcium (Ca(2+)) channels are ubiquitous in excitable cells, and intracellular Ca(2+) transients, in which the channels play key roles, trigger many physiological events. At this time, 10 members of the voltage-gated Ca(2+) channel family in mammals are recognized, and they play diverse roles in the signal transduction system. The CaV1 subfamily (L-type) is involved in contraction, secretion, integration of synaptic input in neurons, regulation of gene expression, and, in specialized sensory cells, synaptic transmission at ribbon synapses. The members of the CaV2 subfamily (P/Q-, N-, and R-types) initiate synaptic transmission at fast synapses. The CaV3 subfamily is important in rhythmically firing cells such as cardiac nodal cells and thalamic neurons. The channels in this family are essential for the cyclic firing of action potentials. This article summarizes the relationships between the molecular and physiological functions of these Ca(2+) channel proteins. PMID- 24479749 TI - T-type Ca channel blockers in patients with chronic kidney disease in clinical practice. AB - Chronic kidney disease (CKD) progressively increases the risk of cardiovascular disease (CVD) and end-stage renal disease (ESRD) in line with its severity. Recent studies have revealed that albuminuria and proteinuria in CKD are risk factors for both ESRD and CVD. Accordingly, reductions in albuminuria and proteinuria are associated with a trend in reduced renal death and cardiovascular events. Renin-angiotensin-aldosterone system inhibitors, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers are recommended as first-choice drugs for the treatment of hypertensive patients with CKD according to several guidelines. However, monotherapy is not sufficient to control blood pressure, particularly in patients with CKD, highlighting the need for combination drug therapy. Calcium channel blockers (CCBs) reduce blood pressure and are useful antihypertensive drugs. Three types of CCBs--the L-, T-, and Ntypes-- are in clinical use. In renal tissue, L-type calcium channels are present only in the afferent arterioles, while N-type and T-type calcium channels are located in both efferent and afferent arterioles. Therefore, CCBs that block either T-type or N-type calcium channels may exert renoprotective effects by dilating the efferent artery and protecting the glomerulus from hyperfiltration injury. It has been established that T-type CCBs exert a renal protective action by ameliorating glomerular microcirculation via vasodilatory activity on both afferent and efferent arterioles. Additionally, blockade of the T-type Ca channel suppresses inflammatory processes, renin-angiotensin-aldosterone system, and oxidative stress. Such effects of T-type CCBs seem to provide good efficacy in terms of the progression of renal outcome and the prevention of cardiovascular events in patients with CKD. PMID- 24479750 TI - Renal microcirculation and calcium channel subtypes. AB - It has recently been reported that voltage-dependent Ca channel subtypes, e.g., L , T-, N-, and P/Q-type, are expressed in renal arterioles and renal tubules, and the inhibition of these channels exerts various effects on renal microcirculation. For example, selective blockade of L-type Ca channels with nifedipine preferentially dilates the afferent arteriole and potentially induces glomerular hypertension. On the other hand, recently developed Ca channel blockers (CCBs) such as mibefradil and efonidipine block both T-type and L-type Ca channels and consequently dilate both afferent and efferent arterioles, leading to lowering of intraglomerular pressure. Interestingly, aldosterone has recently been recognized as a factor exacerbating renal diseases, and its secretion from adrenal gland is mediated by T-type Ca channels. Furthermore, T type CCBs were shown to ameliorate renal dysfunction by suppressing inflammatory processes and renin secretion. On the basis of histological evaluations, N-type Ca channels are present in peripheral nerve terminals innervating both afferent and efferent arterioles. Further, it was suggested that N-type CCBs such as cilnidipine suppress renal arteriolar constriction induced by enhanced sympathetic nerve activity, thereby lowering intraglomerular pressure. Taken together, various Ca channel subtypes are present in the kidney and blockade of selective channels with distinct CCBs exerts diverse effects on renal microcirculation. Inhibition of T-type and N-type Ca channels with CCBs is anticipated to exert pleiotropic effects that would retard the progression of chronic kidney disease through modulation of renal hemodynamic and non hemodynamic processes. PMID- 24479751 TI - L-/N-type calcium channel blockers and proteinuria. AB - The first-line depressor agents for hypertensive patients with chronic kidney disease are the renin-angiotensin system inhibitors because of their antiproteinuric and reno-protective effects. However, only one renin-angiotensin system inhibitor often cannot achieve target blood pressure in patients with injured kidney. Thus, second-line antihypertensives are required. Calcium channel blockers are frequently added on the renin-angiotensin system inhibitors in hypertensive patients with chronic kidney disease. However, they do not always show reno-protective effects because of their glomerular pressure-increasing action; Antihypetensive calcium channel blockers suppress L-type calcium channels, which exist in glomerular afferent but not efferent arterioles, and their afferent arteriole-specific vasodilation causes glomerular hypertension. The decrease in glomerular pressure due to their systemic hypotesive effect is counteracted by the glomerular pressure-incresing action. However, L-/N-type calcium channel blockers inhibits norepinephrine release from the sympathetic nerve terminal by blockade of N-type calcium channels, and dilate both afferent and efferent arterioles, which were innervated sympathetically, resulting in decrease in glomerular pressure. Actually, we have demonstrated that an L-/N-type calcium channel blocker cilnidipine decreased urinary protein more greatly than an L-type calcium channel blocker amlodipine in the renin-angiotensin system inhibitor-treated patients with chronic kidney disease. Thus, L-/N-type calcium channel blockers are one of suitable candidates for the second-line antihypertensives in the renin-angiotensin system inhibitor-treated hypertensive patients with proteinuria. PMID- 24479752 TI - Why do Ca channel blockers be focused on? PMID- 24479753 TI - Clinical science of calcium channel blocker to inhibit hypertensive vascular injury. AB - Calcium channel blockers are the strongest and most widely used antihypertensive drugs in Japan. Calcium channel blockers dilate both artery and arteriole that increases end-organ perfusion, thus possessing few side effects especially for the elderly hypertensive patients. The safety of calcium channel blockers was well established. In this paper, important clinical evidence supporting the effectiveness of calcium channel blockers and improving cardiovascular endpoints will be reviewed. Calcium channel blockers protect end-organs from hypertensive vascular injury. In addition, calcium channel blockers show non-inferiority to angiotensin converting enzyme inhibitors, angiotensin receptor blockers and diuretics regarding cardiovascular endpoints. Furthermore, calcium channel blockers may have superiority to betablockers. Although cardiovascular protection by calcium channel blockers largely depends on their potent blood pressure lowering ability, including central blood pressure, calcium channel blockers can manifest blood pressure-independent vascular protection. Thus, calcium channel blockers are basic antihypertensive drugs, and constitute the treatment of choice to obtain target blood pressure for most hypertensive patients, especially for high-risk population and those with resistant hypertension. An intense treatment of hypertension with adequate doses of calcium channel blockers is mandatory to improve cardiovascular prognosis. PMID- 24479755 TI - Understanding and use of the American Joint Committee on Cancer seventh edition guidelines for cutaneous squamous cell carcinoma: a survey of dermatologic surgeons. AB - BACKGROUND: The seventh edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual was published in 2009, including an updated chapter on cutaneous squamous cell carcinoma (cSCC) and other cutaneous carcinomas. Notable improvements from the previous sixth edition include placement of Merkel cell carcinoma and cSCC of the eyelid in individual chapters, elimination of the 5-cm clinical breakpoint for T3, and addition of high-risk features for upstaging T1 to T2 independent of clinical tumor size. Despite these advances, several publications critical of the AJCC guidelines have surfaced in the literature since their release. OBJECTIVE: To further evaluate the use and applicability of the most-recent AJCC guidelines for cSCC. MATERIALS AND METHODS: A web-based survey of members of the American College of Mohs Surgery to gauge knowledge and application of the guidelines. CONCLUSION: Although physician knowledge of the details of the guidelines was in line with expectations, some areas for improvement (e.g., coexistent immunosuppression incorrectly listed as a high-risk feature) remain. Also, the lack of change in practice, among Mohs surgeons or dermatopathologists, as a result of the guidelines is somewhat troubling and may be an area for further research. PMID- 24479754 TI - Marital status shows a strong protective effect on long-term mortality among first acute myocardial infarction-survivors with diagnosed hyperlipidemia- findings from the MONICA/KORA myocardial infarction registry. AB - BACKGROUND: Reduction of long term mortality by marital status is well established in general populations. However, effects have been shown to change over time and differ considerably by cause of death. This study examined the effects of marital status on long term mortality after the first acute myocardial infarction. METHODS: Data were retrieved from the population-based MONICA (Monitoring trends and determinants on cardiovascular diseases)/KORA (Cooperative Health Research in the Region of Augsburg)-myocardial infarction registry which assesses cases from the city of Augsburg and 2 adjacent districts located in southern Bavaria, Germany. A total of 3,766 men and women aged 28 to 74 years who were alive 28 days after their first myocardial infarction were included. Hazard ratios (HR) for the effects of marital status on mortality after one to 10 years of follow-up are presented. RESULTS: The study population included 2,854 (75.8%) married individuals. During a median follow-up of 5.3 years, with an inter quartile range of 3.3 to 7.6 years, 533 (14.15%) deaths occurred. Among married and unmarried individuals 388 (13.6%) and 145 (15.9%) deaths occurred, respectively. Overall marital status showed an insignificant protective HR of 0.76 (95% confidence interval (CI) 0.47-1.22). Stratified analyses revealed strong protective effects only among men and women younger than 60 who were diagnosed with hyperlipidemia. HRs ranged from 0.27 (95% CI 0.13-0.59) for a two year survival to 0.43 (95% CI 0.27-0.68) for a 10-year survival. Substitution of marital status with co-habitation status confirmed the strata-specific effect [HR: 0.52 (95% CI 0.31-0.86)]. CONCLUSIONS: Marital status has a strong protective effect among first myocardial infarction survivors with diagnosed hyperlipidemia, which diminishes with increasing age. Treatments, recommended lifestyle changes or other attributes specific to hyperlipidema may be underlying factors, mediated by the social support of spouses. Underlying causes should be examined in further studies. PMID- 24479756 TI - A cross-cultural investigation of inhibitory control, generative fluency, and anxiety symptoms in Romanian and Russian preschoolers. AB - The current study focused on the early development of inhibitory control in 5- to 7-year-old children attending kindergarten in two Eastern-European countries, Romania and Russia. These two countries share many aspects of child-rearing and educational practices, previously documented to influence the development of inhibitory control. Using the Lurian-based developmental approach offered by the Developmental Neuropsychological Assessment battery, the study aimed to contribute to cross-cultural developmental neuropsychology by exploring (a) early interrelationships between subcomponents of inhibitory control (response suppression and attention control) and generative fluency (verbal and figural) in these two cultures, as well as (b) the predictive value of external factors (culture and maternal education) and individual differences (age, gender, nonverbal intelligence, trait anxiety) on inhibitory control and fluency outcomes in children from both countries. First, findings in both culture samples suggest that even at this young age, the construct of inhibitory control cannot be considered a unitary entity. Second, differences in maternal education were not predictive of either inhibitory control or fluency scores. However, children's attention control performance varied as a function of culture, and the direction of these cultural effects differed by whether the target outcome involved performance accuracy versus efficiency as an output. Findings also confirmed the previously documented intensive developmental improvement in preschoolers' inhibitory control during this period, influencing measures of response suppression and particularly attention control. Finally, the results further stress the importance of individual differences effects in trait anxiety on attention control efficiency across cultures. PMID- 24479757 TI - Efficient ring perception for the Chemistry Development Kit. AB - BACKGROUND: The Chemistry Development Kit (CDK) is an open source Java library for manipulating and processing chemical information. A key aspect in handling chemical structures is the determination of the chemical rings. The rings of a structure are used areas including descriptors, stereochemistry, similarity, screening and atom typing. The CDK includes multiple algorithms for determining the rings of a structure on demand. Non-unique descriptions of rings were often used due to the slower performance of the unique alternatives. RESULTS: Efficient algorithms for handling chemical ring perception have been implemented and optimised in the CDK. The algorithms provide much faster computation of new and existing types of rings. Several optimisation and implementation considerations are discussed which improve real case usage. The performance is measured on several publicly available data sets and in several cases the new implementations were found to be more than an order of magnitude faster. CONCLUSIONS: Algorithmic improvements allow handling of much larger datasets in reasonable time. Faster computation allows more appropriate rings to be utilised in procedures such as aromaticity. Several areas that require ring perception have also seen a noticeable improvement. The time taken to compute the unique rings is now comparable allowing a correct usage throughout the toolkit. All source code is open source and freely available. PMID- 24479758 TI - Interaction of platelets with poly(vinylidene fluoride-co-hexafluoropropylene) electrospun surfaces. AB - Platelets are the major contributors in the process of thrombosis and in the failure of biomedical implants. A number of factors influence the platelet interaction with foreign surfaces such as surface morphology, surface chemistry, and adsorbed proteins. This study examined the effect of surface topography and chemistry of pristine and fibrinogen-adsorbed solvent cast (SC) and electrospun (ES) samples of poly(vinylidene fluoride-co-hexafluoropropylene) (PVDF-HFP) on platelet adhesion, activation, and aggregation. Qualitative and quantitative studies of fibrinogen adsorption were performed using time-of-flight secondary ion mass spectrometry (ToF-SIMS), while SEM, aggregometry, and liquid scintillation analyses were performed to evaluate platelet adhesion, aggregation, and serotonin release. While little or no platelet adhesion was observed on pristine ES surfaces, considerable adhesion, and measurable aggregation and serotonin release were observed on pristine SC surfaces. Notably, increased adhesion of platelets was observed following fibrinogen adsorption on SC surface with considerable aggregation and serotonin release compared with ES samples, where limited aggregation and platelet adhesion was observed. A further comparison of platelet adhesion, aggregation, and serotonin release was performed with plasma-adsorbed SC and ES surfaces. SC surfaces showed enhanced platelet adhesion, aggregation, and serotonin release compared to ES surfaces. This study shows that the morphology of samples plays a critical role on the biocompatibility of samples by altering the adsorption and adhesion of biomolecules and cells. The low level of adhesion, low aggregation, and serotonin release of platelets, even in the presence of fibrinogen and plasma-derived proteins, suggested that ES samples have the least thrombogenicity. PMID- 24479759 TI - Atomistic origins of high rate capability and capacity of N-doped graphene for lithium storage. AB - Distinct from pure graphene, N-doped graphene (GN) has been found to possess high rate capability and capacity for lithium storage. However, there has still been a lack of direct experimental evidence and fundamental understanding of the storage mechanisms at the atomic scale, which may shed a new light on the reasons of the ultrafast lithium storage property and high capacity for GN. Here we report on the atomistic insights of the GN energy storage as revealed by in situ transmission electron microscopy (TEM). The lithiation process on edges and basal planes is directly visualized, the pyrrolic N "hole" defect and the perturbed solid-electrolyte-interface configurations are observed, and charge transfer states for three N-existing forms are also investigated. In situ high-resolution TEM experiments together with theoretical calculations provide a solid evidence that enlarged edge {0002} spacings and surface hole defects result in improved surface capacitive effects and thus high rate capability and the high capacity are owing to short-distance orderings at the edges during discharging and numerous surface defects; the phenomena cannot be understood previously by standard electron or X-ray diffraction analyses. PMID- 24479760 TI - Tai Chi-based exercise program provided via telerehabilitation compared to home visits in a post-stroke population who have returned home without intensive rehabilitation: study protocol for a randomized, non-inferiority clinical trial. AB - BACKGROUND: The incidence of strokes in industrialized nations is on the rise, particularly in the older population. In Canada, a minority of individuals who have had a stroke actually receive intensive rehabilitation because most stroke patients do not have access to services or because their motor recovery was judged adequate to return home. Thus, there is a considerable need to organize home-based rehabilitation services for everyone who has had a stroke. To meet this demand, telerehabilitation, particularly from a service center to the patient's home, is a promising alternative approach that can help improve access to rehabilitation services once patients are discharged home. METHODS/DESIGN: This non-inferiority study will include patients who have returned home post stroke without requiring intensive rehabilitation. To be included in the study, participants will: 1) not be referred to an Intensive Functional Rehabilitation Unit, 2) have a Rankin score of 2 or 3, and 3) have a balance problem (Berg Balance Scale score between 46 and 54). Participants will be randomly assigned to either the teletreatment group or the home visits group. Except for the delivery mode, the intervention will be the same for both groups, that is, a personalized Tai Chi-based exercise program conducted by a trained physiotherapist (45-minute session twice a week for eight consecutive weeks). The main objective of this research is to test the non-inferiority of a Tai Chi-based exercise program provided via telerehabilitation compared to the same program provided in person at home in terms of effectiveness for retraining balance in individuals who have had a stroke but do not require intensive functional rehabilitation. The main outcome of this study is balance and mobility measured with the Community Balance and Mobility Scale. Secondary outcomes include physical and psychological capacities related to balance and mobility, participants' quality of life, satisfaction with services received, and cost-effectiveness associated with the provision of both types of services. STUDY/TRIAL REGISTRATION: ClinicalTrials.gov: NCT01848080. PMID- 24479762 TI - Roles and relationships between health professionals involved in insulin initiation for people with type 2 diabetes in the general practice setting: a qualitative study drawing on relational coordination theory. AB - BACKGROUND: The majority of care for people with type 2 diabetes occurs in general practice, however when insulin initiation is required it often does not occur in this setting or in a timely manner and this may have implications for the development of complications. Increased insulin initiation in general practice is an important goal given the increasing prevalence of type 2 diabetes and a relative shortage of specialists. Coordination between primary and secondary care, and between medical and nursing personnel, may be important in achieving this. Relational coordination theory identifies key concepts that underpin effective interprofessional work: communication which is problem solving, timely, accurate and frequent and relationships between professional roles which are characterized by shared goals, shared knowledge and mutual respect. This study explores roles and relationships between health professionals involved in insulin initiation in order to gain an understanding of factors which may impact on this task being carried out in the general practice setting. METHOD: 21 general practitioners, practice nurses, diabetes nurse educators and physicians were purposively sampled to participate in a semi-structured interview. Transcripts of the interviews were analysed using framework analysis. RESULTS: There were four closely interlinked themes identified which impacted on how health professionals worked together to initiate people with type 2 diabetes on insulin: 1. Ambiguous roles; 2. Uncertain competency and capacity; 3. Varying relationships and communication; and 4. Developing trust and respect. CONCLUSIONS: This study has shown that insulin initiation is generally recognised as acceptable in general practice. The role of the DNE and practice nurse in this space and improved communication and relationships between health professionals across organisations and levels of care are factors which need to be addressed to support this clinical work. Relational coordination provides a useful framework for exploring these issues. PMID- 24479764 TI - Aggravation of seizure-like events by hydrogen sulfide: involvement of multiple targets that control neuronal excitability. AB - AIMS: Epileptic seizures are well-known neurological complications following stroke, occurring in 3% of patients. However, the intrinsic correlation of seizures with stroke remains largely unknown. Hydrogen sulfide (H2 S) is a gas transmitter that may mediate cerebral ischemic injury. But the role of H2 S in seizures has not been understood yet. We examined the effect of H2 S on seizure like events (SLEs) and underlying mechanisms. METHODS AND RESULTS: Pentylenetetrazole (PTZ)- and pilocarpine-induced rat epileptic seizure models were tested. Low-Mg(2+) /high-K(+) - and 4-aminopyridine (4-AP)-induced epileptic seizure models were examined using patch-clamp recordings in brain slices. It was found that NaHS aggravated both PTZ- and pilocarpine-induced SLEs in rats, while both low-Mg(2+) /high-K(+) - and 4-AP-induced SLEs were also exacerbated by NaHS in brain slices, which may be due to its regulation on the voltage-gated sodium channel, N-methyl-D-aspartic acid receptor (NMDAR), and alpha-amino-3-hydroxy-5 methyl-4-isoxazolepropionic acid receptor (AMPAR) function. Furthermore, these effects were reversed by blocking voltage-gated sodium channel, NMDAR, and AMPAR. CONCLUSIONS: These results suggest a pathological role of increased H2 S level in SLEs in vivo and in vitro. Enzymes that control H2 S biosynthesis could be interesting targets for antiepileptic strategies in poststroke epilepsy treatment. PMID- 24479763 TI - Prognostic analysis of gastric gastrointestinal stromal tumor with synchronous gastric cancer. AB - BACKGROUND: Many patients with gastric gastrointestinal stromal tumor (GIST) and synchronous gastric cancer have been described, most in single case studies. We retrospectively investigated the clinicopathologic features and prognostic effects of gastric GIST in patients with synchronous gastric cancer. METHODS: The study enrolled 170 patients with gastric GIST, who had undergone complete surgical resection (R0) from January 2000 to December 2011. Forty-two patients had synchronous gastric cancer (CA Group), whereas 128 did not (Non-CA Group). The clinicopathologic features and potential prognostic factors in the two groups were compared. RESULTS: Patients in the CA Group had more obvious symptoms, but a lower rate of preoperative diagnosis of gastric GIST (P <0.05). The two groups differed significantly in gender, age, greatest tumor diameter, risk stratification, tumor-associated ulcers, and CD117 and CD34 expression (P <0.05 each). Univariate analysis showed that age, risk stratification, postoperative oral imatinib and synchronous gastric cancer were predictive factors of survival (P <0.05). Cox regression analysis showed that risk stratification, postoperative oral imatinib and synchronous gastric cancer were independent predictors of survival (P <0.05). Stratified analysis showed that the 5-year overall survival rate was lower in patients with synchronous gastric cancer than in those without synchronous gastric cancer. CONCLUSIONS: Gastric GIST with synchronous gastric cancer had a lower rate of preoperative diagnosis, with correct diagnosis often missed. Survival, however, depended primarily on the gastric cancer. PMID- 24479765 TI - An LC-MS/MS method for the determination of salidroside and its metabolite p tyrosol in rat liver tissues. AB - CONTEXT: Salidroside and its metabolite p-tyrosol are two major phenols in the genus Rhodiola L. (Crassulaceae). They have been confirmed to possess various pharmacological properties and are used for the prophylaxis and therapeutics of many diseases. Several analytical methods have been developed for the determination of the two compounds in plant materials and biological plasma matrices. However, these methods are not optimal for biological samples containing complex organic interferences, such as liver and brain tissues. OBJECTIVE: This study aimed to further develop and validate a simple and specific LC-MS/MS method for the determination of salidroside and its metabolite p-tyrosol in rat liver tissues using paracetamol as the internal standard (IS). MATERIALS AND METHODS: Salidroside and p-tyrosol with the IS paracetamol and liver tissues were used as model compounds and biological samples. Samples were processed by protein precipitation (PP) with methanol, the supernatant was dried under nitrogen and the residue was reconstituted in a mobile phase that consisted of a mixture of acetonitrile and water (1:9, v/v). Salidroside and p-tyrosol were detected in negative mode under multiple reaction monitoring (MRM) by a triple quadrupole tandem mass spectrometer coupled with electrospray ionization. RESULTS: Standard curves were linear over the concentration range of 50-2000 ng/mL with correlation coefficients of 0.995 or better for both salidroside and p tyrosol. The intra- and inter-day accuracy for salidroside ranged between 104.90 and 112.73% with a precision of 3.51-14.27%. For p-tyrosol, the intra- and inter day accuracy was between 92.38 and 100.59%, and the precision was 8.54% or less. The stability data showed that no significant degradation occurred under the experimental conditions. The recoveries were 111.44, 108.10, and 102.00% for salidroside at concentrations of 50, 500 and 2000 ng/mL, respectively, and were 105.44, 105.50, and 113.04% for tyrosol at concentrations of 50, 500 and 2000 ng/mL, respectively. The matrix effects were 83.85-92.45% for salidroside and 85.61-92.49% for p-tyrosol at three QC levels. This method was successfully applied to a liver tissue distribution study of salidroside and its metabolite p tyrosol in rats. DISCUSSION AND CONCLUSION: This newly established method is validated as simple, reliable and accurate. It can be used as a valid analytical method for the intrinsic quality control of biological matrices, especially tissue samples. PMID- 24479766 TI - Effects of planned group interactions on the social adaptation of individuals with an intestinal stoma: a quantitative study. AB - AIMS AND OBJECTIVES: To investigate the effects of a planned group interaction method on the social adjustment of individuals with an intestinal stoma. BACKGROUND: Individuals with a stoma often experience physiological, psychological and social problems that affect their social adaptation. DESIGN: Quasi-experimental. METHODS: The population included ileostomy and colostomy patients registered at the Gazi University Health Research and Implementation Centre Stoma therapy Unit between September 2011-June 2012. They were assigned to experimental (n = 23) and control (n = 27) groups based on their willingness to attend planned group interaction meetings. Experimental group members participated in the 'planned group interaction method' for six weeks. Control group members only received routine care services. Weekly group interaction meetings lasted for average of 90 minutes. The Ostomy Adjustment Inventory and Psychosocial Adjustment to Illness Scale-Self-Report Scale were administered to experimental group members on three occasions: prior to the first group meeting, after the six-week meeting process ended and during the first month after group meetings ended. Control group evaluations were conducted simultaneously. RESULTS: Experimental group members' ostomy adjustment mean scores after planned group interaction meetings gradually increased. No changes occurred in the control group's average scores. The experimental and control groups' average psychosocial adjustment scores eventually changed and showed a tendency towards adjustment. Experimental group members aged 51-60 and 61-70, who were married, had primary and higher education, had permanent stomas, had stomas for periods between 12 months or less and 61 months and longer and had sufficient stoma care knowledge demonstrated higher adjustment values (p < 0.05). Furthermore, experimental group members reported they received psychological support during interactions and learned how to solve problems encountered in stoma care and daily life. CONCLUSIONS: Planned group interactions effectively enhanced the social adjustment of patients with a stoma. RELEVANCE TO CLINICAL PRACTICE: Group interaction methods should be included in nursing care practices for individuals with a stoma. PMID- 24479767 TI - Personality and suicidal ideation in the elderly: factorial invariance and latent means structures across age. AB - OBJECTIVES: Suicide among the elderly is a dramatic global health problem. Although fatal attempts are frequent in the elderly, research indicated that they rarely present long-term elaboration of suicidal ideation and communicate their intents. Consequently, risk factor detection and assessment are salient. Although evidence on the association between personality and suicidal ideation in young adults is accumulating, little is known about its relevance in the elderly. The purpose of the present study was to analyze the components of a measurement model that are invariant across young adults and older adults and then investigate the relations among dimensions of personality and suicide risk. We postulated a specific relation pattern a priori and tested the hypotheses statistically in order to examine the models for equivalency of the factorial measurement. METHOD: We investigated 316 young adults and 339 older adults, who were administered self report questionnaires to assess depression, hopelessness, alternative five-factor model of personality, and self-other perception. RESULTS: Multigroup confirmatory factor analyses were conducted, yielding a final model with excellent fit to the data. This model showed a similar pattern of associations between suicidal ideation and personality across both groups. CONCLUSIONS: Although the elderly are exposed to specific life stressors associated with suicidal ideation, our findings suggest that the elderly and young adults may be similar on personality and psychopathology variables predicting suicidal ideation than previously hypothesized. Implications are provided for enhanced assessment and intervention of the elderly high in neuroticism, depression, hopelessness, and with negative self-other perception. PMID- 24479768 TI - Effect of sand versus grass training surfaces during an 8-week pre-season conditioning programme in team sport athletes. AB - This study compared the use of sand and grass training surfaces throughout an 8 week conditioning programme in well-trained female team sport athletes (n = 24). Performance testing was conducted pre- and post-training and included measures of leg strength and balance, vertical jump, agility, 20 m speed, repeat speed (8 * 20 m every 20 s), as well as running economy and maximal oxygen consumption (VO2max). Heart rate (HR), training load (rating of perceived exertion (RPE) * duration), movement patterns and perceptual measures were monitored throughout each training session. Participants completed 2 * 1 h conditioning sessions per week on sand (SAND) or grass (GRASS) surfaces, incorporating interval training, sprint and agility drills, and small-sided games. Results showed a significantly higher (P < 0.05) HR and training load in the SAND versus GRASS group throughout each week of training, plus some moderate effect sizes to suggest lower perceptual ratings of soreness and fatigue on SAND. Significantly greater (P < 0.05) improvements in VO2max were measured for SAND compared to GRASS. These results suggest that substituting sand for grass training surfaces throughout an 8-week conditioning programme can significantly increase the relative exercise intensity and training load, subsequently leading to superior improvements in aerobic fitness. PMID- 24479769 TI - Development of a ReaxFF reactive force field for ammonium nitrate and application to shock compression and thermal decomposition. AB - We have developed a new ReaxFF reactive force field parametrization for ammonium nitrate. Starting with an existing nitramine/TATB ReaxFF parametrization, we optimized it to reproduce electronic structure calculations for dissociation barriers, heats of formation, and crystal structure properties of ammonium nitrate phases. We have used it to predict the isothermal pressure-volume curve and the unreacted principal Hugoniot states. The predicted isothermal pressure volume curve for phase IV solid ammonium nitrate agreed with electronic structure calculations and experimental data within 10% error for the considered range of compression. The predicted unreacted principal Hugoniot states were approximately 17% stiffer than experimental measurements. We then simulated thermal decomposition during heating to 2500 K. Thermal decomposition pathways agreed with experimental findings. PMID- 24479770 TI - Ownership and use of long-lasting insecticidal nets for malaria prevention in Butajira area, south-central Ethiopia: complex samples data analysis. AB - BACKGROUND: Despite the encroaching of endemic malaria to highland-fringe areas above 2000 meters above sea level in Ethiopia, there is limited information on ownership and use of mosquito nets for malaria prevention. Thus, this study was designed to assess long-lasting insecticidal nets (LLIN) possession and use for malaria prevention in highland-fringe of south-central Ethiopia. METHODS: A multi stage sampling technique was employed to obtain household data from randomly selected households using household head interview in October and November 2008. Household LLIN possession and use was assessed using adjusted Odds Ratio obtained from complex samples logistic regression analysis. RESULTS: Only less than a quarter (23.1%) of 739 households interviewed owned LLINs with more differences between low (54.2%) high (3.5%) altitudes (Chi2 =253, P < 0.001). Higher LLIN ownership was observed in illiterate (adj.OR 35.1 [10.6-116.2]), male-headed (adj.OR 1.7 [1.051-2.89]), owning two or more beds (adj.OR 2.7 [1.6-4.6]), not doing draining/refilling of mosquito breeding sites (adj.OR 3.4 [2.1-5.5]) and absence of rivers or streams (adj.OR 6.4 [3.5-11.8]) of household variables. The presence of >=2 LLINs hanging (adj.OR 21.0 [5.2-85.1]), owning two or more LLINs (adj.OR 4.8 [1.3-17.5]), not doing draining/refilling of mosquito breeding sites (adj.OR 4.2 [1.3-13.6]), low wealth status (adj.OR 3.55 [1.04-12.14]), and < 1 km distance from absence of rivers or streams (adj.OR 3.9 [1.2-12.1]) of households was associated with more likely use of LLIN. The LLIN ownership was low in the highlands, and most of the highland users bought the bed nets themselves. CONCLUSIONS: This study found a low household LLIN ownership and use in the highland-fringe rural area. Therefore, improving the availability and teaching effective use of LLIN combined with removal of temporary mosquito breeding places should be prioritized in highland-fringe areas. PMID- 24479771 TI - Investigating uncertainty and emotions in conversations about family health history: a test of the theory of motivated information management. AB - Although the importance of being knowledgeable of one's family health history is widely known, very little research has investigated how families communicate about this important topic. This study investigated how young adults seek information from parents about family health history. The authors used the Theory of Motivated Information Management as a framework to understand the process of uncertainty discrepancy and emotion in seeking information about family health history. Results of this study show the Theory of Motivated Information Management to be a good model to explain the process young adults go through in deciding to seek information from parents about family health history. Results also show that emotions other than anxiety can be used with success in the Theory of Motivated Information Management framework. PMID- 24479772 TI - Thermochromic polymers--function by design. PMID- 24479773 TI - Phenylethanol promotes adhesion and biofilm formation of the antagonistic yeast Kloeckera apiculata for the control of blue mold on citrus. AB - The yeast Kloeckera apiculata strain 34-9 is an antagonist with biological control activity against postharvest diseases of citrus fruit. In a previous study it was demonstrated that K. apiculata produced the aromatic alcohol phenylethanol. In the present study, we found that K. apiculata was able to form biofilm on citrus fruit and embed in an extracellular matrix, which created a mechanical barrier interposed between the wound surface and pathogen. As a quorum sensing molecule, phenylethanol can promote the formation of filaments by K. apiculata in potato dextrose agar medium, whereas on the citrus fruit, the antagonist remains as yeast after being treated with the same concentration of phenylethanol. It only induced K. apiculata to adhere and form biofilm. Following genome-wide computational and experimental identification of the possible genes associated with K. apiculata adhesion, we identified nine genes possibly involved in triggering yeast adhesion. Six of these genes were significantly induced after phenylethanol stress treatment. This study provides a new model system of the biology of the antagonist-pathogen interactions that occur in the antagonistic yeast K. apiculata for the control of blue mold on citrus caused by Penicillium italicum. PMID- 24479774 TI - Cerebrospinal fluid biomarkers for Alzheimer disease and subcortical axonal damage in 5,542 clinical samples. AB - INTRODUCTION: The neuronal loss in Alzheimer disease (AD) has been described to affect grey matter in the cerebral cortex. However, in the elderly, AD pathology is likely to occur together with subcortical axonal degeneration on the basis of cerebrovascular disease. Therefore, we hypothesized that biomarkers for AD and subcortical axonal degeneration would correlate in patients undergoing testing for dementia biomarkers, particularly in older age groups. METHODS: We performed correlation and cluster analyses of cerebrospinal fluid (CSF) biomarker data from 5,542 CSF samples analyzed in our routine clinical neurochemistry laboratory in 2010 through 2012 for the established CSF AD biomarkers total tau (T-tau), phosphorylated-tau (P-tau), amyloid beta1-42 (Abeta42), and for neurofilament light (NFL), which is a protein expressed in large-caliber myelinated axons, the CSF levels of which correlate with subcortical axonal injury. RESULTS: Abeta42, T tau, and P-tau correlated with NFL. By cluster analysis, we found a bimodal data distribution in which a group with a low Abeta42/P-tau ratio (suggesting AD pathology) had high levels of NFL. High levels of NFL also correlated with the presence of an AD biomarker pattern defined by Abeta42/P-tau and T-tau. Only 29% of those with an AD biomarker signature had normal NFL levels. Age was a possible confounding factor for the associations between NFL and established AD biomarkers, but in a logistic regression analysis, both age and NFL independently predicted the AD biomarker pattern. CONCLUSIONS: The association between an AD like signature using the established biomarkers Abeta42, T-tau, and P-tau with increased levels of NFL provides in vivo evidence of an association between AD and subcortical axonal degeneration in this uniquely large dataset of CSF samples tested for dementia biomarkers. PMID- 24479775 TI - Four chlorinated depsidones from a seaweed-derived strain of Aspergillus unguis and their new biological activities. AB - Four chlorinated depsidones (two reported for the second time (1 and 2) and two known (3 and 4)) were isolated from a seaweed-derived Aspergillus unguis strain. Their structures were spectroscopically elucidated. Compounds 1, 3 and 4 strongly inhibited methicillin-resistant Staphylococcus aureus (MRSA) with minimum inhibitory concentrations (MICs) of 2, 2 and 4 MUg/mL and killed Artemia larva with LC50 of 4.1, 1.7 and 2.8 MUg/mL, respectively. Besides, in DNA-damaging test, they also selectively inhibited a DNA repair capacity-defective Escherichia coli strain AB3027(-) (MICs: 2, 32 and 4 MUg/mL, respectively) compared with the wild-type strain AB1157(+) (MICs: over 512, over 512 and 256 MUg/mL, respectively). Furthermore, compound 1 also strongly inhibited cancer cell line A 549 (IC50: 0.5 MUg/mL). The above-mentioned bioactivities were newly reported for compound 1. In contrast, compound 2 did not exhibit significant activity. The structure-activity relationship indicated that a complete lactone ring may be important. PMID- 24479776 TI - Large-scale linear rankSVM. AB - Linear rankSVM is one of the widely used methods for learning to rank. Although its performance may be inferior to nonlinear methods such as kernel rankSVM and gradient boosting decision trees, linear rankSVM is useful to quickly produce a baseline model. Furthermore, following its recent development for classification, linear rankSVM may give competitive performance for large and sparse data. A great deal of works have studied linear rankSVM. The focus is on the computational efficiency when the number of preference pairs is large. In this letter, we systematically study existing works, discuss their advantages and disadvantages, and propose an efficient algorithm. We discuss different implementation issues and extensions with detailed experiments. Finally, we develop a robust linear rankSVM tool for public use. PMID- 24479777 TI - Refined rademacher chaos complexity bounds with applications to the multikernel learning problem. AB - Estimating the Rademacher chaos complexity of order two is important for understanding the performance of multikernel learning (MKL) machines. In this letter, we develop a novel entropy integral for Rademacher chaos complexities. As compared to the previous bounds, our result is much improved in that it introduces an adjustable parameter epsilon to prohibit the divergence of the involved integral. With the use of the iteration technique in Steinwart and Scovel (2007), we also apply our Rademacher chaos complexity bound to the MKL problems and improve existing learning rates. PMID- 24479778 TI - Large margin low rank tensor analysis. AB - We present a supervised model for tensor dimensionality reduction, which is called large margin low rank tensor analysis (LMLRTA). In contrast to traditional vector representation-based dimensionality reduction methods, LMLRTA can take any order of tensors as input. And unlike previous tensor dimensionality reduction methods, which can learn only the low-dimensional embeddings with a priori specified dimensionality, LMLRTA can automatically and jointly learn the dimensionality and the low-dimensional representations from data. Moreover, LMLRTA delivers low rank projection matrices, while it encourages data of the same class to be close and of different classes to be separated by a large margin of distance in the low-dimensional tensor space. LMLRTA can be optimized using an iterative fixed-point continuation algorithm, which is guaranteed to converge to a local optimal solution of the optimization problem. We evaluate LMLRTA on an object recognition application, where the data are represented as 2D tensors, and a face recognition application, where the data are represented as 3D tensors. Experimental results show the superiority of LMLRTA over state-of-the-art approaches. PMID- 24479779 TI - Input statistics and Hebbian cross-talk effects. AB - As an extension of prior work, we studied inspecific Hebbian learning using the classical Oja model. We used a combination of analytical tools and numerical simulations to investigate how the effects of synaptic cross talk (which we also refer to as synaptic inspecificity) depend on the input statistics. We investigated a variety of patterns that appear in dimensions higher than two (and classified them based on covariance type and input bias). We found that the effects of cross talk on learning dynamics and outcome is highly dependent on the input statistics and that cross talk may lead in some cases to catastrophic effects on learning or development. Arbitrarily small levels of cross talk are able to trigger bifurcations in learning dynamics, or bring the system in close enough proximity to a critical state, to make the effects indistinguishable from a real bifurcation. We also investigated how cross talk behaves toward unbiased ("competitive") inputs and in which circumstances it can help the system productively resolve the competition. Finally, we discuss the idea that sophisticated neocortical learning requires accurate synaptic updates (similar to polynucleotide copying, which requires highly accurate replication). Since it is unlikely that the brain can completely eliminate cross talk, we support the proposal that is uses a neural mechanism that "proofreads" the accuracy of the updates, much as DNA proofreading lowers copying error rate. PMID- 24479780 TI - Dissociable forms of repetition priming: a computational model. AB - Nondeclarative memory and novelty processing in the brain is an actively studied field of neuroscience, and reducing neural activity with repetition of a stimulus (repetition suppression) is a commonly observed phenomenon. Recent findings of an opposite trend-specifically, rising activity for unfamiliar stimuli-question the generality of repetition suppression and stir debate over the underlying neural mechanisms. This letter introduces a theory and computational model that extend existing theories and suggests that both trends are, in principle, the rising and falling parts of an inverted U-shaped dependence of activity with respect to stimulus novelty that may naturally emerge in a neural network with Hebbian learning and lateral inhibition. We further demonstrate that the proposed model is sufficient for the simulation of dissociable forms of repetition priming using real-world stimuli. The results of our simulation also suggest that the novelty of stimuli used in neuroscientific research must be assessed in a particularly cautious way. The potential importance of the inverted-U in stimulus processing and its relationship to the acquisition of knowledge and competencies in humans is also discussed. PMID- 24479781 TI - Learning nonlinear statistical regularities in natural images by modeling the outer product of image intensities. AB - It is well known that there exist nonlinear statistical regularities in natural images. Existing approaches for capturing such regularities always model the image intensities by assuming a parameterized distribution for the intensities and learn the parameters. In the letter, we propose to model the outer product of image intensities by assuming a gaussian distribution for it. A two-layer structure is presented, where the first layer is nonlinear and the second layer is linear. Trained on natural images, the first-layer bases resemble the receptive fields of simple cells in the primary visual cortex (V1), while the second-layer units exhibit some properties of the complex cells in V1, including phase invariance and masking effect. The model can be seen as an approximation of the covariance model proposed in Karklin and Lewicki (2009) but has more robust and efficient learning algorithms. PMID- 24479782 TI - Parametric inference in the large data limit using maximally informative models. AB - Motivated by data-rich experiments in transcriptional regulation and sensory neuroscience, we consider the following general problem in statistical inference: when exposed to a high-dimensional signal S, a system of interest computes a representation R of that signal, which is then observed through a noisy measurement M. From a large number of signals and measurements, we wish to infer the "filter" that maps S to R. However, the standard method for solving such problems, likelihood-based inference, requires perfect a priori knowledge of the "noise function" mapping R to M. In practice such noise functions are usually known only approximately, if at all, and using an incorrect noise function will typically bias the inferred filter. Here we show that in the large data limit, this need for a precharacterized noise function can be circumvented by searching for filters that instead maximize the mutual information I[M; R] between observed measurements and predicted representations. Moreover, if the correct filter lies within the space of filters being explored, maximizing mutual information becomes equivalent to simultaneously maximizing every dependence measure that satisfies the data processing inequality. It is important to note that maximizing mutual information will typically leave a small number of directions in parameter space unconstrained. We term these directions diffeomorphic modes and present an equation that allows these modes to be derived systematically. The presence of diffeomorphic modes reflects a fundamental and nontrivial substructure within parameter space, one that is obscured by standard likelihood-based inference. PMID- 24479783 TI - Cutaneous melanoma: preoperative tumor diameter in a general dermatology outpatient setting. AB - BACKGROUND: The ABCD mnemonic for cutaneous melanoma indicates that tumor diameter (D) is typically greater than 6 mm. OBJECTIVE: To determine the distribution of preoperative tumor diameter in a midwestern United States general dermatology practice-based case series. METHODS: Patient records were reviewed for preoperative maximal tumor diameter for primary cutaneous melanomas diagnosed between January 1, 2006, and February 1, 2012. RESULTS: Of 116 tumors for which preoperative measures were available, 38 (32.8%) had a diameter of 6 mm or less. Of these 38 small-diameter (<=6 mm) cases, tumor invasion occurred in 26 (68.4%), compared with 36 of the 78 (46.2%) larger-diameter (>6 mm) cases. Small-diameter tumors were significantly more common in patients younger than 60 and almost twice as common in women than men. CONCLUSIONS: Almost one-third of evaluable tumors in this general dermatology practice-based setting had a preoperative diameter of 6 mm or less, and two-thirds of these small-diameter cases were invasive. The diameter criterion of greater than 6 mm in the ABCD mnemonic is precariously insensitive for a public message. PMID- 24479785 TI - Preliminary pharmacokinetics of morphine and its major metabolites following intravenous administration of four doses to horses. AB - The objective of the current study was to describe the pharmacokinetics of morphine and its metabolites following intravenous administration to the horse. A total of eight horses (two per dose group) received a single intravenous dose of 0.05, 0.1, 0.2, or 0.5 mg/kg morphine. Blood samples were collected up to 72 h postdrug administration, analyzed using LC-MS/MS and pharmacokinetic parameters determined. Behavior, step counts, and gastrointestinal activity were also assessed. The beta and gamma half-life for morphine ranged from 0.675 to 2.09 and 6.70 to 18.1 h, respectively, following administration of the four different IV doses. The volume of distribution at steady-state and systemic clearance ranged from 6.95 to 15.8 L/kg and 28.3 to 35.7 mL . min/kg, respectively. The only metabolites identified in blood samples were the primary metabolites identified in other species, 3-morphine-glucuronide and 6-morphine-glucuronide. Muscle fasciculations were observed at 0.2 and 0.5 mg/kg and ataxia noted at 0.5 mg/kg. Gastrointestinal activity was decreased in all dose groups (for up to 8 h in 7/8 horses and 24 h in one horse). This study extends previous studies and is the first report describing the metabolites of morphine in the horse. Plasma concentrations of morphine-3-glucuronide, a metabolite with demonstrated neuro excitatory activity in mice, far exceeded that of morphine-6-glucuronide. Further study is warranted to assess whether the high levels of the morphine-3 glucuronide contribute to the dose-dependent excitation observed at high morphine doses. PMID- 24479786 TI - Formation of substituted tetrahydropyrans through oxetane ring opening: application to the synthesis of C1-C17 fragment of salinomycin. AB - The stereoselective synthesis of C1-C17 fragment of salinomycin is achieved. The strategy employs a desymmetrization approach and utilizes an intramolecular oxetane opening reaction with O-nucleophile to result in the tetrahydropyran skeleton as the key step. PMID- 24479787 TI - NLRP3 inflammasome: a new target in major depressive disorder. PMID- 24479788 TI - Seeds used for Bodhi beads in China. AB - BACKGROUND: Bodhi beads are a Buddhist prayer item made from seeds. Bodhi beads have a large and emerging market in China, and demand for the beads has particularly increased in Buddhism regions, especially Tibet. Many people have started to focus on and collect Bodhi beads and to develop a Bodhi bead culture. But no research has examined the source plants of Bodhi beads. Therefore, ethnobotanical surveys were conducted in six provinces of China to investigate and document Bodhi bead plants. Reasons for the development of Bodhi bead culture were also discussed. METHODS: Six provinces of China were selected for market surveys. Information was collected using semi-structured interviews, key informant interviews, and participatory observation with traders, tourists, and local residents. Barkhor Street in Lhasa was focused on during market surveys because it is one of the most popular streets in China. RESULTS: Forty-seven species (including 2 varieties) in 19 families and 39 genera represented 52 types of Bodhi beads that were collected. The most popular Bodhi bead plants have a long history and religious significance. Most Bodhi bead plants can be used as medicine or food, and their seeds or fruits are the main elements in these uses. 'Bodhi seeds' have been historically used in other countries for making ornaments, especially seeds of the legume family. Many factors helped form Bodhi bead culture in China, but its foundation was in Indian Buddhist culture. CONCLUSIONS: As one of the earliest adornment materials, seeds played an important role for human production and life. Complex sources of Bodhi beads have different cultural and historical significance. People bought and collected Bodhi beads to reflect their love and admiration for the plants. Thus, the documentation of Bodhi bead plants can serve as a basis for future investigation of Bodhi bead culture and modern Buddhist culture. PMID- 24479789 TI - Quantitative bioluminescence imaging of transgene expression in intact porcine antral follicles in vitro. AB - BACKGROUND: The porcine oocyte maturation in vivo occurs within the ovarian follicle and is regulated by the interactions between oocytes and surrounding follicular components, including theca, granulosa, and cumulus cells, and follicular fluid. Therefore, the antral follicle is an essential microenvironment for efficient oocyte maturation and its developmental competence. Quantitative bioluminescence imaging of firefly luciferase reporter genes in an intact antral follicle would allow investigation of changes in cellular and molecular events and in the context of the whole follicles. In this study, we investigate factors influencing bioluminescence measurements as a first step towards developing a new bioluminescence imaging system for intact antral follicles. METHODS: We analyzed the time course of bioluminescence emitted from transfected living intact follicles using a cationic lipid mediated gene transfer method with increasing doses (1-3 MUg) of firefly luciferase reporter gene (pGL4). In addition, a standard luciferase assay was used to confirm the luciferase expression in granulosa cells in the transfected intact antral follicles. Finally, the dose effects of substrate, D-luciferin, were determined for optimal quantitative bioluminescence imaging of intact porcine antral follicles in vitro. RESULTS: The level of luciferase activity of follicles with 3 MUg pGL4 was significantly (P < 0.05) greater than the 1 MUg and 2 MUg groups at 1 min after D-luciferin injection. The bioluminescence intensity of transfected follicles reached a peak at 1 min, and then it was significantly (P < 0.05) reduced within 2 min after injection of D-luciferin; with the level of bioluminescence emission remained constant from 2.5 to 10 min. The bioluminescence emission was maximal with 300 MUg of D-luciferin. CONCLUSIONS: The results of this study suggested that the investigation of factors influencing bioluminescence measurements is a critical step toward developing a new bioluminescence imaging model. This study is the first to demonstrate that reporter genes can be transferred to intact granulosa cells with a lipid-mediated gene transfer method within intact follicles in vitro, and the level of transgene expression can be assessed by bioluminescence imaging in living intact antral follicles. PMID- 24479790 TI - The "push-down" technique using a novel micro-forceps for microvascular venous coupling. AB - A microvascular coupling system was developed and introduced for clinical application to facilitate fast and safe anastomosis of small vessels. However, operators often encounter some difficulty, particularly in pinning the vascular wall onto the ring-pins. To overcome the difficulty, the authors developed the "push down" technique and made newly-designed micro-forceps. These forceps have been used in 111 venous couplings involving 96 critical anastomoses. This study reports herein the patency results showing effectiveness and safety of the "push down" technique using a prototype micro-forceps in the pinning procedure in a microvascular coupling system. PMID- 24479791 TI - The impact of surgical resident participation in breast reduction surgery- outcome analysis from the 2005-2011 ACS-NSQIP datasets. AB - Breast reduction surgery is a common and effective surgical technique for treating symptomatic macromastia. There is limited data on the impact of resident involvement on outcomes. This study uses the ACS-NSQIP datasets to assess the impact of surgical resident participation in breast reduction surgery. This study reviewed the 2005-2011 ACS-NSQIP databases identifying primary encounters for reduction mammaplasty with CPT code "19318". It characterised surgical complications into three groups: any, major, and wound complications. Propensity scoring and matched analysis were used to account for non-randomised assignment. In total, 4328 patients underwent reduction mammoplasty during the study period. Resident participation was identified in 56.3% of cases. Logistic regression analysis determined the following factors independently associated with resident participation: class II obesity (OR = 0.73, p < 0.001), class III obesity (OR = 0.68, p < 0.001), dyspnea (OR = 1.59, p = 0.04), and ASA physical status of 3 (OR = 1.51, p < 0.001). A propensity score was assigned based on probability of resident involvement and matched cohorts were created and analyzed. A logistic regression analysis of the matched cohort data revealed that resident participation was independently associated with major surgical complications (OR = 2.18, p = 0.008). Prolonged operative (>2 SD) was associated with any (OR = 3.3, p = 0.039) and wound (OR = 10.2, p = 0.028) complications. A separate logistic regression analysis of the unmatched cohort using stratified PGY experience demonstrated that junior PGY was most highly associated with any (OR = 1.93, p = 0.013), major (OR = 2.4, p = 0.034), and wound (OR = 1.9, p = 0.04) complications. Resident participation was associated with added risk of surgical morbidity, and PGY experience was inversely related to risk of surgical complications in breast reduction surgery. PMID- 24479792 TI - Direct effect of radiation on the peripheral nerve in a rat model. AB - Radiation neuropathy is one of the severe complications of radiotherapy. Entrapment neuropathy, caused by surrounding soft tissue fibrosis induced by radiation, plays a key role in the onset of this neuropathy. Meanwhile, the pathophysiology of the direct effect of radiation on the peripheral nerve is not yet fully understood. The aim of this study is to investigate the direct effects of radiation on rat sciatic nerves that are isolated from surrounding soft tissue. In the radiation group (R group), only the exposed sciatic nerve was irradiated with 90 Gy X-radiation. In the sham group (S group), the surgical procedures were completed without radiation. The sciatic functional index (SFI) result demonstrated no statistical differences between the R group and S group. However, even though the surrounding soft tissue was not irradiated, the macroscopic and histological findings of the R group at 24 weeks after radiation showed scar formation around the radiated nerve. These findings on radiation neuropathy indicate that neurohumoral factors derived from the radiated nerve itself may cause fibrosis. The electromyographic and histological examination showed axonal degeneration in the R group. Furthermore, the axon diameter and axon packing density in the R group demonstrated the axonal degeneration, even though it was 0.5 cm more proximal to the radiated portion than the axon packing density in the S group. This appearance was assumed to be "dying-back" neuropathy. It is believed that this study is a first step toward identifying an accurate pathophysiology for intractable radiation-induced peripheral neuropathy. PMID- 24479794 TI - Functional disability and depressive symptoms: longitudinal effects of activity restriction, perceived stress, and social support. AB - OBJECTIVES: This longitudinal study investigates how activity restriction, perceived stress, and social support affect the relationship between functional disability and depressive symptoms. METHOD: This longitudinal study of a Taiwan population analyzed a nationally representative sample of 1268 subjects aged 60 years and over. Path analysis was used to assess interrelations among functional disability, activity restriction, perceived stress, social support, and depressive symptoms over time. RESULTS: The analytical results supported the following relationships: (a) high functional disability were associated with high activity restriction, low social support, and high perceived stress over time, (b) high functional disability, high activity restriction, low social support, and high perceived stress were associated with high levels of depressive symptoms over time, (c) among the four factors, perceived stress exerted the strongest cross-sectional and longitudinal effect on depressive symptoms, and (d) the significant effect of prior functional disability on subsequent depressive symptoms substantially contributed to indirect changes in activity restriction, perceived stress, and social support between waves. CONCLUSION: The findings indicate that functional disability may contribute to subsequent depressive symptoms by reducing activities and social support. Decreased activities and social support increased perceptions of stress, which then increased depressive symptoms during the 8-year follow-up study. PMID- 24479793 TI - Human artificial chromosome-based gene delivery vectors for biomedicine and biotechnology. AB - INTRODUCTION: Human artificial chromosomes (HACs) have several advantages over viruses as gene delivery vectors, including stable episomal maintenance in a single copy and the ability to carry large gene inserts. AREAS COVERED: In this review, we summarise recent work on gene transfer into mammalian cells using the HACs. HACs allow therapeutic transgenes to be expressed in target cells under conditions that recapitulate the physiological regulation of endogenous loci. EXPERT OPINION: Based on the published data, the HAC vectors have a great potential for gene therapy, regenerative medicine, screening of anticancer drugs and biotechnology. PMID- 24479795 TI - Evaluation of chromID strepto B as a screening media for Streptococcus agalactiae. AB - BACKGROUND: Streptococcus agalactiae (Group B Streptococcus, GBS), a leading cause of sepsis and meningitis in infants, can be transmitted vertically from mother to infant during passage through the birth canal. Detection of GBS colonization in perinatal women is a major strategy for the prevention of postpartum neonatal disease. The U.S. Centers for Disease Control and Prevention recommends that all women undergo vaginal-rectal screening for GBS colonization at 35-37 weeks of gestation. ChromID Strepto B (STRB) is a chromogenic GBS screening media on which GBS colonies appear pink or red, while other bacteria are either inhibited or form colonies in other colors. In this study, we compared STRB with a conventional GBS detection method using 5% sheep blood agar (BA) followed by a selective enrichment broth. METHODS: Anovaginal swabs were collected from 1425 women during weeks 35 to 37 of their pregnancies. The swabs were used to inoculate both STRB and BA plates after enrichment with selective Todd Hewitt Broth (THB). A GBS latex agglutination test was used to confirm the identity of isolates from each plate. RESULTS: GBS was recovered from 319 (22.4%) samples with one or both media: 318 on STRB compared to 299 using BA. One false negative was observed on STRB, and 20 false negatives were observed on BA. In addition, non-hemolytic GBS was recovered from 19 (6.0%) samples using STRB. CONCLUSIONS: STRB offers effectiveness and convenience over BA for GBS screening in clinical laboratories. STRB produces fewer false negatives, has a higher detection rate and uses a simple color screen that is ideal for technician-level applications. We recommend STRB as the media of choice for GBS screening. PMID- 24479796 TI - Advances with microRNAs in tumorigenesis and cancer therapy. PMID- 24479798 TI - Genistein inhibits cell growth and invasion through regulation of miR-27a in pancreatic cancer cells. AB - BACKGROUND: Although genistein has been reported to exert its anti-tumor activity, the exact mechanism of its action is poorly elucidated. Recently, it has been found that genistein could regulate the expression of microRNAs. Therefore, our aim in the present study was to find whether genistein regulates specific miR-27a in pancreatic cancer cells. METHODS: We performed our studies using multiple methods including MTT assay, RT-PCR, Western blotting analysis, migration, invasion assay, and transfection. RESULTS: We observed that genistein significantly inhibited the expression of miR-27a in pancreatic cancer cells. Moreover, inhibition of miR-27a suppressed cell growth and induced apoptosis as well as inhibited invasion in pancreatic cancer cells. Furthermore, we found a synergy effect between miR-27a and genistein on cell growth inhibition, apoptosis, and invasion, suggesting that targeting miR-27a may represent a potential strategy for treatment of pancreatic cancer. CONCLUSIONS: Our findings demonstrated that genistein plays a tumor suppressor role in part through inhibition of miR-27a in pancreatic cancer cells. PMID- 24479797 TI - Interrelationships of circulating tumor cells with metastasis and thrombosis: role of microRNAs. AB - Metastasis and thrombosis are serious threats to cancer patients and generally associated with poor prognosis. The elusive mechanisms underlying the pathogenesis of metastasis and thrombosis have been subjects of extensive investigations. The presence of circulating tumor cells (CTCs) is closely related to tumor metastasis, and these cells play an important role in thrombosis in cancer patients. In this review, we describe the latest findings on the role of CTCs in tumor metastasis and cancer-related thrombosis and the regulatory role of microRNAs in CTCs and thrombosis. Additionally, we discuss anticoagulant-based strategies for the prevention of thrombosis and reduction of cancer metastasis and the potential to translate current knowledge on these strategies to the treatment of cancer. PMID- 24479800 TI - Oncogenic microRNAs in the genesis of leukemia and lymphoma. AB - Emerging evidence has shown that microRNAs (miRNAs) can act as oncogenes in the initiation and progression of leukemia and lymphoma. Aberrant expression of oncogenic miRNAs, including miR-155, miR-17-92, miR-21, miR-125b, miR-93, miR-143 p3, miR-196b, and miR-223 promotes leukemogenesis through increasing the leukemic stem/progenitor cell population, promoting cell proliferation, blocking cell differentiation, and diminishing cell apoptosis. In addition, abnormal expression of oncogenic miRNAs, such as miR-155, miR-17-92, the miR15a/16-1 cluster, miR21, miR34a, and miR125b has been implicated in lymphomagenesis. Notably, miR- 155 and miR-17-92 profoundly changed the gene expression signatures and signal transduction pathways in various hematopoietic cells, and triggered leukemogenesis and lymphomagenesis. Therefore, miRNAs play an important role in the genesis of leukemia and lymphoma. Accordingly, oncogenic miRNAs may serve as diagnostic and prognostic factors for patients with leukemia or lymphoma, and could be used as targets for novel anti-leukemia and anti-lymphoma drug discovery. PMID- 24479801 TI - MicroRNAs as anti-cancer therapy. AB - MicroRNAs (miRNAs) are endogenously expressed and evolutionarily conserved small non-coding RNAs, which regulate gene expression. Several studies have shown that they are involved in fundamental biological processes, such as proliferation and apoptosis. MicroRNA dysregulation plays an important role in cancer onset and progression where miRs can function as both tumor promoters (oncomiRs) or tumor suppressors by targeting numerous biomolecules that are important in carcinogenesis. MicroRNA molecules are already entering the clinic as diagnostic and prognostic biomarkers for patient stratification and also as therapeutic targets and agents. Their role as biomarkers and therapeutic targets is appealing but several obstacles have as yet limited our ability to translate this potential into a clinical reality. This review provides a comprehensive overview of miRNAs with established functional relevance in cancer. Furthermore, approaches towards therapeutic miRNA-based intervention are discussed. Those include viral or non viral approaches of miRNA replacement therapy in the case of tumor-suppressing miRNAs and strategies for the inhibition of oncogenic miRNAs. PMID- 24479799 TI - MicroRNAs (miRNAs) as biomarker(s) for prognosis and diagnosis of gastrointestinal (GI) cancers. AB - Gastrointestinal (GI) cancers remain one of the most common malignancies and are the second common cause of cancer deaths worldwide. The limited effectiveness of therapy for patients with advanced stage and recurrent disease is a reflection of an incomplete understanding of the molecular basis of GI carcinogenesis. Major advancements have improved our understanding of pathology and pathogenesis of GI cancers, but high mortality rates, unfavorable prognosis and lack of clinical predictive biomarkers provide an impetus to investigate new sensitive and specific diagnostic and prognostic markers for GI cancers. MicroRNAs (miRNAs) are short (19-24 nucleotides) noncoding RNA molecules that regulate gene expression at the posttranscriptional level thus playing an important role in modulating various biological processes including, but not limited to developmental processes, proliferation, apoptosis, metabolism, differentiation, epithelial mechenchymal transition and are involved in the initiation and progression of various human cancers. Unique miRNA expression profiles have been observed in various cancer types at different stages, suggesting their potential as diagnostic and prognostic biomarkers. Due to their tumor-specific and tissue specific expression profiles, stability, robust clinical assays for detection in serum as well as in formalin-fixed tissue samples, miRNAs have emerged as attractive candidates for diagnostic and prognostic applications. This review summarizes recent research supporting the utility of miRNAs as novel diagnostic and prognostic tools for GI cancers. PMID- 24479802 TI - MicroRNAs in cancer stem cells: new regulators of stemness. AB - In the past decade, cancer stem cells (CSCs) have been isolated, characterized, and studied in a variety of cancers and they are believed to be responsible for tumor initiation and progression. Like normal stem cells, these cells retain self renewal property and therefore, can differentiate into multiple tumor types. Despite this clinical importance, how CSCs are regulated and their exact pathological role are yet to be elucidated. Recent studies have shed light on the potential role of miRNAs in regulating CSCs. In this review, we summarize the current findings of miRNAs in the regulation of CSCs through different self renewal pathways and the potential therapeutic implications of miRNAs in clinical settings by targeting CSCs. PMID- 24479804 TI - MicroRNAs in cancer: lessons from melanoma. AB - Melanoma is a high-grade, poorly differentiated malignant tumor of pigment producing cells (melanocytes), accounting for more than 70% of the skin cancer related deaths. Although new lines of targeted therapy and immunotherapy were introduced lately, durable responses are not common as it is hard to target the elusive metastatic phenotype. microRNAs (miRNAs) are short non-coding RNA molecules that function as specific epigenetic regulators of the transcriptome. miRNAs are involved in a broad spectrum of physiological and pathological processes, including cancer-related functions such as proliferation, cell cycle, migration, invasion, immune evasion and drug resistance. These functions are mostly regulated in melanoma through four molecular deregulated pathways, including the RAS/MAPK pathway, the MITF pathway, the p16INK4A-CDK4-RB pathway and the PI3K-AKT pathway. miRNAs provide a strong platform for delineation of cancer mechanisms. Here we review the diverse roles of miRNAs in melanoma cell biology. Studying miRNA-mediated regulation of aggressive and tumor related features is expected to provide novel mechanistic insights that may pave the way for new diagnostic, prognostic and predictive tools as well as new molecular targets for future therapy. PMID- 24479805 TI - MicroRNAs in breast cancer therapy. AB - Breast cancer is one of the most common type of cancers as well as a principal cause of cancer-related deaths in women worldwide. Although research has provided a better understanding and diagnosis of breast cancer, studies in breast cancer therapeutics are still far from satisfactory. Recent research on microRNAs (miRNAs) has implicated these tiny regulatory molecules in progression of breast cancer with the possibility of exploiting them as diagnostic and/or prognostic biomarkers. The loss of tumor suppressor miRNAs or overexpression of oncogenic miRNAs can lead to breast cancer tumorigenesis or metastasis. However, the next step - linking miRNAs to cancer therapeutics - is still under progression. The roles of miRNAs exhibit much potential in breast cancer therapy, but currently need to be further studied and evaluated in order to better understand how to apply laboratory results to clinical medicine. Here we provide an update on our current understanding of miRNAs as molecular targets for diagnosis, prognosis and therapy of breast cancers. PMID- 24479803 TI - Targeting miRNAs for pancreatic cancer therapy. AB - Pancreatic cancer (PC) is the fourth leading cause of cancer-related deaths in the United States and has a median 5-year survival rate less than 5%. Although surgery offers the best chance for a cure for pancreatic cancer, less than 20% of patients are eligible for potentially curative resection, because in most cases, the cancer has already spread locally or to distant organs at diagnosis, precluding resection. MicroRNAs (miRNAs) are small noncoding, endogenous, single stranded RNAs that are pivotal regulators of posttranscriptional gene expression. Extensive studies of miRNAs over the past several years have revealed that the expression of miRNAs is frequently deregulated in pancreatic cancer patients and that this deregulation contributes to the pathogenesis and aggressiveness of the disease. Currently, investigators are studying the use of miRNAs as diagnostic and/or prognostic biomarkers and therapeutic tools for pancreatic cancer. Rapid discovery of many miRNA targets and their relevant pathways has contributed to the development of miRNA-based therapeutics. In particular, the transcription factor Forkhead box M1 (FOXM1) is overexpressed in the majority of cancer patients, including those with pancreatic cancer. This overexpression is implicated to have a role in tumorigenesis, progression, and metastasis. This important role of FOXM1 affirms its usefulness in therapeutic interventions for pancreatic cancer. In this review, we summarize the current knowledge and concepts concerning the involvement of miRNAs and FOXM1 in pancreatic cancer development and describe the roles of the miRNA-FOXM1 signaling pathway in pancreatic cancer initiation and progression. Additionally, we describe some of the technical challenges in the use of the miRNA-FOXM1 signaling pathway in pancreatic cancer treatment. PMID- 24479806 TI - MiRNAs in human cancers: the diagnostic and therapeutic implications. AB - From chemotherapy and radiotherapy to molecular targeted therapy, in recent decades, we have witnessed the acceleration of cancer treatments. However, nowadays, it has encountered obstacles due to multi-drug resistance, drug-induced toxicity and the insufficient disruption of cancer pathways. Thus, it is required to have more efficient approaches for cancer treatments. MicroRNAs (miRNAs) are perhaps the most researched genes in the last decade. They have been reported to play significant roles in cancers and are considered to be applied in targeted cancer therapies. Here, we will firstly review the implications of miRNAs in clinical use from the aspects of miRNA biogenesis and biological functions, followed by the diagnostic and prognostic values of miRNAs. Furthermore, the application of miRNAs in pre-clinical cancer models and clinical trials regarding miRNAs will also be discussed. Moreover, since miRNA delivery is the biggest challenge for miRNA based therapy, the commonly used delivery methods will then be reviewed. The miRNA combinational therapy with chemotherapy, radiotherapy, molecular targeted therapy and immunotherapy will be reviewed and discussed at last. PMID- 24479807 TI - The miRNAs and epithelial-mesenchymal transition in cancers. AB - The epithelial-mesenchymal transition (EMT) is a process by which epithelial tumor cells acquire migratory and invasive abilities that enable them to spread to other organs. During this process, the tight junction molecule, E-cadherin, is often downregulated through transcription repression by the EMT-inducing transcription factors (EMT-TFs). MicroRNAs (miRNAs) are a class of small noncoding RNA molecules which bind to the complementary sequences within mRNA molecules. They post-transcriptionally govern gene silencing, thus affecting a broad range of physiological conditions, including EMT. In this review, we will discuss some well-known as well as brand-new EMT-related miRNAs and the signaling pathways in the tumor milieu that regulate their expressions and control cancer invasion and metastasis. Finally, we will discuss the application of miRNAs as therapeutic targets for treatment of cancer. PMID- 24479808 TI - Arsenic trioxide targets miR-125b in glioma cells. AB - BACKGROUND: Arsenic trioxide (As2O3) has been demonstrated to suppress tumorigenesis in human glioma. However, the exact molecular mechanisms by which As2O3 exerts its tumor suppressor functions are elusive. Therefore, it is warranted to explore the underlying mechanism of As2O3-mediated anti-tumor activity in glioma. METHODS: To achieve our goal, we used multiple approaches including MTT assay, apoptosis, Real-time RT-PCR, Western blotting, invasion assay, and gene transfection. RESULTS: We observed that A22O3 inhibited cell growth and induced apoptosis as well as suppressed migration and invasion in human glioma cells. Moreover, we found that As2O3 down-regulated miR-125b expression and subsequently up-regulated its target gene Bak1 expression. Furthermore, we identified that As2O3 exerts its anti-tumor activity partly through regulation of miR-125b. CONCLUSIONS: Our present study suggests that As2O3 could be a potential therapeutic agent for treatment of human glioma. PMID- 24479809 TI - Regulation of KRAS-PAK4 axis by microRNAs in cancer. AB - MicroRNAs (miRNAs), often aberrantly expressed in cancer, have been implicated in the regulation of a number of critical cell survival pathways including the genes in the Kras signaling. Kras mutations are observed in more than half of cancers and its inhibition has been the focus of intense research for the past 30 years. However, Kras itself has proven to be non-druggable due in part to the absence of binding pockets for small molecule drugs. These hurdles resulted in researchers shifting their focus on targeting proteins downstream to Kras pathways. P21 activated kinase 4 (PAK4) belongs to the family of serine/threonine kinases comprising of 6 isoforms (PAK 1-6) and is considered as a key effector of Rho family of GTPases downstream of RAS. PAK4 controls critical processes such as cellular motility, proliferation and survival. Recently a number of small molecule PAK4 antagonists have been investigated in preclinical and clinical setting; albeit without any success. Emerging evidence shows that PAK is tightly regulated by a number of miRNAs that are also recognized to promote hyper activation of oncogenic Kras signaling. Therefore, the understanding of the role of miRNAs in the regulation of PAK4 is critical to the development of therapies against this important player in the Kras pathway. Through this review, we bring forward mechanistic insights on PAK4 regulation by aberrantly expressed miRNAs in cancer and its implications on Kras signaling. We anticipate that enhanced knowledge of the miRNA-PAK4 interaction network will allow the development of successful therapies targeting this critical protein to ultimately rein in Kras. PMID- 24479810 TI - Relativistic GVVPT2 multireference perturbation theory description of the electronic states of Y2 and Tc2. AB - The multireference generalized Van Vleck second-order perturbation theory (GVVPT2) method is used to describe full potential energy curves (PECs) of low lying states of second-row transition metal dimers Y(2) and Tc(2), with scalar relativity included via the spin-free exact two-component (sf-X2C) Hamiltonian. Chemically motivated incomplete model spaces, of the style previously shown to describe complicated first-row transition metal diatoms well, were used and again shown to be effective. The studied states include the previously uncharacterized 2(1)Sigma(g)(+) and 3(1)Sigma(g)(+) PECs of Y(2). These states, together with 1(1)Sigma(g)(+), are relevant to discussion of controversial results in the literature that suggest dissociation asymptotes that violate the noncrossing rule. The ground state of Y(2) was found to be X(5)Sigma(u)(-) (similar to Sc(2)) with bond length R(e) = 2.80 A, binding energy D(e) = 3.12 eV, and harmonic frequency omega(e) = 287.2 cm(-1), whereas the lowest 1(1)(g)(+) state of Y(2) was found to lie 0.67 eV above the quintet ground state and had spectroscopic constants R(e) = 3.21 A, D(e) = 0.91 eV, and omega(e) = 140.0 cm(-1). Calculations performed on Tc(2) include study of the previously uncharacterized relatively low-lying 1(5)Sigma(g)(+) and 1(9)Sigma(g)(+) states (i.e., 0.70 and 1.84 eV above 1(1)Sigma(g)(+), respectively). The ground state of Tc(2) was found to be X(3)Sigma(g)(-) with R(e) = 2.13 A, D(e) = 3.50 eV, and omega(e) = 336.6 cm(-1) (for the most stable isotope, Tc-98) whereas the lowest (1)Sigma(g)(+) state, generally accepted to be the ground state symmetry for isovalent Mn(2) and Re(2), was found to lie 0.47 eV above the X(3)Sigma(g)(-) state of Tc(2). The results broaden the range of demonstrated applicability of the GVVPT2 method. PMID- 24479811 TI - Practice and play as determinants of self-determined motivation in youth soccer players. AB - Based upon predictions derived from the Developmental Model of Sports Participation, we tested whether hours in domain-specific play (self-led activities) and practice (coach-led activities) during childhood (~5-12 year) in an elite group of youth soccer players from the UK (N = 144) were related to motivation. Independent analysis of three different age groups (Under 13, 15 and 17 year) did not show relations between play and practice activities during childhood and global measures of motivation. However, secondary analysis showed that when controlling for years in soccer, years in the UK Academy system were negatively related to global indices of self-determined motivation (SDI) and positively related to controlled motivation for the oldest players. Despite predictions, there was no evidence that play during childhood was positively related to more SDI. Prospective research is recommended to enable more robust conclusions about the role of early developmental practice activities, especially early specialisation in a high-performance system, on both skill and psychosocial development. PMID- 24479812 TI - Effect of hospital case-manager nurses on the level of dependence, satisfaction and caregiver burden in patients with complex chronic disease. AB - AIMS AND OBJECTIVES: To determine the medium-term effects of nurse case management on the dependence and satisfaction of patients with complex chronic disease and on caregiver burden. BACKGROUND: Caregiver exhaustion increases the readmission rate of highly dependent patients with complex chronic disease and their consumption of primary care resources. DESIGN: An observational and analytical cohort study was undertaken in multimorbid patients. METHODS: Data were gathered on Barthel Index and Caregiver Burden Index scores, primary care resource consumption, readmission and mortality rates, and patient satisfaction with care and care continuity. Results were compared between nurse case-managed (n = 62) and control (n = 193) multimorbid patients using univariate and bivariate analyses. RESULTS: The study included 255 patients with complex chronic disease (24.32% in management cohort vs. 75.68% in control cohort). The nurse case-managed group had significantly lower Barthel Index and higher Caregiver Burden Index scores and a significantly longer hospital stay. At 90 days postdischarge, no significant intergroup differences were observed in Barthel Index or Caregiver Burden Index scores, primary care resource consumption, readmission rate or mortality rate; the case-managed patients showed a significantly higher satisfaction level with their care and its continuity. CONCLUSIONS: Nurse case management prevents a postdischarge increase in the dependence of multimorbid patients and the burden of their caregivers. RELEVANCE TO CLINICAL PRACTICE: Application of nurse case management can reduce the readmission rate and primary care consumption of patients with chronic complex disease after their hospital stay and prevent an exacerbation of caregiver exhaustion. PMID- 24479813 TI - ANKS1B is a smoking-related molecular alteration in clear cell renal cell carcinoma. AB - BACKGROUND: An association between cigarette smoking and increased risk of clear cell renal cell carcinoma (ccRCC) has been established; however, there are limited data regarding the molecular mechanisms that underlie this association. We used a multi-stage design to identify and validate genes that are associated with smoking-related ccRCC. METHODS: We first conducted a microarray study to compare gene expression patterns in patient-matched ccRCC and normal kidney tissues between patients with (n = 23) and without (n = 42) a history of smoking. Analyses were first stratified on obesity status (the other primary risk factor for ccRCC) and then combined and analyzed together. To identify genes where the fold change in smokers relative to non-smokers was different in tumor tissues in comparison to patient-matched normal kidney tissues, we identified Affymetrix probesets that had a significant tissue type-by-smoking status interaction pvalue. We then performed RT-PCR validation on the top eight candidate genes in an independent sample of 28 smokers and 54 non-smokers. RESULTS: We identified 15 probesets that mapped to eight genes that had candidate associations with smoking related ccRCC: ANKS1B, ACOT6, PPWD1, EYS, LIMCH1, CHRNA6, MT1G, and ZNF600. Using RT-PCR, we validated that expression of ANKS1B is preferentially down-regulated in smoking-related ccRCC. CONCLUSION: We provide the first evidence that ANKS1B expression is down regulated in ccRCC tumors relative to patient-matched normal kidney tissue in smokers. Thus, ANKS1B should be explored further as a novel avenue for early detection as well as prevention of ccRCC in smokers. PMID- 24479814 TI - A new diketopiperazine from the gorgonian coral Menella kanisa. AB - Chemical investigation on the gorgonian Menella kanisa collected from Beibu Gulf led to the isolation of a new diketopiperazine, named menazepine A (1), as well as three known diketopiperazines, namely cyclo(4-hydroxyprolylleucyl) (2), cyclo(Pro-Leu) (3) and cyclo(4-hydroxyprolylphenylalanyl) (4). The structure of the new diketopiperazine was elucidated on the basis of extensive spectroscopic analysis and by comparing the data with those of related metabolites. Compounds 1 4 were also evaluated for brine shrimp lethality. PMID- 24479815 TI - Can a multisensory teaching approach impart the necessary knowledge, skills, and confidence in final year medical students to manage epistaxis? AB - OBJECTIVE: The purpose of this study is to evaluate the efficacy of a multisensory teaching approach in imparting the knowledge, skills, and confidence to manage epistaxis in a cohort of fourth year medical students. METHODS: One hundred and thirty four fourth year medical students were recruited into the study from Aug 2011 to February 2012 in four groups. Students listened to an audio presentation (PODcast) about epistaxis and viewed a video presentation on the technical skills (VODcast). Following this, students completed a 5-minute Individual Readiness Assessment Test (IRAT) to test knowledge accrued from the PODcast and VODcast. Next, students observed a 10-minute expert demonstration of the technical skills on a human cadaver and spent half an hour practicing these techniques on cadaver simulators with expert guidance. The students' confidence was assessed with Confidence Level Questionnaires (CLQs) before and after their laboratory session. The skill level of a subset of students was also assessed with a pre- and post-laboratory Objective Structured Assessment of Technical Skills (OSATS). RESULTS: Eighty two percent of the participants achieved a score of at least 80% on the IRAT. The CLQ instrument was validated in the study. There was a statistically significant improvement between the pre- and post-laboratory CLQ scores (p<0.01) and also between pre- and post-laboratory OSATS scores (p<0.01). Qualitative feedback suggested a student preference for this teaching approach. CONCLUSIONS: This study provides further evidence that a multisensory teaching intervention effectively imparts the necessary knowledge, skill and confidence in fourth year medical students to manage epistaxis. PMID- 24479816 TI - Polymorphisms in the CLDN1 and CLDN7 genes are related to differentiation and tumor stage in colon carcinoma. AB - Tight junction is composed of transmembrane proteins important for maintaining cell polarity and regulating ion flow. Among these proteins are the tissue specific claudins, proteins that have recently been suggested as tumor markers for several different types of cancer. An altered claudin expression has been observed in colon, prostatic, ovarian, and breast carcinoma. The aim of this study was to analyze the allele frequencies of three common single nucleotide polymorphisms (SNPs) in the genes for claudin 1 and claudin 7 in colon cancer (CC) patients and in a control population of healthy blood donors. Pyrosequencing was used to genotype the CLDN1 SNP rs9869263 (c.369C>T), and the CLDN7 SNPs rs4562 (c.590C>T) and rs374400 (c.606T>G) in DNA from 102 formalin fixed paraffin embedded (FFPE) colon cancer tissue, and 111 blood leukocyte DNA from blood/plasma donors. These results were correlated with clinical parameters such as TNM stage, tumor localization, tumor differentiation, complexity index, sex, and age. We found that there was a significant association between the CLDN1 genotype CC in tumor samples and a higher risk of colon cancer development (OR 3.0, p < 0.001). We also found that the CLDN7 rs4562 (c.590C>T) genotype CT had a higher risk of lymph node involvement (p = 0.031) and a lower degree of tumor differentiation (p = 0.028). In the control population, the allele frequencies were very similar to those in the HapMap cohort for CLDN7. The CLDN1 rs9869263 genotype (c.369C>T) was related to increased risk of colon cancer, and the CLDN7 rs4562 genotype (c.590C>T) was related to tumor differentiation and lymph node involvement in colon carcinoma. Further studies are warranted to ascertain their potential uses as biomarkers predicting tumor development, proliferation, and outcome in this disease. PMID- 24479817 TI - I spy with my little eye: cognitive processing of framed physical activity messages. AB - The primary purpose was to examine the relative cognitive processing of gain framed versus loss-framed physical activity messages following exposure to health risk information. Guided by the Extended Parallel Process Model, the secondary purpose was to examine the relation between dwell time, message recall, and message-relevant thoughts, as well as perceived risk, personal relevance, and fear arousal. Baseline measures of perceived risk for inactivity-related disease and health problems were administered to 77 undergraduate students. Participants read population-specific health risk information while wearing a head-mounted eye tracker, which measured dwell time on message content. Perceived risk was then reassessed. Next, participants read PA messages while the eye tracker measured dwell time on message content. Immediately following message exposure, recall, thought-listing, fear arousal, and personal relevance were measured. Dwell time on gain-framed messages was significantly greater than loss-framed messages. However, message recall and thought-listing did not differ by message frame. Dwell time was not significantly related to recall or thought-listing. Consistent with the Extended Parallel Process Model, fear arousal was significantly related to recall, thought-listing, and personal relevance. In conclusion, gain-framed messages may evoke greater dwell time than loss-famed messages. However, dwell time alone may be insufficient for evoking further cognitive processing. PMID- 24479818 TI - Reductive benzylation of C60 imidazoline with a bulky addend. AB - Reductive benzylation of C60 imidazoline with a bulky addend affords two 1,2,3,16 adducts (2 and 4) and one 1,2,3,4-adduct (3). Experimental and computational results indicate that the sterically favored 2 is more stable than the electronically favored 3. However, an opposite stability order is shown for the dianions of 2 and 3. PMID- 24479819 TI - Laparoscopic ureterolysis and omental wrapping in patients with retroperitoneal fibrosis and obstructive uropathy: a single-center experience. AB - OBJECTIVES: To analyze the outcomes with mid- to long-term follow-up of laparoscopic ureterolysis (LU) and omental wrapping in retroperitoneal fibrosis (RPF) with obstructive uropathy. PATIENTS AND METHODS: Records of 9 patients with RPF who had obstructive uropathy at presentation and had undergone LU and omental wrapping at our center during January 2004 to June 2012 were collected and analyzed. RESULTS: Six females and three males underwent LU for RPF. Underlying causes of RPF could not be found in 8 (89%) cases. Two patients underwent bilateral LU. Mean operative time and estimated blood loss were 213 minutes (range, 180-280 minutes) and 119 mL (range, 70-200 mL), respectively. No case required conversion to open surgery. The only significant intraoperative complication (1/9 [11%]) was ureteral injury, which was easily repaired intraoperatively. The postoperative complication rate was 44% (4/9). Most complications (75% [3/4]) were minor and did not need specific treatment. The mean follow-up period was 46 months (range, 4-72 months). The success rate at last follow-up was 89%. CONCLUSIONS: Treatment of RPF is still controversial. Any future prospective randomized comparative trials seem unlikely in view of the low incidence of RPF. LU and omental wrapping in the setting of obstructive uropathy are safe and an effective alternative with a high success rate at mid- to long term follow-up. PMID- 24479820 TI - Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice. AB - Clinical complications associated with atherosclerotic plaques arise from luminal obstruction due to plaque growth or destabilization leading to rupture. Tumour necrosis factor ligand superfamily member 12 (TNFSF12) also known as TNF-related weak inducer of apoptosis (TWEAK) is a proinflammatory cytokine that participates in atherosclerotic plaque development, but its role in plaque stability remains unclear. Using two different approaches, genetic deletion of TNFSF12 and treatment with a TWEAK blocking mAb in atherosclerosis-prone mice, we have analysed the effect of TWEAK inhibition on atherosclerotic plaques progression and stability. Mice lacking both TNFSF12 and Apolipoprotein E (TNFSF12(-/-) ApoE( /-) ) exhibited a diminished atherosclerotic burden and lesion size in their aorta. Advanced atherosclerotic plaques of TNFSF12(-/-) ApoE(-/-) or anti-TWEAK treated mice exhibited an increase collagen/lipid and vascular smooth muscle cell/macrophage ratios compared with TNFSF12(+/+) ApoE(-/-) control mice, reflecting a more stable plaque phenotype. These changes are related with two different mechanisms, reduction of the inflammatory response (chemokines expression and secretion and nuclear factor kappa B activation) and decrease of metalloproteinase activity in atherosclerotic plaques of TNFSF12(-/-) ApoE(-/-) . A similar phenotype was observed with anti-TWEAK mAb treatment in TNFSF12(+/+) ApoE(-/-) mice. Brachiocephalic arteries were also examined since they exhibit additional features akin to human atherosclerotic plaques associated with instability and rupture. Features of greater plaque stability including augmented collagen/lipid ratio, reduced macrophage content, and less presence of lateral xanthomas, buried caps, medial erosion, intraplaque haemorrhage and calcium content were present in TNFSF12(-/-) ApoE(-/-) or anti-TWEAK treatment in TNFSF12(+/+) ApoE(-/-) mice. Overall, our data indicate that anti-TWEAK treatment has the capacity to diminish proinflamatory response associated with atherosclerotic plaque progression and to alter plaque morphology towards a stable phenotype. PMID- 24479822 TI - Improving the quality of health information: a qualitative assessment of data management and reporting systems in Botswana. AB - BACKGROUND: Ensuring that data collected through national health information systems are of sufficient quality for meaningful interpretation is a challenge in many resource-limited countries. An assessment was conducted to identify strengths and weaknesses of the health data management and reporting systems that capture and transfer routine monitoring and evaluation (M&E) data in Botswana. METHODS: This was a descriptive, qualitative assessment. In-depth interviews were conducted at the national (n = 27), district (n = 31), and facility/community (n = 71) levels to assess i) M&E structures, functions, and capabilities; ii) indicator definitions and reporting guidelines; iii) data collection forms and tools; iv) data management processes; and v) links with the national reporting system. A framework analysis was conducted using ATLAS.ti v6.1. RESULTS: Health programs generally had standardized data collection and reporting tools and defined personnel for M&E responsibilities at the national and district levels. Best practices unique to individual health programs were identified and included a variety of relatively low-resource initiatives such as attention to staffing patterns, making health data more accessible for evidence-based decision-making, developing a single source of information related to indicator definitions, data collection tools, and management processes, and utilization of supportive supervision visits to districts and facilities. Weakness included limited ownership of M&E-related duties within facilities, a lack of tertiary training programs to build M&E skills, few standard practices related to confidentiality and document storage, limited dissemination of indicator definitions, and limited functionality of electronic data management systems. CONCLUSIONS: Addressing fundamental M&E system issues, further standardization of M&E practices, and increasing health services management responsiveness to time-sensitive information are critical to sustain progress related to health service delivery in Botswana. In addition to high-resource initiatives, such as investments in electronic medical record systems and tertiary training programs, there are a variety of low-resource initiatives, such as regular data quality checks, that can strengthen national health information systems. Applying best practices that are effective within one health program to data management and reporting systems of other programs is a practical approach for strengthening health informatics and improving data quality. PMID- 24479821 TI - Clostridium perfringens strains from bovine enterotoxemia cases are not superior in in vitro production of alpha toxin, perfringolysin O and proteolytic enzymes. AB - BACKGROUND: Bovine enterotoxemia is a major cause of mortality in veal calves. Predominantly veal calves of beef cattle breeds are affected and losses due to enterotoxemia may account for up to 20% of total mortality. Clostridium perfringens type A is considered to be the causative agent. Recently, alpha toxin and perfringolysin O have been proposed to play an essential role in the development of disease. However, other potential virulence factors also may play a role in the pathogenesis of bovine enterotoxemia. The aim of this study was to evaluate whether strains originating from bovine enterotoxemia cases were superior in in vitro production of virulence factors (alpha toxin, perfringolysin O, mucinase, collagenase) that are potentially involved in enterotoxemia. To approach this, a collection of strains originating from enterotoxemia cases was compared to bovine strains isolated from healthy animals and to strains isolated from other animal species. RESULTS: Strains originating from bovine enterotoxemia cases produced variable levels of alpha toxin and perfringolysin O that were not significantly different from levels produced by strains isolated from healthy calves and other animal species. All tested strains exhibited similar mucinolytic activity independent of the isolation source. A high variability in collagenase activity between strains could be observed, and no higher collagenase levels were produced in vitro by strains isolated from enterotoxemia cases. CONCLUSIONS: Bovine enterotoxemia strains do not produce higher levels of alpha toxin, perfringolysin O, mucinase and collagenase, as compared to strains derived from healthy calves and other animal species in vitro. PMID- 24479823 TI - Hydrocephalus secondary to chronic meningitis. PMID- 24479824 TI - Molecular identification of adenoviruses associated with respiratory infection in Egypt from 2003 to 2010. AB - BACKGROUND: Human adenoviruses of species B, C, and E (HAdV-B, -C, -E) are frequent causative agents of acute respiratory infections worldwide. As part of a surveillance program aimed at identifying the etiology of influenza-like illness (ILI) in Egypt, we characterized 105 adenovirus isolates from clinical samples collected between 2003 and 2010. METHODS: Identification of the isolates as HAdV was accomplished by an immunofluorescence assay (IFA) and confirmed by a set of species and type specific polymerase chain reactions (PCR). RESULTS: Of the 105 isolates, 42% were identified as belonging to HAdV-B, 60% as HAdV-C, and 1% as HAdV-E. We identified a total of six co-infections by PCR, of which five were HAdV-B/HAdV-C co-infections, and one was a co-infection of two HAdV-C types: HAdV 5/HAdV-6. Molecular typing by PCR enabled the identification of eight genotypes of human adenoviruses; HAdV-3 (n = 22), HAdV-7 (n = 14), HAdV-11 (n = 8), HAdV-1 (n = 22), HAdV-2 (20), HAdV-5 (n = 15), HAdV-6 (n = 3) and HAdV-4 (n = 1). The most abundant species in the characterized collection of isolates was HAdV-C, which is concordant with existing data for worldwide epidemiology of HAdV respiratory infections. CONCLUSIONS: We identified three species, HAdV-B, -C and E, among patients with ILI over the course of 7 years in Egypt, with at least eight diverse types circulating. PMID- 24479825 TI - Exenatide dosing in alpacas. AB - In order to investigate whether exenatide could be used to stimulate glucose clearance and insulin secretion in alpacas without causing colic signs, six healthy adult alpacas were injected once a day with increasing subcutaneous doses. A follow-up intravenous glucose injection was given to induce hyperglycemia, and serial blood samples were collected to measure plasma concentrations of glucose, insulin, triglycerides, beta-hydroxybutyrate, and nonesterified fatty acids. The exenatide doses used were saline control (no drug), and 0.02, 0.05, or 0.1 mcg/kg injected subcutaneously. Alpacas had significantly lower plasma glucose concentrations and higher insulin concentrations on all treatment days compared with the control day, but the increase in insulin was significantly greater and lasted significantly longer when the alpacas received the two higher dosages. Two of the alpacas developed mild colic signs at the 0.05 mcg/kg dose and were not evaluated at the highest dose. Based on these findings, the 0.05 mcg/kg dose appears to offer the greatest stimulation of insulin secretion and glucose clearance without excessive risk or severity of complications. PMID- 24479826 TI - Emerging drugs for cystic fibrosis. AB - INTRODUCTION: Cystic fibrosis is an autosomal recessive disease, which is the result of a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pulmonary disease accounts for over 90% of the morbidity and mortality associated with the disease. Conventionally, CF treatment has focused on symptomatic therapy. AREAS COVERED: In the past, the emphasis for the development of CF therapeutics has previously been on addressing complications of the manifestations rather than on the underlying disease process. However, in the past few decades there has been a paradigm shift with new attention on the underlying biological mechanisms and therapies targeted at curing the disease rather than simply controlling it. This review summarizes the current CF therapeutics pipeline. These developing therapies include CFTR gene therapy, CFTR pharmacotherapeutics, osmotically active agents and anti-inflammatory therapies, as well as novel inhaled antibiotics. EXPERT OPINION: The CF therapeutics pipeline currently holds great promise both for novel therapies directly targeting the underlying biological mechanisms of CFTR dysfunction and new symptomatic therapies. While CFTR-directed therapy has the highest potential to improve patients' outcome, it is important to continue to develop better treatment options for all aspects of CF lung disease. PMID- 24479827 TI - Flexibility and explicit solvent in molecular-dynamics-based docking of protein glycosaminoglycan systems. AB - We present Dynamic Molecular Docking (DMD), a novel targeted molecular dynamics based protocol developed to address ligand and receptor flexibility as well as the inclusion of explicit solvent in local molecular docking. A class of ligands for which docking performance especially benefits from overcoming these challenges is the glycosaminoglycans (GAGs). GAGs are periodic, highly flexible, and negatively charged polysaccharides playing an important role in the extracellular matrix via interaction with proteins such as growth factors and chemokines. The goal of our work has been to develop a proof of concept for an MD based docking approach and to analyze its applicability for protein-GAG systems. DMD exploits the electrostatics-driven attraction of a ligand to its receptor, treats both as entirely flexible, and considers solvent explicitly. We show that DMD has high predictive significance for systems dominated by electrostatic attraction and demonstrate its capability to reliably identify the receptor residues contributing most to binding. PMID- 24479829 TI - Does flexible goal adjustment predict life satisfaction in older adults? A six year longitudinal study. AB - OBJECTIVE: The aim of the present study was to investigate the relationship between flexible goal adjustment and life satisfaction (as an enduring component of subjective well-being) using six-year longitudinal data from a sample of older adults. METHODS: The study included 704 participants aged 63-97 years assessed four times over a six-year period. Simultaneous and lagged models were specified and estimated using structural equation modeling. RESULTS: Both simultaneous and lagged coefficients indicated that a high score on flexible goal adjustment significantly predicted subsequent levels of life satisfaction. CONCLUSION: In line with successful aging theory, our findings support the view that the ability to adjust personal goals flexibly is a central resource when unattainable goals are encountered and it contributes to well-being in old age. PMID- 24479830 TI - DNA polymerase preference determines PCR priming efficiency. AB - BACKGROUND: Polymerase chain reaction (PCR) is one of the most important developments in modern biotechnology. However, PCR is known to introduce biases, especially during multiplex reactions. Recent studies have implicated the DNA polymerase as the primary source of bias, particularly initiation of polymerization on the template strand. In our study, amplification from a synthetic library containing a 12 nucleotide random portion was used to provide an in-depth characterization of DNA polymerase priming bias. The synthetic library was amplified with three commercially available DNA polymerases using an anchored primer with a random 3' hexamer end. After normalization, the next generation sequencing (NGS) results of the amplified libraries were directly compared to the unamplified synthetic library. RESULTS: Here, high throughput sequencing was used to systematically demonstrate and characterize DNA polymerase priming bias. We demonstrate that certain sequence motifs are preferred over others as primers where the six nucleotide sequences at the 3' end of the primer, as well as the sequences four base pairs downstream of the priming site, may influence priming efficiencies. DNA polymerases in the same family from two different commercial vendors prefer similar motifs, while another commercially available enzyme from a different DNA polymerase family prefers different motifs. Furthermore, the preferred priming motifs are GC-rich. The DNA polymerase preference for certain sequence motifs was verified by amplification from single primer templates. We incorporated the observed DNA polymerase preference into a primer-design program that guides the placement of the primer to an optimal location on the template. CONCLUSIONS: DNA polymerase priming bias was characterized using a synthetic library amplification system and NGS. The characterization of DNA polymerase priming bias was then utilized to guide the primer-design process and demonstrate varying amplification efficiencies among three commercially available DNA polymerases. The results suggest that the interaction of the DNA polymerase with the primer:template junction during the initiation of DNA polymerization is very important in terms of overall amplification bias and has broader implications for both the primer design process and multiplex PCR. PMID- 24479831 TI - Serum concentrations of cytokines in infants with retinopathy of prematurity. AB - Retinopathy of prematurity (ROP) is the leading cause of blindness in preterm infants. In this study, we investigated the cytokine levels in cord blood of normal preterm neonates and preterm infants developed ROP. Serum levels of 10 cytokines in umbilical cord blood were measured by multiplex protein arrays from 62 healthy preterm neonates and 30 preterm neonate cases who developed ROP at later stage. Results showed that serum levels of cytokines including interleukin 7 (IL-7), monocyte chemotactic protein-1 (MCP-1), macrophage inflammatory protein 1 alpha (MIP-1alpha), and macrophage inflammatory protein 1 beta (MIP-1beta) were significantly increased in cases who developed ROP than in healthy preterm neonates (3.5-fold, 3.2-fold, 3.4-fold, and 2.1-fold, respectively), whereas levels of these four cytokines did not reveal any significant differences between healthy preterm infants and normal infants. When comparing the expression of cytokines in ROP patients with different clinical parameters, ROP cases whose gestational age at delivery earlier than 29.0 weeks demonstrated increased levels of MCP-1 and MIP-1beta than those later than 29.0 weeks (p < 0.05). Also, ROP cases with birth weight less than 1.28 kg revealed significantly higher level of MIP-1beta than those who were heavier than 1.28 kg (p < 0.05). These data indicated that levels of IL-7, MCP-1, MIP-1alpha, and MIP-1beta were associated with increased risk of ROP, in which MIP-1beta may be further correlated with the severity of ROP. PMID- 24479832 TI - Antinociceptive and anti-inflammatory effects of flavonoids PMT1 and PMT2 isolated from Piper montealegreanum Yuncker (Piperaceae) in mice. AB - In this study, we identified the antinociceptive and anti-inflammatory effects of two flavonoids (PMT1 and PMT2) from Piper montealegreanum. The antinociceptive effect was evaluated using the classical tests: acetic acid-induced writhing, formalin and hot plate test. PMT1 and PMT2 (0.1, 1, 30 and 100 MUmol/kg, i.p.) reduced the writhings, with an ID50 of 0.58 and 0.44 MUmol/kg, respectively. Moreover, these flavonoids (100 MUmol/kg, i.p.) inhibited paw-licking time in the neurogenic phase of the formalin test, but only PMT2 was active in the inflammatory phase. However, PMT1 and PMT2 (100 MUmol/kg, i.p.) did not increase the latency time of the animals in the hot plate. In order to evaluate the anti inflammatory effect of these flavonoids, capsaicin-induced ear oedema was carried out. Both flavonoids (100 MUmol/kg, i.p.) were active in this model. These results suggest that PMT1 and PMT2 have antinociceptive and anti-inflammatory activities. PMID- 24479833 TI - Miconazole nitrate bearing ultraflexible liposomes for the treatment of fungal infection. AB - Miconazole nitrate is a widely used antifungal agent, but its use in topical formulations is not efficacious because deep seated fungal infections are difficult to treat with conventional topical formulation. Miconazole nitrate loaded ultraflexible liposomes have been prepared and their topical performance has been compared with conventional liposomes containing miconazole nitrate. Various ultraflexible liposomal formulations were prepared and extensively characterized for vesicular shape, size, entrapment efficiency, degree of deformability and in-vitro skin permeation through rat skin. Higher rate of drug transfer across the skin with ultraflexible liposomal formulations of miconazole nitrate suggests that the drug in its lipo-solubilized state might have gained facilitated entry into the tough barrier consisting of subcutaneous. In-vivo study showed better antifungal activity as compared to traditional liposomes and plain drug solution. This was confirmed through fluoroscence microscopy. It is concluded that prepared ultraflexible liposomes can facilitate improved and localized drug action in the skin, thus providing a better option to deal with deep seated skin problems. PMID- 24479834 TI - New editorial leadership of the World Allergy Organization Journal. PMID- 24479835 TI - Rheumatoid arthritis: an autoimmune disease with female preponderance and cardiovascular risk equivalent to diabetes mellitus: role of cardiovascular magnetic resonance. AB - Rheumatoid arthritis (RA) is a systemic, inflammatory disease with female preponderance, characterized by severe articular and extraarticular manifestations. Cardiovascular (CV) disease in RA usually occurs a decade earlier than age- and sex-matched controls and patients with RA are twice more likely to develop myocardial infarction irrespective of age, history of prior CVD events and traditional CV risk factors. It has been shown that atherosclerotic CV disease in RA shares similarities with CV disease in diabetes mellitus (DM) in terms of clinical presentation and preclinical atherosclerosis. In addition to atherosclerosis, RA also increases risk of non-ischemic heart failure, valvular disease and myopericardial disease. Therefore, RA is considered at least a cardiovascular equivalent to diabetes mellitus. Cardiovascular magnetic resonance (CMR), a non-invasive, nonradiating technique, and due to its capability to perform tissue characterisation, can effectively identify CVdisease acuity and etiology during the course of RA. CMR, by using a combination of function evaluation, oedema-fibrosis detection and stress perfusion-fibrosis imaging can unveil myocarditis, cardiomyopathy, diffuse subendocardial vasculitis, coronary and peripheral artery disease in RA patients, who usually are oligo-asymptomatic. Additionally, CMR is the ideal technique for operator independent, reproducible diagnostic and follow up assessment. However, lack of availability, expertise and high cost still remain serious drawbacks of CMR. PMID- 24479836 TI - Monoclonal antibodies: a target therapy for multiple sclerosis. AB - Multiple sclerosis (MS) is a complex autoimmune disease of the central nervous system. It is characterized by a proinflammatory and neurodegenerative process that results in neuroaxonal damage. Over the last two decades, a wide range of immunomodulatory and immunosuppressive treatments have been used for the management of MS. Several treatments have been developed or are under evaluation for reducing relapses, disease progression and long-term MS-related disability. Recently, a growing interest has emerged for therapeutics with very selective actions, particularly monoclonal antibodies, to target several biological pathways involved in MS. To date, only Natalizumab (Tysabri((r))) has been approved for the treatment of active MS forms. Its therapeutic mechanism is the blockade of the a4-integrin molecule of many leukocytes, which leads to a decrease of immune cells migration, in particular of lymphocytes, across the blood-brain barrier. Furthermore, other promising molecules are under study in clinical trials. In this review, we summarize and discuss the history, pharmacodynamics and safety of monoclonal antibodies that have been approved or are under evaluation for the selective treatment of MS. PMID- 24479837 TI - An auxin-responsive endogenous peptide regulates root development in Arabidopsis. AB - Auxin plays critical roles in root formation and development. The components involved in this process, however, are not well understood. Here, we newly identified a peptide encoding gene, auxin-responsive endogenous polypeptide 1 (AREP1), which is induced by auxin, and mediates root development in Arabidopsis. Expression of AREP1 was specific to the cotyledon and to root and shoot meristem tissues. Amounts of AREP1 transcripts and AREP1-green fluorescent protein fusion proteins were elevated in response to indoleacetic acid treatment. Suppression of AREP1 through RNAi silencing resulted in reduction of primary root length, increase of lateral root number, and expansion of adventitious roots, compared to the observations in wild-type plants in the presence of auxin. By contrast, transgenic plants overexpressing AREP1 showed enhanced growth of the primary root under auxin treatment. Additionally, root morphology, including lateral root number and adventitious roots, differed greatly between transgenic and wild-type plants. Further analysis indicated that the expression of auxin-responsive genes, such as IAA3, IAA7, IAA17, GH3.2, GH3.3, and SAUR-AC1, was significantly higher in AREP1 RNAi plants, and was slightly lower in AREP1 overexpressing plants than in wild-type plants. These results suggest that the novel endogenous peptide AREP1 plays an important role in the process of auxin-mediated root development. PMID- 24479838 TI - Palladium-catalyzed double alkylation of 3-aryl-2-fluoroallyl esters with malonate nucleophiles through the carbon-fluorine bond cleavage. AB - The alkylation of (Z)-3-aryl-2-fluoroallyl acetate with the malonate anion by the [Pd(C3H5)(cod)]BF4/2,2'-bpy catalyst proceeds through the carbon-fluorine bond cleavage, and 2 equiv of the malonate nucleophile was introduced to the allyl substrate. PMID- 24479839 TI - The influence of the initiation of an exercise programme on seroma formation and dehiscence following breast cancer surgery. AB - AIMS AND OBJECTIVES: To verify whether early (first post-operative day) or late initiation (after removal of the continuous suction drain) of a functional rehabilitation exercise programme influences the incidence of seroma formation and dehiscence for women after breast cancer surgery. BACKGROUND: Benefits of early implementation of an exercise programme initiated with women in the first days following breast cancer surgery are widely known. However, the safe initiation of the exercises is still a controversial issue and some authors correlate early initiation of the exercises with an increase in seroma formation. DESIGN: A prospective, randomised, controlled clinical trial. METHODS: Seventy seven women were randomly assigned to initiate the programme on post-operative day 1 (early group = 40) or after removal of the drain (late group = 37) and were monitored until the 45th post-operative day. Patients in the early group were instructed to perform the exercises daily at home, beginning on post-operative day 1, while those of the late group began the exercises after the drain was removed. The assessment for seroma formation and dehiscence was performed on post operative days 7 and 45. RESULTS: There was no statistically significant difference regard to seroma formation between early group and late group. Also there was no association between the presence of dehiscence and early exercises. CONCLUSION: The early initiation of the exercises for women, following breast cancer surgery, constitutes a safe practice for the rehabilitation. However, these findings need to be further explored and confirmed in a larger sample. RELEVANCE TO CLINICAL PRACTICE: Studies showing evidence that early functional rehabilitation process is a safe practice for women having surgery for breast cancer, as well as the present research, are of interest to health professionals who care for these patients and contribute to the wider global clinical community. PMID- 24479840 TI - Synthetic control of retinal photochemistry and photophysics in solution. AB - Understanding how molecular structure and environment control energy flow in molecules is a requirement for the efficient design of tailor-made photochemistry. Here, we investigate the tunability of the photochemical and photophysical properties of the retinal-protonated Schiff base chromophore in solution. Replacing the n-butylamine Schiff base normally chosen to mimic the saturated linkage found in nature by aromatic amines results in the reproduction of the opsin shift and complete suppression of all isomerization channels. Modification of retinal by directed addition or removal of backbone substituents tunes the overall photoisomerization yield from 0 to 0.55 and the excited state lifetime from 0.4 to 7 ps and activates previously inaccessible reaction channels to form 7-cis and 13-cis products. We observed a clear correlation between the presence of polarizable backbone substituents and photochemical reactivity. Structural changes that increase reaction speed were found to decrease quantum yields, and vice versa, so that excited state lifetime and efficiency are inversely correlated in contrast to the trends observed when comparing retinal photochemistry in protein and solution environments. Our results suggest a simple model where backbone modifications and Schiff base substituents control barrier heights on the excited-state potential energy surface and therefore determine speed, product distribution, and overall yield of the photochemical process. PMID- 24479841 TI - Developing renal nurses' buttonhole cannulation skills using e-learning. AB - BACKGROUND: It has previously been shown that nurses can learn clinical nursing skills by e-learning (online), and that many variables will influence how well nurses adopt learned clinical skills using distance education. OBJECTIVES: This study aimed to identify and measure the strength of those factors which would simultaneously influence registered nurses' (RNs') beliefs about their own learning about buttonhole cannulation, using e-learning. DESIGN: An online Likert style survey consisting of a list of statements related to knowledge and skill domains considered crucial in the area of buttonhole cannulation was distributed to 101 RNs before and after completing an e-learning programme. Participants were required to identify their current level of self-confidence in relationship to each of the statements. MEASUREMENTS: Measures of RNs' self-rated abilities to assess and implement buttonhole cannulation after completing a related e-learning program were tested using a Partial Least Squares Analysis (PLS-PATH) programme. RESULTS: The study's results strongly identify that the nurses' ability to meet both clinical and educational outcomes of the renal e-learning module can be predicted by six variables, none of which are directly related to the participants' demographic or clinical backgrounds. CONCLUSION: These findings support the use of e-learning to teach clinical skills to RNs, and demonstrate the value of Partial Least Squares Analysis in determining influential learning factors. PMID- 24479842 TI - Methylene blue is neuroprotective against mild traumatic brain injury. AB - Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Methylene blue (MB) has known energy-enhancing and antioxidant properties. This study tested the hypothesis that MB treatment reduces lesion volume and behavioral deficits in a rat model of mild TBI. In a randomized double blinded design, animals received either MB (n=5) or vehicle (n=6) after TBI. Studies were performed on 0, 1, 2, 7, and 14 days following an impact to the primary forelimb somatosensory cortex. MRI lesion was not apparent 1 h after TBI, became apparent 3 h after TBI, and peaked at 2 days for both groups. The MB treated animals showed significantly smaller MRI lesion volume than the vehicle treated animals at all time points studied. The MB-treated animals exhibited significantly improved scores on forelimb placement asymmetry and foot fault tests than did the vehicle-treated animals at all time points studied. Smaller numbers of dark-stained Nissl cells and Fluoro-Jade((r)) positive cells were observed in the MB-treated group than in vehicle-treated animals 14 days post TBI. In conclusion, MB treatment minimized lesion volume, behavioral deficits, and neuronal degeneration following mild TBI. MB is already approved by the United States Food and Drug Administration (FDA) to treat a number of indications, likely expediting future clinical trials in TBI. PMID- 24479843 TI - Quantitative structure-property relationship modeling: a valuable support in high throughput screening quality control. AB - Evaluation of important pharmacokinetic properties such as hydrophobicity by high throughput screening (HTS) methods is a major issue in drug discovery. In this paper, we present measurements of the chromatographic hydrophobicity index (CHI) on a subset of the French chemical library Chimiotheque Nationale (CN). The data were used in quantitative structure-property relationship (QSPR) modeling in order to annotate the CN. An algorithm is proposed to detect problematic molecules with large prediction errors, called outliers. In order to find an explanation for these large discrepancies between predicted and experimental values, these compounds were reanalyzed experimentally. As the first selected outliers indeed had experimental problems, including hydrolysis or sheer absence of expected structure, we herewith propose the use of QSPR as a support tool for quality control of screening data and encourage cooperation between experimental and theoretical teams to improve results. The corrected data were used to produce a model, which is freely available on our web server at http://infochim.u strasbg.fr/webserv/VSEngine.html . PMID- 24479844 TI - Evaluation of Swiss slaughterhouse data for integration in a syndromic surveillance system. AB - BACKGROUND: We evaluated Swiss slaughterhouse data for integration in a national syndromic surveillance system for the early detection of emerging diseases in production animals. We analysed meat inspection data for cattle, pigs and small ruminants slaughtered between 2007 and 2012 (including emergency slaughters of sick/injured animals); investigating patterns in the number of animals slaughtered and condemned; the reasons invoked for whole carcass condemnations; reporting biases and regional effects. RESULTS: Whole carcass condemnation rates were fairly uniform (1-20/00) over time and between the different types of production animals. Condemnation rates were much higher and less uniform following emergency slaughters. The number of condemnations peaked in December for both cattle and pigs, a time when individuals of lower quality are sent to slaughter when hay and food are limited and when certain diseases are more prevalent. Each type of production animal was associated with a different profile of condemnation reasons. The most commonly reported one was "severe lesions" for cattle, "abscesses" for pigs and "pronounced weight loss" for small ruminants. These reasons could constitute valuable syndromic indicators as they are unspecific clinical manifestations of a large range of animal diseases (as well as potential indicators of animal welfare). Differences were detected in the rate of carcass condemnation between cantons and between large and small slaughterhouses. A large percentage (>60% for all three animal categories) of slaughterhouses operating never reported a condemnation between 2007 and 2012, a potential indicator of widespread non-reporting bias in our database. CONCLUSIONS: The current system offers simultaneous coverage of cattle, pigs and small ruminants for the whole of Switzerland; and traceability of each condemnation to its farm of origin. The number of condemnations was significantly linked to the number of slaughters, meaning that the former should be always be offset by the later in analyses. Because this denominator is only communicated at the end of the month, condemnations may currently only be monitored on a monthly basis. Coupled with the lack of timeliness (30-60 days delay between condemnation and notification), this limits the use of the data for early-detection. PMID- 24479846 TI - Area of ischemia assessed by physicians and software packages from myocardial perfusion scintigrams. AB - BACKGROUND: The European Society of Cardiology recommends that patients with >10% area of ischemia should receive revascularization. We investigated inter-observer variability for the extent of ischemic defects reported by different physicians and by different software tools, and if inter-observer variability was reduced when the physicians were provided with a computerized suggestion of the defects. METHODS: Twenty-five myocardial perfusion single photon emission computed tomography (SPECT) patients who were regarded as ischemic according to the final report were included. Eleven physicians in nuclear medicine delineated the extent of the ischemic defects. After at least two weeks, they delineated the defects again, and were this time provided a suggestion of the defect delineation by EXINI HeartTM (EXINI). Summed difference scores and ischemic extent values were obtained from four software programs. RESULTS: The median extent values obtained from the 11 physicians varied between 8% and 34%, and between 9% and 16% for the software programs. For all 25 patients, mean extent obtained from EXINI was 17.0% (+/- standard deviation (SD) 14.6%). Mean extent for physicians was 22.6% (+/- 15.6%) for the first delineation and 19.1% (+/- 14.9%) for the evaluation where they were provided computerized suggestion. Intra-class correlation (ICC) increased from 0.56 (95% confidence interval (CI) 0.41-0.72) to 0.81 (95% CI 0.71 0.90) between the first and the second delineation, and SD between physicians were 7.8 (first) and 5.9 (second delineation). CONCLUSIONS: There was large variability in the estimated ischemic defect size obtained both from different physicians and from different software packages. When the physicians were provided with a suggested delineation, the inter-observer variability decreased significantly. PMID- 24479847 TI - Synthesis and structure-activity relationship studies of N-terminal analogues of the antimicrobial peptide tridecaptin A(1). AB - Chemical synthesis was used to increase the potency of the antimicrobial lipopeptide tridecaptin A1. Lipid tail modification proved to be an ideal platform for synthesizing structurally simpler analogues that are not readily accessible by isolation. The stereochemical elements of the tridecaptin A1 lipid tail are not essential for antimicrobial activity and could be replaced with hydrophobic aliphatic or aromatic groups. Some simpler analogues displayed potent antimicrobial activity against Gram-negative bacteria, including Campylobacter jejuni, Escherichia coli O157:H7, and multidrug resistant Klebsiella pneumoniae. PMID- 24479848 TI - ESCMID and ECMM joint clinical guidelines for the diagnosis and management of mucormycosis 2013. AB - These European Society for Clinical Microbiology and Infectious Diseases and European Confederation of Medical Mycology Joint Clinical Guidelines focus on the diagnosis and management of mucormycosis. Only a few of the numerous recommendations can be summarized here. To diagnose mucormycosis, direct microscopy preferably using optical brighteners, histopathology and culture are strongly recommended. Pathogen identification to species level by molecular methods and susceptibility testing are strongly recommended to establish epidemiological knowledge. The recommendation for guiding treatment based on MICs is supported only marginally. Imaging is strongly recommended to determine the extent of disease. To differentiate mucormycosis from aspergillosis in haematological malignancy and stem cell transplantation recipients, identification of the reverse halo sign on computed tomography is advised with moderate strength. For adults and children we strongly recommend surgical debridement in addition to immediate first-line antifungal treatment with liposomal or lipid-complex amphotericin B with a minimum dose of 5 mg/kg/day. Amphotericin B deoxycholate is better avoided because of severe adverse effects. For salvage treatment we strongly recommend posaconazole 4*200 mg/day. Reversal of predisposing conditions is strongly recommended, i.e. using granulocyte colony stimulating factor in haematological patients with ongoing neutropenia, controlling hyperglycaemia and ketoacidosis in diabetic patients, and limiting glucocorticosteroids to the minimum dose required. We recommend against using deferasirox in haematological patients outside clinical trials, and marginally support a recommendation for deferasirox in diabetic patients. Hyperbaric oxygen is supported with marginal strength only. Finally, we strongly recommend continuing treatment until complete response demonstrated on imaging and permanent reversal of predisposing factors. PMID- 24479849 TI - PPARgamma and NAD(P)H oxidase system interaction in glycerol-induced acute renal failure: role of gp91phox subunit of NAD(P)H oxidase. AB - Increased NAD(P)H oxidase-dependent free radical generation has been proposed to be a mechanism in glycerol-induced acute renal failure (ARF). Previously, we showed a PPARgamma-mediated regulation of free radical generation in ARF. In this study, we examined NAD(P)H oxidase-dependent pathology in ARF and its connection with PPARgamma using both Sprague-Dawley rats and gp91phox (+/-) mice. Male gp91phox (+/-) or wild type (+/+) mice were distributed into vehicle and ARF group (50% glycerol; 8 mL/kg bw; i.m.). Animals were placed in metabolic cages for 24 hr and were sacrificed under pentobarbital anesthesia. Urine, plasma and kidneys were processed for biochemical and molecular analysis. Glycerol doubled proteinuria in (+/+) mice (68 +/- 4 mg/24 hr) but not in (+/-) mice (43 +/- 9 mg/24 hr). This was associated with a markedly reduced creatinine excretion in (+/+) mice (Con: 0.6 +/- 0.03 & ARF: 0.37 +/- 0.02). Basal plasma and urinary NO was higher in (+/-) mice than the (+/+) type while plasma 8-isoprostane level was lower in (+/-) mice (WT: 165 +/- 20; KO: 100 +/- 15 pg/mL). Glycerol reduced UNOXV in both (+/+) and (+/-) mice although plasma NO was unchanged. Glycerol also doubled 8-isoprostane in (+/+) (363 +/- 22 pg/mL) but not in (+/-) mice (152 +/- 20 pg/mL) and this was associated with an increased NAD(P)H oxidase activity in the (+/+) mice. In ARF, PPARgamma expression was reduced in (+/+) mice but increased in (+/-) mice. PPARgamma activity was also reduced in (+/+) mice but was unchanged in (+/-) mice. We conclude that gp91phox contributes to NAD(P)H oxidase-mediated increased free radical generation in ARF and this may be via reduced PPARgamma. PMID- 24479850 TI - In vitro metabolism of testosterone in the horse liver and involvement of equine CYPs 3A89, 3A94 and 3A95. AB - Testosterone (TES) 6-beta-hydroxylation is a significant metabolic step in the biotransformation of TES in human liver microsomes and reflects cytochrome P450 (CYP) 3A4/5 specific metabolic activity. Several CYP3A enzymes have been annotated in the horse genome, but functional characterization is missing. This descriptive study investigates TES metabolism in the horse liver in vitro and the qualitative contribution of three CYP3A isoforms of the horse. Metabolism of TES was investigated by using equine hepatocyte primary cultures and liver microsomes. Chemical inhibitors were used to determine the CYPs involved in TES biotransformation in equine microsomes. Single CYPs 3A89, 3A94, and 3A95, recombinantly expressed in V79 hamster lung fibroblasts, were incubated with TES and the fluorescent metabolite 7-benzyloxy-4-trifluoromethylcoumarin (BFC). The effect of ketoconazole and troleandomycin was evaluated on single CYPs. Testosterone metabolites were analyzed by HPLC and confirmed by GC/MS. In hepatocyte primary cultures, the most abundant metabolite was androstenedione (AS), whereas in liver microsomes, 6-beta-hydroxytestosterone showed the largest peak. Formation of 6-beta-hydroxytestosterone and 11-beta-hydroxytestosterone in liver microsomes was inhibited by ketoconazole, troleandomycin, and quercetin. Equine recombinant CYP3A95 catalyzed 11-beta-hydroxylation of testosterone (TES). Metabolism of BFC was significantly inhibited by ketoconazole in CYP3A95, whereas troleandomycin affected the activities of CYP3A94 and CYP3A95. Both inhibitors had no significant effect on CYP3A89. Metabolic reactions and effects of inhibitors differed between the equine CYP3A isoforms investigated. This has to be considered in future in vitro studies. PMID- 24479852 TI - Lacosamide for the treatment of epilepsy. AB - INTRODUCTION: Epilepsy is one of the most common neurological disorders. Despite the development of new antiepileptic drugs (AEDs), ~ 30% of epilepsy patients experience recurrent seizures and even more experience side effects. Therefore, there is still need for new AEDs with enhanced effectiveness and tolerability. AREAS COVERED: The article is based on a search using PubMed, including articles published between 1999 and 2013. It is focused on the pharmacokinetic, pharmacological and clinical data of lacosamide (LCM) for the treatment of epilepsy. EXPERT OPINION: Along with favorable tolerability and pharmacokinetic profiles, LCM has been demonstrated to significantly reduce seizure frequency in patients with partial-onset seizures when prescribed as adjunctive treatment at doses of 200 and 400 mg/day. LCM has a unique mechanism of action, selectively enhancing slow inactivation of voltage-gated sodium channels. Its mechanism of action could be exploited to reduce the percentage of pharmacoresistant patients. Although LCM is not FDA approved for treatment of status epilepticus, it has demonstrated promising preliminary results. Large prospective studies are needed to verify these. In addition, the results of ongoing trials will help to confirm if LCM could be used as a monotherapy regimen in the treatment of partial-onset seizures and generalized tonic-clonic seizures. PMID- 24479853 TI - Leisure education reduces stress among older adults. AB - OBJECTIVES: The objectives of this study were to examine whether a leisure education program could facilitate leisure competence among older adults and whether it could also reduce their stress. METHODS: A pre-test-post-test randomized experimental design was conducted. Subjects were randomly assigned to either an experimental group (n = 30) or a control group (n = 30). A leisure education program was used to serve as the intervention. A day before this experiment was carried out, pre-test data were collected using leisure competence and stress scales. Thirty minutes after this experiment ended, post-test data were collected using the same scales. These data were analyzed using an analysis of covariance. RESULTS: The results indicated that the average post-test scores of leisure competence in the experimental group were significantly higher than those in the control group and that the average post-test scores of stress in the experimental group were significantly lower than those in the control group. CONCLUSION: Healthcare practitioners should adopt the provision of leisure education as a priority to facilitate leisure competence and reduce stress among older adults. PMID- 24479854 TI - Differential immunostaining of various types of breast carcinomas for growth hormone-releasing hormone receptor - Apocrine epithelium and carcinomas emerging as uniformly positive. AB - Different classes of breast cancers were explored for their positivity for growth hormone-releasing hormone receptors (GHRH-R) in this pilot study, as no systematic evaluation of such tumors has been performed to date. Seventy-two small primary breast carcinomas were evaluated for GHRH-R expression by immunohistochemistry using a polyclonal antibody and a cutoff value of 10% staining. GHRH-R positivity was detected in 58% of all cases, 20/23 (87%) of invasive lobular carcinomas (ILC) and 22/46 (48%) of invasive ductal carcinomas (IDC). GHRH-R positivity was more frequent in grade 2 tumors (86%), as compared to grade 1 (18%) or grade 3 (47%) cancers. GHRH-R expression was not associated with mitotic scores, the Ki-67 labeling indices or nodal status. IDCs with casting-type calcifications on the mammogram showed positivity for GHRH-R in 9/12 (75%) cases. Most importantly, apocrine epithelium, and all 10 apocrine carcinomas added later to the study were GHRH-R-positive. These preliminary results suggest a greater than average GHRH-R expression in ILCs and IDCs associated with casting-type calcifications on the mammogram. Apocrine carcinomas seem uniformly positive for GHRH-R. Whether these findings could indicate a potential role of GHRH-antagonists in targeted treatment of these types of breast cancer requires further studies. PMID- 24479855 TI - Structural and kinetic studies on adenylosuccinate lyase from Mycobacterium smegmatis and Mycobacterium tuberculosis provide new insights on the catalytic residues of the enzyme. AB - Adenylosuccinate lyase (ASL), an enzyme involved in purine biosynthesis, has been recognized as a drug target against microbial infections. In the present study, ASL from Mycobacterium smegmatis (MsASL) and Mycobacterium tuberculosis (MtbASL) were cloned, purified and crystallized. The X-ray crystal structure of MsASL was determined at a resolution of 2.16 A. It is the first report of an apo-ASL structure with a partially ordered active site C3 loop. Diffracting crystals of MtbASL could not be obtained and a model for its structure was derived using MsASL as a template. These structures suggest that His149 and either Lys285 or Ser279 of MsASL are the residues most likely to function as the catalytic acid and base, respectively. Most of the active site residues were found to be conserved, with the exception of Ser148 and Gly319 of MsASL. Ser148 is structurally equivalent to a threonine in most other ASLs. Gly319 is replaced by an arginine residue in most ASLs. The two enzymes were catalytically much less active compared to ASLs from other organisms. Arg319Gly substitution and reduced flexibility of the C3 loop might account for the low catalytic activity of mycobacterial ASLs. The low activity is consistent with the slow growth rate of Mycobacteria and their high GC containing genomes, as well as their dependence on other salvage pathways for the supply of purine nucleotides. STRUCTURED DIGITAL ABSTRACT: purB and purB bind by x-ray crystallography (View interaction). PMID- 24479856 TI - Phase transfer of noble metal nanoparticles to organic solvents. AB - Nanoparticles are finding increasing application because of their unusual optical properties. Processing these materials would be drastically simplified if they could be routinely dispersed into a wide variety of polar and nonpolar solvents. We report the synthesis of a new bidentate thiol ligand, (Z)-octadec-9-en-1-yl-5 (1,2-dithiolan-3-yl)pentanoate, and demonstrate its ability to phase transfer gold nanospheres (5-70 nm), nanorods, and silver nanoparticles efficiently from water into various organic solvents. The protocol obviates the need for solid phase steps or polymeric ligands. Electronic spectra and electron micrographs demonstrate that the particles are fully dispersed in a variety of organic solvents after transfer. PMID- 24479859 TI - Reliability of ultrasound measurement of automatic activity of the abdominal muscle in participants with and without chronic low back pain. AB - BACKGROUND: Ultrasound (US) imaging has been considered as a non-invasive technique to measure thickness and estimate relative abdominal muscle activity. Although some studies have assessed the reliability of US imaging, no study has assessed the reliability of US measurement of automatic activity of abdominal muscles in positions with different levels of stability in participants with chronic low back pain (cLBP). The purpose of this study was to investigate within day and between-days reliability of US thickness measurements of automatic activity of the abdominal muscles in asymptomatic participants and within-day reliability in those with cLBP. METHODS: A total of 20 participants (10 with cLBP, 10 healthy) participated in the study. The reliability of US thickness measurements at supine lying and sitting positions (sitting on a chair, sitting on a gym ball with both feet on the ground or lifting one foot off the floor) were assessed. We evaluated within-day reliability in all participants and between-days reliability in asymptomatic participants. RESULTS: We found high ICC scores (0.85-0.95) and also small SEM and MDC scores in both groups. The reliability of the measurements was comparable between participants with and without LBP in each position but the SEMs and MDCs was slightly higher in patient group compared with healthy group. It indicates high intra-tester reliability for the US measurement of the thickness of abdominal muscles in all positions. CONCLUSION: US imaging can be used as a reliable method for assessment of automatic activity of abdominal muscles in positions with low levels of stability in participants with and without LBP. PMID- 24479858 TI - Nucleic acid test to diagnose cryptosporidiosis: lab assessment in animal and patient specimens. AB - Diarrheal diseases cause more morbidity and mortality around the world than human immunodeficiency virus (HIV), malaria, or tuberculosis. Given that effective treatment of persistent diarrheal illness requires knowledge of the causative organism, diagnostic tests are of paramount importance. The protozoan parasites of the genus Cryptosporidium are increasingly recognized to be responsible for a significant portion of diarrhea morbidity. We present a novel nucleic acid test to detect the presence of Cryptosporidium species in DNA extracted from stool samples. The assay uses the isothermal amplification technique recombinase polymerase amplification (RPA) to amplify trace amounts of pathogen DNA extracted from stool to detectable levels in 30 min; products are then detected visually on simple lateral flow strips. The RPA-based Cryptosporidium assay (RPAC assay) was developed and optimized using DNA from human stool samples spiked with pathogen. It was then tested using DNA extracted from the stool of infected mice where it correctly identified the presence or absence of 27 out of 28 stool samples. It was finally tested using DNA extracted from the stool of infected patients where it correctly identified the presence or absence of 21 out of 21 stool samples. The assay was integrated into a foldable, paper and plastic device that enables DNA amplification with only the use of pipets, pipet tips, and a heater. The performance of the integrated assay is comparable to or better than polymerase chain reaction (PCR), without requiring the use of thermal cycling equipment. This platform can easily be adapted to detect DNA from multiple pathogens. PMID- 24479860 TI - 1,2,4-triazine analogs as novel class of therapeutic agents. AB - 1,2,4-Triazine nucleus is a prominent structural core system present in numerous pharmacologically active compounds. Till date, various 1,2,4-triazine analogs, possesing a wide range of potent pharmacological activities, have been reported. This review is an attempt to compile the medicinal chemistry aspects of various synthesized 1,2,4-triazine analogs reported so far. PMID- 24479861 TI - Cancer survival for Aboriginal and Torres Strait Islander Australians: a national study of survival rates and excess mortality. AB - BACKGROUND: National cancer survival statistics are available for the total Australian population but not Indigenous Australians, although their cancer mortality rates are known to be higher than those of other Australians. We aimed to validate analysis methods and report cancer survival rates for Indigenous Australians as the basis for regular national reporting. METHODS: We used national cancer registrations data to calculate all-cancer and site-specific relative survival for Indigenous Australians (compared with non-Indigenous Australians) diagnosed in 2001-2005. Because of limited availability of Indigenous life tables, we validated and used cause-specific survival (rather than relative survival) for proportional hazards regression to analyze time trends and regional variation in all-cancer survival between 1991 and 2005. RESULTS: Survival was lower for Indigenous than non-Indigenous Australians for all cancers combined and for many cancer sites. The excess mortality of Indigenous people with cancer was restricted to the first three years after diagnosis, and greatest in the first year. Survival was lower for rural and remote than urban residents; this disparity was much greater for Indigenous people. Survival improved between 1991 and 2005 for non-Indigenous people (mortality decreased by 28%), but to a much lesser extent for Indigenous people (11%) and only for those in remote areas; cancer survival did not improve for urban Indigenous residents. CONCLUSIONS: Cancer survival is lower for Indigenous than other Australians, for all cancers combined and many individual cancer sites, although more accurate recording of Indigenous status by cancer registers is required before the extent of this disadvantage can be known with certainty. Cancer care for Indigenous Australians needs to be considerably improved; cancer diagnosis, treatment, and support services need to be redesigned specifically to be accessible and acceptable to Indigenous people. PMID- 24479862 TI - Neonatal invasive fungal infection in England 2004-2010. AB - Rates of invasive fungal infection are highest among neonates, especially those of low birthweight. This study aimed to describe the current epidemiology of invasive neonatal fungal infections in a UK neonatal infection surveillance network. From 2004 to 2010 prospective multicentre surveillance was conducted by 14 neonatal units using a web-based database. Clinicians then completed a standardized pro forma for each positive fungal blood and/or cerebrospinal fluid culture. The overall incidence was 2.4/1000 neonatal unit admissions and was highest among babies <1000 g (extreme low birthweight, 18.8/1000). Only five infants (6%) were >1500 g. The majority of infections were caused by Candida albicans (59; 69%) and Candida parapsilosis (17; 20%); 33% of infants had received antifungal prophylaxis. Known risk factors (use of central venous catheter, parenteral nutrition, previous antibiotic use) were common among cases. The attributable case fatality rate was 21% (18/84). Extreme low birthweight infants remain at highest risk of invasive fungal infection and prophylaxis should be particularly considered for this group. The number needing to receive prophylaxis to prevent one case varies significantly among units, hence unit specific decisions are required. Further research is still needed into the optimal empiric and therapeutic strategies. PMID- 24479863 TI - Concise synthesis of didebromohamacanthin A and demethylaplysinopsine: addition of ethylenediamine and guanidine derivatives to the pyrrole-amino acid diketopiperazines in oxidative conditions. AB - Oxidative nucleophilic addition of ethylenediamine and guanidine derivatives to pyrrole-amino acid diketopiperazines was shown to provide substituted 5,6-dihydro 2(1H)-piperazinones, quinoxalinones, and 2-aminoimidazolones. On the basis of this methodology, a concise approach to natural products didebromohamacanthin A and demethylaplysinopsine has been demonstrated. PMID- 24479865 TI - Illegal performance enhancing drugs and doping in sport: a picture-based brief implicit association test for measuring athletes' attitudes. AB - BACKGROUND: Doping attitude is a key variable in predicting athletes' intention to use forbidden performance enhancing drugs. Indirect reaction-time based attitude tests, such as the implicit association test, conceal the ultimate goal of measurement from the participant better than questionnaires. Indirect tests are especially useful when socially sensitive constructs such as attitudes towards doping need to be described. The present study serves the development and validation of a novel picture-based brief implicit association test (BIAT) for testing athletes' attitudes towards doping in sport. It shall provide the basis for a transnationally compatible research instrument able to harmonize anti doping research efforts. METHOD: Following a known-group differences validation strategy, the doping attitudes of 43 athletes from bodybuilding (representative for a highly doping prone sport) and handball (as a contrast group) were compared using the picture-based doping-BIAT. The Performance Enhancement Attitude Scale (PEAS) was employed as a corresponding direct measure in order to additionally validate the results. RESULTS: As expected, in the group of bodybuilders, indirectly measured doping attitudes as tested with the picture-based doping-BIAT were significantly less negative (eta2 = .11). The doping-BIAT and PEAS scores correlated significantly at r = .50 for bodybuilders, and not significantly at r = .36 for handball players. There was a low error rate (7%) and a satisfactory internal consistency (rtt = .66) for the picture-based doping-BIAT. CONCLUSIONS: The picture-based doping-BIAT constitutes a psychometrically tested method, ready to be adopted by the international research community. The test can be administered via the internet. All test material is available "open source". The test might be implemented, for example, as a new effect-measure in the evaluation of prevention programs. PMID- 24479868 TI - A game of thrones: neural plasticity in mammalian social hierarchies. AB - Social status is a key regulator of health and reproduction in mammals, including humans. Despite this, relatively little is known about how social status influences the mammalian brain. Furthermore, the extent to which status is an independent construct, i.e., not simply acting as a psychosocial stressor, is yet to be determined. Research to date reveals several promising mechanisms and/or systems associated with social status, including monoamine systems, hypothalamic neuroendocrine axes, and the hippocampus, though whether these differences are the cause or effect of status is often unclear. We review these candidates and propose how best to approach this research question in the future. PMID- 24479864 TI - Paediatric head injuries treated in a children's emergency department from Cluj Napoca, Romania. AB - The aim of the study was to describe paediatric head injuries and identify factors that led to advanced care. Incident cases of head injuries that sought care from December 2008 to October 2010 at Children's Emergency Hospital Cluj Napoca were evaluated. The main outcome was transfer or admission to advanced care. From a total of 3053 children treated for an injury, 1541 (50.4%) presented with head injury. A total of 960 (62.3%) of the children with a head injury required advanced care treatment. Young children were more likely to suffer a head injury than older children, but a higher proportion of older children required advanced care (70.3%). Children who suffered a head injury as a consequence of road traffic were almost five times more likely to require advanced care (OR: 4.97; 3.09-8.06) than being released. Our results suggest that data on injuries provide evidence-based information on the nature of injuries children are prone to, and what activity, type, and mechanism of injury impact Romanian children. PMID- 24479869 TI - Altered aquaporin expression in glaucoma eyes. AB - Aquaporins (AQP) are channels in the cell membrane that mainly facilitate a passive transport of water. In the eye, AQPs are expressed in the ciliary body and retina and may contribute to the pathogenesis of glaucoma and optic neuropathy. We investigated the expression of AQP1, AQP3, AQP4, AQP5, AQP7 and AQP9 in human glaucoma eyes compared with normal eyes. Nine glaucoma eyes were examined. Of these, three eyes were diagnosed with primary open angle glaucoma; three eyes had neovascular glaucoma; and three eyes had chronic angle-closure glaucoma. Six eyes with normal intraocular pressure and without glaucoma were used as control. Immunohistochemistry was performed using antibodies against AQP1, AQP3, AQP4, AQP5, AQP7 and AQP9. For each specimen, optical densities of immunoprecipitates were measured using Photoshop and the staining intensities were calculated. Immunostaining showed labelling of AQP7 and AQP9 in the nonpigmented ciliary epithelium and the staining intensities were significantly decreased in glaucoma eyes (p = 0.003; p = 0.018). AQP7 expression in the Muller cell endfeet was increased (p = 0.046), and AQP9 labelling of the retinal ganglion cells (RGC) showed decreased intensity (p = 0.037). No difference in AQP1, AQP4 and AQP9 expression was found in the optic nerve fibres. This study is the first investigating AQPs in human glaucoma eyes. We found a reduced expression of AQP9 in the retinal ganglion cells of glaucoma eyes. Glaucoma also induced increased AQP7 expression in the Muller cell endfeet. In the ciliary body of glaucoma eyes, the expression of AQP7 and AQP9 was reduced. Therefore, the expression of AQPs seems to play a role in glaucoma. PMID- 24479866 TI - Type II diabetes and impaired glucose tolerance due to severe hyperinsulinism in patients with 1p36 deletion syndrome and a Prader-Willi-like phenotype. AB - BACKGROUND: Deletion of the subtelomeric region of 1p36 is one of the most common subtelomeric deletion syndromes. In monosomy 1p36, the presence of obesity is poorly defined, and glucose metabolism deficiency is rarely reported. However, the presence of a typical Prader-Willi-like phenotype in patients with monosomy 1p36 is controversial. CASE PRESENTATION: In this report, we describe two female patients, one who is 6 years 2 months of age and another who is 10 years 1 month of age, both referred to our hospital for obesity and a Prader-Willi-like phenotype. These patients presented with severe obesity (body mass index [BMI] was 26.4 and 27.7, respectively), hyperphagia and developmental delay. Analysis of basal hormone levels showed normal thyroid function and adrenal function but considerable basal hyperinsulinism (the insulin levels were 54.5 and 49.2 MUU/ml, respectively). In patient 1, glycaemia was 75 mg/dl (HOMA-R 10.09), and the HbA1c level was 6.1%; in patient 2, glycaemia was 122 mg/dl, and the HbA1c level was 6.6% (HOMA-R 14.82). An oral glucose tolerance test demonstrated impaired glucose tolerance and diabetes mellitus with marked insulin resistance (the peak insulin level for each patient was 197 and 279 MUU/mL, respectively, while the 120' insulin level of each patient was 167 and 234 MUU/mL, respectively). CONCLUSION: some patients with monosomy 1p36 may show Prader-Willi-like physical and physiologic characteristics such as obesity and hyperinsulinism with impaired glucose metabolism, which can cause type II diabetes mellitus. Further studies are necessary to evaluate these findings. PMID- 24479870 TI - Clinical role of the nurse: concept analysis. AB - AIMS AND OBJECTIVES: To identify the attributes of the concept 'clinical role of the nurse' in the literature. BACKGROUND: The concept of nurses' clinical role is frequently mentioned in literature, but hardly explored in conceptual terms. This has implications for nursing practice and education. DESIGN: Qualitative and descriptive study, which corresponds to the first phase in the concept development of the qualitative concept analysis method - identification of concept attributes. METHODS: The critical literature analysis method was used to identify the antecedents, defining attributes and consequences of the nurse's clinical role. A systematic literature search was undertaken in International Literature in Health Sciences, Cumulative Index to Nursing and Allied Health Literature and Latin American and Caribbean Health Sciences. RESULTS: The clinical role was shown to be a process of complex interaction between nurse and patient, with critical thinking, informed experience and a sense of clinical autonomy as its antecedents. Consequences of nurses' clinical role include transformations in the organisation and process of nursing practice. A theoretical proposal was elaborated for the concept of the clinical role of the nurse, identifying the defining attributes, antecedents and consequences. CONCLUSIONS: The clinical role of the nurse concept that was developed represents innovative evidence on the theme. Nevertheless, a deeper understanding of nurses' clinical role is needed, as well as refinement of its conceptual components. This study should be integrated into a field research project, designed to illuminate how nurses manifest and articulate the concept in clinical practice. RELEVANCE TO CLINICAL PRACTICE: Knowledge of clinical role attributes, associated with nursing competencies, can contribute to reflection on the dimensions involved in nursing practice and inform not only teaching and professional practice, but also health policies. PMID- 24479872 TI - In vivo-folded metal-metallothionein 3 complexes reveal the Cu-thionein rather than Zn-thionein character of this brain-specific mammalian metallothionein. AB - Metallothionein-3 (MT3) is one of the four mammalian metallothioneins (MT), and is constitutively synthesized in the brain. MT3 acts both intracellularly and extracellularly in this organ, performing functions related to neuronal growth and physiological metal (Zn and Cu) handling. It appears to be involved in the prevention of neurodegenerative disorders caused by insoluble Cu-peptide aggregates, as it triggers a Zn-Cu swap that may counteract the deleterious presence of copper in neural tissues. The literature data on MT3 coordination come from studies either on apo-MT3 reconstitution or the reaction of Zn-MT3 with Cu(2+) , an ion that is hardly present inside cells. To ascertain the MT3 metal binding features in a scenario closer to the reductive cell cytoplasm, a study of the recombinant Zn(2+) , Cd(2+) and Cu(+) complexes of MT3, betaMT3, and alphaMT3, as well as the in vitro Zn(2+) -Cd(2+) and Zn(2+) -Cu(+) replacement processes, is presented here. We conclude that MT3 has a Cu-thionein character that is stronger than that of the MT1 and MT2 isoforms - also present in the mammalian brain - which is mainly contributed by its beta domain. In contrast, the alpha domain retains a high capacity to bind Zn(2+) ions, and, consequently, the entire MT3 peptide shows a peculiar dual ability to handle both metal ions. The nature of the formed Cu(+) -MT3 complexes oscillates from heterometallic Cu6 Zn4 -MT3 to homometallic Cu10 -MT3 major species, in a narrow Cu concentration range. Therefore, the entire MT3 peptide shows a high capacity to bind Cu(+) , provided that this occurs in a nonoxidative milieux. This reflects a peculiar property of this MT isoform, which accurately senses different Cu contents in the environment in which it is synthesized. PMID- 24479873 TI - Immuno-haematologic and virologic responses and predictors of virologic failure in HIV-1 infected adults on first-line antiretroviral therapy in Cameroon. AB - BACKGROUND: Contemporary data on the immunologic, haematologic and virologic responses and predictors of virologic failure after initiation of free antiretroviral treatment in Cameroon are needed to evaluate the current treatment monitoring algorithm and to complement efforts to scale-up and improve on the management of HIV infections. METHODS: This was a cross-sectional study conducted between October 2010 and June 2012. A total of 951 participants aged 18-74 years were recruited from selected approved HIV treatment centres of the Northwest and Southwest regions. This comprised 247 males and 704 females. Demographic, self reported risk behaviours and socioeconomic data were obtained using a structured questionnaire. Full blood and CD4 + T-cell counts were done using standard automated techniques. Determination of viral load (VL) was done using Abbott RealTime HIV-1 m2000TM system. Data was analysed using SPSS version 17. The statistical significance level was P < 0.05. RESULTS: The median duration of antiretroviral therapy (ART) was 24 months. The population mean CD4 + T-cell count was 255.3 cells/MUL [95% CI, 236.8 - 273.9]. Overall, 45.9%, 43.8% and 10.2% of the participants had CD4 + T-cell counts of < 200 cells/MUL, 200-499 cells/MUL and > 500 cells/MUL respectively. Anaemia was present in 26.2% of the participants with 62.3%, 25.7% and 12% described as mild, moderate and severe anaemia respectively. Virologic failure occurred in 23.2% of the participants with 12.3% having VL > 10,000 RNA copies/mL. Meanwhile 76.8% of patients attained adequate viral suppression with 40.8% having undetectable viral load. The age group 18-29 years (p = 0.024), co-infection with tuberculosis (p = 0.014), anaemia (p = 0.028) and distance from the treatment centre (p = 0.011) independently predicted virologic failure. CONCLUSION: The majority of the participants achieved adequate viral suppression after >= 6 months of ART. Despite these favourable immuno-haematologic and virologic outcomes, the National AIDS Control Program should step-up efforts to improve on antiretroviral drug distribution, as well as proper assessment and management of anaemia, foster early diagnosis and treatment of tuberculosis and enhance treatment adherence counselling especially in younger patients. PMID- 24479874 TI - Toward design of magnetic nanoparticle clusters stabilized by biocompatible diblock copolymers for T2-weighted MRI contrast. AB - We report the fabrication of magnetic particles comprised of clusters of iron oxide nanoparticles, 7.4 nm mean diameter, stabilized by a biocompatible, amphiphilic diblock copolymer, poly(ethylene oxide-b-D,L-lactide). Particles with quantitative incorporation of up to 40 wt % iron oxide and hydrodynamic sizes in the range of 80-170 nm were prepared. The particles consist of hydrophobically modified iron oxide nanoparticles within the core-forming polylactide block with the poly(ethylene oxide) forming a corona to afford aqueous dispersibility. The transverse relaxivities (r2) increased with average particle size and exceeded 200 s(-1) mM Fe(-1) at 1.4 T and 37 degrees C for iron oxide loadings above 30 wt %. These experimental relaxivities typically agreed to within 15% with the values predicted using analytical models of transverse relaxivity and cluster (particle core) size distributions derived from cryo-TEM measurements. Our results show that the theoretical models can be used for the rational design of biocompatible MRI contrast agents with tailored compositions and size distributions. PMID- 24479875 TI - High-density lipoprotein subfractions and influence of endothelial lipase in a healthy Turkish population: a study in a land of low high-density lipoprotein cholesterol. AB - PURPOSE: Low concentration of high-density lipoprotein (HDL) is prevalent in Turkey. Endothelial lipase (EL) regulates lipoprotein metabolism. Small, lipid poor HDL particles represent more-efficient cholesterol acceptors than their large, lipid-rich counterparts. The aim of this study was to investigate HDL subfractions and the effect of EL on HDL concentrations in healthy Turkish population. METHODS: 102 healthy subjects were included in the study (mean age 33.6 +/- 10.3 years, 42 female). HDL subfractions were assayed by single precipitation method and EL concentrations were measured by competitive enzyme immunoassay. RESULTS: Mean HDL concentrations were 1.45 +/- 0.37 mmol/L in women, 1.10 +/- 0.30 mmol/L in men. Small HDL subfraction levels did not differ statistically between < 1 mmol/L and >= 1.6 mmol/L total HDL groups. Small HDL was not correlated with EL, low density lipoprotein cholesterol (LDL), triglyceride (TG) and age but positively correlated with total cholesterol and HDL (r = 0.2, p = 0.017; r = 0.2, p = 0.028, respectively). Large HDL was not correlated with age, EL and total cholesterol, and negatively correlated with HDL, LDL, TG (r = - 0.7, p < 0.001; r = - 0.2, p = 0.045; r = - 0.3, p < 0.001, respectively). If subjects were divided into two groups as HDL< 1 mmol/L and HDL > 1.6 mmol/L, mean EL concentrations were 475.83 +/- 521.77 nmol/L and 529.71 +/- 276.92 nmol/L, respectively (p = 0.086). CONCLUSION: There were no differences between small HDL concentrations in the HDL low and high groups. Our data did not support EL to be the reason for low HDL in a healthy Turkish population. Our results in a healthy population may serve as a reference for clinical studies on HDL subfractions. PMID- 24479877 TI - Thyroglobulin increases thyroid cell proliferation via the suppression of specific microRNAs. AB - Thyroglobulin (Tg), stored in the follicular lumen, has also been shown recently to perform two unexpected roles: as an autocrine negative-feedback suppressor of thyroid function in the presence of TSH and as a potent inducer of thyroid cell growth in the absence of TSH. However, the underlying molecular mechanism(s) remain unclear. To elucidate a molecular pathway linking Tg to increased cell proliferation, we examined the regulation of microRNAs (miRNAs) by Tg using an miRNA microarray. We identified 21 miRNAs whose expression was significantly suppressed by Tg in rat thyroid FRTL-5 cells. Using specific miRNA analogs, we determined that miR-16, miR-24, and miR-195 mediate the induction of thyroid cell growth by Tg. The expression of miR-16 and miR-195 target genes, Mapk8, Ccne1, and Cdc6, which were previously shown to be essential for TSH-stimulated thyroid cell growth, were also induced by Tg. Moreover, the Tg-induced expression of these genes was reduced by overexpression of miR-16 and miR-195. Similarly, the induction of c-Myc by Tg was reduced by miR-24 overexpression. These results suggest that Tg could alter thyroid cell proliferation by increasing the expression of cell division-related genes such as Mapk8, Ccne1, Cdc6, and c-Myc through its suppression of specific microRNAs (miR-16, miR-24, and miR-195). In addition, we identified phosphatidylinositol 3-kinase as a key signaling pathway, linking Tg with cell proliferation. The present data support an important role for miRNAs as effectors for the effect of Tg on cell proliferation and perhaps other functions of Tg in the thyroid cell. PMID- 24479876 TI - RIP140 represses the "brown-in-white" adipocyte program including a futile cycle of triacylglycerol breakdown and synthesis. AB - Receptor-interacting protein 140 (RIP140) is a corepressor of nuclear receptors that is highly expressed in adipose tissues. We investigated the role of RIP140 in conditionally immortal preadipocyte cell lines prepared from white or brown fat depots. In white adipocytes, a large set of brown fat-associated genes was up regulated in the absence of RIP140. In contrast, a relatively minor role can be ascribed to RIP140 in the control of basal gene expression in differentiated brown adipocytes because significant changes were observed only in Ptgds and Fabp3. The minor role of RIP140 in brown adipocytes correlates with the similar histology and uncoupling protein 1 and CIDEA staining in knockout compared with wild-type brown adipose tissue (BAT). In contrast, RIP140 knockout sc white adipose tissue (WAT) shows increased numbers of multilocular adipocytes with elevated staining for uncoupling protein 1 and CIDEA. Furthermore in a white adipocyte cell line, the markers of BRITE adipocytes, Tbx1, CD137, Tmem26, Cited1, and Epsti1 were repressed in the presence of RIP140 as was Prdm16. Microarray analysis of wild-type and RIP140-knockout white fat revealed elevated expression of genes associated with cold-induced expression or high expression in BAT. A set of genes associated with a futile cycle of triacylglycerol breakdown and resynthesis and functional assays revealed that glycerol kinase and glycerol 3-phosphate dehydrogenase activity as well as [(3)H]glycerol incorporation were elevated in the absence of RIP140. Thus, RIP140 blocks the BRITE program in WAT, preventing the expression of brown fat genes and inhibiting a triacylglycerol futile cycle, with important implications for energy homeostasis. PMID- 24479878 TI - Efficacy and tolerability of add-on lacosamide in children with Lennox-Gastaut syndrome. AB - OBJECTIVE: Available data on the efficacy of lacosamide in children with Lennox Gastaut syndrome (LGS) are scarce and controversial. We present our experience with lacosamide therapy in children affected by LGS. MATERIAL AND METHODS: Medical charts of all children affected by LGS receiving oral lacosamide adjunctive therapy in six paediatric neurology centres were retrospectively evaluated. Efficacy was determined according to the frequency of countable seizures during the 4 weeks prior to treatment and the frequency in the last 4 weeks of observation. Patients whose seizure frequency was reduced by at least 50% were defined as responders. RESULTS: Eighteen children (mean age 12.3 years) were identified. After a mean follow-up period of 9 months, 33% of patients were responders. None of them was seizure-free during the study period. The overall seizure reduction rate was 29%. The percentage reductions from baseline in tonic seizures and drop-attacks rates were 31% and 20%, respectively. Adverse reactions occurred in 44% of patients. The drug was discontinued in four (22%) patients because of increased seizure frequency (three cases) and walking instability (another patient). CONCLUSIONS: A third of children with LGS were responders after lacosamide adjunctive therapy. Although caution is still necessary when the drug is used in children with LGS, our preliminary observations suggest that lacosamide might be effective and represent a possible therapeutic option in children affected by LGS. PMID- 24479880 TI - Synthesis of pandamarilactone-1. AB - The first total synthesis of pandamarilactone-1, an alkaloid of Pandanus amaryllifolius, is reported. The nine-step synthesis features furan oxidation with singlet oxygen and then spiro-N,O-acetalization and elimination to generate the natural product and further Pandanus alkaloids, pandamarilactonines A-D. PMID- 24479881 TI - World-to-digital-microfluidic interface enabling extraction and purification of RNA from human whole blood. AB - Digital microfluidics (DMF) is a powerful technique for simple and precise manipulation of microscale droplets of fluid. This technique enables processing and analysis of a wide variety of samples and reagents and has proven useful in a broad range of chemical, biological, and medical applications. Handling of "real world" samples has been a challenge, however, because typically their volumes are greater than those easily accommodated by DMF devices and contain analytes of interest at low concentration. To address this challenge, we have developed a novel "world-to-DMF" interface in which an integrated companion module drives the large-volume sample through a 10 MUL droplet region on the DMF device, enabling magnet-mediated recovery of bead-bound analytes onto the device as they pass through the region. To demonstrate its utility, we use this system for extraction of RNA from human whole blood lysates (110-380 MUL) and further purification in microscale volumes (5-15 MUL) on the DMF device itself. Processing by the system was >2-fold faster and consumed 12-fold less reagents, yet produced RNA yields and quality fully comparable to conventional preparations and supporting qRT-PCR and RNA-Seq analyses. The world-to-DMF system is designed for flexibility in accommodating different sample types and volumes, as well as for facile integration of additional modules to enable execution of more complex protocols for sample processing and analysis. As the first technology of its kind, this innovation represents an important step forward for DMF, further enhancing its utility for a wide range of applications. PMID- 24479879 TI - Calcineurin/NFAT signaling and innate host defence: a role for NOD1-mediated phagocytic functions. AB - The calcineurin/nuclear factor of activated T cells (NFATs) signaling pathway plays a central role in T cell mediated adaptive immune responses, but a number of recent studies demonstrated that calcineurin/NFAT signaling also plays a key role in the control of the innate immune response by myeloid cells. Calcineurin inhibitors, such as cyclosporine A (CsA) and tacrolimus (FK506), are commonly used in organ transplantation to prevent graft rejection and in a variety of immune diseases. These immunosuppressive drugs have adverse effects and significantly increase host's susceptibility towards bacterial or fungal infections. Recent studies highlighted the role of NFAT signaling in fungal infection and in the control of the pattern recognition receptor nucleotide binding oligomerization domain-containing protein 1 (NOD1), which predominantly senses invasive Gram-negative bacteria and mediates neutrophil phagocytic functions. This review summarises some of the current knowledge concerning the role of NFAT signaling in the innate immune response and the recent advances on NFAT-dependent inhibition of NOD1-mediated innate immune response caused by CsA, which may contribute to sensitizing transplant recipients to bacterial infection. PMID- 24479882 TI - Bovine Tuberculosis and Brucellosis in Cattle and African Buffalo in the Limpopo National Park, Mozambique. AB - Bovine tuberculosis (BTB) and brucellosis are prevalent in buffaloes of the Kruger National Park (KNP, South Africa). Both diseases were considered to have no or a very low prevalence in wildlife and livestock in and around the Limpopo National Park (LNP, Mozambique). The same applies for tuberculosis in Gonarezhou National Park (GNP, Zimbabwe), but just recently, BTB was detected in buffaloes in the GNP and fears arose that the disease might also spread to the LNP as a result of the partial removal of the fences between the three parks to form the Great Limpopo Transfrontier Park. To assess the status of both diseases in and around LNP, 62 buffaloes were tested for bovine tuberculosis (BTB) and bovine brucellosis. The percentage of positive BTB reactors in buffalo was 8.06% using BovidTB Stat-Pak(r) and 0% with BOVIGAM(r) IFN-gamma test and IDEXX ELISA. The brucellosis seroprevalence in buffalo was found to be 17.72% and 27.42% using Rose Bengal Test (RBT) and ELISA, respectively. In addition, 2445 cattle in and around the LNP were examined for BTB using the single intradermal cervical comparative tuberculin test (SICCT), and an apparent prevalence of 0.98% was found with no significant difference inside (0.5%) and outside (1.3%) the park. This is the first published report on the presence of positive reactors to BTB and bovine brucellosis in buffalo and cattle in and outside the LNP. Monitoring the wildlife-livestock-human interface of zoonotic high-impact diseases such as BTB and brucellosis is of outmost importance for the successful implementation and management of any transfrontier park that aims to improve the livelihoods of the local communities. PMID- 24479883 TI - Micro-RNAs and ovarian cancer: the state of art and perspectives of clinical research. AB - Dysregulation of microRNA (mi-RNA) expression plays a major role in the development and progression of most human malignancies. Members of the miR-200 family, miR-182, miR-214 and miR-221 are frequently up-regulated, whereas miR 100, let-7i, miR-199a, miR-125b, mir-145 and miR-335 are often down-regulated in ovarian cancer compared with normal ovarian tissue. Most mi-RNA signatures are overlapping in different tumor histotypes but some mi-RNAs seem to be histotype specific. For instance, the endometrioid type shares with the serous and clear cell types the up-regulation of miR-200 family members, but also presents over expression of miR-21, miR-202 and miR-205. Clear cell carcinoma has a significantly higher expression of miR-30a and miR-30a*, whereas mucinous histotype has elevated levels of miR-192/194. In vitro and in vivo investigations have shown that several mi-RNAs can modulate the sensitivity of ovarian cancer to platinum and taxane, and clinical studies have suggested that mi-RNA profiling may predict the outcome of patients with this malignancy. Some mi-RNAs could be used as biomarkers to identify patients that might benefit from the addition of molecularly targeted agents (i.e. anti-angiogenic agents, MET inhibitors and poly(ADP-ribose) polymerase (PARP) inhibitors) to standard chemotherapy. Moreover, mi-RNAs could represent potential targets for the development of novel therapies. PMID- 24479884 TI - Abnormal liver function test in hydatidiform moles: a retrospective study comparing the hyperthyroid state and the euthyroid state. AB - INTRODUCTION: The effect of a hyperthyroid or euthyroid state on liver function tests in patients with hydatidiform moles (HM) is not known. The aim of this study was to determine the effect of hyperthyroidism on liver transaminases in HM. PATIENTS AND METHODS: We retrospectively reviewed aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels in 80 patients with HM (23 complete moles and 57 partial moles). RESULTS: Of the 80 HM patients, 52 (65%) were euthyroid and 28 (35%) were hyperthyroid. The number of gravida and the levels of serum beta-human chorionic gonadotropin (beta-HCG), AST, and ALT were significantly higher in the hyperthyroid state than in the euthyroid state (p = 0.033, p = 0.001, p = 0.001 and p = 0.001; respectively). Number of gravida, serum TSH and total T4 were significantly higher in complete HM than partial HM (p < 0.05, p < 0.001, p < 0.05; respectively). CONCLUSIONS: Our results demonstrated that HM-related beta-HCG may activate thyroid cells via TSH-related signalling, resulting in the release of high levels of FT4, FT3, TT3 and TT4, and a subsequent decrease in TSH. PMID- 24479885 TI - Long digital extensor tendon mineralization and cranial cruciate ligament rupture in a dog. AB - OBJECTIVE: To report clinical and histopathologic features of long digital extensor (LDE) tendon mineralization with concurrent cranial cruciate ligament (CCL) rupture in a dog. STUDY DESIGN: Case report. ANIMAL: 1.5-year-old, male castrated, English bulldog mix weighing 31.5 kg. METHODS: Pre- and postoperative orthogonal radiographs, arthroscopic evaluation, arthrotomy with en bloc surgical excision, and histopathologic analysis of the excised LDE tendon. RESULTS: There was radiographic evidence of mineralization in the region of the proximal LDE and stifle instability suggestive of CCL rupture. Arthroscopy, and subsequent arthrotomy, showed complete tearing of the CCL and an intact but grossly thickened LDE. No evidence of avulsion or bony proliferation associated with the LDE was appreciated. Tibial plateau leveling osteotomy (TPLO) and tenectomy of the LDE returned the dog to normal weight-bearing. No evidence of ectopic mineralization in the affected limb or similar clinical signs in the contralateral limb have been observed in 12 months follow-up. CONCLUSIONS: LDE tenectomy followed by stabilization of the stifle by TPLO resulted in a functional outcome. Mineralization without concurrent avulsion of the LDE has not been reported in dogs; however, posterolateral tendon injury in people has been linked to knee instability and cruciate ligament rupture. PMID- 24479886 TI - Dishwasher-related injuries: survey and literature review. AB - Domestic injuries are quite common among children aged 0-4 years old. Hazards lurking in the kitchen area can cause serious injuries in children. Through this study, we aim to raise public awareness of the potential and underreported risk of injuries related to dishwashers. Anonymous questionnaires consisting of 12 questions were distributed to adult females with children under 5 years old, including nurses, secretarial staff and outpatients. Commonly used dishwashers were surveyed by visiting high-street stores, and each brand's user manual was studied. A literature search using Medline and Pubmed was conducted for examining reported dishwasher-related sharp injuries. Forty households filled out survey questionnaires. Their responses indicated that 10% and 12.5% of children participate in unloading or loading dishwashers, respectively. Results showed that the incidence of related injuries was 12.5% among adults and 5% among children, and young children are at risk of sharp injuries in households with dishwashers. The dangerous loading and unloading of sharp objects and the direct involvement of toddlers should be discouraged, with the help of manufacturers. PMID- 24479887 TI - Progesterone-induced migration inhibition in male rat aortic smooth muscle cells through the cSrc/AKT/ERK 2/p38 pathway-mediated up-regulation of p27. AB - Previously, we showed that progesterone (P4) inhibits proliferation and migration of rat aortic smooth muscle cells (RASMCs). The P4-induced migration inhibition in RASMCs resulted from suppression of the Ras homolog gene family, member A (RhoA) activity mediated by cSrc activation. We also observed that P4 increased the formation of p27-RhoA complex in RASMCs. The aim of this study was to further study the involvement of p27 in P4-induced migration inhibition in RASMCs. Treatment with P4 (50 nM) increased the level of p27 protein in RASMCs. Knockdown of p27 abolished the P4-induced increases of the levels of p27 protein and decreases of cell migration in RASMCs. We conducted Western blot analyses and applied pharmacologic inhibitors to delineate the signaling pathway involved in the P4-induced p27 up-regulation and migration inhibition in RASMCs. Our data suggest that P4 increased the levels of p27 in RASMCs through activating the cSrc/AKT/ERK 2/p38 pathway mediated by nongenomic progesterone receptor. The findings of the present study highlight the molecular mechanisms underlying P4 induced migration inhibition in RASMCs. PMID- 24479888 TI - Case of Hermansky-Pudlak syndrome 1 patient with milder symptoms in Japanese. PMID- 24479891 TI - Local thermal injury induces general endothelial cell contraction through p38 MAP kinase activation. AB - Endothelial cells (ECs) of thin-walled blood vessels form a barrier between blood and tissue. As a response to inflammation, the EC junctions widen and gaps form, resulting in compromised barrier functions. Although the mechanisms behind the establishment of these changes are still incompletely understood, one known reason is actomyosin-dependent actin rearrangement. Here, by using atomic force microscopy and a combination of confocal microscopy methods, we are the first to report that thermal injury induces general venular hyperpermeability and that serum from burned rats induces EC actin rearrangement, contraction, as well as tight-junction damage. Inhibition of the p38 mitogen-activated protein kinase (p38MAPK) largely ameliorates resulting vascular dysfunction by significantly reducing EC stress-fiber formation, contraction, volume changes and tight junction damage, thereby greatly reducing the appearance of EC gaps. The findings may be of importance for the design of future pharmacotherapies aiming to ease the severe general vascular dysfunction that follows extensive burns. PMID- 24479890 TI - In vivo dosimetry of thyroid doses from different irradiated sites in children and adolescents: a cross-sectional study. AB - BACKGROUND: Scattered radiation can be assessed by in vivo dosimetry. Thyroid tissue is sensitive to radiation, even at doses <10 cGy. This study compared the scattered dose to the thyroid measured by thermoluminescent dosimeters (TLDs) and the estimated one by treatment planning system (TPS). METHODS: During radiotherapy to sites other than the thyroid of 16 children and adolescents, seventy-two TLD measurements at the thyroid were compared with TPS estimation. RESULTS: The overall TPS/TLD bias was 1.02 (95% LA 0.05 to 21.09). When bias was stratified by treatment field, the TPS overestimated TLD values at doses <1 cGy and underestimated them at doses >10 cGy. The greatest bias was found in pelvis and abdomen: 15.01 (95% LA 9.16 to 24.61) and 5.12 (95% LA 3.04 to 8.63) respectively. There was good agreement in orbit, head, and spine: bias 1.52 (95% LA 0.48 to 4.79), 0.44 (95% LA 0.11 to 1.82) and 0.83 (0.39 to 1.76) respectively. There was small agreement with broad limits for lung and mediastinum: 1.13 (95% LA 0.03 to 40.90) and 0.39 (95% LA 0.02 to 7.14) respectively. CONCLUSIONS: The scattered dose can be measured with TLDs, and TPS algorithms for outside structures should be improved. PMID- 24479892 TI - Comparison of digital and conventional impression techniques: evaluation of patients' perception, treatment comfort, effectiveness and clinical outcomes. AB - BACKGROUND: The purpose of this study was to compare two impression techniques from the perspective of patient preferences and treatment comfort. METHODS: Twenty-four (12 male, 12 female) subjects who had no previous experience with either conventional or digital impression participated in this study. Conventional impressions of maxillary and mandibular dental arches were taken with a polyether impression material (Impregum, 3 M ESPE), and bite registrations were made with polysiloxane bite registration material (Futar D, Kettenbach). Two weeks later, digital impressions and bite scans were performed using an intra oral scanner (CEREC Omnicam, Sirona). Immediately after the impressions were made, the subjects' attitudes, preferences and perceptions towards impression techniques were evaluated using a standardized questionnaire. The perceived source of stress was evaluated using the State-Trait Anxiety Scale. Processing steps of the impression techniques (tray selection, working time etc.) were recorded in seconds. Statistical analyses were performed with the Wilcoxon Rank test, and p < 0.05 was considered significant. RESULTS: There were significant differences among the groups (p < 0.05) in terms of total working time and processing steps. Patients stated that digital impressions were more comfortable than conventional techniques. CONCLUSIONS: Digital impressions resulted in a more time-efficient technique than conventional impressions. Patients preferred the digital impression technique rather than conventional techniques. PMID- 24479893 TI - Evaluation of an individualised programme to promote self-care in sleep-activity in patients with coronary artery disease -- a randomised intervention study. AB - AIMS AND OBJECTIVES: To evaluate the effectiveness of an individualised programme to promote self-care in sleep-activity in patients with coronary artery disease. BACKGROUND: Recent scientific findings have shown that low physical exercise and stress interfere with coronary artery disease patients' sleep quality and sleep efficiency independent of gender, age and co-morbidity. DESIGN: A randomised pretest-post-test control design. METHODS: Forty-seven patients who had undergone a coronary revascularisation procedure and/or pharmacological treatment three to seven weeks earlier at a general hospital were randomised to either an intervention group or a control group. Data collection was carried out by questionnaires, a study-specific sleep diary and actigraphy registration for 10 consecutive 24-hour periods, with a follow-up after three to four months. The intervention group underwent a nurse-led individualised education programme to promote self-care of sleep-activity. Sleep habits and sleep-related lifestyle together formed the basis for setting up individual goals together with the nurse. Individual advice on physical training, relaxation exercise and a CD-based relaxation programme was provided by a physiotherapist. Both groups received a brochure about sleep and stress. RESULTS: At a three- to four-month follow-up, the main improvements were seen in the intervention group regarding sleep quality, sleep duration and sleep efficiency in the sleep diary and sleep efficiency in actigraphy. Statistical improvements in health-related quality of life were revealed. This was not so obvious in the control group. CONCLUSIONS: An individualised intervention programme to promote self-care of sleep-activity including relaxation in patients with coronary artery disease led by a nurse may improve sleep quality. However, a longitudinal study to promote self-care in sleep-activity should be performed using a larger sample and multiple sites with continuous follow-ups to determine whether any positive effects remain stable over time. RELEVANCE TO CLINICAL PRACTICE: Implementation of a multiprofessional individualised programme to promote self-care of sleep-activity including relaxation based on patients' needs, supported by a healthcare team and led by nurses, is important in clinical practice. PMID- 24479895 TI - Surface chemistry of thiomalic acid adsorption on planar gold and gold nanoparticles. AB - The self-assembly of thiomalic acid (TMA) on Au(111) and on preformed Au nanoparticles (AuNPs) protected by weak ligands has been studied by X-ray photoelectron spectroscopy (XPS) and electrochemical techniques. Results show that TMA is adsorbed on the Au(111) surface as thiolate species with a small amount of atomic sulfur (~10%) and a surface coverage lower than that found for alkanethiols due to steric factors. The amount of atomic sulfur markedly increases when the TMA is adsorbed on AuNPs by the ligand exchange method. We propose that the atomic sulfur is produced as a consequence of C-S bond cleavage, a process that is more favorable at defective sites of the AuNPs surface. The bond scission is also assisted by the presence of the electron-withdrawing carboxy moiety in the alpha-position relative to the C-S bond. Moreover, the high local concentration of positively charged species increases the stability of the negatively charged leaving group, leading to a higher amount of coadsorbed atomic sulfur. Our results demonstrate that the terminal functionalities of thiols are conditioning factors in the final structure and composition of the adlayers. PMID- 24479894 TI - Neuron-to-neuron wild-type Tau protein transfer through a trans-synaptic mechanism: relevance to sporadic tauopathies. AB - BACKGROUND: In sporadic Tauopathies, neurofibrillary degeneration (NFD) is characterised by the intraneuronal aggregation of wild-type Tau proteins. In the human brain, the hierarchical pathways of this neurodegeneration have been well established in Alzheimer's disease (AD) and other sporadic tauopathies such as argyrophilic grain disorder and progressive supranuclear palsy but the molecular and cellular mechanisms supporting this progression are yet not known. These pathways appear to be associated with the intercellular transmission of pathology, as recently suggested in Tau transgenic mice. However, these conclusions remain ill-defined due to a lack of toxicity data and difficulties associated with the use of mutant Tau. RESULTS: Using a lentiviral-mediated rat model of hippocampal NFD, we demonstrated that wild-type human Tau protein is axonally transferred from ventral hippocampus neurons to connected secondary neurons even at distant brain areas such as olfactory and limbic systems indicating a trans-synaptic protein transfer. Using different immunological tools to follow phospho-Tau species, it was clear that Tau pathology generated using mutated Tau remains near the IS whereas it spreads much further using the wild type one. CONCLUSION: Taken together, these results support a novel mechanism for Tau protein transfer compared to previous reports based on transgenic models with mutant cDNA. It also demonstrates that mutant Tau proteins are not suitable for the development of experimental models helpful to validate therapeutic intervention interfering with Tau spreading. PMID- 24479897 TI - Pain, well-being, body image and cosmesis: a comparison of single-port and four port laparoscopic cholecystectomy. AB - BACKGROUND: This study aims to compare post-operative pain, well-being, body image and cosmesis in SILS cholecystectomy and four-port laparoscopic cholecystectomy (FPLC). MATERIAL AND METHODS: Forty-two consecutive patients (15 SILS, 27 FPLC) undergoing elective cholecystectomy were included in the study. Peri-operative pain, well-being, body image and cosmesis were evaluated using validated assessment tools. RESULTS: Significantly lower pain scores were reported one week post-operatively in the SILS group (5.6 vs 8.3; p = 0.035). No significant difference was found in analgesic requirements, physical or mental well-being at any time interval. Significantly higher (favourable) body image questionnaire scores were reported in the SILS group at one week (5.4 v 4.5; p < 0.01), two weeks (5.6 vs 4.8; p < 0.01) and one month (5.7 vs 5.0; p < 0.01) post operatively. CONCLUSION: SILS patients have significantly reduced one-week pain scores and there was no significant difference in well-being between the two groups. Patients who underwent SILS had improved body image and cosmesis. If both techniques are found to be equivalent concerning safety, cost, learning curve and availability, SILS may play a key role in the new era of patient choice. PMID- 24479898 TI - Relative anterior safe area for invasive procedures in the human brain: diffusion tensor tractography. AB - OBJECTIVE: Many interventions, including surgery, procedures of shunt operation, or radiotherapy could result in neural injury of the brain. However, research to prevent or minimize injury of neural tracts has been overlooked. MATERIAL AND METHODS: We recruited 41 healthy subjects. Diffusion tensor images were acquired and five neural tracts were reconstructed (corticospinal tract, corticoreticular pathway, arcuate fasciculus, cingulum, and superior longitudinal fasciculus). We defined the safe area, which is an area free from any trajectory of five neural tracts: the medial boundary - the most lateral point free from any trajectory of five neural tracts, the posterior boundary - the most anterior point free from any trajectory of five neural tracts. RESULTS: Medial boundaries of the safe area in the cortex, centrum semiovale, corona radiata, and internal capsule were located at an average of 0 mm, 12.28 mm, 12.43 mm, and 10.34 mm laterally from the midline, respectively, and the posterior boundaries were located at an average of 1.30 mm, 4.26 mm, 7.05 mm, and 5.74 mm from the ACL, respectively. In addition, we found that the common safe areas for all four axial levels were located at 13.44 mm (medial boundary) and 9.35 mm (posterior boundary). CONCLUSION: We identified a relatively safe area for the performance of invasive procedures in the anterior portion of the human brain. PMID- 24479899 TI - Methods for observed-cluster inference when cluster size is informative: a review and clarifications. AB - Clustered data commonly arise in epidemiology. We assume each cluster member has an outcome Y and covariates X. When there are missing data in Y, the distribution of Y given X in all cluster members ("complete clusters") may be different from the distribution just in members with observed Y ("observed clusters"). Often the former is of interest, but when data are missing because in a fundamental sense Y does not exist (e.g., quality of life for a person who has died), the latter may be more meaningful (quality of life conditional on being alive). Weighted and doubly weighted generalized estimating equations and shared random-effects models have been proposed for observed-cluster inference when cluster size is informative, that is, the distribution of Y given X in observed clusters depends on observed cluster size. We show these methods can be seen as actually giving inference for complete clusters and may not also give observed-cluster inference. This is true even if observed clusters are complete in themselves rather than being the observed part of larger complete clusters: here methods may describe imaginary complete clusters rather than the observed clusters. We show under which conditions shared random-effects models proposed for observed-cluster inference do actually describe members with observed Y. A psoriatic arthritis dataset is used to illustrate the danger of misinterpreting estimates from shared random-effects models. PMID- 24479900 TI - Characterization of nZVI mobility in a field scale test. AB - Nanoscale zerovalent iron (nZVI) particles were injected into a contaminated sandy subsurface area in Sarnia, Ontario. The nZVI was synthesized on site, creating a slurry of 1 g/L nanoparticles using the chemical precipitation method with sodium borohydride (NaBH4) as the reductant in the presence of 0.8% wt. sodium carboxymethylcellulose (CMC) polymer to form a stable suspension. Individual nZVI particles formed during synthesis had a transmission electron microscopy (TEM) quantified particle size of 86.0 nm and dynamic light scattering (DLS) quantified hydrodynamic diameter for the CMC and nZVI of 624.8 nm. The nZVI was delivered to the subsurface via gravity injection. Peak normalized total Fe breakthrough of 71% was observed 1m from the injection well and remained above 50% for the 24 h injection period. Samples collected from a monitoring well 1 m from the injection contained nanoparticles with TEM-measured particle diameter of 80.2 nm and hydrodynamic diameter of 562.9 nm. No morphological changes were discernible between the injected nanoparticles and nanoparticles recovered from the monitoring well. Energy dispersive X-ray spectroscopy (EDS) was used to confirm the elemental composition of the iron nanoparticles sampled from the downstream monitoring well, verifying the successful transport of nZVI particles. This study suggests that CMC stabilized nZVI can be transported at least 1 m to the contaminated source zone at significant Fe(0) concentrations for reaction with target contaminants. PMID- 24479901 TI - Fluorescence-lifetime molecular imaging can detect invisible peritoneal ovarian tumors in bloody ascites. AB - Blood contamination, such as bloody ascites or hemorrhages during surgery, is a potential hazard for clinical application of fluorescence imaging. In order to overcome this problem, we investigate if fluorescence-lifetime imaging helps to overcome this problem. Samples were prepared at concentrations ranging 0.3-2.4 MUm and mixed with 0-10% of blood. Fluorescence intensities and lifetimes of samples were measured using a time-domain fluorescence imager. Ovarian cancer SHIN3 cells overexpressing the D-galactose receptor were injected into the peritoneal cavity 2.5 weeks before the experiments. Galactosyl serum albumin rhodamine green (GSA-RhodG), which bound to the D-galactose receptor and was internalized thereafter, was administered intraperitoneally to peritoneal ovarian cancer-bearing mice with various degrees of bloody ascites. In vitro study showed a linear correlation between fluorescence intensity and probe concentration (r(2) > 0.99), whereas the fluorescence lifetime was consistent (range, 3.33 +/- 0.15 3.75 +/- 0.04 ns). By adding 10% of blood to samples, fluorescence intensities decreased to <1%, while fluorescence lifetimes were consistent. In vivo fluorescence lifetime of GSA-RhodG stained tumors was longer than the autofluorescence lifetime (threshold, 2.87 ns). Tumor lesions under hemorrhagic peritonitis were not depicted using fluorescence intensity imaging; however, fluorescence-lifetime imaging clearly detected tumor lesions by prolonged lifetimes. In conclusion, fluorescence-lifetime imaging with GSA-RhodG depicted ovarian cancer lesions, which were invisible in intensity images, in hemorrhagic ascites. PMID- 24479902 TI - Reaction of quinones and guanidine derivatives: simple access to bis-2 aminobenzimidazole moiety of benzosceptrin and other benzazole motifs. AB - A new strategy for the synthesis of 2-aminobenzimidazol-6-ols via a reaction of quinones with guanidine derivatives is reported. Sequential application of this methodology provided a simple access to the first benzosceptrin analogue bearing a bis-2-aminoimidazole moiety. A concomitant addition of two guanidines to the naphtho[1',2':4,5]imidazo[1,2-a]pyrimidine-5,6-dione, which includes the redox neutral debenzylation and guanidine-assisted cleavage of the 2-aminopyrimidine part resulted in the synthesis of the free challenging contiguous bis-2 aminoimidazole moiety of benzosceprins in one step. PMID- 24479903 TI - Spatially resolved electrochemistry in ionic liquids: surface structure effects on triiodide reduction at platinum electrodes. AB - Understanding the relationship between electrochemical activity and electrode structure is vital for improving the efficiency of dye-sensitized solar cells. Here, the reduction of triiodide to iodide in 1-butyl-3-methylimidazolium tetrafluoroborate ([BMIm][BF4]) room temperature ionic liquid (RTIL) is investigated on polycrystalline platinum using scanning electrochemical cell microscopy (SECCM) and correlated to the crystallographic orientation from electron backscatter diffraction (EBSD). Although the rate determining step in all grains was the first electron transfer, significant grain-dependent variations in activity were revealed, with grains with a dominant (110) crystallographic character exhibiting higher catalytic activity compared to those with a major (100) orientation. The SECCM technique is demonstrated to resolve heterogeneity in activity, highlighting that methods incorporating polycrystalline electrodes miss vital details for understanding and optimizing electrocatalysts. An additional advantage of the SECCM over single-crystal techniques is its ability to probe high index facets. PMID- 24479904 TI - A fresh start for everyone. PMID- 24479905 TI - Chief nurse questions the value of displaying staffing level notices. PMID- 24479906 TI - Getting in shape for adventure at the Great Wall. PMID- 24479908 TI - Senior nurses and managers recognised in New Year honours. PMID- 24479909 TI - Provisional guidance for end of life care available in Scotland. PMID- 24479910 TI - NHS England prepares to publish a local breakdown of 'never event' data online. PMID- 24479911 TI - Top managers parachuted in to turn around failing trusts. PMID- 24479912 TI - How will seven-day working actually work? PMID- 24479913 TI - Contributing to the journal. PMID- 24479915 TI - International outlook - mid-staffs lessons travel. PMID- 24479917 TI - Another 'C' is needed: continuity. PMID- 24479918 TI - Vantage point - old institutions offered sanctuary. PMID- 24479919 TI - Guardian of truth. PMID- 24479921 TI - Out for consultation. PMID- 24479923 TI - Care and comfort rounds: improving standards. AB - Person-centred, safe and effective care is at the heart of the fundamentals of caring. However, there are many challenges to achieving this reliably and consistently. This article describes one nursing team's experience of implementing 'care and comfort' rounds, which has led to proactive rather than reactive nursing care delivery. The number of patient falls and the use of call buzzers have reduced, patient experience has been enhanced, a more controlled environment is provided for patients, and staff satisfaction in care delivery has improved. PMID- 24479925 TI - Embedding NHS values: a framework and learning tool to support practice. AB - Multiple healthcare failings point to an NHS culture where care and compassion are no longer guaranteed. The NHS Constitution and values set out in it should have supported and empowered healthcare professionals to improve their working culture, however these have not been widely adopted. This article describes a framework for all healthcare staff that hinges on principles of 'observing practice, praising good practice, challenging poor practice, and escalating if standards are compromised' (OPCE), and which encourages everyone to take responsibility for poor care. PMID- 24479924 TI - Horizontal hostility and verbal violence between nurses in the perinatal arena of health care. AB - The goal of this US study was to determine the frequency of horizontal violence in a perinatal service and its effect on patient outcomes. A 24-question survey instrument was completed online by 63 nurses. The results indicated that labour and delivery wards experience a higher frequency of horizontal violence than other units in the perinatal service. They also showed that the mother and baby unit demonstrates a higher frequency of recipient or victim behaviours. A relationship between horizontal violence and ineffective communication, as well as a relationship between horizontal violence and poor patient outcomes or near misses, was demonstrated. PMID- 24479928 TI - Teaching is Messy. PMID- 24479926 TI - Association of promoter methylation statuses of congenital heart defect candidate genes with Tetralogy of Fallot. AB - BACKGROUND: Although a lower methylation level of whole genome has been demonstrated in Tetralogy of Fallot (TOF) patients, little is known regarding changes in specific gene DNA methylation profiles and the possible associations with TOF. In current study, the promoter methylation statuses of congenital heart defect (CHD) candidate genes were measured in order to further understand epigenetic mechanisms that may play a role in the development of TOF. METHODS: The methylation levels of CHD candidate genes were measured using the Sequenom MassARRAY platform. QRT-PCR was used to analyze the mRNA levels of CHD candidate genes in the right ventricular myocardium of TOF cases and normal controls. RESULTS: Methylation status analysis was performed on the promoter regions of 71 CHD candidate genes (113 amplicons). We found significant differences in methylation status, between TOF cases and controls, in 26 amplicons (26 genes) (p < 0.05). Of the 26 amplicons, 17 were up regulated and 9 were down regulated. Additionally, 14 of them were located in the CpG islands, 7 were located in the CpG island shores, and 5 were covering the regions near the transcription start site (TSS). The methylation status was subsequently confirmed and mRNA levels were measured for 7 represented candidate genes, including EGFR, EVC2, NFATC2, NR2F2, TBX5, CFC1B and GJA5. The methylation values of EGFR, EVC2, TBX5 and CFC1B were significantly correlated with their mRNA levels (p < 0.05). CONCLUSIONS: Aberrant promoter methylation statuses of CHD candidate genes presented in TOF cases may contribute to the TOF development and have potential prognostic and therapeutic significance for TOF disease. PMID- 24479929 TI - Assess students: an overview. AB - Important decisions are often taken about students as a result of the scores they achieve in examinations. It should be possible to make important decisions in relation to student counselling and course development on the basis of evaluation results, but often this is not done. All teachers are involved directly or indirectly with assessing students' competencies and should be familiar with some of the current thinking on assessment. They should ask (and answer) five questions: (1) What should be assessed? (2) How should it be assessed? (3) Why should it be assessed? (4) When should it be assessed? (5) Who should carry out the assessment? PMID- 24479930 TI - Physiology. AB - This paper describes an innovative approach to teaching a traditional subject physiology. There are no lectures, tutorials or practicals. All learning activities are undertaken in small groups, and the course is learner-centred and problem-orientated. Students are required to collect and record their own information and to teach their colleagues what they have learned. Peer evaluation by students is used. The great majority of students enjoy the course and find it valuable. However, the structure of the course is not yet regarded as optimal. It is suggested that the system should complement and supplement traditional methods, rather than replace them entirely. PMID- 24479931 TI - Use of 3-d models in medical education. AB - This article provides a personal account of the way one medical teacher uses cheap, easily-made models in the education of medical undergraduates and postgraduate vocational trainees. It deals with plastic bas-relief models, paper models, plaster of paris models, and models used in endoscopy training. Successful use of such models depends upon their simplicity and on the enthusiasm of the instructor. PMID- 24479932 TI - Against multiple choice questions. AB - In this article, Sir George Pickering argues the case against multiple choice questions in reply to the article which appeared in the last issue of Medical Teacher (1979, 1 (1), 37-42). PMID- 24479933 TI - Neurology Teaching in UK Medical Schools. AB - From time to time, Medical Teacher will publish surveys of topical aspects of medical educational practice in the UK and elsewhere. The first article in this series reports the results of an enquiry into the teaching of the expanding specialty of neurology and neurosurgery in clinical medical schools in the UK. It shows wide differences in the arrangements made for teaching the specialty, and considerable dissatisfaction amongst many teachers with what they regard as insufficient teaching provision. PMID- 24479934 TI - The great american dream shrinks a little. PMID- 24479935 TI - A study in irrelevancy. PMID- 24479940 TI - Common room. AB - Each issue, someone connected with medical education will present a diary of a week in his or her life. The contributor this issue is Hamilton Hall, Assistant Professor in the Department of Surgery, University of Toronto, Canada. PMID- 24479936 TI - Students' Reactions to a Problem-based Student-centred Course. AB - An eight-week course based on a non-traditional instructional format was offered to 136 first-year medical and dental students. The course was problem-based, student-centred and took place in a small tutorial setting. During and at the end of the course students evaluated their own performance, as well as the course itself. Analysis of the results showed that students reacted favourably to this mode of instruction and requested that more courses should be offered utilizing this approach. The performance of students surpassed the expectation of members of the faculty. PMID- 24479941 TI - Student assessment of learning experiences. AB - In this occasional series, we will be printing evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to use or adapt such instruments for your own purposes. PMID- 24479943 TI - Theory and development of a unicompartmental resurfacing system for treatment of medial compartment disease of the canine elbow. AB - Medial compartment disease (MCompD) of the canine elbow can be defined as clinical signs attributable to articular cartilage loss of the medial coronoid process (MCP) of the ulna and medial aspect of the humeral condyle without significant lateral compartment pathology. Whereas outcomes associated with treatment of defined cohorts of dogs with MCompD have not been published, the impressions of many surgeons are that non-surgical management or surgical treatment of the MCP alone does not result in long term highly functional outcomes. Thus, alternative surgical options for treatment of MCompD have been developed including various osteotomies and total elbow replacement (TER) with "successful" outcomes reported in case series. Results and data on safety have been reported for relatively few of these procedures and when reported, major complication rates have been >10% and catastrophic complications have been reported. Accordingly, we sought to develop a surgical technique with the objective of obtaining higher levels of safety and efficacy in the treatment of dogs with MCompD. This report describes the rationale for, and development of, a unicompartmental resurfacing system for treatment of MCompD in the canine elbow. PMID- 24479944 TI - A unique combined source of "CN" from 1,2-dichloroethane and TMSN3 in the copper catalyzed cyanation of a C(sp3)-H bond adjacent to a nitrogen atom. AB - A novel combined metal-free "CN" source from trimethylsilyl azide and 1,2 dichloroethane has been developed and successfully applied to copper-catalyzed oxidative cyanation of alpha-C-H tertiary amines for the synthesis of C1 cyanation tetrahydroisoquinoline derivatives with good to excellent yields for the first time. PMID- 24479945 TI - Validated worldwide supercentenarians, living and recently deceased. PMID- 24479946 TI - The metabolic syndrome: is it the mother's fault? PMID- 24479947 TI - Masculinity, alexithymia, and fear of intimacy as predictors of UK men's attitudes towards seeking professional psychological help. AB - OBJECTIVES: Men's reluctance to access health care services has been under researched even though it has been identified as a potentially important predictor of poorer health outcomes amongst men. Male gender role socialization and male development may be important in accounting for men's underutilization of mental health services in the United Kingdom. METHOD: A cross-sectional online survey was used to administer standardized self-report measures that were subject to regression analysis. Five hundred and eighty-one men from the UK general population completed the survey, and 536 participants formed the final regression analysis. RESULTS: Men who score higher on measures of traditional masculine ideology, normative alexithymia, and fear of intimacy reported more negative attitudes towards seeking professional psychological help. Normative alexithymia fully mediated the effect of fear of intimacy on attitudes towards professional help seeking. In the final regression model, education significantly accounted for a proportion of unique variance in men's help-seeking attitudes. CONCLUSIONS: Hypothesized consequences of male emotional and interpersonal development and male gender role socialization were associated with men's attitudes towards seeking psychological help. These are important factors which could help to improve help seeking and mental health outcomes for men. Limitations of this study and implications for future research are discussed. Statement of contribution What is already known on this subject? Men are less likely to seek help for physical and psychological problems and have poorer health outcomes across nearly all major illness and injury. Men's reluctance to access health care services is believed to be a major contributory factor to poorer health outcomes for men. What does the study add? The study is a large-scale survey of UK men's attitudes towards professional psychological help seeking. Results provide evidence that hypothesized consequences of male gender role socialization and dominant masculine norms are associated with men's attitudes towards seeking professional psychological help. Attitudes towards psychological help seeking were associated with masculinity, alexithymia, and intimacy. Alexithymia fully mediated the effect of intimacy on men's attitudes towards psychological help seeking. Promoting help seeking in men could improve men's emotional well-being and interpersonal functioning. PMID- 24479949 TI - Influence of neighboring groups on the thermodynamics of hydrophobic binding: an added complex facet to the hydrophobic effect. AB - The thermodynamic consequences of systematic modifications in a ligand side chain that binds in a shallow hydrophobic pocket, in the presence and absence of a neighboring ligand carboxylate group, were evaluated using isothermal titration calorimetry (ITC). Data revealed that the carboxylate significantly changes the relative thermodynamic signatures of these modifications, likely via altering the H-bonding/organization status of the hydration waters both in the unbound and the bound states. This carboxylate group was found to be proenthalpic, antientropic in some cases, and antienthalpic, proentropic in others. A remarkable enthalpy entropy compensation relationship was also observed, reflecting the fact that the hydrophobic effect is governed by the thermodynamic status of the associated aqueous environment. This study could improve our understanding of the hydrophobic effect and may enhance our ability to design potent ligands that are capable of modulating biological processes. PMID- 24479948 TI - The utility of exome sequencing for genetic diagnosis in a familial microcephaly epilepsy syndrome. AB - BACKGROUND: Despite remarkable advances in genetic testing, many adults with syndromic epilepsy remain without a molecular diagnosis. The challenge in providing genetic testing for this patient population lies in the extensive genetic heterogeneity associated with epilepsy. Even for the subset of epilepsy patients that present with a defining feature, such as microcephaly, the number of possible genes that would require interrogation by Sanger sequencing is extensive and often prohibitively expensive. CASE PRESENTATION: We report a family of French Canadian descent with four adult children affected with severe intellectual disability, epilepsy and microcephaly born to consanguineous parents and evaluated by the Genetics Service to provide informed genetic counseling to unaffected family members regarding possible recurrence risks. We used whole exome sequencing (WES) of DNA from one affected sibling as a first-line diagnostic tool and compared the prioritization of variants using two strategies: 1) focusing on genes with homozygous variants; and, 2) focusing on genes associated with microcephaly. Both approaches prioritized the same homozygous novel frameshift mutation (p.Arg608Serfs*26) in WDR62, a gene known to cause autosomal recessive primary microcephaly. Sanger sequencing confirmed the presence of the homozygous mutation in the other three affected siblings. CONCLUSIONS: WES and subsequent filtering of the rare variants in a single affected family member led to the rapid and cost-effective identification of a novel homozygous frameshift mutation in WDR62, thereby explaining the severe neurodevelopmental disorder in this family and facilitating genetic counseling. Our findings support WES as an effective first-line diagnostic tool in families presenting with rare genetically heterogeneous neurological disorders. PMID- 24479950 TI - Concentration, activity and biochemical characterization of myeloperoxidase in fresh and post-thaw equine semen and their implication on freezability. AB - Myeloperoxidase (MPO) is a pro-oxidant enzyme associated with decreased motility in thawed equine semen. This study aimed to describe MPO concentration, activity and subunits in raw and thawed semen and to correlate these data with motilities in raw and thawed semen. Semen samples from five stallions were collected four times. Motilities were assessed in raw and thawed semen. MPO assays were performed in raw seminal plasma, raw sperm-rich pellet and thawed semen. Total and active MPO concentrations were, respectively, assayed by enzyme-linked immunosorbent assay and specific immunological extraction followed by enzymatic detection. MPO subunits present in semen were characterized by Western blot. Purified active MPO was added in saline solution and freezing extender to control its activity during freezing procedure. Differences between medians were determined using Kruskal-Wallis test, and correlations were determined using Spearman's test for nonparametric data. Active MPO concentration was low in seminal plasma and thawed semen, but high in pellet (p = 0.0058), as the opposite relation was observed for total MPO concentration (p < 0.0001). In seminal plasma and post-thaw semen, inactive 86-kDa MPO precursor was mainly observed. Purified MPO activity was decreased in the extender (p = 0.0286). MPO activity in pellet was highly correlated with thawed progressive motility (r = -0.5576, p = 0.0086). Inactive MPO precursor and unknown low molecular weight inactive MPO precursor subunits explain low MPO activity in semen. Major MPO activity was observed in pellet, and post-thaw loss of activity is partially explained by MPO inactivation in extender. Thawed semen motility was negatively correlated with MPO activity in pellet, becoming a potential freezability predictor. PMID- 24479951 TI - Coxiella burnetii (Q-Fever) Seroprevalence in Prey and Predators in the United Kingdom: Evaluation of Infection in Wild Rodents, Foxes and Domestic Cats Using a Modified ELISA. AB - Coxiella burnetii, the agent of Q-fever, is recognized as a worldwide zoonosis with a wide host range and potentially complex reservoir systems. Infected ruminants are the main source of infection for humans, but cats and other mammals, including wild rodents, also represent potential sources of infection. There has been a recent upsurge of reported cases in humans, domestic ruminants and wildlife in many parts of the world, and studies have indicated that wild brown rats may act as true reservoirs for C. burnetii and be implicated in outbreaks in livestock and humans. However, investigation of reservoir systems is limited by lack of validated serological tests for wildlife or other non-target species. In this study, serum samples from 796 wild rodents (180 bank voles, 309 field voles, 307 wood mice) 102 wild foxes and 26 domestic cats from three study areas in the UK were tested for the presence of antibodies to C. burnetii using a commercial indirect ELISA kit modified for use in multiple wildlife species. Test thresholds were determined for each species in the absence of species-specific reference sera using a bi-modal latent class mixture model to discriminate between positive from negative results. Based on the thresholds determined, seroprevalence in the wild rodents ranged from 15.6% to 19.1% depending on species (overall 17.3%) and was significantly higher in both foxes (41.2%) and cats (61.5%) than in rodents. This is the first report to quantify seroprevalence to C. burnetii in bank voles, field voles, wood mice, foxes and cats in the UK and provides evidence that predator species could act as indicators for the presence of C. burnetii in rodents. The study demonstrates that wildlife species could be significant reservoirs of infection for both livestock and humans, and the high seroprevalence in domestic cats highlights the potential zoonotic risk from this species. PMID- 24479952 TI - Effects of Carissa opaca fruits extracts on oxidative pulmonary damages and fibrosis in rats. AB - BACKGROUND: Carissa opaca is a Pakistani fruit, traditionally used in the treatment of various human ailments including asthma and pulmonary damage. The present study investigated the protective effects of Carissa opaca against CCl4 induced oxidative stress in rat lungs. METHODS: To assess the protective effects of Carissa opaca, 42 Sprague-Dawley male rats (170-180 g) were randomly divided into 7 groups. Group I was untreated and group II received olive oil intraperitoneally (i.p.) and dimethyl sulfoxide orally. Groups III, IV, V, VI and VII were administered CCl4, 3 ml/kg bodyweight (30% in olive oil i.p.). Group IV was administered 50 mg/kg bodyweight silymarin whereas groups V, VI and VII were treated with 200 mg/kg of various fractions of Carissa opaca after 48 h of CCl4 treatment for eight weeks. Antioxidant profiles in lungs were evaluated by estimating the activities of antioxidant enzymes: catalase, peroxidase, superoxide dismutase, glutathione-S-transferase, glutathione reductase, glutathione peroxidase, quinone reductase and reduced glutathione. CCl4-induced lipid peroxidation was determined by measuring the level of thiobarbituric acid reactive substances (TBARS) with conjugation of DNA damage and histopathology. RESULTS: Administration of CCl4 for 8 weeks significantly reduced (p < 0.05) the activities of antioxidant enzymes and GSH concentration while increasing TBARS content and DNA damage. Co-treatment of various fractions of Carissa opaca and silymarin restored the activities of antioxidant enzymes and glutathione content. Changes in TBARS concentration and DNA fragmentation was significantly decreased (p < 0.05) following Carissa opaca and silymarin treatment in lung. CONCLUSIONS: Histopathological changes in rat lungs induced by CCl4 were significantly restored by co-treatment with Carissa opaca and silymarin. PMID- 24479953 TI - Virtual atmospheric mercury emission network in China. AB - Top-down analysis of virtual atmospheric mercury emission networks can direct efficient demand-side policy making on mercury reductions. Taking China-the world's top atmospheric mercury emitter-as a case, we identify key contributors to China's atmospheric mercury emissions from both the producer and the consumer perspectives. China totally discharged 794.9 tonnes of atmospheric mercury emissions in 2007. China's production-side control policies should mainly focus on key direct mercury emitters such as Liaoning, Hebei, Shandong, Shanxi, Henan, Hunan, Guizhou, Yunnan, and Inner Mongolia provinces and sectors producing metals, nonmetallic mineral products, and electricity and heat power, while demand-side policies should mainly focus on key underlying drivers of mercury emissions such as Shandong, Jiangsu, Zhejiang, and Guangdong provinces and sectors of construction activities and equipment manufacturing. China's interregional embodied atmospheric mercury flows are generally moving from the inland to the east coast. Beijing-Tianjin (with 4.8 tonnes of net mercury inflows) and South Coast (with 3.3 tonnes of net mercury inflows) are two largest net-inflow regions, while North (with 5.3 tonnes of net mercury outflows) is the largest net-outflow region. We also identify primary supply chains contributing to China's virtual atmospheric mercury emission network, which can be used to trace the transfers of production-side and demand-side policy effects. PMID- 24479954 TI - Pretreatment SUVmax predicts progression-free survival in early-stage non-small cell lung cancer treated with stereotactic body radiation therapy. AB - BACKGROUND: This retrospective study aims to assess the usefulness of SUV(max) from FDG-PET imaging as a prognosticator for primary biopsy-proven stage I NSCLC treated with SBRT. METHODS: This study includes 95 patients of median age 77 years, with primary, biopsy-confirmed peripheral stage IA/IB NSCLC. All patients were treated with 60 Gy in 3 fractions with a median treatment time of six days. Local, regional, and distant failures were evaluated independently according to the terms of RTOG1021. Local, regional, and distant control, overall- and progression-free survival were estimated by the Kaplan-Meier method. Cox proportional hazards regression was performed to determine whether SUV(max), age, KPS, gender, tumor size/T stage, or smoking history influenced outcomes. SUV(max) was evaluated as both a continuous and as a dichotomous variable using a cutoff of <5 and >= 5. RESULTS: Median follow-up for the cohort was 16 months. Median OS and PFS were 25.3 and 40.3 months, respectively. SUV with a cutoff value of 5 predicted for OS and PFS (p = .024 for each) but did not achieve significance for LC (p = .256). On Cox univariate regression analysis, SUV as a dichotomous variable predicted for both OS and PFS (p = .027 and p = .030, respectively). Defined as a continuous variable, SUV(max) continued to predict for OS and PFS (p = .032 and p = .003), but also predicted LC (p = .045) and trended toward significance for DC (p = .059). SUV(max) did not predict for OS as a dichotomous or continuous variable. It did, however, predict for PFS as a continuous variable (p = .008), neared significance for local control (p = .057) and trended towards, significance for distant control (p = .092). CONCLUSIONS: SUV(max) appears to be a statistically and clinically significant independent prognostic marker for progression-free survival in patients with stage I NSCLC treated with SBRT. Prospective studies to more accurately define the role of tumor FDG uptake in the prognosis of NSCLC are warranted. PMID- 24479956 TI - Coaxial RuO2-ITO nanopillars for transparent supercapacitor application. AB - Supercapacitive properties of ruthenium oxide (RuO2) nanoparticles electrodeposited onto the indium tin oxide (ITO) nanopillars were investigated. Compared to conventional planar current collectors, this coaxially nanostructured current collector-electrode system can provide increased contact for efficient charge transport, and the internanopillar spacing allows easy access of electrolyte ions. The morphological and electrochemical properties depended on the thickness of the RuO2 layers, i.e., the number of electrodeposition cycles. A maximum specific capacitance, Csp, of 1235 F/g at a scan rate of 50 mV/s was achieved for the 30-cycle deposited RuO2-ITO nanopillars. The other capacitive properties such as electrochemical reversibility and Csp retention at high scan rates also improved greatly. PMID- 24479955 TI - Chemoradiation using cisplatin and S-1 in locally advanced giant squamous cell carcinoma of the buttock. PMID- 24479957 TI - Progressive supranuclear palsy in a family with TDP-43 pathology. AB - A member of a family with an autosomal dominant pattern of frontotemporal dementia (FTD) with a TDP-43 pathological substrate in other members and no mutations in FTD-associated genes developed behavioral variant FTD followed by Progressive Supranuclear Palsy. Autopsy revealed a pure tauopathy of PSP pattern. CONCLUSIONS: The findings raise the possibility of shared pathogenic pathways and a proximal genetic abnormality between PSP and FTLD-43. PMID- 24479958 TI - Clinical value of pre-transplant minimal residual disease in childhood lymphoblastic leukaemia: the results of the French minimal residual disease guided protocol. AB - Minimal residual disease (MRD) is a major predictive factor of the cure rate of acute lymphoblastic leukaemia (ALL). Haematopoietic cell transplantation is a treatment option for patients at high risk of relapse. Between 2005 and 2008, we conducted a prospective study evaluating the feasibility and efficacy of the reduction of immunosuppressive medication shortly after a non-ex vivo T depleted myeloablative transplantation. Immunoglobulin (Ig)H/T-cell receptor MRD 30 d before transplant could be obtained in 122 of the 133 cases of high-risk paediatric ALL enrolled. There were no significant demographic differences except remission status (first or second complete remission) between the 95 children with MRD <10(-3) and the 27 with MRD >=10(-3) . Multivariate analysis identified sex match and MRD as being significantly associated with 5-year survival. MRD >=10(-3) compromised the 5-year cumulative incidence of relapse (43.6 vs. 16.7%). Complete remission status and stem cell source did not modify the relationship between MRD and prognosis. Thus, pre-transplant MRD is still a major predictor of outcome for ALL. The MRD-guided strategy resulted in survival for 72.3% of patients with MRD<10(-3) and 40.4% of those with MRD >=10(-3). PMID- 24479959 TI - Lead excretion in milk of accidentally exposed dairy cattle. AB - Lead (Pb) exposure in dairy cattle is associated with economic losses due to mortality and treatment costs, but with production animals there is also risk to the human food chain. The first objective of this study was to quantify the Pb concentration in milk from Pb-exposed cattle. The second objective was to correlate blood and milk Pb concentrations from individual cows. The third objective was long-term monitoring to determine the duration of milk contamination after exposure ceased. A dairy herd of more than 100 cows was accidentally exposed to Pb-contaminated feed. Milk and blood were collected for Pb analysis. Serial collection of milk samples continued for 2.5 years. The initial concentration of Pb in bulk tank milk was 0.0999 mg l-1. The highest milk Pb concentration from an individual cow was 0.4657 mg l-1 and the highest blood Pb concentration was 1.216 mg l-1. One milk sample collected at the end of the study (day 922) contained 0.0117 mg Pb l-1 of Pb. The calculated relationship between milk (y) and blood (x) Pb concentration was ln(y) = 3.4(x) - 2.21 (R2 = 0.98). PMID- 24479961 TI - Photophysics of flavin derivatives absorbing in the blue-green region: thioflavins as potential cofactors of photoswitches. AB - The purpose of this study was to find flavin derivatives with absorption maxima in the blue-green region of the visible spectrum that might be used as alternative cofactors in blue-light photoreceptors. To this end, the vertical absorption spectra of eight lumiflavin-related compounds were calculated by means of quantum chemical methods. The compounds differ from lumiflavin by the subsitution of an S atom for an O atom at the 2- and/or 4-positions of the isoalloxazine core, the substitution of an N atom for a CH group in the 6- and/or 9-positions, or an extension of the pi system at the 7- and 8-positions. For the three most promising compounds, 2-thio-lumiflavin, 4-thio-lumiflavin, and 2,4 dithio-lumiflavin, the quantum chemical investigations were extended to include geometry relaxations in the excited states, rates for spin-forbidden transitions and an estimate of spectral shifts brought about by polar protic environments. We find these thiocarbonyl compounds to have very promising excited-state properties. They absorb in the blue-green wavelength regime around 500 nm, i.e., substantially red-shifted with respect to lumiflavin that is the cofactor of natural blue-light photoreceptors. Their triplet quantum yields are predicted to be close to unity while their triplet lifetimes are long enough to enable bimolecular photochemical reactions. The combination of these properties makes the thioflavins potentially suitable candidates as cofactors in biomimetic photoswitches. PMID- 24479960 TI - Rapid genetic adaptation precedes the spread of an exotic plant species. AB - Human activities have increasingly introduced plant species far outside their native ranges under environmental conditions that can strongly differ from those originally met. Therefore, before spreading, and potentially causing ecological and economical damage, non-native species may rapidly evolve. Evidence of genetically based adaptation during the process of becoming invasive is very scant, however, which is due to the lack of knowledge regarding the historical genetic makeup of the introduced populations and the lack of genomic resources. Capitalizing on the availability of old non-native herbarium specimens, we examined frequency shifts in genic SNPs of the Pyrenean Rocket (Sisymbrium austriacum subsp. chrysanthum), comparing the (i) native, (ii) currently spreading non-native and (iii) historically introduced gene pool. Results show strong divergence in flowering time genes during the establishment phase, indicating that rapid genetic adaptation preceded the spread of this species and possibly assisted in overcoming environmental constraints. PMID- 24479963 TI - Graduate medical education in the European region. PMID- 24479964 TI - The way we teach: how I did and how I should teach surgery. AB - Combined sessions are an important part of teaching surgery in the first years though they are very demanding of staff. During the Junior/Introductory Course the student should be given plenty of time to acquire understanding of and facility with a whole new vocabulary and to feel at ease talking to the sick. At this stage there should be no formal separate surgery course. Students are introduced to the reality of the clinical encounter and are given a rough outline of the areas in standard texts that they should have read. They are also taught about aspects of theatre drill. During the next years students are encouraged to think about simple clinical problems in an algorithmic way, and simulators are used to teach them how to use the simple surgical tools of the trade. In the last year an 'open round' is run to identify problems and students are provided with self-test material. The residency period should be used to enable student locums and preregistration house officers to achieve a measure of organizational experience, a sense of command, and to extend their communication skills by presenting patients at formal meetings. How students acquire clinical method remains to be established. PMID- 24479966 TI - Towne's Wax Teaching Models. AB - This month sees the centenary of the death of Joseph Towne, wax modeller of world renown. Born in the small English village of Royston, Hertfordshire, his skills were recognized when he came to London at the age of 17 with his first important work, a miniature skeleton in wax (Figure 1). Towne made the acquaintance of the eminent surgeon, Sir Astley Cooper, who gave him a written testimonial verifying the accuracy of the model and a letter of introduction to a colleague of his at Guy's Hospital (World Medicine 1965). Thus started Towne's association with Guy's, which lasted for 53 years. During that time he fashioned some 50 anatomical models and about 650 dermatological ones, all outstanding for their realism, exquisite detail and brilliant colours (Figures 2, 3 and 4). The anatomical models owe much to John Hilton, an eminent surgeon at Guy's, whose book Rest and Pain is still widely read, while Towne's skin collection owes much to Thomas Addison, physician to Guy's. PMID- 24479965 TI - How to: improve lecturing. AB - This article outlines a simple model of the way students learn from lectures and describes nine basic skills of lecturing. It goes on to explore three lecture methods-the classical method, the problem-centred method and the sequential method-from the point of view of their usefulness, requirements and pitfalls. Finally, it proposes five basic steps in the preparation of a lecture. PMID- 24479962 TI - Exposure to chlorpyrifos in gaseous and particulate form in greenhouses: a pilot study. AB - Phase distribution of airborne chemicals is important because intake and uptake mechanisms of each phase are different. The phase distribution and concentrations are needed to determine strategies of exposure assessment, hazard control, and worker protection. However, procedures for establishing phase distribution and concentration have not been standardized. The objective of this study was to compare measurements of an airborne semivolatile pesticide (chlorpyrifos) by phase using two different procedures. Six pesticide applications in two facilities were studied and at each site, samples were collected for three time slots: T1, the first 1 or 2 hr after the commencement of application; T2, a 6-hr period immediately following T1; and T3, a 6-hr period after the required re entry interval (24 hr for chlorpyrifos).Two phase-separating devices were co located at the center of each greenhouse: semivolatile aerosol dichotomous sampler (SADS) using flow rates of 1.8 l x min(-1) and 0.2 l x min(-1), corresponding to a total inlet flow rate of 2.0 l x min(-1) with a vapor phase flow fraction of 0.1; and an electrostatic precipitator (ESP), along with a standard OVS XAD-2 tube. Chlorpyrifos in vapor and particulate form in a SADS sampling train and that in vapor form in an ESP sampling train were collected in OVS tubes. Chlorpyrifos in particulate form in the ESP setting would have been collected on aluminum substrate. However, no chlorpyrifos in particulate form was recovered from the ESP. Overall (vapor plus particle) concentrations measured by OVS ranged 11.7-186.6 MUg/m(3) at T1 and decreased on average 77.1% and 98.9% at T2 and T3, respectively. Overall concentrations measured by SADS were 66.6%, 72.7%, and 102% of those measured by OVS on average at T1, T2, and T3, respectively. Particle fractions from the overall concentrations measured by SADS were 60.0%, 49.2%, and 13.8%, respectively, for T1, T2, and T3. SADS gives better guidance on the distribution of chlorpyrifos than does the ESP, although the accuracy of the concentration distribution cannot be verified in the absence of a standardized procedure for determining phase division. PMID- 24479967 TI - Special article: clinical rotations in postgraduate medical education. AB - This review considers the design and organization of rotations providing training in internal medicine at two levels-general training and higher professional training. The principle of rotation discussed here has also been successfully applied in other disciplines, such as surgery. PMID- 24479968 TI - The New Programmes: Decentralized Medical Education in the USA: The WAMI Programme. AB - This article describes an experiment to provide decentralized medical education in Washington, Alaska, Montana and Idaho-four states sharing common problems of health care provision and education of health professionals, including physicians. Evaluation of eight years' experience with the programme shows that the goals are being met. The basic concept of the WAMI programme is applicable to other health disciplines and/or regions with similar geographic, financial, educational and health care challenges. PMID- 24479969 TI - Controversy: pomr-the case in favour. AB - The subject of medical records is not popular with clinicians these days. Having to see patients in the clinic without their notes is too common an experience, and one which raises the blood pressure of both doctor and patient. Paradoxically though, it does force us reluctantly to concede that these maligned documents do have a purpose. It might even persuade us that it is illogical to attach so much importance to them when they are missing, and to treat them with such indifference when they are not. PMID- 24479970 TI - Personal view: medical education in sweden: urgently needed reforms. AB - I have been licensed as a physician in Sweden for more than 50 years, working for most of this time at the Royal University of Lund, the Royal University of Gothenburg and the Royal University of Uppsala. My experience has been mostly as Professor of Medicine, but I have also had considerable experience in Anatomy, the most important preclinical subject. My researches have resulted in more than 300 articles and books. PMID- 24479971 TI - In brief: patient education resource file. AB - Provision of patient education is often poor because the resources are not available. At the University of Alberta Health Sciences Centre a patient education resource file has been established to help to meet this need. PMID- 24479973 TI - Educational organizations: the Scottish council for postgraduate medical education. AB - It has never been true to say-and how much less is it true today-that once a doctor has passed his final examinations and is entering practice his education has been completed. William Osler wrote at the beginning of this century (Osler 1900): "More clearly than any other, the physician should illustrate the truth of Plato's saying that education is a life-long process. The training at medical school gives a man his direction, points him the way, and furnishes him a chart, fairly incomplete for the voyage, but nothing more." There is a great variation in the way individual doctors continue to learn after completing a formal undergraduate course. Once established in a particular field of practice, they learn from their own experience, from colleagues with whom they work, from attending seminars and lectures, from reading, and from membership of medical clubs and societies; but it is in the interval between graduation and full establishment in practice that the need for training varies most noticeably from one specialty to another. PMID- 24479975 TI - Educational instruments: evaluation of a tutor or discussion group leader. AB - In this occasional series we will be printing evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. PMID- 24479976 TI - Audiovisual programmes:the audiovisual centre, university of london. AB - The aim of this series is to draw teachers' attention to useful sources of audiovisual programmes, to describe the services they provide and to highlight some of their recent titles. PMID- 24479977 TI - Letters. PMID- 24479979 TI - Courses and conferences. PMID- 24479980 TI - Review article: anti-adhesion therapies for inflammatory bowel disease. AB - BACKGROUND: A high proportion of patients with inflammatory bowel disease (IBD) do not achieve clinical remission with the current therapies including mesalazine (mesalamine), immunossupresants (IMS) and antibodies against tumour necrosis factor (anti-TNF). Moreover, IMS and anti-TNF involve a nonnegligible risk for infections and/or malignancies. The anti-adhesion molecules are one of the most interesting new treatments because of their gut-selectivity. AIM: To review the physiopathology of the adhesion molecules and the current drugs targeting this mechanism. METHODS: We performed a literature review in PubMed and in clinicaltrials.gov using the terms 'anti-adhesion molecules', 'inflammatory bowel disease', 'natalizumab', 'vedolizumab', 'AMG181', 'Etrolizumab', 'PF-00547659', 'AJM300', 'Alicaforsen' and 'CCX282-B' up to November 2013. RESULTS: A total of eight drugs were found including those targeting the alpha4beta1, alpha4beta7 or alphaEbeta7 integrins as well as the ICAM-1 and MAdCAM-1 addressins and the chemokine receptor 9. The rationale for these drugs is the blockade of gut-homing T lymphocytes and the ones targeting the alpha4beta7/MAdCAM-1 interaction presented the most promising results in luminal disease. Vedolizumab, an alpha4beta7 antibody, has completed phase 3 trials with very positive results especially for ulcerative colitis. However, many questions remain unanswered such as the effect of these therapies in perianal disease and extraintestinal manifestations. CONCLUSIONS: The blockade of the alpha4beta7/MAdCAM-1 interaction and especially vedolizumab is an effective and safe gut-specific treatment for IBD. Further studies are needed to clarify the efficacy and safety of the other anti-adhesion drugs and to define the specific indications of these therapies in the different scenarios of IBD. PMID- 24479981 TI - Cangrelor for treatment of arterial thrombosis. AB - INTRODUCTION: Percutaneous coronary intervention (PCI) is a highly effective treatment for obstructive coronary artery disease. Oral platelet P2Y12 receptor antagonists reduce ischemic events in patients treated with PCI. However, there are several limitations to their use, including variable pharmacodynamics, a slow onset and offset, and in those patients who are pretreated but subsequently require cardiac surgery, increased bleeding. Cangrelor is an intravenous agent that provides rapid and intensive inhibition of the P2Y12 receptor that quickly dissipates after discontinuation. A recent, Phase III randomized clinical trial of PCI patients demonstrated that cangrelor bolus and infusion reduced ischemic events compared with conventional clopidogrel therapy without increasing major bleeding. AREAS COVERED: This review outlines the pharmacodynamics, pharmacokinetics, and the safety and efficacy of cangrelor for the acute treatment of patients undergoing planned PCI. EXPERT OPINION: Cangrelor is an important addition to the current armamentarium of platelet inhibitors as it significantly reduces periprocedural myocardial infarction and stent thrombosis in a broad spectrum of patients, without increasing major bleeding or the need for transfusion. Cangrelor will have particular benefit in clopidogrel-naive patients with high anatomical complexity and/or increased clinical risk (where the absolute risk for thrombotic and ischemic complications of PCI is greatest). PMID- 24479982 TI - Effects of walking combined with restricted leg blood flow on mTOR and MAPK signalling in young men. AB - Walking combined with blood flow reduction (BFR-walk) elicits muscle hypertrophy. However, the skeletal muscle intracellular signalling behind this response is currently unknown. AIM: To investigate the effects of BFR-walk on mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase (MAPK) signalling pathways in young men. METHODS: Six young men performed 20 min of treadmill walking at 55% of their predetermined maximum oxygen uptake. A pressure cuff belt was applied to the most proximal thigh of only one leg (BFR-Leg, external compression was 240 mmHg), whereas the other leg (CON-Leg) was without BFR during walking. Muscle biopsies were taken from the vastus lateralis of the CON-Leg before exercise and in both legs 3 h after exercise. RESULTS: Erk1/2 phosphorylation levels were significantly (P < 0.05) increased after exercise in both legs; however, only the BFR-Leg saw an increased phosphorylation of p38. For mTOR signalling, there were no changes in Akt, mTOR or S6K1 phosphorylation levels before or after walking. However, eEF2 phosphorylation level was significantly (P < 0.05) lower for the BFR-Leg 3 h after walking compared with CON-Leg. CONCLUSION: BFR-walk exercise may activate some intracellular signalling cascades that are associated with muscle hypertrophy in young men. PMID- 24479983 TI - Pd(II)-catalyzed ortho-C-H oxidation of arylacetic acid derivatives: synthesis of benzofuranones. AB - Pd(II)-catalyzed ortho-C-H acetoxylation of arylacetic acid derivatives is demonstrated with the aid of a novel S-methyl-S-2-pyridylsulfoximine (MPyS) directing group (DG). The alpha-mono- and alpha-unsubstituted arylacetic acid derivatives were readily employed in the ortho-C-H acetoxylations. The oxidation products are hydrolyzed, and the MPyS-DG is easily recovered, providing ready access to o-hydroxyarylacetic acids. 3-Mono- and 3-unsubstituted benzofuranones are synthesized from o-hydroxyarylacetic acids. PMID- 24479984 TI - Personal profile: interview with Tanja Dominko, DVM, PhD. PMID- 24479985 TI - The 24-h recall instrument for home nursing to measure the activity profile of home nurses: development and psychometric testing. AB - Home health care today is challenged by a shift from an acute to a chronic health care model, moving the focus of care from the hospital to home-care setting. This increased focus on care at home emphasizes the need for an efficient, effective, and transparent management of home health care. However, it is not precisely known what home-care nurses do; what kind of care is received by patients; what the performance of home nurses is; and what the impact of the increasing need for home nursing is on the current and future role of home nurses. In this respect, it is necessary to gain a clear insight into the activity profile of home nurses, but there is no gold standard to measure their activities. This study reports on the development and psychometric testing of the '24-hour recall instrument for home nursing' to measure the activity profile of home nurses. Five home nurses in Belgium, simultaneously with the researcher, registered the performed activities in a total of 69 patients, using the 24-h recall instrument for home nursing. The validity and the interrater reliability of this instrument were high: the proportions that observed agreement were very high; the strength of kappa agreement was substantial to almost perfect; the prevalence index showed great variety; and the bias index was low. The findings in this study support the validity evidence based on test content and the interrater reliability of the 24 h recall instrument. This instrument can help to shape practice and policy by making the home nursing profession more transparent: a clear insight into the kind of care that is provided by home nurses and is received by the patients in primary care contributes to the development of a clear definition of the role of home nurses in health care. PMID- 24479986 TI - Non-recurrent inferior laryngeal nerve identification during robotic thyroidectomy. AB - OBJECTIVE: A non-recurrent inferior laryngeal nerve is a rare anomaly in which the nerve enters the larynx directly off the cervical vagus nerve, without descending to the thoracic level. It is very susceptible to damage during surgery. This report describes the important pre-operative radiological evaluations and surgical landmarks in a case of a non-recurrent inferior laryngeal nerve, identified during the recently developed technique of robotic thyroidectomy. CASE REPORT: A 38-year-old woman presented with suspected papillary microcarcinoma, as indicated by aspiration cytology. Pre-operative computed tomography showed a right aberrant subclavian artery that indicated a possible right non-recurrent inferior laryngeal nerve. Using robotic thyroidectomy methods, it was possible to carefully dissect along the thyroid capsule. The laryngeal entrance point of the right non-recurrent inferior laryngeal nerve (a constant anatomical landmark) was successfully identified via the three-dimensional, high-magnification views provided by the robotic endoscope. CONCLUSION: With proper knowledge of radiological and surgical anatomy, and the benefits of high-magnification endoscopic views, a non-recurrent inferior laryngeal nerve can be safely preserved during robotic surgery. PMID- 24479987 TI - Influence of riboflavin on nanoscale zero-valent iron reactivity during the degradation of carbon tetrachloride. AB - Experiments were conducted to investigate the effect of riboflavin on the reactivity of nanoscale zerovalent iron (NZVI) during three reaction cycles of carbon tetrachloride (CT) degradation. The degradation kinetics of CT by NZVI without riboflavin (0.556 +/- 0.044 h(-1)) was 1.5 times higher than that with riboflavin (0.370 +/- 0.012 h(-1)) in the first cycle. Riboflavin was rapidly reduced (65.0 +/- 7.0 h(-1)) by NZVI during CT degradation, resulting in the slow degradation kinetics of CT in the first cycle due to competition for electrons from NZVI between riboflavin and CT. These results indicate that riboflavin is not effective as an electron shuttle for reduction of CT by NZVI. On the other hand, the degradation kinetics of CT by NZVI without riboflavin decreased to 0.122 +/- 0.033 h(-1) in the third cycle, while that with riboflavin was significantly enhanced (0.663 +/- 0.005 h(-1)). The results from X-ray analyses and transmission electron microscopy suggest that the decline in reactivity of NZVI without riboflavin in the third cycle resulted from continuous Fe(0) oxidation to iron oxides on the NZVI surface. In contrast, riboflavin enhanced the reactivity of NZVI by reductive dissolution of passive iron oxides on NZVI surface by reduced riboflavin. The experimental results suggest that riboflavin can play a pivotal role in the prolongation of NZVI reactivity in long-term in situ and ex situ applications of NZVI. PMID- 24479988 TI - Neospora caninum infection during early pregnancy in cattle: how the isolate influences infection dynamics, clinical outcome and peripheral and local immune responses. AB - This work studies the influence of Neospora caninum intra-species diversity on abortion outcome, infection dynamics in terms of parasite dissemination and peripheral-local immune responses in pregnant cattle. Animals were intravenously inoculated at day 70 of pregnancy with 107 tachyzoites of two isolates showing marked differences in virulence in vitro and in pregnant mouse models: Nc-Spain7, a high virulence isolate, and Nc-Spain8, a low-to-moderate virulence isolate. After inoculation, pregnancy was monitored, and dams were culled when foetal death was detected. Foetal mortality occurred in all infected heifers between days 24 and 49 post-infection (pi), however, it was detected sooner in Nc-Spain7 infected animals (median day = 34) than those inoculated with Nc-Spain8 (median day = 41) with a trend towards significance (P < 0.11). Similar histological lesions were observed in placentomes and in most of the foetuses from the two infected groups. However, parasites were more frequently detected in the placenta and foetuses by PCR and in the foetal brain by immunohistochemistry in Nc-Spain7 infected animals. Specific antibodies were detected starting at day 13 post infection in all infected cattle, with higher IgG levels in Nc-Spain7-infected group. IFN-gamma and IL-4 profiles also varied between infected groups in PBMC stimulation assays. Infected animals showed significant increases in their cytokine mRNA levels (IFN-gamma, IL-4, IL-10, IL-12p40 and TNF-alpha) in the caruncle at time of foetal death. Differences between the infected groups were also observed for cytokine profiles. These results demonstrate the influence of the N. caninum isolate on foetal death outcome, infection dynamics and immune responses in cattle. PMID- 24479989 TI - The role of emergency surgery in hydatid liver disease. AB - Hepatic hydatid disease is very common in Libya. In Zliten hospital, we operated 400 patients with hepatic hydatid cysts over period of 20 years. All patients were symptomatic. Their ages varied from 3 to 85 years including 215 female and 185 male patients. Their symptoms varied from abdominal pain to abdominal mass 67 patients were admitted through Accident and Emergency Department with acute presentations including fever, skin rash, jaundice and shock with acute abdominal pain. Those 67 patients had necessary investigations, resuscitation and underwent emergency surgery. The hepatic cysts in all patients were excised, and the obstructive jaundice was cleared in those patients with obstructive jaundice. Unfortunately, one of the patients died two days after the surgery because of multiple organ failure (MOF) Morbidity was wound Infection, bile leak and recurrence rate were all reported in our series. PMID- 24479990 TI - Additional barriers to clinical supervision for allied health professionals working in regional and remote settings. PMID- 24479991 TI - Poor quality diet is associated with overweight status and obesity in patients with polycystic ovary syndrome. AB - BACKGROUND: The high rates of overweight status observed in women with polycystic ovary syndrome (PCOS) may reflect dietary intake, and so it is important to investigate diet quality and its relationship with the rates of overweight status and obesity among these patients. METHODS: A cross-sectional study was conducted in which 100 women with PCOS (Rotterdam criteria) were evaluated considering anthropometric and dietary data. The anthropometric evaluation included the measurement of weight, height, body mass index (BMI), waist circumference (WC), hip circumference and waist-hip ratio. Food intake data were collected from two 24-h dietary recalls to assess dietary patterns using the Brazilian Healthy Eating Index - Revised (BHEI-R). RESULTS: The anthropometric analysis indicated a high prevalence of overweight status, obesity and increased visceral fat (30.0%, 60.0% and 90.0%, respectively). The mean BHEI-R score was 56.1 +/- 12.0 points (range 34.5-77.5 points). Diet quality was negatively correlated with obesity, which was evaluated by BMI (r = -0.248; P = 0.013) and WC (r = -0.278; P = 0.005). CONCLUSIONS: Dietary interventions focused on improvement of diet quality should be targeted to treat patients with PCOS because obesity in these women is associated with worsening endocrine, metabolic and reproductive functions. PMID- 24479992 TI - What is the role of genetic testing in the investigation of patients with suspected platelet function disorders? AB - Inherited platelet function disorders (PFDs), associated with normal or reduced platelet counts, account for a significant proportion of bleeding diatheses. Identification of the underlying genetic defects is difficult in the majority of cases due to the variable clinical expression of the bleeding symptoms and the redundancy of platelet receptor and signalling pathways, which add to the complexity of diagnosis. The gold standard method for phenotyping platelets, light transmission aggregometry (LTA), has allowed classification of functional defects in the majority of patients referred for investigation of suspected PFDs, while DNA-based analysis has primarily played a confirmatory role and been restricted mainly to analysis of candidate genes. Recent advances in next generation sequencing have facilitated the identification of gene defects in patients with PFDs where the underlying genetic defect was previously unknown, especially when combined with genome-wide linkage analysis. These studies have provided new insights into the mechanisms controlling platelet formation and function, and it is likely that, as understanding of the relationships between platelet phenotype and genotype increases and pipelines for the interpretation of genetic variations identified in patients are developed, DNA-based analysis will play an increasingly important role in the first-line investigation of patients with PFDs. PMID- 24479996 TI - Abstracts - AAFITN/ANZSNR 2010 - Asian-Australasian Federation of Interventional and Therapy Neuroradiology & Australian & New Zealand Society of Neuroradiology - Melbourne, Australia - 22-25 April 2010. PMID- 24479995 TI - Anti-depressive mechanism of repetitive transcranial magnetic stimulation in rat: the role of the endocannabinoid system. AB - Repetitive transcranial magnetic stimulation (rTMS) to treat depression has been thoroughly investigated in recent years. However, the underlying mechanisms are not fully understood. In this study, a chronic unpredictable mild stress (CUMS) paradigm was applied to male Sprague Dawley rats. Then rTMS was performed for 7 consecutive days, and the anti-depressive effects were evaluated by the sucrose preference test (SPT), the forced swimming test (FST), and the open-field test (OFT). Hippocampal cannabinoid type I receptor (CB1) expression was measured, and the expression levels of brain-derived neurotrophic factor (BDNF), Bcl-2, and Bax and the number of bromodeoxyuridine (BrdU)-positive cells were also investigated. These parameters were also observed after the selective CB1 receptor antagonist AM251 was used as a blocking agent. The results showed that CUMS induced a significant decrease in sucrose preference, a significant increase in immobility time in the FST, and a significantly decreased horizontal distance in the OFT. In addition, reduced hippocampal CB1 receptor, BDNF, and Bcl-2/Bax protein expression levels in CUMS rats, as well as decreased cell proliferation were also observed in the dentate gyrus. Meanwhile, rTMS treatment up-regulated cell proliferation; elevated CB1 receptor, BDNF, and Bcl-2/Bax expression levels in the hippocampus; and ameliorated depressive-like behaviors. All of these beneficial effects were abolished by AM251. These results indicate that rTMS increases BDNF production and hippocampal cell proliferation to protect against CUMS-induced changes through its effect on CB1 receptors. PMID- 24479997 TI - Ketosis and EEG improvement following viral gastroenteritis in patient with West syndrome. PMID- 24480000 TI - A 'soft option' no more. PMID- 24479999 TI - Identification of suitable plasma-based reference genes for miRNAome analysis of major depressive disorder. AB - BACKGROUND: Mounting evidence has demonstrated microRNA involvement in the set of diverse pathways associated with major depressive disorder (MDD). Reverse transcription quantitative real-time PCR (RT-qPCR) has been widely used in microRNA expression studies. To achieve accurate and reproducible microRNA RT qPCR data, reference genes are required. The goal of this study is to systematically identify suitable reference genes for normalizing RT-qPCR assays of microRNA expression in the plasma of MDD patients. METHODS: Candidate reference genes were selected from plasma samples of both MDD and healthy controls by miRNA microarrays, in addition to a frequently used reference gene - U6 small nuclear RNA. Putative reference genes were thereafter validated by RT qPCR in plasma samples, and analyzed by the four statistical algorithms geNorm, NormFinder, BestKeeper and the comparative delta-Ct method. Finally, the validity of the selected reference genes was assessed with two significantly decreased miRNAs identified by microarray. RESULTS: Five miRNAs (miR-320d, miR-101-3p, miR 106a-5p, miR-423-5p, miR-93-5p) based on microarray data and U6 were identified as putative reference genes. The results of the merged data from four statistical algorithms revealed that the most adequate microRNAs tested for normalization were miR-101-3p and miR-93-5p. Assessment of the validity of the selected reference genes confirms the suitability of applying the combination of miR-101 3p and miR-93-5p as optimal references genes. LIMITATIONS: Relatively small sample size; and lack of other disease groups. CONCLUSIONS: The normalization methods proposed here can contribute to improve studies on MDD biomarker identification and/or pathogenesis by providing more reliable and accurate expression measurements. PMID- 24480001 TI - Allocation of resources using a simulation game. PMID- 24480002 TI - Use modified essay questions. AB - In the second issue of Medical Teacher (1979, 1, 65-70), Professor R. M. Harden gave an overview of assessment in medical education. Here, Professor Knox describes some of the issues involved in one form of assessment-the Modified Essay Question. With careful preparation, this technique can provide a measure of abilities (including attitudes) which cannot easily be assessed by other means. The MEQ can also provide a brisk learning experience in small groups or at a large plenary session. PMID- 24480003 TI - Using computer-controlled interactive manikins in medical education. AB - In the July/August issue of Medical Teacher, Jack Marshall provided an overview of various methods that have been developed to help students learn procedural skills. Here, Stephen Abrahamson and Peggy Wallace describe in detail and offer practical advice on the use of one of these techniques, computer-controlled interactive manikins-simulators which respond to what students are doing to them. The use of static simulators and simulated patients will be the subject of future articles in Medical Teacher. PMID- 24480004 TI - Improving staff-student relations: effects of a humanistic medicine programme. AB - At the University of Maryland School of Medicine, faculty and students are invited to participate in a programme dealing with the psychosocial aspects of medicine and interpersonal skills development (Human Dimensions in Medical Education-HDME). Utilizing a small-group format, this programme encourages discussion of attitudes and feelings on a wide range of topics in an open, supportive environment. Shortly after the programme became fully operational, first-, second- and third-year medical students evaluated their relationships with their faculty advisers using a 25-item questionnaire. Students assigned to advisers who participated in the HDME programme reported higher activity in ten behavioural areas than students of non-HDME advisers, generally reflecting closer personal relationships and greater adviser initiative in establishing relationships. In addition, HDME students felt more at ease approaching their advisers with a personal problem than did students who had not participated in the HDME programme. Programme-related activities were the most frequent source of close relationships between faculty and student programme participants. Overall results emphasized the value of faculty initiative in establishing relationships with students and the impact of opportunities for small-group interaction, whether in academic or social settings, for the development and maintenance of an institutional support system. Such opportunities for personal contact can assist students to deal more easily with the pressures of the educational process, and with conflicts among personal and professional priorities that will characterize their lives as physicians. PMID- 24480005 TI - Medical record review form. AB - In this series we will be printing evaluation instruments, questionnaires, rating scales and similar resource material useful to teachers, evaluators and planners. You may wish to use or adapt such instruments for your own purposes. The feature in this issue has been prepared by Neil McIntyre, B.SC, MD, FRCP, Professor of Medicine and Clinical Sub-Dean, Royal Free Hospital School of Medicine, Rowland Hill Street, London NWS 2QG, UK, from whom further information is available. PMID- 24480006 TI - Self assessment:giving a brief for an educational illustration. AB - This series provides teachers with the opportunity of assessing their knowledge and understanding of some important aspects relating to their work as teachers. Only after you have commited your own answers to paper should you read the answers given. PMID- 24480009 TI - Jottings. PMID- 24480011 TI - Courses and conferences. PMID- 24480012 TI - Chronic cutaneous varicella zoster virus infection complicating dermatomyositis. AB - Chronic cutaneous varicella zoster virus (VZV) infection has not been previously reported or characterized as a complication of dermatomyositis. Two patients with non-malignancy-associated dermatomyositis, treated with long-term prednisone and methotrexate, developed persistent, painless ulcers ultimately established to be secondary to chronic VZV. The absence of pain or a history suggestive of acute VZV, and the lack of characteristic histopathology, resulted in a lengthy delay in diagnosis. Polymerase chain reaction and tissue immunohistochemistry were positive for VZV, and treatment with valacyclovir resulted in complete clearance. Diagnostic testing for VZV should thus be considered in the evaluation of ulcerative lesions in patients with dermatomyositis. The increased incidence of acute VZV in combination with the nature and duration of immunosuppressive treatment in this patient population may be contributory. PMID- 24480013 TI - An experimental test of whether cheating is context dependent. AB - Microbial cells rely on cooperative behaviours that can breakdown as a result of exploitation by cheats. Recent work on cheating in microbes, however, has produced examples of populations benefiting from the presence of cheats and/or cooperative behaviours being maintained despite the presence of cheats. These observations have been presented as evidence for selection favouring cheating at the population level. This apparent contradiction arises when cheating is defined simply by the reduced expression of a cooperative trait and not in terms of the social costs and benefits of the trait under investigation. Here, we use two social traits, quorum sensing and iron-scavenging siderophore production in Pseudomonas aeruginosa, to illustrate the importance of defining cheating by the social costs and benefits. We show that whether a strain is a cheat depends on the costs and benefits associated with the social and abiotic environment and not the absolute expression of a cooperative trait. PMID- 24480014 TI - Response to Letter to the Editor regarding "Australian women's experiences of living with gestational diabetes". PMID- 24480015 TI - Metal-enhanced fluorescence-based core-shell Ag@SiO2 nanoflares for affinity biosensing via target-induced structure switching of aptamer. AB - One of the great challenges in metal-enhanced fluorescence (MEF) technology is the achievement of distance modulation with nanometer accuracy between the fluorophore and metal surface to obtain maximum enhancement. We propose an MEF based core-shell Ag@SiO2 nanoflare for distance control via the thickness of silica shell with cooperation of DNA hybridization. The nanoflare contains a 50 nm spherical silver nanoparticle (Ag NP) core, a 8 nm silica shell, and cyanine (Cy5)-labeled aptamer hybridized with a complementary DNA (cDNA) immobilized onto the shell surface. The formation of the Cy5-labeled aptamer/cDNA duplex on the Ag@SiO2 NP surface results in the confinement of Cy5 to the shell surface and an increase in the fluorescence of Cy5 with a 32-fold enhancement factor in bulk solution (signal-on). In the presence of affinity-binding targets, the Cy5 labeled aptamers confined onto the Ag@SiO2 NP surface dissociate from their cDNA into the solution because of structure switching. The target-induced release of aptamer leads to a reduction in the enhanced fluorescence signal of the labeled Cy5 moiety (signal-off). Thus, the nanoflare can be used as a sensor for target recognition. Using adenosine-5'-triphosphate (ATP) aptamer, detection of ATP has a linear response from 0 to 0.5 mM and a detection limit of 8 MUM. With various types of DNA probes immobilized onto the core-shell Ag@SiO2 NPs, the MEF-based nanoflare has provided an effective platform for the detection and quantification of a broad range of analytes, such as mRNA regulation and detection, cell sorting, and gene profiling. PMID- 24480016 TI - Social cognition and neurocognitive deficits in first-episode schizophrenia. AB - BACKGROUND: Recent research has shown a significant impact of social cognitive domains on real world functioning and prognosis in schizophrenia. However, the correlations between specific aspects of social cognition, neurocognition, IQ and clinical symptoms remain unclear in first-episode schizophrenia. Researchers have speculated about social cognitive subgroups since patients with schizophrenia appear to be a very heterogeneous group. METHODS: Patients with a recent diagnosis of first-episode schizophrenia were tested regarding theory of mind, social perception, neurocognition, IQ, and clinical symptoms. RESULTS: Data from 36 first-episode schizophrenia patients and 36 one to one matched healthy controls were analysed. Principal component analysis in the patient group was used to examine the variance contributed by different aspects of social cognition, neurocognition, and clinical symptoms. CONCLUSIONS: Complex aspects of social cognition explained 24% of the variance in the patient group. The other principal components consisted mainly of aspects of simple perception of theory of mind. Neurocognition and clinical symptoms only explained a minor proportion of the variance in the patient group. The results imply that social cognitive deficits in first-episode schizophrenia come in two distinct versions where one is a complex, cognitive demanding form linked with IQ. The other version is related to simpler forms of social cognition and independent of IQ. These two forms are comparable to the implicit and explicit mentalising discussed in the developmental literature. The two forms of social cognitive deficits are likely to require quite different social cognitive interventions. PMID- 24480017 TI - Editorial comment. PMID- 24480018 TI - Editorial comment. PMID- 24480019 TI - Editorial comment. PMID- 24480020 TI - Reply by authors. PMID- 24480022 TI - The tracheostomy clinical nurse specialist: an essential member of the multidisciplinary team. AB - BACKGROUND: Tracheostomies are a common procedure within the specialties of otolaryngology and intensive care. The ENT department at Monklands Hospital has developed the position of tracheostomy clinical nurse specialist to improve the management of tracheostomy patients. There is evidence to support the development of a multidisciplinary team for the management of tracheostomy patients following intensive care unit treatment; however, the creation of a specific tracheostomy clinical nurse specialist position has not been widely endorsed in the literature. OBJECTIVE: This paper describes the role of the tracheostomy clinical nurse specialist, advocating this position within the multidisciplinary team. PMID- 24480023 TI - A community-based Falls Management Exercise Programme (FaME) improves balance, walking speed and reduced fear of falling. AB - BACKGROUND: Although effective community falls prevention programmes for the older persons have been described, challenges remain in translating proven interventions into daily practice. AIM: To evaluate the efficacy, feasibility and acceptability of a falls prevention programme that can be integrated into daily activities in a group of community-dwelling older adults with risk of falling. METHOD: A cohort study with intervention and comparison groups was designed to evaluate a 36-week group-based falls prevention exercise programme (FaME) in the community setting. Participants were aged 60 years or older, had fallen in the past 12 months, had fear of falling with avoidance of activities or had deficits in balance control. Primary outcome measures included assessment of balance control and mobility; secondary outcome measures included level of physical activity, assessment of fear of falling and health-related quality of life. RESULTS: There were 48 and 51 participants in the intervention and comparison groups, respectively. There were improvements in measurements of balance, walking speed and self-efficacy. The drop out rate was low (14.6% and 3.9% from the intervention and comparison groups, respectively). Overall compliance in the intervention group was 79%. Factors that motivated continued participation include the regular and long-term nature of the programme helping to reinforce their exercise habits, the simplicity of movements and friendliness of the group. CONCLUSION: The FaME programme improves balance, walking speed and reduces fear of falling. It could be widely promoted and integrated into regular health and social activities in community settings. PMID- 24480024 TI - Vaccines against sexually transmitted infections: the way forward. PMID- 24480025 TI - Summary and recommendations from a National Institute of Allergy and Infectious Diseases (NIAID) workshop on "Next Generation Herpes Simplex Virus Vaccines". PMID- 24480026 TI - Preface. PMID- 24480027 TI - The STI vaccine roadmap-a long overdue intervention. PMID- 24480028 TI - Vaccines for sexually transmitted infections: past, present and future. PMID- 24480029 TI - Activation of the alternative sigma factor SigB of Staphylococcus aureus following internalization by epithelial cells - an in vivo proteomics perspective. AB - Staphylococcus aureus is a versatile pathogen that can be a commensal but also cause a wide range of different infections. This broad disease spectrum is a reflection of the complex regulation of a large collection of virulence factors that together with metabolic fitness allow adaptation to different niches. The alternative sigma factor SigB is one of the global regulators mediating this adaptation. However, even if SigB contributes to expression of many virulence factors its importance for successful infection greatly varies with the strain and the infection setting analyzed. We have recently established a proteomics workflow that combines high efficiency cell sorting with sensitive mass spectrometry and allows monitoring of global proteome adaptations with roughly one million bacterial cells. Thus, we can now approach the adaptation of pathogens to the intracellular milieu. In the current study this proteomics workflow was used in conjunction with qRT-PCR and confocal fluorescence microscopy to comparatively analyze the adaptation of the S. aureus wild type strain HG001 and its isogenic sigB mutant to the intracellular milieu of human S9 bronchial epithelial cells. The study revealed fast and transient activation of SigB following internalization by human host cells and the requirement of SigB for intracellular growth. Loss of SigB triggered proteome changes reflecting the different residual growth rates of wild type and sigB mutant, respectively, the resistance to methicillin, adaptation to oxidative stress and protein quality control mechanisms. PMID- 24480030 TI - Lessons in platelet production from inherited thrombocytopenias. AB - Our knowledge of the cellular and molecular mechanisms of platelet production has greatly expanded in recent years due to the opportunity to culture in vitro megakaryocytes and to create transgenic animals with specific genetic defects that interfere with platelet biogenesis. However, in vitro models do not reproduce the complexity of the bone marrow microenvironment where megakaryopoiesis takes place, and experience shows that what is seen in animals does not always happen in humans. So, these experimental models tell us what might happen in humans, but does not assure us that these events really occur. In contrast, inherited thrombocytopenias offer the unique opportunity to verify in humans the actual effects of abnormalities in specific molecules on platelet production. There are currently 20 genes whose defects are known to result in thrombocytopenia and, on this basis, this review tries to outline a model of megakaryopoiesis based on firm evidence. Inherited thrombocytopenias have not yet yielded all the information they can provide, because nearly half of patients have forms that do not fit with any known disorder. So, further investigation of inherited thrombocytopenias will advance not only the knowledge of human illnesses, but also our understanding of human platelet production. PMID- 24480031 TI - The experience of speech recognition software abandonment by adolescents with physical disabilities. AB - INTRODUCTION: There is a high rate of speech recognition software (SRS) abandonment by adolescent students with physical disabilities. PURPOSE: This study sought to describe the experience of adolescents & their parents, who experienced abandonment of SRS. METHODS: Using a narrative inquiry method, semi structured interviews were conducted with three adolescents with a physical disability (and two parents). The individual narratives were transcribed and analyzed using plot-solution and three-dimensional space narrative elements. RESULTS: Participants' descriptions of their experiences of abandonment emerged along four descriptive themes: (a) they didn't tell me the whole story, (b) I know how to use it, it's just not worth the time and effort, (c) it's just not the right fit for me or my needs, (d) there's an easier way! CONCLUSION: Participants believed the SRS was not an adequate fit for their needs or their specific disabilities and so resorted to alternative methods of written communication. A better understanding of the compatibility of the client's needs with the strengths & limitations of the technology, may improve the prescription and intervention process for both therapists & their clients. PMID- 24480032 TI - A systematic review and meta-analysis of interventions for weight management using text messaging. AB - BACKGROUND: Obesity prevalence continues to increase worldwide, with significant associated chronic disease and health cost implications. Among more recent innovations in health service provision is the use of text messaging for health behaviour change interventions including weight management. This review investigates the efficacy of weight management programmes incorporating text messaging. METHODS: Medical and scientific databases were searched from January 1993 to October 2013. Eligibility criteria included randomised controlled trials (RCTs), pseudoRCTs and before and after studies of weight management, among healthy children and adults, that used text messaging and included a nutrition component. Data extraction and quality assessment followed guidelines from PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) and the Evidence Analysis Manual of the American Academy of Nutrition and Dietetics. RESULTS: From 512 manuscripts retrieved, 14 met the inclusion criteria (five manuscripts in children and nine in adults). Duration of interventions ranged from 1 to 24 months. Frequency of text messaging was from daily to fortnightly. Six studies in adults were included in a meta-analysis with mean body weight change as the primary outcome. The weighted mean change in body weight in intervention participants was -2.56 kg (95% confidence interval = -3.46 to -1.65) and in controls -0.37 kg (95% confidence interval = -1.22 to 0.48). CONCLUSIONS: The small body of evidence indicates that text messaging interventions can promote weight loss. However, lack of long-term results indicate that further efficacy studies are required. Future investigations should elucidate the determinants, such as intervention duration, text message frequency and level of interactivity that maximise the success and cost effectiveness of the delivery medium. PMID- 24480033 TI - The ambivalence of losing weight after bariatric surgery. AB - This study is grounded in a phenomenological lifeworld perspective. It aims at providing rich descriptions of lived experience of the process of losing weight after obesity surgery. Two women participated in in-depth interviews four times each during the first postoperative year. Based on the women's experiences, a meaning structure--the ambivalence of losing weight after obesity surgery--was identified across the women's processes of change. This consisted of five core themes: movement and activity--freedom but new demands and old restraints; eating habits and digestion--the complexity of change; appearance--smaller, but looser; social relations--stability and change; and being oneself--vulnerability and self assurance. These core themes changed over time in terms of dominance. The experience of ambivalence is discussed according to a phenomenological perspective of the body as lived experience. PMID- 24480035 TI - Acquiring concepts and features of novel words by two types of learning: direct mapping and inference. AB - This study examined the semantic representation of novel words learnt in two conditions: directly mapping a novel word to a concept (Direct mapping: DM) and inferring the concept from provided features (Inferred learning: IF). A condition where no definite concept could be inferred (No basic-level meaning: NM) served as a baseline. The semantic representation of the novel word was assessed via a semantic-relatedness judgment task. In this task, the learned novel word served as a prime, while the corresponding concept, an unlearned feature of the concept, and an unrelated word served as targets. ERP responses to the targets, primed by the novel words in the three learning conditions, were compared. For the corresponding concept, smaller N400s were elicited in the DM and IF conditions than in the NM condition, indicating that the concept could be obtained in both learning conditions. However, for the unlearned feature, the targets in the IF condition produced an N400 effect while in the DM condition elicited an LPC effect relative to the NM learning condition. No ERP difference was observed among the three learning conditions for the unrelated words. The results indicate that conditions of learning affect the semantic representation of novel word, and that the unlearned feature was only activated by the novel word in the IF learning condition. PMID- 24480036 TI - Linear basal cell carcinoma at the external genitalia. PMID- 24480038 TI - PGE2 production is suppressed by chemically-synthesized Delta7-eicosatrienoic acid in macrophages through the competitive inhibition of COX-2. AB - Delta7-Eicosatrienoic acid (Delta7-ETrA; Delta7,11,14-20:3), an elongation metabolite of pinolenic acid (PNA; Delta5,9,12-18:3), is a rare polyunsaturated fatty acid (PUFA) originally from pine seeds. Incorporation of PNA and Delta7 ETrA into murine macrophages inhibited lipopolysaccharide (LPS)-stimulated prostaglandin E2 (PGE2) production. Due to the lack of availability of the naturally-occurring fatty acid, we synthesized Delta7-ETrA and demonstrated it was capable of suppressing PGE2 production. Using laboratory synthetic techniques involving 2-carbon elongation and argentated column chromatography, Delta7-ETrA was synthesized and isolated. Its identity and purity (>98%) were confirmed by gas chromatography (GC)/GC-mass spectroscopy. Incubation of murine RAW264.7 cells or rat primary peritoneal macrophages with Delta7-ETrA reduced PGE2 production by up to 84%, but slightly down-regulated type-2 cyclooxygenase (COX-2) expression. Delta7-ETrA blocked nuclear factor-kappa B (NF-kappaB) translocation into nucleus and inactivated mitogen-activated protein kinases (MAPK), however, these results might not directly account for its inhibitory effect. Furthermore, PGE2 production reduced by Delta7-ETrA was highly correlated with the extent of Delta7 ETrA incorporation into cellular phospholipids and appeared to be the result of competition between this unusual fatty acid and arachidonic acid (AA) for COX-2. In conclusion, Delta7-ETrA incorporation suppresses PGE2 production by macrophages through competition between Delta7-ETrA and AA for COX-2. PMID- 24480037 TI - Serine and proline-rich ligands enriched via phage-display technology show preferential binding to BCR/ABL expressing cells. AB - BACKGROUND AND OBJECTIVES: Despite the use of targeted therapy, chronic myelogenous leukemia (CML) currently remains incurable with drug therapy, with patients requiring life-long treatment. Developing either a vaccine to prevent the disease or another novel drug to specifically target and eradicate the CML cell will require the identification of CML-associated cell-surface markers and molecules that can bind specifically to the cell surface. In an attempt to discover peptides that bind specifically to cells in the early chronic phase of the disease, we used phage-display technology to identify heptapeptides that bind specifically to the surface of BCR/ABL-expressing fibroblasts. METHODS: An in vitro system using NIH3T3 stably transfected with pGD210 (BCR/ABL) was used as a model for the chronic phase of the disease. The cells were panned using a linear heptapeptide phage library (Ph.D 7.0) in a negative/positive panning strategy with NIH3T3 containing only the plasmid vector as the wild type control. RESULTS: We identified four novel peptides that were enriched through this technique. These peptides contained either multiple proline residues or serine/threonine proline pairs and showed a confirmed binding preference for BCR/ABL+ fibroblasts. The peptide Y-R-A-P-W-P-P also showed a binding affinity for granulocytes from untreated CML patients. CONCLUSION: We have identified several novel peptides that can be used in future studies to identify specific CML cell-surface antigens or provide a novel drug-delivery mechanism. PMID- 24480039 TI - Antrodia salmonea in submerged culture exhibits antioxidant activities in vitro and protects human erythrocytes and low-density lipoproteins from oxidative modification. AB - Antrodia salmonea is well known in Taiwan as a beneficial mushroom. In the present study, we investigated the antioxidant activity of whole fermented broth (AS), filtrate (ASF), and mycelia (ASM) of A. salmonea using different antioxidant models. Furthermore, the effect of A. salmonea on AAPH-induced oxidative hemolysis of human erythrocytes and CuSO4-induced oxidative modification of human low-density lipoproteins (LDLs) was examined. We found that the AS, ASF, and ASM possess effective antioxidant activity against various oxidative systems including superoxide anion scavenging, reducing power, metal chelation, and DPPH radical scavenging. Further, AAPH-induced oxidative hemolysis in erythrocytes was prevented by AS, ASF, and ASM. Notably, AS, ASF, and ASM appear to possess powerful antioxidant activities against CuSO4-induced oxidative modification of LDL as assessed by malondialdehyde (MDA) formation, cholesterol degradation, and the relative electrophoretic mobility of oxidized LDL. It is noteworthy that AS had comparatively strong antioxidant ability compared to ASF or ASM, which is well correlated with the content of their total polyphenols. Thus, A. salmonea may exert antioxidant properties and offer protection from atherogenesis. PMID- 24480040 TI - Influence on functional parameters of intestinal tract induced by short-term exposure to fumonisins contaminated corn chyme samples. AB - The gut is a possible target toward mycotoxin fumonisins (FBs) exposure. The study aims to investigate the effects induced by FBs contaminated-corn chyme samples on functional parameters of human and rat intestine by using Ussing chamber. Fumonisins-contaminated corn and processed corn samples were undergone to in vitro digestion process and then added to luminal side. A reduction (about 90%) of short circuit current (Isc MUA/cm(2)) during exposure of human colon tissues to fumonisins-free corn chyme samples was observed, probably related to increased chyme osmolality. This hyperosmotic stress could drain water towards the luminal compartment, modifying Na(+) and Cl(-) transports. The presence of FBs in corn chyme samples, independently to their concentration, did not affect significantly the Isc, probably related to their interference towards epithelial Na(+) transport, as assessed by using a specific inhibitor (Amiloride). The rat colon tract represents a more accessible model to study FBs toxicity showing a similar functional response to human. In the rat small intestine a significant reduction (about 15%) of Isc parameter during exposure to uncontaminated or FBs contaminated corn chyme samples was observed; therefore such model was not suitable to assess the FBs toxicity, probably because the prevalent glucose and amino acids electrogenic absorption overwhelmed the FBs influence on ionic transport. PMID- 24480041 TI - Impairment of cell cycle progression by sterigmatocystin in human pulmonary cells in vitro. AB - Sterigmatocystin (ST) is a carcinogenic mycotoxin that is commonly found in human food, animal feed and in the indoor environment. Although the correlation between ST exposure and lung cancer has been widely reported in many studies, the cytotoxicity of ST on human pulmonary cells is not yet fully understood. In the current study, we found that ST could induce DNA double-strand breaks in a human immortalized bronchial epithelial cell line (BEAS-2B cells) and a human lung cancer cell line (A549 cells). In addition, the effects of ST on cell cycle arrest were complex and dependent on the tested ST concentration and cell type. Low concentrations of ST arrested cells in the G2/M phase in BEAS-2B cells and in the S phase in A549 cells, while at high concentration both cells lines were arrested in S and G2/M phases. Furthermore, we observed that the modulation of cyclins and CDK expression showed concomitant changes with cell cycle arrest upon ST exposure in BEAS-2B and A549 cells. In conclusion, ST induced DNA damage and affected key proteins involved in cell cycle regulation to trigger genomic instability, which may be a potential mechanism underlying the developmental basis of lung carcinogenesis. PMID- 24480042 TI - alpha-Mangostin-induced apoptosis is mediated by estrogen receptor alpha in human breast cancer cells. AB - In this study, we evaluated the effects of alpha-mangostin on cell growth inhibition and induction of apoptosis in MCF-7 ERalpha-positive human breast cancer cells. Our results showed that alpha-mangostin inhibited MCF-7 cell proliferation whereas ERalpha-negative MDA-MB-231 cells were less sensitive to the agent. Additionally, alpha-mangostin effectively induced apoptosis as evidenced by the appearance of apoptotic nuclei observed with Hoechst 33258 staining and evaluation of sub-G1 DNA contents by flow cytometry. alpha-Mangostin also activated caspases-8, -9, and -7; increased the protein levels of Bax, p53, and cytosolic cytochrome c; and induced PARP cleavage while reducing Bid and Bcl 2 protein expression. In addition, apoptosis-inducing factor (AIF) was transported from mitochondria to the cytosol after alpha-mangostin treatment. alpha-mangostin also induced apoptosis in 17-beta-estradiol (E2)-stimulated MCF-7 cells in parallel with the non-stimulated cells. Moreover, treatment with 10MUM alpha-mangostin for 48h specifically decreased the expression of ERalpha and pS2, an estrogen-responsive gene, in MCF-7 cells. Furthermore, knockdown of ERalpha expression in MCF-7 cells with siRNA attenuated alpha-mangostin-induced cell growth inhibition and caspase-7 activation. These results suggest that ERalpha is required for alpha-mangostin-induced growth inhibition and apoptosis in human breast cancer cells. Therefore, alpha-mangostin may be used to prevent and treat of ER-positive breast cancer. PMID- 24480043 TI - Hypolipidaemic effect of crude extract from Carpobrotus rossii (pigface) in healthy rats. AB - Carpobrotus rossii (CR) was used by the Aboriginal population and early European settlers both as a food and therapeutic agent. Based on the presence of flavonoids in CR and results from our previous in vitro investigations, this study aimed to determine whether consumption of CR crude leaf extract: (a) affected lipoprotein profile, resting glucose, systolic blood pressure and vascular function, and (b) produced toxic effects (haematological measures, organ weight) in healthy rats. Male Hooded-Wistar rats (~230 g) were supplemented for 4 weeks with CR extract in their drinking water (35 mg/kg body weight daily). CR extract produced a significant decrease (18%, p=0.033) in atherogenic lipoproteins (but not high density lipoprotein). CR supplemented animals showed no signs of haematological toxicity and body and organ weight, daily fluid and food consumption and in vitro vascular responsiveness were similar for both groups. CR also increased (40%, p=0.049) the renal concentration of 3-hydroxy-3 methylglutaric acid (HMG), consistent with HMG-containing CR flavonoids being bioavailable, and therefore possessing the potential to interfere with cholesterol synthesis pathways. CR extract appears to be safe to ingest and may reduce cardiovascular risk. PMID- 24480044 TI - Use of laboratory-based surveillance data to estimate the number of people chronically infected with hepatitis B living in Scotland. AB - It is paramount to understand the epidemiology of chronic hepatitis B to inform national policies on vaccination and screening/testing as well as cost effectiveness studies. However, information on the national (Scottish) prevalence of chronic hepatitis B by ethnic group is lacking. To estimate the number of people with chronic hepatitis B in Scotland in 2009 by ethnicity, gender and age, the test data from virology laboratories in the four largest cities in Scotland were combined with estimates of the ethnic distribution of the Scottish population. Ethnicity in both the test data and the Scottish population was derived using a name-based ethnicity classification software (OnoMAP; Publicprofiler Ltd, UK). For 2009, we estimated 8720 [95% confidence interval (CI) 7490-10 230] people aged ?15 years were living with chronic hepatitis B infection in Scotland. This corresponds to 0.2% (95% CI 0.17-0.24) of the Scottish population aged ?15 years. Although East and South Asians make up a small proportion of the Scottish population, they make up 44% of the infected population. In addition, 75% of those infected were aged 15-44 years with almost 60% male. This study quantifies for the first time on a national level the burden of chronic hepatitis B infection by ethnicity, gender and age. It confirms the importance of promoting and targeting ethnic minority groups for hepatitis B testing. PMID- 24480045 TI - Retrospective and prospectively assessed childhood adversity in association with major depression, alcohol consumption and painful conditions. AB - BACKGROUND: Considerable evidence now links childhood adversity to a variety of adult health problems. Unfortunately, almost all of these studies have relied upon retrospective assessment of childhood events, creating a vulnerability to bias. In this study, we sought to examine three associations using data sources that allowed for both prospective and retrospective assessment of childhood events. METHODS: A 1994 national survey of children between the ages of 0 and 11 collected data from a 'person most knowledgeable' (usually the mother) about a child. It was possible to link data for n = 1977 of these respondents to data collected from the same people in a subsequent adult study. The latter survey included retrospective reports of childhood adversity. We examined three adult health outcomes in relation to prospectively and retrospectively assessed childhood adversity: major depressive episodes, excessive alcohol consumption and painful conditions. RESULTS: A strong association between childhood adversities (as assessed by both retrospective and prospective methods) and major depression was identified although the association with retrospective assessment was stronger. Weaker associations were found for painful conditions, but these did not depend on the method of assessment. Associations were not found for excessive alcohol consumption irrespective of the method of assessment. CONCLUSIONS: These findings help to allay concerns that associations between childhood adversities and health outcomes during adulthood are merely artefacts of recall bias. In this study, retrospective and prospective assessment strategies produced similar results. PMID- 24480046 TI - Swing kinematics of male and female skilled golfers following prolonged putting practice. AB - Given that males and females respond differently to endurance-based tasks, prolonged putting practice may provide an avenue to examine gender-related differences in golf swing kinematics. The aim of this project was to determine if 40 min of putting affects thorax and pelvis kinematics during the full swing of males and females. Three-dimensional trunk kinematics were collected during the swings of 19 male (age: 26 +/- 7 years, handicap: 0.6 +/- 1.1) and 17 female (age: 24 +/- 7 years, handicap: 1.4 +/- 1.7) golfers before and after 40 min of putting. Angular displacement at address, top of backswing and ball contact for the pelvis, thorax, and pelvis-thorax interaction were calculated, in addition to the magnitude of peak angular velocity and repeatability of continuous segment angular velocities. Female golfers had less pelvis and thorax anterior-posterior tilt at address, less thorax and thorax-pelvis axial rotation at top of backswing, and less pelvis and thorax axial rotation and pelvis lateral tilt at ball contact pre- to post-putting. Analysis of peak angular velocities revealed that females had significantly lower thorax-pelvis lateral tilt velocity pre- to post-putting. In conclusion, an endurance-based putting intervention affects females' thorax and pelvis orientation angles and velocities to a greater extent than males. PMID- 24480047 TI - Qualitative analysis of the contributions of nutritionists to the development of an online instrument for monitoring the food intake of schoolchildren. AB - BACKGROUND: The Consumo Alimentar e Atividade Fisica de Escolares (CAAFE) questionnaire is an online research tool that has been developed to enable the self-report of physical activity and diet by Brazilian schoolchildren aged 7-10 years. Formative research was conducted with nutritionists during the development of the web-based questionnaire. The suggestions and insights obtained were used to design a tool to monitor schoolchildren's food consumption based on the concept of healthy and unhealthy food indicators. The present study aimed to report the focus group discussions conducted with nutritionists concerning the CAAFE questionnaire. METHODS: Focus group discussions were conducted using a semi structured questionnaire, and these were then analysed thematically. RESULTS: Twenty-four nutritionists participated (four focus groups; average per group: six people); the majority (n = 22) had experience with 7-10-year-old children. Four themes emerged: (i) healthy and unhealthy food indicators; (ii) suggestions for the online instrument; (iii) potential applications; and (iv) challenges for its construction. CONCLUSIONS: Comments made by nutritionists enabled the construction of an instrument that is able to answer questions related to food consumption in schools and at home. PMID- 24480048 TI - Thromboxane synthase expression and correlation with VEGF and angiogenesis in non small cell lung cancer. AB - BACKGROUND: Thromboxane synthase (TXS) metabolizes prostaglandin H2 into thromboxanes, which are biologically active on cancer cells. TXS over-expression has been reported in a range of cancers, and associated with angiogenesis and poor outcome. TXS has been identified as a potential therapeutic target in NSCLC. This study examines a link between TXS expression, angiogenesis, and survival in NSCLC. METHODS: TXS and VEGF metabolite levels were measured in NSCLC serum samples (n=46) by EIA. TXB2 levels were correlated with VEGF. A 204-patient TMA was stained for TXS, VEGF, and CD-31 expression. Expression was correlated with a range of clinical parameters, including overall survival. TXS expression was correlated with VEGF and CD-31. Stable TXS clones were generated and the effect of overexpression on tumor growth and angiogenesis markers was examined in-vitro and in-vivo (xenograft mouse model). RESULTS: Serum TXB2 levels were correlated with VEGF (p<0.05). TXS and VEGF were expressed to a varying degree in NSCLC tissue. TXS was associated with VEGF (p<0.0001) and microvessel density (CD-31; p<0.05). TXS and VEGF expression levels were higher in adenocarcinoma (p<0.0001) and female patients (p<0.05). Stable overexpression of TXS increased VEGF secretion in-vitro. While no significant association with patient survival was observed for either TXS or VEGF in our patient cohort, TXS overexpression significantly (p<0.05) increased tumor growth in-vivo. TXS overexpression was also associated with higher levels of VEGF, microvessel density, and reduced apoptosis in xenograft tumors. CONCLUSION: TXS promotes tumor growth in-vivo in NSCLC, an effect which is at least partly mediated through increased tumor angiogenesis. PMID- 24480049 TI - Genetic diversity of Leishmania donovani/infantum complex in China through microsatellite analysis. AB - The Leishmania strains from different epidemic areas in China were assessed for their genetic relationship. Twenty-nine strains of Leishmania infantum isolated from 1950 to 2001 were subjected to multilocus microsatellite typing (MLMT) using 14 highly polymorphic microsatellite markers. Twenty-two MLMT profiles were recognized among the 29 L. infantum strains, which differed from one another in 13 loci. Bayesian model-based and distance-based analysis of the data inferred two main populations in China. Sixteen strains belonged to one population, which also comprised previously characterized strains of L. infantum non-MON1 and Leishmania donovani. The parasites within this population are assignable to a distinct cluster that is clearly separable from the populations of L. donovani elsewhere, i.e. India, Sri Lanka and East Africa, and L. infantum non-MON1 from Europe. The remaining 13 Chinese strains grouped together with strains of L. infantum MON1 into another population, but formed a separate cluster which genetically differs from the populations of L. infantum MON1 from Europe, the Middle East, Central Asia and North Africa. The existence of distinct groups of L. infantum MON1 and non-MON1/L. donovani suggests that the extant parasites in China may have been restricted there, but not recently introduced from elsewhere. PMID- 24480050 TI - Assessment of an immunomarking technique for the study of dispersal of Culicoides biting midges. AB - Capture-mark-recapture techniques are used to determine the dispersal and survival of arthropods, including vector groups such as Culicoides. An assumption of these studies is that capture and the subsequent marking process does not impact of the survival and behaviour of the marked individual. The small size of Culicoides means that a significant mortality and disruption of normal behaviour such as host-location can be caused by the process of collection. Here we evaluate a technique, novel to the study of dispersal in vectors, to mark Culicoides directly and indirectly without prior capture. The acquisition and subsequent detection of marker protein by Culicoides exposed to a treated substrate was investigated in the laboratory. The technique was then assessed in a small-scale field trial where a defined section of resting habitat was sprayed with an egg white solution and Culicoides caught within the vicinity were tested for the presence of egg protein. It was found that up to 100% of Culicoides acquired the protein marker in the laboratory with no apparent impact on survival. In the field, pools of Culicoides obsoletus collected next to the treated area were found to be positive for the protein, suggesting that the technique could be used in larger-scale studies. The definition of a behaviourally non-invasive technique for marking Culicoides will greatly increase our understanding of the natural dispersal behaviour of Culicoides and other vectors. PMID- 24480051 TI - Multi-locus variable-number tandem repeat analysis (MLVA) reveals heterogeneity of Mycobacterium bovis strains and multiple genotype infections of cattle in Ethiopia. AB - Bovine tuberculosis (BTB) remains a major threat to animal and human health, and obstructs international and inter-regional livestock trade in Ethiopia. Many aspects of epidemiology of BTB and its causative agent, Mycobacterium bovis (M. bovis) are not well known. Aims of the study were to elucidate molecular characteristics of M. bovis strains using MLVA typing method. Further aim was to determine infection pressure associated with occurrence of multiple genotypes in individual infected cattle. Data and samples were collected in the period July 2006-January 2007 in cattle slaughtered at five representative abattoirs across the country. Molecular investigation of the isolates was carried out using multilocus variable-number tandem-repeat analysis (MLVA) of 28 variable numbers of tandem repeat (VNTR) loci, and the results were compared to spoligotyping. This study is believed to contribute to the knowledge of molecular genetics and epidemiology of M. bovis in Ethiopia and elsewhere with similar BTB epidemic situation and livestock production settings. Four-hundred and six tissue samples from 337 carcasses revealing gross pathologic lesions compatible with BTB were collected from five abattoirs. Fifty-eight isolates obtained from cultured samples were subjected to region of difference (RD) analysis and MLVA typing. RD confirmed all isolates as being M. bovis. MLVA revealed a high heterogeneity of M. bovis (19 genotypes) and the discriminatory power of MLVA was higher than for spoligotyping (Hunter-Gaston Diversity Index (HGDI) 0.92 vs. 0.82). Adoption of the nine VNTR loci with ?3 alleles provided good differentiation between the isolates. However, differentiation was optimized when MLVA was combined with spoligotyping (HGDI=0.99). MLVA confirmed infections with multiple genotypes in 38.5% (10/26) of individual animals. In conclusion, the usefulness of MLVA for genotyping M. bovis in high prevalence settings was demonstrated. BTB in Ethiopia is caused by heterogeneous populations of M. bovis and individual carcasses were often infected with different genotypes, indicating a high infection pressure perhaps related to the absence of protective immunity conferred by infection. PMID- 24480052 TI - Congopain genes diverged to become specific to Savannah, Forest and Kilifi subgroups of Trypanosoma congolense, and are valuable for diagnosis, genotyping and phylogenetic inferences. AB - Trypanosoma congolense is the most important agent of nagana, a wasting livestock trypanosomosis in sub-Saharan Africa. This species is a complex of three subgroups (Savannah, Forest and Kilifi) that differ in virulence, pathogenicity, drug resistance, vectors, and geographical distribution. Congopain, the major Cathepsin L-like cysteine protease (CP2) of T. congolense, has been extensively investigated as a pathogenic factor and target for drugs and vaccines, but knowledge about this enzyme is mostly restricted to the reference strain IL3000, which belongs to the Savannah subgroup. In this work we compared sequences of congopain genes from IL3000 genome database and isolates of the three subgroups of T. congolense. Results demonstrated that the congopain genes diverged into three subclades consistent with the three subgroups within T. congolense. Laboratory and field isolates of Savannah exhibited a highly polymorphic repertoire both inter- and intra-isolates: sequences sharing the archetypical catalytic triad clustered into SAV1-SAV3 groups, whereas polymorphic sequences that, in general, exhibited unusual catalytic triad (variants) assigned to SAV4 or not assigned to any group. Congopain homologous genes from Forest and Kilifi isolates showed, respectively, moderate and limited diversity. In the phylogenetic tree based on congopain and homologues, Savannah was closer to Forest than to Kilifi. All T. congolense subgroup nested into a single clade, which together with the sister clade formed by homologues from Trypanosoma simiae and Trypanosoma godfreyi formed a clade supporting the subgenus Nannomonas. A single PCR targeting congopain sequences was developed for the diagnosis of T. congolense isolates of the three subgroups. Our findings demonstrated that congopain genes are valuable targets for the diagnosis, genotyping, and phylogenetic and taxonomic inferences among T. congolense isolates and other members of the subgenus Nannomonas. PMID- 24480053 TI - Pathogen population dynamics in agricultural landscapes: the Ddal modelling framework. AB - Modelling processes that occur at the landscape scale is gaining more and more attention from theoretical ecologists to agricultural managers. Most of the approaches found in the literature lack applicability for managers or, on the opposite, lack a sound theoretical basis. Based on the metapopulation concept, we propose here a modelling approach for landscape epidemiology that takes advantage of theoretical results developed in the metapopulation context while considering realistic landscapes structures. A landscape simulator makes it possible to represent both the field pattern and the spatial distribution of crops. The pathogen population dynamics are then described through a matrix population model both stage- and space-structured. In addition to a classical invasion analysis we present a stochastic simulation experiment and provide a complete framework for performing a sensitivity analysis integrating the landscape as an input factor. We illustrate our approach using an example to evaluate whether the agricultural landscape composition and structure may prevent and mitigate the development of an epidemic. Although designed for a fungal foliar disease, our modelling approach is easily adaptable to other organisms. PMID- 24480054 TI - Isolation and characterization of a California encephalitis serogroup orthobunyavirus from Finnish mosquitoes. AB - The mosquito-borne California encephalitis serogroup viruses of the genus Orthobunyavirus (family Bunyaviridae) include several causative agents of encephalitis in humans. Until recently, Inkoo virus (INKV) was the only orthobunyavirus isolated in Finland, showing high seroprevalence in the population. In this study, we recovered five orthobunyavirus isolates from mosquitoes collected in eastern Finland in the early autumns of 2007 and 2008 by inoculation of Vero cells. The isolates were determined by S, M and L segment sequences to represent the California encephalitis virus species but distinct from INKV (68% polyprotein amino acid (aa) identity). In genetic analyses, isolates clustered together with a number of westernmost Chatanga virus isolates (98% polyprotein aa identity) reported from Russia, forming a distinct phylogroup. However, the sequence homology of this phylogroup to the majority of Chatanga isolates, comprising three different geographically clustered phylogroups, was considerably lower (89-92% polyprotein aa identity). The five new isolates were designated as Mohko isolates of Chatanga virus, according to the village of origin. The isolates were closely related to Snowshoe hare virus (SSHV) and La Crosse virus (LACV) with an aa identity of 87% and 82% within the M segment polyprotein, respectively. The genetic relatedness of Mohko isolates to a number of human pathogenic orthobunyaviruses warrants further investigation on their potential disease associations and further serological analysis is needed to compare them to other Chatanga virus isolates and SSHV to determine their true antigenic relation. PMID- 24480055 TI - Five-year prospective study of paediatric acute otitis media in Rochester, NY: modelling analysis of the risk of pneumococcal colonization in the nasopharynx and infection. AB - During a 5-year prospective study of nasopharyngeal (NP) colonization and acute otitis media (AOM) infections in children during the 7-valent pneumococcal conjugate vaccine (PCV) era (July 2006-June 2011) we studied risk factors for NP colonization and AOM. NP samples were collected at ages 6, 9, 12, 15, 18, 24, and 30 months during well-child visits. Additionally, NP and middle ear fluid (MEF) samples were collected at onset of every AOM episode. From 1825 visits (n = 464 children), 5301 NP and 570 MEF samples were collected and analysed for potential otopathogens. Daycare attendance, NP colonization by Moraxella catarrhalis, and siblings aged <5 years increased the risk of Streptococcus pneumoniae NP colonization. NP colonization with S. pneumoniae, M. catarrhalis, or Haemophilus influenzae and a family history of OM increased the risk of AOM. Risk factors that increase the risk of pneumococcal AOM will be important to reassess as we move into a new 13-valent PCV era, especially co-colonization with other potential otopathogens. PMID- 24480058 TI - Case of lepromatous leprosy misdiagnosed as systemic sclerosis. AB - Hansen's disease (HD) is a chronic granulomatous infectious disease caused by Mycobacterium leprae. The worldwide prevalence rate of HD has decreased gradually over the years. The clinical manifestations of HD are extensive, with involvement of the skin and various organs, and these can resemble those of many rheumatic diseases. Our patient initially presented with gradual sclerotic skin change and slight sclerodactyly with Raynaud's phenomenon, which is frequently observed in systemic sclerosis. However, a skin biopsy with acid-fast stain later confirmed lepromatous leprosy. We report this case to emphasize the role of dermatologists for applying a systematic approach to the skin lesions of HD, which has become difficult to detect because of its rapidly declining prevalence rate. PMID- 24480059 TI - Autochthonous dengue virus infection in Japan imported into Germany, September 2013. AB - In September 2013, dengue virus (DENV) infection was diagnosed in a German traveller returning from Japan. DENV-specific IgM and IgG and DENV NS1 antigen were detected in the patient's blood, as were DENV serotype 2-specific antibodies. Public health authorities should be aware that autochthonous transmission of this emerging virus may occur in Japan. Our findings also highlight the importance of taking a full travel history, even from travellers not returning from tropical countries, to assess potential infection risks of patients. PMID- 24480060 TI - A new laboratory-based surveillance system (Respiratory DataMart System) for influenza and other respiratory viruses in England: results and experience from 2009 to 2012. AB - During the 2009 influenza A(H1N1) pandemic, a new laboratory-based virological sentinel surveillance system, the Respiratory DataMart System (RDMS), was established in a network of 14 Health Protection Agency (now Public Health England (PHE)) and National Health Service (NHS) laboratories in England. Laboratory results (both positive and negative) were systematically collected from all routinely tested clinical respiratory samples for a range of respiratory viruses including influenza, respiratory syncytial virus (RSV), rhinovirus, parainfluenza virus, adenovirus and human metapneumovirus (hMPV). The RDMS also monitored the occurrence of antiviral resistance of influenza viruses. Data from the RDMS for the 2009-2012 period showed that the 2009 pandemic influenza virus caused three waves of activity with different intensities during the pandemic and post pandemic periods. Peaks in influenza A(H1N1)pdm09 positivity (defined as number of positive samples per total number of samples tested) were seen in summer and autumn in 2009, with slightly higher peak positivity observed in the first post-pandemic season in 2010/2011. The influenza A(H1N1)pdm09 virus strain almost completely disappeared in the second postpandemic season in 2011/2012. The RDMS findings are consistent with other existing community-based virological and clinical surveillance systems. With a large sample size, this new system provides a robust supplementary mechanism, through the collection of routinely available laboratory data at minimum extra cost, to monitor influenza as well as other respiratory virus activity. A near real-time, daily reporting mechanism in the RDMS was established during the London 2012 Olympic and Paralympic Games. Furthermore, this system can be quickly adapted and used to monitor future influenza pandemics and other major outbreaks of respiratory infectious disease, including novel pathogens. PMID- 24480062 TI - Hybrid extreme rotation forest. AB - This paper proposes the Hybrid Extreme Rotation Forest (HERF), an innovative ensemble learning algorithm for classification problems, combining classical Decision Trees with the recently proposed Extreme Learning Machines (ELM) training of Neural Networks. In the HERF algorithm, training of each individual classifier involves two steps: first computing a randomized data rotation transformation of the training data, second, training the individual classifier on the rotated data. The testing data is subjected to the same transformation as the training data, which is specific for each classifier in the ensemble. Experimental design in this paper involves (a) the comparison of factorization approaches to compute the randomized rotation matrix: the Principal Component Analysis (PCA) and the Quartimax, (b) assessing the effect of data normalization and bootstrapping training data selection, (c) all variants of single and combined ELM and decision trees, including Regularized ELM. This experimental design effectively includes other state-of-the-art ensemble approaches in the comparison, such as Voting ELM and Random Forest. We report extensive results over a collection of machine learning benchmark databases. Ranking the cross validation results per experimental dataset and classifier tested concludes that HERF significantly improves over the other state-of-the-art ensemble classifier. Besides, we find some other results such as that the data rotation with Quartimax improves over PCA, and the relative insensitivity of the approach to regularization which may be attributable to the de facto regularization performed by the ensemble approach. PMID- 24480064 TI - Abstracts - 12th Congress WFITN - Hotel Hilton - Buenos Aires - Argentina - 9th to 14th November 2013. PMID- 24480063 TI - Antimicrobial resistance in eight US hospitals along the US-Mexico border, 2000 2006. AB - Antimicrobial resistance (AR) is a growing problem worldwide and international travel, cross-border migration, and antimicrobial use may contribute to the introduction or emergence of AR. We examined AR rates and trends along the US Mexico border by analysing microbiology data from eight US hospitals in three states bordering Mexico. Microbiology data were ascertained for the years 2000 2006 and for select healthcare and community pathogens including, three Gram negative (Escherichia coli, Pseudomonas aeruginosa, Klebsiella pneumoniae) and three Gram-positive (Staphylococcus aureus, Enterococcus, Streptococcus pneumoniae) pathogens and 10 antimicrobial-pathogen combinations. Resistance was highest in S. aureus (oxacillin resistance 45.7%), P. aeruginosa (quinolone resistance 22.3%), and E. coli (quinolone resistance 15.6%); six (60%) of the 10 antimicrobial-pathogen combinations studied had a significantly increasing trend in resistance over the study period. Potential contributing factors in the hospital and community such as infection control practices and antimicrobial use (prescription and non-prescription) should be explored further in the US-Mexico border region. PMID- 24480065 TI - UHPH-processed O/W submicron emulsions stabilised with a lipid-based surfactant: physicochemical characteristics and behaviour on in vitro TC7-cell monolayers and ex vivo pig's ear skin. AB - Submicron O/W emulsions formulated with sesame oil plus a lipid-base surfactant, and with or without retinyl acetate (RAC) as a model hydrophobic biomolecule, were prepared by single-pass homogenisation at >= 200 MPa (UHPH) and an initial fluid temperature (Tin) of 24 degrees C. These emulsions were characterised by a monomodal distribution (peak maximum at 260 nm) and a 2-year potential physical stability at ambient temperature. Submicron droplets were investigated in term of (i) physicochemical characteristics (size distribution curves; zeta-potential value), and (ii) impact on TC7-cell monolayers (MTT-assay and cell LDH-leakage). Submicron droplets +/- RAC did not affect or increased significantly (p=0.05) TC7 cell metabolic activity after 4-24h of exposure indicating absence of cellular impairment, except when high amounts of droplets were deposed on TC7-cells. Indeed, the lipid-based surfactant deposed alone on TC7-cells at high concentration, induced some significant (p=0.05) cell LDH-leakage, and therefore cell-membrane damage. Cellular uptake experiments revealed a significant (p=0.05) time-dependent internalisation of RAC from submicron droplets, and cellular transformation of RAC into retinol. The turnover of RAC into retinol and therefore RAC bioaccessibility appeared faster for RAC-micelles of similar size range and prepared at atmospheric pressure with polysorbate 80, than for submicron O/W emulsions. Permeation experiments using pig's ear skin mounted on Franz-type diffusion cells, revealed RAC in dermis-epidermis, in significantly (p=0.05) higher amounts for submicron than coarse pre-emulsions. However, RAC amounts remained low for both emulsion-types and RAC was not detected in the receptor medium of Franz-type diffusion cells. PMID- 24480066 TI - Surface characteristics and electrical properties of PMMA chips for incubation type planar-patch-clamp biosensors. AB - Polymethylmethacrylate (PMMA) plates were successfully applied as sensor chips in an incubation-type planar patch clamp (IPPC). Hot embossing both sides formed the PMMA plates, and a focused ion beam realized micropores. The low seal resistance of the IPPC was investigated by analyzing the surface roughness of the chips. Atomic force microscopy (AFM) showed that the chip surface had a roughness of several nanometers due to the molding process. Coating the molded surface with an anti-adhesive compound further increased the surface roughness of the PMMA chip because the anti-adhesive compound itself had a large roughness and in some case, the compound partially peeled off while detaching the mold. Similarly, coating a chip with extracellular matrix (ECM) poly-l-lysine (PLL) also increased the surface roughness. The measured seal resistance of the PMMA chip for an HEK293 cell was in the range of 4-15 MOmega. The low seal resistance was attributed to the sharp-edge structure of the micropore and the surface roughness of the chip. Nevertheless, the whole cell current was successfully recorded from HEK293 cells expressing channel rhodopsin wide receiver (ChRWR) using salt-bridge-type stable Ag/AgCl electrodes. Another advantage of the PMMA sensor chip was the small parasitic capacitance. PMID- 24480067 TI - Comparison of polymer induced and solvent induced trypsin denaturation: the role of hydrophobicity. AB - Trypsin adsorption from aqueous buffer by various copolymers of allyl glycidyl ether-ethylene glycol dimethacrylate (AGE-EGDM) copolymer with varying crosslink density increases with increasing crosslink density and the effect slowly wears off after reaching a plateau at 50% crosslink density. The copolymer with 25% crosslink density was reacted with different amines with alkyl/aryl side chains to obtain a series of copolymers with 1,2-amino alcohol functional groups and varying hydrophobicity. Trypsin binding capacity again increases with hydrophobicity of the reacting amine and a good correlation between logPoctanol of the amine and protein binding is observed. The bound trypsin is denatured to the extent of 90% in spite of the presence of hydrophilic hydroxyl and amino groups. The behavior was comparable to that in mixtures of aqueous buffer and water-miscible organic co-solvents where the solvent concentration required to deactivate 50% of the enzyme (C50) is dependent on logPoctanol of the co-solvent. PMID- 24480068 TI - Preparation of graphene oxide-based surface plasmon resonance biosensor with Au bipyramid nanoparticles as sensitivity enhancer. AB - A sensitive and selective wavelength-modulation surface plasmon resonance (SPR) biosensor based on graphene oxide (GO) and Au bipyramids (AuBPs) is reported for determination of bovine IgM. GO sheets with lengths of 100-300 nm are synthesized and assembled on amine-modified Au film. The large surface area and abundant functional groups of GO allow the efficient immobilization of antibody. AuBPs are nanoparticles with a penta-twinned crystal structure, which have a sharp localized surface plasmon resonance (LSPR) band because of their high monodispersity. In the optimal conditions, the GO-based biosensor with AuBPs as sensitivity enhancers shows a satisfactory response to bovine IgM in the concentration range of 0.03-32 MUg mL(-1). For contrast, traditional biosensor, GO-based biosensor and GO-based biosensor with Au nanorods (AuNRs) as sensitivity enhancers for antigen detection were also investigated. Consequently, the as prepared GO sheets function as promising support for antibody and GO-based SPR biosensor using AuBPs as enhancers has the highest sensitivity among the four types of biosensors. PMID- 24480069 TI - Collagen receptors integrin alpha2beta1 and discoidin domain receptor 1 regulate maturation of the glomerular basement membrane and loss of integrin alpha2beta1 delays kidney fibrosis in COL4A3 knockout mice. AB - Maturation of the glomerular basement membrane (GBM) is essential for maintaining the integrity of the renal filtration barrier. Impaired maturation causes proteinuria and renal fibrosis in the type IV collagen disease Alport syndrome. This study evaluates the role of collagen receptors in maturation of the GBM, matrix accumulation and renal fibrosis by using mice deficient for discoidin domain receptor 1 (DDR1), integrin subunit alpha2 (ITGA2), and type IV collagen alpha3 (COL4A3). Loss of both collagen receptors DDR1 and integrin alpha2beta1 delays maturation of the GBM: due to a porous GBM filtration barrier high molecular weight proteinuria that more than doubles between day 60 and day 100. Thereafter, maturation of the GBM causes proteinuria to drop down to one tenth until day 200. Proteinuria and the porous GBM cause accumulation of glomerular and tubulointerstitial matrix, which both decrease significantly after GBM maturation until day 250. In parallel, in a disease with impaired GBM-maturation such as Alport syndrome, loss of integrin alpha2beta1 positively delays renal fibrosis: COL4A3(-/-)/ITGA2(-/-) double knockouts exhibited reduced proteinuria and urea nitrogen compared to COL4A3(-/-)/ITGA2(+/-) and COL4A3(-/-)/ITGA2(+/+) mice. The double knockouts lived 20% longer and showed less glomerular and tubulointerstitial extracellular matrix deposition than the COL4A3(-/-) Alport mice with normal integrin alpha2beta1 expression. Electron microscopy illustrated improvements in the glomerular basement membrane structure. MMP2, MMP9, MMP12 and TIMP1 were expressed at significantly higher levels (compared to wild-type mice) in COL4A3(-/-)/ITGA2(+/+) Alport mice, but not in COL4A3(+/+)/ITGA2(-/-) mice. In conclusion, the collagen receptors DDR1 and integrin alpha2beta1 contribute to regulate GBM-maturation and to control matrix accumulation. As demonstrated in the type IV collagen disease Alport syndrome, glomerular cell-matrix interactions via collagen receptors play an important role in the progression of renal fibrosis. PMID- 24480070 TI - Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury. AB - Exacerbated inflammation in renal ischemia-reperfusion injury, the major cause of intrinsic acute renal failure, is a key trigger of kidney damage. During disease endogenous danger signals stimulate innate immune cells via Toll-like receptors (TLR)-2 and -4 and accelerate inflammatory responses. Here we show that production of soluble biglycan, a small leucine-rich proteoglycan, is induced during reperfusion and that it functions as endogenous agonist of TLR-2/4. Biglycan-mediated activation of TLR-2/4 initiates an inflammatory response in native kidneys, which is marked by the release of cytokines and chemokines and recruitment of inflammatory cells. Overexpression of soluble circulating biglycan before ischemic reperfusion enhanced plasma and renal levels of TNF-alpha, CXCL1, CCL2 and CCL5, caused influx of neutrophils, macrophages and T cells and overall worsened renal function in wild type mice. We provide robust genetic evidence for TLR-2/4 requirement insofar as biglycan biological effects were markedly dampened in mice deficient in both innate immune receptors, Tlr2(-/-);Tlr4(-/-) mice. Thus, signaling of soluble biglycan via TLR-2/4 could represent a novel therapeutic target for the prevention and possible treatment of patients with acute renal ischemia-reperfusion injury. PMID- 24480071 TI - Optimizing outcome in SLE: treating-to-target and definition of treatment goals. AB - Patients affected with systemic lupus erythematosus (SLE) display poor-long term prognosis and increased mortality in respect of general population. This may be due to continuous organ damage accrual which is fostered both by persistent disease activity (mainly in the short term) and prolonged corticosteroid exposure (mainly in the long term). The effort of defining novel therapeutic goals to which patients should be treated in order to have their prognosis improved is named treat-to-target. Remission in SLE was shown to be associated with better outcome and prolonged survival; in clinical practice, patients may experience either complete or clinical remission, which are defined as complete clinical/serological healing or no clinical signs of lupus with active serology, respectively. The main treat-to-target in SLE is complete remission, however since longitudinal observations suggest that clinical remission or low disease activity even with minimal corticosteroid intake do improve patients prognosis and survival as well, they may be assumed as acceptable alternative targets. Suitable therapeutic strategies have to be defined in order for these goals to be achieved including early diagnosis, effective treatment and proper corticosteroid tapering which in turn require development of more reliable serum biomarkers for early disease detection and less toxic targeted therapies with a steroid-sparing potential. PMID- 24480073 TI - Gustatory responsiveness to the 20 proteinogenic amino acids in the spider monkey (Ateles geoffroyi). AB - The gustatory responsiveness of four adult spider monkeys to the 20 proteinogenic amino acids was assessed in two-bottle preference tests of brief duration (1min). We found that Ateles geoffroyi responded with significant preferences for seven amino acids (glycine, l-proline, l-alanine, l-serine, l-glutamic acid, l-aspartic acid, and l-lysine) when presented at a concentration of 100mM and/or 200mM and tested against water. At the same concentrations, the animals significantly rejected five amino acids (l-tryptophan, l-tyrosine, l-valine, l-cysteine, and l isoleucine) and were indifferent to the remaining tastants. Further, the results show that the spider monkeys discriminated concentrations as low as 0.2mM l lysine, 2mM l-glutamic acid, 10mM l-proline, 20mM l-valine, 40mM glycine, l serine, and l-aspartic acid, and 80mM l-alanine from the alternative stimulus, with individual animals even scoring lower threshold values. A comparison between the taste qualities of the proteinogenic amino acids as described by humans and the preferences and aversions observed in the spider monkeys suggests a fairly high degree of agreement in the taste quality perception of these tastants between the two species. A comparison between the taste preference thresholds obtained with the spider monkeys and taste detection thresholds reported in human subjects suggests that the taste sensitivity of A. geoffroyi for the amino acids tested here might match that of Homo sapiens. The results support the assumption that the taste responses of spider monkeys to proteinogenic amino acids might reflect an evolutionary adaptation to their frugivorous and thus protein-poor diet. PMID- 24480074 TI - Infralimbic cortex controls core body temperature in a histamine dependent manner. AB - An increase in body temperature accelerates biochemical reactions and behavioral and physiological responses. A mechanism to actively increase body temperature would be beneficial during motivated behaviors. The prefrontal cortex is implicated in organizing motivated behavior; the infralimbic cortex, a subregion of the medial prefrontal cortex, has the necessary connectivity to serve the role of initiating such thermogenic mechanism at the beginning of the appetitive phase of motivated behavior; further, this cortex is active during motivated behavior and its disinhibition produces a marked behavioral and vegetative arousal increase, together with increases in histamine levels. We wanted to explore if this arousal was related to histaminergic activation after pharmacological infralimbic disinhibition and during the appetitive phase of motivated behavior. We measured core temperature and motor activity in response to picrotoxin injection in the infralimbic cortex, as well as during food-related appetitive behavior, evoked by enticing hungry rats with food. Pretreatment with the H1 receptor antagonist pyrilamine decreased thermal response to picrotoxin and enticement and completely blunted motor response to enticement. Motor and temperature responses to enticement were also completely abolished by infralimbic cortex inhibition with muscimol. To assess if this histamine dependent temperature increase was produced by an active sympathetic mediated thermogenic mechanism or was just a consequence of increased locomotor activity, we injected propranolol (i.p.), a beta adrenergic receptor blocker, before picrotoxin injection into the infralimbic cortex. Propranolol reduced the temperature increase without affecting locomotor activity. Altogether, these results suggest that infralimbic activation is necessary for appetitive behavior by inducing a motor and a vegetative arousal increase mediated by central histamine. PMID- 24480072 TI - Amylin activates distributed CNS nuclei to control energy balance. AB - Amylin is a pancreas-derived neuropeptide that acts in the central nervous system (CNS) to reduce food intake. Much of the literature describing the anorectic effects of amylin are focused on amylin's actions in the area postrema, a hindbrain circumventricular structure. Although the area postrema is certainly an important site that mediates the intake-suppressive effects of amylin, several pieces of evidence indicate that amylin may also promote negative energy balance through action in additional CNS nuclei, including hypothalamic and mesolimbic structures. Therefore, this review highlights the distributed neural network mediating the feeding effects of amylin signaling with special attention being devoted to the recent discovery that the ventral tegmental area is physiologically relevant for amylin-mediated control of feeding. The production of amylin by alternative, extra-pancreatic sources and its potential relevance to food intake regulation is also considered. Finally, the utility of amylin and amylin-like compounds as a component of combination pharmacotherapies for the treatment of obesity is discussed. PMID- 24480075 TI - Influence of dopamine D2-type receptors on motor behaviors in the green tree frog, Hyla cinerea. AB - Dopamine modulates a range of behaviors that include motor processes, learning, and incentive motivation. Research supports anatomical conservation of dopaminergic populations in the midbrain across vertebrate species, however, less evidence is available for dopamine receptor distributions. In order to test the behavioral role of dopamine in an anatomically conserved dopaminergic system, the effects of D2-type receptor manipulation on motor behaviors were examined in the anuran amphibian green tree frog, Hyla cinerea. In two different within-subject experiments, frogs were treated with a control treatment, and a high and low dose of either a D2 receptor-specific agonist, quinpirole, or antagonist, haloperidol, then exposed to a testing session to measure changes in swimming and climbing motor behaviors. No treatments resulted in complete immobility or catalepsy, however treatment-specific effects on certain motor behaviors were present. The high quinpirole dose (1mg/kg bw) generally inhibited motor behaviors associated with exiting water and jumping, while both haloperidol treatments (0.12mg/kg bw and 1.2mg/kg bw) generally stimulated motor behaviors associated with exiting water, as predicted based on receptor mechanisms. Performance improvement also appeared in frogs in each experiment, suggesting that the D2 receptor is not involved in the motor learning mechanism in this species. Overall, the results support general conservation of D2 receptors in motor processes in vertebrate species. PMID- 24480076 TI - Differential strain vulnerability to binge eating behaviors in rats. AB - Binge eating is a significantly heritable phenotype, but efforts to detect specific risk genes have fallen short. Identification of animal strain differences in risk for binge eating could highlight genetic differences across individuals of the same species that can be exploited in future animal and molecular genetic research. The current study aimed to explore strain differences in risk for binge eating in Sprague-Dawley versus Wistar female rats using the Binge Eating Resistant/Binge Eating Prone model. A sample of male Sprague-Dawley rats, a known low-risk group for binge eating, was included as a comparison group. A total of 83 rats (23 Wistar females, 30 Sprague-Dawley females, 30 Sprague-Dawley males) completed a protocol of intermittently administered, palatable food. Binge eating prone (BEP) and binge eating resistant (BER) rats were identified using a tertile approach. Sprague-Dawley female rats consumed the highest amount of palatable food and were more likely to be classified as BEP compared to Wistar female and Sprague-Dawley male rats. Wistar female rats were not significantly different from Sprague-Dawley male rats in their palatable food intake and tendency to be classified as BER rather than BEP. Sprague-Dawley female rats appear to be a particularly vulnerable genotype for binge eating. Comparisons between this group and others could help identify specific genetic/biological factors that differentiate it from lower risk groups. The reward system, linked to binge eating in humans, is a possible candidate to explore. Strain differences in the reward system could help increase understanding of individual differences in risk for binge eating in humans. PMID- 24480077 TI - Minocycline add-on to risperidone for treatment of negative symptoms in patients with stable schizophrenia: randomized double-blind placebo-controlled study. AB - The objective of this study was to assess the efficacy and tolerability of minocycline add-on to risperidone in treatment of negative symptoms of patients with chronic schizophrenia. In a randomized double-blind placebo-controlled study, 40 patients with chronic schizophrenia who were stabilized on risperidone for a minimum duration of eight weeks were recruited. The patients were randomly assigned to minocycline (titrated up to 200 mg/day) or placebo in addition to risperidone (maximum dose of 6 mg/day) for eight weeks. Positive and Negative Syndrome Scale (PANSS), Hamilton Depression Rating Scale, and Extrapyramidal Syndrome Rating Scale were used. Thirty-eight patients completed the study. Significant time * treatment interaction for negative [F(2.254,85.638)=59.046, P<0.001] general psychopathology [F(1.703,64.700)=6.819, P=0.001], and positive subscales [F(1.655,62.878)=5.193, P=0.012] as well as total PANSS scores [F(1.677,63.720)=28.420, P<0.001] were observed. The strongest predictors for change in negative symptoms were the treatment group (beta=-0.94, t=-10.59, P<0.001) followed by the change in PANSS positive subscale (beta=-0.185, t= 2.075, P=0.045). Side effect profiles of the two treatment regimens were not significantly different. Minocycline seems to be an efficacious and tolerable short-term add-on to risperidone for treatment of negative and general psychopathology symptoms of schizophrenia. PMID- 24480078 TI - Structural and clinical implications of amino acid substitutions in alpha-L iduronidase: insight into the basis of mucopolysaccharidosis type I. AB - Allelic mutations, predominantly missense ones, of the alpha-l-iduronidase (IDUA) gene cause mucopolysaccharidosis type I (MPS I), which exhibits heterogeneous phenotypes. These phenotypes are basically classified into severe, intermediate, and attenuated types. We previously examined the structural changes in IDUA due to MPS I by homology modeling, but the reliability was limited because of the low sequence identity. In this study, we built new structural models of mutant IDUAs due to 57 amino acid substitutions that had been identified in 27 severe, 1 severe-intermediate, 13 intermediate, 1 attenuated-intermediate and 15 attenuated type MPS I patients based on the crystal structure of human IDUA, which was recently determined by us. The structural changes were examined by calculating the root-mean-square distances (RMSD) and the number of atoms influenced by the amino acid replacements. The results revealed that the structural changes of the enzyme protein tended to be correlated with the severity of the disease. Then we focused on the structural changes resulting from amino acid replacements in the immunoglobulin-like domain and adjacent region, of which the structure had been missing in the IDUA model previously built. Coloring of atoms influenced by an amino acid substitution was performed in each case and the results revealed that the structural changes occurred in a region far from the active site of IDUA, suggesting that they affected protein folding. Structural analysis is thus useful for elucidation of the basis of MPS I. PMID- 24480079 TI - The spread of drug-resistant tuberculosis in children: an Italian case series. AB - Drug-resistant paediatric tuberculosis (TB) is an overlooked global problem. In Italy, the epidemiology of TB has recently changed and data regarding drug resistant forms in the paediatric setting is scanty. The aim of this case series was to report the cases of drug-resistant TB, diagnosed between June 2006 and July 2010 in four Italian tertiary centres for paediatric infectious diseases, in children and adolescents living in Italy. Twenty-two children were enrolled, of these 17 were resistant to one or more drugs and five had multidrug-resistant TB. All but one child were either foreign born or had at least one foreign parent. Twenty-one patients completed their treatment without clinical or radiological signs of activity at the end of treatment, and one patient was lost to follow up. The outcomes were good, with few adverse effects using second-line anti-TB drugs. Although this series is limited, it might already reflect the worrisome increase of drug-resistant TB, even in childhood. PMID- 24480080 TI - Reply to the letter to the editor Re: "Impact of age over 75 years on outcomes after pancreaticoduodenectomy". PMID- 24480081 TI - Surgical specialty and outcomes for carotid endarterectomy: evidence from the National Surgical Quality Improvement Program. AB - BACKGROUND: Carotid endarterectomy (CEA) has been performed since the 1950s and remains one of the most common surgical procedures in the United States. The procedure is performed by cardiothoracic, general, neurologic, and vascular surgeons. This study uses data from the National Surgical Quality Improvement Program (NSQIP) to examine the outcomes after CEA when performed by general or vascular surgeons. MATERIALS AND METHODS: Data included 34,493 CEAs from years 2005 to 2010 recorded in the NSQIP database. Primary outcomes measured were length of stay, 30-d mortality, surgical site infection, cerebrovascular accident, myocardial infarction, and blood transfusion requirement. Secondary outcomes measured were the remaining intraoperative outcomes from the NSQIP database. RESULTS: After controlling for patient and surgical characteristics, patients treated by general surgeons did not have a significantly different LOS or 30-d mortality than those treated by vascular surgeons. Patients of general surgeons had nearly twice the risk of acquiring a surgical site infection (odds ratio [OR] = 1.94; P = 0.012), >1.5 times the risk of cerebrovascular accident (OR = 1.56; P = 0.008), and >1.8 times the risk of blood transfusion (OR = 1.85; P = 0.017) than those of vascular surgeons. Patients of general surgeons had less than half the risk of having a myocardial infarction (OR = 0.34; P = 0.031) than those of vascular surgeons. CONCLUSIONS: Surgical specialty is associated with a wide range of postoperative outcomes after CEA. Additional research is needed to explore practice and cultural differences across surgical specialty that may lead to outcome differences. PMID- 24480082 TI - Spontaneous omental bleeding in the setting of dual anti-platelet therapy with ticagrelor. AB - A 68 year-old man, initially managed with primary percutaneous coronary intervention (PCI) to the right coronary artery (RCA) for an inferior ST elevation myocardial infarction (STEMI) with residual disease requiring coronary artery bypass graft surgery (CABG), re-presented with chest pain. There were no acute ischaemic changes on ECG and his pain settled with nitrates. A day later, he developed left sided abdominal pain and hypovolaemic shock after straining in the toilet. A subsequent computed tomography (CT) scan of his abdomen revealed an omental bleed. He proceeded to emergency laparotomy, recovered well, and was discharged on aspirin and clopidogrel. Apart from dual antiplatelet therapy with aspirin and ticagrelor, and presumed raised intra-abdominal pressure, there were no other identified risk factors for increased bleeding. PMID- 24480083 TI - Response to communication of Paola Romagnani and Giuseppe Remuzzi. PMID- 24480084 TI - Imaging follow-up of endovascular repair of type B aortic dissection with dual source, dual-energy CT and late delayed-phase scans. AB - PURPOSE: To evaluate the diagnostic performance of dual-energy (DE) computed tomography (CT) after thoracic endovascular aortic repair (TEVAR) of type B dissection, and to investigate the value of late delayed (LD) acquisition in endoleak detection and false lumen patency assessment. MATERIALS AND METHODS: Twenty-four patients with TEVAR for type B dissection underwent 53 tripe-phase CT examinations. Single-source unenhanced acquisition was followed by single-source arterial-phase and DE LD phase (300-s delay) imaging. Virtual noncontrast images were generated from DE acquisition. Two blinded radiologists retrospectively evaluated the cases in three reading sessions: session A (triphasic protocol), session B (virtual noncontrast and arterial phase), and session C (virtual noncontrast and arterial and LD phases). Endoleak detection accuracy during sessions B and C compared with session A (reference standard) was investigated. False lumen patency was assessed. Effective radiation dose was calculated. RESULTS: Session A revealed 37 endoleaks in 30 of 53 studies (56.6%). Session B revealed 31 of the 37 endoleaks, with one false-positive case, 83.8% sensitivity, 95.8% specificity, 79.3% negative predictive value, and 96.9% positive predictive value. Session C correctly depicted all 37 endoleaks, with one false-positive case, 100% sensitivity, 95.8% specificity, 100% negative predictive value, and 97.4% positive predictive value. Underestimation of false lumen patency was found in session B (P = .013). Virtual noncontrast imaging resulted in 17% radiation exposure reduction. CONCLUSIONS: Virtual noncontrast imaging can replace standard unenhanced images in follow-up after TEVAR of type B dissection, thus reducing radiation dose. Delayed-phase imaging is valuable in low-flow endoleaks detection and false lumen patency assessment. PMID- 24480085 TI - Inhibition of growth in a rabbit VX2 thigh tumor model with intraarterial infusion of carbon dioxide-saturated solution. AB - PURPOSE: To evaluate the efficacy of intraarterial infusion of CO2-saturated solution in rabbit VX2 thigh tumors. MATERIALS AND METHODS: Fourteen Japanese white rabbits had VX2 tumors implanted in the right femoral muscle 3 weeks before intraarterial infusion. Rabbits were divided into control and CO2 groups (n = 7 each). Fifty milliliters of solution (saline solution and CO2-saturated solution for the control and CO2 groups, respectively) was administered via a 24-gauge catheter in the ipsilateral iliac artery close to the feeding artery of the VX2 tumor. All rabbits were killed for tumor harvest on day 3 after the procedure. Tumor volume was evaluated with in vivo direct caliper measurement and contrast enhanced computed tomography (CT). Tumor apoptotic changes were examined by DNA fragmentation assay and immunoblot analysis. The tumor growth ratio and apoptotic cell rate were analyzed. RESULTS: Body weight was equally increased in both groups, but the mean tumor growth ratio was significantly decreased in the CO2 group compared with the control group (-9.5% +/- 7.9 vs 27.2% +/- 6.6 and 4.1% +/ 4.4 vs 35.7% +/- 4.5 measured by calipers and contrast-enhanced CT, respectively; P < .01). Apoptotic activity in the CO2 group was higher than in the control group (number of apoptotic cells per area, 215.0 +/- 58.7 vs 21.8 +/- 5.4; adjusted relative density of cleaved caspase-3, 0.23 +/- 0.07 vs 0.04 +/- 0.01; P < .01). CONCLUSIONS: Intraarterial infusion of CO2-saturated solution inhibits rabbit VX2 thigh tumor growth by activation of apoptotic cell death through cleaved caspase-3 upregulation. PMID- 24480086 TI - Effect of bulk/incremental fill on internal gap formation of bulk-fill composites. AB - OBJECTIVES: To examine the effects of composite type (bulk-fill/conventional) and placement (4-mm bulk/2-mm increments) on internal marginal adaptation of Class I preparations. METHODS: Cylindrical, Class I, 4-mm*4-mm preparations were made on 50 recently extracted human molars and restored using either a bulk-fill (SureFil SDR Flow (SDR), Quixx (QX), SonicFill (SF), Tetric EvoCeram Bulk (TEC)) or a conventional composite designed for 2-mm increments (Filtek Supreme Ultra (FSU)). Restorations were placed in 1 or 2 increments using the manufacturer's bonding agent and curing light (n=5). Teeth were sectioned occluso-gingivally and dye was placed on the internal margin and visually examined by 3 observers. Gap-free marginal lengths were analysed within three different regions of the sectioned tooth: enamel, mid-dentine, and pulpal floor. RESULTS: Marginal integrity was unaffected by placement method. Bulk-placement demonstrated significantly fewer gap-free margins at the pulpal floor than in enamel, for all materials except SDR. Greater percentages of gap-free margins were found within the mid-dentine than at the pulpal floor for FSU. QX had more gap-free margins in enamel compared with the mid-dentine. Proportion of gap-free margins within enamel and mid dentine was not significantly different for any incrementally placed product. Excluding FSU, gap-free margins within enamel were significantly greater than at the pulpal floor. Notably, significantly more gap-free margins were found within mid-dentine than at the pulpal floor for SF. CONCLUSIONS: No significant differences in gap-free margins were found between placement methods within a given product per location. Except for SDR, percentage of gap-free margins was significantly lower at the pulpal floor interface than at the enamel interface for bulk-fill. PMID- 24480088 TI - Molecular study of X-linked ichthyosis: report of a novel 2-bp insertion mutation in the STS and a very rare case of homozygous female patient. PMID- 24480089 TI - Single-molecule imaging revealed dynamic GPCR dimerization. AB - Single fluorescent-molecule video imaging and tracking in living cells are revolutionizing our understanding of molecular interactions in the plasma membrane and intracellular membrane systems. They have revealed that molecular interactions occur surprisingly dynamically on much shorter time scales (?1s) than those expected from the results by conventional techniques, such as pull down assays (minutes to hours). Single-molecule imaging has unequivocally showed that G-protein-coupled receptors (GPCRs) undergo dynamic equilibrium between monomers and dimers, by enabling the determination of the 2D monomer-dimer equilibrium constant, the dimer dissociation rate constant (typically ~10s(-1)), and the formation rate constant. Within one second, GPCRs typically undergo several cycles of monomer and homo-dimer formation with different partners. PMID- 24480090 TI - White matter connectivity reflects clinical and cognitive status in Huntington's disease. AB - OBJECTIVE: To investigate structural connectivity and the relationship between axonal microstructure and clinical, cognitive, and motor functions in premanifest (pre-HD) and symptomatic (symp-HD) Huntington's disease. METHOD: Diffusion tensor imaging (DTI) data were acquired from 35 pre-HD, 36 symp-HD, and 35 controls. Structural connectivity was mapped between 40 brain regions of interest using tractography. Between-group differences in structural connectivity were identified using network based statistics. Radial diffusivity (RD) and fractional anisotropy (FA) were compared in the white matter tracts from aberrant networks. RD values in aberrant tracts were correlated with clinical severity, and cognitive and motor performance. RESULTS: A network connecting putamen with prefrontal and motor cortex demonstrated significantly reduced tractography streamlines in pre-HD. Symp-HD individuals showed reduced streamlines in a network connecting prefrontal, motor, and parietal cortices with both caudate and putamen. The symp-HD group, compared to controls and pre-HD, showed both increased RD and decreased FA in the fronto-parietal and caudate-paracentral tracts and increased RD in the putamen-prefrontal and putamen-motor tracts. The pre-HDclose, compared to controls, showed increased RD in the putamen-prefrontal and fronto-parietal tracts. In the pre-HD group, significant negative correlations were observed between SDMT and Stroop performance and RD in the bilateral putamen-prefrontal tract. In the symp-HD group, RD in the fronto parietal tract was significantly positively correlated with UHDRS motor scores and significantly negatively correlated with performance on SDMT and Stroop tasks. CONCLUSIONS: We have provided evidence of aberrant connectivity and microstructural integrity in white matter networks in HD. Microstructural changes in the cortico-striatal fibers were associated with cognitive and motor performance in pre-HD, suggesting that changes in axonal integrity provide an early marker for clinically relevant impairment in HD. PMID- 24480092 TI - President's page: Heart Month and the American College of Cardiology: a lesson in partnerships, member values, and patient education. PMID- 24480091 TI - Progressive Parkinsonism by acute dysfunction of excitatory amino acid transporters in the rat substantia nigra. AB - Parkinson's disease (PD) is characterized by the progressive degeneration of substantia nigra (SN) dopamine neurons, involving a multifactorial cascade of pathogenic events. Here we explored the hypothesis that dysfunction of excitatory amino acid transporters (EAATs) might be involved. Acutely-induced dysfunction of EAATs in the rat SN, by single unilateral injection of their substrate inhibitor l-trans-pyrrolidine-2,4-dicarboxylate (PDC), triggers a neurodegenerative process mimicking several PD features. Dopamine neurons are selectively affected, consistent with their sustained excitation by PDC measured by slice electrophysiology. The anti-oxidant N-acetylcysteine and the NMDA receptor antagonists ifenprodil and memantine provide neuroprotection. Besides oxidative stress and NMDA receptor-mediated excitotoxicity, glutathione depletion and neuroinflammation characterize the primary insult. Most interestingly, the degeneration progresses overtime with unilateral to bilateral and caudo-rostral evolution. Transient adaptive changes in dopamine function markers in SN and striatum accompany cell loss and axonal dystrophy, respectively. Motor deficits appear when neuron loss exceeds 50% in the most affected SN and striatal dopamine tone is dramatically reduced. These findings outline a functional link between EAAT dysfunction and several PD pathogenic mechanisms/pathological hallmarks, and provide a novel acutely-triggered model of progressive Parkinsonism. PMID- 24480093 TI - Including systematic reviews in PhD programmes and candidatures in nursing - 'Hobson's choice'? AB - Nowadays, gathering and synthesising evidence, i.e. conducting systematic reviews, is considered an important part of any health service research endeavour. Reviewing the literature, however suggest that it is not yet common that PhD students/doctoral candidates publish systematic reviews or even include a high quality review of the literature as a part of their PhD programme or candidature. Implying that systematic reviewing skills might not be acquired by going through an education on a postgraduate level. Additionally, scholars debating systematic reviews 'to be or not to be' as a part of research training seem to be sparse, especially within the field of nursing. In this issue for debate, we would like to propose that the absence of systematic reviews' in this context might severely hamper the 'up and coming' researchers as well as the research conducted. We envisage that this lack can have a negative impact on international nursing practice, and therefore propose that systematic reviews should be considered, whenever appropriate, as a mandatory part of any PhD programme or candidature. We believe that abilities in systematic reviewing will be a sought after research skills in the near future. Including systematic reviews would promote i) refined, well-grounded adequate research questions, ii) PhDs with broad and elevated methodological skills, iii) an increased level of evidence based nursing praxis. However, to make this a reality, supervisors, PhD students, and candidates would need to understand the value of this kind of research activity. Finally, lobbying University faculty boards and grant providers that are not inclined to view literature reviews as 'proper' research or as an important part of health service research, needs to be put on the agenda. PMID- 24480094 TI - Challenges of implementating a doctoral program in an international exchange in Cuba through the lens of Kanter's empowerment theory. AB - The literature in international education focuses primarily on the experiences of western students in developing countries, international students in western universities, the development of an educational program in a developing country, or internationalization of curricula in western universities. There is little in the literature that addresses the challenges students and participating faculty face when implementing a graduate program in a developing country. The purpose of this paper is to describe and analyze the challenges of implementing a doctoral program in an international exchange through the lens of Kanter's theory of empowerment. Recommendations to address these challenges will be made. PMID- 24480095 TI - Action learning sets in a nursing and midwifery practice learning context: a realistic evaluation. AB - Action learning sets (ALS) are used widely for organisational and workforce development, including in nursing (Anderson and Thorpe, 2004; Pounder, 2009; Young et al., 2010). In the United Kingdom, a multi-faceted educational Pilot programme for new nurses and midwives was implemented to accelerate their clinical practice and leadership development (NHS Education Scotland, 2010). Action Learning Sets were provided for peer support and personal development. The Realistic Evaluation study reported in this paper explored issues of context, mechanism and outcome (Pawson and Tilley, 1997) influencing the action learning experiences of: programme participants (recently qualified nurses and midwives, from different practice settings); and programme supporters. A range of data were collected via: online questionnaires from 66 participants and 29 supporters; three focus groups, each comprising between eight and 10 programme participants; and one focus group with three action learning facilitators. The qualitative data pertaining to the ALS are presented in this paper. Thematic data analysis of context, mechanism and outcome configurations, generated five themes: creating and sustaining a collective learning environment; challenging constructively; collective support; the role of feedback; and effectiveness of ALS. Study outcomes suggest nursing and midwifery action learning should (a) be facilitated positively to improve participants' experience; (b) be renamed to avoid learning methodology confusion; and (c) be outcome focused to evidence impact on practice. PMID- 24480096 TI - Community of practice in healthcare: an investigation on nursing students' perceived respect. AB - In the healthcare setting, Community of Practice (CoP) can be defined as the learning environment where nursing students develop their attitudes toward the nursing profession. Although being part of a CoP is important for nursing students, it can sometimes result in a negative experience where students often perceive a lack of respect. The aim of this study was to expand the knowledge of the CoP in the healthcare setting by analyzing students' perception of respect during clinical placements. Important aspects, such as a professional role concept (role ambiguity and role conflict), tutor support, feedback and relationship with tutors and staff were investigated as predictors of student's perceived respect. A total of 188 Nursing Science Degree undergraduate students were recruited during 2012. Data were analyzed by using regression analysis. The findings supported the importance of role stress, feedback from CoP members, tutor support, and relationship with CoP members on nursing students' perceived respect. The results suggest that when studying nursing students in a CoP, the social context can contribute to affect students' perceived respect. PMID- 24480097 TI - Myths and mysteries of mental health: an interagency collaboration. AB - This paper explores a practice learning collaboration between a group of undergraduate mental health nurses (N = 12) and second year high school pupils, (age 13/14 years old). A case study approach is employed as an example of an interagency learning activity in the undergraduate curriculum. Nursing students and high school teachers worked together to develop five three workshops. Each workshop contained five 'tabletop' group activities around themes such as confidence building; friendship skills and diet and health. The overall aim of the workshops was to provide an atypical experience for mental health nursing students in which the setting is an everyday environment (school); with young people who were not 'patients' or 'clients', and that focuses on health rather than ill health. In addition the activity aimed to broaden school pupils' understanding and knowledge of mental health and well-being. OUTCOME: Pupils completed a closed question evaluation at the end of the workshop that demonstrated the workshops were effective in improving understanding. In addition, the nursing students presented their experience of the interagency activity at a national conference. The paper will explore the social and educational benefits of interagency learning, and concludes that further research is required to identify the significant role schools have to play in developing a nursing workforce that is prepared for care that is centred around the concept of health and well-being and that focuses on the community as the principle for setting for intervention. PMID- 24480098 TI - Comparative epidemiologic study of skin diseases in foreign children and children of Spanish origin in Alicante, Spain. AB - INTRODUCTION: Previous studies in Spain have shown that the foreign and immigrant populations can have different diseases to Spanish-born individuals. However, no comparative study has specifically investigated foreign children in Spain. MATERIAL AND METHODS: The objective of the study was to compare skin diseases in foreign children with those in children born in Spain of Spanish parents. We included all patients under 15 years of age who were seen in our dermatology department between January 2007 and December 2007. RESULTS: During the study period, 3108 pediatric patients were seen in the dermatology department. Of these, 2661 (85.6%) were Spanish and 447 (14.3%) were foreigners. Foreign children sought medical care more often (11.4%) than Spanish children (6%) (P<.001) and made less use of the specialist outpatient clinic (59.6% vs 68.8% [P<.001]) and more use of emergency care. Complaints observed more frequently in the foreign children were scabies (adjusted odds ratio [aOR], 10.6; 95% CI, 4.71 24.10), arthropod bites (aOR, 2.80; 95% CI, 1.14-6.87), hypopigmentation (aOR, 2.61; 95% CI, 1.06-6.44), and atopic dermatitis (aOR, 1.65; 95% CI, 1.19-2.31). Melanocytic nevus was observed more frequently in Spanish children (aOR, .50; 95% CI, .30-.83). CONCLUSIONS: Differences between children born in Spain of Spanish parents and foreign children were found for type of visit and frequency of skin diseases. PMID- 24480099 TI - Aseptic meningitis outbreak caused by echovirus 30 in two regions in Bulgaria, May-August 2012. AB - An aseptic meningitis outbreak emerged in two regions in Bulgaria in 2012 and echovirus 30 (E30) was established as the aetiological agent by cell culture isolation, serological test, and molecular-based techniques. A total of 157 patients with aseptic meningitis were investigated, of which 117 were confirmed as having E30-associated disease. Molecular analysis of 12 E30 isolates revealed 99-100% nucleotide and amino-acid identity between them and a close correlation with a Greek strain involved in an E30 outbreak in 2012. Children aged 5-14 years were mainly affected, which could reflect the absence of E30 epidemics in Bulgaria for a period of 11 years. The first case with E30 isolation (a 2-year old patient from Plovdiv) was notified at the end of April 2012. This was most likely the index case, from which the spread of the virus started, causing sporadic cases first, which later led to an aseptic meningitis outbreak facilitated by person-to-person viral transmission. PMID- 24480100 TI - Foreign bodies. PMID- 24480101 TI - Congenital Ewing's Sarcoma/Peripheral Primitive Neuroectodermal Tumor: A Case Report and Review of the Literature. AB - Ewing's sarcoma (EWS) and peripheral primitive neuroectodermal tumor (pPNET) are small round cell malignancies that develop in soft tissue and bone. They very rarely affect newborns. A diagnosis of EWS/pPNET depends mainly on immunohistochemistry and molecular/genetic assays. Since these tumors are highly aggressive, patient prognosis is typically very poor, and treatment remains a challenge. Here, we report a 13-day-old newborn diagnosed with congenital EWS/pPNET and describe its treatment. PMID- 24480102 TI - Withanolides from Physalis minima and their inhibitory effects on nitric oxide production. AB - Six new withanolides (1-6), including two uncommon 1,10-seco withanolides (1 and 2), together with five known withanolides (7-11), were isolated from the whole plants of Physalis minima Linn.. The structures of new compounds were elucidated through spectroscopic methods, including (1)H, (13)C NMR, 2D-NMR, HRESIMS and circular dichroism (CD). Inhibitory effects of the isolates on nitric oxide (NO) production in lipopolysaccaride-activated RAW264.7 macrophages were evaluated. Compounds 2 and 5 showed strong inhibitory activities with IC50 values of 8.04 and 10.01 MUM, respectively. Compounds 1, 9 and 10 exhibited moderate inhibitory activities with IC50 values from 25.54 to 43.58 MUM. PMID- 24480103 TI - Risk factors and acute ischemic stroke subtypes. AB - BACKGROUND: Acute ischemic stroke (AIS) is influenced by gender, age, and the brain site affected. Better characterization of AIS is necessary for improving guidelines, prevention, and destination of resources. METHODS: Demographics, prestroke conditions, etiology, subtypes, specific hospital outcome, clinical and laboratory parameters, and mortality rates were prospectively registered in 105 southern Italian patients. RESULTS: AIS became more frequent in women than in men after age 65 years. Cryptogenic AIS decreased with age independently of sex and lesion site. Cerebellum-brainstem stroke was more prevalent in men, whereas anterior AIS was more frequent in women. There were no overall differences in 6- and 12-month survival rates based on site or sex; however, mortality rates were high after age 80 years. Chronic kidney disease was more frequent in patients with cerebellum-brainstem stroke, and its prevalence increased significantly with age independently of sex. Association of AIS with arterial hypertension, diabetes, and previous myocardial infarction increased with age, whereas that with active smoking decreased with age, independently of sex and site. CONCLUSION: Specific AIS etiology and blood characteristics associated independently to the youngest and oldest AIS patients, respectively. Chronic kidney disease was a specific predictor of cerebellum-brainstem AIS. AIS mortality showed peculiar association with the oldest patients. PMID- 24480104 TI - The importance of using a proper technique and accurate seeding of regions-of interest in diffusion tensor tractography. PMID- 24480106 TI - Ovarian torsion: Case-control study comparing the sensitivity and specificity of ultrasonography and computed tomography for diagnosis in the emergency department. AB - OBJECTIVE: Evaluate the sensitivity and specificity of pelvic ultrasound (US) and abdominopelvic computed tomography (CT) for the identification of ovarian torsion in women presenting to the emergency department with acute lower abdominal or pelvic pain. MATERIALS AND METHODS: This is a retrospective study of 20 cases of ovarian torsion and 20 control patients, all of whom had both US and CT performed in the emergency department. Two radiologists who were blinded to clinical data interpreted all studies as (1) demonstrating an abnormal ovary or not, and (2) suggestive of torsion or not. Sensitivity, specificity and interobserver variation were calculated for each imaging modality. RESULTS: Pelvic US was interpreted as demonstrating an abnormal ovary in 90.0% of ovarian torsion cases by reader 1, and in 100.0% by reader 2, whereas CT was interpreted as revealing an abnormal ovary in 100.0% of torsion cases by both readers. Pelvic US for ovarian torsion was 80.0% sensitive (95% CI, 58.4-91.9%) and 95.0% specific (95% CI, 76.4-99.1%) for reader 1, while 80.0% sensitive (95% CI, 58.4-91.9%) and 85.0% specific (95% CI, 64.0-95.0%) for reader 2. Interobserver agreement for pelvic US was fair (Kappa=0.60). Abdominopelvic CT for ovarian torsion was 100.0% sensitive (95% CI, 83.9-100.0%) and 85.0% specific (95% CI, 64.0-94.5%) for reader 1, while 90.0% sensitive (95% CI, 69.9-97.2%) and 90.0% specific (95% CI, 69.9-97.2%) for reader 2. Interobserver agreement was excellent (Kappa=0.85). CONCLUSION: The diagnostic performance of CT is not shown to be significantly different from that of US in identifying ovarian torsion in this study. These results suggest that when CT demonstrates findings of ovarian torsion, the performance of another imaging exam (i.e. US) that delays therapy is unlikely to improve preoperative diagnostic yield. PMID- 24480105 TI - Postinterventional MRI findings following MRI-guided laser ablation of osteoid osteoma. AB - OBJECTIVE: To evaluate postinterventional magnetic resonance imaging (MRI) characteristics following MRI-guided laser ablation of osteoid osteoma (OO). MATERIALS AND METHODS: 35 patients treated with MRI-guided laser ablation underwent follow-up MRI immediately after the procedure, after 3, 6, 12, 24, 36, and up to 48 months. The imaging protocol included multiplanar fat-saturated T2w TSE, unenhanced and contrast-enhanced T1w SE, and subtraction images. MR images were reviewed regarding the appearance and size of treated areas, and presence of periablation bone and soft tissue changes. Imaging was correlated with clinical status. RESULTS: Mean follow-up time was 13.6 months. 28/35 patients (80%) showed a postinterventional "target-sign" appearance consisting of a fibrovascular rim zone and a necrotic core area. After an initial increase in total lesion diameter after 3 months, a subsequent progressive inward remodeling process of the zonal compartments was observed for up to 24 months. Periablation bone and soft tissue changes showed a constant decrease over time. MR findings correlated well with the clinical status. Clinical success was achieved in 32/35 (91%). CONCLUSIONS: Evaluation of long-term follow-up MRI after laser ablation of OO identified typical postinterventional changes and thus may contribute to the interpretation of therapeutic success and residual or recurrent OO in suspected cases. PMID- 24480107 TI - Mechanical pacing and induction of ventricular fibrillation by chest compressions: an unexpected phenomenon with possible implications for resuscitation algorithms. PMID- 24480108 TI - Effect of urea and alkylureas on the stability and structural fluctuation of the M80-containing Omega-loop of horse cytochrome c. AB - The effect of denaturants on the structural fluctuation of M80-containing Omega loop of ferrocytochrome c was determined by measuring the rate coefficient of CO association with ferrocytochrome c under varying concentrations of urea and alkylureas (methylurea (MU), N,N'-dimethylurea (DMU), ethylurea (EU), tetramethylurea (TMU)) at pH7.0, 25 degrees C. As denaturant concentration is increased within the subdenaturing limit, the CO-association reaction is decelerated indicating that subdenaturing concentrations of denaturant reduce the structural fluctuation of the Omega-loop. Structural fluctuation of the Omega loop is reduced more for urea and least for TMU. Intermolecular docking between horse cytochrome c and denaturant molecule (urea, MU, DMU, EU and TMU) reveals that polyfunctional interactions between the denaturant and different groups of Omega-loop and other part of protein decrease with an increase of alkyl group on urea molecule, which suggests that the decrease in the extent of restricted dynamics of Omega-loop with a corresponding increase of alkyl groups on urea molecule is due to the decrease of denaturant-mediated cross-linking interactions. These denaturant-mediated interactions are expected to reduce the conformational entropy of protein. Analysis of rate-temperature data shows a progressive decrease in conformational entropy of protein in the native to subdenaturing region. Thermodynamic analysis of denaturant (urea, MU, DMU, EU, TMU) effects on the thermal unfolding of ferrocytochrome c reveals that (i) thermodynamic stability of protein decreases with increasing concentration of denaturant or hydrophobicity of urea derivatives, (ii) water activity plays an important role in stabilization of ferrocytochrome c, and (iii) destabilization of ferrocytochrome c by denaturant occurs through the disturbance of hydrophobic interactions and hydrogen-bonding. PMID- 24480110 TI - Maternal-fetal attachment and prenatal diagnosis of heart disease. AB - OBJECTIVE: To test the hypothesis that there are differences in the level of maternal-fetal attachment before and after fetal echocardiography in the presence or absence of cardiac abnormalities. STUDY DESIGN: Cohort study in which the mothers responded to a validated Maternal-Fetal Attachment Scale. The study compared a group of pregnant women with diagnosis of fetal heart disease (FHD) with a group without this diagnosis ("no fetal heart disease" - NFHD). RESULTS: 197 pregnant women were included, 96 FHD and 101 NFHD. Maternal-fetal attachment at the initial and final periods showed no significant baseline differences between groups (p=0.081). At the final period, migration from medium to high level of attachment was significantly higher in FHD (p=0.017). Transition from medium to high levels comparing the initial and final periods was more pronounced in FHD (p=0.009). CONCLUSION: Diagnosis of fetal heart disease increases the level of maternal-fetal attachment. PMID- 24480109 TI - Improving the specific activity of beta-mannanase from Aspergillus niger BK01 by structure-based rational design. AB - beta-Mannanase has found various biotechnological applications because it is capable of degrading mannans into smaller sugar components. A highly potent example is the thermophilic beta-mannanase from Aspergillus niger BK01 (ManBK), which can be efficiently expressed in industrial yeast strains and is thus an attractive candidate for commercial utilizations. In order to understand the molecular mechanism, which helps in strategies to improve the enzyme's performance that would meet industrial demands, 3D-structural information is a great asset. Here, we present the 1.57A crystal structure of ManBK. The protein adopts a typical (beta/alpha)8 fold that resembles the other GH5 family members. Polysaccharides were subsequently modeled into the substrate binding groove to identify the residues and structural features that may be involved in the catalytic reaction. Based on the structure, rational design was conducted to engineer ManBK in an attempt to enhance its enzymatic activity. Among the 23 mutants that we constructed, the most promising Y216W showed an 18+/-2.7% increase in specific activity by comparison with the wild type enzyme. The optimal temperature and heat tolerance profiles of Y216W were similar to those of the wild type, manifesting a preserved thermostability. Kinetic studies showed that Y216W has higher kcat values than the wild type enzyme, suggesting a faster turnover rate of catalysis. In this study we applied rational design to ManBK by using its crystal structure as a basis and identified the Y216W mutant that shows great potentials in industrial applications. PMID- 24480111 TI - Prediction of intrauterine death and severe preterm delivery in twin pregnancies discordant for major fetal abnormality. AB - OBJECTIVE: To investigate predictors of spontaneous fetal death and preterm delivery in twin pregnancies with one fetus affected by a major structural malformation. STUDY DESIGN: Retrospective study (1999-2012) conducted at a tertiary teaching hospital involving 51 twin pregnancies (dichorionic=31, monochorionic diamniotic=15, monochorionic monoamniotic=4, not established=1) with a major fetal abnormality, enrolled before 26 weeks and managed expectantly. PRIMARY OUTCOMES: spontaneous fetal death, and/or delivery before 32 weeks. Prediction was examined with stepwise logistic regression analysis, and independent variables included: maternal age, gestational age at diagnosis, chorionicity, fetal gender, number and type of fetal abnormalities. Significance level was set at 0.15. RESULTS: Fetal abnormalities were diagnosed at a mean gestation of 21.5+/-3.7 weeks: cardiac abnormalities were observed in 31.4% of abnormal fetuses, abdominal wall defects in 29.4%, central nervous system 21.5%, spine 17.6%, effusions 17.6%, noncardiac thoracic abnormalities 15.7%, genital and urinary system 13.7%, limbs and soft tissue 3.9%, intestinal 1.9% and facial defects 1.9%. Fetal death occurred in 15 (29.4%) abnormal fetuses and was significantly correlated with the number of fetal malformations (p=0.02, OR=2.54, 95% CI=1.14-5.62), presence of effusion/hydrops (p=0.06, OR=4.7, 95% CI=0.95-24) and monochorionic placenta (p=0.11, OR=2.8, 95% CI=0.78-9.8). Normal co-twin fetal death occurred in four cases (7.8%) and was related to monochorionic pregnancies (p=0.14, OR=5.8, 95% CI=0.56-61). Delivery before 32 weeks was observed in 14 (27.5%) pregnancies and was related to presence of effusion/hydrops (p=0.04, OR=5.5, 95% CI=1.07-28). CONCLUSION: Spontaneous fetal death and/or delivery before 32 weeks in twin pregnancies with one fetus affected by a major structural malformation are related to the number of abnormalities diagnosed and presence of fetal effusion or hydrops. PMID- 24480112 TI - Carotid intima-media thickness: a new marker of patients with uterine leiomyoma. AB - OBJECTIVE: To determine whether or not there are any significant differences in carotid intima-media thickness between patients with uterine leiomyoma and controls. STUDY DESIGN: Patients whose ages were between 40 and 50 years, with body mass index <30kg/m(2), and with a pathological diagnosis of uterine leiomyoma constituted the study group. Control subjects had no uterine leiomyoma proven by sonography. Demographic, clinical, and drug history data were collected. Right, left and mean carotid intima-media thickness measurements were obtained by ultrasonography. RESULTS: Carotid intima-media thickness and serum high-density lipoprotein (HDL) levels were significantly different between the groups (p=0.0001 and p=0.001 respectively), being respectively higher and lower in the leiomyoma group than in controls. Stepwise binary logistic regression analysis revealed that uterine leiomyoma development ratio was 159.32 times higher when carotid intima-media thickness was over 0.61mm (p=0.0001). In patients with uterine leiomyoma, carotid intima-media thickness was significantly less in patients taking statins compared to those not on these drugs (p=0.0001). CONCLUSION: The present study demonstrated a positive association between carotid intima-media thickness and the presence of uterine leiomyoma. Conversely, an inverse association was suggested between HDL and uterine leiomyoma. These findings suggest that women with uterine leiomyoma might have an increased risk of subclinical atherosclerosis. PMID- 24480113 TI - Effects of a contraceptive containing drospirenone and ethinyl estradiol on blood pressure and autonomic tone: a prospective controlled clinical trial. AB - BACKGROUND: The use of combined oral contraceptives has been associated with an increased risk of adverse cardiovascular events. Whether these drugs alter cardiac autonomic nervous system control is not completely determined. OBJECTIVE: To evaluate the effect of a contraceptive containing 20mcg of ethinyl estradiol and 3mg of drospirenone on the heart rate variability, baroreflex sensitivity and blood pressure of healthy women. STUDY DESIGN: Prospective controlled trial with 69 healthy women allocated in two groups: 36 volunteers under oral combined contraceptive use and 33 volunteers using of non-hormonal contraceptive methods. Subjects were tested before the introduction of the contraceptive method and 6 months after its use. For data acquisition, we used continuous non-invasive beat to-beat blood pressure curve recordings. Multiple ANOVA was used to determine differences between groups and moments and p< 0.05 was considered statistically significant. RESULTS: At baseline, there were no differences in demographic and autonomic parameters between groups. Comparing cardiac sympatho-vagal modulation, baroreceptor sensitivity and blood pressure measurements between baseline and after 6 months, no significant difference was detected in each group or between groups. CONCLUSION: A contraceptive containing 20mcg of ethinyl estradiol and 3mg of drospirenone causes no significant changes in clinical, hemodynamic and autonomic parameters of normal women. PMID- 24480114 TI - Interstitial cystitis/painful bladder syndrome: epidemiology, pathophysiology and evidence-based treatment options. AB - Interstitial cystitis/painful bladder syndrome (IC/PBS) is a chronic debilitating condition that can have a severely negative impact on a patient's quality of life. Its prevalence ranges from 52 to 500/100,000 in females compared to 8 41/100,000 in males, and its incidence is increasing globally. Treatment algorithms are sub-classified into behavioural, pharmacological, intravesical, interventional and surgical therapies. Short-term (i.e. <1 year) cure rates range from 50% to 75% for non-/minimally-invasive therapies, but repeat administration of a therapeutic agent is required. Although definitive surgical intervention is associated with greater long-term cure rates (>=80%); significant short- and long term adverse effects occur more frequently. Clinicians are likely to experience increasing numbers of patients with IC/PBS as more is understood about its pathophysiology and evolving epidemiology. Therefore urogynaecologists should familiarise themselves with appropriate diagnostic criteria and evidence based therapies to optimise clinical outcomes in this patient cohort. PMID- 24480116 TI - Spectroscopy and solvatochromism studies along with antioxidant and antibacterial activities investigation of azo-azomethine compounds 2-(2 hydroxyphenylimino)methyl)-4-phenyldiazenyl)phenol. AB - The azo-azomethine compounds 2-(2-hydroxyphenylimino)methyl)-4 phenyldiazenyl)phenol (2a-d) were prepared from the reaction of 2-aminophenol with 2-hydroxy-5-(aryldiazenyl)benzaldehyde (1a-d). The structures of all compounds were then characterized by elemental analysis, mass, infrared, UV-vis, (1)H and (13)C NMR spectroscopy. The electronic absorption spectra indicated enol keto tautomeric and positive solvatochromism in compounds (2a-d), which is dependent on the substitution, nature of solvent, pH and environment temperature. The compounds (2a-d) were also evaluated for antibiotic activities by disc diffusion method. Compounds 2a and 2b exhibited antibacterial activities against Staphylococcus aureus and Bacillus cereus, but 2c and 2d were found to have no remarkable antibacterial activity. All the compounds (2a-d) also showed antioxidant activity as determined by 1,1-diphenyl-2-picryl-hydrazyl (DPPH) method. PMID- 24480115 TI - Metformin modulates PI3K and GLUT4 expression and Akt/PKB phosphorylation in human endometrial stromal cells after stimulation with androgen and insulin. AB - OBJECTIVE: To assess the effect of metformin on expression of Akt, ERK, PI3K and GLUT4, proteins associated with the growth factor signaling cascade, in human endometrial stromal cells after stimulation with androgen and insulin. STUDY DESIGN: Primary culture of endometrial stromal cells were stimulated in different groups with estrogen, progesterone, androgen and insulin and treated with metformin for 10min, 24h and 48h. After 14 days, proteins were extracted for Western blot analysis. RESULTS: PI3K and GLUT4 expression were increased in the insulin-treated group and further attenuated when metformin was added. The ERK protein was not affected, whereas the Akt phosphorylation was significantly decreased by the action of metformin. CONCLUSION: Metformin affects human endometrial stromal cells by acting on proteins related to growth factors, usually increasing their expression when combined with insulin. Akt phosphorylation was inhibited by metformin, possibly due to its anti proliferative action. PMID- 24480118 TI - Advantages of early management of facial clefts in Africa. AB - OBJECTIVE: Facial clefts are frequent morphological accidents occurring during the 2nd embryonic month. The management period of these affections varies, depending on the area or on the treatment habits. In the African context, there is lot of stigma surrounding this condition, often leading to rejection or even infanticide of the affected newborn. Such a psychosocial environment requires us to adapt our treatment schedule by initiating an early management. The aim of this study was to show our experience in the early treatment of facial clefts through 70 children operated in their neonatal period. METHODS: It was a retrospective study conducted over 3 years, from 2004 to 2006 at the department of Maxillo-facial surgery and Stomatology in a teaching hospital (CHU Treichville Abidjan) and in a general hospital (Dabou, Cote d'Ivoire). Newborn aged 0 to 28 days, affected with facial cleft and operated in the neonatal period were considered for this study. RESULTS: 70 newborn suffering from facial clefts among which one at least was suffering from cleft lip were selected and operated. The study population was predominantly male (43 out of 70, meaning 61.4%). The distribution according to anatomo-clinical aspect showed 39 cases (55.7%) of cleft lip, 23 cases (32.9%) of cleft lip-alveolar process and 8 cases (11.4%) of cleft lip alveolar process and palate. The results achieved by the early surgical treatment of these affections are not very different from those of the schools which advocate that children should be a little bit older before the surgery. CONCLUSION: The earliness of surgical treatment of facial clefts is borne out by the sociological and psychological context of African environment that promotes rejection and infanticide. Some factors such as anesthetic safety, physiology and anatomy favor an early surgery intervention on facial clefts. PMID- 24480117 TI - Indoxyl sulfate and p-cresyl sulfate in chronic kidney disease. Could these toxins modulate the antioxidant Nrf2-Keap1 pathway? AB - Protein-bound uremic toxins (i.e., indoxyl sulfate or p-cresyl sulfate), produced by intestinal bacteria, are accumulated in the plasma of chronic kidney disease (CKD) patients. These toxins interact negatively with biological functions, having potent oxidative stress-inducing effects and a pathological effect on cardiovascular disease. Recent research in CKD has shown that oxidative stress and inflammation can be compounded by impaired activation of the nuclear factor (erythroid-2-related factor)-2 (Nrf2)-Kelch-like ECH associating protein-1 (Keap1) pathway, a major cellular defense mechanism. However, to date, many questions arise regarding the role of this system in CKD. For example, protein bound uremic toxins promote oxidative stress in CKD patients, but their putative effect on the Nrf2-Keap1 system has yet to be examined in these patients. This review will focus on the putative relationship among protein-bound uremic toxins, oxidative stress, and a possible decreased expression of Nrf2 in CKD. PMID- 24480119 TI - Obstructive sleep apnea (OSA): a complication of acute infectious mononucleosis infection in a child. AB - Independently, obstructive sleep apnea (OSA) and infectious mononucleosis are not uncommon in the pediatric population, but acute onset of OSA, as a respiratory complication in the setting of acute EBV infection is extremely uncommon. Previous reports of this clinical entity are sparse and from nearly two decades ago. Urgent adenotonsillectomy was commonly advocated. This complication may be managed medically with systemic corticosteroids and non-invasive continuous positive airway pressure (CPAP), and a case is presented to highlight an updated management approach to this rarely encountered clinical problem in children. PMID- 24480120 TI - Impact of the pediatric tonsillectomy and polysomnography clinical practice guidelines. AB - OBJECTIVE: To evaluate the effect of the recently published guidelines on Tonsillectomy in Children and Polysomnography for Sleep-Disordered Breathing Prior to Tonsillectomy in Children on physician practice patterns. STUDY DESIGN: Cross-sectional survey. METHOD: Survey of members of the American Academy of Otolaryngology-Head and Neck Surgery. SETTING: Academic tertiary referral center. RESULTS: A total of 280 physicians completed the survey, with a response rate of 41.7%. 93% of respondents had read the clinical practice guidelines. Many respondents had completed a pediatric otolaryngology fellowship (46%). A large group of physicians (46%) continue to prescribe antibiotics within 24h after surgery. One-third of respondents stopped prescribing antibiotics because of the guidelines. Discord between severity of symptoms and tonsil size was the most common reason cited for ordering a polysomnogram prior to tonsillectomy (76%). The most common reason cited for admission post-tonsillectomy was age less than 3 (40%). Less than half of physicians prescribe NSAIDs for pain control (43.8%) despite its safety profile, and only 23% reported that the guidelines influenced their use of NSAIDs postoperatively. Most respondents use intra-operative steroids (90%) as recommended. CONCLUSION: The guidelines are intended to provide evidence based direction in tonsillectomy practices and improve referral patterns for polysomnography prior to tonsillectomy. The majority of the surveyed otolaryngologists reviewed these guidelines and some have changed their practice secondary to the guidelines. However, many physicians continue to prescribe post operative antibiotics and do not use NSAIDs. PMID- 24480121 TI - Appearance of ocular vestibular evoked myogenic potential elicited by bone conducted vibration in a patient with CHARGE syndrome with aplasia of all semicircular canals. AB - We report VEMP results in a patient with aplasia of bilateral semicircular canals and a small vestibular cavity. The patient was a 27-year-old male. The computed tomograph showed absolutely no formation of his semicircular canals, together with hypoplasia of his vestibular cavity and cochlea in both ears. His oVEMP was recorded near the extraocular muscles on the left side when elicited by BCV in the Fz. The clinical profile of this patient suggested that oVEMP elicited by BCV recorded near the extraocular muscles originated from otolithic end organs, and not from semicircular canal afferents. PMID- 24480122 TI - Unruptured translabyrinthine meningocele without CSF otorrhea. AB - Labyrinthine meningocele can be classified into translabyrinthine and perilabyrinthine type. We describe a case of rare unruptured translabyrinthine meningocele (TLM). It is rare to encounter an unruptured TLM because it is usually diagnosed after rupture as a labyrinthine fistula, cerebral spinal fluid otorrhea, and subsequent meningitis. We provide for the first time an intraoperative photo and video of a case of an unruptured TLM that developed through an inner ear malformation in a single-side deaf child, which was preoperatively misdiagnosed as congenital cholesteatoma in preoperative temporal bone computed tomography. TLM without CSF otorrhea in an unruptured state merit attention because of its importance during the workup of congenital cholesteatoma or cochlear implantation in spite of its rarity of reports. PMID- 24480123 TI - Somatotopy and bodily hallucinations. PMID- 24480124 TI - Effects of statins on proinflammatory/prothrombotic biomarkers and on disease activity scores in SLE patients: data from LUMINA (LXXVI), a multi-ethnic US cohort. AB - OBJECTIVES: We sought to determine the effect of statin therapy on the levels of proinflammatory/prothrombotic markers and disease activity scores in patients with SLE in a multi-ethnic, multi-centre cohort (LUMINA). METHODS: Plasma/serum samples from SLE patients placed on statins (n=21) therapy taken before and after at least 6 months of treatment were tested. Disease activity was assessed using SLAM-R scores. Interleukin (IL)-1beta, IL-6, IL-8, tumour necrosis factor (TNF) alpha, vascular endothelial growth factor (VEGF) and soluble CD40 ligand (sCD40L) levels were determined by a multiplex immunoassay. Soluble intercellular cell adhesion molecule (ICAM)-1, vascular cell adhesion molecule (VCAM)-1 and anticardiolipin (aCL) antibodies were evaluated using ELISA assays while high sensitivity C-reactive protein (hsCRP) was assessed by nephelometry. Plasma/serum samples from frequency- matched healthy donors were used as controls. RESULTS: Levels of IL-6, VEGF, sCD40L and TNF-alpha were significantly elevated in SLE patients versus controls. Statin therapy resulted in a significant decrease in SLAM-R scores (p=0.0199) but no significant changes in biomarker levels were observed. There was no significant association of biomarkers with SLAM-R scores. CONCLUSIONS: Statin therapy resulted in significant clinical improvement in SLE patients, underscoring the use of statins in the treatment of SLE. PMID- 24480125 TI - A label-free electrical impedimetric biosensor for the specific detection of Alzheimer's amyloid-beta oligomers. AB - Alzheimer's disease (AD) is the most common form of dementia, with over 37 million sufferers worldwide and a global cost of over $600 billion. There is currently no cure for AD and no reliable method of diagnosis other than post mortem brain examination. The development of a point-of-care test for AD is an urgent requirement in order to provide earlier diagnosis and, thus, useful therapeutic intervention. Here, we present a novel, label-free impedimetric biosensor for the specific detection of amyloid-beta oligomers (AbetaO), which are the primary neurotoxic species in AD. AbetaO have been proposed as the best biomarker for AD and levels of AbetaO in the blood have been found to correlate with cerebrospinal fluid load. The biorecognition element of our biosensor is a fragment of the cellular prion protein (PrP(C), residues 95-110), a highly expressed synaptic protein which mediates the neuronal binding and toxicity of AbetaO. During the layer-by-layer sensor construction, biotinylated PrP(C) (95 110) was attached via a biotin/NeutrAvidin bridge to polymer-functionalised gold screen-printed electrodes. Electrochemical impedance spectroscopy (EIS), cyclic voltammetry and scanning electron microscopy were used to validate biosensor assembly and functionality. EIS was employed for biosensor interrogation in the presence of Abeta oligomers or monomers. The biosensor was specific for the detection of synthetic AbetaO and gave a linear response, without significant detection of monomeric Abeta, down to an equivalent AbetaO concentration of ~0.5 pM. The biosensor was also able to detect natural, cell-derived AbetaO present in conditioned medium. The eventual commercialisation of this biosensor system could allow for the early diagnosis and disease monitoring of AD. PMID- 24480126 TI - Electrochemical aptasensor of cellular prion protein based on modified polypyrrole with redox dendrimers. AB - This work consists of the development of an electrochemical aptasensor based on polyprrole modified with redox dendrimers, able to detect human cellular prions PrP(C) with high sensitivity. The gold surface was modified by conductive polypyrrole film coupled to polyamidoamine dendrimers of fourth generation (PAMAM G4) and ferrocenyl group as redox marker. The aptamers were immobilized on the surface via biotin/streptavidin chemistry. Electrochemical signal was detected by ferrocenyl group incorporated between dendrimers and aptamers layers. We demonstrated that the interaction between aptamer and prion protein led to variation in electrochemical signal of the ferrocenyl group. The kinetics parameters (diffusion coefficient D and heterogeneous constant transfer ket) calculated from electrochemical signals demonstrate that the variation in redox signal results from the lower diffusion process of ions during redox reaction after prion interaction due to bulk effect of larger protein. The association of redox dendrimers with conducting polypyrrole leads to high sensitivity of PrP(C) determination with detection limit of 0.8 pM, which is three orders of magnitude lower, compared to flat ferrocene-functionalized polypyrrole. Detection of PrP(C) in spiked blood plasma has been achieved and demonstrated a recovery up to 90%. PMID- 24480127 TI - An electrochemical DNA sensor for sequence-specific DNA recognization in a homogeneous solution. AB - In this work, a sensitive electrochemical DNA sensor based on an avidin modified electrode and a DNA-functionalized Au nanoparticle (DFNP) was developed. The DNA functionalized Au nanoparticle contained two kinds of DNA, one is hairpin probe DNA with a biotin at the 3' terminal and a thiol at the 5' terminal, the other is methylene blue (MB)-labeled linear signal DNA. Without hybridizing with the target DNA, the loop of the hairpin impeded biotin linked with avidin on electrode. However, after target hybridization, the hairpin was opened and biotin was recognized by avidin which resulted in a DNA-functionalized Au nanoparticle brought on the electrode surface. Electrochemical signals of MB bound to signal DNA were measured by differential pulse voltammetry (DPV). Taking advantage of amplification effects of the AuNP and binding specificity of the hairpin probe, this DNA biosensor greatly simplified the electrochemical DNA detection method and displayed high specificity in DNA detection. By using this new method, we demonstrate that this prototype sensor has been able to detect as low as picomolar DNA targets with excellent differentiation ability even for a single mismatch. PMID- 24480128 TI - Study of glucose biosensor lifetime improvement in 37 degrees C serum based on PANI enzyme immobilization and PLGA biodegradable membrane. AB - Glucose sensors with long life span were fabricated and evaluated in 37 degrees C serum to imitate in vivo conditions. Polyaniline nanofibers were electrodeposited on sensor electrodes for excessive glucose oxidase immobilization to extend the lifetime of sensors. The sensitivity of sensors stored in 37 degrees C bovine serum was stable for 20 days without apparent descents, and still remained 45% of its initial value after 44 days. In order to further improve the life span of sensors, a degradable polymer film, poly lactic-co-glycolic acid (PLGA), was used as an out coating layer of glucose sensors. Results showed that the PLGA coated glucose sensors left 80% of its initial sensitivity after 44 days' storage in 37 degrees C bovine serum. The sensors could be potentially used as long-term implantable devices for real time monitoring of glucose levels. PMID- 24480129 TI - Photoelectrochemical sensor for pentachlorophenol on microfluidic paper-based analytical device based on the molecular imprinting technique. AB - Combining microfluidic paper-based analytical device (MU-PAD) and the molecular imprinting technique, a visible light photoelectrochemical (PEC) sensing platform for the detection of pentachlorophenol (PCP) was established on gold nanoparticles (AuNPs) decorated paper working electrode using polypyrrole functionalized ZnO nanoparticles. Ascorbic acid (AA) was exploited as an efficient and nontoxic electron donor for scavenging photogenerated holes under mild solution medium and facilitating the generation of stable photocurrent. The microfluidic molecular imprinted polymer-based PEC analytical origami device is developed for the detection of PCP in the linear range from 0.01 ng mL(-1) to 100 ng mL(-1) with a low detection limit of 4 pg mL(-1). This disposable microfluidic PEC origami device would provide a new platform for sensitive, specific, and multiplex assay in public health, environmental monitoring, and the developing world. PMID- 24480130 TI - Label-free detection of kanamycin using aptamer-based cantilever array sensor. AB - A label-free detection method of kanamycin using aptamer-based cantilever array sensor was developed. The cantilever array was composed of sensing cantilevers and reference cantilevers. This configuration allowed direct detection of individual cantilever deflections and subsequent determination of differential deflection of sensing/reference cantilever pair. The sensing cantilevers were functionalized with kanamycin aptamer, which was used as receptor molecules while the reference cantilevers were modified with 6-mercapto-1-hexanol (MCH) to eliminate the influence of environmental disturbances. The kanamycin-aptamer interaction induced a change in cantilever surface stress, which caused a differential deflection between the sensing and reference cantilever pair. The surface stress change was linear with kanamycin concentration over the range of 100 MUM-10mM with a correlation coefficient of 0.995. A detection limit of 50 MUM was obtained, at a signal-to-noise ratio of 3. The sensor also showed good selectivity against other antibiotics such as neomycin, ribostamycin and chloramphenicol. The facile method for kanamycin detection may have great potential for investigating more other molecules. PMID- 24480131 TI - Sensitivity evaluation of NBD-SCN towards cysteine/homocysteine and its bioimaging applications. AB - A push-pull fluorogenic reagent, NBD-SCN, was applied for specific detection of cysteine (Cys) and homocysteine (Hcy). Replacing thiocyanato group with Cys/Hcy increased the push-pull characteristic of the probe and resulted in emission of fluorescence. The fluorescent response of the probe toward Cys/Hcy was significantly higher than toward glutathione and other amino acids. The probe showed a 470- and 745-fold fluorescence enhancement at 550 nm and detection limit of 2.99 and 1.43 nM for Cys and Hcy, respectively. Time-dependent fluorescence assays showed that the fluorescence intensity reached a plateau within 20s after addition of Cys and within 10 min after addition of Hcy. Furthermore, the fluorescence images of Cys/Hcy in Raw 264.7 cells were obtained after adding this probe to the cells. These results indicate that NBD-SCN not only possesses good selectivity and sensitivity for Cys/Hcy but also can penetrate cells for Cys/Hcy bioimaging. PMID- 24480132 TI - Quantitative electrochemical detection of cathepsin B activity in complex tissue lysates using enhanced AC voltammetry at carbon nanofiber nanoelectrode arrays. AB - The proteolytic activity of a cancer-related enzyme cathepsin B is measured with alternating current voltammetry (ACV) using ferrocene (Fc) labeled tetrapeptides attached to nanoelectrode arrays (NEAs) fabricated with vertically aligned carbon nanofibers (VACNFs). This combination enables the use of high AC frequencies (~1kHz) with enhanced electrochemical signals. The specific proteolysis of the Fc peptide by cathepsin B produces decay in the ACV peak current versus the reaction time. The exponential component of the raw data can be extracted and defined as the "extracted proteolytic signal" which allows consistent quantitative analyses using a heterogeneous Michaelis-Menten model. A "specificity constant" kcat/KM = (3.68 +/- 0.50) * 10(4)M(-1)s(-1) for purified cathepsin B was obtained. The detections of cathepsin B activity in different concentrations of whole lysate of human breast tissue, tissue lysate spiked with varied concentrations of cathepsin B, and the tissue lysate after immunoprecipitation showed that there is ~13.4 nM higher cathepsin B concentration in 29.1 ug mL(-1) of whole tissue lysate than the immunoprecipitated sample. The well-defined regular VACNF NEAs by e-beam lithography show a much faster kinetics for cathepsin B proteolysis with kcat/KM = 9.2 * 10(4)M(-1)s(-1). These results illustrate the potential of this technique as a portable multiplex electronic system for cancer diagnosis by rapid protease profiling of serum or blood samples. PMID- 24480133 TI - Investigations of an electrochemical platform based on the layered MoS2-graphene and horseradish peroxidase nanocomposite for direct electrochemistry and electrocatalysis. AB - The self-assembly of layered molybdenum disulfide-graphene (MoS2-Gr) and horseradish peroxidase (HRP) by electrostatic attraction into a novel hybrid nanomaterial (HRP-MoS2-Gr) is reported. The properties of the MoS2-Gr were characterized by X-ray diffraction (XRD), high-resolution transmission electron microscopy (TEM), electrochemical impedance spectroscopy (EIS) and cyclic voltammetry (CV). UV-vis and Fourier transform infrared spectroscopy (FT-IR) indicate that the native structure of the HRP is maintained after the assembly, implying good biocompatibility of MoS2-Gr nanocomposite. Furthermore, the HRP MoS2-Gr composite is utilized as a biosensor, which displays electrocatalytic activity to hydrogen peroxide (H2O2) with high sensitivity (679.7 MUA mM(-1)cm( 2)), wide linear range (0.2 MUM-1.103 mM), low detection limit (0.049 MUM), and fast amperometric response. In addition, the biosensor also exhibits strong anti interference ability, satisfactory stability and reproducibility. These desirable electrochemical properties are attributed to the good biocompatibility and electron transport efficiency of the MoS2-Gr composite, as well as the high loading of HRP. Therefore, this biosensor is potentially suitable for H2O2 analysis in environmental, pharmaceutical, food or industrial applications. PMID- 24480135 TI - Are zinc transporter type 8 antibodies a marker of autoimmune thyroiditis in non obese adults with new-onset diabetes? AB - OBJECTIVE: The diagnosis of autoimmune diabetes in non-obese adults is based on the detection of glutamic acid decarboxylase autoantibodies (GADA), islet cell antibodies (ICA) and antibodies to tyrosine phosphatase (IA-2A). Zinc transporter 8 (ZnT8) has been identified as a new autoantigen in patients with type 1 diabetes mellitus. The coincidence of autoimmune thyroiditis (AITD) with diabetes is common; therefore, screening of TSH and thyroid peroxidase antibodies (ATPO) is recommended during the diagnosis of diabetes. In this study, we determined whether the occurrence of islet autoantibodies is associated with a positive titre of ATPO in newly diagnosed adult-onset autoimmune diabetic patients. DESIGN AND METHODS: THE STUDY INVOLVED 80 NON-OBESE ADULTS AGED 44 (INTERQUARTILE RANGE (IQR): 37-51) years with a BMI of 24.0 (IQR: 22.2-26.0) kg/m(2) and new-onset diabetes. The markers of autoimmune diabetes (GADA, ICA, IA-2A and ZnT8A), TSH and thyroid peroxidase antibodies (ATPO) were evaluated. RESULTS: IN THE STUDY POPULATION, 70% (N=56) OF THE SUBJECTS WERE POSITIVE FOR AT LEAST ONE OF THE FOUR ASSESSED MARKERS OF AUTOIMMUNE DIABETES (83.9% GADA, 62.5% ICA, 42.8% IA-2A AND 33% ZNT8A) AND 37.5% OF THE SUBJECTS WERE POSITIVE FOR ATPO. THE ZNT8A-POSITIVE SUBJECTS HAD HIGHER ATPO TITRES THAN THE ZNT8A-NEGATIVE SUBJECTS (172.7 (IQR: 0.36-410.4) vs 92.4 (IQR: 0-23.7) IU/ml, P=0.001). Based on the assessed islet autoantibodies, the occurrence of positive ZnT8A and GADA was found to be related to a positive titre of ATPO using logistic regression (OR=5.48, 95% CI: 1.65 18.14, P=0.006 and OR=3.42, 95% CI: 1.09-10.71, P=0.03 respectively). CONCLUSIONS: In non-obese adults with new-onset diabetes, the presence of GADA and especially ZnT8 autoantibodies increases the risk of AITD. PMID- 24480134 TI - Increased BDNF expression in fetal brain in the valproic acid model of autism. AB - Human fetal exposure to valproic acid (VPA), a widely-used anti-epileptic and mood-stabilizing drug, leads to an increased incidence of behavioral and intellectual impairments including autism; VPA administration to pregnant rats and mice at gestational days 12.5 (E12.5) or E13.5 leads to autistic-like symptoms in the offspring and is widely used as an animal model for autism. We report here that this VPA administration protocol transiently increased both BDNF mRNA and BDNF protein levels 5-6-fold in the fetal mouse brain. VPA exposure in utero induced smaller increases in the expression of mRNA encoding the other neurotrophins, NT3 (2.5-fold) and NT4 (2-fold). Expression of the neurotrophin receptors, trkA, trkB and trkC were minimally affected, while levels of the low affinity neurotrophin receptor, p75(NTR), doubled. Of the nine 5'-untranslated exons of the mouse BDNF gene, only expression of exons I, IV and VI was stimulated by VPA in utero. In light of the well-established role of BDNF in regulating neurogenesis and the laminar fate of postmitotic neurons in the developing cortex, an aberrant increase in BDNF expression in the fetal brain may contribute to VPA-induced cognitive disorders by altering brain development. PMID- 24480136 TI - THRA and DIO2 mutations are unlikely to be a common cause of increased bone mineral density in euthyroid post-menopausal women. AB - OBJECTIVE: A new autosomal dominant disorder due to mutation of THRA, which encodes thyroid hormone receptor alpha, is characterised by severely delayed skeletal development but only slightly abnormal thyroid status. Adult mice with disrupted thyroid hormone action in bone due to a mutation of Thra or deletion of Dio2, encoding the type 2 deiodinase, have high bone mass and mineralisation despite essentially euthyroid status. No individuals with DIO2 mutations have been described and the adult phenotype of patients with THRA mutations is largely unknown. We hypothesised that screening euthyroid adults with high bone mineral density (BMD) could be used to identify individuals with mutations of THRA or DIO2. DESIGN: The Osteoporosis and Ultrasound Study (OPUS) is a 6-year prospective study of fracture-related factors from five European centres. METHODS: A cohort of 100 healthy euthyroid post-menopausal women with the highest BMD was selected from the OPUS population. We sequenced the intron-exon boundaries and critical exons of THRA and DIO2 in these subjects. TSH, free 3,5,3'-l-triiodothyronine, free thyroxine, vitamin D, parathyroid hormone and bone turnover marker concentrations, and BMD measurements were available in all OPUS participants. RESULTS: No coding sequence or splice site mutations affecting THRA or DIO2 were identified. CONCLUSIONS: Mutations affecting THRA or DIO2 are not a common cause of high BMD in healthy euthyroid post-menopausal women. PMID- 24480137 TI - Letter from the guest editor: Interstitial pneumonia and related disorders. PMID- 24480139 TI - Usual interstitial pneumonia: typical and atypical high-resolution computed tomography features. AB - The computed tomography appearances of usual interstitial pneumonia (UIP) are usually characteristic, with basal-predominant, peripheral-predominant reticular abnormality and honeycombing. Important complications that may be detected by the radiologist include pulmonary hypertension, lung cancer, and acute exacerbation. As the number of surgical lung biopsies performed for typical UIP declines, histologic findings of UIP are increasingly found in subjects with atypical computed tomographic features. Potential reasons for such discordance may include variability in pathologist interpretation, sampling error on biopsy, biopsy obtained from nonrepresentative site, coexistence of multiple pathologies within the same lung, and familial pulmonary fibrosis. Multidisciplinary diagnosis is critical in resolving these cases. PMID- 24480138 TI - Histopathologic features of usual interstitial pneumonia and related patterns: what is important for radiologists? AB - In interstitial lung diseases, the diagnosis of idiopathic pulmonary fibrosis is important where pathology and radiology show usual interstitial pneumonia (UIP) pattern. Recently, revised guidelines of idiopathic pulmonary fibrosis were published in which the diagnostic algorithm requires a stricter definition for both pathology and radiology. In spite of the progress, there are issues that still need to be considered especially when facing cases where there may be a lower confidence of UIP diagnosis. As a matter of course, various etiologic backgrounds represent UIP pattern. However, their distinction is important irrespective of the etiology, because the histologic UIP pattern indicates a significantly worse prognosis than other chronic interstitial lung diseases. In this review, we describe the histologic features of UIP, effects of revised guidelines, interobserver agreement, etiologic variations of UIP pattern, and finally we include a few of our hypothetical thoughts on the "UIP bucket." PMID- 24480140 TI - Nonspecific interstitial pneumonia and usual interstitial pneumonia: is differentiation possible by high-resolution computed tomography? AB - Nonspecific interstitial pneumonia (NSIP) is a form of idiopathic interstitial pneumonia characterized histologically by varying degrees of interstitial inflammation and fibrosis that are temporally and morphologically homogeneous in comparison with usual interstitial pneumonia (UIP). Differentiation from UIP is very important because treatment and prognosis are different between NSIP and UIP. Although there are limitations for the differentiation between NSIP and UIP on computed tomography, some computed tomography findings contribute to it. Relatively peribronchovascular distribution, wide extent of areas with ground glass attenuation, and subpleural sparing are more highly seen in patients with NSIP, whereas wide extent of honeycombing and subpleural distribution are more common characteristics in patients with UIP. PMID- 24480141 TI - Connective tissue disease-associated interstitial pneumonia and idiopathic interstitial pneumonia: similarity and difference. AB - Interstitial lung diseases (ILDs) are increasingly recognized in patients with systemic diseases. Patients with early ILD changes may be asymptomatic. Features of ILD overlap among systemic diseases and with idiopathic variety. High resolution computed tomography plays a central role in diagnosing ILDs. Imaging features are often nonspecific. Therapy- and complication-related lung changes would pose difficulty in diagnosing and classifying an ILD. Biology and prognosis of secondary ILDs may differ between different disease-related ILDs and idiopathic variety. Combination of clinical features, serological tests, pulmonary and extrapulmonary imaging findings, and pathology findings may help to diagnose ILDs. PMID- 24480142 TI - High-resolution computed tomography findings of acute respiratory distress syndrome, acute interstitial pneumonia, and acute exacerbation of idiopathic pulmonary fibrosis. AB - Diffuse alveolar damage (DAD) is the pathologic feature of rapidly progressive lung diseases, including acute respiratory distress syndrome, acute interstitial pneumonia, and acute exacerbation of idiopathic pulmonary fibrosis. The clinical significance and limitation of high-resolution computed tomography (HRCT) findings in these diseases were reviewed. The HRCT findings correlate well with pathologic phases (exudative, proliferative, and fibrotic) of DAD, although it cannot detect early exudative phase. Traction bronchiolectasis or bronchiectasis within areas of increased attenuation on HRCT scan is a sign of progression from the exudative to the proliferative and fibrotic phase of DAD. Extensive abnormalities seen on HRCT scans, which are indicative of fibroproliferative changes, were independently predictive of poor prognosis in patients with clinically early acute respiratory distress syndrome, acute interstitial pneumonia, and acute exacerbation of idiopathic pulmonary fibrosis. PMID- 24480143 TI - Chronic hypersensitivity pneumonitis and pulmonary sarcoidosis: differentiation from usual interstitial pneumonia using high-resolution computed tomography. AB - The distinction of chronic hypersensitivity pneumonitis (HP) or advanced-stage sarcoidosis from idiopathic pulmonary fibrosis or usual interstitial pneumonia is important because each disease is managed differently and may have a different prognosis. The analyses of pattern and distribution of lung parenchymal abnormalities on high-resolution computed tomography scans help differentiate among the 3 diseases. In chronic HP, the presence of lobular areas of decreased attenuation and centrilobular small nodules and the absence of lower lung zone predominance are characteristically observed. In advanced-stage sarcoidosis, patchy areas of reticulation, traction bronchiectasis, architectural distortion, honeycomblike cysts, bullae, and paracicatricial emphysema are observed in the upper and middle lung zones. Lung bases are usually spared. In idiopathic pulmonary fibrosis or usual interstitial pneumonia, however, the presence of honeycombing with lower lung zone predominance and the absence of centrilobular small nodules are important findings that allow us to differentiate the disease from chronic HP or advanced-stage sarcoidosis. In the 3 diseases, most important prognosis-predicting factor is the extent of fibrotic score (the extent of honeycombing and reticulation) calculated on high-resolution computed tomography scans or fibrosis estimated on chest radiographs. PMID- 24480144 TI - High-resolution computed tomography features of smoking-related interstitial lung disease. AB - The smoking-related interstitial lung diseases (ILDs) comprise several diseases that often coexist. In this review, the high-resolution computed tomography (CT) features and pathologic correlates of the traditional smoking-related ILDs (respiratory bronchiolitis-associated ILD, desquamative interstitial pneumonia, and pulmonary Langerhans cell histiocytosis) and those ILDs with less clearly defined relationships to smoking are described. The degree to which these entities coexist and overlap is explored on high-resolution CT scans. Emerging evidence about the link between smoking and lung fibrosis (from lung cancer screening trials with CT), and smoking as a factor in ageing of the lung, is also discussed. PMID- 24480145 TI - Single application of topical doxycycline hyclate in the management of recurrent aphthous stomatitis: remarks. PMID- 24480146 TI - The disease burden of hepatitis B, influenza, measles and salmonellosis in Germany: first results of the burden of communicable diseases in Europe study. AB - Setting priorities in the field of infectious diseases requires evidence-based and robust baseline estimates of disease burden. Therefore, the European Centre for Disease Prevention and Control initiated the Burden of Communicable Diseases in Europe (BCoDE) project. The project uses an incidence- and pathogen-based approach to measure the impact of both acute illness and sequelae of infectious diseases expressed in disability-adjusted life years (DALYs). This study presents first estimates of disease burden for four pathogens in Germany. The number of reported incident cases adjusted for underestimation served as model input. For the study period 2005-2007, the average disease burden was estimated at 33 116 DALYs/year for influenza virus, 19 115 DALYs/year for Salmonella spp., 8708 DALYs/year for hepatitis B virus and 740 DALYs/year for measles virus. This methodology highlights the importance of sequelae, particularly for hepatitis B and salmonellosis, because if omitted, the burden would have been underestimated by 98% and 56%, respectively. PMID- 24480147 TI - Relation of aortic stiffness and strain by cardiovascular magnetic resonance imaging to age in repaired tetralogy of fallot. AB - Patients with tetralogy of Fallot (TOF) have abnormal aortic properties. It is not known if this increases the risk for aneurysm formation. We sought to identify clinical and cardiovascular magnetic resonance (CMR) imaging patient characteristics associated with worsened aortic pulse wave velocity (PWV) and aortic strain in patients with repaired TOF. In 124 patients with TOF undergoing CMR (median age 24.6 years, interquartile range 17.8 to 34.2), left and right ventricular volumetric data, aortic PWV, and aortic strain were evaluated. Increased PWV positively correlated with age at repair (r = 0.3, p = 0.001) and cross-sectional ascending aortic area (r = 0.34, p <0.001) and was associated with a history of shunt placement (p = 0.01). Decreased aortic strain also correlated with age at TOF repair (r = -0.5, p <0.001), cross-sectional ascending aortic area (r = -0.43, p <0.001), aortic regurgitation (r = -0.46, p <=0.001), and history of shunt placement (p <0.001). In a multivariate regression model controlling for history of shunt placement, use of cardiac medication, and aortic regurgitation, age at CMR was significantly associated with PWV (p = 0.005), whereas age at repair trended toward significance (p = 0.06). In conclusion, patients with TOF have abnormal aortic properties correlated with greater age, which may be associated with later repair. Longitudinal data are necessary to assess the risk of aortic aneurysm and dissection as the TOF population grows older. Functional imaging of the aorta by CMR may be useful in predicting risk and assessing vascular health. PMID- 24480148 TI - Yersinia pestis and the plague of Justinian 541-543 AD: a genomic analysis. AB - BACKGROUND: Yersinia pestis has caused at least three human plague pandemics. The second (Black Death, 14-17th centuries) and third (19-20th centuries) have been genetically characterised, but there is only a limited understanding of the first pandemic, the Plague of Justinian (6-8th centuries). To address this gap, we sequenced and analysed draft genomes of Y pestis obtained from two individuals who died in the first pandemic. METHODS: Teeth were removed from two individuals (known as A120 and A76) from the early medieval Aschheim-Bajuwarenring cemetery (Aschheim, Bavaria, Germany). We isolated DNA from the teeth using a modified phenol-chloroform method. We screened DNA extracts for the presence of the Y pestis-specific pla gene on the pPCP1 plasmid using primers and standards from an established assay, enriched the DNA, and then sequenced it. We reconstructed draft genomes of the infectious Y pestis strains, compared them with a database of genomes from 131 Y pestis strains from the second and third pandemics, and constructed a maximum likelihood phylogenetic tree. FINDINGS: Radiocarbon dating of both individuals (A120 to 533 AD [plus or minus 98 years]; A76 to 504 AD [plus or minus 61 years]) places them in the timeframe of the first pandemic. Our phylogeny contains a novel branch (100% bootstrap at all relevant nodes) leading to the two Justinian samples. This branch has no known contemporary representatives, and thus is either extinct or unsampled in wild rodent reservoirs. The Justinian branch is interleaved between two extant groups, 0.ANT1 and 0.ANT2, and is distant from strains associated with the second and third pandemics. INTERPRETATION: We conclude that the Y pestis lineages that caused the Plague of Justinian and the Black Death 800 years later were independent emergences from rodents into human beings. These results show that rodent species worldwide represent important reservoirs for the repeated emergence of diverse lineages of Y pestis into human populations. FUNDING: McMaster University, Northern Arizona University, Social Sciences and Humanities Research Council of Canada, Canada Research Chairs Program, US Department of Homeland Security, US National Institutes of Health, Australian National Health and Medical Research Council. PMID- 24480150 TI - Yersinia pestis: one pandemic, two pandemics, three pandemics, more? PMID- 24480149 TI - Brucella arteritis: clinical manifestations, treatment, and prognosis. AB - Brucellosis is the most common bacterial zoonosis, and causes a considerable burden of disease in endemic countries. Cardiovascular involvement is the main cause of mortality due to infection with Brucella spp, and most commonly manifests as endocarditis, peripheral and cerebrovascular aneurysms, or arterial and venous thromboses. We report a case of brucellosis presenting as bacteraemia and aortic endarteritis 18 years after the last known exposure to risk factors for brucella infection. The patient was treated with doxycycline, rifampicin, and gentamicin, and underwent surgical repair of a penetrating aortic ulcer, with a good clinical recovery. We review the signs and symptoms, diagnostic approach, prognosis, and treatment of brucella arteritis. We draw attention to the absence of consensus about the optimum therapy for vascular brucellosis, and the urgent need for additional studies and renewed scientific interest in this major pathogen. PMID- 24480151 TI - Evaluation of the deposition, translocation and pathological response of brake dust with and without added chrysotile in comparison to crocidolite asbestos following short-term inhalation: interim results. AB - Chrysotile has been frequently used in the past in manufacturing brakes and continues to be used in brakes in many countries. This study was designed to provide an understanding of the biokinetics and potential toxicology following inhalation of brake dust following short term exposure in rats. The deposition, translocation and pathological response of brake dust derived from brake pads manufactured with chrysotile were evaluated in comparison to the amphibole, crocidolite asbestos. Rats were exposed by inhalation 6 h/day for 5 days to either brake dust obtained by sanding of brake-drums manufactured with chrysotile, a mixture of chrysotile and the brake dust or crocidolite asbestos. No significant pathological response was observed at any time point in either the brake dust or chrysotile/brake dust exposure groups. The long chrysotile fibers (>20 MUm) cleared quickly with T(1/2) estimated as 30 and 33 days, respectively in the brake dust and the chrysotile/brake dust exposure groups. In contrast, the long crocidolite fibers had a T(1/2)>1000 days and initiated a rapid inflammatory response in the lung following exposure resulting in a 5-fold increase in fibrotic response within 91 days. These results provide support that brake dust derived from chrysotile containing brake drums would not initiate a pathological response in the lung following short term inhalation. PMID- 24480152 TI - Glucocorticoid induced leucine zipper inhibits apoptosis of cardiomyocytes by doxorubicin. AB - Doxorubicin (Dox) is an indispensable chemotherapeutic agent for the treatment of various forms of neoplasia such as lung, breast, ovarian, and bladder cancers. Cardiotoxicity is a major concern for patients receiving Dox therapy. Previous work from our laboratory indicated that glucocorticoids (GCs) alleviate Dox induced apoptosis in cardiomyocytes. Here we have found glucocorticoid-induced leucine zipper (GILZ) to be a mediator of GC-induced cytoprotection. GILZ was found to be induced in cardiomyocytes by GC treatment. Knocking down of GILZ using siRNA resulted in cancelation of GC-induced cytoprotection against apoptosis by Dox treatment. Overexpressing GILZ by transfection was able to protect cells from apoptosis induced by Dox as measured by caspase activation, Annexin V binding and morphologic changes. Western blot analyses indicate that GILZ overexpression prevented cytochrome c release from mitochondria and cleavage of caspase-3. When bcl-2 family proteins were examined, we found that GILZ overexpression causes induction of the pro-survival protein Bcl-xL. Since siRNA against Bcl-xL reverses GC induced cytoprotection, Bcl-xL induction represents an important event in GILZ-induced cytoprotection. Our data suggest that GILZ functions as a cytoprotective gene in cardiomyocytes. PMID- 24480153 TI - A murine model of airway fibrosis induced by repeated naphthalene exposure. AB - The airway epithelium serves as a biological barrier essential for host defense against inhaled pollutants. While chronic epithelial injury, commonly associated with chronic obstructive pulmonary disease and bronchiolitis obliterans syndrome, often results in airway fibrosis, limited animal models of airway fibrosis have been established. Club cells (Clara cells) in the small airways represent an important population of epithelial progenitor cells and also the principal site of localization of the cytochrome P-450 monooxygenase system, which metabolically activates xenobiotic chemicals such as naphthalene by converting them to toxic epoxide intermediates. We hypothesized that repeated exposure to naphthalene may cause prolonged loss of club cells, triggering aberrant local epithelial repair mechanisms that lead to peribronchial fibrosis. We administered intraperitoneal injections of naphthalene to C57/BL6J mice once a week for 14 consecutive weeks. Repeated club cell injury caused by naphthalene triggered regional hyperproliferation of epithelial progenitor cells, while other regions remained denuded or squamated, resulting in fibroblast proliferation and peribronchial collagen deposition associated with upregulation of the fibrogenic cytokines transforming growth factor-beta and connective tissue growth factor. The total collagen content of the lung assessed by measurement of the hydroxyproline content was also increased after repeated exposure to naphthalene. These results lend support to the relevance of repeated injury of airway epithelial cells as a trigger for resting fibroblast proliferation and airway fibrosis. This model of airway fibrosis is simple and easy to reproduce, and may be expected to advance our understanding of the pathogenesis and potential treatment of airway fibrotic disorders. PMID- 24480154 TI - Seizure-related vehicular crashes and falls with injuries for people with epilepsy (PWE) in northeastern Thailand. AB - This cross-sectional study aimed to determine the number and types of falls and vehicular crashes with injuries , as well as some specific behavioral associations in people with epilepsy (PWE) in northeastern Thailand. Two hundred and three patients with epilepsy were randomly recruited from the university epilepsy clinic in Khon Kaen, who then completed an interview and a questionnaire. It was found that 84.5% of the patients were operating a vehicle on a regular basis (more than 3days a week), and 21.6% of those had been in a vehicle crash. Additionally, 25.6% of the patients had been involved in falls with injuries. Forty-three percent of the respondents had been involved in either a vehicular crash or a fall with an injury, with 39.7% of the accidents resulting in moderate to severe injuries. Medication compliance was estimated at 66%, while 59.1% said that they had little or no control over their seizures, and more than half the patients did not feel confident about their ability to take care of themselves or to take their antiepileptic drugs (AEDs) properly. In a multivariate model, the following factors significantly increased the risk of being in either a vehicular crash or a fall with an injury: being single, attaining a secondary or higher education, exercising at least three times a week, napping every day or more frequently, and having poor seizure control. The results of this study suggest that patients' poor medication adherence and lack of confidence in managing their seizures may contribute to accidents. Patients with epilepsy should be counseled to seek less risky behaviors and try to attend classes that provide education on AED management. PMID- 24480155 TI - Efficient neuronal differentiation of mouse ES and iPS cells using a rotary cell culture protocol. AB - Embryonic stem (ES) cells and induced pluripotent stem (iPS) cells hold great promise in regenerative medicine for the treatment of neurodegenerative diseases. Current neuronal differentiation protocols however, are not optimized yet for the high scale production of neural precursors and terminally differentiated neurons. The present investigation reports a novel technique for the scalable production of highly uniformed neurospheres, neural precursors and terminal neurons from mouse ES and iPS cells using retinoic acid and a mechanical rotation procedure. We compared embryoid bodies (EB) and neurosphere morphology, yield of neural precursors and quality of neurons between rotary and static suspension cultures of mouse ES and iPS cells undergoing neural differentiation. Analysis of neurospheres formed under continuous rotation showed increased neurosphere uniformity and a high yield of neural precursors after neurosphere dissociation. Neurospheres formed under rotation conditions were relatively smaller, more uniform and had less dead cells and higher proliferation compared to those formed under static conditions. Neural precursors under rotation conditions matured faster, survived better, differentiated to functional neurons that stained positively for mature neuronal markers, and fired action potentials similar to the statically cultured neurons. This report thus provides a technique for the scalable production of neurons from ES and iPS cells and we suggest that rotation culture procedure can be a routine technique for stem cell neural and neuronal differentiation. PMID- 24480156 TI - Detection of diminished response to cold pressor test in smokers: assessment using phase-contrast cine magnetic resonance imaging of the coronary sinus. AB - PURPOSE: The purposes of this study were to evaluate the reproducibility for measuring the cold pressor test (CPT)-induced myocardial blood flow (MBF) alteration using phase-contrast (PC) cine MRI, and to determine if this approach could detect altered MBF response to CPT in smokers. MATERIALS AND METHODS: After obtaining informed consent, ten healthy male non-smokers (mean age: 28+/-5 years) and ten age-matched male smokers (smoking duration >=5 years, mean age: 28+/-3 years) were examined in this institutional review board approved study. Breath hold PC cine MR images of the coronary sinus were obtained with a 3T MR imager with 32 channel coils at rest and during a CPT performed after immersing one foot in ice water. MBF was calculated as coronary sinus flow divided by the left ventricular (LV) mass which was given as a total LV myocardial volume measured on cine MRI multiplied by the specific gravity (1.05 g/mL). RESULTS: In non-smokers, MBF was 0.86+/-0.25 mL/min/g at rest, with a significant increase to 1.20+/-0.36 mL/min/g seen during CPT (percentage change of MBF (?MBF (%)); 39.2%+/-14.4%, p<0.001). Inter-study reproducibility for ?MBF (%) measurements by different MR technologist was good, as indicated by the intraclass correlation coefficient of 0.93 and reproducibility coefficient of 10.5%. There was no significant difference between smokers and non-smokers for resting MBF (0.85+/-0.32 mL/min/g, p=0.91). However, ?MBF (%) in smokers was significantly reduced (-4.0+/-32.2% vs. 39.2+/-14.4%, p=0.011). CONCLUSION: PC cine MRI can be used to reproducibly quantify MBF response to CPT and to detect impaired flow response in smokers. This MR approach may be useful for monitoring the sequential change of coronary blood flow in various potentially pathologic conditions and for investigating its relationship with cardiovascular risk. PMID- 24480157 TI - Application of machine learning techniques to analyse the effects of physical exercise in ventricular fibrillation. AB - This work presents the application of machine learning techniques to analyse the influence of physical exercise in the physiological properties of the heart, during ventricular fibrillation. To this end, different kinds of classifiers (linear and neural models) are used to classify between trained and sedentary rabbit hearts. The use of those classifiers in combination with a wrapper feature selection algorithm allows to extract knowledge about the most relevant features in the problem. The obtained results show that neural models outperform linear classifiers (better performance indices and a better dimensionality reduction). The most relevant features to describe the benefits of physical exercise are those related to myocardial heterogeneity, mean activation rate and activation complexity. PMID- 24480158 TI - PRoSPer: perceptual similarity queries in medical CBIR systems through user profiles. AB - In this paper, we present a novel approach to perform similarity queries over medical images, maintaining the semantics of a given query posted by the user. Content-based image retrieval systems relying on relevance feedback techniques usually request the users to label relevant/irrelevant images. Thus, we present a highly effective strategy to survey user profiles, taking advantage of such labeling to implicitly gather the user perceptual similarity. The profiles maintain the settings desired for each user, allowing tuning of the similarity assessment, which encompasses the dynamic change of the distance function employed through an interactive process. Experiments on medical images show that the method is effective and can improve the decision making process during analysis. PMID- 24480159 TI - Comprehension of drug toxicity: software and databases. AB - Quantitative structure-property/activity relationships (QSPRs/QSARs) are a tool (in silico) to rapidly predict various endpoints in general, and drug toxicity in particular. However, this dynamic evolution of experimental data (expansion of existing experimental data on drugs toxicity) leads to the problem of critical estimation of the data. The carcinogenicity, mutagenicity, liver effects and cardiac toxicity should be evaluated as the most important aspects of the drug toxicity. The toxicity is a multidimensional phenomenon. It is apparent that the main reasons for the increase in applications of in silico prediction of toxicity include the following: (i) the need to reduce animal testing; (ii) computational models provide reliable toxicity prediction; (iii) development of legislation that is related to use of new substances; (iv) filling data gaps; (v) reduction of cost and time; (vi) designing of new compounds; (vii) advancement of understanding of biology and chemistry. This mini-review provides analysis of existing databases and software which are necessary for use of robust computational assessments and robust prediction of potential drug toxicities by means of in silico methods. PMID- 24480160 TI - Randomized pilot study and qualitative evaluation of a clinical decision support system for brain tumour diagnosis based on SV 1H MRS: evaluation as an additional information procedure for novice radiologists. AB - The results of a randomized pilot study and qualitative evaluation of the clinical decision support system Curiam BT are reported. We evaluated the system's feasibility and potential value as a radiological information procedure complementary to magnetic resonance (MR) imaging to assist novice radiologists in diagnosing brain tumours using MR spectroscopy (1.5 and 3.0T). Fifty-five cases were analysed at three hospitals according to four non-exclusive diagnostic questions. Our results show that Curiam BT improved the diagnostic accuracy in all the four questions. Additionally, we discuss the findings of the users' feedback about the system, and the further work to optimize it for real environments and to conduct a large clinical trial. PMID- 24480161 TI - A hybrid intelligent system for diagnosing microalbuminuria in type 2 diabetes patients without having to measure urinary albumin. AB - Microalbuminuria (MA) is an independent predictor of cardiovascular and renal disease, development of overt nephropathy, and cardiovascular mortality in patients with type 2 diabetes. Detecting MA is an important screening tool to identify people with high risk of cardiovascular and kidney disease. The gold standard to detect MA is measuring 24-h urine albumin excretion. A new method for MA diagnosis is presented in this manuscript which uses clinical parameters usually monitored in type 2 diabetic patients without the need of an additional measurement of urinary albumin. We designed an expert-based fuzzy MA classifier in which rule induction was performed by particle swarm optimization. A variety of classifiers was tested. Additionally, multiple logistic regression was used for statistical feature extraction. The significant features were age, diabetic duration, body mass index and HbA1C (the average level of blood sugar over the previous 3 months, which is routinely checked every 3 months for diabetic patients). The resulting classifier was tested on a sample size of 200 patients with type 2 diabetes in a cross-sectional study. The performance of the proposed classifier was assessed using (repeated) holdout and 10-fold cross-validation. The minimum sensitivity, specificity, precision and accuracy of the proposed fuzzy classifier system with feature extraction were 95%, 85%, 84% and 92%, respectively. The proposed hybrid intelligent system outperformed other tested classifiers and showed "almost perfect agreement" with the gold standard. This algorithm is a promising new tool for screening MA in type-2 diabetic patients. PMID- 24480162 TI - Remote homology detection incorporating the context of physicochemical properties. AB - A new method for remote protein homology detection, called support vector machine incorporating the context of physicochemical properties (SVM-CP), is presented. Recent discriminative methods are based on concatenating information extracted from each protein by considering several physicochemical properties. We show that there are physicochemical properties that reflect the functional or structural characteristics of each specific protein family, but there are also some physicochemical properties that affect the accuracy of the classification techniques. The research highlights the importance of the selection of physicochemical properties in remote homology detection. Most of the methods slide a window over every protein sequence to extract physicochemical information. This extraction is usually performed by giving the same importance to every value in the window, i.e., averaging the physicochemical values in the observation window. SVM-CP takes into account that every residue in a sliding window has a different weight, which reflects the importance or contribution to the representative value of the window. The SVM-CP method reaches a receiver operating characteristic (ROC) score of 0.93462, which is the highest value for a remote homology detection method based on the sequence composition information. PMID- 24480163 TI - Predicting the risk of squamous dysplasia and esophageal squamous cell carcinoma using minimum classification error method. AB - Early detection of squamous dysplasia and esophageal squamous cell carcinoma is of great importance. Adopting computer aided algorithms in predicting cancer risk using its risk factors can serve in limiting the clinical screenings to people with higher risks. In the present study, we show that the application of an advanced classification method, the Minimum Classification Error, could considerably enhance the classification performance in comparison to the logistic regression model and the variable structure fuzzy neural network, as the latest successful methods. The results yield the accuracy of 89.65% for esophageal squamous cell carcinoma, and 88.42% for squamous dysplasia risk prediction. PMID- 24480165 TI - Using HL7 in hospital staff assignments. AB - Hospital staff assignments are the instructions that allocate the hospital staff members to the hospital beds. Currently, hospital administrators make the assignments without accessing the information regarding the occupancy of the hospital beds and the acuity of the patient. As a result, administrators cannot distinguish between occupied and unoccupied beds, and may therefore assign staff to unoccupied beds. This gives rise to uneven and inefficient staff assignments. In this paper, the hospital admission-discharge-transfer (ADT) system is employed both as a data source and an assignment device to create staff assignments. When the patient data is newly added or modified, the ADT system updates the assignment software client with the relevant data. Based on the relevant data, the assignment software client is able to construct staff assignments in a more efficient way. PMID- 24480164 TI - Assessing the variability in respiratory acoustic thoracic imaging (RATHI). AB - Multichannel analysis of lung sounds (LSs) has enabled the generation of a functional image for the temporal and spatial study of LS intensities in healthy and diseased subjects; this method is known as respiratory acoustic thoracic imaging (RATHI). This acoustic imaging technique has been applied to diverse pulmonary conditions, but it is important to contribute to the understanding of RATHI characteristics, such as acoustic spatial distribution, dependence on airflow and variability. The purpose of the current study is to assess the intra subject and inter-subject RATHI variabilities in a cohort of 12 healthy male subjects (24.3+/-1.5 years) using diverse quantitative indices. The indices were obtained directly from the acoustic image and did not require scores from human raters, which helps to prevent inter-observer variability. To generate the acoustic image, LSs were acquired at 25 positions on the posterior thoracic surface by means of airborne sound sensors with a wide frequency band from 75 up to 1000 Hz under controlled airflow conditions at 1.0, 1.5 and 2.0 L/s. To assess intra-subject variability, the degree of similitude between inspiratory acoustic images was evaluated through quadratic mutual information based on the Cauchy Schwartz inequality (I(CS)). The inter-subject variability was assessed by an image registration procedure between RATHIs and X-ray images to allow the computation of average and variance acoustic image in the same coordinate space. The results indicated that intra-subject RATHI similitude, reflected by I(CS global), averaged 0.960+/-0.008, 0.958+/-0.008 and 0.960+/-0.007 for airflows of 1.0, 1.5, and 2L/s, respectively. As for the inter-subject variability, the variance image values for three airflow conditions indicated low image variability as they ranged from 0.01 to 0.04. In conclusion, the assessment of intra-subject and inter-subject variability by similitude indices indicated that the acoustic image pattern is repeatable along different respiratory cycles and across different subjects. Therefore, RATHI could be used to explore different aspects of spatial distribution and its association with regional pulmonary ventilation. PMID- 24480166 TI - Investigating the performance improvement of HRV Indices in CHF using feature selection methods based on backward elimination and statistical significance. AB - In this study, the best combination of short-term heart rate variability (HRV) measures was investigated to distinguish 29 patients with congestive heart failure from 54 healthy subjects in the control group. In the analysis performed, wavelet packet transform based frequency-domain measures and several non-linear parameters were used in addition to standard HRV measures. The backward elimination and unpaired statistical analysis methods were used to select the best one among all possible combinations of these measures. Five distinct typical classifiers with different parameters were evaluated in discriminating these two groups using the leave-one-out cross validation method. Each algorithm was tested 30 times to determine the repeatability of the results. The results imply that the backward elimination method gives better performance when compared to the statistical significance method in the feature selection stage. The best performance (82.75%, 96.29%, and 91.56% for the sensitivity, specificity, and accuracy) was obtained by using the SVM classifier with 27 selected features including non-linear and wavelet-based measures. PMID- 24480167 TI - Vibrational resonance in the FitzHugh-Nagumo system with time-varying delay feedback. AB - In the present paper, the phenomenon of vibrational resonance in a time-varying delayed FitzHugh-Nagumo system that is driven by two-frequency periodic signals is reported. Via a numerical simulation, the periodic vibrational resonances are found to be induced by the time-varying delay feedback under the condition that the delayed feedback strength is small, and then along with the increase of the delayed feedback strength K within the slow period (i.e., the period of low frequency signal), the single resonance turns into multiple resonances. However, if the delayed feedback strength K is big enough, the resonance no longer occurs. More interestingly, the multiple resonances can also turn into a single resonance in a cycle by modulating the amplitude F of high-frequency signal. Furthermore, both the resonance region and the resonance amplitude are found to be able to be controlled by the time-varying delay. Finally, it is found that the regular motion of the system can be enhanced by the time-varying delay feedback and then more regular motion will present if the resonance does not occur. PMID- 24480168 TI - Pulmonary nodule registration in serial CT scans using global rib matching and nodule template matching. AB - We propose an automatic nodule registration method between baseline and follow-up chest CT scans. Initial alignment using the center of the lung volume corrects the gross translational mismatch, and rigid registration using coronal and sagittal maximum intensity projection images effectively refines the rigid motion of the lungs. Nodule correspondences are established by finding the most similar region in terms of density as well as the geometrical constraint. The proposed nodule registration method increased the nodule hit rate (the ratio of the number of successfully matched nodules to total nodule number) from 26% to 100%. PMID- 24480169 TI - Signal peptide discrimination and cleavage site identification using SVM and NN. AB - About 15% of all proteins in a genome contain a signal peptide (SP) sequence, at the N-terminus, that targets the protein to intracellular secretory pathways. Once the protein is targeted correctly in the cell, the SP is cleaved, releasing the mature protein. Accurate prediction of the presence of these short amino-acid SP chains is crucial for modelling the topology of membrane proteins, since SP sequences can be confused with transmembrane domains due to similar composition of hydrophobic amino acids. This paper presents a cascaded Support Vector Machine (SVM)-Neural Network (NN) classification methodology for SP discrimination and cleavage site identification. The proposed method utilises a dual phase classification approach using SVM as a primary classifier to discriminate SP sequences from Non-SP. The methodology further employs NNs to predict the most suitable cleavage site candidates. In phase one, a SVM classification utilises hydrophobic propensities as a primary feature vector extraction using symmetric sliding window amino-acid sequence analysis for discrimination of SP and Non-SP. In phase two, a NN classification uses asymmetric sliding window sequence analysis for prediction of cleavage site identification. The proposed SVM-NN method was tested using Uni-Prot non-redundant datasets of eukaryotic and prokaryotic proteins with SP and Non-SP N-termini. Computer simulation results demonstrate an overall accuracy of 0.90 for SP and Non-SP discrimination based on Matthews Correlation Coefficient (MCC) tests using SVM. For SP cleavage site prediction, the overall accuracy is 91.5% based on cross-validation tests using the novel SVM-NN model. PMID- 24480170 TI - Chaos-based color pathological image encryption scheme using one-time keys. AB - This paper proposes an improved chaos-based color pathological image encryption algorithm, using SHA-2 to generate one-time keys. In order to send different ciphered images to different recipients, the hash value of the plain image and a random number are applied to generate one-time initial conditions for Chebyshev maps, to make the key stream change in every confusion process without changing the common initial values. The permuted image is divided into 256-bit long blocks, the avalanche effect is applied to diffuse the blocks, i.e., each block is XORed with the hash value of the prior block. Simulation results demonstrate that the proposed algorithm is robust against common attacks. PMID- 24480171 TI - A P300-based brain computer interface system for words typing. AB - P300 is an event related potential of the brain in response to oddball events. Brain Computer Interface (BCI) utilizing P300 is known as a P300 BCI system. A conventional P300 BCI system for character spelling is composed of a paradigm that displays flashing characters and a classification scheme which identifies target characters. To type a word a user has to spell each character of the word: this spelling process is slow and it can take several minutes to type a word. In this study, we propose a new word typing scheme by integrating a word suggestion mechanism with a dictionary search into the conventional P300-based speller. Our new P300-based word typing system consists of an initial character spelling paradigm, a dictionary unit to give suggestions of possible words and the second word selection paradigm to select a word out of the suggestions. Our proposed methodology reduces typing time significantly and makes word typing easy via a P300 BCI system. We have tested our system with ten subjects and our results demonstrate an average word typing time of 1.91 min whereas the conventional took 3.36 min for the same words. PMID- 24480172 TI - Mathematical model of wall shear stress-dependent vasomotor response based on physiological mechanisms. AB - Flow-mediated dilation (FMD) is the most commonly used noninvasive method for the assessment of vascular endothelial function; this assessment uses the magnitude of vasodilation according to reactive hyperemia. The physiological mechanism of vasodilation has been well studied; it was recently hypothesized that endothelial function can reversibly be estimated by computational analysis. This leads to more reliable information about cardiovascular risk factors. In this study, we first developed a mathematical model of vasodilation involving both intra- and inter-cellular pathways, which is constructed by integrating small-scale models based on known physiological mechanisms. We evaluated the proposed model with respect to several aspects: reproducibility of the FMD response; analysis of the relationship between FMD and endothelial function; and analysis of underlying mechanisms of low flow-mediated constriction. We confirmed that the simulated results corresponded well with those observed physiologically. Therefore, the results of the present study show that the proposed model has sufficient capability to quantitatively analyze FMD. PMID- 24480173 TI - SITDEM: a simulation tool for disease/endpoint models of association studies based on single nucleotide polymorphism genotypes. AB - The association analysis between single nucleotide polymorphisms (SNPs) and disease or endpoint in genome-wide association studies (GWAS) has been considered as a powerful strategy for investigating genetic susceptibility and for identifying significant biomarkers. The statistical analysis approaches with simulated data have been widely used to review experimental designs and performance measurements. In recent years, a number of authors have proposed methods for the simulation of biological data in the genomic field. However, these methods use large-scale genomic data as a reference to simulate experiments, which may limit the use of the methods in the case where the data in specific studies are not available. Few methods use experimental results or observed parameters for simulation. The goal of this study is to develop a Web application called SITDEM to simulate disease/endpoint models in three different approaches based on only parameters observed in GWAS. In our simulation, a key task is to compute the probability of genotypes. Based on that, we randomly sample simulation data. Simulation results are shown as a function of p-value against odds ratio or relative risk of a SNP in dominant and recessive models. Our simulation results show the potential of SITDEM for simulating genotype data. SITDEM could be particularly useful for investigating the relationship among observed parameters for target SNPs and for estimating the number of variables (SNPs) required to result in significant p-values in multiple comparisons. The proposed simulation tool is freely available at http://www.snpmodel.com. PMID- 24480174 TI - Numerical investigation of ultrasonic attenuation through 2D trabecular bone structures reconstructed from CT scans and random realizations. AB - In this paper, we compare ultrasound interrogations of actual CT-scanned images of trabecular bone with artificial randomly constructed bone. Even though it is known that actual bone does not have randomly distributed trabeculae, we find that the ultrasound attenuations are close enough to cast doubt on any microstructural information, such as trabeculae width and distance between trabeculae, being gleaned from such experiments. More precisely, we perform numerical simulations of ultrasound interrogation on cancellous bone to investigate the phenomenon of ultrasound attenuation as a function of excitation frequency and bone porosity. The theoretical model is based on acoustic propagation equations for a composite fluid-solid material and is solved by a staggered-grid finite-difference scheme in the time domain. Numerical experiments are performed on two-dimensional bone samples reconstructed from CT-scanned images of real human calcaneus and from random distributions of fluid-solid particles generated via the turning bands method. A detailed comparison is performed on various parameters such as the attenuation rate and speed of sound through the bone samples as well as the normalized broadband ultrasound attenuation coefficient. Comparing results from these two types of bone samples allows us to assess the role of bone microstructure in ultrasound attenuation. It is found that the random model provides suitable bone samples for ultrasound interrogation in the transverse direction of the trabecular network. PMID- 24480175 TI - miRClassify: an advanced web server for miRNA family classification and annotation. AB - MicroRNA (miRNA) family is a group of miRNAs that derive from the common ancestor. Normally, members from the same miRNA family have similar physiological functions; however, they are not always conserved in primary sequence or secondary structure. Proper family prediction from primary sequence will be helpful for accurate identification and further functional annotation of novel miRNA. Therefore, we introduced a novel machine learning-based web server, the miRClassify, which can rapidly identify miRNA from the primary sequence and classify it into a miRNA family regardless of similarity in sequence and structure. Additionally, the medical implication of the miRNA family is also provided when it is available in PubMed. The web server is accessible at the link http://datamining.xmu.edu.cn/software/MIR/home.html. PMID- 24480176 TI - Detection and classification of retinal lesions for grading of diabetic retinopathy. AB - Diabetic Retinopathy (DR) is an eye abnormality in which the human retina is affected due to an increasing amount of insulin in blood. The early detection and diagnosis of DR is vital to save the vision of diabetes patients. The early signs of DR which appear on the surface of the retina are microaneurysms, haemorrhages, and exudates. In this paper, we propose a system consisting of a novel hybrid classifier for the detection of retinal lesions. The proposed system consists of preprocessing, extraction of candidate lesions, feature set formulation, and classification. In preprocessing, the system eliminates background pixels and extracts the blood vessels and optic disc from the digital retinal image. The candidate lesion detection phase extracts, using filter banks, all regions which may possibly have any type of lesion. A feature set based on different descriptors, such as shape, intensity, and statistics, is formulated for each possible candidate region: this further helps in classifying that region. This paper presents an extension of the m-Mediods based modeling approach, and combines it with a Gaussian Mixture Model in an ensemble to form a hybrid classifier to improve the accuracy of the classification. The proposed system is assessed using standard fundus image databases with the help of performance parameters, such as, sensitivity, specificity, accuracy, and the Receiver Operating Characteristics curves for statistical analysis. PMID- 24480178 TI - Intraoperative Transesophageal Echocardiographic Evidence of SVC Compression by a Bronchogenic Cyst. PMID- 24480177 TI - Expression of miR-15/107 family microRNAs in human tissues and cultured rat brain cells. AB - The miR-15/107 family comprises a group of 10 paralogous microRNAs (miRNAs), sharing a 5' AGCAGC sequence. These miRNAs have overlapping targets. In order to characterize the expression of miR-15/107 family miRNAs, we employed customized TaqMan Low-Density micro-fluid PCR-array to investigate the expression of miR 15/107 family members, and other selected miRNAs, in 11 human tissues obtained at autopsy including the cerebral cortex, frontal cortex, primary visual cortex, thalamus, heart, lung, liver, kidney, spleen, stomach and skeletal muscle. miR 103, miR-195 and miR-497 were expressed at similar levels across various tissues, whereas miR-107 is enriched in brain samples. We also examined the expression patterns of evolutionarily conserved miR-15/107 miRNAs in three distinct primary rat brain cell preparations (enriched for cortical neurons, astrocytes and microglia, respectively). In primary cultures of rat brain cells, several members of the miR-15/107 family are enriched in neurons compared to other cell types in the central nervous system (CNS). In addition to mature miRNAs, we also examined the expression of precursors (pri-miRNAs). Our data suggested a generally poor correlation between the expression of mature miRNAs and their precursors. In summary, we provide a detailed study of the tissue and cell type-specific expression profile of this highly expressed and phylogenetically conserved family of miRNA genes. PMID- 24480179 TI - Comparison of pulmonary gas exchange according to intraoperative ventilation modes for mitral valve repair surgery via thoracotomy with one-lung ventilation: a randomized controlled trial. AB - OBJECTIVE: Impaired pulmonary gas exchange after cardiac surgeries with cardiopulmonary bypass (CPB) often occurs, and the selection of mechanical ventilation mode, pressure-controlled ventilation (PCV) or volume-controlled ventilation (VCV), may be important for preventing hypoxia and improving oxygenation. The authors hypothesized that patients with PCV would show better oxygenation, compared with VCV, during one-lung ventilation (OLV) for mitral valve repair surgery (MVP) via thoracotomy. DESIGN: Randomized controlled trial. SETTING: University teaching hospital. PARTICIPANTS: Sixty patients in each group. INTERVENTIONS: MVP was performed using thoracotomy with OLV by PCV or VCV. MEASUREMENTS AND MAIN RESULTS: Arterial partial pressure of oxygen (PaO2) and fraction of inspired oxygen (FIO2) were measured before anesthesia induction (T0), at skin incision (T1), after administration of heparin (T2), at 30 minutes after CPB weaning (T3), just before departure from the operating room to the intensive care unit (ICU) (T4), and 1 hour after ICU admission (T5), and PaO2/FIO2 ratio was calculated. Peak inspiratory pressure (PIP) and mean inspiratory pressure (Pmean) were recorded at T1, T2, T3, and T4. No significant difference was noted in the PaO2/FIO2 ratio between the groups at any measured point. PIP in the PCV group at all measured points was lower than that in the VCV group (T1, p<0.001; T2, p<0.001; T3, p<0.001; T4, p=0.025, respectively). Pmean was not different between the two groups at any measured point. CONCLUSIONS: PCV during OLV in patients undergoing MVP via a thoracotomy with OLV showed lower PIP compared with VCV, but this did not improve pulmonary gas exchange. PMID- 24480180 TI - The Asia-Pacific Evaluation of Cardiovascular Therapies (ASPECT) collaboration - improving the quality of cardiovascular care in the Asia Pacific region. AB - BACKGROUND: Clinicians and other stakeholders recognize the need for clinical registries to monitor data in order to improve the outcome and quality of care in the delivery of medical interventions. The establishment of a collaboration across the Asia Pacific Region to inform on variations in patient and procedural characteristics and associated clinical outcomes would enable regional benchmarking of quality. AIMS & METHODS: The aims of the collaboration are a) to identify the characteristics of patients undergoing PCI across the Asia Pacific region, b) to report on outcomes of patients undergoing PCI, c) to develop an appropriate ethnic and region specific risk adjustment model for patients undergoing PCI and d) to establish a registry framework for research, education and training in the area of cardiovascular interventions across the Asia Pacific Region. Descriptive characteristics of patient undergoing PCI over a 12 month period were collated and reported. RESULTS: Representatives from 27 hospitals attended the inaugural meeting with interested parties from Australia, Singapore, Malaysia and Hong Kong. In every country, males predominated PCI activity. Subjects were older and had higher rates of family history of cardiovascular disease in Australia, while Asian subjects had higher rates of diabetes, dyslipidemia and renal failure. STEMI presentation was higher in Australia than in Asia and drug eluting stent use was higher in Asia. Procedural success rates were similar across the region (>95%). CONCLUSIONS: Procedural success was similar across the region despite differing patient characteristics across countries in terms of pre-procedural risk factors and clinical presentation. PMID- 24480182 TI - Novel preprocedural and acute-phase postprocedural predictive factors for contrast-induced kidney injury in CKD patients. PMID- 24480181 TI - Unintentional overestimation of an expected antihypertensive effect in drug and device trials: mechanisms and solutions. AB - In clinical practice we pay close attention to choosing an appropriate intervention for patients and performing it safely. We may put less thought into how to measure the effect without bias. Clinical practice involving noisy values such as blood pressure requires intelligent processing to avoid confusing patients, but applying such discretion in clinical trials may inadvertently disrupt quantification of the benefit of the intervention, in unblinded trials. In this article we explore two sources of bias, which label for convenience "big day bias" and "check once more bias", which can lead to unintentional exaggeration of benefits from both drugs and device-based treatment for hypertension. We show in this article why, as denervation trials become increasingly bias resistant, the reported effect size may reduce. If inadvertent bias affects patients who are denervated in the same way as it affects those receiving antihypertensive drugs, the most meticulous denervation trials may show the effect size falling from around 30 mmHg to around 10 mmHg. Some readers will doubt that these biases could be large enough to matter. We therefore include downloadable spreadsheets that any reader can use to explore how powerfully small biases affect the apparent effect sizes. The results may be surprising. A 10-mmHg reduction, without needing to adhere to an extra drug, would still substantially reduce events in the long term, but crucial to such reasoning is the reliable quantification of the blood pressure effect, free of bias. PMID- 24480183 TI - Long-term predictive value of copeptin after acute myocardial infarction: a cardiac magnetic resonance study. PMID- 24480184 TI - Head-to-head comparison of everolimus-eluting stents versus zotarolimus-eluting stents in patients undergoing percutaneous coronary intervention: a meta analysis. PMID- 24480185 TI - Looking for the pick of the bunch: high-throughput screening of producing microorganisms with biosensors. AB - The engineering of microbial strains for the production of small molecules of biotechnological interest is a time-consuming, laborious and expensive process. This can be mostly attributed to the fact that good producers cannot be readily obtained by high-throughput screening approaches since increased product formation usually does not confer a clear phenotype to producing strain variants. Recently, advances were made in the design and construction of genetically encoded RNA aptamer-based or transcription factor-based biosensors for detecting small molecules at the single-cell level. The first promising examples for the application of these molecular biosensors in combination with fluorescent activated cell sorting as a high-throughput screening device demonstrated the value and potential of these new tools for microbial strain development. PMID- 24480186 TI - Expression, purification, and solubility optimization of peptidyl-tRNA hydrolase 1 from Bacillus cereus. AB - Peptidyl-tRNA hydrolase 1 cleaves the ester bond of peptidyl-tRNA thereby recycling peptidyl-tRNAs generated from premature termination of translation and expression of minigenes and short ORFs. Bacterial Pth1 is essential, highly conserved, and has no essential eukaryotic homolog making it a good target for antibacterial development. Herein we describe the cloning of pth1 gene from Bacillus cereus as an N-terminal hexahistidine fusion protein. Solubility was optimized for overexpression in Escherichia coli. Purity greater than 95% was achieved in one chromatography step. Yields greater than 12mg of purified Pth1 per liter of minimal media were achieved and buffer conditions for long-term solubility were determined. Enzymatic activity of Pth1 from B. cereus was confirmed and quantification of Michaelis-Menten parameters reported. PMID- 24480187 TI - PA tag: a versatile protein tagging system using a super high affinity antibody against a dodecapeptide derived from human podoplanin. AB - Peptide-based epitope tagging technology is universally used in nearly all kind of research projects that involve biochemical characterization of a target protein, but not many systems are fully compatible with purification purpose. By utilizing an anti-human podoplanin antibody NZ-1, we constructed a novel epitope tag system. NZ-1 possesses exceptionally high affinity toward a dodecapeptide dubbed "PA tag", with a characteristic slow dissociation kinetics. Because of its high affinity, PA-tagged proteins in a dilute sample can be captured by immobilized NZ-1 resin in a near complete fashion and eluted by a solution of free PA peptide. This enabled efficient one-step purification of various proteins including soluble (an ectodomain fragment of neuropilin-1) and membrane (epidermal growth factor receptor) proteins expressed in mammalian cells. Mild regeneration condition of the peptide-bound antibody ensures repeated use of the antibody resin, indicating a cost-efficient nature of the system. Together with its outstanding performance in the immunodetection experiments (i.e., Western blotting and flow cytometry), PA tag/NZ-1 system will offer a great chance to facilitate protein production in many biomedical research projects. PMID- 24480188 TI - Diversity of aflatoxin-producing fungi and their impact on food safety in sub Saharan Africa. AB - Crops frequently contaminated by aflatoxins are important sources of revenue and daily nourishment in many portions of sub-Saharan Africa. In recent years, reports have associated aflatoxins with diminished human health and export opportunities in many African Nations. Aflatoxins are highly carcinogenic metabolites mainly produced by members of Aspergillus sect. Flavi. The current study examined aflatoxin-producing fungi associated with maize grain intended for human consumption in 18 sub-Saharan African countries. 4469 Aspergillus sect. Flavi isolates were obtained from 339 samples. The majority (75%) of isolates belonged to the L strain morphotype of A. flavus. Minor percentages were A. tamarii (6%), A. parasiticus (1%), and isolates with S strain morphology (3%). No A. bombycis or A. nomius isolates were detected. Phylogenetic analyses of partial sequences of the nitrate reductase gene (niaD, 1.3kb) and the aflatoxin pathway transcription factor gene (aflR, 1.7kb) were used to verify isolate assignments into species and lineages. Phylogenetics resolved S strain isolates producing only B aflatoxins into two lineages fully supported by sizes of deletions in the gene region spanning the aflatoxin biosynthesis genes cypA (aflU) and norB (aflF). One lineage was the A. flavus S strain with either 0.9 or 1.5kb deletions. The second lineage, recently described from Kenya, has a 2.2kb deletion. Taxa with S strain morphology differed in distribution with strain SBG limited to West Africa and both A. minisclerotigenes and the new lineage from Kenya in Central and East Africa. African A. flavus L strain isolates formed a single clade with L strain isolates from other continents. The sampled maize frequently tested positive for aflatoxins (65%), fumonisins (81%), and deoxynivalenol (40%) indicating the presence of fungi capable of producing the respective toxins. Percentage of samples exceeding US limits for total aflatoxins (regulatory limit), fumonisins (advisory limit), and deoxynivalenol (advisory limit) were 47%, 49%, 4%, respectively. PMID- 24480189 TI - Food matrices and cell conditions influence survival of Lactobacillus rhamnosus GG under heat stresses and during storage. AB - The present study evaluated impact of moisture content and cell conditions on survival of probiotic strain, Lactobacillus rhamnosus GG, under lethal heat stresses and during long-term storage using freeze-dried cells and oils as matrices. Viable cell counts of freeze-dried L. rhamnosus GG cells suspended in oils had only 1-log-reduction after 5min at 80 degrees C and approximately 3-log reduction after 20min, while no or very few viable cells were recorded for freeze dried cells suspended in buffer and cultured cells in oils. Surprisingly, freeze dried cells suspended in oils still contained 4.3 to 6.7logCFU/ml after 5min at 95 degrees C. Long-term storage study indicated that freeze-dried cells suspended in oils kept viable conditions for 4months, and a loss of the viability was only 0.3 to 0.6logCFU/ml. Viable cell counts of cultured cells suspended in oils were not present after 3days to 3months. These results clearly indicate that moisture and cell conditions have a great impact on survival of probiotics under severe heat stress in processing and during long-term storage. Combination of freeze dried cells and oils as carrier provides beneficial options to preserve viability of probiotics in food processes and storage. PMID- 24480190 TI - Rapid detection of Vibrio parahaemolyticus in raw oysters using immunomagnetic separation combined with loop-mediated isothermal amplification. AB - The objective of this study was to develop a method that combined nanoparticle based immunomagnetic separation (IMS) with real-time loop-mediated isothermal amplification (LAMP) for the rapid detection of Vibrio parahaemolyticus. Magnetic nanoparticles were functionalized with monoclonal antibodies that were produced against flagella from V. parahaemolyticus to capture and separate the target cells from raw oysters. After optimization, the immunomagnetic nanoparticles (IMNPs) presented a capture efficiency of 87.3% for 10(5) colony-forming unit (CFU)/mL of V. parahaemolyticus using 2.5MUg of IMNPs within 30min. Although a very low level of non-specific binding was seen among 8 non-V. parahaemolyticus Vibrio spp. and 5 non-Vibrio strains, the IMS-LAMP method identified 133 V. parahaemolyticus strains correctly without the amplification from 54 other strains. The detection limit was about 1.4*10(2)CFU/mL in pure culture and was unaffected by the presence of 10(8)CFU/mL of competing microflora. When applied in spiked oysters, the sensitivity was found to be 1.9*10(3)CFU/g without enrichment. After enrichment for 6-8h, the limit of detectability could be improved to 1.9 to 0.19CFU/g. Hence, the IMS-LAMP assay provided a rapid, simple, and cost-effective method for total V. parahaemolyticus detection. This method will have important implications in the rapid detection of contaminated food in the early stage before distribution. PMID- 24480191 TI - Sensitization of metformin-cytotoxicity by dichloroacetate via reprogramming glucose metabolism in cancer cells. AB - To investigate sensitization of metformin-cytotoxicity, cancer cells were treated with dichloroacetate (DCA), an inhibitor of pyruvate dehydrogenase kinase (PDK). Metformin-cytotoxicity was mainly dependent on glucose availability and reducing power generated by pentose phosphate pathway, whereas DCA cotreatment enhanced metformin-cytotoxicity via reprogramming glucose metabolism by inhibiting PDK and increasing mitochondrial respiration. DCA cotreatment elicited cell death rather than cell survival despite high glucose and high GSH condition. In conclusion, DCA sensitized metformin-cytotoxicity by reprogramming glucose metabolism in part from aerobic glycolysis to mitochondrial oxidation, evidenced by measurements of glucose consumption, lactate release, and the ratio of oxygen consumption rate/extracellular acidification rate. PMID- 24480192 TI - Identifying factors hampering physical activity in longstanding rheumatoid arthritis: what is the role of glucocorticoid therapy? AB - OBJECTIVES: To identify factors hampering the level of physical activity in longstanding rheumatoid arthritis (RA) patients, and to evaluate the effects of glucocorticoid therapy on physical activity. METHODS: Patient characteristics, disease characteristics and cardiovascular parameters were recorded in 170 patients, who participated in a study about glucose metabolism in longstanding RA treated with or without glucocorticoids. Disease activity scores (DAS28) were calculated and x-rays of hands and feet were taken and scored according to the Sharp van der Heijde score (SHS). Participants completed the health assessment questionnaire and short questionnaire to assess health-enhancing physical activity (SQUASH), which reflect physical disability and physical activity, respectively. Adherence rates to recommendations on physical activity were calculated, and patients were categorised as fully adhering, insufficiently adhering (adherence on less than the recommended number of days per week) or inactive (adherence on none of the days). RESULTS: Forty-four percent of the patients showed adherence to the recommended minimum level of physical activity, and 22% were classified as inactive. Higher DAS28 and SHS, glucocorticoid therapy, and presence of cardiovascular risk factors were associated with lower total SQUASH physical activity scores univariately. In a multivariate model, higher age, higher body mass index (BMI), higher DAS28, and higher SHS negatively influenced the score significantly; cardiovascular risk factors and glucocorticoid therapy were no longer significantly influencing physical activity. CONCLUSIONS: Physical activity in longstanding RA is hampered by higher age, higher BMI, higher disease activity, and more radiographic joint damage. Glucocorticoid therapy was not identified as independent risk factor in multivariate analyses. PMID- 24480193 TI - Pyogenic liver abscess as a complication of internal hemorrhoid banding. PMID- 24480194 TI - Xanthogranulomatous inflammation of the sigmoid and small bowel presenting as Crohn's disease. PMID- 24480195 TI - A 58-year-old woman with mesh migration into the transverse colon. PMID- 24480196 TI - More than just skin deep: an unusual cause of bowel perforation. PMID- 24480197 TI - Gastrointestinal metastases of cutaneous melanoma. PMID- 24480198 TI - Solid adrenal mass: not always what it seems. PMID- 24480199 TI - Treatment of pilonidal disease using the Bascom 'Cleft-Lift' procedure. PMID- 24480201 TI - Penetrating posterior urethral injury: successful retrieval of an impacted missile with immediate endoscopic realignment. PMID- 24480200 TI - Total laparoscopic uncut Roux-en-Y gastrojejunostomy after distal gastrectomy. PMID- 24480202 TI - Transanal repair of traumatic rectal injuries without laparotomy and fecal diversion is feasible and safe in select patients. PMID- 24480203 TI - Postsurgical long-term disease-free survival in a case of primary diffuse large B cell lymphoma of the gallbladder without adjuvant therapy. PMID- 24480204 TI - Importance of high clinical suspicion in diagnosing a Marjolin's ulcer with an unusual presentation. PMID- 24480205 TI - Limited surgical exposure with retrograde stenting to address isolated high-grade proximal common carotid artery stenosis involving the ostia. PMID- 24480206 TI - Sacral nerve stimulation in patients with severe fecal incontinence after delivery sphincter injury. PMID- 24480207 TI - Nonoperative management of pneumatosis intestinalis and pneumoperitoneum in mixed connective tissue disease. PMID- 24480208 TI - A brief history of appendicitis: familiar names and interesting patients. PMID- 24480209 TI - Epidural versus subpleural analgesia for pulmonary resections: a comparison of morbidities. AB - There are several methods to mitigate the pain that results from thoracic surgery. All of them may be associated with complications. We analyzed the morbidities associated with epidural and subpleural catheter analgesia in patients undergoing pulmonary resections for lung cancer. We conducted a retrospective review of our prospective lung cancer outcomes database for all patients undergoing lobectomy for lung cancer through a thoracotomy or thoracoscopy. All patients had either an epidural or subpleural catheter placed for pain control. One hundred twenty-nine patients met the inclusion criteria. Patients were stratified based on age and pain management technique and the 30 day outcomes were examined. Ninety-three patients had epidural catheters placed and 36 received subpleural catheters. Baseline demographics were similar except for two variables; the subpleural catheter group had a larger proportion of thoracoscopic surgery and more pack-years smoked. Patients in the epidural group were more likely to experience postoperative pruritus and had longer intensive care unit stays but were less likely to use a patient-controlled anesthesia pump. Patients in the subpleural group were more likely to develop intestinal complications. When a subset analysis was done by age (younger than 70 vs 70 years or older), there were no significant differences in postoperative outcomes in the older group. The younger cohort had more pruritus and longer intensive care unit stays in the epidural group. The differences between subpleural and epidural catheters are minimal across all ages and nonexistent for geriatric patients. Thus, the choice of pain management should be determined by individual patient characteristics and risk factors rather than based on age alone. PMID- 24480210 TI - Clinical characteristics and overall survival in patients with anaplastic pancreatic cancer. AB - Anaplastic pancreatic cancer (APC) is a rare undifferentiated variant of pancreatic ductal adenocarcinoma with poor overall survival (OS). The aim of this study was to evaluate the clinical outcomes of APC compared with differentiated pancreatic ductal adenocarcinoma. We conducted a retrospective review of all patients treated at the Mayo Clinic with pathologically confirmed APC from 1987 to 2011. After matching with control subjects with pancreatic ductal adenocarcinoma, OS was evaluated using Kaplan-Meier estimates and log-rank test. Sixteen patients were identified with APC (56.3% male, median age 57 years). Ten patients underwent exploration of whom eight underwent pancreatectomy. Perioperative morbidity was 60 per cent with no mortality. The median OS was 12.8 months. However, patients with APC who underwent resection had longer OS compared with those who were not resected, 34.1 versus 3.3 months (P = 0.001). After matching age, sex, tumor stage, and year of operation, the median OS was similar between patients with APC and those with ductal adenocarcinoma treated with pancreatic resection, 44.1 versus 39.9 months, (P = 0.763). Overall survival for APC is poor; however, when resected, survival is similar to differentiated pancreatic ductal adenocarcinoma. PMID- 24480211 TI - Who will benefit from noncurative resection in patients with gastric cancer with single peritoneal metastasis? AB - The value of noncurative resection for patients with gastric cancer with single peritoneal metastasis is still debatable. This study was undertaken to evaluate the survival benefit of resection in those patients. From 2006 to 2009, 119 patients with gastric cancer with single peritoneal metastasis were identified during surgery. Sixty-three of them had noncurative resection; the remainder had nonresection. Clinicopathological variables and survival were analyzed. Overall survival of patients in the noncurative resection group was longer than that in the nonresection group (14.869 vs 7.780 months). This survival advantage was still significantly better in the P1/P2 patients who underwent noncurative resection (mean survival time 21.164 vs 7.636 months, P = 0.001), but not in the P3 group (P = 0.489). Multivariate analysis indicated that only noncurative resection retained a significant association with better prognosis in P1/P2 patients. The perioperative mortality rate in the resection group was not significantly higher than that of the noncurative group (P = 0.747). Noncurative resection can prolong the survival of patients with gastric cancer with single P1/P2 peritoneal metastasis. This surgical approach should not be taken into account for those patients with P3 gastric cancer. PMID- 24480212 TI - Ingested foreign bodies: do we need a specific approach when treating inmates? AB - The management of foreign bodies in the gastrointestinal tract is not standardized. Foreign body ingestions in prisoners are always intentional and inmates can be manipulative, which makes medical decision even more difficult. Our objective is to propose a decisional algorithm for management of foreign body ingestion in prisoners. We reviewed the records of 198 admissions for foreign body ingestion for a 10-year period. Type and number of ingested foreign bodies, radiographic findings, outcome as well as the management method including conservative, endoscopic removal, or surgical treatment were analyzed. Most cases were managed conservatively (87.6%). Endoscopy of the upper gastrointestinal tract was performed in 37 cases with a success rate of 46 per cent. In 9.3 per cent of cases, the final treatment was endoscopic. Only five patients required surgical treatment, being emergent just in one case. We advocate conservative treatment for asymptomatic patients with foreign body ingestion. Endoscopic removal is proposed for pointed objects or objects bigger than 2.5 cm located in the stomach. Objects longer than 6 to 8 cm located in the stomach should be removed by endoscopy or laparoscopy. Patients with objects in the small bowel or colon should be treated conservatively unless there are complications or they fail to progress. PMID- 24480213 TI - Recurrence and pseudorecurrence after laparoscopic ventral hernia repair: predictors and patient-focused outcomes. AB - Laparoscopic ventral hernia repair (LVHR) is gaining popularity as an option to repair abdominal wall hernias. Bulging after repair remains common after this technique. This study evaluates the incidence and factors associated with bulging after LVHR. Between 2000 and 2010, 201 patients underwent LVHR at two affiliated institutions. Patients who developed recurrence or pseudorecurrence (seroma or eventration) were analyzed with univariate and multivariate analyses to identify predictors of these complications. Of the 201 patients who underwent LVHR, 40 (19.9%) patients developed a seroma, 63 (31.3%) patients had radiographically proven eventration, and 25 (12.4%) patients had a hernia recurrence. On multivariate analysis, seromas were associated with number of prior ventral hernia repairs, surgical site infections, and prostate disease. Mesh eventration was associated with hernia size and surgical technique. Tissue eventration was associated with primary hernias and surgical technique. Hernia recurrence was associated with incisional hernias and mesh type used. Recurrence and pseudorecurrence are important complications after LVHR. Large hernia size, infections, and surgical technique are important clinical factors that affect outcomes after LVHR. PMID- 24480214 TI - Validation of mucosal sutureless pancreatojejunostomy after pancreatoduodenectomy. AB - Although duct-to-mucosa pancreatojejunostomy has been considered safer than other techniques, this procedure is particularly difficult when the pancreatic duct is small. It has therefore become increasingly necessary to develop a simple mucosal sutureless pancreatojejunostomy technique to replace the conventional hand-sewing one. Two hundred fourteen patients who underwent mucosal sutureless pancreatojejunostomy were classified into two groups: those with a normal pancreatic duct diameter (less than 3 mm, n = 97) and those with a dilated pancreatic duct (3 mm or greater, n = 117). The rate of clinically significant pancreatic fistula (Grade B or C by the International Study Group on Pancreatic Fistula definition) among the patients as a whole was 8 per cent. The overall incidence of pancreatic fistula was significantly higher in the patients with a pancreatic duct diameter of less than 3 mm than in those with a pancreatic duct diameter of 3 mm or greater. However, the incidence of clinically significant pancreatic fistula did not differ between the groups (less than 3 mm, 11%; 3 mm or greater, 5%; P = 0.09). Grade C pancreatic fistula developed in one patient with a pancreatic duct diameter of less than 3 mm and in two with a pancreatic duct diameter 3 mm or greater. Although two patients required reoperation, all of the fistulas were cured and the postoperative mortality rate related to pancreatoduodenectomy was zero. Mucosal sutureless pancreatojejunostomy combined with pancreatic duct stenting is associated with a low rate of clinically significant pancreatic fistula even in patients with a small pancreatic duct diameter less than 3 mm. PMID- 24480215 TI - Traditional versus early-access grafts for hemodialysis access: a single institution comparative study. AB - In those patients requiring urgent hemodialysis, the use of early-access grafts may reduce the need for temporary hemodialysis catheters and their resultant complications such as infection and central venous stenosis. We review a consecutive group of patients undergoing placement of a traditional polytetrafluoroethylene (PTFE) graft as compared with a cohort of patients who underwent insertion of a trilaminate PTFE vascular graft (TPVG). During the period from January 2008 to December 2009, 65 sequential patients received a traditional PTFE graft with 78 subsequent patients having a TPVG inserted. Factors examined included use of temporary hemodialysis catheters during the period of graft maturation, incidence of infection, and primary and secondary graft patency. For all patients, incidence was reported as observed during the first year after graft insertion. With the use of the TPVG, need for temporary hemodialysis catheters was reduced from 91 to 32 per cent, and 1-year overall graft patency was improved from 36 to 77 per cent (P < 0.01). We report that the use of a trilaminate PTFE graft allowed early access, reduced the need for temporary hemodialysis catheters, decreased overall graft complication rates, and significantly improved 1-year patency. PMID- 24480216 TI - Isolated caudate lobe resection for huge hepatocellular carcinoma (10 cm or greater in diameter). AB - Isolated caudate lobectomy for huge hepatocellular carcinoma (HCC) (10 cm or greater in diameter) is a technically demanding surgical procedure that entails the surgeon's experience and precise anatomical knowledge of the liver. We describe our clinical experiences and evaluate the results of partial or total isolated caudate lobectomy for HCC larger than 10 cm in the caudate lobe. En bloc excisions combined with adjacent hepatic parenchyma (as part of extended hepatectomies) were excluded. Twenty-seven patients were included in the study (24 male, three3 female). Median age was 43 years (range, 18 to 81 years). All primary diagnoses were HCC. Twenty-one patients had surgical margins lesser than 1 cm. Tumor embolus within the main trunk of the portal vein was found in five patients by intraoperative ultrasound. Median operative time was 288 minutes (range, 160 to 310 minutes), and estimated intraoperative blood loss was 2260 mL (range, 200 to 7000 mL). Median blood transfusion was 1460 mL (range, 0 to 7200 mL). Postoperative morbidity rate was 44.4 per cent. There were no postoperative deaths. Overall survival rates at 1, 3, and 5 years were 80.2, 52.1, and 27.1 per cent, respectively. Nineteen patients (70.4%) had tumor recurrence as of the last follow-up. The recurrence lesion was treated in most of these patients. Isolated caudate lobectomy for huge HCC is a technically demanding but safe procedure, although the procedure is sometimes extremely difficult. PMID- 24480217 TI - Characteristic risk factors in cirrhotic patients for posthepatectomy complications: comparison with noncirrhotic patients. AB - There seemed to be characteristic risk factors in cirrhotic patients for posthepatectomy complications because these patients have less hepatic reserve as compared with noncirrhotic patients. The aim of the current study was to identify these characteristic risk factors in cirrhotic patients. We performed 419 primary hepatectomies for hepatocellular carcinoma. The patients were divided into the cirrhotic group (n = 198) and the noncirrhotic group (n = 221), and the risk factors for posthepatectomy complications were compared between the groups. Thirty-six cirrhotic patients (18.2%) experienced Clavien's Grade III or more complications. Tumor size, intraoperative blood loss, duration of operation, major hepatectomy (two or more segments), and necessity of blood transfusion were found to be significant risk factors in univariate analyses. Multivariate analysis revealed that major hepatectomy and intraoperative blood loss were independent risk factors for posthepatectomy complications in patients with cirrhosis. On the other hand, the duration of operation was only an independent risk factor for posthepatectomy complication in noncirrhotic patients. Cirrhotic patients should avoid a major hepatectomy and undergo a limited resection preserving as much liver tissue as possible and meticulous surgical procedures to lessen intraoperative blood loss are mandatory to prevent major posthepatectomy complications. PMID- 24480218 TI - Sentinel lymph node biopsy is a reliable method for lymph node evaluation in neoadjuvant chemotherapy-treated patients with breast cancer. AB - Sentinel lymph node (SLN) mapping in patients with breast cancer treated with neoadjuvant chemotherapy has been debated by surgeons as a result of potential compromise of lymphatic drainage. Whether clinicopathologic variables traditionally associated with SLN positivity differ in patients who have been treated with neoadjuvant chemotherapy has not been well studied. Patients diagnosed with breast carcinoma who underwent neoadjuvant chemotherapy, definitive breast surgery, sentinel node biopsy (SNB), and axillary lymph node dissection (ALND) were retrospectively identified over a 75-month period. Clinicopathologic parameters including age, clinical tumor and node stage, neoadjuvant chemotherapy regimen, pathological tumor and node stage, lymphovascular invasion (LVI), SLN and non-SLN involvement, and extranodal extension were recorded. Ninety-seven patients met inclusion criteria. Ninety eight per cent had successful SLN mapping. Eight patients with negative SLNs had positive ALND (false-negative rate, 8.3%). Clinicopathological variables associated with SLN status included clinical axillary status (P = 0.038), pathologic tumor size, and nodal status and LVI (P < 0.001). Extranodal extension was significantly associated with non-SLN status (P = 0.004). In patients achieving a pathologic complete response (PCR), SNB remained feasible and accurate (false-negative rate, 11.6%). Successful SLN mapping in patients who have undergone neoadjuvant chemotherapy is highly accurate with a low false negative rate even in patients who have a PCR. PMID- 24480219 TI - Laparoscopic common bile duct exploration with primary closure for management of choledocholithiasis: a retrospective analysis and comparison with conventional T tube drainage. AB - Laparoscopic common bile duct exploration (LCBDE) had become one of the main options for management of choledocholithiasis. This retrospective comparative study aimed to evaluate on the feasibility and advantages of primary closure versus conventional T-tube drainage of the common bile duct (CBD) after laparoscopic choledochotomy. In this retrospective analysis, 100 patients (47 men and 53 women) with choledocholithiasis who underwent primary closure of the CBD (without T-tube drainage) after LCBDE (Group A) were compared with 92 patients who underwent LCBDE with T-tube drainage (Group B). Both groups were evaluated with regard to biliary complications, hospital stay, and recurrence of stones. The mean operation time was 104.12 minutes for Group A and 108.92 minutes for Group B (P = 0.069). The hospital stay was significantly shorter in Group A than that in Group B (6.95 days and 12.05 days, respectively; P < 0.001). In Group A, bile leakage occurred in two patients on postoperative Day 2 and Day 3, respectively. In Group B, bile leakage noted in one patient after removal of the T-tube on Day 14 after operation (P = 1.000). With a median follow-up time of 40 months for both groups, stone recurrence was noted in two patients in Group A and three patients in Group B (P = 0.672). Primary closure of the CBD is safe and feasible in selected patients after laparoscopic choledochotomy. It results in shorter duration of hospital stay without the need for carrying/care of a T-tube in the postoperative period and similar stone recurrence as that of the conventional method. PMID- 24480220 TI - Evaluation of cervical spine fracture in the elderly: can we trust our physical examination? AB - The purpose of this trial was to compare National Emergency X-Radiography Utilization Study (NEXUS) criteria (NC) with computed tomography (CT) as the gold standard to evaluate cervical spine (C-spine) fractures in elderly blunt trauma patients. We prospectively compared adult blunt trauma patients 65 years or older (E) with younger than 65 years (NE), evaluating the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of NC compared with CT in these two cohorts. A total of 2785 blunt trauma patients were included of whom 320 were E (average age, 75 years) and 2465 were NE (average age, 36 years). Incidence of C-spine fracture was 12.8 per cent (E) versus 7.4 per cent (NE) (P = 0.002). Age was an independent predictor of fracture (P = 0.01). NC had a sensitivity of 65.9 per cent in E and PPV of 19.3 per cent in E (P = 0.001) versus a sensitivity of 84.2 per cent in NE and PPV of 10.6 per cent (P < 0.0001). The specificity was 59.5 per cent for E versus 42.6 per cent for NE (NPV, 92.2% E vs 97.1% NE). This study suggests that NEXUS criteria are not an appropriate assessment tool when applied to severe blunt trauma patients, particularly in the elderly population who had more missed injures than their younger counterparts. CT should be used in all blunt trauma patients regardless of whether they meet NEXUS criteria. PMID- 24480221 TI - Transduodenal ampullectomy for ampullary adenomas: a safe and effective procedure with long-term salutary outcomes. AB - With widespread use of endoscopy, ampullary adenomas are more frequently identified, many of which are not amenable to endoscopic resection. Pancreatoduodenctomy is curative for these lesions but carries high morbidity. The purpose of this study was to determine the safety and efficacy of transduodenal ampullectomy for these lesions. Data were collected on 32 patients who underwent transduodenal ampullectomy from 2002 to 2010. The median age of patients was 64 years. Adenomas were found because of abdominal pain in 34 per cent, jaundice in 22 per cent, and incidentally on endoscopic screening in 16 per cent and on computed tomography scan of the abdomen in 9 per cent. All patients had a preoperative diagnosis of premalignant disease; 6 per cent required intraoperative conversion to pancreaticoduodenectomy after frozen section evaluation documented carcinoma. Of ampullectomies, 97 per cent had clear margins. Follow-up was 28 months. Four (13%) patients developed recurrent disease at 4 years, 2 years, 1.5 years, and 4 months; all had clear margins at ampullectomy and underwent subsequent pancreaticoduodenectomy with invasive malignancy in a single patient. After preoperative biopsy documenting premalignant disease, malignancy at ampullectomy is unusual. Recurrence is uncommon but occurs even with clear margins necessitating diligent follow-up; even with diligent follow-up, recurrence can be malignant. PMID- 24480222 TI - Prognostic role and significance of paraneoplastic syndromes in hepatocellular carcinoma. AB - Patients with hepatocellular carcinoma (HCC) may develop paraneoplastic syndromes in the clinical course. These syndromes include hypercholesterolemia, hypoglycemia, hypercalcemia, and erythrocytosis, among others. This study was designed to assess the role of prognostic influence of paraneoplastic syndromes in patients with HCC. In a cohort of 175 patients with HCC patients, we compared the clinical features of patients with HCC with or without paraneoplastic syndromes. In addition, survival rates of patients with individual paraneoplastic syndromes and those without were also evaluated. Moreover, factors independently predicting prognosis among patients with HCC with or without paraneoplastic syndromes were analyzed. Among 175 patients with HCC, 54 patients presented paraneoplastic syndromes, and the prevalence was 30.9 per cent. There was no difference of clinical characteristics between patients with HCC with and without paraneoplastic syndromes on diagnosis. However, the patients with paraneoplastic syndromes had a significantly less survival rate comparing with those without during a 5-year follow-up. Cox regression analysis demonstrated that high Child Pugh grade, large tumor size, portal vein tumor thrombosis, and distant metastasis were all independent unfavorable prognostic factors for survival of patients with HCC. Paraneoplastic syndromes as independent risk factors play a significant role in the progress of HCC and lead to poor prognosis in patients with HCC. PMID- 24480223 TI - Extremity injuries as predictors of emergency care resource needs among blunt trauma patients in Japan. AB - This study aimed to exhaustively examine associations between prehospital variables and emergency care resource needs among blunt trauma patients. The study included blunt trauma patients aged 15 years or older who were admitted to a tertiary care medical center in Osaka, Japan, from January 2005 to December 2009. The primary end point was a composite measure of overall emergency care resource needs. Predictive variables were easily detectable upper and lower extremity injuries. A multivariate logistic regression model was used to identify associations between the predictive variables and the end point; this model included other covariates known to be associated with emergency care resource needs (demographic characteristics, mechanism of injury, and physiological parameters). Of 982 blunt trauma patients, 81 died, and 573 required overall emergency care resources. Upper extremity injury (odds ratio [OR], 2.60) and lower extremity injury (OR, 4.50) were significantly associated with overall emergency care resource needs after controlling for other covariates. The results of this study suggest that easily detectable extremity injuries may be useful predictors of the emergency care resource needs of trauma patients. Further studies are needed to validate the predictive values of these injuries and to determine ways to use information about extremity injuries to improve triage decisions. PMID- 24480224 TI - Morbidity after insertion of totally implantable venous access ports in oncological patients: results of a retrospective clinical study. PMID- 24480225 TI - Ocular trauma at a level I trauma center: the burden of penetrating injuries. PMID- 24480226 TI - Vacuum-assisted management of enteroatmospheric fistula within the open abdomen. PMID- 24480227 TI - Fall from standing induces significant injuries. PMID- 24480228 TI - Similar outcomes at a lower cost: an argument for open appendectomy in simple appendicitis. PMID- 24480229 TI - The impact of internal stenting of pancreatojejunostomy on the pancreatic fistula rate after pancreaticoduodenectomy. PMID- 24480230 TI - Home school dropout: a twenty-year experience of the matriculation of categorical general surgery residents. PMID- 24480231 TI - Potential cerebroprotective role of pentoxifyllin in preventing the detrimental cerebral consequences of intra-abdominal hypertension. PMID- 24480233 TI - Emergency department pericardial drainage for penetrating cardiac wounds is a viable option for stabilization. AB - BACKGROUND: Penetrating cardiac injuries (PCI) causing tamponade causes subendocardial ischemia, arrhythmias, and cardiac arrest. Pericardial drainage is an important principle, but where drainage should be performed is debated. We hypothesize that drainage in the emergency department (ED) does not delay definitive repair. METHODS: Over a 16-year period, patients sustaining PCI were reviewed. RESULTS: Seventy-eight patients with PCI survived to the operating room (OR), with 39 undergoing ED thoracotomy. An additional 39 patients underwent pericardial drainage, 17 (44%) in the ED and 22 in the OR. Comparing the ED with OR pericardial drainage groups, they had a similar ED systolic pressure (99 +/- 25 vs 99 +/- 34), heart rate (103 +/- 16 vs 85 +/- 37), median time to the OR (20 vs 22 min), and mortality (12% vs 23%). CONCLUSIONS: ED pericardial drainage for PCI did not appear to delay operation and had an acceptably low mortality rate. Pericardial drainage is a viable option for stabilization before definitive surgery when surgical intervention is not immediately available in the hemodynamically marginal patient. PMID- 24480234 TI - Perioperative intensive insulin therapy using an artificial endocrine pancreas with closed-loop glycemic control system: the effects of no hypoglycemia. AB - BACKGROUND: We examined whether perioperative intensive insulin therapy (IIT) using an artificial pancreas (AP) with a closed-loop glycemic control system can be used to prevent hypoglycemia in surgical patients. METHODS: Between 2006 and 2012, perioperative glycemic control using an AP was performed in 427 patients undergoing general surgery. A total of 305 patients undergoing IIT using an AP in the target blood glucose range of 80 to 110 mg/dL were enrolled in the study. Data were collected prospectively and were reviewed or analyzed retrospectively. RESULTS: No patients had hypoglycemia. Perioperative mean blood glucose level and achievement rates in target blood glucose range of 80 to 110 mg/dL were 100.5 +/- 11.9 mg/dL and 88.1% +/- 16.0%, respectively. For the 3 primary operative methods, including hepatic, pancreatic, and esophageal resections, there were no significant differences in glycemic control stability between the types of surgery. CONCLUSION: Perioperative IIT using an AP with a closed-loop glycemic control system can be used to prevent hypoglycemia and maintain stable glycemic control with less variability of blood glucose concentration. PMID- 24480235 TI - Delayed admission to intensive care unit for critically surgical patients is associated with increased mortality. AB - BACKGROUND: Shortage of beds in intensive care units (ICUs) is an increasing common phenomenon worldwide. Consequently, many critically ill patients have to be cared for in other hospital areas without specialized staff, such as general wards, emergency department, post anesthesia care unit (PACU). However, boarding critically ill patients in general wards or emergency department has been associated with higher mortality. The purpose of this study was to evaluate if a delay in ICU admission, waiting in PACU and managed by anesthesiologists, affects their ICU outcomes for critically surgical patients. METHODS: A retrospective cohort of adult critically surgical patients admitted to our ICU between January 2010 and June 2012 were analyzed. ICU admission was classified as either immediate or delayed (waiting in PACU). A general estimation equation was used to examine the relationship of PACU waiting hours before ICU admission with ICU outcomes by adjusting for age, patient sex, comorbidities, surgical categories, end time of operation, operation hours, and clinical conditions. RESULTS: A total of 2,279 critically surgical patients were evaluated. Two thousand ninety-four (91.9%) patients were immediately admitted and 185 (8.1%) patients had delayed ICU admission. There was a significant increase in ICU mortality rates with a delay in ICU admission (P < .001). Prolonged waiting hours in PACU (>= 6 hours) was associated with higher ICU mortality (adjusted odds ratio 5.32; 95% confidence interval 1.25 to 22.60, P = .024). However, longer PACU waiting times was not associated with mechanical ventilation days, ICU length of stay, and ICU cost. CONCLUSION: Prolonged waiting hours in PACU because of ICU bed shortage was associated with higher ICU mortality for critically surgical patients. PMID- 24480236 TI - Epidemiological and molecular features of norovirus infections in Italian children affected with acute gastroenteritis. AB - During a 5-year (2007-2011) surveillance period a total of 435 (15.34%) of 2834 stool specimens from children aged <14 years with acute gastroenteritis tested positive for norovirus and 217 strains were characterized upon partial sequence analysis of the polymerase gene as either genogroup (G)I or GII. Of the noroviruses, 99.2% were GII with the GII.P4 genotype being predominant (80%). GII.P4 variants (Yerseke 2006a, Den Haag 2006b, Apeldoorn 2008, New Orleans 2009) emerged sequentially during the study period. Sequence analysis of the capsid gene of 57 noroviruses revealed that 7.8% were recombinant (ORF1/ORF2) viruses including GII.P7_GII.6, GII.P16_GII.3, GII.P16_GII.13, GII.Pe_GII.2, and GII.Pe_GII.4, never identified before in Italy. GII.P1_GII.1, GII.P2_GII.1, GII.P3_GII.3 and GII.P6_GII.6 strains were also detected. Starting in 2011 a novel GII.4 norovirus with 3-4% nucleotide difference in the polymerase and capsid genes from variant GII.4 New Orleans 2009 was monitored in the local population. Since the epidemiology of norovirus changes rapidly, continuous surveillance is necessary to promptly identify the onset of novel types/variants. PMID- 24480237 TI - Non-radical surgery for small early-stage cervical cancer. Is it time? AB - OBJECTIVES: Non-radical surgery has been proposed in women with early-stage cervical cancer to reduce morbidity. Our objective was to evaluate the outcomes of women with early-stage cervical cancer treated with non-radical surgery. METHODS: Between March 1991 and July 2013, 51 women with early-stage cervical cancer underwent simple hysterectomy or cone biopsy. All patients had assessment of pelvic lymph nodes. Patient demographics, stage, perioperative complications, pathology findings and disease-free interval were collected prospectively. RESULTS: Twenty-six women had squamous cell carcinoma (SCC), 22 adenocarcinoma (AC) and 3 adenosquamous (AS) carcinoma. Thirty women were FIGO stage 1A1, 8 women IA2, and 13 women 1B1. Twenty-two (43%) and 29 (57%) women underwent simple hysterectomy and cone biopsy respectively. Median measurable tumor size was 10mm (range 2-11), and median depth of invasion was 2.0mm (range 0.1-12 mm). Lymphovascular space invasion (LVSI) was present in 18 women (35%). Surgical margins were negative in all women. Two women received adjuvant chemoradiation (one had deep stromal invasion with LVSI, and one had two micrometastases to pelvic nodes). Forty-nine women (96%) had their Foley catheter removed on the day of surgery or post-operative day 1. No intraoperative or postoperative complications occurred and the median blood loss was 100ml. Median follow-up was 21 months (range 1-112). None of the 51 women developed a recurrence during follow-up (95% CI: 0-6%). CONCLUSION: Non-radical surgery in appropriately selected early-stage cervical cancer patients results in a low complication rate and excellent oncologic outcomes. This approach seems to be a reasonable option in well-selected patients. PMID- 24480238 TI - A comparative international study on the management of acute appendicitis between a developed country and a middle income country. AB - BACKGROUND: In the past decade there has been an exponential increase in the use of Computerised Tomography (CT) imaging in the assessment of patients with acute appendicitis. The aim of this study was to compare management approaches and clinical outcomes of acute appendicitis in Sri Lanka and the United Kingdom. METHODS: Data was collected prospectively from 400 patients referred to the General Surgical department with a differential diagnosis of acute appendicitis, 200 at University Kelaniya Sri Lanka (SL group), and 200 at University College London Hospital (UK group). RESULTS: The groups were similar with respect to gender, but the SL group was younger. Preoperative work-up included ultrasound more commonly in SL patients, and CT more commonly in UK patients. More patients underwent appendicectomy in the SL group, however a laparoscopic approach was utilised more often in the UK group (50.5% vs. 11.9%). Post-operative complications were similarly represented in both groups, but re-admission occurred with greater frequency in the UK group (16.2% vs. 0%). Histologically confirmed appendicitis was seen in a significantly greater proportion of SL patients (93.1% vs. 79.8%). Multivariate analysis confirmed male gender, and diagnosis and treatment in Sri Lanka to be only factors significantly associated with positive appendicitis. DISCUSSION: Expensive investigations such as CT do not appear to improve the diagnostic accuracy of appendicitis or prevent complications. This study suggests diagnostic and treatment algorithms in the SL hospital are more accurate and efficient in confirming appendicitis than those seen in the UK hospital under investigation. PMID- 24480239 TI - How does subintimal angioplasty compare to transluminal angioplasty for the treatment of femoral occlusive disease? AB - A best evidence topic in surgery was written according to a structured protocol. The question addressed how subintimal angioplasty (SIA) compares to transluminal angioplasty (TA) for the treatment of femoral occlusive disease. One hundred and thirty two papers were found using the reported search; the 5 which represented the best evidence to answer the question are discussed. The evidence on this subject is limited; there are no randomised controlled trials (RCTs) comparing SIA to TA for pathologically equivalent lesions. However SIA remains a safe and effective alternative to surgical bypass grafting when TA cannot be performed. PMID- 24480240 TI - Local anesthetic infusion pump for pain management following open inguinal hernia repair: a meta-analysis. AB - OBJECTIVES: Open inguinal hernia repair is one of the most painful procedures in day surgery. A continuous ambulatory analgesic is thought to reduce postoperative pain when it is applied to the surgical site. The aim of this study is to evaluate the efficacy of local anesthetic infusion pump following open inguinal hernia repair for the reduction of postoperative pain. METHODS: We conducted a systematic review and meta-analysis of randomized controlled trials (RCTs) that have investigated the outcomes of using an infusion pump for delivering a local anesthetic contrasted to a control group for open inguinal hernia repair. Pain was assessed from Day 1 to Day 5 following the surgery. The secondary outcomes included analgesia use and postoperative complications. RESULTS: We reviewed 5 trials that totaled 288 patients. The analgesic effects of bupivacaine (4 trials) and ropivacaine (one trial) were compared with a placebo group. The pooled mean difference in the score measuring the degree of pain diminished significantly at Day 1 to Day 4 in the experimental group. Two studies have reported that the number of analgesics required also decreased in the experimental group. No bupivacaine-related complication was reported. CONCLUSION: Our results revealed that applying a local anesthetic infusion pump following inguinal hernia repairs was more efficacious for reducing postoperative pain than a placebo. However, the findings were based on a small body of evidence in which methodological quality was not high. The potential benefits of applying a local anesthetic infusion pump to hernia repair must still be adequately investigated using further RCTs. PMID- 24480242 TI - Bronchogenic cyst compressing the superior vena cava and the left atrium. PMID- 24480243 TI - Quantification of left atrial volumes using three-dimensional wall motion tracking echocardiographic technology: comparison with cardiac magnetic resonance. AB - BACKGROUND: Left atrium (LA) size assessment is clinically relevant, but the accuracy of two-dimensional echocardiographic (2D-echo) methods is limited. Three dimensional (3D) echocardiography is an excellent alternative but is far from being used in daily clinical practice. Three-dimensional-wall motion tracking (3D WMT) allows us to obtain volumes in a very simple and rapid manner. The aims of this study were to evaluate the accuracy of 3D-WMT technology to assess LA volume using cardiac magnetic resonance (CMR) as a reference method, to evaluate its reproducibility, and to determine its added clinical value to classify the LA enlargement severity. METHODS AND RESULTS: Seventy consecutive patients referred for a CMR study were prospectively enrolled. They underwent LA volume assessment by means of 2D-echo, 3D-WMT, and CMR. Inter-methods agreement was assessed. The mean age was 56 +/- 18 years and 42 patients (60%) were males. Average maximal LA volume obtained by 2D-echo, 3D-WMT, and CMR were 63.33 +/- 26.82, 79.80 +/- 29.0, and 79.80 +/- 28.99 mL, respectively. Univariate linear regression analysis showed a good correlation between 3D-WMT and CMR (r = 0.83; P < 0.001). The agreement analysis showed a similar result (ICC = 0.83; 95% CI = 0.74-0.89; P < 0.001). Furthermore, the LA enlargement degree was better evaluated with 3D-WMT than with 2D-echo. CONCLUSION: This study validates LA volume measurements obtained using the new and fast 3D-WMT technology, compared with CMR. This method is fast, accurate, and reproducible, and it allows a better classification of left LA enlargement severity compared with 2D-echo. PMID- 24480244 TI - Elevated serum estradiol is associated with higher libido in men on testosterone supplementation therapy. PMID- 24480245 TI - Pancreatic cancer genomics. AB - Pancreatic cancer is one of the most lethal malignancies. The overall median survival even with treatment is only 6-9 months, with almost 90% succumbing to the disease within a year of diagnosis. It is characterised by an intense desmoplastic stroma that may contribute to therapeutic resistance, and poses significant challenges for genomic sequencing studies. It is recalcitrant to almost all therapies and consequently remains the fourth leading cause of cancer death in Western societies. Genomic studies are unveiling a vast heterogeneity of mutated genes, and this diversity may explain why conventional clinical trial designs have mostly failed to demonstrate efficacy in unselected patients. Those that are available offer only marginal benefits overall, but are associated with clinically significant responses in as yet undefined subgroups. This chapter describes our current understanding of the genomics of pancreatic cancer and the potential impact of these findings on our approaches to treatment. PMID- 24480246 TI - Evaluation of the SD BIOLINE Dengue Duo rapid test in the course of acute and convalescent dengue infections in a Mexican endemic region. AB - In this study, we evaluated the performance of a rapid test, the SD BIOLINE Dengue Duo (SD BDD) kit, with a panel of serum samples from 310 Mexican patients with diagnosis of dengue infection previously confirmed by reference enzyme linked immunosorbent assay tests. Eighty-seven negative samples from other febrile illnesses were included as controls. The SD BDD showed an overall sensitivity of 90.65% and specificity of 89.66%. No statistically significant differences were found in the sensitivity of the SD BDD kit compared between primary or secondary infections (87.05% versus 93.57%, respectively, P = 0.0761) and dengue fever or dengue hemorrhagic fever cases (90.77% versus 89.74%, respectively, P = 0.7716). However, a higher sensitivity in the acute phase of dengue infection was found compared with the convalescent phase (93.03% versus 81.82%, respectively, P = 0.0089). These results indicate that the SD BDD kit is a useful tool to diagnose dengue infections, both in primary or secondary infections and mainly during the acute phase. PMID- 24480247 TI - Glutathione S-transferase Mu 2-transduced mesenchymal stem cells ameliorated anti glomerular basement membrane antibody-induced glomerulonephritis by inhibiting oxidation and inflammation. AB - INTRODUCTION: Oxidative stress is implicated in tissue inflammation, and plays an important role in the pathogenesis of immune-mediated nephritis. Using the anti glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) mouse model, we found that increased expression of glutathione S-transferase Mu 2 (GSTM2) was related to reduced renal damage caused by anti-GBM antibodies. Furthermore, mesenchymal stem cell (MSC)-based therapy has shed light on the treatment of immune-mediated kidney diseases. The aim of this study was to investigate if MSCs could be utilized as vehicles to deliver the GSTM2 gene product into the kidney and to evaluate its potential therapeutic effect on anti GBM-GN. METHODS: The human GSTM2 gene (hGSTM2) was transduced into mouse bone marrow-derived MSCs via a lentivirus vector to create a stable cell line (hGSTM2 MSC). The cultured hGSTM2-MSCs were treated with 0.5 mM H2O2, and apoptotic cells were measured by terminal dUTP nick-end labeling (TUNEL) assay. The 129/svj mice, which were challenged with anti-GBM antibodies, were injected with 106 hGSTM2 MSCs via the tail vein. Expression of hGSTM2 and inflammatory cytokines in the kidney was assayed by quantitative PCR and western blotting. Renal function of mice was evaluated by monitoring proteinuria and levels of blood urea nitrogen (BUN), and renal pathological changes were analyzed by histochemistry. Immunohistochemical analysis was performed to measure inflammatory cell infiltration and renal cell apoptosis. RESULTS: MSCs transduced with hGSTM2 exhibited similar growth and differentiation properties to MSCs. hGSTM2-MSCs persistently expressed hGSTM2 and resisted H2O2-induced apoptosis. Upon injection into 129/svj mice, hGSTM2-MSCs migrated to the kidney and expressed hGSTM2. The anti-GBM-GN mice treated with hGSTM2-MSCs exhibited reduced proteinuria and BUN (58% and 59% reduction, respectively) and ameliorated renal pathological damage, compared with control mice. Mice injected with hGSTM2-MSCs showed alleviated renal inflammatory cell infiltration and reduced expression of chemokine (C-C motif) ligand 2 (CCL2), interleukin (IL)-1beta and IL-6 (53%, 46% and 52% reduction, respectively), compared with controls. Moreover, hGSTM2-MSCs increased expression of renal superoxide dismutase and catalase, which may associate with detoxifying reactive oxygen species to prevent oxidative renal damage. CONCLUSIONS: Our data suggest that the enhanced protective effect of GSTM2 transduced MSCs against anti-GBM-GN might be associated with inhibition of oxidative stress-induced renal cell apoptosis and inflammation, through over expression of hGSTM2 in mouse kidneys. PMID- 24480248 TI - Mitochondrial translocation of human telomerase reverse transcriptase in cord blood mononuclear cells of newborns with gestational diabetes mellitus mothers. AB - AIMS: To better understand the role of oxidative stress in fetal programming, we assessed the hypothesis that the mitochondrial translocation of human telomerase reverse transcriptase (hTERT) could protect neonatal mitochondrial DNA (mtDNA) from oxidative damage during pregnancies complicated by gestational diabetes mellitus (GDM). METHODS: 26 GDM mothers and 47 controls and their newborns were enrolled. The plasma levels of 8-isoprostaglandin F(2alpha) in maternal and cord blood were measured to evaluate oxidative stress. Western blotting was then used to assess the mitochondrial localization of hTERT in cord blood mononuclear cells (CBMCs). Finally, the relative mtDNA content was analyzed by real-time PCR. RESULTS: GDM mothers and their newborns had significantly higher levels of oxidative stress than controls. hTERT was localized in both the nuclei and mitochondria of CBMCs, and the increased CBMC mitochondrial hTERT levels were significantly correlated with elevated oxidative stress in newborns. The neonatal mtDNA content in the GDM group was comparable to controls, and was positively correlated with mitochondrial hTERT levels in CBMCs, suggesting that mitochondrial hTERT in CBMCs may have a protective effect on neonatal mtDNA in GDM pregnancies. CONCLUSIONS: This study is the first to suggest that the mitochondrial translocation of hTERT in CBMCs under heightened oxidative stress might protect neonatal mtDNA from oxidative damage in GDM pregnancies. This could be an in utero adaptive response of a fetus that is suffering from elevated oxidative stress, and could help our understanding of the roles of oxidative stress in fetal programming. PMID- 24480249 TI - Echocardiographic markers of left ventricular unloading using a centrifugal-flow rotary pump. PMID- 24480250 TI - Clinical analysis of ANCA-associated renal vasculitis patients with chronic dialysis. AB - OBJECTIVE: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) constitute a subgroup of life-threatening diseases which affects the kidney in more than half of the patients at diagnosis. Currently, little has been published focusing on AAV patients with dialysis. We analysed AAV patients with chronic dialysis to provide more detailed information. METHODS: From 1997 to 2011, AAV patients complicated by renal involvement resulting in end-stage renal disease (ESRD) and had undergone haemodialysis (HD) or peritoneal dialysis (PD) for at least 3 months in Shanghai Ruijin hospital were retrospectively analysed in this study. Their data were also compared to those without dialysis at the same time. RESULTS: We enrolled 49 AAV patients with chronic dialysis. 41 required dialysis at initial presentation and rest 8 progressed to ESRD during follow-up. 19 HD patients died and 6 PD patients died during follow-up, and infection was the most common cause among the patients. There was no significant difference regarding survival between HD patients and PD patients (p>0.05). However anaemia and level of triglyceride was more significantly improved in HD patients at the end of observation (p<0.05, p<0.05 respectively). Compared with patients without dialysis dependency, dialysis patients presented higher percentage of hypertension (p<0.01), more severe renal involvement and higher BVAS (p<0.01). For the outcome, survival was significantly higher in non-dialysis patients (p<0.05). CONCLUSIONS: Patients with AAV experienced a high rate of renal failure and dialysis dependence. Our study suggests that haemodialysis and peritoneal dialysis are two comparable dialysis modalities for AAV patients with ESRD. However, AAV patients with dialysis dependency had worse outcome in comparison with those without dialysis. PMID- 24480251 TI - Multimodal study of the hemodynamic response to hypercapnia in anesthetized aged rats. AB - With aging, the brain undergoes changes in metabolism and perfusion, both of which influence the widely used blood-oxygenation-level-dependent (BOLD) MRI signal. To isolate the vascular effects associated with age, this study measured the response to a hypercapnic challenge using different imaging modalities in 19 young (3 months-old) and 13 old (24 months-old) Long-Evans rats. Intrinsic optical imaging was used to measure oxy (HbO), deoxy (HbR) and total (HbT) hemoglobin concentration changes, laser speckle for cerebral blood flow (CBF) changes, and MRI for the BOLD signal. Older rats had smaller HbO (41% smaller), HbT (50%) and CBF (34%) responses, but the temporal dynamics did not exhibit significant age differences. The ratio of CBV to CBF responses was also smaller in older adults, potentially indicating a change in the compliance of vessels. PMID- 24480252 TI - Human isolates of Listeria monocytogenes in Sweden during half a century (1958 2010). AB - Isolates of Listeria monocytogenes (n = 932) isolated in Sweden during 1958-2010 from human patients with invasive listeriosis were characterized by serotyping and pulsed-field gel electrophoresis (PFGE) (AscI). Of the 932 isolates, 183 different PFGE types were identified, of which 83 were each represented by only one isolate. In all, 483 serovar 1/2a isolates were distributed over 114 PFGE types; 90 serovar 1/2b isolates gave 32 PFGE types; 21 serovar 1/2c isolates gave nine PFGE types; three serovar 3b isolates gave one PFGE type; and, 335 serovar 4b isolates gave 31 PFGE types. During the 1980s in Sweden, several serovar 4b cases were associated with the consumption of European raw soft cheese. However, as cheese-production hygiene has improved, the number of 4b cases has decreased. Since 1996, serovar 1/2a has been the dominant L. monocytogenes serovar in human listeriosis in Sweden. Therefore, based on current serovars and PFGE types, an association between human cases of listeriosis and the consumption of vacuum packed gravad and cold-smoked salmon is suggested. PMID- 24480253 TI - Computational study of the elastic properties of Rheum rhabarbarum tissues via surrogate models of tissue geometry. AB - Plant petioles and stems are hierarchical cellular structures, displaying geometrical features defined at multiple length scales. One or more of the intermediate hierarchical levels consists of tissues in which the cellular distribution is quasi-random, a factor that affects the elastic properties of the tissues. The current work focuses on the finite element analysis (FEA) of the constituent tissues of the plant Rheum rhabarbarum (rhubarb). The geometric model is generated via a recently introduced method: the finite edge centroidal Voronoi tessellation (FECVT), which is capable to capture the gradients of cellularity and diversified pattern of cellular materials, as opposed to current approaches in literature. The effective stiffness of the tissues is obtained by using an accurate numerical homogenization technique via detailed finite element analysis of the models of sub-regions of the tissues. As opposed to a large-scale representative volume element (RVE), statistical volume elements (SVE) are considered in this work to model tissue microstructures that are highly random. 2D finite element analyses demonstrate that the distribution of cells in collenchyma and parenchyma tissue make them stiffer in two different directions, while the overall effect of the combined tissues results in approximately equal stiffness in both directions. The rhubarb tissues, on the other hand, are more compliant than periodic and quasi-uniform random cellular materials by a factor of up to 47% and 44%, respectively. The variations of the stiffness shows the stiffening role that cell shape, size, and graded cellular distribution play in the mechanics of the rhubarb tissue. PMID- 24480254 TI - Effect of functionalization on the adsorption capacity of cellulose for the removal of methyl violet. AB - In this research paper a comparative study has been carried out for the removal of methyl violet dye using unfunctionalized and functionalized cellulose. The functionalization was achieved through esterification of cellulose with furan-2,5 dione. The functionalization of the cellulose was evidenced using BET, FT-IR, SEM and TGA. The adsorption isotherm data was fitted using different isotherm models like Langmuir, Freundlich, Temkin, Flory-Huggins and Dubinin-Kaganer-Radushkevich models and found to follow Langmuir and Temkin isotherm models with high value of correlation coefficients. Functionalized cellulose (106.38 mg g(-1)) showed higher dye removal capability than unfunctionalized cellulose (43.668 mg g(-1)). The kinetics of adsorption was investigated using pseudo first order, second order, Elovich, liquid film diffusion and intra-particle diffusion models. The mechanism of adsorption was found to follow pseudo second order rate equation. Thermodynamic studies showed that the adsorption process was endothermic and spontaneous. PMID- 24480255 TI - Effects of hydroxypropyl degree on physiochemical activities of chitosan from squid pens. AB - Chitosan was prepared by alkaline N-deacetylation of beta-chitin and hydroxypropyl derivatives with different degrees of substitution (DS) were synthesized. It was characterized by Fourier transform infrared (FT-IR) and elemental analysis. The DS of hydroxypropyl chitosan (HPCS) calculated by an element analyzer were 0.42, 0.75, 1.20, 1.82 and 2.25. HPCS showed better foam capacity and stability than that of chitosan, and the effectiveness correlated well with the DS of HPCS. The highest bile acid-binding capacity of all five HPCS reached 56.02 mg/g, which was 4.0-fold higher than that of chitosan. The scavenging ability of HPCS against hydroxyl and ABTS radicals improved with increasing concentration. The correlation between the hydroxypropyl content (DS) of HPCS and scavenging ABTS radical ability was positive. The hydroxyl radicals scavenging activity of HPCS correlated well with its increasing concentration, and EC50 values were below 12.5 mg/mL. These results indicated that hydroxypropylation is a possible approach to obtain chitosan derivatives with desirable physiochemical properties. PMID- 24480256 TI - Postoperative mortality is an inadequate quality indicator for lung cancer resection. AB - BACKGROUND: Postoperative mortality is the most commonly reported surgical quality measure. However, such metrics may be incapable of identifying performance outliers. The purpose of this study was to compare different measures of postoperative mortality after lung cancer resection using a large multiinstitutional database. METHODS: Data were extracted for lung cancer resection patients from the linked Surveillance Epidemiology and End Results Medicare Registry (2006 to 2010), which provides detailed and longitudinal information about Medicare beneficiaries with cancer. Four definitions of postoperative mortality were evaluated: in-hospital, 30-day, perioperative, and 90-day. Hierarchical regression models were used to estimate mortality risk at 30 and 90 days, and provider quality was assessed by comparing observed versus expected mortality. RESULTS: We identified 11,787 lung cancer resection patients from 686 hospitals. The median age was 74 years, and 52% of patients were treated with open lobectomy. Although 30-day, perioperative, and in-hospital mortality rates were between 3% and 4%, 90-day mortality was almost double (6.89%). Clinical variables associated with 90-day mortality included sex, preexisting comorbidities, and procedure type. There were no statistically significant differences in 30-day or 90-day mortality rates among providers. CONCLUSIONS: Currently reported measures of in-hospital and 30-day postoperative mortality do not adequately represent a patient's true mortality risk as mortality almost doubles by 90 days. Because of low occurrence rate and variable provider volumes, neither 30-day nor 90-day mortality is a suitable quality indicator for lung resection. PMID- 24480257 TI - Twenty-year outcome of anomalous origin of left coronary artery from pulmonary artery: management of mitral regurgitation. AB - BACKGROUND: This study is a single-center experience with surgical repair of anomalous origin of left coronary artery from pulmonary artery (ALCAPA) with focus on the management of associated mitral regurgitation (MR). METHODS: We performed a retrospective analysis of cases presenting to a quaternary referral center between November 1990 and October 2011. RESULTS: In all, 25 patients (18 female) presented with a diagnosis of ALCAPA at a median age of 5 months (range, 1.5 to 102). Twenty-one patients (84%) had moderate to severe impairment of left ventricular function with median fractional shortening of 14% (range, 2% to 33%), and 19 patients (76%) had moderate to severe MR. Surgery was performed with direct coronary reimplantation in 16 patients (64%) and intrapulmonary tunnel (Takeuchi repair) in 9 (36%). Four patients had mitral valve repair at time of surgery, all for structural anomalies. Functional MR with a structurally normal mitral valve was not repaired. The median duration of postoperative follow-up was 93 months (range, 9 to 240). There were no early or late deaths, and no patient required mechanical support. Four patients (16%) required surgical or catheter reintervention. At last follow-up, 24 of 25 patients were asymptomatic; the left ventricular function was normal in 22 patients. Moderate MR was present in 4 patients. There was significant improvement in left ventricular function and MR (p < 0.01) during follow-up. CONCLUSIONS: Surgical repair of ALCAPA has good long term results with low mortality and reintervention rates. The majority of MR is functional and will improve with reperfusion, but structural mitral valve abnormalities should be repaired at the time of surgery. PMID- 24480258 TI - Metastasis to subsegmental and segmental lymph nodes in patients resected for non small cell lung cancer: prognostic impact. AB - BACKGROUND: We investigated the prognostic significance of segmental and subsegmental (level 13 and 14) lymph nodes metastasis in patients with resected non-small cell lung cancer (NSCLC). METHODS: The pattern of lymph nodal metastasis was analyzed in 124 patients with pN1 NSCLC. Long-term outcomes were compared for 390 pN0, 124 pN1, and 82 pN2 consecutive patients submitted to planned pulmonary resection for NSCLC between 2000 and 2006. The pN1 status was stratified into 3 groups according to the highest level of lymph node involvement: level 10 (hilar); level 11+12 (lobar + interlobar); and level 13+14 (segmental + subsegmental). RESULTS: The 5-year overall survival (OS) rates for pN0, pN1, and pN2 patients were 93%, 66%, and 25%, respectively. The highest level of lymph node involvement was a significant prognostic indicator; the 5 year OS rate for level 13+14, level 11+12, level 10 pN1, and pN2 was 81%, 58%, 48%, and 25%, respectively. Significant differences were recorded in long-term outcome when pN0 and pN1 level 13+14, pN1 level 13+14, and pN1 level 11+12, pN1 level 11+12 and pN1 level 10 were compared (p < 0.05). The median number of examined level 13+14 lymph nodes was 2 (range 0 to 6) and 57% pN1 patients had metastasis at level 13+14 lymph nodes. CONCLUSIONS: The highest level of lymph node metastases may be used to stratify outcome of patients with pN1 disease. Routine examination of level 13+14 lymph nodes is to be recommended to correctly identify patients at risk of relapse and predict long-term prognosis. PMID- 24480259 TI - Defining the cost of care for lobectomy and segmentectomy: a comparison of open, video-assisted thoracoscopic, and robotic approaches. AB - BACKGROUND: Knowledge about the cost of open, video-assisted thoracoscopic (VATS), or robotic lung resection and drivers of cost is crucial as the cost of care comes under scrutiny. This study aims to define the cost of anatomic lung resection and evaluate potential cost-saving measures. METHODS: A retrospective review of patients who had anatomic resection for early stage lung cancer, carcinoid, or metastatic foci between 2008 and 2012 was performed. Direct hospital cost data were collected from 10 categories. Capital depreciation was separated for the robotic and VATS cases. Key costs were varied in a sensitivity analysis. RESULTS: In all, 184 consecutive patients were included: 69 open, 57 robotic, and 58 VATS. Comorbidities and complication rates were similar. Operative time was statistically different among the three modalities, but length of stay was not. There was no statistically significant difference in overall cost between VATS and open cases (Delta = $1,207) or open and robotic cases (Delta = $1,975). Robotic cases cost $3,182 more than VATS (p < 0.001) owing to the cost of robotic-specific supplies and depreciation. The main opportunities to reduce cost in open cases were the intensive care unit, respiratory therapy, and laboratories. Lowering operating time and supply costs were targets for VATS and robotic cases. CONCLUSIONS: VATS is the least expensive surgical approach. Robotic cases must be shorter in operative time or reduce supply costs, or both, to be competitive. Lessening operating time, eradicating unnecessary laboratory work, and minimizing intensive care unit stays will help decrease direct hospital costs. PMID- 24480260 TI - Bicarotid trunk: how much is "not uncommon"? AB - BACKGROUND: Bicarotid trunk is the most common variation of aortic arch branching patterns. Bicarotid trunk can be a decisive factor in the surgical management of congenital heart defects. Our objective was to determine the prevalence of the bicarotid trunk among pediatric patients with congenital heart defects and to identify whether there is an association between bicarotid trunk and aortic coarctation. METHODS: From a total of 4,371 pediatric cardiac catheterizations between the years 1979 and 2010, a group of 2,033 patients were selected. Prevalence of the aortic coarctation in patients with bicarotid trunk and with a normal branching pattern was determined by evaluating the catheterization reports. In addition, associated congenital defects, vascular anomalies, and genetic syndromes were also assessed. RESULTS: Of 2,033 patients in our database, 84.8% of patients had a normal branching pattern of the aortic arch and 15.2% had a bicarotid trunk. The most frequent congenital heart defects in patients with a bicarotid trunk were ventricular septal defects, valvular pulmonary stenosis, and atrial septal defect. The most common associated vascular anomaly was the aberrant right subclavian artery. Most frequent genetic syndromes were trisomy 21, Williams syndrome, and CHARGE syndrome. CONCLUSIONS: The prevalence of bicarotid trunk of 17.6% among patients with aortic coarctation and 15.2% among the entire population studied made it not at all a rare phenomenon. Because bicarotid trunk can be a risk factor for surgery, the anatomy of the aortic arch needs to be clearly depicted and described. If ultrasonography examination cannot exclude bicarotid trunk, enhanced magnetic resonance imaging or aortic arch angiography may be necessary. PMID- 24480261 TI - Early complete repair of pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals. AB - BACKGROUND: Pulmonary atresia with ventricular septal defect and major aortopulmonary collaterals (PA/VSD/MAPCAs) is a complex and diverse form of congenital heart defect. Although most patients with PA/VSD/MAPCAs can wait until they are 3 to 6 months of age to undergo surgical reconstruction, there are three specific criteria that merit an earlier repair. These 3 criteria are (1) unremitting heart failure; (2) a ductus to one lung and MAPCAs to the other; and (3) hemitruncus to one lung and MAPCAs to the other. The purpose of this study was to evaluate our surgical experience with early complete repair of PA/VSD/MAPCAs. METHODS: This was a retrospective review of patients undergoing complete repair of PA/VSD/MAPCAs within the first 60 days of life. Twenty-seven patients were identified in our database (2002 to 2013) who met these criteria. Fifteen had congestive heart failure, 9 had a ductus plus MAPCAs, and 3 had hemitruncus plus MAPCAs. The median age at surgery was 5 weeks. RESULTS: There was no operative mortality in this cohort of 27 patients. Hemodynamics at the conclusion of the complete repair demonstrated an average right ventricular peak systolic pressure of 32 +/- 5 mm Hg and an average right ventricle to aortic pressure ratio of 0.36 +/- 0.06. The median length of hospital stay was 26 days. There have been 2 subsequent mortalities (7%), with a median follow-up duration of 4 years. Eight of the 27 patients have subsequently undergone conduit replacements at our institution. The hemodynamics at the conclusion of the conduit change were statistically unchanged compared with the hemodynamics after complete repair. CONCLUSIONS: The data demonstrate that early complete repair of PA/VSD/MAPCAs can be accomplished with low mortality and excellent postoperative hemodynamics. These early hemodynamic results are maintained at medium-term follow-up. We conclude that early complete repair is an appropriate choice for this highly select subgroup of patients. PMID- 24480262 TI - Is a shorter bar an effective solution to avoid bar dislocation in a Nuss procedure? AB - BACKGROUND: A variety of expedients to minimize bar dislocation in the Nuss procedure has been reported. The aims of this study were to create a mathematical model to define mechanical stresses acting on bars of different lengths in the Nuss procedure, and to apply this model to clinical scenarios. METHODS: Finite element model analyses were used to outline the mechanical stresses and to mathematically define different cases. Data from a group of patients with procedures carried out using standard Nuss criteria (NC group; bars half an inch shorter than the distance between the mid-axillary lines) were compared with data from a second group treated by applying model-based suggestions (MS group; bars approximately 3 inches shorter than the distance between the mid-axillary lines). RESULTS: Mean patient age in the NC group (48 cases) was 16.4 years old (84% males). The mean operating time was 57 minutes, and the mean bar length was 14.19 inches. There were 5 cases (10.4%) of bar dislocation. Mean patient age in the MS group (88 cases) was 16.2 years old (87% males). The mean operating time was 43 minutes and the mean bar length was 11.67 inches. There was only 1 bar dislocation, a reduction from 10.4% (NC) to 1.1% (MS) odds ratio 0.0989 (confidence interval 0.0112 to 0.8727), p = 0.0373. CONCLUSIONS: A shorter Nuss bar reduces tension on the sutures applied at bar extremities. This leads to enhanced bar stability and a reduced risk that the bar will flip. The use of a shorter Nuss bar may reduce the incidence of bar dislocation. PMID- 24480263 TI - Comparative analysis of rectal dose parameters in image-guided high-dose-rate brachytherapy for cervical cancer with and without a rectal retractor. AB - PURPOSE: The objective of this study was to determine if use of a rectal retractor (RR) in high-dose-rate intracavitary brachytherapy for cervical cancer reduces rectal dose parameters. METHODS AND MATERIALS: We reviewed data obtained from patients treated with intracavitary brachytherapy for cervical cancer with and without an RR. Treatment plans for each brachytherapy fraction were separated into two groups; R group with use of an RR and P group with use of vaginal packing. Dose-volume parameters for high-risk clinical target volume (HR-CTV), rectum, sigmoid, small bowel, and vaginal surface were collected for each fraction. Rectal D2cc and International Commission on Radiation Units & Measurements (ICRU) rectal point doses were compared between groups using Student's t tests. Predictors of higher rectal D2cc were determined by univariate and multivariate regression analyses. RESULTS: Four hundred sixty-three brachytherapy fractions from 114 patients were used for analysis, 377 fractions with a RR (R group) and 86 with vaginal packing only (P group). Both groups were similar except for slightly higher mean HR-CTV and mean bladder volume in P group. Both mean ICRU rectal point dose (241.1 vs. 269.9 cGy, p = 0.006) and rectal D2cc (240.6 vs. 283.6 cGy, p < 0.001) were significantly higher in P group. Point A dose, HR-CTV, stage, and use of an RR were significant predictors of rectal D2cc on multivariate analysis. CONCLUSIONS: Our data show that use of an RR leads to lower rectal dose parameters compared with vaginal packing. Further study is needed to determine if this will lead to less long-term toxicity. PMID- 24480264 TI - Infusion of docosahexaenoic acid protects against myocardial infarction. AB - Most of the cardioprotective effects of long-chain omega 3 fatty acids, namely docosahexaenoic (DHA; 22:6n-3) and eicosapentaenoic (EPA; 20:5n-3), are due to their hypotriglyceridemic and anti-inflammatory effects, which lower the risk for cardiovascular disease and myocardial infarction. Little is known on the direct preventive activities of DHA and EPA on heart function. In isolated hearts, we studied (1) whether infused DHA is able to protect the heart from ischemia/reperfusion damage and (2) the role played by Notch-mediated signal transduction pathways in myocardial infarction. Perfusion with DHA before and before/after induction of ischemia reperfusion significantly diminished cardiac damage and afforded antioxidant protection. Mechanistically, infusion of DHA before and before/after the induction of ischemia differentially modulated the expression of Notch2 and 3 target genes. In particular, DHA increased the expression of Hey1 when infused pre- and pre/post-ischemia; Jagged 1 and the Notch2 receptors increased with DHA pre-ischemia, but not pre/post; Notch2 and 3 receptors as well as Delta increased following DHA administration pre- and (especially) pre/post-ischemia. In conclusion, while the precise nature of the Notch-mediated protection from ischemia/reperfusion afforded by DHA is as yet to be fully elucidated, our data add to the growing body of literature that indicates how systemic administration of DHA provides cardiovascular protection. PMID- 24480265 TI - Exploring the impact of infection-induced immunity on the transmission of Schistosoma japonicum in hilly and mountainous environments in China. AB - Schistosomiasis has long been a threat to villagers in hilly and mountainous areas of southwestern China where the intermediate snail host is abundant. In recent years our group has focused on the development and parameterization of a community-level mathematical model of S. japonicum transmission that accounts for the role of environmental determinants of transmission intensity in Sichuan Province. To date the model has not incorporated acquired immunity. A review of previous epidemiologic data from our study area in Sichuan suggested modeling of acquired immunity as a function of history of infection. To explore the potential impacts on the dynamics of transmission, a mathematical representation of acquired immunity was incorporated, and parameterized based on this epidemiological evidence. It is shown through simulation that the effect of immunity is to reduce the rate of worm development and thereby lower the endemic level significantly. The effect was more striking at increasing levels of a village'tm)s basic reproductive number. Further, residual immunity modestly alters the threshold of external parasite input necessary to trigger re-emergence of transmission and its subsequent rate of development. Despite limitations in our quantitative knowledge of the immunity function, these findings, along with the uncertainties in transmission dynamics at low infection levels, underscore the need for improved diagnostic methods for disease control, especially in potentially re-emergent settings. PMID- 24480267 TI - Reactor production and electrochemical purification of (169)Er: a potential step forward for its utilization in in vivo therapeutic applications. AB - INTRODUCTION: The aim of the present study was to develop and demonstrate a viable method for the reactor production of (169)Er with acceptable specific activity using moderate flux reactor and its purification from (169)Yb following electrochemical pathway based on mercury-pool cathode to avail (169)Er in radionuclidically pure form essential for its therapeutic use. METHODS: Erbium 169 was produced in reactor by neutron bombardment of isotopically enriched (98.2% in (168)Er) erbium target at a thermal neutron flux of ~8*10(13) n.cm( 2).s(-1) for 21 d. A thorough optimization of irradiation parameters including neutron flux, irradiation time and target cooling time was carried out. The influence of different experimental parameters for the quantitative removal (169)Yb from (169)Er was investigated, optimized and based on the results; a two cycle electrochemical separation procedure was adopted. The suitablility of purified (169)Er for application in radiation synovectomy and bone pain palliation was ascertained by carrying out radiolabeling studies with hydroxypaptite (HA) particles and 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraaminomethylene phosphonic acid (DOTMP), respectively. RESULTS: Thermal neutron irradiation of 10mg of isotopically enriched (98.2% in (168)Er) erbium target at a flux of ~8*10(13) n.cm(-2).s(-1) for 21 d followed by a two-step electrochemical separation of (169)Yb impurity yielded ~3.7GBq (100mCi) of (169)Er with a specific activity of ~370MBq/mg (10mCi/mg) and radionuclidic purity of >99.99%. The reliability of this approach was amply demonstrated by performing several production batches, where the performance of each batch remained consistent. The utility of the purified (169)Er was demonstrated in the radiolabeling studies with HA particles and DOTMP, wherein both the radiolabeled products were obtained with high radiolabeling yield (>99%). CONCLUSIONS: A viable strategy for the batch production and purification of (169)Er, suitable for therapeutic applications, has been developed and demonstrated. PMID- 24480266 TI - A heterodimeric [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] alphavbeta3/GRPr-targeting antagonist radiotracer for PET imaging of prostate tumors. AB - INTRODUCTION: In the present study, we describe a (64)Cu-radiolabeled heterodimeric peptide conjugate for dual alphavbeta3/GRPr (alphavbeta3 integrin/gastrin releasing peptide receptor) targeting of the form [RGD-Glu [(64)Cu-NO2A]-6-Ahx-RM2] (RGD: the amino acid sequence [Arg-Gly-Asp], a nonregulatory peptide used for alphavbeta3 integrin receptor targeting; Glu: glutamic acid; NO2A: 1,4,7-triazacyclononane-1,4-diacetic acid; 6-Ahx: 6-amino hexanoic acid; and RM2: (D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2), an antagonist analogue of bombesin (BBN) peptide used for GRPr targeting). METHODS: RGD-Glu-6Ahx-RM2] was conjugated to a NOTA (1,4,7-triazacyclononane-1,4,7 triacetic acid) complexing agent to produce [RGD-Glu-[NO2A]-6-Ahx-RM2], which was purified by reversed-phase high-performance liquid chromatography (RP-HPLC) and characterized by electrospray ionization-mass spectrometry (ESI-MS). Radiolabeling of the conjugate with (64)Cu produced [RGD-Glu-[(64)Cu-NO2A]-6-Ahx RM2 in high radiochemical yield (>=95%). In vivo behavior of the radiolabeled peptide conjugate was investigated in normal CF-1 mice and in the PC-3 human prostate cancer experimental model. RESULTS: A competitive displacement receptor binding assay in human prostate PC-3 cells using (125)I-[Tyr(4)]BBN as the radioligand showed high binding affinity of [RGD-Glu-[(nat)Cu-NO2A]-6-Ahx-RM2] conjugate for the GRPr (3.09+/-0.34 nM). A similar assay in human, glioblastoma U87-MG cells using (125)I-Echistatin as the radioligand indicated a moderate receptor-binding affinity for the alphavbeta3 integrin (518+/-37.5 nM). In vivo studies of [RGD-Glu-[(64)Cu-NO2A]-6-Ahx-RM2] showed high accumulation (4.86+/ 1.01 %ID/g, 1h post-intravenous injection (p.i.)) and prolonged retention (4.26+/ 1.23 %ID/g, 24h p.i.) of tracer in PC-3 tumor-bearing mice. Micro-positron emission tomography (microPET) molecular imaging studies produced high-quality, high contrast images in PC-3 tumor-bearing mice at 4h p.i. CONCLUSIONS: The favorable pharmacokinetics and enhanced tumor uptake of (64)Cu-NOTA-RGD-Glu-6Ahx RM2 warrant further investigations for dual integrin and GRPr-positive tumor imaging and possible radiotherapy. PMID- 24480268 TI - Evaluation of a novel series of fluorine-18-labeled imidazobenzodiazepines as potential new positron emission tomography radioligands for the GABAA receptor. AB - INTRODUCTION: [(11)C]Flumazenil has been used to study the GABAA receptor in many preclinical and clinical studies, but the short half-life of carbon-11 means that this molecule is restricted to use by investigators with access to on-site cyclotron and radiosynthesis facilities. The radiosynthesis of [(18)F]flumazenil has been evaluated by several groups, but the radiochemical yield can be low and inconsistent. We previously reported a series of fluorine-18-labeled imidazobenzodiazepine-based ligands for the GABAA receptor, which had significantly improved radiosynthesis yields. Here we report the in vivo evaluation and comparison of the distribution, metabolism and specificity of the novel ligands in comparison with [(18)F]flumazenil. METHODS: In vivo biodistribution studies, at time points up to 90min post-injection, were performed in naive rats to compare the performance of the novel compounds with particular attention paid to regional brain uptake and clearance. In vivo metabolism studies were carried out to determine the percentage of parent compound remaining in the plasma and brain at selected time points. Blocking studies were carried out, using pre-treatment of the test animals with either bretazenil or unlabeled fluorine-19 test compound, to determine the levels of specific and non-specific binding in selected brain regions. RESULTS: Two of the 12 new compounds were rejected due to poor biodistribution showing significant bone uptake. Some of the compounds showed insufficient whole brain uptake or limited evidence of differential binding to GABAA-rich brain regions to warrant further investigation. Four of the compounds were selected for in vivo metabolism and blocking studies. Overall, the studies indicated that two compounds 3 and 5 showed comparable or improved performance compared with [(18)F]flumazenil, with respect to distribution, metabolic profile and specific binding. CONCLUSIONS: These studies have demonstrated that compounds based on [(18)F]flumazenil, but with alterations to allow improved radiosynthesis, can be prepared which have ideal properties and warrant further evaluation as PET agents for the GABAA receptor. In particular, compounds 3 and 5 show very promising profiles with specific binding and in vivo stability comparable to flumazenil. PMID- 24480269 TI - [(18)F]-(fluoromethoxy)ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propan-2-ol ([(18)F FPTC) a novel PET-ligand for cerebral beta-adrenoceptors. AB - Cerebral beta-adrenergic receptors (beta-ARs) play important roles in normal brain and changes of beta-AR expression are associated with several neuropsychiatric illnesses. Given the high density of beta-AR in several brain regions, quantification of beta-AR levels using PET is feasible. However, there is a lack of radiotracers with suitable biological properties and meeting safety requirements for use in humans. We developed a PET tracer for beta-AR by (18)F fluorination of 1-((9H-carbazol-4-yl)oxy)-3-4(4-((2-(2-(fluoromethoxy) ethoxy)methyl)-1H-1,2,3-triazol-1-yl)propan-2-ol ((18)F-FPTC). METHODS: [(18)F] FPTC was synthesized by Cu(I)-catalyzed alkyne-azide cycloaddition. First, (18)F PEGylated alkyne was prepared by (18)F-fluorination of the corresponding tosylate. Next (18)F-PEGylated alkyne was reacted with an azidoalcohol derivative of 4-hydroxycarbazol in the presence of the phosphoramidite Monophos as a ligand and Cu(I) as a catalyst. After purification with radio-HPLC, the binding properties of [(18)F FPTC were tested in beta-AR-expressing C6-glioma cells in vitro and in Wistar rats in vivo using microPET. RESULTS: The radiochemical yield of (18)F-PEGylated alkyne was 74%-89%. The click reaction to prepare [(18)F]FPTC proceeded in 10min with a conversion efficiency of 96%. The total synthesis time was 55min from the end of bombardment. Specific activities were >120GBq/MUmol. Propranolol strongly and dose-dependently inhibited the binding of both [(125)I] ICYP and [(18)F]FPTC to C6 glioma cells, with IC50 values in the 50-60 nM range. However, although both FPTC and propranolol inhibited cellular [(125)I]ICYP binding, FPTC decreased [(125)I]ICYP uptake by only 25%, whereas propranolol reduced it by 83%. [(18)F]FPTC has the appropriate lipophilicity to penetrate the blood brain barrier (logP +2.48). The brain uptake reached a maximum within 2min after injection of 20-25MBq [(18)F]FPTC. SUV values ranged from 0.4 to 0.6 and were not reduced by propranolol. Cerebral distribution volume of the tracer (calculated from a Logan plot) was increased rather than decreased after propranolol treatment. CONCLUSION: 'Click chemistry' was successfully applied to the synthesis of [(18)F]FPTC resulting in high radiochemical yields. [(18)F]FPTC showed specific binding in vitro, but not in vivo. Based on the logP value and its ability to block [(125)I]ICYP binding to C6 cells, FPTC may be a lead to suitable cerebral beta-AR ligands. PMID- 24480270 TI - Spectroscopy of scattered light for the characterization of micro and nanoscale objects in biology and medicine. AB - The biomedical uses for the spectroscopy of scattered light by micro and nanoscale objects can broadly be classified into two areas. The first, often called light scattering spectroscopy (LSS), deals with light scattered by dielectric particles, such as cellular and sub-cellular organelles, and is employed to measure their size or other physical characteristics. Examples include the use of LSS to measure the size distributions of nuclei or mitochondria. The native contrast that is achieved with LSS can serve as a non invasive diagnostic and scientific tool. The other area for the use of the spectroscopy of scattered light in biology and medicine involves using conducting metal nanoparticles to obtain either contrast or electric field enhancement through the effect of the surface plasmon resonance (SPR). Gold and silver metal nanoparticles are non-toxic, they do not photobleach, are relatively inexpensive, are wavelength-tunable, and can be labeled with antibodies. This makes them very promising candidates for spectrally encoded molecular imaging. Metal nanoparticles can also serve as electric field enhancers of Raman signals. Surface enhanced Raman spectroscopy (SERS) is a powerful method for detecting and identifying molecules down to single molecule concentrations. In this review, we will concentrate on the common physical principles, which allow one to understand these apparently different areas using similar physical and mathematical approaches. We will also describe the major advancements in each of these areas, as well as some of the exciting recent developments. PMID- 24480272 TI - Enhancement of Raman scattering for silver nanoparticles located on electrolessly roughened silicon. AB - To study the effect of roughness of a supporting substrate to Raman enhancement, silver nanoparticles (AgNPs) were prepared on Si with different degrees of roughness. To roughen the surface of silicon, electroless displacement was used first to grow AgNPs on smooth Si. By chemically removing the resulting AgNPs, an electrolessly roughened Si surface can be exposed. A second electroless displacement then was performed to grow new AgNPs on the roughened Si crystal to form surface-enhanced Raman scattering substrates. Another approach, called the protecting method, also was proposed and demonstrated to structure AgNPs on surface-roughened Si. In this second method, electroless displacement also was used to grow AgNPs on the Si crystal. The resulting AgNPs then were protected by thio compounds to control removal of the outer layer of AgNPs, thereby exposing the underlying AgNPs located directly on the electroless roughened Si surface. Results indicate that the structure of AgNPs on roughened Si surfaces provides approximately two orders of magnitude higher enhancement than AgNPs on non roughened Si, and the substrates prepared in this work are highly sensitive, with enhancement factors reaching 10(8). PMID- 24480271 TI - Infrared (IR) spectral markers of bronchial epithelia in victims of fatal burns. AB - Changes in the infrared spectra of bronchial epithelia in victims of fatal burns were investigated. The mechanism of spectral changes on the basis of cellular morphological changes was considered. The ability of spectral parameters to diagnose fatal burns was assessed. Ten cases of fatal burns and 20 control cases were selected. Their lung tissues were removed, and sections were cut and mounted on glass and barium fluoride slides. Spectra of polarized bronchial epithelia were obtained by microscopy based on their morphological changes. In the spectra, 16 major absorbance bands were evaluated to determine their ability to act as positive markers for exposure to fire. Compared with the control group, the bronchial epithelia of the fatal burn victims showed three spectral results. (1) The absorbance of 16 major bands from the spectra of polarized bronchial epithelia in fatal burn victims significantly increased. (2) For the same cell number, the absorbance at 2850, 2920, 2959, and 3084 cm(-1) decreased. (3) The degree of increased or decreased absorbance of bands is related to the degree of polarization. These spectral results suggest that there is a vital reaction induced by the inhalation of hot fumes that includes an increase in the number of bronchial epithelia and a polarization effect. Overall, Fourier transform infrared (FT-IR) microspectroscopy was shown to be a convenient and reliable method to provide objective spectral markers to assist the diagnosis of fatal burns by simultaneously monitoring several specific parameters, although these observations have yet to be applied at forensic scenes. PMID- 24480274 TI - A two-dimensionally coincident second difference cosmic ray spike removal method for the fully automated processing of Raman spectra. AB - Charge-coupled device detectors are vulnerable to cosmic rays that can contaminate Raman spectra with positive going spikes. Because spikes can adversely affect spectral processing and data analyses, they must be removed. Although both hardware-based and software-based spike removal methods exist, they typically require parameter and threshold specification dependent on well considered user input. Here, we present a fully automated spike removal algorithm that proceeds without requiring user input. It is minimally dependent on sample attributes, and those that are required (e.g., standard deviation of spectral noise) can be determined with other fully automated procedures. At the core of the method is the identification and location of spikes with coincident second derivatives along both the spectral and spatiotemporal dimensions of two dimensional datasets. The method can be applied to spectra that are relatively inhomogeneous because it provides fairly effective and selective targeting of spikes resulting in minimal distortion of spectra. Relatively effective spike removal obtained with full automation could provide substantial benefits to users where large numbers of spectra must be processed. PMID- 24480273 TI - In situ measurement technique for simultaneous detection of K, KCl, and KOH vapors released during combustion of solid biomass fuel in a single particle reactor. AB - A quantitative and simultaneous measurement of K, KCl, and KOH vapors from a burning fuel sample combusted in a single particle reactor was performed using collinear photofragmentation and atomic absorption spectroscopy (CPFAAS) with a time resolution of 0.2 s. The previously presented CPFAAS technique was extended in this work to cover two consecutive fragmentation pulses for the photofragmentation of KCl and KOH. The spectral overlapping of the fragmentation spectra of KCl and KOH is discussed, and a linear equation system for the correction of the spectral interference is introduced. The detection limits for KCl, KOH, and K with the presented measurement arrangement and with 1 cm sample length were 0.5, 0.1, and 0.001 parts per million, respectively. The experimental setup was applied to analyze K, KCl, and KOH release from 10 mg spruce bark samples combusted at the temperatures of 850, 950, and 1050 degrees C with 10% of O2. The combustion experiments provided data on the form of K vapors and their release during different combustion phases and at different temperatures. The measured release histories agreed with earlier studies of K release. The simultaneous direct measurement of atomic K, KCl, and KOH will help in the impact of both the form of K in the biomass and fuel variables, such as particle size, on the release of K from biomass fuels. PMID- 24480275 TI - Equivalent width evaluation methods for Doppler, Lorentz, and Voigt profiles. AB - An accurate technique has been developed to calculate the equivalent width of absorption lines. The calculations have been carried out for the pure Doppler and pure Lorentz limiting forms of the equivalent width. A novel expression for the equivalent width for Lorentz profile is given from direct integration of the line profile. The more general case of a Voigt profile leads to an analytical formula that permits a rapid estimate of the equivalent width for a wide range of maximum optical depths. The reliability of the approach is verified using a numerical application calculating the equivalent width for nickel resonance lines at 232.0 and 352.3 nm from atomic absorption (AA) measurements. The dependence of equivalent width on the number density of absorbing atoms is also provided. The results obtained for the equivalent width for the Voigt profile were compared with the data in the available literature obtained by different approaches. PMID- 24480276 TI - Laser-induced breakdown spectroscopy (LIBS) analysis of calcium ions dissolved in water using filter paper substrates: an ideal internal standard for precision improvement. AB - We report an approach for selecting an internal standard to improve the precision of laser-induced breakdown spectroscopy (LIBS) analysis for determining calcium (Ca) concentration in water. The dissolved Ca(2+) ions were pre-concentrated on filter paper by evaporating water. The filter paper was dried and analyzed using LIBS. By adding strontium chloride to sample solutions and using a Sr II line at 407.771 nm for the intensity normalization of Ca II lines at 393.366 or 396.847 nm, the analysis precision could be significantly improved. The Ca II and Sr II line intensities were mapped across the filter paper, and they showed a strong positive shot-to-shot correlation with the same spatial distribution on the filter paper surface. We applied this analysis approach for the measurement of Ca(2+) in tap, bottled, and ground water samples. The Ca(2+) concentrations determined using LIBS are in good agreement with those obtained from flame atomic absorption spectrometry. Finally, we suggest a homologous relation of the strongest emission lines of period 4 and 5 elements in groups IA and IIA based on their similar electronic structures. Our results indicate that the LIBS can be effectively applied for liquid analysis at the sub-parts per million level with high precision using a simple drying of liquid solutions on filter paper and the use of the correct internal standard elements with the similar valence electronic structure with respect to the analytes of interest. PMID- 24480277 TI - Effect of sodium chloride concentration on elemental analysis of brines by laser induced breakdown spectroscopy (LIBS). AB - Leakage of injected carbon dioxide (CO2) or resident fluids, such as brine, is a major concern associated with the injection of large volumes of CO2 into deep saline formations. Migration of brine could contaminate drinking water resources by increasing their salinity or endanger vegetation and animal life as well as human health. The main objective of this study was to investigate the effect of sodium chloride (NaCl) concentration on the detection of calcium and potassium in brine samples using laser-induced breakdown spectroscopy (LIBS). The ultimate goals were to determine the suitability of the LIBS technique for in situ measurements of metal ion concentrations in NaCl-rich solution and to develop a chemical sensor that can provide the early detection of brine intrusion into formations used for domestic or agricultural water production. Several brine samples of NaCl-CaCl2 and NaCl-KCl were prepared at NaCl concentrations between 0.0 and 3.0 M. The effect of NaCl concentration on the signal-to-background ratio (SBR) and signal-to-noise ratio (SNR) for calcium (422.67 nm) and potassium (769.49 nm) emission lines was evaluated. Results show that, for a delay time of 300 ns and a gate width of 3 MUs, the presence of and changes in NaCl concentration significantly affect the SBR and SNR for both emission lines. An increase in NaCl concentration from 0.0 to 3.0 M produced an increase in the SNR, whereas the SBR dropped continuously. The detection limits obtained for both elements were in the milligrams per liter range, suggesting that a NaCl-rich solution does not severely limit the ability of LIBS to detect trace amount of metal ions. PMID- 24480278 TI - Femtosecond and nanosecond dual-laser optical emission spectroscopy of gas mixtures. AB - A method employing an integrated femtosecond (fs) and nanosecond (ns) dual-laser system was developed to generate plasma with desired radical species from gas mixtures via a fs laser pulse and then to excite selected radical species to higher electronic states using a wavelength-tunable ns laser pulse. An optical spectrometer was used to measure the emission spectra and identify the transition from the excited electronic state to the ground state. The proposed technique has been demonstrated for an N2-CO2 mixture with various time delays between the two fs and ns pulses. The results have indicated that the population of selected radical species at the excited electronic state can be increased using the subsequent ns laser pulse, which also enhances the intensity of emission spectra allowing better identifications of the radical species. This technique holds a promise of detection and identification of signature plasma species, particularly for trace elements and long-distance standoff detections. PMID- 24480279 TI - Mid-infrared, long wave infrared (4-12 MUm) molecular emission signatures from pharmaceuticals using laser-induced breakdown spectroscopy (LIBS). AB - In an effort to augment the atomic emission spectra of conventional laser-induced breakdown spectroscopy (LIBS) and to provide an increase in selectivity, mid-wave to long-wave infrared (IR), LIBS studies were performed on several organic pharmaceuticals. Laser-induced breakdown spectroscopy signature molecular emissions of target organic compounds are observed for the first time in the IR fingerprint spectral region between 4-12 MUm. The IR emission spectra of select organic pharmaceuticals closely correlate with their respective standard Fourier transform infrared spectra. Intact and/or fragment sample molecular species evidently survive the LIBS event. The combination of atomic emission signatures derived from conventional ultraviolet-visible-near-infrared LIBS with fingerprints of intact molecular entities determined from IR LIBS promises to be a powerful tool for chemical detection. PMID- 24480280 TI - Spectroscopic study of proflavine adsorption on the carbon nanotube surface. AB - Despite the fact that non-covalent interactions between various aromatic compounds and carbon nanotubes are being extensively investigated now, there is still a lack of understanding about the nature of such interactions. The present paper sheds light on one of the possible mechanisms of interaction between the typical aromatic dye proflavine and the carbon nanotube surface, namely, pi stacking between aromatic rings of these compounds. To investigate such a complexation, a qualitative analysis was performed by means of ultraviolet visible, infrared, and nuclear magnetic resonance spectroscopy. The data obtained suggest that pi-stacking brings the major contribution to the stabilization of the complex between proflavine and the carbon nanotube. PMID- 24480281 TI - In situ pulse diffuse reflection infrared Fourier transform spectroscopy (DRIFTS) mass spectrometry study of the water-gas shift reaction on nickel(II) oxide zinc(II) oxide catalysts. AB - The water-gas shift (WGS) reaction has been studied by pulsing carbon monoxide (CO) into a steady-state water (H2O)-Ar flow over nickel(II) oxide-zinc oxide (NiO-ZnO) catalysts using in situ diffuse reflection infrared Fourier transform spectroscopy (DRIFTS) coupled with a mass spectrometer method using the pulse technique (in situ pulse DRIFTS-MS) for different flow rates (gas hourly space velocity [GHSV] of 24,000-72,000 h(-1)) and reaction temperatures (250-350 degrees C). The results obtained from the in situ pulse DRIFTS-MS revealed that there are two types of water adsorption bands on the surface of the catalyst: (i) molecular adsorption (infrared [IR] bands in the 2500-3600 cm(-1) range and at 1640 cm(-1)), and (ii) dissociative adsorption at 3700 cm(-1), where carboxyl bands are formed at 1461 and 1368 cm(-1) and the gas-phase CO is adsorbed at 2187 and 2111 cm(-1) on the surface of the catalyst. After using a GHSV = 24,000 h(-1) H2O/Ar flow, we probed the existence of two active intermediates via the formation of two hydrogen production peaks. The products of hydrogen gas (H2) and carbon dioxide (CO2) had two pathways: the redox process and the associative process via the intermediate of the carboxyl group. In situ pulse DRIFTS-MS proves to be an effective approach for studying the nature of adsorbed species on the catalyst surface and the nature of the reaction product. PMID- 24480282 TI - A novel near-infrared spectroscopy and chemometrics method for rapid analysis of several chemical components and antioxidant activity of mint (Mentha haplocalyx Briq.) samples. AB - A novel near-infrared spectroscopy (NIRS) method has been researched and developed for the simultaneous analyses of the chemical components and associated properties of mint (Mentha haplocalyx Briq.) tea samples. The common analytes were: total polysaccharide content, total flavonoid content, total phenolic content, and total antioxidant activity. To resolve the NIRS data matrix for such analyses, least squares support vector machines was found to be the best chemometrics method for prediction, although it was closely followed by the radial basis function/partial least squares model. Interestingly, the commonly used partial least squares was unsatisfactory in this case. Additionally, principal component analysis and hierarchical cluster analysis were able to distinguish the mint samples according to their four geographical provinces of origin, and this was further facilitated with the use of the chemometrics classification methods-K-nearest neighbors, linear discriminant analysis, and partial least squares discriminant analysis. In general, given the potential savings with sampling and analysis time as well as with the costs of special analytical reagents required for the standard individual methods, NIRS offered a very attractive alternative for the simultaneous analysis of mint samples. PMID- 24480283 TI - A novel approach for subsurface through-skin analysis of salmon using spatially offset Raman spectroscopy (SORS). AB - In the present study, the possibility of employing spatially offset Raman spectroscopy (SORS) in the qualitative and quantitative characterization of quality parameters of salmon through the skin has been explored. A laboratory based SORS setup comprising an 830 nm laser was employed, and intact samples and model samples made of salmon tissue constituents were used to investigate the penetration of Raman signals through the dark and light part of salmon skin. Intact salmon samples with both dark and light skin were measured at different spatial offsets. When using spatial offsets in the range of 5-6 mm, the results clearly show that information regarding fatty acid composition and carotenoid content could be obtained from both dark and light parts of the skin. Similar information could not be obtained using conventional backscattering Raman spectroscopy. Model samples of ground salmon spiked with either solutions of carotenoids or a range of vegetable oils were also measured, and at a spatial offset of 5 mm, a clear relationship between Raman carotenoid band intensities and carotenoid concentrations in the model samples was revealed. In addition, high correlations for the estimation of iodine values (i.e., fatty acid unsaturation) could be obtained for SORS measurements through light and dark parts of the salmon skin. A crude estimate suggested that information from around 5 mm beneath the surface area of the salmon skin could be obtained. The choice of a laser line in the near-infrared region is a major prerequisite for successful through-skin analysis of salmon. This feasibility study could pave the way for future Raman analysis of intact salmon. PMID- 24480284 TI - Bias tradeoffs in the creation and analysis of protein-protein interaction networks. AB - Networks constructed from aggregated protein-protein interaction data are commonplace in biology. But the studies these data are derived from were conducted with their own hypotheses and foci. Focusing on data from budding yeast present in BioGRID, we determine that many of the downstream signals present in network data are significantly impacted by biases in the original data. We determine the degree to which selection bias in favor of biologically interesting bait proteins goes down with study size, while we also find that promiscuity in prey contributes more substantially in larger studies. We analyze interaction studies over time with respect to data in the Gene Ontology and find that reproducibly observed interactions are less likely to favor multifunctional proteins. We find that strong alignment between co-expression and protein-protein interaction data occurs only for extreme co-expression values, and use this data to suggest candidates for targets likely to reveal novel biology in follow-up studies. BIOLOGICAL SIGNIFICANCE: Protein-protein interaction data finds particularly heavy use in the interpretation of disease-causal variants. In principle, network data allows researchers to find novel commonalities among candidate genes. In this study, we detail several of the most salient biases contributing to aggregated protein-protein interaction databases. We find strong evidence for the role of selection and laboratory biases. Many of these effects contribute to the commonalities researchers find for disease genes. In order for characterization of disease genes and their interactions to not simply be an artifact of researcher preference, it is imperative to identify data biases explicitly. Based on this, we also suggest ways to move forward in producing candidates less influenced by prior knowledge. This article is part of a Special Issue entitled: Can Proteomics Fill the Gap Between Genomics and Phenotypes? PMID- 24480285 TI - Proteomic analysis of osteoarthritic chondrocyte reveals the hyaluronic acid regulated proteins involved in chondroprotective effect under oxidative stress. AB - Osteoarthritis (OA), the most common type of arthritis, is a degenerative joint disease. Oxidative stress is well known to play important roles in cartilage degradation and pathogenesis of OA. The intra-articular injection of hyaluronic acid (IAHA) is accepted as an effective clinical therapy for OA, but we do not yet fully understand the mechanisms underlying the effects of HA on OA chondrocytes under oxidative stress. Here, we show for the first time that IAHA significantly reduces the synovial fluid levels of hydrogen peroxide (H2O2) and superoxide (O2(-)) in patients with knee OA. We also demonstrate that HA suppresses H2O2-induced cell death in human OA chondrocytes. Proteomic approaches (2-DE combined with mass spectrometry) allowed us to identify 13 protein spots corresponding to 12 non-redundant proteins as HA-regulated proteins in OA chondrocytes under oxidative stress. The expression levels of three putative HA regulated proteins (TALDO, ANXA1 and EF2) in control, H2O2-, HA- and HA/H2O2 treated OA chondrocytes were verified by Western blotting and the results indeed support the notion that HA acts in anti-oxidation, anti-apoptosis, and the promotion of cell survival. Our results collectively demonstrate the utility of proteomic approaches and provide new insights into the chondroprotective effects of HA on OA. BIOLOGICAL SIGNIFICANCE: In the present study, we show for the first time that IAHA reduces the levels of H2O2 and O2(-) in synovial fluids from OA patients. We used primary cultured human OA chondrocytes as a model, treated cells with H2O2 to partly mimic their physiological conditions under oxidative stress, and examined the protection effects of HA. The proteomic approach allowed us to identify candidate proteins regulated by H2O2 and/or HA in OA chondrocytes. We found that proteins functioning in stress responses, apoptosis and protein synthesis were consistently regulated by HA in chondrocytes under oxidative stress. These novel results contribute to our understanding of the molecular mechanisms underlying HA-mediated chondroprotection. PMID- 24480286 TI - [Therapy with intravenous gammaglobulins in systemic inflammatory autoimmune diseases: new indications?]. PMID- 24480287 TI - [Lanthanum carbonate abdominal foreign bodies]. PMID- 24480288 TI - [Prevention of hepatic encephalopathy]. AB - Hepatic encephalopathy (HE) is a frequent complication of cirrhosis which, in addition to producing a great social impact, deteriorates the quality of life of patients and is considered a sign of advanced liver disease and therefore a clinical indication for liver transplant evaluation. Patients who have had episodes of HE have a high risk of recurrence. Thus, after the HE episode resolves, it is recommended: control and prevention of precipitating factors (gastrointestinal bleeding, spontaneous bacterial peritonitis, use of diuretics with caution, avoid nervous system depressant medications), continued administration of non-absorbable disaccharides such as lactulose or lactitol, few or non-absorbable antibiotics such as rifaximin and assess the need for a liver transplant as the presence of a HE episode carries a poor prognosis in cirrhosis. PMID- 24480289 TI - [Health related quality of life and kidney transplantation: a comparison with population values at 6 months post-transplant]. AB - BACKGROUND AND OBJECTIVE: Transplantation is an effective treatment for end stage renal failure. The aim of this study was to compare patient's perceived health related quality of life (HRQoL) with population values, at one moth and 6 moths of kidney post-transplantation. PATIENTS AND METHOD: The Questionnaire of Quality of Life in Kidney Disease was administered during the first month and also at the 6 months following transplantation. A comparison with the general population was done with the generic part of the questionnaire. In the statistical analyses, typical standardized scores were used. RESULTS: In this study 72 patients were included with a median age of 57 years. At the 6 month post-transplantation, the patient's HRQoL showed values that were similar to the general population. When we compared the HRQoL at the first month and at the 6 month post-transplantation, the differences of HRQoL were significant in all dimensions, except on the General health and Emotional role. CONCLUSIONS: At 6 moths after transplantation, there was an improvement in the perceived HRQoL that was similar to the general population. PMID- 24480290 TI - [New antiplatelet drugs in coronary artery disease]. AB - The dual antiplatelet therapy with acetylsalicylic acid and clopidogrel has been the mainstay of both acute and chronic phase coronary artery disease, reducing importantly the risk of adverse events. Despite a correct compliance, a non negligible rate of adverse events still happens. New compounds, with improved properties, are now clinically available (such as prasugrel or ticagrelor) or under advanced development. The aim of the present review is the description of these new compounds, particularly prasugrel and ticagrelor. PMID- 24480291 TI - [Assessment and positioning of drugs as equivalent therapeutic alternatives]. PMID- 24480292 TI - [Parvovirus B19 disease in immunocompetent adults. Description of an outbreak in a urban healthcare center in Zaragoza (Spain)]. PMID- 24480293 TI - Enhancer RNAs: the new molecules of transcription. AB - In the past few years, technological advances in nucleotide sequencing have culminated in a greater understanding of the complexity of the human transcriptome. Notably, the discovery that distal regulatory elements known as enhancers are transcribed and such enhancer-derived transcripts (eRNAs) serve a critical function in transcriptional activation has added a new dimension to transcriptional regulation. Here we review recent insights into the tissue specific and temporal-specific gene regulation brought about by the discovery of eRNAs. PMID- 24480295 TI - Formation of disulfide bonds in insect prophenoloxidase enhances immunity through improving enzyme activity and stability. AB - Type 3 copper proteins, including insect prophenoloxidase (PPO), contain two copper atoms in the active site pocket and can oxidize phenols. Insect PPO plays an important role in immunity. Insects and other invertebrates show limited recovery from pathogen invasion and wounds if phenoloxidase (PO) activity is low. In most insect PPOs, two disulfide bonds are present near the C-terminus. However, in Pimpla hypochondriaca (a parasitoid wasp), each PPO contains one disulfide bond. We thus questioned whether the formation of two sulfide bonds in insect PPOs improved protein stability and/or increased insect innate immunity over time. Using Drosophila melanogaster PPO1 as a model, one or two disulfide bonds were deleted to evaluate the importance of disulfide bonds in insect immunity. rPPO1 and mutants lacking disulfide bonds could be expressed and showed PO activity. However, the PO activities of mutants lacking one or two disulfide bonds significantly decreased. Deletion of disulfide bonds also reduced PPO thermostability. Furthermore, antibacterial activities against Escherichia coli and Bacillus subtilis significantly decreased when disulfide bonds were deleted. Therefore, the formation of two disulfide bond(s) in insect PPO enhances antibacterial activity by increasing PO activity and stability. PMID- 24480294 TI - Nuclear pore interactions with the genome. AB - Within the nucleus, chromatin is functionally organized into distinct nuclear compartments. The nuclear periphery, containing Nuclear Pore Complexes (NPCs), plays an important role in the spatial organization of chromatin and in transcriptional regulation. The role of Nuclear Pore Proteins (Nups) in transcription and their involvement in leukemia and viral integration has renewed interest in understanding their mechanism of action. Nups bind to both repressed and active genes, often in a regulated fashion. Nups can associate with chromatin both at the NPC and inside the nucleoplasm. These interactions are guided by evolutionarily conserved mechanisms that involve promoter DNA elements and trans acting factors. These interactions can also lead to interchromosomal clustering of co-regulated genes. Nups affect gene expression by promoting stronger transcription, by limiting the spread of repressed chromatin or by altering chromatin structure. Nups can promote epigenetic regulation by establishing boundary elements and poising recently repressed genes for faster reactivation. PMID- 24480296 TI - L-Rhamnose-binding lectins (RBLs) in channel catfish, Ictalurus punctatus: Characterization and expression profiling in mucosal tissues. AB - Rhamnose-binding lectins (RBLs) have recently emerged as important molecules in the context of innate immunity in teleost fishes. Previously, using RNA-seq technology, we observed marked up-regulation of a RBL in channel catfish (Ictalurus punctatus) gill following a challenge with the bacterial pathogen Flavobacterium columnare. Furthermore, the magnitude of RBL up-regulation positively correlated with disease susceptibility. Moving forward from these findings, we wished to more broadly understand RBL function, diversity, and expression kinetics in channel catfish. Therefore, in the present study we characterized the RBL gene family present in select channel catfish tissues and profiled family member expression after challenge with two different Gram negative bacterial pathogens. Here, six RBLs were identified from channel catfish and were designated IpRBL1a, IpRBL1b, IpRBL1c, IpRBL3a, IpRBL3b, and IpRBL5a. These RBLs contained carbohydrate recognition domains (CRD) ranging from one to three domains and each CRD contained the conserved motifs of -YGR- and -DPC-. Despite a level of structural conservation, the catfish RBLs showed low full length identity with RBLs from outside the order Siluriformes. IpRBL expression after bacterial infection varied depending on both pathogen and tissue type, suggesting that IpRBLs may exert disparate functions or exhibit distinct tissue selective roles in the host immune response to bacterial pathogens. PMID- 24480297 TI - Perioperative beta-blocker use and survival in lung cancer patients. AB - STUDY OBJECTIVE: To assess the effect of perioperative beta blockers on recurrence and overall survival after non-small cell lung cancer surgery. DESIGN: Retrospective study. SETTING: Academic medical center. MEASUREMENTS: The medical records of patients with stage 1, 2, and 3a non-small cell lung cancer were divided into three different groups: those patients who never received beta blockers perioperatively, those receiving nonselective beta blockers within 60 days of surgery, and those taking selective beta blockers within 60 days of surgery. Recurrence-free survival and overall survival were the main clinical endpoints. Univariate log-rank tests and multivariate Cox proportional hazards models were used to assess the effects of selective beta blockers, nonselective beta blockers, or no beta blockers on recurrence-free survival and overall survival. MAIN RESULTS: The analysis included records of 435 patients. Univariate analyses showed that the use of both selective and nonselective beta blockers was associated with decreased recurrence-free survival (P = 0.014) and overall survival (P = 0.009). However, these findings were not sustained after adjusting for possible confounding variables in the multivariate analysis. The hazard ratios for recurrence-free survival (selective beta blockers vs no beta blocker use were: 1.304; 95% confidence intervals [CI] 0.973 - 1.747; P = 0.075; for nonselective beta blockers vs no beta blockers: 0.989; 95% CI 0.639 - 1.532; P = 0.962. The hazard ratios for overall survival were: selective beta blocker use vs no beta blockers: 1.335; 95% CI 0.966 - 1.846; P = 0.080; nonselective beta blocker use vs no beta blocker use: 1.108; 95% CI 0.678 - 1.812; P = 0.682. CONCLUSION: Administration of beta blockers during the perioperative period did not improve recurrence-free or overall survival in patients undergoing resection of non-small cell lung cancer. PMID- 24480298 TI - Digestible indispensable amino acid score and digestible amino acids in eight cereal grains. AB - To determine values for the digestible indispensable amino acid score (DIAAS), it is recommended that ileal amino acid (AA) digestibility values obtained in growing pigs are used to characterise protein quality in different foods. Therefore, an experiment was conducted to determine the standardised ileal digestibility (SID) of AA in eight cereal grains (yellow dent maize, Nutridense maize, dehulled barley, dehulled oats, polished white rice, rye, sorghum and wheat) fed to pigs, where SID values in pigs can be used to calculate approximate DIAAS values in humans. In the present experiment, twenty-four barrows with a T cannula inserted in the distal ileum were allotted to eight diets and fed for three periods to give a total of nine replicate pigs per diet. Each period lasted 14 d, and ileal digesta samples were collected on days 13 and 14. Among the SID values obtained for all cereal grains, values for total indispensable AA were greatest (P< 0.05) in rice and lowest (P< 0.05) in rye and sorghum. The concentrations of SID indispensable AA in rice were less (P< 0.05) than in dehulled oats, but greater (P< 0.05) than in the other cereal grains, and the concentrations of SID indispensable AA in Nutridense maize were greater (P< 0.05) than in yellow dent maize and sorghum, but less (P< 0.05) than in the other cereal grains, except rye. In conclusion, results indicate that to meet dietary requirements for AA in humans, diets based on yellow dent maize or sorghum require more AA supplementation than diets based on other cereal grains. PMID- 24480299 TI - New insights into molecular mechanism(s) underlying the presynaptic action of nitric oxide on GABA release. AB - BACKGROUND: Nitric oxide (NO) is an important presynaptic modulator of synaptic transmission. Here, we aimed to correlate the release of the major inhibitory neurotransmitter GABA with intracellular events occurring in rat brain axon terminals during their exposure to NO in the range of nanomolar-low micromolar concentrations. METHODS: Using [(3)H]GABA and fluorescent dyes (Fluo 4-AM, acridine orange and rhodamine 6G), the following parameters were evaluated: vesicular and cytosolic GABA pools, intracellular calcium concentration, synaptic vesicle acidification, and mitochondrial membrane potential. Diethylamine NONOate (DEA/NO) and S-nitroso-N-acetylpenicillamine (SNAP) were used as NO donors. RESULTS: DEA/NO and SNAP (in the presence of dithiothreitol (DTT)) stimulated external Ca(2+)-independent [(3)H]GABA release, which was not attributed to a rise in intracellular calcium concentration. [(3)H]GABA release coincided with increasing GABA level in cytosol and decreasing the vesicular GABA content available for exocytotic release. There was a strong temporal correlation between NO-induced increase in cytosolic [GABA] and dissipation of both synaptic vesicle proton gradient and mitochondrial membrane potential. Dissipation was reversible, and recovery of both parameters correlated in time with re-accumulation of [(3)H]GABA into synaptic vesicles. The molar ratio of DTT to SNAP determined the rate and duration of the recovery processes. CONCLUSIONS: We suggest that NO can stimulate GABA release via GABA transporter reversal resulting from increased GABA levels in cytosol. The latter is reversible and appears to be due to S nitrosylation of key proteins, which affect the energy status of the pre-synapse. GENERAL SIGNIFICANCE: Our findings provide new insight into molecular mechanism(s) underlying the presynaptic action of nitric oxide on inhibitory neurotransmission. PMID- 24480300 TI - Exacerbation of interstitial granulomatous dermatitis with arthritis by anakinra in a patient with diffuse large B-cell lymphoma. AB - Interstitial granulomatous dermatitis with arthritis (IGDA) is a rare idiopathic skin disorder with variable cutaneous expression, typically associated with a seronegative arthritis. Histopathology of this disorder reveals a granulomatous infiltrate with foci of collagen degeneration in the deep reticular dermis. We present a case of IGDA in a 56-year-old man with diffuse large B-cell lymphoma, exacerbated by the administration of anakinra. PMID- 24480301 TI - Neurodegenerative disease diagnosis using incomplete multi-modality data via matrix shrinkage and completion. AB - In this work, we are interested in predicting the diagnostic statuses of potentially neurodegenerated patients using feature values derived from multi modality neuroimaging data and biological data, which might be incomplete. Collecting the feature values into a matrix, with each row containing a feature vector of a sample, we propose a framework to predict the corresponding associated multiple target outputs (e.g., diagnosis label and clinical scores) from this feature matrix by performing matrix shrinkage following matrix completion. Specifically, we first combine the feature and target output matrices into a large matrix and then partition this large incomplete matrix into smaller submatrices, each consisting of samples with complete feature values (corresponding to a certain combination of modalities) and target outputs. Treating each target output as the outcome of a prediction task, we apply a 2 step multi-task learning algorithm to select the most discriminative features and samples in each submatrix. Features and samples that are not selected in any of the submatrices are discarded, resulting in a shrunk version of the original large matrix. The missing feature values and unknown target outputs of the shrunk matrix is then completed simultaneously. Experimental results using the ADNI dataset indicate that our proposed framework achieves higher classification accuracy at a greater speed when compared with conventional imputation-based classification methods and also yields competitive performance when compared with the state-of-the-art methods. PMID- 24480302 TI - Decoding complex flow-field patterns in visual working memory. AB - There has been a long history of research on visual working memory. Whereas early studies have focused on the role of lateral prefrontal cortex in the storage of sensory information, this has been challenged by research in humans that has directly assessed the encoding of perceptual contents, pointing towards a role of visual and parietal regions during storage. In a previous study we used pattern classification to investigate the storage of complex visual color patterns across delay periods. This revealed coding of such contents in early visual and parietal brain regions. Here we aim to investigate whether the involvement of visual and parietal cortex is also observable for other types of complex, visuo-spatial pattern stimuli. Specifically, we used a combination of fMRI and multivariate classification to investigate the retention of complex flow-field stimuli defined by the spatial patterning of motion trajectories of random dots. Subjects were trained to memorize the precise spatial layout of these stimuli and to retain this information during an extended delay. We used a multivariate decoding approach to identify brain regions where spatial patterns of activity encoded the memorized stimuli. Content-specific memory signals were observable in motion sensitive visual area MT+ and in posterior parietal cortex that might encode spatial information in a modality independent manner. Interestingly, we also found information about the memorized visual stimulus in somatosensory cortex, suggesting a potential crossmodal contribution to memory. Our findings thus indicate that working memory storage of visual percepts might be distributed across unimodal, multimodal and even crossmodal brain regions. PMID- 24480303 TI - Inadequate reinforcement of transmedial disruptions at branch points subtends aortic aneurysm formation in apolipoprotein-E-deficient mice. AB - INTRODUCTION: Infusion of angiotensin-II (Ang-II) in apolipoprotein-E-deficient mice (Apo-E(-/-)) results in suprarenal abdominal aortic aneurysm (AAA) in 30-85% of cases. This study identifies the apparent mechanism by which some animals do, but others do not, develop AAA in this model. METHODS: Male Apo-E(-/-) mice were infused with Ang-II (n=21) or saline (n=6) and sacrificed at 4 weeks. Aortas were excised, embedded in paraffin, sectioned (250 MUm intervals), and stained. Sites of transmedial disruption (TMD) were identified and characterized, and their relationship to the 4 major aortic side branches (celiac, superior mesenteric, and renals) were determined. RESULTS: The frequency of TMDs in Ang-II-infused mice that formed AAA (n=9) was similar to those that did not (n=12) (AAA vs. no AAA: 25 of 36[69%] vs. 28 of 48[58%] branches, P=.3 by chi-square). All TMDs were at branch points. However, in animals with AAA, the mean maximum length of the TMDs was significantly larger (1.94+/-1.6 vs. 0.65+/-0.5mm, P=.007 by Mann Whitney U test), the #mac-2(+) macrophages per 0.01mm(2) of defect area was greater (32+/-10 vs. 19+/-11, P<.02 by Kruskal-Wallis with Conover-Inman post hoc), the % area of attempted repair occupied by collagen was less (17+/-13% vs. 44+/-15%, P=.0009 by Mann Whitney U test), and the density of collagen per unit length of media missing was also markedly less (0.13+/-0.2 vs. 1.14+/-1.0, P=.0001 by Mann Whitney U test). CONCLUSIONS: Reinforcement of transmedial defects at branch points by wall matrix is a key intrinsic player in limiting AAA formation in the Ang-II-infused, Apo E(-/-) mouse and a potentially important mechanism-based therapeutic target for management of small, slowly progressing aneurysms. PMID- 24480304 TI - Fitting CRISPR-associated Cas3 into the helicase family tree. AB - Helicases utilize NTPs to modulate their binding to nucleic acids and many of these enzymes also unwind DNA or RNA duplexes in an NTP-dependent fashion. These proteins are phylogenetically related but functionally diverse, with essential roles in virtually all aspects of nucleic acid metabolism. A new class of helicases associated with RNA-guided adaptive immune systems in bacteria and archaea has recently been identified. Prokaryotes acquire resistance to invading genetic parasites by integrating short fragments of foreign nucleic acids into repetitive loci in the host chromosome known as CRISPRs (Clustered Regularly Interspaced Short Palindromic Repeats). CRISPR-associated gene 3 (cas3) encodes a conserved helicase protein that is essential for phage defense. Here we review recent advances in Cas3 biology, and provide a new phylogenetic framework that positions Cas3 in the helicase family tree. We anticipate that this Cas3 phylogeny will guide future biochemical and structural studies. PMID- 24480305 TI - Impact of changes in mortality on FRAX-derived fracture probabilities. AB - BACKGROUND: Accurate hip fracture incidence and mortality rates are two essential requirements for FRAX calculators. PURPOSE: To investigate the effects of change in mortality on FRAX-derived fracture estimates. METHODS: Lebanese FRAX calculator was updated in 2012 from version 3.00 utilizing WHO mortality data from year 1999, and hip fracture incidence rates from 2007, to version 3.05 utilizing mortality data from 2009, but with identical hip fracture data. FRAX derived estimates from 679 patients were computed using both FRAX versions and compared. Numbers presented as median [25th-75th] percentiles. RESULTS: The 10 year FRAX-derived probability of major osteoporotic fracture and hip fracture increased substantially. Changes were most pronounced in high risk sub-groups. The relative increase in probability of major osteoporotic fracture in individuals with a baseline risk of 10-20% was 79% [19%-127%], and in individuals with a baseline risk >20% it was 125% (N=3). The numbers for relative increase in hip fracture probability were 98% [33%-135%], and 129%, respectively. Similarly, individuals older than 70 years had a 125% [89%-150%] relative increase in probability of major osteoporotic fracture and a 122% [95%-145%] relative increase in hip fracture probability. Using the FRAX-based Lebanese guidelines, FRAX 3.05 led to an additional increase in treatment qualification of 3.8 patients per 100 patients, or a relative increase of 24%. CONCLUSIONS: Updates in mortality values increased FRAX-derived estimates, most substantially in older patients, and those at high risk for fracture. The update results in altering individuals' treatment decisions and modifying country wide osteoporosis management. Our results are relevant to the development and update of FRAX models for countries worldwide, and more importantly those with increasing longevity and possible increase in fracture rates. PMID- 24480306 TI - Immunological shielding by induced recruitment of regulatory T-lymphocytes delays rejection of islets transplanted in muscle. AB - The only clinically available curative treatment of type 1 diabetes mellitus is replacement of the pancreatic islets by allogeneic transplantation, which requires immunosuppressive therapies. Regimens used today are associated with serious adverse effects and impaired islet engraftment and function. The aim of the current study was to induce local immune privilege by accumulating immune suppressive regulatory T-lymphocytes (Tregs) at the site of intramuscular islet transplantation to reduce the need of immunosuppressive therapy during engraftment. Islets were cotransplanted with a plasmid encoding the chemokine CCL22 into the muscle of MHC-mismatched mice, after which pCCL22 expression and leukocyte recruitment were studied in parallel with graft functionality. Myocyte pCCL22 expression and secretion resulted in local accumulation of Tregs. When islets were cotransplanted with pCCL22, significantly fewer effector T lymphocytes were observed in close proximity to the islets, leading to delayed graft rejection. As a result, diabetic recipients cotransplanted with islets and pCCL22 intramuscularly became normoglycemic for 10 consecutive days, while grafts cotransplanted with control plasmid were rejected immediately, leaving recipients severely hyperglycemic. Here we propose a simple method to initially shield MHC mismatched islets by the recruitment of endogenous Tregs during engraftment in order to improve early islet survival. Using this approach, the very high doses of systemic immunosuppression used initially following transplantation can thereby be avoided. PMID- 24480307 TI - A mutation interfering with 5-lipoxygenase domain interaction leads to increased enzyme activity. AB - 5-Lipoxygenase (5-LOX) catalyzes two steps in conversion of arachidonic acid to proinflammatory leukotrienes. Lipoxygenases, including human 5-LOX, consist of an N-terminal C2-like beta-sandwich and a catalytic domain. We expressed the 5-LOX domains separately, these were found to interact in the yeast two-hybrid system. The 5-LOX structure suggested association between Arg(101) in the beta-sandwich and Asp(166) in the catalytic domain, due to electrostatic interaction as well as hydrogen bonds. Indeed, mutagenic replacements of these residues led to loss of two-hybrid interaction. Interestingly, when Arg(101) was mutated to Asp in intact 5-LOX, enzyme activity was increased. Thus, higher initial velocity of the reaction (vinit) and increased final amount of products were monitored for 5-LOX R101D, at several different assay conditions. In the 5-LOX crystal structure, helix alpha2 and adjacent loops (including Asp(166)) of the 5-LOX catalytic domain has been proposed to form a flexible lid controlling access to the active site, and lid movement would be determined by bonding of lid residues to the C2 like beta-sandwich. The more efficient catalysis following disruption of the R101 D166 ionic association supports the concept of such a flexible lid in human 5 LOX. PMID- 24480308 TI - Influence of a constitutive increase in myofilament Ca(2+)-sensitivity on Ca(2+) fluxes and contraction of mouse heart ventricular myocytes. AB - Chronic increases in myofilament Ca(2+)-sensitivity in the heart are known to alter gene expression potentially modifying Ca(2+)-homeostasis and inducing arrhythmias. We tested age-dependent effects of a chronic increase in myofilament Ca(2+)-sensitivity on induction of altered alter gene expression and activity of Ca(2+) transport systems in cardiac myocytes. Our approach was to determine the relative contributions of the major mechanisms responsible for restoring Ca(2+) to basal levels in field stimulated ventricular myocytes. Comparisons were made from ventricular myocytes isolated from non-transgenic (NTG) controls and transgenic mice expressing the fetal, slow skeletal troponin I (TG-ssTnI) in place of cardiac TnI (cTnI). Replacement of cTnI by ssTnI induces an increase in myofilament Ca(2+)-sensitivity. Comparisons included myocytes from relatively young (5-7months) and older mice (11-13months). Employing application of caffeine in normal Tyrode and in 0Na(+) 0Ca(2+) solution, we were able to dissect the contribution of the sarcoplasmic reticulum Ca(2+) pump (SR Ca(2+)-ATPase), the Na(+)/Ca(2+) exchanger (NCX), and "slow mechanisms" representing the activity of the sarcolemmal Ca(2+) pump and the mitochondrial Ca(2+) uniporter. The relative contribution of the SR Ca(2+)-ATPase to restoration of basal Ca(2+) levels in younger TG-ssTnI myocytes was lower than in NTG (81.12+/-2.8% vs 92.70+/-1.02%), but the same in the older myocytes. Younger and older NTG myocytes demonstrated similar contributions from the SR Ca(2+)-ATPase and NCX to restoration of basal Ca(2+). However, the slow mechanisms for Ca(2+) removal were increased in the older NTG (3.4+/-0.3%) vs the younger NTG myocytes (1.4+/-0.1%). Compared to NTG, younger TG-ssTnI myocytes demonstrated a significantly bigger contribution of the NCX (16+/-2.7% in TG vs 6.9+/-0.9% in NTG) and slow mechanisms (3.3+/-0.4% in TG vs 1.4+/-0.1% in NTG). In older TG-ssTnI myocytes the contributions were not significantly different from NTG (NCX: 4.9+/-0.6% in TG vs 5.5+/-0.7% in NTG; slow mechanisms: 2.5+/-0.3% in TG vs 3.4+/-0.3% in NTG). Our data indicate that constitutive increases in myofilament Ca(2+)-sensitivity alter the relative significance of the NCX transport system involved in Ca(2+)-homeostasis only in a younger group of mice. This modification may be of significance in early changes in altered gene expression and electrical stability hearts with increased myofilament Ca-sensitivity. PMID- 24480309 TI - A C-terminal fragment of fibulin-7 interacts with endothelial cells and inhibits their tube formation in culture. AB - We have previously demonstrated that fibulin-7 (Fbln7) is expressed in teeth by pre-odontoblast and odontoblast cells, localized in the basement membrane and dentin matrices, and is an adhesion molecule for dental mesenchyme cells and odontoblasts. Fbln7 is also expressed in blood vessels by endothelial cells. In this report, we show that a recombinant C-terminal Fbln7 fragment (Fbln7-C) bound to Human Umbilical Vein Endothelial Cells (HUVECs) but did not promote cell spreading and actin stress fiber formation. Fbln7-C binding to HUVECs induced integrin clustering at cell adhesion sites with other focal adhesion molecules, and sustained activation of FAK, p130Cas, and Rac1. In addition, RhoA activation was inhibited, thereby preventing HUVEC spreading. As endothelial cell spreading is an important step for angiogenesis, we examined the effect of Fbln7-C on angiogenesis using in vitro assays for endothelial cell tube formation and vessel sprouting from aortic rings. We found that Fbln7-C inhibited the HUVEC tube formation and the vessel sprouting in aortic ring assays. Our findings suggest potential anti-angiogenic activity of the Fbln7 C-terminal region. PMID- 24480311 TI - Expeditious exclusion of acute coronary syndrome diagnosis by combined measurements of copeptin, high-sensitivity troponin, and GRACE score. AB - BACKGROUND: High-sensitivity troponin (HS-TnT) combined with copeptin have been proposed to expedite the diagnostic exclusion of acute myocardial infarction. The Global Registry of Acute Coronary Events (GRACE) has been validated and recommended by the European Society of Cardiology as a prognostic score in the management of acute coronary syndrome (ACS) without ST-segment elevation (non ST+) on the electrocardiogram. Our study examined whether a low GRACE score (<108) combined with negative HS-TnT (<14 ng/L) and copeptin (<14 pmol/L) reliably exclude the diagnosis of non-ST+ ACS, including non-ST-segment elevation myocardial infarction and unstable angina. METHODS: This observational, prospective study included patients presenting with chest pain lasting <6 hours, consistent with non-ST+ ACS. Blood was collected early for measurements of copeptin and HS-TnT. The negative predictive value of combined copeptin, HS-TnT, and GRACE score was calculated in the diagnosis of non-ST+ ACS. The thresholds of positivity were 14 ng/L for HS-TnT, 14 pmol/L for copeptin and 108 for the GRACE score. RESULTS: Among 247 patients retained in the analysis, the diagnosis of ACS was made in 50 (20.4%), including 39 non-ST-segment elevation myocardial infarction and 11 unstable angina. The negative predictive value of combined HS TnT, copeptin and GRACE score was 99%. CONCLUSION: A negative copeptin associated with a negative HS-TnT in a patient presenting with a low GRACE score expedited the diagnostic exclusion of non-ST+ ACS. PMID- 24480312 TI - Joint infectious causation of human cancers. AB - Joint infectious causation of cancer has been accepted in a few well-studied instances, including Burkitt's lymphoma and liver cancer. In general, evidence for the involvement of parasitic agents in oncogenesis has expanded, and recent advances in the application of molecular techniques have revealed specific mechanisms by which host cells are transformed. Many parasites evolve to circumvent immune-mediated detection and destruction and to control critical aspects of host cell reproduction and survival: cell proliferation, apoptosis, adhesion, and immortalization. The host has evolved tight regulation of these cellular processes-the control of each represents a barrier to cancer. These barriers need to be compromised for oncogenesis to occur. The abrogation of a barrier is therefore referred to as an essential cause of cancer. Alternatively, some aspects of cellular regulation restrain but do not block oncogenesis. Relaxation of a restraint is therefore referred to as an exacerbating cause of cancer. In this chapter, we explore past and current evidence for joint infectious causation of cancer in the context of essential and exacerbating causes. We stress that discovery of joint infectious causation may provide great improvements in controlling cancer, particularly through the identification of many additional nonhuman targets for synergistic interventions for prevention and treatment. PMID- 24480310 TI - Allosteric effects of cardiac troponin TNT1 mutations on actomyosin binding: a novel pathogenic mechanism for hypertrophic cardiomyopathy. AB - The majority of hypertrophic cardiomyopathy mutations in (cTnT) occur within the alpha-helical tropomyosin binding TNT1 domain. A highly charged region at the C terminal end of TNT1 unwinds to create a flexible "hinge". While this region has not been structurally resolved, it likely acts as an extended linker between the two cTnT functional domains. Mutations in this region cause phenotypically diverse and often severe forms of HCM. Mechanistic insight, however, has been limited by the lack of structural information. To overcome this limitation, we evaluated the effects of cTnT 160-163 mutations using regulated in vitro motility (R-IVM) assays and transgenic mouse models. R-IVM revealed that cTnT mutations Delta160E, E163R and E163K disrupted weak electrostatic actomyosin binding. Reducing the ionic strength or decreasing Brownian motion rescued function. This is the first observation of HCM-linked mutations in cTnT disrupting weak interactions between the thin filament and myosin. To evaluate the in vivo effects of altering weak actomyosin binding we generated transgenic mice expressing Delta160E and E163R mutant cTnT and observed severe cardiac remodeling and profound myofilament disarray. The functional changes observed in vitro may contribute to the structural impairment seen in vivo by destabilizing myofilament structure and acting as a constant pathophysiologic stress. PMID- 24480313 TI - Neurological and ocular fascioliasis in humans. AB - Fascioliasis is a food-borne parasitic disease caused by the trematode species Fasciola hepatica, distributed worldwide, and Fasciola gigantica, restricted to given regions of Africa and Asia. This disease in humans shows an increasing importance, which relies on its recent widespread emergence related to climate and global changes and also on its pathogenicity in the invasive, biliary, and advanced chronic phases in the human endemic areas, mainly of developing countries. In spite of the large neurological affection capacity of Fasciola, this important pathogenic aspect of the disease has been pronouncedly overlooked in the past decades and has not even appear within the numerous reviews on the parasitic diseases of the central nervous system. The aim of this wide retrospective review is an in-depth analysis of the characteristics of neurological and ocular fascioliasis caused by these two fasciolid species. The terms of neurofascioliasis and ophthalmofascioliasis are restricted to cases in which the direct affection of the central nervous system or the eye by a migrant ectopic fasciolid fluke is demonstrated by an aetiological diagnosis of recovered flukes after surgery or spontaneous moving-out of the fluke through the orbit. Cases in which the ectopic fluke is not recovered and the symptoms cannot be explained by an indirect affection at distance may also be included in these terms. Neurofascioliasis and ophthalmofascioliasis cases are reviewed and discussed. With regard to fascioliasis infection giving an indirect rise to neurological affection, the distribution and frequency of cases are analysed according to geography, sex, and age. Minor symptoms and major manifestations are discussed. Three main types of cases are distinguished depending on the characteristics of their manifestations: genuine neurological, meningeal, and psychiatric or neuropsychic. The impressive symptoms and signs appearing in each type of these cases are included. Brain examination techniques and neuroimaging useful for the diagnosis of neurological cases are exposed. Within fascioliasis infection indirectly causing ocular manifestations, case distribution and frequency are similarly analysed. A short analysis is devoted to clarify the first reports of a human eye infection. The affection of related and close organs is discussed by differentiating between cases of the dorsal spine, pulmonary manifestations, heart and vessel affection, findings in blood vessels, skin and dermatologic reactions, cases of ectopic mature flukes, and upper body locations. The clinical complexity of the puzzling polymorphisms, the disconcerting multifocality of the manifestations, and their changes along the evolution of the disease in the same patient, as well as the differences between the clinical pictures shown by different patients, are highlighted. The many syndromes involved are enumerated. The pathogenic and physiological mechanisms underlying neurofascioliasis and ophthalmofascioliasis caused by ectopic flukes and the physiopathogenic processes indirectly affecting the central nervous system and causing genuine neurological, meningeal, psychiatric, and ocular manifestations are discussed. The diagnosis of neurological and ophthalmologic fascioliasis is analysed in depth, including clinical and paraclinical diagnosis, eosinophilia in the blood and cerebrospinal fluid, differential diagnosis from other parasitic infections such as helminthiases and myiases, an update of human fascioliasis diagnosis, and fluke and/or fluke egg recovery by surgery. Diagnostic analyses with faecal and blood samples for fascioliasis patients are updated. Therapy for patients with major neurological manifestations includes both antiparasitic treatments and anti-inflammatory therapeutics. Prognosis in fascioliasis patients with neurological manifestations is discussed, with emphasis on sequelae and fatal cases, and the care of patients with ophthalmologic manifestations is added. Conclusions indicate that neurological cases are overlooked in human fascioliasis endemic areas and also in developing countries in general. In remote zones, rural health centres and small hospitals in or near the human endemic areas do not dispose of the appropriate equipments for neurological analyses. Moreover, physicians may not be aware about the potential relationship between liver fluke infection and neurological implications, and such cases may therefore remain misdiagnosed, even in developed countries. Priority should henceforth be given to the consideration of neurological and ocular affection in human endemic areas, and efforts should be implemented to assess their characteristics and frequency. Their impact should also be considered when estimating the global burden of fascioliasis. PMID- 24480315 TI - A review of molecular approaches for investigating patterns of coevolution in marine host-parasite relationships. AB - Parasites and their relationships with hosts play a crucial role in the evolutionary pathways of every living organism. One method of investigating host parasite systems is using a molecular approach. This is particularly important as analyses based solely on morphology or laboratory studies of parasites and their hosts do not take into account historical evolutionary interactions that can shape the distribution, abundance and population structure of parasites and their hosts. However, the predominant host-parasite coevolution literature has focused on terrestrial hosts and their parasites, and there still is a lack of studies in marine environments. Given that marine systems are generally more open than terrestrial ones, they provide fascinating opportunities for large-scale (as well as small-scale) geographic studies. Further, patterns and processes of genetic structuring and systematics are becoming more available across many different taxa (but especially fishes) in many marine systems, providing an excellent basis for examining whether parasites follow host population/species structure. In this chapter, we first highlight the factors and processes that challenge our ability to interpret evolutionary patterns of coevolution of hosts and their parasites in marine systems at different spatial, temporal and taxonomic scales. We then review the use of the most commonly utilized genetic markers in studying marine host-parasite systems. We give an overview and discuss which molecular methodologies resolve evolutionary relationships best and also discuss the applicability of new approaches, such as next-generation sequencing and studies utilizing functional markers to gain insights into more contemporary processes shaping host-parasite relationships. PMID- 24480316 TI - New insights into clonality and panmixia in Plasmodium and toxoplasma. AB - Until the 1990s, Plasmodium and Toxoplasma were widely considered to be potentially panmictic species, because they both undergo a meiotic sexual cycle in their definitive hosts. We have proposed that both parasites are able of clonal (nonrecombining) propagation, at least in some cycles. Toxoplasma was soon shown to be a paradigmatic case of clonal population structure in North American and in European cycles. But the proposal provoked an outcry in the case of Plasmodium and still appears as doubtful to many scientists. However, the existence of Plasmodium nonrecombining lines has been fully confirmed, although the origin of these lines is debatable. We discuss the current state of knowledge concerning the population structure of both parasites in the light of the recent developments of pathogen clonal evolution proposed by us and of new hypotheses presented here. PMID- 24480314 TI - Measuring changes in Plasmodium falciparum transmission: precision, accuracy and costs of metrics. AB - As malaria declines in parts of Africa and elsewhere, and as more countries move towards elimination, it is necessary to robustly evaluate the effect of interventions and control programmes on malaria transmission. To help guide the appropriate design of trials to evaluate transmission-reducing interventions, we review 11 metrics of malaria transmission, discussing their accuracy, precision, collection methods and costs and presenting an overall critique. We also review the nonlinear scaling relationships between five metrics of malaria transmission: the entomological inoculation rate, force of infection, sporozoite rate, parasite rate and the basic reproductive number, R0. Our chapter highlights that while the entomological inoculation rate is widely considered the gold standard metric of malaria transmission and may be necessary for measuring changes in transmission in highly endemic areas, it has limited precision and accuracy and more standardised methods for its collection are required. In areas of low transmission, parasite rate, seroconversion rates and molecular metrics including MOI and mFOI may be most appropriate. When assessing a specific intervention, the most relevant effects will be detected by examining the metrics most directly affected by that intervention. Future work should aim to better quantify the precision and accuracy of malaria metrics and to improve methods for their collection. PMID- 24480317 TI - Hypertension and diabetes significantly enhance the risk of cardiovascular disease in patients with psoriatic arthritis. AB - OBJECTIVES: New evidence has lightened the linkage between psoriatic arthritis (PsA) and the development of atherosclerosis and cardiovascular disease (CVD). We aimed to describe the prevalence of cardiovascular events and associated risk factors among patients with PsA. METHODS: Retrospective evaluation of medical records from consecutive PsA patients who fulfilled the CASPAR criteria for PsA attending a specialised spondyloarthritis clinic at a single referral centre. CVD was defined based on the occurrence of coronary artery disease (CAD) or cerebrovascular ischaemic disease events. RESULTS: We evaluated 158 PsA patients, 48.7% females and 51.3% males, aged 53.7+/-13.9 yrs. Mean PsA duration was 13.7+/ 8.9 yrs and polyarticular subtype affected 66 (42%) patients. According to drug therapy, 85 (54%) were using NSAIDs and 21 (13%) low-dose prednisone; 32 (20%) were on anti-TNF agents, 94 (60%) metothrexate, 18 (11%) leflunomide, 13 (8%) sulfasalazine, 5 (3%) other immunossupressors and 4 (2.5%) were on chloroquine. Over half patients (87, 55%) had arterial hypertension (AH); 51 (32%) had dyslipidaemia (DLP), 38 (29%) hypertriglyceridemia and 36 (23%) diabetes mellitus (DM). Lipid profile was similar for both genders with mean total cholesterol= 186.5+/-38.6mg/dl, LDL=112.3+/-30.6 mg/dl, HDL= 47.89+/-14.6 and triglycerides= 127.4+/- 65.6 mg/dl. Of note, 14% PsA patients have had CVD, namely cerebrovascular or coronary heart disease. Sex, age, disease duration, joint involvement subtype, disease activity, CRP and lipid levels were similar among patients with and without CVD. The prevalence of AH (95% vs. 45%, p<0.001), DLP (75% vs. 27.7%, p<0.001) and DM (60% vs. 19%, p<0.001) were significantly greater in PsA patients who have had CVD compared to those without CVD, conferring an odds ratio of 21.0 for AH and of 5.4 for DM. CONCLUSIONS: The high prevalence of CVD in PsA patients is influenced by increased AH and DM. Hence early recognition and specific treatment is mandatory in order to reduce the risk for CVD, avoiding early morbidity and mortality. PMID- 24480318 TI - Autoantibodies and depression: evidence for a causal link? AB - Depression is a leading contributor to the global burden of diseases. Despite advances in research, challenges still exist in managing this disorder. Sufferers of autoimmune diseases are often observed to suffer from depression more often than healthy individuals, an association that cannot be completely accounted for by the impact of the disease on the individual. An association between autoimmunity and depressive symptoms also appears to exist in populations with subclinical symptoms. Moreover, researchers have successfully developed murine models illustrating the ability of autoantibodies to induce depressive-like symptoms. This paper will provide an overview of the association between autoantibodies and occurrence of depressive symptoms. Though current evidence appears to support a role for autoantibodies in the pathogenesis of depression, the majority of studies have examined this relationship cross-sectionally, therefore failing to establish a temporal association. Nonetheless, this novel theory meshes with older and newer neurochemical theories of depression. A better understanding of the immuno-pathogenesis underlying depression presents opportunities for more targeted treatment approaches and more timely and appropriate measures of detection. PMID- 24480319 TI - Emerging strategies to overcome the resistance to current mTOR inhibitors in renal cell carcinoma. AB - The mammalian target of rapamycin (mTOR) has emerged as an attractive cancer therapeutic target. Treatment of metastatic renal cell carcinoma (mRCC) has improved significantly with the advent of agents targeting the mTOR pathway, such as temsirolimus and everolimus. Unfortunately, a number of potential mechanisms that may lead to resistance to mTOR inhibitors have been proposed. In this paper, we discuss the mechanisms underlying resistance to mTOR inhibitors, which include the downstream effectors of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway, the activation of hypoxia-inducible factor (HIF), the PIM kinase family, PTEN expression, elevated superoxide levels, stimulation of autophagy, immune cell response and ERK/MAPK, Notch and Aurora signaling pathways. Moreover, we present an updated analysis of clinical trials available on PubMed Central and www.clinicaltrials.gov, which were pertinent to the resistance to rapalogs. The new frontier of inhibiting the mTOR pathway is to identify agents targeting the feedback loops and cross talks with other pathways involved in the acquired resistance to mTOR inhibitors. The true goal will be to identify biomarkers predictive of sensitivity or resistance to efficiently develop novel agents with the aim to avoid toxicities and to better choose the active drug for the right patient. PMID- 24480320 TI - Membrane rafts as a novel target in cancer therapy. AB - Membrane rafts are distinct plasma membrane microdomains that are enriched in sphingolipids and cholesterol. They organize receptors and their downstream molecules and regulate a number of intracellular signaling pathways. This review presents information on the dependence of several growth factor receptor signaling pathways on membrane rafts. It also discusses the involvement of rafts in the regulation of differentiation, apoptosis and cell migration connected with invasiveness and metastasis. Examples of known synthetic and naturally occurring substances that are known to affect lateral membrane organization in tumor cell growth are discussed as potential or actual therapeutics. PMID- 24480321 TI - Lactobacillus rhamnosus and its cell-free culture supernatant differentially modulate inflammatory biomarkers in Escherichia coli-challenged human dendritic cells. AB - The intestinal immune system maintains a delicate balance between immunogenicity against invading pathogens and tolerance to the commensal microbiota and food antigens. Different strains of probiotics possess the ability to finely regulate the activation of dendritic cells (DC), polarising the subsequent activity of T cells. Nevertheless, information about their underlying mechanisms of action is scarce. In the present study, we investigated the immunomodulatory effects of a potentially probiotic strain, Lactobacillus rhamnosus CNCM I-4036, and its cell free culture supernatant (CFS) on human DC challenged with Escherichia coli. The results showed that the levels of pro-inflammatory cytokines such as IL-1beta, IL 6, IL-8 and IL-12p70 were higher in the cells treated with live L. rhamnosus than in the cells treated with the CFS. In the presence of E. coli, the supernatant was more effective than the probiotic bacteria in reducing the secretion of pro inflammatory cytokines. In addition, live L. rhamnosus potently induced the production of transforming growth factor (TGF)-beta1 and TGF-beta2, whereas the CFS increased the secretion of TGF-beta1. However, in the presence of E. coli, both treatments restored the levels of TGF-beta. The probiotic strain L. rhamnosus CNCM I-4036 and its CFS were able to activate the Toll-like receptor signalling pathway, enhancing innate immunity. The two treatments induced gene transcription of TLR-9. Live L. rhamnosus activated the expression of TLR-2 and TLR-4 genes, whereas the CFS increased the expression of TLR-1 and TLR-5 genes. In response to the stimulation with probiotic/CFS and E. coli, the expression of each gene tested was notably increased, with the exception of TNF-alpha and NFKBIA. In conclusion, the CFS exhibited an extraordinary ability to suppress the production of pro-inflammatory cytokines by DC, and may be used as an effective and safer alternative to live bacteria. PMID- 24480323 TI - Life-history evolution and mitogenomic phylogeny of caecilian amphibians. AB - We analyze mitochondrial genomes to reconstruct a robust phylogenetic framework for caecilian amphibians and use this to investigate life-history evolution within the group. Our study comprises 45 caecilian mitochondrial genomes (19 of them newly reported), representing all families and 27 of 32 currently recognized genera, including some for which molecular data had never been reported. Support for all relationships in the inferred phylogenetic tree is high to maximal, and topology tests reject all investigated alternatives, indicating an exceptionally robust molecular phylogenetic framework of caecilian evolution consistent with current morphology-based supraspecific classification. We used the mitogenomic phylogenetic framework to infer ancestral character states and to assess correlation among three life-history traits (free-living larvae, viviparity, specialized pre-adult or vernal teeth), each of which occurs only in some caecilian species. Our results provide evidence that an ancestor of the Seychelles caecilians abandoned direct development and re-evolved a free-living larval stage. This study yields insights into the concurrent evolution of direct development and of vernal teeth in an ancestor of Teresomata that likely gave rise to skin-feeding (maternal dermatophagy) behavior and subsequently enabled evolution of viviparity, with skin feeding possibly a homologous precursor of oviduct feeding in viviparous caecilians. PMID- 24480322 TI - Chronic inflammation and infection associate with a lower exercise training response in cystic fibrosis adolescents. AB - Considerable heterogeneity among training-induced effects is observed in patients with cystic fibrosis (CF). We previously showed that longitudinal changes in exercise capacity in adolescents with CF were negatively associated with Pseudomonas aeruginosa (P. aeruginosa) colonization and total immunoglobulin G (IgG) levels, independent of age, pulmonary function and bodyweight. This is the first study investigating whether chronic inflammation and infection also associate with the exercise training response in adolescents with CF. Participants performed a home-based exercise training program for 12 weeks. Pulmonary function, anthropometrics, exercise capacity, markers of inflammation and P. aeruginosa colonization status were measured at baseline. Exercise training-induced changes in pulmonary function and exercise capacity were compared between patients with a low and high inflammation-infection status. Participants with CF with high total IgG levels and P. aeruginosa colonization improved significantly less from the exercise training program, with regard to maximal oxygen consumption. These observations support the hypothesis that chronic systemic inflammation and infection leads to devastating effects on skeletal muscles, hampering skeletal muscle tissue to improve from regular physical exercise. Data further suggest that patients with CF should preferentially be encouraged to engage in regular physical exercise when inflammation and infection status is low (e.g. at a young age). PMID- 24480324 TI - Relationship of individual scapular anatomy and degenerative rotator cuff tears. AB - BACKGROUND: The etiology of rotator cuff disease is age related, as documented by prevalence data. Despite conflicting results, growing evidence suggests that distinct scapular morphologies may accelerate the underlying degenerative process. The purpose of the present study was to evaluate the predictive power of 5 commonly used radiologic parameters of scapular morphology to discriminate between patients with intact rotator cuff tendons and those with torn rotator cuff tendons. METHODS: A pre hoc power analysis was performed to determine the sample size. Two independent readers measured the acromion index, lateral acromion angle, and critical shoulder angle on standardized anteroposterior radiographs. In addition, the acromial morphology according to Bigliani and the acromial slope were determined on true outlet views. Measurements were performed in 51 consecutive patients with documented degenerative rotator cuff tears and in an age- and sex-matched control group of 51 patients with intact rotator cuff tendons. Receiver operating characteristic analyses were performed to determine cutoff values and to assess the sensitivity and specificity of each parameter. RESULTS: Patients with degenerative rotator cuff tears demonstrated significantly higher acromion indices, smaller lateral acromion angles, and larger critical shoulder angles than patients with intact rotator cuffs. However, no difference was found between the acromial morphology according to Bigliani and the acromial slope. With an area under the receiver operating characteristic curve of 0.855 and an odds ratio of 10.8, the critical shoulder angle represented the strongest predictor for the presence of a rotator cuff tear. CONCLUSION: The acromion index, lateral acromion angle, and critical shoulder angle accurately predict the presence of degenerative rotator cuff tears. PMID- 24480325 TI - Response to "Ligamentous repair of acute lateral collateral ligament rupture of the elbow". PMID- 24480326 TI - Biomechanical effects of humeral neck-shaft angle and subscapularis integrity in reverse total shoulder arthroplasty. AB - BACKGROUND: The variability in functional outcomes and the occurrence of scapular notching and instability after reverse total shoulder arthroplasty remain problems. The objectives of this study were to measure the effect of reverse humeral component neck-shaft angle on impingement-free range of motion, abduction moment, and anterior dislocation force and to evaluate the effect of subscapularis loading on dislocation force. METHODS: Six cadaveric shoulders were tested with 155 degrees , 145 degrees , and 135 degrees reverse shoulder humeral neck-shaft angles. The adduction angle at which bone contact occurred and the internal and external rotational impingement-free range of motion angles were measured. Glenohumeral abduction moment was measured at 0 degrees and 30 degrees of abduction, and anterior dislocation forces were measured at 30 degrees of internal rotation, 0 degrees , and 30 degrees of external rotation with and without subscapularis loading. RESULTS: Adduction deficit angles for 155 degrees , 145 degrees , and 135 degrees neck-shaft angle were 2 degrees +/- 5 degrees of abduction, 7 degrees +/- 4 degrees of adduction, and 12 degrees +/- 2 degrees of adduction (P < .05). Impingement-free angles of humeral rotation and abduction moments were not statistically different between the neck-shaft angles. The anterior dislocation force was significantly higher for the 135 degrees neck shaft angle at 30 degrees of external rotation and significantly higher for the 155 degrees neck-shaft angle at 30 degrees of internal rotation (P < .01). The anterior dislocation forces were significantly higher when the subscapularis was loaded (P < .01). CONCLUSIONS: The 155 degrees neck-shaft angle was more prone to scapular bone contact during adduction but was more stable at the internally rotated position, which was the least stable humeral rotation position. Subscapularis loading gave further anterior stability with all neck-shaft angles at all positions. PMID- 24480328 TI - Determination of nucleotides in infant milk formulas using novel dendrimer ion exchangers. AB - The main aim of the present study was to develop a method for the separation of 5'-monophosphate nucleotides with the use of ion chromatography. Novel dendrimeric stationary phases were used for this purpose. The effects exerted by the type of anion-exchanger support (silica or polymeric) and the number of stationary phase layers on nucleotide retention were studied. A silica-based dendrimeric anion-exchanger was most suitable for analyzing the studied compounds. An increase in the number of layers enhanced nucleotide retention inside the column. The separation efficiency of the studied compounds was tested at various concentrations of the mobile phase buffer. At higher phosphate buffer concentrations, nucleotide resolutions were achieved in 6min. Three commercially available infant milk formulas were analyzed to verify the applicability of the studied method. Solid phase extraction was used for sample cleanup and concentration. The limit of quantification of nucleotides was 0.40MUg/ml, and the method was linear in the concentration range of 0.40-20.6MUgml(-1.) PMID- 24480327 TI - A high-throughput quantification method of curcuminoids and curcumin metabolites in human plasma via high-performance liquid chromatography/tandem mass spectrometry. AB - Curcuminoids, a mixture of curcumin, demethoxycurcumin (DMC), and bisdemethoxycurcumin (BDMC), have shown a variety of clinical benefits for several human chronic diseases including osteoarthritis, rheumatoarthritis, and type II diabetes. However, the oral bioavailability of curcumin is extremely low due to its avid metabolism to curcumin O-glucuronide (COG), curcumin O-sulfate (COS), tetrahydrocurcumin (THC), and other minor metabolites. This paper reports a unique liquid chromatography/tandem mass spectrometry (LC-MS/MS) method to quantify curcumin, DMC, BDMC, COG, COS, and THC simultaneously in human plasma. These compounds were extracted with ethyl acetate from human plasma, separated on a BetaBasic-8 column, and monitored on a triple quadruple mass spectrometer coupled with API electrospray under a negative ion mode. The linearity of these respective curcuminoids and curcumin metabolites was shown in the range of 2 1000ng/mL with 85-115% accuracy and <=20% precision in human plasma. This method was validated according to the US FDA GLP analytic criteria and applied to characterize the pharmacokinetics of curcumin, COG, and COS in human plasma after an oral dose of bioavailable curcumin (nanoemulsion curcumin). PMID- 24480329 TI - Determination of 3-mercaptopyruvate in rabbit plasma by high performance liquid chromatography tandem mass spectrometry. AB - Accidental or intentional cyanide poisoning is a serious health risk. The current suite of FDA approved antidotes, including hydroxocobalamin, sodium nitrite, and sodium thiosulfate is effective, but each antidote has specific major limitations, such as large effective dosage or delayed onset of action. Therefore, next generation cyanide antidotes are being investigated to mitigate these limitations. One such antidote, 3-mercaptopyruvate (3-MP), detoxifies cyanide by acting as a sulfur donor to convert cyanide into thiocyanate, a relatively nontoxic cyanide metabolite. An analytical method capable of detecting 3-MP in biological fluids is essential for the development of 3-MP as a potential antidote. Therefore, a high performance liquid chromatography tandem mass spectrometry (HPLC-MS-MS) method was established to analyze 3-MP from rabbit plasma. Sample preparation consisted of spiking the plasma with an internal standard ((13)C3-3-MP), precipitation of plasma proteins, and reaction with monobromobimane to inhibit the characteristic dimerization of 3-MP. The method produced a limit of detection of 0.1MUM, a linear dynamic range of 0.5-100MUM, along with excellent linearity (R(2)>=0.999), accuracy (+/-9% of the nominal concentration) and precision (<7% relative standard deviation). The optimized HPLC-MS-MS method was capable of detecting 3-MP in rabbits that were administered sulfanegen, a prodrug of 3-MP, following cyanide exposure. Considering the excellent performance of this method, it will be utilized for further investigations of this promising cyanide antidote. PMID- 24480330 TI - Identification and quantification of 14 phthalates and 5 non-phthalate plasticizers in PVC medical devices by GC-MS. AB - A GC/MS method was developed for the identification and quantification of 14 phthalates: 8 phthalates classified H360 (DBP, DEHP, BBP, DMEP, DnPP, DiPP, DPP and DiBP), 3 phthalates proposed to be forbidden in medical devices (DnOP, DiNP and DiDP) and 3 other phthalates none regulated (DMP, DCHP and DEP) which may interfere with hormone function. In order to identify and quantify other plasticizers that are commonly used in PVC medical devices such as DEHP substitute, 5 non-phthalate plasticizers (ATBC, DEHA, DEHT, TOTM, and DINCH) were included in this study. Analyses are carried out on a GC/MS system with electron impact ionization mode (EI). The separation of plasticizers is obtained on a cross-linked 5%-phenyl/95%-dimethylpolysiloxane capillary column 30m*0.25mm (i.d.)*0.25MUm film thickness using a gradient temperature. Compounds quantification is performed by external calibration using an internal standard. Validation elements on standard solutions were determined using the ISO 12787 standard approach. Plasticizers are extracted from PVC medical devices using THF for dissolving the PVC part of the sample followed by precipitation of the PVC by addition of ethanol. The supernatant is injected into a GC/MS system after dilution in ethanol. Different validation elements, including extraction recoveries for all compounds or for DEHP a cross-validation of the extraction process using the European pharmacopoeia monograph 3.1.14 as reference method, are discussed. Results obtained on 61 medical devices in PVC and 12 raw materials used as plasticizers are given. PMID- 24480331 TI - Hydrodynamic transfection for generation of novel mouse models for liver cancer research. AB - Primary liver cancers, including hepatocellular carcinoma and intrahepatic cholangiocarcinoma, are leading causes of cancer-related death worldwide. Recent large-scale genomic approaches have identified a wide number of genes whose deregulation is associated with hepatocellular carcinoma and intrahepatic cholangiocarcinoma development. Murine models are critical tools to determine the oncogenic potential of these genes. Conventionally, transgenic or knockout mouse models are used for this purpose. However, several limitations apply to the latter models. Herein, we review a novel approach for stable gene expression in mouse hepatocytes by hydrodynamic injection in combination with Sleeping Beauty mediated somatic integration. This method represents a flexible, reliable, and cost-effective tool to generate preclinical murine models for liver cancer research. Furthermore, it can be used as an in vivo transfection method to study biochemical cross talks among multiple pathways along hepatocarcinogenesis and to test the therapeutic potential of drugs against liver cancer. PMID- 24480333 TI - Frequency and cost of claims by injury type from a state workers' compensation fund from 1998 through 2008. AB - OBJECTIVE: To determine which work-related injuries are the most frequent and costly. DESIGN: Secondary analysis of workers' compensation claims data. SETTING: Data were provided by a large, Maryland workers' compensation insurer from 1998 through 2008. PARTICIPANTS: Not applicable. INTERVENTIONS: None. MAIN OUTCOMES MEASURES: For 45 injury types, the number of claims and compensation amount was calculated for total compensation and for medical and indemnity compensation separately. RESULTS: Back and knee injuries were the most frequently occurring single injury types, whereas heart attack and occupational disease were the most expensive in terms of mean compensation. When taking into account both the frequency and cost of injury (mean cost * number occurrences), back, knee, and shoulder injuries were the most expensive single injury types. CONCLUSIONS: Successful prevention and management of back, knee, and shoulder injuries could lead to a substantial reduction in the burden associated with work-related injuries. PMID- 24480334 TI - Validating the traumatic brain injury-4 screening measure for veterans seeking mental health treatment with psychiatric inpatient and outpatient service utilization data. AB - OBJECTIVE: To determine whether a positive screen on the Traumatic Brain Injury-4 (TBI-4) can be used to identify veterans who use more inpatient and outpatient mental health services. DESIGN: Validation cohort. SETTING: Medical center. PARTICIPANTS: Individuals seeking Veterans Health Administration mental health services (N=1493). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: One year of inpatient and outpatient mental health utilization data after the TBI-4 screen date. RESULTS: In the year postmental health intake, those who answered positively to any of the 4 TBI-4 screening questions (criterion 1) or question 2 (criterion 2; ever having been knocked out) had significantly more psychiatric hospitalizations than those who met neither criterion. Those who were positive by criterion 2 also had significantly fewer outpatient mental health contacts. CONCLUSIONS: Veterans screening positive for history of traumatic brain injury on the TBI-4 had more hospital stays in the year postmental health intake. Those who reported having been knocked out also had fewer outpatient mental health visits. These findings may suggest an overall relation in this population between greater needs for mental health care and likelihood of prior injury. For those with a history of loss of consciousness, the reduced use of outpatient care may reflect greater problems engaging in treatment or with preventive aspects of the health care system during non-crisis periods. Using a screener (eg, the TBI-4) could facilitate identification of veterans who might benefit from targeted and intensive outpatient interventions to avoid frequent inpatient psychiatric hospitalization. PMID- 24480332 TI - Structural studies of the spliceosome: zooming into the heart of the machine. AB - Spliceosomes are large, dynamic ribonucleoprotein complexes that catalyse the removal of introns from messenger RNA precursors via a two-step splicing reaction. The recent crystal structure of Prp8 has revealed Reverse Transcriptase like, Linker and Endonuclease-like domains. The intron branch-point cross-link with the Linker domain of Prp8 in active spliceosomes and together with suppressors of 5' and 3' splice site mutations this unambiguously locates the active site cavity. Structural and mechanistic similarities with group II self splicing introns have encouraged the notion that the spliceosome is at heart a ribozyme, and recently the ligands for two catalytic magnesium ions were identified within U6 snRNA. They position catalytic divalent metal ions in the same way as Domain V of group II intron RNA, suggesting that the spliceosome and group II intron use the same catalytic mechanisms. PMID- 24480335 TI - Self-perceived utilization of the paretic arm in chronic stroke requires high upper limb functional ability. AB - OBJECTIVE: To explore potential predictors of self-reported paretic arm use at baseline and after task-specific training (TST) in survivors of stroke. DESIGN: Data were obtained from a randomized controlled trial of somatosensory stimulation and upper limb TST in chronic stroke. SETTING: University laboratory. PARTICIPANTS: Chronic (>=3mo) survivors of stroke (N=33; mean age, 62y; mean stroke duration, 38mo). INTERVENTIONS: Participants received 12 sessions of TST preceded by either active (n=16) or sham (n=17) somatosensory stimulation to all 3 peripheral nerves. MAIN OUTCOME MEASURES: Demographic and clinical characteristics were entered stepwise into multiple linear regression analyses to determine the factors that best predict baseline Motor Activity Log (MAL) amount of use rating and change 3 months after TST. RESULTS: The Action Research Arm Test (ARAT) score predicted the amount of use at baseline (R(2)=.47, P<.001); in using this model, an ARAT score of 54 (maximum of 57) is required to score 2.5 on the MAL (use described as between rarely and sometimes). After TST the change in the ARAT score predicted the change in the amount of use (R(2)=.31, P=.001). The predictive power of the model for change at 3 months increased if the Fugl-Meyer Assessment wrist component score was added (R(2)=.41, P=.001). CONCLUSIONS: Utilization of the paretic upper limb in activities of daily living requires high functional ability. The increase in self-reported arm use after TST is dependent on the change in functional ability. These results provide further guidance for rehabilitation decisions. PMID- 24480336 TI - Effects of wheelchair cushions and pressure relief maneuvers on ischial interface pressure and blood flow in people with spinal cord injury. AB - OBJECTIVE: To investigate the effectiveness and interactions of 2 methods of pressure ulcer prevention, wheelchair cushions and pressure relief maneuvers, on interface pressure (IP) and blood flow of the buttocks. DESIGN: Within-subject repeated measures. SETTING: Rehabilitation center. PARTICIPANTS: Wheelchair users with a spinal cord injury or disorder (N=17). INTERVENTIONS: Participants performed 3 forward leans and 2 sideward leans with different degrees of lean while seated on each of 3 different wheelchair cushions. MAIN OUTCOME MEASURES: IP measured with a custom sensor and blood flow measured with laser Doppler flowmetry were collected at the ischial tuberosity. RESULTS: Pressure relief maneuvers had a significant main effect on the ischial IP (P<.001); all maneuvers except for the small frontward lean resulted in a significant reduction in IP compared with upright sitting. Blood flow significantly varied across postures (P<.001) with flow during upright sitting and small forward leans being significantly lower than during the full and intermediate leans in both the forward and sideward directions. CONCLUSIONS: The results of the study highlight the importance of positioning wheelchair users in a manner that facilitates in seat movement. Regardless of the cushion being used, the pressure relief maneuvers resulted in very large reductions in IPs and significant increases in buttock blood flow. Only the small frontward lean was shown to be ineffective in reducing pressure or increasing blood flow. Because these pressure relief maneuvers involved postural changes that can occur during functional activities, these pressure relief maneuvers can become a part of volitional pressure relief and functional weight shifts. Therefore, clinical instruction should cover both as a means to impart sitting behaviors that may lead to better tissue health. PMID- 24480337 TI - Assessing public health policy approaches to level-up the gradient in health inequalities: the Gradient Evaluation Framework. AB - OBJECTIVES: This paper seeks to introduce and analyse the development of the Gradient Evaluation Framework (GEF) to facilitate evaluation of policy actions for their current or future use in terms of their 'gradient friendliness'. In particular, this means their potential to level-up the gradient in health inequalities by addressing the social determinants of health and thereby reducing decision-makers' chances of error when developing such policy actions. STUDY DESIGN: A qualitative developmental study to produce a policy-based evaluation framework. METHODS: The scientific basis of GEF was developed using a comprehensive consensus-building process. This process followed an initial narrative review, based on realist review principles, which highlighted the need for production of a dedicated evaluation framework. The consensus-building process included expert workshops, a pretesting phase, and external peer review, together with support from the Gradient project Scientific Advisory Group and all Gradient project partners, including its Project Steering Committee. RESULTS: GEF is presented as a flexible policy tool resulting from a consensus-building process involving experts from 13 European countries. The theoretical foundations which underpin GEF are discussed, together with a range of practical challenges. The importance of systematic evaluation at each stage of the policy development and implementation cycle is highlighted, as well as the socio-political context in which policy actions are located. CONCLUSIONS: GEF offers potentially a major contribution to the public health field in the form of a practical, policy relevant and common frame of reference for the evaluation of public health interventions that aim to level-up the social gradient in health inequalities. Further research, including the need for practical field testing of GEF and the exploration of alternative presentational formats, is recommended. PMID- 24480338 TI - Adipocyte-specific transgenic and knockout models. AB - Adipose tissue plays a major role in metabolic homeostasis, which it coordinates through a number of local and systemic effectors. The burgeoning epidemic of metabolic disease, especially obesity and type 2 diabetes, has focused attention on the adipocyte. In this chapter, we review strategies for genetic overexpression and knockout of specific genes in adipose tissue. We also discuss these strategies in the context of different types of adipocytes, including brown, beige, and white fat cells. PMID- 24480339 TI - Imaging white adipose tissue with confocal microscopy. AB - Adipose tissue is composed of a variety of cell types that include mature adipocytes, endothelial cells, fibroblasts, adipocyte progenitors, and a range of inflammatory leukocytes. These cells work in concert to promote nutrient storage in adipose tissue depots and vary widely based on location. In addition, overnutrition and obesity impart significant changes in the architecture of adipose tissue that are strongly associated with metabolic dysfunction. Recent studies have called attention to the importance of adipose tissue microenvironments in regulating adipocyte function and therefore require techniques that preserve cellular interactions and permit detailed analysis of three-dimensional structures in fat. This chapter summarizes our experience with the use of laser scanning confocal microscopy for imaging adipose tissue in rodents. PMID- 24480340 TI - Isolation and study of adipocyte precursors. AB - White adipose tissue (WAT) is a heterogeneous tissue composed of lipid-filled adipocytes and several nonadipocyte cell populations, including endothelial, blood, uncharacterized stromal, and adipocyte precursor cells. Although lipid filled adipocytes account for the majority of WAT volume and mass, nonadipocyte cell populations have critical roles in WAT maintenance, growth, and function. As mature adipocytes are terminally differentiated postmitotic cells, differentiation of adipocyte precursors is required for hyperplastic WAT growth during development and in obesity. In this chapter, we present methods to separate adipocyte precursor cells from other nonadipocyte cell populations within WAT for analysis by flow cytometry or purification by fluorescence activated cell sorting. Additionally, we provide methods to study the adipogenic capacity of purified adipocyte precursor cells ex vivo. PMID- 24480341 TI - Imaging of adipose tissue. AB - Adipose tissue is an endocrine organ that specializes in lipid metabolism and is distributed throughout the body in distinct white adipose tissue (WAT) and brown adipose tissue (BAT) depots. These tissues have opposing roles in lipid metabolism with WAT storing excessive caloric intake in the form of lipid, and BAT burning lipid through nonshivering thermogenesis. As accumulation of lipid in mature adipocytes of WAT leads to obesity and increased risk of comorbidity (Pi Sunyer et al., 1998), detailed understanding of the mechanisms of BAT activation and WAT accumulation could produce therapeutic strategies for combatting metabolic pathologies. As morphological changes accompany alterations in adipose function, imaging of adipose tissue is one of the most important tools for understanding how adipose tissue mass fluctuates in response to various physiological contexts. Therefore, this chapter details several methods of processing and imaging adipose tissue, including bright-field colorimetric imaging of paraffin-sectioned adipose tissue with a detailed protocol for automated adipocyte size analysis; fluorescent imaging of paraffin and frozen sectioned adipose tissue; and confocal fluorescent microscopy of whole mounted adipose tissue. We have also provided many example images showing results produced using each protocol, as well as commentary on the strengths and limitations of each approach. PMID- 24480342 TI - Adipose tissue angiogenesis assay. AB - Changes in adipose tissue mass must be accompanied by parallel changes in microcirculation. Investigating the mechanisms that regulate adipose tissue angiogenesis could lead to better understanding of adipose tissue function and reveal new potential therapeutic strategies. Angiogenesis is defined as the formation of new capillaries from existing microvessels. This process can be recapitulated in vitro, by incubation of tissue in extracellular matrix components in the presence of pro-angiogenic factors. Here, we describe a method to study angiogenesis from adipose tissue fragments obtained from mouse and human tissue. This assay can be used to define effects of diverse factors added in vitro, as well as the role of endogenously produced factors on angiogenesis. We also describe approaches to quantify angiogenic potential for the purpose of enabling comparisons between subjects, thus providing information on the role of physiological conditions of the donor on adipose tissue angiogenic potential. PMID- 24480343 TI - Quantifying size and number of adipocytes in adipose tissue. AB - White adipose tissue (WAT) is a dynamic and modifiable tissue that develops late during gestation in humans and through early postnatal development in rodents. WAT is unique in that it can account for as little as 3% of total body weight in elite athletes or as much as 70% in the morbidly obese. With the development of obesity, WAT undergoes a process of tissue remodeling in which adipocytes increase in both number (hyperplasia) and size (hypertrophy). Metabolic derangements associated with obesity, including type 2 diabetes, occur when WAT growth through hyperplasia and hypertrophy cannot keep pace with the energy storage needs associated with chronic energy excess. Accordingly, hypertrophic adipocytes become overburdened with lipids, resulting in changes in the secreted hormonal milieu. Lipids that cannot be stored in the engorged adipocytes become ectopically deposited in organs such as the liver, muscle, and pancreas. WAT remodeling therefore coincides with obesity and secondary metabolic diseases. Obesity, however, is not unique in causing WAT remodeling: changes in adiposity also occur with aging, calorie restriction, cancers, and diseases such as HIV infection. In this chapter, we describe a semiautomated method of quantitatively analyzing the histomorphometry of WAT using common laboratory equipment. With this technique, the frequency distribution of adipocyte sizes across the tissue depot and the number of total adipocytes per depot can be estimated by counting as few as 100 adipocytes per animal. In doing so, the method described herein is a useful tool for accurately quantifying WAT development, growth, and remodeling. PMID- 24480345 TI - Brown adipose tissue in humans: detection and functional analysis using PET (positron emission tomography), MRI (magnetic resonance imaging), and DECT (dual energy computed tomography). AB - If the beneficial effects of brown adipose tissue (BAT) on whole body metabolism, as observed in nonhuman experimental models, are to be translated to humans, tools that accurately measure how BAT influences human metabolism will be required. This chapter discusses such techniques, how they can be used, what they can measure and also some of their limitations. The focus is on detection and functional analysis of human BAT and how this can be facilitated by applying advanced imaging technology such as positron emission tomography, magnetic resonance imaging, and dual energy computed tomography. PMID- 24480344 TI - Use of osmium tetroxide staining with microcomputerized tomography to visualize and quantify bone marrow adipose tissue in vivo. AB - Adipocytes reside in discrete, well-defined depots throughout the body. In addition to mature adipocytes, white adipose tissue depots are composed of many cell types, including macrophages, endothelial cells, fibroblasts, and stromal cells, which together are referred to as the stromal vascular fraction (SVF). The SVF also contains adipocyte progenitors that give rise to mature adipocytes in those depots. Marrow adipose tissue (MAT) or marrow fat has long been known to be present in bone marrow (BM) but its origin, development, and function remain largely unknown. Clinically, increased MAT is associated with age, metabolic diseases, drug treatment, and marrow recovery in children receiving radiation and chemotherapy. In contrast to the other depots, MAT is unevenly distributed in the BM of long bones. Conventional quantitation relies on sectioning of the bone to overcome issues with distribution but is time-consuming, resource intensive, inconsistent between laboratories and may be unreliable as it may miss changes in MAT volume. Thus, the inability to quantitate MAT in a rapid, systematic, and reproducible manner has hampered a full understanding of its development and function. In this chapter, we describe a new technique that couples histochemical staining of lipid using osmium tetroxide with microcomputerized tomography to visualize and quantitate MAT within the medullary canal in three dimensions. Imaging of osmium staining provides a high-resolution map of existing and developing MAT in the BM. Because this method is simple, reproducible, and quantitative, we expect it will become a useful tool for the precise characterization of MAT. PMID- 24480346 TI - Analyzing the functions and structure of the human lipodystrophy protein seipin. AB - Disruption of the gene BSCL2, which encodes the protein seipin, causes severe generalized lipodystrophy in humans with a near complete absence of adipose tissue. Moreover, cell culture studies have demonstrated that seipin plays a critical cell-autonomous role in adipocyte differentiation. These observations reveal seipin as a critical regulator of human adipose tissue development; however, until recently very little has been known about the potential molecular functions of this intriguing protein. Despite significant recent interest in the function of seipin, our understanding of its molecular role(s) remains limited. The topology of seipin and lack of evidence for any enzymatic domains or activity indicate that it may act principally as a scaffold for other proteins or play a structural role in altering membrane curvature and/or budding. Work in this area has been hampered by several factors, including the lack of homology that might imply testable functions, the poor availability of antibodies to the endogenous protein and the observation that this hydrophobic ER membrane-resident protein is difficult to analyze by standard Western blotting techniques. Here we summarize some of the techniques we have applied to investigate the association of seipin with a recently identified binding partner, lipin 1. In addition, we describe the use of atomic force microscopy (AFM) to image oligomers of the seipin protein. We believe that AFM will offer a valuable tool to examine the association of candidate binding proteins with the seipin oligomer. PMID- 24480347 TI - Differentiation of human pluripotent stem cells into highly functional classical brown adipocytes. AB - We describe a detailed method for directed differentiation of human pluripotent stem cells, including human embryonic stem cells (hESCs) and human induced pluripotent stem cells (hiPSCs), into functional classical brown adipocytes (BAs) under serum-free and feeder-free conditions. It is a two-tiered culture system, based on very simple techniques, a floating culture and a subsequent adherent culture. It does not require gene transfer. The entire process can be carried out in about 10 days. The key point is the usage of our special hematopoietic cytokine cocktail. Almost all the differentiated cells express uncoupling protein 1, a BA-selective marker, as determined by immunostaining. The differentiated cells show characteristics of classical BA as assessed by morphology and gene/protein expression. Moreover, the expression of myoblast marker genes is transiently induced during the floating culture step. hESC/hiPSC-derived BAs show significantly higher oxygen consumption rates (OCRs) than white adipocytes generated from human mesenchymal stem cell. They also show responsiveness to adrenergic stimuli, with about twofold upregulation in OCR by beta-adrenergic receptor (beta-AR) agonist treatments. hESC/hiPSC-derived BAs exert in vivo calorigenic activities in response to beta-AR agonist treatments as assessed by thermography. Finally, lipid and glucose metabolisms are significantly improved in hESC/hiPSC-derived BA-transplanted mice. Our system provides a highly feasible way to produce functional classical BA bearing metabolism-improving capacities from hESC/hiPSC under a feeder-free and serum-free condition without gene transfer. PMID- 24480349 TI - Measurement and manipulation of human adipose tissue blood flow using xenon washout technique and adipose tissue microinfusion. AB - Adipose tissue (AT) is a very active organ, both metabolically and hormonally. These important functions depend on adequate blood flow (BF). Metabolic, hormonal, and vascular processes within AT are highly interconnected and any disruption will invariably impact the others. Therefore, any alteration of ATBF with obesity and/or insulin resistance will impact metabolic and hormonal AT functions. Similarly, metabolic or hormonal changes in AT will lead to ATBF disturbance. Thus, it is plausible that insufficient ATBF alters AT metabolic processes and response to regulatory signals, and may even aggravate the negative impacts of dysfunction in AT. The role of BF in AT metabolism can be evaluated by several techniques, but the xenon washout method is considered the "gold" standard. This technique can be combined with local microinfusion protocols, and the combination allows for precise assessment of mechanisms implicated in ATBF regulation. PMID- 24480348 TI - Analysis and measurement of the sympathetic and sensory innervation of white and brown adipose tissue. AB - Here, we provide a detailed account of how to denervate white and brown adipose tissue (WAT and BAT) and how to measure sympathetic nervous system (SNS) activity to these and other tissues neurochemically. The brain controls many of the functions of WAT and BAT via the SNS innervation of the tissues, especially lipolysis and thermogenesis, respectively. There is no clearly demonstrated parasympathetic innervation of WAT or the major interscapular BAT (IBAT) depot. WAT and BAT communicate with the brain neurally via sensory nerves. We detail the surgical denervation (eliminating both innervations) of several WAT pads and IBAT. We also detail more selective chemical denervation of the SNS innervation via intra-WAT/IBAT 6-hydroxy-dopamine (a catecholaminergic neurotoxin) injections and selective chemical sensory denervation via intra-WAT/IBAT capsaicin (a sensory nerve neurotoxin) injections. Verifications of the denervations are provided (HPLC-EC detection for SNS, ELIA for calcitonin gene-related peptide (proven sensory nerve marker)). Finally, assessment of the SNS drive to WAT/BAT or other tissues is described using the alpha-methyl-para-tyrosine method combined with HPLC-EC, a direct neurochemical measure of SNS activity. These methods have proven useful for us and for other investigators interested in innervation of adipose tissues. The chemical denervation approach has been extended to nonadipose tissues as well. PMID- 24480351 TI - Genome-wide profiling of transcription factor binding and epigenetic marks in adipocytes by ChIP-seq. AB - The recent advances in high-throughput sequencing combined with various other technologies have allowed detailed and genome-wide insight into the transcriptional networks that control adipogenesis. Chromatin immunoprecipitation (ChIP) combined with high-throughput sequencing (ChIP-seq) is one of the most widely used of these technologies. Using these methods, association of transcription factors, cofactors, and epigenetic marks can be mapped to DNA in a genome-wide manner. Here, we provide a detailed protocol for performing ChIP-seq analyses in preadipocytes and adipocytes. We have focused mainly on critical points, limitations of the assay, and quality controls required in order to obtain reproducible ChIP-seq data. PMID- 24480350 TI - Isolation and quantitation of adiponectin higher order complexes. AB - Adiponectin is a circulating bioactive hormone secreted by adipocytes as oligomers ranging in size from 90 kDa trimers and 180 kDa hexamers to larger high molecular weight oligomers that may reach 18- or 36-mers in size. While total circulating adiponectin levels correlate well with metabolic health, it is the relative distribution of adiponectin complexes that is most clinically relevant to glucose sensitivity and inflammation. High molecular weight adiponectin best mirrors insulin sensitivity, while trimeric adiponectin dominates with insulin resistance and adipose tissue inflammation. Experimental animal and in vitro models have also linked the relative fraction of high molecular weight adiponectin to its positive effects. Quantitating adiponectin size distribution thus provides a window into metabolic health and can serve as a surrogate marker for adipose tissue fitness. Here, we present a detailed protocol for isolating and quantitating adiponectin complexes in serum or plasma that has been extensively utilized for both human clinical samples and numerous animal models under various experimental conditions. Examples are presented of different adiponectin distributions and tips are provided for optimization using available equipment. Comparison of this rigorous approach to other available methods is also discussed. In total, this summary is a blueprint for the expanded quantitation and study of adiponectin complexes. PMID- 24480352 TI - Analysis and isolation of adipocytes by flow cytometry. AB - Analysis and isolation of adipocytes via flow cytometry is particularly useful to study their biology. However, the adoption of this technology has often been hampered by the presence of stromal/vascular cells in adipocyte fractions prepared from collagenase-digested adipose tissue. Here, we describe a multistep staining method and gating strategy that effectively excludes stromal contaminants. Initially, we set a gate optimized to the size and internal complexity of adipocytes. Exclusion of cell aggregates is then performed based on fluorescence of a nuclear stain followed by positive selection to collect only those cell events containing lipid droplets. Lastly, negative selection of cells expressing stromal or vascular lineage markers removes any remaining stromal contaminants. These procedures are applicable to simple analysis of adipocytes and their subcellular constituents by flow cytometry as well as isolation of adipocytes by flow sorting. PMID- 24480353 TI - Flow cytometry analyses of adipose tissue macrophages. AB - Within adipose tissue, multiple leukocyte interactions contribute to metabolic homeostasis in health as well as to the pathogenesis of insulin resistance with obesity. Adipose tissue macrophages (ATMs) are the predominant leukocyte population in fat and contribute to obesity-induced inflammation. Characterization of ATMs and other leukocytes in the stromal vascular fraction from fat has benefited from the use of flow cytometry and flow-assisted cell sorting techniques. These methods permit the immunophenotyping, quantification, and purification of these unique cell populations from multiple adipose tissue depots in rodents and humans. Proper isolation, quantification, and characterization of ATM phenotypes are critical for understanding their role in adipose tissue function and obesity-induced metabolic diseases. Here, we present the flow cytometry protocols for phenotyping ATMs in lean and obese mice employed by our laboratory. PMID- 24480355 TI - Ankylosing spondylitis and a diagnostic dilemma: coccydynia. AB - OBJECTIVES: Coccydynia is defined as pain in or around the tail bone area. The most common cause of coccydynia is either a trauma such as a fall directly on to the coccyx or repetitive minor trauma. The etiology remains obscure in up to 30% of patients. The literature on the contribution of rheumatic diseases to coccydynia is scarce. Our objective was to investigate the prevalence of coccydynia in ankylosing spondylitis (AS) patients. METHODS: One hundred and seven consecutive patients with AS were evaluated for coccydynia were enrolled between January and November 2012 for a cross-sectional analysis. Seventy-four consecutive patients were followed for mechanical back pain as controls and the AS patients were interviewed for the presence of coccydynia. The data collected was evaluated on SPSS(r) version 11.5 and Microsoft Excel(r) Programmes. RESULTS: Prevalence of coccydynia in AS (38.3%) was significantly higher than the control group (p<0.0001) in both female and male AS patients (female AS vs. control=40.9% vs. 18.4%, p=0.015 and male AS vs. control=36.5% vs. 8.0%, p=0.005). Both genders were affected equally in the AS group whereas coccydynia was slightly more frequent in female patients in the control group. CONCLUSIONS: Coccydynia is a previously neglected symptom of AS and it is almost three times more common in AS than in non-specific chronic low back pain. Our observation may implicate that inflammatory diseases have a role in the etiology of coccydynia, especially in those without a history of recent or past trauma and coccydynia may be a factor associated with the severity of AS as well. PMID- 24480356 TI - Synthesis and biological evaluation of 1-(isoxazol-5-ylmethylaminoethyl)-4-phenyl tetrahydropyridine and piperidine derivatives as potent T-type calcium channel blockers with antinociceptive effect in a neuropathic pain model. AB - New tetrahydropyridinyl and piperidinyl ethylamine derivatives were designed with hypothetical mapping on pharmacophore model generated from ligand-based virtual screening. The designed compounds were synthesized, and their inhibitory activities on T-type calcium channel were assayed using FDSS and patch-clamp assay. Among them, compounds 7b and 10b showed potent T-type calcium current blocking activity against Ca(v)3.1 (alpha(1G)) and Ca(v)3.2 (alpha(1H)) channel simultaneously. With hERG and pharmacokinetics studies, compounds 7b and 10b were evaluated for the antinociceptive effect on rat model of neuropathic pain. They were significantly effective in decreasing the pain responses to mechanical and cold allodynia induced by spinal nerve ligation. These results suggest that modulation of alpha(1G) and alpha(1H) subtype T-type calcium channels may provide a promising approach for the treatment of neuropathic pain. PMID- 24480357 TI - Development of new LXR modulators that regulate LXR target genes and reduce lipogenesis in human cell models. AB - Four new mimics of 22-S-hydroxycholesterol (22SHC) were synthesized and evaluated using molecular modeling and tested in human muscle cells (primary myotubes) and hepatocytes (HepG2 cells). The new compounds (9, 12, 15a and 15b) showed good interrelationship between docking scores, to both LXRalpha and LXRbeta, and in vitro results. The LXR agonist T0901317 increased the expressions of genes involved in lipogenesis (SCD1, FAS) and cholesterol efflux (ABCA1), but only 22SHC counteracted the up-regulation of SCD1 and FAS by T0901317. Compound 9 and 12 decreased the expression of SCD1, while 9 also decreased the expression of FAS. Compounds 15a showed a significant antagonistic effect on ABCA1 expression, but neither 15a nor 15b were able to counteract the effect of T0901317 on all genes examined. Lipogenesis was increased after T0901317 treatment and only 22SHC significantly counteracted this effect. Treatment with 22SHC and compound 12 reduced lipogenesis compared to control. An increased glucose uptake was observed for all compounds, except for 15b. In summary, the new synthetic 22SHC mimics showed antagonistic effects similar to that of 22SHC, but the new substances were less potent. The sulfonamide 12 showed similar effects to 22SHC and the best effect on gene expression of the new mimics, however, it was not able to reduce the effect of T0901317 as observed for 22SHC. PMID- 24480358 TI - Synthesis and biological evaluation of thiazoline derivatives as new antimicrobial and anticancer agents. AB - N'-(3,4-Diarylthiazol-2(3H)-ylidene)-2-(arylthio)acetohydrazides were synthesized and evaluated for their antimicrobial activity and cytotoxicity against NIH/3T3 cells. Compound 22 bearing 1-phenyl-1H-tetrazole and p-chlorophenyl moieties was found to be the most promising antibacterial agent against Pseudomonas aeruginosa, whereas compound 23 bearing 1-phenyl-1H-tetrazole and p-bromophenyl moieties was the most promising antifungal agent against Candida albicans. The most effective derivatives were also evaluated for their cytotoxicity against C6 glioma cells. The results indicated that compound 17 bearing 1-phenyl-1H tetrazole and nonsubstituted phenyl moieties (IC50 = 8.3 +/- 2.6 MUg/mL) was more effective than cisplatin (IC50 = 13.7 +/- 1.2 MUg/mL) against C6 glioma cells. Compound 17 also exhibited DNA synthesis inhibitory activity on C6 cells. Furthermore, compound 17 showed low toxicity to NIH/3T3 cells (IC50 = 416.7 +/- 28.9 MUg/mL). PMID- 24480359 TI - Semi-synthesis of acylated triterpenes from olive-oil industry wastes for the development of anticancer and anti-HIV agents. AB - A broad set of potential bioactive conjugate compounds has been semi-synthesized through solution- and solid-phase organic procedures, coupling two natural pentacyclic triterpene acids, oleanolic (OA) and maslinic acids (MA), at the hydroxyl groups of the A-ring of the triterpene skeleton, with 10 different acyl groups. These acyl OA and MA derivatives have been tested for their anti proliferative (against the b16f10 murine melanoma cancer cells) and antiviral (as inhibitors of the HIV-1-protease) effects. Several derivatives have shown high levels of early and total apoptosis (up to 90%). Most of the compounds that exhibited anti-proliferative effects also generated ROS, probably involving the activation of an intrinsic apoptotic route. The only four compounds that did not cause the release of ROS could be related to the participation of a probable extrinsic activation of the apoptosis mechanism. A great number of these acyl OA and MA derivatives have proved to be potent inhibitors of the HIV-1-protease, the most active inhibitors having IC50 values between 0.31 and 15.6 MUM, these values being between 4 and 186 times lower than their non-acylated precursors. The potent activities exhibited in the apoptosis-activation processes and in the inhibition of the HIV-1-protease by some OA and MA acylated derivatives imply that these compounds could be used as new, safe, and effective anticancer and/or antiviral drugs. PMID- 24480360 TI - beta-Glucuronidase-responsive prodrugs for selective cancer chemotherapy: an update. AB - The design of novel antitumor agents allowing the destruction of malignant cells while sparing healthy tissues is one of the major challenges in medicinal chemistry. In this context, the use of non-toxic prodrugs programmed to be selectively activated by beta-glucuronidase present at high concentration in the microenvironment of most solid tumors has attracted considerable attention. This review summarizes the major progresses that have been realized in this field over the past ten years. This includes the new prodrugs that have been designed to target a wide variety of anticancer drugs, the prodrugs employed in the course of a combined therapy, the dendritic glucuronide prodrugs and the concept of beta glucuronidase-responsive albumin binding prodrugs. PMID- 24480361 TI - Time perspective and medication adherence among individuals with hypertension or diabetes mellitus. AB - OBJECTIVE: The study determined if time perspective was associated with medication adherence among people with hypertension and diabetes. METHODS: Using the Health Beliefs Model, we used path analysis to test direct and indirect effects of time perspective and health beliefs on adherence among 178 people who participated in a community-based survey near Washington, D.C. We measured three time perspectives (future, present fatalistic, and present hedonistic) with the Zimbardo Time Perspective Inventory and medication adherence by self-report. RESULTS: The total model demonstrated a good fit (RMSEA=0.17, 90% CI [0.10, 0.28], p=0.003; comparative fit index=0.91). Future time perspective and age showed direct effects on increased medication adherence; an increase by a single unit in future time perspective was associated with a 0.32 standard deviation increase in reported adherence. There were no significant indirect effects of time perspective with reported medication adherence through health beliefs. CONCLUSION: The findings provide the first evidence that time perspective plays an under-recognized role as a psychological motivator in medication adherence. PRACTICE IMPLICATIONS: Patient counseling for medication adherence may be enhanced if clinicians incorporate consideration of the patient's time perspective. PMID- 24480362 TI - Human second trimester amniotic fluid cells are able to create embryoid body-like structures in vitro and to show typical expression profiles of embryonic and primordial germ cells. AB - Human amniotic fluid-derived stem cells (AFSCs) represent a novel class of broadly multipotent stem cells sharing characteristics of both embryonic and adult stem cells. However, both the origin of these cells and their actual properties in terms of pluripotent differentiation potential are still debated. In order to verify the presence of features of pluripotency in human second trimester AFSCs, we have investigated the ability of these cells to form in vitro three-dimensional aggregates, known as embryoid bodies (EBs), and to express specific genes of embryonic stem cells (ESCs) and primordial germ cells (PGCs). EBs were obtained after 5 days of AFSC culture in suspension and showed positivity for alkaline phosphatase (AP) staining and for specific markers of pluripotency (OCT4 and SOX2). Moreover, EB-derived cells showed the expression of specific transcripts of the three germ layers. RT-PCR analysis, carried out at different culture times (second, third, fourth, fifth, and eighth passages), revealed the presence of specific markers of ESCs (such as FGF4 and DAPPA4), as well as of markers typical of PGCs and, in particular, genes involved in early stages of germ cell development (Fragilis, Stella, Vasa, c-Kit, Rnf17). Finally, the expression of genes related to the control of DNA methylation (DNMT3A, DNMT3b1, DNMT1, DNMT3L, MBD1, MBD2, MBD3, MDB4, MeCP2), as well as the lack of inactivation of the X-chromosome in female samples, was also demonstrated. Taken together, these data provide further evidence for the presence of common features among human AFSCs, PGCs, and ESCs. PMID- 24480363 TI - Noradrenergic modulation of vicarious trial-and-error behavior during a spatial decision-making task in rats. AB - Deliberation between possible options before making a decision is crucial to responding with an optimal choice. However, the neural mechanisms regulating this deliberative decision-making process are still unclear. Recent studies have proposed that the locus coeruleus-noradrenaline (LC-NA) system plays a role in attention, behavioral flexibility, and exploration, which contribute to the search for an optimal choice under uncertain situations. In the present study, we examined whether the LC-NA system relates to the deliberative process in a T-maze spatial decision-making task in rats. To quantify deliberation in rats, we recorded vicarious trial-and-error behavior (VTE), which is considered to reflect a deliberative process exploring optimal choices. In experiment 1, we manipulated the difficulty of choice by varying the amount of reward pellets between the two maze arms (0 vs. 4, 1 vs. 3, 2 vs. 2). A difficulty-dependent increase in VTE was accompanied by a reduction of choice bias toward the high reward arm and an increase in time required to select one of the two arms in the more difficult manipulation. In addition, the increase of c-Fos-positive NA neurons in the LC depended on the task difficulty and the amount of c-Fos expression in LC-NA neurons positively correlated with the occurrence of VTE. In experiment 2, we inhibited LC-NA activity by injection of clonidine, an agonist of the alpha2 autoreceptor, during a decision-making task (1 vs. 3). The clonidine injection suppressed occurrence of VTE in the early phase of the task and subsequently impaired a valuable choice later in the task. These results suggest that the LC NA system regulates the deliberative process during decision-making. PMID- 24480366 TI - Histone deacetylase inhibitors valproic acid and sodium butyrate enhance prostaglandins release in lipopolysaccharide-activated primary microglia. AB - Modifications of histone deacetylases (HDACs) may be involved in microglia-driven neuroinflammatory responses. Recent studies suggest that several inflammatory molecules can regulate the extent of neurodegeneration and regeneration in the central nervous system (CNS). In the present study, we investigated the effects of HDAC inhibitors (HDACi) valproic acid (VPA) and sodium butyrate (NaBut) on the release of prostaglandins (PGs) in lipopolysaccharide (LPS)-activated microglia. We found that VPA and NaBut significantly enhanced LPS-induced release of PGE2, PGD2 and 8-iso-PGF2alpha. In addition, both compounds increased cyclooxygenase-2 and microsomal prostaglandin E synthase immunoreactivity and gene expression in LPS-stimulated microglia. Interestingly, treatment of activated microglia with HDACi also enhanced the gene expression and the release of different pro inflammatory cytokines. Microglia activation with LPS leads to IkappaB-alpha degradation, as well as p38, ERK1/2 and JNK MAPKs phosphorylation and thus activation, which is not affected by treatment with VPA and NaBut. Furthermore, VPA and NaBut treatment induced histone acetylation at H3-K18 in microglia. We suggest that VPA and NaBut-driven increase in PGs release in LPS-activated microglia might be regulated at the transcriptional level and involves histone hyperacetylation. Our data demonstrate that VPA and NaBut are able to modulate microglia responses to inflammatory insults and thus possibly can regulate the CNS degenerative and regenerative processes. PMID- 24480365 TI - Two functional inhibitory circuits are comprised of a heterogeneous population of fast-spiking cortical interneurons. AB - Cortical fast spiking (FS) interneurons possess autaptic, synaptic, and electrical synapses that serve to mediate a fast, coordinated response to their postsynaptic targets. While FS interneurons are known to participate in numerous and diverse actions, functional subgroupings within this multi-functional interneuron class remain to be identified. In the present study, we examined parvalbumin-positive FS interneurons in layer 4 of the primary somatosensory (barrel) cortex - a brain region well-known for specialized inhibitory function. Here we show that FS interneurons fall into two broad categories identified by the onset of the first action potential in a depolarizing train as: "delayed firing FS interneurons (FSD) and early onset firing FS interneurons (FSE). Subtle variations in action potential firing reveal six subtypes within these two categories: delayed non-accommodating (FSD-NAC), delayed stuttering (FSD-STUT), early onset stuttering (FSE-STUT), early onset-late spiking (FSE-LS), early onset early-spiking (FSE-ES), and early onset accommodating (FSE-AC). Using biophysical criteria previously employed to distinguish neuronal cell types, the FSD and FSE categories exhibit several shared biophysical and synaptic properties that coincide with the notion of specificity of inhibitory function within the cortical FS interneuron class. PMID- 24480364 TI - The role of an inwardly rectifying K(+) channel (Kir4.1) in the inner ear and hearing loss. AB - The KCNJ10 gene which encodes an inwardly rectifying K(+) channel Kir4.1 subunit plays an essential role in the inner ear and hearing. Mutations or deficiency of KCNJ10 can cause hearing loss with EAST or SeSAME syndromes. This review mainly focuses on the expression and function of Kir4.1 potassium channels in the inner ear and hearing. We first introduce general information about inwardly rectifying potassium (Kir) channels. Then, we review the expression and function of Kir4.1 channels in the inner ear, especially in endocochlear potential (EP) generation. Finally, we review KCNJ10 mutation-induced hearing loss and functional impairments. Kir4.1 is strongly expressed on the apical membrane of intermediate cells in the stria vascularis and in the satellite cells of cochlear ganglia. Functionally, Kir4.1 has critical roles in cochlear development and hearing through two distinct aspects of extracellular K(+) homeostasis: First, it participates in the generation and maintenance of EP and high K(+) concentration in the endolymph inside the scala media. Second, Kir4.1 is the major K(+) channel in satellite glial cells surrounding spiral ganglion neurons to sink K(+) ions expelled by the ganglion neurons during excitation. Kir4.1 deficiency leads to hearing loss with the absence of EP and spiral ganglion neuron degeneration. Deafness mutants show loss-of-function and reduced channel membrane-targeting and currents, which can be rescued upon by co-expression with wild-type Kir4.1. This review provides insights for further understanding Kir potassium channel function in the inner ear and the pathogenesis of deafness due to KCNJ10 deficiency, and also provides insights for developing therapeutic strategies targeting this deafness. PMID- 24480368 TI - Mediterranean alcohol-drinking pattern and mortality in the SUN (Seguimiento Universidad de Navarra) Project: a prospective cohort study. AB - Moderate alcohol intake has been related to lower mortality. However, alcohol use includes other dimensions beyond the amount of alcohol consumed. These aspects have not been sufficiently studied as a comprehensive entity. We aimed to test the relationship between an overall alcohol-drinking pattern and all-cause mortality. In a Mediterranean cohort study, we followed 18 394 Spanish participants up to 12 years. A validated 136-item FFQ was used to assess baseline alcohol intake. We developed a score assessing simultaneously seven aspects of alcohol consumption to capture the conformity to a traditional Mediterranean alcohol-drinking pattern (MADP). It positively scored moderate alcohol intake, alcohol intake spread out over the week, low spirit consumption, wine preference, red wine consumption, wine consumed during meals and avoidance of binge drinking. During the follow-up, 206 deaths were identified. For each 2-point increment in a 0-9 score of adherence to the MADP, we observed a 25% relative risk reduction in mortality (95% CI 11, 38%). Within each category of alcohol intake, a higher adherence to the MADP was associated with lower mortality. Abstainers (excluded from the calculations of the MADP) exhibited higher mortality (hazard ratio 1.82, 95% CI 1.14, 2.90) than participants highly adherent to the MADP. In conclusion, better adherence to an overall healthy alcohol-drinking pattern was associated with reduced mortality when compared with abstention or departure from this pattern. This reduction goes beyond the inverse association usually observed for moderate alcohol drinking. Even moderate drinkers can benefit from the advice to follow a traditional MADP. PMID- 24480367 TI - Rat whisker movement after facial nerve lesion: evidence for autonomic contraction of skeletal muscle. AB - Vibrissal whisking is often employed to track facial nerve regeneration in rats; however, we have observed similar degrees of whisking recovery after facial nerve transection with or without repair. We hypothesized that the source of non-facial nerve-mediated whisker movement after chronic denervation was from autonomic, cholinergic axons traveling within the infraorbital branch of the trigeminal nerve (ION). Rats underwent unilateral facial nerve transection with repair (N=7) or resection without repair (N=11). Post-operative whisking amplitude was measured weekly across 10weeks, and during intraoperative stimulation of the ION and facial nerves at ?18weeks. Whisking was also measured after subsequent ION transection (N=6) or pharmacologic blocking of the autonomic ganglia using hexamethonium (N=3), and after snout cooling intended to elicit a vasodilation reflex (N=3). Whisking recovered more quickly and with greater amplitude in rats that underwent facial nerve repair compared to resection (P<0.05), but individual rats overlapped in whisking amplitude across both groups. In the resected rats, non-facial-nerve-mediated whisking was elicited by electrical stimulation of the ION, temporarily diminished following hexamethonium injection, abolished by transection of the ION, and rapidly and significantly (P<0.05) increased by snout cooling. Moreover, fibrillation-related whisker movements decreased in all rats during the initial recovery period (indicative of reinnervation), but re-appeared in the resected rats after undergoing ION transection (indicative of motor denervation). Cholinergic, parasympathetic axons traveling within the ION innervate whisker pad vasculature, and immunohistochemistry for vasoactive intestinal peptide revealed these axons branching extensively over whisker pad muscles and contacting neuromuscular junctions after facial nerve resection. This study provides the first behavioral and anatomical evidence of spontaneous autonomic innervation of skeletal muscle after motor nerve lesion, which not only has implications for interpreting facial nerve reinnervation results, but also calls into question whether autonomic-mediated innervation of striated muscle occurs naturally in other forms of neuropathy. PMID- 24480369 TI - Domestic liquefied petroleum gas: are we using a kitchen bomb? AB - The aim of this study is to understand the aetiological factors and pattern of burns caused by the use of liquefied petroleum gas (LPG). This hospital based study was conducted on consecutive patients admitted with major burns from September 2011 to August 2012. The data was recorded on predesigned data sheet. Age, gender, mode of injury, its exact mechanism, place of incidence, extent of burn and inhalation injury were recorded for every patient. 182 patients with LPG related burn injury were admitted in one year. This is 11% of total burn patients received during the same period (182/1656). 147 incidents caused these burns due to gas leak from various parts of the LPG cooking system. Leakage was either from the cylinder, pipe or stove in 52%, 36% and 2% incidents respectively. Human error accounted for 3% incidents while in 7% the mechanism could not be ascertained. Leakage from 5kg cylinder with pipe was the commonest aetiological factor. There were 14 group casualties with more than one victim involved. LPG related burns are preventable to a large extent. There is a need to improve the safety standards in the LPG stove system. Public awareness needs to be improved. PMID- 24480370 TI - A study of energy-related injuries from hospital admissions among children and adults in South Africa. AB - INTRODUCTION: Burn and ingestion injuries are common in developing countries because of poor access to safe energy sources, crowded living conditions, and insufficient knowledge of potential risks. The purpose of this study is to understand the scope of burn and ingestion injuries due to various energy source usages in South Africa. METHODS: Patients at 16 regional hospitals throughout South Africa presenting with an energy-related injury between 2006 and 2012 were interviewed to obtain demographics and injury characteristics. RESULTS: A total of 12,443 patients were included in this study. Children aged 1-2 years predominantly experienced burn and ingestion injuries (21%). Liquid burns (30%) were more common than flame burns (14%). Chi-squared tests show that age was significantly related to degree of burn, type of burn, and severity of burn (p<0.001). Non-intentional injuries (45%) were more frequent than self-inflicted or assault injuries. Temporal and seasonal injury trends reflect usage patterns. Burn injuries result in longer hospital length of stay than ingestion injuries. CONCLUSION: Non-intentional liquid burns and ingestions to infants and babies were most common in this study, with many injuries also occurring among young adults. It is advised that interventions targeting low-income communities be conducted to increase awareness of burn and ingestion injuries. PMID- 24480371 TI - Segmentation of abdominal organs from CT using a multi-level, hierarchical neural network strategy. AB - Precise measurements on abdominal organs are vital prior to the important clinical procedures. Such measurements require accurate segmentation of these organs, which is a very challenging task due to countless anatomical variations and technical difficulties. Although, several features with various classifiers have been designed to overcome these challenges, abdominal organ segmentation via classification is still an emerging field in order to reach desired precision. Recent studies on multiple feature-classifier combinations show that hierarchical systems outperform composite feature-single classifier models. In this study, how hierarchical formations can translate to improved accuracy, when large size feature spaces are involved, is explored for the problem of abdominal organ segmentation. As a result, a semi-automatic, slice-by-slice segmentation method is developed using a novel multi-level and hierarchical neural network (MHNN). MHNN is designed to collect complementary information about organs at each level of the hierarchy via different feature-classifier combinations. Moreover, each level of MHNN receives residual data from the previous level. The residual data is constructed to preserve zero false positive error until the last level of the hierarchy, where only most challenging samples remain. The algorithm mimics analysis behaviour of a radiologist by using the slice-by-slice iteration, which is supported with adjacent slice similarity features. This enables adaptive determination of system parameters and turns into the advantage of online training, which is done in parallel to the segmentation process. Proposed design can perform robust and accurate segmentation of abdominal organs as validated by using diverse data sets with various challenges. PMID- 24480372 TI - A HIPAA-compliant key management scheme with revocation of authorization. AB - Patient control over electronic protected health information (ePHI) is one of the major concerns in the Health Insurance and Accountability Act (HIPAA). In this paper, a new key management scheme is proposed to facilitate control by providing two functionalities. First, a patient can authorize more than one healthcare institute within a designated time period to access his or her ePHIs. Second, a patient can revoke authorization and add new authorized institutes at any time as necessary. In the design, it is not required to re-encrypt ePHIs for adding and revoking authorizations, and the implementation is time- and cost-efficient. Consent exception is also considered by the proposed scheme. PMID- 24480373 TI - Micafungin for the treatment of invasive aspergillosis. AB - Invasive aspergillosis is a major cause of morbidity and mortality in immunocompromised patients, particularly those with neutropenia and those undergoing bone marrow or stem cell transplants. Micafungin is an echinocandin antifungal drug with activity against all major Candida spp. Currently, micafungin is indicated for treatment of invasive candidiasis, oesophageal candidiasis and prophylaxis of Candida infection in patients undergoing allogeneic haematopoietic stem cell transplantation or patients who are expected to have neutropenia. Micafungin demonstrates in vitro and in vivo activity against Aspergillus spp. It is currently not licensed to treat Aspergillus infections in the UK or USA. This review summarises the current evidence base surrounding the clinical use of micafungin in the treatment of invasive aspergillosis to consider the potential role of micafungin in these patients. There are currently no randomised studies comparing micafungin with standard antifungal therapy. Prospective non-randomised clinical studies, predominantly performed in Japan, involving 492 patients with aspergillosis and 455 febrile patients with chemotherapy-induced neutropenia suggest that micafungin may be as effective as comparator antifungal agents. Other clinical evidence is limited to case reports. Further experience in the form of randomised controlled trials is required to establish the exact role of micafungin in the context of currently available broad-spectrum antifungal agents. PMID- 24480374 TI - Control point analysis comparison for 3 different treatment planning and delivery complexity levels using a commercial 3-dimensional diode array. AB - To investigate the use of "Control Point Analysis" (Sun Nuclear Corporation, Melbourne, FL) to analyze and compare delivered volumetric-modulated arc therapy (VMAT) plans for 3 different treatment planning complexity levels. A total of 30 patients were chosen and fully anonymized for the purpose of this study. Overall, 10 lung stereotactic body radiotherapy (SBRT), 10 head-and-neck (H&N), and 10 prostate VMAT plans were generated on Pinnacle(3) and delivered on a Varian linear accelerator (LINAC). The delivered dose was measured using ArcCHECK (Sun Nuclear Corporation, Melbourne, FL). Each plan was analyzed using "Sun Nuclear Corporation (SNC) Patient 6" and "Control Point Analysis." Gamma passing percentage was used to assess the differences between the measured and planned dose distributions and to assess the role of various control point binning combinations. Of the different sites considered, the prostate cases reported the highest gamma passing percentages calculated with "SNC Patient 6" (97.5% to 99.2% for the 3%, 3mm) and "Control Point Analysis" (95.4% to 98.3% for the 3%, 3mm). The mean percentage of passing control point sectors for the prostate cases increased from 51.8 +/- 7.8% for individual control points to 70.6 +/- 10.5% for 5 control points binned together to 87.8 +/- 11.0% for 10 control points binned together (2%, 2-mm passing criteria). Overall, there was an increasing trend in the percentage of sectors passing gamma analysis with an increase in the number of control points binned together in a sector for both the gamma passing criteria (2%, 2mm and 3%, 3mm). Although many plans passed the clinical quality assurance criteria, plans involving the delivery of high Monitor Unit (MU)/control point (SBRT) and plans involving high degree of modulation (H&N) showed less delivery accuracy per control point compared with plans with low MU/control point and low degree of modulation (prostate). PMID- 24480375 TI - Dosimetric comparison of 3D conformal, IMRT, and V-MAT techniques for accelerated partial-breast irradiation (APBI). AB - The purpose is to dosimetrically compare the following 3 delivery techniques: 3 dimensional conformal radiation therapy (3D-CRT), intensity-modulated arc therapy (IMRT), and volumetric-modulated arc therapy (V-MAT) in the treatment of accelerated partial-breast irradiation (APBI). Overall, 16 patients with T1/2N0 breast cancer were treated with 3D-CRT (multiple, noncoplanar photon fields) on the RTOG 0413 partial-breast trial. These cases were subsequently replanned using static gantry IMRT and V-MAT technology to understand dosimetric differences among these 3 techniques. Several dosimetric parameters were used in plan quality evaluation, including dose conformity index (CI) and dose-volume histogram analysis of normal tissue coverage. Quality assurance studies including gamma analysis were performed to compare the measured and calculated dose distributions. The IMRT and V-MAT plans gave more conformal target dose distributions than the 3D-CRT plans (p < 0.05 in CI). The volume of ipsilateral breast receiving 5 and 10Gy was significantly less using the V-MAT technique than with either 3D-CRT or IMRT (p < 0.05). The maximum lung dose and the ipsilateral lung volume receiving 10 (V10) or 20Gy (V20) were significantly less with both V MAT and IMRT (p < 0.05). The IMRT technique was superior to 3D-CRT and V-MAT of low dose distributions in ipsilateral lung (p < 0.05 in V5 and D5). The total mean monitor units (MUs) for V-MAT (621.0 +/- 111.9) were 12.2% less than those for 3D-CRT (707.3 +/- 130.9) and 46.5% less than those for IMRT (1161.4 +/- 315.6) (p < 0.05). The average machine delivery time was 1.5 +/- 0.2 minutes for the V-MAT plans, 7.0 +/- 1.6 minutes for the 3D-CRT plans, and 11.5 +/- 1.9 minutes for the IMRT plans, demonstrating much less delivery time for V-MAT. Based on this preliminary study, V-MAT and IMRT techniques offer improved dose conformity as compared with 3D-CRT techniques without increasing dose to the ipsilateral lung. In terms of MU and delivery time, V-MAT is significantly more efficient for APBI than for conventional 3D-CRT and static-beam IMRT. PMID- 24480376 TI - Volumetric tumor burden and its effect on brachial plexus dosimetry in head and neck intensity-modulated radiotherapy. AB - To determine the effect of gross tumor volume of the primary (GTV-P) and nodal (GTV-N) disease on planned radiation dose to the brachial plexus (BP) in head and neck intensity-modulated radiotherapy (IMRT). Overall, 75 patients underwent definitive IMRT to a median total dose of 69.96Gy in 33 fractions. The right BP and left BP were prospectively contoured as separate organs at risk. The GTV was related to BP dose using the unpaired t-test. Receiver operating characteristics curves were constructed to determine optimized volumetric thresholds of GTV-P and GTV-N corresponding to a maximum BP dose cutoff of > 66Gy. Multivariate analyses were performed to account for factors associated with a higher maximal BP dose. A higher maximum BP dose (> 66 vs <= 66Gy) correlated with a greater mean GTV-P (79.5 vs 30.8cc; p = 0.001) and ipsilateral GTV-N (60.6 vs 19.8cc; p = 0.014). When dichotomized by the optimized nodal volume, patients with an ipsilateral GTV N >= 4.9 vs < 4.9cc had a significant difference in maximum BP dose (64.2 vs 59.4Gy; p = 0.001). Multivariate analysis confirmed that an ipsilateral GTV-N >= 4.9cc was an independent predictor for the BP to receive a maximal dose of > 66Gy when adjusted individually for BP volume, GTV-P, the use of a low anterior neck field technique, total planned radiation dose, and tumor category. Although both the primary and the nodal tumor volumes affected the BP maximal dose, the ipsilateral nodal tumor volume (GTV-N >= 4.9cc) was an independent predictor for high maximal BP dose constraints in head and neck IMRT. PMID- 24480377 TI - VEGF and Id-1 in pancreatic adenocarcinoma: prognostic significance and impact on angiogenesis. AB - OBJECTIVES: The significance of vascular endothelial growth factor (VEGF) and inhibitor of differentiation/DNA synthesis (Id-1) in tumor neoangiogenesis and tumor progression in pancreatic ductal adenocarcinoma (PDAC) is still unclear. Given the central role of VEGF in cancer angiogenesis and the inconclusive results on Id-1 expression in PDAC, it is of great interest to investigate whether Id-1 and VEGF expression are associated with angiogenesis and prognosis in PDAC. METHODS: Paraffin-embedded specimens from 60 consecutive patients with PDAC were immunostained for VEGF, Id-1 and CD34 and staining quantification was assessed by Image analysis system. The correlations among the expression of individual angiogenic factors and microvessel density (MVD), clinicopathologic features and clinical prognosis were analyzed. RESULTS: Id-1 and VEGF Positive Activity Indices (PAIs) closely correlated with each other. MVD positively correlated with both Id-1 and VEGF expression. More advanced T and N status correlated with more intense expression of Id-1, VEGF and higher MVD. With regard to prognostic significance higher Id-1 PAI (adjusted HR = 1.69, 95%CI: 1.10-2.59, p = 0.017), higher VEGF PAI (adjusted HR = 2.66, 95%CI: 1.09-6.50, p = 0.032), and MVD (adjusted HR = 1.55, 95%CI: 1.27-1.88, p < 0.001) were associated with poorer survival. CONCLUSIONS: VEGF and Id-1 overexpression were found to be associated with high MVD and emerged as adverse prognostic factors in terms of patient survival in PDAC. The potential of selective anti-angiogenic targeting therapy for pancreatic malignancies should prompt further validation of the present findings in studies encompassing larger samples and more elaborate techniques. PMID- 24480378 TI - Incremental use of biomarkers and electrocardiogram in differentiating takotsubo cardiomyopathy from acute myocardial infarction: a potential way to go. PMID- 24480379 TI - Biomarkers to differentiate takotsubo syndrome from acute myocardial infarction: are the corresponding electrocardiograms of any use? PMID- 24480380 TI - Reliability and validity of the Beck Depression Inventory-Fast Screen for medical patients in the general German population. AB - BACKGROUND: The Beck Depression Inventory Fast Screen (BDI-FS) is a self-report instrument for the detection of depression in youths and adults. It measures the severity of the depression, corresponding to the non-somatic criteria for the diagnosis of a major depression according to DSM-5. Until now the psychometric properties of the instrument have not been studied in the general population. METHODS: In 2012, a survey representative for the Federal Republic of Germany was conducted. In addition to the BDI-FS, further self-rating questionnaires as well as a demographic questionnaire were administered. RESULTS: Altogether, 4480 people were surveyed with a return rate of 56.1% (N=2467 persons). Approximately 53% of those surveyed were women. The average age was 49.4 years (SD=18.0), with a range of 14-91 years. For the BDI-FS total-scores, a coefficient alpha of .84 was determined (women: alpha=.83; men: alpha=.85). In addition, a convergent validity (r=.67) was determined with the Patient Health Questionnaire (PHQ-9). The discriminant validity of the BDI-FS can be classified as satisfactory. Based on a confirmatory factor analysis, the one-dimensionality of the BDI-FS could be confirmed, achieving very good fit indices (total sample: RMSEA=.058, CFI=.990, TLI=.986). An additional invariance analysis regarding gender, different age groups and their interaction resulted in strict invariance for the different multi-group analyses. LIMITATIONS: Studies regarding stability have yet to be undertaken. A standard diagnostic interview for depression was not included. CONCLUSION: The results support the reliability and validity of the BDI-FS for use with the general German population. Although in the present studies the BDI FS was superior to the PHQ-9 in terms of its ability to discriminate between depressive and somatic symptoms, in future investigations the diagnostic efficiency of the BDI-FS should be compared with this and other depression inventories (e.g., PHQ-2, PHQ-8, and CES-D). PMID- 24480381 TI - Plastic ingestion by Flesh-footed Shearwaters (Puffinus carneipes): Implications for fledgling body condition and the accumulation of plastic-derived chemicals. AB - To provide much needed quantitative data on the lethal and sublethal effects of plastic pollution on marine wildlife, we sampled breast feathers and stomach contents from Flesh-footed Shearwater (Puffinus carneipes) fledglings in eastern Australia. Birds with high levels of ingested plastic exhibited reduced body condition and increased contaminant load (p < 0.05). More than 60% of fledglings exceed international targets for plastic ingestion by seabirds, with 16% of fledglings failing these targets after a single feeding (range: 0.13-3.21 g of plastic/feeding). As top predators, seabirds are considered sentinels of the marine environment. The amount of plastic ingested and corresponding damage to Flesh-footed Shearwater fledglings is the highest reported for any marine vertebrate, suggesting the condition of the Australian marine environment is poor. These findings help explain the ongoing decline of this species and are worrying in light of increasing levels of plastic pollution in our oceans. PMID- 24480382 TI - Novel dinorcassane- and cassane-type diterpenes from the seeds of Caesalpinia minax. AB - Two novel diterpenes, norcaesalpinin I (1) featuring an unusual ring C-contracted dinorcassane and caesalpinin U (2) possessing a highly oxygenated furanocassane skeleton were isolated from the seeds of Caesalpinia minax. Their structures were determined by different spectroscopic methods. A plausible biosynthetic pathway of 1 was proposed. The cytotoxic activity of compounds 1 and 2 against HepG2 and HeLa human tumor cell lines was evaluated. PMID- 24480383 TI - Steroidal saponins from dragon's blood of Dracaena cambodiana. AB - Six new steroidal saponins, cambodianosides A-F (1-6), together with seven known ones, were isolated from the dragon's blood of Dracaena cambodiana. The structures of 1-6 were elucidated on the basis of detailed spectroscopic analysis, including 1D and 2D NMR techniques and chemical methods. The cytotoxicities of all the isolated compounds were evaluated in vitro against three human cancer cell lines, and compounds 7, 8, and 11 showed significant inhibitory activities. PMID- 24480384 TI - Evaluation of Pharmacy and Therapeutic (P&T) Committee member knowledge, attitudes and ability regarding the use of comparative effectiveness research (CER) in health care decision-making. AB - BACKGROUND: Comparative effectiveness research (CER) is a constellation of research methods designed to improve health care decision making. Educational programs that improve health care decision makers' CER knowledge and awareness may ultimately lead to more cost-effective use of health care resources. OBJECTIVES: This study was conducted to evaluate changes in CER knowledge, attitudes, and ability among Pharmacy and Therapeutics (P&T) Committee members and support staff after attending a tailored educational program. METHODS: Physicians and pharmacists from two professional societies and the Indian Health Service who participated in the P&T process were invited via email to participate in this study. Participants completed a questionnaire, designed specifically for this study, prior to and following the 4-hour live, educational program on CER to determine the impact on their related knowledge, attitudes, and ability to use CER in decision-making. Rasch analysis was used to assess validity and reliability of subsections of the questionnaire and regression analysis was used to assess programmatic impact on CER knowledge, attitude, and ability. RESULTS: One hundred and forty of the 199 participants completed both the pre- and post CER session questionnaires (response rate = 70.4%). Most participants (>75%) correctly answered eight of the ten knowledge items after attending the educational session. More than 60% of the respondents had a positive attitude toward CER both before and after the program. Compared to baseline (pretest), participants reported significant improvements in their perceived ability to use CER after attending the session in these areas: using CER reviews, knowledge of CER methods, identifying problems with randomized controlled trials, identifying threats to validity, understanding of evidence synthesis approaches, and evaluating the quality of CER (all P values < 0.001). The questionnaire demonstrated acceptable reliability and validity evidence (limited evidence of construct under-representation and construct irrelevant variance). CONCLUSIONS: The CER educational program was effective in increasing participants' CER knowledge and self-perceived ability to evaluate relevant evidence. Improving knowledge and awareness of CER and its applicability is a critical first step in improving its use in health care decision making. PMID- 24480385 TI - Retinoids and breast cancer: from basic studies to the clinic and back again. AB - All-trans retinoic acid (ATRA) is the most important active metabolite of vitamin A controlling segmentation in the developing organism and the homeostasis of various tissues in the adult. ATRA as well as natural and synthetic derivatives, collectively known as retinoids, are also promising agents in the treatment and chemoprevention of different types of neoplasia including breast cancer. The major aim of the present article is to review the basic knowledge acquired on the anti-tumor activity of classic retinoids, like ATRA, in mammary tumors, focusing on the underlying cellular and molecular mechanisms and the determinants of retinoid sensitivity/resistance. In the first part, an analysis of the large number of pre-clinical studies available is provided, stressing the point that this has resulted in a limited number of clinical trials. This is followed by an overview of the knowledge acquired on the role played by the retinoid nuclear receptors in the anti-tumor responses triggered by retinoids. The body of the article emphasizes the potential of ATRA and derivatives in modulating and in being influenced by some of the most relevant cellular pathways involved in the growth and progression of breast cancer. We review the studies centering on the cross-talk between retinoids and some of the growth-factor pathways which control the homeostasis of the mammary tumor cell. In addition, we consider the cross talk with relevant intra-cellular second messenger pathways. The information provided lays the foundation for the development of rational and retinoid-based therapeutic strategies to be used for the management of breast cancer. PMID- 24480386 TI - Who is predisposed to insomnia: a review of familial aggregation, stress reactivity, personality and coping style. AB - Insomnia is a common health complaint world-wide. Insomnia is a risk factor in the development of other psychological and physiological disorders. Therefore understanding the mechanisms which predispose an individual to developing insomnia has great transdiagnostic value. However, whilst it is largely accepted that a vulnerable phenotype exists there is a lack of research which aims to systematically assess the make-up of this phenotype. This review outlines the research to-date, considering familial aggregation and the genetics and psychology of stress-reactivity. A model will be presented in which negative affect (neuroticism) and genetics (5HTTLPR) are argued to lead to disrupted sleep via an increase in stress-reactivity, and further that the interaction of these variables leads to an increase in learned negative associations, which further increase the likelihood of poor sleep and the development of insomnia. PMID- 24480387 TI - Biosynthesis and physiology of coenzyme Q in bacteria. AB - Ubiquinone, also called coenzyme Q, is a lipid subject to oxido-reduction cycles. It functions in the respiratory electron transport chain and plays a pivotal role in energy generating processes. In this review, we focus on the biosynthetic pathway and physiological role of ubiquinone in bacteria. We present the studies which, within a period of five decades, led to the identification and characterization of the genes named ubi and involved in ubiquinone production in Escherichia coli. When available, the structures of the corresponding enzymes are shown and their biological function is detailed. The phenotypes observed in mutants deficient in ubiquinone biosynthesis are presented, either in model bacteria or in pathogens. A particular attention is given to the role of ubiquinone in respiration, modulation of two-component activity and bacterial virulence. This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. PMID- 24480388 TI - Novel type of red-shifted chlorophyll a antenna complex from Chromera velia. I. Physiological relevance and functional connection to photosystems. AB - Chromera velia is an alveolate alga associated with scleractinian corals. Here we present detailed work on chromatic adaptation in C. velia cultured under either blue or red light. Growth of C. velia under red light induced the accumulation of a light harvesting antenna complex exhibiting unusual spectroscopic properties with red-shifted absorption and atypical 710nm fluorescence emission at room temperature. Due to these characteristic features the complex was designated "Red shifted Chromera light harvesting complex" (Red-CLH complex). Its detailed biochemical survey is described in the accompanying paper (Bina et al. 2013, this issue). Here, we show that the accumulation of Red-CLH complex under red light represents a slow acclimation process (days) that is reversible with much faster kinetics (hours) under blue light. This chromatic adaptation allows C. velia to maintain all important parameters of photosynthesis constant under both light colors. We further demonstrated that the C. velia Red-CLH complex is assembled from a 17kDa antenna protein and is functionally connected to photosystem II as it shows variability of chlorophyll fluorescence. Red-CLH also serves as an additional locus for non-photochemical quenching. Although overall rates of oxygen evolution and carbon fixation were similar for both blue and red light conditions, the presence of Red-CLH in C. velia cells increases the light harvesting potential of photosystem II, which manifested as a doubled oxygen evolution rate at illumination above 695nm. This data demonstrates a remarkable long-term remodeling of C. velia light-harvesting system according to light quality and suggests physiological significance of 'red' antenna complexes. PMID- 24480389 TI - Effects of rituximab therapy on elastic properties of vascular wall in patients with progressive systemic sclerosis. PMID- 24480390 TI - Cryptosporidium parvum GP60 subtypes in dairy cattle from Buenos Aires, Argentina. AB - Cryptosporidium parvum from 73 dairy calves less than two months old from Buenos Aires province (Argentina) were molecularly characterized using sequence analysis of the GP60 gene. Seventy-five sequences were obtained, and seven different subtypes were identified, all belonging to the IIa subtype family. The most common subtypes were IIaA20G1R1 (27/75), IIaA22G1R1 (16/75), and IIaA18G1R1 (13/75). Subtypes IIaA21G1R1, IIaA23G1R1, IIaA16G1R1 and IIaA19G1R1 were found sporadically. Two samples contained mixed infections with IIaA21G1R1 and IIaA22G1R1. A significant association was found between subtypes and geographic location, whereas there was no relation between subtypes and presence of diarrhea. Three of the subtypes found in this study (IIaA16G1R1, IIaA18G1R1, and IIaA19G1R1) were previously identified in humans. These findings suggest that cattle could play an important role in the transmission of cryptosporidiosis to humans in Buenos Aires province. PMID- 24480392 TI - Affordable Care Act will boost incomes of poorest people, study shows. PMID- 24480391 TI - Interaction of benzo[a]pyrene with other risk factors in hepatocellular carcinoma: a case-control study in Xiamen, China. AB - PURPOSE: Large epidemiologic studies about the relationship between benzo[a]pyrene (B[a]P) and hepatocellular carcinoma (HCC) have been limited. B[a]P diol epoxide (BPDE) is a highly reactive metabolite of B[a]P that binds covalently to form DNA adducts. We evaluated the interaction between B[a]P exposure with other risk factors in HCC, in a case-control study of 345 HCC and 961 healthy controls. METHODS: Concentration of BPDE-DNA adducts in blood was determined by enzyme-linked immunosorbent assay. The interaction between BPDE-DNA adducts and other risk factors on HCC were evaluated by multivariate logistic regression analysis. RESULTS: Mean concentration of BPDE-DNA adducts in blood of cases was significantly higher than that of the controls. The risk of HCC increased with elevated concentration of BPDE-DNA adducts (x(2) = 203.57, Ptrend < .001) and the odds ratio was 7.44 (95% confidence interval, 5.29-10.45) for the first versus fourth quartile of adduct levels. The relative excess risk due to interaction between BPDE-DNA adducts and hepatitis B virus surface antigen and drinking was 34.71 and 54.92, and the attributable proportion due to interaction was 41.53% and 75.59%, respectively. CONCLUSIONS: The high level of BPDE-DNA adducts in blood is associated with HCC and that environmental exposure to B[a]P may increase the risk of HCC, especially among drinkers and populations with hepatitis B virus infection. PMID- 24480393 TI - One in four US families reports financial burdens due to medical costs, government study finds. PMID- 24480394 TI - Spain's largest healthcare privatisation plan is halted. PMID- 24480395 TI - India moves closer to regulating prices of patented drugs. PMID- 24480396 TI - Oral immunotherapy for peanut allergy shows promise but questions remain. PMID- 24480397 TI - Judge allows a caesarean section to go ahead on a patient without her consent. PMID- 24480398 TI - Implicit cognitive processes in binge-eating disorder and obesity. AB - OBJECTIVES: Binge-eating disorder (BED) is characterized by recurrent binge eating episodes, associated eating disorder and general psychopathology, and commonly occurs in obese individuals. Explicit self-esteem and explicit weight bias have been linked to BED, while little is known about implicit cognitive processes such as implicit self-esteem and implicit weight bias. METHODS: Obese participants with BED and an individually matched obese only group (OB) and normal weight control group (CG; each N = 26) were recruited from the community to examine group differences and associations in explicit and implicit self esteem and weight bias, as well as the impact of implicit cognitive processes on global eating disorder psychopathology. Implicit cognitive processes were assessed using the Implicit Association Test. RESULTS: Significantly lower explicit self-esteem, as well as higher exposure to explicit weight bias, compared to CG and OB was found in the BED group. All groups showed positive implicit self-esteem, however, it was significantly lower in BED when compared to CG. BED and CG demonstrated equally high implicit weight bias whereas OB did not. Explicit and implicit measures were not significantly correlated. Global eating disorder psychopathology was predicted by explicit and implicit self-esteem. CONCLUSIONS: The results of the present study add to the importance of implicit self-esteem and implicit weight bias beyond explicit measures in BED, while both were previously shown to be associated with onset and maintenance of BED. In conclusion, implicit cognitive processes should be focused on in interventions for BED to investigate their impact on psychological treatments. PMID- 24480399 TI - Emergency department and 'Google flu trends' data as syndromic surveillance indicators for seasonal influenza. AB - We evaluated syndromic indicators of influenza disease activity developed using emergency department (ED) data - total ED visits attributed to influenza-like illness (ILI) ('ED ILI volume') and percentage of visits attributed to ILI ('ED ILI percent') - and Google flu trends (GFT) data (ILI cases/100 000 physician visits). Congruity and correlation among these indicators and between these indicators and weekly count of laboratory-confirmed influenza in Manitoba was assessed graphically using linear regression models. Both ED and GFT data performed well as syndromic indicators of influenza activity, and were highly correlated with each other in real time. The strongest correlations between virological data and ED ILI volume and ED ILI percent, respectively, were 0.77 and 0.71. The strongest correlation of GFT was 0.74. Seasonal influenza activity may be effectively monitored using ED and GFT data. PMID- 24480400 TI - Supplementation of the diet with Salecan attenuates the symptoms of colitis induced by dextran sulphate sodium in mice. AB - As a water-soluble extracellular beta-glucan produced by Agrobacterium sp. ZX09, Salecan has an excellent toxicological profile and exerts multiple physiological effects. The aims of the present study were to investigate the protective effects of a Salecan diet in the well-defined dextran sulphate sodium (DSS) model of experimental murine colitis and to elucidate the mechanism involved in its effects with special attention being paid to its effect on the production of TNF alpha, a primary mediator involved in the inflammatory response. Male C57BL/6J mice were fed a diet supplemented with either 4 or 8 % Salecan for 26 d and DSS was administered to induce acute colitis during the last 5 d of the experimental period. Several clinical and inflammatory parameters as well as mRNA expression of TNF-alpha and Dectin-1 were evaluated. The results indicated that the dietary incorporation of Salecan attenuated the severity of DSS colitis as evidenced by the decreased disease activity index, reduced severity of anaemia, attenuated changes in colon architecture and reduced colonic myeloperoxidase activity. This protection was associated with the down-regulation of TNF-alpha mRNA levels, which might derive from its ability to increase Dectin-1 mRNA levels. In conclusion, the present study suggests that Salecan contributes to the reduction of colonic damage and inflammation in mice with DSS-induced colitis and holds promise as a new, effective nutritional supplement in the management of inflammatory bowel disease. PMID- 24480401 TI - Long-term survival and differentiation of human neural stem cells in nonhuman primate brain with no immunosuppression. AB - Cellular fate of human neural stem cells (hNSCs) transplanted in the brain of nonhuman primates (NHPs) with no immunosuppression was determined at 22 and 24 months posttransplantation (PTx) regarding survival, differentiation, and tumorigenesis. Survival of hNSCs labeled with magnetic nanoparticles was successfully detected around injection sites in the brain at 22 months PTx by MRI. Histological examination of brain sections with H&E and Prussian blue staining at 24 months revealed that most of the grafted hNSCs were found located along the injection tract. Grafted hNSCs were found to differentiate into neurons at 24 months PTx. In addition, none of the grafted hNSCs were bromodeoxyuridine positive in the monkey brain, indicating that hNSCs did not replicate in the NHP brain and did not cause tumor formation. This study serves as a proof of principle and provides evidence that hNSCs transplanted in NHP brain could survive and differentiate into neurons in the absence of immunosuppression. It also serves as a preliminary study in our scheduled preclinical studies of hNSC transplantation in NHP stroke models. PMID- 24480402 TI - The effect of baseline morphology and its change during treatment on the accuracy of Response Evaluation Criteria in Solid Tumours in assessment of liver metastases. AB - PURPOSE: Tumour response assessment to therapy is crucial in oncology. We analysed the morphology of liver metastases (LM) in gastrointestinal stromal tumour (GIST) patients to determine whether uni-dimensional measurement of lesions by Response Evaluation Criteria in Solid Tumours (RECIST), accurately reflects lesion volume. MATERIALS AND METHODS: The volumes of LM (n=139) from a GIST patient cohort were measured using computed tomography (CT) at baseline, 3, 6 and 12 months after commencement of imatinib therapy. Baseline measurements were obtained by two independent investigators and inter-observer agreement assessed using Bland-Altman plots. Actual lesion volumes (V(ACTUAL)) were measured and compared with volumes based on the RECIST measure (V(RECIST)), and with volumes based on three orthogonal measures (V(ELLIPSOID)) at several time points. RESULTS: At baseline, the inter-observer bias for V(ACTUAL) was just 1.8%. V(RECIST) and V(ELLIPSOID) overestimated V(ACTUAL) by a mean of 35% and only 9% respectively (P<0.0001 for both). At baseline, 44% (61/139) of LM were classified as spheroidal and 56% (78/139) as ellipsoidal. During treatment, only 42% of LM retained their original morphology. The remainder demonstrated significant changes in morphology (from spheroidal to ellipsoidal and vice versa) over time, while the RECIST measure did not reflect such changes. CONCLUSIONS: The morphology of LM in GIST is rarely spherical (an underlying assumption for RECIST) and can change considerably during imatinib therapy. In this setting, measurements using RECIST do not reflect changes in size and morphology. Additionally, whilst V(ELLIPSOID) is a more suitable surrogate for volume estimation, it is still somewhat limited by the morphology and orientation of such lesions. Studies are warranted to further explore the clinical impact of these findings. PMID- 24480403 TI - Chemoradiotherapy, with adjuvant surgery for local control, confers a durable survival advantage in adenocarcinoma and squamous cell carcinoma of the oesophagus. AB - INTRODUCTION: Oesophageal cancer usually presents with systemic disease, necessitating systemic therapy. Neo-adjuvant chemoradiotherapy improves short term survival, but its long-term impact is disputed because of limited accrual, treatment-protocol heterogeneity and a short follow-up of randomised trials. AIMS: Long-term results of two simultaneous randomised controlled trials (RCTs) comparing neo-adjuvant chemo-radiotherapy and surgery (MMT) with surgical monotherapy were examined, and the response of adenocarcinoma (AC) and squamous cell carcinoma (SCC) to identical regimens compared. METHODS: Between 1990 and 1997, two RCTs were undertaken on 211 patients. Patients with AC (n=113) or SCC (n=98) were separately-randomised to identical protocols of MMT or surgical monotherapy. RESULTS: 211 patients were followed to 206 months; 104 patients were randomised to MMT (58 AC and 46 SCC, respectively) and 107 to surgery. MMT provided a significant survival-advantage over surgical monotherapy for AC (P=0.004), SCC (P=0.01). There was a 54% relative risk-reduction in lymph-node metastasis following MMT, compared with surgery (64% versus 29%, P<0.001). MMT produced a pathologic complete response (pCR) in 25% and 31% of AC and SCC, respectively. Survival advantage accrued to MMT, pCR and node-negative patients: AC pCR versus surgical monotherapy (P=0.001); residual disease following MMT versus surgical monotherapy (P=0.008); SCC pCR versus surgical monotherapy (P=0.033). CONCLUSIONS: A survival advantage for MMT persisted long-term in AC and was replicated in SCC. MMT produced loco-regional tumour down-staging to extinction in 25-31% of patients, potentially permitting personalised treatment in this cohort that avoids the morbidity and mortality associated with resection. Node-negative patients with residual localised disease following MMT had a survival advantage over node-negative patients following surgery alone, supporting a systemic effect on micro-metastatic disease. PMID- 24480404 TI - Lipidomics in situ: insights into plant lipid metabolism from high resolution spatial maps of metabolites. AB - The emergence of 'omics' technologies (i.e. genomics, proteomics, metabolomics, etc.) have revealed new avenues for exploring plant metabolism through data-rich experimentation and integration of complementary methodologies. Over the past decade, the lipidomics field has benefited from advances in instrumentation, especially mass spectrometry (MS)-based approaches that are well-suited for detailed lipid analysis. The broad classification of what constitutes a lipid lends itself to a structurally diverse range of molecules that contribute to a variety of biological processes in plants including membrane structure and transport, primary and secondary metabolism, abiotic and biotic stress tolerances, extracellular and intracellular signaling, and energy-rich storage of carbon. Progress in these research areas has been advanced in part through approaches analyzing chemical compositions of lipids in extracts from cells, tissues and/or whole organisms (e.g. shotgun lipidomics), and through visualization approaches primarily through microscopy-based methodologies (e.g. fluorescence, bright field, electron microscopy, etc.). While these techniques on their own provide rich biochemical and biological information, coordinated analyses of the complexity of lipid composition with the localization of these lipids at a high spatial resolution will help to develop a new level of understanding of lipid metabolism within the context of tissue/cellular compartmentation. This review will elaborate on recent advances of one such approach--mass spectrometry imaging (MSI)--that integrates in situ visualization with chemical-based lipidomics. We will illustrate, with an emphasis on oilseed lipid metabolism, how MS imaging can provide new insights and questions related to the spatial compartmentation of lipid metabolism in plants. Further it will be apparent that this MS imaging approach has broad application in plant metabolic research well beyond that of triacylglycerol biosynthesis in oilseeds. PMID- 24480405 TI - A constitutive model of porous SMAs considering tensile-compressive asymmetry behaviors. AB - A constitutive model of the macroscopic behaviors of porous shape memory alloys (SMA) is developed in this work. A yield function for porous SMAs considering both the effect of hydrostatic stress and the tensile-compressive asymmetry is proposed. Combining the constitutive model of dense SMAs and the macroscale and microscale analysis, the evolution equation for the overall transformation strain is then derived. Examples for the response of both dense SMA and porous Ni-Ti SMA subjected to uniaxial tension and compression loads are supplied. Good agreement between the numerical prediction results and the published experimental data is observed. Numerical result shows that the yielding stresses, loop width and length, strain-hardening behaviors of porous SMAs under pure tensile and pure compressive are different. Importantly, the transformation initiation stress is much closer to the experiment result than simulated by Zhao et al. (2005). PMID- 24480406 TI - Differential expression of tyrosine hydroxylase and transporters in the right and left stellate ganglion of socially isolated rats. AB - Chronic isolation stress of adult rat males acted increasing gene expression of tyrosine hydroxylase (TH) and neuronal norepinephrine transporter (NET) in the right stellate ganglia, while vesicular monoamine transporter 2 (VMAT2) level remained unchanged. The stress decreased protein level of TH, as well as mRNA levels for NET and VMAT2 in the left stellate ganglia, but expressed no effect on protein levels of these two transporters. These results demonstrate asymmetry in noradrenergic genes in the right and left stellate ganglia during stress and provide molecular evidence to help explain the difference in response to the stress. PMID- 24480407 TI - Lifelong consequences of early nutritional conditions on learning performance in zebra finches (Taeniopygia guttata). AB - Long-term effects of early developmental conditions on physiological and behavioural traits are common in animals. Yet, such lifelong effects of early life conditions on learning skills received relatively less attention, even though they are expected to have strong fitness effects. To test the lifelong impact of the early environment on associative and reversal learning performance, we tested zebra finches (Taeniopygia guttata) in a reversal learning task about five years after they were raised either under low or high quality food treatments in their first month of life. The early nutritional treatment and its respective growth patterns significantly influenced learning performance: Zebra finches who received a high-quality nutrition early in life gained more weight during the treatment period but needed more trials to associate a cue with a reward. The early growth rate during the treatment phase was linked to how fast the birds detected the food at the onset of training in our learning task as well as to their associative learning performance. However, in the reversal learning step of the task testing for behavioural flexibility, no differences with respect to early nutritional treatments or related growth rates were apparent. We show that early life conditions directly affect the approach to our task and learning abilities over an entire lifetime, emphasizing how crucial the early environment is for understanding adult behaviour throughout life. PMID- 24480408 TI - Illness-dependent conditioned prey avoidance in an amphibian. AB - Conditioned taste avoidance (CTA) helps prevent consumption of dangerous foods. It results from the pairing of a novel food or taste with subsequent aversive consequences, such as illness. Previous studies of CTA in amphibians have produced conflicting results. Establishing the presence or absence of CTA in amphibians is needed to clarify the phylogeny of this phenomenon. This experiment evaluated the ability of the fire-bellied toad Bombina orientalis to avoid a novel food item previously paired with subsequent illness or unpalatable taste. Mealworms, a novel prey item for the subjects, were coated with a solution of either 2% HCl or 3% CuSO4 to make them unpalatable or nauseating, respectively. Lengthy and obvious signs of illness such as face wiping and retching followed the consumption of mealworms coated with CuSO4, whereas consumption of mealworms coated with HCl only resulted in distinct and short lived aversive reactions at the time of consumption. The results showed that consumption of mealworms tainted with CuSO4, but not HCl, rapidly induced prey avoidance. This response was specific to mealworms; the usual food (crickets) was not avoided. The results suggest that CTA following illness is not restricted to amniote vertebrates. PMID- 24480409 TI - Regulation of innate immune responses by transmembrane interactions: lessons from the TLR family. AB - The mammalian innate immune response is responsible for the early stages of defense against invading pathogens. One of the major receptor families facilitating innate immune activation is the Toll-like receptor (TLR) family. These receptors are type 1 membrane proteins spanning the membrane with a single transmembrane domain (TMD). All TLRs form homo- and hetero-dimers within membranes and new data suggest that the single transmembrane domain of some of these receptors is involved in their dimerization and function. Newly identified TLR dimers are continuously reported but only little is known about the importance of the TMDs for their dimer assembly and signaling regulation. Uncontrolled or untimely activation of TLRs is related to a large number of pathologies ranging from cystic fibrosis to sepsis and cancer. In this review we will focus on the contribution of the TMDs of innate immune receptors - specifically TLR2-to their regulation and function. In addition, we will address the current issues remaining to be solved regarding the mechanistic insights of this regulation. This article is part of a Special Issue entitled: Membrane Structure and Function: Relevance in the Cell's Physiology, Pathology and Therapy. PMID- 24480410 TI - Human heat shock protein 70 (Hsp70) as a peripheral membrane protein. AB - While a significant fraction of heat shock protein 70 (Hsp70) is membrane associated in lysosomes, mitochondria, and the outer surface of cancer cells, the mechanisms of interaction have remained elusive, with no conclusive demonstration of a protein receptor. Hsp70 contains two Trps, W90 and W580, in its N-terminal nucleotide binding domain (NBD), and the C-terminal substrate binding domain (SBD), respectively. Our fluorescence spectroscopy study using Hsp70 and its W90F and W580F mutants, and Hsp70-?SBD and Hsp70-?NBD constructs, revealed that binding to liposomes depends on their lipid composition and involves both NBD and SBD. Association of Hsp70 with phosphatidylcholine (PC) liposomes is weak, with insertion of its Trps into the bilayer hydrocarbon region. In the presence of cardiolipin (CL), bis-monoacylglycero phosphate (BMP), or phosphatidylserine (PS) Hsp70 attaches to membranes peripherally, without penetration. Our data suggest that the organelle distribution of Hsp70 is determined by their specific lipid compositions, with Hsp70 associating with the above lipids in mitochondria, lysosomes, and the surface of cancer cells, respectively. NBD and SBD attach to lipids by extended phospholipid anchorage, with specific acidic phospholipids associating with Hsp70 in the extended conformation with acyl chains inserting into hydrophobic crevices within Hsp70, and other chains remaining in the bilayer. This anchorage is expected to cause a stringent orientation of Hsp70 on the surface. Our data further suggest that acidic phospholipids induce a transition of SBD into the molten globule state, which may be essential to allow SBD-substrate interaction also within the hydrophobic bilayer interior acyl chain region. PMID- 24480411 TI - Borna disease virus infection in cats. AB - Bornaviruses are known to cause neurological disorders in a number of animal species. Avian Bornavirus (ABV) causes proventricular dilatation disease (PDD) in birds and Borna disease virus (BDV) causes Borna disease in horses and sheep. BDV also causes staggering disease in cats, characterised by ataxia, behavioural changes and loss of postural reactions. BDV-infection markers in cats have been reported throughout the world. This review summarizes the current knowledge of Borna disease viruses in cats, including etiological agent, clinical signs, pathogenesis, epidemiology and diagnostics, with comparisons to Bornavirus infections in other species. PMID- 24480412 TI - PTPN2 rs1893217 single-nucleotide polymorphism is associated with risk of Behcet's disease in a Chinese Han population. AB - OBJECTIVES: Behcet's disease (BD) is a rare, chronic, relapsing, systemic, immune mediated vasculitis and the etiology remains to be defined. This study investigated single-nucleotide polymorphisms (SNP) of tyrosine-protein phosphatase non-receptor type 2 (PTPN2) and inducible T-cell co-stimulator-ligand gene (ICOSLG) in Chinese Han BD patients and healthy controls because SNPs of these two genes are associated with risk of developing other auto-inflammation diseases. METHODS: A total of 407 BD patients and 679 ethnically matched healthy controls were recruited for genotyping of PTPN2 rs1893217, rs2542151, rs2847297 and rs7234029 SNPs and ICOSLG rs2838519 and rs762421 SNPs using a Sequenom MassArray system. RESULTS: PTPN2 rs1893217 was associated with risk of developing BD (chi2=10.01, pc=0.040), while the PTPN2 rs2542151 genotype had a weak association in basic genotype analysis (chi2=7.49, p=0.024), but it could not withstand the strongest Bonferroni correction (pc=0.14). In contrast, PTPN2 rs2847297 and rs7234029 and ICOSLG rs2838519 and rs762421 did not correlate with BD risk. Moreover, logistic analysis with the additive, dominant and recessive genetic models did not reveal any statistical difference between BD cases and controls (pc>0.05). In addition, associations were observed between the two SNPs (rs1893217, rs2542151) and the patients with gastrointestinal involvement (pc=0.027, pc=0.032, respectively). CONCLUSIONS: PTPN2 variant rs1893217 was associated with risk of BD development in a Han Chinese population. Further study will confirm this finding and investigate the role of PTPN2 in development of BD. PMID- 24480413 TI - Forebrain glycine transporter 1 deletion enhances sensitivity to CS-US discontiguity in classical conditioning. AB - The deletion of glycine transporter 1 (GlyT1) in forebrain neurons can apparently strengthen Pavlovian aversive conditioning, but this phenotype is not expressed if conditioning followed non-reinforced pre-exposures of the to-be-conditioned stimulus (CS). To examine whether GlyT1 disruption may only enhance aversive associative learning under conditions that most favour the formation of CS-US excitatory link, we evaluated the impact of GlyT1 disruption on the trace conditioning procedure whereby a trace interval between a tone CS and a shock US was introduced during conditioning. CS and US occurrences were thus rendered discontiguous, which was expected to impede conditioning compared with contiguous CS-US pairing. Conditioned freezing to the CS was measured in a retention test conducted 48 h after conditioning. The genetic disruption significantly modified the temporal dynamics of the freezing response over the course of the 8-min presentation of the CS, although the immediate conditioned response to the CS was unaffected. The separation between "trace" and "no-trace" conditions was augmented in the mutant mice, but this only became apparent in mid-session; and the augmentation can be attributed to the combined effects of (i) weaker conditioned freezing in the mutant relative to control subjects in the "trace" condition, and (ii) stronger conditioned freezing in mutants relative controls in the "no-trace" condition. The demonstrated increased sensitivity to the effect of CS-US temporal discontiguity further highlights the importance of GlyT1-dependent mechanisms in the regulation of associative learning. PMID- 24480414 TI - Sulfate and organic carbon removal by microbial fuel cell with sulfate-reducing bacteria and sulfide-oxidising bacteria anodic biofilm. AB - Biological sulfur removal can be achieved by reducing sulfate to sulfide with sulfate-reducing bacteria (SRB) and then oxidising sulfide to elemental sulfur (S(0)) with sulfide oxidising bacteria (SOB) for recovery. In sulfate-carbon wastewaters lacking electron acceptor for sulfide, excess sulfide will be produced and accumulated in the reactor. This study applied the microbial fuel cell (MFC) cultivated with the SRB+SOB anodic biofilm for treating the sulfate+organic carbon wastewaters. Excess sulfate ions were efficiently converted to sulfide by SRB cells in the biofilm, while the formed sulfide was diffused to the neighboring SOB cells to be irreversibly converted to S(0) with produced electrons being transferred to the anode. The cell-cell sulfide transport principally determined the electron flux of the MFC. Short diffusional distance of sulfide ions between cells significantly reduced the polarization resistances, hence enhancing performance of the MFC. PMID- 24480415 TI - Simultaneous removal of di-(2-ethylhexyl) phthalate and nitrogen in a laboratory scale pre-denitrification biofilter system. AB - This study demonstrated the excellent di-(2-ethylhexyl) phthalate (DEHP) removal performance of a pre-denitrification biofilter system. Experimental results showed that DEHP removal efficiency remained stable while total nitrogen removal efficiency fluctuated with the nitrate recycle ratio changes when the hydraulic loading rate at 1.1m(3)/m(2)h. DEHP removal efficiency increased from 48% to 82% while the hydraulic loading rate increased from 1.1 to 2.2m(3)/m(2)h. DEHP concentration decreased gradually along the wastewater flow direction in the denitrification biofilter and a plug flow model with the reaction order of 5 and the rate constant of 0.54 was obtained. Both the denitrification biofilter and the nitrification biofilter showed similar DEHP removal performance. The overall DEHP removal efficiency of the system was 83.8%, in which biodegradation contributed 72.3%. Biodegradation plays a key role in DEHP removal in the pre denitrification biofilter system. PMID- 24480416 TI - Effects of ionic strength on membrane fouling in a membrane bioreactor. AB - In this study, the effects of ionic strength on membrane fouling in a membrane bioreactor (MBR) were investigated. Ionic strength in range of 0.005-0.05mol/L exerted no apparent impacts on the resistance of virgin membrane, fouled membrane and pore clogging. Thermodynamic analysis showed existences of a secondary energy minimum and an energy barrier in the process of the sludge flocs approaching to membrane surface. Increase in ionic strength could significantly reduce the energy barrier. It was revealed that there existed a critical ionic strength above that the energy barrier would disappear, facilitating adhesion of the foulants. Cake resistance was not significantly affected by the ionic strength, but highly depended on SMP in supernatant. The high cake resistance caused by SMP could be explained by the osmotic pressure mechanism. The obtained results provided new insights into membrane fouling in MBRs. PMID- 24480417 TI - Neuroinflammation in the fetus exposed to maternal obsessive-compulsive disorder during pregnancy: a comparative study on cord blood tumor necrosis factor-alpha levels. AB - OBJECTIVE: The relationship between maternal psychiatric disorders and fetal neurodevelopment is unclear. Obsessive-compulsive disorder (OCD) is relatively frequent during pregnancy. The study aimed to investigate whether maternal OCD during pregnancy affects fetal circulating tumor necrosis factor-alpha (TNF alpha) levels, an important pro-inflammatory cytokine, by comparing cord blood TNF-alpha levels in newborn infants of women with and without OCD. METHODS: The study sample included 7 women with OCD and 30 healthy women. OCD and other psychiatric diagnoses were screened by means of the Structured Clinical Interview for the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition. The blood sample for the determination of TNF-alpha level was obtained from the umbilical cord during delivery. RESULTS: Cord blood TNF-alpha levels in newborn infants exposed to maternal OCD were significantly higher compared to non-exposed infants. Maternal anxiety symptom level was found to positively correlate with cord blood TNF-alpha levels in newborn infants of women with OCD. CONCLUSION: The study results imply that maternal OCD during pregnancy may lead to neuroinflammation in the developing fetal brain through higher levels of circulating TNF-alpha. PMID- 24480418 TI - Self-disgust in mental disorders -- symptom-related or disorder-specific? AB - BACKGROUND: Dysfunctional disgust experiences occur in a variety of mental disorders. Previous research focused on disgust proneness directed towards stimuli in the external environment. However, self-disgust, the devaluation of one' own physical appearance and personality (personal disgust) as well as one' own behavior (behavioral disgust) has hardly been investigated thus far, although it may play a crucial role in specific psychopathologies. METHODS: We investigated 112 patients diagnosed with different mental disorders (major depression, schizophrenia, borderline personality disorder (BPD), eating disorders, and spider phobia) and 112 matched mentally healthy individuals. Participants answered the Questionnaire for the Assessment of Self-Disgust (QASD) with two subscales 'personal disgust' and 'behavioral disgust', and the Brief Symptom Inventory (BSI) that provides an overview of patients' psychological problems and their intensity. RESULTS: Compared to healthy controls self-disgust was elevated in mental disorders. Personal disgust was more pronounced than behavioral disgust in patients, whereas there was no difference in controls. Patients with BPD and eating disorders reported the highest scores on both subscales. Findings also suggest that self-disgust is related to specific psychological problems. In mental disorders psychoticism and hostility were the best predictors for personal disgust, while anxiety and interpersonal sensitivity predicted behavioral disgust. Additionally, we found disorder-specific predictors for personal disgust (e.g., hostility in schizophrenia). Finally, traumatic events during childhood constitute a risk factor for self-disgust. CONCLUSIONS: The current study provides first evidence for the differential meaning of self disgust for specific mental disorders and symptoms. PMID- 24480419 TI - TIP47 is associated with the hepatitis C virus and its interaction with Rab9 is required for release of viral particles. AB - Hepatitis C virus (HCV) morphogenesis and release are closely linked to lipid metabolism. It has been described recently by our group that TIP47 plays an essential role for the targeting of the NS5A-complexed RNA genome from the replicon complex to the lipid droplet. Moreover, apolipoprotein (apo) E was found to be associated with the viral particle. In light of the fact, that TIP47 harbors an apoE like domain and has a high affinity to lipoproteins, the interaction of TIP47 with the viral particle and the potential relevance for the release of the viral particle were investigated. Coimmunoprecipitations and electron microscopy analysis using immunogold labeling revealed that TIP47 binds to the viral particle and stays associated with the released HCV particle. Silencing of the TIP47 binding partner Rab9 by lentiviral transduction abolishes the viral replication. However, destruction of TIP47-Rab9 interactions by deletion/mutation of the Rab9 binding does not abolish the genome replication domain but prevents the release of HCV particles. The binding of these TIP47 mutants to the viral particle is not affected by destruction of the Rab9 binding domain. Moreover, we found that these TIP47 mutants lacking the binding site for Rab9 misdirect the de novo synthesized viral particles to the autophagosomal/lysosomal compartment where the particles are degraded. From this we conclude that the Rab9-complexed TIP47 plays an essential role for the proper release of hepatitis C viral particles. PMID- 24480420 TI - Role of inhibitory autophosphorylation of calcium/calmodulin-dependent kinase II (alphaCAMKII) in persistent (>24 h) hippocampal LTP and in LTD facilitated by novel object-place learning and recognition in mice. AB - Experience-dependent synaptic plasticity is widely expressed in the mammalian brain and is believed to underlie memory formation. Persistent forms of synaptic plasticity in the hippocampus, such as long-term potentiation (LTP) and long-term depression (LTD) are particularly of interest, as evidence is accumulating that they are expressed as a consequence of, or at the very least in association with, hippocampus-dependent novel learning events. Learning-facilitated plasticity describes the property of hippocampal synapses to express persistent synaptic plasticity when novel spatial learning is combined with afferent stimulation that is subthreshold for induction of changes in synaptic strength. In mice it occurs following novel object recognition and novel object-place recognition. Calmodulin dependent kinase II (CAMKII) is strongly expressed in synapses and has been shown to be required for hippocampal LTP in vitro and for spatial learning in the water maze. Here, we show that in mice that undergo persistent inhibitory autophosphorylation of alphaCAMKII, object-place learning is intact. Furthermore, these animals demonstrate a higher threshold for induction of persistent (>24 h) hippocampal LTP in the hippocampal CA1 region during unrestrained behaviour. The transgenic mice also express short-term depression in response to afferent stimulation frequencies that are ineffective in controls. Furthermore, they express stronger LTD in response to novel learning of spatial configurations compared to controls. These findings support that modulation of alphaCAMKII activity via autophosphorylation at the Thr305/306 site comprises a key mechanism for the maintenance of synaptic plasticity within a dynamic range. They also indicate that a functional differentiation occurs in the way spatial information is encoded: whereas LTP is likely to be critically involved in the encoding of space per se, LTD appears to play a special role in the encoding of the content or features of space. PMID- 24480421 TI - Emotional contagion in mice: the role of familiarity. AB - Empathy is a complex emotional process that involves sharing an emotional state with another organism. The extent to which nonhuman animals are capable of empathizing with others is still far from clear, partly due to a lack of empirical work in this domain, but also due to definitional confusion of empathy with emotional contagion and other related terms. In this study, an observer mouse witnessed a familiar cagemate or an unfamiliar non-cagemate receiving electric foot shocks in an experiment that consisted of three periods: baseline (no shocks), test (shocks) and recovery (no shocks). Freezing behavior in the observer was significantly increased in the cagemate, as opposed to the non cagemate condition during the test period, but not during baseline or recovery, emphasizing the role of familiarity in empathy-like processes. In agreement with this, we also found a correlation that approached significance between the total number of fecal droppings of the observers, as an indication of distress, and those of the demonstrator in the cagemate, but not in the non-cagemate, condition. While the freezing behavior of the demonstrators increased with time, reaching a maximum at the recovery period, the observers froze the most during the test period while the demonstrators were receiving the electric foot shocks. The observation that the freezing response of the observers ceased when the shocks in the adjacent compartment stopped could be due to a decrease in saliency of the demonstrators' behavioral response. Finally, the presence of a cagemate, as compared to a stranger, possibly reduced the demonstrator's pain-induced behavior, suggesting an ameliorating effect of familiarity on stress responses. PMID- 24480422 TI - Intranasal administration of alpha-synuclein aggregates: a Parkinson's disease model with behavioral and neurochemical correlates. AB - Parkinson's disease (PD) is a neurodegenerative disorder in which both alpha synuclein (alpha-syn) and dopamine (DA) have a critical role. Our previous studies instigated a novel PD model based on nasal inoculation with alpha-syn aggregates which expressed parkinsonian-like behavioral and immunological features. The current study in mice substantiated the robustness of the amyloid nasal vector model by examining behavioral consequences with respect to DA-ergic neurochemical corollaries. In vitro generated alpha-syn oligomers and fibrils were characterized using atomic force microscopy and the thioflavin T binding assay. These toxic oligomers or fibrils administered alone (0.48 mg/kg) or their 50:50 combination (total dose of 0.48 mg/kg) were given intranasally for 14 days and "open-field" behavior was tested on days 0, 15 and 28 of the protocol. Behavioral deficits at the end of the 14-day dosing regime and on day 28 (i.e., 14 days after treatment completion) induced rigidity, hypokinesia and immobility. This was accompanied by elevated nigral but not striatal DA, DOPAC and HVA concentrations in response to dual administration of alpha-syn oligomers plus fibrils but not the oligomers by themselves. alpha-Syn fibrils intensified not only the hypokinesia and immobility 14 days post treatment, but also reduced vertical rearing and enhanced DA levels in the substantia nigra. Only nigral DA turnover (DOPAC/DA but not HVA/DA ratio) was augmented in response to fibril treatment but there were no changes in the striatum. Compilation of these novel behavioral and neurochemical findings substantiate the validity of the alpha-syn nasal vector model for investigating parkinsonian-like symptoms. PMID- 24480423 TI - Shrinkage of X cells in the lateral geniculate nucleus after monocular deprivation revealed by FoxP2 labeling. AB - The parallel processing of visual features by distinct neuron populations is a central characteristic of the mammalian visual system. In the A laminae of the cat dorsal lateral geniculate nucleus (dLGN), parallel processing streams originate from two principal neuron types, called X and Y cells. Disruption of visual experience early in life by monocular deprivation has been shown to alter the structure and function of Y cells, but the extent to which deprivation influences X cells remains less clear. A transcription factor, FoxP2, has recently been shown to selectively label X cells in the ferret dLGN and thus provides an opportunity to examine whether monocular deprivation alters the soma size of X cells. In this study, FoxP2 labeling was examined in the dLGN of normal and monocularly deprived cats. The characteristics of neurons labeled for FoxP2 were consistent with FoxP2 being a marker for X cells in the cat dLGN. Monocular deprivation for either a short (7 days) or long (7 weeks) duration did not alter the density of FoxP2-positive neurons between nondeprived and deprived dLGN layers. However, for each deprived animal examined, measurement of the cross sectional area of FoxP2-positive neurons (X cells) revealed that within deprived layers, X cells were smaller by approximately 20% after 7 days of deprivation, and by approximately 28% after 7 weeks of deprivation. The observed alteration to the cross-sectional area of X cells indicates that perturbation of this major pathway contributes to the functional impairments that develop from monocular deprivation. PMID- 24480424 TI - Birth weight alters the response to postnatal high-fat diet-induced changes in meat quality traits and skeletal muscle proteome of pigs. AB - Low birth weight (LBW) exerts persistent effects on the growth and development of offspring. The present study was conducted to test the hypothesis that LBW alters the response of pigs to high-fat (HF) diet-induced changes in meat quality and skeletal muscle proteome. Normal-birth weight (NBW) and LBW piglets were fed a control diet or a HF diet from weaning to slaughter at 110 kg body weight. Most of the meat quality traits were influenced by LBW. Meat quality analysis revealed that LBW piglets had a greater ability to deposit intramuscular lipids than their heavier littermates when fed a HF diet. Increased shear force, lower pH45 min and drip loss were observed in the skeletal muscle of LBW piglets compared with NBW piglets. Proteomic analysis revealed forty-six differentially expressed proteins in the skeletal muscle of LBW and NBW piglets fed the control diet or HF diet. These proteins play a central role in cell structure and motility, glucose and energy metabolism, lipid metabolism, and cellular apoptosis, as well as stress response. Of particular interest is the finding that LBW altered the response to HF diet-induced changes in the expression of proteins related to stress response (heat shock protein) and glucose and energy metabolism (pyruvate kinase, phosphoglycerate mutase, enolase and triosephosphate isomerase). Taken together, our findings revealed that the HF diet-induced changes in the expression of glucose and energy metabolism-related proteins varied between NBW and LBW piglets, which provides a possible mechanism to explain higher intramuscular fat store in LBW pigs when fed a HF diet. PMID- 24480425 TI - Evaluation of in vitro efficacy for decolorization and degradation of commercial azo dye RB-B by Morganella sp. HK-1 isolated from dye contaminated industrial landfill. AB - Reactive Black-B (RB-B) - one of the multi-sulphonated reactive azo dye - is being used extensively in textile as well as paper industries. Reactive azo dyes comprise of a significant group of synthetic compounds categorized as xenobiotics and its abatement from the environment still remains a challenge. In the present study, a newly isolated indigenous bacterial strain Morganella sp. HK-1 was exploited for its ability to decolorize and degrade RB-B dye. The isolate completely degraded RB-B (20 g L(-1)) within 24h under static conditions. Furthermore, the visible and FTIR spectral analysis established the bio degradation of RB-B. The degraded metabolites of RB-B by Morganella sp. HK-1 were identified by GC-MS analysis as disodium 3,4,6-triamino-5-hydroxynaphthalene-2,7 disulfonate, 4-aminophenylsulfonylethyl hydrogen sulfate, naphthalene-1-ol, aniline and benzene. Based on this information, a putative pathway of degradation of RB-B by Morganella sp. HK-1 has been proposed. This study is the first report on elucidation of mechanism of bacterial degradation of RB-B dye. Furthermore, phytotoxicity, genotoxicity and aquatic acute toxicity studies of the parent dye and the bio-degraded dye products revealed drastic reduction in the toxicity of metabolites as compared to the parent dye. This implies that the biotreatment of the dye is of non-toxic nature. This study thus indicates the effectiveness of Morganella sp. HK-1 for the treatment of textile effluents containing sulphonated azo dyes. PMID- 24480426 TI - Global warming and environmental contaminants in aquatic organisms: the need of the etho-toxicology approach. AB - Environmental contaminants are associated with a wide spectrum of pathological effects. Temperature increase affects ambient distribution and toxicity of these chemicals in the water environment, representing a potentially emerging problem for aquatic species with short-, medium- and long-term repercussions on human health through the food chain. We assessed peer-reviewed literature, including primary studies, review articles and organizational reports available. We focused on studies concerning toxicity of environmental pollutants within a global warming scenario. Existing knowledge on the effects that the increase of water temperature in a contaminated situation has on physiological mechanisms of aquatic organisms is presented. Altogether we consider the potential consequences for the human beings due to fish and shellfish consumption. Finally, we propose an etho-toxicological approach to study the effects of toxicants in conditions of thermal increase, using aquatic organisms as experimental models under laboratory controlled conditions. PMID- 24480427 TI - Airborne quinones induce cytotoxicity and DNA damage in human lung epithelial A549 cells: the role of reactive oxygen species. AB - Ambient particulate matter (PM) is associated with adverse health effects. Quinones present in PM are hypothesized to contribute to these harmful effects through the generation of reactive oxygen species (ROS). However, whether the ROS induced by quinones is involved in mediating DNA damage as well as other biological responses in pulmonary cells is less well known. In this study, the toxic effects of five typical airborne quinones, including 1,2-naphthoquinone, 2 methylanthraquinone, 9,10-phenanthrenequinone, 2-methyl-1,4-naphthoquinone, and acenaphthenequinone, on cytotoxicity, DNA damage, intracellular calcium homeostasis, and ROS generation, were studied in human lung epithelial A549 cells. An antioxidant N-acetylcysteine (NAC) was used to examine the involvement of ROS in adverse biological responses induced by quinones. The quinones caused a concentration-dependent viability decrease, cellular LDH release, DNA damage, and ROS production in A549 cells. 1,2-Naphthoquinone, but not the other four quinones, increased intracellular calcium (Ca(2+)) levels in a dose-dependent manner. These toxic effects were abolished by administration of NAC, suggesting that ROS played a key role in the observed toxic effects of quinones in A549 cells. These results emphasize the importance of quinones in PM on the adverse health effects of PMs, which has been underestimated in the past few years, and highlight the need, when evaluating the effects on health and exposure management, to always consider their qualitative chemical compositions in addition to the size and concentration of PMs. PMID- 24480428 TI - Spatial distribution and source apportionment of polycyclic aromatic hydrocarbons (PAHs) in Camphor (Cinnamomum camphora) tree bark from Southern Jiangsu, China. AB - The concentrations and sources of polycyclic aromatic hydrocarbons (PAHs) were investigated in Camphor tree bark from Southern Jiangsu, China. Tree bark samples were collected in August 2012. The Sigma15PAHs concentrations were ranged from 6.18 to 1560 ng g(-1)dry weight (dw), with an average value of 407 ng g(-1)dw. Generally, the concentrations of PAHs in the suburban areas were the highest, followed by urban and rural areas. Principal component analysis and diagnostic ratios results showed that vehicle emission, biomass and coal combustion and industrial emission were the major sources of PAHs in tree bark from Southern Jiangsu. Good correlation was found between tree bark and polyurethane foam (PUF) samplers, indicating that both of them respond well to the gas-phase PAHs monitoring. PMID- 24480429 TI - Biochemical and behavioural responses of the marine polychaete Hediste diversicolor to cadmium sulfide quantum dots (CdS QDs): waterborne and dietary exposure. AB - Cadmium sulfide (CdS) quantum dots are widely used in medical imaging. The aim of this study was to examine toxicity effects of CdS engineered nanoparticles (CdS NPs) compared to soluble Cd, on marine ragworms (Hediste diversicolor) exposed for 14 d to these contaminants (10 MUg Cd L(-1)) in seawater or via their food (contaminated worm tissue). In our experimental media, Dynamic Light Scattering studies showed that the majority of CdS remained in the nanoscale (1-10 nm) with the exception of few aggregates (100-300 nm). Labile Cd fractions released from CdS NPs were estimated by diffusive gradient in thin films, showing that about 50% of CdS NPs remained in nanoparticulate form. Ragworms accumulated Cd in both soluble Cd and CdS NPs in waterborne exposures only. Greater significant changes of biochemical responses were observed in worms exposed to CdS NPs in seawater compared to contaminated food. Catalase and glutathione-S-transferase activities were the most sensitive biochemical biomarkers responding to both Cd treatments for waterborne exposure. Inductions of CAT were higher in diet-exposed worms to Cd as NPs vs soluble form suggesting a specific "nano" effect. Caspase activities increased in worms exposed to soluble Cd and Cd NPs for the two routes of exposure compared to controls. Defences, may be insufficient to prevent reactive oxygen species generation and the associated apoptosis. Behaviour of invertebrates inside sediment showed impairments of body movements in worms exposed to CdS NPs. This study points out oxidative processes as the main consequences of exposure to Cd based NPs in worms. PMID- 24480431 TI - Detection of carbapenemase activities of Bacteroides fragilis strains with matrix assisted laser desorption ionization--time of flight mass spectrometry (MALDI-TOF MS). AB - Today resistance against carbapenems is considered an emerging problem in Bacteroides fragilis. Carbapenemase activities produced by aerobic bacteria have been detected by looking at hydrolysis of carbapenems with MALDI-TOF MS, but this technique was never used for anaerobic bacteria. We have developed a protocol for detection and verification of carbapenemase production in B. fragilis within 2.5 h. Twenty-eight strains of B. fragilis were tested. Of the sixteen cfiA-positive strains all showed hydrolysis of ertapenem, whereas the twelve cfiA-negative strains showed no hydrolysis. Ertapenem hydrolysis could be inhibited with 2,6 Pyridinecarboxylic acid (DPA) in all cfiA-positive strains, verifying the presence of the metallo-beta-lactamase. Here we show a rapid way to detect carbapenemase activities of B. fragilis strains. PMID- 24480430 TI - Intracerebral implantation of autologous peripheral blood stem cells in stroke patients: a randomized phase II study. AB - In our previous study, intracerebral implantation of peripheral blood stem cells (PBSCs) improved functional outcome in rats with chronic cerebral infarction. Based on this finding, a randomized, single blind controlled study was conducted in 30 patients [PBSC group (n = 15) and control group (n = 15)] with middle cerebral artery infarction confirmed on a T2-weighted MRI 6 months to 5 years after a stroke. Only subjects with neurological deficits of intermediate severity based on the National Institute of Health Stroke Scale (NIHSS; range: 9-20) that had been stable for at least 3 months were enrolled. Those in the PBSC group received subcutaneous G-CSF injections (15 ug/kg/day) for 5 consecutive days, and then stereotaxic implantation of 3-8 * 10(6) CD34(+) immunosorted PBSCs. All 30 patients completed the 12-month follow-up. No serious adverse events were noted during study period. Improvements in stroke scales (NIHSS, ESS, and EMS) and functional outcomes (mRS) from baseline to the end of the 12-month follow-up period were significantly greater in the PBSC than the control group. The fiber numbers asymmetry (FNA) scores based on diffusion tensor image (DTI) tractography were reduced in every PBSC-treated subject, but not in the control group. Reduction in the FNA scores correlated well with the improvement in NIHSS. Furthermore, a positive motor-evoked potential (MEP) response by transcranial magnetic stimulation (TMS) appeared in 9 of the 15 subjects in the PBSC group. This phase II study demonstrated that implantation of autologous CD34(+) PBSC was safe, feasible, and effective in improving functional outcome. PMID- 24480432 TI - Choriogonadotropin positive seminoma-a clinicopathological and molecular genetic study of 15 cases. AB - The presence of human chorionic gonadotropin (hCG) positive syncytiotrophoblastic cells (STC) in classic seminoma (CS) is well documented. CS with extensive hCG positive, non-syncytiotrophoblastic tumour cells (without STC) is exceptionally rare. In this study, we present 15 such cases. 168 CSs were retrieved from the Plzen Tumor registry. Cases of mixed germ cell tumors (with CS) and CSs with typical STC were excluded. Cases with completely embedded tumor mass were selected for further study and immunohistochemically examined with anti-hCG. Positive cases were further analyzed by reverse transcriptase polymerase chain reaction. Two groups of hCG-positive CSs were identified. Group 1 comprised 10 patients with a mean patient age of 37.7 years and mean tumor size of 4.96 cm. Eight cases were pT1 (TMN 2009) and 2 cases pT3a. Blood levels of hCG were elevated in 6 of the 10 patients preoperatively. In 2 patients the blood level of hCG was not tested. Mean follow-up period was 6.1 years. No metastatic behavior was noted. All tumors were extensively immunoreactive for hCG in more than 60% of tumor cells. The expression of hCG beta subunit (CGB)-mRNA in tumor tissue was documented. Group 2: Comprised 5 patients with a mean age was 34 years. Mean tumor size was 4.7 cm. Four cases were stage pT1 and 1 case was pT2. The mean follow-up period was 3.1 years. No metastatic behavior was noted. Preoperative blood levels of hCG were elevated in 1/5 of the patient. Strong hCG positivity was limited to scattered single tumor cells distributed throughout the entire tumor. Only weak expression of CGB mRNA was detected. We can conclude that immunohistochemical detection of expression of hCG in CS is not limited to syncytiotrophoblastic cells. In this study, we report two immunohistochemical patterns of hCG expression in classic seminomas: diffuse hCG staining in the majority of tumor cells and scattered hCG-positive cells within the tumor. PMID- 24480433 TI - C3d deposition in the media of renal arterioles is a useful marker for arteriolosclerosis in IgA nephropathy. AB - C3d deposition in peritubular capillaries has been demonstrated to indicate antibody-mediated alloresponse during renal transplantation. C3d deposition in renal arterioles in IgA nephropathy (IgAN), however, is poorly documented. Especially, its significance to the pathology of primary glomerulonephritis remains unclear. This retrospective study included 340 patients with IgAN who underwent renal biopsy at our center. C3d strongly positive deposition in arterioles was observed in 123 (36.2%) of the 340 cases, and weakly positive deposition of C3d was observed in 217 cases (63.8%). In the weakly positive group, C3d mainly deposited in the intima of arterioles. In the strongly positive group, C3d deposited in the intima and the media of arterioles, presenting as the medial thickening and sclerosis of varying severities. The prognosis was worse in the C3d strongly positive group than in the weakly positive group during a 2-year follow-up (P = .027). The predictive value of C3d deposition in the media of arterioles in patients with IgAN may be a useful marker for arteriolosclerosis indicating unfavorable clinical outcomes. PMID- 24480434 TI - The efficacy of surgical treatment of cancer - 20 years later. AB - INTRODUCTION: Cancer treatment will be effective only if it is be based on a valid paradigm of what cancer is and therefore capable of affecting the course of the disease. A review in 1993 found no evidence that surgery affected the course of the disease and an alternative paradigm was proposed. A review of mammography screening trials in 1996 found no benefits from breast cancer screening. This was predicted by this alternative paradigm. This review updates the evidence twenty years later. AIM: To identify evidence that the primary treatment of cancer, surgery, has been shown to affect the course of the disease. If there is no such evidence, then to identify the correct paradigm of what cancer is from other cancer treatments that have been shown to be effective. METHOD: Because surgery has never been shown in a randomised controlled trial to affect the course of cancer seven other indirect methods were used to evaluate its efficacy. RESULTS: None of the seven indirect methods used showed that surgery clearly affects the course of the disease for any type of cancer. The lack of benefits from cancer screening now includes not only from breast cancer but also from bowel, lung, prostate and ovarian cancer screening. This confirms that cancer surgery is based on an invalid paradigm of what cancer is. Survival figures following treatments based on an alternative paradigm that assumes cancer is a systemic disease were found to be superior to those following surgery, reinforcing the conclusion that cancer is a systemic disease and that cancer surgery is unlikely to be of benefit in most cases. CONCLUSION: No benefits can be expected to be achieved from using cancer surgery except in a few immediately life-threatening situations. Surgery appears to be based on an invalid paradigm of what cancer is. Cancer appears to be a systemic disease and therefore standard treatments need to be reassessed in this light. PMID- 24480435 TI - Role of vacuolar ATPase and Skp1 in Sjogren's syndrome. AB - Immune mechanisms alone cannot directly account for exocrine gland dysfunction and extraglandular features such as renal tubular acidosis, neuropathy, hearing loss and fatigue in Sjogren's syndrome (SS). Absence of Vacuolar ATPase (V ATPase) has been reported in SS related renal tubular acidosis (RTA). We hypothesise how defect in V-ATPase could account for decreased neurotransmitter release leading onto exocrine dysfunction, neuroendocrine manifestations and hearing loss which are well described manifestations in SS. S-phase-kinase associated protein-1 (Skp1) is a constituent of RAVE which is involved in V ATPase assembly. It is also a component of SCF ligase which is crucial in NFkappaB signalling. SKP1 also interacts with TRIM 21/Ro 52 which is an autoantigen in SS. By virtue of these interactions, we postulate how a defective skp1 could fit into the existing pathogenesis of SS and also account for increased risk of lymphoma in SS as well as congenital heart block in fetus of mothers with SS. PMID- 24480436 TI - Non-CpG hypermethylation in placenta of mutation-induced intrauterine growth restricted bovine foetuses. AB - The existence of non-CpG methylation in mammalian DNA has mainly been observed in embryonic stem cells, but its functional significance is uncertain. We found an age-dependent non-CpG hypermethylation in DMR at the 3' end of the MIMT1 in the placenta of intrauterine growth restricted foetuses in cattle. Data suggest that this DMR play a role in epigenetic regulation of the PEG3 domain. PMID- 24480437 TI - Effects of Cd2+ on cis-dimer structure of E-cadherin in living cells. AB - E-cadherin, a calcium (Ca(2+))-dependent cell-cell adhesion molecule, plays a key role in the maintenance of tissue integrity. We have previously demonstrated that E-cadherin functions in vivo as a cis-dimer through chemical cross-linking reagents. Ca(2+) plays an important role in the cis-dimer formation of cadherin. However, the molecular mechanisms by which Ca(2+) interacts with the binding sites that regulate cis-dimer structures have not been completely elucidated. As expected for a Ca(2+) antagonist, cadmium (Cd(2+)) disrupts cadherin function by displacing Ca(2+) from its binding sites on the cadherin molecules. We used Cd(2+) as a probe for investigating the role of Ca(2+) in the dynamics of the E cadherin extracellular region that involve cis-dimer formation and adhesion. While cell-cell adhesion assembly was completely disrupted in the presence of Cd(2+), the amount of cis-dimers of E-cadherin that formed at the cell surface was not affected. In our "Cd(2+)-switch" experiments, we did not find that Cd(2+) induced E-cadherin cis-dimer formation in EL cells when they were incubated in low-Ca(2+) medium. In the present study, we demonstrated for the first time the effects of Cd(2+) on the cis-dimer structure of E-cadherin in living cells using a chemical cross-link analysis. PMID- 24480438 TI - Role of nerve growth factor-tyrosine kinase receptor A signaling in paclitaxel induced peripheral neuropathy in rats. AB - The mechanisms underlying paclitaxel-induced peripheral neuropathy remain unknown. Nerve growth factor (NGF) is a representative neurotrophic factor that maintains neuronal function, promotes survival, and mediates neuropathic pain. We investigated expression levels of NGF and its receptors in the dorsal root ganglia (DRG) and spinal dorsal horn (DH) following paclitaxel treatment. Intraperitoneal (I.P.) administration of paclitaxel induced significant mechanical hypersensitivity and cold allodynia in rats, significantly increased the expression of NGF and its receptor tyrosine kinase receptor A (trkA) in the DRG, and increased NGF expression in the DH. In contrast, paclitaxel treatment did not alter the mRNA levels of NGF or its receptors in the DRG, DH, sciatic nerve, or hindpaw skin. Moreover, expression of NEDD4-2, a negative regulator of trkA, was significantly increased in the DRG of paclitaxel-treated rats. Intrathecal (I.T.) administration of the tyrosine kinase receptor inhibitor k252a significantly alleviated mechanical hypersensitivity in paclitaxel-treated rats. Our results suggest that NGF-trkA signaling is involved in mechanical allodynia in paclitaxel-induced neuropathy. PMID- 24480439 TI - KYSS: mass spectrometry data quality assessment for protein analysis and large scale proteomics. AB - We introduce the computer tool "Know Your Samples" (KYSS) for assessment and visualisation of large scale proteomics datasets, obtained by mass spectrometry (MS) experiments. KYSS facilitates the evaluation of sample preparation protocols, LC peptide separation, and MS and MS/MS performance by monitoring the number of missed cleavages, precursor ion charge states, number of protein identifications and peptide mass error in experiments. KYSS generates several different protein profiles based on protein abundances, and allows for comparative analysis of multiple experiments. KYSS was adapted for blood plasma proteomics and provides concentrations of identified plasma proteins. We demonstrate the utility of the KYSS tool for MS based proteome analysis of blood plasma and for assessment of hydrogel particles for depletion of abundant proteins in plasma. The KYSS software is open source and is freely available at http://kyssproject.github.io/. PMID- 24480440 TI - Peroxiredoxin 1 is involved in disassembly of flagella and cilia. AB - Cilia/flagella are evolutionarily conserved cellular organelles. In this study, we demonstrated that Dunaliella salina Peroxiredoxin 1 (DsPrdx1) localized to the flagella and basal bodies, and was involved in flagellar disassembly. The link between DsPrdx1 and flagella of Dunaliella salina (D. salina) encouraged us to explore the function of its human homologue, Homo sapiens Peroxiredoxin 1 (HsPrdx1) in development and physiology. Our results showed that HsPrdx1 was overexpressed, and cilia were lost in esophageal squamous cell carcinoma (ESCC) cells compared with the non-cancerous esophageal epithelial cells Het-1A. Furthermore, when HsPrdx1 was knocked down by short hairpin RNA (shRNA) lentivirus in ESCC cells, the phenotype of cilia lost can be reversed, and the expression levels of tumor suppressor genes LKB1 and p-AMPK were increased, and the activity of the oncogene Aurora A was inhibited compared with those in cells transfected with scrambe-shRNA lentivirus. These findings firstly showed that Prdx1 is involved in disassembly of flagella and cilia, and suggested that the abnormal expression of the cilia-related gene including Prdx1 may affect both ciliogenesis and cancernogenesis. PMID- 24480441 TI - Equatorin is not essential for acrosome biogenesis but is required for the acrosome reaction. AB - The acrosome is a specialized organelle that covers the anterior part of the sperm nucleus and plays an essential role in mammalian fertilization. However, the regulatory mechanisms controlling acrosome biogenesis and acrosome exocytosis during fertilization are largely unknown. Equatorin (Eqtn) is a membrane protein that is specifically localized to the acrosomal membrane. In the present study, the physiological functions of Eqtn were investigated using a gene knockout mouse model. We found that Eqtn(-/-) males were subfertile. Only approximately 50% of plugged females were pregnant after mating with Eqtn(-/-) males, whereas more than 90% of plugged females were pregnant after mating with control males. Sperm and acrosomes from Eqtn(-/-) mice presented normal motility and morphology. However, the fertilization and induced acrosome exocytosis rates of Eqtn deficient sperm were dramatically reduced. Further studies revealed that the Eqtn protein might interact with Syntaxin1a and SNAP25, but loss of Eqtn did not affect the protein levels of these genes. Therefore, our study demonstrates that Eqtn is not essential for acrosome biogenesis but is required for the acrosome reaction. Eqtn is involved in the fusion of the outer acrosomal membrane and the sperm plasma membrane during the acrosome reaction, most likely via an interaction with the SNARE complex. PMID- 24480442 TI - Transcriptional regulation and functional characterization of the oxysterol/EBI2 system in primary human macrophages. AB - Oxysterols such as 7 alpha, 25-dihydroxycholesterol (7alpha,25-OHC) are natural ligands for the Epstein-Barr virus (EBV)-induced gene 2 (EBI2, aka GPR183), a G protein-coupled receptor (GPCR) highly expressed in immune cells and required for adaptive immune responses. Activation of EBI2 by specific oxysterols leads to chemotaxis of B cells in lymphoid tissues. While the ligand gradient necessary for this critical process of the adaptive immune response is established by a stromal cells subset here we investigate the involvement of the oxysterol/EBI2 system in the innate immune response. First, we show that primary human macrophages express EBI2 and the enzymes needed for ligand production such as cholesterol 25-hydroxylase (CH25H), sterol 27-hydroxylase (CYP27A1), and oxysterol 7alpha-hydroxylase (CYP7B1). Furthermore, challenge of monocyte-derived macrophages with lipopolysaccharides (LPS) triggers a strong up-regulation of CH25H and CYP7B1 in comparison to a transient increase in EBI2 expression. Stimulation of EBI2 expressed on macrophages leads to calcium mobilization and to directed cell migration. Supernatants of LPS-stimulated macrophages are able to stimulate EBI2 signaling indicating that an induction of CH25H, CYP27A1, and CYP7B1 results in an enhanced production and release of oxysterols into the cellular environment. This is a study characterizing the oxysterol/EBI2 pathway in primary monocyte-derived macrophages. Given the crucial functional role of macrophages in the innate immune response these results encourage further exploration of a possible link to systemic autoimmunity. PMID- 24480443 TI - Regulation of the adrenoleukodystrophy-related gene (ABCD2): focus on oxysterols and LXR antagonists. AB - The regulation of the ABCD2 gene is recognized as a possible therapeutic target for X-linked adrenoleukodystrophy, a rare neurodegenerative disease caused by mutations in the ABCD1 gene. Up-regulation of ABCD2 expression has indeed been demonstrated to compensate for ABCD1 deficiency, restoring peroxisomal beta oxidation of very-long-chain fatty acids. Besides the known inducers of the ABCD2 gene (phenylbutyrate and histone deacetylase inhibitors, fibrates, dehydroepiandrosterone, thyroid hormone and thyromimetics), this review will focus on LXR antagonists and 22S-hydroxycholesterol, recently described as inducers of ABCD2 expression. Several LXR antagonists have been identified and their possible indication for neurodegenerative disorders will be discussed. PMID- 24480444 TI - ERK2 small interfering RNAs prevent epidural fibrosis via the efficient inhibition of collagen expression and inflammation in laminectomy rats. AB - Laminectomy is a widely accepted treatment for lumbar disorders. Epidural Fibrosis (EF) is a common post-laminectomy or post-discectomy complication, which is thought to cause recurrent pain. RNA interference (RNAi) is a process by which double-stranded RNA triggers the destruction of mRNAs sharing the same sequence. Previously, extra-cellular signal-regulated kinase (ERK) 2 plays crucial roles in suppressing the collagen expression. To investigate the effects of lentiviral ERK2 siRNA on the prevention of post-laminectomy EF formation in a rat model, a controlled double-blinded study was conducted in 75 healthy adult Wistar rats that underwent laminectomy. They were divided randomly into 3 groups according to the treatment method: (1) control group; (2) ERK scrRNA group; (3) ERK siRNA group. All rats were euthanized humanely 4 weeks post-laminectomy. The hydroxyproline content, Rydell score, vimentin cells density, fibroblasts density, inflammatory cells density and inflammatory factors expressions were performed. The hydroxyproline content, Rydell score, vimentin cells density, fibroblasts density, inflammatory cells density and inflammatory factors expressions all suggested better results in ERK siRNA group than other two groups. None of the rats expired and no obvious adverse effects were observed. Local delivery of a lentiviral siRNA targeting ERK2 can prevent epidural scar adhesion in post-laminectomy rat via inhibiting collagen expression and inflammation. PMID- 24480446 TI - The right heart failure dilemma in the era of left ventricular assist devices. PMID- 24480447 TI - Prognostic stratification and treatment of cardiac light chain amyloidosis: a narrow path in the jungle. PMID- 24480445 TI - The 2013 Canadian Cardiovascular Society Heart Failure Management Guidelines Update: focus on rehabilitation and exercise and surgical coronary revascularization. AB - The 2013 Canadian Cardiovascular Society Heart Failure Management Guidelines Update provides focused discussions on the management recommendations on 2 topics: (1) exercise and rehabilitation; and (2) surgical coronary revascularization in patients with heart failure. First, all patients with stable New York Heart Association class I-III symptoms should be considered for enrollment in a tailored exercise training program, to improve exercise tolerance and quality of life. Second, selected patients with suitable coronary anatomy should be considered for bypass graft surgery. As in previous updates, the topics were chosen in response to stakeholder feedback. The 2013 Update also includes recommendations, values and preferences, and practical tips to assist the clinicians and health care workers manage their patients with heart failure. PMID- 24480448 TI - The homoeologous genes encoding chalcone-flavanone isomerase in Triticum aestivum L.: structural characterization and expression in different parts of wheat plant. AB - Chalcone-flavanone isomerase (CHI; EC 5.5.1.6.) participates in the early step of flavonoid biosynthesis, related to plant adaptive and protective responses to environmental stress. The bread wheat genomic sequences encoding CHI were isolated, sequenced and mapped to the terminal segment of the long arms of chromosomes 5A, 5B and 5D. The loss of the final Chi intron and junction of the two last exons was found in the wheat A, B and D genomes compared to the Chi sequences of most other plant species. Each of the three diploid genomes of hexaploid wheat encodes functional CHI; however, transcription of the three homoeologous genes is not always co-regulated. In particular, the three genes demonstrated different response to salinity in roots: Chi-D1 was up-regulated, Chi-A1 responds medially, whereas Chi-B1 was not activated at all. The observed variation in transcriptional activity between the Chi homoeologs is in a good agreement with structural diversification of their promoter sequences. In addition, the correlation between Chi transcription and anthocyanin pigmentation in different parts of wheat plant has been studied. The regulatory genes controlling anthocyanin pigmentation of culm and pericarp modulated transcription of the Chi genes. However, in other organs, there was no strong relation between tissue pigmentation and the transcription of the Chi genes, suggesting complex regulation of the Chi expression in most parts of wheat plant. PMID- 24480449 TI - Identification, stability and expression of Sirt1 antisense long non-coding RNA. AB - Natural antisense transcripts (NATs) exist ubiquitously as pivotal molecules to regulate coding gene expression. Sirtuin 1 (Sirt1) is a NAD-dependent deacetylase which is involved in myogenesis. However, whether Sirt1 transcribes NAT during C2C12 differentiation is still unknown. In this study, we identified a Sirt1 NAT which was designated as Sirt1 antisense long non-coding RNA (AS lncRNA) by sequencing and bioinformatic analysis. The level of Sirt1 AS lncRNA was greater in spleen but less in muscle tissue. The expression of both Sirt1 mRNA and Sirt1 AS lncRNA decreased during C2C12 myogenic differentiation, whereas the levels of miR-34a, which targets Sirt1, increased gradually. We further found that the half life of Sirt1 AS lncRNA was 10h, but that of Sirt1 mRNA was 6h in C2C12 cells treated with 2 MUg/ml Actinomycin D. Therefore, compared with Sirt1 mRNA, Sirt1 AS lncRNA was more stable. Overexpression of Sirt1 AS lncRNA increased the levels of Sirt1 protein, whereas overexpression of Sirt1 AS lncRNA mutant did not affect the level of Sirt1 protein in C2C12 cells. Moreover, downregulation of Sirt1 mRNA caused by miR-34a was counteracted by Sirt1 AS lncRNA in C2C12 cells. Taken together, we identified a novel NAT of Sirt1 which implicated in myogenesis through regulating Sirt1 expression. PMID- 24480451 TI - Radiolabeled NGR phage display peptide sequence for tumor targeting. AB - The asparagine-glycine-arginine (NGR) peptide sequence found by phage display, was radiolabeled with technetium-99m and tested in different tumor models. Similar uptake occurred with ovarian and lung tumor cells. Biodistribution of the radiotracer revealed predominant renal excretion with more substantial uptake in animals bearing ovarian tumor cells. In contrast imaging studies indicated better visualization for lung tumor. NGR peptide was characterized as a promising diagnostic candidate, particularly for lung cancer. Improvements are envisaged using NGR combined with RGD as a heterodimer molecule. PMID- 24480450 TI - Reactive astrocytes promote adhesive interactions between brain endothelium and endothelial progenitor cells via HMGB1 and beta-2 integrin signaling. AB - Endothelial progenitor cells (EPCs) may contribute to neurovascular repair after stroke and neurodegeneration. A key step in this process should involve adhesive interactions between EPCs and the targeted cerebral endothelium. Here, we tested the hypothesis that reactive astrocytes may play a critical role in enhancing adhesive interactions and transmigration of EPCs across cerebral endothelial cells. Transiently seeding EPCs onto a monolayer of RBE.4 rat brain endothelial cells resulted in a time-dependent adherence between the two cell types. Blocking beta2 integrins on EPCs or blocking the receptor for advanced glycation endproducts (RAGE) on endothelial cells significantly decreased EPC-endothelial adherence. Next, we tested whether reactive astrocytes can enhance this process by growing EPCs, brain endothelial cells and astrocytes together in a transwell co-culture system. The presence of reactive astrocytes in the lower chamber significantly promoted adherence between EPCs and endothelial cells in the upper chamber. This process involved the release of soluble HMGB1 from reactive astrocytes that then upregulated endothelial expression of RAGE via Egr1 signaling. Directly adding HMGB1 to the transwell system also promoted EPC endothelial adhesion and accelerated EPC transmigration into the lower chamber. These initial findings provide proof-of-concept that reactive astrocytes promote crosstalk between cerebral endothelium and EPCs. Further investigation of this phenomenon may lead to a better understanding of cell-cell interactions required for neurovascular recovery after stroke. PMID- 24480452 TI - Efficacy of biologic agents in improving the Health Assessment Questionnaire (HAQ) score in established and early rheumatoid arthritis: a meta-analysis with indirect comparisons. AB - OBJECTIVES: The Health Assessment Questionnaire (HAQ) is a validated physical function measure. It is predictive for disability and mortality. The objective of this study was to determine the comparative efficacy of biologic agents in improving HAQ in patients with established RA who failed DMARDs or anti- TNF agents and in early RA (ERA). METHODS: We performed random effects meta-analyses of published randomised, placebo-controlled trials. Outcome was the mean difference in change in HAQ for biologic agents compared to controls (DeltaHAQB DeltaHAQC). Indirect comparisons of the different biologic drugs were conducted using the Q-test based on analysis of variance. Meta-regression was performed using the method of moments. RESULTS: Twenty-eight trials were included: 19 with DMARD-failures; 4 with anti-TNF-failures and 5 ERA. The following biologics were represented: abatacept, adalimumab, certolizumab, etanercept, golimumab, infliximab, rituximab and tocilizumab. Efficacy of biologics at reducing HAQ was significantly different based on prior treatment (p=0.001). In RA patients with DMARD failures, DeltaHAQB-DeltaHAQC was -0.22; 95%CI: -0.24, -0.20 (I2=55%). Infliximab, abatacept and tocilizumab had lower DeltaHAQB-DeltaHAQC compared to other biologics (p<0.02). In anti-TNF-failures, DeltaHAQB-DeltaHAQC was -0.36; 95%CI: -0.42, -0.30 (I2=0%). In ERA, methotrexate-naive trials, DeltaHAQB DeltaHAQC was -0.19; 95% CI: -0.26, -0.13 (I2=0%). There were no significant differences in the efficacy of different biologics for anti-TNF failures and ERA. CONCLUSIONS: Biologic agents were efficacious at lowering HAQ in RA. Differences between agents in RA with DMARD failures were less than the minimally clinically important difference for HAQ; therefore, the clinical significance of these differences is unclear. PMID- 24480453 TI - How lexical is the lexicon? Evidence for integrated auditory memory representations. AB - Previous research has shown that lexical representations must include not only linguistic information (what word was said), but also indexical information (how it was said, and by whom). The present work demonstrates that even this expansion is not sufficient. Seemingly irrelevant information, such as an unattended background sound, is retained in memory and can facilitate subsequent speech perception. We presented participants with spoken words paired with environmental sounds (e.g., a phone ringing), and had them make an "animate/inanimate" decision for each word. Later performance identifying filtered versions of the words was impaired to a similar degree if the voice changed or if the environmental sound changed. Moreover, when quite dissimilar words were used at exposure and test, we observed the same result when we reversed the roles of the words and the environmental sounds. The experiments also demonstrated limits to these effects, with no benefit from repetition. Theoretically, our results support two alternative possibilities: (1) Lexical representations are memory representations, and are not walled off from those for other sounds. Indexical effects reflect simply one type of co-occurrence that is incorporated into such representations. (2) The existing literature on indexical effects does not actually bear on lexical representations - voice changes, like environmental sounds heard with a word, produce implicit memory effects that are not tied to the lexicon. We discuss the evidence and implications of these two theoretical alternatives. PMID- 24480454 TI - Singing with yourself: evidence for an inverse modeling account of poor-pitch singing. AB - Singing is a ubiquitous and culturally significant activity that humans engage in from an early age. Nevertheless, some individuals - termed poor-pitch singers - are unable to match target pitches within a musical semitone while singing. In the experiments reported here, we tested whether poor-pitch singing deficits would be reduced when individuals imitate recordings of themselves as opposed to recordings of other individuals. This prediction was based on the hypothesis that poor-pitch singers have not developed an abstract "inverse model" of the auditory vocal system and instead must rely on sensorimotor associations that they have experienced directly, which is true for sequences an individual has already produced. In three experiments, participants, both accurate and poor-pitch singers, were better able to imitate sung recordings of themselves than sung recordings of other singers. However, this self-advantage was enhanced for poor pitch singers. These effects were not a byproduct of self-recognition (Experiment 1), vocal timbre (Experiment 2), or the absolute pitch of target recordings (i.e., the advantage remains when recordings are transposed, Experiment 3). Results support the conceptualization of poor-pitch singing as an imitative deficit resulting from a deficient inverse model of the auditory-vocal system with respect to pitch. PMID- 24480455 TI - Multiple fMRI system-level baseline connectivity is disrupted in patients with consciousness alterations. AB - INTRODUCTION: In healthy conditions, group-level fMRI resting state analyses identify ten resting state networks (RSNs) of cognitive relevance. Here, we aim to assess the ten-network model in severely brain-injured patients suffering from disorders of consciousness and to identify those networks which will be most relevant to discriminate between patients and healthy subjects. METHODS: 300 fMRI volumes were obtained in 27 healthy controls and 53 patients in minimally conscious state (MCS), vegetative state/unresponsive wakefulness syndrome (VS/UWS) and coma. Independent component analysis (ICA) reduced data dimensionality. The ten networks were identified by means of a multiple template matching procedure and were tested on neuronality properties (neuronal vs non neuronal) in a data-driven way. Univariate analyses detected between-group differences in networks' neuronal properties and estimated voxel-wise functional connectivity in the networks, which were significantly less identifiable in patients. A nearest-neighbor "clinical" classifier was used to determine the networks with high between-group discriminative accuracy. RESULTS: Healthy controls were characterized by more neuronal components compared to patients in VS/UWS and in coma. Compared to healthy controls, fewer patients in MCS and VS/UWS showed components of neuronal origin for the left executive control network, default mode network (DMN), auditory, and right executive control network. The "clinical" classifier indicated the DMN and auditory network with the highest accuracy (85.3%) in discriminating patients from healthy subjects. CONCLUSIONS: FMRI multiple-network resting state connectivity is disrupted in severely brain-injured patients suffering from disorders of consciousness. When performing ICA, multiple-network testing and control for neuronal properties of the identified RSNs can advance fMRI system-level characterization. Automatic data-driven patient classification is the first step towards future single subject objective diagnostics based on fMRI resting state acquisitions. PMID- 24480456 TI - Autosomal dominant inheritance of central centrifugal cicatricial alopecia in black South Africans. AB - BACKGROUND: Central centrifugal cicatricial alopecia (CCCA) is the commonest type of primary scarring alopecia in women of African descent. Little is currently known about the disease genetics. OBJECTIVE: We sought to investigate patterns of inheritance in CCCA and ascertain the contribution of nongenetic factors such as hair-grooming habits to the pathogenesis of the disease. METHODS: Affected individuals with at least 1 available family member were recruited from 2005 through 2012 inclusive for pedigree analysis. CCCA was diagnosed on clinical and histopathological grounds. RESULTS: Fourteen index African families with 31 immediate family members participated in the initial screening. The female to male ratio was 29:2 with an average age of 50.4 years. All patients displayed histologic features typical for CCCA. Pedigree analysis suggested an autosomal dominant mode of inheritance. Hair-grooming habits were found to markedly influence disease expression. LIMITATIONS: Small number of patients is a limitation. CONCLUSION: CCCA can be inherited in an autosomal dominant fashion, with partial penetrance and a strong modifying effect of hairstyling and gender. PMID- 24480457 TI - Fibrolipomatous hamartoma of the nerve: a clinicopathologic report of 13 cases. AB - BACKGROUND: Fibrolipomatous hamartoma of the nerve is a rare benign infiltrating condition of peripheral nerves with prominent cutaneous findings that has not being well described in the dermatologic and dermatopathologic literature. OBJECTIVE: We sought to evaluate the clinical and histopathological features of this rare condition. METHODS: We reviewed the clinicopathologic features of 13 cases to delineate their clinical presentation and histopathologic spectrum. RESULTS: All patients presented with unilateral lesions on the thenar areas, fingers, or both. In 7 cases the lesions presented congenitally and in 6 cases the lesions presented sporadically. Histologically, we found 2 patterns that have only been rarely mentioned before including cases with intraneural perineurioma like features and cases with marked nerve hyperplasia. LIMITATIONS: Only 13 cases were included in our study. CONCLUSIONS: This condition is an uncommon entity. The diagnosis of this disorder can be highly suspected on its macroscopic features. Predilection of the median nerve and the frequent association with macrodactyly are characteristic clinical findings. PMID- 24480458 TI - Effects of hydration status on cognitive performance and mood. AB - Although it is well known that water is essential for human homeostasis and survival, only recently have we begun to understand its role in the maintenance of brain function. Herein, we integrate emerging evidence regarding the effects of both dehydration and additional acute water consumption on cognition and mood. Current findings in the field suggest that particular cognitive abilities and mood states are positively influenced by water consumption. The impact of dehydration on cognition and mood is particularly relevant for those with poor fluid regulation, such as the elderly and children. We critically review the most recent advances in both behavioural and neuroimaging studies of dehydration and link the findings to the known effects of water on hormonal, neurochemical and vascular functions in an attempt to suggest plausible mechanisms of action. We identify some methodological weaknesses, including inconsistent measurements in cognitive assessment and the lack of objective hydration state measurements as well as gaps in knowledge concerning mediating factors that may influence water intervention effects. Finally, we discuss how future research can best elucidate the role of water in the optimal maintenance of brain health and function. PMID- 24480459 TI - Primary purulent pericarditis and secondary endocarditis: a case report. AB - Purulent pericarditis is a rare diagnosis to be made. It is exceedingly rare as a primary infection. We describe the case of an 18-month-old boy who presented with primary purulent pericarditis and developed a secondary endocarditis. Current literature on the subject is reviewed and discussed. PMID- 24480460 TI - Aurora-A controls cancer cell radio- and chemoresistance via ATM/Chk2-mediated DNA repair networks. AB - High expression of Aurora kinase A (Aurora-A) has been found to confer cancer cell radio- and chemoresistance, however, the underlying mechanism is unclear. In this study, by using Aurora-A cDNA/shRNA or the specific inhibitor VX680, we show that Aurora-A upregulates cell proliferation, cell cycle progression, and anchorage-independent growth to enhance cell resistance to cisplatin and X-ray irradiation through dysregulation of DNA damage repair networks. Mechanistic studies showed that Aurora-A promoted the expression of ATM/Chk2, but suppressed the expression of BRCA1/2, ATR/Chk1, p53, pp53 (Ser15), H2AX, gammaH2AX (Ser319), and RAD51. Aurora-A inhibited the focus formation of gammaH2AX in response to ionizing irradiation. Treatment of cells overexpressing Aurora-A and ATM/Chk2 with the ATM specific inhibitor KU-55933 increased the cell sensitivity to cisplatin and irradiation through increasing the phosphorylation of p53 at Ser15 and inhibiting the expression of Chk2, gammaH2AX (Ser319), and RAD51. Further study revealed that BRCA1/2 counteracted the function of Aurora-A to suppress the expression of ATM/Chk2, but to activate the expression of ATR/Chk1, pp53, gammaH2AX, and RAD51, leading to the enhanced cell sensitivity to irradiation and cisplatin, which was also supported by the results from animal assays. Thus, our data provide strong evidences that Aurora-A and BRCA1/2 inversely control the sensitivity of cancer cells to radio- and chemotherapy through the ATM/Chk2 mediated DNA repair networks, indicating that the DNA repair molecules including ATM/Chk2 may be considered for the targeted therapy against cancers with overexpression of Aurora-A. PMID- 24480461 TI - Transport and accumulation of PVP-Hypericin in cancer and normal cells characterized by image correlation spectroscopy techniques. AB - PVP-Hypericin (PVP: polyvinylpyrrolidone) is a potent anti-cancer photosensitizer for photodynamic diagnosis (PDD) and therapy (PDT). However, cellular targets and mechanisms involved in the cancer-selectivity of the photosensitizer are not yet fully understood. This paper gives new insights into the differential transport and localization of PVP-Hypericin in cancer and normal cells which are essential to unravel the mechanisms of action and cancer-selectivity. Temporal (TICS) and spatiotemporal (STICS) image correlation spectroscopy are used for the assessment of PVP-Hypericin diffusion and/or velocity in the case of concerted flow in human cervical epithelial HeLa and human lung carcinoma A549 cells, as well as in human primary dendritic cells (DC) and human peripheral blood mononuclear cells (PBMC). Spatiotemporal image cross-correlation spectroscopy (STICCS) based on organelle specific fluorescent labeling is employed to study the accumulation of the photosensitizer in nucleus, mitochondria, early-endosomes and lysosomes of the cells and to assess the dynamics of co-migrating molecules. Whereas STICS and TICS did not show a remarkable difference between the dynamics of PVP-Hypericin in HeLa, A549 and DC cells, a significantly different diffusion rate of the photosensitizer was measured in PBMC. STICCS detected a stationary accumulation of PVP-Hypericin within the nucleus, mitochondria, early endosomes and lysosomes of HeLa and A549 cells. However, significant flow due to the directed motion of the organelles was detected. In contrast, no accumulation in the nucleus and mitochondria of DC and PBMC could be monitored. PMID- 24480462 TI - Neutralising properties of peptides derived from CXCR4 extracellular loops towards CXCL12 binding and HIV-1 infection. AB - The chemokine receptor CXCR4 interacts with a single endogenous chemokine, CXCL12, and regulates a wide variety of physiological and pathological processes including inflammation and metastasis development. CXCR4 also binds the HIV-1 envelope glycoprotein, gp120, resulting in viral entry into host cells. Therefore, CXCR4 and its ligands represent valuable drug targets. In this study, we investigated the inhibitory properties of synthetic peptides derived from CXCR4 extracellular loops (ECL1-X4, ECL2-X4 and ECL3-X4) towards HIV-1 infection and CXCL12-mediated receptor activation. Among these peptides, ECL1-X4 displayed anti-HIV-1 activity against X4, R5/X4 and R5 viruses (IC50=24 to 76MUM) in cell viability assay without impairing physiological CXCR4-CXCL12 signalling. In contrast, ECL2-X4 only inhibited X4 and R5/X4 strains, interfering with HIV-entry into cells. At the same time, ECL2-X4 strongly and specifically interacted with CXCL12, blocking its binding to CXCR4 and its second receptor, CXCR7 (IC50=20 and 100MUM). Further analysis using mutated and truncated peptides showed that ECL2 of CXCR4 forms multiple contacts with the gp120 protein and the N-terminus of CXCL12. Chemokine neutralisation was mainly driven by four aspartates and the C terminal residues of ECL2-X4. These results demonstrate that ECL2 represents an important structural determinant in CXCR4 activation. We identified the putative site for the binding of CXCL12 N-terminus and provided new structural elements to explain the recognition of gp120 and dimeric CXCR4 ligands. PMID- 24480463 TI - PsMPK1, an SLT2-type mitogen-activated protein kinase, is required for hyphal growth, zoosporogenesis, cell wall integrity, and pathogenicity in Phytophthora sojae. AB - Mitogen-activated protein kinases (MAPKs) play important roles in the regulation of vegetative and pathogenic growth in plant pathogens. Here, we identified an SLT2-type MAP kinase in Phytophthora sojae, PsMPK1, which was transcriptionally induced in sporulating hyphae and the early stages of infection. Silencing of PsMPK1 caused defects in growth and zoosporogenesis, and increased hyphal swellings after the induction of sporangia formation, along with increasing hypersensitivity to cell wall-degrading enzymes. Transmission electron microscopy showed that the cell wall of PsMPK1-silenced mutants was also deleteriously affected. A dark outermost layer in the cell walls disappeared in the mutants, and an additional layer of the mutant cell wall that was deposited abnormally inside an inner bright layer appeared nonhomogeneous and rough compared to the wild type. Pathogenicity assays showed that PsMPK1-silenced transformants lost their pathogenicity on susceptible soybean host plants and triggered stronger cell death. Overall, PsMPK1 is involved in growth, differentiation, cell wall integrity, and pathogenicity in P. sojae. PMID- 24480464 TI - [Benito Daza de Valdes. A XVI century Spanish pioneer in optics]. PMID- 24480465 TI - Papilledema secondary to Burkitt lymphoma. PMID- 24480466 TI - Bergmeister's papilla. PMID- 24480467 TI - [An eye wound that led to the death of a king in the wedding of Philip II and Elizabeth of Valois]. PMID- 24480468 TI - Inhibition of long chain fatty acyl-CoA synthetase (ACSL) and ischemia reperfusion injury. AB - Various triacsin C analogs, containing different alkenyl chains and carboxylic acid bioisoteres including 4-aminobenzoic acid, isothiazolidine dioxide, hydroxylamine, hydroxytriazene, and oxadiazolidine dione, were synthesized and their inhibitions of long chain fatty acyl-CoA synthetase (ACSL) were examined. Two methods, a cell-based assay of ACSL activity and an in situ [(14)C]-palmitate incorporation into extractable lipids were used to study the inhibition. Using an in vivo leukocyte recruitment inhibition protocol, the translocation of one or more cell adhesion molecules from the cytoplasm to the plasma membrane on either the endothelium or leukocyte or both was inhibited by inhibitors 1, 9, and triacsin C. The results suggest that inhibition of ACSL may attenuate the vascular inflammatory component associated with ischemia reperfusion injury and lead to a decrease of infarct expansion. PMID- 24480469 TI - Surface plasmon resonance using the catalytic domain of soluble guanylate cyclase allows the detection of enzyme activators. AB - Soluble Guanylate Cyclase (sGC) is the receptor for the signalling agent nitric oxide (NO) and catalyses the production of the second messenger cyclic guanosine monophosphate (cGMP) from guanosine triphosphate (GTP). The enzyme is an attractive drug target for small molecules that act in the cardiovascular and pulmonary systems, and has also shown to be a potential target in neurological disorders. We have discovered that 5-(indazol-3-yl)-1,2,4-oxadiazoles activate the enzyme in the absence of added NO and shown they bind to the catalytic domain of the enzyme after development of a surface plasmon resonance assay that allows the biophysical detection of intrinsic binding of ligands to the full length sGC and to a construct of the catalytic domain. PMID- 24480470 TI - Administration of growth hormone and nandrolone decanoate alters mRNA expression of the GABAB receptor subunits as well as of the GH receptor, IGF-1, and IGF-2 in rat brain. AB - OBJECTIVE: The illicit use of anabolic androgenic steroids (AAS), especially among young adults, is of major concern. Among AAS users it is common to combine the AAS nandrolone decanoate (ND), with intake of growth hormone (GH) and a connection between gonadal steroids and the GH system has been suggested. Both AAS and GH affect functions in the brain, for example those associated with the hypothalamus and pituitary, and several GH actions are mediated by growth factors such as insulin-like growth factor 1 (IGF-1) and insulin-like growth factor 2 (IGF-2). The GABAergic system is implicated in actions induced by AAS and previous studies have provided evidence for a link between GH and GABAB receptors in the brain. Our aim was to examine the impact of AAS administration and a subsequent administration of GH, on the expression of GABAB receptors and important GH mediators in rat brain. DESIGN: The aim was to investigate the CNS effects of a high-dose ND, and to study if a low, but physiological relevant, dose of GH could reverse the ND-induced effects. In the present study, male rats were administered a high dose of ND every third day during three weeks, and subsequently the rats were given recombinant human GH (rhGH) during ten days. Quantitative PCR (qPCR) was used to analyze gene expression in hypothalamus, anterior pituitary, caudate putamen, nucleus accumbens, and amygdala. RESULTS: In the pituitary gland, the expression of GABAB receptor subunits was affected differently by the steroid treatment; the GABAB1 mRNA expression was decreased whereas a distinct elevation of the GABAB2 expression was found. Administration of ND also caused a decrease of GHR, IGF-1, and IGF-2 mRNA expression in the pituitary while the corresponding expression in the hypothalamus, caudate putamen, nucleus accumbens, and amygdala was unaffected. The rhGH administration did not alter the GABAB2 expression but increased the GABAB1 gene expression in the hypothalamus as compared to the AAS treated group. CONCLUSIONS: These results provide new insights on the impact of ND and GH on the brain and highlight the interaction of these hormones with systems influencing GABAB receptor expression. The physiological significance of the observed effects of these hormones is discussed. PMID- 24480471 TI - Role of ATP-sensitive potassium channels in modulating nociception in rat model of bone cancer pain. AB - Bone cancer pain is a major clinical problem and remains difficult to treat. ATP sensitive potassium (KATP) channels may be involved in regulating nociceptive transmission at the spinal cord level. We determined the role of spinal KATP channels in the control of mechanical hypersensitivity in a rat model of bone cancer pain. The rat model of bone cancer pain was induced by implanting rat mammary gland carcinoma cells (Walker256) into the tibias. KATP modulators (pinacidil and glibenclamide) or the specific Kir6.2-siRNA were injected via an intrathecal catheter. The mechanical withdrawal threshold of rats was tested using von Frey filaments. The Kir6.2 mRNA and protein levels were measured by quantitative PCR and western blots, respectively. Intrathecal injection of pinacidil, a KATP channel opener, significantly increased the tactile withdrawal threshold of cancer cell-injected rats in a dose-dependent manner. In contrast, intrathecal delivery of glibenclamide, a KATP channel blocker, or the specific Kir6.2-siRNA significantly reduced the tactile withdrawal threshold of cancer cell-injected rats. The mRNA and protein levels of Kir6.2 in the spinal cord of cancer cell-injected rats were significantly lower than those in control rats. Our findings suggest that the KATP channel expression level in the spinal cord is reduced in bone cancer pain. Activation of KATP channels at the spinal level reduces pain hypersensitivity associated with bone cancer pain. PMID- 24480472 TI - Quercetin improves hypoxia-ischemia induced cognitive deficits via promoting remyelination in neonatal rat. AB - Myelination failure is associated with perinatal cerebral hypoxia-ischemia (PHI) induced brain injury in premature infants. How to efficiently promote remyelination is crucial for improving cognitive deficits caused by brain injury. Here, we demonstrated that quercetin (Que), a kind of flavonoids, significantly improved cognitive deficits and the behavior of PHI-rat in Morris water maze and open field tasks. After administration of Que to PHI-rat, the number of neogenetic Olig2+ oligodendrocyte progenitor cells (OPCs) was evidently increased in the subventricular zone. Additionally, in corpus callosum (CC), the expression of MBP (myelin basic protein) was increased, and the myelin sheaths reached normal level at 30 days with more compact while less damaged myelin sheaths and more mature oligodendrocytes (OLs) repopulating the CC compared with PHI groups. In a word, our findings indicated that Que could remarkably improve both cognition performance and myelination in the context of PHI-induced brain injury by promoting the proliferation of OPCs and strengthening survival of OLs in vivo. PMID- 24480473 TI - Pitx3 deficient mice as a genetic animal model of co-morbid depressive disorder and parkinsonism. AB - Approximately 40-50% of all patients with Parkinson's disease (PD) show symptoms and signs of depressive disorders, for which neither pathogenic understanding nor rational treatment are available. Using Pit3x-deficient mice, a model for selective nigrostriatal dopaminergic neurodegeneration, we tested depression related behaviors and acute stress responses to better understand how a nigrostriatal dopaminergic deficit increases the prevalence of depressive disorders in PD patients. Pitx3-deficient mice showed decreased sucrose consumption and preference in the two-bottle free-choice test of anhedonia. Acute restraint stress increased c-Fos (known as a neuronal activity marker) expression levels in various brain regions, including the prefrontal cortex, striatum, nucleus accumbens, and paraventricular nucleus of the hypothalamus (PVN), in both Pitx3+/+ and -/- mice. However, the stress-induced increases in c-Fos levels in the cortex, dorsal striatum, and PVN were significantly greater in Pitx3-/- than +/+ mice, suggesting that signs of depressive disorders in parkinsonism are related to altered stress vulnerability. Based on these results, we propose that Pitx3-/- mice may serve as a useful genetic animal model for co-morbid depressive disorder and parkinsonism. PMID- 24480474 TI - Investigation into the role of gap junction modulation of intracortical connectivity in mouse neocortical brain slices. AB - General anesthetics are hypothesized to cause unconsciousness by interrupting communication pathways within the cerebral cortex. A correlate of this has been demonstrated in mouse neocortical slices, where anesthetics disrupt the spread of population field potential activity--resulting in a "decoupling" of activity recorded across spatial locations within the slice. In this study we investigated whether this decoupling can be explained by gap junction blockade, with a particular focus on the connexin36 (Cx36) subtype. Baseline, coupled seizure-like event (SLE) activity was recorded from two extracellular electrodes in slices perfused with no-magnesium artificial cerebrospinal fluid (aCSF). The connexin36 gap junction blocker mefloquine (25 uM) failed to decouple SLE activity in wild type mice (median(range) decoupling rate of 0.70(0.03-3.00)%, not significantly different from controls). Slices from Cx36 knock-out mice exhibited coupled SLE activity under baseline conditions and readily decoupled when exposed to the general anesthetic etomidate. The general gap junction blocker carbenoxolone (CBX, 100 uM) strongly decoupled SLE activity compared to controls in wild-type mice (2.7(0.1-42.5) % compared to 0.03(0.0-0.5)%, p=0.0001). Taken together, the results show that Cx36 gap junction blockade does not cause decoupling of intracortical population activity, but the involvement of other gap junction subtypes cannot be ruled out. PMID- 24480475 TI - Neurotoxicity of coral snake phospholipases A2 in cultured rat hippocampal neurons. AB - The neurotoxicity of two secreted Phospholipases A2 from Brazilian coral snake venom in rat primary hippocampal cell culture was investigated. Following exposure to Mlx-8 or Mlx-9 toxins, an increase in free cytosolic Ca(2+) and a reduction in mitochondrial transmembrane potential (DeltaPsim) became evident and occurred prior to the morphological changes and cytotoxicity. Exposure of hippocampal neurons to Mlx-8 or Mlx-9 caused a decrease in the cell viability as assessed by MTT and LDH assays. Inspection using fluorescent images and ultrastructural analysis by scanning and transmission electron microscopy showed that multiphase injury is characterized by overlapping cell death phenotypes. Shrinkage, membrane blebbing, chromatin condensation, nucleosomal DNA fragmentation and the formation of apoptotic bodies were observed. The most striking alteration observed in the electron microscopy was the fragmentation and rarefaction of the neuron processes network. Degenerated terminal synapses, cell debris and apoptotic bodies were observed among the fragmented fibers. Numerous large vacuoles as well as swollen mitochondria and dilated Golgi were noted. Necrotic signs such as a large amount of cellular debris and membrane fragmentation were observed mainly when the cells were exposed to highest concentration of the PLA2-neurotoxins. PLA2s exposed cultures showed cytoplasmic vacuoles filled with cell debris, clusters of mitochondria presented mitophagy like structures that are in accordance to patterns of programmed cell death by autophagy. Finally, we demonstrated that the sPLA2s, Mlx-8 and Mlx-9, isolated from the Micrurus lemniscatus snake venom induce a hybrid cell death with apoptotic, autophagic and necrotic features. Furthermore, this study suggests that the augment in free cytosolic Ca(2+) and mitochondrial dysfunction are involved in the neurotoxicity of Elapid coral snake venom sPLA2s. PMID- 24480477 TI - Mitochondrial fission: firing up mitochondria in brown adipose tissue. AB - Brown adipose tissue (BAT) is an important site for energy expenditure, for instance to generate heat in times of cold exposure. BAT expansion and activation can increase energy dissipation of an organism. This involves the coordinated activation of mitochondrial metabolism and heat generation through uncoupling of oxidative phosphorylation. In this issue of The EMBO Journal, the Shirihai group uncovers a novel potentiation pathway for BAT energy expenditure. Changes in mitochondrial dynamics, in particular mitochondrial fission, act in synergy with fatty acid-induced uncoupling to activate BAT metabolism in response to the hormone norepinephrine. PMID- 24480476 TI - Functional MR imaging of a simulated balance task. AB - Human postural control, which relies on information from vestibular, visual, and proprioceptive inputs, degrades with aging, and falls are the leading cause of injury in older adults. In the last decade, functional neuroimaging studies have been performed in order to gain a greater understanding of the supraspinal control of balance and walking. It is known that active balancing involves cortical and subcortical structures in the brain, but neuroimaging of the brain during these tasks has been limited. The study of the effect of aging on the functional neuroimaging of posture and gait has only recently been undertaken. In this study, an MRI-compatible force platform was developed to simulate active balance control. Eleven healthy participants (mean age 75+/-5 yr) performed an active balance simulation task by using visual feedback to control anterior posterior center of pressure movements generated by ankle dorsiflexor (DF) and plantarflexor (PF) movements, in a pattern consistent with upright stance control. An additional ankle DF/PF exertion task was performed. During both the active balance simulation and the ankle DF/PF tasks, the bilateral fusiform gyrus and middle temporal gyrus, right inferior, middle, and superior frontal gyrii were activated. No areas were found to be more active during the ankle DF/PF task when compared with the active balance simulation task. When compared to the ankle DF/PF task, the active balance simulation task elicited greater activation in the middle and superior temporal gyrii, insula, and a large cluster that covered the corpus callosum, superior and medial frontal gyrii, as well as the anterior cingulate and caudate nucleus. This study demonstrates the utility in using a force platform to simulate active balance control during MR imaging that elicits activity in cortical regions consistent with studies of active balance and mental imagery of balance. PMID- 24480478 TI - Thinking outside the Osp(G)--kinase activation by E2-ubiquitin. AB - OspG is a secreted effector kinase from the human pathogen Shigella that is required for the reduction of immune responses during Shigella infection. A new study in The EMBO Journal provides a co-crystal structure of OspG bound to UbcH5c~Ub, revealing how a bacterial kinase can be activated by the host ubiquitin conjugation machinery. These results provide molecular insight into an enigmatic microbial virulence factor that thwarts the host immune surveillance system to cause disease. PMID- 24480480 TI - Risk of Coxiella burnetii transmission via embryo transfer using in vitro early bovine embryos. AB - Coxiella burnetii, an obligate intracellular bacterium of worldwide distribution, is responsible for Q fever. Domestic ruminants are the main source of infection for humans. The objectives of this study were to determine (1) whether C. burnetii would adhere to the intact zona pellucida (ZP-intact) of early in vitro produced bovine embryos; (2) whether the bacteria would adhere to or infect the embryos (ZP-free) after in vitro infection; and (3) the efficacy of the International Embryo Transfer Society (IETS) washing protocol. One hundred and sixty, eight- to 16-cell bovine embryos produced in vitro, were randomly divided into 16 batches of 10 embryos. Twelve batches (eight ZP-intact and four ZP-free) were incubated in a medium containing C. burnetii CbB1 (Infectiologie Animale et Sante Publique, Institut National de Recherche Agronomique Tours, France). After 18 hours of incubation at 37 degrees C and 5% CO2 in air, the embryos were washed in 10 successive baths of a PBS and 5% fetal calf serum solution in accordance with the IETS guidelines. In parallel, four batches (two ZP-intact and two ZP-free) were subjected to similar procedures but without exposure to C. burnetii to act as controls. Ten washing fluids from each batch were collected and centrifuged for 1 hour at 13,000* g. The embryos and wash pellets were tested using conventional polymerase chain reaction. C. burnetii DNA was found in all ZP intact and ZP-Free embryos after 10 successive washes. It was also detected in the first four washing fluids for ZP-intact embryos and in the 10th wash fluid for two of the four batches of ZP-free embryos. In contrast, none of the embryos or their washing fluids in the control batches were DNA positive. These results demonstrate that C. burnetii adheres to and/or penetrates the early embryonic cells and the ZP of in vitro bovine embryos after in vitro infection, and that the standard washing protocol recommended by the IETS for bovine embryos, failed to remove it. The persistence of these bacteria after washing makes the embryo a potential means of transmission of the bacterium during embryo transfer from infected donor cows to healthy recipients and/or their offspring. Further studies are required to investigate whether enzymatic and/or antibiotic treatment of bovine embryos infected by C. burnetii would eliminate the bacteria from the ZP and to verify if similarly results are obtained with in vivo-derived embryos. PMID- 24480481 TI - Scrotal circumference of Australian beef bulls. AB - Normal range for scrotal circumference in Australian beef bulls was established using more than 300,000 measurements of breed, management group, age, liveweight, and scrotal circumference. The data used were derived from Australian bull breeders and two large research projects in northern Australia. Most bulls were within 250 to 750 kg liveweight and 300 to 750 days of age. The differences between breeds and variances within breeds were higher when scrotal circumference was predicted from age rather than liveweight, because of variance in growth rates. The average standard deviation for predicted scrotal circumference from liveweight and age was 25 and 30 mm, respectively. Scrotal circumference by liveweight relationships have a similar pattern across all breeds, except in Waygu, with a 50 to 70 mm range in average scrotal circumference at liveweights between 250 and 750 kg. Temperate breed bulls tended to have higher scrotal circumference at the same liveweight than tropically adapted breeds. Five groupings of common beef breeds in Australian were identified, within which there were similar predictions of scrotal circumference from liveweight. It was concluded that liveweight and breed are required to identify whether scrotal circumference is within normal range for Australian beef bulls that experience a wide range of nutritional conditions. PMID- 24480479 TI - FAK dimerization controls its kinase-dependent functions at focal adhesions. AB - Focal adhesion kinase (FAK) controls adhesion-dependent cell motility, survival, and proliferation. FAK has kinase-dependent and kinase-independent functions, both of which play major roles in embryogenesis and tumor invasiveness. The precise mechanisms of FAK activation are not known. Using x-ray crystallography, small angle x-ray scattering, and biochemical and functional analyses, we show that the key step for activation of FAK's kinase-dependent functions- autophosphorylation of tyrosine-397--requires site-specific dimerization of FAK. The dimers form via the association of the N-terminal FERM domain of FAK and are stabilized by an interaction between FERM and the C-terminal FAT domain. FAT binds to a basic motif on FERM that regulates co-activation and nuclear localization. FAK dimerization requires local enrichment, which occurs specifically at focal adhesions. Paxillin plays a dual role, by recruiting FAK to focal adhesions and by reinforcing the FAT:FERM interaction. Our results provide a structural and mechanistic framework to explain how FAK combines multiple stimuli into a site-specific function. The dimer interfaces we describe are promising targets for blocking FAK activation. PMID- 24480482 TI - Attached segment has higher CD34+ cells and CFU-GM than the main bag after thawing. AB - A contiguous segment attached to the cord blood unit (CBU) is required for verifying HLA types, cell viability, and, possibly, potency before transplantation since such a segment is considered to be representative of the CBU. However, little is known regarding the characteristics of contiguous segments in comparison to main bag units due to the difficulty experienced in accessing a large number of cryopreserved CBUs. In this study, we used 245 nonconforming CBUs for allogeneic transplantation. After thawing the cryopreserved CBU, the number of total nucleated cells (TNCs), CD34(+) cells, and CFUs in CB from main bags and segments, as well as cell viability and apoptosis, were examined. The comparative analysis showed that the number of TNCs was significantly higher in CB from main bags, whereas the numbers of CD34(+) cells and CFU-GM were significantly higher in CB from segments. While the cell viability of TNCs in segments was higher, the proportion of apoptotic TNCs was also higher. In contrast, no difference was observed between the proportion of apoptotic CD34(+) cells in main bags and segments. In the correlation analysis, the numbers of TNCs, CD34(+) cells, and CFU-GM in main bags were highly correlated with those in segments, indicating that CB from segments is indeed representative of CB in main bags. Taken together, we conclude that segments have higher CD34(+) cells and CFU-GM and lower TNCs than the main cryopreserved bag, although the two compartments are highly correlated with each other. PMID- 24480483 TI - X-linked adrenoleukodystrophy in women: a cross-sectional cohort study. AB - X-linked adrenoleukodystrophy is the most common peroxisomal disorder. The disease is caused by mutations in the ABCD1 gene that encodes the peroxisomal transporter of very long-chain fatty acids. A defect in the ABCD1 protein results in elevated levels of very long-chain fatty acids in plasma and tissues. The clinical spectrum in males with X-linked adrenoleukodystrophy has been well described and ranges from isolated adrenocortical insufficiency and slowly progressive myelopathy to devastating cerebral demyelination. As in many X-linked diseases, it was assumed that female carriers remain asymptomatic and only a few studies addressed the phenotype of X-linked adrenoleukodystrophy carriers. These studies, however, provided no information on the prevalence of neurological symptoms in the entire population of X-linked adrenoleukodystrophy carriers, since data were acquired in small groups and may be biased towards women with symptoms. Our primary goal was to investigate the symptoms and their frequency in X-linked adrenoleukodystrophy carriers. The secondary goal was to determine if the X-inactivation pattern of the ABCD1 gene was associated with symptomatic status. We included 46 X-linked adrenoleukodystrophy carriers in a prospective cross-sectional cohort study. Our data show that X-linked adrenoleukodystrophy carriers develop signs and symptoms of myelopathy (29/46, 63%) and/or peripheral neuropathy (26/46, 57%). Especially striking was the occurrence of faecal incontinence (13/46, 28%). The frequency of symptomatic women increased sharply with age (from 18% in women <40 years to 88% in women >60 years of age). Virtually all (44/45, 98%) X-linked adrenoleukodystrophy carriers had increased very long-chain fatty acids in plasma and/or fibroblasts, and/or decreased very long-chain fatty acids beta-oxidation in fibroblasts. We did not find an association between the X-inactivation pattern and symptomatic status. We conclude that X-linked adrenoleukodystrophy carriers develop an adrenomyeloneuropathy-like phenotype and there is a strong association between symptomatic status and age. X-linked adrenoleukodystrophy should be considered in the differential diagnosis in women with chronic myelopathy and/or peripheral neuropathy (especially with early faecal incontinence). ABCD1 mutation analysis deserves a place in diagnostic protocols for chronic non-compressive myelopathy. PMID- 24480484 TI - Cortical reorganization after macroreplantation at the upper extremity: a magnetoencephalographic study. AB - With the development of microsurgical techniques, replantation has become a feasible alternative to stump treatment after the amputation of an extremity. It is known that amputation often induces phantom limb pain and cortical reorganization within the corresponding somatosensory areas. However, whether replantation reduces the risk of comparable persisting pain phenomena as well as reorganization of the primary somatosensory cortex is still widely unknown. Therefore, the present study aimed to investigate the potential development of persistent pain and cortical reorganization of the hand and lip areas within the sensory cortex by means of magnetoencephalographic dipole analyses after replantation of a traumatically amputated upper limb proximal to the radiocarpal joint. Cortical reorganization was investigated in 13 patients with limb replantation using air puff stimulation of the phalanges of both thumbs and both corners of the lower lip. Displacement of the centre of gravity of lip and thumb representations and increased cortical activity were found in the limb and face areas of the primary somatosensory cortex contralateral to the replanted arm when compared to the ipsilateral hemisphere. Thus, cortical reorganization in the primary somatosensory cortex also occurs after replantation of the upper extremity. Patients' reports of pain in the replanted body part were negatively correlated with the amount of cortical reorganization, i.e. the more pain the patients reported, the less reorganization of the subjects' hand representation within the primary somatosensory cortex was observed. Longitudinal studies in patients after macroreplantation are necessary to assess whether the observed reorganization in the primary somatosensory cortex is a result of changes within the representation of the replanted arm and/or neighbouring representations and to assess the relationship between the development of persistent pain and reorganization. PMID- 24480485 TI - The Gdap1 knockout mouse mechanistically links redox control to Charcot-Marie Tooth disease. AB - The ganglioside-induced differentiation-associated protein 1 (GDAP1) is a mitochondrial fission factor and mutations in GDAP1 cause Charcot-Marie-Tooth disease. We found that Gdap1 knockout mice (Gdap1(-/-)), mimicking genetic alterations of patients suffering from severe forms of Charcot-Marie-Tooth disease, develop an age-related, hypomyelinating peripheral neuropathy. Ablation of Gdap1 expression in Schwann cells recapitulates this phenotype. Additionally, intra-axonal mitochondria of peripheral neurons are larger in Gdap1(-/-) mice and mitochondrial transport is impaired in cultured sensory neurons of Gdap1(-/-) mice compared with controls. These changes in mitochondrial morphology and dynamics also influence mitochondrial biogenesis. We demonstrate that mitochondrial DNA biogenesis and content is increased in the peripheral nervous system but not in the central nervous system of Gdap1(-/-) mice compared with control littermates. In search for a molecular mechanism we turned to the paralogue of GDAP1, GDAP1L1, which is mainly expressed in the unaffected central nervous system. GDAP1L1 responds to elevated levels of oxidized glutathione by translocating from the cytosol to mitochondria, where it inserts into the mitochondrial outer membrane. This translocation is necessary to substitute for loss of GDAP1 expression. Accordingly, more GDAP1L1 was associated with mitochondria in the spinal cord of aged Gdap1(-/-) mice compared with controls. Our findings demonstrate that Charcot-Marie-Tooth disease caused by mutations in GDAP1 leads to mild, persistent oxidative stress in the peripheral nervous system, which can be compensated by GDAP1L1 in the unaffected central nervous system. We conclude that members of the GDAP1 family are responsive and protective against stress associated with increased levels of oxidized glutathione. PMID- 24480486 TI - Visuoperceptive region atrophy independent of cognitive status in patients with Parkinson's disease with hallucinations. AB - Visual hallucinations are frequent, disabling complications of advanced Parkinson's disease, but their neuroanatomical basis is incompletely understood. Previous structural brain magnetic resonance imaging studies suggest volume loss in the mesial temporal lobe and limbic regions in subjects with Parkinson's disease with visual hallucinations, relative to those without visual hallucinations. However, these studies have not always controlled for the presence of cognitive impairment or dementia, which are common co-morbidities of hallucinations in Parkinson's disease and whose neuroanatomical substrates may involve mesial temporal lobe and limbic regions. Therefore, we used structural magnetic resonance imaging to examine grey matter atrophy patterns associated with visual hallucinations, comparing Parkinson's disease hallucinators to Parkinson's disease non-hallucinators of comparable cognitive function. We studied 50 subjects with Parkinson's disease: 25 classified as current and chronic visual hallucinators and 25 as non-hallucinators, who were matched for cognitive status (demented or non-demented) and age (+/- 3 years). Subjects underwent (i) clinical evaluations; and (ii) brain MRI scans analysed using whole brain voxel-based morphometry techniques. Clinically, the Parkinson's disease hallucinators did not differ in their cognitive classification or performance in any of the five assessed cognitive domains, compared with the non-hallucinators. The Parkinson's disease groups also did not differ significantly in age, motor severity, medication use or duration of disease. On imaging analyses, the hallucinators, all of whom experienced visual hallucinations, exhibited grey matter atrophy with significant voxel-wise differences in the cuneus, lingual and fusiform gyri, middle occipital lobe, inferior parietal lobule, and also cingulate, paracentral, and precentral gyri, compared with the non-hallucinators. Grey matter atrophy in the hallucinators occurred predominantly in brain regions responsible for processing visuoperceptual information including the ventral 'what' and dorsal 'where' pathways, which are important in object and facial recognition and identification of spatial locations of objects, respectively. Furthermore, the structural brain changes seen on magnetic resonance imaging occurred independently of cognitive function and age. Our findings suggest that when hallucinators and non-hallucinators are similar in their cognitive performance, the neural networks involving visuoperceptual pathways, rather than the mesial temporal lobe regions, distinctively contribute to the pathophysiology of visual hallucinations and may explain their predominantly visual nature in Parkinson's disease. Identification of distinct structural MRI differences associated with hallucinations in Parkinson's disease may permit earlier detection of at-risk patients and ultimately, development of therapies specifically targeting hallucinations and visuoperceptive functions. PMID- 24480488 TI - Prescribing exercise training in pulmonary rehabilitation: a clinical experience. AB - Built around exercise training, pulmonary rehabilitation (PR) is a multidisciplinary, evidence-based, comprehensive approach to working with the patient as a whole and not just the pulmonary component of the disease. Integrated into the individualized treatment, this intervention aims to reduce symptoms, optimize functional status, increase participation in daily life, and reduce health care costs through stabilizing or reversing systemic manifestations of the disease. Although there are many other components that should be considered to manage the impairment and symptom burden, supervised exercise training is considered the cornerstone of effective pulmonary rehabilitation. This paper addresses our clinical experience at Institut universitaire de cardiologie et de pneumologie de Quebec to assess and manage exercise training in line with the current recommendations and guidelines surrounding PR. PMID- 24480489 TI - Child marriage in Bangladesh: trends and determinants. AB - This study examines the trends and determinants of child marriage among women aged 20-49 in Bangladesh. Data were extracted from the last six nationally representative Demographic and Health Surveys conducted during 1993-2011. Simple cross-tabulation and multivariate binary logistic regression analyses were adopted. According to the survey conducted in 2011, more than 75% of marriages can be categorized as child marriages. This is a decline of 10 percentage points in the prevalence of child marriage compared with the survey conducted in 1993 1994. Despite some improvements in education and other socioeconomic indicators, Bangladeshi society still faces the relentless practice of early marriage. The mean age at first marriage has increased by only 1.4 years over the last one and half decades, from 14.3 years in 1993-1994 to 15.7 years in 2011. Although the situation on risk of child marriage has improved over time, the pace is sluggish. Both the year-of-birth and year-of-marriage cohorts of women suggest that the likelihood of marrying as a child has decreased significantly in recent years. The risk of child marriage was significantly higher when husbands had no formal education or little education, and when the wives were unemployed or unskilled workers. Muslim women living in rural areas have a greater risk of child marriage. Women's education level was the single most significant negative determinant of child marriage. Thus, the variables identified as important determinants of child marriage are: education of women and their husbands, and women's occupation, place of residence and religion. Programmes to help and motivate girls to stay in school will not only reduce early marriage but will also support overall societal development. The rigid enforcement of the legal minimum age at first marriage could be critical in decreasing child marriage. PMID- 24480490 TI - Is ankle arthrodesis or total ankle replacement the better treatment for end stage arthrosis? PMID- 24480487 TI - Learning to remember: the early ontogeny of episodic memory. AB - Over the past 60 years the neural correlates of human episodic memory have been the focus of intense neuroscientific scrutiny. By contrast, neuroscience has paid substantially less attention to understanding the emergence of this neurocognitive system. In this review we consider how the study of memory development has evolved. In doing so, we concentrate primarily on the first postnatal year because it is within this time window that the most dramatic shifts in scientific opinion have occurred. Moreover, this time frame includes the critical age (~9 months) at which human infants purportedly first begin to demonstrate rudimentary hippocampal-dependent memory. We review the evidence for and against this assertion, note the lack of direct neurocognitive data speaking to this issue, and question how demonstrations of exuberant relational learning and memory in infants as young as 3-months old can be accommodated within extant models. Finally, we discuss whether current impasses in the infant memory literature could be leveraged by making greater use of neuroimaging techniques, such as magnetic resonance imaging (MRI), which have been deployed so successfully in adults. PMID- 24480491 TI - Platelet-rich plasma for foot and ankle pathologies: a systematic review. AB - BACKGROUND: The aim of this article is to review systematically all the literature available on the clinical application of PRP for the treatment of foot and ankle pathologies, to understand its potential and best indications for clinical use. METHODS: A systematic search of the PubMed database was performed. Research criteria were the following: (1) papers in the English language, (2) dealing with the clinical application of PRP for the treatment of orthopedic related conditions affecting the foot and ankle district, (3) with I to IV level of evidence, and (4) reporting clinical results. RESULTS: A total of 17 studies fulfilled the inclusion criteria. Nine papers dealt with Achilles tendon management, 2 articles with plantar fasciitis, 3 papers with talar osteochondral lesions, 2 with PRP application in total ankle replacement, and 1 article with PRP in foot and ankle fusions. The overall evaluation of the results reported does not clearly demonstrate the potential of PRP treatment in any of the specific fields of application. CONCLUSIONS: Considering the literature currently available, no clear indications for using PRP in the foot and ankle district emerged. LEVEL OF EVIDENCE: Level IV, systematic review of Level I, II, III and IV studies. PMID- 24480492 TI - A study to compare the efficacy of corticosteroid therapy with platelet-rich plasma therapy in recalcitrant plantar fasciitis: a preliminary report. AB - BACKGROUND: Plantar fasciitis is one of the commonest, and most frustrating, foot ailments seen in a regular orthopaedic clinic. There are a number of modalities available to treat this condition, of which corticosteroid injection is, perhaps, the most popular. However, recent years have seen an increased interest in the use of platelet-rich plasma (PRP) injections in various clinical situations such as plantar fasciitis. METHODS: We undertook a prospective non-randomized study to compare the efficacy of traditional corticosteroid injection (Steroid group) to PRP injection (PRP group), in a cohort of patients. RESULTS: We studied both groups of patients before and after the injections using Visual Analogue Score (VAS), the Foot & Ankle Disability Index (FADI) and American Foot and Ankle Score (AFAS). Our study confirms that there is significant clinical improvement in PRP group at three months after the injection. CONCLUSION: The use of PRP injection can be an attractive alternative in the treatment of disabling, recalcitrant plantar fasciitis. STUDY DESIGN: Cohort study. LEVEL OF CLINICAL EVIDENCE: Level 3. PMID- 24480494 TI - Lengthening scarf osteotomy for recurrent hallux valgus. AB - BACKGROUND: We describe using the scarf osteotomy to correct a recurrent hallux valgus deformity and lengthen the shortened first metatarsal in symptomatic iatrogenic first brachymetatarsia. METHODS: Thirty-six lengthening scarf osteotomies were undertaken in 31 patients. Clinical and radiographic measures were taken pre and postoperatively. RESULTS: Mean age at presentation was 53.4 years, and mean followup 3.9 years. The mean lengthening achieved was 4.9mm. All osteotomies united with no complications. The mean IMA reduction was 4.0 degrees (p<0.001) and HVA 13.0 degrees (p<0.001). The mean AOFAS score increase was 33.8 (p<0.001). There was a positive trend but no correlation (r=0.28) between amount of metatarsal lengthening and AOFAS score change. CONCLUSIONS: We describe the largest lengthening scarf osteotomy series for recurrent hallux valgus with iatrogenic first brachymetatarsia. The results suggest the procedure is successful, with a low complication rate. We anticipate that restoring first metatarsal length and alignment may reduce biomechanical transfer metatarsalgia over time. PMID- 24480493 TI - Biomechanical comparison of stability of tibiotalocalcaneal arthrodesis with two different intramedullary retrograde nails. AB - BACKGROUND: The aim of the study was to compare the initial construct stability of two retrograde intramedullary nail systems for tibiotalocalcaneal arthrodesis (TTCF) (A3, Small Bone Innovations; HAN, Synthes) in a biomechanical cadaver study. METHODS: Nine pairs of human cadaver bones were instrumented with two different retrograde nail systems. One tibia from each pair was randomized to either rod. The bone mineral density was determined via tomography to ensure the characteristics in each pair of tibiae were similar. All tests were performed in load-control. Displacements and forces were acquired by the sensors of the machine at a rate of 64Hz. Specimens were tested in a stepwise progression starting with six times +/-125N with a frequency of 1Hz for 250cycles each step was performed (1500cycles). The maximum load was then increased to +/-250N for another 14 steps or until specimen failure occurred (up to 3500cycles). RESULTS: Average bone mineral density was 67.4mgHA/ccm and did not differ significantly between groups (t-test, p=.28). Under cyclic loading, the range of motion (dorsiflexion/plantarflexion) at 250N was significantly lower for the HAN-group with 7.2+/-2.3mm compared to the A3-group with 11.8+/-2.9mm (t-test, p<0.01). Failure was registered for the HAN after 4571+/-1134cycles and after 2344+/ 1195cycles for the A3 (t-test, p=.031). Bone mineral density significantly correlated with the number of cycles to failure in both groups (Spearman-Rho, r>.69, p<0.01). CONCLUSIONS: The high specimen age and low bone density simulates an osteoporotic bone situation. The HAN with only lateral distal bend but two calcaneal locking screws showed higher stability (higher number of cycles to failure and lower motion such as dorsiflexion/plantarflexion during cyclic loading) than the A3 with additional distal dorsal bend but only one calcaneal locking screw. Both constructs showed sufficient stability compared with earlier data from a similar test model. CLINICAL RELEVANCE: The data suggest that both implants allow for sufficient primary stability for TTCF in osteoporotic and consequently also in non-osteoporotic bone. LEVEL OF EVIDENCE: Not applicable, experimental basic science study. PMID- 24480495 TI - Medium term outcomes of planovalgus foot correction in children using a lateral column lengthening approach with additional procedures 'a la carte'. AB - BACKGROUND: We report our medium term outcomes following surgery for symptomatic planovalgus malalignment in children. The technique we describe commences with lateral column lengthening and includes subsequent bony and soft tissue procedures which are carried out 'a la carte' in response to the underlying pathology and the behaviour of the foot to the lateral column lengthening. METHODS: Surgery was undertaken on twenty five symptomatic planovalgus feet in 15 patients at a mean age of 12 years and 6 months (5 years 7 months to 16 years and 3 months). The case-mix was principally idiopathic pes planovalgus but included overcorrected club foot and skewfoot deformity. Following lateral column lengthening (using a tricortical interpositional os calcis bone graft) the 'a la carte' elements of the surgery undertaken included both bony and soft tissue elements: heel shift; medial cuneiform osteotomy with iliac crest tricortical bone grafting, peroneus brevis/peroneus longus transfer; plantar fascia release; tibialis posterior advancement. VAS FA and AOFAS scores, clinical findings and complications were recorded. RESULTS: Twelve patients (20 feet) were available for follow up at a mean of 4 years and 6 months years (2 years and 8 months to 6 years and 3 months). VAS FA and AOFAS scores were 82+/-17 (50-99), 87+/-14 (61 100) and 80+/-10 (62-100), respectively. In all patients the reconstituted medial arch was maintained. Three patients (5 feet) required a second corrective procedure. CONCLUSION: We propose lateral column lengthening with additional 'a la carte' procedures in the surgical treatment of symptomatic pes planovalgus in childhood as a reliable corrective surgical procedure on the basis of favourable medium term functional outcomes. PMID- 24480496 TI - Proximal closing wedge lesser metatarsal osteotomy for metatarsophalangeal joint transverse plane realignment. Surgical technique and outcome. AB - BACKGROUND: We describe the surgical technique and outcome of a proximal closing wedge osteotomy of the lesser metatarsals, to treat medial or lateral subluxation of the MTP joints, with toe deviation, when dorsiflexion (MTPJ dorsal subluxation) deformity is not present. METHODS: The principle of surgical correction, is the shift of the metatarsal head in the direction of the deformity, to allow restoration of congruity of the metatarsophalangeal joint. The osteotomies were performed at the proximal metaphyseal level. At the same time, soft tissue release, consisting of division of the inter-metatarsal ligament on the other side of the deformity, allows adequate displacement. RESULTS: Four patients, followed for 12 months, were asymptomatic and very satisfied with the outcome, while clinical and radiographic alignment was maintained. CONCLUSIONS: The described surgical technique can be performed in selected patients with transverse plane deformities of the lesser metatarsals. PMID- 24480497 TI - Cross-cultural adaptation and validation of the Foot Function Index to Spanish. AB - BACKGROUND: The purpose of this study was to adapt and validate the Foot Function Index to the Spanish (FFI-Sp) following the guidelines of the American Academy of Orthopaedic Surgeons. METHODS: A cross-sectional study 80 participants with some foot pathology. A statistical analysis was made, including a correlation study with other questionnaires (the Foot Health Status Questionnaire, EuroQol 5-D, Visual Analogue Pain Scale, and the Short Form SF-12 Health Survey). Data analysis included reliability, construct and criterion-related validity and factor analyses. RESULTS: The principal components analysis with varimax rotation produced 3 principal factors that explained 80% of the variance. The confirmatory factor analysis showed an acceptable fit with a comparative fit index of 0.78. The FFI-Sp demonstrated excellent internal consistency on the three subscales: pain 0.95; disability 0.96; and activity limitation 0.69, the subscale that scored lowest. The correlation between the FFI-Sp and the other questionnaires was high to moderate. CONCLUSIONS: The Spanish version of the Foot Function Index (FFI-Sp) is a tool that is a valid and reliable tool with a very good internal consistency for use in the assessment of pain, disability and limitation of the function of the foot, for use both in clinic and research. PMID- 24480498 TI - Effectiveness of 'in-cast' pneumatic intermittent pedal compression for the pre operative management of closed ankle fractures: a clinical audit. AB - BACKGROUND: Timing of surgery for ankle fractures is largely dependent on the condition of the surrounding soft-tissues. This study aimed to determine the clinical effectiveness of a pre-operative in-cast artero-venous (AV) impulse device in the management of closed ankle fractures requiring surgery. METHODS: A consecutive series of 64 closed ankle fractures were managed using the AV impulse system prior to surgery. Patients were compared to 73 consecutive closed ankle fractures managed surgically in the same unit immediately prior to the implementation of the AV impulse device study. Outcomes measured were time to surgery, length of hospital stay and surgical site infections. RESULTS: Median length of time to surgery, hospital stay duration and surgical site infections were all significantly reduced in the study group as compared to the control group. CONCLUSIONS: In-cast intermittent AV compression foot pumps in the pre operative management of closed ankle fractures were associated with earlier surgery, earlier discharge and reduced complications. PMID- 24480499 TI - A biomechanical evaluation of locked plating for distal fibula fractures in an osteoporotic sawbone model. AB - BACKGROUND: Supination external rotation (SER) injuries are commonly fixed with a one third tubular neutralization plate. This study investigated if a combination locked plate with additional fixation options was biomechanically superior in osteoporotic bone and comminuted fracture models. METHODS: Using an osteoporotic and a comminuted Sawbones model, SER injuries were fixed with a lag screw for simple oblique fibula fractures, and either a one third tubular neutralization plate or a locking plate. Samples were tested in stiffness, peak torque, displacement at failure, and torsion fatigue. RESULTS: There was no statistically significant difference in biomechanical testing for fractures treated with a lag screw and plate. For comminuted fractures, locked plating demonstrated statistically significant stiffer fixation. CONCLUSION: A combination locked plate is biomechanically superior to a standard one third tubular plate in comminuted SER ankle fractures. There was no biomechanical superiority between locked and one third tubular plates when the fracture was amenable to a lag screw. PMID- 24480500 TI - Impact of trimalleolar ankle fractures: how do patients fare post-operatively? AB - BACKGROUND: We aim to evaluate the clinical and functional outcome of trimalleolar fractures and the ability of patients to return to sporting activities. METHODS: A retrospective review of 31 patients with operatively managed trimalleolar fractures was conducted. Their Olerud and Molander scores and ability to return to sports was analyzed at 1 year postoperatively. RESULTS: Dislocations were more likely to result from trimalleolar fractures (p<0.001). 11 (52.4%) of our patients had residual pain at 1 year. 13 (61.9%) and 10 (47.6%) had persistent ankle stiffness and swelling. Out of 12 patients who were involved in sports pre-operatively, only 4 (33.3%) patients were able to return to sports. 3 (25%) patients were unable to do sports at all. Increasing posterior malleolar fragment size correlates with poorer functional outcome. CONCLUSIONS: Patients have poorer functional outcome with increasing posterior malleolar fragment size in trimalleolar fractures. Residual deficits affect the majority of our patients and a notable proportion was unable to return to sporting activities. PMID- 24480501 TI - Bone mass and anthropometry in patients with osteoarthritis of the foot and ankle. AB - BACKGROUND: Patients with hip and knee osteoarthritis (OA) have high bone mineral density (BMD) and high BMI. If the same accounts for patients with foot or ankle OA is unknown. METHODS: We measured BMD and femoral neck (FN) width by dual energy X-ray absorptiometry in 42 women and 19 men with idiopathic OA in the foot or ankle, and in 99 women and 82 men as controls. RESULTS: Women with OA had significant higher BMI than controls. Women with OA had higher BMI-adjusted BMD (p<0.01) and smaller BMI-adjusted FN width (p<0.01) than controls. Men with OA had higher BMI adjusted-BMD (p<0.05) and smaller BMI-adjusted FN width (p<0.01) than controls. CONCLUSION: Patients with OA in the foot or ankle have higher BMD and smaller bone size than being expected by their BMI. This phenotype may provide unfavourable forces across the joint and is hypothetically important for development of OA. PMID- 24480502 TI - Quantitative assessment of the subchondral vascularity of the talar dome: a cadaveric study. AB - BACKGROUND: The arterial supply to the talus has been extensively studied previously but never to specifically examine the subchondral region of the talar dome, a frequent site of localised pathology. This study aims to analyse and quantify the subchondral vascularity of the talar dome. METHODS: We performed cadaveric arterial injection studies. After processing, the vascularity to the subchondral region of the talar dome was visualised and mapped using three dimensional computer technology, then quantified and reported using a nine section anatomical grid. RESULTS: The areas of relative poor perfusion across the talar dome are the posterior/medial, posterior/lateral and middle/medial sections of a nine-section grid. The rest of the subchondral region shows more richly vascularised bone. CONCLUSIONS: The vascularity of the subchondral surface of the talar dome is not uniformly distributed. This may be relevant to the aetiology and management of osteochondral lesions and shows some correlation with their more frequent locations. PMID- 24480503 TI - Effect of radiofrequency microtenotomy on degeneration of tendons: an experimental study on rabbits. AB - INTRODUCTION: Radiofrequency microtenotomy is used to enhance healing by increasing vascularity in the degenerated tendon. In the present study, the effect of radiofrequency microtenotomy (Rf-mt) treatment on tendon degeneration was investigated. MATERIALS AND METHODS: A total of 32 New Zealand rabbits were enrolled in the current study. Experimental degeneration was performed by injecting prostaglandin E1 (PGE1) into the bilateral Achilles tendons of rabbits. After excluding 4 rabbits with an infection on the injection site, 4 other rabbits were sacrificed to define the histopathologic changes in the tendons. The remaining 24 rabbits were divided into 2 groups: the control group and the Rf-mt group. In the control group, the Rf-mt device was only applied to the Achilles tendon without running the device. In the Rf-mt group, the Rf-mt device was applied bilaterally at the fourth energy level for 500ms to an area within 2cm proximal to the insertion site at 0.5cm intervals in order to form a grid. Six rabbits from each group were sacrificed at 6 and 12 weeks. The Achilles tendons were evaluated histopathologically by a modified Movin scale and by immunohistopathologic staining for vascular endothelial growth factor and type 4 collagen. RESULTS: After the PGE1 injection, findings similar to chronic degenerative tendinopathy were observed. The Rf-mt group showed significant improvement in vascularity in the histopathological and immunohistochemical examination (P<0.05). However, there was no significant difference in healing between the control and Rf-mt groups (P>0.05). CONCLUSIONS: Rf-mt treatment increases vascularity in degenerated tendons but does not create difference to facilitate the healing process comparing control group. PMID- 24480504 TI - Ankle position affects dorsalis pedis artery exposure in anterior ankle arthroscopy. AB - BACKGROUND: In anterior ankle arthroscopy, the anterior working area (AWA) is restricted by the presence of the dorsalis pedis artery (DPA) and tendons. Pseudoaneurysms caused by iatrogenic damage to the DPA are difficult to identify intraoperatively. In knee arthroscopy, risk of popliteal artery damage is reduced in the flexed position [1]. This study investigates how DPA movement is affected by dorsiflexion and plantarflexion with the aim of identifying the positions providing the greatest AWA. METHODS: Twelve cadaveric ankles were dissected to access the DPA. While distracted, ankles were progressively dorsiflexed at 5 degrees intervals from maximum plantarflexion. DPA and tibialis anterior tendon (TA) movement at each 5 degrees interval was measured by their respective distances from the inferior border of the medial malleolus. RESULTS: Mean ankle dorsiflexion was 24.58+/-1.30 degrees with all specimens showing anterior DPA and TA movement as dorsiflexion increased. Mean DPA and TA movement at maximum dorsiflexion was 3.58+/-0.29mm and 2.92+/-0.34mm respectively. A ratio of 1:1.23 relates TA and DPA movement (inmm), and a ratio of 10:1.46 relates dorsiflexion angle to DPA movement (inmm). CONCLUSION: Anterior movement of the dorsalis pedis artery during dorsiflexion increases the AWA for anterior arthroscopy. Increasing the AWA with maximal dorsiflexion may prove to be a valuable method for lowering the risk of iatrogenic DPA damage. Additionally, increased AWA may allow the use of larger diameter surgical instruments allowing greater control and a reduction in operation time. PMID- 24480505 TI - An atraumatic turf toe in an elite soccer player--a stress related phenomenon? AB - Plantar plate injuries to the hallux in elite athlete could potentially be career threatening. Reports in the literature are invariably linked to a significant traumatic episode. The occurrence of an atraumatic severe plantar plate injury in the presence of a bipartite sesamoid may suggest a stress related phenomenon. We present a case in an elite soccer player who was treated surgically and returned to top-level competition. The case is reported in detail and differences to other reports in the literature discussed. PMID- 24480506 TI - Simultaneous arthrodiastasis and deformity correction for a patient with ankle osteoarthritis and lower limb deformity: a case report. AB - We here report a case of a 50-year-old male with ankle osteoarthritis and lower limb deformity, for which simultaneous deformity correction and arthrodiastasis were performed. The patient initially experienced an open fracture on the left tibia at 19 years, but it was malunited. The Japanese Society for Surgery score of the foot for the left ankle was 53 points. X-ray and CT imaging showed rotational and angular tibial deformities with shortening by 1.6cm and end-stage osteoarthritis of the left ankle. An external fixator was applied to correct the lower limb deformity, and ankle arthrodiastasis was performed. A good result was achieved in alignment correction and joint function. The patient had an improved clinical score of 98 points at a 2-year followup. We found that external fixation was useful because external fixator is the only appropriate instrument by which arthrodiastasis and deformity correction for ankle osteoarthritis can be simultaneously performed. PMID- 24480507 TI - Isolated medial foot compartment syndrome after ankle sprain. AB - Foot compartment syndrome is a serious potential complication of foot crush injury, fractures, surgery, and vascular injury. An acute compartment syndrome isolated to the medial compartment of the foot after suffering an ankle sprain is a rare complication. We report the case of a 31-year-old man who developed a medial foot compartment syndrome after suffering a deltoid ligament rupture at ankle while playing football. The patient underwent a medial compartment fasciotomy with resolution of symptoms. Compartment syndromes of the foot are rare and have been reported to occur after severe trauma. But, there are some reports in the literature of acute exertional compartment syndrome. In our case, the compartment syndrome appeared after an ankle sprain without vascular injuries associated. PMID- 24480508 TI - Fibula physeal fracture causing syndesmotic diastasis. AB - We report an unusual physeal fibula fracture seen in a 12 year old child. The fragment was rotated and incarcerated in the distal tibiofibular joint causing syndesmotic diastasis. The fragment required open reduction and the fibula was stabilised with k-wires. The patient made an excellent recovery. PMID- 24480509 TI - Hallux valgus deformity of foot with tumoral calcinosis: an unusual presentation. AB - Tumoral calcinosis is an uncommon disorder and characterized by development of calcified masses within the soft tissues near the large joints such as the hip, elbow, and shoulder and rarely occurs in the foot. We report a case of tumoral calcinosis at the first meta-tarso-phalangeal (MTP) joint of foot with hallux valgus deformity associated with bunion which required resection. Surgical excision of the calcific mass alone, without surgery to the minimal hallux valgus, resulted in resolution of symptoms, without recurrence of the lesion. Subsequently, speculative etiology, differential diagnostic considerations as well as the therapeutic interventions for tumoral calcinosis are discussed taking into consideration the current literature. We conclude that tumoral calcinosis should be considered in the differential diagnosis of a painful mass that develops in the small joints of the foot. PMID- 24480510 TI - Oedema of the abductor digiti quinti muscle due to subacute denervation: report of two cases. AB - The clinical presentation of abductor digiti quinti (ADQ) denervation is often non-specific. The diagnosis is generally clinical and may be easily missed. This case report of two patients describes the magnetic resonance imaging (MRI) finding of unilateral oedema and fatty infiltration isolated to the ADQ. A 36 year old woman who presented with laterally located left foot pain was initially diagnosed as having plantar fasciitis. An MRI scan arranged due to the unusual site of the pain showed increased signal intensity within the ADQ muscle on T1 and T2 images indicating fatty infiltration. Short tau inversion recovery (STIR) images showed hyperintensity of the ADQ indicating oedema. The MRI scan of a 45 year old man who presented with a three month history of left heel pain revealed similar findings. These MRI appearances indicate subacute denervation, which, when involving solely the ADQ muscle suggests entrapment of the first branch of the lateral plantar nerve. Consideration of this imaging finding when examining MRI scans of patients with non-specific heel pain has the potential to facilitate diagnosis. PMID- 24480511 TI - Complete spontaneous avascular necrosis of the adult navicula associated with Mee's growth arrest lines of the great and second toenails. AB - Spontaneous total avascular necrosis of the tarsal navicula has been well documented in children (Kohler's disease) but is uncommon in adults where partial necrosis is usually seen after trauma or in Muller-Weiss disease. A case of spontaneous complete navicular osteonecrosis in a 46 year old female is described; she had accompanying Mee's leuchonychial lines in the toenails of the great and second toes only; the lines resolved after 9 months. She has been treated with an excision of the navicula and interpositional iliac crest bone graft talo-cuneiform fusion with resolution of her pain. It is postulated that the combination of the Mee's lines and avascular necrosis of the navicula indicates an occlusion of the dorsalis pedis in a predisposed individual. PMID- 24480512 TI - Clival chordoma of the nasal septum secondary to surgical pathway seeding. AB - EDUCATIONAL OBJECTIVE: At the conclusion of this presentation, the participants should be able to recognize seeding as a form of treatment failure in transseptal resection of clival chordomas. OBJECTIVES: The purpose is to present a case of implanted metastases in the nasal septum after a transseptal approach for resection of clival chordoma and to compare it with other reported cases in the literature. STUDY DESIGN: Case report and literature review. METHODS: The clinical history, radiologic imaging, and pathology of a single patient are reviewed. RESULTS: A 35-year-old female presented with a left intranasal mass that completely occluded the left nasal passage. The patient had a history of clival chordoma treated at an outside institution with multiple partial resections via a transseptal approach and postoperative Gamma Knife radiotherapy. A 2.5 cm mass in the left nasal cavity as well as a 4 cm sellar mass was identified on MRI. Biopsy of the left nasal mass confirmed the diagnosis of chordoma, which was presumed to be secondary to seeding from a previous resection attempt. The patient received no further treatment due to multiple comorbidities. CONCLUSIONS: Recurrence of clival chordoma due to seeding along the surgical pathway is an infrequent mechanism of treatment failure, with only rare cases documented in the literature. When deciding on the appropriate surgical approach, the surgeon must consider the risk of septal seeding during a transseptal approach. The emergence of transnasal endoscopic skull base approaches may reduce the likelihood of surgical pathway tumor seeding. PMID- 24480513 TI - A statistical approach towards the derivation of predictive gene sets for potency ranking of chemicals in the mouse embryonic stem cell test. AB - The embryonic stem cell test (EST) is applied as a model system for detection of embryotoxicants. The application of transcriptomics allows a more detailed effect assessment compared to the morphological endpoint. Genes involved in cell differentiation, modulated by chemical exposures, may be useful as biomarkers of developmental toxicity. We describe a statistical approach to obtain a predictive gene set for toxicity potency ranking of compounds within one class. This resulted in a gene set based on differential gene expression across concentration response series of phthalatic monoesters. We determined the concentration at which gene expression was changed at least 1.5-fold. Genes responding with the same potency ranking in vitro and in vivo embryotoxicity were selected. A leave one-out cross-validation showed that the relative potency of each phthalate was always predicted correctly. The classical morphological 50% effect level (ID50) in EST was similar to the predicted concentration using gene set expression responses. A general down-regulation of development-related genes and up regulation of cell-cycle related genes was observed, reminiscent of the differentiation inhibition in EST. This study illustrates the feasibility of applying dedicated gene set selections as biomarkers for developmental toxicity potency ranking on the basis of in vitro testing in the EST. PMID- 24480514 TI - Kidney biomarkers in MCPA-induced acute kidney injury in rats: reduced clearance enhances early biomarker performance. AB - For improved early detection and assessment of severe acute kidney damage following accidental or intentional ingestion of the herbicide MCPA, we compared a panel of 14 novel kidney injury biomarkers with plasma creatinine. Male Wistar rats received four different oral doses of MCPA and plasma and urine biomarker levels were measured at 8, 24 and 48 h after MCPA exposure. Diagnostic performances using absolute levels, urine levels normalized to urine creatinine or urinary excretion rate were determined by ROC analysis. Plasma creatinine remained the best early biomarker for predicting histological changes at 48 h. The performance of plasma cystatin C in mirroring kidney function was similar to that of plasma creatinine. While urine concentrations were generally less predictive, normalization by urine creatinine greatly improved the performance of several biomarkers. This may be due to an apparent amplification of the biomarker signal on normalizing to creatinine, in the presence of a declining glomerular filtration rate prior to reaching steady state. Normalized 8 h osteopontin and albumin concentrations outperformed other normalized biomarkers in predicting histological changes at later times. Normalized urinary kidney injury molecule-1 at 48 h also correlated well with the degree of kidney damage. PMID- 24480516 TI - A role for mitogen kinase kinase 3 in pulmonary inflammation validated from a proteomic approach. AB - Proteomics is a powerful tool to ascertain which proteins are differentially expressed in the context of disease. We have used this approach on inflammatory cells obtained from patients with asthma to ascertain whether novel drugs targets could be illuminated and to investigate the role of any such target in a range of in vitro and in vivo models of inflammation. A proteomic study was undertaken using peripheral blood mononuclear cells from mild asthmatic subjects compared with healthy subjects. The analysis revealed an increased expression of the intracellular kinase, mitogen activated protein kinase (MKK3), and the function of this protein was investigated further in preclinical models of inflammation using MKK3 knockout mice. We describe a 3.65 fold increase in the expression of MKK3 in CD8(+) T lymphocytes obtained from subjects with asthma compared with healthy subjects using a proteomic approach which we have confirmed in CD8(+), but not in CD4(+) T lymphocytes or human bronchial epithelial cells from asthmatic patients using a Western blot technique. In wild type mice, bacterial lipopolysaccharide (LPS) caused a significant increase in MKK3 expression and significantly reduced airway neutrophilia in MKK3(-/-) mice (median, 25, 75% percentile; wild/LPS; 5.3 (0.7-9.9) * 10(5) cells/mL vs MKK3(-/-)/LPS; 0 (0-1.9) * 10(5) cells/mL, P < 0.05). In contrast, eosinophilia in sensitized wild type mice challenged with allergen (0.5 (0.16-0.65) * 10(5) cells/mL) was significantly increased in MKK3(-/-) mice (2.2 (0.9-3.5) * 10(5) cells/mL, P < 0.05). Our results suggest that asthma is associated with MKK3 over-expression in CD8(+) cells. We have also demonstrated that MKK3 may be critical for airway neutrophilia, but not eosinophilia, suggesting that this may be a target worthy of further consideration in the context of diseases associated with neutrophil activation such as severe asthma and COPD. PMID- 24480515 TI - Therapeutic infusions of ketamine: do the psychoactive effects matter? AB - BACKGROUND: Sub-anesthetic ketamine infusions may benefit a variety of psychiatric disorders, including addiction. Though ketamine engenders transient alterations in consciousness, it is not known whether these alterations influence efficacy. This analysis evaluates the mystical-type effects of ketamine, which may have therapeutic potential according to prior research, and assesses whether these effects mediate improvements in dependence-related deficits, 24h postinfusion. METHODS: Eight cocaine dependent individuals completed this double blind, randomized, inpatient study. Three counter-balanced infusions separated by 48h were received: lorazepam (2mg) and two doses of ketamine (0.41mg/kg and 0.71mg/kg, with the former dose always preceding the latter). Infusions were followed within 15min by measures of dissociation (Clinician Administered Dissociative Symptoms Scale: CADSS) and mystical-type effects (adapted from Hood's Mysticism Scale: HMS). At baseline and 24h postinfusion, participants underwent assessments of motivation to stop cocaine (University of Rhode Island Change Assessment) and cue-induced craving (by visual analogue scale for cocaine craving during cue exposure). RESULTS: Ketamine led to significantly greater acute mystical-type effects (by HMS) relative to the active control lorazepam; ketamine 0.71mg/kg was associated with significantly higher HMS scores than was the 0.41mg/kg dose. HMS score, but not CADSS score, was found to mediate the effect of ketamine on motivation to quit cocaine 24h postinfusion. CONCLUSIONS: These findings suggest that psychological mechanisms may be involved in some of the anti-addiction benefits resulting from ketamine. Future research can evaluate whether the psychoactive effects of ketamine influence improvements in larger samples. PMID- 24480517 TI - The expression of P2X7 receptors on peripheral blood mononuclear cells in patients with primary Sjogren's syndrome and its correlation with anxiety and depression. AB - OBJECTIVES: To study surface expression of P2X7 receptors (P2X7R) on peripheral blood mononuclear cells (PBMC) in patients with primary Sjogren's syndrome (pSS), and its correlation with anxiety and/or depression. METHODS: The Hamilton Anxiety Scale (HAMA) and Hamilton Rating Scale for Depression (HRSD) were used to assess 31 patients with pSS. P2X7R expression on the surface of CD14+ and CD14- PBMC, with or without ATP stimulation, was measured by flow cytometry. IL-1beta and IL 6 levels in blood plasma and supernatant after ATP stimulation were measured by ELISA. Nineteen patients with rheumatoid arthritis (RA), 18 patients with anxiety and/or depression, and 20 healthy cases were used as controls. RESULTS: P2X7R expression was detected in all subjects. Compared with no ATP stimulation, significant up-regulation of P2X7R expression on CD14+ PBMC was observed after ATP stimulation in the pSS group only (p=0.001), while on CD14- PBMC there was significant up-regulation in both the pSS (p<0.001) and anxiety/depression (p=0.003) groups. After ATP stimulation, P2X7R expression on CD14+ PBMC in the pSS group was significantly higher than the RA group (p=0.044), anxiety/depression group (p=0.004) and healthy controls (p=0.002). Moreover, in the pSS group, P2X7R expression on CD14+ PBMC was significantly positively correlated to IL-1beta supernatant levels (r=0.447, p=0.025). Overall, there were 45.2% (14/31) patients with anxiety and 32.3% (10/31) with depression, in the pSS group. P2X7R expression on CD14- PBMC was significantly positively correlated to scores of anxiety (r=0.344, p=0.030) and depression (r=0.319, p=0.045). CONCLUSIONS: Surface expression of P2X7R on PBMC in patients with pSS was significantly higher than controls, suggesting P2X7R may contribute to the complex pathogenesis of pSS and also anxiety and/or depression. PMID- 24480518 TI - Liver cirrhosis. AB - Cirrhosis is an increasing cause of morbidity and mortality in more developed countries, being the 14th most common cause of death worldwide but fourth in central Europe. Increasingly, cirrhosis has been seen to be not a single disease entity, but one that can be subclassified into distinct clinical prognostic stages, with 1-year mortality ranging from 1% to 57% depending on the stage. We review the current understanding of cirrhosis as a dynamic process and outline current therapeutic options for prevention and treatment of complications of cirrhosis, on the basis of the subclassification in clinical stages. The new concept in management of patients with cirrhosis should be prevention and early intervention to stabilise disease progression and to avoid or delay clinical decompensation and the need for liver transplantation. The challenge in the 21st century is to prevent the need for liver transplantation in as many patients with cirrhosis as possible. PMID- 24480519 TI - GC-MS analysis of organic acids in human urine in clinical settings: a study of derivatization and other analytical parameters. AB - In the current paper the analytical conditions for the determination of ten free organic acids by GC-MS are studied with the aim to establish a method for organic acid profiling in human urine to be used as a tool for the detection of metabolic or other health disorders. Studies included the GC-MS method development, the derivatization (trimethylsilylation) reaction conditions, the stability of the standard solutions during storage in the freezer, and the stability of the formed trimethylsilyl derivatives. Best results were obtained at a derivatization temperature of 50 degrees C, and a reaction time of 30 min. Standard solutions were stable for 22 days, derivatized samples were stable at least for 30 h when stored at -24 degrees C. GC-MS analysis achieved sensitive determination of the organic acids under study with limits of detection ranging from 0.03 mmol/mol creatinine for glutaric acid, to 0.34 mmol/mol creatinine for glycolic acid. Within-day and day-to-day assay imprecision was found satisfactory with relative standard deviations being below 10%. The developed method was successfully applied to the quantitative analysis of free organic acids in urine samples obtained from hospitalized children. Creatinine-corrected excretion rates of all analyzed organic acids were within reference intervals. PMID- 24480520 TI - The effect of a minor constituent of essential oil from Citrus aurantium: the role of beta-myrcene in preventing peptic ulcer disease. AB - The monoterpene beta-myrcene has been widely used in cosmetics, food and beverages, and it is normally found in essential oil from citrus fruit. The aim of this study was to investigate the anti-ulcer effects of beta-myrcene on experimental models of ulcers that are induced by ethanol, NSAIDs (non-steroidal anti-inflammatory drugs), stress, Helicobacter pylori, ischaemia-reperfusion injury (I/R) and cysteamine in order to compare with the essential oil of Citrus aurantium and its major compound limonene. The results indicate that the oral administration of beta-myrcene at a dose of 7.50mg/kg has important anti-ulcer activity with significantly decreased gastric and duodenal lesions as well as increased gastric mucus production. The results showed treatment with beta myrcene caused a significant increase in mucosal malondialdehyde level (MDA), an important index of oxidative tissue damage. The beta-myrcene was also endowed with marked enhancement of antioxidant enzyme activity from GR system as evidenced by the decreased activity of superoxide dismutase (SOD) and increased levels of glutathione peroxidase (GPx), glutathione reductase (GR), and total glutathione in gastric tissue. Our results also shown that treatment with beta myrcene is not involved with thioredoxin reductase (TrxR) activity. Our results reveal, for the first time, the importance of beta-myrcene as an inhibitor of gastric and duodenal ulcers and demonstrate that an increase in the levels of gastric mucosa defence factors is involved in the anti-ulcer activity of beta myrcene. PMID- 24480521 TI - 1,4-Bis(5-(naphthalen-1-yl)thiophen-2-yl)naphthalene, a small molecule, functions as a novel anti-HIV-1 inhibitor targeting the interaction between integrase and cellular Lens epithelium-derived growth factor. AB - Translocation of viral integrase (IN) into the nucleus is a critical precondition of integration during the life cycle of HIV, a causative agent of Acquired Immunodeficiency Syndromes (AIDS). As the first discovered cellular factor to interact with IN, Lens epithelium-derived growth factor (LEDGF/p75) plays an important role in the process of integration. Disruption of the LEDGF/p75-IN interaction has provided a great interest for anti-HIV agent discovery. In this work, we reported that one small molecular compound, 1,4-bis(5-(naphthalen-1 yl)thiophen-2-yl)naphthalene(Compound 15), potently inhibit the IN-LEDGF/p75 interaction and affect the HIV-1 IN nuclear distribution at 1 MUM. The putative binding mode of Compound 15 was constructed by a molecular docking simulation to provide structural insights into the ligand-binding mechanism. Compound 15 suppressed viral replication by measuring p24 antigen production in HIV-1IIIB acute infected C8166 cells with EC50 value of 11.19 MUM. Compound 15 might supply useful structural information for further anti-HIV agent discovery. PMID- 24480522 TI - The synergistic effect of 1'-acetoxychavicol acetate and sodium butyrate on the death of human hepatocellular carcinoma cells. AB - It has been suggested that the combined effect of natural products may improve the effect of treatment against the proliferation of cancer cells. In this study, we evaluated the combination of 1'-acetoxychavicol acetate (ACA), obtained from Alpinia galangal, and sodium butyrate, a major short chain fatty acid, on the growth of HepG2 human hepatocellular carcinoma cells and found that treatment had a synergistic inhibitory effect. The number of HepG2 cells was synergistically decreased via apoptosis induction when cells were treated with both ACA and sodium butyrate. In ACA- and sodium butyrate-treated cells, intracellular reactive oxygen species (ROS) levels and NADPH oxidase activities were increased significantly. The decrease in cell number after combined treatment of ACA and sodium butyrate was diminished when cells were pretreated with catalase. These results suggest that an increase in intracellular ROS levels is involved in cancer cell death. AMP-activated protein kinase (AMPK), a cellular energy sensor, plays an essential role in controlling processes related to tumor development. In ACA- and sodium butyrate-treated cells, AMPK phosphorylation was induced significantly, and this induction improved when cells were pretreated with catalase. These results suggest that the increase in intracellular ROS is involved in the increase of AMPK phosphorylation. In normal hepatocyte cells, treatment with ACA and sodium butyrate did not decrease cell numbers or increase ROS levels. In conclusion, combined treatment with ACA and sodium butyrate synergistically induced apoptotic cell death via an increase in intracellular ROS and phosphorylation of AMPK. Our findings may provide new insight into the development of novel combination therapies against hepatocellular carcinoma. PMID- 24480523 TI - Removal of As(III) and As(V) from aqueous solutions using nanoscale zero valent iron-reduced graphite oxide modified composites. AB - Nanoscale zero valent iron (NZVI) has high adsorption capacity of As(III) and As(V), but it is limited in practical use due to its small particle size and aggregation effect. Reduce graphite oxide (RGO) has been used as a support because of its high surface area. In order to utilize the advantage of NZVI and RGO as well as to avoid the disadvantage of NZVI, we loaded NZVI onto RGO via chemical reactions in this study. The adsorption capacity of As(III) and As(V), as determined from the Langmuir adsorption isotherms in batch experiments, was 35.83mgg(-1) and 29.04mgg(-1), respectively. And the adsorption kinetics fitted well with pseudo-second-order model. The residual concentration was found to meet the standard of WHO after the samples were treated with 0.4gL(-1) NZVI-RGO when the initial concentration of As(III) and As(V) were below 8ppm and 3ppm. Especially, when the initial concentration of As(III) was below 3ppm, the residual concentration was within 1ppb; whereas, the residual concentration was undetected when the initial concentration of As(III) was 1ppm. PMID- 24480524 TI - 6th Dysferlin Conference, 3-6 April 2013, Arlington, Virginia, USA. AB - The 2013 Dysferlin Conference, sponsored and organized by the Jain Foundation, was held from April 3-6, 2013 in Arlington, VA. Participants included 34 researcher speakers, 5 dysferlinopathy patients and all 8 members of the Jain Foundation team. Dysferlinopathy is a rare disease that typically robs patients of mobility during their second or third decade of life. The goals of these Dysferlin Conferences are to bring experts in the field together so that they will collaborate with one another, to quicken the pace of understanding the biology of the disease and to build effective platforms to ameliorate disease. This is important because the function of dysferlin and how to compensate for its absence is still not well understood, in spite of the fact that the dysferlin gene was identified more than a decade ago. The objective of this conference, therefore, was to share and discuss the newest unpublished research defining the role of dysferlin in skeletal muscle, why its absence causes muscular dystrophy and possible therapies for dysferlin-deficient muscular dystrophy patients. PMID- 24480525 TI - Dextroposition of the aorta in tetralogy of Fallot. PMID- 24480526 TI - IFITM proteins-cellular inhibitors of viral entry. AB - Interferon inducible transmembrane (IFITM) proteins are a recently discovered family of cellular anti-viral proteins that restrict the replication of a number of enveloped and non-enveloped viruses. IFITM proteins are located in the plasma membrane and endosomal membranes, the main portals of entry for many viruses. Biochemical and membrane fusion studies suggest IFITM proteins have the ability to inhibit viral entry, possibly by modulating the fluidity of cellular membranes. Here we discuss the IFITM proteins, recent work on their mode of action, and future directions for research. PMID- 24480527 TI - Clinically relevant quality assurance (QA) for prostate RapidArc plans: gamma maps and DVH-based evaluation. AB - The aim of this paper is to evaluate clinically relevant quality assurance (QA) tests for RapidArc prostate patients. 26 plans were verified by the COMPASS system that provides an independent angle response and a reconstruction of dose distribution in patient CT model. Plan data were imported from treatment planning system via DICOM. The fluencies, measured by a 2D detector, were used by COMPASS to forward calculate dose in CT patients and reconstruct dose-volume-histogram (DVH). The gamma analysis was performed, using both the criteria 3%-3-mm and 2%-2 mm, for the whole grid patient and the per-structure volume. A DVH-based analysis was accomplished for target and organs-at-risk (OAR). The correlation between gamma passing rates and DVH discrepancies was performed using Pearson's test. Sensitivity, specificity and accuracy of whole and per-structure gamma method were calculated. No significant DVH deviation was observed for target and OAR. Weak correlation between gamma passing rates and dosimetric deviations was observed, all significant r-values were negative. The whole gamma method shows lack of sensitivity to detect dosimetric deviations >5%. Instead, a better balance between sensitivity and specificity was obtained employing per structure gamma both with 3%-3 mm and 2%-2 mm criteria. Because of the poor correlation between DVH goals and gamma passing rates, we encourage the DVH-based gamma passing rates, when it is possible. At least, a gamma method specific for structure was strongly suggested. PMID- 24480528 TI - Critical appraisal of randomized controlled trials: the beginning of thought.... PMID- 24480530 TI - Implantable cardioverter defibrillator deactivation: a hospice quality improvement initiative. AB - BACKGROUND: Dying patients whose implantable cardioverter defibrillators (ICDs) continue to deliver shocks may experience significant pain, and the National Quality Forum has endorsed routine deactivation of ICDs when patients near the end of life. The overarching goal of this quality improvement project was to increase rates of ICD deactivation among hospice patients. MEASURES: ICD deactivation rates pre- vs. post-intervention; and clinicians' knowledge and confidence regarding ICD management. INTERVENTION: A multifaceted intervention included clinical tools, education, and standardized documentation templates in the electronic medical record. OUTCOMES: The proportion of patients whose ICD was deactivated increased after the intervention (pre- vs. post-intervention: 39/68, 57% vs. 47/56, 84%; odds ratio 3.88; 95% confidence interval 1.54-10.37; P = 0.001). Clinicians' knowledge and confidence regarding ICD management improved (pre- vs. post-intervention median questionnaire scores: 5 vs. 9 on a scale of 0 to 10; Wilcoxon signed-rank test Z = -5.01; P < 0.001). CONCLUSIONS/LESSONS LEARNED: A multifaceted intervention can increase rates of ICD deactivation among patients near the end of life. PMID- 24480529 TI - Treating an established episode of delirium in palliative care: expert opinion and review of the current evidence base with recommendations for future development. AB - CONTEXT: Delirium is a highly prevalent complication in patients in palliative care settings, especially in the end-of-life context. OBJECTIVES: To review the current evidence base for treating episodes of delirium in palliative care settings and propose a framework for future development. METHODS: We combined multidisciplinary input from delirium researchers and other purposely selected stakeholders at an international delirium study planning meeting. This was supplemented by a literature search of multiple databases and relevant reference lists to identify studies regarding therapeutic interventions for delirium. RESULTS: The context of delirium management in palliative care is highly variable. The standard management of a delirium episode includes the investigation of precipitating and aggravating factors followed by symptomatic treatment with drug therapy. However, the intensity of this management depends on illness trajectory and goals of care in addition to the local availability of both investigative modalities and therapeutic interventions. Pharmacologically, haloperidol remains the practice standard by consensus for symptomatic control. Dosing schedules are derived from expert opinion and various clinical practice guidelines as evidence-based data from palliative care settings are limited. The commonly used pharmacologic interventions for delirium in this population warrant evaluation in clinical trials to examine dosing and titration regimens, different routes of administration, and safety and efficacy compared with placebo. CONCLUSION: Delirium treatment is multidimensional and includes the identification of precipitating and aggravating factors. For symptomatic management, haloperidol remains the practice standard. Further high-quality collaborative research investigating the appropriate treatment of this complex syndrome is needed. PMID- 24480531 TI - Nurse and physician barriers to spiritual care provision at the end of life. AB - CONTEXT: Spiritual care (SC) from medical practitioners is infrequent at the end of life (EOL) despite national standards. OBJECTIVES: The study aimed to describe nurses' and physicians' desire to provide SC to terminally ill patients and assess 11 potential SC barriers. METHODS: This was a survey-based, multisite study conducted from October 2008 through January 2009. All eligible oncology nurses and physicians at four Boston academic centers were approached for study participation; 339 nurses and physicians participated (response rate=63%). RESULTS: Most nurses and physicians desire to provide SC within the setting of terminal illness (74% vs. 60%, respectively; P=0.002); however, 40% of nurses/physicians provide SC less often than they desire. The most highly endorsed barriers were "lack of private space" for nurses and "lack of time" for physicians, but neither was associated with actual SC provision. Barriers that predicted less frequent SC for all medical professionals included inadequate training (nurses: odds ratio [OR]=0.28, 95% confidence interval [CI]=0.12-0.73, P=0.01; physicians: OR=0.49, 95% CI=0.25-0.95, P=0.04), "not my professional role" (nurses: OR=0.21, 95% CI=0.07-0.61, P=0.004; physicians: OR=0.35, 95% CI=0.17-0.72, P=0.004), and "power inequity with patient" (nurses: OR=0.33, 95% CI=0.12-0.87, P=0.03; physicians: OR=0.41, 95% CI=0.21-0.78, P=0.007). A minority of nurses and physicians (21% and 49%, P=0.003, respectively) did not desire SC training. Those less likely to desire SC training reported lower self-ratings of spirituality (nurses: OR=5.00, 95% CI=1.82-12.50, P=0.002; physicians: OR=3.33, 95% CI=1.82-5.88, P<0.001) and male gender (physicians: OR=3.03, 95% CI=1.67 5.56, P<0.001). CONCLUSION: SC training is suggested to be critical to the provision of SC in accordance with national care quality standards. PMID- 24480532 TI - Methadone for pain and the risk of adverse cardiac outcomes. AB - CONTEXT: There are few studies that describe cardiac adverse events in patients prescribed methadone for pain management. OBJECTIVES: To describe incident cardiac adverse events and risk factors for cardiac adverse events in primary care patients prescribed methadone for pain. METHODS: This was a retrospective, descriptive, cohort study in patients 18 years or older receiving methadone for pain management during 2010. Patients were followed for 12 months and were categorized as "chronic" or "non-chronic" methadone users. The primary outcomes were a cardiac event, at risk for an event, or neither. Patients were grouped on their outcome and were compared on risk factors and methadone monitoring. RESULTS: A total of 1246 patients were included. Thirty (2.4%), 628 (50.4%), and 588 (47.2%) patients had a cardiac event, were at risk for an event, or had neither an event nor a risk factor, respectively. Overall, the rate of QTc prolongation was 49.4% and the rate of adherence to recommended cardiac monitoring was 39.0%. Similar percentages of chronic and non-chronic users had a cardiac event (P > 0.05). Among the patients who had a cardiac event and were at risk for an event, factors independently associated with having had an event included age (odds ratio = 1.06; 95% CI = 1.03-1.09) and a dose 100 mg/day or higher (odds ratio = 6.18; 95% CI = 1.08-35.45). CONCLUSION: Few cardiac adverse events resulting from methadone use for pain were detected. However, a large proportion of patients were at risk for an adverse event, especially patients who were older and had received >= 100 mg/day of methadone. PMID- 24480533 TI - Rewiring juvenile justice: the intersection of developmental neuroscience and legal policy. AB - The past decade has been marked by historic opinions regarding the culpability of juveniles by the US Supreme Court. In 2005, the death penalty was abolished, 5 years later, life without parole for crimes, other than homicide, was banned, and then just last year, mandatory life sentences for any crime was abolished. The court referenced developmental science in all these cases. In this article, we highlight new scientific findings and their relevance to law and policy. PMID- 24480534 TI - An approach to engineer paracetamol crystals by antisolvent crystallization technique in presence of various additives for direct compression. AB - Paracetamol is a popular over-the-counter analgesic and a challenging model drug due to its poor technological and biopharmaceutical properties such as flowability, compressibility, compactibility and wettability. This work was aimed to alter the crystal habit of paracetamol from elongated to polyhedral-angular via particle engineering whilst maintaining the stable polymorphic form (form I: monoclinic form). The engineered paracetamol crystals obtained in the present investigation showed better technological and biopharmaceutical properties in comparison to the commercial paracetamol. Engineered paracetamol crystals were obtained using antisolvent crystallization technique in the presence of various concentrations (0.1, 0.5 and 1%, w/w) of additives, namely, polyvinyl alcohol (PVA), Avicel PH 102 (microcrystalline cellulose), Brij 58, methylcellulose (MC) and polyethylene glycol having different molecular weights (PEGs 1500, 6000 and 8000). Paracetamols crystallized in the presence of Avicel (or physically mixed with Avicel), Brij 58 and PEG 6000 demonstrated the best compactibility over a range of compaction pressures. Brij-crystallized paracetamol provided the fastest dissolution rate among all the paracetamol batches. Paracetamols crystallized in the presence of PVA or Avicel, or physically mixed with Avicel demonstrated a reduced degree of crystallinity in comparison to the other paracetamols. This study showed that the type, the grade and the concentration of additives could influence the physical stability such as flow, crystallinity and polymorphic transformation of paracetamol, the technological and biopharmaceutical properties of paracetamol. Stable polymorphic form of paracetamol with optimal tableting characteristics can be achieved through particle engineering. PMID- 24480535 TI - An unusual cause of chronic otitis media with effusion. AB - OBJECTIVE: To describe an unusual cause for hearing loss in an adult. CASE REPORT: A 37-year-old man presented with a year's history of right-sided hearing loss. He had no history of trauma, or local or systemic infection. He was otherwise well, took no medication and had no allergies. He had a two-year history of low back pain. On examination, he had a retracted right tympanic membrane with no perforation, and a middle-ear effusion. Nasendoscopy was normal. Examination of other systems was unremarkable. Computed tomography of the temporal bones with contrast demonstrated a large, right, intra-cerebral internal carotid artery aneurysm compressing the eustachian tube. After a balloon occlusion test, he underwent endovascular occlusion of the parent vessel. He made a good post-operative recovery. A subsequent abdominal ultrasound excluded an abdominal aneurysm as a cause of his low back pain. His hearing had not improved three days post-operatively, and was to be formally assessed and monitored in the clinic. DISCUSSION: A carotid aneurysm is a rare cause of eustachian tube compression but must be considered in the differential diagnosis of conductive hearing loss. Aneurysms may have systemic causes, and their presence in other systems should be excluded as they may be multiple. PMID- 24480536 TI - Ecdysterone protects gerbil brain from temporal global cerebral ischemia/reperfusion injury via preventing neuron apoptosis and deactivating astrocytes and microglia cells. AB - Ecdysterone (EDS), a common derivative of ecdysteroid, has shown its effects on alleviating cognitive impairment and improving the cognition and memory. However, the mechanisms remain unknown. Using temporal global forebrain ischemia and reperfusion-induced brain injury as a model system, we investigated the roles of EDS in improving cognitive impairment in gerbil. Our results demonstrated that intraperitoneal injection of EDS obviously increased the number of surviving neuron cells by Nissl and neuronal nuclei (NeuN) staining. Indeed, the protecting effects of EDS are because of its ability to prevent the apoptosis of neuron cells as evidenced by TUNEL staining and caspase-3 deactivation in the brain of temporal global forebrain ischemia/reperfusion-treated gerbil. Moreover, EDS administration suppressed the ischemia stimulated activity of astrocytes and microglia cells by inhibiting the production of tumor necrosis alpha (TNF-alpha) in the brain of gerbil. More importantly, these actions of neurons and astrocytes/microglia cells in response to EDS treatment played pivotal roles in ameliorating the cognitive impairment in the ischemia/reperfusion-injured gerbil. In view of these observations, we not only decipher the mechanisms of EDS in reducing the syndrome of ischemia, but also provide novel perspectives to combat ischemic stroke. PMID- 24480537 TI - Endothelial targeting of nanocarriers loaded with antioxidant enzymes for protection against vascular oxidative stress and inflammation. AB - Endothelial-targeted delivery of antioxidant enzymes, catalase and superoxide dismutase (SOD), is a promising strategy for protecting organs and tissues from inflammation and oxidative stress. Here we describe Protective Antioxidant Carriers for Endothelial Targeting (PACkET), the first carriers capable of targeted endothelial delivery of both catalase and SOD. PACkET formed through controlled precipitation loaded ~30% enzyme and protected it from proteolytic degradation, whereas attachment of PECAM monoclonal antibodies to surface of the enzyme-loaded carriers, achieved without adversely affecting their stability and functionality, provided targeting. Isotope tracing and microscopy showed that PACkET exhibited specific endothelial binding and internalization in vitro. Endothelial targeting of PACkET was validated in vivo by specific (vs IgG control) accumulation in the pulmonary vasculature after intravenous injection achieving 33% of injected dose at 30 min. Catalase loaded PACkET protects endothelial cells from killing by H2O2 and alleviated the pulmonary edema and leukocyte infiltration in mouse model of endotoxin-induced lung injury, whereas SOD-loaded PACkET mitigated cytokine-induced endothelial pro-inflammatory activation and endotoxin-induced lung inflammation. These studies indicate that PACkET offers a modular approach for vascular targeting of therapeutic enzymes. PMID- 24480538 TI - Characteristics of platelet gels combined with silk. AB - Platelet gel, a fibrin network containing activated platelets, is widely used in regenerative medicine due the capacity of platelet-derived growth factors to accelerate and direct healing processes. However, limitations to this approach include poor mechanical properties, relatively rapid degradation, and the lack of control of release of growth factors at the site of injection. These issues compromise the ability of platelet gels for sustained function in regenerative medicine. In the present study, a combination of platelet gels with silk fibroin gel was studied to address the above limitations. Mixing sonicated silk gels with platelet gels extended the release of growth factors without inhibiting gel forming ability. The released growth factors were biologically active and their delivery was modified further by manipulation of the charge of the silk protein. Moreover, the silk gel augmented both the rheological properties and compressive stiffness of the platelet gel, tuned by the silk concentration and/or silk/platelet gel ratio. Silk-platelet gel injections in nude rats supported enhanced cell infiltration and blood vessel formation representing a step towards new platelet gel formulations with enhanced therapeutic impact. PMID- 24480539 TI - Registry of the Spanish network of Behcet's disease: a descriptive analysis of 496 patients. AB - OBJECTIVES: To describe the clinical features of a large cohort of 496 Spanish patients with Behcet's disease (BD) and to analyse if patient's sex influenced the initial and cumulated prevalence of disease manifestations. METHODS: Retrospective and descriptive study of 496 patients recruited in sixteen centres on the frame of the Spanish Registry of Behcet Disease Project Group. Demographic and clinical data are presented in addition to treatments and their related adverse effects. Clinical features at disease onset and during follow-up were compared according to the sex of the patients. RESULTS: On the whole series, female to male ratio was 1.2:1.0. Mean age at disease onset was 28.7+/-12.6 years (range 17-73). Oral ulcers were the most frequent initial manifestation presented in 52.0% of patients. During follow-up, eye inflammatory disease was recorded in 45.1% of patients; thrombosis in 19.7% and central nervous system involvement in 13.5%. Men had higher prevalence of ocular involvement and venous thrombosis (52.5% vs. 39.2%, p=0.004 and 26.3% vs. 9.6%, p<0.001, respectively). CONCLUSIONS: Spanish patients with BD presented similar clinical characteristics as their counterpart in the same geographical area and other world regions. In addition, we confirmed that ocular and vascular involvements are more frequent in men than in women. PMID- 24480540 TI - Isolation and mRNA expression analysis of aquaporin isoforms in marine medaka Oryzias dancena, a euryhaline teleost. AB - We have identified six putative aquaporin (AQP) genes from marine medaka Oryzias dancena (named odAQPs 1, 3, 8, 10, 11 and 12). The marine medaka AQP cDNAs encode polypeptides of 259-298 amino acids, respectively. Topology predictions showed six transmembrane domains, five connecting loops, and cytoplasmic N- and C terminal domains, all of which is conserved among AQP molecules. Although asparagine-proline-alanine (NPA) motifs are highly conserved in most odAQP isoforms, several AQPs revealed variant types of motifs such as asparagine proline-proline (NPP), asparagine-proline-valine (NPV) or/and asparagine-proline serine (NPS) motifs. The phylogenic analysis showed that marine medaka AQPs had closet relationship with Japanese ricefish (medaka; Oryzias latipes) counterparts. Reverse transcription (RT)-PCR analyses showed that marine medaka AQP transcripts would be expressed in not only osmoregulatory tissues but also nonosmoregulatory tissues, and also that the expression levels of certain AQP isoforms in nonosmoregulatory tissues were readily comparable or even higher than those in typically known osmoregulatory organs. Although the overall tissue distribution patterns of AQPs were not significantly different between 0- and 30 ppt acclimated fish, the expression levels under different salinities were largely variable among isoforms and tissues. This is the first report to investigate tissue expression profiles of teleostean AQPs 11 and 12 during the long-term acclimation to freshwater and salted water. PMID- 24480541 TI - The laser capture microdissection cannot be replaced with the macrodissection. PMID- 24480542 TI - Defective minor spliceosome mRNA processing results in isolated familial growth hormone deficiency. AB - The molecular basis of a significant number of cases of isolated growth hormone deficiency remains unknown. We describe three sisters affected with severe isolated growth hormone deficiency and pituitary hypoplasia caused by biallelic mutations in the RNPC3 gene, which codes for a minor spliceosome protein required for U11/U12 small nuclear ribonucleoprotein (snRNP) formation and splicing of U12 type introns. We found anomalies in U11/U12 di-snRNP formation and in splicing of multiple U12-type introns in patient cells. Defective transcripts include preprohormone convertases SPCS2 and SPCS3 and actin-related ARPC5L genes, which are candidates for the somatotroph-restricted dysfunction. The reported novel mechanism for familial growth hormone deficiency demonstrates that general mRNA processing defects of the minor spliceosome can lead to very narrow tissue specific consequences. PMID- 24480544 TI - Transient left ventricular wall thickening in a 14-year-old girl with influenza A myocarditis. AB - We describe a case of influenza A myocarditis and transient left ventricular wall thickening in a 14-year-old girl presenting with acute heart failure. Admission echocardiogram revealed significant left ventricular hypertrophy with depressed left ventricular systolic function. The aetiology of the ventricular thickening was demonstrated to be myocardial oedema using cardiac magnetic resonance imaging. The natural course of this unusual clinical presentation of acute myocarditis and the importance of cardiac magnetic resonance imaging in this challenging clinical setting are discussed. PMID- 24480545 TI - Synthesis, crystal structures, in vitro DNA binding, antibacterial and cytotoxic activities of new di- and polynuclear silver(I) saccharinate complexes with tertiary monophosphanes. AB - Four new silver(I) saccharinate (sac) complexes, [Ag(MU-sac)(PPh3)]2 (1), [Ag(MU sac)(PPh2Cy)]2 (2), [Ag(MU-sac)(PPhCy2)]2 (3) and [Ag(MU-sac)(PCy3)]n (4), where PPh3=triphenylphosphane, PPh2Cy=cyclohexyldiphenylphosphane, PPhCy2=dicyclohexylphenylphosphane and PCy3=tricyclohexylphosphane, have been synthesized and fully characterized by elemental analysis, IR, NMR, ESI-MS and single crystal X-ray diffraction. Fluorescence ethidium bromide displacement indicate that all complexes bind to fish sperm (FS) DNA by intercalation with binding constants (KA) of 29.1+/-0.26*10(5)M(-1) for 1, 2.54+/-0.12*10(5)M(-1) for 2, 2.42+/-0.08*10(5)M(-1) for 3, 0.19+/-0.03*10(5)M(-1) for 4. The relative viscosities of the FS-DNA solutions increase with increasing of the complex concentration, providing strong evidence for the intercalation mode. The gel electrophoresis assay further confirms their binding with the pBR322 plasmid DNA. The MIC values of the silver(I) complexes are generally higher than those of AgNO3 and silver sulfadiazine, but 1 presents a promising activity against Salmonellatyphimurium and Staphylococcusaureus. All complexes are highly cytotoxic on human lung carcinoma (A549) and human breast adenocarcinoma (MCF-7) cell lines with IC50 values ranging from 0.82 to 3.13MUM. PMID- 24480546 TI - The height premium in Indonesia. AB - Analyzing the Indonesian Family Life Survey for the year 2007, this paper estimates that a 10 cm increase in physical stature is associated with an increase in earnings of 7.5% for men and 13.0% for women, even after controlling for an extensive set of productivity variables. When the height premium is estimated by sector, it is 12.3% for self-employed men and 18.0% for self employed women; a height premium of 11.1% is also estimated for women in the private sector. In the public sector, however, the height premium estimate is not statistically significant for either men or women. This paper provides further evidence of discrimination based on customers' preferences for tall workers. PMID- 24480543 TI - Triggering ubiquitination of IFNAR1 protects tissues from inflammatory injury. AB - Type 1 interferons (IFN) protect the host against viruses by engaging a cognate receptor (consisting of IFNAR1/IFNAR2 chains) and inducing downstream signaling and gene expression. However, inflammatory stimuli can trigger IFNAR1 ubiquitination and downregulation thereby attenuating IFN effects in vitro. The significance of this paradoxical regulation is unknown. Presented here results demonstrate that inability to stimulate IFNAR1 ubiquitination in the Ifnar1(SA) knock-in mice renders them highly susceptible to numerous inflammatory syndromes including acute and chronic pancreatitis, and autoimmune and toxic hepatitis. Ifnar1(SA) mice (or their bone marrow-receiving wild type animals) display persistent immune infiltration of inflamed tissues, extensive damage and gravely inadequate tissue regeneration. Pharmacologic stimulation of IFNAR1 ubiquitination is protective against from toxic hepatitis and fulminant generalized inflammation in wild type but not Ifnar1(SA) mice. These results suggest that endogenous mechanisms that trigger IFNAR1 ubiquitination for limiting the inflammation-induced tissue damage can be purposely mimicked for therapeutic benefits. PMID- 24480547 TI - Third-party umbilical cord blood-derived regulatory T cells prevent xenogenic graft-versus-host disease. AB - BACKGROUND AIMS: Naturally occurring regulatory T cells (Treg) are emerging as a promising approach for prevention of graft-versus-host disease (GvHD), which remains an obstacle to the successful outcome of allogeneic hematopoietic stem cell transplantation. However, Treg only constitute 1-5% of total nucleated cells in cord blood (CB) (<3 * 106 cells), and therefore novel methods of Treg expansion to generate clinically relevant numbers are needed. METHODS: Several methodologies are currently being used for ex vivo Treg expansion. We report a new approach to expand Treg from CB and demonstrate their efficacy in vitro by blunting allogeneic mixed lymphocyte reactions and in vivo by preventing GvHD through the use of a xenogenic GvHD mouse model. RESULTS: With the use of magnetic cell sorting, naturally occurring Treg were isolated from CB by the positive selection of CD25+ cells. These were expanded to clinically relevant numbers by use of CD3/28 co-expressing Dynabeads and interleukin (IL)-2. Ex vivo expanded Treg were CD4+25+ FOXP3+127(lo) and expressed a polyclonal T-cell receptor, Vbeta repertoire. When compared with conventional T-lymphocytes (CD4+25 cells), Treg consistently showed demethylation of the FOXP3 TSDR promoter region and suppression of allogeneic proliferation responses in vitro. CONCLUSIONS: In our NOD-SCID IL-2Rgamma(null) xenogeneic model of GvHD, prophylactic injection of third-party, CB-derived, ex vivo-expanded Treg led to the prevention of GvHD that translated into improved GvHD score, decreased circulating inflammatory cytokines and significantly superior overall survival. This model of xenogenic GvHD can be used to study the mechanism of action of CB Treg as well as other therapeutic interventions. PMID- 24480548 TI - Impaired postural balance in the morning in patients with knee osteoarthritis. AB - Postural balance (PB) is frequently used as an outcome measure in clinical and research settings when assessing patients with knee osteoarthritis (OA). Pain and stiffness is known to affect PB, and is elevated in the morning and evening in OA patients. The aim of this study was to explore if time-of-day affects PB control in knee OA patients. Centre Of Pressure (COP) excursion was measured (100Hz) by force plate technique at selected time-points (9.00 a.m., 12.30 p.m. and 4.00 p.m.) during a single day in 32 knee OA patients aged 66.0 (10.3) years. A rigorous protocol was followed to ensure comparable testing conditions across time-points. PB control was quantified by the COP variables: velocity moment (mm(2)/s), total sway area (mm(2)), total sway length (mm) and confidence ellipse area (mm(2)). A two-way mixed-effects model showed that PB significantly improved between 9.00 a.m. and 12.30 p.m. in three out of four COP variables. The observed improvement was 11.9% (p=0.011) for velocity moment, 12.2% (p=0.011) for total sway area and 9.4% (p<0.001) for total sway length. PB appears to be impaired in the morning relative to midday in knee OA patients. Thus, it is recommended that time of assessment is standardized between sessions when assessing PB in clinical and research settings in knee OA patients. PMID- 24480549 TI - Analysis of the IGHV region in Burkitt's lymphomas supports a germinal center origin and a role for superantigens in lymphomagenesis. AB - The analysis of immunoglobulin heavy chain variable (IGHV) region may disclose the influence of antigens in Burkitt's lymphomas (BL). IGHV sequences from 38 patients and 35 cell lines were analyzed. IGHV3 subset genes were the most used and IGHV4-34 gene was overrepresented. IGHV genes were mutated in 98.6% of the cases, 36% acquired potential glycosylation sites, and in 52% somatic hypermutation-process was ongoing. Binding motifs for superantigens like Staphylococcal protein A and carbohydrate I/i were preserved in 89% of the cases. IGHV analysis of BL cells supports a germinal center origin and points toward a role for superantigens in lymphomagenesis. PMID- 24480550 TI - Pneumocystis polymerase chain reaction and blood (1->3)-beta-D-glucan assays to predict survival with suspected Pneumocystis jirovecii pneumonia. AB - Pneumocystis polymerase chain reaction (PCR) and blood (1->3)-beta-D-glucan assays are known to be useful for the diagnosis of Pneumocystis pneumonia (PCP). However, their impact on the outcome of clinically suspected PCP patients has not yet been elucidated. Between January 2008 and July 2011, we prospectively observed 190 immunocompromised patients who had ground-glass opacity on chest computed tomography scans and were suspected to have PCP. The blood beta-D-glucan levels of these patients were measured, and PCR was used to detect Pneumocystis jirovecii in the respiratory samples. The 30-day mortality rates and related factors were assessed. The 30-day mortality rate of all included patients was 21.6%. Both beta-D-glucan-positive (10.1%) and PCR-positive patients (15.0%) had significantly lower mortality rates than beta-D-glucan-negative (28.1%) or PCR negative patients (30.1%). All of the 13 definite PCP patients had positive PCR and beta-D-glucan results, received anti-PCP treatments, and survived. Among the 72 patients who were negative for microscopic detection of P. jirovecii but received anti-PCP treatments, positive PCR results (odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.74), a high Sequential Organ Failure Assessment score (OR, 1.42; CI, 1.08-1.88), and positive beta-D-glucan levels (OR 0.25, CI 0.06-1.02) were associated with mortality rates using stepwise logistic regression analyses. A positive Pneumocystis PCR or beta-D-glucan test was a candidate predictor of survival in patients who were suspected of having PCP, even though negative for visual detection by microscopy. PMID- 24480551 TI - A molecular analysis of quinolone-resistant Haemophilus influenzae: validation of the mutations in Quinolone Resistance-Determining Regions. AB - The mechanism of quinolone-resistance is considered to be amino acid mutations in the type II topoisomerase. We validated the genetic mechanisms of quinolone resistance in Haemophilus influenzae. We obtained 29 H. influenzae strains from a nationwide surveillance program in Japan (including 11 quinolone-resistant strains [moxifloxacin: MFLX or levofloxacin MIC >=2 MUg/ml]). We analyzed the sequences of the Quinolone Resistance-Determining Regions (QRDRs) in GyrA, GyrB, ParC and ParE. Furthermore, we induced resistance in susceptible strains by exposing them to quinolone, and investigated the relationship between mutations in the QRDRs and the MICs. Five amino acid substitutions in GyrA (at Ser84 and Asp88) and ParC (at Gly82, Ser84 and Glu88) were found to be closely related to the MICs. The strains with a MFLX MIC of 0.125-1 and 2-4 MUg/ml had one and two mutations, respectively. The strains with a MFLX MIC of >=8 MUg/ml had three or more mutations. The strains with induced resistance with MFLX MICs of 0.5-1 and >=2 MUg/ml also had one and two mutations, respectively. We confirmed that these five mutations strongly contribute to quinolone resistance and found that the degree of resistance is related to the number of the mutations. In addition, the three strains of 18 susceptible strains (16.7%) also had a single mutation. These strains may therefore be in the initial stage of quinolone resistance. Currently, the frequency of quinolone-resistant H. influenzae is still low. However, as has occurred with beta-lactams, an increase in quinolone use may lead to more quinolone-resistant strains. PMID- 24480553 TI - Patient safety must be a priority in all aspects of care. PMID- 24480552 TI - Mannitol-enhanced delivery of stem cells and their growth factors across the blood-brain barrier. AB - Ischemic brain injury in adults and neonates is a significant clinical problem with limited therapeutic interventions. Currently, clinicians have only tPA available for stroke treatment and hypothermia for cerebral palsy. Owing to the lack of treatment options, there is a need for novel treatments such as stem cell therapy. Various stem cells including cells from embryo, fetus, perinatal, and adult tissues have proved effective in preclinical and small clinical trials. However, a limiting factor in the success of these treatments is the delivery of the cells and their by-products (neurotrophic factors) into the injured brain. We have demonstrated that mannitol, a drug with the potential to transiently open the blood-brain barrier and facilitate the entry of stem cells and trophic factors, as a solution to the delivery problem. The combination of stem cell therapy and mannitol may improve therapeutic outcomes in adult stroke and neonatal cerebral palsy. PMID- 24480554 TI - Angiogenesis inhibition and lung-cancer therapy. PMID- 24480555 TI - Pharmacokinetic interactions of dasatinib and docetaxel. PMID- 24480556 TI - The immune system and response to HER2-targeted treatment in breast cancer. AB - The monoclonal antibody trastuzumab targets the growth factor receptor HER2 and has profoundly improved the course of disease and survival of women with HER2 overexpressing breast cancer. Because trastuzumab targets aberrant expression of HER2 in tumours addicted to HER2 activation, its clinical activity is credited largely to inhibition of intracellular signalling. A growing body of preclinical and clinical evidence shows that the immune system contributes substantially to the therapeutic effects of trastuzumab and other monoclonal antibodies in vivo. Furthermore, findings indicate that immune-related markers can provide useful predictive information and that increased clinical activity might follow activation of the immune system. Development of immunomodulatory drugs with remarkable activity in many solid tumours defines a scenario in which the combination of immune modulation with trastuzumab, or other HER2-directed drugs, will result in augmented response and clinical outcome. PMID- 24480557 TI - Opium use: an emerging risk factor for cancer? AB - An estimated 16.5 million people worldwide illicitly use opiates, of whom 4 million use raw opium. We did a systematic review to investigate the association between opium use and cancer incidence and mortality. Opium use was associated with an increased risk of cancers of the oesophagus, stomach, larynx, lung, and urinary bladder. Although the present evidence suggests that these associations are possibly causal, further epidemiological studies (particularly prospective studies that collect detailed data about lifetime opium use and control for a broad range of potential confounders) are needed. PMID- 24480558 TI - Health-related quality of life in small-cell lung cancer: a systematic review on reporting of methods and clinical issues in randomised controlled trials. AB - Small-cell lung cancer represents about 15% of all lung cancers; increasingly, randomised controlled trials of this disease measure the health-related quality of life of patients. In this Systematic Review we assess the adequacy of reporting of health-related quality-of-life methods in randomised controlled trials of small-cell lung cancer, and the potential effect of this reporting on clinical decision making. Although overall reporting of health-related quality of life was acceptable, improvements are needed to optimise the use of health related quality of life in randomised controlled trials. PMID- 24480559 TI - International variations in childhood cancer in indigenous populations: a systematic review. AB - Although the cancer burden in indigenous children has been reported in some countries, up to now, no international comparison has been made. We therefore aimed to assess the available evidence of the burden of childhood cancer in indigenous populations. We did a systematic review of reports on cancer incidence, mortality, and survival in indigenous children worldwide. Our findings highlight the paucity of accessible information and advocate the pressing need for data by indigenous status in countries where population-based cancer registries are established. The true extent of disparities between the burden in the indigenous community needs to be measured so that targeted programmes for cancer control can be planned and implemented. PMID- 24480560 TI - Comparison of iris-claw and posterior chamber collagen copolymer phakic intraocular lenses in keratoconus. AB - PURPOSE: To evaluate the visual and refractive outcomes, predictability, and stability of phakic intraocular lens (pIOL) implantation in keratoconic eyes and compare the results of 2 pIOL models. SETTING: Vissum Instituto Oftalmologico, Alicante, Spain. DESIGN: Retrospective case series. METHODS: An iris-claw (Artiflex) or collagen copolymer posterior chamber pIOL (PC pIOL) (Implantable Collamer Lens) was implanted in eyes with stable keratoconus. The main outcome measures were postoperative changes from the preoperative manifest refraction, uncorrected (UDVA) and corrected (CDVA) distance visual acuities, corneal topography, and endothelial cell count. Alpins vectorial analysis was performed. RESULTS: Twenty eyes received an iris-claw pIOL and 28 eyes, a PC pIOL. The mean spherical equivalent was -9.31 diopters (D) +/- 4.20 (SD) (range -20.75 to -2.75) preoperatively and -0.46 +/- 0.88 D (range -3.25 to 1.00 D) postoperatively (P<.001). No patient lost lines of CDVA. The mean decimal UDVA was 0.08 +/- 0.09 preoperatively and 0.71 +/- 0.26 postoperatively and the mean decimal CDVA, 0.77 +/- 0.24 and 0.87 +/- 0.98, respectively (P<.001). The mean efficacy index was 0.90 +/- 0.26 and the mean safety index, 1.19 +/- 0.29. The mean efficacy index was not statistically different between the PC pIOL (0.88 +/- 0.28) and the iris claw pIOL (0.96 +/- 0.22) (P=.058). Refraction was stable during the follow-up. CONCLUSIONS: Phakic IOL implantation is a suitable refractive surgical option for stable keratoconus. It may be especially indicated for the management of high ametropia and showed good efficacy and safety. Refractive and keratometric stability was confirmed. PMID- 24480561 TI - Surface light scattering in intraocular lenses manufactured with the optimized production process: 12-month results. PMID- 24480562 TI - Suction loss during femtosecond laser-assisted cataract surgery. AB - A 70-year-old woman with senile cataract had femtosecond laser-assisted cataract surgery under local anesthesia in her left eye. Anterior capsulotomy and lens fragmentation were planned with the laser. After the laser was successfully docked, the anterior capsulotomy was performed without complications. During lens fragmentation, the patient moved abruptly. The suction ring lost adhesion, but the laser continued firing for a fraction of a second. Under the operating microscope, a grid pattern was visible in the peripheral cornea. An intraocular lens was implanted without complications. Six weeks after surgery, the achieved visual acuity was 20/20. The misaligned cuts in the cornea were still visible. This case report demonstrates that under certain circumstances, the harmless complication of suction loss can be serious. PMID- 24480563 TI - Modified Wise closure of the conjunctival fornix-based trabeculectomy flap. AB - We present modifications to the Wise fornix-based conjunctival trabeculectomy flap technique that have minimized early wound leakage in our experience. A retrospective chart review of 509 consecutive eyes revealed a 2.9% leak rate in the first postoperative month and 1.6% returned to the operating room to resuture a persistent leak. If meticulously performed, this modified closure technique may provide watertight closure as commonly as limbal-based techniques. PMID- 24480564 TI - Efficacy, safety, predictability, contrast sensitivity, and aberrations after femtosecond laser lenticule extraction. AB - PURPOSE: To compare femtosecond lenticule extraction and small-incision lenticule extraction to treat moderate to high myopia. SETTING: Department of Ophthalmology, Aarhus University Hospital, Aarhus, Denmark. DESIGN: Prospective clinical single-masked paired-eye study. METHODS: An intrastromal lenticule was cut by a femtosecond laser and manually extracted. In femtosecond lenticule extraction, a laser in situ keratomileusis-like flap allowed removal of the lenticule, whereas in small-incision lenticule extraction, it was removed through a small incision. Follow-up was 6 months. RESULTS: Thirty-five patients were treated with femtosecond lenticule extraction in 1 eye and small-incision lenticule extraction in the other. The mean preoperative spherical equivalent was -7.6 diopters (D) +/- 1.0 (SD) (range -6.0 to -9.9 D). After both procedures, 90% of eyes had an uncorrected distance visual acuity of 20/40 or better 1 day postoperatively, increasing to 100% after 6 months. At 6 months, the mean corrected distance visual acuity (CDVA) improved significantly by approximately 1.5 letters on the logMAR chart. No eyes lost or gained 2 lines or more of CDVA after either procedure. The achieved refraction was a mean of -0.04 +/- 0.38 D from the attempted refraction after femtosecond lenticule extraction and -0.09 +/ 0.39 D after small-incision lenticule extraction. After both procedures, 88% of eyes were within +/-0.50 D. Contrast sensitivity was unchanged. The changes in higher-order aberrations were similar. CONCLUSION: The all-femtosecond laser flap based and cap-based techniques produced almost identical results up to 6 months postoperatively in eyes with moderate to high myopia. PMID- 24480565 TI - Computed tomography features of luetic osteitis (otosyphilis) of the temporal bone. AB - OBJECTIVE: We report a missed case of otosyphilis presenting as otic capsule lucencies on temporal bone computed tomography. METHODS: A 58-year-old woman presented with a 15-year history of bilateral, mixed hearing loss together with otic capsule lucencies, subsequently confirmed as otosyphilis. A literature review of otosyphilis was undertaken based on a PubMed search of studies published between 1988 and 2012, using the key words 'otosyphilis', 'otodystrophy', 'otic capsule lucencies' and 'luetic osteitis'. RESULTS AND CONCLUSION: Although rare, otosyphilis is important to recognise as it is one of the few treatable causes of deafness when diagnosed early. The differentiating computed tomography features of luetic osteitis (otosyphilis) of the temporal bone have only rarely been described. We emphasise how these imaging features can be used to distinguish the rare but treatable condition of luetic osteitis from other, more common conditions with similar imaging findings. PMID- 24480566 TI - Immunomodulating polysaccharides from Lessertia frutescens leaves: isolation, characterization and structure activity relationship. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sutherlandia frutescens (syn. Lessertia frutescens) is an indigenous plant in Southern Africa and has been extensively studied from the ethnobotanical point of view. Amongst the various traditional uses, several illnesses involving the immune system have been reported. Due to some of the therapeutic effects observed, in relation to the traditional uses reported by the "khoi san" and "nama" people on cancer related illnesses, the plant has been given the local name kankerbos (cancerbush). Recently the plant has also been used amongst HIV/AIDS patients to stimulate the immune system. MATERIALS AND METHODS: Leaves of Sutherlandia frutescens were extracted sequentially with ethanol, 50% ethanol/water, and water at 50 and 100 degrees C. The polysaccharides were extracted with water and fractionated by ion exchange chromatography and gel filtration to obtain enriched polysaccharide fractions. The bioactivities of the fractions were tested in the complement assay. Some of the fractions were treated with the enzyme pectinase, and the fragments thus produced were separated by gel filtration and their activities tested. Monosaccharide compositions and linkage analyses were determined for the relevant fractions. RESULTS: The leaves of Sutherlandia frutescens contain polysaccharides of the pectin type. Fractions from both the water extracts of 50 and 100 degrees C were bioactive. Fractions chosen for further studies showed that the fragment with the highest M(W) after the pectinase treatment had a substantially higher biological effect than the parent molecules. Based on a comparison of the different fractions it was concluded that galactose-rich regions were important for the bioactivity, these being of the AGII and AGI type, with the latter probably being more important than the former. Fragments rich in xylose also gave higher activity than those without it. CONCLUSIONS: Our theory that the polysaccharides present in the leaves of Sutherlandia frutescens could be of importance as immunomodulating agents was confirmed. It was also shown that certain types of polysaccharides had a higher effect in the complement system than others. Thus both the water extracts obtained at 50 and 100 degrees C contain interesting biologically active polysaccharides. PMID- 24480567 TI - Hepatic differentiation of human embryonic stem cells on microcarriers. AB - Translation of stem cell research to industrial and clinical settings mostly requires large quantities of cells, especially those involving large organs such as the liver. A scalable reactor system is desirable to ensure a reliable supply of sufficient quantities of differentiated cells. To increase the culture efficiency in bioreactor system, high surface to volume ratio needs to be achieved. We employed a microcarrier culture system for the expansion of undifferentiated human embryonic stem cells (hESCs) as well as for directed differentiation of these cells to hepatocyte-like cells. Cells in single cell suspension were attached to the bead surface in even distribution and were expanded to 1*10(6)cells/ml within 2 days of hESC culture with maintenance of the level of pluripotency markers. Directed differentiation into hepatocyte-like cells on microcarriers, both in static culture and stirred bioreactors, induced similar levels of hepatocyte-like cell differentiation as observed with cells cultured in conventional tissue culture plates. The cells expressed both immature and mature hepatocyte-lineage genes and proteins such as asialoglycoprotein receptor-1 (ASGPR-1) and albumin. Differentiated cells exhibited functional characteristics such as secretion of albumin and urea, and CYP3A4 activity could be detected. Microcarriers thus offer the potential for large-scale expansion and differentiation of hESCs induced hepatocyte-like cells in a more controllable bioreactor environment. PMID- 24480568 TI - Mechanism behind autoflocculation of unicellular green microalgae Ettlia texensis. AB - The oleaginous Ettlia texensis is an autoflocculating green microalga that can be used for bio-flocculation of other microalgae species to facilitate harvesting. In this study the mechanism behind autoflocculation of E. texensis was revealed by scanning electron microscopy (SEM) analysis and by characterisation of the cell surface properties. SEM analysis and measurement of extracellular polymeric substances (EPS) showed that autoflocculation of E. texensis is due to the EPS containing mainly glycoproteins patched to the cell surface. Despite the presence of charged groups on the cell surface, they do not seem to attribute to autoflocculation of E. texensis. During bio-flocculation of E. texensis with Chlorella vulgaris EPS structures between both microalgal species were observed. EPS thus not only play a predominant role in autoflocculation of E. texensis but also in bio-flocculation when using this microalga to harvest others. PMID- 24480569 TI - Immobilization of an integral membrane protein for biotechnological phenylacetaldehyde production. AB - Styrene oxide isomerase (SOI) has previously been shown to be an integral membrane protein performing a highly selective, hydrolytic ring opening reaction of epoxides to yield pure aldehydes. Earlier studies had also shown a high sensitivity of SOIs toward their product phenylacetaldehyde which caused an irreversible inhibition and finally complete loss of activity at higher aldehyde concentrations. Here we report on the covalent immobilization of a styrene oxide isomerase (SOI) on SBA-15 silica carriers. The production of the SOI from a Rhodococcus strain was optimized, the enzyme was enriched and immobilized, and finally the biocatalyst was applied in aqueous as well as in two-phase systems. Linkage of the protein to epoxide or amino groups on the SBA-based carriers led to relatively poor stabilization of the enzyme in an aqueous system. But, improved stability was observed toward organic phases like the non-toxic phthalate-related 1,2-cyclohexane dicarboxylic acid diisononyl ester (Hexamol DINCH) which here to our knowledge was used for the first time in a biotechnological application. With this two-phase system and the immobilized SOI, 1.6-2.0* higher product yields were reached and the lifetime of the biocatalyst was tremendously increased. PMID- 24480570 TI - 28S rRNA is inducibly pseudouridylated by the mTOR pathway translational control in CHO cell cultures. AB - The mTOR pathway is a conserved master regulator of translational activity that influences the fate of industrially relevant CHO cell cultures, yet its molecular mechanisms remain unclear. Interestingly, rapamycin specific inhibition of the mTOR pathway in CHO cells was found to down-regulate the small nucleolar RNA U19 (snoRNA U19) by 2-fold via translatome profiling. snoRNA U19 guides the two most conserved pseudouridylation modifications on 28S ribosomal RNA (rRNA) that are important for the biogenesis and proper function of ribosomes. In order to further understand the role of snoRNA U19 as a potential player in the mTOR pathway, we measured 28S rRNA pseudouridylation upon rapamycin treatments and/or snoRNA U19 overexpression conditions, thereby characterizing the subsequent effects on ribosome efficiency and global translation by polysome profiling. We showed that 28S rRNA pseudouridylation was increased by rapamycin treatment and/or overexpression of snoRNA U19, but only the latter condition improved ribosome efficiency toward higher global translation, thus implying that the mTOR pathway induces pseudouridylation at different sites along the 28S rRNA possibly with either positive or negative effects on the cellular phenotype. This discovery of snoRNA U19 as a new downstream effector of the mTOR pathway suggests that cell engineering of snoRNAs can be used to regulate translation and improve cellular growth in CHO cell cultures in the future. PMID- 24480571 TI - Production of 2,3-butanediol from xylose by engineered Saccharomyces cerevisiae. AB - 2,3-Butanediol (2,3-BD) production from xylose that is abundant in lignocellulosic hydrolyzate would make the production of 2,3-BD more sustainable and economical. Saccharomyces cerevisiae can produce only trace amounts of 2,3 BD, but also cannot ferment xylose. Therefore, it is necessary to introduce both 2,3-BD production and xylose assimilation pathways into S. cerevisiae for producing 2,3-BD from xylose. A pyruvate decarboxylase (Pdc)-deficient mutant (SOS4) was used as a host in order to increase carbon flux toward 2,3-BD instead of ethanol. The XYL1, XYL2, and XYL3 genes coding for xylose assimilating enzymes derived from Scheffersomyces stipitis were introduced into the SOS4 strain to enable xylose utilization. Additionally, the alsS and alsD genes from Bacillus subtilis and endogenous BDH1 gene were overexpressed to increase 2,3-BD production from xylose. As a result, the resulting strain (BD4X) produced 20.7g/L of 2,3-BD from xylose with a yield of 0.27g 2,3-BD/g xylose. The titer of 2,3-BD from xylose increased up to 43.6g/L under a fed-batch fermentation. The BD4X strain produced (R, R)-2,3-BD dominantly (>97% of the total 2,3-BD) with trace amounts of meso-2,3-BD. These results suggest that S. cerevisiae might be a promising host for producing 2,3-BD from lignocellulosic biomass for industrial applications. PMID- 24480572 TI - Genetic characterization of 4-cresol catabolism in Corynebacterium glutamicum. AB - Corynebacterium glutamicum uses 4-cresol as sole carbon source for growth. Protocatechuate 3,4-dioxygenase activity had been detected when C. glutamicum was grown with 4-cresol. In this work, we found that 4-cresol was catabolized via 4 hydroxybenzoate and protocatechuate as intermediate metabolites, and a genetic cluster called cre (designated for 4-cresol, creABCDEFGHIR, tagged as ncgl0521 ncgl0531 in NCBI) was identified. The cre gene cluster comprises of 11 genes, and six of them were experimentally confirmed to be involving in 4-cresol catabolism. The genes creD, creE, and creJ were involved in oxidation of 4-cresol into 4 hydroxybenzyl alcohol. The creD encoded a protein showing Mg(2+)-dependent phosphohydrolase activity. The genes creE, creF, creJ encoded a putative P450 system. The creG encoded a NAD(+)-dependent dehydrogenase and catalyzed 4 hydroxybenzyl alcohol to 4-hydroxybenzaldehyde. Two other genes creH and creI were involved in conversion of 4-hydroxybenzyl alcohol to 4-hydroxybenzoate, but their catalytic function is still unknown. Similar genetic clusters with high DNA sequence identity were identified in Arthrobacter and additional Corynebacterium species, suggesting that this genetic organization for 4-cresol catabolism might be more widely distributed in Gram-positive bacteria. PMID- 24480573 TI - Thermostabilization of glutamate decarboxylase B from Escherichia coli by structure-guided design of its pH-responsive N-terminal interdomain. AB - Glutamate decarboxylase B (GadB) from Escherichia coli is a highly active biocatalyst that can convert l-glutamate to gamma-aminobutyrate (GABA), a precursor of 2-pyrrolidone (a monomer of Nylon 4). In contrast to vigorous studies of pH shifting of GadB, mesophilic GadB has not been stabilized by protein engineering. In this study, we improved the thermostability of GadB through structural optimization of its N-terminal interdomain. According to structural analysis, the N-terminal fourteen residues (1-14) of homo-hexameric GadB formed a triple-helix bundle interdomain at acidic pH and contributed to the thermostability of GadB in preliminary tests as the pH shifted from 7.6 to 4.6. GadB thermostabilization was achieved by optimization of hydrophobic and electrostatic interactions at the N-terminal interdomain. A triple mutant (GadB TM: Gln5Asp/Val6Ile/Thr7Glu) showed higher thermostability than the wild-type (GadB-WT), i.e., 7.9 and 7.7 degrees C increases in the melting temperature (Tm) and the temperature at which 50% of the initial activity remained after 10min incubation (T50(10)), respectively. The triple mutant showed no reduction of catalytic activity in enzyme kinetics. Molecular dynamics (MD) simulation at high temperature showed that reinforced interactions of the triple mutant rigidified the N-terminal interdomain compared to the wild-type, leading to GadB thermostabilization. PMID- 24480574 TI - Initial experience with abiraterone acetate in patients with castration-resistant prostate cancer. AB - OBJECTIVE: To describe the results obtained in 25 males with metastatic castration-resistant prostate cancer (MCRPC) treated with abiraterone (AA). A comparative analysis of abiraterone effectiveness and safety between our results and data published in the literature was conducted. MATERIAL AND METHOD: Bi institutional prospective analysis of 25 consecutive patients with MCRPC undergoing treatment with abiraterone, with a mean follow-up 7.9 (3-15) months was carried out. Treatment effectiveness and safety analyses regarding baseline characteristics of patients (age, prior treatments, basal PSA, performance status, pain, metastasis) were conducted. RESULTS: At 13.6 months of follow-up, the overall survival is 80% (CI 95%: 11.8-15.4). Clinical and radiological-free progression survival is 9.5 +/- 1 months (CI 95%: 7.7-11.3) and biochemical response is 6.8 +/- 1 months (CI 95%: 5-8.7). Only the treatment with chemotherapy impaired significantly the response time to AA [6.4 months for radiological-free progression survival (CI 95%: 4.2-8,6) and 4.3 months for biochemical-free progression survival (CI 95%: 2.6-6)]. The incidence of adverse drug events was 36%, all of them grade 1-2/4 and, in no case, suspension or reduction of the dose of AA was needed. CONCLUSIONS: The treatment with AA has been effective in our series, with a tolerability considerably higher than what other studies published. PMID- 24480575 TI - Scleroderma renal crisis following silicone breast implant rupture: a case report and review of the literature. AB - Systemic sclerosis (SSc) is a chronic multisystem autoimmune disorder characterised by progressive functional and structural abnormalities in blood vessels leading to microvascular dysfunction, excessive production and deposition of collagen leading to the fibrosis of skin and internal organs. The aetiology of the disease is unknown. However, exposure to various environmental factors, such as polyvinyl chloride and silica have been thought to play a role in the development of the disease. For this reason, silicone breast implants have been postulated as a cause for a range of autoimmune diseases including systemic sclerosis. This remains as yet unconfirmed. We report the case of a 52-year-old woman who presented with rapid development of skin thickening followed by scleroderma renal crisis (SRC) following rupture of silicone breast implants. This is the first published case of SRC in this setting. The literature on silicone and autoimmunity is reviewed. PMID- 24480576 TI - 3D high-content screening for the identification of compounds that target cells in dormant tumor spheroid regions. AB - Cancer cells in poorly vascularized tumor regions need to adapt to an unfavorable metabolic microenvironment. As distance from supplying blood vessels increases, oxygen and nutrient concentrations decrease and cancer cells react by stopping cell cycle progression and becoming dormant. As cytostatic drugs mainly target proliferating cells, cancer cell dormancy is considered as a major resistance mechanism to this class of anti-cancer drugs. Therefore, substances that target cancer cells in poorly vascularized tumor regions have the potential to enhance cytostatic-based chemotherapy of solid tumors. With three-dimensional growth conditions, multicellular tumor spheroids (MCTS) reproduce several parameters of the tumor microenvironment, including oxygen and nutrient gradients as well as the development of dormant tumor regions. We here report the setup of a 3D cell culture compatible high-content screening system and the identification of nine substances from two commercially available drug libraries that specifically target cells in inner MCTS core regions, while cells in outer MCTS regions or in 2D cell culture remain unaffected. We elucidated the mode of action of the identified compounds as inhibitors of the respiratory chain and show that induction of cell death in inner MCTS core regions critically depends on extracellular glucose concentrations. Finally, combinational treatment with cytostatics showed increased induction of cell death in MCTS. The data presented here shows for the first time a high-content based screening setup on 3D tumor spheroids for the identification of substances that specifically induce cell death in inner tumor spheroid core regions. This validates the approach to use 3D cell culture screening systems to identify substances that would not be detectable by 2D based screening in otherwise similar culture conditions. PMID- 24480577 TI - Understanding the premalignant potential of atypical hyperplasia through its natural history: a longitudinal cohort study. AB - Atypical hyperplasia is a high-risk premalignant lesion of the breast, but its biology is poorly understood. Many believe that atypical ductal hyperplasia (ADH) is a direct precursor for low-grade ductal breast cancer, whereas atypical lobular hyperplasia (ALH) serves as a risk indicator. These assumptions underlie current clinical recommendations. We tested these assumptions by studying the characteristics of the breast cancers that develop in women with ADH or ALH. Using the Mayo Benign Breast Disease Cohort, we identified all women with ADH or ALH from 1967 to 2001 and followed them for later breast cancers, characterizing side of breast cancer versus side of atypia; time to breast cancer; type, histology, and grade of breast cancer, looking for patterns consistent with precursors versus risk indicators. A total of 698 women with atypical hyperplasia were followed a mean of 12.5 years; 143 developed breast cancer. For both ADH and ALH, there is a 2:1 ratio of ipsilateral to contralateral breast cancer. The ipsilateral predominance is marked in the first 5 years, consistent with a precursor phenotype for both ADH and ALH. For both, there is a predominance of invasive ductal cancers with 69% of moderate or high grade. Twenty-five percent are node positive. Both ADH and ALH portend risk for ductal carcinoma in situ and invasive breast cancers, predominantly ductal, with two thirds moderate or high grade. The ipsilateral breast is at especially high risk for breast cancer in the first 5 years after atypia, with risk remaining elevated in both breasts long term. ADH and ALH behave similarly in terms of later breast cancer endpoints. PMID- 24480578 TI - How do individuals with persecutory delusions bring worry to a close? An interpretive phenomenological analysis. AB - BACKGROUND: Worry is a significant problem for individuals with paranoia, leading to delusion persistence and greater levels of distress. There are established theories concerning processes that maintain worry but little has been documented regarding what brings worry to a close. AIMS: The aim was to find out what patients with persecutory delusions report are the factors that bring a worry episode to an end. METHOD: Eight patients with persecutory delusions who reported high levels of worry participated. An open-ended semi-structured interview technique and IPA qualitative analysis was employed to encourage a broad elaboration of relevant constructs. RESULTS: Analyses revealed one theme that captured participants' detailed descriptions of their experience of worry and five themes that identified factors important for bringing worry episodes to a close: natural drift, distraction, interpersonal support, feeling better, and reality testing. CONCLUSIONS: Patients with persecutory delusions report worry being uncontrollable and distressing but are able to identify ways that a period of worry can stop. The present study suggests that building on individuals' distraction techniques, reality testing ability and their social support network could be of benefit. Research is needed to identify the most effective means of bringing paranoid worries to an end. PMID- 24480579 TI - Elevated protoporphyrin in patients with skin cancer receiving taxane chemotherapy. AB - BACKGROUND: Docetaxel and paclitaxel are both taxanes used for treatment of various malignant tumors. Only two case reports have described photohypersensitivity induced by docetaxel and paclitaxel in association with porphyrin aberrations. OBJECTIVES: To examine whether aberrations in the biosynthesis of porphyrins and photohypersensitivity occur among patients receiving taxanes. MATERIALS & METHODS: We examined porphyrin aberrations and photohypersensitivity in 8 patients with skin cancers who received docetaxel or paclitaxel chemotherapy in our department. RESULTS: Aberrations in erythrocyte protoporphyrin were detected in 4 patients, while no such aberration was detected in the control group. Photohypersensitivity to Ultraviolet B (UVB) was detected in 2 patients; one was related to an elevated synthesis of protoporphyrin but the other was not. Photohypersensitivity to Ultraviolet A (UVA) or visible light was not detected. CONCLUSION: Docetaxel and paclitaxel chemotherapy seemed to induce aberrations in porphyrin biosynthesis, although an elevated synthesis of porphyrin did not necessarily cause photohypersensitivity. PMID- 24480580 TI - Self-inflicted lesions of the mouth and lips in mentally retarded young subjects. AB - OBJECTIVE: To evaluate the type and frequency of self-mutilation lesions of the mouth and lips in a large group of institutionalized mentally retarded subjects. SUBJECTS AND METHODS: Two hundred and forty-five institutionalized mentally retarded patients were evaluated clinically by a systematic inspection of the perioral cutis, lips, tongue, oral mucosa, palate, gingivae and teeth. Moreover, the drug therapy taken by each patient was carefully reviewed. RESULTS: Numerous lesions were found involving the tongue, lips, oral mucosa, perioral skin, gingivae and teeth, prevalently supported by a self-mutilation mechanism (such as cheek and tongue biting and nodular traumatic lesions), which were differentially expressed in patients with different degrees of mental retardation. A possible effect of anti-epileptic or neuroleptic drugs was also detected. CONCLUSIONS: These findings indicate that inspection of the oral cavity should always and carefully be performed in all patients with mental retardation and in those with neuroleptic and anti-epileptic drug therapy, in order to avoid or even extinguish self-mutilation of the oral cavity by means of an accurate hydration of the mucosa which might counterbalance some iatrogenic undesired effects. PMID- 24480582 TI - Endoscopic endonasal transplanum transtuberculum resection of a large solid choroid plexus papilloma of the third ventricle. AB - Choroid plexus papilloma (CPP) is a highly vascular solid or mixed solid-cystic tumor. Previously described resection techniques for the more common solid CPP in the third ventricle have all been through the transcranial route. The authors review the literature and describe a patient who, to their knowledge, is the first successful resection of a large, completely solid CPP of the third ventricle through an entirely endoscopic, extended transphenoidal approach. Using modern neuroendoscopic methods and closure techniques, a gross total resection was accomplished and a successful closure without postoperative cerebrospinal fluid leak was achieved despite the presence of preoperative hydrocephalus. For appropriately selected lesions, an extended endonasal skull base resection can be performed successfully for vascular tumors despite the presence of preoperative hydrocephalus. PMID- 24480583 TI - Development of a surveillance scheme for equine influenza in the UK and characterisation of viruses isolated in Europe, Dubai and the USA from 2010-2012. AB - Equine influenza viruses are a major cause of respiratory disease in horses worldwide and undergo antigenic drift. Several outbreaks of equine influenza occurred worldwide during 2010-2012, including in vaccinated animals, highlighting the importance of surveillance and virus characterisation. Virus isolates were characterised from more than 20 outbreaks over a 3-year period, including strains from the UK, Dubai, Germany and the USA. The haemagglutinin-1 (HA1) sequence of all isolates was determined and compared with OIE-recommended vaccine strains. Viruses from Florida clades 1 and 2 showed continued divergence from each other compared with 2009 isolates. The antigenic inter-relationships among viruses were determined using a haemagglutination-inhibition (HI) assay with ferret antisera and visualised using antigenic cartography. All European isolates belonged to Florida clade 2, all those from the USA belonged to Florida clade 1. Two subpopulations of clade 2 viruses were isolated, with either substitution A144V or I179V. Isolates from Dubai, obtained from horses shipped from Uruguay, belonged to Florida clade 1 and were similar to viruses isolated in the USA the previous year. The neuraminidase (NA) sequence of representative strains from 2007 and 2009 to 2012 was also determined and compared with that of earlier isolates dating back to 1963. Multiple changes were observed at the amino acid level and clear distinctions could be made between viruses belonging to Florida clade 1 and clade 2. PMID- 24480584 TI - Genetic characterization of porcine circovirus type 2 in the Korean wild boar population. AB - The porcine circovirus type 2 (PCV2) has reached very high levels in the pig population in South Korea and throughout the world since it was first described in the late 1990s. In this study, we found that the prevalence of PCV2 in the Korean wild boar population was 4.98% (91/1825). Interestingly, 19 PCV2 ORF2 sequences that could be completely sequenced showed that they belonged only to genotype PCV2b, subgroup 1A/B (n=16) and 1C (n=3). We suggest that sites potentially under positive selection are responsible for the antigenicity changes and phenotypic switch patterns in the capsid gene of 55 PCV2s from Korean domestic pigs, but the sites potentially under positive selection in the 19 PCV2 ORF2 genes from Korean wild boar are not responsible for antigenicity. PMID- 24480585 TI - Susceptibility of Japanese Cyprininae fish species to cyprinid herpesvirus 2 (CyHV-2). AB - Cyprinid herpesvirus 2 (CyHV-2) is known as the causative agent of herpesviral haematopoietic necrosis (HVHN) of goldfish (Carassius auratus). Recently, the virus has also been detected from Prussian carp (C. gibelio) and crucian carp (C. carassius) from European and Asian countries. To analyze the risk of spreading to new host species, the susceptibility of other fish species to the virus is essential. In this study experimental infections of indigenous Cyprininae species in Japan were performed by immersion in and intraperitoneal injection of a CyHV-2 isolate. Although Edonishiki, a variety of goldfish, immersed with the virus showed a cumulative mortality of 90%, no mortality was observed in ginbuna C. auratus langsdorfii, nagabuna C. auratus buergeri, nigorobuna C. auratus grandoculis and common carp Cyprinus carpio. Cumulative mortality was 100, 20 and 10% in intraperitoneally injected Edonishiki, ginbuna and nagabuna, respectively. Furthermore all Edonishiki immersed with the virus died. However, even after stimuli of sudden temperature changes, the immersed ginbuna and nagabuna did not die. Moreover no mortality was observed in co-reared Ranchu, another variety of goldfish, with immersed ginbuna and nagabuna although all three Ranchu co-reared with immersed Edonishiki died. CyHV-2 DNA was detected and the virus was re isolated from all dead fish. Moreover CyHV-2 DNA was detected from some of the surviving Carassius spp. These results revealed that susceptibility of Japanese indigenous Cyprininae fish species to CyHV-2 is much lower than for goldfish. In addition, ability of replication of CyHV-2 might be different among Carassius fish species. PMID- 24480586 TI - Forensic molecular pathology: its impacts on routine work, education and training. AB - The major role of forensic pathology is the investigation of human death in relevance to social risk management to determine the cause and process of death, especially in violent and unexpected sudden deaths, which involve social and medicolegal issues of ultimate, personal and public concerns. In addition to the identification of victims and biological materials, forensic molecular pathology contributes to general explanation of the human death process and assessment of individual death on the basis of biological molecular evidence, visualizing dynamic functional changes involved in the dying process that cannot be detected by morphology (pathophysiological or molecular biological vital reactions); the genetic background (genomics), dynamics of gene expression (up-/down-regulation: transcriptomics) and vital phenomena, involving activated biological mediators and degenerative products (proteomics) as well as metabolic deterioration (metabolomics), are detected by DNA analysis, relative quantification of mRNA transcripts using real-time reverse transcription-PCR (RT-PCR), and immunohisto /immunocytochemistry combined with biochemistry, respectively. Thus, forensic molecular pathology involves the application of omic medical sciences to investigate the genetic basis, and cause and process of death at the biological molecular level in the context of forensic pathology, that is, 'advanced molecular autopsy'. These procedures can be incorporated into routine death investigations as well as guidance, education and training programs in forensic pathology for 'dynamic assessment of the cause and process of death' on the basis of autopsy and laboratory data. Postmortem human data can also contribute to understanding patients' critical conditions in clinical management. PMID- 24480587 TI - New insights into the isopenicillin N transport in Penicillium chrysogenum. AB - In Penicillium chrysogenum the beta-lactam biosynthetic pathway is compartmentalized. This fact forces the occurrence of transport processes of penicillin-intermediate molecules across cell membranes. Many aspects around this molecular traffic remain obscure but are supposed to involve transmembrane transporter proteins. In the present work, an in-depth study has been developed on a Major Facilitator-type secondary transporter from P. chrysogenum named as PenM. The reduction of penM expression level reached by penM targeted silencing, leads to a decrease in benzylpenicillin production in silenced transformants, especially in SilM-35. On the contrary, the penM overexpression from a high efficiency promoter increases the benzylpenicillin production and the expression of the biosynthetic genes. Moreover, when the silenced strain SilM-35 is cultured under penicillin production conditions with 6-aminopenicillanic acid supplementation, an increase in the benzylpenicillin production proportional to the 6-aminopenicillanic acid availability is observed. By this phenomenon, it can be concluded that due to the penM silencing the benzylpenicillin transport remains intact but the peroxisomal isopenicillin N import results affected. As a culminating result, obtained by the expression of the fluorescent recombinant PenM-DsRed protein, it was determined that PenM is naturally located in P. chrysogenum peroxisomes. In summary, our experimental results suggest that PenM is involved in penicillin production most likely through the translocation of isopenicillin N from the cytosol to the peroxisomal lumen across P. chrysogenum peroxisomal membrane. PMID- 24480588 TI - Interplay between microRNAs and host pathogen recognition receptors (PRRs) signaling pathways in response to viral infection. AB - Antimicrobial response is greatly influenced by microRNAs (miRNAs) which are the important post-transcriptional regulators of gene expression. Simultaneously, host pathogen recognition receptors (PRRs) engaged by pathogen-associated molecular patterns (PAMPs) also play critical roles in activating innate immunity against microbial infection. Emerging evidences suggest that the interaction between microbial-regulated miRNAs and important PRRs signaling pathways influence host immune response to microbial pathogens. In this manuscript, we describe the roles of miRNAs in virus-regulated innate immune pathways and the crosstalk between miRNAs and PRRs, further breaking out the mechanistic dissection of miRNAs-PRRs in viral infection and the development of the prognosis of disease and novel miRNA-therapeutic strategies targeting immunity. PMID- 24480589 TI - Localization of a filarial phosphate permease that is up-regulated in response to depletion of essential Wolbachia endobacteria. AB - Wolbachia of filarial nematodes are essential, obligate endobacteria. When depleted by doxycycline worm embryogenesis, larval development and worm survival are inhibited. The molecular basis governing the endosymbiosis between Wolbachia and their filarial host is still being deciphered. In rodent filarial nematode Litomosoides sigmodontis, a nematode encoded phosphate permease gene (Ls-ppe-1) was up-regulated at the mRNA level in response to Wolbachia depletion and this gene promises to have an important role in Wolbachia-nematode endosymbiosis. To further characterize this gene, the regulation of phosphate permease during Wolbachia depletion was studied at the protein level in L. sigmodontis and in the human filaria Onchocerca volvulus. And the localization of phosphate permease (PPE) and Wolbachia in L. sigmodontis and O. volvulus was investigated in untreated and antibiotic treated worms. Depletion of Wolbachia by tetracycline (Tet) resulted in up-regulation of Ls-ppe-1 in L. sigmodontis. On day 36 of Tet treatment, compared to controls (Con), >98% of Wolbachia were depleted with a 3 fold increase in mRNA levels of Ls-ppe-1. Anti-Ls-PPE serum used in Western blots showed up-regulation of Ls-PPE at the protein level in Tet worms on day 15 and 36 of treatment. Immunohistology revealed the localization of Wolbachia and Ls-PPE in the embryos, microfilariae and hypodermis of L. sigmodontis female worms and up-regulation of Ls-PPE in response to Wolbachia depletion. Expression of O. volvulus phosphate permease (Ov-PPE) studied using anti-Ov-PPE serum, showed up regulation of Ov-PPE at the protein level in doxycycline treated Wolbachia depleted O. volvulus worms and immunohistology revealed localization of Ov-PPE and Wolbachia and up-regulation of Ov-PPE in the hypodermis and embryos of doxycycline treated worms. Ls-PPE and Ov-PPE are upregulated upon Wolbachia depletion in same tissues and regions where Wolbachia are located in untreated worms, reinforcing a link between Wolbachia and this nematode encoded protein. The function of nematode phosphate permease in the endosymbiosis is unknown but could involve transportation of phosphate to Wolbachia, which encode all the genes necessary for de novo nucleotide biosynthesis. Electron microscopic localization of PPE and Wolbachia and RNAi mediated knock-down of PPE in filarial nematodes will bring further insights to the functions of PPE in the Wolbachia nematode symbiosis. PMID- 24480590 TI - Simultaneous, unilateral plugging of superior and posterior semicircular canal dehiscences to treat debilitating hyperacusis. AB - OBJECTIVE: To describe a case of bilateral superior and posterior semicircular canal dehiscences, and the use of a unilateral transmastoid approach to address both right-sided defects simultaneously. CASE REPORT: In a patient with right sided hyperacusis, bilateral dehiscence of both the superior and the posterior semicircular canals was identified, located adjacent to the common crus, together with a right-sided, anterosuperiorly positioned sigmoid sinus and a high-riding jugular bulb. Results for audiography and cervical vestibular evoked myogenic potential testing were consistent with right-sided semicircular canal dehiscence. At surgery, a right-sided transmastoid approach provided access to plug both defects simultaneously, following posterior mobilisation of the sigmoid sinus. The patient's hyperacusis was completely resolved, with a 10-30 dB improvement in his right ear air conduction hearing, without decrement in bone conduction. CONCLUSION: In properly selected patients, a transmastoid approach can be used to effectively manage superior semicircular canal dehiscence and posterior semicircular canal dehiscence simultaneously. Pre-operative computed tomography is recommended to evaluate the dehiscence sites and to identify complicating vascular anatomy. PMID- 24480591 TI - Antipsychotic drug-associated gene-miRNA interaction in T-lymphocytes. AB - Antipsychotic drugs (APDs) can have a profound effect on the human body that extends well beyond our understanding of their neuropsychopharmacology. Some of these effects manifest themselves in peripheral blood lymphocytes, and in some cases, particularly in clozapine treatment, result in serious complications. To better understand the molecular biology of APD action in lymphocytes, we investigated the influence of chlorpromazine, haloperidol and clozapine in vitro, by microarray-based gene and microRNA (miRNA) expression analysis. JM-Jurkat T lymphocytes were cultured in the presence of the APDs or vehicle alone over 2 wk to model the early effects of APDs on expression. Interestingly both haloperidol and clozapine appear to regulate the expression of a large number of genes. Functional analysis of APD-associated differential expression revealed changes in genes related to oxidative stress, metabolic disease and surprisingly also implicated pathways and biological processes associated with neurological disease consistent with current understanding of the activity of APDs. We also identified miRNA-mRNA interaction associated with metabolic pathways and cell death/survival, all which could have relevance to known side effects of APDs. These results indicate that APDs have a significant effect on expression in peripheral tissue that relate to both known mechanisms as well as poorly characterized side effects. PMID- 24480592 TI - Cardiothoracic interventions in Behcet's disease. AB - OBJECTIVES: Cardiothoracic interventions for cardiovascular complications of Behcet's disease have not been sufficiently elucidated. METHODS: A comprehensive literature search of cardiovascular complications of Behcet's disease was made for year range 2000-2013. The articles on the cardiothoracic procedures for cardiovascular complications of Behcet's disease were screened and analysed. RESULTS: The 221 major cardiothoracic procedures performed in this patient setting included 176 (79.6%) cardiac, 9 (4.1%) thoracic, 31 (14.0%) interventional and 5 (2.3%) hybrid procedures (chi2=478.03, p<0.0001). Of the major cardiac operations, there were 74 (42%) valvular, 58 (33%) aneurysmal, 23 (13.1%) thrombotic, 10 (5.7%) coronary and 11 (6.3%) miscellaneous procedures. The postoperative morbidity, recurrence and mortality rates were 21.4%, 11.7% and 15.0%, and the reintervention rates were 15.4% for recurrence, and 43.2% for morbidity patients. Dehiscence of the prosthetic valve was the major morbidity (52.3%) and the major cause of death (63.6%). The cardiac surgical patients carried the highest mortality rate comparing with thoracic, interventional and hybrid treatment patients. CONCLUSIONS: Cardiovascular operations prevailed thoracic and interventional procedures for the cardiovascular complications of Behcet's disease. Postoperative complications and recurrence rates were high. Aortic valve regurgitation, pulmonary artery aneurysm, and intracardiac and great vessel thrombosis were the most common indications for a cardiothoracic intervention. Dehiscence of the prosthetic valve was the main cause of death of the cardiothoracic interventions. Intense immunosuppressive treatment may reduce the postoperative complications and the need for reinterventions. PMID- 24480593 TI - Transcultural adaptation and validation of the Spanish version of EUROQUEST. AB - INTRODUCTION: The specific diagnosis of toxic encephalopathy (TE) by chronic exposure to neurotoxics presents difficulties, mainly due to lack of consensus of clinical diagnostic criteria. The EUROQUEST (EQ) is a multicultural tool proposed for using in epidemiological studies on neurotoxicity. The aim of this study was to validate the Spanish version of this questionnaire for using as a diagnostic and prevention tool in the workplace. METHODS: After translation and cultural adaptation, leading to a final questionnaire in Spanish, validation was performed by asking a total of 759 people to complete the questionnaire, of whom 292 were workers exposed to neurotoxic solvents, 391 non-exposed workers, and 22 patients diagnosed with chronic alcoholism. RESULTS: In the analysis of the reliability, the Cronbach alpha value for the questionnaire was 0.94, indicating very high internal consistency. The test-retest reproducibility analysis was highly significant (r=0.91, P<.001). In the analysis of the validity, comparing the three study groups, the mean scores of the questions included in each of the dimensions of the test (ANOVA) detected major differences in the dimensions that assess cognitive symptoms, depressive disorders, sleep and psychopathological symptoms. After factor analysis obtained a total of nine axes, allowing a clear distinction between the three study groups. PMID- 24480595 TI - Eversion endarterectomy and re-implantation in carotid stenosis and distal kink. PMID- 24480594 TI - Validation of a Spanish version of the Test Your Memory. AB - OBJECTIVE: To validate a Spanish version of the TYM, a self-administered cognitive screening test designed for the detection of Alzheimer's disease and mild cognitive defect. METHODS: A cross-sectional study was conducted in a neurology outpatient clinic. The TYM was administered to individuals of 50 years o more who came to the clinic for whatever the symptom. Their cognitive state was evaluated regardless of the outcome of TYM. They were categorized into 3 groups: 1) Cognitively normal (739), 2) with mild cognitive impairment (183), 3) with dementia (127). An analysis of items was made and the psychometric properties of the TYM were defined. There was a cross-validation, and the predictive validity of the TYM score, adjusted to the demographic variables, was determined by evaluating their performance in ROC curves. RESULTS: The internal consistency, interobserver reliability, short term and long-term test-retest reliability were adequate. The TYM correlated with the MMSE (r=0.779, P<.0001). The cross validation showed consistent results. With the TYM Score adjusted according to the educational level, a sensitivity of 0.86 with a specificity of 0.88 in the cut-off point of <=40/50 was obtained to identify subjects with cognitive impairment, and a sensitivity of 0.94 with a specificity of 0.89 in the cut-off point of <=36/50 to identify subjects with dementia. CONCLUSIONS: The TYM is a self-administered global cognitive test, possessing excellent psychometric properties and good predictive validity. It can be used as a cognitive screening test in subjects with 4 years or more of formal education. PMID- 24480596 TI - Malathion-induced changes in the haematological profile, the immune response, and the oxidative/antioxidant status of Cyprinus carpio carpio: protective role of propolis. AB - The present study investigated the potential ameliorative effects of propolis against malathion toxicity in the blood and various tissues of carp. The fish were exposed to sublethal concentrations of malathion (0.5 and 1 mg/L) for 10 days, and propolis (10 mg/kg of fish weight) was simultaneously administered. Blood and tissue (liver, kidney, and gill) samples were collected at the end of the experiment and analysed to determine the haematological profile (red blood cell count, haemoglobin concentration, haematocrit level, and erythrocyte indices: mean corpuscular volume, mean corpuscular haemoglobin, and mean corpuscular haemoglobin concentration), immune response (white blood cell count, oxidative radical production, nitroblue tetrazolium (NBT) activity, total plasma protein and total immunoglobulin levels, and the phagocytic activity), and oxidant/antioxidant status (malondialdehyde and reduced glutathione levels and superoxide dismutase, catalase, and glutathione peroxidase activities) of the fish. The findings of this study demonstrate that malathion has a negative effect on the haematological parameters, immune response, and antioxidant enzyme activities of the fish. However, the administration of propolis ameliorated the malathion-induced toxic effects. PMID- 24480597 TI - Experimental increase in telomere length leads to faster feather regeneration. AB - Telomeres - the protective ends of linear chromosomes - reveal themselves not only as a good proxy in terms of longevity, but more recently also as a marker of healthy ageing in laboratory rodents. Telomere erosion is prevented by the activation of telomerase, an enzyme suspected to be also vital for tissue regeneration and which experimental activation improves health state in mice. One emerging hypothesis is that telomerase activity accounts for the frequently reported positive links between telomere lengths and individual quality in a wide range of organisms. Still, we lack an experimental approach testing the exact impact of inter-individual differences in telomere length on individual trait variability. In a first step study, we tested the impact of the TA-65, a plant derived product stimulating the expression and the activity of telomerase, on telomere lengths and flight feather renewal capacity of captive zebra finches (Taenopygia guttata). Telomere length was longer in TA-65 treated finches while their feather grew faster than in controls. Our data support the idea that long telomeres could reflect high telomerase activity, and in so doing be a good predictor of greater telomerase-dependent tissue regeneration, which may ultimately explain variation in organism quality and longevity. PMID- 24480598 TI - [Cooperation]. PMID- 24480599 TI - [White blood cells counts and parasite density in malaria in children aged 6 to 60 months in urban areas of Togo]. AB - Rational use of the artemisinin-based combination therapies in Togo requires laboratory parasitemia values to confirm suspected malaria. This study was conducted to determine the impact of the measured white blood cell (WBC) count on the determination of malaria parasite density among children younger than 5 years old infected with uncomplicated Plasmodium falciparum in Togo. This cross sectional study of 267 children from four pediatric centers diagnosed malaria with both thick and thin blood smears and counted WBCs with a hematology analyzer. The parasite densities, calculated with the number of WBCs and estimated with an assumed count of 8,000/MUL, were compared with the Wilcoxon matched pairs signed-rank test. The children's median age was 35 months (interquartile range [24-48]), with a sex ratio of 1.32. The median WBC value was 8,300 cells/MUL (range: 1,300-24,900 cells/MUL). The median parasitemia value calculated with the absolute WBC count was 35,714 (range: 139-48,860 parasites/MUL) was not statistically different from that estimated with the assumed value of 8,000 cells/MUL - 33 125 parasites/MUL (p = 0.564). This study shows that malaria parasite density obtained by assuming 8000 cells/MUL does not result in overestimations for children aged 6-59 months. PMID- 24480601 TI - Efficacy of reducing agent and surfactant contacting pattern on the performance characteristics of nickel electroless plating baths coupled with and without ultrasound. AB - This article addresses furthering the role of sonication for the optimal fabrication of nickel ceramic composite membranes using electroless plating. Deliberating upon process modifications for surfactant induced electroless plating (SIEP) and combined surfactant and sonication induced electroless plating (SSOEP), this article highlights a novel method of contacting of the reducing agent and surfactant to the conventional electroless nickel plating baths. Rigorous experimental investigations indicated that the combination of ultrasound (in degas mode), surfactant and reducing agent pattern had a profound influence in altering the combinatorial plating characteristics. For comparison purpose, purely surfactant induced nickel ELP baths have also been investigated. These novel insights consolidate newer research horizons for the role of ultrasound to achieve dense metal ceramic composite membranes in a shorter span of total plating time. Surface and physical characterizations were carried out using BET, FTIR, XRD, FESEM and nitrogen permeation experiments. It has been analyzed that the SSOEP baths provided maximum ratio of percent pore densification per unit metal film thickness (PPDdelta) and hold the key for further fine tuning of the associated degrees of freedom. On the other hand SIEP baths provided lower (PPDdelta) ratio but higher PPD. For SSOEP baths with dropwise reducing agent and bulk surfactant, the PPD and metal film thickness values were 73.4% and 8.4 MUm which varied to 66.9% and 13.3 MUm for dropwise reducing agent and drop surfactant case. PMID- 24480600 TI - [Social marketing to increase the rate of cataract surgery in the Sava region of Madagascar]. AB - OBJECTIVE: Lack of information is one of the main reasons why people who are visually impaired or blind as a result of cataracts do not visit eye care centers for surgery that can restore their sight. This study was conducted to determine the best ways to inform the main target groups about the possibility of restoring sight to those whose visual impairment and blindness is due to cataracts and about outreach visits by the mobile eye clinic of FLM SALFA, Sambava, in the Sava region of Madagascar from November 2008 through October 2009. METHODS: Two community eye health workers conducted awareness campaigns and delivered posters to radio stations, religious leaders, and administrative authorities of the 17 most populated municipalities in the region of Sava, two weeks before these visits. All participants who visited the mobile clinic were interviewed, and the ophthalmologist's diagnosis was noted on the questionnaire. RESULTS: Women accounted for 51.5% of the 955 participants. Radio was the most effective means of communication in the region overall, and specifically for reaching men (P=0.044); churches were more successful for reaching women (P = 0.000). Cataract was diagnosed in 16.2% of men and 8.1% of women (p = 0.0001). CONCLUSION: To significantly increase the number of people, especially women, having cataract surgery in the Sava region, it is essential to work closely with the leaders of all religious groups, as well as with radio stations. PMID- 24480602 TI - The Human Umbilical Cord Tissue-Derived MSC Population UCX((r)) Promotes Early Motogenic Effects on Keratinocytes and Fibroblasts and G-CSF-Mediated Mobilization of BM-MSCs When Transplanted In Vivo. AB - Mesenchymal stromal cells (MSCs) play an important role in tissue regeneration mainly through the secretion of trophic factors that enhance the repair of damaged tissues. The main goal of this work was to study the paracrine mechanisms by which an umbilical cord tissue-derived MSC population (UCX((r))) promotes the migration capacity of human dermal fibroblasts and keratinocytes, which is highly relevant for skin regeneration. Furthermore, the differences between paracrine activities of MSCs from the umbilical cord tissue and the bone marrow (BM-MSCs) were also evaluated. In vitro scratch assays revealed that conditioned media (CM) obtained from both growing and stationary-phase UCX((r)) cultures induced human dermal fibroblast (HDF) and keratinocyte (HaCaT) migration. These assays showed that the motogenic activity of UCX((r)) CM to HaCaTs was significantly higher than to HDFs, in opposition to the effect seen with CM produced by BM-MSCs that preferentially induced HDF migration. Accordingly, a comparative quantification of key factors with vital importance in the consecutive stages of wound healing revealed very different secretome profiles between UCX((r)) and BM-MSCs. The relatively higher UCX((r)) expression of EGF, FGF-2, and KGF strongly supports early induction of keratinocyte migration and function, whereas the UCX((r)) specific expression of G-CSF suggested additional roles in mobilization of healing-related cells including CD34(-)/CD45(-) precursors (MSCs) known to be involved in tissue regeneration. Accordingly, in vitro chemotaxis assays and an in vivo transplantation model for chemoattraction confirmed that UCX((r)) are chemotactic to CD34(-)/CD45(-) BM-MSCs via a cell-specific mobilization mechanism mediated by G-CSF. Overall, the results strongly suggest different paracrine activities between MSCs derived from different tissue sources, revealing the potential of UCX((r)) to extend the regenerative capacity of the organism by complementing the role of endogenous BM-MSCs. PMID- 24480603 TI - Preterm infant weight gain is increased by massage therapy and exercise via different underlying mechanisms. AB - OBJECTIVE: To compare the effects of massage therapy (moderate pressure stroking) and exercise (flexion and extension of limbs) on preterm infants' weight gain and to explore potential underlying mechanisms for those effects. METHODS: Weight gain and parasympathetic nervous system activity were assessed in 30 preterm infants randomly assigned to a massage therapy group or to an exercise group. Infants received 10min of moderate pressure massage or passive flexion and extension of the limbs 3 times per day for 5days, and EKGs were collected during the first session to assess vagal activity. RESULTS: Both massage and exercise led to increased weight gain. However, while exercise was associated with increased calorie consumption, massage was related to increased vagal activity. CONCLUSION: Taken together, these findings suggest that massage and exercise lead to increased preterm infant weight gain via different underlying mechanisms. PMID- 24480604 TI - Effect of holding on co-regulation in preterm infants: a randomized controlled trial. AB - OBJECTIVE: To determine whether kangaroo holding of healthy preterm infants over the first eight weeks of an infant's life facilitates co-regulation of salivary cortisol between mother and infant. STUDY DESIGN: Randomized control trial. Infants were assigned to receive 1h of daily kangaroo (skin-to-skin contact on the chest of mother) or blanket holding (dressed and held in mother's arms). A registered nurse visited mothers weekly for eight weeks to encourage holding and provide information about infant development. A control group had no holding restrictions and received weekly brief social visits. SUBJECTS: The study included 79 preterm infants, born between 32 and 35weeks gestational age and were a mean of 15days (+/-5.7) at enrollment. OUTCOME MEASURES: Co-regulation was conceptualized as progressive reduction in the absolute difference between mother and infant cortisol levels across 60min of holding at each holding session. Mother and infant cortisol levels were measured before holding and at 30 and 60min after holding began during three holding sessions (baseline and at two and eight weeks after study initiation). Primary analyses were conducted using hierarchical linear models. RESULTS: There was much variability in cortisol levels. Levels of mother and infant cortisol decreased during holding. No significant co-regulation occurred in any group at any holding session or over time. CONCLUSIONS: Decreasing level of cortisol in both mothers and infants suggests that holding promoted the expected decline in stress hormone levels. However, supported holding methods did not differentially affect co-regulation compared to controls. Holding is pleasurable and stress may need to be present in order for mothers and infants to demonstrate co-regulation in cortisol levels. PMID- 24480605 TI - No sexual dimorphism in human prenatal metacarpal ratios. AB - BACKGROUND: Ratios of digit lengths are studied intensively as markers of prenatal sex hormone levels. AIM: Study sexual dimorphism in ratios of metacarpals, which received less attention. METHODS: We studied six metacarpal ratios in deceased human fetuses of ages 10 to 42weeks. RESULTS AND CONCLUSION: We found no indication of a sexual dimorphism at this early stage of development. PMID- 24480607 TI - A 21st-century approach to age-old problems: the ascension of biologics in clinical therapeutics. AB - Small organic molecules have been the pharmaceutical mainstay of the developed world for some time. However, in recent years, advances within the fields of genomics and proteomics have strengthened and given rise to new biologic therapies. Protein therapies, such as monoclonal antibodies and peptide drugs, have provided patients with pharmaceuticals that offer a higher level of selectivity and effectiveness that would be otherwise undeliverable within the realm of small organics. In addition to protein therapies, DNA-based therapy, such as RNA interference (RNAi) and gene therapy, have gained renewed interest within modern medicine and are potentially poised for a comeback within the biotechnology industry. As we discuss here, the advantages of such therapies continue to accumulate and have kept the biologic market strong. PMID- 24480606 TI - Cord blood biomarkers of vascular endothelial growth (VEGF and sFlt-1) and postnatal growth: a preterm birth cohort study. AB - BACKGROUND: Preterm infants are at risk for postnatal growth failure (PGF). Identification of biomarkers that are associated with neonatal growth may help reduce PGF and associated long-term morbidity. OBJECTIVE: To investigate the associations between cord blood vascular endothelial growth factor (VEGF) and its soluble receptor (sFlt-1) with birth weight (BW) and postnatal growth in premature infants. STUDY DESIGN AND METHODS: From an ongoing birth cohort, 123 premature infants from 23 to 36 weeks gestational age (GA) were studied. Cord blood plasma VEGF and sFlt-1 were measured via enzyme-linked immunoassay. Growth parameters and nutritional information were evaluated. Multivariate logistic regression models were constructed to evaluate the associations of VEGF and sFlt 1 on PGF, defined as weight <10th percentile at 36 weeks corrected age or discharge. RESULTS: VEGF was positively correlated, and sFlt-1 was negatively correlated with BW and BW-for-GA percentiles. Higher cord blood VEGF levels were associated with reduced risk of PGF (OR=0.7; 95% CI=0.5-0.9), while higher sFlt-1 levels appeared to increase the risk of PGF (OR=1.6; 95% CI=1.1-2.4). The above biomarker associations were attenuated after adjustment for maternal preeclampsia, fetal growth restriction and related neonatal characteristics, and when taking into account placental vascular pathologies. Longitudinal growth patterns by mean weight and length percentiles were consistently lower among infants with low VEGF/sFlt-1 ratios. CONCLUSIONS: Our data support that intrauterine regulation of angiogenesis is an important mechanism of fetal and postnatal growth. Cord blood VEGF and sFlt-1 are useful in elucidating how intrauterine processes may have long-standing effects on developing premature infants. PMID- 24480608 TI - The prenatal, perinatal and neonatal risk factors for children's developmental coordination disorder: a population study in mainland China. AB - We initially conducted a population-based study on developmental coordination disorder (DCD) in mainland China to explore the prenatal, perinatal and neonatal risk factors on DCD. A total of 4001 children were selected from 160 classes in 15 public nursery schools. The Movement Assessment Battery for Children-Second Edition (MABC-2) was used to assess the children's motor function. Crude and adjusted odds ratios were estimated to determine the strength of association using a multilevel logistic regression model with a random intercept. Three hundred and thirty children out of 4001 subjects met the DSM-IV criteria for DCD, and 3671 children were non-DCD. Maternal age, threatened abortion, fetal distress during labor, preterm birth, chronic lung disease and newborn pathological jaundice were related with DCD (OR=1.72, 2.72, 9.14, 5.17, 1.43, and 2.54, respectively, each p<0.05). Considered collectively, these risk factors may provide clues to an etiology of DCD. Additionally, the practitioners of maternity and child health care should improve the assessment and monitoring of the prenatal, perinatal and neonatal risk factors for DCD. PMID- 24480610 TI - The self-rated health of British adults with intellectual disability. AB - People with intellectual disability have significantly higher age-adjusted rates of mortality and morbidity than their non-disabled peers. While self-rated health status is commonly used as an indicator of the health status of populations of interest, few studies have explored the self-rated health of adults with intellectual disability. We undertook secondary analysis of de-identified cross sectional data from the first waves of two contemporary UK surveys: the Life Opportunities Survey (n=37,513) and Understanding Society (n=50,976). In the Life Opportunities Survey we identified 316 participants age 16-49 (1.7% of the age restricted sample) as having intellectual disability. In Understanding Society we identified 415 participants age 16-49 (1.5% of the age-restricted sample) as having intellectual disability. Participants with intellectual disability were significantly more likely to report having fair or worse health than their peers (Life Opportunities Survey OR=8.86 (6.54-12.01), p<0.001; Understanding Society OR=13.14 (10.65-16.21), p<0.001). However the strength of this association was significantly attenuated when risk estimates were adjusted to take account of the increased rates of exposure of participants with intellectual disability to socio economic disadvantage and (in the Life Opportunities Survey) exposure to discrimination and violence. PMID- 24480611 TI - Reliability and validity of the Korean version of the trunk control measurement scale (TCMS-K) for children with cerebral palsy. AB - The Trunk Control Measurement Scale (TCMS) was developed by Lieve Heyrman in 2011 to evaluate the clinical features of impaired trunk control ability in patients with cerebral palsy (CP). This study aimed to demonstrate the reliability and validity of the Korean version of the Trunk Control Measurement Scale (TCMS-K) for children with CP. Fifty children with spastic CP (mean age 9.08+/-3.75) participated in the study. They were classified using the Gross Motor Function Classification System and the Manual Ability Classification System. The intraclass correlation coefficient (ICC) value of the inter-rater reliability for the TCMS-K was .987-.998, and the intra-rater reliability was .947-.996. The Spearman rank correlation coefficient between the TCMS-K and the Gross Motor Function Measure-B dimension was .860. The results of the study support that the TCMS-K has a high reliability and validity, which is similar to the original version. Thus, the TCMS-K is a suitable evaluation tool to assess the qualitative performance of trunk control and sitting balance for children with CP, and we expect that it will be a very useful tool for clinicians and researchers. PMID- 24480609 TI - Development of socio-communicative skills in 9- to 12-month-old individuals with fragile X syndrome. AB - We investigated the early socio-communicative development of individuals with fragile X syndrome (FXS) by undertaking a retrospective analysis of family videos. Videos were analyzed to identify existing communicative forms and functions. Analyses were undertaken on seven children who were later diagnosed with FXS. The children were filmed when they were 9-12 months old and before being diagnosed. Fourteen different communicative forms and six different communicative functions were observed. All participants were observed to express the functions of 'Attention to self' and 'Answering', but none indicated 'Requesting action', 'Requesting information', 'Choice making', or 'Imitating'. Results suggest that children with FXS may have a limited range of communicative forms and functions when they are from 9 to 12 months of age. However, further research is necessary to gain a specific developmental profile of socio communicative forms and functions in FXS. PMID- 24480612 TI - Interbirth intervals: Intrafamilial, intragenomic and intrasomatic conflict. AB - BACKGROUND AND OBJECTIVES: Interbirth intervals (IBIs) mediate a trade-off between child number and child survival. Life history theory predicts that the evolutionarily optimal IBI differs for different individuals whose fitness is affected by how closely a mother spaces her children. The objective of the article is to clarify these conflicts and explore their implications for public health. METHODOLOGY: Simple models of inclusive fitness and kin conflict address the evolution of human birth-spacing. RESULTS: Genes of infants generally favor longer intervals than genes of mothers, and infant genes of paternal origin generally favor longer IBIs than genes of maternal origin. CONCLUSIONS AND IMPLICATIONS: The colonization of maternal bodies by offspring cells (fetal microchimerism) raises the possibility that cells of older offspring could extend IBIs by interfering with the implantation of subsequent embryos. PMID- 24480613 TI - Gallium-mediated siderophore quenching as an evolutionarily robust antibacterial treatment. AB - BACKGROUND AND OBJECTIVES: Conventional antibiotics select strongly for resistance and are consequently losing efficacy worldwide. Extracellular quenching of shared virulence factors could represent a more promising strategy because (i) it reduces the available routes to resistance (as extracellular action precludes any mutations blocking a drug's entry into cells or hastening its exit) and (ii) it weakens selection for resistance, as fitness benefits to emergent mutants are diluted across all cells in a cooperative collective. Here, we tested this hypothesis empirically. METHODOLOGY: We used gallium to quench the iron-scavenging siderophores secreted and shared among pathogenic Pseudomonas aeruginosa bacteria, and quantitatively monitored its effects on growth in vitro. We assayed virulence in acute infections of caterpillar hosts (Galleria mellonella), and tracked resistance emergence over time using experimental evolution. RESULTS: Gallium strongly inhibited bacterial growth in vitro, primarily via its siderophore quenching activity. Moreover, bacterial siderophore production peaked at intermediate gallium concentrations, indicating additional metabolic costs in this range. In vivo, gallium attenuated virulence and growth even more so than in infections with siderophore-deficient strains. Crucially, while resistance soon evolved against conventional antibiotic treatments, gallium treatments retained their efficacy over time. CONCLUSIONS: Extracellular quenching of bacterial public goods could offer an effective and evolutionarily robust control strategy. PMID- 24480614 TI - Astaxanthin reduces matrix metalloproteinase expression in human chondrocytes. AB - Astaxanthin is a red carotenoid pigment which exerts multiple biological activities. However, little is known about the effects of astaxanthin on matrix metalloproteinases (MMPs) in OA. The present study investigated the effects of astaxanthin on MMPs in human chondrocytes. Human chondrocytes were pretreated with astaxanthin at 1, 10 or 50MUM, then, cells were stimulated with IL-1beta (10ng/ml) for 24h. MMP-1, MMP-3 and MMP-13 were observed. We found that astaxanthin reduced the expression of MMP-1, MMP-3 and MMP-13 as well as the phosphorylation of two mitogen-activated protein kinases (MAPK) (p38 and ERK1/2) in IL-1beta-stimulated chondrocytes. Astaxanthin also blocked the IkappaB-alpha degradation. These results suggest that astaxanthin may be beneficial in the treatment of OA. PMID- 24480615 TI - Motivational training improves self-efficacy but not short-term adherence with asthma self-management: a randomized controlled trial. AB - BACKGROUND: Adherence to self-management in asthma is poor. AIM: To investigate the effect of disease-unspecific motivational training on self-management adherence in addition to asthma-specific patient education. METHODS: We randomized patients with partly controlled asthma to asthma education, with or without the Zurich Resource Model (ZRM) training. Main elements of the ZRM training are development of action-oriented personal goals and activation of resources to achieve and practice them in daily life. The primary outcome was adherence to self-monitoring and to a written personal action plan during three months. Secondary outcomes included patient-reported self-efficacy. RESULTS: As control patients (n=30) were younger, mostly male and had better asthma control compared with the intervention group (n=30), we adjusted the analyses for these imbalances. Both groups showed excellent adherence to self-monitoring over three months [27 patients (90.0%) in intervention and 25 patients (83.3%) in control group, adjusted odds ratio: 1.28 (0.24-6.78), P=0.78)]. Patients in the ZRM group tended to adjust their medication more often [median 36% days with action (IQR 11 62%)] than control patients [9% (0-43), P=0.18]. In both groups, actions were rarely in accordance with the action plan [median 20% of actions appropriate (IQR 0-37) in intervention and 11% (IQR 0-56) in control group, P=0.92]. After three months, self-efficacy was significantly better with ZRM (adjusted difference on self-efficacy scale 2.31, 95% CI 0.31-4.31, P=0.02). CONCLUSION: Unspecific self management training had no short-term effect on self-management adherence in asthma patients. Self-efficacy improved, but it is uncertain whether this translates into better long-term outcomes. PMID- 24480617 TI - Clinicoradiological characteristics of patients with differentiated thyroid carcinoma and renal metastasis: case series with follow up. AB - BACKGROUND: Renal metastasis is relatively unusual in patients with differentiated thyroid carcinoma. METHODS: The clinicoradiological parameters of a series of patients with differentiated thyroid carcinoma and renal metastasis were assessed, together with follow-up data. RESULTS AND CONCLUSION: The series comprised 4 male patients over the age of 45 years with extensive disease at the primary site. Retro-sternal extension of a large goitre was observed in three patients. The primary tumour was 4 cm or larger in all patients (range, 4-14 cm), and three patients had associated lymph node metastasis. None had any genito urinary symptoms at presentation. Two patients had isolated renal metastases with no other distant metastases, while the others had extensive multi-organ involvement. The bilateral occurrence of lesions was a hallmark, being observed in all cases. Ultrasound-guided fine needle aspiration cytology and 131I scintigraphy were pivotal in confirming the diagnosis. Evidence of 'flip-flop' between 131I study and fluoro-deoxyglucose positron emission tomography was noted in one patient, while the other three demonstrated concordant lesions in both modalities. At a minimum follow-up period of four years after diagnosis, three patients demonstrated stable disease with radioiodine therapy, and one had expired due to a poorly differentiated lung carcinoma which developed subsequently. PMID- 24480616 TI - Influence of sucrose ingestion on brainstem and hypothalamic intrinsic oscillations in lean and obese women. AB - BACKGROUND & AIMS: The study of intrinsic fluctuations in the blood oxygen level dependent signal of functional magnetic resonance imaging can provide insight into the effect of physiologic states on brain processes. In an effort to better understand the brain-gut communication induced by the absorption and metabolism of nutrients in healthy lean and obese individuals, we investigated whether ingestion of nutritive and non-nutritive sweetened beverages differentially engages the hypothalamus and brainstem vagal pathways in lean and obese women. METHODS: In a 2-day, double-blind crossover study, 11 lean and 11 obese healthy women underwent functional magnetic resonance imaging scans after ingestion of 2 beverages of different sucrose content, but identical sweetness. During scans, subjects rested with eyes closed. RESULTS: Blood oxygen level-dependent fluctuations demonstrated significantly greater power in the highest frequency band (slow-3: 0.073-0.198 Hz) after ingestion of high-sucrose compared with low sucrose beverages in the nucleus tractus solitarius for both groups. Obese women had greater connectivity between the right lateral hypothalamus and a reward related brain region and weaker connectivity with homeostasis and gustatory related brain regions than lean women. CONCLUSIONS: In a functional magnetic resonance imaging study, we observed sucrose-related changes in oscillatory dynamics of blood oxygen level-dependent fluctuations in brainstem and hypothalamus in lean and obese women. The observed frequency changes are consistent with a rapid vagally mediated mechanism due to nutrient absorption, rather than sweet taste receptor activation. These findings provide support for altered interaction between homeostatic and reward networks in obese individuals. PMID- 24480618 TI - Generic drug prices and policy in Australia: room for improvement? a comparative analysis with England. AB - OBJECTIVE: To assess the degree to which reimbursement prices in Australia and England differ for a range of generic drugs, and to analyse the supply- and demand-side factors that may contribute to these differences. METHODS: Australian and English reimbursement prices were compared for a range of generic drugs using pricing information obtained from government websites. Next, a literature review was conducted to identify supply- and demand-side factors that could affect generic prices in Australia and England. Various search topics were identified addressing potential supply-side (e.g. market approval, intellectual property protection of patented drugs, generic pricing policy, market size, generic supply chain and discounting practices) and demand-side (consumers, prescribers and pharmacists) factors. Related terms were searched in academic databases, official government websites, national statistical databases and internet search engines. RESULTS: Analysis of drug reimbursement prices for 15 generic molecules (representing 45 different drug presentations) demonstrated that Australian prices were on average over 7-fold higher than in England. Significant supply side differences included aspects of pricing policy, the relative size of the generics markets and the use of clawback policies. Major differences in demand side policies related to generic prescribing, pharmacist substitution and consumer incentives. CONCLUSIONS: Despite recent reforms, the Australian Government continues to pay higher prices than its English counterpart for many generic medications. The results suggest that particular policy areas may benefit from review in Australia, including the length of the price-setting process, the frequency of subsequent price adjustments, the extent of price competition between originators and generics, medical professionals' knowledge about generic medicines and incentives for generic prescribing. WHAT IS KNOWN ABOUT THE TOPIC? Prices of generic drugs have been the subject of much scrutiny over recent years. From 2005 to 2010 the Australian Government responded to observations that Pharmaceutical Benefits Scheme prices for many generics were higher than in numerous comparable countries by instituting several reforms aimed at reducing the prices of generics. Despite this, several studies have demonstrated that prices for generic statins (one class of cholesterol-lowering drug) are higher in Australia compared with England and many other developed countries, and prices of numerous other generics remain higher than in the USA and New Zealand. Recently there has been increasing interest in why these differences exist. WHAT DOES THIS PAPER ADD? By including a much larger range of commonly used and costly generic drugs, this paper builds significantly on the limited previous investigations of generic drug prices in Australia and England. Additionally, this is the first comprehensive investigation of multiple supply- and, in particular, demand-side factors that may explain any price differences between these countries. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? Practitioners may contribute to the higher prices of generic medications in Australia compared with England through relatively low rates of generic prescribing. There are also significant implications for health policy makers, as this paper demonstrates that if Australia achieved the same prices as England for many generic drugs there could be substantial savings for the Pharmaceutical Benefits Scheme. PMID- 24480619 TI - Covered vs. uncovered stents for transjugular intrahepatic portosystemic shunt: a randomized controlled trial. AB - BACKGROUND & AIMS: The first studies comparing covered stents (CS) and bare stents (BS) to achieve Transjugular Intrahepatic Portosystemic Shunt (TIPS) were in favor of CS, but only one randomized study has been performed. Our aim was to compare the primary patency of TIPS performed with CS and BS. METHODS: The study was planned as a multicenter, pragmatic (with centers different in size and experience), randomized, single-blinded (with blinding of patients only), parallel group trial. The primary endpoint was TIPS dysfunction defined as either a portocaval gradient ?12mmHg, or a stent lumen stenosis ?50%. A transjugular angiography with portosystemic pressure gradient measurement was scheduled every 6months after TIPS insertion. RESULTS: 137 patients were randomized: 66 to receive CS, and 71 BS. Patients who were found to have a hepato-cellular carcinoma, or whose procedure was cancelled were excluded, giving a sample of 129 patients (62 vs. 67). Median follow-up for CS and BS were 23.6 and 21.8months, respectively. Compared to BS, the risk of TIPS dysfunction with CS was 0.60 95% CI [0.38-0.96], (p=0.032). The 2-year rate of shunt dysfunction was 44.0% for CS vs. 63.6% for BS. Early post TIPS complications (22.4% vs. 34.9%), risk of hepatic encephalopathy (0.89 [0.53-1.49]) and 2-year survival (70% vs. 67.5%) did not differ in the two groups. The 2-year cost/patient was 20k? [15.9-27.5] for CS vs. 23.4k? [18-37] for BS (p=0.52). CONCLUSIONS: CS provided a significant 39% reduction in dysfunction compared to BS. We did not observe any significant difference with regard to hepatic encephalopathy or death. PMID- 24480620 TI - Single stage treatment of ankylosis of the temporomandibular joint using patient specific total joint replacement and virtual surgical planning. AB - Ankylosis of the temporomandibular joint (TMJ) is a debilitating condition that can result in pain, trismus, and a poor quality of life. It can be caused by injury, infection, and rheumatoid disease. Current management includes gap arthroplasty, interpositional arthroplasty, and reconstruction. Traditionally, joints are reconstructed using stock implants, or the procedure is done in two stages with an additional computed tomography (CT) scan between the resective and reconstructive procedures and use of stereolithographic models to aid the design of the definitive prostheses. We describe a technique for the resection of ankylosis and reconstruction of the joint in a single operation using virtually designed custom-made implants. Five patients with ankylosis of the TMJ had a single stage operation with reconstruction between 2010 and 2012. All had preoperative high-resolution CT with contrast angiography. During an international web-based teleconference between the surgeon and the engineer a virtual resection of the ankylosis was done using the reconstructed CT images. The bespoke cutting guides and implants were designed virtually at the same time and were then manufactured precisely using computer-aided design and manufacture (CAD-CAM) over 6 weeks. After release of the ankylosis and reconstruction, the patients underwent an exercise regimen to improve mouth opening. Follow-up was for a minimum of 6 months. Four patients had one operation, and one patient had two. Median/Mean maximum incisal opening increased from 0.6mm before operation to 25 mm afterwards (range 23-27), and there was minimal surgical morbidity. This new method effectively treats ankylosis of the TMJ in a single stage procedure. Fewer operations and hospital stays, and the maintenance of overall clinical outcome are obvious advantages. PMID- 24480621 TI - Changing trends and the role of medical management on the outcome of patients treated for osteoradionecrosis of the mandible: experience from a regional head and neck unit. AB - This study is a retrospective review of treatment outcomes of osteoradionecrosis (ORN) of the mandible with specific reference to the evolving role of medical management with pentoxifylline, tocopherol, and doxycycline. We reviewed the presentation and management of 71 patients treated for ORN of the mandible at the regional head and neck unit during a 15-year period to January 2011, and categorised them into three grades using the Notani classification: grade I (n=28), grade II (n=16), and grade III (n=27). Twelve patients with grade I ORN, 3 with grade II, and 10 with grade III, were prescribed medical treatment. Of these, three with grade I, and two with grade II ORN were cured, and progression of the disease had halted and there was satisfactory control of symptoms in eight with grade I and four with grade III disease. Patients who failed to respond to conservative treatment were further analysed for the need for free flap reconstruction. Medical management was introduced as a standard treatment in January 2006. Of the 39 patients diagnosed before this, 20 (51%) required resection and free flap reconstruction compared with only 8/32 (25%) after it had been introduced. PMID- 24480622 TI - Tularaemia: a challenging zoonosis. AB - In recent years, several emerging zoonotic vector-borne infections with potential impact on human health have been identified in Europe, including tularaemia, caused by Francisella tularensis. This remarkable pathogen, one of the most virulent microorganisms currently known, has been detected in increasingly new settings and in a wide range of wild species, including lagomorphs, rodents, carnivores, fish and invertebrate arthropods. Also, a renewed concern has arisen with regard to F. tularensis: its potential use by bioterrorists. Based on the information published concerning the latest outbreaks, the aim of this paper is to review the main features of the agent, its biology, immunology and epidemiology. Moreover, special focus will be given to zoonotic aspects of the disease, as tularaemia outbreaks in human populations have been frequently associated with disease in animals. PMID- 24480623 TI - Prevalence and characterization of Staphylococcus aureus and Staphylococcus pseudintermedius isolated from companion animals and environment in the veterinary teaching hospital in Zambia, Africa. AB - The Republic of Zambia consists of only one veterinary teaching school at the University of Zambia (UNZA) where students and veterinarians are exposed to many bacterial pathogens including Staphylococcus aureus (SA) and Staphylococcus pseudintermedius (SP). The aim of this study was the characterization and antimicrobial susceptibility profile of eleven SA and 48 SP isolates from the veterinary hospitals' in- and outpatients and the environment. No isolate was resistant to cefoxitin by disk diffusion test and the corresponding resistance gene mecA was not found. In contrast, the resistance rates of SA to penicillin (63.6%) and trimethoprim-sulfamethoxazole (36.4%) and SP to penicillin (52.1%) and tetracycline (25.0%) were the highest. A variety of sequence types (STs) without a predominant type including numerous novel types were determined, especially for SP (39.6%). The spa typing provided a clonal assignment for all SAs (100%) and 24 SPs (50%) with three and two novel types, respectively. This study has provided an overview of SA and SP in the veterinary teaching hospital at UNZA. However, for a better understanding of these species regarding pathogenesis and transmission, further studies on the prevalence and characterization of SA and SP from veterinary staff, pet owners, and farm animals in Zambia is needed. PMID- 24480624 TI - p300 acetyltransferase regulates androgen receptor degradation and PTEN-deficient prostate tumorigenesis. AB - Overexpression of the histone acetyltransferase p300 is implicated in the proliferation and progression of prostate cancer, but evidence of a causal role is lacking. In this study, we provide genetic evidence that this generic transcriptional coactivator functions as a positive modifier of prostate tumorigenesis. In a mouse model of PTEN deletion-induced prostate cancer, genetic ablation of p300 attenuated expression of the androgen receptor (AR). This finding was confirmed in human prostate cancer cells in which PTEN expression was abolished by RNA interference-mediated attenuation. These results were consistent with clinical evidence that the expression of p300 and AR correlates positively in human prostate cancer specimens. Mechanistically, PTEN inactivation increased AR phosphorylation at serine 81 (Ser81) to promote p300 binding and acetylation of AR, thereby precluding its polyubiquitination and degradation. In support of these findings, in PTEN-deficient prostate cancer in the mouse, we found that p300 was crucial for AR target gene expression. Taken together, our work identifies p300 as a molecular determinant of AR degradation and highlights p300 as a candidate target to manage prostate cancer, especially in cases marked by PTEN loss. PMID- 24480626 TI - Sitting bodily configuration: a study investigating the intra-tester reliability of positioning subjects into a predetermined sitting posture. AB - Sitting posture predominates in lifestyle and workplace, but quantitative postural designation is limited due to divergence of methodology used in the studies. To date, no study has investigated the upper body's habitual or a predetermined sitting posture in healthy individuals assessing together pelvis, spine and head. The objectives were (i) assessment of intra-rater reliability of positioning subjects to a lordotic sitting posture and (ii) comparison of habitual sitting posture (HSP) with the lordotic posture. Another objective was to synthesize and propose an improved 3D model for pelvis, trunk and head to assess quantitatively the postural sagittal configuration. A single session test retest design was employed. After power calculations 25 subjects were recruited. A repeated measure ANOVA revealed significant differences between HSP and the predetermined posture used in the study. Intra-rater reliability was analysed used the intra-class correlation coefficient (ICC) and also standard error of measurement (SEM) and smallest real difference (SRD) were calculated. The ICC values for all angles ranged from 0.85 to 0.98 indicating almost perfect agreement. The SEMs for all angles ranged in degrees from 0.65 to 1.50 and the SRDs from 1.80 to 4.16. This study provides the most specific sagittal measurement of surface spinal curves, head and pelvis position, in reference to a lordotic seated posture. The clinical significance of this study is reinforced by the fact that postural assessment is conducted by body surface evaluation. The results regarding reliability and SEMs established that healthy individuals can be reliably positioned in an upright lordotic sitting posture. PMID- 24480625 TI - Identification of immune factors regulating antitumor immunity using polymeric vaccines with multiple adjuvants. AB - The innate cellular and molecular components required to mediate effective vaccination against weak tumor-associated antigens remain unclear. In this study, we used polymeric cancer vaccines incorporating different classes of adjuvants to induce tumor protection, to identify dendritic cell (DC) subsets and cytokines critical to this efficacy. Three-dimensional, porous polymer matrices loaded with tumor lysates and presenting distinct combinations of granulocyte macrophage colony-stimulating factor (GM-CSF) and various Toll-like receptor (TLR) agonists affected 70% to 90% prophylactic tumor protection in B16-F10 melanoma models. In aggressive, therapeutic B16 models, the vaccine systems incorporating GM-CSF in combination with P(I:C) or CpG-ODN induced the complete regression of solid tumors (<=40 mm(2)), resulting in 33% long-term survival. Regression analysis revealed that the numbers of vaccine-resident CD8(+) DCs, plasmacytoid DCs (pDC), along with local interleukin (IL)-12, and granulocyte colony-stimulating factor (G-CSF) concentrations correlated strongly to vaccine efficacy regardless of adjuvant type. Furthermore, vaccine studies in Batf3(-/-) mice revealed that CD8(+) DCs are required to affect tumor protection, as vaccines in these mice were deficient in cytotoxic T lymphocytes priming and IL-12 induction in comparison with wild-type. These studies broadly demonstrate that three dimensional polymeric vaccines provide a potent platform for prophylactic and therapeutic protection, and can be used as a tool to identify critical components of a desired immune response. Specifically, these results suggest that CD8(+) DCs, pDCs, IL-12, and G-CSF play important roles in priming effective antitumor responses with these vaccines. PMID- 24480628 TI - Parental choice: exploring in-law preferences and their contingencies in the Greek-Cypriot culture. AB - Despite the fact that parents exercise considerable influence over their children's choice of a mate, little is known of their preferences for daughters- and sons-in-law, particularly in a post-industrial context. This research aims to close the gap in our knowledge by making a taxonomic contribution on the qualities desired in an in-law. In particular, parents have rated the desirability of 88 traits in a prospective daughter-in-law and a son-in-law; using principal components analysis, these traits have been classified into 11 broader in-law preferences. On the basis of this classification, four hypotheses were tested: First, parents ascribe different weights to different traits; second, parental preferences are contingent upon the sex of the in-law (i.e., certain traits are valued differently in a son- and in a daughter-in-law); third, parents have a preference for assortative mating (i.e., they want their prospective in-laws and their families to be similar to them); and fourth, in-law preferences are independent of the sex of the parent (i.e., mothers and fathers are in agreement with respect to what qualities they seek in a spouse for their children). The results from two independent studies provide support for the first three hypotheses, but little support for the fourth hypothesis. PMID- 24480627 TI - Association of 25-hydroxyvitamin D and parathyroid hormone with incident hypertension: MESA (Multi-Ethnic Study of Atherosclerosis). AB - OBJECTIVES: This study investigated whether lower 25-hydroxyvitamin D and higher parathyroid hormone concentrations are associated with incident hypertension. BACKGROUND: Disturbances in vitamin D metabolism are plausibly related to hypertension. METHODS: MESA (Multi-Ethnic Study of Atherosclerosis) is a community-based, prospective cohort with baseline measurements obtained between 2000 and 2002. We studied 3,002 men and women free of prevalent cardiovascular disease and hypertension, age 45 to 84 years at baseline. Serum 25-hydroxyvitamin D and intact parathyroid hormone were measured from previously frozen baseline samples using liquid chromatography-mass spectroscopy and a 2-site immunoassay, respectively. We used a complementary log-log model with interval censoring to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for 25 hydroxyvitamin D and parathyroid hormone concentrations with incident hypertension through 2010. RESULTS: During a median follow-up of 9.0 years, 41% of the cohort (n = 1,229) developed hypertension. Mean serum 25-hydroxyvitamin D was 26.3 +/- 11.2 ng/ml and mean parathyroid hormone was 41.2 +/- 17.3 pg/ml. Compared with 25-hydroxyvitamin D >=30 ng/ml, 25-hydroxyvitamin D <20 ng/ml was associated with a greater hypertension risk (HR: 1.28 [95% CI: 1.09 to 1.50]), although the association was attenuated and not statistically significant after adjusting for potential confounders (HR: 1.13 [95% CI: 0.96 to 1.33]). Compared with parathyroid hormone <33 pg/ml, parathyroid hormone >=65 pg/ml was associated with a significantly greater risk of hypertension (HR: 1.27 [95% CI: 1.01 to 1.59]) after adjusting for potential confounders. CONCLUSIONS: Lower 25 hydroxyvitamin D concentrations were not associated with a greater risk of incident hypertension. Higher serum parathyroid hormone concentrations showed a significant, but statistically marginal, relationship to the development of hypertension. These findings will require further confirmation. (Multi-Ethnic Study of Atherosclerosis; NCT00005487). PMID- 24480629 TI - Arthroscopic treatment of tibial spine fracture in children with a cannulated Herbert screw. AB - BACKGROUND: Avulsion fractures of the anterior tibial intercondylar eminence in childhood are rare and are severe injuries of the knee. Since the injury is equivalent in aetiology with ruptures of the anterior cruciate ligament, the treatment requires anatomic reduction and preservation of the stability of the joint. The aim of the study was to demonstrate our experiences with the arthroscopy-guided Herbert-screw fixation in the treatment of displaced tibial eminence fractures in children. METHODS: Between January 2004 and December 2011, a total of eight children were treated surgically with Type II or Type III anterior tibial eminence fractures; another four children with undisplaced, Type I fractures were treated conservatively, applying with cast fixation for 6 weeks. Radiological consolidation, stability and functional outcome were assessed during the follow-up examinations. RESULTS: On the 12th postoperative week, we did not find instability in any of the patients by physical examination. There were only minimal differences found in the functional outcome, comparing the conservatively and operatively treated groups (Lysholm functional scale, average scores: Type I: 97, Type II: 95 and Type III: 94 points). The range of motion (ROM) of the injured knees was identical with healthy sides on the postoperative 6th week. CONCLUSIONS: Our results indicate that the presented method can successfully be applied in the treatment of displaced tibial spine fractures; providing excellent stability and preserving the function of the injured knee in the short-term. PMID- 24480630 TI - On the utilization of hydrological modelling for road drainage design under climate and land use change. AB - Road drainage structures are often designed using methods that do not consider process-based representations of a landscape's hydrological response. This may create inadequately sized structures as coupled land cover and climate changes can lead to an amplified hydrological response. This study aims to quantify potential increases of runoff in response to future extreme rain events in a 61 km(2) catchment (40% forested) in southwest Sweden using a physically-based hydrological modelling approach. We simulate peak discharge and water level (stage) at two types of pipe bridges and one culvert, both of which are commonly used at Swedish road/stream intersections, under combined forest clear-cutting and future climate scenarios for 2050 and 2100. The frequency of changes in peak flow and water level varies with time (seasonality) and storm size. These changes indicate that the magnitude of peak flow and the runoff response are highly correlated to season rather than storm size. In all scenarios considered, the dimensions of the current culvert are insufficient to handle the increase in water level estimated using a physically-based modelling approach. It also appears that the water level at the pipe bridges changes differently depending on the size and timing of the storm events. The findings of the present study and the approach put forward should be considered when planning investigations on and maintenance for areas at risk of high water flows. In addition, the research highlights the utility of physically-based hydrological models to identify the appropriateness of road drainage structure dimensioning. PMID- 24480631 TI - Factors associated with the adoption of a patient education intervention among first responders, King County, Washington, 2010-2011. AB - INTRODUCTION: This study investigated facilitators and barriers to adoption of an at-scene patient education program by firefighter emergency medical technicians (EMTs) in King County, Washington. METHODS: We consulted providers of emergency medical services (EMS) to develop a patient education pamphlet in the form of a tear-off sheet that could be attached to the EMT medical incident report. The pamphlet included resources for at-scene patient education on high blood pressure, blood glucose, falls, and social services. The program was launched in 29 fire departments in King County, Washington, on January 1, 2010, and a formal evaluation was conducted in late 2011. We developed a survey based on diffusion theory to assess 1) awareness of the pamphlet, 2) evaluation of the pamphlet attributes, 3) encouragement by peers and superiors for handing out the pamphlet, 4) perceived behavioral norms, and 5) demographic variables associated with self reported adoption of the at-scene patient education program. The survey was completed by 822 (40.1%) of 2,047 firefighter emergency medical technicians. We conducted bivariate and multivariable analyses to assess associations between independent variables and self-reported adoption of the program. RESULTS: Adoption of the at-scene patient education intervention was significantly associated with positive evaluation of the pamphlet, encouragement from peers and superiors, and perceived behavioral norms. EMS providers reported they were most likely to hand out the pamphlet to patients in private residences who were treated and left at the scene. CONCLUSION: Attributes of chronic disease prevention programs and encouragement from peers and supervisors are necessary in diffusion of patient education interventions in the prehospital care setting. PMID- 24480632 TI - Disability status as an antecedent to chronic conditions: National Health Interview Survey, 2006-2012. AB - INTRODUCTION: A strong relationship exists between disability and poor health. This relationship could exist as a result of disabilities emerging from chronic conditions; conversely, people with disabilities may be at increased risk of developing chronic conditions. Studying health in relation to age of disability onset can illuminate the extent to which disability may be a risk factor for future poor health. METHODS: We used data from the 2006-2012 National Health Interview Survey and conducted weighted logistic regression analyses to compare chronic conditions in adults with lifelong disabilities (n = 2,619) and adults with no limitations (n = 122,395). RESULTS: After adjusting for sociodemographic differences, adults with lifelong disabilities had increased odds of having the following chronic conditions compared with adults with no limitations: coronary heart disease (adjusted odds ratio [AOR] = 2.92; 95% confidence interval [CI], 2.33-3.66) cancer (AOR = 1.61; 95% CI, 1.34-1.94), diabetes (AOR = 2.57; 95% CI, 2.10-3.15), obesity (AOR = 1.81; 95% CI, 1.63-2.01), and hypertension (AOR = 2.18; 95% CI, 1.94-2.45). Subpopulations of people with lifelong disabilities (ie, physical, mental, intellectual/developmental, and sensory) experienced similar increased odds for chronic conditions compared with people with no limitations. CONCLUSION: Adults with lifelong disabilities were more likely to have chronic conditions than adults with no limitations, indicating that disability likely increases risk of developing poor health. This distinction is critical in understanding how to prevent health risks for people with disabilities. Health promotion efforts that target people living with a disability are needed. PMID- 24480633 TI - Public support for smoke-free air strategies among smokers and nonsmokers, New York City, 2010-2012. AB - INTRODUCTION: From 2010 through 2012, the New York City Department of Health and Mental Hygiene engaged in multiple smoke-free-air activities in collaboration with community, institution, and government partners. These included implementing a law prohibiting smoking in all parks and beaches as well as working to increase compliance with existing Smoke-free Air Act provisions. METHODS: We investigated trends in awareness of existing smoke-free rules publicized with new signage and public support for new smoke-free air strategies by using 3 waves of survey data from population-based samples of smoking and nonsmoking adults in New York City (2010-2012). Analyses adjusted for the influence of sociodemographic characteristics. RESULTS: Among both smokers and nonsmokers, we observed increased awareness of smoke-free regulations in outdoor areas around hospital entrances and grounds and in lines in outdoor waiting areas for buses and taxis. Regardless of smoking status, women, racial/ethnic minorities, and adults aged 25 to 44 years were more likely than men, non-Hispanic whites, and adults aged 65 years or older to support smoke-free air strategies. CONCLUSION: New signage was successful in increasing population-wide awareness of rules. Our analysis of the association between demographic characteristics and support for tobacco control over time provide important contextual information for community education efforts on secondhand smoke and smoke-free air strategies. PMID- 24480634 TI - Estrogen-regulated transcription of the uteroglobin gene from the brown hare (Lepus capensis). AB - To get further insights on the estrogen regulation of the uteroglobin (UG) gene, the 5'-flanking region of the UG gene from the brown hare (Lepus capensis) (Lc) was cloned and compared with those from two phylogenetically related species: the rabbit (Orictolagus cuniculus) (Oc) and the volcano rabbit (Romerolagus diazi) (Rd). The Lc-UG gene is very similar to those from rabbits (94%) and volcano rabbits (95%), and shares a number of genetic elements, including an estrogen response element (ERE). The estrogen-regulated transcription of a series of progressive 5'-deletion mutants of the Lc-UG gene, identified a functional ERE in the promoter region exhibiting the same orientation and relative position than that previously described in rabbits. The Lc-ERE is identical to the Oc-ERE, but different from both the Rd-ERE and the consensus ERE (c-ERE) by one nucleotide. We also detected important species-specific differences in the estrogen-regulated transcription of the UG gene. A luciferase reporter driven by 333 base pairs (bp) of the Lc-UG promoter elicited a higher response to estradiol than its related counterparts when expressed in estrogen-sensitive MCF-7 cells. Several ERE-like motifs which failed to act as functional EREs were also identified; one of them exhibited two mismatches in its palindromic sequence, a characteristic exhibited in many other natural occurring EREs, including the Rd-ERE. PMID- 24480635 TI - The essence of insect metamorphosis and aging: electrical rewiring of cells driven by the principles of juvenile hormone-dependent Ca(2+)-homeostasis. AB - In holometabolous insects the fall to zero of the titer of Juvenile Hormone ends its still poorly understood "status quo" mode of action in larvae. Concurrently it initiates metamorphosis of which the programmed cell death of all internal tissues that actively secrete proteins, such as the fat body, midgut, salivary glands, prothoracic glands, etc. is the most drastic aspect. These tissues have a very well developed rough endoplasmic reticulum, a known storage site of intracellular Ca(2+). A persistent high [Ca(2+)]i is toxic, lethal and causal to apoptosis. Metamorphosis becomes a logical phenomenon if analyzed from: (1) the causal link between calcium toxicity and apoptosis; (2) the largely overlooked fact that at least some isoforms of Ca(2+)-ATPases have a binding site for farnesol-like endogenous sesquiterpenoids (FRS). The Ca(2+)-ATPase blocker thapsigargin, like JH a sesquiterpenoid derivative, illustrates how absence of JH might work. The Ca(2+)-homeostasis system is concurrently extremely well conserved in evolution and highly variable, enabling tissue-, developmental-, and species specificity. As long as JH succeeds in keeping [Ca(2+)]i low by keeping the Ca(2+)-ATPases pumping, it acts as "the status quo" hormone. When it disappears, its various inhibitory effects are lifted. The electrical wiring system of cells, in particular in the regenerating tissues, is subject to change during metamorphosis. The possibility is discussed that in vertebrates an endogenous farnesol-like sesquiterpenoid, probably farnesol itself, acts as a functional, but hitherto completely overlooked Juvenile anti-aging "Inbrome", a novel concept in signaling. PMID- 24480636 TI - Clinical and economic outcomes in medication-adherent and -nonadherent patients with type 2 diabetes mellitus in the Republic of Korea. AB - BACKGROUND: The prevalence and social burden of type 2 diabetes mellitus (T2DM) is increasing. Medication adherence is necessary for positive outcomes in patients with T2DM. OBJECTIVE: This study evaluated the association between medication adherence and clinical/economic outcomes in patients with T2DM in the Republic of Korea over a 3-year period. METHODS: This study used data from the Korean National Diabetes Program at 5 hospitals. Medication possession ratios of >=90% and <90% were used to define adherent and nonadherent groups, respectively. The degree of glycemic control, changes in blood pressure and lipid profiles, and health care costs were compared. RESULTS: Of the 608 patients, 472 were medication adherent and 136 were nonadherent. The adherent patients displayed improved fasting blood glucose and hemoglobin A1c during the study. Diastolic blood pressure and total cholesterol were lower at 36 months, and lower low density lipoprotein cholesterol was noted at baseline and 24 months. The total health care costs were $1861, $2060, and $1924, respectively, versus $1617, $1751, and $1602 during the 3-year study period for the adherent group versus the nonadherent group, respectively (P = 0.316, 0.627, and 0.172, respectively), whereas the outpatient drug costs were $1143, $1176, and $1162 in the adherent group versus $925, $778, and $914 in the nonadherent group (P = 0.002, P < 0.001, and P = 0.001). CONCLUSIONS: The adherent patients displayed better glycemic control and lipid profiles. Medication-related expenses were higher in the adherent group, but overall health care costs, including hospitalization costs, were similar between the 2 groups. PMID- 24480637 TI - Pharmacokinetics of pilsicainide hydrochloride for injection in healthy Chinese volunteers: a randomized, parallel-group, open-label, single-dose study. AB - BACKGROUND: Pilsicainide hydrochloride is a class IC antiarrhythmic agent used for the treatment of supraventricular and ventricular arrhythmias and atrial fibrillation. OBJECTIVE: The objective of the present study was to determine the pharmacokinetics (PK) of a pilsicainide hydrochloride injection in healthy Chinese adults. The study was conducted to meet China State Food and Drug Administration requirements for the marketing of the new generic formulation of pilsicainide hydrochloride. METHODS: This Phase I, randomized, parallel-group, open-label, single-dose PK study was conducted in healthy Chinese volunteers. Subjects were randomized to receive a single dose of 0.25-, 0.50-, and 0.75-mg/kg pilsicainide hydrochloride with a 10-minute intravenous infusion. Serial blood and urine samples were collected up to 24 hours after dosing; drug concentrations in plasma and urine were then determined by using LC-MS/MS. The PK parameters of pilsicainide were calculated from the plasma concentration-time data according to noncompartmental methods. Safety profile was evaluated by monitoring adverse events, clinical laboratory parameters, and the results of 12-lead ECGs. RESULTS: Thirty healthy volunteers (mean [SD] age, 28.0 [4.95] years; weight, 59.3 [6.51] kg; height, 165.0 [7.25] cm; body mass index, 21.7 [1.94] kg/m(2)) were randomly divided into 3 groups, each consisting of 5 men and 5 women. After single-dose intravenous administration of 0.25, 0.50, and 0.75 mg/kg of pilsicainide hydrochloride, mean Cmax was 0.34 (0.11), 0.54 (0.15), and 1.05 (0.19) MUg/mL, respectively; AUC0-24 was 0.76 (0.12), 1.61 (0.37), and 2.61 (0.46) h . MUg/mL; and AUC0-infinity was 0.79 (0.13), 1.71 (0.46), and 2.72 (0.50) h . MUg/mL. The ranges for t1/2z, CL, and Vz were 5.19 to 5.98 hours, 4.73 to 5.44 mL/min/kg, and 2.23 to 0.58 L/kg, respectively. The mean urinary recovery rate within 24 hours was 75.0% (12.0%), 65.0% (19.2%), and 66.4% (14.1%). Men and women had significantly different AUC0-24 values in the 0.50-mg/kg dose group (P = 0.044), and Vz showed significant differences between men and women in all 3 dose groups (P = 0.001). According to ECG parameters, PR intervals were significantly prolonged after administration at all 3 doses (P = 0.034, P < 0.001, and P = 0.034); no significant changes were seen in QRS width, QTc interval, or other parameters. CONCLUSIONS: Pilsicainide hydrochloride demonstrated linear PK, and the increase in the exposure of pilsicainide (AUC0-24 and AUC0-infinity) was dose proportional after single doses of 0.25, 0.50, and 0.75 mg/kg. All 3 pilsicainide hydrochloride doses were well tolerated in these Chinese volunteers. ChiCTR-ONC 13003546. PMID- 24480638 TI - Linear control of the flywheel inverted pendulum. AB - The flywheel inverted pendulum is an underactuated mechanical system with a nonlinear model but admitting a linear approximation around the unstable equilibrium point in the upper position. Although underactuated systems usually require nonlinear controllers, the easy tuning and understanding of linear controllers make them more attractive for designers and final users. In a recent paper, a simple PID controller was proposed by the authors, leading to an internally unstable controlled plant. To achieve global stability, two options are developed here: first by introducing an internal stabilizing controller and second by replacing the PID controller by an observer-based state feedback control. Simulation and experimental results show the effectiveness of the design. PMID- 24480639 TI - An expanding world of small RNAs. AB - In ciliated protozoans, small RNAs (sRNAs) are integral to guiding large-scale genomic rearrangements after mating. Sandoval et al. (2014) report in this issue of Developmental Cell the discovery of a class of Paramecium sRNAs, produced by a unique Dicer-like enzyme, that likely provides late stage quality control in this process. PMID- 24480640 TI - Cyclin C: an inducer of mitochondrial division hidden in the nucleus. AB - In response to cellular stress, mitochondria remodel their structure by organelle division and fusion. In this issue of Developmental Cell, Cooper et al. (2014) report that a nuclear protein, cyclin C, is recruited from nuclei to mitochondria upon oxidative stress and promotes mitochondrial division and apoptosis of the cell. PMID- 24480641 TI - Fully interlocking: a story of teamwork among breast epithelial cells. AB - In this issue of Developmental Cell, Forster et al. (2014) show that the basal myoepithelial cell layer directs the final maturation of the adjacent luminal cell sheet during pregnancy. Do all mammary epithelial cells both give and take instructions from others to create the milk production machinery? PMID- 24480642 TI - Auxin-callose-mediated plasmodesmal gating is essential for tropic auxin gradient formation and signaling. AB - In plants, auxin functions as a master controller of development, pattern formation, morphogenesis, and tropic responses. A sophisticated transport system has evolved to allow the establishment of precise spatiotemporal auxin gradients that regulate specific developmental programs. A critical unresolved question relates to how these gradients can be maintained in the presence of open plasmodesmata that allow for symplasmic exchange of essential nutrients and signaling macromolecules. Here we addressed this conundrum using genetic, physiological, and cell biological approaches and identified the operation of an auxin-GSL8 feedback circuit that regulates the level of plasmodesmal-localized callose in order to locally downregulate symplasmic permeability during hypocotyl tropic response. This system likely involves a plasmodesmal switch that would prevent the dissipation of a forming gradient by auxin diffusion through the symplasm. This regulatory system may represent a mechanism by which auxin could also regulate symplasmic delivery of a wide range of signaling agents. PMID- 24480643 TI - The Hox gene Abd-B controls stem cell niche function in the Drosophila testis. AB - Proper niche architecture is critical for stem cell function, yet only few upstream regulators are known. Here, we report that the Hox transcription factor Abdominal-B (Abd-B), active in premeiotic spermatocytes of Drosophila testes, is essential for positioning the niche to the testis anterior by regulating integrin in neighboring somatic cyst cells. Abd-B also non-cell-autonomously controls critical features within the niche, including centrosome orientation and division rates of germline stem cells. By using genome-wide binding studies, we find that Abd-B mediates its effects on integrin localization by directly controlling at multiple levels the signaling activity of the Sev ligand Boss via its direct targets src42A and sec63, two genes involved in protein trafficking and recycling. Our data show that Abd-B, through local signaling between adjucent cell types, provides positional cues for integrin localization, which is critical for placement of the distant stem cell niche and stem cell activity. PMID- 24480646 TI - Improving the coding and classification of ambulance data through the application of International Classification of Disease 10th revision. AB - OBJECTIVES: This paper aims to examine whether an adaptation of the International Classification of Disease (ICD) coding system can be applied retrospectively to final paramedic assessment data in an ambulance dataset with a view to developing more fine-grained, clinically relevant case definitions than are available through point-of-call data. METHODS: Over 1.2 million case records were extracted from the Ambulance Victoria data warehouse. Data fields included dispatch code, cause (CN) and final primary assessment (FPA). Each FPA was converted to an ICD 10-AM code using word matching or best fit. ICD-10-AM codes were then converted into Major Diagnostic Categories (MDC). CN was aligned with the ICD-10-AM codes for external cause of morbidity and mortality. RESULTS: The most accurate results were obtained when ICD-10-AM codes were assigned using information from both FPA and CN. Comparison of cases coded as unconscious at point-of-call with the associated paramedic assessment highlighted the extra clinical detail obtained when paramedic assessment data are used. CONCLUSIONS: Ambulance paramedic assessment data can be aligned with ICD-10-AM and MDC with relative ease, allowing retrospective coding of large datasets. Coding of ambulance data using ICD-10-AM allows for comparison of not only ambulance service users but also with other population groups. WHAT IS KNOWN ABOUT THE TOPIC? There is no reliable and standard coding and categorising system for paramedic assessment data contained in ambulance service databases. WHAT DOES THIS PAPER ADD? This study demonstrates that ambulance paramedic assessment data can be aligned with ICD-10-AM and MDC with relative ease, allowing retrospective coding of large datasets. Representation of ambulance case types using ICD-10-AM-coded information obtained after paramedic assessment is more fine grained and clinically relevant than point-of-call data, which uses caller information before ambulance attendance. WHAT ARE THE IMPLICATIONS FOR PRACTITIONERS? This paper describes a model of coding using an internationally recognised standard coding and categorising system to support analysis of paramedic assessment. Ambulance data coded using ICD-10-AM allows for reliable reporting and comparison within the prehospital setting and across the healthcare industry. PMID- 24480644 TI - TALE factors poise promoters for activation by Hox proteins. AB - Hox proteins form complexes with TALE cofactors from the Pbx and Prep/Meis families to control transcription, but it remains unclear how Hox:TALE complexes function. Examining a Hoxb1b:TALE complex that regulates zebrafish hoxb1a transcription, we find maternally deposited TALE proteins at the hoxb1a promoter already during blastula stages. These TALE factors recruit histone-modifying enzymes to promote an active chromatin profile at the hoxb1a promoter and also recruit RNA polymerase II (RNAPII) and P-TEFb. However, in the presence of TALE factors, RNAPII remains phosphorylated on serine 5 and hoxb1a transcription is inefficient. By gastrula stages, Hoxb1b binds together with TALE factors to the hoxb1a promoter. This triggers P-TEFb-mediated transitioning of RNAPII to the serine 2-phosphorylated form and efficient hoxb1a transcription. We conclude that TALE factors access promoters during early embryogenesis to poise them for activation but that Hox proteins are required to trigger efficient transcription. PMID- 24480645 TI - Membrane shape modulates transmembrane protein distribution. AB - Although membrane shape varies greatly throughout the cell, the contribution of membrane curvature to transmembrane protein targeting is unknown because of the numerous sorting mechanisms that take place concurrently in cells. To isolate the effect of membrane shape, we used cell-sized giant unilamellar vesicles (GUVs) containing either the potassium channel KvAP or the water channel AQP0 to form membrane nanotubes with controlled radii. Whereas the AQP0 concentrations in flat and curved membranes were indistinguishable, KvAP was enriched in the tubes, with greater enrichment in more highly curved membranes. Fluorescence recovery after photobleaching measurements showed that both proteins could freely diffuse through the neck between the tube and GUV, and the effect of each protein on membrane shape and stiffness was characterized using a thermodynamic sorting model. This study establishes the importance of membrane shape for targeting transmembrane proteins and provides a method for determining the effective shape and flexibility of membrane proteins. PMID- 24480647 TI - Robust gene signatures from microarray data using genetic algorithms enriched with biological pathway keywords. AB - Genetic algorithms are widely used in the estimation of expression profiles from microarrays data. However, these techniques are unable to produce stable and robust solutions suitable to use in clinical and biomedical studies. This paper presents a novel two-stage evolutionary strategy for gene feature selection combining the genetic algorithm with biological information extracted from the KEGG database. A comparative study is carried out over public data from three different types of cancer (leukemia, lung cancer and prostate cancer). Even though the analyses only use features having KEGG information, the results demonstrate that this two-stage evolutionary strategy increased the consistency, robustness and accuracy of a blind discrimination among relapsed and healthy individuals. Therefore, this approach could facilitate the definition of gene signatures for the clinical prognosis and diagnostic of cancer diseases in a near future. Additionally, it could also be used for biological knowledge discovery about the studied disease. PMID- 24480648 TI - Biomedical image segmentation using geometric deformable models and metaheuristics. AB - This paper describes a hybrid level set approach for medical image segmentation. This new geometric deformable model combines region- and edge-based information with the prior shape knowledge introduced using deformable registration. Our proposal consists of two phases: training and test. The former implies the learning of the level set parameters by means of a Genetic Algorithm, while the latter is the proper segmentation, where another metaheuristic, in this case Scatter Search, derives the shape prior. In an experimental comparison, this approach has shown a better performance than a number of state-of-the-art methods when segmenting anatomical structures from different biomedical image modalities. PMID- 24480649 TI - Cough after laryngeal herpes zoster: a new aspect of post-herpetic sensory disturbance. AB - OBJECTIVE: Although neurogenic cough is increasingly recognised, its pathophysiology remains obscure. We describe two cases of chronic cough following laryngeal herpes zoster, a rarely described manifestation of varicella-zoster virus reactivation, and suggest that this may be analogous to post-herpetic neuralgia. The same mechanisms may cause both phenomena. CASE REPORTS: We describe two cases of chronic cough persisting for more than three months following an acute attack of laryngeal herpes zoster. CONCLUSION: Neuronal damage by varicella-zoster virus results in irritable nociceptors and deafferentation, mechanisms known to cause post-herpetic neuralgia. When the vagus nerve is affected, as in laryngeal herpes zoster, the result may be a chronic cough. Similar damage may underlie chronic neurogenic cough in other contexts. PMID- 24480650 TI - Modification of the superior gluteal artery perforator flap for reconstruction of sacral sores. AB - BACKGROUND: Despite advances in reconstruction techniques, the treatment of sacral sores remains challenging to plastic surgeons. The superior gluteal artery perforator (SGAP) flap is reliable and preserves the entire contralateral side as a future donor site. The ipsilateral gluteal muscle is preserved, and the inferior gluteal artery flaps are viable. However, dissection of the perforator is tedious and may compromise the perforator vessels. METHODS: Between April 2003 and March 2013, we performed two modified flap-harvesting techniques: a rotational and a tunnel method, with only a short pedicle dissection to cover 30 sacral defects. Patient characteristics including sex, age, cause of sacral defect, flap size, perforator number, use and postoperative complications were recorded. RESULTS: All flaps survived except two, which developed partial flap necrosis and were finally treated by contralateral V-Y advancement flap coverage. The mean follow-up period was 14.8 months (range, 3-24 months). No flap surgery related mortality or recurrence of sacral pressure sores or infected pilonidal cysts were noted. CONCLUSIONS: Perforator-based flaps have become popular in modern reconstructive surgery because of low donor-site morbidity and good preservation of muscle. The advantages of our modification procedure include shorter operative time, lesser bleeding and lesser pedicle trauma, which make the SGAP flaps an excellent choice for sacral sore coverage. PMID- 24480651 TI - Suitable therapy options for sub-clinical and early-stage lymphoedema patients. AB - BACKGROUND: The best therapeutic approach for patients with sub-clinical lymphoedema and symptomatic early-stage lymphoedema has not been determined yet. METHODS: The prognosis of lymphatic function after lymphadenectomy for gynaecological cancer was observed in a cohort study of 192 lower limbs. Lymphatic function was evaluated by indocyanine green lymphography. Splash patterns were examined to determine if patients with this pattern tended to progress to symptomatic lymphoedema, and the efficacy of the compression therapy was also investigated. We also investigated the efficacy of lymphaticovenular anastomosis (LVA) in patients who exhibited a stardust pattern. RESULTS: Patients with splash patterns on lymphography may progress to symptomatic lymphoedema with a significantly higher frequency compared with the others, with a relative ratio of 1.62. Compression therapy did not slow the progression of patients with splash patterns to stardust patterns. LVA for the patients who had recently shown stardust patterns eliminated the need for compression therapy in 44.8% of patients. CONCLUSION: Patients with splash patterns should be followed up carefully for sub-clinical lymphoedema. However, there is no method to completely prevent these patients from developing stardust patterns associated with symptomatic lymphoedema. When patients become symptomatic, their lymphatic function may be improved by LVA. However, the limited effectiveness of this procedure should be clearly explained to patients before surgery. PMID- 24480652 TI - Response to 'The trap door flap: a reliable, reproducible method of anterior pinna reconstruction'. PMID- 24480653 TI - Synthesis of 2-arylbenzothiazole derivatives and their application in bacterial detection. AB - A series of 2-arylbenzothiazole derivatives have been prepared as fluorogenic enzyme substrates in order to detect aminopeptidase, esterase, phosphatase and beta-galactosidase activity in clinically important Gram-negative and Gram positive bacteria. Substrates were incorporated into an agar-based culture medium and this allowed growth of intensely fluorescent bacterial colonies based on hydrolysis by specific enzymes. Substrate 20 targeted L-alanine aminopeptidase activity and was hydrolysed exclusively by a range of Gram-negative bacteria and inhibited the growth of a range of Gram-positive bacteria. Substrate 19a targeted beta-alanyl aminopeptidase activity and generated fluorescent colonies of selected Gram-negative species including Pseudomonas aeruginosa. Substrate 21b targeted C8-esterase activity and resulted in strongly fluorescent colonies of selected species known to harbour such enzyme activity (e.g., Salmonella and Pseudomonas). Most Gram-negative species produced colonies with an intense blue fluorescence due to hydrolysis of phosphatase substrates 24a-c and substrate 24c was also hydrolysed by strains of Staphylococcus aureus. Compounds 26b and 26c targeted beta-galactosidase activity and generated strongly fluorescent colonies with coliform bacteria that produced this enzyme (e.g., Escherichia coli). PMID- 24480654 TI - The podocyte under stress: AKT2 to the rescue. PMID- 24480655 TI - Is there a role for detection of complement-binding antibodies in kidney transplantation? PMID- 24480656 TI - Survivorship care plans: necessary but not sufficient? PMID- 24480657 TI - Navigating the seasons of survivorship in community oncology. AB - Nurses have an important role in the development, implementation, and evaluation of cancer survivorship programs. Growing numbers of cancer survivors challenge community oncology practices to incorporate survivorship care according to new standards and guidelines. In response, one community-based oncology clinic created an advanced practice nurse (APN)-led survivorship program using the concept of Seasons of Survival as a guide. Survivorship care, when based on a more expansive definition of survivorship as beginning at the time of diagnosis, encompasses holistic nursing and multidisciplinary care. The APN assesses each patient's concerns and quality of life using a validated measure to tailor survivorship and supportive care. This article reviews the foundation and structure of the program in detail, describes program implementation using case studies, and outlines the program evaluation process and results. PMID- 24480658 TI - Implementing the commission on cancer standards for survivorship care plans. AB - The number of adult cancer survivors in the United States has exceeded 13 million and continues to rise, yet care for these survivors continues to be poorly coordinated and their needs remain inadequately addressed. As one solution to this growing problem, the Institute of Medicine in 2006 recommended the delivery of a survivorship care plan (SCP) to each patient completing active treatment. The American College of Surgeons Commission on Cancer subsequently published its Program Standard 3.3, requiring accredited programs to implement treatment summaries and SCPs by 2015, to help improve communication, quality, and coordination of care for cancer survivors. As practices and cancer centers around the country have undertaken SCP implementation efforts, myriad barriers to their preparation and delivery have emerged, with time and human resource burden top among these, in addition to a lack of proven outcomes. Fortunately, a growing number of publications document practical and feasible delivery models, and an increasingly robust body of research on stakeholder preferences is available to focus SCP implementation efforts. PMID- 24480659 TI - Screening and evidence-based interventions for distress in patients with cancer: nurses must lead the way. PMID- 24480660 TI - Translating research on the distress thermometer into practice. AB - Distress is commonly experienced by people with cancer. The National Comprehensive Cancer Network (NCCN) developed a guideline for screening and managing distress in 1999 and has updated the guideline on an annual basis ever since. Using the five-phase framework for translational research, this article summarizes research findings related to the guideline and associated distress thermometer for each phase of translational research. The NCCN Distress Management Guideline is a useful tool to screen for and manage distress. However, additional research is needed, particularly in the areas of impact on outcomes of importance to patients. PMID- 24480661 TI - Implementing distress management guidelines in ambulatory oncology: a quality improvement project. AB - Distress assessment and referral to psychosocial services is an essential component of evidence-based oncologic nursing care. Oncology nurses have an opportunity to address patient distress needs through leadership of implementation programs and support for the positive outcomes that engaging in psychosocial services provides. This quality improvement project was conducted to evaluate the feasibility and utility of the National Comprehensive Cancer Network's distress management clinical practice guidelines in ambulatory oncology. A theoretical framework guided the process design that included staff education, screening, and management in a cohort implementation project with historical control. PMID- 24480662 TI - Implementing the new commission on cancer standard on palliative care services. PMID- 24480663 TI - The role of the acute care nurse practitioner in the implementation of the commission on cancer's standards on palliative care. AB - As valuable members of the oncology team, acute care nurse practitioners (ACNPs) are in the perfect position to deliver high-quality palliative care. They are instrumental in coordinating the palliative care needs of their patients. Through proper training, ACNPs are able to assess, plan, implement, and evaluate palliative care interventions. Along with oncology-certified nurses, ACNPs help their patients navigate the complexities of the healthcare system. The skills that the American College of Surgeons Commission on Cancer identified in its standard for palliative care are skills possessed by ACNPs, making them the perfect fit to carry out these standards in healthcare institutions around the United States. PMID- 24480664 TI - Working together. AB - Standards released by the American College of Surgeons Commission on Cancer program in 2012 call for all patients with cancer to have access to palliative care and for institutions to provide skilled and coordinated care as patients traverse through multiple healthcare settings. Many healthcare providers do not understand what palliative care can provide, or how it differs from hospice or end-of-life care. Oncology nurses and advanced practice nurses play an important role in educating healthcare providers, patients, and families about the role of palliative care and implementing it in the care of patients with cancer. PMID- 24480665 TI - Assessing sequence and relationship of regional maturation in corpus callosum and internal capsule in preterm and term newborns by diffusion-tensor imaging. AB - BACKGROUND: Diffusion-tensor imaging (DTI) can be used to investigate water diffusion in living tissue. OBJECTIVE: To investigate sequence and relationship of regional maturation in corpus callosum (CC) and internal capsule (IC) in preterm and term. METHODS: DTI was performed on 11 preterm infants at less than 37 weeks of corrected gestational age (group I), 21 preterm infants at equivalent term (group II), 11 term infants during neonatal period (group III). Apparent diffusion coefficient (ADC) and fractional anisotropy (FA) were measured in: anterior limb of IC (ALIC), posterior limb of IC (PLIC), genu and splenium of CC. RESULTS: FA in splenium was more than that in other regions except genu of group I. Differences of FA between genu and PLIC were significant only in group III. ADC in genu was more than that in other regions but in splenium of groups I and II. Differences of ADC between splenium and ALIC were insignificant except group II. Higher FA and lower ADC in PLIC were gotten compared with those in ALIC. Correlations of FA and of ADC existed in CC and IC. CONCLUSION: Maturation sequence was splenium followed by genu, then by PLIC and last by ALIC in term at neonatal period. Genu's maturation in preterm at equivalent-term was hindered. Regional maturation's correlations existed in CC and IC. PMID- 24480666 TI - A magnetic record of heavy metal pollution in the Yangtze River subaqueous delta. AB - The rapid industrial development in the Yangtze River watershed over the last several decades has drawn great attention with respect to heavy metal pollution to the Yangtze River estuary and nearby coastal areas. In this study, a 236 cm long sediment core was retrieved from the Yangtze River subaqueous delta (122 degrees 36' E, 31 degrees 00' N) in 2008 and analyzed for magnetic properties and geochemical compositions to investigate heavy metal pollution history. The activity of (137)Cs peaked at depth 140 cm, with a broad plateau between 120 cm and 140 cm, suggesting an average sedimentation rate of 3.11 cm yr(-1) for the upper 140 cm layer. Magnetic susceptibility (chi), saturation isothermal remanent magnetization (SIRM), anhysteretic remanent magnetization (chiARM) and heavy metal enrichment factors (EF) all showed an upward increase trend above depth 140 cm, suggesting that increased ferrimagnetic mineral concentration was accompanied by heavy metal enrichment in the sediment. Geochemical and granolumetric analyses showed that sediment sources and particle sizes played minor roles in the variations of magnetic properties. The effect of diagenesis, which can lead to the selective removal of magnetic minerals, was noticeable in the lower part of the core (140-236 cm). Co-variation between magnetic properties (chi, SIRM and chiARM) and EF of Cu and Pb suggests that the elevated ferrimagnetic mineral concentration can be used as an indicator of heavy metal pollution in the reconstruction of environmental changes in estuarine and coastal settings. PMID- 24480667 TI - Microwave, structural, conformational, vibrational studies and ab initio calculations of isocyanocyclopentane. AB - The infrared and Raman spectra (3200-50 cm(-1)) of the gas, liquid or solution, and solid have been recorded of isocyanocyclopentane, c-C5H9NC. FT-microwave studies have also been carried out and 23 transitions were recorded for the envelope-axial (Ax) conformer. Variable temperature (-65 to -100 degrees C) studies of the infrared spectra (3200-400 cm(-1)) dissolved in liquid xenon have been carried out. From these data, both the Ax and envelope-equatorial (Eq) conformers have been identified and their relative stabilities obtained. The enthalpy difference has been determined to be 102+/-10 cm(-1) (1.21+/-0.11 kJ mol(-1)) with the Ax conformer the more stable form. The percentage of the Eq conformer is estimated to be 38+/-1% at ambient temperature. The conformational stabilities have been predicted from ab initio calculations by utilizing several different basis sets up to aug-cc-pVTZ from both MP2(full) and density functional theory calculations by the B3LYP method. Vibrational assignments have been made for the observed bands for both conformers with initial predictions by MP2(full)/6-31G(d) ab initio calculations to obtain harmonic force constants, wavenumbers, infrared intensities, Raman activities and depolarization ratios for both conformers. The structural parameter values for the Ax form are; for the heavy atom distances (A): C=N = 1.176 (3); Calpha-N=1.432 (3); Calpha Cbeta,Cbeta'=1.534 (3); Cbeta-Cgamma,Cgamma'=1.542 (3); Cgamma-Cgamma'=1.554 (3) and angles ( degrees ):?Calpha-N=C=177.8 (5); ?CbetaCalpha-N=110.4 (5); 96% and DXA in 98%. Population DXA frequency decreased markedly after the 7th decade and was performed yearly in 1.2% of the population aged >80 years in North Denmark. The >80 years group had more fragility fractures and lower T-scores (p<0.001) compared to those below 80 years of age, and age >80 years was a dominant risk factor for fragility fracture (OR 2.4, 95% CI 2.0-2.9; p<0.001) and for having diagnosed osteoporosis by DXA (OR 2.1, 95% CI 1.7, 2.5; p<0.001). CONCLUSION: Referral for osteoporosis screening decreased after the 7th decade despite the finding that high age carried the highest risk of osteoporosis by DXA and by fragility fracture. Osteoporosis is a disease of aging, but it is apparently not recognised as such. This is likely to cause undertreatment among the old. PMID- 24480672 TI - Effect of gregarines (Apicomplexa: Sporozoa) on survival and weight loss of Victorwithius similis (Arachnida: Pseudoscorpiones). AB - Gregarines are common intestinal parasites of numerous invertebrate groups. Their effects on host viability and development have been a matter of debate. Although they may not be lethal to the host, they can be harmless commensals, by affecting adaptive traits, or have a beneficial relationship with the host. This study focused on determining prevalence, intensity, and change in infection intensity over time by septate gregarines, and monitoring the effects on survival and weight loss in the pseudoscorpion Victorwithius similis. Individuals (n=24 females, n=55 males and n=41 tritonymphs) were captured in the field, transported to the vivarium and bred under laboratory conditions. A high prevalence of infection was found, with 77.27% of females, 62.50% of males and 73.53% of tritonymphs harboring intense infections. Of the infected pseudoscorpions, 62% of females, 58% of males and 71% of tritonymphs did not show changes in infection intensity over time. The group that maintained intense infections survived longer than those with less intense infections (chi(2)=8.642; p=0.035). Most of the results obtained indicate that relationship studied between gregarines and the pseudoscorpion V. similis might be a case of commensalism. This would explain why the infection level and prevalence was very high, as well as the apparent lack of direct costs to highly infected individuals those with infections. PMID- 24480673 TI - Shell colouration and parasite tolerance in two helicoid snail species. AB - The polymorphism of shell colouration in helicoid snails is a well-known phenomenon attributed to different factors such as predation and climatic effects. Another aspect contributing to this polymorphism could be the interplay of melanin production and phenoloxidase-related immunity. Therefore, in this study we aimed at answering the questions whether there is a differential sensitivity of different snail shell colour morphs to nematode infection, and whether this can be related to differences in phenoloxidase (PO) activity levels using the two helicoid, polymorphic snail species Cepaea hortensis and Cernuella virgata. Snails of both species were artificially infected with the parasitic nematode Phasmarhabditis hermaphrodita, and analysed for mortality and PO activity levels. We found C. virgata to be more severely affected by P. hermaphrodita infection than C. hortensis, and the dark C. virgata morphs to be more resistant to lethal effects of this infection than pale morphs. However, these differences in sensitivity to the parasite could not clearly be related to different PO activity levels. PMID- 24480674 TI - Abstracts - VIII Congress of the WFITN - Venice, Italy - 19-22 October, 2005. PMID- 24480676 TI - The end of hepatitis C. PMID- 24480675 TI - Significantly higher rates of gastrointestinal bleeding and thromboembolic events with left ventricular assist devices. AB - BACKGROUND & AIMS: The risk of gastrointestinal (GI) bleeding (GIB) and thromboembolic events may increase with continuous-flow left ventricular assist devices (CF-LVADs). We aimed to characterize GIB and thromboembolic events that occurred in patients with CF-LVADs and compare them with patients receiving anticoagulation therapy. METHODS: We performed a retrospective analysis of 159 patients who underwent CF-LVAD placement at 2 large academic medical centers (mean age, 55 +/- 13 y). We identified and characterized episodes of GIB and thromboembolic events through chart review; data were collected from a time period of 292 +/- 281 days. We compared the rates of GIB and thromboembolic events between patients who underwent CF-LVAD placement and a control group of 159 patients (mean age, 64 +/- 15 y) who received a cardiac valve replacement and were discharged with anticoagulation therapy. RESULTS: Bleeding events occurred in 29 patients on CF-LVAD support (18%; 45 events total). Sixteen rebleeding events were identified among 10 patients (range, 1-3 rebleeding episodes/patient). There were 34 thrombotic events among 27 patients (17%). The most common source of bleeding was GI angiodysplastic lesions (n = 20; 44%). GIB and thromboembolic events were more common in patients on CF-LVAD support than controls; these included initial GIB (18% vs 4%, P < .001), rebleeding (6% vs none, P = .001), and thromboembolic events (17% vs 8%, P = .01). CONCLUSIONS: Patients with CF-LVADS receiving anticoagulants have a significantly higher risk of GIB and thromboembolic events than patients receiving anticoagulants after cardiac valve replacement surgery. GI angiodysplastic lesions are the most common source of bleeding. PMID- 24480678 TI - A management algorithm based on delayed bleeding after wide-field endoscopic mucosal resection of large colonic lesions. AB - BACKGROUND & AIMS: Bleeding is the main complication of wide-field endoscopic mucosal resection (WF-EMR) for large colonic lesions. Few studies have examined bleeding outcomes after WF-EMR, and there are no evidence-based guidelines for management of bleeding in this group. We analyzed outcomes of patients with clinically significant post-EMR bleeding (CSPEB) and present a management algorithm based on our findings. METHODS: In a prospective study, we collected data from WF-EMR of sessile colorectal polyps 20 mm or larger from 1039 patients who participated in the Australian Colonic Endoscopic resection multicenter study from July 2008 through May 2012. Data included patient and lesion characteristics and procedural, clinical, and histologic outcomes. Patients participated in a structured telephone interview 14 days after the procedure; independent predictors of a moderate or severe outcome by American Society of Gastrointestinal Endoscopists criteria, or any intervention for hemostasis, were identified. RESULTS: Sixty-two patients had CSPEB (6.0%); 34 were managed conservatively (55%) and 27 underwent colonoscopy (44%). One patient had primary embolization. Endoscopic therapy was applied in 21 cases; 14 had active bleeding. Two of the conservatively managed cases underwent colonoscopy for rebleeding after discharge. On multivariable analysis, moderate or severe bleeding events were associated with hemodynamic instability (odds ratio, 12.3; P = .046) and low level of hemoglobin at presentation (odds ratio, 0.50 per 1.0 g/dL; P = .005). Intervention for hemostasis was associated with hourly or more frequent hematochezia (odds ratio, 36.7; P = .001), American Society of Anesthesiologists grade 2 or higher (odds ratio, 20.1; P < .001), and transfusion (odds ratio, 18.7; P = .003). CONCLUSIONS: Based on a multicenter prospective study, CSPEB resolves spontaneously in 55% of patients. We developed a risk factor-based algorithm that might assist physicians in the management of bleeding. Patients responding to initial resuscitation can be observed, with a lower threshold for intervention in those with the identified risk factors. PMID- 24480677 TI - A phase 2 study of tofacitinib, an oral Janus kinase inhibitor, in patients with Crohn's disease. AB - BACKGROUND & AIMS: Tofacitinib, an orally administered Janus kinase inhibitor, blocks signaling through gamma-chain-containing cytokines (interleukins 2, 4, 7, 9, 15, and 21). We performed a phase 2 trial to measure its efficacy in patients with moderate-to-severe active Crohn's disease. METHODS: Patients (N = 139; age, >=18 y) with moderate-to-severe active Crohn's disease were assigned randomly to groups given 1 mg (n = 36), 5 mg (n = 34), or 15 mg (n = 35) tofacitinib or placebo (n = 34), twice daily for 4 weeks, at 48 centers in 12 countries. The primary end point was the proportion of clinical responders at week 4 (decrease from baseline in the Crohn's Disease Activity Index score of >=70 points [Response-70]). Secondary end points included clinical remission (Crohn's Disease Activity Index score of <150 points) at week 4. RESULTS: A clinical response was observed in 36% (P = .467), 58% (P = .466), and 46% (P >= .999) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 47% of patients given placebo. Clinical remission was observed in 31% (P = .417), 24% (P = .776), and 14% (P = .540) of patients given the 1-, 5-, and 15-mg doses of tofacitinib, compared with 21% of patients given placebo. The 15-mg dose of tofacitinib reduced levels of C-reactive protein and fecal calprotectin from baseline. Adverse and serious adverse events were similar among groups. Dose-dependent increases in low- and high-density lipoprotein cholesterol were observed in patients given the 5- or 15-mg doses of tofacitinib. CONCLUSIONS: There were no significant differences in the percentage of patients with moderate-to-severe active Crohn's disease who achieved clinical responses (Response-70) or clinical remission after 4 weeks' administration of tofacitinib (1, 5, or 15 mg) or placebo twice daily. However, a large percentage of patients given placebo achieved Response-70 or remission. Reductions in C-reactive protein and fecal calprotectin levels among patients given the 15-mg dose of tofacitinib indicate its biologic activity. ClinicalTrials.gov number: NCT00615199. PMID- 24480679 TI - Familial clustering of Barrett's esophagus and esophageal adenocarcinoma in a European cohort. AB - BACKGROUND & AIMS: Up to 7% of cases of Barrett's esophagus (BE) or esophageal adenocarcinoma (EAC) in the United States occur in family clusters. We identified first-degree and second-degree relatives of patients with BE and EAC to determine the extent of familial clustering in a European cohort and studied differences between familial and nonfamilial cases. METHODS: A questionnaire was sent to all patients diagnosed with BE or EAC from 2000-2011 at 3 hospitals in the Netherlands (n = 838). Diagnoses of affected relatives were confirmed by using the Dutch Pathology Registry. Familial statuses of BE were defined as definitive (>=1 first-degree or second-degree relative with BE or EAC), possible (>=1 reported relative with BE or esophageal cancer without histologic confirmation), unlikely (no family history), or unknown. RESULTS: A total of 603 patients with BE or EAC (71%) responded and were included in the analysis. Familial BE was definitive for 7% of cases (n = 39, 10% of first-degree relatives affected), possible for 6% (n = 36), unlikely for 49% (n = 297), and unknown for 38% (n = 231). Definitive cases of familial BE were younger at onset of heartburn and EAC diagnosis; their first-degree relatives more frequently had reflux symptoms and a prior upper endoscopy, compared with unlikely cases of familial BE. CONCLUSIONS: In a database analysis of patients diagnosed with BE or EAC in the Netherlands, 7% of cases of BE and EAC were familial. These cases have a younger average age of onset of reflux symptoms and diagnosis of EAC than unlikely familial cases. These findings may indicate that genetic factors contribute to BE susceptibility, with a possible central role of gastroesophageal reflux. PMID- 24480680 TI - Diverticulosis is a disease of civilization. PMID- 24480681 TI - A bundled payment framework for colonoscopy performed for colorectal cancer screening or surveillance. PMID- 24480682 TI - Magnetic resonance imaging findings in acute elbow dislocation: insight into mechanism. AB - PURPOSE: To identify with magnetic resonance imaging the location and severity of ligamentous injury after acute elbow dislocations. Based on observations that many elbow dislocations arise from an initial acute valgus load, we hypothesized that all patients would have a high-grade medial injury but not all would demonstrate injury of the lateral ligaments. METHODS: The medial collateral ligament was subdivided into anterior bands of the anterior bundle of the medial collateral ligament (MCL) and posterior bands of the anterior bundle of the MCL, whereas the lateral collateral ligament was divided into the lateral ulnar collateral ligament and the radial collateral ligament. Distinction on magnetic resonance imaging was made between normal morphology and low-grade partial tear (< 50% of the ligament fibers), high-grade partial tear (>= 50%), and full thickness disruption. The site of disruption was also characterized. RESULTS: Acute magnetic resonance imaging studies for 16 patients were included. No low grade tears or intact evaluations of either the anterior or posterior bands of the anterior bundle of the MCL were observed; most demonstrated complete tears. The lateral ulnar collateral ligament most frequently showed complete disruption but was occasionally intact. The radial collateral ligament infrequently showed full disruption. Complete tears involving either the anterior or posterior portions of the anterior band of the MCL were significantly more common than complete tears involving the ligaments on the lateral side. CONCLUSIONS: After elbow dislocation, complete ligamentous tears were more common on the medial versus the lateral side. Whereas the lateral ligaments were occasionally preserved, this was never observed on the medial side. These data suggest a sequence of failure starting on the medial side with subsequent variable energy dissipation laterally. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic IV. PMID- 24480683 TI - Joint capsule attachment to the extensor carpi radialis brevis origin: an anatomical study with possible implications regarding the etiology of lateral epicondylitis. AB - PURPOSE: To identify the unique anatomical characteristic of the extensor carpi radialis brevis (ECRB) origin and points of differentiation from other extensors and to clarify the specific relationship of the ECRB to the underlying structures. METHODS: We studied the origin of each extensor macroscopically for its muscular and tendinous parts; to identify the relationship between the ECRB origin and the deeper structures, we also examined the attachment of the joint capsule under the ECRB origin. RESULTS: The ECRB simply originated as a tendon without any muscle, whereas other extensors originated as a mixture of tendon and muscle. At the anterior part of the ECRB origin, the thin attachment of the joint capsule (average width, 3.3 mm) lay deep to the ECRB and was distinct. However, at the posterodistal portion, the joint capsule, annular ligament, and supinator were intermingled and originated as a single wide sheet from the humerus (average width, 10.7 mm). CONCLUSIONS: The anterior part of the ECRB origin was delicate, because the ECRB origin was purely tendinous, and the attachment of the articular capsule was thin compared with that of the posterodistal attachment. This thin attachment could be an initial factor leading to the development of lateral epicondylitis. CLINICAL RELEVANCE: The results of the current study may enhance magnetic resonance imaging understanding and may help clarify the etiology of the lateral epicondylitis. PMID- 24480684 TI - Epidemiology of congenital upper limb anomalies in Stockholm, Sweden, 1997 to 2007: application of the Oberg, Manske, and Tonkin classification. AB - PURPOSE: To investigate the epidemiology of congenital upper limb anomalies (CULA) based on the newly proposed Oberg, Manske, and Tonkin (OMT) classification, to compare this classification with the International Federation of Societies for Surgery of the Hand (IFSSH) classification, and to provide incidence rates of the different CULA. METHODS: In this study, the same 562 individuals with a CULA who were analyzed in a previous epidemiologic study based on the IFSSH classification were reclassified according to the OMT classification. All children identified with CULA and born in Stockholm County between January 1, 1997 and December 31, 2007 were included in the study. During the period there were 261,914 live births in Stockholm County, and the population of Stockholm County was 1,949,516 inhabitants at the end of the period. From medical records and available radiographs, all cases were analyzed regarding type of CULA, sex, affected side, associated nonhand anomalies, and occurrence among relatives. Individuals with right and left side anomalies belonging to different OMT subgroups were counted as 2 anomalies; thus, the material consisted of 577 CULA in 562 children. RESULTS: It was possible to organize all CULA into the OMT classification. The largest main category was malformations (429 cases), followed by deformations (124 cases), dysplasias (10 cases), and syndromes (14 cases). We present the relation between the IFSSH and OMT classifications, elucidate difficulties within the OMT classification, and propose additions to the classification. CONCLUSIONS: This study confirms that the OMT classification is useful and accurate, but also points out difficulties. With further refinements, we regard the OMT classification as a needed and appropriate replacement for the IFSSH classification. TYPE OF STUDY/LEVEL OF EVIDENCE: Diagnostic III. PMID- 24480685 TI - Correction of distal phalangeal nonunion using peg bone graft. AB - PURPOSE: To evaluate the outcome of a peg bone graft for treatment of distal phalangeal nonunion, in terms of safety and effectiveness. METHODS: We performed grafts using bone pegs in 13 patients who reported pain and instability of the fingertip as a result of distal phalanx nonunion. Surgical procedures included harvesting cancellous and cortical bone from ilium, radius, or ulna. We made a small incision in the fingertip and placed the bone pegs through the canal created for this access. In a few cases in which the bone peg did not offer mechanical stability, we used K-wires for additional support. RESULTS: All patients had successful union of the distal phalanx without serious complications in either donor or recipient areas. Range of motion improved postoperatively. An additional operation was needed in 1 case. CONCLUSIONS: The use of a peg bone graft in the treatment of distal phalanx nonunion offers easy access to the nonunion area and allows for effortless internal fixation. The bone contact area was increased, resulting in bone union and stability. Therefore, bone peg graft could be considered a potential method for the treatment of distal phalanx nonunion. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24480686 TI - Biomechanical characteristics of suture anchor implants for flexor digitorum profundus repair. AB - PURPOSE: To determine strength and failure characteristics of 2 suture anchors used to repair simulated flexor digitorum profundus avulsions during passive mobilization protocol simulation. METHODS: We simulated avulsion of the flexor digitorum profundus tendon in 30 distal phalanges from fresh-frozen human cadavers. Repair was performed with a 1.3 * 3.7 mm Micro-Mitek suture anchor (3-0 Orthocord suture) and a 2.2 * 4.0-mm Corkscrew suture anchor (2-0 FiberWire suture). All specimens were loaded cyclically from 2 to 15 N at 5 N/s for a total of 500 cycles. Samples were tested to failure at the completion of 500 cycles. Load at failure, load at first noteworthy displacement (> 2 mm), elongation of the system, gap formation at the tendon-bone interface, and the mechanism of failure were assessed. RESULTS: Suture failure at maximum load was the prevalent failure mechanism in both groups. No statistically significant difference in elongation of the tendon-suture complex was observed. The Corkscrew suture anchor showed a significantly superior performance in load to failure, load at first significant displacement, and gap formation at the tendon-bone interface. CONCLUSIONS: The significantly higher load capacity at first displacement (> 2 mm) and the significance of a lower gap formation at the repair site seem to be the most relevant clinical parameters. Based on this concept, the Corkscrew anchor may be superior biomechanically to the Micro-Mitek when considering an early passive mobilization protocol. CLINICAL RELEVANCE: The choice of an appropriate implant may influence the postoperative mobilization protocol and thereby improve currently reported success rates. Defining a biomechanically superior implant will provide an essential basis for further studies in flexor tendon repair research. PMID- 24480687 TI - Outcomes of free adipofascial flaps combined with tenolysis in scarred beds. AB - PURPOSE: To review our outcomes of transferring vascularized free adipofascial flaps used to change the local tissue conditions at the time of tenolysis in adhesion-prone beds. METHODS: Eleven free adipofascial flaps were transplanted in 10 patients after tenolysis on the forearm (3 cases), the dorsum of the hand (5 cases), or the dorsum of the proximal phalanx (3 cases). All recipient areas had badly scarred beds, 7 of which had previously failed tenolyses. In addition to tenolysis (10) or the insertion of bridging tendon grafts (1), arthrolysis of several involved joints and bone fixation for nonunion (3 cases) were carried out simultaneously. The adipofascial flap was then wrapped around the tendons or interposed between the scarred tissue and the freed tendons. In 8 cases, the flap was the lateral arm adipofascial flap, whereas adipose flaps from the toes were used for the fingers. RESULTS: All flaps survived without vascular crisis. In all cases, total active motion was similar to the passive motion obtained at surgery. Average Disabilities of the Arm, Shoulder, and Hand score improved from 69 to 10, and average Patient-Rated Wrist Hand Evaluation score improved from 65 to 9. Secondary surgery was needed to reduce the bulk of the flap in 3 patients. One patient required an additional procedure to obtain an optimum result. CONCLUSIONS: Free adipofascial flaps provided satisfying results in this group of patients. The flaps should be considered when the bed is scarred or after a failed tenolysis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24480688 TI - Cat bite infections of the hand: assessment of morbidity and predictors of severe infection. AB - PURPOSE: To assess the overall morbidity of cat bites to the hand and identify risk factors for hospitalization after such an injury. METHODS: All patients recently treated at our institution for cat bite injuries to the hand were retrospectively reviewed. We identified 193 patients in a 3-year period between January 1, 2009, and December 31, 2011. Patient demographics, medical history, physical examination findings, laboratory values, and long-term follow-up data were collected. Univariate and multivariate statistical regression were used to analyze the data. RESULTS: Thirty percent (n = 57) of patients with cat bites to the hand were hospitalized. The average length of stay for these patients was 3.2 days. Of the hospitalized patients, 67% (n = 38) underwent irrigation and debridement, with 8 patients requiring more than 1 operation. Complications were common among these patients. Risk factors associated with hospitalization included smoking, immunocompromised state, and location of bite over a joint or tendon sheath. Physical examination findings of erythema and swelling at presentation were also associated with increased risk of hospitalization. Time from bite to presentation, white blood cell count, erythrocyte sedimentation rate, and C-reactive protein values at presentation were not associated with hospitalization. CONCLUSIONS: Cat bite injuries to the hand can progress to serious infection. The treatment of such infections often requires hospitalization, intravenous antibiotic therapy, and operative treatment. Clinical findings suggestive of the need for hospitalization include location of the bite over a joint or tendon sheath, erythema, pain, and swelling. These findings should increase concern for a severe infection and warrant hospitalization and urgent consultation with a hand surgeon. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic III. PMID- 24480689 TI - Restoration of prehensile function for motor paralysis in Hopkins syndrome: case report. AB - Hopkins syndrome is a rare cause of poliomyelitis-like paralysis affecting 1 or more extremities after an acute attack of asthma. The exact etiology of Hopkins syndrome is not known. A 4-year-old girl developed acute asthma followed by complete flaccid paralysis of the left upper extremity. She underwent staged reconstruction using the double free muscle transfer technique. Rigorous postoperative physiotherapy was carried out to achieve a good functional outcome. At recent follow-up, 27 months after the first procedure, the patient was able to effectively use the reconstructed hand for most daily activities. She had good control and could perform 2-handed activities. The selection of a suitable operative treatment and suitable donor nerves is critical, and there are no clear guidelines in the literature. The double free muscle transfer can be effectively employed in similar cases to restore grasping function. PMID- 24480690 TI - The effects of aging on upper limb tendon transfers in patients with tetraplegia. AB - PURPOSE: To evaluate the effects of aging on hand function among patients with tetraplegia who had forearm tendon transfer surgery between 1982 and 1990. METHODS: The study used a longitudinal cohort design that compared hand function outcomes in 2012 with those obtained 11 years earlier. A digital analyzer was used to measure key pinch and grip strength, and results were compared with those obtained in 2001 to determine changes in strength over time. The study also evaluated changes in participant's employment status, wheelchair use, and subjective changes in function using the Lamb and Chan questionnaire. RESULTS: Participants had a mean key pinch strength force between 11.5 N (tenodeses) and 32.9 N (active transfers) and grip strength forces between 23 N (tenodeses) and 59 N (active transfers). Since 2001, people with active transfers either maintained strength or experienced decreased strength of 5% to 14%. Thumb tenodesis power decreased 40% to 51%, whereas finger tenodeses power increased 32% to 70%. Three activities in the Lamb and Chan questionnaire were identified by the majority of participants as being worse or much worse over the past 11 years. These were performing a pressure relief and propelling a manual wheelchair on level ground and up a ramp. These findings correspond with the increased number of participants who used a power wheelchair in 2012 (64%) compared with 2001 (26%). Close to half of the participants (46%) were employed compared with the 90% in 2001. CONCLUSIONS: Tendon transfers continued to provide pinch and grip function for individuals with tetraplegia for many years following spinal cord injury. The decrease in strength of those with active transfers over the 11 year period was within the reported aging loss for the normal population. The small number of participants with tenodesis, however, limited our ability to draw meaningful conclusions for this group. TYPE OF STUDY/LEVEL OF EVIDENCE: Prognostic III. PMID- 24480692 TI - Continuous passive motion following elbow arthrolysis. PMID- 24480691 TI - Incidence of failure of continuous peripheral nerve catheters for postoperative analgesia in upper extremity surgery. AB - PURPOSE: To explore the incidence of failure of continuous peripheral nerve blockade (CPNB) after upper extremity operations. METHODS: Patient data regarding postoperative CPNB were retrospectively obtained from our institution's regional anesthesia database. Documented information on the first postoperative day included pain assessment ratings (numerical verbal pain scale, patient-reported breakthrough pain upon perceived return of sensation, appearance of the catheter site, complications, time of return of sensation, day of return of sensation, residual blockade, patient satisfaction with the block, and whether patient would receive the block again). RESULTS: A total of 207 patients received CPNB for postoperative analgesia. The failure rate on the first postoperative day for infraclavicular (133 patients) and supraclavicular (58 patients) CPNB was 19% and 26%, respectively. Interscalene CPNB (16 patients) yielded 3 incidences of failure. No significant difference was found between supraclavicular and infraclavicular block techniques. In addition, no significant differences were found between the incidences of CPNB failures with potentially more painful surgeries involving bone compared with potentially less painful soft tissue procedures. CONCLUSIONS: The CPNB technique used for hand surgery postoperative analgesia was associated with nontrivial failure rates. The potential of CPNB failure and resulting breakthrough pain upon recovery from the primary nerve block is important to help establish patient expectations. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24480693 TI - Pectoralis major transfer for the management of scapula winging secondary to serratus anterior injury or paralysis. AB - Pectoralis major transfer (partial or complete) is the most common transfer to the scapula for winging as a result of serratus anterior paralysis or injury. The most commonly described technique is to transfer the pectoralis major prolonged with tendon allograft or autograft to the scapula. We present a technique that entails direct transfer of the sternal head of the pectoralis major with its bony insertion to the lower scapula. PMID- 24480694 TI - Modified technique for basilar thumb osteoarthritis. AB - The arthroplasty described by Weilby is a reliable procedure for the treatment of stage 2 and 3 basal thumb osteoarthritis. Although the technique provides good pain relief, optimal thumb mobility, and acceptable levels of grip and pinch strength in most cases, it is common to see the thumb collapsing because the interposed knot has disassembled. We have found a more effective way to prepare and stabilize that interposition material. With this modification, we have had less thumb subsidence than with the original technique. PMID- 24480695 TI - Periprosthetic proximal fracture in total wrist arthroplasty. PMID- 24480696 TI - An easy and applicable method for stripping and smoothing the tendon ends: sterile wooden tongue depressor. PMID- 24480697 TI - Posterior interosseus nerve entrapment following Monteggia fracture dislocation. PMID- 24480698 TI - In reply. PMID- 24480699 TI - Inconsistent acronym use. PMID- 24480700 TI - Response to letter to the editor: "RE: On the accuracy of the Head Impact Telemetry (HIT) System used in football helmets". PMID- 24480701 TI - An energy dissipation and cross shear time dependent computational wear model for the analysis of polyethylene wear in total knee replacements. AB - The cost and time efficiency of computational polyethylene wear simulations may enable the optimization of total knee replacements for the reduction of polyethylene wear. The present study proposes an energy dissipation wear model for polyethylene which considers the time dependent molecular behavior of polyethylene, aspects of tractive rolling and contact pressure. This time dependent - energy dissipation wear model was evaluated, along with several other wear models, by comparison to pin-on-disk results, knee simulator wear test results under various kinematic conditions and knee simulator wear test results that were performed following the ISO 14243-3 standard. The proposed time dependent - energy dissipation wear model resulted in improved accuracy for the prediction of pin-on-disk and knee simulator wear test results compared with several previously published wear models. PMID- 24480702 TI - The biomechanical and histological sequelae of common skin banking methods. AB - Human skin allografts are used worldwide as an adjunct for the healing of burns when autograft skin is not available or not indicated. Allograft skin comes from human cadaveric donors, and so must be preserved until use. This study forms the first investigation to compare the mechanical and histological integrity of human split-thickness skin grafts preserved by either glycerolisation or cryopreservation (with or without the cryoprotectant DMSO). Stress relaxation was used to assess mechanical properties, whilst histological analysis allowed for evaluation of structural integrity. Preservation of tissue, whether by freezing or glycerolisation, altered the relaxation behaviours of skin. Young's modulus upon initial loading significantly decreased for skin frozen without cryoprotectant, but remained unchanged for skin frozen with cryoprotectant and skin preserved with glycerol. After 1.5h of stress relaxation, both fresh skin and skin frozen without DMSO displayed similar relaxation rates. Samples frozen with DMSO or preserved with glycerol had increased relaxation rate and had not reached load equilibrium within this time. To understand the structural basis for the biomechanical changes, samples were histologically assessed. All preservation protocols resulted in a similar degree of visible damage, but cryopreservation appeared particularly damaging to the extracellular matrix, whereas glycerolisation caused dramatic separation of the epidermis from the underlying dermis. The mechanical property alterations reveal that preservation results in laxity, which clinically could hinder contact dependent healing properties, but alternatively may increase capacity for coverage. The structural changes confirm that preservation techniques do not conserve grafts in an in vivo state. PMID- 24480703 TI - Compressive mechanical properties of atherosclerotic plaques--indentation test to characterise the local anisotropic behaviour. AB - Accurate material models and associated parameters of atherosclerotic plaques are crucial for reliable biomechanical plaque prediction models. These biomechanical models have the potential to increase our understanding of plaque progression and failure, possibly improving risk assessment of plaque rupture, which is the main cause of ischaemic strokes and myocardial infarction. However, experimental biomechanical data on atherosclerotic plaque tissue is scarce and shows a high variability. In addition, most of the biomechanical models assume isotropic behaviour of plaque tissue, which is a general over-simplification. This review discusses the past and the current literature that focus on mechanical properties of plaque derived from compression experiments, using unconfined compression, micro-indentation or nano-indentation. Results will be discussed and the techniques will be mutually compared. Thereafter, an in-house developed indentation method combined with an inverse finite element method is introduced, allowing analysis of the local anisotropic mechanical properties of atherosclerotic plaques. The advantages and limitations of this method will be evaluated and compared to other methods reported in literature. PMID- 24480704 TI - The influence of vascular anatomy on carotid artery stenting: a parametric study for damage assessment. AB - Carotid artery stenting is emerging as an alternative technique to surgery for the treatment of symptomatic severe carotid stenosis. Clinical and experimental evidence demonstrates that both plaque morphology and biomechanical changes due to the device implantation can be possible causes of an unsuccessful treatment. In order to gain further insights of the endovascular intervention, a virtual environment based on structural finite element simulations was built to emulate the stenting procedure on generalized atherosclerotic carotid geometries which included a damage model to quantify the injury of the vessel. Five possible lesion scenarios were simulated by changing both material properties and vascular geometrical features to cover both presumed vulnerable and stable plaques. The results were analyzed with respect to lumen gain and wall stresses which are potentially related to the failure of the procedure according to previous studies. Our findings show that an elliptic lumen shape and a thinner fibrous cap with an underlying lipid pool result in higher stenosis reduction, while large calcifications and fibrotic tissue are more prone to recoil. The shielding effect of a thicker fibrous cap helps to reduce local compressive stresses in the soft plaque. The presence of a soft plaque reduces the damage in the healthy vascular structures. Contrarily, the presence of hard plaque promotes less damage volume in the fibrous cap and reduces stress peaks in this region, but they seem to increase stresses in the media-intima layer. Finally the reliability of the achieved results was put into clinical perspective. PMID- 24480705 TI - Extracellular matrix integrity affects the mechanical behaviour of in-situ chondrocytes under compression. AB - Cartilage lesions change the microenvironment of cells and may accelerate cartilage degradation through catabolic responses from chondrocytes. In this study, we investigated the effects of structural integrity of the extracellular matrix (ECM) on chondrocytes by comparing the mechanics of cells surrounded by an intact ECM with cells close to a cartilage lesion using experimental and numerical methods. Experimentally, 15% nominal compression was applied to bovine cartilage tissues using a light-transmissible compression system. Target cells in the intact ECM and near lesions were imaged by dual-photon microscopy. Changes in cell morphology (N(cell)=32 for both ECM conditions) were quantified. A two-scale (tissue level and cell level) Finite Element (FE) model was also developed. A 15% nominal compression was applied to a non-linear, biphasic tissue model with the corresponding cell level models studied at different radial locations from the centre of the sample in the transient phase and at steady state. We studied the Green-Lagrange strains in the tissue and cells. Experimental and theoretical results indicated that cells near lesions deform less axially than chondrocytes in the intact ECM at steady state. However, cells near lesions experienced large tensile strains in the principal height direction, which are likely associated with non-uniform tissue radial bulging. Previous experiments showed that tensile strains of high magnitude cause an up-regulation of digestive enzyme gene expressions. Therefore, we propose that cartilage degradation near tissue lesions may be due to the large tensile strains in the principal height direction applied to cells, thus leading to an up-regulation of catabolic factors. PMID- 24480707 TI - Numerical simulation of arterial dissection during balloon angioplasty of atherosclerotic coronary arteries. AB - Balloon angioplasty is a standard clinical treatment for symptomatic coronary artery disease. In this procedure, controlled damage is applied intraluminally to the wall of a stenotic artery. Dissection of the coronary artery is a commonly observed clinical complication of angioplasty; however, not all dissections can be detected angioscopically. This work focuses on studying the dissection mechanisms triggered during the early stages of angioplasty in an atherosclerotic coronary artery, addressing the problem by means of a parametric study based on a simplified finite element model and cohesive interface modeling. Our results emphasize the presence of several damage mechanisms, at different locations, that are triggered near the very beginning of the process and evolve competitively, depending on both geometry and material properties of the atherosclerotic vessel. Small-scale damage was evidenced, which would not be detectable by angiography or intravascular ultrasound, but could potentially be sufficient to stimulate smooth muscle cell activation, promoting late-onset complications such as restenosis. PMID- 24480706 TI - Image-based modeling for better understanding and assessment of atherosclerotic plaque progression and vulnerability: data, modeling, validation, uncertainty and predictions. AB - Medical imaging and image-based modeling have made considerable progress in recent years in identifying atherosclerotic plaque morphological and mechanical risk factors which may be used in developing improved patient screening strategies. However, a clear understanding is needed about what we have achieved and what is really needed to translate research to actual clinical practices and bring benefits to public health. Lack of in vivo data and clinical events to serve as gold standard to validate model predictions is a severe limitation. While this perspective paper provides a review of the key steps and findings of our group in image-based models for human carotid and coronary plaques and a limited review of related work by other groups, we also focus on grand challenges and uncertainties facing the researchers in the field to develop more accurate and predictive patient screening tools. PMID- 24480709 TI - Outcomes of macular hole surgery with short-duration positioning in highly myopic eyes: a case-control study. AB - PURPOSE: To evaluate the outcomes of macular hole (MH) surgery with 3-day prone positioning in highly myopic eyes and to compare them with those from non-highly myopic eyes. DESIGN: Retrospective nested case-control study from a cohort of 496 consecutive patients (496 eyes) who underwent surgery for MH. PARTICIPANTS: Forty seven highly myopic eyes (with axial length >26 mm) were included in the study group and were matched for MH size and duration of symptoms with 47 non-highly myopic control eyes selected from the same cohort. METHODS: All patients underwent pars plana vitrectomy, internal limiting membrane peeling, and 17% hexafluoroethane gas filling. Patients then were advised to maintain strict face down positioning for 3 days only and to avoid the supine position during the night for a minimum of 1 week. MAIN OUTCOME MEASURES: The MH closure rate, the relationship between axial length and closure rate, the best-corrected visual acuity (BCVA), and the surgical complications were analyzed. RESULTS: The mean axial length was 28.5+/-2.2 mm in highly myopic eyes and 23.3+/-1.1 mm in controls (P < 0.001). Closure of the MH was achieved in 39 of 47 eyes (83%) in the study group and in 45 of 47 eyes (95.7%) in the control group (P = 0.045). Anatomic outcomes tended to decrease when axial length increased (P = 0.066). Mean BCVA improved in both groups (0.41+/-0.39 logarithm of the minimal angle of resolution [logMAR] vs. 0.68+/-0.34 logMAR) but was significantly lower in highly myopic eyes (P < 0.001). Retinal detachment occurred in 8.5% of highly myopic patients versus 2.1% of controls, but the difference was not significant. CONCLUSIONS: Macular hole surgery with 3-day postoperative positioning in highly myopic eyes resulted in satisfactory anatomic and functional outcomes. However, the MH closure rate and mean improvement of visual acuity were less favorable than those in control eyes. Longer axial length may increase the risk of anatomic failure. PMID- 24480708 TI - A molecular revolution in uveal melanoma: implications for patient care and targeted therapy. AB - Uveal melanoma is the most common primary intraocular malignancy and has a strong propensity for fatal metastasis. Recent advances in the molecular genetics of uveal melanoma are revolutionizing our understanding of this cancer and the care of patients. The development of a new molecular classification of uveal melanoma based on a widely available 15-gene expression profile now allows patients at high risk of metastasis to be identified early so that individualized management can be offered. The recent discovery of major driver mutations in uveal melanoma provide a rational basis for development of new targeted therapies. Taken together, these advances are transforming our understanding and management of uveal melanoma with the ultimate goal of improving patient outcomes. PMID- 24480710 TI - Oral fluoroquinolones and the incidence of rhegmatogenous retinal detachment and symptomatic retinal breaks: a population-based study. AB - OBJECTIVE: To examine whether oral fluoroquinolone antibiotics are associated with an increase in subsequent rhegmatogenous retinal detachment and symptomatic retinal breaks in a large population-based cohort. DESIGN: Population-based cohort study. PARTICIPANTS AND CONTROLS: Adult residents of Olmsted County, Minnesota, who were prescribed oral fluoroquinolone medications from January 1, 2003, to June 30, 2011. Comparison cohorts consisted of patients prescribed oral macrolide and beta-lactam antibiotics during the study period. METHODS: Procedure codes were used to identify retinal detachment repair and prophylaxis procedures occurring within 1 year of prescription dates. Travel clinic, pro re nata, and self-treatment prescriptions were excluded. Patients with tractional retinal detachment, previous retinal detachment repair, endophthalmitis, and necrotizing retinitis were excluded, as were those with intraocular surgery or severe head/eye trauma <=90 days before the procedure. MAIN OUTCOME MEASURES: Rates of retinal detachment repair and prophylaxis procedures within 7, 30, 90, and 365 days of the first prescription were calculated and compared between antibiotic prescription cohorts using chi-square tests. Retinal detachment repair rates also were compared with the expected Olmsted County, Minnesota, rates using the one sample log-rank test. RESULTS: Oral fluoroquinolones were prescribed for 38,046 patients (macrolide n = 48,074, beta-lactam n = 69,079) during the study period. Retinal detachment repair procedures were performed within 365 days of the first prescription in 0.03% (95% confidence interval [CI], 0.01-0.06) of the fluoroquinolone cohort, 0.02% (95% CI, 0.01-0.03) of the macrolide cohort, and 0.03% (95% CI, 0.02-0.05) of the beta-lactam cohort (P > 0.05). Retinal detachment prophylaxis procedures for symptomatic retinal breaks were performed within 365 days of the first prescription in 0.01% (95% CI, 0.00-0.03) of the fluoroquinolone cohort, 0.02% (95% CI, 0.01-0.04) of the macrolide cohort, and 0.02% (95% CI, 0.01-0.04) of the beta-lactam cohort (P > 0.05). Similar comparisons of treatment rates within 7, 30, and 90 days of the first prescription were all nonsignificant between cohorts. Post-fluoroquinolone retinal detachment repair rates were similar to expected rates (36.8 per 100,000/year vs. 28.8 per 100,000/year for age- and sex-matched historical rates, P = 0.35). CONCLUSIONS: Oral fluoroquinolone use was not associated with an increased risk of rhegmatogenous retinal detachment or symptomatic retinal breaks in this population-based study. PMID- 24480711 TI - Detailed phenotypic and genotypic characterization of bietti crystalline dystrophy. AB - OBJECTIVE: To provide a detailed phenotype/genotype characterization of Bietti crystalline dystrophy (BCD). DESIGN: Observational case series. PARTICIPANTS: Twenty patients from 17 families recruited from a multiethnic British population. METHODS: Patients underwent color fundus photography, near-infrared (NIR) imaging, fundus autofluorescence (FAF) imaging, spectral domain optical coherence tomography (SD-OCT), and electroretinogram (ERG) assessment. The gene CYP4V2 was sequenced. MAIN OUTCOME MEASURES: Clinical, imaging, electrophysiologic, and molecular genetics findings. RESULTS: Patients ranged in age from 19 to 72 years (median, 40 years), with a visual acuity of 6/5 to perception of light (median, 6/12). There was wide intrafamilial and interfamilial variability in clinical severity. The FAF imaging showed well-defined areas of retinal pigment epithelium (RPE) loss that corresponded on SD-OCT to well-demarcated areas of outer retinal atrophy. Retinal crystals were not evident on FAF imaging and were best visualized with NIR imaging. Spectral domain OCT showed them to be principally located on or in the RPE/Bruch's membrane complex. Disappearance of the crystals, revealed by serial recording, was associated with severe disruption and thinning of the RPE/Bruch's membrane complex. Cases with extensive RPE degeneration (N = 5) had ERGs consistent with generalized rod and cone dysfunction, but those with more focal RPE atrophy showed amplitude reduction without delay (N = 3), consistent with restricted loss of function, or that was normal (N = 2). Likely disease-causing variants were identified in 34 chromosomes from 17 families. Seven were novel, including p.Met66Arg, found in all 11 patients from 8 families of South Asian descent. This mutation appears to be associated with earlier onset (median age, 30 years) compared with other substitutions (median age, 41 years). Deletions of exon 7 were associated with more severe disease. CONCLUSIONS: The phenotype is highly variable. Several novel variants are reported, including a highly prevalent substitution in patients of South Asian descent that is associated with earlier-onset disease. Autofluorescence showed sharply demarcated areas of RPE loss that coincided with abrupt edges of outer retinal atrophy on SD OCT; crystals were generally situated on or in the RPE/Bruch's complex but could disappear over time with associated RPE disruption. These results support a role for the RPE in disease pathogenesis. PMID- 24480712 TI - Modelling the growth of plants with a uniform growth logistics. AB - BACKGROUND AND AIMS: The increment model has previously been used to describe the growth of plants in general. Here, we examine how the same logistics enables the development of different superstructures. METHODS: Data from the literature are analyzed with the increment model. Increments are growth-invariant molecular clusters, treated as heuristic particles. This approach formulates the law of mass action for multi-component systems, describing the general properties of superstructures which are optimized via relaxation processes. RESULTS: The daily growth patterns of hypocotyls can be reproduced implying predetermined growth invariant model parameters. In various species, the coordinated formation and death of fine roots are modeled successfully. Their biphasic annual growth follows distinct morphological programs but both use the same logistics. In tropical forests, distributions of the diameter in breast height of trees of different species adhere to the same pattern. Beyond structural fluctuations, competition and cooperation within and between the species may drive optimization. CONCLUSION: All superstructures of plants examined so far could be reproduced with our approach. With genetically encoded growth-invariant model parameters (interaction with the environment included) perfect morphological development runs embedded in the uniform logistics of the increment model. PMID- 24480713 TI - Modeling stochastic gene expression in growing cells. AB - Gene expression is an inherently noisy process. Fluctuations arise at many points in the expression of a gene, as all the salient reactions such as transcription, translation, and mRNA degradation are stochastic processes. The fluctuations become important when the cellular copy numbers of the relevant molecules (mRNA or proteins) are low. For regulated genes, a computational complication arises from the fact that protein synthesis rates depend on the concentrations of the transcription factors that regulate the corresponding genes. Because of the growing cell volume, such rates are effectively time-dependent. We deal with the effects of volume growth computationally using a rather simple method: the growth of the cell volume is incorporated in our simulations by stochastically adding small volume elements to the cell volume. As an application of this method we study a gene circuit with positive autoregulation that exhibits bistability. We show how the region of bistability becomes diminished by increasing the effect of noise via a reduced copy number of the regulatory protein. Cell volume determines the region of bistability for different noise strengths. The method is general and can also be applied to other cases where synthesis rates of proteins are regulated and an appropriate analytical description is difficult to achieve. PMID- 24480714 TI - Are the ESHRE/ESGE criteria of female genital anomalies for diagnosis of septate uterus appropriate? PMID- 24480715 TI - Reply: are the ESHRE/ESGE criteria of female genital anomalies for diagnosis of septate uterus appropriate? PMID- 24480716 TI - Optimization of an absolute sensitivity in a glassy matrix during DNP-enhanced multidimensional solid-state NMR experiments. AB - Thanks to instrumental and theoretical development, notably the access to high power and high-frequency microwave sources, high-field dynamic nuclear polarization (DNP) on solid-state NMR currently appears as a promising solution to enhance nuclear magnetization in many different types of systems. In magic angle-spinning DNP experiments, systems of interest are usually dissolved or suspended in glass-forming matrices doped with polarizing agents and measured at low temperature (down to ~100K). In this work, we discuss the influence of sample conditions (radical concentration, sample temperature, etc.) on DNP enhancements and various nuclear relaxation times which affect the absolute sensitivity of DNP spectra, especially in multidimensional experiments. Furthermore, DNP-enhanced solid-state NMR experiments performed at 9.4 T are complemented by high-field CW EPR measurements performed at the same magnetic field. Microwave absorption by the DNP glassy matrix is observed even below the glass transition temperature caused by softening of the glass. Shortening of electron relaxation times due to glass softening and its impact in terms of DNP sensitivity is discussed. PMID- 24480717 TI - Diagnostic imaging and pacemaker implantation in a domestic goat with persistent left cranial vena cava. AB - Difficulty was encountered with the insertion of a right atrial pacing lead via the left jugular vein during lead and pacemaker implantation in a clinically normal goat as part of an ongoing rapid atrial pacing - induced atrial fibrillation research project. Fluoroscopic visualization of an abnormal lead advancement path prompted angiographic assessment which revealed a persistent left cranial vena cava (PLCVC) and prominent coronary sinus communicating with the right atrium. Angiography facilitated successful advancement and securing of the pacing lead into the right side of the interatrial septum. Cardiac magnetic resonance imaging/magnetic resonance angiography (MRI/MRA) allowed further characterization of this rare venous anomaly. Even though PLCVC has been reported once in a goat, to the authors' knowledge this is the first report to include MRI/MRA characterization of PLCVC and prominent coronary sinus with successful cardiac pacemaker implantation using the PLCVC. PMID- 24480718 TI - Transvenous extraction of an abandoned endocardial pacemaker lead in a dog. AB - A 6-year-old male castrated labrador retriever presented with endocardial pacemaker infection following migration and subsequent repositioning of the pulse generator. An epicardial lead and pulse generator were surgically implanted and the endocardial lead could not be removed with manual traction. The endocardial lead was severed, anchored, and abandoned at the thoracic inlet. The patient presented 4 months later with endocardial lead migration, bacteremia, and suspected glomerulonephritis. The endocardial pacemaker lead was transvenously extracted using a mechanical dilator sheath and locking stylet. This report of transvenous pacemaker lead extraction in a dog addresses the challenges and describes recent advances in extraction devices. PMID- 24480719 TI - Mesenchymal stem cells prevent restraint stress-induced lymphocyte depletion via interleukin-4. AB - Chronic stress has dramatic impacts on the immune system and consequently contributes to the onset and progression of a variety of diseases, including cancer, immune disorders, and infections. Recent studies in animals and humans have demonstrated that mesenchymal stem cells (MSCs) significantly modulate the immune system. Here we show that administration of MSCs in vivo prevents lymphocyte depletion induced by physical restraint stress (12:12-h stress-rest, 2 repetitions) in mice. This effect was found to be exerted not through modulation of glucocorticoid levels in the circulation, but rather through direct effects on lymphocyte apoptosis. By testing various possible protective mechanisms, we found that IL-4 provides a strong anti-apoptosis signal to lymphocytes in the presence of dexamethasone. When neutralizing antibody against IL-4 was co-administered with MSCs to restraint-stressed mice, the protective effect of MSCs was diminished. Furthermore, in mice deficient in STAT6, a key molecule in IL-4 receptor-mediated signaling, MSCs had no effect on restraint stress-induced lymphocyte depletion. Additionally, MSCs administered to stressed mice promoted IL-4 production by splenocytes. This study reveals that MSCs can effectively prevent stress-induced lymphocyte apoptosis in an IL-4-dependent manner and provides novel information for the development of countermeasures against the deleterious effects of stress on the immune system. PMID- 24480720 TI - The shape of a bone scraper: an in vitro pilot study using porcine bone chips. AB - Bone scrapers are commonly used to harvest autologous bone in oral and implant surgery. The angle of the cutting blade is a variable that distinguishes bone scrapers. In the present study, the impact of the angle of the cutting blade on the in vitro characteristics of harvested bone was determined. Bone scrapers with blade angles of 15 degrees , 25 degrees , 35 degrees , 45 degrees , and 55 degrees were used to harvest porcine cortical mandibular bone. The number and characteristics of the cells that grew out from the bone chips were examined. The data showed that, independent of the angle of the cutting blade, viable cells were barely detectable in fresh bone grafts. However, cells with a fibroblastic morphology appeared within 1 week in the culture dishes. After 21 days, the number of cells did not differ significantly between the five preparations. Moreover, cells responded to incubation with bone morphogenetic protein 7 (BMP-7) with an increased alkaline phosphatase activity, irrespective of the preparation. The data suggest that bone scrapers with different cutting angles produce bone chips with comparable in vitro characteristics. PMID- 24480721 TI - The influence of two different invitation letters on Chlamydia testing participation: randomized controlled trial. AB - BACKGROUND: In The Netherlands, screening for chlamydia (the most prevalent sexually transmitted infection worldwide) is a relatively simple and free procedure. Via an invitation letter sent by the public health services (PHS), people are asked to visit a website to request a test kit. They can then do a chlamydia test at home, send it anonymously to a laboratory, and, within two weeks, they can review their test results online and be treated by their general practitioner or the PHS. Unfortunately, the participation rates are low and the process is believed to be not (cost-) effective. OBJECTIVE: The objective of this study was to assess whether the low participation rate of screening for chlamydia at home, via an invitation letter asking to visit a website and request a test kit, could be improved by optimizing the invitation letter through systematically applied behavior change theories and evidence. METHODS: The original letter and a revised letter were randomly sent out to 13,551 citizens, 16 to 29 years old, in a Dutch municipality. Using behavior change theories, the revised letter sought to increase motivation to conduct chlamydia screening tests. The revised letter was tailored to beliefs that were found in earlier studies: risk perception, advantages and disadvantages (attitude), moral norm, social influence, and response- and self-efficacy. Revisions to the new letter also sought to avoid possible unwanted resistance caused when people feel pressured, and included prompts to trigger the desired behavior. RESULTS: No significant differences in test package requests were found between the two letters. There were also no differences between the original and revised letters in the rates of returned tests (11.80%, 581/4922 vs. 11.07%, 549/4961) or positive test results (4.8%, 23/484 vs. 4.1%, 19/460). It is evident that the new letter did not improve participation compared to the original letter. CONCLUSIONS: It is clear that the approach of inviting the target population through a letter does not lead to higher participation rates for chlamydia screening. Other approaches have to be developed and pilot tested. PMID- 24480722 TI - Abstracts - 9th Congress of the WFITN (World Federation of Interventional Neuroradiology) - Jiuhua Resort & Convention Center, Beijing, China - September 9 13, 2007. PMID- 24480723 TI - Seroprevalence of hepatitis E antibodies in a population of recyclable waste pickers in Brazil. AB - BACKGROUND: Hepatitis E virus (HEV) infection represents an important cause of acute viral hepatitis. Selective waste collection is a widespread activity carried out by the urban poor, and recyclable waste pickers have a lifestyle that makes this group highly vulnerable to unfavorable socio-economic and environmental factors. To date, the epidemiology of HEV infection in this population remains unknown. OBJECTIVES: To assess the seroprevalence of hepatitis E-specific antibodies in a population of recyclable waste pickers in Brazil. STUDY DESIGN: Between April 2010 and May 2011, a cross-sectional study was conducted among recyclable waste pickers from all 15 recycling cooperatives in Goiania City, Central Brazil. The participants were tested for serological markers indicative of HEV infection. RESULTS: Of 432 individuals asked to participate in the survey, 431 (99.8%) agreed to participate. Twenty-four of 431 participants were anti-HEV IgG positive by ELISA. Of these, 22 were confirmed positive by immunoblot, resulting in an anti-HEV IgG prevalence of 5.1% (95% CI: 3.4-7.6). In addition, four individuals were anti-HEV IgM positive by ELISA. Of these, three (0.7%; 95% CI: 0.4-2.4) were confirmed anti-HEV IgM positive by immunoblot, but were HEV RNA negative. One was concurrently positive for anti-HEV IgG. Only age>40 years was independently associated with the presence of anti HEV. CONCLUSIONS: These findings demonstrated that the prevalence of HEV antibodies among recyclable waste pickers in Central Brazil is relatively low and increased with age. PMID- 24480724 TI - Paediatric human metapneumovirus infection: epidemiology, prevention and therapy. AB - Since its discovery in 2001, human metapneumovirus (hMPV) has been identified as one of the most frequent causes of upper and lower respiratory tract infections. Although a considerable number of hMPV infections are diagnosed in adults and the elderly, the highest incidence of infection is among children as seropositivity for hMPV approaches 100% by 5-10 years of age. Most of the diseases due to hMPV are mild or moderate, tend to resolve spontaneously, and only require outpatient treatment. However, some may be severe enough to require hospitalisation or, albeit rarely, admission to a paediatric intensive care unit because of acute respiratory failure. Mortality is exceptional, but may occur. The most severe diseases generally affect younger patients, prematurely born children, and children who acquire nosocomial hMPV infection and those with a severe chronic underlying disease. Global hMPV infection has a major impact on national health systems, which is why various attempts have recently been made to introduce effective preventive and therapeutic measures; however, although some are already in the phase of development (including vaccines and monoclonal antibodies), there is currently no substantial possibility of prevention and, despite its limitations, ribavirin is still the only possible treatment. Given the risk of severe disease in various groups of high-risk children and the frequency of infection in the otherwise healthy paediatric population, there is an urgent need for further research aimed at developing effective preventive and therapeutic measures against hMPV. PMID- 24480725 TI - Adrenomedullin alleviates pulmonary artery collagen accumulation in rats with pulmonary hypertension induced by high blood flow. AB - Collagen accumulation is one of the important pathologic changes in the development of pulmonary hypertension. Previous research showed that adrenomedullin (ADM) mitigates the development of pulmonary hypertension. The present study explored the role of ADM in the development of pulmonary artery collagen accumulation induced by high pulmonary blood flow, by investigating the effect of ADM [1.5 MUg/(kg h)] subcutaneously administered by mini-osmotic pump on pulmonary hemodynamics, pulmonary vascular structure and pulmonary artery collagen accumulation and synthesis in rats with high pulmonary blood flow induced by aortocaval shunting. The results showed that ADM significantly decreased mean pulmonary artery pressure (mPAP) and the ratio of right ventricular mass to left ventricular plus septal mass [RV/(LV+SP)], attenuated the muscularization of small pulmonary vessels and relative medial thickness (RMT) of pulmonary arteries in rats with high pulmonary blood flow. Meanwhile, ADM ameliorated pulmonary artery collagen deposition represented by a decrease in lung tissue hydroxyproline, collagens I and III content and pulmonary artery collagens I and III expression, reduced collagen synthesis represented by a decrease in lung tissue procollagens I and III mRNA expression. The results suggest that ADM plays a protective role in the development of pulmonary hypertension induced by high blood flow, by inhibiting pulmonary procollagen synthesis and alleviating pulmonary artery collagen accumulation. PMID- 24480726 TI - Spinal ERK2 activation through delta2-opioid receptors contributes to nociceptive behavior induced by intrathecal injection of leucine-enkephalin. AB - Intrathecal (i.t.) injection of leucine-enkephalin (Leu-ENK), co-administered with peptidase inhibitors, phosphoramidon (an endopeptidase 24.11 inhibitor), and bestatin (a general aminopeptidase inhibitor), produced behaviors consisting of the biting and/or licking of the hindpaw and the tail along with hindlimb scratching directed toward the flank, which peaked at 10-15 min after an injection. This characteristic behavior was not observed in mice treated with i.t. Leu-ENK alone. We also investigated the effect of the extracellular signal regulated kinase (ERK) in spinal processing of nociception induced by i.t. co administration of Leu-ENK with phospharamidon and bestatin. Western blot analysis of phospho-ERK (pERK) showed a significant increase of pERK2 in the lumbar spinal cord in response to i.t. Leu-ENK co-injected with peptidase inhibitors. The MAP kinase-ERK inhibitor, U0126 dose-dependently attenuated the nociceptive behavior and spinal ERK activation to i.t. Leu-ENK co-injected with peptidase inhibitors. Furthermore, the nociceptive behavior and spinal ERK activation evoked by i.t. Leu-ENK in combination with peptidase inhibitors were inhibited by co administration of the non-selective delta-opioid receptor antagonist, naltrindole, the selective delta2-opioid receptor antagonist, naltriben, the non competitive N-methyl-D-aspartate (NMDA) antagonist, MK-801 or the non-selective nitric oxide synthase inhibitor, L-NAME, the selective nNOS inhibitor, N(omega) propyl-L-arginine or the selective iNOS inhibitor, W1400, but not by the selective delta1-receptor antagonist, BNTX (7-benzylidenenaltrexone). These results suggest that spontaneous nociceptive behaviors produced by i.t. co administration of Leu-ENK with peptidase inhibitors may be induced by an activation of the glutamate-NO-ERK pathway through the delta2-opioid receptor in the dorsal spinal cord. PMID- 24480727 TI - Correlation between radiation dose and histopathological findings in patients with gliblastoma treated with boron neutron capture therapy (BNCT). AB - The purpose of this study was to clarify the correlation between the radiation dose and histopathological findings in patients with glioblastoma multiforme (GBM) treated with boron neutron capture therapy (BNCT). Histopathological studies were performed on specimens from 8 patients, 3 had undergone salvage surgery and 5 were autopsied. For histopathological cure of GBM at the primary site, the optimal minimal dose to the gross tumor volume (GTV) and the clinical target volume (CTV) were 68Gy(w) and 44Gy(w), respectively. PMID- 24480728 TI - Quantitative analysis of high-resolution, contrast-enhanced, cone-beam CT for the detection of intracranial in-stent hyperplasia. AB - BACKGROUND: Intracranial in-stent hyperplasia is a stroke-associated complication that requires routine surveillance. OBJECTIVE: To compare the results of in vivo experiments to determine the accuracy and precision of in-stent hyperplasia measurements obtained with modified C-arm contrast-enhanced, cone-beam CT (CE CBCT) imaging with those obtained by 'gold standard' histomorphometry. Additionally, to carry out clinical analyses comparing this CE-CBCT protocol with digital subtraction angiography (DSA). METHODS: A non-binned CE-CBCT protocol (VasoCT) was used that acquires x-ray images with a small field-of-view and applies a full-scale reconstruction algorithm providing high-resolution three dimensional (3D) imaging with 100 um isotropic voxels. In an vivo porcine model, VasoCT cross-sectional area measurements were compared with gold standard vessel histology. VasoCT and DSA were used to calculate in-stent stenosis in 23 imaging studies. RESULTS: Porcine VasoCT cross-sectional stent, lumen, and in-stent hyperplasia areas strongly correlated with histological measurements (r(2)=0.97, 0.93, 0.90; slope=1.14, 1.07, and 0.76, respectively; p<0.0001). Clinical VasoCT percentage stenosis correlated well with DSA percentage stenosis (r(2)=0.84; slope=0.76), and the two techniques were free of consistent bias (Bland-Altman, bias=3.29%; 95% CI -14.75% to 21.33%). An illustrative clinical case demonstrated the advantages of VasoCT, including 3D capability and non-invasive IV contrast administration, for detection of in-stent hyperplasia. CONCLUSIONS: C-arm VasoCT is a high-resolution 3D capable imaging technique that has been validated in an animal model for measurement of in-stent tissue growth. Successful clinical implementation of the protocol was performed in a small case series. PMID- 24480730 TI - Monocyte chemotactic protein-1 -2518 gene polymorphism and susceptibility to spinal tuberculosis. AB - BACKGROUND AND AIMS: Monocyte chemotactic protein-1 (MCP-1) gene polymorphisms play important roles in regulating immunological reactions and may be associated with pulmonary tuberculosis. However, the relationship between the MCP-1 -2518 gene polymorphism and susceptibility to spinal tuberculosis remains unknown. We undertook this study to investigate the relationships between MCP-1 promoter 2518 genotype frequency and allele polymorphisms and susceptibility to spinal tuberculosis in a Chinese Han population. METHODS: Patients with spinal tuberculosis and healthy volunteers were enrolled between December 2004 and December 2010. MCP-1 -2518 polymorphisms in both groups were detected using polymerase chain reaction and DNA sequencing. MCP-1 genotype was analyzed in all patients. Differences in genotype frequencies between groups were compared using chi(2) tests. RESULTS: A total of 208 patients with spinal tuberculosis and 210 healthy volunteers were included. The distribution frequencies of MCP-1 -2518 GG, GA and AA genotypes were 36.1, 50.9 and 13.0%, respectively, in the case group and 25.2, 53.8 and 21.0%, respectively, in the control group (p <0.05). MCP-1 2518 GG genotype was significantly associated with the onset of spinal tuberculosis (OR = 2.306, 95% CI = 1.273-4.178). The G and A allele frequencies were 61.5% and 38.5%, respectively, in the case group, and 52.1% and 47.9% in the control group (p <0.05), the allele "G" of MCP-1 -2518 showed an association with an increased risk for spinal tuberculosis: OR = 1.777, 95% CI = 1.053-2999, p = 0.03 in the dominant model; OR = 1.67, 95% CI = 1.097-2.544, p = 0.016 in the recessive model. CONCLUSIONS: The MCP-1 -2518 GG genotype and presence of the G allele may be associated with susceptibility to spinal tuberculosis in the Chinese Han population. PMID- 24480729 TI - The Healthy Home Offerings via the Mealtime Environment (HOME) Plus study: design and methods. AB - BACKGROUND: Informed and engaged parents and healthful home environments are essential for the health of youth. Although research has shown health benefits associated with family meals, to date, no randomized controlled trial (RCT) has been developed to examine the impact of a family meals intervention on behavioral and health outcomes. METHODS/DESIGN: The Healthy Home Offerings via the Mealtime Environment (HOME) Plus study is a two-arm (intervention versus attention-only control) RCT being conducted in Minneapolis/St. Paul. Built on previous pilot research, HOME Plus aims to increase the frequency and healthfulness of family meals and snacks and reduce children's sedentary behavior, particularly screen time, to promote healthier eating and activity behaviors and prevent obesity. HOME Plus is delivered to families in community settings. The program includes 10 monthly sessions focused on nutrition and activity education, meal planning and preparation skill development. In addition, five motivational goal-setting phone calls are conducted with parents. The primary outcome measure is age- and gender adjusted child BMI-z score at post-intervention by treatment group. Secondary household-level outcomes include family meal frequency, home availability of healthful foods (fruits/vegetables) and unhealthful foods (high-fat/sugary snacks) and beverages (sugar-sweetened beverages), and the quality of foods served at meals and snacks. Secondary child outcomes include dietary intake of corresponding foods and beverages and screen time. CONCLUSIONS: The HOME Plus RCT actively engages whole families of 8-12 year old children to promote healthier eating and activity behaviors and prevent obesity through promotion of family meals and snacks and limited media use. PMID- 24480731 TI - Genistein inhibited amyloid-beta induced inflammatory damage in C6 glial cells. AB - BACKGROUND AND AIMS: beta-amyloid-induced inflammation has been implicated in the early pathologic events in neurodegenerative diseases. The anti-inflammation potential of genistein (GEN) had been proved recently in our previous studies. We undertook this study to investigate the effects of GEN on inflammation induced by beta-amyloid25-35 treatment and the possible molecular mechanisms in C6 glial cells. METHODS: C6 cells were pre-incubated with GEN for 2 h followed by the incubation with beta-amyloid 25-35 (Abeta25-35) for another 24 h. Inflammatory factors were detected by ELISA. The mRNA and protein expression of nuclear factor kappaB (NF-kappaB) p65 was measured using RT-PCR and Western blot, respectively. After inhibiting the NF-kappaBp65 mRNA expression by using short interfering RNAs (siRNAs) technique, the changes of inflammatory factors levels were detected again. RESULTS: GEN inhibited the production of inflammatory factors induced by Abeta25-35 treatment. Abeta25-35 treatment had no effect on the mRNA expression of NF-kappaBp65 but upregulated the protein expression of NF-kappaBp65. However, this upregulation effect on NF-kappaBp65 protein expression was alleviated by GEN pretreatment. After inhibiting NF-kappaBp65 mRNA expression by using siRNA technique, the effects of Abeta25-35 or GEN on the inflammatory factor generation were inhibited. CONCLUSIONS: These results indicated that GEN exhibited anti inflammatory effects through regulating NF-kappaB signaling pathway in Abeta25-35 treated C6 glial cells. PMID- 24480732 TI - Peroxisome proliferator-activated receptor gamma concentrations in newly diagnosed hypertension patients and the metabolic effects of olmesartan. AB - BACKGROUND AND AIMS: We undertook this study to investigate the effects of olmesartan treatment on PPAR-gamma (PPAR-gamma) concentrations and metabolic syndrome (MetS) components in hypertensive (HT) patients. METHODS: The study included 46 newly diagnosed hypertensive patients and 30 healthy controls. All hypertensive patients were given 40 mg of olmesartan, and they were evaluated weekly in the first month and then twice weekly during follow-up visits. At the end of 3 months, MetS components were assessed and serum PPAR-gamma transcription factor concentrations were again measured. RESULTS: MetS was noted in 80.4% of HT patients. Serum PPAR-gamma transcription factor concentration were significantly lower in those with HT compared with the controls (p = 0.005). PPAR-gamma concentrations of controls were 1.14-fold higher than hypertensive patients. HDL levels were significantly increased after treatment (p = 0.004), triglyceride, total cholesterol, fasting blood glucose (FBG), and LDL levels were significantly reduced (p <0.05). There was a tendency toward increased PPAR-gamma concentrations after treatment, but these were not statistically significant (p = 0.154). CONCLUSIONS: Olmesartan treatment was found to generate beneficial effects on MetS parameters in HT patients but did not produce any significant increases in serum PPAR-gamma transcription factor concentration. PMID- 24480733 TI - Time-dependent changes and association between liver free fatty acids, serum lipid profile and histological features in mice model of nonalcoholic fatty liver disease. AB - BACKGROUND AND AIMS: Methionine-choline deficient (MCD) diet duration necessary for development of non-alcoholic fatty liver disease (NAFLD) and the dynamic of lipid profile and fatty acids are not completely established. The study examined dynamics and association between liver free fatty acids (FFA), serum lipid profile and liver morphological changes on MCD diet-induced NAFLD in mice. METHODS: Male C57BL/6 mice (n = 28) were divided into four groups (n = 7 per group): control: fed with standard chow, MCD diet-fed groups: 2, 4 or 6 weeks. After treatment, liver and blood samples were taken for histopathology, serum lipid profile, and liver FFA composition. RESULTS: Hepatic FFA profile showed a decrease in saturated acids, arachidonic and docosahexaenoic acid, whereas proportions of docosapentaenoic, oleic and linoleic acid were increased. Total cholesterol, HDL and triglycerides progressively decreased, whereas LDL level progressively increased. Focal fatty change in the liver appeared after 2 weeks, whereas diffuse fatty change with severe inflammation and ballooned hepatocytes were evident after 6 weeks. CONCLUSIONS: Six-week diet model may be appropriate for investigation of the role of lipotoxicity in the progression of NAFLD. Therefore, supplementation with n-3 polyunsaturated acid like DHA, rather than DPA, especially in the initial stage of fatty liver disease, may potentially have preventive effects and alleviate development of NAFLD/NASH and may also potentially reduce cardiovascular risk by moderating dyslipidemia. PMID- 24480734 TI - Determinations of airborne synthetic musks by polyurethane foam coupled with triple quadrupole gas chromatography tandem mass spectrometer. AB - Synthetic musk is widely used in various scented consumer products. However, the exposure via inhalation is often ignored due to pleasant smells. In addition, the information regarding the distribution of synthetic musk in air is limited. Hence, this research is aimed to develop a highly sensitive and widely applicable method for the determination of airborne synthetic musk. In this study, polyurethane foam (PUF) and filter were employed for active air sampling. Microwave assisted extraction (MAE) and nitrogen evaporator were performed for sample preparation. A gas chromatography coupled with triple quadrupole tandem mass spectrometer (GC/MS-MS) with specific multiple reaction monitoring (MRM) transition pairs was applied for sample analysis. Compared with using selected ion monitoring (SIM) mode traditionally, the sensitivities were improved in this study about an order at least. In terms of air concentration, as low as 0.48ngm( 3) can be determined when sampling at 3.5Lmin(-1) for 8h. The method established was further applied to the analysis of synthetic musk compounds in air samples collected in a cosmetics plant. The results showed that the airborne concentrations of gaseous polycyclic musk, gaseous nitro-musk, and particle-phase polycyclic musk were 6.4*10(2), 4.0*10(1) and 3.1*10(2)ngm(-3), respectively. Meanwhile, Cashmeran, Celstolide, Galaxolide, and Tonalide were found as the dominant musk compounds in the factory investigated. PMID- 24480735 TI - Optimal control of vancomycin-resistant enterococci using preventive care and treatment of infections. AB - The rising prevalence of vancomycin-resistant enterococci (VRE) is a major health problem in intensive care units (ICU) because of its association with increased mortality and high health care costs. We present a mathematical framework for determining cost-effective strategies for prevention and treatment of VRE in the ICU. A system of five ordinary differential equations describes the movement of ICU patients in and out of five VRE-related states. Two control variables representing the prevention and treatment of VRE are incorporated into the system. The basic reproductive number is derived and calculated for different levels of the two controls. An optimal control problem is formulated to minimize VRE-related deaths and costs associated with prevention and treatment controls over a finite time period. Numerical solutions illustrate optimal single and dual allocations of the controls for various cost values. Results show that preventive care has the greatest impact in reducing the basic reproductive number, while treatment of VRE infections has the most impact on reducing VRE-related deaths. PMID- 24480736 TI - Effect of immunotherapy on the response of TICLs to solid tumour invasion. AB - There is clinical evidence that some people have lived with a benign tumour for their entire life time. This is explained by cancer dormancy which is attributed to the interaction of tumour infiltrating cytotoxic lymphocytes (TICLs) with tumour cells. We present two mathematical models to study the mechanism of interaction of TICLs with tumour cells, with and without clinical intervention. Stability analysis and numerical simulations of the models reveal the existence of a stable tumour dormant state. PMID- 24480737 TI - A novel minimal mathematical model of the hypothalamus-pituitary-thyroid axis validated for individualized clinical applications. AB - The hypothalamus-pituitary-thyroid (HPT) axis represents a complex, non-linear thyroid hormone system in vertebrates governed by numerous variables. The common modeling approach until now aims at a comprehensive inclusion of all known physiological influences. In contrast, we develop a parsimonious mathematical model that integrates the hypothalamus-pituitary (HP) complex as an endocrinologic unit based on a parameterized negative exponential function between free thyroxine (FT4) as stimulus and thyrotropin (thyroid stimulating hormone, TSH) as response. Model validation with clinical data obtained from geographically different hospitals revealed a goodness-of-fit largely ranging between 90% < R2 < 99%, each HP characteristic curve being uniquely defined for each individual akin to a fingerprint. Specifically, the HP model represents the afferent feedback limb of the HPT axis while the efferent limb is mathematically depicted by TSH input to the thyroid gland which responds by secreting T4 as its chief output. The complete HPT axis thus forms a closed loop system with negative feedback resulting in an equilibrium state or homeostasis under defined conditions illustrated by the intersection of the HP and thyroid response characteristics. In this treatise, we demonstrate how this mathematical approach facilitates homeostatic set points computation for personalized dosing of thyroid medications of patients to individualized euthyroid states. PMID- 24480738 TI - Optimal experimental design for discriminating between microbial growth models as function of suboptimal temperature. AB - In the field of predictive microbiology, mathematical models play an important role for describing microbial growth, survival and inactivation. Often different models are available for describing the microbial dynamics in a similar way. However, the model that describes the system in the best way is desired. Optimal experimental design for model discrimination (OED-MD) is an efficient tool for discriminating among rival models. In this work the T12-criterion proposed by Atkinson and Fedorov (1975) [1] and applied efficiently by Ucinski and Bogacka (2005) [2] and the Schwaab-approach proposed by Schwaab et al. (2008) [3] and Donckels et al. (2009) [4] will be applied for discriminating among rival models for the microbial growth rate as a function of temperature. The two methods will be tested in silico and their performances will be compared. Results from a simulation study indicate that it is possible to validate the case that one of the proposed models is more accurate for describing the temperature effect on the microbial growth rate. Both methods are able to design inputs with a sufficient discrimination potential. However, it has been observed that the Schwaab-approach provides inputs with a higher discrimination potential in combination with more accurate parameter estimates. PMID- 24480739 TI - Why do young adults with Type 1 diabetes find it difficult to manage diabetes in the workplace? AB - This article explores how and why workplace environments impact diabetes management for adults people with Type 1 diabetes, 23-30 years of age. Interviews were conducted with 35 young adults, 29 women and 6 men. The majority of these interviewees worked in sectors such as banking, technology and administration. Young adults found it difficult to manage diabetes in the workplace for two main reasons: work-related time pressures and the non-routine nature of interviewees' work and working environment. Young adults also found it difficult to get the time to exercise both inside and outside of work. Young adults with Type 1 diabetes need to be provided with the tools and technologies that they need to manage diabetes in modern flexible workplaces. PMID- 24480740 TI - Abstracts - 10th Congress of the WFITN (World Federation of Interventional Neuroradiology) - Montreal, Canada - June 29th-July 3rd, 2009. PMID- 24480741 TI - Ten years of experience with closure of persistent foramen ovale: patient characteristics and outcomes. AB - BACKGROUND: Optimal management of patients with persistent foramen ovale (PFO) following cryptogenic stroke or transient ischemic attack (TIA) suspected for paradoxical embolic events is still unclear. PFO closure has the potential benefit of preventing recurrent embolic events and avoiding serious bleeding resulting from long-term anticoagulation. Despite the widespread usage of closure devices, no randomized trial supports the general percutaneous closure approach. In addition, only mid-term, but not long-term, outcomes have been reported until now. The aim of the study is to assess clinical characteristics and long-term clinical outcome of patients undergoing percutaneous PFO closure. METHODS: Included in this single-center registry trial were 146 consecutive patients who underwent percutaneous closure of PFO at the University Hospital Frankfurt from 2000 to 2009. Periprocedural outcomes and long-term events were assessed. Follow up was available in 146 patients (100%) with a mean follow-up of 7.8+/-3.1 years (cumulative 1148 patient-years). RESULTS: The cerebroischemic event leading to indicate percutaneous PFO closure was TIA (34.9%), stroke without sequels (38.4%), stroke with sequels (24.7%), amaurosis fugax (N=2; 1.4%), and peripheral emboli (N=1; 0.7%). Only one severe periprocedural complication occurred (device dislocation). The majority of patients (N=143; 97.9%) experienced no further events during follow-up. CONCLUSION: This "all-comers" population documents the safety of percutaneous PFO closure. The cardiovascular event rate is slightly lower (0.26 per 100 patient years) compared to the recently published randomized trials and maintained persistently low rate for more than 8 years. PMID- 24480742 TI - Editorial. PMID- 24480743 TI - CRISPR/Cas9 and genome editing in Drosophila. AB - Recent advances in our ability to design DNA binding factors with specificity for desired sequences have resulted in a revolution in genetic engineering, enabling directed changes to the genome to be made relatively easily. Traditional techniques for generating genetic mutations in most organisms have relied on selection from large pools of randomly induced mutations for those of particular interest, or time-consuming gene targeting by homologous recombination. Drosophila melanogaster has always been at the forefront of genetic analysis, and application of these new genome editing techniques to this organism will revolutionise our approach to performing analysis of gene function in the future. We discuss the recent techniques that apply the CRISPR/Cas9 system to Drosophila, highlight potential uses for this technology and speculate upon the future of genome engineering in this model organism. PMID- 24480744 TI - Methylation modifications in eukaryotic messenger RNA. AB - RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA (mRNA), such as N(7)-methylguanosine (m(7)G) at the cap, N(6)-methyl-2'-O-methyladenosine (m(6)Am), 2'-O-methylation (Nm) within the cap and the internal positions, and internal N(6)-methyladenosine (m(6)A) and 5-methylcytosine (m(5)C). Among them, m(7)G cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export. m(6)A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. m(6)A has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein (FTO) and its homolog protein, alkylation repair homolog 5 (ALKBH5). FTO has a special demethylation mechanism that demethylases m(6)A to A through two over-oxidative intermediate states: N(6)-hydroxymethyladenosine (hm(6)A) and N(6) formyladenosine (f(6)A). The two newly discovered m(6)A demethylases, FTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible m(6)A, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field "RNA Epigenetics". 5-methylcytosine (5mC) as an epigenetic mark in DNA has been studied widely, but m(5)C in mRNA is seldom explored. The bisulfide sequencing showed m(5)C is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future perspectives on functional studies. PMID- 24480745 TI - miR-888 in MCF-7 side population sphere cells directly targets E-cadherin. AB - Side population (SP) cells are a small subset of cells isolated from a cultured cancer cell line that exhibit characteristics similar to those of cancer stem cells (CSCs), such as high metastatic and tumorigenic potential. The molecular mechanisms that give rise to the malignant properties of SP cells are not clear. We isolated SP cells from the MCF-7 breast cancer cell line and profiled microRNA (miRNA) expression patterns between SP cell-derived spheroids and non-SP cells. SP spheroids were found to possess 42 up-regulated miRNAs and 27 down-regulated ones (above 5-fold changes). One of the up-regulated miRNAs, miR-888 computationally predicted to participate in the adherens junction (AJ) pathway, was investigated. Over-expression of miR-888 in MCF-7 cells reduced the mRNA levels of all four AJ pathway genes (E-cadherin, ACTG1, PTPRT and CDC42) that were selected for testing, whereas knocking down miR-888 reversed the trends. Western blot and flow cytometric quantitation of the membrane E-cadherin levels showed the same trend of change under these treatments. Luciferase reporter assay showed E-cadherin is a direct target of miR-888. As a potential role in intercellular adhesiveness and maintenance of malignant tissue architecture, the results indicate that miR-888 is a repressor of the AJ pathway in MCF-7 cells and that up-regulation of miR-888 contributes to aggressiveness in MCF-7 SP cells. PMID- 24480746 TI - Efficient gene targeting in zebrafish mediated by a zebrafish-codon-optimized cas9 and evaluation of off-targeting effect. PMID- 24480747 TI - Bacterial community dynamics in a full-scale municipal wastewater treatment plant employing conventional activated sludge process. AB - To elucidate the bacterial community dynamics in a full-scale wastewater treatment plant (WWTP) and the relatedness among bacterial communities in the influent, effluent and sludge, the structure and metabolic ability of the bacterial community throughout a full-scale WWTP employing a conventional activated sludge process was investigated during a period of 10 months. The bacterial community structure was analyzed by terminal-restriction fragment length polymorphism targeting eubacterial 16S rRNA genes, while a Biolog assay was applied to assess the metabolic ability of the activated sludge. Influent bacterial community structure was generally stable. In contrast, the bacterial community structure in the effluent was similar to that in the influent in some cases, while in other cases it was unique and differed greatly from that in the influent and sludge. These results suggest that temporal variations of the effluent bacterial community may be useful to predict the wastewater treatment performance and settleability of activated sludge. The bacterial community structure in the sludge was relatively stable and was rarely impacted by the influent populations. Biolog assay also revealed that activated sludge maintained a remarkably similar metabolic potential of organic compounds over time due to functional redundancy, in which the minor populations played a significant role. PMID- 24480748 TI - Long-term effect of temperature on N2O emission from the denitrifying activated sludge. AB - The long-term effect of various temperature (4 degrees C, 12 degrees C, 20 degrees C, 25 degrees C and 34 degrees C) on nitrous oxide (N2O) emission from lab-scale denitrifying activated sludge was studied in terms of activation energy, abundance of functional gene nosZ and its transcription. Results showed that temperature had a positive effect on N2O emissions as well as the maximum biomass-specific reduction rates of N2O and NO3(-), ranging from 0.006% to 0.681% of (N2O + N2), 17.3-116.2 and 5.2-66.2 mg N g(-1) VSS h(-1), respectively. The activation energies (Ea) for N2O and NO3(-) reduction of 44.1 kJ mol(-1) and 54.9 kJ mol(-1), shed light on differences in denitrifying rate variation. The maximum NO3(-) reduction rates were more sensitive to temperature variation than the corresponding N2O reduction rates under long-term acclimation. As a result, the ratio between N2O and NO3(-) reduction rates declined to 1.87 at 34 degrees C from 3.31 at 4 degrees C, suggesting great potential capacity for N2O losses at high temperature. The copy numbers of denitrifiers as nosZ gene (*10(8) copies mL(-1)) and total bacteria as 16S rRNA gene (*10(10) copies mL(-1)) did not show obvious relationship with temperature, having relative abundance of 0.42% on average. The transcriptional regulation of nosZ gene, in the range of 10(8)-10(5) copies mL(-1), was affected by reductase activity, substrate concentration as well as its duration. The active nosZ gene expression was accompanied with low reductase capacity, high dissolved N2O and the duration of N2O accumulation. These results provide insights into activation energy and gene expression responsible for N2O emission. PMID- 24480749 TI - The effects of N-acylhomoserine lactones, beta-lactam antibiotics and adenosine on biofilm formation in the multi-beta-lactam antibiotic-resistant bacterium Acidovorax sp. strain MR-S7. AB - Bacteria in the natural ecosystem frequently live as adherent communities called biofilms. Some chemical compounds are known to affect biofilm formation. We investigated the effect of exogenous small molecules, N-acylhomoserine lactones (AHLs), beta-lactam antibiotics, and adenosine, on biofilm formation in the beta lactam antibiotic-resistant bacterium Acidovorax sp. strain MR-S7. Biofilm formation was induced by the addition of various types of AHL isomers and beta lactam antibiotics, whereas the addition of adenosine strongly interfered with the biofilm formation. A gene (macP) encoding adenosine deaminase (that converts adenosine to inosine controlling intracellular adenosine concentration) was successfully cloned from MR-S7 genome and heterologously expressed in Escherichia coli. The purified MacP protein clearly catalyzed the deamination of adenosine to produce inosine. A transcriptional analysis revealed that biofilm-inducing molecules, an AHL and a beta-lactam antibiotic, strongly induced not only biofilm formation but also adenosine deaminase gene expression, suggesting that an elaborate gene regulation network for biofilm formation is present in the beta lactam antibiotic-resistant bacterium studied here. PMID- 24480750 TI - Differences in the seasonal variation of brominated and phosphorus flame retardants in office dust. AB - This study documents the temporal variability in concentrations of flame retardants (FRs) in floor dust from three offices in Beijing, China. Dust from Office A (OAD) was collected weekly from March to August, 2012, and sampling of dust from Office B and C (OBD and OCD) was conducted fortnightly (each two weeks) from March to December 2012. With intensive and continuous sampling, we report for the first time on clear and coherent temporal trends of polybrominated diphenyl ethers (PBDEs), novel brominated flame retardants (NBFRs) and phosphorus flame retardants (PFRs) in indoor dust. The observed mean concentrations of ?9PBDEs, ?4NBFRs and ?9PFRs, were 554, 11,100 and 128,000ngg(-1) in OAD; 7560, 5000 and 17,300ngg(-1) in OBD; and 4750, 3550 and 17,200ngg(-1) in OCD, respectively. With exception of PBDEs, concentrations of FRs were elevated in OAD than in OBD and OCD. Two to ten-fold variations were observed between the minimum and maximum concentrations of FRs in the same office, indicating that the sampling moment exerts a substantial influence on the level of FR contamination. Different seasonality was distinctively found between BFRs and PFRs. Except for a few occasional abnormal values, BFR levels in office dust were generally constant among different seasons. The abundance rank order for PFRs was: winter>autumn>summer, with peak values occurring in late winter and early spring. This pattern may be attributable to the fact that PFRs are more sensitive to temperature changes compared to PBDEs and NBFRs owning to their higher volatilities. The absence of significant seasonal variation for BFR concentrations in indoor dust compared to outdoor air and dust concentrations is also discussed. PMID- 24480752 TI - NADPH oxidase 4 promotes cardiac microvascular angiogenesis after hypoxia/reoxygenation in vitro. AB - Microvascular endothelial cell dysfunction plays a key role in myocardial ischemia/reperfusion (I/R) injury, wherein reactive oxygen species (ROS) dependent signaling is intensively involved. However, the roles of the various ROS sources remain unclear. This study sought to investigate the role of NADPH oxidase 4 (Nox4) in the cardiac microvascular endothelium in response to I/R injury. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and subjected to hypoxia/reoxygenation (H/R). Our results showed that Nox4 was highly expressed in CMECs, was significantly increased at both mRNA and protein levels after H/R injury, and contributed to H/R-stimulated increase in Nox activity and ROS generation. Downregulation of Nox4 by small interfering RNA transfection did not affect cell viability or ROS production under normoxia, but exacerbated H/R injury as evidenced by increased apoptosis and inhibited cell survival, migration, and angiogenesis after H/R. Nox4 inhibition also increased prolyl hydroxylase 2 (PHD2) expression and blocked H/R-induced increases in HIF 1alpha and VEGF expression. Pretreatment with DMOG, a specific competitive PHD inhibitor, upregulated HIF-1alpha and VEGF expression and significantly reversed Nox4 knockdown-induced injury. However, Nox2 was scarcely expressed and played a minimal role in CMEC survival and angiogenesis after H/R, though a modest upregulation of Nox2 was observed. In conclusion, this study demonstrated a previously unrecognized protective role of Nox4, a ROS-generating enzyme and the major Nox isoform in CMECs, against H/R injury by inhibiting apoptosis and promoting migration and angiogenesis via a PHD2-dependent upregulation of HIF 1/VEGF proangiogenic signaling. PMID- 24480751 TI - Immunoneuropathogenesis of HIV-1 clades B and C: role of redox expression and thiol modification. AB - Previous studies have shown that, during infection, HIV-1 clade B and clade C differentially contribute to the neuropathogenesis and development of HIV associated neurocognitive disorders (HANDs). The low-molecular-weight tripeptide glutathione (GSH) alters the redox balance and leads to the generation of reactive oxygen species, which play a significant role in the neuropathogenesis of HANDs. We hypothesized that the HIV-1 clade B and clade C viruses and their respective Tat proteins exert differential effects on monocyte-derived immature dendritic cells (IDCs) and neuroblastoma cells (SK-N-MC) by redox activation, which leads to immunoneuropathogenesis. The GSH/GSSG ratio and mRNA expression levels and protein modification of glutathione synthetase (GSS), glutathione peroxidase 1 (GPx1), superoxide dismutase 1 (SOD1), and catalase (CAT) were analyzed in IDCs infected with HIV-1 clade B or clade C as well as in cells treated with the respective Tat proteins. The results indicated that HIV-1 clade B virus and its Tat protein significantly increased the production of reactive oxygen species and reduced the GSH/GSSG ratio and subsequent downregulation of gene expression and protein modification of GSS, GPx1, SOD1, and CAT compared to infection with the clade C virus or treatment with the clade C Tat protein. Thus, our studies demonstrate that HIV-1 clades B and C exert differential effects of redox expression and thiol modification. HIV-1 clade B potentially induces oxidative stress, leading to more immunoneuropathogenesis than infection with HIV 1 clade C. PMID- 24480753 TI - Primary intraosseous adenoid cystic carcinoma of the jaw: clinical and histopathologic analysis. AB - PURPOSE: Adenoid cystic carcinoma (ACC), formerly known as cylindroma, is a malignant epithelial neoplasm typically derived from the salivary glands. Of all salivary gland tumors, the incidence of malignant salivary gland tumor has been 15 to 32% in the parotid glands, 70 to 90% in the sublingual glands, and about 50% in the minor salivary glands. Intraosseous ACC of the jaw has rarely been reported and is poorly understood. The aim of the present study was to analyze this tumor clinically and histopathologically to improve the diagnosis, management, and treatment. MATERIALS AND METHODS: We collected the records of 16 patients with intraosseous ACC from 1998 to 2013, who had been treated at our hospital, including clinical data and follow-up information. We then analyzed the patients' clinical features, diagnosis, treatment, and prognosis. RESULTS: The average age of the 16 patients was 56.8 years, and the male/female ratio was 0.8. The primary manifestations of the tumor were obviously different. Tumor excision was performed and followed by radiotherapy or chemotherapy, or both. The average follow-up period was 57.2 months, and the average follow-up period for patients who were alive and tumor free was 52.3 months. The survival rate was 68.8% after treatment. All these results were generally in agreement with those from previous reports. CONCLUSIONS: The differential diagnosis of intraosseous ACC from other common tumors of jaws should be determined by the clinical, radiographic, and histopathologic subtypes. For treatment, surgery is the first choice for patients, and radiotherapy or chemotherapy might improve the prognosis in the postoperative period. In addition, the histopathologic subtypes and biologic processes of ACC are related to patient prognosis. PMID- 24480754 TI - Human fingernail as interpositional graft material in the treatment of nasal septal perforations. AB - PURPOSE: The etiology of nasal septal perforations involves iatrogenic, traumatic, inflammatory, infectious, neoplastic, and caustic causes. To ensure successful closure, an appropriate interpositional graft material should be selected, and this graft material should be covered with healthy tissue. MATERIALS AND METHODS: The study included 18 New Zealand white rabbits weighing 2 to 2.5 kg. Nasal septal perforations were created in group 1. After the creation of defects in group 2, repair was performed with cartilage graft and bilateral mucoperichondrial advancement flaps. After septal nasal perforations in group 3, the defect was covered with fingernail and bilateral mucoperichondrial flaps. RESULTS: At week 12, the rabbits were sacrificed. The septum site that had been repaired with fingernail was intact. No nail exposition, wound site decomposition, or re-perforation was observed. No findings of a breach of the structural integrity of the fingernails or disintegration were encountered. CONCLUSION: Fingernails can be used as an interpositional graft material in place of cartilage in eligible cases for the repair of nasal septal perforations. Fingernails have several properties that enable their use in such cases, such as form preservation that is similar to cartilage, the lack of live cells, easy availability, and a lack of donor-site morbidity at removal. PMID- 24480755 TI - Would oral and maxillofacial surgeons benefit from theoretical publications in our journal? PMID- 24480756 TI - Late postoperative hemorrhage in a patient with undiagnosed COX-1 deficiency after third molar extractions. AB - Oral maxillofacial surgeons direct invasive procedures that often cause significant bleeding. Uncontrolled hemorrhage is a rare, yet serious, complication that can be seen in patients with thrombocytopathy. Platelets have 3 distinct roles in coagulation: initial adhesion, phospholipid externalization, and platelet aggregation.(1) Several types of platelet deficiencies, including defects of adhesion (Bernard-Soulier syndrome), defects of aggregation (Glanzmann thrombasthenia), and disorders of platelet secretion due to a deficiency of adenosine diphosphate (ADP) or cyclooxygenase-1 (COX-1).(2-4) COX has 2 isoforms: COX-1 and COX-2.(5,6) COX-1 is expressed constitutively in most tissues, and COX 2 is induced primarily by inflammatory mediators.(7,8) Although both isoforms are present in platelets, COX-1 is the major isoform that contributes to coagulation, because it is critically important in the formation of thromboxane A2 (TXA2) by way of the arachidonic acid (AA) pathway.(9) AA is a potent inducer of platelet aggregation.(1,3,4) When AA is exposed to an activating agent, such as ADP, it undergoes a series of enzymatic reactions that culminates in the production of TXA2.(10) TXA2 is the predominant product of the COX-1 pathway and is a major metabolite of AA in platelets. TXA2 is necessary for normal platelet function. Therefore, the inhibition of, or a deficiency in, COX-1 will compromise the AA pathway, thereby reducing platelet secretion and altering normal platelet aggregatory function.(1,3) COX-1 deficiencies are usually caused by drug interactions with the enzyme itself. In addition, studies have identified genetic mutations that can result in COX-1 deficiency.(2) We present the hospital course, management, and diagnosis of a patient with an undiagnosed COX-1 deficiency who had had third molars removed in a private office. To our knowledge, this is the first case of COX-1 deficiency diagnosed after exodontia documented in English studies. In addition, we reviewed the published data of this rare disorder that has significant clinical implications. PMID- 24480757 TI - Diagnosis and management of oral leishmaniasis--case series and literature review. AB - The worldwide prevalence of leishmaniasis is increasing because of ecologic changes and increased medical profession awareness. Furthermore, solitary cases have been recently reported in Western countries. The authors describe the epidemiology, mode of transmission, and diagnosis of leishmaniasis and present 4 oral cases treated with systemic, localized, or combined therapy. The authors suggest that clinicians should maintain a high index of suspicion for atypical, resistant, oral and perioral lesions in individuals with a history of traveling in certain geographic regions. After diagnosis, treatment should be determined jointly by experts from the fields of oral and maxillofacial surgery, oral medicine, and dermatology based on leishmaniasis species and clinical presentation. PMID- 24480758 TI - An algorithm for the treatment of noncondylar mandibular fractures. AB - An algorithm for the treatment of noncondylar mandibular fractures is presented based on outcomes from studies that have been performed during the past 30 years. It is designed to assist clinicians in formulating a treatment plan that can be expected to provide the patient with a predictable outcome. PMID- 24480759 TI - Commentary--Is the bone turnover of the jawbone and its possible over suppression by bisphosphonates of etiological importance for the pathogenesis of the bisphosphonate-related osteonecrosis? PMID- 24480760 TI - The spheno-occipital synchondrosis fuses prematurely in patients with Crouzon syndrome and midface hypoplasia compared with age- and gender-matched controls. AB - PURPOSE: Premature closure of the spheno-occipital synchondrosis (SOS) has been associated with midface hypoplasia in animal models and patients with specific forms of syndromic craniosynostosis. The present study aimed to characterize SOS fusion in patients with Crouzon syndrome. PATIENTS AND METHODS: A case-control study was performed in patients with Crouzon syndrome treated at the Children's Hospital of Philadelphia from 1984 to 2012. The cases included patients with Crouzon syndrome and at least 1 high-quality computed tomography (CT) scan in which SOS patency could be assessed. Age- and gender-matched control CT scans were identified for comparison. The patient age at the CT scan was evaluated as the predictor, with SOS patency identified as the outcome variable. Three independent reviewers with high inter-rater reliability graded the SOS patency as open, partially fused, or completely fused. The Wilcoxon rank sum test was used to compare the Crouzon group and the controls. RESULTS: During the study period, 30 patients were identified with Crouzon syndrome. A total of 24 patients, all with midface hypoplasia and with 112 cranial CT scans, met the inclusion criteria. Accordingly, 112 age- and gender-matched control CT scans were assessed. No patient in the control group had midface hypoplasia. Within the Crouzon group, the average age at complete closure (14.0 +/- 3.4 years) evident on the CT scan was significantly younger than that in the control group (16.6 +/- 2.2 years; P = .0152). The average age when the scans showed complete patency of the SOS in the Crouzon group (1.3 +/- 1.1 years) was significantly younger than that in the control group (3.2 +/- 2.3 years; P = .0001). CONCLUSIONS: The SOS closes significantly earlier in patients with Crouzon syndrome compared with age- and gender-matched controls. The strong statistical correlation supports premature closure of the SOS as a possible mechanistic contributor to midface hypoplasia. PMID- 24480761 TI - Inferior alveolar nerve function after sagittal split osteotomy by reciprocating saw or piezosurgery instrument: prospective double-blinded study. AB - PURPOSE: The aim of this prospective study was to objectively evaluate inferior alveolar nerve (IAN) sensory disturbances in patients who underwent sagittal split ramus osteotomy (SSRO) by comparing 1 side treated with a reciprocating saw with the other side treated with a piezosurgery device. MATERIALS AND METHODS: Clinical evaluation of IAN sensory disturbance was undertaken preoperatively and at 1 week, 4 weeks, 2 months, and 6 months postoperatively in 20 patients who underwent SSRO at the Division of Oral and Maxillofacial Surgery, Araraquara Dental School, Sao Paulo State University. The 20 patients were examined at all periods for IAN functionality by Semmes-Weinstein testing; neither the patients nor the examiner knew which side was treated using piezosurgery or a reciprocating saw. RESULTS: The mean age of the patients was 28.4 years (range, 20 to 48 yr). Before surgery, no patient had impaired function of the IAN in any of the 8 zones in the mental and inferior lip areas. All patients reported feeling the first monofilament at the time of the preoperative test. Seven days postoperatively, all patients reported some kind of altered sensitivity in at least 1 zone evaluated. CONCLUSIONS: The results of this study suggest there was no statistically significant difference in the sensitivity of the labiomental area regarding the instrument used to perform the osteotomy. Future studies will focus on enlarging the sample and evaluating the results. PMID- 24480762 TI - Management of antiresorptive osteonecrosis of the jaws with primary surgical resection. PMID- 24480763 TI - Anterior tibial artery perforator flap for reconstruction of intraoral defects. AB - PURPOSE: The present clinical study assessed the feasibility of using an anterior tibial artery perforator (ATAP) flap for the reconstruction of an intraoral defect after ablative surgery for oral cancer. PATIENTS AND METHODS: A cohort of consecutive patients with oral cancer requiring reconstruction of an intraoral defect using an ATAP flap were enrolled after ablative surgery for oral cancer and ipsilateral neck dissection. RESULTS: Twelve patients had primary oral squamous cell carcinoma (8 with tongue cancer and 4 with buccal cancer). All patients received intraoral defect repair using an ATAP flap from the lower left leg. The flap measured 7 * 4 to 8 * 6 cm(2). Flap thickness was approximately 4.8 mm (3 to 6 mm). Anastomosis of all ATAP flaps was straightforward because of the long and high-caliber vessel pedicle. All flaps survived and yielded excellent esthetic results for intraoral reconstruction. No major complications occurred in any patient. CONCLUSION: The main advantages of the ATAP flap included the thin and pliable tissue characteristics and a long and high-caliber pedicle. For small and medium-size intraoral defects, the ATAP flap is a reliable alternative to the radial forearm free flap. PMID- 24480764 TI - The cost of third molar management. PMID- 24480765 TI - Intraoperative hypertensive crisis secondary to an undiagnosed pheochromocytoma during orthognathic surgery: a case report. AB - Increased blood pressure (BP) during orthognathic surgery may result in excessive blood loss, poor surgical field visualization, and longer surgical time and require blood transfusion. When uncontrollable high BP is encountered in an otherwise healthy patient during orthognathic surgery, the diagnosis of pheochromocytoma should be considered. Pheochromocytomas are rare neuroendocrine tumors of the chromaffin cells of the adrenal medulla or extra-adrenal paraganglia (sympathetic ganglia) that secrete catecholamine. They are present in approximately 0.05 to 0.2% of hypertensive patients. Patients can present with hypertension, tachycardia, headaches, and diaphoresis. The clinical presentation may vary and a wide spectrum of nonspecific symptoms may be encountered. The elevated BP can be intermittent (40%) or permanent (60%). About 10% of pheochromocytomas are hereditary and they can be a feature of multiple endocrine neoplasia type 2. This report describes the case of a 29-year-old patient with a large pheochromocytoma of the right adrenal gland undiagnosed before orthognathic surgery. PMID- 24480766 TI - Recurrent metastatic spread to a percutaneous gastrostomy site in a patient with squamous cell carcinoma of the tongue: a case report and review of the literature. AB - Patients diagnosed with head and neck squamous cell cancer (HNSCC) frequently develop dysphagia and odynophagia owing to advancing disease or as a result of medical interventions. Selected patients diagnosed with advanced HNSCC may require the insertion of a percutaneous endoscopic gastrostomy (PEG) tube as part of their management. During the past 2 decades, there have been increasing reports describing tumor seeding at the PEG exit site, which have caused controversy relating to the technique used in PEG insertion. Although PEG placement is considered a safe procedure for patients with advanced head and neck cancer, the method can lead to tumor seeding, probably from direct traumatic tumor shedding. This report describes a case of tumor implantation at the PEG site in a patient with an advanced SCC of the tongue, with a review of the available literature concerning this rare condition and its possible pathogenesis. PMID- 24480767 TI - Salivary duct carcinoma of the parotid gland: is adjuvant HER-2-targeted therapy required? AB - PURPOSE: Salivary duct carcinoma (SDC) of the parotid gland is a highly aggressive and uncommon tumor. Overexpression of human epidermal growth factor receptor 2 (HER-2) is characteristic of SDC. HER-2 overexpression is considered a poor prognostic marker for SDC, and anti-HER-2 therapy has been suggested as a therapeutic option. MATERIALS AND METHODS: Two patients with SDC were analyzed for HER-2 overexpression and gene amplification using immunohistochemistry and fluorescence in situ hybridization. RESULTS: In 1 patient, no expression of HER-2 was found. In the other patient, HER-2 was demonstrated. The patient with HER-2 overexpression had a worse prognosis, and trastuzumab proved to be an effective treatment. CONCLUSIONS: The present results have also suggested that HER-2 overexpression is associated with a poor prognosis. Therefore, HER-2 status should be evaluated at least in the presence of advanced SDC, and targeted therapy should be considered in the adjuvant setting. PMID- 24480768 TI - Experimental considerations concerning the use of stem cells and tissue engineering for facial nerve regeneration: a systematic review. AB - PURPOSE: Peripheral nerve trauma results in functional loss in the innervated organ, and recovery without surgical intervention is rare. Many surgical techniques can be used for repair in experimental models. The authors investigated the source and delivery method of stem cells in experimental outcomes, seeking to clarify whether stem cells must be differentiated in the injured facial nerve and improve the regenerative process. MATERIALS AND METHODS: The following key terms were used: nervous regeneration, nerve regeneration, facial nerve regeneration, stem cells, embryonic stem cells, fetal stem cells, adult stem cells, facial nerve, facial nerve trauma, and facial nerve traumatism. The search was restricted to experimental studies that applied stem cell therapy and tissue engineering for nerve repair. RESULTS: Eight studies meeting the inclusion criteria were reviewed. Different sources of stem and precursor cells were explored (bone marrow mesenchymal stem cells, adipose-derived stem cells, dental pulp cells, and neural stem cells) for their potential application in the scenario of facial nerve injuries. Different material conduits (vases, collagen, and polyglycolic acid) were used as bridges. Immunochemistry and electrophysiology are the principal methods for analyzing regenerative effects. Although recent studies have shown that stem cells can act as a promising bridge for nerve repair, considerable optimization of these therapies will be required for their potential to be realized in a clinical setting. CONCLUSION: Based on these studies, the use of stem cells derived from different sources presents promising results related to facial nerve regeneration and produces effective functional results. The use of tubes also optimizes nerve repair, thus promoting greater myelination and axonal growth of peripheral nerves. PMID- 24480769 TI - A case of imperforate Wharton duct. AB - Congenital oral masses are rare entities. The establishment of formal fetal diagnostic teams has led to an increased antenatal detection of such lesions. The congenital ranula is a distinct entity from the more familiar variant presenting later in life. The congenital variant may result from an anomaly of the Wharton duct with subsequent dilation of the duct. The variant presenting later in life is the more familiar mucous extravasation phenomenon in the floor of the mouth. Management of the congenital ranula is distinct from its noncongenital counterpart and more conservative and is discussed in the present report. PMID- 24480770 TI - Clinical characteristics of angioleiomyoma of the hard palate: report of a case and an analysis of the reported cases. AB - Angioleiomyoma is a rare, benign tumor often found in the uterine myometrium, gastrointestinal tract, and skin and seldom observed in the oral and maxillofacial region. The most common site of occurrence in the oral cavity is the lip, followed by the palate, buccal mucosa, and tongue. The number of reports associated with angioleiomyoma arising from the hard palate is very small. The tumor is histologically characterized by the proliferation of mature smooth muscle cells and numerous blood vessels. When the diagnosis is difficult, specific immunohistochemistry is used. This report describes a case of angioleiomyoma in which there was a chronically increasing lesion for 5 years on the left hard palate and the means for making a definitive diagnosis was based on previous reports on angioleiomyoma of the palate. PMID- 24480771 TI - Supraomohyoid neck dissection in the management of oral squamous cell carcinoma: special consideration for skip metastases at level IV or V. AB - PURPOSE: The aim of this study was to evaluate the therapeutic safety and prognosis of supraomohyoid neck dissections for oral squamous cell carcinoma, with a special focus on the risk of skip metastases in level IV or V. MATERIALS AND METHODS: A retrospective study was conducted of 637 patients with oral squamous cell carcinoma who were admitted to the department of oral and maxillofacial surgery from September 1995 through July 2010. After completing a diagnostic evaluation, all patients underwent surgery (wide primary excision with supraomohyoid neck dissection, extended supraomohyoid neck dissection, or modified radical or radical neck dissection) and were followed periodically. RESULTS: Levels I, II, and III were the most common sites of occult metastasis. Skip metastases alone at level IV or V and any neck recurrence at level IV or V were not found. Three-year neck recurrence-free survival and disease-specific survival were not significantly different among the patients who underwent supraomohyoid neck dissection, extended supraomohyoid neck dissection, or modified radical or radical neck dissection owing to cN0 to cN(+) disease. CONCLUSIONS: The rate of skip metastasis at level IV or V is very rare and is very difficult to diagnose accurately. The results of this retrospective study show that supraomohyoid neck dissection for oral squamous cell carcinoma is an appropriate treatment. PMID- 24480772 TI - Analysis of temporomandibular joint ankylosis caused by condylar fracture in adults. AB - PURPOSE: To analyze the main causes of temporomandibular joint (TMJ) ankylosis from condylar fracture in adults through a retrospective study. MATERIALS AND METHODS: The history and computed tomographic (CT) scans of patients diagnosed with ankylosis caused by mandibular condyle fracture treated in a closed fashion from 2010 to 2012 were reviewed in the department of oral surgery. According to the relation between the stump of the ramus and the TMJ fossa, condylar fractures were divided into 3 grades: grade 0, in which the ramus stump is in the fossa but without contact to it; grade 1, in which the stump of the ramus is in the fossa and attached to it; and grade 2, in which the stump of the ramus is laterally displaced out of the fossa. Other factors, such as type of condylar fracture, displacement of the fractured fragment, position of the disc, and the presence of concomitant mandibular fractures, also were analyzed for ankylosis development. RESULTS: Of the 51 patients diagnosed with TMJ ankylosis, 13 patients (24 ankylosed joints) had full CT scans from injury to ankylosis, which showed that all condylar fractures were intracapsular fractures (ICFs), with sagittal fractures comprising 70%. Regarding the relation between the stump of the ramus and the TMJ fossa, no joints were classified as grade 0 (0%), 10 joints were classified as grade 1 (41.7%), and 14 joints were classified as grade 2 (58.3%). All discs were displaced with the fracture fragment, and the posterolateral retrodiscal tissue was torn. Among the condyle fractures leading to ankylosis, 77% featured symphysis fractures with widening of the mandibular arch. CONCLUSION: The relation between the ramus stump and the TMJ fossa plays an important role in the prognosis of condylar fracture. Grade 0 is less likely to cause ankylosis; grade 1 is more likely to cause ankylosis and is the relative indication for surgery; and grade 2 is the strongest predictor of ankylosis and is the absolute indication for surgery. Other risk factors are sagittal ICFs and combined mandibular fractures with widening of the mandibular arch. PMID- 24480773 TI - Accuracy of assessing the mandibular canal on cone-beam computed tomography: a validation study. AB - PURPOSE: To establish the accuracy of cone-beam computed tomographic (CBCT) views in determining the position and diameter of the mandibular canal. MATERIALS AND METHODS: Two freshly frozen cadaver heads, 1 dentate and 1 edentate, were used to acquire CBCT scans. Measurements on cross-sectional CBCT images were compared with measurements on digitized histologic sections of the same regions in the mandibles. The Student t test was used for statistical analysis. RESULTS: Comparing CBCT with histologic measurements showed that the position of the mandibular canal differed up to 0.47 mm (standard deviation, 0.29 mm). Mandibular canal diameters were up to 22.8% smaller in the CBCT planes. For the dentate jaw, these differences were statistically significant. CONCLUSION: To be safe, when assessing the mandibular canal position on CBCT views, a 0.76-mm deviation should be taken into account. Because the diameter of the mandibular canal is displayed smaller, an enlargement by 0.74 mm is recommended. PMID- 24480774 TI - Differences in bone remodeling using demineralized bone matrix in bilateral sagittal split ramus osteotomy: a study on volumetric analysis using three dimensional cone-beam computed tomography. AB - PURPOSE: The aim of this study was to examine the effects of demineralized bone matrix (DBM) grafts on bone remodeling during sagittal split ramus osteotomy by measuring 3-dimensional (3D) reconstructed images. PATIENTS AND METHODS: Forty eight patients were selected for this study. In the control group, no grafts were performed. In the DBM group, DBX grafts were placed between the proximal and distal segments. Three-dimensional cone-beam computerized tomographic (3D-CBCT) images were obtained within 1 week, after 3 months (T2), and after 6 months (T3) postoperatively. By measuring the total skeletal volume from the right condylar head to the right mandibular first molar, the volume of the graft site was measured indirectly. Using the data thus obtained, a volume-increasing ratio (percentage) was computed. SimPlant analytical software was used to analyze the 3D reconstructed volumes. RESULTS: The 2 groups showed a significant increase in volume. However, in the same period, the volume-increasing ratios of the 2 groups showed significant differences. In the control group, a significant increase in volume was seen until T2, after which a negligible increase was seen. Conversely, in the DBM group, a significant volume increase continued until T3. CONCLUSION: In orthognathic surgeries, grafting using DBM is a favorable procedure that accelerates bone formation. Therefore, in cases with inevitable large bony gaps, DBM grafts can play a positive role in the stable healing of segments and the prevention of postoperative complications. Moreover, because volumetric analysis using 3D-CBCT analyzing software is a fast and simple method, future studies using this technique are expected to increase. PMID- 24480775 TI - Osteoblastic differentiation and mineralization ability of periosteum-derived cells compared with bone marrow and calvaria-derived cells. AB - PURPOSE: Clinically, bone marrow stromal cells (BMCs) are the most common source of osteoprogenitor cells. Its harvest process, however, is invasive to patients. Previous reports have shown the potential advantages of using periosteum-derived cells (PDCs) as a source of cell-based transplant therapy. The objective of our study was to characterize the osteoblastic differentiation and mineralization ability of PDCs versus BMCs and osteoblasts (OBs). MATERIALS AND METHODS: BMCs, OBs, and PDCs were isolated from 4-week-old male Wistar rats. To characterize the differentiation ability of the cells, MTS assay, alkaline phosphatase (ALP) activity staining, picrosirius red staining, and alizarin red staining were performed. Immunohistochemistry was performed on paraffin sections of calvarial periosteum to determine the presence of mesenchymal stem cells. RESULTS: PDCs showed the greatest proliferation rate compared with BMCs and OBs. Matured collagenous matrix formation was observed in PDCs and BMCs. ALP-positive cells and in vitro mineralization were evident in all cell types analyzed; however, that of PDCs was not comparable to that of the OBs and BMCs. Immunohistochemistry revealed the presence of STRO-1-and CD105-positive cells in the cambium layer of the periosteum. CONCLUSIONS: PDCs have remarkable proliferative ability, but contain only a small population of osteogenic cells compared with BMCs and OBs. Although cell activity can be affected by various factors, such as age, culture condition, additives, and so forth, PDCs are likely not the source of OBs, although they might provide matrices that indirectly aid in bone formation. PMID- 24480776 TI - Letter to the editor. PMID- 24480777 TI - Expression pattern of cellulolytic and xylanolytic genes regulated by transcriptional factors XYR1 and CRE1 are affected by carbon source in Trichoderma reesei. AB - Trichoderma reesei is the most important fungus for the industrial production of enzymes to biomass deconstruction. Most of the genes encoding cellulases and hemicellulases are regulated by the transcription factors CRE1 and XYR1. In this work, the regulation of 22 genes of cellulases and xylanases by these transcription factors was investigated under three different carbon sources. Analysis of gene expression and enzymatic profiles of CMCase, beta-glucosidase, and xylanases showed different regulation that was depended of the carbon source in both Deltaxyr1 and Deltacre1 mutants. In the presence of glucose, the majority of genes evaluated (82%) showed increased expression levels in the Deltacre1 mutant compared to the parental QM9414 strain. In the Deltaxyr1 mutant, it was observed that expression of cellulase and xylanase genes was reduced compared to the parental QM9414 strain, when cultured in the presence of cellulose or sophorose. Interesting, in the presence of glucose, approximately 60% of the analyzed genes had increased expression in the Deltaxyr1 mutant compared to parental strain. Furthermore, no correlation between gene expression and the number of putative binding sites of XYR1 and CRE1 to promoter region of cellulolytic and xylanolytic studied genes was observed. Therefore, these results demonstrated that the regulation of cellulase and xylanase by the transcription factors CRE1 and XYR1 is influenced by different carbon sources. PMID- 24480779 TI - Communicating prognosis and end-of-life care to heart failure patients: a survey of heart failure nurses' perspectives. AB - BACKGROUND: Many heart failure (HF) patients have palliative care needs, but communication about prognosis and end-of-life care is lacking. HF nurses can play an important role in such communication, but their views on this have rarely been sought. AIMS: This study aims to describe HF nurses' perspectives on, and daily practice regarding, discussing prognosis and end-of-life care with HF patients in outpatient care. It further aims to explore barriers, facilitators and related factors for discussing these issues. METHODS: A national survey including nurses from outpatient clinics and primary health care centres was performed. Data was collected using a questionnaire on communication with HF patients about prognosis and end-of-life care. RESULTS: In total, 111 (82%) of the HF nurses completed the questionnaire. Most of them reported that physicians should have the main responsibility for discussing prognosis (69%) and end-of-life care (67%). Most nurses felt knowledgeable to have these discussions, but 91% reported a need for further training in at least one of the areas. Barriers for communication about prognosis and end-of-life care included the unpredictable trajectory of HF, patients' comorbidities and the opinion that patients in NYHA class II-III are not in the end-of-life. CONCLUSION: Although HF nurses feel competent discussing prognosis and end-of-life care with the HF patient, they are hesitant to have these conversations. This might be partly explained by the fact that they consider the physician to be responsible for such conversations, and by perceived barriers to communication. This implies a need for clinical policy and education for HF nurses to expand their knowledge and awareness of the patients' possible needs for palliative care. PMID- 24480778 TI - Specific enrichment of the RNA-binding proteins PCBP1 and PCBP2 in chief cells of the murine gastric mucosa. AB - RNA-binding proteins and corresponding post-transcriptional controls play critical roles in gene expression. The poly-(C) binding proteins, PCBPs (alphaCPs, hnRNPEs), comprise a well-characterized family of abundant RNA-binding proteins that impact on RNA processing in the nucleus as well as mRNA stability and translation in the cytoplasm. Here we demonstrate that PCBP1 and PCBP2 are abundantly expressed in the gastric epithelium with prominent enrichment in specific cell types within the gastric glandular mucosa. The spatial and intracellular patterns of PCBP1 and PCBP2 expression in these regions are highly correlated. Remarkably, we observe that these proteins are present in the nuclear and cytoplasmic compartments of zymogenic chief cells while they are restricted to the nuclear compartment in acid-secreting parietal cells and poorly expressed in pit cells that line the gland exit. This specificity of expression patterns and subcellular localization of PCBP1 and PCBP2, along with their appearance in the precursor tissues of the gastric epithelium during early postnatal development, suggests these RNA-binding proteins play specific roles in cell differentiation and organismal development within the gastric glandular epithelium. PMID- 24480780 TI - Biodistribution studies of two 18F-labeled pyridinylphenyl amides as subtype selective radioligands for the dopamine D3 receptor. AB - INTRODUCTION: Dopamine D3 receptors are implicated in various neuropsychiatric diseases, drug abuse and alcoholism, but specific agents for D3 molecular imaging are lacking. We evaluated two in vitro selective fluorine-18-labeled radioligand candidates ([(18)F]5 and [(18)F]6) for positron emission tomography (PET) imaging of D3 receptor availability in the brain. METHODS: Biodistribution was evaluated in Sprague-Dawley rats using ex vivo autoradiography and small-animal PET. Protein binding studies were conducted in human plasma and cerebrospinal fluid. RESULTS: [(18)F]5 showed rapid blood-brain barrier penetration and fast washout after intravenous injection, whereas the rat brain penetration of [(18)F]6 was lower. The total distribution volume (VT) of [(18)F]5 was 20-26 mL g(-1) throughout brain. Co-injection with the D3 antagonist BP897 resulted in globally increased cerebral washout of [(18)F]5 and [(18)F]6, but SUV analysis and parametric mapping of binding potential (BPND) relative to the cerebellum did not reveal specific binding of either ligand in D3-rich brain regions, i.e. the ventral striatum. However, there was substantial displaceable binding of [(18)F]5, and to a lesser extent [(18)F]6, in the pituitary. CONCLUSION: These radioligands reveal dopamine D3 receptors in the pituitary, but are not suitable for PET imaging of in brain, possibly due to low specific signal relative to the globally high VT. PMID- 24480781 TI - Reduced expression of Phospholipase C beta in hippocampal interneuron during pilocarpine induced status epilepticus in mice. AB - We investigated localization of Phospholipase C beta (PLCbeta1 and PLCbeta4) in laminaes of dorsal hippocampus and different subtypes of hippocampal interneurons in normal Kunming mouse, and their progressive changes during pilocarpine induced status epilepticus (SE) by quantitative immunohistochemistry and real time PCR. PLCbeta1 was observed in the pyramidal layer of CA1-3 area, hilus of the dentate gyrus, whereas PLCbeta4 was mainly expressed in calcium binding protein positive interneurons, i.e. calbindin, calretinin, parvalbumin positive interneurons in the strata oriens, radiatum of the CA area and hilus of the dentate gyrus. During pilocarpine induced SE, a temporary down-regulation of PLCbeta4 in the interneurons of CA area at SE 30min, and a progressive reduction of PLCbeta1/PLCbeta4 in dentate hilar cells were demonstrated. These findings confirm and extend the regional specific distribution of PLCbeta1 and PLCbeta4 immunoreactivity in mouse hippocampus, and suggest that PLCbeta1 and PLCbeta4 may play an important role in maintenance of the status epilepticus. PMID- 24480782 TI - Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing. AB - Radiation therapy (RT) is used for local tumor control through direct killing of tumor cells. Radiation-induced cell death can trigger tumor antigen-specific immune responses, but these are often noncurative. Radiation has been demonstrated to induce immunogenic modulation (IM) in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell mediated killing. Little is known about the mechanism(s) underlying IM elicited by sub-lethal radiation dosing. We have examined the molecular and immunogenic consequences of radiation exposure in breast, lung, and prostate human carcinoma cells. Radiation induced secretion of ATP and HMGB1 in both dying and surviving tumor cells. In vitro and in vivo tumor irradiation induced significant upregulation of multiple components of the antigen-processing machinery and calreticulin cell-surface expression. Augmented CTL lysis specific for several tumor-associated antigens was largely dictated by the presence of calreticulin on the surface of tumor cells and constituted an adaptive response to endoplasmic reticulum stress, mediated by activation of the unfolded protein response. This study provides evidence that radiation induces a continuum of immunogenic alterations in tumor biology, from immunogenic modulation to immunogenic cell death. We also expand the concept of immunogenic modulation, where surviving tumor cells recovering from radiation-induced endoplasmic reticulum stress become more sensitive to CTL killing. These observations offer a rationale for the combined use of radiation with immunotherapy, including for patients failing RT alone. PMID- 24480784 TI - Forensic intelligence framework--Part I: Induction of a transversal model by comparing illicit drugs and false identity documents monitoring. AB - Forensic intelligence is a distinct dimension of forensic science. Forensic intelligence processes have mostly been developed to address either a specific type of trace or a specific problem. Even though these empirical developments have led to successes, they are trace-specific in nature and contribute to the generation of silos which hamper the establishment of a more general and transversal model. Forensic intelligence has shown some important perspectives but more general developments are required to address persistent challenges. This will ensure the progress of the discipline as well as its widespread implementation in the future. This paper demonstrates that the description of forensic intelligence processes, their architectures, and the methods for building them can, at a certain level, be abstracted from the type of traces considered. A comparative analysis is made between two forensic intelligence approaches developed independently in Australia and in Europe regarding the monitoring of apparently very different kind of problems: illicit drugs and false identity documents. An inductive effort is pursued to identify similarities and to outline a general model. Besides breaking barriers between apparently separate fields of study in forensic science and intelligence, this transversal model would assist in defining forensic intelligence, its role and place in policing, and in identifying its contributions and limitations. The model will facilitate the paradigm shift from the current case-by-case reactive attitude towards a proactive approach by serving as a guideline for the use of forensic case data in an intelligence-led perspective. A follow-up article will specifically address issues related to comparison processes, decision points and organisational issues regarding forensic intelligence (part II). PMID- 24480783 TI - An Internet-Based Counseling Intervention With Email Reminders that Promotes Self Care in Adults With Chronic Heart Failure: Randomized Controlled Trial Protocol. AB - BACKGROUND: Chronic heart failure (CHF) is a public health priority. Its age standardized prevalence has increased over the past decade. A major challenge for the management of CHF is to promote long-term adherence to self-care behaviors without overtaxing available health care resources. Counseling by multidisciplinary health care teams helps to improve adherence to self-care behaviors and to reduce the rate of death and hospitalization. In the absence of intervention, adherence to self-care is below recommended standards. OBJECTIVE: This trial aims to establish and evaluate a Canadian e-platform that will provide a core, standardized protocol of behavioral counseling and education to facilitate long-term adherence to self-care among patients with CHF. METHODS: Canadian e-Platform to Promote Behavioral Self-Management in Chronic Heart Failure (CHF-CePPORT) is a multi-site, double blind, randomized controlled trial with a 2 parallel-group (e-Counseling + Usual Care vs e-Info Control + Usual Care) by 3 assessments (baseline, 4-, and 12-month) design. We will identify subjects with New York Heart Association Class II or III systolic heart failure from collaborating CHF clinics and then recruit them (n=278) by phone. Subjects will be randomized in blocks within each site (Toronto, Montreal, and Vancouver). The primary outcome will be improved quality of life, defined as an increased number of subjects with an improvement of >=5 points on the summary score of the Kansas City Cardiomyopathy Questionnaire. We will also assess the following secondary outcomes: (1) diet habits, depression, anxiety, smoking history, stress level, and readiness for change using self-report questionnaires, (2) physical activity level, current smoking status, and vagal-heart rate modulation by physiological tests, and (3) exercise capacity, prognostic indicators of cardiovascular functioning, and medication adherence through medical chart review. The primary outcome will be analyzed using generalized estimation equations with repeated measures on an intention-to-treat basis. Secondary outcomes will be analyzed using repeated-measures linear mixed models with a random effects intercept. All significant main effects or interactions in the statistical models will be followed up with post hoc contrasts using a Bonferroni correction with a 2-sided statistical significance criterion of P<.05. RESULTS: This 3.5-year, proof-of-principle trial will establish the e-infrastructure for a pan-Canadian e-platform for CHF that is comprised of a standardized, evidence based protocol of e-Counseling. CONCLUSIONS: CHF-CePPORT is designed to improve long-term adherence to self-care behaviors and quality of life among patients with CHF. It will demonstrate a distinct Canadian initiative to build capacity for preventive eHealth services for patients with CHF. TRIAL REGISTRATION: ClinicalTrials.gov NCT01864369; http://clinicaltrials.gov/ct2/show/NCT01864369 (Archived by WebCite at http://www.webcitation.org/6Iiv6so7E). PMID- 24480785 TI - Bilateral middle cerebral artery infarction associated with traumatic common carotid artery dissection: a case report and review of literature. AB - Traumatic common carotid artery dissection is very rare, and although it is associated with mild symptoms, it can sometimes be fatal. Therefore, careful examination of common carotid artery dissection and additional pathological examination as appropriate are important during the autopsy of traumatic death patients. A 60-year-old previously healthy drunken woman was run over. She had remained unconscious shortly after the accident, and 15 h later, emerging bilateral cerebral infarction was confirmed using brain computed tomography. Despite conservative management, she died 4 days after the injury due to multiple chest traumas and broad cerebral infarction. A medico-legal autopsy was conducted. According to the autopsy results, microscopically identified common carotid artery dissections with thrombus formation were considered the cause of infarction. In the present case, macroscopic common carotid artery lesions were relatively mild, and this made diagnosis difficult. However, the correct diagnosis was achieved by a combined analysis of the antemortem images and autopsy results. Thus, in such cases, a combined comprehensive analysis of autopsy results and antemortem clinical images is important to determine the exact cause of death. PMID- 24480786 TI - Neonatal outcomes among singleton births after blastocyst versus cleavage stage embryo transfer: a systematic review and meta-analysis. AB - BACKGROUND: Several studies have evaluated outcomes of singleton pregnancies after blastocyst versus cleavage stage embryo transfer. Higher incidences of preterm birth (PTB), very preterm birth (VPTB), low birthweight (LBW) and congenital malformations were identified in a few of them. The objective of our study was to systematically review and meta-analyze pregnancy and neonatal outcomes among singleton births following blastocyst versus cleavage stage embryo transfer. METHODS EMBASE, MEDLINE, EBM Reviews and bibliographies of included studies were searched from their inception until March 2013. Observational studies or clinical trials comparing blastocyst with cleavage stage embryo transfer and reporting on outcomes of PTB (<37 weeks), VPTB (<32 weeks), LBW (<2500 g), very low birthweight (VLBW) (<1500 g) and/or congenital anomalies in singleton neonates were included. Data on the outcomes were extracted by two reviewers. Statistical heterogeneity among studies was evaluated by calculating I(2) values and chi(2) statistics. Meta-analyses were conducted to estimate the pooled unadjusted odds ratio (OR) and the adjusted OR (AOR) with a 95% confidence interval (CI) using the random effect model. RESULTS Six observational studies, of low to moderate risk of bias, were included in this review. There were significantly higher odds of PTB (four studies, 54 792 cleavage stage and 20 724 blastocyst stage births; AOR 1.32, 95% CI 1.19-1.46) and congenital anomalies (two studies, 22 068 cleavage stage and 4517 blastocyst stage births; AOR 1.29, 95% CI 1.03-1.62) among births after blastocyst transfer compared with cleavage stage transfer. There was no difference in the adjusted odds of VPTB (four studies, 54 792 cleavage stage and 20 724 blastocyst stage births; AOR 1.18, 95% CI 0.93-1.49), LBW (four studies, 54 109 cleavage stage and 20 392 blastocyst stage births; AOR 1.06, 95% CI 0.99-1.15) or VLBW (three studies, 22 088 cleavage stage and 5772 blastocyst stage births; AOR 1.01, 95% CI 0.73-1.38). CONCLUSIONS Risk of PTB in IVF singleton pregnancies is significantly higher following blastocyst transfer compared with cleavage stage transfer. Risk of congenital anomalies may also be higher but further studies are needed to confirm this finding and to identify reasons for such outcomes. PMID- 24480787 TI - Autologous fat grafting: in search of the optimal technique. AB - OBJECTIVE: Recent advances in adipose cellular biology have repopularized autologous fat grafting as a method widely used in both reconstructive and aesthetic surgery. This review aims to summarize our current knowledge on autologous fat grafting emphasizing harvesting techniques and processing methods as well as current trends and approaches. METHODS: A thorough search of earlier and recent literature until October 2013 was conducted using the terms autologous fat grafting, autologous fat transfer, lipoaspirate, lipoinjection, fat harvest, and lipotransfer in PubMed and ClinicalTrials.gov databases, and relevant English and German-language articles were included. RESULTS: Findings were categorized in a step-by-step approach of the fat grafting procedure into indications, selection of donor site, techniques for harvesting, processing, and reimplantation of autologous fat. CONCLUSIONS: Further in-depth knowledge will provide definite answers on fat graft survival; demonstrate safe methods to increase cell viability, grafting outcome predictability; and reliability; enhance safety; and strengthen the scientific and clinical establishment of this increasingly promising method. PMID- 24480788 TI - [Bioethics in paediatric training]. PMID- 24480789 TI - Behavior problems among cocaine exposed children: role of physiological regulation and parenting. AB - This study examined interrelations between prenatal cocaine exposure, child autonomic regulation, parenting behavior and child sex on parent-reported behavior problems at 36 months of age. We hypothesized that respiratory sinus arrhythmia (RSA) at 13 months of age would mediate the relation between cocaine exposure and behavior problems. We also hypothesized that child sex, maternal negative affect, and maternal sensitivity observed at 13 months of age would moderate the relation between RSA and behavior problems. Results revealed that cocaine exposure predicted low baseline RSA and low RSA withdrawal during a negative affect task. Low baseline RSA, in turn, predicted fewer behavior problems offering support for an indirect association between cocaine exposure and behavior problems. The association between baseline RSA and behavior problems was further moderated by maternal negative affect such that high baseline RSA was more strongly related to behavior problems under conditions of high compared to low maternal negative affect. Results also revealed a near significant trend for baseline RSA to be more strongly related to behavior problems among boys than girls. These findings highlight several possible pathways toward behavior problems among cocaine exposed children. PMID- 24480791 TI - Association between high antitumor activity of oxaliplatin and cyclophosphamide and constitutional GSTM1 homozygous deletion in an advanced ovarian cancer patient. AB - BACKGROUND: Although the efficiency of oxaliplatin in patients with advanced ovarian cancer has been demonstrated, it is not commonly used. In cells, oxaliplatin is metabolized by the enzymes belonging to the glutathione-S transferase (GST) family. CASE: A 55-year-old woman with advanced ovarian cancer received 6 cycles of paclitaxel and carboplatin after debulking surgery. Six months later, she experienced a clinical recurrence. A second-line chemotherapy combining 500 mg/m2 cyclophosphamide with 100 mg/m2 oxaliplatin was initiated and maintained for 10 cycles. The patient thus experienced a second complete remission that lasted for 6 years. We found that she had deficient GSTM1 enzyme activity with homozygous deletion and normal GSTP1 and GSTT1 activities. CONCLUSION: The association of a homozygous deletion of GSTM1 with hypersensitivity to oxaliplatin and cyclophosphamide combination chemotherapy has not been described to date in ovarian cancer. Further study of its potential interest to personalized second-line therapy in these patients is called for. PMID- 24480790 TI - Association of nonsense mutation in GABRG2 with abnormal trafficking of GABAA receptors in severe epilepsy. AB - Mutations in GABRG2, which encodes the gamma2 subunit of GABAA receptors, can cause both genetic epilepsy with febrile seizures plus (GEFS+) and Dravet syndrome. Most GABRG2 truncating mutations associated with Dravet syndrome result in premature termination codons (PTCs) and are stably translated into mutant proteins with potential dominant-negative effects. This study involved search for mutations in candidate genes for Dravet syndrome, namely SCN1A, 2A, 1B, 2B, GABRA1, B2, and G2. A heterozygous nonsense mutation (c.118C>T, p.Q40X) in GABRG2 was identified in dizygotic twin girls with Dravet syndrome and their apparently healthy father. Electrophysiological studies with the reconstituted GABAA receptors in HEK cells showed reduced GABA-induced currents when mutated gamma2 DNA was cotransfected with wild-type alpha1 and beta2 subunits. In this case, immunohistochemistry using antibodies to the alpha1 and gamma2 subunits of GABAA receptor showed granular staining in the soma. In addition, microinjection of mutated gamma2 subunit cDNA into HEK cells severely inhibited intracellular trafficking of GABAA receptor subunits alpha1 and beta2, and retention of these proteins in the endoplasmic reticulum. The mutated gamma2 subunit-expressing neurons also showed impaired axonal transport of the alpha1 and beta2 subunits. Our findings suggested that different phenotypes of epilepsy, e.g., GEFS+ and Dravet syndrome (which share similar abnormalities in causative genes) are likely due to impaired axonal transport associated with the dominant-negative effects of GABRG2. PMID- 24480792 TI - A novel translational model of percutaneous fetoscopic endoluminal tracheal occlusion - baboons (Papio spp.). AB - INTRODUCTION: Percutaneous fetoscopic endoluminal reversible tracheal occlusion (FETO) was developed to prevent the pulmonary complications of fetal congenital diaphragmatic herniation. There is an urgent need to establish the closest to human translational model of FETO in order to improve fetal outcomes and to determine new clinical approaches and applications. MATERIAL AND METHODS: Seven non-human primates underwent two subsequent surgeries: the first, the FETO in the experimental group (n = 3) or sham operation in the control animals (S-FETO, n = 4) at 132-142 days of gestation (dGA); the second, the reversal of occlusion or sham operation at 162 +/- 5 dGA. Maternal stress axis, complete blood count, and biochemical parameters were evaluated and newborn tracheal radiography was performed. RESULTS: The average pregnancy duration and neonatal weights in the FETO group did not differ from the animals in the S-FETO group. There was no bleeding or premature fetal membrane rupture during the procedures in any of the baboons. The maximal tracheal width was 7.02 +/- 0.6 mm in the FETO versus 5.46 +/- 0.6 mm in S-FETO group. DISCUSSION: This is the very first report of a successful FETO model in non-human primates. Similarities to human tracheomegaly were for the first time documented in any model studied. PMID- 24480793 TI - Multiple spectroscopic and magnetic techniques show that chloroquine induces formation of the MU-oxo dimer of ferriprotoporphyrin IX. AB - Interaction of the antimalarial chloroquine (CQ) with ferriprotoporphyrin IX, Fe(III)PPIX, was investigated in aqueous solution (pH7.4) and as a precipitate from aqueous medium at pH5.0. In solution, spectrophotometric titrations indicated strong association (logKobs 13.3+/-0.2) and a Job plot gave a stoichiometry of 1:2 CQ:Fe(III)PPIX. UV-visible absorbance and magnetic circular dichroism spectra of the complex were compared to various Fe(III)PPIX species. Close similarity to the spectra of the MU-oxo dimer, MU-[Fe(III)PPIX]2O, was revealed. The induction of this species by CQ was confirmed by magnetic susceptibility measurements using the Evans NMR method. The observed low-magnetic moment (2.25+/-0.02 MUB) could only be attributed to antiferromagnetically coupled Fe(III) centers. The value was comparable to that of MU-[Fe(III)PPIX]2O (2.0+/-0.1 MUB). In the solid-state, mass spectrometry confirmed the presence of CQ in the complex. Dissolution of this solid in aqueous solution (pH7.4) resulted in a solution with a UV-visible spectrum consistent with the same 1:2 stoichiometry observed in the Job plot. Magnetic susceptibility measurements made on the solid using an Evans balance produced a magnetic moment (2.3+/-0.1 MUB) consistent with that in solution. Diffusion coefficients of CQ and its complex with Fe(III)PPIX were measured in aqueous solution (3.3+/-0.3 and 0.6+/-0.2*10( 10) m(2).s(-1), respectively). The latter was used in conjunction with an empirical relationship between diffusion coefficient and molar volume to estimate the degree of aggregation. The findings suggest the formation of a 2:4 CQ:Fe(III)PPIX complex in aqueous solution at pH7.4. PMID- 24480794 TI - Cognitive profile of CADASIL patients with R544C Notch3 mutation. AB - BACKGROUND: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is an inherited microangiopathy caused by mutations in the Notch3 gene. In the present study, we aimed to analyze cognitive and neuroimaging profiles of CADASIL patients with R544C mutation. METHODS: Fifty eight consecutive patients with R544C mutation and 26 normal controls were investigated. The patients were divided into two groups depending on the presence (CADASIL with dementia: CADASIL-D) or absence of dementia (CADASIL no dementia: CADASIL-ND). We applied the same neuropsychological test to the three groups. Brain magnetic resonance images were obtained from 58 patients with R544C mutation. Linear regression models were used to assess the impact of lacunes and white matter hyperintensities on cognitive function in the CADASIL-ND group. RESULTS: Compared to controls, the CADASIL-ND group demonstrated significant difficulties concerning measures of attention, executive function, and motor control. The CADASIL-D group was impaired in all cognitive domains that were assessed, except the language domain. After correction for age and educational level, the number of lacunes was associated with lower scores in the Alzheimer's Disease Assessment Scale cognitive subtest and Stroop color test in the CADASIL ND group. CONCLUSIONS: Non-Caucasian CADASIL patients with R544C mutation and Caucasian CADASIL patients show similar patterns of cognitive impairment. PMID- 24480795 TI - Non-clinical safety assessment of Hwangryunhaedok-tang: 13-week toxicity in Crl:CD Sprague Dawley rats. AB - Hwangryunhaedok-tang (Huang-Lian-Jie-Du-Tang in Chinese, Oren-gedoku-to in Japanese) is a traditional herbal medicine with a long history of use for anti inflammatory purposes. In this study, subchronic toxicity of daily oral administration of a Hwangryunhaedok-tang water extract (HHT) at 0, 250, 750, and 2000mg/kg for 13weeks was examined in rats. Mortality, clinical signs, and changes in body weight, food consumption, clinical signs, ophthalmological examination, urinalysis, hematology, serum biochemistry, gross observation, organ weight, and histopathology were monitored in accordance with Good Laboratory Practice and OECD guidelines. We found no mortality or abnormality in clinical signs, body weight, serum biochemistry, or organ weight in HHT-treated groups in either sex. However, there were significant changes in glucose, bilirubin, urobilinogen, protein (only male) in urine after 2000mg/kg/day HHT treatment for both sexes. In hematological examinations, we found a significant decreased number of red blood cells (RBC), whereas, an increased the mean corpuscular volume, number of platelets, and rate of reticulocyte (RET) after 2000mg/kg/day HHT treatment of male rats. In male and female rats, 750 and 2000mg/kg/day HHT treatment decreased the number of RBC and increased RET. Histopathological examinations revealed stomach mucosal erosion in female rats (2000mg/kg/day). No observed-adverse-effect levels were established for 750mg/kg HHT in rats under the conditions of this study. However, other toxicological studies are necessary to evaluate the safety of HHT fully. PMID- 24480796 TI - Effect of inhibiting malonyl-CoA decarboxylase on cardiac remodeling after myocardial infarction in rats. AB - OBJECTIVES: The objective of this study was to determine the effect of inhibiting malonyl-CoA decarboxylase (MCD) on cardiac remodeling following myocardial infarction (MI) in rats. We used an ultrasound (US)-mediated microbubble (MB) approach for targeted delivery of a microRNA (miRNA) interference plasmid to the myocardium to silence MCD expression. METHODS: Five pairs of RNA interference sequences were screened and ranked according to their highest inhibition rates in HEK293 cells. The plasmid with the highest inhibition rate was transfected by US into the rat myocardium after mixing with lipid MB. Twelve and 16 weeks after MI, cardiac function was measured by echocardiography, and glucose transporter-4 (GLUT-4) and high-energy phosphate levels were monitored in the myocardium before and after transfection. RESULTS: Ejection fraction (EF) decreased by 16% in the control MI group, while it decreased by 8% in the MCD inhibition group that utilized the US-mediated MB approach. Concomitant with the improved EF, high energy phosphates were increased and lactic acid was decreased in the left ventricle (LV), with no changes in triglyceride or GLUT-4 levels. CONCLUSIONS: Inhibiting MCD by an US-mediated injection of miRNA into the rat myocardium increased energy reserves in the LV after MI, most likely by limiting lactic acidosis and improving cardiac function without increasing lipid toxicity. PMID- 24480798 TI - Creativity and psychopathology: a systematic review. AB - BACKGROUND: The possible link between creativity and psychopathology has been a long-time focus of research up to the present day. However, the research results in this field are heterogeneous and contradictory. Links between creativity and specific psychiatric disorders have been confirmed and refuted in different studies. This disparity is partly explained by the methodological challenges peculiar to this field. METHODS: In this systematic review of the literature from 1950, research articles in the field of creativity and psychopathology are presented, focusing on the methodology and results of the collected studies. RESULTS: This review confirms the methodological problems and the heterogeneity of the study designs and results. The assessment of psychopathology, but more so of creativity, remains a fundamental challenge. On the whole, study results cautiously confirm an association between creativity and both bipolar disorder and schizotypy. CONCLUSION: The research on creativity and psychopathology is hampered by serious methodological problems. Study results are to be interpreted with caution and future research needs more methodological rigor. PMID- 24480797 TI - A systematic review of the use of atazanavir in women infected with HIV-1. AB - BACKGROUND: Despite increasing numbers of women with HIV worldwide, females are under-represented in clinical trials of antiretrovirals and literature addressing gender differences in clinical outcomes, treatment discontinuation, adverse events and adherence are limited. Most recommendations specific to women in current guidelines relate to pregnant women or women wishing to become pregnant. The purpose of this systematic review is to provide clinicians with an overview of available literature regarding the use of ritonavir-boosted atazanavir (ATV/r) in women. METHODS: The online databases PubMed and EMBASE, HIV-related conference abstracts and reference lists of relevant articles were searched according to predefined terms and limited to items published from 1 October 2007 to 1 October 2012. Updates to conference presentations were checked for substantive journal publication up to 28 November 2013. RESULTS: Of the 294 initial citations retrieved, manual selection identified 19 relevant publications describing gender based analyses of ATV/r. Publications describing gender-based differences in efficacy, safety, tolerability, pharmacokinetics, drug-drug interactions and adherence are critically evaluated. CONCLUSIONS: As part of a combination antiretroviral therapy regimen, ATV/r appears to be a safe, effective and durable option for treatment-naive and early treatment-experienced patients with HIV-1 infection, including non-pregnant and pregnant women. PMID- 24480799 TI - Synthesis and characterization of functional multicomponent nanosized gallium chelated gold crystals. AB - In this communication, we describe a novel synthetic method for fabricating multicomponent gold nanoparticles containing both gallium ions and biomolecules on the surface. Detailed compositional analysis, using STEM-HAADF and EELS spectroscopy, confirmed the crystalline nature of gold and chelation of gallium ions. The presence of the biomolecule was validated using conventional ELISA. PMID- 24480800 TI - Comparison of RECIST 1.0 and RECIST 1.1 on computed tomography in patients with metastatic colorectal cancer. AB - OBJECTIVE: We conducted this study to compare tumor measurement by computed tomography (CT) and tumor response assessment between Response Evaluation Criteria In Solid Tumors (RECIST) 1.0 and RECIST 1.1 in patients with metastatic colorectal cancer (CRC). METHODS: We reviewed the medical records of patients with metastatic CRC who received first-line chemotherapy between January 2004 and December 2012 and compared CT tumor measurement using two RECIST versions. RESULTS: A total of 58 patients who had target lesions according to RECIST 1.0 were included in the study. The number of target lesions recorded by RECIST 1.1 was significantly lower than that by RECIST 1.0, with a decrease experienced in 48 patients (82.7%). Six patients had no target lesions because of the new criteria of RECIST 1.1 for lymph node size. Out of 95 lymph nodes from 58 patients, only 40% were defined as target lesions according to RECIST 1.1. The overall response rate of first-line chemotherapy according to RECIST 1.0 and 1.1 was 41.5 and 40.4%, respectively. The best tumor responses showed almost perfect agreement between RECIST 1.1 and RECIST 1.0 (K = 0.913). Three patients showed disagreement of the best responses between the two RECIST versions. CONCLUSION: RECIST 1.1 showed a highly concordant response assessment with RECIST 1.0 in metastatic CRC and its clinical impact on therapeutic decisions was minimal. PMID- 24480802 TI - Acetylation control of metabolic enzymes in cancer: an updated version. AB - Metabolic reprogramming is one of the critical features in cancer. Tumor cells preferentially utilize glycolysis instead of oxidative phosphorylation in the presence of oxygen, namely 'Warburg Effect'. Recent studies have provided new insights into the Warburg effect, elucidating metabolic-dependent and independent mechanisms of metabolic enzymes regulated by post-translational modifications and providing further evidence for the critical role of these tricks in cancer metabolism and tumorigenesis. Of particular interest, we summarized the latest advances in both the metabolic and the non-metabolic functions of metabolic enzymes via the acetylation regulation in the Warburg effect. In addition, their potential roles in cancer metabolism therapy will also be briefly discussed. PMID- 24480801 TI - Regulation of anti-inflammatory cytokines IL-10 and TGF-beta in mouse dendritic cells through treatment with Clonorchis sinensis crude antigen. AB - Dendritic cells (DCs), which are regarded as the most potent antigen-presenting cells, are involved in innate and adaptive immunity. Upon uptake of pathogens, DCs express cell surface markers and secrete cytokines. In this study, we analyzed production of cytokines and found that interleukin (IL)-10 and transforming growth factor (TGF)-beta production significantly increased in bone marrow-derived DCs and a mouse DC line, DC2.4, after treatment with crude antigen (CA) from liver fluke, Clonorchis sinensis. However, expression patterns of several activation molecules did not change. In addition, following treatment of DC2.4 cells with antigen from the lung fluke, Paragonimus westermani, production of IL-10 and TGF-beta significantly increased compared with groups treated with other parasite antigens, Spirometra erinacei plerocercoid CA and Echinococcus granulosus hydatid cystic fluid. We also found that treatment of DC2.4 cells with C. sinensis CA resulted in rapid and significant phosphorylation of extracellular signal-regulated kinase 1/2, a mitogen-activated protein kinase. Following treatment of DC2.4 cells with C. sinensis CA, treatment with an inhibitor specific to an extracellular signal-regulated kinase inhibited production of IL 10 and TGF-beta. Our results suggest that CA from C. sinensis has a role in the anti-inflammatory function of DC cells by inducing IL-10 and TGF-beta through activation of extracellular signal-regulated kinase 1/2. PMID- 24480803 TI - "They are not taking cigarettes from me . . . I'm going to smoke my cigarettes until the day I die. I don't care if I get cancer": smoking behaviors of men under community supervision in New York City. AB - INTRODUCTION: Cigarette smoking declined from 42.4% in 1965 to 19.3% in 2010 among the general population, but it remains the leading cause of preventable death and illness in the United States, especially among high-risk populations, including those with criminal justice involvement. METHODS: A mixed-methods approach was used to investigate the smoking behaviors of men under parole or probation. Phase I focused on qualitative data of 30 semi-structured interviews of men who were recently released from a state prison and/or jail. Phase II analyzed quantitative data resulting from a study that examined smoking characteristics and treatment approaches of 259 participants, 197 of whom were cigarette smokers. RESULTS: The survey participants' age of tobacco initiation ranged from 7 to 45 years of age. Participants smoked between 1 and 40 cigarettes per day; the mean number of cigarettes smoked per day was 10.37. Men released from prison used cigarettes for more years on average than men released from jail (t[194] = -2.22, p < .05). A linear regression procedure revealed that the influence of friends and family significantly predicted smoking behavior (beta = .25, p < .0001). The qualitative data revealed the following themes: unintended consequences of the prison smoking ban, smoking as anxiety management, smoking cigarettes as part of a daily routine, and barriers to quitting. CONCLUSIONS: Given the rapid growth of individuals under community supervision, public health and policy makers are missing an opportunity to develop strategies that promote smoking cessation treatments, especially among men who are serving parole or probation and during the incarceration period itself. PMID- 24480804 TI - SHP2E76K mutant promotes lung tumorigenesis in transgenic mice. AB - Lung cancer is a major disease carrying heterogeneous molecular lesions and many of them remain to be analyzed functionally in vivo. Gain-of-function (GOF) SHP2 (PTPN11) mutations have been found in various types of human cancer, including lung cancer. However, the role of activating SHP2 mutants in lung cancer has not been established. We generated transgenic mice containing a doxycycline (Dox) inducible activating SHP2 mutant (tetO-SHP2(E76K)) and analyzed the role of SHP2(E76K) in lung tumorigenesis in the Clara cell secretory protein (CCSP) reverse tetracycline transactivator (rtTA)/tetO-SHP2(E76K) bitransgenic mice. SHP2(E76K) activated Erk1/Erk2 (Erk1/2) and Src, and upregulated c-Myc and Mdm2 in the lungs of bitransgenic mice. Atypical adenomatous hyperplasia and small adenomas were observed in CCSP-rtTA/tetO-SHP2(E76K) bitransgenic mice induced with Dox for 2-6 months and progressed to larger adenoma and adenocarcinoma by 9 months. Dox withdrawal from bitransgenic mice bearing magnetic resonance imaging detectable lung tumors resulted in tumor regression. These results show that the activating SHP2 mutant promotes lung tumorigenesis and that the SHP2 mutant is required for tumor maintenance in this mouse model of non-small cell lung cancer. SHP2(E76K) was associated with Gab1 in the lung of transgenic mice. Elevated pGab1 was observed in the lung of Dox-induced CCSP-rtTA/tetO-SHP2(E76K) mice and in cell lines expressing SHP2(E76K), indicating that the activating SHP2 mutant autoregulates tyrosine phosphorylation of its own docking protein. Gab1 tyrosine phosphorylation is sensitive to inhibition by the Src inhibitor dasatinib in GOF SHP2-mutant-expressing cells, suggesting that Src family kinases are involved in SHP2 mutant-induced Gab1 tyrosine phosphorylation. PMID- 24480806 TI - miR-31 is upregulated in oral premalignant epithelium and contributes to the immortalization of normal oral keratinocytes. AB - Oral squamous cell carcinoma (OSCC) is a prevalent malignancy worldwide. MicroRNAs are short non-coding RNAs that regulate gene expression and are crucial for tumorigenesis. Previously, we have identified that miR-31 is frequently upregulated in OSCC and that this miR-31 increase, together with downstream effector modulation, enhances oral carcinogenesis. We have identified higher levels of miR-31 expression in oral potential malignant disorder (OPMD) tissues compared with normal oral mucosa. Exogenous miR-31 and human telomerase reverse transcriptase (hTERT) expression were introduced into cultured normal oral keratinocytes (NOKs), which led to the immortalization; these lines were designated M31OK1 and M31OK3. These immortalized lines maintained the capability to undergo squamous differentiation. In addition, migration by both cell lines was attenuated by hTERT and miR-31 knockdown. M31OK1 carries a p53 gene mutation at codon 273. A serum-tolerant subline, M31OK1-D, exhibits potent anchorage independent growth that is attenuated by knockdown of both hTERT and miR-31. miR 31-targeted factors inhibiting HIF (FIH), which upregulated vascular endothelial growth factor (VEGF), was found crucial for oral tumorigenesis. The proliferation, migration and epithelial-mesenchymal transition of M31OK1-D are associated with downregulation of FIH and upregulation of VEGF, which require miR 31 expression. High miR-31 expression is correlated with higher VEGF expression and lower E-cadherin expression in OPMD tissue. It can be concluded that miR-31 collaborates with hTERT to immortalize NOKs and that this may contribute to early stage oral carcinogenesis. The targeting of downstream factors by miR-31 may further advance the neoplastic progression of immortalized NOKs, allowing them to become malignant. PMID- 24480805 TI - Epigenetic targeting of the Nanog pathway and signaling networks during chemical carcinogenesis. AB - Chemical carcinogenesis has long been synonymous with genotoxicity, which entails DNA damage, genetic mutations and chromosomal abnormalities. The present study investigates a paradigm-shifting model in which epigenetic changes are key contributors to chemical carcinogenesis. Using genome-wide microarray-based analysis followed by conventional validation assays, we have progressively chronicled changes in the epigenetic landscape, as reflected in the patterns of DNA methylation, in the target organ of tumorigenesis in mice treated in vivo with a prototype chemical carcinogen (benzo[a]pyrene). Here, we demonstrate characteristic CpG island gain/loss of methylation and demethylation of repetitive DNA elements in carcinogen-treated mice, dependent on tumor progression. Alterations of the DNA methylome are accompanied by silencing of major DNA methyltransferases. Members of the Nanog pathway that establishes and maintains pluripotency in embryonic stem cells and possibly triggers uncontrolled proliferation of neoplastic cells are preferential targets of aberrant DNA methylation and concomitant gene dysregulation during chemical carcinogenesis. Several components of the MEK/ERK, JAK/STAT3, PI3K/AKT, WNT/beta- catenin and Shh signaling cascades, which are known to modulate Nanog expression, also show concurrent changes in the patterns of DNA methylation and gene expression. Our data support an epigenetic model of chemical carcinogenesis and suggest that surveillance of the epigenetic landscape, particularly at the loci and in the pathways identified in this study, may have utility for early detection and monitoring of the progression of malignancy. PMID- 24480808 TI - Smad7 induces plasticity in tumor-infiltrating Th17 cells and enables TNF-alpha mediated killing of colorectal cancer cells. AB - Transforming growth factor-beta (TGF-beta) is deeply involved in colorectal cancer development and the disruption of the TGF-beta signaling in dysplastic cells is required for tumor to grow. Nevertheless, tumor cells express TGF-beta to escape the immune surveillance mediated by T cells. T-cell expression of Smad7, an intracellular inhibitor of the TGF-beta signaling, protects against colitis-associated colorectal cancer. However, whether Smad7 in T cells might influence colorectal cancer growth independently of chronic inflammation and which T-cell subset is involved in this process is unknown. To address this issue, T-cell-specific Smad7 transgenic mice and wild-type (WT) littermates were subcutaneously transplanted with syngenic MC38 colon carcinoma cells. Smad7Tg mice were resistant to tumor development compared with WT mice and protection was dependent on CD4(+) T cells. Smad7 expression in T cells increased the number of tumor-infiltrating Tbet/ROR-gamma-t double-positive CD4 T cells characterized by the expression of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma but lower IL17A. The low expression of IL17A caused by the Smad7 expression in tumor-infiltrating CD4(+) T cells enabled the TNF-alpha-mediated killing of cancer cells both in vitro and in vivo, thus indicating that the Smad7-mediated plastic effect on T-cell phenotype induces protection against colorectal cancer. PMID- 24480807 TI - Fibulin-3 suppresses Wnt/beta-catenin signaling and lung cancer invasion. AB - The 5 year survival rate of lung cancer is <20%, with most patients dying from distant metastasis. However, the molecular mechanisms underlying lung cancer invasion and metastasis have not been fully characterized. In this study, we found that fibulin-3, a fibulin family extracellular matrix protein, functions as a suppressor of lung cancer invasion and metastasis. Fibulin-3 was downregulated in large fractions of lung tumors and cell lines, and inhibited lung cancer cell invasion and the expression of matrix metalloproteinase-7 (MMP-7), a promoter of lung cancer invasion. The expression levels of fibulin-3 and MMP-7 were inversely correlated in lung tumors. Fibulin-3 inhibited extracellular signal-regulated kinase (ERK) to activate glycogen synthase kinase 3beta and suppress Wnt/beta catenin signaling, which induces MMP-7 expression in lung cancer cells. Furthermore, fibulin-3 expression impeded the growth and metastasis of lung tumors in mice. Collectively, these results suggest that downregulation of fibulin-3 contributes to lung cancer invasion and metastasis by activating Wnt/beta-catenin signaling and MMP-7 expression. PMID- 24480809 TI - miR-656 inhibits glioma tumorigenesis through repression of BMPR1A. AB - Bone morphogenetic protein-2 (BMP-2), a member of the transforming growth factor beta family, plays critical roles in cell differentiation, modeling and regeneration processes in several tissues. BMP-2 is also closely associated with various malignant tumors. microRNAs negatively and posttranscriptionally regulate gene expression and function as oncogenes or tumor suppressors. Herein, we report that miR-656 expression was significantly downregulated in glioma cell lines and tissues. We identified and confirmed that BMP receptor, type 1A (BMPR1A) is a direct target of miR-656. The expression of BMPR1A was negatively correlated with that of miR-656 in human glioma tissues. We further demonstrated that miR-656 suppressed glioma cell proliferation, neurosphere formation, migration and invasion with or without exogenous BMP-2. Engineered knockdown of BMPR1A diminished the antiproliferation effect of miR-656 in vitro. Moreover, the canonical BMP/Smad and non-canonical BMP/mitogen-activated protein kinase (MAPK) pathways were inhibited by miR-656 overexpression. Several cancer-related signaling molecules, including cyclin B, cyclin D1, matrix metalloproteinase-9, p21 and p27, were also involved in miR-656 function in glioma cells. The tumor suppressing function of miR-656 was validated using an in vivo intracranial xenograft mouse model. Notably, ectopic expression of miR-656 markedly reduced tumor size and prolonged the survival of mice treated with or without BMP-2. These results elucidate the function of miR-656 in glioma progression and suggest a promising application for glioma treatment. PMID- 24480810 TI - Reduced TiO2 rutile nanorods with well-defined facets and their visible-light photocatalytic activity. AB - Stable reduced TiO2 rutile nanorods with well-defined facets were prepared by a solvothermal route in the presence of Zn powder. The oxygen vacancy in the TiO2 nanorods, which can be tuned by the amount of Zn, results in a narrow band gap and visible-light photocatalytic activity. PMID- 24480811 TI - Photoelectron spectroscopy of lithium and gold alloyed boron oxide clusters: charge transfer complexes, covalent gold, hyperhalogen, and dual three-center four-electron hyperbonds. AB - We report on the structural and electronic properties and chemical bonding in a series of lithium and gold alloyed boron oxide clusters: B2O3(-), LiB2O3(-), AuB2O3(-), and LiAuB2O3(-). The clusters have been produced by laser vaporization and characterized using photoelectron spectroscopy, in combination with the Coalescence Kick and Basin Hopping global-minimum searches and density-functional theory and molecular orbital theory calculations. Electron affinities of B2O3, LiB2O3, AuB2O3, and LiAuB2O3 neutral clusters are measured to be 1.45 +/- 0.08, 4.25 +/- 0.08, 6.05 +/- 0.08, and 2.40 +/- 0.08 eV, respectively. The experimental and computational data allow the cluster structures to be established for the anions as well as their neutrals. While B2O3(-) (C2v) is bent, the three alloy clusters, LiB2O3(-) (Cinfinityv), AuB2O3(-) (Cs), and LiAuB2O3(-) (Cinfinityv), adopt linear or quasi-linear geometries with a metal center inserted between BO and OBO subunits, featuring charge transfer complexes, covalent gold, hyperhalogen, and dual three-center four-electron (3c-4e) pi hyperbonds. The current results suggest the possibility of altering and fine tuning the properties of boron oxides via alloying, which may lead to markedly different electronic structures and chemical reactivities. The LiB2O3 cluster belongs to the class of oxidizing agents called superhalogens, whereas AuB2O3 is a hyperhalogen species. Dual 3c-4e pi hyperbonds represent a critical bonding element in boron oxides and are considered to be the root of delocalized bonding and aromaticity therein. PMID- 24480812 TI - Development of a 5-item parent questionnaire to screen preschool children for reading problems. AB - OBJECTIVE: To develop a brief tool for screening of emergent literacy skills in preschool children (3-5 years old) in pediatric clinics. METHODS: Parents were given an 8-item questionnaire, and the children were tested with the Get Ready to Read-Revised (GRTR-R) screener. With the GRTR-R score as gold standard, the parent questionnaire was optimized using various combinations of questions and response weights in one half of the sample. The resulting 5-item questionnaire was then validated using the other half of the sample. RESULTS: A total of 203 patients were enrolled. In the validation sample, the 5-item questionnaire had sensitivity and specificity vis-a-vis the GRTR-R of 100% and 78.6% in 5-year-olds (cutoff score of 8) and 78.6% and 68.2% in 4-year-olds (cutoff of 6). The questionnaire did not perform well in 3-year-olds. CONCLUSION: A very brief parent questionnaire may be useful as a first-line screener for early reading problems. PMID- 24480814 TI - Microalgal carotenoids: beneficial effects and potential in human health. AB - Microalgae are huge natural sources of high-value compounds with health-promoting properties. The carotenoids derived from microalgae have significant antioxidant and anti-inflammatory effects, which allow them to provide health benefits. In this article, the bioactivities of microalgal carotenoids are reviewed. Emphasis is placed on astaxanthin, a ketocarotenoid with extraordinary potential for protecting against a wide range of diseases. PMID- 24480813 TI - Urinary incontinence in children as a sign of neurological disorders: need for a high index of suspicion. PMID- 24480815 TI - Regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in Alzheimer's disease patients. AB - BACKGROUND: Alzheimer's disease (AD) is a devastating illness that results in progressive cognitive decline and neuropsychiatric symptoms. The neuropsychiatric symptoms are associated with a rapid decline in cognition and activities of daily living and increased mortality, however the neuroanatomical localisation involved in the development of neuropsychiatric symptoms remains poorly understood. The aim of this study was to identify the association with the regional volume of the insular cortex and each neuropsychiatric symptom in patients with AD. METHODS: Subjects diagnosed with AD (n = 40) were evaluated. Magnetic resonance images were obtained and the insular cortex was subdivided into four subregions through the central sulcus of the insula and bilaterally: right anterior insular cortex, right posterior insular cortex, left anterior insular cortex and left posterior insular cortex. The neuropsychiatric symptoms were assessed using the Neuropsychiatric Inventory. A partial correlation analysis was performed. RESULTS: A significant negative correlation existed between apathy, the irritability subscale score and the volume ratio of the bilateral anterior insular cortex and right posterior insular cortex (r = -0.457, -0.433 and -0.572, respectively, p = 0.032, 0.044 and 0.005, respectively). CONCLUSION: The findings suggest that the regional atrophy of the insular cortex is associated with neuropsychiatric symptoms in AD patients. PMID- 24480816 TI - Autonomous adenomas caused by somatic mutations of the thyroid-stimulating hormone receptor in children. AB - In adults, autonomous adenomas of the thyroid causing hyperthyroidism are relatively common and are most often due to somatic mutations that increase the constitutive activity of the thyroid-stimulating hormone receptor (TSHR). By contrast, autonomous adenomas in hyperthyroid children are exceptional and reports of their clinical and molecular characteristics are few. We reviewed papers describing 16 autonomous adenomas due to a somatic mutation activating the TSHR and diagnosed in patients younger than 18 years, to which we added two of our own unpublished observations in a 4- and 8-year-old with the same TSHR mutation (c.CAG>CAC; p.Asp633His). This revealed that (a) autonomous adenomas occur more often in the right lobe (11 of 14 with available information) and the associated hyperthyroidism tends to be more severe, possibly reflecting the richer vascular supply of the right thyroid lobe, and (b) mutations found in benign adenomas in children have been associated with cancer in adults, suggesting that malignancy requires a second 'hit' at a later age. PMID- 24480817 TI - Antibiotic resistance and detection of the most common mechanism of resistance (MLSB) of opportunistic Corynebacterium. AB - BACKGROUND: Determination of antibiotic resistance of opportunistic Corynebacterium colonizing the nose that cause infections and evaluation of the applicability of a simple method for detecting the most common constitutive-type resistance to macrolides, lincosamides and streptogramin B (MLSB). METHODS: 70 isolates colonizing the nose and 70 clinical isolates of various infection sites were used and identified using APICoryne and 16S rRNA. Minimal inhibitory concentrations (MICs) were determined (Etest) for 12 antibiotics. MLSB was defined based on MIC, a simple method using two disks (erythromycin/clindamycin) and detection of the gene erm X (PCR). RESULTS: There was a high percentage--in both groups at the same level--of strains with MLSB (88.5% colonizing the nose and 87.1% causing infections). Detection with the phenotypic method MLSB was confirmed genetically (erm X) in all cases. In both groups, a high percentage of resistance was found to trimethoprim/sulfamethoxazole (in both groups 71.4%), chloramphenicol (nose 44.2%/infections 37.1%), tetracycline (28 and 45.7%) and beta-lactam antibiotics (18.5 and up to 32.8%). CONCLUSION: Differences in antibiotic resistance were found between strains colonizing the respiratory tract and various infections. Isolates from infections more frequently exhibited multidrug resistance. The possibility of using a simple method was confirmed for MLSB detection, which can be applied to determine drug resistance in routine microbiological diagnostics of infections caused by opportunistic Corynebacterium. PMID- 24480819 TI - Antihypertensive treatment and vascular extracellular matrix remodeling. PMID- 24480820 TI - Is there a role for mechanical valve prostheses in pulmonary valve replacement late after tetralogy of Fallot repair? AB - A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was: What is the role of mechanical valve prostheses in pulmonary valve replacement late after tetralogy of Fallot (TOF) repair? Altogether more than 30 papers were found using the reported search, of which 9 represented the best evidence to answer the clinical question. In addition to this, two papers were found by searching the reference lists of the relevant papers. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. We conclude from the best evidence available that mechanical prosthetic valves do play a role in patients who require pulmonary valve replacement late after repair of TOF. With adequate anticoagulation, they represent a safe alternative to biological valves. Although the literature is very limited, in terms of patient numbers, many of the papers demonstrate an acceptable early mortality rate. There is significant variability in the regimes of anticoagulation in these patients, and the overall reported rate of valvar thrombosis, thromboembolic events and major haemorrhagic complications has also been variable. The overall rate of valvar thrombosis and other thromboembolic events is promising. Thrombotic events were often attributed to poor adherence to the anticoagulation regime. Conversely, 3 papers recorded no thromboembolic events during the follow-up period. Three papers recorded major haemorrhagic events during their follow-up period and concluded that these were a rare outcome. When appropriate anticoagulation is adhered to, mechanical pulmonary prostheses appear to be relatively safe in patients late after repair of TOF. We have also found that the rationale for insertion of mechanical valves in the pulmonary position late after TOF repair varies across centres is still controversial. Furthermore, their use in patients with concomitant pulmonary arterial stenoses may be less advisable as this will prevent future percutaneous interventions of the pulmonary arterial tree. More research is required to accurately compare the haemodynamic properties of mechanical valves in the pulmonary position compared with other valves. Additionally, a more consistent follow-up of these patients in terms of echocardiographic, valve-related and warfarin-related complications is needed. With this information, clearer conclusions may be drawn when considering their role. PMID- 24480821 TI - Is it safe not to drain the pneumonectomy space? AB - A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether it is safe not to position any chest drain into the pneumonectomy space at the conclusion of the procedure. Altogether 381 relevant studies were identified of which 11 represented the best evidence to answer the question. The author, journal, date, country of publication, alternative methods of postpneumonectomy space (PPS) management, complications and relevant outcomes are tabulated. The majority of studies are on the basis of expert opinion or small cohorts. Major cohorts, by which the pneumonectomy outcomes have been examined, demonstrated that the rates of complications related to pneumonectomy space management such as empyema, bronchopleural fistula, mediastinal shift and major bleeding requiring reopening are very low. In a large cohort where 408 patients underwent pneumonectomy the rate of relevant complications was low and also it was concluded that the PPS drainage is not necessary. Two separate expert opinions were in agreement that needle aspiration in the absence of a drainage system is adequate for the management of PPS and avoiding a mediastinal shift. One small cohort and one institutional audit directly examined the impact of a drainage versus no drainage approach in the management of PPS. Although neither study could show a significant superiority of one method over another, they recommended adopting a unified institutional protocol for current departmental practice. They also emphasized that larger cohorts are required to examine the superiority of different strategies for PPS management. In a cohort of 291 patients, it was demonstrated that patients with drainage with underwater seal are more at risk of postpneumonectomy oedema. A recent review published as a book chapter appraised the relevant literature in both humans and animals. The authors concluded that the simplicity of a no drainage system is notable; however, a balanced drainage might be recommended for local protocols. We conclude that although the current evidence is not adequate to examine the different aforementioned approaches, not draining the pneumonectomy space can be performed safely. PMID- 24480822 TI - Alveolar recruitment manoeuvre is safe in children prone to pulmonary hypertensive crises following open heart surgery: a pilot study. AB - OBJECTIVES: To test the tolerance and safety of an alveolar recruitment manoeuvre performed in the immediate postoperative period of corrective open heart surgery in children with congenital heart disease associated with excessive pulmonary blood flow and pulmonary arterial hypertension due to left-to-right shunt. METHODS: Ten infants aged 1-24 months with congenital heart disease associated with excessive pulmonary blood flow and pulmonary artery hypertension (mean pulmonary artery pressure >= 25 mmHg) were evaluated. The alveolar recruitment manoeuvre was performed in the operating theatre right after skin closure, and consisted of three successive stages of 30 s each, intercalated by a 1-min interval of baseline ventilation. Positive end-expiratory pressure was set to 10 cmH2O in the first stage and to 15 cmH2O in the two last ones, while the peak inspiratory pressure was kept at to 30 cmH2O in the first stage and at 35 cmH2O in the latter ones. Haemodynamic and respiratory variables were recorded. RESULTS: There was a slight but significant increase in mean pulmonary artery pressure from baseline to Stage 3 (P = 0.0009), as well as between Stages 1 and 2 (P = 0.0001), and 1 and 3 (P = 0.001), with no significant difference between Stages 2 and 3 (P = 0.06). Upon completion of the third stage, there were significant increases in arterial haemoglobin saturation as measured by pulse oximetry (P = 0.0009), arterial blood partial pressure of oxygen (P = 0.04), venous blood oxygen saturation of haemoglobin (P = 0.03) and arterial oxygen partial pressure over inspired oxygen fraction ratio (P = 0.04). A significant reduction in arterial blood partial pressure of carbon dioxide (P = 0.01) and in end tidal carbon dioxide also occurred (P = 0.009). The manoeuvre was well tolerated and besides a slight and transitory elevation in mean pulmonary artery, no other adverse haemodynamic or ventilatory effect was elicited. CONCLUSIONS: The alveolar recruitment manoeuvre seemed to be safe and well tolerated immediately after open heart surgery in infants liable to pulmonary hypertensive crises. PMID- 24480823 TI - Clinical signs of neurofibromatosis impact on the outcome of malignant peripheral nerve sheath tumors. AB - OBJECTIVE: Malignant peripheral nerve sheath tumors (MPNST) are a rare subtype of sarcoma, with a poor outcome. MPNST are regarded as being sporadic or associated with neurofibromatosis type 1 (NF1). Few comparative overall-survival (OS) data in these 2 subsets of MPNST patients exist. The aim of this retrospective study was to assess OS in sporadic and NF1-associated MPNST patients. METHODS: Fourteen consecutive patients with initial localized as well as initial metastatic MPNST were diagnosed and treated in our department. Patients with sporadic MPNST were assigned to group A and those with NF1-associated MPNST to group B. RESULTS: Eight versus 6 patients were allocated to groups A and B. Primary tumors were located on the extremities in all but 1 patient. Two patients in group A and 4 patients in group B experienced a relapse. Four patients died in each of the 2 groups. Median follow-up was 66.2 and 57.2 months in group A and group B, respectively. Median OS in group A was 46.9 months versus 12.7 months in group B. CONCLUSIONS: In this small, single-center study, sporadic-MPNST patients had a longer median OS than those with NF1-associated MPNST. PMID- 24480825 TI - Tet3-mediated hydroxymethylation of epigenetically silenced genes contributes to bone morphogenic protein 7-induced reversal of kidney fibrosis. AB - Methylation of CpG island promoters is an epigenetic event that can effectively silence transcription over multiple cell generations. Hypermethylation of the Rasal1 promoter contributes to activation of fibroblasts and progression of kidney fibrosis. Here, we explored whether such causative hypermethylation could be reversed through endogenous mechanisms and whether such reversal of hypermethylation is a constituent of the antifibrotic activity of bone morphogenic protein 7 (BMP7). We show that successful inhibition of experimental kidney fibrosis through administration of BMP7 associates with normalization of Rasal1 promoter hypermethylation. Furthermore, this reversal of pathologic hypermethylation was achieved specifically through Tet3-mediated hydroxymethylation. Collectively, our findings reveal a new mechanism that may be exploited to facilitate therapeutic DNA demethylation to reverse kidney fibrosis. PMID- 24480826 TI - Notch ties a knot on fistula maturation. PMID- 24480824 TI - Rituximab in steroid-dependent or frequently relapsing idiopathic nephrotic syndrome. AB - The outcome of steroid-dependent or frequently relapsing nephrotic syndrome of minimal change disease (MCD), mesangial proliferative GN (MesGN), or FSGS may be poor and with major treatment toxicity. This academic, multicenter, off-on trial (ClinicalTrials.gov #NCT00981838) primarily evaluated the effects of rituximab therapy followed by immunosuppression withdrawal on disease recurrence in 10 children and 20 adults with MCD/MesGN (n=22) or FSGS who had suffered >=2 recurrences over the previous year and were in steroid-induced remission for >=1 month. Participants received one dose (n=28) or two doses of rituximab (375 mg/m(2) intravenously). At 1 year, all patients were in remission: 18 were treatment-free and 15 never relapsed. Compared with the year before rituximab treatment, total relapses decreased from 88 to 22 and the per-patient median number of relapses decreased from 2.5 (interquartile range [IQR], 2-4) to 0.5 (IQR, 0-1; P<0.001) during 1 year of follow-up. Reduction was significant across subgroups (children, adults, MCD/MesGN, and FSGS; P<0.01). After rituximab, the per-patient steroid maintenance median dose decreased from 0.27 mg/kg (IQR, 0.19 0.60) to 0 mg/kg (IQR, 0-0.23) (P<0.001), and the median cumulative dose to achieve relapse remission decreased from 19.5 mg/kg (IQR, 13.0-29.2) to 0.5 mg/kg (IQR, 0-9.4) (P<0.001). Furthermore, the mean estimated GFR increased from 111.3+/-25.7 to 121.8+/-29.2 ml/min per 1.73 m(2) (P=0.01), with the largest increases in children and in FSGS subgroups. The mean height z score slope stabilized in children (P<0.01). Treatment was well tolerated. Rituximab effectively and safely prevented recurrences and reduced the need for immunosuppression in steroid-dependent or frequently relapsing nephrotic syndrome, and halted disease-associated growth deficit in children. PMID- 24480827 TI - Epigenetic unsilencing reverses renal fibrosis. PMID- 24480828 TI - Challenges and advances in the treatment of AKI. AB - Treating or preventing AKI requires treating or preventing a rise in serum creatinine as well as the immediate and remote clinical consequences associated with AKI. Because a substantial number of patients with AKI progress to ESRD, identifying patients likely to progress and halting progression are important goals for treating AKI. Many therapies for AKI are being developed, including RenalGuard Therapy, which aims to maintain high urine output; alpha-melanocyte stimulating hormone, with anti-inflammatory and antiapoptotic activities; alkaline phosphatase, which detoxifies proinflammatory substances; novel, small interfering RNA, directed at p53 activation; THR-184, a peptide agonist of bone morphogenetic proteins; removal of catalytic iron, important in free-radical formation; and cell-based therapies, including mesenchymal stem cells in vivo and renal cell therapy in situ. In this review, we explore what treatment of AKI really means, discuss the emerging therapies, and examine the windows of opportunity for treating AKI. Finally, we provide suggestions for accelerating the pathways toward preventing and treating AKI, such as establishing an AKI network, implementing models of catalytic philanthropy, and directing a small percentage of the Medicare ESRD budget for developing therapies to prevent and treat AKI and halt progression of CKD. PMID- 24480829 TI - Colon-specific deletion of epithelial sodium channel causes sodium loss and aldosterone resistance. AB - Aldosterone promotes electrogenic sodium reabsorption through the amiloride sensitive epithelial sodium channel (ENaC). Here, we investigated the importance of ENaC and its positive regulator channel-activating protease 1 (CAP1/Prss8) in colon. Mice lacking the alphaENaC subunit in colonic superficial cells (Scnn1a(KO)) were viable, without fetal or perinatal lethality. Control mice fed a regular or low-salt diet had a significantly higher amiloride-sensitive rectal potential difference (?PDamil) than control mice fed a high-salt diet. In Scnn1a(KO) mice, however, this salt restriction-induced increase in ?PDamil did not occur, and the circadian rhythm of ?PDamil was blunted. Plasma and urinary sodium and potassium did not change with regular or high-salt diets or potassium loading in control or Scnn1a(KO) mice. However, Scnn1a(KO) mice fed a low-salt diet lost significant amounts of sodium in their feces and exhibited high plasma aldosterone and increased urinary sodium retention. Mice lacking the CAP1/Prss8 in colonic superficial cells (Prss8(KO)) were viable, without fetal or perinatal lethality. Compared with controls, Prss8(KO) mice fed regular or low-salt diets exhibited significantly reduced ?PDamil in the afternoon, but the circadian rhythm was maintained. Prss8(KO) mice fed a low-salt diet also exhibited sodium loss through feces and higher plasma aldosterone levels. Thus, we identified CAP1/Prss8 as an in vivo regulator of ENaC in colon. We conclude that, under salt restriction, activation of the renin-angiotensin-aldosterone system in the kidney compensated for the absence of ENaC in colonic surface epithelium, leading to colon-specific pseudohypoaldosteronism type 1 with mineralocorticoid resistance without evidence of impaired potassium balance. PMID- 24480830 TI - Blocking Notch in endothelial cells prevents arteriovenous fistula failure despite CKD. AB - Neointima formation causes the failure of 60% of arteriovenous fistulas (AVFs) within 2 years. Neointima-forming mechanisms are controversial but possibly linked to excess proinflammatory responses and dysregulated Notch signaling. To identify how AVFs fail, we anastomosed the carotid artery to the internal jugular vein in normal and uremic mice and compared these findings with those in failed AVFs from patients with ESRD. Endothelial cells (ECs) of AVFs in uremic mice or patients expressed mesenchymal markers (FSP-1 and/or alpha-SMA) and exhibited increased expression and nuclear localization of Notch intracellular domain compared with ECs of AVFs in pair-fed control mice. Furthermore, expression of VE Cadherin decreased, whereas expression of Notch1 and -4, Notch ligands, the downstream transcription factor of Notch, RBP-Jkappa, and Notch target genes increased in ECs of AVFs in uremic mice. In cultured ECs, ectopic expression of Notch ligand or treatment with TGF-beta1 triggered the expression of mesenchymal markers and induced endothelial cell barrier dysfunction, both of which were blocked by Notch inhibition or RBP-Jkappa knockout. Furthermore, Notch-induced defects in barrier function, invasion of inflammatory cells, and neointima formation were suppressed in mice with heterozygous knockdown of endothelial specific RBP-Jkappa. These results suggest that increased TGF-beta1, a complication of uremia, activates Notch in endothelial cells of AVFs, leading to accelerated neointima formation and AVF failure. Suppression of Notch activation could be a strategy for improving AFV function in uremia. PMID- 24480832 TI - Janus nanobelts: fabrication, structure and enhanced magnetic-fluorescent bifunctional performance. AB - A new nanostructure of magnetic-fluorescent bifunctional Janus nanobelts with Fe3O4/PMMA as one half and Tb(BA)3phen/PMMA as the other half has been successfully fabricated by a specially designed parallel spinneret electrospinning technology. The morphology and properties of the final products were investigated in detail by X-ray diffractometry (XRD), scanning electron microscopy (SEM), energy dispersive spectrometry (EDS), biological microscopy (BM), vibrating sample magnetometry (VSM) and fluorescence spectroscopy. The results revealed that the [Fe3O4/PMMA]//[Tb(BA)3phen/PMMA] magnetic-fluorescent bifunctional Janus nanobelts possess superior magnetic and fluorescent properties due to their special nanostructure. Compared with Fe3O4/Tb(BA)3phen/PMMA composite nanobelts, the magnetic-fluorescent bifunctional Janus nanobelts provided better performance. The new magnetic-fluorescent bifunctional Janus nanobelts have potential applications in novel nano-bio-label materials, drug target delivery materials and future nanodevices due to their excellent magnetic fluorescent properties, flexibility and insolubility. Moreover, the construction technique for the Janus nanobelts is of universal significance for the fabrication of other multifunctional Janus nanobelts. PMID- 24480831 TI - Mapping the temporal pole with a specialized electrode array: technique and preliminary results. AB - Temporopolar cortex plays a crucial role in the pathogenesis of temporal lobe epilepsy and subserves important cognitive functions. Because of its shape and position in the middle cranial fossa, complete electrode coverage of the temporal pole (TP) is difficult to achieve using existing devices. We designed a novel TP electrode array that conforms to the surface of temporopolar cortex and achieves dense electrode coverage of this important brain region. A multi-pronged electrode array was designed that can be placed over the surface of the TP using a straightforward insertion technique. Twelve patients with medically intractable epilepsy were implanted with the TP electrode array for purposes of seizure localization. Select patients underwent cognitive mapping by electrocorticographic (ECoG) recording from the TP during a naming task. Use of the array resulted in excellent TP electrode coverage in all patients. High quality ECoG data were consistently obtained for purposes of delineating seizure activity and functional mapping. During a naming task, significant increases in ECoG power were observed within localized subregions of the TP. One patient developed a transient neurological deficit thought to be related to the mass effect of multiple intracranial recording arrays, including the TP array. This deficit resolved following removal of all electrodes. The TP electrode array overcomes limitations of existing devices and enables clinicians and researchers to obtain optimal multi-site recordings from this important brain region. PMID- 24480834 TI - Thermodynamic constraints on syntrophic acetate oxidation. PMID- 24480836 TI - Effect of perioperative electroacupuncture as an adjunctive therapy on postoperative analgesia with tramadol and ketamine in prostatectomy: a randomised sham-controlled single-blind trial. AB - OBJECTIVES: To study the analgesic effect of electroacupuncture (EA) as perioperative adjunctive therapy added to a systemic analgesic strategy (including tramadol and ketamine) for postoperative pain, opioid-related side effects and patient satisfaction. METHODS: In a sham-controlled participant- and observer-blinded trial, 75 patients undergoing radical prostatectomy were randomly assigned to two groups: (1) EA (n=37; tramadol+ketamine+EA) and (2) control (n=38; tramadol+ketamine). EA (100 Hz frequency) was applied at LI4 bilaterally during the closure of the abdominal walls and EA (4 Hz) was applied at ST36 and LI4 bilaterally immediately after extubation. The control group had sham acupuncture without penetration or stimulation. The following outcomes were evaluated: postoperative pain using the Numerical Rating Scale (NRS) and McGill Scale (SF_MPQ), mechanical pain thresholds using algometer application close to the wound, cortisol measurements, rescue analgesia, Spielberger State Trait Anxiety Inventory (STAI Y-6 item), patient satisfaction and opioid side effects. RESULTS: Pain scores on the NRS and SF_MPQ were significantly lower and electronic pressure algometer measurements were significantly higher in the EA group than in the control group (p<0.001) at all assessments. In the EA group a significant decrease in rescue analgesia was observed at 45 min (p<0.001) and a significant decrease in cortisol levels was also observed (p<0.05). Patients expressed satisfaction with the analgesia, especially in the EA group (p<0.01). Significant delays in the start of bowel movements were observed in the control group at 45 min (p<0.001) and 2 h (p<0.05). CONCLUSIONS: Adding EA perioperatively should be considered an option as part of a multimodal analgesic strategy. PMID- 24480837 TI - Multimodal retinal imaging in a Chinese kindred with familial amyloid polyneuropathy secondary to transthyretin Ile107Met mutation. AB - OBJECTIVE: To investigate the ocular phenotype and gene mutation of a Chinese pedigree with familial amyloid polyneuropathy (FAP) and vitreous amyloidosis. METHODS: A Chinese pedigree with familial amyloid polyneuropathy and vitreous amyloidosis was recruited. Combined phacoemulsification, vitrectomy and intraocular lens implantation were performed on the right eye of the index patient. Ophthalmic investigations were performed before and after surgery. The DNA from the pedigree was sequenced for the transthyretin (TTR) gene. RESULTS: After vitrectomy, the best-corrected visual acuity of the patient improved from counting finger to 20/20. Red-free confocal ophthalmoscopy demonstrated perifoveal ring and several perivessel white sheaths. Optical coherence tomography (OCT) revealed cotton wool like reflections on the vitreoretinal interface. Electroretinogram and autofluorescence was normal. Amyloid was present in the vitreous specimen. A substitution of T to G at nucleotide 381 in exon 4 of TTR DNA (Ile107Met) was found. This mutation co-segregated with phenotype in the pedigree and was not detected in 200 controls. CONCLUSIONS: TTR Ile107Met mutation is associated with vitreous amyloidosis and FAP. OCT and red-free imaging are helpful in identifying amyloid deposits in the retina. PMID- 24480838 TI - Corneal sensitivity and morphology of the corneal subbasal nerve plexus in primary congenital glaucoma. AB - BACKGROUND: To quantify the corneal subbasal nerve density and the total number of nerve fibers in primary congenital glaucoma (PCG) and to evaluate their impact on corneal sensitivity. METHODS: Forty eyes of 26 PCG patients were compared with 40 eyes randomly selected from 40 non-glaucoma patients who populated the control group. Central corneal sensitivity (CCS) was assessed by means of Cochet-Bonnet esthesiometry. The mean subbasal nerve density and the total number of nerve fibers were quantified by laser-scanning confocal microscopy. Normality of data was assessed by Kolmogorov-Smirnov testing. Differences in parameters were assessed with Student's t-test, while correlations with CSS were assessed with Pearson's correlation. RESULTS: Significant differences were identified in the mean subbasal nerve density (2108 +/- 692 MUm in PCG, 2642 +/- 484 MUm in controls, P = 0.003) and in the total number of nerve fibers (12.3 +/- 4.2 in PCG, 15.4 +/- 3.1 in controls, P = 0.02). Both groups presented comparable mean CCS and tortuosity. Both groups presented strong correlations between CCS and mean nerve density (r = 0.57 in PCG, r = 0.67 in controls, all P < 0.05), and between CCS and total number of nerve fibers (r = 0.55 in PCG, r = 0.56 in controls, all P < 0.05). CONCLUSION: PCG exerts significant changes in both the mean subbasal nerve density and the total number of nerve fibers. However, these changes do not appear to affect central corneal sensitivity. PMID- 24480839 TI - Cicatricial changes in ocular pemphigus. AB - PURPOSE: To describe the clinical characteristics of ocular involvement in patients with pemphigus at an ophthalmological referral center. METHODS: A retrospective review was conducted on patients with the immunopathological diagnosis of pemphigus examined between 1 January 2000 and 1 April 2010. Uncorrected distance visual acuity (UDVA), best corrected distance visual acuity (BCVA), ocular symptoms, and ocular surface inflammatory and scarring changes were assessed. RESULTS: A total of 15 patients were identified, with a mean age of 68.27 +/- 14.35 years, and 80% (n=12) were female. Extraocular involvement was reported in one patient. All of the eyes showed cicatricial changes in the conjunctiva. In all, 6 eyes (20%) were classified as stage I; 12 eyes (40%) as stage II; 10 eyes (33%) as stage III; and 2 eyes (7%) as stage IV. A statistically significant association was found between BCVA and the severity of ocular involvement. The mean BCVA logMAR was 1.66 (20/914), with a range from logMAR 0 (20/20) to logMAR 4 (NLP). Other ocular diseases were found in 8 (53.3%), systemic diseases in 10 (66.7%), and the use of pemphigus-inducing drugs in 10 patients (66.7%). CONCLUSIONS: The present report represents the largest series of ocular involvement in pemphigus confirmed by immunopathology. The clinical manifestations varied from conjunctival hyperemia to corneal scarring and perforation. There was a strong association between scarring changes and low BCVA. Ocular and systemic diseases as well as the use of pemphigus-inducing drugs may predispose to ocular cicatricial changes observed in this series. PMID- 24480840 TI - A detailed phenotypic description of autosomal dominant cone dystrophy due to a de novo mutation in the GUCY2D gene. AB - PURPOSE: The purpose of this study is to describe the phenotype of a family with de novo mutation in the GUCY2D. MATERIALS AND METHODS: Five subjects, including two monozygotic twins, underwent ophthalmic clinical examination while some had autofluorescence imaging (AF) and optical coherence tomography (OCT). Symptomatic individuals underwent electrophysiological testing. The youngest subject (21 years) was also evaluated psychophysically. DNA obtained from the individuals was screened for mutations in GUCY2D. Microsatellite markers were used to determine the haplotype of 17p surrounding the GUCY2D gene. RESULTS: The youngest subject had 6/18 visual acuity, an annulus of hyper-autofluorescence in the perifoveal region, and a subfoveal absence of outer segments on OCT. In the older individuals, severe thinning of inner retina and a patchy loss of photoreceptors and retinal pigment epithelium were observed in the perifoveal region. All three showed generalised cone system dysfunction with preserved rod function on electrophysiology. Psychophysical evaluation was consistent with poor cone function. Screening of the GUCY2D gene revealed the mutation p.R838H in all the affected individuals and was absent in the asymptomatic patients. Haplotyping showed that the mutation originated from the unaffected mother. CONCLUSIONS: Autosomal dominant cone dystrophy due to GUCY2D can occur without a history in the antecedents due to a de novo mutation. This is important to consider in any simplex case with a similar phenotype. The phenotype description of this disorder is expanded with detailed description of the OCT findings. This paper describes the concordance of the phenotypic findings in the monozygotic twins. PMID- 24480843 TI - Diagnostic and therapeutic challenges. PMID- 24480842 TI - Characteristics of rhegmatogenous retinal detachment and their relationship to success rates of surgery. AB - PURPOSE: To determine features of rhegmatogenous retinal detachment predictive of anatomical success with surgical procedure. METHODS: All patients undergoing surgery at a tertiary referral practice had contemporaneous data collection in an electronic database. Overall, 847 eyes from 847 patients undergoing surgical procedure for rhegmatogenous retinal detachment were included in this study. RESULTS: Mean age was 62.2 years with 60% male subjects and 56% right eyes. Mean postoperative follow-up was 9.6 months (range, 6 weeks to 10 years). With univariate analysis, the presence of superotemporal breaks was associated with a reduction in the chance of failed primary surgery (P = 0.005); detached inferonasal breaks (P = 0.002), proliferative vitreoretinopathy (PVR) (P < 0.0001), breaks in detached inferior retina (P < 0.0001), fovea off (P = 0.001), and 4-quadrant rhegmatogenous retinal detachment (P < 0.0001) increased the risk of failure. After multivariate analysis PVR, detached inferior breaks, increased number of breaks, and 4-quadrant detachment remained associated with an increased risk of failure, and superotemporal detached breaks with the reduced risk of failure (r(2) = 0.08). For patients without PVR, only inferonasal detached breaks and 3 to 4 quadrants of detachment remained predictive of failure (r(2) = 0.04). For patients with PVR (n = 120), multivariate analysis showed that PVR C4-12 and posterior breaks increased the failure risk and detached superotemporal breaks reduced the risk of failure (r(2) = 0.22). CONCLUSION: Number of breaks, inferior positioning of breaks, the extent of rhegmatogenous retinal detachment, and PVR are associated with failed primary surgery. PMID- 24480841 TI - Development and initial experience with a colored perfluorocarbon liquid for intraocular tamponade in vitreoretinal surgery. AB - PURPOSE: To present the development and initial experience of a novel colored perfluorocarbon liquid (PFCL) in vitreoretinal surgery. METHODS: This was an experimental laboratory study and prospective human interventional study. F6H8 (Fluoron GmbH) was colored by adding 0.3 g/L blue anthraquinone dye. Subsequently, 20% colored F6H8 was prepared by mixing with perfluorooctane or perfluorodecalin (Fluoron GmbH). The novel product is not yet FDA approved for human application. In the laboratory, the colored PFCL was covered with 1) uncolored PFCL, 2) BSS, and 3) silicone oil. Cell toxicity was evaluated in L929 mouse fibroblasts using a growth inhibition assay. Porcine ex vivo eyes were evaluated after vitrectomy followed by intravitreal and subretinal colored PFCL infusion. A pilot, prospective, noncomparative interventional study was conducted in patients with retinal detachment with proliferative vitreoretinopathy (PVR). RESULTS: The density of the colored PFLC mixture was 1.664 g/cm for perfluorooctane and 1.802 g/cm for perfluorodecalin. There was no relevant cell growth inhibition with any concentration of colored PFCL tested. Experiments in pigs revealed that infusion of the colored PFCL caused neither staining of the internal limiting membrane nor intravitreal residual droplets. In the prospective study, 9 eyes (75%) underwent surgery for rhegmatogenous retinal detachment with at least grade C PVR. The colored PFCL enabled retinal break examination and detection of residual intravitreal droplets in all surgeries. There was no case of separation or leakage of the dye from the PFCL solution that could have caused unwanted staining of the vitreous or epiretinal surface. CONCLUSION: The colored PFCL enabled intraoperative maneuvers such as endolaser use. In addition, removal of the colored PFCL was easily achieved at the end of surgery. PMID- 24480844 TI - Platelet PIA1/PIA2 polymorphism and the risk of periprocedural myocardial infarction in patients with acute coronary syndromes undergoing coronary angioplasty. AB - Acute coronary syndromes (ACSs) represent a high-risk condition, as enhanced platelet reactivity importantly influences myocardial perfusion and procedural results after percutaneous coronary intervention (PCI). In fact, higher rate of periprocedural myocardial infarction (PMI) and reduced event-free survival have been reported in these patients. The single nucleotide polymorphism Leu33Pro of platelet glycoprotein IIIa has been related to an increased platelet reactivity, a lower response to antiplatelet agents and higher risk of stent restenosis. Therefore, our aim was to evaluate the impact of this polymorphism on PMI in patients undergoing PCI for non-ST-segment elevation MI (NSTEMI). Our population is represented by 478 consecutive patients undergoing coronary angioplasty for NSTEMI. Cardiac biomarkers were monitored at intervals from 8 to 48 h after the procedure. Genetic analysis was performed to assess the presence of Leu33Pro polymorphism. A total of 156 patients (32.6%) were polymorphic. Clinical features did not differ according to genetic status, neither pharmacological treatment pre and during angioplasty. PlA carriers had lower rate of calcifications (P = 0.01) and higher coronary tortuosity (P = 0.03) at angiography and underwent more frequently to thrombectomy (P = 0.05). PCI-related complications did not differ according to genotype. Leu33Pro polymorphism was not associated with increased risk of periprocedural myonecrosis and PMI even after correction for baseline differences, [odds ratio (OR) (95% confidence interval (CI) = 0.70 (0.44-1.13), P = 0.15 for PMI and OR (95% CI) = 0.77 (0.53-1.11), P = 0.17 for myonecrosis, respectively]. Results were confirmed in high-risk subgroups of patients. In conclusion, among patients undergoing PCI for ACS, the polymorphism Leu33Pro of platelet glycoprotein IIIa is not associated with increased risk of PMI. PMID- 24480846 TI - Solar thermal harvesting for enhanced photocatalytic reactions. AB - The Shockley-Queisser limit predicts a maximum efficiency of 30% for single junction photovoltaic (PV) cells. The rest of the solar energy is lost as heat and due to phenomena such as reflection and transmission through the PV and charge carrier recombination. In the case of photocatalysis, this maximum value is smaller since the charge carriers should be transferred to acceptor molecules rather than conductive electrodes. With this perspective, we realize that at least 70% of the solar energy is available to be converted into heat. This is specifically useful for photocatalysis, since heat can provide more kinetic energy to the reactants and increase the number of energetic collisions leading to the breakage of chemical bonds. Even in natural photosynthesis, at the most 6% of the solar spectrum is used to produce sugar and the rest of the absorbed photons are converted into heat in a process called transpiration. The role of this heating component is often overlooked; in this paper, we demonstrate a coupled system of solar thermal and photocatalytic decontamination of water by titania, the most widely used photocatalyst for various photo reactions. The enhancement of this photothermal process over solely photocatalytic water decontamination is demonstrated to be 82% at 1* sun. Our findings suggest that the combination of solar thermal energy capture with photocatalysis is a suitable strategy to utilize more of the solar spectrum and improve the overall performance. PMID- 24480845 TI - Efficacy and safety of platinum combination chemotherapy re-challenge for relapsed patients with non-small-cell lung cancer after postoperative adjuvant chemotherapy of cisplatin plus vinorelbine. AB - BACKGROUND: There is no standard therapy for relapsed patients who have received postoperative platinum-based adjuvant chemotherapy for resected non-small-cell lung cancer (NSCLC). We investigated the efficacy and safety of platinum combination chemotherapy re-challenge for such patients. METHODS: Medical records from 3 institutes from April 2005 to July 2012 were retrospectively reviewed. Patients who underwent complete surgical resection were eligible if they received postoperative adjuvant chemotherapy consisting of cisplatin plus vinorelbine once and then re-challenge with platinum combination chemotherapy. RESULTS: Sixteen patients were enrolled in this study. After re-challenge with platinum combination chemotherapy, we observed an overall response rate of 31.2% (5/16) and a disease control rate of 81.2% (13/16). Median progression-free survival and overall survival from the start of the re-administration of platinum combination chemotherapy were 6.5 and 28.0 months, respectively. Frequently observed severe adverse events (>=grade 3) included neutropenia (31.2%), thrombocytopenia (31.2%), leukopenia (12.5%) and hyponatremia (12.5%). Frequently observed non hematological toxicities (>=grade 2) were anorexia (37.5%) and nausea (37.5%). CONCLUSION: Re-challenge with platinum combination chemotherapy was effective and safe; therefore, this therapy should be considered as a treatment option for relapsed patients after postoperative cisplatin-based adjuvant chemotherapy for resected NSCLC. PMID- 24480847 TI - An autopsy case of acute and nonalcoholic thiamine-deficient encephalopathy. PMID- 24480848 TI - A five-year self-sustainability analysis of nurse-administered HIV rapid testing in Veterans Affairs primary care. AB - In 2008, nurse-administered HIV oral rapid testing (RT) was introduced at the Veterans Affairs Primary Care Clinic in Downtown Los Angeles. Analysis at five years revealed variable yet increasing rates of HIV RT at that facility despite the fact that no post-launch support was provided by the implementation team. Qualitative interviews among stakeholders conducted at five years revealed the pre-existing implementation practices endemic to this clinic that facilitated this unprecedented success (e.g. history of positive quality improvement implementations, leadership support, clinician involvement at each step of the process to facilitate empowerment, ownership and feasible customisation of the implementation, cohesive communication among clinicians and leadership, training, efficient supply pathway, progressive performance feedback and ongoing encouragement). PMID- 24480849 TI - HIV knowledge, risk perception and avoidant behaviour change among Sierra Leonean refugees in Guinea. AB - A common assumption underpinning health communications design in humanitarian settings is that increasing knowledge and risk perception will lead to appropriate behaviour change. This study compares associations of HIV knowledge and perceived risk with reported HIV-avoidant behaviour changes and sexual health choices from a community survey of 698 sexually experienced male and female Sierra Leonean refugees in Guinea. HIV knowledge was not significantly associated with reported HIV-avoidant changes (OR 1.25; adjusted for gender; 95%CI 0.76 2.04), while perceived HIV risk was negatively associated (OR 0.38, adjusted for age at sexual debut; 95%CI 0.22-0.66). Trying to conceive was the main reason reported for not using condoms or other contraception (28%; 138/498), followed by current pregnancy/lactation (19%; 93/498). Results suggest contextual factors (e.g. desire for children) can be as important as knowledge and risk-perception, and HIV prevention initiatives in stable and chronic humanitarian settings should account for these. PMID- 24480850 TI - High prevalence of asymptomatic sexually transmitted infections in HIV-infected men who have sex with men: a stimulus to improve screening. AB - In Ireland the incidence of sexually transmitted infections (STIs) is steadily increasing while the number of new HIV-diagnoses in men who have sex with men has more than doubled in the past decade. This study investigated the prevalence of STIs in asymptomatic HIV-infected men who have sex with men (MSM) attending a clinic for routine HIV care in the largest HIV-centre in Ireland. Fifty HIV infected MSM were included in the study (mean age [SD] 38years [9], 66% Irish). Sixteen per cent of HIV-infected MSM screened were diagnosed with a STI. Thirty eight per cent reported always using condoms while 4% reported never using condoms, 46% used condoms inconsistently and 10% reported no sexual contacts in the preceding 12 months. Recognising the need to optimise STI screening, a pilot self-screening programme was subsequently introduced to our HIV clinic as a quality improvement initiative. Asymptomatic MSM attending for routine HIV care were invited to have an opportunistic STI screen either provider performed or by self-screening. Seventy-one patients were included in the pilot. Sixty-five (92%) opted for self-collected rectal swabs. Ten STIs were detected in eight patients. This study supports guidelines recommending routine screening for STIs in the care of HIV-infected patients and highlights opportunities to provide relevant screening and education interventions targeting unsafe sexual behaviours. PMID- 24480851 TI - A dual role for SHH during phallus development in a marsupial. AB - The mammalian phallus arises from identical primordia in both sexes and is patterned in part by the key morphogen Sonic hedgehog (SHH). We have investigated SHH and other morphogens during phallus development in the tammar wallaby. In this marsupial, testis differentiation and androgen production occurs just after birth, but it takes a further 50-60 days before the phallus becomes sexually dimorphic. One day before birth, SHH was expressed in both sexes in the urethral epithelium. In males, there was a marked upregulation of SHH, GLI2, and AR at day 50 postpartum, a time when testicular androgen production falls. SHH, GLI2, and AR were downregulated in female pouch young treated with androstanediol from days 24-50, but not when treatments were begun at day 29, suggesting an early window of androgen sensitivity. SHH, GLI2, and AR expression in the phallus of males castrated at day 23 did not differ from controls, but there was an increase in SHH and GLI2 and a decrease in FGF8 and BMP4 expression when the animals were castrated at day 29. These results suggest that the early patterning by SHH is androgen-independent followed by an androgen-dependent window of sensitivity and a sharp rise in SHH expression after androgen withdrawal at day 50. PMID- 24480853 TI - The first supramolecular peptidic hydrogelator containing taurine. AB - The conjugation of taurine with a dipeptide derivative affords a cell compatible, small molecular hydrogelator to form hydrogels that exhibit rich phase transition behaviors in response to sonication and the change of pH or temperature. PMID- 24480852 TI - Unraveling intestinal stem cell behavior with models of crypt dynamics. AB - The definition, regulation and function of intestinal stem cells (ISCs) has been hotly debated. Recent discoveries have started to clarify the nature of ISCs, but many questions remain. This review discusses the current advances and controversies of ISC biology as well as theoretical compartmental models that have been coupled with in vivo experimentation to investigate the mechanisms of ISC dynamics during homeostasis, tumorigenesis, repair and development. We conclude our review by discussing the key lingering questions in the field and proposing how many of these questions can be addressed using both compartmental models and experimental techniques. PMID- 24480854 TI - Molecular mechanisms associated with Angiotensin-converting enzyme-inhibitory peptide activity on vascular extracellular matrix remodeling. AB - OBJECTIVE: This paper aimed to investigate the molecular mechanisms associated with angiotensin-converting enzyme (ACE)-inhibitory peptide activity involved in vascular extracellular matrix (ECM) remodeling. Therefore, changes in collagen fibers, elastic fibers and laminin were assessed in the left common carotid artery (LCCA). METHODS: We selected 10-week-old male spontaneously hypertensive rats to study the expression levels of matrix metalloproteinases (MMPs), transforming growth factor, angiotensin (Ang) II and nuclear factor (NF)-p65 in the wall of carotid arteries. RESULTS: Compared to the control group, laminin expression was significantly increased (p < 0.05) in the vascular endothelium of the LAP (a homemade ACE-inhibitory peptide, named by ourselves) group, whereas the percentage of elastic/collagen fibers in the LCCA vascular area was significantly decreased (p < 0.0001) in the LAP group. Immune blots of MMP-2, MMP 9, NF-p65 and AngII were significantly reduced in the LCCA wall in the LAP group. CONCLUSION: Vascular ECM remodeling may be related to the inhibitory action of LAP on ECM deposition. PMID- 24480856 TI - The incidence and risk factors of infusion-related reactions to rituximab for treating B cell malignancies in a single tertiary hospital. AB - BACKGROUND: Rituximab is a chimeric anti-CD20 human/mouse monoclonal antibody. As its usage has increased, there have been growing concerns about rituximab-related infusion-related reactions (IRRs). OBJECTIVE: The aim of this study is to verify the clinical features and risk factors of IRRs by rituximab, and to help establish clinical guidelines for their prevention. METHODS: We reviewed electronic medical records of all the adult patients who were prescribed rituximab from January 2005 to July 2010 for B cell malignancy at Seoul National University Hospital. RESULTS: A total of 389 cases of IRRs by rituximab (12.5% of a total of 3,104 infusions) were identified in 281 patients (49.4% of a total of 568 patients). IRRs most frequently occurred during the first infusion (40.5%) and abruptly decreased in subsequent infusions to rates of 3-8% (p < 0.001). The incidence of IRRs in patients premedicated with corticosteroid for their first infusion was significantly lower when compared to patients not pretreated with corticosteroid prior to rituximab infusion (8.3 vs. 41.2%, p = 0.017). CONCLUSION: Almost half of all patients in the study experienced IRRs at least once during their scheduled rituximab treatment. Premedication with corticosteroid can be recommended in patients with high risk of IRR in the first infusion. PMID- 24480857 TI - Dengue virus serotype-2 impairs proliferation of healthy donors' T lymphocytes. AB - OBJECTIVES: T lymphocytes are not infected by dengue virus (DENV), nevertheless it is possible that exposure to DENV may affect their function. T lymphocytes from DENV-infected individuals are impaired in their proliferative capacity, although this effect has been attributed to altered function of antigen presenting cells rather than to an intrinsic defect on T lymphocytes. Here we analyzed whether T lymphocytes from healthy donors became impaired in their proliferative capacity following in vitro exposure to DENV serotype-2 (DENV-2), as well as the possible mechanisms for this. METHODS: Isolated CD4+ and CD8+ T lymphocytes from healthy donors were in vitro exposed to DENV-2, before polyclonal activation, cell proliferation, IL-2 synthesis. IL-2Ralpha expression, nuclear translocation of NF-AT and NF-kappaB, and intracellular calcium flux were assessed. RESULTS: In vitro exposure of both CD4+ and CD8+ T lymphocytes from healthy donors to DENV-2 impairs cell proliferation, IL-2 synthesis, and IL 2Ralpha (CD25) cell membrane expression. Signalling wise, exposure to DENV-2 impairs the nuclear translocation of NF-AT, downstream of intracellular calcium mobilization, as well as that of NF-kappaB. CONCLUSION: In the course of a dengue infection, direct exposure of T lymphocytes to DENV could affect cell-mediated immune responses. PMID- 24480859 TI - The effect of endotoxin on the controllability of cardiac rhythm in rats. AB - Decreased heart rate variability (HRV) has both diagnostic and prognostic value in patients with sepsis. However, it is not known whether reduced HRV in sepsis reflects an altered input from the autonomic nervous system or a remodeling of the cardiac pacemaker cells by inflammatory mediators. The present study aimed to investigate the effect of endotoxin on the heart rate dynamics of a denervated isolated heart in rats. Saline or endotoxin was injected into rats and their hearts were isolated and perfused. Atrial electrical activity was recorded and memory length in the time-series was assessed using inverse statistical analysis. Memory was defined as a statistical feature that lasts for a period of time and distinguishes the time-series from a random process. Endotoxaemic hearts exhibited a prolonged memory compared to the controls with respect to observing rare events. This indicates that a sudden decelerating event could potentially affect the cardiac rhythm of an endotoxaemic heart for a longer time than the controls. The prolongation of memory is indirectly linked to a reduced controllability in a complex system; therefore our data may provide evidence for a reduced controllability in cardiac rhythm following endotoxaemia. PMID- 24480860 TI - Impact of high-fat feeding on basic helix-loop-helix transcription factors controlling enteroendocrine cell differentiation. AB - BACKGROUND AND OBJECTIVES: Gut hormones secreted by enteroendocrine cells (EECs) play a major role in energy regulation. Differentiation of EEC is controlled by the expression of basic helix-loop-helix (bHLH) transcription factors. High-fat (HF) feeding alters gut hormone levels; however, the impact of HF feeding on bHLH transcription factors in mediating EEC differentiation and subsequent gut hormone secretion and expression is not known. METHODS: Outbred Sprague-Dawley rats were maintained on chow or HF diet for 12 weeks. Gene and protein expression of intestinal bHLH transcription factors, combined with immunofluorescence studies, were analyzed for both groups in the small intestine and colon. Gut permeability, intestinal lipid and carbohydrate transporters as well as circulating levels and intestinal protein expression of gut peptides were determined. RESULTS: We showed that HF feeding resulted in hyperphagia and increased adiposity. HF-fed animals exhibited decreased expression of bHLH transcription factors controlling EEC differentiation (MATH1, NGN3, NEUROD1) and increased expression of bHLH factors modulating enterocyte expression. Furthermore, HF-fed animals had decreased number of total EECs and L-cells. This was accompanied by increased gut permeability and expression of lipid and carbohydrate transporters, and a decrease in circulating and intestinal gut hormone levels. CONCLUSIONS: Taken together, our results demonstrate that HF feeding caused decreased secretory lineage (that is, EECs) differentiation through downregulation of bHLH transcription factors, resulting in reduced EEC number and gut hormone levels. Thus, impaired EEC differentiation pathways by HF feeding may promote hyperphagia and subsequent obesity. PMID- 24480861 TI - Impact of sleeve gastrectomy on red blood cell aggregation: a 12-month follow-up study. AB - OBJECTIVE: To investigate the effects of weight loss due to laparoscopic sleeve gastrectomy (LSG) on erythrocyte aggregation and the relationship of anthropometric and plasmatic factors, such as plasma viscosity, fibrinogen and lipids, with erythrocyte aggregation. DESIGN AND SUBJECTS: The RBC aggregation and kinetics of the red blood cell aggregation were performed by the Laser assisted Optical Rotational Cell Analyser (LORCA). Before the LSG and 6 and 12 months after the LSG, we evaluated the aggregation index (AI), amplitude (AMP) and aggregation half-time (t1/2), plasma viscosity, fibrinogen, glucose and lipids patterns in 15 non-diabetic obese subjects. RESULTS: The static and kinetic parameters of aggregation in obese patients at each time point after bariatric weight loss surgery were calculated and significant differences were observed at 12 months after surgery. AI and AMP decreased from 69.81+/-5.12% and 27.43+/-2.9 a.u. at baseline to 64.91+/-5.94% and 22.15+/-4.3 a.u. 12 months after surgery, respectively. The t1/2 increased from 1.7 (1.32-2.24) s at baseline compared with 2.02 (1.68-2.42) s at 12 months after the surgery. Plasma viscosity and fibrinogen decreased from 1.50+/-0.093 mPa s and 3.0+/-0.41 g l(-1) at baseline to 1.407+/-0.062 mPa s and to 2.66+/-0.25 g l(-1) 12 months after surgery, respectively. AI correlated positively with BMI (r=0.74, P=0.001), waist circumference (r=0.68, P=0.005), fibrinogen (r=0.52, P=0.045) and plasma viscosity (r=0.76, P=0.001) and negatively with percentages of weight lost after surgery (r=-0.54, P=0.034). Multivariate analyses found that the BMI, fibrinogen and plasma viscosity independently influenced the AI. CONCLUSION: The study demonstrated that weight loss due to restrictive bariatric surgery can beneficially affect red cell aggregation parameters. The improvement of the RBC aggregation behaviours among obese subjects with weight loss due to LSG was associated with changes in plasmatic factors, especially fibrinogen. PMID- 24480863 TI - Obesity and depression in adolescence and beyond: reciprocal risks. AB - OBJECTIVE: Obesity and major depressive disorder (MDD) are associated, but evidence about how they relate over time is conflicting. The goal of this study was to examine prospective associations between depression and obesity from early adolescence through early adulthood. METHODS: Participants were drawn from a statewide, community-based, Minnesota sample. MDD and obesity with onsets by early adolescence (by age 14), late adolescence (between 14 and 20) and early adulthood (ages 20-24) were assessed via structured interview (depression) and study-measured height and weight. RESULTS: Cross-sectional results indicated that depression and obesity with onsets by early adolescence were concurrently associated, but the same was not true later in development. Prospective results indicated that depression by early adolescence predicted the onset of obesity (odds ratio (OR)=3.76, confidence interval =1.33-10.59) during late adolescence among female individuals. Obesity that developed during late adolescence predicted the onset of depression (OR=5.89, confidence interval=2.31-15.01) during early adulthood among female individuals. CONCLUSIONS: For girls, adolescence is a high-risk period for the development of this comorbidity, with the nature of the risk varying over the course of adolescence. Early adolescent onset depression is associated with elevated risk of later onset obesity, and obesity, particularly in late adolescence, is associated with increased odds of later depression. Further investigation into the mechanisms of these effects and the reasons for the observed gender and developmental differences is needed. Prevention programs focused on early-onset cases of depression and adolescent onset cases of obesity, particularly among female individuals, may help in reducing risk for this form of comorbidity. PMID- 24480862 TI - Ethnic variation in the association between sleep and body mass among US adolescents. AB - OBJECTIVE: We investigate whether differences in sleep duration help explain ethnic disparities in body mass index (BMI) among US adolescents. We also evaluate the functional form of the association between sleep duration and BMI, and investigate whether this association varies by sex and ethnicity. PARTICIPANTS AND METHODS: We analyzed restricted-use data from the first two waves of the National Longitudinal Study of Adolescent Health (n=30 133) to evaluate linear and quadratic associations between sleep duration and BMI. Through a series of models that incorporated interaction terms between sex, ethnicity and sleep duration, we also assessed whether (1) sleep duration mediates associations between ethnicity and BMI, and (2) associations between sleep duration and BMI differ for girls and boys from different ethnic groups. RESULTS: A linear association between sleep duration and BMI best fits the data in this large sample of US adolescents. We find no evidence that sleep duration contributes substantially to ethnic disparities in BMI. However, we detect significant differences in the association between sleep duration and BMI by sex and ethnicity. Sleep duration is negatively associated with BMI among White, Hispanic and Asian boys, positively associated with BMI among Black girls and is not related to BMI among Black boys or girls from White, Hispanic or Asian ethnic groups. CONCLUSIONS: Despite significant associations between sleep duration and BMI for certain groups of adolescents, we find no evidence that ethnic differences in sleep duration exacerbate ethnic disparities in BMI. Future research should explore mechanisms that underlie ethnic differences in the association between sleep and BMI. PMID- 24480864 TI - Identification of the 12q15 amplicon within the homogeneously staining regions in the embryonal rhabdomyosarcoma cell line RMS-YM. AB - Gene amplification represents one of the molecular mechanisms of oncogene overexpression in many types of tumors. Homogeneously staining regions (HSRs) are cytogenetic hallmarks of gene amplification. Rhabdomyosarcoma is the most common malignant soft-tissue tumor in children. RMS-YM is an embryonal rhabdomyosarcoma cell line that possesses 3 HSRs. This cytogenetic finding suggests the presence of gene amplifications associated with tumor development or progression in RMS YM. Here, using fluorescence in situ hybridization, we detected high amplification of the MDM2 gene in the HSRs of RMS-YM. We also refined the region of the amplicon and identified that the FRS2 gene and others are amplified in RMS YM. MDM2 and FRS2 play important roles as a regulator of p53 and a mediator of FGF signaling, respectively, and thus are potential molecular targets for therapy in many different tumors. RMS-YM may be useful for studies of the molecular pathways of tumorigenesis and tumor progression in rhabdomyosarcoma and for in vitro evaluation of newly developed therapeutic agents that target MDM2 or FRS2. PMID- 24480865 TI - Phase I study of nedaplatin prior to S-1 in patients with locally advanced head and neck squamous cell carcinoma. AB - BACKGROUND: We previously reported on the regimen of S-1 plus nedaplatin (NDP), with S-1 was administered orally for 14 days and NDP intravenously on day 8. The maximum tolerated dose (MTD) of NDP was determined to be 90 mg/m2. The main toxicities were neutropenia and thrombocytopenia. This result was tolerated, but we believe there is a more effective and tolerable regimen. Thus, we investigated the S-1 regimen administered orally for 14 days, and NDP intravenously on day 1 in patients with locally advanced head and neck squamous cell carcinoma. PATIENTS AND METHODS: Oral administration of S-1 (days 1-14) and intravenous NDP (day 1) were tested for patients with advance head and neck cancer in a phase I setting. The dose of S-1 was fixed and the dose of NDP was escalated from 70 mg/m2, with an increase of 10 mg/m2 per step, to find the MTD. RESULTS: A total of 15 patients were registered. The MTD of NDP was determined to be 100 mg/m2. The main toxicities were neutropenia and thrombocytopenia. The response rate (RR) was 57.1%. CONCLUSIONS: The recommended dose of NDP for a phase II study was determined to be 100 mg/m2. We concluded that our regimen was well tolerated and that the RR was acceptable. PMID- 24480866 TI - Optimal intravascular ultrasound criteria for defining the functional significance of intermediate coronary stenosis: an international multicenter study. AB - OBJECTIVE: We aimed to assess the ideal cut-off value of minimal lumen area (MLA) by intravascular ultrasound (IVUS) and its diagnostic performance to predict ischemia, using a large-scale, pooled analysis. METHODS: Eleven centers worldwide were invited to provide their clinical, IVUS and fractional flow reserve (FFR) data. A total of 881 lesions were enrolled. RESULTS: Angiographic % diameter stenosis (r = -0.373, p < 0.0001) and IVUS MLA (r = 0.289, p < 0.0001) correlated with FFR. Best cut-off value (BCV) of IVUS MLA to define the functional significance (FFR <0.8) was 2.75 mm(2) (AUC 0.646, 95% CI 0.609-0.684). When the diagnostic performance of IVUS MLA was tested according to the lesion location, BCV could be found only in lesions in the proximal artery and the mid-left anterior descending artery. Interestingly, Asians (n = 623) and Westerners (n = 258) showed different demographic and lesion characteristics as well as different BCVs to define ischemia. The BCV for the proximal/mid-left anterior descending artery lesions was 2.75 mm(2) (AUC 0.688, 95% CI 0.635-0.742) in Asians and 3.0 mm(2) (AUC 0.695, 95% CI 0.605-0.786) in Westerners. CONCLUSION: In this pooled analysis, an IVUS MLA of 2.75 mm(2) was the BCV to define the functional significance of intermediate coronary stenosis. However, when IVUS MLA is used to determine the functional significance, both the lesion and patient characteristics should be considered. PMID- 24480867 TI - Prevalence and incident prehypertension and hypertension in postmenopausal Hispanic women: results from the Women's Health Initiative. AB - BACKGROUND: There is a paucity of research on prehypertension and incident hypertension among postmenopausal Hispanic women. The overall objective is to determine the multiple risk factors associated with the prevalence of hypertension status at baseline and incident hypertension at year 3 in postmenopausal Hispanic women. METHODS: For the analyses in this paper, we included a total of 4,680 Hispanic women who participated in the Women's Health Initiative (WHI), a randomized clinical trial and observational study, at baseline (1994-1998) and at third-year follow-up and for whom blood pressure was measured at year 3 (n = 3,848). Multivariable logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of hypertension status, defined as systolic blood pressure >=140 mm Hg and/or diastolic blood pressure >=90 mm Hg, to assess the odds of incident hypertension at year 3 of follow-up in association with the factors included in the baseline models. RESULTS: At year 3 of follow-up, 27.3% of Hispanic women who were normotensive at baseline had progressed to prehypertension, and 9.0% had become hypertensive. Among the prehypertensive participants at baseline, 30.4% had progressed to hypertension. Compared with normotensive Hispanic women, hypertensive participants had a higher number of cardiovascular risk factors: body mass index >=30 kg/m(2) (OR = 3.76; 95% CI = 3.01-4.71), a family history of diabetes, stroke, and/or myocardial infarction (OR = 1.12; 95% CI 1.03-1.23), treated hypercholesterolemia (OR = 1.57; 95% CI = 1.23-1.99), treated diabetes (OR = 2.04; 95% CI = 1.40-2.97), and a history of cardiovascular disease (OR = 2.04; 95% CI = 1.58-2.64). CONCLUSIONS: Hispanic women seem to experience an increased risk of incident hypertension in later adulthood. On a practical level, recommendations for preventive care and population-wide adoption of health behaviors, such as community-focused campaigns to engage in physical activity, may contribute to reductions in hypertension risk factors. CLINICAL TRIALS REGISTRATION: Trial Number NCT00000611. PMID- 24480868 TI - From high- to low-frequency administered interferon-beta for multiple sclerosis: a multicenter study. AB - OBJECTIVES: To investigate whether clinical and magnetic resonance imaging (MRI) outcomes of patients with multiple sclerosis (MS) who required a reduction of administration frequency of interferon-beta (IFNB) were similar to those of patients who did not. METHODS: We identified three subgroups of patients under treatment for 24 months with subcutaneous (sc) high-frequency IFNB-1a or -1b: those continuing to receive IFNB according to the drug label (recommended frequency group), those reducing the administration frequency of sc IFNB-1a or 1b (reduced frequency group), and those switched to once weekly intramuscular (im) IFNB (switched group). All patients were followed for further 24 months. The occurrence of relapse, MRI activity and disability worsening were considered as outcome measures. RESULTS: We identified 308 patients, 201 in the recommended frequency group, 70 in the reduced frequency group, and 37 in the switched group. Patients in the reduced frequency group had increased risk for relapses (HR = 1.95, p < 0.001) and MRI activity (HR = 1.41, p < 0.001), while patients in the switched group had increased risk for relapses (HR = 1.67, p = 0.012), but not for MRI activity (HR = 1.26, p = 0.08) than those in the recommended frequency group. Predictors for disease activity re-start after the reduction of IFNB administration frequency were younger age, higher pre-IFNB relapse rate, and reducing sc IFNB frequency to twice weekly rather than switching to im IFNB-1a once weekly. CONCLUSION: Our findings discourage the reduction of sc IFNB administration frequency, especially in younger patients with a higher pre-IFNB relapse rate. However, switching to im IFNB-1a may be considered in some selected cases. PMID- 24480869 TI - Chest CT scan screening for lung cancer in asbestos occupational exposure: a systematic review and meta-analysis. AB - OBJECTIVE: Lung cancer is the most frequent malignant asbestos-related pathology and remains the most fatal cancer of industrialized countries. In heavy smokers, early detection of lung cancer with chest CT scan leads to a 20% mortality reduction. However, the use of CT scan screening for early detection of lung cancer in asbestos-exposed workers requires further investigation. This study aimed to determine whether CT scan screening in asbestos-exposed workers is effective in detecting asymptomatic lung cancer using a systematic review and meta-analysis. METHODS: We reviewed all cohort studies involving chest CT scan screening in former asbestos-exposed workers. The search strategy used the following keywords: "asbestos," "lung cancer," "screening," and "occupation*" or "work." Databases were PubMed, Cochrane Library, Science Direct, and Embase. RESULTS: Seven studies matched our inclusion criteria. Baseline screening detected 49 asymptomatic lung cancers among 5,074 asbestos-exposed workers. Of the 49 reported lung cancers, at least 18 were in the earliest stage (stage I), accessible to complete removal surgery. The prevalence of all lung cancers detected by CT scan screening in asbestos-exposed workers was 1.1% (95% CI, 0.6% 1.8%). CONCLUSIONS: CT scan screening in asbestos-exposed workers is effective in detecting asymptomatic lung cancer. Detection of lung cancer in asbestos-exposed workers using CT scanning is at least equal to the prevalence in heavy smokers (1%; 95% CI, 0.09%-1.1%) and also shared a similar proportion of stage I diagnoses. Screening asbestos-exposed workers could reduce mortality in proportions previously observed among heavy smokers and, thus, should not be neglected, particularly for individuals combining both exposures. PMID- 24480872 TI - Complexes containing CO2 and SO2. Mixed dimers, trimers and tetramers. AB - Mixed dimers, trimers and tetramers composed of SO2 and CO2 molecules are examined by ab initio calculations to identify all minimum energy structures. While AIM formalism leads to the idea of a pair of C...O bonds in the most stable heterodimer, bound by some 2 kcal mol(-1), NBO analysis describes the bonding in terms of charge transfer from O lone pairs of SO2 to the CO pi* antibonding orbitals. The second minimum on the surface, just slightly less stable, is described by AIM as containing a single O...O chalcogen bond. The NBO picture is that of two transfers in opposite directions: one from a SO2 O lone pair to a pi* antibond of CO2, supplemented by CO2 Olp -> pi*(SO). Decomposition of the interaction energies points to electrostatic attraction and dispersion as the dominant attractive components, in roughly equal measure. The various heterotrimers and tetramers generally retain the dimer structure as a starting point. Cyclic oligomers are favored over linear geometries, with a preference for complexes containing larger numbers of SO2 molecules. PMID- 24480871 TI - Microhemodynamic parameters quantification from intravital microscopy videos. AB - Blood flow and blood-endothelium interactions correspond with the genesis of cardiovascular diseases. Therefore, quantitative analysis of blood flow dynamics at the microcirculation level is of special interest. Regulatory mechanisms mediated by blow flow have been studied in detail using in vitro approaches. However, these mechanisms have not been fully validated in vivo due to technical limitations that arise when quantifying microhemodynamics with the required level of detail. Intravital microscopy combined with high-speed video recordings has been used for the analysis of blood flow in small blood vessels of chronic and acute experimental tissue preparations. This tool can be used to study the interaction between the flowing blood and the vessel walls of arterioles and venules with sufficient temporal and spatial resolution. Our objective was to develop a simple and robust cross-correlation algorithm for the automatic analysis of high-speed video recordings of microcirculatory blood flow. The algorithm was validated using in vitro and in vivo systems. Results indicate that the algorithm's ability to estimate the velocity of local red blood cells as a function of blood vessel radius is highly accurate. They thereby suggest that the algorithm could be used to explore dynamic changes in blood flow under different experimental conditions including a wide range of flow rates and hematocrit levels. The algorithm can also be used to measure volumetric flow rates, radial velocity profiles, wall shear rate, and wall shear stress. Several applications are presently explored, including the analysis of velocity profiles in the branches of arterial bifurcations. This work demonstrates the robustness of the cross-correlation technique in various flow conditions and elucidates its potential application for in vivo determination of blood flow dynamics in the microcirculation. PMID- 24480873 TI - Evaluation of vestibular function in patients with chronic suppurative otitis media. AB - OBJECTIVE: The objective of this study was to assess vestibular functions in patients with chronic suppurative otitis media (CSOM) with and without sensorineural hearing loss. STUDY DESIGN: This was a prospective case study performed at a tertiary referral university hospital. Sixty patients with CSOM were included, and patients with a history of head trauma, diabetes, hypertension, previous ear surgery, use of ototoxic drugs, neurological deficits and suspected fistulae were excluded. PATIENTS AND METHODS: The patients underwent basic audiological evaluation, and clinical and instrumental vestibular evaluation. The incidence and extent of vestibular dysfunction in patients with CSOM were analyzed. RESULTS: A total of 42 males and 16 females with a mean age of 29.5 years were included in this study. Forty ears had tubotympanic disease and 19 had cholesteatoma. There were 14 ears with sensorineural hearing loss. A positive history of vertigo was reported in 53.5% of the cases. Rotatory chair abnormalities were found in 70% of the cases, caloric hypofunction was found in 61.6%, and vestibular myogenic evoked potentials were abnormal in 25%. The only positive correlation with vestibular dysfunction was the duration of disease. CONCLUSIONS: The vestibular system is significantly affected in cases with CSOM. Both semicircular canals and the saccule are affected. All patients with long standing CSOM should be evaluated for vestibular dysfunction irrespective of their hearing levels. PMID- 24480875 TI - Construction of an infectious cDNA clone of a swine genotype 3 HEV strain isolated in Shanghai, China. AB - OBJECTIVES: Infectious cDNA clones are important tools for studying molecular mechanisms in RNA viruses. The aim of this study was to construct an infectious cDNA clone for SAAS-JDY5, which is a genotype 3 HEV strain of swine origin. METHODS: Construction employed overlapping PCR and restriction analysis to ligate nine cDNA fragments into a full-length cDNA clone containing 14 mutations compared to the consensus HEV genome sequence. Megaprimer PCR-directed mutagenesis restored nine non-silent mutations back to the consensus sequence while the other five silent mutations were maintained as genetic markers. RESULTS: HEV proteins were identified by an immunofluorescence assay in Huh7 cells infected with capped RNA transcripts of the full-length cDNA clone, while HEV viremia, fecal HEV RNA and seroconversion were recorded in inoculated Sprague Dawley rats. CONCLUSIONS: Our data confirmed the successful construction of an infectious cDNA clone of swine HEV strain pGEM4z-SAAS-JDY5, and support the use of rats as an HEV infectious model. PMID- 24480874 TI - Fluoxetine administered to juvenile monkeys: effects on the serotonin transporter and behavior. AB - OBJECTIVE: This study examined the long-term effects of fluoxetine administered to juvenile rhesus monkeys who, as young adults, were imaged with positron emission tomography for two serotonergic markers: serotonin transporter (SERT) and serotonin 1A (5-HT1A) receptor. An equal number of monkeys separated from their mothers at birth-an animal model of human childhood stress-were also studied. METHOD: At birth, 32 male rhesus monkeys were randomly assigned to either maternal separation or normal rearing conditions. At age 2, half (N=8) of each group was randomly assigned to fluoxetine (3 mg/kg) or placebo for 1 year. To eliminate the confounding effects of residual drug in the brain, monkeys were scanned at least 1.5 years after drug discontinuation. Social interactions were assessed both during and after drug administration. RESULTS: Fluoxetine persistently upregulated SERT, but not 5-HT1A receptors, in both the neocortex and the hippocampus. Whole-brain voxel-wise analysis revealed that fluoxetine had a significant effect in the lateral temporal and cingulate cortices. In contrast, neither maternal separation by itself nor the rearing-by-drug interaction was significant for either marker. Fluoxetine had no significant effect on the behavioral measures. CONCLUSIONS: Fluoxetine administered to juvenile monkeys upregulates SERT into young adulthood. Implications regarding the efficacy or potential adverse effects of SSRIs in patients cannot be directly drawn from this study. Its purpose was to investigate effects of SSRIs on brain development in nonhuman primates using an experimental approach that randomly assigned long-term SSRI treatment or placebo. PMID- 24480876 TI - Shear-induced endothelial NOS activation and remodeling via heparan sulfate, glypican-1, and syndecan-1. AB - Mammalian epithelial cells are coated with a multifunctional surface glycocalyx (GCX). On vascular endothelial cells (EC), intact GCX is atheroprotective. It is degraded in many vascular diseases. GCX heparan sulfate (HS) is essential for healthy flow-induced EC nitric oxide (NO) release, elongation, and alignment. The HS core protein mechanisms involved in these processes are unknown. We hypothesized that the glypican-1 (GPC1) HS core protein mediates flow-induced EC NO synthase (eNOS) activation because GPC1 is anchored to caveolae where eNOS resides. We also hypothesized that the HS core protein syndecan-1 (SDC1) mediates flow-induced EC elongation and alignment because SDC1 is linked to the cytoskeleton which impacts cell shape. We tested our hypotheses by exposing EC monolayers treated with HS degrading heparinase III (HepIII), and monolayers with RNA-silenced GPC1, or SDC1, to 3 to 24 hours of physiological shear stress. Shear conditioned EC with intact GCX exhibited characteristic eNOS activation in short term flow conditions. After long-term exposure, EC with intact GCX were elongated and aligned in the direction of flow. HS removal and GPC1 inhibition, not SDC1 reduction, blocked shear-induced eNOS activation. EC remodeling in response to flow was attenuated by HS degradation and in the absence of SDC1, but preserved with GPC1 knockdown. These findings clearly demonstrate that HS is involved in both centralized and decentralized GCX-mediated mechanotransduction mechanisms, with GPC1 acting as a centralized mechanotransmission agent and SDC1 functioning in decentralized mechanotransmission. This foundational work demonstrates how EC can transform fluid shear forces into diverse biomolecular and biomechanical responses. PMID- 24480877 TI - Plasma homocysteine and coronary artery calcification in Korean men. AB - BACKGROUND: Homocysteine is an independent risk factor for atherosclerosis, plausibly through induction of endothelial dysfunction and smooth muscle cell proliferation. Under oxidative stress and inflammatory stimuli, vascular smooth muscle cells may undergo osteogenic differentiation, which leads to coronary artery calcification. This study evaluated the association between plasma homocysteine and coronary artery calcification. DESIGN AND METHODS: Coronary artery calcium scores (CACSs) and plasma homocysteine concentrations were measured in 21,235 men (42 +/- 6.5 years) who participated in the Kangbuk Samsung Health Study between 2010 and 2011. Subjects were grouped by quartile of plasma homocysteine. RESULTS: The prevalence of coronary artery calcification (CAC) among the 21,235 men was 13.5%. In the first to fourth homocysteine quartiles, CAC(+) prevalence rates were 12.1%, 12.6%, 13.9%, and 15.3%, respectively. The CAC(+) group had unfavorable cardiometabolic and lipid profiles. In multivariate regression analysis after adjusting for variables with a univariate relationship (p < 0.20), the odds ratio (OR) for the presence of CAC was higher for the highest homocysteine quartile than for the lowest quartile group (OR (95% confidence interval (CI)), 1.275 (1.027, 1.583)), and presence of CAC was positively associated with quartile of homocysteine (p for trend = 0.009). Moreover, absolute plasma homocysteine concentration was positively and significantly related to presence of CAC and to CACS, respectively (OR (95% CI) 1.399 (1.089, 1.796): standardized beta = 0.040, p < 0.001). CONCLUSIONS: This study shows that plasma homocysteine is independently related to coronary artery calcification in Korean men, suggesting that plasma homocysteine concentration may serve as a marker for CAC. PMID- 24480878 TI - Vitamin D status was not associated with 'one-year' progression of coronary artery disease, assessed by coronary angiography in statin-treated patients. AB - BACKGROUND: Low vitamin D status is associated with increased risk of cardiovascular disease and may be involved in atherosclerosis. Our aim was to assess the association between vitamin D status and the progression of coronary artery disease (CAD). METHODS AND RESULTS: We measured 25-hydroxyvitamin D3 (25OHD3) by liquid chromatography tandem mass spectrometry (LC-MS/MS) in plasma from 348 participants with established CAD (84% males, mean +/- standard deviation (SD) age 60 +/- 10 years) of the Western Norway B-vitamin Intervention Trial (WENBIT, 1999-2006). The patients underwent invasive coronary angiography (CA) and percutaneous coronary intervention at baseline and a second CA after 302 +/- 79 days of follow-up. From the angiograms, minimal lumen diameter (MLD) and diameter stenosis (DS) of atherosclerotic lesions were obtained. Significant CAD in non-intervened vessels was found in 309 coronary arteries from 183 participants either at baseline and/or at follow-up. To assess the association between levels of 25OHD3 and CAD progression in non-intervened vessels, we applied a linear quantile fitted mixed effects model with MLD or DS measured at follow-up as a function of continuous 25OHD3 concentrations. There were no statistically significant associations between plasma 25OHD3 concentrations (median: 63.9, 95% confidence interval (CI): 48.1-78.5 nmol/l) measured at baseline and the follow-up measures of either MLD (estimated effect per 10 nmol/l increase of 25OHD3 and 95% CI: -0.015 (-0.032-0.002) mm, p = 0.088) or DS (0.225 (-0.354-0.804) percentage points, p = 0.444). Multivariate adjustment did not alter these results. CONCLUSION: Plasma 25OHD3 levels were not associated with 'one-year' progression of CAD, assessed by CA in statin-treated patients. PMID- 24480879 TI - SIRT1 regulates lamellipodium extension and migration of melanoma cells. AB - Melanoma is highly metastatic, but the mechanism of melanoma cell migration is still unclear. We found that melanoma cells expressed the nicotinamide adenine dinucleotide-dependent protein deacetylase SIRT1 in the cytoplasm. Cell membrane extension and migration of melanoma cells were inhibited by SIRT1 inhibitors or SIRT1 knockdown, whereas SIRT1 activators enhanced elongation of protrusion and cellular motility. In B16F1 cells, growth factor stimulation induced lamellipodium extension, a characteristic feature at the leading edge of migrating cells, and SIRT1 was found in the lamellipodium. SIRT1 inhibitor nicotinamide (NAM) or SIRT1 small interfering RNAs suppressed the lamellipodium extension by serum or platelet-derived growth factor (PDGF). The lamellipodium formation by dominant-active Rac1 was also inhibited by NAM, a SIRT1 inhibitor. NAM inhibited the accumulation of phosphorylated Akt at the submembrane by serum or PDGF. Using fluorescence resonance energy transfer, we found that NAM impaired PDGF-dependent increase in the phosphatidylinositol-3,4,5-trisphosphate level at the leading edge. NAM inhibited the abdominal metastasis of transplanted B16F1 melanoma cells in C57BL6/J mice and improved survival. Finally, SIRT1-knockdown B16F1 cells showed significantly reduced metastasis in transplanted mice compared with that in control B16F1 cells. These results indicate that SIRT1 inhibition is a strategy to suppress metastasis of melanoma cells. PMID- 24480880 TI - IL-17A as an inducer for Th2 immune responses in murine atopic dermatitis models. AB - Atopic dermatitis (AD) is generally regarded as a type 2 helper T (Th2)-mediated inflammatory skin disease. Although the number of IL-17A-producing cells is increased in the peripheral blood and in acute skin lesion of AD patients, the role of IL-17A in the pathogenesis of AD remains unclear. To clarify this issue, we used murine AD models in an IL-17A-deficient condition. In a repeated hapten application-induced AD model, skin inflammation, IL-4 production in the draining lymph nodes (LNs), and hapten-specific IgG1 and IgE induction were suppressed in IL-17A-deficient mice. Vgamma4(+) gammadelta T cells in the skin-draining LNs and Vgamma5(-) dermal gammadelta T cells in the skin were the major sources of IL 17A. Consistently, in flaky-tail (Flg(ft/ft) ma/ma) mice, spontaneous development of AD-like dermatitis and IgE induction were attenuated by IL-17A deficiency. Moreover, Th2 differentiation from naive T cells was promoted in vitro by the addition of IL-17A. Taken together, our results suggest that IL-17A mediates Th2 type immune responses and that IL-17A signal may be a therapeutic target of AD. PMID- 24480882 TI - No evidence for integrated viral DNA in the genome sequence of cutaneous squamous cell carcinoma. PMID- 24480881 TI - Replication of associations between GWAS SNPs and melanoma risk in the Population Architecture Using Genomics and Epidemiology (PAGE) Study. PMID- 24480883 TI - Impact of vancomycin or linezolid therapy on development of renal dysfunction and thrombocytopenia in Japanese patients. AB - BACKGROUND: Vancomycin and linezolid therapies are associated with renal dysfunction and thrombocytopenia, respectively. METHODS: We retrospectively investigated Japanese patients with renal dysfunction or thrombocytopenia possibly associated with vancomycin and linezolid therapies, including 235 patients treated with parenteral vancomycin and 178 treated with parenteral linezolid. RESULTS: Renal dysfunction occurred more frequently in patients receiving vancomycin (24%) than in those receiving linezolid (13%; p = 0.032), whereas thrombocytopenia occurred more frequently in linezolid-treated patients (41%) than in vancomycin-treated patients (17%; p < 0.001). Controlling trough vancomycin concentrations (<20 MUg/ml) protects against renal dysfunction, but thrombocytopenia may occur after >7.5 days of linezolid treatment. CONCLUSION: Controlling trough vancomycin concentrations to <20 MUg/ml protects Japanese patients against renal dysfunction. Linezolid is an appropriate initial therapy for severe infections in patients with acute renal dysfunction, but monitoring of platelet counts is essential after initiation of therapy. PMID- 24480884 TI - Postmortem pump-driven reperfusion of the vascular system of porcine lungs: towards a new model for surgical training. AB - PURPOSE: The objective of this experiment is to establish a continuous postmortem circulation in the vascular system of porcine lungs and to evaluate the pulmonary distribution of the perfusate. This research is performed in the bigger scope of a revascularization project of Thiel embalmed specimens. This technique enables teaching anatomy, practicing surgical procedures and doing research under lifelike circumstances. METHODS: After cannulation of the pulmonary trunk and the left atrium, the vascular system was flushed with paraffinum perliquidum (PP) through a heart-lung machine. A continuous circulation was then established using red PP, during which perfusion parameters were measured. The distribution of contrast-containing PP in the pulmonary circulation was visualized on computed tomography. Finally, the amount of leak from the vascular system was calculated. RESULTS: A reperfusion of the vascular system was initiated for 37 min. The flow rate ranged between 80 and 130 ml/min throughout the experiment with acceptable perfusion pressures (range: 37-78 mm Hg). Computed tomography imaging and 3D reconstruction revealed a diffuse vascular distribution of PP and a decreasing vascularization ratio in cranial direction. A self-limiting leak (i.e. 66.8% of the circulating volume) towards the tracheobronchial tree due to vessel rupture was also measured. CONCLUSIONS: PP enables circulation in an isolated porcine lung model with an acceptable pressure-flow relationship resulting in an excellent recruitment of the vascular system. Despite these promising results, rupture of vessel walls may cause leaks. Further exploration of the perfusion capacities of PP in other organs is necessary. Eventually, this could lead to the development of reperfused Thiel embalmed human bodies, which have several applications. PMID- 24480885 TI - Caries and ABO secretor status in a Hungarian population of children and adolescents: an exploratory study. AB - ABO blood group antigen (ABGA) secretion into the saliva and other body fluids is a well-known phenomenon, and there is evidence to suggest a link between secretor status and the appearance of caries. It has been proposed that secretion of these antigens into the saliva might be caries-preventive, however, this proposition is still a matter of debate. Our aim was to examine the relationship between caries experience and secretor status in a group of Hungarian children and adolescents in a cross-sectional study. Altogether 130 children and adolescents participated in the study (aged 6-18 years). Participants were divided into two groups according to dentition (i.e. mixed and permanent). ABGA were determined from saliva. The DMF-T and dmf-t (decayed, missing, and filled) indices were calculated, as well as the oral health hygiene index-simplified plaque index. Association of these indices with secretor status was examined. In mixed dentition, the mean dmf-t values were significantly lower in the secretor group (2.1 +/- 0.52 SEM), as compared to the nonsecretor group (3.8 +/- 0.93 SEM; p < 0.05, Mann-Whitney U test). The finding that children of mixed dentition are apparently better protected against caries suggests that the assumed protective effect might be associated with deciduous teeth, but given the general paucity of knowledge about this topic, further research is indicated. PMID- 24480886 TI - Outcomes for patients with cancer admitted to the ICU requiring ventilatory support: results from a prospective multicenter study. AB - BACKGROUND: This study was undertaken to evaluate the clinical characteristics and outcomes of patients with cancer requiring nonpalliative ventilatory support. METHODS: This was a secondary analysis of a prospective cohort study conducted in 28 Brazilian ICUs evaluating adult patients with cancer requiring invasive mechanical ventilation (MV) or noninvasive ventilation (NIV) during the first 48 h of their ICU stay. We used logistic regression to identify the variables associated with hospital mortality. RESULTS: Of 717 patients, 263 (37%) (solid tumors = 227; hematologic malignancies = 36) received ventilatory support. NIV was initially used in 85 patients (32%), and 178 (68%) received MV. Additionally, NIV followed by MV occurred in 45 patients (53%). Hospital mortality rates were 67% in all patients, 40% in patients receiving NIV only, 69% when NIV was followed by MV, and 73% in patients receiving MV only (P < .001). Adjusting for the type of admission, newly diagnosed malignancy (OR, 3.59; 95% CI, 1.28-10.10), recurrent or progressive malignancy (OR, 3.67; 95% CI, 1.25-10.81), tumoral airway involvement (OR, 4.04; 95% CI, 1.30-12.56), performance status (PS) 2 to 4 (OR, 2.39; 95% CI, 1.24-4.59), NIV followed by MV (OR, 3.00; 95% CI, 1.09-8.18), MV as initial ventilatory strategy (OR, 3.53; 95% CI, 1.45-8.60), and Sequential Organ Failure Assessment score (each point except the respiratory domain) (OR, 1.15; 95% CI, 1.03-1.29) were associated with hospital mortality. Hospital survival in patients with good PS and nonprogressive malignancy and without tumoral airway involvement was 53%. Conversely, patients with poor functional capacity and cancer progression had unfavorable outcomes. CONCLUSIONS: Patients with cancer with good PS and nonprogressive disease requiring ventilatory support should receive full intensive care, because one-half of these patients survive. On the other hand, provision of palliative care should be considered the main goal for patients with poor PS and progressive underlying malignancy. PMID- 24480887 TI - Torture. Introduction. PMID- 24480888 TI - The illogical logic of music torture. AB - This article draws on research into the use of music in the context of torture- both as a technique of torture and as a means of rehabilitation--to ask what types of musical activities and practices may constitute ill-treatment, up to and including torture. As well as providing information on the ways music is used in the context of torture and cruel, inhuman or degrading treatment or punishment (hereafter: CIDT), the article discusses responses to this issue in the scholarly, legal and therapeutic communities. Pointing to a widespread link between musical practices and humiliation of the prisoner and celebration of the power of those in charge over those held in detention, the author argues that coerced musical practices of any sort in detention are a cause for grave concern. She draws on research into post-traumatic stress disorder (hereafter: PTSD) and the torture-CIDT distinction to argue for an approach to the use of music in detention that places primacy on the dignity of the detained person. PMID- 24480889 TI - 'He plays on the pillory'. The use of musical instruments for punishment in the Middle Ages and the Early Modern Era. AB - Illustrations by the Dutch renaissance artists Pieter Bruegel the Elder and Jan Wierix both show a man imprisoned on a pillory, a former place of enforcement of judicial sentences, and playing a musical instrument. Taken as legal iconographic sources, these illustrations of the old saying 'He plays on the pillory' can be understood as references to a specific kind of punishment used in the Middle Ages and the Early Modern Era. Specifically, delinquents had to wear wooden or iron 'neck violins' or 'neck flutes' while being pilloried or chased through the streets in order to be humiliated in public. As well as this historical fact, there also exists an interpretation that takes the illustrations by Bruegel and Wierix literally. It suggests that these punishment practices originally date back to a more ancient use of real instruments in a penal system that was applied and understood as a 'healing punishment' (poena medicinalis) to banish the ill and re-establish the good in the delinquent, the community and the world as a whole due to musical sounds. By means of legal iconographical and historical methods, this article explores the different nuances of punishment that employed real or symbolic musical instruments. Thus, it examines a historical aspect of 'music in detention' where the (symbolic) sounds do not emanate from the punisher but from the punished themselves. PMID- 24480890 TI - Music and 're-education' in the Soviet Gulag. AB - After the October Revolution, the Bolsheviks announced a new human dimension of penal policy whose goal should be the so-called 're-education' of prisoners. The desired 're-education' was to be realised using two kinds of measures: the physical work of the prisoners, and 'cultural education work'. A varied musical life in groups, 'agitation brigades', ensembles, orchestras and choirs developed within the framework of the 'cultural education work'. Two camps responsible for building canals in the 1930s particularly adopted this musical life: Belbaltlag and Dmitlag. In the latter, a composition competition took place in 1936 in which, among others, the arrested composer Sergey Protopopov took part. Since the 1930s, the Gulag administration had publicised that the measures taken for 're education' concerned primarily criminal prisoners, as opposed to 'political prisoners', who were labelled as foreign to socialist society. Although the 'cultural education work' would not have functioned as well as it did without the cooperation of 'political prisoners', since their participation did not fit into the prescribed ideology, they were often underappreciated or even completely concealed. The following is a depiction of the officially organised musical life in the Gulag in the 1920s and 1930s as a grey zone. Music making and listening represented not only a source of strength for the prisoners, but also brought about situations that meant physical and psychological torture for them. PMID- 24480891 TI - Music and 're-education' in Greek prison camps: from Makronisos (1947-1955) to Giaros (1967-1968). AB - This paper examines the policy of 're-education' for left-wing political prisoners in Greece during the military Junta (1967-1974) at the prison camp on the island of Giaros from 1967 to November 1968. Taking as its starting point the ways folk culture was used to substantiate the Colonels' ideological discourse and to give their rule aesthetic roots as a strategy of legitimization, the paper investigates how this kind of music was instrumentalized as a way of breaking political prisoners in exile. Music from loudspeakers was part of an attempt to make detainees sign Declarations of Loyalty, renouncing their values and their comrades. The 're-education' programme of Giaros is examined here as a remainder of the Greek Civil-War legacy (1946-1949), and particularly of the institutionalized 're-education' and 'rehabilitation' programme of the infamous prison camps on the island of Makronisos (1947-1955). Interviews with former detainees from both historical periods underline the damaging effects of the use of music, highlighting the need to understand music's capacity to degrade, but also torture, individuals instead of uplift and ennoble the soul. PMID- 24480892 TI - Dancing to distraction: mediating 'docile bodies' in 'Philippine Thriller video'. AB - This essay examines the conditions behind the 'Philippine Prison Thriller' video, a YouTube spectacle featuring the 1,500 inmates of Cebu Provincial Detention and Rehabilitation Centre (CPDRC) dancing to Michael Jackson's hit song 'Thriller'. The video achieved viral status after it was uploaded onto the video-sharing platform in 2007, and sparked online debates as to whether this video, containing recorded moving images of allegedly forced dancing, was a form of cruel and inhumane punishment or a novel approach to rehabilitation. The immense popularity of the video inspired creative responses from viewers, and this international popularity caused the CPDRC to host a monthly live dance show held in the prison yard, now in its seventh year. The essay explores how seemingly innocuous products of user-generated-content are imbued with ideologies that obscure or reduce relations of race, agency, power and control. By contextualising the video's origins, I highlight current Philippine prison conditions and introduce how video-maker/programme inventor/prison warden Byron Garcia sought to distance his facility from the Philippine prison majority. I then investigate the 'mediation' of 'Thriller' through three main issues. One, I examine the commodification and transformation from viral video to a thana-tourist destination; two, the global appeal of 'Thriller' is founded on public penal intrigue and essentialist Filipino tropes, mixed with a certain novelty factor widely suffused in YouTube formats; three, how dance performance and its mediation here are conducive to creating Foucault's docile bodies, which operate as a tool of distraction for the masses and ultimately serve the interests of the state far more than it rehabilitates(unconvicted and therefore innocent) inmates. PMID- 24480893 TI - Music and dance make me feel alive: from Mandela's prison songs and dances to public policy. AB - How is it possible for song and dance to exist in political incarceration and manifest itself later as public policy responding to apartheid atrocities? Examining the body of songs, oral history accounts, and eye-witness reports provided by fellow-prisoners of Mandela on Robben Island prison, I uncover a psychological environment mediated through music and dance--within the confines of a political prison. This source of prison music-making by political prisoners in detention, provide us with the artistic expressions of revolutionary songs, parody songs, praise songs, laments, etc. These music genres reflect ontologies embedded in Mandela's juristic imagination. My framework for explaining these ontologies is a theoretical framework I call an aesthetic of function: internal ontologies that speak to the African cultural ground against which external ontologies are expressed in the jurisprudential redress to apartheid atrocities. Examining his external (jurisprudential) ontologies through song and dance, one realizes that the best way for him to have solved the unprecedented public redress of apartheid atrocities is evident in the songs he sang in Robben Island prison. Retribution could have been a logical solution for him. Instead, he turned to truth-telling and reconciliation as public policy. The Truth and Reconciliation Commission's unprecedented breaking of social and jurisprudential boundaries, the claim of agency for both victims and perpetrators, and public policy of South Africa's first democratically elected black president, lie deeply embedded in cultural practices he testified to in his autobiography, "The Long Walk to Freedom". These cultural practices in prison were singing and dancing. This paper complements the music-as-torture trope: here music in detention carries ontological agency. Musical evidence of stylistic features, text, and contextual analyses, and related literary criticism devices, expose Mandela's embedded internal and external ontological cultural practices. Here, song and dance have agency to influence public policy despite the constraints of political detention. PMID- 24480895 TI - Template effects and supramolecular control of photoreactions in solution. AB - A review of supramolecular and template effects on photochemical reactions in solution is presented. Photoinduced [2+2] and [4+4] cycloaddition reactions, isomerization, electron transfer and radical processes are covered, as well as examples of DNA photoligation. PMID- 24480896 TI - Assessment of pregestational insulin resistance as a risk factor of preeclampsia. AB - AIM: To assess the impact that pregestational insulin resistance (PIR) has as a risk factor for preeclampsia (PE). METHODS: Nested case-control study that included patients with PIR and a control group that was randomly selected from pregnancies admitted to the Fetal Medicine Unit between January 2005 and May 2011. Clinical and hemodynamic variables were analyzed by a multiple logistic regression analysis. RESULTS: Of the 13,124 patients admitted during the study period, 119 had a diagnosis of PIR (0.9%). Patients with PIR were older and had a higher body mass index (BMI). PIR was also related to a significantly higher frequency of chronic hypertension (CrHT; 10.1 vs. 2.2%, p < 0.05) and hypothyroidism (5.0 vs. 1.6%, p < 0.05) than in the control group. Moreover, women with PIR were more likely to develop PE (8.4 vs. 4.2%, p < 0.05) and gestational diabetes mellitus (9.2 vs. 2.9%) than the control group. Multivariate analysis showed that maternal age, CrHT and altered uterine artery Doppler sonography during the first and second trimesters were good predictors of PE and that PIR was not. CONCLUSION: Although PIR correlates with PE, conditions related to the latter (CrHT, higher maternal age and increased BMI) may be predominant as risk factors for PE. PMID- 24480897 TI - Ligand density elicits a phenotypic switch in human neutrophils. AB - Neutrophils are mediators of innate immunity and motility is critical to their function. We used microcontact printing to investigate the relationship between density of adhesive ligands and the dynamics of neutrophil motility. We show that neutrophils adopt a well-spread morphology without a uropod on moderate densities of adhesion ligand. As density is increased, the morphology switches to a classic amoeboid shape. In addition to the morphological differences, the dynamics of motility were quantitatively distinct. Well-spread cells without uropods glide slowly with high persistence, while amoeboid cells made frequent directional changes migrating quickly with low persistence. Using an antibody panel against various integrin chains, we show that adhesion and motility on fibronectin are mediated by MAC-1 (alphaMbeta2). The phenotypic switch could be generalized to other surface ligands, such as bovine serum albumin, to which the promiscuous MAC 1 also binds. These results suggest that neutrophils are capable of displaying multiple modes of motility as dictated by their adhesive environment. PMID- 24480898 TI - Skeletal metastatic carcinomas from the Roman period (1st to 5th Century AD) in Hungary. AB - OBJECTIVES: According to paleopathological records, tumors have a great antiquity. The prevalence of cancer in ancient populations might have differed from that in modern humans because of substantial differences in environmental factors, life expectancy and the availability of treatment. This study presents 3 cases of probable skeletal metastatic carcinoma from the Roman period (1st-5th century AD) in Hungary, showing the development of bone metastases of cancer without chemo- and radiotherapy. METHODS: All skeletons were subjected to a careful macroscopic investigation, which was extended by radiological, stereo- and scanning electron microscopic analyses. RESULTS: In 1 case, the mixed nature and localization of the lesions, as well as the sex and age of the individual, suggested breast cancer as the primary focus. In the other 2 cases, based on the mostly osteoblastic nature and the localization of the lesions as well as on the sex and age of the individuals, the most probable diagnostic option is prostate carcinoma with skeletal metastases. CONCLUSIONS: In view of the scarcity of cancer metastases that have been diagnosed in archeological specimens in general, identification of all examples of cancer in antiquity represents an important contribution both to paleopathology and to modern medicine. PMID- 24480899 TI - A randomized controlled trial of 7-day intensive and standard weekly cognitive therapy for PTSD and emotion-focused supportive therapy. AB - OBJECTIVE: Psychological treatments for posttraumatic stress disorder (PTSD) are usually delivered once or twice a week over several months. It is unclear whether they can be successfully delivered over a shorter period of time. This clinical trial had two goals: to investigate the acceptability and efficacy of a 7-day intensive version of cognitive therapy for PTSD and to investigate whether cognitive therapy has specific treatment effects by comparing intensive and standard weekly cognitive therapy with an equally credible alternative treatment. METHOD: Patients with chronic PTSD (N=121) were randomly allocated to 7-day intensive cognitive therapy for PTSD, 3 months of standard weekly cognitive therapy, 3 months of weekly emotion-focused supportive therapy, or a 14-week waiting list condition. The primary outcomes were change in PTSD symptoms and diagnosis as measured by independent assessor ratings and self-report. The secondary outcomes were change in disability, anxiety, depression, and quality of life. Evaluations were conducted at the baseline assessment and at 6 and 14 weeks (the posttreatment/wait assessment). For groups receiving treatment, evaluations were also conducted at 3 weeks and follow-up assessments at 27 and 40 weeks after randomization. All analyses were intent-to-treat. RESULTS: At the posttreatment/wait assessment, 73% of the intensive cognitive therapy group, 77% of the standard cognitive therapy group, 43% of the supportive therapy group, and 7% of the waiting list group had recovered from PTSD. All treatments were well tolerated and were superior to waiting list on nearly all outcome measures; no difference was observed between supportive therapy and waiting list on quality of life. For primary outcomes, disability, and general anxiety, intensive and standard cognitive therapy were superior to supportive therapy. Intensive cognitive therapy achieved faster symptom reduction and comparable overall outcomes to standard cognitive therapy. CONCLUSIONS: Cognitive therapy for PTSD delivered intensively over little more than a week was as effective as cognitive therapy delivered over 3 months. Both had specific effects and were superior to supportive therapy. Intensive cognitive therapy for PTSD is a feasible and promising alternative to traditional weekly treatment. PMID- 24480900 TI - The diagnostic value of transthoracic ultrasonographic features in predicting malignancy in undiagnosed pleural effusions: a prospective observational study. AB - BACKGROUND: Transthoracic ultrasound (US) is an important instrument to identify pleural effusions and safely conduct invasive procedures. It also allows systematic scanning of the pleural surface, though its value remains uncertain for differentiation between malignant (MPE) and nonmalignant pleural effusion (non-MPE) in routine clinical practice. OBJECTIVES: To evaluate the utility of US features to predict malignancy in undiagnosed pleural effusions in a real-life clinical setting. METHODS: The US features of 154 consecutive patients with a pleural effusion were prospectively assessed. Anonymous images were recorded by an operator blinded to the clinical and radiological results. The US findings were classified by independent reviewers and compared to the final diagnosis. RESULTS: A total of 133 patients were included (age 67 +/- 16 years; BMI 25.1 +/- 4.6; 54.1% females). The final diagnosis was MPE in 66 cases and non-MPE in 67 cases. US had an overall sensitivity of 80.3%, a specificity of 83.6%, and positive and negative predictive values of 82.8 and 81.2%, respectively, for the detection of malignancy. US accuracy was 81.9%. The presence of pleural/diaphragmatic nodules, pleural/diaphragmatic thickness >10 mm, and a swirling sign was significantly different between both groups (p < 0.001). Lung air bronchogram sign and a septated US pattern were more common in non-MPE patients (p < 0.01). The existence of nodularity and the absence of air bronchograms were more likely to indicate malignancy (OR 29.0, 95% CI 7.65-110.08 and OR 10.4, 95% CI 1.65-65.752, respectively). CONCLUSIONS: In the presence of an undiagnosed pleural effusion, US morphological characteristics can aid in differentiating MPE from non-MPE. Pleural/diaphragmatic nodularity was the most relevant feature although no finding was pathognomonic of MPE. PMID- 24480901 TI - Does previa location matter? Surgical morbidity associated with location of a placenta previa. AB - OBJECTIVE: To evaluate the effect of placenta previa location (anterior vs posterior) on cesarean morbidity. STUDY DESIGN: Retrospective cohort of women undergoing cesarean for placenta previa. The rate of hysterectomy and blood transfusion in the setting of anterior previa was compared with posterior previa. Planned stratified analysis based on delivery history was performed. Logistic regression was performed to control for potential confounders. RESULT: Two hundred and eighty-five women undergoing cesarean delivery for placenta previa were identified. Women undergoing primary cesareans with an anterior previa had higher rates of blood transfusion (adjusted odds ratio (aOR) 3.13 95% confidence interval (CI) (1.18 to 8.36) and hysterectomy (7.4% vs 0, P=0.001) compared with those with a posterior previa; similarly, women undergoing repeat cesarean with anterior previa had higher rates of hysterectomy (aOR 4.60 95% CI (1.02 to 20.7). The majority of hysterectomies (93.8%) were due to abnormal placentation. CONCLUSION: An anterior placenta previa increases the risk of hysterectomy for both primary and repeat cesareans due to abnormal placentation. In the absence of accreta, blood transfusion remained a significant cause of maternal morbidity in both anterior and posterior placenta previas. This information may be useful for operative planning. PMID- 24480902 TI - Mothers of babies enrolled in a randomized trial immediately after birth report a positive experience. AB - OBJECTIVE: Randomized trials are essential for improving outcomes, but researchers can be hesitant about undertaking clinical trials in newborn babies because of perceived vulnerability of the baby and risk of increasing parental anxiety. There is a paucity of evidence about the parental experience. We investigated mothers' experiences of having their newborn baby participate in a randomized double-blind placebo-controlled trial soon after birth. STUDY DESIGN: Eligible mothers had consented to their baby's participation in the Sugar Babies Study. Mothers of potentially eligible babies were invited to join the study antenatally, but others were approached postnatally. Babies were enrolled in the study soon after birth and remained in the study for 48 h. After 2 weeks the birth mothers were interviewed by phone about their experience. RESULT: Four hundred and eighty-one mothers were enrolled, of whom 310 (64%) gave consent antenatally. All mothers were contacted and 477 (99%) were interviewed. The majority of mothers (458, 96%) reported they would consent to participating again, if they had another eligible baby, and 460 mothers (96%) reported they would recommend participation to family and friends. Nineteen mothers (4%) reported they did not like the heel lance blood tests, which were part of routine clinical care and not part of the trial protocol. CONCLUSION: Most mothers reported the experience of having their newborn baby participate in a clinical trial as positive. Most negative responses were related to aspects of routine care rather than the trial protocol. PMID- 24480903 TI - Cardiac troponin I concentrations as a marker of neurodevelopmental outcome at 18 months in newborns with perinatal asphyxia. AB - OBJECTIVE: To investigate whether creatine kinase-MB (CK-MB) and cardiac troponin I (cTnI) can be used to predict neurodevelopmental outcome at 18 months in infants with perinatal asphyxia (PA). The diagnostic value of cTnI to assess myocardial dysfunction was considered as well. STUDY DESIGN: Retrospective study of 178 neonates admitted with PA. cTnI concentrations measured within 12 h of birth were compared with medium-term outcome assessed with the Bayley Scales of Infant Development. cTnI concentrations measured within 12 h of birth were compared with clinical grade of hypoxic-ischemic encephalopathy (HIE) and with duration of inotropic support. Two-dimensional Doppler and color Doppler findings were recorded. Fractional shortening, tricuspid and mitral regurgitation were evaluated. RESULT: A statistically significant correlation between cTnI concentration and BSID-II score was found (mental development index r -0.69, P<0.05 and psychomotor development index r -0.39, P<0.05). There was no statistically significant correlation between CK-MB and BSID-II score (P>0.05).Serum cTnI concentrations and duration of inotropic support were significantly greater with increasing severity of PA. cTnI was negatively correlated with fraction shortening (r -0.64; P<0.05). The severity of tricuspid regurgitation was correlated with the cTnI concentration (r 0.61; P<0.05). CONCLUSION: In asphyxiated neonates, cTnI concentrations within 12 h of birth correlate with medium-term outcome. Early cTnI concentration correlates with severity of HIE, myocardial dysfunction and with Bayley II scores at 18 months. PMID- 24480904 TI - Deaths and near deaths of healthy newborn infants while bed sharing on maternity wards. AB - OBJECTIVE: Our aim was to evaluate programs promoting bed sharing on maternity wards and determining ways to reduce these risks. STUDY DESIGN: Members of the National Association of Medical Examiners were contacted requesting information on deaths of healthy infants while bed sharing on maternity wards. RESULT: Fifteen deaths and three near deaths are reported. One or more factors that increase the risk of bed sharing were present in all cases. Accidental suffocation was deemed the most likely cause of these incidents. CONCLUSION: Cases of infant deaths and near deaths while bed sharing on maternity wards are under reported. The 'Baby Friendly' (BF) initiative in maternity hospitals to promote breastfeeding is endorsed by the American Academy of Pediatrics and the US Center for Disease Control and Prevention. The BF initiative encourages prolonged skin-to-skin contact and bed sharing. Education of mothers and more efficient monitoring should significantly reduce the risk of maternity ward bed sharing. PMID- 24480906 TI - Sulfurisoma sediminicola gen. nov., sp. nov., a facultative autotroph isolated from a freshwater lake. AB - A novel facultatively autotrophic bacterium, strain BSN1T was isolated from sediment of a freshwater lake in Japan. The cells were rod-shaped, motile and Gram-stain-negative. As sole energy sources for autotrophic growth, the strain oxidized thiosulfate, elemental sulfur and hydrogen. Strain BSN1T was a facultative anaerobe utilizing nitrate as an electron acceptor. Growth was observed at temperatures lower than 34 degrees C, and the optimum growth was observed at 30-32 degrees C. The range of pH for growth was pH 6.8-8.8, and the optimum pH was pH 7.8-8.1. The optimum growth of the isolate occurred at concentrations of NaCl less than 50 mM. The G+C content of genomic DNA was 67 mol%. The major component in the fatty acid profile of strain BSN1T grown on fumarate was summed feature 3 (C16:1omega7c and/or iso-C15:0 2-OH). Phylogenetic analysis based on 16S rRNA gene sequences indicated that the strain was a member of the class Betaproteobacteria, and it showed the highest sequence similarity with Georgfuchsia toluolica G5G6T (96.2%). Phylogenetic analyses were also performed on genes involved in sulfur oxidation. On the basis of its phylogenetic and phenotypic properties, strain BSN1T (=DSM 26916T=NBRC 109412T) is proposed as the type strain of a novel species of a novel genus, Sulfurisoma sediminicola gen. nov., sp. nov. PMID- 24480905 TI - Effects of antenatal magnesium sulfate treatment on cerebral blood flow velocities in preterm neonates. AB - OBJECTIVE: The objective of this study is to investigate the effects of antenatal magnesium sulfate (MgSO4) on cerebral blood flow (CBF) velocities in preterm neonates. STUDY DESIGN: In this prospective case-control study, we included 53 neonates born between 26 and 34 weeks of gestation. Twenty neonates were exposed to MgSO4 antenatally and 33 were not. Serial daily Doppler flow measurements of middle cerebral artery (MCA) were performed. RESULT: Significantly increased MCA mean velocities were found in the MgSO4 group. A progressive increase in serial Doppler measurements of MCA mean velocity from day 1 to day 5 of life was detected in both groups. CONCLUSION: There is significant increase in MCA mean velocities in preterm neonates receiving antenatal MgSO4. This increment in CBF velocities might explain the protective role of MgSO4 in ischemic events and hypoxic brain damage. PMID- 24480907 TI - Chryseobacterium aahli sp. nov., isolated from lake trout (Salvelinus namaycush) and brown trout (Salmo trutta), and emended descriptions of Chryseobacterium ginsenosidimutans and Chryseobacterium gregarium. AB - Two strains (T68T and T62) of a Gram-reaction-negative, yellow-pigmented bacterium containing flexirubin-type pigments were recovered from the kidney of a cultured lake trout (Salvelinus namaycush) and necrotic fins of a brown trout (Salmo trutta) during disease surveillance in 2009. Both isolates possessed catalase and cytochrome oxidase activities and degraded multiple substrates (e.g. gelatin, casein, elastin and Tweens 20 and 80). The mean DNA G+C content of strain T68T was 34.1 mol%. 16S rRNA gene sequencing demonstrated that strains T68T and T62 had nearly identical sequences (>=99 % similarity) and placed the bacterium within the genus Chryseobacterium, where Chryseobacterium ginsenosidimutans THG 15T (97.8%), C. gregarium DSM 19109T (97.7%) and C. soldanellicola PSD1-4T (97.6%) were its closest relatives. Subsequent phylogenetic analyses using neighbour-joining, maximum-parsimony and Bayesian methodologies demonstrated that strains T68T and T62 formed a well-supported clade (bootstrap values of 100 and 97%; posterior probability 0.99) that was distinct from other species of the genus Chryseobacterium. The major fatty acids of strains T68T and T62 were characteristic of the genus Chryseobacterium and included iso-C15:0, summed feature 3 (C16:1omega6c and/or C16:1omega7c), iso C17:0 3-OH, C16:0 and C16:0 3-OH. The mean DNA-DNA relatedness of strain T68T to C. ginsenosidimutans JCM 16719T and C. gregarium LMG 24952T was 24 and 21%, respectively. Based on the results from our polyphasic characterization, strains T68T and T62 represent a novel species of the genus Chryseobacterium, for which the name Chryseobacterium aahli sp. nov. is proposed. The type strain is T68T (=LMG 27338T=ATCC BAA-2540T). Emended descriptions of Chryseobacterium ginsenosidimutans and Chryseobacterium gregarium are also proposed. PMID- 24480908 TI - Characterization of Romboutsia ilealis gen. nov., sp. nov., isolated from the gastro-intestinal tract of a rat, and proposal for the reclassification of five closely related members of the genus Clostridium into the genera Romboutsia gen. nov., Intestinibacter gen. nov., Terrisporobacter gen. nov. and Asaccharospora gen. nov. AB - A Gram-positive staining, rod-shaped, non-motile, spore-forming obligately anaerobic bacterium, designated CRIBT, was isolated from the gastro-intestinal tract of a rat and characterized. The major cellular fatty acids of strain CRIBT were saturated and unsaturated straight-chain C12-C19 fatty acids, with C16:0 being the predominant fatty acid. The polar lipid profile comprised six glycolipids, four phospholipids and one lipid that did not stain with any of the specific spray reagents used. The only quinone was MK-6. The predominating cell wall sugars were glucose and galactose. The peptidoglycan type of strain CRIBT was A1sigma lanthionine-direct. The genomic DNA G+C content of strain CRIBT was 28.1 mol%. On the basis of 16S rRNA gene sequence similarity, strain CRIBT was most closely related to a number of species of the genus Clostridium, including Clostridium lituseburense (97.2%), Clostridium glycolicum (96.2%), Clostridium mayombei (96.2%), Clostridium bartlettii (96.0%) and Clostridium irregulare (95.5%). All these species show very low 16S rRNA gene sequence similarity (<85%) to the type strain of Clostridium butyricum, the type species of the genus Clostridium. DNA-DNA hybridization with closely related reference strains indicated reassociation values below 32%. On the basis of phenotypic and genetic studies, a novel genus, Romboutsia gen. nov., is proposed. The novel isolate CRIBT (=DSM 25109T=NIZO 4048T) is proposed as the type strain of the type species, Romboutsia ilealis gen. nov., sp. nov., of the proposed novel genus. It is proposed that C. lituseburense is transferred to this genus as Romboutsia lituseburensis comb. nov. Furthermore, the reclassification into novel genera is proposed for C. bartlettii, as Intestinibacter bartlettii gen. nov., comb. nov. (type species of the genus), C. glycolicum, as Terrisporobacter glycolicus gen. nov., comb. nov. (type species of the genus), C. mayombei, as Terrisporobacter mayombei gen. nov., comb. nov., and C. irregulare, as Asaccharospora irregularis gen. nov., comb. nov. (type species of the genus), on the basis of additional data collected in this study. In addition, an emendation of the species Peptostreptococcus anaerobius and the order Eubacteriales is provided. PMID- 24480909 TI - Low back pain patient subgroups in primary care: pain characteristics, psychosocial determinants, and health care utilization. AB - OBJECTIVES: In industrialized countries, low back pain (LBP) is one of the leading causes for prolonged sick leave, early retirement, and high health care costs. Providing the same treatments to all patients is neither effective nor feasible, and may impede patients' recovery. Recent studies have outlined the need for subgroup-specific treatment allocation. METHODS: This is a cross sectional study that used baseline data from consecutively recruited patients participating in a guideline implementation trial regarding LBP in primary care. Classification variables were employment status, age, pain intensity, functional capacity (HFAQ), depression (CES-D), belief that activity causes pain (FABQ subscale), 2 scales of the SF-36 (general health, vitality), and days in pain per year. We performed k-means cluster analyses and split-half cross-validation. Subsequently, we investigated whether the resulting groups incurred different direct and indirect costs during a 6-month period before the index consultation. RESULTS: A 4-cluster solution showed good statistical quality criteria, even after split-half cross-validation. "Elderly patients adapted to pain" (cluster 1) and "younger patients with acute pain" (cluster 4) accounted for 55% of all patients. Cluster validation showed the lowest direct and indirect costs in these groups. About 72% of total costs per patient referred to clusters 2 and 3 ("patients with chronic severe pain with comorbid depression" and "younger patients with subacute pain and emotional distress"). DISCUSSION: Our study adds substantially to the knowledge of LBP-related case-mix in primary care. Information on differential health care needs may be inferred from our study, enabling decision makers to allocate resources more appropriately and to reduce costs. PMID- 24480910 TI - Detecting pain in traumatic brain-injured patients with different levels of consciousness during common procedures in the ICU: typical or atypical behaviors? AB - PURPOSE: Pain behaviors such as grimacing and muscle rigidity are recommended for pain assessment in nonverbal populations. However, these behaviors may not be appropriate for critically ill patients with a traumatic brain injury (TBI) depending on their level of consciousness (LOC). This study aimed to validate the use of behaviors for assessing pain of critically ill TBI adults with different LOC. METHODS: Using a repeated measure within subject design, participants (N=45) were observed for 1 minute before (baseline), during, and 15 minutes after 2 procedures: (1) noninvasive blood pressure: NIBP (non-nociceptive); and (2) turning (nociceptive). A behavioral checklist combining 50 items from existing pain assessment tools and video recording were used to describe participants' behaviors. Intrarater and interrater agreements of observed behaviors were also examined. RESULTS: Overall, pain behaviors were observed more frequently during turning (median=4; T=-5.336; P<=0.001) than at baseline (median=1), or during noninvasive blood pressure (median=0). TBI patients' pain behaviors were mostly "atypical" and included uncommon responses such as flushing, sudden eye opening, eye weeping, and flexion of limbs. These behaviors were observed in >=25.0% of TBI participants during turning independent of their LOC, and in 22.2% to 66.7% of conscious participants who reported the presence of pain. Agreements were >92% among and between the 2 raters. CONCLUSIONS: This study support previous findings that critically ill TBI patients could exhibit atypical behaviors when exposed to nociceptive procedures. As such, use of current recommended pain behaviors as part of standardized scales may not be optimal for assessing the analgesic needs of this vulnerable group. PMID- 24480911 TI - Effectiveness of pharmacist-led medication review in chronic pain management: systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness of pharmacist-led medication review in chronic pain management. MATERIALS AND METHODS: Six electronic databases (Medline, Embase, PsycInfo, CINHAL, CENTRAL, International Pharmaceutical Abstracts) reference lists of retrieved articles and relevant websites were searched for randomized controlled trials published in the English language involving adults with chronic pain. Studies were included if one of the intervention arms had received pharmacist-led medication review independently or as part of a multidisciplinary intervention. Risk of bias was assessed for all the included studies. RESULTS: The search strategy yielded 583 unique articles including 5 randomized controlled trials. Compared with control, meta-analysis showed that participants in the intervention group had: a 0.8-point reduction in pain intensity on a 0 to 10 numerical rating scale at 3 months [95% confidence interval (CI), -1.28 to -0.36] and a 0.7-point reduction (95% CI, -1.19 to -0.20) at 6 months; a 4.84 point (95% CI, -7.38 to -2.29) and -3.82 point (95% CI, -6.49 to -1.14) improvement in physical functioning on a 0- to 68-point function subscale of Western Ontario and McMaster Universities Osteoarthritis Index at 3 and 6 months, respectively; and a significant improvement in patient satisfaction equivalent to a "small to moderate effect." DISCUSSION: Pharmacist-led medication review reduces pain intensity and improves physical functioning and patient satisfaction. However, the clinical significance of these findings remain uncertain due to small effect size and nature of reported data within clinical trials that limits recommendation of wider clinical role of pharmacist in chronic pain management. PMID- 24480912 TI - Cold hyperalgesia associated with poorer prognosis in lateral epicondylalgia: a 1 year prognostic study of physical and psychological factors. AB - BACKGROUND: Predictors of outcome in lateral epicondylalgia, which is mainly characterized as a mechanical hyperalgesia, are largely limited to sociodemographic and symptomatic factors. Quantitative sensory testing is used to study altered pain processing in various chronic pain conditions and may be of prognostic relevance. METHODS: The predictive capacity of early measures of physical and psychological impairment on pain and disability and mechanical hyperalgesia, were examined using data from 41 patients assigned to placebo in a prospective randomized controlled trial of unilateral lateral epicondylalgia. Quantitative sensory testing (pressure, cold pain thresholds), motor function (pain-free grip), and psychological factors (Tampa Scale of Kinesiophobia, Hospital Anxiety and Depression Scale) were measured at baseline. The outcome measures were the Patient-rated Tennis Elbow Evaluation (PRTEE) scale and pressure pain threshold (PPT) measured by digital algometry at the affected elbow. Backward stepwise linear regression was used to predict PRTEE and PPT scores at 2 and 12 months. RESULTS: Cold pain threshold was the only consistent predictor for both PRTEE (P<0.034) and PPT (P<0.048). Initial PRTEE was the strongest single predictor of PRTEE at 2 months, whereas female sex was the strongest single predictor of PPT (P<0.002). At 1 year, final models explained 9% to 52% of the variability in pain and disability and mechanical hyperalgesia, respectively. DISCUSSION: Early assessment of cold pain threshold could be a useful clinical tool to help identify patients at risk of poorer outcomes and might provide direction for future research into mechanism-based treatment approaches for these patients. PMID- 24480913 TI - Long-term evaluation of opioid treatment in fibromyalgia. AB - OBJECTIVES: In a 12-month observational study, we evaluated the effect of opioid use on the outcomes in 1700 adult patients with fibromyalgia. METHODS: Data were evaluated using propensity score matching after patients were divided into cohorts based on their baseline medication use: (1) taking an opioid (concurrent use of tramadol was permitted); (2) taking tramadol (but no opioids); and (3) not taking opioids or tramadol. Changes in outcomes were assessed using the Brief Pain Inventory for severity and pain-related interference (BPI-S, BPI-I), Fibromyalgia Impact Questionnaire (FIQ), Patient Health Questionnaire for depression (PHQ-8), Insomnia Severity Index (ISI), Sheehan Disability Scale (SDS), 7-item Generalized Anxiety Disorder Scale (GAD-7), and economic factors. Time-to-opioid or tramadol discontinuation was analyzed using Kaplan-Meier survival analyses. RESULTS: Compared with the opioid cohort, the nonopioid cohort demonstrated significantly greater reductions (P<0.05) in BPI-I, FIQ, PHQ-8, SDS, and ISI; the tramadol cohort compared with the opioid group showed greater reductions on FIQ and ISI. Reductions in BPI-S and GAD-7 did not differ significantly among cohorts. Compared with the opioid cohort, patients in the tramadol cohort had fewer outpatient visits to health care providers. Few significant differences were found between the tramadol and nonopioid cohorts across outcomes. DISCUSSION: Although pain severity was reduced over time in all cohorts, opioid users showed less improvement in pain-related interference with daily living, functioning, depression, and insomnia. Overall, the findings show little support for the long-term use of opioid medications in patients with fibromyalgia given the poorer outcomes across multiple assessment domains associated with this cohort. PMID- 24480914 TI - KRAS (G12D) cooperates with AML1/ETO to initiate a mouse model mimicking human acute myeloid leukemia. AB - BACKGROUND/AIMS: It has been demonstrated that KRAS mutations represent about 90% of cancer-associated mutations, and that KRAS mutations play an essential role in neoplastic transformation. Cancer-associated RAS mutations occur frequently in acute myeloid leukemia (AML), suggesting a functional role for Ras in leukemogenesis. METHODS: We successfully established a mouse model of human leukemia by transplanting bone marrow cells co-transfected with the K-ras (G12D) mutation and AML1/ETO fusion protein. RESULTS: Mice transplanted with AML/ETO+KRAS co-transduced cells had the highest mortality rate than mice transplanted with AML/ETO- or KRAS-transduced cells (115d vs. 150d). Upon reaching a terminal disease stage, EGFP-positive cells dominated their spleen, lymph nodes, peripheral blood and central nervous system tissue. Immunophenotyping, cytologic analyses revealed that AML/ETO+KRAS leukemias predominantly contained immature myeloid precursors (EGFP(+)/c-Kit(+)/Mac-1(-)/Gr 1(-)). Histologic analyses revealed that massive leukemic infiltrations were closely packed in dense sheets that effaced the normal architecture of spleen and thymus in mice transplanted with AML1/ETO + KRAS co-transduced cells. K-ras mRNA and protein expression were upregulated in bone marrow cells of the K-ras group and AML1/ETO + Kras group. The phosphorylation of MEK/ERK was significantly enhanced in the AML1/ETO + Kras group. The similar results of the AML1/ETO + Nras group were consistent with those reported previously. CONCLUSION: Co-transduction of Kras(G12D) and AML1/ETO induces acute monoblastic leukemia. Since expression of mutant K-ras alone was insufficient to induce leukemia, this model may be useful for investigating the multi-step leukemogenesis model of human leukemia. PMID- 24480916 TI - Portal cytokine response and metabolic markers in the early stages of abdominal sepsis in pigs. AB - BACKGROUND: The portal vein could play a major role in disseminating the local inflammation of acute bacterial peritonitis since it is responsible for the venous drainage of the gastrointestinal tract. We hypothesized that after peritoneal exposure to Escherichia coli, a gradient between the portal and systemic levels of cytokines would be expected. METHODS: Acute peritonitis was induced by depositing 200 ml of broth with live E. coli in the peritoneal cavity of the animals in the B-group (n = 7). They were then observed for 4 h and compared with a control group (C-group, n = 7). Tumour necrosis factor alpha (TNF alpha), interleukin (IL)-6, IL-10 and vascular endothelial growth factor were measured repeatedly in the portal vein and the femoral artery. Portal vein metabolic markers (microdialysis), haemodynamics, biochemistry, plasma volume (PV), fluid shifts and total tissue water content were recorded or calculated. RESULTS: The intervention led to PV contraction, increased fluid extravasation, increased pulmonary vascular resistance and reduced urinary output in the B-group as compared with the C-group. The levels of glucose in the portal vein were reduced in both study groups with no between-group differences. The levels of TNF alpha and IL-6 increased markedly in the portal vein as well as in the systemic circulation of the B-group, but no gradient was seen between them. The corresponding levels of TNF-alpha and IL-6 remained low and stable in the C group. CONCLUSION: The portal vein appears to play a minor role in supplying TNF alpha and IL-6 to the systemic circulation after peritoneal exposure to a substantial dose of E. coli. PMID- 24480917 TI - The pinwheel sign: artifact from head rotation during SPECT acquisition for dopamine transporter imaging. AB - This case study illustrates the pattern and significance of the pinwheel sign, a SPECT artifact from rotational head motion that can complicate the diagnosis of Parkinson disease. Monitoring the patient during image acquisition is crucial since rotational motion artifacts are difficult to identify on raw or processed images and may lead to incorrect interpretation of findings. PMID- 24480915 TI - Causes of pulmonary hypertension in the elderly. AB - BACKGROUND: Pulmonary hypertension (PH) is common in elderly patients, but a detailed analysis of the causes of PH in the elderly has not been performed. We hypothesized that pulmonary arterial hypertension (PAH) is rare in elderly patients and sought to describe the characteristics of these patients at a large referral center. METHODS: Clinical and hemodynamic data were collected on consecutive patients >= 65 years of age referred for evaluation of PH. The subtype of PH was determined after standard evaluation using the World Health Organization (WHO) classification. Patients with PH not meeting criteria for PAH with "out-of-proportion" PH related to group 2 or group 3 disease were classified as "other/mixed PH." A model using age, presence of connective tissue disease, and left atrial size was developed to predict the probability of PAH diagnosis. RESULTS: Two hundred forty-six elderly patients were evaluated (mean age, 72.9 +/ 5.5 years, 78% women); 36 had PAH (15%). Idiopathic PAH was rare (four patients, 1.6%). WHO group 2 PH was the most frequent diagnosis (n = 70, 28% of cohort); mixed/other PH (n = 43, 17%) and WHO group 3 PH (n = 34, 14%) were also common diagnoses. Connective tissue disease strongly predicted PAH diagnosis (OR, 27.2; 95% CI, 9.5-77.6). CONCLUSIONS: PAH is an uncommon cause of PH in elderly patients, most frequently associated with connective tissue disease. WHO group 2 PH and mixed disease are common, highlighting a need for careful phenotyping of elderly patients with PH prior to initiating PAH therapy. PMID- 24480918 TI - Optimizing the ventilation-perfusion lung scan for image quality and radiation exposure. AB - Our purpose was to compare the performance of an initial ventilation-perfusion (V/Q) scan protocol with that of a data-driven modified protocol to improve diagnostic quality without increasing radiation dose to the patient. METHODS: The initial V/Q scan protocol consisted of a ventilation scan after inhalation of (99m)Tc-diethylenetriaminepentaacetic acid (DTPA) aerosol for 5 min followed by a (99m)Tc-macroaggregated albumin perfusion scan. Interim analysis after 34 scans under an initial protocol included calculations of ventilation efficiency, perfusion efficiency, and perfusion-to-ventilation counting rate ratio (Q:V). Ventilation efficiency was defined as ventilation counting rate divided by ventilation dose, perfusion efficiency as perfusion counting rate divided by perfusion dose, and Q:V as perfusion counting rate divided by ventilation counting rate. From these data, the protocol was modified to improve the Q:V ratio and was applied to 60 patients. Results from the 94 scans were tabulated, and a comparison of ventilation efficiency, perfusion efficiency, and Q:V between the 2 protocols was statistically analyzed. RESULTS: The initial protocol returned a mean ventilation efficiency of 7.8% (SD, 4.6%; range, 1.4%-19%), mean perfusion efficiency of 100% (SD, 31%; range, 39%-160%), and mean Q:V of 2.4 (SD, 1.9; range, 0.51-9.0). All 3 parameters displayed a wide range. Fifty-four percent of these cases demonstrated an unacceptable Q:V (<=2) indicating that the perfusion dose did not overwhelm the ventilation dose. To improve Q:V, options included decreasing ventilation dose, increasing perfusion dose, or performing the ventilation scan with a much higher dose after the perfusion scan. To minimize radiation, the protocol was modified to decrease the ventilation from 5 min to 2.5 min. The modified protocol yielded a mean ventilation efficiency of 5.1% (SD, 1.8; range, 2.0-11), mean perfusion efficiency of 120% (SD, 27%; range, 65%-170%), and mean Q:V of 3.6 (SD, 1.7; range, 1.2-12). Differences between protocols were statistically significant for ventilation efficiency, perfusion efficiency, and Q:V (P < 0.02). Less than 8% of cases under the modified protocol exhibited an unacceptable Q:V. CONCLUSION: The initial V/Q scan protocol was successfully modified to improve image quality with less radiation. By decreasing the ventilation time by half, the percentage of studies with an unacceptable Q:V decreased from 54% to 8%. This analysis may help others to optimize their V/Q protocols. PMID- 24480919 TI - Uncertainty in measurements of 18F blood concentration and its effect on simplified dynamic PET analysis. AB - The purpose of this study was to assess the accuracy and practicality of well counter- and thyroid probe-based methods, commonly available in nuclear medicine facilities, for measuring the concentration of (18)F-FDG in blood samples. The degree to which the accuracy of such methods influences quantitative analysis of dynamic PET scans was also assessed. METHODS: Thirty-five patients with cancer of the head and neck underwent dynamic PET imaging as part of a study intended to evaluate the utility of quantitative, image-based metrics for assessment of early treatment response. The activity in blood samples from the patients, necessary to provide an estimate of the input function for quantitative analysis, was measured both using a thyroid probe and using a well counter. Three calibration techniques were compared: single-point calibration using a standard solution for the thyroid probe (ProbePoint technique), single-point calibration using a standard solution for the well counter (WellPoint technique), and multiple-point calibration over the full range of expected blood activities for the well counter (WellCurve technique). The WellCurve method was assumed to provide the most accurate estimate of blood activity. The precision of measuring blood volume using a micropipette was also evaluated by obtaining multiple blood samples. Simplified kinetic-analysis multiple-time-point (SKA-M) uptake rates for the primary tumor were calculated for all 35 patients using PET images and each of the 3 methods for assessing blood concentration. RESULTS: Errors in blood activity measurements ranging from -9.5% to 7.6% were found using the ProbePoint method, whereas the error range was much less (from -1.3% to 0.9%) for the WellPoint method. The precision in blood volume measurements ranged from -6% to 12% in the 10 patients assessed. The errors in blood activity and volume measurements were reflected in the SKA-M measurements in the same range. CONCLUSION: The WellPoint method provides a compromise between accuracy and clinical practicality. Random errors in both blood activity and volume measurements accumulate and may compromise parameters--such as the SKA-M estimate of tumor uptake rate--that depend not only on images but also on blood concentration data. PMID- 24480920 TI - 99mTc-octreotide uptake in the uterus and a subserosal myoma mimicking tumoral masses. AB - The diagnostic usefulness of somatostatin receptor scintigraphy in the localization of tumors has been evaluated in several studies. Here, we present the case of a patient with a subserosal myoma diagnosed by (99m)Tc-labeled octreotide acetate scintigraphy. Oval and ring-shaped areas of hyperactivity in the pelvis were confirmed on MR imaging to be the uterus and a subserosal myoma. The presented case indicates that somatostatin receptors may be present in the uterus and in leiomyomas, especially in young women, and demonstrates that somatostatin may be a promising therapy for treatment of myoma. The case also demonstrates that subserosal myoma or dislocation of the uterus can result in a false-positive diagnosis, highlighting the importance of correlative imaging for accurate interpretation of the study. PMID- 24480921 TI - Superamphiphobic surfaces. AB - Superamphiphobicity is an effect where surface roughness and surface chemistry combine to generate surfaces which are both superhydrophobic and superoleophobic, i.e., contact angles (thetaCA) greater than 150 degrees along with low contact angle hysteresis (CAH) not only towards probing water but also for low-surface tension 'oils'. In this review, we summarize the research on superamphiphobic surfaces, including the characterization of superamphiphobicity, different techniques towards the fabrication of surface roughness and surface modification with low-surface-energy materials as well as their functional applications. PMID- 24480922 TI - Identification of BP16 as a non-toxic cell-penetrating peptide with highly efficient drug delivery properties. AB - Antimicrobial peptides are an interesting source of non-cytotoxic drug delivery vectors. Herein, we report on the identification of a new cell-penetrating peptide (KKLFKKILKKL-NH2, BP16) from a set of antimicrobial peptides selected from a library of cecropin-melittin hybrids (CECMEL11) previously designed to be used in plant protection. This set of peptides was screened for their cytotoxicity against breast adenocarcinoma MCF-7, pancreas adenocarcinoma CAPAN-1 and mouse embryonic fibroblast 3T3 cell lines. BP16 resulted to be non-toxic against both malignant and non-malignant cells at concentrations up to 200 MUM. We demonstrated by flow cytometry and confocal microscopy that BP16 is mainly internalized in the cells through a clathrin dependent endocytosis and that it efficiently accumulates in the cell cytoplasm. We confirmed that the cell penetrating properties of BP16 are retained after conjugating it to the breast tumor homing peptide CREKA. Furthermore, we assessed the potential of BP16 as a drug delivery vector by conjugating the anticancer drug chlorambucil to BP16 and to a CREKA-BP16 conjugate. The efficacy of the drug increased between 6 and 9 times when conjugated to BP16 and between 2 and 4.5 times when attached to the CREKA-BP16 derivative. The low toxicity and the excellent cell-penetrating properties clearly suggest that BP16 is a suitable vector for the delivery of therapeutic agents into cells. PMID- 24480923 TI - Male androgen deficiency: a multisystem syndrome. PMID- 24480925 TI - Prognostic significance of the degree of extranodal extension in patients with penile carcinoma. AB - This study sought to assess the prognostic significance of the degree of extranodal extension (ENE) and several other risk factors in pathological ENE penile carcinoma. We analyzed prospectively collected data on a consecutive series of 31 chemotherapy-naive patients with proven ENE who underwent therapeutic regional lymphadenectomy. Postoperative external radiotherapy was then performed. We studied the extent of ENE utilizing a novel grading system and correlated patient grades with their outcome measures. ENE was graded as 1 - if the capsule of the lymph node (LN) was ruptured less than one-third of its circumference or 2 - if the capsule was disrupted more than one-third of its circumference or the entire LN was disrupted. We estimated overall survival (OS) using the Kaplan-Meier method. Multivariate analysis was performed according to the Cox proportional hazards model using factors that were identified as statistically significant in univariate analysis. The incidence rate of ENE was 51.8% in patients with pathological node-positive carcinoma of the penis. The median OS and 5-year survival were 18 months (95% confidence interval (CI), 14.4 21.6) and 23%, respectively. Prognostic variables on univariate analysis were ENE grade 2, >= 3 LNs with ENE, maximal LN >= 35 mm, >= 5 positive LNs and pelvic LN involvement. On multivariate analysis, only ENE grade 2 remained associated with decreased OS (hazard ratio (HR): 6.50). In conclusion, patients with ENE have a poor outcome, and ENE grade 2 is an independent predictive factor of poor OS in patients with pathological ENE penile carcinoma. PMID- 24480926 TI - MicroRNA let-7a: a novel therapeutic candidate in prostate cancer. PMID- 24480927 TI - Cariogenic effects of probiotic Lactobacillus rhamnosus GG in a dental biofilm model. AB - Probiotic bacteria have been suggested to inhibit Streptococcus mutans (SM) and thus prevent dental caries. However, supporting evidence is weak and probiotic species might be cariogenic themselves. Thus, we compared and combined the probiotic Lactobacillus rhamnosus GG (LGG) with SM and analysed the resulting mineral loss (DeltaZ) in dental tissues. We simulated three biofilm compositions (SM, LGG, SM * LGG), two lesion sites (smooth enamel, dentin cavity) and two nutrition supply frequencies (twice/day, 6 times/day) in a multi-station, continuous-culture biofilm model. A total of 240 bovine enamel and dentin samples were cut, polished and embedded. All experimental procedures were performed in independent duplicates, with 10 samples being allocated to each group for each experiment (final sample size n = 20/group). Biofilms were cultured on the specimens and supplied with 2% sucrose medium and artificial saliva in consecutive pulses. After 10 days, DeltaZ and bacterial numbers were assessed. SM * LGG biofilms caused significantly increased DeltaZ compared with SM or LGG biofilms (p < 0.01, Mann-Whitney test), and DeltaZ was significantly increased in dentin cavities compared with smooth enamel lesions (p < 0.01). Bacterial numbers did not significantly differ between biofilms of different species (p > 0.05, ANOVA). Frequent nutrition supply significantly increased bacterial numbers (p < 0.01). Biofilms in dentin cavities compared to smooth enamel harboured significantly more bacteria (p < 0.05). LGG induced mineral loss especially in dentin cavities and under highly cariogenic conditions. LGG did not have inhibitory effects on SM, but rather contributed to the caries process in vitro. PMID- 24480924 TI - Human androgen deficiency: insights gained from androgen receptor knockout mouse models. AB - The mechanism of androgen action is complex. Recently, significant advances have been made into our understanding of how androgens act via the androgen receptor (AR) through the use of genetically modified mouse models. A number of global and tissue-specific AR knockout (ARKO) models have been generated using the Cre-loxP system which allows tissue- and/or cell-specific deletion. These ARKO models have examined a number of sites of androgen action including the cardiovascular system, the immune and hemopoetic system, bone, muscle, adipose tissue, the prostate and the brain. This review focuses on the insights that have been gained into human androgen deficiency through the use of ARKO mouse models at each of these sites of action, and highlights the strengths and limitations of these Cre loxP mouse models that should be considered to ensure accurate interpretation of the phenotype. PMID- 24480928 TI - Mapping of CD8 T cell epitopes in human respiratory syncytial virus L protein. AB - OBJECTIVES: Since it has been reported that in humans there is a relationship between human respiratory syncytial virus (hRSV)-specific cytotoxic T lymphocytes and symptom reduction, and that the polymerase (structural L protein) is highly conserved among different strains, this work aimed to identify the CD8 T cell epitopes H-2(d) restricted within the L sequence for immunization purposes. METHODS: We screened the hRSV strain A2 L protein sequence using two independent algorithms, SYFPEITHI and PRED/(BALB/c), to predict CD8 T cell epitopes. The selected peptides were synthesized and used to immunize BALB/c mice for the evaluation of T cell response. The production of IFN-gamma from splenocytes of hRSV-infected animals stimulated by these peptides was assayed by ELISPOT. RESULTS: Nine peptides showing the best binding scores to the BALB/c MHC-I molecules (H-2K(d), L(d) and D(d)) were selected. Sequence homology analysis showed that these sequences are conserved among different hRSV strains. Two of these peptides induced significant IFN-gamma production by ex vivo-stimulated T cells. CONCLUSIONS: Our results indicate that the hRSV L protein contains H-2(d) restricted epitopes. PMID- 24480929 TI - Quality-adjusted survival following treatment of malignant pleural effusions with indwelling pleural catheters. AB - BACKGROUND: Malignant pleural effusions (MPEs) are a frequent cause of dyspnea in patients with cancer. Although indwelling pleural catheters (IPCs) have been used since 1997, there are no studies of quality-adjusted survival following IPC placement. METHODS: With a standardized algorithm, this prospective observational cohort study of patients with MPE treated with IPCs assessed global health related quality of life using the SF-6D to calculate utilities. Quality-adjusted life days (QALDs) were calculated by integrating utilities over time. RESULTS: A total of 266 patients were enrolled. Median quality-adjusted survival was 95.1 QALDs. Dyspnea improved significantly following IPC placement (P < .001), but utility increased only modestly. Patients who had chemotherapy or radiation after IPC placement (P < .001) and those who were more short of breath at baseline (P = .005) had greater improvements in utility. In a competing risk model, the 1-year cumulative incidence of events was death with IPC in place, 35.7%; IPC removal due to decreased drainage, 51.9%; and IPC removal due to complications, 7.3%. Recurrent MPE requiring repeat intervention occurred in 14% of patients whose IPC was removed. Recurrence was more common when IPC removal was due to complications (P = .04) or malfunction (P < .001) rather than to decreased drainage. CONCLUSIONS: IPC placement has significant beneficial effects in selected patient populations. The determinants of quality-adjusted survival in patients with MPE are complex. Although dyspnea is one of them, receiving treatment after IPC placement is also important. Future research should use patient-centered outcomes in addition to time-to-event analysis. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01117740; URL: www.clinicaltrials.gov. PMID- 24480930 TI - Serological documentation of maternal influenza exposure and bipolar disorder in adult offspring. AB - OBJECTIVE: The authors examined whether serologically confirmed maternal exposure to influenza was associated with an increased risk of bipolar disorder in the offspring and with subtypes of bipolar disorder, with and without psychotic features. METHOD: The study used a nested case-control design in the Child Health and Development Study birth cohort. In all, 85 individuals with bipolar disorder were identified following extensive ascertainment and diagnostic assessment and matched to 170 comparison subjects in the analysis. Serological documentation of maternal exposure to influenza was determined using the hemagglutination inhibition assay. RESULTS: No association was observed between serologically documented maternal exposure to influenza and bipolar disorder in offspring. However, maternal serological influenza exposure was related to a significant fivefold greater risk of bipolar disorder with psychotic features. CONCLUSIONS: The results suggest that maternal influenza exposure may increase the risk for offspring to develop bipolar disorder with psychotic features. Taken together with earlier associations between prenatal influenza exposure and schizophrenia, these results may suggest that prenatal influenza is a risk factor for psychosis rather than for a specific psychotic disorder diagnosis. PMID- 24480931 TI - Effects of selective activation of M1 and M4 muscarinic receptors on object recognition memory performance in rats. AB - Acetylcholine signaling through muscarinic receptors has been shown to benefit memory performance in some conditions, but pan-muscarinic activation also frequently leads to peripheral side effects. Drug therapies that selectively target M1 or M4 muscarinic receptors could potentially improve memory while minimizing side effects mediated by the other muscarinic receptor subtypes. The ability of three recently developed drugs that selectively activate M1 or M4 receptors to improve recognition memory was tested by giving Long-Evans rats subcutaneous injections of three different doses of the M1 agonist VU0364572, the M1 positive allosteric modulator BQCA or the M4 positive allosteric modulator VU0152100 before performing an object recognition memory task. VU0364572 at 0.1 mg/kg, BQCA at 1.0 mg/kg and VU0152100 at 3.0 and 30.0 mg/kg improved the memory performance of rats that performed poorly at baseline, yet the improvements in memory performance were the most statistically robust for VU0152100 at 3.0 mg/kg. The results suggested that selective M1 and M4 receptor activation each improved memory but that the likelihood of obtaining behavioral efficacy at a given dose might vary between subjects even in healthy groups depending on baseline performance. These results also highlighted the potential of drug therapies that selectively target M1 or M4 receptors to improve memory performance in individuals with impaired memory. PMID- 24480932 TI - Direct transformation of arylpropynes to acrylamides via a three-step tandem reaction. AB - A novel and metal-free acrylamides formation between arylpropynes and hydroxylamine hydrochloride through sp(3) C-H and C-C bond cleavage has been achieved with DDQ as an oxidant. The mechanistic study shows that the acrylamides are formed through a three-step tandem sequence, including cross-dehydrogenative coupling (CDC) reaction, aza-Meyer-Schuster rearrangement and Beckmann rearrangement. PMID- 24480933 TI - Iontronic microdroplet array for flexible ultrasensitive tactile sensing. AB - An iontronic microdroplet array (IMA) device, using an ultra-large interfacial capacitance at the highly elastic droplet-electrode contact, has been proposed for flexible tactile sensing applications. The transparent IMA sensors consist of an array of nanoliter droplets sandwiched between two polymeric membranes with patterned transparent electrodes, forming the electrical double layers with remarkable unit-area capacitance. Under external loading, the membrane deformation results in the circumferential expansion at the highly elastic droplet-electrode contact, which offers a completely new capacitive sensing scheme with a dramatic increase in sensitivity. Under the simple device architecture, the IMA has achieved device sensitivity of 0.43 nF kPa(-1) and a minimal detectable pressure of 33 Pa, the highest reported values for its dimension. In addition, the hysteresis of the droplet deformation has been reduced by introducing a layer of hydrophobic coating to the conductive electrode surface, ensuring a fast mechanical response (on the order of several milliseconds). To demonstrate the utility of the transparent flexible IMA sensor, it has been successfully mounted onto a fingertip setting to map different surface topologies and embedded into a wristband to resolve dynamic pressure waves throughout cardiovascular cycles. PMID- 24480934 TI - The use of collagen content as determined by spectral domain polarization sensitive optical coherence tomography to assess colon anastomosis healing in a rat model. AB - BACKGROUND/PURPOSE: Many studies have been undertaken to prevent anastomosis leakage of the colon, and several methods have been used to assess anastomosis healing, such as measurement of bursting pressure or hydroxyproline (a marker of collagen) content at the anastomosis site. However, these methods are inappropriate for comparing anastomosis healing at two time points in the same animals. In the present study, we measured the collagen level by spectral domain polarization-sensitive optical coherence tomography (SD-PS-OCT) to assess anastomosis healing. METHODS: Sprague-Dawley rats were divided into groups C (saline-administered controls; study group) and M [a 5-fluorouracil (5-FU) administered experimental group]. Immediately after end-to-end anastomosis of the colon, SD-PS-OCT images of anastomoses were taken (baseline). Animals were administered saline or 5-FU for 7 days. On the 7th postoperative day, SD-PS-OCT images were acquired, a histopathologic exam was performed, and hydroxyproline levels as well as mRNA expressions of collagen-1 and collagen-3 were measured at the anastomosis site. RESULTS: Fibroblast proliferation and inflammatory cell infiltration were greater in group C than in group M. The mRNA expressions of collagen-1 and collagen-3 were substantially higher in group C. Hydroxyproline levels were higher in group M than in group C. Though collagen levels measured by SD-PS-OCT at 7 days were elevated compared with baseline in group C, no such changes were observed for group M. CONCLUSION: Collagen levels at the colon anastomosis site, measured with SD-PS-OCT, were not increased at 7 days postoperatively versus baseline when 5-FU was injected, but were increased in saline-treated controls. The measurement of collagen content by SD-PS-OCT was found to provide a good means of assessing anastomosis healing, because it allows in situ assessment of collagen contents at baseline and during the postoperative period. PMID- 24480935 TI - In response. PMID- 24480937 TI - Testing a new 10-item scale (Pind's LBP Test) for prediction of sick leave lasting more than three days or more than two weeks after a general practitioner visit for acute low back pain. AB - STUDY DESIGN: A study on acute low back pain (LBP) in consecutive working patients in a multicenter study in general practice. OBJECTIVE: LBP costs are enormous in all countries. New guidelines are difficult to introduce. On the basis of a new, specially developed LBP scale, the aims were to predict the duration of sick leave (SL), and to examine if the guidelines concerning bed rest (BR) and referral to radiographical examination were followed. SUMMARY OF BACKGROUND DATA: Pain intensity and heavy work influence the course of SL. A finger-to-floor distance test assesses the mobility of the spine, and both the finger-to-floor distance test and the straight leg raising test (SLRT) can be used to predict the course of LBP. BR or waiting time for treatment or referral will prolong SL. The expectations of patients and general practitioners are strong outcome predictors as is information about the prognosis. METHODS: A user friendly 10-item questionnaire was specifically developed. The scale included the background date. From a predefined scale the patients were subgrouped into 3 categories in relation to SL: (1) "no SL" or "a few days of SL," (2) "1 week of SL," and (3) "more than 2 weeks of SL." The Fisher exact test was used to compare categorical variables. RESULTS: Twenty-three doctors examined 207 working patients. A total of 114 patients (56%) completed the follow-up questionnaire. The 10-item scale showed a good correlation between the total score at the first general practitioner visit and predictable time of SL according to the 3 periods.The frequency of BR and referral to radiographical examination was low, and perhaps this was a consequence of using the scale. CONCLUSION: The specially developed short and user-friendly 10-item LBP scale was a good predictor of the duration of SL. A low rate of BR and radiographical examination may even be the result of using the scale. LEVEL OF EVIDENCE: N/A. PMID- 24480938 TI - Symptomatic spinal cord kinking due to focal adhesive arachnoiditis, with ossification of the ligamentum flavum: a case report. AB - STUDY DESIGN: A case report. OBJECTIVE: To describe a rare case of symptomatic spinal cord kinking due to focal adhesive arachnoiditis, with ossification of the ligamentum flavum (OLF). SUMMARY OF BACKGROUND DATA: Spinal cord kinking without spinal surgery is rare, and symptomatic spinal cord kinking due to focal adhesive arachnoiditis, with OLF is even rarer. METHODS: A 66-year-old female presented with numbness of the lower extremities and subsequently experienced gait disturbance due to motor weakness. Magnetic resonance imaging of the thoracic spine showed anterior displacement and kinking of the spinal cord from T11 to T12. Laminectomy and OLF resection were performed. The arachnoid membrane at the affected part was markedly thick and seemed cloudy. Adhesiolysis for arachnoid adhesion and release of spinal kinking were performed. RESULTS: She could walk with a cane 6 months postoperatively. One year postoperatively, thoracic computed tomography-myelography showed that the cord was repositioned in the dural sac, and that release of the spinal cord kink was maintained. CONCLUSION: Symptomatic spinal cord kinking due to focal adhesive arachnoiditis, with OLF is a rare clinical condition. It was difficult to diagnose the precise pathology of the spinal cord before surgery. Microsurgical arachnoidolysis resolved the spinal cord kinking, and no recurrence was noted within the follow-up period. LEVEL OF EVIDENCE: N/A. PMID- 24480939 TI - Percutaneous endoscopic intra-annular subligamentous herniotomy for large central disc herniation: a technical case report. AB - STUDY DESIGN: Technical case report. OBJECTIVE: To describe the novel technique of percutaneous endoscopic herniotomy using a unilateral intra-annular subligamentous approach for the treatment of large centrally herniated discs. SUMMARY OF BACKGROUND DATA: Open discectomy for large central disc herniations may have poor long-term prognosis due to heavy loss of intervertebral disc tissue, segmental instability, and recurrence of pain. METHODS: Six consecutive patients who presented with back and leg pain, and/or weakness due to a large central disc herniation were treated using percutaneous endoscopic herniotomy with a unilateral intra-annular subligamentous approach. RESULTS: The patients experienced relief of symptoms and intervertebral disc spaces were well maintained. The annular defects were noted to be in the process of healing and recovery. CONCLUSION: Percutaneous endoscopic unilateral intra-annular subligamentous herniotomy was an effective and affordable minimally invasive procedure for patients with large central disc herniations, allowing preservation of nonpathological intradiscal tissue through a concentric outer-layer annular approach. PMID- 24480940 TI - Do manual therapies help low back pain? A comparative effectiveness meta analysis. AB - STUDY DESIGN: Meta-analysis methodology was extended to derive comparative effectiveness information on spinal manipulation for low back pain. OBJECTIVE: Determine relative effectiveness of spinal manipulation therapies (SMTs), medical management, physical therapies, and exercise for acute and chronic nonsurgical low back pain. SUMMARY OF BACKGROUND DATA: Results of spinal manipulation treatments of nonsurgical low back pain are equivocal. Nearly 40 years of SMT studies were not informative. METHODS: Studies were chosen on the basis of inclusion in prior evidence syntheses. Effect sizes were converted to standardized mean effect sizes and probabilities of recovery. Nested model comparisons isolated nonspecific from treatment effects. Aggregate data were tested for evidential support as compared with shams. RESULTS: Of 84% acute pain variance, 81% was from nonspecific factors and 3% from treatment. No treatment for acute pain exceeded sham's effectiveness. Most acute results were within 95% confidence bands of that predicted by natural history alone. For chronic pain, 66% of 98% was nonspecific, but treatments influenced 32% of outcomes. Chronic pain treatments also fit within 95% confidence bands as predicted by natural history. Though the evidential support for treating chronic back pain as compared with sham groups was weak, chronic pain seemed to respond to SMT, whereas whole systems of clinical management did not. CONCLUSION: Meta-analyses can extract comparative effectiveness information from existing literature. The relatively small portion of outcomes attributable to treatment explains why past research results fail to converge on stable estimates. The probability of treatment superiority matched a binomial random process. Treatments serve to motivate, reassure, and calibrate patient expectations--features that might reduce medicalization and augment self-care. Exercise with authoritative support is an effective strategy for acute and chronic low back pain. PMID- 24480941 TI - How fast pain, numbness, and paresthesia resolves after lumbar nerve root decompression: a retrospective study of patient's self-reported computerized pain drawing. AB - STUDY DESIGN: A single-center retrospective study. OBJECTIVE: To compare the speed of recovery of different sensory symptoms, pain, numbness, and paresthesia, after lumbar nerve root decompression. SUMMARY OF BACKGROUND DATA: Lumbar radiculopathy is characterized by different sensory symptoms like pain, numbness, and paresthesia, which may resolve at different rates after surgical decompression. METHODS: Eighty-five cases with predominant lumbar radiculopathy treated surgically were reviewed. Oswestry Disability Index score, 36-Item Short Form Health Survey scores (Physical Component Summary and Mental Component Summary), and pain drawing at preoperative and at 6 weeks, 3 months, 6 months, and 1-year follow-up were reviewed. Recovery rate between different sensory symptoms were compared in all patients, and between the short-term compression (<6 mo) and long-term compression groups. RESULTS: At baseline, 73 (85.8%) patients had pain, 63 (74.1%) had numbness, and 38 (44.7%) had paresthesia; 28 (32.9%) had all these 3 component of sensory symptoms. Mean pain score improved fastest (55.3% at 6 wk); further resolution until 1 year was slow and not significant compared with each previous visit. Both numbness and paresthesia scores showed a trend of faster recovery during the initial 6-week period (20.5% and 24%, respectively); paresthesia recovery reached a plateau at 3 months postoperatively, but numbness continued a slow recovery until 1-year follow-up. Both Oswestry Disability Index score and Physical Component Summary scores (54.02 +/- 1.87 and 26.29 +/- 0.93, respectively, at baseline) improved significantly compared with each previous visits at 6 weeks and 3 months postoperatively, but further improvement was insignificant. Mental Component Summary showed a similar trend but smaller improvement. The short-term compression group had faster recovery of pain than the long-term compression group. CONCLUSION: In lumbar radiculopathy patients after surgical decompression, pain recovers fastest, in the first 6 weeks postoperatively, followed by paresthesia recovery that plateaus at 3 months postoperatively. Numbness recovers at a slower pace but continues until 1 year. LEVEL OF EVIDENCE: 4. PMID- 24480942 TI - An imaging anatomical study on percutaneous kyphoplasty for lumbar via a unilateral transverse process-pedicle approach. AB - STUDY DESIGN: An imaging anatomical measurement. OBJECTIVE: To investigate the anatomical feasibility of percutaneous kyphoplasty for lumbar osteoporotic vertebral compression fractures via a unilateral transverse process-pedicle approach (TPA). SUMMARY OF BACKGROUND DATA: Kyphoplasty via a unilateral approach has been reported and good clinical results have been achieved. However, because of the lack of an anatomical study, these approaches have yet to be popularized. METHODS: A total of 150 lumbar vertebral bodies of 30 patients were simulated kyphoplasty on the computed tomographic scans through conventional transpedicle approach (CTA) and the TPA, respectively. Anatomical parameters including the distance between the entry point and the midline of the vertebral body, the puncture inclination angle, and the success rate of puncture were measured and compared. RESULTS: The distance between the entry point and the midline from L1 to L5 lumbar levels varied from 20.6 +/- 2.2 mm to 28.6 +/- 2.9 mm in the CTA group and from 23.6 +/- 2.2 mm to 33.6 +/- 2.9 mm in the TPA group. The entry point from L1 to L5 in the TPA group was 3.0 +/- 2.1 mm to 5.1 +/- 2.7 mm more lateral than that in the CTA group. The medial inclination angles from L1 to L5 were 30.2 degrees +/- 6.4 degrees to 47.7 degrees +/- 5.4 degrees in the TPA and 15.3 degrees +/- 6.0 degrees to 22.8 degrees +/- 8.7 degrees in the CTA group. The inclination angles in the TPA group were greater than that in the CTA group and the safe range of the puncture angles was also wider. The success rate was 51.7% in the CTA group and 87.7% in the TPA group. CONCLUSION: The entry point through a TPA was localized at the midline of the transverse process, 3.0 to 5.1 mm outside the lateral margin of the pedicle projection. Compared with CTA, the puncture inclination angle in the TPA approach was much larger with a wider safe puncture range. The TPA approach allowed an easy puncture to meet or surpass the midline of the lumbar vertebral body. LEVEL OF EVIDENCE: N/A. PMID- 24480943 TI - In vivo cervical facet joint capsule deformation during flexion-extension. AB - STUDY DESIGN: Nonrandomized controlled cohort. OBJECTIVE: To characterize subaxial cervical facet joint kinematics and facet joint capsule (FJC) deformation during in vivo, dynamic flexion-extension. To assess the effect of single-level anterior arthrodesis on adjacent segment FJC deformation. SUMMARY OF BACKGROUND DATA: The cervical facet joint has been identified as the most common source of neck pain, and it is thought to play a role in chronic neck pain related to whiplash injury. Our current knowledge of cervical facet joint kinematics is based on cadaveric mechanical testing. METHODS: Fourteen asymptomatic controls and 9 C5-C6 arthrodesis patients performed full range of motion flexion-extension while biplane radiographs were collected at 30 Hz. A volumetric model-based tracking process determined 3-dimensional vertebral position with submillimeter accuracy. FJC fibers were modeled and grouped into anterior, lateral, posterior-lateral, posterior, and posterior-medial regions. FJC fiber deformations (total, shear, and compression-distraction) relative to the static position were determined for each cervical motion segment (C2-C3 through C6-C7) during flexion-extension. RESULTS: No significant differences in the rate of fiber deformation in flexion were identified among motion segments (P = 0.159); however, significant differences were observed among fiber regions (P < 0.001). Significant differences in the rate of fiber deformation in extension were identified among motion segments (P < 0.001) and among fiber regions (P = 0.001). The rate of FJC deformation in extension adjacent to the arthrodesis was 45% less than that in corresponding motion segments in control subjects (P = 0.001). CONCLUSION: In control subjects, FJC deformations are significantly different among vertebral levels and capsule regions when vertebrae are in an extended orientation. In a flexed orientation, FJC deformations are different only among capsule regions. Single-level anterior arthrodesis is associated with significantly less FJC deformation adjacent to the arthrodesis when the spine is in an extended orientation. LEVEL OF EVIDENCE: 4. PMID- 24480944 TI - Estimating EQ-5D values from the Oswestry Disability Index and numeric rating scales for back and leg pain. AB - STUDY DESIGN: Cross-sectional cohort. OBJECTIVE: The purpose of this study is to determine whether the EuroQOL-5D (EQ-5D) can be derived from commonly available low back disease-specific health-related quality of life measures. SUMMARY OF BACKGROUND DATA: The Oswestry Disability Index (ODI) and numeric rating scales (0 10) for back pain (BP) and leg pain (LP) are widely used disease-specific measures in patients with lumbar degenerative disorders. Increasingly, the EQ-5D is being used as a measure of utility due to ease of administration and scoring. METHODS: The EQ-5D, ODI, BP, and LP were prospectively collected in 14,544 patients seen in clinic for lumbar degenerative disorders. Pearson correlation coefficients for paired observations from multiple time points between ODI, BP, LP, and EQ-5D were determined. Regression modeling was done to compute the EQ-5D score from the ODI, BP, and LP. RESULTS: The mean age was 53.3 +/- 16.4 years and 41% were male. Correlations between the EQ-5D and the ODI, BP, and LP were statistically significant (P < 0.0001) with correlation coefficients of -0.77, 0.50, and -0.57, respectively. The regression equation: [0.97711 + (-0.00687 * ODI) + (-0.01488 * LP) + (-0.01008 * BP)] to predict EQ-5D, had an R2 of 0.61 and a root mean square error of 0.149. The model using ODI alone had an R2 of 0.57 and a root mean square error of 0.156. The model using the individual ODI items had an R2 of 0.64 and a root mean square error of 0.143. The correlation coefficient between the observed and estimated EQ-5D score was 0.78. There was no statistically significant difference between the actual EQ-5D (0.553 +/- 0.238) and the estimated EQ-5D score (0.553 +/- 0.186) using the ODI, BP, and LP regression model. However, rounding off the coefficients to less than 5 decimal places produced less accurate results. CONCLUSION: Unlike previous studies showing a robust relationship between low back-specific measures and the Short Form-6D, a similar relationship was not seen between the ODI, BP, LP, and the EQ 5D. Thus, the EQ-5D cannot be accurately estimated from the ODI, BP, and LP. LEVEL OF EVIDENCE: 2. PMID- 24480945 TI - Comparison of 2 methods of incision closure in patients with adolescent idiopathic scoliosis undergoing posterior spinal fusion surgery. AB - STUDY DESIGN: A prospective, randomized, and controlled clinical trial. OBJECTIVE: To compare surgical zipper with subcuticular Monocryl sutures in terms of incision closure time, cosmetic results, and the complication rate in patients with adolescent idiopathic scoliosis (AIS) undergoing posterior spinal fusion (PSF) surgery. SUMMARY OF BACKGROUND DATA: In previous literatures, the application of surgical zipper to incision closure has been reported to be associated with a favorable outcome. However, in the PSF surgery of patients with AIS, the use of surgical zipper has not been described. METHODS: Ninety female patients with AIS undergoing PSF were assigned randomly to 2 incision closure groups either using surgical zipper or using the 4-0 absorbable subcuticular suture. The incision outcome was evaluated with the Hollander Incision Evaluation Score at 7 days, 2 weeks, 6 months, and 1 year after surgery, respectively. Besides, a visual analogue scale was allocated to each patient to rate the cosmetic result of the incision. The 2 groups were compared to determine the differences in terms of incision closure time, the complication rate, and cosmetic results. RESULTS: The incision closure using surgical zipper consumed significantly less time than that using subcuticular suture (45.3 vs. 540.5 s, P < 0.001). As for the cosmetic results, no significant differences of Hollander Incision Evaluation Score scores between the 2 suturing groups were found. Besides, patients' satisfaction with cosmetic outcome on a linear visual analogue scale also revealed similar results between the 2 groups. As for postoperative complications, we found 1 case of mild blister due to allergy to the tape of the dressings and 2 cases of incisional pain in the Monocryl suture group. CONCLUSION: The application of surgical zipper in PSF surgery is a safe and effective method. The ease and the speed of application make surgical zipper an attractive option for incision closure in patients with AIS undergoing PSF. LEVEL OF EVIDENCE: 4. PMID- 24480946 TI - Are 2 questions enough to screen for depression and anxiety in patients with chronic low back pain? AB - STUDY DESIGN: Cross-sectional study. OBJECTIVE: To examine the sensitivity of 2 single-item questions compared with 2 longer questionnaires for screening depression and anxiety among patients with chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Psychosocial factors are frequently identified as risk factors for developing CLBP and as predictors for treatment, and questionnaires are often used to screen for this. Shorter instruments may be easier to use in clinical practice settings. METHODS: A total of 564 patients with 2 to 10 months of at least 50% sickness absence due to nonspecific low back pain were assessed for depression and anxiety with the Mini-International Neuropsychiatric Interview (MINI). Single-item questions for depression and anxiety from the Subjective Health Complaint Inventory and 2 longer questionnaires, the Hospital Anxiety and Depression Scale and Hopkins Symptom Checklist-25, were compared with MINI results, considered the "gold standard" in this study. Sensitivity and specificity of single-item and longer questionnaires and receiver operating characteristic curves were compared. RESULTS: According to MINI, the prevalence of anxiety disorders was 12% whereas that of depressive disorders was 4%. The screening questions showed 95% sensitivity and 56% specificity for depressive disorders and 68% sensitivity and 85% specificity for anxiety disorders. The longer questionnaire, Hospital Anxiety and Depression Scale, showed 91% sensitivity and 85% specificity for depressive disorders and 58% sensitivity and 83% specificity for anxiety disorders. Hopkins Symptom Checklist-25 showed 86% sensitivity and 74% specificity for depressive disorders and 67% sensitivity and 87% specificity for anxiety disorders. For 3 of the anxiety disorders and 2 of the depressive disorders, a perfect sensitivity was found between the screening questions and MINI. CONCLUSIONS: A single-item screening question was sensitive for depression but less sensitive for anxiety. The screening questions further performed equal to 2 widely used questionnaires. Validation of these results in other populations and compared with other short-item screeners is needed. PMID- 24480947 TI - Two-photon-excited fluorescence microscopy as a tool to investigate the efficacy of methylprednisolone in a mouse spinal cord injury model. AB - STUDY DESIGN: Basic imaging experiment. OBJECTIVE: To explore the use of 2-photon excited fluorescence (2PEF) microscopy to investigate the therapeutic effect of methylprednisolone (MP) in mice with spinal cord injury (SCI). SUMMARY OF BACKGROUND DATA: MP can alleviate secondary SCI through its anti-inflammatory effect; however, how MP regulates axonal dynamics in a compression SCI model is not well characterized. We used 2PEF microscopy to trace axonal dynamics in vivo during MP therapy. METHODS: Two types of transgenic mice (weighing 23-25 g) including YFP-H line (n = 18) and CX3CR1-GFP (n = 18) were used for experimental procedure. Each type of mouse was randomly divided into 3 groups, and the sample size of every subgroup was 6. The sham groups including YFP-H line group (n = 6) and CX3CR1-GFP group (n = 6) received laminectomy only (group 1). SCI groups received saline treatment (group 2) and SCI groups received MP treatment (group 3). Hind limb motor function was evaluated using the Basso Mouse Scale. 2PEF microscopy was used to image in vivo axonal dynamics at baseline and at 0.5 hours, 24 hours, 48 hours, and 72 hours postinjury. Histology was employed to examine pathological changes and microglial/macrophage proliferation after all imaging sessions. RESULTS: Group 1 exhibited no significant differences in hind limb motor function before versus after surgery. The Basso Mouse Scale scores were significantly lower in groups 2 and 3 than in group 1 (P < 0.05). Degree of recovery was higher in group 3 than in group 2 at 7 days postinjury (P < 0.05). The axons in group 1 remained intact at all time points. The survival rate of axons in groups 2 and 3 progressively decreased at 48 hours postinjury; at 72 hours postinjury, the axon survival rate was higher in group 3 than group 2 (P < 0.05). Histology revealed that group 3 presented milder damage in injured spinal cord than group 2. Microglial/macrophage proliferation was lower in group 3 than in group 2 (P < 0.05). CONCLUSION: 2PEF microscopy is useful for detecting early changes, indicating axonal disruption in compression SCI. MP therapy may help alleviate axonal progressive damage and reduce the proliferation of microglia/macrophages in acute SCI. LEVEL OF EVIDENCE: N/A. PMID- 24480948 TI - Factors predictive of increased surgical drain output after anterior cervical discectomy and fusion. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To identify factors that are independently associated with increased surgical drain output in patients who have undergone ACDF. SUMMARY OF BACKGROUND DATA: Surgical drains are typically placed after ACDF to reduce the risk of complications associated with neck hematoma. The orthopedic literature has repeatedly challenged the use of surgical drains after many procedures, and there are currently no guidelines for determining which patients are most likely to benefit from drain placement after ACDF. METHODS: Consecutive patients who underwent elective ACDF with surgical drain placement at a single academic institution between January 2011 and February 2013 were identified using billing records. Patient information was abstracted from the medical record. Patients were categorized on the basis of normal or increased total drain output, with increased drain output defined as total drain output 50th percentile (30 mL) or more. A multivariate logistic regression was used to determine which factors were independently associated with increased drain output. RESULTS: A total of 151 patients with ACDF met inclusion criteria. Total drain output was in the range from 0 mL to 265 mL. The average drain output for this cohort was 42.3 +/- 45.5 mL (mean +/- standard deviation). Among all patients in the study, 80 patients had increased drain output (drain output >=50th percentile or 30 mL).Multivariate analysis identified 3 independent predictors of increased drain output: age 50 years or more (odds ratio [OR] = 3.9), number of levels (2 levels, OR = 2.7; 3-4 levels, OR = 17.0), and history of smoking (OR = 2.8). One patient developed a postoperative neck hematoma while a drain was in place. CONCLUSION: Patients with the factors associated with increased drain output identified in the earlier text may benefit most from surgical drain placement after ACDF. Nonetheless, neck hematoma is still possible even with drain use. LEVEL OF EVIDENCE: 3. PMID- 24480949 TI - Morphological characteristics of cervical spine in patients with athetoid cerebral palsy and the accuracy of pedicle screw placement. AB - STUDY DESIGN: A retrospective study. OBJECTIVE: To investigate the morphology of the cervical spine in patients with athetoid cerebral palsy (CP), and to evaluate its relationship with the breach of cervical pedicle screws. SUMMARY OF BACKGROUND DATA: Cervical pedicle screws have been increasingly used in surgery for patients with CP, but screw misplacement is not uncommon. Although the altered morphology of the cervical spine in patients with CP may result in this high breach rate, few studies have examined the cervical pedicle profile. METHODS: We retrospectively analyzed 31 patients with cervical myelopathy with CP, as well as 30 patients with cervical spondylotic myelopathy (CSM), who underwent posterior decompression surgery. The pedicle outer diameter, inner diameter, transverse angle and lateral mass deformity were investigated by obtaining preoperative computed tomographic scans. The accuracy of the placement of 56 pedicle screws used in fusion surgery for 12 patients with CP was also analyzed using postoperative computed tomographic scans. RESULTS: The outer diameter of the pedicle in CP was in the range from 3.3 to 9.6 mm, and was larger than that in CSM at all cervical levels except for C7. Pedicle sclerosis was more frequently observed in CP than in CSM (23% vs. 7.3%, P < 0.001). The transverse angle at C3 and C4 was larger, and lateral mass deformity was more frequently observed in CP than in CSM. The critical breach of pedicle screws in CP was found in 29%. A multivariate analysis revealed that pedicle sclerosis was associated with an increased risk of breach (odds ratio: 6.3; 95% confidence interval: 1.03 39.0; P = 0.047). CONCLUSION: The pedicle diameter in patients with CP was relatively large, but pedicle sclerosis, a wide transverse angle and lateral mass deformity were frequently observed. Sclerotic pedicles were associated with a higher risk of critical breach. LEVEL OF EVIDENCE: N/A. PMID- 24480950 TI - Body mass index as a predictor of complications and mortality after lumbar spine surgery. AB - STUDY DESIGN: Retrospective analysis. OBJECTIVE: A national population-based database was analyzed to characterize the risks of postoperative complications and mortality associated with the patient's body mass index (BMI) after lumbar spinal surgery. SUMMARY OF BACKGROUND DATA: Obesity has been associated with greater perioperative complications and worsened surgical outcomes after lumbar spinal surgery. However, the stratified BMI risks of postoperative complications relative to normal weight patients have not been well characterized. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried to identify patients who underwent lumbar spinal surgery between 2006 and 2011. Patients were stratified into BMI cohorts: normal (18.5 24.99 kg/m), overweight (25.00-29.99 kg/m), class 1 (30.00-34.99 kg/m), class 2 (35.00-39.99 kg/m), and class 3 (>=40 kg/m) obesity. Preoperative patient characteristics and perioperative outcomes were assessed. The relative risks of 30-day postoperative complications and mortality for each BMI cohort were calculated in reference to the normal weight cohort using a 95% confidence interval. RESULTS: A total of 24,196 patients underwent lumbar spine surgery between 2006 and 2011 of which 19,195 (79.3%) were overweight or obese. The risk for deep vein thrombosis increased beginning with overweight patients and compounded for the subsequent obesity classes. The risk for superficial wound infection and pulmonary embolism increased beginning with the class 1 obesity cohort. Furthermore, the relative risk increase for urinary tract infection, acute renal failure, and sepsis was significantly increased only among class 3 obesity patients. Lastly, there was no relative risk increase in 30-day mortality in any cohort after lumbar spine surgery. CONCLUSION: Overweight and obese patients demonstrated an increased risk of postoperative complications relative to normal weight patients. Despite these findings, a BMI 25 kg/m or more was not associated with a greater risk of mortality. Further studies are warranted to characterize the impact of postoperative complications associated with overweight and obese patients on hospital resource utilization and costs after lumbar spine surgery. PMID- 24480951 TI - Evaluating the quality of subgroup analyses in randomized controlled trials of therapist-delivered interventions for nonspecific low back pain: a systematic review. AB - STUDY DESIGN: Systematic review. OBJECTIVE: To evaluate the quality, conduct, and reporting of subgroup analyses performed in randomized controlled trials of therapist-delivered interventions for nonspecific low back pain (NSLBP). SUMMARY OF BACKGROUND DATA: Randomized controlled trials of therapist-delivered interventions for NSLBP to date have, at best, shown small to moderate positive effects. Identifying subgroups is an important research priority. This review evaluates the quality, conduct, and reporting of subgroup analyses performed in the NSLBP literature. METHODS: Multiple electronic databases were searched for randomized controlled trials of therapist-delivered interventions for NSLBP. Of the identified articles, only articles reporting subgroup analyses (confirmatory or exploratory) were included in the final review. Methodological criteria were used to evaluate the quality of subgroup analyses. The quality of conduct and reporting was also evaluated. RESULTS: Thirty-nine articles were included in the final review. Of these, only 3 (8%) tested hypotheses about moderators (confirmatory findings), 18 (46%) generated hypotheses about moderators to inform future research (exploratory findings), and 18 (46%) provided insufficient findings. The appropriate statistical test for interaction was performed in 27 of the articles, of which 10 reported results from interaction tests, 4 incorrectly reported results within individual subgroups, and the remaining articles reported either P values or nothing at all. CONCLUSION: Subgroup analyses performed in NSLBP trials have been severely underpowered, are only able to provide exploratory or insufficient findings, and have rather poor quality of reporting. Using current approaches, few definitive trials of subgrouping in back pain are very likely to be performed. There is a need to develop new approaches to subgroup identification in back pain research. PMID- 24480952 TI - Multivariate analysis on risk factors for postoperative ileus after lateral lumbar interbody fusion. AB - STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To assess for independent risk factors of postoperative ileus (POI) after lateral lumbar interbody fusion (LLIF). SUMMARY OF BACKGROUND DATA: POI is frequently observed in anterior lumbar interbody fusion due to significant bowel manipulation during the approach. LLIF is a minimally invasive approach to the anterior column with reduced bowel manipulation and surgical time. However, there is a paucity of literature on POI after LLIF. METHODS: A retrospective review was performed of records of patients who underwent LLIF from January 2006 to December 2011 at a single institution. Patients with prolonged and recurrent POI were identified by review of hospital stay documentation by a fellowship-trained spine surgeon and a research fellow. POI patients were matched 1:1 to a control cohort without POI. Uni- and multivariate analyses were performed on demographic, comorbidity, surgical indication, medication, and perioperative details to identify independent risk factors for POI. RESULTS: Incidence of prolonged or recurrent POI after LLIF was 7.0% (42/596). Postoperative length of stay was significantly higher for patients with POI (9.9 +/- 4.3 d) than control patients (5.6 +/- 4.1 d) (P < 0.001). The incidence of ileus in the first 100 LLIF cases (11%) was not significantly higher than in the last 100 LLIF cases (6%) (P = 0.21). Independent risk factors were history of gastroesophageal reflux disease (P < 0.01, adjusted odds ratio [aOR]: 24.31), posterior instrumentation (P = 0.002, aOR: 19.48), and LLIF at L1-L2 (P = 0.04, aOR: 7.82). A history of prior abdominal surgery approached significance as an independent protective factor (P = 0.07, aOR: 0.29). CONCLUSION: There was a relatively high incidence of POI after LLIF. Independent risk factors for POI were a history of gastroesophageal reflux disease, posterior instrumentation, and LLIF at L1-L2. A history of prior abdominal surgery approached significance as an independent protective factor. LEVEL OF EVIDENCE: 3. PMID- 24480954 TI - Sentinel Events in Lumbar Spine Surgery. AB - STUDY DESIGN: Retrospective national database analysis. OBJECTIVE: A national population-based database was queried to investigate the incidence and perioperative outcomes associated with sentinel events in lumbar spine surgery. SUMMARY OF BACKGROUND DATA: Sentinel events in lumbar spine surgery can have significant medical, social, economic, and legal implications. The incidence and perioperative outcomes associated with these events have not been well characterized. METHODS: Data from the Nationwide Inpatient Sample was queried from 2002 to 2011. Patients who underwent lumbar spinal surgery were identified. Sentinel events including bowel or peritoneal injury, vascular injury, nerve injury, retention of foreign objects, and wrong-site surgery were identified. Patient demographics, comorbidities (Charlson Comorbidity Index), length of stay, total costs, and perioperative outcomes were assessed. The risk for mortality associated with each sentinel event was calculated using a 95% confidence interval. Statistical analysis was performed with SPSS version 20 and a P value of 0.001 or less denoted significance. RESULTS: A total of 543,146 lumbar spine surgical procedures were recorded from 2002 to 2011, of which 414 (0.8 per 1000 cases) incurred sentinel events. Wrong-site surgical procedures were the most common sentinel events with an incidence of 0.3 per 1000 cases. The incidences for bowel or peritoneal injury, vascular injury, nerve injury, and retention of foreign objects, were 0.06, 0.2, 0.2, and 0.1 per 1000 cases, respectively. There were no significant differences in the mean age (55.9 vs. 56.0, P = 0.911) or comorbidity burden (2.58 vs. 2.63, P = 0.553) between the 2 cohorts. The sentinel event cohort incurred a longer hospitalization, greater costs, and a greater incidence of in-hospital complications, and mortality. Patients with a bowel or peritoneal injury, vascular injury, and wrong-site surgery demonstrated a greater risk of mortality relative to unaffected patients. CONCLUSION: This Nationwide Inpatient Sample analysis demonstrates that sentinel events are associated with a significant increase in hospital resource utilization and worsened postoperative outcomes including death. This study demonstrates the financial and medical burden associated with sentinel events in lumbar spine surgery. LEVEL OF EVIDENCE: 4. PMID- 24480953 TI - Comparison of outcomes after posterior spinal fusion for adolescent idiopathic and neuromuscular scoliosis: does the surgical first assistant's level of training matter? AB - STUDY DESIGN: This was a retrospective review of posterior spinal fusion surgical procedures in patients diagnosed with adolescent idiopathic scoliosis (AIS) or neuromuscular scoliosis (NMS). OBJECTIVE: The purpose was to determine if the first assistant's training experience is associated with outcomes in AIS and NMS surgical procedures. SUMMARY OF BACKGROUND DATA: A previous study found that patients with AIS undergoing posterior spinal fusion with 2 attendings had similar operating times, blood loss, and complication rates compared with those with a resident or fellow first assistant. NMS cases are more complex than AIS cases, but to our knowledge, no previous studies have examined the impact of the first assistant's level of training on NMS outcomes. METHODS: This was a single center retrospective review of 200 patients, 120 with AIS and 80 with NMS, undergoing primary posterior spinal fusion. Minimum follow-up was 2 years. For each diagnosis group, cases assisted by junior orthopedic residents were compared with those assisted by orthopedic fellows. RESULTS: NMS cases were more complex and had higher complication rates than AIS cases (P < 0.05). AIS and NMS cases were similarly distributed among the fellow and junior resident groups (P = 0.63). AIS cases in the fellow and junior resident groups had similar operating times, estimated blood loss (EBL), complications, lengths of stay, and reoperation rates (P > 0.05). In NMS cases, the fellow group had shorter operating times (320 +/- 73 min vs. 367 +/- 104 min, P = 0.035) and greater percent correction at initial and 2-year follow-up (58 +/- 15% vs. 42 +/- 19%, P < 0.001). EBL, complications, lengths of stay, and reoperation rates were similar between the assistant groups in NMS cases (P > 0.05). CONCLUSION: NMS surgical procedures in which fellows serve as the first assistants were associated with shorter operating times and greater percent correction than surgical procedures with junior resident first assistants. LEVEL OF EVIDENCE: 3. PMID- 24480955 TI - Sentinel events in cervical spine surgery. AB - STUDY DESIGN: Retrospective cohort. OBJECTIVE: A national population-based database was queried to investigate the incidence of sentinel events in cervical spine surgery as well as the associated perioperative outcomes. SUMMARY OF BACKGROUND DATA: Sentinel events in cervical spine surgery are potentially catastrophic complications. The incidence and perioperative outcomes associated with sentinel events in cervical spine surgery have not been well characterized. METHODS: The Nationwide Inpatient Sample was queried from 2002 to 2011. Patients who underwent elective cervical spinal surgery were identified. Sentinel events including esophageal perforation, vascular injury, nerve injury, retention of foreign objects, and wrong-site surgery were identified. Patient demographics, comorbidities (Charlson Comorbidity Index), surgical procedures, length of stay, total hospital costs, and postoperative outcomes were assessed. The risk for in hospital mortality associated with each complication was calculated using a 95% confidence interval (CI). Statistical analysis was performed with SPSS version 20, and a P <= 0.001 denoted significance. RESULTS: A total of 251,318 cervical spine procedures were identified between 2002 and 2011, of which 123 patients (0.5 per 1000 cases) incurred sentinel events. Circumferential cervical fusion (anterior-posterior cervical fusion) demonstrated an increased risk of vascular injury (odds ratio [OR], 4.5; CI, 1.8-11.2), whereas cervical total disc replacement was associated with an increased risk of esophageal perforation (OR, 10.9; CI, 1.4-85.2) and nerve injury (OR, 36.4; CI, 1.5-892.3). Posterior cervical fusions were associated with an increased risk of wrong-site surgery (OR, 3.9; CI, 1.5-10.5). The sentinel event cohort incurred longer hospitalization, greater costs, mortality, and greater incidence of postoperative complications. CONCLUSION: This database analysis demonstrates that sentinel events are associated with a significant increase in hospital resource utilization and worsened perioperative outcomes. The type of cervical spine procedure and the number of fusion levels significantly impact the risk of sentinel events. Further research is warranted to understand the etiology of sentinel events in cervical spine surgery and to implement protocols to mitigate the associated risk factors. LEVEL OF EVIDENCE: 4. PMID- 24480956 TI - Efficacy of palonosetron versus ramosetron on preventing opioid-based analgesia related nausea and vomiting after lumbar spinal surgery: a prospective, randomized, and double-blind trial. AB - STUDY DESIGN: A prospective, randomized, and double-blind study. OBJECTIVE: To compare the efficacy of ramosetron and palonosetron on preventing postoperative nausea and vomiting (PONV) associated with opioid-based intravenous patient controlled analgesia (IV-PCAopioid) after lumbar spinal surgery. SUMMARY OF BACKGROUND DATA: IV-PCAopioid, an effective method to control pain after lumbar spinal surgery, accompanies PONV. Ramosetron and palonosetron are novel 5 hydroxytryptamine 3 antagonists known to have longer action duration and higher receptor affinity than their congeners, whereas their relative efficacy has not been validated yet. METHODS: One hundred ninety-six patients were randomly and evenly allocated to receive either 0.3 mg of ramosetron or 0.075 mg of palonosetron 10 minutes before the end of operation. Ramosetron or palonosetron were also added to the IV-PCAopioid, which was continuously infused for 48 hours postoperatively. The incidence and intensity of PONV were serially assessed for 72 hours postoperatively. Intensity of pain, volume of IV-PCAopioid consumption, use of rescue analgesics and antiemetics, and adverse events were also assessed. RESULTS: The overall incidence of PONV was lower in the ramosetron group than the palonosetron group (50% vs. 67%, P = 0.014) without any intergroup difference in the incidence of vomiting. Nausea intensity scores were also lower until 6 (P = 0.041) and 24 hour (P = 0.026) postoperatively in the ramosetron group than the palonosetron group. Pain intensity scores were significantly lower in the ramosetron group than the palonosetron group for 72 hours postoperatively. CONCLUSION: Ramosetron was superior to palonosetron in term of reducing the incidence and severity of nausea associated with IV-PCAopioid after lumbar spinal surgery. This favorable influence of ramosetron on PONV was translated to significant postoperative pain reduction compared with palonosetron. LEVEL OF EVIDENCE: 1. PMID- 24480957 TI - Utility of early postoperative radiographs after posterior spinal fusion for adolescent idiopathic scoliosis. AB - STUDY DESIGN: Retrospective. OBJECTIVE: Evaluate the ability of serial full length spine radiographs to detect clinically significant implant-related (IR) and non-implant-related (NIR) radiographical abnormalities in the first 6 months after routine posterior spinal fusion for adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Patients with AIS are exposed to repeated doses of ionizing radiation during the course of their treatment with potential consequences for their long-term health. Postoperative algorithms for AIS often involve frequent standing plain radiographs during the first 6 months after surgery to detect IR and NIR abnormalities that may impact a patient's clinical course. However, the actual clinical utility of such repeated spine radiographs has not been studied. METHODS: Retrospective chart and radiographical review was conducted at a single institution for patients with AIS after posterior spinal fusion between 2007 and 2012. Radiographical abnormalities identified on full length spine radiographs or additional imaging modalities in the first 6 postoperative months were grouped into IR or NIR findings. The findings were considered clinically significant if they resulted in a deviation from an anticipated postoperative course or additional interventions. RESULTS: For 129 patients, 761 full-length spine radiographs were obtained in the first 6 postoperative months. Eight patients (11 radiographs) had IR or NIR abnormalities, with only 2 of these considered clinically significant. Seven of the remaining 121 were identified to have IR or NIR abnormalities using other imaging modalities, with 2 considered clinically significant. The sensitivity and specificity of a full-length spine radiograph for detecting a clinically significant abnormality was 50% and 95%, respectively. CONCLUSION: Routine full length spine radiographs used with high frequency in the first 6 months after posterior spinal fusion rarely detected a radiographical abnormality that resulted in a meaningful change to a patient's clinical management. Blanket postoperative screening algorithms should be reconsidered to minimize patient radiation exposure. PMID- 24480958 TI - Patients with proximal junctional kyphosis requiring revision surgery have higher postoperative lumbar lordosis and larger sagittal balance corrections. AB - STUDY DESIGN: Case control study. OBJECTIVE: To evaluate risk factors in patients in 3 groups: those without proximal junctional kyphosis (PJK) (N), with PJK but not requiring revision (P), and then those with PJK requiring revision surgery (S). SUMMARY OF BACKGROUND DATA: It is becoming clear that some patients maintain stable PJK angles, whereas others progress and develop severe PJK necessitating revision surgery. METHODS: A total of 206 patients at a single institution from 2002 to 2007 with adult scoliosis with 2-year minimum follow-up (average 3.5 yr) were analyzed. Inclusion criteria were age more than 18 years and primary fusions greater than 5 levels from any thoracic upper instrumented vertebra to any lower instrumented vertebrae. Revisions were excluded. Radiographical assessment included Cobb measurements in the coronal/sagittal plane and measurements of the PJK angle at postoperative time points: 1 to 2 months, 2 years, and final follow up. PJK was defined as an angle greater than 10 degrees . RESULTS: The prevalence of PJK was 34%. The average age in N was 49.9 vs. 51.3 years in P and 60.1 years in S. Sex, body mass index, and smoking status were not significantly different between groups. Fusions extending to the pelvis were 74%, 85%, and 91% of the cases in groups N, P, and S. Instrumentation type was significantly different between groups N and S, with a higher number of upper instrumented vertebra hooks in group N. Radiographical parameters demonstrated a higher postoperative lumbar lordosis and a larger sagittal balance change, with surgery in those with PJK requiring revision surgery. Scoliosis Research Society postoperative pain scores were inferior in group N vs. P and S, and Oswestry Disability Index scores were similar between all groups. CONCLUSION: Patients with PJK requiring revision were older, had higher postoperative lumbar lordosis, and larger sagittal balance corrections than patients without PJK. Based on these data, it seems as though older patients with large corrections in their lumbar lordosis and sagittal balance were at risk for developing PJK, requiring revision surgery. LEVEL OF EVIDENCE: 3. PMID- 24480959 TI - Incidence, risk factors, and outcomes of postoperative airway management after cervical spine surgery. AB - STUDY DESIGN: Retrospective database analysis. OBJECTIVE: To identify the incidence and risk factors for a prolonged intubation or an unplanned reintubation after cervical spine surgery (CSS). SUMMARY OF BACKGROUND DATA: Patients who undergo CSS occasionally require prolonged mechanical ventilation or an unplanned reintubation for airway support. Despite the potential severity of these complications, there are limited data in the published literature addressing this issue. METHODS: The American College of Surgeons National Surgical Quality Improvement Program database was queried to identify patients who underwent a CSS. Patients who required a prolonged intubation more than 48 hours or an unplanned reintubation after CSS were compared with those without airway compromise. Preoperative patient characteristics, intraoperative variables, hospital length of stay, 30-day complication rates, and mortality were compared between the cohorts. An alpha <= 0.001 denoted statistical significance. A multivariate regression model was used to identify independent predictors for a prolonged intubation and an unplanned reintubation. RESULTS: A total of 8648 cervical spine procedures were identified from 2006 to 2011 of which 54 patients (0.62%) required prolonged ventilation and 56 patients (0.64%) underwent a postoperative reintubation. Patients who required postoperative airway management were older and demonstrated a greater comorbidity burden (P < 0.001). In addition, the affected cohorts demonstrated a significantly greater rate of readmissions, reoperations, postoperative complications, and mortality (P < 0.001). Regression analysis identified the independent predictors for prolonged ventilation to include a history of cardiac disease and dialysis along with a low preoperative albumin level (P < 0.05). Similarly, the independent risk factors for a postoperative reintubation included a history of recent weight loss more than 10%, recent operation within 30 days, low preoperative hematocrit, and a high serum creatinine (P < 0.05). CONCLUSION: Postoperative airway management is a rare complication after CSS. A prolonged intubation and an unplanned reintubation carry a greater rate of postoperative complications and mortality. High-risk patients should be identified prior to surgery to mitigate the risk factors for postoperative airway compromise. LEVEL OF EVIDENCE: 3. PMID- 24480960 TI - The influence of distraction force on the intradiscal pressure gradient in the bridged lumbar spine: a biomechanical investigation using a calf model. AB - STUDY DESIGN: A biomechanical calf cadaver study. OBJECTIVE: The purpose of this study was to determine the intradiscal pressure gradient of bridged healthy intervertebral segments in correlation with intraoperative distraction force. SUMMARY OF BACKGROUND DATA: Bisegmental dorsal stabilization and anatomic reduction is a common treatment option for incomplete burst fractures of the lumbar spine. However, it remains unknown to what extent bridging and intraoperative distraction compromises an intact intervertebral disc. METHODS: The L2-L3 intervertebral disc level was evaluated in 6 freshly frozen calf cadaver spines. Pressure measurements were obtained with the spine uninstrumented, after dorsal segmental instrumentation from L1 to L3, and after distraction with 400 N and 800 N. Pressure gradient measurements were accomplished with a balloon pressure sensor placed within the nucleus pulposus of the L2-L3 intervertebral disc. Pressure data were recorded by computer data acquisition. Flexion, extension, and lateral bending moments were applied continuously by a testing machine up to a load moment of 7.5 N.m. The pressure gradients were compared with respect to the effects of added instrumentation and distraction. RESULTS: After segmental bridging the mean pressure gradients were significantly reduced in all movement directions (P < 0.001). However, after dorsal stabilization a continuously rising intervertebral disc pressure was recordable. In contrast, no relevant additional reduction of the intradiscal pressure gradient was detectable after applying distraction forces of 400 N or 800 N. CONCLUSION: In a calf model, a distraction force of up to 800 N leads to no additional reduction of the pressure gradient of bridged healthy lumbar segments under flexion and extension moments. PMID- 24480961 TI - Factors affecting the postoperative progression of thoracic kyphosis in surgically treated adult patients with lumbar degenerative scoliosis. AB - STUDY DESIGN: A retrospective case series of patients treated surgically for degenerative lumbar scoliosis (DLS). OBJECTIVE: To determine incidence and risk factors of progressive global thoracic kyphosis (pGTK) after surgery for DLS. SUMMARY OF BACKGROUND DATA: Sagittal balance affects the surgical treatment of spinal deformity in adults. Little is known about the loss of sagittal balance due to pGTK, or about the risk factors for pGTK, after surgery for DLS. METHODS: We reviewed records from a multicenter database of adults with DLS, treated with posterior spinal fusion. Inclusion required an age of 50 years or more at the time of surgery, an upper instrumented vertebra at T9 and below, more than 5 fused segments, and at least 2 years of follow-up. We included 73 patients with a mean age of 68.3 years (range, 51-77 yr) and a mean follow-up period of 3.6 years (range, 2-11 yr). Independent risk factors for pGTK were identified by logistic regression analysis. RESULTS: Significant pGTK, defined as an increase in thoracic kyphosis of more than 10 degrees from before surgery to the time of final follow-up, was observed in 41% of the patients. Loss of the sagittal vertical axis was larger in patients with pGTK than without (4.7 vs. 1.5 cm; P = 0.02). Risk analysis showed larger lumbar lordosis correction in patients with pGTK. Multivariate logistic regression analysis identified an age greater than 75 (odds ratio, 5.53; P = 0.02, 95% confidence interval [1.4-22.4]) and sacropelvic fusion (odds ratio = 2.66, P = 0.02, 95% confidence interval [1.5-11.1]) as independent risk factors for pGTK. CONCLUSION: The pGTK incidence after surgery for DLS was 41%. Age, sacropelvic fusion, and a larger sagittal correction were identified as pGTK risk factors. Long-term follow-up will provide more data on the clinical impact of pGTK in elderly patients. LEVEL OF EVIDENCE: 3. PMID- 24480962 TI - Opioids compared with placebo or other treatments for chronic low back pain: an update of the Cochrane Review. AB - STUDY DESIGN: Systematic review and meta-analysis. OBJECTIVE: To assess the efficacy of opioids in adults with chronic low back pain (CLBP). SUMMARY OF BACKGROUND DATA: Opioids for CLBP has increased dramatically. However, the benefits and risks remain unclear. METHODS: We updated a 2007 Cochrane Review through October 2012 of randomized controlled trials from multiple databases. Use of noninjectable opioids in CLBP for at least 4 weeks was compared with placebo or other treatments; comparisons with different opioids were excluded. Outcomes included pain and function using standardized mean difference (SMD) or risk ratios with 95% confidence intervals (CIs), and absolute risk difference with 95% CI for adverse effects. Study quality was evaluated using Grading of Recommendations Assessment, Development, and Evaluation criteria. RESULTS: Fifteen trials (5540 participants), including twelve new, met the criteria. Tramadol was better than placebo for pain (SMD, -0.55; 95% CI, -0.66 to -0.44) and function (SMD, -0.18; 95% CI, -0.29 to -0.07). Compared with placebo, transdermal buprenorphine decreased pain (SMD, -2.47; 95% CI, -2.69 to -2.25), but not function (SMD, -0.14; 95% CI, -0.53 to 0.25). Strong opioids (morphine, hydromorphone, oxycodone, oxymorphone, and tapentadol), were better than placebo for pain (SMD, -0.43; 95% CI, -0.52 to -0.33) and function (SMD, -0.26; 95% CI, 0.37 to -0.15). One trial demonstrated little difference with tramadol compared with celecoxib for pain relief. Two trials (272 participants) found no difference between opioids and antidepressants for pain or function. Reviewed trials had low to moderate quality, high drop-out rates, short duration, and limited interpretability of functional improvement. No serious adverse effects, risks (addiction or overdose), or complications (sleep apnea, opioid-induced hyperalgesia, hypogonadism) were reported. CONCLUSION: There is evidence of short term efficacy (moderate for pain and small for function) of opioids to treat CLBP compared with placebo. The effectiveness and safety of long-term opioid therapy for treatment of CLBP remains unproven. PMID- 24480963 TI - Incidence and clinical significance of vascular encroachment resulting from freehand placement of pedicle screws in the thoracic and lumbar spine: analysis of 6816 consecutive screws. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: Evaluate the incidence and clinical significance of vascular encroachment resulting from freehand placement of pedicle screws in the thoracic and lumbosacral spine. SUMMARY OF BACKGROUND DATA: Pedicle screws are routinely used to effectively stabilize all 3 columns of the spine but can be technically demanding to place in the setting of variable anatomy. There is a paucity of data regarding iatrogenic major vascular injuries during posterior instrumentation procedures. METHODS: We retrospectively reviewed the records of all patients undergoing freehand pedicle screw placement without image guidance in the thoracic or lumbar spine during a 7-year period. The incidence and extent of vascular encroachment by a pedicle screw was determined by review of routine postoperative computed tomographic scans obtained within 24 hours of all surgical procedures. Vascular encroachment was defined as a pedicle screw that was touching or deforming the wall of a major vessel. RESULTS: A total of 964 patients received 6816 freehand-placed pedicle screws in the thoracolumbar spine. Fifteen (0.22%) screws that encroached a major vascular structure were identified. Ten (0.29%) thoracic pedicle screws encroached on the aorta, 4 (0.14%) lumbar screws on the common iliac vein, and 1 S1 screw (0.19%) on the internal iliac vein. In consultation with vascular surgery, it was determined whether revision surgery and the technique/approach for the revision procedure should be recommended. Two (0.21%) patients required revision surgery to remove the encroaching pedicle screw (T5 and T8) due to concern for vascular injury. Both patients were asymptomatic and recovered without further complications after revision surgery. CONCLUSION: Vascular encroachment of major vessels occurs rarely in the setting of freehand pedicle screw placement in the thoracolumbar spine. Although rare, delayed vascular injury from errant pedicle screw placement has been reported in the literature. The aorta seems to be the vessel at the highest risk of injury. Routine intraoperative or postoperative computed tomographic scanning allows for early identification of pedicle screws encroaching on vascular structures thereby facilitating early revision surgery. LEVEL OF EVIDENCE: 4. PMID- 24480964 TI - Biomechanical risk factors for proximal junctional kyphosis: a detailed numerical analysis of surgical instrumentation variables. AB - STUDY DESIGN: Biomechanical analysis of proximal junctional kyphosis (PJK) through computer simulations and sensitivity analysis. OBJECTIVE: To gain biomechanical knowledge on the risk of PJK and find surgical solutions to reduce the risks. SUMMARY OF BACKGROUND DATA: PJK is a pathological kyphotic deformity adjacent to the instrumentation. Clinical studies have documented its risk factors, but still little is known on how it is correlated with various individual instrumentation variables. METHODS: Biomechanical spine models of 6 patients with adult scoliosis were developed, validated, and then used to perform 576 simulations, varying the proximal dissection procedure, the implant type at the upper instrumented vertebra, the sagittal rod curvature, and the proximal diameter of the proximal transition rods. Four biomechanical indices--the proximal junctional kyphotic angle, thoracic kyphosis, proximal flexion force, and proximal flexion moment--were assessed. RESULTS: The bilateral complete facetectomy, the posterior ligaments resection, and the combination of both increased the proximal junctional kyphotic angle (respectively, by 10%, 28% and 53%) and the proximal flexion force (4%, 12%, and 22%) and moment (16%, 44%, and 83%). Compared with pedicle screws at upper instrumented vertebra, proximal transverse process hooks reduced the 3 biomechanical indices by approximately 26%. The use of proximal transition rods with reduced proximal diameter from 5.5 mm to 4 mm decreased the proximal junctional kyphotic angle (by 6%) and the proximal flexion force (4%) and moment (8%). The increase of the sagittal rod curvature from 10 degrees to 20 degrees , 30 degrees , and 40 degrees increased the proximal junctional kyphotic angle (by 6%, 13%, and 19%) and the proximal flexion force (3%, 7%, and 10%) and moment (9%, 18%, and 27%). CONCLUSION: Preserving more posterior proximal intervertebral elements, the use of transition rods and transverse process hooks at upper instrumented vertebra, and reducing the global sagittal rod curvature each decreased the 4 biomechanical indices that may be involved in PJK. LEVEL OF EVIDENCE: N/A. PMID- 24480965 TI - Upregulation of NaV1.7 in dorsal root ganglia after intervertebral disc injury in rats. AB - STUDY DESIGN: Animal study. OBJECTIVE: To investigate pain-related expression of NaV1.7 in dorsal root ganglia (DRG) innervating intervertebral discs. SUMMARY OF BACKGROUND DATA: The pathophysiology of discogenic low back pain is not fully understood. Prostaglandins and cytokines produced by degenerated discs can cause pain, but nonsteroidal anti-inflammatory and steroid medications are often ineffective at pain reduction. Tetrodotoxin-sensitive, voltage-gated sodium (NaV) channels are associated with sensory transmission in primary sensory nerves, and the NaV1.7 channel has emerged as an attractive analgesic target. The purpose of this study was to investigate pain-related expression of NaV1.7 in DRG innervating intervertebral discs. METHODS: Using a rodent model of disc puncture, we labeled DRG neurons innervating L5-L6 discs with FluoroGold neurotracer (n = 20). Half of the rats (n = 10) underwent intervertebral disc puncture using a 23 gauge needle (puncture group), and the other half underwent non-puncture sham surgery (non-puncture group). Seven and 14 days after surgery, DRGs from the L1 to L6 levels were harvested, sectioned, and immunostained for NaV1.7, and the proportion of NaV1.7-immunoreactive DRG neurons was evaluated. RESULTS: NaV1.7 was expressed in DRG neurons innervating intervertebral discs from L1 to L5. The ratio of NaV1.7-expressing DRG neurons to total FG-labeled neurons was 7.2% and 7.6% at 1 and 2 weeks after surgery, respectively, in the non-puncture group and 16.2% and 16.3% at 1 and 2 weeks, respectively, in the puncture group. The upregulation of NaV1.7 after puncture was significant at both 1 and 2 weeks after surgery (P < 0.01). CONCLUSION: We found that disc injury increases NaV1.7 expression in DRG neurons innervating injured discs. NaV1.7 may be a therapeutic target for pain control in patients with lumbar disc degeneration. PMID- 24480966 TI - Intraoperative vancomycin use in spinal surgery: single institution experience and microbial trends. AB - STUDY DESIGN: Retrospective case series. OBJECTIVE: To demonstrate the microbial trends of spinal surgical site infections in patients who had previously received crystallized vancomycin in the operative bed. SUMMARY OF BACKGROUND DATA: Prior large, case control series demonstrate the significant decrease in surgical site infection with the administration of vancomycin in the wound bed. METHODS: A single institution, electronic database search was conducted for all patients who underwent spinal surgery who had received prophylactic crystalline vancomycin powder in the wound bed. Patients with a prior history of wound infection, intrathecal pumps, or spinal stimulators were excluded. RESULTS: A total of 981 consecutive patients (494 males, 487 females; mean age, 59.4 yr; range, 16-95 yr) were identified from January 2011 to June 2013. The average dose of vancomycin powder was 1.13 g (range, 1-6 g). Sixty-six patients (6.71%) were diagnosed with a surgical site infection, of which 51 patients had positive wound cultures (5.2%). Of the 51 positive cultures, the most common organism was Staphylococcus aureus. The average dose of vancomycin was 1.3 g in the 38 cases where a gram positive organism was cultured. A number of gram-negative infections were encountered such as Serratia marcescens, Enterobacter aerogenes, Bacteroides fragilis, Enterobacter cloacae, Citrobacter koseri, and Pseudomonas aeruginosa. The average dose of vancomycin was 1.2 g in 23 cases where a gram-negative infection was cultured. Fifteen of the 51 positive cultures (29.4%) were polymicrobial. Eight (53%) of these 15 polymicrobial cultures contained 3 or more distinct organisms. CONCLUSION: Prophylactic intraoperative vancomycin use in the wound bed in spinal surgery may increase the incidence of gram-negative or polymicrobial spinal infections. The use of intraoperative vancomycin may correlate with postoperative seromas, due to the high incidence of nonpositive cultures. Large, randomized, prospective trials are needed to demonstrate causation and dose-response relationship. PMID- 24480967 TI - Using stem and progenitor cells to recapitulate kidney development and restore renal function. AB - PURPOSE OF REVIEW: There is considerable interest in the idea of generating stem and precursor cells that can differentiate into kidney cells and be used to treat kidney diseases. Within this field, we highlight recent research articles focussing on mesenchymal stem cells (MSCs), embryonic stem cells (ESCs), induced pluripotent stem cells (iPSCs) and kidney-derived stem/progenitor cells (KSPCs). RECENT FINDINGS: In preclinical studies, MSCs ameliorate varied acute and chronic kidney diseases. Their efficacy depends on immunomodulatory and paracrine properties but MSCs do not differentiate into functional kidney epithelia. iPSCs can be derived from healthy individuals and from kidney patients by forced expression of precursor genes. Like ESCs, iPSCs are pluripotent and so theoretically they have the potential to form functional kidney epithelia when used therapeutically. KSPCs, existing as cell subsets within adult and developing kidneys, constitute attractive future therapeutic agents. SUMMARY: Results from preclinical studies are encouraging but caution is required regarding potential human therapeutic applications because molecular, morphological and functional characterization of 'kidney cells' generated from ECSs, iPSCs, KSPCs have not been exhaustive. The long-term safety of renal stem and precursor cells needs more study, including potential negative effects on renal growth and their potential for tumor formation. PMID- 24480968 TI - Ectopic transplantation sites for cell-based therapy. AB - PURPOSE OF REVIEW: This review outlines the concept of cell-based therapy to restore tissue function, and addresses four key points to consider in cell transplantation: source, surveillance, safety, and site. Whereas each point is essential, additional attention should be given to transplantation sites if cell therapy is going to be successful in the clinic. Various ectopic locations are discussed, and the strengths and weaknesses of each are compared as suitable candidates for cell therapy. RECENT FINDINGS: Studies in rodents often demonstrate cell transplantation and engraftment in ectopic sites, with little evidence to suggest why it may also work in humans. For example, transplantation to the subcapsular space of the kidney is often performed in rodents, but has not been a good predictor of clinical success. Recent work has shown that the lymph node may be a good site for transplantation of multiple tissue types, and several reasons are highlighted as to why it should be considered for future studies. SUMMARY: The use of cell-based therapy in the clinic has been hampered by the lack of appropriate sites for transplantation. The lymph node is a promising alternative for cell transplantation, and offers hope for clinical application. PMID- 24480970 TI - Interleukin 28B gene polymorphisms and Epstein-Barr virus-associated lymphoproliferative diseases. AB - OBJECTIVES: Single-nucleotide polymorphisms (SNPs) near the interleukin (IL) 28B gene encoding a type III interferon (IFN-lambda) are the most important genetic predictors of treatment response to hepatitis C virus (HCV). This retrospective study was undertaken to determine any association between IL28B SNPs and the development of viraemia in Epstein-Barr virus (EBV)-driven acute infectious mononucleosis (IM) and post-transplant lymphoproliferative disease (PTLD). METHODS: Genomic DNA extracted from plasma from 45 EBV seropositive controls and 46 acute IM, 23 non-PTLD (transplant) and 21 PTLD patients was tested by PCR for 2 SNPs within IL28B. EBV DNA levels were tested in IM and PTLD samples by a real time quantitative PCR. RESULTS: No significant differences were seen in SNP frequencies at rs12979860 and rs8099917 in IM and PTLD patients compared to EBV seropositive controls and transplant patients. EBV DNA levels were lower in IM and PTLD patients with CC (a favourable genotype in HCV) at rs12979860 compared to non-CC genotypes (p = 0.055). Acute IM patients with CC had significantly lower levels of EBV DNA in plasma compared to those with non-CC genotypes (p = 0.011). CONCLUSIONS: Genotype CC may influence anti-viral responses of IFN lambda, thereby allowing better control of EBV viraemia during lymphoproliferation, particularly in IM. PMID- 24480969 TI - Decellularized scaffolds as a platform for bioengineered organs. AB - PURPOSE OF REVIEW: Patients suffering from end-stage organ failure requiring organ transplantation face donor organ shortage and adverse effect of chronic immunosuppression. Recent progress in the field of organ bioengineering based on decellularized organ scaffolds and patient-derived cells holds great promise to address these issues. RECENT FINDINGS: Perfusion-decellularization is the most consistent method to obtain decellularized whole-organ scaffolds to serve as a platform for organ bioengineering. Important advances have occurred in organ bioengineering using decellularized scaffolds in small animal models. However, the function exhibited by bioengineered organs has been rudimentary. Pluripotent stem cells seem to hold promise as the ideal regenerative cells to be used with this approach but the techniques to effectively and reliably manipulate their fate are still to be discovered. Finally, this technology needs to be scaled up to human size to be of clinical relevance. SUMMARY: The search for alternatives to allogeneic organ transplantation continues. Important milestones have been achieved in organ bioengineering with the use of decellularized scaffolds. However, many challenges remain on the way to producing an autologous, fully functional organ that can be transplanted similar to a donor organ. PMID- 24480971 TI - The gene polymorphism of LOX1 predicts the incidence of LVH in patients with essential hypertension. AB - BACKGROUND: Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been shown to play an important role in cardiac remodeling under different pathologic conditions. The role of genetic polymorphisms in the LOX1 gene, however, remains unclear in the development of left ventricular hypertrophy (LVH) for patients with hypertension. METHODS: A total of 536 patients diagnosed with essential hypertension (EH) were recruited in this study. Patients were assigned to the LVH+ (n=143) and LVH- (n=393) groups, respectively. The serum LOX1 level was measured and three single nucleotide polymorphisms (SNPs), i.e. intron 4 (G >A), intron 5(T->G), and 3' UTR (T->C) of the LOX1 gene were genotyped. RESULTS: The genotype frequencies of intron 4 G>A and 3'UTR T>C were not significantly different between the LVH+ and LVH- groups (both P>0.05), however, frequencies of 501G>C were significantly different between those two groups (P=0.007). The 501CC genotype carriers had a markedly higher serum LOX1 level and an increased risk to develop LVH (adjusted OR=2.444, adjusted P=0.002). There was a positive correlation between serum LOX1 level and left ventricular mass index (r=0.907, P<0.001); a cutoff value of 1.0 ng/mL for sLOX-1 was applied to significantly differentiate the LVH+ patients from the LVH- patients with 84% sensitivity and 86% specificity. CONCLUSION: Our data suggest that both the 501>C SNP in the LOX1 gene and the serum LOX1 level may be used to predict the development of LVH among EH patients. PMID- 24480972 TI - Validation of nomograms predicting lymph node involvement in patients with prostate cancer undergoing extended pelvic lymph node dissection. AB - Our aim was to validate Briganti's nomograms predicting the probability of lymph node involvement (LNI) in prostate cancer (PCa). Clinicopathological data of 256 PCa patients who underwent extended pelvic lymph node dissection (ePLND) and radical prostatectomy (RP) were obtained from two Bulgarian institutions. Predicted probabilities of LNI were assessed using Briganti's nomograms based on ePLND. In addition to the established basic LNI predictors, Briganti's nomograms included the number of lymph nodes removed (version 2006) and the number and percentage of positive biopsy cores (versions 2007 and 2012). The accuracy of these nomograms was compared with the updated Memorial Sloan-Kettering Cancer Center (MSKCC) nomogram (version 2011). Receiver-operating characteristics analysis was done to assess the discriminative ability of each of the nomograms applied. All of Briganti's nomograms showed a higher predictive accuracy as compared with the updated MSKCC nomogram. The respective AUC values were calculated as 0.847, 0.837, 0.858 and 0.875 for the four Briganti nomograms, and 0.770 for the updated MSKCC nomogram, respectively. Despite the potential for heterogeneity in patient selection and management, all predictions demonstrated high concordance with actual observations. Compared with other similar prognostic tools the updated Briganti nomogram (version 2012) showed the highest predictive accuracy and should therefore be preferred. PMID- 24480973 TI - Single-cell genetic analysis reveals the composition of initiating clones and phylogenetic patterns of branching and parallel evolution in myeloma. AB - Although intratumor heterogeneity has been inferred in multiple myeloma (MM), little is known about its subclonal phylogeny. To describe such phylogenetic trees in a series of patients with MM, we perform whole-exome sequencing and single-cell genetic analysis. Our results demonstrate that at presentation myeloma is composed of two to six different major clones, which are related by linear and branching phylogenies. Remarkably, the earliest myeloma-initiating clones, some of which only had the initiating t(11;14), were still present at low frequencies at the time of diagnosis. For the first time in myeloma, we demonstrate parallel evolution whereby two independent clones activate the RAS/MAPK pathway through RAS mutations and give rise subsequently to distinct subclonal lineages. We also report the co-occurrence of RAS and interferon regulatory factor 4 (IRF4) p.K123R mutations in 4% of myeloma patients. Lastly, we describe the fluctuations of myeloma subclonal architecture in a patient analyzed at presentation and relapse and in NOD/SCID-IL2Rgamma(null) xenografts, revealing clonal extinction and the emergence of new clones that acquire additional mutations. This study confirms that myeloma subclones exhibit different survival properties during treatment or mouse engraftment. We conclude that clonal diversity combined with varying selective pressures is the essential foundation for tumor progression and treatment resistance in myeloma. PMID- 24480974 TI - Pulmonary medication adherence and health-care use in cystic fibrosis. AB - BACKGROUND: Poor treatment adherence is common in cystic fibrosis (CF) and may lead to worse health outcomes and greater health-care use. This study evaluated associations of adherence to pulmonary medications, age, health-care use, and cost among patients with CF. METHODS: Patients with CF aged >= 6 years were identified in a national commercial claims database. A 12-month medication possession ratio (MPR) was computed for each pulmonary medication and then averaged for a composite MPR (CMPR) for each patient. The CMPR was categorized as low (< 0.50), moderate (0.50-0.80), or high (>= 0.80). Annual health-care use and costs were measured during the first and second year and compared across adherence categories by multivariable modeling. RESULTS: Mean CMPR for the sample (N = 3,287) was 48% +/- 31%. Age was inversely related to CMPR. In the concurrent year, more CF-related hospitalizations were observed among patients with low (event rate ratio [ERR], 1.35; 95% CI, 1.15-1.57) and moderate (ERR, 1.25; 95% CI, 1.05-1.48) vs high adherence; similar associations were observed for all cause hospitalizations and CF-related and all-cause acute care use (hospitalizations + ED) in the concurrent and subsequent year. Rates of CF related and all-cause outpatient visits did not differ by adherence. Low and moderate adherence predicted higher concurrent health-care costs by $14,211 ($5,557-$24,371) and $8,493 (-$1,691 to $19,709), respectively, compared with high adherence. CONCLUSIONS: Worse adherence to pulmonary medications was associated with higher acute health-care use in a national, privately insured cohort of patients with CF. Addressing adherence may reduce avoidable health-care use. PMID- 24480975 TI - Erosion protection by calcium lactate/sodium fluoride rinses under different salivary flows in vitro. AB - This study investigated the effect of a calcium lactate prerinse on sodium fluoride protection in an in vitro erosion-remineralization model simulating two different salivary flow rates. Enamel and dentin specimens were randomly assigned to 6 groups (n = 8), according to the combination between rinse treatments - deionized water (DIW), 12 mM NaF (NaF) or 150 mM calcium lactate followed by NaF (CaL + NaF) - and unstimulated salivary flow rates - 0.5 or 0.05 ml/min - simulating normal and low salivary flow rates, respectively. The specimens were placed into custom-made devices, creating a sealed chamber on the specimen surface connected to a peristaltic pump. Citric acid was injected into the chamber for 2 min, followed by artificial saliva (0.5 or 0.05 ml/min) for 60 min. This cycle was repeated 4*/day for 3 days. Rinse treatments were performed daily 30 min after the 1st and 4th erosive challenges, for 1 min each time. Surface loss was determined by optical profilometry. KOH-soluble fluoride and structurally bound fluoride were determined in specimens at the end of the experiment. Data were analyzed by 2-way ANOVA and Tukey tests (alpha = 0.05). NaF and CaL + NaF exhibited significantly lower enamel and dentin loss than DIW, with no difference between them for normal flow conditions. The low salivary flow rate increased enamel and dentin loss, except for CaL + NaF, which presented overall higher KOH-soluble and structurally bound fluoride levels. The results suggest that the NaF rinse was able to reduce erosion progression. Although the CaL prerinse considerably increased F availability, it enhanced NaF protection against dentin erosion only under hyposalivatory conditions. PMID- 24480976 TI - Fetal growth restriction at the limits of viability. AB - The outcome of early small-for-gestational age and/or intrauterine growth restricted fetuses is reviewed. In these fetuses the outcome appears to be considerably poorer than that of appropriately grown fetuses and this seems mainly to be caused by intrauterine malnutrition rather than by hypoxemia. Active management of intrauterine growth restriction at the limits of viability may not be commenced before 26 weeks of gestation. PMID- 24480977 TI - Alkane activation on crystalline metal oxide surfaces. AB - Advances in the fundamental understanding of alkane activation on oxide surfaces are essential for developing new catalysts that efficiently and selectively promote chemical transformations of alkanes. In this tutorial review, we discuss the current understanding of alkane activation on crystalline metal oxide surfaces, and focus mainly on summarizing our findings on alkane adsorption and C H bond cleavage on the PdO(101) surface as determined from model ultrahigh vacuum experiments and theoretical calculations. These studies show that alkanes form strongly-bound sigma-complexes on PdO(101) by datively bonding with coordinatively-unsaturated Pd atoms and that these molecularly adsorbed species serve as precursors for C-H bond activation on the oxide surface. In addition to discussing the binding and properties of alkane sigma-complexes on PdO(101), we also summarize recent advances in kinetic models to predict alkane dissociation rates on solid surfaces. Lastly, we highlight computations which predict that the formation and facile C-H bond activation of alkane sigma-complexes also occurs on RuO2 and IrO2 surfaces. PMID- 24480978 TI - Painful orgasm in an adolescent after seminal-sparing cystoprostatectomy: a puzzling symptom. AB - An 18-year-old boy, followed up after seminal-sparing cystectomy for bladder rhabdomyosarcoma, presented complaining of recurrent episodes of left scrotal/inguinal pain arising after orgasms. Full work-up ruled out disease recurrence, but showed enlarged seminal vesicles. Ligation of the vas deferens was unsuccessful. The patient was started on alpha-blockers to reduce vas contractions with improvement of symptoms. The possible pathophysiology and treatments of this symptom are discussed. PMID- 24480979 TI - A primate model of the effects of childhood antidepressant treatment. PMID- 24480980 TI - Overexpression of miR-126 inhibits the activation and migration of HSCs through targeting CRK. AB - BACKGROUND & AIMS: MicroRNAs (miRNAs) have been shown to play essential roles in HSCs activation which contributes to hepatic fibrosis. Our previous miRNA microarray results suggested that miR-126 might be decreased during HSCs activation as other studies. The aim of this study is to investigate the role of miR-126 during HSCs activation. METHODS: In this study, the expression of miR-126 during HSCs activation was measured and confirmed by qRT-PCR. Then, miR-126 expression was restored by transfection of lentivirus vector encoding miR-126. Futhermore, cell proliferation was assayed by the cell counting kit-8 (CCK-8), cell migration was assayed by transwell assay, and the markers of activation of HSCs, alpha-SMA and collagen type I, were assayed by qRT-PCR, Western Blotting, Immunostaining and ELISA. Luciferase reporter assay was used to find the target of miR-126, and Western Blotting and Immunostaining was used to validate the target of miR-126. Then, the expression and the role of the target of miR-126 during HSCs activation was further assessed. RESULTS: The expression of miR-126 was confirmed to be significantly decreased during HSCs activation. Overexpression of miR-126 significantly inhibited HSCs migration but did not affect HSCs proliferation. The expression of alpha-SMA and collagen type I were both obviously decreased by miR-126 restoration. CRK was found to be the target of miR-126 and overexpression of miR-126 significantly inhibited CRK expression. And it was found that overexpression of CRK also significantly decreased miR-126 expression and promoted HSCs activation. CONCLUSIONS: Our study showed that overexpression of miR-126 significantly inhibited the activation and migration of HSCs through targeting CRK which can also decrease miR-126 expression and promote HSCs activation. PMID- 24480981 TI - Rh-catalyzed oxidative C-C bond formation and C-N bond cleavage: direct access to C2-olefinated free (NH)-indoles and pyrroles. AB - The rhodium-catalyzed oxidative C2-olefination of indoles and pyrroles containing N-arylcarboxamide directing groups with a range of alkenes and subsequent cleavage of directing groups is described. This method provides direct and efficient access to C2-functionalized free (NH)-heterocycles. PMID- 24480982 TI - Emerging microfluidic devices for cell lysis: a review. AB - Intracellular components containing information about genetic and disease characteristics are key substances to clinical diagnostics. Cell lysis is therefore a crucial step for efficient extraction and the subsequent analysis of intracellular components. With the advent of advanced manufacturing techniques, a number of micro systems have been proposed and applied for manipulating cells on chips. In this paper, we review emerging microfluidic devices for cell lysis. Different lysis mechanisms and related techniques are compared. The technical details, advantages, and limitations of various microfluidic devices are discussed. PMID- 24480983 TI - Children with chronic nonspecific isolated cough. AB - BACKGROUND: This study observed children with chronic nonspecific isolated cough (NIC) to investigate clinical differences between children whose symptoms resolved spontaneously and those who eventually developed asthma and then explored the differences among the children who eventually developed asthma in terms of their time of response to a trial of inhaled corticosteroid (ICS). METHODS: Children with chronic NIC were managed either with a wait-and-review approach or with a 2-week trial with 400 MUg/d inhaled budesonide according to the preference of their parents. Responses were monitored with a validated cough score. Treatment was prolonged to 8 weeks in the case of partial responders. All children were followed up at 3-month intervals. RESULTS: A total of 109 children (median [interquartile range] age, 5 [3.5-9] years; cough duration, [8-16] weeks]) were followed for a mean (+/- SD) time of 21(+/- 5) months. Cough did not recur in 71% (spontaneous resolution) but relapsed in 28% of the children who later responded to ICS treatment again (asthma). Aeroallergen sensitization (relative risk, 2.86; 95% CI, 1.17-6.99) and previous history of chronic cough (relative risk, 2.68; 95% CI, 1.10-6.49) increased the risk of asthma. Cough duration, the cough score, the family history of asthma, and serum eosinophilia were not found discriminative for the final diagnosis. There were no differences among children who eventually developed asthma and responded to either the 2-week or 8-week trial in terms of the study parameters. CONCLUSIONS: Chronic NIC does not recur in the majority of children. Initial response to the ICS trial may be misleading but the trial may be preferred for children who have atopic sensitization, a previous history of chronic cough, or both . PMID- 24480984 TI - Respiratory syncytial virus NS1 protein degrades STAT2 by inducing SOCS1 expression. AB - OBJECTIVES: Respiratory syncytial virus (RSV) nonstructural protein NS1 (NS1) has been shown to block interferon (IFN)-inducible antiviral signaling. The suppressor of cytokine signaling (SOCS) gene family could utilize a feedback loop to block the activation of the JAK/STAT signaling pathway, further inhibiting the activation of host type I IFN. We evaluated the role of the SOCS1 and SOCS3 genes in this antiviral mechanism. MATERIAL AND METHODS: A humanized stable NS1 (rich in GC)-expressing plasmid was constructed, and A549 cells were transfected with it. Expression of the SOCS1, SOCS3, RIG-I, and TLR3 mRNAs was measured with real time PCR. STAT2 and pSTAT2 expression was determined with Western blotting. RESULTS: RSV NS1 upregulated SOCS1 mRNA expression 30-fold increase compared with the baseline level in very early phase (p < 0.01), and silence of RIG-I or TLR3 mRNA did not affect NS1-induced SOCS1 expression. NS1 inhibited IFN-alpha-induced STAT2 phosphorylation and degraded STAT2 in a time-dependent manner compared with the empty-vector control (p < 0.05). CONCLUSION: RSV NS1 upregulates SOCS1 expression in a RIG-I- and TLR3-independent pathway, to inhibit STAT2 phosphorylation. PMID- 24480985 TI - Loss of wild-type Jak2 allele enhances myeloid cell expansion and accelerates myelofibrosis in Jak2V617F knock-in mice. AB - JAK2V617F is the most common mutation found in Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs). Although a majority of MPN patients carry heterozygous JAK2V617F mutation, loss of heterozygosity (LOH) on chromosome 9p (9pLOH) involving the JAK2 locus has been observed in ~30% of MPN patients. JAK2V617F homozygosity via 9pLOH has been associated with more severe MPN phenotype. However, the contribution of 9pLOH in the pathogenesis of MPNs remains unclear. To investigate the roles of wild-type JAK2 (JAK2 WT) and JAK2V617F alleles in the development of MPNs, we have used conditional Jak2 knock-out and Jak2V617F knock-in mice and generated heterozygous, hemizygous and homozygous Jak2V617F mice. Whereas heterozygous Jak2V617F expression results in a polycythemia vera-like MPN in mice, loss of Jak2 WT allele in hemizygous or homozygous Jak2V617F mice results in markedly increased white blood cells, neutrophils, reticulocytes and platelets in the peripheral blood, and significantly larger spleen size compared with heterozygous Jak2V617F mice. Hemizygous or homozygous Jak2V617F mice also exhibit accelerated myelofibrosis compared with mice expressing heterozygous Jak2V617F. Together, these results suggest that loss of Jak2 WT allele increases the severity of the MPN. Thus, the Jak2 WT allele functions as a negative regulator of MPN induced by Jak2V617F. PMID- 24480986 TI - Platelet-derived growth factor alpha mediates the proliferation of peripheral T cell lymphoma cells via an autocrine regulatory pathway. AB - Peripheral T-cell lymphomas not otherwise specified (PTCL/NOS) are very aggressive tumors characterized by consistent aberrant expression of platelet derived growth factor receptor alpha (PDGFRA). In this study, we aimed to identify the determinants of PDGFRA activity in PTCL/NOS and to elucidate the biological consequences of its activation. We observed overexpression of the PDGFRA gene by gene expression profiling in most of the tested PTCLs and confirmed the expression of PDGFRA and phospho-PDGFRA using immunohistochemistry. The integrity of the PDFGRA locus was demonstrated using several different approaches, including massive parallel sequencing and Sanger sequencing. PDGF-AA was found to be expressed and secreted by PTCL/NOS cells and to be necessary and sufficient for PDGFRA phosphorylation ex vivo by sustaining an autocrine stimulation. We documented consistently high PDGF-A expression in primary biopsies and patients' plasma and tracked PDGFRA signaling in primary tumors, achieving evidence of its activation. Indeed, we found that STAT1 and STAT5 are implicated in PDGFRA signaling transduction. Finally, we demonstrated that PDGFRA activation supported tumor cell proliferation and provided the first evidence of the anti-lymphoma activity of PDGRA inhibition in a PTCL/NOS patient. Altogether, our data demonstrated that PDGFRA activity fosters PTCL/NOS proliferation via an autocrine loop. PMID- 24480987 TI - BCR-ABL1-positive microvesicles transform normal hematopoietic transplants through genomic instability: implications for donor cell leukemia. AB - Malignant transformation of normal hematopoietic transplants induced by residual leukemia cells is considered as a pivotal mechanism of donor cell leukemia (DCL). The effects of leukemia cell-derived microvesicles (MVs) in this transformation were examined. We found that MVs derived from K562 leukemia cells contained the breakpoint cluster region-Abelson leukemia gene human homolog 1 (BCR-ABL1) mRNA. Following incubation with BCR-ABL1-positive MVs, mononuclear cells derived from normal transplants exhibited a leukemia-like malignant phenotype both in vitro and in vivo. Horizontal transfer of BCR-ABL1 mRNA from MVs into the recipient cells was critical to the transformation. Relative genomic instability was observed and considered the main mechanism in the recipient cells. MVs contributed to genomic instability by two distinct pathways: via consequent overexpression of activation-induced cytidine deaminase and reactive oxygen species, which mediated DNA breakage and recombination; and via upregulation of methyltransferases and global DNA hypermethylation. We demonstrated that BCR-ABL1 positive MVs could initiate malignant transformation of normal hematopoietic transplants through genomic instability, which might serve as a convenient and operable model for investigating leukemogenesis, especially for DCL. Furthermore, MVs themselves could act as an early warning indicator and a novel tool to detect and prevent the occurrence of DCL. PMID- 24480989 TI - Characteristics, detection methods and treatment of questionable occlusal carious lesions: findings from the national dental practice-based research network. AB - Questionable occlusal carious lesions (QOC) can be defined as an occlusal tooth surface with no cavitation and no radiographic radiolucencies, but caries is suspected due to roughness, surface opacities or staining. An earlier analysis of data from this study indicates 1/3 of patients have a QOC. The objective of this report has been to quantify the characteristics of these common lesions, the diagnostic aids used and the treatment of QOC. A total of 82 dentist and hygienist practitioner-investigators from the USA and Denmark in the National Dental Practice-Based Research Network participated. When consenting patients presented with a QOC, information was recorded about the patient, tooth, lesion and treatments. A total of 2,603 QOC from 1,732 patients were analyzed. The lesions were usually associated with a fissure, on molars, and varied from yellow to black in color. Half presented with a chalky luster and had a rough surface when examined with an explorer. There was an association between color and luster: 10% were chalky-light, 47% were shiny-dark and 42% were mixtures. A higher proportion of chalky than of shiny lesions were light (22 vs. 9%; p < 0.001). Lesions light in color were less common in adults than in pediatric patients (9 vs. 32%; p < 0.001). Lesions that were chalky and light were more common among pediatric than among adult patients (22 vs. 6%; p < 0.001). This is the first study to investigate characteristics of QOC in routine clinical practice. Clinicians commonly face this diagnostic uncertainty. Determining the characteristics of these lesions is relevant when making diagnostic and treatment decisions. PMID- 24480990 TI - Building an ovary: insights into establishment of somatic cell lineages in the mouse. AB - The molecular pathways that drive the differentiation of somatic cell populations in the testis and ovary have been the subjects of intensive research over the past decade. It is now clear that ovarian differentiation is a coordinate event driven by secreted factors including R-spondin1, WNT4, and follistatin and transcriptional regulators such as beta-catenin and FOXL2. These factors direct bipotential somatic cell lineages toward an ovarian fate and simultaneously suppress the emergence of testis-determining processes. This review summarizes the molecular pathways responsible for establishment of the ovary and discusses the current hypotheses on the origin(s) of somatic cell lineages and how these somatic cells acquire the characteristics necessary for their function during ovarian development and maintenance. PMID- 24480991 TI - Marriage, widowhood, divorce and HIV risks among women in sub-Saharan Africa. AB - OBJECTIVE: Studies on associations between marriage and HIV infection among women in sub-Saharan Africa are generally inconclusive. Not enough is known about HIV risks among divorced and widowed women. This study examined the relationship between marital status and HIV infection among women in seven sub-Saharan African countries. METHODS: Retrospective data from the Demographic and Health Surveys were combined with HIV biomarker data from the AIDS Indicator Survey (AIS) for analysis. Random-effects complementary log-log models were applied to examine the relationship between marital status and HIV risks controlling for theoretically relevant covariates. FINDINGS: Compared to never-married women, widowed women were significantly more likely to be HIV positive. Similarly, married women were more likely to be infected with HIV, compared to never-married women in Lesotho and Zimbabwe. In Tanzania and Zimbabwe, divorced women had higher risks of HIV infection, compared to never-married women. CONCLUSION: Findings suggest that specific HIV programs be directed at vulnerable women, in particular those widowed. Similar programs are needed for both poorer and wealthier women. PMID- 24480992 TI - Mapping population and pathogen movements. AB - For most of human history, populations have been relatively isolated from each other, and only recently has there been extensive contact between peoples, flora and fauna from both old and new worlds. The reach, volume and speed of modern travel are unprecedented, with human mobility increasing in high income countries by over 1000-fold since 1800. This growth is putting people at risk from the emergence of new strains of familiar diseases, and from completely new diseases, while ever more cases of the movement of both disease vectors and the diseases they carry are being seen. Pathogens and their vectors can now move further, faster and in greater numbers than ever before. Equally however, we now have access to the most detailed and comprehensive datasets on human mobility and pathogen distributions ever assembled, in order to combat these threats. This short review paper provides an overview of these datasets, with a particular focus on low income regions, and covers briefly approaches used to combine them to help us understand and control some of the negative effects of population and pathogen movements. PMID- 24480993 TI - Conjugated porphyrin arrays: synthesis, properties and applications for functional materials. AB - Conjugated porphyrin arrays that possess delocalised electronic networks have, for the most part, been assembled by using alkene or alkyne type bridging units or by directly connecting individual porphyrin chromophores with multiple bonds to form fused porphyrin arrays. Throughout the last two decades, such conjugated porphyrin arrays have been actively explored due to their attractive electronic, optical and electrochemical properties. This review aims to cover the multitude of synthetic methodologies that have been developed for the construction of conjugated porphyrin arrays as well as to summarise their structure-property relationships and use in various applications such as near infrared (NIR) dyes, nonlinear optical materials and electron-conducting molecular wires. PMID- 24480994 TI - MeOTf-induced carboannulation of arylnitriles and aromatic alkynes: a new metal free strategy to construct indenones. AB - MeOTf-induced carboannulation of arylnitriles and aromatic alkynes for synthesis of indenones under metal-free conditions has been described. When ortho substituted benzonitriles were used, indeno[1,2-c]isoquinolines were formed. PMID- 24480995 TI - One-step synthesis of water-dispersible ultra-small Fe3O4 nanoparticles as contrast agents for T1 and T2 magnetic resonance imaging. AB - Uniform, highly water-dispersible and ultra-small Fe3O4 nanoparticles were synthesized via a modified one-step coprecipitation approach. The prepared Fe3O4 nanoparticles not only show good magnetic properties, long-term stability in a biological environment, but also exhibit good biocompatibility in cell viability and hemolysis assay. Due to the ultra-small sized and highly water dispersibility, they exhibit excellent relaxivity properties, the 1.7 nm sized Fe3O4 nanoparticles reveal a low r2/r1 ratio of 2.03 (r1 = 8.20 mM(-1) s(-1), r2 = 16.67 mM(-1) s(-1)); and the 2.2 nm sized Fe3O4 nanoparticles also appear to have a low r2/r1 ratio of 4.65 (r1 = 6.15 mM(-1) s(-1), r2 = 28.62 mM(-1) s(-1)). This demonstrates that the proposed ultra-small Fe3O4 nanoparticles have great potential as a new type of T1 magnetic resonance imaging contrast agents. Especially, the 2.2 nm sized Fe3O4 nanoparticles, have a competitive r1 value and r2 value compared to commercial contrasting agents such as Gd-DTPA (r1 = 4.8 mM( 1) s (-1)), and SHU-555C (r2 = 69 mM(-1) s(-1)). In vitro and in vivo imaging experiments, show that the 2.2 nm sized Fe3O4 nanoparticles exhibit great contrast enhancement, long-term circulation, and low toxicity, which enable these ultra-small sized Fe3O4 nanoparticles to be promising as T1 and T2 dual contrast agents in clinical settings. PMID- 24480996 TI - Health economics and surgical treatment for Parkinson's disease in a world perspective: results from an international survey. AB - BACKGROUND: Most studies in the field of neurosurgical treatment for movement disorders have been published by a small number of leading centers in developed countries. This study aimed to investigate the clinical practice of stereotactic neurosurgery for Parkinson's disease (PD) worldwide. METHODS: Neurosurgeons were contacted via e-mail to participate in a worldwide survey. The results obtained are presented in order of the countries' economic development according to the World Bank, as well as by the source of financial support. RESULTS: A total of 353 neurosurgeons from 51 countries who had operated on 13,200 patients in 2009 were surveyed. Surgical procedures performed in high-income countries were more commonly financed by a public health care system. In contrast, in lower-middle income and upper-middle-income countries, patients frequently financed surgeries themselves, and ablative surgeries were most commonly performed. Unexpectedly, ablative surgery is still used by about 65% of neurosurgeons, regardless of their country's economic status. CONCLUSIONS: This study provides a previously unavailable picture of the surgical aspects of PD across the globe in relation to health economics and sociodemographic factors. Global educational and training programs are warranted to raise awareness of economically viable surgical options for PD that could be adopted by public health care systems in lower-income countries. PMID- 24480997 TI - Use and outcomes of noninvasive positive pressure ventilation in acute care hospitals in Massachusetts. AB - BACKGROUND: This study determined actual utilization rates and outcomes of noninvasive positive pressure ventilation (NIV) at selected hospitals that had participated in a prior survey on NIV use. METHODS: This observational cohort study, based at eight acute care hospitals in Massachusetts, focused on all adult patients requiring ventilatory support for acute respiratory failure during predetermined time intervals. RESULTS: Of 548 ventilator starts, 337 (61.5%) were for invasive mechanical ventilation and 211 (38.5%) were for NIV, with an overall NIV success rate of 73.9% (ie, avoidance of intubation or death while on NIV or within 48 h of discontinuation). Causal diagnoses for respiratory failure were classified as (I) acute-on-chronic lung disease (23.5%), (II) acute de novo respiratory failure (17.9%), (III) neurologic disorders (19%), (IV) cardiogenic pulmonary edema (16.8%), (V) cardiopulmonary arrest (12.2%), and (VI) others (10.6%). NIV use and success rates for each of the causal diagnoses were, respectively, (I) 76.7% and 75.8%, (II) 37.8% and 62.2%, (III) 1.9% and 100%, (IV) 68.5% and 79.4%, (V) none, and (VI) 17.2% and 60%. Hospital mortality rate was higher in patients with invasive mechanical ventilation than in patients with NIV (30.3% vs 16.6%, P < .001). CONCLUSIONS: NIV occupies an important role in the management of acute respiratory failure in acute care hospitals in selected US hospitals and is being used for a large majority of patients with acute-on chronic respiratory failure and acute cardiogenic pulmonary edema. NIV use appears to have increased substantially in selected US hospitals over the past decade. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT00458926; URL: www.clinicaltrials.gov. PMID- 24480999 TI - Impact of HLA antibodies on graft survival in long-term renal recipients with functional grafts. AB - OBJECTIVES: Accumulating evidence supports the hypothesis that HLA antibodies play an important role in early renal allograft injury. However, the effects of HLA antibodies on long-term graft survival are still poorly understood. In this study, we examined the impact of HLA antibodies on graft survival in long-term renal recipients with functional grafts for 10 years. MATERIAL AND METHODS: In this retrospective study, long-term renal recipients were defined as kidney transplant recipients who had normally functioning renal grafts (serum creatinine level <2.0 mg/dl) for 10 years. Posttransplant serum samples from a total of 92 long-term renal allograft recipients on cyclosporine-based triple maintenance drug therapy (121.6 +/- 0.886 months) were screened for the specificities of anti HLA antibodies. The results of HLA antibodies before the transplantation, assessed using the same test method, were compared with those after their transplantations. Moreover, these 92 patients who received cadaveric renal transplant between January 2000 and December 2002 were followed up for about 10 years (range 107-135 months). RESULTS: 27 patients had HLA-I antibodies and 16 patients had HLA-II antibodies before the transplantation, whereas 12 patients had HLA-I antibodies and 18 patients had HLA-II antibodies after the transplantation. Moreover, the types of HLA antibodies were different from those found before the transplantation. In these renal recipients with functioning renal grafts, the estimated glomerular filtration rate was 66.52 +/- 14.52 ml/min/1.73 m(2) in the HLA antibody-positive group (n = 23) and 69.09 +/- 25.54 ml/min/1.73 m(2) negative in the HLA antibody-negative group (n = 69, p > 0.05). Three patients (3.26%) (3 out of 92) had donor-specific anti-HLA antibodies (DSA). The frequency of DSA in this study was lower than that in the general Chinese Han renal recipient population. CONCLUSIONS: We find that all HLA antibodies in the long-term renal grafts are newly formed after the transplantation. The HLA antibody status has little impact on the renal graft function in the long-term renal recipients. PMID- 24481000 TI - Regulation of autophagy by high glucose in human retinal pigment epithelium. AB - BACKGROUND: Autophagy is a self-degradative process that is important for balancing sources of energy at critical times in development and in response to nutrient stress. Retinal pigment epithelium (RPE) works as the outer blood retina barrier and is vulnerable to energy stress-induced injury. However, the effect of high glucose treatment on autophagy is still unclear in RPE. METHODS: Transmission electron microscopy was used to detect the generation of autophagosome. Small interfering RNA (siRNA) and MTT was used to determine the effect of autophagy on cell viability. Western blots and immunohistochemistry were used to detect the expression pattern of autophagic markers, including LC3 and p62. RESULTS: High glucose treatment results in a significant increase in the generation of autophagosome and altered expression of LC3 and p62. High glucose induced autophagy is independent of mTOR signaling, but is mainly regulated via ROS-mediated ER stress signaling. CONCLUSION: In the scenario of high glucose induced oxidative stress, autophagy may be required for the removal of damaged proteins, and provide a default mechanism to prevent high glucose-induced injury in RPE. PMID- 24480998 TI - Emotion dysregulation in attention deficit hyperactivity disorder. AB - Although it has long been recognized that many individuals with attention deficit hyperactivity disorder (ADHD) also have difficulties with emotion regulation, no consensus has been reached on how to conceptualize this clinically challenging domain. The authors examine the current literature using both quantitative and qualitative methods. Three key findings emerge. First, emotion dysregulation is prevalent in ADHD throughout the lifespan and is a major contributor to impairment. Second, emotion dysregulation in ADHD may arise from deficits in orienting toward, recognizing, and/or allocating attention to emotional stimuli; these deficits implicate dysfunction within a striato-amygdalo-medial prefrontal cortical network. Third, while current treatments for ADHD often also ameliorate emotion dysregulation, a focus on this combination of symptoms reframes clinical questions and could stimulate novel therapeutic approaches. The authors then consider three models to explain the overlap between emotion dysregulation and ADHD: emotion dysregulation and ADHD are correlated but distinct dimensions; emotion dysregulation is a core diagnostic feature of ADHD; and the combination constitutes a nosological entity distinct from both ADHD and emotion dysregulation alone. The differing predictions from each model can guide research on the much-neglected population of patients with ADHD and emotion dysregulation. PMID- 24481002 TI - Development and three-dimensional morphology of the zygomaticotemporal suture in primate skulls. AB - Cranial sutures are an essential part of the growing skull, allowing bones to increase in size during growth, with their morphology widely believed to be dictated by the forces and displacements that they experience. The zygomaticotemporal suture in primates is located in the relatively weak zygomatic arch, and externally it appears a very simple connection. However, large forces are almost certainly transmitted across this suture, suggesting that it requires some level of stability while also allowing controlled movements under high loading. Here we examine the 2- and 3-dimensional (3D) morphology of the zygomaticotemporal suture in an ontogenetic series of Macaca fascicularis skulls. High resolution microcomputed tomography data sets were examined, and virtual and physical 3D replicas were created to assess both structure and general stability. The zygomaticotemporal suture is much more complex than its external appearance suggests, with interlocking facets between the adjacent zygomatic and temporal bones. It appears as if some movement is permitted across the suture in younger animals, but as they approach adulthood the complexity of the suture's interlocking bone facets reaches a level where these movements become minimal. PMID- 24481003 TI - A Herlyn-Werner-Wunderlich syndrome variant with ipsilateral renal absence and a contralateral duplex collecting system in a 26-year-old female. AB - Herlyn-Werner-Wunderlich syndrome (HWWS) is a mullerian duct anomaly typically associated with a uterus didelphys with two cervices and two vaginas, one of which is obstructed. A remarkable case of HWWS with contralateral duplex kidneys and duplication of ureters is described, which, to our knowledge, is a rarely reported variant to date. For this congenital anomaly, a strong suspicion and knowledge of HWWS are essential for a precise diagnosis. PMID- 24481001 TI - DICER1 mutations in childhood cystic nephroma and its relationship to DICER1 renal sarcoma. AB - The pathogenesis of cystic nephroma of the kidney has interested pathologists for over 50 years. Emerging from its initial designation as a type of unilateral multilocular cyst, cystic nephroma has been considered as either a developmental abnormality or a neoplasm or both. Many have viewed cystic nephroma as the benign end of the pathologic spectrum with cystic partially differentiated nephroblastoma and Wilms tumor, whereas others have considered it a mixed epithelial and stromal tumor. We hypothesize that cystic nephroma, like the pleuropulmonary blastoma in the lung, represents a spectrum of abnormal renal organogenesis with risk for malignant transformation. Here we studied DICER1 mutations in a cohort of 20 cystic nephromas and 6 cystic partially differentiated nephroblastomas, selected independently of a familial association with pleuropulmonary blastoma and describe four cases of sarcoma arising in cystic nephroma, which have a similarity to the solid areas of type II or III pleuropulmonary blastoma. The genetic analyses presented here confirm that DICER1 mutations are the major genetic event in the development of cystic nephroma. Further, cystic nephroma and pleuropulmonary blastoma have similar DICER1 loss of function and 'hotspot' missense mutation rates, which involve specific amino acids in the RNase IIIb domain. We propose an alternative pathway with the genetic pathogenesis of cystic nephroma and DICER1-renal sarcoma paralleling that of type I to type II/III malignant progression of pleuropulmonary blastoma. PMID- 24481004 TI - Detection of high-energy compounds using photoluminescent silicon nanocrystal paper based sensors. AB - Luminescent silicon nanocrystals (Si-NCs) surface functionalized with dodecyl groups were exposed to solutions of nitroaromatic compounds including nitrobenzene, nitrotoluene, and dinitrotoluene. It was found that Si-NC luminescence was quenched upon exposure to nitroaromatics via an electron transfer mechanism as indicated by Stern-Volmer analysis. This quenching was exploited and a straightforward paper-based Si-NC sensor was developed. This paper motif was found to be sensitive to solution, vapor, and solid phase nitroaromatics, as well as solution borne RDX and PETN. PMID- 24481005 TI - Microfluidic reactors for photocatalytic water purification. AB - Photocatalytic water purification utilizes light to degrade the contaminants in water and may enjoy many merits of microfluidics technology such as fine flow control, large surface-area-to-volume ratio and self-refreshing of reaction surface. Although a number of microfluidic reactors have been reported for photocatalysis, there is still a lack of a comprehensive review. This article aims to identify the physical mechanisms that underpin the synergy of microfluidics and photocatalysis, and, based on which, to review the reported microfluidic photocatalytic reactors. These microreactors help overcome different problems in bulk reactors such as photon transfer limitation, mass transfer limitation, oxygen deficiency, and lack of reaction pathway control. They may be scaled up for large-throughput industrial applications of water processing and may also find niche applications in rapid screening and standardized tests of photocatalysts. PMID- 24481006 TI - Should cavitation in proximal surfaces be reported in cone beam computed tomography examination? AB - AIM: A clinical study was done to assess the clinical diagnostic accuracy of cone beam computed tomography (CBCT) in detecting proximal cavitated carious lesions in order to determine whether cavitation should be reported when a CBCT examination is available. MATERIALS AND METHODS: 79 adjacent proximal surfaces without restorations in permanent teeth were examined. Patients suspected to have carious lesions after a visual clinical and a bitewing examination participated in a CBCT examination (Kodak 9000 3D, 5 * 3.7 cm field of view, voxel size 0.07 mm). Ethical approval and informed consent were obtained according to the Helsinki Declaration. Radiographic assessment recording lesions with or without cavitation was performed by two observers in bitewings and CBCT sections. Orthodontic separators were placed interdentally between two lesion-suspected surfaces. The separator was removed after 3 days and the surfaces recorded as cavitated (yes/no), i.e. validated clinically. Differences between the two radiographic modalities (sensitivity, specificity and overall accuracy) were estimated by analyzing the binary data in a generalized linear model. RESULTS: For both observers, sensitivity was significantly higher for CBCT than for bitewings (average difference 33%, p < 0.001) while specificity was not significantly different between the methods (p = 0.19). The overall accuracy was also significantly higher for CBCT (p < 0.001). CONCLUSION: CBCT was more accurate in detecting cavitation in proximal surfaces than bitewing radiographs; therefore a CBCT examination performed for other clinical applications should also be assessed for proximal surface cavities in teeth without restorations, and when detected, this pathology must be part of the dentist's report. PMID- 24481007 TI - An unexpected complication of bone marrow aspiration and trephine biopsy: arteriovenous fistula. AB - OBJECTIVE: To report a case of arteriovenous fistula (AVF) following bone marrow aspiration and trephine biopsy. CLINICAL PRESENTATION AND INTERVENTION: A 76-year old man was diagnosed with acute myeloblastic leukemia. Pain and hematoma were detected in his left leg and hip 4 days after bone marrow aspiration and trephine biopsy. A pelvic arteriography was performed, and a diagnosis of AVF was made. CONCLUSION: This case shows that clinicians should be aware of AVF, especially in cases with refractory bleeding after bone marrow aspiration and trephine biopsy despite normal blood coagulation parameters. PMID- 24481010 TI - Mechanically inducible fluorescence colour switching in the formation of organic nanoparticles of an ESIPT molecule. AB - Electrostatic interactions between an ESIPT molecule 2-(5'-amino-2' hydroxyphenyl)benzothiazole (AHBT) and a phenylborate derivative give blue-green emission in acetic acid solution, but interestingly, vigorous (or mechanical) shaking of the solution leads to the formation of organic AHBT nanoparticles, which results in fluorescence colour switching from blue-green to yellow-orange. PMID- 24481011 TI - Activated lymphocytes secretome inhibits differentiation and induces proliferation of C2C12 myoblasts. AB - BACKGROUND/AIMS: ageing is associated with a marked decline in immune function which may contribute to the local environment that can influence the regenerative process of skeletal muscle cells. METHODS: Herein, we focused on determining the effect of an activated immune system secretome on myoblast differentiation and proliferation as possible means to attenuate adverse effects of muscle aging. C2C12 myoblasts were used as model to assess the impact of lymphocyte conditioned media (CM) following anti-CD3/IL-2 activation. RESULTS: Myoblasts cultured with activated lymphocytes CM exhibited reduced morphological and biochemical differentiation (98+/-20, p<0.005) and increased entry to the S Phase of the cell cycle (61%+/-7, p<0.001), when compared with myoblasts cultured with non activated lymphocytes CM. Associated with increased proliferation and reduced differentiation, muscle specific transcription factors MyoD and myogenin were significantly reduced in C2C12 treated with activated lymphocytes CM vs control CM, respectively (myoD: 0.5+/-0.12 fold reduction P<0.005); myogenin: 0.38+/-0.08 fold reduction; p<0.005). Moreover, key protein of proliferation pERK1/2 increased (46+/-11U/ml, p<0.05) whereas mediator of differentiation pAkt decreased (21+/-12U/ml, p<0.05) in C2C12 treated with activated vs. non-activated CM. CONCLUSION: our data demonstrate that, following activation, secretome of the immune system cells elicit marked regulatory effects on skeletal muscle growth and differentiation; enhancing the former with the loss of the latter. PMID- 24481012 TI - Lichen scrofulosorum. AB - Tuberculosis is a common disease. The cutaneous form of tuberculosis known as tuberculid is an uncommon disease and is easily misdiagnosed. Lichen scrofulosorum is a rare form of tuberculid seen in children and young adults with or without other manifestations of tuberculosis. We report a case of a young adult with lichen scrofulosorum along with tuberculous lymphadenitis. The skin lesions responded promptly to antitubercular therapy with complete clearance of the lesions. Identification of the skin manifestation was especially important in this case because the lymph node biopsy was inconclusive, with tissue culture proving the diagnosis only after 4 weeks. PMID- 24481009 TI - Photodissociation mass spectrometry: new tools for characterization of biological molecules. AB - Photodissociation mass spectrometry combines the ability to activate and fragment ions using photons with the sensitive detection of the resulting product ions by mass spectrometry. This combination affords a versatile tool for characterization of biological molecules. The scope and breadth of photodissociation mass spectrometry have increased substantially over the past decade as new research groups have entered the field and developed a number of innovative applications that illustrate the ability of photodissociation to produce rich fragmentation patterns, to cleave bonds selectively, and to target specific molecules based on incorporation of chromophores. This review focuses on many of the key developments in photodissociation mass spectrometry over the past decade with a particular emphasis on its applications to biological molecules. PMID- 24481013 TI - Secondary spontaneous pneumothorax complicating miliary tuberculosis in a young woman. PMID- 24481014 TI - Orbital metastasis as the inaugural presentation of occult rectal cancer. AB - Orbital metastasis is uncommon and occurs in 2-3% of patients with cancer. It is rarely the initial manifestation of a systemic malignancy. It usually indicates extensive haematogenous dissemination of a primary cancer and is associated with poor prognosis. Breast, lungs and prostate cancers are the most common primary cancers leading to orbital metastasis. However, orbital tumour revealing a rectal adenocarcinoma is exceptional. We describe a case of orbital tumour in a 67-year old man with no history of systemic cancer while presenting with ophthalmic symptoms. Investigations revealed rectal adenocarcinoma as the primary malignant tumour. PMID- 24481016 TI - A liver with a highly abnormal appearance. PMID- 24481015 TI - Florid cystic endosalpingiosis, masquerading as malignancy in a young patient: a brief review. AB - Endosalpingiosis is a rare condition characterised by the presence of tubal epithelium outside the fallopian tube. Most of the previous case reports have described this condition in women in their fifth decade or older. We report a case of a woman presenting at 31 years with a history of heavy bleeding during menses and pain in the lower abdomen for the past 2 years. An ultrasound examination showed a left ovarian cyst of 4.3*3.2 cm with multiple septations. CA 125 was within normal range. Laparoscopy was performed with the plan of ovarian cystectomy, peroperatively; there were papillary projections all over the uterus and the peritoneal surface. The left ovary was enlarged with papillary projections on the surface. Multiple biopsies were taken from the surface of the uterus, ovary and the peritoneum as the picture was quite suspicious of malignancy. Histopathological examination gave the picture of endosalpingiosis. The patient underwent laparoscopic ovariotomy with fulguration of lesions 4 months later, in view of persistent pain and discomfort, and increase in the size of the cyst on ultrasound monitoring. Presently, she is free of symptoms. PMID- 24481017 TI - Prolonged spontaneous normocalcaemia in pseudohypoparathyroidism from resorption of soft tissue calcium deposits: a cautionary tale. AB - A 42-year-old man diagnosed with pseudohypoparathyroidism and Albright's hereditary osteodystrophy as an infant was lost to follow-up and remained, unmonitored, on calcitriol and calcium for over 20 years. He presented after having an ST-elevation myocardial infarction. In addition to coronary artery calcifications, he was found to have diffuse subcutaneous and joint calcifications. His calcium, phosphate and parathyroid hormone (PTH) levels were normal, and given the lack of prior documentation in the diagnosis he was instructed to discontinue calcitriol and calcium until further investigations were completed. Despite stopping the medication, his serum calcium remained normal for over 1 year. It was not until 18 months later, when his soft tissue calcium stores were depleted, that he finally developed symptomatic hypocalcaemia and an elevated PTH. This case not only emphasises the importance of long-term follow-up for patients with pseudohypoparathyroidism, but also highlights the potential complications of long-term, unmonitored, calcitriol use. PMID- 24481018 TI - Denosumab should be the treatment of choice for bisphosphonate refractory hypercalcaemia of malignancy. AB - Denosumab, a fully humanised monoclonal antibody, is licensed for treatment of postmenopausal osteoporosis, hormone ablation-induced bone loss and for prevention of skeleton-related events in patients with bone metastases from solid tumours. In pivotal phase 3 randomised trials, denosumab caused profound hypocalcaemia in patients with normocalcaemia despite oral calcium and vitamin D supplementation. This significant hypocalcaemic effect can be exploited to treat hypercalcaemia of malignancy (HCM). Recent reports from the USA suggest that denosumab is an effective treatment of HCM. According to our knowledge, we report the first two cases in UK with bisphosphonate refractory hypercalcaemia who responded to denosumab injections. Our first case gained 7 months of stabilisation of hypercalcaemia following prolonged admissions with life threatening levels, while our second case achieved rapid normalisation of serum calcium levels for the first time in 14 months. We conclude that denosumab should be the treatment of choice for patients with bisphosphonate refractory hypercalcaemia. PMID- 24481019 TI - Borderline tuberculoid leprosy with type 1/reversal reaction. PMID- 24481020 TI - Myxoedema coma: an almost forgotten, yet still existing cause of multiorgan failure. AB - A 48-year-old man was admitted to department of emergency medicine at a tertiary referral hospital due to dizziness and fatigue. Clinical features on admission were non-pitting oedema, dry skin, very sparse hair, a hoarse voice, hypothermia (rectal temperature 28.7 degrees C), macroglossia, sinus bradycardia and slow cerebration. Blood tests revealed severe hypothyroidism. During admission, the patient developed respiratory failure, renal failure, bleeding symptoms and diffuse colitis. The patient was treated with hydrocortisone and levothyroxine and he survived miraculously. This case describes a patient with myxoedema coma with severe hypothermia and cardiac involvement with development of multiorgan dysfunction all linked to the severe depletion of triiodothyronine. PMID- 24481021 TI - Pleomorphic rhabdomyosarcoma of the cerebellopontine angle in an adult: a review of literature. AB - Rhabdomyosarcoma (RMS) is a rare and aggressive neoplasm characterised by rapid growth and metastatic invasion. The most frequent localisation is the skeletal musculature of the limbs. The head and the neck are rarely involved. A 50-year old woman presented to our attention because of a progressively increasing headache, ataxia and vomiting. MRI showed a lesion at the right cerebellopontine angle. Thereafter, the patient was submitted to a piece-meal removal of the neoplasm. Despite the postoperative MRI showed no signs of remnant, 7 months after the surgery, the disease recurred with multiple localisations, and the patient died a few days later. This report is the first description in the literature of a pleomorphic RMS of the cerebellopontine angle. This particular tumour carries a bad prognosis because of the vicinity of nervous structures and of the impossibility of achieving a one-piece resection. More than ever, the adjunctive treatments had to be effective against a potential remnant and in controlling recurrences. PMID- 24481022 TI - Chlorin e6 Conjugated Interleukin-6 Receptor Aptamers Selectively Kill Target Cells Upon Irradiation. AB - Photodynamic therapy (PDT) uses the therapeutic properties of light in combination with certain chemicals, called photosensitizers, to successfully treat brain, breast, prostate, and skin cancers. To improve PDT, current research focuses on the development of photosensitizers to specifically target cancer cells. In the past few years, aptamers have been developed to directly deliver cargo molecules into target cells. We conjugated the photosensitizer chlorin e6 (ce6) with a human interleukin-6 receptor (IL-6R) binding RNA aptamer, AIR-3A yielding AIR-3A-ce6 for application in high efficient PDT. AIR-3A-ce6 was rapidly and specifically internalized by IL-6R presenting (IL-6R(+)) cells. Upon light irradiation, targeted cells were selectively killed, while free ce6 did not show any toxic effect. Cells lacking the IL-6R were also not affected by AIR-3A-ce6. With this approach, we improved the target specificity of ce6-mediated PDT. In the future, other tumor-specific aptamers might be used to selectively localize photosensitizers into cells of interest and improve the efficacy and specificity of PDT in cancer and other diseases.Molecular Therapy-Nucleic Acids (2014) 3, e143; doi:10.1038/mtna.2013.70; published online 21 January 2014. PMID- 24481023 TI - Carcinosarcoma of the Female Urethra. AB - Carcinosarcoma is a rare malignant tumor with a biphasic morphology characterized by the presence of a malignant epithelial and mesenchymal component. It has been reported in many organs, including the genitourinary tract. We describe a case of a 47-year-old woman admitted to our hospital for history of recurrent urinary tract infection, dysuria and discharge of bloody fluid from the urethra at the end of urination. A tender palpable mass under the anterior vaginal wall was found and pathological examination showed a urethral carcinosarcoma. The histopathogenetic hypothesis and clinical management were considered in this report. PMID- 24481024 TI - In vivo imaging of human cholinergic nerve terminals with (-)-5-(18)F fluoroethoxybenzovesamicol: biodistribution, dosimetry, and tracer kinetic analyses. AB - (-)-5-(18)F-fluoroethoxybenzovesamicol ((18)F-FEOBV) is a vesamicol derivative that binds selectively to the vesicular acetylcholine transporter (VAChT) and has been used in preclinical studies to quantify presynaptic cholinergic nerve terminals. This study presents, to our knowledge, the first-in-human experience with (18)F-FEOBV, including radiation dosimetry, biodistribution, tolerability and safety in human subjects, and brain kinetics and methods for quantitative analysis of (18)F-FEOBV. METHODS: Whole-body (18)F-FEOBV scans were obtained in 3 healthy human volunteers. Seven additional subjects underwent dynamic brain imaging 0-120, 150-180, and 210-240 min after bolus injection of (18)F-FEOBV. Arterial blood sampling was performed with chromatographic identification of authentic (18)F-FEOBV to determine the arterial plasma input function. Analysis methods included nonlinear least-squares fitting of a 2-tissue-compartmental model, reference tissue modeling, and late single-scan imaging. RESULTS: No pharmacologic or physiologic changes were observed after intravenous administration of up to 1.3 MUg of (18)F-FEOBV. Radiation dosimetry estimates indicate that more than 400 MBq may be administered without exceeding regulatory radiation dose limits. Kinetic analysis showed brain uptake to be relatively high with single-pass extraction of 25%-35%. VAChT binding estimates varied by a factor of greater than 30 between the striatum and cortex. Coefficients of variation in k3 estimates varied from 15% to 30%. Volume of distribution measures yielded a dynamic range of approximately 15 but with little reduction in variability. Reference tissue approaches yielded more stable estimates of the distribution volume ratio (1 + BPND), with coefficients of variation ranging from 20% in the striatum to 6%-12% in cortical regions. The late static distribution of (18)F-FEOBV correlated highly with the distribution volume ratio estimates from reference tissue models (r = 0.993). CONCLUSION: (18)F-FEOBV PET confirms that the tracer binds to VAChT with the expected in vivo human brain distribution. Both reference tissue modeling and late static scanning approaches provide a robust index of VAChT binding. PMID- 24481025 TI - Small-animal PET imaging of isolated perfused rat heart. AB - The assessment of myocardial radiotracer kinetics, including cardiac extraction fraction and washout, requires the study of isolated perfused hearts to avoid analytic error due to tracer recirculation and systemic metabolites. Analysis of the isolated perfused rat heart by a high-resolution small-animal PET system may offer both reliable evaluation of cardiac tracer kinetics and tomographic images. METHODS: An isolated perfused heart system was modified to accommodate the small PET gantry bore size. Isolated rat hearts were perfused via the Langendorff method under a constant flow of Krebs-Henseleit buffer containing (18)F-FDG with a rate of 5 mL/min and placed in the field of view of the commercially available small-animal PET system. Dynamic PET imaging was then performed, with (18)F-FDG uptake in the isolated perfused heart verified by gamma counter measurements. Additionally, a rat heart of myocardial infarction was also studied in this system with static PET imaging. RESULTS: Dynamic PET acquisition of the isolated heart under constant (18)F-FDG infusion demonstrated continuous increase of activity in the heart. Correlation between cardiac activity (MBq) measured with the PET system and measurements made with the gamma counter were excellent (R(2) = 0.98, P < 0.001, n = 10). Tracer input rate (MBq/min) was also well correlated with cardiac tracer uptake rate (MBq/min) (R(2) = 0.87, P < 0.001, n = 12). PET imaging of the heart with myocardial infarction showed a clear tracer uptake defect corresponding to the location of scar tissue identified by autoradiography and histology. CONCLUSION: Combining the Langendorff method of isolated rat heart perfusion with high-resolution small-animal PET allows for the reliable quantification of myocardial tracer kinetics. This novel assay is readily adapted to available small-animal PET systems and may be useful for understanding myocardial PET tracer kinetics. PMID- 24481026 TI - In vivo imaging of brain estrogen receptors in rats: a 16alpha-18F-fluoro-17beta estradiol PET study. AB - The steroid hormone estrogen is important for brain functioning and is thought to be involved in brain diseases, such as Alzheimer disease and depression. The action of estrogen is mediated by estrogen receptors (ERs). To understand the role of estrogens in brain functioning, it is important to study ERs in the brain. The aims of the present study were to determine whether ERs could be measured in the rat brain by PET with the ER ligand 16alpha-(18)F-fluoro-17beta estradiol ((18)F-FES) and to evaluate whether tracer uptake was affected by endogenous estrogen. METHODS: Small-animal PET was used to determine (18)F-FES uptake in female rats in the diestrous phase of the estrous cycle, the proestrous phase, and after ovariectomy. Coinjection of (18)F-FES with 17beta-estradiol was performed to determine whether tracer binding was specific for ERs. Additionally, (18)F-FES uptake was quantified with kinetic modeling in female rats in the proestrous phase and after ovariectomy and in male rats. RESULTS: The highest levels of uptake of (18)F-FES were found (in descending order) in the pituitary, hypothalamus, bed nucleus of the stria terminalis, and amygdala. Other brain regions showed low levels of brain uptake. The level of (18)F-FES uptake was higher in the pituitary and hypothalamus in rats after ovariectomy than in rats in the proestrous phase. Coinjection with 17beta-estradiol resulted in a decrease in (18)F-FES uptake in the pituitary and hypothalamus. The volume of distribution and binding potential determined with kinetic modeling were higher in the pituitary than in the other brain regions in all 3 groups. No differences were found among the groups. CONCLUSION: (18)F-FES PET imaging of ER availability in the rat brain is feasible for brain regions with high ER densities. PMID- 24481027 TI - Lung ultrasound in community-acquired pneumonia and in interstitial lung diseases. AB - Lung ultrasound (LUS) is an accurate tool for the diagnosis and follow-up of pneumonia in adults as well as in children. LUS is at least as accurate as chest radiography in diagnosing pneumonia. The most important parenchymal criterion is the positive air bronchogram within an echopoor area. Among pleural criteria, basal effusion was most often detected. The presence of multiple diffuse bilateral B-lines on lung examination indicates the interstitial syndrome (IS). For further differential diagnosis, an integrated consideration of history, clinical examination, LUS and echocardiography should be performed. LUS is an excellent tool for IS screening. Repeated LUS control examinations may reflect the dynamics of IS under therapy and so LUS may serve as a therapy guide. . PMID- 24481028 TI - Bugs versus bugs: probiotics, microbiome and allergy. PMID- 24481029 TI - Optimization of molecular organization and nanoscale morphology for high performance low bandgap polymer solar cells. AB - Rational design and synthesis of low bandgap (LBG) polymers with judiciously tailored HOMO and LUMO levels have emerged as a viable route to high performance polymer solar cells with power conversion efficiencies (PCEs) exceeding 10%. In addition to engineering the energy-level of LBG polymers, the photovoltaic performance of LBG polymer-based solar cells also relies on the device architecture, in particular the fine morphology of the photoactive layer. The nanoscale interpenetrating networks composed of nanostructured donor and acceptor phases are the key to providing a large donor-acceptor interfacial area for maximizing the exciton dissociation and offering a continuous pathway for charge transport. In this Review Article, we summarize recent strategies for tuning the molecular organization and nanoscale morphology toward an enhanced photovoltaic performance of LBG polymer-based solar cells. PMID- 24481030 TI - Holistic anaesthesia machine: need for a task force. PMID- 24481031 TI - Endobronchial ultrasound-guided transbronchial needle aspiration vs conventional transbronchial needle aspiration in the diagnosis of sarcoidosis. AB - BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is superior to conventional transbronchial needle aspiration (cTBNA) in the staging of lung cancer. However, its efficiency in diagnosis of sarcoidosis when combined with endobronchial biopsy (EBB) and transbronchial lung biopsy (TBLB) has not been studied. This randomized controlled trial compares diagnostic yield of EBUS-TBNA vs cTBNA in combination with EBB and TBLB. METHODS: Patients with clinical diagnosis of sarcoidosis were randomized 1:1 to EBUS-TBNA or cTBNA. All patients underwent TBLB and EBB. The primary outcome was detection of granulomas. The secondary end points were the individual and cumulative yields of various procedures, serious adverse events, and procedure time. RESULTS: Of the 130 patients, sarcoidosis was diagnosed in 117 (62 cTBNA, 55 EBUS-TBNA). The two groups were similar at baseline. Granulomas were demonstrated in 104 (53 cTBNA, 51 EBUS-TBNA) patients and were similar in two groups (85.5% vs 92.7%, P = .34). Individually, EBUS-TBNA had the highest yield (41 of 55, 74.5%), which was better than cTBNA (30 of 62, 48.4%, P = .004) or EBB (40 of 111, 36.3%, P < .0001) but not TBLB (78 of 112, 69.6%, P = .54). Adding EBB/TBLB to cTBNA led to an increase in granuloma detection, whereas the addition of TBLB (but not EBB) significantly enhanced the yield of EBUS-TBNA. The procedure time was significantly longer with EBUS-TBNA. No major adverse events occurred. CONCLUSIONS: Individually, EBUS-TBNA has the highest diagnostic yield in sarcoidosis, but it should be combined with TBLB for the optimal yield. The diagnostic yield of cTBNA (plus EBB and TBLB) is similar to EBUS-TBNA plus TBLB. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01908868; URL: www.clinicaltrials.gov. PMID- 24481032 TI - Sucrose substitutes affect the cariogenic potential of Streptococcus mutans biofilms. AB - Streptococcus mutans is considered the primary etiologic agent of dental caries and contributes significantly to the virulence of dental plaque, especially in the presence of sucrose. To avoid the role of sucrose on the virulence factors of S. mutans, sugar substitutes are commonly consumed because they lead to lower or no production of acids and interfere with biofilm formation. This study aimed to investigate the contribution of sugar substitutes in the cariogenic potential of S. mutans biofilms. Thus, in the presence of sucrose, glucose, sucralose and sorbitol, the biofilm mass was quantified up to 96 h, the pH of the spent culture media was measured, the expression of biofilm-related genes was determined, and demineralization challenge experiments were conduct in enamel fragments. The presence of sugars or sugar substitutes profoundly affected the expression of spaP, gtfB, gtfC, gbpB, ftf, vicR and vicX in either biofilm or planktonic cells. The substitution of sucrose induced a down-regulation of most genes involved in sucrose-dependent colonization in biofilm cells. When the ratio between the expression of biofilm and planktonic cells was considered, most of those genes were down-regulated in biofilm cells in the presence of sugars and up-regulated in the presence of sugar substitutes. However, sucralose but not sorbitol fulfilled the purpose of reducing the cariogenic potential of the diet since it induced the biofilm formation with the lowest biomass, did not change the pH of the medium and led to the lowest lesion depth in the cariogenic challenge. PMID- 24481033 TI - Intraoperative bleeding in stereotactic biopsies and its implication on postoperative management: can we predict CT findings? AB - BACKGROUND: Stereotactic biopsies are procedures with a high diagnostic yield and a low but serious risk of hemorrhage. Postoperative management remains controversial. OBJECTIVES: To evaluate the predictive value of intraoperative bleeding and its implication on postoperative management. METHODS: Cases of intraoperative bleeding were prospectively documented in a consecutive series comprising 303 patients. Categories were as follows: no bleeding, single drop, <=10 drops and >10 drops. Incidence, size of hemorrhage and neurological deterioration were noted. Hemorrhage on routine postoperative CT scans was correlated with intraoperative findings, sample size, location and pathology. RESULTS: A total of 93 patients (30.7%) showed intraoperative bleeding and 68 (22.4%) showed blood on postoperative CT. In 13 patients (4.3%) the diameter was >1 cm; 19 patients (6.3%) experienced neurological worsening, 9 (3.0%) having postoperative hemorrhage and 3 (1.0%) permanent neurological deficits. Bleeding was associated with postoperative hemorrhage (p < 0.0001). The negative predictive values to rule out any postoperative hemorrhage or hemorrhages >1 cm were 92 and 100%, respectively. Number of samples, location and pathology had no significant influence on postoperative hemorrhage. CONCLUSION: Stereotactic biopsies have a low risk of symptomatic hemorrhages. Intraoperative bleeding is a surveillance parameter of hemorrhage on CT. Therefore, routine postoperative CT may be restricted to patients who show intraoperative bleeding. PMID- 24481034 TI - An FPGA-based rapid wheezing detection system. AB - Wheezing is often treated as a crucial indicator in the diagnosis of obstructive pulmonary diseases. A rapid wheezing detection system may help physicians to monitor patients over the long-term. In this study, a portable wheezing detection system based on a field-programmable gate array (FPGA) is proposed. This system accelerates wheezing detection, and can be used as either a single-process system, or as an integrated part of another biomedical signal detection system. The system segments sound signals into 2-second units. A short-time Fourier transform was used to determine the relationship between the time and frequency components of wheezing sound data. A spectrogram was processed using 2D bilateral filtering, edge detection, multithreshold image segmentation, morphological image processing, and image labeling, to extract wheezing features according to computerized respiratory sound analysis (CORSA) standards. These features were then used to train the support vector machine (SVM) and build the classification models. The trained model was used to analyze sound data to detect wheezing. The system runs on a Xilinx Virtex-6 FPGA ML605 platform. The experimental results revealed that the system offered excellent wheezing recognition performance (0.912). The detection process can be used with a clock frequency of 51.97 MHz, and is able to perform rapid wheezing classification. PMID- 24481035 TI - Reliability, validity, and significance of assessment of sense of contribution in the workplace. AB - The purpose of this study was to assess the validity and reliability of the Sense of Contribution Scale (SCS), a newly developed, 7-item questionnaire used to measure sense of contribution in the workplace. Workers at 272 organizations answered questionnaires that included the SCS. Because of non-participation or missing data, the number of subjects included in the analyses for internal consistency and validity varied from 1,675 to 2,462 (response rates 54.6%-80.2%). Fifty-four workers were included in the analysis of test-retest reliability (response rate, 77.1%). The SCS showed high internal consistency (Cronbach's alpha coefficients in men and women were 0.85 and 0.86, respectively) and test retest reliability (intraclass correlation coefficient = 0.91). Significant (p < 0.001), positive, moderate correlations were found between the SCS score and scores for organization-based self-esteem and work engagement in both genders, which support the SCS's convergent and discriminant validity. The criterion validity of the SCS was supported by the finding that in both genders, the SCS scores were significantly (p < 0.05) and inversely associated with psychological distress and sleep disturbance in crude and in multivariable analyses that adjusted for demographics, organization-based self-esteem, work engagement, effort-reward ratio, workplace bullying, and procedural and interactional justice. The SCS is a psychometrically satisfactory measure of sense of contribution in the workplace. The SCS provides a new and useful instrument to measure sense of contribution, which is independently associated with mental health in workers, for studies in organizational science, occupational health psychology and occupational medicine. PMID- 24481036 TI - Inkjet patterned superhydrophobic paper for open-air surface microfluidic devices. AB - We present a facile approach for the fabrication of low-cost surface biomicrofluidic devices on superhydrophobic paper created by drop-casting a fluoroacrylic copolymer onto microtextured paper. Wettability patterning is performed with a common household printer, which produces regions of varying wettability by simply controlling the intensity of ink deposited over prespecified domains. The procedure produces surfaces that are capable of selective droplet sliding and adhesion, when inclined. Using this methodology, we demonstrate the ability to tune the sliding angles of 10 MUL water droplets in the range from 13 degrees to 40 degrees by printing lines of constant ink intensity and varied width from 0.1 mm to 2 mm. We also formulate a simple model to predict the onset of droplet sliding on printed lines of known width and wettability. Experiments demonstrate open-air surface microfluidic devices that are capable of pumpless transport, mixing and rapid droplet sampling (~0.6 MUL at 50 Hz). Lastly, post treatment of printed areas with pH indicator solutions exemplifies the utility of these substrates in point-of-care diagnostics, which are needed at geographical locations where access to sophisticated testing equipment is limited or non-existent. PMID- 24481037 TI - Unusual intracytoplasmic crystalline inclusions in chronic myelomonocytic leukemia with double minute chromosomes and MYC amplification: a rare case. AB - Chronic myelomonocytic leukemia (CMML) is a clonal hematological disease characterized by the presence of peripheral blood monocytosis and bone marrow dysplasia. Double minute chromosomes (dmin) are rare and intracytoplasmic crystalline inclusions are very rare in hematologic malignancies. We present a case of CMML with dmin and unusual intracytoplasmic crystalline inclusions. To our knowledge, no such case has previously been reported. PMID- 24481038 TI - Zinc and cobalt complexes based on tripodal ligands: synthesis, structure and reactivity toward lactide. AB - The coordination chemistry of a series of pro-ligands ([L1]-[L6]) with cobalt and zinc derivatives has been studied. All complexes have been characterized by multinuclear NMR, elemental analysis, and by single-crystal X-ray diffraction studies. Polymerization of rac-lactide takes place at 130 degrees C in the presence of cobalt and zinc complexes to yield polymers under solvent free conditions with controlled molecular masses and narrow polydispersities. PMID- 24481039 TI - Nicotine exerts neuroprotective effects against beta-amyloid-induced neurotoxicity in SH-SY5Y cells through the Erk1/2-p38-JNK-dependent signaling pathway. AB - Epidemiological data have indicated that smoking tobacco can decrease the risk of developing Alzheimer's disease (AD). Nicotine, a main component of tobacco, has been shown to have therapeutic effects in AD. The aim of the present study was to assess the neuroprotective effects of nicotine against toxicity induced by beta amyloid (Abeta) in relation to cell apoptosis, and to elucidate the role of the activation of the Erk1/2-p38-JNK pathway and the modulation of anti-apoptotic proteins in the nicotine-induced neuroprotective effects. We performed in vitro and in vivo experiments using SH-SY5Y cells and C57BL/6 mice, respectively. The effects of nicotine on cell apoptosis were determined by flow cytmetry and microscopic observation. The effects of nicotine on the expression of anti apoptotic proteins were also determined by western blot analysis. Our results demonstrated that nicotine protected the SH-SY5Y cells against Abeta25-35-induced toxicity by inhibiting apoptosis and upregulating the expression of anti apoptotic proteins. As shown by our in vivo experiments, nicotine effectively ameliorated the impairment in spatial working memory induced by Abeta25-35; this was confirmed by a Morris water maze navigation test and further supported by the upregulation of Bcl-2 in the hippocampus of Abeta25-35-injected mice treated with nicotine. The phosphorylation of Erk1/2, p38 and JNK increased following treatment with nicotine in the SH-SY5Y cells, whereas caspase-3 activation was inhibited by treatment with nicotine prior to exposure to Abeta25-35. Of note, these effects of nicotine against Abeta25-35-induced damage were abolished by inhibitors of Erk1/2, p38 and JNK phosphorylation. These findings suggest that nicotine prevents Abeta25-35-induced neurotoxicity through the inhibition of neuronal apoptosis, and may thus prove to be a potential preventive or therapeutic agent for AD. PMID- 24481040 TI - Atorvastatin protects vascular smooth muscle cells from TGF-beta1-stimulated calcification by inducing autophagy via suppression of the beta-catenin pathway. AB - BACKGROUND: Arterial calcification is a major event in the progression of atherosclerosis. It is reported that statins exhibit various protective effects against vascular smooth muscle cell (VSMC) inflammation and proliferation in cardiovascular remodeling. Although statins counteract atherosclerosis, the molecular mechanisms of statins on the calcium release from VSMCs have not been clearly elucidated. METHODS: Calcium content of VSMCs was measured using enzyme linked immunosorbent assay (ELISA). The expression of proteins involved in cellular transdifferentiation was analyzed by western blot. Cell autophagy was measured by fluorescence microscopic analysis for acridine orange staining and transmission electron microscopy analysis. The autophagic inhibitors (3-MA, chloroquine, NH4Cl and bafilomycin A1) and beta-catenin inhibitor JW74 were used to assess the effects of atorvastatin on autophagy and the involvement of beta catenin on cell calcification respectively. Furthermore, cell transfection was performed to overexpress beta-catenin. RESULTS: In VSMCs, atorvastatin significantly suppressed transforming growth factor-beta1 (TGF-beta1)-stimulated calcification, accompanied by the induction of autophagy. Downregulation of autophagy with autophagic inhibitors significantly suppressed the inhibitory effect of atorvastatin on cell calcification. Moreover, the beneficial effect of atorvastatin on calcification and autophagy was reversed by beta-catenin overexpression. Conversely, JW74 supplement enhanced this effect. CONCLUSION: These data demonstrated that atorvastatin protect VSMC from TGF-beta1-stimulated calcification by inducing autophagy through suppression of the beta-catenin pathway, identifying autophagy induction might be a therapeutic strategy for use in vascular calcification. PMID- 24481041 TI - Lateral junction dynamics lead the way out. AB - Epithelial cell layers need to be tightly regulated to maintain their integrity and correct function. Cell integration into epithelial sheets is now shown to depend on the N-WASP-regulated stabilization of cortical F-actin, which generates distinct patterns of apical-lateral contractility at E-cadherin-based cell-cell junctions. PMID- 24481042 TI - Methyltransferases modulate RNA stability in embryonic stem cells. AB - Emerging data support that RNA methylation plays important roles in RNA processing and metabolism. The methyltransferases Mettl3 and Mettl14 are shown to catalyse N(6)-methyladenosine (m(6)A) RNA modification in embryonic stem cells (ESCs). This m(6)A modification controls RNA metabolism and functions to destabilize mRNAs encoding developmental regulators to help sustain ESC self renewal. PMID- 24481046 TI - Digital PCR on an integrated self-priming compartmentalization chip. AB - An integrated on-chip valve-free and power-free microfluidic digital PCR device is for the first time developed by making use of a novel self-priming compartmentalization and simple dehydration control to realize 'divide and conquer' for single DNA molecule detection. The high gas solubility of PDMS is exploited to provide the built-in power of self-priming so that the sample and oil are sequentially sucked into the device to realize sample self compartmentalization based on surface tension. The lifespan of its self-priming capability was about two weeks tested using an air-tight packaging bottle sealed with a small amount of petroleum jelly, which is significant for a practical platform. The SPC chip contains 5120 independent 5 nL microchambers, allowing the samples to be compartmentalized completely. Using this platform, three different abundances of lung cancer related genes are detected to demonstrate the feasibility and flexibility of the microchip for amplifying a single nucleic acid molecule. For maximal accuracy, within less than 5% of the measurement deviation, the optimal number of positive chambers is between 400 and 1250 evaluated by the Poisson distribution, which means one panel can detect an average of 480 to 4804 template molecules. This device without world-to-chip connections eliminates the constraint of the complex pipeline control, and is an integrated on-chip platform, which would be a significant improvement to digital PCR automation and more user-friendly. PMID- 24481047 TI - Polycystic kidney disease with renal calculi treated by percutaneous nephrolithotomy: a report of 11 cases. AB - OBJECTIVE: To evaluate the efficacy and safety of percutaneous nephrolithotomy (PCNL) in the treatment of congenital autosomal dominant polycystic kidney disease (ADPKD) with renal calculi. METHODS: A total of 11 cases of ADPKD with renal calculi were retrospectively studied. All cases were treated by PCNL and clinical parameters such as age, sex, stone burden, operation time, blood loss, complications and perioperative serum creatinine levels were collected and analyzed. All patients were routinely followed up for 36 months postoperatively and the efficacy and safety of PCNL in the management of ADPKD with renal calculi were assessed. RESULTS: All procedures were successful without conversion to open surgery. The mean stone burden was 3.4 +/- 0.7 cm (range 2.5-4.6 cm). The overall stone clearance rate was 81.8% (9/11). Two patients received extracorporeal shock wave lithotripsy postoperatively because of residual calculi. The mean operation time was 77 +/- 23.5 min (range 45-128 min) and the mean blood loss was 147 +/- 56 ml (range 80-260 ml). The mean preoperative serum creatinine level was 15.13 +/- 3.30 mg/dl (range 9.90-20.14 mg/dl) and the mean postoperative serum creatinine level was 14.28 +/- 2.24 mg/dl (range 10.76-17.28 mg/dl). Four cases had fever postoperatively (36.4%). Three patients had hemorrhage and two patients received blood transfusion. No patient had peripheral viscera injury. Statistical comparison showed that PCNL had no impact on perioperative renal function (p > 0.05). CONCLUSIONS: In spite of anatomical deformation and impairment of renal function, PCNL is an effective and safe procedure in managing ADPKD with renal calculi. PMID- 24481048 TI - Late-life effects of chronic methamphetamine exposure during puberty on behaviour and corticostriatal mono-amines in social isolation-reared rats. AB - Chronic methamphetamine (MA) abuse results in an acute psychosis indistinguishable from paranoid schizophrenia. However, less is known of the interaction between MA use and environmental insults, and how this contributes to late-onset psychopathology. Using social isolation rearing (SIR), a neurodevelopmental animal model of schizophrenia, we investigated the association between changes in corticostriatal mono-amines and putative behaviours related to MA-induced psychosis in isolation and group-housed rats following chronic MA or saline exposure. Weaned male offspring of MA-naive female Wistar rats, either group- or isolation-housed from postnatal day (PND) +21, received saline (2 ml/kg s.c. b.i.d.) or an escalating dose of MA (0.2-6 mg/kg s.c. b.i.d.) for 16 days from PND +35 to +50. On PND +78, offspring were tested for deficits in social interactive behaviour (SIB) and prepulse inhibition (PPI) of startle, with frontal cortex and striatum harvested for the assessment of mono-amine concentrations. SIR significantly reduced rearing time, staying together, approaching and anogenital sniffing (outward-directed SIB), but increased self grooming and locomotor activity (self-directed SIB), and also induced profound deficits in PPI. Pubertal MA exposure in group-housed animals also induced similar alterations in outward- and self-directed SIB and reduced PPI. Combined MA+SIR exposure evoked a similarly intense behavioural response as SIR or MA separately, with no exacerbation evident. Neither treatment separately nor together affected corticostriatal serotonin or noradrenaline levels, although frontal cortical dopamine (DA) levels were significantly increased in SIR and MA+group-housed animals. A trend towards further elevated frontal cortical DA was noted in the MA+SIR treatment group. Striatal DA was unaltered by all treatments. This study provides the first evidence that chronic pubertal MA exposure evokes postpubertal psychosis-like behaviours in rats of similar intensity to that induced by a neurodevelopmental animal model of schizophrenia (SIR). Moreover, the study is unique in that these behavioural changes occur together with associated changes in frontal cortical but not striatal DA, without affecting other mono-amines, and strongly implicates frontal cortical DA changes in the psychotogenic effects of early-life MA exposure or environmental insult. Although MA exposure in animals with a history of environmental insult (i.e. MA+SIR) has similar effects, combined exposure was not additive with regard to behavioural or neurochemical changes. We conclude that a ceiling effect or compensatory mechanisms prevent more pronounced neurobehavioural deficits occurring following MA+SIR treatment, at least under the current study conditions. PMID- 24481049 TI - Intestinal microparticles and inflammatory bowel diseases: incidental or pathogenic? PMID- 24481050 TI - Interleukin 23 in Crohn's disease. AB - : Crohn's disease (CD) is a lifelong inflammatory condition with underlying environmental and genetic components. CD affects multiple parts of the gastrointestinal tract, and it has a growing incidence in Western societies. IL 23 receptor variants have been identified as susceptibility or resistance factors for CD in genome-wide association studies. Accordingly, IL-23 is required for the development of experimental inflammatory bowel disease in many murine models. IL 23 receptor is expressed by both innate and adaptive immune cells, which include Th17, natural killer T, gammadelta T cells, and RORgammat innate lymphoid cells all of which are capable of secreting IL-17A, IL-17F, IL-22, and interferon-gamma upon IL-23 stimulation. During the past decade, pathogenic and protective roles have been described for these cytokines in the inflammatory bowel disease pathogenesis. More recently, innate lymphoid cells have been implicated in disease development. In this review, we have summarized and discussed these findings with an emphasis not only on the contribution of Th17 but also on innate lymphoid cells to disease etiology. PMID- 24481053 TI - The use of modern quality improvement approaches to strengthen African health systems: a 5-year agenda. AB - There is a growing international consensus that African health systems need to improve, but no agreement on how to accomplish this. From the perspective of modern quality improvement (QI), a central issue for low performance in these health systems is the relative neglect of health-care processes. Both health system leaders and international donors have focused their efforts elsewhere, producing noteworthy health gains. But these gains are at risk if health systems do not develop the capacity to study and improve care processes. Substantial experience with QI in Africa shows impressive potential for broad-based process improvement. But this experience also highlights the need for modifying these growing programs to incorporate a more rigorous learning component to address challenges that have emerged recently. The addition of a region-wide knowledge management program could increase the efficiency of each country's QI program by learning from the experiences of other programs. With a coordinated donor initiative, it is reasonable to project that within 5 years, evidence-based improvement will become a norm in health services, and African health systems will approach the model of a learning organization. PMID- 24481051 TI - Quantitative light-induced fluorescence to measure enamel remineralization in vitro. AB - The aim of this study was to compare the ability of quantitative light-induced fluorescence (QLF) and surface microhardness (SMH) to measure the remineralization of enamel subsurface lesions, using a pH-cycling model including treatment with 0-ppm, 550-ppm or 1,100-ppm sodium fluoride (NaF) dentifrices. METHODS: Subsurface lesions were created in human enamel specimens (n = 36) and exposed to a remineralization pH-cycling model for 14 days. The pH-cycling model was performed in an automated system where specimens were subjected to a demineralizing solution for 20 min and treatment for 1 min and were then remineralized for 7 h 39 min, 3 times daily. The treatments consisted of 3 NaF, silica-containing dentifrices (0 ppm F; 550 ppm F; 1,100 ppm F). The outcome variables were: change from baseline in surface hardness and percentage change from baseline in fluorescence. An ANCOVA explored differences between different treatment groups (at the p < 0.05 level). Associations between QLF and SMH were evaluated using Spearman's correlation coefficient. RESULTS: The percentage SMH changes were 14.9 +/- 2.1%, 56.6 +/- 9.6% and 103.9 +/- 14.6% for the 0-, 550- and 1,100-ppm F dentifrices, respectively. The percentage fluorescence changes were 15.6 +/- 7.1%, 59.8 +/- 11.9% and 85 +/- 13.2%, respectively. The differences between all pairwise comparisons were statistically significant for both methods (p = 0.001). QLF correlated with SMH (r = 0.67). CONCLUSIONS: Both the SMH and QLF methods demonstrated a significant F dose response for toothpaste in this in vitro remineralization model, and both methods were able to distinguish treatments with different F levels. PMID- 24481052 TI - The association of hospital quality ratings with adverse events. AB - OBJECTIVE: To understand how patient-reported quality is related to adverse events (AEs). DESIGN: Random sample telephone survey. SETTING: Sixteen acute care Massachusetts hospitals. PARTICIPANTS: Two thousand and five hundred and eight two of 4163 (62% response rate) eligible adult patients. MAIN OUTCOME MEASURES: Patients hospitalized from 1 April 2003 to 1 October 2003 provided global quality ratings and whether they experienced AEs. Service recovery, defined as efforts by a service provider to return customers to a state of satisfaction after a lapse in service, was operationalized as high participation in one's care, timely discharge and disclosure of the circumstances of an AE. RESULTS: Of respondents, 82% rated the quality as high and 23% reported one or more AEs. Patients with no AEs gave higher quality ratings (85 vs. 77 or 62% for patients with 1 or 2+ AEs, respectively, P < 0.001). Patients were more likely to rate the quality high if they reported high participation (86 vs. 53%), or felt discharge timing was just right (85 vs. 64%); for those with AEs, ratings were higher among those reporting disclosure (82 vs. 66%) (all P < 0.01). In adjusted analyses, patients with AEs experiencing all three service recovery components rated their quality higher (86 vs. 68%, P < 0.01). CONCLUSIONS: Patients with AEs rate the quality of care lower than others. However, patients with AEs who experienced 'service recovery' as we defined it rated their quality of care at levels similar to those who did not experience AEs. Hospitals seeking to improve quality ratings might consider efforts to ensure patient safety and to address AEs in a transparent and responsive way. PMID- 24481054 TI - Enantioselective hydroacylation of N-vinylindole-2-carboxaldehydes. AB - We report catalytic, enantioselective intramolecular hydroacylation of N vinylindole-2-carboxaldehydes. These hydroacylation reactions occur in the presence of a readily accessible rhodium catalyst and form chiral, non-racemic 2,3-dihydro-1H-pyrrolo[1,2-a]indol-1-ones in high yields with excellent enantioselectivities. PMID- 24481059 TI - Paraneoplastic pemphigus occurs most commonly in indolent B cell lymphoma. PMID- 24481057 TI - A facile approach for high surface area electrospun TiO2 nanostructures for photovoltaic and photocatalytic applications. AB - A rice-shaped TiO2-ZnO composite was prepared by electrospinning a mixture comprising the precursors of TiO2 and ZnO in polyvinyl acetate polymer dissolved in N,N-dimethyl acetamide. The electrospun nanofibers upon heat treatment in air resulted in collapse of the continuous fiber morphology and the formation of the rice-shaped TiO2-ZnO composite. The TiO2-ZnO composite was then treated with dilute acetic acid under hydrothermal conditions to etch ZnO from the TiO2-ZnO composite to get coral-shaped anisotropic TiO2. The structural anisotropy of TiO2 produced by the selective etching of ZnO resulted in a high surface area of 148 m(2) g(-1) for the TiO2. The initial and final materials were characterized by scanning electron microscopy, transmission electron microscopy, Raman and XPS spectroscopies, powder X-ray diffraction and BET surface area measurements. The utility of the anisotropic TiO2 in photovoltaics and photocatalysis was explored. Dye-sensitized solar cells fabricated using the TiO2 showed a conversion efficiency of 6.54% as against 4.8% for a control experiment with the rice-shaped TiO2. The anisotropic TiO2 also showed good photocatalysis in the degradation of methyl orange dye and phenol. PMID- 24481056 TI - Not all measures of hyperinflation are created equal: lung structure and clinical correlates of gas trapping and hyperexpansion in COPD: the Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study. AB - BACKGROUND: Hyperinflation refers to a nonspecific increase in absolute lung volumes and has a poor prognosis in COPD. The relative contribution of increased airways resistance and increased parenchymal compliance to hyperinflation of each absolute lung volume is poorly understood. We hypothesized that increased residual volume (RV) and RV/total lung capacity (TLC) would be associated with reduced airway lumen dimensions, whereas increased functional residual capacity (FRC), TLC, and reduced inspiratory capacity (IC)/TLC would be associated with emphysema on CT scan. We examined whether clinical characteristics differed accordingly. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) COPD Study recruited smokers aged 50 to 79 years who were free of clinical cardiovascular disease. Gas trapping was defined as RV or RV/TLC greater than the upper limit of normal and hyperexpansion as FRC or TLC greater than the upper limit of normal or IC/TLC less than the lower limit of normal. Airway lumen diameters and percent emphysema < -950 Hounsfield units were quantified on CT images. Analyses were adjusted for age, sex, body size, race/ethnicity, education, and smoking. RESULTS: Among 116 participants completing plethysmography, 15% had gas trapping, 18% has hyperexpansion, and 22% had both. Gas trapping was associated with smaller airway lumen diameters (P = .001), greater dyspnea (P = .01), and chronic bronchitis (P = .03). Hyperexpansion was associated with percent emphysema (P < .001), lower BMI (P = .04), and higher hemoglobin concentration (P = .001). CONCLUSIONS: Gas trapping and hyperexpansion on plethysmography were associated with distinct differences in lung structure and clinical characteristics. Absolute lung volumes should not be considered equivalent in their estimation of hyperinflation and provide insight into the extent of airway and parenchymal abnormalities in COPD. PMID- 24481060 TI - Design and synthesis of chiral Zn2+ complexes mimicking natural aldolases for catalytic C-C bond forming reactions in aqueous solution. AB - Extending carbon frameworks via a series of C-C bond forming reactions is essential for the synthesis of natural products, pharmaceutically active compounds, active agrochemical ingredients, and a variety of functional materials. The application of stereoselective C-C bond forming reactions to the one-pot synthesis of biorelevant compounds is now emerging as a challenging and powerful strategy for improving the efficiency of a chemical reaction, in which some of the reactants are subjected to successive chemical reactions in just one reactor. However, organic reactions are generally conducted in organic solvents, as many organic molecules, reagents, and intermediates are not stable or soluble in water. In contrast, enzymatic reactions in living systems proceed in aqueous solvents, as most of enzymes generally function only within a narrow range of temperature and pH and are not so stable in less polar organic environments, which makes it difficult to conduct chemoenzymatic reactions in organic solvents. In this review, we describe the design and synthesis of chiral metal complexes with Zn2+ ions as a catalytic factor that mimic aldolases in stereoselective C-C bond forming reactions, especially for enantioselective aldol reactions. Their application to chemoenzymatic reactions in aqueous solution is also presented. PMID- 24481062 TI - Risk-association of five SNPs in TOX3/LOC643714 with breast cancer in southern China. AB - The specific mechanism by which low-risk genetic variants confer breast cancer risk is currently unclear, with contradictory evidence on the role of single nucleotide polymorphisms (SNPs) in TOX3/LOC643714 as a breast cancer susceptibility locus. Investigations of this locus using a Chinese population may indicate whether the findings initially identified in a European population are generalizable to other populations, and may provide new insight into the role of genetic variants in the etiology of breast cancer. In this case-control study, 623 Chinese female breast cancer patients and 620 cancer-free controls were recruited to investigate the role of five SNPs in TOX3/LOC643714 (rs8051542, rs12443621, rs3803662, rs4784227, and rs3112612); Linkage disequilibrium (LD) pattern analysis was performed. Additionally, we evaluated how these common SNPs influence the risk of specific types of breast cancer, as defined by estrogen receptor (ER) status, progesterone receptor (PR) status and human epidermal growth factor receptor 2 (HER2) status. Significant associations with breast cancer risk were observed for rs4784227 and rs8051542 with odds ratios (OR) of 1.31 ((95% confidence intervals (CI), 1.10-1.57)) and 1.26 (95% CI, 1.02-1.56), respectively, per T allele. The T-rs8051542 allele was significantly associated with ER-positive and HER2-negative carriers. No significant association existed between rs12443621, rs3803662, and rs3112612 polymorphisms and risk of breast cancer. Our results support the hypothesis that the applicability of a common susceptibility locus must be confirmed among genetically different populations, which may together explain an appreciable fraction of the genetic etiology of breast cancer. PMID- 24481063 TI - Enhanced bonding strength of hydrophobically modified gelatin films on wet blood vessels. AB - The bonding behavior between hydrophobically modified alkaline-treated gelatin (hm-AlGltn) films and porcine blood vessels was evaluated under wet conditions. Hexanoyl (Hx: C6), decanoyl (Dec: C10), and stearyl (Ste: C18) chlorides were introduced into the amino groups of AlGltn to obtain HxAlGltn, DecAlGltn, and SteAlGltn, respectively, with various modification percentages. The hm-AlGltn was fabricated into films and thermally crosslinked to obtain water-insoluble films (t-hm-AlGltn). The 42% modified t-HxAlGltn (t-42HxAlGltn) possessed higher wettability than the 38% modified t-DecAlGltn (t-38DecAlGltn) and the 44% modified t-SteAlGltn (t-44SteAlGltn) films, and the t-42HxAlGltn film showed a high bonding strength with the blood vessel compared with all the hm-AlGltn films. Histological observations indicated that t-42HxAlGltn and t-38DecAlGltn remained on the blood vessel even after the bonding strength measurements. From cell culture experiments, the t-42HxAlGltn films showed significant cell adhesion compared to other films. These findings indicate that the Hx group easily interpenetrated the surface of blood vessels and effectively enhanced the bonding strength between the films and the tissue. PMID- 24481061 TI - Apoptosis signal regulating kinase 1 (ASK1): potential as a therapeutic target for Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common form of dementia, characterized by a decline in memory and cognitive function. Clinical manifestations of AD are closely associated with the formation of senile plaques and neurofibrillary tangles, neuronal loss and cognitive decline. Apoptosis signal regulating kinase 1 (ASK1) is a mediator of the MAPK pathway, which regulates various cellular responses such as apoptosis, cell survival, and differentiation. Accumulating evidence indicates that ASK1 plays a key role in the pathogenesis of neurodegenerative disorders such as Huntington's disease and AD. Of particular interest, ASK1 is associated with many signaling pathways, which include endoplasmic reticulum (ER) stress-mediated apoptosis, Abeta-induced neurotoxicity, tau protein phosphorylation, and insulin signal transduction. Here, we review experimental evidence that links ASK1 signaling and AD pathogenesis and propose that ASK1 might be a new point of therapeutic intervention to prevent or treat AD. PMID- 24481064 TI - shRNA-mediated XRCC2 gene knockdown efficiently sensitizes colon tumor cells to X ray irradiation in vitro and in vivo. AB - Colon cancer is one of the most common tumors of the digestive tract. Resistance to ionizing radiation (IR) decreased therapeutic efficiency in these patients' radiotherapy. XRCC2 is the key protein of DNA homologous recombination repair, and its high expression is associated with enhanced resistance to DNA damage induced by IR. Here, we investigated the effect of XRCC2 silencing on colon tumor cells' growth and sensitivity to X-radiation in vitro and in vivo. Colon tumor cells (T84 cell line) were cultivated in vitro and tumors originated from the cell line were propagated as xenografts in nude mice. The suppression of XRCC2 expression was achieved by using vector-based short hairpin RNA (shRNA) in T84 cells. We found that the knockdown of XRCC2 expression effectively decreased T84 cellular proliferation and colony formation, and led to cell apoptosis and cell cycle arrested in G2/M phase induced by X-radiation in vitro. In addition, tumor xenograft studies suggested that XRCC2 silencing inhibited tumorigenicity after radiation treatment in vivo. Our data suggest that the suppression of XRCC2 expression rendered colon tumor cells more sensitive to radiation therapy in vitro and in vivo, implying XRCC2 as a promising therapeutic target for the treatment of radioresistant human colon cancer. PMID- 24481065 TI - Int6/eIF3e is essential for proliferation and survival of human glioblastoma cells. AB - Glioblastomas (GBM) are very aggressive and malignant brain tumors, with frequent relapses despite an appropriate treatment combining surgery, chemotherapy and radiotherapy. In GBM, hypoxia is a characteristic feature and activation of Hypoxia Inducible Factors (HIF-1alpha and HIF-2alpha) has been associated with resistance to anti-cancer therapeutics. Int6, also named eIF3e, is the "e" subunit of the translation initiation factor eIF3, and was identified as novel regulator of HIF-2alpha. Eukaryotic initiation factors (eIFs) are key factors regulating total protein synthesis, which controls cell growth, size and proliferation. The functional significance of Int6 and the effect of Int6/EIF3E gene silencing on human brain GBM has not yet been described and its role on the HIFs is unknown in glioma cells. In the present study, we show that Int6/eIF3e suppression affects cell proliferation, cell cycle and apoptosis of various GBM cells. We highlight that Int6 inhibition induces a diminution of proliferation through cell cycle arrest and increased apoptosis. Surprisingly, these phenotypes are independent of global cell translation inhibition and are accompanied by decreased HIF expression when Int6 is silenced. In conclusion, we demonstrate here that Int6/eIF3e is essential for proliferation and survival of GBM cells, presumably through modulation of the HIFs. PMID- 24481066 TI - Three-dimensional stratification of bacterial biofilm populations in a moving bed biofilm reactor for nitritation-anammox. AB - Moving bed biofilm reactors (MBBRs) are increasingly used for nitrogen removal with nitritation-anaerobic ammonium oxidation (anammox) processes in wastewater treatment. Carriers provide protected surfaces where ammonia oxidizing bacteria (AOB) and anammox bacteria form complex biofilms. However, the knowledge about the organization of microbial communities in MBBR biofilms is sparse. We used new cryosectioning and imaging methods for fluorescence in situ hybridization (FISH) to study the structure of biofilms retrieved from carriers in a nitritation anammox MBBR. The dimensions of the carrier compartments and the biofilm cryosections after FISH showed good correlation, indicating little disturbance of biofilm samples by the treatment. FISH showed that Nitrosomonas europaea/eutropha related cells dominated the AOB and Candidatus Brocadia fulgida-related cells dominated the anammox guild. New carriers were initially colonized by AOB, followed by anammox bacteria proliferating in the deeper biofilm layers, probably in anaerobic microhabitats created by AOB activity. Mature biofilms showed a pronounced three-dimensional stratification where AOB dominated closer to the biofilm-water interface, whereas anammox were dominant deeper into the carrier space and towards the walls. Our results suggest that current mathematical models may be oversimplifying these three-dimensional systems and unless the multidimensionality of these systems is considered, models may result in suboptimal design of MBBR carriers. PMID- 24481067 TI - S100 family signaling network and related proteins in pancreatic cancer (Review). AB - The occurrence and development of pancreatic cancer is a complex process convoluted by multi-pathogenies, multi-stages and multi-factors. S100 proteins are members of the S100 family that regulate multiple cellular pathways related to pancreatic cancer progression and metastasis. S100 proteins have a broad range of intracellular and extracellular functions, including the regulation of protein phosphorylation and enzyme activity, calcium homeostasis and the regulation of cytoskeletal components and transcriptional factors. S100 proteins interact with receptor for advanced glycation end-products (RAGE), p53 and p21, which play a role in the degradation of the extracellular matrix (ECM) and metastasis, and also interact with cytoskeletal proteins and the plasma membrane in pancreatic cancer progression and metastasis. S100A11 and S100P are significant tumor markers for pancreatic cancer and unfavorable predictors for the prognosis of patients who have undergone surgical resection. Recently, S100A2 has been suggested to be a negative prognostic biomarker in pancreatic cancer, and the expression of S100A6 may be an independent prognostic impact factor. The expression of S100A4 and S100P is associated with drug resistance, differentiation, metastasis and clinical outcome. This review summarizes the role and significance of the S100 family signaling network and related proteins in pancreatic cancer. PMID- 24481068 TI - Environmental control of nucleophilic catalysis in water. AB - The nucleophilic catalysis by a pyridyl group in ester/phosphate ester hydrolysis was modulated by the microenvironmental hydrophobicity around the catalyst. The catalytic efficiency was enhanced thousands or tens of thousands of times and the activity was maintained well below the pKa of the pyridyl group. PMID- 24481069 TI - Arxula adeninivorans recombinant guanine deaminase and its application in the production of food with low purine content. AB - Purines of exogenous and endogenous sources are degraded to uric acid in human beings. Concentrations >6.8 mg uric acid/dl serum cause hyperuricemia and its symptoms. Pharmaceuticals and the reduction of the intake of purine-rich food are used to control uric acid levels. A novel approach to the latter proposition is the enzymatic reduction of the purine content of food by purine-degrading enzymes. Here we describe the production of recombinant guanine deaminase by the yeast Arxula adeninivorans LS3 and its application in food. In media supplemented with nitrogen sources hypoxanthine or adenine, guanine deaminase (AGDA) gene expression is induced and intracellular accumulation of guanine deaminase (Agdap) protein occurs. The characteristics of the guanine deaminase isolated from wild type strain LS3 and a transgenic strain expressing the AGDA gene under control of the strong constitutive TEF1 promoter were determined and compared. Both enzymes were dimeric and had temperature optima of 55 degrees C with high substrate specificity for guanine and localisation in both the cytoplasm and vacuole of yeast. The enzyme was demonstrated to reduce levels of guanine in food. A mixture of guanine deaminase and other purine degradation enzymes will allow the reduction of purines in purine-rich foods. PMID- 24481070 TI - Conditional protein splicing of alpha-sarcin in live cells. AB - Protein splicing technology harnesses the ability of inteins to ligate protein fragments, forming a mature protein. This report describes our effort to engineer rapamycin-dependent protein splicing of a ribotoxin, called alpha-sarcin. Engineering this system required the investigation of important splicing parameters, including extein context and splicing temperature. We show alpha sarcin splicing is dependent on rapamycin, is inducible with rapid kinetics, and triggers apoptosis in HeLa cells. These findings establish a proof-of-concept for a conditional cell ablation strategy. PMID- 24481071 TI - The plant cell reviews aspects of photobiology: it's a matter of stop 'n go. PMID- 24481072 TI - PIFs: systems integrators in plant development. AB - Phytochrome-interacting factors (PIFs) are members of the Arabidopsis thaliana basic helix-loop-helix family of transcriptional regulators that interact specifically with the active Pfr conformer of phytochrome (phy) photoreceptors. PIFs are central regulators of photomorphogenic development that act to promote stem growth, and this activity is reversed upon interaction with phy in response to light. Recently, significant progress has been made in defining the transcriptional networks directly regulated by PIFs, as well as the convergence of other signaling pathways on the PIFs to modulate growth. Here, we summarize and highlight these findings in the context of PIFs acting as integrators of light and other signals. We discuss progress in our understanding of the transcriptional and posttranslational regulation of PIFs that illustrates the integration of light with hormonal pathways and the circadian clock, and we review seedling hypocotyl growth as a paradigm of PIFs acting at the interface of these signals. Based on these advances, PIFs are emerging as required factors for growth, acting as central components of a regulatory node that integrates multiple internal and external signals to optimize plant development. PMID- 24481073 TI - Mathematical models light up plant signaling. AB - Plants respond to changes in the environment by triggering a suite of regulatory networks that control and synchronize molecular signaling in different tissues, organs, and the whole plant. Molecular studies through genetic and environmental perturbations, particularly in the model plant Arabidopsis thaliana, have revealed many of the mechanisms by which these responses are actuated. In recent years, mathematical modeling has become a complementary tool to the experimental approach that has furthered our understanding of biological mechanisms. In this review, we present modeling examples encompassing a range of different biological processes, in particular those regulated by light. Current issues and future directions in the modeling of plant systems are discussed. PMID- 24481077 TI - Co-incubation of human spermatozoa with anti-VDAC antibody reduced sperm motility. AB - BACKGROUND: Voltage-dependent anion channel (VDAC), a channel protein, exists in the outer mitochondrial membrane of somatic cells and is involved in multiple physiological and pathophysiological processes. Up until now, little has been known about VDAC in male germ cells. In the present study, the relationship between VDAC and human sperm motility was explored. METHODS: Highly motile human spermatozoa were incubated in vitro with anti-VDAC antibody. Total sperm motility, straight line velocity (VSL), curvilinear velocity (VCL), and average path velocity (VAP) were recorded. Intracellular free calcium concentration ([Ca(2+)]i), pH value (pHi), and ATP content were determined. RESULTS: Co incubation with anti-VDAC antibody reduced VSL, VCL, and VAP of spermatozoa. Co incubation further reduced [Ca(2+)]i. Anti-VDAC antibody did not significantly alter total sperm motility, pHi and intracellular ATP content. CONCLUSION: The data suggest that co-incubation with anti-VDAC antibody reduces sperm motility through inhibition of Ca(2+) transmembrane flow. In this way, VDAC participates in the modulation of human sperm motility through mediating Ca(2+) transmembrane transport and exchange. PMID- 24481078 TI - Understanding the oriented-attachment growth of nanocrystals from an energy point of view: a review. AB - Since Penn et al. first discovered the oriented attachment growth of crystals, the oriented attachment mechanism has now become a major research focus in the crystal field, and extensive efforts have been carried out over the past decade to systematically investigate the growth mechanism and the statistical kinetic models. However, most of the work mainly focuses on the experimental results on the oriented attachment growth. In contrast to the previous reviews, our review provides an overview of the recent theoretical advances in oriented attachment kinetics combined with experimental evidences. After a brief introduction to the van der Waals interaction and Coulombic interaction in a colloidal system, the correlation between the kinetic models of oriented attachment growth and the interactions is then our focus. The impact of in situ experimental observation techniques on the study of oriented attachment growth is examined with insightful examples. In addition, the advances in theoretical simulations mainly investigating the thermodynamic origin of these interactions at the atomic level are reviewed. This review seeks to understand the oriented attachment crystal growth from a kinetic point of view and provide a quantitative methodology to rationally design an oriented attachment system with pre-evaluated crystal growth parameters. PMID- 24481075 TI - The UV-B photoreceptor UVR8: from structure to physiology. AB - Low doses of UV-B light (280 to 315 nm) elicit photomorphogenic responses in plants that modify biochemical composition, photosynthetic competence, morphogenesis, and defense. UV RESISTANCE LOCUS8 (UVR8) mediates photomorphogenic responses to UV-B by regulating transcription of a set of target genes. UVR8 differs from other known photoreceptors in that it uses specific Trp amino acids instead of a prosthetic chromophore for light absorption during UV-B photoreception. Absorption of UV-B dissociates the UVR8 dimer into monomers, initiating signal transduction through interaction with CONSTITUTIVELY PHOTOMORPHOGENIC1. However, much remains to be learned about the physiological role of UVR8 and its interaction with other signaling pathways, the molecular mechanism of UVR8 photoreception, how the UVR8 protein initiates signaling, how it is regulated, and how UVR8 regulates transcription of its target genes. PMID- 24481076 TI - Multiple layers of posttranslational regulation refine circadian clock activity in Arabidopsis. AB - The circadian clock is a cellular time-keeper mechanism that regulates biological rhythms with a period of ~24 h. The circadian rhythms in metabolism, physiology, and development are synchronized by environmental cues such as light and temperature. In plants, proper matching of the internal circadian time with the external environment confers fitness advantages on plant survival and propagation. Accordingly, plants have evolved elaborated regulatory mechanisms that precisely control the circadian oscillations. Transcriptional feedback regulation of several clock components has been well characterized over the past years. However, the importance of additional regulatory mechanisms such as chromatin remodeling, protein complexes, protein phosphorylation, and stability is only starting to emerge. The multiple layers of circadian regulation enable plants to properly synchronize with the environmental cycles and to fine-tune the circadian oscillations. This review focuses on the diverse posttranslational events that regulate circadian clock function. We discuss the mechanistic insights explaining how plants articulate a high degree of complexity in their regulatory networks to maintain circadian homeostasis and to generate highly precise waveforms of circadian expression and activity. PMID- 24481074 TI - Phototropism: growing towards an understanding of plant movement. AB - Phototropism, or the differential cell elongation exhibited by a plant organ in response to directional blue light, provides the plant with a means to optimize photosynthetic light capture in the aerial portion and water and nutrient acquisition in the roots. Tremendous advances have been made in our understanding of the molecular, biochemical, and cellular bases of phototropism in recent years. Six photoreceptors and their associated signaling pathways have been linked to phototropic responses under various conditions. Primary detection of directional light occurs at the plasma membrane, whereas secondary modulatory photoreception occurs in the cytoplasm and nucleus. Intracellular responses to light cues are processed to regulate cell-to-cell movement of auxin to allow establishment of a trans-organ gradient of the hormone. Photosignaling also impinges on the transcriptional regulation response established as a result of changes in local auxin concentrations. Three additional phytohormone signaling pathways have also been shown to influence phototropic responsiveness, and these pathways are influenced by the photoreceptor signaling as well. Here, we will discuss this complex dance of intra- and intercellular responses that are regulated by these many systems to give rise to a rapid and robust adaptation response observed as organ bending. PMID- 24481079 TI - Molecular changes during neurodevelopment following second-trimester binge ethanol exposure in a mouse model of fetal alcohol spectrum disorder: from immediate effects to long-term adaptation. AB - Fetal alcohol spectrum disorder (FASD) is an umbrella term that refers to a wide range of behavioral and cognitive deficits resulting from prenatal alcohol exposure. It involves changes in brain gene expression that underlie lifelong FASD symptoms. How these changes are achieved from immediate to long-term effects, and how they are maintained, is unknown. We have used the C57BL/6J mouse to assess the dynamics of genomic alterations following binge alcohol exposure. Ethanol-exposed fetal (short-term effect) and adult (long-term effect) brains were assessed for gene expression and microRNA (miRNA) changes using Affymetrix mouse arrays. We identified 48 and 68 differentially expressed genes in short- and long-term groups, respectively. No gene was common between the 2 groups. Short-term (immediate) genes were involved in cellular compromise and apoptosis, which represent ethanol's toxic effects. Long-term genes were involved in various cellular functions, including epigenetics. Using quantitative RT-PCR, we confirmed the downregulation of long-term genes: Camk1g, Ccdc6, Egr3, Hspa5, and Xbp1. miRNA arrays identified 20 differentially expressed miRNAs, one of which (miR-302c) was confirmed. miR-302c was involved in an inverse relationship with Ccdc6. A network-based model involving altered genes illustrates the importance of cellular redox, stress and inflammation in FASD. Our results also support a critical role of apoptosis in FASD, and the potential involvement of miRNAs in the adaptation of gene expression following prenatal ethanol exposure. The ultimate molecular footprint involves inflammatory disease, neurological disease and skeletal and muscular disorders as major alterations in FASD. At the cellular level, these processes represent abnormalities in redox, stress and inflammation, with potential underpinnings to anxiety. PMID- 24481080 TI - Energy drinks, soft drinks, and substance use among United States secondary school students. AB - OBJECTIVES: Examine energy drink/shot and regular and diet soft drink use among United States secondary school students in 2010-2011, and associations between such use and substance use. METHODS: We used self-reported data from cross sectional surveys of nationally representative samples of 8th-, 10th-, and 12th grade students and conducted multivariate analyses examining associations between beverage and substance use, controlling for individual and school characteristics. RESULTS: Approximately 30% of students reported consuming energy drinks or shots; more than 40% reported daily regular soft drink use, and about 20% reported daily diet soft drink use. Beverage consumption was strongly and positively associated with past 30-day alcohol, cigarette, and illicit drug use. The observed associations between energy drinks and substance use were significantly stronger than those between regular or diet soft drinks and substance use. CONCLUSIONS: This correlational study indicates that adolescent consumption of energy drinks/shots is widespread and that energy drink users report heightened risk for substance use. This study does not establish causation between the behaviors. Education for parents and prevention efforts among adolescents should include education on the masking effects of caffeine in energy drinks on alcohol- and other substance-related impairments, and recognition that some groups (such as high sensation-seeking youth) may be particularly likely to consume energy drinks and to be substance users. PMID- 24481081 TI - Early cannabis use is associated with severity of Cocaine-Induced Psychosis among cocaine smokers in Martinique, French West Indies. AB - OBJECTIVES: Cocaine intoxication can induce transient psychotic symptoms. The principal aim of this study was to determine sociodemographic and clinical characteristics associated with cocaine-induced psychosis (CIP) and to identify clinical factors predicting CIP in crack cocaine smokers in Martinique. The second aim was to identify clinical factors associated with severity of CIP, assessed with the Scale for Assessment of Positive Symptoms for Cocaine-Induced Psychosis (SAPS-CIP). METHODS: Fifty-three cocaine-dependent smokers (45 men and 8 women) seeking treatment for cocaine dependence were included. Patients were assessed using the Cocaine Experience Questionnaire (CEQ), an instrument for the identification of cocaine-induced paranoia, and a French version of the SAPS-CIP, for the severity of CIP. RESULTS: Thirty-five (66%) patients reported cocaine induced paranoia on the CEQ (CIP(+) patients). The mean SAPS-CIP total score was 6.1 +/- 3.7, with a significant difference between CIP(+) and CIP(-) patients (P < 0.0001). Age at first cannabis use was associated with occurrence of CIP on the CEQ, and adolescent-onset cannabis use was associated with severity of hallucinations score on the SAPS-CIP. CONCLUSIONS: Cocaine-induced psychosis is frequent in crack cocaine smokers in Martinique, and early cannabis use is associated with the occurrence and the severity of psychotic symptoms during cocaine intoxication in this population. Patients developing psychotic symptoms during cocaine use began smoking cannabis earlier during adolescence than patients without CIP. These results confirm those of previous studies, highlighting the need to better assess early cannabis use in cocaine users, because early cannabis use is associated with severity of CIP. PMID- 24481082 TI - Analyzing methadone-related deaths. PMID- 24481084 TI - An experimental model of urethral stricture in rabbits using holmium laser under urethroscopic direct visualization. AB - OBJECTIVE: To establish an experimental rabbit model of urethral stricture using holmium laser under direct urethroscopic visualization. METHODS: Sixteen adult male New Zealand rabbits were divided into equally-sized control and experimental groups. All rabbits underwent retrograde urethrography and transurethral endoscopy with a 7.5 F urethroscope after intramuscular anesthetic injection. We used a holmium:YAG laser to injure the distal urethra in all rabbits in the experimental group under direct visualization. Thirty days after surgery, all animals were evaluated with retrograde urethrography and urethroscopy. The flow rate of the isolated urethras was measured to evaluate urethral stricture formation. RESULTS: One rabbit in the experimental group (12.5%) died of infection 4 days after surgery. Thirty days after surgery, retrograde urethrography and urethroscopy revealed strictures in all seven surviving rabbits (87.5%) in the experimental group. The mean flow rate of the isolated urethras was significantly lower in the experimental group than in the control group. CONCLUSION: A rabbit model of urethral stricture can be successfully established using holmium laser under direct urethroscopic visualization, providing an ideal object for research concerning the pathogenesis and molecular biology of urethral strictures. PMID- 24481087 TI - [What has changed with the new European Society of Cardiology/European Society of Hypertension guideline?]. PMID- 24481085 TI - Biannual fluoride varnish applications and caries incidence in preschoolers: a 24 month follow-up randomized placebo-controlled clinical trial. AB - Sound evidence on the effectiveness of fluoride varnishes (FV) to reduce caries incidence in preschool children is lacking. OBJECTIVE: To assess whether the application of FV in preschool children at 6-month intervals decreases the incidence of caries and produces any adverse effects. METHODS: A randomized, examiner- and patient-blind, placebo-controlled, parallel-group design, clinical trial, comprising 1- to 4-year-old children, 100 in each group (FV or placebo varnish, PV), was conducted in Rio de Janeiro, Brazil. Two trained pediatric dentists performed the clinical examinations (kappa = 0.85). Dental caries was recorded at the d2 (cavitated enamel) and d3 (dentine) levels using the International Caries Diagnosis and Assessment System. RESULTS: At baseline, the mean age of the participants was 2.4 years (SD 0.9) and the mean d3mfs was 0.8 (SD 1.9). Most of the children brushed their teeth with fluoride toothpaste and consumed fluoridated tap water. After 24 months, 89 and 92 children of the test and the control groups were analyzed, respectively. A total of 32 (35.9%) children in the FV group and 43 (46.7%) in the PV group presented new dentine caries lesions (chi(2) test; p = 0.14), showing relative and absolute risk reductions of 23% (95% CI: -9.5 to 45.9) and 11% (95% CI: -3.5 to 25.0). The mean caries increment differences between the test and control groups were -0.8 (95% CI: -2.0 to 0.4) at the d2 level and -0.7 (95% CI: -1.9 to 0.4) at the d3 level. Only 2 minor complaints regarding the intervention were reported. CONCLUSION: Although safe and well accepted, twice-yearly professional FV application, during 2 years, did not result in a significant decrease in caries incidence. PMID- 24481088 TI - [Stable coronary artery disease management: what has changed in the 2013 European Society of Cardiology guideline?]. PMID- 24481090 TI - Left atrial fibrosis affects left ventricular systolic function in patients with atrial fibrillation. PMID- 24481089 TI - The degree of left atrial structural remodeling impacts left ventricular ejection fraction in patients with atrial fibrillation. AB - OBJECTIVES: The extent of left atrial (LA) wall structural remodeling (fibrosis) detected by late gadolinium enhancement-magnetic resonance imaging (LGE-MRI) is correlated with advanced atrial fibrillation (AF). The concomitant occurrence of AF and left ventricular (LV) dysfunction is not uncommon. We studied the effect of LA fibrosis, a confounder of both AF and LV dysfunction, on LV ejection fraction (EF). STUDY DESIGN: For the analysis, we identified and included 384 patients from our retrospective AF database who underwent LGE-MRI and transthoracic echocardiography prior to AF ablation. Based on the degree of LA fibrosis, patients were categorized into four stages as: Utah 1 (<5% LA fibrosis), Utah 2 (5-20% fibrosis), Utah 3 (20-35% fibrosis), and Utah 4 (>35% fibrosis). RESULTS: The average pre-ablation LVEF was 60.5%+/-8.5% (n=24) in Utah stage 1 patients, 55.7%+/-10.3% (n=240) in Utah stage 2 patients, 51.7+/-11.5% (n=90) in Utah stage 3 patients, and 48.9%+/-11.6% (n=30) in Utah stage 4 patients (p<0.001, one-way ANOVA). The percentage of LA fibrosis was significantly negatively correlated to LVEF pre-ablation in a univariate analysis (p<0.001). In a multivariate model accounting for age, gender, AF type, and comorbidities such as diabetes and hypertension, Utah stage remained a significant predictor of pre-ablation EF (p<0.001). CONCLUSION: Patients with extensive LA fibrosis appear to have depressed LV function pre-ablation, suggesting that structural remodeling in the LA may also be triggering and promoting remodeling within the ventricular myocardium. PMID- 24481091 TI - [Relation between mean platelet volume and subclinical atherosclerosis in patients with metabolic syndrome]. AB - OBJECTIVES: Metabolic syndrome (MetS) is associated with increased cardiovascular morbidity and mortality. There is evidence of platelet activation in MetS. Mean platelet volume (MPV), a determinant of platelet activation, is a newly emerging risk factor for atherothrombosis. Therefore, we investigated the possible association between subclinical atherosclerosis, as evaluated by carotid intima media thickness (CIMT) measurement and MPV, in MetS patients. STUDY DESIGN: Seventy-four patients with MetS were enrolled in the study. Patients were divided into two groups according to CIMT measurement: 35 patients with CIMT >=1.0 mm were in Group 1 and 39 patients with CIMT <1.0 mm were in Group 2. MPV was measured using an automated blood cell counter. RESULTS: The MPV level was significantly higher in patients with CIMT >=1.0 mm than in patients with CIMT <1.0 mm (8.2+/-0.7 vs. 7.8+/-0.6 fl; p=0.01). In our study, we observed that platelet count was lower in KIMK >=1.0 mm group and this finding was also found to be statistically significant. CONCLUSION: The risk of atherosclerosis could be shown by following the MPV values in MetS patients. Therefore, our results suggest that MPV is an important marker for early detection of atherosclerotic risk in patients with MetS. PMID- 24481092 TI - Evaluation of Tp-e interval and Tp-e/QT ratio in patients with rheumatoid arthritis. AB - OBJECTIVES: Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarization and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. The aim of this study was to evaluate ventricular repolarization by using the Tp-e interval and Tp-e/QT ratio in patients with rheumatoid arthritis (RA), and to assess the relation with inflammation. STUDY DESIGN: Ninety-six patients (72 females, 24 males; mean age 43.8+/-11.8 years) with RA and 50 controls (35 females, 15 males; mean age 44.2+/ 11.1 years) were included. From the 12-lead electrocardiogram, Tp-e interval and Tp-e/QT ratio were measured. Blood samples were taken for erythrocyte sedimentation rate (ESR) and plasma levels of C-reactive protein (CRP). These parameters were compared between groups. The relationship between ventricular repolarization and inflammation was assessed by Pearson correlation coefficients. RESULTS: Tp-e interval and Tp-e/QT ratio were increased in RA patients compared to the controls (72.6+/-8.2 vs 66.4+/-8.5 ms, 0.20+/-0.02 vs 0.18+/-0.02; p<0.001 and p<0.001, respectively). The Tp-e interval was significantly correlated with CRP, ESR, and disease activity score (DAS-28) (r=0.56, p<0.001, r=0.57, p<0.001, and r=0.29, p=0.02, respectively). The Tp-e/QT ratio was also correlated with CRP, ESR, and DAS-28 score (r=0.43, p<0.001, r=0.53, p<0.001, and r=0.25, p=0.03, respectively). CONCLUSION: In RA patients, the increased frequency of ventricular arrhythmias may be explained by increased indexes of ventricular repolarization and their relationship with inflammation. PMID- 24481094 TI - [Injured accomplice in mitral stenosis: the right ventricle]. PMID- 24481093 TI - [Evaluation of the long-term effect of percutaneous balloon valvuloplasty on right ventricular function using tissue Doppler imaging in patients with mitral stenosis]. AB - OBJECTIVES: We investigated the effects of percutaneous mitral balloon valvuloplasty (PMBV) on right ventricular function in the long term using tissue Doppler imaging. STUDY DESIGN: Twenty-seven patients who underwent successful PMBV were enrolled in the study. Echocardiographic examination, including color tissue Doppler imaging, was done from the lateral tricuspid annulus 24 hours before the intervention, and the examination was repeated 24 hours and 6 months after the intervention. RESULTS: At 24 hours after the intervention, S wave velocity and A' wave velocity were seen to have increased significantly (9.52+/ 1.85 cm/s vs. 10.92+/-1.20 cm/s, p=0.012; -10.44+/-2.64 cm/s vs. -11.73+/-2.05 cm/s, p=0.029, respectively). E' wave velocity and E'/A' ratio did not change significantly (p>0.05 for both). In the late period, S wave velocity was similar to the value in the early period and significantly higher than the basal level (9.52+/-1.85 cm/s vs. 10.69+/-1.72 cm/s, p=0.023). However, A' wave velocity in the late period was decreased compared to the early period and was not different from the basal level (-10.44+/-2.64 cm/s vs. -10.74+/-2.63 cm/s, p>0.05). The increase in E' wave velocity in the late period when compared to the basal level was found to be statistically significant (-7.85+/-1.54 cm/s vs. -9.21+/-1.81 cm/s, p=0.046). CONCLUSION: Right ventricular systolic function improved in the early period, and this improvement was seen to continue in the late period of PMBV. Diastolic function did not improve in the early period, but did improve in the late period. Right atrium systolic function improved in the early period; however, in the late period, levels were similar to the basal levels. PMID- 24481095 TI - Epicardial fat thickness in patients with psoriasis vulgaris. AB - OBJECTIVES: Psoriasis vulgaris is one of the most common skin disorders. Patients with psoriasis carry an excessive risk of coronary artery disease. Visceral adipose tissue around the heart affects the heart and coronaries by secreting proatherogenic mediators. It can be evaluated easily by measurement of epicardial fat thickness (EFT). The aim of this study was to investigate EFT in patients with psoriasis vulgaris. STUDY DESIGN: One hundred and fifteen adult patients (62 male; mean age 33.6+/-6.0 years) with psoriasis vulgaris (Group 1) and 60 age- and sex-matched healthy individuals (28 male; mean age, 32.5+/-8.3 years) (Group 2) were included in this study. EFT was obtained by transthoracic echocardiography. Disease-specific characteristics of the patients were recorded. Serum glucose, lipid profile and high-sensitive C-reactive protein (hs-CRP) levels were measured. RESULTS: EFT and hs-CRP were significantly higher in Group 1 than in Group 2 (5.7+/-1.2 vs. 4.1+/-1.0 mm, p<0.001 and 0.52+/-0.45 mg/dl vs. 0.19+/-0.17 mg/dl, p<0.001, respectively). The psoriasis disease activity score and hs-CRP were found to be independent predictors of EFT in patients with psoriasis vulgaris (beta=0.21, t=2.67, p=0.01 and beta=0.62, t=7.72, p=0.001, respectively). CONCLUSION: Our findings indicate that EFT was significantly higher in patients with psoriasis vulgaris compared with the controls. It was more prominent in patients with severe disease. PMID- 24481096 TI - Association between endothelial nitric oxide synthase intron 4a/b polymorphism and aortic dissection. AB - OBJECTIVES: The genetic risk factors that contribute to the risk of developing aortic dissection (AD) have been studied. We assessed the association of endothelial nitric oxide synthase (eNOS) gene polymorphism with AD. STUDY DESIGN: Patients who underwent surgery with the diagnosis of AD and survived after the operation in our center between May 2007 and June 2011 were recruited retrospectively. The eNOS intron 4a/b polymorphism was determined by polymerase chain reaction (PCR) using oligonucleotide primers (sense: 5' AGGCCCTATGGTAGTGCCTTT-3'; antisense: 5'-TCTCTTAGTGCTGTGGTCAC-3') that flank the region of the 27 bp VNTR in intron 4. RESULTS: Thirty-nine patients (88%) had type A AD, while the remainder (12%) had type B AD. The distribution of eNOS4 a/b gene polymorphism differed significantly from the control group, with higher frequencies of eNOS 4a/a and 4a/b genotypes in the AD group (x(2)=7.16, p=0.03). CONCLUSION: In this study, the distribution of eNOS genotypes differed between the AD and control groups; however, this polymorphism was not found to be an independent factor for the development of AD. PMID- 24481097 TI - Thrombus attached to suture materials successfully thrombolysed with low-dose tissue plasminogen activator. AB - Mechanical prosthetic heart valve thrombosis is one of the most common complications of valve surgery. We herein describe an unusual clinical vignette. A 60-year-old man who underwent prosthetic mitral valve reoperation suffered from nonobstructive thrombus attached to the elongated suture materials in the postoperative sixth month. The thrombus was precisely depicted by two- and three dimensional transesophageal echocardiography and was successfully lysed with low dose slow infusion of tissue plasminogen activator after failed heparin treatment. PMID- 24481099 TI - A diagnostic dilemma: early repolarization syndrome associated with ventricular fibrillation. AB - An early repolarization (ER) pattern, characterized by J-point elevation, slurring of the terminal part of the QRS and ST-segment elevation, is a common finding on the 12-lead electrocardiogram. It has been suggested that J-point elevation, which was considered benign for many years, may play a critical role in the pathogenesis of idiopathic ventricular fibrillation (VF). Recent studies have shown that an ER pattern in inferior leads or inferolateral leads is associated with increased risk for life-threatening arrhythmias. We report the case of a 52-year-old man with no structural heart disease whose electrocardiogram showed type 2 ER pattern (with evidence of J-point and ST segment elevation in electrocardiogram leads II, III, and aVF). The patient presented with VF. PMID- 24481098 TI - Alternative causes of bioreaction to prosthetic heart valves: three cases with pannus formation. AB - Pannus formation is an infrequent but serious complication of prosthetic heart valve surgery. The cause of pannus is recognized as a bioreaction to the prostheses; histological investigations have shown that pannus comprises collagen and elastic tissues containing endothelial cells, chronic inflammatory cells, and myofibroblasts. However, the detailed mechanism of its formation has not been fully demonstrated. We aimed to evaluate the potential role of vascular endothelial growth factor (VEGF) and matrix metalloproteinase-2 (MMP-2) in the pathogenesis of pannus formation in three patients with mechanical prosthetic heart valves. Pannus specimens removed from the prostheses were fixed in 10% neutral-buffered formalin for 24 hours after surgical removal and paraffin embedded using standard procedures. Serial sections were cut at 4 um for immunohistochemistry analysis. Hematoxylin and eosin (HE) was used in the histological analysis. VEGF and MMP-2 were studied in the immunohistochemistry analysis. Three patients with mechanical prosthetic obstruction due to pannus overgrowth underwent redo valve surgery. In the first and second patients, the mitral prosthesis was explanted along with the pannus overgrowth. The third patient had both aortic and mitral prostheses; the aortic prosthesis was explanted with obstructive pannus formation, whereas the mitral valve was spared with excision of the nonobstructive pannus. The immunohistochemical study demonstrated the expressions of MMP-2 and VEGF in all of the pannus specimens acquired from these cases. VEGF and MMP-2 may play a role in the mechanism of pannus formation as the elements of the chronic active inflammatory process. PMID- 24481100 TI - [Long QT-induced ventricular tachycardia associated with Takotsubo cardiomyopathy]. AB - Takotsubo cardiomyopathy (TC) is a syndrome characterized by transient left ventricular apical ballooning associated with electrocardiogram changes and mimicking acute myocardial infarction in patients without significant coronary disease on angiography. We report an unusual case of a patient who presented with TC associated with long-QT syndrome-induced ventricular tachycardia. QT interval prolongation was normalized and ventricular tachycardias were stopped within the same day with metoprolol treatment. PMID- 24481101 TI - Percutaneous treatment of superior vena cava syndrome caused by chronic thrombosis. AB - Chronic upper extremity deep vein thrombosis (UEDVT) and superior vena cava syndrome (SVCS) are becoming increasingly common due to the use of indwelling catheters and implantable central venous access devices. Hypercoagulable syndromes, malignancy, extrinsic compression, and tumor invasion are other causes. Endovascular management of chronic UEDVT and SVCS is accepted as an important first-line treatment given its high overall success rate and low morbidity as compared with medical and surgical treatments. In this case, we present successful management with stenting of superior vena cava obstruction syndrome as a result of chronic thrombosis. A 48-year-old woman was diagnosed with SVCS one year ago. Despite the use of warfarin therapy, her symptoms (swelling of the face and both upper extremities) progressively increased. It was thus decided to treat the patient with percutaneous angioplasty and stenting. Details of the occlusion were evaluated with computed tomography and venography. The right femoral vein and right jugular vein were used for the intervention. The occlusion was passed with a Miracle 12-g guidewire. After balloon pre-dilatation, two self-expandable stents were implanted. After stent placement, her clinical symptoms improved and she was discharged without complication. PMID- 24481102 TI - Mitral valve with a single leaflet. AB - Congenital anomalies of the mitral valve apparatus are rare. Of such cases, congenital mitral stenosis, atresia, accessory valvular tissue, and cleft mitral valve are more common. Descriptions of unileaflet mitral valves (either partial or complete leaflet agenesis/hypoplasia) are extremely rare and largely limited to a few case reports. We report herein a 45-year-old nulliparous woman presenting to our outpatient clinic with chest discomfort and dyspnea on minimal exertion. Mitral valve with a single leaflet leading to a significant obstruction in left ventricular outflow was seen on transthoracic echocardiography and confirmed with transesophageal two- (2D) and three-dimensional (3D) echocardiography. Metoprolol was prescribed to relieve obstruction and symptoms. PMID- 24481103 TI - [Paravalvular aortic regurgitation after transcatheter aortic valve replacement]. AB - Transcatheter aortic valve replacement (TAVR) is a rapidly evolving technology that has been accepted as a treatment option in patients with severe aortic stenosis who are not suitable for or are at high risk for conventional surgery. Randomized trials have shown that TAVR decreases mortality and improves quality of life in patients who are not suitable for conventional surgery and that TAVR is not inferior to standard surgery in operable but high- risk patients. However, TAVR has several important limitations, the most prominent of which is residual paravalvular aortic regurgitation (PAR). The purpose of this review is to present the mechanism, incidence, assessment, and treatment of PAR after TAVR. PMID- 24481104 TI - Almanac 2013: heart failure. PMID- 24481105 TI - Almanac 2013: stable coronary artery disease. PMID- 24481106 TI - Case images: a giant calcified left ventricular aneurysm. PMID- 24481107 TI - Case images: giant right atrial myxoma mimicking a thrombus. PMID- 24481108 TI - Case images: a rare case of aortic dissection; prolapse of flap into the ventricle. PMID- 24481109 TI - Case images: a rare disease causing mitral regurgitation: posterior mitral leaflet aneurysm. PMID- 24481110 TI - Case images: asymptomatic giant internal carotid artery aneurysm. PMID- 24481111 TI - Evaluating the utility of circulating biomarkers of collagen synthesis in hypertrophic cardiomyopathy. AB - BACKGROUND: In hypertrophic cardiomyopathy (HCM), accumulation of myocardial collagen may play a central role in the pathogenesis of diastolic dysfunction and arrhythmia. Previous studies have suggested that peripheral levels of byproducts of collagen synthesis are reflective of myocardial extracellular matrix metabolism, although this has not been validated in detail. Given the potential clinical utility of such biomarkers, we sought to validate the assumed relationship between peripheral markers and myocardial fibrosis in HCM. METHODS AND RESULTS: Fifty patients with HCM and 25 healthy controls underwent peripheral venous sampling to determine plasma concentrations of key collagen precursors (procollagen I and III N-terminal propeptides [PINP, PIIINP]). Contrast-enhanced cardiac magnetic resonance imaging was performed to quantify regional (by late gadolinium enhancement) and diffuse (by T1 mapping) myocardial fibrosis. Nineteen subjects also underwent simultaneous arterial and coronary sinus blood sampling (to derive transcardiac concentration gradients of PINP, PIIINP, and C-terminal telopeptide of type I collagen) and right heart catheterization. Despite cardiac magnetic resonance evidence of regional (late-gadolinium enhancement quantity, 6.4+/-8.0%) and diffuse (T1 time, 478+/-79 ms) myocardial fibrosis in patients with HCM, peripheral levels of collagen precursors were similar compared with control subjects (PINP, 45.9+/-22.9 versus 53.4+/-25.9 MUg/L; P=0.21; PIIINP, 4.8+/-1.7 versus 4.4+/-1.1 MUg/L; P=0.26). No significant net positive transcardiac concentration gradient was detected for either biomarker of collagen synthesis. CONCLUSIONS: The cardiac contribution to peripheral levels of byproducts of collagen synthesis in patients with HCM is insignificant. Furthermore, peripheral levels of these biomarkers do not accurately reflect myocardial collagen content in these patients. PMID- 24481112 TI - Family history of myocardial infarction increases risk of renal dysfunction in middle age. AB - BACKGROUND/AIMS: Chronic kidney disease (CKD) is common in the general population, may lead to end-stage renal disease, and is most frequently found among males. Familial clustering of kidney diseases has been observed. We aimed to study a potential association between the family history of myocardial infarction (MI) and renal dysfunction. METHODS: 22,297 males and 10,828 females, aged 33-60 years, from a population-based cohort study were studied. Estimated glomerular filtration rate (eGFR) was assessed by the CKD-EPI creatinine equation. Every participant filled in a self-administered questionnaire including family history. Heredity for MI was defined as mother or father having had MI and/or died from MI, and/or brother or sister having had MI. Binary logistic regression and multiple linear regression were used in the analyses. RESULTS: Multiple linear regression revealed a significantly increased risk of renal dysfunction in those with a positive heredity for MI (the whole cohort p = 0.01, males p = 0.000, females p = 0.169). Binary logistic regression showed that males with heredity for MI with a mean age of 43 years have a 2 times higher risk (p = 0.02) of belonging to the group with GFR <45 ml/min/1.73 m(2) compared to those without heredity. For the whole cohort the increased risk was 1.6 times (p = 0.07). There was no significant association for females (p = 0.88). CONCLUSION: These findings demonstrate that a familial burden of MI is associated with renal dysfunction, in men, already in middle age. Genetic variants may underlie predisposition to CKD in those with heredity for MI. PMID- 24481113 TI - Myosin light chain kinase regulates hearing in mice by influencing the F-actin cytoskeleton of outer hair cells and cochleae. AB - Myosin light chain kinase (MLCK) phosphorylates myosin regulatory light chains to facilitate its interaction with actin filaments and produce contractile activity. The outer hair cells (OHCs) in the ear contain large amounts of actin and a variety myosins. The stereociliary and somatic motility of OHCs are closely related to hearing. It appears likely that MLCK may play an important role in acoustic trans-duction. In this study, we analyzed, both in vivo and in vitro, the OHCs of mice bearing a specific deletion of the MLCK gene and the OHCs of control mice. The phenotype was assessed by auditory function [acoustic brainstem responses (ABRs) and distortion product otoacoustic emissions (DPOAEs)], inner ear morphology and histology. MLCK-deficient mice aged 6-7 months showed impaired hearing, a 5- to 10-dB sound pressure level (SPL) increase in the ABR thresholds, when responding to clicks and tones of different frequencies (8 and 16 kHz) (P<0.05). The DPOAE amplitudes of 3-month-old MLCK-deficient mice decreased significantly (>10 dB SPL) at low frequencies (4, 5 and 6 kHz). The OHCs in the MLCK-deficient mice increased with abnormal stereocilia. The staining of F-actin and the phosphorylation of the regulatory light chain in MLCK-deficient OHCs was weak. Our results indicate that MLCK may regulate the structure and the motility of stereocilia through F-actin polymerization. PMID- 24481114 TI - Correlation between inflammatory markers of atherosclerosis and carotid intima media thickness in Obstructive Sleep Apnea. AB - Obstructive Sleep Apnea (OSA) is a sleep-related breathing disorder associated with the development of cardiovascular diseases and atherosclerosis. Systemic inflammation plays an important role in the development of cardiovascular complications in OSA patients. The aim of the study was to evaluate the relationship between carotid intima-media thickness (cIMT) and inflammatory markers plasma levels in OSA patients. We enrolled 80 OSA patients and 40 controls matched for age and body mass index (BMI). The presence and severity of sleep apnea was determined by in-laboratory portable monitoring (PM). Demographic data, blood pressure, heart rate, and cIMT were measured. High-sensitive C Reactive Protein (hsCRP), interleukin (IL)-6, tumor necrosis factor (TNF)-alpha and pentraxin (PTX)-3 serum concentrations were detected. cIMT was higher in OSA patients than controls (0.89 +/- 0.13 mm vs. 0.65 +/- 0.1 mm, p < 0.01). Moderate severe OSA patients (0.95 +/- 0.09 mm) had significantly increased cIMT than mild OSA (0.76 +/- 0.1 mm; p < 0.01) and control (0.65 +/- 0.1 mm; p < 0.01). hsCRP, IL-6, TNF-alpha, and PTX-3 in patients with OSA (1.67 +/- 0.66 mg/L, 2.86 +/- 1.39 pg/mL, 20.09 +/- 5.39 pg/mL, 2.1 +/- 0.59 ng/mL, respectively) were significantly higher than in controls (1.08 +/- 0.53 mg/L, p < 0.01; 1.5 +/- 0.67 pg/mL, p < 0.01; 12.53 +/- 3.48 pg/mL, p < 0.01; 1.45 +/- 0.41 ng/mL, p < 0.01, respectively). Carotid IMT was significantly correlated to CRP (r = 0.44; p < 0.01), IL-6 (r = 0.42; p < 0.01), TNF-alpha (r = 0.53; p < 0.01), and PTX-3 (r = 0.49; p < 0.01). OSA patients showed increased cIMT, CRP, IL-6, TNF-alpha, and PTX-3 levels. Inflammatory markers levels are correlated to cIMT in OSA patients. PMID- 24481115 TI - Penostatin derivatives, a novel kind of protein phosphatase 1b inhibitors isolated from solid cultures of the entomogenous fungus Isaria tenuipes. AB - Protein tyrosine phosphatase 1B (PTP1B) is implicated as a negative regulator of insulin receptor (IR) signaling and a potential drug target for the treatment of type II diabetes and other associated metabolic syndromes. Therefore, small molecular inhibitors of PTP1B can be considered as an attractive approach for the design of new therapeutic agents of type II diabetes diseases. In a continuing search for new protein phosphatase inhibitors from fungi, we have isolated a new compound, named penostatin J (1), together with three known ones, penostatin C (2), penostatin A (3), and penostatin B (4), from cultures of the entomogenous fungus Isaria tenuipes. The structure of penostatin J (1) was elucidated by extensive spectroscopic analysis. We also demonstrate for the first time that penostatin derivatives exhibit the best PTP1B inhibitory action. These findings suggest that penostatin derivatives are a potential novel kind of PTP1B inhibitors. PMID- 24481116 TI - Docking studies in target proteins involved in antibacterial action mechanisms: extending the knowledge on standard antibiotics to antimicrobial mushroom compounds. AB - In the present work, the knowledge on target proteins of standard antibiotics was extended to antimicrobial mushroom compounds. Docking studies were performed for 34 compounds in order to evaluate their affinity to bacterial proteins that are known targets for some antibiotics with different mechanism of action: inhibitors of cell wall synthesis, inhibitors of protein synthesis, inhibitors of nucleic acids synthesis and antimetabolites. After validation of the molecular docking approach, virtual screening of all the compounds was performed against penicillin binding protein 1a (PBP1a), alanine racemase (Alr), d-alanyl-d-alanine synthetase (Ddl), isoleucyl-tRNA sinthetase (IARS), DNA gyrase subunit B, topoisomerase IV (TopoIV), dihydropteroate synthetase (DHPS) and dihydrofolate reductase (DHFR) using AutoDock4. Overall, it seems that for the selected mushroom compounds (namely, enokipodins, ganomycins and austrocortiluteins) the main mechanism of the action is the inhibition of cell wall synthesis, being Alr and Ddl probable protein targets. PMID- 24481117 TI - Returning pleiotropic results from genetic testing to patients and research participants. PMID- 24481118 TI - Theoretical mechanism for selective catalysis of double hydrophosphination of terminal arylacetylenes by an iron complex. AB - The detailed mechanism of the double hydrophosphination of terminal arylacetylenes catalyzed by an iron complex was studied by density functional theory. The calculated results suggest that the reaction proceeds in three steps: active species generation, single hydrophosphination reaction (Cycle 1), double hydrophosphination reaction, viz., active species regeneration (Cycle 2). The results uncovered the selectivity of the iron complex for double hydrophosphination of terminal arylacetylenes. The symmetry of frontier molecular orbitals determines the effectiveness of the catalyst. We also discuss the formation mechanism of the single hydrophosphination product with Z configuration. PMID- 24481119 TI - Solid-state conversion of a MOF to a metal-organo polymeric framework (MOPF) via [2+2] cycloaddition reaction. AB - The bpeb ligands aligned in a slip-stacked manner in a two-fold interpenetrated non-porous metal-organic framework (MOF) [Zn2(bpeb)(bdc)(fa)2] undergo [2+2] cycloaddition reaction in a single-crystal to single-crystal manner to a non interpenetrated 3D structure with a new topology comprising an organic polymer ligand and a 2D coordination polymer. PMID- 24481120 TI - High prevalence of mild cognitive impairment in the elderly: a community-based study in four cities of the Hebei province, china. AB - BACKGROUND: Mild cognitive impairment (MCI) has been suggested as a term for a boundary area between normal aging and dementia. This study was designed to determine the prevalence of MCI in the elderly in the Hebei province, China, and explore its related factors. METHODS: Participants included 2,601 community dwelling people aged 60 years or older who resided in the four major cities of the Hebei province. In stage 1 of the study, the Mini-Mental State Examination and the Montreal Cognitive Assessment were administered for screening purposes. In stage 2, the subjects who screened positive were further examined by neurologists. The diagnosis of MCI was made according to Petersen's criteria. RESULTS: The estimated prevalence of MCI was 21.3%. MCI was more prevalent at age 65-69 (28.3%), and its overall rates among men (24.1%) were higher than those of women (19.9%). The higher prevalence of MCI was associated with very old age (>=80 years old; OR = 2.457, 95% CI = 1.471-4.104), male gender (OR = 1.363, 95% CI = 1.097-1.694), low education level (OR = 2.439, 95% CI = 1.623-3.663), and poor economic status (OR = 2.882, 95% CI = 1.949-4.255). CONCLUSIONS: Our findings show a high prevalence of MCI in the elderly urban population in the Hebei province. Gender, education level, and economic status may have an important role in the etiology of MCI. PMID- 24481121 TI - The role of sLZIP in transcriptional regulation of c-Jun and involvement in migration and invasion of cervical cancer cells. AB - BACKGROUND/AIMS: Matrix metalloproteinase-9 (MMP-9) plays an important role in tumor invasion and metastasis through the breakdown of extracellular matrix. The c-Jun protein, a major component of the AP-1 transcription factor, is elevated in various cancers. Small leucine zipper protein (sLZIP) is a member of the leucine zipper transcription factor family. Although sLZIP is known to be involved in cancer cell migration and invasion, its biological roles in cancer development and the cellular target genes are not fully understood. In this study, we investigated the role of sLZIP in c-Jun expression, and their effects on expression of MMP-9 and migration of cervical cancer cells. METHODS AND RESULTS: sLZIP up-regulates transcription of c-Jun by binding directly to the CRE region in the c-Jun promoter. Elevated c-Jun due to sLZIP leads to activation of MMP-9 transcription by interaction with the AP-1 binding site in the MMP-9 promoter. c Jun siRNA repressed migration and invasion of cervical cancer cells, whereas sLZIP recovered migration and invasion of cells transfected with c-Jun siRNA. Immunohistochemical analysis results revealed a significant correlation between the expressions of sLZIP and MMP-9 in clinical cervical specimens. CONCLUSION: These results indicate that sLZIP plays a role in expression of c-Jun, and migration and invasion of cervical cancer cells via regulation of MMP-9 transcription. PMID- 24481122 TI - Photodynamic therapy in subfoveal and juxtafoveal myopic choroidal neovascularization: a 10-year retrospective analysis. AB - The aim of this study was to evaluate and compare the effects of photodynamic therapy (PDT) in eyes with subfoveal and juxtafoveal choroidal neovascularization (CNV) secondary to pathological myopia. The study was a single-center, 10-year analysis on 19 eyes. Patients underwent best-corrected visual acuity (BCVA) measurement, slit-lamp examination, ophthalmoscopy and fluorescein angiography. Eyes with subfoveal CNV (7 eyes, 37%) progressively worsened during the 10-year follow-up from 0.68 +/- 0.26 to 0.80 +/- 0.47 logMAR, while in the eyes with juxtafoveal CNV (12 eyes, 63%) BCVA improved from 0.59 +/- 0.42 to 0.33 +/- 0.27 logMAR. Prevalence and extension of chorioretinal atrophy (CRA) were greater in eyes with subfoveal compared with juxtafoveal CNV (84 vs. 66%, respectively) and enlargement (10.05 +/- 6.7 vs. 3.53 +/- 4.7 mm(2), respectively). Our results confirm the limited long-term effectiveness of PDT in myopic subfoveal CNV. Satisfactory results can be achieved in juxtafoveal CNV with a better visual outcome and a minor CRA extension. PMID- 24481124 TI - The prognostic value of T1 bladder cancer substaging: a single institution retrospective study. AB - OBJECTIVE: To evaluate the prognostic value of the depth of lamina propria invasion in patients with T1 bladder cancer. SUBJECTS AND METHODS: 200 patients were treated between the years 2002 and 2009. Tumours with depth of invasion above the muscularis mucosae level were categorised as pT1a and those with depth of invasion up to or beyond the muscularis mucosae as pT1b. RESULTS: Categorisation for pT1a and pT1b was performed in 176 of 200 patients (88%). In 10 patients a muscle-invasive tumour was found in re-transurethral resection samples. 131 (79%) of 166 analysed patients had pT1a tumour and 35 (21%) had pT1b tumour. During the follow-up, in 101 (61%) patients the tumour had recurred and in 27 (16.3%) the tumour had progressed. Of all the investigated parameters, T1 substaging (p < 0.0001), grade (p = 0.0003) and the number of bacillus Calmette Guerin instillations (p = 0.0490) were significant in predicting progression. The only significant factor for disease-specific survival was T1 substaging in univariable (p = 0.0008) and multivariable (hazard ratio 4.407) analysis. T1 substaging (p = 0.0149) and tumour multiplicity (p = 0.0448) have a statistically significant prognostic value with respect to overall survival. CONCLUSIONS: Deep invasion of the lamina propria is a significant adverse prognostic factor for tumour progression, disease-specific survival and overall survival. PMID- 24481125 TI - Childhood oral health and SES predictors of caries in 30-year-olds. AB - BACKGROUND/AIMS: To assess whether childhood socio-economic status modifies the relationship between childhood caries and young adult oral health. METHODS: In 1988-1989, a total of 7,673 South Australian children aged 13 years were sampled, with 4,604 children (60.0%) and 4,476 parents (58.3%) responding. In 2005-2006, 632 baseline study participants responded (43.0% of those traced and living in Adelaide). RESULTS: Adjusted analyses showed significant interactions for card status by DMFT at age 13 for decayed, missing and filled teeth at age 30, but not for DMFT. Higher DMFT at age 13 was associated with more decayed teeth at age 30 for those with no health card, while there were similar numbers of decayed teeth for card holders regardless of their DMFT at age 13. While higher DMFT at age 13 was associated with more missing teeth at age 30 for card holders, there were similar numbers of missing teeth for those with no card regardless of their DMFT at age 13. The interaction for filled teeth showed that even though higher DMFT at age 13 was associated with more fillings at age 30 for both card holders and those with no card, this relationship was more pronounced for card holders. CONCLUSIONS: SES modified the relationship between child oral health and caries at age 30 years. Card holders at age 13 were worse off in terms of their oral health at age 30 controlling for childhood oral health, supporting social causation explanations for oral health inequalities. PMID- 24481126 TI - Global metabolic network reorganization by adaptive mutations allows fast growth of Escherichia coli on glycerol. AB - Comparative whole-genome sequencing enables the identification of specific mutations during adaptation of bacteria to new environments and allelic replacement can establish their causality. However, the mechanisms of action are hard to decipher and little has been achieved for epistatic mutations, especially at the metabolic level. Here we show that a strain of Escherichia coli carrying mutations in the rpoC and glpK genes, derived from adaptation in glycerol, uses two distinct metabolic strategies to gain growth advantage. A 27-bp deletion in the rpoC gene first increases metabolic efficiency. Then, a point mutation in the glpK gene promotes growth by improving glycerol utilization but results in increased carbon wasting as overflow metabolism. In a strain carrying both mutations, these contrasting carbon/energy saving and wasting mechanisms work together to give an 89% increase in growth rate. This study provides insight into metabolic reprogramming during adaptive laboratory evolution for fast cellular growth. PMID- 24481127 TI - Modifiable predictors of chronotropic incompetence in male patients with type 2 diabetes. AB - PURPOSE: Type 2 diabetes mellitus (T2DM) is associated with chronotropic incompetence (CI), which may lead to a worse prognosis. It remains uncertain whether CI in T2DM patients is related to patient characteristics that are modifiable by exercise interventions. METHODS: From 33 male T2DM patients and 18 healthy subjects not taking beta-blockers, calcium-antagonists, and/or diuretics, a fasting blood sample was collected, followed by an oral glucose tolerance test, maximal cardiopulmonary exercise test, and body composition analysis. Chronotropic incompetence was defined as the inability to achieve a maximal chronotropic response index (maxCRI) >= 0.80 during exercise testing. By univariate correlations and multivariate regression analysis, relationships between exercise tolerance, body composition, glycemic control, and maxCRI were examined. RESULTS: MaxCRI was significantly lower in T2DM patients (0.85 +/- 0.17) vs healthy controls (1.02 +/- 0.17, P < .01): Chronotropic incompetence was prevalent in 14 T2DM patients (42%) and 1 healthy subject (6%, P < .05). Significant (P < .05) univariate correlations between maxCRI and body mass index (r = -0.59), blood high-density lipoprotein cholesterol (r = 0.34), HbA1c (r = 0.33) and insulin level (r = -0.48), HOMA-IR index (r = -0.45), trunk adipose tissue mass (r = -0.45), waist circumference (r = -0.58), peak cycling power output (r = 0.42), and oxygen uptake (r = 0.33) were found (P < .05). Independent significant relations were found between maxCRI and waist circumference (P < .01) and peak cycling power output (P < .05). CONCLUSIONS: Chronotropic incompetence in male T2DM patients is independently related to exercise tolerance and adipose tissue mass. These data provide further insight into the etiology of CI in male T2DM patients and show that exercise interventions might impact predictors of CI. PMID- 24481128 TI - Extracellular matrix density promotes EMT by weakening cell-cell adhesions. AB - Epithelial to mesenchymal transition (EMT), the process during which epithelial cells lose adhesions with neighbouring cells and get converted to migratory and invasive cells, is closely tied to cancer progression. Cancer progression is also marked by increased deposition and cross linking of fibrillar extracellular matrix (ECM) proteins including collagen and fibronectin, which lead to increase in ECM density and increased cell-matrix adhesions. Thus, an imbalance between cell-matrix and cell-cell adhesions underlies cancer progression. Though several experimental studies have shown a crosstalk between cell-cell and cell-matrix adhesions, the extent to which changes in ECM density can trigger EMT via formation of cell-matrix adhesions and disassembly of cell-cell adhesions remains incompletely understood. In this paper, we have developed a computational framework for studying modulation of cell-cell adhesion by ECM density, integrating findings from multiple studies that connect ECM-mediated adhesion signaling and growth factor signaling with cell-cell adhesion. Here, we have specifically tracked changes in the levels of the E-cadherin-beta catenin (Ebeta) complex in response to alterations in ECM density. Our results illustrate a tug of-war between ECM density and E-cadherin in determining Ebeta levels both for a single cell as well as for a cell population, with increase in ligand density weakening cell-cell adhesions and increase in E-cadherin levels counterbalancing the effect of ECM density. Consistent with model predictions, lower levels of membrane to cytoplasmic ratios of E-cadherin were observed in MCF-7 human breast cancer cells plated on substrates with increasing collagen density. By performing simulations for a heterogeneous population consisting of both normal and EMT cells, we demonstrate that ligand density and the fraction of EMT cells collectively determine the scattering potential of a cell population. Taken together, our findings are in support of a model where increase in cell-matrix adhesions negatively regulates cell-cell adhesions thereby contributing to EMT and enhanced cellular invasion. PMID- 24481129 TI - Epigallocatechin-3-gallate inhibits TF and TNF-alpha expression induced by the anti-beta2GPI/beta2GPI complex in human THP-1 cells. AB - Epigallocatechin-3-gallate (EGCG) is the major polyphenolic component of green tea. The aim of the current study was to investigate the inhibitory effects of EGCG on anti-beta2-glycoprotein I (beta2GPI)/beta2GPI-induced tissue factor (TF) and tumor necrosis factor-alpha (TNF-alpha) expression in the human acute monocytic leukemia cell line, THP-1, as well as the underlying mechanisms. Human THP-1 cells cultured in vitro were treated with lipopolysaccharide (LPS, 500 ng/ml) or with the anti-beta2GPI (10 ug/ml)/beta2GPI (100 ug/ml) complex following pre-treatment with or without EGCG (0-50 ug/ml). The expression levels of TF, TNF-alpha and Toll-like receptor 4 (TLR4) were measured, and the activation of mitogen-activated protein kinases (MAPKs) including p38, extracellular signal-regulated kinase 1/2 (ERK1/2) and c-Jun N-terminal kinase (JNK), and the nuclear factor-kappaB (NF-kappaB) signaling pathway was determined by western blot analysis. The results revealed that the anti-beta2GPI/beta2GPI complex activated the THP-1 cells, resulting in the enhanced expression of the coagulation cytokine, TF, as well as that of the pro-inflammatory cytokine, TNF alpha; these levels were almost comparable to those induced by LPS. Pre-treatment with EGCG decreased the TF and TNF-alpha levels in the THP-1 cells treated with the anti-beta2GPI/beta2GPI complex in a dose-dependent manner and counteracted the upregulation of TLR4 expression (mRNA and protein) which was induced by the anti-beta2GPI/beta2GPI complex or LPS. Furthermore, EGCG suppressed the phosphorylation of p38, ERK1/2 and JNK and blocked the activation of the NF kappaB signaling pathway induced by the anti-beta2GPI/beta2GPI complex or LPS. In conclusion, our results indicate that EGCG decreases the anti-beta2GPI/beta2GPI induced TF and TNF-alpha expression in THP-1 cells possibly through the inhibition of the intracellular signal transduction pathway of TLRs-MAPKs-NF kappaB axis and may serve as a preventive and therapeutic agent for antiphospholipid syndrome (APS). PMID- 24481131 TI - Cereal-based gluten-free food: how to reconcile nutritional and technological properties of wheat proteins with safety for celiac disease patients. AB - The gluten-free diet is, to date, the only efficacious treatment for patients with Celiac Disease. In recent years, the impressive rise of Celiac Disease incidence, dramatically prompted changes in the dietary habit of an increasingly large population, with a rise in demand of gluten-free products. The formulation of gluten-free bakery products presents a formidable challenge to cereal technologists. As wheat gluten contributes to the formation of a strong protein network, that confers visco-elasticity to the dough and allows the wheat flour to be processed into a wide range of products, the preparation of cereal-based gluten-free products is a somehow difficult process. This review focuses on nutritional and technological quality of products made with gluten-free cereals available on the market. The possibility of using flour from naturally low toxic ancient wheat species or detoxified wheat for the diet of celiacs is also discussed. PMID- 24481130 TI - Protective effect of wheat peptides against indomethacin-induced oxidative stress in IEC-6 cells. AB - Recent studies have demonstrated that wheat peptides protected rats against non steroidal anti-inflammatory drugs-induced small intestinal epithelial cells damage, but the mechanism of action is unclear. In the present study, an indomethacin-induced oxidative stress model was used to investigate the effect of wheat peptides on the nuclear factor-kappaB(NF-kappaB)-inducible nitric oxide synthase-nitric oxide signal pathway in intestinal epithelial cells-6 cells. IEC 6 cells were treated with wheat peptides (0, 125, 500 and 2000 mg/L) for 24 h, followed by 90 mg/L indomethacin for 12 h. Wheat peptides significantly attenuated the indomethacin-induced decrease in superoxide dismutase and glutathione peroxidase activity. Wheat peptides at 2000 mg/L markedly decreased the expression of the NF-kappaB in response to indomethacin-induced oxidative stress. This study demonstrated that the addition of wheat peptides to a culture medium significantly inhibited the indomethacin-induced release of malondialdehyde and nitrogen monoxide, and increased antioxidant enzyme activity in IEC-6 cells, thereby providing a possible explanation for the protective effect proposed for wheat peptides in the prevention of indomethacin-induced oxidative stress in small intestinal epithelial cells. PMID- 24481133 TI - Effect of beetroot juice supplementation on aerobic response during swimming. AB - The beneficial effects of beetroot juice supplementation (BJS) have been tested during cycling, walking, and running. The purpose of the present study was to investigate whether BJS can also improve performance in swimmers. Fourteen moderately trained male master swimmers were recruited and underwent two incremental swimming tests randomly assigned in a pool during which workload, oxygen uptake (VO2), carbon dioxide production (VCO2), pulmonary ventilation (VE), and aerobic energy cost (AEC) of swimming were measured. One was a control swimming test (CSW) and the other a swimming test after six days of BJS (0.5 l/day organic beetroot juice containing about 5.5 mmol of NO3-). Results show that workload at anaerobic threshold was significantly increased by BJS as compared to the CSW test (6.3 +/- 1 and 6.7 +/- 1.1 kg during the CSW and the BJS test respectively). Moreover, AEC was significantly reduced during the BJS test (1.9 +/- 0.5 during the SW test vs. 1.7 +/- 0.3 kcal.kg-11.h-1 during the BJS test). The other variables lacked a statistically significant effect with BJS. The present investigation provides evidence that BJS positively affects performance of swimmers as it reduces the AEC and increases the workload at anaerobic threshold. PMID- 24481134 TI - Virulence profile: Frederick M Ausubel. PMID- 24481132 TI - Effect of fructooligosaccharides fraction from Psacalium decompositum on inflammation and dyslipidemia in rats with fructose-induced obesity. AB - Psacalium decompositum, commonly known as "Matarique," is a medicinal plant used in Mexico for diabetes mellitus empirical therapy. Previous studies have shown that the fructooligosaccharides (FOS) present in the roots of this plant exhibit a notable hypoglycemic effect in animal models; this effect might be associated with the attenuation of the inflammatory process and other metabolic disorders. In this study, we examined the effects of FOS fraction administration in a fructose-fed rat model for obesity. Phytochemical chromatographic studies (high performance thin layer chromatography and nuclear magnetic resonance) were performed to verify isolation of FOS. 24 male Wistar rats were maintained for 12 weeks on a diet of 20% HFCS in drinking water and chow. Glucose, cholesterol, triglycerides and liver transaminases levels were measured monthly, after administering FOS fraction intragastrically (150 mg/kg/day for 12 weeks), while the levels of inflammatory cytokines were only quantified at the end of the treatments. Rats treated with FOS fraction decreased body weight, cholesterol, triglycerides, and significantly reduced IL-6, IFN-gamma, MCP-1, IL-1beta and VEGF levels (p < 0.05). These results suggest that P. decompositum has anti inflammatory and hypolipidemic properties that might be used as an alternative treatment for the control of obesity. PMID- 24481135 TI - Sugar and auxin signaling pathways respond to high-temperature stress during anther development as revealed by transcript profiling analysis in cotton. AB - Male reproduction in flowering plants is highly sensitive to high temperature (HT). To investigate molecular mechanisms of the response of cotton (Gossypium hirsutum) anthers to HT, a relatively complete comparative transcriptome analysis was performed during anther development of cotton lines 84021 and H05 under normal temperature and HT conditions. In total, 4,599 differentially expressed genes were screened; the differentially expressed genes were mainly related to epigenetic modifications, carbohydrate metabolism, and plant hormone signaling. Detailed studies showed that the deficiency in S-adenosyl-L-homocysteine hydrolase1 and the inhibition of methyltransferases contributed to genome-wide hypomethylation in H05, and the increased expression of histone constitution genes contributed to DNA stability in 84021. Furthermore, HT induced the expression of casein kinasei (GhCKI) in H05, coupled with the suppression of starch synthase activity, decreases in glucose level during anther development, and increases in indole-3-acetic acid (IAA) level in late-stage anthers. The same changes also were observed in Arabidopsis (Arabidopsis thaliana) GhCKI overexpression lines. These results suggest that GhCKI, sugar, and auxin may be key regulators of the anther response to HT stress. Moreover, phytochrome interacting factor genes (PIFs), which are involved in linking sugar and auxin and are regulated by sugar, might positively regulate IAA biosynthesis in the cotton anther response to HT. Additionally, exogenous IAA application revealed that high background IAA may be a disadvantage for late-stage cotton anthers during HT stress. Overall, the linking of HT, sugar, PIFs, and IAA, together with our previously reported data on GhCKI, may provide dynamic coordination of plant anther responses to HT stress. PMID- 24481138 TI - Is dolphin cognition special? PMID- 24481137 TI - Alterations in the transcriptome of soybean in response to enhanced somatic embryogenesis promoted by orthologs of Agamous-like15 and Agamous-like18. AB - Somatic embryogenesis (SE) is a poorly understood process during which competent cells respond to inducing conditions, allowing the development of somatic embryos. It is important for the regeneration of transgenic plants, including for soybean (Glycine max). We report here that constitutive expression of soybean orthologs of the Arabidopsis (Arabidopsis thaliana) MADS box genes Agamous-like15 (GmAGL15) and GmAGL18 increased embryogenic competence of explants from these transgenic soybean plants. To understand how GmAGL15 promotes SE, expression studies were performed. Particular genes of interest involved in embryogenesis (abscisic acid-insensitive3 and FUSCA3) were found to be directly up-regulated by GmAGL15 by using a combination of quantitative reverse transcription-polymerase chain reaction and chromatin immunoprecipitation. To look more broadly at changes in gene expression in response to GmAGL15, we assessed the transcriptome using the Affymetrix Soybean Genome Array. Interestingly, the gene expression profile of 35Spro:GmAGL15 explants (0 d in culture) was found to resemble nontransgenic tissue that had been induced for SE by being placed on induction medium for 3 d, possibly explaining the more rapid SE development observed on 35Spro:GmAGL15 tissue. In particular, transcripts from genes related to the stress response showed increased transcript accumulation in explants from 35Spro:GmAGL15 tissue. These same genes also showed increased transcript accumulation in response to culturing nontransgenic soybean explants on the medium used to induce SE. Overexpression of GmAGL15 may enhance SE by making the tissue more competent to respond to 2,4-dichlorophenoxyacetic acid induction by differential regulation of genes such as those involved in the stress response, resulting in more rapid and prolific SE. PMID- 24481140 TI - [Ru(eta5-C5H5)(eta6-C10H8)]PF6 as a catalyst precursor for the one-pot direct C-H alkenylation of nitrogen heterocycles. AB - The ruthenium naphthalene complex [Ru(eta(5)-C5H5)(eta(6)-C10H8)](+) is a catalyst precursor for the direct C-H alkenylation of pyridine and related nitrogen heterocycles by terminal alkynes. Stoichiometric studies have demonstrated that the naphthalene ligand may be displaced by either pyridine, 4 methylpyridine or dimethylaminopyridine (DMAP) to give species [Ru(eta(5) C5H5)L3](+) (L = nitrogen-based ligand). Reaction of in situ-generated [Ru(eta(5) C5H5)(py)3](+) (py = pyridine) with PPh3 results in the formation of [Ru(eta(5) C5H5)(PPh3)(py)2](+), the active catalyst for direct alkenylation, some [Ru(eta(5)-C5H5)(PPh3)2(py)](+) is also formed in this reaction. A one-pot procedure is reported which has allowed for the nature of the nitrogen heterocycle and phosphine ligand to be evaluated. The sterically demanding phosphine PCy3 inhibits catalysis, and only trace amounts of product are formed when precursors containing a pentamethylcyclopentadienyl group were used. The greatest conversion was observed with PMe3 when used as co-ligand with [Ru(eta(5) C5H5)(eta(6)-C10H8)](+). PMID- 24481136 TI - Manoyl oxide (13R), the biosynthetic precursor of forskolin, is synthesized in specialized root cork cells in Coleus forskohlii. AB - Forskolin, a complex labdane diterpenoid found in the root of Coleus forskohlii (Lamiaceae), has received attention for its broad range of pharmacological activities, yet the biosynthesis has not been elucidated. We detected forskolin in the root cork of C. forskohlii in a specialized cell type containing characteristic structures with histochemical properties consistent with oil bodies. Organelle purification and chemical analysis confirmed the localization of forskolin and of its simplest diterpene precursor backbone, (13R) manoyl oxide, to the oil bodies. The labdane diterpene backbone is typically synthesized by two successive reactions catalyzed by two distinct classes of diterpene synthases. We have recently described the identification of a small gene family of diterpene synthase candidates (CfTPSs) in C. forskohlii. Here, we report the functional characterization of four CfTPSs using in vitro and in planta assays. CfTPS2, which synthesizes the intermediate copal-8-ol diphosphate, in combination with CfTPS3 resulted in the stereospecific formation of (13R) manoyl oxide, while the combination of CfTPS1 and CfTPS3 or CfTPS4 led to formation of miltiradiene, precursor of abietane diterpenoids in C. forskohlii. Expression profiling and phylogenetic analysis of the CfTPS family further support the functional diversification and distinct roles of the individual diterpene synthases and the involvement of CfTPS1 to CfTPS4 in specialized metabolism and of CfTPS14 and CfTPS15 in general metabolism. Our findings pave the way toward the discovery of the remaining components of the pathway to forskolin, likely localized in this specialized cell type, and support a role of oil bodies as storage organelles for lipophilic bioactive metabolites. PMID- 24481141 TI - Measuring initial enamel erosion with quantitative light-induced fluorescence and optical coherence tomography: an in vitro validation study. AB - BACKGROUND: Measurement of initial enamel erosion is currently limited to in vitro methods. Optical coherence tomography (OCT) and quantitative light-induced fluorescence (QLF) have been used clinically to study advanced erosion. Little is known about their potential on initial enamel erosion. OBJECTIVES: To evaluate the sensitivity of QLF and OCT in detecting initial dental erosion in vitro. METHODS: 12 human incisors were embedded in resin except for a window on the buccal surface. Bonding agent was applied to half of the window, creating an exposed and non-exposed area. Baseline measurements were taken with QLF, OCT and surface microhardness. Samples were immersed in orange juice for 60 min and measurements taken stepwise every 10 min. QLF was used to compare the loss of fluorescence between the two areas. The OCT system, OCS1300SS (Thorlabs Ltd.), was used to record the intensity of backscattered light of both areas. Multiple linear regression and paired t test were used to compare the change of the outcome measures. RESULTS: All 3 instruments demonstrated significant dose responses with the erosive challenge interval (p < 0.05) and a detection threshold of 10 min from baseline. Thereafter, surface microhardness demonstrated significant changes after every 10 min of erosion, QLF at 4 erosive intervals (20, 40, 50 and 60 min) while OCT at only 2 (50 and 60 min). CONCLUSION: It can be concluded that OCT and QLF were able to detect demineralization after 10 min of erosive challenge and could be used to monitor the progression of demineralization of initial enamel erosion in vitro. PMID- 24481142 TI - Structural insights into the functional origin of conjugated microporous polymers: geometry-management of porosity and electronic properties. AB - We report structural insights into the functional origin of conjugated microporous polymers (CMPs), by elucidating the vital role of linkage geometry in controlling the porosity, gas adsorption, conjugation, exciton transport and luminescence. This unprecedented yet crucial role of geometry constitutes a general principle for the rational design of CMPs. PMID- 24481143 TI - Pneumatic lithotripsy versus holmium:YAG laser lithotripsy for the treatment of single ureteral stones: a prospective, single-blinded study. AB - OBJECTIVE: The aim of this prospective single-blinded study was to analyze the stone-free (SF) rates between pneumatic lithotripsy (PL) and laser lithotripsy (LL) for the treatment of single and primary ureteral stones and to evaluate potentially predictive factors of a SF status. MATERIAL AND METHODS: From January 2010 to January 2011, 133 consecutive patients with single and primary ureteral stones were prospectively enrolled. Uni- and multivariate logistic regression were performed to estimate predictive factors of a SF status. RESULTS: The SF rate in the PL group was 80.7 and 86.1% in the LL group (p = 0.002). Success rates with regard of stone position were not significantly different between groups. At univariate logistic regression, middle ureteral stone (OR 3.33, p = 0.04), distal ureteral stone (OR 4.4, p = 0.02), LL (OR 3.05, p = 0.04) and Hounsfield units (HUs) (OR 1.07, p = 0.03) were significantly predictive factors of a SF status. At a multivariate logistic regression, middle ureteral stone (OR 5.58, p = 0.01), distal ureteral stone (OR 7.87, p < 0.01), LL (OR 2.4, p = 0.02) and HUs >=1,200 (OR 1.15, p = 0.02) were significantly associated with a SF status. CONCLUSIONS: LL significantly influences the SF status after ureteroscopy, allowing a higher SF rate when compared to PL. HUs may significantly influence this success rate. PMID- 24481144 TI - Ankle-brachial index, cognitive impairment and cerebrovascular disease in a Chinese population. AB - BACKGROUND: Previous studies have assessed the association between ankle-brachial index (ABI) and cognition, mainly using brief cognitive tests. We investigated whether ABI was associated with cognition independent of neuroimaging markers of cerebrovascular disease. METHODS: Chinese subjects (n = 278, aged >=60 years) were recruited from the ongoing Epidemiology of Dementia in Singapore (EDIS) Study. Ankle and brachial blood pressures were measured, and low ABI was defined as <=0.9. A neuropsychological battery was utilized to determine cognition. Cognitive impairment no dementia (CIND) and dementia were diagnosed according to standard diagnostic criteria. Magnetic resonance imaging (MRI) was used to obtain semiquantitative and quantitative markers of cerebrovascular disease and atrophy. RESULTS: A low ABI was related to the presence of intracranial stenosis (odds ratio, OR = 1.71; 95% confidence interval, CI: 1.13-2.59), but not with the presence of infarcts, microbleeds or grey matter, white matter and white matter lesion volumes. Furthermore, a low ABI was associated with poorer overall cognitive function and CIND-moderate/dementia (OR = 2.26; 95% CI: 1.11-4.59), independent of cardiovascular risk factors, and the MRI markers related to cerebrovascular disease and atrophy. CONCLUSION: We found an association between a low ABI and cognitive impairment, independent of any MRI marker of cerebral small vessel disease or large artery atherosclerotic disease. PMID- 24481145 TI - A genetic polymorphism (rs17251221) in the calcium-sensing receptor is associated with breast cancer susceptibility and prognosis. AB - BACKGROUND: Calcium-sensing receptor (CaSR) is a typical G protein coupled receptor. The rs17251221 SNP is located in an intron of the CaSR gene, and the G allele is considered a gain of function mutation. Previous studies revealed that rs17251221 polymorphisms contribute to the risk of developing certain types of cancers. This study investigated the rs17251221 SNP in breast cancer by analyzing the correlation of the rs17251221 genotype with breast cancer susceptibility, clinicopathological features and prognosis. METHODS: A TaqMan assay was used to genotype the rs17251221 SNP in a case-control study. The expression levels of CaSR in breast cancer tissues were determined using quantitative reverse transcription PCR (qRT-PCR) and western blot analysis. The association of the rs17251221 genotype and the clinicopathological characteristics, as well as the prognosis of the breast cancer patient, was assessed statistically. RESULTS: We found that the AG and GG genotypes were associated with lower mRNA and protein levels of CaSR compared to the AA genotype in breast cancer tissues. We also found that the AG and GG genotypes were associated with breast cancer susceptibility, the patient's age at diagnosis, tumor size, lymph node metastasis and estrogen receptor status of breast cancer tissue. More importantly, we found that the genotypes were prognostic markers for both disease-free survival and overall survival of breast cancer. CONCLUSION: The rs17251221 SNP is a risk factor associated with breast cancer susceptibility, as well as a prognostic indicator. Our data suggest that rs17251221 may be a potential therapeutic target in breast cancer. PMID- 24481146 TI - Dapagliflozin approved for type 2 diabetes. PMID- 24481147 TI - New hypertension guidelines may simplify treatment. PMID- 24481148 TI - New drug and biological product approvals, 2013. PMID- 24481149 TI - Hospitals' performance at medication communication improved, VBP data suggest. PMID- 24481152 TI - Accreditation of nontraditional pharmacy residency programs. PMID- 24481153 TI - Omacetaxine for treatment-resistant or treatment-intolerant adult chronic myeloid leukemia. AB - PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, and safety of a first-in-class protein synthesis inhibitor for use in treatment-resistant chronic myeloid leukemia (CML) are reviewed. SUMMARY: Omacetaxine mepesuccinate (Synribo, Teva Pharmaceuticals) is a potent plant alkaloid isolated from Cephalotaxus (Chinese yew tree) species. It has a mechanism of action distinct from that of the standard first-line therapy for CML, tyrosine kinase inhibitors (TKIs), and has demonstrated efficacy in adult patients with chronic- or accelerated-phase CML who develop intolerance to two or more TKIs or experience multiple TKI treatment failures. Two open-label Phase II trials (combined n = 108) demonstrated that omacetaxine produced a major cytogenetic response in 18.4% of patients with chronic-phase CML and a major hematologic response in 14.3% of patients with accelerated-phase CML (median duration of reponse, 12.5 and 4.7 months, respectively). Symptom improvement or improved overall survival in omacetaxine-treated patients has not been demonstrated. In clinical trials to date, the most common grade 1-4 adverse reactions included thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, and asthenia. The drug is administered subcutaneously on an intermittent schedule (14 days on, 14 days off during induction; 7 days on, 21 days off during maintenance). Research to better delineate omacetaxine's optimal role in the management of CML and other hematologic malignancies (e.g., acute myelogenic leukemia) is ongoing. CONCLUSION: Omacetaxine, a novel protein synthesis inhibitor, provides an alternative therapy for patients with CML who have experienced TKI treatment failures or are intolerant of two or more TKIs. PMID- 24481154 TI - Incorporating multiple mini-interviews in the postgraduate year 1 pharmacy residency program selection process. AB - PURPOSE: The incorporation of the multiple mini-interview (MMI) into the postgraduate year 1 (PGY1) pharmacy residency program selection process was evaluated. METHODS: Four MMI stations evaluating the highest-rated nonacademic attributes of prospective residents (critical thinking, teamwork, ethical reasoning and integrity, and communication and interpersonal skills) were incorporated into the traditional PGY1 residency interview process at an academic medical center. After completion of the interview, candidates and interviewers were surveyed regarding their perceptions of the refined interview process. Data regarding scores on various components of the applicant profile were also compared for significant correlations. Descriptive statistics were calculated for questionnaire responses and individual components of candidate profiles. Pearson's correlation coefficients were calculated between MMI score, traditional interview score, age, grade point average, application score, college of pharmacy rank, and final candidate rank (subjective score). RESULTS: A total of 38 candidates were interviewed, 37 of whom completed the postinterview survey. Candidates agreed that the MMI allowed them to convey their abilities effectively; however, they disagreed that it was more effective than traditional interviews. Candidates did not agree that the MMI caused less anxiety than traditional interviews. All 15 interviewers completed the postinterview survey and believed that the MMI effectively evaluated soft skills and that the MMI was more effective than traditional interviews in assessing candidates' abilities, skills, and thought processes. CONCLUSION: The use of the MMI in a PGY1 pharmacy residency applicant selection process appeared to be well accepted by both candidates and interviewers and likely assesses different attributes than do traditional interview techniques. PMID- 24481155 TI - Multidisciplinary initiative to improve inpatient anticoagulation and management of venous thromboembolism. AB - PURPOSE: The implementation of best practices to optimize inpatient anticoagulation and venous thromboembolism (VTE) management are described. SUMMARY: A multidisciplinary team of pharmacists, hospitalists, computer prescriber-order-entry system (CPOE) experts, and data specialists was assembled. A VTE management best-practices bundle was designed and implemented using education, CPOE upgrades, clinical decision support, triggered consultation, and checklists. Process performance data were collected from CPOE and chart review. A total of 189 patients with 211 identified VTE events were included in the analysis. Compliance with warfarin adjustment by protocol improved significantly, from 70% before the launch of the order set to 96% afterward. Heparin-warfarin overlap nearly tripled, from 26% to 74%, but still over a quarter of postimplementation cases did not meet this quality measure. While low-molecular weight heparin (LMWH) was used appropriately in all six postintervention cases of cancer-related VTE, the result was not a significant improvement over the 68% compliance in the period preceding the order set. The prescription rate of compression stockings after leg DVT was low in both periods. Point estimates for mean length of hospital stay improved but did not reach statistical significance. Measures of mortality and readmission rates were limited by sample size and were not significantly changed. CONCLUSION: Implementation by a multidisciplinary team of a VTE management bundle incorporated CPOE upgrades and other interventions. Laboratory testing before warfarin treatment, warfarin education, warfarin adjustment by protocol, and warfarin-heparin overlap improved after the interventions, but LMWH education, compression stocking use, laboratory testing before heparin treatment, and clinical outcomes did not change significantly. PMID- 24481156 TI - Development of an electronic patient prioritization tool for clinical pharmacist interventions. AB - PURPOSE: A software-based tool to help prioritize inpatients for adverse drug event (ADE) prevention initiatives is described. SUMMARY: The clinical pharmacy department of a New Zealand hospital developed the Assessment of Risk Tool (ART), an application for monitoring prespecified clinical "flags" (some derived from the Institute for Healthcare Improvement's ADE trigger tool) for high-risk medication use and other ADE risk factors. The ART permits ADE risk assessment in virtual real time (i.e., medication-use data and other clinical information are updated multiple times daily). Each of the 38 flags captured by the ART is assigned a weighted score; the item scores are summed to provide a total ART score indicating low, medium, or high ADE risk, and patients are prioritized by the ART score for pharmacist interventions such as clinical review and discharge coordination. In the first 18 months after ART implementation, the average number of patients receiving medication reconciliation each month increased from 280 to 500. During one 8-month period, 765 high-risk patients were prioritized for discharge services and 526 medication errors (MEs) were prevented, including 174 errors deemed to pose a threat of moderate-to-major patient harm. The tool has been well received by clinicians and has generated interest among other New Zealand hospitals. CONCLUSION: By facilitating the identification and monitoring of patients at high risk for MEs and ADEs, the ART has enabled one hospital's clinical pharmacists to conduct interventions such as medication reconciliation and clinical review in a more timely and targeted manner. PMID- 24481157 TI - Delay in indexing articles published in major pharmacy practice journals. AB - PURPOSE: The delay in time from entry in the PubMed database to indexing with medical subject heading (MeSH) terms for articles published in three major pharmacy practice journals was evaluated. METHODS: In April 2013, MEDLINE data were retrieved for articles published in the American Journal of Health-System Pharmacy (AJHP), the Annals of Pharmacotherapy, and Pharmacotherapy between January 1, 2010, and December 31, 2011. Data collected for each article included the PubMed entry date, MeSH indexing date, and publication type. The PubMed entry date was defined as the Entrez date, the date the citation was added to the PubMed database. Medians and interquartile ranges (IQRs) were calculated for the time to indexing of articles and for the age of unindexed articles. The proportion of unindexed articles was also calculated. RESULTS: A total of 1626 publications were reviewed. Overall, the median time to indexing with MeSH terms was 114 days (IQR, 98-141 days): 107 days (IQR, 94-129 days) for AJHP, 131 days (IQR, 104-157 days) for Annals of Pharmacotherapy, and 114 days (IQR, 99-128 days) for Pharmacotherapy. The median age of unindexed articles was 807 days (IQR, 671-807 days). CONCLUSION: An analysis of three major pharmacy practice journals showed that the median time to indexing articles published in 2010 and 2011 was 114 days. While all articles from AJHP and Pharmacotherapy were indexed, 40 articles from Annals of Pharmacotherapy remained unindexed. PMID- 24481158 TI - ASHP guidelines on home infusion pharmacy services. PMID- 24481159 TI - Safety of adult tonsillectomy: a population-level analysis of 5968 patients. AB - IMPORTANCE: Tonsillectomy is one of the most commonly performed otolaryngology procedures. The safety of this procedure in adults is based on small case series. To our knowledge, we report the first population-level analysis of the safety of adult tonsillectomies in the United States. OBJECTIVE: To characterize the mortality, complication, and reoperation rate in adult tonsillectomy. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study of 5968 adult patients who underwent tonsillectomy with records in the database of the American College of Surgeons National Surgical Quality Improvement Program (2005 to 2011). INTERVENTION: Tonsillectomy. MAIN OUTCOMES AND MEASURES: Outcomes of interest included mortality, complications, and reoperation in the 30-day postoperative period. Statistical analysis included chi2 test, t test, and multivariate logistic regression. RESULTS: The 30-day mortality rate was 0.03%, the complication rate was 1.2%, and the reoperation rate was 3.2%. Most patients had a primary diagnosis of chronic tonsillitis and/or adenoiditis (82.9%), and the most common complications were pneumonia (27% of all complications), urinary tract infection (27%), and superficial site infections (16%). Patients who underwent reoperation were more likely to be male (54.0% vs 32.4%; P < .001), white (84.8% vs 75.3%; P = .02), or inpatients (24.3% vs 14.3%; P < .001) and to have postoperative complications (5.3% vs 1.1%; P < .001) than those who did not return to the operating room. On multivariate analysis, male sex (odds ratio [OR], 2.30 [95% CI, 1.67-3.15]), inpatient status (OR, 1.52 [95% CI, 1.04-2.22]), and the presence of a postoperative complication (OR, 4.58 [95% CI, 2.11-9.93]) were independent risk factors for reoperation. CONCLUSIONS AND RELEVANCE: In the United States, adult tonsillectomy is a safe procedure with low rates of mortality and morbidity. The most common posttonsillectomy complications were infectious in etiology, and complications were independently associated with the need for reoperation. PMID- 24481161 TI - Management of neglected periorbital squamous cell carcinoma requiring orbital exenteration. AB - With its perineural invasion capacity, periorbital squamous cell carcinoma (SCC) may easily invade orbital structures. When SCC invades the orbital musculature or the orbit itself, orbital exenteration, one of the most disfiguring operations on the face, is required. We reviewed elderly patients with periorbitally localized SCC requiring orbital exenteration to evaluate reconstructive options and survival. A chart review of patients' records was conducted to identify all patients older than 65 years with periorbital malignancy requiring orbital exenteration from 2006 to 2011. A total of 9 patients who met the criteria were included in the study. The mean age at surgery was 77 +/- 6.7 years, and the mean defect size was 74.2 cm2. All patients had a similar history of late presentation to a doctor because of hesitation to undergo surgery. The temporoparietal fascia flap, galeal flap, free gracilis flap, and free vastus lateralis musculocutaneous flap were the treatment options for reconstruction of the defects. All patients died during follow-up, and the mean survival was 15.7 months (range, 6-36 months). Only 2 of them had relapse before the death. Our small series suggest that elderly patients with periorbital SCC requiring orbital exenteration may not have enough survival to relapse because of the death from different causes without relapse or any sign of spreading cancer. Also, prolonged surgery with free flap reconstruction may increase the risk of postoperative intensive care unit requirement. Because local flaps may work very well for reconstructing the orbital exenteration defects, free flap option should be kept for selected cases. PMID- 24481162 TI - Frontoethmoidal mucocele following pediatric craniofacial surgery. AB - BACKGROUND: Mucoceles occur as a result of accumulation and retention of mucous secretions in a paranasal sinus and are uncommon in the pediatric age group. Persistent or intermittent closure of its ostium through a variety of causes, including previous surgery, is implicated in etiology. The authors report 2 cases of frontoethmoidal mucocele that followed box osteotomies for the treatment of orbital dystopia, with medical literature review and discussion of possible causal factors and events. METHODS: Case histories and radiological imaging are presented on 2 patients presenting with frontoethmoidal mucoceles following craniofacial surgery. Both had transcranial craniofacial techniques where all orbital walls and globe are moved en bloc as a "box." RESULTS: Patient 1, a 12 year-old male patient with Crouzon syndrome, developed mucoceles within 18 months of monobloc distraction surgery and box osteotomies. This was successfully marsupialized with a combined external and endoscopic surgical approach. The second patient, a 15-year-old boy with previously corrected right-sided facial cleft, developed mucocele 9 years following box osteotomies; this was successfully managed by endoscopic drainage. Of 3 other patients having similar box osteotomies in our unit, no other mucoceles were noted as complications. CONCLUSIONS: Mucoceles are a rare complication of craniofacial surgery, and literature review confirms a paucity of reports. Only 1 case has previously been alluded to of mucocele complicating box osteotomy for orbital dystopia. Our 2 cases illustrate and highlight a successful management approach in a multidisciplinary craniofacial unit. PMID- 24481163 TI - Repair of orbital fracture: the antral balloon with implantable reservoir technique. AB - The antral balloon technique is a useful procedure for the treatment of orbital fracture. Its advantages include being able to apply it without any donor-site morbidity. However, the saline injection catheter, which is inserted nasally from the natural ostium, sometimes causes discomfort. We present our new antral balloon technique with an implantable reservoir dome. This technique did not cause patient discomfort because no saline injection catheter was inserted nasally. It contributed to long-term placement of the antral balloon. Of 30 patients, satisfactory symmetries were achieved in 27 patients and the others required subsequent calvarial bone grafting for correction because of residual enophthalmos. PMID- 24481164 TI - Management of a bulky capillary hemangioma in the parapharyngeal space with minimally invasive surgery. AB - In this article, the authors report their management with minimally invasive surgery of a bulky capillary hemangioma in the parapharyngeal space. Parapharyngeal space capillary hemangioma is a rare tumor in adults. Because of its rarity and difficulty to treat, we suggest a multidisciplinary approach in choosing the best treatment, with an accurate follow-up. PMID- 24481165 TI - Lip reconstruction using Karapandzic flap. AB - Reconstruction of the lip may be required after trauma and/or surgical excision of tumor. The lips contribute to form the beginning of the oral cavity, and they are the most common site of oral cancer. Any reconstruction of the lips must include both functional and cosmetic considerations. This case report presents a female patient, aged 22 years old, who was exposed to severe road traffic accident resulting in lower lip loss with both functional and cosmetic disturbances. Surgical reconstruction using Karapandzic flap was carried out at the Maxillofacial Surgery Department at Ramadi Teaching Hospital, Anbar Province, Iraq. A dynamic reconstruction with remaining lip tissue can provide superior results in terms of lip appearance and function. PMID- 24481166 TI - The effect of cigarette smoking on the healing of extraction sockets: an immunohistochemical study. AB - The aim of this study was to investigate immunohistochemically the influence of cigarette smoking on the socket healing after tooth extraction in rats. Eighty four male rats were divided into 3 groups; 2 groups were considered as experimental and the other as control. The animals in test 1 were exposed to smoking regimen before the surgery and after the surgery, but the animals in test 2 were exposed to the smoking regimen only before surgery. All animals' maxillary right central incisors were extracted and killed at the 3rd, 7th, 15th, and 28th day. The samples taken on third day after tooth extraction were stained immunohistochemically with fibronectin antibody and the other with type I collagen antibody. On the third day after tooth extraction, samples in the control group were intense stained (3) (+++); in the test 1 they were slight positive (1) (+) and in the test 2 they were moderate positive (2) (+ +). As a result of scoring type I collagen antibody, there was no statistically significant difference between the groups at seventh day, but there were statistically significant differences between the groups at the 15th and 28th day (P = 0.000 and P = 0.001, respectively). Comparison of the paired intense scores of type I collagen antibody staining according to days within each groups were not statistically significant. As a result, we have found out that the healing process of the tooth extraction socket is negatively affected by cigarette smoke. PMID- 24481167 TI - Coping strategies and psychological distress among mothers of patients with nonsyndromic cleft lip and palate and the family impact of this disorder. AB - The current study aimed to investigate the coping strategies and level of psychological distress in mothers of patients with cleft lip and palate (CLP) and the family impact of this disorder. Participants were mothers of 55 children or adolescents with nonsyndromic CLP recruited from families attending a CLP clinic and 2 university hospitals in Mashhad, northeast of Iran. Family impact, psychological distress, and coping strategies were assessed using validated psychological questionnaires including Family Impact Scale, General Health Questionnaire, and Coping Response Inventory. Findings revealed that mothers relied more on the use of approach-oriented rather than avoidance-oriented coping strategies. According to General Health Questionnaire scores, 38.2% of mothers showed some evidence of psychological distress, and 23.6% were suspected of having severe psychological problems. Regarding the family impact of CLP, mothers reported the greatest impact to be on the family's financial status and parental emotions. Those mothers who used avoidant coping strategies reported a greater family impact of CLP (P = 0.002). Emotional discharge and acceptance coping were significant predictors of family impact (P = 0.037 and P = 0.035, respectively). Mothers of 13- to 18-year-old patients with CLP reported greater use of problem solving coping strategy when compared with mothers of younger patients (P = 0.006). Child's age and coping strategies were not significant predictors of the level of mother's psychological distress. Increased knowledge about how parents cope with their child's craniofacial condition may help caregivers develop a more family-oriented care approach, which is sensitive to the psychosocial needs of parents, children, and their families. PMID- 24481168 TI - Endoscopic endonasal treatment of a large clival giant cell tumor invading the cavernous sinus and temporal lobe. AB - Giant cell tumors (GCTs) are extremely rare lesions, representing less than 5% of all bone tumors. They primarily occur in the long bones. However, a small percentage of these tumors occur in the pelvis, spine, or skull bones. These lesions are usually benign as well as locally aggressive and require complete removal. Nowadays, GCT and other skull base lesions can be treated using the extended endoscopic endonasal approach. We present a case report of a GCT located in the skull base, originating from the clivus and sphenoid bone, invading through the cavernous sinus, and treated using the fully endoscopic endonasal approach. PMID- 24481169 TI - Post-electrical burn calvarial reconstruction using extracorporeal radial forearm flap and polymethylmethacrylate implant--24-year follow-up. PMID- 24481170 TI - Medial orbital wall fracture caused by forceful nose blowing. PMID- 24481172 TI - Electrostatic charge effects on pharmaceutical aerosol deposition in human nasal laryngeal airways. AB - Electrostatic charging occurs in most aerosol generation processes and can significantly influence subsequent particle deposition rates and patterns in the respiratory tract through the image and space forces. The behavior of inhaled aerosols with charge is expected to be most affected in the upper airways, where particles come in close proximity to the narrow turbinate surface, and before charge dissipation occurs as a result of high humidity. The objective of this study was to quantitatively evaluate the deposition of charged aerosols in an MRI based nasal-laryngeal airway model. Particle sizes of 5 nm-30 um and charge levels ranging from neutralized to ten times the saturation limit were considered. A well-validated low Reynolds number (LRN) k-omega turbulence model and a discrete Lagrangian tracking approach that accounted for electrostatic image force were employed to simulate the nasal airflow and aerosol dynamics. For ultrafine aerosols, electrostatic charge was observed to exert a discernible but insignificant effect. In contrast, remarkably enhanced depositions were observed for micrometer particles with charge, which could be one order of magnitude larger than no-charge depositions. The deposition hot spots shifted towards the anterior part of the upper airway as the charge level increased. Results of this study have important implications for evaluating nasal drug delivery devices and for assessing doses received from pollutants, which often carry a certain level of electric charges. PMID- 24481173 TI - A canine model of Alzheimer's disease generated by overexpressing a mutated human amyloid precursor protein. AB - Canines are considered the most authentic model for studying multifactorial human diseases, as these animals typically share a common environment with man. Somatic cell nuclear transfer (SCNT) technology along with genetic engineering of nuclear donor cells provides a unique opportunity for examining human diseases using transgenic canines. In the present study, we generated transgenic canines that overexpressed the human amyloid precursor protein (APP) gene containing well characterized familial Alzheimer's disease (AD) mutations. We successfully obtained five out of six live puppies by SCNT. This was confirmed by observing the expression of green fluorescence protein in the body as a visual transgenic marker and the overexpression of the mutated APP gene in the brain. The transgenic canines developed AD-like symptoms, such as enlarged ventricles, an atrophied hippocampus, and beta-amyloid plaques in the brain. Thus, the transgenic canines we created can serve as a novel animal model for studying human AD. PMID- 24481174 TI - Outcomes of a church-based diabetes prevention program delivered by peers: a feasibility study. AB - PURPOSE: This purpose of this study was to investigate the feasibility and potential health impact of a church-based diabetes prevention program delivered by peers. METHODS: Thirteen at-risk African American adults were recruited to a peer-led diabetes prevention program adapted from the National Diabetes Education Program's Power to Prevent curriculum. The program consisted of 6 core education sessions followed by 6 biweekly telephone support calls. Components of feasibility examined included recruitment, attendance, and retention. Baseline, 8 week, and 20-week assessments measured clinical outcomes (percentage body weight change, waist circumference, lipid panel, blood pressure) and lifestyle behaviors (eg, physical activity and diet). RESULTS: Of the 13 participants enrolled at baseline, 11 completed the intervention. Mean attendance across 6 core sessions was 5.2 classes (87%). At 8 weeks, significant improvements were found for physical activity (P = .031), waist circumference (P = .049), serum cholesterol (P = .036), systolic blood pressure (P = .013), and fat intake (P = .006). At 20 weeks, not only did participants sustain the improvements made following the core intervention, but they also demonstrated additional improvements for HDL (P = .002) and diastolic blood pressure (P = .004). CONCLUSION: Findings suggest that it is feasible to conduct a peer-led diabetes prevention program in a church based setting that has a potentially positive impact on health-related outcomes. PMID- 24481175 TI - Prooxidative-antioxidative balance of cells in different types of renal replacement therapy. AB - BACKGROUND: Patients suffering from chronic kidney disease (CKD) are exposed to increased oxidative stress and disturbances manifesting in the enzymatic and non enzymatic antioxidative defence system. The object of the research was to assess the differences between conservative treatment, peritoneal dialysis and haemodialysis in moderating cellular antioxidative agents. METHODS: The group examined comprised 145 patients. The activities of superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and glucose-6-phosphate dehydrogenase were obtained using kinetic methods. The spectrophotometric method established the concentrations of reduced glutathione, albumin, uric acid, glucose, total protein and lipids. RESULTS: The type of treatment determined significant changes in antioxidative enzyme activities and concentrations of non enzymatic antioxidative compounds. CONCLUSIONS: Peritoneal dialysis provides better antioxidant protection than other types of therapy in CKD and should be considered as first-choice treatment despite more metabolic disorders. PMID- 24481177 TI - The quenching of fluorescence as an indicator of donor-strength in meso arylethynyl BODIPYs. AB - A series of meso arylethynyl BODIPYs (2a-2h) were designed and synthesized by the Pd-catalyzed Sonogashira cross-coupling reaction. The effects of the donor on the photophysical properties of the BODIPYs were explored. The DFT optimized structures and crystal structures show the planar orientation of the donor group with respect to the acceptor BODIPY, which favors a high degree of conjugation and induces strong donor-acceptor interactions. The quenching of fluorescence was correlated with the electron donating strength of the donor. The anthracene, pyrene and triphenylamine were found to have a stronger electron donating ability than the p-methoxyphenyl, phenanthrene, 1-naphthalene, biphenyl, and 2 naphthalene moieties. This was further supported by computational calculations and electrochemical analysis. The single crystal structures of BODIPYs 2d and 2e are reported, which show marvellous supramolecular structures. PMID- 24481176 TI - The ubiquitin system: an essential component to unlocking the secrets of malaria parasite biology. AB - Exploration of the ubiquitin system in eukaryotes has shown that the chemical modification of proteins by ubiquitin, known as ubiquitylation, is an incredibly important post-translational event that is crucial to numerous cellular processes. Ubiquitylation is carried out by a series of enzymes that specifically target proteins to either change their activity or their location or earmark them for degradation. Using a wide range of genome-wide approaches, the ubiquitin system has been shown to be of particular importance in the survival and propagation of the human malaria parasites. In this review, we highlight our current understanding of the ubiquitin system in Plasmodium, and discuss its possible role in the development of drug resistant malaria strains. PMID- 24481179 TI - Editorial. PMID- 24481178 TI - Salient features of the ciliated organ of asymmetry. AB - Many internal organs develop distinct left and right sides that are essential for their functions. In several vertebrate embryos, motile cilia generate an asymmetric fluid flow that plays an important role in establishing left-right (LR) signaling cascades. These 'LR cilia' are found in the ventral node and posterior notochordal plate in mammals, the gastrocoel roof plate in amphibians and Kupffer's vesicle in teleost fish. I consider these transient ciliated structures as the 'organ of asymmetry' that directs LR patterning of the developing embryo. Variations in size and morphology of the organ of asymmetry in different vertebrate species have raised questions regarding the fundamental features that are required for LR determination. Here, I review current models for how LR asymmetry is established in vertebrates, discuss the cellular architecture of the ciliated organ of asymmetry and then propose key features of this organ that are critical for orienting the LR body axis. PMID- 24481180 TI - Why are male malaria parasites in such a rush?: Sex-specific evolution and host parasite interactions. AB - BACKGROUND: Disease-causing organisms are notorious for fast rates of molecular evolution and the ability to adapt rapidly to changes in their ecology. Sex plays a key role in evolution, and recent studies, in humans and other multicellular organisms, document that genes expressed principally or exclusively in males exhibit the fastest rates of adaptive evolution. However, despite the importance of sexual reproduction for many unicellular taxa, sex-biased gene expression and its evolutionary implications have been overlooked. METHODS: We analyse genomic data from multiple malaria parasite (Plasmodium) species and proteomic data sets from different parasite life cycle stages. RESULTS: The accelerated evolution of male-biased genes has only been examined in multicellular taxa, but our analyses reveal that accelerated evolution in genes with male-specific expression is also a feature of unicellular organisms. This 'fast-male' evolution is adaptive and likely facilitated by the male-biased sex ratio of gametes in the mating pool. Furthermore, we propose that the exceptional rates of evolution we observe are driven by interactions between males and host immune responses. CONCLUSIONS: We reveal a novel form of host-parasite coevolution that enables parasites to evade host immune responses that negatively impact upon fertility. The identification of parasite genes with accelerated evolution has important implications for the identification of drug and vaccine targets. Specifically, vaccines targeting males will be more vulnerable to parasite evolution than those targeting females or both sexes. PMID- 24481181 TI - Childhood microbial experience, immunoregulation, inflammation and adult susceptibility to psychosocial stressors and depression in rich and poor countries. PMID- 24481182 TI - Depressive symptoms are not associated with inflammation in younger and older adults in the Philippines. AB - Depression is positively associated with chronic inflammation in industrialized settings with low burdens of infectious disease, but the pattern of association in environments with higher levels of microbial exposure is not known. We measured C-reactive protein (CRP) and interleukin 6 (IL6) in community-based samples of young adults (20-22 years) and older women (35-69 years) in the Philippines. Concentrations of CRP and IL6 were low, and bivariate and multivariate regression analyses indicated no associations between depressive symptoms and inflammation in either sample. Results are interpreted in light of prior research indicating that higher levels of microbial exposure in infancy have lasting effects on the regulation of inflammation, and may prevent the emergence of a relationship between depression and inflammation in adulthood. PMID- 24481183 TI - Clinical consequences of human evolution shaped by cultural trends. AB - Recent reports suggest that increased human population size, decreased negative selection pertaining to some phenotypes and associated genotypes and a possibly increased de novo mutation burden for newborns that relates to paternal age at conception are contributing to an expansion of human genetic diversity. Some of this diversity can be expected to contribute to disease. Because all of the preceding diversity-enhancing factors are to a significant degree consequences of cultural developments, it can be argued that the future clinical burden of the human population will be shaped in part by a human evolutionary trajectory substantially influenced by culturally mediated effects on the number of mutations in the gene pool and on the intensity of selection on some of the phenotypes associated with new genetic variants. PMID- 24481184 TI - Identifying future zoonotic disease threats: Where are the gaps in our understanding of primate infectious diseases? AB - BACKGROUND AND OBJECTIVES: Emerging infectious diseases often originate in wildlife, making it important to identify infectious agents in wild populations. It is widely acknowledged that wild animals are incompletely sampled for infectious agents, especially in developing countries, but it is unclear how much more sampling is needed, and where that effort should focus in terms of host species and geographic locations. Here, we identify these gaps in primate parasites, many of which have already emerged as threats to human health. METHODOLOGY: We obtained primate host-parasite records and other variables from existing databases. We then investigated sampling effort within primates relative to their geographic range size, and within countries relative to their primate species richness. We used generalized linear models, controlling for phylogenetic or spatial autocorrelation, to model variation in sampling effort across primates and countries. Finally, we used species richness estimators to extrapolate parasite species richness. RESULTS: We found uneven sampling effort within all primate groups and continents. Sampling effort among primates was influenced by their geographic range size and substrate use, with terrestrial species receiving more sampling. Our parasite species richness estimates suggested that, among the best sampled primates and countries, almost half of primate parasites remain to be sampled; for most primate hosts, the situation is much worse. CONCLUSIONS AND IMPLICATIONS: Sampling effort for primate parasites is uneven and low. The sobering message is that we know little about even the best studied primates, and even less regarding the spatial and temporal distribution of parasitism within species. PMID- 24481185 TI - Socioeconomic status determines sex-dependent survival of human offspring. AB - BACKGROUND AND OBJECTIVES: In polygynous societies, rich men have many offspring through the marriage of multiple wives. Evolutionary, rich households would therefore benefit more from sons, and according to the Trivers-Willard hypothesis, parents invest more in offspring of the sex that has the best reproductive prospects. We determined the sex differences in number of offspring, sex ratio of offspring, offspring survival and offspring weight in rich and poor households in a polygynous population. METHODOLOGY: We studied a population of 28 994 individuals in Northern Ghana during an 8-year prospective follow-up. We determined the fertility rate for both men and women, sex ratio of 3511 newborn offspring and offspring survival in 16 632 offspring up to reproductive age (<=18 years). Also, we collected 9842 weight measurements of 1470 offspring up to the age of 3 years from growth charts of local clinics. RESULTS: In rich households, men have a lifetime number of 6.0 offspring, while for women this was 3.1. In line with evolutionary predictions, the male:female sex ratio was higher in rich households (0.52; poor households 0.49), sons had lower mortality in rich households (hazard ratio male versus female 1.06, P = 0.64; poor households: hazard ratio male versus female 1.46, P = 0.01) and sons also had higher weights in rich households (P = 0.008). CONCLUSIONS AND IMPLICATIONS: In rich households, men have higher reproductive prospects in this polygynous society and, in line with Trivers-Willard, we registered more sons in rich households, sons had lower mortality and higher weights, maximizing the reproductive output in this society. PMID- 24481187 TI - Epistasis between antibiotic resistance mutations drives the evolution of extensively drug-resistant tuberculosis. AB - BACKGROUND AND OBJECTIVES: Multidrug resistant (MDR) bacteria are a growing threat to global health. Studies focusing on single antibiotics have shown that drug resistance is often associated with a fitness cost in the absence of drug. However, little is known about the fitness cost associated with resistance to multiple antibiotics. METHODOLOGY: We used Mycobacterium smegmatis as a model for human tuberculosis (TB) and an in vitro competitive fitness assay to explore the combined fitness effects and interaction between mutations conferring resistance to rifampicin (RIF) and ofloxacin (OFX); two of the most important first- and second-line anti-TB drugs, respectively. RESULTS: We found that 4 out of 17 M. smegmatis mutants (24%) resistant to RIF and OFX showed a statistically significantly higher or lower competitive fitness than expected when assuming a multiplicative model of fitness effects of each individual mutation. Moreover, 6 out of the 17 double drug-resistant mutants (35%) had a significantly higher fitness than at least one of the corresponding single drug-resistant mutants. The particular combinations of resistance mutations associated with no fitness deficit in M. smegmatis were the most frequent among 151 clinical isolates of MDR and extensively drug-resistant (XDR) Mycobacterium tuberculosis from South Africa. CONCLUSIONS AND IMPLICATIONS: Our results suggest that epistasis between drug resistance mutations in mycobacteria can lead to MDR strains with no fitness deficit, and that these strains are positively selected in settings with a high burden of drug-resistant TB. Taken together, our findings support a role for epistasis in the evolution and epidemiology of MDR- and XDR-TB. PMID- 24481186 TI - Microbial 'Old Friends', immunoregulation and stress resilience. AB - Chronic inflammatory diseases (autoimmunity, allergy and inflammatory bowel diseases) are increasing in prevalence in urban communities in high-income countries. One important factor is reduced exposure to immunoregulation-inducing macro- and microorganisms and microbiota that accompanied mammalian evolution (the hygiene hypothesis or 'Old Friends' mechanism). Reduced exposure to these organisms predisposes to poor regulation of inflammation. But inflammation is equally relevant to psychiatric disorders. Inflammatory mediators modulate brain development, cognition and mood, and accompany low socioeconomic status and some cases of depression in developed countries. The risk of all these conditions (chronic inflammatory and psychiatric) is increased in urban versus rural communities, and increased in immigrants, particularly if they move from a low- to a high-income country during infancy, and often the prevalence increases further in second generation immigrants, suggesting that critical exposures modulating disease risk occur during pregnancy and infancy. Diminished exposure to immunoregulation-inducing Old Friends in the perinatal period may enhance the consequences of psychosocial stressors, which induce increased levels of inflammatory mediators, modulate the microbiota and increase the risk for developing all known psychiatric conditions. In later life, the detrimental effects of psychosocial stressors may be exaggerated when the stress occurs against a background of reduced immunoregulation, so that more inflammation (and therefore more psychiatric symptoms) result from any given level of psychosocial stress. This interaction between immunoregulatory deficits and psychosocial stressors may lead to reduced stress resilience in modern urban communities. This concept suggests novel interpretations of recent epidemiology, and novel approaches to the increasing burden of psychiatric disease. PMID- 24481188 TI - The adolescent transition under energetic stress: Body composition tradeoffs among adolescent women in The Gambia. AB - BACKGROUND AND OBJECTIVES: Life history theory predicts a shift in energy allocation from growth to reproductive function as a consequence of puberty. During adolescence, linear growth tapers off and, in females, ovarian steroid production increases. In this model, acquisition of lean mass is associated with growth while investment in adiposity is associated with reproduction. This study examines the chronological and developmental predictors of energy allocation patterns among adolescent women under conditions of energy constraint. METHODOLOGY: Fifty post-menarcheal adolescent women between 14 and 20 years old were sampled for weight and body composition at the beginning and end of 1 month in an energy-adequate season and 1 month in the subsequent energy-constrained season in a rural province of The Gambia. RESULTS: Chronologically and developmentally younger adolescent girls gain weight in the form of lean mass in both energy-adequate and energy-constrained seasons, whereas older adolescents lose lean mass under conditions of energetic stress (generalized estimating equation (GEE) Wald chi-square comparing youngest tertile with older two tertiles 9.750, P = 0.002; GEE Wald chi-square comparing fast- with slow-growing individuals for growth rate 19.806, P < 0.001). When energy is limited, younger adolescents lose and older adolescents maintain fat (GEE Wald chi-square for interaction of age and season 6.568, P = 0.010; GEE Wald chi-square comparing fast- with slow-growing individuals for interaction of growth rate and season 7.807, P = 0.005). CONCLUSIONS AND IMPLICATIONS: When energy is constrained, the physiology of younger adolescents invests in growth while that of older adolescent females privileges reproductively valuable adipose tissue. PMID- 24481189 TI - Epigenetics, epistasis and epidemics. PMID- 24481191 TI - Grazyna jasienska, the fragile wisdom. PMID- 24481190 TI - Evolutionary biology and anthropology suggest biome reconstitution as a necessary approach toward dealing with immune disorders. AB - Industrialized society currently faces a wide range of non-infectious, immune related pandemics. These pandemics include a variety of autoimmune, inflammatory and allergic diseases that are often associated with common environmental triggers and with genetic predisposition, but that do not occur in developing societies. In this review, we briefly present the idea that these pandemics are due to a limited number of evolutionary mismatches, the most damaging being 'biome depletion'. This particular mismatch involves the loss of species from the ecosystem of the human body, the human biome, many of which have traditionally been classified as parasites, although some may actually be commensal or even mutualistic. This view, evolved from the 'hygiene hypothesis', encompasses a broad ecological and evolutionary perspective that considers host-symbiont relations as plastic, changing through ecological space and evolutionary time. Fortunately, this perspective provides a blueprint, termed 'biome reconstitution', for disease treatment and especially for disease prevention. Biome reconstitution includes the controlled and population-wide reintroduction (i.e. domestication) of selected species that have been all but eradicated from the human biome in industrialized society and holds great promise for the elimination of pandemics of allergic, inflammatory and autoimmune diseases. PMID- 24481192 TI - Testing the evolutionary basis of the predictive adaptive response hypothesis in a preindustrial human population. AB - BACKGROUND AND OBJECTIVES: The thrifty phenotype hypothesis proposes that late life metabolic diseases result from mismatch between early-life and adulthood nutrition. More recently, the predictive adaptive response (PAR) hypothesis has suggested that poor early-life environmental conditions induce metabolic changes that maximize health and fitness in similarly poor adult conditions, but reduce fitness if conditions later improve. Therefore, later-life survival and reproduction should be maximized where environmental conditions during development and adulthood match, but few studies in humans have addressed the consequences of poor early conditions on fitness traits in varying later conditions. METHODOLOGY: We tested key evolutionary predictions of the PAR hypothesis using detailed longitudinal data with several environmental parameters from a natural fertility preindustrial human population, to investigate how combinations of early- and late-life environmental conditions affected annual probabilities of survival and reproduction. RESULTS: We found no suggestion that fitness was maximised when developmental and later-life conditions matched, but rather poor environmental conditions during development or later life and their combinations were associated with lower survival. CONCLUSIONS AND IMPLICATIONS: Our results are more consistent with predictions of 'silver spoon' models, whereby adverse early-life conditions are detrimental to later health and fitness across all environments. Future evolutionary research on understanding metabolic disease epidemiology should focus on determining whether adaptive prediction maximizes infant survival where conditions match during development and immediately after birth, rather than drawing attention to the unlikely long-term fitness benefits of putative metabolic changes associated with poor early nutrition. PMID- 24481193 TI - African variation at Cytochrome P450 genes: Evolutionary aspects and the implications for the treatment of infectious diseases. AB - The genomics revolution has provided a plethora of data from many previously uncharacterized populations. The increase in the amount of genetic data has improved our understanding of why individuals and populations differ in their susceptibility to multiple diseases. It has also enabled researchers to identify how genomic variation, including at the Cytochrome P450 (CYP450) super-family, affects the safety and efficacy of therapeutic drugs. CYP450 metabolize ~90% of clinically administered drugs. Variability in CYP450 expression is known to affect the safety and efficacy of therapeutic drugs, including many used in the treatment and control of infectious diseases. There are inter-ethnic differences in the frequencies of clinically relevant CYP450 variants which affect CYP450 expression. Comparative studies of African populations have identified population structuring at CYP450 genes. This is associated with intra-African differences in the success of drug therapies used in the treatment of infectious diseases. Therapeutic drugs dominate control strategies for infectious diseases and are widely administered through mass drug administration campaigns. However, resistance to chemotherapy is spreading across endemic regions. The most common response has been to increase chemotherapeutic dosages, and administer combination therapies. However, there are few pharmacovigilance data examining how these changes influence adverse drug reactions. This review provides an overview of current knowledge of intra-Africa CYP450 variation, and the known associations with sub-optimal clinical outcomes in the treatment of infectious diseases. In addition, the potential for evolutionary approaches in the study of CYP450 variation is discussed to examine their potential in preventative medicine and intervention strategies within Africa. PMID- 24481194 TI - Stress and sex in malaria parasites: Why does commitment vary? AB - For vector-borne parasites such as malaria, how within- and between-host processes interact to shape transmission is poorly understood. In the host, malaria parasites replicate asexually but for transmission to occur, specialized sexual stages (gametocytes) must be produced. Despite the central role that gametocytes play in disease transmission, explanations of why parasites adjust gametocyte production in response to in-host factors remain controversial. We propose that evolutionary theory developed to explain variation in reproductive effort in multicellular organisms, provides a framework to understand gametocyte investment strategies. We examine why parasites adjust investment in gametocytes according to the impact of changing conditions on their in-host survival. We then outline experiments required to determine whether plasticity in gametocyte investment enables parasites to maintain fitness in a variable environment. Gametocytes are a target for anti-malarial transmission-blocking interventions so understanding plasticity in investment is central to maximizing the success of control measures in the face of parasite evolution. PMID- 24481195 TI - Evidence for gene duplication in the voltage-gated sodium channel gene of Aedes aegypti. AB - BACKGROUND AND OBJECTIVES: Mutations in the voltage-gated sodium channel gene (NaV), known as kdr mutations, are associated with pyrethroid and DDT insecticide resistance in a number of species. In the mosquito dengue vector Aedes aegypti, besides kdr, other polymorphisms allowed grouping AaNaV sequences as type 'A' or 'B'. Here, we point a series of evidences that these polymorphisms are actually involved in a gene duplication event. METHODOLOGY: Four series of methods were employed: (i) genotypying, with allele-specific PCR (AS-PCR), of two AaNaV sites that can harbor kdr mutations (Ile1011Met and Val1016Ile), (ii) cloning and sequencing of part of the AaNaV gene, (iii) crosses with specific lineages and analysis of the offspring genotypes and (iv) copy number variation assays, with TaqMan quantitative real-time PCR. RESULTS: kdr mutations in 1011 and 1016 sites were present only in type 'A' sequences, but never in the same haplotype. In addition, although the 1011Met-mutant allele is widely disseminated, no homozygous (1011Met/Met) was detected. Sequencing revealed three distinct haplotypes in some individuals, raising the hypothesis of gene duplication, which was supported by the genotype frequencies in the offspring of specific crosses. Furthermore, it was estimated that a laboratory strain selected for insecticide resistance had 5-fold more copies of the sodium channel gene compared with a susceptible reference strain. CONCLUSIONS AND IMPLICATIONS: The AaNaV duplication here found might be a recent adaptive response to the intense use of insecticides, maintaining together wild-type and mutant alleles in the same organism, conferring resistance and reducing some of its deleterious effects. PMID- 24481196 TI - Evolutionarily stable anti-cancer therapies by autologous cell defection. AB - Game theory suggests an anti-cancer treatment based on the use of modified cancer cells that disrupt cooperation within the tumor. Cancer cells are harvested from the patient, the genes for the production of essential growth factors are knocked out in vitro and the cells are then reinserted in the tumor, where they lead to its collapse. BACKGROUND AND OBJECTIVES: Current anti-cancer drugs and treatments based on gene therapy are prone to the evolution of resistance, because cancer is a process of clonal selection: resistant cell lines have a selective advantage and therefore increase in frequency, eventually conferring resistance to the whole tumor and leading to relapse. An effective treatment must be evolutionarily stable, that is, immune to the invasion of resistant mutant cells. This study shows how such a treatment can be achieved by autologous cell therapy using modified cancer cells, knocked out for genes coding for diffusible factors like growth factors. METHODOLOGY: The evolutionary dynamics of a population of cells producing diffusible factors are analyzed using a nonlinear public goods game in a structured population in which the interaction neighborhood and the update neighborhood are decoupled. The analysis of the dynamics of the system reveals what interventions can drive the population to a stable equilibrium in which no diffusible factors are produced. RESULTS: A treatment based on autologous knockout cell therapy can be designed to lead to the spontaneous collapse of a tumor, without targeting directly the cancer cells, their growth factors or their receptors. Critical parameters that can make the therapy effective are identified. Concepts from evolutionary game theory and mechanism design, some of which are counterintuitive, can be adopted to optimize the treatment. CONCLUSIONS AND IMPLICATIONS: Although it shares similarities with other approaches based on gene therapy and RNA interference, the method suggested here is evolutionarily stable under certain conditions. This method, named autologous cell defection, can be carried out using existing molecular biology and cell therapy techniques. PMID- 24481197 TI - Hygiene and the world distribution of Alzheimer's disease: Epidemiological evidence for a relationship between microbial environment and age-adjusted disease burden. AB - BACKGROUND AND OBJECTIVES: Alzheimer's disease (AD) shares certain etiological features with autoimmunity. Prevalence of autoimmunity varies between populations in accordance with variation in environmental microbial diversity. Exposure to microorganisms may improve individuals' immunoregulation in ways that protect against autoimmunity, and we suggest that this may also be the case for AD. Here, we investigate whether differences in microbial diversity can explain patterns of age-adjusted AD rates between countries. METHODOLOGY: We use regression models to test whether pathogen prevalence, as a proxy for microbial diversity, across 192 countries can explain a significant amount of the variation in age-standardized AD disability-adjusted life-year (DALY) rates. We also review and assess the relationship between pathogen prevalence and AD rates in different world populations. RESULTS: Based on our analyses, it appears that hygiene is positively associated with AD risk. Countries with greater degree of sanitation and lower degree of pathogen prevalence have higher age-adjusted AD DALY rates. Countries with greater degree of urbanization and wealth exhibit higher age adjusted AD DALY rates. CONCLUSIONS AND IMPLICATIONS: Variation in hygiene may partly explain global patterns in AD rates. Microorganism exposure may be inversely related to AD risk. These results may help predict AD burden in developing countries where microbial diversity is rapidly diminishing. Epidemiological forecasting is important for preparing for future healthcare needs and research prioritization. PMID- 24481198 TI - Patterns of physical and psychological development in future teenage mothers. AB - BACKGROUND AND OBJECTIVES: Teenage childbearing may have childhood origins and can be viewed as the outcome of a coherent reproductive strategy associated with early environmental conditions. Life-history theory would predict that where futures are uncertain fitness can be maximized through diverting effort from somatic development into reproduction. Even before the childbearing years, future teenage mothers differ from their peers both physically and psychologically, indicating early calibration to key ecological factors. Cohort data have not been deliberately collected to test life-history hypotheses within Western populations. Nonetheless, existing data sets can be used to pursue relevant patterns using socioeconomic variables as indices of relevant ecologies. METHODOLOGY: We examined the physical and psychological development of 599 young women from the National Child Development Study who became mothers before age 20, compared to 599 socioeconomically matched controls. RESULTS: Future young mothers were lighter than controls at birth and shorter at age 7. They had earlier menarche and accelerated breast development, earlier cessation of growth and shorter adult stature. Future young mothers had poorer emotional and behavioural adjustment than controls at age 7 and especially 11, and by age 16, idealized younger ages for marriage and parenthood than did the controls. CONCLUSIONS AND IMPLICATIONS: The developmental patterns we observed are consistent with the idea that early childbearing is a component of an accelerated reproductive strategy that is induced by early-life conditions. We discuss the implications for the kinds of interventions likely to affect the rate of teenage childbearing. PMID- 24481199 TI - Wolbachia versus dengue: Evolutionary forecasts. AB - A novel form of biological control is being applied to the dengue virus. The agent is the maternally transmitted bacterium Wolbachia, naturally absent from the main dengue vector, the mosquito Aedes aegypti. Three Wolbachia-based control strategies have been proposed. One is suppression of mosquito populations by large-scale releases of males incompatible with native females; this intervention requires ongoing releases. The other interventions transform wild mosquito populations with Wolbachia that spread via the frequency-dependent fitness advantage of Wolbachia-infected females; those interventions potentially require just a single, local release for area-wide disease control. One of these latter strategies uses Wolbachia that shortens mosquito life, indirectly preventing viral maturation/transmission. The other strategy uses Wolbachia that block viral transmission. All interventions can be undermined by viral, bacterial or mosquito evolution; viral virulence in humans may also evolve. We examine existing theory, experiments and comparative evidence to motivate predictions about evolutionary outcomes. (i) The life-shortening strategy seems the most likely to be thwarted by evolution. (ii) Mosquito suppression has a reasonable chance of working locally, at least in the short term, but long-term success over large areas is challenging. (iii) Dengue blocking faces strong selection for viral resistance but may well persist indefinitely at some level. Virulence evolution is not mathematically predictable, but comparative data provide no precedent for Wolbachia increasing dengue virulence. On balance, our analysis suggests that the considerable possible benefits of these technologies outweigh the known negatives, but the actual risk is largely unknown. PMID- 24481200 TI - Editorial. PMID- 24481201 TI - How effectively can HIV phylogenies be used to measure heritability? AB - BACKGROUND AND OBJECTIVES: The severity of HIV-1 infection, measured by set-point viral load (SPVL), is highly variable between individuals. Its heritability between infections quantifies the control the pathogen genotype has over disease severity. Heritability estimates vary widely between studies, but differences in methods make comparison difficult. Phylogenetic comparative analysis offers measures of phylogenetic signal, but it is unclear how to interpret them in terms of the fraction of variance in SPVL controlled by the virus genotype. METHODOLOGY: We present computational methods which link statistics summarizing phylogenetic signal to heritability, h(2) in order to test for and quantify it. We re-analyse data from Switzerland and Uganda, and apply it to new data from the Netherlands. We systematically compare established and new (e.g. phylogenetic pairs, PP) phylogenetic signal statistics. RESULTS: Heritability estimates varied by method and dataset. Several methods were consistently able to detect simulated heritability above , but none below. Pagel's lambda was the most robust and sensitive. The PP method found no heritability in the Netherlands data, whereas Pagel's lambda found significant heritability only in a narrow subdivision (P = 0.038). Heritability was estimated at h(2) = 0.52 (95% confidence interval 0.00 0.63). CONCLUSIONS AND IMPLICATIONS: This standardized measure, h(2), allows comparability of heritability between cohorts. We confirm high heritability in Swiss data, but neither in Ugandan data nor in the Netherlands, where it is barely significant or undetectable. Existing phylogenetic methods are ill-suited for detecting heritability below , which may nonetheless be biologically important. PMID- 24481202 TI - Genome organization and the role of centromeres in evolution of the erythroleukaemia cell line HEL. AB - BACKGROUND AND OBJECTIVES: The human erythroleukaemia (HEL) cell line has a highly rearranged genome. We matched whole chromosome analysis with cytogenomic microarray data to build a detailed description of these rearrangements. METHODOLOGY: We used a combination of single nucleotide polymorphism array and multiple fluorescence in situ hybridization approaches, and compared our array data with publicly available data for different sublines of HEL. B allele frequencies revealed the fate of each homologue for most chromosomes. RESULTS: At least two instances of the breakage-fusion-bridge cycle appear to have facilitated amplification of oncogenes and deletion of tumour suppressor genes. Because our study included centromere identification, we found that some abnormal chromosomes had centromeres that did not match the identity of the rest of the chromosome. CONCLUSIONS AND IMPLICATIONS: This study highlights the variety of complementary methods required to understand remodelling of the genome in cancer and uncover some of the mechanisms involved. We present evidence of centromere capture as a means of preserving broken chromosome segments. Testing for another highly repetitive DNA region, the nucleolus organizer region, helped identify the steps involved in chromosome 9 copy number aberrations. Increased use of techniques for identifying centromeres and other repetitive DNA regions will add to our understanding of genome remodelling and evolution. The pattern of chromosome 20 aberration in HEL supports an association of 20q11.21 amplification with erythroleukaemia (acute myeloid leukaemia subtype M6) in the context of 20q12 deletion. The differences between the karyotypes in different HEL sublines highlight the constantly evolving genomes of cultured cell lines. PMID- 24481203 TI - Genetic links between post-reproductive lifespan and family size in Framingham. AB - BACKGROUND AND OBJECTIVES: Is there a trade-off between children ever born (CEB) and post-reproductive lifespan in humans? Here, we report a comprehensive analysis of reproductive trade-offs in the Framingham Heart Study (FHS) dataset using phenotypic and genotypic correlations and a genome-wide association study (GWAS) to look for single-nucleotide polymorphisms (SNPs) that are related to the association between CEB and lifespan. METHODOLOGY: We calculated the phenotypic and genetic correlations of lifespan with CEB for men and women in the Framingham dataset, and then performed a GWAS to search for SNPs that might affect the relationship between post-reproductive lifespan and CEB. RESULTS: We found significant negative phenotypic correlations between CEB and lifespan in both women (rP = -0.133, P < 0.001) and men (rP = -0. 079, P = 0.036). The genetic correlation was large, highly significant and strongly negative in women (rG = 0.877, P = 0.009) in a model without covariates, but not in men (P = 0.777). The GWAS identified five SNPs associated with the relationship between CEB and post reproductive lifespan in women; some are near genes that have been linked to cancer. None were identified in men. CONCLUSIONS AND IMPLICATIONS: We identified several SNPs for which the relationship between CEB and post-reproductive lifespan differs by genotype in women in the FHS who were born between 1889 and 1958. That result was not robust to changes in the sample. Further studies on larger samples are needed to validate the antagonistic pleiotropy of these genes. PMID- 24481204 TI - Windfalls and pitfalls: Applications of population genetics to the search for disease genes. AB - Association mapping can be viewed as an application of population genetics and evolutionary biology to the problem of identifying genes causally connected to phenotypes. However, some population-genetic principles important to the design and analysis of association studies have not been widely understood or have even been generally misunderstood. Some of these principles underlie techniques that can aid in the discovery of genetic variants that influence phenotypes ('windfalls'), whereas others can interfere with study design or interpretation of results ('pitfalls'). Here, considering examples involving genetic variant discovery, linkage disequilibrium, power to detect associations, population stratification and genotype imputation, we address misunderstandings in the application of population genetics to association studies, and we illuminate how some surprising results in association contexts can be easily explained when considered from evolutionary and population-genetic perspectives. Through our examples, we argue that population-genetic thinking-which takes a theoretical view of the evolutionary forces that guide the emergence and propagation of genetic variants-substantially informs the design and interpretation of genetic association studies. In particular, population-genetic thinking sheds light on genetic confounding, on the relationships between association signals of typed markers and causal variants, and on the advantages and disadvantages of particular strategies for measuring genetic variation in association studies. PMID- 24481205 TI - Evidence for independent evolution of functional progesterone withdrawal in primates and guinea pigs. AB - BACKGROUND AND OBJECTIVES: Cervix remodeling (CRM) is a critical process in preparation for parturition. Early cervix shortening is a powerful clinical predictor of preterm birth, and thus understanding how CRM is regulated is important for the prevention of prematurity. Humans and other primates differ from most other mammals by the maintenance of high levels of systemic progesterone concentrations. Humans have been hypothesized to perform functional progesterone withdrawal (FPW). Guinea pigs are similar to humans in maintaining high-progesterone concentrations through parturition, thus making them a prime model for studying CRM. Here, we analyze the phylogenetic history of FPW and document gene expression in the guinea pig uterine cervix. METHODOLOGY: Data on progesterone withdrawal were collected from the literature, and character evolution was analyzed. Uterine cervix samples were collected from non-pregnant, mid-pregnant and late pregnant guinea pigs. RNA was extracted and sequenced. Relative transcript levels were estimated and compared among sample groups. RESULTS: The phylogenetic analysis shows that FPW evolved independently in primates and guinea pigs. The transcriptome data confirms that guinea pigs down regulate progesterone receptor toward parturition, in contrast to humans. Some of the similarities between human and guinea pig are: down-regulation of estrogen receptor, up-regulation of VCAN and IGFBP4 as well as likely involvement of prostaglandins. CONCLUSIONS AND IMPLICATIONS: (i) FPW in guinea pigs evolved independently from that in primates. (ii) A small set of conserved gene regulatory changes has been detected. PMID- 24481206 TI - Skin-to-stone distance has no impact on outcomes of percutaneous nephrolithotomy. AB - OBJECTIVE: Skin-to-stone distance (SSD) is a stronger factor than body mass index in predicting the success of shock wave lithotripsy. We aimed to evaluate the impact of SSD on outcomes of percutaneous nephrolithotomy (PCNL). MATERIALS AND METHODS: The medical records of 1,280 patients who had undergone PCNL between April 2007 and February 2012 were evaluated retrospectively. 192 patients who had had preoperative non-contrasted computed tomography and single renal access were included the study. According to this median SSD value, patients were divided into two groups: group 1 (SSD <=94 mm) (n = 92) and group 2 (SSD >94 mm) (n = 90). The groups were compared according to operative and postoperative parameters. RESULTS: We found no significant differences between the two groups with regard to stone-free rate, operation time, fluoroscopy time, hospitalization time, visual analog score of pain, stone burden, transfusion rates and complication rates. On the other hand, the mean body mass index of group 1 was significantly lower than that of group 2 (p < 0.05). CONCLUSIONS: In this retrospective review of patients undergoing PCNL, we found that SSD has no impact on operative and postoperative outcomes. These results were in accordance with the safety of PCNL in obese patients. PMID- 24481207 TI - Risk factors for behavioral abnormalities in mild cognitive impairment and mild Alzheimer's disease. AB - BACKGROUND: Behavioral symptoms are common in both mild cognitive impairment (MCI) and Alzheimer's disease (AD). METHODS: We analyzed the Neuropsychiatric Inventory Questionnaire data of 3,456 MCI and 2,641 mild AD National Alzheimer's Coordinating Center database participants. Using factor analysis and logistic regression we estimated the effects of age, sex, race, education, Mini-Mental State Examination, functional impairment, marital status and family history on the presence of behavioral symptoms. We also compared the observed prevalence of behavioral symptoms between amnestic and nonamnestic MCI. RESULTS: Four factors were identified: affective behaviors (depression, apathy and anxiety); distress/tension behaviors (irritability and agitation); impulse control behaviors (disinhibition, elation and aberrant motor behavior), and psychotic behaviors (delusions and hallucinations). Male gender was significantly associated with all factors. Younger age was associated with a higher prevalence of distress/tension, impulse control and psychotic behaviors. Being married was protective against psychotic behaviors. Lower education was associated with the presence of distress/tension behaviors. Caucasians showed a higher prevalence of affective behaviors. Functional impairment was strongly associated with all behavioral abnormalities. Amnestic MCI patients had more elation and agitation relative to nonamnestic MCI patients. CONCLUSIONS: Younger age, male gender and greater functional impairment were associated with higher overall presence of behavioral abnormalities in MCI and mild AD. Marital status, lower education and race had an effect on selected behaviors. PMID- 24481208 TI - Uterine prolapse complicated by vaginal cancer: a case report and literature review. AB - Primary vaginal cancer is not common, representing 1-2% of all female genital malignancies. We present a case of a third-degree uterine prolapse complicated by an isolated primary vaginal cancer and its surgical treatment. The cervix was clinically normal, but on the nearby prolapsed vaginal wall, a large exogenous hard lesion had developed. A biopsy of the lesion revealed a squamous carcinoma. The patient was asymptomatic and had no recurrence during the last 4 years of follow-up after surgical treatment with radiotherapy. The surgical treatment with or without radiotherapy is the optimum treatment for uterine prolapse with early stage vaginal squamous cell carcinoma, although the majority of vaginal malignancies are treated with radiotherapy. We recommend always performing a biopsy prior to surgery in prolapse-induced ulceration. PMID- 24481209 TI - Michel Dumas and Pierre-Marie Preux: promoting tropical neurology silently--the gist of their contributions. AB - This article presents the contribution by two senior French Neurologists over the past three decades in building, developing and promoting 'tropical neurology' in a number of neglected countries of Asia, Africa and Latin America. It talks about the 'human, dedicational and contributive value' of these two experts who do not come from an English-speaking world. It highlights meaningful changes that have been achieved in different tropical countries as a result of their direct contribution. This overview may likely be a cause for learning and motivation to others to really work in and for tropical countries, where a large proportion of global health burden is to be found. PMID- 24481210 TI - Synthesis of multi-substituted pyrroles using enamides and alkynes catalyzed by Pd(OAc)2 with molecular oxygen as an oxidant. AB - A cyclization reaction between enamides and alkynes catalyzed by palladium(II) acetate is described. In this method, the molecular oxygen serves as an efficient oxidant for the Pd(II)/Pd(0) catalytic cycle. The simple reaction conditions permit this methodology to be used as a general tool for the preparation of multi substituted pyrroles. PMID- 24481211 TI - ELLIPSE Study: a Phase 1 study evaluating the tolerance of bevacizumab nasal spray in the treatment of epistaxis in hereditary hemorrhagic telangiectasia. AB - BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a dominantly inherited genetic vascular disorder in which epistaxis is the most frequent manifestation, responsible for high morbidity. Management of this symptom has no standard, and local treatments are often aggressive. Their efficacy is variable and has not been proven. Anti-angiogenic drugs, such as bevacizumab, are a new treatment strategy. Its systemic administration in patients with HHT improves liver damage related symptoms and epistaxis. To limit the systemic adverse effects of bevacizumab and to ease administration, a local administration seems suitable. PRIMARY OBJECTIVE: To evaluate the tolerance of increasing doses of bevacizumab administered as a nasal spray in patients with HHT-related epistaxis. Secondary objectives were to study the bioavailability and efficacy of bevacizumab against epistaxis when given as a nasal spray. METHODOLOGY: Phase 1, randomized, double blind, placebo-controlled, monocentric study performed sequentially (dose escalation) on 5 groups of 8 patients. Each group was made up of 6 verum and 2 placebos. Five increasing doses of bevacizumab nasal spray (25 mg/mL) were evaluated: 12.5, 25, 50, 75 and 100 mg. RESULTS: A total of 40 patients were included between October 2011 and October 2012. Bevacizumab nasal spray was well tolerated in all patients and the drug was not detected in their serum. No dose limiting toxicity was observed. No efficacy was observed at any dose in this study. CONCLUSION: Based on these results, bevacizumab nasal spray is a safe treatment of epistaxis in HHT. However, a randomized Phase 2 study is needed to determine its efficacy. TRIAL REGISTRATION: ClinicalTrials.gov Identifier #NCT01507480. PMID- 24481213 TI - Systolic blood pressure variability is an important predictor of cardiovascular outcomes in elderly hypertensive patients. AB - OBJECTIVES: In hypertensive persons aged 60 years or below, visit-to-visit SBP variability is directly associated with cardiovascular events, especially stroke. It is unclear whether such a relationship exists for older persons. We investigated whether there is a relationship between visit-to-visit SBP variability and cardiovascular events in an elderly population, and identified the factors associated with increased SBP variability. METHODS: Information from 49771 visits of 5880 patients aged at least 65 years being treated for hypertension in the Second Australian National Blood Pressure study was used. Patients were followed for 4.1 (median) years and had eight (median) doctor visits during the study. SBP variability was defined as within-individual SD of SBP across study follow-up visits. RESULTS: Increased visit-to-visit SBP variability was found to be a strong predictor for future cardiovascular events in this elderly population. The hazard ratio (95% confidence interval) for any first fatal/nonfatal cardiovascular event for highest decile compared with lowest decile of SBP variability was 2.18 (1.52-3.13) after adjusting for sex, age, treatment including other baseline variables, and average on-treatment SBP. A similar effect was observed for stroke (hazard ratio 2.78, 1.28-6.05), myocardial infarction (hazard ratio 4.11, 1.87-9.06), and heart failure (hazard ratio 4.79, 1.82-12.62). Highest SBP variability was also a predictor of post-trial fatal cardiovascular events. Increased visit-to-visit SBP variability was related to age, pulse pressure, changing physicians, smoking, treatment allocation, and the use of multiple BP-lowering drugs. CONCLUSION: These findings suggest that reducing visit-to-visit SBP variability might be an important objective in addition to conventional blood pressure-lowering in elderly hypertensive patients. PMID- 24481215 TI - BoxPlotR: a web tool for generation of box plots. PMID- 24481216 TI - E-CRISP: fast CRISPR target site identification. PMID- 24481217 TI - A blooming genomic desert. PMID- 24481218 TI - Twitching towards the ideal calcium sensor. PMID- 24481220 TI - Speech in Alzheimer's disease: can temporal and acoustic parameters discriminate dementia? AB - AIMS: The study explores how speech measures may be linked to language profiles in participants with Alzheimer's disease (AD) and how these profiles could distinguish AD from changes associated with normal aging. METHODS: We analysed simple sentences spoken by older adults with and without AD. Spectrographic analysis of temporal and acoustic characteristics was carried out using the Praat software. RESULTS: We found that measures of speech, such as variations in the percentage of voice breaks, number of periods of voice, number of voice breaks, shimmer (amplitude perturbation quotient), and noise-to-harmonics ratio, characterise people with AD with an accuracy of 84.8%. DISCUSSION: These measures offer a sensitive method of assessing spontaneous speech output in AD, and they discriminate well between people with AD and healthy older adults. This method of evaluation is a promising tool for AD diagnosis and prognosis, and it could be used as a dependent measure in clinical trials. PMID- 24481219 TI - The potential of optofluidic biolasers. AB - Optofluidic biolasers are emerging as a highly sensitive way to measure changes in biological molecules. Biolasers, which incorporate biological material into the gain medium and contain an optical cavity in a fluidic environment, can use the amplification that occurs during laser generation to quantify tiny changes in biological processes in the gain medium. We describe the principle of the optofluidic biolaser, review recent progress and provide our outlooks on potential applications and directions for developing this technology. PMID- 24481221 TI - Reductive deoxygenation of CO2 by a bimetallic titanium bis(pentalene) complex. AB - The bimetallic bis(pentalene) complex (MU:eta(5),eta(5)-Pn(?))2Ti2 reductively splits CO2 to form a bis(oxo) bridged dimer [(eta(8)-Pn(?))Ti(MU-O)]2, in which the Ti-Ti bond has been cleaved, and the dicarbonyl complex (MU:eta(5),eta(5) Pn(?))2[Ti(CO)]2. PMID- 24481222 TI - The functional repertoire of rabbit antibodies and antibody discovery via next generation sequencing. AB - To gain insight into the functional antibody repertoire of rabbits, the VH and VL repertoires of bone marrow (BM) and spleen (SP) of a naive New Zealand White rabbit (NZW; Oryctolagus cuniculus) and that of lymphocytes collected from a NZW rabbit immunized (IM) with a 16-mer peptide were deep-sequenced. Two closely related genes, IGHV1S40 (VH1a3) and IGHV1S45 (VH4), were found to dominate (~90%) the VH repertoire of BM and SP, whereas, IGHV1S69 (VH1a1) contributed significantly (~40%) to IM. BM and SP antibodies recombined predominantly with IGHJ4. A significant proportion (~30%) of IM sequences recombined with IGHJ2. The VK repertoire was encoded by nine IGKV genes recombined with one IGKJ gene, IGKJ1. No significant bias in the VK repertoire of the BM, SP and IM samples was observed. The complementarity-determining region (CDR)-H3 and -L3 length distributions were similar in the three samples following a Gaussian curve with average length of 12.2 +/- 2.4 and 11.1 +/- 1.1 amino acids, respectively. The amino acid composition of the predominant CDR-H3 and -L3 loop lengths was similar to that of humans and mice, rich in Tyr, Gly, Ser and, in some specific positions, Asp. The average number of mutations along the IGHV/KV genes was similar in BM, SP and IM; close to 12 and 15 mutations for VH and VL, respectively. A monoclonal antibody specific for the peptide used as immunogen was obtained from the IM rabbit. The CDR-H3 sequence was found in 1,559 of 61,728 (2.5%) sequences, at position 10, in the rank order of the CDR-H3 frequencies. The CDR-L3 was found in 24 of 11,215 (0.2%) sequences, ranking 102. No match was found in the BM and SP samples, indicating positive selection for the hybridoma sequence. Altogether, these findings lay foundations for engineering of rabbit V regions to enhance their potential as therapeutics, i.e., design of strategies for selection of specific rabbit V regions from NGS data mining, humanization and design of libraries for affinity maturation campaigns. PMID- 24481223 TI - Molecular basis of the 'anti-aging' effect of spermidine and other natural polyamines - a mini-review. AB - BACKGROUND: Spermidine, a naturally occurring polyamine, has recently emerged as exhibiting anti-aging properties. Its supplementation increases lifespan and resistance to stress, and decreases the occurrence of age-related pathology and loss of locomotor ability. Its mechanisms of action are just beginning to be understood. OBJECTIVES: An up-to-date overview of the so far identified mechanisms of action of spermidine and other polyamines on aging is presented. METHODS: Studies of aging and of the molecular effects of polyamines in general and spermidine in particular are used to synthesize our knowledge on what molecular mechanisms spermidine and other polyamines trigger to positively affect aging. RESULTS: Autophagy is the main mechanism of action of spermidine at the molecular level. However, recent research shows that spermidine can act via other mechanisms, namely inflammation reduction, lipid metabolism and regulation of cell growth, proliferation and death. It is suggested that the main pathway used by spermidine to trigger its effects is the MAPK pathway. CONCLUSIONS: Given that polyamines can interact with many molecules, it is not surprising that they affect aging via several mechanisms. Many of these mechanisms discovered so far have already been linked with aging and by acting on all of these mechanisms, polyamines may be strong regulators of aging. PMID- 24481224 TI - Comparison of 2 techniques of tracheocutaneous fistula closure: analysis of outcomes and health care use. AB - IMPORTANCE: Tracheocutaneous fistula (TCF) can be repaired using various techniques. This research is an outcomes and health care use comparative analysis of 2 commonly used techniques to repair TCF. OBJECTIVES: To compare outcomes and health care use for 2 techniques of TCF repair. DESIGN, SETTING, AND PARTICIPANTS: Retrospective cohort study at a tertiary care children's hospital. The study population comprised 50 consecutive patients aged 11 to 216 months who underwent surgical treatment for persistent TCF between January 2007 and August 2012. INTERVENTIONS: Tracheocutaneous fistula closure was achieved using excision of the TCF alone and healing by secondary intent or excision of the TCF plus primary closure over a drain. MAIN OUTCOMES AND MEASURES: Differences in perioperative and postoperative outcomes. RESULTS: In total, 30 patients underwent excision of a TCF plus primary closure over a drain (closure group), and 20 patients underwent excision of a TCF alone and healing by secondary intent (excision group). Statistically, the closure and excision groups were not significantly different regarding gestational age, age at tracheotomy, duration between decannulation and TCF repair, and duration of tracheostomy. The mean (SD) procedure durations were 9.7 (3.7) minutes for the excision group and 37.4 (25.1) minutes for the closure group (P < .001). The mean (SD) lengths of hospital stay were 0.3 (0.5) day for the excision group and 1.1 (0.9) days for the closure group (P = .001). The mean (SD) lengths of intensive care unit stay were 0.0 (0.0) day for the excision group and 1.0 (1.5) day for the closure group (P = .001). Closure success rates were 20 of 22 for the excision group and 30 of 30 for the closure group (P = .17). Complication rates were 0 of 22 for the excision group and 2 of 30 for the closure group (P = .50). CONCLUSIONS AND RELEVANCE: The rates of success and complications were not significantly different between TCF closure and excision groups. Excision of a TCF alone with healing by secondary intent requires less operating room time and shorter hospital stay, which may suggest more efficient health care use. PMID- 24481225 TI - Decreased intracellular pH induced by cariporide differentially contributes to human umbilical cord-derived mesenchymal stem cells differentiation. AB - BACKGROUND/AIMS: Na+/H+ exchanger 1 (NHE1) is an important regulator of intracellular pH (pHi). High pHi is required for cell proliferation and differentiation. Our previous study has proven that the pHi of mesenchymal stem cells is higher than that of normal differentiated cells and similar to tumor cells. NHE1 is highly expressed in both mesenchymal stem cells and tumor cells. Targeted inhibition of NHE1 could induce differentiation of K562 leukemia cells. In the present paper we explored whether inhibition of NHE1 could induce differentiation of mesenchymal stem cells. METHODS: MSCs were obtained from human umbilical cord and both the surface phenotype and functional characteristics were analyzed. Selective NHE1 inhibitor cariporide was used to treat human umbilical cord-derived mesenchymal stem cells (hUC-MSCs). The pHi and the differentiation of hUC-MSCs were compared upon cariporide treatment. The putative signaling pathway involved was also explored. RESULTS: The pHi of hUC-MSCs was decreased upon cariporide treatment. Cariporide up-regulated the osteogenic differentiation of hUC-MSCs while the adipogenic differentiation was not affected. For osteogenic differentiation, beta-catenin expression was up-regulated upon cariporide treatment. CONCLUSION: Decreased pHi induced by cariporide differentially contributes to hUC-MSCs differentiation. PMID- 24481226 TI - No mutations in the PSMC3IP gene identified in a Swedish cohort of women with primary ovarian insufficiency. AB - Ovarian dysfunction before the age of 40 years, characterized by hypergonadotropic hypogonadism and presenting with either primary or secondary amenorrhea, is called primary ovarian insufficiency (POI). POI has a significant genetic component, but the specific genetic cause is often unknown. A novel candidate gene for POI, PSMC3IP, has recently been identified. The aim of this study was to investigate a group of patients with POI for possible PSMC3IP mutations. Therefore, DNA samples from 50 patients with POI of primarily Swedish origin were used in the study, 27 with secondary amenorrhea (median age of diagnosis 23 years) and 23 with primary amenorrhea. Control material consisting of DNA samples from 95 women without POI was used for investigation of novel sequence variants. All exons and intron/exon boundaries of the PSMC3IP gene were analyzed by PCR and sequencing. As a result, no pathogenic mutation in the PSMC3IP gene was detected in the cohort. A previously unreported variant, NM_016556.3:c.337+33A>G, was detected in heterozygous form in 1 patient with secondary amenorrhea, likely constituting a normal variant. Two reported single nucleotide polymorphisms were detected in the cohort at the expected frequency. In conclusion, PSMC3IP gene mutations are not common causes of POI in this Swedish cohort. PMID- 24481227 TI - The very old on hemodialysis: 8 years' experience in a single unit. AB - BACKGROUND: Elderly patients constitute a significant proportion of chronically dialyzed patients. This study evaluated mortality rates and predictors of mortality among very old patients receiving chronic hemodialysis (HDx). METHODS: A single-center retrospective analysis was carried out on patients >84 years of age who started chronic dialysis between 2004 and 2012. Univariate and multivariate analyses determined which parameters predicted survival. RESULTS: Twenty-nine hemodialyzed patients (19 males) were studied. Mean age was 88 +/- 3 years. Median survival time was 38 months (range 4-96). One-year and 2-year survival probability was 80 and 65%, respectively. The most common cause of death was complicated peripheral vascular disease. Multivariate analysis revealed the following: for each 1 g/dl decrease in serum albumin level, the hazard ratio for patient death was 2.63 (p = 0.017), and for each weekly HDx treatment time decrease of 1 h, the hazard ratio for patient death was 1.40 (p = 0.006). CONCLUSION: Very elderly patients can be hemodialyzed with cautious optimism. PMID- 24481228 TI - A two-ply polymer-based flexible tactile sensor sheet using electric capacitance. AB - Traditional capacitive tactile sensor sheets usually have a three-layered structure, with a dielectric layer sandwiched by two electrode layers. Each electrode layer has a number of parallel ribbon-like electrodes. The electrodes on the two electrode layers are oriented orthogonally and each crossing point of the two perpendicular electrode arrays makes up a capacitive sensor cell on the sheet. It is well known that compatibility between measuring precision and resolution is difficult, since decreasing the width of the electrodes is required to obtain a high resolution, however, this may lead to reduction of the area of the sensor cells, and as a result, lead to a low Signal/Noise (S/N) ratio. To overcome this problem, a new multilayered structure and related calculation procedure are proposed. This new structure stacks two or more sensor sheets with shifts in position. Both a high precision and a high resolution can be obtained by combining the signals of the stacked sensor sheets. Trial production was made and the effect was confirmed. PMID- 24481230 TI - 3D joint speaker position and orientation tracking with particle filters. AB - This paper addresses the problem of three-dimensional speaker orientation estimation in a smart-room environment equipped with microphone arrays. A Bayesian approach is proposed to jointly track the location and orientation of an active speaker. The main motivation is that the knowledge of the speaker orientation may yield an increased localization performance and vice versa. Assuming that the sound produced by the speaker is originated from his mouth, the center of the head is deduced based on the estimated head orientation. Moreover, the elevation angle of the head of the speaker can be partly inferred from the fast vertical movements of the computed mouth location. In order to test the performance of the proposed algorithm, a new multimodal dataset has been recorded for this purpose, where the corresponding 3D orientation angles are acquired by an inertial measurement unit (IMU) provided by accelerometers, magnetometers and gyroscopes in the three-axes. The proposed joint algorithm outperforms a two-step approach in terms of localization and orientation angle precision assessing the superiority of the joint approach. PMID- 24481229 TI - Direct detection of protein biomarkers in human fluids using site-specific antibody immobilization strategies. AB - Design of an optimal surface biofunctionalization still remains an important challenge for the application of biosensors in clinical practice and therapeutic follow-up. Optical biosensors offer real-time monitoring and highly sensitive label-free analysis, along with great potential to be transferred to portable devices. When applied in direct immunoassays, their analytical features depend strongly on the antibody immobilization strategy. A strategy for correct immobilization of antibodies based on the use of ProLinkerTM has been evaluated and optimized in terms of sensitivity, selectivity, stability and reproducibility. Special effort has been focused on avoiding antibody manipulation, preventing nonspecific adsorption and obtaining a robust biosurface with regeneration capabilities. ProLinkerTM-based approach has demonstrated to fulfill those crucial requirements and, in combination with PEG-derivative compounds, has shown encouraging results for direct detection in biological fluids, such as pure urine or diluted serum. Furthermore, we have implemented the ProLinkerTM strategy to a novel nanoplasmonic-based biosensor resulting in promising advantages for its application in clinical and biomedical diagnosis. PMID- 24481231 TI - Monitoring of freeze-thaw cycles in concrete using embedded sensors and ultrasonic imaging. AB - This paper deals with the study of damage produced during freeze-thaw (F-T) cycles using two non-destructive measurement approaches-the first approach devoted to continuous monitoring using embedded sensors during the cycles, and the second one, performing ultrasonic imaging before and after the cycles. Both methodologies have been tested in two different types of concrete specimens, with and without air-entraining agents. Using the first measurement approach, the size and distribution of pores were estimated using a thermoporometrical model and continuous measurements of temperature and ultrasonic velocity along cycles. These estimates have been compared with the results obtained using mercury porosimetry testing. In the second approach, the damage due to F-T cycles has been evaluated by automated ultrasonic transmission and pulse-echo inspections made before and after the cycles. With these inspections the variations in the dimensions, velocity and attenuation caused by the accelerated F-T cycles were determined. PMID- 24481232 TI - Marginal probabilistic modeling of the delays in the sensory data transmission of networked telerobots. AB - Networked telerobots are remotely controlled through general purpose networks and components, which are highly heterogeneous and exhibit stochastic response times; however their correct teleoperation requires a timely flow of information from sensors to remote stations. In order to guarantee these time requirements, a good on-line probabilistic estimation of the sensory transmission delays is needed. In many modern applications this estimation must be computationally highly efficient, e.g., when the system includes a web-based client interface. This paper studies marginal probability distributions that, under mild assumptions, can be a good approximation of the real distribution of the delays without using knowledge of their dynamics, are efficient to compute, and need minor modifications on the networked robot. Since sequences of delays exhibit strong non-linearities in these networked applications, to satisfy the iid hypothesis required by the marginal approach we apply a change detection method. The results reported here indicate that some parametrical models explain well many more real scenarios when using this change detection method, while some non-parametrical distributions have a very good rate of successful modeling in the case that non linearity detection is not possible and that we split the total delay into its three basic terms: server, network and client times. PMID- 24481233 TI - Influence of conductivity and dielectric constant of water-dioxane mixtures on the electrical response of SiNW-based FETs. AB - In this study, we report on the electrical response of top-down, p-type silicon nanowire field-effect transistors exposed to water and mixtures of water and dioxane. First, the capacitive coupling of the back gate and the liquid gate via an Ag/AgCl electrode were compared in water. It was found that for liquid gating smaller potentials are needed to obtain similar responses of the nanowire compared to back gating. In the case of back gating, the applied potential couples through the buried oxide layer, indicating that the associated capacitance dominates all other capacitances involved during this mode of operation. Next, the devices were exposed to mixtures of water and dioxane to study the effect of these mixtures on the device characteristics, including the threshold voltage (V(T)). The V(T) dependency on the mixture composition was found to be related to the decreased dissociation of the surface silanol groups and the conductivity of the mixture used. This latter was confirmed by experiments with constant conductivity and varying water-dioxane mixtures. PMID- 24481234 TI - A MISO UCA beamforming dimmable LED system for indoor positioning. AB - The use of a multiple input single output (MISO) transmit beamforming system using dimmable light emitting arrays (LEAs) in the form of a uniform circular array (UCA) of transmitters is proposed in this paper. With this technique, visible light communications between a transmitter and a receiver (LED reader) can be achieved with excellent performance and the receiver's position can be estimated. A hexagonal lattice alignment of LED transmitters is deployed to reduce the coverage holes and the areas of overlapping radiation. As a result, the accuracy of the position estimation is better than when using a typical rectangular grid alignment. The dimming control is done with pulse width modulation (PWM) to obtain an optimal closed loop beamforming and minimum energy consumption with acceptable lighting. PMID- 24481235 TI - Selenium effects on the metabolism of a Se-metabolizing Lactobacillus reuteri: analysis of envelope-enriched and extracellular proteomes. AB - Selenium (Se) has received great attention in the last few years, as it is considered to be essential for human health (prevention of viral infections, heart diseases and ageing-related diseases). Se deficiency can be counteracted by the administration of selenium-enriched probiotics that are able to convert inorganic selenium into less toxic and more bio-available organic forms. This study was performed on Lactobacillus reuteri Lb2 BM DSM 16143, a probiotic LAB previously demonstrated to be able to fix Se into selenocysteines. The aim was to assess Se influence on its metabolism, by a 2-DE proteomic approach, on two different cellular districts: envelope-enriched and extracellular proteomes. While in the envelope-enriched fraction 15 differentially expressed proteins were identified, in the extracellular proteome no quantitative difference was detected. However, at a molecular level, we observed the insertion of Se into selenocysteine, exclusively under the stimulated conditions. The obtained results confirmed the possibility to use L. reuteri Lb2 BM DSM 16143 as a carrier of organic Se that can be easily released in the gut becoming available for the human host. PMID- 24481236 TI - Preparation and evaluation of carborane-derived inhibitors of prostate specific membrane antigen (PSMA). AB - A series of C-hydroxy carborane derivatives of (S)-2-(3-((S)-5-amino-1 carboxypentyl)ureido)-pentanedioic acid were prepared as a new class of boron rich inhibitors of prostate specific membrane antigen (PSMA), which is overexpressed on prostate cancer tumours and metastases. Closo-, nido- and iodo carborane conjugates were prepared and screened in vitro where the water soluble iodinated cluster had the highest affinity with an IC50 value (73.2 nM) that was comparable to a known PSMA inhibitor 2-(phosphonomethyl)-pentanedioic acid (PMPA, 63.9 nM). The radiolabeled analogue was prepared using (123)I and the biodistribution determined in a prostate cancer model derived from a PSMA positive cell line (LNCaP) at 1, 2, 4, 6 and 24 h post injection (n = 4 per time point). The results showed good initial tumour uptake of 4.17% at 1 h, which remained at that level only decreasing somewhat at 6 h (3.59%). At the latter time point tumour-to-blood and tumour-to-muscle ratios peaked at 3.47 at 25.52 respectively. There was significant off-target binding particularly in the liver and gall bladder and a surprising amount of deiodination in vivo. Notwithstanding, this work demonstrates that carboranes can be used to prepare potent ligands for PSMA creating the opportunity to develop a new class of BNCT agents for prostate cancer. PMID- 24481237 TI - DNA methylation patterns of steroid receptor genes ESR1, ESR2 and PGR in deep endometriosis compromising the rectum. AB - Endometriosis is characterized by the presence of endometrial-like tissue located outside the uterine cavity. Recent evidence suggests that endometriosis may be an epigenetic disease, as well as an estrogen-dependent disease. Based on the unique steroid hormone receptor expression profile observed in endometriotic lesions as compared to eutopic endometrium, the present study aimed to gain further insight into the DNA methylation patterns of alternative promoters of the steroid receptor genes ESR1, ESR2 and PGR in intestinal deep endometriosis, one of the most aggressive forms of endometriosis. The DNA methylation patterns were evaluated by methylation-specific polymerase chain reaction (MS-PCR) after bisulfite modification in 44 endometriotic tissues as well as in 7 matched eutopic endometrium. No differences in the DNA methylation were observed for the ESR1 and ESR2 genes. Methylation of the PGR gene was observed in 39% (17 out of 44) and 19% (7 out of 37) of the cases in the promoter regions B (PGRB) and A (PGRA), respectively. Both PGR promoter regions were methylated in 3 cases. PGRB methylated alleles were detected exclusively in the endometriotic lesions when compared to the eutopic endometrium obtained from the same patient. The effect of DNA methylation in inhibiting the PGR gene expression was corroborated by immuno staining for PgR protein in a subset of tissue samples. The present study demonstrated that epigenetic changes occur in both promoter regions of the PGR gene in intestinal endometriosis. Since eutopic and ectopic tissues do not respond sufficiently to progesterone in women with endometriosis, further study is necessary to evaluate the effect of epigenetic alterations in progesterone resistance in this enigmatic disease. PMID- 24481239 TI - A fast operation of nanometer-scale metallic memristors: highly transparent conductance channels in Ag2S devices. AB - The nonlinear transport properties of nanometer-scale junctions formed between an inert metallic tip and an Ag film covered by a thin Ag2S layer are investigated. Suitably prepared samples exhibit memristive behavior with technologically optimal ON and OFF state resistances yielding to resistive switching on the nanosecond time scale. Utilizing point contact Andreev reflection spectroscopy, we studied the nature of electron transport in the active volume of memristive junctions showing that both the ON and OFF states correspond to truly nanometer scale, highly transparent metallic channels. Our results demonstrate the merits of Ag2S nanojunctions as nanometer-scale memory cells which can be switched by nanosecond voltage pulses. PMID- 24481240 TI - Development of a novel multi-layer microfluidic device towards characterization of drug metabolism and cytotoxicity for drug screening. AB - A novel multi-layer microfluidic device was developed for characterization of drug metabolism in human liver microsomes (HLMs) and their cytotoxicity on cells. The results demonstrated that this platform is robust for low levels of compounds and shows potential for high-throughput drug screening in drug development. PMID- 24481241 TI - Calibration and validation of an innovative approach for estimating general cognitive performance. AB - OBJECTIVE: To evaluate a new approach for creating a composite measure of cognitive function, we calibrated a measure of general cognitive performance from existing neuropsychological batteries. METHODS: We applied our approach in an epidemiological study and scaled the composite to a nationally representative sample of older adults. Criterion validity was evaluated against standard clinical diagnoses. Convergent validity was evaluated against the Mini-Mental State Examination (MMSE). RESULTS: The general cognitive performance factor was scaled to have a mean of 50 and standard deviation of 10 in a nationally representative sample of older adults. A cutoff point of approximately 45, corresponding to an MMSE of 23/24, optimally discriminated participants with and without dementia (sensitivity = 0.94, specificity = 0.90, area under the curve = 0.97). The general cognitive performance factor was internally consistent (Cronbach's alpha = 0.91) and provided reliable measures of functional ability across a wide range of cognitive functioning. It demonstrated minimal floor and ceiling effects, which is an improvement over most individual cognitive tests. CONCLUSIONS: The cognitive composite is a highly reliable measure, with minimal floor and ceiling effects. We calibrated it using a nationally representative sample of adults over the age of 70 in the USA and established diagnostically relevant cutoff points. Our methods can be used to harmonize neuropsychological test results across diverse settings and studies. PMID- 24481244 TI - Frequency-dependent selection drives HBeAg seroconversion in chronic hepatitis B virus infection. AB - HBeAg seroconversion is an important stage in the evolution of a chronic hepatitis B virus (HBV) infection that usually leads to control of viral replication and a reduced risk for liver cirrhosis and cancer. Since current therapies for the HBV-associated liver inflammation that is known as chronic hepatitis B (CHB). Rarely induce permanent HBeAg seroconversion, there is a need to understand the mechanisms responsible for the purpose of identifying new therapeutic targets. Currently, the most widely accepted hypothesis is that the patient's humoral and cellular immune responses to the HBV initiate HBeAg seroconversion. Although we accept that this hypothesis cannot be excluded, we propose an alternative that is consistent with published data on HBeAg seroconversion. We postulate, as others have, that the HBeAg suppresses the immune response to the HBV. However, production of the HBeAg incurs a metabolic cost to the hepatocyte which reduces the replicative capacity of the virus. Consequently, HBeAg-negative viruses replicate faster than HBeAg-positive viruses. HBeAg-negative variants arise de novo; and when their frequency in the population is low they have a replicative advantage. However, they also benefit from the immunosuppressive effects of the HBeAg-positive viruses in the population. As HBeAg-negative variants increase in frequency and HBeAg levels fall, the immune system recognizes the HBV, and HBeAg seroconversion occurs as a consequence of frequency-dependent selection acting on HBeAg-negative variants. This hypothesis explains the wide inter-individual variation in age of seroconversion, the increased rate of seroconversion during anti-viral treatment and the phenomena of both spontaneous and post-treatment HBeAg reversions (in which patients cycle between the HBeAg-positive and negative phases of their infection). PMID- 24481242 TI - IFN-alpha-induced cortical and subcortical glutamate changes assessed by magnetic resonance spectroscopy. AB - Cytokine effects on behavior may be related to alterations in glutamate metabolism. We therefore measured glutamate concentrations in brain regions shown to be affected by inflammatory stimuli including the cytokine interferon (IFN) alpha. IFN-alpha is known to alter neural activity in the dorsal anterior cingulate cortex (dACC) and basal ganglia in association with symptoms of depression and increases in peripheral cytokines including the tumor necrosis factor (TNF) and its soluble receptor. Single-voxel magnetic resonance spectroscopy (MRS) was employed to measure glutamate concentrations normalized to creatine (Glu/Cr) in dACC and basal ganglia of 31 patients with hepatitis C before and after ~ 1 month of either no treatment (n = 14) or treatment with IFN alpha (n = 17). Depressive symptoms were measured at each visit using the Inventory of Depressive Symptoms-Clinician Rating (IDS-C) and the Multidimensional Fatigue Inventory. IFN-alpha was associated with a significant increase in Glu/Cr in dACC and left basal ganglia. Increases in dACC Glu/Cr were positively correlated with scores on the IDS-C in the group as a whole, but not in either group alone. Glu/Cr increases in left basal ganglia were correlated with decreased motivation in the group as a whole and in IFN-alpha-treated subjects alone. No Glu/Cr changes were found in the right basal ganglia, and no significant correlations were found between Glu/Cr and the inflammatory markers. IFN-alpha-induced increases in glutamate in dACC and basal ganglia are consistent with MRS findings in bipolar depression and suggest that inflammatory cytokines may contribute to glutamate alterations in patients with mood disorders and increased inflammation. PMID- 24481245 TI - Robert L. Perlman, evolution & medicine. PMID- 24481246 TI - Interspecific variation in prey capture behavior by co-occurring Nepenthes pitcher plants: evidence for resource partitioning or sampling-scheme artifacts? AB - Pitcher plants of the genus Nepenthes capture a wide range of arthropod prey for nutritional benefit, using complex combinations of visual and olfactory signals and gravity-driven pitfall trapping mechanisms. In many localities throughout Southeast Asia, several Nepenthes different species occur in mixed populations. Often, the species present at any given location have strongly divergent trap structures and preliminary surveys indicate that different species trap different combinations of arthropod prey, even when growing at the same locality. On this basis, it has been proposed that co-existing Nepenthes species may be engaged in niche segregation with regards to arthropod prey, avoiding direct competition with congeners by deploying traps that have modifications that enable them to target specific prey types. We examined prey capture among 3 multi-species Nepenthes populations in Borneo, finding that co-existing Nepenthes species do capture different combinations of prey, but that significant interspecific variations in arthropod prey combinations can often be detected only at sub ordinal taxonomic ranks. In all lowland Nepenthes species examined, the dominant prey taxon is Formicidae, but montane Nepenthes trap few (or no) ants and 2 of the 3 species studied have evolved to target alternative sources of nutrition, such as tree shrew feces. Using similarity and null model analyses, we detected evidence for niche segregation with regards to formicid prey among 5 lowland, sympatric Nepenthes species in Sarawak. However, we were unable to determine whether these results provide support for the niche segregation hypothesis, or whether they simply reflect unquantified variation in heterogeneous habitats and/or ant communities in the study sites. These findings are used to propose improvements to the design of field experiments that seek to test hypotheses about targeted prey capture patterns in Nepenthes. PMID- 24481247 TI - Intraoperative monitoring of bladder and internal anal sphincter innervation: a predictor of erectile function following low anterior rectal resection for rectal cancer? Results of a prospective clinical study. AB - BACKGROUND: The objective was to investigate whether two-dimensional intraoperative neuromonitoring (IONM) of pelvic autonomic nerves has the potential to predict erectile function (EF) following surgery for rectal cancer. METHODS: A consecutive series of 17 sexually active male rectal cancer patients undergoing IONM-based nerve-sparing low anterior rectal resection were evaluated prospectively. IONM was performed by electric stimulation of the pelvic splanchnic nerves with concomitant electromyography of the internal anal sphincter and cystomanometry. Sexual function was assessed using a validated questionnaire. RESULTS: The degree of agreement between electromyography-based and cystomanometry-based IONM with postoperative EF was moderate and good (kappa = 0.43 and kappa = 0.66). Combined assessment yielded the best agreement (kappa = 0.76) with sensitivity of 90%, specificity of 86%, positive predictive value of 90%, negative predictive value of 86%, and overall accuracy of 88%, respectively, in terms of prediction of postoperative EF. CONCLUSION: The method may be suitable to predict male EF following rectal resection. PMID- 24481248 TI - Occupational exposure to cyclophosphamide in nurses at a single center. AB - OBJECTIVE: To evaluate biological and environmental exposure to cyclophosphamide in nurses at a single institution. METHODS: Biological exposure to cyclophosphamide in nurses administering cyclophosphamide compared with two control groups: nononcology nurses not administering cyclophosphamide and community members without recent hospital exposure. Environmental exposure to chemotherapy was measured using surface wipes taken from oncology and nononcology areas in the hospital. RESULTS: More than one third of all nurses and no community controls tested positive for urinary cyclophosphamide. Oncology and nurse controls tested positive in equal numbers. Surface wipes were positive only in the oncology ward. CONCLUSION: We have demonstrated elevated levels of cyclophosphamide in one third of all nurses and cyclophosphamide contamination of surfaces within the oncology patient environment. This suggests that environmental contamination plays a major role in biological exposure to cyclophosphamide. PMID- 24481249 TI - Hemodiafiltration does not have additional benefits over hemodialysis on arterial stiffness, wave reflections and central aortic pressures. AB - BACKGROUND/AIMS: The hypothesis that dialytic modality affects arterial stiffness was never investigated. This study includes comparative evaluation of hemodiafiltration versus hemodialysis on arterial function during first and second weekly dialysis sessions. METHODS: 24 patients receiving hemodiafiltration and another 24 age- and sex-matched controls receiving hemodialysis were included. Patients were evaluated before and after first and second weekly dialysis sessions. Applanation tonometry of peripheral arteries was applied to determine aortic and brachial pulse wave velocity and heart rate-adjusted augmentation index (AIx(75)). RESULTS: Hemodiafiltration and hemodialysis reduced AIx(75), but not aortic and brachial pulse wave velocity. Intradialytic reductions in AIx(75) did not differ between hemodiafiltration and hemodialysis in first and mid-week dialysis. In multivariate linear regression, predictors of intradialytic reduction in AIx(75) were changes in body weight and central aortic systolic blood pressure, but not dialytic modality. CONCLUSION: This study showed that hemodiafiltration has similar effects with hemodialysis on wave reflections and stiffness. PMID- 24481250 TI - Structural analyses of Avocado sunblotch viroid reveal differences in the folding of plus and minus RNA strands. AB - Viroids are small pathogenic circular single-stranded RNAs, present in two complementary sequences, named plus and minus, in infected plant cells. A high degree of complementarities between different regions of the RNAs allows them to adopt complex structures. Since viroids are naked non-coding RNAs, interactions with host factors appear to be closely related to their structural and catalytic characteristics. Avocado sunblotch viroid (ASBVd), a member of the family Avsunviroidae, replicates via a symmetric RNA-dependant rolling-circle process, involving self-cleavage via hammerhead ribozymes. Consequently, it is assumed that ASBVd plus and minus strands adopt similar structures. Moreover, by computer analyses, a quasi-rod-like secondary structure has been predicted. Nevertheless, secondary and tertiary structures of both polarities of ASBVd remain unsolved. In this study, we analyzed the characteristic of each strand of ASBVd through biophysical analyses. We report that ASBVd transcripts of plus and minus polarities exhibit differences in electrophoretic mobility under native conditions and in thermal denaturation profiles. Subsequently, the secondary structures of plus and minus polarities of ASBVd were probed using the RNA selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) method. The models obtained show that both polarities fold into different structures. Moreover, our results suggest the existence of a kissing-loop interaction within the minus strand that may play a role in in vivo viroid life cycle. PMID- 24481251 TI - Analysis of an outbreak of hemorrhagic fever with renal syndrome in college students in Xi'an, China. AB - The aim of the present study was to analyze an outbreak of hemorrhagic fever with renal syndrome (HFRS), caused by a Hantavirus, in college students in the northern urban area of Xi'an in 2012. The outbreak affected six students and included two deaths. The epidemiological survey revealed that both of the deceased cases were misdiagnosed initially, and treatment was delayed. Furthermore, a higher rodent population density and lower HFRS vaccine coverage were observed in the affected area, which indicates a possible role in the outbreak. Rattus norvegicus (Rn) and Mus musculus (Mm) were the predominant host populations in the area. Genotyping revealed that all HVs from patients and rodents were Hantaan virus (HTNV). Sequence analysis of the S segments revealed that the HTNVs reported in this study had high similarity with strains reported in 2011 and 1985, but these viruses diverged from a strain isolated in 1984 and the HTNV prototype strain 76-118. Detection of anti-HV IgG and amplification of the S segment of HTNV from a non-natural HTNV reservoir indicates that further investigations by increased rodent trapping are necessary. PMID- 24481252 TI - Accessory factors promote AlfA-dependent plasmid segregation by regulating filament nucleation, disassembly, and bundling. AB - In bacteria, some plasmids are partitioned to daughter cells by assembly of actin like proteins (ALPs). The best understood ALP, ParM, has a core set of biochemical properties that contributes to its function, including dynamic instability, spontaneous nucleation, and bidirectional elongation. AlfA, an ALP that pushes plasmids apart in Bacillus, relies on a different set of underlying properties to segregate DNA. AlfA elongates unidirectionally and is not dynamically unstable; its assembly and disassembly are regulated by a cofactor, AlfB. Free AlfB breaks up AlfA bundles and promotes filament turnover. However, when AlfB is bound to the centromeric DNA sequence, parN, it forms a segrosome complex that nucleates and stabilizes AlfA filaments. When reconstituted in vitro, this system creates polarized, motile comet tails that associate by antiparallel filament bundling to form bipolar, DNA-segregating spindles. PMID- 24481253 TI - Role of caspase-1 in nuclear translocation of IL-37, release of the cytokine, and IL-37 inhibition of innate immune responses. AB - IL-37 is a fundamental inhibitor of innate immunity. Human IL-37 has a caspase-1 cleavage site and translocates to the nucleus upon LPS stimulation. Here, we investigated whether caspase-1 processing affects IL-37-mediated suppression of LPS-induced cytokines and the release from cells by analyzing a caspase-1 cleavage site mutant IL-37 (IL-37D20A). Nuclear translocation of IL-37D20A is significantly impaired compared with WT IL-37 in transfected cells. LPS-induced IL-6 was decreased in cells expressing WT IL-37 but not IL-37D20A. The function of IL-37 in transfected bone marrow-derived macrophages is nucleotide-binding oligomerization domain-like receptor family, pyrin domain containing 3 (NLRP3) inflammasome-dependent, because IL-37 transfection in apoptosis-associated speck like protein containing a carboxyl-terminal caspase recruitment domain- and NLRP3 deficient cells does not reduce levels of IL-6 and IL-1beta upon LPS stimulation. IL-37-expressing macrophages release both precursor and mature IL-37, but only the externalization of mature IL-37 was dependent on ATP. Precursor and mature IL 37 was also secreted from human dendritic cells and peripheral blood mononuclear cells. To determine whether IL-37 is active in the extracellular compartment, we pretreated IL-37 transgenic mice with IL-37-neutralizing antibodies before LPS challenge. In IL-37-expressing mice, neutralizing IL-37 antibodies reversed the suppression of LPS-induced serum IL-6. In contrast, the addition of neutralizing antibody did not reverse suppression of LPS-induced IL-6 in mouse macrophages transfected with IL-37. Although caspase-1 is required for nuclear translocation of intracellular IL-37 and for secretion of mature IL-37, the release of the IL 37 precursor is independent of caspase-1 activation. IL-37 now emerges as a dual function cytokine with intra- and extracellular properties for suppressing innate inflammation. PMID- 24481255 TI - The key role of nanoparticle seeds during site-selective growth of silver to fabricate core-shell or asymmetric dumbbell heterostructures. AB - Herein, a novel method to induce site-specific deposition of plasmonic silver domain on controlled sites of seeded AgBr nanoparticles is designed. Novel core shell heterostructures and dumbbell heterostructures are fabricated by heterogeneous silver growth. A curved silver shell with thickness up to 5 nm is generated covering the AgBr core in the core-shell metal-semiconductor hybrids. However, in the dumbbell hybrids, a large silver domain is exclusively grown on a single side of the AgBr seed with a solid contact like relationship between the head and the tail. Photogenerated electrons are facilitated to transfer from the semiconductor head to the metal tail enhancing charge separations. The significant role of seed size during seeded silver growth has been demonstrated. PMID- 24481256 TI - Pregnancy outcome in hyperthyroidism: a case control study. AB - BACKGROUND: Data comparing pregnancy outcome in hyperthyroid women with euthyroid women are scarce. Hence, this study was carried out to assess the maternal and fetal outcome in pregnant women with hyperthyroidism to ascertain the effect of disease on pregnancy. METHODOLOGY: This retrospective study was conducted over a period of 28 years. We compared the maternal and fetal outcomes of 208 hyperthyroid women with 403 healthy controls, between women with well-controlled and uncontrolled disease and amongst women diagnosed with hyperthyroidism before and during pregnancy. RESULTS: Maternal outcome: women with hyperthyroidism were at increased risk for preeclampsia (OR = 3.94), intrauterine growth restriction (OR = 2.16), spontaneous preterm labor (OR = 1.73), preterm birth (OR = 1.7), gestational diabetes mellitus (OR = 1.8), and cesarean delivery (OR = 1.47). Hyperthyroid women required induction of labor more frequently (OR = 3.61). Fetal outcome: newborns of hyperthyroid mothers had lower birth weight than normal ones (p = 0.0001). Women with uncontrolled disease had higher odds for still birth (OR = 8.42; 95% CI: 2.01-35.2) and lower birth weight (p = 0.0001). CONCLUSIONS: Obstetrical complications were higher in women with hyperthyroidism than normal women. Outcome was worsened by uncontrolled disease. Women with pregestational hyperthyroidism had better outcomes than those diagnosed with it during pregnancy. PMID- 24481254 TI - PROTEIN DISULFIDE ISOMERASE LIKE 5-1 is a susceptibility factor to plant viruses. AB - Protein disulfide isomerases (PDIs) catalyze the correct folding of proteins and prevent the aggregation of unfolded or partially folded precursors. Whereas suppression of members of the PDI gene family can delay replication of several human and animal viruses (e.g., HIV), their role in interactions with plant viruses is largely unknown. Here, using a positional cloning strategy we identified variants of PROTEIN DISULFIDE ISOMERASE LIKE 5-1 (HvPDIL5-1) as the cause of naturally occurring resistance to multiple strains of Bymoviruses. The role of wild-type HvPDIL5-1 in conferring susceptibility was confirmed by targeting induced local lesions in genomes for induced mutant alleles, transgene induced complementation, and allelism tests using different natural resistance alleles. The geographical distribution of natural genetic variants of HvPDIL5-1 revealed the origin of resistance conferring alleles in domesticated barley in Eastern Asia. Higher sequence diversity was correlated with areas with increased pathogen diversity suggesting adaptive selection for bymovirus resistance. HvPDIL5-1 homologs are highly conserved across species of the plant and animal kingdoms implying that orthologs of HvPDIL5-1 or other closely related members of the PDI gene family may be potential susceptibility factors to viruses in other eukaryotic species. PMID- 24481257 TI - Motorized mobility scooters: the use of training/intervention and technology for improving driving skills in aging adults - a mini-review. AB - BACKGROUND: Motorized mobility scooters (MMS) have become the most acceptable powered assistive device for those with impaired mobility, who have sufficient upper body strength and dexterity, and postural stability. Although several benefits have been attributed to MMS usage, there are likewise risks of use, including injuries and even deaths. OBJECTIVE: The aim of the current review was to summarize results from clinical studies regarding the enhancement of MMS driver safety with a primary focus on improving driving skills/performance using clinical approaches. We addressed three main objectives: (1) to identify and summarize any available evidence (strong, moderate, or weak evidence based on the quality of studies) regarding improved driving skills/performance following training/intervention; (2) to identify types of driving skills/performance that might be improved by training/intervention, and (3) to identify the use of technology in improving MMS performance or training procedure. METHODS: Articles were searched for in the following medical and engineering electronic databases: PubMed, Cochrane Library, Web of Science, ClinicalTrials.gov, PsycINFO, CINAHL, ERIC, EI Compendix, IEEE Explore, and REHABDATA. Inclusion criteria included: aging adults or those with ambulatory problems, intervention or targeted training, and clinical trial. Outcomes included: MMS skills/performance. RESULTS: Six articles met the inclusion criteria and are analyzed in this review. Four of the six articles contained training approaches for MMS drivers including skill trainings using real MMS inside and outside (i.e. in the community) and in a 3D virtual environment. The other two studies contain infrastructural assessments (i.e. the minimum space required for safe maneuverability of MMS users) and additional mobility assistance tools to improve maneuverability and to enhance driving performance. CONCLUSIONS: RESULTS from the current review showed improved driving skills/performance by training, infrastructural assessments, and incorporating mobility assistance tools. MMS driving skills that can be improved through driver training include: weaving, negotiating with and avoiding pedestrian interference, simultaneous reading of signs and obstacle avoidance in path, level driving, forward and reverse driving, figure 8s, turning in place, crossing left slope, maneuvering down a 2-inch curb, and driving up and down inclines. However, several limitations exist in the available literature regarding evidence of improved driving skills/performance following training/intervention, such as small sample sizes, lack of control groups and statistical analysis. PMID- 24481258 TI - Hoarseness and laryngopharyngeal reflux: a survey of primary care physician practice patterns. AB - IMPORTANCE: Current approaches to the diagnosis and subsequent management of specific voice disorders vary widely among primary care physicians (PCPs). In addition, sparse literature describes current primary care practice patterns concerning empirical treatment for vocal disorders. OBJECTIVE: To examine how PCPs manage patients with dysphonia, especially with regard to laryngopharyngeal reflux. DESIGN, SETTING, AND PARTICIPANTS: Prospective, questionnaire-based study by an academic laryngology practice among academic PCPs from all major US geographic regions. MAIN OUTCOMES AND MEASURES: A 16-question web-based survey, distributed via e-mail, concerning management and possible empirical treatment options for patients with dysphonia. RESULTS: Of 2441 physicians who received the e-mail broadcast, 314 (12.9%) completed the survey. Among those who completed the survey, 46.3% were family practitioners, 46.5% were trained in internal medicine, and 7.2% identified as specialists. Among all respondents, 64.0% preferred to treat rather than immediately refer a patient with chronic hoarseness (symptoms persisting for >6 weeks) of unclear origin. Reflux medication (85.8%) and antihistamines (54.2%) were the most commonly selected choices for empirical treatment. Most physician respondents (79.2%) reported that they would treat chronic hoarseness with reflux medication in a patient without evidence of gastroesophageal reflux disease. CONCLUSIONS AND RELEVANCE: Most PCPs who responded to our survey report empirically treating patients with chronic hoarseness of unknown origin. Many physician respondents were willing to empirically prescribe reflux medication as primary therapy, even when symptoms of gastroesophageal reflux disease were not present. These data suggest that PCPs strongly consider reflux a common cause of dysphonia and may empirically treat patients having dysphonia with reflux medication before referral. PMID- 24481259 TI - Direct effect of sodium iodate on neurosensory retina. AB - PURPOSE: To systematically characterize the effects of NaIO3 on retinal morphology and function. METHODS: NaIO3 at 10, 20, or 30 mg/kg was administered by retro-orbital injection into adult C57BL/6J mice. Phenotypic and functional changes of the retina were assessed at 1, 3, 5, and 8 days postinjection by fundus imaging, optical coherence tomography (OCT), ERG, and histology. Direct NaIO3 cytotoxicity on ARPE-19 and 661W cells was quantified using lactate dehydrogenase (LDH) apoptosis assay. Effect of NaIO3 on RPE and photoreceptor gene expression was assessed in vitro and in vivo by quantitative PCR. RESULTS: While little to no change was observed in the 10 mg/kg NaIO3-injected group, significant retinal anomalies, such as RPE atrophy and retinal thinning, were observed in both 20 and 30 mg/kg NaIO3-injected groups. Gene expression analysis showed rapid downregulation of RPE-specific genes, increase in heme oxygenase 1 expression, and induction of the ratio of Bax to Bcl-2. Electroretinographic response loss and photoreceptor gene repression preceded gross morphological changes. High NaIO3 toxicity on 661W cells was observed in vitro along with reactive oxygen species (ROS) induction. NaIO3 treatment also disrupted oxidative stress, phototransduction, and apoptosis gene expression in 661W cells. Exposure of ARPE-19 cells to NaIO3 increased expression of neurotrophins and protected photoreceptors from direct NaIO3 cytotoxicity. CONCLUSIONS: Systematic characterization of changes associated with NaIO3 injection revealed a large variability in the severity of toxicity induced. Treatment with >20 mg/kg NaIO3 induced visual dysfunction associated with rapid suppression of phototransduction genes and induced oxidative stress in photoreceptors. These results suggest that NaIO3 can directly alter photoreceptor function and survival. PMID- 24481261 TI - Low Serum 25-Hydroxyvitamin D Is Associated with Myopia in Korean Adolescents. AB - Purposes: To assess the relationship between serum level of 25-hydroxyvitamin D (25(OH)D) and refractive error in Korean adolescents. Methods: A total of 2,038 adolescent aged 13-18 years, who participated in the Korea National Health and Nutrition Examination Survey (KNHANES) from 2008 to 2011 underwent refractive examination using an autorefractor. Serum 25(OH)D concentration and other potential risk factors were examined. Multivariate regression analysis was performed to investigate the association between serum 25(OH)D and spherical equivalent (SE). Results: Among the participants, 80.1% had myopia (-0.5 D or more myopic) and 8.9% had high myopia (-6.0D or more myopia). The age-adjusted distribution of SE according to serum 25(OH)D concentration showed a positive relationship (r = 0.067, P = 0.012).The myopia group had a significant positive relationship between SE and serum 25(OH)D tertile concentration (P = 0.020), whereas the non-myopia group did not have any significant relationship (P = 0.599).In multiple linear regression analyses, SE was significantly associated with low serum 25(OH)D concentration after adjustment for area of residence, parental income, total energy intake, dietary Ca intake, milk consumption and smoking experience (P=0.047). The prevalence of high myopia was significantly associated with the lowest tertile of serum 25(OH)D concentration after adjustment for the confounding factors (P=0.017). Smoking experience showed inverse associations with both SE and the prevalence of high myopia (P = 0.001 and 0.036) Conclusions: Low serum 25(OH)D concentration was associated with myopia prevalence in Korean adolescents. This relationship was particularly notable in adolescents with high myopia. PMID- 24481260 TI - Assessing residual visual function in severe vision loss. AB - PURPOSE: Vision restoration is a fast-approaching reality for some people with profound vision loss. In order to reliably determine treatment efficacy, accurate assessment of baseline residual visual function is critical. The purpose of this study was to compare residual function as detected on Goldman visual field (GVF) and full-field ERG (ffERG), and correlate with the remaining photoreceptor layer as determined by spectral-domain optical coherence tomography (SD-OCT), in subjects with severe vision loss. METHODS: Fifty-four subjects with advanced retinitis pigmentosa and no discernible signal on ffERG were included. Trace residual function was assessed using discrete Fourier transform (DFT) analysis of the 30-Hz flicker ffERG and the percentage of remaining GVF. The horizontal extent of the outer nuclear layer (ONL) on SD-OCT was assessed. RESULTS: Thirty percent of the study eyes had a 30-Hz flicker response after DFT analysis of the ffERG, and 57% had a measurable GVF. Thirty-five percent had a visible ONL on SD OCT. There was no significant correlation between the magnitude of the 30-Hz flicker response and the percentage of remaining GVF (r = 0.172, P = 0.213) or the extent of remaining central photoreceptors (r = 0.258, P = 0.06). Only 17% of the eyes had all three parameters detected. CONCLUSIONS: Discrete Fourier transform analysis of the 30Hz-flicker ffERG response and GVF can detect trace residual function. Evidence of this residual function is not always supported by the structural correlate of a measurable ONL. Our findings highlight the importance of completing a multimodal assessment to accurately define the important parameters of retinal structure and function in people with profound vision loss. PMID- 24481263 TI - Macular pigment spatial profiles in South Asian and white subjects. AB - PURPOSE: Variability in central macular pigment optical density (MPOD) has been reported among healthy individuals. These variations seem to be related to risk factors of AMD, such as female sex, smoking, and ethnicity. This study investigates variations in the spatial profiles of MPOD among ethnicities. METHODS: Using heterochromatic flicker photometry (HFP), MPOD was measured at seven retinal locations in 54 healthy, young South Asian and 19 white subjects of similar age. Macular pigment spatial profiles were classified as either typical exponential, atypical ring-like, or atypical central dip. RESULTS: Central MPOD was significantly greater in South Asian (0.56 +/- 0.17) compared with white subjects (0.45 +/- 0.18; P = 0.015). Integrated MPOD up to 1.8 degrees (i.e., average MPOD [MPODav(0-1.8)]) was also significantly increased in South Asian (0.34 +/- 0.09) compared to white subjects (0.27 +/- 0.10; P = 0.003). Average MPOD(0-1.8) was significantly increased in all subjects presenting a ring-like profile (0.35 +/- 0.08) or central dip profile (0.39 +/- 0.09), compared with typical exponential profiles (0.28 +/- 0.09; P < 0.0005). We found a statistically significant association between ethnicity and spatial profile type (P = 0.008), whereby an exponential profile was present in 79% of white compared with 41% of the South Asian subjects. CONCLUSIONS: Central MPOD, MPODav(0-1.8), and the prevalence of atypical spatial profiles were significantly increased in South Asian compared with white subjects. Atypical profiles resulted in increased integrated MPOD up to 1.8 degrees , and may therefore offer enhanced macular protection from harmful blue light. PMID- 24481262 TI - Accuracy of noncycloplegic retinoscopy, retinomax autorefractor, and SureSight vision screener for detecting significant refractive errors. AB - PURPOSE: To evaluate, by receiver operating characteristic (ROC) analysis, the ability of noncycloplegic retinoscopy (NCR), Retinomax Autorefractor (Retinomax), and SureSight Vision Screener (SureSight) to detect significant refractive errors (RE) among preschoolers. METHODS: Refraction results of eye care professionals using NCR, Retinomax, and SureSight (n = 2588) and of nurse and lay screeners using Retinomax and SureSight (n = 1452) were compared with masked cycloplegic retinoscopy results. Significant RE was defined as hyperopia greater than +3.25 diopters (D), myopia greater than 2.00 D, astigmatism greater than 1.50 D, and anisometropia greater than 1.00 D interocular difference in hyperopia, greater than 3.00 D interocular difference in myopia, or greater than 1.50 D interocular difference in astigmatism. The ability of each screening test to identify presence, type, and/or severity of significant RE was summarized by the area under the ROC curve (AUC) and calculated from weighted logistic regression models. RESULTS: For detection of each type of significant RE, AUC of each test was high; AUC was better for detecting the most severe levels of RE than for all REs considered important to detect (AUC 0.97-1.00 vs. 0.92-0.93). The area under the curve of each screening test was high for myopia (AUC 0.97-0.99). Noncycloplegic retinoscopy and Retinomax performed better than SureSight for hyperopia (AUC 0.92-0.99 and 0.90-0.98 vs. 0.85-0.94, P <= 0.02), Retinomax performed better than NCR for astigmatism greater than 1.50 D (AUC 0.95 vs. 0.90, P = 0.01), and SureSight performed better than Retinomax for anisometropia (AUC 0.85-1.00 vs. 0.76-0.96, P <= 0.07). Performance was similar for nurse and lay screeners in detecting any significant RE (AUC 0.92-1.00 vs. 0.92-0.99). CONCLUSIONS: Each test had a very high discriminatory power for detecting children with any significant RE. PMID- 24481264 TI - Increased HIF-1alpha expression correlates with cell proliferation and vascular markers CD31 and VEGF-A in uveal melanoma. AB - PURPOSE: Overexpression of hypoxia inducible factor-1 alpha (HIF-1alpha) has been found in several cancers and is thought to correlate with aggressive disease. The purpose of our study was to investigate the influence of HIF-1alpha on clinical outcome in uveal melanoma (UM) along with proliferative (MIB-1) and vascular (CD31, VEGF-A) markers. METHODS: A retrospective analysis was carried out on UM tumors from 88 patients. HIF-1alpha, MIB-1, CD31, and VEGF-A expression, as well as necrosis, were assessed by immunohistochemistry and hematoxylin/eosin on paraffin-embedded UM tumor sections by using a tissue microarray. The bivariate analysis involving HIF-1alpha expression and clinicopathologic covariates was performed by using the chi(2) test. The association of clinicopathologic covariates and HIF-1alpha expression with patient survival was evaluated by using the Kaplan-Meier approach and Cox proportional-hazards regression analysis. RESULTS: Among our study population, 56 patients (63.6%) had high levels of HIF 1alpha expression. High expression of HIF-1alpha was associated with high expression of MIB-1 (P = 0.04), CD31 (P = 0.03), and VEGF-A (P < 0.0001), as well as necrosis (P = 0.04). However, high HIF-1alpha expression was not correlated with cell type, largest macroscopic tumor dimension or thickness, anterior margin, pigmentation, or mitotic figures. Patients with high HIF-1alpha expression did not show a reduced survival when compared to patients with low HIF 1alpha expression (P = 0.92). Finally, HIF-1alpha expression was not increased after irradiation. CONCLUSIONS: An increase in HIF-1alpha expression was significantly associated with proliferative (MIB-1) and vascular (CD31 and VEGF A) markers, as well as necrosis, in UM. However, there was no correlation between high HIF-1alpha expression and patient survival. PMID- 24481265 TI - The effect of ocular rigidity upon the characteristics of saccadic eye movements. AB - PURPOSE: To determine whether variation in ocular rigidity (a quantity that describes the elastic properties of the globe) affects the characteristics of horizontal saccadic eye movements. METHODS: Thirty-three young, visually healthy subjects participated with informed consent in the study. Axial length was measured using the IOLMaster ocular biometer. Ocular rigidity coefficients were determined using Schiotz tonometry. Horizontal saccades were stimulated randomly to 40 degrees in 10 degrees steps. Eye movements were recorded continuously at a sampling rate of 60 Hz using the Viewpoint video-eyetracker. RESULTS: Peak velocity increased significantly with increasing ocular rigidity (F [2,263] = 30.635, P < 0.001). Time to peak velocity (F [2,263] = 27.723, P < 0.001) and total response time (F [2,263] = 21.133, P < 0.001) decreased significantly with increasing ocular rigidity. Ocular rigidity was significantly positively correlated with peak velocity (R(2) = 0.67, P < 0.001), and significantly negatively correlated with time to peak velocity (R(2) = 0.64, P < 0.001), and total response time (R(2) = 0.62, P < 0.001). CONCLUSIONS: The known relationship of ocular rigidity with myopia can be extended to shorter hyperopic eyes, which are found to have higher ocular rigidity. The dynamic characteristics of saccadic eye movements are found to vary systematically with ocular rigidity. These findings suggest that the structural characteristics of the eye are an important factor in determining dynamic characteristics of eye movements. PMID- 24481266 TI - LXR agonist regulates the carcinogenesis of PCa via the SOCS3 pathway. AB - BACKGROUND: Down-regulation of suppressor of cytokine signaling 3 (SOCS3) inhibits prostate cancer (PCa) cell growth. Liver X receptors (LXRs) agonists have been recently introduced for PCa treatment. We postulated that LXR may inhibit the carcinogenesis of PCa via the SOCS3 pathway. METHODS: LNCaP cells were cultured and transfected with SOCS3 small-interfering RNA (SOCS3-siRNA) and control small-interfering RNA (control-siRNA). Then cells were treated with LXR activator (GW3965). The expressions of PCa related transcript factors, e.g. transcription 3 (STAT3), nuclear factor kappa B (NF-kappaB) and activation protein 1(AP1) were detected by western blot assay. In vitro cell proliferation, cell migration, cell invasion and apoptosis were analysed. Nude mice were used for in vivo tumorgenesis. RESULTS: In cells treated with control-siRNA, GW3965 enhanced SOCS3 expression and significantly inhibited the phosphorylation of STAT3, NF-kappaB and AP1 expressions, accompanied by dramatically reduced cellular proliferation rate, immigration and invasion of cultured cells. In cells treated with SOCS3-siRNA, the inhibitory effects of LXR activator on the phosphorylation of STAT3 and expressions of NF-kappaB and AP1 were totally abolished. The cell proliferation rate, immigration and invasion were markedly elevated by SOCS3 gene mutation, even with GW3965 treatment. The in vivo tumorgenesis assay showed that GW3965 significantly reduced the tumor volumes in tumor-bearing nude mice receiving saline injection, but failed to limit the tumor volume in tumor-bearing nude mice receiving SOCS3 antibody injection. CONCLUSION: Our results provide evidence in support of the notion that LXR agonist may regulate the carcinogenesis of PCa via the SOCS3 pathway. PMID- 24481267 TI - MicroRNA-375 targets PDK1 in pancreatic carcinoma and suppresses cell growth through the Akt signaling pathway. AB - MicroRNAs (miRNAs or miRs) are believed to have great potential for use as molecular targets in the diagnosis and treatment of cancer. In this study, we demonstrate that miR-375 is downregulated in pancreatic carcinoma (PC) tissues and PC cell lines. We found that miR-375 negatively regulates the expression of 3 phosphoinositide-dependent protein kinase 1 (PDK1) by directly targeting the 3'UTR of the PDK1 transcript. To investigate the biological roles and the potential mechanisms of action of miR-375, we induced either the up- or downregulation of miR-375 expression by transfecting various PC cells with miR 375 mimics or an inhibitor. Our results revealed that the upregulation of miR-375 inhibited cell growth and induced cell apoptosis, while the downregulation of miR 375 with the inhibitor had the opposite effect. In addition, our data demonstrate that miR-375 suppresses the malignant behavior of PC cells through the Akt signaling pathway rather than mitogen-activated protein kinase (MAPK) signaling pathways. Taken together, our findings indicate that targeting miR-375 by a genetic approach may provide a novel strategy for the treatment of PC. PMID- 24481268 TI - Chorioamnionitis as a risk factor for retinopathy of prematurity: a systematic review and meta-analysis. AB - BACKGROUND: The role of chorioamnionitis (CA) in the development of retinopathy of prematurity (ROP) has not been well established. OBJECTIVE: To conduct a systematic review and meta-analysis of the association between CA and ROP in preterm infants. DATA SOURCES: The authors searched MEDLINE, Embase, CINAHL, Cochrane Central Register of Controlled Trials and PubMed, reviewed reference lists of relevant articles, abstracts and conference proceedings (Society for Pediatric Research, European Society for Paediatric Research 1990-2012), sought results of unpublished trials, and contacted the primary authors of relevant studies. STUDY SELECTION: Studies were included if they had a comparison group, examined preterm infants, and reported primary data that could be used to measure the association between exposure to CA and the development of ROP. DATA EXTRACTION: Two reviewers independently screened the search results, applied inclusion criteria and assessed methodological quality using the Newcastle-Ottawa Scale. One reviewer extracted data and a second reviewer checked data extraction. Summary relative risks (RRs) were calculated using a random effects model. DATA SYNTHESIS: We identified 1,249 potentially relevant studies from the electronic databases. Twenty-seven studies involving 10,590 preterm neonates with 2,562 cases of ROP were included. Taking into account all included studies without adjusting for gestational age (GA), CA was significantly associated with ROP (any stage) [summary RR 1.33 (95% CI 1.14-1.55, I(2) = 77%, pheterogeneity < 0.0001)], and a borderline significant association was observed for severe ROP (stage >=3) [summary RR 1.27 (95% CI 0.99-1.63, I(2) = 74%, pheterogeneity < 0.0001)]. There was no publication bias with Begg's test. However, subgroup analysis of studies adjusting for GA showed no significant association on CA with ROP [summary RR 0.98 (95% CI 0.77-1.26, I(2) = 0%, pheterogeneity = 0.89)]. CONCLUSION: Unadjusted analyses showed that CA was significantly associated with ROP (any stage) as well as with severe ROP (stage >= 3). However, the association disappeared on analysis of studies adjusting for GA. Hence, CA cannot be definitively considered as a risk factor for ROP, and further studies should adjust for potential confounding factors and report results by stage to clarify the association with severe ROP. PMID- 24481269 TI - Elemental bioimaging of manganese uptake in C. elegans. AB - A new method for elemental bioimaging with laser ablation-inductively coupled plasma-mass spectrometry (LA-ICP-MS) was developed and applied to study the uptake of manganese (Mn) in Caenorhabditis elegans (C. elegans). C. elegans is a well-established model organism in neuroscience, genetics and genomics, which has been extensively studied to decipher mechanisms of heavy metal induced toxicity. Knowledge about the distribution of manganese (Mn) and other metals in this organism will be helpful in elucidating pathways and mechanisms of transport, distribution and excretion. The LA-ICP-MS method requires limited sample preparation and can be used rapidly and easily to visualize the Mn distribution in C. elegans. Due to thorough optimization of the analytical parameters, intense Mn signals in C. elegans wild-type (WT) and mutants were obtained at a spatial resolution as small as 4 MUm, thus proving the suitability of LA-ICP-MS to study the uptake of metals in C. elegans. PMID- 24481271 TI - Leflunomide as a rescue treatment in ganciclovir-resistant cytomegalovirus infection in a seronegative renal transplant recipient--a case report. AB - BACKGROUND: Cytomegalovirus (CMV) infection is a frequent complication of immunosuppressive treatment after solid organ and bone marrow transplantation. Prophylaxis and treatment with ganciclovir is successful in most cases, but frequency of infections with ganciclovir-resistant CMV mutants has grown in recent years. Leflunomide, an immunosuppressive drug used in rheumatic diseases and which also exerts antiviral activity, could be a useful treatment option in such cases. CASE REPORT: A 60-year-old, CMV-seronegative patient received a kidney graft from a CMV-seropositive donor. The post-transplant period was complicated by 2 episodes of biopsy-proven graft rejection treated with steroid pulses. CMV viremia was diagnosed 4 weeks after transplantation. The patient received treatment with intravenous ganciclovir and anti-CMV immunoglobulins with consecutive oral valganciclovir therapy. He was admitted to our hospital 6 months after transplantation, with symptoms of CMV infection confirmed by high viral load in his blood. Treatment with double-dose ganciclovir and anti-CMV immunoglobulins did not decrease CMV viremia, so we diagnosed ganciclovir resistant CMV infection. We decided to discontinue mycophenolic acid treatment and start leflunomide 20 mg BID. This therapy led to rapid decrease and final disappearance of CMV viremia. Kidney graft function remained stable during leflunomide treatment. Seroconversion in both IgM and IgG anti-CMV classes was observed. CONCLUSIONS: Treatment with leflunomide is a reasonable option in ganciclovir-resistant infection in kidney transplant recipients, providing effective viral elimination and reconstitution of adaptive anti-CMV immunity without excess risk of graft rejection. PMID- 24481272 TI - FibrilTool, an ImageJ plug-in to quantify fibrillar structures in raw microscopy images. AB - Cell biology heavily relies on the behavior of fibrillar structures, such as the cytoskeleton, yet the analysis of their behavior in tissues often remains qualitative. Image analysis tools have been developed to quantify this behavior, but they often involve an image pre-processing stage that may bias the output and/or they require specific software. Here we describe FibrilTool, an ImageJ plug-in based on the concept of nematic tensor, which can provide a quantitative description of the anisotropy of fiber arrays and their average orientation in cells, directly from raw images obtained by any form of microscopy. FibrilTool has been validated on microtubules, actin and cellulose microfibrils, but it may also help analyze other fibrillar structures, such as collagen, or the texture of various materials. The tool is ImageJ-based, and it is therefore freely accessible to the scientific community and does not require specific computational setup. The tool provides the average orientation and anisotropy of fiber arrays in a given region of interest (ROI) in a few seconds. PMID- 24481273 TI - One-step targeted gene deletion in Candida albicans haploids. AB - The recent discovery of haploids in Candida albicans and the construction of tool strains carrying multiple auxotrophic markers have enabled, for the first time, performing one-step gene deletions in this fungal human pathogen. This breakthrough promises to greatly facilitate the molecular and genetic study of C. albicans biology and pathogenicity. However, the construction of gene-deletion mutants in C. albicans haploids involves many technical difficulties, particularly low transformation efficiency and autodiploidization. Here we describe a highly effective protocol for designing and performing one-step gene deletion in C. albicans haploids, which takes ~11 d to complete (not including plasmid construction, which may take ~2 weeks). A gene deletion cassette is constructed on a plasmid and subsequently released for transformation by lithium acetate incubation or electroporation. Desired gene-deletion mutants are identified and their ploidy is assessed simultaneously by colony PCR before final confirmation by flow cytometry. PMID- 24481274 TI - Deducing the mechanism of action of compounds identified in phenotypic screens by integrating their multiparametric profiles with a reference genetic screen. AB - Cell-based high-content screens are increasingly used to discover bioactive small molecules. However, identifying the mechanism of action of the selected compounds is a major bottleneck. Here we describe a protocol consisting of experimental and computational steps to identify the cellular pathways modulated by chemicals, and their mechanism of action. The multiparametric profiles from a 'query' chemical screen are used as constraints to select genes with similar profiles from a 'reference' genetic screen. In our case, the query screen is the intracellular survival of mycobacteria and the reference is a genome-wide RNAi screen of endocytosis. The two disparate screens are bridged by an 'intermediate' chemical screen of endocytosis, so that the similarity in the multiparametric profiles between the chemical and the genetic perturbations can generate a testable hypothesis of the cellular pathways modulated by the chemicals. This approach is not assay specific, but it can be broadly applied to various quantitative, multiparametric data sets. Generation of the query system takes 3-6 weeks, and data analysis and integration with the reference data set takes an 3 additional weeks. PMID- 24481275 TI - Analysis of microglial migration by a micropipette assay. AB - Microglial cells have important roles in maintaining brain homeostasis, and they are implicated in multiple brain diseases. There is currently interest in investigating microglial migration that results in cell accumulation at focal sites of injury. Here we describe a protocol for rapidly triggering and monitoring microglial migration by using a micropipette assay. This protocol is an adaptation of the axon turning assay using microglial cells. Chemoattractants released from the micropipette tip produce a chemotactic gradient that induces robust microglial migration. In combination with microscopic imaging, this assay allows simultaneous recording of cell movement and subcellular compartment trafficking, along with quantitative analysis. The actual handling time for the assay takes ~2-3 h in total. The protocol is simple, inexpensive and convenient to set up, and it can be adopted to examine cell migration in multiple cell types, including cancer cells with a wide range of chemical signals. PMID- 24481277 TI - Viologen-based ionic liquid crystals: induction of a smectic A phase by dimerisation. AB - The stability of thermotropic ionic liquid crystals is essentially due to micro phase segregation between the ionic heads and the long alkyl chains. Here we show, using newly synthesized viologen dimers, that the structure of the central core is another key parameter to play with in order to tune the mesomorphic behaviour. PMID- 24481278 TI - Fluoroscopic radiation exposure to operating room personnel in spinal surgery. PMID- 24481279 TI - Synthesis and characterisation of magnesium complexes containing sterically demanding N,N'-bis(aryl)amidinate ligands. AB - Condensation reactions of carboxylic acids and anilines in the presence of polyphosphoric acid trimethylsilyl ester (PPSE) afforded a range of sterically demanding N,N'-bis(aryl)amidines, RN{C(R')}N(H)R [R = Mes (Mes = 2,4,6 trimethylphenyl), R' = Cy (Cy = cyclohexyl) L1H; R = Dipp (Dipp = 2,6 diisopropylphenyl), R' = Cy L2H; R = Mes, R' = Ph L3H; R = Dipp, R' = Ph L4H; R = Mes, R' = Dmp (Dmp = 3,5-dimethylphenyl) L5H; R = Dipp, R' = Dmp L6H; R = Dmp, R' = Cy L7H]. Amidines L1H-L7H have been characterised spectroscopically, and for L5H and L6H, by X-ray crystallography. Treatment of the amidines with di-n butylmagnesium in THF solution afforded the monomeric magnesium bis(amidinates) [Mg(L1)2(THF)] 1, [Mg(L2)2] 2, [Mg(L3)2(THF)] 3, [Mg(L5)2(THF)] 5, [Mg(L6)2] 6, [Mg(L7)2] 7, and the magnesium mono(amidinate) complex [Mg(L4)((n)Bu)] 4. These complexes have been characterised spectroscopically, with 1-3, 5 and 6 also being structurally authenticated. Comparison of the magnesium bis(amidinate) complexes reveals that the steric bulk of the amidinate ligand influences both the solid state structure and solution behaviour of these complexes. PMID- 24481280 TI - A new strategy of minimally invasive surgery for cholecystolithiasis: calculi removal and gallbladder preservation. AB - BACKGROUND: Cholecystolithiasis is a common disease. Cholecystectomy is the main treatment method but is associated with various complications in some patients. This study explores a novel, minimally invasive surgery for the removal of calculi and the preservation of the gallbladder using a laparoscope combined with the soft choledochoscope. METHOD: A retrospective analysis was conducted between January 2010 and December 2012 in 65 patients with cholecystolithiasis who underwent the minimally invasive surgery for calculi removal and gallbladder preservation. RESULTS: In 61 cases of gallstone removal, the gallbladder was preserved perfectly with no complications. The other 4 cases were switched to laparoscopic cholecystectomy because of tiny stones blocking the cystic duct or submucosal stones. The success rate was 93.8%. Follow-up included both clinical assessment and ultrasound examination every 6 months after the operation. The patients with preoperative symptoms were symptom-free, and gallbladder function was well preserved. The overall stone recurrence rate was 4.92% at a mean follow up of 26 months (range 6-40). CONCLUSIONS: Using the laparoscope combined with the soft choledochoscope for gallbladder-preserving cholecystolithotomy can remove stones, preserve gallbladder function, and effectively avoid the various complications of cholecystectomy. In our follow-up, gallbladder function was not affected and the stone recurrence rate was quite low. PMID- 24481282 TI - Upon bolting the GTR1 and GTR2 transporters mediate transport of glucosinolates to the inflorescence rather than roots. AB - We recently described the glucosinolate transporters GTR1 and GTR2 as actively contributing to the establishment of tissue-specific distribution of the defense compounds glucosinolates in vegetative Arabidopsis plants. Upon bolting and thereby development of the inflorescence and initiation of seed setting, the spatial distribution of glucosinolates does undergo major changes. Here we investigate the role of GTR1 and GTR2 in establishment of glucosinolate source sink relationships in bolting plants. By in vivo feeding the exogenous p hydroxybenzylglucosinolate to a rosette leaf or the roots of wildtype and a gtr1 gtr2 mutant, we show that this glucosinolate can specifically translocate from the rosette and the roots to the inflorescence in a GTR1- and GTR2-dependent manner. This marks that, upon bolting, the inflorescence rather than the roots constitute the strongest sink for leaf glucosinolates compared with plants in vegetative state. PMID- 24481284 TI - Management of raised intracranial pressure and hyperosmolar therapy. AB - The management of raised intracranial pressure is undergoing rapid change. The choice of medical treatments to reduce intracranial pressure varies between institutions and regions of the world. The mainstay of therapy, however, continues to be the infusion of a hyperosmolar solution to achieve an osmotic gradient to force the exit of water from the brain. This review introduces the basic concepts of raised intracranial pressure, summarises several recent studies that have challenged dogma in the field, and provides practical advice on hyperosmolar treatment, based on personal experience and a critical reading of the literature. PMID- 24481283 TI - Small molecule cardiogenol C upregulates cardiac markers and induces cardiac functional properties in lineage-committed progenitor cells. AB - BACKGROUND/AIMS: Cell transplantation into the heart is a new therapy after myocardial infarction. Its success, however, is impeded by poor donor cell survival and by limited transdifferentiation of the transplanted cells into functional cardiomyocytes. A promising strategy to overcome these problems is the induction of cardiomyogenic properties in donor cells by small molecules. METHODS: Here we studied cardiomyogenic effects of the small molecule compound cardiogenol C (CgC), and structural derivatives thereof, on lineage-committed progenitor cells by various molecular biological, biochemical, and functional assays. RESULTS: Treatment with CgC up-regulated cardiac marker expression in skeletal myoblasts. Importantly, the compound also induced cardiac functional properties: first, cardiac-like sodium currents in skeletal myoblasts, and secondly, spontaneous contractions in cardiovascular progenitor cell-derived cardiac bodies. CONCLUSION: CgC induces cardiomyogenic function in lineage committed progenitor cells, and can thus be considered a promising tool to improve cardiac repair by cell therapy. PMID- 24481285 TI - Acid-labile subunit levels and the association with response to growth hormone treatment in short children born small for gestational age. AB - AIMS: To determine acid-labile subunit (ALS) levels in short small for gestational age (SGA) children and to assess the relationship between ALS levels and several clinical and laboratory characteristics. Also, to assess whether adding ALS levels to a growth prediction model might improve the long-term growth prediction. DESIGN/METHODS: ALS levels were measured in 312 short SGA children at the start of growth hormone (GH) treatment. RESULTS: Median (interquartile range) ALS of all subjects was -0.5 SDS, significantly below the 0 SDS (p < 0.001). In 34 children (11%), ALS levels were <=-2 SDS. ALS SDS correlated significantly with height SDS (r = 0.24, p < 0.001), weight SDS (r = 0.30, p < 0.001), BMI SDS (r = 0.20, p = 0.001), IGF-I SDS (r = 0.56, p < 0.001) and IGFBP-3 SDS (r = 0.67, p < 0.001). ALS SDS was also positively correlated with fasting insulin (r = 0.41, p < 0.001) and glucose levels (r = 0.33, p < 0.001), and HOMA-IR (r = 0.35, p < 0.001). Baseline ALS levels contributed to the long-term growth prediction of GH treatment (5%, p < 0.001). CONCLUSION: Short SGA children tend to have lower ALS levels compared to controls, albeit less reduced than IGF-I and IGFBP-3 levels. Our data suggest that ALS may be involved in glucose homeostasis. Determination of ALS levels before the start of GH treatment in short SGA children contributes moderately to a more accurate prediction of the growth response to GH treatment. PMID- 24481286 TI - Association between endotoxin activity and acute kidney injury in cardiac patients undergoing cardiopulmonary bypass. AB - BACKGROUND/AIMS: Cardiopulmonary bypass (CPB) has been thought to promote endotoxin translocation from the gut. Increased endotoxin activity (EA) has been related to a worsening of organ dysfunction, particularly acute kidney injury (AKI). This study aims to determine if CPB could influence EA after cardiac surgery, and if EA variations are associated with renal dysfunction following CPB. METHODS: This was an observational study of patients subjected to complex cardiac surgery, likely to last for >120 min. Blood samples were obtained before, during and after CPB for EA analysis. AKI occurrence defined by the Acute Kidney Injury Network criteria was evaluated. RESULTS: Eighteen patients were enrolled. EA significantly increased after 12 h following CPB. Variations of EA from baseline were significantly associated with variations of creatinine, i.e. AKI. CONCLUSION: Complex cardiac surgery requiring long CPB promotes EA increases that could be associated with variations of serum creatinine and AKI occurrence. PMID- 24481287 TI - Feasibility and mortality of airway balloon dilation in a live rabbit model. AB - IMPORTANCE: Endoscopic balloon dilation is commonly performed in children with airway stenosis, but guidelines are needed for selecting safe and effective balloon inflation parameters. OBJECTIVE: To determine the feasibility and safety of airway balloon dilation in live rabbits using a range of balloon diameters and pressures. DESIGN AND SETTING: Prospective animal study using 32 adult New Zealand white rabbits with 1-week follow-up performed at an academic animal research facility. INTERVENTIONS: Rabbits underwent endoscopic laryngeal balloon dilation with diameters ranging from 6 to 10 mm and pressures of 5 to 15 atm. MAIN OUTCOMES AND MEASURES: Rabbits were observed for intraoperative complications and postoperative morbidity. RESULTS: All rabbit airways were sized to a 4-0 endotracheal tube (5.4-mm outer diameter). Balloon dilation was performed safely with no intraoperative complications in 25 of 30 cases. One rabbit developed transient cyanosis during balloon inflation. Three rabbits died while undergoing dilation with 10-mm balloons, and another rabbit developed respiratory failure shortly after the procedure. All rabbits that died perioperatively lacked endoscopic evidence of airway obstruction or gross trauma. Four rabbits developed postoperative feeding difficulties that did not correlate with balloon diameter or inflation pressure. CONCLUSIONS AND RELEVANCE: Endoscopic balloon dilation is generally well tolerated in New Zealand white rabbits. Intraoperative mortality from cardiopulmonary arrest reaches 50% when the balloon diameter exceeds the airway diameter by 4.6 mm. Postoperative feeding difficulties may occur with any balloon diameter or inflation pressure. Additional animal studies are necessary to determine the short- and long-term histologic effects of balloon dilation on the airway. PMID- 24481288 TI - Corosolic acid induces apoptotic cell death in HCT116 human colon cancer cells through a caspase-dependent pathway. AB - Corosolic acid (CA), a pentacyclic triterpene isolated from Lagerstroemia speciosa L. (also known as Banaba), has been shown to exhibit anticancer properties in various cancer cell lines. However, the anticancer activity of CA on human colorectal cancer cells and the underlying mechanisms remain to be elucidated. In this study, we investigated the effects of CA on cell viability and apoptosis in HCT116 human colon cancer cells. CA dose-dependently inhibited the viability of HCT116 cells. The typical hallmarks of apoptosis, such as chromatin condensation, a sub-G1 peak and phosphatidylserine externalization were detected by Hoechst 33342 staining, flow cytometry and Annexin V staining following treatment with CA. Western blot analysis revealed that CA induced a decrease in the levels of procaspase-8, -9 and -3 and the cleavage of poly(ADP ribose) polymerase (PARP). The apoptotic cell death induced by CA was accompanied by the activation of caspase-8, -9 and -3, which was completely abrogated by the pan-caspase inhibitor, z-VAD-FMK. Furthermore, CA upregulated the levels of pro apoptotic proteins, such as Bax, Fas and FasL and downregulated the levels of anti-apoptotic proteins, such as Bcl-2 and survivin. Taken together, our data provide insight into the molecular mechanisms of CA-induced apoptosis in colorectal cancer (CRC), rendering this compound a potential anticancer agent for the treatment of CRC. PMID- 24481290 TI - Respiratory function and near infrared spectroscopy recording during cardiopulmonary resuscitation in an extremely preterm newborn. AB - We describe a case highlighting several controversial and important topics regarding neonatal cardiopulmonary resuscitation (CPR). Current neonatal guidelines recommend a 3:1 compression:ventilation ratio; however, the most effective ratio of delivering chest compressions (CC) remains controversial. We report a case of a male infant at 24 weeks' postmenstrual age weighing 650 g on a background of preterm labor. At initial assessment the infant appeared floppy and apneic with a heart rate (HR) of 50-60 beats/min. Mask ventilation was ineffective, thus continuous CC (90/min) with asynchronous ventilations (60/min) was started. HR, blood pressure, oxygen saturation, cerebral oxygenation, respiratory function, and exhaled carbon dioxide (ECO2) were continuously measured during CPR. Return of spontaneous circulation defined as HR >60/min was achieved after 90 s of CPR. Mask leak significantly increased during CC. During bradycardia (HR ~50/min), ECO2 indicated correct tube placement and an increase of ECO2 >12 mm Hg was associated with rapid increase in HR >60/min. PMID- 24481289 TI - A Staphylococcus aureus TIR domain protein virulence factor blocks TLR2-mediated NF-kappaB signaling. AB - Signaling through Toll-like receptors (TLRs), crucial molecules in the induction of host defense responses, requires adaptor proteins that contain a Toll/interleukin-1 receptor (TIR) domain. The pathogen Staphylococcus aureus produces several innate immune-evasion molecules that interfere with the host's innate immune response. A database search analysis suggested the presence of a gene encoding a homologue of the human TIR domain in S. aureus MSSA476 which was named staphylococcal TIR domain protein (TirS). Ectopic expression of TirS in human embryonic kidney, macrophage and keratinocyte cell lines interfered with signaling through TLR2, including MyD88 and TIRAP, NF-kappaB and/or mitogen activated protein kinase pathways. Moreover, the presence of TirS reduced the levels of cytokines MCP-1 and G-CSF secreted in response to S. aureus. The effects on NF-kappaB pathway were confirmed using S. aureus MSSA476 wild type, an isogenic mutant MSSA476DeltatirS, and complemented MSSA476DeltatirS +pTirS in a Transwell system where bacteria and host cells were physically separated. Finally, in a systematic mouse infection model, TirS promoted bacterial accumulation in several organs 4 days postinfection. The results of this study reveal a new S. aureus virulence factor that can interfere with PAMP-induced innate immune signaling in vitro and bacterial survival in vivo. PMID- 24481292 TI - Siderophore-dependent iron uptake systems as gates for antibiotic Trojan horse strategies against Pseudomonas aeruginosa. AB - Pseudomonas aeruginosa is a Gram-negative opportunistic pathogen responsible for nosocomial infections. The prevalence of antibiotic-resistant P. aeruginosa strains is increasing, necessitating the urgent development of new strategies to improve the control of this pathogen. Its bacterial envelope constitutes of an outer and an inner membrane enclosing the periplasm. This structure plays a key role in the resistance of the pathogen, by decreasing the penetration and the biological impact of many antibiotics. However, this barrier may also be seen as the "Achilles heel" of the bacterium as some of its functions provide opportunities for breaching bacterial defenses. Siderophore-dependent iron uptake systems act as gates in the bacterial envelope and could be used in a "Trojan horse" strategy, in which the conjugation of an antibiotic to a siderophore could significantly increase the biological activity of the antibiotic, by enhancing its transport into the bacterium. In this review, we provide an overview of the various siderophore-antibiotic conjugates that have been developed for use against P. aeruginosa and show that an accurate knowledge of the structural and functional features of the proteins involved in this transmembrane transport is required for the design and synthesis of effective siderophore-antibiotic Trojan horse conjugates. PMID- 24481293 TI - Precompetitive activity to address the biological data needs of drug discovery. PMID- 24481294 TI - 2013 FDA drug approvals. PMID- 24481298 TI - Regulatory watch: Where do new medicines originate from in the EU? PMID- 24481299 TI - Court clears the way for Nexium alternative. PMID- 24481301 TI - Mads Krogsgaard Thomsen. Interview by Asher Mullard. PMID- 24481302 TI - Kidney disease: targeting a faulty filter. PMID- 24481303 TI - Phenotypic screening: A more rapid route to target deconvolution. PMID- 24481304 TI - Anticancer drugs: Curbing self-renewal of cancer-initiating cells. PMID- 24481305 TI - Immunological disorders: Spotting the troublemakers. PMID- 24481309 TI - Neurodevelopmental disorders: The gut-microbiome-brain connection. PMID- 24481311 TI - The role of ligand efficiency metrics in drug discovery. AB - The judicious application of ligand or binding efficiency metrics, which quantify the molecular properties required to obtain binding affinity for a drug target, is gaining traction in the selection and optimization of fragments, hits and leads. Retrospective analysis of recently marketed oral drugs shows that they frequently have highly optimized ligand efficiency values for their targets. Optimizing ligand efficiency metrics based on both molecular mass and lipophilicity, when set in the context of the specific target, has the potential to ameliorate the inflation of these properties that has been observed in current medicinal chemistry practice, and to increase the quality of drug candidates. PMID- 24481313 TI - Kinetics of laser-assisted carbon nanotube growth. AB - Laser-assisted chemical vapour deposition (CVD) growth is an attractive mask-less process for growing locally aligned carbon nanotubes (CNTs) in selected places on temperature sensitive substrates. The nature of the localized process results in fast carbon nanotube growth with high experimental throughput. Here, we report on the detailed investigation of growth kinetics related to physical and chemical process characteristics. Specifically, the growth kinetics is investigated by monitoring the dynamical changes in reflected laser beam intensity during growth. Benefiting from the fast growth and high experimental throughput, we investigate a wide range of experimental conditions and propose several growth regimes. Rate limiting steps are determined using rate equations linked to the proposed growth regimes, which are further characterized by Raman spectroscopy and Scanning Electron Microscopy (SEM), therefore directly linking growth regimes to the structural quality of the CNTs. Activation energies for the different regimes are found to be in the range of 0.3-0.8 eV. PMID- 24481314 TI - BMAL1-dependent regulation of the mTOR signaling pathway delays aging. AB - The circadian clock, an internal time-keeping system, has been linked with control of aging, but molecular mechanisms of regulation are not known. BMAL1 is a transcriptional factor and core component of the circadian clock; BMAL1 deficiency is associated with premature aging and reduced lifespan. Here we report that activity of mammalian Target of Rapamycin Complex 1 (mTORC1) is increased upon BMAL1 deficiency both in vivo and in cell culture. Increased mTOR signaling is associated with accelerated aging; in accordance with that, treatment with the mTORC1 inhibitor rapamycin increased lifespan of Bmal1-/- mice by 50%. Our data suggest that BMAL1 is a negative regulator of mTORC1 signaling. We propose that the circadian clock controls the activity of the mTOR pathway through BMAL1-dependent mechanisms and this regulation is important for control of aging and metabolism. PMID- 24481316 TI - Analysis of major known driver mutations and prognosis in resected adenosquamous lung carcinomas. AB - INTRODUCTION: Genotyping for driver mutations is now routinely used to guide clinical care of patients with lung cancer. Adenosquamous lung carcinoma (AdSqLC) is a subtype of cancer that contains both adenocarcinoma and squamous cell carcinoma. However, the incidence, clinicopathologic characteristics, and prognostic implications of major driver mutations in AdSqLCs are not well established. METHODS: Seventy-six resected AdSqLCs and 646 lung adenocarcinomas were screened for known genetic alterations involving EGFR, ERBB2, KRAS, BRAF, PIK3CA, AKT1, RET, and ALK. Tumors showing acinar, lepidic, micropapillary, or papillary growth in glandular component were classified as classical AdSqLC. RESULTS: Of the 76 AdSqLCs, 43 (56.6%) harbored known mutant kinases, including 24 (31.6%) with EGFR mutations, eight (10.5%) with KRAS mutations, two (2.6%) with AKT1 (2.6%) mutations, one (1.3%) with ERBB2 insertion mutation, one (1.3%) with PIK3CA mutation, four (5.3%) with ALK fusions, and three (4%) with KIF5B-RET fusions. No mutation was found in BRAF. The mutational profiles and clinicopathologic characteristics of classical AdSqLC were strikingly similar to that of poorly differentiated adenocarcinoma. However, AdSqLCs with solid growth pattern in glandular component had high frequency of ALK or RET fusions and low EGFR mutation rate. CONCLUSIONS: To our knowledge, this is the first comprehensive study investigating major oncogenic driver mutations in a large cohort of AdSqLC patients in a Chinese population. The findings suggest that it will be clinically valuable to investigate the growth pattern of glandular component in AdSqLCs. PMID- 24481312 TI - PI3K and cancer: lessons, challenges and opportunities. AB - The central role of phosphoinositide 3-kinase (PI3K) activation in tumour cell biology has prompted a sizeable effort to target PI3K and/or downstream kinases such as AKT and mammalian target of rapamycin (mTOR) in cancer. However, emerging clinical data show limited single-agent activity of inhibitors targeting PI3K, AKT or mTOR at tolerated doses. One exception is the response to PI3Kdelta inhibitors in chronic lymphocytic leukaemia, where a combination of cell intrinsic and -extrinsic activities drive efficacy. Here, we review key challenges and opportunities for the clinical development of inhibitors targeting the PI3K-AKT-mTOR pathway. Through a greater focus on patient selection, increased understanding of immune modulation and strategic application of rational combinations, it should be possible to realize the potential of this promising class of targeted anticancer agents. PMID- 24481317 TI - Epidermal growth factor receptor mutations: effect on volume doubling time of non small-cell lung cancer patients. AB - BACKGROUND: The purpose of this study was to retrospectively compare the volume doubling time (VDT) on serial computed tomography (CT) of non-small-cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation with that of NSCLC without the mutation. METHODS: One hundred and two pathologically proven NSCLCs, including 69 patients with lung adenocarcinoma, were reviewed with helical CT. Each tumor underwent at least two CT scans. The VDT was calculated using a modified Schwartz formula. EGFR mutations at exons 18-21 were determined by common fragment analysis and Cycleave method. RESULT: The median VDT of all the patients was 188 days. EGFR mutations were noted in 35 of the 102 patients. The VDT in the 35 patients with EGFR mutations (median 676 days) was longer than that in the 67 patients without EGFR mutations (median 139 days) (p <0.001). By histology subtype, the VDT of adenocarcinoma (305 days) was longer than that of squamous cell carcinoma (81 days) and other types (90 days; p <0.001). CONCLUSION: In NSCLC patients, positive EGFR mutation status may be associated with longer VDT, which seemed to have a slowly progressive and less-aggressive character. More accurate evaluation of VDT may be helpful for understanding the natural history of EGFR mutation-positive NSCLC and treatment with EGFR tyrosine kinase inhibitors. PMID- 24481318 TI - Dendritic CdS assemblies for removal of organic dye molecules. AB - In this paper, novel CdS 3D assemblies are prepared via a facile and effective hydrothermal route using dimethyl sulfoxide as the growth template. Morphologies, microstructures and photocatalytic properties of the as-synthesized products are investigated in detail. It was found that dimethyl sulfoxide played an important role in the formation of CdS assemblies. A possible growth mechanism for CdS assemblies was proposed based on the experimental results. In addition, CdS assemblies exhibit superior photocatalytic activities by the photodegradation of eosin B, Methyl orange (MO) and Rhodamine B (RhB) under visible light irradiation, with a comparison with other CdS nanostructures, P25 and alpha-Fe2O3 powders, demonstrating potential applications in removal of organic dye molecules from waste water. PMID- 24481319 TI - Theory of charge hopping along a disordered polymer chain. AB - We built a model of charge transport in a single disordered polymer chain starting from a model Hamiltonian of the system. The parameters entering the Hamiltonian determine both the density of states (DOS) and the hopping rate unlike the most common modelling strategies of transport in polymeric materials that parametrize both the DOS and the hopping rate from the outset. This model incorporates the effect of variable delocalization of one-electron states and is designed to link atomistic calculations of polymeric systems with full device models in multiscale modelling protocols. The initial and final states for the hopping process are determined by static disorder and further stabilized by polaronic effects. The coupling between these states is due to the residual (and much smaller) dynamic disorder. We find that, at lower static disorder, long distance hopping events become more frequent, i.e. the hopping range and disorder are not unrelated parameters, as commonly assumed. The availability of low energy relatively delocalized states promotes long range displacement of charge and it can be at the origin of the high mobility observed in some polymers. The description of the hopping rates from the model Hamiltonian also allows the identification of the breakdown of the incoherent transport limit. PMID- 24481320 TI - Measuring antimicrobial use in hospitalized patients: a systematic review of available measures applicable to paediatrics. AB - OBJECTIVES: The optimal measure to use for surveillance of antimicrobial usage in hospital settings, especially when including paediatric populations, is unknown. This systematic review of literature aims to list, define and compare existing measures of antimicrobial use that have been applied in settings that included paediatric inpatients, to complement surveillance of resistance. METHODS: We identified cohort studies and repeated point-prevalence studies presenting data on antimicrobial use in populations of inpatients or validations/comparisons of antimicrobial measures through a systematic search of literature using MEDLINE, EMBASE, CINAHL and LILACS (1975-2011) and citation tracking. Study populations needed to include hospitalized paediatric patients. Two reviewers independently extracted data on study characteristics and results. RESULTS: Overall, 3878 records were screened and 79 studies met selection criteria. Twenty-six distinct measures were found, the most frequently used being defined daily doses (DDD)/patient-days and exposed patients/patients. Only two studies compared different measures quantitatively, showing (i) a positive correlation between proportion of exposed patients and antimicrobial-days/patient-days and (ii) a strong correlation between doses/patient-days and agent-days/patient-days (r = 0.98), with doses/patient-days correlating more with resistance rates (r = 0.80 versus 0.55). CONCLUSIONS: The measure of antimicrobial use that best predicts antimicrobial resistance prevalence and rates, for surveillance purposes, has still not been identified; additional evidence on this topic is a necessity. PMID- 24481321 TI - Impact of test methodology, media type and ion content on the susceptibility of Acinetobacter spp. to tigecycline. PMID- 24481322 TI - Plasma cotinine levels in cigarette smokers: impact of mental health and other correlates. AB - BACKGROUND/AIMS: We examined in cigarette smokers whether cotinine was associated with depressive and/or anxiety disorders. METHODS: Data were derived from 1,026 smoking adults with and without depressive and/or anxiety disorders participating in the Netherlands Study of Depression and Anxiety (NESDA). Depressive and anxiety disorders were ascertained with the DSM-IV Composite International Diagnostic Interview. Cigarette consumption was inquired about during an interview. Cotinine was assessed in plasma. RESULTS: Currently depressed and/or anxious smokers (n=692) reported smoking a higher number of cigarettes per day (CPD) than smokers with a remitted disorder (n=190) and smokers with no lifetime disorder (n=144). After controlling for CPD and other covariates, depressed and/or anxious smokers had lower cotinine levels compared to smokers with no lifetime disorder (B=-56.0, p=0.001). In the full regression model, CPD was positively associated with cotinine levels, whereas current depression and/or anxiety and high body mass index were inversely associated with cotinine. CONCLUSION: After considering CPD, the presence of current depressive and/or anxiety disorders was associated with lower cotinine levels, which may point to a different smoking topography or a faster cotinine metabolism in individuals with affective disorders. The latter could help to explain the higher number of cigarettes smoked and poorer cessation rates among depressed or anxious patients. PMID- 24481323 TI - The potential association between postmenopausal hormone use and primary open angle glaucoma. AB - IMPORTANCE: Retinal ganglion cells are known to express estrogen receptors and prior studies have suggested an association between postmenopausal hormone (PMH) use and decreased intraocular pressure, suggesting that PMH use may decrease the risk for primary open-angle glaucoma (POAG). OBJECTIVE: To determine whether the use of 3 different classes of PMH affects the risk for POAG. DESIGN, SETTING, AND PARTICIPANTS: Retrospective longitudinal cohort analysis of claims data from women 50 years or older enrolled in a US managed-care plan for at least 4 years in which enrollees had at least 2 visits to an eye care provider during the period 2001 through 2009. EXPOSURE: Postmenopausal hormone medications containing estrogen only, estrogen + progesterone, and estrogen + androgen, as captured from outpatient pharmacy claims over a 4-year period. MAIN OUTCOMES AND MEASURES: Hazard ratios (HRs) for developing incident POAG. RESULTS: Of 152,163 eligible enrollees, 2925 (1.9%) developed POAG. After adjustment for confounding factors, each additional month of use of PMH containing estrogen only was associated with a 0.4% reduced risk for POAG (HR, 0.996 [95% CI, 0.993-0.999]; P = .02). The risk for POAG did not differ with each additional month of use of estrogen + progesterone (HR, 0.994 [95% CI, 0.987-1.001]; P = .08) or estrogen + androgen (HR, 0.999 [95% CI, 0.988-1.011]; P = .89). CONCLUSIONS AND RELEVANCE: Use of PMH preparations containing estrogen may help reduce the risk for POAG. If prospective studies confirm the findings of this analysis, novel treatments for this sight-threatening condition may follow. PMID- 24481324 TI - Nonalcoholic fatty liver disease is a negative risk factor for prostate cancer recurrence. AB - Nonalcoholic fatty liver disease (NAFLD) is closely related to the metabolic syndrome, which is associated with an increased risk of various malignancies. In this study, we investigated the association between NAFLD and prostate cancer biochemical recurrence (BCR) after radical prostatectomy. Consecutive prostate cancer patients who underwent radical prostatectomy were enrolled from two hospitals in Korea and randomly assigned to the training (n=147) or validation set (n=146). The presence of NAFLD, BMI, preoperative prostate-specific antigen, and histological findings including Gleason score (GSc) were analyzed in regard to their association with BCR. NAFLD was diagnosed based on ultrasonography or unenhanced computed tomography images. BCR-free survival rates were calculated using the Kaplan-Meier method. In the training set, 32 (21.8%) patients developed BCR during a median follow-up period of 51 (inter-quartile range, 35-65) months. In the multivariate analysis, the presence of NAFLD (hazard ratio (HR), 0.36; 95% CI, 0.14-0.97; P=0.04) was an independent negative predictive factor of BCR after adjustment for pathological GSc. Applied to the validation set, the presence of NAFLD maintained its prognostic value for longer time-to-BCR (HR, 0.17; 95% CI, 0.06-0.49; P=0.001). In the subgroup analysis of patients with NAFLD, NAFLD fibrosis score was a single independent negative predictor for BCR (HR, 0.54; 95% CI, 0.30-0.98; P=0.04). Our study demonstrated that NAFLD may play a protective role against BCR after radical prostatectomy for prostate cancer. Further study is warranted to elucidate the mechanism of protective effect in patients with NAFLD. PMID- 24481325 TI - GPER-mediated proliferation and estradiol production in breast cancer-associated fibroblasts. AB - Cancer-associated fibroblasts (CAFs) are crucial co-mediators of breast cancer progression. Estrogen is the predominant driving force in the cyclic regulation of the mammary extracellular matrix, thus potentially affecting the tumor associated stroma. Recently, a third estrogen receptor, estrogen (G-protein coupled) receptor (GPER), has been reported to be expressed in breast CAFs. In this study, GPER was detected by immunohistochemical analysis in stromal fibroblasts of 41.8% (59/141) of the primary breast cancer samples. GPER expression in CAFs isolated from primary breast cancer tissues was confirmed by immunostaining and RT-PCR analyses. Tamoxifen (TAM) in addition to 17beta estradiol (E2) and the GPER agonist G1 activated GPER, resulting in transient increases in cell index, intracellular calcium, and ERK1/2 phosphorylation. Furthermore, TAM, E2, and G1 promoted CAF proliferation and cell-cycle progression, both of which were blocked by GPER interference, the selective GPER antagonist G15, the epidermal growth factor receptor (EGFR) inhibitor AG1478, and the ERK1/2 inhibitor U0126. Importantly, TAM as well as G1 increased E2 production in breast CAFs via GPER/EGFR/ERK signaling when the substrate of E2, testosterone, was added to the medium. GPER-induced aromatase upregulation was probably responsible for this phenomenon, as TAM- and G1-induced CYP19A1 gene expression was reduced by GPER knockdown and G15, AG1478, and U0126 administration. Accordingly, GPER-mediated CAF-dependent estrogenic effects on the tumor-associated stroma are conceivable, and CAF is likely to contribute to breast cancer progression, especially TAM resistance, via a positive feedback loop involving GPER/EGFR/ERK signaling and E2 production. PMID- 24481327 TI - MR imaging-detectable metabolic alterations in attention deficit/hyperactivity disorder: from preclinical to clinical studies. AB - MR spectroscopy represents one of the most suitable in vivo tool to assess neurochemical dysfunction in several brain disorders, including attention deficit/hyperactivity disorder. This is the most common neuropsychiatric disorder in childhood and adolescence, which persists into adulthood (in approximately 30% 50% of cases). In past years, many studies have applied different MR spectroscopy techniques to investigate the pathogenesis and effect of conventional treatments. In this article, we review the most recent clinical and preclinical MR spectroscopy results on subjects with attention deficit/hyperactivity disorder and animal models, from childhood to adulthood. We found that the most investigated brain regions were the (pre)frontal lobes and striatum, both involved in the frontostriatal circuits and networks that are known to be impaired in this pathology. Neurometabolite alterations were detected in several regions: the NAA, choline, and glutamatergic compounds. The creatine pool was also altered when an absolute quantitative protocol was adopted. In particular, glutamate was increased in children with attention deficit/hyperactivity disorder, and this can apparently be reversed by methylphenidate treatment. The main difficulties in reviewing MR spectroscopy studies were in the nonhomogeneity of the analyzed subjects, the variety of the investigated brain regions, and also the use of different MR spectroscopy techniques. As for possible improvements in future studies, we recommend the use of standardized protocols and the analysis of other brain regions of particular interest for attention deficit hyperactivity disorder, like the hippocampus, limbic structures, thalamus, and cerebellum. PMID- 24481328 TI - Surgical and clinical confirmation of temporal bone CT findings in patients with otosclerosis with failed stapes surgery. AB - BACKGROUND AND PURPOSE: Prior descriptions of imaging after failed stapes procedures for otosclerosis predated currently available CT technology and/or failed to assess commonly used metallic implants. The purpose of this study was to correlate temporal bone CT findings with clinically and intraoperatively determined causes of surgical failure. MATERIALS AND METHODS: All patients with otosclerosis undergoing stapedectomy between December 1999 and December 2010 were identified from a search of neurotology clinical records. Patients presenting because of failed stapes surgery and having temporal bone CT scans at the time of revision surgery or clinical evaluation were included. Imaging and clinical records were retrospectively evaluated by a medical student, radiology resident, and senior neuroradiologist. Stapes prosthesis complications and relevant anatomic CT findings were correlated to clinical and intraoperative findings. RESULTS: Twenty-two of 340 patients met inclusion criteria. Temporal bone CT findings were correlated to intraoperative findings in 17 of 22 patients and to clinical findings in 5 of 22 patients. Surgically confirmed abnormalities included 7 of 7 incus erosions, 3 of 6 piston re-sizings, 3 of 5 granulation tissues, 3 of 5 prosthesis disconnections, 3 of 4 obliterative otosclerosis, 2 of 2 oval window dislocations, and 1 labyrinthine ossificans. Clinically confirmed abnormalities included 2 cases each of superior semicircular canal dehiscence, and wrong piston size, and 1 each of piston disconnection, labyrinthine ossificans, and intravestibular footplate. CONCLUSIONS: CT evaluation in the setting of failed stapes surgery is challenging. Many postoperative complications such as piston migration, incus necrosis, and overt vestibular penetration are well recognized on temporal bone CT. Of particular note, superior semicircular canal dehiscence is an important contraindication to stapes surgery. PMID- 24481326 TI - Genetically engineered ERalpha-positive breast cancer mouse models. AB - The majority of human breast cancers are estrogen receptor-positive (ER+), but this has proven challenging to model in genetically engineered mice. This review summarizes information on 21 mouse models that develop ER+ mammary cancer. Where available, information on cancer pathology and gene expression profiles is referenced to assist in understanding which histological subtype of ER+ human cancer each model might represent. ESR1, CCDN1, prolactin, TGFalpha, AIB1, ESPL1, and WNT1 overexpression, PIK3CA gain of function, as well as loss of P53 (Trp53) or STAT1 are associated with ER+ mammary cancer. Treatment with the PPARgamma agonist efatutazone in a mouse with Brca1 and p53 deficiency and 7,12 dimethylbenz(a)anthracene exposure in combination with an activated myristoylated form of AKT1 also induce ER+ mammary cancer. A spontaneous mutant in nude mice that develops metastatic ER+ mammary cancer is included. Age of cancer development ranges from 3 to 26 months and the percentage of cancers that are ER+ vary from 21 to 100%. Not all models are characterized as to their estrogen dependency and/or response to anti-hormonal therapy. Strain backgrounds include C57Bl/6, FVB, BALB/c, 129S6/SvEv, CB6F1, and NIH nude. Most models have only been studied on one strain background. In summary, while a range of models are available for studies of pathogenesis and therapy of ER+ breast cancers, many could benefit from further characterization, and opportunity for development of new models remains. PMID- 24481329 TI - Familial adhesive arachnoiditis associated with syringomyelia. AB - Adhesive arachnoiditis is a rare condition, often complicated by syringomyelia. This pathologic entity is usually associated with prior spinal surgery, spinal inflammation or infection, and hemorrhage. The usual symptoms of arachnoiditis are pain, paresthesia, and weakness of the low extremities due to the nerve entrapment. A few cases have had no obvious etiology. Previous studies have reported one family with multiple cases of adhesive arachnoiditis. We report a second family of Belgian origin with multiple cases of arachnoiditis and secondary syringomyelia in the affected individuals. PMID- 24481330 TI - Mapping of glycine distributions in gliomas. AB - BACKGROUND AND PURPOSE: Increased glycine concentration in the brain is associated with altered metabolism in cancer and can be detected by using in vivo MR spectroscopy. This has been proposed as a marker for grade IV gliomas; however, little is known about the potential significance and frequency of in vivo glycine observation. The purpose of this study was to examine the rate of occurrence and spatial distribution of glycine observation with respect to other MR imaging parameters. MATERIALS AND METHODS: Data from volumetric whole-brain MR spectroscopic imaging of 59 subjects with glioma were analyzed with glycine included in the spectral model. The associations of the signal amplitude and spatial distributions of glycine with findings from contrast-enhanced T1, perfusion, and diffusion MR imaging were then examined. RESULTS: Glycine was detected in 24% of all studies, though with a wide range of signal amplitude and extent of the spatial distributions. While more commonly seen in grade IV tumors (42% of studies), relatively large concentrations were also detected in grade II and III gliomas. Coanalysis with other metabolites indicated a strong association with choline and that glycine was frequently seen to be overlapping with, and adjacent to, areas of high lactate concentration. Increased glycine was always associated with contrast enhancement and areas of increased cerebral blood flow, but without any clear association with other image parameters. CONCLUSIONS: Detection of increased glycine in gliomas appears to identify a subgroup of tumors and areas of increased proliferation. PMID- 24481331 TI - The impact of arterial collateralization on outcome after intra-arterial therapy for acute ischemic stroke. AB - BACKGROUND AND PURPOSE: Although intra-arterial therapy for acute ischemic stroke is associated with superior recanalization rates, improved clinical outcomes are inconsistently observed following successful recanalization. There is emerging concern that unfavorable arterial collateralization, though unproven, predetermines poor outcome. We hypothesized that poor leptomeningeal collateralization, assessed by preprocedural CTA, is associated with poor outcome in patients with acute ischemic stroke undergoing intra-arterial therapy. MATERIALS AND METHODS: We retrospectively analyzed patients with acute ischemic stroke with intracranial ICA and/or MCA occlusions who received intra-arterial therapy. The collaterals were graded on CTA. Univariate and multivariate analyses were used to investigate the association between the dichotomized leptomeningeal collateral score and functional outcomes at 3-months mRS <=2, mortality, and intracranial hemorrhages. RESULTS: Eighty-seven patients were included. The median age was 66 years (interquartile range, 54-76 years) and the median NIHSS score at admission was 18 (interquartile range, 14-20). The leptomeningeal collateral score 3 was found to have significant association with the good functional outcome at 3 months: OR = 3.13; 95% CI, 1.25-7.825; P = .016. This association remained significant when adjusted for the use of IV tissue plasminogen activator: alone, OR = 2.998; 95% CI, 1.154-7.786; P = .024; and for IV tissue plasminogen activator and other confounders (age, baseline NIHSS score, and Thrombolysis in Cerebral Infarction grades), OR = 2.985; 95% CI, 1.027-8.673; P = .045. CONCLUSIONS: We found that poor arterial collateralization, defined as a collateral score of <3, was associated with poor outcome, after adjustment for recanalization success. We recommend that future studies include collateral scores as one of the predictors of functional outcome. PMID- 24481332 TI - Inter- and intraobserver agreement in scoring angiographic results of intra arterial stroke therapy. AB - BACKGROUND AND PURPOSE: Angiographic results are commonly used as surrogate markers of the success of intra-arterial therapies for acute stroke. Inter- and intraobserver agreement in judging angiographic results remain poorly characterized. Our goal was to assess 2 commonly used revascularization scales. MATERIALS AND METHODS: A portfolio of 148 pre- and post treatment images of 37 cases of proximal anterior circulation occlusions was electronically sent to 12 expert observers who were asked to grade treatment outcomes according to recanalization (of arterial occlusive lesion) or reperfusion (TICI) scales. Three expert observers had to score treatment outcomes by using a similar portfolio of 32 patients or when they had full access to all angiographic data, twice for each method 3-12 months apart. Results were analyzed by using kappa statistics. RESULTS: Agreement among 9 responding observers was moderate for both the TICI (kappa = 0.45 +/- 0.01) and arterial occlusive lesion (kappa = 0.39 +/- 0.16) scales. Agreement was similar (moderate) when 3 observers had access to a portfolio (kappa = 0.59 +/- 0.06 and 0.49 +/- 0.07, respectively) or to the full angiographic data (kappa = 0.54 +/- 0.06 and 0.59 +/- 0.07, respectively). Intraobserver agreement was "fair to moderate" for both methods. Interobserver agreement became "substantial" (>0.6) when outcomes were dichotomized into "success" (TICI 2b, 3; arterial occlusive lesion II, III or "failure"; the results were judged more favorably when the arterial occlusive lesion rather than the TICI scale was used. CONCLUSIONS: There is an important variability in the assessment of angiographic outcomes of endovascular treatments, invalidating comparisons among publications. A simple dichotomous judgment can be used as a surrogate outcome when treatments are assessed by the same observers in randomized trials. PMID- 24481333 TI - Bioactive versus bare platinum coils in the treatment of intracranial aneurysms: the MAPS (Matrix and Platinum Science) trial. AB - BACKGROUND AND PURPOSE: The ability of polymer-modified coils to promote stable aneurysm occlusion after endovascular treatment is not well-documented. Angiographic aneurysm recurrence is widely used as a surrogate for treatment failure, but studies documenting the correlation of angiographic recurrence with clinical failure are limited. This trial compares the effectiveness of Matrix(2) polyglycolic/polylactic acid biopolymer-modified coils with bare metal coils and correlates the angiographic findings with clinical failure (ie, target aneurysm recurrence), a composite end point that includes any incident of posttreatment aneurysm rupture, retreatment, or unexplained death. MATERIALS AND METHODS: This was a multicenter randomized noninferiority trial with blinded end point adjudication. We enrolled 626 patients, divided between Matrix(2) and bare metal coil groups. The primary outcome was target aneurysm recurrence at 12 +/- 3 months. RESULTS: At 455 days, at least 1 target aneurysm recurrence event had occurred in 14.6% of patients treated with bare metal coils and 13.3% of Matrix(2) (P = .76, log-rank test) patients; 92.8% of target aneurysm recurrence events were re-interventions for aneurysms that had not bled after treatment, and 5.8% of target aneurysm recurrence events resulted from hemorrhage or rehemorrhage, with or without retreatment. Symptomatic re-intervention occurred in only 4 (0.6%) patients. At 455 days, 95.8% of patients with unruptured aneurysms and 90.4% of those with ruptured aneurysms were independent (mRS <= 2). Target aneurysm recurrence was associated with incomplete initial angiographic aneurysm obliteration, presentation with rupture, and a larger aneurysmal dome and neck size. CONCLUSIONS: Tested Matrix(2) coils were not inferior to bare metal coils. Endovascular coiling of intracranial aneurysms was safe, and the rate of technical success was high. Target aneurysm recurrence is a promising clinical outcome measure that correlates well with established angiographic measurements. PMID- 24481334 TI - Guanine nucleotide-binding protein alpha subunit hypofunction in children with short stature and disproportionate shortening of the 4th and 5th metacarpals. AB - BACKGROUND: GNAS encodes the alpha subunit of the stimulatory G protein (Gsalpha). Maternal inherited Gsalpha mutations cause pseudohypoparathyroidism type Ia (PHP-Ia), associated with shortening of the 4th and 5th metacarpals. AIMS: Here we investigated the Gsalpha pathway in short patients with distinct shortening of the 4th and 5th metacarpals. METHODS: In 571 children with short stature and 4 patients with PHP-Ia metacarpal bone lengths were measured. In identified patients we analysed the Gsalpha protein function in platelets, performed GNAS sequencing, and epigenetic analysis of four significant differentially methylated regions. RESULTS: In 51 patients (8.9%) shortening of the 4th and 5th metacarpals was more pronounced than their height deficit. No GNAS coding mutations were identified in 20 analysed patients, except in 2 PHP-Ia patients. Gsalpha activity was reduced in all PHP-Ia patients and in 25% of the analysed patients. No significant methylation changes were identified. CONCLUSIONS: Our findings suggest that patients with short stature and distinct metacarpal bone shortening could be part of the wide variety of PHP/PPHP, therefore it was worthwhile analysing the Gsalpha protein function and GNAS gene in these patients in order to further elucidate the phenotype and genotype of Gsalpha dysfunction. PMID- 24481335 TI - Endoplasmic reticulum stress activates transglutaminase 2 leading to protein aggregation. AB - Aberrant activation of transglutaminase 2 (TGase2) contributes to a variety of protein conformational disorders such as neurodegenerative diseases and age related cataracts. The accumulation of improperly folded proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), which promotes either repair or degradation of the damaged proteins. Inadequate UPR results in protein aggregation that may contribute to the development of age related degenerative diseases. TGase2 is a calcium-dependent enzyme that irreversibly modifies proteins by forming cross-linked protein aggregates. Intracellular TGase2 is activated by oxidative stress which generates large quantities of unfolded proteins. However, the relationship between TGase2 activity and UPR has not yet been established. In the present study, we demonstrated that ER stress activated TGase2 in various cell types. TGase2 activation was dependent on the ER stress-induced increase in the intracellular calcium ion concentration but not on the TGase2 protein expression level. Enzyme substrate analysis revealed that TGase2-mediated protein modification promoted protein aggregation concurrently with decreasing water solubility. Moreover, treatment with KCC009, a TGase2 inhibitor, abrogated ER stress-induced TGase2 activation and subsequent protein aggregation. However, TGase2 activation had no effect on ER stress-induced cell death. These results demonstrate that the accumulation of misfolded proteins activates TGase2, which further accelerates the formation of protein aggregates. Therefore, we suggest that inhibition of TGase2 may be a novel strategy by which to prevent the protein aggregation in age related degenerative diseases. PMID- 24481340 TI - It all comes back to staffing. PMID- 24481341 TI - Hard of hearing is not deaf. PMID- 24481337 TI - Homeostatic control of regulatory T cell diversity. AB - Regulatory T (TReg) cells constitute an essential counterbalance to adaptive immune responses. Failure to maintain appropriate TReg cell numbers or function leads to autoimmune, malignant and immunodeficient conditions. Dynamic homeostatic processes preserve the number of forkhead box P3-expressing (FOXP3(+)) TReg cells within a healthy range, with high rates of cell division being offset by apoptosis under steady-state conditions. Recent studies have shown that TReg cells become specialized for different environmental contexts, tailoring their functions and homeostatic properties to a wide range of tissues and immune conditions. In this Review, we describe new insights into the molecular controls that maintain the steady-state homeostasis of TReg cells and the cues that drive TReg cell adaptation to inflammation and/or different locations. We highlight how differing local milieu might drive context-specific TReg cell function and restoration of immune homeostasis, and how dysregulation of these processes can precipitate disease. PMID- 24481342 TI - Newly licensed RNs. PMID- 24481343 TI - Newly licensed RNs. PMID- 24481336 TI - Apoptotic cell clearance: basic biology and therapeutic potential. AB - The prompt removal of apoptotic cells by phagocytes is important for maintaining tissue homeostasis. The molecular and cellular events that underpin apoptotic cell recognition and uptake, and the subsequent biological responses, are increasingly better defined. The detection and disposal of apoptotic cells generally promote an anti-inflammatory response at the tissue level, as well as immunological tolerance. Consequently, defects in apoptotic cell clearance have been linked with various inflammatory diseases and autoimmunity. Conversely, under certain conditions, such as the killing of tumour cells by specific cell death inducers, the recognition of apoptotic tumour cells can promote an immunogenic response and antitumour immunity. Here, we review the current understanding of the complex process of apoptotic cell clearance in physiology and pathology, and discuss how this knowledge could be harnessed for new therapeutic strategies. PMID- 24481345 TI - Missed care. PMID- 24481344 TI - Newly licensed RNs. PMID- 24481346 TI - New AHA-ACC guidelines could lead to major changes in clinical practice. PMID- 24481347 TI - Equalizing mental health coverage. PMID- 24481348 TI - Caveats about testosterone therapy. PMID- 24481351 TI - Report outlines best practices in patient-centered outcomes research. PMID- 24481353 TI - Nursing care left undone in European hospitals. PMID- 24481355 TI - Can a nurse be worked to death? PMID- 24481356 TI - Do prophylactic antibiotics reduce UTI risk after urodynamic studies? PMID- 24481359 TI - Training colored nurses at Tuskegee. 1910. PMID- 24481366 TI - The sterile cockpit: an effective approach to reducing medication errors? PMID- 24481371 TI - Lessons learned from litigation: the case of Eric Decker. PMID- 24481372 TI - TOXNET: information on toxicology and environmental health. PMID- 24481373 TI - Hard facts about soft skills. AB - This is the third article in a series on leadership coordinated by the American Organization of Nurse Executives (AONE) that highlights how nurses are leading change efforts in hospitals. It describes work done in conjunction with the AONE's Care Innovation and Transformation initiative, which provides leadership development and educational opportunities to nurse managers and staff aimed at supporting nurses at the point of care in making changes to improve the quality and safety of patient care. PMID- 24481374 TI - A nursing career built on crises. PMID- 24481375 TI - A foreign place. PMID- 24481376 TI - The phenomenology of emotion experience in first-episode psychosis. AB - BACKGROUND: Although it has been suggested that disturbances in emotion experience and regulation play a central role in the aetiology and psychopathology of schizophrenia spectrum disorders, the phenomenology of emotion experience in schizophrenia remains under-researched. SAMPLING AND METHODS: In depth interviews were conducted twice with each of the 20 participants (firstly at admission and secondly 6 months later). Data collection and analysis were guided by the principles of phenomenological study of lived experience. RESULTS: The emotion experiences described by our participants vary greatly in both quality and intensity, but appear to have a common phenomenology. Anxiety is reported as the basic emotion which buffers, transforms and sometimes supplants all others. Emotions in general are experienced as foreign, unstable and perturbing, thereby contributing greatly to feelings of ambivalence, perplexity and an unstable sense of self in general. CONCLUSIONS: The findings of this study have important therapeutic and theoretical implications because they suggest that emotion experiences in schizophrenia spectrum disorders may underlie a wide range of psychopathological phenomena in both the cognitive and social functioning domains. Due to the relatively small sample size and its selection from psychotherapeutic units, the results may not be generalizable to all schizophrenia patients. PMID- 24481377 TI - Transition metal-promoted biomimetic steps in total syntheses. AB - This review summarizes the state-of-the-art on the use of transition metals in synthetic steps inspired by biosynthesis. After an introduction showing the importance of metals in life processes, with special emphasis on biosynthetic processes, their place in biomimetic synthesis will be described. Topics include oxidative cyclizations for polyether synthesis, electrophilic and radical cyclizations of polyprenoids, the role of palladium in electrocyclizations, oxidative biaryl couplings and other rearrangement steps. PMID- 24481378 TI - Enhanced photoluminescence in CaMoO4:Eu3+ by Gd3+ co-doping. AB - We have studied the luminescence property of CaMoO4:Eu(3+). The emission peaks at 590 ((5)D0->(7)F1) and 613 nm ((5)D0->(7)F2) for Eu(3+) are observed after excitation at 266 nm (i.e. Mo-O charge transfer band). The peak intensity of the latter dominates over the former indicating an asymmetric environment of Eu(3+) in EuO8 polyhedron or parity mixing. Luminescence intensity increases significantly with co-doping of Gd(3+). This is ascribed to energy transfer from Mo-O/Gd(3+) to Eu(3+). Luminescence intensity increases with annealing up to 900 degrees C due to the extent of decrease of non-radiative rates. Very high asymmetric values (A21) of 12-16 are found indicating a red emitter. As-prepared samples are dispersible in polar solvents like water, ethanol, methanol, dimethyl sulfoxide (DMSO) and ethylene glycol (EG); and among them, optimum luminescence is found in methanol. Polymer film shows red emission. The quantum yields of as prepared 2 and 10 at% Gd(3+) co-doped CaMoO4:Eu(3+) under 277 nm (UV excitation) are 21 and 80%, respectively. PMID- 24481380 TI - Leptospirosis is an important multi-species zoonotic disease in New Zealand. PMID- 24481381 TI - Preventing death and injury to child motor vehicle passengers: achieving best practice requires simplifying restraint choice for parents and setting best practice as the societal norm. PMID- 24481382 TI - A cluster of three cases of leptospirosis in dairy farm workers in New Zealand. AB - AIMS: We report a cluster of three cases of leptospirosis on a New Zealand dairy farm, with regard to clinical, laboratory, and environmental findings. The cluster is discussed against the annual incidence of leptospirosis in humans and cattle, and the vaccination of cattle as one means of preventing human cases on farms. METHDOS: The three cases were investigated by case interview and review of clinical and laboratory information. A site visit was made to the farm to assess environmental risk. Relevant veterinary information relating to the cattle herds was reviewed. RESULTS: Most of the symptoms exhibited by the three patients were consistent with primary phase leptospirosis. Different methods of laboratory diagnosis were used with each case. However, two cases were confirmed as leptospirosis and in both the causative agent was Leptospira borgpetersenii serovar (sv) Hardjo. The third case had a milder illness, received doxycycline early, and was regarded as a 'probable' case as there were no confirmatory diagnostic results. All three cases had worked on the same dairy farm during their incubation period, where the highest risk environment was the milking shed and potential exposure to urine splashes from infected cattle. Also there were inadequacies in the herd vaccination programme. CONCLUSIONS: There are options for minimising risk to dairy farm workers in New Zealand. No human vaccine exists in this country. Leptospira borgpetersenii serovar (sv) Hardjo (serovar Hardjo) is endemic in New Zealand dairy cattle without causing apparent disease. L. Pomona is a sporadic infection but can cause abortions. A cattle vaccine against these serovars was introduced in New Zealand in 1979, after which there was a general fall in notifications of human cases of leptospirosis. This was attributed to the overall decrease in these two serovars among the livestock population. Vaccination of farm livestock for leptospirosis is an integral factor in preventing human cases. We note the New Zealand initiative to combine vaccination with a risk management programme operated by veterinarians, called Leptosure, to reduce the risk of human leptospirosis on dairy farms. The efficacy of using doxycycline as a prophylaxis for preventing human infection in trials is reviewed. Other preventative strategies include the use of personal protective equipment to cover the mouth and nose, eyes and all skin breaks, farm workers and rural clinicians being aware of the signs and symptoms of leptospirosis, and prompt treatment of cases with antibiotics. PMID- 24481383 TI - Chronic pain in New Zealand: a community sample. AB - AIM: The 2010 New Zealand Chronic Pain Survey aimed to gather information from people who experience chronic pain about their pain, mental health, disabilities, and acceptance of pain. METHODS: In December 2010, surveys were distributed in paper or online to GPs, hospitals, pain clinics asking for people with chronic pain to respond. The survey was open for 6 weeks. RESULTS: There were 142 responses to the survey. Most people reported more than one cause of their pain, and pain in more than one site. Although respondents reported a wide range of causes of their pain, most people were unsure of the cause, or endorsed injury or arthritis as the cause. The most common site of pain was the lower back, followed by the pelvis and joints. Levels of disability were high. Pain was significantly correlated with depression and anxiety, and negatively correlated with acceptance. CONCLUSION: New Zealanders experience chronic pain stemming from multiple origins, with multiple causes. Consistent with international data, the experience of pain causes high levels of mental health issues and disability, but can be modulated by acceptance. Future studies should examine treatment availability and effectiveness. PMID- 24481384 TI - An assessment of an outcome of injury questionnaire using a Pacific model of health and wellbeing. AB - AIM: To use a Pacific model of health to describe relationships between questions within a structured questionnaire developed for a prospective study of injured New Zealand residents' outcomes and important elements of Pacific people's health; and identify health issues of particular importance for Pacific peoples that future studies may consider including. METHOD: The Fonofale model of Pacific health identifies culture, family, physical, spiritual, and 'other' elements (e.g. socioeconomic status and service use) as important. In consultation with Pacific researchers, each question from a Prospective Outcomes of Injury Study (POIS) questionnaire was assessed. Relationship between the type and number of POIS questions were considered in relation to each of the Fonofale elements. RESULTS: Two-thirds of the POIS questions were able to be placed within a single element of the Fonofale model; remaining questions were placed into multiple elements. The POIS questionnaire strongly addressed the physical, mental and 'other' Fonofale elements. Culture, spirituality and family elements were not strongly addressed. CONCLUSIONS: The Fonofale model identified areas of strength in the POIS questionnaire, and areas of limitation. Researchers undertaking population studies or surveys could consider using a Pacific model to help inform structured questionnaire development. PMID- 24481385 TI - Incidence of maternal sensitisation to Rh(D) in Christchurch, New Zealand and reasons for prophylaxis failures. AB - AIM: To estimate the current incidence of maternal sensitisation to Rh(D) and examine reasons for prophylaxis failures. METHOD: Retrospective chart review of new sensitisations to Rh(D) detected in antenatal records, between 2005 and 2012 in Christchurch, New Zealand and systematic examination of circumstances likely to have caused prophylaxis failures. RESULTS: Fifty-four new sensitisations in an at-risk population of about 4624 in 8 years means an incidence of roughly 1.1%. In 86.6% of 45 sensitisations where information was available, there was a recognised sensitising event including previous deliveries while in 13.3% there were none. Of those with recognised sensitising events, 46.1% had anti-D prophylaxis per local guidelines, in 12.8%, prophylaxis was given though it did not conform, entirely, to guideline. No prophylaxis at all was given to 41% despite a sensitising event being recognised. CONCLUSION: The incidence of maternal sensitisation to Rh(D) in Christchurch, New Zealand, is as expected given our prophylaxis regimen. Half the sensitisations were associated with complete or partial failure to follow local guidelines. Better adherence to this may reduce incidence of sensitisation. It is also thrice as high as might be expected with a routine antenatal anti-D prophylaxis (RAADP) program. An economic analysis of RAADP in New Zealand will be useful. PMID- 24481386 TI - Postgraduation retention of medical students from Otago and Auckland medical programmes. AB - AIM: Auckland and Otago medical programmes have different methods for selecting students. This study compared postgraduate retention in New Zealand (NZ) of medical graduates from the two medical programmes, to assess whether different selection methods influenced retention. Other variables assessed included entrance category and age at graduation. METHODS: Anonymised databases were created of all graduates from the Otago Faculty of Medicine (1999-2011) and the Auckland medical programme (2000-2012). Demographic and entry category data were recorded. Retention was defined as presence on the NZ Medical Register in December 2012. Risk differences (RD) were calculated to compare retention between the two medical programmes using the Mantel-Haenszel method. The influence of medical programme entrance category on retention was also tested. The influence of covariates on retaining graduates on the register was evaluated using a multiple logistic regression model. RESULTS: The postgraduate retention of graduates of the two medical programmes over 13 years was identical (Auckland 74.9%, Otago 73.6%, P=0.48). Retention of graduate and non-graduate entry students from both medical programmes was similar by 6 years after graduation. Age during medical school did not affect retention. DISCUSSION: University of attendance had no effect on postgraduation retention of students on the NZ Medical Register, suggesting that retention is not influenced by the different student selection methods at each programme. The data presented shows that New Zealand graduates regardless of programme completed show a similar profile in terms of retention. PMID- 24481387 TI - Molecular epidemiology of group A streptococcus from pharyngeal isolates in Auckland, New Zealand, 2013. AB - AIMS: To describe the molecular epidemiology of emm types associated with circulating pharyngeal group A streptococcus (GAS) isolates in Auckland, New Zealand. METHODS: GAS isolates were collected over a 10-day period from a community pathology provider in Auckland. PCR analysis and sequencing of the emm gene was performed at the Institute of Environmental Science and Research. RESULTS: A total of 52 emm types were identified from 278 GAS isolates. The three most common emm types were emm1, emm89 and emm12. Overall, the experimental 30 valent GAS M protein vaccine covered 19 / 52 (37%) of emm types in our study. DISCUSSION: Our study provides baseline data on the circulating pharyngeal GAS emm types in Auckland. Future clinical and molecular surveillance of GAS pharyngitis is essential in the context of ongoing GAS vaccine development. PMID- 24481388 TI - 'A child restraint for every child on every trip'. AB - Child passenger injury from road traffic crashes is a leading contributor to New Zealand's paediatric trauma-related mortality and morbidity. New Zealand has significantly higher rates of child passenger injury than internationally comparable countries. Correctly used child restraints can prevent death and severe injury of child passengers. Despite huge efforts by individuals and Non Government Organisations to promote up-to-date height-based legislation and to distribute child restraints, the New Zealand Government has a tepid commitment to promoting child passenger safety. Further change is needed, in both our child restraint legislation and practice. This paper highlights the recommendations from a Paediatric Society of New Zealand Position Statement for the correct use of child restraints. This information should be used by all health professionals to advocate for and implement this important injury prevention initiative. PMID- 24481389 TI - Relief from cancer chemotherapy side effects with pharmacologic vitamin C. AB - Fatigue is a common, often debilitating, side effect of cancer chemotherapy. Pharmacologic vitamin C has been used as an alternative treatment for the disease itself but its effects on fatigue have not often been documented. Here we report on the case of a woman with recurrent breast cancer, undergoing weekly chemotherapy, with lethargy as a major symptom. Vitamin C (50 g/session) was administered twice weekly and quality of life and multidimensional fatigue symptomology questionnaires were undertaken. Dramatic decreases in fatigue and insomnia were observed, as well as increased cognitive functioning. There were no adverse side effects of i.v. vitamin C. PMID- 24481390 TI - Congestion bleeding of the head and neck following myocardial infarction. AB - We present an unusual case of congestion bleeding of the head and neck following myocardial infarction. A 51-year-old man presented with widespread facial petechiae and subconjunctival haemorrhages following a collapse associated with evolving electrocardiographic changes. Emergency coronary artery stent placement was undertaken. No cardiopulmonary resuscitation (CPR) was performed. We hypothesise that the presence of facial petechiae in our case following transient loss of consciousness due to a presumed ventricular arrhythmia in the setting of acute myocardial ischaemia, may have been precipitated by a Valsalva manoeuvre on regaining consciousness with sudden acute increase in venous pressure and consequent venous congestion of the head and neck, and that congestion bleeding of the face may occur in acute cardiac events without a history of CPR. PMID- 24481391 TI - Medical image. Pituitary metastasis. PMID- 24481392 TI - Medical image. First branchial cleft anomaly. PMID- 24481393 TI - Marketing and supplying alcohol to young people. PMID- 24481394 TI - Dizziness caused by medications. PMID- 24481395 TI - Emergency departments' cost and primary care. PMID- 24481396 TI - Mortality from coronary heart disease: the (unnoticed) elephant in the room. PMID- 24481397 TI - Is the benefit/risk ratio for cardiac defibrillators implanted in an older population (age 75 or more) still favourable? PMID- 24481398 TI - Elderly locums. PMID- 24481399 TI - Children of the outer Cook Islands have lower BMI compared to their urban peers. PMID- 24481400 TI - Association between smoking and deaths due to colorectal malignant carcinoma: a national population-based case-control study in China. AB - BACKGROUND: This study explored the association between smoking and colorectal malignant carcinoma (CRC) in the Chinese population at the national level for the first time. METHODS: In the China Nationwide Retrospective Mortality Survey conducted during 1989-1991, 12,942 CRC cases among 1,136,336 all-cause deaths aged >=30 years were randomly assigned 25,884 control interviews from 325,255 surviving spouses of all-cause deaths across 103 urban and rural areas. RESULTS: Compared with non-smokers, smoking significantly increased the risk of CRC specific mortality by 9.8% (odds ratio (OR)=1.098, 95% confidence interval (CI)=1.046-1.153) adjusted for sex, age, and residence. There were significant dose-response relationships between smoking and CRC, such as smoking years, cigarettes smoked daily, and age at onset of smoking. Long-term heavy smokers aged >=50 years with >=30 smoking years and >=20 cigarettes daily had an excess risk of CRC deaths of 30.2% (OR=1.302, 95% CI=1.214-1.397). The strongest association between these smoking variables, such as long-term heavy smokers (OR=1.604, 95% CI=1.341-1.919), and CRC was observed among rural men. CONCLUSIONS: Quitting smoking at any time would likely be beneficial to CRC prevention. Long-term heavy smokers and rural men should be viewed as special targets for smoking prevention and cessation programs. PMID- 24481401 TI - Long-term outcome after local recurrence of soft tissue sarcoma: a retrospective analysis of factors predictive of survival in 135 patients with locally recurrent soft tissue sarcoma. AB - BACKGROUND: The aim of this study was to identify prognostic indicators of survival in patients with locally recurrent soft tissue sarcoma (STS) through a long-term follow-up. METHODS: We retrospectively assessed the relationship between post-recurrence survival (PRS) and potential prognostic factors in 135 patients who had experienced local recurrence, which was suitable for further surgical treatment. The median follow-up time after initial recurrence was 12.3 years (95% confidence interval (CI): 10.4-14.2 years). RESULTS: The 5-year estimate of the PRS rate was 53.1% (95% CI: 44.3-61.2%) for the entire series. Patients with negative margins after the final surgery experienced improved survival compared with patients with positive margins (5-year survival: 46.7% (35.2-57.5%) vs 35.5% (23.4-47.8%); P=0.01). In a multivariate analysis, the significant prognostic indicators for PRS were histologic grade, tumour site, time to initial recurrence, the number of recurrences and the surgical margin status attained at the last resection. CONCLUSIONS: Complete surgical resection with microscopically clear margins is desirable in patients with locally recurrent STS. However, when achieving clear surgical margins will require major functional impairment of the extremity, a radical surgical approach should be weighed for the patient in each case. PMID- 24481402 TI - TGFBI expression is an independent predictor of survival in adjuvant-treated lung squamous cell carcinoma patients. AB - BACKGROUND: Transforming growth factor beta-induced protein (TGFBI) is a secreted protein that mediates cell anchoring to the extracellular matrix. This protein is downregulated in lung cancer, and when overexpressed, contributes to apoptotic cell death. Using a small series of stage IV non-small cell lung cancer (NSCLC) patients, we previously suggested the usefulness of TGFBI as a prognostic and predictive factor in chemotherapy-treated late-stage NSCLC. In order to validate and extend these results, we broaden the analysis and studied TGFBI expression in a large series of samples obtained from stage I-IV NSCLC patients. METHODS: TGFBI expression was assessed by immunohistochemistry in 364 completely resected primary NSCLC samples: 242 adenocarcinomas (ADCs) and 122 squamous cell carcinomas (SCCs). Kaplan-Meier curves, log-rank tests and the Cox proportional hazards model were used to analyse the association between TGFBI expression and survival. RESULTS: High TGFBI levels were associated with longer overall survival (OS, P<0.001) and progression-free survival (PFS, P<0.001) in SCC patients who received adjuvant platinium-based chemotherapy. Moreover, multivariate analysis demonstrated that high TGFBI expression is an independent predictor of better survival in patients (OS: P=0.030 and PFS: P=0.026). CONCLUSIONS: TGFBI may be useful for the identification of a subset of NSCLC who may benefit from adjuvant therapy. PMID- 24481403 TI - Is elective nodal irradiation beneficial in patients with pathologically negative lymph nodes after neoadjuvant chemotherapy and breast-conserving surgery for clinical stage II-III breast cancer? A multicentre retrospective study (KROG 12 05). AB - BACKGROUND: To evaluate the effects of elective nodal irradiation (ENI) in clinical stage II-III breast cancer patients with pathologically negative lymph nodes (LNs) (ypN0) after neoadjuvant chemotherapy (NAC) followed by breast conserving surgery (BCS) and radiotherapy (RT). METHODS: We retrospectively analysed 260 patients with ypN0 who received NAC followed by BCS and RT. Elective nodal irradiation was delivered to 136 (52.3%) patients. The effects of ENI on survival outcomes were evaluated. RESULTS: After a median follow-up period of 66.2 months (range, 15.6-127.4 months), 26 patients (10.0%) developed disease recurrence. The 5-year locoregional recurrence-free survival and disease-free survival (DFS) for all patients were 95.5% and 90.5%, respectively. Pathologic T classification (0-is vs 1 vs 2-4) and the number of LNs sampled (<13 vs >=13) were associated with DFS (P=0.0086 and 0.0012, respectively). There was no significant difference in survival outcomes according to ENI. Elective nodal irradiation also did not affect survival outcomes in any of the subgroups according to pathologic T classification or the number of LNs sampled. CONCLUSIONS: ENI may be omitted in patients with ypN0 breast cancer after NAC and BCS. But until the results of the randomised trials are available, patients should be put on these trials. PMID- 24481404 TI - A nomogram predicting pulmonary metastasis of hepatocellular carcinoma following partial hepatectomy. AB - BACKGROUND: Pulmonary metastasis (PM) following curative hepatectomy for hepatocellular carcinoma (HCC) is indicative of a poor prognosis. This study aimed to develop a nomogram to identify patients at high risks of PM. METHODS: A primary cohort of patients who underwent curative hepatectomy for HCC at the Eastern Hepatobiliary Surgery Hospital from 2002 to 2010 was prospectively studied. A nomogram predicting PM was constructed based on independent risk factors of PM. The predictive performance was evaluated by the concordance index (c-index), calibration curve and decision curve analysis (DCA). During the study period, a validation cohort was included at the First Affiliated Hospital of Fujian Medical University. RESULTS: Postoperative PMs were detected in 106 out of 620 and 45 out of 218 patients, respectively, in two cohorts. Factors included in the nomogram were microvascular invasion, serum alpha-fetoprotein, tumour size, tumour number, encapsulation and intratumoral CD34 staining. The nomogram had a c index of 0.75 and 0.82 for the two cohorts for predicting PM, respectively. The calibration curves fitted well. In the two cohorts, the DCA demonstrated positive net benefits by the nomogram, within the threshold probabilities of PM >10%. CONCLUSION: The nomogram was accurate in predicting PM following curative hepatectomy for HCC. PMID- 24481405 TI - Focal amplification of the androgen receptor gene in hormone-naive human prostate cancer. AB - BACKGROUND: Androgen receptor (AR)-gene amplification, found in 20-30% of castration-resistant prostate cancer (CRPCa) is proposed to develop as a consequence of hormone-deprivation therapy and be a prime cause of treatment failure. Here we investigate AR-gene amplification in cancers before hormone deprivation therapy. METHODS: A tissue microarray (TMA) series of 596 hormone naive prostate cancers (HNPCas) was screened for chromosome X and AR-gene locus specific copy number alterations using four-colour fluorescence in situ hybridisation. RESULTS: Both high level gain in chromosome X (>=4 fold; n=4, 0.7%) and locus-specific amplification of the AR-gene (n=6, 1%) were detected at low frequencies in HNPCa TMAs. Fluorescence in situ hybridisation mapping whole sections taken from the original HNPCa specimen blocks demonstrated that AR-gene amplifications exist in small foci of cells (<= 600 nm, <=1% of tumour volume). Patients with AR gene-locus-specific copy number gains had poorer prostate cancer specific survival. CONCLUSION: Small clonal foci of cancer containing high level gain of the androgen receptor (AR)-gene develop before hormone deprivation therapy. Their small size makes detection by TMA inefficient and suggests a higher prevalence than that reported herein. It is hypothesised that a large proportion of AR-amplified CRPCa could pre-date hormone deprivation therapy and that these patients would potentially benefit from early total androgen ablation. PMID- 24481406 TI - Intakes of folate, methionine, vitamin B6, and vitamin B12 with risk of esophageal and gastric cancer in a large cohort study. AB - BACKGROUND: Nutrients in the one-carbon metabolism pathway may be involved in carcinogenesis. Few cohort studies have investigated the intakes of folate and related nutrients in relation to gastric and esophageal cancer. METHODS: We prospectively examined the association between self-reported intakes of folate, methionine, vitamin B6, and vitamin B12 and gastric and esophageal cancer in 492,293 men and women. RESULTS: We observed an elevated risk of esophageal squamous cell carcinoma with low intake of folate (relative risk (95% confidence interval): Q1 vs Q3, 1.91 (1.17, 3.10)), but no association with high intake. Folate intake was not associated with esophageal adenocarcinoma, gastric cardia adenocarcinoma, or non-cardia gastric adenocarcinoma. The intakes of methionine, vitamin B6, and vitamin B12 were not associated with esophageal and gastric cancer. CONCLUSION: Low intake of folate was associated with increased risk of esophageal squamous cell carcinoma. PMID- 24481407 TI - Pharmacokinetic modeling optimizes inhibition of the 'undruggable' EWS-FLI1 transcription factor in Ewing Sarcoma. AB - Transcription factors have long been deemed 'undruggable' targets for therapeutics. Enhanced recognition of protein biochemistry as well as the need to have more targeted approaches to treat cancer has rendered transcription factors approachable for therapeutic development. Since transcription factors lack enzymatic domains, the specific targeting of these proteins has unique challenges. One challenge is the hydrophobic microenvironment that affects small molecules gaining access to block protein interactions. The most attractive transcription factors to target are those formed from tumor specific chromosomal translocations that are validated oncogenic driver proteins. EWS-FLI1 is a fusion protein that results from the pathognomonic translocation of Ewing sarcoma (ES). Our past work created the small molecule YK-4-279 that blocks EWS-FLI1 from interacting with RNA Helicase A (RHA). To fulfill long-standing promise in the field by creating a clinically useful drug, steps are required to allow for in vivo administration. These investigations identify the need for continuous presence of the small molecule protein-protein inhibitor for a period of days. We describe the pharmacokinetics of YK-4-279 and its individual enantiomers. In vivo studies confirm prior in vitro experiments showing (S)-YK-4-279 as the EWS-FLI1 specific enantiomer demonstrating both induction of apoptosis and reduction of EWS-FLI1 regulated caveolin-1 protein. We have created the first rat xenograft model of ES, treated with (S)-YK-4-279 dosing based upon PK modeling leading to a sustained complete response in 2 of 6 ES tumors. Combining laboratory studies, pharmacokinetic measurements, and modeling has allowed us to create a paradigm that can be optimized for in vivo systems using both in vitro data and pharmacokinetic simulations. Thus, (S)-YK-4-279 as a small molecule drug is ready for continued development towards a first-in-human, first-in-class, clinical trial. PMID- 24481408 TI - Influence of temperature on the capacitance of ionic liquid electrolytes on charged surfaces. AB - In this work using molecular dynamics simulations we examine the temperature dependence of the differential capacitance of room temperature ionic liquid electrolytes near electrified surfaces. For electrodes with atomically flat surfaces our simulations show very weak temperature dependence of the differential capacitance (DC) with a slight decrease of DC with increasing temperature. For atomically corrugated surfaces where the ion dimensions are comparable to the size of the surface corrugation patterns, the influence of temperature on DC is much more pronounced. At low temperatures the DC dependence on electrode potential shows large variations with well-defined maxima and minima. However, with increasing temperature these features are significantly flattened. Also for these corrugated surfaces an abnormal positive slope of DC vs. temperature is observed in the narrow range of relatively low voltages. Analysis of changes in the electric double layer structure as a function of temperature allowed us to propose a new mechanism explaining the observed trends in capacitance as a function of temperature and surface topography. The obtained simulation results are discussed in light of available experimental data and help to discriminate between contradictory experimentally observed trends in DC temperature dependence reported for ionic liquid based electrolytes in the literature. PMID- 24481410 TI - Serum carboxymethyllysine, an advanced glycation end product, and age-related macular degeneration: the Age, Gene/Environment Susceptibility-Reykjavik Study. AB - IMPORTANCE Advanced glycation end products have been implicated in the pathogenesis of age-related macular degeneration (AMD). OBJECTIVE To investigate the relationship between serum carboxymethyllysine (CML), a major circulating advanced glycation end product, and AMD in older adults. DESIGN, SETTING, AND PARTICIPANTS Cross-sectional study of a population-based sample of 4907 older adults (aged >=66 years) in the Age, Gene/Environment Susceptibility-Reykjavik Study in Iceland. EXPOSURES Serum CML and risk factors for AMD. MAIN OUTCOMES AND MEASURES Early or late AMD, assessed through fundus images taken through dilated pupils using a 45 degrees digital camera and grading for drusen size, type, area, increased retinal pigment, retinal pigment epithelial depigmentation, neovascular lesions, and geographic atrophy using the modified Wisconsin Age Related Maculopathy Grading System. RESULTS Of the 4907 participants, 1025 (20.9%) had early AMD and 276 (5.6%) had late AMD. Mean (SD) serum CML concentrations among adults with no AMD, early AMD, and late AMD (exudative AMD and pure geographic atrophy) were 618.8 (195.5), 634.2 (206.4), and 638.4 (192.0) ng/mL, respectively (to convert to micromoles per liter, multiply by 0.00489; P = .07). Log serum CML (per 1-SD increase) was not associated with any AMD (early and late AMD) (odds ratio = 0.97; 95% CI, 0.90-1.04; P = .44) or with late AMD (odds ratio = 0.94; 95% CI, 0.82-1.08; P = .36) in respective multivariable logistic regression models adjusting for age, sex, body mass index, smoking, and renal function. CONCLUSIONS AND RELEVANCE Higher serum CML concentration had no significant cross-sectional association with prevalent AMD in this large population-based cohort of older adults in Iceland. PMID- 24481411 TI - How to monitor the brain during immediate neonatal transition and resuscitation? A systematic qualitative review of the literature. AB - BACKGROUND: The brain is vulnerable to injury and dysfunction during transition after birth in neonates. Clinical assessment of the neurological status immediately following birth is difficult, especially during resuscitation. OBJECTIVE: Our aim was to review physiological monitoring of the brain during immediate postnatal transition - the first 15 min after birth. METHODS: A systematic search of PubMed and EMBASE was performed using the following terms: newborn, neonate, neonates, transition, after-birth, delivery room, cerebral, brain, monitoring, neurology, oxygenation, saturation, activity, imaging, perfusion, Doppler, and blood flow. Additional articles were identified by manual search of cited references. Only human studies describing cerebral changes during the first 15 min after birth were included. RESULTS: Six studies were identified, which described sequential measurements of cerebral perfusion using Doppler sonography, one of these in combination with continuous monitoring of cerebral tissue oxygenation with near-infrared spectroscopy (NIRS). A further 15 studies were identified that used NIRS to continuously monitor cerebral tissue oxygenation. In one study, cerebral activity was continuously monitored with an additional amplitude-integrated encephalogram. CONCLUSION: Monitoring the brain provides additional information during immediate transition and may help to guide resuscitation. Doppler sonography is technically challenging during resuscitation and is therefore of limited value. NIRS provides continuous monitoring and is feasible even in very-low-birth-weight infants. In the future, an amplitude integrated encephalogram might give further information on the status of the brain, but before any of these modalities can routinely be recommended during neonatal resuscitation, clinical trials targeting stable brain function parameters are needed. PMID- 24481413 TI - Cerebral microbleeds and fatigue in stroke. AB - BACKGROUND AND PURPOSE: Poststroke fatigue (PSF) is a frequent and persistent problem in stroke survivors. The neuroanatomical model of PSF remains unclear. This study examined the association between PSF and cerebral microbleeds (CMBs). METHODS: The sample comprised 199 patients with acute ischemic stroke. A psychiatrist who was blind to the subjects' radiological data administered the Chinese version of the Fatigue Severity Scale. PSF was defined as a Fatigue Severity Scale score of 4.0 or more. The locations of CMBs were evaluated with magnetic resonance imaging within 7 days of admission. RESULTS: Of the 199 patients screened, 47 (23.6%) had PSF. The PSF group had a higher Geriatric Depression Scale score (p < 0.001) and a trend for a higher age (p = 0.074). The proportion of patients with deep CMBs was significantly higher in the PSF group (66.0 vs. 48.7%; p = 0.038). The presence of deep CMBs was a significant independent predictor of PSF with an odds ratio of 2.68 (p = 0.016). CONCLUSION: The results suggest that deep CMBs are associated with a higher risk of PSF. Further studies are needed to clarify whether CMBs affect the clinical presentation, treatment response and outcome of PSF. PMID- 24481412 TI - IKKbeta inhibitor in combination with bortezomib induces cytotoxicity in breast cancer cells. AB - Bortezomib is a proteasome inhibitor with remarkable clinical antitumor activity in multiple myeloma (MM) and is under evaluation in clinical trials in various types of cancer including breast cancer. Although the initial rationale for its use in cancer treatment was the inhibition of NF-kappaB activity by blocking proteasomal degradation of IkappaBalpha, direct evidence indicating inhibition of constitutive NF-kappaB activity by bortezomib in tumor cells in patients has not yet been reported. Moreover, recent studies have shown that bortezomib activates constitutive NF-kappaB activity via stimulating the canonical pathway in MM cells. In this study, we first examined protein expression of IkappaBalpha after bortezomib treatment. We observed that bortezomib upregulated the phosphorylation and downregulated IkappaBalpha protein expression in a dose- and time-dependent manner in MCF7 and T47D cells, associated with phosphorylation of IKKbeta. Since IkappaBalpha is an inhibitor of nuclear translocation of NF-kappaB, we further examined alteration of NF-kappaB activity by bortezomib. Importantly, bortezomib significantly upregulates NF-kappaB activity in both MCF7 and T47D in a dose dependent fashion, demonstrated by electrophoretic mobility shift analysis (EMSA). Furthermore, immunocytochemical analysis confirmed enhanced nuclear translocation of p65 NF-kappaB (RelA) by bortezomib treatment. Supershift assay showed supershifted bands by anti-p65 and -p50 antibodies. Taken together, these results indicate that bortezomib activates the canonical NF-kappaB pathway in both cell lines. Finally, we demonstrated that IKKbeta inhibitor enhanced cytotoxicity, associated with inhibition of NF-kappaB activity induced by bortezomib in MCF7 and T47D breast cancer cells. PMID- 24481414 TI - Juvenile 'cryptogenic' stroke from noncompaction in a neuromuscular disease. AB - Juvenile, 'cryptogenic' stroke from left-ventricular hypertrabeculation/noncompaction (LVHT) missed on transthoracic echocardiography (TTE) but present on transesophageal echocardiography (TEE) has not been reported before. A 31-year-old Caucasian male experienced a small acute embolic ischemic stroke in the anterior territory of the left median-cerebral artery. He had a history of epilepsy until the age of 12 years with rare seizures, headache 6 weeks prior to admission and a speech disturbance lasting 2 h. He smoked 20 cigarettes per day. An intensive diagnostic work-up including TTE did not reveal the cause of the stroke. Upon TEE, however, LVHT was found. Cardiac MRI did not reveal intraventricular thrombi. There were mild indications for a neuromuscular disorder. LVHT may be a risk factor for cardioembolic stroke. Patients with cryptogenic stroke and normal TTE should undergo TEE. Patients with LVHT should undergo neurological investigation to look for neuromuscular disorders. (c) 2014 S. Karger AG, Basel. PMID- 24481415 TI - The prognostic value of midregional proatrial natriuretic peptide in patients with hemorrhagic stroke. AB - BACKGROUND: Atrial natriuretic peptide (ANP) is a well-known prognostic marker of outcome and mortality in patients with cardiovascular disease. Midregional proatrial natriuretic peptide (MR-proANP) is a stable fragment of the ANP precursor hormone. As a prognostic marker after ischemic stroke, it reliably predicts poststroke mortality and functional outcome. This study aimed to analyze the prognostic value of MR-proANP in patients with hemorrhagic stroke, i.e. subarachnoid (SAH) and intracerebral hemorrhage (ICH). METHODS: MR-proANP was analyzed in patients with spontaneous SAH or spontaneous ICH. All patients were prospectively randomized into two treatment arms: (1) a prophylactic normothermia group with a target core temperature 36.5 degrees C using endovascular cooling, and (2) a control group with conventional stepwise predefined fever management using antipyretic medication and surface cooling. Blood samples were obtained on admission and on days 4 and 7. Measurement of MR-proANP was performed in serum using sandwich immunoassay. The primary endpoint was functional outcome [assessed by the Glasgow Outcome Score (GOS)] and the secondary endpoints were mortality within 180 days after hemorrhagic stroke and influence of temperature on MR proANP. A favorable outcome was defined as GOS 4-5, and the patients were considered to have a poor outcome with a 180-day GOS score between 1 and 3. RESULTS: Analysis of MR-proANP was performed in 24 patients with spontaneous SAH and 22 patients with spontaneous ICH. MR-proANP was elevated on days 4 and 7 as compared to baseline levels (p < 0.05 and p < 0.001, respectively). High MR proANP levels (>120 pmol/l) were associated with increased mortality and poor outcome (after 180 days; p < 0.05, respectively). There was no significant difference regarding MR-proANP serum concentrations between the endovascular and the control groups. CONCLUSIONS: Increased levels of MR-proANP are independently associated with poor functional outcome and increased mortality after 180 days in patients with hemorrhagic stroke. Endovascular temperature control had no significant influence on MR-proANP levels. PMID- 24481416 TI - PTEN regulation of the proliferation and differentiation of auditory progenitors through the PTEN/PI3K/Akt-signaling pathway in mice. AB - The organ of Corti, which is the sensory organ of hearing, consists of a single row of inner hair cells and three rows of outer hair cells in mice. The auditory hair cells develop from auditory progenitors. Hair cell development is related to several genes, including PTEN. Homozygous null mutant (PTEN(-/-)) mice die at around embryonic day 9, when hair cells are extremely immature. Moreover, in heterozygous PTEN knockout mice, it was found that PTEN regulates the proliferation of auditory progenitors. However, little is known about the molecular mechanism underlying this regulation. In the present study, we generated PTEN conditional knockout in the inner ear of mice and studied the aforementioned molecular mechanisms. Our results showed that PTEN knockout resulted in supernumerary hair cells, increased p-Akt level, and decreased p27(kip1) level. Furthermore, the presence of supernumerary hair cells could be explained by the delayed withdrawal of auditory progenitors from the cell cycle. The increased p-Akt level correlates with p27(kip1) downregulation in the cochlea in the Pax2-PTEN mice. The reduced p27(kip1) could not maintain the auditory progenitors in the nonproliferative state and some progenitors continued to divide. Consequently, additional progenitors differentiated into supernumerary hair cells. We suggest that PTEN regulates p27(kip1) through p-Akt, thereby regulating the proliferation and differentiation of auditory progenitors. PMID- 24481417 TI - Nestin regulates proliferation, migration, invasion and stemness of lung adenocarcinoma. AB - Lung cancer is the most common cancer and the most common cause of cancer-related death in the world. Nestin, a class VI intermediate filament, is known to be a cancer stem cell (CSC) marker as well as a neuroepithelial stem cell marker. High expression levels of nestin are reported in several types of cancers including lung, pancreatic and prostate cancers. Nestin is thought to regulate tumor cell proliferation, migration, invasion and CSC properties. Here, we confirmed nestin expression in non-small cell lung cancer (NSCLC): Immunohistochemical analysis in surgical specimens detected nestin protein expression in the cytoplasm of 20 of 48 adenocarcinoma (AD) cases (41.7%) and 25 of 47 squamous cell carcinoma cases (53.2%). Nestin immunoreactivity significantly correlated with not only tumor size and lymph node metastasis in NSCLC, but also poor survival in surgical patients with AD. High and moderate expression levels of nestin were confirmed in several lung AD cell lines including H1975 and PC-3. Nestin inhibition by shRNA decreased proliferation, migration, invasion and sphere formation in AD cells. Correspondingly, nestin upregulation by nestin gene transfection resulted in the opposite changes. Moreover, Akt inhibitor IV effectively decreased nestin expression via SRY-box containing protein 2 (Sox2) downregulation and overcame the enhanced sphere formation induced by nestin upregulation. Overall, our results show that nestin correlates with the aggressiveness and stemness of AD. Regulation of nestin via Akt/Sox2 is, thus, a promising candidate for novel therapeutic approaches to eradicate CSCs in lung AD. PMID- 24481418 TI - Vascular access in resuscitation: is there a role for the intraosseous route? AB - Intraosseous vascular access is a time-tested procedure which has been incorporated into the 2010 American Heart Association Guidelines for Cardiopulmonary Resuscitation. Intravenous access is often difficult to achieve in shock patients, and central line placement can be time consuming. Intraosseous vascular access, however, can be achieved quickly with minimal disruption of chest compressions. Newer insertion devices are easy to use, making the intraosseous route an attractive alternative for venous access during a resuscitation event. It is critical that anesthesiologists, who are often at the forefront of patient resuscitation, understand how to properly use this potentially life-saving procedure. PMID- 24481419 TI - Human factors engineering in patient safety. PMID- 24481421 TI - Epidemiology, course and outcome of acute polymorphic psychotic disorder: implications for ICD-11. AB - BACKGROUND: The proposed revision of the ICD-10 category of 'acute and transient psychotic disorders' (ATPDs), subsuming polymorphic, schizophrenic or predominantly delusional syndromes, would restrict their classification to acute polymorphic psychotic disorder, reminiscent of the clinical concepts of bouffee delirante and cycloid psychosis. SAMPLING AND METHODS: We selected all subjects aged 15-64 years (n = 5,426) who were listed in the Danish Psychiatric Central Register with a first-admission diagnosis of ATPDs in 1995-2008 and estimated incidence rates, course and outcome up to 2010. RESULTS: Although about half of ATPD patients tended to experience transition to another category over a mean follow-up period of 9.3 years, acute polymorphic psychotic disorder fared better in terms of cases with a single episode of psychosis and temporal stability than the subtypes featuring schizophrenic or predominantly delusional symptoms. Acute polymorphic psychotic disorder was more common in females, while cases with acute schizophrenic features predominated in younger males and evolved more often into schizophrenia and related disorders. CONCLUSIONS: These findings suggest that acute polymorphic psychotic disorder exhibits distinctive features and challenge the current approach to the classification of ATPDs. PMID- 24481420 TI - Recent progress with microtubule stabilizers: new compounds, binding modes and cellular activities. AB - Nature has yielded numerous classes of chemically distinct microtubule stabilizers. Several of these, including paclitaxel (Taxol) and docetaxel (Taxotere), are important drugs used in the treatment of cancer. New microtubule stabilizers and novel formulations of these agents continue to provide advances in cancer therapy. In this review we cover recent progress in the chemistry and biology of these diverse microtubule stabilizers focusing on the wide range of organisms that produce these compounds, their mechanisms of inhibiting microtubule-dependent processes, mechanisms of drug resistance, and their interactions with tubulin including their distinct binding sites and modes. A new potential role for microtubule stabilizers in neurodegenerative diseases is reviewed. PMID- 24481423 TI - CITED1 confers stemness to Wilms tumor and enhances tumorigenic responses when enriched in the nucleus. AB - Wilms tumor (WT) is the most common childhood kidney cancer and retains gene expression profiles reminiscent of the embryonic kidney. We have shown previously that CITED1, a transcriptional regulator that labels the self-renewing, multipotent nephron progenitor population of the developing kidney, is robustly expressed across all major WT disease and patient characteristics. In this malignant context, CITED1 becomes enriched in the nucleus, which deviates from its cytosolic predominance in embryonic nephron progenitors. We designed the current studies to test the functional and mechanistic effects of differential CITED1 subcellular localization on WT behavior. To mimic its subcellular distribution observed in clinical WT specimens, CITED1 was misexpressed ectopically in the human WT cell line, WiT49, as either a wild-type (predominantly cytosolic) or a mutant, but transcriptionally active, protein (two point mutations in its nuclear export signal, CITED1DeltaNES; nuclear-enriched). In vitro analyses showed that CITED1DeltaNES enhanced WiT49 proliferation and colony formation in soft agar relative to wild-type CITED1 and empty vector controls. The nuclear-enriched CITED1DeltaNES cell line showed the greatest tumor volumes after xenotransplantation into immunodeficient mice (n=15 animals per cell line). To elucidate CITED1 gene targets in this model, microarray profiling showed that wild-type CITED1 foremost upregulated LGR5 (stem cell marker), repressed CDH6 (early marker of epithelial commitment of nephron progenitors), and altered expression of specific WNT pathway participants. In summary, forced nuclear enrichment of CITED1 in a human WT cell line appears to enhance tumorigenicity, whereas ectopic cytosolic expression confers stem-like properties and an embryonic phenotype, analogous to the developmental context. PMID- 24481425 TI - [Efficacy and adverse effects of oral antidiabetic agents]. AB - The management of type 2 diabetes is still a challenge and a conundrum for treatment intensity and choice of pharmaceutical agent. There is also uncertainty about possible cardiovascular adverse effects. PMID- 24481426 TI - [Clinical competence evaluation using the Objective Structured Clinical Examination (OSCE) in medical internship at UNAM]. AB - INTRODUCTION: The Objective Structured Clinical Examination (OSCE) is a widely used measurement tool to assess clinical competence in the health sciences. There is little published evidence of its use in Mexican medical schools. OBJECTIVE: To assess clinical competence in medical students with an OSCE, before and after the Medical Internship. METHODS: Prospective cohort study, pre- post-test research design. The assessed population was medical students at UNAM Faculty of Medicine in Mexico in their Internship year. The instrument was an 18-stations OSCE, three stations per academic area of the Internship curriculum. RESULTS: We assessed the clinical competence of 278 students in a pretest OSCE when starting the Internship year, and tested them 10 months later with an equivalent post-test OSCE. The sample of students was 30.4% of the total Internship population. Test reliability with Cronbach's alpha was 0.62 in the pre-test and 0.64 in the post test. The global mean score in the pretest OSCE was 55.6 +/- 6.6 and in the post test 63.2 +/- 5.7 (p < 0.001), with a Cohen's d of 1.2. CONCLUSIONS: The clinical competence of medical students measured with an OSCE is higher after the medical internship year. This difference suggests that the internship can influence the development of clinical competence in medical students. PMID- 24481424 TI - Markers of inflammation, oxidative stress, and endothelial dysfunction and the 20 year cumulative incidence of early age-related macular degeneration: the Beaver Dam Eye Study. AB - IMPORTANCE Modifying levels of factors associated with age-related macular degeneration (AMD) may decrease the risk for visual impairment in older persons. OBJECTIVE To examine the relationships of markers of inflammation, oxidative stress, and endothelial dysfunction to the 20-year cumulative incidence of early AMD. DESIGN, SETTING, AND PARTICIPANTS This longitudinal population-based cohort study involved a random sample of 975 persons in the Beaver Dam Eye Study without signs of AMD who participated in the baseline examination in 1988-1990 and up to 4 follow-up examinations in 1993-1995, 1998-2000, 2003-2005, and 2008-2010. EXPOSURES Serum markers of inflammation (high-sensitivity C-reactive protein, tumor necrosis factor-alpha receptor 2, interleukin-6, and white blood cell count), oxidative stress (8-isoprostane and total carbonyl content), and endothelial dysfunction (soluble vascular cell adhesion molecule-1 and soluble intercellular adhesion molecule-1) were measured. Interactions with complement factor H (rs1061170), age-related maculopathy susceptibility 2 (rs10490924), complement component 3 (rs2230199), and complement component 2/complement factor B (rs4151667) were examined using multiplicative models. Age-related macular degeneration was assessed from fundus photographs. MAIN OUTCOMES AND MEASURES Early AMD defined by the presence of any size drusen and the presence of pigmentary abnormalities or by the presence of large-sized drusen (>=125-MUm diameter) in the absence of late AMD. RESULTS The 20-year cumulative incidence of early AMD was 23.0%. Adjusting for age, sex, and other risk factors, high sensitivity C-reactive protein (odds ratio comparing fourth with first quartile, 2.18; P = .005), tumor necrosis factor-alpha receptor 2 (odds ratio, 1.78; P = .04), and interleukin-6 (odds ratio, 1.78; P = .03) were associated with the incidence of early AMD. Increased incidence of early AMD was associated with soluble vascular cell adhesion molecule-1 (odds ratio per SD on the logarithmic scale, 1.21; P = .04). CONCLUSIONS AND RELEVANCE We found modest evidence of relationships of serum high-sensitivity C-reactive protein, tumor necrosis factor alpha receptor 2, interleukin-6, and soluble vascular cell adhesion molecule-1 to the 20-year cumulative incidence of early AMD independent of age, smoking status, and other factors. It is not known whether these associations represent a cause and effect relationship or whether other unknown confounders accounted for the findings. Even if inflammatory processes are a cause of early AMD, it is not known whether interventions that reduce systemic inflammatory processes will reduce the incidence of early AMD. PMID- 24481427 TI - [Comparison of macular volume change after photocoagulation, in eyes with diabetic macular edema, with and without visual improvement]. AB - OBJECTIVE: To compare the changes in macular volume after photocoagulation between eyes with diabetic macular edema with and without visual improvement. METHODS: Non-experimental, retrospective, longitudinal, comparative study in eyes with diabetic macular edema; the sample was divided in groups: eyes with visual improvement three weeks after photocoagulation (group 1) and eyes without it (group 2). The means of macular volume changes (potential, absolute and percentage) were compared between groups (Student's t test). RESULTS: 115 eyes, 50 from group 1 and 65 from group 2; mean macular volume before and after photocoagulation and mean potential, absolute, and percentage volume changes did not differ between groups. 13.9% of the sample had visual improvement and a significant volume reduction; the proportion of the latter did not differ between groups (p = 0.3). Macular volume and visual acuity decreased significantly in eyes without previous visual deficiency (p = 0.012); it was more common to find eyes without visual improvement with a non-significant volume reduction, than finding eyes with visual improvement and a significant macular volume reduction. CONCLUSION: The reduction of macular volume was not enough to explain visual improvement. Optimizing the outcome in patients with diabetic macular edema requires the identification of functional features with a prognostic value. PMID- 24481428 TI - [Endovascular management of residual intracranial aneurysms after surgical clipping]. AB - OBJECTIVES: To identify and evaluate the cerebral aneurysm remnants after clipping and the endovascular treatment in our institution. METHODS AND MATERIALS: We made a clinical ambispective collection of all aneurysms microsurgically clipped during four years and we analyzed their endovascular treatment. RESULTS: There were 290 cerebral aneurysms; in 270 a digital subtraction angiography was made. Ten aneurysm remnants were found (3.7%); of these, a second operation was performed on two, and coil placement was done in six patients. CONCLUSION: The cerebral aneurysm remnants after clipping in our institution are equivalent to international results. The endovascular treatment of this aneurysm is safe and effective. PMID- 24481429 TI - [Life style and metabolic control in DiabetIMSS program]. AB - OBJECTIVE: To compare the lifestyle and metabolic control of diabetes patients included and not included in the DiabetIMSS program. METHODS: Subjects with diabetes in the DiabetIMSS program and the general clinic were divided into three groups: group 1 first attended the program, group 2 were enrolled during the study, and group 3 had not been included the program. Demographic and clinical aspects were measured and the IMEVID instrument was applied. RESULTS: We included 539 type-2 diabetes patients, predominantly females (73.3%), mainly of primary school level, and more frequently on double-drug therapy. There were clinical differences between the three groups for program leavers in terms of weight, waist, blood pressure, fasting glucose, HbA1c, triglycerides, and IMEVID qualification, all p < 0.05; correlation analysis of the variables with the qualification of IMEVID was significant at p < 0.05. The higher number of variable control targets was for leavers (71% of group); those who were enrolled in the study was 32%, and who had not was 17.2%. CONCLUSIONS: There are significant differences in lifestyle and control target parameters in subjects who completed the DiabetIMSS program. PMID- 24481430 TI - [Diagnostic assessment of knowledge and competencies in medical students at the end of the second year of medical school: the challenge of building an airplane while it's flying]. AB - INTRODUCTION: In Latin America there is almost no published information about knowledge retention and formative assessment of competencies in medical students, during medical school training and curricular changes. OBJECTIVE: To assess knowledge level and clinical competencies in medical students at the end of the second year in a new curriculum. METHODS: Observational, cross-sectional study in UNAM Faculty of Medicine students. A diagnostic evaluation was performed in the first class of the "Plan of Studies 2010" curriculum, as part of an integral program evaluation strategy. The assessment had two components: theoretical and practical. RESULTS: 456 (87%) of the 524 students that successfully completed the second year of Plan 2010 were assessed. The written test had 211 items, a mean score of 60 +/- 14.5, mean difficulty index of 0.60, reliability with Cronbach's alpha of 0.85. The OSCE mean global score was 58 +/- 9, Cronbach's alpha of 0.36, and G-coefficient of 0.48, and results were provided for each station. Results by area of knowledge, course, and station were reported. CONCLUSIONS: The results in general are acceptable, compared with previous written evaluations at the end of the second year, suggesting that the new program is achieving its educational goals. Competencies were formally assessed for the first time in our Institution, establishing a starting point for follow-up. The study provided useful information to the institution, teachers and students. PMID- 24481431 TI - [A 35-year report of the study of group on gastrointestinal cancer in Mexico City: variations in frequency of different digestive tract neoplasms among different socioeconomic statuses]. AB - BACKGROUND: Since the middle of the last century, North America and occidental countries have reported variations in the frequency of gastrointestinal neoplasms. Several environmental factors, mainly nutritional and dietary exposure, as well as habits have contributed to these changes. We have documented these changes in Mexico during the last 35 years. AIMS: To define the epidemiologic changes of gastrointestinal neoplasms during the last three decades in our population. METHODS: We summarized the evidence of an observational study, registering the frequency of different gastrointestinal malignancies from four institutions of socioeconomically different populations in Mexico City during 35 years. The Mexican National Academy of Medicine supported this effort. During this period, two nutritional surveys took place, letting us define the relationship between dietary changes and cancer occurrence. RESULTS: Replacement of gastric cancer by colorectal cancer as the leading gastrointestinal malignancy. Relationship between cancer and diet changes. Increase of esophageal adenocarcinoma in relation to epidermoid carcinoma secondary to gastroesophageal reflux and Barrett's esophagus rising incidence. Gall bladder cancer had a high frequency in one institution, probably related to genetic and racial factors. CONCLUSIONS: This epidemiologic data should lead us to implement sanitary measures for the prevention, early diagnosis, and appropriate treatment of gastrointestinal neoplasms. PMID- 24481432 TI - [The gold standard in diabetic foot treatment: total contact cast]. AB - In patients with diabetes, foot complications remain one of the main health issues, with ulcers representing one of the most common. These ulcerations originate from repetitive trauma on a foot with neuropathy. Inadequate care of the diabetic foot may lead to one of the gravest complications of the diabetic foot: amputation. The key to the treatment of the diabetic foot is the control of comorbidities (glucose levels and vascular disease), debridement, exudate control with the available modern dressings, treatment of infection, and offloading the affected foot. A common error in this basic treatment is the method used for offloading, leading to delayed healing as a result, and maybe even amputation. For this purpose we propose the total contact cast considered the "gold standard" in diabetic foot offloading. The objective of the present review is to present the existing evidence in the medical literature on the effectiveness of its use for healing diabetic foot ulcers and hence preventing amputations. PMID- 24481433 TI - [Differentiated thyroid cancer: an ancient disease with new knowledge]. AB - Differentiated thyroid cancer is the most common endocrine malignancy and its incidence appears to be rising rapidly with a good prognosis. However, the involvement of different medical specialties has changed the focus of treatment and triggered a number of controversies. In the absence of controlled trials, the guidelines for treatment are founded on prognostic factors for survival and local control, the effects of the treatments, and comorbidities. Recently, the major advances in the field of genetics and molecular biology have been applied in the treatment of iodine refractory disease, and the use of tracers and recombinant hormones have succeeded in improving adjuvant treatment. Based on this information, we present this review with the aim of updating the knowledge of an ancient disease. PMID- 24481434 TI - [Blood Safety in the XXI century. Transfusion transmitted infectious diseases. International and Mexican view]. AB - Currently worldwide, the transfusion of blood components cannot be done without residual risks, as compared to those countries with a high human development index, mostly in Europe, that have blood donation systems based on 100% repeat volunteer donors and use molecular biology techniques in screening for infectious diseases. In Latin America and the Caribbean countries, prevention of transfusion transmissible diseases requires special and different strategies due to several factors: the high prevalence of replacement donors, their specific geographical location, climate, genetic, and sociocultural status of the population make them vulnerable to endemic diseases such as dengue, malaria, and Chagas disease. Thus it is necessary to create local approaches to increase blood safety and achieve the goals set by the Pan American Health Organization. PMID- 24481435 TI - [Lyme disease: an update]. AB - Lyme disease is an emerging infection caused by the spirochete Borrelia burgdorferi. It is the most common vector-borne disease in the USA and Europe, and it is transmitted to humans through the bite of ticks of the genus Ixodes. Its animal reservoirs are the white-tailed deer, the white-footed mouse, and other small mammals. It is considered the new "great imitator", with its diagnosis being a major challenge. Traditionally it is divided into four stages, early localized disease, early disseminated, late disease, and the post-Lyme syndrome. Clinical manifestations may be both cutaneous and systemic, and can have cardiovascular, neurological, and musculoskeletal involvement. Diagnosis is based on clinical findings and can be confirmed by serologic studies (ELISA and Western Blot). The best preventive method is to avoid exposure to vectors. The aim of treatment with antibiotics (doxycycline and cephalosporins) is to relieve symptoms and prevent sequelae. PMID- 24481436 TI - [Trichoepithelioma: a retrospective study 1993-2012 - Dr Manuel Gea Gonzalez General Hospital]. AB - BACKGROUND: Trichoepithelioma is a benign follicular tumor, affects young female adults, and has three clinical forms: solitary, multiple, or desmoplastic. Diagnosis represents a clinical challenge for the dermatologist. There are many differential diagnoses, and the most important is basal cell carcinoma because they share histological features. It has good prognosis and therefore treatment is usually for aesthetic purposes, even though it is associated with recurrence. METHODS: This is a retrospective study carried out from January 1993 to December 2012 of all the patients who were diagnosed by histopathology to have trichoepithelioma in the dermatology department of the Dr. Manuel Gea Gonzalez General Hospital. RESULTS: There were 47 cases, of which 70.2% were female, with an average age of 43.6 years. Solitary trichoepithelioma was the most frequent clinical form (66%) and only three of 14 cases of multiple trichoepithelioma had a positive family history. PMID- 24481437 TI - [Multiple primary melanoma: a clinical case and review of the literature]. AB - Patients with a first primary melanoma are known to have an increased risk of being diagnosed with another primary melanoma. We present the case of a 42-year old male patient with multiple primary melanoma who was admitted to the dermatology department at the general hospital "Dr Manuel Gea Gonzalez" in Mexico City. Incidence, risk factors and prognosis are discussed in this review. PMID- 24481438 TI - [Successful home-made fecal transplant for an elderly woman]. AB - Recurrent clostridium difficile infection (CDI) is a challenge for infectious disease specialists. A third of first recurrences will fail antibiotic therapy. Several mechanisms have been proposed to explain this, such as persistence of spores, inadequate antibody response, and altered gut microbiota. Standard recommendations for CDI treatment include metronidazole and vancomycin. Fecal transplant has proven to be an effective therapy for recurrent CDI. Infusion of stools can be administered to the upper or lower gastrointestinal tract during an endoscopic procedure or using nasogastric/duodenal or rectal tubes. Elderly persons have an increased incidence of recurrent infection and have a higher mortality rate. We propose a home-based delivery method using a 5 ml syringe for intrarectal infusion of stools. PMID- 24481439 TI - [The undergraduate program in forensic science: a national challenge]. AB - The challenge in achieving an ideal state of justice is that each "proof" has the highest degree of reliability. This is the main responsibility of the forensic scientist. Up to now, criminal investigations in Mexico have been supported by forensic work from a wide variety of disciplinary backgrounds that give testimony in a particular area, even though they may have become forensic witnesses in a complementary and experiential manner. In January 2013, the Universidad Nacional Autonoma de Mexico (UNAM) approved the "Forensic Science" undergraduate program that, in collaboration with various academic entities and government institutions, will develop forensic scientists trained in science, law, and criminology. This is focused on contributing to the national demand that the justice system has more elements to procure and administer justice in dealing with crime. PMID- 24481440 TI - Novel osmotin attenuates glutamate-induced synaptic dysfunction and neurodegeneration via the JNK/PI3K/Akt pathway in postnatal rat brain. AB - The glutamate-induced excitotoxicity pathway has been reported in several neurodegenerative diseases. Molecules that inhibit the release of glutamate or cause the overactivation of glutamate receptors can minimize neuronal cell death in these diseases. Osmotin, a homolog of mammalian adiponectin, is a plant protein from Nicotiana tabacum that was examined for the first time in the present study to determine its protective effects against glutamate-induced synaptic dysfunction and neurodegeneration in the rat brain at postnatal day 7. The results indicated that glutamate treatment induced excitotoxicity by overactivating glutamate receptors, causing synaptic dysfunction and neuronal apoptosis after 4 h in the cortex and hippocampus of the postnatal brain. In contrast, post-treatment with osmotin significantly reversed glutamate receptor activation, synaptic deficit and neuronal apoptosis by stimulating the JNK/PI3K/Akt intracellular signaling pathway. Moreover, osmotin treatment abrogated glutamate-induced DNA damage and apoptotic cell death and restored the localization and distribution of p53, p-Akt and caspase-3 in the hippocampus of the postnatal brain. Finally, osmotin inhibited glutamate-induced PI3K-dependent ROS production in vitro and reversed the cell viability decrease, cytotoxicity and caspase-3/7 activation induced by glutamate. Taken together, these results suggest that osmotin might be a novel neuroprotective agent in excitotoxic diseases. PMID- 24481441 TI - Ibuprofen enhances the anticancer activity of cisplatin in lung cancer cells by inhibiting the heat shock protein 70. AB - Hsp70 is often overexpressed in cancer cells, and the selective cellular survival advantage that it confers may contribute to the process of tumour formation. Thus, the pharmacological manipulation of Hsp70 levels in cancer cells may be an effective means of preventing the progression of tumours. We found that the downregulation of Hsp70 by ibuprofen in vitro enhances the antitumoural activity of cisplatin in lung cancer. Ibuprofen prominently suppressed the expression of Hsp70 in A549 cells derived from lung adenocarcinoma and sensitized them to cisplatin in association with an increase in the mitochondrial apoptotic cascade, whereas ibuprofen alone did not induce cell death. The cisplatin-dependent events occurring up- and downstream of mitochondrial disruption were accelerated by treatment with ibuprofen. The increase in cisplatin-induced apoptosis caused by the depletion of Hsp70 by RNA interference is evidence that the increased apoptosis by ibuprofen is mediated by its effect on Hsp70. Our observations indicate that the suppression of Hsp70 by ibuprofen mediates the sensitivity to cisplatin by enhancing apoptosis at several stages of the mitochondrial cascade. Ibuprofen, therefore, is a potential therapeutic agent that might allow lowering the doses of cisplatin and limiting the many challenge associated with its toxicity and development of drug resistance. PMID- 24481443 TI - MiR-216a: a link between endothelial dysfunction and autophagy. AB - Endothelial dysfunction and impaired autophagic activity have a crucial role in aging-related diseases such as cardiovascular dysfunction and atherosclerosis. We have identified miR-216a as a microRNA that is induced during endothelial aging and, according to the computational analysis, among its targets includes two autophagy-related genes, Beclin1 (BECN1) and ATG5. Therefore, we have evaluated the role of miR-216a as a molecular component involved in the loss of autophagic function during endothelial aging. The inverse correlation between miR-216a and autophagic genes was conserved during human umbilical vein endothelial cells (HUVECs) aging and in vivo models of human atherosclerosis and heart failure. Luciferase experiments indicated BECN1, but not ATG5 as a direct target of miR 216a. HUVECs were transfected in order to modulate miR-216a expression and stimulated with 100 MUg/ml oxidized low-density lipoprotein (ox-LDL) to induce a stress repairing autophagic process. We found that in young HUVECs, miR-216a overexpression repressed BECN1 and ATG5 expression and the ox-LDL induced autophagy, as evaluated by microtubule-associated protein 1 light chain 3 (LC3B) analysis and cytofluorimetric assay. Moreover, miR-216a stimulated ox-LDL accumulation and monocyte adhesion in HUVECs. Conversely, inhibition of miR-216a in old HUVECs rescued the ability to induce a protective autophagy in response to ox-LDL stimulus. In conclusion, mir-216a controls ox-LDL induced autophagy in HUVECs by regulating intracellular levels of BECN1 and may have a relevant role in the pathogenesis of cardiovascular disorders and atherosclerosis. PMID- 24481442 TI - GLI2 induces genomic instability in human keratinocytes by inhibiting apoptosis. AB - Abnormal Sonic Hedgehog signalling leads to increased transcriptional activation of its downstream effector, glioma 2 (GLI2), which is implicated in the pathogenesis of a variety of human cancers. However, the mechanisms underlying the tumorigenic role of GLI2 remain elusive. We demonstrate that overexpression of GLI2-beta isoform, which lacks the N-terminal repressor domain (GLI2DeltaN) in human keratinocytes is sufficient to induce numerical and structural chromosomal aberrations, including tetraploidy/aneuploidy and chromosomal translocations. This is coupled with suppression of cell cycle regulators p21(WAF1/CIP1) and 14-3 3sigma, and strong induction of anti-apoptotic signalling, resulting in a reduction in the ability to eliminate genomically abnormal cells. Overexpression of GLI2DeltaN also rendered human keratinocytes resistant to UVB-mediated apoptosis, whereas inhibition of B-cell lymphoma 2 (BCL-2) restored endogenous (genomic instability (GIN)) and exogenous (UVB) DNA damage-induced apoptosis. Thus, we propose that ectopic expression of GLI2 profoundly affects the genomic integrity of human epithelial cells and contributes to the survival of progenies with genomic alterations by deregulating cell cycle proteins and disabling the apoptotic mechanisms responsible for their elimination. This study reveals a novel role for GLI2 in promoting GIN, a hallmark of human tumors, and identifies potential mechanisms that may provide new opportunities for the design of novel forms of cancer therapeutic strategies. PMID- 24481444 TI - Pro-apoptotic Sorafenib signaling in murine hepatocytes depends on malignancy and is associated with PUMA expression in vitro and in vivo. AB - The multi-kinase inhibitor Sorafenib increases the survival of patients with advanced hepatocellular carcinoma (HCC). Current data suggest that Sorafenib inhibits cellular proliferation and angiogenesis and promotes apoptosis. However, the underlying pro-apoptotic molecular mechanisms are incompletely understood. Here we compared the pro-apoptotic and anti-proliferative properties of Sorafenib in murine hepatoma cells and syngeneic healthy hepatocytes in vitro and in animal models of HCC and liver regeneration in vivo. In vitro, we demonstrate that cell cycle activity and expression of anti-apoptotic Bcl-2 like proteins are similarly downregulated by Sorafenib in Hepa1-6 hepatoma cells and in syngeneic primary hepatocytes. However, Sorafenib-mediated activation of caspase-3 and induction of apoptosis were exclusively found in hepatoma cells, but not in matching primary hepatocytes. We validated these findings in vivo by applying an isograft HCC transplantation model and partial hepatectomy (PH) in C57BL/6 mice. Sorafenib treatment activated caspase-3 and thus apoptosis selectively in small tumor foci that originated from implanted Hepa1-6 cells but not in surrounding healthy hepatocytes. Similarly, Sorafenib did not induce apoptosis after PH. However, Sorafenib treatment transiently inhibited cell cycle progression and resulted in mitotic catastrophe and enhanced non-apoptotic liver injury during regeneration. Importantly, Sorafenib-mediated apoptosis in hepatoma cells was associated with the expression of p53-upregulated-modulator-of-apoptosis (PUMA). In contrast, regenerating livers after PH revealed downregulation of PUMA and were completely protected from Sorafenib-mediated apoptosis. We conclude that Sorafenib induces apoptosis selectively in hepatoma cells but not in healthy hepatocytes and can additionally increase non-apoptotic hepatocyte injury in the regenerating liver. PMID- 24481445 TI - Macrophages commit postnatal endothelium-derived progenitors to angiogenesis and restrict endothelial to mesenchymal transition during muscle regeneration. AB - The damage of the skeletal muscle prompts a complex and coordinated response that involves the interactions of many different cell populations and promotes inflammation, vascular remodeling and finally muscle regeneration. Muscle disorders exist in which the irreversible loss of tissue integrity and function is linked to defective neo-angiogenesis with persistence of tissue necrosis and inflammation. Here we show that macrophages (MPs) are necessary for efficient vascular remodeling in the injured muscle. In particular, MPs sustain the differentiation of endothelial-derived progenitors to contribute to neo-capillary formation, by secreting pro-angiogenic growth factors. When phagocyte infiltration is compromised endothelial-derived progenitors undergo a significant endothelial to mesenchymal transition (EndoMT), possibly triggered by the activation of transforming growth factor-beta/bone morphogenetic protein signaling, collagen accumulates and the muscle is replaced by fibrotic tissue. Our findings provide new insights in EndoMT in the adult skeletal muscle, and suggest that endothelial cells in the skeletal muscle may represent a new target for therapeutic intervention in fibrotic diseases. PMID- 24481446 TI - A positive feedback loop between EBP2 and c-Myc regulates rDNA transcription, cell proliferation, and tumorigenesis. AB - The oncoprotein c-Myc is a key transcription factor with essential functions in the nucleolus (NO) to regulate ribosomal RNA (rRNA) synthesis, ribosome biogenesis, and cell proliferation. Yet, the mechanism that regulates the distribution and function of nucleolar c-Myc is still not completely understood. In this study, we identified nucleolar protein ENBA1 binding protein 2 (EBP2) as a novel functional binding partner of c-Myc. We found that coexpression of EBP2 markedly relocalized c-Myc from the nucleus to the NO, whereas depletion of EBP2 reduced the nucleolar distribution of c-Myc. Further study indicated that EBP2 is a direct binding partner of c-Myc and can block the degradation of c-Myc in a FBW7 (F-box and WD repeat domain containing 7)-independent manner. Moreover, EBP2 is a transcriptional target of c-Myc. c-Myc can bind to the promoter of EBP2 and positively regulate the EBP2 expression. Both protein and mRNA levels of EBP2 are upregulated in lung cancer samples and positively correlated with c-Myc expression. Functionally, EBP2 promotes c-Myc-mediated rRNA synthesis and cell proliferation. Collectively, our study indicates that EBP2 is a novel binding partner of c-Myc that regulates the function of nucleolar c-Myc, cell proliferation, and tumorigenesis via a positive feedback loop. PMID- 24481447 TI - CDK5-induced p-PPARgamma(Ser 112) downregulates GFAP via PPREs in developing rat brain: effect of metal mixture and troglitazone in astrocytes. AB - The peroxisome proliferator-activated receptor gamma (PPARgamma), a group of ligand-activated transcriptional factors, is expressed in glial fibrillary acidic protein (GFAP)-immunoreactive astrocytes. Here, we investigated the role of PPARgamma in regulating GFAP using a mixture of As, Cd and Pb (metal mixture, MM) that induces apoptosis and aberrant morphology in rat brain astrocytes. We observed a phospho PPARgamma (serine 112 (S112)) (p-PPARgamma (S112))-mediated downregulation of GFAP in the MM-exposed astrocytes. We validated this using pure PPARgamma agonist, troglitazone (TZ). As reported with MM, TZ induced astrocyte damage owing to reduced GFAP. In silico analysis in the non-coding region of GFAP gene revealed two PPARgamma response elements (PPREs); inverted repeat 10 and direct repeat 1 sequences. Gel shift and chromatin immunoprecipitation assays demonstrated enhancement in binding of p-PPARgamma (S112) to the sequences, and luciferase reporter assay revealed strong repression of GFAP via PPREs, in response to both MM and TZ. This indicated that suppression in GFAP indeed occurs through direct regulation of these elements by p-PPARgamma (S112). Signaling studies proved that MM, as well as TZ, activated the cyclin-dependent kinase 5 (CDK5) and enhanced its interaction with PPARgamma resulting into increased p PPARgamma (S112). The p-CDK5 levels were dependent on proximal activation of extracellular signal-regulated protein kinase 1/2 and downstream Jun N-terminal kinase. Taken together, these results are the first to delineate downregulation of GFAP through genomic and non-genomic signaling of PPARgamma. It also brings forth a resemblance of TZ with MM in terms of astrocyte disarray in developing brain. PMID- 24481448 TI - miR-1207-5p and miR-1266 suppress gastric cancer growth and invasion by targeting telomerase reverse transcriptase. AB - hTERT is the catalytic subunit of the telomerase complex. Elevated expression of hTERT is associated with the expansion and metastasis of gastric tumor. In this study, we aimed to identify novel tumor suppressor miRNAs that restrain hTERT expression. We began our screen for hTERT-targeting miRNAs with a miRNA microarray. miRNA candidates were further filtered by bioinformatic analysis, general expression pattern in different cell lines, gain-of-function effects on hTERT protein and the potential of these effects to suppress hTERT 3' untranslated region (3'UTR) luciferase activity. The clinical relevance of two miRNAs (miR-1207-5p and miR-1266) was evaluated by real-time RT-PCR. The effects of these miRNAs on cell growth, cell cycle and invasion of gastric cancer cells were measured with CCK-8, flow cytometry and transwell assays. Finally, the ability of these miRNAs to suppress the transplanted tumors was also investigated. Fourteen miRNAs were identified using a combination of bioinformatics and miRNA microarray analysis. Of these fourteen miRNAs, nine were expressed at significantly lower levels in hTERT-positive cell lines compared with hTERT-negative cell lines and five could downregulate hTERT protein expression. Only miR-1207-5p and miR-1266 interacted with the 3' UTR of hTERT and the expression levels of these two miRNAs were significantly decreased in gastric cancer tissues. These two miRNAs also inhibited gastric tumor growth in vitro and in vivo. Altogether, miR-1207-5p and miR-1266 were determined to be hTERT suppressors in gastric cancer, and the delivery of these two miRNAs represents a novel therapeutic strategy for gastric cancer treatment. PMID- 24481449 TI - CD70-restricted specific activation of TRAILR1 or TRAILR2 using scFv-targeted TRAIL mutants. AB - To combine the CD27 stimulation inhibitory effect of blocking CD70 antibodies with an antibody-dependent cellular cytotoxicity (ADCC)-independent, cell death inducing activity for targeting of CD70-expressing tumors, we evaluated here fusion proteins of the apoptosis-inducing TNF family member TRAIL and a single chain variable fragment (scFv) derived from a high-affinity llama-derived anti human CD70 antibody (lalphahCD70). A fusion protein of scFv:lalphahCD70 with TNC TRAIL, a stabilized form of TRAIL, showed strongly enhanced apoptosis induction upon CD70 binding and furthermore efficiently interfered with CD70-CD27 interaction. Noteworthy, introduction of recently identified mutations that discriminate between TRAILR1 and TRAILR2 binding into the TRAIL part of scFv:lalphahCD70-TNC-TRAIL resulted in TRAIL death receptor-specific fusion proteins with CD70-restricted activity. PMID- 24481450 TI - Control of glioma cell death and differentiation by PKM2-Oct4 interaction. AB - Glioma stem cells are highly resistant to cell death and as such are supposed to contribute to tumor recurrence by eluding anticancer treatments. Here, we show that spheroids that contain rat neural stem cells (NSCs) or rat glioma stem cells (cancer stem cells, CSCs) express isoforms 1 and 2 of pyruvate kinase (PKM1 and PKM2); however, the expression of PKM2 is considerably higher in glioma spheroids. Silencing of PKM2 enhances both apoptosis and differentiation of rat and human glioma spheroids. We establish that PKM2 was implicated in glioma spheroid differentiation through its interaction with Oct4, a major regulator of self-renewal and differentiation in stem cells. The small molecule Dichloroacetate (DCA), a pyruvate dehydrogenase kinase inhibitor, increases the amount of PKM2/Oct4 complexes and thus inhibited Oct4-dependent gene expression. Taken together, our results highlight a new molecular pathway through which PKM2 can manage gliomagenesis via the control of glioma stemness by Oct4. PMID- 24481451 TI - The use of a neutral peptide aptamer scaffold to anchor BH3 peptides constitutes a viable approach to studying their function. AB - The B-cell CLL/lymphoma-2 (Bcl-2) family of proteins are important regulators of the intrinsic pathway of apoptosis, and their interactions, driven by Bcl-2 homology (BH) domains, are of great interest in cancer research. Particularly, the BH3 domain is of clinical relevance, as it promotes apoptosis through activation of Bcl-2-associated x protein (Bax) and Bcl-2 antagonist killer (Bak), as well as by antagonising the anti-apoptotic Bcl-2 family members. Although investigated extensively in vitro, the study of the BH3 domain alone inside cells is more problematic because of diminished secondary structure of the unconstrained peptide and a lack of stability. In this study, we report the successful use of a novel peptide aptamer scaffold - Stefin A quadruple mutant - to anchor and present the BH3 domains from Bcl-2-interacting mediator of cell death (Bim), p53 upregulated modulator of apoptosis (Puma), Bcl-2-associated death promoter (Bad) and Noxa, and demonstrate its usefulness in the study of the BH3 domains in vivo. When expressed intracellularly, anchored BH3 peptides exhibit much the same binding specificities previously established in vitro, however, we find that, at endogenous expression levels, Bcl-2 does not bind to any of the anchored BH3 domains tested. Nonetheless, when expressed inside cells the anchored PUMA and Bim BH3 alpha-helices powerfully induce cell death in the absence of efficient targeting to the mitochondrial membrane, whereas the Noxa helix requires a membrane insertion domain in order to kill Mcl-1-dependent myeloma cells. Finally, the binding of the Bim BH3 peptide to Bax was the only interaction with a pro-apoptotic effector protein observed in this study. PMID- 24481452 TI - The aryl hydrocarbon receptor mediates raloxifene-induced apoptosis in estrogen receptor-negative hepatoma and breast cancer cells. AB - Identification of new molecular targets for the treatment of breast cancer is an important clinical goal, especially for triple-negative breast cancer, which is refractory to existing targeted treatments. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor known primarily as the mediator of dioxin toxicity. However, the AhR can also inhibit cellular proliferation in a ligand-dependent manner and act as a tumor suppressor in mice, and thus may be a potential anticancer target. To investigate the AhR as an anticancer target, we conducted a small molecule screen to discover novel AhR ligands with anticancer properties. We identified raloxifene, a selective estrogen receptor (ER) modulator currently used in the clinic for prevention of ER-positive breast cancer and osteoporosis in post-menopausal women, as an AhR activator. Raloxifene directly bound the AhR and induced apoptosis in ER-negative mouse and human hepatoma cells in an AhR-dependent manner, indicating that the AhR is a molecular target of raloxifene and mediates raloxifene-induced apoptosis in the absence of ER. Raloxifene selectively induced apoptosis of triple-negative MDA-MB-231 breast cancer cells compared with non-transformed mammary epithelial cells via the AhR. Combined with recent data showing that raloxifene inhibits triple-negative breast cancer xenografts in vivo (Int J Oncol. 43(3):785-92, 2013), our results support the possibility of repurposing of raloxifene as an AhR-targeted therapeutic for triple-negative breast cancer patients. To this end, we also evaluated the role of AhR expression on survival of patients diagnosed with breast cancer. We found that higher expression of the AhR is significantly associated with increased overall survival and distant metastasis-free survival in both hormone-dependent (ER-positive) and hormone-independent (ER and progesterone receptor (PR) negative) breast cancers. Together, our data strongly support the possibility of using the AhR as a molecular target for the treatment of hormone-independent breast cancers. PMID- 24481453 TI - Roles of Wnt/beta-catenin signaling in the gastric cancer stem cells proliferation and salinomycin treatment. AB - The Wnt1 protein, a secreted ligand that activates Wnt signaling pathways, contributes to the self-renewal of cancer stem cells (CSCs) and thus may be a major determinant of tumor progression and chemoresistance. In a series of gastric cancer specimens, we found strong correlations among Wnt1 expression, CD44 expression, and the grade of gastric cancer. Stable overexpression of Wnt1 increased AGS gastric cancer cells' proliferation rate and spheroids formation, which expressed CSC surface markers Oct4 and CD44. Subcutaneous injection of nude mice with Wnt1-overexpressing AGS cells resulted in larger tumors than injection of control AGS cells. Salinomycin, an antitumor agent, significantly reduced the volume of tumor caused by Wnt1-overexpressing AGS cells in vivo. This is achieved by inhibiting the proliferation of CD44+Oct4+ CSC subpopulation, at least partly through the suppression of Wnt1 and beta-catenin expression. Taken together, activation of Wnt1 signaling accelerates the proliferation of gastric CSCs, whereas salinomycin acts to inhibit gastric tumor growth by suppressing Wnt signaling in CSCs. These results suggest that Wnt signaling might have a critical role in the self-renewal of gastric CSCs, and salinomycin targeting Wnt signaling may have important clinical applications in gastric cancer therapy. PMID- 24481454 TI - Zinc depletion regulates the processing and secretion of IL-1beta. AB - Sterile inflammation contributes to many common and serious human diseases. The pro-inflammatory cytokine interleukin-1beta (IL-1beta) drives sterile inflammatory responses and is thus a very attractive therapeutic target. Activation of IL-1beta in sterile diseases commonly requires an intracellular multi-protein complex called the NLRP3 (NACHT, LRR, and PYD domains-containing protein 3) inflammasome. A number of disease-associated danger molecules are known to activate the NLRP3 inflammasome. We show here that depletion of zinc from macrophages, a paradigm for zinc deficiency, also activates the NLRP3 inflammasome and induces IL-1beta secretion. Our data suggest that zinc depletion damages the integrity of lysosomes and that this event is important for NLRP3 activation. These data provide new mechanistic insight to how zinc deficiency contributes to inflammation and further unravel the mechanisms of NLRP3 inflammasome activation. PMID- 24481458 TI - Fat mass- and obesity-associated (FTO) gene and antipsychotic-induced weight gain: an association study. AB - OBJECTIVES: Genetic variation in the fat mass- and obesity-associated gene (FTO) has been associated with obesity in the general population. In this study we have investigated these variants for association with antipsychotic-induced weight gain (AIWG). METHODS: A total of 218 patients with chronic schizophrenia or schizoaffective disorder treated mostly with clozapine or olanzapine for up to 14 weeks were included in the study. We analyzed 4 polymorphisms in intron 1 of the FTO gene (rs1421085, rs8050136, rs9939609, rs9930506) for association with AIWG using ANCOVA. RESULTS: No statistically significant associations were observed between the single nucleotide polymorphisms and AIWG. However, patients homozygous for the A-allele of rs9939609 gained numerically higher weight than the other genotypic groups (AA: 5.26 +/- 6.7%; TA: 4.66 +/- 5.6%; TT: 4.21 +/- 5.3%). CONCLUSION: Our current observations suggest that the FTO gene variants investigated may not play a major role in AIWG. PMID- 24481457 TI - Plasminogen activator urokinase expression reveals TRAIL responsiveness and supports fractional survival of cancer cells. AB - Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL/TNFSF10/Apo2L) holds promise for cancer therapy as it induces apoptosis in a large variety of cancer cells while exerting negligible toxicity in normal ones. However, TRAIL can also induce proliferative and migratory signaling in cancer cells resistant to apoptosis induced by this cytokine. In that regard, the molecular mechanisms underlying the tumor selectivity of TRAIL and those balancing apoptosis versus survival remain largely elusive. We show here that high mRNA levels of PLAU, which encodes urokinase plasminogen activator (uPA), are characteristic of cancer cells with functional TRAIL signaling. Notably, decreasing uPA levels sensitized cancer cells to TRAIL, leading to markedly increased apoptosis. Mechanistic analyses revealed three molecular events taking place in uPA-depleted cells: reduced basal ERK1/2 prosurvival signaling, decreased preligand decoy receptor 2 (DcR2)-death receptor 5 (DR5) interaction and attenuated recruitment of DcR2 to the death-inducing signaling complex upon TRAIL challenge. These phenomena were accompanied by increased FADD and procaspase-8 recruitment and processing, thus guiding cells toward a caspase-dependent cell death that is largely independent of the intrinsic apoptosis pathway. Collectively, our results unveil PLAU mRNA levels as marker for the identification of TRAIL-responsive tumor cells and highlight a key role of uPA signaling in 'apoptosis versus survival' decision making processes upon TRAIL challenge. PMID- 24481459 TI - Silencing the receptor of activated C-kinase 1 (RACK1) suppresses tumorigenicity in epithelial ovarian cancer in vitro and in vivo. AB - Epithelial ovarian cancer (EOC) is a fatal disease for women due to lack of effective diagnostic biomarkers and therapeutic targets. Thus, it is important to identify and develop specific markers to formulate novel therapeutic methods for advanced and recurrent ovarian cancer. We found that the receptor of activated C kinase 1 (RACK1) was elevated in most EOCs compared to normal ovarian tissue, and its expression levels correlated with key pathological characteristics including clinical stage and metastasis by quantitative PCR and immunohistochemistry. In addition, we found that downregulation of RACK1 expression using an RNA silencing approach in SKVO3 tumor cells significantly suppressed the proliferation, migration and invasion in vitro and tumor growth in vivo. Furthermore, it is found that RACK1 silencing was able to significantly suppress constitutive phosphorylation of Akt and MAPK, which may contribute to the inhibition of tumor growth. These results suggest that RACK1 can act as a new promising diagnostic biomarker and a potential anticancer therapeutic target for EOC. PMID- 24481460 TI - ZNF703 acts as an oncogene that promotes progression in gastric cancer. AB - ZNF703, a member of the NET/Nlz family of zinc finger transcription factors, contributes to aspects of developmental growth and patterning across evolutionarily diverse species. ZNF703 has been identified as a novel oncogene in human breast cancer. In the present study, we investigated the expression of ZNF703 in gastric carcinoma and attempted to determine, using cell line models, its biological actions. Using immunohistochemistry, we analyzed the ZNF703 protein expression in 120 clinicopathologically characterized gastric cancer cases. Using RNA interference, we investigated the effects of ZNF703 depletion on tumor proliferation and metastasis in vitro. We found that ZNF703 was overexpressed in invasive gastric carcinoma tissues, and its expression levels were closely correlated with the depth of invasion, node metastasis and venous invasion. RNA interference-mediated silencing of the ZNF703 gene in SGC7901 cells inhibited cell proliferation and migration significantly. The results showed that ZNF703 acts as a gastric cancer oncogene and should be considered a therapeutic target for metastatic gastric cancer. PMID- 24481461 TI - Stimulation of beta-catenin and colon cancer cell growth by the KDM4B histone demethylase. AB - The linchpin of colorectal cancer is the oncoprotein and transcriptional cofactor beta-catenin, whose overexpression is causative for the neoplastic transformation of colon cells. However, the molecular details of beta-catenin dependent gene transcription in cancer cells are still not comprehensively explored. Here, we show that the histone demethylase KDM4B was upregulated in colon and rectal adenocarcinomas and required for efficient growth and clonogenic activity of human HT-29 colon cancer cells. Moreover, KDM4B formed complexes with beta catenin in vitro and in vivo, which involved its central amino acids 353-740. In addition, KDM4B also interacted with the DNA-binding protein TCF4, which is the main factor recruiting beta-catenin to chromatin in the intestine. KDM4B downregulation resulted in reduced expression of the beta-catenin/TCF4 target genes JUN, MYC and Cyclin D1, all of which encode for oncoproteins. Collectively, our data indicate that KDM4B overexpression supports beta-catenin mediated gene transcription and thereby contributes to the genesis of colorectal tumors. Accordingly, inhibition of the KDM4B histone demethylase may represent a novel avenue of fighting colorectal cancer, one of the major causes of cancer death throughout the world. PMID- 24481462 TI - Comprehensive prospective cognitive and physical function assessment in elderly patients undergoing transcatheter aortic valve implantation. AB - OBJECTIVE: Transcatheter aortic valve implantation (TAVI) is occasionally associated with stroke and silent cerebral ischemia, which may affect cognitive and functional performance. The aim of this study was to evaluate the changes in cognitive performance and functional status following TAVI. METHODS: We performed a comprehensive prospective functional, cognitive and quality of life (QOL) evaluation in consecutive patients who underwent TAVI using the CoreValve device (Medtronic Inc.). The evaluation was performed at baseline and 1 month after the procedure and included the 36-item Short-Form Health Survey for QOL assessment, Mini-Mental State Examination (MMSE), quantitative clock drawing test (Rouleau), color trails test, Cognistat evaluation, Barthel Index and Duke Activity Status Index. RESULTS: A total of 36 patients completed the full pre- and post-TAVI evaluation. Mean age was 82.2 +/- 4.2 years (52.8% men); 94.5% of patients had low functional class (New York Heart Association III/IV), and 13.9% had prior stroke. After the procedure, all patients had improved functional status and valve hemodynamics. At 1 month, there was a significant improvement in the MMSE and Cognistat evaluations (from 25.9 +/- 3.3 to 27.6 +/- 2.4, p < 0.001, and from 5 +/- 1 to 5.7 +/- 0.7, p = 0.001, respectively). CONCLUSIONS: Our preliminary results of a comprehensive assessment of patients undergoing TAVI indicate favorable results for both functional performance and cognitive function early after the procedure. PMID- 24481465 TI - Effects of abscisic acid on nucleic acid metabolism in maize coleoptiles. AB - Following treatment with ABA an inhibition of total RNA synthesis was observed after 30 hours. Total soluble ribonuclease activity did not change during the first 8 hours, after which an increase could be observed.Separation of nucleic acids with polyacrylamide gel electrophoresis indicated that synthesis of soluble RNA was less inhibited by ABA than synthesis of ribosomal RNA.Effects of 5-FU and ABA on ribosomal RNA precursor were investigated. It could be shown that 5-FU did not inhibit ribosomal precursor synthesis, but that ABA did so. PMID- 24481463 TI - Copper-mediated cross-coupling-cyclization-oxidation: a one-pot reaction to construct polysubstituted pyrroles. AB - A novel and efficient procedure for the synthesis of polysubstituted pyrroles has been developed in this work. The polysubsituted pyrroles were synthesized directly from terminal alkenes, amines and beta-keto esters through cross coupling-cyclization-oxidation in the presence of a catalytic amount of cuprous chloride. This method provides a one-pot synthesis route from terminal alkenes to polysubstituted pyrroles for the first time and opens a new area in cuprous catalysis. PMID- 24481466 TI - Effects of abscisic acid on the soluble RNA polymerase activity in maize coleoptiles. AB - Effects of abscisic acid (ABA) on the polymerase activity have been investigated. The specific activity of the RNA polymerase enzyme decreased when coleoptiles were preincubated for 6 hours or longer in 3.8*10(-5)M ABA. Inhibition of RNA synthesis could however already be detected after 3 hours ABA treatment.Inclusion of (RS) cis-trans ABA in the grinding medium decreased the polymerase activity; inclusion of (RS) trans-trans ABA in the medium only had a small effect on the activity. Addition of (RS) cis-trans and (RS) trans-trans ABA to the RNA polymerase assay system also gave a slight inhibition of activity.The strong inhibition when (RS) cis-trans ABA was included in the grinding medium indicates that the hormone interacts with an activator molecule which is not present in the partly purified RNA polymerase solution.It is suggested that ABA may have more than one mode of action. PMID- 24481467 TI - Flower inhibition in Kalanchoe blossfeldiana. Bioassay of an endogenous long-day inhibitor and inhibition by (+/-) abscisic acid and xanthoxin. AB - The inhibition of flowering in Kalanchoe by crude sap expressed from leaves held in non-inductive long-day conditions is described, using a bioassay technique of leaf injection, which confirms the existence of a transferable inhibitor.This technique has also revealed that +/- abscisic acid and Xanthoxin are inhibitory to flowering at 50 and 100 ppm respectively. The previously known inhibitory effects of gibberellic acid on flowering have also been confirmed. PMID- 24481468 TI - The influence of blue light on dark-germinating seeds of Nemophila insignis. AB - After inhibition of Nemophila insignis seeds by far-red (FR) light, a short exposure to blue (Bl) will not induce germination again but stimulation by red (R), with reversion by FR, can be observed. Germination is inhibited by long exposures to Bl (maxima at 455 and 475 nm). These radiations are absorbed either directly by phytochrome or through intermediary pigments such as flavoproteins. PMID- 24481469 TI - Relationship between transport and metabolism of alpha-naphthaleneacetic acid, beta-naphthaleneacetic acid and alpha-decalylacetic acid in segments of Coleus. AB - Transportand metabolism of alpha-naphthaleneacetic acid beta-naphthaleneacetic acid, and alpha-decalylacetic acid, all labelled with (14)C in the carboxyl, group, were studied. Only alpha-naphthaleneacetic acid is transported in a polar way. Most of the radioactivity in the tissue is in a low molecular form, either free or as immobilization products. The immobilization of beta-naphthaleneacetic acid is similar to that of alpha-naphthaleneacetic acid. Immobilization of alpha decalylacetic acid is typically different. Bioassays showed alpha naphthaleneacetic acid as the sole biologically active component. It is concluded that stereo requirements necessary for biological activity are also required for polar auxin transport. It is further concluded that the observed specificity of the transport system is not related to the formation of immobilization products. PMID- 24481470 TI - Metabolism of indole-3-acetaldoxime in plants. AB - Living tissues of diverse plants representing 17 families were infiltrated with indole-3-acetaldoxime (IAAld oxime) in phosphate buffer, pH 6, and incubated for 3 hours at 25 degrees C. Indole compounds were then extracted, separated and identified by paper or thin-layer chromatography (TLC). Indole-3-acetic acid (IAA) was quantitatively determined. Every tissue tested converted the oxime to IAA and tryptophol (T-ol). While accumulation of indole-3-acetonitrile (IAN) was observed in the non-acidic fractions of extracts of tissues of 8 species, indole 3-acetaldehyde (IAAld) accumulated in only a single tissue viz. Amaranthus shoot.IAAld oxime undergoes spontaneous hydrolysis at pH values below 4.7 leading to the formation of IAAld. Ce l-free preparations of etiolated Avena coleoptiles appear to contain an enzyme system capable of hydrolysing the oxime to IAAld. In the presence of such preparations, more IAAld and IAA are formed at all tested durations than the spontaneously formed IAAld. In the presence of bisulfite or semicarbazide, no IAA is formed, suggesting the intermediary formation of IAAld. The compound trapped with sodium bisulfite resembles very closely synthetic IAAld in its IR spectrum.In intact tissues, therefore, IAAld oxime appears to be first hydrolysed to IAAld which is then partly oxidized to IAA and mostly reduced to T ol. Besides other evidence, formation of T-ol in every instance is believed to indicate the intermediary formation of IAAld. The nitrile pathway is considered to be only of minor importance in normal IAA biogenesis in the majority of higher plants. PMID- 24481471 TI - [CO2-fixation and translocation in benthic marine algae : I. Kinetics of (14)CO 2 assimilation in Laminaria saccharina]. AB - When discs punched out of the median part of the phylloid of Laminaria saccharina Lamour. were exposed to H(14)CO3 (-) in the light for periods of 10 sec to 10 min, (14)C was rapidly incorporated into various photosynthetic products. As compared with dark fixation, (14)C-photosynthesis increased exponentially during the first 60 sec of incubation in H(14)CO3 (-). Fixation rates were found to be 76 MUmol CO2.dm(-2).h(-1) or 100 MUmol CO2.mg(-1) chlorophyll a.h(-1). Eighty five per cent of the total (14)C assimilated after 10 sec was fixed in phosphoglycerate and in the sugar monophosphates, 2% in the sugar diphosphates, and only 3.5% in malate and aspartate. While the radioactivity of malate and aspartate only rose to a constant level, the percentage of the total (14)C in phosphoglycerate and-to a lower extent-that in the sugar monophosphates rapidly decreased with the duration of light exposure. Simultaneously, mannitol and glycine+serine became labelled with 43% and 32% respectively of the total (14)C after 10 min light fixation. In the dark, the percentage of the total (14)C in malate decreased with the time of H(14)CO(2-)-incubation, while there was a remarkable increase in radioactivity of aspartate and glutamate. Within 60 min darkness no labelling of mannitol was found.From the present results it is concluded that the photosynthetic carbon cycle first described by Bassham and Calvin operates in Laminaria saccharina. PMID- 24481472 TI - [The lag-phase of the effect of 5-FUDR on the DNA-synthesis and elongation growth in Sinapis alba]. AB - In the seedlings of Sinapis alba, the lag-phase between the application of 5-FUDR and the beginning of the inhibition of elongation growth and the inhibition of DNA-synthesis has been studied. The elongation was retarded after 7 h, and then, depending on the concentration of the FUDR, was completely stopped. In the cotyledons the DNA-synthesis was strongly reduced after about 50 minutes, and in the hypocotyls a lag-phase of less than 30 minutes was observed. With the addition of thymidine the DNA-synthesis was immediately resumed, while the growth began with a lag-phase of 5-7 h. In every case the change in the DNA-synthesis preceded the change in the elongation growth. The inhibition of elongation growth could, therefore, be the consequence of inhibition of DNA-synthesis. PMID- 24481473 TI - [Occurrence and localization of a flavonol-converting enzyme in plants]. AB - The occurrence and distribution of an enzyme converting flavonols to 2,3 dihydroxy flavanones has been measured in various plants and found to occur in all plants tested.In garbanzo bean, Cicer arietinum L., the enzyme is found mainly in roots, hypocotyls, epicotyls and cytoledons while the other organs, rich in flavonols, possess much lower levels of the enzyme. In garbanzo seedlings the enzyme is formed between the second and sixth day after germination and appears parallel to the phenylalanine ammonia-lyase. The data indicate that the enzymes for both flavonol biosynthesis and turnover are formed simultaneously. These results further support earlier observations that regulation of flavonoid formation and regulation of turnover seem to be dependent on each other.The activity of the flavonol-converting enzyme does not increase in Cicer arietinum plants transferred to darkness though under such conditions flavonol turnover is accelerated.In Pisum sativum, Glycine max and Sinapis alba the flavonol converting enzyme is more evenly distributed over all organs, so that a correlation between flavonol content and enzyme is less obvious.The data are discussed with respect to intracellular regulation of flavonol turnover. PMID- 24481474 TI - Carotenoid pigments in the Bryum ventricosum Dicks 1785 from the Pletvicki Lakes (Yugoslavia). AB - Investigations have been carried out on the carotenoids in Bryum ventricosum Dicks (Bryophyta) from the Pletwicki Lakes (Yugoslavia). The presence of the carotenoids alpha-carotene, cryptoxanthin, lutein (epoxy and free), zeaxanthin, violaxanthin, and neoxanthin was determined by means of column and thin-layer chromatography. PMID- 24481475 TI - A nickel-accumulating plant from Western Australia. AB - A small shrub Hybanthus floribundus (Lindl.) F. Muell. Violaceae growing in Western Australia accumulates nickel and cobalt to a very high degree. Values of up to 23% nickel in leaf ash may represent the highest relative accumulation of a metal on record. The high accumulation of nickel poses interesting problems in plant physiology and plant biochemistry. PMID- 24481476 TI - Safety and effectiveness of endovascular treatment of stroke with unknown time of onset. AB - BACKGROUND: Currently, treatment options for patients with strokes with unknown time of onset (UKO) remain limited. With the advance of neuroimaging and endovascular treatment (EVT), selected patients might have a chance of a therapeutic option. We sought to compare clinical outcome after EVT in patients with known time of stroke onset (KO) and in those with UKO. METHODS: We prospectively registered consecutive patients with acute large artery occlusion of the anterior territory who underwent EVT. Multimodal MR or Alberta Stroke Program early CT score (ASPECTS) and transcranial color-coded Duplex sonography were used to select patients for EVT. Recanalization, periprocedural complications, intracranial hemorrhage (ICH) and outcome were recorded. Symptomatic ICH (sICH) was defined as a worsening of >=4 points in the National Institutes of Health Stroke Scale (NIHSS) score within 36 h in any bleeding. Favorable outcome was defined as a modified Rankin score <=2 at 3 months. RESULTS: A total of 141 patients were studied, 109 with KO and 32 with UKO. Mean age was 66.5 versus 64.7 years (p = 0.005) and median baseline NIHSS was 18 versus 17 (p = 0.095), respectively. Prior IV tPA was more frequently administered to KO patients (62.4 vs. 9.4%, p < 0.001), whereas patient selection using multimodal MR was more frequent in patients with UKO (78.1 vs. 45.4%, p < 0.001). Median time from stroke onset or from the last time the patient was seen well to groin puncture and to recanalization was significantly longer in patients with UKO, but no differences were found in the duration of the procedure. For KO/UKO patients recanalization was seen in 77.1 vs. 65.7% (p = 0.084), sICH occurred in 10 versus 0% (p = 0.061) and favorable outcome at 3 months was achieved in 41.3 versus 50% (p = 0.382), respectively. CONCLUSIONS: Clinical outcomes in this series of EVT in ischemic stroke patients due to large anterior arterial occlusion with salvageable brain are similar for patients treated with KO and UKO. These data support a randomized study of EVT in extended or uncertain time windows.. PMID- 24481477 TI - Natural product biosynthesis in Medicago species. AB - The genus Medicago, a member of the legume (Fabaceae) family, comprises 87 species of flowering plants, including the forage crop M. sativa (alfalfa) and the model legume M. truncatula (barrel medic). Medicago species synthesize a variety of bioactive natural products that are used to engage into symbiotic interactions but also serve to deter pathogens and herbivores. For humans, these bioactive natural products often possess promising pharmaceutical properties. In this review, we focus on the two most interesting and well characterized secondary metabolite classes found in Medicago species, the triterpene saponins and the flavonoids, with a detailed overview of their biosynthesis, regulation, and profiling methods. Furthermore, their biological role within the plant as well as their potential utility for human health or other applications is discussed. Finally, we give an overview of the advances made in metabolic engineering in Medicago species and how the development of novel molecular and omics toolkits can influence a better understanding of this genus in terms of specialized metabolism and chemistry. Throughout, we critically analyze the current bottlenecks and speculate on future directions and opportunities for research and exploitation of Medicago metabolism. PMID- 24481478 TI - A triarylboron-based fluorescent temperature indicator: sensitive both in solid polymers and in liquid solvents. AB - A novel triarylboron compound, MPB, exhibiting reversible thermochromic dual fluorescence in solid-state polymers and in liquid solvents was designed and synthesized. The fluorescent solid-state polymer with MPB can serve as a highly sensitive self-reference temperature indicator with a concentration independent feature. PMID- 24481480 TI - Preferred binding of gain-of-function mutant p53 to bidirectional promoters with coordinated binding of ETS1 and GABPA to multiple binding sites. AB - Gain-of-function mutant p53 is thought to induce gene expression in part by binding transcription factors bound to promoters for genes that mediate oncogenesis. We investigated the mechanism of mutant p53 binding by mapping the human genomic binding sites for p53 R273H using ChIP-Seq and showed them to localize to ETS DNA sequence motifs and locations with ETS1 and GABPA binding, both within promoters and distal to promoters. Strikingly, p53 R273H showed statistically significant and substantial binding to bidirectional promoters, which are enriched for inverted repeated ETS DNA sequence motifs. p53 R273H exhibited an exponential increase in probability of binding promoters with a higher number of ETS motifs. Both ETS1 and GABPA also showed an increase in the probability of binding to promoters with a higher number of ETS motifs. However, despite this increase in probability of binding by p53 R273H and ETS1, there was no increase in the binding signal, suggesting that the number of ETS1 and p53 R273H proteins bound per promoter is being limited. In contrast, GABPA did exhibit an increase in binding signal with higher numbers of ETS motifs per promoter. Analysis of the distance between inverted pairs of ETS motifs within promoters and binding by p53 R273H, ETS1 and GABPA, showed a novel coordination of binding for the three proteins. Both ETS1 and p53 R273H exhibited preference for binding promoters with distantly spaced ETS motifs in face-to-face and back to-back orientations, and low binding preference to promoters with closely spaced ETS motifs. GABPA exhibited the inverse pattern of binding by preferring to bind promoters with closely spaced ETS motifs. Analysis of the helical phase between ETS motifs showed that ETS1 and p53 R273H exhibited a low preference for binding promoters with ETS motifs on the same face of the DNA helix. We propose a model for the binding of ETS1 and p53 R273H in which two inverted ETS motifs on a looped DNA helix are juxtaposed for ETS1 binding as a homodimer, with p53 R273H bound to ETS1. We propose that the formation of this DNA loop and protein-bound complex prevents additional binding of ETS1 and p53 R273H proteins to other proximal binding sites. PMID- 24481481 TI - Upgrading of residues of bracts, stems and hearts of Cynara cardunculus L. var. scolymus to functional fractions enriched in soluble fiber. AB - Since only the central portion of the immature flowers of artichoke (Cynara cardunculus L. var. scolymus) is consumed (<20%) it is interesting to upgrade its residues to render value added products. In this research, bracts (B), hearts (H) or stems (S) were used to isolate fractions enriched in soluble fiber. Extraction was performed in citrate buffer with or without hemicellulase. Additionally, the effect of preheating (70 degrees C - 5 min) prior to extraction was also tested. Polysaccharides were precipitated with ethanol and the fractions obtained were freeze-dried. The presence of the enzyme increased fiber yields and preheating produced an additional increment, especially from stems (~21%). Isolated fibers were constituted by 70-84% of carbohydrates and 2-25% of proteins, and contained phenolics (2.1-8.2 g/100 g). Carbohydrates included uronic acids (12-25%) and neutral sugars (NS, 4-55%) of pectins, and inulin (13-55%). The lowest protein and NS contents and the highest inulin content were obtained with the enzyme and preheating. The behavior of fractions isolated with higher yields was characterized, observing a pseudoplastic behavior in water and gelation with Ca(2+). They also showed antioxidant activity and an inhibitory effect against herpes simplex virus type 1 without cytotoxicity. The isolated fractions retaining bioactive compounds can be useful as functional food ingredients. PMID- 24481482 TI - Intraspecific mass scaling of metabolic rates in grass carp (Ctenopharyngodon idellus). AB - We assessed the intraspecific mass scaling of standard metabolic rate (SMR), maximum metabolic rate (MMR), excess post-exercise oxygen consumption (EPOC), and erythrocyte size in grass carp (Ctenopharyngodon idellus), with body masses ranging from 4.0 to 459 g. SMR and MMR scaled with body mass with similar exponents, but neither exponent matched the expected value of 0.75 or 1, respectively. Erythrocyte size scaled with body mass with a very low exponent (0.090), suggests that while both cell number and cell size contribute to the increase in body mass, cell size plays a smaller role. The similar slopes of MMR and SMR in grass carp suggest a constant factorial aerobic scope (FAS) as the body grows. SMR was negatively correlated with FAS, indicating a tradeoff between SMR and FAS. Smaller fish recovered faster from the exhaustive exercises, and the scaling exponent of EPOC was 1.075, suggesting a nearly isometric increase in anaerobic capacity. Our results provide support for the cell size model and suggest that variations of erythrocyte size may partly contribute to the intraspecific scaling of SMR. The scaling exponent of MMR was 0.863, suggesting that the metabolism of non-athletic fish species is less reliant on muscular energy expenditure, even during strenuous exercise. PMID- 24481483 TI - Effectiveness of intraocular pressure-lowering medication determined by washout. AB - IMPORTANCE While medication efficacy is well documented in clinical trials, less is known of medication effectiveness in real-world clinical settings. OBJECTIVE To assess the effectiveness of intraocular pressure (IOP)-lowering medications in patients with open-angle glaucoma. DESIGN, SETTING, AND PARTICIPANTS Prospective, multicenter, interventional cohort from the prerandomization phase of a randomized clinical trial at multiple ophthalmology clinics. A total of 603 patients (603 eyes) with primary open-angle glaucoma who were using up to 3 glaucoma medications were included. INTERVENTIONS One IOP measurement was made while the patient was using his or her usual medications to lower IOP (ON IOP). Eligible participants underwent washout of all IOP-lowering drops, and the diurnal IOP was measured 2 to 4 weeks later (OFF IOP). MAIN OUTCOMES AND MEASURES Difference between OFF IOP and ON IOP. The hypothesis was formulated after data collection. RESULTS The mean (SD) ON IOPs for participants using 0 (n = 102), 1 (n = 272), 2 (n = 147), or 3 (n = 82) medications were 24.2 (3.2), 17.5 (3.2), 17.2 (3.1), and 17.2 (3.1) mm Hg, respectively. Patients not using medication had a mean (SD) IOP decrease of 0.2 (2.8) mm Hg at the OFF visit. Patients using 1, 2, and 3 medications had mean (SD) IOP increases of 5.4 (3.0), 6.9 (3.3), and 9.0 (3.8) mm Hg, respectively, at the OFF visit. The percentages of patients with less than a 25% increase in IOP were 38%, 21%, and 13% for those using 1, 2, and 3 medications, respectively. CONCLUSIONS AND RELEVANCE Discontinuation of 1, 2, and 3 medications was associated with a clinically significant increase in IOP, although with smaller effects for the second and third medications compared with the first medication. A substantial proportion of patients showed only small changes in IOP after medication washout, suggesting either that they were not using the medication effectively or that the medication itself, although used properly, was not lowering the IOP. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01085357. PMID- 24481484 TI - Frailty in the older adult: will you recognize the signs? AB - With the rapid aging of the oldest old, it is inevitable that nurse practitioners will encounter frail patients across care settings. Presented through a case study, this article addresses the clinical characteristics of frailty, strategies to prevent this geriatric syndrome, and recommendations for care. PMID- 24481485 TI - Club drugs: coming to a patient near you. AB - Club drugs have become increasingly popular with young adults and adolescents. Although users report similar effects of these drugs, they are pharmacologically and physiologically different. Understanding these differences and recognizing trends and effects of club drugs is essential for nurse practitioners. PMID- 24481487 TI - Moderate swimming exercise and caffeine supplementation reduce the levels of inflammatory cytokines without causing oxidative stress in tissues of middle-aged rats. AB - The levels of circulatory inflammatory markers, including interleukin (IL) IL 1beta, IL-6, tumor necrosis factor-alpha (TNF-alpha) and interferon (INF-gamma), are known to increase associated to aging. Caffeine has been reported to produce many beneficial effects for health. Exercise is considered to be a safe medicine to attenuate inflammation and cellular senescence. The purpose of the present study was to investigate the effects of a moderate-intensity swimming exercise (3 % of body weight, 20 min per day, 4 weeks) and sub-chronic supplementation with caffeine (30 mg/kg, 4 weeks) on the serum cytokine levels in middle-aged (18 months) Wistar rats. The effects of swimming exercise and caffeine on oxidative stress in muscle and liver of middle-aged rats were also investigated. The two way ANOVA of pro-inflammatory cytokine levels demonstrated a significant exercise x caffeine interaction for IL-1beta (F (1, 16) = 9.5772; p = 0.0069), IL-6 (F (1, 16) = 8.0463; p = 0.0119) and INF-gamma (F (1, 16) = 15.078; p = 0.0013). The two way ANOVA of TNF-alpha levels revealed a significant exercise * caffeine interaction (F (1, 16) = 9.6881; p = 0.00670). Swimming exercise and caffeine supplementation increased the ratio of reduced glutathione/oxidized glutathione in the rat liver and gastrocnemius muscle. Hepatic and renal markers of damage were not modified. In conclusion, a moderate-intensity swimming exercise protocol and caffeine supplementation induced positive adaptations in modulating cytokine levels without causing oxidative stress in muscle and liver of middle-aged rats. PMID- 24481486 TI - The regulatory peptide pidotimod facilitates M2 macrophage polarization and its function. AB - Pidotimod is a synthetic dipeptide with biological and immunological activity in innate immune responses. It has been reported that pidotimod could promote functional maturation of dendritic cells, but little is known about the regulation of macrophages. Recent studies have demonstrated that M1 or M2 polarized macrophages are of great importance for responses to microorganism infection or host mediators. The aim of this study was to determine the effectiveness of pidotimod on mouse bone marrow-derived macrophage polarization and its function. The results showed that pidotimod had no influence on M1 polarized macrophage. While interestingly, a significant increase of M2 marker gene expression (Arg1, Fizz1, Ym1, MR) was observed (p < 0.01) in IL-4-induced M2 macrophage treated with pidotimod. In addition, cell surface expression of mannose receptor was dramatically enhanced using fluorescence activated cell sorter (FACS) analysis. Furthermore, the function of M2 macrophage was also determinated. The results showed that the supernatant of pidotimod-treated M2 macrophage could increase the migration (p < 0.05) and enhance the wound closure rate (p < 0.05) of MLE-12 cells. Collectively, it could be concluded that pidotimod significantly facilitated IL-4-induced M2 macrophage polarization and improves its function. PMID- 24481488 TI - CD40L gene therapy tilts the myeloid cell profile and promotes infiltration of activated T lymphocytes. AB - CD40 ligand (CD40L) is a potent stimulator of tumor immunity via its activation of dendritic cells, which in turn initiate T-cell activation. However, T cells are inhibited by suppressive myeloid cells, which constitute an important part of immune evasion. We hypothesized that CD40L may revert the function of suppressive myeloid cells to generate a T-cell stimulatory environment, and this was investigated in the murine bladder cancer model MB49/C57BL/6. Upon intratumoral adenoviral CD40L (AdCD40L) gene therapy, the infiltration of CD11b(+)Gr-1(+) cells was significantly reduced, whereas activated T cells were increased. In vitro, CD40L-expressing MB49 cells tilted the myeloid subpopulations in favor of granulocytic CD11b(+)Gr-1(high) myeloid cells instead of monocytic CD11b(+)Gr 1(int/low) myeloid cells. Further, the level of macrophages in splenocyte co cultures with MB49 cells was evaluated. In cultures with MB49 cells expressing CD40L, the overall level of macrophages was reduced and the remaining cells were differentiated into M1-like cells. Hence, these data support that CD40L tilts myeloid immune cell populations in favor of anti-tumor immunity (M1) instead of immunosuppression (CD11b(+)Gr-1(int/low) and M2), and this was accompanied by an increased level of activated T cells in the tumor tissue. PMID- 24481489 TI - In vitro and in vivo radiosensitization of human glioma U251 cells induced by upregulated expression of SLC22A18. AB - Our previous study showed that solute carrier family 22 (organic cation transporter) member 18 (SLC22A18) downregulation via promoter methylation was associated with the development and progression of glioma, and the elevated expression of SLC22A18 was found to increase the sensitivity of glioma U251 cells to the anticancer drug 1,3-bis(2-chloroethyl)-1-nitrosourea. In this study, we investigated the possible upregulated expression of SLC22A18-induced enhancement of radiosensitivity of human glioma U251 cells in order to provide evidence in support of further clinical investigations. Stably overexpressing SLC22A18 human glioma U251 cells were generated to investigate the effect of SLC22A18 on the sensitivity of cells to irradiation in vitro using clonogenic survival assay. The apoptosis of U251 cells was examined with terminal deoxynucleotidyl transferase mediated dUTP nick end labeling assay. DNA damage and repair were measured using gammaH2AX foci. The effect of SLC22A18 on the in vivo tumor radiosensitivity was investigated in the orthotopic mice model. Upregulated expression of SLC22A18 enhanced the radiosensitivity of glioma U251 cells and also enhanced irradiation induced apoptosis of U251 cells, but irradiation-induced apoptosis did not correlate with radiosensitizing effect of upregulated expression of SLC22A18. The repair of irradiation-induced double-strand-breaks was retarded in stably overexpressing SLC22A18 U251 cells. In the orthotopic mice model, the upregulated expression of SLC22A18 in U251 cells enhanced the effect of irradiation treatment and increased the survival time of mice. These results show that upregulated expression of SLC22A18 radiosensitizes human glioma U251 cells by suppressing DNA repair capacity. PMID- 24481490 TI - Hydrophobicity alone can not trigger aggregation in protonated mammalian serum albumins. AB - Amyloid fibrils are associated with neurodegenerative disorders and are formed by a number of proteins. In this study, the amyloid-forming behavior of several different serum albumins was examined at pH 3.5 i.e., about two pH units below their isoelectric points (pI ~ 5.5) to examine the roles played by negative charge and hydrophobicity of exogenously added surfactants such as SDS, SDBS and AOT. The propensities of SDS, SDBS and AOT to promote the formation of amyloid fibrils were investigated by using measurements of turbidity, Rayleigh scattering, ThT and CR dye binding, DLS as well as far-UV CD. At submicellar concentrations of SDS and SDBS (0.5-2.5 mM) amyloid fibrils were formed by all albumins studied whereas at higher concentrations amyloid fibril formation was completely inhibited. Interestingly AOT promoted amyloid fibril formation up to 11 mM without any inhibition. The interaction between the albumins and the surfactants was exothermic, as confirmed by isothermal titration calorimetry (ITC). From the turbidity, Rayleigh scattering and dynamic light scattering data, it was concluded that amyloid induction was promoted most by AOT followed by SDBS and SDS. Similar studies were performed at pH 7.4 i.e., about two units of pH above the albumins pI, and no amyloid fibrils were formed. From these studies we conclude that negatively charged surfactants induce amyloid fibril formation in serum albumins with the help of electrostatic and hydrophobic interactions. Besides the study performed at pH 7.4 indicates that hydrophobic interactions alone can not induce aggregation in serum albumins. PMID- 24481491 TI - Indole-3-acetic acid producing root-associated bacteria on growth of Brazil Pine (Araucaria angustifolia) and Slash Pine (Pinus elliottii). AB - Araucaria forests in Brazil today correspond to only 0.7 % of the original 200 km(2) of natural forest that covered a great part of the southern and southeastern area of the Atlantic Forest and, although Araucaria angustifolia is an endangered species, illegal exploitation is still going on. As an alternative to the use of hardwoods, Pinus elliottii presents rapid growth and high tolerance to climatic stress and low soil fertility or degraded areas. Thus, the objective of this study was to evaluate the effect of IAA-producing bacteria on the development of A. angustifolia and P. elliottii. We used five bacterial strains previously isolated from the rhizosphere of A. angustifolia, which produce quantities of IAA ranging from 3 to 126 MUg mL(-1). Microbiolized seeds were sown in a new gnotobiotic system developed for this work, that allowed the quantification of the plant hormone IAA produced by bacteria, and the evaluation of its effect on seedling development. Also, it was shown that P. elliottii roots were almost as satisfactory as hosts for these IAA producers as A. angustifolia, while different magnitudes of mass increases were found for each species. Thus, we suggest that these microbial groups can be helpful for the development and reestablishment of already degraded forests and that PGPR isolated from Araucaria rhizosphere have the potential to be beneficial in seedling production of P. elliottii. Another finding is that our newly developed gnotobiotic system is highly satisfactory for the evaluation of this effect. PMID- 24481492 TI - Early time course of FLAIR signal intensity differs between acute ischemic stroke patients with and without hyperintense acute reperfusion marker. AB - BACKGROUND: In animal models of stroke, the time course of blood-brain barrier (BBB) disruptions has been elaborately studied. In human patients, leakage of gadolinium into cerebrospinal fluid (CSF) space, visualized on MRI fluid attenuated inversion recovery (FLAIR) images, is considered a sign of BBB disruptions. It was termed 'hyperintense acute reperfusion marker' (HARM) and was associated with hemorrhages. However, the time course of the leakage is unknown and difficult to study in human patients. Also, the association of HARM with signal intensities and enhancement in the parenchyma on FLAIR images has not been thoroughly researched. METHODS: We analyzed imaging data of acute ischemic stroke patients who underwent repetitive MRI examinations within the first 36 h after the time of symptom onset. HARM was evaluated on FLAIR images. Regions of interest (ROI) of the hyperintensities on diffusion-weighted imaging (DWI) were determined for each time point and mirrored to the contralateral side. The ROI were furthermore corrected for CSF-filled space, using apparent diffusion coefficient (ADC) images. The corrected ROI were used to determine mean signal intensities of the lesions relative to the contralateral side on FLAIR, ADC and B0 images for each time point. RESULTS: The 18 included patients (5 females; median age: 69 years; median NIHSS score: 5) received 3-5 MRI examinations on the first day and 1-2 examinations on day 2 after stroke. Eight of the patients (44.4%) showed HARM on at least 1 examination. In 6 of these patients, HARM was already seen at the second examination, at the earliest 3.5 h after symptom onset. The HARM-positive patients had higher relative signal intensities (rSI) on FLAIR images in the parenchyma corresponding to the DWI-positive tissue compared with the HARM-negative patients. This difference between groups was statistically significant for the 2nd and 3rd examination (medians of 4.31 and 6.37 h from symptom onset, p < 0.001 and p = 0.005, respectively). No significant difference in rSI between groups was seen for ADC or B0 images. CONCLUSION: HARM does not only represent a contrast medium leakage from the pial system into the CSF space. It is accompanied by a markedly increased rSI in the early ischemic lesion on FLAIR images, which is likely due to parenchymal enhancement. The lack of differences on B0 images excludes a pure T2 effect. PMID- 24481496 TI - Unexpected dehomologation of primary alcohols to one-carbon shorter carboxylic acids using o-iodoxybenzoic acid (IBX). AB - A novel and efficient transformation of primary alcohols to one-carbon shorter carboxylic acids using IBX is reported. Mechanistic studies revealed that the combination of IBX and molecular iodine produces a different active hypervalent iodine species. PMID- 24481495 TI - Ultraviolet radiation-induced inflammation activates beta-catenin signaling in mouse skin and skin tumors. AB - UVB-induced inflammation, in particular the overexpression of cyclooxygenase-2 (COX-2) and prostaglandin (PG) E2, has been implicated in photocarcinogenesis. UVB-induced COX-2 has been associated with beta-catenin signaling in keratinocytes. However, a definitive role for COX-2 in the activation of beta catenin signaling as well as its role in UVB-induced skin tumors has not been established. We report that exposure of the skin to UVB resulted in a time- and dose-dependent activation of beta-catenin in C3H/HeN mice. This response was COX 2-dependent as UVB-exposed COX-2-deficient mice exhibited significantly lower levels of UVB-induced activation of beta-catenin. Moreover, treatment of mice with indomethacin, a COX-2 inhibitor, and an EP2 antagonist inhibited UVB-induced beta-catenin signaling. Exposure of SKH-1 hairless mice to UVB radiation (180 mJ/cm2) 3 times a week for 24 weeks resulted in activation of beta-catenin signaling in UVB-irradiated skin as well as UVB-induced skin tumors. Concomitantly, the levels of CK1alpha and GSK-3beta, which are responsible for beta-catenin signaling, were reduced while the levels of c-Myc and cyclin D1, which are downstream targets of beta-catenin, were increased. To further verify the role of UVB-induced inflammation in activation of beta-catenin signaling, a high-fat-diet model was used. Administration of high-fat diet exacerbated UVB induced inflammation. Administration of the high-fat diet enhanced beta-catenin signaling and the levels of its downstream targets (c-Myc, cyclin D1, cyclin D2, MMP-2 and MMP-9) in UVB-exposed skin and skin tumors in SKH-1 mice. These data suggest that UV-induced COX-2/PGE2 stimulates beta-catenin signaling, and that beta-catenin activation may contribute to skin carcinogenesis. PMID- 24481493 TI - In vivo cell biology in zebrafish - providing insights into vertebrate development and disease. AB - Over the past decades, studies using zebrafish have significantly advanced our understanding of the cellular basis for development and human diseases. Zebrafish have rapidly developing transparent embryos that allow comprehensive imaging of embryogenesis combined with powerful genetic approaches. However, forward genetic screens in zebrafish have generated unanticipated findings that are mirrored by human genetic studies: disruption of genes implicated in basic cellular processes, such as protein secretion or cytoskeletal dynamics, causes discrete developmental or disease phenotypes. This is surprising because many processes that were assumed to be fundamental to the function and survival of all cell types appear instead to be regulated by cell-specific mechanisms. Such discoveries are facilitated by experiments in whole animals, where zebrafish provides an ideal model for visualization and manipulation of organelles and cellular processes in a live vertebrate. Here, we review well-characterized mutants and newly developed tools that underscore this notion. We focus on the secretory pathway and microtubule-based trafficking as illustrative examples of how studying cell biology in vivo using zebrafish has broadened our understanding of the role fundamental cellular processes play in embryogenesis and disease. PMID- 24481497 TI - Moderators of the relationship between masculinity and sexual prejudice in men: friendship, gender self-esteem, same-sex attraction, and religious fundamentalism. AB - Masculinity has been found to predict the sexual prejudice of heterosexual men against gay men. The present study investigated the role of four variables as moderators of the relationships between two masculinity constructs (endorsement of traditional masculinity ideology and gender role conflict) and sexual prejudice in men. The hypothesized moderators were: direct and indirect friendships with gay men, gender self-esteem, acknowledged same-sex attraction, and religious fundamentalism. A total of 383 men completed 8 scales plus a demographic questionnaire. Direct friendship strengthened the positive relationship between masculinity ideology and sexual prejudice, contrary to hypothesis. This finding could mean that high masculinity ideology scores reduced the likelihood that a man with many gay friends would let go of his prejudice. Direct friendship did not moderate the relationship between gender role conflict and sexual prejudice nor did indirect friendship moderate either relationship; however, both forms of friendship predicted prejudice, as hypothesized. Gender self-esteem strengthened the positive relationships between both masculinity variables and sexual prejudice as hypothesized. Same-sex attraction weakened the relationship between gender role conflict and sexual prejudice as hypothesized, but contrary to hypothesis did not moderate the relationship between masculinity ideology and sexual prejudice. Religious fundamentalism predicted prejudice, but showed no significant moderation. The results were discussed in terms of limitations and suggestions for future research and application. In conclusion, this line of investigation appears promising and should be continued and the present findings can be utilized in anti-prejudice social marketing campaigns and in counseling. PMID- 24481498 TI - Politics of diagnostic criteria: specifiers of pedophilic disorder in DSM-5. PMID- 24481499 TI - Transcatheter closure of right-to-left atrial shunt in patients with platypnea orthodeoxia syndrome associated with aortic elongation. AB - Platypnea-orthodeoxia is a rare condition characterized by dyspnea and oxygen desaturation induced by the upright position and relieved by recumbency. The most common cause of this syndrome is right-to-left shunt through interatrial communications such as patent foramen ovale (PFO) or atrial septal defect (ASD). In addition, this syndrome can be caused by other extracardiac components, including pulmonary emphysema, pericardial disease, and prominent Eustachian valve. We experienced 3 cases of this syndrome, including 1 patient with PFO and 2 patients with ASD. Computer tomography imaging revealed aortic elongation and compression of the right atrium by ascending aorta in all of 3 patients. Transcatheter closure of PFO or ASD was successfully performed in all patients, including immediate improvements of symptoms and oxygen saturation without any complications. PMID- 24481502 TI - Effect of orbital decompression on diplopia in thyroid-related orbitopathy. AB - PURPOSE: To determine the incidence of new-onset diplopia and evolution of preexisting diplopia in patients with thyroid-related orbitopathy undergoing orbital decompression surgery. METHODS: A retrospective chart review was conducted of patients who had undergone orbital decompression for thyroid-related orbitopathy between 1999 and 2008 in one of the authors' practice (D.J.). A total of 217 orbits in 123 patients were identified. The clinical indication for decompression surgery (i.e., exposure keratitis, optic neuropathy, or improvement of cosmesis) was recorded in each case, as was the presence of pre- and postoperative diplopia. The surgical technique (1-, 2-, or 3-wall decompression) was noted for each patient. RESULTS: Review of the charts of patients who underwent orbital decompression surgery for thyroid-related orbitopathy revealed a preoperative prevalence of diplopia of 26% and a postoperative prevalence of 40.7%. Amongst the patients with preoperative diplopia (n = 32), 28.1% (n = 9) had complete resolution of their diplopia after decompression, while 65.6% (n = 21) remained stable and 6.3% (n = 2) worsened. The incidence of new-onset diplopia was 29.7% in this case series of orbital decompression using a transcaruncular and swinging eyelid approach for medial wall and strut-sparing floor decompression. Rates of new-onset diplopia were significantly higher when periorbita was opened (40.0%, n = 82) compared with when it was left intact (11.8%, n = 37) CONCLUSIONS:: It has previously been reported in the literature that orbital decompression for thyroid-related orbitopathy can cause diplopia in a significant number of cases. This provides the rational for performing orbital decompression prior to strabismus surgery in the management of thyroid-related orbitopathy. In this case series, the authors noted resolution of diplopia in a significant proportion (28.1%) of patients with preexisting diplopia. This is rarely commented on in other articles but is important in the preoperative discussion. An incidence of new-onset diplopia of 29.7% was identified. Opening the periorbita was associated with an increased incidence of new-onset diplopia. PMID- 24481501 TI - Insights into the mechanisms underlying the antiproliferative potential of a Co(II) coordination compound bearing 1,10-phenanthroline-5,6-dione: DNA and protein interaction studies. AB - The very high antiproliferative activity of [Co(Cl)(H2O)(phendione)2][BF4] (phendione is 1,10-phenanthroline-5,6-dione) against three human tumor cell lines (half-maximal inhibitory concentration below 1 MUM) and its slight selectivity for the colorectal tumor cell line compared with healthy human fibroblasts led us to explore the mechanisms of action underlying this promising antitumor potential. As previously shown by our group, this complex induces cell cycle arrest in S phase and subsequent cell death by apoptosis and it also reduces the expression of proteins typically upregulated in tumors. In the present work, we demonstrate that [Co(Cl)(phendione)2(H2O)][BF4] (1) does not reduce the viability of nontumorigenic breast epithelial cells by more than 85 % at 1 MUM, (2) promotes the upregulation of proapoptotic Bax and cell-cycle-related p21, and (3) induces release of lactate dehydrogenase, which is partially reversed by ursodeoxycholic acid. DNA interaction studies were performed to uncover the genotoxicity of the complex and demonstrate that even though it displays K b (+/- standard error of the mean) of (3.48 +/- 0.03) * 10(5) M(-1) and is able to produce double-strand breaks in a concentration-dependent manner, it does not exert any clastogenic effect ex vivo, ruling out DNA as a major cellular target for the complex. Steady-state and time-resolved fluorescence spectroscopy studies are indicative of a strong and specific interaction of the complex with human serum albumin, involving one binding site, at a distance of approximately 1.5 nm for the Trp214 indole side chain with log K b ~4.7, thus suggesting that this complex can be efficiently transported by albumin in the blood plasma. PMID- 24481503 TI - Cicatricial ectropion in grzybowski type of multiple eruptive keratoacanthomas. AB - A 41-year-old woman previously diagnosed with generalized eruptive keratoacanthomas of Grzybowski type presented with bilateral lower eyelid cicatrical ectropions. She had previously undergone multiple resections of syringomatous adenomas of both nipples, facial keratoacanthomas, and a lower left lip squamous cell carcinoma. Her facial and periocular skin was thickened with a cobblestone appearance. Cicatricial ectropions involved both upper and lower eyelids. Donor skin was harvested from the dorsum of the foot as this was the only disease-free area on her body, and she achieved a stable result with reduced tearing and improved appearance. PMID- 24481504 TI - Excision and delayed reconstruction with paraffin section histopathological analysis for periocular sebaceous carcinoma. AB - PURPOSE: To evaluate the use of excision and delayed reconstruction with rapid paraffin section analysis in patients with sebaceous carcinoma (SC) of the periocular region. METHODS: A retrospective study of patients with SC. Patients were identified from a contemporaneously maintained database and medical notes reviewed. Data were collected on known risk factors. Standard management started with conjunctival mapping biopsies. The tumor was excised with a 3-mm clinical margin and sent in formalin for histopathological analysis. The patient went home with dressings and returned 3 days later. Further excision or reconstruction was performed as indicated. Follow-up data were collected. RESULTS: Seventeen patients had excision and delayed reconstruction with paraffin section control. Ten had clear margins after 1 excision, and 7 were clear after 2 excisions. Reconstructive technique varied according to the defect. Three patients developed further tumor. One of these had a local recurrence treated with further excision and reconstruction. One developed a multicentric tumor with regional metastasis, and the third patient developed distant metastasis. Two patients died from SC. Average follow up was 5 years (2-9 years). CONCLUSIONS: Excision and delayed reconstruction using paraffin section histopathological analysis are in widespread use for the management of basal cell carcinomas in the periocular region. While some authors advocate the use of Mohs' micrographic surgery in patients with SC, this technique has been questioned due to the possible misinterpretation of subtle intraepithelial pagetoid spread with frozen section analysis. To preserve the function of the eyelid and ease of reconstruction, it is important to try and preserve as much healthy tissue as possible while effecting a successful excision. Excision and delayed reconstruction offer an excellent option for the management of this rare and highly malignant tumor. PMID- 24481505 TI - Successful "medical" orbital decompression with adjunctive rituximab for severe visual loss in IgG4-related orbital inflammatory disease with orbital myositis. AB - IgG4-related disease (IgG4-RD) is an inflammatory condition of unknown etiology that can cause tumefactive lesions in a number of tissues and organs, including the orbit and ocular adnexa. Diagnostic criteria for IgG4-RD, including pathology and clinical features and pathology, have been recently proposed. This study presents the first case of unilateral acute visual loss secondary to IgG4-related orbital inflammatory disease with orbital myositis that was complicated by severe compressive optic neuropathy. After initial treatment with pulsed intravenous methylprednisolone, followed by rituximab and radiotherapy, there was a marked improvement in orbital inflammation and clinical and radiological improvement in the compressive optic neuropathy. After 9 months of follow up, the orbital inflammatory disease remained in remission. PMID- 24481506 TI - Orbital amyloidosis masquerading as metastatic breast carcinoma. AB - One of the most common causes of enophthalmos is previous orbital fracture. In a patient with a known history of breast carcinoma, enophthalmos is concerning for metastatic disease. This report presents a patient with a history of scirrhous breast carcinoma and enophthalmos who was found to have orbital amyloidosis. This is the first report of enophthalmos as the presenting sign of orbital amyloidosis. PMID- 24481507 TI - Periocular sebaceous cell carcinoma following chemical burn: a unique case of a Marjolin ulcer. AB - This study reports a unique case of a Marjolin ulcer in a patient who presented with periocular sebaceous cell carcinoma 16 years after a lye chemical burn. A 68 year-old woman presented with a long history of irregular and tender right upper and lower eyelid margins, periocular erythema, madarosis, trichiasis, ptosis, and chemosis, occurring many years after chemical burn to the area. After eyelid biopsy established the diagnosis of sebaceous cell carcinoma, subsequent map biopsies of the conjunctival surface revealed extensive sebaceous cell carcinoma with pagetoid spread, necessitating anterior exenteration for definitive treatment. This report describes the first case in which a sebaceous cell carcinoma has arisen in the area of a chemical burn. Sebaceous cell carcinomas should be included in the spectrum of Marjolin ulcers, and ophthalmologists should be aware of this entity when evaluating patients with a history of a burn to the eyelids. PMID- 24481508 TI - Basaloid squamous cell carcinoma of the conjunctiva. AB - Basaloid squamous cell carcinoma is a distinct variant of squamous cell carcinoma, and it is more aggressive and has a poorer prognosis than conventional squamous cell carcinoma. Basaloid squamous cell carcinoma has been reported to arise from many organs, mainly in the upper aerodigestive tract. Herein, the authors present a 77-year-old woman with a basaloid squamous cell carcinoma over her limbal conjunctiva in the OD. PMID- 24481509 TI - The efficacy of a novel mobile phone application for goldmann ptosis visual field interpretation. AB - PURPOSE: To evaluate the efficacy of a novel mobile phone application that calculates superior visual field defects on Goldmann visual field charts. METHODS: Experimental study in which the mobile phone application and 14 oculoplastic surgeons interpreted the superior visual field defect in 10 Goldmann charts. Percent error of the mobile phone application and the oculoplastic surgeons' estimates were calculated compared with computer software computation of the actual defects. Precision and time efficiency of the application were evaluated by processing the same Goldmann visual field chart 10 repeated times. RESULTS: The mobile phone application was associated with a mean percent error of 1.98% (95% confidence interval[CI], 0.87%-3.10%) in superior visual field defect calculation. The average mean percent error of the oculoplastic surgeons' visual estimates was 19.75% (95% CI, 14.39%-25.11%). Oculoplastic surgeons, on average, underestimated the defect in all 10 Goldmann charts. There was high interobserver variance among oculoplastic surgeons. The percent error of the 10 repeated measurements on a single chart was 0.93% (95% CI, 0.40%-1.46%). The average time to process 1 chart was 12.9 seconds (95% CI, 10.9-15.0 seconds). CONCLUSIONS: The mobile phone application was highly accurate, precise, and time-efficient in calculating the percent superior visual field defect using Goldmann charts. Oculoplastic surgeon visual interpretations were highly inaccurate, highly variable, and usually underestimated the field vision loss. PMID- 24481510 TI - Nasal glioma presenting with strabismus. AB - Congenital midline nasal masses are rare anomalies that occur in about 1 in 20,000 to 40,000 live births. Nasal gliomas are thought to be collections of heterotopic tissue of neurogenic origin, which have lost their intracranial connection. It rarely cause ocular distortion and deformity in the medial orbital wall. We describe here a case of a 12-month-old baby girl diagnosed as extranasal glioma at the lateral nasal wall and medial orbital wall presenting with strabismus and subsequently treated in our service and perform a literature review. PMID- 24481511 TI - Two-dimensional video analysis of the upper eyelid motion during spontaneous blinking. AB - PURPOSE: To validate and to report the results of a new inexpensive video-based method to measure upper eyelid motion during spontaneous blinks. METHODS: Spontaneous blinks were simultaneously recorded in 21 healthy adult subjects for 5 minutes with magnetic search coil (MSC) and a portable video system (VDS) composed by a commercial high-speed camera coupled to a laptop computer and a blue light-emitting diode. Agreement between the 2 methods was assessed using qualitative comparison of the eyelid motion traces and Bland-Altman plots. RESULTS: The blink traces registered with both methods were virtually identical. With the either method, the relationship between amplitude and maximum velocity was well fitted by linear regression with mean r values = 0.81 (MSC) and 0.85 (VDS). Bland-Altman plots showed good agreement between methods. The mean +/- SE differences of amplitude (0.06 +/- 0.17 mm) and maximum velocity (5.0 +/- 3.4 mm/s) were not significant. With the VDS, it was also possible to quantify the horizontal component of the blink movements. The amplitude of the horizontal shift of the eyelid during blinks was 40% of the vertical downward phase of the movement. CONCLUSIONS: Blinking kinematics can be precisely measured using a simple and inexpensive video system suitable for clinical settings. PMID- 24481512 TI - Granular cell tumor masquerading as a chalazion: a case report. AB - Granular cell tumors were first described in the 1920s and since then have been commonly found throughout the body. They are rarely found in periorbital, orbital, and ocular structures. The authors present a patient with a 2-year history of a lesion that had been previously excised as a presumed chalazion without pathologic analysis. The lesion recurred, and histopathological analysis following complete resection revealed a granular cell tumor. This case is an example of a rare periocular tumor. Although only an isolated case, it provides support for the recommendation that excised lesions be sent to pathologic study, particularly those with an atypical clinical course. PMID- 24481513 TI - Eighteen-point abobotulinum toxin a upper face rejuvenation: an eye plastic perspective on 845 subjects. AB - PURPOSE: To report the method and results of 18-point Abobotulinum toxin A (ABO BTA, Dysport) upper face rejuvenation on 845 subjects. METHODS: In a retrospective chart review, all subjects (the first cycle of injection) with ABO BTA upper face rejuvenation from 2003 to 2009 were included. Excluded were subjects with facial spastic disorders, injection after upper face lifting, and aberrant regeneration of facial nerves. Upper face rejuvenation included 18 points of injection at forehead creases (4), frown lines (5), bunny line (1), crow's feet (4 on both sides), and lower eyelid crease (4 on both sides). They were revisited in 10 to 14 days for assessment of the effects and possible touch up injection. Demographics, year of injection, topical anesthetic usage, touch-up injection, and adverse effects (AE) were recorded. RESULTS: There were 845 subjects (85.8% women) whose age was below 40 in 49.3%. All but 68 (8%) were happy with the touch-up visit, 10 to 14 days after injection. Touch-up injection was performed in 8% of subjects mainly for the eyebrow asymmetry. AE (22/845, 2.6%) were bruise (15/845, 1.8%), blepharoptosis (3/845, 0.3%), remained eyebrow asymmetry after touch-up injection (2/845, 0.2%), and headache (2/845, 0.2%). They were significantly more in subjects with touch-up injection, younger than 40 years, and in the first and second year of experience (especially for the bruise). CONCLUSIONS: Eighteen-point ABO-BTA upper face rejuvenation had a low rate of AE in this series in which majority was bruise at the lateral canthal area. They were significantly more in the first years of experience, subjects younger than 40, and who had touch-up injections. PMID- 24481514 TI - Delayed electron-hole pair recombination in iron(III)-oxo metal-organic frameworks. AB - The photodynamic properties of a series of Fe(III)-MOFs have been examined via redox reactions with N,N,N',N'-tetramethyl-p-phenylenediamine as an electron donor and methyl viologen as an electron acceptor. Furthermore, photogeneration of long-lived species in MIL-88B(Fe) has been proven via transient absorption spectroscopy. PMID- 24481516 TI - CCR9 as a prognostic marker and therapeutic target in hepatocellular carcinoma. AB - The chemokine receptor CCR9 was recently implicated in tumor biology. In the present study, our objective was to evaluate the clinical significance and potential role of CCR9 in hepatocellular carcinoma (HCC). CCR9 expression was detected by immunohistochemistry, quantitative PCR (qPCR) and western blotting in HCC patients. The prognostic significance of CCR9 expression was assessed. The functional roles of CCR9 in HCC were investigated using MTT, BrdU, colony formation assay and flow cytometry. CCR9 was significantly elevated in HCC tissue samples. High CCR9 expression was correlated with multiple tumor nodes, high Edmondson-Steiner grade and vascular invasion. Multivariate analysis showed that CCR9 expression was an independent prognostic factor for the overall survival (OS) of HCC patients. Further investigations revealed that ectopic expression of CCR9 enhanced cell proliferation and tumorigenicity in HCC cells, whereas CCR9 silencing impaired cell proliferation and tumorigenicity, which was mediated through downregulation of the cell cycle regulators p21, p27 as well as upregulation of cyclin D1. These results suggest that CCR9 can act as a novel prognostic marker and therapeutic target for HCC. PMID- 24481515 TI - A review of plant-pharmaceutical interactions: from uptake and effects in crop plants to phytoremediation in constructed wetlands. AB - Pharmaceuticals are commonly found both in the aquatic and the agricultural environments as a consequence of the human activities and associated discharge of wastewater effluents to the environment. The utilization of treated effluent for crop irrigation, along with land application of manure and biosolids, accelerates the introduction of these compounds into arable lands and crops. Despite the low concentrations of pharmaceuticals usually found, the continuous introduction into the environment from different pathways makes them 'pseudo-persistent'. Several reviews have been published regarding the potential impact of veterinary and human pharmaceuticals on arable land. However, plant uptake as well as phytotoxicity data are scarcely studied. Simultaneously, phytoremediation as a tool for pharmaceutical removal from soils, sediments and water is starting to be researched, with promising results. This review gives an in-depth overview of the phytotoxicity of pharmaceuticals, their uptake and their removal by plants. The aim of the current work was to map the present knowledge concerning pharmaceutical interactions with plants in terms of uptake and the use of plant based systems for phytoremediation purposes. PMID- 24481517 TI - Fractionation of the enzymes of the barley aleurone layer: Evidence for a soluble mode of enzyme release. AB - Aleurone cells of barley (Hordeum vulgare L.) contain microbodies as determined by histochemical localization with diaminobenzidine. These microbodies can be isolated from both water and gibberellic acid (GA3) treated cells and identified on sucrose density gradients as glyoxysomes on the basis of their buoyant densities (1.25 g cm(-3)) and their enzyme complement. Fractionation of aleurone layer homogenates by differential centrifugation after varying times of exposure to GA3, however, does not indicate the presence of a discrete secretory vesicle containing either alpha-amylase or beta-1,3-glucanase. Cytological evidence also suggests that at least beta-1,3-glucanase is not released from these cells by means of a discrete secretory vesicle. PMID- 24481518 TI - An investigation of glycolate excretion in two species of blue-green algae. AB - The amount of (14)C-glycolate excreted by Oscillatoria sp. and Anabaena flos aquae is less than 1% of the (14)C fixed by the algae during photosynthesis. Transfer of cells grown on 5% CO2 in air to a medium of low bicarbonate concentration or treatment of the cells with isonicotinyl hydrazide (INH) during photosynthesis, caused little increase in glycolate excretion. alpha Hydroxysulfonates failed to stimulate massive excretion of glycolate. Although these blue-green algae excreted little glycolate, a significant proportion of the photosynthetically fixed carbon was excreted in the form of basic, neutral and acidic compounds, and such excretion was greater in 5% CO2-grown cells than in air-grown cells. PMID- 24481520 TI - A specific bioassay for the inhibition of flowering. AB - A bioassay for the inhibition of flowering involving the in vitro culture of excised, partially-induced, apices of Viscaria candida is described. This bioassay has been used to detect flowering inhibition in extracts from Kalanchoe blossfeldiana. PMID- 24481519 TI - Detection and quantitative determination of abscisic acid by immunological assay. AB - Antibodies with specificity towards abscisic acid (ABA) were produced in rabbits. These antibodies were used for assaying ABA by the inhibition of inactivation of modified bacteriophage. For this assay conjugates of ABA with bacteriophage T4 were prepared and characterized. Such chemically modified bacteriophages were completely inactivated by the specific anti-ABA serum and this inactivation was inhibited by free ABA. The identification and quantitative determination of ABA in plant extracts by this method are demonstrated and the method is compared with a common bioassay. PMID- 24481521 TI - The changes in glutamic dehydrogenase activity following illumination of etiolated barley seedlings. AB - Changes in NADH- and NADPH-linked glutamic dehydrogenase (GDH) activity have been measured following illumination of etiolated barley leaves. Both activities initially increase, then decrease to below the etiolated value. The latter change is dependent upon prior illumination but independent of the presence of roots or added ammonium sulphate. Subsequently a sustained increase of both activities occurs. Possible reasons for these changes and alterations in the ratio of the two GDH activities are discussed. PMID- 24481522 TI - A circadian rhythm in the level of carbon dioxide compensation in Bryophyllum fedtschenkoi with zero values during the transient. AB - Detached shoots of Bryophyllum fedtschenkoi maintained in a closed system in the light exhibited an endogenous circadian rhythm in CO2 compensation. The rhythm was sensitive to changes in light intensity and temperature. At 15 degrees C it damped rapidly in light of 78 J m(-2) s(-1), but at 10 degrees C a rhythm of considerable amplitude was evident at this same light intensity. During the transient (i.e. the temporary state of the rhythm before it acquired its steady state) low compensation values between 0 and 5 ppm CO2 were achieved. When the plants were maintained at a higher light intensity prior to the measurements, the period of low compensation during the transient was extended, and zero values were obtained under some conditions.Studies of gas exchange at opposite phases of the rhythm revealed: (i) that the rate of uptake of (14)CO2 differed, both in light and darkness (the epidermis was removed during these observations to avoid interference from stomatal rhythms); (ii) 'photorespiration', estimated by extrapolation of the graph relating photosynthetic rate and CO2 concentration, was highest during the peaks of the rhythm in CO2 compensation; (iii) estimates of the capacity for 'photorespiration' by the glycine-1-(14)C assay indicated highest values during the troughs of the rhythm. These findings are discussed in relation to the C4-acid metabolism of this species. Low CO2 compensation is probably due to the activity of phosphoenolpyruvate carboxylase and not to the absence of processes involving CO2 evolution. PMID- 24481523 TI - [Inhibition of respiratory enzymes in mitochondria of green leaves]. AB - 1. Of the buffer substances introduced by Good, only N-2-hydroxy-ethylpiperazine N-2-ethanesulfonic acid (HEPES) and N-tris(hydroxymethyl)-methyl-2 aminoethanesulfonic acid (TES) were found suitable for the isolation of mitochondria by means of density gradient centrifugation in a silica sol. Addition of 1% polyvinylpyrrolidone remarkably reduced the respiration rate and diminished the respiratory control, whereas 2% dextran improved the rates. 2. Fifty mM malonate inhibited succinate oxidation by 55-72% compared with the controls; in addition an uncoupling effect was observed. Similar results were obtained with 2.5 mM amytal. 3. Antimycin A, in contrast, did not affect the respiratory control, while the respiration rate was depressed to 55% of that in the control. 4. Azide (20 mM) had only a slight effect on the two parameters of leaf mitochondria. 5. It can be concluded that mitochondria of leaf cells are provided with the same respiratory enzymes as those of other plant materials. PMID- 24481524 TI - The effect of SO 3 (--) on the activity of ribulose-1,5-diphosphate carboxylase in isolated spinach chloroplasts. AB - SO 3 (--) inhibits the activity of ribulose-1,5-diphosphate carboxylase in isolated spinach chloroplasts. It shows a non-competitive inhibition pattern with respect to ribulose-1,5-diphosphate and Mg(++) but a competitive one with respect to HCO 3 (-) . The K i -values are 14 mM SO 3 (--) and 9.5 mM SO 3 (-) respectively for the non-competitive inhibition but only 3.0 mM SO 3 (--) in the case of competitive inhibition with HCO 3 (--) as a substrate. Thus it is concluded that the competitive inhibition type will predominate at low SO 3 (--) and low internal CO2 concentrations. PMID- 24481525 TI - [On the light-dependent influx of ions in leaves of Elodea densa. Comparison of the influxes of K(+) and Cl (-) ions]. AB - The light-dependent influxes of K(+) and Cl(-) in detached leaves of Elodea densa were measured using (36)Cl(-) and (42)K(+) or (86)Rb(+) as tracers.The K(+) and Cl(-) influxes were enhanced by light and also in the dark after a preillumination. The rate of influx decayed in the dark according to a first order reaction with a half-time of 25 or 27 sec.DCMU inhibits the light-dependent K(+) influx more severely in the presence of CO2 than in its absence in an atmosphere of N2 containing a trace of oxygen. This is similar to the effect of DCMU on the Cl(-) influx. CCCP(1), atebrin (quinacrine) and Dio-9 all affect the influx of K(+) and Cl(-) in a comparable way. CCCP exerts the strongest effect at low light intensities; atebrin and Dio-9 inhibit strongly even at high intensities when the ion influxes are light-saturated. The influence of these two inhibitors in attributed to an effect at the cellular membranes in addition to an effect on photophosphorylation. The effect of CCCP is ascribed to uncoupling of photophosphorylation, as photosynthesis is inhibited by about the same concentration as is ion influx.In far-red light the relative quantum yields of K(+) and Cl(-) influx drop to a similar degree as does the quantum yield of photosynthesis. Estimated values of the quantum requirement of ion influx are given. The quantum requirement in air is higher than in an atmosphere of N2. It is a function of ion concentration and is lower at higher external concentrations.The results indicate that the K(+) and Cl(-) influxes are partially coupled. The linkage of the ion influxes with the energy sources in the light and a possible contribution of a pseudocyclic photophosphorylation are discussed. PMID- 24481526 TI - [The dependence of the concentration of plastid quinones and pigments in Zea mays and Atriplex rosea on the light intensity and the age of the plants]. AB - The concentration of lipophilic plastid quinones (plastoquinone, plastoquinol, alpha-tocopherol, alpha-tocoquinone) in the C4-plants Zea mays and Atriplex rosea is lower than in the already studied C3-plants.In Zea mays the concentration of plastid quinones increases only a little with the age of the plant and then decreases again, while the concentration of quinones in Atriplex rosea constantly rises during the whole test period of 10 weeks.The ratio of chlorophyll a:b is 3,5 in Zea mays and 3,6 in Atriplex rosea.The data lead to the supposition that the concentration of photosystem-II-components is lower than the concentration of photosystem-I-components. We assume that especially in the bundle sheath chloroplasts there is a lack of quinones. In the case of Zea mays this could be the reason for the low system-II-activity which has been found by Anderson et al. (1971). PMID- 24481527 TI - The activity of uridine diphosphate-D-glucose: Nicotinamide-adenine dinucleotide oxidoreductase in cambial tissue and differentiating xylem isolated from sycamore trees. AB - The activity of UDPGlc: NAD oxidoreductase is measured in enzyme preparations obtained from sycamore cambium and xylem tissue. The activity of this enzyme is greater in xylem than in cambium whether expressed on a specific activity basis or on a per-cell basis. It is suggested that, in developing xylem, direct oxidation of UDPGlc may contribute significantly to the biosynthesis of polysaccharide precursors. PMID- 24481528 TI - One-step generation of knockout pigs by zygote injection of CRISPR/Cas system. PMID- 24481530 TI - Where long noncoding RNAs meet DNA methylation. AB - DNA methylation is a fundamental epigenetic mechanism governing regulation of gene expression during mammalian development. A recent study published in Nature shows a novel long noncoding RNA (lncRNA) arising from the CEBPA gene locus (termed ecCEBPA) that is critical for regulation of DNA methylation at this site through the association of ecCEBPA with DNA methyltransferase 1, DNMT1. PMID- 24481529 TI - Multifaceted roles of miR-1s in repressing the fetal gene program in the heart. AB - miRNAs are an important class of regulators that play roles in cellular homeostasis and disease. Muscle-specific miRNAs, miR-1-1 and miR-1-2, have been found to play important roles in regulating cell proliferation and cardiac function. Redundancy between miR-1-1 and miR-1-2 has previously impeded a full understanding of their roles in vivo. To determine how miR-1s regulate cardiac function in vivo, we generated mice lacking miR-1-1 and miR-1-2 without affecting nearby genes. miR-1 double knockout (miR-1 dKO) mice were viable and not significantly different from wild-type controls at postnatal day 2.5. Thereafter, all miR-1 dKO mice developed dilated cardiomyopathy (DCM) and died before P17. Massively parallel sequencing showed that a large portion of upregulated genes after deletion of miR-1s is associated with the cardiac fetal gene program including cell proliferation, glycolysis, glycogenesis, and fetal sarcomere associated genes. Consistent with gene profiling, glycogen content and glycolytic rates were significantly increased in miR-1 dKO mice. Estrogen-related Receptor beta (Errbeta) was identified as a direct target of miR-1, which can regulate glycolysis, glycogenesis, and the expression of sarcomeric proteins. Cardiac specific overexpression of Errbeta led to glycogen storage, cardiac dilation, and sudden cardiac death around 3-4 weeks of age. We conclude that miR-1 and its primary target Errbeta act together to regulate the transition from prenatal to neonatal stages by repressing the cardiac fetal gene program. Loss of this regulation leads to a neonatal DCM. PMID- 24481531 TI - Triptolide induces apoptotic cell death of multiple myeloma cells via transcriptional repression of Mcl-1. AB - Triptolide, a diterpenoid trioxide purified from the Chinese herb Tripterygium wilfordii Hook F, has been used as a natural medicine in China for hundreds of years. Several reports have demonstrated that triptolide inhibits the proliferation of cancer cells in vitro and reduces the growth of several types of tumors in vivo. To address the potential of triptolide as a novel therapeutic agent for patients with multiple myeloma, we investigated the effects of triptolide on the induction of apoptosis in human multiple myeloma cells in vitro. Triptolide rapidly induces apoptotic cell death in various myeloma cell lines. Triptolide-induced apoptosis in myeloma cells is associated with the loss of mitochondrial transmembrane potential (?psim), the release of cytochrome c and Smac/DIABLO from mitochondria into the cytosol, and the activation of caspase-3 and caspase-9. Furthermore, triptolide induces a rapid decline in the levels of Mcl-1 protein that correlates with caspase activation and induction of apoptosis. Inhibition of Mcl-1 synthesis by triptolide occurs at the level of mRNA transcription and is associated with an inhibition of phosphorylation of RNA polymerase II CTD. These results indicate that Mcl-1 is an important target for triptolide-induced apoptosis in myeloma cells that occurs via inhibition of Mcl-1 mRNA transcription coupled with rapid protein degradation through the ubiquitin proteasome pathway. PMID- 24481532 TI - Preparation and cytocompatibility evaluation for hydrosoluble phosphorous acid derivatized cellulose as tissue engineering scaffold material. AB - Chemical modification of cellulose by phosphorylation enhances its bioactivity and provides new derivatives and materials with specific end uses. In the present study, cellulose derivatized with phosphorous acid was obtained using the reaction of microcrystalline cellulose with phosphorous acid-urea mixture, in molten state, in comparison with others methods that used different solvents and catalysts. Completely water soluble films with a substitution degree close to one were obtained and characterized by analytical and spectral analysis (FT-IR, (31)P NMR), contact angle, metallographic microscopy and atomic force microscopy (AFM). 31P NMR spectra of derivatized cellulose showed a signal at 2.58 ppm (assigned to P-O-C6) while the doublets at 4.99-5.29 and at 7.38 ppm were assigned to P-O-C2 and P-O-C3, respectively; thus, the formation of monosubstituted phosphorous acid esters of cellulose is advocated. Contact angle measurements showed that the work of adhesion is more important in water than in ethylene glycol, for the phosphorous acid derivatized cellulose. The cytocompatibility of this hydrosoluble derivatized cellulose was tested by direct contact and also by indirect assays on normal human dermal fibroblasts and on osteoblast-like cells (human osteosarcoma). Cell growth on phosphorylated cellulose pellicle and the results from viability assays had shown a good cytocompatibility and lack of toxicity. Phosphorous acid derivatized cellulose would offer a promising biomaterial, useful as scaffolds for new biopolymer composites, and subject for further development as an ionic crosslinker. PMID- 24481533 TI - Osseointegration of bioactive microarc oxidized amorphous phase/TiO2 nanocrystals composited coatings on titanium after implantation into rabbit tibia. AB - The amorphous phase/TiO2 nanocrystals (APTN) composited coatings were prepared on Ti implants for biomedical applications. The Ti implants without and with the APTN composited coatings both do not cause any adverse effects after implantation into the rabbit tibia. The osseointegration of Ti implants after covering the APTN coatings is improved pronouncedly, greatly increasing the interface bonding strength between the implants and newly formed bones. In addition, it is interesting that the newly formed bone tissues appear in the micro-pores of the APTN coatings, promoting the interface bonding between the implants and new bones by the mechanical interlock. Moreover, the Ti implant with the APTN coatings formed at higher applied voltage exhibit higher shear strength and displacement during the pushing out experiment probably due to its better osseointegration. PMID- 24481534 TI - TiNi shape memory alloy coated with tungsten: a novel approach for biomedical applications. AB - This study explores the use of DC magnetron sputtering tungsten thin films for surface modification of TiNi shape memory alloy (SMA) targeting for biomedical applications. SEM, AFM and automatic contact angle meter instrument were used to determine the surface characteristics of the tungsten thin films. The hardness of the TiNi SMA with and without tungsten thin films was measured by nanoindentation tests. It is demonstrated that the tungsten thin films deposited at different magnetron sputtering conditions are characterized by a columnar microstructure and exhibit different surface morphology and roughness. The hardness of the TiNi SMA was improved significantly by tungsten thin films. The ion release, hemolysis rate, cell adhesion and cell proliferation have been investigated by inductively coupled plasma atomic emission spectrometry, CCK-8 assay and alkaline phosphatase activity test. The experimental findings indicate that TiNi SMA coated with tungsten thin film shows a substantial reduction in the release of nickel. Therefore, it has a better in vitro biocompatibility, in particular, reduced hemolysis rate, enhanced cell adhesion and differentiation due to the hydrophilic properties of the tungsten films. PMID- 24481535 TI - Morphological changes in Proteus mirabilis O18 biofilm under the influence of a urease inhibitor and a homoserine lactone derivative. AB - Proteus mirabilis is a pathogenic gram-negative bacterium that frequently causes kidney infections, typically established by ascending colonization of the urinary tract. The present study is focused on ureolytic activity and urease inhibition in biofilms generated by P. mirabilis O18 cells. Confocal microscopy revealed morphological alterations in biofilms treated with urea and a urease inhibitor (acetohydroxamic acid, AHA), as some swarmer cells were found to protrude from the biofilm. The presence of a quorum-sensing molecule (N-butanoyl homoserine lactone, BHL) increased biofilm thickness and its ureolytic activity. Laser interferometric determination of diffusion showed that urea easily diffuses through P. mirabilis biofilm, while AHA is blocked. This may suggest that the use of urease inhibitors in CAUTIs may by less effective than in other urease associated infections. Spectroscopic studies revealed differences between biofilm and planktonic cells indicating that polysaccharides and nucleic acids are involved in extracellular matrix and biofilm formation. PMID- 24481536 TI - Asymmetric cell division in Mycobacterium tuberculosis and its unique features. AB - Recently, several reports showed that about 80 % of mid-log phase Mycobacterium smegmatis, Mycobacterium marinum, and Mycobacterium bovis BCG cells divide symmetrically with 5-10 % deviation in the septum position from the median. However, the mode of cell division of the pathogenic mycobacterial species, Mycobacterium tuberculosis, remained unclear. Therefore, in the present study, using electron microscopy, fluorescence microscopy of septum- and nucleoid stained live and fixed cells, and live cell time-lapse imaging, we show the occurrence of asymmetric cell division with unusually deviated septum/constriction in 20 % of the 15 % septating M. tuberculosis cells in the mid-log phase population. The remaining 80 % of the 15 % septating cells divided symmetrically but with 2-5 % deviation in the septum/constriction position, as reported for M. smegmatis, M. marinum, and M. bovis BCG cells. Both the long and the short portions of the asymmetrically dividing M. tuberculosis cells with unusually deviated septum contained nucleoids, thereby generating viable short and long cells from each asymmetric division. M. tuberculosis short cells were acid fast positive and, like the long cells, further readily underwent growth and division to generate micro-colony, thereby showing that they were neither mini cells, spores nor dormant forms of mycobacteria. The freshly diagnosed pulmonary tuberculosis patients' sputum samples, which are known for the prevalence of oxidative stress conditions, also contained short cells at the same proportion as that in the mid-log phase population. The probable physiological significance of the generation of the short cells through unusually deviated asymmetric cell division is discussed. PMID- 24481538 TI - Objective outcomes analysis following microvascular gracilis transfer for facial reanimation: a review of 10 years' experience. AB - IMPORTANCE Objective assessment of smile outcome after microvascular free gracilis transfer is challenging, and quantification of smile outcomes in the literature is inconsistent. OBJECTIVE To report objective excursion and symmetry outcomes from a series of free gracilis cases and investigate the predictive value of intraoperative measurements on final outcomes. DESIGN, SETTING, AND PARTICIPANTS A retrospective medical chart review was undertaken of all patients who underwent microvascular free gracilis transfer for smile at our institution over the past 10 years. MAIN OUTCOMES AND MEASURES Outcome measures included the following: smile excursion, angle of smile with respect to the vertical midline, and facial symmetry during repose and with smile. Measurements were obtained using an automated tool for assessment of facial landmarks (FACE-Gram). An exhaustive set of intraoperative parameters including degree of recoil of the gracilis muscle following harvest, the degree to which the muscle foreshortened during stimulation of the obturator nerve, final stretched length of the inset muscle, surgeon assessment of neurorrhaphy and pulse pressure, ischemia time, number of sutures used during neurorrhaphy, nerve used to innervate the flap, and surgeon assessment of oral commissure overcorrection were recorded and placed into a linear regression model to investigate correlations with smile. RESULTS From March 2003 to March 2013, 154 microvascular free gracilis transfers were performed for facial reanimation at our institution, 14 (9%) of which were deemed failures. Of the remaining 140 flaps, 127 fulfilled inclusion criteria and constituted the study cohort. Smile excursion, angle excursion, and symmetry of the oral commissure at repose and with smile all improved following gracilis free flap (P < .05). Associations between selected outcomes measures and intraoperative gracilis measurements were identified. CONCLUSIONS AND RELEVANCE Facial reanimation using free gracilis transfer results in quantifiable improvements in oral commissure excursion and facial symmetry both at rest and with smiling. Associations between contractility and internal recoil of the flap and final outcome were identified. LEVEL OF EVIDENCE 4 PMID- 24481539 TI - Multi-modality imaging for stent edge assessment. AB - Optical coherence tomography (OCT) has a sufficiently high resolution to allow assessment of stent edge dissection (ED). The aims of the present study were as follows: (1) evaluation of the frequency of stent ED using OCT; (2) comparison of stent ED detection rates obtained using angiography, intravascular ultrasound (IVUS), and OCT; and (3) IVUS-Virtual Histology (IVUS-VH) evaluation of plaque composition at the site of stent EDs detected by OCT after percutaneous coronary intervention (PCI). Fifty-eight consecutive patients (59 lesions, 100 stent edges) who underwent balloon-expandable stent implantation and post-stent assessment with OCT and IVUS-VH were included. OCT revealed stent ED in 24.0 % (24 of 100) of stent edges after PCI with a balloon-expandable stent. In contrast, ED was detected in only 3.0 % (3 of 100) of stent edges using angiography and 4.0 % (4 of 100) of stent edges using IVUS. Plaque evaluation using IVUS-VH showed that the percent necrotic core (21.2 +/- 8.3 vs. 13.4 +/- 10.7 %, p = 0.001) and absolute dense calcium (2.9 +/- 2.4 vs. 1.3 +/- 2.2 mm(3), p = 0.0104) and dense calcium (13.8 +/- 9.3 vs. 5.4 +/- 5.8 %, p < 0.001) volumes were greater in the ED group than in the non-ED group. Thus, OCT is superior to conventional coronary angiography and IVUS in the identification of stent ED. In addition, the plaque composition at the ED site is characterized by a necrotic core and greater dense calcium levels than those observed at the non-ED site. PMID- 24481540 TI - Impact of sleep-disordered breathing on myocardial damage and metabolism in patients with chronic heart failure. AB - Sleep-disordered breathing (SDB) has a critical association with mortality and morbidity of patients with chronic heart failure (CHF). Troponin T is a marker of ongoing myocardial damage and predicts adverse clinical outcomes in patients with CHF. Carnitine plays an important role in the utilization of fatty acids in the myocardium. It has been reported that myocardial carnitine levels decrease in the failing heart. We hypothesized that plasma troponin T and carnitine are increased due to the leakage from damaged cardiomyocytes or the alteration of myocardial metabolism in CHF patients with SDB. We examined the relation of plasma troponin T and carnitine levels with severity of SDB in CHF. We used portable sleep monitor and measured the apnea-hypopnea index (AHI), plasma levels of high sensitive troponin T and carnitine in 131 CHF patients. These patients were divided into three groups based on AHI: group A (None-mild SDB AHI < 15/h, n = 45), group B (Moderate SDB 15 <= AHI < 30/h, n = 32) and group C (Severe SDB AHI >= 30/h, n = 54). Levels of high-sensitive troponin T and plasm total carnitine were significantly higher in group C than in groups A and B [high-sensitive troponin T; group A 0.009 (0.005-0.016), group B 0.012 (0.006-0.021), group C 0.021 (0.011-0.039) ng/ml, total carnitine; group A 61.0 +/- 15.1, group B 65.0 +/- 13.5, group C 73.3 +/- 17.5 MUmol/l, P < 0.01 vs. group A and P < 0.05 vs. group B, respectively]. Furthermore, in the multiple regression analysis, the independent factors to determine plasma levels of log (high-sensitive troponin T) were high-sensitive C-reactive protein and AHI, and the independent factors to determine plasma levels of carnitine were glomerular filtration rate and AHI. The present study suggests that SDB is associated with latent myocardial damage and alteration of myocardial carnitine metabolism in patients with CHF, presented by higher circulating troponin T and carnitine levels. PMID- 24481541 TI - Do comprehensive, coordinated, recovery-oriented services alter the pattern of use of treatment services? Mental health treatment study impacts on SSDI beneficiaries' use of inpatient, emergency, and crisis services. AB - Current arrangements for financing and delivering behavioral health services to U.S. working-age adults with severe and persistent mental disorders (SPMD) have major inadequacies in funding for and access to critical elements of a recovery oriented, comprehensive, and coordinated package of community-based treatment and rehabilitation services. This study presents results from a nation-wide 2-year randomized trial, involving 2,238 SSDI beneficiaries with SPMD, of a comprehensive intervention including evidence-based treatment and employment services. Estimates of impacts of the MHTS service intervention package, from a variety of regression specifications, showed clearly significant treatment group reductions in four outcomes (hospital stays and days, ER visits for mental health problems, and psychiatric crisis visits); these estimates suggest annual inpatient hospital treatment cost savings in excess of approximately $900 to 1,400. Negative estimated MHTS effects on three other utilization outcomes (hospital stays and days for mental health problems, overall ER visits) generally did not achieve statistical significance. Possible study implications for cost offsets from further expansions/replications of the MHTS intervention model are considered within the context of health reform. PMID- 24481543 TI - Myocardial infarction as a complication in acute stroke: results from the austrian stroke unit registry. AB - BACKGROUND: Patients with transient ischemic attack (TIA) and stroke have an increased risk for subsequent cardiac events including myocardial infarction (MI), which might be associated with a worse clinical outcome. Rapid identification of stroke patients at higher risk for MI might foster intensified cardiac monitoring or certain therapeutic strategies. However, information regarding acute MI as a complication of stroke in the very acute phase is limited. Moreover, there are no systematic data on the occurrence of MI following intracerebral hematoma. We thus aimed to assess the frequency, clinical characteristics and short-term outcome of patients suffering from acute MI in the stroke unit setting. METHODS: We analyzed 46,603 patients from 32 Austrian stroke units enrolled in the prospective Austrian Stroke Unit Registry because of TIA/acute stroke over a 6-year period (January 1, 2007 to January 13, 2013). A total of 41,619 patients (89.3%) had been treated for TIA/ischemic stroke and 4,984 (10.7%) for primary intracerebral hemorrhage (ICH). Acute MI was defined according to clinical evaluation, ECG findings and laboratory assessments. Patients with evidence for MI preceding the cerebrovascular event were not considered. RESULTS: Overall, 421 patients (1%) with TIA/ischemic stroke and 17 patients (0.3%) with ICH suffered from MI during stroke unit treatment for a median duration of 3 days. Patients with TIA/ischemic stroke and MI were significantly older, clinically more severely affected and had more frequently vascular risk factors, atrial fibrillation and previous MI. Total anterior circulation and left hemispheric stroke syndromes were more often observed in MI patients. Patients with MI not only suffered from worse short-term outcome including a higher mortality (14.5 vs. 2%; p < 0.001) at stroke unit discharge, but also acquired more stroke complications like progressive stroke and pneumonia. Multivariate analyses identified previous MI and stroke severity at admission (according to the National Institutes of Health and Stroke Scale score) as factors independently associated with the occurrence of MI on the stroke unit. CONCLUSIONS: While quite rare in the acute phase after stroke, MI is associated with a poor short-term outcome including a higher mortality. Patients with previous MI and severe stroke syndromes appear to be at particular risk for MI as an early complication in the stroke unit setting. Further studies are needed to determine whether increased vigilance and prolonged (cardiac) monitoring or certain therapeutic approaches could improve the outcome in these high-risk patients. PMID- 24481542 TI - Clinicopathologic characteristics of brain tumors are associated with the presence and patterns of TP53 mutations: evidence from the IARC TP53 Database. AB - Biological diversity in the development and progression of brain tumors may be based on the consequences of the nature of the TP53 mutation in the cancer sample. This study was designed to estimate the possible impact of the presence and spectrum of TP53 mutations on clinical variability of brain tumors using the IARC TP53 Database (R17). Somatic and germline mutation patterns differ in brain tumor carriers. The most frequent mutation in sporadic brain tumors is mutation R273C, which is relatively rare in grade 4 tumors compared with lower-grade tumors (p = 1.2 * 10(-5), OR 0.43, 95% CI 0.29-0.63). Mutations at all hot spots, DNA contact mutations, and mutations in the conserved regions of the TP53 gene are also more common in grade 1-3 tumors than in grade 4 tumors. The frequencies of missense mutations at hotspot codons and DNA contact mutations gradually decrease in all three age groups studied, indicating the role of these mutations in early-onset tumors. The role of TP53 somatic mutations in the development of brain tumors has been elucidated in the individual-participant meta-analysis that provided, for the first time, strong evidence that mean age at the onset of sporadic brain tumor is significantly lower in patients with mutated compared with wild-type TP53 in all groups stratified by tumor grade. The presence and patterns of TP53 mutations are associated mainly with the age at the onset and with the development of less malignant brain tumors. Malignant degeneration of brain tumors may depend on other genetic determinants. PMID- 24481544 TI - Vasoactive intestinal peptide receptor-based imaging and treatment of tumors (Review). AB - Vasoactive intestinal peptide receptors (VIPRs) are members of the G-protein coupled receptor superfamily. These receptors are overexpressed in many common malignant tumors and play a major role in the progression and angiogenesis of a number of malignancies. Therefore, VIPRs may be a valuable target for the molecular imaging of tumors and therapeutic interventions. The specific natural ligand or its analogs can be labeled with a radionuclide and used for tumor receptor imaging, which could be used to visualize VIPR-related surface protein expression in vivo and to monitor the in vivo effects of molecular drugs on tumors. Moreover, the involvement of VIPRs in malignant transformation and angiogenesis renders them potential therapeutic targets for cancer treatment. A variety of VIP antagonists and cytotoxic VIP conjugates have been synthesized and evaluated for VIPR-targeted molecular therapy. The importance of VIPRs in tumor biology and the ability to predict responses to targeted therapy and monitor drug interventions suggest that VIP receptor-based imaging and treatment will be critical for the early diagnosis and management of cancer. Here, we review the current literature regarding VIPRs and their natural ligands and the involvement of VIPRs in tumor growth and angiogenesis, with an emphasis on the present use of VIPRs for the molecular imaging of tumors and therapies targeting VIPRs. PMID- 24481545 TI - Tenascin-C causes neuronal apoptosis after subarachnoid hemorrhage in rats. AB - The role of tenascin-C (TNC), a matricellular protein, in brain injury is unknown. The aim of this study was to examine if TNC causes neuronal apoptosis after subarachnoid hemorrhage (SAH), a deadly cerebrovascular disorder, using imatinib mesylate (a selective inhibitor of platelet-derived growth factor receptor [PDGFR] that is reported to suppress TNC induction) and recombinant TNC. SAH by endovascular perforation caused caspase-dependent neuronal apoptosis in the cerebral cortex irrespective of cerebral vasospasm development at 24 and 72 h post-SAH, associated with PDGFR activation, mitogen-activated protein kinases (MAPKs) activation, and TNC induction in rats. PDGFR inactivation by an intraperitoneal injection of imatinib mesylate prevented neuronal apoptosis, as well as MAPKs activation and TNC induction in the cerebral cortex at 24 h. A cisternal injection of recombinant TNC reactivated MAPKs and abolished anti apoptotic effects of imatinib mesylate. The TNC injection also induced TNC itself in SAH brain, which may internally augment neuronal apoptosis after SAH. These findings suggest that TNC upregulation by PDGFR activation causes neuronal apoptosis via MAPK activation, and that the positive feedback mechanisms may exist to augment neuronal apoptosis after SAH. TNC-induced neuronal apoptosis would be a new target to improve outcome after SAH. PMID- 24481546 TI - Building a social neuroscience of autism spectrum disorder. AB - Autism spectrum disorder (ASD) is an early onset neurodevelopmental disorder marked by impairments in reciprocal social interaction, communication, and the presence of repetitive or restricted interests and behaviors. Despite great phenotypic heterogeneity and etiologic diversity in ASD, social dysfunction is the unifying feature of ASD. This chapter focuses on understanding the neural systems involved in the processing of social information and its disruption in ASD by reviewing the conceptual background and highlighting some recent advances. In addition, work investigating an alternative interpretation of autistic dysfunction, problems with interconnectivity, and consequent difficulties with complex information processing are addressed. PMID- 24481547 TI - Neuronal-glial mechanisms of exercise-evoked stress robustness. AB - Stress robustness by definition, incorporates both stress resistance (organisms endure greater stressor intensity or duration before suffering negative consequences) and stress resilience (organisms recover faster after suffering negative consequences). Factors that influence stress robustness include the nature of the stressor, (i.e., controllability, intensity, chronicity) and features of the organism (i.e., age, genetics, sex, and physical activity status). Here we present a novel hypothesis for how physically active versus sedentary living promotes stress robustness in the face of intense uncontrollable stress. Advances in neurobiology have established microglia as an active player in the regulation of synaptic activity, and recent work has revealed mechanisms for modulating glial function, including cross talk between neurons and glia. This chapter presents supporting evidence that the physical activity status of an organism may modulate stress-evoked neuronal-glial responses by changing the CX3CL1-CX3CR1 axis. Specifically, we propose that sedentary animals respond to an intense acute uncontrollable stressor with excessive serotonin (5-HT) and noradrenergic (NE) activity and/or prolonged down-regulation of the CX3CL1-CX3CR1 axis resulting in activation and proliferation of hippocampal microglia in the absence of pathogenic signals and consequent hippocampal-dependent memory deficits and reduced neurogenesis. In contrast, physically active animals respond to the same stressor with constrained 5-HT and NE activity and rapidly recovering CX3CL1-CX3CR1 axis responses resulting in the quieting of microglia, and protection from negative cognitive and neurobiological effects of stress. PMID- 24481548 TI - Hypoxia-mediated histone acetylation and expression of N-myc transcription factor dictate aggressiveness of neuroblastoma cells. AB - Cells of solid malignancies generally adapt to entire lack of oxygen. Hypoxia induces the expression of several genes, which allows the cells to survive. For DNA transcription, it is necessary that DNA structure is loosened. In addition to structural characteristics of DNA, its epigenetic alterations influence a proper DNA transcription. Since histones play a key role in epigenetics, changes in expression levels of acetylated histones H3 and H4 as well as of hypoxia inducible factor-1alpha (HIF-1alpha) in human neuroblastoma cell lines cultivated under standard or hypoxic conditions (1% O2) were investigated. Moreover, the effect of hypoxia on the expression of two transcription factors, c-Myc and N myc, was studied. Hypoxic stress increased levels of acetylated histones H3 and H4 in UKF-NB-3 and UKF-NB-4 neuroblastoma cells with N-myc amplification, whereas almost no changes in acetylation of these histones were found in an SK-N-AS neuroblastoma cell line, the line with diploid N-myc status. An increase in histone H4 acetylation caused by hypoxia in UKF-NB-3 and UKF-NB-4 corresponds to increased levels of N-myc transcription factor in these cells. PMID- 24481549 TI - Permeability improvements of electropolymerized polypyrrole films using dissolvable nano-CaCO3 particle templates. AB - The electropolymerisation of N-substituted pyrroles on a dissolvable calcium carbonate nanoparticle template was investigated in order to improve the film permeabilities in aqueous solution. After deposition of CaCO3 nanoparticles on the electrode surface, poly(pyrrole-ammonium) or poly(pyrrole-NTA) (NTA: nitrilotriacetic acid) were electrogenerated around the template structures of the electrodes using potentiostatic methods. The dissolution of nanoparticles in acidic medium leads to the formation of nano-porous structures increasing, therefore, the polypyrrole permeability in aqueous solutions. Histidine-tagged glucose oxidase, chosen as an enzyme model, was immobilised on the modified polypyrrole-NTA via the NTA-Cu(2+)-histidine interactions to validate the proposed method. The described setup led to a twofold increase in the maximum current density from 5 to 10 MUA cm(-2) after template dissolution. PMID- 24481550 TI - Tellurite reduction by Escherichia coli NDH-II dehydrogenase results in superoxide production in membranes of toxicant-exposed cells. AB - Tellurite, the most soluble tellurium oxyanion, is extremely harmful for most microorganisms. Part of this toxicity is due to the generation of reactive oxygen species that in turn cause oxidative stress. However, the way in which tellurite interferes with cellular processes is not well understood to date. Looking for new cellular tellurite targets, we decided to evaluate the functioning of the electron transport chain in tellurite-exposed cells. In this communication we show that the E. coli ndh gene, encoding NDH-II dehydrogenase, is significantly induced in toxicant-exposed cells and that the enzyme displays tellurite-reducing activity that results in increased superoxide levels in vitro. PMID- 24481551 TI - Retention and surface changes of zirconia primary crowns with secondary crowns of different materials. AB - OBJECTIVES: To evaluate zirconia as a substitute for gold alloy in primary crowns facing secondary crowns manufactured with different materials, in terms of long term retention force changes, wear, and phase transformation was aimed. MATERIALS AND METHODS: A total of 12 groups, each containing six samples, consisting of gold alloy primary crown-electroformed gold secondary crowns (AA), zirconia primary crown-electroformed gold secondary crowns (ZA) and zirconia primary crown casted non-precious alloy secondary crowns (ZC) with conus angles of 0 degrees , 2 degrees , 4 degrees , and 6 degrees were evaluated. Samples were subjected to 10,000 insertion-separation cycles in artificial saliva and retention force was measured. X-ray diffraction and scanning electron microscope analysis were performed on the sample surfaces. RESULTS: The highest retention forces were obtained from ZC-0 degrees group (72.09-71.26 N) and the lowest were obtained from ZA-4 degrees (12.73-19.44 N) and ZA-6 degrees (5.36-19.73 N) groups in the beginning and after 10,000 cycles, respectively. Retention force increased as the conus angle decreased. The monoclinic phase ratio of the zirconia primary crowns decreased after the experiments. No wear was observed in zirconia primary crowns except for the ZC-0 degrees and ZC-2 degrees groups. The use of zirconia primary crowns resulted in a less excursive retention force. CONCLUSIONS: A more predictable and less excursive retention force can be obtained using a hard and rigid primary crown material like zirconia. CLINICAL RELEVANCE: Despite a lack of knowledge about the aging of zirconia without a veneer layer in the oral environment, zirconia primary crowns are more advantageous in terms of retention force development and wear. PMID- 24481552 TI - Visual acuity of dentists in their respective clinical conditions. AB - OBJECTIVES: This study examined the impact of age and magnification on the near visual acuity of dentists in their private practice under simulated clinical conditions. MATERIALS AND METHODS: Miniaturized visual tests were fixed in posterior teeth of a dental phantom head and brought to 31 dentists in their respective private practice. The visual acuity of these dentists (n = 19, >=40 years; n = 12, <40 years) was measured in a clinical setting under the following conditions: (a) natural visual acuity, distance of 300 mm; (b) natural visual acuity, free choice of the distance; and (c) loupe and additional light source, if available. RESULTS: The visual acuity under the different clinical conditions varied widely between individuals. The older group of dentists had a lower median visual acuity value under all clinical conditions. This difference was highly significant for natural visual acuity at a free choice of distance (p < 0.0001). For younger dentists (<40 years), visual acuity could be significantly improved by reducing the eye-object distance (p = 0.001) or by using loupes (p = 0.008). For older dentists (>=40 years), visual acuity could be significantly improved by using loupes (p = 0.0005). CONCLUSIONS: Visual performance decreased with increasing age under the specific clinical conditions of each dentist's private practice. Magnification aids can compensate for visual deficiencies. CLINICAL RELEVANCE: The question of whether findings obtained under standardized conditions are valuable for the habitual setting of each dentist's private practice seems clinically relevant. PMID- 24481553 TI - Carnosol induces apoptosis through generation of ROS and inactivation of STAT3 signaling in human colon cancer HCT116 cells. AB - Carnosol, an active constituent of rosemary, has been reported to possess anti inflammatory and anticancer activities. However, the molecular mechanisms underlying the anticancer effects of carnosol remain poorly understood. In the present study, we found that carnosol significantly reduced the viability of human colon cancer (HCT116) cells in a concentration- and time-dependent manner. Treatment of cells with carnosol induced apoptosis, which was associated with activation of caspase-9 and -3 and the cleavage of poly-(ADP-ribose) polymerase (PARP). Incubation with carnosol elevated the expression of Bax and inhibited the levels of Bcl-2 and Bcl-xl. Carnosol induced expression of p53 and inhibited that of murine-double minute-2 (Mdm2). Moreover, carnosol generated reactive oxygen species (ROS), and pretreatment with N-acetyl cysteine abrogated carnosol-induced cleavage of caspase-3 and PARP. The constitutive phosphorylation, the DNA binding and reporter gene activity of signal transducer and activator of transcription-3 (STAT3) was diminished by treatment with carnosol. To further elucidate the molecular mechanisms of STAT3 inactivation, we found that carnosol attenuated the phosphorylation of Janus-activated kinase-2 (Jak2) and Src kinase. Pharmacological inhibition of Jak2 and Src inhibited STAT3 phosphorylation. Furthermore, carnosol attenuated the expression of STAT3 target gene products, such as survivin, cyclin-D1, -D2, and -D3. Taken together, our study provides the first report that carnosol induced apoptosis in HCT116 cells via generation of ROS, induction of p53, activation of caspases and inhibition of STAT3 signaling pathway. PMID- 24481554 TI - Epidemiology of GB virus type C among patients infected with HIV in Singapore. AB - Several studies have shown that individuals co-infected with GB virus type C (GBV C), and human immunodeficiency virus (HIV) have slower progression to acquired immunodeficiency syndrome (AIDS) and a prolonged lifespan, compared to those infected with only HIV. In Singapore, despite the steadily increasing number of HIV infections in recent years, there are no studies documenting the extent of GBV-C/HIV co-infection in this group of patients. To fill this dearth of information, two GBV-C screening assays was performed on 80 archived HIV-1 positive samples from the National University Hospital. The overall prevalence of GBV-C co-infection among patients infected with HIV in this study was 10% (8/80). Phylogenetic analysis of the eight dual-infection cases revealed that genotypes 3 (4/8, 50%) and 2a (2/8, 25%) were the main genotypes circulating among these Singaporean HIV patients. One case each of genotypes 2b (1/8, 12.5%) and 4 (1/8, 12.5%), which have not been described previously in Singapore, were identified. These findings hint at the complex epidemiology of GBV-C in different patient groups and a larger study would be needed to characterize, and understand the potential clinical impact of GBV-C co-infection on the patients. PMID- 24481555 TI - Receptor potentials and action potentials in Drosera tentacles. AB - Voltage fluctuations identified as receptor potentials can be detected with electrodes applied to the mucilage surrounding the head of a tentacle of Drosera intermedia if the head is stimulated by contact with a live insect, by the touch of a clean, inert object, or by application of salt solutions. Associated with a low receptor potential are action potentials, which occur at a frequency dependent on the magnitude of the receptor potential. These action potentials can be detected with electrodes applied to any region of the stalk of the tentacle. Inflection of the lower stalk follows the occurrence of action potentials. Inflection is minute for isolated action potentials but large and rapid when several occur within a brief interval.The apparent amplitude of action potentials recorded from the stalk is independent of receptor potential amplitude, but that of action potentials recorded from the mucilage commonly decreases as the receptor potential deviates from the baseline and increases as it returns. It is suggested that variation of apparent amplitude of the action potentials may result from postulated variation in the resistance of receptor membranes. PMID- 24481556 TI - Properties of action potentials in Drosera tentacles. AB - Action potentials of Drosera tentacles resemble those of vertebrate peripheral nerves in that they appear to be comprised of relatively uniform spikes, variable shoulders or negative after-potentials, and variable positive after-potentials. The peaking of the spike corresponds to a period of great refractoriness, while action potentials of low amplitude may be fired readily during the negative after potential. The action potentials fired during the negative after-potential appear to be unlike those of peripheral nerves in that they are of abnormally brief duration. Also apparently different from the case in peripheral nerves is the dependence of the duration of an action potential on the interval separating it from the preceding action potential.Action potentials propagate from the neck of the stalk to its base at about 5 mm s(-1) at room temperature. Propagation may be reversed artificially, consistent with the possibility that the neuroid cells are electrically coupled. PMID- 24481557 TI - Isolation and identification of the gibberellins of Cucumis sativus and Cucumis melo. AB - Thin-layer chromatography, gas-liquid chromatography, and mass spectrometry were used to identify gibberellins isolated from mature seeds of both Cucumis sativus (cucumber) and Cucumis melo (muskmelon). The gibberellins were extracted and purified by organic solvent fractionation, paper and thin-layer chromatography, and crystallization. Seeds of C. sativus were found to contain gibberellins A1, A3, A4, and A7 with A1 the predominant species. Seeds of C. melo contained gibberellins A1 and A3 and a trace of A5. Direct probe mass spectrometry of the gibberellins proved successful for identification purposes. Distinctive molecular ions and fragmentation patterns were obtained for each gibberellin. PMID- 24481558 TI - Maleic hydrazide as an antimetabolite of uracil. AB - When labelled uracil was supplied to the solution bathing the cambial surfaces of bark strips of willow, uptake into the sieve elements took place as evidenced by the appearance of radioactivity in the honeydew of aphids feeding on the strips. When maleic hydrazide (MH) was also applied an inhibition of uracil uptake was observed. However uracil seemed to have no effect on MH uptake. The type of inhibition described above showed similarities to classical competitive inhibitors of enzymes. PMID- 24481559 TI - [Comparison of specific synthesis of RNA in synchronized Euglena gracilis (Z) grown on lactate medium in the dark and in the light, and a study of the mitochondria]. AB - Synchronization of Euglena gracilis (Z) on lactate medium is shown to be independent of illumination. The existence of a mitochondrial cycle in lightgrown as well as in dark-grown Euglena is demonstrated. When RNA synthesis is studied by pulse labeling with tritiated uracil in synchronously growing cells, a discontinuous RNA synthesis is found. Two peaks of preferential RNA synthesis in dark-grown cells and three peaks in light-grown cells are seen; the significance of the third peak of RNA synthesis in light-grown Euglena is discussed. PMID- 24481560 TI - Enzymatic production of the plant growth inhibitor, xanthoxin. AB - Incubation of violaxanthin with lipoxygenase and linoleate gave rise to the plant growth inhibitor, xanthoxin; and the yields were reduced to 1/10 and 1/20 by the omission of lipoxygenase and both lipoxygenase and linoleate respecively. PMID- 24481561 TI - Relationship between carbohydrate movement and the symbiosis in lichens with green algae. AB - When isolated in pure culture, four genera of lichen algae were able to produce the polyol which is known to move from the alga to the fungus in lichens with these algae. This conclusion corrects earlier suggestions that the mobile polyol is only formed by the alga in the lichen thallus. Stichococcus produced sorbitol and it is therefore suggested that, in lichens with this alga, sorbitol moves between the symbionts. Hyalococcus and Stichococcus had a similar pattern of incorporation of H(14)CO 3 (-) in the light, suggesting a close relationship between these algae which are only separated now on morphological grounds.The pattern of incorporation of H(14)CO 3 (-) in the light into Cladonia cristatella and its alga (Trebouxia erici) in culture indicates that in the cultured algae more (14)C was incorporated into ethanol insoluble substances and lipids and less into ribitol than in the lichen. The pattern in a joint culture of the alga and the fungus of C. cristatella was approximately intermediate between that of the lichen and the alga. However, only a small amount of (14)C fixed by the alga reached the fungus in the joint culture, and it is therefore suggested that the presence of the fungus without morphological differentiation into a lichen thallus is not sufficient to promote the alga to release carbohydrate. PMID- 24481562 TI - Embryoid formation by fragments of cotyledons and hypocotyls in Cucurbita pepo. AB - After a prolonged culture on Murashige-Skoog medium the primary explants of hypocotyls and cotyledons of the pumpkin develop embryoid-producing callus tissue. Ten separate strains of such tissue have been obtained and have now been in culture for more than one year, continuing to produce embryoids. PMID- 24481563 TI - Effects of binge ethanol on lipid homeostasis and oxidative stress in a rat model of nonalcoholic fatty liver disease. AB - Excess fat accumulation renders the liver more vulnerable to ethanol, but it is still unclear how alcohol enhances lipid dysmetabolism and oxidative stress in a pre-existing steatosis condition. The effects produced by binge ethanol consumption in the liver of male Wistar rats fed a standard (Ctrl) or a high-fat diet HFD were compared. The liver status was checked through tissue histology and standard serum parameters. Alteration of hepatic lipid homeostasis and consequent oxidative unbalance were assessed by quantifying the mRNA expression of the lipid regulated peroxisome proliferator-activated receptors (PPARs), of the cytochromes CYP2E1 and CYP4A1, and of some antioxidant molecules such as the metallothionein isoforms MT1 and MT2 and the enzymes catalase and superoxide dismutase. The number of adipose differentiation-related protein (ADRP)-positive lipid droplets (LDs) was evaluated by immunohistochemical staining. As a response to the double insult of diet and ethanol the rat liver showed: (1) a larger increase in fat accumulation within ADRP-positive LDs; (2) stimulation of lipid oxidation in the attempt to limit excess fat accumulation; (3) induction of antioxidant proteins (MT2, in particular) to protect the liver from the ethanol-induced overproduction of oxygen radicals. The data indicate an increased susceptibility of fatty liver to ethanol and suggest that the synergistic effect of diet and ethanol on lipid dysmetabolism might be mediated, at least in part, by PPARs and cytochromes CYP4A1 and CYP2E1. PMID- 24481564 TI - Trait anxiety, information modality, and responses to communications about prenatal genetic testing. AB - Decisions to undergo invasive prenatal diagnostic procedures can be anxiety provoking. Individuals receive information about these procedures in one of three modalities: written text, audio (verbal description), or video. We examined whether modality influences emotional responses and testing decisions, and whether trait anxiety, a disposition linked with heightened sensitivity to threatening information, moderates these effects. New Zealand adults (N = 176) completed a trait anxiety measure before random allocation to view a text, audio, or video message about amniocentesis and chorionic villus sampling. Participants completed measures of child related worry, anticipated emotional distress, anticipated coping efficacy, perceived likelihood of miscarriage, and testing interest. High-anxious individuals reported greater distress and lower coping efficacy in response to the video message compared to the audio message. They also reported greater miscarriage likelihood in response to the video message compared to the text message. These findings suggest that use of video, assumed to be most informative for educating patients, could induce greater distress about prenatal testing in individuals prone to anxiety. PMID- 24481566 TI - Neuroprotection by the synthetic neurosteroid enantiomers ent-PREGS and ent-DHEAS against Abeta25-35 peptide-induced toxicity in vitro and in vivo in mice. AB - RATIONALE: Pregnenolone sulfate (PREGS) and dehydroepiandrosterone sulphate (DHEAS) are pro-amnesic, anti-amnesic and neuroprotective steroids in rodents. In Alzheimer's disease (AD) patient's brains, their low concentrations are correlated with high levels of Abeta and tau proteins. The unnatural enantiomer ent-PREGS enhanced memory in rodents. We investigated here whether ent-PREGS and ent-DHEAS could be neuroprotective in AD models. OBJECTIVE: The effects of PREGS, ent-PREGS, DHEAS and ent-DHEAS against Abeta25-35 peptide-induced toxicity were examined in vitro on B104 neuroblastoma cells and in vivo in mice. METHODS: B104 cells pretreated with the steroids before Abeta25-35 were analysed by flow cytometry measuring cell viability and death processes. Mice injected intracerebroventricularly with Abeta25-35 and the steroids were analysed for their memory abilities. Additionally, lipid peroxidation levels in the hippocampus were measured. RESULTS: ent-PREGS and PREGS significantly attenuated the Abeta25-35-induced decrease in cell viability. Both steroids prevented the Abeta25-35-induced increase in late apoptotic cells. PREGS further attenuated the ratio of necrotic cells. ent-DHEAS and DHEAS significantly reduced the Abeta25-35 induced toxicity and prevented the cells from entering late apoptosis and necrosis. All steroids stimulated neurite outgrowth per se and prevented the Abeta25-35-induced decrease. In vivo, ent-PREGS and ent-DHEAS significantly attenuated the Abeta25-35-induced decrease in memory (spontaneous alternation and passive avoidance) and an increase in lipid peroxidation levels. In contrast to the natural steroids, both enantiomers prevented amnesia when injected 6 h before Abeta25-35 in contrast to the natural steroids. CONCLUSION: The unnatural steroids ent-PREGS and ent-DHEAS are potent neuroprotective agents and could be effective therapeutical tools in AD. PMID- 24481567 TI - Assessment of the kappa opioid agonist, salvinorin A, as a punisher of drug self administration in monkeys. AB - RATIONALE: Drugs can function as punishers. However, work on the study of drugs as punishers is limited, as is the range of compounds known to function as punishers. Kappa opioid agonists, which have received much experimental attention as potential therapeutics for drug abuse, reportedly produce aversive effects. However, kappa agonists have yet to be tested as punishers of behavior. OBJECTIVE: The goal of the current study was to determine if a kappa agonist could function as a punisher of drug self-administration. METHOD: In separate experiments, monkeys were allowed to choose in a two-lever choice design between intravenous injections of equal doses of either cocaine (0.1 mg/kg/injection on each lever) or remifentanil (0.1 MUg/kg/injection on each lever) when one of the two options was mixed with various doses of the kappa agonist, salvinorin A. RESULTS: Choice for the cocaine and remifentanil options that were combined with salvinorin A decreased as a function of salvinorin A dose in all monkeys. However, operant response rates were not systematically affected by salvinorin A administration. CONCLUSION: The present findings demonstrate that the kappa agonist, salvinorin A, can punish self-administration of a psychotimulant, cocaine, and a mu opioid, remifentanil. In consideration of these findings, it may be possible to curtail the abuse of some drugs by contingently delivering kappa agonists (e.g., as combination formularies for prescription medications). PMID- 24481565 TI - Impacts of stress and sex hormones on dopamine neurotransmission in the adolescent brain. AB - RATIONALE: Adolescence is a developmental period of complex neurobiological change and heightened vulnerability to psychiatric illness. As a result, understanding factors such as sex and stress hormones which drive brain changes in adolescence, and how these factors may influence key neurotransmitter systems implicated in psychiatric illness, is paramount. OBJECTIVES: In this review, we outline the impact of sex and stress hormones at adolescence on dopamine neurotransmission, a signaling pathway which is critical to healthy brain function and has been implicated in psychiatric illness. We review normative developmental changes in dopamine, sex hormone, and stress hormone signaling during adolescence and throughout postnatal life, then highlight the interaction of sex and stress hormones and review their impacts on dopamine neurotransmission in the adolescent brain. RESULTS AND CONCLUSIONS: Adolescence is a time of increased responsiveness to sex and stress hormones, during which the maturing dopaminergic neural circuitry is profoundly influenced by these factors. Testosterone, estrogen, and glucocorticoids interact with each other and have distinct, brain region-specific impacts on dopamine neurotransmission in the adolescent brain, shaping brain maturation and cognitive function in adolescence and adulthood. Some effects of stress/sex hormones on cortical and subcortical dopamine parameters bear similarities with dopaminergic abnormalities seen in schizophrenia, suggesting a possible role for sex/stress hormones at adolescence in influencing risk for psychiatric illness via modulation of dopamine neurotransmission. Stress and sex hormones may prove useful targets in future strategies for modifying risk for psychiatric illness. PMID- 24481568 TI - Atomoxetine reduces anticipatory responding in a 5-choice serial reaction time task for adult zebrafish. AB - Deficits in impulse control are related to a number of psychiatric diagnoses, including attention deficit hyperactivity disorder, addiction, and pathological gambling. Despite increases in our knowledge about the underlying neurochemical and neuroanatomical correlates, understanding of the molecular and cellular mechanisms is less well established. Understanding these mechanisms is essential in order to move towards individualized treatment programs and increase efficacy of interventions. Zebrafish are a very useful vertebrate model for exploring molecular processes underlying disease owing to their small size and genetic tractability. Their utility in terms of behavioral neuroscience, however, hinges on the validation and publication of reliable assays with adequate translational relevance. Here, we report an initial pharmacological validation of a fully automated zebrafish version of the commonly used five-choice serial reaction time task using a variable interval pre-stimulus interval. We found that atomoxetine reduced anticipatory responses (0.6 mg/kg), whereas a high-dose (4 mg/kg) methylphenidate increased anticipatory responses and the number of trials completed in a session. On the basis of these results, we argue that similar neurochemical processes in fish as in mammals may control impulsivity, as operationally defined by anticipatory responses on a continuous performance task such as this, making zebrafish potentially a good model for exploring the molecular basis of impulse control disorders and for first-round drug screening. PMID- 24481569 TI - Deletion of the GABAA alpha2-subunit does not alter self administration of cocaine or reinstatement of cocaine seeking. AB - RATIONALE: GABAA receptors containing alpha2-subunits are highly represented in brain areas that are involved in motivation and reward, and have been associated with addiction to several drugs, including cocaine. We have shown previously that a deletion of the alpha2-subunit results in an absence of sensitisation to cocaine. OBJECTIVE: We investigated the reinforcing properties of cocaine in GABAA alpha2-subunit knockout (KO) mice using an intravenous self-administration procedure. METHODS: alpha2-subunit wildtype (WT), heterozygous (HT) and KO mice were trained to lever press for a 30 % condensed milk solution. After implantation with a jugular catheter, mice were trained to lever press for cocaine (0.5 mg/kg/infusion) during ten daily sessions. Responding was extinguished and the mice tested for cue- and cocaine-primed reinstatement. Separate groups of mice were trained to respond for decreasing doses of cocaine (0.25, 0.125, 0.06 and 0.03 mg/kg). RESULTS: No differences were found in acquisition of lever pressing for milk. All genotypes acquired self administration of cocaine and did not differ in rates of self-administration, dose dependency or reinstatement. However, whilst WT and HT mice showed a dose dependent increase in lever pressing during the cue presentation, KO mice did not. CONCLUSIONS: Despite a reported absence of sensitisation, motivation to obtain cocaine remains unchanged in KO and HT mice. Reinstatement of cocaine seeking by cocaine and cocaine-paired cues is also unaffected. We postulate that whilst not directly involved in reward perception, the alpha2-subunit may be involved in modulating the "energising" aspect of cocaine's effects on reward seeking. PMID- 24481570 TI - Efficacy of olanzapine monotherapy for treatment of bipolar I depression: a randomized, double-blind, placebo controlled study. AB - RATIONALE AND OBJECTIVE: Depression symptoms are now recognized to be the predominant cause of disability for bipolar disorder (BD) patients. The treatment strategies for the depressed phase of BD remain more anecdotal than data-based. Olanzapine has been investigated as an alternative to antidepressants and a mood stabilizer for acute bipolar depression. The purpose of this study was to assess the efficacy of olanzapine monotherapy for bipolar I depression. METHOD: Sixty eight patients with bipolar I depression were randomly assigned to treatment with olanzapine (mean final dose 14.4 mg/day) (n=34) or placebo (n=34) in a double blind parallel-group study design. Planned assessments included Montgomery-Asberg Depression Rating Scale (MADRS), Young Mania Rating Scale (YMRS), Clinical Global Impressions-Severity of Illness scale (CGI-S), Clinical Global Impressions Improvement scale (CGI-I), Hamilton Depression scale (HAMD), Hamilton Anxiety scale (HAMA), and Treatment Emergent Symptom Scale (TESS). RESULTS: Of the 68 patients who were randomly assigned, 57 (83.8 %) completed treatments. Improvements in MADRS total score, CGI-S, CGI-I, and HAMD in the olanzapine group were significantly greater relative to those in the placebo group during the 8 week follow-up period (p<0.001, p=0.0017, p=0.007, and p<0.001, respectively). Rates of categorical treatment response and remission in the olanzapine group (50.0 % and 35.3 %, respectively) were significantly higher than those in the placebo group (20.6 %, p=0.011 and 11.8 %, p=0.022, respectively). At the 8-week treatment, the mean weight and the total cholesterol, triglyceride, and low density lipoprotein cholesterol levels increased significantly in the olanzapine group (p=0.037, p=0.029, p=0.030, and p=0.028, respectively). CONCLUSIONS: Olanzapine is effective in the treatment of bipolar I depression but is associated with significant metabolic side effects. PMID- 24481571 TI - Autism spectrum disorders--an emerging area in psychopharmacology. PMID- 24481572 TI - Implanted neural progenitor cells regulate glial reaction to brain injury and establish gap junctions with host glial cells. AB - Transplantation of neural stem/progenitor cells (NPCs) in the lesioned brain is able to restore morphological and physiological alterations induced by different injuries. The local microenvironment created at the site of grafting and the communication between grafted and host cells are crucial in the beneficial effects attributed to the NPC implants. We have previously described that NPC transplantation in an animal model of central axotomy restores firing properties and synaptic coverage of lesioned neurons and modulates their trophic factor content. In this study, we aim to explore anatomical relationships between implanted NPCs and host glia that might account for the implant-induced neuroprotective effects. Postnatal rat subventricular zone NPCs were isolated and grafted in adult rats after transection of the medial longitudinal fascicle. Brains were removed and analyzed eight weeks later. Immunohistochemistry for different glial markers revealed that NPC-grafted animals displayed significantly greater microglial activation than animals that received only vehicle injections. Implanted NPCs were located in close apposition to activated microglia and reactive astrocytes. The gap junction protein connexin43 was present in NPCs and glial cells at the lesion site and was often found interposed within adjacent implanted and glial cells. Gap junctions were identified between implanted NPCs and host astrocytes and less frequently between NPCs and microglia. Our results show that implanted NPCs modulate the glial reaction to lesion and establish the possibility of communication through gap junctions between grafted and host glial cells which might be involved in the restorative effects of NPC implants. PMID- 24481573 TI - Glioblastoma-associated stromal cells (GASCs) from histologically normal surgical margins have a myofibroblast phenotype and angiogenic properties. AB - Glioblastoma (GB) displays diffusely infiltrative growth patterns. Dispersive cells escape surgical resection and contribute to tumour recurrence within a few centimeters of the resection cavity in 90% of cases. We know that the non neoplastic stromal compartment, in addition to infiltrative tumour cells, plays an active role in tumour recurrence. We isolated a new stromal cell population from the histologically normal surgical margins of GB by computer-guided stereotaxic biopsies and primary culture. These GB-associated stromal cells (GASCs) share phenotypic and functional properties with the cancer-associated fibroblasts (CAFs) described in the stroma of carcinomas. In particular, GASCs have tumour-promoting effects on glioma cells in vitro and in vivo. Here, we describe a quantitative proteomic analysis, using iTRAQ labelling and mass spectrometry, to compare GASCs with control stromal cells derived from non-GB peripheral brain tissues. A total of 1077 proteins were quantified and 67 proteins were found to differ between GASCs and control stromal cells. Several proteins changed in GASCs are related to a highly motile myofibroblast phenotype, and to wound healing and angiogenesis. The results for several selected proteins were validated by western blotting or flow cytometry. Furthermore, the effect of GASCs on angiogenesis was confirmed using the orthotopic U87MG glioma model. In conclusion, GASCs, isolated from GB histologically normal surgical margins and found mostly near blood vessels, could be a vascular niche constituent establishing a permissive environment, facilitating angiogenesis and possibly colonization of recurrence-initiating cells. We identify various proteins as being expressed in GASCs: some of these proteins may serve as prognostic factors for GB and/or targets for anti-glioma treatment. PMID- 24481575 TI - Pure endoscopic removal of epidermoid tumors of the cerebellopontine angle. AB - PURPOSE: Epidermoid tumors located in the cerebellopontine angle (CPA) are challenging lesions because they tend to grow slowly in the subarachnoid cisterns around delicate neurovascular structures and often extend into surgical anatomic corners. The aim of this paper is to demonstrate the advantages and limitations of purely endoscopic removal of the CPA epidermoids. METHODS: Six patients harboring an epidermoid tumor located in the CPA were treated using an endoscope controlled microsurgical technique. A retrosigmoid suboccipital approach was used in all patients. The cerebellomedullary cistern and the cisterna magna were opened to allow cerebrospinal fluid drainage and cerebellar drop, thus yielding a wide and straight working channel to the CPA. Then, the tumor and its capsule were removed by the modified microsurgical instruments. RESULT: The symptoms caused by mass effect of the lesion resolved after surgery. There were no deaths, but permanent deficits occurred in one patient whose cranial nerves VII/VIII complex was accidentally lesioned. Tumors and their capsules were totally removed in five cases. All patients were discharged 3-5 days after surgery. To date, no recurrences have been observed (follow-up range 14-50 months). CONCLUSION: The endoscope-controlled microsurgical technique enables a safe tumor removal even when parts of the lesion are not visible in a straight line in CPA epidermoids. By angled endoscopic lenses, tumor extending into adjacent cranial compartments or surgical anatomic corners can be removed through a single small craniotomy without retracting neurovascular structures. PMID- 24481576 TI - Neuroendoscopic biopsy of pediatric brain tumors with small ventricle. AB - PURPOSE: Intraventricular endoscopic procedures to resect or biopsy peri- or intraventricular tumors may have not been used in patients with small ventricles due to the presumed difficulties with ventricular cannulation and the perceived risk of morbidity. The purpose of this study is to review the feasibility and safety of neuroendoscopic procedures in the biopsy of pediatric brain tumors with a small ventricle. METHODS: Between January 2006 and January 2013, 72 children were identified with brain tumors confirmed by transventricular endoscopic biopsy. Patients were divided into non-hydrocephalus and hydrocephalus groups, and the ratio of the two groups was 20:52. RESULTS: In 20 pediatric brain tumors with small ventricle, the targeted lesion was successfully approached under the guidance of neuronavigation. Navigational tracking was especially helpful in entering small ventricles and in approaching the third ventricle through the narrow foramen of Monro. The histopathologic diagnosis was established in all 20 patients: nine germinomas, three mixed germ cell tumors, two pilomyxoid astrocytomas, and two pilocytic astrocytomas. The tumor biopsy sites were the suprasellar area (n = 10), pineal area (n = 4), lateral ventricular wall (n = 4), and mammillary body (n = 1). There were no major morbidities related to the endoscopic procedure. CONCLUSION: Neuroendoscopic biopsy or resection of peri- or intraventricular tumors in pediatric patients without hydrocephalus is feasible. Navigation-guided neuroendoscopic procedures improved the accuracy of the neuroendoscopic approach and minimized brain trauma. The absence of ventriculomegaly in patients with brain tumor may not serve as a contraindication to neuroendoscopic tumor biopsy. PMID- 24481577 TI - Use of complementary and alternative medicine by a sample of Turkish primary headache patients. AB - OBJECTIVE: Complementary and alternative medicine (CAM) is increasingly being used as adjunctive treatment in primary headache syndromes in many countries. In the Turkish population, no epidemiologic data have been reported about awareness and usage of these treatments in patients with headache. METHODS: One hundred and ten primary headache patients attending three headache clinics completed a questionnaire regarding their headaches, the known modalities and the use and effect of CAM procedures for their headaches. RESULTS: The mean age of the patients was 34.7+/-9.6 years (32.8-36.5). Almost two-thirds of patients had completed high school and university, and one-third of patients were housewives. Migraine without aura (45.5%) was the most frequently diagnosed type of headache followed by migraine with aura (19.1%) and tension-type headache (18.2%). In 43.6% of the patients, headache frequency was 5-10 per month. The most frequently known CAM modalities were massage (74.5%), acupuncture (44.5%), yoga (31.8%), exercise (28.2%), psychotherapy (25.5%), and rosemary (23.6%). The most frequently used CAM treatments were massage (51%) and exercise (11%). Only massage was reported to be beneficial in one-third of the primary headache patients; the other modalities were not. CONCLUSION: Our findings suggest that the subgroup of primary headache patients in Turkey seek and use alternative treatments, frequently in combination with standard treatments. Neurologists should become more knowledgeable regarding CAM therapies; further randomized and controlled clinical researches with large sample sizes are needed. PMID- 24481578 TI - The effectiveness of subcutaneously implanted epidural ports for relief of severe pain in patients with advanced-stage gynecological cancer: a prospective study. AB - OBJECTIVE: We aimed to evaluate the effectiveness of subcutaneously implanted epidural ports (SIEP) in the management of patients with advanced-stage gynecologic cancer-related severe chronic pain who do not respond to intravenous tramadol infusion, transdermal fentanyl, and oral morphine administration or who cannot tolerate the unacceptable and unmanageable side effects of these drugs. METHODS: In this prospectively designed study, SIEP to permit the administration of morphine were implanted for relief of severe chronic pain in 21 cases with stage IV gynecological cancer (ovarian [n=6], endometrium [n=3], cervix [n=10], vaginal [n=1], and vulvar [n=1]). In order to define the level of pain, visual analogue scale (VAS) and patient satisfaction score (PSS) were used before and on the 5th, 15th, and 30th days after epidural port application. RESULTS: The mean overall survival period of the cases undergoing epidural port application was 80 days (range: 31-560). In terms of pain parameters, values at the end of the 5th, 15th and 30th days (VAS2, VAS3 and VAS4) were significantly lower than the value before morphine application via SIEP (VAS1) (p<0.01). PSSs at the 5th, 15th and 30th days were significantly higher than the PSS before port implantation (p<0.05). Pain management was started with 2 mg morphine with a maximum of 4 mg morphine administered into the epidural space per day. No clinically detected infectious condition or morphine-related side effects that required treatment occurred during the follow-up. CONCLUSION: Morphine administration via SIEP provided excellent pain relief without creating side effects, increased patient quality of life, and contributed to the patient's ability to enjoy life. PMID- 24481579 TI - [Efficacy of intravenous dexketoprofen trometamol compared to intravenous paracetamol for postoperative pain management after day-case operative hysteroscopy: randomized, double-blind, placebo-controlled study]. AB - OBJECTIVE: Adequate pain management following day-case surgery allows early ambulation of patients. In this study, we aimed to compare postoperative analgesic efficacy of intravenous (iv) dexketoprofen vs. iv paracetamol following day-case operative hysteroscopy. METHODS: One hundred and fourteen American Society of Anesthesiologists (ASA) I-II patients scheduled for day-case operative hysteroscopy were recruited and randomized to three groups in the study. Group D received 50 mg iv dexketoprofen trometamol, Group P 1000 mg iv paracetamol and Group C normal saline solution. Visual Analogue Scale (VAS) pain intensity, pain relief, sedation, nausea-vomiting, other side effects, and additional opioid analgesic requirement were noted at postoperative 15 minutes (min), 30 min, 1 hour (h), 2 h, and 3 h. Patients with VAS>=40 mm received meperidine 0.25 mg/kg as rescue analgesic medication. RESULTS: VAS scores at 15 min, 30 min, 1 h, and 2 h were significantly lower in Group D compared to Group C. VAS scores at 15 min and 30 min were significantly lower in Group D compared to Group P. The percentages of patients who required opioid treatment were 34%, 60%, and 63% in Groups D, P and C, respectively (p<0.05). Total delivered opioid dose was 0.10+/ 0.16 mg/kg, 027+/-0.33 mg/kg and 0.28+/-0.25 mg/kg in Groups D, P and C, respectively (p<0.05). Pain relief score was significantly better in Group D at postoperative 15 min when compared with Group C (p<0.05). CONCLUSION: Our study demonstrated that iv dexketoprofen has superior efficacy for postoperative pain management following day-case operative hysteroscopy when compared with paracetamol and placebo. PMID- 24481580 TI - Perioperative dexketoprofen or lornoxicam administration for pain management after major orthopedic surgery: a randomized, controlled study. AB - OBJECTIVE: Non-steroidal anti-inflammatory drugs (NSAIDs) are recommended for multimodal postoperative pain management. The purpose of this study was to evaluate the postoperative pain relief and opioid-sparing effects of dexketoprofen and lornoxicam after major orthopedic surgery. METHODS: After obtaining ethical committee approval and informed consent, 120 patients undergoing elective hip or knee replacement under general anesthesia were randomized to receive two intravenous injections of 50 mg dexketoprofen (GD), 8 mg lornoxicam (GL) or saline as placebo (GP) intravenously. Postoperatively, patient-controlled analgesia (PCA) morphine was started as a 0.01 mg.kg-1 bolus dose, with lockout time of 10 minutes without continuous infusion. Pain assessment was made using the Visual Analogue Scale (VAS) at rest or during movement at postoperative 1, 2, 4, 6, 8, 12, and 24 hours. RESULTS: The three groups were similar in terms of age, gender, American Society of Anesthesiologists (ASA) class, number of patients who underwent hip or knee surgery, weight, height, and operation duration. Patients in GD and GL demonstrated significantly reduced pain scores at rest and active motion compared to GP, with lower scores in the dexketoprofen group. Patients in GD and GL used significantly less morphine in the postoperative period compared to GP. The total morphine consumption of patients in GD was lower than in GL. CONCLUSION: Intravenous application of 50 mg dexketoprofen twice a day and 8 mg lornoxicam twice a day improved analgesia and decreased morphine consumption following major orthopedic surgery. When the two active drugs were compared, it was found that dexketoprofen was superior to lornoxicam in terms of analgesic efficacy and opioid consumption. PMID- 24481581 TI - Preemptive analgesic efficacy of dexketoprofen trometamol on impacted third molar surgery. AB - OBJECTIVE: The aim of this study was to compare the pre-emptive analgesic efficacy of intravenous (IV) dexketoprofen trometamol (DT) and placebo, following impacted mandibular third molar surgery. METHODS: Twenty patients over 18 year old who needed bilateral lower third molar extractions were included in this prospective, randomized and placebo-controlled clinical trial. Patients whom had taken DT 50 mg of before their one extraction, took placebo before their other extraction which had been performed on the opposite side. A total of 40 observations were made. Pain scores were evaluated with a Verbal Rating Scale (VRS) after surgery. Moreover; the time to first analgesic requirement use, additional analgesic need of patients, patient and doctor satisfaction, side effects were also determined. RESULTS: During the first 12 hours, the VRS values in DT group were significantly lower than those of placebo group patients (p<0.05). In placebo group, the time to first analgesic requirement use was significantly earlier than that of patients in DT group (p<0.05). Additional analgesic need of placebo group were significantly greater, when compared with the analgesic need of DT group patients (p<0.05). Among the DT group patients, patient and physician satisfaction was greater, which was statistically significant (p<0.05). CONCLUSION: Preemptive use of IV DT is more effective than placebo for using as preemptive analgesia for acute postoperative pain control in patients underwent removal of an impacted mandibular third molar surgery. PMID- 24481582 TI - Ultrasound-guided psoas compartment block and general anesthesia for arthroscopic knee surgery: a case report. AB - Anesthetizing the lumbar plexus at its origin facilitates a more "complete" psoas compartment block compared to peripheral approaches. It is usually performed using surface anatomical landmarks, and the site for local anesthetic injection is confirmed by observing quadriceps muscle contraction to peripheral nerve stimulation. Ultrasound may provide guidance alone or together with the aid of nerve stimulation during nerve blocks. We present a 48-year-old male patient, American Society of Anesthesiologists (ASA) physical status II, who refused spinal anesthesia, and underwent knee arthroscopy with ultrasound-guided psoas compartment block and general anesthesia. Following the standard monitoring and lateral decubitus positioning, the vertebral body, psoas, erector spinae, and quadratus lumborum muscles and hyperechoic nerve roots of the patient were visualized at the level of L4-5 with curvilinear ultrasound probe. The needle was inserted with ultrasound guidance, and correct tip position was confirmed with quadriceps contraction. Then, the mixture of 30 mL local anesthetic (10 mL 2% lidocaine and 20 ml 5% levobupivacaine) was injected at the estimated position of the lumbar plexus (junction of the posterior third and anterior two-thirds of the psoas muscle). He also received general anesthesia for the surgery. Anesthesia and surgical procedures were completed successfully without any additional anesthetic/analgesic requirement or complication. The postoperative period was pain-free both at rest and during mobilization for 24 hours. This case report shows that ultrasound-guided psoas compartment block is feasible and efficient for peri- and postoperative analgesia during knee arthroscopy. PMID- 24481583 TI - [A case of combined thoracic epidural anesthesia-interscalene block application in high-risk mastectomy patients: a case report]. AB - Recent advances in surgical and anesthetic techniques have facilitated general anesthesia and surgical possibilities in the higher-risk patient group. Although general anesthesia is the only preferred approach for breast surgery, there have been many clinical trials about breast surgery that has been achieved with regional anesthesia techniques. It is known that regional anesthesia application decreases the preoperative stress, postoperative morbidity and mortality. Additionally, this application positively affects the early start of feeding and mobilization. Regional anesthesia techniques like high thoracic epidural anesthesia, cervical epidural anesthesia and paravertebral block have been applied successfully in mastectomy operations. Combined thoracic epidural anesthesia-interscalene block technique may also be a good alternative to general or cervical, high thoracic epidural anesthesia. We aimed herein to present a case who underwent successful mastectomy and axillary dissection under combined thoracic epidural anesthesia-interscalene block. PMID- 24481584 TI - Systemic toxicity to local anesthesia in an infant undergoing circumcision. AB - A circumcision was planned for a four-month-old infant under local anesthesia. After the application of lidocaine, the infant stopped crying, and then generalized tonic-clonic convulsions and a diffuse erythematous rash developed. The patient was immediately monitored, ventilation was provided, and 1 mg midazolam was given intramuscularly. After insertion of a cannula, sodium thiopental 50 mg was given intravenously, the patient's convulsions were controlled, and endotracheal intubation was performed. The patient was extubated 30 minutes later. However, the patient was re-intubated due to his noisy breathing, and 10 mg prednisolone was given intravenously due to mild edema seen in the larynx during endotracheal intubation. Two hours after the second intubation, the patient started to breath spontaneously and opened his eyes; he was extubated and transferred to the intensive care unit. Two days later the patient was discharged. Systemic toxicity to the local anesthesia was considered in this patient. All precautions need to be considered during the application of local anesthesia in pediatric patients, including proper indication, monitoring of the patient in the preoperative period, establishment of venous access, and readiness to apply cardiopulmonary resuscitation in the event of local anesthetic toxicity. The maximum dose of local anesthesia should be considered and it should be diluted during application. PMID- 24481585 TI - Neuroprotection of posttreatment with risperidone, an atypical antipsychotic drug, in rat and gerbil models of ischemic stroke and the maintenance of antioxidants in a gerbil model of ischemic stroke. AB - Risperidone, an atypical antipsychotic drug, has been discovered to have some beneficial effects beyond its original effectiveness. The present study examines the neuroprotective effects of risperidone against ischemic damage in the rat and gerbil induced by transient focal and global cerebral ischemia, respectively. The results showed that pre- and posttreatment with 4 mg/kg risperidone significantly protected against neuronal death from ischemic injury. Many NeuN-immunoreactive neurons and a few F-J B-positive cells were found in the rat cerebral cortex and gerbil hippocampal CA1 region (CA1) in the risperidone-treated ischemia groups compared with those in the vehicle-treated ischemia group. In addition, treatment with risperidone markedly attenuated the activation of microglia in the gerbil CA1. On the other hand, we found that treatment with risperidone significantly maintained the antioxidants levels in the ischemic gerbil CA1. Immunoreactivities of superoxide dismutases 1 and 2, catalase, and glutathione peroxidase were maintained in the stratum pyramidale of the CA1; the antioxidants were very different from those in the vehicle-treated ischemia groups. In brief, our present findings indicate that posttreatment as well as pretreatment with risperidone can protect neurons in the rat cerebral cortex and gerbils CA1 from transient cerebral ischemic injury and that the neuroprotective effect of risperidone may be related to attenuation of microglial activation as well as maintenance of antioxidants. PMID- 24481586 TI - The adherens junction-associated protein 1 is a negative transcriptional regulator of MAGEA2, which potentiates temozolomide-induced apoptosis in GBM. AB - Previous studies identified the frequent loss of adherens junction-associated protein 1 (AJAP1) expression in glioblastoma (GBM) and its correlation with worse survival. AJAP1 may suppress glioma cell migration, which plays an important role in tumor progression in malignant gliomas such as GBM. However, the role of AJAP1 in cell cycle arrest or apoptosis and resistance to chemotherapy remains unclear. Based on microarray screening results, quantitative PCR and luciferase plasmid reporter constructs were used to evaluate the possible regulatory role of AJAP1 on MAGEA2 expression and function. Cell death assays, TUNEL and other markers of apoptosis were utilized to detect cell apoptosis. Restoration of AJAP1 expression in glioma cells was analyzed after temozolomide exposure. AJAP1 suppressed the expression of MAGEA2 and inhibited the transcriptional activity of MAGEA2 in glioma cells. As AJAP1 expression decreased MAGEA2 protein expression apoptosis increased moderately. Consistent with increased cell death, the induced loss of MAGEA2 expression correlated with increased caspase 3/7 activity, BCL2/BAX ratio and TUNEL signal. AJAP1 expression enhanced cell death in the presence of temozolomide. This study suggests AJAP1 may also function as a pro-apoptotic factor and potentiate cell death by temozolomide in glioma cells. This effect may be partially explained by AJAP1-mediated gene regulation of MAGEA2. PMID- 24481587 TI - Material deprivation affects high sexual risk behavior among young people in urban slums, South Africa. AB - Young people in urban slums adopt HIV risk behaviors influenced by their neighborhood factors. Three critical factors in urban slums of Southern and Eastern Africa--the region most affected by the HIV epidemic in the world--are unmet needs of housing, food, and health care, which are associated with HIV sexual risks. Yet, there has been limited attention on how the combination of unmet needs of housing, food, and health care--i.e., material deprivation-relates to sexual risk behavior among young people in urban slums. Cross-sectional data were extracted from the LoveLife survey in South African four provinces--KwaZulu Natal, Mpumalanga, Eastern Cape, and Gauteng, to examine the association between material deprivation and sexual risk behavior among young people aged 18-23 years (263 males, 267 females) in urban slums. Adjusted logistic regression models showed that material deprivation was significantly associated with increased odds of high sexual risk taking for young men (adjusted OR = 1.20; 95 % CI = 1.10, 5.58) and young women (adjusted OR = 1.43; 95 % CI = 1.35, 3.28). Financial difficulty--a proxy for other deprivations--was the most salient influence on young women's high sexual risk taking (adjusted OR = 2.11; 95 % CI = 1.66, 2.70). Localized behavioral HIV prevention interventions should target young people in deprived households. PMID- 24481588 TI - Differential effect of methyl-, butyl- and propylparaben and 17beta-estradiol on selected cell cycle and apoptosis gene and protein expression in MCF-7 breast cancer cells and MCF-10A non-malignant cells. AB - Parabens are alkyl esters of p-hydroxybenzoic acid used widely as antimicrobial preservatives in consumer products, including pharmaceuticals, foods and cosmetics. We showed previously that methyl-, butyl- and propylparaben parabens, even at low doses, stimulate the proliferation of MCF-7 breast cancer cells and non-transformed MCF-10A breast epithelial cells. The present study was undertaken to determine whether this represents a direct effect on cell cycle and apoptotic gene expression. MCF-7 and MCF-10A cells were exposed to methyl, butyl- and propylparaben (20 nm) or 17beta-estradiol (10 nm). Cell cycle and apoptotic gene expression were evaluated by real-time polymerase chain reaction and protein expression by Western blot. 17beta-estradiol upregulated G1 /S phase genes and downregulated cell cycle progression inhibitors in both MCF-7 and MCF-10A. Upregulation of Bcl-xL and downregulation of caspase 9 was observed in MCF-7, while upregulation of Bcl-xL, BCL2L2 and caspase 9 was noted in MCF-10A. Cyclins in MCF-7 cells were not affected by any of the parabens. Methyl- and butylparaben had no effect on the expression of selected apoptotic genes in MCF-7. In MCF-10A, all parabens tested increased the expression of G1 /S phase genes, and downregulated cell cycle inhibitors. Methylparaben increased pro-survival gene. Butylparaben increased BCL2L1 gene, as did 17beta-estradiol, while propylparaben upregulated both the extrinsic and intrinsic apoptotic pathways. There are differences in cell cycle and apoptosis gene expression between parabens and 17beta-estradiol in MCF-7 cells. In MCF-10A cells, most of the genes activated by parabens were comparable to those activated by 17beta-estradiol. PMID- 24481589 TI - Simultaneous characterisation of fifty coumarins from the roots of Angelica dahurica by off-line two-dimensional high-performance liquid chromatography coupled with electrospray ionisation tandem mass spectrometry. AB - INTRODUCTION: The root of Angelica dahurica is a traditional Chinese medicine that used for the treatment of headache, toothache, abscess, furunculosis and acne. Coumarins were the major bioactive constituents of A. dahurica, hence it is worthwhile developing a method to simultaneously characterise them, especially those in trace amounts. OBJECTIVE: To develop an efficient method for the simultaneous characterisation of coumarins in A. dahurica. METHODS: A method using off-line two-dimensional high-performance liquid chromatography coupled with electrospray tandem mass spectrometry (off-line 2D-HPLC-ESI/MS(n) ) was developed. RESULTS: In total 50 coumarins, including 32 linear furanocoumarins, 16 bifuranocoumarins and two non-furanocoumarins, were identified from the roots of A. dahurica. The possible MS fragmentations of these coumarins are also proposed. CONCLUSION: The method described here allows rapid and convenient identification of the coumarins in A. dahurica, and may be applied to other herbal medicines containing linear furanocoumarins. PMID- 24481590 TI - Sterilization of Escherichia coli O157:H7 using micro corona ionizer. AB - We demonstrated in vitro sterilization of Escherichia coli O157:H7 bacteria on agar by a pin-between-planes micro corona ionizer. The gap between the pin and the grid was ~1.1 mm, the length of the grid was ~2.1 mm and the height was ~1.0 mm. The effective pin radius and discharge length were both approximated to be 200 MUm. Ozone generation rates of ~2.3 * 10(-3) mg/s, ~2.7 * 10(-3) mg/s and ~3.5 * 10(-3) mg/s at 1,500 V were calculated for relative humidity (RH) of 35 %, 25 % and 10 % respectively. Analytical ozone generation rate increases as RH decreases and it is consistent with experimental observations. Using target and control petri dishes with E. coli plated agar, the sterilization capability of the micro corona ionizer at 37 degrees C for 24 h was evaluated. A ~60 % reduction in bacterial colony was shown with plate counting and its kill radius could be tuned from ~ 20 mm to ~5 mm by reducing the duty cycle from 100 % to 50 % with 30 min pulse width. The results suggested that the micro corona ionizer might be suitable as a tunable ozone source in wound dressing for chronic wound management. PMID- 24481591 TI - Expression and clinical significance of estrogen-regulated long non-coding RNAs in estrogen receptor alpha-positive ovarian cancer progression. AB - Estrogen (E2) has long been implicated in epithelial ovarian cancer (EOC) progression. The effects of E2 on cancer progression can be mediated by numerous target genes, including coding RNAs and, more recently, non-coding RNAs (ncRNAs). Among the ncRNAs, long ncRNAs (lncRNAs) have emerged as new regulators in cancer progression; therefore, our aim was to determine whether the expression of any lncRNAs is regulated by E2 and, if so, whether a subset of these lncRNAs have some clinical significance in EOC progression. A microarray was performed to identify E2-regulated lncRNAs in E2 receptor (ER) alpha-positive EOC cells. Bioinformatics analyses of lncRNAs were conducted, focusing on gene ontology and pathway analyses. Quantitative real-time polymerase chain reactions were performed to confirm the expression of certain lncRNAs in ERalpha-positive EOC tissues. The correlation between certain lncRNA expression and clinicopathological factors as well as prognosis in ERalpha-positive EOC patients was then analyzed. We showed that 115 lncRNAs exhibited significant changes in E2 treated SKOV3 cells compared with untreated controls. Most of these lncRNAs were predicated to have potential to contribute to cancer progression. Notably, three candidates (TC0100223, TC0101686 and TC0101441) were aberrantly expressed in ERalpha-positive compared to ERalpha-negative EOC tissues, showing correlations with some malignant cancer phenotypes such as advanced FIGO stage and/or high histological grade. Furthermore, multivariate analysis indicated that TC0101441 was an independent prognostic factor for overall survival. Taken together, these results indicate for the first time that E2 can modulate lncRNA expression in ERalpha-positive EOC cells and that certain lncRNAs are correlated with advanced cancer progression and suggestive of a prognostic indicator in ERalpha-positive EOC patients. Knowledge of these E2-regulated lncRNAs could aid in the future understanding of the estrogenic effect on EOC progression and may assist in the clinical design of new target therapies based on a perspective of lncRNA. PMID- 24481592 TI - Establishment and biological characterization of a novel cell line derived from hepatoid adenocarcinoma originated at the ampulla of Vater. AB - Hepatoid adenocarcinoma is a rare gastrointestinal tumor and mostly reported in the stomach. Effective chemotherapy has yet to be developed to improve poor prognosis. The present study was undertaken to establish a useful cell line derived from a hepatoid adenocarcinoma, possibly leading to a new therapeutic strategy. The new human cell line VAT-39 was established from a metastatic lymph node of a 69-year-old Japanese male patient with hepatoid adenocarcinoma of the ampulla of Vater. The primary tumor and metastatic lymph node were composed of hepatoid adenocarcinoma cells exhibiting immunohistochemical reactivity for alpha fetoprotein (AFP) and glypican-3 (GPC3). In the metastatic lymph node, Periodic acid-Schiff (PAS) staining clarified diffuse deposition of glycogen in the cytoplasm, indicating analogous characteristics to the primary hepatoid adenocarcinoma. Moreover, VAT-39 cells produced high levels of AFP in the cultured medium, and reverse-transcriptase polymerase chain reaction (RT-PCR) verified increased expression of GPC3 mRNA in this cell line. Further, we evaluated the sensitivity to major chemotherapeutic drugs against the bile duct cancer. Neither 5-fluorouracil nor gemcitabine showed particular sensitivity to this cell line. The tumorigenicity of the cultured cells was confirmed in athymic nude mice and the histological features of the explanted tumor were similar to the VAT-39 cell line. The present VAT-39 is the first hepatoid adenocarcinoma cell line that originates from the ampulla of Vater and it will be applicable for basic biological studies searching for new strategies of molecular targeted chemotherapy to this disease. PMID- 24481593 TI - Parallel implementation of 3D protein structure similarity searches using a GPU and the CUDA. AB - Searching for similar 3D protein structures is one of the primary processes employed in the field of structural bioinformatics. However, the computational complexity of this process means that it is constantly necessary to search for new methods that can perform such a process faster and more efficiently. Finding molecular substructures that complex protein structures have in common is still a challenging task, especially when entire databases containing tens or even hundreds of thousands of protein structures must be scanned. Graphics processing units (GPUs) and general purpose graphics processing units (GPGPUs) can perform many time-consuming and computationally demanding processes much more quickly than a classical CPU can. In this paper, we describe the GPU-based implementation of the CASSERT algorithm for 3D protein structure similarity searching. This algorithm is based on the two-phase alignment of protein structures when matching fragments of the compared proteins. The GPU (GeForce GTX 560Ti: 384 cores, 2GB RAM) implementation of CASSERT ("GPU-CASSERT") parallelizes both alignment phases and yields an average 180-fold increase in speed over its CPU-based, single-core implementation on an Intel Xeon E5620 (2.40GHz, 4 cores). In this paper, we show that massive parallelization of the 3D structure similarity search process on many-core GPU devices can reduce the execution time of the process, allowing it to be performed in real time. GPU-CASSERT is available at: http://zti.polsl.pl/dmrozek/science/gpucassert/cassert.htm. PMID- 24481594 TI - Molecular dynamic simulations reveal the mechanism of binding between xanthine inhibitors and DPP-4. AB - We apply molecular docking, molecular dynamics (MD) simulation, and binding free energy calculation to investigate and reveal the binding mechanism between five xanthine inhibitors and DPP-4. The electrostatic and van der Waals interactions of the five inhibitors with DPP-4 are analyzed and discussed. The computed binding free energies using MM-PBSA method are in qualitatively agreement with experimental inhibitory potency of five inhibitors. The hydrogen bonds of inhibitors with Ser630 and Asp663 can stabilize the inhibitors in binding sites. The van der Waals interactions, especially the key contacts with His740, Asn710, Trp629, and Tyr666 have larger contributions to the binding free energy and play important roles in distinguishing the variant bioactivity of five inhibitors. PMID- 24481595 TI - A modern neuroscience approach to chronic spinal pain: combining pain neuroscience education with cognition-targeted motor control training. AB - Chronic spinal pain (CSP) is a severely disabling disorder, including nontraumatic chronic low back and neck pain, failed back surgery, and chronic whiplash-associated disorders. Much of the current therapy is focused on input mechanisms (treating peripheral elements such as muscles and joints) and output mechanisms (addressing motor control), while there is less attention to processing (central) mechanisms. In addition to the compelling evidence for impaired motor control of spinal muscles in patients with CSP, there is increasing evidence that central mechanisms (ie, hyperexcitability of the central nervous system and brain abnormalities) play a role in CSP. Hence, treatments for CSP should address not only peripheral dysfunctions but also the brain. Therefore, a modern neuroscience approach, comprising therapeutic pain neuroscience education followed by cognition-targeted motor control training, is proposed. This perspective article explains why and how such an approach to CSP can be applied in physical therapist practice. PMID- 24481596 TI - Toward a rehabilitation treatment taxonomy: summary of work in progress. PMID- 24481597 TI - Static and dynamic plantar pressures in children with and without sever disease: a case-control study. AB - BACKGROUND: Calcaneal apophysitis (Sever disease) has been reported to be the most common cause of heel pain in athletic children. OBJECTIVE: The study aim was to compare plantar pressure, plantar surface contact area, distribution of body weight across the lower extremities, and prevalence of gastrocnemius ankle equinus and gastrocnemius-soleus ankle equinus (which can cause decreases in ankle dorsiflexion range of motion) in children with and without Sever disease. DESIGN: This was a case-control study. METHODS: Participants were 56 male students enrolled in a soccer academy. Twenty-eight participants had Sever disease (Sever disease group), and 28 participants were healthy (control group). Dynamic and static peak plantar pressures, plantar surface contact area, and body weight distribution were assessed with pedobarography. A goniometer was used to assess gastrocnemius and gastrocnemius-soleus ankle dorsiflexion range of motion. RESULTS: Both maximum and average peak pressures and percentages of body weight supported by each heel were significantly higher in the symptomatic feet of participants in the Sever disease group than in the control group. Twenty-six participants with Sever disease but only 8 participants in the control group exhibited bilateral gastrocnemius ankle equinus. LIMITATIONS: A limitation of the study is that measurements were obtained from participants who were symptomatic. CONCLUSIONS: Higher heel plantar pressures under dynamic and static conditions appear to be associated with Sever disease. It is unclear, however, whether these higher pressures are a predisposing factor contributing to the disease or a result of the condition. Gastrocnemius ankle equinus also may be a predisposing factor for Sever disease. Further research is needed to identify other biomechanical factors associated with the disease to enhance prevention and treatment strategies. PMID- 24481598 TI - Arm and trunk movement kinematics during seated reaching within and beyond arm's length in people with stroke: a validity study. AB - BACKGROUND: Kinematic analysis is commonly used to objectively measure upper extremity movement performance after stroke. However, the concurrent validity and predictive validity of arm-trunk kinematics during reaching within and beyond arm's length have not been studied. OBJECTIVE: The aim of this study was to estimate the concurrent validity of kinematic measures before and after treatment and the predictive validity for reaching within and beyond arm's length after stroke. DESIGN: This was a secondary analysis study. METHODS: Ninety-seven participants with stroke (mean age=55.9 years [SD=10.9]) received intensive treatment every weekday for 3 to 4 weeks. Kinematic reaching tasks and the Wolf Motor Function Test (WMFT) were used before and after treatment. The validity of the kinematic measures was estimated in relation to WMFT scores. RESULTS: Of the 8 kinematic variables that were measured, index movement time before treatment (R2=.227-.362) and trunk movement time and trunk displacement after treatment (R2=.095-.346) had the strongest association with the WMFT at both reaching distances. Trunk movement time and trunk displacement before treatment explained 6.9% to 14.9% of the variance in the WMFT after treatment. Kinematic variables explained 6.9% to 49.3% and 9.4% to 38.7% of the variance in the WMFT during a task within arm's length and beyond arm's length, respectively. LIMITATIONS: The study has limited generalizability. CONCLUSIONS: Different kinematic variables may partially reflect motor function before and after treatment to a limited degree. Although the predictive validity was modest, trunk movement may be considered a prognostic determinant of motor function after treatment. A reaching task within arm's length may be a more suitable measure of kinematic performance for describing motor function than a reaching task beyond arm's length. PMID- 24481599 TI - Bioorganometallic chemistry with IspG and IspH: structure, function, and inhibition of the [Fe(4)S(4)] proteins involved in isoprenoid biosynthesis. AB - Enzymes of the methylerythritol phosphate pathway of isoprenoid biosynthesis are attractive anti-infective drug targets. The last two enzymes of this pathway, IspG and IspH, are [Fe4 S4 ] proteins that are not produced by humans and catalyze 2 H(+) / 2 e(-) reductions with novel mechanisms. In this Review, we summarize recent advances in structural, mechanistic, and inhibitory studies of these two enzymes. In particular, mechanistic proposals involving bioorganometallic intermediates are presented, and compared with other mechanistic possibilities. In addition, inhibitors based on substrate analogues as well as developed by rational design and compound-library screening, are discussed. The results presented support bioorganometallic catalytic mechanisms for IspG and IspH, and open up new routes to anti-infective drug design targeting [Fe4 S4 ] clusters in proteins. PMID- 24481600 TI - Wavepacket splitting and two-pathway deactivation in the photoexcited visual pigment isorhodopsin. AB - Isorhodopsin is the visual pigment analogue of rhodopsin. It shares the same opsin environment but it embeds 9-cis retinal instead of 11-cis. Its photoisomerization is three times slower and less effective. The mechanistic rationale behind this observation is revealed by combining high-level quantum mechanical/molecular-mechanical simulations with ultrafast optical spectroscopy with sub-20 fs time resolution and spectral coverage extended to the near infrared. Whereas in rhodopsin the photoexcited wavepacket has ballistic motion through a single conical intersection seam region between the ground and excited states, in isorhodopsin it branches into two competitive deactivation pathways involving distinct conical intersection funnels. One is rapidly accessed but unreactive. The other is slower, as it features extended steric interactions with the environment, but it is productive as it follows forward bicycle pedal motion. PMID- 24481601 TI - Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis. AB - Squamous esophageal epithelium adapts to acid reflux-mediated injury by proliferation and differentiation via signal transduction pathways. Induction of the Wnt antagonist Dickkopf-1 (Dkk1) is involved in tissue repair during inflammation and cellular injury. In this study, we aimed to identify the biological role of Dkk1 in human reflux esophagitis with respect to cell growth and regulation of Wnt signaling. Esophageal biopsies from reflux-esophagitis patients (n = 15) and healthy individuals (n = 10) were characterized in terms of Dkk1 expression. The role of Dkk1 in response to acid-mediated epithelial injury was analyzed by cellular assays in vitro utilizing squamous esophageal epithelial cell lines (EPC1-hTERT, EPC2-hTERT, and HEEC). Dkk1 was significantly overexpressed in human reflux-esophagitis tissue compared with healthy esophageal mucosa at transcriptional and translational levels. After acute and chronic acid (pH 4) exposure, esophageal squamous epithelial cell lines expressed and secreted high levels of Dkk1 in response to stress-associated DNA injury. High extracellular levels of human recombinant Dkk1 inhibited epithelial cell growth and induced cellular senescence in vitro, as demonstrated by reduced cell proliferation, G0/G1 cell cycle arrest, elevated senescence-associated beta galactosidase activity, and upregulation of p16. Acid pulsing induced Dkk1 mediated senescence, which was directly linked to the ability of Dkk1 to antagonize the canonical Wnt/beta-catenin signaling. In healthy esophageal mucosa, Dkk1 expression was associated with low expression of transcriptionally active beta-catenin, while in reflux-esophagitis tissue, Dkk1 overexpression correlated with increased senescence-associated beta-galactosidase activity and p16 upregulation. The data indicate that, in human reflux esophagitis, Dkk1 functions as a secreted growth inhibitor by suppressing Wnt/beta-catenin signaling and promoting cellular senescence. These findings suggest a significant role for Dkk1 and cellular senescence in esophageal tissue homeostasis during reflux esophagitis. PMID- 24481602 TI - Altered expression and function of canalicular transporters during early development of cholestatic liver injury in Abcb4-deficient mice. AB - Deficiency of ABCB4 is associated with several forms of cholestasis in humans. Abcb4(-/-) mice also develop cholestasis, but it remains uncertain what role other canalicular transporters play in the development of this disease. We examined the expression of these transporters in Abcb4(-/-) mice compared with their wild-type littermate controls at ages of 10 days and 3, 6, and 12 wk. Elevated plasma bile acid levels were already detected at 10 days and at all ages thereafter in Abcb4(-/-) mice. The expression of Bsep, Mrp2, Atp8b1, Abcg5, and Abcg8 liver proteins did not change at 10 days, but Bsep, Mrp2, and Atp8b1 were reduced, whereas Abcg5 and Abcg8 expression were increased in Abcb4(-/-) mice at all later ages. Lower bile acid concentrations were also detected in the bile of 6-wk-old Abcb4(-/-) mice. Immunofluorescence labeling revealed distorted canalicular architecture in the liver tissue by 12 wk in Abcb4(-/-) mice. Whereas Bsep and Mrp2 remained associated with the apical membrane, Atp8b1 was now localized in discrete punctuate structures adjacent to the canalicular membrane in these mice. Expression of Bsep mRNA was increased in the livers of 10-day-old Abcb4(-/-) mice, whereas Ost-alpha was decreased. By 12 wk, Bsep, Mrp2, and Abcg5 mRNA were all increased, whereas Ost-alpha and Ntcp were reduced. These findings indicate that canalicular transporters that determine the formation of bile are altered early in the development of cholestasis in Abcb4(-/-) mice and may contribute to the pathogenesis of cholestasis in this disorder. PMID- 24481604 TI - Water-perfused esophageal high-resolution manometry: normal values and validation. AB - Water-perfused high-resolution manometry (HRM) catheters with 36 unidirectional pressure channels have recently been developed, but normal values are not yet available. Furthermore, the technique has not been validated and compared with solid-state HRM. We therefore aimed to develop normal values for water-perfused HRM and to assess the level of agreement between water-perfused HRM and solid state HRM. We included 50 healthy volunteers (mean age 35 yr, range 21-64 yr; 15 women, 35 men). Water-perfused HRM and solid-state HRM were performed in a randomized order. Normal values were calculated as 5th and 95th percentile ranges, and agreement between the two systems was assessed with intraclass correlation coefficient (ICC) statistics. The 5th-95th percentile range was 3.0 6.6 cm/s for contractile front velocity (CFV), 141.6-3,674 mmHg.s.cm for distal contractile integral (DCI), 6.2-8.7 s for distal contraction latency (DL), and 1.0-18.8 mmHg for integrated relaxation pressure (IRP 4s). Mean (SD) and ICC for water-perfused HRM and solid-state HRM were 4.4 (1.1) vs. 3.9 (0.9) cm/s, ICC: 0.49 for CFV; 1,189 (1,023) vs. 1,092 (1,019) mmHg.s.cm, ICC: 0.90 for DCI; 7.4 (0.8) vs. 6.9 (0.9) s, ICC: 0.50 for DL; and 8.1 (4.8) vs. 7.9 (5.1), ICC: 0.39 for IRP 4s. The normal values for this water-perfused HRM system are only slightly different from previously published values with solid-state HRM, and moderate to good agreement was observed between the two systems, with only small differences in outcome measures. PMID- 24481603 TI - Computational modeling of anoctamin 1 calcium-activated chloride channels as pacemaker channels in interstitial cells of Cajal. AB - Interstitial cells of Cajal (ICC) act as pacemaker cells in the gastrointestinal tract by generating electrical slow waves to regulate rhythmic smooth muscle contractions. Intrinsic Ca(2+) oscillations in ICC appear to produce the slow waves by activating pacemaker currents, currently thought to be carried by the Ca(2+)-activated Cl(-) channel anoctamin 1 (Ano1). In this article we present a novel model of small intestinal ICC pacemaker activity that incorporates store operated Ca(2+) entry and a new model of Ano1 current. A series of simulations were carried out with the ICC model to investigate current controversies about the reversal potential of the Ano1 Cl(-) current in ICC and to predict the characteristics of the other ion channels that are necessary to generate slow waves. The model results show that Ano1 is a plausible pacemaker channel when coupled to a store-operated Ca(2+) channel but suggest that small cyclical depolarizations may still occur in ICC in Ano1 knockout mice. The results predict that voltage-dependent Ca(2+) current is likely to be negligible during the slow wave plateau phase. The model shows that the Cl(-) equilibrium potential is an important modulator of slow wave morphology, highlighting the need for a better understanding of Cl(-) dynamics in ICC. PMID- 24481605 TI - Colonic myofibroblast cell line stimulates colonoid formation. AB - A stable and efficient system for the culture of murine colon epithelial cells or crypts is required to facilitate studies of the dynamics and factors affecting colon stem cell niche and crypt formation. Survival of colonic epithelial cells or crypts in vitro was not established until recently, when it was found that exogenous Wnt3A and R-spondin could promote cell survival and formation of spheroids (colonospheres) or some advanced organoids with well-developed crypts (colonoids). However, after 6-8 days in these culture conditions, only small numbers of colonospheres form organoids with crypt-like structures (colonoids). This study describes the use of a myofibroblast cell line and a coculture system that increases the efficiency of colonoid formation from isolated crypts. The enhanced coculture system has significantly improved colonoid-forming efficiency compared with results from previous systems. Crypt formation can be detected as early as day 2. The coculture system will facilitate the characterization of the colon stem cell niche and the changes that occur as a result of perturbations or mutations in colon stem or epithelial cells, such as those that favor precancerous adenoma or cancer. PMID- 24481606 TI - Autosomal recessive agammaglobulinemia: a novel non-sense mutation in CD79a. AB - This study describes the fifth case worldwide of autosomal recessive agammaglobulinemia due to a novel non-sense mutation in CD79a gene with a severe unusual onset due to an invasive central nervous system infection. PMID- 24481607 TI - Severe combined immunodeficiency in Serbia and Montenegro between years 1986 and 2010: a single-center experience. AB - Severe combined immunodeficiency (SCID), including the 'variant' Omenn syndrome (OS), represent a heterogeneous group of monogenic disorders characterized by defect in differentiation of T- and/or B lymphocytes and susceptibility to infections since birth. In the period of 25 years, between January 1986 and December 2010, a total of 21 patients (15 SCID, 6 OS) were diagnosed in Mother & Child Health Institute of Serbia, a tertiary-care teaching University hospital and a national referral center for patients affected with primary immunodeficiency (PID). The diagnoses were based on anamnestic data, clinical findings, and immunological and genetic analysis. The median age at the onset of the first infection was the 2nd month of life. Seven (33 %) patients had positive family history for SCID. Out of five male infants with T-B+NK- SCID phenotype, mutation analysis revealed interleukin-2 (common) gamma-chain receptor (IL2RG) mutations in 3 with positive X-linked family history, and Janus-kinase (JAK)-3 gene defects in the other two. Six patients had T-B-NK+ SCID phenotype and further 6 features of OS, 11 of which had recombinase-activating gene (RAG1or RAG2) and 1 Artemis gene mutations. One child with T+B+NK+ SCID phenotype as well had proven RAG mutation. One child each with T-B+NK+ SCID phenotype, CD8 lymphopenia and unknown phenotype remained without known underlying genetic defect. Of the eight patients who underwent hematopoetic stem cell transplant (HSCT) 5 survived, the other 13 died between 2 days and 12 months after diagnosis was made. Early diagnosis of SCID, before onset of severe infections, offers possibility for HSCT and cure. Education of primary-care pediatricians, in particular including awareness of the risk of using live vaccines and non irradiated blood products, should improve prognosis of SCID in our setting. PMID- 24481608 TI - Rhythms as photoperiodic timers in the control of flowring in Chenopodium rubrum L. AB - In C. rubrum, the amount of flowering that is induced by a single dark period interrupting continuous light depends upon the duration of darkness. A rhythmic oscillation in sensitivity to the time that light terminates darkness regulates the level of flowering. The period length of this oscillation is close to 30 hours, peaks of the rhythm occurring at about 13, 43 and 73 h of darkness.Phasing of the rhythm by 6-, 12- and 18-h photoperiods was studied by exposing plants to a given photoperiod at different phases of the free-running oscillation in darkness. The shift in phase of the rhythm was then determined by varying the length of the dark period following the photoperiod; this dark period was terminated by continuous light.With a 6-h photoperiod the timing of both the light-on and light-off signals is shown to control rhythm phasing. However, when the photoperiod is increased to 12 or 18 h, only the light-off signal determines phasing of the rhythm. In prolonged periods of irradiation-12 to 62 h light-a "durational" response to light overrides any interaction between the timing of the light period and the position of the oscillation at which light is administered. Such prolonged periods of irradiation apparently suspend or otherwise interact with the rhythm so that, in a following dark period, it is reinitiated at a fixed phase relative to the time of the light-off signal to give a peak of the rhythm 13 h after the dusk signal.In daily photoperiodic cycles rhythm phasing by a 6-h photocycle was also estimated by progressively increasing the number of cycles given prior to a single dark period of varied duration.In confirmation of Bunning's (1936) hypothesis, calculated and observed phasing of the rhythm controlling flowering in c. rubrum accounts for the photoperiodic response of this species. Evidence is also discussed which indicates that the timing of disappearance of phytochrome Pfr may limit flowering over the early hours of darkness. PMID- 24481609 TI - The effectiveness of internal oxygen transport in a mesophyte (Pisum sativum L.). AB - The effectiveness of oxygen movement through pea seedlings has been assessed firstly by assaying for radial oxygen loss along the roots using the cylindrical Pt electrode technique, and secondly by measuring root growth in various oxygen free media.It was found that roots would grow in oxygen-free 3% agar to a length exceeding 20 cm, but when such plants were removed to oxygen-free 0.05% agar oxygen could not be detected in the apical segments in roots longer than 9.5 cm unless respiratory activity was curtailed by cooling.If the greater part of the root was retained in 3% agar and only the apical region exposed to 0.05% agar and assayed, oxygen loss always occurred. It was concluded that the 3% agar has a jacketing effect substantially reducing oxygen leakage from the root surface and thus allowing more oxygen to channel down to the apical regions.Root growth in unstirred air-saturated 0.05% agar matched the growth in oxygen-free 3% agar. Root growth in unstirred oxygen-free 0.05% agar was arrested at c. 9 cm.It is suggested that the effect produced by the aerated unstirred 0.05% agar is consistent with a jacketing effect mitigating oxygen loss from the root and that a growth of 9 cm in unstirred deoxygenated agar is consistent with a smaller jacketing effect due to the unstirred medium.It is proposed that the accumulation of respiratory tissue will eventually render inadequate any jacketing effect. Further aerobic development at this stage will require a supply of oxygen from the rooting medium. PMID- 24481610 TI - Uridine diphosphate-sugar metabolism by sycamore (Acer pseudoplatanus) cambial tissue. AB - Extracts of sycamore cambial tissue convert UDP-glucose into UDP-glucuronic acid, and the latter into UDP-xylose and UDP-rhamnose. None of the corresponding galactose series of monosaccharides was formed indicating the absence of epimerases, postulated as an important feature of differentiation. UDP-glucose is formed in greater quantities than any of its nucleoside analogues and it is suggested that UDP-glucose plays a more important role in carbohydrate metabolism in this tissue. PMID- 24481611 TI - On the kinetics of phytochrome photoconversion in vivo. AB - Samples for spectrophotometric measurement of phytochrome in vivo are not optically thin. For different cross sections of the sample, the rate constant of a photochemical reaction will, therefore, have different values. We have developed a mathematical model, based on the assumption that the rate of phytochrome phototransformation is proportional to the light intensity and that the light intensity gradient in the sample is exponential. Kinetic curves computed with this model conform closely with the measurements. The simplest explanation of the observed kinetics is that there is only one type of phytochrome and that the light intensity gradient in samples that are not too thin, is close to exponential. PMID- 24481612 TI - Trehalase activity in dormant and activated spores of Phycomyces blakesleeanus. AB - Heat treatment of Phycomyces sporangiospores, which breaks dormancy, causes a very rapid 10- to 15fold increase in trehalase activity; soon after the heat shock the enzyme activity decays. This phenomenon can be repeated several times by repeating the heat shocks. Prolonging the heat treatment over the minimum required time delays the decay of enzyme activity. Cycloheximide does not prevent the rise in enzyme activity. It is suggested that heat treatment converts temporarily an inactive form of trehalase into an active one. Optimal enzyme activity is obtained at pH 7.5 and the enzyme requires metal ions for maximal activity. The possible role of trehalase in the spore-activation process is discussed. PMID- 24481613 TI - [The influence of inhibitors of protein synthesis on the secretion of the carbohydratous trapping slime of Drosophyllum lusitanicum]. AB - The secretion of the carbohydratous trapping slime of Drosophyllum is known to be mediated by the Golgi apparatus. In order to determine whether this secretion depends on the synthesis of new membrane material or runs for a long time by the cycling of membrane molecules, the influence of several inhibitors of protein synthesis was studied. Cycloheximide decreases the secretion of polysaccharides drastically, whereas puromycin and the amino acid analogues fluorophenylalanine and ethionine have little or no influence. An attempt is made to find explanations for these results, which, although contradictory, have parallels in the literature. PMID- 24481614 TI - [Enhancement of the germination inhibiting effect of abscisic acid on Lactuca fruits by sucrose and glucose]. AB - Some sugars, especially sucrose and glucose, and some inorganic salts have been found to enhance in low concentrations the germination inhibiting effect of abscisic acid (ABA) in lettuce. There is evidence from gas chromatographic analysis and from bioassays of seed extracts that this stimulation is due to increased uptake of ABA from solution in the presence of glucose and sucrose. PMID- 24481615 TI - Cell division and plant development from protoplasts of carrot cell suspension cultures. AB - Cell regeneration and sustained division have been observed in protoplasts from carrot cell suspension cultures. Carrot plants were produced from the protoplasts by embryogenesis. PMID- 24481616 TI - Embryoids derived from isolated protoplasts of carrot. AB - Protoplasts isolated enzymatically from carrot root tissues developed into cell clusters in a liquid medium containing coconut milk and naphthaleneacetic acid (NAA) or 2,4-dichlorophenoxyacetic acid (2,4-D). Cells of the resulting calluses differentiated into embryoids on an agar medium containing coconut milk or kinetin. PMID- 24481617 TI - Glucosyltransferase activity in a water extract of maize pollen. AB - Glucosyltransferase activity was extracted from maize pollen in distilled water. The enzymatic reaction required UDP-glucose, mercaptoethanol and Ca(++), and had a pH optimum at 8.2. Either kampferol or quercetin served as a substrate. Michaelis-Menten constants obtained were 0.6*10(-4) M for quercetin and 0.74*10( 3)M for UDP-glucose. Ammonium-sulfate precipitation of the enzyme gave a 4fold purification. PMID- 24481618 TI - Probing the physicochemical interactions of 3-hydroxy-benzo[a]pyrene with different monoclonal and recombinant antibodies by use of fluorescence line narrowing spectroscopy. AB - Characterization of interactions between antigens and antibodies is of utmost importance both for fundamental understanding of the binding and for development of advanced clinical diagnostics. Here, fluorescence line-narrowing (FLN) spectroscopy was used to study physicochemical interactions between 3 hydroxybenzo[a]pyrene (3OH-BaP, as antigen) and a variety of solvent matrices (as model systems) or anti-polycyclic aromatic hydrocarbon antibodies (anti-PAH). We focused the studies on the specific physicochemical interactions between 3OH-BaP and different, previously obtained, monoclonal and recombinant anti-PAH antibodies. Control experiments performed with non-binding monoclonal antibodies and bovine serum albumin (BSA) indicated that nonspecific interactions did not affect the FLN spectrum of 3OH-BaP. The spectral positions and relative intensities of the bands in the FLN spectra are highly dependent on the molecular environment of the 3OH-BaP. The FLN bands correlate with different vibrational modes of 3OH-BaP which are affected by interactions with the molecular environment (pi-pi interactions, H-bonding, or van-der-Waals forces). Although the analyte (3OH-BaP) was the same for all the antibodies investigated, different binding interactions could be identified from the FLN spectra on the basis of structural flexibility and conformational multiplicity of the antibodies' paratopes. PMID- 24481620 TI - Microextraction techniques. PMID- 24481619 TI - Analysis of individual mitochondria via fluorescent immunolabeling with Anti TOM22 antibodies. AB - Mitochondria are responsible for maintaining a variety of cellular functions. One such function is the interaction and subsequent import of proteins into these organelles via the translocase of outer membrane (TOM) complex. Antibodies have been used to analyze the presence and function of proteins comprising this complex, but have not been used to investigate variations in the abundance of TOM complex in mitochondria. Here, we report on the feasibility of using capillary cytometry with laser-induced fluorescence to detect mitochondria labeled with antibodies targeting the TOM complex and to estimate the number of antibodies that bind to these organelles. Mitochondria were fluorescently labeled with DsRed2, while antibodies targeting the TOM22 protein, one of nine proteins comprising the TOM complex, were conjugated to the Atto-488 fluorophore. At typical labeling conditions, 94% of DsRed2 mitochondria were also immunofluorescently labeled with Atto-488 Anti-TOM22 antibodies. The calculated median number of Atto-488 Anti-TOM22 antibodies bound to the surface of mitochondria was ~2,000 per mitochondrion. The combination of fluorescent immunolabeling and capillary cytometry could be further developed to include multicolor labeling experiments, which enable monitoring several molecular targets at the same time in the same or different organelle types. PMID- 24481621 TI - Medical applications of breath hydrogen measurements. AB - In this article, technical developments in breath analysis and its applications in the field of clinical diagnosis and the monitoring of various symptoms, particularly molecular hydrogen in breath, are introduced. First, a brief overview of the current uses of the hydrogen breath test is provided. The principles of the test and how hydrogen can be used as a biomarker for various symptoms, and monitoring microbial metabolism, are introduced. Ten case-study applications of breath hydrogen measurements for which hydrogen exhibits beneficial effects for diagnosis, including the contexts of oxidative stress, gastrointestinal disease, and metabolic disorders, are discussed. The technologies and problems involved in breath hydrogen testing, sampling, pretreatment, and detection in exhaled breath are discussed, and research including current analytical systems and new sensors is focused on in the context of hydrogen detection. PMID- 24481622 TI - Potential of FTIR spectroscopy for analysis of tears for diagnosis purposes. AB - It has been widely reported that the tear film, which is crucially important as a protective barrier of the eye, undergoes biochemical changes as a result of a wide range of ocular pathology. This tends to suggest the possibility of early detection of ocular diseases on the basis of biochemical analysis of tears. However, studies of tears by conventional methods of biomolecular and biochemical analysis are often limited by methodological difficulties. Moreover, such analysis could not be applied in the clinic, where structural and morphological analyses by, mainly, slit-lamp biomicroscopy remains the recommended method. In this study, we assessed, for the first time, the potential of FTIR spectroscopy combined with advanced chemometric processing of spectral data for analysis of raw tears for diagnosis purposes. We first optimized sampling and spectral acquisition (tears collection method, tear sample volume, and preservation of the samples) for accurate spectral measurement. On the basis of the results, we focused our study on the possibility of discriminating tears from normal individuals from those of patients with different ocular pathologies, and showed that the most discriminating spectral range is that corresponding to variations of CH2 and CH3 of lipid aliphatic chains. We also report more subtle discrimination of tears from patients with keratoconus and those from patients with non-specific inflammatory ocular diseases, on the basis of variations in spectral ranges attributed notably to lipid and carbohydrate vibrations. Finally, we also succeeded in distinguishing tears from patients with early-stage and late stage keratoconus on the basis of spectral features attributed to protein structure. Therefore, this study strongly suggests that FTIR spectral analysis of tears could be developed as a valuable and cost-saving tool for biochemical-based detection of ocular diseases, potentially before the appearance of the first morphological signs of diseases. Combined with supervised modelling methods and with use of a spectral data base acquired for representative patients, such a spectral approach could be a useful addition to current methods of clinical analysis for improvement of patient care. PMID- 24481624 TI - Derivatization of pinacolyl alcohol with phenyldimethylchlorosilane for enhanced detection by gas chromatography-mass spectrometry. AB - A derivatization procedure for the qualitative gas chromatography-mass spectrometry (GC-MS) analysis of pinacolyl alcohol (PA) that employs phenyldimethylchlorosilane (PhDMClS) and the promoter N-methylimidazole is described. While PA, underivatized, can be detected using conventional gas chromatographic methods, its polarity and low boiling point make its detection in complex matrices challenging. The silylation procedure described herein generates a PA-derivative exhibiting an increased on-column retention time, thus shifting its GC-MS signal away from commonly encountered, volatile, interfering analytes. Derivatized PA could be distinguished from other PhDMClS-derivatized isomeric alcohols by its unique retention time and mass spectrum. The derivatization was demonstrated to perform well in the GC-MS analysis and identification of PA in samples from Proficiency Tests administered by the Organisation for the Prohibition of Chemical Weapons (OPCW). PMID- 24481623 TI - Chemiluminescent detection of cell apoptosis enzyme by gold nanoparticle-based resonance energy transfer assay. AB - We report a new chemiluminescence resonance energy transfer (CRET) technique, using gold nanoparticles (AuNPs) as efficient energy acceptor, for homogeneous measurement of cell apoptosis enzyme with high sensitivity. In the design of the CRET system, we chose the highly sensitive chemiluminescence (CL) reaction between luminol and hydrogen peroxide catalysed by horseradish peroxidase (HRP) because the CL spectrum of luminol (lambda max 425 nm) partially overlaps the visible absorption bands of AuNPs. In this system, the peptide substrate (DEVD) of caspase 3 was linked to the AuNP surface by Au-S linkage. HRP was attached to the AuNP surface by means of a bridge formed by the streptavidin-biotin reaction. CRET occurred as a result of formation of AuNP-peptide-biotin-streptavidin-HRP complexes. The CL of luminol was significantly reduced, because of the quenching effect of AuNPs. The quenched CL was recovered after cleavage of DEVD by caspase 3, an enzyme involved in the apoptotic process. Experimental conditions were systematically investigated. Under the optimum conditions the increase of the CL signal was linearly dependent on caspase 3 concentration within the concentration range 25 pmol L(-1) to 800 pmol L(-1) and the detection limit of caspase 3 was as low as 20 pmol L(-1), one order of magnitude lower than for FRET sensors based on graphene oxides. Our method was successfully used to detect drug-induced apoptosis of cells. This approach is expected to be extended to other assays, i.e., using other enzymes, analytes, CL substances, and even other nanoparticles (e.g., quantum dots and graphene). PMID- 24481626 TI - Johann Conrad Brunner (1653-1727) and the first description of syringomyelia. AB - INTRODUCTION: Johann Conrad Brunner (1653-1727) was a European anatomist and physician whose research concerning the pancreas and duodenum has made him a prominent figure in medicine. However, Brunner should also be recognized for his descriptions of syringomyelia, which were originally published in 1688 and included in the second edition of Theophilus Boneti's compendium of postmortem examinations, the Sepulchretum, which was published in 1700. CONCLUSIONS: Our current understanding of syringomyelia is based on the early observations of researchers such as Johann Conrad Brunner. PMID- 24481625 TI - Development of a mixed-effect pharmacokinetic model for vehicle modulated in vitro transdermal flux of topically applied penetrants. AB - Transient flux profiles from in vitro flow-through cell experiments exhibit different characteristics depending upon the properties of the penetrants and vehicle mixtures applied. To enable discrimination of the chemical properties contributing to these differences, a consistent mathematical model should first be developed. A mixed effects modeling framework was used so that models can be estimated with as few parameters as possible, while also quantifying variability and accounting for correlation in the data. The models account for diffusion and binding within the membrane as well as dynamics on the diffusion coefficient. The models explain key features of the data, such as: lag time, sharp peaks in flux, two terminal phases, and low flux profiles. The models with dynamic diffusivity fit the data better than those without-particularly the sharp peaks. The significance of changing diffusivity over time suggests that vehicle effects are transient and are more accurately estimated when dynamics are modeled. PMID- 24481627 TI - Serum levels of matrix metalloproteinase-9 predict lymph node metastasis in breast cancer patients. AB - Matrix metalloproteinases (MMPs) are proteolytic enzymes that play important roles in cancer progression and metastasis. Although serum MMP expression is known to correlate with the primary lesion of breast cancer, there has yet to be a study regarding the correlation between serum MMP expression and metastatic lesions, particularly lymph nodes. The present study evaluated the correlation of serum and lymph node MMP expression with axillary node metastasis. The preoperative serum levels of MMP-2 and MMP-9 in 77 patients with breast cancer and in 10 patients with benign breast tumor were determined by ELISA and zymography. One hundred and twelve axillary lymph nodes were collected for zymography during breast cancer surgery. Significantly higher serum levels of MMP 2 and MMP-9 were found in breast cancer patients compared to patients with benign tumor. High serum levels of MMP-2 and MMP-9 were significantly associated with node metastasis. ELISA and zymography results for serum MMP-2 and MMP-9 correlated significantly, with a Pearson correlation coefficient (r) of 0.76 for MMP-2 (P=0.001) and 0.81 for MMP-9 (P=0.001). In terms of lymph node, total MMP 2, MMP-9 and MMP-9 activity were significantly higher in metastatic than in non metastatic nodes. There was a correlation between serum and lymph node MMP-9 levels on zymographic measurements (r=0.34, P=0.011), but not in terms of MMP-2 levels. Serum MMP-9 levels may have a diagnostic value for predicting axillary node metastasis. PMID- 24481628 TI - Effect of alignment on a liquid crystal/split-ring resonator metasurface. AB - A metasurface comprising a two-dimensional array of split-ring resonators with resonance frequencies in the near-infrared region is fabricated and embedded in a uniformly aligned liquid crystal. The change of the dielectric permittivity in proximity to the plasmonic structure by the replacement of air with the liquid crystal results in a decrease in resonance frequencies. The resonance shift can be attributed to the interaction of the evanescent field of the excited resonant plasmon modes with the liquid crystal. This shift in resonance frequency is found to depend on the liquid-crystal alignment and to vary for different modes. Also, the resulting effects of changes in temperature or applied external electric field on the metasurface depend on the liquid-crystal alignment and may differ from mode to mode. These observations indicate that the characteristic frequencies of the resonant split-ring resonator modes may depend on different evanescent field components interacting with the liquid crystal. Consequently, certain design rules should be taken into account for the development of tunable metasurfaces based on liquid crystals. PMID- 24481629 TI - Telomere elongation in parthenogenetic stem cells. PMID- 24481630 TI - Structure basis for the unique specificity of medaka enteropeptidase light chain. PMID- 24481631 TI - Colonization process of Arabidopsis thaliana roots by a green fluorescent protein tagged isolate of Verticillium dahliae. PMID- 24481633 TI - [SGLT-2 inhibition with canagliflozin: a new option for the treatment of type 2 diabetes]. PMID- 24481632 TI - Dual phosphorylation of Sin1 at T86 and T398 negatively regulates mTORC2 complex integrity and activity. AB - Mammalian target of rapamycin (mTOR) plays essential roles in cell proliferation, survival and metabolism by forming at least two functional distinct multi-protein complexes, mTORC1 and mTORC2. External growth signals can be received and interpreted by mTORC2 and further transduced to mTORC1. On the other hand, mTORC1 can sense inner-cellular physiological cues such as amino acids and energy states and can indirectly suppress mTORC2 activity in part through phosphorylation of its upstream adaptors, IRS-1 or Grb10, under insulin or IGF-1 stimulation conditions. To date, upstream signaling pathways governing mTORC1 activation have been studied extensively, while the mechanisms modulating mTORC2 activity remain largely elusive. We recently reported that Sin1, an essential mTORC2 subunit, was phosphorylated by either Akt or S6K in a cellular context-dependent manner. More importantly, phosphorylation of Sin1 at T86 and T398 led to a dissociation of Sin1 from the functional mTORC2 holo-enzyme, resulting in reduced Akt activity and sensitizing cells to various apoptotic challenges. Notably, an ovarian cancer patient-derived Sin1-R81T mutation abolished Sin1-T86 phosphorylation by disrupting the canonical S6K-phoshorylation motif, thereby bypassing Sin1 phosphorylation-mediated suppression of mTORC2 and leading to sustained Akt signaling to promote tumorigenesis. Our work therefore provided physiological and pathological evidence to reveal the biological significance of Sin1 phosphorylation-mediated suppression of the mTOR/Akt oncogenic signaling, and further suggested that misregulation of this process might contribute to Akt hyper-activation that is frequently observed in human cancers. PMID- 24481634 TI - [Canagliflozin monotherapy: clinical study data in type 2 diabetes mellitus]. PMID- 24481635 TI - [Oral add-on therapy to metformin in type 2 diabetes mellitus: a direct comparison beween canagliflozin and glimepiride]. PMID- 24481636 TI - [Oral add-on therapy to metformin in type 2 diabetes mellitus: a direct comparison between canagliflozin and sitagliptin]. PMID- 24481637 TI - Combination of gemcitabine, L-asparaginase, and oxaliplatin (GELOX) is superior to EPOCH or CHOP in the treatment of patients with stage IE/IIE extranodal natural killer/T cell lymphoma: a retrospective study in a cohort of 227 patients with long-term follow-up. AB - Optimal treatment strategies for localized extranodal natural killer/T cell lymphoma (ENKTL) have not been fully defined. We retrospectively compared the efficacy and safety of combined gemcitabine, L-asparaginase, and oxaliplatin (GELOX) (n=38), continuous infusion of etoposide, vincristine and doxorubicin, with cyclophosphamide and prednisone (EPOCH) (n=54), or combined cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) (n=135) as induction chemotherapy in patients who were newly diagnosed with stage I/II ENKTL. After induction chemotherapy, the complete response (CR) rate and overall response rate (ORR) for the GELOX group were significantly higher than those in the EPOCH group (68.4 vs. 42.6%, P=0.011 for CR and 86.8 vs. 68.5%, P=0.038 for ORR). Both EPOCH and GELOX groups can attain much higher CR rates than CHOP group (CR rate was 31.8%, P<0.05). The 3-year overall survival (OS) and progression free survival (PFS) rate were significantly better in GELOX group than in EPOCH or CHOP group (87.0 vs. 54.0 vs. 54.0% for OS, P<0.05; 72.0 vs. 50.0 vs. 43.0% for PFS, P<0.05). However, no significant differences were found between EPOCH and CHOP groups in OS or PFS (P=0.765 for OS, and 0.421 for PFS). The safety profiles were acceptable in all three groups. In conclusion, GELOX is superior to EPOCH or CHOP in the treatment of patients with stage I/II ENKTL. Further clinical trials of ENKTL should use asparaginase-based regimens as the standard chemotherapy. PMID- 24481638 TI - Sca1+ murine pituitary adenoma cells show tumor-growth advantage. AB - The role of tumor stem cells in benign tumors such as pituitary adenomas remains unclear. In this study, we investigated whether the cells within pituitary adenomas that spontaneously develop in Rb+/- mice are hierarchically distributed with a subset being responsible for tumor growth. Cells derived directly from such tumors grew as spheres in serum-free culture medium supplemented with epidermal growth factor and basic fibroblast growth factor. Some cells within growing pituitary tumor spheres (PTS) expressed common stem cell markers (Sca1, Sox2, Nestin, and CD133), but were devoid of hormone-positive differentiated cells. Under subsequent differentiating conditions (matrigel-coated growth surface), PTS expressed all six pituitary hormones. We next searched for specific markers of the stem cell population and isolated a Sca1(+) cell population that showed increased sphere formation potential, lower mRNA hormone expression, higher expression of stem cell markers (Notch1, Sox2, and Nestin), and increased proliferation rates. When transplanted into non-obese diabetic-severe combined immunodeficiency gamma mice brains, Sca1(+) pituitary tumor cells exhibited higher rates of tumor formation (brain tumors observed in 11/11 (100%) vs 7/12 (54%) of mice transplanted with Sca1(+) and Sca1(-) cells respectively). Magnetic resonance imaging and histological analysis of brain tumors showed that tumors derived from Sca1(+) pituitary tumor cells were also larger and plurihormonal. Our findings show that Sca1(+) cells derived from benign pituitary tumors exhibit an undifferentiated expression profile and tumor-proliferative advantages, and we propose that they could represent putative pituitary tumor stem/progenitor cells. PMID- 24481639 TI - Three-dimensional sonographic virtual cystoscopy in a case of placenta percreta. PMID- 24481640 TI - A phase III randomized trial of high-dose CEOP + filgrastim versus standard-dose CEOP in patients with non-Hodgkin lymphoma: 10-year follow-up data: Australasian Leukaemia and Lymphoma Group (ALLG) NHL07 trial. AB - Increasing dose intensity (DI) of chemotherapy for patients with aggressive non Hodgkin lymphoma (NHL) may improve outcomes at the cost of increased toxicity. This issue was addressed in a randomized trial aiming to double the DI of myelosuppressive drugs. Between 1994 and 1999, 250 patients with previously untreated aggressive NHL were randomized to treatment with six cycles of 3-weekly standard (s) or intensive (i) chemotherapy: s-CEOP-cyclophosphamide 750, epirubicin 75, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5; i-CEOP-cyclophosphamide 1,500, epirubicin 150, vincristine 1.4 mg/m(2) all on day 1, and prednisolone 100 mg days 1-5. Primary endpoint was 5-year overall survival (OS). Relative to s-CEOP patients, i-CEOP patients achieved a 78% increase in the DI of cyclophosphamide and epirubicin. Despite this, there was no significant difference in any outcome: 5-year OS (56.7% i-CEOP; 55.1% s-CEOP; P = 0.80), 5-year progression free survival (PFS; 41% i-CEOP; 43% s-CEOP; P = 0.73), 5-year time to progression (TTP; 44% i-CEOP; 47% s-CEOP; P = 0.72), or complete remission (CR) + unconfirmed CR (CRu) rates (53% i-CEOP; 59% s-CEOP; P = 0.64). Long-term follow up at 10 years also showed no significant differences in OS, PFS, or TTP. The i-CEOP arm had higher rates of febrile neutropenia (70 vs. 26%), hospitalisations, blood product utilisation, haematological and gastrointestinal toxicities, and lower quality of life scores during treatment, although without significant differences 6-month later. In the treatment of aggressive NHL in the prerituximab era, increasing DI did not result in improved outcomes, while at the same time lead to increased toxicity. PMID- 24481641 TI - Spatial and temporal distribution of trunk-injected imidacloprid in apple tree canopies. AB - BACKGROUND: Pesticide use in orchards creates drift-driven pesticide losses which contaminate the environment. Trunk injection of pesticides as a target-precise delivery system could greatly reduce pesticide losses. However, pesticide efficiency after trunk injection is associated with the underinvestigated spatial and temporal distribution of the pesticide within the tree crown. This study quantified the spatial and temporal distribution of trunk-injected imidacloprid within apple crowns after trunk injection using one, two, four or eight injection ports per tree. RESULTS: The spatial uniformity of imidacloprid distribution in apple crowns significantly increased with more injection ports. Four ports allowed uniform spatial distribution of imidacloprid in the crown. Uniform and non-uniform spatial distributions were established early and lasted throughout the experiment. The temporal distribution of imidacloprid was significantly non uniform. Upper and lower crown positions did not significantly differ in compound concentration. Crown concentration patterns indicated that imidacloprid transport in the trunk occurred through radial diffusion and vertical uptake with a spiral pattern. CONCLUSION: By showing where and when a trunk-injected compound is distributed in the apple tree canopy, this study addresses a key knowledge gap in terms of explaining the efficiency of the compound in the crown. These findings allow the improvement of target-precise pesticide delivery for more sustainable tree-based agriculture. PMID- 24481642 TI - Facilitating the use of non-standard in vivo studies in health risk assessment of chemicals: a proposal to improve evaluation criteria and reporting. AB - To improve data availability in health risk assessment of chemicals and fill information gaps there is a need to facilitate the use of non-standard toxicity studies, i.e. studies not conducted according to any standardized toxicity test guidelines. The purpose of this work was to propose criteria and guidance for the evaluation of reliability and relevance of non-standard in vivo studies, which could be used to facilitate systematic and transparent evaluation of such studies for health risk assessment. Another aim was to propose user friendly guidance for reporting of non-standard studies intended to promote an improvement in reporting of studies that could be of use in risk assessment. Requirements and recommendations for the design and execution of in vivo toxicity studies were identified from The Organisation for Economic Co-operation and Development (OECD) test guidelines, and served as basis for the data evaluation criteria and reporting guidelines. Feedback was also collected from experts within the field of toxicity testing and risk assessment and used to construct a two-tiered framework for study evaluation, as well as refine the reporting guidelines. The proposed framework emphasizes the importance of study relevance and an important aspect is to not completely dismiss studies from health risk assessment based on very strict criteria for reliability. The suggested reporting guidelines provide researchers with a tool to fulfill reporting requirements as stated by regulatory agencies. Together, these resources provide an approach to include all relevant data that may fill information gaps and reduce scientific uncertainty in health risk assessment conclusions, and subsequently also in chemical policy decisions. PMID- 24481643 TI - Rapid synthesis of fused N-heterocycles by transition-metal-free electrophilic amination of arene C-H bonds. AB - We disclose an efficient and operationally simple protocol for the preparation of fused N-heterocycles starting from readily available 2-nitrobiaryls and PhMgBr under mild conditions. More than two dozen N-heterocycles, including two bioactive natural products, have been synthesized using this method. A stepwise electrophilic aromatic cyclization mechanism was proposed by DFT calculations. PMID- 24481644 TI - Oligodendrogenesis and myelinogenesis during postnatal development effect of glatiramer acetate. AB - Myelinogenesis in the mammal nervous system occurs predominantly postnatally. Glatiramer acetate (GA), a drug for the treatment for multiple sclerosis (MS), has been shown to induce immunomodulation and neuroprotection in the inflamed CNS in MS and in experimental autoimmune encephalomyelitis (EAE). Here we investigated whether GA can affect myelinogenesis and oligodendrogenesis in the developing nervous system under nonpathological conditions. Towards this end we studied myelination in mice injected daily by GA, at postnatal Days 7-21. Immunohistological and ultrastructural analyses revealed significant elevation in the number of myelinated axons as well as in the thickness of the myelin encircling them and their resulting g-ratios, in spinal cords of GA-injected mice compared with their PBS-injected littermates, at postnatal Day 14. Elevation in myelinated axons was detected also in the peripheral ventral roots of the motor nerves. GA induced also an increase in axonal diameter, implying an effect on the overall development of the nervous system. A prominent elevation in the amount of progenitor oligodendrocytes and their BrdU incorporation, as well as in mature oligodendrocytes indicated that the effect of GA is linked to increased proliferation and differentiation along the oligodendroglial maturation cascade. In addition, elevation in insulin-like growth factor (IGF-1) and brain-derived neurotrophic factor (BDNF) was found in the white matter of the GA-injected mice. Furthermore, a functional advantage in rotating rod test was exhibited by GA injected mice over their littermates at postnatal Day 21. These cumulative findings corroborate the beneficial effect of GA on oligodendrogenesis and myelination. PMID- 24481646 TI - Building clinical networks: a developmental evaluation framework. AB - BACKGROUND: Clinical networks have been designed as a cross-organisational mechanism to plan and deliver health services. With recent concerns about the effectiveness of these structures, it is timely to consider an evidence-informed approach for how they can be developed and evaluated. OBJECTIVE: To document an evaluation framework for clinical networks by drawing on the network evaluation literature and a 5-year study of clinical networks. METHOD: We searched literature in three domains: network evaluation, factors that aid or inhibit network development, and on robust methods to measure network characteristics. This material was used to build a framework required for effective developmental evaluation. RESULTS: The framework's architecture identifies three stages of clinical network development; partner selection, network design and network management. Within each stage is evidence about factors that act as facilitators and barriers to network growth. These factors can be used to measure progress via appropriate methods and tools. The framework can provide for network growth and support informed decisions about progress. CONCLUSIONS: For the first time in one place a framework incorporating rigorous methods and tools can identify factors known to affect the development of clinical networks. The target user group is internal stakeholders who need to conduct developmental evaluation to inform key decisions along their network's developmental pathway. PMID- 24481645 TI - Tailoring chimeric ligands for studying and biasing ErbB receptor family interactions. AB - Described is the development and application of a versatile semisynthetic strategy, based on a combination of sortase-mediated coupling and tetrazine ligation chemistry, which can be exploited for the efficient incorporation of tunable functionality into chimeric recombinant proteins. To demonstrate the scope of the method, the assembly of a set of bivalent ligands, which integrate members of the epidermal growth factor (EGF) ligand family, is described. By using a series of bivalent EGFs with variable intraligand spacing, the differences in structure were correlated with the ability to bias signaling in the ErbB receptor family in a cell motility assay. Biasing away from EGFR-HER2 dimerization with a bivalent EGF was observed to reduce cell motility in an intraligand distance-dependent fashion, thus demonstrating the utility of the approach for acutely perturbing receptor-mediated cell signaling pathways. PMID- 24481647 TI - MicroRNA-378 functions as an onco-miR in nasopharyngeal carcinoma by repressing TOB2 expression. AB - Increasing evidence indicates that microRNAs (miRNAs) has been implicated in the progression and metastasis of numerous cancers. In particular, abnormal expression of miR-378 has been observed in various cancers and is associated with cell survival, migration, invasion, angio-genesis and tumor growth. Our previous studies have shown that miR-378 was decreased in nasopharyngeal carcinoma (NPC) plasma and was negatively correlated with NPC progression. However, the tissue expression of miR-378 and its biological function remained unknown in NPC. In this study, we report for the first time that expression level of miR-378 was commonly upregulated in both NPC tissues and NPC cell lines compared to normal healthy nasopharyngeal epithelial samples and human nasopharyngeal epithelial cell lines (NP69), respectively, and was opposite to the reported results in plasma. Functional studies showed that upregulation of miR-378 dramatically promoted cell proliferation, colony formation, migration and invasion in vitro, as well as tumor growth in vivo. Bioinformatics analyses were performed to predict the target genes of miR-378, and the following mechanistic investigations revealed that miR-378 overexpression was able to downregulate the expression of transducer of ERBB2 (TOB2), a potential tumor suppressor, and miR-378 silencing enhanced TOB2 expression. In clinical specimens, TOB2 was widely repressed in tumor tissues accompanied by miR-378 overexpression. Taken together, this study indicates that miR-378 regulates TOB2 and may function as an onco-miR in NPC progression, providing a potential target for gene therapy of NPC. PMID- 24481648 TI - Ponatinib enhances anticancer drug sensitivity in MRP7-overexpressing cells. AB - The presence of acquired multidrug resistance (MDR) is one of the primary impediments to the success of chemotherapy. MDR is often a result of overexpression of ATP-binding cassette (ABC) transporters, which are involved in the extrusion of therapeutic drugs. Recently, it was shown that several ABC transporters could be modulated by specific tyrosine-kinase inhibitors (TKIs). Ponatinib, a multi-targeted TKI, inhibits the activity of BCR-ABL with very high potency and broad specificity, including the T315I mutation which confers resistance to other TKIs. It was reported that ponatinib was capable of reversing breast cancer resistance protein (BCRP)- and P-glycoprotein (P-gp)-mediated MDR. In the present study, we report for the first time that ponatinib also potentiates the cytotoxicity of widely used therapeutic substrates of MRP7, such as paclitaxel, docetaxel, vincristine and vinblastine. Ponatinib significantly enhances the accumulation of [3H]-paclitaxel in cells expressing MRP7. Furthermore, accumulation of [3H]-paclitaxel was achieved by inhibition of MRP7 mediated transport. Ponatinb limited drug export via MRP7 by multiple mechanisms. In addition to inhibition of pump function, ponatinib also downregulated MRP7 protein expression in a time- and concentration-dependent manner. Thus, ponatinib may represent a potential reversal agent for the treatment of MDR and may be useful for combination therapy in MDR cancer patients in clinical practice. PMID- 24481650 TI - Deciphering the subunit composition of multimeric proteins by counting photobleaching steps. AB - The limit of subdiffraction imaging with fluorescent proteins currently lies at 20 nm, and therefore most protein complexes are too small (2-5 nm) to spatially resolve their individual subunits by optical means. However, the number and stoichiometry of subunits within an immobilized protein complex can be resolved by the observation of photobleaching steps of individual fluorophores or co localization of single-molecule fluorescence emission in multiple colors. We give an overview of the proteins that have been investigated by this approach and the different techniques that can be used to immobilize and label the proteins. This minireview should serve as a guideline for scientists who want to employ single molecule subunit counting for their research. PMID- 24481649 TI - A cross-sectional survey assessing sources of movement-related fear among people with fibromyalgia syndrome. AB - Fear of movement may contribute to functional limitations and loss of well-being among individuals with fibromyalgia (FM). The objectives of this study were to assess factors contributing to movement-related fear and to explore relationships among these factors, function and wellness, in a widespread population of people with FM. This was an internet survey of individuals with FM. Respondents completed a battery of surveys including the Fibromyalgia Impact Questionnaire- Revised (FIQR), Tampa Scale of Kinesiophobia (TSK), Activities-Specific Balance Confidence Scale (ABC), Primary Care Posttraumatic Stress Disorder screen (PC PTSD), Vertigo Symptom Scale (VSS-SF), a joint hypermobility syndrome screen (JHS), and screening questions related to obsessive-compulsive personality disorder (OCPD), physical activity, work status, and demographics. Analysis included descriptive statistics, Pearson product-moment correlations, and linear regression. Over a 2-year period, 1,125 people (97.6 % female) completed the survey battery. Kinesiophobia was present in 72.9 % of the respondents, balance confidence was compromised in 74.8 %, PTSD likely in 60.4 %, joint hypermobility syndrome likely in 46.6 %, and OCPD tendencies in 26.8 %. The total FIQR and FIQR perceived function subscores were highly correlated (p < 0.0005, r > 0.4) with pain, kinesiophobia, balance confidence, and vertigo. Reported activity level had poor correlation (r < 0.25) with all measured variables. Pain, ABC, VSS, and TSK predicted FIQR and FIQR-pf, explaining 65 and 48 % of the variance, respectively. Kinesiophobia, balance complaints, vertigo, PTSD, and joint hypermobility were common in this population of people with FM. Sources of movement-related fear correlated to overall wellness and perceived function as measured by the FIQR and FIQR-pf. PMID- 24481651 TI - Do individual and situational factors explain the link between predrinking and heavier alcohol consumption? An event-level study of types of beverage consumed and social context. AB - AIM: Predrinking (drinking in private settings before going to licensed premises) has been shown to be positively associated with amount of alcohol consumed. The present study assesses whether this association is explained by general drinking patterns or situational factors, including drinking duration, beverage type and drinking companions. METHODS: In a sample of 183 young adults from French speaking Switzerland, data on alcohol consumption, whereabouts and drinking companions were collected using questionnaires sent to participants' cell phones at five time points from 5 p.m. to midnight every Thursday, Friday and Saturday over five consecutive weeks. Means and proportion tests and multilevel models were conducted based on 6650 assessments recorded on 1441 evenings. RESULTS: Over the study period, predrinkers drank more frequently than did non-predrinkers and, among males, predrinkers drank more heavily. Predrinking was related to increased drinking duration and thus total consumption in the evenings. Larger groups of people were reported for predrinking compared with off-premise only drinking situations. Among women, the consumption of straight spirits (i.e. not mixed with soft drinks) while predrinking was associated with higher total evening alcohol consumption. Among men, drinking with exclusively male friends or female friends while predrinking was associated with higher consumption. CONCLUSION: Heavier drinking on predrinking evenings mainly results from longer drinking duration, with individual and situational factors playing a smaller role. Prevention efforts on reducing the time that young adults spend drinking and harm reduction measures such as restriction of access to on-premise establishments once intoxicated are recommended. PMID- 24481652 TI - The dosage-response curve for auxin-induced cell elongation: A reevaluation. AB - The dosage-response curve for auxin-induced growth of coleoptile sections has been reevaluated, using initial growth rates than rates obtained hours after application of auxin. The curve is sigmoid rather than the "classical" bell shape; i.e., the growth rate increases as the IAA concentration is raised from 10(-8) M, but then the same optimal rate prevails over the range of 3*10(-7) to 10(-3) M. In the absence of sucrose this sigmoid shape persists, but with sucrose present the shape slowly changes into a modified bell-shaped curve. It is suggested that the classical bell-shaped curve is due, at least in part, to an auxin-sucrose interaction, and that it is not a true reflection of the kinetics of auxin-induced elongation. PMID- 24481653 TI - Electron-probe microanalysis of silicon in the epidermis of rice (Oryza sativa L.) internodes. AB - Electron-probe X-ray microanalysis showed that significant amounts of silicon are accumulated in the entire epidermal system of the rice internode except in the stomatal apparatuses. Thus, there is a lack of specific sites for Si deposition from levels just above the base to the tip of the rice internode. In the intercalary meristem region, 1 cm above the base of the internode, point-count data indicate more Si accumulation in the dumb-bell shaped silica cells than in the long epidermal cells. Above this region, Si is accumulated essentially in a uniform pattern in all epidermal cells. Such a pattern for Si accumulation in rice internodes markedly contrasts with that for Avena internodes and may explain, in part, why rice plants have a higher percentage Si (dry weight basis) in their shoots. The adaptive significance of this silicification pattern in rice is discussed. PMID- 24481654 TI - Temperature and the translocation of photosynthate through the leaf of Lolium temulentum. AB - Localized cooling of a 2 cm length of the leaf blade of the grass Lolium temulentum to 0 degrees C, had only a small effect on the mass transfer of assimilates from the distal part of the leaf. There was no evidence of a reduction in the velocity of movement of (14)C-labelled assimilates through the low temperature zone, and the retention of assimilates along the pathway of movement was reduced by low temperature. In contrast to the longitudinal movement, lateral movement of (14)C, induced by steam killing sections of the leaf, was extremely sensitive to temperature and showed no sign of acclimatization, even after 3 days at low temperature. These results suggest that, although loading sugars into the transport system was sensitive to temperature, the movement of assimilates was not directly controlled by metabolic processes along the pathway. PMID- 24481655 TI - Exploration of the nitrogen transport system of a nodulated legume using (15)N. AB - Feeding experiments using (15)N2 or (15)NO3 are described investigating the transport of nitrogen in the field pea (Pisum arvense L.). Nitrogen assimilated by root or nodules moves preferentially upwards to the shoot through the xylem. Parts of the root below or distal to a region of assimilation can benefit from this nitrogen but do so to a much greater extent when the shoot is left attached than when it has been removed. A considerable proportion of the nitrogen received by a shoot from the root or nodules is apparently returned to the root in the translocation stream, this "cycled" nitrogen being especially important in the nutrition of outlying parts of nodulated roots growing in media lacking combined nitrogen.Nitrogen from nitrate fed to a mature leaf is exported in quantity to all parts of the plant except older regions of the shoot. Leaf and stem segments immediately above the fed leaf, and the root and its nodules receive large shares of this nitrogen, although the root's share declines noticeably as the plant ages.The root appears to be extremely inactive in transferring nitrogen from the downward translocation stream across to the stream of nitrogen leaving the root in the xylem. This may act as a major obstacle to the free circulation and mixing of nitrogen within the plant body.A scheme is proposed embracing the main quantitative features of the transport system for nitrogen in the species. PMID- 24481656 TI - Polyphenol synthesis in cell suspension cultures of Paul's Scarlet rose. AB - 1. In dark-grown cell suspension cultures of Paul's Scarlet rose (Rosa sp.), polyphenol accumulation is essentially restricted to late- and post-exponential phase cells. The range of polyphenols synthesised is extensive, involving at least fourteen different compounds which show a characteristic pattern of development over the growth cycle. 2. The duration of polyphenol accumulation is largely determined by the availability of carbohydrate, while the initiation and initial rate of synthesis is largely influenced by a complex of factors of which auxin concentration and light are most important. High 2,4-D concentrations (5x10(-5)M) supress accumulation by delaying initiation and reducing the subsequent rate of synthesis. High intensity illumination (6000 Lux) partially reverses the inhibition of polyphenol synthesis at 5x10(-5)M 2,4-D, and enhances accumulation at lower auxin concentrations (5x10(-7)M 2,4-D). 3. Illuminated cultures also accumulate anthocyanin. Initiation of pigment synthesis is insensitive to the auxin concentration of the medium, and higher hormonal levels (5x10(-5)M 2,4-D) increase net anthocyanin accumulation by prolonging the period over which it is synthesised. PMID- 24481657 TI - Effects of auxin on polyphenol accumulation and the development of phenylalanine ammonia-lyase activity in darkgrown suspension cultures of Paul's Scarlet rose. AB - 1. Under a variety of cultural conditions, including variation in initial auxin and carbohydrate levels, there appears to be a close correlation between phenylalanine ammonia-lyase (PAL) activity and polyphenol synthesis, although there is some discrepancy in timing between the maximum rate of polyphenol accumulation and the period of maximum enzyme content. The diverse responses of the two parameters to cycloheximide and actinomycin-D inhibition suggest that at certain phases of development, PAL is not a rate-limiting step in polyphenol synthesis. 2. Based on the sensitivity to antibiotic inhibitors, it is concluded that PAL is synthesised de novo, that it is subject to rapid turnover at all stages of development and that continuous RNA synthesis is required to sustain the increase in PAL levels. 3. When added to lag- and early exponential-phase cells high 2,4-D concentrations retard the development of PAL activity with a concomitant delay in polyphenol accumulation. Once the increase in PAL activity has started, the early stage of development of the enzyme is less sensitive to high hormone levels than is polyphenol synthesis. It is suggested, therefore, that in addition to inhibiting the initiation of PAL synthesis, high auxin levels may also inhibit some other component(s) of the biosynthetic pathway. High 2,4-D levels (10(-3)M) do not inhibit the activity of PAL in vitro. PMID- 24481658 TI - [Evidence that the multiple molecular forms of glutamate dehydrogenase from pea seedlings are conformers]. AB - The multiple molecular forms of glutamate dehydrogenase from pea seedlings (Pisum sativum, var. Spath's Violetta) have been investigated. When protein preparations are subjected to electrophoresis on polyacrylamide gels, the glutamate dehydrogenase can be localized by substrate staining. Shoots show seven activity bands, whereas roots have one main zone and several faint ones. SO2-fumigation generates typical alterations of the shoot zymogram. The molecular weight of all the distinct enzyme components is identical and has been shown to be 210000. Urea denaturation with subsequent renaturation of the various glutamate dehydrogenase preparations from roots, shoots and SO2-fumigated shoots results in the formation of one identical activity band on polyacrylamide gels. The results discussed here give much evidence that the multiple molecular forms of glutamate dehydrogenase from pea seedlings are conformers. PMID- 24481659 TI - Cytokinins in the xylem sap of grape vine canes: Changes in activity during cold storage. AB - Xylem sap extracted under suction from dormant grape vine canes (one-year-old woody stems) had only slight cytokinin activity compared with sap from growing canes when tested on soybean callus. Highest activity was detected in sap from canes harvested whilst dormant and subsequently stored for six months in sealed plastic bags at 1 degrees . The significance of the findings is discussed. PMID- 24481660 TI - Systems metabolic engineering design: fatty acid production as an emerging case study. AB - Increasing demand for petroleum has stimulated industry to develop sustainable production of chemicals and biofuels using microbial cell factories. Fatty acids of chain lengths from C6 to C16 are propitious intermediates for the catalytic synthesis of industrial chemicals and diesel-like biofuels. The abundance of genetic information available for Escherichia coli and specifically, fatty acid metabolism in E. coli, supports this bacterium as a promising host for engineering a biocatalyst for the microbial production of fatty acids. Recent successes rooted in different features of systems metabolic engineering in the strain design of high-yielding medium chain fatty acid producing E. coli strains provide an emerging case study of design methods for effective strain design. Classical metabolic engineering and synthetic biology approaches enabled different and distinct design paths towards a high-yielding strain. Here we highlight a rational strain design process in systems biology, an integrated computational and experimental approach for carboxylic acid production, as an alternative method. Additional challenges inherent in achieving an optimal strain for commercialization of medium chain-length fatty acids will likely require a collection of strategies from systems metabolic engineering. Not only will the continued advancement in systems metabolic engineering result in these highly productive strains more quickly, this knowledge will extend more rapidly the carboxylic acid platform to the microbial production of carboxylic acids with alternate chain-lengths and functionalities. PMID- 24481662 TI - EMMPRIN co-expressed with matrix metalloproteinases predicts poor prognosis in patients with osteosarcoma. AB - Several studies have focused on the relationships between the expression of extracellular matrix metalloproteinase inducer (EMMPRIN) and the prognosis of patients with malignant tumors. However, few of these have investigated the expression of EMMPRIN in osteosarcoma. We examined expression levels of EMMPRIN immunohistochemically in 53 cases of high-grade osteosarcoma of the extremities and analyzed the correlation of its expression with patient prognosis. The correlation between matrix metalloproteinases (MMPs) and EMMPRIN expression and the prognostic value of co-expression were also analyzed. Staining positivity for EMMPRIN was negative in 7 cases, low in 17, moderate in 19, and strong in 10. The overall and disease-free survivals (OS and DFS) in patients with higher EMMPRIN expression (strong-moderate) were significantly lower than those in the lower (weak-negative) group (0.037 and 0.024, respectively). In multivariate analysis, age (P=0.004), location (P=0.046), and EMMPRIN expression (P=0.038) were significant prognostic factors for overall survival. EMMPRIN expression (P=0.024) was also a significant prognostic factor for disease-free survival. Co-expression analyses of EMMPRIN and MMPs revealed that strong co-expression of EMMPRIN and membrane-type 1 (MT1)-MMP had a poor prognostic value (P=0.056 for DFS, P=0.006 for OS). EMMPRIN expression and co-expression with MMPs well predict the prognosis of patients with extremity osteosarcoma, making EMMPRIN a possible therapeutic target in these patients. PMID- 24481661 TI - Gene set enrichment analysis of the NF-kappaB/Snail/YY1/RKIP circuitry in multiple myeloma. AB - The presence of a dysregulated NF-kappaB/Snail/YY1/RKIP loop was recently established in metastatic prostate cancer cells and non-Hodgkin's lymphoma; however, its involvement in multiple myeloma (MM) has yet to be investigated. Aim of the study was to investigate the role of the NF-kappaB/Snail/YY1/RKIP circuitry in MM and how each gene is correlated with the remaining genes of the loop. Using gene set enrichment analysis and gene neighbours analysis in data received from four datasets included in the Multiple Myeloma Genomics Portal of the Multiple Myeloma Research Consortium, we identified various enriched gene sets associated with each member of the NF-kappaB/Snail/YY1/RKIP circuitry. In each dataset, the 20 most co-expressed genes with the circuitry genes were isolated subjected to Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment. Among many, we highlighted on FNDC3B, TPD52, BBX, MBNL1 and MFAP2. Many co-expressed genes participated in the regulation of metabolic processes and nucleic acid binding, or were transcription factor binding genes and genes with metallopeptidase activity. The transcription factors FOXO4, GATA binding factor, Sp1 and AP4 most likely affect the expression of the NF-kappaB/Snail/YY1/RKIP circuitry genes. Computational analysis of various GEO datasets revealed elevated YY1 and RKIP levels in MM vs. the normal plasma cells, as well as elevated RKIP levels in MM vs. normal B lymphocytes. The present study highlights the relationships of the NF-kappaB/Snail/YY1/RKIP circuitry genes with specific cancer-related gene sets in multiple myeloma. PMID- 24481663 TI - Interactions of time of day and sleep with between-session habituation and extinction memory in young adult males. AB - Within-session habituation and extinction learning co-occur as do subsequent consolidation of habituation (i.e., between-session habituation) and extinction memory. We sought to determine whether, as we predicted: (1) between-session habituation is greater across a night of sleep versus a day awake; (2) time-of day accounts for differences; (3) between-session habituation predicts consolidation of extinction memory; (4) sleep predicts between-session habituation and/or extinction memory. Participants (N = 28) completed 4-5 sessions alternating between mornings and evenings over 3 successive days (2 nights) with session 1 in either the morning (N = 13) or evening (N = 15). Twelve participants underwent laboratory polysomnography. During 4 sessions, participants completed a loud-tone habituation protocol, while skin conductance response (SCR), blink startle electromyography (EMG), heart-rate acceleration and heart-rate deceleration (HRD) were recorded. For sessions 1 and 2, between session habituation of EMG, SCR and HRD was greater across sleep. SCR and HRD were generally lower in the morning. Between-session habituation of SCR for sessions 1 and 2 was positively related to intervening (first night) slow wave sleep. In the evening before night 2, participants also underwent fear conditioning and extinction learning phases of a second protocol. Extinction recall was tested the following morning. Extinction recall was predicted only by between-session habituation of SCR across the same night (second night) and by intervening REM. We conclude that: (1) sleep augments between-session habituation, as does morning testing; (2) extinction recall is predicted by concurrent between-session habituation; and (3) both phenomena may be influenced by sleep. PMID- 24481664 TI - An investigation of the causes of cocrystal dissociation at high humidity. AB - The dissociation at high humidity of cocrystals formed between caffeine and theophylline with a series of dicarboxylic acids is investigated and found to be driven by the partial dissolution of the acid, rather than by the formation of caffeine/theophylline hydrate. It is shown that partial dissociation occurs under all humidity conditions, and that cocrystals of compounds which do not form hydrates also dissociate by this mechanism. The observations made in this study indicate that cocrystal instability at high humidity will be a widespread issue, especially for cocrystals where the two coformers have widely differing aqueous solubilities, as is likely for systems where cocrystallisation is being used as means of improving the aqueous solubility, or dissolution rate, of a compound. PMID- 24481665 TI - Thrombosis and survival in essential thrombocythemia: a regional study of 1,144 patients. AB - To identify prognostic factors affecting thrombosis-free survival (TFS) and overall survival (OS), we report the experience of a Regional cooperative group in a real-life cohort of 1,144 patients with essential thrombocythemia (ET) diagnosed from January 1979 to December 2010. There were 107 thrombotic events (9.4%) during follow-up [60 (5.3%) arterial and 47 (4.1%) venous thromboses]. At univariate analysis, risk factors for a shorter TFS were: age >60 years (P < 0.0054, 95% CI 1.18-2.6), previous thrombosis (P < 0.0001, 95% CI 1.58-4.52) and the presence of at least one cardiovascular risk factor (P = 0.036, 95% CI 1.15 3.13). Patients with a previous thrombosis occurred >=24 months before ET diagnosis had a shorter TFS compared to patients with a previous thrombosis occurred <24 months (P = 0.0029, 95% CI 1.5-6.1); furthermore, patients with previous thrombosis occurred <24 months did not show a shorter TFS compared with patients without previous thrombosis (P = 0.303, 95% CI 0.64-3.21). At multivariate analysis for TFS, only the occurrence of a previous thrombosis maintained its prognostic impact (P = 0.0004, 95% CI 1.48-3.79, RR 2.36). The 10 year OS was 89.9% (95% CI 87.3-92.5): at multivariate analysis for OS, age >60 years (P < 0.0001), anemia (P < 0.0001), male gender (P = 0.0019), previous thromboses (P = 0.0344), and white blood cell >15 * 10(9) /l (P = 0.0370) were independent risk factors. Previous thrombotic events in ET patients are crucial for TFS but their importance seems related not to the occurrence per se but mainly to the interval between the event and the diagnosis. PMID- 24481666 TI - Genetic inactivation of PERK signaling in mouse oligodendrocytes: normal developmental myelination with increased susceptibility to inflammatory demyelination. AB - The immune-mediated central nervous system (CNS) demyelinating disorder multiple sclerosis (MS) is the most common neurological disease in young adults. One important goal of MS research is to identify strategies that will preserve oligodendrocytes (OLs) in MS lesions. During active myelination and remyelination, OLs synthesize large quantities of membrane proteins in the endoplasmic reticulum (ER), which may result in ER stress. During ER stress, pancreatic ER kinase (PERK) phosphorylates eukaryotic translation initiation factor 2alpha (elF2alpha), which activates the integrated stress response (ISR), resulting in a stress-resistant state. Previous studies have shown that PERK activity is increased in OLs within the demyelinating lesions of experimental autoimmune encephalomyelitis (EAE), a model of MS. Moreover, our laboratory has shown that PERK protects OLs from the adverse effects of interferon-gamma, a key mediator of the CNS inflammatory response. Here, we have examined the role of PERK signaling in OLs during development and in response to EAE. We generated OL specific PERK knockout (OL-PERK(ko/ko) ) mice that exhibited a lower level of phosphorylated elF2alpha in the CNS, indicating that the ISR is impaired in the OLs of these mice. Unexpectedly, OL-PERK(ko/ko) mice develop normally and show no myelination defects. Nevertheless, EAE is exacerbated in these mice, which is correlated with increased OL loss, demyelination, and axonal degeneration. These data indicate that although not needed for developmental myelination, PERK signaling provides protection to OLs against inflammatory demyelination and suggest that the ISR in OLs could be a valuable target for future MS therapeutics. PMID- 24481667 TI - Angiography-assisted computed tomography for the detection and intervention of a subtle aneurysm of the omentum. AB - Intra-abdominal hemorrhage caused by omental artery rupture is a rare condition traditionally diagnosed via exploratory laparotomy in hemodynamically unstable patients. We experienced a case in which contrast-enhanced multidetector computed tomography (MDCT) and digital subtraction angiography did not identify the rupture site, whereas CT during left omental arteriography depicted a small 4-mm aneurysm. The lesion was then embolized with microcoils and N-butyl cyanoacrylate lipiodol glue. We consider that performing a CT during selective arteriography could be useful in cases in which the rupture site is unclear with other imaging techniques such as contrast-enhanced MDCT and digital subtraction angiography. PMID- 24481668 TI - Translation and cultural adaptation of the Hirschsprung's Disease/Anorectal Malformation Quality of life Questionnaire (HAQL) into Swedish. AB - PURPOSE: Children with anorectal malformation or Hirschsprung's Disease (HD) often have functional problems with constipation or incontinence. The Hirschsprung's Disease/Anorectal malformation Quality of life Questionnaire (HAQL) developed in the Netherlands is a disease-specific instrument measuring the quality of life (QoL) of children and adolescents with fecal incontinence. HAQL includes several domains with questions concerning diet, laxatives, constipation, diarrhea, urine and fecal incontinence, in addition to social and emotional functioning, body image, and physical symptoms. The purpose of the study was to translate and culturally adapt the HAQL questionnaire into Swedish. METHOD: The translation was carried out according to accepted translation guidelines and a backward/forward translation method was used. RESULTS: The translation correlated well with the original. All in all the Swedish and the Dutch versions agreed well. The Swedish translators chose to use a more simplified language in the questionnaires intended for the children, but used another choice of words in the proxy version and the adolescents' version. CONCLUSIONS: The translation of the HAQL instrument into Swedish gives us a disease-specific QoL instrument for children and adolescents born with HD and anorectal malformations (ARM). The translated and culturally adapted HAQL instrument is included in a survey regarding children and adolescents born with ARM. PMID- 24481669 TI - The activation of sulfur hexafluoride at highly reduced low-coordinate nickel dinitrogen complexes. AB - The greenhouse gas sulfur hexafluoride is the common standard example in the literature of a very inert inorganic small molecule that is even stable against O2 in an electric discharge. However, a reduced beta-diketiminate nickel species proved to be capable of converting SF6 into sulfide and fluoride compounds at ambient standard conditions. The fluoride product complex features an unprecedented [NiF](+) unit, where the Ni atom is only three-coordinate, while the sulfide product exhibits a rare almost linear [Ni(MU-S)Ni](2+) moiety. The reaction was monitored applying (1)H NMR, IR and EPR spectroscopic techniques resulting in the identification of an intermediate nickel complex that gave insight into the mechanism of the eight-electron reduction of SF6. PMID- 24481670 TI - Mesenchymal stem cells show little tropism for the resting and differentiated cancer stem cell-like glioma cells. AB - Intrinsic resistance of glioma cells to radiation and chemotherapy is currently hypothesized to be partially attributed to the existence of cancer stem cells. Emerging studies suggest that mesenchymal stem cells may serve as a potential carrier for delivery of therapeutic genes to disseminated glioma cells. However, the tropism character of mesenchymal stem cells for cancer stem cell-like glioma cells has rarely been described. In this study, we obtained homologous bone marrow-derived (BM-) and adipose tissue-derived (AT-) mesenchymal stem cells (MSCs), fibroblast, and cancer stem cell-like glioma cells (CSGCs) from tumor bearing mice, and compared the tropism character of BM- and AT-MSCs for CSGCs with various form of existence. To characterize the cell proliferation and differentiation, the spheroids of CSGCs were cultured on the surface of the substrate with different stiffness, combined with or withdrew basic fibroblast growth factor (bFGF) and epidermal growth factor (EGF) in medium. Our results showed that the CSGCs during the process of cell proliferation, but not in resting and differentiated status, display strong tropism characteristics on both BM- and AT-MSCs, as well as the expression of their cell chemokine factors which mediate cell migration. If the conclusion is further confirmed, it may expose a fatal flaw of MSCs as tumor-targeted delivery of therapeutic agents in the treatment of the CSGCs, even other cancer stem cells, because there always exist a part of cancer stem cells that are in resting status. Overall, our findings provide novel insight into the complex issue of the MSCs as drug delivery in the treatment of brain tumors, especially in tumor stem cells. PMID- 24481671 TI - Evaluation of established and new reference lines for the standardization of transperineal ultrasound. AB - OBJECTIVES: To examine the performance of a new reference line for the assessment of pelvic organ descent by transperineal ultrasound. METHODS: We compared our newly proposed reference line, between two hyperechoic contours of the symphysis pubis (Line 3), with the horizontal reference line proposed by Dietz and Wilson (Line 1) and the central pubic line proposed by Schaer et al. (Line 2). Ultrasound volumes of 94 women obtained in routine clinical practice were analyzed. The perpendicular distance from the reference lines to the internal sphincter and the most dependent part of the bladder base was measured for volumes obtained at rest, on pelvic floor muscle contraction, on Valsalva maneuver and during coughing. Measurements were repeated 4 months later by the same examiner. Rates of assessment were calculated, and intrarater reliability was evaluated using Bland-Altman plots and intraclass correlation coefficients. RESULTS: Line 2 had to be excluded from reliability analysis because of an assessment rate of only 12%, whereas Lines 1 and 3 could be assessed in 100% of volumes. The intrarater repeatability of Lines 1 and 3 was shown to be very similar. CONCLUSION: In this comparison of three potential reference lines for the assessment of pelvic organ descent by transperineal ultrasound, the central pubic line was shown to be inferior owing to poor visibility in our volumes. Inter-rater reliability analysis and validation studies are required to confirm our results. PMID- 24481672 TI - Molecular characterisation and detection of resistance to succinate dehydrogenase inhibitor fungicides in Botryotinia fuckeliana (Botrytis cinerea). AB - BACKGROUND: Succinate dehydrogenase inhibitors (SDHIs), interfering with fungal respiration, are considered to be fungicides at medium to high risk of resistance. Boscalid was the first molecule belonging to the SDHIs that was introduced for the control of Botryotinia fuckeliana. A range of different target site mutations leading to boscalid resistance have been found in field populations of the fungus. The different types of mutation confer different cross resistance profiles towards novel SDHIs, such as the recently introduced fungicide fluopyram. This study combines the determination of cross-resistance profiles and the setting-up of methods for fast molecular detection of the mutations. RESULTS: By means of in vitro tests, a range of SdhB mutations were characterised for resistance levels towards boscalid and fluopyram. SdhB mutations conferring P225L and P225F substitutions conferred high resistance to boscalid and high or moderate resistance to fluopyram respectively. Mutants carrying the N230I replacement were moderately resistant to both SDHIs. Substitutions at position H272 responsible for a high level of resistance to boscalid conferred sensitivity (H272R), hypersensitivity (H272Y) or moderate resistance (H272V) to fluopyram. Allele-specific (AS) PCR was developed and used for genotyping 135 B. fuckeliana isolates. The assay confirmed the strict association between resistance profiles and allelic variants of the SdhB gene. Real-time AS-PCR proved to be sensitive and specific for quantitative detection of different SDHI-resistant genotypes. CONCLUSION: Fluopyram-resistant mutants are currently rarely detected in the field sprayed with boscalid, but this may change with intensive exposure of the fungal population to fluopyram. PCR assays/methods developed in the study provide tools for fast monitoring of field populations and observing possible changes in population composition following fluopyram introduction, useful for the setting-up of appropriate preventive measures. PMID- 24481673 TI - Attitudes of mothers of children with down syndrome towards noninvasive prenatal testing. AB - Noninvasive prenatal testing (NIPT) allows for highly sensitive detection of Down syndrome early in pregnancy with no risk of miscarriage, therefore potentially increasing the number of pregnancies identified with Down syndrome. This study assesses how mothers of children with Down syndrome perceive NIPT, especially the impact they think it will have on their families and other families with children who have Down syndrome. Seventy-three self-reported mothers of children with Down syndrome responded to an anonymous online survey emailed to, and posted on, message boards of various Down syndrome support groups and networks. Data analysis included chi-square tests and thematic analysis. Fifty-nine percent of respondents indicated they would use NIPT in the future; respondents who had not used prenatal testing in the past were significantly less likely to report interest in using NIPT in the future than those who had prenatal testing previously (p < .001). Many respondents felt NIPT could lead to increased terminations (88 %), increased social stigma (57 %), and decreased availability of services for individuals with Down syndrome (64 %). However, only 16 % believed availability of new noninvasive tests would be the most important factor in determining the number of pregnancies with Down syndrome terminated in the future. Additionally, 48 % believed health care providers give biased or incorrect information about Down syndrome at the time of diagnosis, and 24 % felt this incorrect information leads to terminations of pregnancies affected with Down syndrome. Results suggest although mothers of children with Down syndrome believe new noninvasive testing will lead to an increase in termination of pregnancies with Down syndrome, they do not think it is the MOST important factor. They also highlight the need to provide a diagnosis of Down syndrome in a balanced and objective manner. PMID- 24481674 TI - Activation of oxygen on gold and silver nanoparticles assisted by surface plasmon resonances. AB - Surface plasmon resonances (SPRs) have been found to promote chemical reactions. In most oxidative chemical reactions oxygen molecules participate and understanding of the activation mechanism of oxygen molecules is highly important. For this purpose, we applied surface-enhanced Raman spectroscopy (SERS) to find out the mechanism of SPR-assisted activation of oxygen, by using p aminothiophenol (PATP), which undergoes a SPR-assisted selective oxidation, as a probe molecule. In this way, SPR has the dual function of activating the chemical reaction and enhancing the Raman signal of surface species. Both experiments and DFT calculations reveal that oxygen molecules were activated by accepting an electron from a metal nanoparticle under the excitation of SPR to form a strongly adsorbed oxygen molecule anion. The anion was then transformed to Au or Ag oxides or hydroxides on the surface to oxidize the surface species, which was also supported by the heating effect of the SPR. This work points to a promising new era of SPR-assisted catalytic reactions. PMID- 24481675 TI - Transitive inference by pigeons: does the geometric presentation of the stimuli make a difference? AB - In studies of transitive inference (TI), nonhuman animals are typically trained with the following 5-term task: A+B-, B+C-, C+D-, D+E- where the letters stand for arbitrary stimuli and [+] indicates that choice is reinforced and [-] indicates that choice is not reinforced. A TI effect is found when, given the untrained test pair BD, subjects choose B. TI effects have been found in many nonhuman species. Although reinforcement history has been posited as an account of the TI effect, it has failed to account for a variety of conditions under which TI effects have been found. A more cognitive account of TI is that organisms are able to form a representation of the series (A>B>C>D>E). In support of this hypothesis, Roberts and Phelps (Psychol Sci 5:368-374, 1994) found that presentation of the pairs of stimuli in a linear arrangement facilitated TI performance by rats, whereas presentation of the pairs of stimuli in a circular arrangement did not. Using methods adapted from Roberts and Phelps, we trained pigeons on either a linear or a circular arrangement of stimuli with the 5-term task. Results indicated that on the BD test pair, pigeons trained with a circular arrangement did not differ from those trained with a linear arrangement. Furthermore, we found that memory for training pairs was variable and was highly correlated with degree of TI. The results suggest that regardless of how pigeons are able to represent the stimuli, choice was not affected by the spatial arrangement of the stimuli during training. PMID- 24481676 TI - OCT3 and SOX2 promote the transformation of Barrett's esophagus to adenocarcinoma by regulating the formation of tumor stem cells. AB - Barrett's esophagus (BE) is a type of precancerosis and a key risk factor for esophagus adenocarcinoma (EAC). Tumor stem cells may be the source for BE transforming to EAC. Octamer transcription factor-3/4 (OCT3/4) and SOX2 are the main transcriptional controlling factors and markers of tumor stem cells. In the present study, we observed that the expressions of OCT3/4, SOX2, TCL1 and AKT1 in BE were elevated compared to normal esophagus but were decreased compared to EAC. Moreover, we isolated a few stem-like cells in OE33 cells which showed similar biological behavior to tumor stem cells. Notably, we found that downregulation of OCT3/4 expression by siRNA inhibited the ability of clone formation and invasion of OE33 cells, and decreased the formation of side population cells and slow cycle cells. Therefore, we concluded that OCT3/4 and SOX2 play a critical role in the transformation of BE to EAC by regulating the formation of tumor stem cells and the TCL1/AKT1 pathway. PMID- 24481677 TI - DBZ, a CNS-specific DISC1 binding protein, positively regulates oligodendrocyte differentiation. AB - Recent studies have shown changes in myelin genes and alterations in white matter structure in a wide range of psychiatric disorders. Here we report that DBZ, a central nervous system (CNS)-specific member of the DISC1 interactome, positively regulates the oligodendrocyte (OL) differentiation in vivo and in vitro. In mouse corpus callosum (CC), DBZ mRNA is expressed in OL lineage cells and expression of DBZ protein peaked before MBP expression. In the CC of DBZ-KO mice, we observed delayed myelination during the early postnatal period. Although the myelination delay was mostly recovered by adulthood, OLs with immature structural features were more abundant in adult DBZ-KO mice than in control mice. DBZ was also transiently upregulated during rat OL differentiation in vitro before myelin marker expression. DBZ knockdown by RNA interference resulted in a decreased expression of myelin-related markers and a low number of cells with mature characteristics, but with no effect on the proliferation of oligodendrocyte precursor cells. We also show that the expression levels of transcription factors having a negative-regulatory role in OL differentiation were upregulated when endogenous DBZ was knocked down. These results strongly indicate that OL differentiation in rodents is regulated by DBZ. PMID- 24481679 TI - Body fat composition impacts the hematologic toxicities and pharmacokinetics of doxorubicin in Asian breast cancer patients. AB - Body surface area (BSA)-based dosing leads to wide inter-individual variations in drug pharmacokinetics and pharmacodynamics, whereas body composition has been shown to be a more robust determinant of efficacy and toxicity of certain chemotherapeutic agents. We correlated various parameters of body composition with doxorubicin pharmacokinetics and hematologic toxicities in Asian patients with locally advanced or metastatic breast cancer. Our analysis included 84 patients from two studies who received pre- or post-operative single-agent doxorubicin; pharmacokinetic parameters were available for 44 patients. Body composition parameters were derived from CT cross-sectional images and population pharmacokinetic analysis was conducted using mixed-effects modeling. Higher intra abdominal fat volume and fat ratio (intra-abdominal:total abdominal fat volume) correlated with greater incidence of grade 4 leukopenia on cycle 1 day 15 (mean intra-abdominal fat volume: 97.4 +/- 46.5 cm(3) vs 63.4 +/- 30.9 cm(3), p = 0.014; mean fat ratio: 0.43 +/- 0.11 vs 0.33 +/- 0.09, p = 0.012, grade 4 vs grade 0-3 leukopenia). On subset analysis, this relationship was maintained even in underweight patients. Concordantly, there were positive correlations between doxorubicin AUC and intra-abdominal fat volume as well as total abdominal fat volume (r (2) = 0.324 and 0.262, respectively, all p < 0.001). BSA and muscle volume did not predict for doxorubicin pharmacokinetics or toxicities. High-intra abdominal fat volume but not BSA predicted for greater doxorubicin exposure and hematologic toxicities, suggesting that body composition is superior to BSA in determining doxorubicin pharmacokinetics and pharmacodynamics. Body composition has an emerging role in chemotherapy dose determination. PMID- 24481678 TI - Neural stem cell transplants improve cognitive function without altering amyloid pathology in an APP/PS1 double transgenic model of Alzheimer's disease. AB - Neural stem cells (NSCs) are capable of self-renewal and are multipotent. Transplantation of NSCs may represent a promising approach for treating neurodegenerative disorders associated with cognitive decline, such as Alzheimer disease (AD) characterized by extensive loss of neurons. In this study, we investigated the effect of NSC transplantation on cognitive function in the amyloid precursor protein/presenilin-1 (APP/PS1) transgenic mouse, an AD mouse model with age-dependent cognitive deficits. We found that NSCs bilaterally transplanted into hippocampal regions improved spatial learning and memory function in these mice, but did not alter Abeta pathology. Immunohistochemical analyses determined that NSCs proliferated, migrated, and differentiated into three neuronal cell types. The improvement in cognitive function was correlated with enhanced long-term potentiation (LTP) and an increase in the neuron expression of proteins related to cognitive function: N-methyl-D-aspartate (NMDA) 2B unit, synaptophysin (SYP), protein kinase C zeta subtypes (PKCzeta), tyrosine receptor kinase B (TrkB), and brain-derived neurotrophic factor (BDNF). Taken together, our data indicated that injected NSCs can rescue cognitive deficits in APP/PS1 transgenic mice by replacing neuronal cell types expressing multiple cognition-related proteins that enhance LTP. PMID- 24481680 TI - Andrographolide prevents human breast cancer-induced osteoclastic bone loss via attenuated RANKL signaling. AB - Bone metastasis is a common and serious complication in advanced cancers such as breast cancer, prostate cancer, and multiple myeloma. Agents that prevent bone loss could be used to develop an alternative therapy for bone metastasis. RANKL, a member of the tumor necrosis factor superfamily, has been shown to play a significant role in cancer-associated bone loss. In this study, we examined the efficacy of the natural compound andrographolide (AP), a diterpenoid lactone isolated from the traditional Chinese and Indian medicinal plant Andrographis paniculata, in reducing breast cancer-induced osteolysis. AP prevented human breast cancer-induced bone loss by suppressing RANKL-mediated and human breast cancer cell-induced osteoclast differentiation. Molecular analysis revealed that AP prevented osteoclast function by inhibiting RANKL-induced NF-kappaB and ERK signaling pathway in lower dose (20 MUM), as well as inducing apoptosis at higher dose (40 MUM). Thus, AP is a potent inhibitor of breast cancer-induced bone metastasis. PMID- 24481681 TI - Estimating risks for variants of unknown significance according to their predicted pathogenicity classes with application to BRCA1. AB - Sequence-based testing of disease-susceptibility genes has identified many variants of unknown significance (VUSs) whose pathogenicity is unknown at the time of their measurement. Female breast cancer cases aged 20-49 years at diagnosis and who have VUSs in BRCA1 and no mutations in BRCA2 have previously been identified through the population-based Los Angeles County Cancer Surveillance Program. These nominal BRCA1 VUSs have been classified as "low," "medium," and "high" risk by four classification methods: Align-GVGD, Polyphen, Grantham matrix scores, and sequence conservation in mammalian species. Average hazard ratios (HRs) for classes of variants, i.e., the age-specific incidences of cancer for carriers of such variants divided by the population incidences, were estimated from the cancer family histories of first- and second-degree relatives of the index cases using modified segregation analysis. The study sample comprised 270 index cases and 4,543 of their relatives. There was weak evidence that the risk of breast cancer increases with the degree of sequence conservation (P = 0.03) and that missense variants at highly conserved sites are associated with a 5.6-fold (95 % confidence interval 1.4-22.2; P = 0.05) increased incidence of breast cancer. An upper bound of 2.3 is given for the average breast cancer HRs corresponding to variants classified as "low risk" by any of the four VUS classification methods. In summary, we have given a method to estimate cancer risks for groups of VUSs by combining existing classification methods with traditional penetrance analyses. This analysis suggests that classification methods for BRCA1 variants based on sequence conservation might be useful in a clinical setting. We have shown in principle that our method can be used to classify VUSs into clinically useful risk categories, but our specific findings should not be put into clinical practice unless confirmed by larger studies. PMID- 24481682 TI - Providers of follow-up care in a population-based sample of breast cancer survivors. AB - To describe which providers provide breast cancer survivorship care, we conducted a longitudinal survey of nonmetastatic breast cancer patients identified by the SEER registries of Los Angeles and Detroit. Multinomial logistic regression examined the adjusted odds of surgeon compared with a medical oncologist follow up or primary care provider compared with medical oncologist follow-up, adjusting for age, race/ethnicity, insurance, tumor stage, receipt of chemotherapy, endocrine therapy use, and visit to a medical oncologist at the time of diagnosis. Results were weighted to account for sample selection and nonresponse. 844 women had invasive disease and received chemotherapy or endocrine therapy. 65.2 % reported medical oncologists as their main care provider at 4 years, followed by PCP/other physicians (24.3 %) and surgeons (10.5 %). Black women were more likely to receive their follow-up care from surgeons (OR 2.47, 95 % CI 1.16 5.27) or PCP/other physicians (OR 2.62, 95 % CI 1.47-4.65) than medical oncologists. Latinas were more likely to report PCP/other physician follow-up than medical oncologists (OR 2.33, 95 % CI 1.15-4.73). Compared with privately insured women, Medicaid recipients were more likely to report PCP/other physician follow-up (OR 2.52, 95 % CI 1.24-5.15). Women taking endocrine therapy 4 years after diagnosis were less likely to report surgeons or PCP/other physicians as their primary provider of breast cancer follow-up care. Different survivorship care patterns emerge on race/ethnicity and insurance status. Interventions are needed to inform patients and providers on the recommended sources of breast cancer follow-up. PMID- 24481685 TI - Capsule commentary on Zhang et al., Race/ethnicity, disability, and medication adherence among medicare beneficiaries with heart failure. PMID- 24481684 TI - Annual financial impact of well-differentiated thyroid cancer care in the United States. AB - BACKGROUND: Well-differentiated thyroid cancer (WDTC) is a prevalent disease, which is increasing in incidence faster than any other cancer. Substantial direct medical care costs are related to the diagnosis and treatment of newly diagnosed patients as well as the ongoing surveillance of patients who have a long life expectancy. Prior analyses of the aggregate health care costs attributable to WDTC in the United States have not been reported. METHODS: A stacked cohort cost analysis was performed on the US population from 1985 to 2013 to estimate the number of WDTC survivors in 2013. Incidence rates, and cancer-specific and overall survival were based on Surveillance, Epidemiology, and End Results (SEER) data. Current and projected direct medical care costs attributable to the care of patients with WDTC were then estimated. Health care-related costs and event probabilities were based on Medicare reimbursement schedules and the literature. RESULTS: Estimated overall societal cost of WDTC care in 2013 for all US patients diagnosed after 1985 is $1.6 billion. Diagnosis, surgery, and adjuvant therapy for newly diagnosed patients (41%) constitutes the greatest proportion of costs, followed by surveillance of survivors (37%), and nonoperative death costs attributable to thyroid cancer care (22%). Projected 2030 costs (in 2013 US dollars) based on current incidence trends exceed $3.5 billion. CONCLUSIONS: Health care costs of WDTC are substantial. Unlike other cancers, the majority of the cost is incurred in the initial and continuing phases of care. With the projected increasing incidence, population, and survival trends, costs will continue to escalate. PMID- 24481687 TI - Capsule commentary on Capp et al., National study of health insurance type and reasons for emergency department use. PMID- 24481686 TI - Brief training of student clinicians in shared decision making: a single-blind randomized controlled trial. AB - BACKGROUND: Shared decision making is a crucial component of evidence-based practice, but a lack of training in the "how to" of it is a major barrier to its uptake. OBJECTIVE: To evaluate the effectiveness of a brief intervention for facilitating shared decision making skills in clinicians and student clinicians. DESIGN: Multi-centre randomized controlled trial. PARTICIPANTS: One hundred and seven medical students, physiotherapy or occupational therapy students undertaking a compulsory course in evidence-based practice as part of their undergraduate or postgraduate degree from two Australian universities. INTERVENTION: The 1-h small-group intervention consisted of facilitated critique of five-step framework, strategies, and pre-recorded modelled role-play. Both groups were provided with a chapter about shared decision making skills. MAIN MEASURES: The primary outcome was skills in shared decision making and communicating evidence [Observing Patient Involvement (OPTION) scale, items from the Assessing Communication about Evidence and Patient Preferences (ACEPP) Tool], rated by a blinded assessor from videorecorded role-plays. SECONDARY OUTCOMES: confidence in these skills and attitudes towards patient-centred communication (Patient Practitioner Orientation Scale (PPOS)). KEY RESULTS: Of participants, 95 % (102) completed the primary outcome measures. Two weeks post-intervention, intervention group participants scored significantly higher on the OPTION scale (adjusted group difference = 18.9, 95 % CI 12.4 to 25.4), ACEPP items (difference = 0.9, 95 % CI 0.5 to 1.3), confidence measure (difference = 13.1, 95 % CI 8.5 to 17.7), and the PPOS sharing subscale (difference = 0.2, 95 % CI 0.1 to 0.5). There was no significant difference for the PPOS caring subscale. CONCLUSIONS: This brief intervention was effective in improving student clinicians' ability, attitude towards, and confidence in shared decision making facilitation. Following further testing of the longer-term effects of this intervention, incorporation of this brief intervention into evidence-based practice courses and workshops should be considered, so that student clinicians graduate with these important skills, which are typically neglected in clinician training. PMID- 24481688 TI - Three-month B vitamin supplementation in pre-school children affects folate status and homocysteine, but not cognitive performance. AB - BACKGROUND: Suboptimal vitamin B status might affect cognitive performance in early childhood. We tested the hypothesis that short-term supplementation with folic acid and selected B vitamins improves cognitive function in healthy children in a population with relatively low folate status. METHODS: We screened 1,002 kindergarten children for suboptimal folate status by assessing the total urinary para-aminobenzoylglutamate excretion. Two hundred and fifty low ranking subjects were recruited into a double blind, randomized, controlled trial to receive daily a sachet containing 220 MUg folic acid, 1.1 mg vitamin B2, 0.73 mg B6, 1.2 MUg B12 and 130 mg calcium, or calcium only for 3 months. Primary outcomes were changes in verbal IQ, short-term memory and processing speed between baseline and study end. Secondary outcomes were urinary markers of folate and vitamin B12 status, acetyl-para-aminobenzoylglutamate and methylmalonic acid, respectively, and, in a subgroup of 120 participants, blood folate and plasma homocysteine. RESULTS: Pre- and post-intervention cognitive measurements were completed by 115 children in the intervention and 122 in the control group. Compared to control, median blood folate increased by about 50% (P for difference, P < 0.0001). Homocysteine decreased by 1.1 MUmol/L compared to baseline, no change was seen in the control group (P for difference P < 0.0001) and acetyl-para-aminobenzoylglutamate was 4 nmol/mmol higher compared to control at the end of the intervention (P < 0.0001). We found no relevant differences between the groups for the cognitive measures. CONCLUSION: Short-term improvement of folate and homocysteine status in healthy children does not appear to affect cognitive performance. PMID- 24481689 TI - Effect of maternal protein restriction during pregnancy and postweaning high-fat feeding on diet-induced thermogenesis in adult mouse offspring. AB - PURPOSE: Prenatal undernutrition followed by postweaning feeding of a high-fat diet results in obesity in the adult offspring. In this study, we investigated whether diet-induced thermogenesis is altered as a result of such nutritional mismatch. METHODS: Female MF-1 mice were fed a normal protein (NP, 18% casein) or a protein-restricted (PR, 9% casein) diet throughout pregnancy and lactation. After weaning, male offspring of both groups were fed either a high-fat diet (HF; 45% kcal fat) or standard chow (C, 7% kcal fat) to generate the NP/C, NP/HF, PR/C and PR/HF adult offspring groups (n = 7-11 per group). RESULTS: PR/C and NP/C offspring have similar body weights at 30 weeks of age. Postweaning HF feeding resulted in significantly heavier NP/HF offspring (P < 0.01), but not in PR/HF offspring, compared with their chow-fed counterparts. However, the PR/HF offspring exhibited greater adiposity (P < 0.01) v the NP/HF group. The NP/HF offspring had increased energy expenditure and increased mRNA expression of uncoupling protein-1 and beta-3 adrenergic receptor in the interscapular brown adipose tissue (iBAT) compared with the NP/C mice (both at P < 0.01). No such differences in energy expenditure and iBAT gene expression were observed between the PR/HF and PR/C offspring. CONCLUSIONS: These data suggest that a mismatch between maternal diet during pregnancy and lactation, and the postweaning diet of the offspring, can attenuate diet-induced thermogenesis in the iBAT, resulting in the development of obesity in adulthood. PMID- 24481690 TI - Coffee and caffeine intake and risk of endometriosis: a meta-analysis. AB - PURPOSE: The potential association between endometriosis and coffee/caffeine consumption has been analysed in several epidemiological studies. In order to establish whether caffeine influences the risk of endometriosis, we provide to summarize the evidence from published studies on this issue. METHODS: We performed a meta-analysis of epidemiological studies published up to January 2013. We computed summary relative risks (RR) of endometriosis for any, high and low versus no coffee/caffeine consumption. RESULTS: We identified a total eight studies, six case-control and two cohort studies, including a total of 1,407 women with endometriosis. The summary RR for any versus non-consumption were 1.26 [95% confidence interval (CI) 0.95-1.66] for caffeine and 1.13 (95% CI 0.46-2.76) for coffee consumption; the overall estimate was 1.18 (95% CI 0.92-1.49). The summary RR were 1.09 (95% CI 0.84-1.42) and 1.09 (95% CI 0.89-1.33) for high and low caffeine consumption as compared to no consumption, respectively. CONCLUSION: The present meta-analysis provided no evidence for an association between coffee/caffeine consumption and the risk of endometriosis. Coffee/caffeine consumption, as currently used in diet, does not carry a health risk. PMID- 24481691 TI - [Commentary on "Primary adaptive vs. secondary wound closure in hand infections - differences and benefits" by D. Schmauss, T. Finck, J. A. Lohmeyer, M. Reidel, H. G. Machens and K. Megerle]. PMID- 24481692 TI - [Primary adaptive vs. secondary wound closure in hand infections - differences and benefits]. AB - BACKGROUND: Hand infections are common surgical emergencies. There are still controversial opinions regarding the ideal timing of wound closure after radical debridement of the infection. The aim of this retrospective study was to compare the outcome of primary adaptive and secondary wound closures after operative debridement in patients with hand infections. METHODS: We retrospectively analysed all infections of the hand treated operatively in our hospital in the years 2011 and 2012 with a follow-up of at least 6 months. We included 16 patients with primary adaptive wound closure (PWC) and 12 patients with secondary wound closure (SWC) in this study. The evaluated parameters were the need for re operations, the length of hospital stay, the overall satisfaction with the treatment, the characteristics of the scar and the mobility of the hand. RESULTS: No patient had to be re-operated after PWC or SWC, respectively. Patients in the PWC group were kept significantly shorter as inpatients in comparison to patients in the SWC group (3.0 days vs. 5.1 days; p=0.048). Overall patient satisfaction with the treatment and the scar was comparable for both groups, as was the re establishment of the mobility of the treated hand to preoperative levels. CONCLUSION: This study shows that wounds after radical debridement for infection of the hand can be closed primarily adaptive without disadvantages for the patient. The length of hospitalisation is significantly shorter if the wound is closed primarily adaptive, a fact that is important for patient comfort and the socio-economic system. Both, primary adaptive and secondary wound closures generally have good outcomes with possible advantages for primary adaptive wound closures concerning the characteristics of the scar. PMID- 24481693 TI - Effect of senescence and hormone treatment on the activity of a beta-1,3-glucan hydrolase in Nicotiana glutinosa leaves. AB - A high level of activity of a beta-1,3-glucan hydrolase is present in leaves of Nicotiana glutinosa and the enzyme is also present in the roots, midribs, petioles and stems. By comparison, very low levels of beta-1,4-glucan hydrolase are found throughout the plant. The activity of the beta-1,3-glucan hydrolase in leaves aged on the plant was found to increase 14-fold during the course of leaf senescence and to reach a maximum in yellow-green leaves. Detached leaves and leaf discs floated on water in the dark showed similar patterns of change.The increase in beta-1,3-glucan hydrolase activity during senescence is apparently not due to the loss of an inhibitor from young green leaves or to the formation of an enzyme activator in yellow leaves. The enzyme in yellow leaves was electrophoretically indistinguishable from that in green leaves. The hydrolase is not firmly attached to the cell walls and is not present in the particulate fraction sedimenting at 105400xg for 60 min. Within the leaf cell it is therefore likely to be located either in the cytoplasm or in an easily disrupted structure such as a vacuole.The relationship of the hydrolase to leaf senescence was investigated by examining the effect of plant hormones on the changes in level of hydrolase, protein and chlorophyll in leaf discs during senescence. IAA (10 MUM) and GA3 (50 MUM) did not alter the normal patterns of change, whilst Kin (50 MUM) delayed the loss of protein and chlorophyll and also delayed and decreased the rise in hydrolase activity. In contrast, ABA (190 MUM) which increased the rate of loss of protein and chlorophyll, also caused a decrease in the rate and extent of the rise in hydrolase.Possible functions of the hydrolase in the leaf are discussed. PMID- 24481694 TI - The effect of stratification on endogenous cytokinin levels in seeds of Acer saccharum. AB - Stratification of sugar maple seed resulted in high levels of cytokinins after 20 days. A further increase in the chilling period led to a decrease in cytokinins. Most of the cytokinin activity detected was due to compound(s) that co chromatographed with zeatin.It is concluded that this increase in cytokinins may result in the breaking of dormancy, perhaps by overcoming the effect of endogenous inhibitors. PMID- 24481695 TI - Seed dormancy in Acer: Endogenous germination inhibitors and dormancy in Acer pseudoplatanus L. AB - Dormant seeds of Acer pseudoplatanus L. contain two zones of inhibition on paper chromatograms in "10:1:1" as detected by the lettuce and cress seed germination, and the wheat coleoptile bioassays. One zone at Rf 0.6-0.8 was partitioned into ethyl acetate at acid pH and was shown to contain ABA by its behaviour on GLC and isomerization under ultra-violet light. The other zone at Rf 0.9 was detected only in the germination bioassays and was partitioned into ethyl acetate over a range of pH indicating the presence of one or more neutral compounds.The inhibitors present in the embryo of dormant sycamore seeds inhibited the germination of non-dormant sycamore seeds at relatively low concentrations. A comparison with the effects of application of exogenous ABA indicated that endogenous ABA could not solely account for the inhibitory activity of seed extracts, which appeared to be due partly to the presence of ABA and partly to that of neutral compounds present in the embryo. Leaching treatments that removed dormancy led to a decrease in the level of inhibitors present mainly in the basic fraction. The exogenous application of kinetin to dormant sycamore seeds increased germination whereas gibberellic acid had no effect. Similar responses were obtained with lettuce seeds inhibited by the basic fraction of dormant sycamore seeds.It is suggested that an inhibitor-cytokinin interaction may be involved in the dormancy of sycamore seeds. PMID- 24481696 TI - The effect of light on endogenous cytokinin levels in seeds of Rumex obtusifolius. AB - Exposure of Rumex obtusifolius seed to red light resulted in a rapid increase in extractable cytokinins. This increase can be reversed if the red light treatment is immediately followed by far-red irradiation. In germinating seed hardly any cytokinin activity could be detected in the butanol and aqueous extracts. An increase in the amount of activity present in the petroleum ether extracts of these seeds was, however, observed.The present findings suggest that cytokinin activity in light-sensitive seeds could be under the control of phytochrome. PMID- 24481697 TI - Hormonal regulation of germination and early seedling development in Acer pseudoplatanus (L.). AB - Dormancy of intact sycamore (Acer pseudoplatanus) seeds was broken by chilling (5 degrees C) for several weeks in moist conditions. Treatment of unchilled seeds with kinetin induced some germination, but gibberellin was ineffective. This stimulation by kinetin was not suppressed by the added presence of abscisic acid during incubation.The chilling requirement of intact seeds was eliminated by removal of the testa, and the naked embryos developed with no morphological abnormalities. During early growth of isolated embryos in the light, two distinct developmental processes were recognised. One involved initial elongation of the radicle accompanied by geotropic curvature and was stimulated by kinetin but not by gibberellin, while the other involved unrolling of the cotyledons, which was accelerated by gibberellin but much less by kinetin. Abscisic acid strongly suppressed both developmental processes when applied alone, inhibited cotyledon expansion in the presence of gibberellin, but failed to overcome the promotory effects of kinetin on radicle growth. Experiments with CCC indicated that under natural conditions the unrolling of the cotyledons is dependent upon endogenous gibberellin. Radicle growth of isolated embryos was unimpaired by incubation in the dark, but cotyledon expansion of water incubated embryos was poor, and although it was accelerated by gibberellin, the responses in all treatments were slower than in the corresponding light grown samples.It is suggested that endogenous cytokinins are primary factors in the initiation of radicle growth, while gibberellins are important in cotyledon expansion. Abscisic acid appears to have an inhibitory role in both processes, and the interactions of these regulators in the control of germination and development are discussed. PMID- 24481698 TI - The early ontogeny of embryoids and callus from pollen and subsequent organogenesis in anther cultures of Datura metel and rice. AB - Haploidy induction through anther culture has been examined in Datura metel and rice with a view to tracing the precise sequence of development of the pollen, either directly or through an intervening callus, into an embryo and seedling. In D. metel, the vegetative cell of the young pollen grain assumes the major role in formation of embryos whereas the generative cell and its few derivatives degenerate. Embryos and seedlings arising directly from pollen without an intervening callus phase always proved to be haploids, whereas those differentiating from pollen-derived callus gave haploid, diploid and even triploid plants. Cytological analysis of callus tissue showed cells of various ploidy levels ranging from haploid to triploid, and in rare instances even with higher chromosome numbers.In rice anther cultures the embryoids arose from an initial callus phase. Of 15 different rice cultivars tried, only four produced a callus, and in only one, was there differentiation of plants, both haploid and diploid ones. Among other species tried, egg plant has also yielded plantlets through a callus phase whereas only callus production has been achieved in jute, tea and petunia. No response has been obtained in wheat, maize, cotton and coconut.Coconut milk (CM) appears to be the most important component of the medium for the initial induction of embryoids and callus in anther cultures of most of the species tried. However, further growth and differentiation of plants may require a simpler medium; in D. metel, continued culture on CM led to dedifferntiation. PMID- 24481699 TI - Embryogenesis and germination in rye (Secale cereale L.) : 1. Fine structure of the developing embryo. AB - Cells of the young embryo contain highly differentiated organelles. During maturation and dehydration, complexity is reduced, the many layers of endoplasmic reticulum associated with electron lucent bodies become reduced to a few residual crescents, lipid droplets distributed in the cytoplasm migrate to and become closely appressed to the plasmalemma, mitochondrial cristae are reduced in number and dictyosomes are compacted. PMID- 24481700 TI - Localization and activity of various peptidases in germinating barley. AB - Germinating barley grains contain at least eight different peptidases: three carboxypeptidase (pH optima 4.8, 5.2, and 5.7), three aminopeptidases which act on aminoacyl-beta-naphthylamides (pH opitima in the hydrolysis of di- and tripeptides at pH 5.8-6.5), and two peptidases which hydrolyse Ala-Gly and Leu Tyr optimally at pH 7.8 and 8.6 respectively. We have determined the activities of these enzymes in the different tissues of non-germinated grains and followed the changes in the activities during a 5-day germination at 16 degrees C.The aleurone layers contain high activities of all three groups of peptidases; there are no changes in the activities of the five aminopeptidases on germination, while the carboxypeptidases exhibit a small increase of activity. The starchy endosperms contain high carboxypeptidase activities, which increase during germination, but are totally devoid of the five aminopeptidases.All the peptidases exhibit high activities in the scutella; the carboxypeptidases and the enzymes acting on Ala-Gly and Leu-Tyr increase in activity during germination, while the "naphthylamidase" activities remain constant.The three peptidase groups occur in the seedling as well, but compared to the other tissues the carboxypeptidase activities are very small and the "naphthylamidase" activities are very high. The last-named enzymes seem to be characteristic for growing tissues.The starchy endosperm contains about two thirds of the total reserve proteins of the grain. Its internal pH during germination is 5.0-5.2, a value at which all the carboxypeptidases are highly active. As these enzymes are present in high concentrations in this tissue, it is probable that they have a central role in the mobilization of the reserve proteins during germination. The high peptidase activities of the scutellum, on the other hand, suggest that some of the hydrolysis products are absorbed as peptides and these are further hydrolysed to amino acids in this tissue. PMID- 24481701 TI - Isolation of protoplasts from cereal leaves. AB - Mature leaves of Secale cereale cut into narrow strips and incubated for 18 h in a mixture of cellulase (Meicelase) and pectinase (Pectinol R10) produced quantities of protoplasts. Under the same conditions leaves of Triticum aestivum, Hordeum vulgare and Avena sativa also produce protoplasts but in lower yields. The wheat and rye protoplasts in culture appear to regenerate a cell wall but only a very small proportion undergo cell division. PMID- 24481702 TI - Abscisic acid in pea shoots. AB - The (+)-abscisic acid content of pea shoots has been determined using gas-liquid chromatography. In both tall and dwarf cultivars no significant difference was observed between plants grown in the dark or under red light. Nor was the difference between the tall and dwarf cultivars themselves significant. PMID- 24481703 TI - A study in transfer learning: leveraging data from multiple hospitals to enhance hospital-specific predictions. AB - BACKGROUND: Data-driven risk stratification models built using data from a single hospital often have a paucity of training data. However, leveraging data from other hospitals can be challenging owing to institutional differences with patients and with data coding and capture. OBJECTIVE: To investigate three approaches to learning hospital-specific predictions about the risk of hospital associated infection with Clostridium difficile, and perform a comparative analysis of the value of different ways of using external data to enhance hospital-specific predictions. MATERIALS AND METHODS: We evaluated each approach on 132 853 admissions from three hospitals, varying in size and location. The first approach was a single-task approach, in which only training data from the target hospital (ie, the hospital for which the model was intended) were used. The second used only data from the other two hospitals. The third approach jointly incorporated data from all hospitals while seeking a solution in the target space. RESULTS: The relative performance of the three different approaches was found to be sensitive to the hospital selected as the target. However, incorporating data from all hospitals consistently had the highest performance. DISCUSSION: The results characterize the challenges and opportunities that come with (1) using data or models from collections of hospitals without adapting them to the site at which the model will be used, and (2) using only local data to build models for small institutions or rare events. CONCLUSIONS: We show how external data from other hospitals can be successfully and efficiently incorporated into hospital-specific models. PMID- 24481705 TI - Nanotherapeutics--product development along the "nanomaterial" discussion. AB - Nanomaterials have become part of formulation development in the pharmaceutical industry and offer exciting opportunities in the area of targeted drug delivery. But they may also exert unexpected toxicities and potentially pose a threat to human health and the environment. Since the Scientific Committee on Emerging and Newly Identified Health Risks recommended a definition of "nanomaterials" for implementation into the existing and upcoming regulatory framework in the European Union, a discussion about safety requirements of new nanoscale products has emerged. At the same time, the Food and Drug Administration of the United States still observes recent developments in this area. Although the impact on the pharmaceutical product chain is still uncertain, guidelines on risk assessment in food products and cosmetics are available and offer a preview of future developments in the regimens of pharmaceuticals. PMID- 24481707 TI - Naming the body (or the bones): Human remains, anthropological/medical collections, religious beliefs, and restitution. AB - Human bones and biological remains conserved in anthropological, medical, and archaeological collections are foci of ethical debate, as recently illustrated by the affair of Charles Byrne's bones. In the near future, curators will have to choose between global conservation of all (or almost all) anthropological collections and systematic restitution to their original communities or families. Various proposals and examples of restitution and nonrestitution are given (with justifications) in order to support the concept that the body (especially the dead body) is not property. We propose that the only element supporting arguments in favor of restitution could be the name of the individual, highlighting the importance of all identification processes for such "artifacts." This is undoubtedly a universal value: naming the dead, identifying and then burying the person, i.e., reversing the progression along the timeline from individual to scientific specimen. Such elements could be of great interest to all universities and medical institutions that keep human remains in their collections for educational or historical purposes when they are confronted with ethical problems and/or repatriation requests. PMID- 24481706 TI - 1,25(OH)2D3 induces a mineralization defect and loss of bone mineral density in genetic hypercalciuric stone-forming rats. AB - Genetic hypercalciuric stone-forming (GHS) rats, bred to maximize urine (u) calcium (Ca) excretion, demonstrate increased intestinal Ca absorption, increased bone Ca resorption, and reduced renal Ca reabsorption, all leading to elevated uCa compared to the parental Sprague-Dawley (SD) rats. GHS rats have increased numbers of vitamin D receptors (VDRs) at each site, with normal levels of 1,25(OH)2D3 (1,25D), suggesting their VDR is undersaturated with 1,25D. We have shown that 1,25D induces a greater increase in uCa in GHS than SD rats. To examine the effect of the increased VDR on the osseous response to 1,25D, we fed GHS and SD rats an ample Ca diet and injected either 1,25D [low dose (LD) 12.5 or high dose (HD) 25 ng/100 g body weight/day] or vehicle (veh) daily for 16 days. Femoral areal bone mineral density (aBMD, by DEXA) was decreased in GHS+LD and GHS+HD relative to GHS+veh, while there was no effect on SD. Vertebral aBMD was lower in GHS compared to SD and further decreased in GHS+HD. Both femoral and L6 vertebral volumetric BMD (by MUCT) were lower in GHS and further reduced by HD. Histomorphometry indicated a decreased osteoclast number in GHS+HD compared to GHS+veh or SD+HD. In tibiae, GHS+HD trabecular thickness and number increased, with a 12-fold increase in osteoid volume but only a threefold increase in bone volume. Bone formation rate was decreased in GHS+HD relative to GHS+veh, confirming the mineralization defect. The loss of BMD and the mineralization defect in GHS rats contribute to increased hypercalciuria; if these effects persist, they would result in decreased bone strength, making these bones more fracture-prone. The enhanced effect of 1,25D in GHS rats indicates that the increased VDRs are biologically active. PMID- 24481708 TI - Spectroscopic and computational study of a nonheme iron nitrosyl center in a biosynthetic model of nitric oxide reductase. AB - A major barrier to understanding the mechanism of nitric oxide reductases (NORs) is the lack of a selective probe of NO binding to the nonheme FeB center. By replacing the heme in a biosynthetic model of NORs, which structurally and functionally mimics NORs, with isostructural ZnPP, the electronic structure and functional properties of the FeB nitrosyl complex was probed. This approach allowed observation of the first S=3/2 nonheme {FeNO}(7) complex in a protein based model system of NOR. Detailed spectroscopic and computational studies show that the electronic state of the {FeNO}(7) complex is best described as a high spin ferrous iron (S=2) antiferromagnetically coupled to an NO radical (S=1/2) [Fe(2+)-NO(.)]. The radical nature of the FeB -bound NO would facilitate N-N bond formation by radical coupling with the heme-bound NO. This finding, therefore, supports the proposed trans mechanism of NO reduction by NORs. PMID- 24481709 TI - Direct meso-alkynylation of metalloporphyrins through gold catalysis for hemoprotein engineering. AB - A method was developed for the direct functionalization of metalloporphyrins at the methine protons (meso positions) to yield asymmetric alkynylated derivatives by using gold catalysis and hypervalent iodine reagents. This single-step procedure was applied to b-type heme and the product was incorporated into a gas sensor heme protein. The terminal alkyne allows fluorophore labeling through copper(I)-catalyzed azide-alkyne cycloaddition (CuAAC). Hemoproteins with this type of engineered cofactor have several potential applications in labeling and imaging technologies. Additionally, the alkyne provides a handle for modulating porphyrin electron density, which affects cofactor redox potential and ligand affinity. This method will be helpful for investigating the chemistry of natural heme proteins and for designing artificial variants with altered properties and reactivities. PMID- 24481710 TI - Impact of electronic documentation on Pap screening rates in an urban health center. AB - Providers and non-physician staff in primary care settings have reported barriers to full electronic health record (EHR) utilization. This study evaluates the effectiveness of EHR use for accurately documenting cervical cancer screening in a community healthcare setting, and proposes strategies to improve documentation. An electronic query generated data on average-risk patients aged 21-64 who had a medical visit at Fenway Health in 2012 and were overdue for a Papanicolaou (Pap) test according to the 2012 American Society for Colposcopy and Cervical Pathology guidelines. We then conducted a manual review of these records to determine the accuracy of EHR documentation. Of a total 5,279 patients, the electronic query classified 2,982 (56.5%) as up-to-date (UTD) for a Pap and 2,297 patients (43.5%) as overdue. Upon manual review, 65 (2.2%) patients thought to be UTD were actually overdue. Of those 2,297 patients classified by the query as overdue, 816 (35.5%) were reclassified as UTD due to evidence of a recent Pap in their chart that was not extractable by electronic query and 208 (9.1%) were ineligible for a Pap; only 1,272 patients (55.4%) of the 2,297 classified by the query were truly overdue. The cervical cancer screening rate indicated by electronic query was 56.5 %; after manual review, the adjusted rate was 73.6%. Overall, 1,090 patients (20.6%) were misclassified by the query. Inefficient EHR use can have serious implications for clinical practice and performance measures. Primary care practices need to develop mechanisms to capture outside medical records and create a team-based approach to facilitate accurate EHR documentation. PMID- 24481711 TI - Temporal aspects of psychosocial predictors of increased fruit and vegetable intake in adults with severe obesity: mediation by physical activity. AB - Effective and reliable obesity treatments are lacking because of a poor understanding of the health behavior change process. Community-based organizations with the capacity to train existing staff members are particularly well-positioned to implement evidence-based treatment protocols to impact obesity related behaviors such as unhealthy eating and lack of physical activity. The aim of this study was to assess temporal aspects of psychosocial predictors (self regulation, mood, and self-efficacy) on increased fruit and vegetable intake in adults with severe obesity, while also accounting for mediation by physical activity volume. A 6-month, randomized field investigation was conducted. Severely obese adults volunteered for behavioral support of physical activity coupled with nutrition education (n = 73) or cognitive-behavioral methods for nutrition change (n = 71). Improvements in self-regulation, mood, self-efficacy, fruit and vegetable intake (FV), and physical activity (PA) were significant, with significantly greater self-regulation at month 6 for the cognitive behavioral group. Increase in FV was predicted by changes in the above psychosocial variables over 6 months, with mood change over 3 months also a significant predictor. Change in PA mediated the above relationships, with a reciprocal effect between changes in PA and FV. Findings have implications for the large-scale behavioral treatment of obesity. PMID- 24481712 TI - Knockdown of HMGB1 inhibits growth and invasion of gastric cancer cells through the NF-kappaB pathway in vitro and in vivo. AB - High mobility group box 1 (HMGB1) as a novel inflammatory molecule has been shown to be involved in a variety of cell physiological and pathological behaviors including immune response, inflammation and cancer. Evidence suggests that HMGB1 plays a critical role in the development and progression of multiple malignancies. However, the underlying molecular mechanisms for the HMGB1-mediated growth and invasion of gastric cancer have not yet been elucidated. The present study investigated the expression of HMGB1 in gastric adenocarcinoma (GAC) and the mechanisms by which it contributes to tumor growth and invasion. The correlation between HMGB1 expression and clinicopathological characteristics of GAC patients was assessed by immunohistochemical assay through tissue microarray procedures. The RNA and protein expressions of HMGB1 and downstream factors were detected by quantitative PCR and western blot assays; cell proliferation and invasion were determined by MTT, wound-healing and 3D-Matregel assays, subcutaneous SGC-7901 tumor models were established to verify tumor growth in vivo. We demonstrated that, the expression of HMGB1 was significantly increased in the nucleus of GAC tissues compared with that in adjacent non-cancer tissues (88.6 vs.70.5%, P<0.001), and correlated with the metastatic lymph node of GAC (P=0.018). Furthermore, knockdown of HMGB1 by shRNA inhibited cell proliferative activities and invasive potential, and downregulated the expression of NF-kappaB p65, PCNA and MMP-9 in GAC cells (SGC-7901 and AGS). The tumor volumes in SGC7901 subcutaneous nude mouse models treated with Lv-shHMGB1 was significantly smaller than those of the nonsense sequence group. Taken together, these findings suggest that increased expression of HMGB1 is associated with tumor metastasis of GAC, and knockdown of HMGB1 suppresses growth and invasion of GAC cells through the NF kappaB pathway in vitro and in vivo, suggesting that HMGB1 may serve as a potential therapeutic target for GAC. PMID- 24481713 TI - Italian recommendations for Lambert-Eaton myasthenic syndrome (LEMS) management. AB - Lambert-Eaton myasthenic syndrome (LEMS) is a pre-synaptic disorder of the neuromuscular and autonomic transmission mediated by antibodies to voltage-gated calcium channels at the motor nerve terminal. LEMS is a quite rare and probably under-diagnosed disease: the onset may be slow and clinical signs are typically fluctuating, thus adding to the delay in diagnosis. LEMS weakness typically involves lower and upper limbs and the proximal muscles are predominantly affected. A significant proportion of patients also have dysfunction of the autonomic nervous system that may include dry mouth, constipation, blurred vision, impaired sweating, and orthostatic hypotension. LEMS recognition is based on clinical, electrophysiological and immunological criteria. Nearly 50-60% of patients with LEMS have an underlying tumour that, in almost all cases, is a small-cell lung cancer; the onset of neurological symptoms generally precedes tumour detection. A careful screening for the early detection of the possible associated cancer is a crucial step for optimal disease management. The Italian Working Group on Myasthenic Syndromes developed diagnostic and therapeutic algorithms that could serve in routine clinical practice as tools for a patient tailored approach. PMID- 24481714 TI - David Hubel (1926-2013): the man who developed our understanding of vision. PMID- 24481715 TI - Epileptic seizure as initial and only manifestation of neuroborreliosis: case report. PMID- 24481717 TI - The effect of textile-based inductive coil sensor positions for heart rate monitoring. AB - In the research related to heart rate measurement, few studies have been done using magnetic-induced conductivity sensing methods to measure the heart rate. The aim of this study was to analyze the effect of the position of a textile based inductive coil sensor on the measurement of the heart rate. In order to assess the capability of the textile-based inductive coil sensor and the repeatability of measured cardiac muscle contractions, we proposed a new quality index based on the morphology of measured signals using a textile-based inductive coil sensor. We initially explored eight potential positions of the inductive sensor in a pilot experiment, followed by three sensor positions in the main experiment. A simultaneously measured electrocardiography (ECG) signal (Lead II) which was used as a reference signal for a comparison of the R-peak location with signals obtained from selected positions of the textile-based inductive coil sensor. The result of the main experiment indicated that the total quality index obtained from the sensor position 'P3', which was located 3 cm away from the left side from the center front line on the chest circumference line, was the highest (QI value = 1.30) among the three positions across all the subjects. This finding led us to conclude that (1) the position of the textile-based inductive coil sensor significantly affected the quality of the measurement results, and that (2) P3 would be the most appropriate position for the textile-based inductive coil sensor for heart rate measurements based on the magnetic-induced conductivity sensing principle. PMID- 24481716 TI - Plasma miR-122 and miR-192 as potential novel biomarkers for the early detection of distant metastasis of gastric cancer. AB - The aim of the present study was to ascertain whether plasma levels of specific microRNAs (miRNAs) are associated with distant metastasis (DM) in gastric cancer (GC). miRNA profiling was performed on 12 pairs of samples of gastric cancer with distant metastasis (GC/DM) and gastric cancer with no distant metastasis (GC/NDM); 14 differentially expressed miRNAs were identified for further inspection. Validation of these 14 miRNAs using quantitative reverse transcription PCR (qRT-PCR) on an independent validation set identified 2 differentially expressed miRNAs (miR-122 and miR-192). further validation of these two candidate miRNAs was conducted in a disease control set, a self-paired plasma set and finally in gastric cell lines in vitro. The results revealed that when compared with GC/NDM and healthy controls (HCs), plasma levels of miR-122 were significantly lower and plasma levels of miR-192 were significantly higher in GC/DM samples (both P<0.01). The plasma miR-122 level was again lower and the plasma miR-192-level was again higher in patients with GC/DM than in patients with benign gastric ulcer (BGC) and chronic gastritis (CG) (P<0.01). Compared to the level in patients with pre-distant metastases, miR-122 was significantly decreased while miR-192 was markedly elevated in patients with post-distant metastases (P<0.01). In CTC105 and CTC141 cells, miR-122 levels were moderately lower and miR-192 levels were markedly higher when compared to the levels in the GES-1 cells. ROC analyses showed that the AUC for plasma miR-122 was 0.808 (95% CI, 0.712-0.905; P<0.01), and the AUC for plasma miR-192 was 0.732 (95% CI, 0.623 0.841; P<0.01) for distinguishing GC/DM from GC/NDM. High expression of miR-122 in plasma independently contributed to a more favorable prognosis for GC (hazard ratio, 0.262; 95% CI, 0.164-0.816; P=0.038; Cox regression analysis), whereas the miR-192 level was not associated with the overall survival time. Our results demonstrated that assessment of decreased circulating miR-122 and elevated circulating miR-192 levels has the potential to improve early detection of DM in GC. Higher plasma levels of miR-122 in GC may indicate a favorable prognosis. PMID- 24481718 TI - An efficient anonymous authentication scheme for wireless body area networks using elliptic curve cryptosystem. AB - With the development of wireless networks and medical sensors, wireless body area networks are playing more and more important role in the field of healthcare service. The data transmitted in WBANs is very sensitive since it will be used in clinical diagnoses or measurements. Therefore, security and privacy of communication in WBANs derive increasing attentions from the academia and industry. In this paper, we propose an identity (ID)-based efficient anonymous authentication scheme for WBANs using elliptic curve cryptosystem (ECC). Due to the ID-based concept, there is no certificate is needed in the proposed scheme. Moreover, the proposed scheme not only provides mutual authentication between the client and the application provider but also provides client anonymity. Performance analysis shows that improvements of 50.58% and 3.87% in the client side and the application provider side separately. Then the proposed scheme is more suitable for WBANs. PMID- 24481719 TI - A randomized phase 2 trial of erlotinib versus pemetrexed as second-line therapy in the treatment of patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. AB - BACKGROUND: The current study was undertaken to investigate the efficacy and safety of erlotinib versus pemetrexed as second-line therapy for patients with advanced epidermal growth factor receptor (EGFR) wild-type and EGFR fluorescence in situ hybridization (FISH)-positive lung adenocarcinoma. METHODS: In this open label, randomized, phase 2 study, patients with EGFR wild-type and EGFR FISH positive adenocarcinoma who had developed disease progression after 1 prior platinum-based chemotherapy were randomly assigned (1:1) to receive erlotinib or pemetrexed until the time of disease progression or death, unacceptable toxicity, or a request for discontinuation by the patient. The primary endpoint was progression-free survival (PFS). RESULTS: A total of 123 patients were enrolled (61 in the erlotinib arm and 62 in the pemetrexed arm). The median PFS was 4.1 months (95% confidence interval [95% CI], 1.6 months-6.6 months) in the erlotinib group versus 3.9 months (95% CI, 2.7 months-5.1 months) in the pemetrexed group. The difference in PFS between the 2 treatment groups was not significant (hazard ratio, 0.92; 95% CI, 0.62-1.37 [P= .683]). The objective response rate appeared to be higher among patients receiving erlotinib compared with those receiving pemetrexed (19.7% vs 8.1%; P= .062). The 3 most commonly recorded adverse events were rash (54.1%), fatigue (19.7%), and diarrhea (16.4%) in the erlotinib group and fatigue (25.8%), nausea (24.2%), and anorexia (14.5%) in the pemetrexed group. CONCLUSIONS: There were no significant differences noted with regard to efficacy between erlotinib and pemetrexed in the second-line setting for patients with advanced EGFR wild-type and EGFR FISH-positive lung adenocarcinoma. Both regimens appear to be effective treatment options for these patients. PMID- 24481720 TI - Recurrent and second primary squamous cell carcinoma of the head and neck: when and how to reirradiate. AB - BACKGROUND: Local and/or regional recurrence and metachronous primary tumor arising in a previously irradiated area are rather frequent events in patients with head and neck squamous cell carcinoma (HNSCC). Re-treatment is associated with an increased risk of serious toxicity and impaired quality of life (QOL) with an uncertain survival advantage. METHODS: We analyzed the literature on the efficacy and toxicity of photon/electron-based external beam reirradiation for previously irradiated patients with HNSCC of non-nasopharyngeal origin. Studies were grouped according to the radiotherapy technique used for reirradiation. Patient selection criteria, target volume identification method, tumor dose, fractionation schedule, systemic therapy administration, and toxicities were reviewed. RESULTS: In addition to disease-related factors, current comorbidities and preexisting organ dysfunction must be considered when selecting patients for reirradiation. As morbidity from re-treatment may be considerable and differ depending on which mode of re-treatment is used, it is important to give patients information on potential morbidity outcomes so that an informed choice can be made within a shared decision-making context. With improved dose distribution and adequate imaging support, including positron emission tomography-CT, modern radiotherapy techniques may improve local control and reduce toxicity of reirradiation. A reirradiation dose of >=60 Gy and a volume encompassing the gross tumor with up to a 5-mm margin are recommended. Concomitant administration of systemic therapeutics and reirradiation is likely to be of similar benefit as observed in large randomized studies of upfront therapy. CONCLUSION: Reirradiation, administered either with or without concurrent systemic therapy, is feasible and tolerable in properly selected patients with recurrent or a new primary tumor in a previously irradiated area of the head and neck, offering a meaningful survival (in the range of 10% to 30% at 2 years). Whenever feasible, salvage surgery is the method of choice for curative intent; patients at high risk for local recurrence should be advised that postoperative reirradiation is expected to increase locoregional control at the expense of higher toxicity and without survival advantage compared to salvage surgery without reirradiation. (c) 2014 Wiley Periodicals, Inc. Head Neck 37: 134-150, 2015. PMID- 24481721 TI - Intraoperative radiotherapy-containing multidisciplinary management of trunk-wall soft-tissue sarcomas. AB - PURPOSE: A joint analysis of data from centers within the intraoperative radiotherapy (IORT)-Spanish cooperative initiative was performed to investigate the main contributions of IORT to the multidisciplinary treatment of trunk-wall soft-tissue sarcoma (TW-STS). MATERIALS AND METHODS: Patients with a histologic diagnosis of TW-STS (primary tumor 53 %; locally recurrent 47 %) with absence of distant metastases, undergoing surgery with radical intent and IORT (median dose 12.5 Gy) were considered eligible for participation in this study. In addition, all primary tumors received external-beam radiotherapy (median dose 50 Gy). RESULTS: From 1986 to 2012, a total of 68 patients were analyzed in the study from three Spanish institutions. With a median follow-up time of 53 months (range 4-316), 5-year local control (LC) was 58 %. Five-year IORT in-field control, disease-free survival (DFS) and overall survival were 70, 45 and 51 %, respectively. On multivariate analysis, only microscopically involved margin (R1) resection status retained significance in relation to LC (HR 3.97, p < 0.001). In regard to IORT in field control, incomplete resection (HR 3.23, p = 0.008) and recurrent disease status (HR 2.52, p = 0.04) retained a significant association in multivariate analysis. CONCLUSION: From this joint analysis emerges the fact that margin and disease status influences local and central control, but DFS remains modest, given the high risk of distant metastases. Intensified local treatment needs to be tested in the context of more efficient concurrent, neo-, and adjuvant systemic therapy. PMID- 24481722 TI - Extra cardiac findings in cardiovascular MR: why cardiologists and radiologists should read together. AB - PURPOSE: To assess prevalence and significance of extra cardiac findings (ECF) in clinical routine cardiovascular magnetic resonance (CMR) studies reported by cardiologists alone versus cardiologist and radiologist working together. METHODS: One-thousand-seventy-four consecutive patients presenting at our institution for CMR work-up of multiple cardiovascular disease entities were enrolled retrospectively in two groups (cardiologists reading alone vs. cardiologists and radiologist reading together). RESULTS: In 1,074 routine CMR studies a total of 357 ECF's were identified in 235 patients yielding a prevalence of 21.9 %. Of these 357 ECF's more than one-third were previously known. In the remaining 223 previously unknown findings 118 (52.9 %) were considered as major ECF's (92 patients), and 105 (47.1 %) were considered as minor ECF's (69 patients). Cardiologists reading alone reported 23 previously unknown ECF's in 23 patients, versus 200 previously unknown ECF in 138 patients by cardiologists and radiologists working together, p < 0.0001. Nevertheless, highly significant ECF's with major prognostic implications, such as the initial diagnosis of malignancy in an individual with no history of cancer, are extremely rare (n = 3, 0.3 %). Cardiologists alone, as well as cardiologists and radiologists working together seem to do well with reporting of such extremely important ECF's. CONCLUSIONS: The prevalence of all ECF's was 21.9 %, and 14.9 % of previously unknown ECF's, respectively. However, the prevalence of highly significant ECF's was low. Joint reading with cardiologists and radiologists may increase the number of ECF's detected in CMR studies, but it remains unclear if this could result in an improved long-term outcome of patients undergoing routine CMR. PMID- 24481723 TI - Effect of intramyocardial bone marrow-derived mononuclear cell injection on cardiac sympathetic innervation in patients with chronic myocardial ischemia. AB - Intramyocardial bone marrow cell injection has been associated with improvements in myocardial perfusion and left ventricular function. The current substudy of a randomized, placebo-controlled, double-blinded study, investigated the effect of intramyocardial bone marrow cell injection on myocardial sympathetic innervation in patients with chronic myocardial ischemia. In a total of 16 patients (64 +/- 8 years, 13 men), early and late iodine-123 metaiodobenzylguanidine (MIBG) imaging was performed before and 3 months after intramyocardial bone marrow cell injection. No improvements were observed in global early H/M ratio (P = 0.40), late H/M ratio (P = 0.43) and cardiac washout rate (P = 0.98). However, late 123 I MIBG SPECT defect score showed a trend to improvement in the bone marrow cell group (from 31.0 +/- 7.1 to 28.1 +/- 14.9) as compared to the placebo group (from 33.6 +/- 8.5 to 34.5 +/- 9.8, P = 0.055 between groups). This trend was mainly driven by a substantial improvement in three bone marrow cell-treated patients, which all had diabetes and severe MIBG defects. In these patients, the extent and severity of MIBG defects improved substantially independent of myocardial perfusion and cell injection sites. The present study does not demonstrate improvements in global cardiac sympathetic nerve innervation after intramyocardial bone marrow cell injection in patients with chronic myocardial ischemia. However, regional analysis of sympathetic nerve innervation reveals improvements in three diabetic patients independent of myocardial perfusion, suggestive of a therapeutic effect on diabetic cardiac sympathetic dysinnervation. PMID- 24481724 TI - Cardiac magnetic resonance in cocaine-induced myocardial damage. AB - A 54-year-old male with history of cocaine abuse underwent trans-thoracic echocardiography that showed hyper-echogenicity of the basal segments of the septum and infero-lateral wall of the left ventricle. The patient underwent cardiac CT that reported diffuse non-obstructive CAD. Cardiac MR showed LGE patterns consistent with non-ischemic myocardial damage associated with cocaine abuse. PMID- 24481725 TI - Simultaneous LC/ESI-MS separation method for the enantioseparation of some new anticonvulsant drugs. AB - A sensitive and specific method for the simultaneous determination of the enantiomeric purity of 2,6-dimethylphenoxyacetyl derivatives as trans or cis racemic and enantiomeric forms with 2- or 4-aminocyclohexanol moiety (1, 2, 3, 6) and their amine analogs (8, 9) was developed. The compounds studied are known for their anticonvulsant activity and the most interesting pharmacological results were those for (+/-)-trans-2-(2,6-dimethylphenoxy)-N-(2 hydroxycyclohexyl)acetamide (1) as well as (+/-)-trans-2-[(2,6 dimethylphenoxy)ethyl]aminocyclohexanol (8). The analytical method for determining the enantiomeric purity of the compounds studied is based on direct separation of the analytes using a chiral stationary phase (Chiralpak AS column). The mass spectrometric analysis was done on a coupled liquid chromatograph-mass spectrometer system with an electrospray ionization source (LC/ESI-MS). For the compounds 1, 8, and 9, the method allows an excellent separation of enantiomers, with a resolution higher than 3.2, and a tailing factor of less than 1.67 with a final enantiomer purity better than 97.5%. PMID- 24481726 TI - Anti-inflammatory effects of 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone via NF kappaB inactivation in lipopolysaccharide-stimulated RAW 264.7 macrophage. AB - The anti-inflammatory mechanism of 5-hydroxy-3,6,7,8,3',4'-hexamethoxyflavone (5HHMF), a polyhydroxyflavone isolated from the marine algae Hizikia fusiforme, was investigated in RAW 264.7 murine macrophage cells. Western blot and reverse transcriptase PCR analyses indicated that adding 5HHMF to cultured cells significantly reduced the production of nitric oxide and prostaglandin E2 and downregulated inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-stimulated RAW 264.7 cells. In addition, 5HHMF inhibited the release of pro-inflammatory cytokines, such as tumor necrosis factor-alpha and interleukin-1beta, and decreased the transcriptional levels. In particular, 5HHMF significantly inhibited the LPS-induced nuclear factor-kappaB (NF-kappaB) translocation from the cytosol to the nucleus, which was associated with the abrogation of inhibitory IkappaBalpha degradation and subsequent decreases in nuclear p65 levels. In conclusion, these results suggested that the anti-inflammatory activities of 5HHMF may be attributed to the inhibition of iNOS, COX-2 and cytokine expression by attenuating NF-kappaB activation via IkappaBalpha degradation in macrophages. PMID- 24481727 TI - Reply: To PMID 23907778. PMID- 24481728 TI - YY1-C/EBPalpha-miR34a regulatory circuitry is involved in renal cell carcinoma progression. AB - Renal cell carcinoma (RCC) is a common urological malignancy. It remains unclear, however, whether Yin Yang 1 (YY1) plays a functional role in the development of human RCC. In the present study, we demonstrated that levels of YY1 were significantly increased in primary RCC tissues when compared to these levels in the matched healthy tissues. YY1 knockdown inhibited cell growth, migration and invasion of RCC cells. Additionally, we highlighted a positive feedback-loop pathway resulting in YY1 upregulation. We observed that overexpression of YY1 caused repression of C/EBPalpha and the inhibition of C/EBPalpha led to the suppression of miR-34a. Since YY1 is a direct target of miR-34a, the low level of miR-34a increased the expression of YY1, promoting the aggressiveness of RCC cells. Furthermore, this feedforward mechanism was found in RCC tissues. We observed that miR-34a was downregulated in the pools of cancer tissues when compared to that of the normal tissues. The expression of miR-34a displayed an inverse correlation with YY1, but a positive correlation with C/EBPalpha. In conclusion, our study highlights the importance of a novel regulatory circuitry for YY1 activation in maintaining the aggressive phenotypes of RCC. PMID- 24481730 TI - Prognostic value of intraductal carcinoma of the prostate in radical prostatectomy specimens. AB - BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) is an adverse prognostic factor for radical prostatectomy (RP). The endpoint in most IDC-P studies is increased prostate-specific antigen (PSA) levels. The aim of this study was to evaluate whether IDC-P in RP specimens is an adverse prognostic factor for progression-free survival (PFS) and cancer-specific survival (CSS). METHODS: We retrospectively evaluated 206 high-risk prostate cancer patients treated with RP and analyzed data on age, serum PSA level at diagnosis, biopsy Gleason score (bGS), surgical margin (SM), clinical T stage (cT), extraprostatic extension (EPE), seminal vesicle invasion (SVI), lymph node metastasis (LN), and neoadjuvant therapy. RESULTS: An IDC-P component was found in 104 cases. Forty four patients experienced clinical failure, and 20 patients died of the disease. Patients with IDC-P showed a higher bGS and stage (including cT, EPE, SVI, and LN) than those without IDC-P. In univariate analysis, IDC-P, PSA level, bGS, SM, cT, SVI, LN, and EPE (P < 0.0001) were significantly associated with PFS. IDC-P (P = 0.0004), PSA level (P < 0.0001), SM (P = 0.0013), cT (P = 0.0019), SVI (P = 0.0012), and LN (P = 0.0002) were significantly associated with CSS. In multivariate analysis, IDC-P (P = 0.0038), and cT (P = 0.0001) were significantly associated with PFS. IDC-P (P = 0.0238) and PSA level (P = 0.0112) were significantly associated with CSS. CONCLUSIONS: IDC-P in RP specimens was an independent risk factor for PFS and CSS and could predict clinical outcomes. PMID- 24481731 TI - Isolation of protein bodies on sucrose gradients. AB - Storage protein bodies from sunflower cotyledons during early stages of seed germination were isolated on sucrose density gradients by isopycnic centrifugation. The density of this organelle on the gradients ranged between 1.26 and 1.36 g cm(-3). A proteinase with a pH optimum of 5.2 was associated with this organelle, and is probably responsible for degradation of storage protein. A NADH-dependent cytochrome-c reductase, a membrane marker enzyme with a pH optimum of 8.4, was also present in this organelle fraction. PMID- 24481732 TI - Dormancy regulation by morphactin in aerial tubers of Begonia evansiana. AB - The sprouting of aerial tubers of Begonia evansiana was promoted by treatment with morphactin. As with cytokinins, the promotion of sprouting occurred in both the immature and mature tubers. Unlike cytokinins, however, morphactin did not stimulate tuber enlargement. The sprout-inhibiting action of applied gibberellin (GA) was overcome by morphactin. The possible mechanism of the inhibitory action of GA is diseussed in relation to apical dominance. PMID- 24481733 TI - The effect of paraquat on flax cotyledon leaves: Changes in fine structure. AB - Changes in the fine structure of flax (Linum usitatissimum) cotyledon leaf cells treated with the herbicide paraquat (1,1'-dimethyl-4,4'-bipyridylium ion.) were investigated. After 6 h treatment under constant illumination, tonoplast breakdown was evident. This was followed by a rapid and progressive deterioration of cell contents including the disruption of mitochondria, and the breakdown of chloroplast thylakoid membrane structure with the accumulation of osmiophilic plastoglobuli. There was no apparent deterioration after 18 h paraquat treatment in darkness but by 30 h there was a limited breakdown of chloroplast membranes. PMID- 24481734 TI - The effect of paraquat on flax cotyledon leaves: Physiological and biochemical changes. AB - Some of the physiological and biochemical changes which were found to occur during paraquat (1,1'-dimethyl-4,4'-bipyridylium ion) treatment of cotyledon leaves of Linium usitatissimum, are reported. Results showed an inhibition of photosynthetic CO2 uptake and electron flow of isolated chloroplasts. An increase in membrane permeability, changes in the level of the major lipid components and of malondialdehyde. These are correlated with ultrastructural changes and the discussion includes a proposed mode of action for the herbicides. PMID- 24481729 TI - Epilepsy related to developmental tumors and malformations of cortical development. AB - Structural abnormalities of the brain are increasingly recognized in patients with neurodevelopmental delay and intractable focal epilepsies. The access to clinically well-characterized neurosurgical material has provided a unique opportunity to better define the neuropathological, neurochemical, and molecular features of epilepsy-associated focal developmental lesions. These studies help to further understand the epileptogenic mechanisms of these lesions. Neuropathological evaluation of surgical specimens from patients with epilepsy associated developmental lesions reveals two major pathologies: focal cortical dysplasia and low-grade developmental tumors (glioneuronal tumors). In the last few years there have been major advances in the recognition of a wide spectrum of developmental lesions associated with a intractable epilepsy, including cortical tubers in patients with tuberous sclerosis complex and hemimegalencephaly. As an increasing number of entities are identified, the development of a unified and comprehensive classification represents a great challenge and requires continuous updates. The present article reviews current knowledge of molecular pathogenesis and the pathophysiological mechanisms of epileptogenesis in this group of developmental disorders. Both emerging neuropathological and basic science evidence will be analyzed, highlighting the involvement of different, but often converging, pathogenetic and epileptogenic mechanisms, which may create the basis for new therapeutic strategies in these disorders. PMID- 24481735 TI - Some properties of two forms of nitrite reductase from corn (Zea mays L.) scutellum. AB - Nitrite reductase from corn scutellum-a non-chlorophyllous tissue-can use methyl viologen, benzyl viologen or ferredoxin as electron donor. Little or no reduction occurs with nicotinamide or flavin nucleotides. Activity is inhibited by p chloromercuribenzoate and by cyanide. Organic chelates, with the exception of bathocuproine disulphonate and bathophenanthroline disulphonate, are not inhibitory. Ammonia is the reaction product. Ion exchange chromatography resolves the nitrite reductase activity into two peaks with apparently represent two forms of the enzyme. Both have a molecular weight of 61-63000 as determined by molecular exclusion chromatography, and a pH optimum of 6.7-6.8. Although their properties are generally similar, they show a marked difference in thermal stability, ionic charge and behaviour during isoelectric focusing. Nitrite reductase is found largely in the soluble fraction although some particulate activity is also obtained. Both forms of the enzyme are present in the soluble and particulate fractions. PMID- 24481736 TI - Plasmalemma structure in relation to microfibril biosynthesis in Oocystis. AB - The plasmalemma of Oocystis apiculata, W. West when freezeetched has been shown to bear granules of several sizes. At the earliest stage of development the outer face of the plasmalemma of the naked autospore has small (8.5 nm diameter) granules aligned in rows, in pairs. These rows are stacked together forming extensive "granule-bands" over the plasmalemma surface. The orientation of these "granule-bands" corresponds exactly to one of the major microfibril directions. Occasionally, the bands are reduced to patches, some of which are at right angles to each other. Banding of granules on the inner plasmalemma face of naked autospores is also seen. During development the plasmalemma is seen to change so that in the final stages it bears reticulate invaginations, the granule bands occurring within them. The significance of the "granulebands" in terms of cellulose microfibril biosynthesis is discussed. PMID- 24481737 TI - Urate oxidase in peroxisomes from maize root tips. AB - Peroxisomes isolated from maize root tips contained urate oxidase, although the supplementary enzymes allantoinase, allantoicase and NADH-glyoxylate reductase were not detected. Some glutamate-oxalacetate transaminase was present in peroxisomes. Enzymes of two other pathways occuring in plant peroxisomes, namely glycolate metabolism and the glyoxylate cycle, were not present. The root peroxisome thus resembles peroxisomes of the Arum spadix and supports the concept that peroxisomes constitute a dynamic and differentiating system. PMID- 24481738 TI - Reproduction induced by blue light in female gametophytes of Laminaria saccharina. AB - In red light at 15 degrees C, female gametophytes of Laminaria saccharina continue to grow indefinitely without becoming fertile, but 6-12 hours' irradiation with blue light induces the production of eggs. At lower temperatures, some gametophytes become fertile in red light, but blue irradiation increases the percentage of fertile gametophytes. PMID- 24481739 TI - [G-1-P as precursor for starch synthesis in bundle sheath cells of Zea mays]. AB - After illumination intact leaves of Zea mays contain sucrose and starch. The latter is located mainly in the bundle sheath cells. When 0.5 mm wide leaf strips are incubated with sucrose solution, the starch deposit in the bundle-sheath chloroplasts is greatly increased by light. When isolated bundle sheath cells are suspended in water or solutions of sucrose and various metabolites they are not capable of synthesizing starch. An appreciable production of starch in the chloroplasts of isolated bundle sheath cells can be observed only in the presence of glucose-1-phosphate. PMID- 24481740 TI - Differential effects of mannitol on gibberellin-regulated phospholipid synthesis and enzyme activities of the CDP-choline pathway in barley aleurone cells. AB - When barley aleurone layers are treated with gibberellic acid (GA3) in the presence of increasing concentrations (0.2-0.8 M) of mannitol, the rate of (32)Pi incorporation into phospholipids becomes progressively inhibited. Mannitol does not affect this process in aleurone layers not treated with GA3, nor does it appreciably inhibit GA3-effected increases of (32)Pi incorporation into organic phosphates or the activities of the particulate enzymes of the CDP-choline pathway. These results suggest that some of the early events controlled by GA3 can be separated from later activities regulated by the hormone, including alpha amylase synthesis. PMID- 24481741 TI - Enhancement of senescence by far-red light. AB - Far-red light was demonstrated to accelerate senescence in mature, green tissue of intact thalli of Marchantia polymorpha. The red/far-red reversibility of this phenomenon proves the involvement of phytochrome. As a daily exposure to 5 min red light is sufficient to prevent aging of the tissue, photosynthesis does not play a specific role in this response. PMID- 24481742 TI - Antimicrobial compounds from mangrove plants: A pharmaceutical prospective. AB - Mangroves are salt-tolerant forest ecosystem that extends between tropical and subtropical intertidal regions of the world. Mangroves are biochemically unique vegetation that produce wide array of natural products with immense medicinal potential. These plants are the most valuable resources and provide economic and ecological benefits to the coastal people. Natural products from these plants are of great interest as they provide innumerable direct and indirect benefits to human beings for the discovery of novel antimicrobial and other bioactive compounds. They possess active metabolites with some novel chemical structures that belong to diverse chemical classes such as alkaloids, phenol, steroids, terpenoids and tannins. Several mangrove species have been used in traditional medicine or have few applications as insecticide and pesticide. To date, several mangroves, and their associated species and solvent extracts are screened for antimicrobial activity along with the presence of potent bioactive compounds. The present article emphasizes and creates awareness about the potential mangrove plants and their associates as a source of biologically active compounds with potent antimicrobial properties. This paper also elaborates the mechanisms of action and various methods for screening of antimicrobial compounds. PMID- 24481743 TI - Zhuanggu Jianxi Decoction () limits interleukin-1 beta-induced degeneration chondrocytes via the caveolin-p38 MAPK signal pathway. AB - OBJECTIVE: To evaluate the effect of Zhuanggu Jianxi Decoction (, ZGJXD) on interleukin-1 beta (IL-1 beta)-induced degeneration of chondrocytes (CDs) as well as the activation of caveolin-p38 mitogen-activated protein kinase (MAPK) signal pathway, investigating the possible molecular mechanism that ZGJXD treats osteoarthritis. METHODS: Serum pharmacology was applied in the present study, where ZGJXD was orally administrated to New Zealand rabbits and then ZGJXD containing serum (ZGJXD-S) was collected for following in vitro experiments. CDs were isolated aseptically from New Zealand rabbits and then cultured in vitro. Upon IL-1 beta stimulation, the degeneration of CDs was verified by inverted microscope, toluidine blue stain and type II collagen immunocytochemistry. After IL-1 beta-stimulated CDs were intervened with blank control serum, ZGJXD-S, together with or without SB203580 (a specific inhibitor of p38 MAPK) for 48 h, caveolin-1 protein expression and the phosphorylation level of p38 were determined by Western blotting, and the mRNA expression of IL-1 beta, tumor necrosis factor alpha (TNF-alpha), matrix metalloproteinase 3 (MMP-3) and MMP-13 were examined by real-time polymerase chain reaction. RESULTS: IL-1 beta stimulation induced degeneration of CDs, increased caveolin-1 expression and p38 phosphorylation, up-regulated the mRNA level of IL-1 beta, TNF-alpha, MMP-3 and MMP-13. However, the IL-1 beta-induced activation of caveolin-p38 signaling and alteration in the expression of p38 downstream target genes were suppressed by ZGJXD-S and/or SB203580 in CDs. CONCLUSION: ZGJXD can prevent CDs degeneration via inhibition of caveolin-p38 MAPK signal pathway, which might be one of the mechanisms that ZGJXD treats osteoarthritis. PMID- 24481744 TI - Direct targeting of Rab-GTPase-effector interactions. AB - Small GTPases are molecular switches using GDP/GTP alternation to control numerous vital cellular processes. Although aberrant function and regulation of GTPases are implicated in various human diseases, direct targeting of this class of proteins has proven difficult, as GTPase signaling and regulation is mediated by extensive and shallow protein interfaces. Here we report the development of inhibitors of protein-protein interactions involving Rab proteins, a subfamily of GTPases, which are key regulators of vesicular transport. Hydrocarbon-stapled peptides were designed based on crystal structures of Rab proteins bound to their interaction partners. These modified peptides exhibit significantly increased affinities and include a stapled peptide (StRIP3) that selectively binds to activated Rab8a and inhibits a Rab8a-effector interaction in vitro. PMID- 24481745 TI - Thermosensitive injectable hydrogel enhances the antitumor effect of embelin in mouse hepatocellular carcinoma. AB - Embelin, an active ingredient of traditional herbal medicine, is used to treat many diseases such as cancer. However, embelin is hydrophobic and insoluble in water, which makes it unsuitable for in vivo applications. In this study, we constructed an embelin-loaded thermosensitive injectable hydrogel system that we named Embelin/PECT(gel) based on the amphiphilic triblock copolymer of poly (epsilon-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone)-poly (ethylene glycol)-poly (epsilon-caprolactone-co-1,4,8-trioxa[4.6]spiro-9-undecanone) (PECT). The cytotoxicity and the antitumor effects of Embelin/PECT(gel) on mouse hepatic cancers were investigated in vitro and in vivo. Results indicated that embelin was formulated in PECT hydrogel and could be continuously released from Embelin/PECT(gel) , showing a higher cytotoxicity for H22 cells in vitro compared with free embelin. The aqueous solution of Embelin/PECT(gel) transformed into gel at the injection site within seconds, which later eroded and degraded over time in vivo. A single local peritumoral injection of Embelin/PECT(gel) in liver at a low dosage of 0.5 mg per mouse exhibited a significant antitumor effect, which was comparable to the antitumor effect of the embelin solution treatment at a total dose of 6 mg per mouse in mouse hepatic cancer. Embelin/PECT(gel) , as a drug delivery system in liver, represents a novel therapeutic drug candidate for the clinical treatment of advanced hepatocellular carcinoma. PMID- 24481746 TI - Total synthesis of the antimitotic marine macrolide (-)-leiodermatolide. AB - Leiodermatolide is an antimitotic macrolide isolated from the marine sponge Leiodermatium sp. whose potentially novel tubulin-targeting mechanism of action makes it an exciting lead for anticancer drug discovery. In pursuit of a sustainable supply, we report a highly stereocontrolled total synthesis (3.2% yield) based on a convergent sequence of palladium-mediated fragment assembly and macrolactonization. Boron-mediated aldol reactions were used to configure the three key fragments 2, 5, and 6 by employing the appropriate enantiomer of the lactate-derived ketone 7. PMID- 24481747 TI - Comparison of high-resolution X-ray and micro-CT for experimental evaluation of intracranial stent prototypes: quality evaluation beyond CE mark. AB - INTRODUCTION: As digital mammography and micro-computed tomography (CT) have been used for evaluation of stents deployed in experimental animal models, we compared the two methods regarding their sensitivity to detect abnormalities in three prototypes of intracranial stents. METHODS: Three different prototypes of intracranial stents (n = 84) were implanted in various animal models. Explanted stents were examined using digital mammography and micro-CT. The images were compared with respect to maintenance of material and form and the stents were compared to one another. Histological analysis was performed as well. RESULTS: In the open-cell stents, expansion of the stent cells was detected in the majority of cases (57.1 %) using micro-CT and less frequently using mammography (42.3 %). The closed-cell stent revealed kink stenoses in mammography as well as in micro CT (3/7, 42.9 %). Detailed reconstructions of micro-CT images showed high-grade kink stenoses of the flow-diverter stent in two extremely curved vessels. Strut breaks were observed more frequently using micro-CT (6/84, 7.1 %) than by mammography (4/84, 4.8 %). Histology confirmed all changes of stent architecture. CONCLUSION: Significant changes of stent architecture can be observed and assessed even in the two-dimensional mammographic images. The use of micro-CT is recommended to detect subtle changes like single strut breaks and for three dimensional information. PMID- 24481749 TI - Comparing the force ripple during asynchronous and conventional stimulation. AB - INTRODUCTION: Asynchronous stimulation has been shown to reduce fatigue during electrical stimulation; however, it may also exhibit a force ripple. We quantified the ripple during asynchronous and conventional single-channel transcutaneous stimulation across a range of stimulation frequencies. METHODS: The ripple was measured during 5 asynchronous stimulation protocols, 2 conventional stimulation protocols, and 3 volitional contractions in 12 healthy individuals. RESULTS: Conventional 40 Hz and asynchronous 16 Hz stimulation were found to induce contractions that were as smooth as volitional contractions. Asynchronous 8, 10, and 12 Hz stimulation induced contractions with significant ripple. CONCLUSIONS: Lower stimulation frequencies can reduce fatigue; however, they may also lead to increased ripple. Future efforts should study the relationship between force ripple and the smoothness of the evoked movements in addition to the relationship between stimulation frequency and NMES-induced fatigue to elucidate an optimal stimulation frequency for asynchronous stimulation. PMID- 24481748 TI - Spinal and paraspinal pneumococcal infections-a review. AB - Spinal and paraspinal infections caused by Streptococcus pneumoniae remain a rare event. We present two cases from our institution, discuss the pathophysiology, and present a literature review of an additional 50 cases of spinal pneumococcal infections. Spinal epidural abscess and vertebral osteomyelitis as well as paraspinal abscesses caused by pneumococcus were included in the analysis. As has been reported for spinal infections due to other bacteria, persistent localized back pain with an elevation in inflammatory markers was almost universal. The lumbar spine was the most commonly involved. Pneumococcus was most frequently isolated from material obtained at the site of the infection; blood cultures were a less common source. The majority of patients with neurologic deficits had spinal epidural abscess or phlegmon, and had a higher mortality. Most patients were treated with 6 weeks of parenteral antimicrobials, and surgical intervention was not associated with a mortality benefit. PMID- 24481750 TI - Measuring Sexual Victimization: On What Fronts is the Jury Still Out and Do We Need it to Come In? AB - Rennison and Addington use National Crime Victimization Survey (NCVS) data to document the fact that college women experience violent victimization at a lower rate than women of the same age who do not attend college, which refutes the idea that women in college are at increased risk of being victimized. The measurement of victimization, especially sexual victimization, is, however, a topic that has be the source of much debate. Bureau of Justice Statistics is currently exploring what are the best methods for measuring sexual victimization within the NCVS, and recent methodological research, which is summarized in this article, could inform this process. Although consensus has seemingly been forming around come methods, such as using self-administered survey instruments and behaviorally specific questions when trying to measure sexual victimization, the jury is still out on some other design fronts. What is not clear is whether we need the jury to come in, so to speak. Some methodological variation might be acceptable, especially if the various methods being considered are producing similar results. PMID- 24481751 TI - Interpersonal violence on college campuses: understanding risk factors and working to find solutions. AB - This commentary discusses the contributions of Drs. Antonia Abbey and Catherine Kaukinen to our understanding of risk factors for sexual and physical aggression among college students. Major contributions of their work are outlined. These include Abbey's contributions to our understanding of trajectories of sexually aggressive behavior among college men, risk factors for engaging in sexual aggression among men, and the role of alcohol in sexual aggression. In addition, Kaukinen's work has increased our understanding of the frequency of violence in college dating relationships as well as the association of violent relationships with health risk behaviors. Directions for future research are also outlined including a need to identify trajectories of violence risk as well as a need to understand the complex interrelationships among health risk behaviors and interpersonal violence. Finally, implications for practice and university policy are discussed, including a focus on the development of effective preventive strategies and proactive responses to violence. PMID- 24481752 TI - Cloning and identification of a novel thyroid hormone receptor beta isoform expressed in the pituitary gland. AB - We have previously identified a novel Trbeta isoform (TrbetaDelta) in the rat, in which a novel exon N (108 bps) was found between exon 3 and exon 4 of TrbetaDelta, which represents the only difference between TrbetaDelta and Trbeta1. In this study, we searched for an elongated Trbeta2-like subtype with one additional exon N. We successfully isolated the entire mRNA/cDNA of a novel elongated Trbeta2 isoform via PCR in the rat pituitary gland. The mRNA/cDNA was only 108 bps (exon N) longer than that Trbeta2, and the extension of the sequence was between exon 3 and 4 of Trbeta. The whole sequence of this novel Trbeta isoform has been published in NCBI GenBank (HM043807.1); it is named TRbeta2Delta (Trbeta2Delta). In adult rat pituitary tissue, quantitative real-time RT-PCR analysis showed that the mRNA levels of Trbeta2Delta and Trbeta2 were roughly equal (P > 0.05). We cloned, expressed, and purified the His-Trbeta2Delta protein [recombinant TRbeta2Delta (rTRbeta2Delta)]. SDS-PAGE and western blotting revealed that the molecular weight of rTRbeta2Delta was 58.2 kDa. Using a radioligand binding assay and an electrophoretic mobility shift assay, rTRbeta2Delta-bound T3 with high affinity and recognized thyroid hormone response element (TRE) binding sites. Finally, in vitro transfection experiments further confirmed that rTRbeta2Delta binding T3 significantly promotes the transcription of target genes via the TRE. Here, we have provided evidence suggesting that rTRbeta2Delta is a novel functional TR isoform. PMID- 24481754 TI - Thoracic imaging. PMID- 24481753 TI - Type II phosphatidylinositol 4-kinases interact with FcepsilonRIgamma subunit in RBL-2H3 cells. AB - Ligation of high-affinity IgE receptor I (FcepsilonRI) on RBL-2H3 cells leads to recruitment of FcepsilonRI and type II phosphatidylinositol 4-kinases (PtdIns 4 kinases) into lipid rafts. Lipid raft integrity is required for the activation of type II PtdIns 4-kinases and signal transduction through FcepsilonRIgamma during RBL-2H3 cell activation. However, the molecular mechanism by which PtdIns 4 kinases are coupled to FcepsilonRI signaling is elusive. Here, we report association of type II PtdIns 4-kinase activity with FcepsilonRIgamma subunit in anti-FcepsilonRIgamma immunoprecipitates. FcepsilonRIgamma-associated PtdIns 4 kinase activity increases threefold upon FcepsilonRI ligation in anti FcepsilonRIgamma immunoprecipitates. Biochemical characterization of PtdIns 4 kinase activity associated with FcepsilonRIgamma reveals that it is a type II PtdIns 4-kinases. Canonical tyrosine residues mutation in FcepsilonRIgamma ITAM (Y65 and Y76) reveals that these two tyrosine residues in gamma subunit are required for its interaction with type II PtdIns 4-kinases. PMID- 24481755 TI - Chest radiography: new technological developments and their applications. AB - Digital chest radiography is still the most common radiological examination. With the upcoming three-dimensional (3D) acquisition techniques the value of radiography seems to diminish. But because radiography is inexpensive, readily available, and requires very little dose, it is still being used for the first line detection of many cardiothoracic diseases. In the last decades major technical developments of this 2D technique are being achieved. First, hardware developments of digital radiography have improved the contrast to noise, dose efficacy, throughput, and workflow. Dual energy acquisition techniques reduce anatomical noise by splitting a chest radiograph into a soft tissue image and a bone image. Second, advanced processing methods are developed to enable and improve detection of many kinds of disease. Digital bone subtraction by a software algorithm mimics the soft tissue image normally acquired with dedicated hardware. Temporal subtraction aims to rule out anatomical structures clotting the image, by subtracting a current radiograph with a previous radiograph. Finally, computer-aided detection systems help radiologists for the detection of various kinds of disease such as pulmonary nodules or tuberculosis. PMID- 24481756 TI - Chest tomosynthesis: technical and clinical perspectives. AB - The recent implementation of chest tomosynthesis is built on the availability of large, dose-efficient, high-resolution flat panel detectors, which enable the acquisition of the necessary number of projection radiographs to allow reconstruction of section images of the chest within one breath hold. A chest tomosynthesis examination obtains the increased diagnostic information provided by volumetric imaging at a radiation dose comparable to that of conventional chest radiography. There is evidence that the sensitivity of chest tomosynthesis may be at least three times higher than for conventional chest radiography for detection of pulmonary nodules. The sensitivity increases with increasing nodule size and attenuation and decreases for nodules with subpleural location. Differentiation between pleural and subpleural lesions is a known pitfall due to the limited depth resolution in chest tomosynthesis. Studies on different types of pathology report increased detectability in favor of chest tomosynthesis in comparison to chest radiography. The technique provides improved diagnostic accuracy and confidence in the diagnosis of suspected pulmonary lesions on chest radiography and facilitates the exclusion of pulmonary lesions in a majority of patients, avoiding the need for computed tomography (CT). However, motion artifacts can be a cumbersome limitation and breathing during the tomosynthesis image acquisition may result in severe artifacts significantly affecting the detectability of pathology. In summary, chest tomosynthesis has been shown to be superior to chest conventional radiography for many tasks and to be able to replace CT in selected cases. In our experience chest tomosynthesis is an efficient problem solver in daily clinical work. PMID- 24481757 TI - New applications of magnetic resonance imaging for thoracic oncology. AB - Since the clinical introduction of magnetic resonance imaging (MRI), the chest has been one of its most challenging applications, and since the 1980s many physicists and radiologists have been trying to evaluate images for various lung diseases as well as mediastinal and pleural diseases. However, thoracic MRI could not yield image quality sufficient for a convincing diagnosis within an acceptable examination time, so MRI did not find acceptance as a substitute for computed tomography (CT) and other modalities. Until the 2000, thoracic MRI was generally used only for select, minor clinical indications. Within the past decade, however, technical advances in sequencing, scanners and coils, adaptation of parallel imaging techniques, utilization of contrast media, and development of postprocessing tools have been developed. In addition, pulmonary functional MRI has been extensively researched, and MR is being assessed as a new research and diagnostic tool for pulmonary diseases. State-of-the art thoracic MRI now has the potential as a substitute for traditional imaging techniques and/or to play a complimentary role in patient management. In this review, we focus on these advances in MRI for thoracic oncologic imaging, especially for pulmonary nodule assessment, lung cancer staging, mediastinal tumor diagnosis and malignant mesothelioma evaluation, prediction of postoperative lung function, and prediction or evaluation of therapeutic effectiveness. We also discuss the potential and limitations of these advances for routine clinical practice in comparison with other modalities such as CT, positron emission tomography (PET), PET/CT, or nuclear medicine studies. PMID- 24481758 TI - Acute pulmonary embolism: from morphology to function. AB - This article reviews the current diagnostic strategies for patients with suspected pulmonary embolism (PE) focusing on the current first choice imaging modality, computed tomographic pulmonary angiography (CTPA). Diagnostic strengths and weaknesses and associated cost-effectiveness of the diagnostic pathways will be discussed. The radiation dose risk of these pathways will be described and techniques to minimize dose will be reviewed. Finally the impact of new dual energy applications which have the potential to provide additional functional information will be briefly reviewed. Imaging plays a vital role in the diagnostic pathway for clinically suspected PE. CT has been established as the most robust morphologic imaging tool for the evaluation of patients with suspected PE. This conclusion is based on the high diagnostic utility of CT for the detection of PE and its unique capacity for accurate diagnosis of conditions that can mimic the clinical presentation of PE. Although current cost effectiveness evaluations have established CT as integral in the PE diagnostic pathway, failure to acknowledge the impact of alternate diagnosis represents a current knowledge gap. The emerging dual energy capacity of current CT scanners offers the potential to evaluate both pulmonary vascular morphology and ventilation perfusion relationships within the lung parenchyma at high spatial resolution. This dual assessment of lung morphology and lung function at low (< 5 millisievert) radiation dose represents a substantial advance in PE imaging. PMID- 24481759 TI - Integrated cardiothoracic imaging with computed tomography. AB - The respiratory and the cardiovascular systems are intimately connected. Because of the high degree of morphological and functional interaction, pathophysiological processes in one compartment are likely to induce adaptive changes in the other. Computed tomography (CT) plays a central role in the diagnostic work up of both thoracic and cardiac disorders. Historically, these two systems have been evaluated separately; however, CT technology has evolved remarkably over recent decades. Up-to-date advanced imaging strategies allow for a combined assessment of the cardiopulmonary unit. Besides improved techniques of electrocardiogram (ECG)-synchronization for obtaining both morphological and functional information, latest advances of dual-source CT (DSCT) have shown great promise for even more comprehensive integrated cardiothoracic imaging. PMID- 24481760 TI - Thoracic applications of dual energy. AB - Computed tomography (CT) is the core imaging modality for the evaluation of thoracic disorders. With the recently developed dual-energy CT (DECT) technique, the clinical utility of CT in the management of pulmonary diseases can be expanded. The most actively investigated principle of dual energy is material decomposition based on attenuation differences at different energy levels. This technique provides two key insights into lung physiology, that is, regional perfusion and ventilation. This functional information is obtained in addition to morphologic information because high-resolution thoracic anatomy is entirely preserved on dual-energy thoracic CT. The second major possibility offered by DECT is virtual monochromatic imaging that represents a new option for standard chest CT in daily routine. In this review, imaging principles and clinical applications of dual-energy thoracic CT are described. Knowledge of the applications of DECT may lead to wider use of this technique in the field of respiratory disorders. PMID- 24481761 TI - Functional magnetic resonance imaging of the lung. AB - Beyond being a substitute for X-ray, computed tomography, and scintigraphy, magnetic resonance imaging (MRI) inherently combines morphologic and functional information more than any other technology. Lung perfusion: The most established method is first-pass contrast-enhanced imaging with bolus injection of gadolinium chelates and time-resolved gradient-echo (GRE) sequences covering the whole lung (1 volume/s). Images are evaluated visually or semiquantitatively, while absolute quantification remains challenging due to the nonlinear relation of T1-shortening and contrast material concentration. Noncontrast-enhanced perfusion imaging is still experimental, either based on arterial spin labeling or Fourier decomposition. The latter is used to separate high- and low-frequency oscillations of lung signal related to the effects of pulsatile blood flow. Lung ventilation: Using contrast-enhanced first-pass perfusion, lung ventilation deficits are indirectly identified by hypoxic vasoconstriction. More direct but still experimental approaches use either inhalation of pure oxygen, an aerosolized contrast agent, or hyperpolarized noble gases. Fourier decomposition MRI based on the low-frequency lung signal oscillation allows for visualization of ventilation without any contrast agent. Respiratory mechanics: Time-resolved series with high background signal such as GRE or steady-state free precession visualize the movement of chest wall, diaphragm, mediastinum, lung tissue, tracheal wall, and tumor. The assessment of volume changes allows drawing conclusions on regional ventilation. With this arsenal of functional imaging capabilities at high spatial and temporal resolution but without radiation burden, MRI will find its role in regional functional lung analysis and will therefore overcome the sensitivity of global lung function analysis for repeated short-term treatment monitoring. PMID- 24481762 TI - Risks, benefits, and risk reduction strategies in thoracic CT imaging. AB - Chest computed tomography (CT) is a useful tool for diagnosing various thoracic conditions and has become the diagnostic imaging modality of choice for many diseases. Recent discussions about the radiation dose from CT have attracted the attention of medical professionals and the general public. This article discusses radiation dose with an emphasis on chest CT and on current techniques for patient dose reduction. Four techniques are discussed in detail, including tube current modulation, automatic exposure control, automatic tube voltage selection, and iterative image reconstruction. Adopting these techniques in routine clinical practice can dramatically reduce radiation dose levels. PMID- 24481763 TI - Lung cancer screening: the radiologist's perspective. AB - Lung cancer is the leading cause of cancer death worldwide and accounts for more deaths than breast, prostate, colon, and pancreatic cancers combined. A distinct minority (15%) of lung cancers are diagnosed at an early stage; 5-year survival (all lung cancers) approximates 15%. Randomized, controlled trials in the 1960s and 1970s found that chest radiographic screening did not confer a survival benefit for high-risk patients. Recently, however, the randomized, controlled National Lung Screening Trail (NLST) provided category 1 evidence that low-dose computed tomography (CT) screening conferred a significant survival benefit for screened individuals: lung cancer-specific mortality was reduced by 20% after 6.5 years of follow-up; even all-cause mortality decreased by 6%. The positive outcome triggered many national medical societies in the United States to recommend lung cancer screening in high-risk individuals. However, the favorable results of the NLST trial have not yet been reproduced. Currently, nine randomized, controlled trials are being or have been performed in various European countries. In contrast to the NLST study, three published European studies found no benefit from low-dose CT scanning in at-risk patients. Additional studies are required to establish the benefit and risks associated with repetitive low-dose CT for screening at-risk patients. Many unanswered questions remain. Who should be screened and how often? What is the appropriate workup when lesions are noted in asymptomatic individuals? What is the risk of cumulative radiation exposure from repetitive low-dose CT scans? What is the responsibility of health care personnel to evaluate nonpulmonary issues detected by CT (e.g., coronary calcifications). In this review, we address these and other questions that arise. Further, implementation of screening programs may be logistically difficult, require additional personnel and computer software, and will incur significant health care costs. PMID- 24481764 TI - Noninvasive imaging of pulmonary hypertension. AB - Pulmonary hypertension is defined as a resting mean pulmonary arterial pressure of 25 mm Hg or more determined at right heart catheterization. The challenges for imaging in patients with suspected PH are fivefold: the imaging modality should have a high diagnostic accuracy with regard to the presence of PH; it should be able to characterize the underlying disease, and allow for quantification of its extent by measuring pulmonary hemodynamics. Finally, it should provide prognostic information, and can be used for monitoring of therapy. There have been tremendous improvements in assessment of PH by computed tomography (CT) and magnetic resonance (MR) technology in recent years. This overview tries to elucidate the potential role of each imaging modality and summarizes the most important results that have been achieved so far. In general, after implementation of multidetector technology, CT is superior to MR in assessment of parenchymal and vascular pathologies of the lung, and with electrocardiogram triggered data acquisition allows for assessment of cardiac structures. The implementation of iodine maps as surrogate for lung perfusion will enable functional assessment of lung perfusion by CT. MR imaging is the reference standard for assessment of cardiac structure and function and allows for physiologic assessment of the pulmonary vasculature. New developments show that with MR techniques, an estimation of hemodynamic parameters such as mean pulmonary arterial pressure and pulmonary vascular resistance will be possible. Actually, CT and MR imaging should be considered as complementary investigations providing comprehensive information in patients with pulmonary hypertension. PMID- 24481765 TI - Imaging assessment of lung tumor angiogenesis: insights and innovations. AB - Lung cancer is the leading cause of cancer death in the United States. It is estimated that more than 228,000 new cases will be diagnosed in 2013, accounting for approximately 159,000 or 27% of all cancer deaths. Survival in these patients remains poor despite advances in surgery, definitive radiotherapy, and chemotherapy for primary and metastatic non-small cell lung cancer. Five-year relative survival rates remain at 27% for regional disease and 54% for node negative disease. With the increasing personalization of therapy, there remains a need for better prognostic and predictive markers to direct patient management in lung cancer. Hypoxia and angiogenesis play an important role in the development and progression of lung cancer. Targeted and non-targeted imaging techniques in the preclinical and clinical setting, combined with advanced postprocessing techniques to assess tumor heterogeneity, may enable clinicians to better characterize lung tumors, and to predict and assess response to treatment. In this review, we summarize our current understanding of angiogenesis in lung cancer and discuss the available imaging techniques to assess this in the preclinical and clinical setting. PMID- 24481766 TI - High-resolution CT of interstitial lung disease: a continuous evolution. AB - Before the advent of high-resolution computed tomography (HRCT), the role of imaging, chest radiography in particular, in the management of patients with interstitial lung disease was limited. In the past 25 years, this has radically changed. HRCT has transformed the diagnostic landscape by providing detailed cross-sectional imaging of the lungs, which permit ready identification of a variety of different interstitial lung diseases. Although the position of HRCT as the dominant imaging technique for interstitial lung disease has remained unchallenged since its introduction in the late 1980s, the roles assumed by HRCT have undergone a steady evolution. This evolution has occurred in stages. The first investigations of HRCT in interstitial lung disease during the late 1980s and early 1990s marked a golden era of HRCT-pathologic correlative studies, typified by the work of Muller and Miller. It was this groundbreaking work that defined basic HRCT patterns, correlated to histopathologic appearances, which underpin the pattern recognition approach used to interpret HRCT images to this day. Subsequently, attention turned to issues of disease reversibility and responsiveness and how this could be predicted by HRCT. At the turn of the millennium, the previously long accepted belief in histopathological diagnosis as the reference standard in interstitial lung disease gave way to a growing perception that histopathology was not infallible. This change in diagnostic thinking arguably has had the biggest impact on how HRCT's role subsequently evolved. Recently, HRCT data have been integrated with pulmonary function in staging models to predict prognosis particularly in idiopathic fibrosing lung disease. This article reviews these stages of evolution. The emergence of the multidisciplinary approach to diagnosis will also be considered. PMID- 24481767 TI - PET-CT: current applications and new developments in the thorax. AB - Positron emission tomography computed tomography(PET-CT) imaging has emerged as an essential clinical diagnostic tool in the evaluation of thoracic abnormalities. Currently, its primary role is for tumor imaging; it helps to differentiate benign from malignant nodules, stage tumors, determine response, and follow patients after therapy is complete. It has also been used for nononcologic diseases, but the indications are less well defined. PET is a fundamental component of the molecular imaging initiative, and as new more specific imaging probes and better instrumentation are developed, PET-CT is certain to improve diagnostic accuracy and become even more integrated into the imaging armamentarium. PMID- 24481768 TI - A selected group of large common fragile site genes have decreased expression in oropharyngeal squamous cell carcinomas. AB - The common fragile sites (CFSs) are large regions of profound genomic instability found in all individuals. The frequent deletions and other alterations in these regions in multiple cancers has led to the discovery of a number of extremely large genes contained within these regions and several of the large CFS genes have already been demonstrated to function as tumor suppressors involved in the formation of many different cancers. To study the large CFS genes in oropharyngeal squamous cell carcinoma (OPSCC), we did RNA seq analysis from 11 head and neck cancer patients. This revealed that there are six large CFS genes which consistently had decreased expression in the tumor samples compared to their matched normal tissues. These six genes are PARK2, DLG2, NBEA, CTNNA3, DMD, and FHIT. PARK2 and FHIT are located within the two most frequently expressed CFSs and both have been demonstrated to function as tumor suppressors, while the other large genes are found to have frequent alterations in multiple cancers. Validation experiments using real time PCR indicated that over 60% of OPSCC tumors showed decreased expression for all six genes. Both HPV-positive and HPV negative OPSCCs had similar proportions with loss of expression of these genes. Our results suggest that this selected group of large genes might serve as potential tumor suppressors involved in the development of OPSCCs. Further studies are needed to investigate whether the decreased expression observed is due to genomic instability within the CFS regions or the selection for alterations of specific large CFS genes. PMID- 24481770 TI - No increase in blood transfusions during liver transplantation since the withdrawal of aprotinin. AB - The aims of this study were to determine whether the withdrawal of aprotinin (APRO) led to an increased bleeding risk in patients undergoing orthotopic liver transplantation (OLT). A retrospective analysis compared consecutive patients undergoing OLT and treated with aprotinin (APRO group; n = 100) with a group in which aprotinin was not used (no-APRO group; n = 100). Propensity score matching was then performed for each group to identify 2 matched cohorts. Patients were matched by their primary diagnoses and Model for End-Stage Liver Disease scores. This resulted in 2 matched cohorts with 55 patients in each group. None of the patients in the APRO group had significant fibrinolysis. In the no-APRO group, 23.6% of the patients developed fibrinolysis (P < 0.003). Tranexamic acid was used in 61.5% of the patients (n = 8) in the no-APRO group in whom lysis was present, and this resolved the fibrinolysis in all but 1 of these patients. There were no differences in red blood cell, fresh frozen plasma, platelet concentrate, or cryoprecipitate transfusions between the 2 groups. In conclusion, we have shown a significant increase in the prevalence of fibrinolysis during OLT since the withdrawal of APRO. However, there has been no increase in transfusion requirements. PMID- 24481769 TI - Impact of multiple balloon inflations during primary percutaneous coronary intervention on infarct size and long-term clinical outcomes in ST-segment elevation myocardial infarction: real-world postconditioning. AB - Interrupting myocardial reperfusion with intermittent episodes of ischemia (i.e., postconditioning) during primary percutaneous coronary intervention (PPCI) has been suggested to protect myocardium in ST-segment elevation myocardial infarction (STEMI). Nevertheless, trials provide inconsistent results and any advantage in long-term outcomes remains elusive. Using a retrospective study design, we evaluated the impact of balloon inflations during PPCI on enzymatic infarct size (IS) and long-term outcomes. We included 634 first-time STEMI patients undergoing PPCI with an occluded infarct-related artery and adequate reperfusion thereafter and divided these into: patients receiving 1-3 inflations in the infarct-related artery [considered minimum for patency/stent placement (controls); n = 398] versus >=4 [average cycles in clinical protocols (postconditioning analogue); n = 236]. IS, assessed by peak creatine kinase, was lower in the postconditioning analogue group compared with controls [median (interquartile range) 1,287 (770-2,498) vs. 1,626 (811-3,057) UI/L; p = 0.02], corresponding to a 21 % IS reduction. This effect may be more pronounced in women, patients without diabetes/hypercholesterolemia, patients presenting within 3-6 h or with first balloon re-occlusion <=1 min. No differences were observed in 4-year mortality or MACCE between groups. Four or more inflations during PPCI reduced enzymatic IS in STEMI patients under well-defined conditions, but did not translate into improved long-term outcomes in the present study. Large-scale randomized trials following strict postconditioning protocols are needed to clarify this effect. PMID- 24481771 TI - Quality control of bone marrow aspirates: additional steps toward a safer and more efficient procedure. PMID- 24481772 TI - A case of neuroleptic malignant syndrome in an infant. PMID- 24481773 TI - Cx43 in mesenchymal stem cells promotes angiogenesis of the infarcted heart independent of gap junctions. AB - Mesenchymal stem cells (MSCs) with elevated levels of connexin 43 (Cx43) have been shown to exhibit improved protection for ischemic hearts. However, it remains unclear whether Cx43 is involved in the paracrine actions of angiogenesis, the major mechanism of cell therapy. In the present study, an in vitro model with deprivation of oxygen and a murine myocardial infarction model with permanent ligation of the left anterior-descending (LAD) coronary artery were used to determine whether gap junctions in MSCs promote angiogenesis. It was observed that MSCs that overexpressed Cx43 (MSCs-Cx43), improve the cardiac function of infarcted myocardium as compared with control MSCs (MSCs-vector) and MSCs with Cx43 knocked down by small interfering RNA (MSCs-siCx43), accompanied with a reduction of infarct size and an increase in the vascular density and maturity. Increased levels of representative angiogenic factors [vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF)] were produced by MSCs-Cx43 compared with MSCs-siCx43 in vivo and in vitro. However, neither Cx43 formed gap junction specific inhibitor (Cx43 mimetic peptide) or gap junction opener (antiarrhythmic peptide) affected the production of VEGF and bFGF in MSCs under hypoxic stress. These data support the hypothesis that Cx43 in MSCs promotes angiogenesis in the infarcted heart, independent of gap junction formation. PMID- 24481774 TI - Biography, pandemic time and risk: Pregnant women reflecting on their experiences of the 2009 influenza pandemic. AB - During the 2009 H1N1 pandemic, it was identified that women in the third trimester of pregnancy were particularly at risk of serious respiratory distress. At-risk women were advised to seek vaccination, avoid contact with anyone unwell, maintain hygiene routines and stop smoking. We examine this situation of emergent and intense risk produced at the intersection of individual biography and the historical event of a public health emergency. We examine how pregnant women took account of risk, how they negotiated incomplete and at times contradictory advice and shaped courses of action that assisted them to manage the emerging terrain of pandemic threat. Public health risk management advice was endorsed, although choosing vaccination was fraught. Social distancing, too, was seen as a valuable risk moderation strategy. However, time, and specifically the intersection of individual pregnancy timelines with the pandemic's timeline, was also seen as an important risk management resource. The implications of this mix of sanctioned and temporal risk management practices are discussed. PMID- 24481775 TI - Hypertension, platelets, and inflammatory responses. PMID- 24481776 TI - The clinical characteristics of patients with hip fractures in typical locations and atypical femoral fractures. AB - The pathophysiology of atypical fractures is unknown. We compared characteristics of patients with atypical femoral fractures and hip fractures in typical locations of the femur. Patients with atypical fracture reported a longer duration of use of bisphosphonates, had higher body mass index, and higher total hip bone mineral density. Further studies are needed. INTRODUCTION: This study aims to describe the characteristics of patients with typical and atypical fractures of the femur assessed in a tertiary care osteoporosis center. METHODS: We abstracted clinical, laboratory, and radiographic data on subjects with a history of a low-impact fracture at the femur and/or hip (confirmed by review of radiograph and/or radiology report) from January 2008 to October 2011. Available radiographs were reviewed and fracture categorized as typical or atypical by a radiologist blinded to the original diagnosis. RESULTS: Radiology reports were available for 72 subjects: 40 hip fractures in typical locations (typical fracture), 16 atypical femoral fracture (atypical fracture), and 16 were excluded. While both those with typical and atypical fractures reported taking bisphosphonates at the time of fracture, duration of use was longer with atypical fractures (104.2+/-42.0 months) compared with typical (71.1+/-62.8 months) (p=0.04). Body mass index (BMI) was higher in patients with atypical fractures (26.2+/-3.2 kg/m2) than in those with typical (23.1+/-4.3 kg/m2) (p=0.006). Total bone mineral density (BMD) was higher in patients with atypical fracture (0.795+/ 0.102) versus typical (0.686+/-0.130) (p=0.003) Previous history of cancer was reported by 7 of 16 patients with atypical and 7 of 40 patients with typical fracture (p=0.04). CONCLUSIONS: Compared to those with typical fractures, patients with atypical fracture report a longer duration of use of bisphosphonates, higher BMI, and higher total hip BMD. Future studies should examine if these differences contribute to the pathophysiology of atypical fractures. PMID- 24481777 TI - Left Ventricular endocardial pacing by the interventricular septum route. PMID- 24481778 TI - Implantable cardioverter-defibrillators for treatment of sustained ventricular arrhythmias in patients with Chagas' heart disease: comparison with a control group treated with amiodarone alone. AB - AIMS: Evidence is inconclusive concerning the benefit of implantable cardioverter defibrillators (ICDs) for secondary prevention of mortality in patients with Chagas' heart disease (ChHD). The aim of this study was to compare the outcomes of ChHD patients with life-threatening ventricular arrhythmias (VAs), who were treated either with ICD implantation plus amiodarone or with amiodarone alone. METHODS AND RESULTS: The ICD group [76 patients; 48 men; age, 57 +/- 11 years; left ventricular ejection fraction (LVEF), 39 +/- 12%] and the historical control group treated with amiodarone alone (28 patients; 18 men; age, 54 +/- 10 years; LVEF, 41 +/- 10%) had comparable baseline characteristics, except for a higher use of beta-blockers in the ICD group (P < 0.0001). Amiodarone was also used in 90% of the ICD group. Therapy with ICD plus amiodarone resulted in a 72% reduced risk of all-cause mortality (P = 0.007) and a 95% reduced risk of sudden death (P = 0.006) compared with amiodarone-only therapy. The survival benefit of ICD was greatest in patients with LVEF < 40% (P = 0.01) and was not significant in those with LVEF >= 40% (P = 0.15). Appropriate ICD therapies occurred in 72% of patients and the rates of interventions were similar across patients with LVEF < 40% and >=40%. CONCLUSION: Compared with amiodarone-only therapy, ICD implantation plus amiodarone reduced the risk of all-cause mortality and sudden death in ChHD patients with life-threatening VAs. Patients with LVEF < 40% derived significantly more survival benefit from ICD therapy. The majority of ICD treated patients received appropriate therapies regardless of the LV systolic function. PMID- 24481779 TI - Electrophysiological and haemodynamic effects of vernakalant and flecainide in dyssynchronous canine hearts. AB - AIMS: About one-third of patients with mild dyssynchronous heart failure suffer from atrial fibrillation (AF). Drugs that convert AF to sinus rhythm may further slowdown ventricular conduction. We aimed to investigate the electrophysiological and haemodynamic effects of vernakalant and flecainide in a canine model of chronic left bundle branch block (LBBB). METHODS AND RESULTS: Left bundle branch block was induced in 12 canines. Four months later, vernakalant or flecainide was administered using a regime, designed to achieve clinically used plasma concentrations of the drugs, n = 6 for each drug. Epicardial electrical contact mapping showed that both drugs uniformly prolonged myocardial conduction time. Vernakalant increased QRS width significantly less than flecainide (17 +/- 13 vs. 34 +/- 15%, respectively). Nevertheless, both drugs equally decreased LVdP/dtmax by ~15%, LVdP/dtmin by ~10%, and left ventricular systolic blood pressure by ~5% (P = n.s. between drugs). CONCLUSIONS: Vernakalant prolongs ventricular conduction less than flecainide, but both drugs had a similar, moderate negative effect on ventricular contractility and relaxation. Part of these reductions seems to be related to the increase in dyssynchrony. PMID- 24481780 TI - Epigenetic induction of tissue inhibitor of matrix metalloproteinase-3 by green tea polyphenols in breast cancer cells. AB - Aberrant epigenetic silencing of the tissue inhibitor of matrix metalloproteinase 3 (TIMP-3) gene that negatively regulates matrix metalloproteinases (MMPs) activity has been implicated in the pathogenesis and metastasis of breast cancer. In the present study, we demonstrate that green tea polyphenols (GTP) and its major constituent, epigallocatechin-3-gallate (EGCG) mediate epigenetic induction of TIMP-3 levels and play a key role in suppressing invasiveness and gelatinolytic activity of MMP-2 and MMP-9 in breast cancer cells. Treatment of MCF-7 and MDA-MB-231 breast cancer cells with 20 uM EGCG and 10 ug/mL GTP for 72 h significantly induces TIMP-3 mRNA and protein levels. Interestingly, investigations into the molecular mechanism revealed that TIMP-3 repression in breast cancer cells is mediated by epigenetic silencing mechanism(s) involving increased activity of the enhancer of zeste homolog 2 (EZH2) and class I histone deacetylases (HDACs), independent of promoter DNA hypermethylation. Treatment of breast cancer cells with GTP and EGCG significantly reduced EZH2 and class I HDAC protein levels. Furthermore, transcriptional activation of TIMP-3 was found to be associated with decreased EZH2 localization and H3K27 trimethylation enrichment at the TIMP-3 promoter with a concomitant increase in histone H3K9/18 acetylation. Our findings highlight TIMP-3 induction as a key epigenetic event modulated by GTPs in restoring the MMP:TIMP balance to delay breast cancer progression and invasion. PMID- 24481781 TI - Histone demethylase JARID1B promotes cell proliferation but is downregulated by N Myc oncoprotein. AB - Myc oncoproteins induce tumor initiation and promote tumor progression by modulating gene transcription. We have previously shown that N-Myc represses gene transcription by recruiting histone deacetylases to Sp1-binding site-enriched regions of target gene promoters. The histone demethylase JARID1B plays a dual role in cancer. In the present study, we examined published microarray gene expression datasets and found that JARID1B was commonly repressed by Myc oncoproteins and histone deacetylases in cancer cell lines of various organ origins. Chromatin immunoprecipitation assays demonstrated that N-Myc repressed JARID1B expression by direct binding to the Sp1-binding site-enriched region of the JARID1B gene promoter, and cell proliferation assays showed that transcriptional repression of JARID1B reduced neuroblastoma cell proliferation. Our findings suggest that Myc-mediated transcriptional repression of JARID1B counterintuitively inhibits Myc-regulated cell proliferation and potentially tumorigenesis. PMID- 24481783 TI - Rhodium(II)-catalyzed nondirected oxidative alkenylation of arenes: arene loading at one equivalent. AB - A bimetallic Rh(II) catalyst promoted the C-H alkenylation of simple arenes at 1.0 equivalent without the use of a directing group. A phosphine ligand as well as cooperative reoxidation of Rh(II) with Cu(TFA)2 and V2O5 proved essential in providing monoalkenylated products in good yields and selectivities, especially with di- and trisubstituted arenes. PMID- 24481782 TI - Impact of ester promoieties on transdermal delivery of ketorolac. AB - Different types of ketorolac ester prodrugs incorporating tert-butyl (KT), benzyl (KB), heptyl (KH), and diketorolac heptyl (DKH) promoieties were synthesized for the comparison of percutaneous penetration. The prodrugs were characterized according to their melting point, capacity factor, lipophilicity, solubility in 30% ethanol/buffer, enzymatic hydrolysis, in vitro skin permeation, hair follicle accumulation, and in vivo skin tolerance. Interactions between the prodrugs and esterases were predicted by molecular docking. Both equimolar suspensions and saturated solutions in 30% ethanol/pH 7.4 buffer were employed as the applied dose. All of the prodrugs exhibited a lower melting point than ketorolac. The lipophilicity increased in the following order: ketorolac < KT < KB < KH < DKH. The prodrugs were rapidly hydrolyzed to the parent drug in esterase medium, skin homogenate, and plasma, with KT and KB exhibiting higher degradation rates. KT exhibited the highest skin permeation, followed by KB. The flux of KT and KB exceeded that of ketorolac by 2.5-fold and twofold, respectively. KH and DKH did not improve ketorolac permeation but exhibited a sustained release behavior. KT and KH revealed selective absorption into follicles and a threefold greater follicular uptake compared with ketorolac. KB, KH, and DKH slightly but significantly increased transepidermal water loss (TEWL) after consecutive administration for 7 days, whereas ketorolac and KT exhibited no influence on TEWL. According to the experimental results, it can be concluded that an optimal balance between lipophilicity and aqueous solubility is important in the design of a successful prodrug. The acceptable skin tolerance for safe application is also an important consideration. PMID- 24481785 TI - Differences in sexual behaviors among unmarried sexually active students at 2- and 4-year colleges. AB - Sexual risk behaviors are common among college students, but differences between 2- and 4-year students have not been explicitly tested. Survey data from 9,748 unmarried sexually active Minnesota college students (in 2010 or 2011) were used multilevel logistic regression models to test differences in eight high risk sexual health behaviors and outcomes between students attending 2- vs. 4-year colleges. Odds of sex without a condom, sex without reliable birth control, unplanned pregnancy, and STIs were significantly lower among 4-year students than 2-year students, after adjusting for demographic covariates. Health promotion approaches targeted to the needs of 2- or 4-year students may be needed. For example, messaging and outreach efforts encouraging condom use may be especially beneficial for sexual health programs at 2-year colleges. PMID- 24481784 TI - Reactivation of human polyomaviruses in immunocompromised states. AB - Infection with various human polyomaviruses (HPyVs) is prevalent, with rates as high as 80 % within the general population. Primary infection occurs during childhood through respiratory or urino-oral transmission. While the majority of individuals exhibit asymptomatic latent infection, those immunocompromised persons are at risk for viral reactivation and disease progression resulting in conditions such as progressive multifocal leukoencephalopathy (PML), trichodysplasia spinulosa, Merkel cell carcinoma, and polyomavirus associated nephropathy. Individuals with altered immune systems due to HIV, organ transplantation, lymphoproliferative diseases, and monoclonal antibody therapy are particularly susceptible to reactivation of various HPyVs. While the specific factors that induce lytic infection have yet to be defined, it is evident that dysfunctional host cellular immune responses allow active infection to occur. Immunosuppressant conditions, such as in chronic alcohol abuse, may serve as added risk factors for reactivation of HPyVs. Since the human HPyV family is rapidly expanding, continuing studies are needed to characterize the role that known and newly discovered HPyVs play in human disease. PMID- 24481786 TI - Ethylene as a natural agent inducing plumular hook formation in pea seedlings. AB - Removing endogenous ethylene by hypobaric treatment, or displacing it with carbon dioxide inhibits hook development in etiolated pea seedlings. When seedlings are returned to a normal atmosphere, hook formation occurs in darkness. Addition of ethylene accelerates this process. When ethylene induces hook formation, cell division in the hook tissue is rather inhibited by the gas. These data suggest that endogenous ethylene causes formation of the hook by inducing expansion of certain cells. PMID- 24481787 TI - The in-vitro acid-growth response: Relation to in-vivo growth responses and auxin action. AB - We have examined in detail the characteristics of the hydrogen-ion extension response in frozen-thawed Avena coleoptile sections (in-vitro acid-growth response). These data allow us to compare the in vitro response with the in-vivo extension responses initiated by auxin and hydrogen ions. The in-vitro response has three characteristics in common with the in-vivo responses: a similar Q10 (3 4 between 15 and 25 degrees C, but almost 1 between 25 and 35 degrees ); a minimum yield stress; and a lack of stored growth (i.e., an inability to induce a potential for growth during periods of reduced wall tension). Both the in-vivo and in-vitro acid-growth responses have a threshold pH of about 4.5 and give an optimum response at pH values of 3 and below. These similarities suggest that the in-vitro and in-vivo acid-growth responses have a common wall-loosening and wall extension mechanism. We have also examined the effects of Pronase, sodium lauryl sulfate (SLS), elevated temperatures, calcium, and potassium ions on the in-vitro acid-growth response. We suggest that hydrogen ions do not activate wall associated enzymes, but act to hydrolyze non-enzymatically some acid-labile linkages in the cell wall. Furthermore, we suggest that auxin induces cell elongation either by causing the release of hydrogen ions from the protoplast or by causing the appearance in the wall of an enzyme which can hydrolyse the acid labile linkages. PMID- 24481788 TI - Models for mesophyll cell arrangement in leaves of ryegrass (Lolium perenne L.). AB - Three models for mesophyll cell arrangement in leaves of Lolium perenne L. are described. It is shown that mesophyll cells may be represented as spheres packed in a tetragonal lattice. The need to quantify mesophyll cell arrangement is discussed in relation to leaf photosynthesis.The variation on measurements of some anatomical features of leaves is examined and discussed. PMID- 24481789 TI - The effect of inhibitors of protein and nucleic acid synthesis on nucleolar size and enzyme induction in Jerusalem artichoke tuber slices. AB - The effects of various inhibitors of protein and nucleic acid synthesis on the development of invertase activity and increased nucleolar volume in discs excised from tubers of artichoke tissue are compared. The results are discussed with reference to the current theories relevant to the action of the inhibitors and to the nature of the increase in nucleolar volume. PMID- 24481790 TI - Photosensitized inhibitor formation in isolated, aging chloroplasts. AB - The possible mechanism which leads to inactivation phenomena at high intensities of blue light during the color-sensitive phase in the time course of the Hill reaction was investigated in more detail. The following results were obtained: a) The inhibition of the Hill reaction is also observed during but not prior to the color-sensitive state if the supernatant of a blue-illuminated chloroplast suspension is used as a medium for a fresh assay in red light. b) Addition of linolenic acid, which leads to a stimulation of electron transport in intact chloroplasts, intensifies the inhibition at the blue-light-sensitive stage. c) The content of malondialdehyde, an indicator for free-radical-type breakdown of unsaturated fatty acids, increases selectively after blue-light exposure during the color-sensitive phase of the Hill reaction. This result was obtained with both the thiobarbituric-acid test and fluorescence measurements of Schiff-base type conjugates. d) The gas chromatograms of total chloroplast lipids show a different spectrum for plastids exposed to blue light when compared to a non illuminated control sample. The changes imply alterations in the composition of long-chain fatty acids. These results warrant the conclusion that the blue-light inhibition is closely linked to fatty-acid breakdown which is sensitized by light absorbed by pigments detached from the photosynthetic centers during the process of chloroplast aging in vitro. PMID- 24481791 TI - [The activity of phosphoglucose-isomerase and phosphoglucomutase during morphogenesis of nucleate and anucleate cells of Acetabularia]. AB - The activity of two enzymes of the UDP-glucose and UDP-galactose biosynthetic pathway-phosphoglucose-isomerase and phosphoglucomutase-have been followed during morphogenesis of the unicellular green alga Acetabularia mediterranea. We have found that the increase in enzyme activities during morphogenesis represents de novo synthesis. The kinetic constants (K m, K i) of phosphoglucose-isomerase are similar to those found for the enzyme from rabbit muscle; mannose-6-phosphate was found to be a competitive inhibitor.The increase in activity of phosphoglucose isomerase parallels the linear increase in total protein, neither showing changes with cap formation. In contrast, the activity of phosphoglucomutase is enhanced markedly when cap formation starts.Whether the nucleus is present or absent does not affect the above mentioned properties of the two enzymes. From this fact we conclude that the enzyme syntheses are regulated by the cytoplasm, probably at the level of translation. Contributions of DNA from chloroplasts and mitochondria can be excluded because in anucleate cells, which have an already established gradient of m-RNA, actinomycin D (10 MUg/ml) has no effect on the synthesis of these enzymes.There are also differences in the spatial distribution of the two enzymes. We were able to show that both enzymes are synthesized unequally in different regions of the cells. PMID- 24481792 TI - Rooted leaves for physiological experiments. AB - Rooted leaves provide convenient material for investigating various physiological processes. Details are given for producing rooted leaves of species with tuberous roots, e.g. Sweet potato (Ipomoea batatas) and Dahlia (Dahlia variabilis) and species with tap roots, e.g. Sugar beet (Beta vulgaris) and Runner bean (Phaseolus coccineus). The storage root formed on a single sugar-beet leaf develops concentric cambia suggesting that their formation is not determined by particular leaves. PMID- 24481793 TI - The use of nurse culture in the development of haploid clones in tomato. AB - A nurse culture procedure and an appropriate medium are described for obtaining vigorous haploid clones originating from single tomato pollen grains. The grains are plated on filter-paper disks mounted over intact anthers placed on a modified Murashige and Skoog medium. The plating efficiencies of such pollen cells ranges between 0 and 60%. The variability in the plating efficiencies and the potential use of this technique over that of anther culture are discussed. PMID- 24481795 TI - High-resolution CT with histopathological correlates of the classic metaphyseal lesion of infant abuse. AB - BACKGROUND: The classic metaphyseal lesion (CML) is a common high specificity indicator of infant abuse and its imaging features have been correlated histopathologically in infant fatalities. OBJECTIVE: High-resolution CT imaging and histologic correlates were employed to (1) characterize the normal infant anatomy surrounding the chondro-osseous junction, and (2) confirm the 3-D model of the CML previously inferred from planar radiography and histopathology. MATERIALS AND METHODS: Long bone specimens from 5 fatally abused infants, whose skeletal survey showed definite or suspected CMLs, were studied postmortem. After skeletal survey, selected specimens were resected and imaged with high-resolution digital radiography. They were then scanned with micro-CT (isotropic resolution of 45 MUm(3)) or with high-resolution flat-panel CT (isotropic resolutions of 200 MUm(3)). Visualization of the bony structures was carried out using image enhancement, segmentation and isosurface extraction, together with volume rendering and multiplanar reformatting. These findings were then correlated with histopathology. RESULTS: Study of normal infant bone clarifies the 3-D morphology of the subperiosteal bone collar (SPBC) and the radiographic zone of provisional calcification (ZPC). Studies on specimens with CML confirm that this lesion is a fracture extending in a planar fashion through the metaphysis, separating a mineralized fragment. This disk-like mineralized fragment has two components: (1) a thick peripheral component encompassing the SPBC; and (2) a thin central component comprised predominantly of the radiologic ZPC. By manipulating the 3-D model, the varying appearances of the CML are displayed. CONCLUSION: High resolution CT coupled with histopathology provides elucidation of the morphology of the CML, a strong indicator of infant abuse. This new information may prove useful in assessing the biomechanical factors that produce this strong indicator of abusive assaults in infants. PMID- 24481797 TI - Biological standards for potency assignment to fibrinolytic agents used in thrombolytic therapy. AB - Thrombolytic drugs are used for the treatment of thrombotic disorders such as acute myocardial infarction, acute ischemic stroke, and pulmonary embolism. Biological standards are used for potency assignment to the range of fibrinolytic proteins used in thrombolytic therapy. The World Health Organization (WHO) International Standards are primary reference materials, calibrated in arbitrary units (international unit), assigned by collaborative study using the range of assay methods available at the time. Provided the standard and test material are equivalent, adhering to the principle of measuring like versus like, the exact nature of the assay method is unimportant. This approach has been applied successfully for several decades since the advent of fibrinolytic treatment, ensuring consistency for potency labeling and the correct dosing of patients. The emergence of generic biosimilar products and new recombinant variants poses a challenge to this system, where functional differences impact on the relative biological activity in different assay systems. A more demanding system of standardization may therefore be required on the basis of international reference materials with associated reference methods. WHO recognizes this, and where possible and practical is seeking to incorporate concepts of traceability, uncertainty, and commutability to International Standards. However, some caution is needed because limitations on the characterization of many complex biologicals remain real, and a flexible approach is required on the basis of real-world needs. PMID- 24481798 TI - AOA names Mayo Clinic academic leader as new editor in chief. PMID- 24481799 TI - Leg length discrepancy and osteoarthritic knee pain in the elderly. PMID- 24481800 TI - Sleep problems, posttraumatic stress, and mood disorders among active-duty service members. AB - CONTEXT: Sleep problems among active-duty service members are pervasive and complicate the recovery from comorbid posttraumatic stress and mood disorders. OBJECTIVE: To better understand chronic sleep problems among active-duty service members. METHODS: Medical records for active-duty service members who completed enhanced sleep assessments during an 18-month period beginning in October 2010 at the Walter Reed National Military Medical Centers' Psychiatry Continuity Service were retrospectively reviewed. Sleep assessment measures included the Pittsburgh Insomnia Rating Scale, the Alcohol Use Disorders Identification Test, the Zung Self-Rating Depression Scale, the Zung Self-Rating Anxiety Scale, the Posttraumatic Stress Disorder Checklist - Military Version, the Epworth Sleepiness Scale, the Pre-Sleep Arousal Scale, and a home sleep study. RESULTS: A total of 76 records met the study criteria. Twenty-two participants (29%) had an apnea/hypopnea index that suggested mild to moderate sleep apnea. Service members with higher self-reported posttraumatic stress scores also reported a higher degree of both somatic and cognitive factors interfering with sleep initiation. Compared with those who had low self-reported posttraumatic stress scores, service members with high posttraumatic stress scores also had less total sleep time (mean difference, 38 minutes) and higher scores on the apnea/hypopnea index, the respiratory disturbance index, and the oxygen saturation index. CONCLUSION: Enhanced sleep assessments that include traditional self-report tests and a home sleep study can help identify previously undiscovered behavioral and respiratory problems among service members, particularly those with higher posttraumatic stress scores. PMID- 24481801 TI - OMT associated with reduced analgesic prescribing and fewer missed work days in patients with low back pain: an observational study. AB - CONTEXT: Randomized controlled trials (RCTs) are considered the standard for establishing practice guidelines; however, they are expensive and time-consuming, and often the generalizability of the results is limited. OBJECTIVES: To conduct an observational study using the findings of the American Osteopathic Association's Clinical Assessment Program (AOA-CAP) low back pain module, and to compare these findings with those of a major back pain-related RCT to determine the validity and generalizability of this pseudoexperimental model. METHODS: Data were abstracted from the AOA-CAP for Residencies platform from April 1, 2006, through October 5, 2007, with a diagnosis code consistent with low back pain. Process and outcome measures were compared after segregating a similar patient population to an RCT that compared "osteopathic spinal manipulation" with standard care. RESULTS: A total of 1013 medical records were abstracted and entered into the AOA-CAP low back pain module. Mean (standard deviation [SD]) age was 44.7 (15.9) years, and body mass index was 29.6 (8.1). The eligible patients comprised 415 men (41.0%) and 598 women (59.0%), and common comorbid disease was found in 69 patients (6.8%). Activities of daily living were limited in 402 patients (42.4%), whereas 546 (57.6%) had no limitations. Previous exacerbations of low back pain occurred in 653 patients (65.9%). Most patients had no sensory or proprioception deficit (729 [87.7%]), and motor function was normal in 636 patients (74.5%). Normal ankle and knee reflexes were found in 744 of 814 (91.4%) and 755 of 829 (89.0%) patients, respectively. Osteopathic manipulative treatment (OMT) was performed on the lumbar spine (576 patients [56.9%]), thoracic spine (411 [40.6%]), sacrum/pelvis (440 [43.4%]), rib (261 [25.8%]), and lower extremity (256 [25.3%]). A segregated patient cohort (n=539) showed statistically significant differences between patients who received OMT and those who did not with the use of analgesics, steroids, spinal injections, straight-leg raising, and days off or limited work duties. CONCLUSION: The observational findings of the present study, which suggest that analgesic medication use is lower in patients who receive OMT, align with previous findings of RCTs and support the generalizability of these findings. PMID- 24481802 TI - Preventing early cardiovascular death in patients with familial hypercholesterolemia. AB - Familial hypercholesterolemia (FH) is an autosomal dominant disorder resulting in severe elevation of total and low-density lipoprotein cholesterol levels. There are more than 600,000 individuals in the United States with FH. Individuals with FH tend to experience premature cardiovascular disease and often die from sudden cardiac death at a young age. Statins alone or in combination with other lipid lowering medications are effective in managing FH and preventing cardiovascular events. For patients who do not respond to or are intolerant of pharmacotherapy, low-density lipoprotein apheresis is available as a nonpharmacologic treatment option. Despite the prevalence of FH, it is undiagnosed and untreated in the majority of patients. Screening, combined with appropriate drug therapy, can save lives. The authors review the screening, diagnosis, and management of FH. PMID- 24481803 TI - Mini-medical school programs are an effective tool to introduce students to osteopathic medicine. AB - CONTEXT: Mini-medical school programs are designed to give participants, usually high school students, a more realistic perception of medicine and to leave students with a stronger desire to pursue a career in medicine. OBJECTIVE: To determine if the annual High School Mini-Medical School program hosted by the West Virginia School of Osteopathic Medicine increased interest in osteopathic medicine among high school students. DESIGN: A survey was conducted before and after the program to test the program's effectiveness. SETTING: West Virginia School of Osteopathic Medicine's Clinical Education Center. PARTICIPANTS: High school students from Charleston, Fairmont, and the Greenbrier Valley in West Virginia. INTERVENTIONS: The participants attended an outreach program designed to interest them in a career in medicine and specifically osteopathic medicine. RESULTS: Sixty-nine participants came away with an improved understanding of a physician's life and medical school after the program. There was a mean increase in positive responses for the survey items "I understand what medical school life is truly like" (P=.0066) and "I understand what life as a doctor is really like" (P=.0004). PARTICIPANTS left the program with a stronger desire to pursue a career in medicine (P<.0001). CONCLUSION: Mini-medical school programs are an effective tool to inspire high school students to pursue careers in medicine, including osteopathic medicine. PMID- 24481804 TI - The "diplomate in osteopathy": from "school of bones" to "school of medicine". AB - This article is the second installment in a series of 6 articles on the history of and controversies related to the DO degree. This article examines how Andrew Taylor Still made the transition from informally training apprentices to launching a formal chartered institution-the American School of Osteopathy. In its first decade of existence, Still expanded both the length and breadth of the curriculum and transformed his college from what he called a "school of bones" to a "school of medicine." As this shift was occurring, J. Martin Littlejohn, then the dean of the American School of Osteopathy, questioned whether the DO degree was the appropriate degree to award its graduates. PMID- 24481805 TI - Orthotic correction of postural unleveling in a patient with ankylosing spondylitis. AB - The authors describe the case of a patient with ankylosing spondylitis who was treated with orthotic devices for postural unleveling. The patient described specific pre-existing postural problems, both static and dynamic, that had been present for many years. A unilateral 9-mm gel heel lift was used, followed by custom-molded orthotic devices that incorporated the heel lift. The patient reported immediate resolution of these symptoms after orthotic treatment, as well as increased functionality and satisfaction in activities of daily living, which coincided with the leveling of his posture. The orthotic devices were used until the patient underwent total hip arthroplasty, at which point the orthotic treatment was discontinued. PMID- 24481806 TI - Osteopathic manipulative treatment in the management of biliary dyskinesia. AB - Biliary dyskinesia is a functional gastrointestinal disorder of the gallbladder and sphincter of Oddi. Diagnosis is made on the basis of symptoms of biliary colic in the absence of cholelithiasis and gallbladder inflammation. Palpatory findings of tissue texture changes at midthoracic levels (T6-T9) may correspond to visceral dysfunction related to the biliary system. Osteopathic manipulative treatment (OMT) of the T6-T9 segments can remove the feedback related to the somatic component, thereby affecting nociceptive facilitation at the spinal level and allowing the body to restore autonomic balance. Few reports in the current literature provide examples of treatment for patients with biliary dyskinesia using OMT. The author describes the case of a 51-year-old woman who presented with symptoms consistent with biliary dyskinesia. Her biliary colic completely resolved after OMT. Osteopathic evaluation and OMT should be considered a safe and effective option for conservative management of biliary dyskinesia. PMID- 24481807 TI - Orbital myositis. PMID- 24481808 TI - My mommy is a surgeon. PMID- 24481809 TI - It's all about the footnotes: 2014 vaccine schedules. PMID- 24481811 TI - Experimental charge density study of a silylone. AB - An experimental and theoretical charge density study confirms the interpretation of (cAAC)2Si as a silylone to be valid. Two separated VSCCs present in the non bonding region of the central silicon are indicative for two lone pairs. In the experiment, both the two crystallographically independent Si-C bond lengths and ellipticities vary notably. It is only the cyclohexyl derivative that shows significant differences in these values, both in the silylones and the germylones. Only by calculating increasing spheres of surrounding point charges we were able to recover the changes in the properties of the charge density distribution caused by weak intermolecular interactions. The nitrogen-carbene carbon bond seems to have a significant double-bond character, indicating a singlet state for the carbene carbon, which is needed for donor acceptor bonding. Thus the sum of bond angles at the nitrogen atoms seems to be a reasonable estimate for singlet versus triplet state of cAACs. PMID- 24481810 TI - Determinants of cognitive performance in children relying on cyanogenic cassava as staple food. AB - While risk factors for konzo are known, determinants of cognitive impairment in konzo-affected children remain unknown. We anchored cognitive performance (KABC II scores) to serum levels of free-thyroxine (free-T4), thyroid-stimulating hormone (TSH), albumin, and motor proficiency (BOT-2 scores) in 40 children including 21 with konzo (median age: 9 years) and 19 without konzo (median age: 8 years). A multiple regression model was used to determine variables associated with changes in KABC-II scores. Age (beta: -0.818, 95% CI: -1.48, -0.152) (p = 0.018), gender (beta: -5.72; 95% CI: -9.87, -1.57 for females) (p = 0.009), BOT-2 score (beta: 0.390; 95% CI: 0.113, 0.667) (p = 0.008), and free-T4 (beta: 1.88; 95% CI: 0.009, 3.74) (p = 0.049) explained 61.1 % of variation in KABC-II scores. Subclinical hypothyroidism was not associated with poor cognition. A crude association was found between serum albumin and KABC-II scores (beta: 1.26; 95 % CI: 0.136, 2.39) (p = 0.029). On spot urinary thiocyanate reached 688 MUmol/l in children without konzo and 1,032 MUmol/L in those with konzo. Female gender and low serum albumin are risk factors common to cognitive and proportionally associated motor deficits in children exposed to cassava cyanogens. The two types of deficits may share common mechanisms. PMID- 24481812 TI - FHOD1 regulates stress fiber organization by controlling the dynamics of transverse arcs and dorsal fibers. AB - The formin FHOD1 (formin homology 2 domain containing protein 1) can act as a capping and bundling protein in vitro. In cells, active FHOD1 stimulates the formation of ventral stress fibers. However, the cellular mechanisms by which this phenotype is produced and the physiological relevance of FHOD1 function are not currently understood. Here, we first show that FHOD1 controls the formation of two distinct stress fiber precursors differentially. On the one hand, it inhibits dorsal fiber growth, which requires the polymerization of parallel bundles of long actin filaments. On the other hand, it stimulates transverse arcs that are formed by the fusion of short antiparallel actin filaments. This combined action is crucial for the maturation of stress fibers and their spatio temporal organization, and a lack of FHOD1 function perturbs dynamic cell behavior during cell migration. Furthermore, we show that the GTPase-binding and formin homology 3 domains (GBD and FH3) are responsible for stress fiber association and colocalization with myosin. Surprisingly, a version of FHOD1 that lacks these domains nevertheless retains its full capacity to stimulate arc and ventral stress fiber formation. Based on our findings, we propose a mechanism in which FHOD1 promotes the formation of short actin filaments and transiently associates with transverse arcs, thus providing tight temporal and spatial control of the formation and turnover of transverse arcs into mature ventral stress fibers during dynamic cell behavior. PMID- 24481813 TI - The formation of proximal and distal definitive endoderm populations in culture requires p38 MAPK activity. AB - Endoderm formation in the mammal is a complex process with two lineages forming during the first weeks of development, the primitive (or extraembryonic) endoderm, which is specified in the blastocyst, and the definitive endoderm that forms later, at gastrulation, as one of the germ layers of the embryo proper. Fate mapping evidence suggests that the definitive endoderm arises as two waves, which potentially reflect two distinct cell populations. Early primitive ectoderm like (EPL) cell differentiation has been used successfully to identify and characterise mechanisms regulating molecular gastrulation and lineage choice during differentiation. The roles of the p38 MAPK family in the formation of definitive endoderm were investigated using EPL cells and chemical inhibitors of p38 MAPK activity. These approaches define a role for p38 MAPK activity in the formation of the primitive streak and a second role in the formation of the definitive endoderm. Characterisation of the definitive endoderm populations formed from EPL cells demonstrates the formation of two distinct populations, defined by gene expression and ontogeny, that were analogous to the proximal and distal definitive endoderm populations of the embryo. Formation of the proximal definitive endoderm was found to require p38 MAPK activity and is correlated with molecular gastrulation, defined by the expression of brachyury (T). Distal definitive endoderm formation also requires p38 MAPK activity but can form when T expression is inhibited. Understanding lineage complexity will be a prerequisite for the generation of endoderm derivatives for commercial and clinical use. PMID- 24481814 TI - Androgen receptor complexes probe DNA for recognition sequences by short random interactions. AB - Owing to the tremendous progress in microscopic imaging of fluorescently labeled proteins in living cells, the insight into the highly dynamic behavior of transcription factors has rapidly increased over the past decade. However, a consistent quantitative scheme of their action is still lacking. Using the androgen receptor (AR) as a model system, we combined three different fluorescence microscopy assays: single-molecule microscopy, photobleaching and correlation spectroscopy, to provide a quantitative model of the action of this transcription factor. This approach enabled us to distinguish two types of AR-DNA binding: very brief interactions, in the order of a few hundred milliseconds, and hormone-induced longer-lasting interactions, with a characteristic binding time of several seconds. In addition, freely mobile ARs were slowed down in the presence of hormone, suggesting the formation of large AR-co-regulator complexes in the nucleoplasm upon hormone activation. Our data suggest a model in which mobile hormone-induced complexes of transcription factors and co-regulators probe DNA by briefly binding at random sites, only forming relatively stable transcription initiation complexes when bound to specific recognition sequences. PMID- 24481815 TI - STAT3 and MCL-1 associate to cause a mesenchymal epithelial transition. AB - Embryo implantation is effected by a myriad of signaling cascades acting on the embryo-endometrium axis. Here we show, by using MALDI TOF analysis, far-western analysis and colocalization and co-transfection studies, that STAT3 and MCL-1 are interacting partners during embryo implantation. We show in vitro that the interaction between the two endogenous proteins is strongly regulated by estrogen and progesterone. Implantation, pregnancy and embryogenesis are distinct from any other process in the body, with extensive, but controlled, proliferation, cell migration, apoptosis, cell invasion and differentiation. Cellular plasticity is vital during the early stages of development for morphogenesis and organ homeostasis, effecting the epithelial to mesenchymal transition (EMT) and, the reverse process, mesenchymal to epithelial transition (MET). STAT3 functionally associates with MCL-1 in the mammalian breast cancer cell line MCF7 that overexpresses STAT3 and MCL-1, which leads to an increased rate of apoptosis and decreased cellular invasion, disrupting the EMT. Association of MCL-1 with STAT3 modulates the normal, anti-apoptotic, activity of MCL-1, resulting in pro apoptotic effects. Studying the impact of the association of STAT3 with MCL-1 on MET could lead to an enhanced understanding of pregnancy and infertility, and also metastatic tumors. PMID- 24481816 TI - Scyl1 scaffolds class II Arfs to specific subcomplexes of coatomer through the gamma-COP appendage domain. AB - Coatomer (COPI)-coated vesicles mediate membrane trafficking in the early secretory pathway. There are at least three subclasses of COPI coats and two classes of Arf GTPases that couple COPI coat proteins to membranes. Whether mechanisms exist to link specific Arfs to specific COPI subcomplexes is unknown. We now demonstrate that Scy1-like protein 1 (Scyl1), a member of the Scy1-like family of catalytically inactive protein kinases, oligomerizes through centrally located HEAT repeats and uses a C-terminal RKXX-COO(-) motif to interact directly with the appendage domain of coatomer subunit gamma-2 (also known as COPG2 or gamma2-COP). Through a distinct site, Scyl1 interacts selectively with class II Arfs, notably Arf4, thus linking class II Arfs to gamma2-bearing COPI subcomplexes. Therefore, Scyl1 functions as a scaffold for key components of COPI coats, and disruption of the scaffolding function of Scyl1 causes tubulation of the endoplasmic reticulum (ER)-Golgi intermediate compartment (ERGIC) and the cis Golgi, similar to that observed following the loss of Arf and Arf-guanine nucleotide-exchange factor (GEF) function. Our data reveal that Scyl1 is a key organizer of a subset of the COPI machinery. PMID- 24481817 TI - N-WASP-directed actin polymerization activates Cas phosphorylation and lamellipodium spreading. AB - Tyrosine phosphorylation of the substrate domain of Cas (CasSD) correlates with increased cell migration in healthy and diseased cells. Here, we address the mechanism leading to the phosphorylation of CasSD in the context of fibronectin induced early spreading of fibroblasts. We have previously demonstrated that mechanical stretching of CasSD exposes phosphorylation sites for Src family kinases (SFKs). Surprisingly, phosphorylation of CasSD was independent of myosin contractile activity but dependent on actin polymerization. Furthermore, we found that CasSD phosphorylation in the early stages of cell spreading required: (1) integrin anchorage and integrin-mediated activation of SFKs, (2) association of Cas with focal adhesion kinase (FAK), and (3) N-WASP-driven actin-assembly activity. These findings, and analyses of the interactions of the Cas domains, indicate that the N-terminus of Cas associates with the FAK-N-WASP complex at the protrusive edge of the cell and that the C-terminus of Cas associates with the immobilized integrin-SFK cluster. Thus, extension of the leading edge mediated by actin polymerization could stretch Cas during early cell spreading, priming it for phosphorylation. PMID- 24481818 TI - Regulation of Src trafficking and activation by the endocytic regulatory proteins MICAL-L1 and EHD1. AB - Localization of the non-receptor tyrosine kinase Src to the cell periphery is required for its activation and to mediate focal adhesion turnover, cell spreading and migration. Inactive Src localizes to a perinuclear compartment and the movement of Src to the plasma membrane is mediated by endocytic transport. However, the precise pathways and regulatory proteins that are responsible for SRC transport are incompletely understood. Here, we demonstrate that Src partially colocalizes with the endocytic regulatory protein MICAL-L1 (molecule interacting with CasL-like protein 1) in mammalian cells. Furthermore, MICAL-L1 is required for growth-factor- and integrin-induced Src activation and transport to the cell periphery in HeLa cells and human fibroblasts. Accordingly, MICAL-L1 depletion impairs focal adhesion turnover, cell spreading and cell migration. Interestingly, we find that the MICAL-L1 interaction partner EHD1 (EH domain containing protein 1) is also required for Src activation and transport. Moreover, the MICAL-L1-mediated recruitment of EHD1 to Src-containing recycling endosomes is required for the release of Src from the perinuclear endocytic recycling compartment in response to growth factor stimulation. Our study sheds new light on the mechanism by which Src is transported to the plasma membrane and activated, and provides a new function for MICAL-L1 and EHD1 in the regulation of intracellular non-receptor tyrosine kinases. PMID- 24481820 TI - Sepsis biomarkers: an omics perspective. AB - Sepsis is a common cause of death in hospitalized patients worldwide. The early detection of sepsis remains a great challenge for clinicians, and delayed diagnosis frequently undermines treatment efforts, thereby contributing to high mortality. Omics technologies allow high-throughput screening of sepsis biomarkers. This review describes currently available and novel sepsis biomarkers in the context of genomics, transcriptomics, proteomics, and metabolomics. The combination of these technologies can help refine the diagnosis of sepsis. This review paper serves as a reference for future studies that employ an integrated, multi-omics approach to disease identification. PMID- 24481819 TI - Cerebral cavernous malformation proteins at a glance. AB - Loss-of-function mutations in genes encoding KRIT1 (also known as CCM1), CCM2 (also known as OSM and malcavernin) or PDCD10 (also known as CCM3) cause cerebral cavernous malformations (CCMs). These abnormalities are characterized by dilated leaky blood vessels, especially in the neurovasculature, that result in increased risk of stroke, focal neurological defects and seizures. The three CCM proteins can exist in a trimeric complex, and each of these essential multi-domain adaptor proteins also interacts with a range of signaling, cytoskeletal and adaptor proteins, presumably accounting for their roles in a range of basic cellular processes including cell adhesion, migration, polarity and apoptosis. In this Cell Science at a Glance article and the accompanying poster, we provide an overview of current models of CCM protein function focusing on how known protein protein interactions might contribute to cellular phenotypes and highlighting gaps in our current understanding. PMID- 24481821 TI - Is the aerobic capacity at the time of cardiopulmonary exercise testing useful in predicting survival following liver transplantation? PMID- 24481822 TI - A case of septic pulmonary embolism associated with renal abscess mimicking pulmonary metastases of renal malignancy. AB - We report the case of a 46-year-old woman with acute febrile symptom who had multiple pulmonary nodules and a renal mass. She underwent (18)F fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) to find a hidden malignancy and the cause of her fever. FDG PET/CT images demonstrated a renal mass and multiple lung nodules with intense FDG uptake, which was suspicious of a renal malignancy with multiple pulmonary metastatic lesions. CT-guided biopsies of the pulmonary and renal lesions only showed chronic inflammatory infiltrates without evidence of malignancy. She was diagnosed with septic pulmonary embolism from a renal abscess. One month after antibiotic treatment, the follow-up chest and abdomen CT showed improvement of the lung and renal lesions. This is the first case demonstrating the FDG PET/CT finding of septic pulmonary embolism associated with renal abscess in the published literature. PMID- 24481823 TI - (18)F-FDG PET as a single imaging modality in pediatric neuroblastoma: comparison with abdomen CT and bone scintigraphy. AB - OBJECTIVE: The purpose of this study was to evaluate the diagnostic performance of (18)F-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a single imaging agent in neuroblastoma in comparison with other imaging modalities. METHODS: A total of 30 patients with pathologically proven neuroblastoma who underwent FDG PET for staging were enrolled. Diagnostic performance of FDG PET and abdomen CT was compared in detecting soft tissue lesions. FDG PET and bone scintigraphy (BS) were compared in bone metastases. Maximal standardized uptake value (SUVmax) of primary or recurrent lesions was calculated for quantitative analysis. RESULTS: Tumor FDG uptake was detected in 29 of 30 patients with primary neuroblastoma. On initial FDG PET, SUVmax of primary lesions were lower in early stage (I-II) than in late stage (III-IV) (3.03 vs. 5.45, respectively, p = 0.019). FDG PET was superior to CT scan in detecting distant lymph nodes (23 vs. 18 from 23 lymph nodes). FDG PET showed higher accuracy to identify bone metastases than BS both on patient-based analyses (100 vs. 94.4 % in sensitivity, 100 vs. 77.8 % in specificity), and on lesion-based analyses (FDG PET: 203 lesions, BS: 86 lesions). Sensitivity and specificity of FDG PET to detect recurrence were 87.5 % and 93.8, respectively. CONCLUSION: FDG PET was superior to CT in detecting distant LN metastasis and to BS in detecting skeletal metastasis in neuroblastoma. BS might be eliminated in the evaluation of neuroblastoma when FDG PET is performed. PMID- 24481824 TI - Protective effect of luteolin on cigarette smoke extract-induced cellular toxicity and apoptosis in normal human bronchial epithelial cells via the Nrf2 pathway. AB - Luteolin, one of the most common abundant flavonoids in vegetables and herbs, has antitumor effects on various tumors by inducing apoptosis, antioxidant effects and inhibition of angiogenesis. However, the potential chemoprevention of luteolin on lung cell damage and its related mechanism(s) are not fully known. The present study evaluated the protective effects of luteolin on cigarette smoke extract (CSE)-induced toxicity and apoptosis in normal human bronchial epithelial (NHBE) cells and explored its underlying mechanism(s). MTT assay showed that pretreatment with luteolin increased CSE-decreased cell viability (p<0.05). Luteolin increased cellular glutathione (GSH) levels but decreased reactive oxygen species (ROS) generation (p<0.05). Cytometry assay and western blot analysis showed that luteolin attenuated CSE-induced apoptosis and apoptosis related protein activation, including caspase-3, -8 and -9 (p<0.05). The expression of CSE-induced NAD(P)H: quinone oxidoreductase 1 (NQO1) and heme oxygenase-1 (HO-1) were decreased significantly by luteolin (p<0.05). Furthermore, luteolin attenuated CSE-induced apoptosis, noticeably reduced CSE induced expression of NF-E2-related factor 2 (Nrf2), NQO1 and HO-1 using a small interfering RNA (siRNA) transfection assay. The data demonstrated that CSE induced oxidative damage and apoptosis through the Nrf2 pathway was inhibited by luteolin and it may serve as a chemopreventive agent for the prevention and treatment of lung cancer. PMID- 24481825 TI - Incidence of hip pain in a prospective cohort of asymptomatic volunteers: is the cam deformity a risk factor for hip pain? AB - BACKGROUND: Although cam-type femoroacetabular impingement is commonly associated with labral chondral damage and hip pain, a large proportion of asymptomatic individuals will have this deformity. PURPOSE: To determine the incidence of hip pain in a prospective cohort of volunteers who had undergone magnetic resonance imaging (MRI) of their hips. STUDY DESIGN: Case control study; Level of evidence, 3. METHODS: A total of 200 asymptomatic volunteers who underwent an MRI of both hips were followed for a mean time of 4.4 years (range, 4.01-4.95 years). Thirty were lost to follow-up, leaving 170 individuals (77 males, 93 females) with a mean age of 29.5 years (range, 25.7-54.5 years). All patients were blinded to the results of their MRI. All completed a follow-up questionnaire inquiring about the presence of hip pain or a history of hip pain lasting longer than 6 weeks since the original MRI. Each patient was asked to draw where the pain was on a body diagram. RESULTS: Eleven patients (5 males, 6 females; 6.5% of sample; mean age, 29.9 years; range, 25.7-45.6 years) reported hip pain, of which 3 (1 male, 2 females) had bilateral pain for a total of 14 hips. Seven of the 14 painful hips had a cam-type deformity at the time of the initial MRI versus 37 of the 318 nonpainful hips (P = .0002). This gave a relative risk of 4.3 (95% confidence interval [CI], 2.3-7.8) of developing hip pain if cam deformity was present. Those 14 painful hips had a significantly greater alpha angle at the radial 1:30 clock position than did those who did not develop pain with a cam deformity: 61.5 degrees (range, 57.3 degrees -65.7 degrees ) versus 57.9 degrees (range, 56.9 degrees -59.1 degrees ), respectively (P = .05). A significantly greater proportion of patients (12%) with limited internal rotation <=20 degrees (versus 2.7% with internal rotation >20 degrees ) went on to develop hip pain (P = .009; relative risk = 3.1 [95% CI, 1.6-6.0]). CONCLUSION: The presence of a cam deformity represents a significant risk factor for the development of hip pain. An elevated alpha angle at the 1:30 clock position and decreased internal rotation are associated with an increased risk of developing hip pain. However, not all patients with a cam deformity develop hip pain, and further research is needed to better define those at greater risk of developing degenerative symptoms. PMID- 24481826 TI - The effectiveness of preventive programs in decreasing the risk of soccer injuries in Belgium: national trends over a decade. AB - BACKGROUND: Although characterized by a relatively high injury rate, soccer is the world's most popular sport. In Belgium, the national Royal Belgian Football Association involves about 420,000 licensed players, whose injury reports are collected in a nationwide registry. Over a period of 10 years, the association has introduced the Federation Internationale de Football Association preventive programs and has initiated a stringent postponement policy of competition in case of nonoptimal weather conditions. HYPOTHESIS: The authors questioned whether these preventive programs effectively decreased the incidence of soccer-related injuries. STUDY DESIGN: Descriptive epidemiology study. METHODS: The authors compared the incidence, location, timing, and severity of all registered soccer injuries in Belgium during 2 complete seasons separated by a decade (1999-2000 vs 2009-2010). RESULTS: A total of 56,364 injuries were reported, with an average of 6.8 injuries per 100 players per season. There was a 21.1% reduction in injury rate in the second season (rate ratio = 0.789; 95% confidence interval, 0.776 0.802), predominantly caused by a significant reduction in injuries during the winter period. In both seasons, an injury peak was noted during the first 3 months of the season. Recreational players had a higher risk for injury than national-level players (7.2 vs 4.4 injuries per 100 players per season; rate ratio = 1.64; 95% confidence interval, 1.59-1.69). The relative proportion of severe injuries was higher for female players and male youth players in general. CONCLUSION: The introduction of injury preventive programs has led to a significant reduction of soccer-related injuries, especially during the winter period. However, there is still room for improvement, and preventive programs can become more effective when specific parameters are targeted, such as adequate conditioning of players in the preseason. PMID- 24481827 TI - Clinical profiling in cartilage regeneration: prognostic factors for midterm results of matrix-assisted autologous chondrocyte transplantation. AB - BACKGROUND: Matrix-assisted autologous chondrocyte transplantation (MACT) was developed to overcome the limitations of first-generation autologous chondrocyte implantation. Although short-term/midterm results are now available for a small series of patients, the literature still lacks studies on large cohorts of patients evaluated at midterm/long-term follow-up. PURPOSE: Not all patients can have the same benefit from this procedure. The aim of this study is to analyze a large cohort of patients treated with hyaluronan-based MACT to perform clinical profiling and to highlight the patient- and lesion-specific aspects that play a key role in determining the prognosis. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: A total of 142 patients were treated for lesions involving the femoral condyles and trochleae; 133 knees were followed up yearly for 7 years. The average size of the defects was 2.3 +/- 1.0 cm2. The origin was traumatic in 44 cases and degenerative in 57 cases, and 32 knees were affected by osteochondritis dissecans (OCD). The clinical outcome was analyzed using the International Knee Documentation Committee (IKDC), EuroQol visual analog scale, and Tegner scores. The influence of the following factors was analyzed: sex, age, body mass index, site, lesion origin, lesion size, previous or combined surgery, and symptom duration. RESULTS: A marked improvement in all scores was found: the IKDC subjective score increased from the basal level of 39.6 +/- 14.4 to 71.9 +/- 19.8 (P < .0005) at 12 months; a further improvement was observed at 24 months (77.0 +/- 20.5; P < .0005). The results were stable over time up to the 7-year evaluation (77.4 +/- 22.1). The failure rate was 10.7%. Better results were seen in the trochleae, and among femoral condyles, the following factors were found to influence the clinical outcome positively: traumatic and OCD origin, male sex, short symptom duration (for traumatic lesions), small lesion size (for OCD), young age, and no previous surgery. CONCLUSION: Treatment with MACT provides good and stable clinical results. Injury origin, sex, symptom duration, lesion size, lesion site, age, and previous surgery might determine the final outcome and can be used as a sort of clinical profiling to guide the surgeon in the choice of this procedure and in giving realistic expectations to patients requiring cartilage treatment. PMID- 24481828 TI - Platelet-rich plasma as a treatment for patellar tendinopathy: a double-blind, randomized controlled trial. AB - BACKGROUND: Previous studies have shown improvement in patellar tendinopathy symptoms after platelet-rich plasma (PRP) injections, but no randomized controlled trial has compared PRP with dry needling (DN) for this condition. PURPOSE: To compare clinical outcomes in patellar tendinopathy after a single ultrasound-guided, leukocyte-rich PRP injection versus DN. STUDY DESIGN: Randomized controlled trial; Level of evidence, 1. METHODS: A total of 23 patients with patellar tendinopathy on examination and MRI who had failed nonoperative treatment were enrolled and randomized to receive ultrasound-guided DN alone (DN group; n = 13) or with injection of leukocyte-rich PRP (PRP group; n = 10), along with standardized eccentric exercises. Patients and the physician providing follow-up care were blinded. Participants completed patient-reported outcome surveys before and at 3, 6, 9, 12, and >=26 weeks after treatment during follow-up visits. The primary outcome measure was the Victorian Institute of Sports Assessment (VISA) score for patellar tendinopathy at 12 weeks, and secondary measures included the visual analog scale (VAS) for pain, Tegner activity scale, Lysholm knee scale, and Short Form (SF-12) questionnaire at 12 and >=26 weeks. Results were analyzed using 2-tailed paired and unpaired t tests. Patients who were dissatisfied at 12 weeks were allowed to cross over into a separate unblinded arm. RESULTS: At 12 weeks after treatment, VISA scores improved by a mean +/- standard deviation of 5.2 +/- 12.5 points (P = .20) in the DN group (n = 12) and by 25.4 +/- 23.2 points (P = .01) in the PRP group (n = 9); at >=26 weeks, the scores improved by 33.2 +/- 14.0 points (P = .001) in the DN group (n = 9) and by 28.9 +/- 25.2 points (P = .01) in the PRP group (n = 7). The PRP group had improved significantly more than the DN group at 12 weeks (P = .02), but the difference between groups was not significant at >=26 weeks (P = .66). Lysholm scores were not significantly different between groups at 12 weeks (P = .81), but the DN group had improved significantly more than the PRP group at >=26 weeks (P = .006). At 12 weeks, 3 patients in the DN group failed treatment and subsequently crossed over into the PRP group. These patients were excluded from the primary >=26-week analysis. There were no treatment failures in the PRP group. No adverse events were reported. Recruitment was stopped because interim analysis demonstrated statistically significant and clinically important results. CONCLUSION: A therapeutic regimen of standardized eccentric exercise and ultrasound-guided leukocyte-rich PRP injection with DN accelerates the recovery from patellar tendinopathy relative to exercise and ultrasound-guided DN alone, but the apparent benefit of PRP dissipates over time. PMID- 24481830 TI - Natural products as potential drug permeation enhancer in transdermal drug delivery system. AB - Permeation enhancers are defined as substances that are capable of promoting penetration of drugs into skin and transdermal therapeutic systems offers a more reliable mean of administering drug through the skin. Skin is a natural barrier so it is necessary to employ enhancement strategies to improve topical bioavailability. This review explores that natural products have got potential to enhance the permeation of the drug through skin by reversibly reducing the skin barrier resistance. The use of natural products is the most reliable means of permeation enhancement of transdermally administered drugs and permits the delivery of broader classes of drugs through the stratum corneum. They are safe, non-toxic, pharmacologically inert, non-irritating, and non-allergenic to use as permeation enhancers. The present review initially highlights the current status of natural products on the basis of SAR studies which have shown significant enhancer activities. PMID- 24481829 TI - Integrity of cortical perineuronal nets influences corticospinal tract plasticity after spinal cord injury. AB - The rapid decline of injury-induced neuronal circuit remodelling after birth is paralleled by the accumulation of chondroitin sulphate proteoglycans (CSPGs) in the extracellular matrix, culminating with the appearance of perineuronal nets (PNNs) around parvalbumin-expressing GABAergic interneurons. We used a spinal cord injury (SCI) model to study the interplay between integrity of PNN CSPGs in the sensorimotor cortex, anatomical remodelling of the corticospinal tract (CST) and motor recovery in adult mice. We showed that thoracic SCI resulted in an atrophy of GABAergic interneurons in the axotomized hindlimb cortex, as well as in a more widespread downregulation of parvalbumin expression. In parallel, spontaneous changes in the integrity of CSPG glycosaminoglycan (GAG) chains associated with PNNs occurred at the boundary between motor forelimb and sensorimotor hindlimb cortex, a region previously showed to undergo reorganization after thoracic SCI. Surprisingly, full digestion of CSPG GAG chains by intracortical chondroitinase ABC injection resulted in an aggravation of motor deficits and reduced sprouting of the axotomized CST above the lesion. Altogether, our data show that changes in the expression pattern of GABAergic markers and PNNs occur in regions of the sensorimotor cortex undergoing spontaneous reorganization after SCI, but suggest that these changes have to be tightly controlled to be of functional benefit. PMID- 24481831 TI - Introduction and meeting recap. PMID- 24481832 TI - Reply to quality control of bone marrow aspirates: additional steps toward a safer and more efficient procedure. PMID- 24481833 TI - Two-dimensional programmable manipulation of magnetic nanoparticles on-chip. AB - A novel device is designed for on-chip selective trap and two-dimensional remote manipulation of single and multiple fluid-borne magnetic particles using field controlled magnetic domain walls in circular nanostructures. The combination of different ring-shaped nanostructures and field sequences allows for remote manipulation of magnetic particles with high-precision along any arbitrary pathway on a chip surface. PMID- 24481834 TI - Breaking news on the enantioselective intermolecular Heck reaction. AB - Glowing results with less phosphorus: Tremendous progress has been made recently in asymmetric intermolecular Heck chemistry. Previously unprecedented enantioselective Heck-Matsuda reactions have been accomplished, and mixed phosphine/phosphine oxides have been shown to be superior ligands in enantioselective Mizoroki-Heck reactions. All of this was achieved with chiral ligands containing few or even no phosphorus donors (see scheme). PMID- 24481835 TI - Growth inhibition and induction of apoptosis in SGC-7901 human gastric cancer cells by evodiamine. AB - Evodiamine is one of the major bioactive compounds isolated and purified from the fruit of Fructus Evodiae. Numerous studies have indicated that evodiamine exhibits activity against human tumor cells. In the present study, the effect of evodiamine on the proliferation and apoptosis of SGC-7901 human gastric cancer cells and the correlative mechanisms were investigated. This may provide further experimental evidence of the pharmacological actions of evodiamine and a strategy for its use as a novel chemotherapeutic drug. Following treatment with evodiamine, the typical morphological changes of apoptosis were observed in human SGC-7901 cells. Cell cycle analysis indicated that evodiamine induced G2/M phase arrest in SGC-7901 cells and flow cytometry revealed that evodiamine induced apoptosis. Analysis of the enzymatic activity demonstrated that evodiamine increased the activity of caspase-3, -8 and -9 in SGC-7901 cells. The protein expression of caspase-3, -8 and -9 and Bax increased, and the expression of Bcl-2 decreased following treatment with evodiamine. These results suggest that evodiamine is able to inhibit the proliferation of SGC-7901 cells by inhibiting the cell cycle at G2/M phase and inducing apoptosis in SGC-7901 cells by activating caspase-3, -8 and -9, and altering the expression of caspase-3, Bax and Bcl-2. PMID- 24481836 TI - Ca2+ nanosparks: shining light on the dyadic cleft but missing the intensity of its signal. PMID- 24481837 TI - MiR-92a: at the heart of lipid-driven endothelial dysfunction. PMID- 24481838 TI - Hippo activation in arrhythmogenic cardiomyopathy. PMID- 24481839 TI - Do endothelial cells eat tryptophan to die? PMID- 24481840 TI - Reprogramming the cardiac field. PMID- 24481841 TI - Perspectives for induced pluripotent stem cell technology: new insights into human physiology involved in somatic mosaicism. AB - Induced pluripotent stem cell technology makes in vitro reprogramming of somatic cells from individuals with various genetic backgrounds possible. By applying this technology, it is possible to produce pluripotent stem cells from biopsy samples of arbitrarily selected individuals with various genetic backgrounds and to subsequently maintain, expand, and stock these cells. From these induced pluripotent stem cells, target cells and tissues can be generated after certain differentiation processes. These target cells/tissues are expected to be useful in regenerative medicine, disease modeling, drug screening, toxicology testing, and proof-of-concept studies in drug development. Therefore, the number of publications concerning induced pluripotent stem cells has recently been increasing rapidly, demonstrating that this technology has begun to infiltrate many aspects of stem cell biology and medical applications. In this review, we discuss the perspectives of induced pluripotent stem cell technology for modeling human diseases. In particular, we focus on the cloning event occurring through the reprogramming process and its ability to let us analyze the development of complex disease-harboring somatic mosaicism. PMID- 24481842 TI - Engineering adolescence: maturation of human pluripotent stem cell-derived cardiomyocytes. AB - The discovery of human pluripotent stem cells (hPSCs), including both human embryonic stem cells and human-induced pluripotent stem cells, has opened up novel paths for a wide range of scientific studies. The capability to direct the differentiation of hPSCs into functional cardiomyocytes has provided a platform for regenerative medicine, development, tissue engineering, disease modeling, and drug toxicity testing. Despite exciting progress, achieving the optimal benefits has been hampered by the immature nature of these cardiomyocytes. Cardiac maturation has long been studied in vivo using animal models; however, finding ways to mature hPSC cardiomyocytes is only in its initial stages. In this review, we discuss progress in promoting the maturation of the hPSC cardiomyocytes, in the context of our current knowledge of developmental cardiac maturation and in relation to in vitro model systems such as rodent ventricular myocytes. Promising approaches that have begun to be examined in hPSC cardiomyocytes include long term culturing, 3-dimensional tissue engineering, mechanical loading, electric stimulation, modulation of substrate stiffness, and treatment with neurohormonal factors. Future studies will benefit from the combinatorial use of different approaches that more closely mimic nature's diverse cues, which may result in broader changes in structure, function, and therapeutic applicability. PMID- 24481843 TI - Cardiac mitochondria and reactive oxygen species generation. AB - Mitochondrial reactive oxygen species (ROS) have emerged as an important mechanism of disease and redox signaling in the cardiovascular system. Under basal or pathological conditions, electron leakage for ROS production is primarily mediated by the electron transport chain and the proton motive force consisting of a membrane potential (DeltaPsi) and a proton gradient (DeltapH). Several factors controlling ROS production in the mitochondria include flavin mononucleotide and flavin mononucleotide-binding domain of complex I, ubisemiquinone and quinone-binding domain of complex I, flavin adenine nucleotide binding moiety and quinone-binding pocket of complex II, and unstable semiquinone mediated by the Q cycle of complex III. In mitochondrial complex I, specific cysteinyl redox domains modulate ROS production from the flavin mononucleotide moiety and iron-sulfur clusters. In the cardiovascular system, mitochondrial ROS have been linked to mediating the physiological effects of metabolic dilation and preconditioning-like mitochondrial ATP-sensitive potassium channel activation. Furthermore, oxidative post-translational modification by glutathione in complex I and complex II has been shown to affect enzymatic catalysis, protein-protein interactions, and enzyme-mediated ROS production. Conditions associated with oxidative or nitrosative stress, such as myocardial ischemia and reperfusion, increase mitochondrial ROS production via oxidative injury of complexes I and II and superoxide anion radical-induced hydroxyl radical production by aconitase. Further insight into cellular mechanisms by which specific redox post translational modifications regulate ROS production in the mitochondria will enrich our understanding of redox signal transduction and identify new therapeutic targets for cardiovascular diseases in which oxidative stress perturbs normal redox signaling. PMID- 24481846 TI - Angiogenesis and cardiac hypertrophy: maintenance of cardiac function and causative roles in heart failure. AB - Cardiac hypertrophy is an adaptive response to physiological and pathological overload. In response to the overload, individual cardiac myocytes become mechanically stretched and activate intracellular hypertrophic signaling pathways to re-use embryonic transcription factors and to increase the synthesis of various proteins, such as structural and contractile proteins. These hypertrophic responses increase oxygen demand and promote myocardial angiogenesis to dissolve the hypoxic situation and to maintain cardiac contractile function; thus, these responses suggest crosstalk between cardiac myocytes and microvasculature. However, sustained pathological overload induces maladaptation and cardiac remodeling, resulting in heart failure. In recent years, specific understanding has increased with regard to the molecular processes and cell-cell interactions that coordinate myocardial growth and angiogenesis. In this review, we summarize recent advances in understanding the regulatory mechanisms of coordinated myocardial growth and angiogenesis in the pathophysiology of cardiac hypertrophy and heart failure. PMID- 24481844 TI - Linker of nucleoskeleton and cytoskeleton complex proteins in cardiac structure, function, and disease. AB - The linker of nucleoskeleton and cytoskeleton (LINC) complex, composed of proteins within the inner and the outer nuclear membranes, connects the nuclear lamina to the cytoskeleton. The importance of this complex has been highlighted by the discovery of mutations in genes encoding LINC complex proteins, which cause skeletal or cardiac myopathies. Herein, this review summarizes structure, function, and interactions of major components of the LINC complex, highlights how mutations in these proteins may lead to cardiac disease, and outlines future challenges in the field. PMID- 24481845 TI - Mammalian target of rapamycin signaling in cardiac physiology and disease. AB - The protein kinase mammalian or mechanistic target of rapamycin (mTOR) is an atypical serine/threonine kinase that exerts its main cellular functions by interacting with specific adaptor proteins to form 2 different multiprotein complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). mTORC1 regulates protein synthesis, cell growth and proliferation, autophagy, cell metabolism, and stress responses, whereas mTORC2 seems to regulate cell survival and polarity. The mTOR pathway plays a key regulatory function in cardiovascular physiology and pathology. However, the majority of information available about mTOR function in the cardiovascular system is related to the role of mTORC1 in the unstressed and stressed heart. mTORC1 is required for embryonic cardiovascular development and for postnatal maintenance of cardiac structure and function. In addition, mTORC1 is necessary for cardiac adaptation to pressure overload and development of compensatory hypertrophy. However, partial and selective pharmacological and genetic inhibition of mTORC1 was shown to extend life span in mammals, reduce pathological hypertrophy and heart failure caused by increased load or genetic cardiomyopathies, reduce myocardial damage after acute and chronic myocardial infarction, and reduce cardiac derangements caused by metabolic disorders. The optimal therapeutic strategy to target mTORC1 and increase cardioprotection is under intense investigation. This article reviews the information available regarding the effects exerted by mTOR signaling in cardiovascular physiology and pathological states. PMID- 24481848 TI - Perceptions of adolescents, parents, and school personnel from a predominantly Cuban American community regarding dating and teen dating violence prevention. AB - The purpose of this study was to explore perceptions of dating relationships and teen dating violence prevention within a predominantly Cuban American community in Miami-Dade County. Eight focus groups (n = 74 participants) with adolescents of Hispanic origin (n = 29), their parents (n = 29), and school personnel (n = 16) were conducted and analyzed using content analysis. Four themes characterized the nature and context of dating relationships among adolescents of Hispanic origin: YOLO -You Only Live Once, cultural unity but social division, dating is not going out, and the social environment challenges healthy relationships. The information generated from this study can be used to develop culturally tailored teen dating violence prevention programs targeting youth of Hispanic origin. PMID- 24481849 TI - What does "presumed consent" might presume? Preservation measures and uncontrolled donation after circulatory determination of death. AB - One of the most controversial aspects in uncontrolled (out-of-hospital) donation of organs after circulatory death (uDCD) is the initiation of preservation measures before death. I argue that in so-called opting-out systems only under very stringent conditions we might presume consent to the instauration of those measures. Given its current legal framework, I claim that this is not the case of Spain, a well-known country in which consent is presumed-albeit only formally-and where uDCD is currently practiced. PMID- 24481847 TI - Integrins and integrin-associated proteins in the cardiac myocyte. AB - Integrins are heterodimeric, transmembrane receptors that are expressed in all cells, including those in the heart. They participate in multiple critical cellular processes including adhesion, extracellular matrix organization, signaling, survival, and proliferation. Particularly relevant for a contracting muscle cell, integrins are mechanotransducers, translating mechanical to biochemical information. Although it is likely that cardiovascular clinicians and scientists have the highest recognition of integrins in the cardiovascular system from drugs used to inhibit platelet aggregation, the focus of this article will be on the role of integrins specifically in the cardiac myocyte. After a general introduction to integrin biology, the article will discuss important work on integrin signaling, mechanotransduction, and lessons learned about integrin function from a range of model organisms. Then we will detail work on integrin related proteins in the myocyte, how integrins may interact with ion channels and mediate viral uptake into cells, and also play a role in stem cell biology. Finally, we will discuss directions for future study. PMID- 24481850 TI - Multitasking versus multiplexing: Toward a normative account of limitations in the simultaneous execution of control-demanding behaviors. AB - Why is it that behaviors that rely on control, so striking in their diversity and flexibility, are also subject to such striking limitations? Typically, people cannot engage in more than a few-and usually only a single-control-demanding task at a time. This limitation was a defining element in the earliest conceptualizations of controlled processing; it remains one of the most widely accepted axioms of cognitive psychology, and is even the basis for some laws (e.g., against the use of mobile devices while driving). Remarkably, however, the source of this limitation is still not understood. Here, we examine one potential source of this limitation, in terms of a trade-off between the flexibility and efficiency of representation ("multiplexing") and the simultaneous engagement of different processing pathways ("multitasking"). We show that even a modest amount of multiplexing rapidly introduces cross-talk among processing pathways, thereby constraining the number that can be productively engaged at once. We propose that, given the large number of advantages of efficient coding, the human brain has favored this over the capacity for multitasking of control-demanding processes. PMID- 24481851 TI - Brain processing of task-relevant and task-irrelevant emotional words: an ERP study. AB - Although there is evidence for preferential perceptual processing of written emotional information, the effects of attentional manipulations and the time course of affective processing require further clarification. In this study, we attempted to investigate how the emotional content of words modulates cerebral functioning (event-related potentials, ERPs) and behavior (reaction times, RTs) when the content is task-irrelevant (emotional Stroop Task, EST) or task-relevant (emotional categorization task, ECT), in a sample of healthy middle-aged women. In the EST, the RTs were longer for emotional words than for neutral words, and in the ECT, they were longer for neutral and negative words than for positive words. A principal components analysis of the ERPs identified various temporospatial factors that were differentially modified by emotional content. P2 was the first emotion-sensitive component, with enhanced factor scores for negative nouns across tasks. The N2 and late positive complex had enhanced factor scores for emotional relative to neutral information only in the ECT. The results reinforce the idea that written emotional information has a preferential processing route, both when it is task-irrelevant (producing behavioral interference) and when it is task-relevant (facilitating the categorization). After early automatic processing of the emotional content, late ERPs become more emotionally modulated as the level of attention to the valence increases. PMID- 24481852 TI - Reduced susceptibility to confirmation bias in schizophrenia. AB - Patients with schizophrenia (SZ) show cognitive impairments on a wide range of tasks, with clear deficiencies in tasks reliant on prefrontal cortex function and less consistently observed impairments in tasks recruiting the striatum. This study leverages tasks hypothesized to differentially recruit these neural structures to assess relative deficiencies of each. Forty-eight patients and 38 controls completed two reinforcement learning tasks hypothesized to interrogate prefrontal and striatal functions and their interaction. In each task, participants learned reward discriminations by trial and error and were tested on novel stimulus combinations to assess learned values. In the task putatively assessing fronto-striatal interaction, participants were (inaccurately) instructed that one of the stimuli was valuable. Consistent with prior reports and a model of confirmation bias, this manipulation resulted in overvaluation of the instructed stimulus after its true value had been experienced. Patients showed less susceptibility to this confirmation bias effect than did controls. In the choice bias task hypothesized to more purely assess striatal function, biases in endogenously and exogenously chosen actions were assessed. No group differences were observed. In the subset of participants who showed learning in both tasks, larger group differences were observed in the confirmation bias task than in the choice bias task. In the confirmation bias task, patients also showed impairment in the task conditions with no prior instruction. This deficit was most readily observed on the most deterministic discriminations. Taken together, these results suggest impairments in fronto-striatal interaction in SZ, rather than in striatal function per se. PMID- 24481853 TI - Totally laparoscopic pylorus-preserving gastrectomy for early gastric cancer in the middle stomach: technical report and surgical outcomes. AB - INTRODUCTION: The feasibility, safety, and improved quality of postoperative life following laparoscopy-assisted pylorus-preserving gastrectomy (LAPPG) with a hand sewn anastomosis via a mini-laparotomy for early gastric cancer (EGC) have been previously established. Here we describe the surgical procedure of totally laparoscopic pylorus-preserving gastrectomy (TLPPG) using an intracorporeal delta shaped anastomosis technique, and the short-term surgical outcomes of 60 patients with EGC in the middle stomach are reported. METHODS: After lymphadenectomy and mobilization of the stomach, intraoperative gastroscopy was performed in order to verify the location of the tumor, and then the distal and proximal transecting lines were established, 5 cm from the pyloric ring and just proximal to Demel's line, respectively. Following transection of the stomach, a delta-shaped intracorporeal gastrogastrostomy was made with linear staplers. RESULTS: There were no intraoperative complications or conversions to open surgery. Mean operation time and blood loss were 259 min and 28 mL, respectively. Twelve patients (20.0%) experienced postoperative complications classified as grade II using the Clavien-Dindo classification, with the most frequent complication being gastric stasis (6 cases, 10.0 %). The incidence of severe complications classified as grade III or above was 1.7%; only one patient required reoperation and intensive care due to postoperative intraabdominal bleeding and subsequent multiple organ failure. CONCLUSION: TLPPG with an intracorporeal delta-shaped anastomosis was found to be a safe procedure, although it tended to require a longer operating time than the well-established LAPPG with a hand-sewn gastrogastrostomy. PMID- 24481854 TI - DNA methylation downregulated mir-10b acts as a tumor suppressor in gastric cancer. AB - BACKGROUND: MicroRNAs act as tumor suppressors or oncogenes. The pathological roles of miRNAs in gastric tumorigenesis are largely unknown. Although miR-10b was identified as an miRNA deregulator expressed in gastric cancer (GC), there also exists some debate on whether miR-10b is acting as tumor suppressor or oncogene in GC. METHODS: Quantitative RT-PCR was employed to investigate the level of miR-10b in GC tissues and matched adjacent normal tissues (n = 100). In vitro cell proliferation, apoptosis assays, cell migration, and invasion assays were performed to elucidate the biological effects of miR-10b. Because silencing of miRNA by promoter CpG island methylation may be an important mechanism in tumorigenesis, GC cells were treated with 5-aza-2'-deoxycytidine and trichostatin A, and expression changes of miR-10b were subsequently examined by quantitative RT-PCR. Furthermore, the methylation status of the CpG island upstream of miR-10b was analyzed by methylation-specific PCR in GC tissues (n = 29). RESULTS: We showed here that miR-10b was significantly downregulated in GC cell lines and tissues as demonstrated by quantitative real-time PCR. Overexpression of miR-10b in MGC-803 and HGC-27 dramatically suppressed cell proliferation, migration, invasion, and induced apoptosis. Moreover, we demonstrated that T-cell lymphoma invasion and metastasis (Tiam1) was a target of miR-10b. Furthermore, 5-aza-2' deoxycytidine and trichostain A increased miR-10b expression, and the methylation level was high in the CpG islands upstream of miR-10b gene. CONCLUSIONS: Taken together, these findings suggest that miR-10b may function as a novel tumor suppressor and is partially silenced by DNA hypermethylation in GC. PMID- 24481856 TI - Stimuli-responsive microjets with reconfigurable shape. AB - Flexible thermoresponsive polymeric microjets are formed by the self-folding of polymeric layers containing a thin Pt film used as catalyst for self-propulsion in solutions containing hydrogen peroxide. The flexible microjets can reversibly fold and unfold in an accurate manner by applying changes in temperature to the solution in which they are immersed. This effect allows microjets to rapidly start and stop multiple times by controlling the radius of curvature of the microjet. This work opens many possibilities in the field of artificial nanodevices, for fundamental studies on self-propulsion at the microscale, and also for biorelated applications. PMID- 24481855 TI - Evaluation of the novel near-infrared fluorescence tracers pullulan polymer nanogel and indocyanine green/gamma-glutamic acid complex for sentinel lymph node navigation surgery in large animal models. AB - BACKGROUND: This study aimed to examine tracers designed to overcome the disadvantages of indocyanine green (ICG), which disperses quickly to multiple lymph nodes, using a near-infrared (NIR) imaging system in animal models. METHODS: Diluted ICG, ICG/poly-gamma-glutamic acid (PGA) complex, and IRDye900 conjugated pullulan-cholesterol nanoprobe "near-infrared polynagogel" (NIR-PNG) were injected into the stomachs of dogs and pigs, and the patterns of dispersion were observed using an NIR imaging system. To compare retention times, fluorescence signals were evaluated in the stomach and small bowel of animals 1 week after injection. RESULTS: A diluted concentration (~0.1 mg/ml) of ICG was optimal for NIR imaging compared with the conventional concentration (5 mg/ml) for visual inspection. When injected into the stomach, the signals of ICG and ICG/PGA complex were relatively large at the injection site, and signals were detected at multiple sentinel nodes and lymph nodes beyond them. The NIR-PNG signal intensity was relatively small at the injection site and limited to only one sentinel node with no additional node. When evaluated 1 week after injection, only the NIR-PNG signal was detected in the canine stomach, and the signal intensity at the lymph nodes of the porcine small bowel was the highest with NIR PNG, followed by ICG/PGA complex and finally ICG. CONCLUSION: NIR-PNG showed the best characteristics of less dispersion and longer retention in the sentinel nodes, and ICG/PGA complex remained longer than diluted ICG. These tracers could potentially be used as optimal tracers for sentinel node navigation surgery in gastric cancer. PMID- 24481857 TI - Maintenance of luminal pH and protease activity in lysosomes/late endosomes by vacuolar ATPase in chlorpromazine-treated RAW264 cells accumulating phospholipids. AB - Cationic amphiphilic drugs (CADs) inhibit phospholipases competitively/uncompetitively. It has also been reported that CADs spontaneously accumulate in acidic organelles and increase their luminal pH, which may lead to deactivation of phospholipid-metabolising enzymes, causing cellular phospholipid accumulation. Recently, however, contradictory results have also been reported in that the luminal pH is not increased by CAD treatment. In this study, we examined whether the lysosomal/late endosomal acidic pH was maintained by vacuolar ATPase (v-ATPase) after treatment with chlorpromazine (CPZ) as a model CAD. The activity of lysosomal protease after CPZ treatment was also measured. Oregon Green-dextran tetramethylrhodamine conjugate was employed to determine the luminal pH of the lysosomes/late endosomes in RAW264 cells. The luminal pH remained acidic after treatment with CPZ for 23 h, and the lysosomal protease activity was not decreased by 5-min CPZ treatment. Co-treatment with CPZ and bafilomycin A1 (v ATPase inhibitor) raised the luminal pH. These results suggest that the lysosomal/late endosomal pH is not affected by a 23-h CPZ treatment. In addition, lysosomal enzymes presumably maintain their activity when CPZ accumulates. Our results imply that the pH homeostasis in lysosomes/late endosomes is strictly maintained even after a longer treatment with CADs. PMID- 24481858 TI - General practitioners' psychosocial resources, distress, and sickness absence: a study comparing the UK and Finland. AB - BACKGROUND: Many countries, including the UK and Finland, face difficulties in recruiting GPs and one reason for these difficulties may be due to negative psychosocial work environments. OBJECTIVE: To compare psychosocial resources (job control and participative safety), distress and sickness absences between GPs from the UK and those from Finland. We also examined differences in how psychosocial resources are associated with distress and sickness absence and how distress is associated with sickness absence for both countries. METHODS: Two independent cross-sectional surveys conducted in general practice in the UK and Finland. Analyses of covariance were used for continuous outcome variables and logistic regression for dichotomized variable (sickness absence) adjusted for gender, qualification year and response format. RESULTS: UK GPs reported more opportunities to control their work and had higher levels of participative safety but were more distressed than Finnish GPs. Finnish GPs were 2.3 (95% confidence interval = 1.8-3.1) times more likely to report sickness absence spells than UK GPs. Among Finnish GPs, job control opportunities and high participative safety were associated with lower levels of distress, but not among UK GPs. Among UK GPs, higher distress was associated with 2.1 (95% confidence interval = 1.3-3.6) times higher likelihood of sickness absence spells, but among Finnish GPs there were no such association. CONCLUSION: In Finland, primary health care organizations should try to improve participative safety and increase control opportunities of physicians to decrease GP distress, whereas in the UK, other work or private life factors may be more important. PMID- 24481859 TI - Bladder and bowel symptoms in cervical and endometrial cancer survivors. AB - BACKGROUND: Previous studies likely underestimate the prevalence of bowel and bladder symptoms in gynecologic cancer survivors. We sought to estimate the prevalence of these symptoms in cervical and endometrial cancer survivors who had completed treatment 1 year previously compared with non-cancer controls, and to examine factors associated with more severe symptoms in survivors. METHODS: As part of a larger quality of life study, survivors who were 1-year posttreatment for cervical or endometrial cancer (n = 104) completed measures of bladder and bowel symptoms. An age-matched and race/ethnicity-matched sample of women with no history of cancer was recruited for comparison purposes. RESULTS: Survivors reported a higher prevalence of bladder symptoms, specifically storage and incontinence symptoms, than non-cancer controls. Prevalence rates for bowel symptoms in survivors were higher than those reported in previous studies. Greater symptom severity was associated with younger age, lower annual incomes, and less education. Other correlates included higher body mass index and history of smoking. As hypothesized, more severe symptoms were associated with radical hysterectomy and pelvic radiation. CONCLUSIONS: Bladder and bowel symptoms are more prevalent in cervical and endometrial cancer survivors than non-cancer controls. Future research should replicate these findings in a larger, prospective study. PMID- 24481860 TI - Response of sphagnum peatland testate amoebae to a 1-year transplantation experiment along an artificial hydrological gradient. AB - Peatland testate amoebae (TA) are well-established bioindicators for depth to water table (DWT), but effects of hydrological changes on TA communities have never been tested experimentally. We tested this in a field experiment by placing Sphagnum carpets (15 cm diameter) collected in hummock, lawn and pool microsites (origin) at three local conditions (dry, moist and wet) using trenches dug in a peatland. One series of samples was seeded with microorganism extract from all microsites. TA community were analysed at T0: 8-2008, T1: 5-2009 and T2: 8-2009. We analysed the data using conditional inference trees, principal response curves (PRC) and DWT inferred from TA communities using a transfer function used for paleoecological reconstruction. Density declined from T0 to T1 and then increased sharply by T2. Species richness, Simpson diversity and Simpson evenness were lower at T2 than at T0 and T1. Seeded communities had higher species richness in pool samples at T0. Pool samples tended to have higher density, lower species richness, Simpson diversity and Simpson Evenness than hummock and/or lawn samples until T1. In the PRC, the effect of origin was significant at T0 and T1, but the effect faded away by T2. Seeding effect was strongest at T1 and lowest vanished by T2. Local condition effect was strong but not in line with the wetness gradient at T1 but started to reflect it by T2. Likewise, TA-inferred DWT started to match the experimental conditions by T2, but more so in hummock and lawn samples than in pool samples. This study confirmed that TA responds to hydrological changes over a 1-year period. However, sensitivity of TA to hydrological fluctuations, and thus the accuracy of inferred DWT changes, was habitat specific, pool TA communities being least responsive to environmental changes. Lawns and hummocks may be thus better suited than pools for paleoecological reconstructions. This, however, contrasts with the higher prediction error and species' tolerance for DWT with increasing dryness observed in transfer function models. PMID- 24481861 TI - Elaidic acid increases hepatic lipogenesis by mediating sterol regulatory element binding protein-1c activity in HuH-7 cells. AB - The liver is the major organ responsible for lipid biosynthesis. Sterol regulatory element-binding proteins (SREBP) are major transcription factors that regulate the expression of genes regulating fatty acid and cholesterol biosynthesis. Here we show that elaidic acid upregulates hepatic de-novo fatty acid and cholesterol synthesis in HuH-7 cells. To define the molecular mechanism involved in this unique regulation on hepatic lipogenesis, luciferase reporter gene assays were performed in HEK293 cells to compare the regulation of sterol regulatory element (SRE) that is present in SREBP-target promoter by elaidic acid and oleic acid. The results show that elaidic acid potently induced SRE luciferase activity, whereas oleic acid inhibited this activity. Furthermore, elaidic acid increased SREBP-1c mRNA, while oleic acid did not alter it. Oleic acid inhibited mature form of SREBP-1 protein level, while elaidic acid did not show inhibitory effects. In addition, elaidic acid was also found to increase several selected lipogenic genes that are involved in fatty acids and sterol synthesis. These data demonstrate a unique role of elaidic acid, the most abundant trans fatty acid, in modulating hepatic lipogenesis. PMID- 24481862 TI - Assessing peer advisor intervention fidelity using video skits in a peer support implementation trial. AB - In community-based interventions involving lay health workers, or "community health workers," peer-client interactions are not typically observed by investigators, creating challenges in assessing intervention fidelity. In the context of a community-based randomized controlled trial of the effectiveness of peer support on diabetes outcomes of people with diabetes in rural Alabama, a region characterized by poverty and low literacy, we developed a video assessment tool that assessed participant perceptions of peer-client interactions. The video assessment consisted of four short skits on areas of emphasis during peer training: directive versus nondirective counseling style and setting a specific versus a more general goal. The video tool was evaluated for association with questionnaire-derived measures of counseling style and goal setting among 102 participants. For counseling style, 44% of participants reported that their peer advisor was most similar to the nondirective skit. For goal setting, 42% reported that their peer advisor was most similar to the specific goal skit. There was no statistically significant relationship between skit selection and questionnaire derived measures. The video assessment was feasible, but results suggest that video and questionnaire assessments in this population yield different results. Further validation to better understand the differences between questionnaire reports and video assessment is warranted. PMID- 24481863 TI - A role of junction-mediated interactions in cells of the male reproductive tract: impact of prenatal, neonatal, and prepubertal exposure to anti-androgens on adult reproduction. AB - Male sexual development and male reproductive functions are dependent on the normal action of androgens, and an unbalanced ratio of the active androgens can lead to varying degrees of structural and functional abnormalities within the reproductive organs. Endocrine balance can be disturbed by environmental and pharmaceutical anti-androgens (i.e. vinclozolin, phthalates, procymidone, and flutamide) that antagonize normal androgen action. Such chemical compounds enter the cell, bind to the receptor and inactivate transcription leading to disruption of androgen-mediated signaling. Assembling and functioning of cell junctions in hormone-dependent tissues, such as testis, epididymis and prostate appeared to be controlled by steroid hormones, predominantly by androgens. This review presents recent findings on the tight junction proteins mainly responsible for normal functioning of the barrier within the testis, epididymis and prostate, anchoring junction proteins that play a crucial role in normal cell-cell adhesion, and gap junction proteins through which intercellular communication takes place in the male reproductive tract. The review gives examples of animal models that are used in endocrine disruption studies with a focus on the author's own data from studies in the pig. PMID- 24481865 TI - Liver transplantation for hepatocellular carcinoma with allografts from donors after circulatory death: is the tumor recurrence genuinely increased? PMID- 24481866 TI - Plasma tumor necrosis factor-alpha and C-reactive protein as biomarker for survival in head and neck squamous cell carcinoma. AB - PURPOSE: Tumor TNM staging is the main basis for prognosis and treatment decision for head and neck squamous cell carcinoma (HNSCC) despite significant heterogeneity in terms of outcome among patients with the same clinical stage. In this study, a possible role of plasma interleukin-2 (IL-2), interleukin-6 (IL-6), granulocyte-macrophage colony-stimulating factor (GM-CSF), tumor necrosis factor alpha (TNF-alpha) and C-reactive protein (CRP) as biomarkers for survival of HNSCC patients was investigated. METHODS: In this prospective study, plasma levels of IL-2, IL-6, GM-CSF, TNF-alpha and CRP in patients (n = 100) and controls (n = 48) were analyzed. RESULTS: Significantly elevated levels of CRP and TNF-alpha (p < 0.001) were found in the patients. Combination of upregulated CRP and TNF-alpha in the patient plasma was significantly related to shorter patient survival, independent of clinical stage. CONCLUSIONS: Our findings indicate that CRP and TNF-alpha might be suitable as biomarkers in combination with tumor TNM staging for predicting survival and individualized treatment of HNSCC patients. Plasma CRP and TNF-alpha analysis are simple, rapid, cost effective and suitable for clinical practice. PMID- 24481867 TI - Type D personality is unrelated to major adverse cardiovascular events in patients with coronary artery disease treated by intracoronary stenting. AB - BACKGROUND: Previous research in cardiac patients suggested that type D personality, defined as a combination of negative affectivity (NA) and social inhibition (SI), was associated with adverse outcome. PURPOSE: The objective of this prospective study was to examine the independent prognostic value of type D in patients with coronary artery disease (CAD). METHODS: A total of 465 patients completed the Type D Scale (DS14) questionnaire before undergoing stent implantation and were followed up for 5 years. RESULTS: In a Cox regression model adjusted for selected confounders, we found a trend towards NA for the prediction of nonfatal major adverse cardiovascular event (MACE, hazard ratio (HR) = 1.07, 95 % confidence intervals (CIs) = 0.99-1.14, p = 0.074), while, in contrast, SI was a significant and independent predictor of better outcome (HR = 0.92, 95 % CI = 0.86-0.99, p = 0.027). CONCLUSIONS: In a cohort of CAD patients, the type D pattern was not linked to adverse outcome, whereas SI was negatively associated with MACE. PMID- 24481868 TI - Cyclophosphamide-induced alterations of the micturition reflex in a novel in situ urinary bladder model in the anesthetized rat. AB - AIMS: Cyclophosphamide-induced cystitis alterations have been reported to occur both at efferent and afferent level in the micturition reflex arc. In particular, the stretching of the bladder wall causing urothelial release of ATP has been proposed as one of the pivotal mechanisms causing these alterations. To evaluate functional changes at efferent and afferent levels of the micturition reflex following cyclophosphamide treatment we have applied a novel in situ half bladder rat model. METHODS: Male Sprague-Dawley rats were treated with either saline or cyclophosphamide (100 mg/kg), and stretch-, electric-, methacholine-, and ATP induced responses were thereafter measured at 60-72 hr postinjection under pentobarbitone anesthesia. In the novel in situ half bladder model, the urinary bladder was prepared via a midline incision, where the two halves were separated all the way to the urethra as previously described. RESULTS: Following bladder stretch of 30-80 mN, of the half that was not used for tension measurement, the cyclophosphamide-treated animals evoked significant two- to threefold larger contractile responses as compared to saline-treated control animals. A sensitization of the afferent arm was shown in cyclophosphamide-treated animals, since afferent stimulation evoked similar responses as in control animals despite that the efferent pelvic nerve stimulation displayed a lower contraction frequency relationship in cyclophosphamide-treated animals. Atropine reduced the stretch(reflex)-evoked contraction by up to 50% in control and 75-80% in cyclophosphamide-treated rats. Subsequent addition of PPADS further reduced the contractions. CONCLUSION: The micturition reflex response is increased following cyclophosphamide-induced cystitis, as compared to control. The likely cause is sensitization at mechanosensor level in the micturition arc, which overrides the decrement of the efferent cholinergic effects. PMID- 24481869 TI - 3D-transistor array based on horizontally suspended silicon nano-bridges grown via a bottom-up technique. AB - Integrated surround-gate field-effect-transistors enabled by bottom-up synthesis of nano-bridges are demonstrated. Horizontally oriented silicon nano-bridge devices are fabricated avoiding the rigorous processes for aligning and contacting nanowires grown via a bottom-up technique. Evaluation of electrical properties and a memory device application of the transistors are presented. PMID- 24481864 TI - Role of p75 neurotrophin receptor in stem cell biology: more than just a marker. AB - p75(NTR), the common receptor for both neurotrophins and proneurotrophins, has been widely studied because of its role in many tissues, including the nervous system. More recently, a close relationship between p75(NTR) expression and pluripotency has been described. p75(NTR) was shown to be expressed in various types of stem cells and has been used to prospectively isolate stem cells with different degrees of potency. Here, we give an overview of the current knowledge on p75(NTR) in stem cells, ranging from embryonic to adult stem cells, and cancer stem cells. In an attempt to address its potential role in the control of stem cell biology, the molecular mechanisms underlying p75(NTR) signaling in different models are also highlighted. p75(NTR)-mediated functions include survival, apoptosis, migration, and differentiation, and depend on cell type, (pro)neurotrophin binding, interacting transmembrane co-receptors expression, intracellular adaptor molecule availability, and post-translational modifications, such as regulated proteolytic processing. It is therefore conceivable that p75(NTR) can modulate cell-fate decisions through its highly ramified signaling pathways. Thus, elucidating the potential implications of p75(NTR) activity as well as the underlying molecular mechanisms of p75(NTR) will shed new light on the biology of both normal and cancer stem cells. PMID- 24481871 TI - Structure-based approach to improve a small-molecule inhibitor by the use of a competitive peptide ligand. AB - Structural information about the target-compound complex is invaluable in the early stage of drug discovery. In particular, it is important to know into which part of the initial compound additional interaction sites could be introduced to improve its affinity. Herein, we demonstrate that the affinity of a small molecule inhibitor for its target protein could be successfully improved by the constructive introduction of the interaction mode of a competitive peptide. The strategy involved the discrimination of overlapping and non-overlapping peptide compound pharmacophores by the use of a ligand-based NMR spectroscopic approach, INPHARMA. The obtained results enabled the design of a new compound with improved affinity for the platelet receptor glycoprotein VI (GPVI). The approach proposed herein efficiently combines the advantages of compounds and peptides for the development of higher-affinity druglike ligands. PMID- 24481870 TI - Implications of genome-wide association studies in novel therapeutics in primary biliary cirrhosis. AB - Genome-wide association studies (GWAS) have revolutionized the search for genetic influences on complex disorders, such as primary biliary cirrhosis (PBC). Recent GWAS have identified many disease-associated genetic variants. These, overall, highlighted the remarkable contribution of key immunological pathways in PBC that may be involved in the initial mechanisms of loss of tolerance and the subsequent inflammatory response and chronic bile duct damage. Results from GWAS have the potential to be translated in biological knowledge and, hopefully, clinical application. There are a number of immune pathways highlighted in GWAS that may have therapeutic implications in PBC and in other autoimmune diseases, such as the anti-interleukin-12/interleukin-23, nuclear factor-kb, tumor necrosis factor, phosphatidylinositol signaling and hedgehog signaling pathways. Further areas in which GWAS findings are leading to clinical applications either in PBC or in other autoimmune conditions, include disease classification, risk prediction and drug development. In this review we outline the possible next steps that may help accelerate progress from genetic studies to the biological knowledge that would guide the development of predictive, preventive, or therapeutic measures in PBC. PMID- 24481873 TI - Parkinson's disease and pseudo-ventricular tachycardia. PMID- 24481872 TI - Cell therapy for type 1 diabetes. AB - Cell therapy in the form of human islet transplantation has been a successful form of treatment for patients with type 1 diabetes for over 10 years, but is significantly limited by lack of suitable donor material. A replenishable supply of insulin-producing cells has the potential to address this problem; however to date success has been limited to a few preclinical studies. Two of the most promising strategies include differentiation of embryonic stem cells and induced pluripotent stem cells towards insulin-producing cells and transdifferentiation of acinar or other closely related cell types towards beta-cells. Here, we discuss recent progress and challenges that need to be overcome in taking cell therapy to the clinic. PMID- 24481874 TI - Rationale and design of LAPLACE-2: a phase 3, randomized, double-blind, placebo- and ezetimibe-controlled trial evaluating the efficacy and safety of evolocumab in subjects with hypercholesterolemia on background statin therapy. AB - Low-density lipoprotein cholesterol (LDL-C) levels are significantly associated with atherosclerotic cardiovascular disease (ASCVD) risk, and studies using interventions that lower LDL-C levels have been shown to reduce the risk of ASCVD events and mortality. Statin treatment is the current first-line therapy for lowering LDL-C and reducing ASCVD risk. However, many patients are still unable to reach recommended LDL-C goals on maximally tolerated statin therapy. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9, including evolocumab (previously AMG 145), dramatically lowered LDL-C in phase 2 clinical trials when administered alone or in combination with a statin. The aim of this phase 3 study is to evaluate the efficacy of 12 weeks of subcutaneous evolocumab (vs placebo) administered every 2 weeks or every month in combination with a statin in patients with hypercholesterolemia and mixed dyslipidemia. This study will also provide comparative efficacy, safety, and tolerability data between evolocumab and ezetimibe when added to background atorvastatin therapy. PMID- 24481875 TI - Taraxacum mongolicum extract exhibits a protective effect on hepatocytes and an antiviral effect against hepatitis B virus in animal and human cells. AB - In order to validate the antiviral effect against hepatitis B virus (HBV) of Taraxacum mongolicum (T. mongolicum), the protective effect on hepatocytes, and antiviral properties against duck hepatitis B virus (DHBV) and HBV of T. mongolicum extract (TME) were evaluated in chemically-injured neonatal rat hepatocytes, DHBV-infected duck fetal hepatocytes and HBV-transfected HepG2.2.15 cells, respectively. The results demonstrated that TME at 50-100 ug/ml improved D galactosamine (D-GalN), thioacetamide (TAA) and tert-butyl hydroperoxide (t-BHP) injured rat hepatocytes, and produced protection rates of 42.2, 34.6 and 43.8% at 100 ug/ml, respectively. Furthermore, TME at 1-100 ug/ml markedly inhibited DHBV DNA replication. Additionally, TME at 25-100 ug/ml reduced HBsAg and HBeAg levels and produced inhibition rates of 91.39 and 91.72% at 100 ug/ml, respectively. TME markedly inhibited HBV DNA replication at 25-100 ug/ml. The results demonstrate the potent antiviral effect of T. mongolicum against HBV effect. The protective of TME effect on hepatocytes may be achieved by its ability to ameliorate oxidative stress. The antiviral properties of TME may contribute to blocking protein synthesis steps and DNA replication. Furthermore, major components of TME were quantificationally analyzed. These data provide scientific evidence supporting the traditional use of TME in the treatment of hepatitis. PMID- 24481876 TI - Impact of an intensive follow-up program on the postpartum glucose tolerance testing rate. AB - OBJECTIVE: Gestational diabetes mellitus (GDM) is a strong risk factor for the development of diabetes. We assessed the impact of a 1-year intensive follow-up demonstration program, using direct nurse and outreach worker case management, aimed at increasing compliance with postpartum oral glucose tolerance testing (OGTT). STUDY DESIGN: During the year of implementation, a nurse or bilingual outreach worker contacted patients to encourage attendance at their scheduled postpartum 2-h 75-g OGTT and assisted in overcoming obstacles to testing. All patients with GDM seen in our specialty clinic the previous year served as a control group for comparison. RESULTS: One hundred eighty-one patients treated during the year prior to implementation were compared to the 207 in the demonstration program. Baseline characteristics were similar in both groups. After the program's implementation, postpartum OGTT adherence increased from 43.1 to 59.4 % (p < 0.01, hazard ratio 1.59; 95 % confidence interval 1.20-2.12). Had the program been in place the previous year, we calculated that 12 additional cases of diabetes or prediabetes would have been detected, increasing the total number from 33 to 45 such cases. CONCLUSION: Implementation of direct nurse and outreach worker case management leads to a modest, but important increase in adherence to postpartum OGTT testing. PMID- 24481877 TI - Epithelial sodium channel enhanced osteogenesis via cGMP/PKGII/ENaC signaling in rat osteoblast. AB - The amiloride-sensitive epithelial sodium channel (ENaC) is a major contributor to intracellular sodium homeostasis. In addition to epithelial cells, osteoblasts (Obs) express functional ENaCs. Moreover, a correlation between bone Na content and bone disease has been reported, suggesting that ENaC-mediated Na(+) regulation may influence osteogenesis. Obs were isolated and cultured by enzyme digestion. Cell proliferation and differentiation were evaluated by WST-8 assay kit and AKP assay kit respectively. PKGII expression was silenced by siRNA. The mRNA expression was investigated by semi-quantitative PCR and the protein expression was determined by Western-blot. The cell-permeable cGMP analog 8-(4 chlorophenylthio)-cGMP (8-pCPT-cGMP) increased alpha-ENaC channel expression in primary rat Obs as indicated by RT-PCR. In addition, 8-pCPT-cGMP stimulation enhanced expression of the mRNA encoding cGMP-dependent protein kinases II (PKGII). The cGMP analog also promoted osteoblast proliferation, differentiation and induced the expression of several osteogenic genes, including core binding factor al, osteocalcin, alkaline phosphatase, collagen type I, and osteopontin. Furthermore, the expression of alpha-ENaC, the main functional subunit of ENaC, was reduced when a small interfering RNA specific for PKGII was introduced into Obs. Treatment with 8-pCPT-cGMP in cells transfected with the siRNA for PKGII partially reversed downregulated alpha-ENaC mRNA expression. Our results suggest that 8-pCPT-cGMP stimulates proliferation, differentiation, and osteogenic gene expression in Obs through cGMP/PKGII-dependent regulation of ENaC channel expression. The cGMP/PKGII signaling pathway is a potential target for pharmaceutical interventions to treat metabolic bone diseases. PMID- 24481878 TI - Inhibition of microRNA miR-92a induces apoptosis and inhibits cell proliferation in human acute promyelocytic leukemia through modulation of p63 expression. AB - MicroRNAs (miRNAs) are endogenous non-coding RNAs, 19-25 nucleotides in length involved in post-transcriptional regulation of gene expression of great majority of the human protein coding genes. Different aspects of cellular activities like cell growth, proliferation, and differentiation are regulated by miRNAs through their interaction with particular RNA species. In many tumors up or down regulation of different miRNAs has been reported. Human miR-17-92 gene cluster is located on 13q31.3, rooming several miRNAs including miR-17-5p, miR-17-3p, miR 18, miR-19a, miR-20a and miR-92a. Amplification or overexpression of this cluster has been reported in acute myeloid leukemia, acute lymphoblastic leukemia and several other cancer types. Here, we performed inhibition of miR-92a in an acute promyelocytic leukemia (APL) cell line (HL-60) using locked nucleic acid (LNA) antagomir. In different time points after LNA-anti-miR92a transfection, MTT assay and annexin/propidium iodide staining were performed. These assessments indicate that miR-92a inhibition can extensively decrease the viability of these cells which is mainly due to induction of apoptosis. Western blot analysis of p63 protein also revealed that miR-92a inhibition resulted in p63 expression, hence activation of cellular pathways which are normally controlled by p63 protein are retrieved. These findings could open up a path to the miRNAs based therapeutic approach for treatment of APL. PMID- 24481879 TI - Association of ESR1 and C6orf97 gene polymorphism with osteoporosis in postmenopausal women. AB - The estrogen receptor 1 (ESR1) and Chromosome 6 Open Reading Frame 97 (C6orf97) gene polymorphisms were earlier reported to be associated with osteoporosis in the European cohort. The aim of this study was to investigate the association of four single nucleotide polymorphisms (SNP) with bone mineral density (BMD), fracture, vertebral fracture, bone turnover or 25-hydroxyvitamin D [25(OH)D] in 1,753 randomly selected postmenopausal women in China. Vertebral fracture, BMD of lumbar spine (2-4), femoral neck and total hip were measured respectively. Serum N-terminal procollagen of type 1 collagen (P1NP), beta-isomerized type I collagen C-telopeptide breakdown products (beta-CTX) and 25(OH)D3 were also determined. Binary logistic regression revealed significant associations between fracture risk with rs1999805 (P=0.041, OR 1.633, 95%CI 1.020-2.616) and rs6929137 (P=0.005, OR 1.932, 95%CI 1.226-3.045) in recessive model. Significant association was also observed between vertebral fracture risk and rs1038304 (P=0.039, OR 0.549, 95%CI 0.311-0.969) in recessive model. Liner regression analyses showed that only the CC group of rs4870044 was significantly associated with total hip in dominant model (P=0.034). Our findings suggest that ESR1 and C6orf97 gene polymorphism is associated with fracture and vertebral fracture risk in Chinese postmenopausal women. PMID- 24481880 TI - Study on the interaction of a copper(II) complex containing the artificial sweetener aspartame with human serum albumin. AB - A copper(II) complex containing aspartame (APM) as ligand, Cu(APM)2Cl2.2H2O, was synthesized and characterized. In vitro binding interaction of this complex with human serum albumin (HSA) was studied at physiological pH. Binding studies of this complex with HSA are useful for understanding the Cu(APM)2Cl2.2H2O-HSA interaction mechanism and providing guidance for the application and design of new and more efficient artificial sweeteners drive. The interaction was investigated by spectrophotometric, spectrofluorometric, competition experiment and circular dichroism. Hyperchromicity observed in UV absorption band of Cu(APM)2Cl2.2H2O. A strong fluorescence quenching reaction of HSA to Cu(APM)2Cl2.2H2O was observed and the binding constant (Kf) and corresponding numbers of binding sites (n) were calculated at different temperatures. Thermodynamic parameters, enthalpy change (?H) and entropy change (?S) were calculated to be -458.67 kJ mol(-1) and -1,339 J mol(-1 )K(-1) respectively. According to the van't Hoff equation, the reaction is predominantly enthalpically driven. In conformity with experimental results, we suggest that Cu(APM)2Cl2.2H2O interacts with HSA. In comparison with previous study, it is found that the Cu(II) complex binds stronger than aspartame. PMID- 24481881 TI - Perfectionism in pediatric anxiety and depressive disorders. AB - Although perfectionism has been identified as a factor in many psychiatric disorders across the life span, it is relatively understudied in pediatric anxiety and depressive disorders. Furthermore, there exists little cohesion among previous research, restricting the conclusions that can be made across studies. In this review, research associating perfectionism with pediatric anxiety and depression is examined and a framework is presented synthesizing research to date. We focus on detailing the current understanding of how perfectionism develops and interacts with other developmental features characteristic of anxiety and depression in children and potential pathways that result in anxiety and depressive disorders. This includes: how perfectionism is measured in children, comparisons with relevant adult literature, the development of perfectionism in children and adolescents, mediators and moderators of the link between perfectionism and anxiety and depression, and the role of perfectionism in treatment and prevention of these disorders. We also present research detailing perfectionism across cultures. Findings from these studies are beginning to implicate perfectionism as an underlying process that may contribute broadly to the development of anxiety and depression in a pediatric population. Throughout the review, difficulties, limitations, and gaps in the current understanding are presented while offering suggestions for future research. PMID- 24481883 TI - Respiratory syncytial virus and seasonal influenza cause similar illnesses in children with sickle cell disease. AB - BACKGROUND: Respiratory syncytial virus (RSV) is a cause of acute chest syndrome (ACS) in sickle cell disease (SCD), but its clinical course and acute complications have not been well characterized. We compared RSV to seasonal influenza infections in children with SCD. PROCEDURE: We defined cases as laboratory-confirmed RSV or seasonal influenza infection in inpatients and outpatients <18 years of age with SCD from 1 September 1993 to 30 June 2011. We used Fisher's exact test to compare proportions, Student's t-test or Wilcoxon rank-sum test to compare continuous variables, and logistic regression to evaluate associations. RESULTS: We identified 64 children with RSV and 91 with seasonal influenza. Clinical symptoms, including fever, cough, and rhinorrhea were similar for RSV and influenza, as were complications, including ACS and treatments for SCD. In a multivariable logistic regression model, older age (OR 1.2 per year, 95% CI [1.02-1.5], P = 0.04), increased white blood cell count at presentation (OR 1.1 per 1,000/MUl increase, 95% CI [1.03-1.3], P = 0.008), and a history of asthma (OR 7, 95% [CI 1.3-37], P = 0.03) were independently associated with increased risk of ACS in children with RSV. The hospitalization rate for children with SCD and RSV (40 per 1,000 <5 years and 63 per 1,000 <2 years) greatly exceeds the general population (3 in 1,000 <5 years). CONCLUSIONS: We conclude that RSV infection is often associated with ACS and similar in severity to influenza infection in febrile children with SCD. PMID- 24481882 TI - Reducing the neural search space for hominid cognition: what distinguishes human and great ape brains from those of small apes? AB - Differences in the psychological capacities of closely related species are likely due to differences in their brains. Here, we review neuroanatomical comparisons between hominids (i.e., great apes and humans) and their closest living relatives, the hylobatids (i.e., small apes). We report the differences in quantitative, as well as qualitative, neural characteristics on the basis of 19 comparative studies that each included representatives of all hominid genera and at least one genus of hylobatid. The current data are patchy, based on a small number of hylobatids and few neuroanatomical features. Yet a systematic interspecies comparison could help reduce the neuroanatomical search space for the neural correlates underlying psychological abilities restricted to hominids. We illustrate the potential power of this approach by discussing the neural features of visual self-recognition. PMID- 24481885 TI - Restoring penis sensation in patients with low spinal cord lesions: the role of the remaining function of the dorsal nerve in a unilateral or bilateral TOMAX procedure. AB - AIMS: The recently developed TOMAX-procedure restores unilateral genital sensation, improving sexual health in men with a low spinal lesion (LSL). It connects one dorsal nerve of the penis (DNP) to the intact ipsilateral ilioinguinal nerve. We proposed bilateral neurotization for full sensation of the glans but this entails cutting both DNPs, risking patients' erection/ejaculation ability. The objective was to select patients for a bilateral TOMAX-procedure by measuring remaining DNP function, and perform the first bilateral cases. METHODS: In 30 LSL patients with no penile- but normal groin sensation selected for a unilateral TOMAX-procedure the integrity of the sacral-reflex-arc and DNP function was tested pre-operatively using bilateral needle electromyography (EMG) bulbocavernosus reflex (BCR) measurements, and an interview about reflex erections (RE) ability. RESULTS: In 13 spina bifida- and 17 spinal cord injury patients [median age 29.5 years (range 13-59 years), spinal lesion T12 (incomplete) to sacral], seven (23%) patients reported RE, four (57%) with intact BCR, and of nine (30%) patients with intact BCR, four reported RE (44%). CONCLUSIONS: Even patients with a LSL and no penile sensation can have signs of remaining DNP function, but cutting both DNPs to restore full glans sensation in a bilateral TOMAX-procedure might interfere with their RE/ejaculation. To avoid this risk, we propose a selecting-protocol for a unilateral- or bilateral procedure using RE and BCR measurements. Using this protocol, three patients were bilaterally operated with promising preliminary results. Full sensation of the glans could lead to further improvement in sexual function. PMID- 24481884 TI - Social support, self-efficacy for decision-making, and follow-up care use in long term cancer survivors. AB - OBJECTIVE: Cancer survivors play an important role in coordinating their follow up care and making treatment-related decisions. Little is known about how modifiable factors such as social support are associated with active participation in follow-up care. This study tests associations between social support, cancer-related follow-up care use, and self-efficacy for participation in decision-making related to follow-up care (SEDM). We also identified sociodemographic and clinical factors associated with social support among long term survivors. METHODS: The FOllow-up Care Use among Survivors study is a cross sectional, population-based survey of breast, prostate, colon, and gynecologic cancer survivors (n=1522) 4-14 years post-diagnosis. Multivariable regression models were used to test associations between perceived social support (tangible and emotional/informational support modeled separately), follow-up care use (past 2 years), and SEDM, as well as to identify factors associated with perceived support. RESULTS: Neither support type was associated with follow-up care use (all p>0.05), although marital status was uniquely, positively associated with follow-up care use (p<0.05). Both tangible support (B for a standard deviation increase (SE)=9.75(3.15), p<0.05) and emotional/informational support (B(SE)=12.61(3.05), p<0.001) were modestly associated with SEDM. Being married, having adequate financial resources, history of recurrence, and better perceived health status were associated with higher perceived tangible and emotional support (all p<0.05). CONCLUSIONS: While perceived social support may facilitate survivor efficacy for participation in decision-making during cancer follow-up care, other factors, including marital satisfaction, appear to influence follow up care use. Marital status and social support may be important factors to consider in survivorship care planning. PMID- 24481887 TI - Community health facility preparedness for a cholera surge in Haiti. AB - With increasing population displacement and worsening water insecurity after the 2010 earthquake, Haiti experienced a large cholera outbreak. Our goal was to evaluate the strengths and weaknesses of seven community health facilities' ability to respond to a surge in cholera cases. Since 2010, Catholic Relief Services (CRS) with a number of public and private donors has been working with seven health facilities in an effort to reduce morbidity and mortality from cholera infection. In November 2012, CRS through the Centers for Disease Control and Prevention (CDC)'s support, asked the Johns Hopkins Center for Refugee and Disaster Response to conduct a cholera surge simulation tabletop exercise at these health facilities to improve each facility's response in the event of a cholera surge. Using simulation development guidelines from the Pan American Health Organization and others, a simulation scenario script was produced that included situations of differing severity, supply chain, as well as a surge of patients. A total of 119 hospital staff from seven sites participated in the simulation exercise including community health workers, clinicians, managers, pharmacists, cleaners, and security guards. Clinics that had challenges during the simulated clinical care of patients were those that did not appropriately treat all cholera patients according to protocol, particularly those that were vulnerable, those that would need additional staff to properly treat patients during a surge of cholera, and those that required a better inventory of supplies. Simulation-based activities have the potential to identify healthcare delivery system vulnerabilities that are amenable to intervention prior to a cholera surge. PMID- 24481886 TI - Trauma-Focused Early Intensive Cognitive Behavioral Intervention (TF-EICBI) in children and adolescent survivors of suicide bombing attacks (SBAs). A preliminary study. AB - OBJECTIVES: To describe and evaluate the impact of an early intervention (Trauma Focused Early Intensive Cognitive Behavioral Intervention, TF-EICBI) in children and adolescents who were victims of suicide bombing attacks (SBAs) in Israel. DESIGN: Description of an intervention and preliminary experience in its use. SETTING: An acute trauma center of a Child and Adolescent Psychiatric Unit in a Department of Psychiatry of a university-affiliated medical center. PARTICIPANTS: Ten children and adolescents who were victims of SBAs and underwent early interventions (EIG) were compared to 11 adolescent victims who received no intervention (NEIG). The EIG included all the children and adolescent survivors of various SBAs that had occurred during 1 year who presented to our hospital after the TF-EICBI was implemented (June 2001). The NEIG comprised all adolescents girls <18 years of age at follow-up who survived one SBA (at the "Dolphinarium" Discotheque) before the TF-EICBI was available. MAIN OUTCOME MEASURES: At the time of the 1-year post-SBA follow-up, all 21 subjects were assessed by the Structured Clinical Interview for Axis 1 DSMIII R Disorders (SCID), and the Child Behavior Checklist (CBCL). RESULTS: One (10 percent) EI subject and four (36.4 percent) NEI subjects had post-traumatic stress disorder. The mean CBCL total score and most of the mean CBCL behavior problem scores were significantly higher (p < 0.021) among the NEI group members. CONCLUSIONS: Intervention was effective in preventing and lowering mental morbidity of children and adolescents after SBAs. PMID- 24481888 TI - Ethical dilemmas related to predictions and warnings of impending natural disaster. AB - Scientists and policy makers issuing predictions and warnings of impending natural disaster are faced with two major challenges, that is, failure to warn and issuing a false alarm. The consequences of failure to warn can be serious for society overall, for example, significant economic losses, heavy infrastructure and environmental damage, large number of human casualties, and social disruption. Failure to warn can also have serious for specific individuals, for example, legal proceedings against disaster research scientists, as in the L'Aquila earthquake affair. The consequences of false alarms may be less serious. Nevertheless, false alarms may violate the principle of nonmaleficence (do no harm), affect individual autonomy (eg, mandatory evacuations), and may result in the "cry wolf" effect. Other ethical issues associated with natural disasters include the promotion of global justice through international predisaster technical assistance and postdisaster aid. Social justice within a particular country is promoted through greater postdisaster aid allocation to the less privileged. PMID- 24481889 TI - Lessons learned from a landslide catastrophe in Rio de Janeiro, Brazil. AB - INTRODUCTION: On January, 2011, a devastating tropical storm hit the mountain area of Rio de Janeiro State in Brazil, resulting in flooding and mudslides and leaving 30,000 individuals displaced. OBJECTIVE: This article explores key lessons learned from this major mass casualty event, highlighting prehospital and hospital organization for receiving multiple victims in a short period of time, which may be applicable in similar future events worldwide. METHODS: A retrospective review of local hospital medical/fire department records and data from the Health and Security Department of the State were analyzed. Medical examiner archives were analyzed to determine the causes of death. RESULTS: The most common injuries were to the extremities, the majority requiring only wound cleaning, debridement, and suture. Orthopedic surgeries were the most common operative procedures. In the first 3 days, 191 victims underwent triage at the hospital with 50 requiring admission to the hospital. Two hundred fifty patients were triaged at the hospital by the end of the fifth day. The mortis cause for the majority of deaths was asphyxia, either by drowning or mud burial. CONCLUSION: Natural disasters are able to generate a large number of victims and overwhelm the main channels of relief available. Main lessons learned are as follows: 1) prevention and training are key points, 2) key measures by the authorities should be taken as early as possible, and 3) the centralization of the deceased in one location demonstrated greater effectiveness identifying victims and releasing the bodies back to families. PMID- 24481890 TI - Syrian revolution: a field hospital under attack. AB - BACKGROUND: Syrian revolution that began on March 15, 2011 represents not only a political crisis but also a humanitarian one where many relief attempts for saving civil injured were tried. METHODS: A secret field hospital organized by the medical Arab union was set in Al-Bab town in the district of Aleppo. Egyptian volunteer physicians were the operating team who reached Syria through the Turkish border. Medical supplies were delivered from Turkey and medical equipment were taken from the government hospital which was not running at that time. Many Syrian volunteers helped in running this field hospital most of them were non medical personnel who were trained to help in some medical purposes. RESULTS: Total number of cases referred to the hospital was 75. Surgical intervention was needed for 28 patients. Most common procedures needed were vascular procedures (32 percent), orthopedic procedures (32 percent), and abdominal exploration (25 percent). Median injury severity score (ISS) for admitted patients were 21 with interquartile range (14-21). Two patients died intraoperatively due to massive bleeding. CONCLUSION: Setting up a field hospital in such an area with unsafe conditions needs good communication with medical and relief organizations in the site of crisis, selection of a location as near as possible to the Turkish border, developing a convenient triaging plan, and training nonmedical volunteers to do simple tasks. PMID- 24481891 TI - First responder and physician liability during an emergency. AB - First responders, especially emergency medical technicians and paramedics, along with physicians, will be expected to render care during a mass casualty event. It is highly likely that these medical first responders and physicians will be rendering care in suboptimal conditions due to the mass casualty event. Furthermore, these individuals are expected to shift their focus from individually based care to community- or population-based care when assisting disaster response. As a result, patients may feel they have not received adequate care and may seek to hold the medical first responder or physician liable, even if they did everything they could given the emergency circumstances. Therefore, it is important to protect medical first responders and physicians rendering care during a mass casualty event so that their efforts are not unnecessarily impeded by concerns about civil liability. In this article, the author looks at the standard of care for medical first responders and physicians and describes the current framework of laws limiting liability for these persons during an emergency. The author concludes that the standard of care and current laws fail to offer adequate liability protection for medical first responders and physicians, especially those in the private sector, and recommends that states adopt clear laws offering liability protection for all medical first responders and physicians who render assistance during a mass casualty event. PMID- 24481892 TI - Mainland China nurses' willingness to report to work in a disaster. AB - A cross-sectional study among a convenience sample of nurses in China was conducted to understand the factors affecting Chinese nurses' willingness to report to work in a disaster. A total of 946 questionnaires were collected. Nearly 90 percent of nurses regarded disaster self-help information, an evacuation plan, and contingency measures a must in preparing for disaster care. Many nurses indicated willingness to work during a disaster that may threaten the safety of their family members than when there is a life-threatening infectious disease outbreak (83.6 and 69.6 percent, p = 0.000). Nurses with longer years of clinical experience were more willing to work in both situations (p = 0.014 and 0.000). Fear of contracting an infectious disease and spreading it to family members was a major factor for nurses' unwillingness to report to work. Hospital administrators should understand their workforce's willingness in reporting to work and provide appropriate disaster training and support to maximize workforce in a disaster. PMID- 24481893 TI - Effectiveness of three just-in-time training modalities for N-95 mask fit testing. AB - OBJECTIVE: To compare and contrast three different training modalities for fit testing N-95 respirator face masks. DESIGN: Block randomized interventional study. SETTING: Urban university. PARTICIPANTS: Two hundred eighty-nine medical students. INTERVENTIONS: Students were randomly assigned to video, lecture, or slide show to evaluate the effectiveness of the methods for fit testing large groups of people. MAIN OUTCOME MEASURES: Ease of fit and success of fit for each instructional technique. RESULTS: Mask 1 was a Kimberly-Clark duckbill N-95 respirator mask, and mask 2 was a 3MTM carpenters N-95 respirator mask. "Ease of fit" was defined as the ability to successfully don a mask in less than 30 seconds. "Success of fit" was defined as the ability to correctly don a mask in one try. There were no statistical differences by training modality for either mask regarding ease of fit or success of fit. CONCLUSION: There were no differences among video presentation, small group demonstration, and self directed slide show just-in-time training modalities for ease of fit or success of fit N-95 respirator mask fitting. Further study is needed to explore more effective fit training modalities. PMID- 24481894 TI - A community outreach influenza vaccination drive as a model for mass disaster prophylaxis. AB - In October 2012, more than 120 student and faculty volunteers from six different health professional schools (medical, pharmacy, and nursing) vaccinated 430 individuals against influenza at five point of distribution sites in Winnebago County, IL, at no cost to the recipients. In total, 18 organizations, including faith-based and nonprofit groups, organized this vaccination drive, targeting an at-risk population of homeless and impoverished individuals. Preclinical students were provided just-in-time training in vaccine administration and Incident Command System methodology. This community-wide collaborative effort uniquely demonstrates the effectiveness of student volunteerism in emergency preparedness, as well as providing a model for mass prophylaxis in a disaster scenario. PMID- 24481896 TI - Solid-phase incorporation of an ATRP initiator for polymer-DNA biohybrids. AB - The combination of polymers with nucleic acids leads to materials with significantly advanced properties. To obviate the necessity and complexity of conjugating two macromolecules, a polymer initiator is described that can be directly covalently linked to DNA during solid-phase synthesis. Polymer can then be grown from the DNA bound initiator, both in solution after the DNA-initiator is released from the solid support as well as directly on the solid support, simplifying purification. The resulting polymer-DNA hybrids were examined by chromatography and fluorescence methods that attested to the integrity of hybrids and the DNA. The ability to use DNA-based supports expands the range of readily available molecules that can be used with the initiator, as exemplified by direct synthesis of a biotin polymer hybrid on solid-support. This method expands the accessibility and range of advanced polymer biohybrid materials. PMID- 24481897 TI - Gate control of percolative conduction in strongly correlated manganite films. AB - Gate control of percolative conduction in a phase-separated manganite system is demonstrated in a field-effect transistor geometry, resulting in ambipolar switching from a metallic state to an insulating state. PMID- 24481898 TI - Biological re-description of a genetically typed, single oocyst line of the turkey coccidium, Eimeria meleagrimitis Tyzzer 1929. AB - For the purpose of re-describing the Eimeria species that infect the turkey (Meleagris gallopavo) and to establish benchmark biological information linked to genetic markers for each species, a strain of Eimeria meleagrimitis Tyzzer 1929 was obtained from a litter sample from a turkey farm in Minnesota, USA in 2008. Multiple pure lines were derived by infecting turkey poults with a single oocyst; one of these lines was then used to re-describe biological and morphological features of E. meleagrimitis in the turkey and to designate a neotype of E. meleagrimitis in the turkey. Oocyst morphometrics of this line matched those of this species as originally described by Tyzzer (Am J Hyg 10:269-383, 1929). Three asexual generations of merogony (the first generation of meronts large in size and the second and third generations small) were detected in the intestines before the onset of gametogony; no developmental stages were detected in the cecal pouches. No mortality was induced by this line of E. meleagrimitis even when turkey poults were infected with high doses of oocysts (up to 5 * 10(5) oocysts/bird) and despite the ability of E. meleagrimitis to induce severe mucosal damage in the upper and middle duodenum. Macroscopic lesions were characterized to provide a graded lesion scoring guide that should assist assessment of the severity of infections with this species in infected turkeys. The pathogenicity of the strain was investigated, and a significant reduction in weight gain and feed conversion ratio was observed with doses of 10(4) oocysts/bird or more. The maximum yield of oocysts in the feces was obtained when birds were inoculated with 5 * 10(3) oocysts. PMID- 24481899 TI - Spatial-temporal variation of parasites in Cnemidophorus ocellifer (Teiidae) and Tropidurus hispidus and Tropidurus semitaeniatus (Tropiduridae) from Caatinga areas in northeastern Brazil. AB - Parasites are natural regulators of their host populations. Despite this, little is known about variations in parasite composition (spatially or temporally) in environments subjected to water-related periodic stress such as the arid and semiarid regions. The objective of this study was to evaluate the spatial temporal variation in endoparasite species' abundance and richness in populations of Neotropical Cnemidophorus ocellifer, Tropidurus hispidus, and Tropidurus semitaeniatus lizards in the semiarid northeast of Brazil. The location influenced the abundance of parasites in all analyzed lizard species, while season (dry and rainy) only influenced the total abundance for T. hispidus. In all seasons, males significantly showed more endoparasites than females in all lizard species, although for T. hispidus, this difference was only found in the dry season. Seasonal variations affect the abundance patterns of parasites. Likely, variables include environmental variations such as humidity and temperature, which influence the development of endoparasite eggs when outside of the host. Further, the activity of the intermediate hosts and the parasites of heteroxenous life cycles could be affected by an environmental condition. The variation in the abundance of parasites between the sampling areas could be a reflection of variations in climate and physiochemical conditions. Also, it could be due to differences in the quality of the environment in which each host population lives. PMID- 24481900 TI - The field efficacy of garlic extract against Dermanyssus gallinae in layer farms of Babol, Iran. AB - Dermanyssus gallinae (Acari: Mesostigmata) is the most important hematophagous ectoparasite in layer farms in many countries. The reproduction rate of the parasite is rapid and can be completed in a week under favorable conditions. The parasite has direct and indirect effects on birds. It can also act as a vector for some important pathogens. Many researchers have investigated the effects of essential oils, plant extracts, oriental medicinal plant extracts, and silica against red mite. They can be used as killing agents or repellents. In the present study, the effect of garlic (Allium sativum) extract was investigated for controlling red mite infestation in a layer farm in Babol, North of Iran. Our results showed that the extract was effective and we obtained a 96% success after two successive sprays. PMID- 24481901 TI - Trematode reproduction in the molluscan host: an ultrastructural study of the germinal mass in the rediae of Himasthla elongata (Mehlis, 1831) (Digenea: Echinostomatidae). AB - The germinal mass in Himasthla elongata rediae was studied in detail using transmission electron microscopy. It was shown to be a specialized reproductive organ consisting of germinal cells at various maturation stages, supporting cells and stem cells. The germinal mass also contains early cercarial embryos emerging as a result of cleavage division of mature germinal cells. The stem cells that give rise to germinal cells have heterochromatin-rich nuclei with distinct nucleoli and scarce cytoplasm containing mainly free ribosomes and few mitochondria. The differentiating germinal cells undergo a growth, which is accompanied by an emergence of annulate lamellae and the nuage in their cytoplasm, a noticeable development of RER and Golgi apparatus and an increase in the number of mitochondria. The mitochondria form a large group at one of the cell poles. During differentiation, the nucleus and nucleolus of the germinal cell enlarge while the chromatin becomes gradually less condensed. The supporting tissue of the germinal mass is made up of cells connected by septate junctions. These supporting cells are distinctly different in cellular shape and nuclear ultrastructure. Their outgrowths form a tight meshwork housing stem cells, germinal cells and early cercarial embryos. The cytoplasm of the supporting cells in the mesh area is separated into fine parallel layers by labyrinthine narrow cavities communicating with the intercellular space. The supporting tissue contains differentiating and degenerating cells which indicates its renewal. The results of this ultrastructural study lend support to the hypothesis that the germinal cells of digeneans are germ line cells. PMID- 24481902 TI - Effect of dinitolmide intercalated into Montmorillonite on E. tenella infection in chickens. AB - To enhance the anti-coccidial effect of dinitolmide and reduce its residual, the dinitolmide/MMT compounds were synthesized by the method of solution intercalation via dinitolmide intercalated into Na + -montmorillonite (Na + MMT). The structure of compounds was characterized by X-ray diffraction and Fourier transformed infrared. Its anti-coccidial effect was examined by Eimeria tenella infection experiment. One hundred fifty AA broiler chickens were divided into five groups. Chickens were orally inoculated with 5 * 10(4) E. tenella oocysts after dinitolmide was given. Their curative effects were observed. The results showed that intercalated dinitolmide expanded the basal spacing (d 001) of MMT from 12.6 to 15.2 A. The IR bands of amide group in dinitolmide/MMT were detected at 1,533 cm(-1) which showed that dinitolmide was successfully intercalated into the interlayer spaces of MMT. The dinitolmide/MMT showed higher anti-coccidian oocyst activity compared with dinitolmide (p < 0.05). The dinitolmide/MMT compound can significantly increase body weight gains and reduce bloody diarrhea, lesion score, and oocyst excretion. The anti-coccidia index of dinitolmide/MMT group (165.21) is much higher than dinitolmide group (88.84). The dinitolmide/MMT hybrid systems can be more effective in control of coccidiosis in comparison to dinitolmide. PMID- 24481903 TI - Comparison of dynamic expressions of Tim-3 and PD-1 in the brains between toxoplasmic encephalitis-resistant BALB/c and -susceptible C57BL/6 mice. AB - T cells and IFN-gamma are essential for controlling the reactivation of toxoplasmic encephalitis (TE), regardless of whether mice are susceptible or resistant to TE. It has been demonstrated that CD8(+) T cells exhausted in chronic Toxoplasma gondii infection result in TE reactivation in C57BL/6 mice. However, this phenomenon had not been reported in genetically TE-resistant BALB/c mice. To explore the immune mechanism of TE in different backgrounds of mice, the dynamic expressions of Tim-3, programmed cell death 1 (PD-1), and their ligands (galectin-9, PD-L1, PD-L2) in brain tissues were compared between TE-resistant BALB/c and -susceptible C57BL/6 mice infected with Prugniaud (Pru, a type II strain) of T. gondii in this study. Compared with infected BALB/c mice, there were remarkable pathological changes with significantly higher histological scores in the brains of C57BL/6 mice at 14, 35, 50, and 70 days postinfection (p.i., P < 0.01); significantly increased mRNA expressions of Tim-3 at 35 (P < 0.05) and 70 (P < 0.01) days p.i.; and significantly increased PD-1 at all the times p.i. (P < 0.01) in the brains of infected C57BL/6 mice. Furthermore, there were significantly increased mRNA expressions of PD-L1 in the brain of C57BL/6 mice than that in BALB/c mice at all the times p.i. (P < 0.01). Although the mRNA expressions of galectin-9 (ligand of Tim-3) were increased in the brains of both lineages of mice at all the times p.i., it showed no differences between the two lineages of mice. Our data suggest that the differences of Tim-3 and PD-1/PD-L1 expressions may contribute to the different immune responses between TE-resistant BALB/c and -susceptible C57BL/6 mice infected with Pru strain of T. gondii. PMID- 24481904 TI - Invasive species and their parasites: eastern cottontail rabbit Sylvilagus floridanus and Trichostrongylus affinis (Graybill, 1924) from Northwestern Italy. AB - The eastern cottontail Sylvilagus floridanus is a native American lagomorph. Within the genus Sylvilagus, the eastern cottontail is the species with the widest distribution. From 1950s, the species was introduced to several European countries. A rapid territorial expansion of the introduced eastern cottontails has been observed in many areas of Italy. The eastern cottontail has been demonstrated to play a main role as carrier of exotic parasites. To date, three nematode species, exotic in Italian ecosystems, have been reported from introduced S. floridanus. However, its parasite fauna biodiversity is richer in native populations of the American continent. The aim of this work was to further investigate the gastrointestinal parasites of S. floridanus, to evaluate the potential presence of other exotic species. During 2010, 101 hosts were examined, and three nematodes were collected from their digestive tract. Two parasite species (Obeliscoides cuniculi, Trichostrongylus calcaratus) were already reported in Italy; the isolation of Trichostrongylus affinis is instead the first report of this nematode in Italy and in Europe as a whole. This study wants to highlight the great risks related to the introduction of allochthonous species. The impact of the invasion by alien animal species may be particularly severe for public and animal health, due to the potential introduction of new pathogens. The good number of exotic parasites found in introduced eastern cottontails, together with the few sanitary surveys carried out, suggests that an epidemiological survey, with specimens from multiple localities on a wider geographic range, could lead to interesting findings on parasites of native and alien lagomorphs in Europe. PMID- 24481905 TI - Partial reverse of the TCA cycle is enhanced in Taenia crassiceps experimental neurocysticercosis after in vivo treatment with anthelminthic drugs. AB - Neurocysticercosis (NCC) is the most common helminthic infection and neglected disease of the central nervous system. It is the leading cause of acquired epilepsy and seizures worldwide. Therefore, to study this important neglected disease, it is important to use experimental models. There is no report in the literature on how the parasite's metabolism reacts to antihelminthic treatment when it is still within the central nervous system of the host. Therefore, the aim of this study was to investigate the energetic metabolism of cysticerci experimentally inoculated in the encephala of BALB/c mice after treatment with low dosages (not sufficient to kill the parasite) of albendazole (ABDZ) and praziquantel (PZQ). BALB/c mice were intracranially inoculated with Taenia crassiceps cysticerci and, after 30 days, received treatment with low dosages of ABDZ and PZQ. After 24 h of treatment, the mice were euthanized, and the cysticerci were removed and analyzed through high-performance liquid chromatography (HPLC) to quantify the organic acids related to the energetic metabolism of the parasite. The partial reverse of the TCA cycle was enhanced by the ABDZ and PZQ treatments both with the higher dosage, as the organic acids of this pathway were significantly increased when compared to the control group and to the other dosages. In conclusion, it was possible to detect the increase of this pathway in the parasites that were exposed to low dosages of ABDZ and PZQ, as it is a mechanism that would amplify the energy production in a hostile environment. PMID- 24481906 TI - Cross-resistance, genetics, and realized heritability of resistance to fipronil in the house fly, Musca domestica (Diptera: Muscidae): a potential vector for disease transmission. AB - Houseflies, Musca domestica (L.), are ubiquitous pests that have the potential to spread a variety of pathogens to humans, poultries, and dairies. Pesticides are commonly used for the management of this pest. Fipronil is a GABA-gated chloride channel-inhibiting insecticide that has been commonly used for the management of different pests including M. domestica throughout the world. Many pests have developed resistance to this insecticide. A field-collected strain of M. domestica was selected with fipronil for continuous 11 generations to assess the cross-resistance, genetics, and realized heritability for designing a resistance management strategy. Laboratory bioassays were performed using the feeding method of mixing insecticide concentrations with 20% sugar solutions and cotton soaks dipped in insecticide solutions were provided to tested adult flies. Bioassay results at G12 showed that the fipronil-selected strain developed a resistance ratio of 140-fold compared to the susceptible strain. Synergism bioassay with piperonyl butoxide (PBO) and S,S,S,-tributyl phosphorotrithioate (DEF) indicated that fipronil resistance was associated with microsomal oxidase and also esterase. Reciprocal crosses between resistant and susceptible strains showed an autosomal and incompletely dominant resistance to fipronil. The LC50 values of F1 and F'1 strains were not significantly different and dominance values were 0.74 and 0.64, respectively. The resistance to fipronil was completely recessive (D(ML) = 0.00) at the highest dose and incompletely dominant at the lowest dose (D(ML) = 0.87). The monogenic resistance based on chi-square goodness of fit test and calculation of the minimum number of segregating genes showed that resistance to fipronil is controlled by multiple genes. The fipronil resistance strain confirmed very low cross-resistance to emamectin benzoate and spinosad while no cross-resistance to chlorpyrifos and acetamiprid when compared to that of the field population. The heritability values were 0.112, 0.075, 0.084, 0.008, and 0.052 for fipronil, emamectin benzoate, spinosad, acetamiprid, and chlorpyrifos, respectively. It was concluded that fipronil resistance in M. domestica was autosomally inherited, incompletely dominant, and polygenic. These findings would be helpful for the better and successful management of M. domestica. PMID- 24481907 TI - Two novel myxosporean species (Myxosporea: Bivalvulida), Myxobolus marumotoi n. sp. and Cardimyxobolus japonensis n. sp., from the dark sleeper, Odontobutis obscura, in Japan. AB - Two new myxosporean species, Myxobolus marumotoi n. sp. and Cardimyxobolus japonensis n. sp. (Myxozoa: Myxosporea: Bivalvulida), are described from the dark sleeper, Odontobutis obscura, in Japan, based on their morphological and molecular characterizations. Plasmodia of M. marumotoi n. sp. (Myxobolidae) grew in the myofiber of trunk muscles, forming pseudocysts. The rounded spore was relatively large, measuring 13.3-15.0 MUm (average 13.8) in length, 14.2-15.0 MUm (14.6) in width, and 10.0-11.7 MUm (10.8) in thickness, with two subspherical polar capsules of 7.9-9.6 MUm (8.4) in length by 5.4-6.3 MUm (5.9) in width (n = 15). The polar capsules were directed toward the apex of the spore, packing five to six spirals of the polar filament. Plasmodia of C. japonensis n. sp. (Ortholineidae) were surrounded by thin fibrous tissue, forming cysts in the lamina propria of the alimentary tract. The spore was ovoid, wider than long, in valvular view and spindle-shaped in sutural view. It measured 8.8-10.4 MUm (9.4) in length, 11.3-12.5 MUm (11.9) in width, and 5.2-6.7 MUm (5.8) in thickness, with two ovoid polar capsules of 4.2-5.0 MUm (4.7) in length by 2.9-3.8 MUm (3.3) in width (n = 15). The shell valves of spores often showed a flattened anterior border and semicircular posterior border, and the two polar capsules were directed toward opposite lateral sides. In addition, the sporoplasm contained an iodinophilous vacuole. Almost complete small-subunit (SSU) rDNA sequences, except for primer flanking regions, were obtained for both species; 1,996 bp long for the former and 1,588 bp long for the latter. On phylogenetic trees based on the SSU rDNA sequences of representative species of Bivalvulida, M. marumotoi n. sp. and C. japonensis n. sp. formed a distinct branch in the Henneguya/Myxobolus clade or near but outside this clade, respectively. This study is the first report of the genetic characterization for the genus Cardimyxobolus. PMID- 24481909 TI - A diffuse intrinsic pontine glioma roadmap: guiding research toward a cure. PMID- 24481908 TI - In vitro development of Haemoproteus parasites: the efficiency of reproductive cells increase during simultaneous sexual process of different lineages. AB - Recent in vitro experimental studies reported the complex patterns of haemosporidian (Haemosporida) between-lineage interactions, which prevent mixing of lineages during simultaneous sexual process. Numerous anomalous ookinetes have been observed; these are not involved in sporogony. Massive development of such ookinetes might influence parasite transmission but is insufficiently investigated. The simultaneous sexual process of several lineages is a common phenomenon in vectors due to high prevalence of haemosporidian co-infections in wildlife. It remains unclear if the number of anomalous ookinetes changes during dual-infection sporogony in comparison with the single-infection process. We calculated proportions of the anomalous and normal ookinetes, which developed during single-infection (control) and dual-infection experiments in vitro conditions. Three mitochondrial cytochrome b lineages belonging to three Haemoproteus spp. (Haemosporida, Haemoproteidae) were isolated from naturally infected passerine birds. Sexual process and ookinete development were initiated in vitro by mixing blood containing mature gametocytes of two different parasites; the following experiments were performed: (1) Haemoproteus tartakovskyi (lineage hSISKIN1) * Haemoproteus lanii (lineage hRBS4) and (2) Haemoproteus belopolskyi (hHIICT3) * H. lanii (hRBS4). Genetic difference between lineages was 5.0-5.9%. Normal and anomalous ookinetes developed in all control and dual-infection experiments. The number of anomalous ookinetes markedly decreased, and normal ookinetes increased in all dual-infection experiments in comparison with those in controls, except for H. belopolskyi, in which proportion of the anomalous and normal ookinetes did not change. This study shows that simultaneous sexual process of two genetically distant lineages of haemosporidian parasites might increase the efficiency of reproductive cells, resulting in the development of a greater number of normal ookinetes. The marked increase of the number of normal ookinetes, which is involved in sporogony, indicates the success of sporogony in dual infections. Some haemosporidian lineages might benefit from simultaneous sporogony. Widespread avian Haemoproteus spp. are convenient and laboratory-friendly organisms for in vitro experimental research addressing between-lineage interaction in parasites during the sexual process. PMID- 24481910 TI - Clinical features, use of evidence-based therapies, and cardiovascular outcomes among patients with chronic kidney disease following non-ST-elevation acute coronary syndrome. AB - BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of cardiovascular events following acute coronary syndrome (ACS). The underlying pathobiology and optimal treatments for this population continue to be evaluated. HYPOTHESIS: Patients with CKD will receive fewer evidence-based therapies and experience high rates of adverse cardiovascular events in both the short- and long term. METHODS: The MERLIN-TIMI 36 (Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes-Thrombolysis in Myocardial Infarction 36) trial randomized non-ST-elevation ACS patients to ranolazine or placebo, with no exclusion for renal dysfunction (except dialysis). We conducted a prespecified analysis among 6543 patients based on the degree of CKD. RESULTS: Patients with worse renal function were older with more comorbidities (P < 0.0001 for each). They were less likely to receive evidence based cardiovascular medicines (P < 0.04 for each). Rates of an early invasive management strategy varied based on renal function; however, among patients with the highest TIMI risk scores, the rates of an early invasive management strategy were similar regardless of glomerular filtration rate (GFR) (Pinteraction = 0.005). Lower GFR was associated with increased rates of cardiovascular disease or myocardial infarction in the short and long term, even after adjustment (GFR <30 vs >=90 mL/min/1.73 m(2) ; hazard ratio [HR]: 3.24 [95% confidence interval {CI}: 1.26-8.38] through 7 days and HR: 2.12 [95% CI: 1.33-3.39] through 1 year). The effect of ranolazine vs placebo on clinical outcomes was similar among those with and without CKD (Pinteraction = not significant). CONCLUSIONS: Following ACS, patients with renal dysfunction had more cardiovascular risk factors but were less likely to receive evidence-based medical therapies. A strong graded, independent relationship between the degree of CKD and poor clinical outcomes was observed over time. Continued efforts to optimize ACS treatment strategies in patients with CKD are warranted. PMID- 24481911 TI - Introduction: signaling in plants. AB - Jun and Fos, b-ZIP transcription factors, form a heterodimer and bind to DNA enhancer elements, thereby regulating the expression of target genes. The present study was undertaken to investigate the molecular mechanism underlying nuclear translocation of the Jun/Fos complex. For this purpose, normal rat kidney cells were microinjected with a DNA expression vector containing wild-type or mutant c- or v-jun together with c- or v-fos, followed by detection of the subcellular localization of Jun or Fos by immunofluorescence staining. The nuclear accumulation of Fos was markedly enhanced by the presence of wild-type Jun, but not by Jun mutants lacking nuclear targeting or zipper dimerization functions, implying that Jun and Fos mutually interact via their leucine zippers and translocate from the cytoplasm to the nucleus using the markedly stronger nuclear localization signal of Jun. PMID- 24481912 TI - Signal perception in plant pathogen defense. AB - Highly sensitive and specific recognition systems for microbial pathogens are essential for disease resistance in plants. Structurally diverse elicitors from various pathogens have been identified and shown to trigger plant defense mechanisms. Elicitor recognition by the plant is assumed to be mediated by receptors. Plant receptors for fungus-derived elicitors appear to reside preferentially in the plasma membrane, whereas viral and bacterial elicitors may enter the plant cell and are perceived intracellularly. Receptor activation initiates an intracellular signal transduction cascade leading to stimulation of a characteristic set of plant defense responses. Isolation of plant elicitor receptors and their encoding genes is expected to provide significant information on the molecular basis of signal perception and intracellular signal generation in plant-pathogen interactions. PMID- 24481913 TI - Ion channels in plant signaling. AB - Plant ion channel activities are rapidly modulated in response to several environmental and endogenous stimuli such as light, pathogen attack and phytohormones. Electrophysiological as well as pharmacological studies provide strong evidence that ion channels are essential for the induction of specific cellular responses, implicating their tight linkage to signal transduction cascades. Ion channels propagate signals by modulating the membrane potential or by directly affecting cellular ion composition. In addition, they may also be effectors at the end of signaling cascades, as examplified by ion channels which determine the solute content of stomatal guard cells. Plant channels are themselves subject to regulation by a variety of cellular factors, including calcium, pH and cyclic nucleotides. In addition, they appear to be regulated by (de)-phosphorylation events as well as by direct interactions with cytoskeletal and other cellular proteins. This review summarizes current knowledge on the role of ion channels in plant signaling. PMID- 24481914 TI - Calcium signaling in plants. AB - Changes in the cytosolic concentration of calcium ions ([Ca(2+)]i) play a key second messenger role in signal transduction. These changes are visualized by making use of either Ca(2+)-sensitive fluorescent dyes or the Ca(2+)-sensitive photoprotein, aequorin. Here we describe the advances made over the last 10 years or so, which have conclusively demonstrated a second messenger role for [Ca(2+)]i in a few model plant systems. Characteristic changes in [Ca(2+)]i have been seen to precede the responses of plant cells and whole plants to physiological stimuli. This has had a major impact on our understanding of cell signaling in plants. The next challenge will be to establish how the Ca(2+) signals are encrypted and decoded in order to provide specificity, and we discuss the current understanding of how this may be achieved. PMID- 24481915 TI - Hyperthermia-induced apoptosis and the inhibition of DNA laddering by zinc supplementation and withdrawal of calcium and magnesium in suspension culture of tobacco cells. AB - In the present paper we report examination of stereotypic hallmarks of apoptosis in heat-treated tobacco cells. Hyperthermia (44 degrees C, 4 h) caused apoptosis in 53.6% of cells when assayed 24 h after heat treatment. The induction of apoptosis by heat treatment was confirmed by flow cytometric assay. Cytological observations revealed condensation of the cytoplasm and nucleus, as well as nuclear collapse. DNA ladders were observed in DNA extracted from heat-treated cells, whereas DNA from control cells remained undegraded. The terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end labeling (TUNEL) assay revealed that 51.8% of the heat-treated cells (44 degrees C, 4 h) show positive reaction after a 24-h recovery. When cells were cultured in a medium supplemented with 0.4-5.0 mM ZnSO4, internucleosomal DNA fragmentation induced by heat shock was completely negated. Strikingly, when cells were cultured in Ca(2+) and/or Mg(2+) free medium for 44 h followed by heat treatment, DNA laddering was not observed. The results suggest hyperthermia-induced apoptosis and a correlation between the regulation of endonucleases and heat shock signal in apoptotic tobacco cells. PMID- 24481916 TI - Menadione-induced apoptosis and the degradation of lamin-like proteins in tobacco protoplasts. AB - Detection of stereotypic hallmarks of apoptosis during cell death induced by menadione, including DNA laddering and the formation of apoptotic bodies, is reported. Comet assay and the TdT-mediated dUTP nick end labelling (TUNEL) procedure were also performed to detect DNA fragmentation. Inhibition of DNA fragmentation by Ac-Asp-Glu-Val-Asp-aldehyde (Ac-DEVD-CHO) and phenylmethylsulfosyl (PMSF) implicated the involvement of caspase-like proteases in menadione-induced apoptosis in plants. We further studied the cleavage of lamin-like proteins during apoptosis in menadione-treated tobacco protoplasts. In animals, it has been reported that the solubilization of nuclear lamina and lamin degradation occurs during apoptotic cell death. However, little is known about the fate of lamins in apoptotic plant cells. Our study provided evidence that lamin-like proteins degraded into 35-kDa fragments in tobacco protoplasts induced by menadione, and this preceded DNA fragmentation. The results thus indicated that proteolytic cleavage of nuclear lamins was also conserved in programmed cell death in plants. PMID- 24481917 TI - Total synthesis of the monoterpenoid indole alkaloid (+/-)-aspidophylline A. AB - Aspidophylline A belongs to the akuammiline alkaloid family, the members of which possess intriguing cagelike structures and diverse biological activities. Herein we report a 15-step synthesis of this alkaloid from conveniently available starting materials. The key elements of the synthesis include an intramolecular oxidative coupling to create the tetracyclic furoindoline motif of the natural product and a [Ni(cod)2 ]-mediated cyclization to install its piperidine ring. PMID- 24481918 TI - uPA-uPAR molecular complex is involved in cell signaling during neuronal migration and neuritogenesis. AB - BACKGROUND: In the development of the central nervous system (CNS), neuronal migration and neuritogenesis are crucial processes for establishing functional neural circuits. This relies on the regulation exerted by several signaling molecules, which play important roles in axonal growth and guidance. The urokinase-type plasminogen activator (uPA)-in association with its receptor triggers extracellular matrix proteolysis and other cellular processes through the activation of intracellular signaling pathways. Even though the uPA-uPAR complex is well characterized in nonneuronal systems, little is known about its signaling role during CNS development. RESULTS: In response to uPA, neuronal migration and neuritogenesis are promoted in a dose-dependent manner. After stimulation, uPAR interacts with alpha5- and beta1-integrin subunits, which may constitute an alphabeta-heterodimer that acts as a uPA-uPAR coreceptor favoring the activation of multiple kinases. This interaction may be responsible for the uPA-promoted phosphorylation of focal adhesion kinase (FAK) and its relocation toward growth cones, triggering cytoskeletal reorganization which, in turn, induces morphological changes related to neuronal migration and neuritogenesis. CONCLUSIONS: uPA has a key role during CNS development. In association with its receptor, it orchestrates both proteolytic and nonproteolytic events that govern the proper formation of neural networks. PMID- 24481919 TI - Diagnostic accuracy of FDG-PET cancer screening in asymptomatic individuals: use of record linkage from the Osaka Cancer Registry. AB - BACKGROUND: Whole-body cancer screening with multimodalities including [(18)F] fluorodeoxyglucose positron emission tomography (FDG-PET) detects a wide range of tumors. This program has been recognized as an option for opportunistic screening, particularly in Japan. However, reports on diagnostic accuracy have been limited. We aimed to evaluate the detectability and related properties of this screening program among asymptomatic individuals in a community setting. METHODS: The study participants were 1,762 residents of Osaka Prefecture, Japan, who underwent opportunistic cancer screening at Higashitemma Clinic for the first time between November 2004 and December 2005. FDG-PET cancer screening was performed with several imaging modalities (e.g., FDG-PET, computed tomography, magnetic resonance imaging and ultrasonography) and fecal occult blood test. Screening records were linked to the Osaka cancer registry within 1 year after the screening to determine sensitivity, specificity and positive predictive values. RESULTS: After excluding 12 participants with cancer detected before the screening, 33 were identified by the cancer registry to have primary cancers. Of these, the present screening program found that 28 were positive (6 prostate, 5 lung, 5 colorectal, 5 thyroid, 3 liver and 4 others). Sensitivity, specificity and positive predictive values were 84.8 % (28/33, 95 % confidence interval 69.1 93.3), 86.8 % (1,491/1,718, 85.1-88.3) and 10.1 % (28/277, 6.4-12.9), respectively. CONCLUSIONS: FDG-PET cancer screening with multimodalities reasonably and accurately detects existing asymptomatic cancer. However, the numbers of false negatives and false positives were not insignificant. Facilities that provide the screening should inform participants of relevant information, including the limitations of this program. PMID- 24481920 TI - The CENP-O complex requirement varies among different cell types. AB - CENP-U (CENP-50) is a component of the CENP-O complex, which includes CENP-O, CENP-P, CENP-Q, CENP-R, and CENP-U and is constitutively localized at kinetochores throughout the cell cycle in vertebrates. Although CENP-U deficiency results in some mitotic defects in chicken DT40 cells, CENP-U-deficient chicken DT40 cells are viable. To examine the functional roles of CENP-U in an organism dependent context, we generated CENP-U-deficient mice. The CENP-U-deficient mice died during early embryogenesis (approximately E7.5). Thus, conditional CENP-U deficient mouse ES cells were generated to analyze CENP-U-deficient phenotypes at the cell level. When CENP-U was disrupted in the mouse ES cells, all CENP-O complex proteins disappeared from kinetochores. In contrast, other kinetochore proteins were recruited in CENP-U-deficient mouse ES cells as CENP-U-deficient DT40 cells. However, the CENP-U-deficient ES cells died after exhibiting abnormal mitotic behavior. Although CENP-U was essential for cell viability during mouse early embryogenesis, CENP-U-deficient mouse embryonic fibroblast cells were viable, similar to the DT40 cells. Thus, although both DT40 and ES cells with CENP-U deficiency have similar mitotic defects, cellular responses to mitotic defects vary among different cell types. PMID- 24481921 TI - Autologous albumin enhances the humoral immune response to capsular polysaccharide covalently coattached to bacteria-sized latex beads. AB - Abundant autologous proteins, like serum albumin, should be immunologically inert. However, individuals with no apparent predisposition to autoimmune disease can develop immune responses to autologous therapeutic proteins. Protein aggregation is a potential major trigger of these responses. Adsorption of proteins to particles provides macromolecular size and may generate structural changes in the protein, resembling aggregation. Using aldehyde/sulfate latex beads coated with murine serum albumin (MSA), we found that BALB/c mice mounted MSA-specific IgG responses that were dependent on CD4(+) T cells. IgGs were specific for MSA adsorbed to solid surfaces and noncross-reactive with human, bovine, or pig albumins. T cells induced in response to MSA augmented the primary and induced boosted secondary IgG and IgM responses specific for the T cell independent antigen, capsular polysaccharide of Streptococcus pneumoniae type 14 (PPS14), when the latter was attached to the same bead. Similar to the anti-MSA IgG response, the boosted PPS14-specific IgG secondary response was CD4(+) T-cell dependent, displayed a typical carrier effect, and was enhanced by, but did not require, Toll-like receptor stimulation. These results provide a potential mechanism for the induction of responses to autoantigens unable to induce specific T-cell responses, and provide new insights into polysaccharide-specific immunity. PMID- 24481923 TI - A supramolecular approach for the facile solubilization and separation of covalently functionalized single-walled carbon nanotubes. AB - Through a combination of an electronic-type selective diazonium-based attachment of a Hamilton receptor unit onto the carbon nanotube framework and a supramolecular recognition approach of a cyanuric acid derivative, we herein introduce a highly promising strategy for the tuning of carbon nanotube solubility and, directly related to that, a solution-based easy and straightforward separation of covalently functionalized carbon nanotube derivatives with respect to their unfunctionalized counterparts. The supramolecular complexation of the cyanuric acid derivative provides the driving force for the dramatically increased dispersibility and for the long-time stability of the individualized single-walled carbon nanotube derivatives in chloroform. The selective covalent functionalization of metallic carbon nanotubes can easily be analyzed with the aid of scanning Raman microscopy techniques. The functional derivatives have furthermore been characterized by UV/Vis-NIR and fluorescence spectroscopy as well as by mass spectrometric coupled thermogravimetric analysis. The investigation of the supramolecular complexation is based on an in-depth UV/Vis-NIR analysis and atomic force microscopy investigations. PMID- 24481922 TI - Massive accumulation of osteoclastic giant cells in rapid destructive hip disease. AB - The term rapid destructive hip disease (RDHD) designates a rare coxarthropathy characterized by a rapid destruction of the femoral head within a few weeks to several months. The etiology and pathogenesis of RDHD are not understood. The goal of this study was to define the histological and histomorphometric hallmarks of RDHD to provide a basis for a deeper understanding of the underlying mechanisms. Fifteen consecutive RDHD patients (mean age 78.9 +/- 6.4 years, 14 females) demonstrated the characteristic radiographic appearance of vanishing femoral head bone stock without signs of reactive anabolic changes. Histologic and histomorphometric analyses revealed severe bone resorption with significantly increased numbers of morphologically altered giant osteoclasts, the formation of giant cell granulomas both in bone marrow and the synovium and significantly increased osteoblast numbers and osteoid as compared to controls with primary osteoarthritis (OA). These results suggest that in RDHD, an unknown stimulus leads to a massive activation of osteoclasts and this in turn provokes a reactive increase in osteoblast activity that is too weak to counteract the rapid destruction of the hip, thus providing a rationale for a prospective systematic search for the stimuli upstream of the massively increased osteoclast activation in RDHD. PMID- 24481924 TI - Malignancy in routine tonsillectomy specimens: a systematic literature review. AB - The aim of this systematic literature review was to investigate the prevalence of unsuspected tonsillar malignancy in routine tonsillectomy specimens and to discuss whether histological examination is indicated in tonsillectomy specimens from patients without well-defined risk factors. PRISMA 2009 guidelines were considered and applied whenever possible. Articles on prevalence of unsuspected tonsillar malignancy in routine tonsillectomy specimens were selected. Unsuspected tonsillar malignancy was defined as a malignant histological diagnosis after routine tonsillectomy without the presence of the following risk factors: tonsillar asymmetry, visible lesion, tonsillar firmness, cervical adenopathy, unexpected weight loss and constitutional symptoms, history of malignancy, previous radiotherapy, or immunodeficiency. We identified 37 articles comprising 72,322 patients. A total of 11 patients (0.015 %) had unsuspected malignancy. Considering the adult population only, 12 studies including 6,434 patients were identified. Three patients (0.05 %) had unsuspected malignancy. Regarding paediatric data, 21 studies including 21,223 children were identified. Three children (0.01 %) had unsuspected malignancy. The rarity of unsuspected malignancy in clinically benign tonsils fails to provide adequate justification for routine histological examination. National guidelines or statements by ENT societies are warranted. PMID- 24481925 TI - The death of marriage? The effects of new forms of legal recognition on marriage rates in the United States. AB - Some conservative groups argue that allowing same-sex couples to marry reduces the value of marriage to opposite-sex couples. This article examines how changes in U.S. legal recognition laws occurring between 1995 and 2010 designed to include same-sex couples have altered marriage rates in the United States. Using a difference-in-differences strategy that compares how marriage rates change after legal recognition in U.S. states that alter legal recognition versus states that do not, I find no evidence that allowing same-sex couples to marry reduces the opposite-sex marriage rate. Although the opposite-sex marriage rate is unaffected by same-sex couples marrying, it decreases when domestic partnerships are available to opposite-sex couples. PMID- 24481926 TI - Farm-related trauma in the west of Ireland: an occupational hazard. AB - BACKGROUND: Farm fatalities in Ireland remain at their highest recorded levels despite the introduction and implementation of several farm safety initiatives during recent years. AIMS: The aim of this study was to examine all farm-related morbidity and mortality presenting to a general hospital in the west of Ireland. METHODS: A consecutive series of all farm-related fatal and non-fatal injuries presenting to our institution over a 7-year period (2005-2011) was compiled by examining the hospital inpatient enquiry system and mortuary records. RESULTS: One hundred and thirty patients were admitted to Mayo General Hospital with non fatal farm-related injuries during the study period. This cohort was comprised 104 males and 26 females with an average age at presentation of 46 (range 19-75) years. The most common mechanism of non-fatal injury was animal attack. The mean length of hospital stay, mean length of ICU stay and total number of bed days used were 5.2, 5.3 and 677 days, respectively. There were seven farm-related fatalities during the same study period. Four were livestock-related, two due to machinery accident and one due to fall of a heavy object. The post-mortem findings were analysed in each case. CONCLUSIONS: This analysis outlines the incidence and severity of fatal and non-fatal injuries sustained in the farming workplace and presenting to a general hospital serving a rural catchment population. Greater awareness of our results may help reduce the longterm incidence and magnitude of such injuries. PMID- 24481927 TI - Characterization of opioid overdose and response in a high-risk community corrections sample: a preliminary study. AB - Opiate overdose is an increasingly common cause of death, yet could be easily treated with available opioid antagonists. Opiate use is very common in criminal justice populations, and individuals recently released from prisons or jails are an especially vulnerable group for both overdose and death, particularly in the immediate postrelease period. Participants (N = 478) were individuals under community corrections supervision who were surveyed about their opioid use, overdose history, medical history, and demographics. Most participants were male (67.4 percent) and either African American (52.4 percent) or Caucasian (44.2 percent) with an average age of 35 years (SD = 11.1). Two hundred twenty participants (46 percent) reported lifetime use of opioids, whereas 88 (40 percent) reported experiencing an opioid-related overdose. Relative to those with no history of opioid overdose or lifetime opioid use, participants with a history of opioid overdose were more likely to be Caucasian, female, and report higher educational attainment; more likely to be willing to receive additional training about overdose; and reported double to triple the rates of witnessing an overdose or knowing someone who had died from overdose -78 percent and 69 percent, respectively. The rates of actions taken when witnessing overdose were relatively low: 59 percent had called 911, 33 percent had taken someone to a hospital with 23 percent providing no intervention, and only 4 percent having used an opioid antagonist, naloxone. These findings suggest that while opioid overdose is a significant problem in the criminal justice population, affected individuals are open to instruction in effective strategies, such as naloxone training, to prevent fatal opioid overdose. PMID- 24481928 TI - Physician management of moderate-to-severe acute pain: results from the Physicians Partnering Against Pain (P3) study. AB - OBJECTIVE: To evaluate differences among physician specialties in the management of acute pain including prescribing practices and management of opioid-related side effects. DESIGN AND PARTICIPANTS: The Physicians Partnering Against Pain (P3) survey was a nationwide study of US physicians and their patients with severe to moderate acute pain (<3 months). MAIN MEASURES: Physicians were surveyed about volume of patients with moderate-to-severe acute pain in their practice, frequency of prescribing opioid analgesics, percentage of these patients returning for a follow-up visit after treatment, reasons patients discontinue treatment, frequency of recommending or prescribing treatment for opioid-related gastrointestinal (GI) side effects, and frequency of patients taking opioid analgesics that take additional treatments to manage GI side effects. RESULTS: The 5,982 participating physicians represented primary care physicians (PCPs; 52 percent), pain specialists (25 percent), and other specialists (23 percent). PCPs and other specialists were less likely than pain specialists to prescribe opioid analgesics to patients (25.8 percent, 29.5 percent, and 44.8 percent, respectively). The vast majority of pain specialists (78 percent) also indicated that more than three quarters of their patients returned for a follow-up visit compared with only 40 percent of PCPs and 65 percent of other specialists. When ranking the reasons why they think patients discontinue opioid analgesics, pain specialists ranked unacceptable side effects higher than PCPs and other specialists. PCPs and pain specialists were more likely than other specialists to recommend or prescribe treatments to manage opioid-related side effects, such as nausea, vomiting, and constipation (38.3 percent, 38.5 percent, and 23.1 percent, respectively). CONCLUSION: The P(3) Study confirms the challenge of pain management while balancing tolerability of opioid treatments from the physician perspective. PMID- 24481929 TI - Awareness of, experience with, and attitudes toward buprenorphine among opioid users visiting a New York City syringe exchange program. AB - OBJECTIVE: To examine awareness of, experience with, and attitudes toward buprenorphine, to begin to understand why opioid users may not access buprenorphine treatment. Factors associated with attitudes toward buprenorphine were also explored. DESIGN: Cross-sectional study. SETTING: A community-based organization's syringe exchange program in mobile units at nine street-side outreach sites in New York City. PARTICIPANTS: One hundred eighty-six adult opioid users visiting a syringe exchange program. MAIN OUTCOME MEASURES: Awareness of, experiences with, and attitudes toward buprenorphine. RESULTS: Most (68.5 percent) participants were aware of buprenorphine, 27.8 percent had taken buprenorphine, and 58.6 percent knew someone who had taken buprenorphine. Of the 98 who had taken or knew someone who had taken buprenorphine, 85.7 percent endorsed positive attitudinal statements about its effectiveness, and up to 31.6 percent endorsed statements about its limited access. Participants' attitudes about the need for formal buprenorphine treatment were mixed. Current heroin users were more likely than nonusers to have heard of buprenorphine (76.0 percent vs 61.5 percent, p < 0.05), have taken buprenorphine (46.8 percent vs 9.6 percent, p < 0.01), endorse buprenorphine's effectiveness (96.3 percent vs 72.7 percent, p < 0.01), and believe that illicit and prescribed buprenorphine have similar benefits (35.2 percent vs 13.6 percent, p < 0.02) CONCLUSIONS: Most opioid users visiting a syringe exchange program had positive attitudes about buprenorphine's effectiveness, and few believed that buprenorphine was difficult to access. Attitudes about the benefits of illicit versus prescribed buprenorphine use were inconsistent. Understanding awareness of, experience with, and attitudes toward buprenorphine is important, as these factors are likely to influence opioid users' decisions about engaging in buprenorphine treatment. PMID- 24481930 TI - Comparison of 75 and 150 MUg doses of intrathecal morphine for postoperative analgesia after transurethral resection of the prostate under spinal anesthesia. AB - OBJECTIVE: The administration of single dose intrathecal (IT) morphine with local anesthetics during spinal anesthesia produces an effective postoperative analgesia. In this study, we evaluated the efficacy and safety of two different doses of IT morphine with bupivacaine for postoperative analgesia after transurethral resection of prostate (TURP). STUDY DESIGN: Prospective, randomized study. SETTING: Urology Department. PATIENTS, PARTICIPANTS: Sixty patients who were scheduled to undergo TURP with spinal anesthesia. METHODS: Patients were allocated to receive IT morphine (75 MUg) with bupivacaine heavy (group I) and IT morphine (150 MUg) with bupivacaine heavy (group II). Postoperative pain was evaluated by Visual Analogous Scale during 24 hours. The need for rescue analgesia, adverse effects and patient satisfaction were recorded. RESULTS: Groups were comparable with respect to demographic data. VAS scores were similarly low in both groups. However, the request for analgesia was significantly higher in group I (27 percent) than group II (7 percent; p = 0.04). The incidence of postoperative nausea was similarly low in both groups. No patients reported pruritis in group I where as six patients (20 percent) reported mild pruritis not necessitating treatment in group II (p = 0.036) Patients satisfaction was similarly high in both the groups. CONCLUSIONS: IT morphine 150 MUg reduced the need for rescue analgesia compared to IT morphine 75 MUg in patients undergoing TURP under spinal anesthesia. As the incidence of pruritis was low with no treatment, IT morphine 150 MUg may be a suitable dose for postoperative analgesia for patients undergoing TURP under spinal anesthesia. PMID- 24481931 TI - Opioid overuse pain syndrome (OOPS): the story of opioids, prometheus unbound. AB - Throughout history, opioids have effectively alleviated pain but not without the risk of addiction and death. Seductive and dangerous, full of promise and destruction, opioids are both revered and feared by Western culture. Their exponential use in "developed countries" is now an enormous public health problem and requires us to harness their properties with scientific rigor and adequate safeguards. The use of opioids for the treatment of chronic nonterminal pain (CNTP) has been a relatively new phenomenon which has coincided with the proclamation by the Joint Commission on Accreditation of Health Care Organization in 2000 that pain assessment be the "fifth vital sign," notwithstanding the fact that pain is a symptom and not a sign.(1) Nonetheless, this resulted in a culture of a marked increase in use of opioids for acute and chronic pain management. Consequently, there are many unintended outcomes which include opioid-induced hyperalgesia increased diversion, addiction, and death. Understandably, this has resulted in many regulatory responses from such agencies such as the Drug Enforcement Administration (DEA) and state medical boards. This article proposes a clinically relevant paradigm of opioid overuse pain syndrome. The goal of this article is to inform the clinicians of the complicated neurobiology of opioids. It is our hope that scientists rather than government regulators dictate the appropriate response to the epidemic of over prescription of opioids. A similar designation of "medication overuse headache" has resulted in near extinction of excessive use of opioids in the field of headache medicine. PMID- 24481932 TI - Clinical applications of oxymorphone. AB - Oxymorphone (14-hydroxydihydromorphinone), a pyridine ring unsubstituted pyridomorphinan, a semisynthetic opioid analgesic derived from thebaine, first developed in the year 1914 and has been available as oxymorphone hydrochloride parenteral forms in the United States since 1959, when the US Food and Drug Administration approved it. Over the years, it has been used for the alleviation of moderate-to-severe pain. Pharmacological considerations, new and traditional formulations, clinical indications, and recent study populations are examined in this review. Specific considerations for oxymorphone interactions are focused on as well as specific side effects and end organ considerations. Although discovered many decades ago and used as parenteral formulation, the newer oral preparations of oxymorphone (immediate release and extended release) that were approved in 2006 can provide additional options for customizing therapy to accommodate various patient needs. This newer oral formulation could make this powerful agent an important drug in the armamentarium of the healthcare provider caring for patients with pain. PMID- 24481933 TI - Sequence comparison and phylogenetic analysis of hepatitis C virus genotype 3 polymerase. AB - Hepatitis C virus (HCV) is a worldwide health problem with high morbidity and mortality. HCV polymerase is an attractive target for the development of antiviral strategies. The aim of the present study was to report the sequence variation in the HCV NS5B gene from genotype 3 patient samples. The gene was amplified, cloned and sequenced. A nucleotide and amino acid sequence comparison of conserved motifs of HCV NS5B from the current reported sequences and previously reported genotype 3 sequences was performed. The sequence comparison indicated that the motifs A, B, C and F and beta loop sequences are conserved in the reported sequences, while sequence variation was observed in motifs D and E. Amino acids E18, Y191, C274, Y276 and H502, which are involved in the interaction between template and primer, are highly conserved in the reported sequences. R48, R158, D225, S367, R386 and R394 amino acids interact with initiating GTP, and are also highly conserved in the reported sequences. A phylogenetic tree revealed that the sequences are clustered with sequences from India. HCV polymerase lacks proofreading ability and has high error rates. The present study revealed that the residues that form the important motifs of HCV NS5B remain conserved. However, it was observed that numerous place changes in the nucleotide sequences did not affect the amino acid sequences of HCV NS5B. The conserved motifs are strong targets for the development of peptide vaccines against HCV. PMID- 24481934 TI - Oppositional Defiant Disorder Is Better Conceptualized as a Disorder of Emotional Regulation. AB - OBJECTIVE: It has been reported that Oppositional Defiant Disorder (ODD) can be differentiated into distinct subtypes associated with different outcomes in adulthood. We examined whether ODD is conceptually independent and coherent, and whether ODD and Conduct Disorder (CD) are expressions of the same core deficit. METHOD: The data come from a sample of 4,380 children for whom SNAP rating scales were available. Parallel analysis was performed on the eight-item ODD diagnostic items and on the SNAP-90 scale. These were factor analyzed and the components were correlated. RESULTS: ODD has one underlying factor, whereas the parent-rated SNAP has nine underlying factors. ODD items grouped together with emotional lability and irritability items, which did not group with CD. Confirmatory factor analysis supported the separation of ODD and CD but not ODD and emotion dysregulation. CONCLUSION: The expanded ODD factor more likely captures a disorder of emotion regulation, rather than a disruptive behavior disorder. PMID- 24481935 TI - Clinical and genomic evaluation of 201 patients with Phelan-McDermid syndrome. AB - This study is the first to describe age-related changes in a large cohort of patients with Phelan-McDermid syndrome (PMS), also known as 22q13 deletion syndrome. Over a follow-up period of up to 12 years, physical examinations and structured interviews were conducted for 201 individuals diagnosed with PMS, 120 patients had a focused, high-resolution 22q12q13 array CGH, and 92 patients' deletions were assessed for parent-of-origin. 22q13 genomic anomalies include terminal deletions of 22q13 (89 %), terminal deletions and interstitial duplications (9 %), and interstitial deletions (2 %). Considering different age groups, in older patients, behavioral problems tended to subside, developmental abilities improved, and some features such as large or fleshy hands, full or puffy eyelids, hypotonia, lax ligaments, and hyperextensible joints were less frequent. However, the proportion reporting an autism spectrum disorder, seizures, and cellulitis, or presenting with lymphedema or abnormal reflexes increased with age. Some neurologic and dysmorphic features such as speech and developmental delay and macrocephaly correlated with deletion size. Deletion sizes in more recently diagnosed patients tend to be smaller than those diagnosed a decade earlier. Seventy-three percent of de novo deletions were of paternal origin. Seizures were reported three times more often among patients with a de novo deletion of the maternal rather than paternal chromosome 22. This analysis improves the understanding of the clinical presentation and natural history of PMS and can serve as a reference for the prevalence of clinical features in the syndrome. PMID- 24481936 TI - Quality and safety in pediatric hematology/oncology. AB - Many principles of quality of care and patient safety are at the foundation of pediatric hematology/oncology. However, we still see too many errors, continue to have problems with communication, and the culture in many of our areas is still one of worrying about retribution when mentioning a problem. This review explores why specialists in pediatric hematology/oncology should be leaders in the field of quality and safety in healthcare. PMID- 24481937 TI - Successful transcatheter aortic valve implantation in a Hodgkin lymphoma patient with severe aortic stenosis. AB - Transcatheter aortic valve implantation (TAVI) has emerged as an acceptable treatment modality for patients with severe aortic stenosis (AS) who are deemed unsuitable for conventional surgical aortic valve replacement. TAVI not only provides the treatment of AS, but also makes some other diseases treatable by relieving hemodynamic distress resulting from AS. In this case report, we presented a 74-year-old patient with Hodgkin's lymphoma (HL) that had been left untreated due to the development of acute pulmonary edema caused by severe degenerative AS during chemotherapy. This is the first report of the use of TAVI in a patient with HL. PMID- 24481938 TI - An indeterminate result of QuantiFERON-TB Gold In-Tube for miliary tuberculosis due to a high level of IFN-gamma production. AB - The QuantiFERON-TB Gold In-Tube((r)) test has excellent specificity for Mycobacterium tuberculosis. However, diagnosis of miliary tuberculosis remains challenging, and the interpretation of QuantiFERON((r)) results in immunocompromised individuals has not been fully established. Here, we present a patient with military tuberculosis who showed an indeterminate QuantiFERON((r)) result. A 76-year-old male presented with fever and pancytopenia. Radiological tests did not show the classical miliary pattern. Acid-fast staining and polymerase chain reaction of several specimens were negative for M. tuberculosis. The QuantiFERON((r)) responses were indeterminate on two separate tests, as interferon-gamma (IFN-gamma) concentration was high in the negative control. The patient did not respond to anti-microbiological therapy, and developed sepsis and disseminated intravascular coagulation, leading to lethal intracranial hemorrhage. An autopsy showed miliary tuberculosis and aplastic anemia. A literature review suggests a tendency towards indeterminate or false-negative QuantiFERON((r)) results in immunocompromised individuals or patients with miliary tuberculosis due to low production of IFN-gamma. Our patient, however, showed substantial amounts of IFN-gamma despite lymphocytopenia, which has not been reported in the literature. The present case suggests that indeterminate results of QuantiFERON((r)) should be interpreted with caution, as IFN-gamma production in patients with miliary tuberculosis can vary significantly, even with sustained lymphocytopenia. PMID- 24481939 TI - Chimerism status is correlated to acute graft-versus-host disease after allogeneic stem cell transplantation. AB - To evaluate the correlation between chimerism status and acute graft-versus-host disease (aGVHD) following allogeneic hematopoietic stem cell transplantation. Chimerism of peripheral blood of 124 patients was monitored at regular intervals post-transplant. The chimerism of 124 post-transplant cases of CD3(+)T lymphocytes, 107 cases of CD3(-)CD56(+)CD16(+)NK lymphocytes, 49 cases of CD15(+) granulocytes, and 27 cases of CD19(+)B lymphocytes sorted by fluorescence activated cell sorter were analyzed by polymerase chain reaction amplification of short tandem repeats. Differences were found in the time between establishment of full donor T-cell chimerism and the occurrence of aGVHD (P = 0.035, two related samples test). Patients with >=69 % donor chimerism on day +7 in T-cells had higher rates of aGVHD. This study may provide a rational basis for treatment with adoptive immunotherapy at an earlier time, such as day 7 after SCT, than at present to prevent aGVHD. PMID- 24481940 TI - Clinical significance of anti-endothelial cell antibody in allogeneic hematopoietic stem cell transplantation recipients with graft-versus-host disease. AB - Anti-endothelial cell antibody (AECA) is well known to reflect endothelial injury. Graft-versus-host disease (GVHD), a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT), is also closely associated with endothelial injury. We hypothesized that AECA may be associated with GVHD. To investigate the clinical significance of AECA in allo-HSCT recipients with GVHD, we detected AECA by cyto-enzyme-linked immunosorbent assay (cyto-ELISA) in allo-HSCT recipients with acute and/or chronic GVHD (aGVHD and cGVHD). Incidences of anti-HMEC-1 AECA (anti-HMEC) and anti-EA.hy926 AECA (anti-EAHY) were significantly higher in patients with grade II-IV than grade 0-I aGVHD (P = 0.049, P = 0.011, respectively). There was no difference in the incidence of AECA between patients with and without cGVHD. Patients with anti-EAHY positive in the early stage post-transplant demonstrated a higher incidence of cGVHD (P = 0.044). In patients with grade 0-I aGVHD, AECA-positive patients had higher overall survival and disease-free survival (P < 0.05), and tended to have lower incidences of relapse and transplant-related mortality. Our data suggest that AECA plays an important role in the pathogenesis of GVHD. PMID- 24481941 TI - Microenvironment of adult T-cell leukemia/lymphoma-associated nodal lesions. AB - Adult T-cell leukemia/lymphoma (ATLL) is a human malignancy associated with the retrovirus, human T-cell leukemia virus type I (HTLV-I). In a previous series of studies, our group and others characterized the histopathological changes in HTLV I-associated lymph node lesions. In addition to the pleomorphic and anaplastic large cell types of typical ATL lymphoma, we identified lymph nodes with an unusual Hodgkin's disease-like histology (Hodgkin-like ATLL) in HTLV-I-positive patients, with Hodgkin-like ATLL showing prodromal clinical features. We also reported HTLV-I-associated lymphadenitis, characterized by non-neoplastic HTLV-I associated lymph node lesions. It has become clear that the biological and clinical behavior of malignant lymphoma is not only determined by the properties of the lymphoma cells themselves, but also largely by the interaction of these cells with their nonmalignant microenvironment. In this review, we discuss the pathological variations of microenvironments, which are important for clarification of the histological features associated with HTLV-I. PMID- 24481942 TI - Peripheral T cell lymphoma in Asia. AB - Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of mature T- and NK-cell neoplasms, the incidence of which is higher in Asian countries than in Western countries. Although its etiology is mainly unknown, several risk factors (such as genetic factors, abnormal immunity, environmental factors, and infectious causes) have been proposed. PTCL are classified based on a combination of several parameters, including morphology, site of presentation, viral status, immunophenotype, and specific genetic alterations. Their classification is ongoing, with the emergence of new entities and refinement of existing entities because of the development of diagnostic markers and new genetic alterations. This review presents epidemiologic data for PTCL in Asia, together with recent progress in the pathology of PTCL compared with the WHO 2008 classification. PMID- 24481943 TI - Molecular genetics of peripheral T-cell lymphomas. AB - Peripheral T-cell lymphomas (PTCL) are rare neoplasms that in most instances respond poorly to conventional chemotherapies. Four varieties--PTCL not otherwise specified (NOS), angioimmunoblastic T-cell lymphoma (AITL), ALK+ anaplastic T cell lymphoma (ALCL), and ALK- ALCL--account for about 60 % of them. Their classification is difficult because of the wide spectrum of morphologic features and the lack of robust immunohistochemical markers. Thus, high-throughput technologies can importantly contribute to their better understanding. In particular, gene expression profiling has cleared the borders among PTCL/NOS, ALK ALCL and AITL. In fact, gene signatures have been developed even from formalin fixed paraffin-embedded tissue samples that definitely distinguish one tumor from the other(s). This has important practical implications: for instance on routine diagnostics PTCL/NOS expressing CD30 can be easily confused with ALK- ALCL, but has a much worse prognosis. Therefore, the clear-cut distinction between the two conditions is pivotal to understand the results of ongoing trials with Brentuximab Vedotin, targeting the CD30 molecule. Besides improving the diagnosis, molecular studies have provided the rationale for the usage of novel drugs in the setting of PTCLs, such as ALK inhibitors in ALK+ ALCL, anti angiogenetic drugs in AITL, and tyrosine kinase inhibitors in PTCL/NOS and ALK+ and ALK- ALCLs. PMID- 24481944 TI - Prognostic significance of flow cytometric residual disease, dysregulated neutrophils/monocytes, and hematogones in adult acute myeloid leukemia in first remission. AB - Fifty-one consecutive non-M3 acute myeloid leukemia (AML) patients who had achieved morphologic complete remission (mCR) after induction chemotherapy were enrolled in the present study. Three characteristics of bone marrow (BM) composition analyzed by flow cytometry were combined to determine the prognostic impact. A standardized panel of reagents was used to detect residual disease of aberrant myeloid progenitor cells (RD), identify neutrophils/monocytes with dysregulated immunophenotype (dysregulated neutro/mono) and quantify the appearance of CD34(+) B-progenitor-related cluster (hematogones) simultaneously in post-induction BM of adult AML patients. Patients who had detectable RD >=0.2 % exhibited significantly lower median leukemia-free survival (LFS) than those who did not (13.5 vs. 48.0 months; P = 0.042). Dysregulated neutro/mono abnormalities assessed by this flow cytometric scoring system (FCSS >=2) predicted shorter LFS (8.0 vs. 39.0 months; P = 0.008). While B-progenitor related cluster size >=5 % predicted improved outcome, with longer LFS (not reached vs. 13.5 months; P = 0.023) and better overall survival (not reached vs. 24.0 months; P = 0.027). The proposed RD/dysregulated neutro/mono/hematogones score showed a new risk groups with different LFS in the overall patients (P = 0.0006) as well as in the subgroup of intermediate cytogenetic risk (P = 0.001). The RD/dysregulated neutro/mono/hematogones score assessed by flow cytometry for adult AML in mCR may offer a rapid and practical risk assessment providing better refinement in risk-adapted management after induction chemotherapy. PMID- 24481945 TI - Assessing restoration potential of semi-natural grasslands by landscape change trajectories. AB - Species-rich semi-natural grasslands have rapidly declined and become fragmented in Northern Europe due to ceased traditional agricultural practices and animal husbandry. Restoration actions have been introduced in many places to improve the habitat conditions and increase the area to prevent any further losses of their ecological values. However, given the limited resources and long time span needed for successful restoration, it is essential to target activities on sites having a suitable initial state and where the effects of restoration are most beneficial for the habitat network. In this paper we present a conceptual framework for evaluating the restoration potential of partially overgrown and selectively managed semi-natural grasslands in a moderately transformed agricultural environment in south-western Finland. On the basis of the spatio-temporal landscape trajectory analysis, we construct potential restoration scenarios based on expected semi-natural grassland characteristics that are derived from land productivity, detected grassland continuum, and date of overgrowth. These scenarios are evaluated using landscape metrics, their feasibility is discussed and the effects of potential restoration are compared to the present extent of open semi-natural grasslands. Our results show that landscape trajectory analysis and scenario construction can be valuable tools for the restoration planning of semi-natural grasslands with limited resources. The approach should therefore be considered as an essential tool to find the most optimal restoration sites and to pre-evaluate the effects. PMID- 24481946 TI - Psychometric properties of the network relationship inventory-social provision version in Chinese youth. AB - Given the lack of psychometric research on friendship measures in non-Western countries, this study examined the psychometric properties of the Chinese version of the network relationship inventory-social provision version (NRI-SPV-C) in a sample of 200 young adolescents living in China (91 boys; M age = 13.21 years). Results from confirmatory factor analysis demonstrated that a hierarchical structure model with two second-order factors (Social Support, Negative Interactions) and nine first-order factors (Companionship, Intimacy, Instrumental Aid, Nurturance, Affection, Admiration, Reliable Alliance, Conflict, and Antagonism) was the best-fitting model. High internal consistency and high construct reliability were found for all factors. Girls reported higher levels of Social Support compared with boys, though no gender differences emerged for Negative Interactions. Social Support was positively associated with youth's friendship satisfaction (Satisfaction), whereas Negative Interactions was negatively associated with Satisfaction. Findings suggest the NRI-SPV-C may be a fruitful measure for assessing youth's friendship quality in China. PMID- 24481947 TI - Upward retraction for lymphaticovenular anastomosis in the deep fat layer. PMID- 24481948 TI - Differences in T-cell responses between Mycobacterium tuberculosis and Mycobacterium africanum-infected patients. AB - In The Gambia, Mycobacterium tuberculosis (Mtb) and Mycobacterium africanum (Maf) are major causes of tuberculosis (TB). Maf is more likely to cause TB in immune suppressed individuals, implying differences in virulence. Despite this, few studies have assessed the underlying immunity to the two pathogens in human. In this study, we analyzed T-cell responses from 19 Maf- and 29 Mtb-infected HIV negative patients before and after TB chemotherapy following overnight stimulation of whole blood with TB-specific antigens. Before treatment, percentages of early secreted antigenic target-6(ESAT-6)/culture filtrate protein 10(CFP-10) and purified protein derivative-specific single-TNF-alpha-producing CD4(+) and CD8(+) T cells were significantly higher while single-IL-2-producing T cells were significantly lower in Maf- compared with Mtb-infected patients. Purified protein derivative-specific polyfunctional CD4(+) T cells frequencies were significantly higher before than after treatment, but there was no difference between the groups at both time points. Furthermore, the proportion of CD3(+) CD11b(+) T cells was similar in both groups pretreatment, but was significantly lower with higher TNF-alpha, IL-2, and IFN-gamma production in Mtb- compared with that of Maf-infected patients posttreatment. Our data provide evidence of differences in T-cell responses to two mycobacterial strains with differing virulence, providing some insight into TB pathogenesis with different Mtb strains that could be prospectively explored as biomarkers for TB protection or susceptibility. PMID- 24481950 TI - Contribution of intimal smooth muscle cells to cholesterol accumulation and macrophage-like cells in human atherosclerosis. AB - BACKGROUND: Intimal smooth muscle cells (SMCs) contribute to the foam cell population in arterial plaque, and express lower levels of the cholesterol exporter ATP-binding cassette transporter A1 (ABCA1) in comparison with medial arterial SMCs. The relative contribution of SMCs to the total foam cell population and their expression of ABCA1 in comparison with intimal monocyte derived macrophages, however, are unknown. Although the expression of macrophage markers by SMCs following lipid loading has been described, the relevance of this phenotypic switch by SMCs in human coronary atherosclerosis has not been determined. METHODS AND RESULTS: Human coronary artery sections from hearts explanted at the time of transplantation were processed to clearly delineate intracellular and extracellular lipids and allow costaining for cell-specific markers. Costaining for oil red O and the SMC-specific marker SM alpha-actin of foam cell-rich lesions revealed that 50+/-7% (average+/-standard error of the mean, n=14 subjects) of total foam cells were SMC derived. ABCA1 expression by intimal SMCs was significantly reduced between early and advanced atherosclerotic lesions, with no loss in ABCA1 expression by myeloid lineage cells. Costaining with the macrophage marker CD68 and SM alpha-actin revealed that 40+/-6% (n=15) of CD68-positive cells originated as SMCs in advanced human coronary atherosclerosis. CONCLUSIONS: These findings suggest SMCs contain a much larger burden of the excess cholesterol in human coronary atherosclerosis than previously known, in part, because of their relative inability to release excess cholesterol via ABCA1 in comparison with myeloid lineage cells. Our results also indicate that many cells identified as monocyte-derived macrophages in human atherosclerosis are in fact SMC derived. PMID- 24481951 TI - An unusual case of posterior nutcracker syndrome. PMID- 24481949 TI - Increased pericyte coverage mediated by endothelial-derived fibroblast growth factor-2 and interleukin-6 is a source of smooth muscle-like cells in pulmonary hypertension. AB - BACKGROUND: Pericytes and their crosstalk with endothelial cells are critical for the development of a functional microvasculature and vascular remodeling. It is also known that pulmonary endothelial dysfunction is intertwined with the initiation and progression of pulmonary arterial hypertension (PAH). We hypothesized that pulmonary endothelial dysfunction, characterized by abnormal fibroblast growth factor-2 and interleukin-6 signaling, leads to abnormal microvascular pericyte coverage causing pulmonary arterial medial thickening. METHODS AND RESULTS: In human lung tissues, numbers of pericytes are substantially increased (up to 2-fold) in distal PAH pulmonary arteries compared with controls. Interestingly, human pulmonary pericytes exhibit, in vitro, an accentuated proliferative and migratory response to conditioned media from human idiopathic PAH endothelial cells compared with conditioned media from control cells. Importantly, by using an anti-fibroblast growth factor-2 neutralizing antibody, we attenuated these proliferative and migratory responses, whereas by using an anti-interleukin-6 neutralizing antibody, we decreased the migratory response without affecting the proliferative response. Furthermore, in our murine retinal angiogenesis model, both fibroblast growth factor-2 and interleukin-6 administration increased pericyte coverage. Finally, using idiopathic PAH human and NG2DsRedBAC mouse lung tissues, we demonstrated that this increased pericyte coverage contributes to pulmonary vascular remodeling as a source of smooth muscle-like cells. Furthermore, we found that transforming growth factor-beta, in contrast to fibroblast growth factor-2 and interleukin-6, promotes human pulmonary pericyte differentiation into contractile smooth muscle-like cells. CONCLUSIONS: To the best of our knowledge, this is the first report of excessive pericyte coverage in distal pulmonary arteries in human PAH. We also show that this phenomenon is directly linked with pulmonary endothelial dysfunction. PMID- 24481952 TI - Effects of Er:YAG laser on bond strength of self-etching adhesives to caries affected dentin. AB - The erbium:yttrium-aluminum-garnet (Er:YAG) laser may be effective the bond strength of adhesive systems on dentine surfaces, the chemical composition and aggressiveness of adhesive systems in clinical practice. The purpose of this study was to evaluate the effects of the Er:YAG laser system with the bonding ability of two different self-etching adhesives to caries-affected dentine in primary molars. Ninety mid-coronal flat dentine surfaces obtained from sound and caries-affected human primary dentine were treated with an Er:YAG laser or a bur. The prepared surfaces were restored with an adhesive system (Xeno V; Clearfil S3) and a compomer (Dyract Extra). The restored teeth were sectioned with a low-speed saw and 162 samples were obtained. The bond strength of the adhesive systems was tested using the micro-tensile test method. The data were statistically analyzed. A restored tooth in each group was processed for scanning electron microscopy evaluation. The values of the highest bond strength were obtained from the Clearfil S3-Er:YAG laser-sound dentine group in all groups. (24.57 +/- 7.27 MPa) (P > 0.05). The values of the lowest bond strength were obtained from the Xeno V Er:YAG laser-sound dentine group in all groups (11.01 +/- 3.89 MPa). It was determined that the Clearfil S3 increased the bond strength on the surface applied with Er:YAG laser according to the Xeno V. PMID- 24481954 TI - Did life begin in hot water? PMID- 24481953 TI - One-year outcome of patients with atrial fibrillation undergoing coronary artery stenting: an analysis of the AFCAS registry. AB - BACKGROUND: Most evidence regarding the efficacy and safety of the antithrombotic regimens for patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention with stent (PCI-S) derives from small, single-center, retrospective datasets. To obtain further data on this issue, we carried out the prospective, multicenter, observational Management of patients with Atrial Fibrillation undergoing Coronary Artery Stenting (AFCAS) registry (Clinicaltrials.gov identifier NCT00596570). HYPOTHESIS: We hypothesize that the antithrombotic treatment of AF patients undergoing PCI-S is variable and the clinical outcome may vary according to the different regimens. METHODS: Consecutive AF patients undergoing PCI-S at 17 European institutions were included and followed for 1 year. Outcome measures included: (1) major adverse cardiac/cerebrovascular events (MACCE), including all-cause death, myocardial infarction, repeat revascularization, stent thrombosis, or stroke/transient ischemic attack, and (2) bleeding, and were compared according to the antithrombotic regimen adopted. A propensity-score analysis was carried out to adjust for baseline and procedural differences. RESULTS: Out of the 975 patients enrolled, 914 were included in the final analysis. The mean CHADS2 score was 2.2 +/- 1.2, and 71% of patients had a CHADS2 score >=2. Triple therapy (TT) of vitamin K antagonist (VKA), aspirin, and clopidogrel was prescribed to 74% of patients, dual antiplatelet therapy to 18%, and VKA plus clopidogrel to 8%. At 1 year follow-up, no significant differences were found in the occurrence of MACCE and bleeding among the 3 antithrombotic regimens, even when adjusted for propensity score. CONCLUSIONS: In this large, real-world population of AF patients undergoing PCI-S, TT was the antithrombotic regimen most frequently prescribed. Although several limitations need to be acknowledged, in our study the 1-year efficacy and safety of TT, dual antiplatelet therapy, and VKA plus clopidogrel was comparable. PMID- 24481955 TI - Expressions of miR-15a and its target gene HSPA1B in the spermatozoa of patients with varicocele. AB - Hyperthermia and oxidative stresses are the two central elements contributing to varicocele-related sperm damage. Growing evidence indicates that microRNAs (miRNAs) are involved in the regulation of the heat and oxidative stress responses. In this study, we analyzed the expressions of several stress-related miRNAs in the sperm and found that the expression of miR-15a was significantly decreased in patients with varicocele compared with the control. Furthermore, miR 15a repressed the expression of HSPA1B, which is a typical stress-induced chaperone protein, through directly binding its 3'-UTR. The expressions of miR 15a and HSPA1B exhibited an inverse correlation in sperm. Our results provide a valuable insight into the varicocele-related sperm impairment and male infertility, and may help to develop potential therapeutic targets and novel biomarkers for male infertility. PMID- 24481957 TI - Monocyclometalated gold(III) monoaryl complexes--a new class of triplet phosphors with highly tunable and efficient emission properties. AB - Highly tunable and rich phosphorescent emission properties based on the stable monocyclometalated gold(III) monoaryl structural motif are reported. Monochloro complexes of the type cis-[(N^C)Au(C6 H2 (CF3)3)(Cl)] N^C=2-phenylpyridine (ppy)] (1), [N^C=benzo[h]quinoline (bzq)] (2), [N^C=2-(5-Methyl-2-thienyl)pyridine (5m thpy)] (3) were successfully prepared in modest to good yields by reacting an excess of 2, 4, 6-tris(trifluoromethyl)phenyl lithium (LiFmes) with the corresponding dichloride complexes cis-[(N^C)AuCl2]. Subsequent replacement of the chloride ligand in 1 with strong ligand field strength such as cyanide and terminal alkynes resulted in complexes of the type cis-[(ppy)Au(Fmes)(R)] R=CN (4), I (5), C=C-C6 H5 (6) and C=C-C6 H4 N(C6 H5)-p (7). Single crystal X-ray diffraction studies of all the complexes except 7 were performed to further corroborate their chemical identity. Thermogravimetric analysis (TGA) studies of the uncommon cis configured aryl alkyne complex 7 confirmed the high stability of this complex. Detailed photophysical investigations carried out in solution at room temperature, at 77 K (2-MeTHF) in rigidified media, solid state and 5 wt % PMMA revealed the phosphorescent nature of emission in these complexes. Additionally, their behavior was found to be governed based on both the nature of the cyclometalated ligand and the electronic properties of the ancillary ligands. Highly efficient interligand charge transfer in complex 7 provides access to a wide range of emission colors (solvent-dependent) from deep blue to red with phosphorescence emission quantum yield of 30 % (441 nm) and 39 % (622 nm) in solution and solid state, respectively, and is the highest reported for any Au(III) complexes. DFT and TDDFT calculations carried out further validated the observations and assignments based on the photophysical experimental findings. PMID- 24481956 TI - Expression of genes involved in the embryo-maternal interaction in the early pregnant canine uterus. AB - Although there is no acute luteolytic mechanism in the absence of pregnancy in the bitch, a precise and well-timed embryo-maternal interaction seems to be required for the initiation and maintenance of gestation. As only limited information is available about these processes in dogs, in this study, the uterine expression of possible decidualization markers was investigated during the pre-implantation stage (days 10-12) of pregnancy and in the corresponding nonpregnant controls. In addition, the expression of selected genes associated with blastocyst development and/or implantation was investigated in embryos flushed from the uteri of bitches used for this study (unhatched and hatched blastocysts). There was an upregulated expression of prolactin receptor (PRLR) and IGF2 observed pre-implantation. The expression of PRL and of IGF1 was unaffected, and neither was the expression of progesterone- or estrogen receptor beta (ESR2). In contrast, (ESR1) levels were elevated during early pregnancy. Prostaglandin (PG)-system revealed upregulated expression of PGE2-synthase and its receptors, PTGER2 and PTGER4, and of the PG-transporter. Elevated levels of AKR1C3 mRNA, but not the protein itself, were noted. Expression of prostaglandin endoperoxide synthase 2 (PTGS2) remained unaffected. Most of the transcripts were predominantly localized to the uterine epithelial cells, myometrium and, to a lesser extent, to the uterine stroma. PGES (PTGES) mRNA was abundantly expressed in both groups of embryos and appeared higher in the hatched ones. The expression level of IGF2 mRNA appeared higher than that of IGF1 mRNA in hatched embryos. In unhatched embryos IGF1, IGF2, and PTGS2 mRNA levels were below the detection limit. PMID- 24481959 TI - The new risk variant CACNA1C and brain circuits in schizophrenia. PMID- 24481960 TI - Defining a stimuli-response relationship in compensatory lung growth following major resection. AB - Major lung resection is a robust model that mimics the consequences of loss-of functioning lung units. We previously observed in adult canines, following 42% and 58% lung resection, a critical threshold of stimuli intensity for the initiation of compensatory lung growth. To define the range and limits of this stimuli-response relationship, we performed morphometric analysis on the remaining lobes of adult dogs, 2-3 years after surgical removal of ~ 70% of lung units in the presence or absence of mediastinal shift. Results were expressed as ratios to that in corresponding control lobes. Lobar expansion and extravascular tissue growth (~ 3.8- and ~ 2.0-fold of normal, respectively) were heterogeneous; the lobes remaining next to the diaphragm exhibited a greater response. Tissue growth and capillary formation, indexed by double-capillary profiles, increased, regardless of mediastinal shift. Septal collagen fibers increased up to 2.7-fold, suggesting a greater need for structural support. Compared with previous cohorts following less-extensive resection, tissue volume and gas-exchange surface areas increased significantly only in the infracardiac lobe following 42% resection, exceeded two- to threefold in all lobes following 58% resection, and then exhibited diminished gains following ~ 70% resection. In contrast, alveolar capillary formation increased with incremental resection without reaching an upper limit. Overall structural regrowth was most vigorous and uniform following 58% resection. The diminishment of gains in tissue growth, following ~ 70% resection, could reflect excessive or maldistributed mechanical stress that threatens septal integrity. Results also suggest additional independent stimuli of alveolar-capillary formation, possibly related to the postresection augmentation of regional perfusion. PMID- 24481961 TI - Emergence of airway smooth muscle mechanical behavior through dynamic reorganization of contractile units and force transmission pathways. AB - Airway hyperresponsiveness (AHR) in asthma remains poorly understood despite significant research effort to elucidate relevant underlying mechanisms. In particular, a significant body of experimental work has focused on the effect of tidal fluctuations on airway smooth muscle (ASM) cells, tissues, lung slices, and whole airways to understand the bronchodilating effect of tidal breathing and deep inspirations. These studies have motivated conceptual models that involve dynamic reorganization of both cytoskeletal components as well as contractile machinery. In this article, a biophysical model of the whole ASM cell is presented that combines 1) crossbridge cycling between actin and myosin; 2) actin myosin disconnectivity, under imposed length changes, to allow dynamic reconfiguration of "force transmission pathways"; and 3) dynamic parallel-to serial transitions of contractile units within these pathways that occur through a length fluctuation. Results of this theoretical model suggest that behavior characteristic of experimentally observed force-length loops of maximally activated ASM strips can be explained by interactions among the three mechanisms. Crucially, both sustained disconnectivity and parallel-to-serial transitions are necessary to explain the nature of hysteresis and strain stiffening observed experimentally. The results provide strong evidence that dynamic rearrangement of contractile machinery is a likely mechanism underlying many of the phenomena observed at timescales associated with tidal breathing. This theoretical cell level model captures many of the salient features of mechanical behavior observed experimentally and should provide a useful starting block for a bottom-up approach to understanding tissue-level mechanical behavior. PMID- 24481962 TI - The hydrostatic pressure indifference point underestimates orthostatic redistribution of blood in humans. AB - The hydrostatic indifference point (HIP; where venous pressure is unaffected by posture) is located at the level of the diaphragm and is believed to indicate the orthostatic redistribution of blood, but it remains unknown whether HIP coincides with the indifference point for blood volume (VIP). During graded (+/- 20 degrees ) head-up (HUT) and head-down tilt (HDT) in 12 male volunteers, we determined HIP from central venous pressure and VIP from redistribution of both blood, using ultrasound imaging of the inferior caval vein (VIPui), and fluid volume, by regional electrical admittance (VIPadm). Furthermore, we evaluated whether inflation of medical antishock trousers (to 70 mmHg) affected HIP and VIP. Leaving cardiovascular variables unaffected by tilt, HIP was located 7 +/- 4 cm (mean +/- SD) below the 4th intercostal space (IC-4) during HUT and was similar (7 +/- 3 cm) during HDT and higher (P < 0.0001) than both VIPui (HUT: 22 +/- 16 cm; HDT: 13 +/- 7 cm) and VIPadm (HUT: 29 +/- 9 cm; HDT: 20 +/- 9 cm below IC-4). During HUT antishock trousers elevated both HIP and VIPui [to 3 +/- 5 cm (P = 0.028) and 17 +/- 7 cm below IC-4 (P = 0.051), respectively], while VIPadm remained unaffected. By simultaneous recording of pressure and filling of the inferior caval vein as well as fluid distribution, we found HIP located corresponding to the diaphragm while VIP was placed low in the abdomen, and that medical antishock trousers elevated both HIP and VIP. The low indifference point for volume shows that the gravitational influence on distribution of blood is more profound than indicated by the indifference point for venous pressure. PMID- 24481963 TI - Mechanical interactions between adjacent airways in the lung. AB - The forces of mechanical interdependence between the airways and the parenchyma in the lung are powerful modulators of airways responsiveness. Little is known, however, about the extent to which adjacent airways affect each other's ability to narrow due to distortional forces generated within the intervening parenchyma. We developed a two-dimensional computational model of two airways embedded in parenchyma. The parenchyma itself was modeled in three ways: 1) as a network of hexagonally arranged springs, 2) as a network of triangularly arranged springs, and 3) as an elastic continuum. In all cases, we determined how the narrowing of one airway was affected when the other airway was relaxed vs. when it narrowed to the same extent as the first airway. For the continuum and triangular network models, interactions between airways were negligible unless the airways lay within about two relaxed diameters of each other, but even at this distance the interactions were small. By contrast, the hexagonal spring network model predicted that airway-airway interactions mediated by the parenchyma can be substantial for any degree of airway separation at intermediate values of airway contraction forces. Evidence to date suggests that the parenchyma may be better represented by the continuum model, which suggests that the parenchyma does not mediate significant interactions between narrowing airways. PMID- 24481964 TI - Pulmonary vasodilation by acetazolamide during hypoxia: impact of methyl-group substitutions and administration route in conscious, spontaneously breathing dogs. AB - Acetazolamide (ACZ) prevents hypoxic pulmonary vasoconstriction (HPV) in isolated lungs, animals, and humans, but not by carbonic anhydrase (CA) inhibition. We studied administration routes in, and certain structural aspects of, ACZ critical to HPV inhibition. Analogs of ACZ during acute hypoxia were tested in unanesthetized dogs. Dogs breathed normoxic gas for 1 h (inspired O2 fraction = 0.21), followed by 10% O2 for 2 h (hypoxia) in these protocols: 1) controls; 2) ACZ intravenously (2 mg . kg(-1) . h(-1)); 3) ACZ orally (5 mg/kg, 12 and 1 h before the experiment); 4) inhaled ACZ (750 mg); 5) methazolamide (MTZ) intravenously (3 mg . kg(-1) . h(-1)); and 6) N-methyl-acetazolamide (NMA) intravenously (10 mg . kg(-1) . h(-1)). In controls, mean pulmonary arterial pressure (MPAP) increased 7 mmHg, and pulmonary vascular resistance (PVR) 224 dyn . s . cm(-5) with hypoxia (P < 0.05). With intravenous and inhaled ACZ, MPAP and PVR did not change during hypoxia. With oral ACZ, HPV was only slightly suppressed; MPAP increased 5 mmHg and PVR by 178 dyn . s . cm(-5) during hypoxia. With MTZ and NMA, the MPAP rise (4 +/- 2 mmHg) was reduced, and PVR did not increase during hypoxia compared with normoxia (MTZ intravenous: 81 +/- 77 and 68 +/- 82 dyn . s . cm(-5) with NMA intravenous). Inhaled ACZ prevents HPV, but not without causing systemic CA inhibition. NMA, a compound lacking CA inhibiting effects by methylation at the sulfonamide moiety, and MTZ, a CA-inhibiting analog methylated at the thiadiazole ring, are only slightly less effective than ACZ in reducing HPV. PMID- 24481965 TI - Angiotensin II and the JNK pathway mediate urotensin II expression in response to hypoxia in rat cardiomyocytes. AB - Cardiomyocyte hypoxia causes cardiac hypertrophy through cardiac-restricted gene expression. Urotensin II (UII) cooperates with activating protein 1 (AP1) to regulate cardiomyocyte growth in response to myocardial injuries. Angiotensin II (AngII) stimulates UII expression, reactive oxygen species (ROS) production, and cardiac hypertrophy. This study aimed to evaluate the expression of UII, ROS, and AngII as well as their genetic transcription after hypoxia treatment in neonatal cardiomyocytes. Cultured neonatal rat cardiomyocytes were subjected to hypoxia for different time periods. UII (Uts2) protein levels increased after 2.5% hypoxia for 4 h with earlier expression of AngII and ROS. Both hypoxia and exogenously added AngII or Dp44mT under normoxia stimulated UII expression, whereas AngII receptor blockers, JNK inhibitors (SP600125), JNK siRNA, or N acetyl-l-cysteine (NAC) suppressed UII expression. The gel shift assay indicated that hypoxia induced an increase in DNA-protein binding between UII and AP1. The luciferase assay confirmed an increase in transcription activity of AP1 to the UII promoter under hypoxia. After hypoxia, an increase in (3)H-proline incorporation in the cardiomyocytes and expression of myosin heavy chain protein, indicative of cardiomyocyte hypertrophy, were observed. In addition, hypoxia increased collagen I expression, which was inhibited by SP600125, NAC, and UII siRNA. In summary, hypoxia in cardiomyocytes increases UII and collagen I expression through the induction of AngII, ROS, and the JNK pathway causing cardiomyocyte hypertrophy and fibrosis. PMID- 24481966 TI - Ovarian steroids affect prostaglandin production in equine endometrial cells in vitro. AB - This study aimed to evaluate the influence of ovarian steroids on equine endometrial epithelial and stromal cells, specifically i) prostaglandin (PG) production in a time-dependent manner, ii) specific PG synthases mRNA transcription and protein expression, and iii) cell proliferation. After passage I, cells were exposed to vehicle, oxytocin (OT, positive control, 10(-7) M), progesterone (P4, 10(-7) M), 17beta estradiol (E2, 10(-9) M), or P4+E2 for 12, 24, 48, or 72 h. Following treatment, PG concentration was determined using the direct enzyme immunoassay (EIA) method. Alterations in PG synthases mRNA transcriptions, PG synthases protein expression, and cell proliferation in response to the treatments were determined after 24 h using real-time PCR, western blot, or 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide respectively. After 24 h, E2 and P4+E2 increased PGE2 and PGF2alpha secretion as well as specific prostaglandin-endoperoxide synthase-2 (PTGS2), PGE2 synthases (PGES), and PGF2alpha synthases (PGFS) expression in the epithelial cells (P<0.05). Additionally, E2 and P4+E2 increased PTGS2 expression in stromal cells after 24 h (P<0.05). In stromal cells, P4+E2 increased PGE2 production as well as PGES expression after 24 h (P<0.05). Both E2 and P4+E2 increased PGF2alpha production by stromal cells after 24 h (P<0.05). Ovarian steroids affected proliferation of stromal and epithelial cells during the 24-h incubation period (P<0.05). We provide evidence that ovarian steroids affect PG production in equine endometrial cells, upregulating PTGS2, PGES, and PGFS expression. Ovarian steroid-stimulated PG production could be an important mechanism occurring in the equine endometrium that is involved in the regulation of the estrous cycle and early pregnancy. PMID- 24481967 TI - Hypercholesterolemia-induced priming of hematopoietic stem and progenitor cells aggravates atherosclerosis. AB - Modulation of hematopoietic stem and progenitor cells (HSPCs) determines immune cell function. In this study, we investigated how hypercholesterolemia affects HSPC biology and atherosclerosis. Hypercholesterolemia induced loss of HSPC quiescence, characterized by increased proliferation and expression of cyclin B1, C1, and D1, and a decreased expression of Rb, resulting in a 3.6- fold increase in the number of HSPCs in hypercholesterolemic Ldlr(-/-) mice. Competitive bone marrow (BM) transplantations showed that a hypercholesterolemic BM microenvironment activates HSPCs and skews their development toward myeloid lineages. Conversely, hypercholesterolemia-primed HSPCs acquired an enhanced propensity to generate myeloid cells, especially granulocytes and Ly6C(high) monocytes, even in a normocholesterolemic BM microenvironment. In conformity, macrophages differentiated from hypercholesterolemia-primed HSPCs produced 17.0% more TNF-alpha, 21.3% more IL-6, and 10.5% more MCP1 than did their normocholesterolemic counterparts. Hypercholesterolemia-induced priming of HSPCs generated leukocytes that more readily migrated into the artery, which resulted in a 2.1-fold increase in atherosclerotic plaque size. In addition, these plaques had a more advanced phenotype and exhibited a 1.2-fold increase in macrophages and 1.8-fold increase in granulocytes. These results identify hypercholesterolemia-induced activation and priming of HSPCs as a novel pathway in the development of atherosclerosis. Inhibition of this proinflammatory differentiation pathway on the HSPC level has the potential to reduce atherosclerosis. PMID- 24481968 TI - Maternal diet amplifies the hepatic aging trajectory of Cidea in male mice and leads to the development of fatty liver. AB - The importance of the early environment on long-term heath and life span is well documented. However, the molecular mechanisms mediating these effects remain poorly understood. Male offspring from a maternal protein restriction model, in which animals are exposed to a low-protein diet while in utero and then are cross fostered to normally fed dams, demonstrate low birth weight, catch-up growth, and reduced life span (recuperated offspring). In the current study, we used microarray analysis to identify hepatic genes that changed with age. Cell death inducing DNA fragmentation factor, alpha subunit-like effector A (Cidea), a transcriptional coactivator that has been implicated in lipid accumulation demonstrated one of the largest age-associated increases in expression (200-fold, P<0.001). This increase was exaggerated ~3-fold in recuperated offspring. These demonstrated increased hepatic lipid accumulation, higher levels of transcription factors important in lipid regulation, and greater oxidative stress. In vitro analysis revealed that Cidea expression was regulated by oxidative stress and DNA methylation. These findings suggest that maternal diet modulates the age associated changes in Cidea expression through several mechanisms. This expression affects hepatic lipid metabolism in these animals and thus provides a mechanism by which maternal diet can contribute to the metabolic health and ultimately the life span of the offspring. PMID- 24481969 TI - A rare case of Cryptococcus luteolus-related tenosynovitis. AB - A 68-year-old male with type II diabetes mellitus presented with a nodule over the metacarpophalangeal joint of his right second finger after being spurred on the hand by a domestic turkey 2 weeks prior to onset of clinical symptoms. He was diagnosed with cryptococcal tenosynovitis caused by Cryptococcus luteolus identified by DNA sequencing. Complete clinical resolution was achieved with synovectomy and debridement followed by 1 year of fluconazole 800 mg daily. PMID- 24481970 TI - Recommendations for the management of cerebral and cerebellar infarction with swelling: a statement for healthcare professionals from the American Heart Association/American Stroke Association. AB - BACKGROUND AND PURPOSE: There are uncertainties surrounding the optimal management of patients with brain swelling after an ischemic stroke. Guidelines are needed on how to manage this major complication, how to provide the best comprehensive neurological and medical care, and how to best inform families facing complex decisions on surgical intervention in deteriorating patients. This scientific statement addresses the early approach to the patient with a swollen ischemic stroke in a cerebral or cerebellar hemisphere. METHODS: The writing group used systematic literature reviews, references to published clinical and epidemiology studies, morbidity and mortality reports, clinical and public health guidelines, authoritative statements, personal files, and expert opinion to summarize existing evidence and to indicate gaps in current knowledge. The panel reviewed the most relevant articles on adults through computerized searches of the medical literature using MEDLINE, EMBASE, and Web of Science through March 2013. The evidence is organized within the context of the American Heart Association framework and is classified according to the joint American Heart Association/American College of Cardiology Foundation and supplementary American Heart Association Stroke Council methods of classifying the level of certainty and the class and level of evidence. The document underwent extensive American Heart Association internal peer review. RESULTS: Clinical criteria are available for hemispheric (involving the entire middle cerebral artery territory or more) and cerebellar (involving the posterior inferior cerebellar artery or superior cerebellar artery) swelling caused by ischemic infarction. Clinical signs that signify deterioration in swollen supratentorial hemispheric ischemic stroke include new or further impairment of consciousness, cerebral ptosis, and changes in pupillary size. In swollen cerebellar infarction, a decrease in level of consciousness occurs as a result of brainstem compression and therefore may include early loss of corneal reflexes and the development of miosis. Standardized definitions should be established to facilitate multicenter and population-based studies of incidence, prevalence, risk factors, and outcomes. Identification of patients at high risk for brain swelling should include clinical and neuroimaging data. If a full resuscitative status is warranted in a patient with a large territorial stroke, admission to a unit with neurological monitoring capabilities is needed. These patients are best admitted to intensive care or stroke units attended by skilled and experienced physicians such as neurointensivists or vascular neurologists. Complex medical care includes airway management and mechanical ventilation, blood pressure control, fluid management, and glucose and temperature control. In swollen supratentorial hemispheric ischemic stroke, routine intracranial pressure monitoring or cerebrospinal fluid diversion is not indicated, but decompressive craniectomy with dural expansion should be considered in patients who continue to deteriorate neurologically. There is uncertainty about the efficacy of decompressive craniectomy in patients >=60 years of age. In swollen cerebellar stroke, suboccipital craniectomy with dural expansion should be performed in patients who deteriorate neurologically. Ventriculostomy to relieve obstructive hydrocephalus after a cerebellar infarct should be accompanied by decompressive suboccipital craniectomy to avoid deterioration from upward cerebellar displacement. In swollen hemispheric supratentorial infarcts, outcome can be satisfactory, but one should anticipate that one third of patients will be severely disabled and fully dependent on care even after decompressive craniectomy. Surgery after a cerebellar infarct leads to acceptable functional outcome in most patients. CONCLUSIONS: Swollen cerebral and cerebellar infarcts are critical conditions that warrant immediate, specialized neurointensive care and often neurosurgical intervention. Decompressive craniectomy is a necessary option in many patients. Selected patients may benefit greatly from such an approach, and although disabled, they may be functionally independent. PMID- 24481971 TI - Plaque inflammation and unstable morphology are associated with early stroke recurrence in symptomatic carotid stenosis. AB - BACKGROUND AND PURPOSE: Although symptomatic carotid stenosis is associated with 3-fold increased risk of early stroke recurrence, the pathophysiologic mechanisms of high early stroke risk have not been established. We aimed to investigate the relationship between early stroke recurrence after initial symptoms and histological features of plaque inflammation and instability in resected carotid plaque. METHODS: Carotid endarterectomy tissue from consecutive patients with ipsilateral stenosis>=50% and recent symptoms were analyzed using a validated histopathologic algorithm (Oxford Plaque Study [OPS] system). Nonprocedural stroke recurrence before carotid endarterectomy was ascertained at 7, 28, and 90 days after initial symptoms. RESULTS: Among 44 patients meeting eligibility criteria, 27.3% (12/44) had stroke recurrence after initial stroke/transient ischemic attack but before carotid endarterectomy. Compared with patients without recurrence, stroke recurrence was associated with dense macrophage infiltration (OPS grade>=3; 91.7% versus 37.5%; P=0.002), extensive (>25%) fibrous cap disruption (90.9% versus 37%; P=0.004), neovascularization (OPS grade>=2; 83.3% versus 43.8%; P=0.04), and low plaque fibrous content (OPS grade<2; 50% versus 6.3%; P=0.003). Early recurrence rates were 82.3% (confidence interval, 49.2% 98.8%) in patients with extensive plaque macrophage infiltration (OPS grade>=3) compared with 22.2% (confidence interval, 3.5%-83.4%) in those with OPS grade<3 (log-rank P=0.009). On multivariable Cox regression, including OPS macrophage grade (>=3 or <3), age, and severity of stenosis (50%-69% or >=70%), plaque inflammation was the only variable independently predicting stroke recurrence (adjusted hazard ratio, 9; confidence interval, 1.1-70.6; P=0.04). CONCLUSIONS: Plaque inflammation and other vulnerability features were associated with highest risk of stroke recurrence and may represent therapeutic targets for future stroke prevention trials. PMID- 24481972 TI - Thrombolysis in patients with mild stroke: results from the Austrian Stroke Unit Registry. AB - BACKGROUND AND PURPOSE: Apart from missing the approved time window of 4.5 hours, one frequent cause for withholding recombinant tissue plasminogen activator (rt PA) treatment in patients with ischemic stroke is presentation with mild deficit on admission. We analyzed in a large cohort of patients whether rt-PA treatment is beneficial for this group of patients. METHODS: From a total of 54 917 patients with ischemic stroke prospectively enrolled in the Austrian Stroke Unit Registry, 890 patients with mild deficit defined as <=5 points in the National Institutes of Health Stroke Scale treated with and without rt-PA were matched for age, sex, prestroke disability, stroke severity, hypertension, diabetes mellitus, hypercholesterolemia, stroke cause, and clinical stroke syndrome. Functional outcome was assessed using the modified Rankin Scale at 3 months. For data visualization, weighted averages of outcome differences were computed for all age severity combinations and mapped to a color. For quantification of effect sizes, numbers need to treat were calculated. RESULTS: rt-PA-treated patients with mild deficit had a better outcome after 3 months compared with matched cases without rt-PA treatment (odds ratio [OR], 1.49; 95% confidence interval [CI], 1.17-1.89; P<0.001). In rt-PA-treated patients with mild deficit, the numbers need to treat ranged from 8 to 14. Improvement achieved by rt-PA treatment was observed along the entire age range. CONCLUSIONS: In our study, intravenous rt-PA treatment was beneficial for patients with mild deficit. Given the observational nature of these results, our data might serve as an incentive for future randomized controlled trials to provide a basis for optimal patient selection. PMID- 24481973 TI - You may delay, but time will not! PMID- 24481974 TI - Venous phase of computed tomography angiography increases spot sign detection, but intracerebral hemorrhage expansion is greater in spot signs detected in arterial phase. AB - BACKGROUND AND PURPOSE: Variability in computed tomography angiography (CTA) acquisitions may be one explanation for the modest accuracy of the spot sign for predicting intracerebral hemorrhage expansion detected in the multicenter Predicting Hematoma Growth and Outcome in Intracerebral Hemorrhage Using Contrast Bolus CT (PREDICT) study. This study aimed to determine the frequency of the spot sign in intracerebral hemorrhage and its relationship with hematoma expansion depending on the phase of image acquisition. METHODS: PREDICT study was a prospective observational cohort study of patients with intracerebral hemorrhage presenting within 6 hours from onset. A post hoc analysis of the Hounsfield units of an artery and venous structure were measured on CTA source images of the entire PREDICT cohort in a core laboratory. Each CTA study was classified into arterial or venous phase and into 1 of 5 specific image acquisition phases. Significant hematoma expansion and total hematoma enlargement were recorded at 24 hours. RESULTS: Overall (n=371), 77.9% of CTA were acquired in arterial phase. The spot sign, present in 29.9% of patients, was more frequently seen in venous phase as compared with arterial phase (39% versus 27.3%; P=0.041) and the later the phase of image acquisition (P=0.095). Significant hematoma expansion (P=0.253) and higher total hematoma enlargement (P=0.019) were observed more frequently among spot sign-positive patients with earlier phases of image acquisition. CONCLUSIONS: Later image acquisition of CTA improves the frequency of spot sign detection. However, spot signs identified in earlier phases may be associated with greater absolute enlargement. A multiphase CTA including arterial and venous acquisitions could be optimal in patients with intracerebral hemorrhage. PMID- 24481975 TI - Prevalence and outcomes of symptomatic intracranial large artery stenoses and occlusions in China: the Chinese Intracranial Atherosclerosis (CICAS) Study. AB - BACKGROUND AND PURPOSE: We aimed to establish the prevalence, characteristics, and outcomes of intracranial atherosclerosis (ICAS) in China by a large, prospective, multicenter study. METHODS: We evaluated 2864 consecutive patients who experienced an acute cerebral ischemia<7 days after symptom onset in 22 Chinese hospitals. All patients underwent magnetic resonance angiography, with measurement of diameter of the main intracranial arteries. ICAS was defined as >=50% diameter reduction on magnetic resonance angiography. RESULTS: The prevalence of ICAS was 46.6% (1335 patients, including 261 patients with coexisting extracranial carotid stenosis). Patients with ICAS had more severe stroke at admission and stayed longer in hospitals compared with those without intracranial stenosis (median National Institutes of Health Stroke Scale score, 3 versus 5; median length of stay, 14 versus 16 days; both P<0.0001). After 12 months, recurrent stroke occurred in 3.27% of patients with no stenosis, in 3.82% for those with 50% to 69% stenosis, in 5.16% for those with 70% to 99% stenosis, and in 7.27% for those with total occlusion. Cox proportional hazards regression analyses showed that the degree of arterial stenosis, age, family history of stroke, history of cerebral ischemia or heart disease, complete circle of Willis, and National Institutes of Health Stroke Scale score at admission were independent predictors for recurrent stroke at 1 year. The highest rate of recurrence was observed in patients with occlusion with the presence of >=3 additional risk factors. CONCLUSIONS: ICAS is the most common vascular lesion in patients with cerebrovascular disease in China. Recurrent stroke rate in our study was lower compared with those of previous clinical trials but remains unacceptably high in a subgroup of patients with severe stenosis. PMID- 24481977 TI - Endocarditis is a common stroke mechanism in hemodialysis patients. AB - BACKGROUND AND PURPOSE: Hemodialysis patients are at high risk for ischemic stroke, and previous studies have noted a high rate of cardioembolism in this population. The aim of this study was to determine ischemic stroke causes among hemodialysis patients and elucidate specific cardioembolic stroke mechanisms. METHODS: This study is a retrospective cross-sectional study of hemodialysis patients admitted with acute stroke to the University of Pennsylvania Health System between 2003 and 2010. Strokes were classified using modified Trial of Org 10,172 in Acute Stroke Treatment (TOAST) criteria as large vessel, cardioembolism, small vessel, atypical, multiple causes, or cryptogenic. Cardioembolic strokes were further characterized for specific mechanism. RESULTS: We identified 52 patients hospitalized with acute stroke while receiving hemodialysis. Mean age was 64+/-13 years, 56% were female, and 67% were black. Stroke subtypes included 3 (6%) large vessel, 20 (38%) cardioembolism, 6 (11%) small vessel, 3 (6%) other, 4 (8%) with multiple causes, and 16 (31%) were unknown. Among patients who had an echocardiogram performed, 5 of 52 (10%; 95% confidence interval, 1%-18%) had a patent foramen ovale. Cardioembolic stroke mechanisms included 6 with infective endocarditis (accounting for 12% of all strokes). CONCLUSIONS: Cardioembolism and cryptogenic stroke are the predominant stroke mechanisms among hemodialysis patients. Infective endocarditis was identified frequently relative to other stroke cohorts, and a raised index of suspicion is warranted in the hemodialysis population. PMID- 24481976 TI - Effect of a novel video game on stroke knowledge of 9- to 10-year-old, low-income children. AB - BACKGROUND AND PURPOSE: Improving actionable stroke knowledge of a witness or bystander, which in some cases are children, may improve response to an acute stroke event. METHODS: We used a quasiexperimental pre-test post-test design to evaluate actionable stroke knowledge of 210 children aged 9 to 10 years in response to a single, 15-minute exposure to a stroke education video game conducted in the school computer laboratory. After immediate post-test, we provided remote password-protected online video game access and encouraged children to play at their leisure from home. An unannounced delayed post-test occurred 7 weeks later. RESULTS: Two hundred ten children completed pretest, 205 completed immediate post-test, whereas 198 completed delayed post-test. One hundred fifty-six (74%) children had Internet access at home, and 41 (26%), mostly girls, played the video game remotely. There was significant improvement in stroke symptom composite scores, calling 911, and all individual stroke knowledge items, including a distractor across the testing sequence (P<0.05). Children who played the video game remotely demonstrated significant improvement in knowledge of 1 symptom (sudden imbalance) compared with children who did not (P<0.05), although overall composite scores showed no difference. CONCLUSIONS: Stroke education video games may represent novel means for improving and sustaining actionable stroke knowledge of children. PMID- 24481978 TI - Synthesis of bis(heteroaryl) ketones by removal of benzylic CHR and CO groups. AB - A copper-catalyzed method for synthesis of diaryl ketones (Ar-CO-Ar') through removal of benzylic -CH2-, -CO-, and -CHR- groups from Ar-CO-CXR-Ar' has been discovered. A number of symmetrical and unsymmetrical heterocyclic ketones, which are usually difficult to synthesize, can be prepared in good to excellent yields. This method was applied to the synthesis of the nonsteroidal anti-inflammatory drug suprofen (47% yield over three steps). Based on preliminary mechanistic and kinetic studies, an active Cu/O2 species is proposed to mediate the rearrangement reaction. PMID- 24481979 TI - Pharmacological inhibition of the chemokine C-C motif chemokine ligand 2 (monocyte chemoattractant protein 1) accelerates liver fibrosis regression by suppressing Ly-6C(+) macrophage infiltration in mice. AB - Macrophages constitute a major proinflammatory component during chronic liver diseases and are considered a key factor in promoting hepatic fibrosis. However, there is increasing evidence that distinct monocyte and macrophage subsets exert critical functions in regression from organ fibrosis as well. Experimental mouse models of fibrosis regression have identified "restorative" macrophages as Ly-6C (Ly6C, Gr1) low-expressing, monocyte-derived cells. We investigated molecular pathways balancing proinflammatory and restorative macrophages during fibrosis regression as well as pharmacologically augmenting beneficial macrophage functionality in fibrosis resolution. Therefore, we employed a Spiegelmer-based inhibitor of the chemokine, C-C motif chemokine ligand 2 (CCL2; monocyte chemoattractant protein 1), termed mNOX-E36, in the regression phase of two murine models of toxic (CCl4 ) and metabolic (methionine-choline-deficient diet) liver fibrosis. Although inflammation rapidly declined after cessation of injury, we observed a transient influx of Ly-6C(+) infiltrating monocytes (iMPhi), which are characterized by typical macrophage morphology, up-regulated expression of CCR2, and the pro-inflammatory cytokine, tumor necrosis factor (TNF), in injured liver. By inhibiting the early influx of Ly-6C(+) iMPhi by the CCL2 inhibitor, mNOX-E36, the intrahepatic macrophage equilibration shifted toward the "restorative" Ly-6C(-) subset of iMPhi. Consequently, fibrosis resolution was significantly accelerated upon mNOX-E36 administration in both models. Blocking transient recruitment of infiltrating Ly-6C(+) monocytes, but not direct effects of the inhibitor on the remaining macrophages, resulted in reduced intrahepatic levels of proinflammatory cytokines. CONCLUSION: Transient CCL2-dependent recruitment of infiltrating Ly-6C(+) monocytes during fibrosis regression counteracts scar resolution by perpetuating inflammatory reactions through release of proinflammatory cytokines such as TNF. Pharmacological inhibition of Ly-6C(+) monocyte recruitment using the CCL2-inhibitor, mNOX-E36, accelerates regression from toxic and metabolic liver fibrosis in two independent experimental models. PMID- 24481980 TI - Ibrutinib in B-cell Lymphomas. AB - The standard frontline therapy for diffuse large B-cell lymphoma (DLBCL), follicular lymphoma (FL), and mantle cell lymphoma (MCL) includes the use of chemoimmunotherapy and/or radiation therapy. When patients with these diseases relapse or are refractory to therapy, their diseases are considered incurable outside of the setting of an autologous or allogeneic stem cell transplant, which many patients are not candidates for due to age or comorbidities. The oral Bruton's tyrosine kinase (BTK) inhibitor, ibrutinib, targets the B-cell receptor (BCR) signaling pathway that is critical in the survival of these malignancies. It has shown promising activity in certain subtypes of DLBCL, in relapsed or refractory FL, and in relapsed or refractory MCL for which it has recently received FDA approval and should be considered for use in patients in first relapse. Ibrutinib is an oral therapy taken daily that has been well tolerated by patients. Given the high response rates, tolerability, and acceptable toxicities of ibrutinib therapy, it is now being evaluated in combination therapy both in relapsed B-cell malignancies and frontline studies in DLBCL and MCL. Several other promising agents targeting different kinases in the BCR signaling pathway also are currently under investigation. PMID- 24481981 TI - Predator facilitation or interference: a game of vipers and owls. AB - In predator-prey foraging games, the prey's reaction to one type of predator may either facilitate or hinder the success of another predator. We ask, do different predator species affect each other's patch selection? If the predators facilitate each other, they should prefer to hunt in the same patch; if they interfere, they should prefer to hunt alone. We performed an experiment in a large outdoor vivarium where we presented barn owls (Tyto alba) with a choice of hunting greater Egyptian gerbils (Gerbillus pyramidum) in patches with or without Saharan horned vipers (Cerastes cerastes). Gerbils foraged on feeding trays set under bushes or in the open. We monitored owl location, activity, and hunting attempts, viper activity and ambush site location, and the foraging behavior of the gerbils in bush and open microhabitats. Owls directed more attacks towards patches with vipers, and vipers were more active in the presence of owls. Owls and vipers facilitated each other's hunting through their combined effect on gerbil behavior, especially on full moon nights when vipers are more active. Owls forced gerbils into the bushes where vipers preferred to ambush, while viper presence chased gerbils into the open where they were exposed to owls. Owls and vipers took advantage of their indirect positive effect on each other. In the foraging game context, they improve each other's patch quality and hunting success. PMID- 24481982 TI - Bears are simply voles writ large: social structure determines the mechanisms of intrinsic population regulation in mammals. AB - The literature reveals opposing views regarding the importance of intrinsic population regulation in mammals. Different models have been proposed; adding importance to contrasting life histories, body sizes and social interactions. Here we evaluate current theory based on results from two Scandinavian projects studying two ecologically different mammal species with contrasting body sizes and life history traits: the root vole Microtus oeconomus and the brown bear Ursus arctos. We emphasize four inter-linked behavioral aspects-territoriality, dispersal, social inhibition of breeding, and infanticide-that together form a density-dependent syndrome with potentially regulatory effects on population growth. We show that the two species are similar in all four behaviors and thus the overall regulatory syndrome. Females form matrilineal assemblages, female natal dispersal is negatively density dependent and breeding is suppressed in philopatric young females. In both species, male turnover due to extrinsic mortality agents cause infanticide with negative effects on population growth. The sex-biased and density-dependent dispersal patterns promote the formation of matrilineal clusters which, in turn, leads to reproductive suppression with potentially regulatory effects. Hence, we show that intrinsic population regulation interacting with extrinsic mortality agents may occur irrespective of taxon, life history and body size. Our review stresses the significance of a mechanistic approach to understanding population ecology. We also show that experimental model populations are useful to elucidate natural populations of other species with similar social systems. In particular, such experiments should be combined with methodical innovations that may unravel the effects of cryptic intrinsic mechanisms such as infanticide. PMID- 24481983 TI - Infusion of human umbilical cord-derived mesenchymal stem cells effectively relieves liver cirrhosis in DEN-induced rats. AB - Cirrhosis is the long-term outcome of chronic hepatic injury and no effective therapy is currently available for this disease. Mesenchymal stromal cells (MSCs) are multipotent cells that are easily acquired and amplified, and may be potential candidates for cell therapy against cirrhosis. This study aimed to determine the therapeutic effects of human umbilical cord-derived MSCs (hUCMSCs) for the treatment of liver cirrhosis and identify an effective method for engrafting MSCs. The model of liver cirrhosis was established by induction of diethylnitrosamine (DEN) in rats. The isolated hUCMSCs were identified by morphology, flow cytometry and multilineage differentiation; they were injected into the vein of DEN-induced rats at varied cell doses and infusion times. Biochemical analyses of the serum and histopathological analysis of the liver tissues were performed to evaluate the therapeutic effects of hUCMSCs in all treatment groups. The results indicated that isolated hUCMSCs were capable of self-replication and differentiated into multiple lineages, including osteoblast , adipocyte- and hepatocyte-like cells. Compared with the control group, administration of hUCMSCs at different cell doses and infusion times relieved DEN induced cirrhosis to varying degrees. The therapeutic effects of hUCMSCs on liver cirrhosis gradually improved with increased cell dose and infusion times. The improvement of cirrhosis was due to the capacity of hUCMSCs to breakdown collagen fibers in the liver. It was demonstrated that infusion of hUCMSCs effectively relieved liver cirrhosis by facilitating the breakdown of collagen fibers in a dose-dependent manner and multiple infusions caused a relatively greater improvement in cirrhosis compared with a single infusion of hUCMSCs. PMID- 24481984 TI - Six-month utilization of psychotherapy by older adults with depressive symptoms. AB - We explored psychotherapy utilization patterns for community-dwelling older adults with depressive symptoms identified during a statewide initiative designed for identifying risk of substance misuse. Individuals screening negative for substance misuse, but positive for depressive symptoms, agreed to participate in monthly interviews conducted over 6 months (n = 144). Results showed that 39 (27%) received psychotherapy, of which nearly two-thirds reported four or fewer visits. Mental health counselors were the most frequently reported service providers (50-62.5%). Location of service varied considerably. This study documents low rates of psychotherapy use and few visits. Current efforts to increase psychotherapy access are discussed. PMID- 24481985 TI - Laribacter hongkongensis: an emerging pathogen of infectious diarrhea. AB - Laribacter hongkongensis is relatively a new name in the list of bacterial pathogens for gastroenteritis and travelers' diarrhea. Addition of another name increases burden on the enteric infections as a whole. L. hongkongensis belongs to Neisseriaceae family of beta subclass Proteobacteria. L. hongkongensis was initially isolated in Hong Kong from blood and empyema of an alcoholic cirrhotic patient in 2001, followed by reports from Korea and China, representing a total of 38 articles in PubMed until April 2013. As of now, there is no report from Indian subcontinent where infectious diarrhea is very much prevalent and a major burden. This review provides information about the microbiological characteristics, consideration of an emerging pathogen, relative pathogenicity, genome and proteome content, resistance toward multiple antibiotics, adaptability to different stress, and other features since its time of discovery. Investigation for this bacterium may avoid misidentification as other microbial flora. Further studies like the geographical distribution, type of infection, disease burden, pathogenicity, or genomic exploration of this bacterium will be useful in characterizing them properly. This bacterium may possibly be the emerging threat to public health. PMID- 24481986 TI - Dyserythropoiesis in a child with pyruvate kinase deficiency and coexistent unilateral multicystic dysplastic kidney. AB - Pyruvate kinase (PK) deficiency is the commonest enzyme deficiency in the glycolytic pathway leading to hemolytic anemia secondary to decreased Adenosine Triphosphate (ATP) synthesis in the red cells. synthesis. PK deficiency due to mutations in the PKLR (1q21) gene leads to highly variable clinical presentation ranging from severe fetal anemia to well compensated anemia in adults. We describe dyserythropoiesis in the bone marrow of a child with transfusion dependent anemia and unilateral multicystic dysplastic kidney (MCDK) mimicking Congenital Dyserythropoietic Anemia type I (CDA type I). Persistently low erythrocyte PK levels and double heterozygous mutations present in the PKLR gene confirmed the diagnosis of PK deficiency. PMID- 24481987 TI - Digestion in adult females of the leaf-footed bug Leptoglossus zonatus (Hemiptera: Coreidae) with emphasis on the glycoside hydrolases alpha-amylase, alpha-galactosidase, and alpha-glucosidase. AB - The leaffooted bug, Leptoglossus zonatus (Hemiptera: Coreidae) is an emerging pest of several crops around the World and up to now very little is known of its digestive system. In this article, glycoside hydrolase (carbohydrase) activities in the adult midgut cells and in the luminal contents of L. zonatus adult females were studied. The results showed the distribution of digestive carbohydrases in adults of this heteropteran species in the different intestinal compartments. Determination of the spatial distribution of alpha-glucosidase activity in L. zonatus midgut showed only one major molecular form, which was not equally distributed between soluble and membrane-bound isoforms, being more abundant as a membrane-bound enzyme. The majority of digestive carbohydrases were found in the soluble fractions. Activities against starch, maltose and the synthetic substrate NPalphaGlu were found to show the highest levels of activity, followed by enzymes active against galactosyl oligosaccharides. Based on ion-exchange chromatography elution profiles and banding patterns in mildly denaturing electrophoresis, both midgut alpha-amylases and alpha-galactosidases showed at least two isoforms. The data suggested that the majority of carbohydrases involved in initial digestion were present in the midgut lumen, whereas final digestion of starch and of galactosyl oligosaccharides takes place partially within the lumen and partially at the cell surface. The complex of carbohydrases here described was qualitatively appropriate for the digestion of free oligosaccharides and oligomaltodextrins released by alpha-amylases acting on maize seed starch granules. PMID- 24481988 TI - A novel autofocusing method using the angle of Hilbert space for microscopy. AB - Autofocusing technology is indispensable for routine use of microscopes on a large scale in biological field. The autofocusing method using the angle of Hilbert space is brought forward to measure whether the image is focused or not. The angle of Hillbert space can be used to evaluate accurately the similarity degree of two images. The experiment results show that the autofocusing method can decrease the computational cost and get accuracy for real-time biological and biomedical images with noise robustness. The focus curves are smooth and possess the unimodality, the monotonicity and the symmetry. Compared with other classic and optimum focus method, the Hilbert method demonstrates its robustness to noise and can improve the focus speed. The experiments showed that the proposed method can increase the overall performance of an autofocus system and has strong applicability in various autofocusing algorithms. PMID- 24481989 TI - Plasmacytoid dendritic cells license regulatory T cells, upon iNKT-cell stimulation, to prevent autoimmune diabetes. AB - Invariant NKT (iNKT)-cell stimulation with exogenous specific ligands prevents the development of type 1 diabetes (T1D) in NOD mice. Studies based on anti-islet T-cell transfer showed that iNKT cells prevent the differentiation of these T cells into effector T cells in the pancreatic lymph nodes (PLNs). We hypothesize that this defective priming could be explained by the ability of iNKT cells to induce tolerogenic dendritic cells (DCs) in the PLNs. We evaluated the effect of iNKT-cell stimulation on T1D development by transferring naive diabetogenic BDC2.5 T cells into proinsulin 2(-/-) NOD mice treated with a long-lasting alpha galactosylceramide regimen. In this context, iNKT cells induce the conversion of BDC2.5 T cells into Foxp3(+) Treg cells in the PLNs accumulating in the pancreatic islets. Furthermore, tolerogenic plasmacytoid DCs (pDCs) characterized by low MHC class II molecule expression and TGF-beta production are critical in the PLNs for the recruitment of Treg cells into the pancreatic islets by inducing CXCR3 expression. Accordingly, pDC depletion in alpha-galactosylceramide-treated proinsulin 2(-/-) NOD mice abrogates the protection against T1D. These findings reveal that upon repetitive iNKT-cell stimulation, pDCs are critical for the recruitment of Treg cells in the pancreatic islets and the prevention of T1D development. PMID- 24481990 TI - Is adrenal venous sampling mandatory before surgical decision in case of primary hyperaldosteronism? AB - BACKGROUND: Primary hyperaldosteronism (PHA) is a cause of secondary arterial hypertension potentially curable by laparoscopic unilateral adrenalectomy. We describe the follow-up of these patients according to their medical or surgical treatment. METHODS: We report a retrospective single-center study of 91 patients with PHA from 1998 to 2012. Treatment was guided by computed tomography (CT) scans. Preoperative adrenal vein sampling (AVS) was performed when the CT scan did not show single solitary unilateral nodules on the adrenal glands. During the follow-up, we considered hypertension to be cured in patients with normal blood pressure without antihypertensive medication (AM), and improvement was defined by a decrease in AM. RESULTS: A total of 28 patients received only AM. Of the 62 patients who underwent a unilateral adrenalectomy, 46 (74 %) had an adrenal adenoma, 14 (22 %) a hyperplasia, and the adrenal gland was normal in two cases. Hypertension was cured in 24 cases (38 %), and 28 patients (45 %) showed improvement with a reduction in AM. Predictive factors for a cure were gender, age, number of preoperative AMs, preoperative arterial systolic blood pressure, and plasma renin activity. All patients who presented with hypokalemia were cured postoperatively. We performed 38 AVS and nine of these patients were operated on based on the AVS findings, with an improvement of 100 % of arterial blood pressure after surgery. CONCLUSION: Laparoscopic unilateral adrenalectomy for PHA cured or improved hypertension in 84 % of patients. Preoperative AVS is mandatory for surgical decision making if the CT scan shows bilateral or no lesions associated with PHA. PMID- 24481991 TI - Incidence and epidemiology of casualties treated at the Dutch role 2 enhanced medical treatment facility at multi national base Tarin Kowt, Afghanistan in the period 2006-2010. AB - BACKGROUND: To improve care for the injured service member, we have analyzed battle casualty patterns and mechanisms. This study is the first documented report of wounding patterns and mechanisms of battle casualties treated at the Dutch role 2 enhanced medical treatment facility at the multi-national base Tarin Kowt, Uruzgan, Afghanistan. METHODS: Participants were selected from the trauma registry at the Dutch role 2 enhanced medical treatment facility if they fitted the criteria 'battle casualty' and 'disease non-battle injury' between August 2006 and August 2010. RESULTS: The trauma registry query resulted in 2,736 casualties, of which 60 % (N = 1,635) were classified as 'disease non-battle casualties' and 40 % (N = 1,101) as 'battle casualties'. The battle casualties sustained 1,617 combat wounds, resulting in 1.6 wounds per battle casualty. These injuries were predominately caused by explosions (55 %) and gunshots (35 %). The wounding pattern was as follows: head and neck (21 %), thorax (13 %), abdomen (14 %), upper extremity (20 %), and lower extremity (33 %). CONCLUSIONS: The wounding patterns seen at the Dutch role 2 enhanced medical treatment facility at the multi-national base Tarin Kowt resemble the patterns as recorded by other coalition partners. The wounding patterns differ with previous conflicts: a greater proportion of head and neck wounds, and a lower proportion of truncal wounds. PMID- 24481992 TI - How should surgical safety be taught? PMID- 24481993 TI - Do we still need studies on the value of the TIVAD for cancer patients? PMID- 24481994 TI - The protective effect of parity in hormone receptor-positive, Ki-67 expressing breast cancer. AB - BACKGROUND: Epidemiologic studies showed that the experience of pregnancy is associated with a reduced risk of breast cancer. We hypothesized that parity may differentially be associated with the development of invasive breast cancer by each subtype. METHODS: We reviewed the clinical, radiological, and pathological records of women diagnosed with invasive ductal carcinoma of the breast at Samsung Medical Center between 2005 and 2009. Clinicopathologic results were assessed by chi(2) and Fisher's exact tests with a Bonferroni correction for categorical variables, and by the Kruskal-Wallis test for nonparametric continuous variables. A multinomial logistic regression model was used for multivariate analysis. RESULTS: Among a total of 3,095 patients, 283 (9.14 %) patients were nulliparous. Older age, higher pN, and expression of HER2 were associated with parity. In the analysis between parity and molecular subtypes, parity also had a variable influence on breast cancer subtypes (p = 0.032). Intergroup analysis with multiple comparison showed that luminal B subtype was related to nulliparity compared with HER2-positive subtypes (p = 0.03). CONCLUSIONS: The effect of parity on the development of breast cancer differed by hormone receptor and HER2 expression. It seems that parity might have a protective effect against hormone receptor-positive breast cancer, especially cancers expressing HR+ and Ki-67. Further basic research to define and understand this result is ongoing. PMID- 24481995 TI - Is LOE test useful to recognize LCA insufficiency? PMID- 24481997 TI - Methotrexate re-challenge for recurrent primary central nervous system lymphoma. AB - The prognosis of primary CNS lymphoma (PCNSL) recurring after methotrexate is poor (objective response rates [ORR] = 26-53 %; 1-year overall survival [OS] = 35 57 %). Salvage PCNSL chemotherapies have been based on the use of different agents to avoid cross-resistance; however, methotrexate is the most active agent in PCNSL, and methotrexate re-challenge may be an effective strategy for recurrent disease. We report our experience with methotrexate re-challenge in PCNSL. We reviewed 39 patients with histologically confirmed PCNSL who responded to methotrexate at initial diagnosis, experienced disease relapse and received methotrexate re-challenge. At the time of re-challenge, median age was 66 and median Karnofsky performance score (KPS) was 70. Median time from initial diagnosis was 26 m. Twenty-six patients were at first relapse and 13 at second or later relapse. At re-challenge, methotrexate was given in combination with other agents to 33 patients and as a single agent to six. The objective response rate was 85 %, with a complete response in 29 (75 %) patients, partial response in four (10 %) and disease progression in six (15 %). At median follow-up of 26 m, the median progression-free survival was 16 m; 1-year OS was 79 % (95 % CI 63-89) and median OS was 41 m. KPS was a prognostic factor for progression free survival (p = 0.04). In this population selected by previous methotrexate response, methotrexate re-challenge was a safe and effective strategy, indicating chemosensitivity was retained. Efficacy compared favorably to other salvage treatments suggesting methotrexate re-challenge should be considered in recurrent PCNSL patients who previously responded to methotrexate. PMID- 24481996 TI - Epidemiology and etiopathogenesis of pituitary adenomas. AB - Pituitary adenomas are usually benign monoclonal tumours presenting either due to hypersecretion of pituitary hormones, and/or due to local space occupying effects and hyposecretion of some or all of the pituitary hormones. Some pituitary adenomas cause prominent symptoms, while others may result in slowly developing, insidious, non-specific complains delaying accurate diagnosis, with a third group remaining symptomless and recognised only incidentally. Therefore, it is a challenge to accurately determine the prevalence and incidence of pituitary adenomas in the general population. The vast majority of pituitary adenomas occur sporadically, but familial cases are now increasingly recognised. Hereditary predisposition, somatic mutations and endocrine factors were shown to have a pathophysiologic role in the initiation and progression of pituitary adenomas, which interestingly almost always remain benign. Here, we summarize the available epidemiological data and the known pathogenesis of the pituitary adenomas. PMID- 24481998 TI - Use of liposomal doxorubicin-cyclophosphamide combination in breast cancer patients with brain metastases: a monocentric retrospective study. AB - Brain metastases (BM) can affect up to 45 % of a high-risk breast cancer (BC) population. Liposomal doxorubicin (LD)-based chemotherapy has demonstrated efficacy in the treatment of BC and LD crosses the blood-brain barrier. The aim of this retrospective study is to evaluate the efficacy of the LD cyclophosphamide (CTX) combination in BM related to BC. Patients diagnosed with BM related to BC and treated with the LD-CTX combination were eligible. BM objective response rate (BM-ORR), BM disease control rate (BM-DCR), BM progression-free survival, overall survival (OS) and safety were analyzed. 29 patients were eligible. The median time from metastatic diagnosis to brain involvement was 12 months. BM was more frequently observed in HER2+ patients. On average, three courses of chemotherapy were administered without grade 3-4 limiting adverse events. After three cycles, BM-ORR and BM-DCR were 41.4 and 58.6 % respectively versus 50 and 62.5 % when no prior radiotherapy was administered. From BM diagnosis, OS was 23 months. A high BM-ORR is observed with the LD-CTX combination in patients with BM related to BC. This is an attractive therapeutic option for these patients, especially when no prior whole brain radiotherapy has been administered. PMID- 24481999 TI - Medical adherence to acne therapy: a systematic review. AB - BACKGROUND: Poor adherence of acne patients to treatment may equate to poor clinical efficacy, increased healthcare costs, and unnecessary treatments. Authors have investigated risk factors for poor medical adherence and how to improve this difficult problem in the context of acne. OBJECTIVE: This systematic review aims to describe what methods have been used to measure adherence, what is known about acne patients' adherence to treatment, and the factors affecting adherence. METHODS: A MEDLINE search was performed for randomized controlled trials published between 1978 and June 2013, focusing on patient adherence to prescribed acne medications. A test for equality of proportions was performed on studies of similar design to collectively analyze adherence to oral versus topical medication. The self-reported adherence data collected from these clinical trials were then compared with adherence data from a pharmacy database study. RESULTS: Studies varied in modalities of data collection, but the majority utilized subjective methods. Topical therapies were more often studied than oral. The overall oral adherence rate, as calculated by a test of equality of proportions, was 76.3%, while the overall topical adherence rate was 75.8% (p=0.927). The occurrence of side effects and young age were cited as the top reasons for poor adherence, followed by forgetfulness. LIMITATIONS: The MEDLINE search resulted in a limited sample of adherence studies. In addition, there is currently no standardized or fully validated method of measurement, allowing for variability in what was considered 'adherent'. Lastly, data collected via subjective methods cannot guarantee reliable results. CONCLUSIONS: Overall, the values reflected a population adherent to both topical and oral medications, with no significant difference in adherence between the two. However, the methodologies used by many of the studies were weak, and the findings are not consistent with results of more objective measures of adherence. The leading factors that contribute to poor adherence may be reduced with enhanced patient consultation, reminder systems, and education. PMID- 24482000 TI - Dose reduction in standard head CT: first results from a new scanner using iterative reconstruction and a new detector type in comparison with two previous generations of multi-slice CT. AB - PURPOSE: Computed tomography (CT) accounts for more than half of the total radiation exposure from medical procedures, which makes dose reduction in CT an effective means of reducing radiation exposure. We analysed the dose reduction that can be achieved with a new CT scanner [Somatom Edge (E)] that incorporates new developments in hardware (detector) and software (iterative reconstruction). METHODS: We compared weighted volume CT dose index (CTDI(vol)) and dose length product (DLP) values of 25 consecutive patients studied with non-enhanced standard brain CT with the new scanner and with two previous models each, a 64 slice 64-row multi-detector CT (MDCT) scanner with 64 rows (S64) and a 16-slice 16-row MDCT scanner with 16 rows (S16). We analysed signal-to-noise and contrast to-noise ratios in images from the three scanners and performed a quality rating by three neuroradiologists to analyse whether dose reduction techniques still yield sufficient diagnostic quality. RESULTS: CTDI(Vol) of scanner E was 41.5 and 36.4 % less than the values of scanners S16 and S64, respectively; the DLP values were 40 and 38.3 % less. All differences were statistically significant (p < 0.0001). Signal-to-noise and contrast-to-noise ratios were best in S64; these differences also reached statistical significance. Image analysis, however, showed "non-inferiority" of scanner E regarding image quality. CONCLUSIONS: The first experience with the new scanner shows that new dose reduction techniques allow for up to 40 % dose reduction while still maintaining image quality at a diagnostically usable level. PMID- 24482001 TI - Macroscopic inspection of ape feces: what's in a quantification method? AB - Macroscopic inspection of feces has been used to investigate primate diet. The limitations of this method to identify food-items to species level have long been recognized, but ascertaining aspects of diet (e.g., folivory) are achievable by quantifying food-items in feces. Quantification methods applied include rating food-items using a scale of abundance, estimating their percentage volume, and weighing food-items. However, verification as to whether or not composition data differ, depending on which quantification method is used during macroscopic inspection, has not been done. We analyzed feces collected from ten adult chimpanzees (Pan troglodytes schweinfurthii) of the Kanyawara community in Kibale National Park, Uganda. We compare dietary composition totals obtained from using different quantification methods and ascertain if sieve mesh size influences totals calculated. Finally, this study validates findings from direct observation of feeding by the same individuals from whom the fecal samples had been collected. Contrasting diet composition totals obtained by using different quantification methods and sieve mesh sizes can influence folivory and frugivory estimates. However, our findings were based on the assumption that fibrous matter contained pith and leaf fragments only, which remains to be verified. We advocate macroscopic inspection of feces can be a valuable tool to provide a generalized overview of dietary composition for primate populations. As most populations remain unhabituated, scrutinizing and validating indirect measures are important if they are to be applied to further understand inter- and intra-species dietary variation. PMID- 24482003 TI - Multifunctional porous microspheres based on peptide-porphyrin hierarchical co assembly. AB - Photocatalytically active, multi-chambered, biomolecule-based microspheres were prepared by hierarchical co-assembly of simple dipeptides and porphyrins. The colloidal microspheres are highly hydrated and consist of a network of J aggregate nanoscale substructures that serve as light-harvesting antennae with a relatively broad spectral cross-section and considerable photostability. These optical properties can be exploited in photocatalytic reactions involving inorganic or organic species. Taken together, these structural and functional features suggest that soft porous biomolecule-based colloids are a plausible photosynthetic model that could be developed towards demonstrating aspects of primitive abiotic cellularity. PMID- 24482004 TI - Iridium-catalyzed asymmetric hydrogenation of 3,3-disubstituted allylic alcohols in ethereal solvents. AB - Ir-phosphinomethyl-oxazoline complexes have been identified as efficient, highly enantioselective catalysts for the asymmetric hydrogenation of 3,3-disubstituted allylic alcohols and related homoallylic alcohols. In contrast to other N,P ligand complexes, which require weakly coordinating solvents, such as dichloromethane, these catalysts perform well in more ecofriendly THF or 2-MeTHF. Their synthetic potential was demonstrated with the formal total synthesis of four bisabolane sesquiterpenes. PMID- 24482005 TI - Simplifying influenza vaccination during pandemics: sublingual priming and intramuscular boosting of immune responses with heterologous whole inactivated influenza vaccine. AB - The best approach to control the spread of influenza virus during a pandemic is vaccination. Yet, an appropriate vaccine is not available early in the pandemic since vaccine production is time consuming. For influenza strains with a high pandemic potential like H5N1, stockpiling of vaccines has been considered but is hampered by rapid antigenic drift of the virus. It has, however, been shown that immunization with a given H5N1 strain can prime the immune system for a later booster with a drifted variant. Here, we investigated whether whole inactivated virus (WIV) vaccine can be processed to tablets suitable for sublingual (s.l.) use and whether s.l. vaccine administration can prime the immune system for a later intramuscular (i.m.) boost with a heterologous vaccine. In vitro results demonstrate that freeze-drying and tableting of WIV did not affect the integrity of the viral proteins or the hemagglutinating properties of the viral particles. Immunization experiments revealed that s.l. priming with WIV (prepared from the H5N1 vaccine strain NIBRG-14) 4 weeks prior to i.m. booster immunization with the same virus strongly enhanced hemagglutination-inhibition (HI) titers against NIBRG-14 and the drifted variant NIBRG-23. Moreover, s.l. (and i.m.) immunization with NIBRG-14 also primed for a subsequent heterologous i.m. booster immunization with NIBRG-23 vaccine. In addition to HI serum antibodies, s.l. priming enhanced lung and nose IgA responses, while i.m. priming enhanced lung IgA but not nose IgA levels. Our results identify s.l. vaccination as a user-friendly method to prime for influenza-specific immune responses toward homologous and drifted variants. PMID- 24482006 TI - A two-stage model of orientation integration for Battenberg-modulated micropatterns. AB - The visual system pools information from local samples to calculate textural properties. We used a novel stimulus to investigate how signals are combined to improve estimates of global orientation. Stimuli were 29 * 29 element arrays of 4 c/deg log Gabors, spaced 1 degrees apart. A proportion of these elements had a coherent orientation (horizontal/vertical) with the remainder assigned random orientations. The observer's task was to identify the global orientation. The spatial configuration of the signal was modulated by a checkerboard pattern of square checks containing potential signal elements. The other locations contained either randomly oriented elements ("noise check") or were blank ("blank check"). The distribution of signal elements was manipulated by varying the size and location of the checks within a fixed-diameter stimulus. An ideal detector would only pool responses from potential signal elements. Humans did this for medium check sizes and for large check sizes when a signal was presented in the fovea. For small check sizes, however, the pooling occurred indiscriminately over relevant and irrelevant locations. For these check sizes, thresholds for the noise check and blank check conditions were similar, suggesting that the limiting noise is not induced by the response to the noise elements. The results are described by a model that filters the stimulus at the potential target orientations and then combines the signals over space in two stages. The first is a mandatory integration of local signals over a fixed area, limited by internal noise at each location. The second is a task-dependent combination of the outputs from the first stage. PMID- 24482008 TI - Interventions for the treatment of twin-twin transfusion syndrome. AB - BACKGROUND: Twin-twin transfusion syndrome, a condition affecting monochorionic twin pregnancies, is associated with a high risk of perinatal mortality and morbidity. A number of treatments have been introduced to treat the condition but it is unclear which intervention improves maternal and fetal outcome. OBJECTIVES: The objective of this review was to evaluate the impact of treatment modalities in twin-twin transfusion syndrome. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 May 2013). SELECTION CRITERIA: Randomised and quasi-randomised studies of amnioreduction versus laser coagulation, septostomy versus laser coagulation or septostomy versus amnioreduction. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed eligibility and extracted data. We contacted study authors for additional information. MAIN RESULTS: Three studies (253 women and 506 babies) were included. All three trials were judged to be of moderate quality. One study compared amnioreduction with septostomy (71 women), whilst the other two studies compared amnioreduction with endoscopic laser coagulation (182 women). Not all trials provided outcome data that could be included in all meta-analyses. Amnioreduction compared with laser coagulation Although there was no difference in overall death between amnioreduction and laser coagulation (average risk ratio (RR) 0.87; 95% confidence interval (CI) 0.55 to 1.38 adjusted for clustering, two trials) or death of at least one infant per pregnancy (RR 0.91; 95% CI 0.75 to 1.09, two trials), or death of both infants per pregnancy (average RR 0.76; 95% 0.27 to 2.10, two trials), more babies were alive without neurological abnormality at the age of six years in the laser group than in the amnioreduction groups (RR 1.57; 95% CI 1.05 to 2.34 adjusted for clustering, one trial). There were no significant differences in the babies alive at six years with major neurological abnormality treated by laser coagulation or amnioreduction (RR 0.97; 95% CI 0.34 to 2.77 adjusted for clustering, one trial). Outcomes for death in this 2013 update are different from the previous 2008 update, where improvements in perinatal death and death of both infants per pregnancy were shown in the laser intervention arm. The NIHCD trial included in this update exerts an opposite direction of effects to the Eurofetus study, which was previously the only included laser study, hence the difference in outcome. Amnioreduction compared with septostomy There are no differences in overall death (RR 0.83; 95% CI 0.47 to 1.47, adjusted for clustering, one trial), death of at least one infant per pregnancy (RR 0.80; 95% CI 0.48 to 1.35, one trial), or death of both infants per pregnancy (RR 0.90; 95% CI 0.37 to 2.22, one trial) or gestational age at birth (RR 1.20; 95% CI -0.81 to 3.21, one trial) between amnioreduction and septostomy. AUTHORS' CONCLUSIONS: Endoscopic laser coagulation of anastomotic vessels should continue to be considered in the treatment of all stages of twin twin transfusion syndrome to improve neurodevelopmental outcomes.Further research targeted towards assessing the effect of treatment on milder (Quintero stage 1 and 2) and more severe (Quintero stage 4) forms of twin-twin transfusion syndrome is required. Studies should aim to assess long-term outcomes of survivors. PMID- 24482011 TI - FH535 inhibits the proliferation of HepG2 cells via downregulation of the Wnt/beta-catenin signaling pathway. AB - Hepatocellular carcinoma (HCC) is a primary cancer of the liver. Target therapy may improve prognosis of HCC. In the present study, we evaluated the inhibition of the Wnt/beta-catenin pathway as a potential therapeutic approach. HepG2 cells were treated with the beta-catenin inhibitor FH535. beta-catenin protein expression was semi-quantitatively assessed using western blot analysis. Cell proliferation was examined with a 3-(4,5-dimethyl-2-yl)-5-(3 carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium salt (MTS) assay. The mRNA expression of nitric oxide synthase (iNOS) was detected by reverse transcription polymerase chain reaction. The Griess assay was used to determine nitric oxide (NO) concentration. FH535 inhibited the proliferation of HepG2 cells and decreased beta-catenin protein expression. mRNA expression of iNOS, a target gene of the Wnt/beta-catenin pathway, was decreased in FH535-treated HepG2 cells compared to the control group. NO production was also reduced by FH535. In conclusion, the beta-catenin inhibitor FH535 may inhibit HCC cell proliferation via downregulation of the Wnt/beta-catenin pathway. Thus, targeting this pathway may be useful in HCC therapy. PMID- 24482009 TI - On the role of physiological fluctuations in quantitative gradient echo MRI: implications for GEPCI, QSM, and SWI. AB - PURPOSE: Physiological fluctuations in biological tissues adversely affect MR images if present during signal acquisition. This problem is especially important for quantitative MRI. The goal of the studies reported in this study was to reduce the contributions of physiological fluctuations in quantitative MRI based on T2* tissue relaxation properties. Specifically, in this study we deal with GEPCI, QSM, and SWI techniques and propose methods allowing for substantial improvement of their results. METHODS: We used a navigator imbedded in a multi gradient-echo sequence to record and correct MR signal phase fluctuations at each phase encoding step. All GEPCI, QSM, and SWI images were then reconstructed from a single acquisition. We used a keyhole-type approach to further average out effects of physiological fluctuations. Voxel spread function technique was used to correct for macroscopic field inhomogeneities. RESULTS: Brains of normal subjects and subjects with multiple sclerosis were studied. We demonstrated that our used strategies substantially reduced the width of the R2* = 1/T2* distribution within human brains and significantly improved quantification of tissue damage in multiple sclerosis. We also showed improved quality of the SWI and QSM images. CONCLUSION: The strategies used in this study greatly reduced physiologically induced artifacts in GEPCI, QSM, and SWI, improving the reliability of these techniques. PMID- 24482010 TI - mGlu3 receptor blockade inhibits proliferation and promotes astrocytic phenotype in glioma stem cells. AB - We have characterised, using both in vivo and in vitro methods, the effects of the metabotropic glutamate receptor subtype 3 (mGlu3) antagonist (LY341495) and agonist (LY379268) on the proliferation and differentiation of glioma stem cells (GSC). For in vitro studies, a CCK-8 assay was used to determine the cell proliferation, flow cytometry was performed to determine cell cycle phases, and immunohistochemistry and laser confocal microscopy were employed to detect CD133 expression. For in vivo studies, GSCs were injected into nude mice treated with either LY379268 or LY341495 and the growth of the tumours was measured after 3 weeks. When compared with controls, the proliferation rates and proportion of cells in S phase within the LY341495 treated group decreased in a time-dependent manner. In the presence of differentiation medium containing LY341495, GSC differentiation was diverted into an astrocyte rather than neuronal phenotype. The growth rate and volume of tumours injected into nude mice was reduced in LY341495 treated mice compared with controls. Thus pharmacological blockade of mGlu3 receptor signalling pathway significantly inhibits the growth and proliferation of GSCs both in vitro and in vivo while promoting differentiation to astrocytes. These results further implicate mGlu3 in the biology of glioma and as a target for continued research. PMID- 24482012 TI - Off-pump versus on-pump coronary artery bypass grafting. AB - Coronary artery bypass grafting (CABG) remains the preferred treatment in patients with complex coronary artery disease. However, whether the procedure should be performed with or without the use of cardiopulmonary bypass, referred to as off-pump and on-pump CABG, is still up for debate. Intuitively, avoidance of cardiopulmonary bypass seems beneficial as the systemic inflammatory response from extracorporeal circulation is omitted, but no single randomized trial has been able to prove off-pump CABG superior to on-pump CABG as regards the hard outcomes death, stroke or myocardial infarction. In contrast, off-pump CABG is technically more challenging and may be associated with increased risk of incomplete revascularization. The purpose of the review is to summarize the current literature comparing outcomes of off-pump versus on-pump coronary artery bypass surgery. PMID- 24482013 TI - The potential of FDG PET/CT for early diagnosis of cardiac device and prosthetic valve infection before morphologic damages ensue. AB - Diagnosis of cardiac mechanical device or prosthesis valve infection, and more importantly accurate localization of the infection site, such as defibrillator pocket, pacemaker lead, annular or peri-annular valve ring abscesses remain clinically challenging. Inconclusive diagnosis can lead to delayed antibiotic therapy, device extraction or surgical intervention, which may have dire consequences to the patient. Among patients with suspected cardiac mechanical device or prosthetic valve infection, recent publications advocate the use of (18)F-fluoro-2-deoxyglucose positron emission tomography computed tomography (FDG PET/CT), particularly when anatomy based imaging studies, such as echocardiography or CT, are uncertain or negative. A potential advantage of FDG PET/CT is in its detection of inflammatory cells early in the infection process, before morphologic damages ensue. However, there are many unanswered questions in the literature. There is a need for standardization amongst the various imaging studies, such as dietary preparation, duration and timing of image acquisition, image processing with and without CT attenuation correction, and more importantly image interpretation criteria. The answer for these issues awaits well designed, prospective studies. PMID- 24482014 TI - A new insight into fecal hemoglobin concentration-dependent predictor for colorectal neoplasia. AB - We sought to assess how much of the variation in incidence of colorectal neoplasia is explained by baseline fecal hemoglobin concentration (FHbC) and also to assess the additional predictive value of conventional risk factors. We enrolled subjects aged 40 years and over who attended screening for colorectal cancer with the fecal immunochemical test (FIT) in Keelung community-based integrated screening program. The accelerated failure time model was used to train the clinical weights of covariates in the prediction model. Datasets from two external communities were used for external validation. The area under curve (AUC) for the model containing only FHbC was 83.0% (95% CI: 81.5-84.4%), which was considerably greater than the one containing only conventional risk factors (65.8%, 95% CI: 64.2-67.4%). Adding conventional risk factors did not make significant additional contribution (p = 0.62, AUC = 83.5%, 95% CI: 82.1-84.9%) to the predictive model with FHbC only. Males showed a stronger linear dose response relationship than females, yielding gender-specific FHbC predictive models. External validation confirms these results. The high predictive ability supported by a dose-dependent relationship between baseline FHbC and the risk of developing colorectal neoplasia suggests that FHbC may be useful for identifying cases requiring closer postdiagnosis clinical surveillance as well as being an early indicator of colorectal neoplasia risk in the general population. Our findings may also make contribution to the development of the FHbC-guided screening policy but its pros and cons in connection with cost and effectiveness of screening should be evaluated before it can be applied to population-based screening for colorectal cancer. PMID- 24482015 TI - Variable response to propranolol treatment of kaposiform hemangioendothelioma, tufted angioma, and Kasabach-Merritt phenomenon. PMID- 24482016 TI - Anatomical location of erosions at the metatarsophalangeal joints in patients with rheumatoid arthritis. AB - OBJECTIVE: The aim of this study was to identify the anatomical location of erosions at the MTP joints in patients with RA using high-resolution 3T MRI. METHODS: In 24 patients with RA, the more symptomatic forefoot was imaged using 3T MRI. T1-weighted, intermediate-weighted and T2-weighted fat-suppressed sequences were acquired through the MTP joints, together with three-dimensional volumetric interpolated breath-hold examination (3D VIBE) and T1-weighted fat suppressed post-gadolinium contrast sequences. Images were scored for bone erosion in the distal and proximal part of the MTP joints using the RA MRI scoring (RAMRIS) system. The base of the proximal phalanx and the head of the metatarsal were divided into quadrants to determine the location of erosions (octants) in the dorsal-medial, dorsal-lateral, plantar-medial and plantar lateral regions. RESULTS: Seventeen females and seven males with a mean age of 55.5 years and disease duration of 10.6 years (range 0.6-36) were included. Eighteen patients were RF positive, the mean 44-joint DAS for CRP and ESR (DAS44CRP and DAS44ESR) were 2.5 (s.d. 0.8) and 2.6 (s.d. 0.9), respectively. In this cohort of patients with RA, irrespective of MTP joint location, octants located in the proximal part (metatarsal) of the joint and the plantar aspect of the joint were more eroded. CONCLUSION: This is the first study to report the anatomical location of erosions at the MTP joints in patients with RA. We noted that erosions were more commonly seen on the plantar aspect of the metatarsal head in RA, supporting the hypothesis of a relationship between biomechanical demands and bone changes in the forefoot. PMID- 24482017 TI - Risks of circulatory diseases among Mayak PA workers with radiation doses estimated using the improved Mayak Worker Dosimetry System 2008. AB - The new Mayak Worker Dosimetry System 2008 (MWDS-2008) was published in 2013 and supersedes the Doses-2005 dosimetry system for Mayak Production Association (PA) workers. It provides revised external and internal dose estimates based on the updated occupational history data. Using MWDS-2008, a cohort of 18,856 workers first employed at one of the main Mayak PA plants during 1948-1972 and followed up to 2005 was identified. Incidence and mortality risks from ischemic heart disease (IHD) (International Classification of Diseases (ICD)-9 codes 410-414) and from cerebrovascular diseases (CVD) (ICD-9 codes 430-438) were examined in this cohort and compared with previously published risk estimates in the same cohort based on the Doses-2005 dosimetry system. Significant associations were observed between doses from external gamma-rays and IHD and CVD incidence and also between internal doses from alpha-radiation and IHD mortality and CVD incidence. The estimates of excess relative risk (ERR)/Gy were consistent with those estimates from the previous studies based on Doses-2005 system apart from the relationship between CVD incidence and internal liver dose where the ERR/Gy based on MWDS-2008 was just over three times higher than the corresponding estimate based on Doses-2005 system. Adjustment for smoking status did not show any effect on the estimates of risk from internal alpha-particle exposure. PMID- 24482018 TI - Candesartan cilexetil 32 mg/hydrochlorothiazide 25 mg in unselected patients with high or very high cardiovascular risk: efficacy, safety, and metabolic impact. AB - BACKGROUND AND OBJECTIVES: Safety and efficacy of the fixed-dose combination candesartan cilexetil 32 mg/hydrochlorothiazide 25 mg has been demonstrated in a number of randomized clinical trials. Because stringent inclusion and exclusion criteria prohibit many high-risk patients from being investigated in clinical trials we aimed to assess the effectiveness, tolerability, and safety in a large unselected cohort of high-risk patients in primary care. The primary objective was the efficacy of candesartan cilexetil 32 mg/hydrochlorothiazide 25 mg in lowering the office-based blood pressure (BP). Secondary objectives were changes of metabolic parameters and safety. METHODS: A multicenter, non-interventional study of patients with a BP >= 140 mmHg systolic and/or 90 mmHg diastolic and additional cardiovascular risk factors. Patients received the fixed-dose combination of candesartan cilexetil 32 mg and hydrochlorothiazide 25 mg for 24 weeks. RESULTS: A total of 3,390 patients with a mean age of 61.7 +/- 10.6 years, 57.8 % being male, and a mean body mass index of 29.7 kg/m(2) were documented. Of these, 70.9 % had at least one additional cardiovascular risk factor such as coronary artery disease (45.5 %) or diabetes mellitus (44.5 %). Baseline BP was 159.6 +/- 15.3 over 93.5 +/- 9.5 mmHg. BP at 24 weeks was reduced by 32.3 +/- 15.8 systolic and 16.1 +/- 10.2 mmHg diastolic compared with baseline (p < 0.001 each). Systolic BP (SBP) and diastolic BP (DBP) was normalized (<140/<90 mmHg) in 57.4 % of non-diabetic patients. An SBP <140 mmHg or SBP reduction of >= 20 mmHg was achieved by 77.9 % non-diabetic patients. Fasting plasma glucose (-5.9 mg/dL), glycosylated hemoglobin (-0.18 %), low-density lipoprotein cholesterol ( 8.5 mg/dL) and triglycerides (-20.3 mg/dL) were reduced significantly, high density lipoprotein was increased by 0.18 %, while potassium and creatinine levels remained stable. The proportion of patients with adverse drug reactions (ADRs) was 1.3 % (n = 61 events in 45 patients). There were ten serious ADRs in eight patients; four patients died without causal relationship to study drug. CONCLUSIONS: The results confirm previous randomized clinical trial data supporting the effectiveness, tolerability, and safety of this fixed-dose combination in an unselected patient population with high cardiovascular risk. PMID- 24482020 TI - Real-time monitoring of auxin vesicular exocytotic efflux from single plant protoplasts by amperometry at microelectrodes decorated with nanowires. AB - Recent biochemical results suggest that auxin (IAA) efflux is mediated by a vesicular cycling mechanism, but no direct detection of vesicular IAA release from single plant cells in real-time has been possible up to now. A TiC@C/Pt QANFA micro-electrochemical sensor has been developed with high sensitivity in detection of IAA, and it allows real-time monitoring and quantification of the quantal release of auxin from single plant protoplast by exocytosis. PMID- 24482022 TI - Double C(arom)-H activation associated with etheral oxygen insertion to phenazine architecture in oxidisable ruthenium(III) complexes: a mechanistic insight. AB - Three examples of unusual double aromatic C?H bond activation associated with insertion of etheral oxygen atom to phenazine architecture in Ru(III) complexes are reported. The chemical transformations have led to the formation of new Ru(IV) complexes with angular pentacyclo heterocyclic ligands. A mechanistic investigation indicates that the overall process is a combination of successive steps involving air (O2 ) and H2 O. PMID- 24482021 TI - Valproic acid: a new candidate of therapeutic application for the acute central nervous system injuries. AB - Acute central nervous system (CNS) injuries, including stroke, traumatic brain injury (TBI), and spinal cord injury (SCI), are common causes of human disabilities and deaths, but the pathophysiology of these diseases is not fully elucidated and, thus, effective pharmacotherapies are still lacking. Valproic acid (VPA), an inhibitor of histone deacetylation, is mainly used to treat epilepsy and bipolar disorder with few complications. Recently, the neuroprotective effects of VPA have been demonstrated in several models of acute CNS injuries, such as stroke, TBI, and SCI. VPA protects the brain from injury progression via anti-inflammatory, anti-apoptotic, and neurotrophic effects. In this review, we focus on the emerging neuroprotective properties of VPA and explore the underlying mechanisms. In particular, we discuss several potential related factors in VPA research and present the opportunity to administer VPA as a novel neuropective agent. PMID- 24482023 TI - Studying IFN-gamma, IL-17 and FOXP3 in pediatric lupus nephritis. AB - BACKGROUND: We studied the cytokines secreted by the inflammatory T cell subgroups (IFN-gamma and IL-17) and FOXP3 expression in lupus nephritis (LN) and analyzed associations with clinical and histopathological parameters. METHODS: Renal tissue samples of 39 LN patients were studied. Immunohistochemical staining was carried out with antibodies against IFN-gamma, IL-17, and FOXP3. RESULTS: Both IFN-gamma (+) and IL-17+ cells were statistically higher in LN tissues when compared with controls (p < 0.01). The cells in the tubulointerstitium were CD3 + CD4+ displaying a Th1 and Th17 phenotype, whereas the less intense population in the glomeruli was CD3-CD4-. Interstitial CD3 + CD4+ FOXP3+ cells were also significantly higher in LN biopsies than in control tissues (p < 0.01). IFN-gamma (+) and IL-17+ cells were more intense among class IV LN as compared to class II, III LN (p < 0.01 and p = 0.001, respectively). Subsequently, when IL-17 and IFN gamma staining was compared between the proliferative LN classes, class III and IV patients had more intense staining compared to class II (all p < 0.05). IFN gamma immunostaining correlated positively with serum creatinine and negatively with albumin levels and glomerular filtration rate (GFR). IL-17 immunostaining correlated with proteinuria, requirement for pulse steroids, and SLEDAI renal score, and negatively with GFR. Furthermore, glomerular and interstitial IL-17 and IFN-gamma stainings were significantly associated with various parameters of histological activity (p < 0.05). CONCLUSION: We suggest that IFN-gamma and IL-17 could have a role in the pathogenesis and progression of LN. The Th1 and Th17 cells may be imperative in the severity of LN. Recognizing the complexity of the immune pathways involved in lupus reminds us that targeting B cells only may not suffice to control the progression of the inflammation. PMID- 24482024 TI - Draining the edema: a new role for aquaretics? AB - Investigations into edema formation in nephrotic syndrome have mostly focused on the primary role of sodium. While there is controversy about whether sodium retention is an inherent aspect of nephrotic syndrome (overfill hypothesis) or a secondary consequence (underfill hypothesis), the critical role of sodium in driving fluid retention is generally accepted. Consequently, treatment of edema is based on enhancing renal sodium excretion, using saluretics to block tubular reabsorption of sodium. However, there is also evidence of renal water retention: urine in nephrotic patients is typically highly concentrated (unless urinary concentrating ability is impaired by loop diuretics), and vasopressin levels are commonly elevated. Consequently, aquaretics, i.e., drugs that inhibit renal water reabsorption, may constitute effective treatments for nephrotic edema. In fact, these drugs are already approved for the treatment of non-nephrotic edematous states, such as those encountered in congestive heart or liver failure. In this edition of Pediatric Nephrology, two case reports raise the possibility that aquaretics may also be helpful in the treatment of nephrotic edema. These case reports provide no solid evidence for such treatment, and there clearly are serious concerns about inducing critical hypovolemia with potentially catastrophically consequences, such as thrombosis and shock. Yet these concerns similarly apply to saluretics, which clinicians routinely use in the treatment of edema. In addition, the described powerful effect of aquaretics with respect to the resolution of edema, as well as our understanding of the underlying physiology, argue for a more systematic, yet careful assessment of these drugs in the treatment of nephrotic syndrome. PMID- 24482025 TI - Chimpanzees form long-term memories for food locations after limited exposure. AB - Remembering the location of fruiting trees for extended periods of time has been hypothesized to play a major role in the evolution of primate cognition. Such ability would be especially useful when paired with a fast learning mechanism capable of consolidating long-term memory after minimal exposure. We investigated whether chimpanzees (Pan troglodytes) can remember different food locations after minimal exposure (i.e., 1-2 trials) both after 24 hr and after 3-month. We released pairs of chimpanzees in their indoor enclosure (the enclosure of group A measured 430 m(2) and group B's measured 175 m(2) ) and tested them for four consecutive days (Baseline, Test, Retest, and Post-test). During the Test and Retest food was hidden in the same location whereas no food was hidden during the Baseline and Post-test days (control trials). Subjects were tested with four different locations and assessed for their retention after 24 hr and 3-month since the initial food discovery. Results revealed that chimpanzees accurately remembered the locations in which they found the food after one or two exposures to them, and both after 24 hr and a 3-month retention interval. PMID- 24482027 TI - Report from the 2nd annual RICiFa meeting (International Meeting on Pharmaceutical Sciences 2012). PMID- 24482026 TI - Mixed polyethylene glycol-modified breviscapine-loaded solid lipid nanoparticles for improved brain bioavailability: preparation, characterization, and in vivo cerebral microdialysis evaluation in adult Sprague Dawley rats. AB - Breviscapine is used in the treatment of ischemic cerebrovascular diseases, but it has a low bioavailability in the brain due to its poor physicochemical properties and the activity of P-glycoprotein efflux pumps located at the blood brain barrier. In the present study, breviscapine-loaded solid lipid nanoparticles (SLN) coated with polyethylene glycol (PEG) derivatives were formulated and evaluated for their ability to enhance brain bioavailability. The SLNs were either coated with polyethylene glycol (40) (PEG-40) stearate alone (Bre-GBSLN-PS) or a mixture of PEG-40 stearate and 1,2-distearoyl-sn-glycero-3 phosphoethanolamine-N-PEG2000 (DSPE-PEG2000) (Bre-GBSLN-PS-DSPE) and were characterized both in vitro and in vivo. The mean particle size, polydispersity index, and entrapment efficiency for Bre-GBSLN-PS and Bre-GBSLN-PS-DSPE were 21.60 +/- 0.10 and 22.60 +/- 0.70 nm, 0.27 +/- 0.01 and 0.26 +/- 0.04, and 46.89 +/- 0.73% and 47.62 +/- 1.86%, respectively. The brain pharmacokinetic parameters revealed that the brain bioavailability of breviscapine from the Bre-GBSLN-PS and Bre-GBSLN-PS-DSPE was significantly enhanced (p < 0.01) with the area under concentration-time curve (AUC) of 1.59 +/- 0.39 and 1.42 +/- 0.58 MUg h/mL of breviscapine, respectively, in comparison to 0.11 +/- 0.02 MUg h/mL from the commercial breviscapine injection. The ratios of the brain AUC for scutellarin in comparison with the plasma scutellarin AUC for commercial breviscapine injection, Bre-GBSLN-PS, and Bre-GBSLN-PS-DSPE were 0.66%, 2.82%, and 4.51%, respectively. These results showed that though both SLN formulations increased brain uptake of breviscapine, Bre-GBSLN-PS-DSPE which was coated with a binary combination of PEG 40 stearate and DSPE-PEG2000 had a better brain bioavailability than Bre-GBSLN PS. Thus, the coating of SLNs with the appropriate PEG derivative combination could improve brain bioavailability of breviscapine and can be a promising tool for brain drug delivery. PMID- 24482028 TI - Health literacy in vascular and interventional radiology: a comparative analysis of online patient education resources. AB - PURPOSE: The Internet is frequently accessed by patients as a resource for medical knowledge. However, the provided material is typically written at a level well above the recommended 7th grade level. A clear understanding of the capabilities, limitations, risks, and benefits of interventional radiology by patients, both current and prospective, is hindered when the textual information offered to the public is pitched at a level of sophistication too high for general comprehension. METHODS: In January 2013, all 25 patient education resources from the Cardiovascular and Interventional Radiology Society of Europe (CIRSE) Web site ( http://www.cirse.org ) and all 31 resources from the Society of Interventional Radiology (SIR) Web site ( http://www.sirweb.org ) were analyzed for their specific level of readability using ten quantitative scales: Flesch Reading Ease, Flesch-Kincaid Grade Level, Simple Measure of Gobbledygook, Gunning fog index, New Fog Count, Coleman-Liau index, FORCAST formula, Fry graph, Raygor Readability Estimate, and New Dale-Chall. RESULTS: Collectively, the patient education resources on the CIRSE Web site are written at the 12.3 grade level, while the resources on the SIR Web site are written at the 14.5 grade level. CONCLUSION: Educational health care materials available on both the CIRSE and the SIR Web sites are presented in language in the aggregate that could be too difficult for many lay people to fully understand. Given the complex nature of vascular and interventional radiology, it may be advantageous to rewrite these educational resources at a lower reading level to increase comprehension. PMID- 24482029 TI - Treatment of chyle leak by percutaneous alcohol sclerosis of the cisterna chyli: a case report. PMID- 24482030 TI - Systematic review and meta-analysis of thermal ablation versus surgical nephrectomy for small renal tumours. AB - PURPOSE: A systematic review was undertaken to provide a meta-analysis of clinical trials comparing thermal ablation with surgical nephrectomy for small renal tumours. METHODS: PubMed (MEDLINE), EMBASE, AMED, and Scopus were searched in August 2013 for eligible prospective or retrospective comparative trials following the PRISMA selection process. Thermal ablation was compared with surgical nephrectomy. Quality of included studies was assessed on the Newcastle Ottawa Scale (NOS). The primary endpoint was disease-free survival and was analyzed on the log-hazard scale. Secondary outcome measures included complications, local recurrence, and decline of renal function. Hazard ratios (HR) and risk ratios (RR) were calculated with a random effects model, and meta regression analysis was performed to explore clinical heterogeneity. RESULTS: Six clinical trials (1 randomized and 5 cohort; 6-8 stars on the NOS scale) involving 587 patients with small renal tumors (mean size 2.5 cm) treated with either thermal ablation (percutaneous or laparoscopic application of radiofrequency or microwave) or surgical nephrectomy (open or laparoscopic) were analyzed. Overall complication rate was significantly lower in the ablation group (7.4 vs. 11%; RR: 0.55, 95% confidence interval [CI]: 0.31-0.97, p = 0.04). Postoperative decline of eGFR was higher in case of nephrectomy (mean difference: -14.6 ml/min/1.73 m(2), 95% CI: -27.96 to -1.23, p = 0.03). Local recurrence rate was the same in both groups (3.6 vs. 3.6%; RR: 0.92, 95% CI: 0.4-2.14, p = 0.79) and disease-free survival also was similar up to 5 years (HR: 1.04, 95% CI: 0.48-2.24, p = 0.92). CONCLUSIONS: Thermal ablation of small renal masses produces oncologic outcomes similar to surgical nephrectomy and is associated with significantly lower overall complication rates and a significantly less decline of renal function. More randomized, controlled trials are necessary. PMID- 24482031 TI - Combination of percutaneous osteosynthesis and vertebroplasty of thoracolumbar split fractures under CT and fluoroscopy guidance: a new technique. AB - OBJECTIVES: The purpose of our study was to evaluate the technical feasibility of the combination involving percutaneous screw fixation and vertebroplasty in split fractures of thoracolumbar spine. METHODS: Institutional review board approval and informed consent were obtained. Ten consecutive adult patients who had posttraumatic vertebral split fractures (Magerl A2) were prospectively treated by an interventional radiologist under computed tomography and fluoroscopy guidance. Using a bilateral route under local anesthesia, one 4.0-mm cannulated screw was placed on one side to fix the fracture, and on the other side, vertebroplasty was performed. Follow-up ranging from 12 to 24 months was assessed using visual analog scale (VAS) and Oswestry disability index (ODI) RESULTS: Combined procedures were performed on thoracic and lumbar vertebrae, creating both osteosynthesis and cement bridge between the displaced fragment and the rest of the vertebral body. Mean VAS measurements +/- standard deviation (SD) decreased from 7.5 +/- 1.5 preoperatively to 3.2 +/- 1.9 at 1 day, 2.1 +/- 1.2 at 1 month, and 1.9 +/- 1.4 at the last examination (P < 0.001). Mean ODI scores +/- SD decreased from 65.3 +/- 16.2, preoperatively, to 16.1 +/- 5.0 at the final examination (P < 0.001). CONCLUSIONS: This study suggests that type A2 vertebral fractures could be successfully stabilized by the combination of percutaneous osteosynthesis and vertebroplasty. PMID- 24482033 TI - Recombinant biglycan promotes bone morphogenetic protein-induced osteogenesis. AB - The aim of this study was to determine the effects of glutathione-S-transferase fused recombinant biglycan (GST-BGN) on craniofacial bone regeneration. We recently demonstrated a positive effect of tissue-derived BGN on bone morphogenetic protein 2 (BMP-2) function, which is exerted likely via the BGN core protein. Here, we investigated the effects of GST-BGN lacking any posttranslational modifications on BMP-2 function in vitro and in vivo. In the C2C12 cell culture system, BMP-2-induced Smad 1/5/8 phosphorylation and alkaline phosphatase activity were both enhanced by the addition of GST-BGN. For the in vivo effect, we employed a Sprague-Dawley rat mandible defect model utilizing 1 ug (optimal) or 0.1 ug (suboptimal) of BMP-2 combined with 0, 2, 4, or 8 ug of GST-BGN. At 2 weeks post-surgery, newly formed bone was evaluated by microcomputed tomography and histologic analyses. The results revealed that the greatest amounts of bone within the defect were formed in the groups of suboptimal BMP-2 combined with 4 or 8 ug of GST-BGN. Also, bone was well organized versus that formed by the optimal dose of BMP. These results indicate that recombinant BGN is an efficient substrate to promote low-dose BMP-induced osteogenesis. PMID- 24482034 TI - A generalized genetic random field method for the genetic association analysis of sequencing data. AB - With the advance of high-throughput sequencing technologies, it has become feasible to investigate the influence of the entire spectrum of sequencing variations on complex human diseases. Although association studies utilizing the new sequencing technologies hold great promise to unravel novel genetic variants, especially rare genetic variants that contribute to human diseases, the statistical analysis of high-dimensional sequencing data remains a challenge. Advanced analytical methods are in great need to facilitate high-dimensional sequencing data analyses. In this article, we propose a generalized genetic random field (GGRF) method for association analyses of sequencing data. Like other similarity-based methods (e.g., SIMreg and SKAT), the new method has the advantages of avoiding the need to specify thresholds for rare variants and allowing for testing multiple variants acting in different directions and magnitude of effects. The method is built on the generalized estimating equation framework and thus accommodates a variety of disease phenotypes (e.g., quantitative and binary phenotypes). Moreover, it has a nice asymptotic property, and can be applied to small-scale sequencing data without need for small-sample adjustment. Through simulations, we demonstrate that the proposed GGRF attains an improved or comparable power over a commonly used method, SKAT, under various disease scenarios, especially when rare variants play a significant role in disease etiology. We further illustrate GGRF with an application to a real dataset from the Dallas Heart Study. By using GGRF, we were able to detect the association of two candidate genes, ANGPTL3 and ANGPTL4, with serum triglyceride. PMID- 24482035 TI - Benzodiazepine-associated hepatic encephalopathy significantly increased healthcare utilization and medical costs of Chinese cirrhotic patients: 7-year experience. AB - BACKGROUND AND OBJECTIVES: In cirrhosis, hypersensitivity to benzodiazepines (BZD) and precipitating hepatic encephalopathy (HE) have been reported. The aim of this study was to evaluate the safety, economic impact and modifiable factors that are associated with the excess risk of BZD-associated HE in cirrhotic patients. METHODS: Between July 2005 and March 2012, 1,612 Chinese cirrhotic patients with and without using long-t 1/2-BZD or short-t 1/2-BZD were enrolled and followed up for 6 months. RESULTS: Among BZD users, the per-person HE-related healthcare utilization and medical costs were found to have progressively increased from 2005 to 2012. Cirrhotic BZD users had a higher percentage of smoking, alcohol drinking, simultaneous consumption of non-BZD drugs, and had a higher incidence of non-cirrhotic chronic illness than non-BZD users. Multivariate analysis indicated that hypoalbuminemia (<3 g/dL), long-acting (t 1/2 > 12-h), high-dosage (>1.5 defined daily dose equivalents) and long-duration (>2-months) BZD use, carrier of variant genotypes (AG + GG) of GABRA 1 (rs2290732) and having the wild genotype (TT) of GABRG 2 (rs211037) were significant predictors of the development of BZD-associated HE in cirrhotic patients. Additionally, synergistic effects of the above significant predictors on BZD-associated HE risk could be identified. CONCLUSIONS: Our study confirms the clinical and economic impact of BZD-associated HE in cirrhotic BZD-users. Accordingly, extra caution is needed when treating cirrhotic BZD users with the above risk factors in order to avoid the BZD-associated HE in cirrhotic patients. PMID- 24482036 TI - Analysis of U2 small nuclear RNA fragments in the bile differentiates cholangiocarcinoma from primary sclerosing cholangitis and other benign biliary disorders. AB - BACKGROUND AND OBJECTIVES: Up to now the diagnosis of early stage cholangiocarcinoma (CC) has remained difficult, with low sensitivities reported for current diagnostic methods. Based on recent promising findings about circulating U2 small nuclear RNA fragments (RNU2-1f) as novel blood-based biomarkers for pancreatic and colorectal adenocarcinoma, we studied the utility of RNU2-1f as a diagnostic marker of CC in bile fluid. METHODS: Bile fluid was collected from patients with CC (n = 12), controls (patients with choledocholithiasis) (n = 11) and with primary sclerosing cholangitis (PSC; n = 11). RNU2-1f levels were measured by real-time polymerase chain reaction normalized to cel-54. RESULTS: Measurement of RNU2-1f levels in bile fluids enabled the differentiation of patients with CC from controls in all cases. Furthermore, RNU2-1f levels in bile fluids of patients with CC were significantly higher than in patients with PSC, resulting in a receiver-operating characteristic curve area of 0.856, with sensitivity of 67 % and specificity of 91 %. CONCLUSIONS: Our data suggest that the measurement of RNU2-1 fragments detected in the bile fluid can be used as a diagnostic marker for CC and should be included in future prospective diagnostic studies for this disease entity. PMID- 24482037 TI - Calcium channel blockers for primary Raynaud's phenomenon. AB - BACKGROUND: Calcium channel blockers are the most commonly prescribed drugs for people with primary Raynaud's phenomenon. Primary Raynaud's phenomenon is a common condition characterised by an exaggerated vasospastic response to cold or emotion: classically the digits (fingers and toes) turn white, then blue, then red. OBJECTIVES: To assess the effects of different calcium channel blockers for primary Raynaud's phenomenon as determined by attack rates, severity scores, participant-preference scores and physiological measurements. SEARCH METHODS: The Cochrane Peripheral Vascular Diseases Group Trials Search Co-ordinator (TSC) searched the Specialised Register (last searched February 2013) and the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 1). In addition the TSC searched clinical trials databases. SELECTION CRITERIA: Randomised controlled trials evaluating the effects of oral calcium channel blockers for the treatment of primary Raynaud's phenomenon. DATA COLLECTION AND ANALYSIS: Three review authors independently assessed the trials for inclusion and their quality, and extracted the data. Data extraction included adverse events. We contacted trial authors for missing data. MAIN RESULTS: We included seven randomised trials with 296 participants. Although overall all the trials were classed as being at low or unclear risk of bias, the sample size of the included trials was small and there was unclear reporting of outcomes. Four trials examined nifedipine and the remainder nicardipine. Comparisons were with placebo in six trials and with both dazoxiben and placebo in one trial (only the nifedipine versus placebo data were used within this review). Treatment with oral calcium channel blockers was minimally effective in primary Raynaud's phenomenon at decreasing the frequency of attacks (standardised mean difference of 0.23; 95% confidence interval (CI) 0.08 to 0.38, P = 0.003). This translates to 1.72 (95% CI 0.60 to 2.84) fewer attacks per week on calcium channel blockers compared to placebo. One trial provided details on duration of attacks reporting no statistically significant difference between the nicardipine and placebo groups (no P value reported). Only two trials provided any detail of statistical comparisons of (unvalidated) severity scores between treatment groups: one of these trials (60 participants) reported a mean severity score of 1.55 on placebo and 1.36 on nicardipine, difference 0.2 (95% CI of difference 0 to 0.4, no P value reported) and the other trial (three participants only with primary Raynaud's phenomenon) reported a median severity score of 2 on both nicardipine and placebo treatment (P > 0.999). Participant-preference scores were included in four trials, but in only two were results specific to participants with primary Raynaud's phenomenon, and scoring systems differed between trials: scores differed between treatments in only one trial, in which 33% of participants on placebo and 73% on nifedipine reported improvement in symptoms (P < 0.001). Physiological measurements were included as outcome measures in five trials (different methodologies were used in each): in none of these trials were any statistically significant between-treatment group differences found. Treatment with calcium channel blockers appeared to be associated with a number of adverse reactions, including headaches, flushing and oedema (swelling). AUTHORS' CONCLUSIONS: The randomised controlled trials included in this review provide moderate-quality evidence that oral calcium channel blockers are minimally effective in the treatment of primary Raynaud's phenomenon as measured by the frequency of attacks. However, the results of this review were limited by small sample sizes in the included studies and by variable data quality, particularly with regard to outcome measures. PMID- 24482038 TI - Long-term outcome of 4,040 children diagnosed with pediatric low-grade gliomas: an analysis of the Surveillance Epidemiology and End Results (SEER) database. AB - BACKGROUND: Children with pediatric low-grade gliomas (PLGG) are known to have excellent 10-year survival rates; however the outcomes of adult survivors of PLGG are unknown. We identified patients diagnosed with PLGG diagnosed between 1973 and 2008 through the Surveillance Epidemiology and End Results (SEER) database to examine outcomes of adult survivors of PLGG. PROCEDURE: Four thousand and forty patients with either WHO grade I or II PLGG were identified and outcome data retrieved. Two analyses were performed to assess survival and risk of death from tumor. Competing risks analysis was conducted and cumulative incidence curves of death due to disease were generated. Cox proportional hazards regression was performed, with adjustment for non-disease death. Kaplan-Meier curves for overall cancer specific survival (OS) were also generated. RESULTS: The 20-year OS was 87% +/- 0.8% and the 20-year cumulative incidence of death due to glioma was 12% +/- 0.8%. The incidence of death after transition to adulthood (age greater than 22 years) was slightly lower, with 20-year cumulative incidence of disease death of 7% +/- 1.8%. Year of diagnosis, age of diagnosis, histology, WHO grade, primary site, radiation, and degree of initial resection were prognostic in univariate analysis, while the administration of radiation was the greatest risk of death in multivariate analysis of OS (hazard ratio = 3.9). CONCLUSIONS: PLGGs are associated with an excellent long-term survival, with a low likelihood of PLGG related death in adult survivors. Treatment strategies for pediatric tumors should therefore aim for disease control during childhood and adolescence with an emphasis on minimizing long-term treatment induced toxicities. PMID- 24482040 TI - Coupling of an N-heterocyclic carbene on iron with alkynes to form eta5 cyclopentadienyl-diimine ligands. AB - A cyclometalated N-heterocyclic carbene ligand in a half-sandwich iron complex was found to couple with alkynes, leading to a unique type of ring opening of the carbene ligand and the formation of ferrocenyl-diimine complexes. An intermediary iron complex obtained from the reaction with phenylacetylene reveals that the ring opening follows the formation of a fused heterocycle consisting of an imidazole ring and two alkynes. PMID- 24482039 TI - Evaluation of structured patient education in occupational skin diseases: a systematic assessment of the disease-specific knowledge. AB - PURPOSE: The aim of this study was to evaluate the effectiveness of patient education in occupational skin diseases (OSD) regarding changes of the disease specific knowledge. METHODS: One hundred and five patients participated in structured patient education as part of an interdisciplinary outpatient prevention measure. In a prospective one-group pre-post-design, the disease specific knowledge was assessed with the validated "Occupational Skin Diseases Knowledge Questionnaire" (OSD-KQ) before (T0) and after the intervention (T1). A subcohort (n = 68) was examined 2-3 months later (T2). RESULTS: The mean OSD-KQ score significantly improved from 38.5 (59.2% of correct answers, T0) to 55.6 (85.5% of correct answers, T1). A pronounced heterogeneity was observed among the participants regarding the pre-interventional knowledge (10.8-84.6% of correct answers, T0) and the individual knowledge gain. Patients who worked in health related occupations scored significantly higher. Age and sex did not influence the knowledge. In a subcohort, a significantly improved disease-specific knowledge of 52.3 (80.5% of correct answers) could still be found 2-3 months after the intervention (T2). CONCLUSIONS: Structured patient education significantly improves the disease-specific knowledge in patients with OSD. The study indicates not only positive short- but also sustainable long-term effects on the knowledge gain. The OSD-KQ can serve as a tool to evaluate and improve patient education. Health educators need to be aware of the heterogeneity regarding the participants' knowledge and take this into account during educational practice. Additional counseling may be necessary to meet the individual learners' needs. PMID- 24482041 TI - Intertumor heterogeneity of non-small-cell lung carcinomas revealed by multiplexed mutation profiling and integrative genomics. AB - Non-small-cell lung cancer (NSCLC) is a heterogeneous disease, with a burden of genomic alterations exceeding most other tumors. The goal of our study was to evaluate the frequencies of co-occurring mutations and copy-number aberrations (CNAs) within the same tumor and to evaluate their potential clinical impact. Mass-spectrometry based mutation profiling using a customized lung cancer panel evaluating 214 mutations across 26 key NSCLC genes was performed on 230 nonsquamous NSCLC and integrated with genome-wide CNAs and clinical variables. Among the 138 cases having at least one mutation, one-third (41, 29.7%) showed two or more mutations, either in the same gene (double mutation) or in different genes (co-mutations). In epidermal growth factor receptor (EGFR) mutant cancers, there was a double mutation in 18% and co-mutations in the following genes: TP53 (10%), PIK3CA (8%), STK11 (6%) and MET (4%). Significant relationships were detected between EGFR mutation and 1p, 7p copy gains (harboring the EGFR gene) as well as 13q copy loss. KRAS mutation was significantly related with 1q gain and 3q loss. For Stage I, tumors harboring at least one mutation or PIK3CA mutation were significantly correlated with poor prognosis (p-value = 0.02). When combining CNAs and mutational status, patients having both KRAS mutation and the highest related CNA (3q22.3 copy loss) showed a significant poorer prognosis (p value = 0.03). Our study highlights the clinical relevance of studying tumor complexity by integrative genomic analysis and the need for developing assays that broadly screen for both "actionable" mutations and copy-number alterations to improve precision of stratified treatment approaches. PMID- 24482042 TI - Photon dose mixed in monoenergetic neutron calibration fields using 7Li(p,n)7Be reaction. AB - The ambient dose equivalents H*(10) of photons mixed in the 144, 250 and 565 keV monoenergetic neutron fields were evaluated using measurements from an NaI(Tl) detector and calculations done using the MCNP-ANT code. It was found that H*(10) of the photons produced in the target assembly dominates the dose, particularly near the target. The H*(10) of the photons produced in other materials in the field increases with the increase in distance from the target and could not be neglected at a large distance from the target. The ratios of the H*(10) of the mixed photons to that of the monoenergetic neutrons for 144, 250 and 565 keV neutron fields, were evaluated to be below 5.5, 6.9 and 1.5 %, respectively. The ratios were calculated at calibration points between 100 and 500 cm from the target. PMID- 24482043 TI - Pectoral muscle detection in mammograms using local statistical features. AB - Mammography is a primary imaging method for breast cancer diagnosis. It is an important issue to accurately identify and separate pectoral muscles (PM) from breast tissues. Hough-transform-based methods are commonly adopted for PM detection. But their performances are susceptible when PM edges cannot be depicted by straight lines. In this study, we present a new pectoral muscle identification algorithm which utilizes statistical features of pixel responses. First, the Anderson-Darling goodness-of-fit test is used to extract a feature image by assuming non-Gaussianity for PM boundaries. Second, a global weighting scheme based on the location of PM was applied onto the feature image to suppress non-PM regions. From the weighted image, a preliminary set of pectoral muscles boundary components is detected via row-wise peak detection. An iterative procedure based on the edge continuity and orientation is used to determine the final PM boundary. Our results on a public mammogram database were assessed using four performance metrics: the false positive rate, the false negative rate, the Hausdorff distance, and the average distance. Compared to previous studies, our method demonstrates the state-of-art performance in terms of four measures. PMID- 24482044 TI - MicroRNA-34a/c function as tumor suppressors in Hep-2 laryngeal carcinoma cells and may reduce GALNT7 expression. AB - A family of small non-coding RNAs, ~22 nt in length, known as microRNAs (miRNAs), regulating ~30% of all human gene expression, have been reported to be involved in the pathogenesis of a number of types of cancers, including laryngeal squamous cell carcinoma (LSCC). In the current study, miR-34a and miR-34c were observed to be downregulated in human LSCC tissues. Ectopic expression of miR-34a and miR-34c in Hep-2 cells significantly induced the cell proliferation and migration ability in vitro. UDP-N-acetyl-alpha-D-galactosamine:polypeptide-N acetylgalactosaminyltransferase 7 (GALNT7), whose expression is negatively regulated by miR-34a and miR-34c in Hep-2 cells, is confirmed to be a novel direct target gene of miR-34a and miR-34c. In conclusion, the current results suggest that miR-34a and miR-34c may function as tumor suppressors in LSCC through downregulation of GALNT7. The study of miR-34a, miR-34c and its novel target, GALNT7, may serve as novel potential makers for LSCC therapy. PMID- 24482045 TI - Filling carbon nanotubes with Prussian blue nanoparticles of high peroxidase-like catalytic activity for colorimetric chemo- and biosensing. AB - Facile filling of multiwalled carbon nanotubes (MWCNTs) with Prussian blue nanoparticles (PBNPs) of high peroxidase-like catalytic activity was performed to develop novel colorimetric sensing protocols for assaying H2O2 and glucose. Fine control of PBNP growth was achieved by modulating the concentration ratio of K3 [Fe(CN)6] and FeSO4 precursors in an acidic solution containing ultrasonically dispersed MWCNTs, and thus size-matched PBNPs could be robustly immobilized in the cavities of the MWCNTs (MWCNT-PBin). Unlike other reported methods involving complicated procedures and rigorous preparation/separation conditions, this mild one-pot filling method has advantages of easy isolation of final products by centrifugation, good retention of the pristine outer surface of the MWCNT shell, and satisfactory filling yield of (24+/-2) %. In particular, encapsulation of PBNPs of poor dispersibility and limited functionality in dispersible and multifunctional MWCNT shells creates new and valuable opportunities for quasihomogeneous-phase applications of PB in liquid solutions. The MWCNT-PBin nanocomposites were exploited as a peroxidase mimic for the colorimetric assay of H2O2 in solution by using 3,3',5,5'-tetramethylbenzidine (TMB) as reporter, and they gave a linear absorbance response from 1 MUM to 1.5 mM with a limit of detection (LOD) of 100 nM. Moreover, glucose oxidase (GOx) was anchored on the outer surface of MWCNT-PBin to form GOx/MWCNT-PBin bionanocomposites. The cooperation of outer-surface biocatalysis with peroxidase-like catalysis of interior PB resulted in a novel cooperative colorimetric biosensing mode for glucose assay. The use of GOx/MWCNT-PBin for colorimetric biosensing of glucose gave a linear absorbance response from 1 MUM to 1.0 mM and an LOD of 200 nM. The presented protocols may be extended to other multifunctional nanocomposite systems for broad applications in catalysis and biotechnology. PMID- 24482047 TI - Exploring the spatio-temporal relationship between two key aeroallergens and meteorological variables in the United Kingdom. AB - Constructing accurate predictive models for grass and birch pollen in the air, the two most important aeroallergens, for areas with variable climate conditions such as the United Kingdom, require better understanding of the relationships between pollen count in the air and meteorological variables. Variations in daily birch and grass pollen counts and their relationship with daily meteorological variables were investigated for nine pollen monitoring sites for the period 2000 2010 in the United Kingdom. An active pollen count sampling method was employed at each of the monitoring stations to sample pollen from the atmosphere. The mechanism of this method is based on the volumetric spore traps of Hirst design (Hirst in Ann Appl Biol 39(2):257-265, 1952). The pollen season (start date, finish date) for grass and birch were determined using a first derivative method. Meteorological variables such as daily rainfall; maximum, minimum and average temperatures; cumulative sum of Sunshine duration; wind speed; and relative humidity were related to the grass and birch pollen counts for the pre-peak, post peak and the entire pollen season. The meteorological variables were correlated with the pollen count data for the following temporal supports: same-day, 1-day prior, 1-day mean prior, 3-day mean prior, 7-day mean prior. The direction of influence (positive/negative) of meteorological variables on pollen count varied for birch and grass, and also varied when the pollen season was treated as a whole season, or was segmented into the pre-peak and post-peak seasons. Maximum temperature, sunshine duration and rainfall were the most important variables influencing the count of grass pollen in the atmosphere. Both maximum temperature (pre-peak) and sunshine produced a strong positive correlation, and rain produced a strong negative correlation with grass pollen count in the air. Similarly, average temperature, wind speed and rainfall were the most important variables influencing the count of birch pollen in the air. Both wind speed and rain produced a negative correlation with birch pollen count in the air and average temperature produced a positive correlation. PMID- 24482049 TI - A light-activated metal complex targets both DNA and RNA in a fluorescent in vitro transcription and translation assay. AB - A coupled in vitro transcription and translation (IVTT) assay that uses GFP as a fluorescent reporter allowed the potency of a light-activated cytotoxic ruthenium agent to be quantified. The compound inhibits the function of both DNA and mRNA only upon light activation. The IVTT functional assay provides estimates of potency that are consistent with cellular cytotoxicity values, in marked contrast to the values obtained from traditional DNA-damage assays. PMID- 24482051 TI - Meroterpenes from an algicolous strain of Penicillium echinulatum. AB - One new meroterpene, arisugacin K (1), and four known ones, arisugacin J (2), arisugacin G (3), arisugacin C (4), and territrem C (5), were isolated from the culture of Penicillium echinulatum pt-4, an endophytic fungus isolated from the marine red alga Chondrus ocellatus. The structure and the absolute configuration of 1 were unambiguously elucidated by spectroscopic analyses and quantum chemical calculations, which further resulted in the assignments of absolute configurations for the other arisugacins and territrems. Compound 1 showed inhibitory activity against Escherichia coli with an inhibition diameter 8 mm at 30 ug/disk and 4 exhibited lethality against Artemia salina with an LC50 of 48.6 ug/ml. PMID- 24482052 TI - Effect of PGPR Serratia marcescens BC-3 and AMF Glomus intraradices on phytoremediation of petroleum contaminated soil. AB - Soil contamination caused by petroleum hydrocarbons has become a worldwide environmental problem. Microorganism combined with phytoremediation appears to be more effective for removal and/or degradation of petroleum hydrocarbons from impacted soils. The current study investigated the effect of inoculated with PGPR Serratia marcescens BC-3 alone or in combination with AMF Glomus intraradices on the phytoremediation of petroleum-contaminated soil. Pot experiments were conducted to analyze the effect on plant and soil for 90 days in greenhouse. The inoculation treatments showed higher plant biomass and antioxidant enzyme activities than the non inoculation control. Inoculation treatments also improved rhizosphere microbial populations in petroleum contaminated soil. The degradation rate of total petroleum hydrocarbons with PGPR and AMP co-inoculation treatment was up to 72.24 %. The results indicated that plant combined with microorganisms for remediation of petroleum hydrocarbons would be a feasible method. PMID- 24482053 TI - Clinicopathologic significance of Sox2, CD44 and CD44v6 expression in intrahepatic cholangiocarcinoma. AB - Embryonic stem cells (ESC) and cancer stem cells (CSC) have a capacity for self renewal and differentiation into multiple cell lineages. Sox2 plays a critical role in ESC and has been shown to participate in carcinogenesis and tumor progression in many human cancers. CD44 and CD44v6 are putative CSC markers and their association with tumor progression, metastasis, and tumor relapse after treatment has been demonstrated. We evaluated the immunoexpression of Sox2, CD44, and CD44v6 in 85 cases of Intrahepatic cholangiocarcinomas (IHCC) and assessed their prognostic significance. Sox2 expression showed a significant association with lymph node metastasis (p = 0.025), T4 stage (p = 0.046), and worse overall survival (p = 0.047). Greater expression of Sox2 was observed in IHCC with poor differentiation, vascular invasion, and stage IV, without statistical significance (p > 0.05). CD44 expression showed an association with periductal infiltrative type (p = 0.034), poor differentiation (p = 0.012), and vascular invasion (p = 0.009). CD44v6 expression was evident in patients with stage IV (p = 0.019). These results demonstrated that Sox2 expression is associated with aggressive behavior and poor overall survival in IHCC. PMID- 24482054 TI - Transfemoral implantation of Edwards Sapien XT aortic valve without previous valvuloplasty: role of 2D/3D transesophageal echocardiography. AB - BACKGROUND: Balloon valvuloplasty (BAV) has been considered a mandatory step before TAVI. However, it might be related to cerebrovascular microembolizations, atrioventricular conduction disturbances, and hemodynamic instability. The aim of this study is to describe transesophageal echocardiography characteristics of patients that could benefit from direct transfemoral transcatheter aortic valve implantation (TAVI) of Edwards SAPIEN XT, without previous BAV. METHODS AND RESULTS: A total of 16 patients with direct implantation of an Edwards SAPIEN XT valve are included. Preprocedural echocardiographic findings were exhaustively analyzed and described. From 32 patients elected for transfemoral TAVI with an Edwards SAPIEN XT, 16 of them (50%) were selected for direct implantation using the Edwards SAPIEN XT valve of size 23 mm (n = 5), 26 mm (n = 8), or 29 mm (n = 3). Patients selection for direct TAVI presented three echocardiographic conditions: central effective orifice, moderate to severe calcification of the aortic valve apparatus preserving leaflets movement, and symmetric distribution of calcium with absent to moderate central aortic regurgitation. Mean age was 81.4 +/- 7.4, 75% female, with a mean logistic Euroscore 18.2 +/- 11.2. Preprocedural mean valve gradient was 43.6 +/- 16.3. Mean effective orifice area was 0.7 +/- 0.2. There was no valve embolization and the success rate was 100%. Postdilation was performed in one patient (6.25%). New permanent pacing was needed in two patients (12.5%). CONCLUSIONS: TAVI without previous BAV is feasible and safe. 2D/3D TEE is an essential tool to select the patients that could benefit from this technique. PMID- 24482055 TI - Tradition over trend: Neighboring chimpanzee communities maintain differences in cultural behavior despite frequent immigration of adult females. AB - The notion of animal culture has been well established mainly through research aiming at uncovering differences between populations. In chimpanzees (Pan troglodytes verus), cultural diversity has even been found in neighboring communities, where differences were observed despite frequent immigration of individuals. Female chimpanzees transfer at the onset of sexual maturity at an age, when the behavioral repertoire is fully formed. With immigrating females, behavioral variety enters the group. Little is known about the diversity and the longevity of cultural traits within a community. This study is building on previous findings of differences in hammer selection when nut cracking between neighboring communities despite similar ecological conditions. We now further investigated the diversity and maintenance of cultural traits within one chimpanzee community and were able to show high levels of uniformity in group specific behavior. Fidelity to the behavior pattern did not vary between dispersing females and philopatric males. Furthermore, group-specific tool selection remained similar over a period of 25 years. Additionally, we present a study case on how one newly immigrant female progressively behaved more similar to her new group, suggesting that the high level of similarity in behavior is actively adopted by group members possibly even when originally expressing the behavior in another form. Taken together, our data support a cultural transmission process in adult chimpanzees, which leads to persisting cultural behavior of one community over time. PMID- 24482056 TI - [Point-of-care diagnostics compared to standard coagulation tests in multiple trauma. Pros and cons]. AB - The haemostasiological management of patients with multiple injuries requires rapid and adequate therapy decisions due to the highly dynamic surroundings. For this, diagnostic techniques which have the ability to detect and differentiate coagulation disorders that are commonly present in multiple trauma patients are necessary. Widely used routine coagulation tests (e.g., aPTT or PT) sensitively measure impairments of the intrinsic or extrinsic pathway, but without further identification or differentiation. Important influencing parameters like acidosis, hypothermia, fibrinolysis or polymerization dysfunction but especially the clot quality are not detectable. Moreover, the turn around times of these tests are about 30-60 min. However, thrombelastography measures clot strength and stability in whole blood under the present conditions of the injured patient. Impairments of clot quality can be differentiated. Because of the visualization of the clot formation, a patient's coagulation capacity can be assessed within minutes. Admittedly the use of these point-of-care devices in the operation theatre requires human and temporal resources. PMID- 24482057 TI - [Perioperative coagulation management in multiple trauma patients based on viscoelastic test results]. AB - Exsanguination represents the most common and potentially preventable cause of death in major trauma patients. Rapid surgical intervention coupled with an early and aggressive hemostatic therapy not only results in survival benefits of coagulopathic trauma patients, but also reduces the incidence of complications and costs. Standard coagulation tests are not suitable to adequately characterize the complexity of trauma-induced coagulopathy (TIC). This fact has led to a renaissance of viscoelastic tests, such as rotational thromboelastometry (ROTEM(r)) and thrombelastography (TEG(r)), which can be used as point-of-care monitors. In some trauma centers treatment algorithms have been developed, where hemostatic therapy is based on viscoelastic test results. Shock and tissue trauma activate profibrinolytic pathways which in turn result in premature dissolution of formed clots. Tranexamic acid rapidly and inexpensively blocks hyperfibrinolysis. ROTEM(r)/TEG(r) measurements revealed that diminished clot strength is associated with an increased bleeding tendency. Depending on the underlying cause, administration of fibrinogen concentrate and/or platelet concentrate administration improves clot firmness. Thrombin generation is initially less compromised and can be improved by the administration of plasma, prothrombin complex concentrate, or with restrictiveness by recombinant activated factor VII. PMID- 24482058 TI - [Coagulation therapy in multiple trauma without point-of-care testing]. AB - Analysis of blood coagulation with thrombelastometry (ROTEMTM) and thrombelastography (TEGTM) and analysis of thrombocyte function by a MultiplateTM assay is possible in only a few hospitals in Germany. Recently, the grade of recommendation (GoR) for point-of-care (POC) testing in official guidelines was increased and is now classified as GoR 1C. If a POC-based option is not available alternatives must be used. Besides blood products (RBC, FFP, TC), coagulation factor concentrates are used to treat trauma-induced coagulopathy. The benefits of therapy with factor concentrates are fewer immunological and infection side effects as well as faster effects after administration of specific coagulation factors. A good outcome in patients with multiple trauma is only possible by an adequate transfusion regime and administration of coagulation factors. PMID- 24482059 TI - Ovulation triggers in anovulatory women undergoing ovulation induction. AB - BACKGROUND: Anovulation is a common cause of infertility. Drugs used to treat anovulation include selective oestrogen receptor modulators, aromatase inhibitors and gonadotrophins. Ovulation triggers are used with these drugs, as a surrogate for the hormonal surge seen in spontaneous menstrual cycles, to control the timing of ovulation and the timing of sexual intercourse. Ovulation triggers given without reliable evidence of oocyte maturity could be inappropriately timed; they increase costs, and the need to time intercourse precisely after the ovulation trigger is given adds to psychological stress.This is an update of a Cochrane review first published in Issue 3, 2008, of the Cochrane Database of Systematic Reviews. OBJECTIVES: To determine the benefits and harms of administering an ovulation trigger to anovulatory women receiving treatment with ovulation-inducing agents in comparison with spontaneous ovulation following ovulation induction. SEARCH METHODS: We updated searches of the Menstrual Disorders and Subfertility Group (MDSG) Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO to November 2013. We checked conference proceedings, trial registries and reference lists and contacted researchers. SELECTION CRITERIA: Parallel-group, randomised, controlled trials (RCTs) evaluating the administration of an ovulation trigger to anovulatory women receiving treatment with ovulation-inducing agents. DATA COLLECTION AND ANALYSIS: We independently assessed trial eligibility and trial quality and extracted data. We calculated odds ratios (ORs) with 95% confidence intervals (CIs) for dichotomous data and used the random-effects model in meta analyses when significant heterogeneity was present. We assessed overall quality of the evidence by using the GRADE approach. MAIN RESULTS: No new trials were identified. This review includes two RCTs with low risk of bias that compared urinary human chorionic gonadotrophin (hCG) versus no treatment in anovulatory women receiving clomiphene citrate. Urinary hCG did not result in an increase in live birth rate over no hCG (OR 0.97, 95% CI 0.52 to 1.83; two trials, 305 participants, I(2) = 16%; low-quality evidence), but very serious imprecision around the effect estimate reduces our confidence in the apparent lack of effect of hCG as an ovulation trigger in clomiphene-induced cycles in anovulatory women.Among this review's secondary outcomes, urinary hCG may not increase ovulation rate (OR 0.99, 95% CI 0.36 to 2.77; two trials, 305 participants, I(2) = 55%; low-quality evidence), clinical pregnancy rate (OR 1.02, 95% CI 0.56 to 1.89; two trials, 305 participants, I(2) = 35%; low-quality evidence) or miscarriage rate in pregnant women (OR 1.19, 95% CI 0.17 to 8.23; two trials, 54 participants, I(2) = 0%; low-quality evidence). Multiple pregnancies and preterm deliveries were uncommon, and ovarian hyperstimulation syndrome, adverse events and deaths were not reported as outcomes in either trial. We found no trials evaluating other ovulation triggers. AUTHORS' CONCLUSIONS: Evidence is inadequate to recommend or refute the use of urinary hCG as an ovulation trigger in anovulatory women treated with clomiphene citrate. We found no trials evaluating the use of ovulation triggers in anovulatory women treated with other ovulation inducing agents. PMID- 24482060 TI - Can we consider standard microsurgical anastomosis on the posterior tibial perforator network? An anatomical study. AB - PURPOSE: The main vessels in an injured leg can be spared with perforator-to perforator anastomosis. However, supermicrosurgery is not a routine procedure for all plastic surgeons. Our objective was to establish if the diameter of the perforators of the leg could allow anastomosis with standard microsurgical procedures. METHODS: Twenty lower legs harvested from ten fresh cadavers were dissected. Arterial and venous vessels were injected with colored latex. The limbs were then dissected in a suprafascial plane. All the perforating arteries of a diameter >0.8 mm were located and their external diameter, the number and external diameter of the venae comitantes were reported. RESULTS: We found at least three tibial posterior artery perforators with diameters >0.8 mm per leg with a mean external diameter of 1.1 mm and one vena comitans in almost all cases (96 %). The vena comitans was usually bigger than the perforating artery with a mean diameter of 1.6 mm. After statistical analysis, we were able to locate two main perforator clusters: at the junctions of the upper two-thirds of the leg and of the lower two-thirds of the leg. CONCLUSION: The low-morbidity concept of perforator-to-perforator anastomosis can apply to posterior tibial artery perforators without using supermicrosurgical techniques. This is of high interest for open leg fractures where main vessels could be injured. We hope that the results of our study will incite surgeons to consider sparing of main vessels for coverage of open leg fractures whether surgical teams master supermicrosurgery or not. PMID- 24482061 TI - Social and material deprivation and the cost-effectiveness of an intervention to promote physical activity: cohort study and Markov model. AB - BACKGROUND: We developed a method to model the cost-effectiveness at different levels of deprivation of an intervention to promote physical activity. METHODS: The cost-effectiveness of a brief intervention in primary care was estimated by means of a Markov model stratified by deprivation quintile. Estimates for disease incidence, mortality, depression prevalence and health service utilization were obtained from 282 887 participants in the UK Clinical Practice Research Datalink with linked deprivation scores. Discounted results were compared for least deprived and most deprived quintiles. RESULTS: An effective intervention to promote physical activity continuing for 5 years gave an increase in life years free from disease: least deprived 54.9 (95% interval 17.5-93.5) per 1000 participants entering model; most deprived 74.5 (22.8-128.0) per 1000. The overall incremental quality adjusted life years were: least deprived, 3.7 per 1000 and most deprived, 6.1 per 1000 with probability cost-effective at L30 000 per QALY being 52.5 and 63.3%, respectively. When the intervention was modelled to be 30% less effective in the most deprived than the least deprived quintile, the probability cost-effective was least deprived 52.9% and most deprived 55.9%. CONCLUSION: Physical activity interventions may generate greater health benefits in deprived populations. When intervention effectiveness is attenuated in deprived groups, cost-effectiveness may sometimes still be similar to that in the most affluent groups. Even with favourable assumptions, evidence was insufficient to support wider use of presently available brief primary care interventions in a universal strategy for primary prevention. PMID- 24482062 TI - Role of T-type channels in vasomotor function: team player or chameleon? AB - Low-voltage-activated T-type calcium channels play an important role in regulating cellular excitability and are implicated in conditions, such as epilepsy and neuropathic pain. T-type channels, especially Cav3.1 and Cav3.2, are also expressed in the vasculature, although patch clamp studies of isolated vascular smooth muscle cells have in general failed to demonstrate these low voltage-activated calcium currents. By contrast, the channels which are blocked by T-type channel antagonists are high-voltage activated but distinguishable from their L-type counterparts by their T-type biophysical properties and small negative shifts in activation and inactivation voltages. These changes in T channel properties may result from vascular-specific expression of splice variants of Cav3 genes, particularly in exon 25/26 of the III-IV linker region. Recent physiological studies suggest that T-type channels make a small contribution to vascular tone at low intraluminal pressures, although the relevance of this contribution is unclear. By contrast, these channels play a larger role in vascular tone of small arterioles, which would be expected to function at lower intra-vascular pressures. Upregulation of T-type channel function following decrease in nitric oxide bioavailability and increase in oxidative stress, which occurs during cardiovascular disease, suggests that a more important role could be played by these channels in pathophysiological situations. The ability of T-type channels to be rapidly recruited to the plasma membrane, coupled with their subtype-specific localisation in signalling microdomains where they could modulate the function of calcium-dependent ion channels and pathways, provides a mechanism for rapid up- and downregulation of vasoconstriction. Future investigation into the molecules which govern these changes may illuminate novel targets for the treatment of conditions such as therapy-resistant hypertension and vasospasm. PMID- 24482063 TI - Targeting of CaV3.2 T-type calcium channels in peripheral sensory neurons for the treatment of painful diabetic neuropathy. AB - Pain-sensing sensory neurons (nociceptors) of the dorsal root ganglion (DRG) can become sensitized (hyperexcitable) in response to pathological conditions such as diabetes, which in turn may lead to the development of painful peripheral diabetic neuropathy (PDN). Because of insufficient knowledge about the mechanisms for this hypersensitization, current treatment for painful PDN has been limited to somewhat nonspecific systemic drugs having significant side effects or potential for abuse. Recent studies have established that the CaV3.2 isoform of T channels makes a previously unrecognized contribution to sensitization of pain responses by enhancing excitability of nociceptors in animal models of type 1 and type 2 PDN. Furthermore, it has been reported that the glycosylation inhibitor neuraminidase can inhibit the native and recombinant CaV3.2 T-currents in vitro and completely reverse mechanical and thermal hyperalgesia in diabetic animals with PDN in vivo. Understanding details of posttranslational regulation of nociceptive channel activity via glycosylation may facilitate development of novel therapies for treatment of painful PDN. Pharmacological targeting the specific pathogenic mechanism rather than the channel per se may cause fewer side effects and reduce the potential for drug abuse in patients with diabetes. PMID- 24482064 TI - Anion-controlled switching of an X ligand into a Z ligand: coordination non innocence of a stiboranyl ligand. AB - The tetravalent platinum stiboranyl complex [(o-(Ph2P)C6H4)2(o-C6Cl4O2)Sb]PtCl2Ph (2) has been synthesized by reaction of [(o-(Ph2P)C6H4)2SbClPh]PtCl (1) with o chloranil. In the presence of fluoride anions, the stiboranyl moiety of 2 displays non-innocent behavior and is readily converted into a fluorostiborane unit. This transformation, which is accompanied by elimination of a chloride ligand from the Pt center, results in the formation of [(o-(Ph2P)C6H4)2(o C6Cl4O2)SbF]PtClPh (3). Structural, spectroscopic, and computational studies show that the conversion of 2 into 3 is accompanied by a cleavage of the covalent Pt Sb bond present in 2 and formation of a longer and weaker Pt->Sb interaction in 3. These results show that this new Pt-Sb platform supports the fluoride-induced metamorphosis of a stiboranyl X ligand into a stiborane Z ligand. PMID- 24482065 TI - Hyperuricemia and renal risk. AB - Asymptomatic mild hyperuricemia has been reported in association with a number of conditions associated with chronic kidney disease, including hypertension, insulin resistance, cerebrovascular and cardiac disease. Experimental studies indicate that serum uric acid may directly and indirectly promote renal damage by several pathogenetic mechanisms both at cellular and tissue level. While there is currently no consensus on the usefulness of urate lowering therapy with the aim of preventing chronic renal disease, growing evidence indicates a relationship between changes of serum uric acid over time and renal morbidity. The present manuscript will briefly review the evidence in favor and against an independent role for SUA in the pathogenesis of renal disease. PMID- 24482066 TI - Efficacy of levofloxacin in the treatment of BK viremia: a multicenter, double blinded, randomized, placebo-controlled trial. AB - BACKGROUND AND OBJECTIVES: BK virus reactivation in kidney transplant recipients can lead to progressive allograft injury. Reduction of immunosuppression remains the cornerstone of treatment for active BK infection. Fluoroquinolone antibiotics are known to have in vitro antiviral properties, but the evidence for their use in patients with BK viremia is inconclusive. The objective of the study was to determine the efficacy of levofloxacin in the treatment of BK viremia. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: Enrollment in this prospective, multicenter, double-blinded, placebo-controlled trial occurred from July 2009 to March 2012. Thirty-nine kidney transplant recipients with BK viremia were randomly assigned to receive levofloxacin, 500 mg daily, or placebo for 30 days. Immunosuppression in all patients was adjusted on the basis of standard clinical practices at each institution. Plasma BK viral load and serum creatinine were measured monthly for 3 months and at 6 months. RESULTS: At the 3-month follow-up, the percentage reductions in BK viral load were 70.3% and 69.1% in the levofloxacin group and the placebo group, respectively (P=0.93). The percentage reductions in BK viral load were also equivalent at 1 month (58% versus and 67.1%; P=0.47) and 6 months (82.1% versus 90.5%; P=0.38). Linear regression analysis of serum creatinine versus time showed no difference in allograft function between the two study groups during the follow-up period. CONCLUSIONS: A 30-day course of levofloxacin does not significantly improve BK viral load reduction or allograft function when used in addition to overall reduction of immunosuppression. PMID- 24482067 TI - Treatment of BK viremia after renal transplantation: are fluoroquinolones a false dawn? PMID- 24482068 TI - Accuracy of GFR estimation in obese patients. AB - BACKGROUND AND OBJECTIVES: Adequate estimation of renal function in obese patients is essential for the classification of patients in CKD category as well as the dose adjustment of drugs. However, the body size descriptor for GFR indexation is still debatable, and formulas are not validated in patients with extreme variations of weight. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: This study included 209 stages 1-5 CKD obese patients referred to the Department of Renal Function Study at the University Hospital in Lyon between 2010 and 2013 because of suspected renal dysfunction. GFR was estimated with the Chronic Kidney Disease and Epidemiology equation (CKD-EPI) and measured with a gold standard method (inulin or iohexol) not indexed (mGFR) or indexed to body surface area determined by the Dubois and Dubois formula with either real (mGFRr) or ideal (mGFRi) body weight. Mean bias (eGFR-mGFR), precision, and accuracy of mGFR were compared with the results obtained for nonobese participants (body mass index between 18.5 and 24.9) who had a GFR measurement during the same period of time. RESULTS: Mean mGFRr (51.6 +/- 24.2 ml/min per 1.73 m(2)) was significantly lower than mGFR, mGFRi, and eGFRCKD-EPI. eGFRCKD-EPI had less bias with mGFR (0.29; 1.7 to 2.3) and mGFRi (-1.62; -3.1 to 0.45) compared with mGFRr (8.7; 7 to 10). This result was confirmed with better accuracy for the whole cohort (78% for mGFR, 84% for mGFRi, and 72% for mGFRr) and participants with CKD stages 3-5. Moreover, the Bland Altman plot showed better agreement between mGFR and eGFRCKD EPI. The bias between eGFRCKD-EPI and mGFRr was greater in obese than nonobese participants (8.7 versus 0.58, P<0.001). CONCLUSIONS: This study shows that, in obese CKD patients, the performance of eGFRCKD-EPI is good for GFR <= 60 ml/min per 1.73 m(2). Indexation of mGFR with body surface area using ideal body weight gives less bias than mGFR scaled with body surface area using real body weight. PMID- 24482070 TI - Cancer prevention by adult-onset calorie restriction after infant exposure to ionizing radiation in B6C3F1 male mice. AB - Children are especially sensitive to ionizing radiation and chemical carcinogens, and limiting their cancer risk is of great public concern. Calorie restriction (CR) is a potent intervention for suppressing cancer. However, CR is generally not appropriate for children. This study, therefore, examined to see if adult onset CR influences the lifetime cancer risk in mice after early-life exposure to ionizing radiation. Infant male mice (1-week-old) were exposed to 3.8 Gy X-rays, fed a control 95 kcal/week or CR 65 kcal/week diet from 7 weeks of age (adult stage), and their lifespan and tumor development were assessed. Irrespective of CR, X-rays shortened lifespan by 38%, and irrespective of irradiation CR extended lifespan by 20%. Thymic lymphoma (TL) and early-occurring non-TL were induced by radiation. The liver and Harderian gland were more susceptible to radiation induced tumors than the lungs and non-thymic lymphoid tissues (late occurring). CR reduced the risk of hepatocellular carcinoma, late-occurring non-TL, lung tumor, Harderian tumor, and hemangioma but had less impact on TL and early occurring non-TL. Most notably, the effects of X-rays on induction of lung tumors, late-occurring non-TL and hemangioma were essentially canceled by CR. The ability of CR to prevent late-occurring tumors was the same for non-irradiated and irradiated mice, indicating that the mechanism by which CR influences cancer is independent of irradiation. Our results indicate that adult-onset CR significantly inhibits late-occurring tumors in a tissue-dependent manner regardless of infant radiation exposure. PMID- 24482069 TI - FAP neuropathy and emerging treatments. AB - Transthyretin familial amyloid polyneuropathy (TTR-FAP) classically presents as a length dependent small fiber polyneuropathy in endemic countries like Portugal. In nonendemic countries, it may mimic a variety of chronic polyneuropathies, with several phenotypes: ataxic, upper limb onset neuropathy, or motor. In these cases, there is usually a late onset and no positive family history. TTR gene sequencing appears the most pertinent first-line test for diagnosis. Cardiac involvement of various severities is common in FAP. Liver transplantation remains the standard antiamyloid therapy with better results in Val30Met TTR-FAP of early onset. Antiamyloid medication has been developed. (1) TTR stabilizers: Tafamidis was the first drug approved in Europe in stage 1 (walking unaided) TTR-FAP to slow progression of the disease; diflunisal has been assessed in a phase 3 clinical trial; (2) TTR gene silencing is a new strategy to inhibit production of both mutant and nonmutant TTR with antisense oligonucleotides or SiRNA (2 ongoing phase 3 clinical trials). PMID- 24482071 TI - TiO2 nanotube arrays modified with Cr-doped SrTiO3 nanocubes for highly efficient hydrogen evolution under visible light. AB - In recent decades, solar-driven hydrogen production over semiconductors has attracted tremendous interest owing to the global energy and environmental crisis. Among various semiconductor materials, TiO2 exhibits outstanding photocatalytic properties and has been extensively applied in diverse photocatalytic and photoelectric systems. However, two major drawbacks limit practical applications, namely, high charge-recombination rate and poor visible light utilization. In this work, heterostructured TiO2 nanotube arrays grafted with Cr-doped SrTiO3 nanocubes were fabricated by simply controlling the kinetics of hydrothermal reactions. It was found that coupling TiO2 nanotube arrays with regular SrTiO3 nanocubes can significantly improve the charge separation. Meanwhile, doping Cr cations into SrTiO3 nanocubes proved to be an effective and feasible approach to enhance remarkably the visible-light response, which was also confirmed by theoretical calculations. As a result, the rate of photoelectrochemical hydrogen evolution of these novel heteronanostructures is an order of magnitude larger than those of TiO2 nanotube arrays and other previously reported SrTiO3 /TiO2 nanocomposites under visible-light irradiation. Furthermore, the as-prepared Cr-doped SrTiO3 /TiO2 heterostructures exhibit excellent durability and stability, which are favorable for practical hydrogen production and photoelectric nanodevices. PMID- 24482073 TI - Endoscopic release for carpal tunnel syndrome. AB - BACKGROUND: Carpal tunnel syndrome (CTS) is the most common compressive neuropathy of the upper extremity. It is caused by increased pressure on the median nerve between the transverse carpal ligament and the carpal bones. Surgical treatment consists of the release of the nerve by cutting the transverse carpal ligament. This can be done either with an open approach or endoscopically. OBJECTIVES: To assess the effectiveness and safety of the endoscopic techniques of carpal tunnel release compared to any other surgical intervention for the treatment of CTS. More specifically, to evaluate the relative impact of endoscopic techniques in relieving symptoms, producing functional recovery (return to work and return to daily activities) and reducing complication rates. SEARCH METHODS: This review fully incorporates the results of searches conducted up to 5 November 2012, when we searched the Cochrane Neuromuscular Disease Group Specialized Register, CENTRAL, MEDLINE and EMBASE. There were no language restrictions. We reviewed the reference lists of relevant articles and contacted trial authors. We also searched trial registers for ongoing trials. We performed a preliminary screen of searches to November 2013 to identify any additional recent publications. SELECTION CRITERIA: We included any randomised controlled trials (RCTs) and quasi-RCTs comparing endoscopic carpal tunnel release (ECTR) with any other surgical intervention for the treatment of CTS. DATA COLLECTION AND ANALYSIS: We used standard methodological procedures expected by the Cochrane Collaboration. MAIN RESULTS: Twenty-eight studies (2586 hands) were included. Twenty-three studies compared ECTR to standard open carpal tunnel release (OCTR), five studies compared ECTR with OCTR using a modified incision, and two studies used a three-arm design to compare ECTR, standard OCTR and modified OCTR.At short term follow-up (three months or less), only one study provided data for overall improvement. We found no differences on the Symptom Severity Scale (SSS) (scale zero to five) (five studies, standardised mean difference (SMD) -0.13, 95% CI 0.47 to 0.21) or on the Functional Status Scale (FSS) (scale zero to five) (five studies, SMD -0.23, 95% CI -0.60 to 0.14) within three months postoperatively between ECTR and OCTR. Pain scores favoured ECTR over conventional OCTR (two studies, SMD -0.41, 95% CI -0.65 to -0.18). No difference was found between ECTR and OCTR (standard and modified) when pain was assessed on non-continuous dichotomous scales (five studies, RR 0.69, 95% CI 0.33 to 1.45). Also, no difference was found in numbness (five studies, RR 1.14; 95% CI 0.76 to 1.71). Grip strength was increased after ECTR when compared with OCTR (six studies, SMD 0.36, 95% CI 0.09 to 0.63). This corresponds to a mean difference (MD) of 4 kg (95% CI 1 to 6.9 kg) when compared with OCTR, which is probably not clinically significant.In the long term (more than three months postoperatively) there was no significant difference in overall improvement between ECTR and OCTR (four studies, RR 1.04, 95% CI 0.95 to 1.14). SSS and FSS were also similar in both treatment groups (two studies, MD 0.02, 95% CI -0.18 to 0.22 for SSS and MD 0.01, 95% CI -0.14 to 0.16 for FSS). ECTR and OCTR did not differ in the long term in pain (six studies, RR 0.88, 95% CI 0.57 to 1.38) or in numbness (four studies, RR 0.64, 95% CI 0.31 to 1.35). Results from grip strength testing favoured ECTR (two studies, SMD 1.13, 95% CI 0.56 to 1.71), corresponding to an MD of 11 kg (95% CI 6.2 to 18.81). Participants treated with ECTR returned to work or daily activities eight days earlier than participants treated with OCTR (four studies, MD -8.10 days, 95% CI -14.28 to -1.92 days).Both treatments were equally safe with only a few reports of major complications (mainly with complex regional pain syndrome) (15 studies, RR 1.00, 95% CI 0.38 to 2.64).ECTR resulted in a significantly lower rate of minor complications (18 studies, RR 0.55, 95% CI 0.38 to 0.81), corresponding to a 45% relative drop in the probability of complications (95% CI 62% to 19%). ECTR more frequently resulted in transient nerve problems (ie, neurapraxia, numbness, and paraesthesiae), while OCTR had more wound problems (ie, infection, hypertrophic scarring, and scar tenderness). ECTR was safer than OCTR when the total number of complications were assessed (20 studies, RR 0.60, 95% CI 0.40 to 90) representing a relative drop in the probability by 40% (95% CI 60% to 10%).Rates of recurrence of symptoms and the need for repeated surgery were comparable between ECTR and OCTR groups.The overall risk of bias in studies that contribute data to these results is rather high; fewer than 25% of the included studies had adequate allocation concealment, generation of allocation sequence or blinding of the outcome assessor.The quality of evidence in this review may be considered as generally low. Five of the studies were presented only as abstracts, with insufficient information to judge their risk of bias. In selection bias, attrition bias or other bias (baseline differences and financial conflict of interest) we could not reach a safe judgement regarding a high or low risk of bias. Blinding of participants is impossible due to the nature of interventions.We identified three further potentially eligible studies upon updating searches just prior to publication. These compared ECTR with OCTR (two studies) or mini-open carpal tunnel release (one study) and will be fully assessed when we update the review. AUTHORS' CONCLUSIONS: In this review, with support from low quality evidence only, OCTR and ECTR for carpal tunnel release are about as effective as each other in relieving symptoms and improving functional status, although there may be a functionally significant benefit of ECTR over OCTR in improvement in grip strength. ECTR appears to be associated with fewer minor complications compared to OCTR, but we found no difference in the rates of major complications. Return to work is faster after endoscopic release, by eight days on average. Conclusions from this review are limited by the high risk of bias, statistical imprecision and inconsistency in the included studies. PMID- 24482072 TI - Predictors of being overweight or obese in survivors of pediatric acute lymphoblastic leukemia (ALL). AB - BACKGROUND: A high prevalence of obesity has been increasingly recognized in survivors of pediatric ALL. However, longitudinal patterns of weight change during and after treatment, and associated factors, are less well elucidated. PROCEDURE: In a retrospective cohort of 83 pediatric patients with ALL diagnosed between 1985 and 2010, we examined body mass index (BMI) status at several key time points: diagnosis; end of induction; end of consolidation; every 6 months during maintenance; and yearly for up to 5 years post-treatment. RESULTS: At diagnosis, 21% were overweight (BMI = 85-94.9th percentile) or obese (BMI >= 95th percentile). At the end of treatment and 5 years post-treatment, approximately 40% were overweight or obese. The mean BMI z-score was 0.2 (58th percentile) at diagnosis and increased significantly during induction (Delta = 0.5, P < 0.0001). It increased again during the first 6 months of maintenance (Delta = 0.2, P < 0.01) and did not significantly change over the remainder of maintenance (BMI z score at the end of treatment = 0.8, 79th percentile) and 5 years post-treatment (BMI z-score = 0.7, 76th percentile). High BMI z-score at diagnosis was associated with an increased risk of being overweight/obese at treatment completion (OR = 2.9, 95% CI: 1.6-5.1). Weight gain during treatment was associated with being overweight/obese 5 years post-treatment (OR = 3.8, 95% CI: 1.1-12.5). CONCLUSION: Children with ALL are at risk of becoming overweight/obese early in treatment. Increases in weight are maintained throughout treatment and beyond. Lifestyle interventions are needed targeting weight control early during treatment, particularly for patients overweight/obese at diagnosis and those who experience substantial weight gain during treatment. PMID- 24482074 TI - Ageing and degenerative changes of the intervertebral disc and their impact on spinal flexibility. AB - PURPOSE: Degeneration of the intervertebral disc is associated with various morphological changes of the disc itself and of the adjacent structures, such as reduction of the water content, collapse of the intervertebral space, disruption and tears, and osteophytes. These morphological changes of the disc are linked to alterations of the spine flexibility. This paper aims to review the literature about the ageing and degenerative changes of the intervertebral disc and their link with alterations in spinal biomechanics, with emphasis on flexibility. METHODS: Narrative literature review. RESULTS: Clinical instability of the motion segment, usually related to increased flexibility and hypothesized to be connected to early, mild disc degeneration and believed to be responsible for low back pain, was tested in numerous in vitro studies. Despite some disagreement in the findings, a trend toward spinal stiffening with the increasing degeneration was observed in most studies. Tests about tears and fissures showed inconsistent results, as well as for disc collapse and dehydration. Vertebral osteophytes were found to be effective in stabilizing the spine in bending motions. CONCLUSIONS: The literature suggests that the degenerative changes of the intervertebral disc and surrounding structures lead to subtle alteration of the mechanical properties of the functional spinal unit. A trend toward spinal stiffening with the increasing degeneration has been observed in most studies. PMID- 24482075 TI - Darbepoetin alfa once every 2 weeks effectively maintained hemoglobin in dialysis patients in an observational study: Austrian cohort of ALTERNATE. AB - ALTERNATE is an international observational study evaluating biweekly darbepoetin alfa (DA) in adult dialysis patients in clinical practice. Austrian ALTERNATE results are presented here (n = 505). The follow-up study ALTERNATE follow-up (AFU) followed Austrian ALTERNATE patients for an additional 12 months (n = 135). Data were collected 6 months before and 12 months after conversion to biweekly dosing and during 12 months of follow-up. The primary measures were hemoglobin concentration 12 months after conversion and at the end of AFU, respectively. Mean (95 % CI) hemoglobin (g/dL) was 11.87 (11.75-11.99) at conversion, 11.71 (11.58-11.83) at month 12, and 11.66 (11.45-11.86) at end of AFU. Geometric mean (95 % CI) weekly dose (MUg/wk) was 32.97 (30.80-35.30) at conversion, 29.90 (26.71-33.46) 12 months after conversion, and 24.38 (18.40-30.35) at end of AFU. The studies show that hemoglobin and dose could be effectively maintained over an extended period of time after conversion from higher frequency erythropoiesis stimulating agents to biweekly DA. PMID- 24482076 TI - A case of obstructive jaundice due to autoimmune pancreatitis and a review of the literature. AB - A 33-year-old man presented with jaundice, mild pancreatitis, and some weight loss. Laboratory tests showed cholestatic icterus. Imaging revealed distal bile duct obstruction and a mass in the head of the pancreas suspicious for cancer. Besides the enlargement of the head, the whole pancreatic parenchyma was altered. Therefore, autoimmune pancreatitis was considered. Endoscopic ultrasound biopsy found pancreatic tissue with lymphoplasmacytic inflammation and fibrosis. IgG4 serum concentration was within normal range. Due to the benign histology, a therapeutic attempt with prednisolone was initiated. The radiologic changes improved within 2 weeks, which supported the diagnosis of autoimmune pancreatitis. Bile duct obstruction and radiologic abnormalities of the pancreas completely resolved after a 4-month course of steroid treatment. Within 10 months, no relapse occurred. In context with this case, the recent literature was reviewed and the international consensus diagnostic criteria for autoimmune pancreatitis are summarized. PMID- 24482077 TI - Left cardiac sympathetic denervation in patients with heart failure: a new indication for an old intervention? AB - Heart failure (HF) is characterized by an autonomic imbalance with withdrawal of vagal activity and increased sympathetic activity. Novel non-pharmacological approaches to HF aimed at increasing vagal activity are being proposed. Left cardiac sympathetic denervation (LCSD) has been shown to modify favorably the outcome of several disorders characterized by life-threatening arrhythmias triggered by increased sympathetic activity. The present manuscript discusses the rationale and the limited experimental and clinical experience suggesting a potential role for LCSD in the treatment of patients with advanced heart failure. Possible future clinical applications of LCSD may include HF patients who are intolerant to beta-adrenergic blockade, HF patients who have frequent implantable cardioverter-defibrillator shocks, and HF patients in countries where the likelihood of receiving a device is limited, but the capability to perform a one in a lifetime procedure is present. PMID- 24482078 TI - Inhibition of Mycobacterium tuberculosis transaminase BioA by aryl hydrazines and hydrazides. AB - 7,8-Diaminopelargonic acid synthase (BioA) of Mycobacterium tuberculosis is a recently validated target for therapeutic intervention in the treatment of tuberculosis (TB). Using biophysical fragment screening and structural characterization of compounds, we have identified a potent aryl hydrazine inhibitor of BioA that reversibly modifies the pyridoxal-5'-phosphate (PLP) cofactor, forming a stable quinonoid. Analogous hydrazides also form covalent adducts that can be observed crystallographically but are incapable of inactivating the enzyme. In the X-ray crystal structures, small molecules induce unexpected conformational remodeling in the substrate binding site. We compared these conformational changes to those induced upon binding of the substrate (7 keto-8-aminopelargonic acid), and characterized the inhibition kinetics and the X ray crystal structures of BioA with the hydrazine compound and analogues to unveil the mechanism of this reversible covalent modification. PMID- 24482079 TI - Intravascular ultrasound-guided management of large thrombus burden in an aneurysmal coronary artery in a young male. AB - Management of acute thrombotic occlusion of coronary artery aneurysms is challenging with a lack of randomized trial evidence. We report an unusual case of a 30-year-old Indian Australian male who presented with an extensive anterior STEMI because of very large thrombus burden in a dilated proximal left anterior descending artery. A relatively conservative treatment approach comprising emergency aspiration thrombectomy and ongoing infusion of glycoprotein IIb/IIIa inhibitor, guided by surveillant inpatient angiography and intravascular ultrasound, helped achieve a satisfactory outcome in a complex setting in which percutaneous coronary angioplasty and stenting were not desirable. (c) 2014 Wiley Periodicals, Inc. PMID- 24482080 TI - Propane activation by palladium complexes with chelating bis(NHC) ligands and aerobic cooxidation. AB - The development of efficient aerobic oxidation methods remains a challenge for the selective functionalization of C-H bonds in alkanes. Herein we report the development of a C-H functionalization procedure for propane by using a palladium catalyst with chelating bis(N-heterocyclic carbene) ligands in trifluoroacetic acid together with a vanadium co-catalyst. Halides play a decisive role in the reaction. The experimental results are presented together with supporting kinetic data and an isotope effect. The reaction can be run with dioxygen as the oxidant if vanadium salts and halides are present in the reaction mixture. Experimental as well as computational results favor a mechanism involving C-H activation by palladium(II), followed by oxidation to palladium(IV) by bromine. PMID- 24482081 TI - Uptake and metabolism of radioactive gibberellins by barley aleurone layers. AB - When aleurone layers were treated with labeled gibberellin A1 ((3)H-GA1), gibberellin A5 ((3)H-GA5) and the methyl ester of (3)H-GA5 ((3)H-GA5-ME), radioactivity was accumulated by the tissue for a period of 20-30 h. After this time, radioactivity was released into the medium. Concomitantly, ribonuclease was also liberated by the tissue. The radioactivity accumulated by aleurone layers was associated with polar metabolites of the respective GAs, and the extent of extent of accumulation was a function of the degree of GA metabolism (GA5 ME>GA5>GA1). Accumulation of radioactivity was inhibited in the cold and by the metabolic poisons NaF and dinitrophenol. This was thought to be due to inbition of GA metabolism. The accumulation of (3)H-GA1 in aleurone tissue did not reach saturation when unlabeled GA3 up to 10(-2) M was added to the incubation medium. PMID- 24482082 TI - Photosynthesis by carrot tissue cultures. AB - (14)CO2-fixation rates in green carrot callus cultres (about 35 MUg chlorophyll/g fresh wt) were determined in gaseous and liquid media using a range of light intensities and CO2 concentrations. Main products of light-dependent CO2-fixation were sucrose, alanine, glutamine, serine/glycine and malic acid. In darkness, glutamine and malic acid were formed.Light CO2-fixation rates were about ten times higher than dark fixation rates and reached 50-90 MUmol/mg chlorophyll/h in 10000 lux, 1% CO2 in air. Net O2-evolution by the tissue was demonstrated polarographically under these conditions. Light CO2-fixation rates were linearly related to chlorophyll levels while dark fixation was independent of chlorophyll content. Lowered O2 partial pressures in gaseous conditions increased (14)CO2 fixation rates. Ribulose diphosphate carboxylase and phosphoenol pyruvate carboxylase activities and their distribution in subcellular fractions were examined.When carrot tissue cultures were grown for two or four weeks on agar media lacking a carbohydrate source, in 10000 lux and 1% CO2 in either air or N2, dry weight increases were obtained although chlorophyll levels eventually declined. PMID- 24482083 TI - The effect of indole-3-acetic acid on coleoptile extension growth in the absence of protein synthesis. AB - In wheat coleoptile sections cycloheximide inhibited over 90% of (14)C-leucine incorporation into protein within 10 minutes of its application. Even after 2 hour pretreatments with cycloheximide, IAA stimulated extension, suggesting that its growth-promoting action did not directly involve protein synthesis.Kinetic experiments with cycloheximide indicate that incorporation of a structural factor (possibly protein from a previously synthesised pool) into cell walls might be the rate-limiting process affected by IAA. PMID- 24482084 TI - [The influence of CO2 and pH on (32)P-labelling of polyphosphates and organic phosphates in Ankistrodesmus braunii in the light]. AB - The effect of CO2 on the (32)P-labelling of polyphosphates and acid-soluble organic phosphates is studied in synchronously grown cultures of the green alga Ankistrodesmus braunii, using trichloroacetic acid treatment and acid hydrolysis for the fractionation of the phosphorus compounds.Three per cent CO2 in nitrogen causes an inhibition of the labelling of polyphosphates but a marked increase of (32)P in organic phosphates, whereas oxygen (CO2-free air) produces the reverse effect. Polyphosphates and ATP are the fractions most stimulated by O2, while stable organic phosphates show the strongest inhibition. Labelling of nucleic acids is relatively indifferent to both oxygen and CO2. Three per cent CO2 in air causes the same distribution of (32)P-labelling as 3 per cent CO2 in N2. (32)P labelling is strongly dependent on the pH of the medium. In the absence of CO2, polyphosphate labelling is highest in the acidic range, whereas organic phosphates and ATP show optimum labelling and the highest percentage of the total (32)P in the alkaline pH range. The effect of CO2 is strongest between pH 5 and 6, that of oxygen between pH 8 and 9. Apparently the pH of the medium exerts a considerable influence upon the phosphate metabolism inside the cells.Increasing concentration of CO2 lead to the same change of (32)P-labelling in nitrogen as in air and to saturation at about 1 per cent CO2 under the conditions used. The curves are in good agreement with those of O2-evolution at increasing concentrations of CO2, but they show completely different rates.Young cells respond to CO2 and O2 differently from cells in the photosynthetically most active stage. In young cells both gasses are less effective.The effect of CO2 is explained by a strong increase in noncyclic photophosphorylation which can proceed only slowly in N2. ATP-consumption connected with high rates of CO2 fixation may be the reason for the low rates of (32)P-labelling in the polyphosphate fraction when CO2 is present. The influence of external pH on (32)P labelling is partly due to the pH-dependence of phosphate uptake, but the different response of several fractions to the pH of the medium suggests that the pH of the cytoplasm and possibly even the pH of the interior of the chloroplasts is affected by the external pH. The effect of O2 in the absence of CO2 or at low CO2-concentrations is explained by the well-known inhibition of photosynthesis by oxygen. Increasing concentrations of CO2 reverse this inhibition and correspondingly change the distribution of (32)P between the phosphate fractions. The change in sensitivity to CO2 and O2 with the cell age is consistent with the change in the rates of maximum photosynthetic CO2-fixation. PMID- 24482085 TI - [Chalcone-flavanone isomerase activity and accumulation of phenylpropanoid compounds in anthers]. AB - Chalcone-flavanone isomerase from the anthers of Lilium candidum and Tulipa cv. "Apeldoorn" exhibits a distinct substrate specificity. The enzyme catalyses only the isomerization of 2',4,4',6'-tetrahydroxychalcone, whereas it is not active with 2',4,4'-trihydroxychalcone.During the final stage in the development of the anthers, differing isomerase activities were observed. Maximum enzyme activity was measured at a point when the concentration of chalcones was decreasing rapidly and the concentration of flavonols was increasing. These findings strongly support the suggestion that the isomerase plays an important role in flavonoid metabolism. PMID- 24482086 TI - Some observations on coleoptile cell ultrastructure in ungerminated grains of rice (Oryza sativa L). AB - The ultrastructure of coleoptile cells of ungerminated rice grains has been examined following fixation in glutaraldehyde and osmium tetroxide. In many respects the cell structure resembles that reported for other dormant seed tissues: the cells contain protein bodies and lipid droplets, mitochondria and plastids show little internal structure but cytoplasm invaginates into many plastids; golgi cisternae cannot be discerned. Rough ER is present as cisternae surrounding protein bodies, as occasional regions of parallel layers, and in concentric whorls where it alternates with smooth paired membranes of an unknown nature. The ribosomes on the ER are at least partly arranged into regular rows. Various crystalline, presumably proteinaceous, inclusions lie in the groundplasm, plastids and nuclei. PMID- 24482087 TI - [Dependence of nitrite assimilation in green algae on energy supplied by respiration and photosynthesis]. AB - Inhibitors and uncouplers of phosphorylation, i.e., arsenate, 2.4-dinitrophenol (DNP), pentachlorophenol (PCP), and carbonyl cyanide m-chlorophenylhydrazone (CCCP), inhibit the assimilation of nitrite by the green alga Ankistrodesmus braunii in the dark and in the light. In a medium containing nitrate, these inhibitors interrupt nitrate reduction at the level of nitrite. In phosphatedeficient algae, the assimilation of nitrite can be decreased by a concomitant, energy-dependent uptake of chloride and phosphate ions. These results support the assumption that high-energy phosphate is required for the assimilation of nitrite.CO2 and glucose (after pre-illumination) increase nitrite assimilation in the light. Photosynthetic nitrite reduction is inhibited by 3 (3',4'-dichlorophenyl)-1,1-dimethyl urea (DCMU), an inhibitor of oxygen evolution, and by disalicylidene-propanediamine-(1,3) (DSPD), an inhibitor of the photosynthetic reduction of ferredoxin. PMID- 24482088 TI - Monomethyl-4-chloroindolyl-3-acetyl-L-aspartate and absence of indolyl-3-acetic acid in immature seeds of Pisum sativum. AB - A new auxin-related metabolite has been isolated from immature seeds of Pisum sativum and its structure has been determined as monomethyl-4-chloroindolyl-3 acetyl-L-aspartate. Neither indolyl-3-acetic acid nor its methyl ester have been detected in immature seeds by gas-liquid chromatographic analysis. PMID- 24482089 TI - A curious case of haemolysis, seizure and acute renal failure associated with pregnancy. AB - Differential diagnosis between thrombotic microangiopathies in pregnancy is challenging due to overlapping clinical and pathological findings and the rapid progression of disease. We present here an unusual case of Haemolysis, Elevated Liver enzymes and Low Platelets (HELLP) syndrome, which represents this diagnostic dilemma. The patient was treated with steroids and plasma exchange, leading to a favourable outcome. Subsequent genetic testing for complement dysregulation revealed a previously unknown variant in intron 3 of the gene coding for the alternative complement pathway factor H: (c.350+9T>C). We discuss here the diagnostic dilemma presented, the treatment pathway in the current literature, and the potential involvement of complement deregulation in severe HELLP. This case underlines the complexity in the diagnosis and management of pregnancy-related thrombotic microangiopathies. PMID- 24482090 TI - Effects of turmeric on uremic pruritus in end stage renal disease patients: a double-blind randomized clinical trial. AB - BACKGROUND: Uremic pruritus as a symptom that affects hemodialysis (HD) patients can decrease the quality of life and increase morbidity in these patients. The aim of this study was to evaluate the effects of turmeric on uremic pruritus in HD patients. SUBJECTS AND METHODS: This was a double-blind placebo-controlled trial conducted on 100 HD patients suffering from pruritus. Patients (mean age 53.3 +/- 15.8 years) were randomized into two groups: turmeric and placebo. The pruritus score and biochemical determinants including high-sensitivity C-reactive protein (hs-CRP) were compared before and at the end of the study between the two groups. RESULTS: The mean decrease in hs-CRP was significantly higher in the turmeric than the placebo group (-0.8 +/- 2.6 vs. 0.4 +/- 8.7 mg/l, p = 0.012). Also reduction of pruritus scores was greater in the turmeric than the placebo group (13.6 +/- 2.6 vs. 7.2 +/- 2.6, p = 0.001). No side effect was observed during the study due to the use of turmeric. CONCLUSIONS: This study demonstrates the possible efficacy of turmeric in decreasing hs-CRP and uremic pruritus in end stage renal disease patients. Future studies are needed to further evaluate the efficacy and safety of turmeric. PMID- 24482091 TI - Pulmonary Langerhans cell histiocytosis (PLCH): a new UK register. AB - Pulmonary Langerhans cell histiocytosis (PLCH) is a rare interstitial lung disease of unknown aetiology. We aimed to characterise a UK-wide cohort of patients with PLCH and compare diagnostic and management methods in specialist and non-specialist centres. 106 cases (53 hospitals) identified. Complete data received in 67 cases (53.7% female, age 37.1+/-14.4 years). 96% current or ex smokers. Treatment; smoking cessation (79%), corticosteroids (30.6%), cytotoxic therapy (26.9%) and lung transplant (6%). Patients at specialist centres received cytotoxic drugs more often (p=0.0001) and survival appeared higher. This dataset indicates a more even gender distribution than previously documented. It suggests variation in clinical management and outcomes achieved dependent on clinical experience. PMID- 24482092 TI - Temporal discrimination, a cervical dystonia endophenotype: penetrance and functional correlates. AB - The pathogenesis of adult-onset primary dystonia remains poorly understood. There is variable age-related and gender-related expression of the phenotype, the commonest of which is cervical dystonia. Endophenotypes may provide insight into underlying genetic and pathophysiological mechanisms of dystonia. The temporal discrimination threshold (TDT)-the shortest time interval at which two separate stimuli can be detected as being asynchronous-is abnormal both in patients with cervical dystonia and in their unaffected first-degree relatives. Functional magnetic resonance imaging (fMRI) studies have shown that putaminal activation positively correlates with the ease of temporal discrimination between two stimuli in healthy individuals. We hypothesized that abnormal temporal discrimination would exhibit similar age-related and gender-related penetrance as cervical dystonia and that unaffected relatives with an abnormal TDT would have reduced putaminal activation during a temporal discrimination task. TDTs were examined in a group of 192 healthy controls and in 158 unaffected first-degree relatives of 84 patients with cervical dystonia. In 24 unaffected first-degree relatives, fMRI scanning was performed during a temporal discrimination task. The prevalence of abnormal TDTs in unaffected female relatives reached 50% after age 48 years; whereas, in male relatives, penetrance of the endophenotype was reduced. By fMRI, relatives who had abnormal TDTs, compared with relatives who had normal TDTs, had significantly less activation in the putamina and in the middle frontal and precentral gyri. Only the degree of reduction of putaminal activity correlated significantly with worsening of temporal discrimination. These findings further support abnormal temporal discrimination as an endophenotype of cervical dystonia involving disordered basal ganglia circuits. PMID- 24482093 TI - An experimental examination of peers' influence on adolescent girls' intent to engage in maladaptive weight-related behaviors. AB - OBJECTIVE: Social psychological theories provide bases for understanding how social comparison processes may impact peer influence. This study examined two peer characteristics that may impact peer influence on adolescent girls' weight related behavior intentions: body size and popularity. METHOD: A school-based sample of 66 9th grade girls (12-15 years old) completed an experimental paradigm in which they believed they were interacting with other students (i.e., "e confederates"). The body size and popularity of the e-confederates were experimentally manipulated. Participants were randomly assigned to one of the three experimental conditions in which they were exposed to identical maladaptive weight-related behavior norms communicated by ostensible female peers who were either: (1) Thin and Popular; (2) Thin and Average Popularity; or (3) Heavy and Average Popularity. Participants' intent to engage in weight-related behaviors was measured pre-experiment and during public and private segments of the experiment. RESULTS: A significant effect of condition on public conformity was observed. Participants exposed to peers' maladaptive weight-related behavior norms in the Heavy and Average condition reported significantly less intent to engage in weight-related behaviors than participants in either of the thin-peer conditions (F(2) = 3.93, p = .025). Peer influence on private acceptance of weight-related behavior intentions was similar across conditions (F(2) = .47, p = .63). DISCUSSION: Body size comparison may be the most salient component of peer influence processes on weight-related behaviors. Peer influence on weight-related behavior intention also appears to impact private beliefs. Considering peer norms in preventive interventions combined with dissonance-based approaches may be useful. PMID- 24482094 TI - Acclimation of brackish water pearl spot (Etroplus suratensis) to various salinities: relative changes in abundance of branchial Na(+)/K (+)-ATPase and Na (+)/K (+)/2Cl (-) co-transporter in relation to osmoregulatory parameters. AB - The present study was conducted to elucidate the osmoregulatory ability of the fish pearl spot (Etroplus suratensis) to know the scope of this species for aquaculture under various salinities. Juvenile pearl spot were divided into three groups and acclimated to freshwater (FW), brackish water (BW) or seawater (SW) for 15 days. The fish exhibited effective salinity tolerance under osmotic challenges. Although the plasma osmolality and Na(+), K(+) and Cl(-) levels increased with the increasing salinities, the parameters remained within the physiological range. The muscle water contents were constant among FW-, BW- and SW-acclimated fish. Two Na+/K+-ATPase alpha-isoforms (NKA alpha) were expressed in gills during acclimation in FW, BW and SW. Abundance of one isoform was up regulated in response to seawater acclimation, suggesting its role in ion secretion similar to NKA alpha1b, while expression of another isoform was simultaneously up-regulated in response to both FW and SW acclimation, suggesting the presence of isoforms switching phenomenon during acclimation to different salinities. Nevertheless, NKA enzyme activities in the gills of the SW and FW individuals were higher (p < 0.05) than in BW counterparts. Immunohistochemistry revealed that Na(+)/K(+)-ATPase immunoreactive (NKA-IR) cells were mainly distributed in the interlamellar region of the gill filaments in FW groups and in the apical portion of the filaments in BW and SW groups. The number of NKA-IR cells in the gills of the FW-acclimated fish was almost similar to that of SW individuals, which exceeded that of the BW individuals. The NKA-IR cells of BW and SW were bigger in size than their FW counterparts. Besides, the relative abundance of branchial Na(+)/K(+)/2Cl(-) co-transporter showed stronger evidence in favor of involvement of this protein in hypo-osmoregulation, requiring ion secretion by the chloride cells. To the best of our knowledge, this is the first study reporting the wide salinity tolerance of E. suratensis involving differential activation of ion transporters and thereby suggesting its potential as candidate for fish farming under different external salinities. PMID- 24482095 TI - Chronic stress due to high stocking density in open sea cage farming induces variation in biochemical and immunological functions in Asian seabass (Lates calcarifer, Bloch). AB - Stocking density is an important factor in cage aquaculture of finfish. Effects of high stocking density (35 fish cubic m(-1)) on a range of biochemical and immunological parameters in Asian seabass reared in open sea floating net cages were compared to fish held in relatively low density (15 fish cubic m(-1)). The results revealed that chronic stress due to high stocking density induced variations in most of the parameters studied as evidenced by increased cortisol and glucose levels and decreased activity of lysozyme, myeloperoxidase and complement. Production of reactive oxygen species, total leucocyte count and total serum protein were also decreased, whereas anti-protease, alkaline phosphatase and acid phosphatase activities were increased in high stocking density group when compared to low stocking-density group. Effects of chronic stress due to high stocking density were discussed in relation to variations in these parameters. PMID- 24482096 TI - In vitro effect of isotocin on ovarian tunica albuginea contractility of gilthead seabream (Sparus aurata L.) in different reproductive conditions. AB - Contractions of ovarian tunica albuginea, the teleostean cystovary wall layer containing smooth muscle fibres, facilitate oocytes and fluids movements within the ovary, oocytes ovulation and spawning. Fish isotocin, the homologue hormone of mammalian oxytocin, plays a significant role in ovulation, oviduct contraction and spawning. In the present study, ovarian wall spontaneous contraction, as well as isotocin in vitro effect on tunica albuginea contractility, was analysed in female seabream in different reproductive conditions: vitellogenesis, regressing (post-spawning) and extensive atresia. Tunica albuginea spontaneous contractility was recorded using ovary wall strips mounted in an organ bath containing modified Ringer's solution. The strips were then exposed to cumulative doses of isotocin (6, 30, 60 MUg/ml). Female seabream in regressing condition exhibited the highest level of tunica albuginea spontaneous contraction amplitude compared with the other two groups. Only fish in vitellogenesis state showed a significant increase in contraction amplitude after isotocin administration at the dose of 30 MUg/ml. The same group exhibited also a significant isotocin dose-dependent decrease in the contractile frequency. These results confirm the involvement of isotocin in stimulating tunica albuginea contractile activity during the oestrogen-regulated phase of vitellogenesis, whereas the absence of significant effects of isotocin on ovarian contractility in fish at the regressing state might be ascribed to the occurrence of a contractile activity autonomously regulated by the internal pacemaker system. The absence of exposed isotocin receptors could explain the lack of effects of the isotocin administration in seabream showed extensive atresia of the follicular cells. PMID- 24482097 TI - Contribution of the ROS-p53 feedback loop in thuja-induced apoptosis of mammary epithelial carcinoma cells. AB - The adverse side-effects associated with chemotherapy during cancer treatment have shifted considerable focus towards therapies that are targeted but devoid of toxic side-effects. In the present study, the antitumorigenic activity of thuja, the bioactive derivative of the medicinal plant Thuja occidentalis, was evaluated, and the molecular mechanisms underlying thuja-induced apoptosis of functional p53-expressing mammary epithelial carcinoma cells were elucidated. Our results showed that thuja successfully induced apoptosis in functional p53 expressing mammary epithelial carcinoma cells. Abrogation of intracellular reactive oxygen species (ROS), prevention of p53-activation, knockdown of p53 or inhibition of its functional activity significantly abridged ROS generation. Notably, under these conditions, thuja-induced breast cancer cell apoptosis was reduced, thereby validating the existence of an ROS-p53 feedback loop. Elucidating this feedback loop revealed bi-phasic ROS generation as a key mediator of thuja-induced apoptosis. the first phase of ROS was instrumental in ensuring activation of p53 via p38MAPK and its nuclear translocation for transactivation of Bax, which induced a second phase of mitochondrial ROS to construct the ROS-p53 feedback loop. Such molecular crosstalk induced mitochondrial changes i) to maintain and amplify the thuja signal in a positive self-regulatory feedback manner; and ii) to promote the mitochondrial death cascade through cytochrome c release and caspase-driven apoptosis. These results open the horizon for developing a targeted therapy by modulating the redox status of functional p53-expressing mammary epithelial carcinoma cells by thuja. PMID- 24482098 TI - One-pot synthesis of fused pyrroles through a key gold-catalysis-triggered cascade. AB - A two-step, one-pot synthesis of fused pyrroles is realized by firstly condensing an N-alkynylhydroxammonium salt with a readily enolizable ketone under mild basic conditions and then subjecting the reaction mixture to a gold catalyst, which triggers a cascade reaction involving a facile initial [3.3]-sigmatropic rearrangement of the gold-catalysis product, that is, an N,O dialkenylhydroxamine. The reaction provides a facile access to polycyclic pyrroles in moderate to good yields. PMID- 24482099 TI - Salivary cortisol is a useful tool to assess the early response to pasireotide in patients with Cushing's disease. AB - PURPOSE: Late night salivary cortisol (LNSC) is useful for diagnosing hypercortisolism and monitoring patients with Cushing's disease (CD) following pituitary surgery. It may also be a better index of cortisol secretion than serum cortisol or urinary free cortisol (UFC). No data regarding the role of LNSC in the early monitoring of patients with CD receiving drug therapy has been published. We investigated the value of LNSC in monitoring the short-term efficacy of pasireotide. METHODS: Seven patients who were enrolled in a phase II study investigating the efficacy of pasireotide in CD (CSOM230B2208) were included in this analysis. Patients self-administered subcutaneous pasireotide 600 MUg bid for 15 days. LNSC and UFC levels were assessed at baseline and day 15. RESULTS: At baseline, all patients had elevated LNSC which was correlated significantly with UFC levels (r = 0.97, P = .0002). At day 15, LNSC was reduced in six patients. LNSC decreases were observed from day 1 (-20%) and persisted until day 15 (overall mean reduction from baseline -51%), with the greatest decrease on day 5 (-58%). At day 15, UFC levels were decreased in all patients and normalized in one that restored also salivary cortisol rhythm. CONCLUSIONS: In patients with CD, pasireotide rapidly reduced and normalized both UFC and LNSC levels. LNSC may be a simple, non-invasive biomarker to assess the early response to pasireotide, particularly in determining whether cortisol rhythm is normalized in patients with normalized UFC levels. Further studies are warranted. PMID- 24482100 TI - Hereditary gene mutations in Korean patients with isolated erythrocytosis. AB - Most cases of erythrocytosis occur secondary to chronic tissue hypoxia or as a clonal disease such as polycythemia vera with somatic mutations in the Janus kinase 2 (JAK2) gene. Rarely, erythrocytosis is caused by hereditary gene mutations. This study investigated hereditary gene mutations in 38 unrelated Korean patients with isolated erythrocytosis without (1) JAK2 mutation and (2) secondary causes of erythrocytosis other than smoking history. Direct sequencing analyses were performed on six genes associated with hereditary erythrocytosis [HBB, exon 2 and exon 3 of HBA2, VHL, EGLN1 (previously PHD2), exon 12 of EPAS1 (previously HIF2A), and exons 5-8 of EPOR]. As a result, mutations were detected in five patients (three never smokers and two current smokers) out of 38 patients (13.2 %). The mutations detected in those five patients were EPOR:p.W439*, EPOR:p.G212C, HBB:p.H98Q (or conventionally H97Q, Hb Malmo [beta 97(FG4) His > Gln]), HBB:p.V138M (V137M), and EGLN1:p.L279Tfs43*, all in heterozygous state. No patient had mutations in HBA2, VHL, or in EPAS1. This study indicates that workup for hereditary gene mutations is needed for isolated erythrocytosis with or without smoking history. PMID- 24482101 TI - Serum immunoglobulin free light chain and heavy/light chain measurements in POEMS syndrome. AB - POEMS (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) syndrome is a rare plasma cell dyscrasia. Nearly all patients present with a lambda-restricted monoclonal gammopathy. Most patients with POEMS syndrome have been reported to have a normal serum free light chain ratio (sFLC R), but the underlying mechanism is still unclear. We assessed the serum free light chains in 83 patients with newly diagnosed POEMS syndrome. The clinical and laboratory data associated with this disorder were collected to identify factors affecting sFLC-R. Fifty-six patients (67 %) showed elevated serum free lambda light chains, but only 11 patients (13 %) had an abnormal sFLC-R. A comparison of patients with and without abnormal sFLC-Rs indicated that the latter group had more common splenomegaly and worse renal function. However, the introduction of an extended renal range for sFLC-R did not dramatically improve the diagnostic value of sFLC-R in these patients. Further analyses identified a correlation between the serum free kappa light chain and the uninvolved immunoglobulin in patients with an IgAlambda clone, implying that the activation of polyclonal immunoglobulin production could mask the presumed skewing of the sFLC-R induced by the underlying monoclonal gammopathy. Therefore, a serum heavy/light chain (sHLC) assay was performed in a subset of patients with stored serum samples available, and the prevalence of abnormal sHLC ratios was high in these patients. In summary, the overproduction of polyclonal immunoglobulin accounts for the high frequency of normal sFLC-R in patients with POEMS syndrome. The sHLC assay may provide unique information about this disorder. PMID- 24482102 TI - AIDS-Associated Cardiac Lymphoma-A Review: Apropos a Case Report. AB - Despite treatment with potent and effective combination antiretroviral medications, the incidence of non-Hodgkin lymphoma (NHL) in the population living with HIV/AIDS remains significantly higher than that in noninfected individuals. The majority of the HIV-infected patients with NHL present with advanced stage extranodal disease of the B-cell phenotype. Lymphomas are the second most common tumors involving the heart in HIV-infected patients. Although the heart may serve as the primary focus of the lymphoma, in most HIV-related cases, cardiac lymphomatous involvement is part of a metastatic process that originated elsewhere. PMID- 24482103 TI - Rhodococcus equi pericarditis in a patient living with HIV/AIDS. AB - INTRODUCTION: Rhodococcus equi, previously called Corynebacterium equi, is known to cause pneumonia in foals and swine. Although it was known to cause infection rarely in humans, R equi infection in humans has increased with the advent of HIV and increased use of immunosuppressants. CASE: We report a case of a 48-year-old male patient with newly diagnosed HIV/AIDS presenting with recurrent R equi bacteremia, pericardial effusion, and pericardial cyst. The infection was treated with drainage of the pericardial effusion and cyst and 2 weeks of intravenous vancomycin and 6 months of oral azithromycin and levofloxacin. DISCUSSION: Rhodococcus equi causes pericarditis and pericardial effusion. It can be effectively treated with debridement, drainage, and a prolonged course of antibiotics. In vitro antibiotic susceptibility should be checked as resistance to antibiotics can develop, especially if drainage is inadequate. PMID- 24482104 TI - Evaluation of an HIV adherence counseling program in La Romana, Dominican Republic. AB - Research has demonstrated that adherence to antiretroviral therapy (ART) results in lower rates of morbidity and mortality associated with HIV infection, yet adherence remains a challenge in resource-limited settings like the Dominican Republic. Clinica de Familia La Romana addressed this problem with an education based adherence program for adult patients new to ART, and this retrospective cohort study aimed to evaluate the impact of this intervention. Appointment adherence and biological markers were assessed in cases and controls through 12 months. A total of 101 participants were included, with 61 controls and 40 cases. The baseline CD4 count was 162 and 157 cells/mm3 in controls and cases, respectively. Cases showed a 15-fold increase in CD4 count compared with a 2.5 fold increase in controls. Cases were more likelyto adhere to appointments with adherence rates of 86% versus 76% in controls. There was no difference between the rates of treatment abandonment, transfer of care, or death. PMID- 24482105 TI - The Impact of Key HIV Intervention Components as Predictors of Sexual Barrier Use: The Zambia Partner Project. AB - Behavioral interventions have utilized a variety of strategies and components to reduce HIV risk. This article describes the partner intervention, a couple-based group HIV risk reduction intervention implemented in 6 urban community health clinics in Lusaka, Zambia, and examines the components of the intervention and their relationship with condom use. Couple members completed assessments on condom use, acceptability, willingness to use condoms, communication, intimate partner violence (IPV), self-efficacy, and HIV information at baseline and 6 months' follow-up. This study examined the relative impact of elements of the intervention as predictors of condom use. Changes in acceptability had the greatest overall influence on condom use, followed by social support, relationship consensus, and willingness to use condoms. Changes in self-efficacy, IPV, negotiation, and information had no influence. Results support the use of multidimensional approaches in behavioral interventions and highlight the importance of identifying critical elements of interventions to maximize risk reduction outcomes. PMID- 24482106 TI - Health care practices and associated service needs in a sample of HIV-positive incarcerated men in Puerto Rico: implications for retention in care. AB - OBJECTIVE: This report describes the HIV-related health care practices and associated support service needs of a sample of HIV-positive incarcerated men in Puerto Rico. METHODS: Data are derived from a random sample of HIV-positive incarcerated men (n = 37) in Puerto Rico who completed a brief survey. Analysis included descriptive statistics to examine lifetime prevalence of substance use, selected health care practices, receipt of services, and hepatitis C virus (HCV) infection. RESULTS: Most men (97.3%) reported history of alcohol or drug use, prior incarceration, and drug use as the main risk factors for HIV infection (73.0%). In all, 83.8% of the men reported having had their first HIV screening test in a correctional facility, 55.6% reported intermittent HIV therapy, and most (83.8%) had also been diagnosed with HCV. CONCLUSIONS: Correctional facilities can be important settings for engaging high-risk populations in health care, capturing and enrolling unidentified HIV/HCV infections for clinical care, and engaging in substance abuse treatment. In order for these public health outcomes to be achieved, it is important to consider strategies to optimize care inside prison and in the community. PMID- 24482107 TI - Fecal incontinence: the role of the urologist. AB - Fecal incontinence is the involuntary loss of solid or liquid stool. While the true prevalence of fecal incontinence is difficult to discern, it is estimated that almost 9 % of non-institutionalized women in the US experience this condition. Disorders leading to fecal urgency alone are usually related to rectal storage abnormalities while incontinence is often a result of anatomic or neurologic disruption of the anal sphincter complex. Many risk factors exist for fecal incontinence and include female sex, increasing age, higher body mass index (BMI), limited physical activity, smoking, presence of neuropsychiatric conditions, higher vaginal parity and history of obstetrical trauma, presence of chronic diarrhea and irritable bowel syndrome, or history of rectal surgery, prostatectomy and radiation. Evaluation of fecal incontinence involves a careful patient history and focused physical exam. Diagnostic tests include endorectal ultrasonography, anal manometry, anal sphincter electromyography, and defecography. Treatment strategies include behavioral, medical and surgical therapies as well as neuromodulation. Treatment is based on the presumed etiology of the condition and a multi-modal approach is often necessary to achieve the maximum benefit for patients. PMID- 24482108 TI - Neurological findings and genetic alterations in patients with Kostmann syndrome and HAX1 mutations. AB - OBJECTIVES: To describe the clinical profile and the prevalence of severe congenital neutropenia (SCN) and HAX1 mutations, so-called Kostmann syndrome, in France. STUDY DESIGN: Two pedigrees were identified from the French registry. RESULTS: The study included five subjects (three males), which represent 0.7% of the 759 SCN cases registered in France. The age at diagnosis was 0.3 years (range: 0.1-1.2 years) and the median age at the last follow-up was 7.3 years (range: 1.2-17.8 years). A novel large homozygous deletion of the HAX1 gene (exons 2-5) was found in one pedigree; while, a homozygous frameshift mutation was identified in exon 3 (c.430dupG, p.Val144fs) in the second pedigree. Severe bacterial infections were observed in four patients, including two cases of sepsis, one case of pancolitis, a lung abscess, and recurrent cellulitis and stomatitis. During routine follow-up, the median neutrophil value was 0.16 * 10(9)/L, associated with monocytosis (2 * 10(9)/L). Bone marrow (BM) smears revealed a decrease of the granulocytic lineage with no mature myeloid cells above the myelocytes. One patient died at age 2 from neurological complications, while two other patients, including one who underwent a hematopoietic stem cell transplantation (HSCT) at age 5, are living with very severe neurological retardation. CONCLUSIONS: SCN with HAX1 mutations, is a rare sub type of congenital neutropenia, mostly observed in population from Sweden and Asia minor, associating frequently neurological retardation, when the mutations involved the B isoform of the protein. PMID- 24482109 TI - Sarcopenia and its relationship with osteoarthritis: risk factor or direct consequence? AB - PURPOSE: The aim of this review is to evaluate the clinical role of sarcopenia in patients affected by osteoarthritis (OA) of major joints. METHODS: An online database research was performed, in order to retrieve all articles investigating the relationship between sarcopenia and OA. No peer-reviewed journal was excluded. Papers in English, French, Spanish and Italian language were considered. After consulting the full-text article, five studies have been included in the review. RESULTS: Of the five studies included, four are prospective studies and only one is a cross-sectional study which retrieved data retrospectively. A total of 4,231 patients, presenting a mean age of 62.0 years, were studied. Three studies evaluated only female subjects. Weight, height and body mass index were reported in all the articles. Knee OA has been assessed using the Kellgren-Lawrence grading system and the American college of rheumatology criteria. Alterations of the lean body mass on body weight ratio have been reported to be as a significant predictive parameter in two studies. Relationship between radiographic OA and an increase in the leg lean mass has been observed in one study. CONCLUSIONS: We cannot support neither the thesis of a direct effect of sarcopenia on OA development nor the opposite relation, because the up-to-date literature lacks basic science studies concerning these topics. The absence of clinical studies regarding measurements and tools to compare sarcopenia and OA do not allow to definitely clarify this relationship. PMID- 24482111 TI - Development of a potential method based on microchip electrophoresis with fluorescence detection for the sensitive determination of intracellular thiols in RAW264.7 cells. AB - This paper, for the first time, reported the development of a simple, rapid, and reliable method for the separation and sensitive determination of four thiol compounds including homocysteine, cysteine, glutathione, and N-acetylcysteine based on glass MCE with fluorescence detection using a highly reactive fluorogenic probe, 1,3,5,7-tetramethyl-8-phenyl-(2-maleimide)-difluoroboradiaza-s indacene (TMPAB-o-M), as the labeling reagent. TMPAB-o-M reacted selectively with thiols to produce highly fluorescent derivatives and the highest derivatization efficiency was achieved within 6 min in physiological conditions. After the optimization of separation conditions, a baseline separation of the four thiol compounds was achieved with the detection limits ranging from 2 nM for glutathione to 4 nM for cysteine (S/N = 3) and RSDs (n = 5) in the range of 3.2 3.8%. The proposed method was significantly sensitive compared to those using electrochemical or even LIF detection in MCE-based setup reported previously, and applied to the determination of intracellular thiols in macrophage RAW264.7 cells. PMID- 24482112 TI - In response to "is nasopharyngoscopy necessary in adult-onset otitis media with effusion?". PMID- 24482110 TI - Drug development for intraperitoneal chemotherapy against peritoneal carcinomatosis from gastrointestinal cancer. AB - Intraperitoneal (IP) chemotherapy for peritoneal carcinomatosis (PC) from gastrointestinal cancer has been investigated and applied clinically for several decades. Cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy have been considered to be the optimal treatment options for selected patients with colorectal and gastric cancers with PC. Accumulating evidence suggests that the administration of IP paclitaxel for patients with PC from gastric cancer may improve the patient survival. The pharmacokinetics of such treatment should be considered to optimize IP chemotherapy. In addition, newly emerging molecular targeted therapies and research into new drug delivery systems, such as nanomedicine or controlled absorption/release methods, are essential to improve the effects of IP chemotherapy. This review summarizes the current status and future prospects of IP chemotherapy for the treatment of gastrointestinal cancer. PMID- 24482113 TI - Fixed pattern noise in localization microscopy. AB - Localization microscopy vastly improves the resolution achieved by fluorescence microscopy by fitting the positions of individual fluorophores. We examine the reconstructions produced by different fitting algorithms for instances of fixed pattern noise--systematic tendencies to alter estimated emitter positions according to their subpixel location in a way that does not reflect the ground truth structure. We show that while not readily visible at standard empirical signal strengths, fixed pattern noise can occur when performing sub-pixel fitting, and that its degree varies according to the algorithm used and the relative size of the pixels compared to the point spread function. For pixel sizes in the range 80-170 nm, this results in variations in accuracy of the order of 2-4 nm-comparatively small for many applications, but non-negligible in scenarios where very high accuracy is sought. PMID- 24482114 TI - Clusthaplo: a plug-in for MCQTL to enhance QTL detection using ancestral alleles in multi-cross design. AB - KEY MESSAGE: We enhance power and accuracy of QTL mapping in multiple related families, by clustering the founders of the families on their local genomic similarity. MCQTL is a linkage mapping software application that allows the joint QTL mapping of multiple related families. In its current implementation, QTLs are modeled with one or two parameters for each parent that is a founder of the multi cross design. The higher the number of parents, the higher the number of model parameters which can impact the power and the accuracy of the mapping. We propose to make use of the availability of denser and denser genotyping information on the founders to lessen the number of MCQTL parameters and thus boost the QTL discovery. We developed clusthaplo, an R package ( http://cran.r project.org/web/packages/clusthaplo/index.html ), which aims to cluster haplotypes using a genomic similarity that reflects the probability of sharing the same ancestral allele. Computed in a sliding window along the genome and followed by a clustering method, the genomic similarity allows the local clustering of the parent haplotypes. Our assumption is that the haplotypes belonging to the same class transmit the same ancestral allele. So their putative QTL allelic effects can be modeled with the same parameter, leading to a parsimonious model, that is plugged in MCQTL. Intensive simulations using three maize data sets showed the significant gain in power and in accuracy of the QTL mapping with the ancestral allele model compared to the classical MCQTL model. MCQTL_LD (clusthaplo outputs plug in MCQTL) is a versatile and powerful tool for QTL mapping in multiple related families that makes use of linkage and linkage disequilibrium (web site http://carlit.toulouse.inra.fr/MCQTL/ ). PMID- 24482115 TI - A viral RNA structural element alters host recognition of nonself RNA. AB - Although interferon (IFN) signaling induces genes that limit viral infection, many pathogenic viruses overcome this host response. As an example, 2'-O methylation of the 5' cap of viral RNA subverts mammalian antiviral responses by evading restriction of Ifit1, an IFN-stimulated gene that regulates protein synthesis. However, alphaviruses replicate efficiently in cells expressing Ifit1 even though their genomic RNA has a 5' cap lacking 2'-O methylation. We show that pathogenic alphaviruses use secondary structural motifs within the 5' untranslated region (UTR) of their RNA to alter Ifit1 binding and function. Mutations within the 5'-UTR affecting RNA structural elements enabled restriction by or antagonism of Ifit1 in vitro and in vivo. These results identify an evasion mechanism by which viruses use RNA structural motifs to avoid immune restriction. PMID- 24482116 TI - ESCRT machinery is required for plasma membrane repair. AB - Plasma membrane damage can be triggered by numerous phenomena, and efficient repair is essential for cell survival. Endocytosis, membrane patching, or extracellular budding can be used for plasma membrane repair. We found that endosomal sorting complex required for transport (ESCRT), involved previously in membrane budding and fission, plays a critical role in plasma membrane repair. ESCRT proteins were recruited within seconds to plasma membrane wounds. Quantitative analysis of wound closure kinetics coupled to mathematical modeling suggested that ESCRTs are involved in the repair of small wounds. Real-time imaging and correlative scanning electron microscopy (SEM) identified extracellular buds and shedding at the site of ESCRT recruitment. Thus, the repair of certain wounds is ensured by ESCRT-mediated extracellular shedding of wounded portions. PMID- 24482118 TI - High-energy surface X-ray diffraction for fast surface structure determination. AB - Understanding the interaction between surfaces and their surroundings is crucial in many materials-science fields, such as catalysis, corrosion, and thin-film electronics, but existing characterization methods have not been capable of fully determining the structure of surfaces during dynamic processes, such as catalytic reactions, in a reasonable time frame. We demonstrate an x-ray-diffraction-based characterization method that uses high-energy photons (85 kiloelectron volts) to provide unexpected gains in data acquisition speed by several orders of magnitude and enables structural determinations of surfaces on time scales suitable for in situ studies. We illustrate the potential of high-energy surface x-ray diffraction by determining the structure of a palladium surface in situ during catalytic carbon monoxide oxidation and follow dynamic restructuring of the surface with subsecond time resolution. PMID- 24482117 TI - Phonetic feature encoding in human superior temporal gyrus. AB - During speech perception, linguistic elements such as consonants and vowels are extracted from a complex acoustic speech signal. The superior temporal gyrus (STG) participates in high-order auditory processing of speech, but how it encodes phonetic information is poorly understood. We used high-density direct cortical surface recordings in humans while they listened to natural, continuous speech to reveal the STG representation of the entire English phonetic inventory. At single electrodes, we found response selectivity to distinct phonetic features. Encoding of acoustic properties was mediated by a distributed population response. Phonetic features could be directly related to tuning for spectrotemporal acoustic cues, some of which were encoded in a nonlinear fashion or by integration of multiple cues. These findings demonstrate the acoustic phonetic representation of speech in human STG. PMID- 24482119 TI - Nickel-catalyzed C-H alkylations: direct secondary alkylations and trifluoroethylations of arenes. AB - A versatile nickel catalyst allowed for C-H alkylations of unactivated arenes with challenging secondary alkyl bromides and chlorides. The high catalytic efficacy also set the stage for direct secondary alkylations of indoles as well as C-H trifluoroethylations with ample substrate scope. PMID- 24482121 TI - Progestational agents for treating threatened or established preterm labour. AB - BACKGROUND: Prematurity is not only the leading cause of perinatal morbidity and mortality but is associated with long-term impairment. Studies of various tocolytic agents have shown mixed results with little effect in improving pregnancy duration and insufficient data to confirm a definite beneficial effect on neonatal morbidity or mortality. Progesterone is known to have an inhibitory effect on uterine contractility and is thought to play a key role in the maintenance of pregnancy until term. OBJECTIVES: To determine if the use of progestational agents is effective as a form of treatment or co-treatment for women with threatened or established preterm labour with intact membranes. SEARCH METHODS: We searched the Cochrane Pregnancy and Childbirth Group's Trials Register (31 August 2013), CENTRAL (The Cochrane Library 2013, Issue 10), MEDLINE (1966 to August 31 2013) and Embase (1974 to 31 August 2013). We checked the reference lists of all included studies to identify any additional studies and communicated with authors and the pharmaceutical industry. SELECTION CRITERIA: Randomised controlled trials that compared progestational agents, given either alone or in combination with other tocolytics, with a control group receiving another tocolytic, placebo or no treatment, for the treatment of preterm labour. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. MAIN RESULTS: Eight studies were included in this review, involving 563 women, but only seven studies, involving 538 women, contributed data for analyses. There are some data suggesting that the use of progestational agents results in a reduction of preterm deliveries at less than 37 weeks of gestation and an increase in birthweight. The use of a progestational agent may also reduce the frequency of uterine contractions, prolong pregnancy and attenuate the shortening of cervical length. However, the analysis was limited by the relatively small number of available studies. The power of the meta-analysis was also limited by the varying types, dosages and routes of administration of progesterone. AUTHORS' CONCLUSIONS: There is insufficient evidence to advocate progestational agents as a tocolytic for women presenting with preterm labour. PMID- 24482120 TI - A voxel-based morphometry and diffusion tensor imaging analysis of asymptomatic Parkinson's disease-related G2019S LRRK2 mutation carriers. AB - BACKGROUND: Patients with Parkinson's disease have reduced gray matter volume and fractional anisotropy in both cortical and sub-cortical structures, yet changes in the pre-motor phase of the disease are unknown. METHODS: A comprehensive imaging study using voxel-based morphometry and diffusion tensor imaging tract based spatial statistics analysis was performed on 64 Ashkenazi Jewish asymptomatic first degree relatives of patients with Parkinson's disease (30 mutation carriers), who carry the G2019S mutation in the leucine-rich repeat kinase 2 (LRRK2) gene. RESULTS: No between-group differences in gray matter volume could be noted in either whole-brain or volume-of-interest analysis. Diffusion tensor imaging analysis did not identify group differences in white matter areas, and volume-of-interest analysis identified no differences in diffusivity parameters in Parkinson's disease-related structures. CONCLUSIONS: G2019S carriers do not manifest changes in gray matter volume or diffusivity parameters in Parkinson's disease-related structures prior to the appearance of motor symptoms. PMID- 24482122 TI - Cleavage of E-cadherin and beta-catenin by calpain affects Wnt signaling and spheroid formation in suspension cultures of human pluripotent stem cells. AB - The envisioned clinical and industrial use of human pluripotent stem cells and their derivatives has given major momentum to the establishment of suspension culture protocols that enable the mass production of cells. Understanding molecular changes accompanying the transfer from adherent to suspension culture is of utmost importance because this information can have a direct effect on the development of optimized culture conditions. In this study we assessed the gene expression of human embryonic stem cells and induced pluripotent stem cells grown in surface-adherent culture (two-dimensional) versus free-floating suspension culture spheroids (three-dimensional). We combined a quantitative proteomic approach based on stable isotope labeling by amino acids in cell culture with deep-sequencing-based transcriptomics. Cells in three-dimensional culture showed reduced expression of proteins forming structural components of cell-cell and cell-extracellular matrix junctions. However, fully unexpected, we found up regulation of secreted inhibitors of the canonical Wnt signaling pathway and, concomitantly, a reduction in the level of active beta-catenin and in the expression of Wnt target genes. In Western blot analyses the cysteine protease calpain was shown to cleave E-cadherin and beta-catenin under three-dimensional culture conditions. Our data allowed the development of a model in which calpain cleavage of E-cadherin induces the disintegration of focal cell contacts and generates a 100-kDa E-cadherin fragment required for the formation of three dimensional cell-cell contacts in spheroids. The parallel release of beta-catenin and its potential activation by calpain cleavage are counterbalanced by the overexpression of soluble Wnt pathway inhibitors. According to this model, calpain has a key function in the interplay between E-cadherin and beta-catenin mediated intercellular adhesion and the canonical Wnt signaling pathway. Supporting this model, we show that pharmacological modulation of calpain activity prevents spheroid formation and causes disassembly of preexisting spheroids into single cells, thereby providing novel strategies for improving suspension culture conditions for human pluripotent stem cells in the future. PMID- 24482125 TI - Analysis of Intracellular Calcium Signaling in Human Embryonic Stem Cells. AB - Measurement of changes in intracellular calcium concentration is one of the most common and useful tools for studying signal transduction pathways or cellular responses in basic research and drug screening purposes as well. Increasing number of such applications using human pluripotent stem cells and their derivatives requires development of calcium signal measurements for this special cell type. Here we describe a modified protocol for analysis of calcium signaling events in human embryonic stem cells, which can be used for other pluripotent cell types (such as iPSC) or their differentiated offspring as well. PMID- 24482123 TI - Mass spectrometry-based workflow for accurate quantification of Escherichia coli enzymes: how proteomics can play a key role in metabolic engineering. AB - Metabolic engineering aims to design high performance microbial strains producing compounds of interest. This requires systems-level understanding; genome-scale models have therefore been developed to predict metabolic fluxes. However, multi omics data including genomics, transcriptomics, fluxomics, and proteomics may be required to model the metabolism of potential cell factories. Recent technological advances to quantitative proteomics have made mass spectrometry based quantitative assays an interesting alternative to more traditional immuno affinity based approaches. This has improved specificity and multiplexing capabilities. In this study, we developed a quantification workflow to analyze enzymes involved in central metabolism in Escherichia coli (E. coli). This workflow combined full-length isotopically labeled standards with selected reaction monitoring analysis. First, full-length (15)N labeled standards were produced and calibrated to ensure accurate measurements. Liquid chromatography conditions were then optimized for reproducibility and multiplexing capabilities over a single 30-min liquid chromatography-MS analysis. This workflow was used to accurately quantify 22 enzymes involved in E. coli central metabolism in a wild type reference strain and two derived strains, optimized for higher NADPH production. In combination with measurements of metabolic fluxes, proteomics data can be used to assess different levels of regulation, in particular enzyme abundance and catalytic rate. This provides information that can be used to design specific strains used in biotechnology. In addition, accurate measurement of absolute enzyme concentrations is key to the development of predictive kinetic models in the context of metabolic engineering. PMID- 24482126 TI - Prevalence of aspirin resistance in Asian-Indian patients with stable coronary artery disease. AB - OBJECTIVE: To evaluate the prevalence of pharmacological resistance to aspirin therapy by measuring platelet functions using the technique of light transmission aggregometry. BACKGROUND: Aspirin is the cornerstone of antiplatelet therapy in patients with coronary artery disease (CAD). However, a substantial proportion of patients manifest breakthrough thrombotic events despite regular intake of aspirin suggesting therapeutic resistance to aspirin. METHODS: We prospectively studied 126 patients with stable coronary artery disease at a tertiary center, who were recruited after ensuring compliance with a single formulation of aspirin (enteric coated aspirin 150 mg). Platelet aggregation was measured using light transmission aggregometry with ADP (10 uM) and Arachidonic acid (0.5 mg/mL). Pharmacological aspirin resistance was defined as the combined demonstration of mean platelet aggregation of >=70% with 10 uM ADP and a mean aggregation of >=20% with 0.5 mg/mL A.A. Patients satisfying either one of the above criteria were defined as semi-responders. Patients satisfying neither criterion were defined as "aspirin responders". RESULTS: Out of 126 patients with stable CAD, 64 % were responders, 36% were non responders (semi-responders = 34% and resistant = 2%). Of the laboratory parameters, only the total leukocyte count was significantly associated with the presence of aspirin resistance (P < 0.03). CONCLUSION: Pharmacological resistance to aspirin is noted in 36% (semi-responders = 34% and resistant = 2%) of Asian Indian patients with stable CAD. Long-term follow up of these patients will assist in determining the clinical importance of this phenomenon. (c) 2014 Wiley Periodicals, Inc. PMID- 24482127 TI - Spontaneous electrical activity in shoots of Ipomoea, Pisum and Xanthium. AB - Extracellular recordings from light-grown shoots of Ipomoea and Xanthium contain trains of spontaneous fluctuations which resemble action potentials. The rise time of the putative action potentials is usually in the range from 1 to 50 ms. Their duration is most frequently between 100 and 400 ms, but they may be either briefer or, in the presence of unusual shoulders, much longer. Their separation interval is typically between 0.1 and 10 s. The trains may last from 1 s to over 2 h.Spontaneous fluctuations also occur individually in shoots of Ipomoea, Xanthium, and Pisum. Although the shapes, rise times, and durations of the individual fluctuations fall within the same range as do those of repetitive fluctuations, a greater number of the individual spikes have a relatively slow time course and a higher apparent amplitude. At times, recordings have periods of activity which appear to result from the superposition of numerous individual fluctuations.There is no evidence that any of the fluctuations propagate, but propagation cannot be excluded on the basis of the extracellular recordings. The fluctuations occur in both dark and light. There is no strong evidence for the occurrence of spontaneous fluctuations in roots. PMID- 24482124 TI - The interplay of light and oxygen in the reactive oxygen stress response of Chlamydomonas reinhardtii dissected by quantitative mass spectrometry. AB - Light and oxygen are factors that are very much entangled in the reactive oxygen species (ROS) stress response network in plants, algae and cyanobacteria. The first obligatory step in understanding the ROS network is to separate these responses. In this study, a LC-MS/MS based quantitative proteomic approach was used to dissect the responses of Chlamydomonas reinhardtii to ROS, light and oxygen employing an interlinked experimental setup. Application of novel bioinformatics tools allow high quality retention time alignment to be performed on all LC-MS/MS runs increasing confidence in protein quantification, overall sequence coverage and coverage of all treatments measured. Finally advanced hierarchical clustering yielded 30 communities of co-regulated proteins permitting separation of ROS related effects from pure light effects (induction and repression). A community termed redox(II) was identified that shows additive effects of light and oxygen with light as the first obligatory step. Another community termed 4-down was identified that shows repression as an effect of light but only in the absence of oxygen indicating ROS regulation, for example, possibly via product feedback inhibition because no ROS damage is occurring. In summary the data demonstrate the importance of separating light, O2 and ROS responses to define marker genes for ROS responses. As revealed in this study, an excellent candidate is DHAR with strong ROS dependent induction profiles. PMID- 24482128 TI - Corrigendum. PMID- 24482129 TI - The detection and estimation of the growth inhibitor xanthoxin in plants. AB - The plant growth inhibitor xanthoxin which can be prepared in vitro by the oxidation of certain xanthophylls has been identified in the ether extracts of the shoots of a wide variety of higher plants. Gas liquid chromatography of an acetylated derivative has been used for its quantitative estimation.Evidence is provided that xanthoxin is a true endogenous inhibitor and that violaxanthin or a related xanthophyll epoxide is its biogenetic precursor. The importance of xanthoxin and its relationship with abscisic acid and other plant growth inhibitors is discussed. PMID- 24482130 TI - [Action of deoxyuridine on the inhibition of the rhizogenesis and the hypocotyl growth observed in the presence of 5-bromodeoxyuridine in the cuttings of etiolated tomato seedlings]. AB - 1. At relatively low concentrations, UdR generally enhances the inhibition caused by 5-BUdR. When the concentration of UdR is progressively increased, an inversion of the effects of UdR is observed; this inversion may go as far as complete reversal of the inhibition caused by 5-BUdR in the case of hypocotyl growth. 2. The comparison of the effects of CdR with those of UdR in the presence of 5-BUdR makes plausible the hypothesis that CdR acts only after being deaminated in vivo to UdR. 3. A hypothesis is suggested to explain the particular shape of the curves of the action of UdR obtained in the presence of 5-BUdR. PMID- 24482131 TI - Effects of the steroidal alkaloid tomatine in auxin bioassays and its interaction with indole-3-acetic acid. AB - The steroidal alkaloid tomatine did not enhance elongation of oat coleoptile and first internode sections, or of wheat coleoptile sections. Higher concentrations of the alkaloid inhibited elongation and interacted antagonistically with IAA. Although 10(-4) M tomatine alone did not influence elongation of oat coleoptile sections, it did reduce growth response to exogenous IAA. Tomatine concentrations less than 10(-4) M did not influence response to IAA. The auxin activity of tomatine, reported by Vendrig, was therefore not confirmed. PMID- 24482132 TI - Effects of light quality on apical dominance in Xanthium strumarium and the associated changes in endogenous levels of abscisic acid and cytokinins. AB - Apical dominance in Xanthium strumarium was influenced by the quality of illumination received at the end of the photoperiod. The involvement of the red/far-red regions of the spectrum was apparent. The persistence of the effects was partially dependent on the age of the individual buds concerned. Plants receiving 30 minutes of illumination from tungsten lamps after a 16-hour photoperiod from fluorescent tubes failed to branch, whereas plants given an identical photoperiod, both in terms of day-length and photosynthetically available light energy, but lacking the far-red from tungsten lamps, branched profusely.The influence of the spectral distribution of illumination on the levels of cytokinins and abseisic acid in the plant, and the correlation with the degree of branching, is presented and discussed. The cytokinin content was much higher in inhibited than released buds. The cytokinins present were probably not able to particinate in bud growth because of an accumulation of inhibitors resembling abscisic acid. The concentration of the inhibitors in inhibited buds was 50 to 250 times that occurring in all other plant parts examined. PMID- 24482133 TI - [Three-dimensional reconstruction of the cell of a green flagellate based on serial section electron microscopy]. AB - Cells (+gametes) of Chlamydomonas reinhardii were ultrasectioned serially, and electron micrographs were taken of complete cells. On this basis the model of one typical cell was constructed at a magnification of 36000x. The photographs of the model shown in this paper give a good impression of the architecture and organization of this unicellular organism. This is the first time, to our knowledge, that a whole green plant cell has been reconstructed on a uniform scale. The method of the construction is described. PMID- 24482134 TI - [Does differential pressure of amyloplasts on a complex endomembrane system cause geoperception in roots?]. AB - In the root cap of Lepidium sativum a complex of multiple rough endoplasmic reticulum develops above the morphological lower transverse cell walls during ontogenesis of the columella cells ("statocysts"). The cisternae of the ER complex are preferentially oriented parallel to the transverse walls. In normal vertical exposure of the roots the amyloplasts ("statoliths") lie above the ER complex. They do not touch the plasma membrane, but possibly they press against the ER-complex and thereby bring about geotropic equilibrium.In each storey of the root cap the transverse walls together with their ER-complexes have a parabolic shape. Therefore the surface areas of the central ER-complexes form a right angle and those of the peripheral ER-complexes an acute angle with the organ axis.Owing to the shape of the whole ER-complex within each storey, the amyloplasts in the physically upper peripheral columella cells do not press against the membranes of the ER in the case of horizontal exposition. On the other hand in the physically lower part the amyloplasts are still situated above the ER-complex and can press on the ER.Geoperception in roots may be a function of pressure exerted differentially by amyloplasts on the ER-complex. PMID- 24482135 TI - Cytokinin activity from the phloem sap of Xanthium strumarium L. AB - Excretory products from aphids feeding on flowering and vegetative Xanthium plants contained a cytokinin active in the soybean-callus assay. No cytokinin activity was found in honeydew collected from aphids feeding on a chemically defined diet. Soybean-callus assays indicated that honeydew from aphids feeding on flowering plants contained more cytokinin than honeydew from vegetative plants. PMID- 24482136 TI - Abdominal echinococcosis: outcomes of conservative surgery. AB - BACKGROUND: Hydatid disease, infection with the larval stage of the cestode Echinococcus spp., represents a substantial disease burden worldwide. We report here the outcomes of conservative surgery in patients with abdominal echinococcosis. METHODS: We carried out a retrospective review of patients who underwent conservative surgery for abdominal hydatid disease during the period January 2008 to December 2011. Perioperative outcomes were analysed after a mean follow-up of 24 months (range 6-36 months). RESULTS: Thirty patients (mean age 40.4 years; male:female=7:3) underwent surgery. Most (29 patients) had a hepatic hydatid cyst and underwent partial cystectomy with omentoplasty; surgery was open in 22 cases (73%), laparoscopic in six cases (20%) and laparoscopic converted to open in one case (3%); one patient with a splenic cyst underwent open splenectomy. Cystobiliary communication was present in 10 cases (3%). Postoperative complications included transient biliary leak in two cases (7%), grade 1 surgical site infection in five cases (17%) and respiratory tract infection in three cases (10%), with no mortality. Mean hospital stay was 17 +/- 9.2 days. None of the patients had recurrence of disease on follow-up imaging. CONCLUSION: Conservative surgery offers an effective approach for abdominal echinococcosis, with minimal morbidity or recurrence, and is an alternative to radical procedures. PMID- 24482137 TI - Inactivation of Akt by arsenic trioxide induces cell death via mitochondrial mediated apoptotic signaling in SGC-7901 human gastric cancer cells. AB - Arsenic trioxide (As2O3) has been recognized as a potential chemotherapeutic agent, yet the details concerning its mechanism of action in solid cancers remain undetermined. The present study assessed the role of Akt in the cell death induced by As2O3. The MTT assay showed that As2O3 suppressed the proliferation of SGC-7901 cells in a dose- and time-dependent manner. Characteristic apoptotic changes were observed in the As2O3-treated cells by Hoechst 33342 staining, and FACS analysis showed that As2O3 caused dose-dependent apoptotic cell death. As2O3 activated caspase-3 and -9, and PARP cleavage in a dose-dependent manner. Compromised mitochondrial membrane potential and an increased protein level of Bax indicated involvement of mitochondia. As2O3 decreased the levels of p-Akt (Ser473), p-Akt (Thr308) and p-GSK-3beta (Ser9), suggesting that As2O3 inactivated Akt kinase. In addition, LY294002 (a PI3 kinase inhibitor) augmented the apoptosis induced by As2O3. These results demonstrated that inhibition of PI3K/Akt signaling was involved in As2O3-induced apoptosis of gastric cancer SGC 7901 cells. PMID- 24482138 TI - Pulmonary outcomes in patients with Hodgkin lymphoma treated with involved field radiation. AB - BACKGROUND: Abnormalities in pulmonary function tests (PFT) and clinical symptoms have been reported in up to one third of patients with Hodgkin lymphoma (HL) treated with irradiation. The purpose of this study is to describe the prevalence of pulmonary complications in HL patients treated using contemporary protocols. PROCEDURES: Eligible patients at Children's Hospital Los Angeles from 1999 to 2009 were identified from the radiation oncology database. Clinical features, radiographic findings, PFT, and radiation details were retrospectively ascertained. RESULTS: The median age at diagnosis of 65 patients with HL was 13.6 years and the median follow-up was 3.7 years. The median prescribed radiation dose was 21 Gy. The prevalence of clinical symptoms was low: chronic cough (3%), dyspnea (9.2%), and supplemental oxygen requirement (1.5%). Radiological interstitial lung changes were observed in 31% of the patients. PFT results following irradiation were available in 38 patients. Forced expiratory volume in 1 second (FEV1) and forced expiratory flow 25-75% (FEF25-75%) were decreased in 13% and 11% of patients respectively. Residual volume (RV) was elevated in 21%. Total Lung capacity (TLC) was decreased in 8%. Age at irradiation (P = 0.004), maximum lung dose (P = 0.03), and volume of lung receiving >25 Gy were associated with development of adverse pulmonary outcomes on univariate analysis. On multivariate analysis, older age was associated with worse outcomes. CONCLUSION: In survivors of pediatric HL, involved field irradiation was accompanied by a low prevalence of pulmonary symptoms but substantial subclinical dysfunction. Older age at irradiation was associated with worse pulmonary outcomes. PMID- 24482139 TI - School victimization and substance use among adolescents in California. AB - Substance use and violence co-occur among adolescents. However, the extant literature focuses on the substance use behaviors of perpetrators of violence and not on victims. This study identifies patterns of school victimization and substance use and how they co-occur. The California Healthy Kids Survey was used to identify latent classes/clusters of school victimization patterns and lifetime and frequency of recent (past month) alcohol, tobacco, and marijuana use (N = 419,698). Demographic characteristics (age, gender, and race/ethnicity) were included as predictors of latent class membership. Analyses revealed four latent classes of school victimization: low victimization (44.4 %), moderate victimization (22.3 %), verbal/relational victimization (20.8 %), and high victimization (with physical threats; 12.5 %). There were also four classes of substance use: non-users (58.5 %), alcohol experimenters (some recent alcohol use; 25.8 %), mild poly-substance users (lifetime use of all substances with few days of recent use; 9.1 %), and frequent poly-substance users (used all substances several times in the past month; 6.5 %). Those in the high victimization class were twice as likely to be frequent poly-substance users, and mild poly-substance use was most salient for those in the verbal victimization class. Few studies have explored latent patterns of substance use and violence victimization concurrently. The findings indicate substantial heterogeneity in victimization and substance use among youth in California schools with implications for targeted and tailored interventions. Understanding how certain types of victimization are associated with particular patterns of substance use will provide schools with opportunities to screen for concurrent behavioral health problems among youth. PMID- 24482140 TI - Adolescent peer networks and the potential for the diffusion of intervention effects. AB - Many evaluation studies assess the direct effect of an intervention on individuals, but there is an increasing interest in clarifying how interventions can impact larger social settings. One process that can lead to these setting level effects is diffusion, in which intervention effects spread from participants to non-participants. Diffusion may be particularly important when intervention participation rates are low, as they often are in universal family based prevention programs. We drew on socialization and diffusion theories to articulate how features of peer networks may promote the diffusion of intervention effects. Then, we tested the measurement properties of ten social network analytic (SNA) measures of diffusion potential. Data were from 42 networks (n = 5,784 students) involved in the PROSPER intervention trial. All families of sixth-grade students were invited to participate in a family based substance use prevention program, and 17 % of the families attended at least one session. We identified two dimensions of network structure--social integration and location of intervention participants in their peer network--that might promote diffusion. Analyses demonstrated that these SNA measures varied across networks and were distinct from traditional analytic measures that do not require social network analysis (i.e., participation rate, how representative participants are of the broader population). Importantly, several SNA measures and the global network index predicted diffusion over and above the effect of participation rate and representativeness. We conclude by recommending which SNA measures may be the most promising for studying how networks promote the diffusion of intervention effects and lead to setting-level effects. PMID- 24482141 TI - Prognostic significance of impaired chronotropic response to pharmacologic stress Rb-82 PET. AB - BACKGROUND: An impaired chronotropic response to exercise is an accepted risk marker but the relationship between heart rate reserve (HRR) with pharmacologic stress is less well-established. The primary aim of this analysis was to evaluate the prognostic significance of HRR in patients undergoing rest/stress myocardial perfusion positron emission tomography (PET) in estimating coronary artery disease (CAD) mortality. METHODS: This subset analysis from the PET Prognosis Multicenter Registry includes a total of 2,398 patients undergoing rest/stress Rb PET from three participating sites. The HRR from rest to peak stress was categorized into tertiles of <= 4, 5-14, and >= 15 beats per minute (bpm). At stress, the % abnormal myocardium was categorized as <5%, 5-9.9%, and >= 10%. We estimated CAD mortality using univariable and multivariable Cox proportional hazard models. RESULTS: CAD mortality was 12.8%, 3.4%, and 0.8%, respectively, for HRR measurements of <= 4, 5-14, and >= 15 bpm (P < 0.0001). In a multivariable model, the HRR was independently predictive of CAD mortality (P < 0.0001) with adjusted hazard ratios elevated 3.5- and 8.4-fold for HRR of 5-14 and <= 4 versus >= 15 bpm. In a multivariable model, both the HRR and stress MPI % abnormal myocardium were independently and highly predictive of CAD mortality. Moreover, the net reclassification improvement was 0.18 for the HRR when compared to a model including risk factors, symptoms, rest HR, and PET variables (P = 0.0008). For those with >= 10% abnormal myocardium on stress PET, there was a graded relationship between HRR and CAD mortality with adjusted hazards exceeding 50-fold for measurements of 5-14 and <= 4 bpm (P < 0.0001) compared to stress MPI with <5% abnormal myocardium and a HRR >= 15 bpm. CONCLUSION: A diminished HRR to vasodilator stress is a novel but increasingly important predictor of CAD mortality. HRR measurements of <= 4, 5-14, and >= 15 bpm were independently predictive of CAD mortality and underscore the importance of optimizing readily available novel markers of risk as highly relevant to identifying high and low risk patient subsets. PMID- 24482142 TI - Clinical decision support systems in myocardial perfusion imaging. AB - Diagnostic imaging is becoming more complicated, physicians are also required to master an ever-expanding knowledge base and take into account an ever increasing amount of patient-specific clinical information while the time available to master this knowledge base, assemble the relevant clinical data, and apply it to specific tasks is steadily shrinking. Compounding these problems, there is an ever increasing number of aging "Baby Boomers" who are becoming patients coupled with a declining number of cardiac diagnosticians experienced in interpreting these studies. Hence, it is crucial that decision support tools be developed and implemented to assist physicians in interpreting studies at a faster rate and at the highest level of up-to-date expertise. Such tools will minimize subjectivity and intra- and inter-observer variation in image interpretation, help achieve a standardized high level of performance, and reduce healthcare costs. Presently, there are many decision support systems and approaches being developed and implemented to provide greater automation and to further objectify and standardize analysis, display, integration, interpretation, and reporting of myocardial perfusion SPECT and PET studies. This review focuses on these systems and approaches. PMID- 24482143 TI - A direct, modular, and efficient construction of the P-C-P structural motif through coupling of manganese carbyne complexes with phosphines. AB - Easily available carbyne complexes of manganese were used as a source of carbyne fragments in an unconventional synthesis of backbone-substituted diphosphinomethanes and cyclic P-ylides upon coupling with secondary or tertiary phosphines, respectively, followed by demetalation under mild conditions. PMID- 24482144 TI - Successful application of belimumab in two patients with systemic lupus erythematosus experiencing a flare during tocilizumab treatment. AB - This case report describes two female lupus patients who both received biological treatment with tocilizumab and with belimumab. The disease course was remarkably similar in both cases. Tocilizumab resulted in a transient improvement in pleurisy and arthritis but was then followed by a clinical flare accompanied by an increase in autoantibodies and a drop in complement levels. Alike, both patients experienced a rapid and sustained improvement after institution of belimumab. The clinical benefit obtained is currently stable under ongoing belimumab therapy. PMID- 24482145 TI - Simultaneous cytoplasmic and nuclear protein expression of melanoma antigen-A family and NY-ESO-1 cancer-testis antigens represents an independent marker for poor survival in head and neck cancer. AB - The prognosis of head and neck squamous cell carcinoma (HNSCC) patients remains poor. The identification of high-risk subgroups is needed for the development of custom-tailored therapies. The expression of cancer-testis antigens (CTAs) has been linked to a worse prognosis in other cancer types; however, their prognostic value in HNSCC is unclear because only few patients have been examined and data on CTA protein expression are sparse. A tissue microarray consisting of tumor samples from 453 HNSCC patients was evaluated for the expression of CTA proteins using immunohistochemistry. Frequency of expression and the subcellular expression pattern (nuclear, cytoplasmic, or both) was recorded. Protein expression of melanoma antigen (MAGE)-A family CTA, MAGE-C family CTA and NY-ESO 1 was found in approximately 30, 7 and 4% of tumors, respectively. The subcellular expression pattern in particular had a marked impact on the patients' prognosis. Median overall survival (OS) of patients with (i) simultaneous cytoplasmic and nuclear expression compared to (ii) either cytoplasmic or nuclear expression and (iii) negative patients was 23.0 versus 109.0 versus 102.5 months, for pan-MAGE (p < 0.0001), 46.6 versus 50.0 versus 109.0 for MAGE-A3/A4 (p = 0.0074) and 13.3 versus 50.0 versus 100.2 months for NY-ESO-1 (p = 0.0019). By multivariate analysis, these factors were confirmed as independent markers for poor survival. HNSCC patients showing protein expression of MAGE-A family members or NY-ESO-1 represent a subgroup with an extraordinarily poor survival. The development of immunotherapeutic strategies targeting these CTA may, therefore, be a promising approach to improve the outcome of HNSCC patients. PMID- 24482147 TI - Dependence of the efficiency improvement of black-dye-based dye-sensitized solar cells on alkyl chain length of quaternary ammonium cations in electrolyte solutions. AB - Dependence of the suppression of the backward electron transfer reaction from the TiO2 photoelectrode to I3(-) in the electrolyte on the alkyl chain length of the quaternary ammonium cation has been investigated for further efficiency improvement of high-performance cosensitized dye-sensitized solar cells (DSCs). The tetraheptylammonium cation was found to be more effective than the tetraethylammonium and tetrabutylammonium cations for the suppression of the backward electron transfer reaction without changing the conduction band energy of TiO2. 12.0% conversion efficiency, which is the second highest efficiency for DSCs based on ruthenium sensitizers, was achieved in the cosensitized DSC with Black dye and D131 by using an electrolyte solution containing a moderate concentration of tetraheptylammonium iodide. PMID- 24482146 TI - Behcet's disease ocular attack score 24: evaluation of ocular disease activity before and after initiation of infliximab. AB - PURPOSE: We developed a novel scoring system for uveitis due to Behcet's disease (BD), termed Behcet's disease ocular attack score 24 (BOS24), and examined its validity and usefulness by estimating changes in ocular disease activities both before and after initiation of infliximab therapy. METHODS: BOS24 consists of a total 24 points divided into 6 parameters of ocular inflammatory symptoms. To examine the validity of our scoring system, 5 uveitis specialists examined the severity of 50 ocular attacks in clinical charts using both our system and a physician's impression score (grade 1-10). In addition, ocular disease activities both before and after initiation of infliximab were retrospectively examined in 150 cases of ocular BD using BOS24. RESULTS: The average BOS24 for the 5 doctors was highly correlated with the average physician's impression score (p < 0.0001), whereas the coefficient of variance for BOS24 among doctors was much lower than that for the physician's impression score (p < 0.0001). Summation of BOS24 over a 6-month period (BOS24-6M) was significantly reduced after starting infliximab therapy (p < 0.0001). The average BOS24 for individual ocular attacks was also significantly decreased after starting infliximab, with scores for the posterior pole and fovea notably improved. CONCLUSIONS: BOS24 was highly related to severity noted by the physician's impression and had a low level of variability among the examined doctors. Using our novel scoring system, infliximab therapy was shown to reduce not only the frequency of ocular attacks, but also the severity of each attack. BOS24 is a promising tool for evaluating ocular BD activities. PMID- 24482148 TI - Simvastatin prevents neuroinflammation by inhibiting N-methyl-D-aspartic acid receptor 1 in 6-hydroxydopamine-treated PC12 cells. AB - This study investigates the impact of simvastatin on neuroinflammation in experimental parkinsonian cell models. 6-Hydroxydopamine (6-OHDA)-treated pheochromocytoma-12 (PC12) cells were used to investigate the neuroprotective nature of simvastatin. After incubation with 6-OHDA, simvastatin, and/or N-methyl D-aspartic acid receptor 1 (NMDAR1) siRNA for 24 hr, test kits were used to detect the levels of lactate dehydrogenase (LDH) and glutamate released from PC12 cells exposed to different culture media. The mRNA levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-1beta, and IL-6 were determined by RT-PCR, and the protein levels were analyzed by Western blot. NMDAR1 were also determined by RT-PCR and the protein levels were analyzed by Western blot. LDH and glutamate levels in 6-OHDA-incubated PC12 cells increased compared with those in the controls, and incubation with simvastatin inhibited this elevation. Silencing of NMDAR1 with siRNA inhibited the expression of LDH and glutamate to a degree similar to simvastatin. The expression levels of NMDAR1, TNF-alpha, IL-1beta, and IL-6 were significantly upregulated after treatment with 6-OHDA. The 6-OHDA stimulated mRNA and protein levels of the proinflammatory cytokines NMDAR1, TNF alpha, IL-1beta, and IL-6 were reduced by simvastatin. Silencing of NMDAR1 with siRNA decreased the NMDAR1, TNF-alpha, IL-1beta, and IL-6 mRNA and protein expression levels in 6-OHDA-stimulated PC12 cells. Simvastatin could also inhibit the expression of NMDAR1 and cytokines to a degree similar to silencing of NMDAR1 with siRNA. Our results suggest that NMDAR1 modulation could explain the anti inflammatory mechanisms of simvastatin in experimental parkinsonian cell models. PMID- 24482149 TI - In reference to Laser versus conventional fenestration in stapedotomy for otosclerosis: a systematic review. PMID- 24482150 TI - Study suggests varenicline safe and effective among adults with stable depression. PMID- 24482151 TI - Cholinesterase inhibitors should not be prescribed for mild cognitive impairment. PMID- 24482152 TI - Can the biomass-ratio hypothesis predict mixed-species litter decomposition along a climatic gradient? AB - BACKGROUND AND AIMS: The biomass-ratio hypothesis states that ecosystem properties are driven by the characteristics of dominant species in the community. In this study, the hypothesis was operationalized as community weighted means (CWMs) of monoculture values and tested for predicting the decomposition of multispecies litter mixtures along an abiotic gradient in the field. METHODS: Decomposition rates (mg g(-1) d(-1)) of litter from four herb species were measured using litter-bed experiments with the same soil at three sites in central France along a correlated climatic gradient of temperature and precipitation. All possible combinations from one to four species mixtures were tested over 28 weeks of incubation. Observed mixture decomposition rates were compared with those predicted by the biomass-ratio hypothesis. Variability of the prediction errors was compared with the species richness of the mixtures, across sites, and within sites over time. KEY RESULTS: Both positive and negative prediction errors occurred. Despite this, the biomass-ratio hypothesis was true as an average claim for all sites (r = 0.91) and for each site separately, except for the climatically intermediate site, which showed mainly synergistic deviations. Variability decreased with increasing species richness and in less favourable climatic conditions for decomposition. CONCLUSIONS: Community-weighted mean values provided good predictions of mixed-species litter decomposition, converging to the predicted values with increasing species richness and in climates less favourable to decomposition. Under a context of climate change, abiotic variability would be important to take into account when predicting ecosystem processes. PMID- 24482153 TI - Clonal growth and plant species abundance. AB - BACKGROUND AND AIMS: Both regional and local plant abundances are driven by species' dispersal capacities and their abilities to exploit new habitats and persist there. These processes are affected by clonal growth, which is difficult to evaluate and compare across large numbers of species. This study assessed the influence of clonal reproduction on local and regional abundances of a large set of species and compared the predictive power of morphologically defined traits of clonal growth with data on actual clonal growth from a botanical garden. The role of clonal growth was compared with the effects of seed reproduction, habitat requirements and growth, proxied both by LHS (leaf-height-seed) traits and by actual performance in the botanical garden. METHODS: Morphological parameters of clonal growth, actual clonal reproduction in the garden and LHS traits (leaf specific area - height - seed mass) were used as predictors of species abundance, both regional (number of species records in the Czech Republic) and local (mean species cover in vegetation records) for 836 perennial herbaceous species. Species differences in habitat requirements were accounted for by classifying the dataset by habitat type and also by using Ellenberg indicator values as covariates. KEY RESULTS: After habitat differences were accounted for, clonal growth parameters explained an important part of variation in species abundance, both at regional and at local levels. At both levels, both greater vegetative growth in cultivation and greater lateral expansion trait values were correlated with higher abundance. Seed reproduction had weaker effects, being positive at the regional level and negative at the local level. CONCLUSIONS: Morphologically defined traits are predictive of species abundance, and it is concluded that simultaneous investigation of several such traits can help develop hypotheses on specific processes (e.g. avoidance of self-competition, support of offspring) potentially underlying clonal growth effects on abundance. Garden performance parameters provide a practical approach to assessing the roles of clonal growth morphological traits (and LHS traits) for large sets of species. PMID- 24482154 TI - Olfactory-related cortical atrophy is associated with olfactory dysfunction in Parkinson's disease. AB - BACKGROUND: Olfactory dysfunction is often associated with Parkinson's disease (PD) and can precede characteristic motor symptoms by several years. Olfactory related cortical atrophy has been reported in PD, although the extent and association between cortical atrophy and olfactory dysfunction have been controversial. The present study examined whether olfactory dysfunction is associated with gray matter (GM) volume in brain regions subserving primary and secondary olfactory processing. METHODS: High-resolution T1-weighted brain MRIs were acquired from 40 PD without dementia and 40 matched controls along with smell identification scores. Brain volumes were compared using voxel-based morphometry. RESULTS: Compared to controls, PD patients sustained greater GM loss localized to bilateral piriform cortex (PC) and orbitofrontal cortex (OFC). Reduced olfactory performance in PD was significantly associated with lower GM volumes in PC and OFC. CONCLUSIONS: Both primary and secondary olfactory cortical atrophy occurred in PD and were associated with olfactory dysfunction. PMID- 24482156 TI - New accurate benchmark energies for large water clusters: DFT is better than expected. AB - In this work, we use MP2 and coupled-cluster with single, double, and perturbative triple excitations [CCSD(T)] as well as their corresponding explicitly correlated (F12) counterparts to compute the interaction energies of water icosamers. The incremental scheme is used to compute benchmark energies at the CCSD(T)/CBS(45) and CCSD(T)(F12*)/cc-pVQZ-F12 level of theory. The four structures, dodecahedron, edge sharing, face sharing, and fused cubes, are part of the WATER27 test set and therefore, highly accurate interaction energies are required. All methods applied in this work lead to new benchmark energies for these four systems. To obtain these values, we carefully analyze the convergence of the interaction energies with respect to the basis set. Furthermore, we investigate the influence of the basis set superposition error and the core valence correlation. The interaction energies are: dodecahedron -198.6 kcal/mol, edge sharing -209.7 kcal/mol, face sharing -208.0 kcal/mol, and fused cubes 208.0 kcal/mol. For water clusters, we recommend to use the PW6B95 density functional of Truhlar in combination with Grimme's dispersion correction (D3), as the mean absolute error is 0.9 and the root mean-squared deviation is only 1.4 kcal/mol. PMID- 24482155 TI - Acute and chronic psychostimulant treatment modulates the diurnal rhythm activity pattern of WKY female adolescent rats. AB - The psychostimulants considered the gold standard in the treatment of attention deficit hyperactivity disorder, one of the most common childhood disorders, are also finding their way into the hands of healthy young adults as brain augmentation to improve cognitive performance. The possible long-term effects of psychostimulant exposure in adolescence are considered controversial, and thus, the objective of this study was to investigate whether the chronic exposure to the psychostimulant amphetamine affects the behavioral diurnal rhythm activity patterns of female adolescent Wistar-Kyoto (WKY) rat. The hypothesis of this study is that change in diurnal rhythm activity pattern is an indicator for the long-term effect of the treatment. Twenty-four rats were divided into two groups, control (N = 12) and experimental (N = 12), and kept in a 12:12-h light/dark cycle in an open-field cage. After 5-7 days of acclimation, 11 days of consecutive non-stop behavioral recordings began. On experimental day 1 (ED1), all groups were given an injection of saline. On ED2 to ED7, the experimental group was injected with 0.6 mg/kg amphetamine followed by 3 days of washout from ED8 to ED10, and amphetamine re-challenge on ED11 similar to ED2. The locomotor movements were counted by the computerized animal activity monitoring system, and the cosinor statistical test analysis was used to fit a 24-h curve of the control recording to the activity pattern after treatment. The horizontal activity, total distance, number of stereotypy, vertical activity, and stereotypical movements were analyzed to find out whether the diurnal rhythm activity patterns were altered. Data obtained using these locomotor indices of diurnal rhythm activity pattern suggest that amphetamine treatment significantly modulates the locomotor diurnal rhythm activity pattern of female WKY adolescent rats. PMID- 24482157 TI - One-pot synthesis of N-acetyl- and N-glycolylneuraminic acid capped trisaccharides and evaluation of their influenza A(H1 N1) inhibition. AB - Human lung epithelial cells natively offer terminal N-acetylneuraminic acid (Neu5Ac) alpha(2->6)-linked to galactose (Gal) as binding sites for influenza virus hemagglutinin. N-Glycolylneuraminic acid (Neu5Gc) in place of Neu5Ac is known to affect hemagglutinin binding in other species. Not normally generated by humans, Neu5Gc may find its way to human cells from dietary sources. To compare their influence in influenza virus infection, six trisaccharides with Neu5Ac or Neu5Gc alpha(2->6) linked to Gal and with different reducing end sugar units were prepared using one-pot assembly and divergent transformation. The sugar assembly made use of an N-phthaloyl-protected sialyl imidate for chemoselective activation and alpha-stereoselective coupling with a thiogalactoside. Assessment of cytopathic effect showed that the Neu5Gc-capped trisaccharides inhibited the viral infection better than their Neu5Ac counterparts. PMID- 24482158 TI - Personality and externalizing behavior in the transition to young adulthood: the additive value of personality facets. AB - PURPOSE: The directionality of effects in the associations between personality and externalizing behavior (i.e., delinquency, soft drugs use, and alcohol abuse) is unclear. Moreover, previous studies only examined personality trait domains when examining these associations, whereas personality facets underlying these broad domains provide more specificity. To address these limitations, the present study examined the directionality of effects between externalizing behavior and personality while employing a facet-level approach to personality. METHODS: Cross lagged panel models were employed to four annual measurement waves of longitudinal data on 485 Belgian-Caucasian late adolescents (87.4 % female; M age = 18.63 years, SD = 0.61). Participants filled out the NEO-FFI as a measure of personality, the Deviant Behavior Scale as a measure of delinquency, and single items for soft drugs use and alcohol abuse on all four measurement occasions. RESULTS: The incremental value of personality facets over broad trait domains was demonstrated, as it was often the case that only some, but not all, facets underlying a specific trait domain were significantly associated with specific externalizing behaviors. Furthermore, linkages between personality and externalizing behavior were shown to be complex. Depending on the personality trait domain or facet and the specific behavior under investigation, the directionality of effects may differ. CONCLUSIONS: To capture the full complexity of the linkages between personality and externalizing behavior, a facet approach to personality is recommended. This information is potentially important for clinicians, as it indicates which specific aspects of a broad trait domain affect, and are affected by, specific externalizing behaviors. PMID- 24482159 TI - Sintered anorganic bone graft increases autocrine expression of VEGF, MMP-2 and MMP-9 during repair of critical-size bone defects. AB - This study aimed to evaluate morphometrically the bone formation and immunohistochemically the expression of vascular endothelial growth factor (VEGF) and metalloproteinase (MMP)-2 and -9 during the healing of critical-size defects treated with sintered anorganic bone (sAB). The 8-mm diameter full-thickness trephine defects created in the parietal bones of rats were filled with sAB (test group) or blood clot (CSD-control group). At 7, 14, 21, 30, 90 and 180 days postoperatively (n = 6/period) the volume of newly formed bone and total number of immunolabeled cells (Ntm) for each protein were determined. Bone formation was smaller and faster in the CSD-control group, stabilizing at 21 days (6.74 mm(3)). The peaks of VEGF, MMP-2 and MMP-9 occurred at 7 and 14 days in fibroblasts and osteoblasts, with mean reduction of 0.80 time at 21 days, keeping constant until 180 days. In the test group, sAB provided continuous bone formation between particles throughout all periods. The peak of MMP-2 was observed at 7-14 days in connective tissue cells and for VEGF and MMP-9 at 30 days in osteoblasts and osteocytes. Ntm for VEGF, MMP-2 and MMP-9 were in average, respectively, 3.70, 2.03 and 5.98 times higher than in the control group. At 180 days, newly formed bone (22.9 mm(3)) was 3.74 times greater in relation to control. The physical and chemical properties of sAB allow increased autocrine expression of VEGF, MMP-2 and MMP-9, favoring bone formation/remodeling with very good healing of cranial defects when compared to natural repair in the CSD-control. PMID- 24482161 TI - Overview of skeletal development. AB - Development of cartilage and bone, the core components of the mouse skeletal system, depends on the well-coordinated proliferation and differentiation of skeletogenic cells, including chondrocytes and osteoblasts. These cells differentiate from common progenitor cells originating in the mesoderm and neural crest. Multiple signaling pathways and transcription factors tightly regulate differentiation and proliferation of skeletal cells. In this chapter, we overview the process of mouse skeletal development and discuss major regulators of skeletal cells at each developmental stage. PMID- 24482160 TI - Should we target obesity in advanced heart failure? AB - OPINION STATEMENT: Obesity is a risk factor for the development of heart failure (HF), but has been associated with improved survival in patients with established HF. Weight loss should clearly be recommended and supported for obese individuals without cardiac pathology to prevent cardiomyopathy development. Clinical recommendations at the other end of the obesity heart failure spectrum are also relatively clear. Morbidly obese individuals (BMI >= 40 kg/m(2)) aged <50 years with severely depressed systolic function and NYHA class III-IV symptoms should be considered for malabsorptive bariatric surgery at an experienced center. The goal is either improved systolic function and symptoms, or sufficient weight loss for heart transplant eligibility. Recommendations for patients falling between these extremes are more challenging. Overweight and mildly obese HF patients (25 35 kg/m(2)) may be somewhat protected from cardiac cachexia and weight loss is not expected to enhance survival, but may offer symptomatic benefits. PMID- 24482162 TI - Overview of skeletal repair (fracture healing and its assessment). AB - The study of postnatal skeletal repair is of immense clinical interest. Optimal repair of skeletal tissue is necessary in all varieties of elective and reparative orthopedic surgical treatments. However, the repair of fractures is unique in this context in that fractures are one of the most common traumas that humans experience and are the end-point manifestation of osteoporosis, the most common chronic disease of aging. In the first part of this introduction the basic biology of fracture healing is presented. The second part discusses the primary methodological approaches that are used to examine repair of skeletal hard tissue and specific considerations for choosing among and implementing these approaches. PMID- 24482163 TI - Generation of closed transverse fractures in small animals. AB - The most common procedure that has been developed for use in rats and mice to model fracture healing is described. The nature of the regenerative processes that may be assessed and the types of research questions that may be addressed with this model are briefly outlined. The detailed surgical protocol to generate closed simple transverse fractures is presented, and general considerations when setting up an experiment using this model are described. PMID- 24482164 TI - The murine femoral bone graft model and a semiautomated histomorphometric analysis tool. AB - Preclinical studies of bone repair remain a high priority because of unresolved clinical problems associated with treating critical segmental defects and complications of fracture healing. Over the last decade, the murine femoral allograft model has gained popularity due to its standardized surgery and potential for examining a vast array of radiographic, biomechanical, and histological outcome measures. Here, we describe these methods and a novel semiautomated histomorphometric approach to quantify the amount of bone, cartilage, and undifferentiated mesenchymal tissue in demineralized paraffin sections of allografted murine femurs using the Visiopharm Image Analysis Software System. PMID- 24482165 TI - Surgical induction of posttraumatic osteoarthritis in the mouse. AB - Given the prevalence and the scope of the personal and societal burden of OA, investigators have become increasingly interested in understanding the pathogenic basis of disease and developing novel disease-modifying OA therapies. Because of the well-documented central role that joint trauma plays in the initiation of knee OA, large animal and rodent models of knee injury that accurately recapitulate the OA disease process have become increasingly widespread over the past decade. To enable study in the context of defined genetic backgrounds, investigative teams have informally developed standardized protocols for injuring the mouse knee that aim to induce a reproducible degenerative process both in terms of severity and temporal pacing of disease progression. One such procedure, the meniscal/ligamentous injury (MLI) model of posttraumatic OA, is described in detail in this chapter. The description provided here sets the stage for both inexperienced and established investigators to employ the MLI procedure, or other similar surgical destabilization methods, to initiate the development of posttraumatic OA in the mouse. Successful application of this method provides a preclinical platform to study the mechanisms driving the pathogenesis of OA and to develop chondroprotective/regenerative strategies to treat it. PMID- 24482166 TI - A mouse model of flexor tendon repair. AB - Mouse models offer invaluable cellular and molecular tools for the study of human pathologies including those associated with fibrotic and musculoskeletal diseases. In this methods manuscript, we describe a mouse model of repair and segmental reconstruction of flexor tendons, which in our laboratory has been an invaluable model to study tendon scarring and adhesions. Specifically, we describe in details all the surgical procedures involved, as well as the associated endpoint biomechanical assessments including a novel test of the flexion of the metatarsophalangeal joint as a measure of adhesions, and a standard protocol for biomechanical assessment of the tensile strength of the tendon and repair tissue. PMID- 24482167 TI - Cartilage explant cultures. AB - To investigate chondrocyte biology in an organized structure, limb explant cultures have been established that allow the cultivation of the entire cartilaginous skeletal elements. In these organ cultures, the arrangement of chondrocytes in the cartilage elements and their interaction with the surrounding perichondrium and joint tissue are maintained. Chondrocyte proliferation and differentiation can thus be studied under nearly in vivo conditions. Growth factors and other soluble agents can be administered to the explants, and their effect on limb morphogenesis, gene expression, and cell-matrix interactions can be studied. Co-treatment with distinct growth factors and their inhibitors as well as use of transgenic mice will allow one to decipher the epistatic relationship between different signaling systems and other regulators of chondrocyte differentiation. Here we describe the protocol to culture cartilage explants ex vivo and discuss the advantages and disadvantages of the culture system. PMID- 24482168 TI - Renal capsule transplantations to assay skeletal angiogenesis. AB - Renal capsule transplantation is a very helpful method to grow embryonic tissues or tumors in a vascular environment, allowing long-term engraftment and biological analyses. This chapter describes the surgical procedure for the transplantation of embryonic skeletal elements in the renal capsule of adult mice and points out the manipulations that can be applied for assaying the role of angiogenesis during bone development. PMID- 24482169 TI - Whole-mount skeletal staining. AB - The first step in almost every investigation of skeletal phenotypes is analysis of whole-mount skeletal preparations. Whole-mount skeletal staining permits evaluation of the shapes and sizes of skeletal elements in their appropriate locations. The technique is thus the major method for detecting changes in skeletal patterning. Because cartilage and bone can be distinguished by differential staining, this technique is also a powerful means to assess the pace of skeletal maturation. This protocol covers staining of the pre- and postnatal mouse skeleton using Alcian blue and Alizarin red to identify cartilage and bone, respectively. PMID- 24482170 TI - Tips and techniques for processing and sectioning undecalcified murine bone specimens. AB - Preparation of mineralized tissue specimens for bone-specific staining encompasses a critical sequence of histological techniques that provides visualization of tissue and cellular morphology. Bone specimens are fixed in 10 % neutral-buffered formalin, dehydrated in graded ethanol (EtOH) solutions (and optionally cleared in xylene), infiltrated and embedded in polymethyl methacrylate (methyl methacrylate), classically sliced into 4-10 micrometer (MUm) sections, and stained with bone-specific histological stains such as von Kossa (with either nuclear fast red solution counterstain or MacNeal's tetrachrome counterstain), modified Goldner's trichrome, and alizarin red S stain. Here, we describe the tissue processing of mineralized mouse bones from dissection to staining for histological analysis by light microscopy. PMID- 24482171 TI - Preparation of thin frozen sections from nonfixed and undecalcified hard tissues using Kawamot's film method (2012). AB - A method for preparing hard tissue sections by using an adhesive film is described. The method produces very thin (to one-micrometer thick) frozen sections from adult mouse and rat bone. The bone tissue is freeze-embedded with water-soluble medium and then cut with a disposable tungsten carbide blade after mounting the adhesive film onto the cut surface. The sections are stained on the adhesive film and preserved between the adhesive film and glass slide. All the steps including the embedding, cutting, staining, and mounting are completed within only 20 min. The soft and hard tissues are preserved satisfactorily and the bone marrow is also preserved perfectly. Cells such as osteoblasts, fibroblasts, and osteoclasts are clearly identified, and the osteoid layer of bone is clearly observed. The sections are applicable to many types of staining such as histology, histochemistry, enzyme histochemistry, immunohistochemistry, and in situ hybridization. The immunohistochemistry can be carried out with nonfixed and undecalcified sections. In addition to these applications, the sections are used for observing the PGF fluorescence. The sections are also usable for studying the distribution of water-soluble materials in the tissues. Furthermore, the sections are very useful for gene analysis using LMD technique and for imaging mass spectrometry. PMID- 24482172 TI - Demineralized murine skeletal histology. AB - Cartilage and bone are specialized skeletal tissues composed of unique extracellular matrices. Bone, in particular, has a highly calcified or mineralized matrix that makes microtomy and standard histological studies very challenging. Therefore, methods to appropriately fix and decalcify mineralized skeletal tissues have been developed to allow for paraffin processing and standard microtomy. In this chapter, we illustrate methods for tissue grossing, fixation, decalcification, paraffin processing, embedding, sectioning, and routine histological staining of demineralized murine skeletal tissues. We also discuss methods for decalcified frozen sectioning of skeletal tissues with and without the use of a tape-transfer system. PMID- 24482173 TI - Beta-galactosidase staining in the skeleton. AB - The lacZ gene, encoding for the beta-galactosidase enzyme, is widely used as a reporter gene in bone biology due to the ease of visualization in situ on whole mount or on tissue sections. In this protocol we provide detailed methods for visualizing this reporter gene for both in vivo and in vitro studies. In addition, we describe a few tips for troubleshooting for mineralized tissues such as the skeleton. PMID- 24482174 TI - Whole-mount in situ hybridization on murine skeletogenic tissues. AB - Whole-mount in situ hybridization (WISH) is a highly sensitive method for spatial and temporal visualization of RNA transcripts throughout an entire tissue. This method is an excellent tool for studying both embryonic development and disease. It is based on sequence complementation between a Digoxigenin (DIG)-labeled antisense RNA probe and the sense RNA transcript of interest in the tissue. The labeled probe is then visualized by immunohistochemical methods using an antibody conjugated to alkaline phosphatase that catalyzes a color reaction. PMID- 24482175 TI - Nonradioactive in situ hybridization on skeletal tissue sections. AB - Spatial and temporal visualization of RNA transcripts in tissue is a key tool in studying both developmental and pathological processes. In situ hybridization is a highly sensitive method for RNA transcript detection. It is based on sequence complementation between a labeled RNA probe and the RNA transcript of interest. The labeled probe is then detected by immunohistochemical methods using an antibody conjugated to an enzyme that catalyzes the generation of chromogenic or fluorescent signals, which indicate the location of the transcript. PMID- 24482176 TI - Radioactive in situ hybridization to detect gene expression in skeletal tissue sections. AB - In situ hybridization (ISH) using RNA probes is a valuable technique to characterize gene expression patterns in animal tissues. It provides valuable spatial information about gene expression. Compared to the nonradioactive alternatives,(35)S radioactive ISH generally provides higher sensitivity. Here, we describe the procedure for(35)S ISH on paraffin sections from the skeletal tissues of mouse embryos. PMID- 24482178 TI - TUNEL assay on skeletal tissue sections to detect cell death. AB - At least two distinct modalities of cell death, apoptosis and necrosis, can be distinguished based on differences in morphological, biochemical, and molecular changes of dying cells. Cell death is involved both in physiological and pathological conditions of the skeleton: for example, apoptosis is a crucial event during limb development. Therefore, detection of cell death by using a simple stain is a powerful tool to study molecular and cellular mechanisms of skeletal development and repair. PMID- 24482177 TI - Proliferation assays (BrdU and EdU) on skeletal tissue sections. AB - Assessing cell proliferation in situ is an important phenotyping component of skeletal tissues from development to adult stages and disease. Various methods exist including immunostaining for proteins and protein modifications associated with specific steps of the cell cycle, but the gold standard is to quantify the percentage of DNA-synthesizing cells. The thymidine analog 5-bromo-2' deoxyuridine (BrdU) has been widely used in the last decades for this purpose, with the inconvenience that its detection is lengthy and requires harsh treatment of tissue sections to give access of anti-BrdU antibody to nucleosides in genomic DNA. In 2008, Salic and Mitchison developed a new method and proved it to be quicker, simpler, and highly sensitive in non-skeletal tissues. This method relies on incorporation of 5-ethynyl-2'-deoxyuridine (EdU) into de novo DNA. This other thymidine analog is readily detected by click chemistry, i.e., covalent cross-linking of its ethynyl group with a fluorescent azide, a molecule small enough to diffuse freely through native tissues and DNA. Here, we describe and compare the BrdU and EdU approaches in skeletal tissues and conclude that in these tissues too EdU provides an easy and very sensitive alternative to BrdU. PMID- 24482179 TI - Analysis of chondrogenesis using micromass cultures of limb mesenchyme. AB - High-density micromass cultures of embryonic mesenchymal cells have proved to be an invaluable model for studying the entire chondrogenic program, from precartilaginous condensations through to chondrocyte hypertrophy. This culture model also provides a powerful system in which to explore the function of various factors in the commitment and differentiation of mesenchymal cells to the chondrogenic lineage. In this regard, micromass cultures provide a consistent and robust model for investigating the effects of genetic manipulations on skeletal phenotypes and for delineating their molecular basis. In this methods chapter, the derivation and use of micromass cultures from murine limb buds are described, but these techniques are also applicable to other organisms and mesenchymal cell sources. PMID- 24482180 TI - Isolation and culture of murine primary chondrocytes. AB - To identify factors that are necessary and sufficient for chondrocyte hypertrophic differentiation and cartilage matrix mineralization, primary chondrocyte culture models have been developed. Here we describe the isolation, short-term and long-term culture, and analysis of primary costal chondrocytes from the mouse. Briefly, sternae and rib cages from neonatal pups are dissected, and chondrocytes are isolated via enzymatic digestions. Chondrocytes are then plated at high density and cultured in the presence of ascorbic acid and beta glycerophosphate as well as various recombinant proteins to promote or inhibit hypertrophic differentiation. We also describe the use of adenoviruses to recombine floxed alleles and over-express genes within these cultures. Finally, we detail methods for alkaline phosphatase and alizarin red staining that are used to visualize chondrocyte maturation and cartilage matrix mineralization. PMID- 24482181 TI - Bone marrow stromal cell assays: in vitro and in vivo. AB - Populations of bone marrow stromal cells (BMSCs, also known as bone marrow derived "mesenchymal stem cells") contain a subset of cells that are able to recapitulate the formation of a bone/marrow organ (skeletal stem cells, SSCs). The biological properties of BMSC cultures are assessed by a variety of assays, both in vitro and in vivo. Application of these assays in an appropriate fashion provides a great deal of information on the role of BMSCs, and the subset of SSCs, in health and in disease. PMID- 24482182 TI - Isolation and culture of neonatal mouse calvarial osteoblasts. AB - This chapter describes the isolation and culture of neonatal mouse calvarial osteoblasts. This primary cell population is obtained by sequential enzymatic digestion of the calvarial bone matrix and is capable of differentiating in vitro into mature osteoblasts that deposit a collagen extracellular matrix and form mineralized bone nodules. Maturation of the cultures can be monitored by gene expression analyses and staining for the presence of alkaline phosphatase or matrix mineralization. This culture system, therefore, provides a powerful model to test how various experimental conditions, such as the manipulation of gene expression, may affect osteoblast maturation and/or function. PMID- 24482183 TI - RANKL-based osteoclastogenic assays from murine bone marrow cells. AB - Osteoclasts are the only cell type in the body to resorb bone. Osteoclasts play a critical role in physiologic and pathologic bone remodeling. Many genetic mouse models affect the skeleton by regulating osteoclast function directly or indirectly. This protocol describes a procedure for generating osteoclasts from mouse bone marrow cells using macrophage colony stimulating factor and receptor activator of NF-kappaB ligand. PMID- 24482184 TI - Hematopoietic stem cell cultures and assays. AB - The adult hematopoietic system is repopulated in its entirety from a rare cell type known as hematopoietic stem cells (HSCs) that reside in the marrow space throughout the skeletal system. Here we describe the isolation and identification of HSCs both phenotypically and functionally. PMID- 24482185 TI - Cancer patients' function, symptoms and supportive care needs: a latent class analysis across cultures. AB - PURPOSE: Patient-reported outcomes (PROs) are an umbrella term covering a range of outcomes, including symptoms, functioning, health-related quality of life, and supportive care needs. Research regarding the appropriate PRO questionnaires to use is informative. A previously published latent class analysis (LCA) examined patterns of function, symptoms, and supportive care needs in a sample of US cancer patients. The current analysis investigated whether the findings from the original study were replicated in new samples from different countries and whether a larger sample combining all the data would affect the classes identified. METHODS: This secondary analysis of data from 408 Japanese and 189 Canadian cancer patients replicated the methods used in the original LCA using data from 117 US cancer patients. In all samples, subjects completed the EORTC QLQ-C30 and Supportive Care Needs Survey Short Form-34 (SCNS-SF34). We first dichotomized individual function, symptom, and need domain scores. We then performed LCA to investigate the patterns of domains for each of the outcomes, both in the individual country samples and then combining the data from all three samples. RESULTS: Across all analyses, class assignment was made by level of function, symptoms, or needs. In individual samples, only two-class models ("high" vs. "low") were generally identifiable while in the combined sample, three-class models ("high" vs. "moderate" vs. "low") best fit the data for all outcomes. CONCLUSIONS: In this analysis, the level of burden experienced by patients was the key factor in defining classes. PMID- 24482186 TI - Amplification with hearing aids for patients with tinnitus and co-existing hearing loss. AB - BACKGROUND: Tinnitus is described as the perception of sound or noise in the absence of real acoustic stimulation. In the current absence of a cure for tinnitus, clinical management typically focuses on reducing the effects of co morbid symptoms such as distress or hearing loss. Hearing loss is commonly co morbid with tinnitus and so logic implies that amplification of external sounds by hearing aids will reduce perception of the tinnitus sound and the distress associated with it. OBJECTIVES: To assess the effects of hearing aids specifically in terms of tinnitus benefit in patients with tinnitus and co existing hearing loss. SEARCH METHODS: We searched the Cochrane Ear, Nose and Throat Disorders Group Trials Register; the Cochrane Central Register of Controlled Trials (CENTRAL); PubMed; EMBASE; CINAHL; Web of Science; Cambridge Scientific Abstracts; ICTRP and additional sources for published and unpublished trials. The date of the search was 19 August 2013. SELECTION CRITERIA: Randomised controlled trials and non-randomised controlled trials recruiting adults with subjective tinnitus and some degree of hearing loss, where the intervention involves amplification with hearing aids and this is compared to interventions involving other medical devices, other forms of standard or complementary therapy, or combinations of therapies, no intervention or placebo interventions. DATA COLLECTION AND ANALYSIS: Three authors independently screened all selected abstracts. Two authors independently extracted data and assessed those potentially suitable studies for risk of bias. For studies meeting the inclusion criteria, we used the mean difference (MD) to compare hearing aids with other interventions and controls. MAIN RESULTS: One randomised controlled trial (91 participants) was included in this review. We judged the trial to have a low risk of bias for method of randomisation and outcome reporting, and an unclear risk of bias for other criteria. No non-randomised controlled trials meeting our inclusion criteria were identified. The included study measured change in tinnitus severity (primary measure of interest) using a tinnitus questionnaire measure, and change in tinnitus loudness (secondary measure of interest) on a visual analogue scale. Other secondary outcome measures of interest, namely change in the psychoacoustic characteristics of tinnitus, change in self reported anxiety, depression and quality of life, and change in neurophysiological measures, were not investigated in this study. The included study compared hearing aid use to sound generator use. The estimated effect on change in tinnitus loudness or severity as measured by the Tinnitus Handicap Inventory score was compatible with benefits for both hearing aids or sound generators but no difference was found between the two alternative treatments (MD -0.90, 95% confidence interval (CI) -7.92 to 6.12) (100-point scale); moderate quality evidence. No negative or adverse events were reported. AUTHORS' CONCLUSIONS: The current evidence base for hearing aid prescription for tinnitus is limited. To be useful, future studies should make appropriate use of blinding and be consistent in their use of outcome measures. Whilst hearing aids are sometimes prescribed as part of tinnitus management, there is currently no evidence to support or refute their use as a more routine intervention for tinnitus. PMID- 24482187 TI - Low- and high-frequency transcutaneous electrical acupoint stimulation induces different effects on cerebral MU-opioid receptor availability in rhesus monkeys. AB - Although systematic studies have demonstrated that acupuncture or electroacupuncture (EA) analgesia is based on their accelerating endogenous opioid release to activate opioid receptors and that EA of different frequencies is mediated by different opioid receptors in specific areas of the central nervous system, there is little direct, real-time evidence to confirm this in vivo. The present study was designed to investigate the effects of transcutaneous electrical acupoint stimulation (TEAS), an analogue of EA, at low and high frequencies on MU-opioid receptor (MOR) availability in the brain of rhesus monkeys. Monkeys underwent 95-min positron emission tomography (PET) with (11) C carfentanil three times randomly while receiving 0, 2, or 100 Hz TEAS, respectively. Each TEAS was administered in the middle 30 min during the 95-min PET scan, and each session of PET and TEAS was separated by at least 2 weeks. The results revealed that 2 Hz but not 100 Hz TEAS evoked a significant increase in MOR binding potential in the anterior cingulate cortex, the caudate nucleus, the putamen, the temporal lobe, the somatosensory cortex, and the amygdala compared with 0 Hz TEAS. The effect remained after the end of TEAS in the anterior cingulate cortex and the temporal lobe. The selective increase in MOR availability in multiple brain regions related to pain and sensory processes may play a role in mediating low-frequency TEAS efficacy. PMID- 24482188 TI - Antitumor effects of heparin-polyethyleneimine nanogels delivering claudin-3 targeted short hairpin RNA combined with low-dose cisplatin on ovarian cancer. AB - Cisplatin is normally administered in chemotherapy for ovarian cancer, but is accompanied by severe dose-dependent toxicity. The combination of cisplatin with other antitumor agents may be a useful alternative for achieving higher antitumor efficiency and lower toxicity. Claudin-3 (CLDN3), a commonly upregulated gene in 90% of ovarian cancers, has been identified as a novel therapeutic target of ovarian cancer. Therefore, in the present study, we constructed a recombinant plasmid carrying an shRNA targeting CLDN3 (pshCLDN3), and investigated the antitumor effects of the combination therapy of pshCLDN3 and a low-dose of cisplatin for the treatment of ovarian cancer. Heparin-polyethyleneimine (HPEI) nanogel, a novel gene carrier with superior biodegradability, excellent blood compatibility and low-toxicity, was used to deliver pshCLDN3 into ovarian cancer cells. The knockdown efficiency was determined by western blot analysis and CLDN3 immunostaining. Nude mice bearing intraperitoneal ovarian carcinomas were treated with pshCLDN3/HPEI complexes, low-dose cisplatin, pshCLDN3/HPEI plus low-dose cisplatin or control agents, respectively. The results showed that pshCLDN3/HPEI effectively suppressed the expression of CLDN3 in ovarian cancer. The combination therapy of pshCLDN3/HPEI and low-dose cisplatin exhibited enhanced antitumor activity, when compared with either agent alone, as evidenced by mean tumor weight analysis, Ki-67 immunostaining analysis and TUNEL assay, without obvious systemic toxicity. These results indicate that pshCLDN3/HPEI combined with low dose cisplatin demonstrates apparent synergistic antitumor activity without marked toxicity. Our study offers a novel therapeutic strategy for the treatment of ovarian cancer. PMID- 24482189 TI - Clinical evaluation of heart failure patients: what good are biomarkers bringing us? PMID- 24482190 TI - Cadmium and lead interactive effects on oxidative stress and antioxidative responses in rice seedlings. AB - Interactive effects of two heavy metal pollutants Cd and Pb in the growth medium were examined on their uptake, production of reactive oxygen species (ROS), induction of oxidative stress and antioxidative defence responses in Indica rice (Oryza sativa L.) seedlings. When rice seedlings in sand culture were exposed to 150 MUM Cd (NO3)2 or 600 MUM Pb (CH3COO)2 individually or in combination for 8-16 days, a significant reduction in root/shoot length, fresh weight, relative water content, photosynthetic pigments and increased production of ROS (O2- and H2O2) was observed. Both Cd and Pb were readily taken up by rice roots and localisation of absorbed metals was greater in roots than in shoots. When present together in the growth medium, uptake of both the metals Cd and Pb declined by 25-40%. Scanning electron microscope (SEM) imaging of leaf stomata revealed that Pb caused more distortion in the shape of guard cells than Cd. Dithizone staining of roots showed localisation of absorbed Cd on root hairs and epidermal cells. Both Cd and Pb caused increased lipid peroxidation, protein carbonylation, decline in protein thiol and increase in non-protein thiol. The level of reduced forms of non-enzymic antioxidants glutathione (GSH) and ascorbate (AsA) and their redox ratios (GSH/AsA) declined, whereas the activities of antioxidative enzymes superoxide dismutase (SOD) and guaiacol peroxidase (GPX) increased in metal treated seedlings compared to controls. In-gel activity staining also revealed increased intensities of SOD and GPX isoforms with metal treatments. Catalase (CAT) activity increased during early days (8 days) of metal exposure and declined by 16 days. Results suggest that oxidative stress is an important component in expression of Cd and Pb toxicities in rice, though uptake of both metals gets reduced considerably when present together in the medium. PMID- 24482191 TI - Expression and functional analysis of putative vacuolar Ca2+-transporters (CAXs and ACAs) in roots of salt tolerant and sensitive rice cultivars. AB - Vacuolar Ca2+-transporters could play an important role for salt tolerance in rice (Oryza sativa L.) root. Here, we compared the expression profiles of putative vacuolar cation/H+ exchanger (CAX) and calmodulin-regulated autoinhibited Ca2+-ATPase (ACA) in rice roots of salt tolerant cv. Pokkali and salt sensitive cv. IR29. In addition to five putative vacuolar CAX genes in the rice genome, a new CAX gene (OsCAX4) has been annotated. In the present study, we isolated the OsCAX4 gene and showed that its encoded protein possesses a unique transmembrane structure and is potentially involved in transporting not only Ca2+ but also Mn2+ and Cu2+. These six OsCAX genes differed in their mRNA expression pattern in roots of tolerant versus sensitive rice cultivars exposed to salt stress. For example, OsCAX4 showed abundant expression in IR29 (sensitive) upon prolonged salt stress. The mRNA expression profile of four putative vacuolar Ca2+ ATPases (OsACA4-7) was also examined. Under control conditions, the mRNA levels of OsACA4, OsACA5, and OsACA7 were relatively high and similar among IR29 and Pokkali. Upon salt stress, only OsACA4 showed first a decrease in its expression in Pokkali (tolerant), followed by a significant increase. Based on these results, a role of vacuolar Ca2+ transporter for salt tolerance in rice root was discussed. PMID- 24482192 TI - Inhibition of root growth by narciclasine is caused by DNA damage-induced cell cycle arrest in lettuce seedlings. AB - Narciclasine (NCS) is an Amaryllidaceae alkaloid isolated from Narcissus tazetta bulbs. Its phytotoxic effects on plant growth were examined in lettuce (Lactuca sativa L.) seedlings. Results showed that high concentrations (0.5-5 MUM) of NCS restricted the growth of lettuce roots in a dose-dependent manner. In NCS-treated lettuce seedlings, the following changes were detected: reduction of mitotic cells and cell elongation in the mature region, inhibition of proliferation of meristematic cells, and cell cycle. Moreover, comet assay and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay indicated that higher levels NCS (0.5-5 MUM) induced DNA damage in root cells of lettuce. The decrease in meristematic cells and increase in DNA damage signals in lettuce roots in responses to NCS are in a dose-dependent manner. NCS-induced reactive oxygen species accumulation may explain an increase in DNA damage in lettuce roots. Thus, the restraint of root growth is due to cell cycle arrest which is caused by NCS-induced DNA damage. In addition, it was also found that NCS (0.5-5 MUM) inhibited the root hair development of lettuce seedlings. Further investigations on the underlying mechanism revealed that both auxin and ethylene signaling pathways are involved in the response of root hairs to NCS. PMID- 24482194 TI - Percutaneous balloon mitral valvuloplasty under neuroprotection: Too Early for Knighthood. AB - The case describes the successful percutaneous balloon mitral valvuloplasty under neuroprotection in a patient with severe symptomatic mitral stenosis and persistent left atrial appendage thrombus despite chronic warfarin therapy. Although the procedure was uneventful for any systemic embolism, the limitations of this approach are highlighted with authors still advocating that surgery remains the benchmark treatment for these patients. (c) 2014 Wiley Periodicals, Inc. PMID- 24482193 TI - Sulfate-dependent acetate oxidation under extremely natron-alkaline conditions by syntrophic associations from hypersaline soda lakes. AB - So far, anaerobic sulfate-dependent acetate oxidation at high pH has only been demonstrated for a low-salt-tolerant syntrophic association of a clostridium 'Candidatus Contubernalis alkalaceticum' and its hydrogenotrophic sulfate reducing partner Desulfonatronum cooperativum. Anaerobic enrichments at pH 10 inoculated with sediments from hypersaline soda lakes of the Kulunda Steppe (Altai, Russia) demonstrated the possibility of sulfate-dependent acetate oxidation at much higher salt concentrations (up to 3.5 M total Na(+)). The most salt-tolerant purified cultures contained two major components apparently working in syntrophy. The primary acetate-fermenting component was identified as a member of the order Clostridiales forming, together with 'Ca. Contubernalis alkalaceticum', an independent branch within the family Syntrophomonadaceae. A provisional name, 'Ca. Syntrophonatronum acetioxidans', is suggested for the novel haloalkaliphilic clostridium. Two phylotypes of extremely haloalkaliphilic sulfate-reducing bacteria of the genus Desulfonatronospira were identified as sulfate-reducing partners in the acetate-oxidizing cultures under extreme salinity. The dominant phylotype differed from the two species of Desulfonatronospira described so far, whilst a minor component belonged to Desulfonatronum thiodismutans. The results proved that, contrary to previous beliefs, sulfate-dependent acetate oxidation is possible, albeit very slowly, in nearly saturated soda brines. PMID- 24482195 TI - Conformational properties and orientational order of a de Vries liquid crystal investigated through NMR spectroscopy. AB - Solid-state and liquid-state NMR spectroscopic techniques are used to describe at molecular level the behaviour of a de Vries liquid crystal (namely the mesogen 9HL) at the SmA-SmC* transition, which is characterized by the absence of the layer shrinkage, typical of non-de Vries smectogens. Previous (2)H NMR studies on the same smectogen, performed at a different magnetic field (from 4.70 to 18.80 T), provided evidence of the occurrence of a tilt of one of the three phenyl rings, constituting the aromatic core of 9HL, at the SmA-SmC* phase transition. In this work, the study is extended to the whole rigid aromatic core of the 9HL. In particular, the variable temperature behavior of the mesogen studied by 1D (13)C NMR cross-polarization (CP) and 2D (1)H-(13)C PDLF (proton-encoded (13)C detected, local field) NMR experiments made possible the characterization of the conformational and orientational properties in the two smectic phases. These results are compared with various proposed models invoked to describe the SmA SmC* transition in de Vries smectogens at a molecular level. PMID- 24482198 TI - The electronic ground state of [Fe(CO)3 (NO)](-) : a spectroscopic and theoretical study. AB - During the past 10 years iron-catalyzed reactions have become established in the field of organic synthesis. For example, the complex anion [Fe(CO)3 (NO)](-) , which was originally described by Hogsed and Hieber, shows catalytic activity in various organic reactions. This anion is commonly regarded as being isoelectronic with [Fe(CO)4 ](2-) , which, however, shows poor catalytic activity. The spectroscopic and quantum chemical investigations presented herein reveal that the complex ferrate [Fe(CO)3 (NO)](-) cannot be regarded as a Fe(-II) species, but rather is predominantly a Fe(0) species, in which the metal is covalently bonded to NO(-) by two pi-bonds. A metal-N sigma-bond is not observed. PMID- 24482197 TI - Redefining successful therapy in obstructive sleep apnea: a call to arms. PMID- 24482196 TI - Effect of time from diagnosis to start of radiotherapy on children with diffuse intrinsic pontine glioma. AB - BACKGROUND: Children with diffuse intrinsic pontine glioma (DIPG) continue to have poor outcomes, and radiotherapy (RT) is the only temporarily effective treatment. In this retrospective analysis, we studied the effect of time from diagnosis to start of RT on event-free survival (EFS) and overall survival (OS) in children with DIPG. METHODS: Records of children (n = 95) with DIPG treated with RT at a single institution between April 1999 and September 2009 were analyzed. RT was delivered at doses of 54.0-55.8 Gy at 1.8 Gy per fraction, and children were followed prospectively. The effect of gender, race, interruption during treatment course, age at diagnosis, duration of symptoms prior to diagnosis, use of protocol-based chemotherapy, and time from diagnosis to initiation of RT on EFS and OS was assessed by the Cox proportional hazards model. RESULTS: Time as a continuous variable from diagnosis to start of RT did not affect outcome. Time dichotomized to <=14 days significantly affected OS (hazard ratio [HR] = 1.70, P = 0.014) and race other than white or black affected EFS (HR = 2.32, P = 0.017). The 95 patients had a 6-month EFS and OS of 60 +/- 5% and 94.7 +/- 2.3%, respectively, and a 12-month EFS and OS of 11.6 +/- 3.1% and 49.5 +/- 5%, respectively. CONCLUSIONS: Time as a continuous variable did not affect OS or EFS in our cohort; however, children treated within 2 weeks of diagnosis had poor outcomes. Although rapid initiation of RT is desirable, our findings do not support intensive efforts aimed at shortening delays from diagnosis to start of RT. PMID- 24482199 TI - IntraVAD, an intra-ventricular assistive device for heart failure patients: design and proof of concept simulations. AB - Ventricular assistive devices are approved by Food and Drug Administration as an alternative to heart transplant for congestive heart failure patients. Unlike other devices requiring open-heart surgery, thin active flexible membrane of IntraVAD, made of ionic polymer-metal composites and shape memory alloys (SMA), enables transcatheter implantation and eliminates thoracotomy. Actuation mechanism of the device mimics the natural motion of the heart, applies almost no shear stress on blood cells, and leaves no stagnant points. Hence, it reduces hemolysis and thrombosis risks. The first step in designing the device is defining the objectives based on hemodynamics of eligible patients. A 3 dimensional model is extracted from magnetic resonance images of a subject to provide a precise representation of the inner shape of the ventricle. Numerical solution to the mathematical model of the behavior of ionic polymer-metal composites is then used to check their compliancy with the objectives. Different actuator designs are evaluated to perform the desired motions and address the cardiac insufficiency. Using an iterative design and simulation process, various geometric and material parameters affecting the performance of the device are optimized, including those of the antagonistic two-way SMA actuators. Although methods and results provided here are for the left ventricle, the same are also applicable to the right ventricle. PMID- 24482201 TI - Induced production of invertase in sugar-beet root by gamma-irradiation: Role of RNA. AB - Gamma-irradiation dosages between 100 and 200 krad greatly stimulate the development of invertase activity in sugar-beet tissue. However, exposure of tissue to 800 krad virtually eliminates the production of invertase. The production of the enzyme in control and irradiated tissue requires RNA and protein synthesis. Failure of 5-fluorouracil to inhibit the development of invertase implies that the synthesis of ribosomal RNA is not required for enzyme production. A close correlation between irradiation-stimulated methylation of sRNA and enzyme production is noted. We suggest that the synthesis or modification of some RNA required for the translation of "masked invertase RNA" is stimulated by gamma-irradiation. PMID- 24482200 TI - Hepatitis C virus genotype 1b increases cumulative lifetime risk of hepatocellular carcinoma. AB - The association between subtypes of hepatitis C virus (HCV) and risk of hepatocellular carcinoma (HCC) remained inconclusive and evaluated in both case control and cohort studies. In the case-control study, 397 HCC cases from medical centers were compared with 410 community-based non-HCC controls. All of them were anti-HCV-seropositive, HBsAg-seronegative with serum HCV RNA levels >=1,000 IU/mL. Logistic regression models were used to estimate the odds ratio (OR) with 95% confidence interval (95% CI) of HCV subtype after controlling for other HCC risk factors. In the cohort study, 866 anti-HCV-seropositive individuals were followed from 1991 to 2008 to assess the long-term HCC predictability of HCV subtypes. Newly developed HCC cases were ascertained by follow-up health examinations and computerized linkage with national databases. The percentage of HCV 1b subtype was higher among HCC cases than controls (64 vs. 55%, p < 0.001). Participant infected with HCV 1b had a higher mean serum HCV RNA level (2.0 * 10(6) IU/mL) than those infected with HCV non-1b (1.2 * 10(6) IU/mL, p < 0.001). The multivariate-adjusted OR (95% CI) of developing HCC for HCV 1b comparing to non-1b was 1.43 (1.02-2.02). After the long-term follow-up, the cumulative lifetime (30-80 years old) HCC risk was 19.2 and 29.7% for patients infected with HCV non-1b and 1b, respectively (p < 0.001). The multivariate-adjusted hazard ratio (95% CI) was 1.85 (1.06-3.22) for HCV 1b compared to non-1b. HCV subtype 1b, the most prevalent subtype in Taiwan, was associated with an increased HCC risk and a proactive clinical management is suggested for patients with HCV 1b. PMID- 24482202 TI - Soluble electron-transport activities in fresh and aged turnip tissue. AB - A soluble (supernatant) fraction from turnips catalyses the reduction of both FeCN and DCPIP but usually not cytochrome c in the presence of either NADH or NADPH. Slicing and aging turnip tissue induces an increase in these activities as well as the development of an NADH-cytochrome c reductase activity.(NH4)2SO4 and Sephadex fractionation indicated that at least three enzymes were involved: an NADH-cytochrome-c reductase, an NADH-FeCN reductase, and an NAD(P)H-DCPIP and FeCN reductase. While the latter reductase had an acid pH optimum, indicating vacuolar origin, the NADH-cytochrome-c and FeCN reductases both had neutral pH optima, indicating cytoplasmic origin. Characterization of the NADH-specific reductases indicated that NADH-FeCN reductase may be a soluble form of the microsomal membrane NADH dehydrogenase but that NADH-cytochrome-c reductase may be normally soluble and possibly involved in cyanide-sensitive NADH oxidation.The induced development of all three reductases was inhibited by 6-methylpurine, ethionine and cycloheximide, indicating dependence on both RNA and protein synthesis. The inhibition by cycloheximide could be reversed but this reversion required a 20-h washing-out period to be complete. PMID- 24482203 TI - The effect of thiouracil on the viability of eggs and embryogeny in Pteridium aquilinum. AB - Gametophytes of Pteridium aquilinum fed for six days with 50 and 75 p.p.m. thiouracil ceased to produce archegonia, but archegonia already initiated completed their development. Eggs produced in the presence of 50 p.p.m. thiouracil were viable, but embryogenesis was retarded. Gametophytes fed with 75 p.p.m. thiouracil mostly remained barren after insemination, the eggs being inviable, but others produced outgrowths from the archegoniate region which were either gametophytic, or sporophytic with a tendency to revert morphologically and functionally to gametophytic tissue.Thiouracil administered after fertilization either prevented embryogenesis, or retarded it, the sporophytes then being deformed and often showing a tendency to produce gametophytic tissue. The embryo became less sensitive to short periods of thiouracil as it developed, possibly because of the appearance of relatively quiescent regions, serving as reservoirs of unaffected cells.The results are held to support the view that the genes responsible for sporophytic growth become activated during oogenesis, and that the cytoplasm of the mature egg already contains the information leading to this kind of growth. PMID- 24482204 TI - Electrical coupling between cells of higher plants: A direct demonstration of intercellular communication. AB - Electrical coupling between adjacent cells of Elodea canadensis has been demonstrated using a microelectrode technique in which the membrane potentials were recorded during the passage of a current pulse from the vacuole of one cell to the external solution. The changes in membrane potential resulting from the passage of the current may be simulated by an equivalent circuit in which the tonoplast:plasmalemma:plasmodesmata resistances are in the ratio 1.0:5.6:2.2. On this basis, the specific resistances are 3.1 kOmega cm(2) for the plasmalemma, 1.0 kOmega cm(2) for the tonoplast and 0.051 kOmega cm(2) for the junction between the cells. Although the plasmodesmata permit the passage of current, it is estimated that they have a resistance about 60 times higher than would be the case if they were completely open channels. Electrical coupling has also been demonstrated between parenchymal cells in oat coleoptiles and between cortical cells in maize roots. The significance of these findings is discussed in relation to the symplastic transport of ions and other small molecules and in relation to the quantitative measurement of membrane resistance in multicellular tissue. PMID- 24482205 TI - [Iron content and electron donor specificity of the nitrate reductase from Ankistrodesmus]. AB - Nitrate reductase (EC 1.6.6.1-2) purified from nitrogen-deficient cells of Ankistrodesmus braunii has the same characteristics previously described for the enzyme from Chlorella fusca. Nitrogen-deficient cells were chosen as a source for nitrate reductase because of a pronounced rise of enzymatic activity after about 20 days of growth, which surpassed even the specific activity present in normal cells. This nitrate reductase exhibits a twofold specificity towards NADH and NADPH which shows a constant ratio during enzyme purification and cannot be separated by gelfiltration or density gradient centrifugation. By growing Ankistrodesmus in the presence of radioactive (55)Fe, the incorporation of this metal into the purified enzyme could be demonstrated. A scheme is presented for the enzymatic mechanism of nitrate reduction in green algae. PMID- 24482206 TI - [Action of 8-azaguanine on cellular division of Chlorella pyrenoidosa : I. Selective inhibition of nuclear DNA synthesis]. AB - Synchronized Chlorella cell cultures were supplemented with 8-azaguanine at different times in their life-cycle. The number of cells obtained after one cycle depended on the time at which the analogue was added to the cultures. The results suggest that, during one cycle, the successive cellular divisions are controlled by a specific "stimulus".When supplied to the cultures during at least one entire cycle, 8-azaguanine inhibited the replication of the nuclear DNA, whereas satellite DNAs continued to replicate. The possibility of a reversal of the phenomenon by guanosine has been studied. PMID- 24482207 TI - [The influence of the plasmotype on the regulation of the activity of L phenylalanine ammonia-lyase (studies on Oenothera forms of the section Raimannia)]. AB - The regulation of the activity of L-phenylalanine ammonia-lyase (PAL) in seedlings of the complex heterocygotes Oenothera berteriana (with the chromosome complexes B and I) and Oenothera odorata (with the complexes v and I) and of their progeny was investigated. The following main results were obtained:The plasmotype (plasmon) has a significant effect upon the amount of increase of the activity of PAL during illumination with continuous far-red light (Figs. 2-5). Combined with the genotypes v.I, B.I and l.v the plasmotype of Oenothera berteriana effects a higher maximal activity after 20 hrs than the plasmotype of Oenothera odorata. This influence of the plasmon is constantly inherited.The influence of the chromosome complexes is characterized by the order I-v-l-B; the I-complex causes the highest, the B-complex the lowest increase in PAL activity.Cytoplasm and plastids have no apparent influence either on the PAL activity in darkgrown seedlings or on the amount of increase of PAL-activity which is brought about by wounding (Fig. 7). Therefore it can be concluded that the plasmotype affects very specifically the light-induced PAL-synthesis.There is no evidence so far for the existence of isoenzymes of PAL in the seedlings of Oenothera forms.Because of various correlations between light-induced PAL activity and anthocyanin formation (Table 2), it can be supposed that the plasmon takes part in the regulation of anthocyanin formation by directing the PAL activity. By the technique of simultaneous irradiation it is demonstrated that anthocyanin formation under continuous illumination with far-red is mediated by phytochrome (Fig. 6).The possibility of explaining the influence of the plasmotype of Oenothera forms on various phytochrome dependent reactions on the basis of a pleiotropic mechanism is discussed. PMID- 24482208 TI - The conversion of mevalonic acid into gibberellin A12-aldehyde in a cell-free system from Cucurbita pepo. AB - A cell-free system prepared from immature seed of Cucurbita pepo incorporates the label from mevalonate-2-(14)C into ent-kaur-16-en-19-oic acid (I), ent-7alpha hydroxy-kaur-16-en-19-oic acid (II), and ent-gibberell-16-en-7-al-19-oic acid (III) (gibberellin A12-aldehyde). The products were identified by gas liquid chromatography and by combined gas chromatography-mass spectrometry of the methylated and trimethylsilylated fractions. The radioactivity of the compounds was established by recrystallisation to constant specific radioactivity. Gibberellin A12 (IV), also detected in the system after incubation by combined gas chromatographymass spectrometry may be an artefact, derived from gibberellin A12-aldehyde by a non-enzymatic conversion.With gibberellin A12-aldehyde, the cell-free biosynthesis of an ent-gibberellane has been achieved for the first time. PMID- 24482209 TI - Abscisic acid associated with wilting in dwarf and tall Pisum sativum. AB - Wilting tall or dwarf peas produced a marked increase in abscisic acid (ABA). Evidence from light- and dark-grown peas does not support the concepts that differences in ABA are associated with differences in height or that ABA is a correlative inhibitor of stem elongation. PMID- 24482210 TI - Timing and presence of an attachment person affect sensitivity of aggression tests in shelter dogs. AB - Different test series have been developed and used to measure behaviour in shelter dogs in order to reveal individuals not suitable for re-homing due to their aggressive tendencies. However, behavioural tests previously validated on pet dogs seem to have relatively low predictability in the case of shelter dogs. Here, we investigate the potential effects of (1) timing of the behaviour testing and (2) presence of a human companion on dogs' aggressive behaviour. In Study I, shelter dogs (n=25) showed more aggression when tested in a short test series two weeks after they had been placed in the shelter compared to their responses in the same test performed 1-2 days after arrival. In Study II, the occurrence of aggressive behaviour was more probable in pet dogs (n=50) in the presence than in the absence of their passive owner. We conclude that the sensitivity of aggression tests for shelter dogs can be increased by running the test in the presence of a caretaker, and after some period of acclimatisation to the new environment. This methodology could also provide better chances for successful adoption. PMID- 24482211 TI - Correlation of clinical symptoms and function with fatty degeneration of infraspinatus in rotator cuff tear. AB - PURPOSE: The aim of this study was to analyse the correlation of clinical symptoms and function with the fatty degeneration of the infraspinatus in rotator cuff tears. METHODS: A total of 152 patients who had rotator cuff tears was enroled retrospectively. The infraspinatus muscle was divided into two compartments according to the bundle of fibres, and the patients were divided into four groups that reflected fatty degeneration. The muscle strength of the shoulder and clinical symptoms was investigated. RESULTS: The severity of the rotator cuff tear and retraction increased with fatty degeneration of both the superior and inferior parts in the infraspinatus muscles. Because of the increasing fatty degeneration of the superior part of the infraspinatus, the shoulder strength index (SSI) of abduction had poor results. Additionally, as the fatty degeneration of the inferior part of the infraspinatus increased, the SSI of abduction and external rotation had worse results. CONCLUSIONS: Fatty degeneration of the superior part of the infraspinatus has no correlation with the power of external rotation but has a negative correlation with the power of abduction. Moreover, fatty degeneration of the inferior part of the infraspinatus has a negative correlation with both the power of abduction and external rotation. LEVEL OF EVIDENCE: Retrospective study, Level IV. PMID- 24482212 TI - Extension gap needs more than 1-mm laxity after implantation to avoid post operative flexion contracture in total knee arthroplasty. AB - PURPOSE: In total knee arthroplasty (TKA), a high soft-tissue tension in extension at the time of operation would cause a post-operative flexion contracture. However, how tight the extension gap should be during surgery to avoid a post-operative flexion contracture remains unclear. The hypothesis is that some laxity in the intraoperative extension gap is necessary to avoid the post-operative flexion contracture. METHODS: A posterior-stabilized TKA was performed for 75 osteoarthritic knees with a varus deformity. The intraoperative extension gap was measured using a tensor device that provides the gap length and the angle between the femoral component and the tibial cut surface. The medial component gap was defined as the gap calculated by subtracting the selected thickness of the tibial component, including the polyethylene liner, from the extension gap at the medial side. Then, the patients were divided into three groups according to the medial component gap, and post-operative extension angle measured 1 year after the surgery was compared between each groups. RESULTS: One year post-operatively, a flexion contracture of more than 5 degrees was found in 0/34 patients when the medial component gap was more than 1 mm, in 2/26 (8%) patients when the gap was between 0 and 1 mm, and in 3/15 (20%) patients when the gap was <0 mm. Three factors were associated significantly with the post operative extension angle: age, preoperative extension angle, and medial component gap. CONCLUSION: The intraoperative extension gap is related to the post-operative extension angle. Surgeons should leave more than 1-mm laxity after the implantation to avoid the post-operative flexion contracture. As a clinical relevance, this study clarified the optimal extension gap to avoid the post operative flexion contracture. LEVEL OF EVIDENCE: Prospective comparative study, Level II. PMID- 24482213 TI - Hip arthroscopy: from the beginning to the future--an innovator's perspective. AB - Hip arthroscopy is one of the fastest-growing areas of orthopaedic surgery. There are many reasons for this, including a better understanding of the pathophysiology of damage to the hip joint, improvements in imaging and technology advancements in arthroscopic instrumentation. This manuscript documents the historical development of hip arthroscopy, in general, as well as advances and ideas that have led to common techniques with regard to portal placement, traction and instrumentation. These advances have led to expanding indications for hip arthroscopy. This manuscript ends with some thoughts about the future of hip arthroscopy from the perspective of one of the leaders who helped shape hip arthroscopy, as it is performed today. PMID- 24482214 TI - The importance of the third knee compartment on outcome following total knee arthroplasty. PMID- 24482215 TI - Mega prosthetic distal femoral arthroplasty for non-tumour indications: does the indication affect the functional outcome and survivorship? AB - PURPOSE: To report the functional outcome, implant survival, and patient mortality after mega prosthetic distal femoral arthroplasty according to the surgical indication. METHODS: A prospective database was compiled for 45 consecutive patients undergoing distal femoral arthroplasty, of which 26 had fractures of the distal femur (group 1) and 19 underwent revision of a total knee arthroplasty (group 2). There were 17 males and 28 females with a median age of 74.5 years. Short form (SF)-12 scores were recorded pre-operatively (before the fracture or revision) and 1 year post-operatively, at which point a Toronto Extremity Salvage Score (TESS) was also obtained. Length of hospital stay and return to place of domicile was obtained from the hospital database. Mortality status was obtained from the General Register Office for Scotland. No patient was lost to follow-up. RESULTS: The 1-year physical (52.4) and mental (63.4) components of the SF-12 score and the TESS (70.5 %) did not significantly differ between the groups (n.s.). The fracture group, however, had a longer length of stay (8 vs. 19 days, p = 0.001) and were also less likely to return to their original domicile (odds ratio 9.5, p = 0.02). The overall implant survival rate was 85 % at 5 years, which was worse for the fracture group (80 vs. 90 %, n.s.). The 5-year mortality rate for the revision group was 17 %, whereas the fracture group demonstrated a greater mortality rate of 43 % (n.s.). CONCLUSION: The functional outcome, revision rate, and mortality of patients undergoing distal femoral arthroplasty for non-tumour reasons are not influenced by indication, but patients undergoing surgery for fractures of the distal femur have a longer length of stay and are less likely to return home. Distal femoral arthroplasty should be considered as a management option for non-tumour salvage procedures of the distal femur. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 24482216 TI - Can the tibial slope be measured on lateral knee radiographs? AB - PURPOSE: The posterior tibial slope influences both the natural knee stability as well as the stability and kinematics after total knee arthroplasty (TKA). Exact definition of the posterior tibial slope (PTS) requires lateral radiographs of the lower limb. Only lateral knee radiographs are routinely obtained after TKA, however. The purpose of the present study therefore was to analyse the relationship between PTS measurement results on short and expanded lateral knee radiographs. METHODS: The PTS was measured on 100 consecutive lateral radiographs of the lower limb using the mechanical and three diaphyseal axes with various distances below the tibial plateau. RESULTS: Significant differences between PTS results were found for all three diaphyseal axes, with the smallest differences and the strongest correlation for a diaphyseal axis at 16 and 20 cm below the tibial plateau. Using short distances below the tibial plateau (6 and 10 cm) resulted in an overestimation of the PTS of 3 degrees , on average. CONCLUSION: The PTS measurements in long lateral knee radiographs are more accurate compared to short radiographs. On short lateral knee radiographs, only a estimation of the PTS can be carried out. LEVEL OF EVIDENCE: Diagnostic study, Level II. PMID- 24482217 TI - Anterior medial meniscal root avulsions due to malposition of the tibial tunnel during anterior cruciate ligament reconstruction: two case reports. AB - The meniscal roots are essential for preserving the native biomechanical and structural properties of the tibiofemoral joint. Meniscus root avulsions, which disrupt the normal meniscus anchoring points, have been reported to result in deleterious biomechanics and clinical outcomes. In this series, two cases of iatrogenic medial meniscus anterior root avulsions after anterior cruciate ligament (ACL) reconstruction are reported. Iatrogenic medial meniscus anterior root avulsions after malpositioning of the tibial tunnels during ACL reconstruction have not been previously reported in the literature and may account for poor long-term outcomes seen in some patients after ACL reconstruction. Therefore, careful attention must be paid to correct tibial tunnel placement during ACL reconstruction. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24482218 TI - The impact of sensory deficits after harvesting hamstrings autograft for ACL reconstruction. AB - PURPOSE: The aim of this study was threefold: to investigate the incidence of sensory deficits after harvesting hamstrings autografts, to localise and measure the area of altered sensibility and to investigate the impact of any sensory deficit on the patients daily life. METHODS: A consecutive series of sixty-one patients were examined for sensory deficits related to harvest of hamstrings tendons 10 years after having had an anterior cruciate ligament reconstruction. A neurological examination of the leg was performed to investigate for potential altered sensibility and to quantify the extent of the lesion. The patients answered the anterior knee symptoms (AKS) questionnaire and additional questions regarding impact on activities of daily life by any sensory deficit. RESULTS: Eighty-five per cent of the examined patients had sensory deficits--experienced as numbness (78 %) and paraesthesia (16 %)--distal to the site of tendon harvesting. The mean affected area was 70 (SD 62) cm(2). No patients experienced sensory deficit symptoms to such a degree that it affected their activities of daily life, but the group with sensory deficit had significantly more AKS than patients without sensory deficit, as evaluated by the AKS score (P = 0.02). The most commonly reported complaints were related to strenuous activities and kneeling knee position. CONCLUSIONS: This long-term evaluation shows that sensory deficit after hamstring tendons harvesting affects a majority of patients and is probably permanent. Most patients reported this as being only mildly bothersome, but they have significantly more AKS as assessed by the AKS questionnaire. In clinical practice, patients should be counselled prior to tendon harvesting on the incidence and characteristic of the sensory deficit along with other possible peri- and postoperative complications. LEVEL OF EVIDENCE: Case series, Level IV. PMID- 24482220 TI - A silver bite: crystalline heterometallic architectures based on Ag-pi interactions with a bis-dipyrrin zinc helicate. AB - An unprecedented mode of assembly of helical motives and Ag(I) ions in the crystalline state is described. The combination of a Zn(II) helicate based on a 2,2'-bisdpm bearing peripheral benzonitrile moieties with AgX salts, leads to the formation of a tetranuclear core containing Ag-pi interactions. Depending on the coordinating ability of the X(-) anion and the solvents used, the tetranuclear complex self-assembles into coordination polymers of varying dimensionality. From the sequence of coordination events (Ag-pi or Ag-peripheral site), one may envisage two possible construction scenarios. However, the Ag-pi as primary event seems reasonable owing to the rather weak binding propensity of the nitrile group and the chelating nature of the pi-clefts. PMID- 24482219 TI - Association of rheumatic diseases with early exit from paid employment in Portugal. AB - To examine the association between rheumatic diseases (RD) and other chronic morbidity with early exit from paid employment in the Portuguese population. The study population consisted of all people between 50 and 64 years of age (3,762 men and 4,241 women) who participated in the Portuguese National Health Survey, conducted in 2005/2006. Data were collected on demographics, ill-health, lifestyle, and socioeconomic factors. Logistic regression was used to estimate the isolated effect of rheumatic diseases and other chronic diseases on the likelihood of exit from paid employment. At the time of the survey, 45.1 % of the Portuguese population with ages between 50 and 64 years old were not employed. In the nonemployed population, 31.6 % self-reported "poor" to "very poor" health, whereas 16.4 % did so in the employed population. A larger average number of major chronic diseases per capita were also found in those not employed (1.9 vs. 1.4, p < 0.001). In the multivariate models, chronic diseases were associated with early exit from paid employment. In particular, rheumatic diseases were more prevalent (43.4 vs. 32.1 %) and associated with early exit from work (OR 1.31; CI 1.12-1.52, p = 0.001). This study suggests an association between RD and other major chronic diseases with early exit from paid employment in Portugal. Thus, health and social protection policies should target these chronic disorders in order to better address sustainability issues and social protection effectiveness. PMID- 24482221 TI - Compound heterozygotes and beta-thalassemia: top-down mass spectrometry for detection of hemoglobinopathies. AB - We have shown previously that liquid extraction surface analysis of dried blood spots coupled to high resolution top-down MS may be applied for the diagnosis of hemoglobin (Hb) variants FS, FAS, FC, FAC, FAD in newborn samples. The objective of the current work was to determine whether the structural variant HbE, compound heterozygote variants FSC and FSD, and beta-thalassemia were amenable to diagnosis by this approach. Anonymized residual neonatal dried blood spot samples, taken as part of the routine newborn screening program, were analyzed by liquid extraction surface analysis coupled to high resolution MS/MS. The samples had been previously screened and were known to be FAE, FSC, FSD, or beta thalassemia. Manual analysis of the mass spectra revealed that, in all cases, the variants may be confirmed. Direct surface sampling MS should be considered as an alternative to current screening techniques for the diagnosis of Hb variants. PMID- 24482222 TI - ELR-CXC chemokine antagonism and cisplatin co-treatment additively reduce H22 hepatoma tumor progression and ameliorate cisplatin-induced nephrotoxicity. AB - Cisplatin (cis-diamminedichloroplatinum) is one of the most commonly used agents for the chemotherapy of various types of cancers, but its use is limited by its dose-dependent side-effects (e.g., nephrotoxicity). The ELR-CXC chemokines are potent tumor growth, metastatic and angiogenic factors and can foster tumor resistance to chemotherapeutic agents. They are also potent proinflammatory agents. The aim of the present study was to evaluate the added effects of combining cisplatin chemotherapy with ELR-CXC chemokine antagonism in a mouse H22 hepatoma cancer cell model. The mice were injected with tumor cells and were then treated with cisplatin (12.5 or 2 mg/kg doses), either alone or together with the chemokine antagonist CXCL8(3-72)K11R/G31P (G31P) (50 ug/kg). At varying time points renal function was examined using blood urea nitrogen (BUN) and serum creatinine (SCr) as read-outs for the toxic effects of cisplatin, while tumor growth and metastasis were assessed as endpoints. High-dose cisplatin therapy reduced the tumor burden by 52%, while co-delivery of G31P further augmented the tumor growth-suppressive effects of this dose of cisplatin to 71%; G31P by itself and low-dose cisplatin reduced the tumor burden by 19 and 39%, respectively. G31P also reduced the nephrotoxic effects of high-dose cisplatin to the effects observed in the low-dose cisplatin-treated animals. These data confirm the beneficial effects of combined cisplatin chemotherapy and ELR-CXC chemokine anatagonism in the context of both tumor progression and adverse side-effects. PMID- 24482223 TI - Introduction: science, technology and human rights: lessons learned from the right to water and sanitation. PMID- 24482224 TI - Heparin prevents intracellular hyaluronan synthesis and autophagy responses in hyperglycemic dividing mesangial cells and activates synthesis of an extensive extracellular monocyte-adhesive hyaluronan matrix after completing cell division. AB - Growth-arrested rat mesangial cells (RMCs) at a G0/G1 interphase stimulated to divide in hyperglycemic medium initiate intracellular hyaluronan synthesis that induces autophagy/cyclin D3-induced formation of a monocyte-adhesive extracellular hyaluronan matrix after completing cell division. This study shows that heparin inhibits the intracellular hyaluronan synthesis and autophagy responses, but at the end of cell division it induces synthesis of a much larger extracellular monocyte-adhesive hyaluronan matrix. Heparin bound to RMC surfaces by 1 h, internalizes into the Golgi/endoplasmic reticulum region by 2 h, and was nearly gone by 4 h. Treatment by heparin for only the first 4 h was sufficient for its function. Streptozotocin diabetic rats treated daily with heparin showed similar results. Glomeruli in sections of diabetic kidneys showed extensive accumulation of autophagic RMCs, increased hyaluronan matrix, and influx of macrophages over 6 weeks. Hyaluronan staining in the glomeruli of heparin-treated diabetic rats was very high at week 1 and decreased to near control level by 6 weeks without any RMC autophagy. However, the influx of macrophages by 6 weeks was as pronounced as in diabetic glomeruli. The results are as follows: 1) heparin blocks synthesis of hyaluronan in intracellular compartments, which prevents the autophagy and cyclin D3 responses thereby allowing RMCs to complete cell division and sustain function; 2) interaction of heparin with RMCs in early G1 phase is sufficient to induce signaling pathway(s) for its functions; and 3) influxed macrophages effectively remove the hyaluronan matrix without inducing pro-fibrotic responses that lead to nephropathy and proteinurea in diabetic kidneys. PMID- 24482225 TI - Pulsatile hormonal signaling to extracellular signal-regulated kinase: exploring system sensitivity to gonadotropin-releasing hormone pulse frequency and width. AB - Gonadotropin-releasing hormone (GnRH) is secreted in brief pulses that stimulate synthesis and secretion of pituitary gonadotropin hormones and thereby mediate control of reproduction. It acts via G-protein-coupled receptors to stimulate effectors, including ERK. Information could be encoded in GnRH pulse frequency, width, amplitude, or other features of pulse shape, but the relative importance of these features is unknown. Here we examine this using automated fluorescence microscopy and mathematical modeling, focusing on ERK signaling. The simplest scenario is one in which the system is linear, and response dynamics are relatively fast (compared with the signal dynamics). In this case integrated system output (ERK activation or ERK-driven transcription) will be roughly proportional to integrated input, but we find that this is not the case. Notably, we find that relatively slow response kinetics lead to ERK activity beyond the GnRH pulse, and this reduces sensitivity to pulse width. More generally, we show that the slowing of response kinetics through the signaling cascade creates a system that is robust to pulse width. We, therefore, show how various levels of response kinetics synergize to dictate system sensitivity to different features of pulsatile hormone input. We reveal the mathematical and biochemical basis of a dynamic GnRH signaling system that is robust to changes in pulse amplitude and width but is sensitive to changes in receptor occupancy and frequency, precisely the features that are tightly regulated and exploited to exert physiological control in vivo. PMID- 24482226 TI - Targeted metabolomics connects thioredoxin-interacting protein (TXNIP) to mitochondrial fuel selection and regulation of specific oxidoreductase enzymes in skeletal muscle. AB - Thioredoxin-interacting protein (TXNIP) is an alpha-arrestin family member involved in redox sensing and metabolic control. Growing evidence links TXNIP to mitochondrial function, but the molecular nature of this relationship has remained poorly defined. Herein, we employed targeted metabolomics and comprehensive bioenergetic analyses to evaluate oxidative metabolism and respiratory kinetics in mouse models of total body (TKO) and skeletal muscle specific (TXNIP(SKM-/-)) Txnip deficiency. Compared with littermate controls, both TKO and TXNIP(SKM-/-) mice had reduced exercise tolerance in association with muscle-specific impairments in substrate oxidation. Oxidative insufficiencies in TXNIP null muscles were not due to perturbations in mitochondrial mass, the electron transport chain, or emission of reactive oxygen species. Instead, metabolic profiling analyses led to the discovery that TXNIP deficiency causes marked deficits in enzymes required for catabolism of branched chain amino acids, ketones, and lactate, along with more modest reductions in enzymes of beta-oxidation and the tricarboxylic acid cycle. The decrements in enzyme activity were accompanied by comparable deficits in protein abundance without changes in mRNA expression, implying dysregulation of protein synthesis or stability. Considering that TXNIP expression increases in response to starvation, diabetes, and exercise, these findings point to a novel role for TXNIP in coordinating mitochondrial fuel switching in response to nutrient availability. PMID- 24482227 TI - Tyrosine phosphorylation of Wiskott-Aldrich syndrome protein (WASP) by Hck regulates macrophage function. AB - We have shown previously that tyrosine phosphorylation of Wiskott-Aldrich syndrome protein (WASP) is important for diverse macrophage functions including phagocytosis, chemotaxis, podosome dynamics, and matrix degradation. However, the specific tyrosine kinase mediating WASP phosphorylation is still unclear. Here, we provide evidence that Hck, which is predominantly expressed in leukocytes, can tyrosine phosphorylate WASP and regulates WASP-mediated macrophage functions. We demonstrate that tyrosine phosphorylation of WASP in response to stimulation with CX3CL1 or via Fcgamma receptor ligation were severely reduced in Hck(-/-) bone marrow-derived macrophages (BMMs) or in RAW/LR5 macrophages in which Hck expression was silenced using RNA-mediated interference (Hck shRNA). Consistent with reduced WASP tyrosine phosphorylation, phagocytosis, chemotaxis, and matrix degradation are reduced in Hck(-/-) BMMs or Hck shRNA cells. In particular, WASP phosphorylation was primarily mediated by the p61 isoform of Hck. Our studies also show that Hck and WASP are required for passage through a dense three dimensional matrix and transendothelial migration, suggesting that tyrosine phosphorylation of WASP by Hck may play a role in tissue infiltration of macrophages. Consistent with a role for this pathway in invasion, WASP(-/-) BMMs do not invade into tumor spheroids with the same efficiency as WT BMMs and cells expressing phospho-deficient WASP have reduced ability to promote carcinoma cell invasion. Altogether, our results indicate that tyrosine phosphorylation of WASP by Hck is required for proper macrophage functions. PMID- 24482228 TI - Crystal structure and characterization of the glycoside hydrolase family 62 alpha L-arabinofuranosidase from Streptomyces coelicolor. AB - alpha-L-arabinofuranosidase, which belongs to the glycoside hydrolase family 62 (GH62), hydrolyzes arabinoxylan but not arabinan or arabinogalactan. The crystal structures of several alpha-L-arabinofuranosidases have been determined, although the structures, catalytic mechanisms, and substrate specificities of GH62 enzymes remain unclear. To evaluate the substrate specificity of a GH62 enzyme, we determined the crystal structure of alpha-L-arabinofuranosidase, which comprises a carbohydrate-binding module family 13 domain at its N terminus and a catalytic domain at its C terminus, from Streptomyces coelicolor. The catalytic domain was a five-bladed beta-propeller consisting of five radially oriented anti-parallel beta-sheets. Sugar complex structures with l-arabinose, xylotriose, and xylohexaose revealed five subsites in the catalytic cleft and an l-arabinose binding pocket at the bottom of the cleft. The entire structure of this GH62 family enzyme was very similar to that of glycoside hydrolase 43 family enzymes, and the catalytically important acidic residues found in family 43 enzymes were conserved in GH62. Mutagenesis studies revealed that Asp(202) and Glu(361) were catalytic residues, and Trp(270), Tyr(461), and Asn(462) were involved in the substrate-binding site for discriminating the substrate structures. In particular, hydrogen bonding between Asn(462) and xylose at the nonreducing end subsite +2 was important for the higher activity of substituted arabinofuranosyl residues than that for terminal arabinofuranoses. PMID- 24482229 TI - Wnt protein-mediated satellite cell conversion in adult and aged mice following voluntary wheel running. AB - Muscle represents an abundant, accessible, and replenishable source of adult stem cells. Skeletal muscle-derived stem cells, called satellite cells, play essential roles in regeneration after muscle injury in adult skeletal muscle. Although the molecular mechanism of muscle regeneration process after an injury has been extensively investigated, the regulation of satellite cells under steady state during the adult stage, including the reaction to exercise stimuli, is relatively unknown. Here, we show that voluntary wheel running exercise, which is a low stress exercise, converts satellite cells to the activated state due to accelerated Wnt signaling. Our analysis showed that up-regulated canonical Wnt/beta-catenin signaling directly modulated chromatin structures of both MyoD and Myf5 genes, resulting in increases in the mRNA expression of Myf5 and MyoD and the number of proliferative Pax7(+)Myf5(+) and Pax7(+) MyoD(+) cells in skeletal muscle. The effect of Wnt signaling on the activation of satellite cells, rather than Wnt-mediated fibrosis, was observed in both adult and aged mice. The association of beta-catenin, T-cell factor, and lymphoid enhancer transcription factors of multiple T-cell factor/lymphoid enhancer factor regulatory elements, conserved in mouse, rat, and human species, with the promoters of both the Myf5 and MyoD genes drives the de novo myogenesis in satellite cells even in aged muscle. These results indicate that exercise stimulated extracellular Wnts play a critical role in the regulation of satellite cells in adult and aged skeletal muscle. PMID- 24482230 TI - Structural insights into the interaction between a potent anti-inflammatory protein, viral CC chemokine inhibitor (vCCI), and the human CC chemokine, Eotaxin 1. AB - Chemokines play important roles in the immune system, not only recruiting leukocytes to the site of infection and inflammation but also guiding cell homing and cell development. The soluble poxvirus-encoded protein viral CC chemokine inhibitor (vCCI), a CC chemokine inhibitor, can bind to human CC chemokines tightly to impair the host immune defense. This protein has no known homologs in eukaryotes and may represent a potent method to stop inflammation. Previously, our structure of the vCCI.MIP-1beta (macrophage inflammatory protein-1beta) complex indicated that vCCI uses negatively charged residues in beta-sheet II to interact with positively charged residues in the MIP-1beta N terminus, 20s region and 40s loop. However, the interactions between vCCI and other CC chemokines have not yet been fully explored. Here, we used NMR and fluorescence anisotropy to study the interaction between vCCI and eotaxin-1 (CCL11), a CC chemokine that is an important factor in the asthma response. NMR results reveal that the binding pattern is very similar to the vCCI.MIP-1beta complex and suggest that electrostatic interactions provide a major contribution to binding. Fluorescence anisotropy results on variants of eotaxin-1 further confirm the critical roles of the charged residues in eotaxin-1. In addition, the binding affinity between vCCI and other wild type CC chemokines, MCP-1 (monocyte chemoattractant protein-1), MIP-1beta, and RANTES (regulated on activation normal T cell expressed and secreted), were determined as 1.1, 1.2, and 0.22 nm, respectively. To our knowledge, this is the first work quantitatively measuring the binding affinity between vCCI and multiple CC chemokines. PMID- 24482231 TI - Cluster of differentiation 166 (CD166) regulated by phosphatidylinositide 3 Kinase (PI3K)/AKT signaling to exert its anti-apoptotic role via yes-associated protein (YAP) in liver cancer. AB - Cluster of differentiation 166 (CD166 or Alcam) is a cell surface molecule that can be greatly induced in liver cancer cells after serum deprivation, suggesting its role in influencing cell survival. However, whether and how CD166 acts as an anti-apoptotic regulator needs to be further investigated. Here, we report that gene silencing of CD166 promoted apoptosis via down-regulation of Bcl-2 in liver cancer cells. PI3K/AKT signaling was found to up-regulate CD166 expression independently of transcription. We also revealed that CD166 promoted both AKT expression and activity, thus providing a novel positive regulatory feedback between PI3K/AKT signaling and CD166. Moreover, Yes-associated protein (YAP) was identified as a CD166 downstream effecter, which can partly rescue CD166 knockdown-induced apoptosis and reduced in vivo cancer cell growth. Mechanically, CD166 modulated YAP expression and activity through at least two different ways, transcriptional regulation of YAP through cAMP-response element-binding protein and post-transcriptional control of YAP stability through inhibition to AMOT130. We also showed that CD9 enhanced CD166-mediated regulation of YAP via a mechanism involving facilitating CD166-CD166 homophilic interaction. Tissue microarray analysis revealed that CD166 and YAP were up-regulated and closely correlated in liver cancer samples, demonstrating the importance of their relationship. Taken together, this work summarizes a novel link between CD166 and YAP, explores the interplay among related important signaling pathways, and may lead to more effective therapeutic strategies for liver cancer. PMID- 24482232 TI - Transcriptional repression of histone deacetylase 3 by the histone demethylase KDM2A is coupled to tumorigenicity of lung cancer cells. AB - Dysregulated expression of histone methyltransferases and demethylases is an emerging epigenetic mechanism underlying cancer development and metastasis. We recently showed that the histone H3 lysine 36 (H3K36) demethylase KDM2A (also called FBXL11 and JHDM1A) is necessary for tumorigenic and metastatic capabilities of KDM2A-overexpressing non-small cell lung cancer (NSCLC) cells. Here, we report that KDM2A transcriptionally represses the histone deacetylase 3 (HDAC3) gene by removing methyl groups from dimethylated H3K36 at the HDAC3 promoter in KDM2A-overexpressing NSCLC cells. KDM2A depletion reduced expression levels of cell cycle-associated genes (e.g. CDK6) and cell invasion-related genes (e.g. NANOS1); these levels were rescued by ectopic expression of KDM2A but not its catalytic mutant. These genes were occupied and down-regulated by HDAC3. HDAC3 knockdown significantly recovered the proliferation and invasiveness of KDM2A-depleted NSCLC cells as well as the levels of CDK6 and NANOS1 expression in these cells. Similar to their previously reported functions in other cell types, CDK6 and NANOS1 were required for the proliferation and invasion, respectively, of KDM2A-overexpressing NSCLC cells. In a mouse xenograft model, HDAC3 depletion substantially restored the tumorigenic ability of KDM2A knockdown cells. These findings reveal a novel cancer-epigenetic pathway in which the antagonistic effect of KDM2A on HDAC3 expression releases cell cycle-associated genes and cell invasion-related genes from HDAC3 repression and indicate the importance of this pathway for tumorigenicity and invasiveness of KDM2A-overexpressing NSCLC cells. PMID- 24482233 TI - Proteasomal degradation of gamma-aminobutyric acidB receptors is mediated by the interaction of the GABAB2 C terminus with the proteasomal ATPase Rtp6 and regulated by neuronal activity. AB - Regulation of cell surface expression of neurotransmitter receptors is crucial for determining synaptic strength and plasticity, but the underlying mechanisms are not well understood. We previously showed that proteasomal degradation of GABAB receptors via the endoplasmic reticulum (ER)-associated protein degradation (ERAD) machinery determines the number of cell surface GABAB receptors and thereby GABAB receptor-mediated neuronal inhibition. Here, we show that proteasomal degradation of GABAB receptors requires the interaction of the GABAB2 C terminus with the proteasomal AAA-ATPase Rpt6. A mutant of Rpt6 lacking ATPase activity prevented degradation of GABAB receptors but not the removal of Lys(48) linked ubiquitin from GABAB2. Blocking ERAD activity diminished the interaction of Rtp6 with GABAB receptors resulting in increased total as well as cell surface expression of GABAB receptors. Modulating neuronal activity affected proteasomal activity and correspondingly the interaction level of Rpt6 with GABAB2. This resulted in altered cell surface expression of the receptors. Thus, neuronal activity-dependent proteasomal degradation of GABAB receptors by the ERAD machinery is a potent mechanism regulating the number of GABAB receptors available for signaling and is expected to contribute to homeostatic neuronal plasticity. PMID- 24482234 TI - Sry HMG box protein 9-positive (Sox9+) epithelial cell adhesion molecule-negative (EpCAM-) biphenotypic cells derived from hepatocytes are involved in mouse liver regeneration. AB - It has been shown that mature hepatocytes compensate tissue damages not only by proliferation and/or hypertrophy but also by conversion into cholangiocyte-like cells. We found that Sry HMG box protein 9-positive (Sox9(+)) epithelial cell adhesion molecule-negative (EpCAM(-)) hepatocyte nuclear factor 4alpha-positive (HNF4alpha(+)) biphenotypic cells showing hepatocytic morphology appeared near EpCAM(+) ductular structures in the livers of mice fed 3,5-diethoxycarbonyl-1,4 dihydrocollidine (DDC)-containing diet. When Mx1-Cre:ROSA mice, which were injected with poly(I:C) to label mature hepatocytes, were fed with the DDC diet, we found LacZ(+)Sox9(+) cells near ductular structures. Although Sox9(+)EpCAM(-) cells adjacent to expanding ducts likely further converted into ductular cells, the incidence was rare. To know the cellular characteristics of Sox9(+)EpCAM(-) cells, we isolated them as GFP(+)EpCAM(-) cells from DDC-injured livers of Sox9 EGFP mice. Sox9(+)EpCAM(-) cells proliferated and could differentiate to functional hepatocytes in vitro. In addition, Sox9(+)EpCAM(-) cells formed cysts with a small central lumen in collagen gels containing Matrigel(r) without expressing EpCAM. These results suggest that Sox9(+)EpCAM(-) cells maintaining biphenotypic status can establish cholangiocyte-type polarity. Interestingly, we found that some of the Sox9(+) cells surrounded luminal spaces in DDC-injured liver while they expressed HNF4alpha. Taken together, we consider that in addition to converting to cholangiocyte-like cells, Sox9(+)EpCAM(-) cells provide luminal space near expanded ductular structures to prevent deterioration of the injuries and potentially supply new hepatocytes to repair damaged tissues. PMID- 24482235 TI - Regulation of induced pluripotent stem (iPS) cell induction by Wnt/beta-catenin signaling. AB - Wnt signaling has been implicated in promoting somatic cell reprogramming. However, its molecular mechanisms remain unknown. Here we report that Wnt/beta catenin enhances iPSCs induction at the early stage of reprogramming. The augmented reprogramming induced by beta-catenin is not due to increased total cell population or activation of c-Myc. In addition, beta-catenin interacts with reprogramming factors Klf4, Oct4, and Sox2, further enhancing expression of pluripotency circuitry genes. These studies reveal novel mechanisms underlying the regulation of reprogramming somatic cells to pluripotency by Wnt/beta-catenin signaling. PMID- 24482236 TI - Glutaredoxin-1 up-regulation induces soluble vascular endothelial growth factor receptor 1, attenuating post-ischemia limb revascularization. AB - Glutaredoxin-1 (Glrx) is a cytosolic enzyme that regulates diverse cellular function by removal of GSH adducts from S-glutathionylated proteins including signaling molecules and transcription factors. Glrx is up-regulated during inflammation and diabetes, and Glrx overexpression inhibits VEGF-induced EC migration. The aim was to investigate the role of up-regulated Glrx in EC angiogenic capacities and in vivo revascularization in the setting of hind limb ischemia. Glrx-overexpressing EC from Glrx transgenic (TG) mice showed impaired migration and network formation and secreted higher levels of soluble VEGF receptor 1 (sFlt), an antagonizing factor to VEGF. After hind limb ischemia surgery Glrx TG mice demonstrated impaired blood flow recovery, associated with lower capillary density and poorer limb motor function compared with wild type littermates. There were also higher levels of anti-angiogenic sFlt expression in the muscle and plasma of Glrx TG mice after surgery. Noncanonical Wnt5a is known to induce sFlt. Wnt5a was highly expressed in ischemic muscles and EC from Glrx TG mice, and exogenous Wnt5a induced sFlt expression and inhibited network formation in human microvascular EC. Adenoviral Glrx-induced sFlt in EC was inhibited by a competitive Wnt5a inhibitor. Furthermore, Glrx overexpression removed GSH adducts on p65 in ischemic muscle and EC and enhanced NF-kappaB activity, which was responsible for Wnt5a-sFlt induction. Taken together, up regulated Glrx induces sFlt in EC via NF-kappaB-dependent Wnt5a, resulting in attenuated revascularization in hind limb ischemia. The Glrx-induced sFlt explains part of the mechanism of redox-regulated VEGF signaling. PMID- 24482237 TI - Phosphorylation of myosin II-interacting guanine nucleotide exchange factor (MyoGEF) at threonine 544 by aurora B kinase promotes the binding of polo-like kinase 1 to MyoGEF. AB - We previously reported that phosphorylation of myosin II-interacting guanine nucleotide exchange factor (MyoGEF) by polo-like kinase 1 (Plk1) promotes the localization of MyoGEF to the central spindle and increases MyoGEF activity toward RhoA during mitosis. In this study we report that aurora B-mediated phosphorylation of MyoGEF at Thr-544 creates a docking site for Plk1, leading to the localization and activation of MyoGEF at the central spindle. In vitro kinase assays show that aurora B can phosphorylate MyoGEF. T544A mutation drastically decreases aurora B-mediated phosphorylation of MyoGEF in vitro and in transfected HeLa cells. Coimmunoprecipitation and in vitro pulldown assays reveal that phosphorylation of MyoGEF at Thr-544 enhances the binding of Plk1 to MyoGEF. Immunofluorescence analysis shows that aurora B colocalizes with MyoGEF at the central spindle and midbody during cytokinesis. Suppression of aurora B activity by an aurora B inhibitor disrupts the localization of MyoGEF to the central spindle. In addition, T544A mutation interferes with the localization of MyoGEF to the cleavage furrow and decreases MyoGEF activity toward RhoA during mitosis. Taken together, our results suggest that aurora B coordinates with Plk1 to regulate MyoGEF activation and localization, thus contributing to the regulation of cytokinesis. PMID- 24482240 TI - Around a quarter of all older people have disability during the last 2 years of life, with prevalence higher among women and those aged over 80 years. PMID- 24482239 TI - MLK3-MKK3/6-P38MAPK cascades following N-methyl-D-aspartate receptor activation contributes to amyloid-beta peptide-induced apoptosis in SH-SY5Y cells. AB - Amyloid-beta peptide (Abeta) has been implicated in the development of Alzheimer's disease (AD), but the underlying molecular mechanisms remain unclear. The present study explores the proapoptosis signaling evoked by N-methyl-D aspartate (NMDA) receptors in Abeta neurotoxicity. Oligomeric Abeta25-35 incubation resulted in significant apoptosis of neuronal SH-SY5Y cells. Preadministration of the potent NMDA receptor antagonist MK801 promoted neuronal survival. Both NVP-AAM077 and Ro25-6981, GluN2A- and GluN2B-subunit-selective NMDA receptor antagonists, respectively, showed effects similar to those of MK801, supporting a critical role of GluN2A- or GluN2B-containing NMDA receptors in Abeta neurotoxicity. Exposure to oligomeric Abeta25-35 increased the phosphorylation (activation) of mixed-lineage kinase 3 (MLK3), dual-specific mitogen-activated protein kinase kinase 3/6 (MKK3/6), and P38 mitogen-activated protein kinase (P38MAPK) in SH-SY5Y cells. Inhibition of P38MAPK activation by SB239063 had a neuroprotective effect. K252a attenuated the phosphorylation of MLK3, MKK3/6, and P38MAPK but also partially prevented SH-SY5Y cells apoptosis. MK801, NVP-AAM077, and Ro25-6981, abrogated the MLK3-MKK3/6-P38MAPK activation induced by oligomeric Abeta25-35. These results suggest that the activation of GluN2A- or GluN2B-containing NMDA receptors is responsible for the activation of MLK3-MKK3/6-P38MAPK cascades, which contributes to Abeta-mediated cell apoptosis. PMID- 24482238 TI - Origin of the proton-transfer step in the cofactor-free (1H)-3-hydroxy-4 oxoquinaldine 2,4-dioxygenase: effect of the basicity of an active site His residue. AB - Dioxygenases catalyze a diverse range of chemical reactions that involve the incorporation of oxygen into a substrate and typically use a transition metal or organic cofactor for reaction. Bacterial (1H)-3-hydroxy-4-oxoquinaldine 2,4 dioxygenase (HOD) belongs to a class of oxygenases able to catalyze this energetically unfavorable reaction without any cofactor. In the quinaldine metabolic pathway, HOD breaks down its natural N-heteroaromatic substrate using a mechanism that is still incompletely understood. Experimental and computational approaches were combined to study the initial step of the catalytic cycle. We have investigated the role of the active site His-251/Asp-126 dyad, proposed to be involved in substrate hydroxyl group deprotonation, a critical requirement for subsequent oxygen reaction. The pH profiles obtained under steady-state conditions for the H251A and D126A variants show a strong pH effect on their kcat and kcat/Km constants, with a decrease in kcat/Km of 5500- and 9-fold at pH 10.5, respectively. Substrate deprotonation studies under transient-state conditions show that this step is not rate-limiting and yield a pKa value of ~ 7.2 for WT HOD. A large solvent isotope effect was found, and the pKa value was shifted to ~ 8.3 in D2O. Crystallographic and computational studies reveal that the mutations have a minor effect on substrate positioning. Computational work shows that both His-251 and Asp-126 are essential for the proton transfer driving force of the initial reaction. This multidisciplinary study offers unambiguous support to the view that substrate deprotonation, driven by the His/Asp dyad, is an essential requirement for its activation. PMID- 24482241 TI - Infrared thermometers for assessing fever in children: the ThermoScan PRO 4000 ear thermometer is more reliable than the Temporal Scanner TAT-500. PMID- 24482242 TI - A recessive genetic model and runs of homozygosity in major depressive disorder. AB - Genome-wide association studies (GWASs) of major depressive disorder (MDD) have yet to identify variants that surpass the threshold for genome-wide significance. A recent study reported that runs of homozygosity (ROH) are associated with schizophrenia, reflecting a novel genetic risk factor resulting from increased parental relatedness and recessive genetic effects. Here, we explore the possibility of such a recessive model in MDD. In a sample of 9,238 cases and 9,521 controls reported in a recent mega-analysis of 9 GWAS we perform an analysis of ROH and common variants under a recessive model. Since evidence for association with ROH could reflect a recessive mode of action at loci, we also conducted a genome-wide association analyses under a recessive model. The genome wide association analysis using a recessive model found no significant associations. Our analysis of ROH suggested that there was significant heterogeneity of effect across studies in effect (P = 0.001), and it was associated with genotyping platform and country of origin. The results of the ROH analysis show that differences across studies can lead to conflicting systematic genome-wide differences between cases and controls that are unaccounted for by traditional covariates. They highlight the sensitivity of the ROH method to spurious associations, and the need to carefully control for potential confounds in such analyses. We found no strong evidence for a recessive model underlying MDD. PMID- 24482244 TI - Potentially malignant disorders of the oral cavity: current practice and future directions in the clinic and laboratory. AB - Despite commendable progress in the prevention, detection, and treatment of a wide variety of solid tumor types, oral squamous cell carcinoma (OSCC) remains a significant health burden across the globe. OSCC carcinogenesis involves accumulation of genetic alterations that coincide with the multistep malignant transformation of normal oral epithelium. OSCC is often first diagnosed at late stages of the disease (advanced regional disease and/or metastasis). Delayed diagnosis precludes successful treatment and favorable outcomes. In clinical practice, opportunities exist to identify patients with oral potentially malignant disorders (OPMDs), which precede the development of cancer. This review addresses the current status of laboratory and clinical research on OPMDs, with emphasis on leukoplakia and erythroplakia. OSF is also presented, though there is a paucity of published studies on this disorder. We focus on findings that could translate into earlier diagnosis and more efficacious treatment of those lesions with significant malignant potential. We explore how markers of OPMD malignant transformation might be implemented into current diagnostic practice to help clinicians objectively stratify patients into treatment/follow-up groups according to relative risk. We provide an overview of recently concluded and ongoing OPMD chemoprevention trials. We describe laboratory OPMD models that can be used to not only to reveal the genetic and molecular intricacies of oral cancer but also to develop novel screening methods and therapeutic approaches. Finally, we call for targeted screening programs of at-risk populations in order to facilitate diagnosis and treatment of OPMD and early OSCC. PMID- 24482245 TI - Contributions of the Na+/K+-ATPase, NKCC1, and Kir4.1 to hippocampal K+ clearance and volume responses. AB - Network activity in the brain is associated with a transient increase in extracellular K(+) concentration. The excess K(+) is removed from the extracellular space by mechanisms proposed to involve Kir4.1-mediated spatial buffering, the Na(+)/K(+)/2Cl(-) cotransporter 1 (NKCC1), and/or Na(+)/K(+) ATPase activity. Their individual contribution to [K(+)]o management has been of extended controversy. This study aimed, by several complementary approaches, to delineate the transport characteristics of Kir4.1, NKCC1, and Na(+)/K(+)-ATPase and to resolve their involvement in clearance of extracellular K(+) transients. Primary cultures of rat astrocytes displayed robust NKCC1 activity with [K(+)]o increases above basal levels. Increased [K(+)]o produced NKCC1-mediated swelling of cultured astrocytes and NKCC1 could thereby potentially act as a mechanism of K(+) clearance while concomitantly mediate the associated shrinkage of the extracellular space. In rat hippocampal slices, inhibition of NKCC1 failed to affect the rate of K(+) removal from the extracellular space while Kir4.1 enacted its spatial buffering only during a local [K(+)]o increase. In contrast, inhibition of the different isoforms of Na(+)/K(+)-ATPase reduced post-stimulus clearance of K(+) transients. The astrocyte-characteristic alpha2beta2 subunit composition of Na(+)/K(+)-ATPase, when expressed in Xenopus oocytes, displayed a K(+) affinity and voltage-sensitivity that would render this subunit composition specifically geared for controlling [K(+)]o during neuronal activity. In rat hippocampal slices, simultaneous measurements of the extracellular space volume revealed that neither Kir4.1, NKCC1, nor Na(+)/K(+)-ATPase accounted for the stimulus-induced shrinkage of the extracellular space. Thus, NKCC1 plays no role in activity-induced extracellular K(+) recovery in native hippocampal tissue while Kir4.1 and Na(+)/K(+)-ATPase serve temporally distinct roles. PMID- 24482246 TI - Stimulating thoracic epidural placement via a lumbar approach causes significant spinal cord damage in a porcine model. AB - BACKGROUND: Continuous thoracic epidural analgesia is a valuable and common technique for analgesia but involves risk to the spinal cord. There is significant pediatric experience safely placing thoracic epidurals via a caudal approach. The use of a stimulating catheter offers the advantage of real-time confirmation of appropriate catheter placement. We hypothesize that the tip of a stimulating epidural catheter can be reliably advanced to the thoracic epidural space with lumbar insertion in a porcine model. METHODS: This prospective experimental porcine study evaluated the feasibility of placing the tip of a stimulating epidural catheter to a predefined thoracic epidural location after percutaneous lumbar epidural access in six live pigs. After the lumbar epidural space was accessed, a stimulating epidural catheter was advanced until the targeted thoracic myotome was stimulated. The final position of the catheter in relation to the targeted location was determined by fluoroscopy. All animals were euthanized at the end of the experiment, necropsy and spinal cord histology were then performed to assess the extent of spinal cord damage. RESULTS: In all animals the epidural catheter tip could be accurately advanced to the targeted thoracic myotome. Gross subdural bleeding occurred in three of the six animals and deep spinal damage was observed in two of the six animals. In one animal, the catheter was placed in the subarachnoid space. CONCLUSIONS: Accurate access to the thoracic epidural space is possible via a lumbar approach using a stimulating epidural catheter. Based on gross and histopathological examination, this technique resulted in frequent complications, including subdural hemorrhage, deep spinal cord damage, and subarachnoid catheter placement. PMID- 24482247 TI - Comparison of propofol and volatile agents for maintenance of anesthesia during elective craniotomy procedures: systematic review and meta-analysis. AB - BACKGROUND: Both propofol and volatile anesthetics are commonly used for maintenance of anesthesia in patients undergoing neurosurgical procedures. The effects of these two classes of drugs on cerebral hemodynamics have been compared in many clinical trials The objectives of this review were to evaluate the cerebral hemodynamic effects, operative conditions, recovery profiles, postoperative complications, and neurological outcomes of propofol-based vs volatile-based anesthesia for craniotomy. METHODS: MEDLINE(r), EMBASETM, Cochrane, and other relevant databases were searched for randomized controlled trials that compared propofol-maintained anesthesia with volatile-maintained anesthesia in adult patients undergoing elective craniotomy. The primary outcome measure was the intraoperative brain relaxation score. Secondary outcome measures included intraoperative cerebral hemodynamics (intracranial pressure [ICP], cerebral perfusion pressure [CPP]), cardiovascular changes, recovery profiles, postoperative complications, and clinical outcomes (neurological morbidity, mortality, quality of life). A meta-analysis was conducted using a random effects model to compare the outcomes of the two anesthetic techniques. RESULTS: Fourteen studies (1,819 patients) met inclusion criteria and were analyzed. Brain relaxation scores were similar between the two groups after dural opening; however, ICP was lower (weighted mean difference of -5.2 mmHg; 95% confidence interval -6.81 to -3.6) and CPP was higher (weighted mean difference of 16.3 mmHg; 95% confidence interval 12.2 to 20.46) in patients receiving propofol maintained anesthesia. Postoperative complications and recovery profiles were similar between the two groups, except for postoperative nausea and vomiting being less frequent with propofol-maintained anesthesia. There were inadequate data to perform a meta-analysis on clinical outcome. CONCLUSION: Propofol maintained and volatile-maintained anesthesia were associated with similar brain relaxation scores, although mean ICP values were lower and CPP values higher with propofol-maintained anesthesia. There are inadequate data to compare clinically significant outcomes such as neurological morbidity or mortality. PMID- 24482248 TI - The effect of cholesterol on membrane dynamics on different timescales in lipid bilayers from fast field-cycling NMR relaxometry studies of unilamellar vesicles. AB - The general applicability of fast field-cycling nuclear magnetic resonance relaxometry in the study of dynamics in lipid bilayers is demonstrated through analysis of binary unilamellar liposomes composed of 1,2-dioleoyl-sn-glycero-3 posphocholine (DOPC) and cholesterol. We extend an evidence-based method to simulating the NMR relaxation response, previously validated for single-component membranes, to evaluate the effect of the sterol molecule on local ordering and dynamics over multiple timescales. The relaxometric results are found to be most consistent with the partitioning of the lipid molecules into affected and unaffected portions, rather than a single averaged phase. Our analysis suggests that up to 25 mol%, each cholesterol molecule orders three DOPC molecules, providing experimental backup to the findings of many molecular dynamics studies. A methodology is established for studying dynamics on multiple timescales in unilamellar membranes of more complex compositions. PMID- 24482243 TI - Anti-angiogenic therapy for cancer: current progress, unresolved questions and future directions. AB - Tumours require a vascular supply to grow and can achieve this via the expression of pro-angiogenic growth factors, including members of the vascular endothelial growth factor (VEGF) family of ligands. Since one or more of the VEGF ligand family is overexpressed in most solid cancers, there was great optimism that inhibition of the VEGF pathway would represent an effective anti-angiogenic therapy for most tumour types. Encouragingly, VEGF pathway targeted drugs such as bevacizumab, sunitinib and aflibercept have shown activity in certain settings. However, inhibition of VEGF signalling is not effective in all cancers, prompting the need to further understand how the vasculature can be effectively targeted in tumours. Here we present a succinct review of the progress with VEGF-targeted therapy and the unresolved questions that exist in the field: including its use in different disease stages (metastatic, adjuvant, neoadjuvant), interactions with chemotherapy, duration and scheduling of therapy, potential predictive biomarkers and proposed mechanisms of resistance, including paradoxical effects such as enhanced tumour aggressiveness. In terms of future directions, we discuss the need to delineate further the complexities of tumour vascularisation if we are to develop more effective and personalised anti-angiogenic therapies. PMID- 24482249 TI - Allometry, merism, and tooth shape of the upper deciduous M2 and permanent M1. AB - The aims of this study were to investigate the effect of allometry on the shape of dm(2) and M(1) crown outlines and to examine whether the trajectory and magnitude of scaling are shared between species. The sample included 160 recent Homo sapiens, 28 Upper Paleolithic H. sapiens, 10 early H. sapiens, and 33 H. neanderthalensis (Neandertal) individuals. Of these, 97 were dm(2) /M(1) pairs from the same individuals. A two-block partial least squares analysis of paired individuals revealed a significant correlation in crown shape between dm(2) and M(1) . A principal component analysis confirmed that Neandertal and H. sapiens dm(2) and M(1) shapes differ significantly and that this difference is primarily related to hypocone size and projection. Allometry accounted for a small but significant proportion of the total morphological variance. We found the magnitude of the allometric effect to be significantly stronger in Neandertals than in H. sapiens. Procrustes distances were significantly different between the two tooth classes in Neandertals, but not among H. sapiens groups. Nevertheless, we could not reject the null hypothesis that the two species share the same allometric trajectory. Although size clearly contributes to the unique shape of the Neandertal dm(2) and M(1) , the largest H. sapiens teeth do not exhibit the most Neandertal-like morphology. Hence, additional factors must contribute to the differences in dm(2) and M(1) crown shape between these two species. We suggest an investigation of the role of timing and rate of development on the shapes of the dm(2) and M(1) may provide further answers. PMID- 24482250 TI - Diabetic retinopathy and pregnancy. AB - Diabetes mellitus and pregnancy have reciprocal influences between them, therefore diabetes mellitus may complicate the course of pregnancy as well as pregnancy can worsen the performance of diabetes especially at the fundus oculi. Several factors seem to play a role in retinal neovascularization. Actually it's not possible to understand the mechanisms underlying this progression. Moreover chronic hyperglycemia leads to several events such as: the activation of aldose reductase metabolic pathway, the activation of the diacylglycerol-protein kinase C, the non-enzymatic glycation of proteins with formation of advanced glycation endproducts and the increase of hexosamines pathway. Although every structure of the eye can be affected by diabetes, retinal tissue, with all its vessels, is particularly susceptible. Pregnancy may promote the onset of diabetic retinopathy, in about 10 % of cases, as well as contribute to its worsening when already present. The proliferative retinopathy must always be treated; treatment should be earlier in pregnant women compared to non-pregnant women. Pregnancy can also cause macular edema; it spontaneously regresses during the postpartum and therefore does not require immediate treatment. In summary, collaboration between the various specialists is primary to ensure the best outcomes for both mother's health and sight, and fetus' health. PMID- 24482256 TI - A new postural force production index to assess propulsion effectiveness during handcycling. AB - The aim of this study was to propose a new index called Postural Force Production Index (PFPI) for evaluating the force production during handcycling. For a given posture, it assesses the force generation capacity in all Cartesian directions by linking the joint configuration to the effective force applied on the handgrips. Its purpose is to give insight into the force pattern of handcycling users, and could be used as ergonomic index. The PFPI is based on the force ellipsoid, which belongs to the class of manipulability indices and represents the overall force production capabilities at the hand in all Cartesian directions from unit joint torques. The kinematics and kinetics of the arm were recorded during a 1-min exercise test on a handcycle at 70 revolutions per minute performed by one paraplegic expert in handcycling. The PFPI values were compared with the Fraction Effective Force (FEF), which is classically associated with the effectiveness of force application. The results showed a correspondence in the propulsion cycle between FEF peaks and the most favorable postures to produce a force tangential to the crank rotation (PFPI). This preliminary study opens a promising way to study patterns of force production in the framework of handcycling movement analysis. PMID- 24482258 TI - A computational fluid dynamics study of propulsion due to the orientation effects of swimmer's hand. AB - The aim of the article is to determine the hydrodynamic characteristics of a swimmer's scanned hand model for various possible combinations of both the angle of attack and the sweepback angle, simulating separate underwater arm stroke phases of front crawl swimming. An actual swimmer's hand with thumb adducted was scanned using an Artec L 3D scanner. ANSYS Fluent code was applied for carrying out steady-state computational fluid dynamics (CFD) analysis. The hand model was positioned in nine different positions corresponding to the swimmer's hand orientations (angle of attack and sweepback angle) and velocities observed during the underwater hand stroke of front crawl. Hydrodynamic forces and coefficients were calculated. Results showed significantly higher drag coefficient values in the pull phase, when compared with previous studies under a steady-state flow condition. The mean value of the ratio of drag and lift coefficients was 2.67 +/- 2.3 in underwater phases. The mean value of the ratio of drag and lift forces was 2.73 +/- 2.4 in underwater phases. Moreover, hydrodynamic coefficients were not almost constant throughout different flow velocities, and variation was observed for different hand positions corresponding to different stroke phases. The current study suggests that the realistic variation of both the orientation angles influenced higher values of drag, lift and resultant coefficients and forces. PMID- 24482259 TI - The development of a custom-built portable impact-testing device for assessing the cushioning properties of athletic socks. AB - Despite manufacturer claims that athletic socks attenuate force during exercise, no device exists to assess this. Therefore, this study outlines the development of a custom-built impact-testing device for assessing the cushioning properties of socks. The device used a gravity-driven impact striker (8.5 kg), released from 0.05 m, which impacted a no-sock, sock or a basic shoe/sock condition in the vertical axis. A load cell (10,000 Hz) assessed peak impact force, time to peak impact force and loading rate. Reliability was investigated between day, between trial and within trial. Excellent reliability (coefficient of variation < 5% adjusted for 95% confidence limits) was reported for peak impact force in all conditions, with no evidence of systematic bias. Good reliability (coefficient of variation < 10% adjusted for 68% confidence limits) was reported for time to peak impact force and loading rate with some evidence of systematic bias. It was concluded that the custom-built impact-testing device was reliable and sensitive for the measurement of peak impact force on socks. PMID- 24482260 TI - Studies on the antioxidant activities of some new chromone compounds. AB - Recent reviews evidence that the naturally occurring compounds containing the chromone skeleton exhibit antiradical activities, providing protection against oxidative stress. The antioxidant activities of 13 new synthesized chromonyl-2,4 thiazolidinediones, chromonyl-2,4-imidazolidinediones and chromonyl-2 thioxoimidzolidine-4-ones were evaluated using in vitro antioxidant assays, including superoxide anion radical (O2(-*)), hydroxyl radical (HO(*)), 2,2 diphenyl-1-picryl-hydrazyl free radical (DPPH(*)) scavenging capacity and total antioxidant capacity ferric ion reducing activity. Superoxide anion radical was produced using potassium superoxide/18-crown-6-ether dissolved in dimethylsulfoxide, and the Fenton-like reaction (Fe(II) + H2O2) was a generator of hydroxyl radicals. Chemiluminescence, spectrophotometry, electron paramagnetic resonance (EPR) and 5,5-dimethyl-1-pyrroline-N-oxide (DMPO) as the spin trap were the measurement techniques. The results showed that the majority of the chromone derivatives tested showed a strong scavenging effect towards free radicals, similar to the chemiluminescence reaction with superoxide anion radical with a high activity, inhibition of the DMPO-OOH radical EPR signal (24-58%), the DMPO OH radical EPR signal (4-75%) and DPPH radical EPR signal (6-100%) at 1 mmol/L. Several of the examined compounds exhibited the high reduction potentials. The results obtained show that the new synthesized chromone derivatives may directly scavenger reactive oxygen species and thus may play a protective role against oxidative damage. PMID- 24482261 TI - Gender and the experience of moral distress in critical care nurses. AB - BACKGROUND: Nursing practice is complex, as nurses are challenged by increasingly intricate moral and ethical judgments. Inadequately studied in underrepresented groups in nursing, moral distress is a serious problem internationally for healthcare professionals with deleterious effects to patients, nurses, and organizations. Moral distress among nurses has been shown to contribute to decreased job satisfaction and increased turnover, withdrawal from patients, physical and psychological symptoms, and intent to leave current position or to leave the profession altogether. RESEARCH QUESTION: Do significant gender differences exist in the moral distress scores of critical care nurses? RESEARCH DESIGN: This study utilized a quantitative, descriptive methodology to explore moral distress levels in a sample of critical care nurses to determine whether gender differences exist in their mean moral distress scores. PARTICIPANTS AND RESEARCH CONTEXT: Participants (n = 31) were critical care nurses from an American Internet nursing community who completed the Moral Distress Scale Revised online over a 5-day period in July 2013. ETHICAL CONSIDERATIONS: Institutional review board review approved the study, and accessing and completing the survey implied informed consent. FINDINGS: The results revealed a statistically significant gender difference in the mean moral distress scores of participants. Females reported statistically significantly higher moral distress scores than did males. Overall, the moral distress scores for both groups were relatively low. DISCUSSION: The findings of a gender difference have not previously been reported in the literature. However, other findings are consistent with previous studies on moral distress. CONCLUSION: Although the results of this study are not generalizable, they do suggest the need for continuing research on moral distress in underrepresented groups in nursing, including cultural and ethnic groups. PMID- 24482262 TI - Vocation and altruism in nursing: the habits of practice. AB - BACKGROUND: At a time when British nursing has been under scrutiny for an apparent lack of compassion in education and practice, this paper based offers a perspective on the notions of vocation and altruism in nursing. OBJECTIVES: To understand the vocational and altruistic motivations of nurses through the application of Pierre Bourdieu's concepts of 'symbolic capital', 'field' and 'habitus' through a long interview with nurse respondents. RESEARCH DESIGN: A reflexive qualitative study was undertaken using the long interview. A thematic analysis of the data, using a qualitative data software package for analysis, was undertaken. The ideas of Pierre Bourdieu (Habitus, Capital and Field) were used to analyse and explain the content of community nurses' 'talk'. PARTICIPANTS: Twelve Community Nurses working in a variety of local primary care settings volunteered to participate in the study. It was a self-selecting convenience sample of nurses responding to an invitation to be interviewed. RESEARCH CONTEXT: A study in support of a doctoral thesis conducted within NHS primary care settings with registered nurses. ETHICAL CONSIDERATIONS: The key considerations for this study were to be mindful of the possibility of emotional harm or distress being caused to the respondents during the retelling of their experiences. It was also essential to ensure that the locations or names of patients or staff (if discussed) were anonymised. Ethical approval was sought and granted by both the Local NHS Primary Care and the University Ethics committees before the study commenced. FINDINGS: The nurse respondents had highly individual and at times contradictory views on their motivations to nurse including their views on vocation and altruism in nursing careers. DISCUSSION: Bourdieu's ideas apply well to the nursing context and provided a useful theoretical framework to explore the social and cultural influences on nursing careers. Gender is important consideration in all aspects of nursing but class and educational experience is an important dimension in the stories nurses tell. CONCLUSION: The culturally determined experiences of these nurses in practice offer an authentic and realistic insight into the complex motives and predispositions of community nurses. This paper argues that nurse motivations whether vocational or altruistic, are better understood as culturally, rather than spiritually, driven. PMID- 24482263 TI - The development of the patient privacy scale in nursing. AB - BACKGROUND: The developments in technology and communication channels, increasing workload, and carelessness cause problems regarding patient privacy and confidentiality in nursing services. RESEARCH OBJECTIVES: The study was conducted to develop a patient privacy scale to identify whether nurses observe or violate patient privacy at workplace. RESEARCH DESIGN: This research was a methodological and descriptive study. PARTICIPANTS AND RESEARCH CONTEXT: Participants were 354 nurses working at private hospitals and hospitals affiliated with the Ministry of Health in Istanbul/Turkey. Data were collected with a questionnaire about the demographic characteristics of nurses and their opinions about patient privacy and with patient privacy scale. ETHICAL CONSIDERATIONS: After getting permission from the top management of hospitals, information about the study was given to nurses. Those willing to participate were informed that participation was voluntary and invited to give written consent before data collection. FINDINGS: The content validity index of scale was 0.91, Cronbach's alpha was 0.93, Spearman Brown and Guttman coefficients were 0.85, the upper and lower 27% test was 29.65, and item-total correlation values ranged from 0.47 to 0.71. The scale had five subscales. In addition, 49% of the nurses stated that patient privacy was always observed in their services/units. They appraised with a mean score of 4.51 +/- 0.49 for the total scale, 4.39 +/- 0.61 for confidentiality of personal information and private life, 4.39 +/- 0.70 for sexual privacy, 4.56 +/- 0.57 for the privacy of those unable to protect themselves, 4.60 +/- 0.59 for physical privacy, and 4.60 +/- 0.52 for ensuring a favorable environment. DISCUSSION: The findings of this study were in contrast with the results of some international studies which determined the violation of the patient privacy. CONCLUSION: The patient privacy scale is a valid and reliable tool to collect data on whether nurses observe or violate patient privacy, and the nurses generally reported observing or paying attention to patient privacy in all hospitals and especially private hospitals. PMID- 24482264 TI - Rapid identification of targeted transgene integrations in ES cells by fluorescence detection. AB - The generation of transgenic animals with a gain-of-function mutation is commonly achieved by procedures based on random DNA integration. The resulting transgenic founder lines are unique, not reproducible and have variable expression patterns. In contrast, the targeted integration of transgenes into a predetermined neutral genomic position solves most of the inadequacies of random integration methods. However, homologous recombination (HR) in mouse embryonic stem cells (ESCs) currently requires careful design of the targeting vector and a laborious procedure to identify clones with the correct insertion event. Here, we introduce a feasible strategy that employs a heterozygous double fluorescent reporter ESC line for simple identification of a knock-in HR event via detection of endogenous fluorescence expression. Following positive selection using antibiotics, the system offers a second selection step to identify targeted clones by the loss of one of two fluorescence reporters in lieu of the time consuming Southern blotting and PCR analysis routinely applied in conventional targeting experiments. Moreover, the method allows for the simple detection of chimerism (negating the need for appropriate coat colour combinations) and enables the early detection of germline transmission by fluorescence reporter expression in F1 neonates. PMID- 24482266 TI - Not enough skeletons in the closet: collections-based anatomical research in an age of conservation conscience. AB - The emergence of new technologies and improved computing power helped to introduce a renewed vitality in morphological research in recent decades. This is especially apparent in the new advances made in understanding the evolutionary morphology of the skeletal system in extinct and extant squamate reptiles. The new data generated as a result of the recent increase in attention are relevant not only for systematic analyses but also are valuable in their own right for contributing to holistic perspectives on organismal evolution, mosaic evolution in the rates of change in different anatomical systems, and broader patterns of macroevolution. A global community of morphological researchers now can share data through online digital collections, but opportunities for continued advance are hindered because we lack even basic data on patterns of variation of the skeletal system for virtually all squamate lineages. Most work on skeletal morphology of squamates is based on a sample size of n = 1; this is an especially noticeable phenomenon for studies relying on X-ray computed tomography technology. We need new collections of skeletal specimens, both material and digital, and new approaches to the study of skeletal morphology. Promising areas for continued research include the recent focus on skeletal elements not traditionally included in morphological studies (especially systematic analyses based upon morphological data) and efforts to elucidate patterns of variation and phylogenetically informative features of disarticulated skeletal elements. PMID- 24482265 TI - Large scale in-silico identification and characterization of simple sequence repeats (SSRs) from de novo assembled transcriptome of Catharanthus roseus (L.) G. Don. AB - Transcriptomic data of C. roseus offering ample sequence resources for providing better insights into gene diversity: large resource of genic SSR markers to accelerate genomic studies and breeding in Catharanthus . Next-generation sequencing is an efficient system for generating high-throughput complete transcripts/genes and developing molecular markers. We present here the transcriptome sequencing of a 26-day-old Catharanthus roseus seedling tissue using Illumina GAIIX platform that resulted in a total of 3.37 Gb of nucleotide sequence data comprising 29,964,104 reads which were de novo assembled into 26,581 unigenes. Based on similarity searches 58 % of the unigenes were annotated of which 13,580 unique transcripts were assigned 5016 gene ontology terms. Further, 7,687 of the unigenes were found to have Cluster of Orthologous Group classifications, and 4,006 were assigned to 289 Kyoto Encyclopedia of Genes and Genome pathways. Also, 5,221 (19.64 %) of transcripts were distributed to 81 known transcription factor (TF) families. In-silico analysis of the transcriptome resulted in identification of 11,004 SSRs in 26.62 % transcripts from which 2,520 SSR markers were designed which exhibited a non-random pattern of distribution. The most abundant was the trinucleotide repeats (AAG/CTT) followed by the dinucleotide repeats (AG/CT). Location specific analysis of SSRs revealed that SSRs were preferentially associated with the 5'-UTRs with a predicted role in regulation of gene expression. A PCR validation of a set of 48 primers revealed 97.9 % successful amplification, and 76.6 % of them showed polymorphism across different Catharanthus species as well as accessions of C. roseus. In summary, this study will provide an insight into understanding the seedling development and resources for novel gene discovery and SSR development for utilization in marker-assisted selective breeding in C. roseus. PMID- 24482267 TI - Force-spectrum relations for molecular optical force probes. AB - Force probes allow real-time monitoring of forces acting in different regions of large molecules and are potentially suited for the investigation of structural changes occurring in macromolecules during, e.g., folding processes. Such information is crucial for the understanding of mechanochemical reactivity. To this end, small molecular force probes can be incorporated into large molecules. Some of the available systems are based on mechanochromism, the change of the UV/Vis absorption spectrum of a molecule under mechanical stress. Herein we propose the idea of using molecular force probes in which the point-group symmetry is reduced as a result of mechanical deformation. This effect leads to significant and characteristic changes in the UV/Vis, IR, and Raman spectra of the deformed molecules, which were determined using computational methods. Beneficially, these changes are reversible and occur even if the applied forces are small. PMID- 24482268 TI - Breast milk concentrations of amiodarone, desethylamiodarone, and bisoprolol following short-term drug exposure: two case reports. AB - Two cases of mothers given postpartum short-term administration of amiodarone, with and without bisoprolol, are described along with determinations of amiodarone and (+/-)-bisoprolol in the breast milk. In one mother given a cumulative total of amiodarone of 8 g over 1 week, concentrations 11 days after the drug had been stopped were initially deemed sufficient to pose a risk to an infant. Over the next 5 days the concentrations steadily dropped with amiodarone and desethylamiodarone concentrations being found to be at a level comprising minimal risk to the infant. Bisoprolol was not found in the expressed breast milk. In the second case the mother was given a single 150 mg dose of amiodarone and breast milk concentrations were measured on postpartum days 4 and 5. Breast milk amiodarone concentrations were very low and of little concern clinically had the mother breast fed her baby. The risk to the baby of ingesting breast milk after amiodarone administration postpartum depends on the duration of amiodarone exposure, with a single dose posing minimal risk. Bisoprolol does not appear to accumulate to any great extent in breast milk. PMID- 24482269 TI - Ribonuclease in styles. AB - 1. Ribonuclease (RNase) activity in styles with conducting tissue is about 20 times higher than that of open styles with a stylar canal. 2. RNase activity is localized in or between the cells of the conducting tissue. 3. Activity is not influenced by pollination. 4. Stylar RNase has a temperature optimum at 45 degrees C and a pH optimum at pH 6.5. 5. Purification of RNase from Petunia styles showed the presence of 2-3 active fractions. 6. DEP, 10 MUg/ml is an efficient RNase inhibitor and its use helps in the isolation of polysomes from stylar tissue. PMID- 24482270 TI - Aspects of phytochrome decay in etiolated seedlings under continuous Illumination. AB - The rate of total phytochrome decay in the dicotyledons Amaranthus caudatus, Mirabilis jalapa and Pisum sativum under continuous illumination with red, incandescent, and blue light depends on the PFR/Ptotal maintained by each source. Amaranthus is an exception to this in that there is a deviation from firstorder decay kinetics under continuous illumination with incancdescent light. This deviation is probably not related to the chlorophyll present in the Amaranthus sample since chlorophyll-rich Pisum buds have the same phytochrome decay rate as epicotyl tissue under continuous incandescent light. Reports of a prolonged lag phase before the onset of first-order decay kinetics of phytochrome in Pisum have not been confirmed and the small lag phase observed in the present work can be accounted for by the time required to attain the PFR/Ptotal ratio characteristic of blue light in a carotenoid rich tissue. In the monocotyledon, Avena sativa, and perhaps monocotyledons in general, decay rate is maximal at a low PFR concentration and the decay curve is the same under continuous red, incandescent and blue light. This dicotyledon/monocotyledon difference with respect to saturation of phytochrome decay does not correlate with the other dicotyledon/monocotyledon difference, the presence or absence of dark reverions of PFR to PR, since the dicotyledons Amaranthus and Mirabilis that lack reversion still show no saturation of decay. Possible growth control by the PFR/Ptotal ratio is discussed in relation to environmental changes in light quality. PMID- 24482271 TI - Phaseic acid: Occurrence in cotton fruit; Acceleration of abscission. AB - Phaseic acid was tentatively identified in cotton fruit; this is the second report of its natural occurrence. It was found in cotton fruit of all ages, from very young to fully mature fruit. It accelerates abscission in the excised nodes of cotton seedlings, but has only about one-tenth of the abscission-promoting activity of abscisic acid. PMID- 24482272 TI - Electrical properties of parenchymal cell membranes in the oat coleoptile. AB - Parenchymal cells of oat (Avena sativa) coleoptiles had an osmotic concentration of 410 mM (determined by plasmolysis); of this only 22 mM was K(+) and 1 mM Na(+) (flame photometry). Cells were impaled with micropipette electrodes. Iontophoretic injection of the dye Niagara sky-blue from the micropipette showed that the tip of the electrode penetrated the vacuole. When sections of tissue were immersed in a solution of 22 mM KCl, 1 mM CaCl2, and 50 mM glucose, average membrane potential was found to be 38.5 mV inside negative specific membrane resistance was ~510 Omega cm(2), and specific membrane capacitance, ~2 MUf cm( 2). The cell membranes showed <25% retification and no electrical excitability. Electrotonic coupling of adjacent cells could not be demonstrated. PMID- 24482273 TI - Fine structure of abscission zones : IV. Effect of ethylene on the ultrastructure of abscission cells of tobacco flower pedicels. AB - The effect of ethylene on abscission of flower pedicels of tobacco plants has been investigated. For the first 2 h of exposure to C2H4, the pedicels bend rather than break in response to applied force, but after 2.5 h exposure they break at the abscission zone under an applied force of 40 g. The break strength of the abscission zone decreases exponentially with time to 5 g at 5 h after beginning of the C2H4 treatment. An examination of the tissue at the fine structural level 2 h after exposure to C2H4 reveals the accumulation of rough endoplasmic reticulum (RER) in the abscission cells. Rough ER becomes increasingly abundant by 3-5 h exposure of the tissue to C2H4. There is approximately a 30 fold increase in RER by 5 h of exposure, as compared to untreated tissue.Loss in the integrity of the membranes of microbodies occurs by 5 h exposure of the tissue to C2H4. As cell wall degradation proceeds, fibrous material, vesicular structures, and electron dense bodies-the latter often appearing striated-develop in the disintegrating wall. Little change is seen in the structure of nuclei, mitochondria, chloroplasts and in the crystalloid cores of microbodies during the first 5 h of exposure of the tissue to C2H4. However, disorganization of cytoplasmic components does occur in cells where cell wall breakdown is at an advanced stage. PMID- 24482274 TI - [Polysaccharide metabolism in the cell walls of growing Phaseolus aureus seedlings]. AB - Quantitative determinations of the cell wall constituents (pectin, hemicellulose and alpha-cellulose) of growing Phaseolus aureus seedlings showed marked changes during early growth. The cell walls of the 2 to 4 days old seedlings were composed of approximately 30% alpha-cellulose, 50% hemicelluloses and 20% pectin. After four weeks the proportion of the different fractions had changed to approximately 60% alpha-cellulose, 30% hemicelluloses and 10% pectin. Quantitative sugar determinations on these polysaccharide fractions have shown that mainly the non-cellulosic fractions (hemicelluloses and pectin) underwent considerable changes in sugar composition during growth. The hemicelluloses contained non-cellulosic polysaccharides with a high glucose content, which were not starch. These were broken down in the cell walls during growth.In a series of experiments in which (14)C-glucose was injected into the hypocotyls of four days old Phaseolus aureus seedlings, the transport of radioactivity to the different plant organs and its incorporation into the cell wall polysaccharides of the bean stem were studied. The major part of the radioactivity was incorporated into the cell wall of the stem tissue. Minor amounts were transported to the roots and leaves. Of the cell wall polysaccharides of the stem, the hemicellulosic fraction showed a higher rate of incorporation of the (14)C-glucose than the alpha cellulose in the early stages of growth. With increasing age of the plant, radioactivity was transferred from the hemicellulosic fraction to the alpha cellulose, suggesting turnover of polysaccharides in the growing cell wall. PMID- 24482275 TI - The effect of low temperature on sucrose, ATP and potassium concentrations and fluxes in the sieve tubes of willow. AB - Experiments have been performed on the effect of localised low (0 degrees C) temperature application on solute concentration and fluxes in the sieve elements of willow. Sieve tube exudate was obtained via the severed stylets of the aphid Tuberolachnus salignus (Gmelin). In stem segments, low temperature caused a fall in both the concentration and flux of sucrose. No recovery was observed during a 24 h cold application period. The concentrations of ATP and potassium were generally also reduced, though the effect on the fluxes of these solutes was not as marked. Both ATP and potassium appear to be translocated along the sieve tubes of stem segments as evidenced by girdling experiments. In leafy cuttings low temperature consistently reduced the concentration of sucrose in the sieve tube exudate. These data are discussed in relation to previous work on low temperature effects on the phloem transport system of willow. PMID- 24482276 TI - Effect of actinomycin D on the formation of enzymes in Jerusalem artichoke tuber slices. AB - The formation of both peroxidase and phenol oxidase was induced by culturing slices of Jerusalem artichoke tubers. Actinomycin D inhibited the formation of enzymes only when added before the termination of the lag phase (10 h after slicing). The data suggest that 4 to 6 h after slicing, tissues produce a mRNA which does not become fully operative until a translation mechanism has been activated. PMID- 24482277 TI - Evidence against an effect of plant hormones on thermal denaturation of pea nucleoprotein. AB - Pea (Pisum sativum L.) nucleohistone and chromatin which had been treated both in vivo and in vitro with indoleacetic acid and gibberellic acid were thermally denatured in low and high ionic strength media. Contrary to previous reports, the hormones had no effect on thermal denaturation profiles. The previously observed biphasic nature of the profiles obtained at high ionic strength is explained. PMID- 24482278 TI - A distinction between the actions of abscisic acid, gibberellic acid and cytokinins in light-sensitive lettuce seed. AB - Using isolated lettuce seed embryos it can be shown that the inhibitory effect of abscisic acid upon germination is reversed solely by cytokinin. In the intact seed, however, gibberellic acid is also required for this reversal to be manifested in germination. PMID- 24482279 TI - Synergism between cytokinins and nitrate in induction of nitrate reductase activity in fenugreek cotyledons. PMID- 24482280 TI - Clinical value of dna content assessment in endometrial cancer. AB - Endometrial carcinoma (EC) is the most common gynecologic cancer in industrialized countries. Traditional prognostic markers include FIGO stage, histologic subtype and histologic grade. DNA ploidy was introduced as a prognostic marker 30 years ago, and the majority of published literature demonstrates significant associations between tumor aneuploidy and poorer prognosis in EC. However, ploidy analysis is not routinely implemented in the clinic. We reviewed the literature on clinical value of ploidy measured by DNA content as a prognostic marker, and its potential role as a predictive marker in EC. PubMed was searched for papers evaluating the prognostic or predictive role of ploidy in EC. Search criteria were "DNA ploidy prognosis/predictive value endometrial cancer/carcinoma". Only articles written in English, published year 2000 or later were included. The majority of the studies demonstrated highly significant correlation between DNA index (DI) and survival, in univariate analysis including stages I-IV, and in subgroup analysis of stage I and stage I II EC. Several studies also showed significant association between DI and survival in multivariate analysis. Few studies have evaluated DI as a prognostic marker in a prospective setting. No studies evaluating DI as a predictive marker in EC were identified. In other cancer types, ploidy has been linked to prediction of response to hormonal therapy and chemotherapy. Ploidy assessment in EC by DI is a strong prognostic marker. Still, its clinical applicability needs validation in a routine diagnostic, prospective setting with sufficient number of patients, characterized by state of the art histopathological evaluation and surgical staging. (c) 2014 Clinical Cytometry Society. PMID- 24482281 TI - The relationship of freeze tolerance with intracellular compounds in baker's yeasts. AB - Freeze-tolerant baker's yeasts are required for the processing of frozen doughs. The present study was carried out to investigate the cell survival rate after frozen storage and the change of fermentability in dough due to frozen storage, and to discuss quantitatively the relationship of freeze tolerance with intracellular trehalose, amino acids, and glycerol, using six types of baker's yeasts as the test materials. The experimental results showed that the fermentability of yeast cells in frozen dough was strongly correlated with the cell survival rate. The baker's yeast with a higher level of cell survival rate had a larger increase in the total intracellular compound content after frozen storage, and the cell survival rate increased linearly with increasing total intracellular compound content in frozen yeast cells. Trehalose was a primary compound affecting freeze tolerance, followed by glutamic acid, arginine, proline, asparagic acid, and glycerol. The basic information provided by the present study is useful for exploring the freeze-tolerance mechanisms of baker's yeast cells, breeding better freeze-tolerant baker's yeast strains, and developing more effective cryoprotectants. PMID- 24482282 TI - Identification of potential vaccine candidates against Streptococcus pneumoniae by reverse vaccinology approach. AB - In the past few decades, genome-based approaches have contributed significantly to vaccine development. Our aim was to identify the most conserved and immunogenic antigens of Streptococcus pneumoniae, which can be potential vaccine candidates in the future. BLASTn was done to identify the most conserved antigens. PSORTb 3.0.2 was run to predict the subcellular localization of the proteins. B cell epitope prediction was done for the immunogenicity testing. Finally, BLASTp was done for verifying the extent of similarity to human proteome to exclude the possibility of autoimmunity. Proteins failing to comply with the set parameters were filtered at each step. Based on the above criteria, out of the initial 22 pneumococcal proteins selected for screening, pavB and pullulanase were the most promising candidate proteins. PMID- 24482283 TI - Enantioselective total synthesis of dysidavarone A, a novel sesquiterpenoid quinone from the marine sponge Dysidea avara. AB - Dysidavarone A, a structurally unprecedented sesquiterpenoid quinone, was synthesized in 30 % overall yield in a longest liner sequence of 13 steps from commercially available o-vanillin. A highly strained and bridged eight-membered carbocyclic core was established by the C7-C21 carbon bond formation through a copper enolate mediated Michael addition to the internal quinone ring. PMID- 24482284 TI - Neurally adjusted ventilatory assist (NAVA) in pediatric intensive care--a randomized controlled trial. AB - BACKGROUND: Neurally adjusted ventilatory assist (NAVA) has been shown to improve patient-ventilator synchrony during invasive ventilation. The aim of this trial was to study NAVA as a primary ventilation mode in pediatric intensive care and to compare it with current standard ventilation modes. METHODS: One hundred seventy pediatric intensive care patients were randomized to conventional ventilation or NAVA. The primary endpoints were time on the ventilator and the amount of sedation needed. To enable comparison between sedative agents, a "sedative unit" was defined for each drug. RESULTS: The median time on the ventilator was 3.3 hr in the NAVA group and 6.6 hr in the control group (P = 0.17), and the length of stay in the PICU 49.5 hr in the NAVA group and 72.8 hr in the control group (P = 0.10, per protocol P = 0.03). The amount of sedation needed in the total patient population did not differ between the groups (P = 0.20), but when postoperative patients were excluded (19 vs. 20 patients), the amount was significantly lower in the NAVA group (0.80 vs. 2.23 units/hr, P = 0.03). Lower peak inspiratory pressure and a lower inspired oxygen fraction were found in the NAVA group (P = 0.001 for both). Arterial blood CO2 tensions were slightly higher in the NAVA group up to 32 hr of treatment (P = 0.008). There were no significant differences in the other ventilatory or vital parameters, arterial blood gas values or complications. CONCLUSIONS: We found NAVA to be a safe and feasible primary ventilation mode for use with children. It outscored standard ventilation in some aspects, as it was able to enhance oxygenation even at lower airway pressures and led to reduced use of sedatives during longer periods of treatment. PMID- 24482286 TI - The impact of legislative standards on batterer intervention program practices and characteristics. AB - Changes in social policy are often pursued with the goal of reducing a social problem by improving prevention efforts, intervention program practices, or participant outcomes. State legislative standards for intimate partner violence intervention programs have been adopted nearly universally across the US, however, we do not know whether such standards actually achieve the intended goal of affecting programs' policies and practices. To assess the effect that batterer intervention program (BIP) standards have on policies and practices of programs, this study used longitudinal surveys collected as part of an ongoing evaluation conducted from 2001 to the present to compare intervention program (N = 74) characteristics and practices at three time points before and after the adoption of standards in Oregon. Analyses were conducted to examine all BIPs in Oregon at each time point, as well as change among a subset of programs in existence at all survey assessments. Results indicate that across all programs, the use of mixed gender group co-facilitation increased by 14% between 2004 and 2008, while program length increased by approximately 12 weeks. However, other practices such as programs' coordination with community partners were unchanged. Analyses of within-program change revealed fewer differences, with only program length increasing significantly over the three assessments. These and other findings indicate that while standards affected program length as intended, other practices commonly addressed by legislative standards remained unchanged. The findings provide needed information regarding programs' compliance with components of the standards, the potential need for compliance monitoring, and the potential impact of state standards on program effectiveness and on the prevalence of intimate partner violence. PMID- 24482285 TI - CD40 signaling drives B lymphocytes into an intermediate memory-like state, poised between naive and plasma cells. AB - Immunological memory comprising of antigen-specific B and T cells contributes to the acquisition of long-term resistance to pathogens. Interactions between CD40 on B cells and CD40L on T cells are responsible for several aspects of acquired immune responses including generation of memory B cells. In order to gain insights into events leading to memory B cell formation, we analyzed the genome wide expression profile of murine naive B cells stimulated in the presence of anti-CD40. We have identified over 8,000 genes whose expression is altered minimally 1.5-fold at least at one time point over a 3-day time course. The array analysis indicates that changes in expression level of maximum number of these genes occur within 24 h of anti-CD40 treatment. In parallel, we have studied the events following CD40 ligation by examining the expression of known regulators of naive B cell to plasma cell transition, including Pax5 and BLIMP1. The expression profile of these regulatory genes indicates firstly, that CD40 signaling activates naive B cells to a phenotype that is intermediate between the naive and plasma cell stages of the B cell differentiation. Secondly, the major known regulator of plasma cell differentiation, BLIMP1, gets irreversibly downregulated upon anti-CD40 treatment. Additionally, our data reveal that CD40 signaling mediated BLIMP1 downregulation occurs by non-Pax5/non-Bcl6 dependent mechanisms, indicating novel mechanisms at work that add to the complexity of understanding of B cell master regulatory molecules like BLIMP1 and Pax5. PMID- 24482287 TI - Adipocytes derived from PA6 cells reliably promote the differentiation of dopaminergic neurons from human embryonic stem cells. AB - The PA6 stromal cell line comprises a heterogeneous population of cells that can induce both mouse and human embryonic stem cells to differentiate into dopaminergic neurons. This ability of PA6 cells has been termed stromal cell derived inducing activity (SDIA). The level of SDIA has been found to vary considerably between and within batches of PA6 cells. Not only are the molecular mechanisms that underlie SDIA unknown but also the cell type(s) within the heterogeneous PA6 cultures that underlie SDIA remain poorly defined. In this study, we reveal that adipocytes, which are present within the heterogeneous PA6 cell population, robustly release the factors mediating SDIA. Furthermore, we report that the coculture of human embryonic stem cells with PA6-derived adipocytes reliably induces their differentiation into midbrain dopaminergic neurons. PMID- 24482289 TI - How to use antistreptolysin O titre. AB - Group A streptococcus (GAS) is the cause of a wide range of acute suppurative and, following a latent period, non-suppurative diseases such as rheumatic fever and poststreptococcal glomerulonephritis. Diagnosis of the latter group requires evidence of preceding GAS infection. The bacteria produce a range of extracellular antigens, including streptolysin O, which induce an antibody response in the host. A rise in antistreptolysin O titre (ASOT) is indicative of preceding GAS infection. In clinical practice, often only a single ASOT measurement is available and its timing in relation to a possible GAS infection is unknown. Interpretation of the result in this context is liable to misdiagnosis. In order to optimise diagnosis of preceding GAS infection, at least two sequential ASOT measurements, together with simultaneous assay for anti-DNase B, a second antistreptococcal antibody, is recommended. PMID- 24482290 TI - Birth month associations with height, head circumference, and limb lengths among Peruvian children. AB - Associations between season of birth and body size, morbidity, and mortality have been widely documented, but it is unclear whether different parts of the body are differentially sensitive, and if such effects persist through childhood. This may be relevant to understanding the relationship between early life environment and body size and proportions. We investigated associations between birth month and anthropometry among rural highland (n = 162) and urban lowland (n = 184) Peruvian children aged 6 months to 8 years. Stature; head-trunk height; total limb, ulna, tibia, hand, and foot lengths; head circumference; and limb measurements relative to head-trunk height were converted to internal age-sex-specific z scores. Lowland and highland datasets were then analyzed separately for birth month trends using cosinor analysis, as urban conditions likely provide a more consistent environment compared with anticipated seasonal variation in the rural highlands. Among highland children birth month associations were significant most strongly for tibia length, followed by total lower limb length and stature, with a peak among November births. Results were not significant for other measurements or among lowland children. The results suggest a prenatal or early postnatal environmental effect on growth that is more marked in limb lengths than trunk length or head size, and persists across the age range studied. We suggest that the results may reflect seasonal variation in maternal nutrition in the rural highlands, but other hypotheses such as variation in maternal vitamin D levels cannot be excluded. PMID- 24482291 TI - Genetic diversity of 3' region of glycoprotein D gene of bovine herpesvirus 1 and 5. AB - Bovine herpesviruses 1 (BoHV-1) and 5 (BoHV-5) are closely related alphaherpesviruses of cattle. While BoHV-1 is mainly associated with respiratory/genital disease and rarely associated with neurological disease, BoHV 5 is the primary agent of meningoencephalitis in cattle. The envelope glycoprotein D of alphaherpesviruses (BoHV-1/gD1 and BoHV-5/gD5) is involved in the early steps of virus infection and may influence virus tropism and neuropathogenesis. This study performed a sequence analysis of the 3' region of gD gene (gD3') of BoHV-1 isolates recovered from respiratory/genital disease (n = 6 and reference strain Cooper) or from neurological disease (n = 7); and from seven typical neurological BoHV-5 isolates. After PCR amplification, nucleotide (nt) sequencing, and aminoacid (aa) sequence prediction; gD3' sequences were compared, identity levels were calculated, and selective pressure was analyzed. The phylogenetic reconstruction based on nt and aa sequences allowed for a clear differentiation of BoHV-1 (n = 14) and BoHV-5 (n = 7) clusters. The seven BoHV-1 isolates from neurological disease are grouped within the BoHV-1 branch. A consistent alignment of 346 nt revealed a high similarity within each viral species (gD1 = 98.3 % nt and aa; gD5 = 97.8 % nt and 85.8 % aa) and an expected lower similarity between gD1 and gD5 (73.7 and 64.1 %, nt and aa, respectively). The analysis of molecular evolution revealed an average negative selection at gD3'. Thus, the phylogeny and similarity levels allowed for differentiation of BoHV-1 and BoHV-5 species, but not further division in subspecies. Sequence analysis did not allow for the identification of genetic differences in gD3' potentially associated with the respective clinical/pathological phenotypes, yet revealed a lower level of gD3' conservation than previously reported. PMID- 24482293 TI - Maternal residential proximity to sources of extremely low frequency electromagnetic fields and adverse birth outcomes in a UK cohort. AB - Studies have suggested that exposure to extremely low frequency electromagnetic fields (ELF-EMF) may be associated with increased risk of adverse birth outcomes. This study tested the hypothesis that close proximity to residential ELF-EMF sources is associated with a reduction in birth weight and increased the risk of low birthweight (LBW), small for gestational age (SGA) and spontaneous preterm birth (SPTB). Closest residential proximity to high voltage cables, overhead power lines, substations or towers during pregnancy was calculated for 140356 singleton live births between 2004 and 2008 in Northwest England. Associations between proximity and risk for LBW, SGA and SPTB were calculated, as well as associations with birth weight directly. Associations were adjusted for maternal age, ethnicity, parity and for part of the population additionally for maternal smoking during pregnancy. Reduced average birth weight of 212 g (95% confidence interval (CI): -395 to -29 g) was found for close proximity to a source, and was largest for female births (-251 g (95% CI: -487 to -15 g)). No statistically significant increased risks for any clinical birth outcomes with residential proximity of 50 m or less were observed. Living close (50 m or less) to a residential ELF-EMF source during pregnancy is associated with suboptimal growth in utero, with stronger effects in female than in males. However, only a few pregnant women live this close to high voltage cables, overhead power lines, substations or towers, likely limiting its public health impact. PMID- 24482292 TI - Vocal patterns in infants with autism spectrum disorder: canonical babbling status and vocalization frequency. AB - Canonical babbling is a critical milestone for speech development and is usually well in place by 10 months. The possibility that infants with autism spectrum disorder (ASD) show late onset of canonical babbling has so far eluded evaluation. Rate of vocalization or "volubility" has also been suggested as possibly aberrant in infants with ASD. We conducted a retrospective video study examining vocalizations of 37 infants at 9-12 and 15-18 months. Twenty-three of the 37 infants were later diagnosed with ASD and indeed produced low rates of canonical babbling and low volubility by comparison with the 14 typically developing infants. The study thus supports suggestions that very early vocal patterns may prove to be a useful component of early screening and diagnosis of ASD. PMID- 24482294 TI - Organozinc pivalate reagents: segregation, solubility, stabilization, and structural insights. AB - The pivalates RZnOPiv?Mg(OPiv)X?n LiCl (OPiv=pivalate; R=aryl; X=Cl, Br, I) stand out amongst salt-supported organometallic reagents, because apart from their effectiveness in Negishi cross-coupling reactions, they show more resistance to attack by moist air than conventional organometallic compounds. Herein a combination of synthesis, coupling applications, X-ray crystallographic studies, NMR (including DOSY) studies, and ESI mass spectrometric studies provide details of these pivalate reagents in their own right. A p-tolyl case system shows that in [D8]THF solution these reagents exist as separated Me(p-C6H4)ZnCl and Mg(OPiv)2 species. Air exposure tests and X-ray crystallographic studies indicate that Mg(OPiv)2 enhances the air stability of aryl zinc species by sequestering H2O contaminants. Coupling reactions of Me(p-C6H4)ZnX (where X=different salts) with 4-bromoanisole highlight the importance of the presence of Mg(OPiv)2. Insight into the role of LiCl in these multicomponent mixtures is provided by the molecular structure of [(THF)2Li2(Cl)2(OPiv)2Zn]. PMID- 24482295 TI - Relict endemism of extant Rhineuridae (Amphisbaenia): testing for phylogenetic niche conservatism in the fossil record. AB - Rhineurid amphisbaenians are represented by a rich Cenozoic fossil record in North America, but today conisist of a single living species restricted to the Florida Peninsula. Such relict endemism may be the result of phylogenetic niche conservatism (PNC), the retention of ancestral traits preventing expansion into new environments. Most tests of PNC derive ancestral niche preferences from species' extant ecologies, while ignoring valuable paleontological information. To test if PNC contributes to the restricted distribution of modern Rhineura floridana, we compare the species' current environmental preferences (temperature, precipitation and soil) to paleoenvironmental data from the rhineurid fossil record. We find no evidence of PNC in modern R. floridana, as it also occurred in Florida during drier glacial periods. Ancient rhineurids also exhibit tolerance to changing climates, having undergone a shift from subtropical humid to semi-arid savanna conditions during the Eocene-Oligocene transition. However, rhineurids nearly disappear from North America after the middle Miocene, potentially due to the onset of prolonged freezing temperatures following the mid Miocene Climatic Optimum. This physiological limit of environmental tolerances could be interpreted as PNC for the entire family, but also characterizes much of Amphisbaenia, emphasizing the relevance of the temporal as well as phylogenetic scale at which PNC is investigated. PMID- 24482296 TI - A tetrapod-like repertoire of innate immune receptors and effectors for coelacanths. AB - The recent availability of both robust transcriptome and genome resources for coelacanth (Latimeria chalumnae) has led to unique discoveries for coelacanth immunity such as the lack of IgM, a central component of adaptive immunity. This study was designed to more precisely address the origins and evolution of gene families involved in the initial recognition and response to microbial pathogens, which effect innate immunity. Several multigene families involved in innate immunity are addressed, including: Toll-like receptors (TLRs), retinoic acid inducible gene 1 (RIG1)-like receptors (RLRs), the nucleotide-binding domain and leucine-rich repeat containing proteins (NLRs), diverse immunoglobulin domain containing proteins (DICP) and modular domain immune-type receptors (MDIRs). Our analyses also include the tripartite motif-containing proteins (TRIM), which are involved in pathogen recognition as well as the positive regulation of antiviral immunity. Finally, this study addressed some of the downstream effectors of the antimicrobial response including IL-1 family members, type I and II interferons (IFN) and IFN-stimulated effectors (ISGs). Collectively, the genes and gene families in coelacanth that effect innate immune functions share characteristics both in content, structure and arrangement with those found in tetrapods but not in teleosts. The findings support the sister group relationship of coelacanth fish with tetrapods. PMID- 24482297 TI - Alteration of select gene expression patterns in individuals infected with HIV-1. AB - Multiple human proteins have been shown to both support and restrict viral replication, and confirmation of virus-associated changes in the expression of these genes is relevant for future therapeutic efforts. In this study a well characterized panel of 49 individuals either infected with HIV-1 or uninfected was compiled and analyzed for the effect of HIV infection status, viral load, and antiretroviral treatment on specific gene expression. mRNA was extracted and reverse transcribed from purified CD4+ cells, and quantitative real-time PCR was utilized to scrutinize differences in the expression of four host genes that have been demonstrated to either stimulate (HSP90 and LEDGF/p75) or restrict (p21/WAF1 and APOBEC3G) proviral integration. HIV infection status was associated with slight to moderate alterations in the expression of all four genes. After adjusting for age, mRNA expression levels of HSP90, LEDGF/p75 and APOBEC3G were found to all be decreased in infected patients compared to healthy controls by 1.43-, 1.26-, and 4.71-fold, respectively, while p21/WAF1 expression was increased 2.35-fold. Furthermore, individuals receiving raltegravir exhibited a 1.28-fold reduction in LEDGF/p75 compared to those on non-raltegravir antiretroviral treatment. Identification of these and similar HIV-induced changes in gene expression may be valuable for delineating the extent of host cell molecular mechanisms stimulating viral replication. PMID- 24482298 TI - Lower Limb Movement Preparation in Chronic Stroke: A Pilot Study Toward an fNIRS BCI for Gait Rehabilitation. AB - Background Thus far, most of the brain-computer interfaces (BCIs) developed for motor rehabilitation used electroencephalographic signals to drive prostheses that support upper limb movement. Only few BCIs used hemodynamic signals or were designed to control lower extremity prostheses. Recent technological developments indicate that functional near-infrared spectroscopy (fNIRS)-BCI can be exploited in rehabilitation of lower limb movement due to its great usability and reduced sensitivity to head motion artifacts. Objective The aim of this proof of concept study was to assess whether hemodynamic signals underlying lower limb motor preparation in stroke patients can be reliably measured and classified. Methods fNIRS data were acquired during preparation of left and right hip movement in 7 chronic stroke patients. Results Single-trial analysis indicated that specific hemodynamic changes associated with left and right hip movement preparation can be measured with fNIRS. Linear discriminant analysis classification of totHB signal changes in the premotor cortex and/or posterior parietal cortex indicated above chance accuracy in discriminating paretic from nonparetic movement preparation trials in most of the tested patients. Conclusion The results provide first evidence that fNIRS can detect brain activity associated with single-trial lower limb motor preparation in stroke patients. These findings encourage further investigation of fNIRS suitability for BCI applications in rehabilitation of patients with lower limb motor impairment after stroke. PMID- 24482299 TI - The complete mitochondrial genome of Cervaphis quercus (Insecta: Hemiptera: Aphididae: Greenideinae). AB - The mitochondrial genome of Cervaphis quercus has been sequenced and annotated. The entire genome of 15,272 bp encodes two ribosomal RNA genes (rrnL and rrnS), 22 transfer RNA (tRNA) genes, 13 protein-coding genes and a control region. The genome has the same gene order as that found in the inferred ancestral insect. Nucleotide composition is highly A+T biased. All protein-coding genes use standard mitochondrial initiation codons. Secondary structure models of the two ribosomal RNA genes of C. quercus are similar to those proposed for other insects. All tRNAs have the classic clover-leaf structure, except for the dihydrouridine (DHU) arm of trnS (AGN), which forms a simple loop. The presence of structural elements in the control region is also discussed, with an emphasis on the possible regulation of replication and/or transcription. Comparison with mitochondrial genomes of other aphid species shows their gene arrangements are conserved; however, the variety of repeat regions in species from a different aphid subfamily, Aphidinae, suggests that they resulted from independent evolutionary events. PMID- 24482300 TI - Response to letter by Aramugakani et al. PMID- 24482302 TI - The global burden of neck pain: estimates from the global burden of disease 2010 study. AB - OBJECTIVE: To estimate the global burden of neck pain. METHODS: Neck pain was defined as pain in the neck with or without pain referred into one or both upper limbs that lasts for at least 1 day. Systematic reviews were performed of the prevalence, incidence, remission, duration and mortality risk of neck pain. Four levels of severity were identified for neck pain with and without arm pain, each with their own disability weights. A Bayesian meta-regression method was used to pool prevalence and derive missing age/sex/region/year values. The disability weights were applied to prevalence values to derive the overall disability of neck pain expressed as years lived with disability (YLDs). YLDs have the same value as disability-adjusted life years as there is no evidence of mortality associated with neck pain. RESULTS: The global point prevalence of neck pain was 4.9% (95% CI 4.6 to 5.3). Disability-adjusted life years increased from 23.9 million (95% CI 16.5 to 33.1) in 1990 to 33.6 million (95% CI 23.5 to 46.5) in 2010. Out of all 291 conditions studied in the Global Burden of Disease 2010 Study, neck pain ranked 4th highest in terms of disability as measured by YLDs, and 21st in terms of overall burden. CONCLUSIONS: Neck pain is a common condition that causes substantial disability. With aging global populations, further research is urgently needed to better understand the predictors and clinical course of neck pain, as well as the ways in which neck pain can be prevented and better managed. PMID- 24482301 TI - Efficacy and safety of the anti-IL-12/23 p40 monoclonal antibody, ustekinumab, in patients with active psoriatic arthritis despite conventional non-biological and biological anti-tumour necrosis factor therapy: 6-month and 1-year results of the phase 3, multicentre, double-blind, placebo-controlled, randomised PSUMMIT 2 trial. AB - OBJECTIVE: Assess ustekinumab efficacy (week 24/week 52) and safety (week 16/week 24/week 60) in patients with active psoriatic arthritis (PsA) despite treatment with conventional and/or biological anti-tumour necrosis factor (TNF) agents. METHODS: In this phase 3, multicentre, placebo-controlled trial, 312 adults with active PsA were randomised (stratified by site, weight (<=100 kg/>100 kg), methotrexate use) to ustekinumab 45 mg or 90 mg at week 0, week 4, q12 weeks or placebo at week 0, week 4, week 16 and crossover to ustekinumab 45 mg at week 24, week 28 and week 40. At week 16, patients with <5% improvement in tender/swollen joint counts entered blinded early escape (placebo->45 mg, 45 mg->90 mg, 90 mg >90 mg). The primary endpoint was >=20% improvement in American College of Rheumatology (ACR20) criteria at week 24. Secondary endpoints included week 24 Health Assessment Questionnaire-Disability Index (HAQ-DI) improvement, ACR50, ACR70 and >=75% improvement in Psoriasis Area and Severity Index (PASI75). Efficacy was assessed in all patients, anti-TNF-naive (n=132) patients and anti TNF-experienced (n=180) patients. RESULTS: More ustekinumab-treated (43.8% combined) than placebo-treated (20.2%) patients achieved ACR20 at week 24 (p<0.001). Significant treatment differences were observed for week 24 HAQ-DI improvement (p<0.001), ACR50 (p<=0.05) and PASI75 (p<0.001); all benefits were sustained through week 52. Among patients previously treated with >=1 TNF inhibitor, sustained ustekinumab efficacy was also observed (week 24 combined vs placebo: ACR20 35.6% vs 14.5%, PASI75 47.1% vs 2.0%, median HAQ-DI change -0.13 vs 0.0; week 52 ustekinumab-treated: ACR20 38.9%, PASI75 43.4%, median HAQ-DI change -0.13). No unexpected adverse events were observed through week 60. CONCLUSIONS: The interleukin-12/23 inhibitor ustekinumab (45/90 mg q12 weeks) yielded significant and sustained improvements in PsA signs/symptoms in a diverse population of patients with active PsA, including anti-TNF-experienced PsA patients. PMID- 24482304 TI - Nanoparticle doping in nematic liquid crystals: distinction between surface and bulk effects by numerical simulations. AB - Doping nematic liquid crystals with small amounts of nanoparticles can significantly alter the electro-optic response of the nematic host. Some of these effects result from nanoparticles influencing the liquid crystal/substrate interface, while other effects are caused by nanoparticles in the bulk. So far, little attention has been paid to the influence of surface interactions on the determination of bulk properties. In the present study, these effects are investigated experimentally and confirmed by numerical simulations. The splay type Freedericksz-transition of the nematic liquid crystal 5CB doped with CdSe quantum dots is investigated, as these dispersions are known from earlier studies to affect the initial alignment layers. In comparison, dispersions of chemically and thermally stable silanized gold nanoparticles in the apolar nematic host FELIX-2900-03 are analyzed, which are expected to be bulk-active only. A data fitting routine is presented which allows a distinction between bulk and surface effects of nanoparticle doping. For the quantum dots, an increase of pretilt angle proportional to the doping concentration is found, as well as a slight decrease of the anchoring energy of molecules at the confining substrates. The silanized gold particles show no influence on the boundary conditions up to doping concentrations of 2.5 % (w). For higher concentrations an increase of pretilt angle is reported. PMID- 24482303 TI - Contrast coating for the surface of flat polyps at CT colonography: a marker for detection. AB - OBJECTIVES: To assess the frequency of oral contrast coating of flat polyps, which may promote detection, and influencing factors within a screening CT colonography (CTC) population. METHODS: This was a retrospective, observational study performed at one institution. From 7,426 individuals, 123 patients with 160 flat polyps were extracted. Flat polyps were defined as plaque-like, raised at most 3 mm in height and reviewed for contrast coating. Factors including demographic variables such as age and sex, and polyp variables such as polyp size, location and histology were analysed for effect on coating. RESULTS: Of 160 flat polyps (mean size 9.4 mm +/- 3.6), 78.8 % demonstrated coating. Mean coat thickness was 1.5 mm +/- 0.6; 23.8 % (n = 30) demonstrated a thin film of contrast. Large size (>=10 mm) and proximal colonic location (relative to splenic flexure) were predictive variables by univariate logistic regression [OR (odds ratio) 3.4 (CI 1.3-8.9; p = 0.011), 2.0 (CI 1.2-3.5; p = 0.011), respectively]. Adenomas (OR 0.37, CI 0.14-1.02; p = 0.054) and mucosal polyps or venous blebs (OR 0.07, CI 0.02-0.25; p < 0.001) were less likely to coat than serrated/hyperplastic lesions. Age and sex were not predictive for coating (p = 0.417, p = 0.499, respectively). CONCLUSIONS: Surface contrast coating is common for flat polyps at CTC, promoted by large size, proximal location and serrated/hyperplastic histology. Given the difficulty in detection, recognition may aid in flat polyp identification. KEY POINTS: * Oral contrast coats the surface of most flat colorectal polyps at CT colonography. * Large size, proximal colonic location and serrated/hyperplastic histology increase polyp coating. * Contrast coating increases diagnostic confidence for flat polyps. * Contrast coating may help in flat polyp detection at CTC. PMID- 24482305 TI - Curcumin ameliorates rat experimental autoimmune neuritis. AB - Experimental autoimmune neuritis (EAN) is a helper T cell-mediated autoimmune demyelinating inflammatory disease of the peripheral nervous system that serves as an animal model for human Guillain-Barre syndrome. Curcumin, a naturally occurring polyphenolic phytochemical isolated from the medicinal plant Curcuma longa, has anti-inflammatory activities. Here we investigated the therapeutic effects and potential mechanisms of curcumin in EAN rats. Exogenous curcumin treatment (100 mg/kg/day) significantly delayed the onset of EAN neurological signs, ameliorated EAN neurological severity, and reduced body weight loss of EAN rats. In EAN sciatic nerves, curcumin treatment suppressed the inflammatory cell accumulation and the expression of interferon (IFN)-gamma, tumor necrosis factor alpha, interleukin (IL)-1beta, and IL-17. Furthermore, curcumin treatment significantly decreased the percentage of CD4(+) T helper cells in EAN spleen and suppressed concanavalin A-induced lymphocyte proliferation in vitro. In addition, curcumin altered helper T cell differentiation by decreasing IFN-gamma(+) CD4(+) Th1 cells in EAN lymph node and spleen. In summary, our data demonstrate that curcumin could effectively suppress EAN by attenuating inflammation, indicating that curcumin might be a candidate for treatment of autoimmune neuropathies. PMID- 24482306 TI - Emotional reactivity in bipolar depressed patients. AB - OBJECTIVE: Emotional reactivity in bipolar affective disorders has received increased attention as a relevant issue with regard to the ability to respond to emotional external stimuli for individual real world adaptation. We investigated emotional reactivity using the International Affective Picture System (IAPS) paradigm in bipolar patients during the depressive phase compared to healthy controls. METHOD: Twenty-three bipolar patients with a major depressive episode without manic symptoms and 27 healthy control subjects were recruited. They were asked to judge their emotional reactivity while viewing 90 pictures selected from the IAPS. Their ratings were categorized according to the emotional valence and arousal in response to pleasant, neutral, and unpleasant stimuli. RESULTS: The patients showed lower valence ratings for neutral pictures compared to healthy subjects. No significant between-group differences were found for the pleasant and unpleasant pictures. Higher activation for patients to all emotional stimuli was seen. CONCLUSION: Patients during the depressive phase gave more negative valence to neutral images. This can suggest that they are more pessimistic in the way they perceive the environment as more reactive to emotional cues. PMID- 24482307 TI - Summarizing craniofacial genetics and developmental biology (SCGDB). AB - This overview article highlights active areas of research in craniofacial genetics and developmental biology as reflected in presentations given at the 34th annual meeting of the Society of Craniofacial Genetics and Developmental Biology (SCGDB) in Montreal, Quebec on October 11, 2011. This 1-day meeting provided a stimulating occasion that demonstrated the present status of research in craniofacial genetics and developmental biology and where the field is heading. To accompany the abstracts published in this issue I have selected several themes that emerged from the meeting. After discussing the basis on which craniofacial defects/syndromes are classified and investigated, I address the multi-gene basis of craniofacial syndromes with an examination of the roles of Sox9 and FGF receptors in normal and abnormal craniofacial development. I then turn to the knowledge being gained from population-wide and longitudinal cohort studies and from the discovery of new signaling centers that regulate craniofacial development. PMID- 24482308 TI - Device implantation and complications: time to recalibrate our expectations? PMID- 24482309 TI - Nasal versus oral aerosol delivery to the "lungs" in infants and toddlers. AB - OBJECTIVES: The oral route has been considered superior to the nasal route for aerosol delivery to the lower respiratory tract (LRT) in adults and children. However, there are no data comparing aerosol delivery via the oral and nasal routes in infants. The aim of this study was to compare nasal and oral delivery of aerosol in anatomically correct replicas of infants' faces containing both nasal and oral upper airways. METHODS: Three CT-derived upper respiratory tract ("URT") replicas representing infants/toddlers aged 5, 14 and 20 months were studied and aerosol delivery to the "lower respiratory tract" (LRT) by either the oral or nasal route for each of the replicas was measured at the "tracheal" opening. A radio-labeled (99mDTPA) normal saline solution aerosol was generated by a soft-mist inhaler (SMIRespimat(r) Boehringer Ingelheim, Germany) and aerosol was delivered via a valved holding chamber (Respichamber(r) TMI, London, Canada) and an air-tight mask (Unomedical, Inc., McAllen, TX). A breath simulator was connected to the replicas and an absolute filter at the "tracheal" opening captured the aerosol representing "LRT" dose. Age-appropriate mask dimensions and breathing patterns were employed for each of the airway replicas. Two different tidal volumes (Vt ) were used for comparing the nasal versus oral routes. RESULTS: Nasal delivery to the LRT exceeded that of oral delivery in the 5- and 14-month models and was equivalent in the 20-month model. Differences between nasal and oral delivery diminished with "age"/size. Similar findings were observed with lower and higher tidal volumes (Vt ). CONCLUSION: Nasal breathing for aerosol delivery to the "LRT" is similar to, or more efficient than, mouth breathing in infant/toddler models, contrary to what is observed in older children and adults. Pediatr Pulmonol. 2015; 50:276-283. (c) 2014 Wiley Periodicals, Inc. PMID- 24482310 TI - Banning of methyl bromide for seed treatment: could Ditylenchus dipsaci again become a major threat to alfalfa production in Europe? AB - In Europe, the stem and bulb nematode Ditylenchus dipsaci has been listed as a quarantine pest by EPPO: without any control, it may cause complete failure of alfalfa crops. Movement of nematodes associated with seeds is considered to be the highest-risk pathway for the spread of this pest. Since the 2010 official withdrawal of methyl bromide in Europe, and in the absence of any alternative chemical, fumigation of contaminated seed batches is no longer possible, which makes the production of nematode-free alfalfa seeds difficult to achieve and leads to unmarketable seed batches. Thermotherapy is being considered as a realistic alternative strategy, but its efficiency still remains to be validated. The combination of the currently available methods (i.e. use of resistant cultivars, seed production according to a certification scheme, mechanical sieving, seed batch inspection) could significantly reduce the likelihood of seed contamination. However, it does not guarantee a total eradication of the nematode. Although it is already widely distributed all over Europe, reclassification of D. dipsaci as a regulated non-quarantine pest to reduce the possibility of further introductions and the rate of spread of this pest appears to be a risky strategy because of the lack of up-to-date documented data to evaluate damage thresholds and determine acceptable tolerance levels. PMID- 24482311 TI - Controlled release from magnetoliposomes aqueous suspensions exposed to a low intensity magnetic field. AB - Recently, the use of liposomes loaded with magnetic nanoparticles (magnetoliposomes, (MLs)) has been intensely growing as a new drug delivery system. With the use of alternating magnetic fields, it is possible to remotely control the delivery of a drug or any other macromolecule loaded inside the MLs. In this experiment, the release of a fluorescent dye from MLs is achieved through an alternating magnetic field of 20 kHz and amplitude below 100 A/m, and without a macroscopic temperature increase. PMID- 24482312 TI - Luminescent materials: locking pi-conjugated and heterocyclic ligands with boron(III). AB - Multidisciplinary research on novel organic luminescent dyes is propelled by potential applications in plastic electronics and biomedical sciences. The construction of sophisticated fluorescent dyes around a tetrahedral boron(III) center is a particular approach that has fueled the creativity of chemists. Success in this enterprise has been readily achieved with simple synthetic protocols, the products of which display unusual spectroscopic behavior. This account is a critical review of recent advances in the field of boron(III) complexes (excluding BODIPYs and acetylacetonate boron complexes) involving species displaying similar coordination features, and we outline their potential development in several disciplines. PMID- 24482314 TI - On the Unidentifiability of the Fixed-Effects 3PL Model. AB - The paper offers a general review of the basic concepts of both statistical model and parameter identification, and revisits the conceptual relationships between parameter identification and both parameter interpretability and properties of parameter estimates. All these issues are then exemplified for the 1PL, 2PL, and 1PL-G fixed-effects models. For the 3PL model, however, we provide a theorem proving that the item parameters are not identified, do not have an empirical interpretation and that it is not possible to obtain consistent and unbiased estimates of them. PMID- 24482313 TI - Immunostimulation in chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS): a one-year prospective, double-blind, placebo-controlled study. AB - PURPOSE: Inflammation/immunological dysfunction are discussed etiological causes of chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS). OM-89 is an orally immunostimulating agent. We performed a phase three multicentre, randomized, double-blind, placebo-controlled, long-term (12 months) study with OM-89 produced with a different lysis process in patients with moderate-to-severe CP/CPPS type III. METHODS: Patients were randomized to OM-89 or placebo. Primary efficacy variable was difference of responders at the end of treatment (month 9) in patients receiving OM-89 versus placebo. RESULTS: Two hundred and three patients were screened, 185 patients (47.8 +/- 8.4 years) (90 % of CP/CPPS type IIIb) were enrolled in 30 centers and included in the safety set. Ninety-four were randomized to OM-89, 91 to placebo. One hundred and seventy-six patients were subjected to the full analysis (FAS), 150 to the per protocol set (PPS). Baseline NIH-CPSI score in FAS was 21.8 +/- 3.8 (OM-89) and 23.0 +/- 5.6 (placebo). At primary efficacy endpoint (month 9), in the OM-89 group, 67.0 % in FAS (PPS 72.7 %) and in the placebo group, 64.3 % in FAS (PPS 64.4 %) were responders [FAS: OR 1.19, p = 0.59; PPS: p = 0.19]. Mean relative decrease in NIH-CPSI was 40.5 and 44.0 % in the FAS. Treatment-related adverse events were low: 8.5 % with OM-89 and 5.5 % with placebo. Because of small numbers, no conclusion could be drawn regarding the potential benefit of OM-89 in CP/CPPS IIIa. CONCLUSIONS: This placebo-controlled study evaluating OM-89 in patients with CP/CPPS showed a significant and long-lasting (12 months) favorable response with OM-89, but also with placebo. OM-89 was safe and well tolerated. EUDRACT: 2007-004609-85. PMID- 24482315 TI - Liquid-crystal science from 1888 to 1922: building a revolution. AB - The saga of liquid crystals started with their discovery in 1888 by the botanist Friedrich Reinitzer, who unexpectedly observed "two melting points" for crystals extracted from the root of a carrot. At the end of the nineteenth century, most scientists did not believe in the existence of "liquid crystals" as promoted by the crystallographer Otto Lehmann. The controversies were very vivid; to the point that the recognition of mesomorphic states of matter by the scientific community required more than two decades. In the end, liquid crystals have changed our vision of matter by shattering the three-state paradigm. Since the mid-1970s, liquid crystals have revolutionized the worldwide information-display industry and now play a host of key roles in various technologies. PMID- 24482316 TI - Iodine-enhanced micro-CT imaging: methodological refinements for the study of the soft-tissue anatomy of post-embryonic vertebrates. AB - The now widespread use of non-destructive X-ray computed tomography (CT) and micro-CT (uCT) has greatly augmented our ability to comprehensively detail and quantify the internal hard-tissue anatomy of vertebrates. However, the utility of X-ray imaging for gaining similar insights into vertebrate soft-tissue anatomy has yet to be fully realized due to the naturally low X-ray absorption of non mineralized tissues. In this study, we show how a wide diversity of soft-tissue structures within the vertebrate head-including muscles, glands, fat deposits, perichondria, dural venous sinuses, white and gray matter of the brain, as well as cranial nerves and associated ganglia-can be rapidly visualized in their natural relationships with extraordinary levels of detail using iodine-enhanced (i-e) uCT imaging. To date, Lugol's iodine solution (I2 KI) has been used as a contrast agent for uCT imaging of small invertebrates, vertebrate embryos, and certain isolated parts of larger, post-embryonic vertebrates. These previous studies have all yielded promising results, but visualization of soft tissues in smaller invertebrate and embryonic vertebrate specimens has generally been more complete than that for larger, post-embryonic vertebrates. Our research builds on these previous studies by using high-energy uCT together with more highly concentrated I2 KI solutions and longer staining times to optimize the imaging and differentiation of soft tissues within the heads of post-embryonic archosaurs (Alligator mississippiensis and Dromaius novaehollandiae). We systematically quantify the intensities of tissue staining, demonstrate the range of anatomical structures that can be visualized, and generate a partial three-dimensional reconstruction of alligator cephalic soft-tissue anatomy. PMID- 24482317 TI - Does low-dose prolonged steroid therapy affect the natural history of chronic hepatitis C? AB - Chronic hepatitis C patients may require steroids due to other comorbidities. However, there is not enough information to consider steroids as beneficial or harmful drugs on natural history of chronic hepatitis C. The aim of the present study was to examine the effect of low-dose prolonged therapy with corticosteroids with or without azathioprine on these study patients. A retrospective-prospective observational study was established. Twenty-eight patients with chronic hepatitis C and treated with corticosteroids at low-dose (<=30 mg/day) with or without azathioprine for more than 6 months were included. AST, ALT, HCV RNA, and liver fibrosis were determined, and results were compared with a control group of non-treated chronic hepatitis C patients. The mean age was 47 +/- 10 years. The male proportion was 43%. The mean dose of prednisone was 9 +/- 5 mg/day (range: 2.5-30 mg/day). The mean treatment time was 76 +/- 80 months (range: 7-349 months). Thirty six percent received concomitant azathioprine. Transaminases decreased significantly only within the first 3 months of treatment, with non-significant changes thereafter. Corticosteroids led to a non-significant increase in HCV RNA. Knodell Histology Activity Index decreased (from 8.5 +/- 3.7 to 4.7 +/- 1.7; P = 0.1). Fibrosis progression per year (final fibrosis stage-initial fibrosis stage/time between explorations, in years), was lower in treated cases than in control group (0.054 +/- 0.25 units vs. 0.196 +/- 0.6 units, P = 0.26). In conclusion, corticosteroid treatment caused a significant initial decrease in transaminases, non-significant changes in HCV RNA, and a trend to a slower fibrosis progression in comparison to a control group. Therefore, corticosteroids did not accelerate progression of chronic hepatitis C. PMID- 24482318 TI - Comparative anatomy of the lower jaw and dentition of Pseudopus apodus and the interrelationships of species of subfamily Anguinae (Anguimorpha, Anguidae). AB - The morphology of the lower jaw and teeth of the legless lizard Pseudopus apodus (Anguimorpha, Anguidae, Anguinae) from Eurasia are described in detail and compared with those of other species of the subfamily Anguinae. The lower jaw anatomy of Pseudopus, especially the dentary and teeth, clearly differs from the genera Ophisaurus and Anguis. Even so, Ophisaurus is largely uniform in its lower jaw morphology across species. The teeth of North American Ophisaurus are slender cylinders, the shafts are mesiodistally compressed and bulge lingually; the apices are curved lingually and posteriorly and have weakly developed cutting edges. Southeast Asian and North African Ophisaurus present conical teeth, with broadened bases, apices more distinctly curved lingually and posteriorly, and cutting edges that are distinctly developed. The lingual surfaces of the tooth apices are striated in Ophisaurus and Pseudopus. The lower jaw of Ophisaurus is in many respects similar to that in Anguis, however, the teeth of Anguis are longer and markedly curved posteriorly. The result of the phylogenetic analysis rendered six equally parsimonious trees. Anguis appears in three alternative positions, as the sister taxon to a clade formed by Ophisaurus and Pseudopus, as the sister taxon of Ophisaurus, or as forming a clade with Ophisaurus which is the sister group to Pseudopus. PMID- 24482319 TI - Evolutionary relationships of Pemphigus and allied genera (Hemiptera: Aphididae: Eriosomatinae) and their primary endosymbiont, Buchnera aphidicola. AB - Aphids harbor primary endosymbionts, Buchnera aphidicola, in specialized cells within their body cavities. Aphids and Buchnera have strict mutualistic relationships in nutrition exchange. This ancient association has received much attention from researchers who are interested in endosymbiotic evolution. Previous studies have found parallel phylogenetic relationships between non galling aphids and Buchnera at lower taxonomic levels (genus, species). To understand whether relatively isolated habitats such as galls have effect on the parallel relationships between aphids and Buchnera, the present paper investigated the phylogenetic relationships of gall aphids from Pemphigus and allied genera, which induce pseudo-galls or galls on Populus spp. (poplar) and Buchnera. The molecular phylogenies inferred from three aphid genes (COI, COII and EF-1alpha) and two Buchnera genes (gnd, 16S rRNA gene) indicated significant congruence between aphids and Buchnera at generic as well as interspecific levels. Interestingly, both aphid and Buchnera phylogenies supported three main clades corresponding to the galling locations of aphids, namely leaf, the joint of leaf blade and petiole, and branch of the host plant. The results suggest phylogenetic conservatism of gall characters, which indicates gall characters are more strongly affected by aphid phylogeny, rather than host plants. PMID- 24482320 TI - Resistance to herbicides inhibiting the biosynthesis of very-long-chain fatty acids. AB - Herbicides that act by inhibiting the biosynthesis of very-long-chain fatty acids (VLCFAs) have been used to control grass weeds in major crops throughout the world for the past 60 years. VLCFA-inhibiting herbicides are generally highly selective in crops, induce similar symptoms in susceptible grasses and can be found within the herbicide groups classified by the HRAC as K3 and N. Even after many years of continuous use, only 12 grass weed species have evolved resistance to VLCFA-inhibiting herbicides. Here, the cases of resistance that have evolved in major grass weed species belonging to the Avena, Echinochloa and Lolium genera in three different agricultural systems are reviewed. In particular we explore the possible reasons why VLCFA herbicides have been slow to select resistant weeds, outline the herbicide mode of action and discuss the resistance mechanisms that are most likely to have been selected. PMID- 24482321 TI - Mixed IR/Vis two-dimensional spectroscopy: chemical exchange beyond the vibrational lifetime and sub-ensemble selective photochemistry. AB - Two-dimensional exchange spectroscopy (2D EXSY) is a powerful method to study the interconversion (chemical exchange) of molecular species in equilibrium. This method has recently been realized in femtosecond 2D-IR spectroscopy, dramatically increasing the time resolution. However, current implementations allow the EXSY signal (and therefore the chemical process of interest) only to be tracked during the lifetime (T1 ) of the observed spectroscopic transition. This is a severe limitation, as typical vibrational T1 are only a few ps. An IR/Vis pulse sequence is presented that overcomes this limit and makes the EXSY signal independent of T1 . The same pulse sequence allows to collect time-resolved IR spectra after electronic excitation of a particular chemical species in a mixture of species with strongly overlapping UV/Vis spectra. Different photoreaction pathways and dynamics of coexisting isomers or of species involved in different intermolecular interactions can thus be revealed, even if the species cannot be isolated because they are in rapid equilibrium. PMID- 24482322 TI - Chronic suppurative lung disease in a developing country: impact on child and parent. AB - OBJECTIVES: To investigate the impact of chronic suppurative lung disease (CSLD) on growth and lung function in the child as well as quality of life of the child and parent. METHODS: Cross-sectional study in 60 children with CSLD, bronchiectasis (including cystic fibrosis) and bronchiolitis obliterans. Thirty five parents were interviewed while the remaining patients' data were collated from medical notes. Anthropometric measurements at first diagnosis and at interview were compared. The most recent lung function was also collected. The Parent Cough-Specific Quality of Life (PC-QOL) and the Depression, Anxiety and Stress (DASS21) questionnaires were administered to parents. RESULTS: The median (range) age at diagnosis was 1.3 (0.2-11) years. The median (IQR) duration between anthropometric measurements was 35 (15, 59) months. Children with cystic fibrosis (CF) had improvements both in weight and BMI, whereas children with non CF CSLD had no improvements in any growth parameter. Seventy-eight percent of children who performed spirometry had values <80% of normal predicted value. PC QOL scores were low. Frequent exacerbations (more than twice in the past 6 months) and cough (more than 2 days/week) were not associated with significantly lower PC-QOL scores. Seventy-seven percent of interviewed parents had abnormal DASS21 scores with 54% being stressed and 51% being depressed. Mental health was better in parents of children with CF. CONCLUSION: CSLD had a negative impact on growth, lung function, and quality of life. Children with CF had a better outcome in growth as well as better parental mental health compared to children with other etiologies. Pediatr Pulmonol. 2014; 49:435-440. (c) 2013 Wiley Periodicals, Inc. PMID- 24482323 TI - A new miniaturized lizard from the late Eocene of France and Spain. AB - We report here a new lizard genus and species shared by two late Eocene localities situated at both versants of the present Pyrenees (South-Western Europe), one located in France (Escamps, MP19), and the other in Catalonia, Spain (Sossis, MP17a). The recovered specimens are remarkable because of their small size and peculiar morphology. Features of the dentary are interpreted as adaptations to a fossorial or semi-fossorial lifestyle, although such modifications obscure the exact phylogenetic relationships of the new taxon. We suggest that it might represent a further example of scincoid lizard that independently achieved adaptations for burrowing or surface-dwelling. This taxon reinforces the hypotheses that link the Southern Pyrenean assemblages to those from France rather than to those of the rest of the Iberian Peninsula, which are supposed to be somehow isolated and endemic to a certain degree during the middle and late Eocene, forming part of the so-called Western Iberian Bioprovince. PMID- 24482324 TI - Phylogenetic analysis provides evidence of interactions between Italian heterosexual and South American homosexual males as the main source of national HIV-1 subtype C epidemics. AB - The HIV-1 clade C is prevalent worldwide and spread from Africa to South East Asia and South America early in the course of the epidemic. As a consequence of migration waves about 13% of the Italian HIV-1 epidemic is sustained by this clade. Two hundred fifty-four C pol sequences from the Italian ARCA database collected during 1997-2011 were analyzed. Epidemiological networks and geographical fluxes were identified through phylogeny using Bayesian approaches. Patients' country of origin was Italy, Africa, South America, and South East Asia for 44.9%, 23.6%, 4.7%, and 1.6%, respectively. Heterosexuals and men having sex with men accounted for 83.2% and 16.8%, respectively. Modality of infection was distributed differently: heterosexuals were largely prevalent among Italians (84.1%) and Africans (95.3%), while men having sex with men predominated among South Americans (66.7%). Eight significant clusters encompassing 111 patients (43.7%) were identified. Comparison between clustering and non-clustering patients indicated significant differences in country of origin, modality of infection and gender. Men having sex with men were associated to a higher probability to be included in networks (70% for men having sex with men vs. 30.3% for heterosexuals). Phylogeography highlighted two significant groups. One contained Indian strains and the second encompassed South Americans and almost all Italian strains. Phylogeography indicated that the spread of C subtype among Italians is related to South American variant. Although Italian patients mainly reported themselves as heterosexuals, homo-bisexual contacts were likely their source of infection. Phylogenetic monitoring is warranted to guide public health interventions aimed at controlling HIV infection. PMID- 24482327 TI - Quantum cognition: key issues and discussion. AB - Quantum cognition is an emerging field that uses mathematical principles of quantum theory to help formalize and understand cognitive systems and processes. The topic on the potential of using quantum theory to build models of cognition (Volume 5, issue 4) introduces and synthesizes its new development through an introduction and six core articles. The current issue presents 14 commentaries on the core articles. Five key issues surface, some of which are interestingly controversial and debatable as expected for a new emerging field. PMID- 24482328 TI - Comments on quantum probability theory. AB - Quantum probability theory (QP) is the best formal representation available of the most common form of judgment involving attribute comparison (inside judgment). People are capable, however, of judgments that involve proportions over sets of instances (outside judgment). Here, the theory does not do so well. I discuss the theory both in terms of descriptive adequacy and normative appropriateness. PMID- 24482325 TI - A tool to measure shared clinical understanding following handoffs to help evaluate handoff quality. AB - BACKGROUND: Information exchanged during handoffs contributes importantly to a team's shared mental model. There is no established instrument to measure shared clinical understanding as a marker of handoff quality. OBJECTIVE: To study the reliability, validity, and feasibility of the pediatric cardiology Patient Knowledge Assessment Tool (PKAT), a novel instrument designed to measure shared clinical understanding for pediatric cardiac intensive care unit patients. DESIGN: To estimate reliability, 10 providers watched 9 videotaped simulated handoffs and then completed a PKAT for each scenario. To estimate construct validity, we studied 90 handoffs in situ by having 4 providers caring for an individual patient each complete a PKAT following handoff. Construct validity was assessed by testing the effects of provider preparation and patient complexity on agreement levels. SETTING: A 24-bed pediatric cardiac intensive care unit in a freestanding children's hospital. RESULTS: Video simulation results demonstrated score reliability. Average inter-rater agreement by item ranged from 0.71 to 1.00. During in situ testing, agreement by item ranged from 0.41 to 0.87 (median 0.77). Construct validity for some items was supported by lower agreement rates for patients with increased length of stay and increased complexity. DISCUSSION: Results suggest that the PKAT has high inter-rater reliability and can detect differences in understanding between handoff senders and receivers for routine and complex patients. Additionally, the PKAT is feasible for use in a real-time clinical environment. The PKAT or similar instruments could be used to study effects of handoff improvement efforts in inpatient settings. PMID- 24482329 TI - Toward a physical theory of quantum cognition. AB - Recently, mathematical models based on quantum formalism have been developed in cognitive science. The target articles in this special issue of Topics in Cognitive Science clearly illustrate how quantum theoretical formalism can account for various aspects of human judgment and decision making in a quantitatively and mathematically rigorous manner. In this commentary, we show how future studies in quantum cognition and decision making should be developed to establish theoretical foundations based on physical theory, by introducing Taketani's three-stage theory of the development of science. Also, implications for neuroeconomics (another rapidly evolving approach to human judgment and decision making) are discussed. PMID- 24482330 TI - Quantum random walks and decision making. AB - How realistic is it to adopt a quantum random walk model to account for decisions involving two choices? Here, we discuss the neural plausibility and the effect of initial state and boundary thresholds on such a model and contrast it with various features of the classical random walk model of decision making. PMID- 24482331 TI - Alternative probability theories for cognitive psychology. AB - Various proposals for generalizing event spaces for probability functions have been put forth in the mathematical, scientific, and philosophic literatures. In cognitive psychology such generalizations are used for explaining puzzling results in decision theory and for modeling the influence of context effects. This commentary discusses proposals for generalizing probability theory to event spaces that are not necessarily boolean algebras. Two prominent examples are quantum probability theory, which is based on the set of closed subspaces of a Hilbert space, and topological probability theory, which is based on the set of open sets of a topology. Both have been applied to a variety of cognitive situations. This commentary focuses on how event space properties can influence probability concepts and impact cognitive modeling. PMID- 24482332 TI - Quantum and concept combination, entangled measurements, and prototype theory. AB - We analyze the meaning of the violation of the marginal probability law for situations of correlation measurements where entanglement is identified. We show that for quantum theory applied to the cognitive realm such a violation does not lead to the type of problems commonly believed to occur in situations of quantum theory applied to the physical realm. We briefly situate our quantum approach for modeling concepts and their combinations with respect to the notions of "extension" and "intension" in theories of meaning, and in existing concept theories. PMID- 24482333 TI - Cognitive anthropology's contributions to cognitive science: a cultural human mind, a methodological trajectory, and ethnography. PMID- 24482334 TI - A biological/computational approach to culture(s) is cognitive science. PMID- 24482335 TI - Orienting cognitive science to evolution and development. PMID- 24482336 TI - Diversifying the knowledge base. PMID- 24482337 TI - Modeling collaborative coordination requires anthropological insights. PMID- 24482338 TI - Does cognitive science need anthropology? PMID- 24482339 TI - Why anthropology remains integral to cognitive science. PMID- 24482340 TI - Current trends in cultural particularism: the problem does seem to lie with anthropology. PMID- 24482341 TI - Maximizing students' retention via spaced review: practical guidance from computational models of memory. AB - During each school semester, students face an onslaught of material to be learned. Students work hard to achieve initial mastery of the material, but when they move on, the newly learned facts, concepts, and skills degrade in memory. Although both students and educators appreciate that review can help stabilize learning, time constraints result in a trade-off between acquiring new knowledge and preserving old knowledge. To use time efficiently, when should review take place? Experimental studies have shown benefits to long-term retention with spaced study, but little practical advice is available to students and educators about the optimal spacing of study. The dearth of advice is due to the challenge of conducting experimental studies of learning in educational settings, especially where material is introduced in blocks over the time frame of a semester. In this study, we turn to two established models of memory-ACT-R and MCM-to conduct simulation studies exploring the impact of study schedule on long term retention. Based on the premise of a fixed time each week to review, converging evidence from the two models suggests that an optimal review schedule obtains significant benefits over haphazard (suboptimal) review schedules. Furthermore, we identify two scheduling heuristics that obtain near optimal review performance: (a) review the material from MU-weeks back, and (b) review material whose predicted memory strength is closest to a particular threshold. The former has implications for classroom instruction and the latter for the design of digital tutors. PMID- 24482344 TI - On the fossil record of the Gekkota. AB - Gekkota is often interpreted as sister to all remaining squamates, exclusive of dibamids, or as sister to Autarchoglossa. It is the only diverse lineage of primarily nocturnal lizards and includes some of the smallest amniotes. The skeleton of geckos has often been interpreted as paedomorphic and/or "primitive" but these lizards also display a wide range of structural specializations of the postcranium, including modifications associated with both scansorial locomotion and limb reduction. Although the concept of "Gekkota" has been variously applied by different authors, we here apply a rigorous apomorphy based definition, recent advances in gekkotan morphology and phylogenetics, and diverse comparative material to provide a comprehensive assessment of 28 known pre-Quaternary geckos, updating the last such review, published three decades ago. Fossils evaluated include both sedimentary fossils and amber-embedded specimens. Known Cretaceous geckos are exclusively Asian and exhibit character combinations not seen in any living forms. Cenozoic gekkotans derive from sites around the world, although Europe is especially well represented. Paleogene geckos are largely known from disarticulated remains and show similarities to Sphaerodactylidae and Diplodactylidae, although resemblances may be plesiomorphic in some cases. Many Neogene gekkotans are referable to living families or even genera, but their geographic occurrences are often extralimital to those of modern groups, as is consistent with paleoclimatic conditions. The phylogenetic placement of fossil gekkotans has important repercusions for timetree calibration, but at present only a small number of fossils can be confidently assigned to even family level groupings, limiting their utility in this regard. PMID- 24482343 TI - Modeling the emergence of lexicons in homesign systems. AB - It is largely 4ledged that natural languages emerge not just from human brains but also from rich communities of interacting human brains (Senghas, ). Yet the precise role of such communities and such interaction in the emergence of core properties of language has largely gone uninvestigated in naturally emerging systems, leaving the few existing computational investigations of this issue at an artificial setting. Here, we take a step toward investigating the precise role of community structure in the emergence of linguistic conventions with both naturalistic empirical data and computational modeling. We first show conventionalization of lexicons in two different classes of naturally emerging signed systems: (a) protolinguistic "homesigns" invented by linguistically isolated Deaf individuals, and (b) a natural sign language emerging in a recently formed rich Deaf community. We find that the latter conventionalized faster than the former. Second, we model conventionalization as a population of interacting individuals who adjust their probability of sign use in response to other individuals' actual sign use, following an independently motivated model of language learning (Yang, , ). Simulations suggest that a richer social network, like that of natural (signed) languages, conventionalizes faster than a sparser social network, like that of homesign systems. We discuss our behavioral and computational results in light of other work on language emergence, and other work of behavior on complex networks. PMID- 24482345 TI - SIRT1 inhibition by sirtinol aggravates brain edema after experimental subarachnoid hemorrhage. AB - Secondary brain injury following subarachnoid hemorrhage (SAH) is poorly understood. We utilized a rat model of SAH to investigate whether SIRT1 has a protective role against brain edema via the tumor suppressor protein p53 pathway. Experimental SAH was induced in adult male Sprague-Dawley rats by prechiasmatic cistern injection. Brain SIRT1 protein levels were examined in the sham controls and in rats 6, 12, 24, 48, and 72 hr after SAH induction. The SIRT1 inhibitor sirtinol was administered by intracerebroventricular infusion. Neurological functions, blood-brain barrier (BBB) disruption, and brain water content were assessed. Endothelial cell apoptosis, caspase 3 protein expression, p53 acetylation, and matrix metalloproteinase-9 (MMP-9) activity were examined. Compared with the control, SIRT1 protein expression increased remarkably, reaching a maximum at 24 hr after SAH. Sirtinol treatment significantly lowered SIRT1 expression, accompanied by deteriorated neurologic function, BBB disruption, brain edema, increased endothelial cell apoptosis, and increased MMP 9 gelatinase activity compared with the rats treated with vehicle only. Our results suggest that increased expression of endogenous SIRT1 may play a neuroprotective role against brain edema after SAH. PMID- 24482346 TI - Increased risk of cardiovascular events in patients with herpes zoster: a population-based study. AB - The association between herpes zoster and cardiovascular complications remains vague with limited study on the association between these two disorders. This study evaluated the risk of cardiovascular diseases in patients with herpes zoster. From insurance claims data of Taiwan, 19,483 patients with herpes zoster diagnosed in 1998-2008 and 77,932 subjects without herpes zoster were identified in this study. Both cohorts were followed up until the end of 2010 to measure the incidence of arrhythmia and coronary artery disease. The incidence rate ratio and adjusted hazard ratio (HR) of the cardiovascular complications with 95% confidence interval (CI) were estimated. The incidence of arrhythmia was 1.17 fold greater in the herpes zoster cohort than in the non-herpes zoster cohort (13.2 vs. 11.3 per 1,000 person-years), with an adjusted HR of 1.16 (P < 0.01). The coronary artery disease incidence in the herpes zoster cohort was 1.16-fold higher than that in the non-herpes zoster cohort (9.02 vs. 7.83 per 1,000 person years), with an adjusted HR of 1.11 (P < 0.01). Over the stratified follow-up years, adjusted HRs were 1.22 (95% CI = 1.12-1.34) for arrhythmia and 1.14 (95% CI = 1.02-1.28) for coronary artery disease within 2 years after herpes zoster diagnosis. The risk measured for these disorders declined over time. Comorbidities of hypertension, diabetes, and hyperlipidemia also contributed to these cardiovascular disorders with greater extent. It is concluded that the contribution of herpes zoster to the risk of arrhythmia and cardiovascular diseases is less strong than that of hypertension, diabetes, and hyperlipidemia. PMID- 24482347 TI - Hyperglycemia as a potential prognostic factor of idiopathic sudden sensorineural hearing loss. AB - OBJECTIVE: Hyperglycemia is not identified as a significant prognostic factor for idiopathic sudden sensorineural hearing loss in any literature. Therefore, we investigated the prognostic value of hyperglycemia in predicting hearing recovery. STUDY DESIGN: A retrospective cohort study. SETTING: Tertiary university hospital. SUBJECTS AND METHODS: Patients were classified into 3 groups according to their glucose tolerance using the 75-gram oral glucose tolerance test and hemoglobin A1c test as follows: (1) a normal glucose tolerance group, (2) a prediabetes group, which included patients with impaired glucose tolerance and/or impaired fasting glucose levels, and (3) a diabetes mellitus group. RESULTS: Among 94 patients with idiopathic sudden sensorineural hearing loss, 45 were classified into the normal glucose tolerance group, 28 into the prediabetes group, and 21 into the diabetes mellitus group. The recovery rate of the normal glucose tolerance group was not higher than that of the diabetes mellitus group (P = .140). However, when the prediabetes and diabetes mellitus groups were collectively defined as the impaired glucose regulation (hyperglycemia) group, the hearing recovery rate of the normal glucose tolerance (normoglycemia) group was significantly better than that of the impaired glucose regulation group (P = .038). CONCLUSION: We suggest that hyperglycemia may be a potential negative prognostic factor for hearing recovery in idiopathic sudden sensorineural hearing loss. Further interventional studies should be followed to determine whether hearing outcomes of the impaired glucose regulation group may be improved to the same extent as those of the normal glucose tolerance group after strict glycemic control. PMID- 24482348 TI - The role of immediate postoperative systemic corticosteroids when utilizing a steroid-eluting spacer following sinus surgery. AB - OBJECTIVE: Steroid-eluting spacers can improve local drug delivery immediately following endoscopic sinus surgery and reduce the recurrence of inflammation warranting systemic corticosteroids. For chronic rhinosinusitis with nasal polyposis, the need for systemic corticosteroids immediately following endoscopic sinus surgery when using a steroid-eluting spacer has not been studied. STUDY DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Academic rhinology practice. SUBJECTS AND METHODS: Chronic rhinosinusitis patients with nasal polyposis who failed medical therapy and elected endoscopic sinus surgery were enrolled. Patients were randomized into either the treatment arm (postoperative prednisone 30 mg daily * 7 days; n = 18) or placebo arm (postoperative placebo pill daily * 7 days; n = 18). Outcomes were evaluated at 1 week, 3 weeks, and 2 months postoperatively. Primary outcome was endoscopic grading at postoperative month 2 using the Lund-Kennedy system. Secondary outcome included disease-specific quality of life using the Sinonasal Outcome Test (SNOT 22) survey. Patient enrollment occurred from January 2012 through February 2013 (NCT01564355). RESULTS: Both arms received significant improvement in endoscopic grading and disease-specific quality of life from baseline compared to 2-month follow-up (P < .001). There were no significant differences in mean endoscopic scores between the postoperative prednisone and control groups at 1 week (P = .715), 3 weeks (P = .883), or 2 months (P = .343). There were no significant differences in SNOT-22 scores between groups at all follow-up points (all P > .119). CONCLUSION: Minimizing systemic corticosteroid use in patients with chronic rhinosinusitis with nasal polyposis may avoid adverse events. Results from this study suggest that postoperative systemic corticosteroids immediately following endoscopic sinus surgery may not provide improved outcomes when utilizing a steroid-eluting spacer. PMID- 24482350 TI - Osmocapsules for direct measurement of osmotic strength. AB - Monodisperse microcapsules with ultra-thin membranes are microfluidically designed to be highly sensitive to osmotic pressure, thereby providing a tool for the direct measurement of the osmotic strength. To make such osmocapsules, water in-oil-in-water double-emulsion drops with ultra-thin shells are prepared as templates through emulsification of core-sheath biphasic flow in a capillary microfluidic device. When photocurable monomers are used as the oil phase, the osmocapsules are prepared by in-situ photopolymerization of the monomers, resulting in semipermeable membranes with a relatively large ratio of membrane thickness to capsule radius, approximately 0.02. These osmocapsules are buckled by the outward flux of water when they are subjected to a positive osmotic pressure difference above 125 kPa. By contrast, evaporation-induced consolidation of middle-phase containing polymers enables the production of osmocapsules with a small ratio of membrane thickness to capsule radius of approximately 0.002. Such an ultra-thin membrane with semi-permeability makes the osmocapsules highly sensitive to osmotic pressure; a positive pressure as small as 12.5 kPa induces buckling of the capsules. By employing a set of distinct osmocapsules confining aqueous solutions with different osmotic strengths, the osmotic strength of unknown solutions can be estimated through observation of the capsules that are selectively buckled. This approach provides the efficient measurement of the osmotic strength using only a very small volume of liquid, thereby providing a useful alternative to other measurement methods which use complex setups. In addition, in-vivo measurement of the osmotic strength can be potentially accomplished by implanting these biocompatible osmocapsules into tissue, which is difficult to achieve using conventional methods. PMID- 24482349 TI - Epidemiology of vocal fold paralyses after total thyroidectomy for well differentiated thyroid cancer in a Medicare population. AB - OBJECTIVES: The population-level incidence of vocal fold paralysis after thyroidectomy for well-differentiated thyroid carcinoma (WDTC) is not known. This study aimed to measure longitudinal incidence of postoperative vocal fold paralyses and need for directed interventions in the Medicare population undergoing total thyroidectomy for WDTC. STUDY DESIGN: Retrospective cohort study. SETTING: US population. SUBJECTS AND METHODS: Subjects were Medicare beneficiaries. SEER-Medicare data (1991-2009) were used to identify beneficiaries who underwent total thyroidectomy for WDTC. Incident vocal fold paralyses and directed interventions were identified. Multivariate analyses were used to determine factors associated with odds of developing these surgical complications. RESULTS: Of 5670 total thyroidectomies for WDTC, 9.5% were complicated by vocal fold paralysis (8.2% unilateral vocal fold paralysis [UVFP]; 1.3% bilateral vocal fold paralysis [BVFP]). Rate of paralyses decreased 5% annually from 1991 to 2009 (odds ratio 0.95; 95% confidence interval, 0.93-0.97; P < .001). Overall, 22% of patients with vocal fold paralysis required surgical intervention (UVFP 21%, BVFP 28%). Multivariate logistic regression revealed that the odds of postthyroidectomy paralysis increased with each additional year of age, with non-Caucasian race, with particular histologic types, with advanced stage, and in particular registry regions. CONCLUSION: Annual rates of postthyroidectomy vocal fold paralyses are decreasing among Medicare beneficiaries with WDTC. High incidence in this aged population is likely due to a preponderance of temporary paralyses, which is supported by the need for directed intervention in less than a quarter of affected patients. Further population-based studies are needed to refine the population incidence and risk factors for paralyses in the aging population. PMID- 24482351 TI - Adoption of recommended practices and basic technologies in a low-income setting. AB - OBJECTIVE: In global health considerable attention is focused on the search for innovations; however, reports tracking their adoption in routine hospital settings from low-income countries are absent. DESIGN AND SETTING: We used data collected on a consistent panel of indicators during four separate cross sectional, hospital surveys in Kenya to track changes over a period of 11 years (2002-2012). MAIN OUTCOME MEASURES: Basic resource availability, use of diagnostics and uptake of recommended practices. RESULTS: There appeared little change in availability of a panel of 28 basic resources (median 71% in 2002 to 82% in 2012) although availability of specific feeds for severe malnutrition and vitamin K improved. Use of blood glucose and HIV testing increased but remained inappropriately low throughout. Commonly (malaria) and uncommonly (lumbar puncture) performed diagnostic tests frequently failed to inform practice while pulse oximetry, a simple and cheap technology, was rarely available even in 2012. However, increasing adherence to prescribing guidance occurred during a period from 2006 to 2012 in which efforts were made to disseminate guidelines. CONCLUSIONS: Findings suggest changes in clinical practices possibly linked to dissemination of guidelines at reasonable scale. However, full availability of basic resources was not attained and major gaps likely exist between the potential and actual impacts of simple diagnostics and technologies representing problems with availability, adoption and successful utilisation. These findings are relevant to debates on scaling up in low-income settings and to those developing novel therapeutic or diagnostic interventions. PMID- 24482352 TI - Intravenous drug delivery in neonates: lessons learnt. AB - Intravenous drug administration presents a series of challenges that relate to the pathophysiology of the neonate and intravenous infusion systems in neonates. These challenges arise from slow intravenous flow rates, small drug volume, dead space volume and limitations on the flush volume in neonates. While there is a reasonable understanding of newborn pharmacokinetics, an appreciation of the substantial delay and variability in the rate of drug delivery from the intravenous line is often lacking. This can lead to difficulties in accurately determining the pharmacokinetic and pharmacodynamic relationship of drugs in the smallest patients. The physical variables that affect the passage of drugs through neonatal lines need to be further explored in order to improve our understanding of their impact on the delivery of drugs by this route in neonates. Through careful investigation, the underlying causes of delayed drug delivery may be identified and administration protocols can then be modified to ensure predictable, appropriate drug input kinetics. PMID- 24482353 TI - Growth charts for Chinese Down syndrome children from birth to 14 years. AB - OBJECTIVE: To establish Down syndrome (DS)-specific growth charts for Hong Kong Chinese children. DESIGN AND SETTING: Growth data were collected from (1) members of the Hong Kong Down Syndrome Association (cross-sectional); (2) DS children attending special schools or living in residential homes (cross-sectional); and (3) the paediatric departments of seven public hospitals (retrospective). PATIENTS: 425 DS children (57% males and 43% females) born in 1977-2000, yielding 4987 observations. MAIN OUTCOME MEASURES: The LMS method was used to construct reference centile curves of weight, height, body mass index (BMI) from birth until 14 years and head circumference for the first 4 years. RESULTS: The median birth length was 49.8 cm and height at age 14 was 146.7 cm for DS boys. Corresponding figures for DS girls were 49.5 and 142.1 cm. The median birth weight was 3.0 kg for DS boys and 2.9 kg for DS girls. At age 14, 26% DS boys (BMI >22.6 kg/m(2)) and 12% DS girls (BMI >23.3 kg/m(2)) were overweight. The median head circumference at birth was 32.8 cm for boys and 32.0 cm for girls. CONCLUSIONS: Chinese DS children had a shorter stature, lower weight and tendency to be overweight than local non-DS children. Their growth patterns differed from those of Chinese DS children in Taiwan, and DS children in the USA and Sweden. Growth retardation was most salient during the first year of life. PMID- 24482354 TI - Homology of the jaw muscles in lizards and snakes-a solution from a comparative gnathostome approach. AB - Homology or shared evolutionary origin of jaw adductor muscles in lizards and snakes has been difficult to establish, although snakes clearly arose within the lizard radiation. Lizards typically have temporal adductors layered lateral to medial, and in snakes the muscles are arranged in a rostral to caudal pattern. Recent work has suggested that the jaw adductor group in gnathostomes is arranged as a folded sheet; when this theory is applied to snakes, homology with lizard morphology can be seen. This conclusion revisits the work of S.B. McDowell, J Herpetol 1986; 20:353-407, who proposed that homology involves identity of m. levator anguli oris and the loss of m. adductor mandibulae externus profundus, at least in "advanced" (colubroid) snakes. Here I advance the folded sheet hypothesis across the whole snake tree using new and literature data, and provide a solution to this homology problem. PMID- 24482355 TI - Fluorescence-encoded gold nanoparticles: library design and modulation of cellular uptake into dendritic cells. AB - In order to harness the unique properties of nanoparticles for novel clinical applications and to modulate their uptake into specific immune cells we designed a new library of homo- and hetero-functional fluorescence-encoded gold nanoparticles (Au-NPs) using different poly(vinyl alcohol) and poly(ethylene glycol)-based polymers for particle coating and stabilization. The encoded particles were fully characterized by UV-Vis and fluorescence spectroscopy, zeta potential and dynamic light scattering. The uptake by human monocyte derived dendritic cells in vitro was studied by confocal laser scanning microscopy and quantified by fluorescence-activated cell sorting and inductively coupled plasma atomic emission spectroscopy. We show how the chemical modification of particle surfaces, for instance by attaching fluorescent dyes, can conceal fundamental particle properties and modulate cellular uptake. In order to mask the influence of fluorescent dyes on cellular uptake while still exploiting its fluorescence for detection, we have created hetero-functionalized Au-NPs, which again show typical particle dependent cellular interactions. Our study clearly prove that the thorough characterization of nanoparticles at each modification step in the engineering process is absolutely essential and that it can be necessary to make substantial adjustments of the particles in order to obtain reliable cellular uptake data, which truly reflects particle properties. PMID- 24482356 TI - Xanthones from Swertia mussotii as multitarget-directed antidiabetic agents. AB - Oxidative stress has been suggested to play a causative role in the development of obesity-induced insulin resistance and type 2 diabetes. Given the antioxidant potency of previously reported xanthones isolated from Swertia mussotii. These natural products were further evaluated against other targets in diabetes, aldose reductase and alpha-glucosidase, in order to identify novel multitarget-directed antidiabetic agents. Among the 14 xanthones screened, 1,3,7,8 tetrahydroxyxanthone (6), 1,3,5,8-tetrahydroxyxanthone (7), and 2,3,6,8 tetrahydroxyxanthone-7C-(beta-D-glucoside) (12) were confirmed as good antioxidants and alpha-glucosidase inhibitors. Xanthone 7 was also confirmed as a potent inhibitor of aldose reductase (ALR2). Xanthone 7 was the most active alpha glucosidase and ALR2 inhibitor, with IC50 values of 5.2+/-0.3 MUM and 88.6+/-1.6 nM, respectively, while compound 12 was shown to be the most active antioxidant. Given the overall profile, xanthone 7 is considered to be the most promising multitarget antidiabetic agent, and may have potential for the treatment of both diabetes and diabetic complications. PMID- 24482357 TI - Conventional transmission electron microscopy. AB - Researchers have used transmission electron microscopy (TEM) to make contributions to cell biology for well over 50 years, and TEM continues to be an important technology in our field. We briefly present for the neophyte the components of a TEM-based study, beginning with sample preparation through imaging of the samples. We point out the limitations of TEM and issues to be considered during experimental design. Advanced electron microscopy techniques are listed as well. Finally, we point potential new users of TEM to resources to help launch their project. PMID- 24482358 TI - An overview of the South American fossil squamates. AB - The evolution of squamates in South America is the result of the complex geological and paleoclimatic history of this part of the world. The incomplete and episodic fossil record allows us to know only a small part of this evolution. Most Mesozoic squamate remains come from the Patagonian region, but remarkable specimens have also been recovered from Brazil. Both major squamate clades (Iguania and Scleroglossa) are present in the South American Mesozoic. Remains of Mesozoic snakes are common and diverse in Cretaceous deposits, including some of the most primitive terrestrial forms. Paleogene and Neogene squamate remains have been recognized from Argentina, Bolivia, Brazil, Colombia, Ecuador, Peru, and Venezuela. Paleogene lizard record appears to be scarce in comparison to that of the Mesozoic, whereas snakes show an important Paleogene diversity. At least two extant boid snakes appeared during this epoch (Boa and Corallus). The South American Miocene included some extant genera of Iguania, Teiidae, and Boidae but extinct genera were also present. "Colubrids" appeared at the early Miocene, whereas the first viperid is known from the late Miocene. Most of the Paleogene and early Neogene squamate families and genera have been recognized outside their current range of distribution following favorable climatic conditions for ectothermic vertebrates. During the latest Miocene and Pliocene few extant squamate taxa are found to occur outside their present distribution. The earliest amphisbaenian of South America is known from the Pliocene. Most Pleistocene and Holocene squamate remains are assigned to living genera, and some extant species were recognized. PMID- 24482359 TI - DNA-regulated upconverting nanoparticle signal transducers for multivalued logic operation. PMID- 24482360 TI - Toward drug repurposing in epigenetics: olsalazine as a hypomethylating compound active in a cellular context. AB - DNA hypomethylating drugs that act on DNA methyltransferase (DNMT) isoforms are promising anticancer agents. By using a well-characterized live-cell system to measure DNA methylation revisions (imprints), we characterize olsalazine, an approved anti-inflammatory drug, as a novel DNA hypomethylating agent. The cell based screen used in this work is highly tractable, internally controlled, and well-suited for a drug repurposing strategy in epigenetics. Olsalazine very closely mimics the action of 5-aza-2'-deoxycytidine, a known hypomethylating drug, with minimal cytotoxicity at the concentrations tested. Olsalazine was identified by a rapid computer-guided similarity search of a database of approved drugs to a previously identified inhibitor of DNMTs. PMID- 24482361 TI - Correlation of morphology with photocurrent generation in a polymer blend photovoltaic device. AB - Morphological effects on photovoltaic (PV) properties are studied through scanning photocurrent (PC) and photoluminescence (PL) microscopy of a solution processed, polymer blend PV device composed of PFB [poly(9,9'-dioctylfluorene-co bis-N,N-(4-butylphenyl)-bis-N,N-phenyl-1,4-phenylenediamine] and F8BT [poly(9,9' dioctylfluorene-co-benzothiadiazole]. As PFB and F8BT have unique absorbance bands, it is possible to selectively excite only F8BT (488 nm) or both PFB and F8BT (408 nm). Local voltage-dependent photocurrent (LVPC) measurements from particular regions of interest in the PV show that the diode characteristics between different morphologies are essentially the same, except in regard to the magnitude of PC generated. A local PL spectrum is measured simultaneously with PC generation at each pixel in the image maps. Through integration of the local PL spectrum over particular wavelength ranges, PL image maps are created of PFB-PL (435 to 475 nm), F8BT-PL (530 to 570 nm), exciplex-PL (620 to 685 nm) and total PL (entire spectrum). These data allow direct correlation of PC generation with local chemical composition variations within the PV device. PL image maps show morphological variations on the order of 0.5 to 1 um of alternating PFB-rich and F8BT-rich phases. While illuminating only F8BT (488 nm light), the PFB-rich phases produce the most PC, however, while illuminating both polymers but mostly PFB (408 nm light), the F8BT-rich phases produce the most PC. These results show that in the morphology where the light absorbing material is less concentrated, the PC generation is increased. Additionally, the exciplex-PL is found to not be a significant radiative loss mechanism of charge carriers for PC generation. PMID- 24482362 TI - Bis-arylidene oxindoles as anti-breast-cancer agents acting via the estrogen receptor. AB - We report a new family of bis-arylidene oxindole derivatives that show highly selective estrogen receptor (ER)-mediated anticancer activity at low-nanomolar concentrations in ER-positive (ER+) breast cancer cells. In terms of cell growth inhibition, IC50 values for these compounds in ER+ breast cancer cells are two to three orders of magnitude lower than in ER-negative (ER-) breast cancer cells and non-cancer cells. In comparison with known bis-arylidene drugs, these compounds are at least three orders of magnitude more toxic than tamoxifen and 1.5-4-fold more toxic than 4-hydroxytamoxifen in ER+ MCF-7 cancer cells. These oxindoles inhibit ER transactivation, and their anticancer activities are inhibited in ER depleted MCF-7 cells. Some of these nonsteroidal molecules also exhibit essential properties of selective ER down-regulation. From the development of two series of bis-arylidene oxindole-based compounds, we report a new series of anticancer agents for estrogen-responsive breast cancer. PMID- 24482363 TI - The atlas-axis complex in chamaeleonids (Squamata: Chamaeleonidae), with description of a new anatomical structure of the skull. AB - The comparative vertebral morphology of different chamaeleonid genera has been generally neglected and some aspects such as the comparative anatomy of the neck region remain poorly known. The atlas and axis of all chamaeleonid genera (Brookesia, Rieppeleon, Archaius, Rhampholeon, Nadzikambia, Bradypodion, Chamaeleo, Calumma, Furcifer, Kinyongia, and Trioceros) are studied here. Considerable morphological differences are revealed. Additionally, some taxa exhibit sexual dimorphism in the atlas and axis. An extremely long, divided posterodorsal process is present in males of the Trioceros johnstoni + Trioceros jacksonii clade. The solid and well-developed morphology of the posterodorsal process in males of this taxon could reflect its competitive behavior-males fight with their horns and attempt to dislodge one another from branches during encounters. An additional area of insertion for the cervical musculature may indicate an incremental cervical musculature mass and cross sectional area that can add extra support and stability to the head and assist during combat involving lateral pushing. This character is not present in females. Heterochronic processes have played a role in the evolution of chamaeleonids, as evidenced in many characters of the atlas-axis complex. A new hypothesis of an anterior shifting of synapophyses of the axis is erected and a new derived anatomical structure of the parietal of Chamaeleo calyptratus is described (the processus parietalis inferior). The presence of the processus parietalis inferior is associated with the evolution of the dorsally elevated parietal crest. PMID- 24482364 TI - Cobalt complexes with pyrazole ligands as catalyst precursors for the peroxidative oxidation of cyclohexane: X-ray absorption spectroscopy studies and biological applications. AB - [CoCl(MU-Cl)(Hpz(Ph))3]2 (1) and [CoCl2(Hpz(Ph))4] (2) were obtained by reaction of CoCl2 with HC(pz(Ph))3 and Hpz(Ph), respectively (Hpz(Ph)=3-phenylpyrazole). The compounds were isolated as air-stable solids and fully characterized by IR and far-IR spectroscopy, MS(ESI+/-), elemental analysis, cyclic voltammetry (CV), controlled potential electrolysis, and single-crystal X-ray diffraction. Electrochemical studies showed that 1 and 2 undergo single-electron irreversible Co(II)->Co(III) oxidations and Co(II)->Co(I) reductions at potentials measured by CV, which also allowed, in the case of dinuclear complex 1, the detection of electronic communication between the Co centers through the chloride bridging ligands. The electrochemical behavior of models of 1 and 2 were also investigated by density functional theory (DFT) methods, which indicated that the vertical oxidation of 1 and 2 (that before structural relaxation) affects mostly the chloride and pyrazolyl ligands, whereas adiabatic oxidation (that after the geometry relaxation) and reduction are mostly metal centered. Compounds 1 and 2 and, for comparative purposes, other related scorpionate and pyrazole cobalt complexes, exhibit catalytic activity for the peroxidative oxidation of cyclohexane to cyclohexanol and cyclohexanone under mild conditions (room temperature, aqueous H2O2). In situ X-ray absorption spectroscopy studies indicated that the species derived from complexes 1 and 2 during the oxidation of cyclohexane (i.e., Ox-1 and Ox-2, respectively) are analogous and contain a Co(III) site. Complex 2 showed low in vitro cytotoxicity toward the HCT116 colorectal carcinoma and MCF7 breast adenocarcinoma cell lines. PMID- 24482365 TI - PTEN is a potent suppressor of small cell lung cancer. AB - Small cell lung carcinoma (SCLC) is a highly metastatic tumor type with neuroendocrine features and a dismal prognosis. PTEN mutations and PIK3CA activating mutations have been reported in SCLC but the functional relevance of this pathway is unknown. The PTEN/PIK3CA pathway was interrogated using an AdenoCre-driven mouse model of SCLC harboring inactivated Rb and p53. Inactivation of one allele of PTEN in Rb/p53-deleted mice led to accelerated SCLC with frequent metastasis to the liver. In contrast with the high mutation burden reported in human SCLC, exome analyses revealed a low number of protein-altering mutations in mouse SCLC. Inactivation of both alleles of PTEN in the Rb/p53 deleted system led to nonmetastatic adenocarcinoma with neuroendocrine differentiation. This study reveals a critical role for the PTEN/PI3K pathway in both SCLC and lung adenocarcinoma and provides an ideal system to test the phosphoinositide 3-kinase (PI3K) pathway inhibitors as targeted therapy for subsets of patients with SCLC. IMPLICATIONS: The ability of PTEN inactivation to accelerate SCLC in a genetic mouse model suggests that targeting the PTEN pathway is a therapeutic option for a subset of human patients with SCLC. VISUAL OVERVIEW: http://mcr.aacrjournals.org/content/early/2014/04/28/1541-7786.MCR-13 0554/F1.large.jpg. PMID- 24482366 TI - Resolving overlapping GC-MS signals with a multistep screening chemometric approach for the fast determination of pesticides. AB - For the rapid analysis of multicomponent mixtures using GC-MS, a chemometric multistep screening approach was proposed to extract the signals of the components from the overlapping signals measured with a very fast temperature program. At first, independent component analysis was used to find all the possible mass spectra from the overlapping signal in the moving windows along the retention time, and iterative target transformation factor analysis was employed to validate the existence of the extracted spectra from each window. Then, identical signals in the validated spectra were excluded using match ratio as a criterion. Finally, the chromatographic profiles for each spectrum were calculated using non-negative immune algorithm, and the spectra with a reasonable profile were taken as the identified components. A mixture of 53 pesticides was analyzed with a very fast temperature program of 7 min. A total of 48 pesticides and 16 interferences were identified from the overlapping GC-MS signal. PMID- 24482367 TI - A model of the anterior esophagus in snakes, with functional and developmental implications. AB - The gross anatomy of the mouth of snakes has always been interpreted as an evolutionary response to feeding demands. In most alethinophidian species, their anatomy allows limited functional independence of right and left sides and the roof and floor of the mouth as well as wide separation of the tips of the mandibles. However, locations of the tongue and glottis in snakes suggest extraordinary rearrangement of pharyngeal structures characteristic of all vertebrates. Serial histological sections through the heads of a number of colubroid species show muscularis mucosal smooth muscle fibers appearing in the paratracheal gutter of the lower jaw at varying levels between the eye and ear regions. Incomplete muscularis externa elements appear beneath the paratracheal gutter more caudally but typically at otic levels. Both muscle layers encompass more of the gut wall at more posterior levels, encircling the gut at the level of the atlas or axis. The pattern in snakes suggests developmental dissociation of dorsal and ventral splanchnic derivatives and extensive topological rearrangements of some ventral pharyngeal arch derivatives typical of most tetrapods. When snakes swallow large prey, the effective oral cavity becomes extremely short ventrally. The palatomaxillary arches function as ratchets packing the prey almost directly into the esophagus. Our findings raise questions about germ layer origins and regulation of differentiation of gut regions and derivatives in snakes and suggest that significant aspects of the evolution of lepidosaurs may be difficult to recover from bones or molecular sequence data alone. PMID- 24482369 TI - Role of the FUL-SHP network in the evolution of fruit morphology and function. AB - Arabidopsis research in the last decade has started to unravel the genetic networks directing gynoecium and fruit patterning in this model species. Only recently, the work from several groups has also started to address the conservation of these networks in a wide number of species with very different fruit morphologies, and we are now beginning to understand how they might have evolved. This review summarizes recent advances in this field, focusing mainly on MADS-box genes with a well-known role in dehiscence zone development, while also discussing how these studies may contribute to expand our views on fruit evolution. PMID- 24482368 TI - Class I BASIC PENTACYSTEINE factors regulate HOMEOBOX genes involved in meristem size maintenance. AB - The BASIC PENTACYSTEINE (BCP) family is a poorly characterized plant transcription factor family of GAGA BINDING PROTEINS. In Arabidopsis, there are seven members (BPC1-7) that are broadly expressed, and they can potentially bind more than 3000 Arabidopsis GAGA-repeat-containing genes. To date, BPCs are known to be direct regulators of the INNER NO OUTER (INO), SEEDSTICK (STK), and LEAFY COTYLEDON 2 (LEC2) genes. Because of the high functional redundancy, neither single knockout nor double bpc mutant combinations cause aberrant phenotypes. The bpc1-2 bpc2 bpc3 triple mutant shows several pleiotropic developmental defects, including enlargement of the inflorescence meristem and flowers with supernumerary floral organs. Here, we demonstrated through expression analysis and chromatin immunoprecipitation assays that this phenotype is probably due to deregulation of the expression of the SHOOTMERISTEMLESS (STM) and BREVIPEDICELLUS/KNAT1 (BP) genes, which are both direct targets of BPCs. Moreover, we assigned a role to BPCs in the fine regulation of the cytokinin content in the meristem, as both ISOPENTENYLTRANSFERASE 7 (IPT7) and ARABIDOPSIS RESPONSE REGULATOR 7 (ARR7) genes were shown to be overexpressed in the bpc1-2 bpc2 bpc3 triple mutant. PMID- 24482370 TI - Spread the news: systemic dissemination and local impact of Ca2+ signals along the phloem pathway. AB - We explored the idea of whether electropotential waves (EPWs) primarily act as vehicles for systemic spread of Ca(2+) signals. EPW-associated Ca(2+) influx may trigger generation and amplification of countless long-distance signals along the phloem pathway given the fact that gating of Ca(2+)-permeable channels is a universal response to biotic and abiotic challenges. Despite fundamental differences, both action and variation potentials are associated with a sudden Ca(2+) influx. Both EPWs probably disperse in the lateral direction, which could be of essential functional significance. A vast set of Ca(2+)-permeable channels, some of which have been localized, is required for Ca(2+)-modulated events in sieve elements. There, Ca(2+)-permeable channels are clustered and create so called Ca(2+) hotspots, which play a pivotal role in sieve element occlusion. Occlusion mechanisms play a central part in the interaction between plants and phytopathogens (e.g. aphids or phytoplasmas) and in transient re-organization of the vascular symplasm. It is argued that Ca(2+)-triggered systemic signalling occurs in partly overlapping waves. The forefront of EPWs may be accompanied by a burst of free Ca(2+) ions and Ca(2+)-binding proteins in the sieve tube sap, with a far-reaching impact on target cells. Lateral dispersion of EPWs may induce diverse Ca(2+) influx and handling patterns (Ca(2+) signatures) in various cell types lining the sieve tubes. As a result, a variety of cascades may trigger the fabrication of signals such as phytohormones, proteins, or RNA species released into the sap stream after product-related lag times. Moreover, transient reorganization of the vascular symplasm could modify cascades in disjunct vascular cells. PMID- 24482371 TI - Chemico-physical synthesis of surfactant- and ligand-free gold nanoparticles and their anti-galvanic reduction property. AB - Galvanic reduction (GR) is a classic reaction. In simple terms, metals can reduce less reactive (or more noble) metal ions, while the opposite--metals reduce more reactive (or less noble) metal ions--should not occur. However, recently we found that anti-galvanic reduction (AGR) occurred to thiolated gold and silver nanoparticles. However, the essential issue whether the occurrence of AGR requires the assistance of reductive thiolate ligands or not still remained unanswered. In this work, by using a novel protocol (chemical reduction and physical ablation), we synthesized surfactant- and ligand-free gold nanoparticles. We found that these as-prepared nanoparticles can reduce silver ions and copper ions, thus illustrating that AGR is not dependent on reductive ligands. Further experiments demonstrated that AGR is applicable to other metal (such as Pt and Pd) nanoparticles and that the AGR process is size-dependent. Finally, it was found that the Raman scattering signals of Rhodamine 6G are distinctly enhanced on the gold nanoparticles that had been reacted with silver ions, which indicates the use of AGR for tuning the property of nanoparticles. PMID- 24482372 TI - Assay of melamine in milk products with a pH-mediated stacking technique in capillary electrophoresis. AB - A pH-mediated stacking method in capillary electrophoresis as an assay for low concentrations of melamine in milk products was established. Real samples were treated with acetone and sodium acetate and injected directly after centrifugation and filtration. Several experimental factors, such as buffer pH, buffer concentration, sample matrix, injection/sweeping ratio, sweeping time/voltages, separation voltages, as well as sample pretreatment, which affected stacking and separation, were investigated and optimized. Under the selected condition, a low LOD of 0.01 MUmol/L (S/N = 5) and a wide range of linearity of 0.01~1.0 MUmol/L could be easily achieved with a good reproducibility (RSDs < 5.8% for both migration time and peak area) and an acceptable recovery of 94.0~103.2% (for milk, infant formula, yogurt, and milk products). The proposed method was suitable for routine assay of melamine in real milk samples. PMID- 24482373 TI - Arterial stiffness is associated with carotid intraplaque hemorrhage in the general population: the Rotterdam study. AB - OBJECTIVE: The relation between arterial stiffness and atherosclerosis, and specifically the influence of arterial stiffness on plaque composition, is largely unknown. In a population-based study, we investigated the association between arterial stiffness and the presence and composition of carotid atherosclerotic plaques. APPROACH AND RESULTS: Arterial stiffness was measured in 6527 participants (67.0+/-8.6 years) using aortic pulse wave velocity (PWV). Presence of carotid atherosclerotic plaques was assessed with ultrasound. Subsequently, 1059 subjects with carotid plaques (>2.5 mm) underwent MRI to assess plaque composition (presence of intraplaque hemorrhage, lipid, and calcification). Generalized estimation equation analyses adjusted for age, sex, mean arterial pressure, heart rate, carotid wall thickening, pulse pressure, and traditional cardiovascular risk factors were used to study the association between PWV and the presence and composition of carotid atherosclerotic plaques. In multivariable analysis, higher PWV was independently related to higher prevalence of carotid atherosclerotic plaque on ultrasound (odds ratio for highest quartile of PWV compared with lowest quartile, 1.24 [95% confidence interval, 1.02-1.51]). Furthermore, higher PWV was associated with intraplaque hemorrhage (age- and sex-adjusted odds ratio per SD increase in PWV, 1.20 [1.04 1.38] and calcification, 1.18 [1.03-1.35]), but not with lipid. After adjustment for cardiovascular risk factors, PWV remained significantly associated with intraplaque hemorrhage (1.20 [1.01-1.43]). Additional adjustment for pulse pressure did not materially affect the effect estimate (1.19 [1.00-1.42]). CONCLUSIONS: Higher PWV is associated with presence and composition of carotid atherosclerotic plaques, in particular with intraplaque hemorrhage. These findings provide further clues for understanding the development of vulnerable atherosclerotic plaque. PMID- 24482374 TI - Metformin protects endothelial function in diet-induced obese mice by inhibition of endoplasmic reticulum stress through 5' adenosine monophosphate-activated protein kinase-peroxisome proliferator-activated receptor delta pathway. AB - OBJECTIVE: 5' Adenosine monophosphate-activated protein kinase (AMPK) interacts with peroxisome proliferator-activated receptor delta (PPARdelta) to induce gene expression synergistically, whereas the activation of AMPK inhibits endoplasmic reticulum (ER) stress. Whether the vascular benefits of antidiabetic drug metformin (AMPK activator) in diabetes mellitus and obesity is mediated by PPARdelta remains unknown. We aim to investigate whether PPARdelta is crucial for metformin in ameliorating ER stress and endothelial dysfunction induced by high fat diet. APPROACH AND RESULTS: Acetylcholine-induced endothelium-dependent relaxation in aortae was measured on wire myograph. ER stress markers were determined by Western blotting. Superoxide production in mouse aortae and NO generation in mouse aortic endothelial cells were assessed by fluorescence imaging. Endothelium-dependent relaxation was impaired and ER stress markers and superoxide level were elevated in aortae from high-fat diet-induced obese mice compared with lean mice. These effects of high-fat diet were reversed by oral treatment with metformin in diet-induced obese PPARdelta wild-type mice but not in diet-induced obese PPARdelta knockout littermates. Metformin and PPARdelta agonist GW1516 reversed tunicamycin (ER stress inducer)-induced ER stress, oxidative stress, and impairment of endothelium-dependent relaxation in mouse aortae as well as NO production in mouse aortic endothelial cells. Effects of metformin were abolished by cotreatment of GSK0660 (PPARdelta antagonist), whereas effects of GW1516 were unaffected by compound C (AMPK inhibitor). CONCLUSIONS: Metformin restores endothelial function through inhibiting ER stress and oxidative stress and increasing NO bioavailability on activation of AMPK/PPARdelta pathway in obese diabetic mice. PMID- 24482375 TI - Arguing the case for the autotaxin-lysophosphatidic acid-lipid phosphate phosphatase 3-signaling nexus in the development and complications of atherosclerosis. AB - The structurally simple glycero- and sphingo-phospholipids, lysophosphatidic acid (LPA) and sphingosine-1-phosphate, serve as important receptor-active mediators that influence blood and vascular cell function and are positioned to influence the events that contribute to the progression and complications of atherosclerosis. Growing evidence from preclinical animal models has implicated LPA, LPA receptors, and key enzymes involved in LPA metabolism in pathophysiologic events that may underlie atherosclerotic vascular disease. These observations are supported by genetic analysis in humans implicating a lipid phosphate phosphatase as a novel risk factor for coronary artery disease. In this review, we summarize current understanding of LPA production, metabolism, and signaling as may be relevant for atherosclerotic and other vascular disease. PMID- 24482376 TI - Group VIA phospholipase A2 mediates enhanced macrophage migration in diabetes mellitus by increasing expression of nicotinamide adenine dinucleotide phosphate oxidase 4. AB - OBJECTIVE: We previously demonstrated that nicotinamide adenine dinucleotide phosphate oxidase 4 (Nox4) mediates increased monocyte priming and chemotaxis under conditions of diabetic metabolic stress, and emerging data indicate that group VIA phospholipase A2 (iPLA2beta) also participates in regulating monocyte chemotaxis. Here, we examined relationships between iPLA2beta expression and Nox4 action in mouse peritoneal macrophages subjected to diabetic metabolic stress. APPROACH AND RESULTS: Increased iPLA2beta expression and activity were observed in macrophages from low-density lipoprotein receptor knockout mice that were fed a high-fat diet, and this was associated with time-dependent increases in atherosclerotic lesion size and macrophage content. Incubating macrophages with 30 mmol/L D-glucose, 100 MUg/mL low-density lipoprotein, or both (D-glucose+low density lipoprotein) induced a robust increase in iPLA2beta expression and activity and in cell migration in response to monocyte chemoattractant protein-1. The increases in iPLA2beta activity and cell migration were prevented by a bromoenol lactone iPLA2beta suicide inhibitor or an iPLA2beta antisense oligonucleotide. Incubating macrophages under conditions that mimic diabetic metabolic stress ex vivo resulted in increased Nox4 expression and activity and hydrogen peroxide generation compared with controls. Bromoenol lactone prevented those effects without affecting Nox2 expression. Nox4 inhibition eliminated diabetic metabolic stress-induced acceleration of macrophage migration. Lysophosphatidic acid restored Nox4 expression, hydrogen peroxide generation, and migration to bromoenol lactone-treated cells, and a lysophosphatidic acid receptor antagonist abrogated iPLA2beta-mediated increases in Nox4 expression. CONCLUSIONS: Taken together, these observations identify iPLA2beta and lysophosphatidic acid derived from its action as critical in regulating macrophage Nox4 activity and migration in the diabetic state in vivo and under similar conditions ex vivo. PMID- 24482378 TI - Through the looking glass: the spectacle in gymnophthalmid lizards. AB - The anatomy and development of the eyelids in squamate reptiles are still relatively unknown, considering its variation within the group. The neotropical Gymnophthalmini are traditionally characterized by having lost the eyelids, but their structure is not well described. In this study, the embryonic development and the adult morphology of the gymnophthalmid eye, with special attention to the eyelids, the nictitating membrane, and the spectacle are described. The eye in some Gymnophthalmini is covered by a spectacle, formed by the embryonic fusion of the dorsal and ventral eyelids, a character possibly synapomorphic to the tribe. The genus Tretioscincus, which floats either as sister to all other Gymnophthalmini, or is nested within the group, is unique in showing functional and movable eyelids. Thus, the presence of functional eyelids can be either considered as the primitive condition for the gymnophthalmini or as a re acquisition of the character, showing the importance of a well-established phylogenetic hypothesis for understanding morphological evolution. PMID- 24482377 TI - HIV-1 matrix protein p17 promotes lymphangiogenesis and activates the endothelin 1/endothelin B receptor axis. AB - OBJECTIVE: AIDS-related lymphomas are high grade and aggressively metastatic with poor prognosis. Lymphangiogenesis is essential in supporting proliferation and survival of lymphoma, as well as tumor dissemination. Data suggest that aberrant lymphangiogenesis relies on action of HIV-1 proteins rather than on a direct effect of the virus itself. HIV-1 matrix protein p17 was found to accumulate and persist in lymph nodes of patients even under highly active antiretroviral therapy. Because p17 was recently found to exert a potent proangiogenic activity by interacting with chemokine (C-X-C motif) receptors 1 and 2, we tested the prolymphangiogenic activity of the viral protein. APPROACH AND RESULTS: Human primary lymph node-derived lymphatic endothelial cells were used to perform capillary-like structure formation, wound healing, spheroids, and Western blot assays after stimulation with or without p17. Here, we show that p17 promotes lymphangiogenesis by binding to chemokine (C-X-C motif) receptor-1 and chemokine (C-X-C motif) receptor-2 expressed on lymph node-derived lymphatic endothelial cells and activating the Akt/extracellular signal-regulated kinase signaling pathway. In particular, it was found to induce capillary-like structure formation, sprout formation from spheroids, and increase lymph node-derived lymphatic endothelial cells motility. The p17 lymphangiogenic activity was, in part, sustained by activation of the endothelin-1/endothelin receptor B axis. A Matrigel plug assay showed that p17 was able to promote the outgrowth of lymphatic vessels in vivo, demonstrating that p17 directly regulates lymphatic vessel formation. CONCLUSIONS: Our results suggest that p17 may generate a prolymphangiogenic microenvironment and plays a role in predisposing the lymph node to lymphoma growth and metastasis. This finding offers new opportunities to identify treatment strategies in combating AIDS-related lymphomas. PMID- 24482379 TI - Preparation of monodisperse ferrite nanocrystals with tunable morphology and magnetic properties. AB - The synthesis of monodisperse magnetic ferrite nanomaterials plays an important role in several scientific and technological areas. In this work, dibasic spinel MFe2O4 (M=Mg, Ni, Co, Fe, Mn) and polybasic spinel ferrite MCoFeO4 (M=Mg, Ni, Mn, MgNi) nanocrystals were prepared by the calcination of layered double hydroxide (LDH) precursors at 900 degrees C, which was confirmed by X-ray diffraction (XRD) and Fourier transform infrared (FTIR) spectroscopy. Scanning electron microscopy (SEM) and transmission electron microscopy (TEM) images demonstrate that the as-obtained spinel ferrites present a single-crystalline nature with uniform particle size and good dispersibility. The composition, morphology, and particle size can be effectively tuned by changing the metal ratio, basicity, reaction time, and temperature of the LDH precursors. In addition, these spinel ferrites show high magnetic saturation values in the range 21.7-84.3 emu g(-1), which maintain a higher level than the previously reported magnetic nanoparticles. Therefore, this work provides a facile approach for the design and fabrication of spinel ferrites with controllable nanostructure and improved magnetism, which could potentially be used in magnetic and biological fields, such as recording media, sensors, drug delivery, and intracellular imaging. PMID- 24482381 TI - The NADPH oxidase inhibitor imipramine-blue in the treatment of Burkitt lymphoma. AB - Burkitt lymphoma is a rare malignancy arising from B cells. Current chemotherapeutic regimens achieve excellent overall survival rates in children, but less impressive rates in adults. There are cases with poor outcome caused by toxic effects of the therapy, tumor lysis syndrome, or metastatic spread of lymphomas to the central nervous system. Modulators of reactive oxygen species are currently discussed as potential drugs for the treatment of cancer. The NADPH oxidase 4 inhibitor imipramine-blue might satisfy the aforementioned requirements, and was studied here. We used MTT assay, crystal violet assay, and thymidine 3H-incorporation assay to analyze the effects of imipramine-blue on Burkitt lymphoma (BL2, BL2B95, BL30B95, BL41B95), neuroblastoma (KELLY, SH-SY5Y, SMS-KAN), cervix carcinoma (HeLa), breast cancer (MDA-MB231), angiosarcoma (AS M), human embryonic kidney (HEK293WT), and nonmalignant (FLP1) cell lines. The effects of imipramine-blue on BL2B95 cells in vivo were investigated in xenografts on the chick chorioallantoic membrane (CAM). We report that imipramine blue is a potent growth inhibitor for several cancer cell lines in vitro with IC(50) values comparable to those of doxorubicin (0.16-7.7 MUmol/L). Tumor size of BL2B95 cells inoculated in the CAM was reduced significantly (P < 0.05) after treatment with 10 MUmol/L imipramine-blue. Lymphogenic dissemination of BL2B95 and the formation of blood and lymphatic vessels in experimental tumors were not affected. We show that imipramine-blue can be used to decrease the viability of cancer cell lines in vitro and in vivo. Imipramine-blue reduces the size of experimental Burkitt lymphoma significantly but does not affect the dissemination of BL2B95 cells, angiogenesis, and lymphangiogenesis. PMID- 24482380 TI - V-ATPase inhibition regulates anoikis resistance and metastasis of cancer cells. AB - Fighting metastasis is a major challenge in cancer therapy and novel therapeutic targets and drugs are highly appreciated. Resistance of invasive cells to anoikis, a particular type of apoptosis induced by loss of cell-matrix contact, is a major prerequisite for their metastatic spread. Inducing anoikis in metastatic cancer cells is therefore a promising therapeutic approach. The vacuolar-ATPase (V-ATPase), a proton pump located at the membrane of acidic organelles, has recently come to focus as an antimetastatic cancer target. As V ATPase inhibitors have shown to prevent invasion of tumor cells and are able to induce apoptosis, we proposed that V-ATPase inhibition induces anoikis-related pathways in invasive cancer cells. We used the V-ATPase inhibitor archazolid to investigate the mechanism of anoikis induction in various metastatic cancer cells (T24, MDA-MB-231, 4T1, 5637) in vitro. Anoikis induction by archazolid was characterized by decreased c-FLIP expression and caspase-8 activation as well as reduction of active integrin-beta1 and an early increase of the proapoptotic protein BIM. However, we observed that archazolid also induces mechanisms opposing anoikis such as degradation of BIM mediated by extracellular signal regulated kinase (ERK), Akt and Src kinases at later time points and induction of reactive oxygen species. Still, intravenous injection of archazolid-treated 4T1 Luc2 mouse breast cancer cells resulted in reduced metastasis in mouse lungs. Thus, V-ATPase inhibition is not only an interesting option to reduce cancer metastasis, but also to better understand anoikis resistance and to find choices to fight against it. PMID- 24482382 TI - Risk stratification for in-hospital mortality after cardiac surgery: external validation of EuroSCORE II in a prospective regional registry. AB - OBJECTIVES: To evaluate performance of the European System for Cardiac Operation Risk Evaluation (EuroSCORE II), to assess the influence of model updating and to derive a hierarchical tree for modelling the relationship between EuroSCORE II risk factors and hospital mortality after cardiac surgery in a large prospective contemporary cohort of consecutive adult patients. METHODS: Data on consecutive patients, who underwent on-pump cardiac surgery or off-pump coronary artery bypass graft intervention, were retrieved from Puglia Adult Cardiac Surgery Registry. Discrimination, calibration, re-estimation of EuroSCORE II coefficients and hierarchical tree analysis of risk factors were assessed. RESULTS: Out 6293 procedures, 6191 (98.4%) had complete data for EuroSCORE II assessment with a hospital mortality rate of 4.85% and EuroSCORE II of 4.40 +/- 7.04%. The area under the receiver operator characteristic curve (0.830) showed good discriminative ability of EuroSCORE II in distinguishing patients who died and those who survived. Calibration of EuroSCORE II was preserved with lower predicted than observed risk in the highest EuroSCORE II deciles. At logistic regression analysis, the complete revision of the model had most of re-estimated regression coefficients not statistically different from those in the original EuroSCORE II model. When missing values were replaced with the mean EuroSCORE II value according to urgency and weight of intervention, the risk score confirmed discrimination and calibration obtained over the entire sample. A recursive tree building algorithm of EuroSCORE II variables identified three large groups (55.1, 17.1 and 18.1% of procedures) with low-to-moderate risk (observed mortality of 1.5, 3.2 and 6.4%) and two groups (3.8 and 5.9% of procedures) at high risk (mortality of 14.6 and 32.2%). Patients with low-to-moderate risk had good agreement between observed events and predicted frequencies by EuroSCORE II, whereas those at greater risk showed an underestimation of expected mortality. CONCLUSIONS: This study demonstrates that EuroSCORE II is a good predictor of hospital mortality after cardiac surgery in an external validation cohort of contemporary patients from a multicentre prospective regional registry. The EuroSCORE II predicts hospital mortality with a slight underestimation in high risk patients that should be further and better evaluated. The EuroSCORE II variables as a risk tree provides clinicians and surgeons a practical bedside tool for mortality risk stratification of patients at low, intermediate and high risk for hospital mortality after cardiac surgery. PMID- 24482383 TI - Coronary artery bypass grafting-related bleeding complications in real-life acute coronary syndrome patients treated with clopidogrel or ticagrelor. AB - OBJECTIVES: Ticagrelor reduces thrombotic events compared with clopidogrel in patients with acute coronary syndrome, but may also increase bleeding complications. Coronary artery bypass grafting (CABG)-related bleeding complications have not previously been compared in clopidogrel and ticagrelor treated patients outside the controlled environment of clinical trials. METHODS: Four hundred and five consecutive CABG patients with acute coronary syndrome were included in a prospective observational study. The patients were treated with aspirin and ticagrelor (n = 173) or aspirin and clopidogrel (n = 232). Ticagrelor/clopidogrel was discontinued 5 days before surgery whenever deemed possible. Major bleeding complications according to modified blood conservation using antifibrinolytics in a randomized trial criteria (postoperative blood loss >1500 ml/12 h, re-exploration, red blood cell transfusion >10 units or death because of bleeding) were compared in all patients and when ticagrelor/clopidogrel was discontinued >=5 days (n = 280), 2-4 days (n = 40) or 0-1 day before surgery (n = 85). RESULTS: Major bleeding complications did not differ significantly between ticagrelor- and clopidogrel-treated patients when all patients were compared (14.5 vs 13.8%, P = 0.89). Likewise, there were no significant differences between ticagrelor and clopidogrel when either drug was discontinued >=5 days before surgery (6.8 vs 9.9%, P = 0.40) or 2-4 days before surgery (6.3 vs 25.0%, P = 0.21). When ticagrelor/clopidogrel was discontinued 0 1 day before surgery, there was a strong trend towards higher incidence of major bleeding in ticagrelor-treated patients (41.0 vs 21.7%, P = 0.063). CONCLUSIONS: There was no difference in major bleeding complications overall or when ticagrelor or clopidogrel was used in accordance with guidelines. In patients on dual antiplatelet medication up to 1 day before surgery, there tended to be more bleeding complications in ticagrelor-treated patients. PMID- 24482384 TI - Oxidative stress during extracorporeal circulation. AB - There is an increased oxidative stress response in patients having cardiac surgery, haemodialysis or extracorporeal membrane oxygenation that is related to poorer outcomes and increased mortality. Exposure of the patients' blood to the artificial surfaces of these extracorporeal devices, coupled with inflammatory responses, hyperoxia and the pathophysiological aspects of the underlying illness itself, all contribute to this oxidative stress response. Oxidative stress occurs when there is a disruption of redox signalling and loss of control of redox balance. Ongoing oxidative stress occurring during extracorporeal circulation (ECC) results in damage to lipids, proteins and DNA and contributes to morbidity and mortality. This review discusses reactive species generation and the potential clinical consequences of oxidative stress during ECC as well as provides an overview of some current antioxidant compounds that are available to potentially mitigate the oxidative stress response. PMID- 24482386 TI - Predictors of long-term survival following radical surgery for malignant pleural mesothelioma. AB - OBJECTIVES: The aim of radical surgery for malignant pleural mesothelioma (MPM) is to achieve greater survival than from chemotherapy alone. Although adverse overall prognostic factors have already been determined, our aim was to identify the most important factors affecting long-term survival arbitrarily defined as >24 months. METHODS: We retrospectively reviewed the records of 252 patients (35 females; 193 epithelioid and 59 biphasic; 112 extrapleural pneumonectomy (EPP); 140 extended pleurectomy decortication (EPD)) who survived for at least 90 postoperative days. We tested for factors affecting overall cancer-related mortality and specific clinical factors predicting the 24-month survival. RESULTS: The overall median survival was 18.2 (SE 1.3, 95% CI 15.8-20.7 months). There was no difference in survival between EPP and EPD (P = 0.92). One hundred and twenty-eight patients received induction, adjuvant or palliative chemotherapy. Seventy-seven (30.6%) patients survived for >24 months. On univariate analysis, age at operation over 60 years (P = 0.044), pT4 stage (P = 0.041), any lymph node metastases (P = 0.002), biphasic cell type (P = 0.00) and no administration of chemotherapy (P = 0.00) were associated with decreased survival. On multivariate analysis, age <60 (P = 0.018, OR = 0.7), epithelioid disease (P = 0.001, OR = 0.56) and negative nodes (P = 0.009, OR = 0.67) were associated with increased survival and no administration of chemotherapy (P = 0.00, OR = 1.9) with decreased survival. Factors predicting survival over 24 months included: age at operation under 60 (P = 0.014), epithelioid histology (P <= 0.00), negative nodes (P = 0.002) and chemotherapy (P = 0.022). CONCLUSIONS: These results support a policy of accurate preoperative tissue diagnosis, nodal staging and induction chemotherapy prior to radical surgery for MPM, which can result in long-term survival. Trials investigating the role of surgery should be focused on confirming and refining these selection criteria. PMID- 24482385 TI - Adipocytokine resistin correlates with oxidative stress and myocardial injury in patients undergoing cardiac surgery. AB - OBJECTIVES: Adipocytokines are hormones regulating energy metabolism and appetite and according to recent reports also inflammatory responses including ischaemia reperfusion injury. Based on experimental data, we hypothesized that the levels of adipocytokines adiponectin, adipsin, leptin and/or resistin would correlate with myocardial injury, inflammation and oxidative stress during cardiac surgery. METHODS: Thirty-two patients undergoing an elective on-pump coronary artery bypass graft surgery (CABG) with cardiopulmonary bypass (CPB) were recruited into the study. Blood samples were collected after the induction of anaesthesia, and at the onset of CPB, 1 and 15 min after the removal of aortic cross-clamp and 4 and 24 h after the onset of CPB. Samples were analysed for levels of four adipocytokines (adiponectin, adipsin, leptin and resistin) and markers of oxidative stress [myeloperoxidase (MPO) and 8-isoprostane], inflammation [interleukin-6 (IL-6)] and myocardial injury [troponin T (TnT)]. RESULTS: Adiponectin and adipsin concentrations declined, while leptin and resistin levels increased significantly by 24 h after the onset of the operation. Interestingly, basal levels of resistin (r = 0.41, P = 0.020) as well as the maximal increase occurring in resistin levels during the 24-h follow-up (r = 0.49, P = 0.005) correlated positively with TnT release. In addition, the reperfusion-induced elevation in resistin levels correlated positively with oxidative stress measured as increases in MPO concentrations. CONCLUSIONS: As an original finding, we report here that resistin levels correlate with oxidative stress and myocardial injury in patients undergoing cardiac surgery. In addition, leptin levels were increased on the first postoperative day, but only minor declines were found in adiponectin and adipsin levels. Resistin has been implicated in unfavourable metabolic, cardiovascular and inflammatory responses: it may thus serve as a useful biomarker or a drug target in conditions complicated by ischaemia reperfusion injury. PMID- 24482387 TI - The fate of the bicuspid valve aortopathy after aortic valve replacement. AB - OBJECTIVES: The fate of the aortic dimensions in patients with a bicuspid aortic valve (BAV) after aortic valve replacement (AVR) is unclear. We investigated the evolution of aortic root and ascending aorta dimensions in patients with a BAV after AVR. To neutralize the effect of pathological transvalvular haemodynamics on aortic dimensions, we evaluated our hypotheses in patients with normal transvalvular haemodynamics after a subcoronary autograft procedure, which preserves intact the native aortic wall. METHODS: We excluded patients operated on for endocarditis; who developed autograft insufficiency > trivial and who required autograft reoperation during the follow-up. We included 448 patients (361 with BAV; 340 males; 44.6 +/- 11.4 years; mean follow-up: 7.5 +/- 3.9 years). Valve phenotype was determined during surgery. Annual echocardiographic examinations (n = 3336) were performed (follow-up completeness: 98%). To allow for somatometric, gender and age influences, z-values of measurements were calculated from the general population (GP) and analysed using longitudinal methods. RESULTS: The increase in ascending aorta did not differ from that expected in the GP (0.04 z-values/year; P = 0.06). No difference could be observed in diameter increase rates between BAV and tricuspid aortic valve patients (TAV) (0.04 vs 0.06 z-values/year; P = 0.3), as well as between BAV phenotypes. The sinus increase did not differ from that expected in the GP (0.03 z-values/year; P = 0.1), and no significant differences could be observed between BAV phenotypes. In patients undergoing aortoplasty (n = 70), no significant difference in the rates of ascending aorta and sinus increase could be observed, compared with the GP. CONCLUSION: For the time period of this study and in patients with normal aortic root haemodynamics after AVR, ascending aorta dimensions over time are similar to that of the matched GP. Patients with a BAV did not exhibit higher rates of ascending aorta dilatation after AVR than patients with TAV. At least for the first postoperative decade, transvalvular haemodynamics appear to exhibit a greater influence than the genetic component of BAV on the development of the BAV aortopathy. PMID- 24482388 TI - The Yasui operation for patients with adequate-sized ventricles and ventricular septal defect associated with obstructions of the aortic arch and left ventricular outflow tract. AB - OBJECTIVE: To review the surgical outcome of the Yasui operation in patients with adequate-sized ventricles and ventricular septal defect (VSD) associated with obstructions of the aortic arch and left ventricular outflow tract (LVOT). METHODS: Since 1985, 17 patients have undergone the Yasui operation at our institution. Interrupted aortic arch was present in 11 patients and coarctation of the aorta/hypoplastic arch was present in 6. Twelve patients had aortic stenosis, and 5 patients had aortic atresia. The minimum diameter of the LVOT and the z-score in patients with aortic stenosis were 3.7 +/- 0.4 mm and -9.2 +/- 1.2, respectively. Primary repair was performed in 6 patients, and 11 patients were staged, with bilateral pulmonary artery banding (PAB) in 8, arch repair with PAB in 2 and Norwood operation in 1. The mean age and body weight at the time of the Yasui operation was 4.7 +/- 5.3 months and 4.5 +/- 1.8 kg, respectively. The ascending aorta and aortic arch were reconstructed by Damus-Kaye-Stansel (DKS) anastomosis with graft interposition in 2, DKS with direct anastomosis in 6 and Norwood-type reconstruction in 9. VSD was enlarged in 6 patients. Right ventricle to pulmonary artery continuity was established with a valved conduit in 14 patients, the Lecompte manoeuvre in 2 patients and another method in 1 patient. The mean duration of the follow-up was 7.6 +/- 9.2 years. RESULTS: There was 1 early death due to myocardial infarction and 1 late death due to non-cardiac cause. The actuarial survival at 10 years was 87.8%. Six patients underwent reoperation, including 5 conduit exchanges, 2 LVOT repairs and 2 aortic arch repairs. The freedom from reoperation for all causes at 5 and 10 years were 71.3 and 28.5%, respectively. In the last echo study, LVOT flow velocity was 1.2 +/- 0.8 m/s, and neoaortic valve regurgitation was mild in 1 patient and trivial or absent in the remaining patients. CONCLUSIONS: The results of the Yasui operation were excellent, showing low mortality and good mid-term left ventricular function without outflow tract stenosis or neoaortic valve insufficiency. Bilateral PAB as initial palliation is a useful option in symptomatic neonates. PMID- 24482390 TI - Left ventricular function can be continuously monitored with an epicardially attached accelerometer sensor. AB - OBJECTIVES: Preservation of left ventricular (LV) function is crucial for a beneficial outcome in high-risk patients undergoing cardiac surgery. The present study evaluated a motion sensor (accelerometer) for continuous monitoring of LV performance during changes in global and regional LV function. METHODS: In 11 pigs, an accelerometer was sutured to the epicardium on the anterior apical LV region. Global LV function was modulated by esmolol, epinephrine and fluid loading, whereas regional LV dysfunction was induced by a 3-min occlusion of left anterior descending (LAD) coronary artery. Epicardial acceleration in the circumferential direction was obtained by the accelerometer, and from this signal, epicardial velocity was calculated. Peak systolic velocity was measured and used as an index of LV performance. The accelerometer was compared with left ventricular stroke work (LVSW), ejection fraction and myocardial strain by echocardiography. RESULTS: Accelerometer peak systolic velocity and LVSW changed significantly during all interventions, affecting global LV function. Systolic velocity by the accelerometer increased during epinephrine and fluid loading from 14.1 [10.2; 17.3] to 25.4 [16.7; 28.5] (P < 0.05) and 14.8 [12.5; 18.5] cm/s (P < 0.05), respectively. Esmolol infusion significantly decreased accelerometer peak systolic velocity to 9.4 [7.3; 10.7] cm/s (P < 0.05). Minor changes were seen in the echocardiographic measurements, with significant changes only observed in myocardial strain during the interventions with esmolol and epinephrine. Regional LV dysfunction was clearly detected by the accelerometer during LAD occlusion, and peak systolic velocity was reduced from 14.1 [10.2; 17.3] to 5.7 [5.0; 6.8] cm/s (P < 0.05). The accelerometer demonstrated higher sensitivity and specificity for the detection of myocardial ischaemia than LVSW and ejection fraction. For all interventions, accelerometer peak systolic velocity correlated strongly with LVSW (r = 0.81, P < 0.01) and myocardial strain (r = 0.80; P < 0.01). CONCLUSIONS: It was possible to obtain accurate information on LV performance by the use of an epicardially attached accelerometer. The method allows continuous monitoring of LV function and may therefore improve perioperative monitoring of cardiac surgery patients. PMID- 24482389 TI - Tumours of the thymus: a cohort study of prognostic factors from the European Society of Thoracic Surgeons database. AB - OBJECTIVES: A retrospective database was developed by the European Society of Thoracic Surgeons, collecting patients submitted to surgery for thymic tumours to analyse clinico-pathological prognostic predictors. METHODS: A total of 2151 incident cases from 35 institutions were collected from 1990 to 2010. Clinical pathological characteristics were analysed, including age, gender, associated myasthenia gravis stage (Masaoka), World Health Organization histology, type of thymic tumour [thymoma, thymic carcinoma (TC), neuroendocrine thymic tumour (NETT)], type of resection (complete/incomplete), tumour size, adjuvant therapy and recurrence. Primary outcome was overall survival (OS); secondary outcomes were the proportion of incomplete resections, disease-free survival and the cumulative incidence of recurrence (CIR). RESULTS: A total of 2030 patients were analysed for OS (1798 thymomas, 191 TCs and 41 NETTs). Ten-year OS was 0.73 (95% confidence interval 0.69-0.75). Complete resection (R0) was achieved in 88% of the patients. Ten-year CIR was 0.12 (0.10-0.15). Predictors of shorter OS were increased age (P < 0-001), stage [III vs I HR 2.66, 1.80-3.92; IV vs I hazard ratio (HR) 4.41, 2.67-7.26], TC (HR 2.39, 1.68-3.40) and NETT (HR 2.59, 1.35 4.99) vs thymomas and incomplete resection (HR 1.74, 1.18-2.57). Risk of recurrence increased with tumour size (P = 0.003), stage (III vs I HR 5.67, 2.80 11.45; IV vs I HR 13.08, 5.70-30.03) and NETT (HR 7.18, 3.48-14.82). Analysis using a propensity score indicates that the administration of adjuvant therapy was beneficial in increasing OS (HR 0.69, 0.49-0.97) in R0 resections. CONCLUSIONS: Masaoka stages III-IV, incomplete resection and non-thymoma histology showed a significant impact in increasing recurrence and in worsening survival. The administration of adjuvant therapy after complete resection is associated with improved survival. PMID- 24482391 TI - Blood conservation strategies in cardiac surgery: more is better. AB - OBJECTIVES: Recent data show that up to 50% of heart procedures require blood transfusion, which can have adverse long- and short-term outcomes for the patient. This led to the updated 2011 Society of Thoracic Surgery (STS)/Society of Cardiovascular Anesthesiologists (SCA) guidelines in an attempt to adopt more effective blood conservation techniques. We present our results after the implementation of a more aggressive strategy for intraoperative blood conservation in cardiac surgery. METHODS: Our cardiac surgery database was reviewed retrospectively, comparing outcomes from two different time periods, after the implementation of a more effective two-way blood conservation strategy beginning in March 2012: more aggressive intraoperative autologous donation (IAD) based on a newly constructed nomogram, and the use of a shorter length circuit of the cardiopulmonary bypass (CPB) which allowed for lower fluid volume as a prime. The method of retrograde autologous priming (RAP) was the same for both time periods. RESULTS: A total of 1126 patients (Group 1) were studied in a 12-month period (March 2012-February 2013) after the implementation of the new strategy, and compared with 3758 patients (Group 2) of the previous 36-month period (March 2009-February 2012). There was a significant reduction in the percent change of the intraoperative haematocrit between Groups 1 and 2 (14 vs 28%, P = 0.01), with an increase in the mean IAD volume (655 vs 390 ml, P = 0.02) and a reduction in the CPB priming volume (1000 vs 1600 ml, P = 0.03). Group 1 required significantly less blood transfusions in the perioperative period (29 vs 49%, P = 0.02) and had significantly reduced postoperative rates of respiratory failure (3 vs 7%, P = 0.03), pneumonia (1 vs 3.1%, P = 0.01), chest tube output (350 vs 730 ml, P = 0.01), reoperation for bleeding (1.2 vs 2.5%, P = 0.04) and length of stay (6.1 vs 8.2 days, P = 0.05). CONCLUSIONS: Blood conservation is safe and effective in reducing transfusions in cardiac surgery, minimizing perioperative morbidity and mortality. Aggressive IAD and low CPB prime, along with effective RAP, is the three-way blood conservation strategy that leads to improved outcomes in cardiac surgery. PMID- 24482392 TI - Determination of strobilurin fungicides in cotton seed by combination of acetonitrile extraction and dispersive liquid-liquid microextraction coupled with gas chromatography. AB - The simultaneous determination of four strobilurin fungicides (picoxystrobin, kresoxim-methyl, trifloxystrobin, and azoxystrobin) in cotton seed by combining acetonitrile extraction and dispersive liquid-liquid microextraction was developed prior to GC with electron capture detection. Several factors, including the type and volume of the extraction and dispersive solvents, extraction condition and time, and salt addition, were optimized. The analytes were extracted with acetonitrile from cotton seed and the clean-up was carried out by primary secondary amine. Afterwards, 60 MUL of n-hexane/toluene (1:1, v/v) with a lower density than water was mixed with 1 mL of the acetonitrile extract, then the mixture was injected into 7 mL of distilled water. A 0.1 mL pipette was used to collect a few microliters of n-hexane/toluene from the top of the aqueous solution. The enrichment factors of the analytes ranged from 36 to 67. The LODs were in the range of 0.1 * 10(-3) -2 * 10(-3) mg/kg. The relative recoveries varied from 87.7 to 95.2% with RSDs of 4.1-8.5% for the four fungicides. The good performance of the method, compared with the conventional pretreatments, has demonstrated it is suitable for determining low concentrations of strobilurin fungicide residues in cotton seed. PMID- 24482393 TI - Unusual soft-tissue preservation of a crocodile lizard (Squamata, Shinisauria) from the green river formation (Eocene) and shinisaur relationships. AB - We describe an unusual squamate fossil from the Green River Formation (Uintan, Eocene) from the Piceance Creek Basin, Colorado, USA. The new specimen, USNM PAL 540708, is a small fossil squamate skin lacking skeletal elements. It is preserved as a part and counterpart in fine-grained limestone. Recovery of a fossil organism's skin (not a shed, but a true skin) is unusual and is most often accompanied by bone preservation. Phylogenetic analysis of a combined morphology (phenotype) and genetic data set reveals that USNM PAL 540708 is a shinisaur and reaffirms that shinisaurs are more closely related to varanids than to Xenosaurus. Shinisaur fossils are very rare, with only three species having been described (Dalinghosaurus longidigitus, Bahndwivici ammoskius, and Merkurosaurus ornatus). Despite differences in the relative size of scales, the new fossil demonstrates that shinisaurs have remained unchanged in the distribution of scales and patterns of scale size during the Cenozoic. This, paired with the osteological similarity between another Green River fossil (Bahndwivici ammoskius) demonstrates considerable overall conservatism within shinisaurs over the past 50 million years. PMID- 24482394 TI - Metal complexes of carbaporphyrinoid systems. AB - The cavities of carbaporphyrinoid systems provide unique environments for the formation of organometallic species. These systems commonly act as either dianionic or trianionic ligands, and may stabilize unusual oxidation states such as silver(III). Although the metalation of N-confused porphyrins has been explored in great detail, the formation of metallo-derivatives of other carbaporphyrinoids remains far less well explored. Nevertheless, exciting advances have been made on the metalation of carbaporphyrins, azuliporphyrins, benziporphyrins and related macrocycles. PMID- 24482395 TI - Aptamer-affinity column clean-up coupled with ultra high performance liquid chromatography and fluorescence detection for the rapid determination of ochratoxin A in ginger powder. AB - Aptamers are single-stranded oligonucleotides with high affinity and specificity and are widely used in targets separation and enrichment. Here, an aptamer affinity column (AAC) was firstly prepared in-house through a covalent immobilization strategy. Then, ochratoxin A (OTA) in ginger powder was absorbed and enriched using the new aptamer-based clean-up technology for the first time, and was further analyzed by ultra high performance liquid chromatography with fluorescence detection. After optimization, the average recoveries for blank samples spiked with OTA at 5, 15, and 45 MUg/kg ranged from 85.36 to 96.83%. Furthermore, the AAC exhibited a similar accuracy as an immunoaffinity column to clean up OTA in ginger powder. Above all, it exhibited better reusability, twice that of the immunoaffinity column, had lower toxicity and cost, and took less time. Of 25 contaminated ginger powder samples, OTA contamination levels ranged from 1.51 to 4.31 MUg/kg, which were lower than the European Union (EU) regulatory limits. All the positive samples were further confirmed by ultra-fast LC with MS/MS. In conclusion, the method of clean-up based on the AAC coupled to ultra-HPLC with fluorescence detection was rapid, specific, and sensitive for the quantitative analysis of OTA in a complex matrix. PMID- 24482396 TI - Geometric morphometric analysis of the breast-shoulder apparatus of lizards: a test case using Jamaican anoles (Squamata: Dactyloidae). AB - The breast-shoulder apparatus (BSA) is a structurally and kinematically complex region of lizards. Compared with the pelvic region it has received little attention, even though its morphological variation is known to be extensive. This variability has seldom been the focus of functional explanation, possibly because the BSA has been difficult to explore as a composite entity. In this study we apply geometric morphometric techniques to the analysis of the BSA in an attempt to more fully understand its configuration in relation to differential use in locomotion. Our approach centers upon the Jamaican radiation of anoline lizards (genus Norops) as a tractable, small monophyletic assemblage consisting of species representing several ecomorphs. We hypothesized that the different species and ecomorphs would exhibit variation in the configuration of the BSA. Our findings indicate that this is so, and is expressed in the component parts of the BSA, although it is subtle except for Norops valencienni (twig ecomorph), which differs greatly in morphology (and behavior) from its island congeners. We further found similarities in the BSA of N. grahami, N. opalinus (both trunk crown ecomorphs), and N. garmani (crown giant). These outcomes are promising for associating morphology with ecomorphological specialization and for furthering our understanding of the adaptive response of the BSA to demands on the locomotor system. PMID- 24482397 TI - Nanomolar bifenthrin alters synchronous Ca2+ oscillations and cortical neuron development independent of sodium channel activity. AB - Bifenthrin, a relatively stable type I pyrethroid that causes tremors and impairs motor activity in rodents, is broadly used. We investigated whether nanomolar bifenthrin alters synchronous Ca(2+) oscillations (SCOs) necessary for activity dependent dendritic development. Primary mouse cortical neurons were cultured 8 or 9 days in vitro (DIV), loaded with the Ca(2+) indicator Fluo-4, and imaged using a Fluorescence Imaging Plate Reader Tetra. Acute exposure to bifenthrin rapidly increased the frequency of SCOs by 2.7-fold (EC50 = 58 nM) and decreased SCO amplitude by 36%. Changes in SCO properties were independent of modifications in voltage-gated sodium channels since 100 nM bifenthrin had no effect on the whole-cell Na(+) current, nor did it influence neuronal resting membrane potential. The L-type Ca(2+) channel blocker nifedipine failed to ameliorate bifenthrin-triggered SCO activity. By contrast, the metabotropic glutamate receptor (mGluR)5 antagonist MPEP [2-methyl-6-(phenylethynyl)pyridine] normalized bifenthrin-triggered increase in SCO frequency without altering baseline SCO activity, indicating that bifenthrin amplifies mGluR5 signaling independent of Na(+) channel modification. Competitive [AP-5; (-)-2-amino-5-phosphonopentanoic acid] and noncompetitive (dizocilpine, or MK-801 [(5S,10R)-(+)-5-methyl-10,11 dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate]) N-methyl-d-aspartate antagonists partially decreased both basal and bifenthrin-triggered SCO frequency increase. Bifenthrin-modified SCO rapidly enhanced the phosphorylation of cAMP response element-binding protein (CREB). Subacute (48 hours) exposure to bifenthrin commencing 2 DIV-enhanced neurite outgrowth and persistently increased SCO frequency and reduced SCO amplitude. Bifenthrin-stimulated neurite outgrowth and CREB phosphorylation were dependent on mGluR5 activity since MPEP normalized both responses. Collectively these data identify a new mechanism by which bifenthrin potently alters Ca(2+) dynamics and Ca(2+)-dependent signaling in cortical neurons that have long term impacts on activity driven neuronal plasticity. PMID- 24482399 TI - Lipoprotein CD0873 is a novel adhesin of Clostridium difficile. AB - Clostridium difficile is a cause of antibiotic-associated diarrhea and colitis, a healthcare-associated intestinal disease. Colonization of the gut is a critical step in the course of infection. The C. difficile lipoprotein CD0873 was identified as a putative adhesin through a bioinformatics approach. Surface exposure of CD0873 was confirmed and a CD0873 mutant was generated. The CD0873 mutant showed a significant reduction in adherence to Caco-2 cells and wild-type bacteria preincubated with anti-CD0873 antibodies showed significantly decreased adherence to Caco-2 cells. In addition, we demonstrated that purified recombinant CD0873 protein alone associates with Caco-2 cells. This is the first definitive identification of a C. difficile adhesin, which now allows work to devise improved measures for preventing and treating disease. PMID- 24482398 TI - Respiratory syncytial virus and other respiratory viral infections in older adults with moderate to severe influenza-like illness. AB - BACKGROUND: Few studies have prospectively assessed viral etiologies of acute respiratory infections in community-based elderly individuals. We assessed viral respiratory pathogens in individuals >=65 years with influenza-like illness (ILI). METHODS: Multiplex reverse-transcriptase polymerase chain reaction identified viral pathogens in nasal/throat swabs from 556 episodes of moderate-to severe ILI, defined as ILI with pneumonia, hospitalization, or maximum daily influenza symptom severity score (ISS) >2. Cases were selected from a randomized trial of an adjuvanted vs nonadjuvanted influenza vaccine conducted in elderly adults from 15 countries. RESULTS: Respiratory syncytial virus (RSV) was detected in 7.4% (41/556) moderate-to-severe ILI episodes in elderly adults. Most (39/41) were single infections. There was a significant association between country and RSV detection (P = .004). RSV prevalence was 7.1% (2/28) in ILI with pneumonia, 12.5% (8/64) in ILI with hospitalization, and 6.7% (32/480) in ILI with maximum ISS > 2. Any virus was detected in 320/556 (57.6%) ILI episodes: influenza A (104/556, 18.7%), rhinovirus/enterovirus (82/556, 14.7%), coronavirus and human metapneumovirus (each 32/556, 5.6%). CONCLUSIONS: This first global study providing data on RSV disease in >=65 year-olds confirms that RSV is an important respiratory pathogen in the elderly. Preventative measures such as vaccination could decrease severe respiratory illnesses and complications in the elderly. PMID- 24482400 TI - Theoretical analysis of the local orientation effect and the lift-hyperlayer mode of rodlike particles in field-flow fractionation. AB - We investigated theoretically the effects of the cross-stream migration and the local average orientation of rodlike particles on the shape-based separation using field-flow fractionation. The separation behavior was analyzed by comparing the retention ratios of spheres and rods. The retention ratio of a rod was evaluated through the derivation of its cross-sectional concentration profile by considering the rod migration and the local average orientation. Our study in various flow conditions showed that the rod migration, caused by the hydrodynamic interaction with a wall, can affect the separation behavior as a lift-hyperlayer mode. We also demonstrated that the local average orientation, which is a function of a local shear rate and a rotational diffusivity, results in the transverse diffusivity that is different from its perpendicular diffusivity. These results suggest that the experimental separation behaviors of rods in field flow fractionation may not be fully explained by the current theory based on the normal mode and the steric mode. We also characterized each condition where one of the normal mode, the steric mode of spheres, and the lift-hyperlayer mode of rods is dominant. PMID- 24482401 TI - A solvato-fluorochromic macrocycle of multiple anthracene fluorophores in close proximity. AB - A fluorescent macrocycle containing four anthracene panels linked by meta phenylene spacers and amino hinges was synthesized. The macrocycle adopts a twisted, compressed conformation that places embedded anthracene fluorophores in close contact. Emission from the convoluted macrocycle is highly solvatochromic and significantly enhanced as compared with that of the partial structures. PMID- 24482402 TI - What's so special about squamates? PMID- 24482403 TI - Stress contagion: physiological covariation between mothers and infants. AB - Emotions are not simply concepts that live privately in the mind, but rather affective states that emanate from the individual and may influence others. We explored affect contagion in the context of one of the closest dyadic units, mother and infant. We initially separated mothers and infants; randomly assigned the mothers to experience a stressful positive-evaluation task, a stressful negative-evaluation task, or a nonstressful control task; and then reunited the mothers and infants. Three notable findings were obtained: First, infants' physiological reactivity mirrored mothers' reactivity engendered by the stress manipulation. Second, infants whose mothers experienced social evaluation showed more avoidance toward strangers compared with infants whose mothers were in the control condition. Third, the negative-evaluation condition, compared with the other conditions, generated greater physiological covariation in the dyads, and this covariation increased over time. These findings suggest that mothers' stressful experiences are contagious to their infants and that members of close pairs, like mothers and infants, can reciprocally influence each other's dynamic physiological reactivity. PMID- 24482404 TI - Synchronized separation of seven medications representing most commonly prescribed antihypertensive classes by using reversed-phase liquid chromatography: Application for analysis in their combined formulations. AB - A reversed-phase high-performance liquid chromatography method was developed for the simultaneous determination of the diuretic, hydrochlorothiazide, along with six drugs representing the most commonly prescribed antihypertensive pharmacological classes such as atenolol, a selective beta1 blocker, amlodipine besylate, a calcium channel blocker, moexipril hydrochloride, an angiotensin converting-enzyme inhibitor, valsartan and candesartan cilexetil, which are angiotensin II receptor blockers, and aliskiren hemifumarate, a renin inhibitor, using irbesartan as an internal standard. The chromatographic separation was achieved using acetonitrile/sodium phosphate dibasic buffer (0.02 M, pH 5.5) at a flow rate of 1 mL/min in gradient elution mode at ambient temperature on a stationary phase composed of an Eclipse XDB-C18 (4.6 * 150 mm, 5 MUm) column. UV detection was carried out at 220 nm. The method was validated according to ICH guidelines. Linearity, accuracy, and precision were satisfactory over the concentration ranges of 2-40 MUg/mL for hydrochlorothiazide and candesartan cilexetil, 20-120, 10-160, 5-40, 20-250, and 5-50 MUg/mL for atenolol, valsartan, moexipril hydrochloride, aliskiren hemifumarate, and amlodipine besylate, respectively. The method was successfully applied for the determination of each of the studied drugs in their combined formulations with hydrochlorothiazide. The developed method is suitable for the quality control and routine analysis of the cited drugs in their pharmaceutical dosage forms. PMID- 24482405 TI - Profound reduction of ovarian estrogen by aromatase inhibition in obese women. AB - OBJECTIVE: It was hypothesized that aromatase inhibitor (AI)-induced interruption of estradiol negative feedback would modulate the reproductive hormone profile of obese women. METHODS: Regularly cycling women aged 18-40 years with a BMI of 18 25 kg/m(2) (normal weight, n = 10) or >30 kg/m(2) (obese; n = 12) were given AI daily for 7 days. Urinary hormone profiles were compared between groups. Fourteen eumenorrheic, normal weight women not receiving AI stimulation served as historical controls. Urinary metabolites for LH, FSH, estradiol (E1c), and progesterone (Pdg) were measured and normalized to a 28-day cycle. Serum estrone and estradiol were measured in the late follicular phase. RESULTS: Whole-cycle LH, FSH, and luteal Pdg excretion did not differ between obese (BMI = 37.1 + 7 kg/m(2) ) and normal weight women treated with AIs, although LH was greater in stimulated compared with unstimulated normal weight women. Whole cycle mean E1c was lower in AI-stimulated obese and normal weight participants compared with nonstimulated normal weight controls, but obese women treated with AI excreted far less E1c (467.7 +/- 217.4 MUg/mg Cr) than AI-treated normal weight women (911.4 +/- 361.8 MUg/mg Cr; P = 0.02). Follicular phase serum estrone and estradiol were also lower in AI-treated obese women versus AI-treated normal weight women (61.7 +/- 22.8 and 18.3 +/- 3.7 pg/ml versus 99.1 +/- 30.5 and 37.7 +/- 5.9 pg/ml, respectively; P = 0.034 and 0.005). CONCLUSIONS: Normal gonadotropin output and luteal function occur at the expense of reduced E1c excretion in AI-treated women, and this discrepancy is particularly evident in obese women. PMID- 24482406 TI - Children's arithmetic development: it is number knowledge, not the approximate number sense, that counts. AB - In this article, we present the results of an 11-month longitudinal study (beginning when children were 6 years old) focusing on measures of the approximate number sense (ANS) and knowledge of the Arabic numeral system as possible influences on the development of arithmetic skills. Multiple measures of symbolic and nonsymbolic magnitude judgment were shown to define a unitary factor that appears to index the efficiency of an ANS system, which is a strong longitudinal correlate of arithmetic skills. However, path models revealed that knowledge of Arabic numerals at 6 years was a powerful longitudinal predictor of the growth in arithmetic skills, whereas variations in magnitude-comparison ability played no additional role in predicting variations in arithmetic skills. These results suggest that verbal processes concerned with learning the labels for Arabic numerals, and the ability to translate between Arabic numerals and verbal codes, place critical constraints on arithmetic development. PMID- 24482407 TI - The anatomical record is alive with leapin' lizards and slitherin' snakes. PMID- 24482408 TI - Analysis of ibuprofen enantiomers in rat plasma by liquid chromatography with tandem mass spectrometry. AB - A sensitive and selective method for the analysis of ibuprofen enantiomers by LC MS/MS was developed and validated for the purpose of application in pharmacokinetic studies in small experimental animals. Aliquots of 200 MUL plasma were submitted to liquid-liquid extraction with hexane/diisopropylether (50:50 v/v) in acid pH. Separation was accomplished in a Chirex(r) 3005 (250 * 4.6 mm, 5 MUm) column at 25 degrees C with a mobile phase that consisted of 0.01 M ammonium acetate in methanol at a flow rate of 1.1 mL/min. The mass spectrometer consisted of an ESI interface operating at negative ionization mode and multiple reaction monitoring. The transitions 205 > 161 and 240 > 197 were monitored for ibuprofen enantiomers and fenoprofen (internal standard), respectively. Method validation included the evaluation of the matrix effect, stability, linearity, lower LOQ, within-run and between-run precision, and accuracy. The lower LOQ was 25 ng/mL for each ibuprofen enantiomer, and the calibration curves showed good linearity in the range 0.025-50 MUg/mL. The method was successfully applied in the investigation of pharmacokinetic disposition of ibuprofen enantiomers in rats treated orally with 25 mg/kg of the racemate. Enantioselective kinetic disposition was observed with accumulation of (+)-(S)-ibuprofen in rats following single oral administration. PMID- 24482410 TI - Comparison of spermatozoa parameters, fine structures, and energy-related factors among tetraploid, hyper-tetraploid, and hyper-triploid loaches (Misgurnus anguillicaudatus). AB - To evaluate the influence of ploidy elevation and aneuploidy on spermatozoa in the loach Misgurnus anguillicaudatus, we investigated some parameters (motility, concentration, and viability), fine structures (gross morphology, head size, and flagellum length), and energy-related biochemical factors (volume of mitochondrial mass per cell and ATP content) in diploid, hyper-diploid, and hexaploid-range spermatozoa produced in natural tetraploid, hyper-tetraploid, and hyper-triploid male loaches, respectively. Diploid spermatozoa exhibited vigorous movement and sufficient duration of motility similar to those in haploid spermatozoa. They had longer flagella, higher numbers and larger volume of mitochondria, and higher ATP content than haploid spermatozoa of wild-type diploids. No differences were observed in parameters and morphological characteristics between diploid and hyper-diploid spermatozoa. In contrast, the hexaploid-range spermatozoa of hyper-triploid males exhibited poor progressive motility in spite of a higher ATP content of spermatozoa. Spermatozoa with no flagella (36.0%) or multiple flagella (18.6%) were also observed in hyper triploids. Ratios of head to flagellum length in hexaploid-range spermatozoa were significantly different from those of haploid spermatozoa. In addition to the normal 9+2 microtubule structure of the flagellum, an abnormal 9+1 microtubule structure was also observed in the spermatozoa of hyper-triploids. PMID- 24482411 TI - Are hemipenial spines related to limb reduction? A spiny discussion focused on gymnophthalmid lizards (Squamata: Gymnophthalmidae). AB - Calcified spines in the hemipenial surface occur convergently in several gymnophthalmid lizard species and in advanced snakes. Based on the pronounced degrees of limb reduction in these distantly related lineages, such hemipenial structures were suggested to play a functional role in couple-anchoring during copulation, partly assuming the function of the limbs during mating. Herein, we assessed the hemipenial morphology of virtually all the valid genera of the family Gymnophthalmidae to test for a phylogenetic correlation between limb reduction and the presence of calcified hemipenial spines. The occurrence of calcified structures was mapped on the two most comprehensive phylogenies of the family. We concluded that spiny hemipenes are by no means necessarily associated with reduction of limbs. Conversely, the presence of well-developed hemipenial spines in specific limb-reduced taxa does not allow one to disregard the possibility that in some instances such structures might indeed be functionally associated with couple-anchoring, improving the success of mating. PMID- 24482412 TI - Dose-volumetric parameters for predicting hypothyroidism after radiotherapy for head and neck cancer. AB - OBJECTIVE: To investigate predictors affecting the development of hypothyroidism after radiotherapy for head and neck cancer, focusing on radiation dose volumetric parameters, and to determine the appropriate radiation dose-volumetric threshold of radiation-induced hypothyroidism. METHODS: A total of 114 patients with head and neck cancer whose radiotherapy fields included the thyroid gland were analysed. The purpose of the radiotherapy was either definitive (n = 81) or post-operative (n = 33). Thyroid function was monitored before starting radiotherapy and after completion of radiotherapy at 1 month, 6 months, 1 year and 2 years. A diagnosis of hypothyroidism was based on a thyroid stimulating hormone value greater than the maximum value of laboratory range, regardless of symptoms. In all patients, dose volumetric parameters were analysed. RESULTS: Median follow-up duration was 25 months (range; 6-38). Forty-six percent of the patients were diagnosed as hypothyroidism after a median time of 8 months (range; 1-24). There were no significant differences in the distribution of age, gender, surgery, radiotherapy technique and chemotherapy between the euthyroid group and the hypothyroid group. In univariate analysis, the mean dose and V35-V50 results were significantly associated with hypothyroidism. The V45 is the only variable that independently contributes to the prediction of hypothyroidism in multivariate analysis and V45 of 50% was a threshold value. If V45 was <50%, the cumulative incidence of hypothyroidism at 1 year was 22.8%, whereas the incidence was 56.1% if V45 was >=50% (P = 0.034). CONCLUSIONS: The V45 may predict risk of developing hypothyroidism after radiotherapy for head and neck cancer, and a V45 of 50% can be a useful dose-volumetric threshold of radiation-induced hypothyroidism. PMID- 24482413 TI - Twenty-six cases of advanced ampullary adenocarcinoma treated with systemic chemotherapy. AB - OBJECTIVE: Ampullary adenocarcinoma is a rare disease entity and little information regarding these tumors is available. The aim of the present study was to clarify the treatment outcome of systemic chemotherapy in patients with advanced ampullary adenocarcinoma. METHODS: This study consisted of a retrospective review of data obtained from patients diagnosed as having advanced ampullary adenocarcinoma who received non-surgical treatment at a single institution between 1997 and 2010. RESULTS: We identified 26 patients (15 men, 11 women; median age, 62.0 years) who received treatment for advanced ampullary adenocarcinoma. Twelve patients had Stage IV disease and 14 had recurrences. The chemotherapy regimens consisted of 5-fluorouracil-based regimens (5-fluorouracil + cisplatin, n = 3; tegafur-uracil + doxorubicin, n = 5 and tegafur, gimeracil and oteracil potassium, n = 3) and gemcitabine-based regimens (gemcitabine, n = 10 and gemcitabine + cisplatin, n = 5). The overall response rate was 7.7%. The median progression-free survival period was 3.2 months (2.5 months in the 5 fluorouracil group vs. 3.5 months in the gemcitabine group), and the median overall survival time was 9.1 months (8.0 months in the 5-fluorouracil group vs. 12.3 months in the gemcitabine group). The median overall survival was significantly longer in stage IV disease than in recurrent disease. The histological phenotype was determined in 10 of the 26 patients. Eight patients had intestinal-type adenocarcinomas and remaining two patients had pancreatobiliary-type adenocarcinomas. CONCLUSIONS: The treatment outcome of patients with advanced ampullary adenocarcinoma was poor. Further development of novel treatments is necessary to improve the prognosis. PMID- 24482414 TI - Feasibility re-evaluation of 75 mg/m2 docetaxel in Japanese patients with previously treated non-small cell lung cancer. AB - OBJECTIVE: The primary objective of this study was to re-evaluate the feasibility of docetaxel at doses of up to 75 mg/m2 in Japanese patients with previously treated non-small cell lung cancer. METHODS: Patients received escalated doses of docetaxel at 70 mg/m2 (level 1) or 75 mg/m2 (level 2) every 3 weeks until disease progression or unacceptable toxicities. Dose escalation was decided on the basis of dose-limiting toxicity in the first cycle of chemotherapy. RESULTS: At dose level 1, dose-limiting toxicity--Grade 3 febrile neutropenia--was observed in one of the six patients and at dose level 2, it was seen in one of the first six patients. Therefore, an additional 14 patients were enrolled at dose level 2, as originally planned. Among the total of 20 patients at dose level 2, 6 (<33%) developed dose-limiting toxicity in the first cycle: febrile neutropenia in 5 and pneumonia in 1. Finally, 10 (50%) of the 20 patients experienced toxicities that met the dose-limiting toxicity criteria, including 8 with febrile neutropenia throughout the treatment period, but this was manageable with dose reduction or appropriate supportive care. Other observed toxicities were predictable from the safety profile of decetaxel and were also well managed. Four partial responses were observed, giving an overall response rate of 15.4%. The median progression free survival period of the patients overall was 4.0 months (95% confidence interval 1.4-6.6 months). CONCLUSIONS: Although docetaxel administration at an initial dose of 75 mg/m2 requires careful attention because of the high incidence of febrile neutropenia, this dose is considered feasible according to the protocol definition in Japanese patients with previously treated non-small cell lung cancer. PMID- 24482415 TI - EGFR mutation of adenocarcinoma in congenital cystic adenomatoid malformation/congenital pulmonary airway malformation: a case report. AB - An 80-year-old man underwent right upper lobectomy for the resection of multiple cysts accompanied by a nodule. The pathological diagnosis was adenocarcinoma with surrounding atypical epithelial cell proliferation in a Type 1 congenital cystic adenomatoid malformation/congenital pulmonary airway malformation. There was epidermal growth factor receptor mutation in the adenocarcinoma and surrounding atypical epithelial cells that had proliferated. Malignant transformation of congenital cystic adenomatoid malformation/congenital pulmonary airway malformation may be related to the epidermal growth factor receptor pathway in this case, with atypical epithelial cell proliferation as a precursor. We emphasize the importance of complete resection of congenital cystic adenomatoid malformation/congenital pulmonary airway malformation and the possibility of treatment with epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor-mutated cases. PMID- 24482416 TI - Effects of thermal stress on hepatic melanomacrophages of Eupemphix nattereri (Anura). AB - Melanomacrophages are the pigmented cells present in the hematopoietic organs. Besides melanin, hemosiderin and lipofuscin are also observed in the melanomacrophages. For the liver, however, numerous studies relate these cells to immunological and metabolic functions. Therefore, the aim of this study is to evaluate the hepatic metabolism by quantifying melanin, hemosiderin and lipofuscin in the anuran Eupemphix nattereri submitted to varying thermal conditions. E. nattereri adult males were separated into three groups, as follows: (i) five animals in the control group were kept at room temperature (27 degrees C); (ii) 30 animals were submitted to hyperthermic (35.1 degrees C); and (iii) 30 to hypothermic (18.9 degrees ) conditions. In each experiment, the animals were analyzed and separated into two different treatments: (1) immediately after undergoing the stress; and, (2) after recovering from the stress caused by the stimulus, at three distinct times (12 hr, 24 hr, and 48 hr). Both hyperthermia and hypothermia decreased hepatic pigmentation after thermal stress. The recovered animals of both experimental treatments showed as much pigmentation as the control animals. Thermal stress alters hemosiderin and lipofuscin as well, which may be related to liver function catabolism. In conclusion, liver pigmentation decreased due to temperature variation and duration of thermal stimulation to which the animals were exposed. The increase in temperature rather than hypothermia led to more drastic physiological disorders. In this study, we observed that thermal stress for a short period compromises the morphology and liver function, as observed by the changing pigmentation of melanomacrophages. These analyses can be used as biomarkers of environmental effects. PMID- 24482417 TI - Miniaturized molecularly imprinted polymer extraction method for the gas chromatographic analysis of flavonoids. AB - In this study, the use of monolithic molecularly imprinted polymers in a micropipette tip format allowing the simple and fast extraction of flavonoids from standard solutions and a black tea sample is demonstrated. The imprinted polymer employed quercetin, methacrylic acid or 4-vinylpyridine, and ethylene glycol dimethacrylate as template, functional monomer, and cross-linker, respectively. Surface morphologies of the quercetin-imprinted polymers and the corresponding nonimprinted polymers were characterized by SEM. Extraction of flavonoid standards was performed to evaluate the selectivity and recovery with these imprinted and nonimprinted polymers. Flavonoid compositions in aliquots eluted from the tips were identified using fast GC with flame ionization detection. Maximum specific capacities of 0.2, 5.7, and 16.0 mg/g for catechin, morin, and quercetin, respectively, were obtained with the imprinted polymer prepared with methacrylic acid, with the corresponding recoveries of 99.8, 98.8, and 95.4%, respectively. Efficient extraction by the quercetin-imprinted polymer of epicatechin, catechin, and quercetin from an apple-flavored black tea sample was achieved, with GC-MS employed for compound identification for both the tea and extracted samples. PMID- 24482418 TI - Cadmium contaminated soil affects retinogenesis in lizard embryos. AB - Lizards are soil surface animals that represent an important link between invertebrates and higher predators. Being part of wild fauna, they can be affected by contamination from anthropic activities and in particular, pesticides and chemical substances of various nature that reach the soil surface directly or through fall out. Among these substances, heavy metals such as cadmium may exert particularly marked toxic effect on both adult and embryos. In lizards, recent studies show that cadmium may cause developmental defects, including alteration of eye development, with appearance of unilateral microphthalmia and retinal folding. In the present study, the effects of cadmium incubation on retinal development were investigated demonstrating that cadmium interferes with cell cycle regulation by increasing proliferation. An increased expression of Otx2 and Pax6 genes, markers of retinal differentiation, was also found. However, the cellular localization of Pax6 and Otx2 transcripts did not change in treated embryos: in the early stages of retinogenesis, the two genes were expressed in all retinal cells; in the differentiated retina, Otx2 remained in the cellular bodies of retinal cells forming the nuclear and the ganglion layers, whereas Pax6 was expressed only in the cells of the inner nuclear and the ganglion layers. Data suggest that the increased expression of Pax6 and Otx2 could be ascribed to the hyperproliferation of retinal cells rather than to an effective gene overexpression. PMID- 24482419 TI - Variability of blood alcohol content (BAC) determinations: the role of measurement uncertainty, significant figures, and decision rules for compliance assessment in the frame of a multiple BAC threshold law. AB - The measurement of blood-alcohol content (BAC) is a crucial analytical determination required to assess if an offence (e.g. driving under the influence of alcohol) has been committed. For various reasons, results of forensic alcohol analysis are often challenged by the defence. As a consequence, measurement uncertainty becomes a critical topic when assessing compliance with specification limits for forensic purposes. The aims of this study were: (1) to investigate major sources of variability for BAC determinations; (2) to estimate measurement uncertainty for routine BAC determinations; (3) to discuss the role of measurement uncertainty in compliance assessment; (4) to set decision rules for a multiple BAC threshold law, as provided in the Italian Highway Code; (5) to address the topic of the zero-alcohol limit from the forensic toxicology point of view; and (6) to discuss the role of significant figures and rounding errors on measurement uncertainty and compliance assessment. Measurement variability was investigated by the analysis of data collected from real cases and internal quality control. The contribution of both pre-analytical and analytical processes to measurement variability was considered. The resulting expanded measurement uncertainty was 8.0%. Decision rules for the multiple BAC threshold Italian law were set by adopting a guard-banding approach. 0.1 g/L was chosen as cut-off level to assess compliance with the zero-alcohol limit. The role of significant figures and rounding errors in compliance assessment was discussed by providing examples which stressed the importance of these topics for forensic purposes. PMID- 24482420 TI - Determination of allergenic hydroperoxides in essential oils using gas chromatography with electron ionization mass spectrometry. AB - Fragrance monoterpenes are widely used commercially due to their pleasant scent. In previous studies, we have shown that air-exposed monoterpenes form hydroperoxides that are strong skin sensitizers. Methods for detection and quantification of the hydroperoxides in essential oils and scented products are thus desirable. Due to thermolability and low UV absorbance, this is a complicated task. We have recently developed a sensitive LC-ESI-MS method, but with limited structural information and separation efficiency for positional isomers and stereoisomers. In the present study, we investigated derivatization with a trimethyl silyl reagent and subsequent GC with electron ionization MS for the determination of monoterpene hydroperoxides. All investigated monoterpene hydroperoxides could be chromatographed as thermostable trimethyl silyl derivatives and yielded the fragment m/z 89 ([OSi(CH3)3](+)) at a higher extent compared to corresponding alcohols. Limonene-2-hydroperoxide and four other hydroperoxide isomers of limonene were separated and detected in sweet orange oil autoxidized for two months. The concentration of limonene-2-hydroperoxide isomers was found to be 19 MUg/mg in total. Also isomers of linalyl acetate hydroperoxide and linalool hydroperoxide were detected in autoxidized petitgrain oil (two months). The presented GC-MS method showed concentrations in the same order as previous LC-MS/MS analysis of the same type of oils. PMID- 24482421 TI - Another one bites the dust: bite force and ecology in three caviomorph rodents (Rodentia, Hystricognathi). AB - Mammals have developed sophisticated strategies adapting to particular locomotor modes, feeding habits, and social interactions. Many rodent species have acquired a fossorial, semi-fossorial, or even subterranean life-style, converging on morphological, anatomical, and ecological features but diverging in the final arrangement. These ecological variations partially depend on the functional morphology of their digging tools. Muscular and mechanical features (e.g., lever arms relationship) of the bite force were analyzed in three caviomorph rodents with similar body size but different habits and ecological demands of the jaws. In vivo forces were measured at incisors' tip using a strain gauge load cell force transducer whereas theoretical maximal performance values, mechanical advantages, and particular contribution of each adductor muscle were estimated from dissections in specimens of Ctenomys australis (subterranean, solitary), Octodon degus (semi-fossorial, social), and Chinchilla laniger (ground-dweller, colonial). Our results showed that C. australis bites stronger than expected given its small size and C. laniger exhibited the opposite outcome, while O. degus is close to the expected value based on mammalian bite force versus body mass regressions; what might be associated to the chisel-tooth digging behavior and social interactions. Our key finding was that no matter how diverse these rodents' skulls were, no difference was found in the mechanical advantage of the main adductor muscles. Therefore, interspecific differences in the bite force might be primarily due to differences in the muscular development and force, as shown for the subterranean, solitary and territorial C. australis versus the more gracile, ground-dweller, and colonial C. laniger. PMID- 24482422 TI - The importance of relationship in understanding the experiences of spouse mental health carers. AB - The burden of caring for family members with mental illness has been researched extensively; however, knowledge of spouse carers' experiences is limited. In this article, we explore this from a carers' perspective, with 28 spouse carers, using qualitative open-ended semistructured interviews and a grounded theory approach informed by the social interactionism tradition to collect and analyze the data. We present six interrelated themes around the central theme of this being "a real and genuine relationship." The findings indicate that caring for a spouse with severe mental illness is a unique role compared with other caring roles. First and foremost, spouse carers strive for the relationship with their partner and accommodate mental illness into their lives to protect the relationship. Because of this, they often lead surreal lives marked by significant emotional pressure and isolation. This has implications for how mental health service providers work with and support spouse carers. PMID- 24482423 TI - Young adults' strategies for managing social support during weight-loss attempts. AB - Obesity and being overweight often result in serious health problems. Despite growing awareness of the dangers associated with being overweight, many individuals struggle to lose weight. Investigators have identified social support as a key element in weight-loss attempts. Unfortunately, little has been done to investigate how people solicit social support from members of their pre-existing social network without a structured intervention. To address this limitation, I conducted in-depth interviews with 25 participants. Through grounded theory analysis of these interviews, I developed a typology of support management strategies used by overweight young adults when attempting to lose weight. I outline these strategies, their perceived success, and implications for future research in this article. PMID- 24482424 TI - Imaging mass spectrometry to discriminate breast from pancreatic cancer metastasis in formalin-fixed paraffin-embedded tissues. AB - Diagnosis of the origin of metastasis is mandatory for adequate therapy. In the past, classification of tumors was based on histology (morphological expression of a complex protein pattern), while supportive immunohistochemical investigation relied only on few "tumor specific" proteins. At present, histopathological diagnosis is based on clinical information, morphology, immunohistochemistry, and may include molecular methods. This process is complex, expensive, requires an experienced pathologist and may be time consuming. Currently, proteomic methods have been introduced in various clinical disciplines. MALDI imaging MS combines detection of numerous proteins with morphological features, and seems to be the ideal tool for objective and fast histopathological tumor classification. To study a special tumor type and to identify predictive patterns that could discriminate metastatic breast from pancreatic carcinoma MALDI imaging MS was applied to multitissue paraffin blocks. A statistical classification model was created using a training set of primary carcinoma biopsies. This model was validated on two testing sets of different breast and pancreatic carcinoma specimens. We could discern breast from pancreatic primary tumors with an overall accuracy of 83.38%, a sensitivity of 85.95% and a specificity of 76.96%. Furthermore, breast and pancreatic liver metastases were tested and classified correctly. PMID- 24482425 TI - Beta-thymosin gene polymorphism associated with freshwater invasiveness of alewife (Alosa pseudoharengus). AB - Predicting the success of a species' colonization into a novel environment is routinely considered to be predicated on niche-space similarity and vacancy, as well as propagule pressure. The role genomic variation plays in colonization success (and the interaction with environment) may be suggested, but has not rigorously been documented. To test an hypothesis that previously observed ecotype-specific polymorphisms between anadromous and landlocked alewife (Alosa pseudoharengus) populations are an adaptive response to osmoregulatory challenges rather than a result of allele sampling at founding, we examined multiple anadromous and landlocked (colonized) populations for their allelic profiles at a conserved region (3'-UTR end) of a beta-thymosin gene whose protein product plays a central role in the organization of cytoskeleton. The putatively ancestral beta thymosin allele was prevalent in anadromous populations, whereas a newly derived allele was overrepresented in landlocked populations; a third allele was exclusive to the anadromous populations. We also conducted a complementary set of salinity exposure experiments to test osmoregulatory performance of the alewife ecotypes in contrasting saline environments. The pattern of variation and results from these challenges indicate a strong association of beta-thymosin with colonization success and a transition from species with an anadromous life history to one with only a freshwater component. PMID- 24482426 TI - Bacterial biofilm formation and treatment in soft tissue fillers. AB - Injection of soft tissue fillers plays an important role in facial reconstruction and esthetic treatments such as cosmetic surgery for lip augmentation and wrinkle smoothening. Adverse events are an increasing problem, and recently, it has been suggested that bacteria are the cause of a vast fraction these. We developed a novel mouse model and evaluated hyaluronic acid gel, calcium hydroxyl apatite microspheres, and polyacrylamide hydrogel for their potential for sustaining bacterial infections and their possible treatments. We were able to culture Pseudomonas aeruginosa, Staphylococcus epidermidis, and Probionibacterium acnes in all three gels. When contaminated gels were left for 7 days in a mouse model, we found sustainment of bacterial infection with the permanent gel, less with the semi-permanent gel, and no growth within the temporary gel. Evaluation of treatment strategies showed that once the bacteria had settled (into biofilms) within the gels, even successive treatments with high concentrations of relevant antibiotics were not effective. Our data substantiate bacteria as a cause of adverse reactions reported when using tissue fillers, and the sustainability of these infections appears to depend on longevity of the gel. Most importantly, the infections are resistant to antibiotics once established but can be prevented using prophylactic antibiotics. PMID- 24482427 TI - Reactive oxygen species-scavenging nanomedicines for the treatment of oxidative stress injuries. AB - This Progress Report describes a development of two types of reactive oxygen species (ROS)-scavenging nanomedicines for the treatment of oxidative stress injuries, referred to as pH-sensitive redox nanoparticle (RNP(N) ) and pH insensitive redox nanoparticle (RNP(O) ), which are prepared by self-assembling amphiphilic block copolymers possessing nitroxide radicals as a side chain of hydrophobic segment via amine and ether linkages, respectively. Due to a protonation of amino groups in hydrophobic core, RNP(N) disintegrates in low pH environments such as ischemic, inflamed, and tumor tissues, resulting in increased ROS-scavenging activity because of the exposed nitroxide radicals from the core. Utilizing pH-responsiveness of RNP(N) , it shows remarkable therapeutic effects on oxidative stress injuries such as renal and cerebral ischemia reperfusion injuries after intravenous administration. Moreover, RNP(N) shows an enhancement of the activity of anticancer drugs by suppression of activation of transcription factors in tumor due to the ROS scavenging. On the other hand, orally administered RNP(O) has notable characteristics such as preferential accumulation in mucosa and inflamed area of gastrointestinal tract and no uptake into blood stream. Based on these characters, RNP(O) shows a remarkable therapeutic effect for the gastrointestinal inflammation without any adverse effects. Thus, ROS-scavenging nanomedicines have therapeutic efficacy in numerous oxidative stress diseases. PMID- 24482428 TI - Anatomy of the crus and pes of neotropical iguanian lizards in relation to habitat use and digitally based grasping capabilities. AB - Ecomorphological studies of lizards have explored the role of various morphological traits and how these may be associated with, among other things, habitat use. We present an analysis of selected traits of internal morphology of the hind limbs of Neotropical iguanian lizards and their relationship to habitat use. Considering that one of the most widely-held hypotheses relating to the origin of grasping is associated with the exploitation of the narrow-branch arboreal habitat, we include subdivisions of this designation as two of our ecologically defined categories of habitat exploitation for analysis, and compare lizards assigned to these categories to the features displayed by terrestrial lizards. The influence of phylogeny in shaping the morphology of lizards was assessed by using the comparative method. K values were significant for several osteological traits. Most of the K values for the variables based upon muscle and tendon morphometric characters (13 out 21), by contrast, had values <1, suggesting that their variation cannot be explained by phylogeny alone. Results of our phylogenetic and conventional ANCOVA analyses reveal that the characters highlighted through the application of the comparative method are not absolutely related to habitat in terms of the categories considered here. It appears that the bauplan of the lizard pes incorporates a morphological configuration that is sufficiently versatile to enable exploitation of almost all of the available habitats. As unexpected as conservation of internal gross morphology appears, it represents a means of accommodating to environmental challenges by apparently permitting adequacy for all situations examined. PMID- 24482429 TI - Unemployment among breast cancer survivors. AB - AIM: Though about 20% of working age breast cancer survivors do not return to work after treatment, few studies have addressed risk factors for unemployment. The majority of studies on occupational consequences of breast cancer focus on non-employment, which is a mixture of sickness absence, unemployment, retirement pensions and other reasons for not working. Unemployment in combination with breast cancer may represent a particular challenge for these women. The aim of the present study is therefore to analyze the risk for unemployment in the years following diagnosis and treatment for breast cancer. METHOD: This study included 14,750 women diagnosed with breast cancer in Denmark 2001-2009 identified through a population-based clinical database and linked with information from Danish administrative population based registers for information on labour market affiliation, socio-demography and co-morbid conditions. Multivariable analyses were performed by Cox's proportional hazard models. RESULTS: Two years after treatment, 81% of patients were still part of the work force, 10% of which were unemployed. Increasing duration of unemployment before breast cancer was associated with an adjusted HR = 4.37 (95% CI: 3.90-4.90) for unemployment after breast cancer. Other risk factors for unemployment included low socioeconomic status and demography, while adjuvant therapy did not increase the risk of unemployment. CONCLUSIONS: Duration of unemployment before breast cancer was the most important determinant of unemployment after breast cancer treatment. This allows identification of a particularly vulnerable group of patients in need of rehabilitation. PMID- 24482430 TI - Do work-related mechanical and psychosocial factors contribute to the social gradient in long-term sick leave: a prospective study of the general working population in Norway. AB - AIMS: A social gradient in long-term sick leave (LTSL) rates is well established, but only a few studies have examined to what extent this gradient may be explained by mechanical and psychosocial work environment factors. METHODS: A randomly drawn cohort from the general population in Norway, aged 18-69 years, was interviewed in the second half of 2009 (n=12,255, response at baseline 60.9%) and followed up in national registries to the end of 2010. Eligible respondents were registered with an active employee relationship of at least 100 actual working days in 2009 and 2010 (n=6758). Based on administrative register data, respondents were coded into five educational levels (university/college >=4 years was set as the reference group). Eight work-related psychosocial factors and 10 mechanical exposures were measured. The outcome of interest was medically confirmed LTSL >=40 working days during 2010. RESULTS: In total, 9.4% (635 individuals) were classified with LTSL during 2010. There was a strong social gradient ranging from 12.4% (elementary) to 3.3% (university/college >=4 years) among men. The corresponding figures among women were 15.4 and 4.6%. Adjusting for work-related mechanical and psychosocial factors explained between 41 and 44% of the social gradient in men. Among women, the corresponding figures were 31 and 54%. CONCLUSIONS: Work-related mechanical and psychosocial factors contribute to the social gradient in LTSL. The work-related factors that accounted for this gradient were rather similar for men and women. PMID- 24482431 TI - Decreased cognitive functions at the age of 66, as measured by the MMSE, associated with having left working life before the age of 60: results from the SNAC study. AB - AIMS: The age of retirement has financial implications as we tend to live longer, with the result that an increasing number of older inhabitants have to share limited financial resources. However, this is not only a financial issue. It is also of interest to investigate factors related to health and quality of life associated with the age of retirement. The aim of this study was to investigate changes in mood, activity level, and cognition at the age of 66 associated with leaving working life before 60. METHODS: Baseline and follow-up data on 840 participants of the Swedish National Study on Aging and Care - Blekinge was used. Mood was measured by the Montgomery-Asberg Depression Scale and activity level by 27 survey items. Cognition was measured by the Mini Mental State Examination. RESULTS: Retirement before 60 years of age was not associated with lower cognitive functions and a higher score on depression at baseline, but retirees were less active. Six years later, at the age of 66, a decline in their cognition was found. Retirees were still not more depressed but less active. In a logistic regression analysis, being retired increased the odds ratio for cognitive decline by 1.36-times (OR 2.36) when gender, activity level, education level, and depression were adjusted for. CONCLUSIONS: Participants who retired before the age of 60 declined in cognitive ability over the 6-year study period. PMID- 24482432 TI - Perturbation of auxin homeostasis caused by mitochondrial FtSH4 gene-mediated peroxidase accumulation regulates arabidopsis architecture. AB - Reactive oxygen species and auxin play important roles in the networks that regulate plant development and morphogenetic changes. However, the molecular mechanisms underlying the interactions between them are poorly understood. This study isolated a mas (More Axillary Shoots) mutant, which was identified as an allele of the mitochondrial AAA-protease AtFtSH4, and characterized the function of the FtSH4 gene in regulating plant development by mediating the peroxidase dependent interplay between hydrogen peroxide (H2O2) and auxin homeostasis. The phenotypes of dwarfism and increased axillary branches observed in the mas (renamed as ftsh4-4) mutant result from a decrease in the IAA concentration. The expression levels of several auxin signaling genes, including IAA1, IAA2, and IAA3, as well as several auxin binding and transport genes, decreased significantly in ftsh4-4 plants. However, the H2O2 and peroxidases levels, which also have IAA oxidase activity, were significantly elevated in ftsh4-4 plants. The ftsh4-4 phenotypes could be reversed by expressing the iaaM gene or by knocking down the peroxidase genes PRX34 and PRX33. Both approaches can increase auxin levels in the ftsh4-4 mutant. Taken together, these results provided direct molecular and genetic evidence for the interaction between mitochondrial ATP dependent protease, H2O2, and auxin homeostasis to regulate plant growth and development. PMID- 24482433 TI - Genome-wide prediction of highly specific guide RNA spacers for CRISPR-Cas9 mediated genome editing in model plants and major crops. PMID- 24482434 TI - OsRFPH2-10, a ring-H2 finger E3 ubiquitin ligase, is involved in rice antiviral defense in the early stages of rice dwarf virus infection. PMID- 24482435 TI - H3K27me3 and H3K4me3 chromatin environment at super-induced dehydration stress memory genes of Arabidopsis thaliana. AB - Pre-exposure to a stress may alter the plant's cellular, biochemical, and/or transcriptional responses during future encounters as a 'memory' from the previous stress. Genes increasing transcription in response to a first dehydration stress, but producing much higher transcript levels in a subsequent stress, represent the super-induced 'transcription memory' genes in Arabidopsis thaliana. The chromatin environment (histone H3 tri-methylations of Lys 4 and Lys 27, H3K4me3, and H3K27me3) studied at five dehydration stress memory genes revealed existence of distinct memory-response subclasses that responded differently to CLF deficiency and displayed different transcriptional activities during the watered recovery periods. Among the most important findings is the novel aspect of the H3K27me3 function observed at specific dehydration stress memory genes. In contrast to its well-known role as a chromatin repressive mechanism at developmentally regulated genes, H3K27me3 did not prevent transcription from the dehydration stress-responding genes. The high H3K27me3 levels present during transcriptionally inactive states did not interfere with the transition to active transcription and with H3K4me3 accumulation. H3K4me3 and H3K27me3 marks function independently and are not mutually exclusive at the dehydration stress-responding memory genes. PMID- 24482437 TI - Crystal structure of a multilayer packed major light-harvesting complex: implications for grana stacking in higher plants. PMID- 24482438 TI - FERONIA receptor kinase controls seed size in Arabidopsis thaliana. PMID- 24482439 TI - Deaths by suicide and their relationship with general and psychiatric hospital discharge: 30-year record linkage study. AB - BACKGROUND: Studies have rarely explored suicides completed following discharge from both general and psychiatric hospital settings. Such research might identify additional opportunities for intervention. AIMS: To identify and summarise Scottish psychiatric and general hospital records for individuals who have died by suicide. METHOD: A linked data study of deaths by suicide, aged >=15 years from 1981 to 2010. RESULTS: This study reports on a UK data-set of individuals who died by suicide (n = 16 411), of whom 66% (n = 10 907) had linkable previous hospital records. Those who died by suicide were 3.1 times more frequently last discharged from general than from psychiatric hospitals; 24% of deaths occurred within 3 months of hospital discharge (58% of these from a general hospital). Only 14% of those discharged from a general hospital had a recorded psychiatric diagnosis at last visit; an additional 19% were found to have a previous lifetime psychiatric diagnosis. Median time between last discharge and death was fourfold greater in those without a psychiatric history. Diagnoses also revealed that less than half of those last discharged from general hospital had had a main diagnosis of 'injury or poisoning'. CONCLUSIONS: Suicide prevention activity, including a better psychiatric evaluation of patients within general hospital settings deserves more attention. Improved information flow between secondary and primary care could be facilitated by exploiting electronic records of previous psychiatric diagnoses. PMID- 24482436 TI - An XA21-associated kinase (OsSERK2) regulates immunity mediated by the XA21 and XA3 immune receptors. AB - The rice XA21 immune receptor kinase and the structurally related XA3 receptor confer immunity to Xanthomonas oryzae pv. oryzae (Xoo), the causal agent of bacterial leaf blight. Here we report the isolation of OsSERK2 (rice somatic embryogenesis receptor kinase 2) and demonstrate that OsSERK2 positively regulates immunity mediated by XA21 and XA3 as well as the rice immune receptor FLS2 (OsFLS2). Rice plants silenced for OsSerk2 display altered morphology and reduced sensitivity to the hormone brassinolide. OsSERK2 interacts with the intracellular domains of each immune receptor in the yeast two-hybrid system in a kinase activity-dependent manner. OsSERK2 undergoes bidirectional transphosphorylation with XA21 in vitro and forms a constitutive complex with XA21 in vivo. These results demonstrate an essential role for OsSERK2 in the function of three rice immune receptors and suggest that direct interaction with the rice immune receptors is critical for their function. Taken together, our findings suggest that the mechanism of OsSERK2-meditated regulation of rice XA21, XA3, and FLS2 differs from that of AtSERK3/BAK1-mediated regulation of Arabidopsis FLS2 and EFR. PMID- 24482440 TI - 22q11.2 deletion carriers and schizophrenia-associated novel variants. AB - The penetrance of schizophrenia risk in carriers of the 22q11.2 deletion is high but incomplete, suggesting the possibility of additional genetic defects. We performed whole exome sequencing on two individuals with 22q11.2 deletion, one with schizophrenia and the other who was psychosis-free. The results revealed novel genetic variants related to neuronal function exclusively in the person with schizophrenia (frameshift: KAT8, APOH and SNX31; nonsense: EFCAB11 and CLVS2). This study paves the way towards a more complete understanding of variant dose and genetic architecture in schizophrenia. PMID- 24482442 TI - Non-fatal repetition of self-harm in Taipei City, Taiwan: cohort study. AB - BACKGROUND: Repeat self-harm is an important risk factor for suicide. Few studies have explored risk factors for non-fatal repeat self-harm in Asia. AIMS: To investigate the risk of non-fatal repeat self-harm in a large cohort of patients presenting to hospital in Taipei City, Taiwan. METHOD: Prospective cohort study of 7601 patients with self-harm presenting to emergency departments (January 2004 December 2006). Survival analysis was used to examine the rates, timing and factors associated with repeat self-harm. RESULTS: In total 778 (10.2%) patients presented to hospital with one or more further episodes of self-harm. The cumulative risk of non-fatal repetition within 1 year of a self-harm episode was 9.3% (95% CI 8.7-10.1). The median time to repetition within 1 year was 105 days. Females had a higher incidence of repeat self-harm than males (adjusted hazard ratio 1.25, 95% CI 1.05-1.48) but males had shorter median time to repetition (107 v. 80 days). Other independent risk factors for repeat self-harm within 1 year of an index episode were: young age, self-harm by medicine overdose and increasing number of repeat episodes of self-harm. CONCLUSIONS: The risk of non fatal repeat self-harm in Taipei City is lower than that seen in the West. Risk factors for repeat non-fatal self-harm differ from those for fatal self-harm. The first 3 months after self-harm is a crucial period for intervention. PMID- 24482441 TI - Vitamin-mineral treatment of attention-deficit hyperactivity disorder in adults: double-blind randomised placebo-controlled trial. AB - BACKGROUND: The role of nutrition in the treatment of attention-deficit hyperactivity disorder (ADHD) is gaining international attention; however, treatments have generally focused only on diet restriction or supplementing with one nutrient at a time. AIMS: To investigate the efficacy and safety of a broad based micronutrient formula consisting mainly of vitamins and minerals, without omega fatty acids, in the treatment of ADHD in adults. METHOD: This double-blind randomised controlled trial assigned 80 adults with ADHD in a 1:1 ratio to either micronutrients (n = 42) or placebo (n = 38) for 8 weeks (trial registered with the Australian New Zealand Clinical Trials Registry: ACTRN12609000308291). RESULTS: Intent-to-treat analyses showed significant between-group differences favouring active treatment on self- and observer- but not clinician-ADHD rating scales. However, clinicians rated those receiving micronutrients as more improved than those on placebo both globally and on ADHD symptoms. Post hoc analyses showed that for those with moderate/severe depression at baseline, there was a greater change in mood favouring active treatment over placebo. There were no group differences in adverse events. CONCLUSIONS: This study provides preliminary evidence of efficacy for micronutrients in the treatment of ADHD symptoms in adults, with a reassuring safety profile. PMID- 24482443 TI - Hunting complex differential gene interaction patterns across molecular contexts. AB - Heterogeneity in genetic networks across different signaling molecular contexts can suggest molecular regulatory mechanisms. Here we describe a comparative chi square analysis (CPchi(2)) method, considerably more flexible and effective than other alternatives, to screen large gene expression data sets for conserved and differential interactions. CPchi(2) decomposes interactions across conditions to assess homogeneity and heterogeneity. Theoretically, we prove an asymptotic chi square null distribution for the interaction heterogeneity statistic. Empirically, on synthetic yeast cell cycle data, CPchi(2) achieved much higher statistical power in detecting differential networks than alternative approaches. We applied CPchi(2) to Drosophila melanogaster wing gene expression arrays collected under normal conditions, and conditions with overexpressed E2F and Cabut, two transcription factor complexes that promote ectopic cell cycling. The resulting differential networks suggest a mechanism by which E2F and Cabut regulate distinct gene interactions, while still sharing a small core network. Thus, CPchi(2) is sensitive in detecting network rewiring, useful in comparing related biological systems. PMID- 24482444 TI - Structure of a rare non-standard sequence k-turn bound by L7Ae protein. AB - Kt-23 from Thelohania solenopsae is a rare RNA kink turn (k-turn) where an adenine replaces the normal guanine at the 2n position. L7Ae is a member of a strongly conserved family of proteins that bind a range of k-turn structures in the ribosome, box C/D and H/ACA small nucleolar RNAs and U4 small nuclear RNA. We have solved the crystal structure of T. solenopsae Kt-23 RNA bound to Archeoglobus fulgidus L7Ae protein at a resolution of 2.95 A. The protein binds in the major groove displayed on the outer face of the k-turn, in a manner similar to complexes with standard k-turn structures. The k-turn adopts a standard N3 class conformation, with a single hydrogen bond from A2b N6 to A2n N3. This contrasts with the structure of the same sequence located in the SAM-I riboswitch, where it adopts an N1 structure, showing the inherent plasticity of k turn structure. This potentially can affect any tertiary interactions in which the RNA participates. PMID- 24482445 TI - A bacteriophage transcription regulator inhibits bacterial transcription initiation by sigma-factor displacement. AB - Bacteriophages (phages) appropriate essential processes of bacterial hosts to benefit their own development. The multisubunit bacterial RNA polymerase (RNAp) enzyme, which catalyses DNA transcription, is targeted by phage-encoded transcription regulators that selectively modulate its activity. Here, we describe the structural and mechanistic basis for the inhibition of bacterial RNAp by the transcription regulator P7 encoded by Xanthomonas oryzae phage Xp10. We reveal that P7 uses a two-step mechanism to simultaneously interact with the catalytic beta and beta' subunits of the bacterial RNAp and inhibits transcription initiation by inducing the displacement of the sigma(70)-factor on initial engagement of RNAp with promoter DNA. The new mode of interaction with and inhibition mechanism of bacterial RNAp by P7 underscore the remarkable variety of mechanisms evolved by phages to interfere with host transcription. PMID- 24482446 TI - Temozolomide is an active agent in children with recurrent medulloblastoma/primitive neuroectodermal tumor: an Italian multi-institutional phase II trial. AB - BACKGROUND: The aim of this study was to assess the objective response rate (ORR) of children and young adults with recurrent medulloblastoma/primitive neuroectodermal tumor (MB/PNET) treated with temozolomide (TMZ). The secondary purpose was to analyze the toxicity profile of TMZ when administered orally for 5 days in 3 divided daily doses every 28 days. METHODS: Forty-two patients with recurrent MB/PNET, aged 21 years and younger, were recruited. Patients were treated with oral TMZ. Starting doses ranged from 120 to 200 mg/m(2)/day based on previous treatments. A craniospinal MRI was performed prior to the first cycle of TMZ and following every 2 cycles of treatment. RESULTS: Median age was 10 years (range, 2-21 years). Forty of 42 patients were assessed for response and toxicity. The objective response rate was 42.5%: 6 patients achieved a complete response, 11 had a partial response, and 10 had stable disease. Progression-free survival rates for all patients at 6 and 12 months were 30% and 7.5%, respectively. Their median overall survival rates at 6 and 12 months were 42.5% and 17.5%, respectively. No major extrahematological effects or life-threatening events were reported. The most common grade 3/4 toxicity included thrombocytopenia (17.5%), neutropenia (7.5%), and anemia (2.5%). CONCLUSIONS: TMZ proved to be an effective agent in children and young adults with MB/PNET, heavily pre-treated, with a tolerable toxicity profile. PMID- 24482448 TI - The need to continually redefine the goals of surgery for glioblastoma. PMID- 24482447 TI - Atypical neurological complications of ipilimumab therapy in patients with metastatic melanoma. AB - BACKGROUND: Ipilimumab is a novel FDA-approved recombinant human monoclonal antibody that blocks cytotoxic T-lymphocyte antigen-4 and has been used to treat patients with metastatic melanoma. Immune-related neurological adverse effects include inflammatory myopathy, aseptic meningitis, posterior reversible encephalopathy syndrome, Guillain-Barre syndrome, myasthenia gravis-type syndrome, sensorimotor neuropathy, and inflammatory enteric neuropathy. To date, there is no report for ipilimumab-induced chronic inflammatory demyelinating polyneuropathy (CIDP), transverse myelitis (TM), or concurrent myositis and myasthenia gravis-type syndrome. Our objective is to raise early recognition of atypical neurological adverse events and to share our therapeutic approach. METHODS: We report 3 cases of metastatic melanoma treated with ipilimumab in which the patients developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively, at the MD Anderson Cancer Center between July 2012 and June 2013. Patients consented to release of medical information for publication/educational purposes. RESULTS: Our 3 cases of metastatic melanoma treated with ipilimumab developed CIDP, TM, and concurrent myositis and myasthenia gravis-type syndrome, respectively. The median time to onset of immune related adverse events following ipilimumab treatment ranged from 1 to 2 weeks. Ipilimumab was discontinued due to the severe neurological symptoms. Plasmapheresis was initiated in the patients with CIDP and concurrent myositis and myasthenia gravis-type syndrome; high-dose intravenous steroids were given to the patient with TM, and significant clinical response was demonstrated. CONCLUSIONS: Ipilimumab could induce a wide spectrum of neurological adverse effects. Our findings support the standard treatment of withholding or discontinuing ipilimumab. Plasmapheresis or high-dose intravenous steroids may be considered as the initial choice of treatment for severe ipilimumab-related neurological adverse events. Improvement of neurological symptoms may be seen within 2 weeks. PMID- 24482449 TI - Stephen E. Malawista (1934-2013): infection and rheumatic disease. PMID- 24482450 TI - Visa labyrinth. PMID- 24482455 TI - Human evolution. Neandertals and moderns made imperfect mates. PMID- 24482456 TI - Ecology. Ecosystems say 'pass the salt!'. PMID- 24482457 TI - Medicine. Suspect drug research blamed for massive death toll. PMID- 24482458 TI - Crowdsourcing. Online video game plugs players into remote-controlled biochemistry lab. PMID- 24482459 TI - Transgenic animals. Editing of targeted genes proved possible in monkeys. PMID- 24482460 TI - Biomedical research. Antioxidants could spur tumors by acting on cancer gene. PMID- 24482462 TI - Cryptography. Quantum spy games. PMID- 24482461 TI - The dangerous professor. PMID- 24482463 TI - Sea turtle funding dries up. PMID- 24482464 TI - Fueling innovation. PMID- 24482465 TI - Research tax credits: an important tool. PMID- 24482466 TI - The changing role of Medieval women. PMID- 24482468 TI - Conservation. Drug policy as conservation policy: narco-deforestation. PMID- 24482469 TI - Development. Chemical warfare in the battle of the sexes. PMID- 24482470 TI - Applied physics. When electrons leave holes in organic solar cells. PMID- 24482471 TI - Atmospheric science. Methane on the rise--again. PMID- 24482472 TI - Applied physics. Selecting the direction of sound transmission. PMID- 24482473 TI - Botany. Pathogen specialization. PMID- 24482474 TI - Genetics. A unified process for neurological disease. PMID- 24482475 TI - Plant science. Delayed gratification--waiting to terminate stem cell identity. PMID- 24482477 TI - Sound isolation and giant linear nonreciprocity in a compact acoustic circulator. AB - Acoustic isolation and nonreciprocal sound transmission are highly desirable in many practical scenarios. They may be realized with nonlinear or magneto-acoustic effects, but only at the price of high power levels and impractically large volumes. In contrast, nonreciprocal electromagnetic propagation is commonly achieved based on the Zeeman effect, or modal splitting in ferromagnetic atoms induced by a magnetic bias. Here, we introduce the acoustic analog of this phenomenon in a subwavelength meta-atom consisting of a resonant ring cavity biased by a circulating fluid. The resulting angular momentum bias splits the ring's azimuthal resonant modes, producing giant acoustic nonreciprocity in a compact device. We applied this concept to build a linear, magnetic-free circulator for airborne sound waves, observing up to 40-decibel nonreciprocal isolation at audible frequencies. PMID- 24482478 TI - A mechanosensory pathway to the Drosophila circadian clock. AB - Circadian clocks attune the physiology of virtually all living organisms to the diurnal cycles of their environments. In metazoan animals, multiple sensory input pathways have been linked to clock synchronization with the environmental cycle (entrainment). Extrinsic entrainment cues include light and temperature. We show that (12-hour:12-hour) cycles of vibration and silence (VS) are sufficient to synchronize the daily locomotor activity of wild-type Drosophila melanogaster. Behavioral synchronization to VS cycles required a functional clock and functional chordotonal organs and was accompanied by phase-shifts of the daily oscillations of PERIOD protein concentrations in brain clock neurons. The feedback from mechanosensory-and particularly, proprioceptive-organs may help an animal to keep its circadian clock in sync with its own, stimulus-induced activities. PMID- 24482476 TI - Exome sequencing links corticospinal motor neuron disease to common neurodegenerative disorders. AB - Hereditary spastic paraplegias (HSPs) are neurodegenerative motor neuron diseases characterized by progressive age-dependent loss of corticospinal motor tract function. Although the genetic basis is partly understood, only a fraction of cases can receive a genetic diagnosis, and a global view of HSP is lacking. By using whole-exome sequencing in combination with network analysis, we identified 18 previously unknown putative HSP genes and validated nearly all of these genes functionally or genetically. The pathways highlighted by these mutations link HSP to cellular transport, nucleotide metabolism, and synapse and axon development. Network analysis revealed a host of further candidate genes, of which three were mutated in our cohort. Our analysis links HSP to other neurodegenerative disorders and can facilitate gene discovery and mechanistic understanding of disease. PMID- 24482479 TI - Reversal of female infertility by Chk2 ablation reveals the oocyte DNA damage checkpoint pathway. AB - Genetic errors in meiosis can lead to birth defects and spontaneous abortions. Checkpoint mechanisms of hitherto unknown nature eliminate oocytes with unrepaired DNA damage, causing recombination-defective mutant mice to be sterile. Here, we report that checkpoint kinase 2 (Chk2 or Chek2), is essential for culling mouse oocytes bearing unrepaired meiotic or induced DNA double-strand breaks (DSBs). Female infertility caused by a meiotic recombination mutation or irradiation was reversed by mutation of Chk2. Both meiotically programmed and induced DSBs trigger CHK2-dependent activation of TRP53 (p53) and TRP63 (p63), effecting oocyte elimination. These data establish CHK2 as essential for DNA damage surveillance in female meiosis and indicate that the oocyte DSB damage response primarily involves a pathway hierarchy in which ataxia telangiectasia and Rad3-related (ATR) signals to CHK2, which then activates p53 and p63. PMID- 24482480 TI - Savanna vegetation-fire-climate relationships differ among continents. AB - Ecologists have long sought to understand the factors controlling the structure of savanna vegetation. Using data from 2154 sites in savannas across Africa, Australia, and South America, we found that increasing moisture availability drives increases in fire and tree basal area, whereas fire reduces tree basal area. However, among continents, the magnitude of these effects varied substantially, so that a single model cannot adequately represent savanna woody biomass across these regions. Historical and environmental differences drive the regional variation in the functional relationships between woody vegetation, fire, and climate. These same differences will determine the regional responses of vegetation to future climates, with implications for global carbon stocks. PMID- 24482481 TI - Effector specialization in a lineage of the Irish potato famine pathogen. AB - Accelerated gene evolution is a hallmark of pathogen adaptation following a host jump. Here, we describe the biochemical basis of adaptation and specialization of a plant pathogen effector after its colonization of a new host. Orthologous protease inhibitor effectors from the Irish potato famine pathogen, Phytophthora infestans, and its sister species, Phytophthora mirabilis, which is responsible for infection of Mirabilis jalapa, are adapted to protease targets unique to their respective host plants. Amino acid polymorphisms in both the inhibitors and their target proteases underpin this biochemical specialization. Our results link effector specialization to diversification and speciation of this plant pathogen. PMID- 24482482 TI - Development-inspired reprogramming of the mammalian central nervous system. AB - In 2012, John Gurdon and Shinya Yamanaka shared the Nobel Prize for the demonstration that the identity of differentiated cells is not irreversibly determined but can be changed back to a pluripotent state under appropriate instructive signals. The principle that differentiated cells can revert to an embryonic state and even be converted directly from one cell type into another not only turns fundamental principles of development on their heads but also has profound implications for regenerative medicine. Replacement of diseased tissue with newly reprogrammed cells and modeling of human disease are concrete opportunities. Here, we focus on the central nervous system to consider whether and how reprogramming of cell identity may affect regeneration and modeling of a system historically considered immutable and hardwired. PMID- 24482483 TI - Timing mechanism dependent on cell division is invoked by Polycomb eviction in plant stem cells. AB - Plant floral stem cells divide a limited number of times before they stop and terminally differentiate, but the mechanisms that control this timing remain unclear. The precise temporal induction of the Arabidopsis zinc finger repressor KNUCKLES (KNU) is essential for the coordinated growth and differentiation of floral stem cells. We identify an epigenetic mechanism in which the floral homeotic protein AGAMOUS (AG) induces KNU at ~2 days of delay. AG binding sites colocalize with a Polycomb response element in the KNU upstream region. AG binding to the KNU promoter causes the eviction of the Polycomb group proteins from the locus, leading to cell division-dependent induction. These analyses demonstrate that floral stem cells measure developmental timing by a division dependent epigenetic timer triggered by Polycomb eviction. PMID- 24482484 TI - Editorial: Optimizing iTreg differentiation: STATs in the balance. PMID- 24482485 TI - Editorial: Pulmonary resident memory CD8 T cells: here today, gone tomorrow. PMID- 24482486 TI - Editorial: Bone marrow progenitors share their experiences with their offspring. PMID- 24482487 TI - Assortativity coefficient-based estimation of population patterns of sexual mixing when cluster size is informative. AB - OBJECTIVES: Population sexual mixing patterns can be quantified using Newman's assortativity coefficient (r). Suggested methods for estimating the SE for r may lead to inappropriate statistical conclusions in situations where intracluster correlation is ignored and/or when cluster size is predictive of the response. We describe a computer-intensive, but highly accessible, within-cluster resampling approach for providing a valid large-sample estimated SE for r and an associated 95% CI. METHODS: We introduce needed statistical notation and describe the within cluster resampling approach. Sexual network data and a simulation study were employed to compare within-cluster resampling with standard methods when cluster size is informative. RESULTS: For the analysis of network data when cluster size is informative, the simulation study demonstrates that within-cluster resampling produces valid statistical inferences about Newman's assortativity coefficient, a popular statistic used to quantify the strength of mixing patterns. In contrast, commonly used methods are biased with attendant extremely poor CI coverage. Within-cluster resampling is recommended when cluster size is informative and/or when there is within-cluster response correlation. CONCLUSIONS: Within-cluster resampling is recommended for providing valid statistical inferences when applying Newman's assortativity coefficient r to network data. PMID- 24482489 TI - Prevalence of HIV, syphilis, and HCV infection and associated risk factors among male clients of low-paying female sex workers in a rural county of Guangxi, China: a cross-sectional study. AB - BACKGROUND: The purpose of this study was to examine prevalence of HIV, syphilis and hepatitis C virus (HCV) infection as well as related risk factors among a group of male clients of low-paying female sex workers (FSW) (eg, women who usually encounter their clients on the street or small establishments in rural or less developed areas, or who charge low fees for each sexual service) in a rural county of China. METHOD: Cross-sectional study conducted in 2011 in a rural county of Guangxi in China. A total of 102 clients who reported information on demographics and HIV risks (eg, inconsistent condom use) and provided blood sample to test for HIV, HCV and syphilis were included in the data analysis. Both bivariate and multivariate analyses were employed to explore risk factors of HIV, HCV and syphilis infection. RESULTS: Most of participants were of Han ethnicity with a mean age of 61.8 years. The majority of them lived in rural areas and worked as farmers with limited disposable cash incomes. The sample reported a high rate of unprotected sex with FSW in the last sex episode (83.7%) and inconsistent condom use in the last 6 months (95.9%). The overall prevalence of HIV, HCV and syphilis was 1.9%, 1.0% and 18.4%, respectively. CONCLUSIONS: Findings suggest that male clients, especially the elderly ones, are at a high risk of HIV infection given prevalent unprotected sex and high prevalence of syphilis. Culturally-appropriate, age-specific interventions are urgently needed to curb the HIV/sexually transmitted infection epidemic among this at-risk population in China. PMID- 24482488 TI - High-risk human papillomavirus viral load and persistence among heterosexual HIV negative and HIV-positive men. AB - OBJECTIVES: High-risk human papillomavirus (HR-HPV) viral load is associated with HR-HPV transmission and HR-HPV persistence in women. It is unknown whether HR-HPV viral load is associated with persistence in HIV-negative or HIV-positive men. METHODS: HR-HPV viral load and persistence were evaluated among 703 HIV-negative and 233 HIV-positive heterosexual men who participated in a male circumcision trial in Rakai, Uganda. Penile swabs were tested at baseline and 6, 12 and 24 months for HR-HPV using the Roche HPV Linear Array, which provides a semiquantitative measure of HPV shedding by hybridisation band intensity (graded: 1-4). Prevalence risk ratios (PRR) were used to estimate the association between HR-HPV viral load and persistent detection of HR-HPV. RESULTS: HR-HPV genotypes with high viral load (grade:3-4) at baseline were more likely to persist than HR HPV genotypes with low viral load (grade: 1-2) among HIV-negative men (month 6: adjPRR=1.83, 95% CI 1.32 to 2.52; month 12: adjPRR=2.01, 95% CI 1.42 to 3.11), and HIV-positive men (month 6: adjPRR=1.33, 95% CI 1.06 to 1.67; month 12: adjPRR=1.73, 95% CI 1.18 to 2.54). Long-term persistence of HR-HPV was more frequent among HIV-positive men compared with HIV-negative men (month 24: adjPRR=2.27, 95% CI 1.47 to 3.51). Persistence of newly detected HR-HPV at the 6 month and 12-month visits with high viral load were also more likely to persist to 24 months than HR-HPV with low viral load among HIV-negative men (adjPRR=1.67, 95% CI 0.88 to 3.16). CONCLUSIONS: HR-HPV genotypes with high viral load are more likely to persist among HIV-negative and HIV-positive men, though persistence was more common among HIV-positive men overall. The results may explain the association between high HR-HPV viral load and HR-HPV transmission. PMID- 24482491 TI - Left ventricular assist devices in patients with end-stage heart failure: suggestion of an alternative treatment based on clinically well-known concepts. AB - Encouraging results were obtained by using left ventricular assist devices (LVADs) in patients with end-stage heart failure (HF) that exhibits extremely high mortality and who were not candidates for heart transplantation. By using this so-called destination therapy (DT), a substantial percentage of these patients achieved sufficient improvement in cardiac function to permit the explantation of the device. The combination of mechanical and pharmacological therapy increased the frequency and durability of myocardial recovery as compared with other therapeutic approaches. Although cardiac transplantation, LVADs, and cardiac resynchronization therapy have provided a major advance in DT, their limitations stimulate the search for alternative therapies. We discuss the limitations of these 3 treatment options for end-stage HF. Also, we propose and discuss the possible advantages of a new intracorporeal procedure that works continuously as intraaortic balloon counterpulsation without an extracorporeal or intracorporeal computer-controlled mechanism. PMID- 24482490 TI - Direct analysis of sialylated or sulfated glycosphingolipids and other polar and neutral lipids using TLC-MS interfaces. AB - Gangliosides and sulfatides (STs) are acidic glycosphingolipids (GSLs) that have one or more sialic acids or sulfate substituents, in addition to neutral sugars, attached to the C-1 hydroxyl group of the ceramide long chain base. TLC is a widely employed and convenient technique for separation and characterization of GSLs. When TLC is directly coupled to MS, it provides both the molecular mass and structural information without further purification. Here, after development of the TLC plates, the structural analyses of acidic GSLs, including gangliosides and STs, were investigated using the liquid extraction surface analysis (LESATM) and CAMAG TLC-MS interfaces coupled to an ESI QSTAR Pulsar i quadrupole orthogonal TOF mass spectrometer. Coupling TLC with ESI-MS allowed the acquisition of high resolution mass spectra of the acidic GSLs with high sensitivity and mass accuracy, without the loss of sialic acid residues that frequently occurs during low-pressure MALDI MS. These systems were then applied to the analysis of total lipid extracts from bovine brain. This allowed profiling of many different lipid classes, not only gangliosides and STs, but also SMs, neutral GSLs, and phospholipids. PMID- 24482492 TI - Upregulation of IGF2 expression during vascular calcification. AB - The process of vascular calcification shares many similarities with that of skeletal mineralisation and involves the deposition of hydroxyapatite crystals in arteries and cardiac valves. However, the cellular mechanisms responsible have yet to be fully elucidated. In this study, we employed microarray analysis to demonstrate the upregulation of more than >9000 genes during the calcification of murine vascular smooth muscle cells (VSMCs), of which the most significantly, differentially expressed gene was Igf2. Following the validation of increased IGF2 expression by RT-qPCR and immunoblotting in calcifying murine VSMCs, IGF2 expression was further demonstrated in the calcified aorta of the Enpp1(-/-) mouse model of medial aortic calcification. Having confirmed that IGF1R and IGF2R were expressed in cultured murine VSMCs, cell-signalling studies in these cells revealed that IGF2 (50 ng/ml) significantly stimulated the phosphorylation of Akt and Erk1/2 (P<0.05). These results potentially indicate that IGF2 may mediate VSMC calcification via the stimulation of Erk1/2 and Akt signalling. This study suggests that the increased IGF2 expression in calcifying VSMCs may reflect the well-established prenatal role of IGF2, particularly as the osteogenic phenotypic transition of VSMCs in a calcified environment recapitulates many of the events occurring during embryonic development. A full understanding of the importance of IGF2 in this pathological process will lead to a better understanding of the aetiology of vascular calcification. PMID- 24482494 TI - Is rituximab one for all ages and each sex? AB - In this issue of Blood, Pfreundschuh et al report that young males treated with rituximab-based immunochemotherapy in contrast to elderly males benefit as much as females from rituximab immunochemotherapy and patients with more rapid rituximab clearance have reduced therapeutic benefit. PMID- 24482493 TI - Enucleate or replicate? Ask the cytoskeleton. AB - In this issue of Blood, Sui and colleagues have identified novel and interesting roles for Tropomodulin (Tmod)-3, a protein involved with actin filament organization, in erythroid proliferation, survival, and enucleation. PMID- 24482495 TI - Less strength and more fractures for MGUS bones. AB - In this issue of Blood, Farr et al showed that patients with monoclonal gammopathy of undetermined significance (MGUS) have increased cortical bone porosity and reduced bone strength,1 conditions that can lead to the increased fracture risk, which has been reported in MGUS patients. PMID- 24482496 TI - Delta-1 provides pleasant stem cell environs. AB - In this issue of Blood, Csaszar et al show that in ex vivo cultures of CD341 cells, simultaneous reduction of interleukin-6 receptor (IL-6R) expression on myeloid progenitor cells by Delta-1 treatment combined with removal of soluble IL 6R using a dynamically fed culture system, reduces mature myeloid cell production, leading to enhanced expansion of primitive hematopoietic stem cells. PMID- 24482497 TI - Inhibitory FcgammaRIIb and CD20 internalization. AB - In this issue of Blood, Vaughan et al demonstrate that certain antibodies that are used therapeutically in lymphoma treatment (e.g., rituximab) undergo Fcg receptor IIb (FcgRIIb)-mediated internalization from the B-cell surface in a manner that is independent of activation of FcgRIIb with important implications for the design of antibody-based therapeutics (see figure). PMID- 24482498 TI - Hanging tough: CMV-specific CD8+ T cells in CLL. AB - In this issue of Blood, te Raa et al report that cytomegalovirus (CMV)-specific CD8+ T-cell function is preserved in chronic lymphocytic leukemia (CLL), on a background of global T-cell dysfunction. PMID- 24482499 TI - 28 days later: eosinophils stop viruses. AB - In this issue of Blood, Percopo et al provide intriguing new evidence supporting a role for eosinophils in protecting mice against the lethal effects of respiratory virus infection. PMID- 24482500 TI - Anemia: a comprehensive global estimate. AB - In this issue of Blood, Kassebaum et al estimate that the global anemia prevalence in 2010 was 32.9%, resulting in 68.4 million years lived with disability (YLD). The results emphasize the important contribution made by anemia to the overall global burden of disease and should help focus attention and resources toward this problem. PMID- 24482501 TI - Correcting 2 more myths regarding transplants for AML in second remission. PMID- 24482502 TI - Association of a single-nucleotide polymorphism in the SH2B3 gene with JAK2V617F positive myeloproliferative neoplasms. PMID- 24482503 TI - Hepatitis E transmission by transfusion of Intercept blood system-treated plasma. PMID- 24482504 TI - Draft Genome Sequence of Pseudoalteromonas sp. Strain NW 4327 (MTCC 11073, DSM 25418), a Pathogen of the Great Barrier Reef Sponge Rhopaloeides odorabile. AB - To date, only one marine sponge pathogen (Pseudoalteromonas sp. strain NW 4327) has fulfilled Koch's postulates. We report the 4.48-Mbp draft genome sequence of this strain, which is pathogenic to the Great Barrier Reef sponge Rhopaloeides odorabile. The sequence provides valuable information on sponge-pathogen interactions, including the mode of transmission and associated virulence factors. PMID- 24482505 TI - Draft Genome Sequence of Advenella kashmirensis Strain W13003, a Polycyclic Aromatic Hydrocarbon-Degrading Bacterium. AB - Advenella kashmirensis strain W13003 is a polycyclic aromatic hydrocarbon (PAH) degrading bacterium isolated from PAH-contaminated marine sediments. Here, we report the 4.8-Mb draft genome sequence of this strain, which will provide insights into the diversity of A. kashmirensis and the mechanism of PAH degradation in the marine environment. PMID- 24482506 TI - First Complete Genome Sequence of Escherichia albertii Strain KF1, a New Potential Human Enteric Pathogen. AB - Escherichia albertii has been recently recognized as an emerging human and bird enteric pathogen. Here, we report the first complete chromosome nucleotide sequence of a clinical isolate of E. albertii strain KF1, which may provide information about the pathogenic potential of this new species and the mechanisms of evolution of enteropathogenic Escherichia spp. PMID- 24482507 TI - Genome Sequence of the Thermophilic Cyanobacterium Thermosynechococcus sp. Strain NK55a. AB - The genome of the unicellular cyanobacterium Thermosynechococcus sp. strain NK55a, isolated from the Nakabusa hot spring, Nagano Prefecture, Japan, comprises a single, circular, 2.5-Mb chromosome. The genome is predicted to contain 2,358 protein-encoding genes, including genes for all typical cyanobacterial photosynthetic and metabolic functions. No genes encoding hydrogenases or nitrogenase were identified. PMID- 24482508 TI - Trypanosoma cruzi Clone Dm28c Draft Genome Sequence. AB - Trypanosoma cruzi affects millions of people worldwide. Clinical variability of Chagas disease can be due to the genetic variability of this parasite, requiring further genome studies. Here we report the genome sequence of the T. cruzi Dm28c clone (TcI), a strain related to the sylvatic cycle of the parasite. PMID- 24482509 TI - Genome Sequence of an Alphabaculovirus Isolated from Choristoneura murinana. AB - The genome sequence of a baculovirus from Choristoneura murinana is 124,689 bp, with a G+C content of 50%, and contains 148 putative open reading frames. The virus is a member of the group I alphabaculoviruses and is most closely related to several other viruses that infect Choristoneura species. PMID- 24482510 TI - Genome sequence of a hepatitis e virus of genotype 3e from a chronically infected kidney transplant recipient. AB - Hepatitis E virus (HEV) is an emerging cause of acute and chronic hepatitis in immunocompromised patients in Europe. We report the genome sequence of a genotype 3e HEV from a chronically infected kidney transplant recipient in southeastern France, the second HEV genome sequence from a transplant recipient and the first of subtype 3e. PMID- 24482511 TI - Draft Genome Sequence of the Gammaproteobacterial Strain MOLA455, a Representative of a Ubiquitous Proteorhodopsin-Producing Group in the Ocean. AB - Strain MOLA455 is a marine gammaproteobacterium isolated from the bay of Banyuls sur-Mer, France. Here, we present its genome sequence and annotation. Genome analysis revealed the presence of genes associated with a possibly photoheterotrophic lifestyle that uses a proteorhodopsin protein. PMID- 24482512 TI - Draft Genome Sequence of Sphingobium sp. Strain C100, a Polycyclic Aromatic Hydrocarbon-Degrading Bacterium from the Deep-Sea Sediment of the Arctic Ocean. AB - Sphingobium sp. strain C100 was isolated from a polycyclic aromatic hydrocarbon (PAH)-degrading consortium from the deep-sea sediment of the Arctic Ocean. It can degrade two- to four-ring PAHs at 25 degrees C. Here we present the draft genome sequence of this strain, which is 4,776,810 bp with a G+C content of 63.9%. PMID- 24482513 TI - Draft Genome Sequence of Pseudomonas chlororaphis YL-1, a Biocontrol Strain Suppressing Plant Microbial Pathogens. AB - Pseudomonas chlororaphis YL-1 was isolated from soybean root tips and showed a broad range of antagonistic activities to microbial plant pathogens. Here, we report the high-quality draft genome sequence of YL-1, which consists of a chromosome with an estimated size of 6.8 Mb with a G+C value of 63.09%. PMID- 24482514 TI - Complete Genome Sequence of Ehrlichia muris Strain AS145T, a Model Monocytotropic Ehrlichia Strain. AB - We report here the complete genome sequence of Ehrlichia muris strain AS145(T), which was isolated from a wild mouse in 1983 in Japan. E. muris establishes persistent infections in laboratory mice and is widely used as a surrogate pathogen in a murine model of ehrlichiosis. PMID- 24482515 TI - Complete Genome Sequence of Mycoplasma ovis Strain Michigan, a Hemoplasma of Sheep with Two Distinct 16S rRNA Genes. AB - We report the complete genome sequence of Mycoplasma ovis strain Michigan. Its single circular chromosome has 702,511 bp and contains 2 copies of the 16S rRNA gene, one corresponding to M. ovis and the other to "Candidatus Mycoplasma haemovis." All housekeeping genes and the 5S-23S rRNA genes are present in single copies. PMID- 24482516 TI - Complete Genome Sequence of Pseudomonas sp. Strain TKP, Isolated from a gamma Hexachlorocyclohexane-Degrading Mixed Culture. AB - Pseudomonas sp. strain TKP does not degrade gamma-hexachlorocyclohexane (gamma HCH), but it persistently coexists with the gamma-HCH-degrading Sphingobium sp. strain TKS in a mixed culture enriched by gamma-HCH. Here, we report the complete genome sequence of strain TKP, which consists of one circular chromosome with a size of 7 Mb. PMID- 24482517 TI - Draft Genome Sequences of Three Strains of Bacteroides pyogenes Isolated from a Cat and Swine. AB - Here, we report the draft genome sequences of Bacteroides pyogenes JCM 6294(T), JCM 6292, and JCM 10003, which were isolated from a cat and swine and were recently classified into a single species, B. pyogenes. Comparative analyses of these genomes revealed the diversification of B. pyogenes strains isolated from different animals. PMID- 24482518 TI - Whole-Genome Sequence Characterization of a Beak and Feather Disease Virus in a Wild Regent Parrot (Polytelis anthopeplus monarchoides). AB - The whole-genome sequence of beak and feather disease virus (BFDV) from a wild Australian regent parrot (Polytelis anthopeplus monarchoides) was characterized. The genome consists of 1,993 bp and has a typical stem-loop structure between open reading frame 1 (ORF1) and ORF2. This is the first evidence of BFDV infection as well as the complete genome sequence for this host species, globally. PMID- 24482519 TI - Complete genome sequence of a porcine parvovirus strain isolated in central china. AB - We report here the complete genome sequence of the porcine parvovirus (PPV) strain J-PPV, isolated from central China. Our data, together with sequence data for PPV isolates from other regions of China, will help in understanding the epidemiology and molecular characteristics of PPV field isolates in China. PMID- 24482520 TI - F1 and tbilisi are closely related brucellaphages exhibiting some distinct nucleotide variations which determine the host specificity. AB - We report on the 41,143-bp genome of brucellaphage F1, a podovirus that infects several Brucella species. The F1 genome is almost identical to the genome of brucellaphage Tb. However, some structural proteins of the phages exhibit extensive polymorphisms and might be responsible for their different host ranges. PMID- 24482521 TI - Draft Genome Sequence of Urease-Producing Sporosarcina pasteurii with Potential Application in Biocement Production. AB - We describe here the draft genome sequence of Sporosarcina pasteurii, a urease producing bacterium with potential applications in biocement production. PMID- 24482522 TI - Draft Genome Sequences of Three Alkaliphilic Bacillus Strains, Bacillus wakoensis JCM 9140T, Bacillus akibai JCM 9157T, and Bacillus hemicellulosilyticus JCM 9152T. AB - Here, we report the draft genome sequences of the type strains of three cellulolytic or hemicellulolytic alkaliphilic Bacillus species: Bacillus wakoensis, Bacillus akibai, and Bacillus hemicellulosilyticus. The genome information for these three strains will be useful for studies of alkaliphilic Bacillus species, their evolution, and biotechnological applications for their enzymes. PMID- 24482523 TI - Draft Genome Sequence of Pseudomonas nitroreducens Strain TX1, Which Degrades Nonionic Surfactants and Estrogen-Like Alkylphenols. AB - Pseudomonas nitroreducens TX1 ATCC PTA-6168 was isolated from rice field drainage in Taiwan. The bacterium is of special interest because of its capability to use nonionic surfactants (alkylphenol polyethoxylates) and estrogen-like compounds (4 t-octylphenol and 4-nonylphenol) as a sole carbon source. This is the first report on the genome sequence of P. nitroreducens. PMID- 24482524 TI - Draft Genome Sequence of Bacillus thuringiensis Strain BrMgv02-JM63, a Chitinolytic Bacterium Isolated from Oil-Contaminated Mangrove Soil in Brazil. AB - Here, we report the draft genome sequence and the automatic annotation of Bacillus thuringiensis strain BrMgv02-JM63. This genome comprises a set of genes involved in the metabolism of chitin and N-acetylglucosamine utilization, thus suggesting the possible role of this strain in the cycling of organic matter in mangrove soils. PMID- 24482525 TI - Draft Genome Sequence of the Aquatic Phosphorus-Solubilizing and -Mineralizing Bacterium Bacillus sp. Strain CPSM8. AB - Bacillus sp. strain CPSM8 is an efficient solubilizer and mineralizer of phosphorus. Here, we present the 4.39-Mb draft genome sequence of the strain, providing insight into the phosphorus-releasing genes related to productivity in aquatic habitats. PMID- 24482526 TI - Draft Genome Sequence of a Mycobacterium avium Complex Isolate from a Broadbill Bird. AB - We report the draft genome sequence of a Mycobacterium avium complex isolate. This isolate has an estimated genome size of 5.1 Mb with an average GC content of 68.9% and is predicted to carry 4,497 protein-encoding genes and 317 pseudogenes. PMID- 24482527 TI - Genome Sequence of the Emerging Plant Pathogen Dickeya solani Strain RNS 08.23.3.1A. AB - Here we present the genome sequence of Dickeya solani strain RNS 08.23.3.1A (PRI3337), isolated from Solanum tuberosum. Dickeya solani, recently described on potato cultures in Europe, is a proposed new taxon closely related to the Dickeya dianthicola and Dickeya dadantii species. PMID- 24482528 TI - Draft Genome Sequence of Gordonia alkanivorans Strain CGMCC6845, a Halotolerant Hydrocarbon-Degrading Bacterium. AB - Gordonia alkanivorans strain CGMCC6845 is a halotolerant hydrocarbon-degrading bacterium isolated from petroleum-contaminated saline soil. Here we present the 5.0-Mb draft genome sequence of this strain, which will improve our understanding of the diversity of G. alkanivorans and the mechanisms of microbial hydrocarbon degradation in saline environment. PMID- 24482529 TI - London has highest proportion of people attending emergency departments. PMID- 24482531 TI - Phylogenomics of "Candidatus Hepatoplasma crinochetorum," a lineage of mollicutes associated with noninsect arthropods. AB - Bacterial gut communities of arthropods are highly diverse and tightly related to host feeding habits. However, our understanding of the origin and role of the symbionts is often hindered by the lack of genetic information. "Candidatus Hepatoplasma crinochetorum" is a Mollicutes symbiont found in the midgut glands of terrestrial isopods. The only available nucleotide sequence for this symbiont is a partial 16S rRNA gene sequence. Here, we present the 657,101 bp assembled genome of Candidatus Hepatoplasma crinochetorum isolated from the terrestrial isopod Armadillidium vulgare. While previous 16S rRNA gene-based analyses have provided inconclusive results regarding the phylogenetic position of Candidatus Hepatoplasma crinochetorum within Mollicutes, we performed a phylogenomic analysis of 127 Mollicutes orthologous genes which confidently branches the species as a sister group to the Hominis group of Mycoplasma. Several genome properties of Candidatus Hepatoplasma crinochetorum are also highlighted compared with other Mollicutes genomes, including adjacent tryptophan tRNA genes, which further our understanding of the evolutionary dynamics of these genes in Mollicutes, and the presence of a probably inactivated CRISPR/Cas system, which constitutes a testimony of past interactions between Candidatus Hepatoplasma crinochetorum and mobile genetic elements, despite their current lack in this streamlined genome. Overall, the availability of the complete genome sequence of Candidatus Hepatoplasma crinochetorum paves the way for further investigation of its ecology and evolution. PMID- 24482532 TI - Comparative genomics provide insights into evolution of trichoderma nutrition style. AB - Saprotrophy on plant biomass is a recently developed nutrition strategy for Trichoderma. However, the physiology and evolution of this new nutrition strategy is still elusive. We report the deep sequencing and analysis of the genome of Trichoderma longibrachiatum, an efficient cellulase producer. The 31.7-Mb genome, smallest among the sequenced Trichoderma species, encodes fewer nutrition-related genes than saprotrophic T. reesei (Tr), including glycoside hydrolases and nonribosomal peptide synthetase-polyketide synthase. Homology and phylogenetic analyses suggest that a large number of nutrition-related genes, including GH18 chitinases, beta-1,3/1,6-glucanases, cellulolytic enzymes, and hemicellulolytic enzymes, were lost in the common ancestor of T. longibrachiatum (Tl) and Tr. dN/dS (omega) calculation indicates that all the nutrition-related genes analyzed are under purifying selection. Cellulolytic enzymes, the key enzymes for saprotrophy on plant biomass, are under stronger purifying selection pressure in Tl and Tr than in mycoparasitic species, suggesting that development of the nutrition strategy of saprotrophy on plant biomass has increased the selection pressure. In addition, aspartic proteases, serine proteases, and metalloproteases are subject to stronger purifying selection pressure in Tl and Tr, suggesting that these enzymes may also play important roles in the nutrition. This study provides insights into the physiology and evolution of the nutrition strategy of Trichoderma. PMID- 24482533 TI - The imprinted NPAP1 gene in the Prader-Willi syndrome region belongs to a POM121 related family of retrogenes. AB - We have recently shown that the human Nuclear pore-associated protein (NPAP1)/C15orf2 gene encodes a nuclear pore-associated protein. This gene is one of several paternally expressed imprinted genes in the genomic region 15q11q13. Because the Prader-Willi syndrome is known to be caused by the loss of function of paternally expressed genes in 15q11q13, a phenotypic contribution of NPAP1 cannot be excluded. NPAP1 appears to be under strong positive Darwinian selection in primates, suggesting an important function in primate biology. Interestingly, however, in contrast to all other protein-coding genes in 15q11q13, NPAP1 has no ortholog in the mouse. Our investigation of the evolutionary origin of NPAP1 showed that the gene is specific to primate species and absent from the 15q11q13 orthologous regions in all nonprimate mammals. However, we identified a group of paralogous genes, which we call NPAP1L, in all placental mammals except rodents. Phylogenetic analysis revealed that NPAP1, NPAP1L, and another group of genes (UPF0607), which is also restricted to primates, are closely related to the vertebrate transmembrane nucleoporin gene POM121, although they lack the transmembrane domain. These three newly identified groups of genes all lack conserved introns, and hence, are likely retrogenes. We hypothesize that, in the common ancestor of placentals, the POM121 gene retrotransposed and gave rise to an NPAP1-ancestral retrogene NPAP1L/NPAP1/UPF0607. Our results suggest that the nuclear pore-associated gene NPAP1 originates from the vertebrate nucleoporin gene POM121 and--after several steps of retrotransposition and duplication-has been subjected to genomic imprinting and positive selection after integration into the imprinted SNRPN-UBE3A chromosomal domain. PMID- 24482537 TI - "Silent" adrenal tumours should be monitored for changes, say researchers. PMID- 24482534 TI - Adaptive change inferred from genomic population analysis of the ST93 epidemic clone of community-associated methicillin-resistant Staphylococcus aureus. AB - Community-associated methicillin-resistant Staphylococcus aureus (CA-MRSA) has emerged as a major public health problem around the world. In Australia, ST93 IV[2B] is the dominant CA-MRSA clone and displays significantly greater virulence than other S. aureus. Here, we have examined the evolution of ST93 via genomic analysis of 12 MSSA and 44 MRSA ST93 isolates, collected from around Australia over a 17-year period. Comparative analysis revealed a core genome of 2.6 Mb, sharing greater than 99.7% nucleotide identity. The accessory genome was 0.45 Mb and comprised additional mobile DNA elements, harboring resistance to erythromycin, trimethoprim, and tetracycline. Phylogenetic inference revealed a molecular clock and suggested that a single clone of methicillin susceptible, Panton-Valentine leukocidin (PVL) positive, ST93 S. aureus likely spread from North Western Australia in the early 1970s, acquiring methicillin resistance at least twice in the mid 1990s. We also explored associations between genotype and important MRSA phenotypes including oxacillin MIC and production of exotoxins (alpha-hemolysin [Hla], delta-hemolysin [Hld], PSMalpha3, and PVL). High-level expression of Hla is a signature feature of ST93 and reduced expression in eight isolates was readily explained by mutations in the agr locus. However, subtle but significant decreases in Hld were also noted over time that coincided with decreasing oxacillin resistance and were independent of agr mutations. The evolution of ST93 S. aureus is thus associated with a reduction in both exotoxin expression and oxacillin MIC, suggesting MRSA ST93 isolates are under pressure for adaptive change. PMID- 24482538 TI - Protecting intellectual property is vital for medical innovation, says UK report. PMID- 24482539 TI - Safety of benzodiazepines and opioids in very severe respiratory disease: national prospective study. AB - OBJECTIVE: To evaluate the safety of benzodiazepines and opioids in patients with very severe chronic obstructive pulmonary disease (COPD). DESIGN: Population based longitudinal consecutive cohort study. SETTING: Centres prescribing long term oxygen therapy in Sweden. PATIENTS: 2249 patients starting long term oxygen therapy for COPD in Sweden between 2005 and 2009 in the national Swedevox Register. MAIN OUTCOME MEASURES: Effects of benzodiazepines and opioids on rates of admission to hospital and mortality, adjusted for age, sex, arterial blood gases, body mass index (BMI), performance status, previous admissions, comorbidities, and concurrent drugs. RESULTS: 1681 (76%) patients were admitted to hospital, and 1129 (50%) died under observation. No patient was lost to follow up. Benzodiazepines and opioids were not associated with increased admission: hazard ratio 0.98 (95% confidence interval, 0.87 to 1.10) and 0.98 (0.86 to 1.10), respectively. Benzodiazepines were associated with increased mortality (1.21, 1.05 to 1.39) with a dose response trend. Opioids also had a dose response relation with mortality: lower dose opioids (<= 30 mg oral morphine equivalents a day) were not associated with increased mortality (1.03, 0.84 to 1.26) in contrast with higher dose opioids (1.21, 1.02 to 1.44). Concurrent benzodiazepines and opioids in lower doses were not associated with increased admissions (0.86, 0.53 to 1.42) or mortality (1.25, 0.78 to 1.99). Associations were not modified by being naive to the drugs or by hypercapnia. CONCLUSIONS: Lower dose opioids are not associated with increased admissions or deaths in patients with COPD and might be safe for symptom reduction in severe respiratory disease. PMID- 24482541 TI - Prognostic stratification in older adults commencing dialysis. AB - BACKGROUND: Accurate prognostic models could inform treatment decisions for older adults with end-stage renal disease who are considering dialysis and might identify patients more appropriate for conservative care or hospice. METHODS: In a cohort of patients aged >= 67 years commencing dialysis in the United States between January 1, 2008 and June 30, 2009, we compared the discrimination of three existing instruments (the Liu index; the French Renal Epidemiology and Information Network score; and hospice eligibility criteria) for the prediction of 6-month mortality. We estimated the odds of death associated with each prognostic index using logistic regression with and without adjustment for age. Predictive indices were compared using the concordance ("c")-statistic. RESULTS: Of 44,109 eligible patients, 10,289 (23.3%) died within 6 months of dialysis initiation. The c-statistic for the Liu, Renal Epidemiology and Information Network, hospice eligibility criteria, and combined Liu/hospice eligibility criteria scores without and with age were 0.62/0.65, 0.63/0.66, 0.65/0.68, and 0.68/0.70, respectively. Discrimination was poorer at older ages, especially for the Liu and Renal Epidemiology and Information Network scores. Although sensitivity was poor, a Renal Epidemiology and Information Network score >= 9 or an hospice eligibility criteria >= 3 had relatively high specificity. CONCLUSIONS: Existing prognostic indices based on administrative data perform poorly with respect to prediction of 6-month mortality in older patients with end stage renal disease commencing dialysis. PMID- 24482542 TI - Health literacy among young adults: a short survey tool for public health and health promotion research. AB - Health literacy (HL) is context-specific. In public health and health promotion, HL in the private realm refers to individuals' knowledge and skills to prevent disease and to promote health in everyday life. However, there is a scarcity of measurement tools explicitly geared to private realm contexts. Our aim was to develop and test a short survey tool that captures different dimensions of HL in the context of family and friends. We used cross-sectional data from the Swiss Federal Surveys of Adolescents from 2010 to 2011, comprising 7983 males and 366 females between 18 and 25 years. HL was assessed through a set of eight items (self-reports). We used principal component analysis to explore the underlying factor structure among these items in the male sample and confirmatory factor analysis to verify the factor structure in the female sample. The results showed that the tested item set represented dimensions of functional, interactive and critical HL. Two sub-dimensions, understanding versus finding health-relevant information, denoted functional HL. Interactive and critical HL were each represented with two items. A sum score based on all eight items (Cronbach's alpha: 0.64) showed expected positive associations with own and parental education among males and females (p < 0.05). The short item set appears to be a feasible measurement tool to assess HL in the private realm. Its broader application in survey studies may help to improve our understanding of how this form of HL is distributed in the general population. PMID- 24482540 TI - A genomic portrait of the genetic architecture and regulatory impact of microRNA expression in response to infection. AB - MicroRNAs (miRNAs) are critical regulators of gene expression, and their role in a wide variety of biological processes, including host antimicrobial defense, is increasingly well described. Consistent with their diverse functional effects, miRNA expression is highly context dependent and shows marked changes upon cellular activation. However, the genetic control of miRNA expression in response to external stimuli and the impact of such perturbations on miRNA-mediated regulatory networks at the population level remain to be determined. Here we assessed changes in miRNA expression upon Mycobacterium tuberculosis infection and mapped expression quantitative trait loci (eQTL) in dendritic cells from a panel of healthy individuals. Genome-wide expression profiling revealed that ~40% of miRNAs are differentially expressed upon infection. We find that the expression of 3% of miRNAs is controlled by proximate genetic factors, which are enriched in a promoter-specific histone modification associated with active transcription. Notably, we identify two infection-specific response eQTLs, for miR-326 and miR-1260, providing an initial assessment of the impact of genotype environment interactions on miRNA molecular phenotypes. Furthermore, we show that infection coincides with a marked remodeling of the genome-wide relationships between miRNA and mRNA expression levels. This observation, supplemented by experimental data using the model of miR-29a, sheds light on the role of a set of miRNAs in cellular responses to infection. Collectively, this study increases our understanding of the genetic architecture of miRNA expression in response to infection, and highlights the wide-reaching impact of altering miRNA expression on the transcriptional landscape of a cell. PMID- 24482545 TI - Benchmarking of Decision-Support Tools Used for Tiered Sustainable Remediation Appraisal. AB - Sustainable remediation comprises soil and groundwater risk-management actions that are selected, designed, and operated to maximize net environmental, social, and economic benefit (while assuring protection of human health and safety). This paper describes a benchmarking exercise to comparatively assess potential differences in environmental management decision making resulting from application of different sustainability appraisal tools ranging from simple (qualitative) to more quantitative (multi-criteria and fully monetized cost benefit analysis), as outlined in the SuRF-UK framework. The appraisal tools were used to rank remedial options for risk management of a subsurface petroleum release that occurred at a petrol filling station in central England. The remediation options were benchmarked using a consistent set of soil and groundwater data for each tier of sustainability appraisal. The ranking of remedial options was very similar in all three tiers, and an environmental management decision to select the most sustainable options at tier 1 would have been the same decision at tiers 2 and 3. The exercise showed that, for relatively simple remediation projects, a simple sustainability appraisal led to the same remediation option selection as more complex appraisal, and can be used to reliably inform environmental management decisions on other relatively simple land contamination projects. PMID- 24482543 TI - Adenylate cyclase 1 (ADCY1) mutations cause recessive hearing impairment in humans and defects in hair cell function and hearing in zebrafish. AB - Cyclic AMP (cAMP) production, which is important for mechanotransduction within the inner ear, is catalyzed by adenylate cyclases (AC). However, knowledge of the role of ACs in hearing is limited. Previously, a novel autosomal recessive non syndromic hearing impairment locus DFNB44 was mapped to chromosome 7p14.1-q11.22 in a consanguineous family from Pakistan. Through whole-exome sequencing of DNA samples from hearing-impaired family members, a nonsense mutation c.3112C>T (p.Arg1038*) within adenylate cyclase 1 (ADCY1) was identified. This stop-gained mutation segregated with hearing impairment within the family and was not identified in ethnically matched controls or within variant databases. This mutation is predicted to cause the loss of 82 amino acids from the carboxyl tail, including highly conserved residues within the catalytic domain, plus a calmodulin-stimulation defect, both of which are expected to decrease enzymatic efficiency. Individuals who are homozygous for this mutation had symmetric, mild to-moderate mixed hearing impairment. Zebrafish adcy1b morphants had no FM1-43 dye uptake and lacked startle response, indicating hair cell dysfunction and gross hearing impairment. In the mouse, Adcy1 expression was observed throughout inner ear development and maturation. ADCY1 was localized to the cytoplasm of supporting cells and hair cells of the cochlea and vestibule and also to cochlear hair cell nuclei and stereocilia. Ex vivo studies in COS-7 cells suggest that the carboxyl tail of ADCY1 is essential for localization to actin-based microvilli. These results demonstrate that ADCY1 has an evolutionarily conserved role in hearing and that cAMP signaling is important to hair cell function within the inner ear. PMID- 24482546 TI - Interaction of Novel Ionic Liquids with Soils. AB - With the constant development of new ionic liquids, the understanding of the chemical fate of these compounds also needs to be updated. To this effect, the interaction of a number of novel ionic liquids with soils was determined. Therefore, three novel headgroups (ammonium, phosphonium, or pyrrolidinium) with single or quaternary substitution were tested on a variety of soils with high-to low organic matter content and high-to-low cation exchange capacity, thereby trying to capture the full range of possible soil interactions. It was found that the ionic liquids with single butyl alkyl chain interacted more strongly with the soils (especially with a higher cation exchange capacity), at lower concentrations, than the quad-substituted ionic liquids. However, the quad substituted ionic liquids interacted more strongly at higher concentrations, due to the double-layer formation, and induced stronger dipole interaction with previously sorbed molecules. PMID- 24482544 TI - Stress reactivity in maltreated and comparison male and female young adolescents. AB - The purpose of the present report was to examine the association of recent maltreatment experiences with cortisol reactivity in young adolescents. The ethnically diverse sample consisted of boys and girls 9 to 12 years of age. The maltreatment group (N = 303) all had recent, substantiated reports to protective services for neglect, physical abuse, sexual abuse, and/or emotional maltreatment. The comparison group (N = 151) was recruited from the same neighborhoods and was demographically similar to the maltreatment group. Cortisol reactivity was assessed by a laboratory stressor, a modified version of the Trier Social Stress Test for Children. Statistical analyses indicated that the maltreated young adolescents showed a blunted or attenuated response to the stressor as compared with those in the comparison group. This attenuated response was especially pronounced for those whose maltreatment included physical and/or sexual abuse. A main effect for gender was also found with boys having higher cortisol than girls. Implications for treatment of mental and physical health problems associated with child maltreatment and for prevention of developmental problems across the life span are discussed. PMID- 24482547 TI - Racism and Illicit Drug Use Among African American Women: The Protective Effects of Ethnic Identity, Affirmation, and Behavior. AB - Though recent evidence indicates that rates of illicit drug use among African American women are now higher than the national average, little is known about the etiology of substance use in this population. In addition, the effects of racism and other cultural factors are understudied and may be unique amongst African American women. This cross-sectional study explores risk and protective factors for drug use among 204 African American women. More specifically, associations between racism experiences and drug use are investigated in the context of potential moderating influences (i.e., psychosocial resources, social safety net variables, and cultural identity and practices). Findings suggest that racism is associated with drug use, but that its effects diminish with age. In addition, results suggest that psychosocial resources, social safety net factors and culturally specific factors like ethnic community membership and engagement in cultural practices afford African American women some protection against the detrimental effects of racism. PMID- 24482548 TI - Bayesian modeling of temporal dependence in large sparse contingency tables. AB - In many applications, it is of interest to study trends over time in relationships among categorical variables, such as age group, ethnicity, religious affiliation, political party and preference for particular policies. At each time point, a sample of individuals provide responses to a set of questions, with different individuals sampled at each time. In such settings, there tends to be abundant missing data and the variables being measured may change over time. At each time point, one obtains a large sparse contingency table, with the number of cells often much larger than the number of individuals being surveyed. To borrow information across time in modeling large sparse contingency tables, we propose a Bayesian autoregressive tensor factorization approach. The proposed model relies on a probabilistic Parafac factorization of the joint pmf characterizing the categorical data distribution at each time point, with autocorrelation included across times. Efficient computational methods are developed relying on MCMC. The methods are evaluated through simulation examples and applied to social survey data. PMID- 24482549 TI - Case Definition and Design Sensitivity. AB - In a case-referent study, cases of disease are compared to non-cases with respect to their antecedent exposure to a treatment in an effort to determine whether exposure causes some cases of the disease. Because exposure is not randomly assigned in the population, as it would be if the population were a vast randomized trial, exposed and unexposed subjects may differ prior to exposure with respect to covariates that may or may not have been measured. After controlling for measured pre-exposure differences, for instance by matching, a sensitivity analysis asks about the magnitude of bias from unmeasured covariates that would need to be present to alter the conclusions of a study that presumed matching for observed covariates removes all bias. The definition of a case of disease affects sensitivity to unmeasured bias. We explore this issue using: (i) an asymptotic tool, the design sensitivity, (ii) a simulation for finite samples, and (iii) an example. Under favorable circumstances, a narrower case definition can yield an increase in the design sensitivity, and hence an increase in the power of a sensitivity analysis. Also, we discuss an adaptive method that seeks to discover the best case definition from the data at hand while controlling for multiple testing. An implementation in R is available as SensitivityCaseControl. PMID- 24482550 TI - Parallel Development of Risk Behaviors in Adolescence: Potential Pathways to Co occurrence. AB - This study used data from 5,382 adolescents from the 1997 U.S. National Longitudinal Survey of Youth (NLSY97) to investigate developmental pathways of alcohol use, marijuana use, sexual risk behaviors, and delinquency across ages 14 to 20, examine interrelationships among these risk behaviors across adolescence, and evaluate association between risk behavior trajectories and depressive symptoms in adolescence. Group-based dual trajectory modeling, examining trajectories of two outcomes over time, revealed strong interrelationships among developmental trajectories of the four risk behaviors, and indicated potential pathways to co-occurring risk behaviors. Adolescents with higher levels of alcohol use or marijuana use were more likely to engage in higher levels of early sexual risk-taking and delinquency. Moreover, adolescents involved in higher levels of delinquency were at higher risk for engaging in early sexual risk taking. Also belonging to the highest risk trajectory of any of the four risk behaviors was positively associated with depressive symptoms in adolescence. PMID- 24482551 TI - COOH-terminated SAMs on gold fabricated from an azobenzene derivative with a 1,2 dithiolane headgroup. AB - Well-defined and homogeneous, contamination-free self-assembled monolayers (SAMs) were fabricated by the chemisorption of lip-NH-p-C6H4-N=N-p-C6H4-COOH (lip = alpha-lipoyl) onto gold. This adsorbate species is composed of a 1,2-dithiolane based headgroup, an azobenzene-based (and hence photochromic) spacer unit and a carboxylic acid functional group. The SAM constituents are covalently attached to the substrate by the bidentate thiolate anchor groups and exhibit a strongly tilted binding configuration. PMID- 24482552 TI - The Socioemotional Outcomes of Young Children of Teenage Mothers by Paternal Coresidence. AB - To date, no study has examined the implications of biological fathers' coresidence for the socioemotional development of children of teenage mothers. Previous research suggests competing hypotheses. Men who father children with teenage women have low education and earnings and are disproportionately likely to be antisocial. However, teenage mothers are less distressed when fathers are more involved caregivers. The current study follows a multi-city sample of children born to teenage women (n = 509) for their first three years of life in the Fragile Families and Child Wellbeing Study. Children whose biological father coresided continuously (20%) were more likely to be securely attached to their mother and had fewer externalizing problems than other children at age 3. Paternal coresidence did not increase household income, and it only marginally lowered maternal parenting stress. PMID- 24482553 TI - Psychosocial risk assessment in organizations: Concurrent validity of the brief version of the Management Standards Indicator Tool. AB - The Management Standards Indicator Tool (MSIT) is a 35-item self-report measure of the psychosocial work environment designed to assist organizations with psychosocial risk assessment. It is also used in work environment research. Edwards and Webster presented a 25-item version of the MSIT based on the deletion of items having a factor loading of < .65. Stress theory and research suggest that psychosocial hazard exposures may result in harm to the health of workers. Thus, using data collected from three UK organizations (N = 20,406) we compared the concurrent validity of the brief and full versions of the MSIT by exploring the strength of association between each version of the instrument and a measure of psychological wellbeing (GHQ-12 and Maslach Burnout Inventory). Analyses revealed that the brief instrument offered similar but not always equal validity to that of the full version. The results indicate that use of the brief instrument, which would be less disruptive for employees, would not elevate the risk of false negative or false positive findings in risk assessment. PMID- 24482554 TI - Toxicity biomarkers among US children compared to a similar cohort in France: a blinded study measuring urinary porphyrins. AB - The purpose of this blinded study was to evaluate potential environmental toxicity in a cohort of neurotypical children (n = 28) living in a suburban area of north-central Texas in the United States (US) with a comparable age- and gender-matched cohort of neurotypical children (n = 28) living in a suburban area of southeastern France using urinary porphyrin testing: uroporphyrin (uP), heptacarboxyporphyrin (7cxP), hexacarboxyporphyrin (6cxP), pentacarboxyporphyrin (5cxP), precoproporphyrin (prcP), and coproporphyrin (cP). Results showed significantly elevated 6cxP, prcP (an atypical, mercury-specific porphyrin), and cP levels, and increasing trends in 5cxP levels, among neurotypical children in the USA compared to children in France. Data suggest that in US neurotypical children, there is a significantly increased body-burden of mercury (Hg) compared to the body-burden of Hg in the matched neurotypical children in France. The presence of lead contributing to the higher levels of cP also needs to be considered. Further, other factors including genetics can not be completely ruled out. PMID- 24482555 TI - Social Dominance Orientation Relates to Believing Men Should Dominate Sexually, Sexual Self-Efficacy, and Taking Free Female Condoms Among Undergraduate Women and Men. AB - Gendered-based power affects heterosexual relationships, with beliefs in the U.S. prescribing that men dominate women sexually. We draw on social dominance theory to examine whether women's and men's level of support for group-based hierarchy (i.e., social dominance orientation; SDO) helps explain gender-based power beliefs and dynamics in heterosexual relationships. We conducted a laboratory study at a Northeastern U.S. university among 357 women and 126 men undergraduates who reported being heterosexual and sexually active, testing three sets of hypotheses. First, as hypothesized, women endorsed SDO and the belief that men should dominate sexually less than men did. Second, as hypothesized, among women and men, SDO was positively correlated with the belief that men should dominate sexually, and negatively correlated with sexual self-efficacy (confidence in sexual situations) and number of female condoms (a woman controlled source of protection) taken. Third, structural equation modeling, controlling for age, family income, number of sexual partners in the past month, and perceived HIV/AIDS risk, supported the hypothesis that among women and men, the belief that men should dominate sexually mediates SDO's association with sexual self-efficacy. The hypothesis that the belief that men should dominate sexually mediates SDO's association with number of female condoms taken was supported for women only. The hypothesis that sexual self-efficacy mediates SDO's association with number of female condoms taken was not supported. Results suggest SDO influences power beliefs and dynamics in heterosexual relationships. Although female condoms are an important woman-controlled source of protection, power-related beliefs may pose a challenge to their use. PMID- 24482556 TI - [Experiences and impact of an ethics of research training.] AB - This article has the purpose to describe achievements and impact of the ethics of research training at the Interdisciplinary Center for Studies on Bioethics of the University of Chile, which has served as incentive, motivation and guide for professionals which require knowledge, regulations application and dialogue skills to reflect on problems of this discipline. Furthermore, it describes how this knowledge generates a multiplying effect in aspects such as participation in scientific ethical review committees, course organization and the creation and development of research lines, which generate publications by post degree students. It also narrates didactic contents and strategies which could be applied in ethics and bioethics courses for oral health students and concludes mentioning practical applications of this training for teaching, research and institutional development. PMID- 24482559 TI - Differential privacy based on importance weighting. AB - This paper analyzes a novel method for publishing data while still protecting privacy. The method is based on computing weights that make an existing dataset, for which there are no confidentiality issues, analogous to the dataset that must be kept private. The existing dataset may be genuine but public already, or it may be synthetic. The weights are importance sampling weights, but to protect privacy, they are regularized and have noise added. The weights allow statistical queries to be answered approximately while provably guaranteeing differential privacy. We derive an expression for the asymptotic variance of the approximate answers. Experiments show that the new mechanism performs well even when the privacy budget is small, and when the public and private datasets are drawn from different populations. PMID- 24482558 TI - Surface initiated atom transfer radical polymerization grafting of sodium styrene sulfonate from titanium and silicon substrates. AB - This study investigates the grafting of poly-sodium styrene sulfonate (pNaSS) from trichlorosilane/10-undecen-1-yl 2-bromo-2-methylpropionate functionalized Si and Ti substrates by atom transfer radical polymerization (ATRP). The composition, molecular structure, thickness, and topography of the grafted pNaSS films were characterized with x-ray photoelectron spectroscopy (XPS), time-of flight secondary ion mass spectrometry (ToF-SIMS), variable angle spectroscopic ellipsometry (VASE), and atomic force microscopy (AFM), respectively. XPS and ToF SIMS results were consistent with the successful grafting of a thick and uniform pNaSS film on both substrates. VASE and AFM scratch tests showed the films were between 25 and 49 nm thick on Si, and between 13 and 35 nm thick on Ti. AFM determined root-mean-square roughness values were ~2 nm on both Si and Ti substrates. Therefore, ATRP grafting is capable of producing relatively smooth, thick, and chemically homogeneous pNaSS films on Si and Ti substrates. These films will be used in subsequent studies to test the hypothesis that pNaSS grafted Ti implants preferentially adsorb certain plasma proteins in an orientation and conformation that modulates the foreign body response and promotes formation of new bone. PMID- 24482560 TI - Nitroglycerine in HUTT - An explosion in Our Understanding of Unexplained Syncope? PMID- 24482557 TI - Surface characterization of nanomaterials and nanoparticles: Important needs and challenging opportunities. AB - This review examines characterization challenges inherently associated with understanding nanomaterials and the roles surface and interface characterization methods can play in meeting some of the challenges. In parts of the research community, there is growing recognition that studies and published reports on the properties and behaviors of nanomaterials often have reported inadequate or incomplete characterization. As a consequence, the true value of the data in these reports is, at best, uncertain. With the increasing importance of nanomaterials in fundamental research and technological applications, it is desirable that researchers from the wide variety of disciplines involved recognize the nature of these often unexpected challenges associated with reproducible synthesis and characterization of nanomaterials, including the difficulties of maintaining desired materials properties during handling and processing due to their dynamic nature. It is equally valuable for researchers to understand how characterization approaches (surface and otherwise) can help to minimize synthesis surprises and to determine how (and how quickly) materials and properties change in different environments. Appropriate application of traditional surface sensitive analysis methods (including x-ray photoelectron and Auger electron spectroscopies, scanning probe microscopy, and secondary ion mass spectroscopy) can provide information that helps address several of the analysis needs. In many circumstances, extensions of traditional data analysis can provide considerably more information than normally obtained from the data collected. Less common or evolving methods with surface selectivity (e.g., some variations of nuclear magnetic resonance, sum frequency generation, and low and medium energy ion scattering) can provide information about surfaces or interfaces in working environments (operando or in situ) or information not provided by more traditional methods. Although these methods may require instrumentation or expertise not generally available, they can be particularly useful in addressing specific questions, and examples of their use in nanomaterial research are presented. PMID- 24482562 TI - Transmural "Scar-to-Scar" Reentrant Ventricular Tachycardia. AB - We describe a scar-related reentrant ventricular tachycardia circuit with a proximal segment in an endocardial basal septal scar and an exit in a region of slow conduction in a non-overlapping region of epicardial basal lateral scar. The 12-lead EKG demonstrates criteria for a basal lateral epicardial VT, however the same morphology could be produced with a longer stim-latency with pace mapping or VT induction from the endocardial septal region of scar. A significant segment of myocardium demonstrated no endocardial or epicardial scar on electroanatomic mapping, suggesting the presence of a mid-myocardial isthmus. Further evidence was provided by assessment of unipolar settings. The epicardial VT that initially appeared to originate from the basal lateral epicardial region, was successfully treated with radiofrequency ablation of the lateral aspect of the endocardial septal scar. PMID- 24482561 TI - Randomized Prospective Comparison of Two Protocols for Head-up Tilt Testing in Patients with Normal Heart and Recurrent Unexplained Syncope. AB - BACKGROUND: This randomized study was aimed to compare the diagnostic value of two head-up tilt testing protocols using sublingual nitroglycerin for provocation in patients with recurrent unexplained syncope and normal heart. METHODS: The patients with normal findings in physical examination, electrocardiography and echocardiography were randomly submitted to one of upright tilt test protocols. The only difference between two protocols was that nitroglycerin was administered after a five minute resting phase in supine position during protocol B. We also considered eighty normal persons as the control group. RESULTS: Out of 290 patients that underwent tilt testing, 132 patients were in group A versus 158 patients in group B. Both groups had an identical distribution of clinical characteristics. Tilt test was positive in 79 patients in group A (25 in passive phase, 54 in active phase) versus 96 patients in group B (43 in passive phase, 53 in active phase). There was no significant difference between results in two groups (P value= 0.127). Forty cases were tested with protocol A and forty underwent tilt testing with protocol B. Tilt test was positive in 4 cases with protocol A versus 3 cases in protocol B. The positive rates of tilt testing with protocol A was 60% while it was 61% in protocol B. The specificity of testing with protocol A was 90% and it was 92.5% in protocol B. CONCLUSIONS: According to our data, adding a period of rest and returning to supine position before nitroglycerin administration had no additional diagnostic yield. PMID- 24482563 TI - Pacemaker failure due to loss of fluid seal in a patient with a 5/6mm pacemaker header port and a 5mm unipolar lead. AB - INTRODUCTION: Before IS-1 (3.2 mm) standardization of pacemaker leads and connectors, 5/6 mm connector ports accomodated 5mm or 6mm diameter lead connector pins. CASE REPORT: A patient with sick sinus syndrome underwent implantation of a 5mm unipolar atrial lead, mated to a 5/6mm connector port Medtronic Spectrax Sx 5985 pacemaker. Pulse generator reached ERI in 2006, with change out to a Medtronic Sigma SSR306 (5/6mm connector port) and preservation of the 5mm lead. She was admitted in 2010 for atrial lead non capture from blood leak and corrosion of the header-connector pin apparatus. DISCUSSION: 5/6mm pacemaker header ports have a 5mm flexible sealing ring at the port entrance to seal 5mm or 6mm lead connector pins. The inner barrel diameter of the connector port is 6mm and insertion of a 5mm lead results in a 0.5mm tolerance circumferentially. Should the seal be compromised, blood can corrode the apparatus. To minimize this, we can employ (a) a cinching tie to further seal the silicone ring (b) universal adaptor sleeves (c) splice kits (d) lead adaptor kits. Aging leads, adaptor kits or sleeves themselves can result in lead failure. It may be safer to re-implant the entire system. CONCLUSIONS: A 5/6mm configuration pacemaker header connector port allows for significant tolerances when a 5 mm lead is used. Consideration must be made to prevent leaks. PMID- 24482564 TI - Balloon venoplasty of subclavian vein and brachiocephalic junction to enable left ventricular lead placement for cardiac resynchronisation therapy. AB - This report describes the successful implantation of a LV lead using balloon venoplasty to overcome a very tight stenosis of the right subclavian vein / brachiocephalic junction for cardiac resynchronisation therapy (CRT-P) in a patient with a right sided CRT-P system and a failed epicardial LV lead. It is important for device implanters to be familiar with interventional equipments and techniques such as balloon venoplasty to overcome difficult venous access. PMID- 24482565 TI - Local Anaesthesia Suppressing Idiopathic Ventricular Tachycardia: - A Cause of Non-inducible Arrhythmia During Electrophysiology Study. AB - A 13 year old boy having idiopathic ventricular tachycardia had non-inducible tachycardia twice on electrophysiology (EP) study due to suppression of arrhythmia by local anaesthetic agent, lignocaine. This case report demonstrates a cause of non-inducibility or arrhythmia during EP study and effect of lignocaine in suppression of idiopathic ventricular tachycardia. PMID- 24482566 TI - Spontaneous documentation of bidirectional block during pulmonary vein isolation keep an eye on the electrograms! AB - In the present case, we describe the abrupt transformation of intra-pulmonary vein activity from rapid firing to dissociated ectopic activity during sinus rhythm, as an easily identifiable, though rare to encounter, sign which documents the achievement of bidirectional block. PMID- 24482567 TI - Response to "anatomic twist to a straightforward ablation". PMID- 24482568 TI - Authors' reply to "anatomic twist to a straightforward ablation'. PMID- 24482569 TI - Parent-Adolescent Discrepancies in Perceived Parenting Characteristics and Adolescent Developmental Outcomes in Poor Chinese Families. AB - We examined the relationships between parent-adolescent discrepancies in perceived parenting characteristics (indexed by parental responsiveness, parental demandingness, and parental control) and adolescent developmental outcomes (indexed by achievement motivation and psychological competence) in poor families in Hong Kong. A sample of 275 intact families having at least one child aged 11 16 experiencing economic disadvantage were invited to participate in the study. Fathers and mothers completed the Parenting Style Scale and Chinese Parental Control Scale, and adolescents completed the Social-Oriented Achievement Motivation Scale and Chinese Positive Youth Development Scale in addition to paternal and maternal Parenting Style Scale and Chinese Parental Control Scale. Results indicated that parents and adolescents had different perceptions of parental responsiveness, parental demandingness, and paternal control, with adolescents generally perceived lower levels of parenting behaviors than did their parents. While father-adolescent discrepancy in perceived paternal responsiveness and mother-adolescent discrepancy in perceived maternal control negatively predicted adolescent achievement motivation, mother-adolescent discrepancy in perceptions of maternal responsiveness negatively predicted psychological competence in adolescents experiencing economic disadvantage. The present findings provided support that parent-child discrepancies in perceived parenting characteristics have negative impacts on the developmental outcomes of adolescents experiencing economic disadvantage. The present study addresses parent-child discrepancies in perceived parental behaviors as "legitimate" constructs, and explores their links with adolescent psychosocial development, which sheds light for researchers and clinical practitioners in helping the Chinese families experiencing economic disadvantage. PMID- 24482570 TI - Patterns in Relationship Violence Among African American Women: Future Research and Implications for Intervention. AB - The impact of intimate partner violence (IPV) on those most at risk, HIV-positive women of color, has received little attention. This study examined IPV in HIV positive and HIV-negative African American women. Victim characteristics and factors contributing to IPV and psychological sequelae were identified. Structured interviews were administered and analyzed at baseline, at 6 months, and at 12 months. HIV-positive women were less educated, were less employed, had lower incomes, had more depressive symptoms at all time points, and were more likely to report IPV at baseline and 6 months compared to HIV-negative women. Among HIV-positive depressed women, those reporting IPV were more depressed than those without IPV. Suggestions for studies with couples examining relationship dynamics, including risks for IPV and HIV transmission, and for interventions are discussed. PMID- 24482571 TI - A critical analysis of user satisfaction surveys in addiction services: opioid maintenance treatment as a representative case study. AB - BACKGROUND: Satisfaction with services represents a key component of the user's perspective, and user satisfaction surveys are the most commonly used approach to evaluate the aforementioned perspective. The aim of this discursive paper is to provide a critical overview of user satisfaction surveys in addiction treatment and harm reduction services, with a particular focus on opioid maintenance treatment as a representative case. METHODS: We carried out a selective critical review and analysis of the literature on user satisfaction surveys in addiction treatment and harm reduction services. RESULTS: Most studies that have reported results of satisfaction surveys have found that the great majority of users (virtually all, in many cases) are highly satisfied with the services received. However, when these results are compared to the findings of studies that use different methodologies to explore the patient's perspective, the results are not as consistent as might be expected. It is not uncommon to find that "highly satisfied" patients report significant problems when mixed-methods studies are conducted. To understand this apparent contradiction, we explored two distinct (though not mutually exclusive) lines of reasoning, one of which concerns conceptual aspects and the other, methodological questions. CONCLUSION: User satisfaction surveys, as currently designed and carried out in addiction treatment and harm reduction services, do not significantly help to improve service quality. Therefore, most of the enthusiasm and naivete with which satisfaction surveys are currently performed and interpreted - and rarely acted on in the case of nonoptimal results - should be avoided. A truly participatory approach to program evaluation is urgently needed to reshape and transform patient satisfaction surveys. PMID- 24482572 TI - Epidemiological, humanistic, and economic burden of illness of lower limb spasticity in adults: a systematic review. AB - BACKGROUND: The purpose of this study was to investigate the epidemiological, humanistic, and economic burden of illness associated with adult lower limb spasticity (LLS) and its complications. METHODS: A systematic search of MEDLINE and EMBASE identified 23 studies published between January 2002 and October 2012 that assessed the epidemiology, impact, and resource use associated with LLS. A hand-search of four neurology conferences identified abstracts published between 2010 and 2012. RESULTS: LLS was found to occur in one third of adults after stroke, half to two thirds with multiple sclerosis, and three quarters with cerebral palsy. LLS limits mobility and reduces quality of life. No clear association was found between LLS and occurrence of pain, development of contractures, or risk of falls. CONCLUSION: The evidence on the burden of LLS and its complications is surprisingly limited given the condition's high prevalence among adults with common disorders, such as stroke. Further research is needed to clarify the impact of LLS, including the likelihood of thrombosis in spastic lower limbs. The dearth of high-quality evidence for LLS suggests a lack of awareness of, and interest in, the problem, and therefore, the unmet need among patients and their carers. PMID- 24482573 TI - Is higher body temperature beneficial in ischemic stroke patients with normal admission CT angiography of the cerebral arteries? AB - BACKGROUND: Low body temperature is considered beneficial in ischemic stroke due to neuroprotective mechanisms, yet some studies suggest that higher temperatures may improve clot lysis and outcomes in stroke patients treated with tissue plasminogen activator (tPA). The effect of increased body temperature in stroke patients treated with tPA and with normal computed tomography angiography (CTA) on admission is unknown. We hypothesized a beneficial effect of higher body temperature in the absence of visible clots on CTA, possibly due to enhanced lysis of small, peripheral clots. METHODS: Patients with ischemic stroke admitted to our Stroke Unit between February 2006 and April 2013 were prospectively registered in a database (Bergen NORSTROKE Registry). Ischemic stroke patients treated with tPA with normal CTA of the cerebral arteries were included. Outcomes were assessed by the modified Rankin Scale (mRS) after 1 week. An excellent outcome was defined as mRS=0, and a favorable outcome as mRS=0-1. RESULTS: A total of 172 patients were included, of which 48 (27.9%) had an admission body temperature >=37.0 degrees C, and 124 (72.1%) had a body temperature <37.0 degrees C. Body temperature >=37.0 degrees C was independently associated with excellent outcomes (odds ratio [OR]: 2.8; 95% confidence interval [CI]: 1.24 6.46; P=0.014) and favorable outcomes (OR: 2.8; 95% CI: 1.13-4.98; P=0.015) when adjusted for confounders. CONCLUSION: We found an association between higher admission body temperature and improved outcome in tPA-treated stroke patients with normal admission CTA of the cerebral arteries. This may suggest a beneficial effect of higher body temperature on clot lysis in the absence of visible clots on CTA. PMID- 24482577 TI - Implementation of innovative pulsed xenon ultraviolet (PX-UV) environmental cleaning in an acute care hospital. AB - It is widely acknowledged that the hospital environment is an important reservoir for many of the pathogenic microbes associated with health care-associated infections (HAIs). Environmental cleaning plays an important role in the prevention and containment of HAIs, in patient safety, and the overall experience of health care facilities. New technologies, such as pulsed xenon ultraviolet (PX UV) light systems are an innovative development for enhanced cleaning and decontamination of hospital environments. A portable PX-UV disinfection device delivers pulsed UV light to destroy microbial pathogens and spores, and can be used in conjunction with manual environmental cleaning. In addition, this technology facilitates thorough disinfection of hospital rooms in 10-15 minutes. The current study was conducted to evaluate whether the introduction of the PX-UV device had a positive impact on patient satisfaction. Satisfaction was measured using the Hospital Consumer Assessment of Healthcare Providers and Systems (HCAHPS) survey. In 2011, prior to the introduction of the PX-UV system, patient HCAHPS scores for cleanliness averaged 75.75%. In the first full quarter after enhanced cleaning of the facility was introduced, this improved to 83%. Overall scores for the hospital rose from 76% (first quarter, 2011) to 87.6% (fourth quarter, 2012). As a result of this improvement, the hospital received 1% of at risk reimbursement from the inpatient prospective payment system as well as additional funding. Cleanliness of the hospital environment is one of the questions included in the HCAHPS survey and one measure of patient satisfaction. After the introduction of the PX-UV system, the score for cleanliness and the overall rating of the hospital rose from below the fiftieth to the ninety-ninth percentile. This improvement in the patient experience was associated with financial benefits to the hospital. PMID- 24482574 TI - Increased prevalence of coronary artery disease risk markers in patients with chronic hepatitis C--a cross-sectional study. AB - OBJECTIVE: Chronic hepatitis C is a global health problem and has been associated with coronary artery disease. Our aim was to examine the prevalence of coronary artery disease risk markers including endothelial biomarkers in patients with chronic hepatitis C and matched comparisons without manifest cardiovascular disease or diabetes in a cross-sectional design. METHODS: Sixty patients with chronic hepatitis C (mean age 51 years) were recruited from the Department of Infectious Diseases at Copenhagen University Hospital, and compared with 60 age matched non-hepatitis C virus-infected individuals from a general population survey. We examined traditional coronary artery disease risk factors, metabolic syndrome, carotid intima media thickness, and a range of endothelial biomarkers. RESULTS: Patients with chronic hepatitis C had more hypertension (40% versus 25%, prevalence ratio [PR] 1.6; 95% confidence interval [CI] 0.9-2.7) and smoked more (53% versus 38%, PR 1.4; 95% CI 0.9-2.1). The two groups had similar body mass index (mean 25.0 versus 25.7 kg/m(2)), whereas those with chronic hepatitis C had less dyslipidemia (including significantly lower low-density lipoprotein and cholesterol/high-density lipoprotein ratio), higher glycosylated hemoglobin level (mean 6.2 versus 5.7, difference of means 0.5; 95% CI 0.3-0.8), and a higher prevalence of metabolic syndrome (28% versus 18%, PR 1.6; 95% CI 0.8-3.0). Increased carotid intima media thickness above the standard 75th percentile was seen more frequently in chronic hepatitis C (9% versus 3%, PR 1.7; 95% CI 0.4 6.7), though difference of means was only 0.04 mm (95% CI 0.00-0.10). Patients with chronic hepatitis C had increased hsCRP (high-sensitivity C-reactive protein), sICAM-1 (soluble intercellular adhesion molecule-1), sVCAM-1 (soluble vascular cell adhesion molecule-1), and soluble E-selectin, but lower levels of tPAI-1 (tissue-type plasminogen activator inhibitor-1), MMP9 (matrix metallopeptidase 9), and MPO (myeloperoxidase) than their comparisons. CONCLUSION: Our findings indicate that patients with chronic hepatitis C have increased prevalence of several coronary artery disease risk markers. These results may be important when evaluating the appropriateness of screening for coronary artery disease and its risk factors in chronic hepatitis C. PMID- 24482578 TI - Clinical Evaluation of Abiraterone in the Treatment of Metastatic Prostate Cancer. AB - Treatment of castration-resistant prostate cancer remains an area of unmet medical need. Evidence suggests that this entity continues to be driven by androgens and androgen receptor (AR) signaling. Abiraterone acetate, a pregnenolone derivative, is an oral selective and irreversible inhibitor of the key steroidogenic enzyme CYP17. It possesses dual 17-alpha hydroxylase and C17,20 lyase blocking activity, the result of which is decreased gonadal and extra gonadal androgen synthesis. Abiraterone was first approved by the US Food and Drug Administration (FDA) in 2011 following the demonstration of superior survival compared with placebo in the post-docetaxel population. Since that time, more evidence has been generated from preclinical studies and clinical trials which have considerably enhanced our understanding of this complex disease. In this paper, we review the development of abiraterone acetate, its pharmacological characteristics, and its effects on the androgen-AR signaling axis, along with the combined experience from clinical trials. We also discuss some of the ongoing trials using this agent, as well as potential mechanisms of abiraterone resistance, novel bio-marker development, and future directions using AR-directed therapies. PMID- 24482579 TI - Protein hydrolysates in sports and exercise: a brief review. AB - Protein can be hydrolyzed, producing small chains of amino acids called peptides. Several studies have shown that protein hydrolysates containing mostly di- and tripeptides are absorbed more rapidly than free form amino acids and much more rapidly than intact proteins. In addition, there is recent evidence that protein hydrolysate ingestion has strong insulinotropic effect. Thus, recovery sports drinks containing protein hydrolysates may be of great value. Key PointsProtein hydrolysates containing mostly di- and tripeptides are absorbed more rapidly than free form amino acids and much more rapidly than intact proteins.Oral intake of protein hydrolysates and amino acids in combination with carbohydrates can result in an insulinotropic effect as much as 100% greater than with the intake of carbohydrates only.Recovery sports drinks containing protein hydrolysates and insulinotropic amino acids may be of great value, but more research is needed before firm conclusions can be drawn. PMID- 24482576 TI - Triple-negative breast cancer risk in women is defined by the defect of estrogen signaling: preventive and therapeutic implications. AB - Epidemiologic studies strongly support that triple-negative breast cancers (TNBCs) may be distinct entities as compared with estrogen receptor (ER)+ tumors, suggesting that the etiologic factors, clinical characteristics, and therapeutic possibilities may vary by molecular subtypes. Many investigations propose that reproductive factors and exogenous hormone use differently or even quite inversely affect the risk of TNBCs and ER+ cancers. Controversies concerning the exact role of even the same risk factor in TNBC development justify that the biological mechanisms behind the initiation of both TNBCs and non-TNBCs are completely obscure. To arrive at a comprehensive understanding of the etiology of different breast cancer subtypes, we should also reconsider our traditional concepts and beliefs regarding cancer risk factors. Malignancies are multicausal, but the disturbance of proper estrogen signaling seems to be a crucial risk factor for the development of mammary cancers. The grade of defect in metabolic and hormonal equilibrium is directly associated with TNBC risk for women during their whole life. Inverse impact of menopausal status or parity on the development of ER+ and ER- breast cancers may not be possible; these controversial results derive from the misinterpretation of percentage-based statistical evaluations. Exogenous or parity-associated excessive estrogen supply is suppressive against breast cancer, though the lower the ER expression of tumors, the weaker the anticancer capacity. In women, the most important preventive strategy against breast cancers - included TNBCs - is the strict control and maintenance of hormonal equilibrium from early adolescence through the whole lifetime, particularly during the periods of great hormonal changes. PMID- 24482580 TI - High altitude and free radicals. AB - High altitude exposure results in decreased oxygen pressure and an increased formation of reactive oxygen and nitrogen species (RONS), which is often associated with increases in oxidative damage to lipids, proteins and DNA. Exposure to high altitude appears to decrease the activity and effectiveness of antioxidant enzymes system. Moreover, during high altitude exposure several RONS generating source are activated, including mitochondrial electron transport chain, xanthine oxidase, and nitric oxide synthase (NO). Physical exercise at high altitude can further enhance the oxidative stress. The available information suggests that RONS are involved and are even a causative factor of acute mountain sickness. Supplementation of antioxidant seems to be a necessary step to prevent or decrease to high altitude exposure associated oxidative stress. Key PointsReactive oxygen and nitrogen speciesHigh altitude-induced oxidative stressAntioxidant down regulation by altitudeExercise and altitude associated oxidative stress. PMID- 24482581 TI - Reduced muscle pain intensity rating during repeated cycling trials. AB - The purpose of this study was to investigate muscle pain intensity rating using a 10-point category-ratio pain intensity scale during self-paced cycling exercise within three trials. Eleven subjects (age 21.4 +/- 2.6 years; VO2 peak 3.3 +/- 0.9 L.min(-1)) performed a 60-min cycling trial on three occasions. During each trial subjects cycled at the utmost work intensity for 60-min. To simulate competitive training, 1-min maximal effort sprints were performed every 10-mins into the trial. Ambient temperature and relative humidity were set at 33 +/- 0.7 (o)C and 63 +/- 2.0%, respectively. During exercise, subjects ranked the muscle pain intensity at 5 min intervals and following each sprint effort. Simple main effects revealed that muscle pain intensity ratings were significantly lower in trial 3 compared with trial 1 at the 50 min [F = 4.5(2 30); p = 0.015, eta(2) = 0.05], 55 min [F = 4.89(2, 30); p = 0.011; eta(2) = 0.05], and 60 min [F = 3.6(2, 30); p = 0.034; eta(2) = 0.04] time interval. Repeated measures ANOVA revealed a significant increase in the mean distance cycled amongst the trials (p < 0001). These results indicate an attenuation in muscle pain intensity rating with endurance exercise training when performed over three trials. The reduced pain intensity rating may be due to adjustments in cadence and gear selection amongst the trials. Key PointsMuscle pain intensity rating was significantly reduced with three repeated cycling endurance trials.Attenuation in muscle pain intensity rating appeared at 50, 55, 60 mins into exercise within the third trial.The attenuation in muscle pain intensity with training is apparent despite an increase in cycling distance performance.The decline in muscle pain rating and increased cycling performance may be associated with adjustment in cadence and gear selection amongst the endurance trails. PMID- 24482583 TI - The effect of cryotherapy on three dimensional ankle kinematics during a sidestep cutting maneuver. AB - Although cryotherapy is commonly used in the treatment of acute and chronic athletic injuries, the deleterious effects of limb cooling, such as decreased nerve and muscle function, slowed sensation and inhibition of normal relaxes, may put an athlete at increased risk of additional injury. The purpose of this study was to determine the effects of cryotherapy on subtalar and ankle joint kinematics of healthy athletes performing a sidestep 45 degrees cut. We hypothesized that greater joint displacements and velocities would be seen after icing. Twenty one subjects performed a 45 degrees sidestep cut prior to and after limb cooling. Retroreflective markers were placed on the subject's shank and foot while 6 high-speed cameras were used to collect the kinematic data. In this test-retest controlled laboratory study, a repeated measures ANOVA was performed on the PRE and POST icing data for the minimum and maximum joint displacements and velocities. No statistical differences were noted between the PRE and POST icing conditions. The results indicate that a 10-minute icing treatment did not have an effect on either the movement patterns or angular velocities. Our results do not support any change in practice of icing injured ankles for ten minutes during halftime of athletic events. Key PointsCryotherapy does not affect ankle/subtalar joint movement.SUBJECTS UTILIZE TWO DIFFERENT LANDING PATTERNS: sagittal plane or frontal plane dominant. PMID- 24482582 TI - Measuring oxygen cost during level walking in individuals with acquired brain injury in the clinical setting. AB - This study examined the test-retest reliability of oxygen cost (ml.kg(-1).min( 1)) during level walking in individuals with acquired brain injury (ABI). Ten individuals with ABI (5 men, 5 women) (Traumatic brain injury, 1, central pontine myelinolysis, 1, stroke 8) and 21 healthy controls (11 men, 10 women). Measurements of gross and net (walking minus resting) oxygen consumption (ml.kg( 1).min(-1)), and oxygen cost (ml.kg(-1).min(-1)) during level walking at self selected speeds. Measurements were taken on two occasions within one week. Oxygen cost was significantly lower (p < 0.05) in individuals with ABI on the second test versus the first test. Percentage variability in oxygen cost from test to re test ranged from 14.7 to 17.3% in the control group and from 17.4 to 20.8% in the brain injury group. Clinical populations may demonstrate a significant decrease in oxygen cost between testing occasions. Individuals require at least one period of familiarisation if oxygen cost is used as an outcome measure during level walking in clinical groups. The amount of familiarisation has yet to be investigated in individuals with ABI. Key PointsIndividuals with brain injury during level walkingMay demonstrate a significant decrease in oxygen cost between testing occasions.May require at least one period of familiarisation if oxygen cost is used as an outcome measureThe degree of familiarisation required in this clinical group needs further investigation. PMID- 24482584 TI - A kinematic study of finswimming at surface. AB - Finswimming is a sport of speed practiced on the surface or underwater, in which performance is based on whole-body oscillations. The present study investigated the undulatory motion performed by finswimmers at the surface. This study aiming to analyze the influence of the interaction of gender, practice level, and race distance on selected kinematic parameters. Six elite and six novices finswimmers equipped with joints markers (wrist, elbow, shoulder, hip, knee, and ankle) were recorded in the sagittal plane. The position of these anatomical marks was digitized at 50 Hz. An automated motion analysis software yielded velocity, vertical amplitude, frequency, and angular position. Results showed that stroke frequency decreased whereas the mean amplitude of all joints increased with increasing race distance (p < 0.01). Mean joint amplitude for the upper limbs (wrist, elbow and shoulder) was smaller for experts than for novices. Whereas that of the ankle was larger, so that the oscillation amplitude increased from shoulder to ankle. Elite male finswimmers were pitching more acutely than female. Moreover, elite male finswimmers showed a smaller knee bending than novices and than elite females (p < 0.01). This indicated that elite male finswimmers attempt to reduce drag forces thanks to a weak knee bending and a low upper limbs pitch. To sum up, gender, expertise, and race distance affect the performance and its kinematics in terms frontal drag. Expertise in finswimming requires taking advantage of the mechanical constraints pertaining to hydrodynamic constraints in order to optimize performance. Key PointsFinswimmers are at one and the same time a propelling and a propelled body. This study investigates the undulatory motion performed by finswimmers at the surface.Elite male finswimmers were pitching more acutely than female swimmers and showed a smaller knee bending than both novices and elite female swimmers.Finswimmers tended to perform a dolphin-like motion, which is used underwater situation and optimizes hydrodynamics. PMID- 24482585 TI - Turf toe in a taekwandoo player: case report. AB - Metatarsophalengeal joint injuries of great toe termed as ''turf toe" can occur in many sportive activities. However, it has not been reported before in taekwondoo players. These injuries may result in significant morbidity. Turf toe injuries, which are mainly treated with conservative methods, occasionally require surgery. In this case report, we present a surgically treated turf toe in a taekwondoo player. Key PointsMTP joint injury may occur when the joint is forced into hyperextension repeatedly if the exercise is being performed bare foot on hard and artificial surfaces.Surgery should be taken into consideration as a choice of treatment of Turf Toe. PMID- 24482587 TI - Symposium - macronutrient utilization during exercise: implications for performance and supplementation. PMID- 24482586 TI - Can Renal Hematoma Occur without a Direct Trauma During Exercise? A Case Report. AB - Renal injury can occur during sports activity. Although it is, generally, associated with contact trauma, it is known that the renal injury can be developed during training without a direct trauma. The diagnosis of renal injuries should not be based solely on urine analysis. Computed tomography scan is necessary diagnose possible renal injuries. Key PointsRenal injuries may develop during sporting activities without a direct trauma.CT scan is necessary in order to diagnose possible renal injuries and to grade accurately the degree of injury. PMID- 24482588 TI - Dietary fat and sports nutrition: a primer. AB - The general public's view of macronutrients has undergone sweeping changes in recent years. Dietary fats are a key example. Since the anti-fat health education initiatives of the 1980s and early 1990s, certain dietary fats have been increasingly recognized as actually beneficial to health. Athletes, like the mainstream populace, are now getting the message that wise dietary fat (triacylglycerol) choices offer essential fatty acids, blood lipid management, maintained endocrine and immune function, inflammation control, metabolic effects and even potential body composition and performance benefits. Toward this end, many companies now sell specialty dietary fat supplements and recognized health authorities have begun recommending them to certain populations. This review will cover data regarding the physiology, dietary needs, food sources, and potential benefits and risks most relevant to athletes. Practical suggestions for incorporating healthy fats will be made. Both food-source and supplemental intakes will be addressed with interrelationships to health throughout. Key PointsNutrition education initiatives over recent years have sent contrasting messages on dietary fat to the public.Variations in chemical structure among triacylglycerols and their component fatty acids induce very different biological effects.Manipulating fat as a percentage of total kcal affects athletes.Athletes have special needs for which dietary fat may prove beneficial. PMID- 24482590 TI - Regulation of muscle glycogen repletion, muscle protein synthesis and repair following exercise. AB - Recovery from prolonged strenuous exercise requires that depleted fuel stores be replenished, that damaged tissue be repaired and that training adaptations be initiated. Critical to these processes are the type, amount and timing of nutrient intake. Muscle glycogen is an essential fuel for intense exercise, whether the exercise is of an aerobic or anaerobic nature. Glycogen synthesis is a relatively slow process, and therefore the restoration of muscle glycogen requires special considerations when there is limited time between training sessions or competition. To maximize the rate of muscle glycogen synthesis it is important to consume a carbohydrate supplement immediately post exercise, to continue to supplement at frequent intervals and to consume approximately 1.2 g carbohydrate.kg(-1) body wt.h(-1). Maximizing glycogen synthesis with less frequent supplementation and less carbohydrate can be achieved with the addition of protein to the carbohydrate supplement. This will also promote protein synthesis and reduce protein degradation, thus having the added benefit of stimulating muscle tissue repair and adaptation. Moreover, recent research suggests that consuming a carbohydrate/protein supplement post exercise will have a more positive influence on subsequent exercise performance than a carbohydrate supplement. Key PointsFor rapid recovery from prolonged exercise, it is important to replenish muscle glycogen stores and initiate muscle tissue repair and adaptation.To maximize muscle glycogen replenishment, it is important to consume a carbohydrate supplement as soon after exercise as possible.Consume the carbohydrate frequently, such as every 30 minutes, and provide about 1.2 to 1.5 g of carbohydrate.kg(-1) body wt.h(-1).Efficiency of muscle glycogen storage can be increased significantly with the addition of protein to a carbohydrate supplement (~4 to 1 carbohydrate to protein ratio).The addition of protein to a carbohydrate supplement also has the added advantage of limiting post exercise muscle damage and promoting muscle protein accretion. PMID- 24482589 TI - Protein - Which is Best? AB - Protein intake that exceeds the recommended daily allowance is widely accepted for both endurance and power athletes. However, considering the variety of proteins that are available much less is known concerning the benefits of consuming one protein versus another. The purpose of this paper is to identify and analyze key factors in order to make responsible recommendations to both the general and athletic populations. Evaluation of a protein is fundamental in determining its appropriateness in the human diet. Proteins that are of inferior content and digestibility are important to recognize and restrict or limit in the diet. Similarly, such knowledge will provide an ability to identify proteins that provide the greatest benefit and should be consumed. The various techniques utilized to rate protein will be discussed. Traditionally, sources of dietary protein are seen as either being of animal or vegetable origin. Animal sources provide a complete source of protein (i.e. containing all essential amino acids), whereas vegetable sources generally lack one or more of the essential amino acids. Animal sources of dietary protein, despite providing a complete protein and numerous vitamins and minerals, have some health professionals concerned about the amount of saturated fat common in these foods compared to vegetable sources. The advent of processing techniques has shifted some of this attention and ignited the sports supplement marketplace with derivative products such as whey, casein and soy. Individually, these products vary in quality and applicability to certain populations. The benefits that these particular proteins possess are discussed. In addition, the impact that elevated protein consumption has on health and safety issues (i.e. bone health, renal function) are also reviewed. Key PointsHigher protein needs are seen in athletic populations.Animal proteins is an important source of protein, however potential health concerns do exist from a diet of protein consumed from primarily animal sources.With a proper combination of sources, vegetable proteins may provide similar benefits as protein from animal sources.Casein protein supplementation may provide the greatest benefit for increases in protein synthesis for a prolonged duration. PMID- 24482591 TI - Post-exercise muscle glycogen repletion in the extreme: effect of food absence and active recovery. AB - Glycogen plays a major role in supporting the energy demands of skeletal muscles during high intensity exercise. Despite its importance, the amount of glycogen stored in skeletal muscles is so small that a large fraction of it can be depleted in response to a single bout of high intensity exercise. For this reason, it is generally recommended to ingest food after exercise to replenish rapidly muscle glycogen stores, otherwise one's ability to engage in high intensity activity might be compromised. But what if food is not available? It is now well established that, even in the absence of food intake, skeletal muscles have the capacity to replenish some of their glycogen at the expense of endogenous carbon sources such as lactate. This is facilitated, in part, by the transient dephosphorylation-mediated activation of glycogen synthase and inhibition of glycogen phosphorylase. There is also evidence that muscle glycogen synthesis occurs even under conditions conducive to an increased oxidation of lactate post-exercise, such as during active recovery from high intensity exercise. Indeed, although during active recovery glycogen resynthesis is impaired in skeletal muscle as a whole because of increased lactate oxidation, muscle glycogen stores are replenished in Type IIa and IIb fibers while being broken down in Type I fibers of active muscles. This unique ability of Type II fibers to replenish their glycogen stores during exercise should not come as a surprise given the advantages in maintaining adequate muscle glycogen stores in those fibers that play a major role in fight or flight responses. Key PointsEven in the absence of food intake, skeletal muscles have the capacity to replenish some of their glycogen at the expense of endogenous carbon sources such as lactate.During active recovery from exercise, skeletal muscles rich in type II fibers replenish part of their glycogen stores even in the absence of food intake.Post-exercise muscle glycogen synthesis in the fasted state is facilitated, in part, by the transient dephosphorylation-mediated activation of glycogen synthase and inhibition of glycogen phosphorylase. PMID- 24482592 TI - Validity and reliability of physical activity measures in greek high school age children. AB - The aim of this study was to determine the validity and reliability of 3 physical activity questionnaires in Greek high school children. Forty children participated in the study aged M = 13.73 (SD 0.8 years). The validation study was conducted by comparing an accelerometer (MTI/CSA Model 7164) to 3 questionnaires: a) Three-day Physical Activity Record (3DPAR), b) Four by One-Day Recall Physical Activity Questionnaire (4BY1RPAQ) and c) Physical Activity and Life Style Questionnaire (PALQ). Validity of the 3 self-report questionnaires was assessed against the MTI/CSA accelerometer by comparing the scores obtained by each instrument on the first week of measurement. Reliability was assessed with two consecutive measurements performed two weeks apart. The measures of reliability were assessed by Intra Class Correlation, Typical Error and Limits of Agreement. A two-way ANOVA for repeated measures was performed. Repeated measures were week and day; in order to determine differences between the two scores obtained with the two measurements for MTI/CSA, 3DPAR and 4BY1RPAQ. A paired Student's t-test was performed for the two scores obtained with the PALQ. Post-hoc multiple comparisons were performed using the Bonferroni test. Significance for all parts of the analysis was determined at an alpha level of p < 0.05. A paired Student's t-test was performed for the two scores obtained with the PALQ. Results of this study indicated that reliability measured by intra class correlations (ICC) were for MTI/CSA (ICC = 0.52, p < 0.05), 3DPAR (ICC = 0.97, p < 0.01), 4BY1RPAQ (ICC = 0.70, p < 0.01), and PALQ (ICC = 0.52, p < 0.01). Significant Pearson product moment correlation coefficients (r) were observed between MTI/CSA and the other instruments, as a measure of validity: 3DPAR (r = 0.63, p < 0.01), 4BY1RPAQ (r = 0.62, p < 0.01), and PALQ (r = 0.53, p < 0.01). The reliability of the four instruments used in this study was acceptable. Validity correlations were also significant for the three self-report instruments used in this study. Key PointsThe PALQ demonstrated a moderate reliability (0.52) and validity (0.53) in recording physical activity.A relatively high correlation was observed between the MTI/CSA and 3DPAR and a moderate correlation was observed between MTI/CSA and the 4BY1RPAQ tested in this study.Only a combination of the available instruments would be able to respond to the interpersonal and intrapersonal variability when assessing physical activity in children and adolescents. Self-report instruments and accelerometers are probably able to quantify only gross fluctuations in physical activity.All 4 instruments used in this study were valid and reliable in recording physical activity when used with children, since the instruments were able to detect changes in physical activity and the respective energy cost. PMID- 24482593 TI - Motor Imagery Boosts Proprioceptive Neuromuscular Facilitation in the Attainment and Retention of Range-of -Motion at the Hip Joint. AB - This study examined the effect of proprioceptive neuromuscular facilitation (PNF) coupled with an internal mental imagery technique (PNFI) on both the attainment and retention of increased range-of-movement (ROM) at the hip joint. Twenty-four young adult subjects were randomly allocated to PNF, PNFI, and control treatments administered in fifteen sessions over a three-week period. ROM was assessed prior to training then at the completion of sessions 1 day, 3, 7, and 14 during training, then 28 days after program completion. Analysis-of-Variance with repeated measures showed both significant treatment (p < 0.01) and time effects (p < 0.05). Mean change of ROM values were always larger under the PNFI condition and significantly different (p < 0.05) at day 1 and 3 following training program completion. Thereafter, the diminution of ROM was comparable to the PNF condition. Mean ROM increment relative to baseline was 7.55 and 9.45 degrees for PNF and PNFI respectively receding to 5.86 and 6.5 degrees at twenty-eight days following treatment cessation. Motor imagery coupled with PNF to enhance and retain ROM yields superior results to physical training used alone and can benefit both athletes and those undergoing rehabilitation. Key PointsA Proprioceptive Neuromuscular Facilitation (PNF) technique applied to enhance range-of-movement (ROM) at the hip joint was successful.The effect produced greater gains in participants who received and applied a motor imagery technique to supplement the regular PNF.Both effects receded by about 50% across a no practice period of 21 days.Incorporation of motor imagery with physical therapy deemed worthwile. PMID- 24482594 TI - Changes in Running Speeds in a 100 KM Ultra-Marathon Race. AB - The purpose of this study was to determine if runners who completed a 100 km ultramarathon race in the fastest times changed their running speeds differently compared to those runners who ran an overall slower race. Times were taken from the race results of the 1995 100 km IAU World Challenge in Winschoten, Netherlands. Race times and 10 km split times were analyzed. Runners (n = 67) were divided into groups of ten with the last group consisting of seven runners. The mean running speed for each 10 km segment was calculated using each runner's 10 km split times. Mean running speed was calculated using each runner's race time. The first 10 km split time was normalized to 100, with all subsequent times adjusted accordingly. The mean running speed for each group at each 10 km split was then calculated. The faster runners started at a faster running speed, finished the race within 15 % of their starting speed, and maintained their starting speed for longer (approximately 50 km) before slowing. The slower runners showed a greater percentage decrease in their mean running speed, and were unable to maintain their initial pace for as long. It is concluded that the faster runners: 1) ran with fewer changes in speed, 2) started the race at a faster running speed than the slower runners, and 3) were able to maintain their initial speed for a longer distance before slowing. Key PointsFaster runners in the 100 km race;ran with fewer changes in running speed compared to the slower runners;started the race at a faster running speed than the slower runners;were able to maintain their initial running speed for longer distances than slower runners. PMID- 24482595 TI - Relationship between Fat Oxidation and Lactate Threshold in Athletes and Obese Women and Men. AB - The first aim of this study was to determine the exercise intensity that elicited the highest rate of fat oxidation in sedentary, obese subjects (OB; n=10 men, n=10 women) compared with endurance athletes (AT; n=10 men, n=10 women). The second aim was to investigate the relationship between VO2 at the intensity eliciting the highest rate of fat oxidation and the corresponding VO2 at the lactate threshold. Peak oxygen consumption (VO2peak) was determined in 20 AT and 20 OB using an incremental exercise protocol on a cycle ergometer. Based on their VO2peak values, subjects completed a protocol requiring them to exercise for 20 min at three different workloads (55, 65 and 75% VO2peak), randomly assigned on two separate occasions. The oxidation rates of fat and carbohydrate were measured by indirect calorimetry. The highest rates of fat oxidation were at 75 % VO2peak (AT), and at 65 % VO2peak (OB). The rate of fat oxidation was significantly higher in AT (18.2 +/- 6.1) compared with OB women (10.6 +/- 4.5 kJ min(-1).kg( 1)) (p < 0.01). There was no significant difference in the rate of fat oxidation for the men (AT 19.7 +/- 8.1 vs. OB 17.6 +/- 8.2 kJ min(-1).kg(-1)). AT reached LT at a significantly (p < 0.01) higher exercise intensity expressed in VO2peak than obese subjects (AT women 76.4 +/- 0.1, men 77.3 +/- 0.1 vs. OB women, 49.7 +/- 0.1, men 49.5 +/- 0.1% VO2peak). A significant correlation was found between VO2 at LT and VO2 (L.min(-1)) eliciting the maximal rate of fat oxidation in athletes (women; r = 0.67; p = 0.03; men: r = 0.75; p = 0.01) but not in the obese. In summary, we observed higher rates of fat oxidation at higher relative work rates in AT compared with OB. A significant correlation was found between LT and the exercise intensity eliciting a high rate of fat oxidation in AT (r=0.89; p < 0.01) but not in OB. Cardiorespiratory fitness, defined as VO2peak, seems to be important in defining the relationship between a high rate of fat oxidation and LT. Key PointsWithin the tested intensities of 55, 65 and 75% VO2peak athletes reached higher rates of fat oxidation at higher relative work rates compared with obese subjects.We found in obese women and men the intensity of the highest rate of fat oxidation at 65% VO2peak.Between the lactate threshold and the intensity eliciting a high rate of fat oxidation a significant correlation was found in athletes but not in obese subjects. PMID- 24482597 TI - The Reliability of 1- and 3Rm Tests of Unilateral Strength in Trained and Untrained Men and Women. AB - The purpose of this study was to determine the reliability of the 1- and 3RM tests for the modified unilateral squat. Thirty untrained (22 women, 8 men) and 22 trained (12 women, 10 men) subjects participated in the study. The trained group had a minimum of 1 year lower-body training experience but had not participated in unilateral training prior to the study. After practicing proper technique with light loads, the subjects used the barbell squat to complete a 1- and 3RM pretest and posttest. In each group half of the subjects completed the 1RM tests prior to the 3RM tests while half of the subjects completed the 3RM tests first. A rest period of 48 hours was allowed between each test. Twenty subjects, randomly selected from the two groups, completed a third session of the 1RM test 3 days after the 1RM posttest. Intraclass correlation coefficients were recorded. Differences between pre- and posttest measures were determined by the paired-sample t-test. The 1- and 3RM tests were found to be significantly reliable for trained men, r = 0.98 and r = 0.97, untrained men, r = 0.99 and r = 0.97, trained women r = 0.99 and r = 0.94, and untrained women, r = 0.97 and r = 0.87, respectively. Posttest scores for the 1- and 3RM tests significantly improved above baseline levels in each group (p < 0.05). Strength scores did not significantly increase during the third 1RM test (p = 0.22). The data indicate that the modified unilateral squat can be measured with high reliability using the 1- and 3RM tests. The improved posttest scores indicate that a pretest session should take place before recording baseline measurements. Key PointsThe modified unilateral squat is a reliable test for trained and untrained men and women.The 1RM and 3RM tests are reliable and safe for trained and untrained subjects.A practice session and pretest should be conducted prior to baseline testing. PMID- 24482596 TI - Effect of moderate altitude on peripheral muscle oxygenation during leg resistance exercise in young males. AB - Training at moderate altitude (~1800m) is often used by athletes to stimulate muscle hypoxia. However, limited date is available on peripheral muscle oxidative metabolism at this altitude (1800AL). The purpose of this study was to determine whether acute exposure to 1800AL alters muscle oxygenation in the vastus lateralis muscle during resistance exercise. Twenty young active male subjects (aged 16 - 21 yr) performed up to 50 repetitions of the parallel squat at 1800AL and near sea level (SL). They performed the exercise protocol within 3 h after arrival at 1800 AL. During the exercise, the changes in oxygenated hemoglobin (OxyHb) in the vastus lateralis muscle, arterial oxygen saturation (SpO2), and heart rate were measured using near infrared continuous wave spectroscopy (NIRcws) and pulse oximetry, respectively. Changes in OxyHb were expressed by Deff defined as the relative index of the maximum change ratio (%) from the resting level. OxyHb in the vastus lateralis muscle decreased dramatically from the resting level immediately after the start of exercise at both altitudes. The Deff during exercise was significantly (p < 0.001) lower at 1800AL (60.4 +/- 6.2 %) than at near SL (74.4 +/- 7.6 %). SpO2 during exercise was significantly (p < 0.001) lower at 1800AL (92.0 +/- 1.7 %) than at near SL (96.7 +/- 1.2 %). Differences (SL - 1800AL) in Deff during exercise correlated fairly strongly with differences in SpO2 during exercise (r = 0.660). These results suggested that acute exposure to moderate altitude caused a more dramatical decrease in peripheral muscle oxygenation during leg resistance exercise. It is salient to note, therefore, that peripheral muscle oxygenation status at moderate altitude could be evaluated using NIRcws and that moderate altitudes might be effectively used to apply hypoxic stress on peripheral muscles. Key PointsThe change in muscle oxygenation during the parallel squat at 1800 altitude and near sea level was investigated using near infrared continuous wave spectroscopy (NIRcws)The muscle oxygenation during exercise at 1800 altitude decreased more dramatically compared to sea level.NIRcws could help to provide a better understanding of exercising muscle metabolism at moderate altitude. PMID- 24482599 TI - Large-scale production and evaluation of marker-free indica rice IR64 expressing phytoferritin genes. AB - Biofortification of rice (Oryza sativa L.) using a transgenic approach to increase the amount of iron in the grain is proposed as a low-cost, reliable, and sustainable solution to help developing countries combat anemia. In this study, we generated and evaluated a large number of rice or soybean ferritin over accumulators in rice mega-variety IR64, including marker-free events, by introducing soybean or rice ferritin genes into the endosperm for product development. Accumulation of the protein was confirmed by ELISA, in situ immunological detection, and Western blotting. As much as a 37- and 19-fold increase in the expression of ferritin gene in single and co-transformed plants, respectively, and a 3.4-fold increase in Fe content in the grain over the IR64 wild type was achieved using this approach. Agronomic characteristics of a total of 1,860 progenies from 58 IR64 single independent transgenic events and 768 progenies from 27 marker-free transgenic events were evaluated and most trait characteristics did not show a penalty. Grain quality evaluation of high-Fe IR64 transgenic events showed quality similar to that of the wild-type IR64. To understand the effect of transgenes on iron homeostasis, transcript analysis was conducted on a subset of genes involved in iron uptake and loading. Gene expression of the exogenous ferritin gene in grain correlates with protein accumulation and iron concentration. The expression of NAS2 and NAS3 metal transporters increased during the grain milky stage. PMID- 24482600 TI - Optimized breeding strategies for multiple trait integration: I. Minimizing linkage drag in single event introgression. AB - From a breeding standpoint, multiple trait integration (MTI) is a four-step process of converting an elite variety/hybrid for value-added traits (e.g. transgenic events) using backcross breeding, ultimately regaining the performance attributes of the target hybrid along with reliable expression of the value-added traits. In the light of the overarching goal of recovering equivalent performance in the finished conversion, this study focuses on the first step of MTI, single event introgression, exploring the feasibility of marker-aided backcross conversion of a target maize hybrid for 15 transgenic events, incorporating eight events into the female hybrid parent and seven into the male parent. Single event introgression is conducted in parallel streams to convert the recurrent parent (RP) for individual events, with the primary objective of minimizing residual non recurrent parent (NRP) germplasm, especially in the chromosomal proximity to the event (i.e. linkage drag). In keeping with a defined lower limit of 96.66 % overall RP germplasm recovery (i.e. <=120 cM NRP germplasm given a genome size of 1,788 cM), a breeding goal for each of the 15 single event conversions was developed: <8 cM of residual NRP germplasm across the genome with ~1 cM in the 20 cM region flanking the event. Using computer simulation, we aimed to identify optimal breeding strategies for single event introgression to achieve this breeding goal, measuring efficiency in terms of number of backcross generations required, marker data points needed, and total population size across generations. Various selection schemes classified as three-stage, modified two stage, and combined selection conducted from BC1 through BC3, BC4, or BC5 were compared. The breeding goal was achieved with a selection scheme involving five generations of marker-aided backcrossing, with BC1 through BC3 selected for the event of interest and minimal linkage drag at population size of 600, and BC4 and BC5 selected for the event of interest and recovery of the RP germplasm across the genome at population size of 400, with selection intensity of 0.01 for all generations. In addition, strategies for choice of donor parent to facilitate conversion efficiency and quality were evaluated. Two essential criteria for choosing an optimal donor parent for a given RP were established: introgression history showing reduction of linkage drag to ~1 cM in the 20 cM region flanking the event and genetic similarity between the RP and potential donor parents. Computer simulation demonstrated that single event conversions with <8 cM residual NRP germplasm can be accomplished by BC5 with no genetic similarity, by BC4 with 30 % genetic similarity, and by BC3 with 86 % genetic similarity using previously converted RPs as event donors. This study indicates that MTI to produce a 'quality' 15-event-stacked hybrid conversion is achievable. Furthermore, it lays the groundwork for a comprehensive approach to MTI by outlining a pathway to produce appropriate starting materials with which to proceed with event pyramiding and trait fixation before version testing. PMID- 24482601 TI - Optimized breeding strategies for multiple trait integration: II. Process efficiency in event pyramiding and trait fixation. AB - Multiple trait integration (MTI) is a multi-step process of converting an elite variety/hybrid for value-added traits (e.g. transgenic events) through backcross breeding. From a breeding standpoint, MTI involves four steps: single event introgression, event pyramiding, trait fixation, and version testing. This study explores the feasibility of marker-aided backcross conversion of a target maize hybrid for 15 transgenic events in the light of the overall goal of MTI of recovering equivalent performance in the finished hybrid conversion along with reliable expression of the value-added traits. Using the results to optimize single event introgression (Peng et al. Optimized breeding strategies for multiple trait integration: I. Minimizing linkage drag in single event introgression. Mol Breed, 2013) which produced single event conversions of recurrent parents (RPs) with <=8 cM of residual non-recurrent parent (NRP) germplasm with ~1 cM of NRP germplasm in the 20 cM regions flanking the event, this study focused on optimizing process efficiency in the second and third steps in MTI: event pyramiding and trait fixation. Using computer simulation and probability theory, we aimed to (1) fit an optimal breeding strategy for pyramiding of eight events into the female RP and seven in the male RP, and (2) identify optimal breeding strategies for trait fixation to create a 'finished' conversion of each RP homozygous for all events. In addition, next-generation seed needs were taken into account for a practical approach to process efficiency. Building on work by Ishii and Yonezawa (Optimization of the marker based procedures for pyramiding genes from multiple donor lines: I. Schedule of crossing between the donor lines. Crop Sci 47:537-546, 2007a), a symmetric crossing schedule for event pyramiding was devised for stacking eight (seven) events in a given RP. Options for trait fixation breeding strategies considered selfing and doubled haploid approaches to achieve homozygosity as well as seed chipping and tissue sampling approaches to facilitate genotyping. With selfing approaches, two generations of selfing rather than one for trait fixation (i.e. 'F2 enrichment' as per Bonnett et al. in Strategies for efficient implementation of molecular markers in wheat breeding. Mol Breed 15:75-85, 2005) were utilized to eliminate bottlenecking due to extremely low frequencies of desired genotypes in the population. The efficiency indicators such as total number of plants grown across generations, total number of marker data points, total number of generations, number of seeds sampled by seed chipping, number of plants requiring tissue sampling, and number of pollinations (i.e. selfing and crossing) were considered in comparisons of breeding strategies. A breeding strategy involving seed chipping and a two-generation selfing approach (SC + SELF) was determined to be the most efficient breeding strategy in terms of time to market and resource requirements. Doubled haploidy may have limited utility in trait fixation for MTI under the defined breeding scenario. This outcome paves the way for optimizing the last step in the MTI process, version testing, which involves hybridization of female and male RP conversions to create versions of the converted hybrid for performance evaluation and possible commercial release. PMID- 24482602 TI - A segmental duplication encompassing S-haplotype triggers pollen-part self compatibility in Japanese pear (Pyrus pyrifolia). AB - Self-compatible mutants of self-incompatible crops have been extensively studied for research and agricultural purposes. Until now, the only known pollen-part self-compatible mutants in Rosaceae subtribe Pyrinae, which contains many important fruit trees, were polyploid. This study revealed that the pollen-part self-compatibility of breeding selection 415-1, a recently discovered mutant of Japanese pear (Pyrus pyrifolia) derived from gamma-irradiated pollen, is caused by a duplication of an S-haplotype. In the progeny of 415-1, some plants had three S-haplotypes, two of which were from the pollen parent. Thus, 415-1 was able to produce pollen with two S-haplotypes, even though it was found to be diploid: the relative nuclear DNA content measured by flow cytometry showed no significant difference from that of a diploid cultivar. Inheritance patterns of simple sequence repeat (SSR) alleles in the same linkage group as the S-locus (LG 17) showed that some SSRs closely linked to S-haplotypes were duplicated in progeny containing the duplicated S-haplotype. These results indicate that the pollen-part self-compatibility of 415-1 is not caused by a mutation of pollen S factors in either one of the S-haplotypes, but by a segmental duplication encompassing the S-haplotype. Consequently, 415-1 can produce S-heteroallelic pollen grains that are capable of breaking down self-incompatibility (SI) by competitive interaction between the two different S factors in the pollen grain. 415-1 is the first diploid pollen-part self-compatible mutant with a duplicated S haplotype to be discovered in the Pyrinae. The fact that 415-1 is not polyploid makes it particularly valuable for further studies of SI mechanisms. PMID- 24482603 TI - Self-(in)compatibility inheritance and allele-specific marker development in yellow mustard (Sinapis alba). AB - Yellow mustard (Sinapis alba) has a sporophytic self-incompatibility reproduction system. Genetically stable self-incompatible (SI) and self-compatible (SC) inbred lines have recently been developed in this crop. Understanding the S haplotype of different inbred lines and the inheritance of the self-(in)compatibility (SI/SC) trait is very important for breeding purposes. In this study, we used the S-locus gene-specific primers in Brassica rapa and Brassica oleracea to clone yellow mustard S-locus genes of SI lines Y514 and Y1130 and SC lines Y1499 and Y1501. The PCR amplification results and DNA sequences of the S-locus genes revealed that Y514 carried the class I S haplotype, while Y1130, Y1499, and Y1501 had the class II S haplotype. The results of our genetic studies indicated that self incompatibility was dominant over self-compatibility and controlled by a one-gene locus in the two crosses of Y514 * Y1499 and Y1130 * Y1501. Of the five S-locus gene polymorphic primer pairs, Sal-SLGI and Sal-SRKI each generated one dominant marker for the SI phenotype of Y514; Sal-SLGII and Sal-SRKII produced dominant marker(s) for the SC phenotype of Y1501 and Y1499; Sal-SP11II generated one dominant marker for Y1130. These markers co-segregated with the SI/SC phenotype in the F2 populations of the two crosses. In addition, co-dominant markers were developed by mixing the two polymorphic primer pairs specific for each parent in the multiplex PCR, which allowed zygosity to be determined in the F2 populations. The SI/SC allele-specific markers have proven to be very useful for the selection of the desirable SC genotypes in our yellow mustard breeding program. PMID- 24482604 TI - Development of user-friendly functional molecular markers for VvDXS gene conferring muscat flavor in grapevine. AB - High fruit and wine quality combined with good climatic adaptation and disease resistance are essential objectives of grape breeding. While several molecular markers are available for pyramiding resistance to fungal pathogens, molecular tools for predicting fruit composition are still scarce. Muscat flavor, caused by the accumulation of monoterpenoids in the berry, is an important target trait for breeding, sought after in both table grapes and wine. Four missense mutations in the VvDXS gene in grape germplasm have been shown to be tightly linked to muscat flavor. Here we present highly reproducible and breeder-friendly functional markers for each of the targeted polymorphisms developed by using either the multiplexed minisequencing SNaPshotTM method, the high-resolution melting (HRM) assay or the cleaved amplified polymorphic sequence system. A total of 242 grapevine accessions were analyzed to optimize these different genotyping methods and to provide allele-specific markers for accurate selection of muscat flavor at early stages of grape breeding programs. The HRM and the minisequencing SNaPshot multiplex assays allow for high-throughput automated screening and are suitable for large-scale breeding programs and germplasm characterization. PMID- 24482605 TI - Effects of the physicochemical properties of titanium dioxide nanoparticles, commonly used as sun protection agents, on microvascular endothelial cells. AB - Until now, the potential effects of titanium dioxide (TiO2) nanoparticles on endothelial cells are not well understood, despite their already wide usage. Therefore, the present work characterizes six TiO2 nanoparticle samples in the size range of 19 * 17 to 87 * 13 nm, which are commonly present in sun protection agents with respect to their physicochemical properties (size, shape, zeta potential, agglomeration, sedimentation, surface coating, and surface area), their interactions with serum proteins and biological impact on human microvascular endothelial cells (relative cellular dehydrogenase activity, adenosine triphosphate content, and monocyte chemoattractant protein-1 release). We observed no association of nanoparticle morphology with the agglomeration and sedimentation behavior and no variations of the zeta-potential (-14 to -19 mV) in dependence on the surface coating. In general, the impact on endothelial cells was low and only detectable at concentrations of 100 MUg/ml. Particles containing a rutile core and having rod-like shape had a stronger effect on cell metabolism than those with anatase core and elliptical shape (relative cellular dehydrogenase activity after 72 h: 60 vs. 90 %). Besides the morphology, the nanoparticle shell constitution was found to influence the metabolic activity of the cells. Upon cellular uptake, the nanoparticles were localized perinuclearly. Considering that in the in vivo situation endothelial cells would come in contact with considerably lower nanoparticle amounts than the lowest-observable adverse effects level (100 MUg/ml), TiO2 nanoparticles can be considered as rather harmless to humans under the investigated conditions. PMID- 24482606 TI - Effect of silica nanoparticles on clay swelling and aqueous stability of nanoparticle dispersions. AB - The results of the effects of electrolyte type and concentration, nanoparticle concentration, pH, and temperature on the mobility and aqueous stability of polyethylene glycol (PEG)-coated silica nanoparticles are presented. Nanoparticle mobility was evaluated based on the ability to inhibit montmorillonite swelling in aqueous solutions through visual swelling tests, and the results were quantified in terms of the swelling index. The presence of PEG-coated silica nanoparticles was found to have a positive influence on the inhibition of clay swelling only in the presence of electrolytes. Quantification of nanoparticle stability in the presence of montmorillonite particles was achieved using ultraviolet-visible (UV-vis) spectrophotometry. At the highest concentration of montmorillonite dispersion studied, interaction between the dispersed montmorillonite particles and PEG-coated silica nanoparticles resulted in nanoparticle aggregation as indicated by increased turbidity and absorbance readings. Both nanoparticle concentration and montmorillonite dispersion concentration, in addition to the presence and concentration of NaCl, were found to strongly influence the stability of the mixture. PMID- 24482607 TI - Occupational safety and health criteria for responsible development of nanotechnology. AB - Organizations around the world have called for the responsible development of nanotechnology. The goals of this approach are to emphasize the importance of considering and controlling the potential adverse impacts of nanotechnology in order to develop its capabilities and benefits. A primary area of concern is the potential adverse impact on workers, since they are the first people in society who are exposed to the potential hazards of nanotechnology. Occupational safety and health criteria for defining what constitutes responsible development of nanotechnology are needed. This article presents five criterion actions that should be practiced by decision-makers at the business and societal levels-if nanotechnology is to be developed responsibly. These include (1) anticipate, identify, and track potentially hazardous nanomaterials in the workplace; (2) assess workers' exposures to nanomaterials; (3) assess and communicate hazards and risks to workers; (4) manage occupational safety and health risks; and (5) foster the safe development of nanotechnology and realization of its societal and commercial benefits. All these criteria are necessary for responsible development to occur. Since it is early in the commercialization of nanotechnology, there are still many unknowns and concerns about nanomaterials. Therefore, it is prudent to treat them as potentially hazardous until sufficient toxicology, and exposure data are gathered for nanomaterial-specific hazard and risk assessments. In this emergent period, it is necessary to be clear about the extent of uncertainty and the need for prudent actions. PMID- 24482608 TI - Dynamic regulation of mitochondrial genome maintenance in germ cells. AB - Mitochondria play a crucial role in the development and function of germ cells. Mitochondria contain a maternally inherited genome that should be transmitted to offspring without reactive oxygen species-induced damage during germ line development. Germ cells are also involved in the mitochondrial DNA (mtDNA) bottleneck; thus, the appropriate regulation of mtDNA in these cells is very important for this characteristic transmission. In this review, we focused on unique regulation of the mitochondrial genome in animal germ cells; paternal elimination and the mtDNA bottleneck in females. We also summarized the mitochondrial nucleoid factors involved in various mtDNA regulation pathways. Among them, mitochondrial transcription factor A (TFAM), which has pleiotropic and essential roles in mtDNA maintenance, appears to have putative roles in germ cell regulation. PMID- 24482609 TI - Time-dependent changes in cardiovascular function during copulatory behavior induced by the hand method in the male dog. AB - PURPOSE: Ejaculation in the male dog consists of three fractions. Observation of behavior and measurement of heart rate (HR), and plasma noradrenaline (NA) and adrenaline (Ad) concentrations were researched sequentially, and a fundamental examination of the features of sympathetic nerve activity during copulatory behavior induced by the hand method in the male dog was undertaken. METHODS: We investigated the breeding capability of male dogs. HR, plasma NA level and plasma Ad levels were measured during ejaculation induced by the hand method. RESULTS: HR was 125.8 +/- 6.0 beats/min at rest, and peaked during mounting at 195.2 +/- 8.2 beats/min. Moreover, HR at 3 min after the first fraction decreased to values similar to those at rest. Plasma NA and Ad concentrations during copulatory behavior induced by the hand method did not differ significantly from those at rest. However, although there was no significant difference, plasma NA concentration during ejaculation of the third fraction peaked at about 1.8 times the baseline value. CONCLUSIONS: In the male dog, excitation of sympathetic nerves of long duration during erection of the penis and ejaculation is questionable. However, inhibition of sympathetic nerves and activation of parasympathetic nerves is thought to occur during erection of the penis and ejaculation. PMID- 24482610 TI - Mapping the new molecular landscape: social dimensions of epigenetics. AB - Epigenetics is the study of changes in gene expression caused by mechanisms other than changes in the DNA itself. The field is rapidly growing and being widely promoted, attracting attention in diverse arenas. These include those of the social sciences, where some researchers have been encouraged by the resonance between imaginaries of development within epigenetics and social theory. Yet, sustained attention from science and technology studies (STS) scholars to epigenetics and the praxis it propels has been lacking. In this article, we reflexively consider some of the ways in which epigenetics is being constructed as an area of biomedical novelty and discuss the content and logics underlying the ambivalent promises being made by scientists working in this area. We then reflect on the scope, limits and future of engagements between epigenetics and the social sciences. Our discussion is situated within wider literatures on biomedicine and society, the politics of "interventionist STS," and on the problems of "caseness" within empirical social science. PMID- 24482611 TI - Recollections of sexual socialisation among marginalised heterosexual black men. AB - This paper describes the sexual socialisation process of marginalised, drug-using heterosexual black men, focusing primarily on the sources and content of sexual information. Analysing qualitative interview data, we discovered that the men in our sample both learn about sex and become sexually active at an early age. They most often learn about sex from the media and least often learn about sex from family members. The content of sexual information varies in specifics, but overall tends to equate sex with pleasure, encourage sexual activity with multiple partners, and emphasise using protection. Our goal is to use this data to better understand how sexual socialisation contributes to the prevalence of multiple sexual partners and high rates of HIV among heterosexual black men in order to inform future risk-reduction intervention programmes. PMID- 24482612 TI - Forging Hispanic communities in new destinations: A case study of Durham, NC. AB - The Chicago School of urban sociology and its extension in the spatial assimilation model have provided the dominant framework for understanding the interplay between immigrant social and spatial mobility. However, the main tenets of the theory were derived from the experience of pre-war, centralized cities; scholars falling under the umbrella of the Los Angeles school have recently challenged the extent to which they are applicable to the contemporary urban form, which is characterized by sprawling, decentralized, and multi-nucleated development. Indeed, new immigrant destinations, such as those scattered throughout the American Southeast, are both decentralized and lack prior experience with large scale immigration. Informed by this debate this paper traces the formation and early evolution of Hispanic neighborhoods in Durham, NC, a new immigrant destination. Using qualitative data we construct a social history of immigrant neighborhoods and apply survey and census information to examine the spatial pattern of neighborhood succession. We also model the sorting of immigrants across neighborhoods according to personal characteristics. Despite the many differences in urban form and experience with immigration, the main processes forging the early development of Hispanic neighborhoods in Durham are remarkably consistent with the spatial expectations from the Chicago School, though the sorting of immigrants across neighborhoods is more closely connected to family dynamics and political economy considerations than purely human capital attributes. PMID- 24482613 TI - In Appreciation of an Outstanding Surgeon-in-Chief. PMID- 24482614 TI - Late tourniquet release and drain clamping reduces postoperative blood loss in total knee arthroplasty. AB - BACKGROUND: Many studies have investigated the effect of tourniquet release time and closed suction drainage in total knee arthroplasty (TKA). However, controversy remains as to the advisability of preclosure tourniquet release and the advisability of closed suction drain use following total knee arthroplasty. QUESTIONS/PURPOSES: The aim of the study was to investigate if there is a benefit of performing tourniquet release after skin closure, along with drain clamping, for the first 6h following TKA. METHODS: Ninety-six patients underwent TKA between May 2009 and April 2010. Fourteen of these were excluded because of systemic diseases and simultaneous bilateral TKA. Twenty-nine of these were excluded due to use of a patellar component and posterior cruciate ligament (PCL) sacrificing systems. Thus, 53 patients that underwent PCL-retaining cemented TKA were reviewed retrospectively. In the control group (group C), the tourniquet was released before skin closure, an attempt at hemostasis was made, and a compressive bandage was applied. The drain was not clamped in these patients. The test group of 23 patients (group T) had tourniquet release after skin closure and after the compressive bandage was applied. The drain was clamped for the first 6h after surgery. The two groups were compared as to the amount of drained blood, postoperative change in hemoglobin, postoperative complications, and knee function. RESULTS: We found that drained blood and hemoglobin drop were significantly lower in group T compared with group C. There was no difference regarding postoperative complications and knee function. CONCLUSION: We conclude that tourniquet release after skin closure and compressive dressing followed by 6h of drain clamping reduces postoperative blood loss in TKR surgery. PMID- 24482615 TI - Minimum distraction gap: how much ankle joint space is enough in ankle distraction arthroplasty? AB - BACKGROUND: The success of ankle distraction arthroplasty relies on the separation of the tibiotalar articular surfaces. QUESTION/PURPOSE: The purpose of this study was to find the minimum distraction gap needed to ensure that the tibiotalar joint surfaces would not contact each other with full weight-bearing while under distraction. METHODS: Circular external fixators were mounted to nine cadaver ankle specimens. Each specimen was then placed into a custom-designed load chamber. Loads of 0, 350, and 700N were applied to the specimen. Radiographic joint space was measured and joint contact pressure was monitored under each load. The external fixator was then sequentially distracted, and the radiographic joint space was measured under the three different loads. The experiment was stopped when there was no joint contact under 700N of load. The radiographic joint space was measured and the initial (undistracted) radiographic joint space was subtracted from it yielding the distraction gap. The minimum distraction gap (mDG) that would provide total unloading was calculated. RESULTS: The average mDG was 2.4 mm (range, 1.6 to 4.0 mm) at 700N of load, 4.4 mm (range, 3.7 to 5.8 mm) at 350N of load, and 4.9 mm (range, 3.7 to 7.0 mm) at 0N of load. CONCLUSION: These results suggest that if the radiographic joint space of on a standing X-ray of an ankle undergoing distraction arthroplasty shows a minimum of 5.8 mm of DG, then there will be no contact between joint surfaces during full weight-bearing. Therefore, 5 mm of radiographic joint space, as recommended historically, may not be adequate to prevent contact of the articular surfaces during weight-bearing. PMID- 24482616 TI - Mid-term results following ulna shortening osteotomy. AB - BACKGROUND: Successful short-term results of diaphyseal ulna shortening osteotomy are documented in both idiopathic and post-traumatic ulnar impaction. QUESTIONS/PURPOSES: The purpose of this study was to evaluate the mid-term outcomes of ulnar shortening osteotomy with respect to radiographic assessment of corrected alignment and healing as well as patient satisfaction, pain, and function assessed using the Disability of the Arm, Shoulder, and Hand (DASH) score. PATIENTS AND METHODS: This retrospective case series included follow-up of 33 patients with ulnar impaction syndrome following ulna shortening osteotomy at a minimum of 5 years. Patient-rated outcomes included satisfaction, pain assessment, and DASH score. Pre- and postoperative radiographs were reviewed to quantify ulnar variance and osteotomy union rates. Subsequent operations were also recorded. RESULTS: Average follow-up was 10 years (range, 5-20 years). Eighty-eight percent of patients reported they were either satisfied or very satisfied with the procedure and 91% reported they would have the same procedure again. Average pain rating was 2 out of 10 at final follow-up. The mean DASH score was 11 (range, 0-39). Removal of hardware was performed in 10 patients (30%). The overall rate of reoperation was 45%. CONCLUSIONS: Ulna shortening osteotomy yields reliable midterm satisfaction and pain relief in patients with idiopathic and post-traumatic ulnar impaction syndrome. Reoperation is frequent. Consistent with results of short-term follow-up, plate irritation requiring removal remains the most common cause for reoperation over time. PMID- 24482617 TI - Clinical and morphologic factors associated with suture anchor refixation of labral tears in the hip. AB - BACKGROUND: The acetabular labrum is critical to hip function. Surgical options for treatment of a damaged labrum include removal, debridement, and refixation using suture anchors. QUESTIONS/PURPOSES: The purpose of this study is to determine if certain patient demographic and osseous morphological factors result in increased labral damage requiring refixation. METHODS: Data was collected prospectively from a consecutive series of 334 procedures performed from August 2010 to June 2011 for femoroacetabular impingement. Demographic data, including age, sex, and race, was collected from patient charts. Three-dimensional (3D) CT scans were reviewed to retrieve alpha angles, acetabular version, femoral version, and lateral center edge angle on the symptomatic hip. RESULTS: In 238 (71.3%) of the procedures, the labrum required refixation using suture anchors with a mean of 2.74 anchors being used. Of males, 78.8% required suture anchors and 62.3% of females required suture anchors. Among procedures requiring suture anchors, significantly more suture anchors were used in males (2.92) than females (2.47). Regression analysis showed a positive association between alpha angle, acetabular retroversion at 1 and 2 o'clock, and the number of suture anchors used. The mean alpha angle in the cohort that required suture anchors (63.1 degrees ) was significantly greater than the cohort that did not (59.4 degrees ). CONCLUSION: This study found femoral deformities to contribute more to labral damage than acetabular deformities and highlighted the importance of preoperative 3D CT scans. This study provides demographic and morphologic factors to review preoperatively to evaluate if extensive labral damage is present and if suture anchor refixation will be required. PMID- 24482618 TI - An association can be found between hounsfield units and success of lumbar spine fusion. AB - BACKGROUND: Measuring Hounsfield units (HUs) from computed tomography (CT) scans has recently been proposed as a tool for assessing vertebral bone quality, as it has been associated with bone mineral density, compressive strength, and fracture risk. Vertebral bone quality is believed to be an important determinant of outcome and complication rates following spine surgery and potentially influences success of interbody spinal fusion. QUESTIONS/PURPOSES: The purpose of this study was to investigate the association between HU on CT scans and fusion success in patients with lateral transpsoas surgery for lumbar interbody fusion (LIF). METHODS: The CT scans of 28 patients with a combined 52 levels of stand-alone LIF were evaluated at a minimum of 12 weeks postoperatively. Coronal and sagittal images were evaluated for evidence of fusion, and HU values were collected from axial images. HU measurements were also taken from vertebral bodies proximal to the construct to evaluate global bone quality. RESULTS: Of the 52 LIF levels, 73% were assessed as fused and 27% were nonunited at the time of evaluation. The successful fusion levels had significantly higher HU measurements than the nonunion levels (203.3 vs. 139.8, p < 0.001). Patients with successful fusion constructs also had higher global bone density when vertebral bodies proximal to the construct were compared (133.7 vs. 107.3, p < 0.05). CONCLUSION: With the aging population and increasing prevalence of osteoporosis, preoperative assessment of bone quality prior to spinal fusion deserves special consideration. We found that a successful lumbar fusion was associated with patients with higher bone density, as assessed with HU, both globally and within the fusion construct, as compared to patients with CT evidence of nonunion. PMID- 24482619 TI - Early results of sacro-iliac joint fixation following long fusion to the sacrum in adult spine deformity. AB - BACKGROUND: The sacro-iliac joint (SIJ) is the largest joint in the human body. When the lumbar spine is fused to the sacrum, motion across the SIJ is increased, leading to increased degeneration of the SIJ. Degeneration can become symptomatic in up to 75% of the cases when a long lumbar fusion ends with a sacral fixation. If medical treatments fail, patients can undergo surgical fixation of the SIJ. QUESTIONS/PURPOSES: This study reports the results of short-term complications, length of stay, and clinical as well as radiographic outcomes of patients undergoing percutaneous SIJ fixation for SIJ pain following long fusions to the sacrum for adult scoliosis. METHODS: A retrospective review of all the patients who underwent a percutaneous fixation of the SIJ after corrective scoliosis surgery was performed in a single specialized scoliosis center between the years 2011-2013. Ten SIJ fusions were performed in six patients who failed conservative care for SIJ arthritis. Average age was 50 (range 25-60 years). The patients were 15.3 years in average after the original surgical procedure (range 4-25 years). Average post-operative follow-up was 10.25 months (range 15-4 months). The medical charts of the patients were reviewed for hospital stay, complications, pre- and post-operative pain, quality of life, and satisfaction with surgery using the visual analogues score (VAS), Scoliosis Research Society (SRS)22 and Oswestry Disability Index (ODI) questionnaires. Images were reviewed for fixation of the SIJ, fusion, and deviation of the implants from the SIJ. RESULTS: There were no complications in surgery or post-operatively. Discharge was on post operative day 2 (range 1-4 days). Leg VAS score improved from 6.5 to 2.0 (P < 0.005; minimal clinically important difference (MCID) 1.6). Back VAS score decreased from 7.83 to 2.67 mm (P < 0.005; MCID 1.2). ODI scores dropped from 22.2 to 10.5 (P = 0.0005; MCID 12.4). SRS22 scores increased from 2.93 to 3.65 (P = 0.035; MCID 0.2) with the largest increases in the pain, function, and satisfaction domains of the questionnaires. CONCLUSION: Fixation of the SIJ in patients that fail conservative care for SIJ arthritis after long fusions ending in the sacrum provides a reduction in back pain and improved quality of life in the short and medium range follow-up period. PMID- 24482620 TI - Evaluation and Management of Periprosthetic Joint Infection-an International, Multicenter Study. AB - BACKGROUND: Controversies still exist regarding the optimal diagnostic and therapeutic strategies in patients with prosthetic joint infections (PJI). QUESTIONS/PURPOSES: How effective are preoperative and intraoperative cultures in isolating organisms and how do these culture results compare to one another? What are the results of surgical treatment of PJI in the hip and knee in an international, tertiary referral center cohort? PATIENTS AND METHODS: One hundred sixteen patients (N = 59 hip PJI, N = 57 knee PJI) were recruited prospectively to registries at three international, tertiary referral centers between December 2008 to November 2011. Retrospective review of prospective registry data including demographics, microbiology results, and operative reports was performed. RESULTS: Preoperative synovial fluid aspiration yielded an organism in only 45.2% and 44.4% of cases, respectively, for knee and hip PJI. False-negative rates of preoperative aspiration relative to intraoperative culture were 56% and 46% in hip and knee PJI, respectively, with discordance rates of 25% and 21.4%, respectively. Rates of negative intraoperative cultures were 15% in hip PJI and 20.7% in knee PJI. Open debridement with prosthetic retention was the most common initial revision procedure performed (48.3% of hip PJI and 63.8% of knee PJI). This method of revision was successful in 41.3% of hip PJI and 59.4% of knee PJI. Initial failure rates for prosthetic revision was lower than debridement with prosthetic retention but remained substantial in both hip PJI (initial success of one-stage exchange 60% and two-stage exchange 70%) and knee PJI (initial success of one-stage exchange 80% and two-stage exchange 75%). CONCLUSION: Diagnosis and treatment of PJI remains challenging with difficulty in isolating the offending organism and with high rates of prosthetic revision and initial treatment failures. Future advances in organism isolation and international standardization of treatment protocols may improve patient outcomes. PMID- 24482621 TI - Prevention of surgical site infection in total joint arthroplasty: an international tertiary care center survey. AB - BACKGROUND: Prevention strategies are critical to reduce infection rates in total joint arthroplasty (TJA), but evidence-based consensus guidelines on prevention of surgical site infection (SSI) remain heterogeneous and do not necessarily represent this particular patient population. QUESTIONS/PURPOSES: What infection prevention measures are recommended by consensus evidence-based guidelines for prevention of periprosthetic joint infection? How do these recommendations compare to expert consensus on infection prevention strategies from orthopedic surgeons from the largest international tertiary referral centers for TJA? PATIENTS AND METHODS: A review of consensus guidelines was undertaken as described by Merollini et al. Four clinical guidelines met inclusion criteria: Centers for Disease Control and Prevention's, British Orthopedic Association, National Institute of Clinical Excellence's, and National Health and Medical Research Council's (NHMRC). Twenty-eight recommendations from these guidelines were used to create an evidence-based survey of infection prevention strategies that was administered to 28 orthopedic surgeons from members of the International Society of Orthopedic Centers. The results between existing consensus guidelines and expert opinion were then compared. RESULTS: Recommended strategies in the guidelines such as prophylactic antibiotics, preoperative skin preparation of patients and staff, and sterile surgical attire were considered critically or significantly important by the surveyed surgeons. Additional strategies such as ultraclean air/laminar flow, antibiotic cement, wound irrigation, and preoperative blood glucose control were also considered highly important by surveyed surgeons, but were not recommended or not uniformly addressed in existing guidelines on SSI prevention. CONCLUSION: Current evidence-based guidelines are incomplete and evidence should be updated specifically to address patient needs undergoing TJA. PMID- 24482622 TI - A computerized order entry system was adopted with high user satisfaction at an orthopedic teaching hospital. AB - BACKGROUND: Computerized provider order entry (CPOE) has been considered essential for the reduction of medical errors and increased patient safety. Assessment of staff perception regarding a CPOE system is important for satisfaction and adoption. Incorporation of user feedback can greatly improve the functionality of a system and promote user satisfaction. QUESTIONS/PURPOSES: This study aims to develop an informatics staff satisfaction survey instrument and to understand what components of computerized prescriber order entry (CPOE) contribute to staff satisfaction and its variability over time. METHODS: The 22 question survey was developed by a multidisciplinary group and focused on patient data including demographics, orders, medications, laboratory, and radiology data. The questions were designed to understand if clinicians (1) could easily access the information needed to properly take care of patients, (2) could act upon the information once acquired, (3) could obtain the information clearly, and (4) were alerted to potential errors. The survey was distributed just prior to "go-live," 6 and 12 months after go-live. Responses were given on a five-point Likert scale. RESULTS: The survey results post-implementation showed user satisfaction with CPOE. Satisfaction regarding the ease of obtaining orders, medication, and lab data had a significant improvement at 6 and 12 months post-implementation, p < 0.001. Satisfaction that the computerized order entry system provided information needed to take care of their patients improved, p < 0.01. At 1 year post implementation, user satisfaction declined from 6 months earlier but still demonstrated an overall increase in satisfaction from pre-implementation. CONCLUSION: Compared prior to go-live, clinicians are satisfied or very satisfied across multiple spheres and multiple disciplines. At all time points, clinicians were able to obtain information required to take care of their patients. However, post-go-live, it was easier to obtain and act upon as well as more clear and understandable. PMID- 24482623 TI - Measuring the value of program adaptation: a comparative effectiveness study of the standard and a culturally adapted version of the arthritis self-help program. AB - BACKGROUND: Arthritis remains an important public health problem. QUESTIONS/PURPOSES: This study aims to determine the effects of an adapted (vs. the original) Arthritis Self-Help Program (ASHP) among older adults. Specifically, this study sought to determine (1) whether the adapted ASHP improved attendance, retention, and adherence with the use of self-management exercises, and (2) if the original ASHP's beneficial outcomes were maintained following program adaptation. PATIENT AND METHODS: Individuals age >=60 with self reported arthritis were recruited from eight New York City senior centers. Participants were assessed at baseline to assess their demographic and clinical status and at 6 and 24 weeks to ascertain study outcomes using validated measures. RESULTS: Two-hundred-one participants (64 non-Hispanic African Americans, 86 Hispanics, and 51 non-Hispanic Whites) enrolled. Participants in the adapted (vs. original) ASHP had better average attendance in the six session program (4.7 vs. 3.2 classes attended, p < 0.01) and program retention (93% vs. 74%, p < 0.01). Adherence with use of the self-management exercises (number of days using endurance, stretching, and relaxation exercises) was similar in both groups. Significant positive physical/psychosocial outcomes were documented in both the adapted and original program. CONCLUSION: The adapted ASHP improved program attendance and retention while maintaining improvements in physical and psychosocial functions. These results support future efforts to employ controlled designs to quantify the benefits of adapted evidence-based programs to ensure that adaptation maintains program effectiveness. PMID- 24482624 TI - Coupling device and distal femoral replacement for periprosthetic supracondylar femur fractures with an ipsilateral total knee and hip replacement. AB - BACKGROUND: Periprosthetic supracondylar fractures in the setting of an ipsilateral total knee and hip replacement are a rare but serious orthopedic challenge. DESCRIPTION OF TECHNIQUE: In this unique situation, we consider insertion of a custom coupling device with a distal femoral replacement as an appropriate surgical solution that allows for stability and preserves hip and knee functionality, while not relying on the poor healing potential of the remaining intercalary femoral bone. PATIENTS AND METHODS: We report the outcomes of two patients who underwent this custom coupling procedure. RESULTS: These custom devices resulted in successful outcomes with restoration of ambulatory function and range of motion at greater than 14 months follow-up. CONCLUSIONS: We found that this technique provides sufficient stability and preserves functionality in a difficult-to-treat patient population. The results indicate that this technique may be considered as an alternative to more invasive procedures including total femoral replacement and complete femoral allograft constructs. PMID- 24482625 TI - Arthroscopic subscapularis bankart technique as a salvage procedure for failed anterior shoulder stabilization. AB - BACKGROUND: Shoulder instability is a relatively common problem. Even with contemporary surgical techniques, instability can recur following both open and arthroscopic fixation. Surgical management of capsular insufficiency in anterior shoulder stabilization represents a significant challenge, particularly in young, active patients. There are a limited number of surgical treatment options. The Laterjet technique can present with a number of intraoperative challenges and postoperative complication. DESCRIPTION OF TECHNIQUE: We report an arthroscopic subscapularis tenodesis technique as a salvage procedure for challenging glenohumeral instability cases. Sutures are passed through the subscapularis tendon and capsule before they are tied as one in the subdeltoid psace. The rotator interval is closed with superior and medial advancement of anterior and inferior tissue. This technical note carefully describes this procedure with useful technical tips, illustrations, and diagrams. PATIENTS AND METHODS: Two clinical cases are described involving patients with recurrent instability following failed surgery who were successfully managed with this procedure. RESULTS: Both cases described resulted in improved shoulder stability, range of motion, and function following management with this surgical technique. This arthroscopic subscapularis tenodesis procedure is proposed as a useful alternative repair technique for cases of recurrent instability after failed surgery with isolated capsular insufficiency. CONCLUSION: It is believed that this arthroscopic subscapularis tenodesis technique can potentially provide similar outcomes to open bone block stabilization procedures, while reducing the risks associated with those procedures. PMID- 24482626 TI - Surgical treatment of isolated patellofemoral osteoarthritis. AB - BACKGROUND: Isolated patellofemoral (PF) osteoarthritis (OA) affects 9% of persons older than 40 years. Nonoperative treatment should be exhausted fully before surgical treatment. QUESTIONS/PURPOSES: The purpose of this article is to review the literature after 2008 with the aim of answering the following question: Which of the following surgical procedures has the highest survival rate and the lowest revision rate in advanced isolated PF OA: patellofemoral arthroplasty (PFA), total knee arthroplasty (TKA) or lateral facetectomy. METHODS: The search engine was MedLine. The keywords used were: PF OA and PFA. Three hundred and fifty-three articles were found between 2008 and 25 July 2013. Of those, only 23 were selected and reviewed because they were strictly focused on the topic and the question of this article. RESULTS: The types of studies reported so far have a low level of evidence (levels III and IV). Most of them are prospective case series (level IV). Some are systematic reviews of level III studies. Reported survival rate of lateral facetectomy is 85% at 5 years, 67% at 10 years and 47% at 20 years. Reported failure rate of lateral facetectomy is 26% at 10 years and 16% at 12 years. The reported average time of reoperation is 8 years and 37% of such procedures fail. Survival rate of PFA has been reported to be 87.5% on average (range, 60-100%). The revision rate of PFA is 20%. Recent improvements in PFA design have resulted in improvements in short-and medium-term results, similar to those of TKA. CONCLUSIONS: There is still no gold standard for the surgical treatment of isolated PF OA. However, PFA or TKA appear to be the most recommendable treatment in cases that do not respond to conservative treatment. PMID- 24482627 TI - Recovery after cervical decompression surgery for the treatment of crowned dens syndrome causing progressive neurological decline: a case report. PMID- 24482628 TI - Shoulder instability after total shoulder arthroplasty: a case of arthroscopic repair. PMID- 24482629 TI - Symptomatic bipartite medial cuneiform treated with fluoroscopic and ultrasound guided injections. PMID- 24482630 TI - Letter to the editor: in vitro elution characteristics of vancomycin in a composite calcium phosphate/calcium sulfate bone substitute. PMID- 24482631 TI - Contextual inhibition of fatty acid synthesis by metformin involves glucose derived acetyl-CoA and cholesterol in pancreatic tumor cells. AB - Metformin, a generic glucose lowering drug, inhibits cancer growth expressly in models that employ high fat/cholesterol intake and/or low glucose availability. Here we use a targeted tracer fate association study (TTFAS) to investigate how cholesterol and metformin administration regulates glucose-derived intermediary metabolism and macromolecule synthesis in pancreatic cancer cells. Wild type K ras BxPC-3 and HOM: GGT(Gly) -> TGT(Cys) K12 transformed MIA PaCa-2 adenocarcinoma cells were cultured in the presence of [1,2-13C2]-d-glucose as the single tracer for 24 h and treated with either 100 MUM metformin (MET), 1 mM cholesteryl hemisuccinate (CHS), or the dose matching combination of MET and CHS (CHS-MET). Wild type K-ras cells used 11.43 % (SD = +/-0.32) of new acetyl-CoA for palmitate synthesis that was derived from glucose, while K-ras mutated MIA PaCa-2 cells shuttled less than half as much, 5.47 % [SD = +/-0.28 (P < 0.01)] of this precursor towards FAS. Cholesterol treatment almost doubled glucose-derived acetyl-CoA enrichment to 9.54 % (SD = +/-0.24) and elevated the fraction of new palmitate synthesis by over 2.5-fold in MIA PaCa-2 cells; whereby 100 MUM MET treatment resulted in a 28 % inhibitory effect on FAS. Therefore, acetyl-CoA shuttling towards its carboxylase, from thiolase, produces contextual synthetic inhibition by metformin of new palmitate production. Thereby, metformin, mutated K-ras and high cholesterol each contributes to limit new fatty acid and potentially cell membrane synthesis, demonstrating a previously unknown mechanism for inhibiting cancer growth during the metabolic syndrome. PMID- 24482632 TI - Metabolite profiling reveals new insights into the regulation of serum urate in humans. AB - Serum urate, the final breakdown product of purine metabolism, is causally involved in the pathogenesis of gout, and implicated in cardiovascular disease and type 2 diabetes. Serum urate levels highly differ between men and women; however the underlying biological processes in its regulation are still not completely understood and are assumed to result from a complex interplay between genetic, environmental and lifestyle factors. In order to describe the metabolic vicinity of serum urate, we analyzed 355 metabolites in 1,764 individuals of the population-based KORA F4 study and constructed a metabolite network around serum urate using Gaussian Graphical Modeling in a hypothesis-free approach. We subsequently investigated the effect of sex and urate lowering medication on all 38 metabolites assigned to the network. Within the resulting network three main clusters could be detected around urate, including the well-known pathway of purine metabolism, as well as several dipeptides, a group of essential amino acids, and a group of steroids. Of the 38 assigned metabolites, 25 showed strong differences between sexes. Association with uricostatic medication intake was not only confined to purine metabolism but seen for seven metabolites within the network. Our findings highlight pathways that are important in the regulation of serum urate and suggest that dipeptides, amino acids, and steroid hormones are playing a role in its regulation. The findings might have an impact on the development of specific targets in the treatment and prevention of hyperuricemia. PMID- 24482634 TI - Resilience through participation and coping-enabling social environments: the case of HIV-affected children in sub-Saharan Africa. AB - Many children and youths living in low-resource and high-HIV-prevalence communities in sub-Saharan Africa are presented with daily hardships that few of us can even imagine. It is therefore no surprise that most research reporting on the experiences of HIV-affected children in resource-poor settings focuses on their poor health and development outcomes, casting them as victims. However, there is a growing trend to draw on more strengths-based conceptualisations in the study and support of HIV-affected children and youths. In this introduction to a special issue of The African Journal of AIDS Research, we cement this trend by providing a theoretical exposition and critique of the 'coping' and 'resilience' concepts and draw on the 11 empirical studies that make up this special issue to develop a framework that appropriates the concepts for a particular context and area of study: HIV-affected children in sub-Saharan Africa. The articles included here show, albeit in different ways and to different degrees, that the resilience of HIV-affected children in the region is an outcome of their agency and interactions with their social environment. Policy actors and practitioners working to support HIV-affected children in Africa should take heed of the proposed framework and draw on the research presented here to build coping-enabling social environments-presenting children and youths in Africa with greater opportunity to actively deal with hardship and work towards a more promising future. PMID- 24482635 TI - Detection of heterozygous c.1708C>T and c.1978C>G thyroid peroxidase (TPO) mutations in Iraqi patients with toxic and nontoxic goiter. AB - Sixty-three Arabic patients (16 males and 47 females) with thyroid toxic and nontoxic goiter who attended the endocrinologist in Nuclear Medicine Hospital and Al Yarmok Nuclear Medicine Department in Baghdad, Iraq were examined for thyroid peroxidase (TPO) gene mutations. A total of ten heterozygous mutations have been identified in the human TPO gene associated with thyroid toxic and nontoxic goiter. These mutations involved transition or transversion of cysteine either by thymine or guanine at the position 1708 of the exon 10 (c.1708C>T) and the position 1978 of the exon 11 (c.1978C>G). From a total of ten detected mutations, two c.1978C>G mutations were detected in nontoxic goiter patients and eight (two c.1708C>T and six c.1978C>G mutations) were detected in toxic goiter. In conclusion, this study identified ten TPO mutations associated with toxic and nontoxic goiter that have not been yet reported in Iraq, and most of them are detected among females (90 %) and adults age between 30 and 50 years old (80 %). PMID- 24482636 TI - Isolation and identification of Vibrio parahaemolyticus from seawater and sediment samples in the southern coast of the Caspian Sea. AB - The objectives of this study were to investigate the occurrence of Vibrio parahaemolyticus in the seawater and its sediment by molecular techniques and conventional microbiological methods. Of 300 samples analyzed, 20.3 % was recorded positive for V. parahaemolyticus. Of the 62 strains isolated, 26 (8.3 %) were obtained from the seawater samples, and 36 (12 %); from sediments. Only three strains (4.83 %) showed hemolytic activity in Wagatsuma agar. The results of this study demonstrated the presence of V. parahaemolyticus in the southern coast of the Caspian Sea (Northern Iran). Furthermore, the PCR approach proved useful for reliable confirmation of species identification. V. parahaemolyticus is an important human pathogen responsible for food-borne gastroenteritis worldwide. These findings indicated the potential sanitary risk associated with the presence of pathogenic V. parahaemolyticus in the Caspian Sea. PMID- 24482633 TI - Testicular Germ Cell Tumors: A Paradigm for the Successful Treatment of Solid Tumor Stem Cells. AB - Treatment of testicular germ cell tumors (TGCTs) has been a success primarily due to the exquisite responsiveness of this solid tumor to cisplatin-based therapy. Despite the promise of cure for the majority of TGCT patients, the effectiveness of therapy for some patients is limited by toxicity and the problem of resistance. There is compelling rationale to further understand the biology of TGCTs in order to better treat other solid tumors and to address the shortcomings of present TGCT therapies. TGCTs contain undifferentiated pluripotent stem cells, known as embryonal carcinoma, that share many properties with human embryonic stem cells. The importance of cancer stem cells in the initiation, progression and treatment of solid tumors is beginning to emerge. We discuss TGCTs in the context of solid tumor curability and targeted cancer stem cell therapy. PMID- 24482637 TI - A systematic cost-effectiveness analysis of pregabalin in the management of fibromyalgia: an Iranian experience. AB - INTRODUCTION: Fibromyalgia is a neuropathic syndrome which is more common in adult females. Pregabalin is the first medicine which was approved by the United States Food and Drug Administration for treatment of fibromyalgia. In this study we aimed to evaluate the cost-efficacy of pregabalin in the treatment of fibromyalgia in Iran. MATERIAL AND METHODS: To evaluate the efficacy of pregabalin, a systematic review was carried out by conducting a wide literature search for the main outcomes of interest that were pain score reduction from the baseline and the percentage of patients with more than 50% pain reduction. To evaluate costs of treatment, only the direct medical costs were considered. The calculated incremental cost-effectiveness ratio (ICER) were compared with one and three times the gross domestic product (GDP) per capita as the threshold to evaluate the economic condition of treatment to be "highly cost-effective", "cost effective" or "not cost-effective". RESULTS: Out of 4012 searched reports, only four reports were included in the study, all of which were randomized controlled trials with placebo controls. The calculated ICERs for pregabalin 450 mg/day and 600 mg/day with both available forms of brand and generic medicines in the country were in the range of 44-1170 US dollars (USD) and 48-814 USD, which in all cases could be considered as highly cost-effective. Pregabalin 150 mg/day based on available evidence does not have significant efficacy in comparison to placebo. But for pregabalin 300 mg/day, no decision can be made based on current data. CONCLUSIONS: Our analysis indicated that generic pregabalin in the treatment doses of 450 mg/day and 600 mg/day is highly cost-effective. PMID- 24482638 TI - Infarct size reduction by cyclosporine A at reperfusion involves inhibition of the mitochondrial permeability transition pore but does not improve mitochondrial respiration. AB - INTRODUCTION: Ischemic postconditioning (PoCo) and cyclosporine A (CysA) given prior to reperfusion reduce myocardial infarct size after ischemia/reperfusion. Ischemic postconditioning's protection is characterized by better preservation of mitochondrial respiration and calcium retention capacity. Protection by CysA is not entirely clear. Cyclosporine A inhibits not only mitochondrial permeability transition pore (mPTP) opening but also the phosphatase calcineurin. We have investigated whether CysA mediates protection not only by mPTP inhibition but also through a more upstream inhibition of calcineurin with subsequently better preserved mitochondrial respiration. MATERIAL AND METHODS: Anesthetized pigs were subjected to 90 min ischemia and 10 min reperfusion initiated with either PoCo (6 * 20 s reperfusion/re-occlusion; n = 9), CysA infusion (5 mg/kg i.v.; 5 min before reperfusion; n = 4), or immediate full reperfusion (IFR; n = 8). Mitochondria were isolated from myocardial tissue for measurement of respiration and calcium retention capacity. RESULTS: In mitochondria from ischemic/reperfused myocardium, ADP-stimulated complex I respiration was similar between CysA (116 +/ 11 nmol O2/min/mg protein) and IFR (117 +/-8), but better preserved with PoCo (160 +/-9; p < 0.05). Calcium retention capacity was greater with both PoCo and CysA (1096 +/-45 and 1287 +/-128 nmol Ca(2+)/mg protein) than with IFR (756 +/ 103; p < 0.05). CONCLUSIONS: Cyclosporine A's protection is not associated with improved mitochondrial respiration. Protection is unlikely related to an upstream calcineurin inhibition, but is indeed secondary to mPTP inhibition. PMID- 24482639 TI - Mutation spectrum of GATA4 associated with congenital atrial septal defects. AB - INTRODUCTION: Congenital atrial septal defect (ASD) is the second commonest form of cardiac developmental anomaly, responsible for substantial morbidity and mortality in affected individuals. Previous studies have implicated genetic defects in the pathogenesis of ASD. However, ASD is largely a genetically heterogeneous disease and the genetic determinants for ASD in the majority of patients remain to be identified. MATERIAL AND METHODS: The entire coding region of GATA4, a gene encoding a zinc-finger transcription factor essential for normal cardiac morphogenesis, was sequenced in 220 unrelated patients with ASD. The available relatives of the patients harboring the identified mutations and 200 unrelated ethnicity-matched control individuals were genotyped. RESULTS: Four heterozygous missense GATA4 mutations, p.P36S, p.H190R, p.S262A, and p.V399G, were identified in four unrelated patients with ASD, respectively. These mutations were neither detected in 200 control individuals nor described in the human SNP database. Alignment of multiple GATA4 protein sequences across species indicated that the affected amino acids were highly conserved evolutionarily. Genetic analysis of the available relatives of the mutation carriers showed that in each family the mutation co-segregated with ASD. CONCLUSIONS: The findings expand the spectrum of mutations in GATA4 linked to ASD and provide new insight into the molecular etiology associated with ASD, suggesting the potential implications for the genetic diagnosis and gene-specific therapy for this prevalent cardiovascular abnormality in humans. PMID- 24482640 TI - Neutrophil apoptosis: impact of granulocyte macrophage colony stimulating factor on cell survival and viability in chronic kidney disease and hemodialysis patients. AB - INTRODUCTION: Altered neutrophil apoptosis might be responsible for recurrent bacterial infections encountered in hemodialysis (HD) and chronic kidney disease (CKD) patients. This work was designed to assess the neutrophil apoptotic activity and the impact of implementation of granulocyte macrophage colony stimulating factor (GM-CSF), as a survival factor, on neutrophil apoptosis among these patients. MATERIAL AND METHODS: Twenty-five patients on regular HD along with 34 CKD patients on conservative treatment, as well as 15 healthy controls, were investigated for apoptotic rate via assessment of neutrophil expression of Annexin-V by flow cytometry, before and after 20 h culture in absence and presence of GM-CSF. Neutrophil viability was determined using light microscopy. The preservation of neutrophil activation in these patients was analyzed by flow cytometric CD18 neutrophil expression. Chronic inflammatory state was evaluated by estimating C-reactive protein (CRP) and soluble intercellular adhesion molecule-1 (sICAM-1). Obtained data were statistically analyzed. RESULTS: Compared to controls, both HD and CKD groups had a significant increase of Annexin-V and CD18 expression and significant decrease in neutrophil viability. Culture of their neutrophils with GM-CSF showed significant decrease of apoptosis accompanied by improvement of neutrophil viability compared to their cultured cells without GM-CSF. These patients also showed significant elevation of CRP and sICAM-1. CONCLUSIONS: Granulocyte macrophage colony stimulating factor demonstrated an evident impact on improving in vitro neutrophil survival and viability in HD and CKD patients. Therefore, this may represent promising preventive and/or therapeutic strategies against infection frequently observed in these patients and causing morbidity and mortality. PMID- 24482641 TI - SN50 enhances the effects of LY294002 on cell death induction in gastric cancer cell line SGC7901. AB - INTRODUCTION: In the previous study, we found that the inhibition of phosphatidylinositol 3-kinase (PI3K) by LY294002 induced SGC7901 cell death in vitro. We did not know whether SN50, which is a specific inhibitor of nuclear factor kappaB (NF-kappaB), could increase the cell death induction of gastric cancer of LY294002 in vitro, and we also wanted to know the mechanism of it, which might be applied to clinical tumor therapy. MATERIAL AND METHODS: The 3 (4,5-dimethylthiazol-2-yl-2,5-diphenyltetrazolium bromide (MTT) assay was used to determine the cytotoxic effects of the drugs. Mitochondrial membrane potential was measured using the fluorescent probe JC-1. Hoechst 33258 staining was used to detect apoptosis and necrosis morphological changes after LY294002 and/or SN50 treatment. Expression of p53, PUMA and Beclin1 were determined with real-time polymerase chain reaction (RT-PCR) analysis. We used transmission electron microscopy to identify ultrastructural changes in SGC7901 cells after LY294002 and/or SN50 treatment. RESULTS: In this study, we found that treating the human gastric cancer cells SGC7901 with SN50 could significantly enhance the effects of LY294002 on inducing cell death after 24 h, compared to the control group (p < 0.05). Detection of mitochondrial potential and transmission electron microscopic examination indicated that the rate of cell death increased progressively. The expression of p53, PUMA and Beclin1 was up-regulated. CONCLUSIONS: The NF-kappaB inhibitor SN50 could enhance the role of LY294002 on inducing cell death of human gastric cancer cells SGC7901, which might be a promising new approach to gastric cancer therapy. PMID- 24482642 TI - CXCL12-G801A polymorphism modulates risk of colorectal cancer in Taiwan. AB - INTRODUCTION: The chemokine CXCL12, designated stromal cell-derived factor-1 (SDF 1), plays a significant role in many cancer metastases. Previous studies have shown that CXCL12-G801A, a single nucleotide polymorphism (SNP) in the 3' untranslated region, correlates with breast and lung cancer in Iran. The aim of this study was to evaluate the association of the gene variant CXCL12-G801A with colorectal cancer (CRC) in a Taiwanese cohort. MATERIAL AND METHODS: In this study, we used a denaturing high performance liquid chromatography (DHPLC) method to analyze the frequencies of CXCL12-G801A polymorphic variants between CRC patients (n = 258) and healthy controls (n = 300) in Taiwan. RESULTS: The SNP distribution was higher in CRC patients with TNM stage II (117/258) than healthy controls (52/300). We observed a significant increase in the G/A plus A/A genotype of the CXCL12-G801A polymorphism in CRC patients (45.35%) compared with healthy controls (17.33%). The analysis of allelic frequencies in both groups revealed that CRC patients have a higher frequency of A allele (23.45%) than healthy controls (8.67%). Furthermore, among older CRC patients, the frequency of the CXCL12-G801A genotype was significantly increased (p = 0.0148). CONCLUSIONS: Our observations suggest that the CXCL12-G801A genotype may be associated with some clinical manifestations in CRC patients in Taiwan. PMID- 24482643 TI - Vitamin C modulates DNA damage induced by hydrogen peroxide in human colorectal adenocarcinoma cell lines (HT29) estimated by comet assay in vitro. AB - INTRODUCTION: Cancer cells, compared to normal cells, are under increased oxidative stress associated with oncogenic transformation, alterations in metabolic activity, and increased generation of reactive oxygen species. MATERIAL AND METHODS: We investigated the ability of vitamin C to reduce the damage induced by hydrogen peroxide, in human colorectal adenocarcinoma cells in vitro by the comet assay. Additionally, we measured the kinetics and efficacy of the repair of DNA damage after incubation with vitamin C in the presence of H2O2. RESULTS: The obtained results showed that 1 h pre-incubation with vitamin C and exposure to H2O2 for the last 10 min of incubation caused a statistically significant (p < 0.05) increase in DNA migration in comet tails in all experimental series. For the 10 uM, 25 uM, 50 uM, 100 uM vitamin C concentrations the levels of DNA damage were as follows: 18.6%, 21.1%, 25.3% and 27.2%, respectively, as compared to the untreated cells (3.26%). However, in comparison with H2O2 alone (29.1%), we observed a statistically significant (p < 0.05) decrease of the genotoxic effect in HT29 cells induced by H2O2 for the two lowest of concentrations of vitamin C: 10 uM and 25 uM. The HT29 cells were able to achieve effective repair of the damaged DNA within 60 and 120 min after incubation with the tested compounds. All the values obtained in the test were statistically significant (p < 0.05). CONCLUSIONS: Vitamin C caused a weaker DNA damaging effect of hydrogen peroxide and positively influences the level of oxidative DNA damage in HT29 cells (decrease ~ 30%). We noted that DNA damage was effectively repaired during 120 min postincubation in the tested cells and that oxidative damage was the major type of damage. PMID- 24482644 TI - Association of temporomandibular dysfunction with the 102T-C polymorphism in the serotonin receptor gene in Brazilian patients. AB - INTRODUCTION: Serotonin is a key neurotransmitter in the central nervous system. It has been suggested that serotoninergic dysfunction mediates the pathophysiology of temporomandibular dysfunction (TMD). Polymorphisms in the serotonin receptor gene (HTR2A) can alter its transcription, affecting the number of receptors in the serotoninergic system, altering nociceptive pain and hyperalgesia in TMD. The aim of this study is to investigate the association of the 102T-C polymorphism in the HTR2A gene in Brazilian patients with TMD. MATERIAL AND METHODS: This cross-sectional study examined 100 patients, of both genders, with TMD as index cases and 100 healthy volunteers as controls, also of both genders. DNA was extracted from peripheral blood leukocytes, and the site that encompassed the polymorphism in the HTR2A gene was amplified by polymerase chain reaction followed by restriction fragment length polymorphism (PCR-RFLP). RESULTS: Our results revealed that there were significantly more females among index cases compared with the control group (p < 0.05). The CC genotype of the 102T-C polymorphism was more frequent in patients with TMD vs. controls (OR: 2.25; 95% CI: 1.13-4.46; p < 0.05). CONCLUSIONS: The present study supports the view that the 102T-C polymorphism in the HTR2A gene is associated with TMD in this studied Brazilian population. PMID- 24482647 TI - Expression analysis of intercellular adhesion molecule-2 (ICAM-2) in the context of classical cardiovascular risk factors in acute coronary syndrome patients. AB - INTRODUCTION: Cardiopulmonary diseases are the most common cause of hospitalization and death. Often the basic problem is endothelial dysfunction leading to elevated expression of adhesion proteins as well as increased adhesion and aggregation of blood cells. The goal of the study was to assess expression level of intercellular adhesive molecule-2 (ICAM-2) in patients with acute coronary syndrome (ACS). MATERIAL AND METHODS: The obtained data were analysed in the context of the occurrence of classical cardiovascular risk factors. The two studied groups consisted of 60 ACS patients and 20 healthy individuals who both were qualified based on electrocardiography (ECG), transthoracic echocardiography and biochemical tests. The ACS patients additionally had coronary angiography performed. The number of ICAM-2 gene mRNA molecules was evaluated on the basis of QRT-PCR reaction kinetics. To compare the results the Mann-Whitney U test was used. Results were judged statistically significant if p < 0.05. RESULTS: Analysis of the results showed a significantly higher number of ICAM-2 gene mRNA copies in ACS patients compared to healthy subjects (140920 +/-105207 and 15023 +/-14325, respectively). Furthermore, our results indicate a correlation between obesity (p = 0.012) and positive burdening family history (p = 0.041) and increased ICAM-2 levels in patients with ACS. CONCLUSIONS: Increased ICAM-2 gene expression in ACS patients is probably symptomatic of endothelium dysfunction and may be responsible for intensified adhesion and aggregation processes as well as for appearance of acute coronary syndrome. These results indicate a correlation between obesity and burdening family history on the one hand, and increased ICAM 2 levels in patients with ACS, on the other. PMID- 24482645 TI - Treatment of non-ST-elevation myocardial infarction and ST-elevation myocardial infarction in patients with chronic kidney disease. AB - Renal dysfunction is frequent in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS). Chronic kidney disease (CKD) is associated with very poor prognosis and is an independent predictor of early and late mortality and major bleeding in patients with NSTE-ACS. Patients with NSTE-ACS and CKD are still rarely treated according to guidelines. Medical registers reveal that patients with CKD are usually treated with too high doses of antithrombotics, especially anticoagulants and inhibitors of platelet glycoprotein (GP) IIb/IIIa receptors, and therefore they are more prone to bleeding. Drugs which are excreted mainly or exclusively by the kidney should be administered in a reduced dose or discontinued in patients with CKD. These drugs include enoxaparin, fondaparinux, bivalirudin, and small molecule inhibitors of GP IIb/IIIa inhibitors. In long-term treatment of patients after myocardial infarction, anti platelet therapy, lipid-lowering therapy and beta-blockers are used. Chronic kidney disease patients before qualification for coronary interventions should be carefully selected in order to avoid their use in the group of patients who could not benefit from such procedures. This paper presents schemes of non-ST and ST segment elevation myocardial infarction treatment in CKD patients in accordance with the current recommendations of the European Society of Cardiology (ESC). PMID- 24482646 TI - Carotid artery stenting - current status of the procedure. AB - Surgical carotid endarterectomy (CEA) was long considered the standard approach for the treatment of atherosclerotic carotid artery disease. This was based on results of several randomized trials demonstrating its effectiveness over the best medical therapy. In the past two decades, patients identified high-risk for surgery were offered carotid artery stenting (CAS) as a less invasive option. Despite its initial limitations, CAS has evolved into an elaborate method currently considered to be equivalent and in selected patients even preferable to CEA. However, outcomes of both procedures are highly operator dependent and a simple stratifying method to prioritize CAS, CEA or medical therapy only has not yet been proposed. In addition, recently published randomized trials highlighted the importance of proper patient selection and rigorous training contributing to low absolute rates of (procedural) adverse events. This review discusses the history and evidence for carotid revascularization and briefly presents technical aspects and innovations in CAS. PMID- 24482648 TI - Efficacy and safety of a biodegradable polymer sirolimus-eluting stent in primary percutaneous coronary intervention: a randomized controlled trial. AB - INTRODUCTION: With long-term follow-up, whether biodegradable polymer drug eluting stents (DES) is efficient and safe in primary percutaneous coronary intervention (PCI) remains a controversial issue. This study aims to assess the long-term efficacy and safety of DES in PCI for ST-segment elevation myocardial infarction (STEMI). MATERIAL AND METHODS: A prospective, randomized single-blind study with 3-year follow-up was performed to compare biodegradable polymer DES with durable polymer DES in 332 STEMI patients treated with primary PCI. The primary end point was major adverse cardiac events (MACE) at 3 years after the procedure, defined as the composite of cardiac death, recurrent infarction, and target vessel revascularization. The secondary end points included in-segment late luminal loss (LLL) and binary restenosis at 9 months and cumulative stent thrombosis (ST) event rates up to 3 years. RESULTS: The rate of the primary end points and the secondary end points including major adverse cardiac events, in segment late luminal loss, binary restenosis, and cumulative thrombotic event rates were comparable between biodegradable polymer DES and durable polymer DES in these 332 STEMI patients treated with primary PCI at 3 years. CONCLUSIONS: Biodegradable polymer DES has similar efficacy and safety profiles at 3 years compared with durable polymer DES in STEMI patients treated with primary PCI. PMID- 24482649 TI - Association of corrected QT interval with long-term mortality in patients with syncope. AB - INTRODUCTION: The electrocardiographic parameters QRS duration, QRS-T angle and QTc can predict mortality in patients with cardiovascular disease. The prgnostic value of these parameters in hospitalized patients with syncope needs investigation. MATERIAL AND METHODS: We retrospectively studied 590 consecutive patients hospitalized with syncope. After excluding patients with baseline abnormal rhythm, QT- prolonging medications, and missing data, 459 patients were analyzed. Baseline demographic characteristics, co-morbidities, medication use, San Francisco Syncope Rule (SFSR) and Osservatorio Epidemiologico sulla Sincope nel Lazio (OESIL) score and data on mortality were collected. The categorical variables and continuous variables of the 2 groups of patients with prolonged QTc and normal QTc interval were analyzed by Fischer's exact test and Mann-Whitney Test. A stepwise Cox regression model was used for time to death analysis. RESULTS: Of 459 patients, prolonged QTc interval was observed in 122 (27%). Mean follow-up was 41 months. Patients with prolonged QTc interval had higher prevalence of cardiovascular disease, OESIL score, high risk SFSR, hypertension, dyslipidemia, coronary artery disease, congestive heart failure, and increased mortality. Stepwise Cox regression analysis showed that significant independent prognostic factors for time to death were prolonged QTc interval (p = 0.005), age (p = 0.001), diabetes mellitus (p = 0.001) and history of malignancy (p = 0.006). QRS duration and QRS-T angle were not independent predictors of mortality. CONCLUSIONS: A prolonged QTc interval is an independent predictor of long-term mortality in hospitalized patients with syncope. PMID- 24482650 TI - Mean platelet volume is elevated in patients with patent foramen ovale. AB - INTRODUCTION: Platelets play a major role in thromboembolic events. Increased mean platelet volume (MPV) indicates higher platelet reactivity and also a tendency to thrombosis. Patent foramen ovale (PFO), persistence of the fetal anatomic shunt between right and left atria, is strongly associated with cryptogenic stroke. The aim of this study is to determine the relationship between MPV and PFO and if such an association exists, whether higher MPV levels may require antiplatelet therapy before a thromboembolic event happens, together with a literature review. MATERIAL AND METHODS: Thirty patients (15 women, 15 men), free of any cerebrovascular events, were diagnosed with PFO by transesophageal echocardiography (TEE), enrolled as the study group. Thirty consecutive patients (16 women and 14 men), who were diagnosed as normal in TEE, were enrolled as the control group. These two groups were compared according to MPV and anatomical features of the right atrium. RESULTS: There was no significant difference between study and control groups in clinical features and also no difference was observed in platelet counts; however, MPV in the PFO group was significantly higher than the control group (8.38 +/-0.93 fl and 7.45 +/-0.68 fl respectively). CONCLUSIONS: Our results indicate that elevated MPV may be detected in patients with PFO. This might be one of the explanations for the relationship between PFO and cryptogenic stroke; however, larger cohorts are warranted in order to define further mechanisms. PMID- 24482651 TI - Antithrombotic therapy - predictor of early and long-term bleeding complications after transcatheter aortic valve implantation. AB - INTRODUCTION: Dual antiplatelet therapy (DAPT) - aspirin and clopidogrel - is recommended after transcatheter aortic valve implantation (TAVI) without an evidence base. The main aim of the study was to estimate the impact of antithrombotic therapy on early and late bleeding. Moreover, we assessed the impact of patients' characteristics on early bleeding and the influence of bleeding on prognosis. MATERIAL AND METHODS: Between 2009 and 2011, 83 consecutive TAVI patients, age 81.1 +/-7.2 years, were included. Bleeding complications were defined by the Valve Academic Research Consortium (VARC) scale. The median follow-up was 12 +/-15.5 months (range: 1 to 23) and included 68 (81.9%) patients. RESULTS: Early bleeding occurred in 51 (61.4%) patients. Vitamin K antagonists (VKA) pre-TAVI (p = 0.001) and VKA + clopidogrel early post TAVI (p = 0.04) were the safest therapies; in comparison to the safest one, peri procedural DAPT (p = 0.002; p = 0.05) or triple anticoagulant therapy (TAT) (p = 0.003, p = 0.05) increased the risk for early bleeding. Predictors for early bleeding were: clopidogrel pre-TAVI (OR: 4.43, 95% CI: 1.02-19.24, p = 0.04), preceding percutaneous coronary intervention (PCI) (10.08, OR: 95% CI: 1.12 90.56, p = 0.04), anemia (OR: 4.00, 95% CI: 1.32-12.15, p = 0.01), age > 85 years (OR: 5.96, 95% CI: 1.47-24.13, p = 0.01), body mass index (BMI) (OR: 0.86, 95% CI: 0.74-0.99, p = 0.04). Late bleeding occurred in 35 patients (51.4%) on combined therapy, and none on VKA or clopidogrel monotherapy (p = 0.04). Bleeding complications did not worsen the survival. CONCLUSIONS: This study seems to suggest that advanced age, BMI, and a history of anemia increased the risk for early bleeding after TAVI. Clopidogrel pre-TAVI should be avoided; therefore, time of preceding PCI should take into account discontinuation of clopidogrel in the pre-TAVI period. Vitamin K antagonists with clopidogrel seems to be the safest therapy in the early post-TAVI period, similarly as VKA/clopidogrel monotherapy in long-term prophylaxis. PMID- 24482652 TI - Prognostic value of tissue factor in patients with abdominal aortic and iliac arterial aneurysms - preliminary study. AB - INTRODUCTION: The decision on the time and choice of strategy of treatment of abdominal aortic aneurysm must be especially carefully balanced. The aim of the study was to evaluate the tissue factor (TF) plasma level as a potential factor useful in anticipation of abdominal aortic aneurysm and/or iliac arterial aneurysm via comparison of plasma TF level in patients with ruptured and non ruptured aneurysms. MATERIAL AND METHODS: The study included 33 patients with aneurysm (17 operated on electively because of non-ruptured aneurysm and 16 operated on emergently due to ruptured aneurysm), 33 claudicant patients with atherosclerosis of the abdominal aorta and iliac arteries with normal diameter of arteries, and 30 healthy controls. Plasma TF level was assessed by ELISA method using the IMUBIND Tissue Factor ELISA Kit (American Diagnostica Inc.). RESULTS: The study showed an increased TF level in patients with aneurysm (134 +/-54 pg/ml) and in patients with atherosclerosis without concomitant aneurysm (91 +/ 30 pg/ml) in comparison with the control group (62 +/-20 pg/ml), respectively p < 0.001 and p = 0.008. A significantly higher TF plasma level was observed in patients with ruptured abdominal aortic aneurysms (160 +/-57 pg/ml) as compared to patients with non-ruptured aortic aneurysms (109 +/-39 pg/ml) or peripheral arterial occlusive disease (91 +/-30 pg/ml), respectively p < 0.001 and p < 0.001. The difference in TF level between the group with non-ruptured aortic aneurysms (109 +/-39 pg/ml) and the patients with atherosclerosis without aneurysm (91 +/-30 pg/ml) was not statistically significant. CONCLUSIONS: No difference in TF level between patients with non-ruptured AAA/IAA and patients with aortic and iliac atherosclerosis without aneurysm indicates that an increased TF plasma level is not specific for any of the above-mentioned vascular pathologies. PMID- 24482653 TI - Surgical treatment of lower limb ischemia in diabetic patients - long-term results. AB - INTRODUCTION: Lower limb ischemia may cause nonhealing ulcers, infection, amputation and even mortality in diabetic patients. In this study, we review our data of ischemic lower limb revascularization procedures in diabetic patients and present the early, mid- and long-term results. MATERIAL AND METHODS: From March 2004 to September 2008, 83 patients with lower limb ischemia in Fontaine class III and IV underwent distal arterial bypass procedures. Saphenous vein grafts were used for below-knee arterial bypasses in all patients. In 16 (19%) patients femoropopliteal bypasses were performed with PTFE grafts. Short-term and long term surgical results were evaluated. RESULTS: Ulcer recovery was determined in 36% of patients. Graft patency was 95% and 1 death (1%) occurred in short-term follow-up. In long-term follow-up the total effectiveness rate was 74%. Graft patency was 79% and 6 deaths (7%) occurred during the follow-up. CONCLUSIONS: Lower limb ischemia is a serious event in patients with diabetes mellitus. The consequences may include increased mortality and morbidity in this particular patient population. However, distal arterial revascularizations are considerably effective procedures to avoid amputation, to eliminate symptoms, to promote ulcer recovery and to help the patient participate in social life with acceptable short, mid- and long-term follow-up results. PMID- 24482654 TI - Role of cytological characteristics of benign thyroid nodules on effectiveness of their treatment with levothyroxine. AB - INTRODUCTION: Levothyroxine (LT4) therapy has been used for the treatment of euthyroid nodular goiter, but there are controversial results about its usefulness. We aimed to evaluate the possible role of benign nodules' cytological characteristics in response to LT4 therapy. MATERIAL AND METHODS: In total, 93 patients with 128 nodules were included in the study; 74 of the nodules were treated with LT4 (group 1), and 54 of them had no medication (group 2). The subgroups consisted of adenomatous nodules, colloid nodules and cystic nodules. RESULTS: In group 1, mean thyroid volume and mean nodule volume were reduced significantly (p = 0.002 and p = 0.022, respectively) with low-normal level thyrotropin (TSH) suppression (between 0.3 mIU/ml and 1.0 mIU/ml), while there were no significant changes in group 2. When we evaluated changes of the initial and last nodule volumes in cytological subgroups, only colloid nodules in group 1 had significant reduction (p = 0.040) and the others had no significant changes. By omitting the colloid nodules, when the other nodules were revaluated, there were no significant changes in either group. CONCLUSIONS: On the basis of these results, obtained from a large sample of Anatolian patients, it is possible that LT4 therapy leads to significant reductions of both thyroid volume and nodule size in colloid nodules, but not in other kinds of benign nodules. PMID- 24482655 TI - FK506 attenuates thymic output in patients with myasthenia gravis. AB - INTRODUCTION: Myasthenia gravis (MG) is an antibody-mediated, T-cell-dependent autoimmune disease. The symptoms are caused by high-affinity IgG against the muscle acetylcholine receptor (AChR) at the neuromuscular junction. The production of these antibodies in B-cells depends on AChR-specific CD4(+) T-cells and the thymus gland seems to play a significant role in the pathogenesis of MG. Altered thymic T-cell export seems to be associated with a pathological mechanism in myasthenia gravis. Tacrolimus (FK506) has recently been used to treat MG. MATERIAL AND METHODS: We examined the effects of tacrolimus on thymic T-cell export in patients with MG. Sixteen patients with nonthymomatous and/or thymectomized MG were treated with oral administrations of tacrolimus. To assess the effect of tacrolimus on the thymic output, we assayed the levels of T-cell receptor excision circle (TREC), a molecular marker of thymus emigrants. RESULTS: T-cell receptor excision circle was not significantly different from those in age matched controls before tacrolimus therapy, but they were partially decreased 4 months after tacrolimus therapy. T-cell receptor excision circle levels were significantly decreased in the thymomatous group (p < 0.05), but not in the nonthymomatous group. Tacrolimus treatment significantly attenuated TREC levels in cultured CD4(-)CD8(+) cells (p < 0.05), but total cell counts were not significantly changed. CONCLUSIONS: These results indicate that TREC levels may become a marker of the curative effect of tacrolimus therapy for thymomatous MG, and that tacrolimus suppresses not only activating T-lymphocytes, but also naive T-cells. PMID- 24482656 TI - Combined bipolar radiofrequency surgery of the tongue base and uvulopalatopharyngoplasty for obstructive sleep apnea. AB - INTRODUCTION: The aim of the study was to investigate the effectiveness of combined bipolar radiofrequency surgery of the tongue base (RFBT) and uvulopalatopharyngoplasty (UPPP) in a single session for obstructive sleep apnea and whether this combination is safe and well tolerated. MATERIAL AND METHODS: Seventy-nine patients with obstructive sleep apnea and both palatal and retroglossal obstruction underwent UPPP with bipolar RFBT. The control group consisted of 35 patients treated by UPPP alone. RESULTS: The apnea-hypopnea index significantly decreased from 28.7 to 14.1. The oxygen desaturation index decreased from 15.1 to 10.3. Mean oxygen saturation was unchanged. Subjectively, the Epworth Sleepiness Scale was significantly improved from 10.6 to 7.3, and the snoring level decreased from 8.4 to 6.0. The overall treatment success rate increased from 41.9% for UPPP alone to 51.7% for UPPP + RFBT. No serious adverse events occurred. Two patients had postoperative bleeding from the tonsillar bed after UPPP. Four patients had ulceration of the base of the tongue after RFBT with spontaneous cure. One patient had a taste change in half of the tongue that resolved within two months. CONCLUSIONS: Combined bipolar RFBT and UPPP in a single session is well tolerated and safe surgery in the treatment of obstructive sleep apnea. It is effective in reducing respiratory parameters and subjective symptoms of obstructive sleep apnea. Further advantages are a single session, simple feasibility, bipolar technique and short time of the procedure. PMID- 24482657 TI - Microchimerism in twins. AB - INTRODUCTION: The aim of this paper was to report the occurrence of peripheral blood chimerism in newborns from bigeminal pregnancies. MATERIAL AND METHODS: Cord blood collected from 50 pairs of twins constituted the biological material studied. Analyses included: DNA isolation, quantitative and qualitative assessment of DNA preparations, hybridization analysis of SLS type as well as of MLS type, and analysis of microsatellite sequences with regard to polymorphisms using polymerase chain reaction. RESULTS: The presence of additional fragments of DNA in peripheral blood lymphocytes was found in four out of fifty pairs of monozygotic twins (8%) at locus D7S21 (7p22, n = 3) and locus D12S11 (12q24.3, n = 1). In these cases, the presence of additional DNA fragments was also proved by analysis of microsatellite sequence polymorphisms at loci HUMPLA2A1 (pancreatic phospholipase A-2, 12q23), HUMCYARO (cytochrome P450, 15q21.1) and HUMvWF (von Willebrand factor, 12p13). CONCLUSIONS: The results of our study confirm the occurrence of chimerism in twins and constitutes the starting point for further studies aimed at determining the clinical significance of chimerism in twins both for women and fetuses. PMID- 24482659 TI - Mental health status among younger generation around Chernobyl. AB - INTRODUCTION: In order to improve our understanding of how to approach the younger generation around Chernobyl, we screened mental health status among young adults born after the accident living in the Gomel region, Belarus. MATERIAL AND METHODS: We enrolled 697 medical students who were born after the accident. Participants were asked to answer self-administered questionnaires including the General Health Questionnaire (GHQ-12). RESULTS: GHQ-12 scores were 1.80 +/-2.28 (mean +/- SD) among all 697 subjects. When logistic regression analysis was performed with confounding factors, "economic situation" and "association of diseases and/or poor health condition with radiation exposure" were significantly associated with poor mental status. CONCLUSIONS: Our findings suggest that anxiety about radiation exposure among highly educated medical students in the Gomel region, although they were born after the accident, affects their poor mental health status. PMID- 24482658 TI - Prevalence of ocular manifestations in systemic sclerosis patients. AB - INTRODUCTION: Systemic sclerosis (scleroderma, SSc) is a severe chronic connective tissue disease caused by immune system disorders and changes in the structure and functions of blood vessels, which consequently leads to enhanced tissue fibrosis. The aim of the study was to evaluate changes in the organ of vision in systemic sclerosis patients. MATERIAL AND METHODS: Overall the study involved 27 patients with systemic sclerosis. The control group comprised 27 age- and gender-matched healthy individuals. All the study subjects underwent complete ophthalmological examination that in systemic sclerosis patients additionally involved fluorescein angiography. RESULTS: OPHTHALMOLOGICAL EXAMINATION REVEALED HIGHER INCIDENCE OF THE FOLLOWING ABNORMALITIES IN THE STUDY GROUP, COMPARED TO THE CONTROL: symptoms of dry eye syndrome (19 eyes, p < 0.02), astigmatism(in 30 eyes, p < 0.01), posterior subcapsular cataract (10 eyes, p < 0.05), increased intraocular pressure (> 21 mm Hg were observed in 11 eyes, p < 0.002) and vascular abnormalities within fundus in fluorescein angiography (20 eyes). CONCLUSIONS: In patients with systemic sclerosis numerous abnormalities within the vision of organ may be found. Regular ophthalmological examinations are essential among the mentioned group. The examination should be particularly focused on the presence of retinal vascular abnormalities. PMID- 24482660 TI - Hospital pharmacists' knowledge about and attitude toward HIV/AIDS and patients living with HIV/AIDS in Kedah, Malaysia. AB - INTRODUCTION: The current study aims to explore the knowledge, attitude, and perception of hospital pharmacists towards HIV/AIDS and patients living with HIV/AIDS (PLWHA) in the state of Kedah, Malaysia. MATERIAL AND METHODS: This was a cross-sectional study conducted among the hospital pharmacists in three government hospitals in Kedah, using a self-administered 43-item questionnaire. Data analysis was done using non-parametric and multinomial regression. RESULTS: A total of 75 respondents participated in this study, resulting in a response rate of 60.8%. The majority were found to be well aware of the causes of HIV/AIDS. However, about 34 (45.3%) believed erroneously that HIV/AIDS cannot be transmitted through tattooing or body piercing. Nearly 25 (33.3%) of the respondents believed that preventing the use of intravenous drugs may not be effective to prevent HIV/AIDS and endorsed social isolation as a measure to prevent HIV/AIDS. The majority (66.6%) had negative attitudes and about 20% held extremely negative attitudes. Findings from regression modelling revealed that hospital (-2 log likelihood = 215.182, chi(2) = 18.060, Df = 8, p = 0.021) and gender (-2 log likelihood = 213.643, chi(2) = 16.521, Df = 8, p = 0.035) were more likely to affect the attitudes of respondents. CONCLUSIONS: Overall, more than one third of the respondents were found to have negative attitudes towards PLWHA. Gender, job experience, and hospitals with more HIV/AIDS patient visits were the main factors affecting attitudes. PMID- 24482661 TI - Effects of ischemic phrenic nerve root ganglion injury on respiratory disturbances in subarachnoid hemorrhage: an experimental study. AB - INTRODUCTION: Phrenic nerves have important roles on the management of respiration rhythm. Diaphragm paralysis is possible in phrenic nerve roots ischemia in subarachnoid hemorrhage (SAH). We examined whether there is a relationship between phrenic nerve root ischemia and respiratory disturbances in SAH. MATERIAL AND METHODS: This study was conducted on 5 healthy control and 14 rabbits with experimentally induced SAH by injecting autologous blood into their cisterna magna. Animals were followed up via monitors for detecting the heart and respiration rhythms for 20 days and then decapitaed by humanely. Normal and degenerated neuron densities of phrenic nerve root at the level of C4 dorsal root ganglia (C4DRG) were estimated by Stereological methods. Between the mean numerical density of degenerated neurons of C4DRG and respiratory rate/minute of groups were compared statistically. RESULTS: Phrenic nerve roots, artery and diaphragm muscles degeneration was detected in respiratory arrest developed animals. The mean neuronal density of C4DRG was 13272 +/-1201/mm3 with a mean respiration rate of 23 +/-4/min in the control group. The mean degenerated neuron density was 2.240 +/-450/mm(3) and respiration rhythm was 31 +/-6/min in survivors. But, the mean degenerated neuron density was 5850 +/-650/mm(3) and mean respiration rhythm was 34 +/-7/min in respiratory arrest developed animals (n = 7). A linear relationship was noticed between the degenerated neuron density of C4DRG and respiraton rate (r = -0.758; p < 0.001). CONCLUSIONS: Phrenic nerve root ischemia may be an important factor in respiration rhythms deteriorations in SAH which has not been mentioned in the literature. PMID- 24482662 TI - Effects of captopril on factors affecting gastric mucosal integrity in aspirin induced gastric lesions in Sprague-Dawley rats. AB - INTRODUCTION: Captopril is an angiotensin-converting enzyme inhibitor, which is used as an antihypertensive agent and has shown antioxidant properties. This study aims at determining the effects of captopril on factors affecting gastric mucosal integrity in aspirin-induced gastric lesions. MATERIAL AND METHODS: Eighteen male Sprague-Dawley (200-250 g) rats that were given aspirin (40 mg/100 g body weight) were divided into three groups: the control, captopril (1 mg/100 g body weight daily) and ranitidine (2.5 mg/100 g body weight twice daily) groups. Ranitidine and captopril were given orally for 28 days. Rats in all groups were sacrificed and the parameters measured. RESULTS: Captopril reduced gastric acidity, and increased gastric glutathione (GSH) and prostaglandin E2 (PGE2) significantly in comparison to the control group. Captopril also reduced malondialdehyde (MDA) and gastric lesions insignificantly compared to the control group. Ranitidine healed the lesions significantly compared to the control group. There was no difference between ranitidine and captopril on the severity of lesions, gastric acidity, MDA and GSH. Captopril increased PGE2 compared to ranitidine (p < 0.05). CONCLUSIONS: Captopril has desirable effects on the factors affecting gastric mucosal integrity (acidity, PGE2 and GSH) and is comparable to ranitidine in ulcer healing. PMID- 24482663 TI - Effects of intravenous human umbilical cord blood CD34+ stem cell therapy versus levodopa in experimentally induced Parkinsonism in mice. AB - INTRODUCTION: Parkinsonism is a neurodegenerative disease with impaired motor function. The current research was directed to investigate the effect of CD34+ stem cells versus levodopa in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced Parkinsonism. MATERIAL AND METHODS: Mice were divided into 4 groups; saline-injected, MPTP: received four MPTP injections (20 mg/kg, i.p.) at 2 h intervals, MPTP groups treated with levodopa/carbidopa (100/10 mg/kg/twice/day for 28 days) or single intravenous injection of 10(6) CD34+ stem cells/mouse at day 7 and allowed to survive until the end of week 5. RESULTS: Levodopa and stem cells improved MPTP-induced motor deficits; they abolished the difference in stride length, decreased percentage of foot slip errors and increased ambulation, activity factor and mobility duration in parkinsonian mice (p < 0.05). Further, they significantly (p < 0.05) increased striatal dopamine (85.3 +/-4.3 and 110.6 +/-5.3) and ATP levels (10.6 +/-1.1 and 15.5 +/-1.14) compared to MPTP (60.1 +/ 3.9 pmol/g and 3.6 +/-0.09 mmol/g, respectively) (p < 0.05). Moreover, mitochondrial DNA from mice treated with levodopa or stem cells was in intact form; average concentration was (52.8 +/-3.01 and 107.8 +/-8.6) and no appreciable fragmentation of nuclear DNA was found compared to MPTP group. Regarding tyrosine hydroxylase (TH) immunostaining, stem cell group showed a marked increase of percentage of TH-immunopositive neurons (63.55 +/-5.2) compared to both MPTP (37.6 +/-3.1) and levodopa groups (41.6 +/-3.5). CONCLUSIONS: CD34+ cells ameliorated motor, biochemical and histological deficits in MPTP-parkinsonian mice, these effects were superior to those produced by levodopa that would be promising for the treatment of PD. PMID- 24482664 TI - Pancreatobiliary and peripancreatobiliary tuberculosis: a rare cause of obstructive jaundice. PMID- 24482665 TI - Coronary artery dissection, traumatic liver and spleen injury after cardiopulmonary resuscitation - a case report and review of the literature. PMID- 24482666 TI - Rare cardiovascular anomaly: congenital unilateral absence of the pulmonary artery. PMID- 24482667 TI - Frontiers in Human Neuroscience: The Golden Triangle and Beyond. AB - The development and application of neuroimaging methods offers powerful means to study brain functions, but the resulting knowledge is more likely to be beneficial when combined with conceptual analyses that decompose complex psychological constructs into component structures, representations, processes, and computations; converging measures that gauge neural events at different temporal and spatial scales; behavioral measures that permit fine-grain analyses of brain-behavior associations; and experimental (e.g., lesion studies and/or transcranial magnetic stimulation) and nonhuman animal studies that test the putative role of specific brain structures, circuits, or processes. In addition, quantitative meta-analyses are important to move beyond idiosyncrasies of individual studies, and neurodevelopmental investigations can contribute to our understanding of brain-behavior associations. PMID- 24482668 TI - HLA mismatches and hematopoietic cell transplantation: structural simulations assess the impact of changes in peptide binding specificity on transplant outcome. AB - The success of hematopoietic cell transplantation from an unrelated donor depends in part on the degree of Human Histocompatibility Leukocyte Antigen (HLA) matching between donor and patient. We present a structure-based analysis of HLA mismatching, focusing on individual amino acid mismatches and their effect on peptide binding specificity. Using molecular modeling simulations of HLA-peptide interactions, we find evidence that amino acid mismatches predicted to perturb peptide binding specificity are associated with higher risk of mortality in a large and diverse dataset of patient-donor pairs assembled by the International Histocompatibility Working Group in Hematopoietic Cell Transplantation consortium. This analysis may represent a first step toward sequence-based prediction of relative risk for HLA allele mismatches. PMID- 24482669 TI - The role of palliative radiotherapy for haemostasis in unresectable gastric cancer: a single-institution experience. AB - PURPOSE: To evaluate the outcomes of patients with gastric cancer bleeding who had been treated with palliative radiotherapy with haemostatic intent. METHODS AND MATERIALS: Fifty-two gastric cancer patients aged 52-92 years (median 78 years) with active bleeding or anaemia resulting from inoperable gastric cancer were treated with short-course radiotherapy. Responses to radiotherapy treatment were evaluated based on the changes of haemoglobin level, number of transfusions received before and after radiotherapy, and overall median survival. RESULTS: Thirty-nine (75%) patients received single 8 Gy fraction, and 13 (25%) patients received 20 Gy in five daily fractions. The need for transfusion was evaluable in 44 patients, and the response rate was 50%, with less requirement for blood transfusions within four weeks of radiotherapy. There was also an increase in mean haemoglobin level (0.66 +/- 1.12 g/dl, p < 0.01) after radiotherapy in 35 evaluable patients. The overall median survival (calculated from last day of treatment to date of death) was 160 days (95% CI of 119-201 days), making actuarial 12-month survival 15%. CONCLUSION: Palliative short-course radiotherapy is a reasonably effective treatment that can provide durable palliation of bleeding in gastric cancer. PMID- 24482670 TI - Clinical Robotic Surgery Association Fifth Worldwide Congress, Washington DC, 3-5 October 2013: Robotic Colorectal Surgery. AB - The colorectal session was one of the most successful and well attended sessions at the Fifth Worldwide Clinical Robotic Surgery Association Congress because of the increasing interest and diffusion of robotic techniques in this specific field. This session was structured as follows: two technical focuses, one on rectal resection and the other on right colectomies; a journal club with two hot topic papers presented by the authors; a face-to-face on single-port laparoscopic versus robotic surgery; an update on the transanal approach; and three lectures, on the oncologic safety of robotic total mesorectal excision, on the use of fluorescence in colorectal surgery, and finally an update on the ongoing ROLARR trial (laparoscopic versus robotic rectal resection). PMID- 24482671 TI - Highlights from the 2013 national cancer research institute conference. AB - Cancer research is a multifaceted endeavour that incorporates not only a myriad of techniques and specialties but also encompasses a huge range of disease types. The National Cancer Research Institute (NCRI) is a UK partnership comprising 21 charity and government funders of cancer research along with the Association of British Pharmaceutical Industry. Each year, the NCRI hosts the largest cancer meeting in the UK; bringing together members of the UK cancer research community, research leaders from around the world, health professionals, service users, research funders, and industry to discuss the latest findings in cancer research from a wide range of disciplines. The 2013 NCRI Conference attracted over 1700 delegates and 150 speakers from 15 different countries. The conference programme covered a large range of topic areas including prevention, screening, model systems, the provision of information, survivorship, and end-of-life care. This conference report gives an overview of the plenary sessions at the conference as well as highlights from the parallel sessions. PMID- 24482672 TI - The ethics of clinical trials. AB - Over the past decades, randomised controlled trials (RCTs) have prevailed over clinical judgement, case reports, and observational studies and became the gold evidential standard in medicine. Furthermore, during the same time frame, RCTs became a crucial part of the regulatory process whereby a new therapeutic can gain access to the drug market. Today, clinical trials are large and tightly regulated enterprises that have to comply with ethical requirements while maintaining high epistemic standards, a balance that becomes increasingly difficult as the research questions become more sophisticated. In this review, the author will discuss some of the most important ethical issues surrounding RCTs, with an eye to the most recent debates and the context of oncological research in particular. PMID- 24482673 TI - Association between estrogen receptor alpha gene (ESR1) PvuII (C/T) and XbaI (A/G) polymorphisms and hip fracture risk: evidence from a meta-analysis. AB - BACKGROUND AND OBJECTIVE: Genetic factors are important in the pathogenesis of fractures. Notably, estrogen receptor alpha (ESR1) has been suggested as a possible candidate gene for hip fractures; however, published studies of ESR1 gene polymorphisms have been hampered by small sample sizes and inconclusive or ambiguous results. The aim of this meta-analysis is to investigate the associations between two novel common ESR1 polymorphisms (intron 1 polymorphisms PvuII-rs2234693: C>T and XbaI-rs9340799: A>G) and hip fracture. METHODS: Crude odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the association. RESULTS: Five case-control and three cohort studies were assessed, including a total of 1,838 hip fracture cases and 14,972 healthy controls. This meta-analysis revealed that the PvuII T allele is a highly significant risk factor for hip fracture susceptibility, with an effect magnitude similar in male and pre-menopausal and post-menopausal female patients. In stratified analysis based on ethnicity, the PvuII T allele remained significantly correlated with increased risk of hip fracture in Caucasian populations; this correlation, however, was not found in Asian populations. Unlike the PvuII polymorphism, we did not find significant differences in the XbaI (A>G) polymorphism allele or genotype distributions of hip fracture patients and controls. We also found no obvious association between the XbaI polymorphism and hip fracture in any of the racial or gender subgroups. CONCLUSION: Our findings show that the ESR1 PvuII T allele may increase the risk of hip fracture and that the XbaI polymorphism is not associated with hip fracture. PMID- 24482676 TI - Fluorescence-based classification of Caribbean coral reef organisms and substrates. AB - A diverse group of coral reef organisms, representing several phyla, possess fluorescent pigments. We investigated the potential of using the characteristic fluorescence emission spectra of these pigments to enable unsupervised, optical classification of coral reef habitats. We compiled a library of characteristic fluorescence spectra through in situ and laboratory measurements from a variety of specimens throughout the Caribbean. Because fluorescent pigments are not species-specific, the spectral library is organized in terms of 15 functional groups. We investigated the spectral separability of the functional groups in terms of the number of wavebands required to distinguish between them, using the similarity measures Spectral Angle Mapper (SAM), Spectral Information Divergence (SID), SID-SAM mixed measure, and Mahalanobis distance. This set of measures represents geometric, stochastic, joint geometric-stochastic, and statistical approaches to classifying spectra. Our hyperspectral fluorescence data were used to generate sets of 4-, 6-, and 8-waveband spectra, including random variations in relative signal amplitude, spectral peak shifts, and water-column attenuation. Each set consisted of 2 different band definitions: 'optimally-picked' and 'evenly-spaced.' The optimally-picked wavebands were chosen to coincide with as many peaks as possible in the functional group spectra. Reference libraries were formed from half of the spectra in each set and used for training purposes. Average classification accuracies ranged from 76.3% for SAM with 4 evenly-spaced wavebands to 93.8% for Mahalanobis distance with 8 evenly-spaced wavebands. The Mahalanobis distance consistently outperformed the other measures. In a second test, empirically-measured spectra were classified using the same reference libraries and the Mahalanobis distance for just the 8 evenly-spaced waveband case. Average classification accuracies were 84% and 87%, corresponding to the extremes in modeled water-column attenuation. The classification results from both tests indicate that a high degree of separability among the 15 fluorescent spectra functional groups is possible using only a modest number of spectral bands. PMID- 24482677 TI - Sleep extension improves neurocognitive functions in chronically sleep-deprived obese individuals. AB - BACKGROUND: Sleep deprivation and obesity, are associated with neurocognitive impairments. Effects of sleep deprivation and obesity on cognition are unknown, and the cognitive long-term effects of improvement of sleep have not been prospectively assessed in short sleeping, obese individuals. OBJECTIVE: To characterize neurocognitive functions and assess its reversibility. DESIGN: Prospective cohort study. SETTING: Tertiary Referral Research Clinical Center. PATIENTS: A cohort of 121 short-sleeping (<6.5 h/night) obese (BMI 30-55 kg/m(2)) men and pre-menopausal women. INTERVENTION: Sleep extension (468+/-88 days) with life-style modifications. MEASUREMENTS: Neurocognitive functions, sleep quality and sleep duration. RESULTS: At baseline, 44% of the individuals had an impaired global deficit score (t-score 0-39). Impaired global deficit score was associated with worse subjective sleep quality (p = 0.02), and lower urinary dopamine levels (p = 0.001). Memory was impaired in 33%; attention in 35%; motor skills in 42%; and executive function in 51% of individuals. At the final evaluation (N = 74), subjective sleep quality improved by 24% (p<0.001), self-reported sleep duration increased by 11% by questionnaires (p<0.001) and by 4% by diaries (p = 0.04), and daytime sleepiness tended to improve (p = 0.10). Global cognitive function and attention improved by 7% and 10%, respectively (both p = 0.001), and memory and executive functions tended to improve (p = 0.07 and p = 0.06). Serum cortisol increased by 17% (p = 0.02). In a multivariate mixed model, subjective sleep quality and sleep efficiency, urinary free cortisol and dopamine and plasma total ghrelin accounted for 1/5 of the variability in global cognitive function. LIMITATIONS: Drop-out rate. CONCLUSIONS: Chronically sleep-deprived obese individuals exhibit substantial neurocognitive deficits that are partially reversible upon improvement of sleep in a non-pharmacological way. These findings have clinical implications for large segments of the US population. TRAIL REGISTRATION: www.ClinicalTrials.gov NCT00261898. NIDDK protocol 06-DK-0036. PMID- 24482678 TI - Effects of a post-weaning cafeteria diet in young rats: metabolic syndrome, reduced activity and low anxiety-like behaviour. AB - Among adolescents, overweight, obesity and metabolic syndrome are rapidly increasing in recent years as a consequence of unhealthy palatable diets. Animal models of diet-induced obesity have been developed, but little is known about the behavioural patterns produced by the consumption of such diets. The aim of the present study was to determine the behavioural and biochemical effects of a cafeteria diet fed to juvenile male and female rats, as well as to evaluate the possible recovery from these effects by administering standard feeding during the last week of the study. Two groups of male and female rats were fed with either a standard chow diet (ST) or a cafeteria (CAF) diet from weaning and for 8 weeks. A third group of males (CAF withdrawal) was fed with the CAF diet for 7 weeks and the ST in the 8th week. Both males and females developed metabolic syndrome as a consequence of the CAF feeding, showing overweight, higher adiposity and liver weight, increased plasma levels of glucose, insulin and triglycerides, as well as insulin resistance, in comparison with their respective controls. The CAF diet reduced motor activity in all behavioural tests, enhanced exploration, reduced anxiety-like behaviour and increased social interaction; this last effect was more pronounced in females than in males. When compared to animals only fed with a CAF diet, CAF withdrawal increased anxiety in the open field, slightly decreased body weight, and completely recovered the liver weight, insulin sensitivity and the standard levels of glucose, insulin and triglycerides in plasma. In conclusion, a CAF diet fed to young animals for 8 weeks induced obesity and metabolic syndrome, and produced robust behavioural changes in young adult rats, whereas CAF withdrawal in the last week modestly increased anxiety, reversed the metabolic alterations and partially reduced overweight. PMID- 24482679 TI - Intimate partner violence and pregnancy: a systematic review of interventions. AB - BACKGROUND: Intimate partner violence (IPV) around the time of pregnancy is a widespread global health problem with many negative consequences. Nevertheless, a lot remains unclear about which interventions are effective and might be adopted in the perinatal care context. OBJECTIVE: The objective is to provide a clear overview of the existing evidence on effectiveness of interventions for IPV around the time of pregnancy. METHODS: Following databases PubMed, Web of Science, CINAHL and the Cochrane Library were systematically searched and expanded by hand search. The search was limited to English peer-reviewed randomized controlled trials published from 2000 to 2013. This review includes all types of interventions aiming to reduce IPV around the time of pregnancy as a primary outcome, and as secondary outcomes to enhance physical and/or mental health, quality of life, safety behavior, help seeking behavior, and/or social support. RESULTS: We found few randomized controlled trials evaluating interventions for IPV around the time of pregnancy. Moreover, the nine studies identified did not produce strong evidence that certain interventions are effective. Nonetheless, home visitation programs and some multifaceted counseling interventions did produce promising results. Five studies reported a statistically significant decrease in physical, sexual and/or psychological partner violence (odds ratios from 0.47 to 0.92). Limited evidence was found for improved mental health, less postnatal depression, improved quality of life, fewer subsequent miscarriages, and less low birth weight/prematurity. None of the studies reported any evidence of a negative or harmful effect of the interventions. CONCLUSIONS AND IMPLICATIONS: Strong evidence of effective interventions for IPV during the perinatal period is lacking, but some interventions show promising results. Additional large-scale, high-quality research is essential to provide further evidence about the effect of certain interventions and clarify which interventions should be adopted in the perinatal care context. PMID- 24482680 TI - Exercise training attenuates hypertension and cardiac hypertrophy by modulating neurotransmitters and cytokines in hypothalamic paraventricular nucleus. AB - AIMS: Regular exercise as an effective non-pharmacological antihypertensive therapy is beneficial for prevention and control of hypertension, but the central mechanisms are unclear. In this study, we hypothesized that chronic exercise training (ExT) delays the progression of hypertension and attenuates cardiac hypertrophy by up-regulating anti-inflammatory cytokines, reducing pro inflammatory cytokines (PICs) and restoring the neurotransmitters balance in the hypothalamic paraventricular nucleus (PVN) in young spontaneously hypertensive rats (SHR). In addition, we also investigated the involvement of nuclear factor kappaB (NF-kappaB) p65 and NAD(P)H oxidase in exercise-induced effects. METHODS AND RESULTS: Moderate-intensity ExT was administrated to young normotensive Wistar-Kyoto (WKY) and SHR rats for 16 weeks. SHR rats had a significant increase in mean arterial pressure and cardiac hypertrophy. SHR rats also had higher levels of glutamate, norepinephrine (NE), phosphorylated IKKbeta, NF-kappaB p65 activity, NAD(P)H oxidase subunit gp91(phox), PICs and the monocyte chemokine protein-1 (MCP-1), and lower levels of gamma-aminobutyric acid (GABA) and interleukin-10 (IL-10) in the PVN. These SHR rats also exhibited higher renal sympathetic nerve activity (RSNA), and higher plasma levels of PICs, and lower plasma IL-10. However, ExT ameliorates all these changes in SHR rats. CONCLUSION: These findings suggest that there are the imbalances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN of SHR rats, which at least partly contributing to sympathoexcitation, hypertension and cardiac hypertrophy; chronic exercise training attenuates hypertension and cardiac hypertrophy by restoring the balances between excitatory and inhibitory neurotransmitters and between pro- and anti-inflammatory cytokines in the PVN; NF-kappaB and oxidative stress in the PVN may be involved in these exercise-induced effects. PMID- 24482681 TI - Heavy metal accumulation by periphyton is related to eutrophication in the Hai River Basin, Northern China. AB - The Hai River Basin (HRB) is one of the most polluted river basins in China. The basin suffers from various types of pollutants including heavy metals and nutrients due to a high population density and rapid economic development in this area. We assessed the relationship between heavy metal accumulation by periphyton playing an important role in fluvial food webs and eutrophication in the HRB. The concentrations of the unicellular diatoms (type A), filamentous algae with diatoms (type B), and filamentous algae (type C) varied along the river, with type A dominating upstream, and types B then C increasing in concentration further downstream, and this was consistent with changes in the trophic status of the river. The mean heavy metal concentrations in the type A, B and C organisms were Cr: 18, 18 and 24 mg/kg, respectively, Ni: 9.2, 10 and 12 mg/kg, respectively, Cu: 8.4, 19 and 29 mg/kg, respectively, and Pb: 11, 9.8 and 7.1 mg/kg respectively. The bioconcentration factors showed that the abilities of the organisms to accumulate Cr, Ni and Pb decreased in the order type A, type B, then type C, but their abilities to accumulate Cu increased in that order. The Ni concentration was a good predictor of Cr, Cu and Pb accumulation by all three periphyton types. Our study shows that heavy metal accumulation by periphyton is associated with eutrophication in the rivers in the HRB. PMID- 24482682 TI - Sequence similarity of Clostridium difficile strains by analysis of conserved genes and genome content is reflected by their ribotype affiliation. AB - PCR-ribotyping is a broadly used method for the classification of isolates of Clostridium difficile, an emerging intestinal pathogen, causing infections with increased disease severity and incidence in several European and North American countries. We have now carried out clustering analysis with selected genes of numerous C. difficile strains as well as gene content comparisons of their genomes in order to broaden our view of the relatedness of strains assigned to different ribotypes. We analyzed the genomic content of 48 C. difficile strains representing 21 different ribotypes. The calculation of distance matrix-based dendrograms using the neighbor joining method for 14 conserved genes (standard phylogenetic marker genes) from the genomes of the C. difficile strains demonstrated that the genes from strains with the same ribotype generally clustered together. Further, certain ribotypes always clustered together and formed ribotype groups, i.e. ribotypes 078, 033 and 126, as well as ribotypes 002 and 017, indicating their relatedness. Comparisons of the gene contents of the genomes of ribotypes that clustered according to the conserved gene analysis revealed that the number of common genes of the ribotypes belonging to each of these three ribotype groups were very similar for the 078/033/126 group (at most 69 specific genes between the different strains with the same ribotype) but less similar for the 002/017 group (86 genes difference). It appears that the ribotype is indicative not only of a specific pattern of the amplified 16S-23S rRNA intergenic spacer but also reflects specific differences in the nucleotide sequences of the conserved genes studied here. It can be anticipated that the sequence deviations of more genes of C. difficile strains are correlated with their PCR-ribotype. In conclusion, the results of this study corroborate and extend the concept of clonal C. difficile lineages, which correlate with ribotypes affiliation. PMID- 24482683 TI - Cognitive and kidney function: results from a British birth cohort reaching retirement age. AB - BACKGROUND: Previous studies have found associations between cognitive function and chronic kidney disease. We aimed to explore possible explanations for this association in the Medical Research Council National Survey of Health and Development, a prospective birth cohort representative of the general British population. METHODS: Cognitive function at age 60-64 years was quantified using five measures (verbal memory, letter search speed and accuracy, simple and choice reaction times) and glomerular filtration rate (eGFR) at the same age was estimated using cystatin C. The cross-sectional association between cognitive function and eGFR was adjusted for background confounding factors (socioeconomic position, educational attainment), prior cognition, and potential explanations for any remaining association (smoking, diabetes, hypertension, inflammation, obesity). RESULTS: Data on all the analysis variables were available for 1306 1320 study members (depending on cognitive measure). Verbal memory and simple and choice reaction times were strongly associated with eGFR. For example, the lowest quartile of verbal memory corresponded to a 4.1 (95% confidence interval 2.0, 6.2) ml/min/1.73 m(2) lower eGFR relative to the highest quartile. Some of this association was explained by confounding due to socioeconomic factors, but very little of it by prior cognition. Smoking, diabetes, hypertension, inflammation and obesity explained some but not all of the remaining association. CONCLUSIONS: These analyses support the notion of a shared pathophysiology of impaired cognitive and kidney function at older age, which precedes clinical disease. The implications of these findings for clinical care and research are important and under-recognised, though further confirmatory studies are required. PMID- 24482685 TI - Effects of 1,25(OH)2D3 in immune response regulation of systemic lupus erithematosus (SLE) patient with hypovitamin D. AB - Vitamin D deficiency has been associated with pathogenesis of autoimmune diseases including SLE; however, there were still lack of data about the effects of administration of vitamin D in immune regulation in SLE patients. The aim of this study was to investigate the effects of calcitriol/1,25(OH)2D3 on dendritic cells maturation and Th17 and Treg cells activation in SLE patients with hypovitamin D. The monocytes and lymphocytes of five SLE patients with hypovitamin D were divided into 4 groups, P0 (0 nM/control), P1 (1 nM), P2 (10 nM), and P3 (100 nM) as cultured samples. Flowcytometry analysis was used to evaluate dendritic cell maturation (the percentage of CD40, CD86, and HLA-DR expression) and the amount of Th17 and Treg cells (the percentage of Th17 and Treg cells). Cytokines production of IL-12, IL-17A, and TGF-beta measured by ELISA. This study showed significant differences in CD40, CD86, HLA-DR expressions, and Th17 percentage in 10 nM of 1,25(OH)2D3 compared to that of control. For cytokines secretion, there was also significant difference between IL-12p70 and IL-17A levels in 10 nM of 1,25(OH)2D3 compared to that of control. The 1,25(OH)2D3 increased Treg cells and TGF-beta level but not significant. Our study concluded that 1,25(OH)2D3 inhibited dendritic cells maturation and Th17 cells activation in SLE patients. The 1,25(OH)2D3 increased Treg cells but not significant. PMID- 24482684 TI - Short-term Mg deficiency upregulates protein kinase C isoforms in cardiovascular tissues and cells; relation to NF-kB, cytokines, ceramide salvage sphingolipid pathway and PKC-zeta: hypothesis and review. AB - Numerous recent,epidemiological studies reveal that Western populations are growing more and more deficient in daily Mg intake which have been linked to etiology of cardiovascular (CV) diseases. A growing body of evidence suggests that a major missing link to this dilemma may reside within the sphingolipid ceramide pathways. For the past 25 years , our labs have been focusing on these pathways in Mg-deficient mammals. The objective of this paper is two-fold: 1) to test various hypotheses and 2) to review the current status of the field and how protein kinase C isoforms may be pivotal to solving some of the CV attributes of Mg deficiency. Below, we test the hypotheses that: 1) short-term dietary deficiency of magnesium (MgD) would result in the upregulation of protein kinase C (PKC) isoforms in left ventricular (LV) and aortic smooth muscle (ASM) and serum; 2) MgD would result in a release of select cytokines and an upregulation of NF-kB in LV and ASM, and in primary cultured aortic smooth muscle cells (PCASMC); 3) MgD would result in an activation of the sphingolipid salvage pathway in LV and ASM, and in PCASMC; 4) MgD would result in a synthesis of sphingosine, but not sphinganine, in PCASMC which could be inhibited by fumonisin B1 (FB) an inhibitor of ceramide synthase (CS), but not scyphostatin an inhibitor of neutral sphingomyelinase (N-SMase); 5) incubation of PCASMC (in low Mg(2+)) with the PKC-mimic PMA would result in release and synthesis of NF-kB, cytokines, and ceramide but not sphingosine. The new data indicate that short-term MgD (10% normal dietary intake) result in an upregulation of all three classes of PKC isoforms in LV, aortic muscle and in serum coupled to the upregulation of ceramide, NF-kB activation, and cytokines. High degrees of linear correlation were found to exist between upregulation of PKC isoforms, p65 and cytokine release, suggesting cross-talk between these molecules and molecular pathways. Our experiments with PCASMCs demonstrated that MgD caused a pronounced synthesis of sphingosine (but not sphinganine), which could be inhibited with fumonisin B1, but not by scyphostatin; use of PMA stimulation released ceramide but not sphingosine suggesting a role for the "sphingolipid salvage pathway" in MgD vascular muscle. Use of different PKC pharmacological inhibitors suggested that although all three classes of PKC molecules, i.e., classical, novel, and atypical, play roles in MgD-induced synthesis/release of ceramide, sphingosine, and cytokines as well as activation of NF-kB, to varying degrees, PKC-zeta appears to play a greater role in these events than any of the other PKC isoforms; a specific PKC-zeta inhibitory peptide inhibited formation of sphingosine. Even low levels of water-borne Mg (e.g., 15 mg/l/day) either prevented or ameliorated the upregulation of all three classes of PKC isoforms. An attempt is made to integrate our new data with previous information in order to possibly explain many of the cardiovascular effects of MgD. PMID- 24482686 TI - MiRNA-107 inhibits proliferation and migration by targeting CDK8 in breast cancer. AB - BACKGROUND: MicroRNAs (miRNAs) are small, non-coding RNAs (18-25 nucleotides) that post-transcriptionally modulate gene expression by negatively regulating the stability or translational efficiency of their target mRNAs. The aim of this study was to investigate the expression pattern of microRNA-107 (miR-107) in human breast cancer, and its potential role in disease pathogenesis. METHODS: Quantitative reverse transcription-polymerase chain reaction (qRT-PCR) was performed to determine the expression level of miR-107 in 30 breast cancer specimens and adjacent normal breast tissues. MTT and colony formation assays, transwell and wound healing test, cell cycle assays were conducted to explore the potential function of miR-107 in human MDA-MB-231 breast cancer cells. Luciferase reporter assays were employed to validate regulation of a putative target of miR 107. The effect of modulating miR-107 on endogenous levels of this target were subsequently confirmed via Western blotting. RESULTS: miR-107 expression was relatively decreased in breast cancer specimens compared with adjacent normal tissues (P<0.01). Overexpression of miR-107 suppressed MDA-MB-231 cell proliferation and migration, meanwhile the cells were arrested at G0/G1 phase. Luciferase assays using a reporter carrying a putative miR-107 target site in the 3', untranslated region (3'-UTR) of CDK8 revealed that miR-107 directly targets CDK8. Overexpression of miR-107 led to downregulation of CDK8 at the mRNA and protein level, as assessed by Western blotting. CONCLUSIONS: miR-107 may play an important role in breast cancer progression, which might negatively regulate the expression of CDK8 and inhibit the proliferation and migration of MDA-MB-231 cell line. PMID- 24482687 TI - Hypoxia induced changes of SePP1 expression in rat preadipocytes and its impact on vascular fibroblasts. AB - Human adipose tissues secret a lot of cytokines involved in physiological and pathological activities. Inflammation around blood vessels is positively related to the severity of atherosclerosis. This study was to investigate the impact of adipokine SePP1 on vascular fibroblasts (VF) under a hypoxia condition might provide new evidence and methods for treatment of atherosclerosis. The mRNA and protein expression of IL-6, MCP-1 and SePP1 were detected in preadipocytes under normoxic (21% O2) and hyperoxic (4% O2) conditions, and the impact of IL-6, MCP-1 and SePP1 on VF was investigated. The preadipocytes were cultured under normoxic and hypoxic conditions. Then, the cell growth, and the mRNA and protein expression of inflammatory cytokines (IL-6, MCP-1 and SePP1) were detected. The VF were cultured in the medium collected from preadipocytes maintained under hypoxic and normoxic conditions, and the phenotypes, migration and type I collagen protein of VF were determined. Results showed that under the hypoxic condition, the proliferation of preadipocytes increased significantly (P<0.05), and the mRNA and protein expression of IL-6 and MCP-1 elevated markedly (P<0.05). However, the SePP1 expression reduced dramatically (P<0.05). After co-culture with VF, the VF transformed into myofibroblasts, accompanied by increased migration and elevated type I collagen expression (P<0.05). Thus, hypoxia may accumulate visceral fat and induce inflammatory state of preadipocytes, with reduced SePP1 expression, which might be involved in the occurrence and development of atherosclerosis. PMID- 24482688 TI - Soft tissue calcified in mandibular angle area observed by means of panoramic radiography. AB - The aim of this research is to determine the prevalence of soft tissue calcifications detectable on panoramic radiographs, in the mandibular angle area. 3,028 digital panoramic radiographs taken between June 2009 and June 2011 were evaluated. Soft tissue calcifications found in the mandibular angle area were recorded according to gender, age and bilaterality. Data were analyzed with the Chi squared test and Fisher's exact test, with alpha< 0.05 being considered statistically significant. The panoramic radiographs analyzed revealed a total of 79 calcifications (2.61%) in 75 individuals, of which 55.7% were women and 44.3% were men. The calcifications found were tonsilloliths (56%), carotid artery calcification (29%), sialoliths (11%), calcified lymph nodes (4%). A statistically significant link was found between being over age 40 with tonsilloliths (p<0.001) and calcifications of the carotid artery (p<0.001). In terms of gender, men had a higher likelihood of tonsilloliths (p=0.007). Conclusions There is a low prevalence of soft tissue calcifications detectable on panoramic radiographs, which increases with age. PMID- 24482689 TI - Effect of epigallocatechin gallate on ischemia-reperfusion injury: an experimental study in a rat epigastric island flap. AB - Epigallocatechin gallate (EGCG), a polyphenol derived from green tea, is known to have potent antioxidant and anti-inflammatory properties. The aim of this study was to investigate the protective effects of EGCG against ischemia reperfusion injury in the epigastric artery island flap model in rats. The experiment was designed with two groups (control n=40, experiment n=40) of rats with epigastric artery island flaps. Each main group was randomly divided into five sub-groups to apply ischemia at different time intervals (0, 3, 6, 9 and 12 hours). Thirty minutes prior to reperfusion, 100 MUmol/kg of EGCG was injected intraperitoneally, and this injection was repeated after 12 hours and continued as a daily injection. Similarly, 2 ml of sterile saline was administered to the rats in the control groups. Superoxide dismutase, glutathione peroxidase, malondialdehyde and tumor necrosis factor alpha levels, together with neutrophil counts, were measured in the tissues taken from the distal portions of the flaps 24 hours after reperfusion. Additionally, flap necrosis was examined on the seventh day after reperfusion. Superoxide dismutase levels were significantly lower in all control groups, and Malondialdehyde and Tumor Necrosis Factor Alpha levels were significantly higher in all control groups. Glutathione peroxidase levels were found to be significantly lower in the control groups after 0, 3, 9 and 12 hours of ischemia. There was no statistically significant difference between the groups undergoing 0, 3, 9 or 12 hours of ischemia with regard to the neutrophil count. Partial flap necrosis occurred in the 9-hour ischemia groups, and significantly lower rates of necrosis were observed in the experimental groups compared to the control groups. The findings of our study showed that EGCG has a protective effect against ischemia-reperfusion injury in skin flaps in the epigastric island flap model. PMID- 24482690 TI - CRMP-5 interacts with tubulin to promote growth cone development in neurons. AB - Collapsin response mediator proteins (CRMPs) have been reported to control axonal guidance during neuronal development and degeneration. Among these proteins, CRMP 5 has been indicated to play an important role in growth cone development. However, the mechanisms underlying the linkage between growth cone development and the cytoskeleton remain to be elucidated. Here, we report that CRMP-5 interacts with tubulin to mediate growth cone development in cultured hippocampal neurons. We found that CRMP-5 physically interacted with tubulin in the growth cones of developing neurons. CRMP-5 colocalized with tubulin in lamellipodia in HEK293 cells and in the growth cones of cultured hippocampal neurons. Genetic silencing of CRMP-5 using RNA interference led to abnormal growth cone morphology in neurons. Overexpression of CRMP-5 led to significantly increased filopodial formation and enlarged growth cones. These results suggest that CRMP-5 interacts with tubulin to regulate growth cone dynamics, thus complying with the restrictive intracellular guidance cues. PMID- 24482691 TI - Stability of tibial defect reconstruction with fibular graft and unilateral external fixation: a finite element study. AB - Tibial defect is generally caused by high-energy injury, tumor, osteomyelitis, development deformity and bone non-union after internal fixation. This study was to determine stability of tibial defect reconstruction with fibular graft (FG) of different lengths by single free vascularized fibular graft (SFVFG) and double barrel free vascularized fibular graft (DBFVFG). The left lower extremity of a male volunteer was scanned with computer tomography scanner. The contours of the tibia and fibula were extracted and the geometry of both bones rebuilt. From this intact model, the models of tibial defect reconstruction with fibular graft and external fixation were developed. Inter-fragmentary motion (IFM) and Von Mises stress on the fibular bone flap, and the locations of maximum Von Mises stress were introduced to quantify the biomechanical environment. Under the condition of the same graft length, the Von Mises stress value in DBFVFG group was 1.37 to 1.77 times higher than that in SFVFG group. When the length of graft was greater than 15 cm in the SFVFG group, the IFM exceeded 1 mm, but the IFM of the graft in the DBFVFG group was always less than 1 mm. The maximum Von Mises stress of models was frequently located at the second or third pin-bone interface. Thus, external fixation can provide a stable biomechanical environment for the reconstruction of tibial defect by both SFVFG and DBFVFG. The second or third pin bone interface requires intensive care and that in the reconstruction of tibial defect by SFVFG, the graft length should not exceed 15 cm. PMID- 24482692 TI - ICAM-1 +469 A/G polymorphism and cancer risk: a meta-analysis involving 9375 subjects. AB - BACKGROUND: The ICAM-1 +469 A/G polymorphism has been implicated in susceptibility to cancer, but the results were inconclusive. The present meta analysis aimed to investigate the association between the ICAM-1 +469 A/G polymorphism and cancer risk. METHODS: We searched PubMed, Embase to identify studies that evaluated the association between the ICAM-1 +469 A/G polymorphism and cancer risk. Data were extracted and statistical analysis was performed by using the software Revman 5.1 and STATA 12.0. RESULTS: A total of 14 studies involving 9375 subjects were included. The results suggested that ICAM-1 +469 A/G polymorphism had no associated with cancer risk (OR=0.91, 95% CI: 0.76-1.08, P=0.27 for GG+AG vs. AA). Subgroup analysis by cancer type indicated the there was no associated between this polymorphism and breast cancer (OR=0.91, 95% CI: 0.72-1.15, P=0.43 for GG+AG vs. AA), but it was associated with decreased risk of colorectal cancer (OR=0.59, 95% CI: 0.41-0.85, P=0.005 for GG+AG vs. AA). Subgroup analysis by ethnicity revealed a decreased risk of cancer among Caucasians (OR=0.88, 95% CI: 0.78-0.99, P=0.03 for GG+AG vs. AA) CONCLUSION: The evidence from current meta-analysis doesn't support the ICAM-1 +469 A/G polymorphism as a risk factor for cancer. Further studies are needed to validate these findings. PMID- 24482693 TI - Diagnostic accuracy of interferon gamma-induced protein 10 for tuberculosis: a meta-analysis. AB - The diagnostic accuracy of tuberculosis (TB) remains a clinical challenge, and a number of studies have used the interferon gamma-induced protein 10 (IP-10) in the diagnosis of TB. The aim of the present meta-analysis was to determine the overall accuracy of IP-10 in the diagnosis of TB. A systematic review of studies published in English from Medline, Embase and Cochrane Library was conducted and the data concerning the accuracy of IP-10 in the diagnosis of TB were pooled. The methodological quality of each study was assessed by QUADAS (quality assessment for studies of diagnostic accuracy). Statistical analysis was performed by employing Meta-Disc 1.4 soft-ware and STATA. The overall test performance was summarized using receiver operating characteristic curves. 14 studies, based on 2075 subjects, met the inclusion criteria. The summary estimates for IP-10 in the diagnosis of TB were: sensitivity 0.73 (95% CI, 0.71-0.76), specificity 0.83 (95% CI, 0.81-0.86), positive likelihood ratio 7.08 (95% CI, 3.94-12.72), negative likelihood ratio 0.26 (95% CI, 0.20-0.35) and diagnostic odds ratio 29.50 (95% CI, 14.43-60.30), and the area under the curve was 0.88. Our findings suggest that IP-10 may improve the accuracy of TB diagnosis, while the results of IP-10 assays should be interpreted in parallel with conventional test results and other clinical findings. PMID- 24482694 TI - Prevention and treatment of recurrent laryngeal nerve injury in thyroid surgery. AB - AIM: To summary the experience for prevention and treatment of recurrent laryngeal nerve (RLN) injury in thyroid surgery. METHODS: Clinical features of 623 patients who received thyroid surgery from January 2010 to December 2012 were analyzed retrospectively, and the features of RLN injury and intraoperative as well as postoperative treatments were reviewed. RESULTS: RLN injury occurred in 31 patients (4.98%), in which, unilateral RLN injury occurred in 27 patients and bilateral RLN injuries occurred in 4 patients (temporary injury in 28 patients and permanent injury in 3 patients). 6 patients underwent RLN anastomosis during surgery and exhibited transient hoarseness after surgery. RLN exploration and decompression was given in 1 patient and the patient got normal vocal cord motion 2 months after surgery. 1 patient with bilateral injuries received tracheotomy and CO2 laser resection of arytenoid cartilage and achieved recovery 1 year later. CONCLUSIONS: In order to prevent RLN injury, the anatomic variations of RLN should be mastered. Routine exposure of RLN can effectively prevent the injury in patients receiving the second or multiple surgeries. Early interventions for RLN injury include mainly early discovery, early exploration and early anastomosis, and the function of RLN in some patients can recover completely. Subsequent treatments mainly focus on the improvement of the voice, expansion of glottis and melioration of dyspnea. PMID- 24482695 TI - Curcumin treatment alters ERK-1/2 signaling in vitro and inhibits nasopharyngeal carcinoma proliferation in mouse xenografts. AB - Curcumin, a plant phenol, has been used for centuries in traditional medicines for its anti-inflammatory and anti-neoplastic properties. The compound is believed to act on a range of proteins involved in cell cycle regulation. In this study, the effect of curcumin on ERK-1/2 pathway protein expression and on proliferation of nasopharyngeal carcinoma cells was investigated. CNE-2Z nasopharyngeal carcinoma cells were cultured with 10, 20, 40, or 80 MUM curcumin for 24 h before proliferation was assessed by MTT colorimetry. Cell proliferation was increasingly inhibited as the concentration of curcumin increased (P<0.005). Additionally, Western blotting revealed that expression of p-ERK-1/2, MMP-9, and TIMP-1 was altered following curcumin treatment, also in a dose-dependent manner. Expression of p-ERK-1/2 and MMP-9 decreased, while expression of TIMP-1 increased (P<0.05). Finally, CNE-2Z cells were xenografted under the skin of 18 nude mice. Mice were treated with vehicle only (control), 24 mg/kg curcumin (low-dose group), or 50 mg/kg curcumin (high-dose group) every other day for 40 days beginning 24 h after xenografting. Compared to tumors from the control group, the volume and weight of xenograft tumors was significantly lower in both curcumin groups, with a higher magnitude of difference in the high-dose curcumin group (P<0.05). These results indicate that curcumin treatment can inhibit proliferation of nasopharyngeal carcinoma cells and alter expression of proteins in the ERK-1/2 signaling pathway. Therefore, curcumin warrants further investigation as a potential treatment for nasopharyngeal cancer. PMID- 24482696 TI - Diagnostic performance of lung ultrasound in the diagnosis of pneumonia: a bivariate meta-analysis. AB - BACKGROUND AND OBJECTIVE: Pneumonia is a common disease with both high morbidity and mortality, the diagnosis of pneumonia remains a clinical challenge. Many studies have been conducted to identify the usefulness of lung ultrasound for the diagnosis of pneumonia, but with inconsistent and inconclusive results. The present study aimed to establish the overall diagnostic accuracy of lung ultrasound in diagnosing pneumonia. METHODS: Based on a comprehensive search of the Pubmed, Embase, and the Cochrane database, we identified out-come data from all articles estimating diagnostic accuracy with lung ultrasound for pneumonia. Quality was assessed with the Quality Assessment for Diagnostic Accuracy Studies. Results from different studies were pooled using a bivariate meta-analysis. Summary receiver operating characteristic curve was used to assess the overall performance of lung ultrasound-based assays. RESULTS: Nine studies containing 1080 subjects were included in this meta-analysis. The summary estimates for lung ultrasound in the diagnosis of pneumonia in the studies included were as follows: sensitivity, 0.97 (95% CI: 0.93-0.99); specificity, 0.94 (95% CI: 0.85-0.98); DOR, 507.99 (95% CI: 128.11-2014.34); positive likelihood ratio, 15.62 (95% CI: 6.31-38.68); negative likelihood ratio, 0.03 (95% CI: 0.01-0.08); The area under the summary receiver operating characteristic curve was 0.99 (95% CI: 0.98-1.00). CONCLUSION: Lung ultrasound is a capable of diagnosing pneumonia with high accuracy and is a promising attractive alternative to chest radiography and thoracic CT scan. PMID- 24482697 TI - A new surgery for recurrent or persist stress urinary incontinence in females after primary mid-urethral slings. AB - OBJECTIVE: To retrospectively evaluate the efficacy of a new complementary mid urethral sling surgery (Tong's hammock anterior, THA) in treatment of recurrent or persist stress urinary incontinence (SUI) in females after primary synthetic mid-urethral slings (MUSs). METHODS: THA was performed in 27 females with recurrent or persist SUI after primary MUSs from June 2005 and July 2010. These patients were followed up for one year, and clinical data including main complaints, operation duration, blood loss, efficacy and complications were reviewed. RESULTS: All 27 SUI patients were treated with THA surgery, a trans vaginal mid-urethral sling on the descending pubic ramus. The average operation time was 39 min (range: 25-70 min), average blood loss was 70 ml (range: 20-120 ml). After urinary catheter removal, all patients could micturate and their average residual urine was 25.2 ml (range: 0-80 ml). The average hospital stay was 4.7 days (rage: 3-7 days). SUI symptom was persistent in 2 patients after THA surgery and the effective rate reached 92.5%. At 3 months, 6 months and 1 year after surgery, the effective rate was 92.5% (25/27), 92% (23/25) and 87.5% (21/24), respectively. 6 months after THA surgery, 2 were lost to follow up; 1 had recurrent SUI at 1 year and 1 had mesh erosion, 1 died of other diseases, and operative complications were absent after surgery. CONCLUSIONS: THA surgery is an effective method for treating recurrent or persistent SUI after primary MUSs. It is cheap, efficient, and easy to handle. PMID- 24482698 TI - Salivary sIg-A response against the recombinant Ag38 antigen of Mycobacterium tuberculosis Indonesian strain. AB - An evaluation of the humoral response based on secretory immunoglobulin A levels in the saliva of pulmonary tuberculosis (TB) acid-fast bacillus-positive (TB AFB+) patients against a recombinant 38 kDa antigen (Ag38-rec) is reported. A total of 60 saliva samples consist of 30 TB-AFB+ patients and 30 healthy controls were tested against 500 ng of semi-purified antigen using the dot blot method. Results showed that the protein antigen could differentiate between healthy individuals and TB-AFB(+) patients. Whole saliva demonstrated better reactivity than centrifuged saliva. The Ag38-rec protein indicated statistically comparable sensitivity (80% versus 90%), but lower specificity (36.6% versus 70%) compared with purified protein derivative (PPD). Surprisingly, both antigens similarly recognized secretory immunoglobulin A in the saliva of the healthy group (50% versus 50%, respectively). These findings suggest that the Ag38-rec protein originating from a local strain of Mycobacterium tuberculosis may be used for TB screening, however require purity improvement. PMID- 24482699 TI - Serum microRNA-499 and microRNA-208a as biomarkers of acute myocardial infarction. AB - OBJECTIVE: Acute myocardial infarction (AMI) is a most serious cardiovascular disease with high morbidity and mortality. Novel biomarkers for AMI are explored continuous. MicroRNAs (miRNAs, miRs) are present in the circulation in a consistent, stable, and reproducible manner, attracting major interest of using circulating miRNAs as biomarkers. In plasma, miR-208a and miR-499 are considered to be the best candidate for AMI diagnosis. However, serum has slightly higher miRNA yields compared to plasma and the majority of archived samples are stored in form of serum, marking interesting to determine whether miR-208a and miR-499 in serum can be used as biomarkers for AMI. METHODS: AMI was induced by coronary ligation and the serum and heart tissues were collected. The levels of miR-208a and miR-499 in serum and heart tissues were determined using TaqMan-based miRNA quantitative real-time polymerase chain reactions (qRT-PCRs). RESULTS: Serum miR 208a was increased by 36-fold and 51-fold while miR-499 was elevated by 103-fold and 95-fold at 4 h and 24 h after AMI. Moreover, the expression level of miR-499 was significantly decreased in the myocardial infarct zone comparing to the remote zone or the sham group while miR-208a remained unchanged. CONCLUSION: Serum miR-499 and miR-208a might be potential biomarkers for AMI. miR-499 might be released from damaged heart to the circulation. PMID- 24482700 TI - Alternative option in patients with multisegmental left anterior descending coronary artery disease for providing complete myocardial revascularization. AB - OBJECTIVES: The basic aim of surgical interventions in patients with coronary artery disease is to complete myocardial revascularization. In such patients, however, complementary revascularization techniques may require in patients with multisegmental left anterior descending disease. Among the different procedures, we performed an alternative option in patients with multisegmental lad disease for providing complete myocardial revascularization. METHODS: This study consists of retrospective analysis of consecutive eight patients between january 2008 and august 2013. In all patients, the surgical procedure consisted of standard aortic and right atrial cannulations followed by coronary artery bypass grafting with cardiopulmonary bypass. At the lesions of non-lad vessels distal anastomoses were performed with saphenous vein graft. After that lad arteriotomies were performed at the proximal and the distal segment of coronary stenosis, and a bridge was formed with a short segment valveless svg. The left internal mammary artery was anastomosed on the bridge. RESULTS: This innovative technique was performed successfully in all the patients. There were no morbidity and in-hospital mortality. At follow-up 1 year control, all the patients have no complications. In 2 patients, control angiogram showed a patent lima to a bridge anastomosis. CONCLUSIONS: Although our series has a small group population, we advocate that this is a safe, easy, and efficient technique for providing complete revascularization in multisegmental lad disease. This technique could be performed with the good result and easy implementation. It perfuses both the proximal and the distal segments of the multisegmental lad stenoses. PMID- 24482701 TI - A single CT for attenuation correction of both rest and stress SPECT myocardial perfusion imaging: a retrospective feasibility study. AB - PURPOSE: In the effort to reduce radiation exposure to patients undergoing myocardial perfusion imaging (MPI) with SPECT/CT, we evaluate the feasibility of a single CT for attenuation correction (AC) of single-day rest (R)/stress (S) perfusion. METHODS: Processing of 20 single isotope and 20 dual isotope MPI with perfusion defects were retrospectively repeated in three steps: (1) the standard method using a concurrent R-CT for AC of R-SPECT and S-CT for S-SPECT; (2) the standard method repeated; and (3) with the R-CT used for AC of S-SPECT, and the S CT used for AC of R-SPECT. Intra-Class Correlation Coefficients (ICC) and Choen's kappa were used to measure intra-operator variability in sum scoring. RESULTS: The highest level of intra-operator reliability was seen with the reproduction of the sum rest score (SRS) and sum stress score (SSS) (ICC > 95%). ICCs were > 85% for SRS and SSS when alternate CTs were used for AC, but when sum difference scores were calculated, ICC values were much lower (~22% to 27%), which may imply that neither CT substitution resulted in a reproducible difference score. Similar results were seen when evaluating dichotomous outcomes (sum scores difference of >= 4) when comparing different processing techniques (kappas ~0.32 to 0.43). CONCLUSIONS: When a single CT is used for AC of both rest and stress SPECT, there is disproportionately high variability in sum scoring that is independent of user error. This information can be used to direct further investigation in radiation reduction for common imaging exams in nuclear medicine. PMID- 24482702 TI - ERK/CANP rapid signaling mediates 17beta-estradiol-induced proliferation of human breast cancer cell line MCF-7 cells. AB - OBJECTIVE: 17beta-estradiol (E2) exerts its functions through both genomic and non-genomic signaling pathways. Because E2 is important in breast cancer development, we investigated whether its actions in promoting breast cancer cell proliferation occur through the non-genomic signaling pathway via extracellular signal-regulated kinase 1/2 (ERK1/2)/calcium-activated neutral protease (CANP). METHODS: MCF-7 breast cancer cells were treated with ERKl/2 inhibitor (PD98059) or CANP inhibitor (calpeptin) before exposure to 1*10(-8) M E2. MTT colorimetry and flow cytometry were used to analyze effects on cell proliferation and cell cycle progression, respectively. Expression of phosphorylated-ERK (p-ERK), total ERK, and Capn4 proteins were assessed by Western blotting. RESULTS: Cell proliferation increased in cells treated with E2 for 24 h (P<0.05), and the proportion of cells in G0/G1 was decreased, accompanied by accelerated G1/S. Calpeptin pre-treatment significantly inhibited the E2-induced proliferation of MCF-7 cells (P<0.05), while also ameliorating the effects of E2 on cell cycle progression. Further, expression of p-ERK was rapidly up-regulated (after 10 min) by E2 (P<0.05), an effect that persisted 16 h after E2 exposure but which was significantly inhibited by PD98059 (P<0.05). CONCLUSIONS: Finally, expression of Capn4 protein was rapidly up-regulated in E2-exposed cells (P<0.05), but this change was significantly inhibited by PD98059 or calpeptin (P<0.05) pre treatment. Thus, the rapid, non-genomic ERK/CANP signaling pathway mediates E2 induced proliferation of human breast cancer cells. PMID- 24482703 TI - Impact and clinical significance of pedicle length on spinal canal and intervertebral foramen area. AB - The aim of this study was to measure changes in the cross-sectional area of the spinal canal and the area of the intervertebral foramen for each pedicle segment before and after the pedicle extension using computer-simulated transpedicular osteotomy to provide a theoretical basis for clinical decompression in the lumbar spinal canal. Using spiral CT scanning of the original lumbar spine, a finite element model was established. The pedicle was cut and extended by 2 mm, 4 mm, 6 mm, and 8 mm for respective modeling. The changes in the area of each plane of the vertebral canal and the area of the intervertebral foramen were measured. With the gradual extension of the pedicle, the areas of the spinal canal and intervertebral foramen also significantly increased compared with those of the original lumbar spine (P<0.05). The extension of the pedicle using transpedicular osteotomy can significantly increase the cross-sectional area of the lumbar canal and the area of the intervertebral foramen. This finding provides a new theoretically practicable method for the clinical decompression of the lumbar spinal canal. PMID- 24482704 TI - Our experience of 200 patients: usage and maintenance of long-term oxygen therapy and non-invasive ventilation devices at home. AB - OBJECTIVE: To evaluate the patients' attitudes about the devices, of which they use for long-term respiratory support at home. METHOD: 200 consecutive patients were questioned about the treatment and devices of respiratory support at home by face to face questionnaire. Their records were taken from the archives of Social Security Agency. RESULTS: 123 (61.5%) of the patients were men and 77 (38.5%) were women. The mean age was 65.8 +/- 11.9 (15-92) years. The most frequently prescribed device was oxygen concentrator and BIPAP was the one that follows. The most common indications were hypoxic and hypercapnic respiratory failure due to COPD. The devices were prescribed by the state university hospitals, most commonly. The average daily oxygen usage duration was 16.3 +/- 3.1 hours, the average duration was 7.4 +/- 3.1 hours, for BIPAP. Twenty one (11.4%) of the patients, who were treated with LTOT, stated that they were taking oxygen less than 15 hours a day. Higher education levels of the patients was correlated with the higher rates of visiting the companies - that they bought the devices- both for information about and control of the devices (p=0.002). The rate of visiting companies/firms was significantly higher in patients, who use BIPAP and respiratory support combined with it (p=0.010). Twenty three (47.9%) of the 48 patients, who notified that their devices were impaired, waited for repairment by the firm, 20 (41.6%) investigated special repair facilities and the rest (10.5%) rented a new device. CONCLUSION: Effective and continuous technical maintenance support must be provided to the patients, who are treated with long-term respiratory support at home. PMID- 24482705 TI - Using focus groups to design a psychoeducation program for patients with schizophrenia and their family members. AB - The purpose of this project was to determine what factors to be considered in planning a psychoeducation program to better meet the needs of patients with schizophrenia and their family members. METHODS: Three focus group sessions were conducted and recorded, transcribed, and analyzed by members of the research team. RESULTS: Patients hoped to grasp the fullest possible knowledge about schizophrenia, whereas the factors influencing the efficacy of the schizophrenia health education curriculum included: discrimination, non-understanding of family members, easy to forget, unreasonable timetable. Health education was mainly in the form of classroom teaching. CONCLUSIONS: 1. At present, there are a few psychiatric education courses in China; 2. Patients and their family members are eager to acquire knowledge about the contents of schizophrenia; 3. Misconceptions would hinder the rehabilitation of patients; 4. Worry about being discriminated; 5. There is a different knowledge demand between the patients and their family members. PMID- 24482706 TI - Expression of E6, p53 and p21 proteins and physical state of HPV16 in cervical cytologies with and without low grade lesions. AB - The aim of this study was to determine the correlation between expression of HPV16 E6, p53 and p21 proteins and the physical state of HPV16 in cervical cytologies without squamous intraepithelial lesions (Non-SIL) and with low grade squamous intraepithelial lesions (LSIL), both with HPV16 infection. 101 liquid based cytological samples were analyzed. 50 samples were without squamous intraepithelial lesions (Non-IL) and 51 samples of low grade squamous intraepithelial lesions (LSIL), both with HPV16 infection. HPV16 infection was determined by PCR-RFLP, and the physical state of HPV16 by in situ hybridization with tyramide-amplification. The expression of E6, p53 and p21 proteins was evaluated by immunocytochemistry. The expression of HPV16 E6 protein was significantly higher in LSIL that in Non-SIL samples (p=0.006). We found a significant correlation between E6 expression and the physical state of HPV16 in Non-SIL (p=0.049). Our results suggest that high expression of E6 in LSIL is an early event of cervical carcinogenesis and perhaps can be used as an early marker. PMID- 24482707 TI - Epicardial adipose tissue thickness is increased in patients with cardiac syndrome X. AB - BACKGROUND: Cardiac syndrome X (CSX) is defined as normal coronary arteries with angina pectoris and a positive stress test. Epicardial adipose tissue (EAT) plays an important role in inflammatory process in cardiovascular system, therefore EAT may affect the pathogenesis of different cardiovascular disease. The aim of this study was to investigate the EAT thickness in patients with CSX and compare normal subjects. METHODS: We prospectively enrolled 30 consecutive patients with CSX. The control group consisted of 30 age and sex-matched individuals with anginal chest pain and a negative treadmill or myocardial perfusion scan test. EAT thickness was measured by transthoracic echocardiography. RESULTS: There were no differences in baseline clinical, biochemical and echocardiographic characteristics between CSX patients and the control group. Patients with CSX had significantly increased EAT thickness than those of the controls (3.43 +/- 0.88 vs. 2.34 +/- 0.89 mm, p=0.0001). CONCLUSION: We found that EAT thickness is increased in patients with CSX. This finding suggests that EAT may contribute to the etiopathogenesis of the CSX. PMID- 24482709 TI - Preoperative usages of levosimendan in patients undergoing coronary artery bypass grafting. AB - OBJECTIVES: Levosimendan (LS) is a new inotropic drug which belongs to the group of drugs known as calcium sensitizers. It is different from other inotropic agents by its inotropic and vasodilatory actions without an increase in myocardial oxygen consumption and considered as a good choice in high-risk patients undergoing cardiac surgery. We aimed to investigate the proper time of the administration and the effect of prophylactic usage of LS in patients with low left ventricular ejection fraction (LVEF) undergoing coronary artery bypass grafting (CABG). METHODS: Forty patients who underwent isolated CABG with LVEF) less than 30% were evaluated retrospectively. Patients were divided into 3 groups according to the induction time of LS during different phases of the operation and compared to a non-LS control group. LS infusion (0.2 MUg/kg/min) was applied 12 hours before the operation in Group 1 (G1) (n=10), after the induction of anaesthesia in Group 2 (G2) (n=10) and during the pump removal period in Group 3 (G3) (n=10) and non-LS control group 4 (G4) (n=10). Demographic data, operative characteristics, hemodynamic parameters and serum lactate, troponin, creatinine levels were compared between groups before and after LS treatment during pre and postoperative period. Data were evaluated by Fisher exact, Kruskal-Wallis, Mann Whitney U, Chi-square and Wilcoxon rank tests. RESULTS: We found that the duration of tracheal intubation, the intensive care unit stay and the hospital stay were significantly decreased in G1 and G2 when compared to the patients in G3 and G4. During postoperative period, in G1 and G2 one (10%) patient from each required intraaortic balloon pump (IABP), while in G3 two (20%) patients and in G4 five (50%) patients required IABP. Cardiac index (CI) was significantly increased in all groups from baseline to intensive care unit (ICU)1h and ICU24h. When groups compared each other significant increase was found in G1-G4 (p=0.001) and G2-G4 (p=0.007) at ICU1h. There was a significant increase in % EF especially in G1-G4 (p=0.011) and G2-G4 (p=0.007) at ICU1h. Systemic vascular resistance index significantly decreased in G1 and G2 in comparison to G3 and G4. However there was no significant decrease in pulmonary capillary wedge pressure of all 4 groups before and after LS. There was a significant decrease in mean pulmonary arterial pressure in G1 and G2 according to G4. Compared with the other groups preoperatively LS-treated patients (G1 and G2) had lower postoperative troponin I, serum lactate and creatinine concentrations. CONCLUSIONS: Our study shows that the elective preoperative initiation of LS especially 12 hours before the operation onset is associated with better improvement on cardiac functions as well as with lower mortality and complication rates, lower use of additional inotropic and vasopressor drugs, less need for intra-aortic balloon pump support and shorter length of stay in the ICU in patients with high perioperative risk or compromised left ventricular function. As a result, patients who received an infusion of LS 12 hours before surgery showed an evidence of less myocardial damage which suggested the preconditioning effect of the drug. PMID- 24482710 TI - Monitoring of peri-distal gastrectomy carbohydrate antigen 19-9 level in gastric juice and its significance. AB - Gastric carcinoma is one of the most common and deadly malignancies nowadays, and carbohydrate antigen 19-9 (CA 19-9) in gastric juice has been rarely studied. To compare peri-distal gastrectomy (DG) gastric juice and serum CA 19-9 and reveal its significance, we selected 67 patients diagnosed with gastric carcinoma who underwent DG, and collected their perioperative gastric juice whose CA 19-9 was detected, with serum CA 19-9 monitored as a comparison. We found that: gastric juice CA 19-9 pre-gastrectomy was significantly correlated with tumor TNM classification, regarding tumor size, level of gastric wall invaded, differentiated grade and number of metastatic lymph nodes as influencing factors, while serum CA 19-9 revealed little information; gastric juice CA 19-9 was significantly correlated with radical degree, and regarded number of resected lymph nodes and classification of cutting edge as impact factors; thirteen patients whose gastric juice CA 19-9 rose post-DG showed features indicating poor prognosis; the difference of gastric juice CA 19-9 between pre- and post gastrectomy was correlated with tumor TNM classification and radical degree, and regarded tumor size, number of resected metastatic and normal lymph nodes, sum of distances from tumor to cutting edges and classification of cutting edge as influential factors. We conclude that peri-DG gastric juice CA 19-9 reveals much information about tumor and radical gastrectomy, and may indicate prognosis; while serum CA 19-9 has limited significance. PMID- 24482711 TI - Ultrasound-guided vacuum-assisted breast biopsy using Mammotome biopsy system for detection of breast cancer: results from two high volume hospitals. AB - Ultrasound-guided vacuum-assisted breast biopsy (VABB) has been recently regarded as a feasible, effective, minimally invasive and safe method for removal of benign breast lesions without serious complications. The frequency of detection of noninvasive malignant breast lesions by ultrasound-guided VABB is increasing. The aim of this study was to evaluate the role of the ultrasound-guided VABB using Mammotome biopsy system in the early detection of breast cancer. Retrospective review between January 2008 to March 2013 the First Affiliated Hospital, Zhejiang University School of Medicine and Taizhou Hospital, Wenzhou Medical College. From January 2008 to March 2013, a total of 5232 ultrasound guided VABB procedures were performed in 3985 patients whose mean ages were 36.3 years (range: 16-73). The histological results of 5232 ultrasound-guided VABB were retrospectively reviewed. Ultrasonography follow-up was performed at 3 to 6 month intervals in order to assess recurrence. Two hundred twenty three high risk lesions (comprising 59 papilloma, 57 papillomatosis, and 107 atypical hyperplasia) and 61 malignant lesions (comprising 23 ductal carcinoma in situ, 21 lobular carcinoma in situ, 12 infiltrating ductal carcinoma, and 5 infiltrating mucinous carcinoma) were identified. Sensitivity (100%) and diagnostic accuracy (100%) regarding the detection of malignancy were excellent for ultrasound-guided VABB using Mammotome biopsy system. Our results indicate that ultrasound-guided VABB using Mammotome biopsy system is an accurate technique for the sampling, diagnosis, and early detection of breast cancer. It is recommended that the Mammotome biopsy system could be as the method of choice for detecting nonpalpable early breast cancer. PMID- 24482712 TI - Association of LRP5 gene polymorphism with type 2 diabetes mellitus and osteoporosis in postmenopausal women. AB - This study was to explore the association of low-density lipoprotein receptor related protein 5 (LRP5) gene polymorphism with bone mineral density (BMD), bone turnover markers and glycometabolism in postmenopausal women with type 2 diabetes mellitus (T2DM) and/or osteoporosis (OP) in Shanghai. 354 unrelated Han Chinese post-menopausal women were recruited from Shanghai and divided into 4 groups: OP group (n=90), T2DM group (n=96), T2DM + OP group (n=90) and control group (n=78). The LRP5 genotypes were determined by DNA sequencing. The BMD was measured by dual-energy X-ray absorptiometry. The bone transformation indicators and glycometabolism index (HbA1c and Fasting insulin) were also detected. The association of LRP5 polymorphism with BMD, bone turnover markers and glycometabolism was evaluated. Result showed that, In OP group, the BMD of L2-4 was higher in patients with rs3736228 CC genotype than those with CT/TT genotypes (P<0.05). After adjustment for age, body mass index (BMI) and years of menopause, A1330V polymorphism was still associated with BMD of L2-4 (P<0.01). In the control group, HbA1c was significantly higher in patients with A1330V CC genotype than those with CT/TT genotypes (P<0.05), but no significant difference was found after adjustment for BMI, age and years of menopause (P>0.05). Thus, LRP5 gene is an impressionable gene in postmenopausal women with OP in Shanghai. T2DM patients have a high BMD when compared with controls, which may be related to BMI and FINS. LRP5 genotype is not an impressionable gene in postmenopausal women with T2DM in Shanghai. PMID- 24482713 TI - Effect of steroid and cyclosporine in membranous nephropathy that is resistant to steroid and/or cytotoxic treatment. AB - Membranous Nephropathy (MN) is a glomerular disease characterized by proteinuria. The etiology is unknown in many cases, while in some patients MN may be secondary to infection, to other diseases, or to exposure to drugs and toxic substances. The prognosis of the disease is variable, 1/3 of patients can have spontaneous remission; patients with nephrotic proteinuria, those with advanced tubulointerstitial changes and those with increased serum creatinine at presentation have a poorer prognosis. Although MN is one of the most common causes of adult-onset Nephrotic Syndrome (NS), its management is still controversial. Corticosteroids have been used for many years as the basic treatment, though with controversial results. Controversial results have been obtained with cytotoxic agents. Cyclosporine has been shown to be effective in the treatment of this disease. We have evaluated the results of 23 patients (14 males, 9 females aged between 26-53) diagnosed with Idiopathic MN (IMN) who have received cyclosporine because of the relapse or persistence after steroid and/or cytotoxic treatment. At the end of a 12-month follow-up, 8 patients had (34.8%) complete remission, 8 (34.8%) had partial remission, 2 (8.7%) had persistent proteinuria and 5 patients (21.7%) had no response to the treatment. There was a significant decrease in proteinuria throughout the study. There was no significant difference in total protein, albumin and creatinine levels between before and after the treatment. Our results indicate that patients with MN who do not respond well or have-relapse after steroid and/or cytotoxic therapy, should be offered cyclosporine. We think that in the future; long-term studies which are prospective and randomized with an extensive number of patients will be effective on the treatment of MN. PMID- 24482708 TI - Right-sided infective endocarditis: recent epidemiologic changes. AB - BACKGROUND: Infective endocarditis (IE) has been increasingly reported, however, little is available regarding recent development of right-sided IE. METHODS: Right-sided IE was comprehensively analyzed based on recent 51/3-year literature. RESULTS: Portal of entry, implanted foreign material, and repaired congenital heart defects were the main predisposing risk factors. Vegetation size on the right-sided valves was much smaller than those beyond the valves. Multiple logistic regression analysis revealed that predisposing risk factors, and vegetation size and locations were independent predictive risks of patients' survival. CONCLUSIONS: Changes of right-sided IE in the past 51/3 years included younger patient age, and increased vegetation size, but still prominent Staphylococcus aureus infections. Complication spectrum has changed into more valve insufficiency, more embolic events, reduced abscess formation, and considerably decreased valve perforations. With effective antibiotic regimens, prognoses of the patients seemed to be better than before. PMID- 24482714 TI - Therapeutic effect of transplanting bone mesenchymal stem cells on the hind limbs' motor function of rats with acute spinal cord injury. AB - PURPOSE: To research the therapeutic effect of the allograft of bone mesenchymal stem cells (BMSCs) on hind limbs' motor function of rats that underwent acute injury to their spinal nerve. DESIGN: 40 Wistar rat samples with the acute injury to the spinal cord were established and divided into the transplantation group and the control group, 20 for each group; One week after injury, BMSCs were slowly injected into the center of the injured spinal cord of the rats, and the physiological saline was injected into the control group. MAIN OUTCOME MEASURES: The rehabilitation of the motor function of the rats' hind limbs was observed; furthermore, eight weeks after the injury, the protein disparity of the nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) between the two groups of rats was noted. RESULTS: The rehabilitation of the hind limbs' motor function of the transplantation group was significantly better than that of the control group from the third week on after injury, and the difference was of significance (P<0.05). CONCLUSIONS: Transplanting BMSCs can boost the protein expression of NGF and BDNF in the rats which undergo acute injury to their spinal nerves. It can, therefore, significantly improve the rehabilitation of the motor function of their hind limbs. The improvement is associated with the transplantation of BMSCs which are beneficial for regeneration and repair of the rat's spinal nerves. PMID- 24482715 TI - Daytime sleepiness and sleep habits as risk factors of traffic accidents in a group of Turkish public transport drivers. AB - AIM: To explore the association of daytime sleepiness, sleep complaints and sleep habits with self-reported car crashes among public transport drivers. METHODS: A cross-sectional descriptive study was carried out on male professional public drivers in two different cities using a validated, self-administered sleep questionnaire which comprised of symptoms suggesting sleep disorders, a subjective report of daytime sleepiness and driving characteristics. The subjects (mean age+/-SD, 40+/-11 years) were divided into two groups: (1) accident group and (2) no accident group. RESULTS: Forty nine (15.3%) of the 320 public drivers reported that they had at least one sleepiness related motor vehicle accident and/or near-missed accident (Group 1). The mean age, body mass index and annual distance driven were similar in both groups. Although Group 1 reported less sleep time per night, more witnessed apneas, abnormal sleep, alcohol use and had higher mean Epworth Sleepiness Scale scores than Group 2, multivariate analysis of risk factors revealed that only daytime sleepiness increase the risk of traffic accidents [OR: 1.32 (1.19-1.47)]. CONCLUSION: These results suggest that self reported sleepiness is a predictive sign of traffic accidents due to driver sleepiness. PMID- 24482716 TI - Does adrenaline spraying over thyroidectomy area reduce bleeding? AB - BACKGROUND: Means to prevent and control intra- or postoperative bleeding remain a topic of utmost importance in thyroidectomy. In this randomised clinical trial, we used adrenaline spraying to see if it helps bleeding control and reduces drainage and hematoma formation after thyroidectomy. METHODS: After total thyroidectomy, 1 mg/ml adrenaline solution in 10 ml saline was sprayed all over the operation area by a syringe in 40 patients of "Adrenaline (+) Group". In the other 40 patients in "Adrenaline (-) Group", only standart total thyroidectomy was performed. Drainage amounts of 24 hours were recorded. RESULTS: Among 80 patients, 66 (82.5%) were female and 14 (17.5%) were male. The daily drainage amounts of the Adrenaline (+) Group were found statistically significantly lower than the Adrenaline (-) Group (p<0.05). In both of the groups, thyroid volumes were significantly correlated with the drainage amounts. "p" values were 0.008 and <0.001 in Adrenaline (+) and Adrenaline (-) Groups, respectively. CONCLUSIONS: Preliminary experience using adrenaline has been encouraging and it is useful as an adjunct to thyroid surgery in order to prevent hemorrhagia and give up drain placement. But prospective randomized trials using adequate patient numbers are still needed to validate efficacy and safety. PMID- 24482717 TI - Parathyroid allotransplantation in rabbits without cultivation. AB - Permanent hypoparathyroidism is a serious clinical situation. Allotransplantation of the parathyroid cells is relatively new approach to treatment. Non-cultivated allotransplantation in rabbits is not tried before. In this research parathyroidectomy was performed in six female New Zealand white rabbits. After division of surgically removed tissues into two, cryopreservation after cell isolation was done. Non-cultivated cross allotransplantation was performed under immunosuppression. Serum calcium and phosphorus levels were observed 15 days and histopathological analyses of the transplanted parathyroid tissues were studied. Significant changes in serum calcium and phosphorus levels during the experiment were observed (p=0.001 for both). Calcium levels which were significantly dropped to 6.66+/-0.7 mg/dL after parathyroidectomy and progressively increased up to 15.98+/-1.25 mg/dL at the end of the experiment (p=0.004). Phosphorus levels which were increased to 9.38+/-0.63 mg/dL after parathyroidectomy and stabilized to 4.46+/-1.06 mg/dL at the end of the experiment (p=0.007). All allotransplanted parathyroid tissues showed normal tissue architecture without evidence of cellular rejection. In conclusion allotransplantation of the parathyroid tissues without cultivation may be considered as an alternative and safe approach for the treatment of permanent hypoparathyroidism. PMID- 24482718 TI - Mucinous metaplasia in urothelial tract may be the precancerous lesion of mucinous adenocarcinoma: report of two cases and review of literature. AB - Primary mucinous lesions of the urinary system are extremely rare. We describe two cases of primary mucinous lesions of the urothelial tract. One case is of mucinous metaplasia in the bladder of a 40-year-old man presenting with frequent urination, urgency, and gross hematuria. The other case is of mucinous adenocarcinoma in the pelvis of an otherwise healthy 67-year-old man with left nephrolithiasis. The histological images of the two cases demonstrate a spectrum from benign mucinous metaplasia to malignant mucinous adenocarcinoma, and suggest that mucinous metaplasia in urothelial tract may be the precancerous lesion of mucinous adenocarcinoma. PMID- 24482719 TI - Destructive osteoblastoma with secondary aneurysmal bone cyst of cervical vertebra in an 11-year-old boy: case report. AB - STUDY DESIGN: A case report and review of previous literature are presented. OBJECTIVE AND BACKGROUND: The objective of this manuscript was to report a case of destructive osteoblastoma with secondary aneurysmal bone cyst of cervical vertebra in a child, and discuss the pathogenesis of this disease. The combination of osteoblastoma and aneurysmal bone cyst in the cervical spine is rare in primary bone neoplasm. To the authors' knowledge, only one case in a child has been reported. METHOD: Plain X-rays, technetium bone scanning, CT scan and MRI indicated an expansile, partially sclerotic lesion of the C4 involving the body of vertebra and appendix. The lesion was excised through anterior and posterior approach. RESULTS: After operation the tumor was removed completely. There has been no sign of tumor recurrence or clinical or radiologic sign of instability in the follow-up investigations. CONCLUSIONS: We report a rare case of destructive osteoblastoma with Secondary aneurysmal bone cyst of cervical vertebra in a child, a full investigation indicated that complete resection of the tumor can prevent recurrence and malignant transformation. Long-term follow up is needed to declare a lifelong cure of the disease. PMID- 24482720 TI - Image characteristics of computer tomography urography in pelvic lipomatosis. AB - Pelvic lipomatosis is a rare disease where fat tissue deposition is observed in spaces of the pelvic area. The disease has a wide range of presenting obstruction symptoms varying from lower urinary tract symptoms to bowel symptoms. In this report, we described the clinical findings, classical radiological features and treatment in an elderly male patient with pelvic lipomatosis. PMID- 24482721 TI - Radiological and clinical features of peripheral keratocystic odontogenic tumor. AB - Peripheral Keratocystic odontogenic tumor (PKCOT) is rare and has not been reported with imaging findings. AIM: The aim of this study was to explore CT and MR imaging characteristics of two PKCOTs in lateral facial deep region (LFDR), and to present a review of the literature regarding their anatomic locations and characteristics of epidemiology and Radiology. METHODS AND MATERIAL: Eighteen PKCOTs, sixteen from the previous literatures and two new cases of the authors, were reviewed. Fifteen of them had original sites in the gingival, one in buccal space and two in LFDR. CT imaging features were based on one PKCOT in the buccal space and two in LFDR. MR imaging features on one PKCOT in LFDR, and conventional radiographic characteristics on eight PKCOTs were analyzed. RESULTS: The subjects' ages ranged from 37 to 81 years, with a mean of 54.7 years. The male and female ratio was 1:1.14, with no predilection for either gender. Buccal space (6%) and LFDR (11%) were relatively rare original sites to PKCOTs, compared to gingival (83%). PKCOTs were clearly depicted on CT and MR imaging as they had cystic changes. Contents of the cysts were further analyzed by using different series of MRI. No radiological features were found on radiographs except one subject with minimal bone resorption in the alveolar crest. CONCLUSIONS: LFDR is rare original site for PKCOT. PKCOT should be included as one of differential diagnosis of a cystic lesion found in LFDR on CT and MR imaging. PMID- 24482722 TI - A case of EBV positive diffuse large B-cell lymphoma of the adolescent. AB - EBV positive diffuse large B-cell lymphoma (DLBCL) can happen to the elderly, seldom to the young. The case of EBV positive DLBCL has rarely been reported in the adolescent. We report a rare case of EBV positive DLBCL in a 17-year-old man with normal immune state. He was diagnosed by morphology, immunohistochemistry, in situ hybridization for EBV, Flow cytometer, IG/TCR gene rearrangement and cytogenetic study. The occurrence of this case suggests that EBV-positive DLBCL can happen to adolescent patients with normal immune state and cytogenetic study takes an important role in the diagnosis of adolescent EBV-positive DLBCL. PMID- 24482723 TI - Surgical treatment and radiotherapy of epidermoid cyst with malignant transformation in cerebellopontine angle. AB - We report surgical treatment and radiotherapy of an extremely rare case of malignant epidermoid cyst located in cerebellopontine angle. MRI and CT demonstrated the lesion with partial enhancement and calcification. During operation, we found the tumor attached tightly to surrounding tissue. Finally we achieved near total resection of it. Histopathology confirmed the diagnosis of epidermoid cyst with malignant transformation. With adjuvant radiotherapy, the patient underwent excellent recovery, and follow-up MRI demonstrated no obvious residue or recurrence of the tumor. Malignant epidermoid cyst can be diagnosed radiologically in combination with clinical presentation. Maximal removal plus adjuvant radiotherapy is the treatment of choice, although the general prognosis of it is poor. PMID- 24482724 TI - Brown-Sequard syndrome associated with unusual spinal cord injury by a screwdriver stab wound. AB - INTRODUCTION: Stab wounds resulting in spinal cord injuries are very rare. In direct central back stabbings, the layers of muscles and the spinal column tends to deflect blades, rarely causing injuries to the spinal cord. We report an unusual case of traumatic spinal cord injury by a screwdriver stab, presented as Brown-Sequard syndrome and discuss possible pitfalls on the surgical treatment. CASE REPORT: A 34 year-old man was brought to the emergency department after a group assault with a single screwdriver stab wound on the back. Neurological examination revealed an incomplete Brown-Sequard syndrome, with grade IV motor deficit on the left leg and contralateral hemihypoalgesia below T9 level. Radiological evaluation showed a retained 9 cm screwdriver that entered and trespassed the spinal canal at T6 level, reaching the posterior mediastinum with close relation to the thoracic aorta. Vascular injury could not be excluded. The joint decision between the neurosurgery and the vascular surgery teams was the surgical removal of the screwdriver under direct visualization. A left mini thoracotomy was performed. Simultaneously, a careful dissection was done and screwdriver was firmly pulled back on the opposite path of entry under direct visualization of the aorta. The neurological deficit was maintained immediately after the surgical procedure. Follow-up visit after 1 year showed minor motor deficit and good healing. CONCLUSIONS: It is important to consider all aspects of secondary injury on the surgical planning of penetrating spinal cord injury. The secondary injury can be minimized with multidisciplinary planning of the surgical procedure. PMID- 24482725 TI - Intractable angina pectoris after coronary artery bypass surgery in Takayasu arteritis involving the aorta ventralis and main coronary artery in a young girl. AB - We report a case of sudden death in Takayasu arteritis after coronary artery bypass. A 22-year-old girl visited our hospital in June 2009 because of paroxysmal chest tightness and shortness of breath for 2 years. She was diagnosed as Takayasu arteritis, the limited stenosis of upper aorta ventralis, low perfusion pressure changes of double renal artery and double lower limbs artery, left ventricular mural thrombus and patent foramen ovale. The coronary artery bypass grafting was conducted. However, the symptoms were recurrent 2 months later. PMID- 24482726 TI - Soft tissue perineurioma with peripheral lymphoid cuff of the tongue: a case report and literature review. AB - Perineurioma are rare tumors, derived from nerve sheath perineurial cells. Soft tissue perineurioma are extraordinarily rare in the tongue, with only one previous report in a child to our knowledge. Herein, we describe the first case of an adult patient who had a soft tissue perineurioma localized to the tongue, with emphasis on the clinic pathologic and immunohistochemical features of this tumor, and review the previously reported soft tissue cases. Besides, we first describe the histologic feature of peripheral lymphoid cuff in perineurioma. PMID- 24482727 TI - Simple strategy of anesthesia for the neonate with tracheoesophageal fistula: a case report. AB - A 3-day-old neonate, given a diagnosis of esophageal atresia (EA) with tracheoesophageal fistula (TEF), which is large and just above the carina, was scheduled for TEF repair. Routine anesthetic management focuses on adequate ventilation and avoidance of gastric distension during positive pressure ventilation. Using a balloon-tipped embolectomy catheter or a Fogarty catheter to block the fistula under the guidance of fiberoptic scope has been described. In most of the medical centers, however, the pediatric fiberoptic scope may not be available. We present a case of a newborn undergoing type C EA/TEF repair and describe a simple intra-operative technique that could temporarily occlude the gastroesophageal junction, allowing stable vital signs of patient and definitive repair of the tracheoesophageal fistula. PMID- 24482728 TI - Breast reconstruction with autologous fat graft; does platelet-rich plasma affect patient's survival? PMID- 24482729 TI - Integrated interventions for improving negative emotions and stress reactions of young women receiving total hysterectomy. AB - 50% of women had obvious abnormal emotions before hysterectomy and hysterectomy can cause strong mental stress reaction. This study was to investigate the impact of psychological health education based integrated interventions on the preoperative negative emotions and stress of patients younger than 45 years receiving total hysterectomy. Forty patients undergoing total hysterectomy were randomly divided into psychological intervention (PI) group and control group (n=20 per group). Patients in PI received peri-operative psychological intervention (supportive psychotherapy, health education, individual depth psychotherapy, family and society supportive care, education on anesthesia and surgery etc.); Interventions were not used in control group. Hamilton Anxiety Scale and Hamilton Depression Rating Scale were used to evaluate patients in two groups on admission (T1) and before surgery (T2; after interventions in PI group). Serum levels of cortisol and IL-6 were detected at T1, T2 and the second day after surgery (T3). Results showed that 1) Patients had obvious anxiety and depression symptoms before and after total hysterectomy. For patients in PI group, the Hamilton Anxiety Scale (HAMA) score decreased from 14.4+/-5.9 to 9.1+/ 4.2 and the Hamilton Depressing Scale (HAMD) score from 17.8+/-3.5 to 9.4+/-6.8 after interventions; 2) In PI group, the serum cortisol was 13.4+/-3.9 MUg/dl at T2 and 14.2+/-4.8 MUg/dl at T3 which were significantly lower than that at T1 (16.6+/-4.0 MUg/dl) and that in the control group at T2 (13.4+/-3.9/15.5+/-4.3 MUg/dl, t=2.10, P<0.05). Thus, preoperative integrated intervention based on psychological health education can improve peri-operative negative emotions and psychological stress in young patients undergoing hysterectomy. PMID- 24482730 TI - Rational Design of Novel Pyridinol-Fused Ring Acetaminophen Analogues. AB - Acetaminophen (ApAP) is an electron donor capable of reducing radicals generated by redox cycling of hemeproteins. It acts on the prostaglandin H synthases (cyclooxygenases; COXs) to reduce the protoporphyrin radical cation in the peroxidase site of the enzyme, thus preventing the intra-molecular electron transfer that generates the Tyr385 radical required for abstraction of a hydrogen from arachidonic acid to initiate prostaglandin synthesis. Unrelated to this pharmacological action, metabolism of ApAP by CYPs yields an iminoquinone electrophile that is responsible for the hepatotoxicity, which results from high doses of the drug. We synthesized novel heterocyclic phenols predicted to be electron donors. Two of these inhibited the oxygenation of arachidonic acid by PGHS-1 and myoglobin and also were shown to be more metabolically stable and exhibited less direct cytotoxicity than acetaminophen. They are leading candidates for studies to determine whether they are free of the metabolism-based hepatotoxicity produced by acetaminophen. PMID- 24482731 TI - Goal Setting to Promote a Health Lifestyle. AB - The purpose of this parallel-group study was to determine whether a feasibility study based on newsletters and telephone counseling would improve goal-setting constructs; physical activity (PA); and fruit and vegetable (F & V) intake in a sample of older adults. Forty-three older adults (M age = 70 years, >70% Asian, 54% female) living in Honolulu, Hawaii were recruited and randomly assigned to either a PA or F & V intake condition. All participants completed measures of PA, F & V intake, and goal setting mechanisms (i.e., specificity, difficulty, effort, commitment, and persistence) at baseline and 8-weeks. Paired t-tests were used to evaluate changes across time. We found that F & V participants significantly increased F & V intake and mean scores of goal specificity, effort, commitment, and persistence (all p < .05). No statistically significant changes in PA or goal setting mechanisms were observed for participants in the PA condition. Overall, our results show that a short-term intervention using newsletters and motivational calls based on goal-setting theory was effective in improving F & V intake; however, more research is needed to determine whether these strategies are effective for improving PA among a multiethnic sample of older adults. PMID- 24482733 TI - Robotic Assisted, Total Laparoscopic, and Total Abdominal Hysterectomy for Management of Uterine Cancer. AB - OBJECTIVES: The purpose was to compare robotic assisted total laparoscopic hysterectomy (TRH), laparoscopic assisted hysterectomy (TLH) and total abdominal hysterectomy (TAH) with surgical staging +/- lymphadenectomy for the management of uterine cancer. METHODS: Institutional review board approval was obtained and patient characteristics, pathologic data, and data related to the surgical procedure were collected from chart review. Data were analyzed with SAS statistical software. RESULTS: A total of 102 TRHs were compared to 115 TLHs and 79 TAHs. There were more grade I and endometrial intraepithelial (EIN) lesions in the preoperative pathology of TLHs (P < 0.01). Pelvic lymphadenectomy was performed in 71 (70%) TRH, 46 (58%) TAH, and 28 (24%) TLH cases (P < 0.01). Mean surgical time was 203, 133 and 132 minutes for TRHs, TLHs, and TAHs (P < 0.05). Estimated blood loss was 69, 86, and 215 ml for TRH, TLH, and TAH (P < 0.05). Blood transfusions were 19% in TAHs versus 3% and 2% in TLHs and TRHs (P < 0.01). There were fewer wound infections (2% vs. 10%) in TRHs versus TAHs (P < 0.01). Length of stay was shorter for the TRH and TLH groups (P < 0.05). CONCLUSION: Despite longer surgical times, benefits of minimally invasive technology included shortened length of stay, decreased wound infections, transfusions, and blood loss. In our population, procedure selection for TLH versus TRH may have been influenced by lower preoperative grade, with reservation of robotic technology for cases anticipated to be more complex, and therefore justifying increased technology costs and operating times. PMID- 24482732 TI - beta-phenylethylamine, a small molecule with a large impact. AB - During a screen of bacterial nutrients as inhibitors of Escherichia coli O157:H7 biofilm, the Prubeta research team made an intriguing observation: among 95 carbon and 95 nitrogen sources tested, beta-phenylethylamine (PEA) performed best at reducing bacterial cell counts and biofilm amounts, when supplemented to liquid beef broth medium. This review article summarizes what is known about PEA. After some starting information on the chemistry of the molecule, we focus on PEA as a neurotransmitter and then move on to its role in food processing. PEA is a trace amine whose molecular mechanism of action differs from biogenic amines, such as serotonin or dopamine. Especially low or high concentrations of PEA may be associated with specific psychological disorders. For those disorders that are characterized by low PEA levels (e.g. attention deficit hyperactivity disorder), PEA has been suggested as a 'safe' alternative to drugs, such as amphetamine or methylphenidate, which are accompanied by many undesirable side effects. On the food processing end, PEA can be detected in food either as a result of microbial metabolism or thermal processing. PEA's presence in food can be used as an indicator of bacterial contamination. PMID- 24482734 TI - Searching for Alternatively Spliced Variants of Phospholipase Domain-Containing 2 (Pnpla2), a Novel Gene in the Retina. AB - PURPOSE: Ensembl and other expressed sequence tag (EST) databases reveal putative alternative splice variants in mouse and rat for Pnpla2, the gene encoding pigment epithelium-derived factor-receptor (PEDF-R). The purpose of this study was to obtain experimental evidence for Pnpla2 splice variants in mouse. MATERIALS AND METHODS: Cultures of a mouse cell line derived from photoreceptors (661W cells) and mouse eye, heart, adipose, kidney, and liver tissues were used. Messenger RNA (mRNA) was isolated from cells and tissues, and complementary DNA (cDNA) was synthesized. Polymerase chain reaction (PCR) primer pairs were designed to flank the putative splice sites. Exon exclusion real time PCR was used to reduce amplification of the full-length Pnpla2 transcript and enhance amplification of low abundant splice variants. PCR products were resolved by agarose gel electrophoresis and detected with a UV transilluminator. Recombinant plasmids containing a human full-length PNPLA2 cDNA or a PNPLA2 cDNA lacking exon 5b (E5b) were controls to validate the techniques. Total cell lysates from 661W cells were prepared. PEDF-R protein detection was performed using western blots. RESULTS: PCR products for Pnpla2 transcripts obtained from 661W cells or various mouse tissues resolved into a single band following amplification with multiple primer pairs. Simultaneous amplification of two PNPLA2 cDNAs at various molar ratios prevented the detection of lower abundant transcripts. However, even when the cDNA for the full-length Pnpla2 transcript was significantly excluded using the exon exclusion method, no bands corresponding to Pnpla2 splice variants were detectable. Nonetheless, western blots of total 661W cell lysates with two different antibodies revealed isoforms for the PEDF-R protein. CONCLUSIONS: The data provide evidence for the existence of a single, full-length Pnpla2 transcript that could give rise to a single protein product that undergoes posttranslational processing. PMID- 24482736 TI - IGFBP3 promotes esophageal cancer growth by suppressing oxidative stress in hypoxic tumor microenvironment. AB - Insulin-like growth factor binding protein 3 (IGFBP3), a hypoxia-inducible gene, regulates a variety of cellular processes including cell proliferation, senescence, apoptosis and epithelial-mesenchymal transition (EMT). IGFBP3 has been linked to the pathogenesis of cancers. Most previous studies focus upon proapoptotic tumor suppressor activities of IGFBP3. Nevertheless, IGFBP3 is overexpressed in certain cancers including esophageal squamous cell carcinoma (ESCC), one of the most aggressive forms of squamous cell carcinomas (SCCs). The tumor-promoting activities of IGFBP3 remain poorly understood in part due to a lack of understanding as to how the tumor microenvironment may influence IGFBP3 expression and how IGFBP3 may in turn influence heterogeneous intratumoral cell populations. Here, we show that IGFBP3 overexpression is associated with poor postsurgical prognosis in ESCC patients. In xenograft transplantation models with genetically engineered ESCC cells, IGFBP3 contributes to tumor progression with a concurrent induction of a subset of tumor cells showing high expression of CD44 (CD44H), a major cell surface receptor for hyaluronic acid, implicated in invasion, metastasis and drug resistance. Our gain-of-function and loss-of function experiments reveal that IGFBP3 mediates the induction of intratumoral CD44H cells. IGFBP3 cooperates with hypoxia to mediate the induction of CD44H cells by suppressing reactive oxygen species (ROS) in an insulin-like growth factor-independent fashion. Thus, our study sheds light on the growth stimulatory functions of IGFPB3 in cancer, gaining a novel mechanistic insight into the functional interplay between the tumor microenvironment and IGFBP3. PMID- 24482737 TI - Mutation of the retinoblastoma tumor suppressor gene sensitizes cancers to mitotic inhibitor induced cell death. AB - The retinoblastoma gene Rb is a prototype tumor suppressor, which encodes a protein that is inactivated in a broad range of human cancers through different mechanisms. Rb functions to regulate cell proliferation, differentiation, as well as cell death. Therefore, even though Rb inactivation promotes cancer development, this may also open up certain vulnerabilities of cancers that can potentially be targeted with drug intervention. Based on the assumption that cancers that have mutation, deletion, or rearrangement in the Rb locus represent strong loss of Rb function while cancers with WT Rb on average retain some Rb function, we searched Genomics of Drug Sensitivity in Cancer database to identify cancer drugs that are particularly effective to cancers with Rb genomic alterations. Three mitotic inhibitors were identified from this analysis. We further tested the effects of two mitotic inhibitors, Taxol and STLC, on prostate and breast cancer cells. We demonstrate that the Rb status affects cancer cell sensitivity to these mitotic drugs and that the sensitizing effects of Rb are mediated in part by its regulation of the cell cycle checkpoint protein Mad2. Since the mitotic inhibitors identified in our analysis inhibit mitosis through distinct targets, it is possible that the Rb functional status may serve as a general biomarker for cancer sensitivity to mitotic inhibitors. Because the Rb pathway is inactivated in a large number of human cancers, identification of agents that are particularly effective or ineffective based on the Rb status in cancers can potentially be used generally to matching patients with appropriate treatments to achieve better therapeutic outcome. PMID- 24482738 TI - A novel experimental hypoxia chamber for cell culture. AB - Tissue hypoxia is a common pathophysiological process. Since 1990s, numerous studies have focused on investigating cellular adaptation to experimental hypoxia. A modular incubator chamber made of solid materials has frequently been used in the experiments that require hypoxic conditions. Here, we introduce a novel and inflatable chamber for hypoxia experiments. In experiments detecting hypoxia-induced accumulation of hypoxia-inducible factor 1alpha (HIF-1alpha) and hypoxia-induced expression of HIF-1-regulated genes, the new chamber yielded reproducible and comparable results as the modular incubator chamber did. The new chamber did not create inner chamber pressure during its use. Other properties of the new chamber were low-cost, easy to use, and leakage-free. Moreover, the size of the new chamber was adjustable, and the smaller one could be placed onto an inverted microscope for real-time studies. The successful examples of real-time studies included the real-time recording of GFP-HIF-1alpha fusion nuclear translocation and endothelial cell tubular formation. PMID- 24482735 TI - Beyond laser microdissection technology: follow the yellow brick road for cancer research. AB - Normal biological tissues harbour different populations of cells with intricate spacial distribution patterns resulting in heterogeneity of their overall cellular composition. Laser microdissection involving direct viewing and expertise by a pathologist, enables access to defined cell populations or specific region on any type of tissue sample, thus selecting near-pure populations of targeted cells. It opens the way for molecular methods directed towards well-defined populations, and provides also a powerful tool in studies focused on a limited number of cells. Laser microdissection has wide applications in oncology (diagnosis and research), cellular and molecular biology, biochemistry and forensics for tissue selection, but other areas have been gradually opened up to these new methodological approaches, such as cell cultures and cytogenetics. In clinical oncology trials, molecular profiling of microdissected samples can yield global "omics" information which, together, with the morphological analysis of cells, can provide the basis for diagnosis, prognosis and patient-tailored treatments. This remarkable technology has brought new insights in the understanding of DNA, RNA, and the biological functions and regulation of proteins to identify molecular disease signatures. We review herein the different applications of laser microdissection in a variety of fields, and we particularly focus attention on the pre-analytical steps that are crucial to successfully perform molecular-level investigations. PMID- 24482739 TI - Biomarkers and endosalpingiosis in the ovarian and tubal microenvironment of women at high-risk for pelvic serous carcinoma. AB - INTRODUCTION: BRCA mutations increase the risk for development of high-grade pelvic serous carcinomas. Tissue biomarkers distinguishing women at high-risk (HR) for ovarian cancer from those at low-risk (LR) may provide insights into tumor initiation pathways. METHODS: A prospective study of 47 HR women (40% BRCA carriers) undergoing risk-reducing salpingo-oophorectomy and 48 LR controls undergoing salpingo-oophorectomy was performed. Ovarian/tubal tissues were harvested. Immunohistochemical analysis of candidate proteins CSF-1, CSF-1R, ErbB4 is presented, with scores separately analyzed in epithelium and stroma, in ampulla, fimbria, ovary, and ovarian endosalpingiosis (ES). Comparison was performed between HR and LR groups. RESULTS: Elevated levels of CSF-1 (p=0.005) or ErbB4 (p=0.005) in the ovarian epithelium, or ErbB4 (p=0.005) in the ovarian stroma, were significantly associated with both the HR status and carrying a BRCA mutation, as was nuclear ErbB4 staining. Ovarian ES, an entity which likely derives from the tubal mucosal epithelium, was also associated with HR (p=0.038) and BRCA mutation status (p=0.011). Among the BRCA carriers only, markers also found association when present in the tube as well as in ovarian ES (p < 0.05). ROCs were generated including in the regression model both CSF-1 and ErbB4 expression levels. A model including CSF-1 in ovarian epithelium, ErbB4 in ovarian stroma, and younger age achieves AUC=0.87 (73% sensitivity, 93% specificity) of detection of the HR status. In BRCA carriers, CSF-1 in ovarian epithelium alone achieves AUC=0.85. CONCLUSIONS: Our data suggest that elevated levels of CSF-1/ErbB4 in the adnexae correlate with HR/BRCA carrier status. CSF 1/CSF-1R signaling is active in ovarian cancer progression; our data suggests a role in its initiation. ErbB4, in particular nuclear ErbB4, may have a role in tumor initiation as well. Ovarian ES, an entity which may represent a latent precursor to low-grade pelvic serous carcinomas, was surprisingly associated with both HR status and the BRCA carrier cohort. In line with these findings, both ErbB4 and CSF-1R expression in ovarian ES correlated with carrying a BRCA mutation. This analysis, which needs to be validated, indirectly suggests a potential link between ovarian ES and the development of pelvic serous carcinoma in women who are BRCA mutation carriers. PMID- 24482740 TI - PCOS and obesity: insulin resistance might be a common etiology for the development of type I endometrial carcinoma. AB - Endometrial cancer (EC) is the most common gynecological malignancy in women and is the leading cause of cancer-related deaths worldwide. Estrogenic stimulation significantly increases endometrial cell proliferation, and both insulin resistance and hyperinsulinemia are associated with the development of EC in women. It has long been known that insulin resistance occurs in women with polycystic ovary syndrome (PCOS) and/or obesity, but one important unanswered question is whether the insulin resistance associated with PCOS and obesity is part of the etiology of the initiation and development of EC. Therefore, research efforts to understand the common and specific underlying endometrial responses to insulin resistance in women with PCOS and obesity could provide further therapeutic options for early endometrial carcinoma. PMID- 24482741 TI - Mouse induced pluripotent stem cell microenvironment generates epithelial mesenchymal transition in mouse Lewis lung cancer cells. AB - Induced pluripotent stem (iPS) cells may be a powerful tool in regenerative medicine, but their potential tumorigenicity is a significant challenge for the clinical use of iPS cells. Previously, we succeeded in converting miPS cells into cancer stem cells (CSCs) under the conditions of tumor microenvironment. Both stem cells and tumor cells are profoundly influenced by bi-directional communication with their respective microenvironment, which dictates cell fate determination and behavior. The microenvironment derived from iPS cells has not been well studied. In this paper, we have investigated the effects of secreted factors from Nanog-mouse iPS (miPS) cells on mouse Lewis lung cancer (LLC) cells that are found in the conditioned media. The results demonstrated that miPS cells secrete factors that can convert the epithelia phenotype of LLC cells to a mesenchymal phenotype, and that can promote tumorigenisity, migration and invasion. Furthermore, LLC cells that have been exposed to miPS conditioned medium became resistant to apoptosis. These various biological effects suggest that the miPS microenvironment contain factors that can promote an epithelial mesenchymal transition (EMT) through an active Snail-MMP axis or by suppressing differentiation in LLC cells. PMID- 24482742 TI - Determination of Rottlerin, a Natural Protein Kinases C Inhibitor, in Pancreatic Cancer Cells and Mouse Xenografts by RP-HPLC Method. AB - Rottlerin is a natural polyphenolic ketone isolated from the pericarps of Mallotus phillippinensis. In previous studies we showed that parenteral administration of rottlerin reduced tumor growth in murine xenograft models of pancreatic cancer. The aim of this study was to develop a simple and validated method for the quantitative determination of rottlerin in plasma and tumor tissues of mice fed a rottlerin diet. A xenograft model of pancreatic cancer was prepared by injection of 2*106 HPAF-II cells subcutaneously into nude mice. One week before tumor implantation, mice were randomly allocated to standard diet (AIN76A) and standard diet supplement with 0.012% rottlerin (n=6 per group). Mice were sacrificed after 6 weeks on diets. Rottlerin was extracted from the plasma and tissues using protein precipitation-extraction and analyzed by reverse-phase HPLC-DAD method. The same HPLC method was also applied to determine rottlerin levels in conditioned culture media and in cell lysates from HPAF-II cells exposed to 25 uM concentration of rottlerin. A substantial amount of rottlerin was detected in tumor (2.11 +/- 0.25 nmol/g tissue) and plasma (2.88 +/- 0.41 uM) in mice fed rottlerin diet. In addition, significant levels of rottlerin (57.4 +/ 5.4 nmol/mg protein) were detected in cell lysates from rottlerin-treated HPAF II cells. These data indicate that rottlerin is efficiently absorbed in cells and tissues both in vivo and in vitro and suggest a strong potential for rottlerin as a preventive or adjuvant supplement for pancreatic cancer. PMID- 24482743 TI - Identification of the ssDNA-binding protein of bacteriophage T5: Implications for T5 replication. AB - In a recent study, we identified and characterized the long-elusive replicative single-stranded DNA-binding protein of bacteriophage T5, which we showed is related to the eukaryotic transcription coactivator PC4. Here, we provide an extended discussion of these data, report several additional observations and consider implications for the recombination-dependent replication mechanism of the T5 genus, which is still poorly understood. PMID- 24482745 TI - Regulation of tumor-associated high-endothelial venules by dendritic cells: A new opportunity to promote lymphocyte infiltration into breast cancer? AB - Accumulating evidence suggests that high-endothelial venules (HEVs) represent major gateways for the infiltration of lymphocytes within neoplastic lesions. However, the origin of these vessels in human neoplasms remains elusive. We have recently discovered a link between lymphotoxin beta-producing dendritic cells and tumor-associated HEVs. PMID- 24482744 TI - Antitumor immune responses mediated by dendritic cells: How signals derived from dying cancer cells drive antigen cross-presentation. AB - Dendritic cells (DCs) are essential for the induction of adaptive immune responses against malignant cells by virtue of their capacity to effectively cross-present exogenous antigens to T lymphocytes. Dying cancer cells are indeed a rich source of antigens that may be harnessed for the development of DC-based vaccines. In particular, malignant cells succumbing to apoptosis, rather than necrosis, appear to release antigens in a manner that allows for the elicitation of adaptive immune responses. In this review, we describe the processes that mediate the cross-presentation of antigens released by apoptotic cancer cells to CD8+ T lymphocytes, resulting in the activation of protective tumor-specific immune responses. PMID- 24482746 TI - Role of non-classical MHC class I molecules in cancer immunosuppression. AB - Growing neoplasms employ various mechanisms to evade immunosurveillance. The expression of non-classical MHC class I molecules by both immune and malignant cells in the tumor microenvironment constitute of the strategies used by tumors to circumvent the cytotoxic activity of effector cells of the immune system. The overexpression of HLA-G, -E, and -F is a common finding across a variety of malignancies. However, while the presence of HLA-G and HLA-E has been recently correlated with poor clinical outcome, information on the clinicopathological significance of HLA-F is limited. In the present review, we summarize studies on non-classical MHC class I molecules with special emphasis on their role in the modulation of anticancer immune responses. PMID- 24482748 TI - FSTL1 promotes bone metastasis by causing immune dysfunction. AB - In spite of significant advances in our understanding of the metastatic process, the relationship between the dissemination of primary neoplasms to the bones and antitumor immunity remains poorly understood. We have recently identified follistatin-like 1 (FSTL1), a soluble protein secreted by snail family zinc finger 1 (SNAI1)-expressing cancer cells, as a key determinant of bone metastasis that operates by inducing a systemic state of immune dysfunction. PMID- 24482749 TI - Boosting leukemia-specific T cell responses in patients following stem cell transplantation. AB - Whole tumor cell-based vaccines administered within the first 2 to 3 months after allogeneic stem cell transplantation stand out as a promising approach to enhance graft-vs.-leukemia responses. Herein, the implications of this finding for the development of strategies to improve the outcome of patients subjected to allogeneic stem cell transplantation are discussed. PMID- 24482751 TI - Examining the presentation of tumor-associated antigens on peptide-pulsed T2 cells. AB - Peptide-pulsed T2 cells are routinely used to study T-cell activation by MHC restricted peptides derived from tumor-associated antigens (TAAs). Nevertheless, the capacity of T2 cells to present antigenic epitopes remains to be precisely quantified, primarily due to the detection limits imposed by available methods. Since naturally-processed TAA-derived epitopes have been shown to be displayed at levels as low as 10-150 copies per cell, highly sensitive detection and quantification techniques are essential to assess the natural degree of T-cell sensitivity. Here, we report the use of soluble, high-affinity T-cell receptors (TCRs) coupled with single-molecule fluorescence microscopy to quantify three reported TAA-derived epitopes on peptide-pulsed T2 cells, dissecting the relationship between concentration of exogenous peptide, number of epitopes presented, and activation of epitope-specific T cells. Our findings indicate that peptide concentrations in the low nanomolar range are required for T2 cells to present TAAs in extents that are comparable to those of malignant cells. PMID- 24482750 TI - Longitudinal confocal microscopy imaging of solid tumor destruction following adoptive T cell transfer. AB - A fluorescence-based, high-resolution imaging approach was used to visualize longitudinally the cellular events unfolding during T cell-mediated tumor destruction. The dynamic interplay of T cells, cancer cells, cancer antigen loss variants, and stromal cells-all color-coded in vivo-was analyzed in established, solid tumors that had developed behind windows implanted on the backs of mice. Events could be followed repeatedly within precisely the same tumor region before, during and after adoptive T cell therapy-thereby enabling for the first time a longitudinal in vivo evaluation of protracted events, an analysis not possible with terminal imaging of surgically exposed tumors. T cell infiltration, stromal interactions, and vessel destruction, as well as the functional consequences thereof, including the elimination of cancer cells and cancer cell variants were studied. Minimal perivascular T cell infiltrates initiated vascular destruction inside the tumor mass eventually leading to macroscopic central tumor necrosis. Prolonged engagement of T cells with tumor antigen-crosspresenting stromal cells correlated with high IFNgamma cytokine release and bystander elimination of antigen-negative cancer cells. The high-resolution, longitudinal, in vivo imaging approach described here will help to further a better mechanistic understanding of tumor eradication by T cells and other anti-cancer therapies. PMID- 24482747 TI - Trial Watch: Lenalidomide-based immunochemotherapy. AB - Lenalidomide is a synthetic derivative of thalidomide currently approved by the US Food and Drug Administration for use in patients affected by multiple myeloma (in combination with dexamethasone) and low or intermediate-1 risk myelodysplastic syndromes that harbor 5q cytogenetic abnormalities. For illustrative purposes, the mechanism of action of lenalidomide can be subdivided into a cancer cell-intrinsic, a stromal, and an immunological component. Indeed, lenalidomide not only exerts direct cell cycle-arresting and pro-apoptotic effects on malignant cells, but also interferes with their physical and functional interaction with the tumor microenvironment and mediates a robust, pleiotropic immunostimulatory activity. In particular, lenalidomide has been shown to stimulate the cytotoxic functions of T lymphocytes and natural killer cells, to limit the immunosuppressive impact of regulatory T cells, and to modulate the secretion of a wide range of cytokines, including tumor necrosis factor alpha, interferon gamma as well as interleukin (IL)-6, IL-10, and IL-12. Throughout the last decade, the antineoplastic and immunostimulatory potential of lenalidomide has been investigated in patients affected by a wide variety of hematological and solid malignancies. Here, we discuss the results of these studies and review the status of clinical trials currently assessing the safety and efficacy of this potent immunomodulatory drug in oncological indications. PMID- 24482752 TI - CD137L-stimulated dendritic cells are more potent than conventional dendritic cells at eliciting cytotoxic T-cell responses. AB - Dendritic cells (DCs) are highly potent initiators of adaptive immune responses and, as such, represent promising tools for immunotherapeutic applications. Despite their potential, the current efficacy of DC-based immunotherapies is poor. CD137 ligand (CD137L) signaling has been used to derive a novel type of DCs from human peripheral blood monocytes, termed CD137L-DCs. Here, we report that CD137L-DCs induce more potent cytotoxic T-cell responses than classical DCs (cDCs). Furthermore, in exploring several DC maturation factors for their ability to enhance the potency of CD137L-DCs, we found the combination of interferon gamma (IFNgamma) and the mixed Toll-like receptor (TLR)7/8 agonist R848, to display the highest efficacy in potentiating the T-cell co-stimulatory activity of CD137L-DCs. Of particular importance, CD137L-DCs were found to be more efficient than cDCs in activating autologous T cells targeting the cytomegalovirus (CMV)-derived protein pp65. Specifically, CD137L-DC-stimulated T cells were found to secrete higher levels of IFNgamma and killed 2-3 times more HLA-matched, pp65-pulsed target cells than T cells activated by cDCs. Finally, in addition to stimulating CD8+ T cells, CD137L-DCs efficiently activated CD4+ T cells. Taken together, these findings demonstrate the superior potency of CD137L stimulated DCs in activating CMV-specific, autologous T cells, and encourage the further development of CD137L-DCs for antitumor immunotherapy. PMID- 24482753 TI - Murine leukemia virus envelope gp70 is a shared biomarker for the high sensitivity quantification of murine tumor burden. AB - The preclinical development of anticancer drugs including immunotherapeutics and targeted agents relies on the ability to detect minimal residual tumor burden as a measure of therapeutic efficacy. Real-time quantitative (qPCR) represents an exquisitely sensitive method to perform such an assessment. However, qPCR-based applications are limited by the availability of a genetic defect associated with each tumor model under investigation. Here, we describe an off-the-shelf qPCR based approach to detect a broad array of commonly used preclinical murine tumor models. In particular, we report that the mRNA coding for the envelope glycoprotein 70 (gp70) encoded by the endogenous murine leukemia virus (MuLV) is universally expressed in 22 murine cancer cell lines of disparate histological origin but is silent in 20 out of 22 normal mouse tissues. Further, we detected the presence of as few as 100 tumor cells in whole lung extracts using qPCR specific for gp70, supporting the notion that this detection approach has a higher sensitivity as compared with traditional tissue histology methods. Although gp70 is expressed in a wide variety of tumor cell lines, it was absent in inflamed tissues, non-transformed cell lines, or pre-cancerous lesions. Having a high-sensitivity biomarker for the detection of a wide range of murine tumor cells that does not require additional genetic manipulations or the knowledge of specific genetic alterations present in a given neoplasm represents a unique experimental tool for investigating metastasis, assessing antitumor therapeutic interventions, and further determining tumor recurrence or minimal residual disease. PMID- 24482755 TI - Cognitive Emotion Regulation and Written Exposure Therapy for Posttraumatic Stress Disorder. AB - We examined the extent to which cognitive emotion-regulation (ER) strategies moderated posttraumatic stress disorder (PTSD) treatment outcome among 40 motor vehicle accident survivors. Participants were randomly assigned to either a brief written exposure therapy (WET) condition or a waitlist condition and were assessed pre- and posttreatment and at a 3-month follow-up. Positive-reappraisal and putting-into-perspective strategies at baseline interacted with condition to predict symptom change over time. Both strategies predicted greater reductions in PTSD in the waitlist group, suggesting facilitation of natural recovery. However, positive reappraisal was associated with smaller reductions in PTSD in the WET group, suggesting that this strategy may interfere with treatment. Treatment also reduced use of the maladaptive ER strategy of rumination. These results provide evidence that putting-into-perspective and positive-reappraisal strategies are beneficial in the absence of treatment and that certain types of ER strategies may reduce response to WET, highlighting the importance of future research examining ER during treatment. PMID- 24482754 TI - Customized Prediction of Short Length of Stay Following Elective Cardiac Surgery in Elderly Patients Using a Genetic Algorithm. AB - OBJECTIVE: To develop a customized short LOS (<6 days) prediction model for geriatric patients receiving cardiac surgery, using local data and a computational feature selection algorithm. DESIGN: Utilization of a machine learning algorithm in a prospectively collected STS database consisting of patients who received cardiac surgery between January 2002 and June 2011. SETTING: Urban tertiary-care center. PARTICIPANTS: Geriatric patients aged 70 years or older at the time of cardiac surgery. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Predefined morbidity and mortality events were collected from the STS database. 23 clinically relevant predictors were investigated for short LOS prediction with a genetic algorithm (GenAlg) in 1426 patients. Due to the absence of an STS model for their particular surgery type, STS risk scores were unavailable for 771 patients. STS prediction achieved an AUC of 0.629 while the GenAlg achieved AUCs of 0.573 (in those with STS scores) and 0.691 (in those without STS scores). Among the patients with STS scores, the GenAlg features significantly associated with shorter LOS were absence of congestive heart failure (CHF) (OR = 0.59, p = 0.04), aortic valve procedure (OR = 1.54, p = 0.04), and shorter cross clamp time (OR = 0.99, p = 0.004). In those without STS prediction, short LOS was significantly correlated with younger age (OR = 0.93, p < 0.001), absence of CHF (OR = 0.53, p = 0.007), no preoperative use of beta blockers (OR = 0.66, p = 0.03), and shorter cross clamp time (OR = 0.99, p < 0.001). CONCLUSION: While the GenAlg-based models did not outperform STS prediction for patients with STS risk scores, our local-data-driven approach reliably predicted short LOS for cardiac surgery types that do not allow STS risk calculation. We advocate that each institution with sufficient observational data should build their own cardiac surgery risk models. PMID- 24482756 TI - A new specimen of the Early Cretaceous bird Hongshanornis longicresta: insights into the aerodynamics and diet of a basal ornithuromorph. AB - The discovery of Hongshanornis longicresta, a small ornithuromorph bird with unusually long hindlimb proportions, was followed by the discovery of two closely related species, Longicrusavis houi and Parahongshanornis chaoyangensis. Together forming the Hongshanornithidae, these species reveal important information about the early diversity and morphological specialization of ornithuromorphs, the clade that contains all living birds. Here we report on a new specimen (DNHM D2945/6) referable to Hongshanornis longicresta that contributes significant information to better understand the morphology, trophic ecology, and aerodynamics of this species, as well as the taxonomy of the Hongshanornithidae. Most notable are the well-preserved wings and feathered tail of DNHM D2945/6, which afford an accurate reconstruction of aerodynamic parameters indicating that as early as 125 million years ago, basal ornithuromorphs had evolved aerodynamic surfaces comparable in size and design to those of many modern birds, and flight modes alike to those of some small living birds. PMID- 24482757 TI - Effects of reduced dissolved oxygen concentrations on physiology and fluorescence of hermatypic corals and benthic algae. AB - While shifts from coral to seaweed dominance have become increasingly common on coral reefs and factors triggering these shifts successively identified, the primary mechanisms involved in coral-algae interactions remain unclear. Amongst various potential mechanisms, algal exudates can mediate increases in microbial activity, leading to localized hypoxic conditions which may cause coral mortality in the direct vicinity. Most of the processes likely causing such algal exudate induced coral mortality have been quantified (e.g., labile organic matter release, increased microbial metabolism, decreased dissolved oxygen availability), yet little is known about how reduced dissolved oxygen concentrations affect competitive dynamics between seaweeds and corals. The goals of this study were to investigate the effects of different levels of oxygen including hypoxic conditions on a common hermatypic coral Acropora yongei and the common green alga Bryopsis pennata. Specifically, we examined how photosynthetic oxygen production, dark and daylight adapted quantum yield, intensity and anatomical distribution of the coral innate fluorescence, and visual estimates of health varied with differing background oxygen conditions. Our results showed that the algae were significantly more tolerant to extremely low oxygen concentrations (2-4 mg L(-1)) than corals. Furthermore corals could tolerate reduced oxygen concentrations, but only until a given threshold determined by a combination of exposure time and concentration. Exceeding this threshold led to rapid loss of coral tissue and mortality. This study concludes that hypoxia may indeed play a significant role, or in some cases may even be the main cause, for coral tissue loss during coral-algae interaction processes. PMID- 24482758 TI - Being there: a brief visit to a neighbourhood induces the social attitudes of that neighbourhood. AB - There are differences between human groups in social behaviours and the attitudes that underlie them, such as trust. However, the psychological mechanisms that produce and reproduce this variation are not well understood. In particular, it is not clear whether assimilation to the social culture of a group requires lengthy socialization within that group, or can be more rapidly and reversibly evoked by exposure to the group's environment and the behaviour of its members. Here, we report the results of a two-part study in two neighbourhoods of a British city, one economically deprived with relatively high crime, and the other affluent and lower in crime. In the first part of the study, we surveyed residents and found that the residents of the deprived neighbourhood had lower levels of social trust and higher levels of paranoia than the residents of the affluent neighbourhood. In the second part, we experimentally transported student volunteers who resided in neither neighbourhood to one or the other, and had them walk around delivering questionnaires to houses. We surveyed their trust and paranoia, and found significant differences according to which neighbourhood they had been sent to. The differences in the visitors mirrored the differences seen in the residents, with visitors to the deprived neighbourhood reporting lower social trust and higher paranoia than visitors to the affluent one. The magnitudes of the neighbourhood differences in the visitors, who only spent up to 45 min in the locations, were nearly as great as the magnitudes of those amongst the residents. We discuss the relevance of our findings to differential psychology, neighbourhood effects on social outcomes, and models of cultural evolution. PMID- 24482759 TI - Development of a novel clinical scoring system for on-farm diagnosis of bovine respiratory disease in pre-weaned dairy calves. AB - Several clinical scoring systems for diagnosis of bovine respiratory disease (BRD) in calves have been proposed. However, such systems were based on subjective judgment, rather than statistical methods, to weight scores. Data from a pair-matched case-control study on a California calf raising facility was used to develop three novel scoring systems to diagnose BRD in preweaned dairy calves. Disease status was assigned using both clinical signs and diagnostic test results for BRD-associated pathogens. Regression coefficients were used to weight score values. The systems presented use nasal and ocular discharge, rectal temperature, ear and head carriage, coughing, and respiratory quality as predictors. The systems developed in this research utilize fewer severity categories of clinical signs, require less calf handling, and had excellent agreement (Kappa > 0.8) when compared to an earlier scoring system. The first scoring system dichotomized all clinical predictors but required inducing a cough. The second scoring system removed induced cough as a clinical abnormality but required distinguishing between three levels of nasal discharge severity. The third system removed induced cough and forced a dichotomized variable for nasal discharge. The first system presented in this study used the following predictors and assigned values: coughing (induced or spontaneous coughing, 2 points), nasal discharge (any discharge, 3 points), ocular discharge (any discharge, 2 points), ear and head carriage (ear droop or head tilt, 5 points), fever (>=39.2 degrees C or 102.5 degrees F, 2 points), and respiratory quality (abnormal respiration, 2 points). Calves were categorized "BRD positive" if their total score was >=4. This system correctly classified 95.4% cases and 88.6% controls. The second presented system categorized the predictors and assigned weights as follows: coughing (spontaneous only, 2 points), mild nasal discharge (unilateral, serous, or watery discharge, 3 points), moderate to severe nasal discharge (bilateral, cloudy, mucoid, mucopurlent, or copious discharge, 5 points), ocular discharge (any discharge, 1 point), ear and head carriage (ear droop or head tilt, 5 points), fever (>=39.2 degrees C, 2 points), and respiratory quality (abnormal respiration, 2 points). Calves were categorized "BRD positive" if their total score was >=4. This system correctly classified 89.3% cases and 92.8% controls. The third presented system used the following predictors and scores: coughing (spontaneous only, 2 points), nasal discharge (any, 4 points), ocular discharge (any, 2 points), ear and head carriage (ear droop or head tilt, 5 points), fever (>=39.2 degrees C, 2 points), and respiratory quality (abnormal respiration, 2 points). Calves were categorized "BRD positive" if their total score was >=5. This system correctly classified 89.4% cases and 90.8% controls. Each of the proposed systems offer few levels of clinical signs and data-based weights for on-farm diagnosis of BRD in dairy calves. PMID- 24482760 TI - Composable languages for bioinformatics: the NYoSh experiment. AB - Language WorkBenches (LWBs) are software engineering tools that help domain experts develop solutions to various classes of problems. Some of these tools focus on non-technical users and provide languages to help organize knowledge while other workbenches provide means to create new programming languages. A key advantage of language workbenches is that they support the seamless composition of independently developed languages. This capability is useful when developing programs that can benefit from different levels of abstraction. We reasoned that language workbenches could be useful to develop bioinformatics software solutions. In order to evaluate the potential of language workbenches in bioinformatics, we tested a prominent workbench by developing an alternative to shell scripting. To illustrate what LWBs and Language Composition can bring to bioinformatics, we report on our design and development of NYoSh (Not Your ordinary Shell). NYoSh was implemented as a collection of languages that can be composed to write programs as expressive and concise as shell scripts. This manuscript offers a concrete illustration of the advantages and current minor drawbacks of using the MPS LWB. For instance, we found that we could implement an environment-aware editor for NYoSh that can assist the programmers when developing scripts for specific execution environments. This editor further provides semantic error detection and can be compiled interactively with an automatic build and deployment system. In contrast to shell scripts, NYoSh scripts can be written in a modern development environment, supporting context dependent intentions and can be extended seamlessly by end-users with new abstractions and language constructs. We further illustrate language extension and composition with LWBs by presenting a tight integration of NYoSh scripts with the GobyWeb system. The NYoSh Workbench prototype, which implements a fully featured integrated development environment for NYoSh is distributed at http://nyosh.campagnelab.org. PMID- 24482761 TI - The Xanthomonas Ax21 protein is processed by the general secretory system and is secreted in association with outer membrane vesicles. AB - Pattern recognition receptors (PRRs) play an important role in detecting invading pathogens and mounting a robust defense response to restrict infection. In rice, one of the best characterized PRRs is XA21, a leucine rich repeat receptor-like kinase that confers broad-spectrum resistance to multiple strains of the bacterial pathogen Xanthomonas oryzae pv. oryzae (Xoo). In 2009 we reported that an Xoo protein, called Ax21, is secreted by a type I-secretion system and that it serves to activate XA21-mediated immunity. This report has recently been retracted. Here we present data that corrects our previous model. We first show that Ax21 secretion does not depend on the predicted type I secretion system and that it is processed by the general secretion (Sec) system. We further show that Ax21 is an outer membrane protein, secreted in association with outer membrane vesicles. Finally, we provide data showing that ax21 knockout strains do not overcome XA21-mediated immunity. PMID- 24482762 TI - PhyloSift: phylogenetic analysis of genomes and metagenomes. AB - Like all organisms on the planet, environmental microbes are subject to the forces of molecular evolution. Metagenomic sequencing provides a means to access the DNA sequence of uncultured microbes. By combining DNA sequencing of microbial communities with evolutionary modeling and phylogenetic analysis we might obtain new insights into microbiology and also provide a basis for practical tools such as forensic pathogen detection. In this work we present an approach to leverage phylogenetic analysis of metagenomic sequence data to conduct several types of analysis. First, we present a method to conduct phylogeny-driven Bayesian hypothesis tests for the presence of an organism in a sample. Second, we present a means to compare community structure across a collection of many samples and develop direct associations between the abundance of certain organisms and sample metadata. Third, we apply new tools to analyze the phylogenetic diversity of microbial communities and again demonstrate how this can be associated to sample metadata. These analyses are implemented in an open source software pipeline called PhyloSift. As a pipeline, PhyloSift incorporates several other programs including LAST, HMMER, and pplacer to automate phylogenetic analysis of protein coding and RNA sequences in metagenomic datasets generated by modern sequencing platforms (e.g., Illumina, 454). PMID- 24482763 TI - Rapid microfluidic immunoassays of cancer biomarker proteins using disposable inkjet-printed gold nanoparticle arrays. PMID- 24482765 TI - Isolation and characterisation of degradation impurities in the cefazolin sodium drug substance. AB - Two unknown impurities were detected in the cefazolin sodium bulk drug substance using gradient reversed-phase high-performance liquid chromategraphy (HPLC). These impurities were isolated by preparative HPLC and characterized by using spectroscopic techniques like LC-MS, LC-MS/MS, 1D, 2D NMR, and FT-IR. Based on the spectral data, the impurities have been characterized as N-(2,2 dihydroxyethyl)-2-(1H-tetrazol-1-yl)acetamide (Impurity-I) and 2-{carboxy[(1H tetrazol-1-ylacetyl)amino]methyl}-5-methylidene-5,6-dihydro-2H-1,3-thiazine-4 carboxylic acid (Impurity-II). The structures of these impurities were also established unambiguously by co-injection into HPLC to confirm the retention time. To the best of our knowledge, these two impurities were not reported elsewhere. PMID- 24482766 TI - Development and Validation of a Stability-Indicating RP-HPLC Method for the Simultaneous Determination of Phenoxyethanol, Methylparaben, Propylparaben, Mometasone Furoate, and Tazarotene in Topical Pharmaceutical Dosage Formulation. AB - A stability-indicating RP-HPLC method has been developed and validated for the simultaneous determination of phenoxyethanol (PE), methylparaben (MP), propylparaben (PP), mometasone furoate (MF), and tazarotene (TA) in topical pharmaceutical dosage formulation. The desired chromatographic separation was achieved on the Waters X-BridgeTM C18 (50*4.6mm, 3.5MU) column using gradient elution at 256 nm detection wavelength. The optimized mobile phase consisted of 0.1%v/v orthophosphoric acid in water as solvent-A and acetonitrile as solvent-B. The method showed linearity over the range of 5.88-61.76 MUg/mL, 0.18-62.36 MUg/mL, 0.17-6.26 MUg/mL, 0.47-31.22 MUg/mL, and 0.44-30.45 MUg/mL for PE, MP, PP, MF, and TA, respectively. The recovery for all of the components was in the range of 98-102%. The stability-indicating capability of the developed method was established by analysing the forced degradation samples, in which the spectral purity of PE, MP, PP, MF, and TA along with the separation of degradation products from the analyte peaks was achieved. The proposed method was successfully applied for the quantitative determination of PE, MP, PP, MF, and TA in a cream sample. PMID- 24482767 TI - Stability-Indicating RP-HPLC Method for the Simultaneous Estimation of Doxofylline and Terbutalinesulphate in Pharmaceutical Formulations. AB - An isocratic, stability-indicating, reversed-phase high-performance liquid chromatography (RP-HPLC) method was developed for the quantitative determination of doxofylline and terbutaline sulphate, used for the treatment of respiratory problems. The chromatographic separation was achieved on a Zorbax-SB Phenyl 250 * 4.6mm * 5 MUm column with the mobile phase consisting of a mixture of 25 mM ammonium acetate (pH 5.0) : acetonitrile (85:15 %v/v) at a flow rate of 1.0 ml/min. The eluate was monitored at 274 nm using a PDA detector. Forced degradation studies were performed on the bulk sample of doxofylline and terbutaline sulphate using acid (0.1N HCl), base (0.1N NaOH), oxidation (10% hydrogen peroxide), photolytic, and thermal degradation conditions. Good resolution was observed between the degradants and analytes. Degradation products resulting from the stress studies did not interfere with the detection of doxofylline and terbutaline sulphate, thus the assay is stability-indicating. The method has the requisite accuracy, selectivity, sensitivity, and precision for the simultaneous estimation of doxofylline and terbutaline sulphate in bulk and pharmaceutical dosage forms. The limit of quantitation and limit of detection were found to be 1.16 MUg/ml and 0.38 MUg/ml for doxofylline, 2.08 MUg/ml and 0.62 MUg/ml for terbutaline sulphate, respectively. PMID- 24482764 TI - Pharmacological and phytochemical appraisal of selected medicinal plants from jordan with claimed antidiabetic activities. AB - Plant species have long been regarded as possessing the principal ingredients used in widely disseminated ethnomedical practices. Different surveys showed that medicinal plant species used by the inhabitants of Jordan for the traditional treatment of diabetes are inadequately screened for their therapeutic/preventive potential and phytochemical findings. In this review, traditional herbal medicine pursued indigenously with its methods of preparation and its active constituents are listed. Studies of random screening for selective antidiabetic bioactivity and plausible mechanisms of action of local species, domesticated greens, or wild plants are briefly discussed. Recommended future directives incurring the design and conduct of comprehensive trials are pointed out to validate the usefulness of these active plants or bioactive secondary metabolites either alone or in combination with existing conventional therapies. PMID- 24482768 TI - Chemometrics-Assisted UV Spectrophotometric and RP-HPLC Methods for the Simultaneous Determination of Tolperisone Hydrochloride and Diclofenac Sodium in their Combined Pharmaceutical Formulation. AB - Chemometrics-assisted UV spectrophotometric and RP-HPLC methods are presented for the simultaneous determination of tolperisone hydrochloride (TOL) and diclofenac sodium (DIC) from their combined pharmaceutical dosage form. Chemometric methods are based on principal component regression and partial least-square regression models. Two sets of standard mixtures, calibration sets, and validation sets were prepared. Both models were optimized to quantify each drug in the mixture using the information included in the UV absorption spectra of the appropriate solution in the range 241-290 nm with the intervals lambda = 1 nm at 50 wavelengths. The optimized models were successfully applied to the simultaneous determination of these drugs in synthetic mixture and pharmaceutical formulation. In addition, an HPLC method was developed using a reversed-phase C18 column at ambient temperature with a mobile phase consisting of methanol:acetonitrile:water (60:30:10 v/v/v), pH-adjusted to 3.0, with UV detection at 275 nm. The methods were validated in terms of linearity, accuracy, precision, sensitivity, specificity, and robustness in the range of 3-30 MUg/mL for TOL and 1-10 MUg/mL for DIC. The robustness of the HPLC method was tested using an experimental design approach. The developed HPLC method, and the PCR and PLS models were used to determine the amount of TOL and DIC in tablets. The data obtained from the PCR and PLS models were not significantly different from those obtained from the HPLC method at 95% confidence limit. PMID- 24482769 TI - Stability-Indicating UPLC Method for Tramadol HCl Impurities in the Tramadol Injection after Dilution by Infusion Fluids (5% Dextrose and 0.9% Sodium Chloride). AB - A novel, rapid, and sensitive ultra-performance liquid chromatography (UPLC) method has been developed and validated as per ICH guidelines for the determination of tramadol HCl impurities in the tramadol HCl injection after reconstitution by infusion fluids (5% dextrose and 0.9% sodium chloride). The tramadol HCl injection is for the treatment of patients with moderate-to-severe pain. The stability of the reconstituted solution is critical before intravenous injection. The literature search resulted in few published articles on assays of tramadol in infusion fluids by conventional HPLC. No attempts have yet been made to determine the impurities in infusion fluids, as the concentration of tramadol after reconstitution is extremely low (0.4 mg/mL) and that of impurities is even lower. The proposed method is novel as it allows the quantitation of the impurities of tramadol HCl and is based on modern chromatographic techniques like UPLC. The method was developed using the Waters Acquity BEH C18 column with a mobile phase consisting of a gradient mixture of solvent A (trifluroacetic acid buffer) and solvent B (methanol: acetonitrile). The model stability study was designed by diluting the tramadol HCl injection in the 5% dextrose injection and 0.9% sodium chloride injection. Each mixture was kept under storage at room temperature (25 +/- 2 degrees C) for testing at initial, 2, 4, 8, 12, 18 & 24 hours. The validation study illustrates that the proposed method is suitable for the determination of tramadol and its impurities. The proposed method makes use of the LC-MS-compatible mobile phase. It can be useful for the determination of tramadol HCl and its impurities in plasma samples and other pharmaceutical dosage forms. PMID- 24482770 TI - Development and Validation of a Stability-Indicating Assay of Etofenamate by RP HPLC and Characterization of Degradation Products. AB - A validated stability-indicating RP-HPLC method for etofenamate (ETF) was developed by separating its degradation products on a C18 (250 mm * 4.6 mm 5 MUm) Qualisil BDS column using a phosphate buffer (pH-adjusted to 6.0 with orthophosphoric acid) and methanol in the ratio of 20:80 % v/v as the mobile phase at a flow rate of 1.0 mL/min. The column effluents were monitored by a photodiode array detector set at 286 nm. The method was validated in terms of specificity, linearity, accuracy, precision, detection limit, quantification limit, and robustness. Forced degradation of etofenamate was carried out under acidic, basic, thermal, photo, and peroxide conditions and the major degradation products of acidic and basic degradation were isolated and characterized by (1)H NMR, (13)C-NMR, and mass spectral studies. The mass balance of the method varied between 92-99%. PMID- 24482771 TI - Determination of Cephalexin Monohydrate in Pharmaceutical Dosage Form by Stability-Indicating RP-UFLC and UV Spectroscopic Methods. AB - An ultra-fast liquid chromatographic method and two UV spectroscopic methods were developed for the determination of cephalexin monohydrate in pharmaceutical dosage forms. Isocratic separation was performed on an Enable C18G column (250 mm * 4.6 mm i.d., 5 MUm) using methanol:0.01 M TBAHS (50:50, v/v) as the mobile phase at a flow rate of 1.0 ml/min. The PDA detection wavelength was set at 254 nm. The UV spectroscopic method was performed at 261 nm and at 256-266 nm for the AUC method using a phosphate buffer (pH=5.5). The linearity was observed over a concentration range of 1.0-120 MUg/ml for UFLC and both of the UV spectroscopic methods (correlation coefficient=0.999). The developed methods were validated according to ICH guidelines. The relative standard deviation values for the intraday and interday precision studies were < 2%, and the accuracy was > 99% for all of the three methods. The developed methods were used successfully for the determination of cephalexin in dry syrup formulation. PMID- 24482772 TI - Design of Experiment (DOE) Utilization to Develop a Simple and Robust Reversed Phase HPLC Technique for Related Substances' Estimation of Omeprazole Formulations. AB - A simple, fast, and sensitive reversed-phase HPLC method with UV detection was developed for the quantitation of omeprazole and its eleven related compounds (impurities) in pharmaceutical formulation using the Thermo Accucore C-18 (50 mm * 4.6 mm, 2.6 MUm) column. The separation among all the compounds was achieved with a flow rate of 0.8 mL min(-1) employing a gradient program of mobile phase A [0.08 M glycine buffer pH 9.0: acetonitrile; 95:05 (v/v)] and mobile phase B [acetonitrile: methanol; 65:35 (v/v)]. The chromatographic detection was carried out at a wavelength of 305 nm. The method was validated for specificity, linearity, and recovery. The huskiness of the method was determined prior to validation using the Design of Experiments (DOE). The ANOVA analysis of DOE with a 95% confidence interval (CI) confirmed the buffer pH of mobile phase A (p <0.0001) and column temperature (p<0.0001) as significant Critical Method Parameters (CMPs). PMID- 24482773 TI - Ant Plant (Myrmecodia tuberosa) Hypocotyl Extract Modulates TCD4+ and TCD8+ Cell Profile of Doxorubicin-Induced Immune-Suppressed Sprague Dawley Rats In Vivo. AB - Myrmecodia tuberosa Jack (Rubiaceae) has been used as part of traditional Indonesian remedies for a wide range of therapeutic usages in West Papua. Our preliminary study revealed the significant potency of these plant extracts and fractions as an immunomodulator by an in vitro technique on Balb/c mice. This study explored the effect of M. tuberosa hypocotyl ethanol extract on the TCD4+ and TCD8+ cell profiles of doxorubicin (Dox)-induced immune-suppressed Sprague Dawley (SD) rats by an in vivo method. Dried powder of M. tuberosa hypocotyl was macerated in 95% ethanol. Following solvent evaporation in a vacuum, the ethanol extract (EE) was partitioned to yield an n-hexane fraction (FH) and residue (FNH). FNH was further partitioned to yield ethyl acetate (FEtOAc) and water fractions (FW). The extract and fractions in the concentrations 10, 20, 50, and 100 MUg/mL were tested on macrophage cells by the latex bead method, while the proliferation of lymphocyte cells was evaluated by the MTT assay. The total phenolic and flavonoid contents of those fractions were evaluated. The active fraction was administrated orally on Dox-induced SD rats for 28 days by an in vivo method to observe the TCD4+ and TCD8+ cell profiles. The in vivo assay showed that the FNH could maintain the number of TCD4+ cells, but not the number of TCD8+ cells. The ED50 observed was 24.24 mg/kg BW. Steroid/terpenoid compounds were detected in this fraction along with the phenolics and flavonoids. The FNH contained 3.548 +/- 0.058% GAE of total phenolics and 0.656 +/- 0.026% QE of total flavonoids. M. tuberosa hypocotyl extract is a potent immunomodulatory agent and may act as co-chemotherapy in Dox use. PMID- 24482774 TI - Effect of Tephrosia purpurea (L.) Pers. Leaves on Gentamicin-Induced Nephrotoxicity in Rats. AB - The aim of the study was to evaluate the nephroprotective and nephrocurative effects of Tephrosia purpurea (L.) Pers. leaves against gentamicin-induced acute renal injury in albino rats. The maximum free radical scavenging activity of the ethanolic extract was the basis for the selection of this extract for the in vivo study. Gentamicin (40 mg/kg, s.c.) was administered to induce toxicity in the toxic group and the ethanolic extract (200 mg/kg p.o.) was administered in all treated groups. Blood urea and serum creatinine levels were monitored to assess the effects. The antioxidant potential was also evaluated by the estimation of reduced glutathione (GSH) and malondialdehyde (MDA). Gentamicin intoxication caused significant increases in blood urea and serum creatinine levels as compared to the normal control. In the preventive regimen, the extract (200 mg/kg, p.o.) showed significant reductions in the elevated blood urea and serum creatinine. Histopathological changes were in accordance with the biochemical findings. Also in the curative regimen, the blood urea and serum creatinine levels revealed significant curative effects. In our in vivo antioxidant activity, the GSH level was significantly (P< 0.05) increased in the extract treated groups, whereas MDA was reduced significantly (P< 0.05). Further thin layer chromatography (TLC) and high-performance thin layer chromatography (HPTLC) led us to ascertain the presence of rutin and quercetin in the extract. We were able to isolate and characterize an isolate from the ethanolic extract and characterize it on the basis of chromatographic, melting point, FTIR, NMR, and mass spectroscopic studies. The findings suggest that the ethanol extract of Tephrosia purpurea leaves possesses marked nephroprotective and curative activities without any toxicity. The proposed mechanisms for the claimed activity are antioxidant activity and the inhibition of an overproduction of NO and Cox-2 expression. These activities may be attributed to the presence of phenolics and flavonoidal compounds like rutin and quercetin. Thus, it can be said that Tephrosia purpurea could offer a promising role in the treatment of acute renal injury caused by nephrotoxins like gentamicin. PMID- 24482775 TI - Accelerated Stability Testing of a Clobetasol Propionate-Loaded Nanoemulsion as per ICH Guidelines. AB - The physical and chemical degradation of drugs may result in altered therapeutic efficacy and even toxic effects. Therefore, the objective of this work was to study the stability of clobetasol propionate (CP) in a nanoemulsion. The nanoemulsion formulation containing CP was prepared by the spontaneous emulsification method. For the formulation of the nanoemulsion, Safsol, Tween 20, ethanol, and distilled water were used. The drug was incorporated into an oil phase in 0.05% w/v. The lipophilic nature of the drug led to the O/W nanoemulsion formulation. This was characterized by droplet size, pH, viscosity, conductivity, and refractive index. Stability studies were performed as per ICH guidelines for a period of three months. The shelf life of the nanoemulsion formulation was also determined after performing accelerated stability testing (40 degrees C +/- 2 degrees C and 75% +/- 5% RH). We also performed an intermediate stability study (30 degrees C +/- 2 degrees C/65% RH +/- 5% RH). It was found that the droplet size, conductivity, and refractive index were slightly increased, while the viscosity and pH slightly decreased at all storage conditions during the 3-month period. However, the changes in these parameters were not statistically significant (p>=0.05). The degradation (%) of the optimized nanoemulsion of CP was determined and the shelf life was found to be 2.18 years at room temperature. These studies confirmed that the physical and chemical stability of CP were enhanced in the nanoemulsion formulation. PMID- 24482776 TI - Application of an amine functionalized biopolymer in the colonic delivery of glycyrrhizin: a design and in vivo efficacy study. AB - In our current study, a newer amine functionalized guar gum derivative was studied for its efficacy in colonic drug delivery. Glycyrrhizic acid mono ammonium salt was used as the model drug. Drug-loaded microparticles were formulated by ionic crosslinking using sodium tripolyphosphate. The Scanning Electron Microscopic study revealed spherical particles of sizes from 4.9 +/- 3.8 MUm to 6.9 +/- 3.9 MUm. The FT-IR studies presented a possible interaction between the drug and the polymer. The drug was encapsulated in amorphous form as observed from the powder X-Ray Diffraction studies. A cumulative drug release study was carried out in simulated gastric, intestinal, and colonic fluids. The cumulative drug release studies presented a burst release followed by a sustained release of the drug in simulated colonic fluid containing rat cecal contents. The drug-polymer ratio was optimised using a 3(2) factorial design by taking the amounts of glycyrrhizic acid (X1) and guar gum alkyl amine (X2) as the independant variables. The percent cumulative drug release at 240 mins (Q240), 720 mins (Q720), and at 1,440 mins (Q1440) were considered as the dependant variables. The efficacy of the optimized formulation was studied in a 2,4,6 trinitrobenzene sulfonic acid-induced rat colitis model. The tissue's nitric oxide, malondialdehyde, and myeloperoxidase activities were found to be much lower in the microparticle-treated group compared to free drug-treated group. The histology of the colonic tissue from the treated group of animals revealed almost no infiltration of inflammatory cells in the tissue for the microparticle-treated group of animals. The synthesized amine derivative of guar gum was found to be better in vitro with a better in vivo efficacy in the colonic delivery of glycyrrhizic acid monoammonium salt and can be considered as a newer modified biopolymer for colonic drug delivery. PMID- 24482777 TI - Comparison study of oral iron preparations using a human intestinal model. AB - Iron deficiency and related iron deficiency anaemia (IDA) are the most prevalent nutritional disorders worldwide. The standard treatment involves supplementation with solid or liquid iron supplement preparations, usually based on a ferrous salt such as ferrous sulphate, ferrous fumarate, or ferrous gluconate. In the present study, we compared iron uptake and absorption from various solid and liquid iron supplement preparations currently available in the United Kingdom using the well-characterised human epithelial adenocarcinoma cell line Caco-2. Intracellular ferritin protein formation by the Caco-2 cell was considered an indicator of cellular iron uptake and absorption. We investigated the effects of formulation ingredients at a defined pH on iron uptake and absorption, and designed a novel two-stage dissolution-absorption protocol that mimicked physiological conditions. Our experiments revealed wide variations in the rate of dissolution between the various solid iron preparations. Conventional-release ferrous iron tablets dissolved rapidly (48 +/- 4 mins to 64 +/- 4 mins), whereas modified-released tablets and capsules took significantly longer to undergo complete dissolution (274 +/- 8 to 256 +/- 8 mins). Among the solid iron preparations, ferrous sulphate conventional-release tablets demonstrated the highest iron absorption, whereas modified-release ferrous preparations demonstrated uniformly low iron absorption, as compared to the control (P < 0.05). Taken together, our results demonstrate that there are wide-ranging variations in dissolution times and iron uptake from oral iron preparations, with the physical characteristics of the preparation as well as the form of iron playing a key role. PMID- 24482778 TI - Ascorbic Acid for the safe use of a sunscreen agent: accumulation of nano zinc oxide and titanium dioxide on the skin. AB - OBJECTIVE: Physical UV absorbers such as titanium dioxide or zinc oxide have been found to be highly protective against ultraviolet radiation. Sun protection factor depends on the accumulation of the minerals on the skin. UV-absorbing agents must accumulate within the upper skin layers in order to provide a dense light-absorbing layer and guarantee water resistance. The aim of this work was to increase the skin deposition and efficacy of sunscreens without increasing their skin permeation. The application possibility of EDX to determine the quantitative elemental composition of zinc and titanium on the skin surface was studied. METHOD: The changes induced in the skin deposition of physical UV absorbers in conjunction with ascorbic acid were studied. In vitro skin permeation and X-ray elemental analysis were carried out to determine the mineral skin deposition effect of ascorbic acid. KEY FINDINGS: Results indicate that ascorbic acid may significantly increase the skin deposition (p < 0.05) of these minerals on the skin without increasing their skin permeation (p > 0.05). Flow through diffusion cell and X-ray elemental analyses appear to be complementary and show that ascorbic acid is able to increase accumulation of sunscreen on the skin. PMID- 24482779 TI - Liposomes for topical use: a physico-chemical comparison of vesicles prepared from egg or soy lecithin. AB - Developments in nanotechnology and in the formulation of liposomal systems provide the opportunity for cosmetic dermatology to design novel delivery systems. Determination of their physico-chemical parameters has importance when developing a nano-delivery system. The present study highlights some technological aspects/characteristics of liposomes formulated from egg or soy lecithins for topical use. Alterations in the pH, viscosity, surface tension, and microscopic/macroscopic appearance of these vesicular systems were investigated. The chemical composition of the two types of lecithin was checked by mass spectrometry. Caffeine, as a model molecule, was encapsulated into multilamellar vesicles prepared from the two types of lecithin: then zeta potential, membrane fluidity, and encapsulation efficiency were compared. According to our observations, samples prepared from the two lecithins altered the pH in opposite directions: egg lecithin increased it while soy lecithin decreased it with increased lipid concentration. Our EPR spectroscopic results showed that the binding of caffeine did not change the membrane fluidity in the temperature range of possible topical use (measured between 2 and 50 degrees C). Combining our results on encapsulation efficiency for caffeine (about 30% for both lecithins) with those on membrane fluidity data, we concluded that the interaction of caffeine with the liposomal membrane does not change the rotational motion of the lipid molecules close to the head group region. In conclusion, topical use of egg lecithin for liposomal formulations can be preferred if there are no differences in the physico-chemical properties due to the encapsulated drugs, because the physiological effects of egg lecithin vesicles on skin are significantly better than that of soy lecithin liposomes. PMID- 24482780 TI - Erratum to "intranasal delivery of chitosan nanoparticles for migraine therapy" [sci pharm. 2013; 81: 843-854]. PMID- 24482781 TI - The utility of human challenge studies in vaccine development: lessons learned from cholera. AB - Experiments in which virulent infectious organisms are administered to healthy adult volunteers with the intent to deliberately induce infection have been practiced for centuries. Many useful applications have developed from these experiments such as the provision of evidence of microbial pathogenicity and the identification of key virulence factors. Challenge studies have also played an important role in the evaluation of preliminary efficacy of potential vaccine candidates. Over the past 40 years, these experimental human challenge studies have found particular utility with regards to the development of both living and nonliving attenuated cholera vaccines. This review highlights some of the important contributions made by these challenge studies to cholera vaccine research. PMID- 24482782 TI - The NIHSS Score and its Components can Predict Cortical Stroke. AB - BACKGROUND: Neuroprotective agents have the potential to reduce ischemia to penumbra of the cortex, but are time-sensitive. To quickly determine whether a cortical stroke is present without imaging, we created a scoring system based on the NIH stroke scale (NIHSS) that can accurately predict cortical damage in an acute ischemic stroke (AIS). METHODS: Patients treated with tPA for AIS were retrospectively assessed through prospectively acquired databases at two stroke centers. Stroke was classified as cortical vs. non-cortical stroke. The total NIHSS score, cortical components (gaze, visual fields, language, and neglect) and cortical score (sum of cortical components) were analyzed for site 1 and then validated for site 2 for sensitivity and positive predictive value (PPV) for a cortical stroke. RESULTS: An acute infarct was detected in 194/239 (81%) patients at site 1 and 122/174 (70%) at site 2 on diffusion-weighted MRI. Cortical involvement was found in 71% (site 1) and 75% (site 2). The median cortical score was 25% of the total NIHSS score at both sites. NIHSS >= 4 had the highest sensitivity; PPV was 90% for any cortical sign with >= 2 points. The best combination of sensitivity and PPV was cortical score/NIHSS score >=10%. DISCUSSION: If a trial targeting cortical stroke required that the cortical score represent at least 10% of the total NIHSS score with no imaging, less than 10% of patients with cortical stroke would be missed and less than 18% of patients would be misclassified as having a cortical stroke. PMID- 24482783 TI - Two new entities: newly developed diagnostic criteria for temporomandibular disorders, and the Journal of Oral & Facial Pain and Headache. PMID- 24482785 TI - Tailored treatments in temporomandibular disorders: where are we now? A systematic qualitative literature review. AB - AIMS: To conduct a systematic review to evaluate the evidence of possible benefits of tailored treatments for temporomandibular disorders (TMD) based on randomized controlled trials (RCTs). METHODS: Reports of RCTs investigating treatments tailored to TMD patients' psychosocial characteristics were systematically searched for through March 2013 in the following databases: Cochrane Central Register of Controlled Trials, PubMed, and Web of Science. The methodological quality of the RCTs was assessed using the Cochrane Collaboration's tool for assessing risk of bias. RESULTS: Seven reports met the inclusion criteria. In all studies a subgroup of TMD patients, mainly identified by multidimensional diagnostic systems such as the Research Diagnostic Criteria for TMD Axis II or Multidimensional Pain Inventory, were offered a treatment intervention hypothesized to be suitable for that particular patient group. The quality of the trials was compromised in all cases. Two studies focused on well functioning TMD patients. In both studies, self-care gave results equal to or better than usual conservative TMD treatment. The treatments were targeted for patients with compromised psychosocial adaptation in five studies, and typically included a cognitive behavioral treatment component. In all trials the results supported the efficacy of tailored treatment, albeit in one trial only in the short-term. CONCLUSION: The identified studies offer cautious support to the notion that treatment targeted to different psychosocial subgroups of TMD pain patients may be beneficial. PMID- 24482786 TI - Fatigue mediates the relationship between pain interference and distress in patients with persistent orofacial pain. AB - AIMS: To test the role of fatigue and its subtypes (general, physical, emotional, mental, and vigor) in mediating the relationship between psychological distress and pain interference. METHODS: Retrospective, de-identified records were examined for 431 patients seeking treatment for persistent orofacial pain. Primary diagnoses of participants were muscle pain (29.8%), joint pain (26.0%), neuropathic pain (19.5%), and other (ie, fibromyalgia, centrally mediated myalgia, tendonitis, dental pain, cervical spine displacement, and no diagnosis; 24.7%). Mediation models were tested with distress as the independent variable, interference as the dependent variable, and fatigue or its subtypes as the mediators. RESULTS: After controlling for pain duration and average levels of pain, total fatigue mediated the relationship between distress and interference. Fatigue subtypes partially mediated the relationship between distress and interference, but mediation was strongest with the composite fatigue variable. The results, however, should be interpreted cautiously, as data were collected at a single time point and do not imply causality. CONCLUSION: These results suggest that interventions targeted specifically at fatigue symptoms may be helpful for reducing interference and improving quality of life in patients with persistent orofacial pain. PMID- 24482784 TI - Diagnostic Criteria for Temporomandibular Disorders (DC/TMD) for Clinical and Research Applications: recommendations of the International RDC/TMD Consortium Network* and Orofacial Pain Special Interest Group?. AB - AIMS: The original Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) Axis I diagnostic algorithms have been demonstrated to be reliable. However, the Validation Project determined that the RDC/TMD Axis I validity was below the target sensitivity of >= 0.70 and specificity of >= 0.95. Consequently, these empirical results supported the development of revised RDC/TMD Axis I diagnostic algorithms that were subsequently demonstrated to be valid for the most common pain-related TMD and for one temporomandibular joint (TMJ) intra articular disorder. The original RDC/TMD Axis II instruments were shown to be both reliable and valid. Working from these findings and revisions, two international consensus workshops were convened, from which recommendations were obtained for the finalization of new Axis I diagnostic algorithms and new Axis II instruments. METHODS: Through a series of workshops and symposia, a panel of clinical and basic science pain experts modified the revised RDC/TMD Axis I algorithms by using comprehensive searches of published TMD diagnostic literature followed by review and consensus via a formal structured process. The panel's recommendations for further revision of the Axis I diagnostic algorithms were assessed for validity by using the Validation Project's data set, and for reliability by using newly collected data from the ongoing TMJ Impact Project-the follow-up study to the Validation Project. New Axis II instruments were identified through a comprehensive search of the literature providing valid instruments that, relative to the RDC/TMD, are shorter in length, are available in the public domain, and currently are being used in medical settings. RESULTS: The newly recommended Diagnostic Criteria for TMD (DC/TMD) Axis I protocol includes both a valid screener for detecting any pain-related TMD as well as valid diagnostic criteria for differentiating the most common pain-related TMD (sensitivity >= 0.86, specificity >= 0.98) and for one intra-articular disorder (sensitivity of 0.80 and specificity of 0.97). Diagnostic criteria for other common intra-articular disorders lack adequate validity for clinical diagnoses but can be used for screening purposes. Inter-examiner reliability for the clinical assessment associated with the validated DC/TMD criteria for pain related TMD is excellent (kappa >= 0.85). Finally, a comprehensive classification system that includes both the common and less common TMD is also presented. The Axis II protocol retains selected original RDC/TMD screening instruments augmented with new instruments to assess jaw function as well as behavioral and additional psychosocial factors. The Axis II protocol is divided into screening and comprehensive self report instrument sets. The screening instruments' 41 questions assess pain intensity, pain-related disability, psychological distress, jaw functional limitations, and parafunctional behaviors, and a pain drawing is used to assess locations of pain. The comprehensive instruments, composed of 81 questions, assess in further detail jaw functional limitations and psychological distress as well as additional constructs of anxiety and presence of comorbid pain conditions. CONCLUSION: The recommended evidence-based new DC/TMD protocol is appropriate for use in both clinical and research settings. More comprehensive instruments augment short and simple screening instruments for Axis I and Axis II. These validated instruments allow for identification of patients with a range of simple to complex TMD presentations. PMID- 24482787 TI - Frequency of pain and correlation with clinical and histologic parameters in T1 squamous cell carcinoma of the tongue: a retrospective pilot study. AB - AIMS: To conduct a pilot retrospective study to investigate the frequency of pain among patients with early-stage oral squamous cell carcinoma (OSCC) of the tongue and to correlate the pain with clinical and histopathologic parameters. METHODS: Twenty-four archival cases of T1 OSCC of the tongue were reviewed. No power analysis was conducted due to the pilot nature of the study. Tumors were classified into two groups according to the presence or not of pain (P+ and P- groups). Clinical and histopathologic parameters, such as grade of differentiation, depth of invasion, and presence of vascular, muscular, and perineural invasion were recorded. Statistical analyses included parametric (Student t) and nonparametric (chi-square) tests. RESULTS: Pain was reported by 13 of the 24 patients. In the P+ group, 11 of the 13 had moderately differentiated and 2 well-differentiated tumors; in contrast, P- patients had moderately differentiated tumors in 5 of the cases and well-differentiated tumors in 6 cases (P = .082). Vascular invasion was observed in 5 of the 13 P+ and 5 of the 11 P- patients, muscular invasion in 5 P+ and 2 P- patients, and perineural invasion in 4 P+ and 1 P- patients, respectively. The mean depth of invasion was 1.51 mm for P+ patients and 1.25 mm for P- patients. Only lymphoplasmocytic infiltration differed significantly, with P+ tumors exhibiting more intense inflammation (P = .041). CONCLUSION: Despite the limited number of cases, the results of this study suggest that painful OSCCs of the tongue may be associated with more intense inflammation. PMID- 24482788 TI - Painful traumatic trigeminal neuropathy: an open study on the pharmacotherapeutic response to stepped treatment. AB - AIMS: To evaluate pharmacotherapeutic success in patients with painful traumatic trigeminal neuropathy (PTTN) and to identify patient or pain characteristics that may predict treatment outcome. METHODS: Pharmacotherapy was instituted for PTTN patients and was based on widely accepted protocols for neuropathic pain and conducted in an open fashion. Outcome was assessed by employing prospective diaries recording pain intensity measured with an 11-point (0 to 10) verbal pain score (VPS). Individual characteristics in the patients and their influence on outcome were analyzed. Treatment results in the PTTN patients were compared with those in classical trigeminal neuralgia (CTN) patients, who were used as a comparative cohort. Data were analyzed with a Pearson chi-square test for nominal variables and with an independent samples t test or analysis of variance for continuous variables. RESULTS: A total of 145 patients were included: 91 with PTTN and 54 with CTN. In PTTN patients, 11% had a >= 50% reduction in pain intensity. Higher VPS scores in the PTTN patients were associated with a significantly reduced response to therapy (P = .03). No other pain-related or demographic parameters were associated with treatment outcome in the PTTN patients. Also the response rate of PTTN patients was significantly inferior to that of CTN patients, 74.1% of whom attained a significant reduction in pain intensity (P < .001). CONCLUSION: This study underpins the poor pharmacotherapeutic prognosis of PTTN. The results support findings on neuropathic pain in other sites and point to the need for further research and reexamination of current PTTN treatment protocols. PMID- 24482789 TI - Antinociceptive effects of mirtazapine, pregabalin, and gabapentin after chronic constriction injury of the infraorbital nerve in rats. AB - AIMS: To clarify the antiallodynic effects of the alpha2-adrenergic receptor antagonist mirtazapine compared with those of gabapentin and pregabalin in a rat model of orofacial neuropathic pain. METHODS: Mirtazapine (10, 30, and 100 MUg), gabapentin (10, 30, and 100 MUg), and pregabalin (3, 10, and 30 MUg) were administered intrathecally to eight male Sprague-Dawley rats with orofacial neuropathic pain induced by chronic constriction injury of the infraorbital nerve that had been carried out 2 weeks previously. Stimulation using von Frey filaments (1.0 to 15.0 g) applied to skin innervated by the injured infraorbital nerve enabled the measurement of mechanical thresholds 0 to 180 minutes after drug injection. Time-course data for the dose-response effects were analyzed using two-way analysis of variance and the posthoc Tukey-Kramer multiple comparison test. RESULTS: Intrathecal administration of not only gabapentin and pregabalin but also mirtazapine reversed the lowered mechanical nociceptive thresholds produced by the nerve injury. The ED50 (95% confidence interval) was (in MUg) 49.00 (39.71-58.29) for mirtazapine, 54.84 (46.12-63.56) for gabapentin, and 13.47 (11.24-15.69) for pregabalin. CONCLUSION: Intraspinal administration of either mirtazapine, gabapentin, or pregabalin reverses the lowered facial mechanical thresholds produced in a rat model of trigeminal neuropathic pain. PMID- 24482790 TI - Changes of temporomandibular joint and semaphorin 4D/Plexin-B1 expression in a mouse model of incisor malocclusion. AB - AIMS: To investigate the changes in condylar cartilage and subchondral bone of the temporomandibular joint (TMJ) in a mouse model of incisor malocclusion. METHODS: By bonding a single (single group) or a pair (pair group) of metal tube(s) to the left incisor(s), a crossbite-like relationship was created between left-side incisors in mice. The morphological changes in the TMJ condyles were examined by hematoxylin and eosin and toluidine blue staining. Indices of osteoclastic activity, including tartrate-resistant acid phosphatase (TRAP) staining and macrophage colony stimulating factor (M-CSF) were investigated by histochemistry or real-time polymerase chain reaction (PCR). The osteoblastic activity was indexed by osteocalcin expression. Expressions of semaphorin 4D and its receptor, Plexin-B1, were detected by real-time PCR. Two-way analysis of variance was used to assess the differences between groups. RESULTS: One week and 3 weeks after bonding the metal tube(s), cartilage degradation and subchondral bone loss were evident histologically. Both indices of osteoclastic activity (TRAP and M-CSF) were significantly increased in cartilage and subchondral bone after bonding the metal tube(s). Osteocalcin expression in cartilage was significantly increased at week 3, while its expression in subchondral bone was significantly increased at week 1 but decreased at week 3. The semaphorin 4D expression in cartilage and subchondral bone was significantly decreased at week 1 but significantly increased at week 3. For Plexin-B1 expression, a significant increase was detected in subchondral bone at week 3. CONCLUSION: Bonding a single or a pair of metal tube(s) to left incisor(s) is capable of inducing remodeling in the TMJ, which involved cartilage degradation and alteration of osteoclastic and osteoblastic activity. PMID- 24482791 TI - Numb chin syndrome: a rare and often overlooked symptom. AB - Numb chin syndrome (NCS) describes a sensory neuropathy characterized by numbness in the distribution of the terminal branch of the mandibular division of the trigeminal nerve. Benign as well as malignant diseases are known to cause NCS. This is often misdiagnosed, and in some cases the symptom may lead to a late detection of malignancy. Reports of 10 cases in which NCS was the presenting and isolated symptom, caused by extracranial malignancies, drugs, or dental/surgical interventions, are presented. This article outlines the symptoms and the diagnostic approaches taken, provides a short review of the etiology and pathogenesis, and proposes diagnostic criteria and treatment of NCS. Both medical practitioners and dentists need to be aware of the relationship between malignancies and paresthesia of the chin or complete loss of sensation in partial segments of the jaw. In addition, dentists should be aware of the diagnostic limitations of an orthopantomogram to detect underlying diseases beyond localized dental disorders. PMID- 24482793 TI - An antibody-free microfluidic paper-based analytical device for the determination of tear fluid lactoferrin by fluorescence sensitization of Tb3+. AB - An inkjet-printed microfluidic paper-based analytical device (MUPAD) for the detection of lactoferrin has been developed. The analyte concentration dependent fluorescence emission, caused by the sensitization of pre-deposited terbium (Tb(3+)) upon complexation with lactoferrin on the paper device, is captured using a digital camera. The dynamic response range (0.5-3 mg mL(-1)) and the limit of detection (0.30 mg mL(-1)) of the MUPAD are suitable for the analysis of normal human tears and the detection of eye disorders. Finally, lactoferrin concentrations in human tear samples were analyzed by the MUPADs and the assay results corresponded within 6% error to those obtained by an immunoassay (ELISA). The MUPADs provide a simple, rapid and accurate method for lactoferrin detection in tear fluid. Results are obtained within 15 min of a single application of 2.5 MUL of sample. To the best of our knowledge, this is the first report of a device for lactoferrin quantification relying neither on an immunoassay nor on high cost analytical instrumentation. PMID- 24482794 TI - Protein binding for detection of small changes on a nanoparticle surface. AB - Protein adsorption on nanoparticles is closely associated with the physicochemical properties of particles, in particular, their surface properties. We synthesized two batches of polyacrylic acid-coated nanoparticles under almost identical conditions except for the heating duration and found differences in the head-group structure of the polyacrylic acid. The structure change was confirmed by NMR and MS. The two batches of particles had varied binding affinities to a selected group of proteins. Computational work confirmed that the head group of the polymer on the surface of a nanoparticle could directly interact with a protein, and small structural changes in the head group were sufficient to result in a significant difference in the free energy of binding. Our results demonstrate that protein adsorption is so sensitive to the surface properties of particles that it can reveal even small variations in the structure of a nanoparticle surface ligand, and should be useful for quick assessment of nanoparticle properties. PMID- 24482795 TI - Proteomic evaluation of citrate-coated silver nanoparticles toxicity in Daphnia magna. AB - Recent decades have seen a strong increase in the promise and uses of nanotechnology. This is correlated with their growing release in the environment and there is concern that nanomaterials may endanger ecosystems. Silver nanoparticles (AgNPs) have some of the most varied applications, making their release into the environment unavoidable. In order to assess their potential toxicity in aquatic environments, the acute toxicity of citrate-coated AgNPs to Daphnia magna was measured and compared to that of AgNO3. AgNPs were found to be ten times less toxic by mass than silver ions, and most of this toxicity was removed by ultracentrifuging. At the protein level, the two forms of silver had different impacts. Both increased protein thiol content, while only AgNP increased carbonyl levels. In 2DE of samples labelled for carbonyls, no feature was significantly affected by both compounds, indicating different modes of toxicity. Identified proteins showed functional overlap between the two compounds: vitellogenins (vtg) were present in most features identified, indicating their role as a general stress sensor. In addition to vtg, hemoglobin levels were increased by the AgNP exposure while 14-3-3 protein (a regulatory protein) carbonylation levels were reduced by AgNO3. Overall, this study confirms the previously observed lower acute toxicity of AgNPs, while demonstrating that the toxicity of both forms of silver follow somewhat different biologic pathways, potentially leading to different interactions with natural compounds or pollutants in the aquatic environment. PMID- 24482796 TI - Truxene-cored pi-expanded triarylborane dyes as single- and two-photon fluorescent probes for fluoride. AB - Fluoride anion (F(-)) significantly affects chemical, biological, and environmental processes. Fluoride recognition and detection have received increasing attention. Convenient, effective, and sensitive fluorescent probes for F(-) should urgently be designed and synthesized. In this study, we describe a strategy for constructing two triarylborane-based fluoride fluorescent probes: 2,7,12-tri(2-(5-(dimesitylboryl)thiophen-2-yl)ethynyl)-5,5',10,10',15,15' hexaethyltruxene (C3B3) with pi-3A (acceptor) configuration and 2,7-di(N,N diphenylamino)-12-(5-(dimesitylboryl)thiophen-2-yl)-5,5',10,10',15,15' hexaethyltruxene (N2SB) with 2D (donor)-pi-A configuration. The loss of color of the tetrahydrofuran solution of these probes from greenish yellow suggests that they can conveniently monitor F(-) at a low concentration (10 MUM) free of apparatus. The different structural features of these probes varied their fluorescent responses to F(-). The single-photon fluorescence intensity of C3B3 declined to 90% upon the addition of 4.5 equivalents of F(-) to its tetrahydrofuran solution. However, the single-photon fluorescence intensity of N2SB was enhanced six-fold upon addition of 2.5 equivalents of the F(-). Under the experimental conditions, the detection limits of the two probes for F(-) can reach 12-13 MUM (C3B3) and 3-5 MUM (N2SB). The ability of the two probes in detecting F(-) in their toluene solutions in the two-photon mode was also investigated. The sensitive two-photon fluorescence responses of both probes make them excellent two-photon fluorescence probes. PMID- 24482797 TI - Contact angle changes induced by immunocomplex formation. AB - Immunoassays analyzing interactions between antigens and antibodies can be affected by capillary action together with binding affinity. This paper studies contact-angle changes of bacterial suspensions on antibody immobilized surfaces. The capillary action and the dried pattern of the bacterial suspensions are analyzed and correlated with specific- and nonspecific bindings between bacteria and antibodies. PMID- 24482798 TI - On-line surface plasmon resonance biosensing of vascular endothelial growth factor signaling in intact-human hepatoma cell lines. AB - Surface plasmon resonance (SPR) monitoring of biorecognition events at intracellular levels is a valuable tool for studying the angiogenic response of carcinoma living cells during tumor growth and proliferation. We report here a comparative study of two different strategies to detect human hepatoma cell interactions between transmembrane vascular endothelial growth factor receptor (VEGFR2) and vascular endothelial growth factor (VEGF). To monitor VEGFR2 activation after VEGF stimulation, intact hepatocellular carcinoma HepG2 or Huh7 cells (2 * 10(5) cells per mL) were directly immobilized on the sensor chip. Distinguishable SPR sensorgrams were obtained for each cell line depending on the time required for VEGFR2 activation. SPR signals for VEGF-VEGFR2 binding were inhibited by the VEGFR inhibitor, CBO-P11. The SPR response after VEGF stimulation/inhibition was in good agreement with the results observed by immunoblotting analysis. In a second approach we used intact cell lines as analytes. SPR analysis was done by injecting HepG2 and HuH7 cell suspensions (2-4 * 10(4) cells per mL) onto a sensor surface previously immobilized with VEGF via a thiol self-assembled monolayer (SAM). Specificity and reproducibility were evaluated reusing the same chip surface over more than 60 complete regeneration cycles. Comparison between both methods yielded differences in terms of reliability, making the latter strategy more effective for the analysis of real samples. The investigation of VEGF signaling in intact human hepatoma living cells by SPR monitoring comprises a novel and promising design for the study of tumor angiogenesis via downregulation of VEGF and VEGFR2 pathways. Further investigation on VEGFR activation and vascular function could contribute to establish a robust and meaningful tool for early cancer diagnostics. PMID- 24482799 TI - Electrochemical biosensing of non-electroactive targets using ferrocene-labeled magnetic particles and CNT wiring. AB - We show that target binding onto ferrocene-modified magnetic microparticles (MP Fc) promotes physical sheltering of the labels. This can be measured electrochemically by CNT wiring, which enhances ten-fold the signals registered compared to direct detection of the MPs alone. As a proof of concept, detection of detergents and antibodies is accomplished. In these preliminary experiments, random binding of 0.01% Tween 20 onto MP-Fc was detectable both voltametrically and impedimetrically after a 2 min incubation. Furthermore, affinity capture of 4 MUg mL(-1) of biotinylated antibody by streptavidin MP-Fc could be measured in less than 30 min and even in the presence of 1 mg mL(-1) of BSA. PMID- 24482800 TI - Oxidized polyethylene films for orienting polar molecules for linear dichroism spectroscopy. AB - Stretched polyethylene (PE) films have been used to orient small molecules for decades by depositing solutions on their surface and allowing the solvent to evaporate leaving the analyte absorbed on the polymer film. However, the non polar hydrophobic nature of PE is an obstacle to aligning polar molecules and biological samples. In this work PE film was treated with oxygen plasma in order to increase surface hydrophilicity. Different treatment conditions were evaluated using contact angle measurement and X-ray photoelectron spectroscopy. Treated PE (PE(OX)) films are shown to be able to align molecules of different polarities including progesterone, 1-pyrenecarboxaldehyde, 4',6-diamidino-2-phenylindole (DAPI) and anthracene. The degree of alignment of each molecule was studied by running series of linear dichroism (LD) experiments and the polarizations of electronic transition moments were determined. For the first time optimal conditions (such as stretching factor and concentration of the sample) for stretched film LD were determined. PE(OX) aligning ability was compared to that of normal PE films. Progesterone showed a slightly better alignment on PE(OX) than PE. 1-Pyrenecarboxaldehyde oriented differently on the two different films which enabled transition moment assignment for this low symmetry molecule. DAPI (which does not align on PE) aligned well on PE(OX) and enabled us to obtain better LD data than had previously been collected with polyvinyl alcohol. Anthracene alignment and formation of dimers and higher order structures were studied in much more detail than previously possible, showing a variety of assemblies on PE and PE(OX) films. PMID- 24482801 TI - An interference-free and rapid electrochemical lateral-flow immunoassay for one step ultrasensitive detection with serum. AB - Point-of-care testing (POCT) of biomarkers in clinical samples is of great importance for rapid and cost-effective diagnosis. However, it is extremely challenging to develop an electrochemical POCT technique retaining both ultrasensitivity and simplicity. We report an interference-free electrochemical lateral-flow immunoassay that enables one-step ultrasensitive detection with serum. The electrochemical-chemical-chemical (ECC) redox cycling combined with an enzymatic reaction of an enzyme label is used to obtain high signal amplification. The ECC redox cycling involving Ru(NH3)6(3+), enzyme product, and tris(3-carboxyethyl)phosphine (TCEP) depends on pH, because the formal potentials of an enzyme product and TCEP increase with decreasing pH although that of Ru(NH3)6(3+) is pH-independent. With consideration of the pH dependence of ECC redox cycling, a noble combination of enzyme label, substrate, and product [beta galactosidase, 4-amino-1-naphthyl beta-D-galactopyranoside, and 4-amino-1 naphthol, respectively] is introduced to ensure fast and selective ECC redox cycling of the enzyme product along with a low background level. The selective ECC redox cycling at a low applied potential (0.05 V vs. Ag/AgCl) minimizes the interference effect of electroactive species (L-ascorbic acid, acetaminophen, and uric acid) in serum. A detection limit of 0.1 pg mL(-1) for troponin I is obtained only 11 min after serum dropping without the use of an additional solution. Moreover, the lateral-flow immunoassay is applicable to the analysis of real clinical samples. PMID- 24482802 TI - Directing traffic into the future. PMID- 24482803 TI - An improved reference measurement procedure for triglycerides and total glycerides in human serum by isotope dilution gas chromatography-mass spectrometry. AB - BACKGROUND: Triglycerides are widely tested in clinical laboratories using enzymatic methods for lipid profiling. As enzymatic methods can be affected by interferences from biological samples, this together with the non-specific nature of triglycerides measurement makes it necessary to verify the accuracy of the test results with a reference measurement procedure. Several such measurement procedures had been published. These procedures generally involved lengthy and laborious sample preparation steps. In this paper, an improved reference measurement procedure for triglycerides and total glycerides was reported which simplifies the sample preparation steps and greatly shortens the time taken. METHODS: The procedure was based on isotope dilution gas chromatography-mass spectrometry (IDGC-MS)with tripalmitin as the calibration standard. Serum samples were first spiked with isotope-labeled tripalmitin. For the measurement of triglycerides, the serum samples were subjected to lipid extraction followed by separation of triglycerides from diglycerides and monoglycerides. Triglycerides were then hydrolyzed to glycerol, derivatized and injected into the GC-MS for quantification. For the measurement of total glycerides, the serum samples were hydrolyzed directly and derivatized before injection into the GC-MS for quantification. RESULTS: All measurement results showed good precision with CV <1%. A certified reference material (CRM) of lipids in frozen human serum was used to verify the accuracy of the measurement. The obtained values for both triglycerides and total glycerides were well within the certified ranges of the CRM, with deviation <0.4% from the certified values. The relative expanded uncertainties were also comparable with the uncertainties associated with the certified values of the CRM. The validated procedure was used in an External Quality Assessment (EQA) Program organized by our laboratory to establish the assigned values for triglycerides and total glycerides. PMID- 24482805 TI - Hypoxia-inducible factor 1alpha in breast cancer prognosis. AB - BACKGROUND: Recent studies have assessed the relationship between hypoxia inducible factor 1alpha (HIF-1alpha) expression and prognosis in breast cancer patients with inconsistent conclusions. To comprehensively and quantitatively summarize the evidence on the survival of patients with breast cancer, a meta analysis was performed. METHODS: Systematic literature searching was applied to the databases of PubMed, Embase and Web of science until April 1, 2013. Pooled HR with 95% CI was used to evaluate the association between HIF-1alpha expression and survival in breast cancer patients. RESULTS: Fourteen papers including 2933 patients were subjected to the final analysis. Of these, 7 provided data on overall survival (OS), 8 on disease-free survival (DFS), 3 on distant metastasis free survival (DMFS) and 3 on relapse-free survival (RFS). We observed that high expression of HIF-1alpha in breast cancer patients was an indicator of poor prognosis on OS (HR = 1.46, 95% CI: 1.12-1.92, P = 0.006), DFS (HR = 1.91, 95% CI: 1.43-2.57, P<0.001), DMFS (HR=2.17 95% CI: 1.16-4.05, P=0.015) and RFS (HR=1.33 95% CI: 1.09-1.61, P=0.005). Significant heterogeneity was observed in the analyses of OS and DFS. Subgroup analyses by the cut-off value and antibody for IHC were conducted. CONCLUSION: High expression of HIF-1alpha indicated a poor prognosis for patients with breast cancer. PMID- 24482804 TI - Increased freezing and decreased positive affect in postinstitutionalized children. AB - BACKGROUND: Early neglect is associated with increased risk of internalizing disorders in humans and with increased fear behavior in animals. When children are adopted out of orphanages in which they experienced institutional neglect, anxiety and depressive disorders often are not seen until adolescence. What has not been examined is whether even young children adopted from institutional care exhibit heightened fear or behavioral inhibition. METHOD: Children adopted between 15 and 35 months from institutional care were examined twice during their first year postadoption and compared with children of the same age reared in their birth families. A modified version of the Laboratory Temperament Assessment Battery for Preschoolers was used with the children being exposed to two mechanical toys designed to be highly arousing and fear eliciting. Because children in institutions tend to exhibit low levels of positive affect, the children were also examined during exposure to two positive stimuli. Sessions were videotaped and coded by observers blind to the study purpose. RESULTS: Postinstitutionalized children froze more in fear vignettes and were less positive in both fear and positive vignettes than nonadopted children. Group differences did not diminish significantly from the first session to the next, 6 months later. CONCLUSIONS: Children exposed to early institutional neglect exhibit emotional biases that are consistent with their previously demonstrated risk for the development of internalizing disorders. PMID- 24482806 TI - Non-invasive prenatal testing using cell-free fetal DNA in maternal circulation. AB - The identification of cell-free fetal DNA (cffDNA) in maternal circulation has made non-invasive prenatal testing (NIPT) possible. Maternal plasma cell free DNA is a mixture of maternal and fetal DNA, of which, fetal DNA represents a minor population in maternal plasma. Therefore, methods with high sensitivity and precision are required to detect and differentiate fetal DNA from the large background of maternal DNA. In recent years, technical advances in the molecular analysis of fetal DNA (e.g., digital PCR and massively parallel sequencing (MPS)) has enabled the successful implementation of noninvasive testing into clinical practice, such as fetal sex assessment, RhD genotyping, and fetal chromosomal aneuploidy detection.With the ability to decipher the entire fetal genome from maternal plasma DNA, we foresee that an increased number of non-invasive prenatal tests will be available for detecting many single-gene disorders in the near future. This review briefly summarizes the technical aspects of the NIPT and application of NIPT in clinical practice. PMID- 24482807 TI - Association of serum IgG4 and soluble interleukin-2 receptor levels with epicardial adipose tissue and coronary artery calcification. AB - OBJECTIVES: Immunoglobulin G4 (IgG4)-related immuno-inflammation may play a role in the development of coronary artery disease (CAD). We analyzed the association of serum IgG4 and soluble interleukin-2 receptor (sIL-2R) levels with epicardial fat volume (EFV) and coronary artery calcification (CAC). METHODS: Serum IgG4 and sIL-2R levels were measured in 267 patients who underwent 320-slice cardiac computed tomography. RESULTS: THE median serum levels of IgG4 and sIL-2R were higher in patients with CAD than in those without. Serum IgG4 levels were significantly greater in patients with EFV within the second and fourth quartile (>=75 mL) than in those with low EFV (b75 mL) (33.5 mg/dL vs. 22.5 mg/dL). On the other hand, serum sIL-2R levels were significantly higher in patients with CAC than in those without (409 U/mL vs. 345 U/mL). In age- and gender-adjusted logistic regression analysis, the fourth quartile of IgG4 (>=56.7 mg/dL) was associated with EFV within the second and fourth quartile (>=75 mL) with an odds ratio of 3.13. CONCLUSION: Serum IgG4 levels were greater in patients with EFV within the second and fourth quartile, whereas serum sIL-2R levels were increased in patients with CAC. These two biomarkers may reflect different mechanisms underlying development of cardiovascular remodeling. PMID- 24482808 TI - Clinical application of catalytically cleavable fluorescence probe technology for multiplexing quantification of BCR-ABL1 fusion transcripts. AB - BACKGROUND: Accurate measurement of BCR-ABL1 fusion transcripts is critical for therapeutic stratification in patients with chronic myelogenous leukemia (CML). Previous studies have reported the variable performance of the existing quantitative reverse transcription polymerase chain reaction (RQ-PCR). Here, we developed a one-step multiplex RQ-PCR method based on the catalytically cleavable fluorescence probe technology for quantification of BCR-ABL1 transcripts. METHODS: Performance was evaluated with respect to the limit of detection (LoD), linearity, precision, and comparison on the VIIA7 Real-Time PCR system. Multiplex RQ-PCR was performed by the one-step and one-well reaction without the hands-on time. RESULTS: Our assay showed a LoD of 1.5 pg with linearity in the range of more than 4 logs of dilution. Intraassay, interassay, and total percent CVs at the concentration of 150 ng were 12.8%, 22.6%, and 28.0%, respectively. The assay correlated well with Asuragen's BCR/ABL1 QuantTM kit over a 6 log concentration range (r=0.9967). CONCLUSION: Our assay demonstrated comparable performance characteristics in comparison with previous RQ-PCR based on the TaqMan probe technology.We conclude that our method could be a reliable tool in the clinical setting. PMID- 24482809 TI - Fibrinogen Hangzhou: congenital dysfibrinogenemia caused by the novel missense mutation in FGG (gamma308Asn->Thr). PMID- 24482810 TI - [Recanalization of thrombosis of the superior vena cava via an Aspirex catheter]. PMID- 24482811 TI - [KAMRA Model--correction of presbyopia in emmetropic patients]. PMID- 24482812 TI - [Presbyopic LASIK in 1-year analysis]. PMID- 24482813 TI - [After corneal PIOL-implantation, watch endothelium strongly]. PMID- 24482814 TI - Identification of cis-regulatory variations in the IL6R gene through the inheritance assessment of allelic transcription. AB - BACKGROUND: The level of circulating interleukin-6 receptor in human blood varies depending on the genetic and/or physiological causes, and has been implicated in the development of chronic inflammatory diseases. METHOD: The cis-regulatory effects of genetic variations on the transcription of interleukin-6 receptor gene, IL6R,were studied by assessing allelic transcriptions in the immortalized lymphocytes derived from unrelated and familial samples. RESULTS: The assays for allelic transcription in the cells from unrelated subjects demonstrated an extensive and variable range of allelic transcriptional imbalances, suggesting an operation of multiple cis-regulations with varying degrees on the locus. Analysis of the familial samples illustrated the Mendelian inheritance of allelic transcriptions,enabling us to assign each haplotype allele into one of the 3 transcriptional strengths. A comparison of the allele structures based on the transcriptional attributes highlighted 2 SNP variations, rs952146 and rs4845617, as being associated with higher allelic transcription. Consistently, lymphocytes that were homozygous for the 2SNPs exhibited differences in their transcript levels depending on the haplotypes. CONCLUSION: Inheritance assessment of allelic transcription of IL6R identified 2 SNPs that are associated with transcriptional variation in cis. GENERAL SIGNIFICANCE: Our results not only demonstrate genetic variations that are associated with IL6R transcription in cis but also demonstrate an effective genetic approach for isolating cis-regulatory variations. PMID- 24482815 TI - [Reply]. PMID- 24482817 TI - CD1d favors MHC neighborhood, GM1 ganglioside proximity and low detergent sensitive membrane regions on the surface of B lymphocytes. AB - BACKGROUND: Cluster of differentiation 1 (CD1) represents a family of proteins which is involved in lipid-based antigen presentation. Primarily, antigen presenting cells, like B cells, express CD1 proteins. Here, we examined the cell surface distribution of CD1d, a subtype of CD1 receptors, on B lymphocytes. METHODS: Fluorescence labeling methods, including fluorescence resonance energy transfer (FRET),were employed to investigate plasma membrane features of CD1d receptors. RESULTS: High FRET efficiency was observed between CD1d and MHC I heavy chain (MHC I-HC), beta2-microglobulin(beta2m) and MHC II proteins in the plasma membrane. In addition, overexpression of CD1d reduced the expression of MHC II and increased the expression of MHC I-HC and beta2m proteins on the cell surface. Surprisingly, beta2m dependent CD1d isoform constituted only ~15% of the total membrane CD1d proteins. Treatment of B cells with methyl-beta-cyclodextrin (MbetaCD) / simvastatin caused protein rearrangement; however, FRET demonstrated only minimal effect of these chemicals on the association between CD1d and GM1 ganglioside on cell-surface.Likewise, a modest effect was only observed in a co culture assay between MbetaCD/simvastatin treated C1R-CD1d cells and invariant natural killer T cells on measuring secreted cytokines (IFNgamma and IL4). Furthermore,CD1d rich regions were highly sensitive to low concentration of Triton X-100. Physical proximity between CD1d, MHC and GM1 molecules was also detected in the plasma membrane. CONCLUSIONS: An intricate relationship between CD1d, MHC, and lipid species was found on the membrane of human B cells. GENERAL SIGNIFICANCE: Organization of CD1d on the plasma membrane might be critical for its biological functions. PMID- 24482818 TI - [Radius reed osteotomy for supination deformity in children with obstetrical brachial plexus palsy]. AB - We report our experience and results in the use of reed pronating osteotomy in supination deformities secondary to obstetrical brachial plexus injury. This retrospective study involved 11 patients with paralytic supination of the forearm due to a brachial plexus injury. Other causes of paralytic supination were excluded. The surgical technique consisted of a proximal osteotomy of the ulna fixed by an intramedullary nail and a stable elastic reed osteotomy of the radius. The minimum postoperative follow-up was 2 years. Four boys and seven girls mean aged 8 years (5-12) were operated on between 2000 and 2010. The mean preoperative supination was measured at 63 degrees . The final position average pronation was 37 degrees . Loss of pronation was measured at 15 degrees . No complication was observed. With a mean follow-up of 4 years (2-12), the reed osteotomy of radius associated with a proximal transverse osteotomy of ulna has proven itself effective for correction of paralytic supination of the forearm without complication or reoperation. PMID- 24482816 TI - Palmitate interaction with physiological states of myoglobin. AB - BACKGROUND: Previous studies have shown that palmitate (PA) can bind specifically and non-specifically to Fe(III)MbCN. The present study has observed PA interaction with physiological states of Fe(II)Mb, and the observations support the hypothesis that Mb may have a potential role in facilitating intracellular fatty acid transport. METHODS: 1H NMR spectra measurements of the Mb signal during PA titration show signal changes consistent with specific and non-specific binding. RESULTS: Palmitate (PA) interacts differently with physiological states of Mb. Deoxy Mb does not interact specifically or non-specifically with PA, while the carbonmonoxy myoglobin (MbCO) interaction with PA decreases the intensity of selective signals and produces a 0.15ppmupfield shift of the PAmethylene peak. The selective signal change upon PA titration provides a basis to determine an apparent PA binding constant,which serves to create a model comparing the competitive PA binding and facilitated fatty acid transport of Mb and fatty acid binding protein(FABP). CONCLUSIONS: Given contrasting PA interaction of ligated vs. unligated Mb, the cellular fatty acid binding protein(FABP) and Mb concentration in the cell, the reported cellular diffusion coefficients, the PA dissociation constants from ligated Mb and FABP, a fatty acid flux model suggests that Mb can compete with FABP transporting cellular fatty acid. GENERAL SIGNIFICANCE: Under oxygenated conditions and continuous energy demand, Mb dependent fatty acid transport could influence the cell's preference for carbohydrate or fatty acid as a fuel source and regulate fatty acid metabolism. PMID- 24482819 TI - Authors' response. PMID- 24482820 TI - Tiotropium and the risk of death in COPD. PMID- 24482821 TI - Structural biology: More than a crystallographer. PMID- 24482822 TI - [Biopsy or MRT for sacroiliitis?]. PMID- 24482823 TI - [NSAIDs and X-ray progression in AS]. PMID- 24482824 TI - Saxagliptin, alogliptin, and cardiovascular outcomes. PMID- 24482825 TI - [Femoral defect reconstruction after malignant bone tumors using allografts]. PMID- 24482826 TI - [Is it beneficial to double the cytostatics in childhood soft tissue sarcoma?]. PMID- 24482827 TI - [Value of ifosfamide in neoadjuvant therapy for osteosarcoma]. PMID- 24482828 TI - [Comment on ''expanding disease definitions in guidelines and expert panel ties to industry: a cross-sectional study of common conditions in the United States'' Moynihan RN, Cooke GP, Doust JA, et al. PLoS Medicine; 10(8): e1001500]. PMID- 24482830 TI - Support our buoys. PMID- 24482831 TI - Open invitation. PMID- 24482829 TI - Assessment of beta-cell function in young patients with type 2 diabetes: arginine stimulated insulin secretion may reflect beta-cell reserve. AB - OBJECTIVE: Simple methods for the evaluation of dynamic b-cell function in epidemiological and clinical studies of patients with type 2 diabetes (T2D) are needed. The aim of this study was to evaluate the dynamic beta-cell function in young patients with T2D with different disease durations and treatments. METHODS: Overall, 54 subjects with T2D from the Diabetes Incidence Study in Sweden (DISS) and 23 healthy control participants were included in this cross-sectional study. Beta-cell function was assessed by intravenous (i.v.) administration of arginine followed by i.v. glucose. The acute insulin and C-peptide responses to arginine (AIRarg and Ac-pepRarg, respectively) and to glucose (AIRglu and Ac-pepRglu, respectively)were estimated.Homeostasis model assessment of b-cell function(HOMA b) andCpeptide assessments were also used for comparisons between patients with T2D and control participants. RESULTS: AIRarg and Ac-pepRarg, but not AIRglu and Ac-pepRglu, could differentiate between patients with different disease durations. AIRglu values were 89% (P < 0.001) lower and AIRarg values were 29% (P < 0.01) lower in patients with T2D compared with control participants. HOMA-b and fasting plasma C-peptide levels did not differ between the T2D and control groups. CONCLUSION: In young patients with T2D, the insulin secretory response to i.v. glucose is markedly attenuated, whereas i.v. arginine-stimulated insulin release is better preserved and can distinguish between patients with different disease duration and antidiabetic therapies. This suggests that the i.v. arginine stimulation test may provide an estimate of functional beta-cell reserve. PMID- 24482832 TI - Crystal clear. PMID- 24482833 TI - Policy: Crystallography needs a governing body. PMID- 24482834 TI - History: Women in crystallography. PMID- 24482835 TI - Policy: NIH plans to enhance reproducibility. PMID- 24482838 TI - [Fractures in adolescents: Often an OP is unnoticed]. PMID- 24482836 TI - A variational Bayes discrete mixture test for rare variant association. AB - Recently, many statistical methods have been proposed to test for associations between rare genetic variants and complex traits. Most of these methods test for association by aggregating genetic variations within a predefined region, such as a gene. Although there is evidence that "aggregate" tests are more powerful than the single marker test, these tests generally ignore neutral variants and therefore are unable to identify specific variants driving the association with phenotype. We propose a novel aggregate rare-variant test that explicitly models a fraction of variants as neutral, tests associations at the gene-level, and infers the rare-variants driving the association. Simulations show that in the practical scenario where there are many variants within a given region of the genome with only a fraction causal our approach has greater power compared to other popular tests such as the Sequence Kernel Association Test (SKAT), the Weighted Sum Statistic (WSS), and the collapsing method of Morris and Zeggini (MZ). Our algorithm leverages a fast variational Bayes approximate inference methodology to scale to exome-wide analyses, a significant computational advantage over exact inference model selection methodologies. To demonstrate the efficacy of our methodology we test for associations between von Willebrand Factor (VWF) levels and VWF missense rare-variants imputed from the National Heart, Lung, and Blood Institute's Exome Sequencing project into 2,487 African Americans within the VWF gene. Our method suggests that a relatively small fraction (~10%) of the imputed rare missense variants within VWF are strongly associated with lower VWF levels in African Americans. PMID- 24482837 TI - A versatile omnibus test for detecting mean and variance heterogeneity. AB - Recent research has revealed loci that display variance heterogeneity through various means such as biological disruption, linkage disequilibrium (LD), gene-by gene (G * G), or gene-by-environment interaction. We propose a versatile likelihood ratio test that allows joint testing for mean and variance heterogeneity (LRT(MV)) or either effect alone (LRT(M) or LRT(V)) in the presence of covariates. Using extensive simulations for our method and others, we found that all parametric tests were sensitive to nonnormality regardless of any trait transformations. Coupling our test with the parametric bootstrap solves this issue. Using simulations and empirical data from a known mean-only functional variant, we demonstrate how LD can produce variance-heterogeneity loci (vQTL) in a predictable fashion based on differential allele frequencies, high D', and relatively low r2 values. We propose that a joint test for mean and variance heterogeneity is more powerful than a variance-only test for detecting vQTL. This takes advantage of loci that also have mean effects without sacrificing much power to detect variance only effects. We discuss using vQTL as an approach to detect G * G interactions and also how vQTL are related to relationship loci, and how both can create prior hypothesis for each other and reveal the relationships between traits and possibly between components of a composite trait. PMID- 24482839 TI - Journal introduction. PMID- 24482840 TI - Report on one health approach: Risk Management for Neurocysticercosis workshop- 28th June 2013, Pretoria, South Africa. PMID- 24482842 TI - Nurturing the F1 by Caveman. PMID- 24482841 TI - The medical dictionary 'tongue-in-cheek' edition. PMID- 24482843 TI - Online dating and conjugal bereavement. AB - This study examined self-presentation in the online dating profiles of 241 widowed and 280 divorced individuals between 18 and 40 years old. A content analysis of open-ended user-generated profiles assessed the presence or absence of various themes, including the user's marital status, the backstory of their lost relationship, and whether they engaged in sense-making regarding that lost relationship. Results indicated that about one-third of widowed individuals discussed their loss in their profiles. In addition, about one-third of the widowed profiles included explicit reference to a philosophy of life, and about 16% mentioned sense-making or cognitive reappraisals of their bereavement. Many profiles included some articulation of a vision of a future partnership. Results also revealed a significant correlation between widowed individuals including a backstory and their likelihood of exhibiting sense-making in their profiles. Finally, unlike the widowed users, divorcees provided much briefer mentions of their lost relationships, used less sense-making language, and were less likely to articulate an explicit vision of future partnerships. Overall, the results suggest that for widowed individuals, online dating sites may function as venues to explore their past experiences and engage in the construction of a post-loss identity or a post-loss "ideal self". PMID- 24482844 TI - The support needs and experiences of suicidally bereaved family and friends. AB - This study aimed to identify what suicidally bereaved persons', particularly close relatives' and loved ones' perceptions of their need for support were and their experiences of support directed at meeting those needs. A total of 166 persons who were bereaved by suicide completed a questionnaire consisting of both closed and open-ended questions. Overall, 94% of participants indicated a need for help to manage their grief but only 44% received help. Most participants indicated a great or significant need for help. In addition, only 40% of those who received professional support felt satisfied with it. The authors concluded that there is a significant gap between need for support and the quality and provision of professional support services. PMID- 24482845 TI - Predictors of complicated grief: a systematic review of empirical studies. AB - A systematic review of the literature on predictors of complicated grief (CG) was undertaken with the aim of clarifying the current knowledge and to inform future planning and work in CG following bereavement. Predictors of CG prior to the death include previous loss, exposure to trauma, a previous psychiatric history, attachment style, and the relationship to the deceased. Factors associated with the death include violent death, the quality of the caregiving or dying experience, close kinship relationship to the deceased, marital closeness and dependency, and lack of preparation for the death. Perceived social support played a key role after death, along with cognitive appraisals and high distress at the time of the death. Inconsistent definitions of CG and measurement tools were noted in the earlier studies reviewed. Limitations identified in the studies included use of cross-sectional designs, heterogeneous samples, high attrition, demographic differences between cases and controls, differences in length of time since death, and differences in types of death experienced. Notwithstanding these limitations, some consistent findings have emerged. Further research into conceptualizations of CG in terms of attachment theory and constructivist and cognitive-behavioral concepts of finding purpose and meaning after bereavement is warranted. PMID- 24482846 TI - Communicating social support to grieving clients: the veterinarians' view. AB - This exploratory study examines veterinarians' perceptions of how they offer social support to grieving clients. Because many clients cannot find the social support they would like from other sources when grieving the death of a pet, the role of the vet in offering support becomes increasingly important. The results indicate that vets perceive that they do offer social support; however, they have not been provided with training in how to do so. Limitations to the study and future directions are also discussed. PMID- 24482847 TI - Meaning-making in memories: a comparison of memories of death-related and low point life experiences. AB - Because of their extensive experience with death and dying, hospice volunteers may be more successful at engaging in meaning-making regarding their death related experiences than their low point life experiences (e.g., job loss). Consequently, their memories of death-related experiences will manifest more meaning-making strategies (e.g., bendfit-finding) than their low point memories. Fifty-two hospice volunteers wrote memory narratives of death-related and low point experiences and provided ratings of their memories. Results show that death memory narratives exhibit more meaning-making strategies, are rated as more emotionally positive, and are more frequently rehearsed. The long-term significance of the use of meaning-making strategies is discussed. PMID- 24482848 TI - Memory keepers: a narrative study on siblings never known. AB - Drawing on literature relevant to the impact of sibling death, the authors examined the invisible loss of siblings never known. This article presents findings of a phenomenological study of 15 adult siblings who "storied" the psychological presence and power of a deceased infant sibling never known but who acted as memory keepers for their unknown sibling. Transcriptions of the 15 interviews were analyzed usng NVivo software to support development of thematic categories. The initial 29 subthemes were collapsed into 3 overarching themes of personal loss/ unacknowledged loss, continuing bonds/memory keeping and sense making. The participants' experiences reflect support for unaddressed and unacknowledged loss for the phenomenon of loss of an unknown sibling. The retrospective narratives echo their perceived roles as memory keepers of their unknown siblings. For many participants, the research process itself was the first recognition of a sense of loss. PMID- 24482849 TI - Birth month affects longevity. AB - The authors examined the association between birth month and longevity for major league baseball players. Players born in the month of November had the greatest longevities whereas those born in June had the shortest life spans. These differences remained after controlling for covariates such as birth year, career length, age at debut, height, and player position. The authors determined that the most likely explanation is that those born during seasons when mortalities are highest are constitutionally weakened and more likely to succumb to life threatening conditions later in life. PMID- 24482850 TI - Effects of a visiting service for older widowed individuals: a randomized clinical trial. AB - The loss of the partner is an important risk factor for developing serious psychological problems. In this study the authors examined the effect of the visiting service on the mental health and quality of life of older widowed individuals. They conducted a pragmatic randomized trial. All respondents were randomly assigned to a visiting service (n = 110) or a control condition (n = 106) and were interviewed at baseline, at 6 months, and at 12 months after baseline. The visiting service was not more effective than the control condition in the overall sample. However, socially lonely, physically ill, or low-educated respondents improved more in the experimental group than in the control group. PMID- 24482851 TI - Measuring meaning: searching for and making sense of spousal loss in late-life. AB - Despite much recent theorizing, evidence regarding the temporal relationship of sense-making to adjustment following bereavement remains relatively sparse. This study examined the role of searching for and making sense of loss in late-life spousal bereavement, using prospective, longitudinal data from the Changing Lives of Older Couples (CLOC) project (N = 250). Searching at 6 and 18 months post-loss predicted both contemporaneous and subsequent grief. Sense-making was not related to grief for this sample. In contrast, sense-making at 6 months and 18 months predicted positive affect at 48 months, although searching had no prospective effect on this outcome. Searching at 6 months predicted depression at 18 months. Results are interpreted in terms of meaning-oriented theories of bereavement and processes promoting both adaptive and maladaptive outcomes. PMID- 24482852 TI - Imagining the impact of different consent systems on organ donation: the decisions of next of kin. AB - Next of kin play an important role in organ donation. The aim of this study was to assess the extent to which explicitness of consent to organ donation by the deceased impacts the likelihood that next of kin will agree to organ donation of the deceased by using hypothetical cases. Results indicate that that people say they are more willing to agree to donate organs of those who explicitly consented to donate than those whose permission to donate is presumed. The degree of explicitness for the consent to donate by the deceased appears to influence the next of kin's decision about whether to agree to donation. This variation might explain the absence of differences in efficiency between various types of consent systems. PMID- 24482853 TI - Self-consciousness and death cognitions from a terror management perspective. AB - Two studies explored the connection between self-consciousness and death cognitions. In Study 1 (n = 56), a positive association was found between accessibility of death-related thoughts and the ruminative dimension of self consciousness. In Study 2 (n = 212), a mortality salience induction led to higher validation of cultural worldviews (a more severe perception of social transgressions) than a control group, but only among individuals with lower self consciousness, whereas participants characterized by higher self-consciousness did not make increased use of this cultural anxiety buffer. Rather, their naturally heightened death awareness led them to react to social transgressors in a neutral condition in the way usually found only after a mortality salience induction. Gender could not alternatively account for these findings. The results are explained in terms of terror management theory. It is suggested that a high level of self-consciousness may serve as an internal death reminder, leading to greater cultural worldview validation on a regular basis. PMID- 24482854 TI - Loss and disorganization from an attachment perspective. AB - In this article, it is hypothesized that disorganizing, disorienting, and unresolved states of mind about loss experiences, as classified by the Adult Attachment Interview (AAI) coding system, may offer insight into the bereaved mind and may guide clinical treatment approaches. This article discusses pre-loss attachment organizations and the disorganizing/disorienting markers of unresolved loss found in the AAI. Although sometimes subtle in nature, the unresolved, disorganized, and disorienting indices--defined as lapses in monitoring of reason, discourse and behavior--provide concrete markers for assessing the degree of resolution for loss experiences. An attachment-based grief treatment model can add to existing models implemented in prolonged grief disorder treatment. PMID- 24482855 TI - An evaluation of a suicide bereavement peer support program. AB - Peer support, a cornerstone in recovery programs for mental illness and addiction, has not been widely applied to service programs for survivors of suicide. In 2004-2006 Canadian Mental Health Association Suicide Services in Calgary, Alberta, introduced the Peer Support Program for adults, an adjunct to conventional individual and group intervention. This article reports on a mixed methods evaluation of the Peer Support Program. Hogan's Grief Response Checklist and the qualitative data tracked positive outcomes for both the peer supporters and the clients. This study challenges the unspoken assumption that survivors of suicide, due to their vulnerability, require the services of highly skilled professionals and would not be in a position to offer unsupervised support to peers. Rather it supports an intervention protocol that consists of peer supporters and professionals working collaboratively to offer cost-effective, client-centered services. PMID- 24482857 TI - The experiences of parents readjusting to the workplace following the death of a child by suicide. AB - Suicide among young people has become a growing concern in life in the 21st century and is a tragedy faced by an increasing number of families and in particular parents. This study set out to focus on the experiences of parents reentering the workplace following the death of a child by suicide. Although the immediate aftermath of experiencing traumatic death has been studied, we know less about the longer-term effects on life tasks such as returning to work. A sample of bereaved parents was interviewed and their responses thematically analyzed. The three major areas of experience related by parents were social and emotional aspects of readjusting to the workplace, followed by changes in cognitive, emotional and physical functioning and their changed attitudes toward work and life. Limitations of the study include the transferability of findings to other populations and to less close-knit cultures. The implications for employee adjustment and employers and co-workers' responses are considered. A fuller picture of adjustment might emerge from future studies that seek to document all parties' experiences during this period of transition. PMID- 24482856 TI - Effects of directed written disclosure on grief and distress symptoms among bereaved individuals. AB - Bereavement-specific written disclosure trials have generally demonstrated null effects, but these studies have not directed the focus of writing. This randomized controlled trial compared directed writing that focused on either sense-making or benefit-finding, both associated with adjustment to loss, to traditional, non-directed emotional disclosure and a control condition. Bereaved undergraduates (n = 68) completed three 20-min writing sessions over 1 week. Intervention effects were found on prolonged grief disorder, depressive, and posttraumatic stress symptoms 3 months postintervention, and the benefit-finding condition appeared particularly efficacious. Physical health improved over time in all treatment groups. Findings suggested that directing written disclosure on topics associated with adjustment to bereavement may be useful for grieving individuals. PMID- 24482858 TI - Suicide postvention as suicide prevention: improvement and expansion in the United States. AB - The authors asserted the need for increased postvention efforts for suicide survivors, individuals left behind to grieve the loss of a loved one by suicide, because they have an increased risk for suicide. Indeed, Shneidman (1972) asserted that suicide postvention efforts serve the dual purpose of assisting survivors through the grief process and preventing suicide for future generations. First, the authors briefly discussed the increased risk for suicide among survivors. Second, the authors overviewed the potential benefits of postvention programs and current strategies for suicide postvention in the United States. Finally, they recommended plans for suicide postvention program development such as states should include efforts to create or expand traditional postvention services as well as active survivor outreach to link survivors to these services. PMID- 24482859 TI - Music therapy with bereaved teenagers: a mixed methods perspective. AB - Qualitative investigations have indicated that music therapy groups may be beneficial for bereaved teenagers. The existing relationship between young people and music serves as a platform for connectedness and emotional expression that is utilised within a therapeutic, support group format. This investigation confirms this suggestion through grounded theory analysis of focus group interviews. Changes in self-perception were not found as a result of participation, however practically significant results were found on adolescent coping. These cannot be generalized because of the small sample size. Grief specific tools are recommended for use in future investigations in order to capture the emotional impact of music therapy grief work with adolescents. PMID- 24482860 TI - The cerebral oximetry marketplace. What's available and which features matter. PMID- 24482861 TI - The path to alarm safety. A plan for reducing alarm hazards. PMID- 24482862 TI - Patient fall risk associated with bed-exit alarm reset time. PMID- 24482863 TI - Swollen lithium polymer batteries in Nova Biomedical StatStrip blood glucose meters may prevent network connection and battery charging. PMID- 24482864 TI - [Study of allergen skin prick tests on different region of forearm]. AB - OBJECTIVE: To investigate the variation on different regions of the forearm when taking the allergen skin prick tests(SPTs). METHOD: Forty-one patients with hyper reactive nasal symptoms were included. SPTs were done on the proximal, telecentric, middle region of right forearm and telecentric region of left forearm with house dust mite and histamine. The average diameter of wheal and the reactive grade were calculated and analyzed. RESULT: The diameters of the wheal on equal position of two forearms were similar (P > 0.05). The intension of SPTs reaction decreased from proximal to telecentric region of the same forearm (P < 0.05). CONCLUSION: The intension of SPTs reaction on different region of forearm are quite different, which should be noticed in clinical practice. PMID- 24482865 TI - Sinus pressure. Bilateral maxillary sinusitis that was not responding to the original antibiotic. PMID- 24482866 TI - Nasal discharge. Mucormycosis sinusitis. PMID- 24482867 TI - Fissures near mouth. Angular cheilitis (perleche). PMID- 24482868 TI - Soreness around mouth. Contact dermatitis and angular cheilitis (perleche). PMID- 24482869 TI - A clinical pharmacologic perspective on the detection and assessment of adverse drug reactions. AB - The study of a new drug includes the assessment of its pharmacologic effects, benefits (efficacy), and risks (safety). Most recent drug discontinuations in the United States and the United Kingdom have been associated with problems of safety. The assessment of clinical drug safety is difficult. Those assessing drug safety are confronted with the need to make causality assessment judgments of drug-related events. Several procedures for assessing causality of adverse reactions have been proposed; however, none of them is completely satisfactory. Global introspection (the unaided judgment based on knowledge and experience) and the currently available standardized decision aids (questionnaires or algorithms) have serious limitations that hamper their use. There is a need for better procedures. PMID- 24482870 TI - Medicaid restructuring. PMID- 24482871 TI - Medicaid eligibility. PMID- 24482872 TI - Medicaid copayments. PMID- 24482873 TI - Medicaid provider tax. PMID- 24482874 TI - Benefits and services. PMID- 24482875 TI - Medicaid waivers. PMID- 24482876 TI - Federal Medicaid policy. PMID- 24482877 TI - Medicaid reimbursement. PMID- 24482878 TI - Access to health insurance: State Children's Health Insurance Program. PMID- 24482879 TI - Access to health insurance. PMID- 24482880 TI - Quality of healthcare. PMID- 24482881 TI - Medical errors and patient safety. PMID- 24482882 TI - Medical malpractice and tort reform. PMID- 24482883 TI - Mandated benefits. PMID- 24482884 TI - Managed care. PMID- 24482885 TI - Healthcare information technology. PMID- 24482886 TI - Emergency care. PMID- 24482887 TI - Healthcare facilities. PMID- 24482888 TI - Healthcare workforce. PMID- 24482889 TI - Pharmaceuticals and medical devices: business practices. PMID- 24482890 TI - Pharmaceuticals and medical devices: Medicare Part D. PMID- 24482891 TI - Pharmaceuticals and medical devices: cost savings. PMID- 24482892 TI - Pharmaceuticals and medical devices: medical devices. PMID- 24482893 TI - Pharmaceuticals and medical devices: FDA oversight. PMID- 24482894 TI - Healthcare reform administrative rulemaking. PMID- 24482895 TI - Healthcare reform delivery reform. PMID- 24482897 TI - Healthcare reform insurance market reform. PMID- 24482898 TI - Healthcare reform payment reform. PMID- 24482899 TI - Healthcare reform state specific responses. PMID- 24482900 TI - Interventions for restoring patency of occluded central venous catheter lumens (Review). PMID- 24482901 TI - [Endoscopic balloon dilatation of esophageal strictures in children]. AB - OBJECTIVES: To evaluate the effectiveness and safety of endoscopic balloon dilatation in children with esophageal stenosis. PATIENTS AND METHODS: Retrospective study of patients treated in the last 5 years, diagnosed with esophageal stricture. Response to dilatation was defined as excellent when there was no need for any additional dilatation for recurrent dysphagia, satisfactory when they set out to 5 sessions, acceptable with more than 5 sessions, and inadequate if there was no improvement of dysphagia with dilation. The treatment was effective when dysphagia remained grade 0 or 1 was kept for more than 12 months after the last dilatation session. RESULTS: 576 procedures were performed in 89 children, with an average of 6,47 per patient (range 1-33). The esophageal stenosis was secondary to esophageal atresia repair in 51 cases (57,3%), injury by caustic in 19 patients (21,3%) and gastroesophageal reflux 11 cases (12,3%); compromised aged between 1-202 months (mean 36,1). Response to dilatation was excellent in 11 patients (13.9%), satisfactory in 27 (34.1%), fair in 25 (31.6%), and inadequate in 16(20.2%). Ten patients (8.9%) were lost to follow up. Thirty four (38.2%) patients were diagnosed with concomitant gastroesophageal reflux disease, every one recieved medical management and 7 (20,5%) underwent antireflux surgery. The treatment was effective in 63 cases (79.7%) and ineffective in 16 (20.2%), most of the latter with gastroesophageal reflux. There were 8 complications (1,38%), all esophageal perforations. CONCLUSIONS: Endoscopic balloon dilatation can be accomplished safely and effectively as a first-line therapy for the management of esophageal stenosis. PMID- 24482902 TI - [Study of the expression of neural stem cell markers in neuroblastoma tumor samples and correlation with prognostic factors]. AB - INTRODUCTION: The existence of cancer stem cells (CSC) in neuroblastoma (NB) has been associated with the development of metastasis, resistance to chemotherapy and recurrence. Our objective is to analyze the expression of proliferation and differentiation markers of neural progenitor cells in NB samples, and to correlate this expression with clinical variables such as histology, genetics and response to conventional therapy. MATERIAL AND METHODS: We performed a retrospective-experimental study with neuroblastoma samples obtained from biopsies or tumor resections between 2010-2012 in our Hospital. Fluorescence immunohistochemistry was used to analyze the expression of the different markers: CD44, CD74, CD133, tyrosine hydroxylase, endothelin receptors type A (ETA) and B (ETB), p75, nestina y and Phox2b, all of them related to neural stem cell biology. The level of expression of the markers was then correlated with clinical variables. RESULTS: Nestin expression was positive in 72.2% of samples and ETA in 66.7%. PHOX2B and CD74 expression were lower, being positive in less than 30%. The markers CD44, ETB and PHOX2B were expressed in more aggressive tumors. ETA expression correlated significantly with unfavorable histology tumors (p= 0.01), N-myc amplification (p= 0.05) and recurrence/progression (p= 0.05). CONCLUSION: The expression of CD44, ETB and ETA was associated with more aggressive tumors and poor prognostic factors. These markers are in the membrane of neural stem cells and may be useful to identify and isolate by flow cytometry CSCs of NB for the study of new therapeutic targets. PMID- 24482903 TI - [Management of pediatric urolithiasis in our center]. AB - OBJECTIVES: To determine clinical, epidemiological and therapeutic characteristics of pediatric urolithiasis in our institution. MATERIAL AND METHODS: We reviewed retrospectively patients diagnosed with urolithiasis between 1998 and 2010 in our hospital. RESULTS: A total of 32 patients (19 males and 13 females) with a mean age of 4.5 years (SD 1.9) were studied. 72% had a history of metabolic or nephro-urological malformations. The most common presentation was urinary tract infection (53%) and abdominal pain (21%). The diagnosis was made by ultrasound, with compatible X-ray in 18 cases. The most common location was pyelocalyceal level, affecting the left kidney mostly. A 38% had multiple stones with a size of 11 mm medium (3-30 mm). Ureteroscopy was used 16 times for stones in the bladder and distal ureter, with an effectiveness of 75%, and 2 patients required laparoscopic trocar cystotomy for removal. 8 extracorporeal lithotripsy procedures were performed (25% success) and 8 percutaneous nephrolithotomy procedures (37.5% success). In 3 patients we decided to perform a lumbotomy due to the size of the calculi, and, in 1 patient nephrectomy was necessary due to malfunction. The most common complication was lithiasis recurrence in 10 patients, most with multiple stones or metabolic alterations, and favourable outcome for the rest. CONCLUSIONS: Pediatric urolithiasis is uncommon, showing an increased incidence in patients with a history of metabolic and urologic pathology; it is important to do additional studies. In the last few years, it has been demonstrated that surgical treatment using minimally invasive procedures is effective and safe. PMID- 24482904 TI - [Robotic pyeloplasty: first experiences]. AB - OBJECTIVE: To analyze our initial experience with the practice of robotic pyeloplasty and describe its advantages over laparoscopic and open surgery. PATIENTS AND METHODS: Retrospective study of the pediatric cases of pyeloplasty assisted by the robot da Vinci between March 2010 and May 2013. In all cases a transperitoneal approach was used with placement of 4 trocars (3 robotic trocars and 1 conventional laparoscopic). The technique used was the dismembered pyeloplasty Anderson-Hynes type. RESULTS: We operated 15 patients (12 men and 3 women) with a median age at surgery of 11 years (r: 5-18). The median weight was 40 kilos (r: 19-82). Five patients had a previous open pyeloplasty performed several years ago. All patients except but one were completed by robot. The only conversion to open surgery was performed because of difficulty in placing the double-J catheter due to a stenosis at the ureterovesical junction. They were no other intraoperative complications. The median operative time was 180 minutes (r: 110-252) and the median time for the robot docking 14 minutes (r: 4-50). The average hospital stay was 3.47 days (SD: 3). Mean follow-up was 16.97 months (SD: 10.24) and currently all patients are asymptomatic. CONCLUSIONS: Our initial experience seems to demonstrate that, coinciding with the literature, robotic pyeloplasty improves the results of laparoscopic pyeloplasty, retaining all its advantages and radically shortening the learning curve. PMID- 24482905 TI - [Puberal gynecomastia: a comparison between the inferior periareolar approach and the concentric circle technique]. AB - BACKGROUND/PURPOSE: The main reason to indicate the surgical treatment in pubertal gynecomastia is the psychological effect on the adolescent. The aim of this paper is to describe our experience in the surgical treatment of this condition, comparing the results obtained depending on the type of approach used. MATERIAL AND METHODS: In our department, the approach for the subtotal mastectomy depends mainly on the gynecomastia grade. We use an inferior periareolar incision in grades I and II, and a concentric circle technique in grade III of Simon's classification. A retrospective review was conducted to identify all adolescent patients that underwent to gynecomastia surgical treatment between 2007 and 2012. We compared the results obtained in each incision group by parametric statistical tests, RESULTS: A total of 29 mastectomies were performed in 15 patients. The mean age of surgery was 13.75 +/- 1.06 years ([11-15] years). The presentation in all cases consisted in a progressive increase in size of the mammary gland, without associated symptoms. In half of patients there was a history of obesity or overweight. We performed the concentric circle technique in 5 patients (CCT group) and inferior periareolar incision in 10 (IPI-group). There was a higher incidence of pathologic scarring in the CCT-group, and this difference was statistically significant (p = 0.007). No recurrences were observed after a mean follow-up of 15.86 +/- 19.47 months ([3-60) months). CONCLUSIONS: Long term results were satisfactory in both groups. Despite of the higher incidence of hypertrophic and keloid scars observed in concentric circle technique, it remains aesthetically advantageous in cases of gynecomastia with extra skin. PMID- 24482906 TI - [Renal epithelioid angiomyolipoma]. AB - Epithelioid angiomyolipoma of renal origin are a very rare variant of the classic angiomyolipomas but with the peculiarity to present malignant potential. Its diagnosis is usually after surgery because the tumor simulates both clinical and radiological features of renal cell carcinoma. We report a case of a 14 year old patient who was diagnosed with this disease as an incidental finding, and that after she underwent partial nephrectomy for three years is currently asymptomatic with no signs of disease recurrence. PMID- 24482907 TI - [Hibernoma and cervical rib: two rare diseases, the same manifestation]. AB - The hibernoma is a rare benign tumor of soft tissue, derived from remnants of fetal brown adipose tissue. A cervical rib is a supernumerary or accessory rib derived from the 7th cervical vertebra. CLINCAL CASE: 2-year-old girl, previously healthy, referenced to Pediatrics consultation, for left supraclavicular mass. No history of infectious diseases or systemic symptoms. At exam presented mass in supraclavicular left region, 1.5 to 2 cm in diameter, hard, mobile, non-adherent to the deep planes. Laboratory tests exclude an infectious or lymphoproliferative disease. In cervical radiograph we observed bilateral cervical ribs. Cervical ultrasound revealed calcified nodule 0.8 cm, compatible with calcified adenopathy. Biopsy was performed and histology revealed a hibernoma, which was completely removed surgically. This case illustrates the association of two diagnoses, uncommon in children. These were made during the investigation of lymphadenopathies, a frequent reason for pediatrics consultation. PMID- 24482908 TI - [Esophageal impaction of button batteries in childhood. How to avoid tragedy!]. AB - INTRODUCTION: Ingestion of button batteries (PB) represents less than 2% of all foreign bodies, but its incidence is increasing. Esophageal impaction produces severe damages, which can be devastating. Our aim is to present 3 new cases and the therapeutic protocol followed in our center. MATERIAL AND METHODS: We report 3 children who presented esophageal foreign body impaction, displaying a PB with the "double halo sign" on the radiograph, being situated in the upper, medium and low esophageal in each case. The protocol followed included: radiography of the neck, chest and abdomen; high doses of corticosteroids, inhibitors of proton pump, antibiotics and urgent endoscopy removal. A nasogastric tube was placed in the same act. RESULTS: The PB had been impacted for 10.3 hours (5-14) but had inflammation and necrosis of the esophageal mucosa. We applied the specified protocol. Oral feeding was initiated 8 +/- 2 days after with a normal esophagogastric study, which was repeated a month later to exclude stenosis. CONCLUSION: Adherence to a diagnostic and therapeutic protocol prevents the complications of esophageal impaction of button batteries. We consider the double halo image pathognomonic of the PB. PMID- 24482910 TI - [Successful conservative management of a multiple renal abscess in a child]. AB - Renal abscesses are uncommon in children but their consequences could be serious, including sepsis, severe renal damage or loss of the kidney. The following report describes a three-year-old girl diagnosed of multiple renal abscess in the left kidney after a first episode of fever. The case is significant due to the uncommon presentation of a urinary tract infection as a multiple abscess, the extension of the injuries (there were 4 abscesses in the kidney) and the conservative therapy with intravenous antibiotics which was selected in order to preserve renal tissue. PMID- 24482909 TI - [Magnet intestinal lesions. Case series]. AB - The ingestion of foreign bodies is a common trouble in the pediatric population, and most of cases occur between 6 months and 3 years. In general the vast majority of foreign bodies are not associated with morbidity or mortality. Ingestion of two or more magnets can lead to obstruction, fistulas, ulceration, perforation and bowel volvulus. In this series we present 4 cases of patients ingesting multiple magnets and who due to the ingested foreign body characteristics and clinical profile required surgical treatment. PMID- 24482911 TI - [Exanthema of unknown origin in human and cow]. PMID- 24482912 TI - [Cardiac pacemaker as target of hackers? (interview by Dr. Beate Schumacher)]. PMID- 24482913 TI - [Report: from premature infant to the aged]. PMID- 24482914 TI - [Family medicine can only only be learned in the family practice]. PMID- 24482915 TI - [Multiple vascular changes in a patient. How do the symptoms fit together?]. PMID- 24482916 TI - [Geriatric emergencies. Often the status is more serious than it seems]. PMID- 24482918 TI - [Naturopathy consultation. How do you strengthen the immune response?]. PMID- 24482917 TI - [Elderly patient with only minor trauma... - ...and then he must be moved to the intensive care unit with delirium]. PMID- 24482919 TI - [Osteoporosis therapy. Drugs for strong bones]. PMID- 24482920 TI - [Preventing osteoporosis. A lot of calcium often helps little]. PMID- 24482921 TI - [Meta analysis. Vitamin D alone does not prevent osteoporosis]. PMID- 24482922 TI - [Phytotherapy in acute respiratory tract infections. "Compliance is often better" (interview by Philipp Gratz)]. PMID- 24482923 TI - [Pain, malnutrition, pseudocysts. Chronic pancreatitis needs comprehensive treatment]. PMID- 24482924 TI - [Opportunity makes the murderer]. PMID- 24482925 TI - ["Sunburn" from the endoscope]. PMID- 24482926 TI - [Only the occlusion or eliminating all stenoses?]. PMID- 24482927 TI - [Lacunar stroke: aggressively lowering blood pressure?]. PMID- 24482929 TI - [Intermittent pneumatic compression reduces risk of thrombosis]. PMID- 24482928 TI - [White hair turns brown]. PMID- 24482930 TI - [Increased risk of thrombosis in women smokers]. PMID- 24482931 TI - [How accurate is the internet as a source of health information?]. PMID- 24482932 TI - [High time for heart valve replacement]. PMID- 24482933 TI - [Stress and cardiovascular illness]. PMID- 24482934 TI - [Stress-cardiomyopathy--a psychological phenomenon?]. PMID- 24482935 TI - [Paroxysmal hypertension]. PMID- 24482936 TI - [Smoke-associated diseases--guidance of smokers]. PMID- 24482937 TI - [Obstructive sleep apnea--non-surgical therapeutic options]. PMID- 24482938 TI - [Aims of the diabetes passport]. PMID- 24482939 TI - [Difficult wounds & vacuum assisted closure (VAC)]. PMID- 24482940 TI - Mucormycosis--a formidable challenge. PMID- 24482941 TI - Mucormycosis in patients without cancer: a case series from A tertiary care hospital in South India. AB - BACKGROUND: Mucormycosis (Zygomycosis) is a life-threatening infection. We attempted to analyse clinical features and risk factors of Mucormycosis cases in a tertiary care referral institution in India, in patients without underlying malignancy. METHODS: We retrospectively analyzed data of patients diagnosed as having Mucormycosis over a 10 year period of 2000-2010. Patients with a histopathology report and/or a Microbiology report of Zygomycetes or Mucor from a biopsy specimen were included in the study. RESULTS: Out of the 27 cases, rhino orbital/rhino-cerebral involvement occurred in 12 (44.4%) patients, pulmonary involvement in 3 (11.1%) cases, soft tissue involvement in 11 (40.7%) cases and gastrointestinal involvement in one patient (3.7%). Diabetes mellitus is the main risk factor, followed by renal failure and trauma. Mean ESR value of these patients was 118 mm/1 hour. Mean WBC count was 20 x 10(9)/L, and neutrophil count 82%. The mean absolute neutrophil count (ANC) was 16.8 x 10(9)/L. CONCLUSION: The interesting finding in our study was the presence of neutrophilic leucocytosis and high ESR in most of the patients. In a predisposed individual, especially in a diabetic, in countries with high environmental fungal burden; presence of high ESR and neutrophilic leucocytosis with a compatible clinical presentation should raise suspicion of Mucormycosis. PMID- 24482942 TI - Echocardiographic assessment of left atrial volume index in elderly patients with anterior wall myocardial infarction. AB - Enlarged left atrium (LA) predicts outcomes in patients with heart failure, atrial fibrillation and stroke. Left atrial volume (LAV) especially when corrected for body size (LAVi), is a more accurate representation of true LA size. Therefore we studied left atrial volume index (LAVi) in elderly patients with left ventricle anterior infarction and correlated LAVi with left ventricle ejection fraction (LVEF) and transmitral Doppler flow. We found LAVi was significantly raised in elderly patients who suffered from AMI (26.7 + 2.1 vs 10.8 + 2.9) (p < 0.005). There was significant negative correlation of LAVi with LVEF, E wave peak velocity and decceleration time. PMID- 24482943 TI - Evaluation of risk of atherosclerosis in Indian adults. AB - OBJECTIVE: To investigate interrelationship of arterial measurements with metabolic syndrome (MS) components and zinc status in apparently healthy Indian adults. METHODS: Anthropometry and biochemical data were recorded in 110 men and 139 women (25-50 yr). Carotid Intima media thickness (CIMT), stiffness (beta), pulse wave velocity (PWV), elasticity modulus (Ep), and arterial compliance (AC) of the right carotid artery were evaluated ultrasonically. According to definition of MS, subjects were categorized as MS-1, MS-2, MS-3. Further, normal and MS subjects were divided as zinc sufficient and deficient. RESULTS: In all, 12.1% subjects had 3 risk factors for MS. Mean CIMT, beta, Ep and PWV were significantly higher by 6%, 11.6%, 29.5% and 12.4% in subjects with MS than normal (p < 0.05). AC showed significant decline in MS subjects by only 3% than normal (p < 0.05). Serum zinc was inversely correlated with beta, Ep and PWV in both the genders in subjects with MS (p < 0.05). A synergistic effect of serum zinc deficiency with MS further envisages the elevated risk of arterial stiffness. CONCLUSION: Risk of atherosclerosis is marked by increase in stiffness parameters even in presence of a single MS risk and zinc deficiency may further aggravate the risk indicating need for early diagnosis. PMID- 24482944 TI - Biomarkers for early detection of risk in female patients with coronary artery disease: pilot study. AB - In women with coronary artery disease (CAD), clinical presentation is different enough from men which leads to missed or delayed diagnosis. Biomarkers can be used for assessment of CAD patients. In case control study, we analyzed blood samples of 30 controls, 30 cases of Unstable Angina (UA) and 30 cases of Myocardial Infarction (MI) for Pro-inflammatory markers (hs-CRP, IL-6, ICAM-1) and Pregnancy Associated Plasma Protein-A (PAPP-A). Based on discriminant analysis, hs-CRP is the potential marker to discriminate cases of UA from controls while PAPP-A is the reliable marker which can discriminate the cases of MI from UA and controls. PMID- 24482945 TI - Intramuscular ACTH stimulation test for assessment of adrenal function. AB - OBJECTIVES: Adrenal insufficiency is often diagnosed by short synacthen test using intravenous Injection Synacthene, which is not marketed in India officially. To overcome this problem this study was planned to validate and use Acton Prolongatum (Ferring pharmaceuticals) as intramuscular ACTH stimulation test for evaluation of adrenal function. METHODS: This study was planned in two groups. First group called validation group, was studied for validation of intramuscular ACTH test and second group called study group, was evaluated for efficacy of intramuscular ACTH test to detect adrenal insufficiency. Twenty five units of ACTH (Acton Prolongatum) was injected intramuscularly and blood sample was collected after 60 minutes for estimation of cortisol. All subjects with one hour post ACTH cortisol < 18.0 microg/dl were diagnosed as having adrenal insufficiency. RESULTS: This study was carried out in 61 subjects in validation group and 89 patients in study group. Basal and post ACTH serum cortisol were within normal range in healthy adults, patients with diabetes mellitus and primary hypothyroidism in validation group. Basal cortisol ranged from 4.67-18.39 microg/dl and post ACTH serum cortisol ranged from 20.01-44.95 microg/dl in these groups. Patients with known adrenal insufficiency had significantly low basal cortisol level than controls (2.86 +/- 2.66 vs. 10.35 +/- 4.37 microg/dl, p < 0.001), and post ACTH serum cortisol was < 18.0 microg/dl in all. Among study group 37 patients (41.6%) were diagnosed as adrenal insufficiency using post ACTH cortisol levels. Basal cortisol (< 3.0 microg/dl) could detect only 60% of these patients. Basal cortisol level has sensitivity of 60% and specificity of 100% to detect AI when compared to ACTH stimulated cortisol levels. CONCLUSION: Intramuscular ACTH test using Acton Prolongatum is effective in evaluation of adrenal function in all suspected cases of primary or secondary adrenal insufficiency. Basal cortisol has poor sensitivity to diagnose AI. PMID- 24482946 TI - Electrical disturbance in heart by smokeless tobacco. AB - Smokeless tobacco use in the form of chewed tobacco or snuff is common in various parts of the world, including India. It is well known that smokeless tobacco consumption is responsible for cancer but less is known about its role as a risk factor for cardiovascular disease. Nicotine, the main constituent of tobacco smoke is responsible for the elevated risk of the cardiovascular disease and sudden coronary death associated with smoking, presumably by provoking cardiac arrhythmias. This review discusses some of the acute and chronic cardiac effects of smokeless tobacco on cardiovascular disease with special reference to the electrical disturbance as well as comparing nicotine kinetics between smoking and smokeless tobacco. It would further enhance the clamor to urge people to quit all forms of tobacco consumption. PMID- 24482947 TI - Intrathoracic schwannoma presenting with massive haemoptysis. PMID- 24482948 TI - Klippel-Trenaunay syndrome of the upper limb--a rare congenital anomaly. PMID- 24482949 TI - Rhino-orbital-cerebral infection by Syncephalastrum racemosusm. AB - Invasive rhino-sinusitis infection has been known to be caused by zygomycetes commonly belonging to the genera Rhizopus, Mucor and Rhizomucor. We report a middle aged diabetic gentleman who had invasive rhino-orbital-cerebral infection with Syncephalastrum racemosum. This genera belonging to zygomycetes group of fungi which usually causes skin and soft tissue infection but invasive infection with this fungus is rarely known. PMID- 24482950 TI - Aromatase deficiency: an unusual cause for primary amenorrhea with virilization. AB - The most common cause for menstrual abnormality and virilization in children and adolescents would be congenital adrenal hyperplasia. An elevated 17(OH) progesterone is invariably seen in this condition. Aromatase deficiency can also lead to a similar presentation but differs in several aspects. The age of onset of the clinical manifestations, the phenotype, biochemical abnormalities and karyotype help us to arrive at a definitive diagnosis. However sometimes the history is atypical, biochemical abnormalities may overlap between the different conditions and prior treatment may modify the clinical features. We report here a young adult with a late presentation of aromatase deficiency to highlight the differences between the two conditions. A 27 year old lady presented to us with history of primary amenorrhea and masculine voice. She lacked feminine secondary sexual characters, had eunuchoid body habitus and prominent clitoromegaly. Consanguinity in the parents, a neonatal sibling death and elevated basal 17(OH) progesterone in the patient suggested a possibility of congenital adrenal hyperplasia. But the eunuchoid body habitus raised FSH and lack of response to dexamethasone led to a diagnosis of aromatase deficiency. Variability in the degree of aromatase deficiency is known such that maternal virilization may not occur in pregnancy. Aromatase deficiency should be suspected when a patient presents with primary amenorrhea, absence of female secondary sexual characters, virilization and tall stature with eunuchoid body proportions, and biochemical features of ovarian failure. In our country one should be aware that late presentation and prior treatment may modify disease expression and contribute to the diagnostic challenge. PMID- 24482951 TI - Leucocytosis in a case of sarcoidosis with pleural involvement--an unknown association. AB - A case of biopsy-proven sarcoidosis with pleural and lung parenchymal involvement is reported. The resolution of neutrophilia and other disease manifestations with azathioprine points towards sarcoidosis being the probable cause. GG, 45 years old male, presented with fever and right-sided chest pain with biochemical features of granulomatous hepatitis and apparently unexplained leucocytosis. Azathioprine 100 mg daily was started; he improved dramatically within 3 weeks with disappearance of pain and normalization of alkaline phosphatase and leucocytosis. All clinical, biochemical and hematological parameters improved subsequently. There were no significant side effects and the patient is doing well after more than three years on azathioprine. The resolution of neutrophilia on treatment of sarcoidosis suggests a causal relationship. However, further follow-up is essential to screen for future hematological abnormalities. PMID- 24482952 TI - Inferior sinus venosus atrial septal defect. AB - One case of inferior vena cava type sinus venosus defect is reported. It is likely to be missed on transthoracic echocardiography. Transesophageal echocardiography is useful. Unlike superior sinus venosus defect which are easily visible on transesophageal echocardiography, a careful search is needed to detect inferior sinus venosus defects. All patients with unexplained right ventricular volume overload on transthoracic echocardiography should have transesophageal echocardiography to see for sinus venosus atrial septal defects. PMID- 24482953 TI - Adult type 3 Gaucher disease as manifestation of R463C/Rec Nci I mutation: first reported case in the world literature. AB - Gaucher disease is the most common lysosomal storage disorder. It is autosomal recessive in nature and results from mutations in the GBA gene coding for acid beta glucosidase. It is classified into three types based on CNS involvement and its severity. Type 3, or chronic neuronopathic Gaucher disease, generally has an onset in childhood and by definition, includes all patients with any form of neurologic involvement who have survived the first few years of life. Here we present a 36 year old male patient presenting with hip pain showing bilateral avascular necrosis of femoral head with massive splenomegaly and on evaluation, showed mental retardation, seizures, bilateral vertical and horizontal gaze palsies and eventually turned out to be type 3b Gaucher disease. This is the first case of Type 3 Gaucher disease being reported from India with mutation analysis and only case of Type 3 Gaucher disease in world literature showing R463C/Rec Nci I mutation. PMID- 24482954 TI - A case of deadly "TEN". AB - A 50 year old male, presented to us with fever and severe skin and mucous membrane lesions, and was diagnosed to be suffering from a deadly medical emergency: Toxic Epidermal Necrolysis: (TEN) which has been discussed in detail. PMID- 24482955 TI - Sir Magdi Yacoub. PMID- 24482956 TI - Medical philately. James Young Simpson & painless labor. PMID- 24482957 TI - Pentoxifylline in severe alcoholic hepatitis: a prospective, randomised trial. PMID- 24482958 TI - Author's reply: To PMID 23029716. PMID- 24482959 TI - Sarcomatoid hepatocellular carcinoma with bilateral adrenal metastases. PMID- 24482960 TI - Leukaemoid reaction (paraneoplastic syndrome) in adenocarcinoma of gall bladder. PMID- 24482961 TI - Art of initiation of antiretroviral therapy (in ARV naive patients). PMID- 24482962 TI - Clinical profile and response to first-line ARV in HIV patients from Eastern UP and Bihar: a retrospective study. AB - BACKGROUND AND OBJECTIVES: Spectrum of infections in Human Immunodeficiency Virus (HIV) infected patient from Eastern UP and Bihar has not been systemically evaluated. This study was conducted with the following objectives; a) explore the spectrum of clinical conditions associated with HIV disease, b)the difference between clinical and investigatory parameters in those patients who presented with infection from those who present without infection and c) to evaluate the effect of anti-retroviral (ARV) therapy. METHODS: 1248 subjects who fulfilled the inclusion criteria were enrolled for the study from May 2007 to November 2008. Patients were evaluated for their baseline characteristics along with CD4 count and followed up for at least for 6 months after initiation of ARV (6-24 months). RESULT AND INTERPRETATION: In this retrospective study, tuberculosis (58.96%) was the commonest infection followed by chronic diarrhoea (26.56%) and various skin infections. Males had significantly higher incidence (p value < .001) of infection as compared to females. There was a significant difference between the patients who presented with infection from those who presented without infection for their baseline weight (42.3 vs 45.42), haemoglobin (9.06 vs 9.91), mean CD4 count at baseline (107.38 vs 128.38/microL) and CD4 count after 6 month of therapy (298.09 vs 322.98/microL). Mortality was also significantly high (p value < 0.05) in those who presented with infection (19.95% vs 15.1%), although there was no difference between these two groups on their improvement in CD4 count from baseline after 6 months of therapy. CONCLUSION: Among the spectrum of infection in HIV patient from North East part of India, tuberculosis was commonest, followed by skin infections and chronic diarrhoea. Patients who presented with infection at the time of initial presentation had a low haemoglobin, body weight and CD4 count and had high initial mortality but if they survived they show similar response to ARV therapy as patients who presented without infection. PMID- 24482964 TI - SPECT in asymptomatic diabetics with and without microalbuminuria. AB - OBJECTIVE: To identify coronary artery disease (CAD) in asymptomatic diabetics with the help of myocardial perfusion single photon emission computed tomography (MPS), a non-invasive imaging modality and its correlation in diabetics with or without microalbuminuria. METHODS: This study included 99 patients in the age group of 30 to 80 years who were asymptomatic but possessed one or more risk factors for CAD. These patients were divided into two groups, diabetics with and without microalbuminuria (Micral). Thirty eight patients were Micral positive and 61 were Micral negative. Ischemia was detected by MPS and compared with coronary angiographic findings in both the groups. RESULTS: Amongst the 99 diabetic patients, MPS was positive in 39 patients. Out of 39 MPS positive patients, 31(79.5%) were micral positive and 8 (20.5%) were micral negative. Out of 38 micral positive patients, 31 patients were positive on MPS and 27 had significant angiographic (CAG) findings. Those with micral positive and MPS positive had multivessel CAD by CAG. It was seen that MPS status was 91.4% sensitive, 74.1% specific and had 82.1% positive predictive values (PPV) and 87.0% negative predictive value (NPV) for detection of significant CAD. CONCLUSION: Microalbuminuria is an inexpensive screening tool and a powerful independent predictor for major cardiovascular events in patients with type 2 diabetes mellitus. MPS is a sensitive, non invasive diagnostic test for identification of CAD in asymptomatic diabetic patients. PMID- 24482963 TI - Regulation of adiponectin secretion in human subcutaneous and omental adipose tissue: effects of pioglitazone and endothelin-1: a pilot study. AB - OBJECTIVE: The study was designed to test the effect of anti-diabetic agent pioglitazone and Endothelin-1 (ET-1) on adiponectin secretion from human adipose tissue in depot dependent manner. METHODS: Subcutaneous adipose tissue (SAT) and omental adipose tissues (OAT) were obtained from 19 subjects, including 6 non obese controls, 7 obese and 6 obese T2DM patients. Adipose tissue was treated with pioglitazone and ET1. Adiponectin secreted into the culture medium after treatment at different time interval (0, 24, 48, 96 hours) was determined by ELISA and normalized for cellular DNA content. RESULTS: Basal adiponectin secretion from both the depots significantly associated with serum adiponectin, BMI, waist and HOMA-IR. Though no depot-specific difference was found in adiponectin secretion from SAT and OAT in our population, significant reduction in adiponectin secretion was observed in SAT of obese and T2DM patients compared to controls. Responsiveness to pioglitazone treatment was more in SAT, while ET1 inhibits adiponectin secretion in OAT. CONCLUSION: These data suggest that, SAT, appears to be major contributor to regulation of adiponectin in circulation. Pioglitazone stimulate adiponectin secretion in SAT compared to OAT in diabetic patients while ET-1 inhibiting adiponectin secretion in OAT of diabetic patients. We need to focus on mechanism underlying these regulatory agents mediated stimulation or inhibition of adiponectin secretion in human adipose tissue. PMID- 24482965 TI - Biologics in SLE: the current status. AB - Systemic lupus erythematosus (SLE) can be a severe and potentially life threatening disease that often represents a therapeutic challenge because of its heterogeneous organ manifestations. Only glucocorticoids, hydroxychloroquine, mycophenolate mofetil, azathioprine, cyclophosphamide, and very recently belimumab have been approved for SLE therapy. Dependence on glucocorticoids and resistance to the approved therapeutic agents, as well as substantial toxicity, are frequent. B-cells abnormalities leading to autoantibody production play a central role in Systemic Lupus Erythematosus (SLE) pathogenesis. The targets of these biological therapies are directed toward the B cell depletion, interference in the co-stimulation signals and the blockade of cytokines. Biologic agents targeting specific pathways (i.e. T-B lymphocyte interaction, cytokines and complement) have been also proposed as new tools for SLE treatment. B-cell targeted therapies, including anti-B lymphocyte stimulator (BLyS) and anti-CD20 monoclonal antibodies are at forefront of new SLE treatment. Results from randomized trials in systemic lupus erythematosus (SLE) have been very disappointing, with lack of efficacy for some drugs and development of severe side-effects such as infections for others. Fortunately, as more and more trials of biologics in the treatment of lupus are being performed, the first promising results have been achieved. Today, belimumab is expected to become the first approved drug for use in lupus in several decades. In this review we will focus on biological drugs whose potential efficacy have been evaluated in open-label and randomized clinical trials. Biologics provide encouraging results that represent a possible option in the treatment of refractory lupus. Thus we review recent clinical trials in patients with systemic lupus erythematosus (SLE), with emphasis on outcomes and on mechanisms by which the biological agents suppress autoimmunity. PMID- 24482966 TI - Peripartum cardiomyopathy. AB - Peripartum cardiomyopathy (PPCM) is a rare type of cardiomyopathy of unknown aetiology associated with significant mortality and morbidity and characterized by heart failure in late pregnancy or puerperium. Recently PPCM workshop committee has recommended inclusion of echocardiographic features of LV dysfunction to redefine PPCM. Subsequent pregnancies are associated with a very high mortality in these patients and hence should be avoided. Women with PPCM continue to have significant mortality despite the use of conventional drugs for managing heart failure. Use of newer drugs such as immunoglobulin, pentoxifylline, bromocriptine, and cabergoline along with newer interventions such as plasmapheresis, immunoadsorption, ventricular assist devices and last but not the least the heart transplantation hold promise for future. PMID- 24482967 TI - Methotrexate-induced accelerated nodulosis in seropositive rheumatoid arthritis. PMID- 24482968 TI - FDG-PET scan in management of pulmonary sarcoidosis. PMID- 24482969 TI - Cushing's disease: establishing the diagnosis and management approach. AB - A 64 year old lady, with a background history of type 2 diabetes mellitus and hypertension, presented with general deterioration of general health, poor glycemic control, difficulty in controlling blood pressure and difficulty in walking. She had past medical history of adenocarcinoma of the oesophagus, treated with surgery and subsequent chemotherapy. General examination revealed high blood glucose and blood pressure and a Cushingoid facies. Overnight dexamethasone suppression test and urinary free cortisol levels confirmed Cushing's syndrome and High dose dexamethasone suppression test showed partial suppression. CT scan of the abdomen showed bilateral hyperplasia of the adrenals with nodularity on the left side, raising the possibility of an adrenal adenoma. ACTH levels were elevated thereby ruling out autonomously functioning adrenal nodule, however increasing the possibility of ectopic ACTH secretion due to the previous medical history. MRI of the pituitary confirmed the presence of an adenoma, thereby pointing to the diagnosis of pituitary dependant Cushing's disease. The patient could not undergo further invasive investigation or surgery due to septicaemia. Medical management of Cushing's syndrome was resorted to in the interim with Ketoconazole, showing excellent response. This case depicts the need for a high index of suspicion for the diagnosis, the importance of organizing specific investigations in the appropriate order to arrive at a diagnosis and an effective management plan. PMID- 24482970 TI - Atrial myxoma: a rare cause of ischemic stroke. AB - Arial myxoma can present as stroke and should be considered as a differential diagnosis of stroke in young individuals. We present here a 42 years female who presented with sudden loss of conciousness. After extensive work up for young stroke, left atrial myxoma was detected and tumor was removed surgically and histopathological report was consistent with the atrial myxoma. PMID- 24482971 TI - Radial pseudoaneurysm following trans-radial coronary angiography. AB - A case of pseudoaneurysm of right radial artery following transradial coronary angiography is reported. Adequate hemostasis is the key to prevention. Prolonged ultrasonography guided compression of neck of pseudoaneurysm or injection of procoagulants in the cavity of pseudoaneurysm can help non surgical closure. PMID- 24482972 TI - Gonadal dysgenesis due to isochromosome formation of long arm of X chromosome. AB - Isochromosome involving the long arm of X chromosome is a rare structural rearrangement of the X chromosome, leading to Gonadal dysgenesis. These patients present as phenotypic females with amenorrhea and growth failure. Often other associated features like endocrine abnormalities and skeletal deformities are found. They are chromatin positive cases and are only diagnosed by karyotyping. Hashimoto's thyroiditis is a rare association with isochromosome X. PMID- 24482973 TI - Eugene Braunwald. PMID- 24482975 TI - Profile of 'Paederus dermatitis outbreak' in boys hostel of a rural medical college in the north India. PMID- 24482974 TI - Medical philately. Ferdinand Sauerbruch: pioneer thoracic surgeon. PMID- 24482976 TI - IV tPA use in a tertiary care hospital: observations over two time periods. PMID- 24482977 TI - Nitrous fumes-induced acute lung injury in a goldsmith. PMID- 24482978 TI - A note on the A1chieve study and the importance of disseminating our results. PMID- 24482979 TI - Importance of observational studies in understanding regional clinical practice: rationale and design of the A1chieve study. PMID- 24482981 TI - Current glycemic status and diabetes related complications among type 2 diabetes patients in India: data from the A1chieve study. AB - BACKGROUND: According to the ICMR-INDIAB study, there are 62.4 million people living with diabetes in India. Type 2 diabetes (T2DM) is a progressive disease and hampers the quality of life of the patients due to micro and macrovascular complications. There are few studies on the status of glycemic control in the country. Such data would be useful to allocate health resources and plan measures for instituting better control of diabetes. METHODS: The A1chieve study was an observational study of patients 66,726 with T2DM who were initiated, on or switched to, insulin analogues, alone or in combination with oral glucose lowering drugs at the discretion of their physician in accordance with local, routine clinical practice. This study reports on the participants in India from the A1chieve study. RESULTS: Baseline data of A1chieve study in 20,554 Indian T2DM patients showed that the mean HbA(1c) was 9.2%. Diabetes control was worse in those with longer duration of diabetes (9.9 +/- 5.5 years). Use of insulin was clearly suboptimal showing evidence of clinical inertia. The prevalence of both macrovascular and microvascular complications was high due to poor glycemic control. The prevalence of neuropathy was the most common complication followed by cardiovascular (23.6%), renal (21.1%) and eye (16.6%) complications. The prevalence of foot ulcer was 5.1%. Many patients had multiple complications. CONCLUSION: Glycemic control in India is poor and this has resulted in a high prevalence of complications. This emphasizes the fact that effective control of T2DM is urgently needed to prevent or reduce the risk of developing the complications of diabetes in Indian T2DM patients. PMID- 24482980 TI - Why is premixed insulin the preferred insulin? Novel answers to a decade-old question. AB - A wide range of sources have been used to create an equally wide range of types of insulin (rapid acting, fast acting, premixed, intermediate acting and long acting). While some of these insulins are no longer in clinical use, others are being used extensively across the world. Premixed insulin is the most frequently prescribed and used insulin in Asia; basal insulin is more extensively used in USA. As compared with basal insulin alone, premixed regimens tend to lower HbA1c to a larger degree while providing enhanced convenience. It is a challenge for diabetologists to assess the conflicting guidelines and decide which one to follow. This is especially true with regard to choosing appropriate insulin for initiation of therapy. Besides, ethnicity may play a key role in determining choice of insulin therapy among different populations. Here, the authors discuss the various factors, pharmacological as well as psychological, that have made premixed insulins the preferred insulin for type 2 diabetes in India and the many parts of Asia. The authors utilize well known theories of psychology, namely generalization, cognitive dissonance and concordance to provide a rational explanation for the preference for premixed insulin that Indian people with diabetes, and their physicians, have. PMID- 24482983 TI - Initiation of insulin aspart to Indian subjects on OADs show significant improvement in glycaemic outcomes: the A1chieve observational study. AB - The prevalence of diabetes is increasing worldwide and India stands second next only to china. The management of diabetes in real life settings needs to be evaluated for deriving better management practices. A1chieve observational study evaluated the use of modern insulin in real life settings. This was a 24-week, international, prospective, multicenter, non-interventional, observational study of people with type 2 diabetes. India recruited with 20,554 subjects and a total of 1815 patients were enrolled to receive insulin aspart as bolus insulin therapy of whom 1450 (79.9%) were insulin naive and 365 (20.1%) were insulin users. At the end of 24 weeks, only one SAE was reported in this study and overall hypoglycemia events per patient year decreased from 2.49 (348 episodes) to 0.17 (20 episodes). There were no major hypoglycemic episodes reported in either insulin naive or insulin treated subjects. There was a significant improvement in the HbA(1c) values from the baseline in both insulin naive and insulin users. The mean HbA(1c) value was reduced from 9.5 to 7.4 (p < 0.001) for insulin naive subjects and from 9.2 to 7.7 (p < 0.001) in insulin experienced subjects. Fasting plasma glucose values decreased by 70 mg/dL and 50 mg/dL in insulin naive and insulin experienced, respectively and the difference from baseline was statistically significant (P < 0.001). The post prandial glucose value was also significantly (p < 0.001) reduced by 105 mg/dL for insulin naive subjects and 55 mg/dL for insulin experienced subjects. The composite end point was achieved by 46.6% of insulin naive and 38.1% of insulin-experienced subjects. The study concluded with good HbA(1c) reduction along with lower incidence of hypoglycemia and better health related quality of life outcomes in both in insulin naive and insulin experienced subjects who used insulin aspart as bolus insulin treatment. PMID- 24482982 TI - Initiating therapy or switching to biphasic insulin aspart improves glycaemic control in type 2 diabetes: an Indian experience from the A1chieve study. AB - Biphasic insulin aspart 30 (BIAsp 30) has been used in patients for almost a decade; There is a wealth of knowledge from clinical trials to document its efficacy and safety and suggest that BIAsp 30 is an option for initiation and intensification of insulin therapy in patients with type 2 diabetes mellitus (T2DM). The A1chieve was a non-interventional study that explored the safety and effectiveness of initiating or switching to insulin analogues in routine clinical practice in more than 60,000 patients from 28 different countries. In this manuscript, we discuss the findings from the subgroup of the Indian cohort who were treated with BIAsp 30. In a cohort of 15287 who were on BIAsp 30, 12645 (83%) were insulin naive and 2642 (17%) had been on insulin therapy earlier. Glycaemic parameters were high at baseline. Mean (SD) HbA1c was 9.2% (1.3) in the these and was comparable in the insulin naive and insulin experienced groups. After 24 weeks of therapy with BIAsp 30, there were reductions in HbA1c in both the insulin naive group, [-1.8 (1.3)] and insulin experienced group [-1.6 (1.3)]. Fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels were also reduced significantly from baseline [-3.4 (2.7) and -4.8 (3.8) mmol/L, respectively, p < 0.05). Overall, hypoglycaemia decreased from 1.33 events/patient years at baseline to 0.19 events/patient years at 24 weeks. There was also an increase in quality of life score as evaluated by EQ-5D questionnaire. Initiating insulin therapy with or switching to BIAsp 30 in patients with poor glycaemic control leads to an improvement in glycaemic profile with no major hypoglycaemia or clinically significant weight gain. Therapy with BIAsp 30 also improves the quality of life in patients with type 2 diabetes. PMID- 24482984 TI - Addition of insulin aspart with basal insulin is associated with improved glycemic control in Indian patients with uncontrolled type 2 diabetes mellitus: the A1chieve observational study. AB - Insulin aspart (IAsp) has been used in patients for more than a decade. A plethora of data is available, from clinical trials, to document its efficacy and safety and suggest that IAsp is a favorable choice to be used in a basal-bolus regimen. The A1chieve@ was a non-interventional study that explored the safety and effectiveness of initiating or switching to insulin analogues in routine clinical practice in more than 60,000 patients from 28 different countries. In this manuscript, we discuss the findings from the subgroup of the Indian cohort who were treated with insulin aspart (IAsp), in addition to a basal insulin analogue (insulin detemir, IDet). In a cohort of 343, who were on IAsp + IDet, 175 (51%) were insulin naive and 168 (49%) had been on insulin therapy earlier. Glycaemic parameters were high at baseline. Mean HbA1c was 9.3% in them and was comparable in both insulin naive and insulin experienced groups. After 24 weeks of therapy with IAsp + basal insulin, there were reductions in HbA1c in both the insulin naive group, (-1.6) and insulin experienced group (-1.5). Fasting plasma glucose (FPG) and postprandial plasma glucose (PPG) levels were also reduced significantly from baseline (-77 and - 110 mg/dL, respectively, p < 0.001). Overall, hypoglycaemia decreased from 0.97 (baseline) to 0.18 events/patient years (24 weeks). There was also an increase in quality of life score as evaluated by EQ-5D questionnaire. Addition of IAsp with a basal insulin in patients with poor glycaemic control leads to an improvement in glycaemic profile with no major hypoglycaemia or clinically significant weight gain along with an improvement in the quality of life in patients with type 2 diabetes. PMID- 24482985 TI - Improvement of glycemic control with addition of insulin detemir to existing antidiabetic therapy: a sub-group analysis of A1chieve observational study. AB - BACKGROUND: The A1chieve study evaluated safety and effectiveness of insulin analogues in a large and diverse population. This report presents a subgroup analysis of the A1chieve observational study pertaining to India. OBJECTIVE: To assess safety and effectiveness of initiation or intensification of insulin detemir in patients with type 2 diabetes mellitus (T2DM) not achieving adequate glycemic control. METHODS: The A1chieve study was a prospective, multi-center, open-label, non-interventional study of 24-weeks duration. In this post-hoc analysis, Indian patients with T2DM who did not achieve their glycemic targets, and were started with or switched to insulin detemir, were evaluated at baseline and after 24 weeks of therapy for safety and effectiveness. Adverse events (AE) noted during the course of therapy were recorded. Additionally Glycemic, non glycemic parameters and quality of life indices were reported. Appropriate statistical analysis was carried out to assess the statistical significance. RESULTS: The Indian cohort of 2707 patients with T2DM treated with insulin detemir included 2336 (86.29%) insulin-naive and 371 (13.71%) insulin-experienced patients. No adverse drug reaction (ADR) was noted over 24 weeks, one patient (out of 2707) reported serious adverse event. Major hypoglycemia was reported in 0.5% (0.08 events/patient year) patients and reduced to 0% (0 events/patient year) over 24 weeks. After 24 weeks' treatment with insulin detemir, an overall reduction in HbA(1c) of 2.1% was noted (p < 0.001), with a 2.1% (p < 0.001) and 2% (p < 0.001) reduction in insulin-naive and insulin-experienced groups, respectively. A significant reduction in fasting ([mean +/- SD] -3.8 +/- 2.5 mmol/L) and postprandial (-5.2 +/- 3.9 mmol/L) blood glucose (FPG and PPG) was also observed (p < 0.001 for both). At end of the study, 24.4% patients achieved the ADA target of < 7.0% and 14.3% patients achieved the AACE target of < 6.5% for HbA(1c). A significant improvement in quality of life indices like ED-5D (0.31 +/- 0.29; p < 0.001) and EQ-VAS (21.7 +/- 16.7; p < 0.001) was noticed. CONCLUSION: In patients with T2DM not achieving their glycemic targets addition of basal insulin detemir was well tolerated and reported improvement in glycemic control. PMID- 24482986 TI - Insulin analogue therapy improves quality of life in patients with type 2 diabetes in India: the A1chieve study. AB - AIMS: To determine the effects on quality of life after starting insulin with, or switching to, insulin analogue therapies in Indians with type 2 diabetes mellitus in the 24-week, prospective, observational A1chieve study. METHODS: Health related quality of life (HRQoL) was assessed at baseline and at 24 weeks by the validated EQ-5D questionnaire (visual analogue score [VAS] and five dimensions) in 20,554 people who had started using basal insulin detemir, mealtime insulin aspart (with or without a basal insulin) or biphasic insulin aspart 30. RESULTS: Quality of life improved in both insulin-naive and insulin experienced patients in all treatment groups. At the start of the study, 63.2% of the insulin-naive patients reported problems with walking but after 24 weeks, only 15.2% reported difficulties. At baseline all HrQOL parameters were deteriorated in Indian cohort and the improvement observed was highly significant and well appreciated. The improvement was seen across all insulin regimen and all regions around India. CONCLUSION: Compared with baseline scores, HRQoL improvement was seen after 24 weeks of treatment with all insulin analogue therapies PMID- 24482987 TI - [Extend a helping hand in disaster 6,000 miles away from home--the Israeli Field Hospital in the Philippines]. PMID- 24482988 TI - [Medical research in Israel in 2013]. PMID- 24482990 TI - [Who is responsible for determining the fetal criteria for termination of pregnancy before the age of viability?]. PMID- 24482989 TI - [Forty years to Yom Kippur War]. PMID- 24482992 TI - [4-dimensional computed tomography for localization of parathyroid adenoma]. AB - INTRODUCTION: In about 85% of patients with primary hyperparathyroidism (pHPT) only a single parathyroid gland is diseased. The operation of choice in this group of patients is minimally invasive parathyroidectomy (MIP). In order to perform an MIP, the diseased gland should be identified prior to surgery. This is not always possible with the routine imaging studies including parathyroid sestamibi scan and ultrasound. Four-dimensional computed tomography (4D-CT) scanning was developed in order to identify an enlarged parathyroid gland. Several characteristics make it possible to identify glands of this type and to differentiate it from other neck nodes. PURPOSE: To evaLuate the accuracy of 4D CT in the identification of parathyroid adenoma/s in order to perform an MIP. METHODS: A total of 69 patients underwent parathyroidectomy for pHPT during the period July 2010 to June 2012. The 4D-CT was performed on 27 patients. Data were retrospectively extracted from the patients' charts including imaging studies, operative notes, number and LocaLization of glands excised and pathological reports. RESULTS: The 4D-CT was positive for a single adenoma in 26 patients confirmed in surgery. In 4 of those patients, one or two additional glands were found enlarged during surgery. Sixteen patients underwent an MIP, 3 patients had a unilateraL exploration and in 8 cases a biLateraL exploration was performed. The 4D-CT had a sensitivity of 81.4% and a positive predictive value of 100% in this group of patients. CONCLUSIONS: The 4D-CT is another tool for the identification of enlarged parathyroid gLand/s before surgery. Further study is needed to determine its place in the current armamentarium of pre-operative localization studies. PMID- 24482991 TI - [Common complaint, forgotten diagnosis: spontaneous intracranial hypotension syndrome]. AB - Violation of the balance between the production and absorption rate of the cerebrospinal fluid (CSF) might result in hydrocephalus or the spontaneous intracranial hypotension syndrome (SIH), which is usually presented with a unique type of headache. Several hypotheses have been suggested regarding the pathogenesis of this syndrome, including spinal CSF leakage due to located damage to the spinal dura. Another theory suggests increased CSF absorption from the spinal epidural space caused by declined inferior vena cava pressure. SIH is characterized by typical radiological findings, including the presence of subdural collections or hematomas, sagging of the brain parenchyma and the cerebellar tonsils, and brain meninges enhancement. Spinal imaging studies may help in locating the CSF leakage site when it exists. The diagnosis is based on the presence of orthostatic headaches together with typical clinical and imaging characteristics, after the exclusion of any recent medical interventions or other possible etiologies for the presence of SIH. The main treatment includes autologous epidural bloodpatch, even though symptomatic relief may be achieved with supportive or medical treatment alone. The presence of subdural collections or hematomas among patients presenting with orthostatic headaches suggests the need for further clinical and imaging evaluation prior to the surgical drainage, whenever possible. Two patients who were recently treated in our institution are presented, together with a proposed management algorithm. PMID- 24482993 TI - [New guidelines to decrease x-ray use may increase unnecessary antibiotic use]. AB - BACKGROUND: The newly reLeased guidelines of infectious disease societies suggest abstaining from performing routine chest radiographs in the diagnosis of community acquired pneumonia in clinically stable children, based upon studies where the measured outcome is time to resolution of the disease not antibiotic use. However, the impact of possible over-treatment with antibiotics that might result from this clinical approach is not discussed. OBJECTIVES: The goal of this study was to quantify how many children with clinicaL signs suggestive of pneumonia would have been given unnecessary antibiotic treatment had the chest radiograph not been performed. METHODS: In a system of urgent care centers, we reviewed the medical records of patients > 2 months and <10 years with the chief complaint of fever, cough or dyspnea who had a chest X-ray performed upon their evaluation. Demographic and cLinical data were obtained with the final reports of X-rays interpreted by senior radiologists. An X-ray was considered positive if an infiltrate or pneumonia was noted in the report. RESULTS: There were 3343 children over a one year period who met the inclusion criteria. A total of 877 had findings suggestive of pneumonia on the basis of physical examination. Of these, 433 (48.6%) had normal chest radiographs. Among those with negative X rays, 305 (68.8%) had rates or crepitus on auscultation. CONCLUSIONS: Reliance on physical examination alone in the diagnosis of community-acquired pneumonia (CAP) in children may over-diagnose cases of pneumonia in a clinically significant manner. Further consideration of this possibility is needed before widely disseminating guidelines that advocate antibiotic treatment based on clinical diagnosis alone. PMID- 24482994 TI - [Thoracic nocardiosis with thoracic manifestations in two immunocompetent patients]. AB - Nocardiosis is a rare infectious disease caused by bacteria of the genus nocardia, which causes considerable morbidity and mortality. We report two unusual cases of nocardiosis in young, immunocompetent patients; the first case involved a nocardia farcinica pulmonary and chest-wall infection, while the second was an anterior mediastinal nocardia asiaticum infection mimicking a mediastinal tumor. These cases reflect the need for a broad differential diagnosis during exploration of thoracic findings, white the potentially ambiguous presentation of nocardiosis must be considered. PMID- 24482995 TI - [Paradigm shift in the management of metastatic epidural spinal cord compression: the importance of preserving ambulation]. AB - In 2005, a Landmark study showed that direct decompressive surgery, followed by postoperative external beam radiotherapy (EBRT) is superior to EBRT alone in patients with metastatic epidural spinal cord compression (MESCC). Patients undergoing both surgery and EBRT had similar median survival but experienced longer ambulation than with EBRT alone. Additional studies have shown improvements in quality-of-life, higher cost-effectiveness, improved pain control, and higher functional status with surgery plus EBRT. Improved neurological outcome also improved the patients' ability to undergo postoperative adjuvant therapy. According to our experience, even patients over 65 or patients with aggressive primary tumors and additional metastases have benefited from surgical intervention, living longer than expected with preservation of ambulation and sphincter control until death or shortly before. Preserving ambulation is critical. With current surgical devices and techniques, patients with MESCC who present with a single area of cord compression, back pain, neurological deficit, or progressive deformity, may benefit from surgery prior to adjuvant radiation-based treatment or chemotherapy. PMID- 24482996 TI - [Metastatic spinal cord compression: diagnosis and treatment]. AB - Metastatic epidural spinal cord compression is a common complication of cancer that can cause pain and potentiaLly irreversible loss of neurologic function. In most cases this syndrome is caused by compression of the thecal sac and the spinal cord by extradural metastatic mass. The most important steps in minimizing the potential neurologic sequelae are early diagnosis and rapid therapeutic intervention. MRI is generally the preferred imaging modality because of its noninvasive ability to study the entire thecal sac. Surgery and radiotherapy are the primary approaches to treat tumor compressing the spinal cord. PMID- 24482997 TI - [Cardiopulmonary stress test--physiological basis and key variables]. AB - A recent report in Harefuah introduced cardiopulmonary exercise testing (CPX) and its role in evaluating effort intolerance. Despite the fact that multiple guideline documents and scientific statements have been published in the last few years by the leading European and American societies, summarizing the incremental information supplemented by the addition of ventilatory gas exchange measurements, CPX continues to be underutilized by the practicing clinician. The reasons for this are many and include the requirement for additional equipment, the lack of understanding of the physiological basis by the practicing clinicians, and the seemingly complicated graphical report of this technique. We shall review the physiological basis of the technique, and summarize the key CPX variables and their clinical implications. PMID- 24482998 TI - [Phytosterols: another way to reduce LDL cholesterol levels]. AB - Phytosterols are sterols found naturally in various oils from plants. Phytosterols compete with cholesterol for a place in the mixed micelles, needed for cholesterol absorption by the small intestine. As a result, cholesterol absorption, either from food or from bile salts is lowered by about 50%, leading to a towering of about 10% of blood cholesterol level, despite an increase in hepatic cholesterol synthesis. This reduction is achieved when phytosterols are given both as monotherapy, and in addition to statin therapy. The average Western diet contains about 400-800 mg of phytosterols per day, while the dose needed for lowering the blood cholesterol level is about 2-3 grams per day. Therefore, for the purpose of reducing blood cholesterol, they should be given either as phytosterol-enriched food or as supplements. The reduction in the level of LDL choLesterol achieved with phytosterols may reduce the risk of coronary disease by about 25%. Hence, the American Heart Association recommended the consumption of phytosterols, as part of a balanced diet, for towering blood cholesterol levels. PMID- 24482999 TI - [Trance(s)--music and more]. AB - The recent amendment, of the Israeli regulation for nutrition labeling on the packaged food label, as published in the government registry, mandates the labeling of trans fatty acids. The relationship between the types of fatty acids and the risk of developing heart disease is well known and has been researched for many years. As part of efforts of the health authorities around the world and in Israel to reduce morbidity and mortality from chronic diseases, the authorities act to reduce consumption of trans fatty acids and saturated fatty acids. This article reviews the major changes that have taken place in reducing the consumption of trans fatty acids in recent years. This includes the evidence which pointed to the negative effects of their use, the Latest recommendations of several leading health leading organization regarding optimal consumption of fats in particular and regarding nutrition in general. It also entails trends in the world food industry towards the reduction in trans fatty acids use, and policies countries are implementing in order to reduce the world's consumption of trans fatty acids, including the updating of nutritional labeling regulations in Israel. PMID- 24483000 TI - [Short-and long-term effects of cannabinoids on memory, cognition and mental illness]. AB - Marijuana is considered the most commonly used drug in the world, with estimated millions of users. There is dissent in the medical world about the positive and negative effects of marijuana, and recently, a large research effort has been directed to that domain. The main influencing drug ingredient is THC, which acts on the cannabinoid system and binds to the CB1 receptor. The discovery of the receptor led to the finding of an endogenous ligand, anandamide, and another receptor-CB2. The researchers also discovered that cannabinoids have extensive biological activity, and its short and long-term effects may cause cognitive and emotional deficiencies. Findings show that the short-term effects, such as shortterm memory and verbal Learning, are reversible. However, despite the accumulation of evidence about long-term cognitive damage due to cannabis use, it is difficult to find unequivocal results, arising from the existence of many variables such as large differences between cannabis users, frequency of use, dosage and endogenous brain compensation. Apart from cognitive damage, current studies investigate how marijuana affects mental illness: a high correlation between cannabis use and schizophrenia was found and a high risk to undergo a psychotic attack. Furthermore, patients with schizophrenia who used cannabis showed a selective neuro-psychological disruption, and similar cognitive deficiencies and brain morphological changes were found among healthy cannabis users and schizophrenia patients. In contrast to the negative effects of marijuana including addiction, there are the medical uses: reducing pain, anxiety and nausea, increasing appetite and an anti-inflammatory activity. Medicalization of marijuana encourages frequent use, which may elevate depression. PMID- 24483001 TI - [Guidelines for the diagnosis and treatment of the fibromyalgia syndrome]. AB - Over the past years, considerable progress has been made in understanding the pathogenesis of the fibromyatgia syndrome and the evidence based approach to the diagnosis and management has been significantty extended. The purpose of the current project is to develop practicat and evidence based guidetine recommendations for the Israeli health care system. A panet of physicians with clinical and research experience in the fibromyalgia field was convened under the auspices of the Israeli Rheumatology Association. A systematic review was performed on the current literature regarding the diagnosis and treatment of fibromyalgia. Using an interactive discussion procedure, recommendations were reached and expert opinion was introduced where evidence was considered incomplete. The panel recommendations underline the importance of concomitant and integrated medical therapy, such as serotonin and noradrenaline reuptake inhibitor (SNRI) anti-depressants or gamma-aminobutyric acid (GABA) related anti epileptics, with regular aerobic physical exercise. PMID- 24483006 TI - [Cautionary note on use of INSTANT-VIEW M-1 to avoid incomplete reaction]. PMID- 24483007 TI - Incorrect first aid treatment information about stonefish envenomation on medical websites. PMID- 24483008 TI - [Cyanamide-ethanol reaction induced shock: report of a case and literature review]. AB - Cyanamide is a known alcohol deterrent, and it may cause severe cyanamide-ethanol reaction if a patient consumes high amounts of alcohol during treatment. We report a rare case of cyanamide-ethanol reaction-induced shock in a 73-year-old man who was taking cyanamide for the treatment of alcohol dependence. The patient complained of acute onset of dyspnea after drinking. On arrival, he was in a state of shock. We immediately started hydration and administered 0.3 mg adrenaline by intramuscular injection. However, the patient's general condition did not improve. We could rescue him only after a high dose of adrenaline was administered by continuous intravascular injection. In general, in the treatment of cyanamide-ethanol reaction-induced shock, adrenaline or noradrenaline should be used instead of dopamine. Some cases of severe cyanamide-ethanol reactions have been recently reported in Japan. We performed a literature review and have discussed these cases in the text. PMID- 24483009 TI - [Triage DOA screening in a case of methamphetamine and its analogue poisoning]. AB - CASE REPORT: A 20-year-old woman presented with the chest pain, nausea, respiratory strange feeling, and a large quantity of sweating. On the stimulant zone of 8 groups of drugs of Triage DOA screening it showed an equivocal positivity while all of the other zones gave negative results. She denied taking drugs. No injection scar was found. And she was then hospitalized because little was known about her symptoms. When the unconscious patient was discovered at rest room inside hospital the next day, she was transferred to emergency and critical care center. In the same screening test positivity on the stimulant zone was observed, and furthermore both amphetamine and methamphetamine were detected by GCMS analysis. For 4 days positivity on the stimulant zone lasted. From the fact of disturbance of consciousness, restlessness, excitation and tachycardia, respiration disorder, and the pupil dilatation drug poisoning was deeply suspected. DISCUSSION: While the stimulant zone of Triage DOA showed the equivocal positivity when 7 hours has elapsed until she became aware of abnormality and hospitalized, in the same screening of 30 hours later positivity was verified clearly. Several problems derived from the detection method, pharmacokinetic factors and pharmacodynamic aspect were discussed as for the difference of the results detected. PMID- 24483010 TI - [Case of iodism complicated with severe airway stenosis due to pharyngolaryngeal edema]. AB - A 22-year-old man was admitted to our hospital with dilute iodine tincture poisoning. He had ingested 150 mL in a suicide attempt. On arrival, he was in need of urgent airway management as he was repeatedly vomiting. Although we had difficulty with endotracheal intubation because of remarkable pharyngolaryngeal mucosal edema induced by dilute iodine tincture, we managed to secure the airway. On the 2nd day, laryngoscope showed severe mucosal erosion from the upper to middle pharynx and epiglottis. On the 4th day, we performed a tracheoctomy in anticipation of prolonged airway management. On the 16th day, laryngoscopy showed improvement in each of the 2nd day findings. On the 30th day, the patient was transferred to a psychiatric hospital. Generally, iodine poisoning induces multiple organ disorders and there have been several reports describing iatrogenic iodine poisoning. However, cases of severe airway stenosis due to ingestion of iodine are very rare. Presently, members of the public can easily purchase dilute iodine tincture in Japan, therefore emergency medical personnel should be aware of iodine poisoning as a method of suicide attempt. PMID- 24483012 TI - [Transition of acetylsalicylic acid serum concentration in a case of overdose]. PMID- 24483011 TI - [Case of honey intoxication in Japan]. AB - A 63-year-old woman presented with a 4-hr history of sneezing, visual disturbance, and dyspnea after drinking foreign honey dissolved in hot water. Severe hypotension (56/30 mmHg) and bradycardia (55 beats/min) were identified on arrival. She was immediately administered intravenous atropine (0.5 mg) and a bolus injection of Ringer solution (2,000 mL). Circulatory abnormality dramatically improved immediately after atropine injection and she was discharged on hospital day 2. We speculate that the patient suffered from honey intoxication because of manifestations such as hypotension and bradycardia, which are commonly seen in patients intoxicated by honey. PMID- 24483013 TI - [Two cases of ant sting anaphylaxis]. PMID- 24483014 TI - [Instrumental analysis for the diagnosis of poisonings]. PMID- 24483015 TI - [Practical analysis of toxic substances useful for clinical toxicology. (4). 4-O methylpyridoxine (MPN ; ginkotoxine)]. PMID- 24483016 TI - [Accidental exposures to cleaning products in food services]. PMID- 24483017 TI - [Practical guidelines for the management and treatment of infections caused by MRSA]. PMID- 24483018 TI - [Simultaneous screening method for Bordetella species by conventional PCR assay]. AB - A simultaneous screening method using conventional PCR was developed for the detection and discrimination of Bordetella pertussis, Bordetella parapertussis, and Bordetella holmesii. A formulated multiprex method employing 4 kinds of paired primers on amplification of 4 corresponding different insertion sequences (IS481, IS1001, IS1002 and hIS1001) enabled rapid screening and identification. The detection limits of each DNA extracted from 3 kinds of Bordetella species were 5fg/microL for each. Obscure existences of B. pertussis and B. holmesii at low levels were confirmed with the LAMP method. This multiplex assay was applied to the clinical specimens obtained from patients with pertussis-like symptoms at sentinel clinics under the epidemiological surveillance of infectious diseases of Hyogo prefecture in FY2012. Among 42 nasopharyngeal swabs, B. pertussis was detected from 12 samples including 8 samples collected at outbreak in nursery school. The use of this method for the surveillance of infectious agents enabled us to search for 3 kinds of Bordetella species at once with low costs. PMID- 24483019 TI - [A clinical study of pulmonary Mycobacterium abscessus infection]. AB - Pulmonary Mycobacterium abscessus infection is resistant to many antibiotics and is difficult to treat. We retrospectively analyzed the clinical characteristics of pulmonary infection due to M. abscessus. Eleven cases diagnosed as having pulmonary M. abscessus infection at Osaka Red Cross Hospital from January. 2008, to June, 2012 were enrolled in this study. The average age of the 11 cases was 63 years (all were females). Nine cases showed underlying diseases, comprising 5 cases with Mycobacterium avium complex lung infection, 3 with old pulmonary tuberculosis, and 3 with bronchiectasis. The radiological examination revealed that 10 cases showed the small nodular type, 7 showed the bronchiectatic type, 4 showed a cavity lesion and 4 showed infiltrative shadows. A microbiological definite diagnosis was made from sputum in 10 cases and bronchial lavage fluid in one. As treatment for M. abscessus pulmonary infection, combined multi-drug chemotherapy was carried out in 7 of the 11 cases. No patients were successfully treated with antibiotics alone, whereas 4 patients had no exacerbation of radiological findings without any treatment. One patient received antibiotics including clarithromycin, amikacin and levofloxacin for 2 to 12 months following surgical excision and her sputum cultures have been maintained as negative over the long-term. During the study, none of the 11 patients were known to have died. In this study, we found that M. abscessus pulmonary infection is more common among females, and is found frequently in patients with M. avium complex lung infection. We also found that the clinical course of M. abscessus pulmonary infection was different among patients. We think this is because M. abscessus was shown to comprise three closely related species. M. abscessus is extremely difficult to eradicate, and surgical resection of localized disease or the main lesion or cavity may be significantly effective in preventing the progression of disease. PMID- 24483020 TI - [One-year surveillance study of antimicrobial resistance in major bacteria except for MRSA isolated in eight medical facilities in Kumamoto prefecture]. AB - To investigate the current status of drug-resistant bacteria (except MRSA) in Kumamoto prefecture, a study was conducted to determine the isolation numbers and ratios of extended-spectrum beta-lactamase (ESBL)-Escherichia coli, ESBL Klebsiella species, ESBL-Proteus mirabilis, two-drug resistant Pseudomonas aeruginosa, (resistant to two drugs either carbapenems, quinolones and aminoglycosides) multi-drug-resistant Pseudomonas aeruginosa, multi-drug resistant Acinetobacter baumannii, and vancomyacin-resistant Enterococcii in eight general hospitals from May in 2009 to April in 2010. ESBL-E. coli was mostly isolated, and two-drug resistant P. aeruginosa came second. The isolation ratio of overall drug-resistant bacteria did not increase, while the isolation ratio of two-drugs resistant P. aeruginosa declined, suggesting that infection control was successfully conducted in these hospitals. However, the isolation numbers of ESBL-Klebsiella spp. and two-drug resistant P. aeruginosa were variable in each hospital. Furthermore, drug-resistant bacteria were occasionally spread into another medical facilities by patients transferred from these hospitals, indicating that sharing information on drug-resistant bacteria between medical facilities is required. PMID- 24483021 TI - [An analysis of the correlation between guidelines-concordant treatment and the treatment outcome on nursing and healthcare-associated pneumonia patients]. AB - BACKGROUND: The nursing and healthcare-associated pneumonia (NHCAP) guidelines recommend broad-spectrum antibiotics usage when the presence of multidrug resistant pathogens is anticipated. However, it has not been proved that guidelines-concordant treatment improves the outcome. PURPOSE: To clarify the impact of guidelines-concordant treatment on the outcome of NHCAP patients. METHOD: This was a single-center, medical record based retrospective study. The outcomes of NHCAP patients who were treated with guidelines-concordant antibiotics were compared with those of the patients who were not so treated. Then, along with other parameters such as pneumonia severity or patient backgrounds, we analyzed what parameters affected the outcome of NHCAP. RESULT: Two hundred and twenty-six admissions were analyzed. Guidelines-concordant treatment did not show significant correlation with 30 days mortality, in hospital mortality or treatment failure. A multivariate analysis showed a significant correlation between the treatment outcome and no parameters other than "Classified into severe-group of community-acquired pneumonia". Even in the analysis limited to the patients who were actually proved to possess drug resistant pathogens, the antibiotic coverage of the pathogens did not show any correlation with the outcomes. CONCLUSION: NHCAP guidelines-concordant treatment might not improve the patient outcome. PMID- 24483022 TI - [A rapidly progressive case of mediastinitis in which the patient developed inflammation of the soft tissue surrounding the pulmonary artery]. AB - A 51-year-old male patient with no underlying illness developed a fever of 38-39 degrees C in June 2009. The fever persisted for 4 days and, because elevated hepatobiliary enzymes, leukocytopenia and thrombocytopenia were observed, along with chest CT findings of inflammation of the soft tissues surrounding the left pulmonary artery, the patient was admitted for further examination. Three days after admission, the patient's blood pressure rapidly decreased, resulting in respiratory failure. Rapid proliferation of the soft tissue surrounding the pulmonary artery and mediastinum was observed on an emergency chest CT. Malignant lymphoma was initially considered as a possible differential diagnosis; however, neither pleural effusion nor infiltration of malignant cells could be observed on bone marrow examination. In addition, because the patient responded well to antibiotics, a diagnosis of acute mediastinitis was reached. Mediastinal drainage was not performed because the quantity of accumulated fluid was small and because the patient, both in terms of his clinical symptoms and imaging results, showed improvement with the continuation of antibiotics alone. The patient was ambulatory and was discharged after 24 days of hospitalization. Acute mediastinitis often follows a rapidly progressive and fatal course without specific symptoms. In the event of unknown infection following an aggressive course, as in the present case, acute mediastinitis must be considered with the goal of early diagnosis and treatment. PMID- 24483023 TI - [An adult case of acute pericarditis and glomerulonephritis associated with human parvovirus B19 infection]. AB - We report herein on a 52-year-old Japanese woman with acute pericarditis and glomerulonephritis associated with human parvovirus B19 infection, who had no significant medical history. The patient was admitted for progressive edema and upper abdominal pain. On physical examination, she had hypertension, generalized edema and upper abdominal tenderness. Urinalysis revealed protein (1+), and occult blood (+/-), with cellular casts. Echocardiography revealed pericardial effusion measuring 3-9mm in diameter. A serological test showed elevation of serum IgM antibodies for parvovirus B19. At the end of two weeks, generalized edema and glomerulonephritis improved spontaneously, and pericardial effusion was resolved three weeks after admission. This case would appear to be a very rare case indicating a direct relationship between human parvovirus B19 infection and acute pericarditis in a healthy adult patient. PMID- 24483024 TI - [A case of lung paragonimiasis superinfection with hookworm presenting difficulty in discrimination]. AB - A 40-year-old woman, who was born in Thailand and moved to Japan 20 years previously, was admitted to our university hospital because of eosinophilia and abnormal chest radiography findings over a 6-month period. The chest CT showed multiple cavitary nodules in the subpleural area and a tubular structure that extended from each cavity to the pleura. Immunological examination revealed an elevation of antibody titers against Ancylostoma duodenale, Paragonimiasis miyazakii and Paragonimiasis westermanii based on an ELISA assay. In addition, hookworm eggs were found in the stool. We firstly administered pyrantel pamoates, following which the eggs become undetectable. Nevertheless, eosinophilia and abnormal chest CT findings persisted. We diagnosed the patient as having a superinfection with paragonimiasis and hookworm, then administered praziquantel. Subsequently, the number of eosinophils returned to a normal level and the abnormal shadow in the chest CT images diminished without scarring. The final diagnosis was a superinfection of paragonimiasis and hookworm. PMID- 24483025 TI - [A case of septic pulmonary embolism due to Peptostreptococcus micros with multiple infection of the head and neck]. AB - A 46-year-old man with no underlying diseases visited our hospital with otorrhea, ocular motility disorder of the left eye, dizziness and loss of appetite which had lasted for two months. Chest radiography and computed tomography (CT) showed bilateral multiple pulmonary nodules and cavities. Furthermore, CT of the head and neck revealed bilateral mastoiditis, a left orbital abscess and a deep neck abscess. Peptostreptococcus micros was cultured from blood and otorrhea specimens. In addition, P. micros DNA was detected with the polymerase chain reaction (PCR) method in the specimens from the site of culture-negative lesions (i.e. sputum, bronchoalveolar lavage, neck abscess). Thus, we diagnosed the lung lesions as septic pulmonary embolisms (SPEs). The clinical findings of the head and neck had improved following antibiotics treatment for five weeks, and follow up chest radiography and CT showed that all lesions almost disappeared. Since some SPE patients demonstrate a slow progression, SPE should be included in the differential diagnosis of multiple pulmonary nodules such as Wegener's glanulomatosis or neoplasm. PMID- 24483027 TI - [Silencing of the STAT3 gene expression activity and cancer cells metastatic potential at in vitro studies]. AB - INTRODUCTION: The STAT proteins are the mediators in the signal transduction in between extracellular environment and nucleus. Based on its own activity STATs regulate expression of genes involved in normal and pathological cellular processes. Constitutive STAT3 activation, the results of different cytokines inductions, has been shown in many primary human cancers. STAT3, as an oncogenic protein, plays an important role in the regulation of autonomous properties of cancer cells. MATERIAL AND METHODS: In this study the effectiveness of the STAT3 gene expression activity silencing with RNA interference method was assessed. pSUPER.neo shRNA coding expression vector: shRNA-STAT3 and control vectors: shRNA SCR, and pGFP were used. Effects of silencing of the examined gene was described as the phenotype changes of modulated HeLa (CCL-2) cancer cell line. To characterize modulated cancer cells phenotype changes two methods were applied: Wound Healing Assay and the stimulation to the apoptosis with anisomycin. RESULTS: According to control cells, the silencing of the STAT3 gene expression activity reduced the mobility of modulated cells as well after 24 as after 48 hours after modulation. Also, after anisomycin stimulation the increasing in apoptotic modulated cell death was seen. CONCLUSIONS: The inhibition of the activity of the STAT3 gene decreases HeLa cell migration, moreover the blocked STAT3 ability to the antyapoptotic gene expression activation leads to the increased susceptibility to apoptotic cell death. PMID- 24483026 TI - [12-lead ECG teletransmission in emergency medicine teams' actions]. AB - INTRODUCTION: Sudden health-threatening conditions with cardiovascular aetiology constitute a great number of all interventions of emergency medicine teams. Diagnostic and therapeutic abilities of modern cardiology lead to the necessity of introducing diagnostic methods which enable effective pre-hospital diagnostics in patients with circulatory system diseases also in emergency medicine. The ECG teletransmissions performed by emergency medicine teams prior to hospitalization increase the accuracy of the diagnosis and thus improve the organization of medical transport of patients to the medical centres appropriate to their medical condition. MATERIAL AND METHODS: A 12-lead ECG teletransmission system and a system of teleconsultations was set up in September 2009 at the Voivodship Emergency Service and Medical Transport Station (WSPRiTS) "Meditrans" in Warsaw. The system consists of: emergency medicine teams and the Teletransmission Centre located in the Cardiac Department of WSPRiTS "Meditrans. The WSPRiTS "Meditrans" emergency medicine teams and helicopter emergency medicine teams performed standard ECGs at the place of the incident, sending them then via telephone to the Teletransmission Centre. Performing an ECG is recommended in the following cases: a pain in the chest, collapse and syncope, perceptible cardiac arrhythmia, dyspnoea and in any case when the head of the emergency medicine team (ZRM) took the decision to perform an ECG. The ECG record as well as the information about the patient supplied by the head of the team were analyzed by a consulting doctor on 24-hour duty at the receiving station. On basis of the received information the doctor from the Teletransmission Centre instructed the ZRM as to further procedure with the patient. There were 20117 ECG teletransmissions performed within the analyzed period. RESULTS: In the period between September 2009 and September 30th, 2012 there were 20 117 12-lead ECG teletransmissions performed, where 18139 (90.2%) were successful. 1978 (9.8%) were unsuccessful. 19 997 ECG transmissions were sent from WSPRiTS "Meditrans"ambulances and 120 by helicopter emergency teams. Women constituted 55% and men 45% of the investigated population of patients. The average age was 61 years. The average ECG transmission time was 7 minutes 10 seconds and did not extend the time of emergency medicine actions. The analysis of collected data revealed that ZRMs applied the teletransmission system particularly in cases others than acute coronary syndromes - 16 998 (93.7%) cases. The most frequent reasons to perform an ECG and consultation were pains in the chest - 23% cases, cardiac arrhythmias (18%) and collapses and syncope (13%). Among cardiac arrhythmias, arterial fibrillations (11%) were most often stated and in this group 79% cases were paroxysmal arrhythmias. During the 3 years 1141 cases of acute coronary syndromes were diagnosed in the pre-hospital period, what constituted only 6.3% of all teletransmissions. During a 9-month period 389 transports were carried out to primary health care centres from where the ECG records were then transferred to the Teletransmission Centre. In 117 cases (30%) the consultant changed the initial decision and patients were transported to other medical centres withour interventional cardiology departments. CONCLUSIONS: The system of ECG teletransmissions and consultations was appreciated by ZRMs and significantly supported their actions. The system should be supervised and coordinated by emergency medicine centres such as the Teletransmission Centre, Emergency Departments or Emergency Rooms. ECG teletransmissions make it possible to extend the paramedics and nurses' competences as regards emergency medical actions with patients with circulatory system diseases. The introduction of ECG teletransmissions from the place of the incident and the doctor's consultation have led to the optimization of transport of patients to appropriate in respect to their condition medical centres. PMID- 24483028 TI - [An example of multi-stage reconstruction of a full-thickness abdominal wall defect]. AB - Abdominal wall reconstruction is a highly complex procedure that may requires a multiple stages surgical operations. The aim of a such reconstruction is to close the abdominal wall defect and to create a support for the internal organs. It's a challenge for both general and reconstructive surgery. An incomplete thickness defects of the abdominal wall are so much easier to challenge than complete ones. Also the size of the primary defect determines the way and stages of the operation. Such defects can occur in necrotizing fasciitis of the abdominal wall, after abdominal walls tumors removal, in traffic accidents or after "open abdomen" procedures (acute severe pancreatitis). In this paper the authors present a case of 62-yo patient which was operated because of large intestine perforation with various complications of which the most serious was the abdominal wall defect. PMID- 24483029 TI - [Severe complications of total pelvic floor repair using polypropylene mesh--case report]. AB - The authors present a case of 58 years old woman suffering from complex pelvic floor pathology diagnosed with rectal prolapse, genitary organs prolapse, descending pelvic floor, rectocele and enterocele as well as advanced diverticular disease of the left colon. She suffered from chronic constipation. The surgery consisted of left hemicolectomy, hysterectomy, reconstruction of the pelvic floor and sacrocoloporectopexy using polypropylene mesh. The out-come complicated mesenteric vessels thrombosis, small bowel perforations and intraabdominal abscesses. Despite intensive care and subsequent ileal resections, debridement and drainage of the abscesses the patient died five months after beacause of multi organs insufficiency. PMID- 24483030 TI - [The avulsion of subclavian artery from brachiocephalic trunk and subclavian vein from right brachiocephalic vein with brachial plexus injury]. AB - The detachment of subclavian artery from brachiocephalic trunk and subclavian vein from right brachiocephalic vein with brachial plexus injury. INTRODUCTION: Traumas of large vessels of mediastinal and shoulder girdle cause significant life risk and constitute serious diagnostic and therapeutic problems because of lack of time for accurate treatment planning. Particularly difficult to treat are blunt trauma of large arteries in patients under the influence of drugs or with a progressive hypovolemic shock. AIM: The aim of this dissertation is presenting my own experience in treating a seventeen-year-old motorcyclist who was under the influence of alcohol suffered a detachment of subclavian artery and subclavian vein from mediastinal large vessels following a traffic accident. MATERIAL AND METHODS: Seventeen-year-old motorcyclist who was under the influence of alcohol alcohol hit a concrete pole at a speed of 130 km/h. The patient was brought to the hospital in a state of hypovolemic shock, pulse 126/min, blood pressure 80/60 mmHg, without pulse on the right upper limb. The right upper limb was cold, without active movements, pressure and pain sense. The right shoulder was tumid. The right lung without audible murmurs. Pulses on carotid arteries were perceptible. The thoracic plain film x-ray showed a shading on right half of thorax, widening of the upper mediastinum, fracture of right clavicle and the rear right shoulder sprain. Passive movements in the right elbow were correct. The patient was taken to the operating theatre because of progressive hypovolemic shock and was operated in emergency regimen. The transverse thoracotomy was made by both the intercostals spaces between the second and third rib. The thoracotomy showed that subclavian artery from brachiocephalic trunk and subclavian vein from right brachiocephalic vein were detachment. The subclavian vein was ligated and the brachiocephalic vein was sewn (phleborrhaphy). The subclavian artery was connected with brachiocephalic trunk by a synthetic vascular graft so that the received pulse at the periphery of the upper limb. The thyrocervical trunk, costocervical trunk and damaged intercostal vessels at the first, second and third rib were also ligated. The sprained shoulder was set. During the operation, there was no sight that even one of fascicles of brachial plexus was interrupted. The next day pateint was reoperated because of hemorrhage to right pleura. The rest of intercostal vessels at the first, second and third rib were ligated. RESULTS: The postoperative course was uneventful surgery. After operation was found that ulnar and radial nerve were demaged. The right lung expansion was achieved, upper limb had pulse, wounds healed as needed. The patient was transferred to the neurosurgical treatment. CONCLUSION: The quick decision to conduct operations without accurate diagnosis was the only factor for patient survival. PMID- 24483031 TI - [19-year old male with Crohn's disease complicated by retroperitoneal abscesses and coxarthritis dexter]. AB - The article presents the case of a patient with Crohn's disease in whom an infection of the complex ileo-caecal be spread into the retroperitoneal space and the right hip. PMID- 24483032 TI - [Difficult and unusual diagnostic and therapeutic gastric Schwannoma case]. AB - Schwannoma is a rare, usually benign, generally slow growing, asymptomatic mesenchymal neoplasm derived from nerve cells. In the gastrointestinal tract the most common localization is stomach and the gastric schwannomas represent about 0.2% of all gastric neoplasms. We present a case of 44-years-old male admitted to 2nd Department of General Surgery and Oncological Surgery Medical University for treatment of a submucosal gastric tumor detected in upper gastrointestinal endoscopy, endoscopic ultrasonography and computed tomography (CT). Patient presented with no gastrointestinal disorders and the random endoscopy revealed a gastric tumor, but the biopsy of the lesion showed no carcinomas' cells and the suspicion of GIST. CT confirms the presence of the 5 cm large gastric tumor and intraabdominal lymphadenopathy. The patient was directed to surgery because of the malignant risk. The subtotal gastrectomy with BII anastomosis was performed and no perioperative complications were observed. The postoperative histopathological examination revealed a typical morphology and immunophenotype of tumor. The neoplastic cells were immunoreactive with S-100 protein, but lacked immunoreactivity with CD 117, CD 34 and smooth-muscle actin (SMA). The histopathologic features and immunohistochemical staining pattern were consistent with a gastric schwannoma. The lymph nodes resected, during the operation revealed reactive inflammatory changes without evidence of neoplastic cells and any malignancy. 10-month after the surgery patient has no complains but the follow up will be continued. This case underscores the importance of including gastric schwannomas in the differential diagnosis when preoperative imaging studies reveal a submucosal, exophytic gastric mass. PMID- 24483033 TI - [Treatment of esophageal anastomotic leak with self-expanding metal stent]. AB - Esophageal anastomotic leak after resection surgery is very hard to treat and Has a high mortality rate. Surgical treatment is extremely difficult, burdened by complications of subsequent postoperative complications (inability to repair). The authors present a case of a patient who underwent a resection of upper stomach and lower esophagus due to adenocarcinoma of the esophagus- stomach junction (Siewert II). A digestive tract X-ray with water-soluble kontrast was performer after seven days- it show and anastomotic leak. However, the patient was hemodynamically stable. It enabled to implant a self-expanding metal stent (Ultraflex) to the place of leak. In this case the procedure was successful, and radiological examination on the 14th day confirmed closure of the leak. Implantation of a self-expanding metal prosthesis as a way to treat anastomotic leak is a therapeutic option worth recommendation. PMID- 24483034 TI - [Treatment of Fournier's gangrene]. AB - Fournier's gangrene is a necrotizing fasciitis and soft-tissue infection of the perineal region. The clinical course of the disease, in many cases, is fulminant. This case presents a patient with symptoms of Fournier's gangrene that developed during hospitalization following a vehicular accident. The disease was diagnosed six days into hospitalization. The patient underwent numerous surgical procedures. Escherichia coli and Enterococcus faecalis were found in a culture of the surgical wound. Because of the progressing septic shock, the patient was admitted to the Intensive Care Unit. Treatment was based on extensive soft tissue debridement, antibiotic and hyperbaric-oxygen therapy. The patient was discharged 7 weeks after hospitalization. PMID- 24483035 TI - [Fournier's gangrene--a case report]. AB - Fournier's gangren is a rare infectious disease characterized by rapidly necrotising fasciitis of the genital, perineal and perianal regions caused by mixed aerobic and anaerobic bacterial flora. The authors report a case of man with Fournier's gangrene in course of perianal abscess. PMID- 24483036 TI - [Clitoromegaly--treatment with the harmonic knife (case description)]. AB - Clitoromegaly, state when clitoris is non-physiologically large, most frequently occurs among patients with endocrine disorders (adrenal-genital syndrome, hormonally active tumors producing androgens, the use of anabolic steroids) or genetic. Less often the clitoromegaly is idiopathic of unknown etiology. There are no fixed standards for the size of organ, but it is assumed that not being in erect clitoris due to sexual arousal has a diameter of no more than 1/2 cm. To assess the size and shape of the clitoris can be used five Prader scale. However, it is most commonly used to assess the genitals of intersex. To the Clinic of Gynecology Oncology and Gynecology reported a 33 year old female patient because of escalating discomfort in sexual life. Patient associated her discomfort with her overly enlarged and painful clitoris preventing its proper coexistence. Gynecological survey found the correct size uterus and appendages. Vestibule of the vagina and the vagina of normal length and width. Larger and smaller labia developed properly. Clitoris increased to approximately 4x2 cm, not swollen, moving, with a uniform consistency. Except clitoromegaly in initial examination no abnormalities were found. Prior to surgery the patient has identified karyotype (46 XX) and has made designation of the levels of sex hormones and sonographic examination. In conducting these studies there was no answer found for the reason of clitoromegaly, there was the idiopathic overgrowth stated. Because of the pain during cohabitation associated with clitoromegaly, the patient was classified for reducing operation of this organ. For fear of the possibility of organ dysfunction, excessive bleeding and the appearance of postoperative adhesions abandoned classical surgical technique. It was decided to use in this operation, the harmonic knife. The use of harmonic knife allows avoiding introperative bleeding and precise, a partial reduction of the clitoris to the considered correct size without damaging of the organ structures. A month after surgery, the patient started having satisfying sex without feeling any pain and preserving proper function of the clitoris. PMID- 24483037 TI - [Augustyn Thugutt: his professional and private life and the age he lived in]. PMID- 24483039 TI - [Decreased insulin resistance with amino acids, extracts and antioxidants in patients with polycystic ovary syndrome]. AB - BACKGROUND: The polycystic ovary syndrome (PCOS) it is a metabolic disorder with insulin resistance associated. Have been recently described contributor factors in the presence of insulin resistance that need to be studied. These factors can be the nutrients in the daily diet, final products of the advanced glycated end products (AGEs), reactive derivatives of non enzymatic glucose-protein reactions either produced endogenously or ingested from dietary sources. The aim was to modifies the food intake to know the contribution on improve insulin resistance. OBJECTIVE: Compare different diets and changes in insulin resistance in patients with polycystic ovary syndrome. MATERIAL AND METHODS: As longitudinal, prospective and descriptive study, were included women with age among 18 to 40 years who received a compound with amino acids, extracts and anti-oxidants to dose of 660mg every 8 hours for 6 months. The inclusion approaches included the insulin resistance presence HOMA-IR > 2.6, elevated LH, and presence of ovaries with cysts by ultrasound. Statistical analysis with ANOVA one way to p <0.05. RESULTS: Were included a total of 30 patients, of which 28 patients had improvement in the insulin resistance from the 3 months, but until the 6 months they had significant difference (p<0.05), compared with 24 women from control group. CONCLUSION: With this result is demonstrated that it is necessary to modify the diet and to offer alimentary support to avoid the oxidative stress that takes impairment the insulin signaling with the subsequent insulin resistance. PMID- 24483041 TI - [VVF: laparoscopic versus open surgical abdominal]. AB - BACKGROUND: Vesico vaginal fistula is the most common acquired fistula of the urinary tract that originates from an abnormal communication between the bladder and vagina, its main manifestation is transvaginal urine output and significantly affects the quality of life of women suffer. OBJECTIVE: To compare the success and complications of open abdominal versus laparoscopic surgical treatment of patients with vesicovaginal fistula (VVF). MATERIAL AND METHODS: A retrospective, observational, comparative study of patients with a diagnosis of VVF. We included patients with a diagnosis of VVF with full clinical documentation and at least one evaluation after 3 months of surgery. All patients underwent surgical closure type O'Conor and grouped into two groups: Group I: Open abdominal and group II: Laparoscopic. Age, body mass index (BMI), size, location of the fistula, surgical time, intraoperative bleeding, and length of hospital stay were compared. RESULTS: Twenty seven patients with a diagnosis of VVF were evaluated. Eighteen patients had open abdominal surgery (group I) and 9 laparoscopic (group II). The average age was 42.8 vs 41.4 years, the average size of the VVF was 0.9 vs 1.3 cm, the success rate was 94.4 vs 77%, p> 0.05, for group I and II respectively. There were differences in favor of group II with respect to days of using transurethral catheter, days of hospitalization and postoperative bleeding, p<0.05. CONCLUSIONS: In our experience we believe that the laparoscopic approach is an excellent alternative to traditional abdominal approach, although it requires experience in laparoscopic pelvic surgery. PMID- 24483040 TI - [Clinic characteristics of patients with trophoblastic gestational disease complicate with hypertension]. AB - BACKGROUND: The molar pregnancy is complicated with hypertension before 20 weeks, divided into complete mole and partial mole, and in diploid and triploid hydatidiform mola depending on the fetal chromosomes. OBJECTIVE: To determine clinical and laboratory characteristics of patients with hydatidiform mole with and without hypertension, and choriocarcinoma, correlate serum chorionic gonadotropin (hCG) and hypertension. MATERIAL AND METHODS: We reviewed 55 cases with histopathologically proven mole, separately analyzed clinical, laboratory and hCG. RESULTS: The prevalence of mole with hypertension was 1:7; with the choriocarcinoma is 1:11. The age and sexual initiation of mole with hypertension was higher (p = .004 and .002 respectively), liver transaminase AST (p =. 004) and lactate dehydrogenase are higher in the group with hypertension (p =. 000). Positive correlation was obtained r = .246 p =. 044 statistically significant between mean arterial pressure and hCG. We reviewed 31 cases of 28 national and international articles, in patients with diploid hydatidiform the product is allowed to live normal and high blood pressure is showing mild preeclampsia, while partial moles are triploid, malformed products, incompatible with life and with hypertension severe like severe pre-eclampsia. CONCLUSIONS: The molar pregnancy is partially diagnosed with hypertension in our environment, is not properly analyzed and that most of the products of curettage were not performed genetic testing. The hCG probably participate in the hypertensive disorders of pregnancy. PMID- 24483042 TI - [Reasons for abandonment of hormone replacement therapy with tibolone in menopausal women]. AB - BACKGROUND: Hormone replacement therapy (HRT) with tibolone used in the management of menopause has low rates of acceptance and compliance in the first year. Few studies analyze the reasons for abandoning the use of tibolone. OBJECTIVE: To analyze the reasons for abandoned tibolone hormone replacement therapy in postmenopausal women and the effects of the drug through the years in the treatment. MATERIAL AND METHODS: In a cross-sectional study, were included 261 menopausal women between 40 and 60 year old who attended their disease control at the Gynaecological Endocrinology serving in the National Medical Center Northwest in Obregon City, Sonora, Mexico during 2010-2011. The variables studied included: age, type of menopause, time of use of HRT with tibolone, abandonment reason, development of hypertension, dyslipidemia, hypothyroidism and diabetes mellitus. RESULTS: A total of 21 women discontinued treatment (8.60%, 95% CI -3 to 19), p=0.0001. The reasons for abandonment included, 42.9% gynecological reasons (23.8% breast disease, 14.3% and 4.8% cervical condition ovarian pathology, p=0.0001). Liver disease and vascular occurred in 28.6%, p=0.050. CONCLUSION: The women studied have adequate adherence to treatment with tibolone (>90%). We don't show an increased risk of cardiovascular or metabolic disease in women studied. Further studies are needed to explore the long-term clinical course, therapeutic response and complications in menopausal patients who use HRT with tibolone. PMID- 24483043 TI - [Prenatal ultrasonic diagnosis and follow-up of fetal splenic cysts: report of two cases. Review of the literature]. AB - Congenital splenic cysts are rare entities wich are not frequently diagnosed in prenatal sonographies and there is only a few literature wich report these medical cases. The aim of this article is to introduce this sonographic discovery and study whether there are impacts for the newborn, association with cormosomopathy or fetal pathology. We describe two medical cases of fetal splenic cysts wich were diagnosed in our service by ultrasonography at 29 and 32 weeks of gestation, their antenatal monitoring and postnatal evolution. Besides theses, it is made a review of this entity in medical literature, examination about the: etiology, prenatal diagnosis, prenatal and postnatal following and complications. In conclusion, the congenital splenic cyst has a good prognosis with an spontaneous postnatal resolution in the majority of the cases. No association was observed between cromosopathy or fetal pathology with the examined cases. PMID- 24483044 TI - [Skene cyst: report of a case and review of the literature]. AB - Paraurethral cyst or Skene cysts are rare at any age but particularly in newborns. In infants typically present as cystic formations, raised similar to a dermoid cyst. The treatment is established based on the findings, pathology and the age of the patient may be observational, puncture the cyst or surgical. We present a newborn with acute renal failure secondary to skene's cysts. PMID- 24483045 TI - [Laparoscopic management of a spontaneous live monochorionic monoamniotic twin tubal ectopic pregnancy. A case report]. AB - We present a case of a spontaneous live monochorionic monoamniotic twin tubal ectopic pregnancy detected by transvaginal ultrasound scan after medical therapy with single dose of methotrexate failed. The incidence of this type of ectopic pregnancies is probably arising due to the increasing use of the assisted reproduction techniques, but they are underdiagnosed and mistreated, as surgical approach seems to be the most adequate in these cases. PMID- 24483046 TI - [Uterus Didelphys, obstructed hemivagina and ipsilateral renal agenesis as a presentation of a case of the Herlyn-Wemer-Wunderlich syndrome. Literature review]. AB - The Herlyn-Werner-Wunderlich syndrome is a rare congenital anomaly of the Mullerian ducts. Mullerian malformations result from defective fusion of the Mullerian ducts during development of the female reproductive system. These malformations are associated with an increased probability of adverse obstetric events. The syndrome is characterized by uterus didelphys with obstructed hemivagina, and ipsilateral renal agenesis. Patients with this syndrome are asymptomatic until menarche, and can follow other complications. CASE REPORT: A 12 year-old female patient presented with a clinical picture of acute abdomen and a previous history of cyclical dysmenorrhea. A diagnosis of uterus didelphys associated with right hematometracolpos was made following an exploratory laparotomy. Resection of the right obstructed hemivagina was subsequently performed using a vaginal approach. A subsequent computed tomography seen identified renal agenesis ipsilateral to the obstructed hemivagina. IN CONCLUSION: The Herlyn-Werner-Wunderlich syndrome is a rare Mullerian anomaly. The characteristics of the syndrome may result in missed diagnosis until detailed evaluation is carried out. We therefore advise clinicians to look for Mullerian duct anomalies whenever a renal malformation is discovered in a fetus or girl postnatal. Early diagnosis of the syndrome and its associated anomalies are essential to provide adequate therapy, and to reduce reproductive complications through radical treatments. Conservative treatment is effective and has a good prognosis for the patient's reproductive function. PMID- 24483047 TI - [The gynecological cancer pain. 1958]. PMID- 24483048 TI - [Surgery of pain in pelvic cancers. 1958]. PMID- 24483049 TI - [Some aspects of pain in gynecology and obstetrics. 1958]. PMID- 24483050 TI - [Functional gynecological pain. 1958]. PMID- 24483051 TI - [Ginecologia y Obstetricia de Mexico]. PMID- 24483052 TI - [Estimate of the variability in the evaluation of semen analysis]. AB - BACKGROUND: Masculine Infertility diagnosis continues depending in a great number of cases of the analysis of the semen. However, appropriate interpretation of the seminal analysis implies to consider two factors, the dependability of the laboratory and the medical knowledge about the meaning of the seminal alterations. OBJECTIVE: Compare the results of the semen analysis among clinical laboratories. MATERIAL AND METHODS: It was used the semen samples of the patients that need a semen analysis for their study. The sample was collected in the biological fluids assessment laboratory (A) and was evaluated the sperm count, morphology and motility. They were distributed to the other laboratories, andrology laboratory (B) and Assisted Reproduction laboratory (C). It was calculated the coefficients of variation intra-observer and inter-observer and descriptive statistics. RESULTS: It was analyzed 28 semen samples by one technician in laboratory A, one in laboratory B and four in the laboratory C, using the World Health Organization (WHO) recommendations for reporting sperm count, motility and morphology. There is an inter-laboratory variability of the parameters studied in the sperm morphology with statistical difference (p < 0.001). The observed mean coefficients of variation intraobserver (CVs) were 3.6% for sperm count, 20.3%for motility and 9.4% for sperm morphology. The mean CVs inter- laboratory results were as follows: 25.7% for sperm concentration, 52.2% for sperm motility and 82.6% for sperm morphology. CONCLUSIONS: There is an inter laboratory variability for the analysis of the semen samples between the 3 laboratories studied for the semen parameters studied. PMID- 24483053 TI - [Acceptance of the vaccine against human papilloma virus from mothers to daughters aged 9 to 13 years old]. AB - BACKGROUND: If you consider that at some point in life 50% of sexually active women have had an infection with the human papilloma virus is indisputable that any attempt to reduce the prevalence worth undertaking it. The vaccine to prevent HIV infection has not enjoyed the same degree of acceptance than others, hence the interest in knowing some of the reasons that has not achieved universal vaccination. OBJECTIVE: To examine human papillomavirus (HPV) vaccine acceptability among mothers with adolescents girls between 9 and 13 years old. METHODS: The mothers were interrogated about HVP vaccine acceptability, reasons provided for acceptance or non-acceptance and if mothers know that vaccine is offered free for public health institutions RESULTS: We interview a 250 mothers with 281 daughters, 38 daughters have already received the vaccine. Eighty nine percent of the mothers reacted positively to the possibility of vaccinating theirs daughters. The reasons of vaccine non-acceptance were because not knowing enough about infection, mother felt that their daughters were not at risk for acquiring HVP infection, the vaccine is new and mothers unknown side effects. Thirty nine percent of the mothers want to know more about the vaccine safety, 21% about length protection duration and 16% concerning about if the vaccine is effective. Fifty seven per cent of the mothers know that Health Secretary offers vaccine free. Mothers whom have been vaccinated their daughters, had daughters with lower age (9.8 +/- 0.9 vs 10.8 +/- 1.3 years, p = 0.0001), were more frequently married (79 vs 51%, p = 0.002) and more likely to report that they had heard about VPH vaccine from some source (100 vs 66%, p = 0.0001) that mothers have not yet vaccinated their daughters. CONCLUSIONS: The acceptability of VPH vaccine was 89%. Continued health education and propaganda is needed to promote a better knowledge of VPH vaccine. PMID- 24483054 TI - [Intrahepatic cholestasis of pregnancy: a case report and review of the literature]. AB - Intrahepatic cholestasis of pregnancy has a prevalence of 1/1000 to 1/10000. Its etiology is multifactorial, involving genetic an hormonal factors, associated with adverse perinatal and obstetric outcomes. Report the case of patient 25 years old, with 32 weeks of gestation, which presents severe pruritus, jaundice, altered liver function tests and lipid profile, with presumptive diagnosis of intrahepatic cholestasis of pregnancy. Making weekly monitoring analytical biochemistry, test of fetal wellbeing, symptomatic management, with abdominal pregnancy termination at 35 weeks, for lack of clinical improvement, increase in metabolic disorders and intrauterine growth restriction, after induction of fetal lung maturity, with good obstetric and perinatal outcome. Definitive diagnosis by liver biopsy. PMID- 24483055 TI - [Internal hernia to the broad ligament: report of a rare case solved with laparoscopy and review of the literature]. AB - We note a specific case report of a 38 year old patient, who presented to an emergency room with an 8-hour history of a continuous and progressive, abdominal pain syndrome. Without fever, nausea, vomiting, or urinary tract symptoms, and with a 36-hour history of constipation. We established as a first possibility the clinical diagnosis of, acute appendicitis vs. an ovarian cyst complication, such as rupture or torsion. After the initial basic diagnostic tests, we decided to do a laparoscopic approach for purposes of diagnosis and treatment. PMID- 24483056 TI - [Co-infection with Neisseria gonorrhoeae and Actinomyces naeslundii]. AB - OBJECTIVE: To report a case of co-infection with Neisseria gonorrhoeae and Actinomyces naeslundii in a woman with an intrauterine device. CASE REPORT: A 36 year-old woman with IUD, who entered to the hospital because of suprapubic abdominal pain, fever and foul-smelling vaginal discharge. RESULTS: We identified Neisseria gonorrhoeae and Actinomyces naeslundii and despite antibiotic treatment, ultrasound allowed objectify pelvic inflammatory disease and appendiceal involvement, which led to its surgical removal and bilateral salpingectomy. CONCLUSIONS: The surgical approach allowed to solve the box co. PMID- 24483057 TI - [Sacrococcygeal teratoma: report of a case and review of the literature]. AB - Sacrococcygeal teratoma is the most common tumor in infants. About 80% of these tumors are types 1 and 2, and are unlikely to cause metastases whose incidence is 10% in the neonatal period, against nearly 100% at the age of 3 years. These tumors can acquire huge and contain large proportions depriving blood flows to the developing fetus, the tumor hypervascularity generates a hyperdynamic state in the fetus, and that as the tumor grows, it increases its flow to behave as a short circuit and to be similar to that of the lower limbs of the fetus, increasing venous return and cardiac output, heart failure causing fetal and maternal eclampsia. PMID- 24483058 TI - [Chronological data for the History of the Associacion Mexicana de Ginecologia y Obstetricia. 1950]. PMID- 24483059 TI - [Hypoagalactia and agalactia treatment with oxytocin. 1958]. PMID- 24483060 TI - [Intramuscular iron in anemias more frequent in gynecology and obstetrics. 1958]. PMID- 24483061 TI - [Effects of selective cutting on the carbon density and net primary productivity of a mixed broadleaved-Korean pine forest in Northeast China]. AB - To accurately quantify forest carbon density and net primary productivity (NPP) is of great significance in estimating the role of forest ecosystems in global carbon cycle. By using the forest inventory and allometry approaches, this paper measured the carbon density and NPP of the virgin broadleaved-Korean pine (Pinus koraiensis) forest and of the broadleaved-Korean pine forest after 34 years selective-cutting (the cutting intensity was 30%, and the cutting trees were in large diameter class). The total carbon density of the virgin and selective cutting broadleaved-Korean pine forests was (397.95 +/- 93.82) and (355.61 +/- 59.37) t C x hm(-2), respectively. In the virgin forest, the carbon density of the vegetation, debris, and soil accounted for 31.0%, 3.1%, and 65.9% of the total carbon pool, respectively; in the selective-cutting forest, the corresponding values were 31.7%, 2.9%, and 65.4%, respectively. No significant differences were observed in the total carbon density and the carbon density of each component between the two forests. The total NPP of the virgin and selective cutting forests was (36.27 +/- 0.36) and (6.35 +/- 0.70) t C x hm(-2) x a(-1), among which, the NPP of overstory, understory, and fine roots in virgin forest and selective-cutting forest accounted for 60.3%, 2.0%, and 37.7%, and 66.1%, 2.0%, and 31.2%, respectively. No significant differences were observed in the total NPP and the contribution rate of each component between the two forests. However, the ratios of the needle and broadleaf NPPs of the virgin and selective cutting forests were 47.24:52.76 and 20.48:79.52, respectively, with a significant difference. The results indicated that the carbon density and NPP of the broadleaved-Korean pine forest after 34 years selective-cutting recovered to the levels of the virgin broadleaved-Korean pine forest. PMID- 24483062 TI - [Variation characteristics of CO2 flux in Phyllostachys edulis forest ecosystem in subtropical region of China]. AB - By using eddy covariance technique, this paper studied the CO2 flux in a Phyllostachys edulis forest ecosystem with high-efficiency management in Zhejiang Province of China from December, 2010 to November, 2011, and analyzed the variations of net ecosystem exchange (NEE), ecosystem respiration (RE), and gross ecosystem exchange (GEE). During the study period, the monthly NEE was always negative, with the maximum (-99.33 g C x m(-2)) in July and the minimum (-23.49 g C x m(-2)) in November, and the seasonal change showed a bimodal shape. The average diurnal change of the monthly CO2 flux varied greatly from -0.30 g CO2 x m(-2) x s(-1) (January) to -0.60 g CO2 x m(-2) x s(-1) (September). The NEE at the time point of positive and negative conversion had obvious seasonal characteristics. The yearly RE changed in unimodal shape, with the maximum in summer and the minimum in winter. The RE at nighttime had significant negative correlation with soil temperature. The yearly NEE, RE, and GEE were -668.40, 932.55, and -1600.95 g C x m(-2) x a(-1), respectively, among which, the NEE occupied 41.8% of the GEE. As compared with other ecosystems, P. edulis forest ecosystem had a strong capability in carbon sequestration. PMID- 24483063 TI - [Spatial distribution patterns of soil organic carbon under Elacagnus angustifolia--Achnatherum splendens community in an arid area of Northwest China]. AB - An investigation was conducted to study the relationships of soil organic carbon (SOC) content with root biomass and soil moisture content as well as the accumulation mechanisms of SOC under the Elacagnus angustifolia-Achnatherum splenden community in Ningxia Hui Autonomous Region of Northwest China. The results showed that the SOC content decreased gradually with increasing soil depth, and changed gently in both horizontal and vertical directions. The correlations of the SOC content and its affecting factors varied with soil depth. In 0-30 cm layer, the SOC content was significantly negatively correlated with soil moisture content; in 60-150 cm layer, the SOC content was significantly positively correlated with soil moisture content and root biomass. Partial regression analysis indicated that the root biomass density in 0-30 cm soil layer contributed significantly to the variance of SOC content. In 60-150 cm layer, the SOC content was mainly affected by root system and soil moisture content; in 30 60 cm layer, no significant correlations were observed between the SOC content and the root biomass and soil moisture content. There was an obvious difference in the accumulation mechanism of SOC in different soil layers and at different locations of E. angustifolia--A. splendens community. PMID- 24483064 TI - [Effects of elevated ozone on Pinus armandii growth: a simulation study with open top chamber]. AB - By using open-top chamber (OTC) and the techniques of dendrochronology, this paper studied the growth of Pinus armandii under elevated ozone, and explored the evolution dynamics and adaptation mechanisms of typical forest ecosystems to ozone enrichment. Elevated ozone inhibited the stem growth of P. armandii significantly, with the annual growth of the stem length and diameter reduced by 35.0% and 12.9%, respectively. The annual growth of tree-ring width and the annual ring cells number decreased by 11.5% and 54.1%, respectively, but no significant change was observed in the diameter of tracheid. At regional scale, the fluctuation of ozone concentration showed significant correlation with the variation of local vegetation growth (NDVI). PMID- 24483065 TI - [Effects of harvest disturbance on soil CH4 flux in a secondary hardwood forest in Northeast china]. AB - From June, 2007 to October, 2009, a measurement with static chamber/gas chromatograph techniques was conducted on the soil CH4 flux in a typical secondary hardwood forest in Northeast China under the effects of different harvest disturbances, i.e., uncut (control), clear cutting (including both farming and reforestation after clear cutting), 50% stand volume removed, and 25% stand volume removed. In all of the four treatments, the soil was the sink of atmospheric CH4, but cutting decreased the soil CH4 uptake flux, with the order of uncut (-85.03 microg CH4 x m;(-2) x h(-1)) > 50% stand volume removed (-80.31 microg CH4 x m(-2) x h(-1)) > 25% stand volume removed (-70.97 microg CH4 x m( 2)h(-1)) > farming after clear cutting (-65.57 microg CH4 x m(-2) x h(-1)) > reforestation after clear cutting (-62.02 miocrog CH4 x m(-2) x h(-1)). During the study period, the seasonal patterns of the soil CH4 uptake flux in all treatments were similar, with a higher value in growth season and a lower one in winter. After the harvest disturbance, the soil temperature, humidity, and NO(3-) N, and NH(4+)-N contents were all increased, and the soil CH4 flux had a significant quadratic correlation with soil temperature, and a negative linear correlation with soil moisture content. It was suggested that the increase of the soil moisture, NO(3-)-N, and NHa(4+)-N contents after the forest harvest was the main cause of the decrease of the soil CH4 uptake flux. PMID- 24483066 TI - [Simulation of water and carbon fluxes in harvard forest area based on data assimilation method]. AB - Model simulation and in situ observation are the two most important means in studying the water and carbon cycles of terrestrial ecosystems, but have their own advantages and shortcomings. To combine these two means would help to reflect the dynamic changes of ecosystem water and carbon fluxes more accurately. Data assimilation provides an effective way to integrate the model simulation and in situ observation. Based on the observation data from the Harvard Forest Environmental Monitoring Site (EMS), and by using ensemble Kalman Filter algorithm, this paper assimilated the field measured LAI and remote sensing LAI into the Biome-BGC model to simulate the water and carbon fluxes in Harvard forest area. As compared with the original model simulated without data assimilation, the improved Biome-BGC model with the assimilation of the field measured LAI in 1998, 1999, and 2006 increased the coefficient of determination R2 between model simulation and flux observation for the net ecosystem exchange (NEE) and evapotranspiration by 8.4% and 10.6%, decreased the sum of absolute error (SAE) and root mean square error (RMSE) of NEE by 17.7% and 21.2%, and decreased the SAE and RMSE of the evapotranspiration by 26. 8% and 28.3%, respectively. After assimilated the MODIS LAI products of 2000-2004 into the improved Biome-BGC model, the R2 between simulated and observed results of NEE and evapotranspiration was increased by 7.8% and 4.7%, the SAE and RMSE of NEE were decreased by 21.9% and 26.3%, and the SAE and RMSE of evapotranspiration were decreased by 24.5% and 25.5%, respectively. It was suggested that the simulation accuracy of ecosystem water and carbon fluxes could be effectively improved if the field measured LAI or remote sensing LAI was integrated into the model. PMID- 24483067 TI - [Fine root biomass and carbon storage in surface soil of Cinnamomum camphora plantation in rainy area of West China]. AB - Fine root in forest ecosystems plays an important role in global C cycle. In this study, a measurement was made on the fine root biomass and carbon storage in the surface soil (0-30 cm) of a 31 year-old Cinnamomum camphora plantation in the Rainy Area of West China in November, 2010-December, 2011. The total biomass and carbon storage of the fine roots (living and dead) in the surface soil were 1592.29 kg x hm(-2) and 660.68 kg C x hm(-2), in which, living fine roots accounted for 91.1% and 91.8% respectively. The total biomass and carbon storage of the first five order living roots and dead roots decreased significantly with increasing soil depth, and the living root biomass and carbon storage increased significantly with root order. The sum of the biomass and carbon storage of living and dead fine roots was the largest in autumn and the smallest in winter, but the biomass and carbon storage of the dead fine roots were the largest in winter and the smallest in summer. The biomass and carbon storage of the first two order roots were the largest in summer and the smallest in winter, while those of the last three order roots were the largest in autumn and the smallest in winter. The spatial heterogeneity of soil moisture and nutrients was the main factor affecting the fine root biomass and carbon storage. PMID- 24483068 TI - [Effects of drought stress on the root growth and photosynthetic characters of Dactylis glomerata seedlings]. AB - Taking the drought-sensitive Dactylis glomerata line "01998" and drought-tolerant cultivar "Baoxing" as test materials, a pot experiment was conducted to study the effects of drought stress on the seedlings root growth, physiological characteristics, and leaf photosynthesis, aimed to approach the differences in the drought-tolerance mechanism of different D. glomerata lines (cultivars). Under drought stress, the root vitality and root number of "01998" and "Baoxing" presented a trend of increased first and decreased then. When the soil relative moisture content decreased to 30%, the root vitality and root number of "01998" and "Baoxing" increased significantly and reached the maximum. Drought stress decreased the relative water content, leaf chlorophyll content, net photosynthesis, transpiration, and stomatal conductance, but increased the electric conductivity and intercellular CO2 concentration of "01998" and "Baoxing". Under drought stress, the leaf area per plant of both "01998" and "Baoxing" decreased, and the underground and aboveground plant biomass of "01998" decreased while that of "Baoxing" had less change. PMID- 24483069 TI - [Effects of different water harvesting modes on alfalfa planting in semi-arid areas of Northwest China]. AB - A field experiment with complete random design was conducted to investigate the effects of different mulching materials [common plastic film (CMR), biodegradable mulch film (BMR), and soil crust (SR)] and different ratios of furrow to ridge (60 cm:30 cm, 60 cm:45 cm, and 60 cm:60 cm) on the runoff efficiency, soil water storage, soil water content, and hay yield and water use efficiency of alfalfa in semiarid areas of the Loess Plateau. The runoff efficiency in treatments SR, BMR, and CMR was 32.0%, 90.7%, and 96.4%, respectively. In the early growth period of alfalfa (from April to June) , the soil water storage between the treatments had no significant difference, but in the late growth period (from July to September), the soil water storage in CMR and BMR was significantly higher than that in SR. The soil water storage in SR was significantly higher than that in traditional planting (TP). At budding stage, the soil water storage in TP, SR, BMR, and CMR was 223.27, 248.56, and 277. 81, and 284.16 mm, respectively. In the whole growth period, the hay yield of alfalfa in TP, SR, BMR, and CMR was 4112.1, 3397.5, 4317.8, and 4523.8 kg x hm(-2), and the water use efficiency was 11.08, 10.48, 14.56, and 14.95 kg x mm(-1) x hm(-2), respectively. The ratio of furrow to ridge had no significant effects on the water use efficiency in the same treatments. When the ratio of furrow to ridge was 60 cm:44 cm, the hay yield in CMR and BMR reached the maximum. PMID- 24483070 TI - [Runoff process in forested basin of Hun River-Taizi River, Northeast China: a simulation study]. AB - Based on the hydrological data from the Beikouqian and Nandianyu stations in the upstream of Hun River and Taizi River as well as the meteorological data from the Qingyuan, Xinbin, and Benxi County stations, Northeast China in 1998-2007, a distributed hydrological model (DHS-VM) was applied to simulate the hydrological process in Hun-Tai basin. The scientific applicability of the model was validated, and the reference values of the most sensitive model parameters were provided. The simulated monthly runoff Nash-Suttclife coefficient (E value) for the source region of Hun River in calibration period (1998-2002) and validation period (2003-2007) was 0.9675 and 0. 8957, respectively, which could better reappear the monthly runoff process in this source region. The simulated monthly and annual runoff E values for the upstream of Taizi River were greater than 0.6, indicating that this model had good applicability in Hun-Tai basin, and the calibrated parameter scheme had a good reliability. This paper established a solid framework for the hydrological study over ungauged basin, and constructed a reasonable parameter scheme. PMID- 24483071 TI - [Relationships between Dendrobium quality and ecological factors based on partial least square regression]. AB - A total of eleven ecological factors values were obtained from the ecological suitability database of the geographic information system for traditional Chinese medicines production areas (TCM-GIS), and the relationships between the chemical components of Dendrobium and the ecological factors were analyzed by partial least square (PLS) regression. There existed significant differences in the chemical components contents of the same species of Dendrobium in different areas. The polysaccharides content of D. officinale had significant positive correlation with soil type, the accumulated dendrobine in D. nobile was significantly positively correlated with annual precipitation, and the erianin content of D. chrysotoxum was mainly affected by air temperature. The principal component analysis (PCA) showed that Zhejiang Province was the optimal production area for D. officinale, Guizhou Province was the most appropriate planting area for D. nobile, and Yunnan Province was the best production area of D. chrysotoxum. PMID- 24483072 TI - [Variation characteristics of maize yield and fertilizer utilization rate on an upland yellow soil under long term fertilization]. AB - An analysis was made on the 16-year experimental data from the long term fertilization, experiment of maize on a yellow soil in Guizhou of Southwest China. Four treatments, i. e. , no fertilization (CK), chemical fertilization (165 kg N x hm(-2), 82.5 kg P2O5 x hm(-2), and 82.5 kg K2O x hm(-2), NPK), organic manure (30555 kg x hm(-2), M), and combined applicatioin of chemical fertilizers and organic manure (NPKM), were selected to analyze the variation trends of maize yield and fertilizer use efficiency on yellow soil under effects of different long term fertilization modes, aimed to provide references for evaluating and establishing long term fertilization mode and promote the sustainable development of crop production. Overall, the maize yield under long term fertilization had an increasing trend, with a large annual variation. Treatment NPKM had the best yield-increasing effect, with the maize yield increased by 4075.71 kg x hm(-2) and the increment being up to 139.2%. Long term fertilization increased the fertilizer utilization efficiency of maize. In treatment M, the nitrogen and phosphorus utilization rates were increased significantly by 35.4% and 18.8%, respectively. Treatment NPK had obvious effect in improving potassium utilization rate, with an increment of 20% and being far higher than that in treatments M (8.7%) and NPKM (9.2%). The results showed that long term fertilization, especially the combined application of chemical fertilizers and organic manure, was of great importance in increasing crop yield and fertilizer use efficiency. PMID- 24483073 TI - [Effects of phosphorus fertilization on leaf area index, biomass accumulation and allocation, and phosphorus use efficiency of intercropped maize]. AB - A 2-year field experiment was conducted in 2011 and 2012 to investigate the effects of phosphorus (P) fertilization on the leaf area index (LAI), dry matter accumulation (DMA), and P use efficiency (PUE) of maize in wheat/maize/soybean intercropping system. Five P fertilization rates were installed, i.e., 0, 45, 90, 135, and 180 kg P2O5 x hm(-2) for wheat, marked as WP0, WP1, WP2, WP3, and WP4, respectively, and 0, 37.5, 75, 112.5, and 150 kg P2O5 x hm(-2) for maize, marked as MP0, MP1, MP2, MP3, and MP4, respectively. During the coexisted growth periods of wheat and maize, P fertilization increased the LAI, leaf area duration (LAD), and stem and leaf DMA of maize significantly. After the jointing stage of maize, the maize LAI, LAD, DMA, and crop growth rate (CGR) all decreased after an initial increase with the increasing P rate, with the maximum growth in treatment MP2 or MP3. During the reproductive stage of maize, the maize dry mass translocation from vegetative to reproductive organ increased with increasing P fertilization rate, and the grain yield of both maize and whole cropping system increased firstly and decreased then, with the maximum grain yield of maize and whole cropping system being 6588 and 11955 kg x hm(-2) in treatment P3, respectively. The P apparent recovery efficiency of maize was the highest (26.3%) in treatment MP2, being 82.6%, 38.4%, and 152.9% higher than that in MP1 (14.4%), MP3 (19.0%), and MP4 (10.4%), respectively. In sum, for the wheat/maize/soybean intercropping system, applying appropriate amount of P fertilizer could promote maize growth, alleviate the impact of wheat on maize, and consequently, increase the P apparent recovery efficiency of maize. In this study, the appropriate P fertilization rate was 75-112.5 kg P2O5 x hm(-2). PMID- 24483074 TI - [Effects of rape cropping in summer fallow period on dryland soil moisture content and winter wheat yield]. AB - Taking the fallow land with wheat stubble after harvesting as the control, a 4 year field experiment was conducted in a dryland of east Gansu, Northwest China to investigate the effects of rape cropping in summer fallow period on the soil moisture content, wheat yield, and water use efficiency (WUE). The rape was sown at 6 dates. There was a significant difference (P < 0.05) in the soil moisture content in summer fallow period when the rape was sown at different dates. When the rape was sown on August 5, the soil water storage efficiency was 58.5%, and the wheat yield and WUE were increased by 7.5% and 5.9%, respectively, as compared with the control. Averagely, cropping rape in fallow period could increase the wheat yield by 16. 1% in dry year and 6.8% in normal year. It was suggested that rape cropping in summer fallow period would benefit the wheat yield and drought resistance of drylands in Northwest China. PMID- 24483075 TI - [Experiment precision and comprehensive environmental evaluation of regional wheat trials in rainfed regions of China]. AB - Based on the grain yield data of regional trials with 233 winter- and spring wheat cultivars (lines) in rainfed farmlands at 82 locations in four subregions of China in 2003-2009, this paper studied the experiment precision (EP), variety comparison precision (VCP), and testing-site discrimination ability and representativeness of national regional trials, and comprehensively evaluated the trial environment. The results showed that in one-location-one-year experiments, the average coefficient of variation (CV) and the relative least significant difference (RLSD) were 6.1% and 10.5%, respectively, and in multi-location-one year experiments, the CV was all within 8.2%, and the CV and RLSD were mostly well controlled, indicating that the trials had a high precision. The testing site discrimination ability was the highest in the northwest spring wheat subregion, but showed less difference in the other subregions. The testing-site representativeness was the best in the northeast spring wheat subregion, and the worst in the northwest spring wheat subregion. On the basis of the comprehensive consideration of the testing-site discrimination ability and representativeness, and by using the parameters of the environmental comprehensive assessment (r(g)h) of GGE model, it was shown that the proportion of the ideal trial locations for wheat in our rainfed farmlands was only 32.4%. Among the wheat production regions, the proportions of the ideal trial locations were in the order of northwest spring wheat subregion (40.9%) > northeast spring wheat subregion (33.3%) > Huang-Huai winter wheat subregion (30.4%) > north winter wheat subregion PMID- 24483076 TI - [Screening of wild barley genotypes with high phosphorus use efficiency and their rhizosphere soil inorganic phosphorus fractions]. AB - A pot experiment was conducted to investigate the differences of 16 wild barley genotypes in phosphorus (P) uptake and use efficiency under the same P supply levels and the characteristics of inorganic P fractions in rhizosphere and non rhizosphere soils of high P use efficiency genotypes. There existed greater differences in the P use efficiency for dry matter production at jointing stage (CV = 11.6%) and flowering stage (CV = 12.4%), and in the P use efficiency for grain yield at maturing stage (CV = 13.7%) among the genotypes. The biomass, P accumulation amount, and P use efficiency for dry matter production of high P use efficiency genotypes (IS-22-30 and IS-22-25) were significantly higher than those of low P use efficiency genotype (IS-07-07), and the grain yield of IS-22-30 and IS-22-25 was 3.10 and 3.20 times of that of IS-07-07, respectively. When supplied 0 and 30 mg x P kg(-1), the concentrations of available P and water soluble P in rhizosphere soils were significantly lower than those in non-rhizosphere soils, especially for the water soluble P. The concentrations of inorganic P fractions in the rhizosphere and non-rhizosphere soils were in the order of Ca10-P > O-P > Fe-P > Al-P > Ca2-P > Ca8-P. When supplied 30 mg x P kg(-1), the Ca8-P concentration in high P use efficiency genotypes rhizosphere soils at jointing and flowering stages was significantly lower than that in low P use efficiency genotype rhizosphere soil, but the Ca2-P concentration was in adverse. When no P was supplied, the concentrations of Ca2-P and Ca8-P in high P use efficiency genotypes rhizosphere soils were significantly higher than those in low P use efficiency genotype rhizosphere soil, and the Ca10-P concentration in the rhizosphere soils of all genotypes decreased. When supplied 30 mg x P kg(-1), the Fe-P and O-P concentrations in high P use efficiency genotypes rhizosphere soils were significantly higher than that in low P use efficiency genotype rhizosphere soil, but the Al-P concentration presented an opposite trend. Under no P supply, the Al-P, Fe-P, and O-P concentrations in high P use efficiency genotypes rhizosphere soils were significantly lower than those in low P use efficiency genotype rhizosphere soil. It was suggested that under low P stress, the capabilities of high P use efficiency genotypes in activating and absorbing soil A1-P and Ca2-P were stronger than those of low P use efficiency genotype. PMID- 24483077 TI - [Yield formation of different single-season rice (Oryza sativa L. ) types and its relationships with meteorological factors in Yunnan Province of Southwest China]. AB - By using the 1994-2010 observation data of paddy rice growth period and yield from 14 agro-meteorological stations at different altitudes in Yunnan Province, this paper studied the rice yield formation and the effects of meteorological factors on low-yield rice yield components. According to the systematic cluster analysis of rice yield components and the rice types at the 14 stations, the rice was divided into 4 types, i. e., low-yield japonica rice, low-yield indica rice, high-yield japonica rice, and high-yield indica rice. The analysis of the yield components of the 4 rice types showed that there was a significant positive correlation between the spikelet number per square meter (sqm) and the rice yield. The yield of low-yield japonica was mainly affected by the seed setting rate and the spikelet number per sqm. For the other three rice types, the spikelet number per sqm had greater effects on the rice yield. The low-yield japonica rice was mainly affected by low temperature. At booting stage, low temperature decreased the spikelet number and the productive panicle number of unit sqm. At booting and flowering stages, low temperature increased the empty grain rate, and the effects of average temperature, average maximum temperature, and cold accumulated temperature were greater. At pre-milk stage, low temperature increased the unfilled grain rate, and meanwhile, decreased the 1000-grain mass. The yield components of low-yield indica rice were obviously affected by multiple meteorological factors. A certain degree of warming at tillering and jointing stages was not beneficial to the increase of productive panicle number per sqm of low-yield indica rice, but the more sunshine hours and the greater average diurnal temperature range at tillering stage was beneficial to the increase of the productive panicle number per sqm. There was a parabolic relationship between the temperature and sunshine hours at tillering and jointing stages and the spikelet number per panicle. The low temperature at flowering stage affected the empty grain rate of low-yield indica rice to a certain extent, while the high temperature and less rain at pre-milk stage not only increased the unfilled grain rate, but also distinctly reduced the 1000-grain mass. PMID- 24483078 TI - [Responses of winter wheat seedling growth and allelochemical content to elevated CO2 and O3 concentrations]. AB - By using open-top chamber (OTC), a pot experiment was conducted to study the effects of elevated CO2 (550 microL x L(-1)), O3 (60 microL x L(-1)), and their interaction (CO2 550 microL x L(-1) plus O3 60 microL x L(-1)) on the seedling dry mass and allelochemical DIMBOA content of seven winter spring cultivars. Under elevated CO2, there existed significant differences in the shoot dry mass and DIMBOA content among the test wheat cultivars. As compared with the control (CO2 370 microL x L(-1); O3 40 microL x L(-1)), the shoot and root dry mass of cultivar Bima-1 under elevated CO2 increased by 36.8% and 24.7%, respectively, and the DIMBOA content increased by 5.7%-184.6%. Elevated O3 decreased the seedling dry mass except for Bima-1 and Shan-139, but increased the DIMBOA content of all the cultivars, with an increment of 0.5-3 folds. Under the interaction of elevated CO2 and O3, the root dry mass of all cultivars decreased, and the shoot dry mass, root dry mass, and DIMBOA content of Changwu-134 had the greatest decrement of 8.2%, 27.9%, and 35.5%, respectively. In contrast to the decrease of the DIMBOA content of Changwu-134, Yuanfeng-175 and Lankao-217, the DIMBOA content of Shan-139 increased by 84.6%. The cluster analysis indicated that both the treatments and the cultivars had significant effects on the DIMBOA content, the cultivars Shan-139, Lankao-217, and Changwu-134 under the elevated CO2 or O3 could be grouped together, whereas the DIMBOA content of Shan-139 in all treatments increased. These findings suggested that DIMBOA could be used as a specific indicator for resistance breeding under climate change, especially under elevated O3 and CO2. PMID- 24483080 TI - [Changes of organic soil substrate properties with different cultivation years and their effects on cucumber growth in solar greenhouse]. AB - This paper studied the changes of organic soil substrate properties with increasing cultivation years and their effects on the cucumber growth in solar greenhouse. The results showed that with increasing cultivation years, the physical and chemical properties of organic soil substrate deteriorated, which was manifested in the increase of bulk density and the decrease of total porosity, pH, and available nutrient contents. The numbers of bacteria and actinomycetes in the substrate decreased with increasing cultivation years, while that of fungi was in reverse. The cucumber growth was also affected to a certain extent, manifesting in the decrease of plant height and leaf area, the decline of photosynthetic efficiency, and the decrease of yield and quality. It would be necessary to restore the fertility of organic soil substrate after 3-year cultivation. PMID- 24483079 TI - [Effects of paclobutrazol on the yield, quality, and related enzyme activities of different quality type peanut cultivars]. AB - Selecting high-protein peanut cultivar KB008, high-fat cultivar Hual7, and high O/L cultivar Nongda818 as test materials, a field experiment was conducted in 2011 and 2012 to study the effects of foliar spraying paclobutrazol (PBZ) at late flowering stage on the kernel yield and quality and the activities of leaf carbon and nitrogen metabolism enzymes of the cultivars. Spraying PBZ increased the pod yield of the cultivars significantly via increasing the pod number per plant, decreasing the pod number per kilogram, and increasing the percentage of double kernel. Spraying PBZ also increased the kernel fat and soluble sugar contents but decreased the kernel protein content to varying degrees, and increased the O/L ratio of high-fat cultivar Hual7 significantly. PBZ increased the kernel fat content while decreased the kernel protein content of Nongda818 significantly, but had little effects on the kernel protein or fat content of the other two cultivars. Spraying PBZ decreased the leaf nitrate reductase activity of the three cultivars at their pod setting stage, and the leaf glutamine synthetase and glutamate dehydrogenase activities at pod setting and filling stages, with the largest decrement for Nongda818 and the smaller one for KB008 and H17. Spraying PBZ decreased the leaf glutamate oxaloacetic transaminase and glutamate pyruvate transaminase activities of the three cultivars at their pod setting and filling stages, illustrating that the decrease of the nitrogen metabolism enzyme activities after spraying PBZ was the main reason of the decreased kernel protein content of the cultivars. PBZ increased the leaf sucrose synthase and sucrose phosphate synthase activities at pod setting and filling stages, being significant for Nongda818. PBZ improved the leaf phosphoenolpyruvate carboxylase and ribulose bisphosphate carboxylase activities of the three cultivars at their pod setting and filling stages, being most significant for Nongda818. It was suggested that the increase of the carbon metabolism enzyme activities was the physiological basis of the improvement of kernel fat content after spraying PBZ. PMID- 24483081 TI - [Satellite remote sensing retrieval of canopy nitrogen nutritional status of apple trees at blossom stage]. AB - Taking Qixia City of Shandong, China as the study area, and based on the Landsat 5 TM and ALOS AVNIR-2 images, the canopy retrieval reflectance of apple trees at blossom stage was acquired. In combining with the measured reflectance of sample trees, the nitrogen-sensitive spectral indices were constructed and selected. By using the sensitive spectral indices as the independent variables, the nitrogen retrieval models were established, and the model with the best accuracy was used for spatial retrieve. The correlations between the spectral indices and the nitrogen nutritional status were in the order of canopy > leaf > flower. The sensitive indices were mainly composed of green, red, and near infrared bands. The accuracy of the retrieval models was in the order of support vector regression > multi-variable stepwise regression > one-variable regression. The retrieval results based on different images were similar, and showed that the leaf nitrogen content was mainly of grades 3-4 (27-33 g x kg(-1)), and the canopy nitrogen nutrient indices were mainly of grades 2-4 (TM: 38-47 g x kg(-1); ALOS: 32-41 g x kg(-1)). The spatial distribution of the retrieval nitrogen nutritional status based on different images also showed the similar trend, i. e., the nitrogen nutritional status was higher in the north and south than that in the middle part of the study area, and the areas with the high grades of leaf nitrogen and canopy nitrogen were mainly located in Sujiadian Town and Songshan subdistrict in the northwest, Zangjiazhuang Town and Tingkou Town in the northeast, and Shewopo Town in the south, which were consistent with the distribution of the key towns for apple production in Qixia City. This study provided a feasible method for the acquisition of nitrogen nutritional status of apple trees on macroscopic scale, and also, provided reference for other similar remote sensing retrievals. PMID- 24483082 TI - [Effects of elevated rhizosphere CO2 concentration on the photosynthetic characteristics, yield, and quality of muskmelon]. AB - By using aeroponics culture system, this paper studied the effects of elevated rhizosphere CO2 concentration on the leaf photosynthesis and the fruit yield and quality of muskmelon during its anthesis-fruiting period. In the fruit development period of muskmelon, as compared with those in the control (350 microL CO2 x L (-1)), the leaf chlorophyll content, net photosynthetic rate (Pn), stomatal conductance (Gs), intercellular CO2 concentration (Ci), and the maximal photochemical efficiency of PS II (Fv/Fm) in treatments 2500 and 5000 microL CO2 x L(-1) decreased to some extents, but the stomatal limitation value (Ls) increased significantly, and the variation amplitudes were larger in treatment 5000 microL CO2 x L(-1) than in treatment 2500 microL CO2 x L(-1). Under the effects of elevated rhizosphere CO2 concentration, the fruit yield per plant and the Vc and soluble sugar contents in fruits decreased markedly, while the fruit organic acid content was in adverse. It was suggested that when the rhizosphere CO2 concentration of muskmelon during its anthesis-fruiting period reached to 2500 microL x L(-1), the leaf photosynthesis and fruit development of muskmelon would be depressed obviously, which would result in the decrease of fruit yield and quality of muskmelon. PMID- 24483083 TI - [Water productivity of apple orchards with different planting densities in semi arid mountainous regions of Loess Plateau, Northwest China: a simulation study]. AB - By adopting the revised WinEPIC model, a simulation study was conducted to investigate the responses of the apple yield and deeper soil moisture content to 7 planting densities in the appl orchards in Yan'an of Shaanxi and in Jingning of Gansu in 1965-2009. Under the 7 planting densities, the annual yields of the 4-45 years apple orchards increased rapidly at early growth stage, and then decreased with fluctuation after reached the maximum. The higher the planting density, the higher the annual yield was obtained at early growth stage, but the yield at late growth stage fluctuated dramatically with annual precipitation. The orchards with different planting densities had the similar soil water stress process, i. e., no water stress at early growth stage, and water stress occurred and fluctuated dramatically with increasing planting years. The days of water stress at late growth stage changed oppositely to annual precipitation. At early growth stage, the soil available moisture content in 0-15 m layer under the 7 planting densities all decreased rapidly with strong fluctuation, ranged in a low level of 0-600 mm after 17-22 years in Yan' an and after 13-20 years in Jingning. The soil moisture content in 0-15 m layer changed similarly under different planting densities, i. e., decreased gradually with the deepening of soil desiccation, and the stable depth of drying layer could reach 12 m. Considering the apple yield and the soil available moisture content in 0-15 m layer, the reasonable planting density of apple orchard was 650-800 plants x hm(-2) in Yan'an and 550-700 plants x hm(-2) in Jingning. PMID- 24483084 TI - [Sizes of soil macropores and related main affecting factors on a vegetated basalt slope]. AB - The landslide on vegetated slopes caused by extreme weather has being increased steadily, and the preferential flow in soil macropores plays an important role in the landslide. By using water breakthrough curve and Poiseuille equation, this paper estimated the radius range, amount, and average volume of soil macropores on a vegetated basalt slope of Maka Mountain, Southwest China, and analyzed the distribution of the soil macropores and the main affecting factors. In the study area, the radius of soil macropores ranged from 0.3 to 1.8 mm, mainly between 0.5 and 1.2 mm. The large-radius macropores (1.4-1.8 mm) were lesser, while the small radius macropores (< 1.4 mm) were more. With the development of soil profile, soil macropores were more in upper layers and lesser in deeper layers. The average volume of the macropores contributed 84.7% to the variance of steady effluent rate. Among the factors affecting the average volume of the large macropores, vegetations root mass had a linear relationship, with the correlation coefficient being 0.70, and soil organic matter content also had a linear relationship, with the correlation coefficient being 0.64. PMID- 24483085 TI - [Effects of land use change on soil labile organic carbon in Central Jiangxi of China]. AB - Selecting the 15-year abandoned land (AL) and three forest lands [Phyllostachys edulis plantation (PE), Schima superba secondary forest (SS), and Cunninghamia Lanceolata plantation (CL)] in Anfu County of Jiangxi Province as test objects, this paper studied the effects of land use change on the soil organic carbon (SOC) pool and soil labile organic carbon (SLOC) contents. The soil organic carbon (SOC), microbial biomass carbon (MBC), hot- water extractable carbon (HWC), and readily oxidizable carbon (ROC) contents in the test lands were all in the order of PE>CL>SS>AL. As compared with those in AL, the SOC content, soil carbon stock, and soil labile organic carbon (SLOC) contents in the three forest lands all decreased with increasing soil depth, and had an obvious accumulation in surface soil. The proportions of different kinds of SLOC to soil total organic carbon differed markedly, among which, ROC had the highest proportion, while MBC had the smallest one. There existed significant relationships between SOC, MBC, HWC, and ROC. The MBC, HWC, and ROC contained higher content of active carbon, and were more sensitive to the land use change, being able to be used as the indicators for evaluating the soil quality and fertility in central Jiangxi Province. PMID- 24483086 TI - [Characteristics of rain season atmospheric PM2.5 concentration and its water soluble ions contents in forest parks along an urban-rural gradient in Guangzhou City of South China]. AB - During the rainy season (April-September) of 2012, the atmospheric particulate matter with a diameter less than 2.5 mm (PM2.5) were sampled from the forest parks in the urban area, suburban area, and rural area of Guangzhou City. The mass concentration of PM2.5 and its water-soluble ions (SO4(2-), NO3-, NO2-, Cl-, F-, Na+, NH4+, Ca2+, K+, and Mg2+) contents were also measured. In the forest parks in the urban area, suburban area, and rural area, the diurnal variation of PM2.5 mass concentration was 21.8-161.7, 19.4-156.3, and 17.2-66.5 microg x m( 3), with an arithmetic average being 55.9, 49.8, and 44.4 microg x m(-3), respectively. SO4(2-), Na+, and NH4+ were the main components of water-soluble ions in the PM2.5, and the SO4(2-) had the highest content and decreased gradually from urban to rural forest parks. The contribution of the SO2 and NOx in the PM2.5 from coal combustion to the forest parks was larger than that from vehicle exhaust, but presented a decreasing trend from urban to rural forest parks, indicating that vehicle exhaust had a greater contribution to the atmospheric SO2 and NOx in the urban forest park. In the sampling period, the contribution of sea salt to the water soluble fractions (especially K+) of the PM2.5 was greater for the suburban forest park than for the other two parks. The equivalent concentration of the NH4+ in the PM2.5 was far less than those of the SO4(2-) and NO3-, with a neutralization ratio being much lower than 1.0, which suggested that the PM2.5 had a higher acidity. The PM2.5 acidity had an increasing trend from rural to urban forest parks. PMID- 24483087 TI - [Assessment of groundwater vulnerability to nitrate in He'nan Province of China based on principal component regression]. AB - According to the hydrological and morphological characteristics, He'nan Province was divided into mountainous region and plain region. The level of rich water, infiltration modulus of precipitation, fertilization level per unit area, proportions of vegetable planting area, and soil texture were selected as the common indices, and the slope and groundwater depth were selected as specific indices to assess the groundwater vulnerability to nitrate. Principal component regression analysis was adopted to determine the index weights, and the spatial distribution of groundwater vulnerability to nitrate in He'nan Province was assessed with ArcGIS 9.2. In the Province, the groundwater vulnerability to nitrate was mainly at low and medium level, and the region with this vulnerability level accounted for 68.4% of the total. The high vulnerability region accounted for 19.8%, and the extremely high vulnerability region occupied 11.8%. The main factors affecting the groundwater vulnerability to nitrate in plain region were soil texture, fertilization level, and infiltration modulus of precipitation, while those in mountainous region were fertilization level, soil texture, and slope. This study provided a theoretical basis for reasonable fertilization and agricultural environment management. PMID- 24483088 TI - [Characteristics and adaptation of seasonal drought in southern China under the background of climate change. V. Seasonal drought characteristics division and assessment in southern China]. AB - Zoning seasonal drought based on the study of drought characteristics can provide theoretical basis for formulating drought mitigation plans and improving disaster reduction technologies in different arid zones under global climate change. Based on the National standard of meteorological drought indices and agricultural drought indices and the 1959-2008 meteorological data from 268 meteorological stations in southern China, this paper analyzed the climatic background and distribution characteristics of seasonal drought in southern China, and made a three-level division of seasonal drought in this region by the methods of combining comprehensive factors and main factors, stepwise screening indices, comprehensive disaster analysis, and clustering analysis. The first-level division was with the annual aridity index and seasonal aridity index as the main indices and with the precipitation during entire year and main crop growing season as the auxiliary indices, dividing the southern China into four primary zones, including semi-arid zone, sub-humid zone, humid zone, and super-humid zone. On this basis, the four primary zones were subdivided into nine second level zones, including one semi-arid area-temperate-cold semi-arid hilly area in Sichuan-Yunnan Plateau, three sub-humid areas of warm sub-humid area in the north of the Yangtze River, warm-tropical sub-humid area in South China, and temperate cold sub-humid plateau area in Southwest China, three humid areas of temperate tropical humid area in the Yangtze River Basin, warm-tropical humid area in South China, and warm humid hilly area in Southwest China, and two super-humid areas of warm-tropical super-humid area in South China and temperate-cold super-humid hilly area in the south of the Yangtze River and Southwest China. According to the frequency and intensity of multiple drought indices, the second-level zones were further divided into 29 third-level zones. The distribution of each seasonal drought zone was illustrated, and the zonal drought characteristics and their impacts on the agricultural production were assessed. Accordingly, the drought prevention measures were proposed. PMID- 24483089 TI - [Characteristics of soil denitrifying enzyme activity in riparian zones with different land use types in Chongming Island, Shanghai of China]. AB - By using acetylene inhibition method, this paper studied the soil denitrifying enzyme activity (DEA) and its affecting factors in the riparian zone with different land use types (cropland riparian, forested riparian, and grassy riparian zones) in Chongming Island, Shanghai of China. The riparian soil DEA was (0.69 +/- 0.11)--(134.93 +/- 33.72) microg N x kg(-1) x h(-1), which differed obviously among different land types, with a decreasing trend of forested riparian zone > cropland riparian zone > grassy riparian zone. The soil DEA was significantly (P < 0.05) higher in 0-10 cm in 10-30, 30-50, and 50-70 cm layers. There were significant positive relationships between soil DEA and soil TOC, TN, and NO(3-)-N (P < 0.01). Land use change mainly altered the soil natural structure and soil physical and chemical properties, decreased the accumulation of soil organic carbon, and affected the soil nitrogen transformation, and thus, inhibited the occurrence of riparian soil denitrification. PMID- 24483090 TI - [Ecological function evaluation and related management strategies of river ecosystem in Taizi River basin, North China]. AB - By the method of index evaluation at reach scale, this paper evaluated the ecological functions of aquatic biodiversity maintenance, habitat maintenance, water quality sustainment, and hydrological support of the river system in Taizi River basin of North China. The dominant ecological functions and the total ecological function were determined after sorting and summing. All the reaches in the basin were divided into four hierarchies of ecological functions. Overall, the total ecological function showed a spatially degrading trend from the mountainous region to the plain. Based on the evaluation results of the total function and dominant functions, six ecosystem management strategies were proposed. For the reaches with the functions of aquatic biodiversity- and habitat maintenance, the primary ecological management strategies included ecological conservation, ecological maintenance, and ecological restoration; for the reaches with the functions of water quality sustainment and hydrological support, the primary strategies of ecological management included limited development, development optimization, and exploitation. PMID- 24483091 TI - [Effects of biochars produced from different sources on arsenic adsorption and desorption in soil]. AB - By using OECD Guideline 106 batch equilibrium method, this paper studied the characteristics of As (V) adsorption and desorption in brown soil as affected by the biochars produced from dairy manure, pine needle, and corn straw. When the addition amount of the biochars was 0.5%, the maximum adsorption amount of As (V) was decreased in the order of dairy manure biochar > pine needle biochar > corn straw biochar, which was related to the basic characteristics of the biochars. The adsorption isotherm of As (V) could be well fitted by Langmuir model (R2 = 0.997). In comparing with CK, both the adsorption capacity (lgKf = 1.99-2.10) and the adsorption intensity (1/N = 0.413-0.449) of As (V) were low, and the main adsorption mechanism was physical adsorption. The desorption rate of As (V) (14.5%-18.7%) was decreased in the order of dairy manure biochar > pine needle biochar > corn straw biochar. The addition of the biochars decreased the adsorption of As (V) by brown soil, which could induce the increase of the bioavailability of As, and strengthen the toxicity of As in soil. PMID- 24483092 TI - [Responses of functional diversity of aquatic insect community to land use change in middle reach of Qiantang River, East China]. AB - Based on the biological traits such as life history, resistance ability against environmental disturbance, and physiological characteristics of aquatic insects, and by using the fourth-corner statistical method, this paper studied the responses of the functional diversity of aquatic insect community to land use change in the middle reach of Qiantang River, Zhejiang Province of East China. For the test aquatic insect community, some of its biological traits were sensitive to land use change, and altered along human disturbance gradients as expected. With the increasing intensity of human disturbance, the maximal insect body length decreased gradually, the dominant respiration pattern evolved from gill respiration to tegument respiration, and the abundance of burrowers increased significantly. At the same time, the functional diversity measured as Rao's quadratic entropy was significantly higher in reference sites than in disturbed sites (P < 0.001), demonstrating that the changes in the functional diversity of the aquatic community were mainly induced by the land use change caused by human activities, which resulted in the decline of stream water quality and habitat quality and the variations of aquatic insect community composition and biological traits. The aquatic insect biological traits and functional diversity could be the potentially effective indicators in the stream health assessment in the future. PMID- 24483093 TI - [Parasitic and lethal effects of Trichoderma longibrachiatum on Heterodera avenae: microscopic observation and bioassay]. AB - A laboratory experiment was conducted to study the parasitic and lethal effects of Trichoderma longibrachiatum conidia suspension on Heterodera avenae cysts. Different concentrations (1.5 x 10(5)-1.5 x 10(7) cfu x mL(-1)) of T. longibrachiatum conidia suspension had strong parasitic and lethal effects on H. avenae cysts, and the effects differed significantly among the different concentrations. When treated with the T. longibrachiatum conidia suspension at a concentration of 1.5 x 10(7) cfu x mL(-1), 96.7% of the H. avenae cysts were parasitized by the conidia at the 18th day, and the hatching rate of the cysts was inhibited by 91.2% at the 22nd day. The microscopic observation showed that at the initial parasitic stage, T. longibrachiatum conidia suspension adhered or parasitized on the cyst surface, germinated a large number of hyphae, and grew on the cyst surface, making the development of cyst embryo stopped and the contents in cysts flocculated, and even, some cysts started to deform, and small dark brown vacuoles formed on the cyst surface. At the later parasitic stage, the cysts were penetrated by dense mycelium, cysts were broken, their contents exosmosed, and the mycelium on the integument of some cysts produced conidiophores, on which, conidium were adhered or parasitized. It was considered that T. longibrachiatum could be used as a potential high-efficient bioagent to control the occurrence and damage of H. avenae. PMID- 24483094 TI - [Effects of Trichoderma longbrachitum and Streptomyces jingyangensis combination on the growth and disease resistance of tobacco seedlings]. AB - An agar plate antagonism experiment in combining with in vivo screening experiment was conducted to study the affinity and bacteriostasis spectrum of the combination of biocontrol agents Trichoderma longbrachitum and Streptomyces jingyangensis to Nicotiana tabacum seedlings, with the effects of each agent and their combination on the N. tabacum seedlings growth, induced resistance, and resistance to Phytophthora nicotianae analyzed. The two agents had no interactive inhibitory effect and showed higher affinity to N. tabacum, and the agents themselves as well as their metabolites had higher bacteriostasis activities and wider bacteriostasis spectrum to P. nicotiaonae, Pythium aphanidermatum, and Alternaria alternate in different habitats. The combination of the two agents affected the morphological characteristics of the seedlings underground and aboveground parts, promoted the growth of root, stem, and leaf, and increased the root volume, total surface area, length, and average diameter as well as the stem height and size and the leaf length, width, and biomass, with these promotion effects being superior than those of the single-agent treatment. The combination of the two agents also increased the activities of the defensive enzymes superoxide dismutase, catalase, phenylalanine ammonia lyase, and peroxidase in the seedlings root significantly, with the relative control efficiency against P. nicotianae reached 69.3%, as compared to the conventional treatment. This study showed that the combination of T. longbrachitum and S. jingyangensis was a compatible combination with higher affinity and efficiency. This combination showed a synergistic effect of the two agents in plant disease control and in promoting plant growth, being able to promote the tobacco seedlings growth and control the P. nicotianae effectively. PMID- 24483095 TI - [Effects of nano-selenium on antioxidant capacity and histopathology of Cyprinus carpio liver under fluoride stress]. AB - To evaluate the protection effect of nano-selenium (NSe) on the antioxidant capacity and histopathology of Cyprinus carpio liver under fluoride stress, a total of 750 C. carpio individuals were randomly divided into five groups, i. e., no fluoride stress and NSe addition (CK), fluoride (100 mg F- x L(-1))-stressed (FS), and fluoride-stressed plus NSe added with a dosage of 0.1 mg Se x L(-1) (NSe L), 0.5 mg Se x L(-1) (NSe M), and 1.0 mg Se x kg(-1)(NSe H). The NSe was mixed with fish foods, and the fishes of FS and NSe groups were exposed to the fluoride stress for 30 days. As compared with CK, fluoride stress decreased the SOD, CAT, and GSH-Px activities and increased the MDA content of C. carpio liver, and induced a definite damage on the histopathology of the liver. Compared with FS, NSe increased the liver SOD, CAT, and GSH-Px activities, decreased the liver MDA content, and mitigated the damage of fluoride stress on the histopathology of the liver. The results demonstrated that in some extent, the addition of NSe into fish foods could alleviate the decline of the antioxidant capacity of C. carpio liver and the damage on the liver histopathology caused by fluoride stress. PMID- 24483096 TI - [Toxic effect of nodularin on the apoptosis of grass carp (Ctenopharyngodon idellus) lymphocytes and related mechanisms]. AB - Nodularin is a new kind of cyanobacterial toxins found in water blooms worldwide, and fish is very easily to suffer from the negative effects induced by this toxin. This study found that nodularin could induce the apoptosis of Ctenopharyngodon idellus lymphocytes in vitro. The observation of transmission electron microscopy showed that under the impacts of nodularin, the lymphocytes presented typical apoptosis features, such as obvious cytoplasm condensation and nuclear chromatin agglutination and marginalization. The DNA ladder fragmentation further confirmed the occurrence of the apoptosis of the lymphocytes. After incubated with 1, 10, and 100 microg x L(-1) of nodularin for 12 h, the percentages of apoptotic lymphocytes reached 19.4%, 31.6%, and 71.6%, respectively, suggesting a dose-dependent manner. The nodularin-induced apoptosis was related to the increase of intracellular reactive oxygen species (ROS), decline of mitochondrial transmembrane electric potential, up-regulation of intracellular Ca2+, down-regulation of Bcl-2, and up-regulation of Bax. Meanwhile, the activation of Caspase-3 and Caspase-9 were involved in the process of apoptosis. These results strongly indicated that nodularin could induce the apoptosis of fish lymphocytes via mitochondria pathway. PMID- 24483098 TI - [Horizontal transfer of antibiotic resistance genes in the environment]. AB - The transfer of antibiotic resistance genes (ARGs), a new type of environmental pollutants, could have more adverse effects on the environment than the ARGs themselves, while the horizontal gene transfer (HGT) could be the most important propagation pathways of the ARGs, being one of the reasons for the growing pollution of ARGs in the environment. This paper systematically elaborated the molecular elements of the horizontal transfer of ARGs and the related affecting factors, which was of significance for investigating the molecular mechanisms of the horizontal transfer of the ARGs. In combining with the phylogenetic mechanisms of multiple antibiotic resistances, this paper also provided effective strategies to reduce the transfer and proliferation of ARGs in the environment. Based on the present contamination situations, the further researches on the horizontal transfer of ARGs in the environment were prospected. PMID- 24483097 TI - [County-scale N2O emission inventory of China's manure management system]. AB - Manure is one of the two largest contributors to China's N2O emission. By using the county-scale activity data and the regional emission factors and related parameters with spatial differentiation in China in 2008, this paper assessed the N2O emission loading, sources profile, spatial pattern, and uncertainty, aimed to establish a high-resolution N2O emission inventory of China's manure management system in 2008. As compared with the research results based on the IPCC, EDGAR, and other works, the proposed emission inventory was more reliable and comprehensive. The total China' s N2O emission from manure in 2008 was estimated as 572 Gg, among which, the emission from the manure except pasture/range/paddock was 322 Gg (56.3%), from the manure in pasture/range/paddock was 180 Gg (31.5%), and the indirect emission from atmospheric volatilized N deposition and leaching/runoff was 45.8 Gg (8.0%) and 1.23 Gg (0.2%), respectively. The spatial pattern of China's N2O emission from manure was more centralized, and mainly concentrated in Jilin, Shandong, Sichuan, Hunan, Henan, Heilongjiang, and Liaoning provinces, contributing 52.4% of the total emission, and more than 25% being from 84 counties (only < 3% of the whole counties). The proposed emission inventory had a higher spatial resolution and accuracy. Different with this inventory, the IPCC underestimated the direct emission while overestimated the indirect emission, with the regions of higher emission rate being underestimated by -1.5%-6.0% and those of lower emission rate being overestimated by 1.6%-13%. As for the EDGAR, the regions of higher emission rate were underestimated by -18. 8--50.0%, and those of lower emission rate were mostly overestimated by 25% 54.1%. PMID- 24483099 TI - [Process and mechanism of plants in overcoming acid soil aluminum stress]. AB - Aluminum (Al) stress is one of the most important factors affecting the plant growth on acid soil. Currently, global soil acidification further intensifies the Al stress. Plants can detoxify Al via the chelation of ionic Al and organic acids to store the ionic Al in vacuoles and extrude it from roots. The Al extrusion is mainly performed by the membrane-localized anion channel proteins Al(3+) activated malate transporter (ALMT) and multi-drug and toxin extrusion (MATE). The genes encoding ABC transporter and zinc-finger protein conferred plant Al tolerance have also been found. The identification of these Al-resistant genes makes it possible to increase the Al resistance of crop plants and enhance their production by the biological methods such as gene transformation and mark associated breeding. The key problems needed to be solved and the possible directions in the researches of plant Al stress resistance were proposed. PMID- 24483100 TI - [Watershed water environment pollution models and their applications: a review]. AB - Watershed water environment pollution model is the important tool for studying watershed environmental problems. Through the quantitative description of the complicated pollution processes of whole watershed system and its parts, the model can identify the main sources and migration pathways of pollutants, estimate the pollutant loadings, and evaluate their impacts on water environment, providing a basis for watershed planning and management. This paper reviewed the watershed water environment models widely applied at home and abroad, with the focuses on the models of pollutants loading (GWLF and PLOAD), water quality of received water bodies (QUAL2E and WASP), and the watershed models integrated pollutant loadings and water quality (HSPF, SWAT, AGNPS, AnnAGNPS, and SWMM), and introduced the structures, principles, and main characteristics as well as the limitations in practical applications of these models. The other models of water quality (CE-QUAL-W2, EFDC, and AQUATOX) and watershed models (GLEAMS and MIKE SHE) were also briefly introduced. Through the case analysis on the applications of single model and integrated models, the development trend and application prospect of the watershed water environment pollution models were discussed. PMID- 24483101 TI - [Puzzles and hypotheses of acupuncture]. AB - Some results of clinical trials from the West on traditional acupuncture with modern research design have puzzled the acupuncture community. These include (1) what is the implication of acupuncture, (2) whether acupuncture point has its specificity, and 3) why practical experience in the East is quite different from research observations in the West. Three hypotheses, namely, Acupuncture Healing Effect, Pan-acupoint Phenomenon, and Hard Acupuncture and Soft Acupuncture, are proposed here to explain these sensitive issues. Further investigation with scientific approach may prove or reject these hypotheses. The resolving of these issues will shed light on the re-evaluation of traditional acupuncture and promote the maturation of modern acupuncture theory. PMID- 24483102 TI - [Auxiliary treatment of HBV correlated hepatic failure by Chinese herbs: a systematic review of randomized controlled trials]. AB - OBJECTIVE: To evaluate the effectiveness and safety of Chinese herbs as an adjuvant treatment for hepatitis virus B (HBV)-related hepatic failure. METHODS: Data were retrieved through the Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Library, PubMed, CNKI, VIP, Wanfang Database, and ChiCTR by key words or free words such as hepatic failure, severe hepatitis, HBV, Chinese medicine, randomization, and control. Appendix references of related papers were taken as supplementary indices. According to requirement for Cochrane systematic evaluation, randomized clinical trials on assessing the effectiveness and safety of Chinese herbs as main or adjuvant treatment in treating HBV-related hepatic failure were methodologically assessed, data extracted and analyzed. RESULTS: Totally 21 trials on Chinese herbal medicine therapy versus standard medical therapy (involving 1 881 patients) were included. Most trials had unclear risk bias. In 5 studies on the mortality, 3 trials showed that the mortality was lower in the test group than in the control group [RR 0.40, 95% CI (0.20, 0.79), P = 0.0002]. In 6 randomized control trials, totally 20 papers reported the control of complications. Eight results showed Chinese herbal medicine therapy had better effect in controlling complications. The recurrence rate and assessment of the survival quality were reported. Considering secondary indicators, four trials showed Chinese herbal medicine therapy had better effect in lowering the ineffective rate, decreasing total bilirubin (TBIL), and elevating prothrombin activity (PTA). Other prescriptive analyses found that the overall effect on secondary indicators was better in the test group than in the control group, but not all the indicators were statistically different. Adverse reactions were only reported in two papers, showing no severe adverse reaction. CONCLUSION: According to present evidence, till now, we could not judge whether Chinese herbs, as an adjuvant treatment, could do any favor for lowering the incidence and recurrence of hepatic failure patients, and improving their survival qualities. PMID- 24483103 TI - [Intervention of chronic hepatitis B liver fibrosis patients in different stages by syndrome typing and different activating blood removing stasis methods: a clinical study]. AB - OBJECTIVE: To observe the clinical efficacy of treating chronic hepatitis B liver fibrosis (CHBLF) in different stages by syndrome typing and different activating blood removing stasis methods (ABRSM). METHODS: Totally 100 CHBLF patients of vital qi deficiency blood stasis syndrome (VQDBSS) treated at the Department of Liver Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences from July 2008 to December 2011, were randomly assigned to the treatment group and the control group, 50 in each group. Those in the treatment group were treated by self-formulated decoctions for activating blood nourishing blood (ABNB), activating blood removing stasis (ABRS), and activating blood softening hard mass (ABSHM) according to their stages of disease conditions (mild, moderate, and severe). Those in the control group were treated with Compound Biejia Ruangan Tablet (CBRT). Integrals of Chinese medical syndromes, liver functions [mainly including alanine aminotransferase (ALT), albumin/globulin (A/ G)], ultrasonographic examinations of liver (mainly including echoes of liver, width of spleens, width of portal vein), four indicators of serum hepatic fibrosis [including serum hyaluronic acid (HA), laminin (LN), type IV collagen (IV-C), type III collagen peptide (P-III-P)] were statistically analyzed. The therapeutic course was 6 months for all. RESULTS: Compared with before treatment in the same group, the integrals of Chinese medical syndromes both decreased after treatment in the two groups (P < 0.05). The width of spleens decreased in the treatment group more obviously after treatment than before treatment (P < 0.05). Compared with the control group, the integrals of Chinese medical syndromes and the width of spleens were more obviously improved in the treatment group, showing statistical difference (P < 0.05). Compared with before treatment in the same group, levels of ALT, HA, and LN significantly decreased, and the level of A/G significantly increased after treatment in the two groups, showing statistical difference (P < 0.05). Compared with the control group, the A/G level, HA, and LN were more obviously improved in the treatment group, showing statistical difference (P < 0.05). The total effective rate was 76% in the treatment group and 46% in the control group, showing statistical difference (P < 0.05). CONCLUSIONS: Treating CH-BLF in different stages by ABRSM got better effect than using CBRT alone. It could favorably improve clinical symptoms of CHBLF patients and their serum biochemical indicators. PMID- 24483104 TI - [Hemorheology visualization clinical research in elderly hypertension patients of different Chinese medical syndrome types]. AB - OBJECTIVE: To observe blood flow features in elderly hypertension patients of different Chinese medical syndrome types and to test their correlation with rheological properties of red blood cells (RBCs) by applying micro-channel array flow analyzer (MC-FAN). METHODS: Recruited were 109 elderly hypertension patients were assigned to phlegm-stasis blocking collateral group (35 cases), yin deficiency yang hyperactivity group (42 cases), Shen deficiency group (32 cases) according to Chinese medical syndrome typing. Besides, another 21 elderly healthy subjects were recruited as the control group. The hemorheology visualization testing of elderly hypertension patients was detected using MC-FAN. The erythrocyte deformation index (DI), erythrocyte aggregation index (EAI), and erythrocyte related plasma ATPase activity were observed. The correlation between the transiting time (TT) of blood hemorheology visualization and rheological indicators of RBCs were analyzed. RESULTS: The hemorheology visualization TT was significantly prolonged more in the phlegm-stasis blocking collateral group than in the yin deficiency yang hyperactivity group, the Shen deficiency group, and the control group (P < 0.05). Compared with the control group, the DI was significantly lower in the phlegm-stasis blocking collateral group than in the yin deficiency yang hyperactivity group, the Shen deficiency group, and the control group (P < 0.05) when the shear rate was 100 s(-1). Compared with the control group, the plasma Na+ -K(+) -ATPase activity and the plasma Ca2+ -Mg2+ ATPase activity were significantly lower in elderly hypertension patients (P < 0.01). Among the three groups, plasma Ca2+ -Mg2+ -ATPase activity was significantly lower in the phlegm stasis blocking collateral group than in the Shen deficiency group (P < 0. 05). The hemorheology visualization TT (10, 30, 60, and 100 microL) was negatively correlated with DI. The hemorheology visualization TT at 100 microL was positively correlated with EAI. CONCLUSION: Changes of hemorheology visualization TT of elderly hypertension patients were significant and correlated with traditional EAI. PMID- 24483105 TI - [Routine western medicine treatment plus qishen yiqi dripping pill for treating patients with chronic heart failure: a systematic review of randomized control trials]. AB - OBJECTIVE: To systematically review the safety and efficacy of Qishen Yiqi Dripping Pill (QYDP) as a complementary treatment for chronic heart failure (CHF) patients. METHODS: CNKI, VIP, Wanfang Data, PubMed and Cochrane Library were retrieved for papers on randomized control trials of treating CHF patients by routine western medical treatment plus QYDP. The quality of inclusive literatures was assessed by methods from Cochrane Handbook. Valid data were extracted and analyzed by Meta-analysis using RevMan 5.1.0 Software. RESULTS: Totally 17 trials and 1840 patients in line with standard were included. Results of Meta-analysis showed, compared with the routine Western medical treatment group, additional use of QYDP could decrease re-admission rate [RR = 0.52, 95% CI (0.33, 0.81), P = 0.004] and the mortality rate, improve the clinical efficacy [RR = 1.18, 95% CI (1.12, 1.25), P < 0.01] and cardiac function [RR = 1.18, 95% CI (1.10, 1.27),P < 0.01], increase left ventricular ejection fraction (LVEF) [WMD = 5.57, 95% CI (4.16, 6.97), P < 0.01] of CHF patients. Subgroup analysis of LVEF showed that additional use of QYDP could further improve LVEF [ WMD = 8.34, 95% CI (6.23, 10.45), P < 0.01] of CHF patients and increase the distance of their 6-min walk test [WMD = 94.39, 95% CI (71.89, 116.89), P < 0.01]. But there was no statistical difference in plasma brain natriuretic peptide (BNP) between the two groups. No obvious adverse reaction and liver or kidney damage was reported during the trial. CONCLUSIONS: Compared with the Western medical treatment, additional use of QYDP was safe and could further improve clinical efficacy. However, larger and high-quality clinical trials are necessary for further evidence. PMID- 24483106 TI - [Treating HIV/AIDS patients by shenlin fuzheng capsule and qingdu capsule: an analysis of clinical effectiveness]. AB - OBJECTIVE: To analyze the clinical effectiveness of Shenling Fuzheng Capsule (SFC) and Qingdu Capsule (QC) in treating HIV/AIDS patients. METHODS: Totally 220 patients with complete clinical data, who received consecutive treatment for 6 months were selected from the database. They were assigned to two groups whether they would rather receive antiretroviral drugs, the Chinese medicine (CM) treatment group and the integrative medicine (IM) group. The 129 patients in the CM group were treated with SFC or QC, while the 91 patients in the IM group were treated with SFC or QC combined highly active antiretroviral agents. Total score and single score of clinical symptoms and signs, Karnofsky Performance Status (KPS), and changes of body weight before treatment, 3 and 6 months after treatment were compared. CD4+ cell counts were compared between before treatment and 6 months after treatment. RESULTS: The total score of clinical symptoms and signs were lower at 3 and 6 months of treatment than before treatment respectively (P < 0.01). The single score of clinical symptoms and signs such as cough, weakness, shortness of breath, vomit, spontaneous perspiration, hair loss,and chest pain were also lowered at 3 and 6 months of treatment (P < 0.05, P < 0.01), and the KPS increased (P < 0.05). The body weight increased (P < 0.05) and CD4 cell counts decreased (P < 0.05) in the CM group. There was no statistical difference in body weight or CD4 cell counts in the IM group between before and after treatment. CONCLUSION: SFC and QC could improve clinical symptoms and signs of HIV/ AIDS patients, but failed to deter the decrease of CD4+ cell counts. PMID- 24483107 TI - [Preliminary study on features of syndrome distribution and cluster analysis for AIDS patients with pulmonary infection]. AB - OBJECTIVE: To investigate Chinese medical features of acquired immunodeficiency syndrome (AIDS) patients with pulmonary infection. METHODS: Using cluster analysis method, Chinese medical syndromes of 196 AIDS patients with pulmonary infection were analyzed. The distribution features of each syndrome type were analyzed according to the severity and CD4+ numerical analysis. RESULTS: Basic Chinese medical syndrome types could be summed up as three kinds: exterior invasion of wind heat and phlegm heat obstructing Fei syndrome (61 cases, 31.1%), Fei-Pi deficiency and Fei stagnation of phlegm syndrome (64 cases, 32.7%), Fei Shen deficiency and yin deficiency induced inner heat syndrome (71 cases, 36.2%). There was statistical difference in the severity degree and the distribution of CD4 among the three syndrome types (P < 0.05). CONCLUSIONS: AIDS patients with pulmonary infection involve Fei, Shen, and Pi. The pathogenic factors were related to "wind", "heat", "phlegm", and "xu". The Chinese medical syndrome distribution was closely correlated with patients' immunity. PMID- 24483108 TI - [Relevant pathogenesis of heat and phlegm in infantile viral pneumonia: an analysis by association rules]. AB - OBJECTIVE: To study the application of association rules in Chinese medical pathogeneses and pathologies of heat and phlegm in infantile viral pneumonia. METHODS: Association rules were applied to analyze dynamic changes of heat and phlegm correlated symptoms and signs in 297 infants with respiratory syncytial virus (RSV) pneumonia, thus understanding its evolution or pathogenesis. RESULTS: Heat and phlegm co-exist in infantile viral pneumonia. In their relationship, heat was more likely to affect phlegm, but phlegm was less likely to affect heat. Under the intervention of drugs, the possibility of heat induced by phlegm was gradually reduced. But the possibility of phlegm induced by heat was not obvious as time went by. CONCLUSIONS: Heat and phlegm have a close relationship in the pathogenesis of infantile viral pneumonia. The intervention of drugs could reduce the pathologic evolution of phlegm causing heat. However, it has little effect on the pathologic evolution of heat causing phlegm. PMID- 24483109 TI - [Research on the correlation between Chinese medical syndrome types and objective indices of Wilson's disease]. AB - OBJECTIVE: To explore the correlation between Chinese medical syndrome types of Wilson's disease (WD) and clinical materials as well as physical and chemical indices. METHODS: Totally 116 WD patients were typed by Chinese medical syndrome. The correlation between Chinese medical syndrome types and clinical materials as well as physical and chemical indices were analyzed using binary stepwise Logistic regression by SPSS 19.0 Software, taking the common Chinese medical syndrome types as the dependent variable and clinical materials as well as physical and chemical indices as the independent variables. RESULTS: Gan Galibladder dampness-heat syndrome (GGDHS, 35.3%). Gan-stagnation and Pi deficiency syndrome (GSPDS, 13.8%), Gan-Shen yin deficiency syndrome (GSYDS, 13.8%), and phlegm-dampness retention syndrome (PDRS, 12.1%) were most often seen. GGDHS was positively correlated with grade of K-F ring, total bilirubin (TBIL), alanine transaminase (ALT), laminin (LN) (P < 0.01). GSYDS was positively correlated with TBIL (P < 0.01). PDRS was positively correlated with clinical types, ceruloplasmin (CP), aspartate aminotransferase (AST), and total protein (TP) (P < 0.01, P < 0.05). Qi blood deficiency syndrome was positively correlated with disease course, blood ammonia, blood urea nitrogen (BUN), and LN (P < 0.01, P < 0.05). CONCLUSIONS: Chinese medical syndrome types were correlated with clinical materials, physical and chemical indices in WD patients, which could provide experimental reference for Chinese medical syndrome typing. GGDHS, GSPDS, GSYDS, and PDRS were most often seen. PMID- 24483110 TI - [Treating knee osteoarthritis by Chinese medicine and its correlation study with CT changes of infrapatellar fat pad]. AB - OBJECTIVE: To observe the efficacy of Jianbu Tongluo Xunzheng Liquid (JTXL) in treating knee osteoarthritis (KOA), and to explore the correlation between changes of infrapatellar fat pad scanned by CT and the efficacy. METHODS: Totally 105 KOA outpatients were randomly assigned to three groups, i.e., the treatment group, the control group, and the combination group, 35 in each group. Patients in the treatment group were fumigated by JTXL, 30 min each time, once daily, 10 times as a course of treatment, 3 courses in total. Those in the control group received intra-articular injection of Sodium Hyaluronate Injection (SHI), 3 mL each time, once per 6 days, 5 times in total. Those in the combination group were treated by fumigation of JTXL + intra-articular injection of SHI in the same way as the aforesaid two groups. All patients were treated for 30 days. Their clinical efficacy and changes of infrapatellar fat pad scanned by CT were observed, and their correlation was analyzed. RESULTS: The total effective rate was 88.57% in the combination group, better than that of the control group (74.29%) and the treatment group (80.00%; both P < 0.05). Besides, the score for knee joint functions at Hospital for Special Surgery (HSS) was better in the combination group than the other two groups (P < 0.05). The anteroposterior diameter, exterior-interior diameter, the superior-inferior diameter were shortened, and the density decreased in the treatment group and the combination group (P < 0.05). Besides, they were superior to those of the control group (P < 0.05). CONCLUSIONS: Changes of infrapatellar fat pad scanned by CT only existed in the combination group and the treatment group, indicating changes of CT scanning was only correlated with effect on changing physicochemical properties of infrapatellar fat pad. Treatment by Chinese medicine could omnipotently and balanced regulate functions and structures of every tissue. Therefore, CT could be taken as a better method for clinical efficacy observation by Chinese medicine. PMID- 24483111 TI - [Effect of ronggan mixture on immunoregulation and hepatocyte apoptosis-related factors in concanavalin A induced acute immunological liver injury mice]. AB - OBJECTIVE: To explore the effect of Ronggan Mixture (RM) on immunoregulation and hepatocyte apoptosis-related factors in concanavalin A (Con A) induced acute immunological liver injury mice. METHODS: Totally 60 hepatitis B virus (HBV) transgenic mice were randomly divided into 6 groups, i.e., the blank control group, the model group, the RM group, the Herba Artemisiae Scopariae (HAS) group, the Yinchenhao Decoction (YD) group, and the Bifendate group, 10 mice in each group. The acute immunological liver injury model was established by tail vein injection of ConA. Fourteen days before modeling, normal saline was administered to mice in the blank control group and the model group. RM, YD, HAS decoction, and Bifendate solution was respectively given to mice in the RM group, the YD group, the HAS group, and the Bifendate group. The medication was performed once daily. One h after the last gastrogavage, phosphate buffer solution (PBS) was injected to mice in the blank control group from the tail vein. Modeling was conducted by injecting Con A at 3 microg/g body weight from the tail vein. Mice were sacrificed 8 h after modeling. Blood or tissue samples were collected to detect lab indicators such as alanine aminotransferase (ALT), aspartate aminotransferase (AST), total bilirubin (TBil), tumor necrosis factor alpha (TNF alpha), interferon gamma (INF-gamma), IL-4, IL-10, Fas, FasL, Bax, and bcl-2. RESULTS: There was significant difference in all lab indicators between the normal group and the blank control group (P < 0.05, P < 0.01). Compared with the model group, ALT and AST levels were significantly lower in the RM group and the Bifendate group (P < 0.01); TBil significantly decreased in the RM group (P < 0.01). The expression level of TNF-alpha decreased in the RM group (P <0.05). The expression level of IFN-gamma decreased in the RM group and the YD group (P < 0.05). The expression level of IL-4 could be elevated in all medicated groups (P < 0.05). RM could elevate the expression level of IL-10 (P < 0.05). The expression level of Fas in the liver tissue decreased in the RM group and the YD group (P < 0.05). The expression level of FasL decreased and the expression of bcl-2 gene increased in the RM group (both P < 0.05). The expression level of Bax was down-regulated in the RM group and the YD group (P < 0.05). The ratio of bcl 2/Bax was up-regulated in the RM group (P < 0.05). Meanwhile, RM showed better effect in decreasing expressions of ALT and AST than HAS (P < 0.05). The effect of increasing IL-10 expression levels was better in the RM group than in the YD group (P < 0.01). The effect of decreasing expressions of Fas and FasL was better in the RM group than in the HAS group, the YD group, and the Bifendate group (P < 0.05). The effect of enhancing the expression of IL-10 in the liver tissue was better in the RM group than in the HAS group (P < 0. 05). CONCLUSION: RM had protective effect on Con A induced acute immunological liver injury mice, which might be achieved by changing the immunological balance of Thl/Th2 factors (decreasing expressions of TNF-alpha and IFN-gamma, elevating expressions of IL 10 and IL-4) and regulating hepatocyte apoptosis-related factors (down-regulating gene expressions of Fas, FasL, and Bax; up-regulating bcl-2 gene expression, and up-regulating the bcl-2/Bax ratio). PMID- 24483112 TI - [Preliminary study of establishing and assessing IBS-D model rats of gan stagnation and Pi deficiency syndrome]. AB - OBJECTIVE: To establish a new disease-syndrome-symptom integrated diarrhea predominant irritable bowel syndrome (IBS-D) rat model of Gan stagnation and Pi deficiency syndrome (GSPDS). METHODS: (1) The model establishment method: We combined mother-infant separation, chronic restraint, and senna gavage to establish a new IBS-D model of GSPDS. Totally 48 experimental rats were divided into the normal group (Group A), the mother-infant separation group (Group B), the chronic restraint group (Group C), and the senna gavage group (Group D), the mother-infant separation + senna gavage group (Group E), and the mother-infant separation + chronic restraint + senna gavage group (Group F), 8 in each group. (2) The model evaluation method: We used pain threshold indicating colorectal distension to represent for the visceral sensitivity, thus evaluating the establishment of "disease" model; open field test and serum D-xylose levels to evaluate the establishment of GSPDS model; defecation numbers of grain and loose stool rate to evaluate the establishment of diarrhea symptom. RESULTS: (1) Compared with Group A, the body weight gained less in Group F, showing statistical difference (P < 0.05). (2) The pain threshold significantly decreased in Group F, showing statistical difference when compared with Group A (P < 0.05). (3) Compared with Group A, the total cross number, the standing number, and the decoration number in Group F significantly decreased (P < 0.05). (4) Compared with Group A, the serum D-xylose level of Group F significantly decreased (P < 0.05). (5) Compared with Group A, the defecation numbers of grain and the loose stool rate significantly increased, showing statistical difference (P < 0.05). CONCLUSIONS: A new disease-syndrome-symptom integrated IBS-D animal model of GSPDS successfully established might be a better animal model used for studying IBS by Chinese medicine. However, further studies are needed. PMID- 24483113 TI - [Effect of huazhuo jiedu hewei recipe on the mechanism of angiogenesis in precancerous lesions of gastric cancer rats]. AB - OBJECTIVE: To explore the possible angiogenesis mechanism of Huazhuo Jiedu Hewei Recipe (HJHR) in preventing and treating precancerous lesions of gastric cancer (PLGC). METHODS: Totally 66 Wistar rats were randomly divided into 6 groups, i.e., the normal control group, the model group, the retinoic acid (RA) group, the high dose HJHR group, the middle dose HJHR group, the low dose HJHR group, 11 in each group. PLGC model was duplicated by inserting a spring with Helicobacter. Corresponding medicines were administered to rats in each medicated group once daily by gastrogavage, 2 mL each time for 12 successive weeks. The effect of HJHR on hypoxia induced factor (HIF-1alpha) and vascular endothelial growth factor (VEGF) of PLGC in chronic atrophic gastritis (CAG) rats' gastric mucosa was observed by immunohistochemical assay and Western blot method. RESULTS: Compared with the normal control group, the expression of VEGF and HIF-1alpha increased in the model group (P < 0.05). Compared with the model group, the expression of VEGF and HIF-1alpha decreased in each medicated group (P < 0.05). Besides, they were lower in the high and middle dose HJHR groups than in the RA group and the low dose HJHR group (P < 0. 05). There was no statistical difference between the low dose HJHR group and the RA group (P > 0.05). CONCLUSION: HJHR could prevent and treat PLGC of CAG rats possibly through decreasing the expression of HIF-1alpha and VEGF in a dose-dependent manner. PMID- 24483114 TI - [Protection of huanglian jiedu decoction on systemic and vascular immune responses of high fat induced apoE(-/-) mice]. AB - OBJECTIVE: To observe the effect of Huanglian Jiedu IJecoction (HJU) on systemic and vascular immune responses of high fat diet fed apoE deficient (apoE(-/-)) mice. METHODS: Eight wild type C57BL6 mice were recruited as the wild type common food group. Totally 24 apoE(-/-) mice were randomly divided into the ApoE'common food group, the ApoE(-/-) hyperlipidemia group, and the ApoE(-/-) hyperlipidemia plus HJD group, 8 in each group. In the present study, the common food mice and high fat fed mice were fed with a chow diet or a high cholesterol diet for 4 weeks. HJD was given to mice in the ApoE(-/-) hyperlipidemia plus HJD group at the daily dose of 5 g/kg by gastrogavage, while equal volume of pure water was given to mice in the rest groups by gastrogavage. Four weeks later, the plasma levels of blood lipids, the ratio of peripheral blood mononuclear cells, and expressions of Toll-like receptor 4 (TLR-4) and CD36 on the monocytes were detected. The pathological changes and expressions of cytokines in local aorta were detected. The plasma cytokine levels in response to lipopolysaccharide (LPS) were analyzed. Results (1) Compared with the wild type common food group, TO, TG, and LDL-O significantly increased in the ApoE(-/-) common food group (P < 0. 05, P < 0.01). Compared with the ApoE(-/-) common food group, TC and LDL-C significantly increased in the hyperlipidemia group (P < 0. 05). There was no statistical difference in each index between the ApoE(-/-) hyperlipidemia group and the ApoE(-/-) hyperlipidemia plus HJD group (P > 0.05). (2) Compared with the wild type common food group, no obvious change of the ratio of peripheral blood mononuclear cells happened, the TLR4 expression level significantly increased in the ApoE'common food group (P < 0. 05). Compared with the ApoE common food group, the ratio of peripheral blood mononuclear cells and the TLR4 expression level significantly increased in the ApoE' hyperlipidemia group (P < 0.05). Compared with the ApoE(-/-) hyperlipidemia group, the ratio of peripheral blood mononuclear cells and the TLR4 expression level significantly decreased. Besides, the CD36 expression level also significantly decreased (P<0.05). (3) After stimulated by LPS for 3 h, compared with the wild type common food group, plasma TNF-ct and IL-b expressions significantly increased in the ApoE(-/-) common food group (P < 0.05). Compared with the ApoE(-/-) common food group, plasma expressions of IL-12, TNF-alpha, MCP-1, and IL-10 increased, but with no statistical difference in the ApoE(-/-) hyperlipidemia group (P > 0.05). After 4 week intervention of HJD, compared with the ApoE(-/-) hyperlipidemia group, the MCP-1 expression was significantly down-regulated, while the IL-10 expression significantly increased, showing statistical difference (P < 0.05). Compared with the wild type common food group, mRNA expression levels of IFN-gamma, MCP-1 , TNF alpha, IL-10, and IL-1beta significantly increased (P < 0. 05, P < 0.01). Compared with the ApoE(-/-) common food group, not only mRNA expression levels of IFN-gamma, MCP-1, TNF-alpha, and IL-1beta, further significantly increased, but also IL-12, IL-10, and TGF-beta significantly increased (P < 0. 05, P < 0. 01). After 4-week intervention of HJD, compared with the ApoE(-/-) hyperlipidemia group, mRNA expression levels of MCP-1, TNF-alpha, IL-1beta, and IL-12 significantly decreased in the ApoE(-/-) hyperlipidemia plus HJD group (P < 0.05, P < 0.01). CONCLUSIONS: High fat diet induced systemic reaction and inflammatory reactions of local vessels. The local inflammatory response of vessels exceeded systemic inflammatory response. Intervention of HJD could attenuate inflammatory response, especially in local arteries. Meanwhile, it enhanced systemic anti inflammatory reactions. PMID- 24483115 TI - [Effect of danshen injection on adult cardiac stem cell transplantation in myocardial infarction mice]. AB - OBJECTIVE: To study the effect of combined use of Danshen Injection (Dl) on acute myocardial infarction (AMI) mice undergoing adult cardiac stem cell transplantation. METHODS: Thirty mice were randomly divided into 3 groups, 10 in each group, i.e., the high dose Dl group (at the daily dose of 5 g/kg) , the low dose Dl group (at the daily dose of 0. 5 g/kg), and the model control group. The AMI model was constructed by surgical ligation of the left anterior descending artery, and 2 x 10(6) -3 x 10(6) cardiac stem cells in vitro cultured were injected to the peripheral infracted zone immediately after successful modeling. All mice were administered with Dl by gastrogavage one week before myocardial infarction (Ml) and one week after Ml. Mice were sacrificed one week after Ml. Immunostaining was performed. The microvessel density (MVD) was detected using CD31 . The cell proliferation was detected using Ki67. The myocardial fibrosis degree was detected using Masson staining. The cell apoptosis of peripheral infracted zone was detected by TUNEL. Protein expressions of Akt and phospho-Akt were detected using Western blot. RESULTS: MVD and Ki67 positive cell number increased more in the high dose DI group than in the low dose DI group and the model control group (P < 0.05). The myocardial fibrosis degree and the cell apoptosis of peripheral infracted zone significantly decreased in the high dose DI group than in the low dose DI group and the model control group (P <0. 05). The phospho-Akt expression level significantly increased in the high dose DI group than in the low dose DI group and the model control group (P < 0.05). Compared with the model control group, the total Akt level significantly increased in the high dose and low dose DI groups (P < 0.05). But there was no statistical difference the high dose DI group and the low dose DI group (P > 0.05). CONCLUSION: Treating AMI by adult cardiac stem cell transplantation combined with DI could increase the MVD and cell proliferation, reduce cell apoptosis and fibrosis levels, thus improving the transplantation efficiency of adult cardiac stem cells. PMID- 24483116 TI - [Effect of compound danshen dripping pill combined with intravenous transplantation of human umbilical cord blood mononuclear cells on local inflammatory response in the myocardium of rabbits with acute myocardial infarction]. AB - OBJECTIVE: To investigate effect of Compound Danshen Dripping Pill (CDDP) on the inflammatory response of the myocardium of acute myocardial infarction (AMI) rabbits, to observe the therapeutic effect of CDDP combined intravenous transplantation of human umbilical cord blood mononuclear cells (HUCBMCs) on inflammatory response, pro-inflammatory cytokine tumor necrosis factor alpha (TNF alpha) , and heart function in the myocardium of AMI rabbits, and to explore the possible protective mechanisms of the combined therapy. METHODS: The AMI model was successfully established by ligation of the left anterior coronary artery (LAD) in 40 healthy rabbits.Then they were randomly divided into four groups, i.e., the control group, the CDDP group, the transplantation group, and the combined group, 10 in each group. Rabbits in the control group received intravenous injection of 0.5 mL normal saline via ear vein within 24 h after AMI and then intragastric infusion of normal saline at 5 mL per day. Rabbits in the CDDP group received intravenous injection of 0.5 mL normal saline via ear vein within 24 h after AMI and then intragastric infusion of solution obtained by solving 270 mg CDDP in 5 mL normal saline per day. Rabbits in the transplantation group received intravenous injection of 0.5 mL normal saline labeled with green fluorescent protein (GFP) containing 3 x 10(7) of HUCBMCs via ear vein within 24 h after AMI and then intragastric infusion of normal saline at 5 mL per day. Rabbits in the combined group received intravenous injection of 0.5 mL normal saline labeled with GFP containing 3 x 10(7) of HUCBMCs via ear vein within 24 h after AMI and then intragastric infusion of solution obtained by solving 270 mg CDDP in 5 mL normal saline per day. At week 1 and 4 after treatment, cardiac function indices such as left ventricular fractional shorting (LVFS) and left ventricular ejection fraction (LVEF) were performed by echocardiography; the number of transplanted cells in the myocardium was found by GFP positive cells counted with fluorescence microscopy.The white blood cells in the myocardium stained with HE were determined by light microscope. The expressions of TNF-alpha protein in the myocardium were detected by immunohistochemical assay. RESULTS: (1) Compared with the control group at week 1 and 4 after treatment, the LVEF and LVFS were significantly improved in the CDDP, transplantation, and combined groups (P < 0.05). The cardiac function was significantly improved in the combined group than in the CDDP group and the transplantation group (P < 0.05). But there was no statistical difference in the latter two groups. (2) Compared with the control group, the number of white blood cells and the expression of TNF alpha protein decreased significantly in the CDDP, transplantation, and combined groups at week 1 and 4 respectively after treatment. The number of white blood cells and expressions of TNF-alpha protein were significantly lower in the combined group than in the CDDP group and the transplantation group (P <0.05). But there was no statistical difference in the latter two groups. (3) GFP positive cells were found to be distributed in the peri-myocardial infarction area in the transplantation group and the combined group at week 1 and 4 after transplantation. Besides, the number of the GFP positive cells was much more in the combined group than in the transplantation group (P < 0.05). CONCLUSIONS: The findings indicated that the combination of CDDP with intravenous transplantation of HUCBMCs in the treatment of AMI rabbits could elevate the survival rate of transplanted cells, and further improve the heart function. The possible mechanisms might be related to attenuating local inflammation of myocardium, and inhibiting enhanced expressions of pro-inflammatory cytokine TNF-alpha protein. PMID- 24483117 TI - [Influence and long-term effects of three methods for regulating and invigorating fei-shen on T lymphocyte subsets and CD4+ CD25+ in COPD rats]. AB - OBJECTIVE: To evaluate the therapeutic and long-term effects of three methods for regulating and invigorating Fei-Shen [reinforcing Fei and invigorating Pi (RFIP), reinforcing Fei and invigorating Shen (RFIS), benefiting qi and nourishing Shen (BQNS)] on T lymphocyte subsets and CD4+ CD25+ in rats with chronic obstructive pulmonary disease (COPD). METHODS: Totally 120 rats were randomly divided into the control group, the model group, the RFIP group, the RFIS group, the BQNS group, and the aminophylline group, 20 in each group. Except those in the control group, the rest rats were exposed to cigarette smoking and bacterial infection to prepare the COPD rat model. Rats in the RFIP group, the RFIS group, the BQNS group, and the aminophylline group were administrated with Bufei Jianpi Recipe, Bufei Yishen Recipe, Yiqi Zishen Recipe, and aminophylline from week 9 to 20. After rats were sacrificed at week 20 and 32, lung pathological impairments and the levels of T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+ / CD8+) and CD4+ CD25+ in the peripheral blood and the bronchoalveolar lavage fluid (BALF) were detected. RESULTS: At week 20 and 32, the impairments in the lungs were obvious in rats of the model group, while the levels of CD3+, CD4+, CD8+, and CD4+ CD25+ were significantly lower in the peripheral blood and the BALF in the model group than in the controls group (P < 0.05, P < 0.01), and they were higher in the four groups than in the model group (P < 0.05, P < 0.01). However, the levels of CD3+ and CD4+ in the peripheral blood and the BALF were higher in the three TCM treated groups than in the aminophylline group (P < 0.05, P < 0.01). CD4+ in the peripheral blood in the RFIP group was higher than in the RFIS group and the BQNS group (P < 0.01). At week 20, the ratio of CD4+ /CD8+ was higher in the RFIP group than in the aminophylline group (P < 0.01). CD4+ was higher in the three TCM-treated groups than in the aminophylline group (P < 0.05, P < 0.01). At week 32, the ratio of CD4+ / CD+ in the three TCM- and aminophylline-treated groups was higher than that of the model group (P < 0.05). CD4+ in the RFIP group and the RFIS group was higher than that of the aminophylline group (P < 0.05, P < 0.01). Compared with that at week 20, the ratio of CD4+/CD8+ in the BALF group was significantly higher in the RFIP at week 32 (P < 0.05). The CD4+ CD25+ levels in the peripheral blood and BALF of the BQNS group was significantly lower (P < 0.05). CONCLUSIONS: The efficacy and long-term effects of three methods for regulating and invigorating Fei-Shen might be possibly associated with regulating T lymphocyte subsets (CD3+, CD4+, CD8+, CD4+ / CD8+) and CD4+ CD25+ levels. Of them, RFIP showed significant effects in regulating CD4+ and CD4+ / CD8+ in the peripheral blood and BALF. PMID- 24483118 TI - [Effects of Brucea javanica oil emulsion on human papilloma virus type 16 infected cells and mechanisms research]. AB - OBJECTIVE: To explore the in vitro inhibitive effect and underlying mechanisms of Brucea Javanica oil emulsion (BJOE) on human papilloma virus (HPV) type 16 infected cells. METHODS: The HPV16 E61E7 immortalized human ectocervical Ect1/E6E7 cell line and the CaSki cell line were selected as the in vitro models of premalignant cervical lesion and cervical cancer respectively. After treated with BJOE at different concentrations (5, 10, 20, and 40 microg/mL) at the operation time points (24, 48, and 72 h), the effects of BJOE on proliferative activities were measured by MTT assay. The morphologic changes of cell apoptosis stained with Hochest 33,258 were observed by fluorescence microscope. The effect on the cell apoptosis rate was analyzed by Annexin V-FITC/PI double-labeled flow cytometry. The mRNA expressions of HPV16 E6 and E7 were determined by semi quantitative RT-PCR. The protein expressions of HPV16 E6, E7 oncogene, and specifically interacted p53, Rb antioncogene were stained by immunocytochemical staining (Elivison two-step procedure). RESULTS: (1) The proliferative activities of the Ect1/E6E7 cell and the CaSki cell treated with BJOE at different concentrations (5, 10, 20, and 40 p g/mL) at the operation time points (24, 48, and 72 h) were obviously inhibited, showing dose- and time-dependent manners (P <0.05). (2) Typical changes of apoptosis were observed in both HPV 16 positive cell lines after treated with BJOE. The cell apoptosis rates increased markedly after being cultured with BJOE at different concentrations (5, 10, and 20 microg/mL) for 48 h (P < 0.05). (3) After treated with BJOE at different concentrations (5, 10, and 20 microg/mL) for 48 h, the HPV16 E6 and E7 mRNA relative expressions in both HPV 16 positive cell lines decreased significantly (P < 0.05). (4) After treated with BJOE at different concentrations (5, 10, and 20 microg/ mL), the expressions of HPV16 E6, E7, and mutant p53 protein decreased gradually (P < 0.05), while the Rb protein expression increased gradually (P < 0.05). CONCLUSIONS: BJOE showed obvious in vitro inhibitory effects on HPV type 16 infected cells. Its underlying mechanisms might be possibly associated with down-regulating expressions of HPV16 E6 and E7 oncogenes. PMID- 24483119 TI - [Effect of fengshining capsule on reactive oxygen species-mediated T cell activation and apoptosis of synovium]. AB - OBJECTIVE: To study the effect of intracellular reactive oxygen species (ROS) levels on T cell activation and apoptosis of synovial cells in collagen induced arthritis (CIA) rats, and to explore the mechanism of Fengshining Capsule (FSN) in the treatment of rheumatoid arthritis (RA). METHODS: Sixty rats were randomly divided into the normal control group, the CIA model group, the Tripterygium Poly glycoside Tablet (TPT) group, the low dose FSN group (at the daily dose of 0.33 g/kg), the middle dose FSN group (at the daily dose of 0.66 g/kg), and the high dose FSN group (at the daily dose of 1.32 g/kg), 10 in each group. T lymphocyte subsets were detected by flow cytometry. The content of interferon-gamma (IFN gamma) and interleukin-4 (IL-4) in plasma of rats were detected by ELISA. Its expression of hydroxyl radicals was detected by ultraviolet spectrophotometry. Caspase-3 and Caspase-9 protein expressions were measured by Western blot. RESULTS: Compared with the CIA model group, the levels of ROS were elevated in each dose FSN group (P < 0.01). The level of CD4+ / CD8 was significantly reduced in the middle dose FSN group (P < 0.01). The content of IFN-gamma was obviously lowered in each dose FSN group (P < 0.01), while that of IL-4 was obviously elevated in the high dose FSN group (P < 0.01). Meanwhile, the expression of Caspase-9 and Caspase-3 significantly increased in each dose FSN group (P < 0.05). Besides, the average gray scale of Caspase-9 was significantly higher in the low and middle FSN groups than in the TPT group (P < 0.05, P < 0.01). CONCLUSION: The mechanism of FSN for regulating the immune hyperfunction and inhibiting the proliferation of synovial cells in CIA rats might be associated with up-regulating in vivo ROS levels. PMID- 24483120 TI - [National Natural Science Foundation of China promotes the development of Chinese medicine in China--an analysis of Chinese medicine project funded by National Natural Science Foundation of China in the last decade]. AB - In recent years, projects funded by the Division V III of Health Sciences of the National Natural Science Foundation of China (NSFC) increased steadily, which enhanced the process of modernization of Chinese medicine (CM). We analyzed CM projects funded by NSFC during 2003 -2012, which aimed to provide reference to experts in the CM field. PMID- 24483121 TI - [Activating blood circulation to remove stasis and therapeutic angiogenesis of coronary heart disease]. AB - Therapeutic angiogenesis comes into sight as a new strategy for coronary atherosclerotic heart disease (CAHD). The therapeutic method of activating blood circulation to remove stasis has shown confirmative effect upon both fundamental researches and clinical trials of CAHD. Thus, the new proposition may provide a better treatment plan for CAHD to study on therapeutic angiogenesis with the therapeutic method of activating blood circulation to remove stasis. The author reviewed relevant theories and the latest researches, on the basis of combining diseases identification and syndrome typing, discussed the state quo and achievement of therapeutic angiogenesis in CAHD by Chinese herbal medicines (CHM) of activating blood circulation to remove stasis from fundamental and clinical researches and action mechanisms from standpoints of Chinese herbal compounds, single Chinese herb, effective herbal chemical composition, thus providing references for future researches. PMID- 24483122 TI - [Progress of counter transport of cholesterol and its Chinese medical intervention]. PMID- 24483123 TI - [Progress of treating nasopharyngeal carcinoma by Chinese pharmacy and radiotherapy]. PMID- 24483124 TI - [Modern research progress of fei in Chinese medicine]. PMID- 24483127 TI - Measuring hospital falls prevention safety climate. AB - Abstract The prevention of falls is a key safety priority for hospitals. There are no tools that examine the safety climate from a falls prevention perspective. The aim of this study was to measure the falls prevention safety climate at an Australian metropolitan hospital. The Victorian Safety Climate Survey (SCS) was used to examine the general safety climate, with four items replicated and modified to examine the falls prevention climate. Data (n = 458) for the six SCS domains compared favourably with statewide data. The falls prevention items were correlated with the original items from which they were derived but responses regarding falls prevention tended to be less positive than patient safety more broadly. Priorities for improvement identified using a falls safety climate survey can inform the development of falls prevention strategies and form the basis of a more comprehensive tool to explore the falls prevention safety climate. PMID- 24483128 TI - Metals and organic compounds in the biosynthesis of cannabinoids: a chemometric approach to the analysis of Cannabis sativa samples. AB - Illicit production and trade of Cannabis sativa affect many societies. This drug is the most popular and easy to produce. Important information for the authorities is the production locality and the indicators of a particular production. This work is an attempt to recognise correlations between the metal content in the different parts of C. sativa L., in soils where plants were cultivated and the cannabinoids content, as a potential indicator. The organic fraction of the leaves of Cannabis plants was investigated by GC-FID analysis. In addition, the determination of Cu, Fe, Cr, Mn, Zn, Ca and Mg was realised by spectroscopic techniques (FAAS and GFAAS). In this study, numerous correlations between metal content in plants and soil, already confirmed in previous publications, were analysed applying chemometric unsupervised methods, that is, principal component analysis, factor analysis and cluster analysis, in order to highlight their role in the biosynthesis of cannabinoids. PMID- 24483129 TI - Nanoscale characterization of TiO(2) films grown by atomic layer deposition on RuO(2) electrodes. AB - Topography and leakage current maps of TiO2 films grown by atomic layer deposition on RuO2 electrodes using either a TiCl4 or a Ti(O-i-C3H7)4 precursor were characterized at nanoscale by conductive atomic force microscopy (CAFM). For both films, the leakage current flows mainly through elevated grains and not along grain boundaries. The overall CAFM leakage current is larger and more localized for the TiCl4-based films (0.63 nm capacitance equivalent oxide thickness, CET) compared to the Ti(O-i-C3H7)4-based films (0.68 nm CET). Both films have a physical thickness of ~20 nm. The nanoscale leakage currents are consistent with macroscopic leakage currents from capacitor structures and are correlated with grain characteristics observed by topography maps and transmission electron microscopy as well as with X-ray diffraction. PMID- 24483130 TI - Reproductive outcomes after resection of intrauterine septum. AB - Pre-and post-septal resection reproductive outcomes were compared in women with infertility and prior pregnancy losses operated on for uterine septum from 2003 to 2010. The major indications for surgery were primary infertility (n = 41, 33.1%), secondary infertility (n = 21, 16.9%) and prior pregnancy losses (n = 52, 41.9%). A total of 74 women (59.7%) had an incomplete septum and 50 (40.3%) had a complete septum. Re-hysteroscopy was done in two women (1.6%); 40 (32.3%) women were lost to follow-up after resection; 63 of the remaining 84 (75.0%) conceived and there were a total of 98 pregnancies. A cerclage was done in 28 (32.9%) of these pregnancies. Miscarriage and live birth rates were 92.9% and 4.1% pre- and 32.1% and 61.2% post-resection, respectively. Hysteroscopic septal resection significantly improves reproductive performance in women with infertility and prior pregnancy losses. PMID- 24483131 TI - Affective priming in the valent/neutral categorisation task is due to affective matching, not encoding facilitation: reply to Spruyt. AB - Spruyt obtained an affective congruency effect in a valent/neutral categorisation task, which contrasts with the absence of such an effect in the same task that was reported by Werner and Rothermund. The crucial difference between the two studies is that Spruyt presented only valent primes, whereas Werner and Rothermund presented equal amounts of valent and neutral primes and targets in their experiments. Removing the neutral primes introduces a confound of affective matches with the required response. Affective congruency effects in Spruyt's study can be explained straightforwardly in terms of such an affective matching strategy. To demonstrate the influence of matching strategies in the valent/neutral task without neutral primes, we conducted an experiment in which we induced an affective mismatching strategy. In support of our reasoning, this study revealed an affective incongruency effect in the valent/neutral categorisation task. We conclude that affective congruency as well as incongruency effects in the valent/neutral categorisation task reflect post lexical affective (mis-)matching strategies rather than encoding facilitation. PMID- 24483132 TI - Synchronous laparoscopic low anterior and transanal endoscopic microsurgery total mesorectal resection. AB - BACKGROUND: Laparoscopic low anterior resection (Lap LAR) and total mesorectal excision (TME) is the standard minimally invasive surgery (MIS) for mid and low rectal tumours. However, the pelvic resection in particular for bulky tumour in the narrow male pelvis has always been a challenge for surgeons. Transanal endoscopic microsurgery (TEM) is a well-established technique and synchronous abdomino-perineal excision of rectum (APER) is also a standard procedure. Hence, we applied the same concept to Synchronous Lap LAR and Transanal-TME. MATERIAL AND METHODS: Transanal TME was carried out with TEM instruments and rectoscope. Synchronous Lap LAR was performed and dissection joined to the pelvic part. The specimen was then retrieved via extension of the left lower quadrant port. An anvil was inserted into the proximal colon and intracorporeal transrectal anastomosis was performed to reconstitute the continuity of the bowel. RESULTS: We reported the feasibility of transanal total mesorectal excision (TME) by combination of Synchronous Lap LAR and TEM. We operated on three cases, two male patients and one female patient. We performed an intracorporeal transanal stapled coloanal anastomosis in all of them using the KOL perineal set (Touchstone, Suzhou, Jiangsu, China). The trans-abdominal and transanal dissection can be joined together with ease and accuracy. CONCLUSIONS: Transanal total mesorectal excision (TME) by synchronous Lap LAR and TEM is feasible. We combine operative techniques which are well established, currently available and cost-effective for bulky tumour in the narrow pelvis. PMID- 24483133 TI - The short-term outcomes of conventional and single-port laparoscopic surgery for rectal cancer: a comparative non-randomized study. AB - BACKGROUND: Single-port laparoscopic surgery (SPLS) has evolved as an alternative method to conventional laparoscopic surgery (CLS). The aim of this study is to evaluate the results of SPLS compared to CLS in the treatment of rectal cancer. MATERIAL AND METHODS: Prospectively collected data of patients who had undergone either CLS (n = 194) or SPLS (n = 36) for rectal cancer in the period between 2009 and 2012 were retrospectively analyzed. RESULTS: Median operative time was higher in patients with SPLS (p = 0.01), but the median operative blood loss was significantly lower (p = 0.006). No significant difference was found in intraoperative- (p = 0.14) or postoperative complication rate (p = 0.4) or 30-day mortality (p = 0.62). A tendency towards fewer late complications in the SPLS group was seen (11.1% vs. 25.3%), but the difference was not significant (p = 0.084). CONCLUSION: SPLS for rectal cancer is a safe method in a selected group of patients. Further studies are needed to confirm the benefits of SPLS. Operative time is longer, but the intraoperative blood loss is reduced. PMID- 24483134 TI - Optimization of the Enzymatic Hydrolysis of Lupin (Lupinus) Proteins for Producing ACE-Inhibitory Peptides. AB - Recently, the enzymatic hydrolysis of Lupinus albus and Lupinus angustifolius proteins with pepsin was showed to produce peptides able to inhibit the angiotensin-converting enzyme (ACE). The objective of the present work was to test different hydrolytic enzymes and to investigate three lupin species (L. albus, L. angustifolius, Lupinus luteus) with the final goal of selecting the best enzyme/species combination for an efficient production of ACE-inhibitory peptide mixtures. Pepsin gave peptides with the best IC50 values (mean value on three species 186 +/- 10 MUg/mL), followed by pepsin + trypsin (198 +/- 16 MUg/mL), chymotrypsin (213 +/- 83 MUg/mL), trypsin (405 +/- 54 MUg/mL), corolase PP (497 +/- 32 MUg/mL), umamizyme (865 +/- 230 MUg/mL), and flavourzyme (922 +/- 91 MUg/mL). The three species showed similar activity scales, but after pepsin + trypsin and chymotrypsin treatments, L. luteus peptide mixtures resulted to be significantly the most active. This investigation indicates that lupin proteins may be a valuable source of ACE-inhibitory peptides, which may explain the activity observed in experimental and clinical studies and foresee the application of lupin proteins into functional foods or dietary supplements. PMID- 24483136 TI - Pharmacokinetics, pharmacodynamics and pre-clinical characteristics of ophthalmic drugs that bind VEGF. AB - Drugs that prevent the binding of VEGF to its trans-membrane cognate receptors have revolutionized the treatment of the most important chorioretinal vascular disorders: exudative age-related macular degeneration, diabetic macular edema, and retinal vein occlusions. Pegaptanib, which binds to VEGF165 and longer isoforms, ranibizumab and bevacizumab, which bind all VEGF-A isoforms, and aflibercept, which binds VEGF-A, VEGF-B, and placental growth factor, all bind VEGF165 with high affinity. The drugs have relatively long half-lives (7 to 10 days) after intravitreal depot injections and clinical durations of action that usually exceed 4 weeks. Plasma VEGF concentrations decrease after intravitreal injections of bevacizumab and aflibercept because their systemic half-lives are extended by their Fc fragments. Extensive in vitro and in vivo testing shows that the drugs prevent VEGF-mediated activation of endothelial cells while exhibiting little evidence of toxicity. Further anti-VEGF drug development is on-going. PMID- 24483137 TI - Synthetic antiferromagnetic nanoparticles as potential contrast agents in MRI. AB - We present the top-down synthesis of a novel type of MRI T2 contrast agent with great control over size and shape using a colloidal lithography technique. The resulting synthetic antiferromagnetic nanoparticles (SAF-NPs) yield improved relaxivities compared to superparamagnetic iron oxide alternatives (SPIONs). For T2 weighted imaging, the outer sphere relaxation theory has shown that the sensitivity of a T2 contrast agent is dependent on the particle size with an optimal size that exceeds the superparamagnetic limit of SPIONs. With the use of the interlayer exchange coupling effect, the SAF-NPs presented here do not suffer from this limit. Adjusting the outer sphere relaxation theory for spherical particles to SAF-NPs, we show both theoretically and experimentally that the SAF NP size can be optimized to reach the r2 maximum. With measured r2 values up to 355 s(-1) mM(-1), our SAF-NPs show better performance than commercial alternatives and are competitive with the state-of-the-art. This performance is confirmed in an in vitro MRI study on SKOV3 cells. PMID- 24483135 TI - Topical treatment with probiotic Lactobacillus brevis CD2 inhibits experimental periodontal inflammation and bone loss. AB - BACKGROUND AND OBJECTIVE: An increasing body of evidence suggests that the use of probiotic bacteria is a promising intervention approach for the treatment of inflammatory diseases with a polymicrobial etiology. The objective of this study was to determine whether Lactobacillus brevis CD2 could inhibit periodontal inflammation and bone loss in experimental periodontitis. MATERIAL AND METHODS: Periodontitis was induced by placing a silk ligature around the second maxillary molar of mice treated with L. brevis CD2 (8 * 10(5) CFU in 1 mm(2) lyopatch) or placebo, which were placed between the gingiva and the buccal mucosa near the ligated teeth. The mice were killed after 5 d and bone loss was measured morphometrically, gingival expression of proinflammatory cytokines was determined by quantitative real-time polymerase chain reaction, and CFU counts of periodontitis-associated bacteria were determined after aerobic and anaerobic culture. To determine the role of arginine deiminase released by L. brevis CD2, soluble extracts with or without formamidine (arginine deiminase inhibitor) were tested in in vitro cellular activation assays. RESULTS: Mice topically treated with L. brevis CD2 displayed significantly decreased bone loss and lower expression of tumor necrosis factor, and interleukin-1beta, -6 and -17A as compared to placebo-treated mice. Moreover, L. brevis CD2-treated mice displayed lower counts of anaerobic bacteria but higher counts of aerobic bacteria than placebo-treated mice. In in vitro assays, the anti-inflammatory effects of soluble L. brevis CD2 extracts were heavily dependent on the presence of functional arginine deiminase, an enzyme that can inhibit nitric oxide synthesis. CONCLUSION: These data provide proof-of-concept that the probiotic L. brevis CD2 can inhibit periodontitis through modulatory effects on the host response and the periodontal microbiota. PMID- 24483138 TI - Birth volume and the quality of obstetric care in rural hospitals. AB - BACKGROUND: Childbirth is the most common reason for hospitalization in the United States. Assessing obstetric care quality is critically important for patients, clinicians, and hospitals in rural areas. METHODS: The study used hospital discharge data from the Statewide Inpatient Databases, Healthcare Cost and Utilization Project, Agency for Healthcare Research and Quality, for 9 states (Colorado, Iowa, Kentucky, New York, North Carolina, Oregon, Vermont, Washington, and Wisconsin) to identify all births in rural hospitals with 10 or more births/year in 2002 (N = 94,356) and 2010 (N = 103,880). Multivariate logistic regression was used to assess the relationship between hospital annual birth volume, measured as low (10-110), medium (111-240), medium-high (241-460) or high (>460), and 3 measures of obstetric care quality (low-risk cesarean rates for term, vertex, and singleton pregnancies with no prior cesarean; nonindicated cesarean; and nonindicated induction) and 2 patient safety measures (episiotomy and perineal laceration). RESULTS: The odds of low-risk and nonindicated cesarean were lower in medium-high and high-volume rural hospitals compared with low volume hospitals after controlling for maternal demographic and clinical factors. In low-volume hospitals, odds of labor induction without medical indication were higher than in medium-volume hospitals, but not significantly different from medium-high or high-volume hospitals. Odds of episiotomy were greater in medium high or high-volume hospitals than in low-volume hospitals. The likelihood of perineal laceration did not differ significantly by birth volume. CONCLUSIONS: Obstetric quality and safety outcomes vary significantly across rural hospitals by birth volume. Better performance is not consistently associated with either lower or higher volume facilities. PMID- 24483140 TI - Characterization of a resorbable poly(ester urethane) with biodegradable hard segments. AB - The rapid growth of regenerative medicine and drug delivery fields has generated a strong need for improved polymeric materials that degrade at a controlled rate into safe, non-cytotoxic by-products. Polyurethane thermoplastic elastomers offer several advantages over other polymeric materials including tunable mechanical properties, excellent fatigue strength, and versatile processing. The variable segmental chemistry in developing resorbable polyurethanes also enables fine control over the degradation profile as well as the mechanical properties. Linear aliphatic isocyanates are most commonly used in biodegradable polyurethane formulations; however, these aliphatic polyurethanes do not match the mechanical properties of their aromatic counterparts. In this study, a novel poly(ester urethane) (PEsU) synthesized with biodegradable aromatic isocyanates based on glycolic acid was characterized for potential use as a new resorbable material in medical devices. Infrared spectral analysis confirmed the aromatic and phase separated nature of the PEsU. Uniaxial tensile testing displayed stress-strain behavior typical of a semi-crystalline polymer above its Tg, in agreement with calorimetric findings. PEsU outperformed aliphatic PCL-based polyurethanes likely due to the enhanced cohesion of the aromatic hard domains. Accelerated degradation of the PEsU using 0.1 M sodium hydroxide resulted in hydrolysis of the polyester soft segment on the surface, reduced molecular weight, surface cracking, and a 30% mass loss after four weeks. Calorimetric studies indicated a disruption of the soft segment crystallinity after incubation which corresponded with a drop in initial modulus of the PEsU. Finally, cytocompatibility testing with 3T3 mouse fibroblasts exhibited cell viability on PEsU films comparable to a commercial poly(ether urethane urea) after 24 h followed by 85% cell viability at 72 h. Overall, this new resorbable polyurethane shows strong potential for use in wide range of biomedical applications. PMID- 24483141 TI - Enhanced N2 dissociation on Ru-loaded inorganic electride. AB - Electrides, i.e. salts in which electrons serve as anions, are promising materials for lowering activation energies of chemical reactions. Ab initio simulations are used to investigate the effect of the electron anions in a prototype mayenite-based electride (C12A7:e(-)) on the mechanism of N2 dissociation. It is found that both atomic and molecular nitrogen species chemisorb on the electride surface and become negatively charged due to the electron transfer from the substrate. However, charging alone is not sufficient to promote dissociation of N2 molecules. In the presence of Ru, N2 adsorbs with the formation of a cis-Ru2N2 complex and the N-N bond weakens due to both the electron transfer from the substrate and interaction with Ru. This complex transforms into a more stable trans-Ru2N2 configuration, in which the N2 molecule is dissociated, with the calculated barrier of 116 kJ mol(-1) and the overall energy gain of 72 kJ mol(-1). In contrast, in the case of the stoichiometric mayentie, the cis-Ru2N2 is ~34 kJ mol(-1) more stable than the trans-Ru2N2, while the cis-trans transition has a barrier of 192 kJ mol(-1). Splitting of N2 is promoted by a combination of the strong electron donating power of C12A7:e(-), ability of Ru to capture N2, polarization of Ru clusters, and electrostatic interaction of negatively charged N species with the surface cations. PMID- 24483142 TI - Fitting direct covariance structures by the MSTRUCT modeling language of the CALIS procedure. AB - This paper demonstrates the usefulness and flexibility of the general structural equation modelling (SEM) approach to fitting direct covariance patterns or structures (as opposed to fitting implied covariance structures from functional relationships among variables). In particular, the MSTRUCT modelling language (or syntax) of the CALIS procedure (SAS/STAT version 9.22 or later: SAS Institute, 2010) is used to illustrate the SEM approach. The MSTRUCT modelling language supports a direct covariance pattern specification of each covariance element. It also supports the input of additional independent and dependent parameters. Model tests, fit statistics, estimates, and their standard errors are then produced under the general SEM framework. By using numerical and computational examples, the following tests of basic covariance patterns are illustrated: sphericity, compound symmetry, and multiple-group covariance patterns. Specification and testing of two complex correlation structures, the circumplex pattern and the composite direct product models with or without composite errors and scales, are also illustrated by the MSTRUCT syntax. It is concluded that the SEM approach offers a general and flexible modelling of direct covariance and correlation patterns. In conjunction with the use of SAS macros, the MSTRUCT syntax provides an easy-to-use interface for specifying and fitting complex covariance and correlation structures, even when the number of variables or parameters becomes large. PMID- 24483143 TI - Emerging challenges for the drinking water industry. PMID- 24483144 TI - Syntheses of hydroxamic acid-containing bicyclic beta-lactams via palladium catalyzed oxidative amidation of alkenes. AB - Palladium-catalyzed oxidative amidation has been used to synthesize hydroxamic acid-containing bicyclic beta-lactam cores. Oxidative cleavage of the pendant alkene provides access to the carboxylic acid in one step. PMID- 24483145 TI - "Why me?": Characterological self-blame and continued victimization in the first year of middle school. AB - This study examines the role of characterological self-blame as a unique risk factor associated with other known risk factors (depression and its behavioral and social correlates) for continued victimization across the 1st year of middle school. Relying on a large, ethnically diverse sample of 1,698 young adolescents (M(age) = 11.57, SD = .39; 55% female), self-report assessments in the fall and spring included perceptions of victim status, depressive symptoms, friendships, aggression, and responses to a hypothetical victimization vignette assessing both appraisals (characterological self-blame) and behavioral reactions (helpless responding). In addition to depression, characterological self-blame emerged as the most consistent unique risk factor for subsequent victimization. Mediation analysis suggested that the continuity of victimization between fall and spring could be partially explained by increases in characterological self-blame and depressive symptoms. In addition, cross-lagged panel analyses indicated reciprocal relations between peer victimization and characterological self-blame, suggesting cyclical processes. The study findings suggest that attribution retraining in the beginning of middle school might help prevent escalating risk for continued peer victimization. PMID- 24483147 TI - An integrated analysis of plant and bacterial gene expression in symbiotic root nodules using laser-capture microdissection coupled to RNA sequencing. AB - Rhizobium-induced root nodules are specialized organs for symbiotic nitrogen fixation. Indeterminate-type nodules are formed from an apical meristem and exhibit a spatial zonation which corresponds to successive developmental stages. To get a dynamic and integrated view of plant and bacterial gene expression associated with nodule development, we used a sensitive and comprehensive approach based upon oriented high-depth RNA sequencing coupled to laser microdissection of nodule regions. This study, focused on the association between the model legume Medicago truncatula and its symbiont Sinorhizobium meliloti, led to the production of 942 million sequencing read pairs that were unambiguously mapped on plant and bacterial genomes. Bioinformatic and statistical analyses enabled in-depth comparison, at a whole-genome level, of gene expression in specific nodule zones. Previously characterized symbiotic genes displayed the expected spatial pattern of expression, thus validating the robustness of our approach. We illustrate the use of this resource by examining gene expression associated with three essential elements of nodule development, namely meristem activity, cell differentiation and selected signaling processes related to bacterial Nod factors and redox status. We found that transcription factor genes essential for the control of the root apical meristem were also expressed in the nodule meristem, while the plant mRNAs most enriched in nodules compared with roots were mostly associated with zones comprising both plant and bacterial partners. The data, accessible on a dedicated website, represent a rich resource for microbiologists and plant biologists to address a variety of questions of both fundamental and applied interest. PMID- 24483139 TI - S-layers: principles and applications. AB - Monomolecular arrays of protein or glycoprotein subunits forming surface layers (S-layers) are one of the most commonly observed prokaryotic cell envelope components. S-layers are generally the most abundantly expressed proteins, have been observed in species of nearly every taxonomical group of walled bacteria, and represent an almost universal feature of archaeal envelopes. The isoporous lattices completely covering the cell surface provide organisms with various selection advantages including functioning as protective coats, molecular sieves and ion traps, as structures involved in surface recognition and cell adhesion, and as antifouling layers. S-layers are also identified to contribute to virulence when present as a structural component of pathogens. In Archaea, most of which possess S-layers as exclusive wall component, they are involved in determining cell shape and cell division. Studies on structure, chemistry, genetics, assembly, function, and evolutionary relationship of S-layers revealed considerable application potential in (nano)biotechnology, biomimetics, biomedicine, and synthetic biology. PMID- 24483148 TI - Naphthylamine-rhodamine-based ratiometric fluorescent probe for the determination of Pd2+ ions. AB - A naphthylamine-rhodamine hybrid ratiometric and colorimetric fluorescent probe (RN) was designed and synthesized. RN can identify Pd(2+) ions with high selectivity and sensitivity. Furthermore, the probe can be used to monitor Pd(2+) ions in live mice by fluorescence imaging. PMID- 24483146 TI - Discovery of genetic biomarkers contributing to variation in drug response of cytidine analogues using human lymphoblastoid cell lines. AB - BACKGROUND: Two cytidine analogues, gemcitabine and cytosine arabinoside (AraC), are widely used in the treatment of a variety of cancers with a large individual variation in response. To identify potential genetic biomarkers associated with response to these two drugs, we used a human lymphoblastoid cell line (LCL) model system with extensive genomic data, including 1.3 million SNPs and 54,000 basal expression probesets to perform genome-wide association studies (GWAS) with gemcitabine and AraC IC50 values. RESULTS: We identified 11 and 27 SNP loci significantly associated with gemcitabine and AraC IC50 values, respectively. Eleven candidate genes were functionally validated using siRNA knockdown approach in multiple cancer cell lines. We also characterized the potential mechanisms of genes by determining their influence on the activity of 10 cancer-related signaling pathways using reporter gene assays. Most SNPs regulated gene expression in a trans manner, except 7 SNPs in the PIGB gene that were significantly associated with both the expression of PIGB and gemcitabine cytotoxicity. CONCLUSION: These results suggest that genetic variation might contribute to drug response via either cis- or trans- regulation of gene expression. GWAS analysis followed by functional pharmacogenomics studies might help identify novel biomarkers contributing to variation in response to these two drugs and enhance our understanding of underlying mechanisms of drug action. PMID- 24483150 TI - Successful ABO incompatible renal transplantation following rituximab and DFPP after failed immunoadsorption. AB - Effective antibody removal using PE, DFPP and IA has led to increased access to live donor organs through ABOi RT for patients with chronic kidney disease. However, there have been no head-to-head comparator studies between these modalities, and the choice of technique is usually influenced by cost and institutional preference. We describe the clinical course of a child undergoing ABOi RT, in whom IA without preconditioning with rituximab did not achieve a satisfactory reduction in the antibody titers, who went on to have a successful living donor RT following rituximab and DFPP. PMID- 24483149 TI - Epidemiology of respiratory viral infections in children enrolled in a study of influenza vaccine effectiveness. AB - BACKGROUND: Influenza-like illness (ILI) confers a high annual morbidity in young children. We report the epidemiology of ILIs in children who participated in an influenza vaccine effectiveness study during the 2010 Southern Hemisphere influenza season in Sydney, Australia. METHODS: Children aged 0.5-3 years were prospectively recruited from child care centres (CCCs). We classified them as fully vaccinated, partially vaccinated and unvaccinated according to their receipt of unadjuvanted vaccines containing influenza A (H1N1)pdm09. For 13 weeks commencing 30 July 2010, parents reported when their children developed an ILI (fever >=37.8 degrees C/feverishness plus >=1 respiratory symptom) and collected nose and/or throat swabs for multiplex respiratory virus polymerase chain reaction (PCR) testing. Health impacts were assessed by telephone interview at enrolment and two weeks after each ILI. RESULTS: There were 124 ILIs reported in 105 of 381 enrolled children. Swabs were taken in 117 ILIs: 175 viruses were identified from 103 swabs. Adeno- and rhinoviruses were most frequently identified; 44% of swabs yielded multiple viruses. No virus was associated with more severe symptoms, although rhinovirus-related ILIs lasted longer. Nose swabs had a higher virus detection rate than throat swabs. Influenza-vaccinated children were 1.6 times (P = 0.001) more likely than unvaccinated children to have a non-influenza ILI. CONCLUSION: Adeno- and rhinoviruses were the most common viruses causing ILI. Swabs taken by parents are an effective method for sample collection. Influenza-like illness was more common in children vaccinated against influenza in this observational study, but prior health-seeking behaviour may have contributed to this difference. PMID- 24483152 TI - alpha-Internexin: a novel biomarker for pancreatic neuroendocrine tumor aggressiveness. AB - PURPOSE: We aimed to test whether alpha-internexin could be a molecular biomarker of tumor aggressiveness and prognosis in pancreatic neuroendocrine tumors (PNETs). PATIENTS AND METHODS: Using immunohistochemical staining and Western blot, we detected the expression of alpha-internexin in 350 tumors from 343 patients, of whom 257 were followed up. Methylation of alpha-internexin promoter was examined by bisulfite sequencing to identify the crucial region that determines gene expression. Methylation of gene promoter in tumors was quantitatively measured by denaturing high performance liquid chromatography (DHPLC). We correlated alpha-internexin expression with clinicopathological characteristics. RESULTS: alpha-Internexin was expressed in 53% of 350 PNETs. The reduced expression of alpha-internexin was significantly associated with advanced stage (P < .0001), metastases (P < .0001), and recurrence (P = .003). alpha Internexin expression was found in 57.1% of 212 surviving patients and in 17.1% of 35 deceased patients (P < .0001). Reduced expression of alpha-internexin was associated with shorter overall survival in PNET patients (log rank P < .0001) as well as in patients with noninsulinoma and nonfunctional (NF)-PNETs (log rank P = 0.0073 and P = 0.010, respectively). The crucial region of alpha-internexin promoter (-149 to +96 nucleotides [nt]) was identified, and the hypomethylation of this area in PNETs was significantly associated with gene expression (P = .015). CONCLUSION: alpha-Internexin can be a useful prognostic biomarker for PNETs. PMID- 24483153 TI - A novel point mutation of the human glucocorticoid receptor gene causes primary generalized glucocorticoid resistance through impaired interaction with the LXXLL motif of the p160 coactivators: dissociation of the transactivating and transreppressive activities. AB - CONTEXT: Primary generalized glucocorticoid resistance is a rare genetic disorder characterized by generalized, partial, target-tissue insensitivity to glucocorticoids. The molecular basis of the condition has been ascribed to inactivating mutations in the human glucocorticoid receptor (hGR) gene. OBJECTIVE: The objective of the study was to present three new cases caused by a novel mutation in the hGR gene and to delineate the molecular mechanisms through which the mutant receptor impairs glucocorticoid signal transduction. DESIGN AND RESULTS: The index case (father) and his two daughters presented with increased urinary free cortisol excretion and resistance of the hypothalamic-pituitary adrenal axis to dexamethasone suppression in the absence of clinical manifestations suggestive of Cushing syndrome. All subjects harbored a novel, heterozygous, point mutation (T->G) at nucleotide position 1724 of the hGR gene, which resulted in substitution of valine by glycine at amino acid 575 of the receptor. Compared with the wild-type receptor, the hGRalphaV575G demonstrated a significant (33%) reduction in its ability to transactivate the mouse mammary tumor virus promoter in response to dexamethasone, a 50% decrease in its affinity for the ligand, and a 2.5-fold delay in nuclear translocation. Although it did not exert a dominant negative effect on the wild-type receptor and preserved its ability to bind to DNA, hGRalphaV575G displayed significantly enhanced (~80%) ability to transrepress the nuclear factor-kappaBeta signaling pathway. Finally, the mutant receptor hGRalphaV575G demonstrated impaired interaction with the LXXLL motif of the glucocorticoid receptor-interacting protein 1 coactivator in vitro and in computer-based structural simulation via its defective activation function-2 (AF-2) domain. CONCLUSIONS: The natural mutant receptor hGRalphaV575G causes primary generalized glucocorticoid resistance by affecting multiple steps in the glucocorticoid signaling cascade, including the affinity for the ligand, the time required for nuclear translocation, and the interaction with the glucocorticoid-interacting protein-1 coactivator. PMID- 24483154 TI - Age- and sex-specific reference intervals across life span for insulin-like growth factor binding protein 3 (IGFBP-3) and the IGF-I to IGFBP-3 ratio measured by new automated chemiluminescence assays. AB - CONTEXT: Measurement of IGF-binding protein-3 (IGFBP-3) can aid the diagnosis of GH-related diseases. Furthermore, epidemiological studies suggest that IGFBP-3 and the molar IGF-I to IGFBP-3 ratio are associated with clinical end points like cancer or cardiovascular disease. However, their clinical use is limited by the lack of validated reference intervals. OBJECTIVE: The objective of the study was the establishment of age- and sex-specific reference intervals for IGFBP-3 and the molar IGF-I to IGFBP-3 ratio by newly developed automated immunoassays. SETTING: This was a multicenter study with samples from 11 cohorts from the United States, Canada, and Europe. PARTICIPANTS: A total of 14 970 healthy subjects covering all ages from birth to senescence participated in the study. MAIN OUTCOME MEASURES: Concentrations of IGFBP-3 and the IGF-I to IGFBP-3 ratio as determined by the IDS iSYS IGF-I and IGFBP-3 assays were measured. RESULTS: Both the concentration of IGFBP-3 and the IGF-I to IGFBP-3 ratio are mainly determined by age. IGFBP-3 concentrations increase until the age of 22 years, with a plateau being visible between 15 and 25 years. Determined by the high peripubertal peak in IGF-I, the peak in the IGF-I to IGFBP-3 ratio occurs already around the age of 15 years, with a slightly earlier and higher peak in females. Beyond the age of 60 years, IGFBP-3 concentrations remain higher in females, whereas IGF-I as well as the IGF-I to IGFBP-3 ratio remains significantly higher in males. CONCLUSIONS: We present an extensive set of assay-specific age- and sex adjusted normative data for concentrations of IGFBP-3 and the molar IGF-I to IGFBP-3 ratio and demonstrate distinct sex specific differences across the life span. PMID- 24483155 TI - Improved survival among patients with complicated type 2 diabetes in Denmark: a prospective study (2002-2010). AB - CONTEXT: It is unclear to what extent recent advances in diabetes care have reduced the excess mortality in patients with complicated type 2 diabetes. OBJECTIVE: The aim of this study was to estimate time trends in mortality among patients with complicated type 2 diabetes at the Steno Diabetes Center relative to the general Danish background population. DESIGN, SETTING, AND STUDY PARTICIPANTS: We performed a longitudinal follow-up study from 2002 to 2010 of 5844 patients with type 2 diabetes at the Steno Diabetes Center, Denmark. All cause and cause-specific mortality was identified from the national death register. MAIN OUTCOME MEASURES: Poisson regression was used to model mortality rates by sex, age, age of diabetes onset, and calendar time. RESULTS: A total of 1341 deaths occurred (802 men and 539 women) during 32,913 person-years of follow up. Total mortality rates in the diabetes population decreased by 5.5% (95% confidence interval 2.9%-8.0%) per year in men and by 3.3% (0.0%-6.4%) per year in women. Among men but not women, this decline was significantly steeper than the decline in mortality in the Danish background population (men, -3.0% [-5.6% to -0.4%]; women, -1.4 [-4.6% to 2.0%]). The decline in overall mortality was explained by a decline in cardiovascular mortality for both men and women. CONCLUSION: Overall and cardiovascular mortality have decreased during the last decade among Danish patients with complicated type 2 diabetes, and for men, the decline in mortality was more pronounced than in the general population. PMID- 24483156 TI - Insulin is inversely associated with bone mass, especially in the insulin resistant population: the Korea and US National Health and Nutrition Examination Surveys. AB - BACKGROUND: Insulin is an important osteotropic hormone but may be negatively associated with bone mass after adjustment for body mass index in adolescent populations. However, the association between insulin and bone mass in adults remains unclear. OBJECTIVE: The objective of the study was to investigate whether insulin was associated with bone mass in adults and, if so, whether the association was positive or negative. DESIGN: This study had a cross-sectional design, using data from the Fourth Korea National Health and Nutrition Examination Survey (KNHANES) 2008-2009 and the US National Health and Nutrition Examination Survey (NHANES) 1999-2006. SETTING: The setting for the study was the Korean and US population. PARTICIPANTS: A total of 7271 KNHANES and 3399 NHANES participants were included. MAIN OUTCOME MEASURES: Anthropometric parameters and bone mass data, fasting glucose and insulin, height, weight, and markers related to insulin resistance were measured. RESULTS: After adjusting for confounding factors, there was an inverse relationship between insulin and total body bone mineral content in the KNHANES and NHANES subjects. In a stratified analysis, an association between insulin and bone mass was apparent, especially in the highest homeostatic model of assessment of insulin resistance quartile in the Korean subjects. However, this association was seen only in men in the US subjects. CONCLUSIONS: There is an inverse relationship between insulin and total body bone mineral content after adjustment for confounding factors in Korean and US subjects, especially in the insulin-resistant population. This strongly suggests that the adverse influence of insulin on bone mass likely reflects the effects of other factors associated with insulin resistance rather than being a direct action of insulin itself. PMID- 24483157 TI - The HIV protease inhibitor nelfinavir down-regulates RET signaling and induces apoptosis in medullary thyroid cancer cells. AB - CONTEXT: Mutations of RET tyrosine kinase are associated with the development of medullary thyroid cancer (MTC). The heat shock protein (HSP) 90 chaperone is required for folding and stability of RET mutants. HSP90 is a molecular target for the HIV protease inhibitor nelfinavir (NFV). OBJECTIVE: We hypothesized that treatment with NFV may lead to the inhibition of RET signaling and induction of apoptosis in MTC cells. DESIGN: Two human MTC cell lines, TT and MZ-CRC-1, which harbor endogenous C634W or M918T RET mutations, respectively, were exposed to clinically achievable concentrations of NFV. JC-1 staining and caspase-3 cleavage assays were performed to measure mitochondrial membrane potential and apoptosis. Activation of RET signaling was examined by Western blot. Autophagy was monitored by the detection of the light-chain 3BII. Expression of HSP90 and LC3B were examined in 36 human MTCs. RESULTS: At a therapeutic serum concentration (10 MUM), NFV inhibited the viability of TT and MZ-CRC-1 cells by 55% and 10%, respectively. In a dose-dependent manner, NFV inhibited cyclin D1 and caused caspase-3 cleavage. NFV decreased the level of RET protein and blocked the activation of RET downstream targets (phosphorylated ERK, phosphorylated AKT, and p70S6K/pS6). NFV induced metabolic stress, activated AMP-activated protein kinase and increased autophagic flux. Pharmacological inhibition of autophagy (chloroquine) augmented NFV-inducible cytotoxicity, suggesting that autophagy was protective in NFV-treated cells. NFV led to mitochondrial membrane depolarization and induced both oxidative stress and DNA damage. An antioxidant (n acetylcysteine) attenuated DNA damage and prevented NFV-inducible apoptosis. HSP90 overexpression was found in 17 of 36 human MTCs and correlated with metastases and RET mutations. LC3B was detected in 20 of 36 human MTCs. CONCLUSIONS: NFV has a wide spectrum of activity against MTC cells, and its cytotoxicity can be augmented by inhibiting autophagy. Expression of NFV molecular targets in metastatic MTC suggests that NFV has a potential to become a thyroid cancer therapeutic agent. PMID- 24483158 TI - The effect of PDRN, an adenosine receptor A2A agonist, on the healing of chronic diabetic foot ulcers: results of a clinical trial. AB - CONTEXT: Foot ulcer is the principal cause of hospitalization for patients with diabetes. Polydeoxyribonucleotide (PDRN), an adenosine A2A receptor agonist, improves wound healing in diabetic mice. OBJECTIVE: The aim of this study was to evaluate the effect of PDRN on chronic ulcer healing in patients with diabetes. DESIGN AND SETTING: This randomized, double-blind, placebo-controlled trial, involved two medical centers in Italy. INTERVENTION: Patients with diabetes showing hard-to-heal ulcers (Wagner grade 1 or 2) were randomly assigned to receive placebo (n = 106) or PDRN (n = 110). The treatments (PDRN and placebo) were performed for 8 weeks by intramuscular and perilesional route [corrected]. MAIN OUTCOME MEASURES: The primary outcome was complete ulcer healing. Secondary outcomes were the days needed to complete wound closure and the reepithelialization of wound surface (as percentage of the original area). RESULTS: After 8 weeks, 91 placebo and 101 PDRN subjects completed the study. Complete healing was achieved in 18.9% [95% confidence interval (CI) 11.4-26.3] of placebo and in 37.3% (95% CI 28.2-46.3) of PDRN-treated patients (P = .0027). After 8 weeks, PDRN increased the closure of foot ulcers in diabetic subjects (hazard ratio 2.20; 95% CI 1.29-3.75; P = .004). The median time to complete wound healing was 49 days for placebo (range 28-56 d) and 30 days for PDRN treated subjects (range 14-56 d; P = .0027). The median epithelialized area of the ulcers (expressed as percentage) was 49.3% in the placebo and 82.2% in the PDRN group (P < .001). CONCLUSIONS: PDRN facilitates the healing of Wagner 1 or 2 diabetic foot ulcers. PMID- 24483159 TI - A comparison of measured and calculated free 25(OH) vitamin D levels in clinical populations. AB - OBJECTIVE: Our goal was to compare direct quantitation of circulating free 25 hydroxyvitamin D (25(OH)D)levels to calculated free 25(OH)D levels and their relationships to intact PTH (iPTH), a biomarker of 25(OH)D effect, in humans with a range of clinical conditions. PATIENTS AND METHODS: Serum samples and clinical data were collected from 155 people: 111 without cirrhosis or pregnancy (comparison group), 24 cirrhotic patients with albumin <2.9 g/dL, and 20 pregnant women (second and third trimester). Total 25(OH)D (LC/MS/MS), free 25(OH)D (immunoassay), vitamin D binding protein (DBP) (immunoassay), albumin, and iPTH (immunoassay) were measured. RESULTS: Total 25(OH)D, DBP, and albumin were lowest in patients with cirrhosis, but measured free 25(OH)D was highest in this group (P < .001). DBP was highest in pregnant women (P < .001), but measured free 25(OH)D did not differ from the comparison group. Calculated free 25(OH)D was positively correlated with measured free 25(OH)D (P < .0001) but explained only 13% of the variability with calculated values higher than measured. African Americans had lower DBP than other ethnic populations within all clinical groups (P < .03), and differences between measured and calculated free 25(OH)D were greatest in African Americans (P < .001). Measured free 25(OH)D was correlated with total 25(OH)D (P < .0001; r(2) = 0.51), but calculated free 25(OH)D was not. Similarly, both measured free 25(OH)D (P < .02) and total 25(OH)D (P < .05) were correlated with iPTH, but calculated free 25(OH)D was not. CONCLUSIONS: Calculated free 25(OH)D levels varied considerably from direct measurements of free 25(OH)D with discrepancies greatest in the data for African Americans. Differences in DBP binding affinity likely contributed to estimation errors between the races. Directly measured free 25(OH)D concentrations were related to iPTH, but calculated estimates were not. Current algorithms to calculate free 25(OH)D may not be accurate. Further evaluation of directly measured free 25(OH)D levels to determine its role in research and clinical management of patients is needed. PMID- 24483161 TI - Cushing's syndrome due to a bronchial ACTH-secreting carcinoid successfully treated with radiofrequency ablation (RFA). AB - CONTEXT: The ectopic production of ACTH is responsible for approximately 10% of cases of Cushing's syndrome. Whenever possible, once hypercortisolemia is under control with medical therapy, the final treatment consists of surgical excision of the tumor. We report a case of a patient with high surgical risk and poor response to medical therapy in which hypercortisolemia has been successfully treated with radiofrequency ablation of the bronchial carcinoid tumor. CASE PRESENTATION: A 43-year-old woman came to our hospital because of severe and rapidly worsening signs and symptoms of hypercortisolism over the previous 3 months. Hormonal tests suggested the presence of Cushing's syndrome due to ectopic ACTH production. Imaging studies detected an 8-mm pulmonary nodule with fluorine-18-fluorodeoxyglucose uptake localized in the middle right lobe. The patient started therapy with ketoconazole with poor response. Middle right lobectomy was indicated but, due to the patient's very high surgical risk, a thermal ablation with radiofrequency of the bronchial nodule was performed. OUTCOMES AND RESULTS: After the procedure, ACTH and cortisol levels dropped and fluorine-18-fluorodeoxyglucose positron emission tomography showed complete response to treatment. Clinical conditions progressively improved, and 6 weeks later, the patient underwent middle lobectomy without complications. Histology showed a 0.7-cm ACTH-producing typical bronchial carcinoid tumor. CONCLUSIONS: Thermal ablation with radiofrequency allows achieving a rapid control of hypercortisolism with subsequent improvement of symptoms. This procedure should therefore be considered as a viable therapeutic option in those cases of bronchial ACTH-secreting tumors in which the surgical approach is initially contraindicated. PMID- 24483160 TI - Autonomous and continuous adaptation of a bihormonal bionic pancreas in adults and adolescents with type 1 diabetes. AB - CONTEXT: A challenge for automated glycemic control in type 1 diabetes (T1D) is the large variation in insulin needs between individuals and within individuals at different times in their lives. OBJECTIVES: The objectives of the study was to test the ability of a third-generation bihormonal bionic pancreas algorithm, initialized with only subject weight; to adapt automatically to the different insulin needs of adults and adolescents; and to evaluate the impact of optional, automatically adaptive meal-priming boluses. DESIGN: This was a randomized controlled trial. SETTING: The study was conducted at an inpatient clinical research center. PATIENTS: Twelve adults and 12 adolescents with T1D participated in the study. INTERVENTIONS: Subjects in each age group were randomized to automated glycemic control for 48 hours with or without automatically adaptive meal-priming boluses. MAIN OUTCOME MEASURES: Mean plasma glucose (PG), time with PG less than 60 mg/dL, and insulin total daily dose were measured. RESULTS: The 48-hour mean PG values with and without adaptive meal-priming boluses were 132 +/ 9 vs 146 +/- 9 mg/dL (P = .03) in adults and 162 +/- 6 vs 175 +/- 9 mg/dL (P = .01) in adolescents. Adaptive meal-priming boluses improved mean PG without increasing time spent with PG less than 60 mg/dL: 1.4% vs 2.3% (P = .6) in adults and 0.1% vs 0.1% (P = 1.0) in adolescents. Large increases in adaptive meal priming boluses and shifts in the timing and size of automatic insulin doses occurred in adolescents. Much less adaptation occurred in adults. There was nearly a 4-fold variation in the total daily insulin dose across all cohorts (0.36-1.41 U/kg . d). CONCLUSIONS: A single control algorithm, initialized only with subject weight, can quickly adapt to regulate glycemia in patients with TID and highly variable insulin requirements. PMID- 24483162 TI - Adverse pregnancy outcome among teenagers: a reality? AB - The objective of this retrospective analysis was to evaluate maternal, fetal and neonatal outcomes in primi-adolescent pregnancies in Kuwait. Case records of primigravidae under 29 years of age, attending the antenatal clinic at our tertiary hospital, between January 2002 and December 2010, were analysed. The study group (up to 19 years of age at first pregnancy) consisted of 3,863 women and the control group (20-29 years of age at first pregnancy) comprised of 4,416 women. Maternal obstetric, fetal and neonatal complications were compared between the groups. Rates of ectopic pregnancy, pre-eclampsia, eclampsia, preterm labour, premature rupture of membrane and caesarean section were significantly higher among adolescents < 15 years of age; the risk then decreased steadily with age and became comparable with the control group after 16 years of age. PMID- 24483163 TI - Aberrant phenotype and transcriptome expression during fiber cell wall thickening caused by the mutation of the Im gene in immature fiber (im) mutant in Gossypium hirsutum L. AB - BACKGROUND: The immature fiber (im) mutant of Gossypium hirsutum L. is a special cotton fiber mutant with non-fluffy fibers. It has low dry weight and fineness of fibers due to developmental defects in fiber secondary cell wall (SCW). RESULTS: We compared the cellulose content in fibers, thickness of fiber cell wall and fiber transcriptional profiling during SCW development in im mutant and its near isogenic wild-type line (NIL) TM-1. The im mutant had lower cellulose content and thinner cell walls than TM-1 at same fiber developmental stage. During 25 ~ 35 day post-anthesis (DPA), sucrose content, an important carbon source for cellulose synthesis, was also significantly lower in im mutant than in TM-1. Comparative analysis of fiber transcriptional profiling from 13 ~ 25 DPA indicated that the largest transcriptional variations between the two lines occurred at the onset of SCW development. TM-1 began SCW biosynthesis approximately at 16 DPA, whereas the same fiber developmental program in im mutant was delayed until 19 DPA, suggesting an asynchronous fiber developmental program between TM-1 and im mutant. Functional classification and enrichment analysis of differentially expressed genes (DEGs) between the two NILs indicated that genes associated with biological processes related to cellulose synthesis, secondary cell wall biogenesis, cell wall thickening and sucrose metabolism, respectively, were significantly up-regulated in TM-1. Twelve genes related to carbohydrate metabolism were validated by quantitative reverse transcription PCR (qRT-PCR) and confirmed a temporal difference at the earlier transition and SCW biosynthesis stages of fiber development between TM-1 and im mutant. CONCLUSIONS: We propose that Im is an important regulatory gene influencing temporal differences in expression of genes related to fiber SCW biosynthesis. This study lays a foundation for cloning the Im gene, elucidating molecular mechanism of fiber SCW development and further genetic manipulation for the improvement of fiber fineness and maturity. PMID- 24483164 TI - Angiotensin-converting enzyme inhibitor captopril reverses the adverse cardiovascular effects of polymerized hemoglobin. AB - AIM: Cell-free hemoglobin-based oxygen carriers (HBOCs) may increase the risk of myocardial infarction and death. We studied the effect of an angiotensin converting enzyme (ACE) inhibitor on HBOC-induced adverse cardiovascular outcomes and elucidated the underlying mechanisms. RESULTS: With a dog cardiopulmonary bypass model, we demonstrated that a high-dose HBOC (3%, w/v) did not reduce-but aggravated-cardiac ischemia/reperfusion injury. Animals administered a high-dose HBOC experienced coronary artery constriction and depression of cardiac function. Exposure of isolated coronary arteries or human umbilical vein endothelial cells to high-dose HBOC caused impaired endothelium-dependent relaxation, increased endothelial cell necrosis/apoptosis, and elevated NAD(P)H oxidase expression (gp91(phox), p47(phox), p67(phox), and Nox1) and reactive oxygen species (ROS) production. All observed adverse outcomes could be suppressed by the ACE inhibitor captopril (100 MUM). Co-incubation with free radical scavenger tempol or NAD(P)H oxidase inhibitor apocynin had no effect on captopril action, suggesting that the positive effects of captopril are ROS- and NAD(P)H oxidase dependent. ACE inhibition by captopril also contributed to these effects. In addition, bioavailable nitrite oxide (NO) reduced by high-dose HBOC was preserved by captopril. Furthermore, HBOC, at concentrations greater than 0.5%, inhibited large conductance Ca(2+)-activated K(+) channel currents in vascular smooth muscle cells in a dose-dependent manner, although captopril failed to improve current activity, providing additional evidence that captopril's effects are mediated by the endothelium, but not by the smooth muscle. INNOVATION AND CONCLUSION: Captopril alleviates high-dose HBOC-induced endothelial dysfunction and myocardial toxicity, which is mediated by synergistic depression of NAD(P)H oxidase subunit overproduction and increases in vascular NO bioavailability. PMID- 24483166 TI - Antibacterial activity of plumbagin derivative-rich Plumbago indica root extracts and chemical stability. AB - The extraction studies and a one-step purification of the crude extract of Plumbago indica using silica-gel vacuum chromatography provided a plumbagin derivative-rich P. indica root extract (PPE). The PPE was standardised to contain total plumbagin derivatives not less than 13% w/w. Antibacterial activities of the standardised PPE and three naphthoquinones, plumbagin, elliptinone and 3,3' biplumbagin, against Propionibacterium acnes, Staphylococcus aureus and Staphylococcus epidermidis were evaluated by using the microdilution assay. The bactericidal activities of the PPE against these bacteria were much stronger than those of elliptinone and 3,3'-biplumbagin and almost equal to those of plumbagin. Stability of the PPE was determined under various conditions through a period of four months. The PPE was stable over a period of four months when stored as a dried powder but only in a well-closed container protected from light under 4 +/- 2 degrees C. PMID- 24483167 TI - The impact of maternal age over forty years on the caesarean section rate: six year experience at a busy district general hospital. AB - A retrospective study over a 6-year period was undertaken to determine the trend in age at booking for antenatal care at West Hertfordshire Hospitals NHS Trust and to investigate the relationship between maternal age at booking for antenatal care and mode of delivery. Between 2006 and 2011, there was an 80% increase in the number of women over the age of 40 years booking for antenatal care. The overall caesarean section rate in this cohort of women increased from 34.6% in 2006 to 53.7% in 2011, comprising of an increase in both elective and emergency caesarean sections. It appears that increasing maternal age may explain a significant proportion of the rising caesarean section rate in our unit. PMID- 24483168 TI - Uroflowmetric assessment in participants with Angelman syndrome. AB - OBJECTIVE: To asses possible bladder dysfunctions and lower urinary tract symptoms (LUTS) in individuals with Angelman syndrome (AS), since remarkable voiding characteristics were found in previous studies on toilet training and incontinence in AS. METHOD: Uroflowmetric analysis, a non-invasive technique to assess the voiding pattern, was conducted in six participants with AS. RESULTS: Pathological uroflow patterns were found in five participants; staccato flows in three participants, interrupted flows in one and both interrupted and staccato flows in another participant. Small quantities or urine were found in four participants, large amounts in one and one participant had normal voided volumes. CONCLUSIONS: Results indicate that different conditions such as dysfunctional voiding are present in AS and future studies should further assess these in greater detail. Possible treatment of LUTS and incontinence includes adequate liquid intake, timed voidings, treatment of constipation, and allowing enough time on toilet to stimulate relaxation. PMID- 24483169 TI - Should we encourage allergen immunotherapy during pregnancy? AB - Primary prevention of allergy is a laudable goal, but one that has unfortunately proven difficult to achieve. Many different strategies have been reported to date, but unequivocal supporting data for any single strategy does not exist. Any successful strategy must lead to immunomodulation and must be encountered very early on life, likely in utero. Reports of early bacterial and farm animal exposures lend supportive data to the concept of immune regulation via early fetal exposure, howeve attempts at clinical applications of this, such as probiotics has not been completely successful. One practical, clinical method for achieving a similar immune modulation to these exposures would be providing atopic women with allergy immunotherapy while pregnant (or perhaps even preconception). Allergy immunotherapy is associated with favorable immune modulation and some data suggest that these changes if produced in mother can influence the atopic status of offspring. PMID- 24483170 TI - Use an overhead projector. AB - The overhead projector is a very useful adjunct to other teaching aids. It is easy to operate, flexible, and the lecturer can work it himself while facing the audience. Transparencies can be produced quickly and simply, and since they are large enough to be studied without viewing equipment, sets of transparencies can be kept in libraries for the benefit of students revising particular subjects. PMID- 24483171 TI - Select medical students. AB - Reliable and rational methods of selecting medical students are necessary if valid decisions are to be made concerning each of the enormous number of ap plications to medical school. Not only academic aptitude but also broader sociolegal concerns must be taken into account. The advantages and disadvantages of aptitude tests, reliance on premedical academic achievement, admissions interview and personality tests are considered, and a plea made for heterogeneity and variety among the criteria used to evaluate candidates. PMID- 24483172 TI - What is a Medical Teacher's Job? AB - Medical teaching is somewhat more complex now than it used to be, especially if one accepts that it should be for the benefit of the learner and not only for the satisfaction of the teacher. Twelve functions which the medical teacher should assume are described. Teachers should feel satisfied if they fulfil only a few of these tasks, because the present educational environment does not greatly help them along this road. PMID- 24483173 TI - Medical sociology. AB - At Guy's Hospital Medical School the student's preconception of the relationship between medicine and society is challenged in a clinical situation and during a series of seminars. By confronting students with their own ideas rather than those of the teacher, learning is facilitated. PMID- 24483174 TI - The Fassa Project-A Medical School without Walls. AB - A combination of a shortage and maldistribution of health manpower and growing public discontent about the quality of care available, associated with heightened expectations, has put a great strain on the health care delivery system of Iran, which even massive importation of foreign doctors has not eased. The Fassa project was conceived to address health needs by training first medical then other health personnel, based on the philosophy of community orientation, problem based learning and student-based curriculum, combined with innovations in staff and student selection and training. This paper gives an account of what was planned and has taken place since the first intake of students in April 1978. Early results seem to indicate that students, no matter how rigid their past educational experience or how passive their learning habits, respond eagerly and most capably when given a chance. PMID- 24483175 TI - For multiple choice questions. AB - Multiple Choice Questions (MCQs) have been used in examinations of some medical schools in the UK for more than 20 years, and for at least as long in the USA. It is rare for a medical student not to meet an MCQ paper at some time in his career, and MCQs are widely used in postgraduate examinations. Most of the current controversy related to MCQ tests is concerned more with the advantages and disadvantages of the various types of question used, the place of the 'don't know' option and the methods by which papers are scored and analysed, than whether the format has a place among assessment methods. Yet it cannot be denied that the topic of MCQs still generates suspicion and antagonism in some quarters, both among students and teachers. It is, therefore, appropriate that we should stand back and consider the technique objectively. PMID- 24483176 TI - Sexualitv in the phvsician-patient relatioiship. AB - Medical school training in sexuality focusses primarily on the problems of the patient. This paper describes a learning module designed to provide the medical student with learning activities which enable him/her to cope with personal sexual attitudes and feelings in regard to the patient. Anecdotes illustrating how students have responded to their increased awareness are included. A questionnaire survey indicated that 93 per cent of the students found the module helpful. PMID- 24483177 TI - Preferred learning style index. AB - In this occasional series, we will be printing evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. PMID- 24483179 TI - Common room. AB - Each issue, someone connected with medical eduuation will present a diary of a week in his or her life. Our first contributor, Richard Wakeford, is not strictly a Medical Teacher; he works for the Regius Professor of Physic and the Dean at the new clinical medical school at Combridge University, monitoring the two-year course there. PMID- 24483180 TI - Audiovisual programmers. AB - The aim of this series is to draw teachers' attention to useful sources of audiovisual programmes, to describe the services they provide, and to highlight some of their recent titles. PMID- 24483182 TI - Courses and conferences. PMID- 24483184 TI - Fast and efficient multitransgenic modification of human pluripotent stem cells. AB - Human pluripotent stem cells (hPSCs) represent a prime cell source for pharmacological research and regenerative therapies because of their extensive expansion potential and their ability to differentiate into essentially all somatic lineages in vitro. Improved methods to stably introduce multiple transgenes into hPSCs will promote, for example, their preclinical testing by facilitating lineage differentiation and purification in vitro and the subsequent in vivo monitoring of respective progenies after their transplantation into relevant animal models. To date, the establishment of stable transgenic hPSC lines is still laborious and time-consuming. Current limitations include the low transfection efficiency of hPSCs via nonviral methods, the inefficient recovery of genetically engineered clones, and the silencing of transgene expression. Here we describe a fast, electroporation-based method for the generation of multitransgenic hPSC lines by overcoming the need for any preadaptation of conventional hPSC cultures to feeder-free conditions before genetic manipulation. We further show that the selection for a single antibiotic resistance marker encoded on one plasmid allowed for the stable genomic (co-)integration of up to two additional, independent expression plasmids. The method thereby enables the straightforward, nonviral generation of valuable multitransgenic hPSC lines in a single step. Practical applicability of the method is demonstrated for antibiotic based lineage enrichment in vitro and for sodium iodide symporter transgene-based in situ cell imaging after intramyocardial cell infusion into explanted pig hearts. PMID- 24483185 TI - High CD56++CD16- natural killer (NK) cells among suboptimal immune responders after four years of suppressive antiretroviral therapy in an African adult HIV treatment cohort. AB - BACKGROUND: Up to 40% of HIV-infected individuals receiving Highly Active Antiretroviral Therapy (HAART) have poor CD4+ T-cell recovery. The role of natural killer (NK) cells in immune recovery during HAART is not well understood. We described the profiles of NK cell subsets and their expression of activating receptor, NKG2D and cytotoxicity receptor NKp46 among suboptimal immune responders to despite four years of suppressive HAART. METHODS: A case control study utilized frozen peripheral blood mononuclear cells (PBMC) from a cohort of HIV-infected adults that initiated HAART in 2004/5, at CD4 < 200 cells/MUl. Cases were 'suboptimal' responders; patients within the lowest quartile of CD4+ T-cell reconstitution, with a median CD4 count increase of 129 (-43-199) cells/MUl (difference between CD4 count at baseline and after 4 years of HAART) and controls were 'super-optimal' responders; patients within the highest quartile of CD4 T-cell reconstitution with a median CD4 count increase of 528 (416-878) cells/MUl). Expression of NK cell lineage markers (CD56+/-CD16+/-) and receptors NKG2D and NKp46, was measured among PBMC from 29 cases of 'suboptimal' responders' and 23 controls of 'super-optimal responders', and compared among 'suboptimal' and 'super-optimal' responders. NK cell populations were compared using the Holm Sidak multiple comparison test and p values < 0.05 were considered statistically significant. Data was analyzed using FLOWJO and GraphPad Prism 6. RESULTS: 'Suboptimal responders' had a higher proportion of cytokine producing CD56(++)CD16(+/-) (CD56bri) NK cells than the 'super-optimal responders' p = 0.017, and CD56(neg) NK cells were lower among suboptimal than super-optimal responders (p = 0.007). The largest NK cell subset, CD56(dim), was comparable among suboptimal responders and 'super-optimal immune responders'. Expression of NKG2D and NKp46 receptors on NK cell subsets (CD56(bri), CD56(neg) and CD56(dim)), was comparable among 'suboptimal' and 'super-optimal' immune responders. CONCLUSIONS: The pro-inflammatory CD56++CD16-- NK cells were higher among 'suboptimal' responders relative to 'super-optimal' responders, despite four years of suppressive HAART. Alteration of NK cell populations could inhibit host immune responses to infections among suboptimal responders. We recommend further analysis of NK cell function among suboptimal immune responders in order to inform targeted interventions to optimize immune recovery among HAART-treated adults. PMID- 24483186 TI - Theranostic nanotechnologies: moving beyond imaging drug localization? PMID- 24483187 TI - New considerations in the preparation of nucleic acid-loaded extracellular vesicles. PMID- 24483188 TI - Galactosylated block copolymers: a versatile nano-based tool for effective intracellular drug delivery? PMID- 24483190 TI - Conference report: 2nd Medicon Valley Inhalation Symposium. AB - 2nd Medicon Valley Inhalation Symposium 16 October 2013, Lund, Sweden The 2nd Medicon Valley Inhalation Symposium was arranged by the Medicon Valley Inhalation Consortium. It was held at the Medicon Village, which is the former AstraZeneca site in Lund, Sweden. It was a 1 day symposium focused on inhaled drug delivery and inhalation product development. 120 delegates listened to 11 speakers. The program was organized to follow the value chain of an inhalation product development. This year there was a focus on inhaled biomolecules. The inhaled delivery of insulin was covered by two presentations and a panel discussion. The future of inhaled drug delivery was discussed together with an overview of the current market situation. Two of the inhalation platforms, capsule inhalers and metered-dose inhalers, were discussed in terms of the present situation and the future opportunities. Much focus was on the regulatory and intellectual aspects of developing inhalation products. The manufacturing of a dry powder inhaler requires precision filling of powder, and the various techniques were presented. The benefits of nebulization and nasal delivery were illustrated with some case studies and examples. The eternal challenge of poor compliance was addressed from an industrial design perspective and some new approaches were introduced. PMID- 24483191 TI - Interview with Richard H Guy by Hannah Coaker. PMID- 24483192 TI - Marked antitumor effect of NK012, a SN-38-incorporating micelle formulation, in a newly developed mouse model of liver metastasis resulting from gastric cancer. AB - BACKGROUND: Gastric cancer with liver metastasis (LM) is associated with poor prognosis due to rapid progression. It is, therefore, important to develop a quantitative and highly reproducible animal model of LM using human gastric cancer cells. METHODS: Cells of a human gastric cancer cell line, HSC-57, were injected into the portal vein to produce LMs. Cells from some of these metastatic foci were expanded in vitro and subsequently implanted into the portal veins of mice. This procedure was repeated nine times. The antitumor effects of CPT-11 and NK012 were compared using the LM model. RESULTS: The potent metastatic clone 57L9 was obtained. NK012 exerted a stronger antitumor effect than CPT-11 against 57L9 cells integrated with the luciferase gene (57L9Luc). The survival rates on day 131 in the 57L9Luc mouse model were 100% and 0% for the NK012 and CPT-11 groups, respectively. CONCLUSION: This 57L9Luc LM model was found to be useful for monitoring the responses to NK012 and CPT-11. PMID- 24483194 TI - Nanoscale particulate systems for multidrug delivery: towards improved combination chemotherapy. AB - While combination chemotherapy has led to measurable improvements in cancer treatment outcomes, its full potential remains to be realized. Nanoscale particles such as liposomes, nanoparticles and polymer micelles have been shown to increase delivery to the tumor site while bypassing many drug resistance mechanisms that limit the effectiveness of conventional therapies. Recent efforts in drug delivery have focused on coordinated, controlled delivery of multiple anticancer agents encapsulated within a single particle system. In this review, we analyze recent progress made in multidrug delivery in three main areas of interest: co-delivery of antineoplastic agents with drug sensitizers, sequential delivery via temporal release particles and simultaneous delivery of multiple agents. Future directions of the field, in light of recent advances with molecularly targeted agents, are suggested and discussed. PMID- 24483193 TI - Effect of naive and radiolabeled rhTRAIL on the cervical cancer xenografts in mice. AB - BACKGROUND: There is a need for novel treatments of advanced cervical cancer. We investigated the utility of recombinant human TNF-related apoptosis-inducing ligand (rhTRAIL), a molecule capable of inducing apoptosis in cancer cells, for the therapy of CasKi cervical cancer xenografts in nude mice. RESULTS: CasKi cells proved to be sensitive in vitro to rhTRAIL with an IC50 of 120 ng/ml. (125)I-tagged rhTRAIL specifically accumulated in CasKi tumors in mice with the highest uptake of 9.4% ID/g at 2 h post-injection. Both naive and 200 uCi (188)Re tagged rhTRAIL administered in the amount of 0.35 mg/kg body weight significantly retarded CasKi tumor growth to the same extent in mice without the side effects of cisplatin chemotherapeutic control. CONCLUSION: rhTRAIL is a promising novel agent for treatment of advanced cervical cancer. PMID- 24483195 TI - New views and insights into intracellular trafficking of drug-delivery systems by fluorescence fluctuation spectroscopy. AB - Biomaterials in the nanometer size range can be engineered for site-specific delivery of drugs after injection into the blood circulation. However, translation of such nanomedicines from the bench to the bedside is still hindered by many extracellular and intracellular barriers. To realize the concept of targeted drug delivery with nanomedicines, research groups are studying intensively the extra- and intra-cellular mechanisms involved as a response to the physicochemical properties of the nanomedicines. In this review, we highlight the contributions of fluorescence fluctuations spectroscopy techniques to better understand, and in turn to bypass, the major hurdles to therapeutic delivery, focusing mostly on the intracellular dynamics of drug-delivery systems. PMID- 24483196 TI - Magnetic therapeutic delivery using navigable agents. AB - For treating cancer in particular, therapeutic agents have evolved in complexity in an effort to enhance targeting efficacy. So far, efforts towards the synthesis alone of new therapeutics have attracted most attention. However, present cancer treatments frequently fail because of severe side effects related to the fact that the drug accumulates in insufficient concentration at the tumor site, while being distributed over healthy tissues and organs. More recently, advanced engineering principles have been considered for the development of platforms and drug-loaded vehicles to deliver payloads to the area to be treated by navigating them using the most direct route in order to improve tumor killing effects while minimizing toxic side effects caused by drug activity in nontargeted regions. If the introduction of engineering and principles of robotics to provide complementary techniques in targeted cancer therapy prove to be beneficial, it could influence future delivery methods and the synthesis of therapeutic carriers. PMID- 24483197 TI - Critical gases for critical issues: CO2 technologies for oral drug delivery. AB - In recent years, CO2-based technologies have gained considerable interest in the pharmaceutical industry for their potential applications in drug formulation and drug delivery. The exploitation of peculiar properties of gases under supercritical conditions has been studied in the last 20 years with mixed results. Promising drug-delivery technologies, based on supercritical CO2, have mostly failed when facing challenges of industrial scaleability and economical viability. Nevertheless, a 'second generation' of processes, based on CO2 around and below critical point has been developed, possibly offering technology-based solutions to some of the current issues of pharmaceutical development. In this review, we highlight the most recent advancements in this field, with a particular focus on the potential of CO2-based technologies in addressing critical issues in oral delivery, and briefly discuss the future perspectives of dense CO2-assisted processes as enabling technologies in drug delivery. PMID- 24483200 TI - The enigma of metformin-associated lactic acidosis. PMID- 24483201 TI - 'True apothecary thy drugs art quick'--are we providing our pain patients the means to self-poison? PMID- 24483202 TI - Diphoterine(r) for alkali splashes to the skin. PMID- 24483203 TI - Water-based solutions are the best decontaminating fluids for dermal corrosive exposures: a mini review--letter to the editor. PMID- 24483204 TI - Evolutionary development of redox regulation in chloroplasts. AB - SIGNIFICANCE: The post-translational modification of thiol groups stands out as a key strategy that cells employ for metabolic regulation and adaptation to changing environmental conditions. Nowhere is this more evident than in chloroplasts-the O2-evolving photosynthetic organelles of plant cells that are fitted with multiple redox systems, including the thioredoxin (Trx) family of oxidoreductases functional in the reversible modification of regulatory thiols of proteins in all types of cells. The best understood member of this family in chloroplasts is the ferredoxin-linked thioredoxin system (FTS) by which proteins are modified via light-dependent disulfide/dithiol (S-S/2SH) transitions. RECENT ADVANCES: Discovered in the reductive activation of enzymes of the Calvin-Benson cycle in illuminated chloroplast preparations, recent studies have extended the role of the FTS far beyond its original boundaries to include a spectrum of cellular processes. Together with the NADP-linked thioredoxin reductase C-type (NTRC) and glutathione/glutaredoxin systems, the FTS also plays a central role in the response of chloroplasts to different types of stress. CRITICAL ISSUES: The comparisons of redox regulatory networks functional in chloroplasts of land plants with those of cyanobacteria-prokaryotes considered to be the ancestors of chloroplasts-and different types of algae summarized in this review have provided new insight into the evolutionary development of redox regulation, starting with the simplest O2-evolving organisms. FUTURE DIRECTIONS: The evolutionary appearance, mode of action, and specificity of the redox regulatory systems functional in chloroplasts, as well as the types of redox modification operating under diverse environmental conditions stand out as areas for future study. PMID- 24483205 TI - Novel clues for ultrasonographic diagnosis of reflux in pregnant women: a pilot study. AB - The aim of the present study was to define some novel radiological clues that may aid in the ultrasonographic diagnosis of gastroesophageal reflux in pregnant women. A total of 84 pregnant women, consisting of 42 reflux patients and 42 controls were included in the study. Reflux and control groups were compared in terms of age and our novel ultrasonographic landmarks related to oesophageal structure. While the two groups did not differ in terms of age, they were significantly different from each other with respect to: single layer, single wall oesophageal thickness; double layer, double wall oesophageal thickness; oesophageal hiatal diameter; perioesophageal fat pad thickness; hypoechogenic single wall muscularis mucosa and lamina propria thickness. Owing to our newly defined radiological clues, ultrasonography may have a 'greater than expected' role in the diagnosis of gastroesophageal reflux in pregnant women. However, further studies must be performed to document the actual diagnostic potential of these radiological tips. PMID- 24483207 TI - Mn-Ni content-dependent structures and electrochemical behaviors of serial Li(1.2)Ni(0.13+x)Co(0.13)Mn(0.54-x)O(2) as lithium-ion battery cathodes. AB - In this paper, a citric acid-assisted sol-gel route has been successfully used for the nanofabrication of serial solid solutions in a chemical formula of Li1.2Ni0.13+xCo0.13Mn0.54-xO2 at the x value of -0.06, -0.03, 0, 0.03, or 0.06. Powdered X-ray diffraction (XRD) results indicate that all the solid solutions possess the well-established structural characteristics for a homogeneous solid solution of Li2MnO3 and LiNi1/3+xCo1/3Mn1/3-xO2 components with an increasing Li2MnO3 content along with the decrease of x value. Scanning electron microscope (SEM) observation and elemental analyses show that these samples are composed of polyhedral nanoparticles with a chemical composition similar to that of the corresponding raw materials. Applied as lithium-ion battery cathodes, the initial Coulombic efficiency, cycling stability, and rate capability of solid solutions are determined by their chemical compositions, giving an optimal x value within the range of -0.03 and 0.03. That is, the variation of x value in the formula Li1.2Ni0.13+xCo0.13Mn0.54-xO2 should exert a great influence on the electrochemical performances of these cathodes. Anyways, these suggest an effective strategy to understand the relationship between the Mn-Ni content dependent crystal structures and electrochemical behaviors of solid solutions. PMID- 24483206 TI - Gas-phase reaction of methyl isothiocyanate and methyl isocyanate with hydroxyl radicals under static relative rate conditions. AB - Gaseous methyl isothiocyanate (MITC), the principal breakdown product of the soil fumigant metam sodium (sodium N-methyldithiocarbamate), is an inhalation exposure concern to persons living near treated areas. Inhalation exposure also involves gaseous methyl isocyanate (MIC), a highly reactive and toxic transformation product of MITC. In this work, gas-phase hydroxyl (OH) radical reaction rate constants of MITC and MIC have been determined using a static relative rate technique under controlled laboratory conditions. The rate constants obtained are 15.36 * 10(-12) cm(3) molecule(-1) s(-1) for MITC and 3.62 * 10(-12) cm(3) molecule(-1) s(-1) for MIC. The average half-lives of MITC and MIC in the atmosphere are estimated to be 15.7 and 66.5 h, respectively. The molar conversion of MITC to MIC for OH radical reactions is 67% +/- 8%, which indicates that MIC is the primary product of the MITC-OH reaction in the gas phase. PMID- 24483208 TI - Dielectric and other properties of polyimide aerogels containing fluorinated blocks. AB - The dielectric and other properties of a series of low-density polyimide block copolymer aerogels have been characterized. Two different anhydride-capped polyimide oligomers were synthesized: one from 2,2-bis(3,4 dicarboxyphenyl)hexafluoropropane dianhydride (6FDA) and 4,4'-oxidianiline (ODA) and the other from biphenyl-3,3',4,4'-tetracarboxylic dianhydride and ODA. The oligomers were combined with 1,3,5-triaminophenoxybenzene to form a block copolymer networked structure that gelled in under 1 h. The polyimide gels were supercritically dried to give aerogels with relative dielectric constants as low as 1.08. Increasing the amount of 6FDA blocks by up to 50% of the total dianhydride decreased the density of the aerogels, presumably by increasing the free volume and also by decreasing the amount of shrinkage seen upon processing, resulting in a concomitant decrease in the dielectric properties. In this study, we have also altered the density independent of fluorine substitution by changing the polymer concentration in the gelation reactions and showed that the change in dielectric due to density is the same with and without fluorine substitution. The aerogels with the lowest dielectric properties and lowest densities still had compressive moduli of 4-8 MPa (40 times higher than silica aerogels at the same density), making them suitable as low dielectric substrates for lightweight antennas for aeronautic and space applications. PMID- 24483209 TI - A hybrid method for provincial scale energy-related carbon emission allocation in China. AB - Achievement of carbon emission reduction targets proposed by national governments relies on provincial/state allocations. In this study, a hybrid method for provincial energy-related carbon emissions allocation in China was developed to provide a good balance between production- and consumption-based approaches. In this method, provincial energy-related carbon emissions are decomposed into direct emissions of local activities other than thermal power generation and indirect emissions as a result of electricity consumption. Based on the carbon reduction efficiency principle, the responsibility for embodied emissions of provincial product transactions is assigned entirely to the production area. The responsibility for carbon generation during the production of thermal power is borne by the electricity consumption area, which ensures that different regions with resource endowments have rational development space. Empirical studies were conducted to examine the hybrid method and three indices, per capita GDP, resource endowment index and the proportion of energy-intensive industries, were screened to preliminarily interpret the differences among China's regional carbon emissions. Uncertainty analysis and a discussion of this method are also provided herein. PMID- 24483211 TI - Solid-supported odorless reagents for the dithioacetalization of aldehydes and ketones. AB - A solid supported, odorless reagent for the dithioacetalization of aldehydes and ketones has been developed. The new reagent provides the dimercaptoalkane equivalent in combination with stoichiometric amounts of immobilized acid and enables the formation of dithianes and dithiolanes from aldehydes without any additives in good to very good yields with high purities. The reaction is chemoselective for aldehydes, but ketones can be reacted to the corresponding dithioketals if an additional Lewis acid such as BF3 is added. PMID- 24483212 TI - Food allergy as defined by component resolved diagnosis. AB - The diagnosis of food allergy, as assessed by skin tests or in vitro tests with allergen extracts, has insufficient diagnostic performance and needs to be confirmed by food challenges. However, the availability of molecular allergens (recombinant or highly purified) for laboratory methods has profoundly changed the diagnostic approach to food allergy. In fact, the allergy diagnosis conducted at the molecular level, which is defined internationally as component resolved diagnosis (CRD), allows to characterize more precisely the sensitization profile of the individual patient, distinguishing the sensitizations to allergens that are strongly associated with a given source (genuine sensitizers) from those to molecules that are common to many sources (panallergens) or cross-react with other components from the same family or from other families. This review provides an update on the allergen molecules from foods, including plant foods and animal foods, and on the techniques to detect them, by means of a single reagent (singleplex) or an array of molecules tested at the same time (multiplex). Such testing offers detailed information on the sensitization profile of patients and enables the physician to suitably manage their allergy. Moreover, identifying the real causative allergens will be crucial when allergen immunotherapy for food allergy will be introduced in the near future. We also address patents concerning food allergens in this review. PMID- 24483213 TI - Externalizing the private experience of pain: a role for co-speech gestures in pain communication? AB - Despite the importance of effective pain communication, talking about pain represents a major challenge for patients and clinicians because pain is a private and subjective experience. Focusing primarily on acute pain, this article considers the limitations of current methods of obtaining information about the sensory characteristics of pain and suggests that spontaneously produced "co speech hand gestures" may constitute an important source of information here. Although this is a relatively new area of research, we present recent empirical evidence that reveals that co-speech gestures contain important information about pain that can both add to and clarify speech. Following this, we discuss how these findings might eventually lead to a greater understanding of the sensory characteristics of pain, and to improvements in treatment and support for pain sufferers. We hope that this article will stimulate further research and discussion of this previously overlooked dimension of pain communication. PMID- 24483214 TI - A profile of farmers and other employed Canadians with chronic back pain: a population-based analysis of the 2009-2010 Canadian community health surveys. AB - PURPOSE: Chronic back disorders (CBDs) are a serious public health issue, both in the general population and among farmers. However, it is not clear whether all individuals with CBD should be treated the same, or if some subpopulations have special needs. This study's purpose was to determine the demographic, socioeconomic, co-morbidity, and other health characteristics of Canadian farmers and nonfarmers with self-reported CBD. METHODS: We performed a secondary analysis of the 2009-2010 Canadian Community Health Survey to develop a profile of adults with CBD comparing farmers (N = 350) to nonfarmer employed persons (N = 11,251). In addition to descriptive analysis, multiple logistic regression was used to control for possible confounding. FINDINGS: Our results indicate that farmers with CBD are significantly more likely to be older, less educated, and more often male and living rurally than nonfarmers with CBD. We found no difference between rates and type of co-morbidities between farmers and nonfarmers. However, the sociodemographic differences between farmers and nonfarmers with CBD may impact the design of effective interventions and have implications for health services planning and health care delivery. The information presented is anticipated to help address the identified need for musculoskeletal disorder prevention in agriculture. PMID- 24483216 TI - One cheer for Scotland. PMID- 24483215 TI - Characteristics of etiological diagnostic workup across the past 10 years in patients with spontaneous intracerebral hemorrhage in a large general hospital. AB - OBJECTIVE: A swift and accurate diagnosis of etiology would lay the foundation of targeted management for patients with spontaneous intracerebral hemorrhage (SICH). It is unclear what the status of diagnostic workup related to etiology is in Chinese hospitals which treat the majority of the hemorrhagic patients in the world. We aim to demonstrate characteristics on diagnostic workup implemented routinely in both departments of Neurology and Neurosurgery in patients with SICH. METHODS: We enrolled patients with SICH from March 2002 to December 2011 from Chengdu stroke registry. Data on diagnostic workup were extracted. RESULTS: A total of 2264 patients diagnosed as SICH with rapid neuroimaging (computed tomography (CT) or magnetic resonance imaging (MRI)) scan were included. Patients in the department of Neurosurgery had a lower median Glasgow Coma Scale (GCS) score and a longer median length of stay. They had a significantly lower proportion of hyperlipidemia and heart disease, but a higher proportion of hypertension, alcohol consumption and history of stroke (all p < 0.05). Following diagnostic workups were more frequently undertaken in the Neurological Department than in the neurosurgical Department: digital subtraction angiography (DSA), plain CT, plain MRI, carotid duplex ultrasound (all p < 0.001). However, computed tomography angiography (CTA), contrast-enhanced MRI, and brain biopsy (all p < 0.001) were implemented more in the Neurosurgical Department. While no difference in the proportion of magnetic resonance angiography (MRA) was found between the two departments, the intracranial vascular imaging (workup contains at least one of CTA, MRA and DSA) was performed more frequently in the Department of Neurosurgery (29.8% vs. 9.1%, p < 0.001). The independent predictors contribute to the implementation of vascular examinations were gender, age, GCS score on admission, department of patients admitted in and the year patients were hospitalized in (all p < 0.05). CONCLUSIONS: Younger patients, females, with severe stroke onset (evaluated by GCS score), admitted in Department of Neurosurgery and hospitalized in recent years had undertaken more examinations on intracranial vascular. It is an urgency to explore a practical scheme of diagnostic workup for the etiology of SICH. PMID- 24483217 TI - How to: organize effective laboratory teaching in medicine. Part 1, purposes. AB - Practical work is alive and well, but very different from the traditional 'exercises' and 'demonstrations' of 20 years ago. In the first of two articles the author describes occasions on which laboratory teaching can be most successfully used, ways in which laboratory instructions can be written and preparatory work organized, together with methods of monitoring progress. Examples are given of ways in which effective laboratory work for medical students can be designed. PMID- 24483218 TI - The Way we Teach: Human Sexuality. AB - Three years ago I was invited to start a course in human sexuality at St George's Hospital Medical School with the support of the Nuffield Foundation. It was based on my four previous years of experience teaching this subject in the USA at the University of Pennsylvania Medical School. The original course at St George's consisted of one whole-day and 11 two-hour sessions, given at weekly intervals for 15 fifth-year medical students during their obstetrics and gynaecology or psychiatry rotation (Stanley 1977). PMID- 24483219 TI - Teaching procedural skills - an overview. AB - This paper provides an overview of various methods that have been developed to help students learn procedural skills. Future issues of Medical Teacher will describe each of the methods in depth. PMID- 24483220 TI - The Problem with POMR. AB - In this article, Dr Michael Simpson argues the case against unquestioning acceptance of problem orientated medical records, in reply to the article which appeared in the last issue of Medicd Teacher (1979, 1, 147-1511. PMID- 24483221 TI - Many hazards, few challenges. AB - Aarhus is the second largest city in Denmark, with a population of245,413. Its university, founded in 1928, was the second to be established in Denmark - over 400 years after the University of Copenhagen was founded in 1497. Following the European tradition, medical education in Denmark is confined to the universities. In the same tradition, there were no formal educational requirements for admission until 1976. PMID- 24483210 TI - Nutrient sensing and signaling in the yeast Saccharomyces cerevisiae. AB - The yeast Saccharomyces cerevisiae has been a favorite organism for pioneering studies on nutrient-sensing and signaling mechanisms. Many specific nutrient responses have been elucidated in great detail. This has led to important new concepts and insight into nutrient-controlled cellular regulation. Major highlights include the central role of the Snf1 protein kinase in the glucose repression pathway, galactose induction, the discovery of a G-protein-coupled receptor system, and role of Ras in glucose-induced cAMP signaling, the role of the protein synthesis initiation machinery in general control of nitrogen metabolism, the cyclin-controlled protein kinase Pho85 in phosphate regulation, nitrogen catabolite repression and the nitrogen-sensing target of rapamycin pathway, and the discovery of transporter-like proteins acting as nutrient sensors. In addition, a number of cellular targets, like carbohydrate stores, stress tolerance, and ribosomal gene expression, are controlled by the presence of multiple nutrients. The protein kinase A signaling pathway plays a major role in this general nutrient response. It has led to the discovery of nutrient transceptors (transporter receptors) as nutrient sensors. Major shortcomings in our knowledge are the relationship between rapid and steady-state nutrient signaling, the role of metabolic intermediates in intracellular nutrient sensing, and the identity of the nutrient sensors controlling cellular growth. PMID- 24483222 TI - Letters. PMID- 24483226 TI - Wellcome audiovisual presentations. PMID- 24483225 TI - Summary statement of student learning progress. AB - In this series, we will be printing evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to use or adapt such instruments for your own purposes. The feature in this issue has been prepared by R. G. McAuley, MD, Chairman, Undergraduate MD Program, McMaster University, Faculty of Health Sciences, 1200 Main Street West, Hamilton, Ontario L8S 459, Canada, from whom further information is available. PMID- 24483227 TI - Computer simulated patient management. PMID- 24483231 TI - Relationship between problems related to child late effects and parent burnout after pediatric hematopoietic stem cell transplantation. AB - A few studies have indicated that parents' reactions to a child's serious disease may entail long-term stress for the parents. However, further knowledge of its consequences is valuable. The aim of the study was to investigate the occurrence of burnout in a Swedish national sample of parents of children who had undergone HSCT and survived. Burnout (Shirom-Melamed Burnout Questionnaire) and estimations of the child's health status (Lansky/Karnofsky estimations and study-specific questions) were self-reported by 159 mothers and 123 fathers. In addition, physicians made estimations of the child's health status (Lansky/Karnofsky estimations). Nonparametric tests revealed that burnout symptoms occurred more often among fathers of children who had undergone transplantation within the last five yr compared to fathers of children with no history of serious disease (34.4% vs. 19.9%). Burnout among mothers and fathers was associated with the child's number and severity of health impairments up to five yr after the child underwent HSCT (Spearman's rho for mothers 0.26-0.36 and for fathers 0.36-0.61). In conclusion, chronic stress in parents after a child's HSCT seems to abate eventually. However, parents should be monitored and offered adequate support when needed. Moreover, the situation of fathers in the often mother-dominated pediatric setting should receive more attention in research as well as in the clinic. PMID- 24483230 TI - Increased cortical extracellular adenosine correlates with seizure termination. AB - OBJECTIVE: Seizures are currently defined by their electrographic features. However, neuronal networks are intrinsically dependent on neurotransmitters of which little is known regarding their periictal dynamics. Evidence supports adenosine as having a prominent role in seizure termination, as its administration can terminate and reduce seizures in animal models. Furthermore, microdialysis studies in humans suggest that adenosine is elevated periictally, but the relationship to the seizure is obscured by its temporal measurement limitations. Because electrochemical techniques can provide vastly superior temporal resolution, we test the hypothesis that extracellular adenosine concentrations rise during seizure termination in an animal model and humans using electrochemistry. METHODS: White farm swine (n = 45) were used in an acute cortical model of epilepsy, and 10 human epilepsy patients were studied during intraoperative electrocorticography (ECoG). Wireless Instantaneous Neurotransmitter Concentration Sensor (WINCS)-based fast scan cyclic voltammetry (FSCV) and fixed potential amperometry were obtained utilizing an adenosine specific triangular waveform or biosensors, respectively. RESULTS: Simultaneous ECoG and electrochemistry demonstrated an average adenosine increase of 260% compared to baseline, at 7.5 +/- 16.9 s with amperometry (n = 75 events) and 2.6 +/- 11.2 s with FSCV (n = 15 events) prior to electrographic seizure termination. In agreement with these animal data, adenosine elevation prior to seizure termination in a human patient utilizing FSCV was also seen. SIGNIFICANCE: Simultaneous ECoG and electrochemical recording supports the hypothesis that adenosine rises prior to seizure termination, suggesting that adenosine itself may be responsible for seizure termination. Future work using intraoperative WINCS-based FSCV recording may help to elucidate the precise relationship between adenosine and seizure termination. PMID- 24483229 TI - Aetiology, incidence and morphology of the C-shaped root canal system and its impact on clinical endodontics. AB - The C-shaped root canal constitutes an unusual root morphology that can be found primarily in mandibular second permanent molars. Due to the complexity of their structure, C-shaped root canal systems may complicate endodontic interventions. A thorough understanding of root canal morphology is therefore imperative for proper diagnosis and successful treatment. This review aims to summarize current knowledge regarding C-shaped roots and root canals, from basic morphology to advanced endodontic procedures. To this end, a systematic search was conducted using the MEDLINE, BIOSIS, Cochrane Library, EMBASE, Google Scholar, Web of Science, PLoS and BioMed Central databases, and many rarely cited articles were included. Furthermore, four interactive 3D models of extracted teeth are introduced that will allow for a better understanding of the complex C-shaped root canal morphology. In addition, the present publication includes an embedded best-practice video showing an exemplary root canal procedure on a tooth with a pronounced C-shaped root canal. The survey of this unusual structure concludes with a number of suggestions concerning future research efforts. PMID- 24483232 TI - Striga hermonthica MAX2 restores branching but not the Very Low Fluence Response in the Arabidopsis thaliana max2 mutant. AB - Seed germination of Striga spp. (witchweeds), one of the world's most destructive parasitic weeds, cannot be induced by light but is specifically induced by strigolactones. It is not known whether Striga uses the same components for strigolactone signaling as host plants, whether it has endogenous strigolactone biosynthesis and whether there is post-germination strigolactone signaling in Striga. Strigolactones could not be detected in in vitro grown Striga, while for host-grown Striga, the strigolactone profile is dominated by a subset of the strigolactones present in the host. Branching of in vitro grown Striga is affected by strigolactone biosynthesis inhibitors. ShMAX2, the Striga ortholog of Arabidopsis MORE AXILLARY BRANCHING 2 (AtMAX2) - which mediates strigolactone signaling - complements several of the Arabidopsis max2-1 phenotypes, including the root and shoot phenotype, the High Irradiance Response and the response to strigolactones. Seed germination of max2-1 complemented with ShMAX2 showed no complementation of the Very Low Fluence Response phenotype of max2-1. Results provide indirect evidence for ShMAX2 functions in Striga. A putative role of ShMAX2 in strigolactone-dependent seed germination of Striga is discussed. PMID- 24483233 TI - Bladder acellular matrix conjugated with basic fibroblast growth factor for bladder regeneration. AB - Basic fibroblast growth factor (bFGF) plays an important role in wound repair and tissue regeneration. Considerable research has been focused on the exploration of bFGF delivery systems for maintaining efficient local concentration at the injury sites. In this study, bFGF was chemically crosslinked to the bladder acellular matrix (BAM) to create specific binding between bFGF and BAM. The BAM scaffold conjugated with bFGF (CL-BAM/bFGF) could bind more bFGF and achieve controlled release of bFGF, which promoted human fibroblasts to proliferate in vitro and accelerated cellularization and vascularization after subcutaneous implantation. Using the rat bladder reconstruction model, the CL-BAM/bFGF group showed better tissue regeneration compared with the other groups. In summary, CL-BAM/bFGF could prevent the diffusion of bFGF from BAM and maintain its activity. Thus, the scaffold conjugated with growth factor systems could be an effective way for maintaining local therapy dosage at the target site in wound repair and tissue regeneration. PMID- 24483234 TI - Does elevating the fetal head prior to delivery using a fetal pillow reduce maternal and fetal complications in a full dilatation caesarean section? A prospective study with historical controls. AB - A caesarean section at full dilatation (CSFD) can be technically demanding and has consistent association with increased intraoperative trauma. There is evidence that the incidence of caesarean sections at full dilation is on the rise. We report on a prospective study of 50 women undergoing CSFD using a fetal pillow (FP) to elevate the fetal head. Data were compared with historical controls of 124 women without FP use on uterine extensions, uterine incision delivery interval, blood loss, need for transfusion, operating time, length of stay, intensive care unit admission. The FP elevated the fetal head in all 50 women (p < 0.001). We found that patients in the FP group had a lower incidence of extensions (p = 0.03), shorter operating time (p < 0.001), uterine incision to delivery interval (p < 0.001) and shorter length of hospital stay (p < 0.001). Blood loss > 1,000 ml and admission to ICU was also lower but were not statistically significant. There were no significant differences in the fetal complications studied, APGAR scores, admission to neonatal intensive care unit, seizures, neonatal injury or death. PMID- 24483235 TI - Validation and implementation of a method for microarray gene expression profiling of minor B-cell subpopulations in man. AB - BACKGROUND: This report describes a method for the generation of global gene expression profiles from low frequent B-cell subsets by using fluorescence activated cell sorting and RNA amplification. However, some of the differentiating compartments involve a low number of cells and therefore it is important to optimize and validate each step in the procedure. METHODS: Normal lymphoid tissues from blood, tonsils, thymus and bone marrow were immunophenotyped by the 8-colour Euroflow panel using multiparametric flow cytometry. Subsets of B-cells containing cell numbers ranging from 800 to 33,000 and with frequencies varying between 0.1 and 10 percent were sorted, subjected to mRNA purification, amplified by the NuGEN protocol and finally analysed by the Affymetrix platform. RESULTS: Following a step by step strategy, each step in the workflow was validated and the sorting/storage conditions optimized as described in this report. First, an analysis of four cancer cell lines on Affymetrix arrays, using either 100 ng RNA labelled with the Ambion standard protocol or 1 ng RNA amplified and labelled by the NuGEN protocol, revealed a significant correlation of gene expressions (r >= 0.9 for all). Comparison of qPCR data in samples with or without amplification for 8 genes showed that a relative difference between six cell lines was preserved (r >= 0.9). Second, a comparison of cells sorted into PrepProtect, RNAlater or directly into lysis/binding buffer showed a higher yield of purified mRNA following storage in lysis/binding buffer (p < 0.001). Third, the identity of the B-cell subsets validated by the cluster of differentiation (CD) membrane profile was highly concordant with the transcriptional gene expression (p-values <0.001). Finally, in normal bone marrow and tonsil samples, eight evaluated genes were expressed in accordance with the biology of lymphopoiesis (p-values < 0.001), which enabled the generation of a gene-specific B-cell atlas. CONCLUSION: A description of the implementation and validation of commercially available kits in the laboratory has been examined. This included steps for cell sorting, cell lysis/stabilization, RNA isolation, RNA concentration and amplification for microarray analysis. The workflow described in this report will enable the generation of microarray data from minor sorted B-cell subsets. PMID- 24483236 TI - Rapamycin inhibits acrolein-induced apoptosis by alleviating ROS-driven mitochondrial dysfunction in male germ cells. AB - OBJECTIVES: Acrolein (Acr) is a highly reactive alpha, beta-unsaturated aldehyde, which can induce reactive oxygen species (ROS) generation. Several factors, including lipid peroxidation, clinical use of cyclophosphamide, fried foods, automobile exhausts, smoking and aging can increase its concentration in blood serum. Mounting evidence has suggested that Acr-induced ROS might reduce quality of sperm. Thus, the aim of this study was to examine reproductive toxicity of Acr caused ROS in vitro and find a means to alleviate it. MATERIALS AND METHODS: We investigated the effects of Acr on male germ cell (MGC)-derived GC-1 cells in vitro. Dihydroethidium and DCFH-DA fluorescent dyes were used to determine generation of intracellular ROS. RESULTS: We found that Acr induced ROS generation, which was accompanied by reduced Bcl2/Bax ratio, substantial decline in mitochondrial membrane potential, and further promoted apoptosis of MGCs. Furthermore, Rapamycin was capable of alleviating Acr-induced ROS, reducing ROS induced apoptosis by increasing ratio of Bcl2/Bax mRNA and proteins, and protecting MGC mitochondrial membranes. CONCLUSION: Rapamycin inhibited Acr induced apoptosis by alleviating ROS-driven mitochondrial dysfunction in MGCs. PMID- 24483237 TI - Revised and updated nomenclature for highly pathogenic avian influenza A (H5N1) viruses. AB - The divergence of the hemagglutinin gene of A/goose/Guangdong/1/1996-lineage H5N1 viruses during 2011 and 2012 (807 new sequences collected through December 31, 2012) was analyzed by phylogenetic and p-distance methods to define new clades using the pre-established nomenclature system. Eight new clade designations were recommended based on division of clade 1.1 (Mekong River Delta), 2.1.3.2 (Indonesia), 2.2.2 (India/Bangladesh), 2.2.1.1 (Egypt/Israel), and 2.3.2.1 (Asia). A simplification to the previously defined criteria, which adds a letter rather than number to the right-most digit of fifth-order clades, was proposed to facilitate this and future updates. PMID- 24483239 TI - Hydrogel containing nanoparticle-stabilized liposomes for topical antimicrobial delivery. AB - Adsorbing small charged nanoparticles onto the outer surfaces of liposomes has become an effective strategy to stabilize liposomes against fusion prior to "seeing" target bacteria, yet allow them to fuse with the bacteria upon arrival at the infection sites. As a result, nanoparticle-stabilized liposomes have become an emerging drug delivery platform for treatment of various bacterial infections. To facilitate the translation of this platform for clinical tests and uses, herein we integrate nanoparticle-stabilized liposomes with hydrogel technology for more effective and sustained topical drug delivery. The hydrogel formulation not only preserves the structural integrity of the nanoparticle stabilized liposomes, but also allows for controllable viscoeleasticity and tunable liposome release rate. Using Staphylococcus aureus bacteria as a model pathogen, we demonstrate that the hydrogel formulation can effectively release nanoparticle-stabilized liposomes to the bacterial culture, which subsequently fuse with bacterial membrane in a pH-dependent manner. When topically applied onto mouse skin, the hydrogel formulation does not generate any observable skin toxicity within a 7-day treatment. Collectively, the hydrogel containing nanoparticle-stabilized liposomes hold great promise for topical applications against various microbial infections. PMID- 24483240 TI - Psychrophilin E, a new cyclotripeptide, from co-fermentation of two marine alga derived fungi of the genus Aspergillus. AB - Chemical investigation of the mycelial extract of a mixed culture of two marine alga-derived fungal strains of the genus Aspergillus has yielded one new cyclotripeptide, psychrophilin E (1), the recently reported oxepin-containing alkaloids, protuboxepin A (2) and oxepinamide E (3), together with three other polyketide derivatives (4-6). The chemical structure and relative and absolute configurations of psychrophilin E (1) were unambiguously established based on HRMS, 1D, 2D NMR and chiral-phase HPLC analysis of its hydrolysate. All the isolated compounds were assessed for their anti-proliferative activity against four different human cancer cell lines and some of them revealed selective activities. PMID- 24483241 TI - Effect of manure application on abundance of antibiotic resistance genes and their attenuation rates in soil: field-scale mass balance approach. AB - The development of models for understanding antibiotic resistance gene (ARG) persistence and transport is a critical next step toward informing mitigation strategies to prevent the spread of antibiotic resistance in the environment. A field study was performed that used a mass balance approach to gain insight into the transport and dissipation of ARGs following land application of manure. Soil from a small drainage plot including a manure application site, an unmanured control site, and an adjacent stream and buffer zone were sampled for ARGs and metals before and after application of dairy manure slurry and a dry stack mixture of equine, bovine, and ovine manure. Results of mass balance suggest growth of bacterial hosts containing ARGs and/or horizontal gene transfer immediately following slurry application with respect to ermF, sul1, and sul2 and following a lag (13 days) for dry-stack-amended soils. Generally no effects on tet(G), tet(O), or tet(W) soil concentrations were observed despite the presence of these genes in applied manure. Dissipation rates were fastest for ermF in slurry-treated soils (logarithmic decay coefficient of -3.5) and for sul1 and sul2 in dry-stack-amended soils (logarithmic decay coefficients of -0.54 and 0.48, respectively), and evidence for surface and subsurface transport was not observed. Results provide a mass balance approach for tracking ARG fate and insights to inform modeling and limiting the transport of manure-borne ARGs to neighboring surface water. PMID- 24483238 TI - Oxidative stress, redox signaling, and autophagy: cell death versus survival. AB - SIGNIFICANCE: The molecular machinery regulating autophagy has started becoming elucidated, and a number of studies have undertaken the task to determine the role of autophagy in cell fate determination within the context of human disease progression. Oxidative stress and redox signaling are also largely involved in the etiology of human diseases, where both survival and cell death signaling cascades have been reported to be modulated by reactive oxygen species (ROS) and reactive nitrogen species (RNS). RECENT ADVANCES: To date, there is a good understanding of the signaling events regulating autophagy, as well as the signaling processes by which alterations in redox homeostasis are transduced to the activation/regulation of signaling cascades. However, very little is known about the molecular events linking them to the regulation of autophagy. This lack of information has hampered the understanding of the role of oxidative stress and autophagy in human disease progression. CRITICAL ISSUES: In this review, we will focus on (i) the molecular mechanism by which ROS/RNS generation, redox signaling, and/or oxidative stress/damage alter autophagic flux rates; (ii) the role of autophagy as a cell death process or survival mechanism in response to oxidative stress; and (iii) alternative mechanisms by which autophagy-related signaling regulate mitochondrial function and antioxidant response. FUTURE DIRECTIONS: Our research efforts should now focus on understanding the molecular basis of events by which autophagy is fine tuned by oxidation/reduction events. This knowledge will enable us to understand the mechanisms by which oxidative stress and autophagy regulate human diseases such as cancer and neurodegenerative disorders. PMID- 24483244 TI - A prospective cohort study of pain with intrauterine device insertion among women with and without vaginal deliveries. AB - The purpose of this prospective cohort study was to compare pain during IUD insertion between women with a history of vaginal delivery and women without a history of vaginal delivery. First-time IUD users chose either the CuT380A or the levonorgestrel IUS. We enrolled 49 women with previous vaginal delivery and 49 women with no history of vaginal delivery (either only caesarean deliveries or nulliparous). The mean pain score on a 0-100 mm visual analog scale during insertion in the vaginal delivery group was 34.7 (SD 31.6) compared with 51.2 (SD 29.2) in the group without previous vaginal delivery (p = 0.009). In multivariable analysis controlling for age, breast-feeding, expected pain, baseline anxiety, insertion timing (6-12 weeks postpartum, 2-4 weeks post abortion or interval), and insertion difficulty, history of vaginal delivery was associated with a 15.5 point reduction in pain (95% CI, -27.4, -3.7). Other significant predictors of pain were 'expected pain' and 'insertion difficulty'. PMID- 24483245 TI - The balance of intestinal Foxp3+ regulatory T cells and Th17 cells and its biological significance. AB - Balanced mucosal immunity in the gut is critical for host homeostasis and defense. Th17 cells are a subset of IL-17-producing CD4+ T cells, which play a crucial role in clearing pathogens during host defense reactions and in inducing tissue inflammation in autoimmune diseases. CD4+CD25+ Foxp3+ regulatory T cells (Tregs) are recognized as one of the major regulatory factors in immune tolerance and inflammatory responses. Since both Tregs and Th17 cells pertain to the gut immune system, their inter-regulation and balance represent a novel mechanism for maintaining the intestinal immune and inflammatory homeostasis. Accordingly, the imbalance and dysregulation of Tregs and Th17 cells in the intestine is closely associated with intestinal autoimmune disorders like the inflammatory bowel diseases. In this review, we discuss the characteristics of gut Tregs and Th17 cells and their role in gut diseases. PMID- 24483246 TI - The use of multiple qualitative methods to characterize communication events between physicians and nurses. AB - Despite the importance of communication to patient safety in hospital settings, we know surprisingly little about communication patterns between physicians and nurses, particularly on general medical-surgical units. Poor communication is the leading cause of preventable adverse events in hospitals, as well as a major root cause of sentinel events. The literature provides little guidance on what qualitative methods are best for capturing different types of communication events and patterns. The purpose of this study was to develop a methodology for identifying and characterizing communication events between physicians and nurses to better understand communication patterns on general medical-surgical units. We used a sequential qualitative mixed method design beginning with general observation, progressing to shadowing and focus groups of physicians and nurses who worked on two medical-surgical units at one academically affiliated U.S. Department of Veterans Affairs (VA) hospital. Each data collection method (observation, shadowing, and focus groups) had its own advantages and disadvantages for capturing communication events and patterns. Through observation we were able to see the "what": communication activities. Shadowing was most useful for understanding "how" physicians and nurses communicated. Focus groups helped answer "why" certain patterns emerged and allowed us to further explore communication events within a group setting. By using all three methods we were able to more thoroughly characterize communication events than by using a single method alone, providing a more holistic picture of how communication occurs on an inpatient medical-surgical unit. PMID- 24483247 TI - Enantioselective cycloaddition of munchnones onto [60]fullerene: organocatalysis versus metal catalysis. AB - Novel chiral catalytic systems based on both organic compounds and metal salts have been developed for the enantioselective [3 + 2] cycloaddition of munchnones onto fullerenes and olefins. These two different approaches proved to be efficient and complementary in the synthesis of optically active pyrrolino[3,4:1,2][60]fullerenes with high levels of enantiomeric excess and moderate to good conversions. Further functionalization of the pyrrolinofullerene carboxylic acid derivatives has been carried out by esterification and amidation reactions. PMID- 24483248 TI - Development of barley (Hordeum vulgare L.) lines with altered starch granule size distribution. AB - Microscope analysis of starches prepared from 139 barley genotypes identified a Japanese genotype, Kinai Kyoshinkai-2 (KK-2), with altered starch granule size distribution. Compared to normal barley starch, KK-2 produced consistently higher volumes of starch granules with 5-15 MUm diameter and reduced volumes of starch granules with >15 MUm diameter when grown in different environments. A cross between KK-2 and normal starch cultivar CDC Kendall was made and led to the production of 154 F5 lines with alterations to the normal 7:3:1 distribution for A-:B-:C-type starch granule volumes. Three F5 lines showed unimodal starch granule size distribution due to apparent lack of very small (<5.0 MUm diameter) C-type starch granules, but the phenotype was accompanied by reduced grain weight and total starch concentration. Five F5 lines produced a significantly larger population of large (>15 MUm diameter) A-type starch granules as compared to normal starch and showed on average a 10:4:1 distribution for A-:B-:C-type starch granule volumes. The unusual starch phenotypes displayed by the F5 lines confirm starch granule size distribution in barley can be genetically altered. PMID- 24483249 TI - Cell cycle regulation of homologous recombination in Saccharomyces cerevisiae. AB - Homologous recombination (HR) contributes to maintaining genome integrity by facilitating error-free repair of DNA double-strand breaks (DSBs) primarily during the S and G2 phases of the mitotic cell cycle, while nonhomologous end joining (NHEJ) is the preferred pathway for DSB repair in G1 phase. The decision to repair a DSB by NHEJ or HR is made primarily at the level of DSB end resection, which is inhibited by the Ku complex in G1 and promoted by the Sae2 and Mre11 nucleases in S/G2 . The cell cycle regulation of HR is accomplished both at the transcription level and at the protein level through post translational modification, degradation and subcellular localization. Cyclin dependent kinase Cdc28 plays an established key role in these events, while the role of transcriptional regulation and protein degradation are less well understood. Here, the cell cycle regulatory mechanisms for mitotic HR in Saccharomyces cerevisiae are reviewed, and evolutionarily conserved principles are highlighted. PMID- 24483250 TI - A concise synthesis of carolacton. AB - A synthesis of carolacton, a myxobacterial natural product that has profound effects on Streptococcus mutans biofilms, is reported. The synthesis proceeds via a longest linear sequence of 14 steps from an Evans beta-ketoimide and enabled preliminary evaluations of the effects of late-stage intermediates on S. mutans biofilms. These studies suggest that further investigations into carolacton's structure-function relationships are warranted. PMID- 24483251 TI - The bond strength of endodontic sealers to root dentine exposed to different gutta-percha solvents. AB - AIM: To evaluate the effects of various gutta-percha solvents on the push-out bond strength of several root canal sealers on root dentine. METHODOLOGY: The root canals of 210 single-rooted human teeth were prepared with the ProTaper System (Dentsply Maillefer, Ballaigues, Switzerland) up to a master apical file size of F4, and the following variables evaluated for bond strength: solvent type (chloroform, eucalyptol and orange oil), time (2 and 5 min), sealer type (AH Plus, MTA Fillapex and Sealapex) and root thirds (coronal, middle and apical). After canal filling, three 1-mm-thick slices were obtained from each root sample, and the bond strength of the test materials was measured using a push-out test set-up at a cross-head speed of 1 mm min(-1) . The data were analysed using four way factorial anova (P = 0.05). RESULTS: Bond strength was significantly affected by solvent type and time (P < 0.001). The use of chloroform for 5 min in the root canal decreased bond strength of all sealers (P < 0.001). Eucalyptol and orange oil did not affect the bond strength of the sealers (P > 0.05). In all conditions, the push-out bond strength was highest for AH Plus and lowest for MTA Fillapex (P < 0.001). Bond strength values decreased in a corono-apical direction in all groups (P < 0.001). CONCLUSIONS: Chloroform used for 5 min during retreatment decreased the bond strength of AH Plus, Sealapex and MTA Fillapex to root dentine. PMID- 24483252 TI - Complications of cerebral angiography in children younger than 3 years of age. AB - OBJECT: The therapeutic potential for cerebral angiography (CA) in young children is expanding. However, its use in this patient population is limited by presumed higher complication rates among children. Therefore, to improve the accuracy of counseling of the parents/guardians of these patients and to identify modifiable risk factors, the authors evaluated complications after CA in young children. METHODS: The authors reviewed data for 309 consecutive cerebral angiograms obtained in 87 children younger than 36 months of age from 2004 to 2010 at a single institution. They analyzed demographics, diagnosis, angiographic findings, and complications. RESULTS: The patient population comprised 40 boys and 47 girls; mean age was 14.36 months (range 1-36 months) and mean weight was 10.8 kg (range 3.7-21.0 kg). For 292 of the 309 procedures, intraarterial chemotherapy was administered; the remaining 17 procedures were for vascular malformations, stroke, tumor embolization, and intracranial hemorrhage. The rate of neurological complications was 0.0%. The rate of nonneurological complications was 2.9%: 7 cases of contrast allergy or bronchospasm, 1 groin hematoma (body weight 7 kg), and 1 transient femoral artery occlusion (body weight 10.8 kg). The rate of radiographic complications was 1.3%: 1 case of transient asymptomatic intraarterial dissection and 3 cases of asymptomatic vasospasm. Postprocedural MRI was performed for 33.3% of patients with no evidence of ischemia. There were no delayed complications. Mean follow-up time was 16.6 months. No association was found between complications and age, duration of anesthesia, number of vessels catheterized, size of the sheath, or diagnostic versus interventional procedures. Despite a trend toward a higher rate of complications for patients who weighed less than 15 kg, this finding was not significant (p = 0.35). CONCLUSIONS: The rate of complications for CA in young children is comparable to rates reported for older children and lower than rates reported for adults. When appropriately indicated, CA should not be omitted from the therapeutic strategy of children younger than 36 months of age. PMID- 24483253 TI - Intraoperative phosphorus-32 brachytherapy plaque for multiply recurrent high risk epidural neuroblastoma. AB - Achieving local control is a crucial component in the management of neuroblastoma, but this may be complicated in the setting of prior radiation treatment, especially when the therapeutic target is in proximity to critical structures such as the spinal cord. The authors describe a pediatric patient with multiply recurrent neuroblastoma and prior high-dose radiation therapy to the spine who presented with progressive epidural disease. The patient was managed with resection and intraoperative high-dose-rate brachytherapy using a phosphorus 32 ((32)P) plaque previously developed for the treatment of brain and spine lesions. PMID- 24483254 TI - Osteosarcoma of the cranial vault and skull base in pediatric patients. AB - Cranial osteosarcoma is very rare in children, rendering the development of optimal treatment algorithms challenging. The authors present 3 cases of pediatric cranial osteosarcoma: a primary calvarial tumor, a cranial metastasis, and a primary osteosarcoma of the cranial base. A review of the literature demonstrates significant variation in the management of cranial osteosarcomas and the outcome for patients with these tumors. This series and literature review is presented to improve the understanding of pediatric cranial osteosarcoma and to reinforce the importance of maximal resection in optimizing outcome. PMID- 24483255 TI - Utility of delayed surgical repair of neonatal brachial plexus palsy. AB - OBJECT: Neonatal brachial plexus palsy (NBPP) represents a significant health problem with potentially devastating consequences. The most common form of NBPP involves the upper trunk roots. Currently, primary surgical repair is performed if clinical improvement is lacking. There has been increasing interest in "early" surgical repair of NBPPs, occurring within 3-6 months of life. However, early treatment recommendations ignore spontaneous recovery in cases of Erb's palsy. This study was undertaken to evaluate the optimal timing of surgical repair in this group with respect to quality of life. METHODS: The authors formulated a decision analytical model to compare 4 treatment strategies (no repair or repair at 3, 6, or 12 months of life) for infants with persistent NBPPs. The model derives data from a critical review of published studies and projects health related quality of life and quality-adjusted life years over a lifetime. RESULTS: When evaluating the quality of life of infants with NBPP, improved outcomes are seen with delayed surgical repair at 12 months, compared with no repair or repair at early and intermediate time points, at 3 and 6 months, respectively. ANOVA showed that the differences among the 4 groups are highly significant (F = 8369; p < 0.0001). Pairwise post hoc comparisons revealed that there are highly significant differences between each pair of strategies (p < 0.0001). Meta regression showed no evidence of improved outcomes with more recent treatment dates, compared with older ones, for either nonsurgical or for surgical treatment (p = 0.767 and p = 0.865, respectively). CONCLUSIONS: These data support a delayed approach of primary surgical reconstruction to optimize quality of life. Early surgery for NBPPs may be an overly aggressive strategy for infants who would otherwise demonstrate spontaneous recovery of function by 12 months. A randomized, controlled trial would be necessary to fully elucidate the natural history of NBPP and determine the optimal time point for surgical intervention. PMID- 24483256 TI - Predicting endoscopic third ventriculostomy success in childhood hydrocephalus: an artificial neural network analysis. AB - OBJECT: Artificial neural networks (ANNs) can be used as a measure for the clinical decision-making process. The aim of this study was to develop an ANN model to predict endoscopic third ventriculostomy (ETV) success at 6 months and to compare the findings with those obtained using traditional predictive measures in childhood hydrocephalus. METHODS: The ANN, ETV Success Score (ETVSS), CURE Children's Hospital of Uganda (CCHU) ETV (CCHU ETV) Success Score, and logistic regression models were applied to predict outcomes. The cause of hydrocephalus, patient age, whether choroid plexus cauterization (CPC) was performed, previous shunt surgery, sex, type of hydrocephalus, and body weight were considered as input variables for an established ANN model. Data from hydrocephalic children who underwent ETV were applied, and the computer program that analyzes the data was trained to predict successful ETV by using several input variables. Successful ETV outcome was defined as the absence of ETV failure within 6 months of follow-up. Then, sensitivity analysis was performed for the established ANN model to identify the most important variables that predict outcome. The area under a receiver operating characteristic curve, accuracy rate of the prediction, and Hosmer-Lemeshow statistics were measured to test different prediction models. RESULTS: Data for 168 patients (80 males and 88 females; mean age 1.4 +/- 2.6 years) were analyzed. Data from patients were divided into 3 groups: a training group (n = 84), a testing group (n = 42), and a validation group (n = 42). The successful ETV outcome rate, defined as the absence of ETV failure within 6 months of follow-up, was 47%. Etiology, age, CPC status, type of hydrocephalus, and previous shunt placement were the most important variables that were indicated by the ANN analysis. Compared with the ETVSS, CCHU ETV Success Score, and the logistic regression models, the ANN model showed better results, with an accuracy rate of 95.1%, a Hosmer-Lemeshow statistic of 41.2, and an area under the curve of 0.87. CONCLUSIONS: The findings show that ANNs can predict ETV success at 6 months with a high level of accuracy in childhood hydrocephalus. The authors' results will need to be confirmed with further prospective studies. PMID- 24483258 TI - Exercise test in pediatric renal transplant recipients and its relationship with their cardiac function. AB - Pediatric kidney transplant recipients are at increased risk of CVD. Exercise test is a good method to evaluate exercise capacity, cardiorespiratory fitness, and risk of potential CVDs. The aim of this study was to assess the exercise capacity in this population and determine its relationship with their cardiac function using conventional and tissue Doppler echocardiography. Exercise test, conventional and tissue Doppler echocardiography were performed on 44 kidney transplant children (age ranging 11-20, 59% male) with acceptable renal function, and the results were compared with their normal healthy counterparts. Our transplant patients achieved significantly lower maximal heart rate, maximal heart rate ratio, total energy expenditure during the exercise, and maximal O2 consumption (Max VO2 ) than the normal group (p < 0.05). No correlation was found between hemoglobin (Hb) level, dialysis duration, kidney function, and the exercise test parameters. Kidney transplant patients had preserved systolic despite diminished diastolic cardiac function compared to the normal children. Our pediatric renal transplant recipients had severely impaired diastolic dysfunction and significantly reduced MaxVO2 compared with their healthy counterparts. No correlation was found between MaxVO2 and measured indices of systolic and diastolic cardiac function. PMID- 24483257 TI - Gold nanorod enhanced two-photon excitation fluorescence of photosensitizers for two-photon imaging and photodynamic therapy. AB - Plasmon enhancement of optical properties is both fundamentally important and appealing for many biological and photonic applications. Although metal-enhanced two-photon excitation fluorescence has been demonstrated in the solid substrates, there is no report on metal enhanced overall two-photon excitation fluorescence in the colloid system. Here we systematically investigated gold nanorod enhanced one- and two-photon excitation fluorescence of a porphyrin molecule, T790. The separation distance between the metal core and T790 was varied by adjusting the silica shell thickness from 13 to 42 nm. One- and two-photon excitation fluorescence intensities of T790 were found to strongly depend on the thickness of silica shell that separates gold nanorod and T790. The optimum one- and two photon excitation fluorescence enhancement was found to occur at shell thicknesses of 34 and 20 nm, with enhancement factors of 2.1 and 11.8, respectively. Fluorescence lifetime of T790 steadily decreased as the shell thickness decreased. The observed two-photon excitation fluorescence enhancement is ascribed to a combination effect of local electric field amplification and competition between increased radiative and non-radiative decay rates. Core-shell nanoparticles that displayed enhanced two-photon excitation fluorescence were also found to exhibit significantly improved singlet oxygen generation capability under two-photon excitation. The applications of these nanoparticles as effective agents for two-photon cell imaging and nano-photosensitizers for two-photon photodynamic therapy with improved efficiency have also been demonstrated in HepG2 cancer cells. The combined advantages of enhanced two-photon excitation fluorescence and two-photon induced singlet oxygen generation make these core shell nanoparticles as attractive agents for two-photon imaging guided two-photon photodynamic therapy. PMID- 24483259 TI - All Change at the GMC. PMID- 24483260 TI - How to...: Organize Effective Laboratory Teaching in Medicine. Part 2, Design. AB - In this second article on laboratory teaching in medicine, the authors discuss the design of laboratory manuals and displays, the design of laboratory exercises to meet important goals of medical teaching, and the sequencing of curricula involving laboratory work. Readers are encouraged to consider laboratory classes in their own disciplines and within their own institutions, and to answer the questions set out in a check list provided by the authors at the end of the article. PMID- 24483261 TI - Common room. AB - Our diarist this issue is Harry von Bolhuis, a fifth-year medical student at the Medical Faculty of Erasmus University, Rotterdam, who is currently doing his junior internship. Harry is also a student assistant, or mentor, in the Department of Pathology, a job for which he received about nine months' training. Mentors guide Small-group exercises in which cognitive and affective learning processes are integrated. PMID- 24483262 TI - The Way we Teach...: Paediatrics. AB - Outpatient teaching is allocated more time in the formal eight-week paediatrics programme than any other activity. Students in residence are required to witness as many procedures as possible and to be as active as they can in helping house officers to look after children. Ward teaching is conducted on the understanding that students have done the background work. Other components of the course are seminars, which utilize MCQs; projects, to be completed by each student and presented to the rest of the firm; case conferences, which are difficult to organize and not very popular; sessions to improve communication, with videotaped recordings of interviews with simulated patients to encourage discussion. Students are asked to complete two questionnaires in order to provide feedback. They are graded on their performance during the attachment. There is also a formal clinical examination with both internal and external examinations at the end of their appointment. PMID- 24483263 TI - Using instructor-patients to teach physical examination skills. AB - In the last issue of Medical Teacher, Dr Jack Marshall provided an overview of the methods being used to teach students basic clinical skills and to evaluate their performances (Medical Teacher, 1979, 1, 190-194). Here, the authors describe the use of instructor-patients to teach and evaluate physical examination techniques. The main emphasis is on the recruitment, training and performance of these non-physician instructors. It is concluded that the introduction of lay instructors in any phase of the teaching of physical diagnosis leads to great precision in identifying what has to be learned, what are the optimum techniques and what constitutes an acceptable performance. PMID- 24483264 TI - The new clinical curriculum at the royal free hospital school of medicine. PMID- 24483265 TI - Medical education in the developing world - new approaches needed. AB - Existing health care systems fail to reach more than 20 per cent of people in most developing countries. Change of emphasis towards primary health care will be achieved at best slowly, if ever, through the existing university teaching structure. Provision needs to be made for the on-going training of all health personnel who work in rural areas and slums. Developments in distance teaching techniques, if applied to health, should be both effective and cheap. PMID- 24483266 TI - Group activity record. AB - In this occasional series we will be printing evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to use or adapt such instruments for your own purposes. The feature in this issue has been prepared by C. A. Adsett, MD, Head, Section of Psychiatry, McMaster University Medical Centre, 120 Main Street West, Hamilton, Ontario L8S 4JP, Canada. PMID- 24483268 TI - Self assesment. PMID- 24483267 TI - Jottings. PMID- 24483271 TI - Developing cellular systems in vitro to simulate regeneration. AB - In the past two decades cellular systems in vitro have progressed from predominantly monocellular testing models to study toxic effects of new biomaterials for replacement to relevant human coculture systems for regeneration, often a combination of progenitor cells with novel biomaterials. Considerable progress has been made in understanding cellular crosstalk and its contribution to the vascularization of bone. Future challenges include using the established "physiological", i.e. non-activated, stem cell niches as a platform to develop coculture models which will enable the true in situ regenerative niche to be investigated. Hypoxia and a changing inflammatory status are factors which need to be incorporated. Major advances in polymer synthesis permitting incorporation of specific biologically relevant signals in hydrogels will help make this a reality. PMID- 24483272 TI - Access to medical and supportive care for rural and remote cancer survivors in northern British Columbia. AB - BACKGROUND: Rural cancer survivors (RCS) potentially have unique medical and supportive care experiences when they return to their communities posttreatment because of the availability and accessibility of health services. However, there is a limited understanding of cancer survivorship in rural communities. PURPOSE: The purpose of this study is to describe RCS experiences accessing medical and supportive care postcancer treatment. METHODS: Interviews and focus groups were conducted with 52 RCS residing in northern British Columbia, Canada. The data were analyzed using qualitative content analysis methods. RESULTS: General Population RCS and First Nations RCS experienced challenges accessing timely medical care close to home, resulting in unmet medical needs. Emotional support services were rarely available, and, if they did exist, were difficult to access or not tailored to cancer survivors. Travel and distance were barriers to medical and psychological support and services, not only in terms of the cost of travel, but also the toll this took on family members. Many of the RCS lacked access to trusted and useful information. Financial assistance, for follow-up care and rehabilitation services, was rarely available, as was appropriate employment assistance. CONCLUSION: Medical and supportive care can be inaccessible, unavailable, and unaffordable for cancer survivors living in rural northern communities. PMID- 24483273 TI - The presence of a supporting person during delivery affects cord blood haematopoietic stem cells. AB - Several randomised trials have shown that support during labour improves the outcomes of both mother and the newborn. There is a lack of information concerning the influence of the supporting person on cord blood haematopoietic stem cells (CB HSCs), thus, these cells have been determined to be a suitable graft source for haematopoietic transplantations. This study was aimed to examine the relation between the presence of the accompanying person during labour and some features of CB HSCs. Interestingly, we found that supported deliveries were characterised by lower CB volume and lower counts of HSCs and mononuclear cells in CB. We concluded that the presence of a supporting person during labour seems to affect the yield of HSCs. PMID- 24483274 TI - Glucose metabolism transporters and epilepsy: only GLUT1 has an established role. AB - The availability of glucose, and its glycolytic product lactate, for cerebral energy metabolism is regulated by specific brain transporters. Inadequate energy delivery leads to neurologic impairment. Haploinsufficiency of the glucose transporter GLUT1 causes a characteristic early onset encephalopathy, and has recently emerged as an important cause of a variety of childhood or later-onset generalized epilepsies and paroxysmal exercise-induced dyskinesia. We explored whether mutations in the genes encoding the other major glucose (GLUT3) or lactate (MCT1/2/3/4) transporters involved in cerebral energy metabolism also cause generalized epilepsies. A cohort of 119 cases with myoclonic astatic epilepsy or early onset absence epilepsy was screened for nucleotide variants in these five candidate genes. No epilepsy-causing mutations were identified, indicating that of the major energetic fuel transporters in the brain, only GLUT1 is clearly associated with generalized epilepsy. PMID- 24483275 TI - The essential role of NGATHA genes in style and stigma specification is widely conserved across eudicots. AB - Carpel development and evolution are central issues for plant biology. The conservation of genetic functions conferring carpel identity has been widely studied in higher plants. However, although genetic networks directing the development of characteristic features of angiosperm carpels such as stigma and style are increasingly known in Arabidopsis thaliana, little information is available on the conservation and diversification of these networks in other species. Here, we have studied the functional conservation of NGATHA transcription factors in widely divergent species within the eudicots. We determined by in situ hybridization the expression patterns of NGATHA orthologs in Eschscholzia californica and Nicotiana benthamiana. Virus-induced gene silencing (VIGS)-mediated inactivation of NGATHA genes in both species was performed and different microscopy techniques were used for phenotypic characterization. We found the expression patterns of EcNGA and NbNGA genes during flower development to be highly similar to each other, as well as to those reported for Arabidopsis NGATHA genes. Inactivation of EcNGA and NbNGA also caused severe defects in style and stigma development in both species. These results demonstrate the widely conserved essential role of NGATHA genes in style and stigma specification and suggest that the angiosperm-specific NGATHA genes were likely recruited to direct a carpel-specific developmental program. PMID- 24483276 TI - Colloidal tin-germanium nanorods and their Li-ion storage properties. AB - We report a facile colloidal synthesis of tin-germanium (Sn-Ge) heterostructures in the form of nanorods with a small aspect ratio of 1.5-3 and a length smaller than 50 nm. In the two-step synthesis, presynthesized Sn nanoparticles act as a low-melting-point catalyst for decomposing the Ge precursor, bis[bis(trimethylsilyl)amido]Ge(II), and for crystallization of Ge via solution liquid-solid growth mechanism. Creation of such Sn-Ge nanoheterodimers can serve as a well-controlled method of mixing these nearly immiscible chemical elements for the purpose of obtaining Sn-Ge nanocomposite electrodes for high-energy density Li-ion batteries. Comparable mass content of Sn and Ge leads to synergistic effects in electrochemical performance: high charge storage capacity above 1000 mAh g(-1) at a relatively high current density of 1 A g(-1) is due to high theoretical capacity of Ge, while high rate capability is presumably caused by the enhancement of electronic transport by metallic Sn. At a current density of 4 A g(-1), Sn-Ge nanocomposite electrodes retain up to 80% of the capacity obtained at a lower current density of 0.2 A g(-1). Temporally separated lithiation of both elements, Sn and Ge, at different electrochemical potentials is proposed as a main factor for the overall improvement of the cycling stability. PMID- 24483277 TI - Hydrophobins are required for conidial hydrophobicity and plant root colonization in the fungal biocontrol agent Clonostachys rosea. AB - BACKGROUND: Filamentous fungi produce small cysteine rich surface active amphiphilic hydrophobins on the outer surface of cell walls that mediate interactions between the fungus and the environment. The role of hydrophobins in surface hydrophobicity, sporulation, fruit body formation, recognition and adhesion to host surface and virulence have been reported. The aim of the present study was to characterize the biological function of hydrophobins in the fungal biocontrol agent Clonostachys rosea in order to understand their potential roles in biocontrol mechanisms. RESULTS: Based on the presence of hydrophobin domains, cysteine spacing patterns and hydropathy plots, we identified three class II hydrophobin genes in C. rosea. Gene expression analysis showed basal expression of Hyd1, Hyd2 and Hyd3 in all conditions tested with the exception of induced Hyd1 expression in conidiating mycelium. Interestingly, up-regulation of Hyd1, Hyd2 and Hyd3 was found during C. rosea self interaction compared to interactions with the fungal plant pathogens Botrytis cinerea or Fusarium graminearum in dual culture assays. Phenotypic analysis of C. rosea deletion and complementation strains showed that Hyd1 and Hyd3 are jointly required for conidial hydrophobicity, although no difference in mycelia hydrophobicity was found between wild type (WT) and mutant strains. Interestingly, mutant strains showed increased growth rates, conidiation and enhanced tolerances of conidia to abiotic stresses. Antagonism tests using in vitro dual culture and detached leaf assays showed that the mutant strains were more aggressive towards B. cinerea, F. graminearum or Rhizoctonia solani, and that aggression was partly related to earlier conidial germination and enhanced tolerance of mutant strains to secreted fungal metabolites. Furthermore, in vitro Arabidopsis thaliana root colonization assays revealed reduced root colonization ability of the DeltaHyd3 strain, but not for the DeltaHyd1 strain. Furthermore, enhanced root colonization ability for the DeltaHyd1DeltaHyd3 strain was found in comparison to WT. CONCLUSIONS: These results show a role for hydrophobins in conidial hydrophobicity, control of conidial germination under stress conditions, and in root colonization in C. rosea. However, functional studies of Hyd2 remains to be performed in order to fully assess the role of hydrophobins in C. rosea. PMID- 24483278 TI - Engineering of protein folding and secretion-strategies to overcome bottlenecks for efficient production of recombinant proteins. AB - SIGNIFICANCE: Recombinant protein production has developed into a huge market with enormous positive implications for human health and for the future direction of a biobased economy. Limitations in the economic and technical feasibility of production processes are often related to bottlenecks of in vivo protein folding. RECENT ADVANCES: Based on cell biological knowledge, some major bottlenecks have been overcome by the overexpression of molecular chaperones and other folding related proteins, or by the deletion of deleterious pathways that may lead to misfolding, mistargeting, or degradation. CRITICAL ISSUES: While important success could be achieved by this strategy, the list of reported unsuccessful cases is disappointingly long and obviously dependent on the recombinant protein to be produced. Singular engineering of protein folding steps may not lead to desired results if the pathway suffers from several limitations. In particular, the connection between folding quality control and proteolytic degradation needs further attention. FUTURE DIRECTIONS: Based on recent understanding that multiple steps in the folding and secretion pathways limit productivity, synergistic combinations of the cell engineering approaches mentioned earlier need to be explored. In addition, systems biology-based whole cell analysis that also takes energy and redox metabolism into consideration will broaden the knowledge base for future rational engineering strategies. PMID- 24483279 TI - From the editor. PMID- 24483281 TI - Gender as a moderator of the relation among social support functions and life satisfaction in older Malaysians. AB - The aim of this study was to examine the moderating role of gender on relations among social support functions and life satisfaction in older Malaysians. The study sample was 1,800 older residents in a community; all were at least 60 years old. This study was a cross-sectional and corelational survey, and the data were collected by multistage stratified sampling. This study revealed that fewer social support functions, and therefore less life satisfaction, were available for females than for males. The results of moderated regression analyses demonstrated that gender interacted only on the relationship between positive social interaction support and tangible support with life satisfaction. Specifically, at a high tangible support level, females had lower life satisfaction when compared to a low tangible support level. There may be a need for new programs and services to provide other aspects of social support to older female adults to improve and maintain life satisfaction in later life. PMID- 24483280 TI - The psychological and health consequences of caring for a spouse with dementia: a critical comparison of husbands and wives. AB - Caring for someone with dementia can be demanding, particularly for spouses living with the care recipient. The main goal of this study was to clarify differences in the experience of caregivers who were husbands and wives with respect to burden, health, healthy behaviors, presence of difficult care recipient behaviors, social supports, and the quality of the premorbid relationship. The results of this study support research demonstrating a difference between the caregiving experiences of women and men. It is becoming increasingly apparent that female gender is a marker that places them at increased risk of high burden and less support. PMID- 24483282 TI - Sequins, sass, and sisterhood: an exploration of older women's belly dancing. AB - Disempowering stereotypes plague public perceptions of older women's bodies, particularly within Western contemporary societies. Consequently, as women age, their bodies often become sources of shame, discomfort, and ridicule. Belly dance, as a form of recreative leisure, provides a unique and somewhat unexpected space for women to subvert such perceptions. Based on qualitative interviews with older American women who belly dance, this article examines the ways in which this form of recreation provides participants a means of (re)gaining mobility, (re)claiming social space, (re)building social support, and (re)defining what it means to be sensual later in life. PMID- 24483283 TI - Stressors, coping resources, functioning, and role limitations among older korean immigrants: gender differences. AB - This study explored the differential impacts of stressors and coping resources on the functioning and roles of 246 older Korean immigrant men and women. Older Korean immigrant women were significantly more likely than men to have acculturation and socioeconomic stressors, physical/social functioning problems, and role limitations. English-language barriers and lack of transportation were significantly related to lower functioning and higher role limitations of older Korean women compared to those of older men. Providing social and health care services with bilingual and transportation services to older Korean immigrant women is recommended to increase their physical/social functioning and role performance. PMID- 24483284 TI - Role ambiguity among women providing care for ex-husbands. AB - Twenty-one women were interviewed regarding their caregiving experiences for ill or dying ex-husbands. Emergent in the analyses was the variety of ways in which they experienced role ambiguity as ex-wife caregivers. This article describes the role ambiguity ex-wife caregivers encountered interpersonally through interactions with network members, institutionally in dealing with professionals and the workplace, and intrapersonally in confusion over their roles and feelings. Consequences of role ambiguity are discussed, and recommendations for policy and practice are made in light of the aging population, changing family forms, and women's care roles. PMID- 24483287 TI - Environmental performance of green building code and certification systems. AB - We examined the potential life-cycle environmental impact reduction of three green building code and certification (GBCC) systems: LEED, ASHRAE 189.1, and IgCC. A recently completed whole-building life cycle assessment (LCA) database of NIST was applied to a prototype building model specification by NREL. TRACI 2.0 of EPA was used for life cycle impact assessment (LCIA). The results showed that the baseline building model generates about 18 thousand metric tons CO2-equiv. of greenhouse gases (GHGs) and consumes 6 terajoule (TJ) of primary energy and 328 million liter of water over its life-cycle. Overall, GBCC-compliant building models generated 0% to 25% less environmental impacts than the baseline case (average 14% reduction). The largest reductions were associated with acidification (25%), human health-respiratory (24%), and global warming (GW) (22%), while no reductions were observed for ozone layer depletion (OD) and land use (LU). The performances of the three GBCC-compliant building models measured in life-cycle impact reduction were comparable. A sensitivity analysis showed that the comparative results were reasonably robust, although some results were relatively sensitive to the behavioral parameters, including employee transportation and purchased electricity during the occupancy phase (average sensitivity coefficients 0.26-0.29). PMID- 24483288 TI - 'Anteroposterior placenta': a novel, simple sonographic feature indicating benign vaginal bleeding in early pregnancy. AB - This study proposes a sonographic feature of the placenta in association with benign vaginal bleeding. A total of 286 normal singleton pregnancies were examined for 'anteroposterior, AP, placenta', which was reported when the placenta was attached to both anterior and posterior walls of the uterus in sagittal transabdominal ultrasound scans. Pregnancies were followed up by week 20. AP placenta, vaginal bleeding and spontaneous abortion were documented in 61 (21.3%), 44 (15.4%) and 2 (0.7%) pregnant women, respectively. AP placenta was significantly more common in the group with vaginal bleeding (54.5% vs 1.3%, p < 0.001, odds ratio = 6.65 with a 0.95 confidence interval of 3.34-13.24). Abortions occurred only in patients with vaginal bleeding and no AP placenta (10% vs 0%; p = 0.20). In a normal clinical pregnancy with no known risk of miscarriage, the presence of an AP placenta usually forecasts a benign vaginal bleeding/spotting in first 20 weeks of gestation. PMID- 24483289 TI - Propolis chemical composition and honeybee resistance against Varroa destructor. AB - Propolis is known as honeybee chemical defence against infections and parasites. Its chemical composition is variable and depends on the specificity of the local flora. However, there are no data concerning the relationship between propolis chemical composition and honeybee colony health. We tried to answer this question, studying the chemical composition of propolis of bee colonies from an apiary near Avignon, which are tolerant to Varroa destructor, comparing it with colonies from the same apiary which are non-tolerant to the mites. The results indicated that non-tolerant colonies collected more resin than the tolerant ones. The percentage of four biologically active compounds - caffeic acid and pentenyl caffeates - was higher in propolis from tolerant colonies. The results of this study pave the way to understanding the effect of propolis in individual and social immunity of the honeybees. Further studies are needed to clarify the relationship between propolis chemical composition and honeybee colony health. PMID- 24483291 TI - New insights into the side-face structure, growth aspects, and reactivity of Ag(n) nanoprisms. AB - We report an improved synthesis of colloidal Ag(n) nanoprisms using carboxyl compounds (citrate or succinate) and long chain macromolecules (polyvinylpyrrolidone (PVP)). The side-facet structure of the triangular nanostructure was determined in detail using electron tomography in scanning transmission mode (3D STEM) and HRTEM. It has been found that they are built up by {100} facets with a single parallel twin plane. The best conditions for producing uniform Ag nanoprisms with tunable sizes and high yields in the presence of carboxyl compounds additive system are described, and a growth mechanism is proposed. This approach provides also a route to synthesize Ag nanodisks and Au-Ag alloyed nanoprisms. PMID- 24483290 TI - High frequency of PTEN mutations in nevi and melanomas from xeroderma pigmentosum patients. AB - We examined nevi and melanomas in 10 xeroderma pigmentosum (XP) patients with defective DNA repair. The lesions had a lentiginous appearance with markedly increased numbers of melanocytes. Using laser capture microdissection, we performed DNA sequencing of 18 benign and atypical nevi and 75 melanomas (melanoma in situ and invasive melanomas). The nevi had a similar high frequency of PTEN mutations as melanomas [61% (11/18) versus 53% (39/73)]. Both had a very high proportion of UV-type mutations (occurring at adjacent pyrimidines) [91% (10/11) versus 92% (36/39)]. In contrast to melanomas in the general population, the frequency of BRAF mutations (11%, 7/61), NRAS mutations (21%, 13/62), and KIT mutations (21%, 6/28) in XP melanomas was lower than for PTEN. Phospho-S6 immunostaining indicated activation of the mTOR pathway in the atypical nevi and melanomas. Thus, the clinical and histological appearances and the molecular pathology of these UV-related XP nevi and melanomas were different from nevi and melanomas in the general population. PMID- 24483293 TI - Pediatric drug development: formulation considerations. AB - Absence of safe, effective and appropriate treatment is one of the main causes of high mortality and morbidity rates among the pediatric group. This review provides an overview of pharmacokinetic differences between pediatric and adult population and their implications in pharmaceutical development. Different pediatric dosage forms, their merits and demerits are discussed. Food and Drug Administration Act of 1997 and the Best Pharmaceuticals for Children Act 2002 added 6 months patent extension and exclusivity incentives to pharmaceutical companies for evaluation of medicinal products in children. Prescription Drug User Fee Act and Food and Drug Administration Amendments Act of 2007 made it mandatory for pharmaceutical companies to perform pediatric clinical studies on new drug products. Drug development program should include additional clinical bridge studies to evaluate differences in pharmacokinetics and pharmacodynamics of drugs in adult and child populations. Additionally, pharmaceutical development should consider ease of administration, palatability, appropriate excipients, stability and therapeutic equivalency of pediatric dosage forms. Pediatric population is diverse with individual preferences and demand for custom made dosage formulations. Practically it is not feasible to have different pharmaceutical dosage forms for each group. Hence, an appropriate dosage form that can be administered across pediatric population is warranted. PMID- 24483295 TI - Direct probing of the structure and electron transfer of fullerene/ferrocene hybrid on Au(111) electrodes by in situ electrochemical STM. AB - The electron donor-acceptor dyads are an emerging class of materials showing important applications in nonlinear optics, dye-sensitized solar cells, and molecular electronics. Investigation of their structure and electron transfer at the molecular level provides insights into the structure-property relationship and can benefit the design and preparation of electron donor-acceptor dyad materials. Herein, the interface adstructure and electron transfer of buckyferrocene Fe(C60Me5)Cp, a typical electron donor-acceptor dyad, is directly probed using in situ electrochemical scanning tunneling microscopy (STM) combined with theoretical simulations. It is found that the adsorption geometry and assembled structure of Fe(C60Me5)Cp is significantly affected by the electrochemical environments. In 0.1 M HClO4 solution, Fe(C60Me5)Cp forms well ordered monolayers and multilayers on Au(111) surfaces with molecular dimer as the building block. In 0.1 M NaClO4 solution, typical six-fold symmetric close packed monolayer with vertically adsorbed Fe(C60Me5)Cp is formed. Upon electrochemical oxidation, the oxidized Fe(C60Me5)Cp shows higher brightness in an STM image, which facilitates the direct visualization of the interfacial electrochemical electron transfer process. Theoretical simulation indicates that the electrode potential-activated, one-electron transfer from Fe(C60Me5)Cp to the electrode leads to the change of the delocalization character of the frontier orbital in the molecule, which is responsible for the STM image contrast change. This result is beneficial for understanding the structure and property of single electron donor-acceptor dyads. It also provides a direct approach to study the electron transfer of electron donor-acceptor compounds at the molecular level. PMID- 24483296 TI - Diagnosis and monitoring of cytomegalovirus infection by the quantification of viral load in dried blood spots samples. AB - Cytomegalovirus (CMV) represents the major infectious cause of birth defects, as well as an important pathogen for immune-compromised individuals. Several studies described the use of dried blood spots (DBS) for the detection of CMV DNA for late diagnosis of congenital CMV infection in cases of strong clinical suspicion. In the article under evaluation, Limaye et al. perform for the first time the quantification of CMV in pairs of finger-stick DBS and plasma samples collected from transplant patients. The work concluded that finger-stick DBS could be an alternative sample type for quantification of CMV load that correlates well with plasma levels. Prospective trials to evaluate the use of DBS for monitoring CMV load in transplant recipients will be required. PMID- 24483297 TI - Prediction of central compartment lymph node metastasis in papillary thyroid microcarcinoma. AB - OBJECTIVES: We aimed to determine the predictive factors for central compartment lymph node metastasis (LNM) in papillary thyroid microcarcinoma (PTMC). DESIGN AND PATIENTS: We undertook a retrospective study of 291 patients treated for PTMC. The following criteria were assessed to predict the presence of central compartment LNM: sex, age, tumour multifocality, tumour size, tumour bilaterality, extracapsular spread (ECS), lateral neck LNM, coexistence of chronic lymphocytic thyroiditis, BRAF(V) (600E) mutation and ultrasonography (US) features. Univariate and multivariate analyses were performed to identify clinicopathological characteristics and US findings in predicting central compartment LNM from PTMC. RESULTS: The central compartment LNM affected 133 (45.7%) of 291 patients. With use of univariate and multivariate analyses, male gender (OR 2.020; P = 0.039), tumour size (>5 mm) (OR 3.687; P = 0.015), ESC (OR 2.330; P = 0.044), lateral LNM (OR 15.075; P = 0.000) and BRAF(V) (600E) mutation (OR 2.464; P = 0.000) were independently correlated with central compartment LNM. Age, tumour multifocality, tumour bilaterality, coexistence of chronic lymphocytic thyroiditis and US characteristics were not significantly related to the presence of central compartment LNM. We have also developed a nomogram to predict the probability of central compartment LNM for an individual patient. The sensitivity was 71.9% and specificity was 70.3%, with an under the receiver operating characteristic (ROC) curve of 0.772. CONCLUSIONS: A prophylactic neck dissection of the central compartment should be considered particularly in PTMC patients with male gender, a >5 mm tumour size, ECS of the tumours, lateral LNM and positive BRAF(V) (600E) mutation. PMID- 24483300 TI - Continuing Education-Where Does it Begin? PMID- 24483298 TI - Correlation between species-specific metabolite profiles and bioactivities of blueberries (Vaccinium spp.). AB - Metabolite profiling of three blueberry species (Vaccinium bracteatum Thunb., V. oldhamii Miquel., and V. corymbosum L.) was performed using gas chromatography time-of-flight-mass spectrometry (GC-TOF-MS) and ultraperformance liquid chromatography-quadrupole-time-of-flight-mass spectrometry (UPLC-Q-TOF-MS) combined multivariate analysis. Partial least-squares discriminant analysis clearly showed metabolic differences among species. GC-TOF-MS analysis revealed significant differences in amino acids, organic acids, fatty acids, sugars, and phenolic acids among the three blueberry species. UPLC-Q-TOF-MS analysis indicated that anthocyanins were the major metabolites distinguishing V. bracteatum from V. oldhamii. The contents of anthocyanins such as glycosides of cyanidin were high in V. bracteatum, while glycosides of delphinidin, petunidin, and malvidin were high in V. oldhamii. Antioxidant activities assessed using ABTS and DPPH assays showed the greatest activity in V. oldhamii and revealed the highest correlation with total phenolic, total flavonoid, and total anthocyanin contents and their metabolites. PMID- 24483301 TI - Pathology. AB - A system of learning pathology based on new teaching methods is described and compared with traditional teaching. The Integrated Pathology Audiovisual Learning System (IPALS) is the product of an international team of pathologists and consists of three tiers. Tier I deals with general pathology, Tier II with the pathology of organ systems, and Tier III with diseases in individual organs. Each unit consists of a textbook with basic definitions, a set of slides and one or more short lessons on tape as a commentary. The importance of teaching in small groups and of clinical-pathological conferences is explained. Autopsy demonstrations and the use of gross and microscopical specimens should, of course, complement the system. The system is in use at many universities all over the world, most extensively at the universities of Oslo and Rotterdam. The advantages and disadvantages of the system and the students' and teachers' reactions to it are discussed. PMID- 24483299 TI - Transglutaminase-based chemo-enzymatic conjugation approach yields homogeneous antibody-drug conjugates. AB - Most chemical techniques used to produce antibody-drug conjugates (ADCs) result in a heterogeneous mixture of species with variable drug-to-antibody ratios (DAR) which will potentially display different pharmacokinetics, stability, and safety profiles. Here we investigated two strategies to obtain homogeneous ADCs based on site-specific modification of deglycosylated antibodies by microbial transglutaminase (MTGase), which forms isopeptidic bonds between Gln and Lys residues. We have previously shown that MTGase solely recognizes Gln295 within the heavy chain of IgGs as a substrate and can therefore be exploited to generate ADCs with an exact DAR of 2. The first strategy included the direct, one-step attachment of the antimitotic toxin monomethyl auristatin E (MMAE) to the antibody via different spacer entities with a primary amine functionality that is recognized as a substrate by MTGase. The second strategy was a chemo-enzymatic, two-step approach whereby a reactive spacer entity comprising a bio-orthogonal thiol or azide function was attached to the antibody by MTGase and subsequently reacted with a suitable MMAE-derivative. To this aim, we investigated two different chemical approaches, namely, thiol-maleimide and strain-promoted azide alkyne cycloaddition (SPAAC). Direct enzymatic attachment of MMAE-spacer derivatives at an 80 molar excess of drug yielded heterogeneous ADCs with a DAR of between 1.0 to 1.6. In contrast to this, the chemo-enzymatic approach only required a 2.5 molar excess of toxin to yield homogeneous ADCs with a DAR of 2.0 in the case of SPAAC and 1.8 for the thiol-maleimide approach. As a proof-of concept, trastuzumab (Herceptin) was armed with the MMAE via the chemo-enzymatic approach using SPAAC and tested in vitro. Trastuzumab-MMAE efficiently killed BT 474 and SK-BR-3 cells with an IC50 of 89.0 pM and 21.7 pM, respectively. Thus, the chemo-enzymatic approach using MTGase is an elegant strategy to form ADCs with a defined DAR of 2. Furthermore, the approach is directly applicable to a broad variety of antibodies as it does not require prior genetic modifications of the antibody sequence. PMID- 24483302 TI - Assess clinical competence-an overview. AB - Assessment of a doctor's or student's clinical competence is of key importance. The examiner should ask what competencies he is attempting to assess and how he can best assess them; whether, for example, by using an objective structured clinical examination (OSCE), patient management problems (PMP), supervisors' reports, project work or assignments, or by auditing case records. He should consider the functions of the clinical examination, in particular its role in providing feedback to the student and teacher. With regard to timing there is a place for both in-course and end-of-course assessment of clinical competence. Finally, in considering who should undertake the assessment, the role of the student or doctor in assessing his own competence should not be overlooked. PMID- 24483303 TI - The telephone in continuing medical education-the Saskatchewan experience. PMID- 24483304 TI - Tulp's Dissection. PMID- 24483305 TI - Assessment in medicine-the multiple choice question controversy. PMID- 24483306 TI - Graduate medical education in europe. PMID- 24483307 TI - No. 1: monitoring the new shorter clinical course at cambridge. AB - This is the first in an occasional series of articles describing innovations, successful and unsuccessful, in medical education. I t is hoped that they may encourage others to attempt similar experiments4r warn them away from unprofitable avenues of development. The new Clinical Medical School at the University of Cambridge, UK, has established a project to monitor and evaluate its new, shorter course. The background to this unusual decision is described in this article, which then reviews possible evaluation methods, problems, and the planned strategy. The activities include measures of the school's 'ethos', the teaching/learning process, aspects of its cost, and the quality of its 'product' the medical graduate. Experiences during the first 18 months of the project are reported. PMID- 24483308 TI - Community-based Practitioners as Medical Student Preceptors-Dispelling an Old Myth. AB - This study was designed to compare the teaching abilities of community-based preceptors and university-based clinical faculty, as judged by two matched groups of students. On only one of 13 dimensions of clinical teaching was there a significant difference between the preceptors and university-based faculty: preceptors were reported to use demonstrations less than their university-based colleagues. The study shows that despite their other commitments and lack of formal training in didactic skills, community-based practitioners can provide sound educational experiences and, in the students' opinions, are as competent teachers as clinical, university-based faculty. PMID- 24483309 TI - Against the grand medical round. PMID- 24483310 TI - Common room. AB - Periodically, someone connected with medical education will present a diary of a week in his or her life. The contributor this issue is A. Michael Davies, Professor of Medical Ecology. Hebrew University-Hadassah Medical School and Director, Brookdale Institute for Gerontology and Adult Human Development, Jerusalem, Israel. PMID- 24483312 TI - Conference reportx. PMID- 24483313 TI - [Comparative study of three Western models of deontological codes for dentists]. AB - We performed a comparative analysis of the codes of ethics of three official organizations in Dentistry professional ethics: Code of Ethics for Dentists in the European Union, drawn up by the Council of European Dentists (CED); Codigo Espanol de Etica y Deontologia Dental, published by the Consejo General de Colegios de Odontologos y Estomatologos de Espana (CGCOE); and Principles of Ethics and Code of Professional Conduct, of the American Dental Association (ADA). The analysis of the structure of the codes allows the discovery of different approaches governing professional ethics according to the ethical and legislative tradition from which they derive. While there are common elements inherent in Western culture, there are nuances in the grounds, the layout and wording of articles that allows to deduce the ethical foundations that underlie each code, and reflects the real problems encountered by dentists in the practice of their profession. PMID- 24483314 TI - [Interprofessional ethical shared values for an integral healthcare]. AB - Healthcare today requires the rapport of diverse professionals to give a comprehensive response to the needs and requirements of the population's health. Codes of ethics are the normative expression of secular reflection on the ethical values of the professions. In this study we aim to identify ethical values shared by various professionals codes of conduct and propose a method for evaluating the ethical estimate. For this reason, we have reviewed codes of ethics of the medical, nursing, physiotherapy, podiatry and psychology professions, identifying 30 values. These values were classified into two groups, depending on if these are shared by the 5 professionals codes or not (VIP vs VP). In order to provide a method for estimating common values it has been designed a survey likert type. Is possible to conclude there are ethical formally shared values identifiable in professional codes of conduct and it is possible to measure the estimate of ethical values accepted by health professionals. This measurement can be an effective aid to apply management methods of human resources that make it possible to achieve the comprehensive assistance based on inter-professional teams. PMID- 24483315 TI - [What objection? What conscience? Philosophical reflections on conscientious objection]. AB - This article offers some reflections on conscientious objection from a conceptual standpoint, and not technical and not legislative. In the author's approach, all ethics (law's ethics also) has to do with individual choices that contribute to the identity of the person, and it's formed through the constant confrontation with truth and goodness of each decision freely taken. The law and legal systems, far from being a neutral and opaque framework, have to be based on an effective concern for justice, and this judgment is sent to each man have to obey the rules, which, being subject to human decisions, are at risk of opposing the truth. This truth remains accessible to the correct knowledge and manifests, among many other fields, in the areas of law, human rights, and professions. PMID- 24483316 TI - [Death with dignity - dignity life. A debate]. AB - Since 2010 in the Autonomous Community of Andalusia passed into law "derechos y garantias de la dignidad de las personas en el proceso de muerte". At national level, in Spain, it's disputed the need to legalize this delicate aspect therefore already been made some projects for legalization. This advised to review the pros and cons of some legislative implementation experiences and case mix in countries where it has already occurred. This paper undertakes the study of the implementation of the Death with Dignity Act in Oregon and highlight is what were the immediate consequences and risks that has produced a law of this nature. PMID- 24483317 TI - [IPS an ethical paradigm for biomedical research]. AB - One of the greatest advances in molecular and cell biology was the discovery of the Induced Pluripotent Stem cells (iPS) in mice, by Shinya Yamanka and his team in 2006. The possibility that these cells can be generated also in humans opens up unexpected ways of development for biomedicine. Its main contribution is the creation of a strong protocol that takes into account three major advances in biology such as; nuclear transfer techniques, the discovery of transcription factors associated with pluripotency and the isolation of mouse embryonic stem cells. A protocol that can be easily replicated in other laboratories to have the oportunity to design tests that allow modeling of many incurable diseases, drug testing for human cells or explore the possibilities of autologous transplants of tissues or organs. Yamanaka ethical motivation to find an alternative to embryonic stem cells (ES) and prevent the destruction of embryos produced by In Vitro Fertilization techniques (IVF), has proved to be a research model, in which the intuition of the ethical principles and its application in advanced biotechnology projects, has meant the opening of a whole new way of understanding the biology of embryonic development. It is clear that development, biologically understood (puede ser tambien "treated"; tratado), is not a one-way street. The possibilities to deepen into the foundations of molecular biology and genetics, along with the expectations of its clinical applications have earned Yamanka the Nobel Prize in Medicine 2012, along with another great scholar Sir John Gurdon, discoverer of nuclear transfer techniques. PMID- 24483318 TI - [The embryonic stem cells research. Example of biotechnology progress under extra scientific pressure]. AB - The possibility to isolate, cultivate, preserve, characterize and differentiate Human Embryonic Stem Cells (ES) discovered by James Thomson and his colleagues in 1998 was a milestone in the history of Stem Cell Research. Immediately after this discovery many speculations were made about the therapeutic possibilities of ES, motivated by ideological, political and economic aspects. The episode made clear the lack of scientific rationality and ethics when assessing realities as meaningful as those of human embryos obtained by in vitro fertilization techniques (IVF) or human eggs. Therapeutic Cloning as a promise to produce "tailored" Stem Cells reported by Hwang and his team in 2004, ended up being a scandal within the scientific community. The technical difficulties and ethical controversies that arose from obtaining ES were insurmountable. In 2010 only two clinical trials were reported using these cells. Those trials were abandoned in late 2011 arguing financial reasons. The discovery of Induced Pluripotent Stem Cell (iPS) in 2006 in mice and in 2007 in humans, represented the possibility of obtaining pluripotent stem cells without the need to destroy embryos. Today, the absence of clinical trials using ES, caused by financial difficulties as a result of its ineffectiveness, anticipates that the use of ES will be limited to certain experimental controls. Probably, the main contribution of Embryonic Stem Cells will be the understanding that biomedical research should follow an ethically and rationally based rigorous method that cannot be ignore. PMID- 24483319 TI - [The epistemological statute of the bioethics]. AB - The article exposes the theoretical debate brings over of the configuration epistemological of the Bioethics. There is realized a descriptive and critical analysis of the principal contributions. Sample like the Bioethics always has had difficulties to be defined; the limits and the internal characteristics of the definite thing have suffered important modifications in his short history. Another present, not less substantial problem, it owes to the different manners of understanding it and therefore to that there does not exist Bioethical univocal concept. Finally, there sign three essential features that sustain his conceptual base, and that to ours to deal, are still for resolving. PMID- 24483320 TI - [The Brustle v. Greenpeace case and the end of pre-implantation embryos discrimination]. AB - In October 2011 the Court of Justice of the European Union pronounced the sentence in the case Brustle v. Greenpeace. This sentence resolves the preliminary ruling interposed by the Bundesgerichtshof. The object of the preliminary ruling was the interpretation of the expression "human embryos", on 44/98/CE Guideline, in order to resolve the litigation between Brustle, a German neurobiologist, and Greenpeace. Brustle have patented a process for obtaining stem cells using cells originally extracted from human embryos, Greenpeace have filed a lawsuit against this patent. The article analyzes the meaning of this sentence in the light of the discrimination of the pre-implantation embryos in Spanish law. The content of the Biopatent Guideline, the Opinions of the European Group on Ethics of Science and New Technologies related to it, the EUJC verdict and the Conclusions of the General Advocate are analyzed. We will pay special attention to the final verdict given on November 27, 2012, by the German Federal Court of Justice. The paper also considers the repercussion of Brustle case at the European level, examining the activity of the European Parliament, in the frame of the discussion of the program Horizon 2020, and the citizen's initiative "One of us". At the Spanish level, the paper underlines the need to reform the laws of Human Assisted Reproduction and of Biomedical Investigation. PMID- 24483321 TI - A new unstable variant of the fetal hemoglobin HBG2 gene: Hb F-Turritana [(G) gamma64(E8)Gly->Asp, HBG2:c.194G>A] found in cis to the Hb F-Sardinia gene [(A) gamma(E19)Ile->Thr, HBG1:c.227T>C]. AB - A new variant of the fetal hemoglobin (Hb) was observed in a newborn baby subjected to phototherapy due to jaundice, by means of electrophoretic and chromatographic techniques. The variant Hb resulted unstable by the isopropanol stability test. After HBG2 gene sequencing, the G to A transversion at codon 64, position eight of the E helix, was found, which corresponds to the Asp for Gly amino acid substitution. The new variant was called Hb F-Turritana [(G) gamma64(E8)Gly->Asp, HBG2:c.194G>A]. Incoming aspartic acid residue, bulky and negatively charged, may be responsible for alteration of the heme pocket steric configuration and for instability. The new abnormal HBG2 gene was found to be associated in cis with the mutated HBG1 gene, which characterizes the Hb F Sardinia [(A) gamma (E19)Ile->Thr, HBG1:c.227T>C] variant. PMID- 24483323 TI - Successful outcome of allogeneic stem cell transplantation in Seckel syndrome. AB - Seckel syndrome is a rare autosomal recessive disease, genetically heterogeneous, characterized by short stature, prenatal microcephaly, intellectual disability, dysmorphic features, chromosomal instability, and hematological disorders. We report the case of a six-yr-old boy with Seckel syndrome and aplastic anemia who underwent successful allogeneic bone marrow transplantation from ten of ten HLA matched unrelated donor. Currently the patient is on D+771, in good health conditions and with no further complications. In conclusion, this case indicates that bone marrow transplantation is an acceptable therapeutic option for Seckel syndrome complicated by hematological alterations. PMID- 24483324 TI - Fabrication of transferable Al(2)O(3) nanosheet by atomic layer deposition for graphene FET. AB - Without introducing defects in the monolayer of carbon lattice, the deposition of high-kappa dielectric material is a significant challenge because of the difficulty of high-quality oxide nucleation on graphene. Previous investigations of the deposition of high-kappa dielectrics on graphene have often reported significant degradation of the electrical properties of graphene. In this study, we report a new way to integrate high-kappa dielectrics with graphene by transferring a high-kappa dielectric nanosheet onto graphene. Al2O3 film was deposited on a sacrificial layer using an atomic layer deposition process and the Al2O3 nanosheet was fabricated by removing the sacrificial layer. Top-gated graphene field-effect transistors were fabricated and characterized using the Al2O3 nanosheet as a gate dielectric. The top-gated graphene was demonstrated to have a field-effect mobility up to 2200 cm(2)/(V s). This method provides a new method for high-performance graphene devices with broad potential impacts reaching from high-frequency high-speed circuits to flexible electronics. PMID- 24483322 TI - Event-related potential responses to the acute and chronic effects of alcohol in adolescent and adult Wistar rats. AB - BACKGROUND: This study explored the hypothesis that adolescent ethanol (EtOH) exposure may cause long-lasting changes in EtOH sensitivity by exploring the age related effects of acute alcohol on intoxication and on event-related potential (ERP) responses to acoustic stimuli in EtOH-naive adolescent and adult male Wistar rats and in adult rats that were exposed to chronic EtOH/control conditions during adolescence. METHODS: EtOH-naive adolescent (postnatal day 32 [PD32]) and adult male rats (PD99) were included in the first study. In a second study, rats were exposed to 5 weeks of EtOH vapor (blood EtOH concentrations at 175 mg%) or air from PD24 to 59 and allowed to mature until PD90. In both studies, rats were implanted with cortical recording electrodes, and the effects of acute EtOH (0.0, 1.5, and 3.0 g/kg) on behavioral and ERP responses were assessed. RESULTS: Adolescents were found to have higher amplitude and longer latency P3a and P3b components at baseline as compared to adult rats, and EtOH was found to produce a robust dose-dependent increase in the latency of the P3a and P3b components of the auditory ERP recorded in cortical sites in both adolescents and adults. However, EtOH produced significantly larger delays in P3a and P3b latencies in adults as compared to adolescents. Acute EtOH administration was also found to produce a robust dose-dependent increase in the latency of the P3a and P3b components in adult animals exposed to EtOH vapor as adolescents and air exposed controls; however, larger acute EtOH-induced increases in P3a and P3b latencies were seen in controls as compared to adolescent vapor exposed rats. CONCLUSIONS: Adolescent rats have a less intense P3 latency response to acute EtOH administration when compared to adult rats. Exposure to chronic EtOH during adolescence can cause "retention" of the adolescent phenotype of reduced P3 latency sensitivity to EtOH. PMID- 24483325 TI - Management of a second trimester miscarriage in a woman with an incarcerated retroverted uterus. PMID- 24483326 TI - Soluble phenylpropanoids are involved in the defense response of Arabidopsis against Verticillium longisporum. AB - Verticillium longisporum is a soil-borne vascular pathogen causing economic loss in rape. Using the model plant Arabidopsis this study analyzed metabolic changes upon fungal infection in order to identify possible defense strategies of Brassicaceae against this fungus. Metabolite fingerprinting identified infection induced metabolites derived from the phenylpropanoid pathway. Targeted analysis confirmed the accumulation of sinapoyl glucosides, coniferin, syringin and lignans in leaves from early stages of infection on. At later stages, the amounts of amino acids increased. To test the contribution of the phenylpropanoid pathway, mutants in the pathway were analyzed. The sinapate-deficient mutant fah1 2 showed stronger infection symptoms than wild-type plants, which is most likely due to the lack of sinapoyl esters. Moreover, the coniferin accumulating transgenic plant UGT72E2-OE was less susceptible. Consistently, sinapoyl glucose, coniferyl alcohol and coniferin inhibited fungal growth and melanization in vitro, whereas sinapyl alcohol and syringin did not. The amount of lignin was not significantly altered supporting the notion that soluble derivatives of the phenylpropanoid pathway contribute to defense. These data show that soluble phenylpropanoids are important for the defense response of Arabidopsis against V. longisporum and that metabolite fingerprinting is a valuable tool to identify infection-relevant metabolic markers. PMID- 24483327 TI - My epilepsy story--Muir Maxwell Trust. PMID- 24483329 TI - Co-release of cells and polymeric nanoparticles from sacrificial microfibers enhances nonviral gene delivery inside 3D hydrogels. AB - Hydrogels can promote desirable cellular phenotype by mimicking tissue-like stiffness or serving as a gene delivery depot. However, nonviral gene delivery inside three-dimensional (3D) hydrogels remains a great challenge, and increasing hydrogel stiffness generally results in further decrease in gene delivery efficiency. Here we report a method to enhance nonviral gene delivery efficiency inside 3D hydrogels across a broad range of stiffness using sacrificial microfibers for co-releasing cells and polymeric nanoparticles (NPs). We fabricated hydrolytically degradable alginate as sacrificial microfibers, and optimized the degradation profile of alginate by varying the degree of oxidization. Scanning electron microscopy confirmed degradation of alginate microfibers inside hydrogels, leaving behind microchannel-like structures within 3D hydrogels. Sacrificial microfibers also serve as a delivery vehicle for co releasing encapsulated cells and NPs, allowing cell attachment and spreading within the microchannel surface upon microfiber degradation. To examine the effects of sacrificial microfibers on nonviral gene delivery inside 3D hydrogels, alginate microfibers containing human embryonic kidney 293 cells and polymeric NPs were encapsulated within 3D hydrogel scaffolds with varying stiffness (9, 58, and 197 kPa). Compared with cells encapsulated in bulk hydrogels, we observed up to 15-fold increase in gene delivery efficiency using sacrificial microfibers, and gene delivery efficiency increased as hydrogel stiffness increased. The platform reported herein provides a strategy for enhancing nonviral gene delivery inside 3D hydrogels across a broad range of stiffness, and may aid tissue regeneration by engaging both mechanotransduction and nonviral gene delivery. PMID- 24483328 TI - Voltage-Gated Proton Channels as Novel Drug Targets: From NADPH Oxidase Regulation to Sperm Biology. AB - SIGNIFICANCE: Voltage-gated proton channels are increasingly implicated in cellular proton homeostasis. Proton currents were originally identified in snail neurons less than 40 years ago, and subsequently shown to play an important auxiliary role in the functioning of reactive oxygen species (ROS)-generating nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Molecular identification of voltage-gated proton channels was achieved less than 10 years ago. Interestingly, so far, only one gene coding for voltage-gated proton channels has been identified, namely hydrogen voltage-gated channel 1 (HVCN1), which codes for the HV1 proton channel protein. Over the last years, the first picture of putative physiological functions of HV1 has been emerging. RECENT ADVANCES: The best-studied role remains charge and pH compensation during the respiratory burst of the phagocyte NADPH oxidase (NOX). Strong evidence for a role of HV1 is also emerging in sperm biology, but the relationship with the sperm NOX5 remains unclear. Probably in many instances, HV1 functions independently of NOX: for example in snail neurons, basophils, osteoclasts, and cancer cells. CRITICAL ISSUES: Generally, ion channels are good drug targets; however, this feature has so far not been exploited for HV1, and hitherto no inhibitors compatible with clinical use exist. However, there are emerging indications for HV1 inhibitors, ranging from diseases with a strong activation of the phagocyte NOX (e.g., stroke) to infertility, osteoporosis, and cancer. FUTURE DIRECTIONS: Clinically useful HV1-active drugs should be developed and might become interesting drugs of the future. PMID- 24483330 TI - Cervical cancer screening: exploring Appalachian patients' barriers to follow-up care. AB - This article describes a community-based Patient Navigation (PN) project conducted to identify potential barriers to seeking follow-up cervical cancer care in southeastern Kentucky. Patient navigators (PNs) were placed in cervical cancer programs within county public health departments where they interviewed patients about their perceived barriers to seeking follow-up care after receiving a positive Pap test result. Participants identified various potential barriers at three levels: the individual/personal level, the health care system level and the community/environmental level. One identified barrier that was unique to this study was a lack of consistency between follow-up recommendations and follow-up guidelines for patients under age 21. Implications are discussed. PMID- 24483331 TI - Risk and preventive factors for type 2 diabetes and heart disease among foreign born older Vietnamese Americans. AB - The 2009 California Health Interview Survey (CHIS) data was used to examine associations of bodyweight, lifestyles, and demographic variables with type 2 diabetes (T2DM) and heart disease among foreign-born older Vietnamese adults. CHIS consisted of 709 Vietnamese Americans aged 50 to 85. Thirteen percent reported T2DM and 11% had heart disease. Using logistic regression, body mass index >= 24, age >= 65, and female were significantly associated with T2DM. There was significant interaction effect of alcohol consumption and psychological distress with T2DM. The interaction of vegetable consumption, poverty, and length of living in the U.S. was significantly associated with heart disease. PMID- 24483332 TI - Social workers in pediatric primary care: communication, gender, and scope of practice. AB - While many child mental health issues manifest themselves in primary care, few pediatricians have received mental health training, and their communication with social workers may be limited due to unfamiliarity with mental health professions. The purpose of this study was to use ethnographic interviews to investigate factors affecting communication satisfaction between social workers and pediatricians. The study found that scope of practice issues were a communication barrier. This barrier is significant because health reform may lead social workers and pediatricians to collaborate more frequently in the future. PMID- 24483333 TI - Connection versus disconnection: examining culturally competent care in the neonatal intensive care unit. AB - Culturally competent health care is of critical importance; however, it is presented as a frequent challenge in health care settings. This study explored cross-cultural care from the health care provider perspective within two tertiary level Neonatal Intensive Care Units (NICUs). Fifty eight inter-professional health care providers (HCP) participated in focus groups. Participants identified perceived care-related experiences of newly immigrated parents whose infant received care in the NICU as well as health care provider perspectives on delivering that care. Results identified core processes of "connection" and "disconnection," which appeared to have a substantial bearing on NICU experience and interaction. Connection comprised congruity, synergy, and "fit," and resulted in an enhanced relationship between the family and HCP. Disconnection, in contrast, entailed a lack of "fit" and in some cases, misunderstanding and/or conflict between the family and a member or members of the health care team. Connection and disconnection occurred at various junctures of NICU care. These junctures reflected interaction between the family and HCP at the bedside and/or at the level of the unit, hospital, or community at large. Implications for practice, policy, and research are discussed. PMID- 24483334 TI - Implementing a mental health and primary care partnership program in Placer County, California. AB - Individuals with serious mental illness are at an increased risk for developing co-morbid chronic physical illnesses, such as diabetes and cardiovascular disease. This article is a descriptive piece about an intervention to decrease physical health risks in this population through a partnership effort between a primary care clinic and mental health agency in rural Placer County, California. The project was conducted as a part of the CalMEND Pilot Collaborative to Integrate Primary Care and Mental Health Services, which took place in five California counties in 2010-2011. A description of the program elements, conceptual models, key measures, and the process of program implementation is provided. Benefits were observed in areas of quality assurance, intra- and inter agency teamwork, and access to adequate primary care for this population. PMID- 24483335 TI - The prevalence and characteristics of homelessness in the NSW substance treatment population: implications for practice. AB - This study examines the prevalence and characteristics of homelessness episodes in Australian substance misuse treatment. A dataset containing all closed substance treatment episodes in NSW, Australia from July 2006 to June 2011 was used. Statistical analysis was used to determine any relationships between demographic and treatment variables and homelessness. Of the 213, 129 treatment episodes in the dataset 12.8% have some form of homelessness. Non-government and residential services have the highest prevalence of homelessness. Sex, age, and drug type have weak relationships with homelessness. Leaving against the advice of the treatment provider is more common in episodes where homelessness is a factor. Homelessness is a problem experienced by a significant proportion of the substance treatment population and treatment providers have an opportunity and an obligation to address it in their treatment delivery. PMID- 24483336 TI - Lactobacillus GG restoration of the gliadin induced epithelial barrier disruption: the role of cellular polyamines. AB - BACKGROUND: Celiac disease is characterized by enhanced intestinal paracellular permeability due to alterations of function and expression of tight junction (TJ) proteins including ZO-1, Claudin-1 and Occludin. Polyamines are pivotal in the control of intestinal barrier function and are also involved in the regulation of intercellular junction proteins. Different probiotic strains may inhibit gliadin induced toxic effects and the Lactobacillus rhamnosus GG (L.GG) is effective in the prevention and treatment of gastrointestinal diseases. Aims of the study were to establish in epithelial Caco-2 cells whether i) gliadin affects paracellular permeability and polyamine profile; ii) co-administration of viable L.GG, heat killed L.GG (L.GG-HK) or its conditioned medium (L.GG-CM) preserves the intestinal epithelial barrier integrity. Additionally, the effects of L.GG on TJ protein expression were tested in presence or absence of polyamines. RESULTS: Administration of gliadin (1 mg/ml) to Caco-2 cells for 6 h caused a significant alteration of paracellular permeability as demonstrated by the rapid decrease in transepithelial resistance with a concomitant zonulin release. These events were followed by a significant increase in lactulose paracellular transport and a slight lowering in ZO-1 and Occludin expression without affecting Claudin-1. Besides, the single and total polyamine content increased significantly. The co administration of viable L.GG (10(8) CFU/ml), L.GG-HK and L.GG-CM with gliadin significantly restored barrier function as demonstrated by transepithelial resistance, lactulose flux and zonulin release. Viable L.GG and L.GG-HK, but not L.GG-CM, led to a significant reduction in the single and total polyamine levels. Additionally, only the co-administration of viable L.GG with gliadin significantly increased ZO-1, Claudin-1 and Occludin gene expression compared to control cells. When Caco-2 cells treated with viable L.GG and gliadin were deprived in the polyamine content by alpha-Difluoromethylornithine, the expression of TJ protein mRNAs was not significantly different from that in controls or cells treated with gliadin alone. CONCLUSIONS: Gliadin modifies the intestinal paracellular permeability and significantly increases the polyamine content in Caco-2 cells. Concomitant administration of L.GG is able to counteract these effects. Interestingly, the presence of cellular polyamines is necessary for this probiotic to exert its capability in restoring paracellular permeability by affecting the expression of different TJ proteins. PMID- 24483337 TI - Hippo pathway effectors control cardiac progenitor cell fate by acting as dynamic sensors of substrate mechanics and nanostructure. AB - Stem cell responsiveness to extracellular matrix (ECM) composition and mechanical cues has been the subject of a number of investigations so far, yet the molecular mechanisms underlying stem cell mechano-biology still need full clarification. Here we demonstrate that the paralog proteins YAP and TAZ exert a crucial role in adult cardiac progenitor cell mechano-sensing and fate decision. Cardiac progenitors respond to dynamic modifications in substrate rigidity and nanopattern by promptly changing YAP/TAZ intracellular localization. We identify a novel activity of YAP and TAZ in the regulation of tubulogenesis in 3D environments and highlight a role for YAP/TAZ in cardiac progenitor proliferation and differentiation. Furthermore, we show that YAP/TAZ expression is triggered in the heart cells located at the infarct border zone. Our results suggest a fundamental role for the YAP/TAZ axis in the response of resident progenitor cells to the modifications in microenvironment nanostructure and mechanics, thereby contributing to the maintenance of myocardial homeostasis in the adult heart. These proteins are indicated as potential targets to control cardiac progenitor cell fate by materials design. PMID- 24483338 TI - Risk of a venous thromboembolic episode due to caesarean section and BMI: a study in northern Denmark covering 2000-2010. AB - BMI significantly influences the risk of venous thromboembolism after emergency caesarean delivery compared with vaginal delivery. PMID- 24483340 TI - Mechanically robust superhydrophobic polymer surfaces based on protective micropillars. AB - Considerable attention is currently being devoted less to the question of whether it is possible to produce superhydrophobic polymer surfaces than to just how robust they can be made. The present study demonstrates a new route for improving the mechanical durability of water-repellent structured surfaces. The key idea is the protection of fragile fine-scale surface topographies against wear by larger scale sacrificial micropillars. A variety of surface patterns was manufactured on polypropylene using a microstructuring technique and injection molding. The surfaces subjected to mechanical pressure and abrasive wear were characterized by water contact and sliding angle measurements as well as by scanning electron microscopy and roughness analysis based on optical profilometry. The superhydrophobic polypropylene surfaces with protective structures were found to maintain their wetting properties in mechanical compression up to 20 MPa and in abrasive wear tests up to 120 kPa. For durable properties, the optimal surface density of the protective pillars was found to be about 15%. The present approach to the production of water-repellent polymer surfaces provides the advantages of mass production and mechanical robustness with practical applications of structurally functionalized surfaces. PMID- 24483341 TI - Life cycle environmental impact of high-capacity lithium ion battery with silicon nanowires anode for electric vehicles. AB - Although silicon nanowires (SiNW) have been widely studied as an ideal material for developing high-capacity lithium ion batteries (LIBs) for electric vehicles (EVs), little is known about the environmental impacts of such a new EV battery pack during its whole life cycle. This paper reports a life cycle assessment (LCA) of a high-capacity LIB pack using SiNW prepared via metal-assisted chemical etching as anode material. The LCA study is conducted based on the average U.S. driving and electricity supply conditions. Nanowastes and nanoparticle emissions from the SiNW synthesis are also characterized and reported. The LCA results show that over 50% of most characterized impacts are generated from the battery operations, while the battery anode with SiNW material contributes to around 15% of global warming potential and 10% of human toxicity potential. Overall the life cycle impacts of this new battery pack are moderately higher than those of conventional LIBs but could be actually comparable when considering the uncertainties and scale-up potential of the technology. These results are encouraging because they not only provide a solid base for sustainable development of next generation LIBs but also confirm that appropriate nanomanufacturing technologies could be used in sustainable product development. PMID- 24483339 TI - AJAP1 is dysregulated at an early stage of gliomagenesis and suppresses invasion through cytoskeleton reorganization. AB - AIMS: Down-regulation of AJAP1 in glioblastoma multiforme (GBM) has been reported. However, the expression profiles of AJAP1 in gliomas and the underlying mechanisms of AJAP1 function on invasion are still poorly understood. METHODS: The gene profiles of AJAP1 in glioma patients were studied among four independent cohorts. Confocal imaging was used to analyze the AJAP1 localization. After AJAP1 overexpression in GBM cell lines, cellular polarity, cytoskeleton distribution, and antitumor effect were investigated in vitro and in vivo. RESULTS: AJAP1 expression was significantly decreased in gliomas compared with normal brain in REMBRANDT and CGCA cohorts. Additionally, low AJAP1 expression was associated with worse survival in GBMs in REMBRANDT and TCGA U133A cohorts and was significantly associated with classical and mesenchymal subtypes of GBMs among four cohorts. Confocal imaging indicated AJAP1 localized in cell membranes in low grade gliomas and AJAP1-overexpressing GBM cells, but difficult to assess in high grade gliomas due to its absence. AJAP1 overexpression altered the cytoskeleton and cellular polarity in vitro and inhibited the tumor growth in vivo. CONCLUSIONS: AJAP1 is dysregulated at an early stage of gliomagenesis and may suppress glioma cell invasion and proliferation, which suggests that AJAP1 may be a potential diagnostic and prognostic marker for gliomas. PMID- 24483343 TI - Mad Men as health communication: health-related themes in the hit AMC television series. AB - As a popular contemporary text, the appeal of cable television's Mad Men (AMC) lies in its capacity to highlight the differences between 1960s sensibilities and 21st-century assumptions. Viewers can enjoy a sense of superiority by recognizing the "folly" of the beliefs and actions of the characters with the benefit of historic hindsight, as well as noting the evolution of technology, philosophy, and human rights. Health-related scenes and themes in the series are a particularly interesting focus for analysis. We employ Burke's four master tropes as an analytical lens and argue that the dominant dramatic technique of irony, particularly in the form that we call strategic anachronism-derived from an audience's enjoyment of historical hindsight-highlights the racism, sexism, homophobia, and overall conservatism of the early 1960s while simultaneously serving to obfuscate the ways in which we still have much to critique in the delivery of contemporary health care and other body politics. PMID- 24483342 TI - Antioxidant and cytotoxic activities investigation of tomato seed extracts. AB - Biological activities of different varieties of tomato seed extracts were evaluated to verify the potential antioxidant and/or antiproliferative activity of the bioactive metabolites present in them. Findings demonstrated that among all the varieties investigated (San Marzano Rosso, San Marzano Giallo, Corbarino, Black Tomato and San Marzano/Black Tomato hybrid) San Marzano Rosso seed extract exhibited the highest free radical-scavenging activity with 68% of 2,2-Diphenyl-1 picrylhydrazyl radical inhibition, and the best cytotoxic activity evaluated by using the brine shrimp test (LD50: 23,198 ppm) and 3-(4,5-dimethylthiazol-2-yl) 2,5-phenyl-2H-tetrazolium bromide assay on A375 cell line (IC50: 137.7 MUg/mL). PMID- 24483344 TI - Turning gold into "diamond": a family of hexagonal diamond-type Au-frameworks interconnected by triangular clusters in the Sr-Al-Au system. AB - A new homologous series of intermetallic compounds containing three-dimensional (3-d) tetrahedral frameworks of gold atoms, akin to hexagonal diamond, have been discovered in four related Sr-Au-Al systems: (I) hexagonal SrAl3-xAu4+x (0.06(1) <= x <= 0.46(1), P62m, Z = 3, a = 8.633(1)-8.664(1) A, c = 7.083(2)-7.107(1) A); (II) orthorhombic SrAl2-yAu5+y (y <= 0.05(1); Pnma, Z = 4, a = 8.942(1) A, b = 7.2320(4) A, c = 9.918(1) A); (III) Sr2Al2-zAu7+z (z = 0.32(2); C2/c, Z = 4, a = 14.956(4) A, b = 8.564(2) A, c = 8.682(1) A, beta = 123.86(1) degrees ); and (IV) rhombohedral Sr2Al3-wAu6+w (w ~ 0.18(1); R3c, Z = 6, a = 8.448(1) A, c = 21.735(4) A). These remarkable compounds were obtained by fusion of the pure elements and were characterized by X-ray diffraction and electronic structure calculations. Phase I shows a narrow phase width and adopts the Ba3Ag14.6Al6.4 type structure; phase IV is isostructural with Ba2Au6Zn3, whereas phases II and III represent new structure types. This novel series can be formulated as Srx[M3]1-xAu2, in which [M3] (= [Al3] or [Al2Au]) triangles replace some Sr atoms in the hexagonal prismatic-like cavities of the Au network. The [M3] triangles are either isolated or interconnected into zigzag chains or nets. According to tight-binding electronic structure calculations, the greatest overlap populations belong to the Al-Au bonds, whereas Au-Au interactions have a substantial nonbonding region surrounding the calculated Fermi levels. QTAIM analysis of the electron density reveals charge transfer from Sr to the Al-Au framework in all four systems. A study of chemical bonding by means of the electron-localizability indicator indicates two- and three-center interactions within the anionic Al-Au framework. PMID- 24483345 TI - The comprehensive clinical management of multiple myeloma and related-plasma cell disorders. AB - Whilst we think of multiple myeloma and related plasma cell disorders as incurable to date, never before has there been such hope and enthusiasm about advances in the research and treatment of these various diseases. Translational research is very much at the forefront of progress for further refining targeted therapies and continuing to improve clinical efficacy. Whilst some of these advances in the last decade have been truly dramatic in their scope and timing, it is also worth noting that relatively incremental changes have favorably impacted on patient outcome, and this comprehensive clinical management review captures these accordingly. We hope therefore that this concise overview will give readers, be they specialist hemato-oncologists, or other providers and researchers in the field, an enlightening insight into the exciting future of therapeutic opportunities, as well as a practical 'hands on' approach. PMID- 24483347 TI - Response evaluation and monitoring of multiple myeloma. AB - Monitoring multiple myeloma (MM) is essential during the evaluation of response to each therapy line, after transplantation and at the time of relapse or progression in all patients. An initial complete workup, including appropriate protein studies in serum and urine is mandatory. The use of uniform criteria is particularly important in the context of clinical trials. Complete remission (CR) definition, the goal for the majority of patients, is now in constant evolution, with immunophenotypic and molecular minimal residual disease measurement in bone marrow as well as imaging techniques. Identification of relapse/progression with traditional and novel techniques for eventual prompt intervention with rescue treatment is a current issue of debate. PMID- 24483348 TI - Experimental research on a novel iodine-125 seed strand connected using magnesium alloy AZ31. AB - BACKGROUND AND PURPOSE: Aim of this research is to study the in vivo degradation and biocompatibility in rabbits and the dose distribution of novel iodine-125 seed strands connected using magnesium alloy AZ31. METHOD: Thirty-three New Zealand rabbits were divided into three Groups (A, B, and C). All rabbits in Groups A and C were implanted with VX2 tumors. For Group A, radioactive iodine 125 seed strands were implanted into the VX2 tumors. For Group B, non-radioactive iodine-125 seed strands were implanted into thigh muscle. Rabbits in Group C were used as controls. Displacement of the seed strands was assessed using X-ray and CT. Blood and urine samples were collected from all groups to measure changes in magnesium ion concentrations. The changing effect of alloy AZ31 tube according to dose distribution of iodine-125 was evaluated using the Monte Carlo method. RESULTS: In Groups A and B, 14 days after implantation, majority of the magnesium alloy tubes were fragmented, and 28 days after implantation, the magnesium alloy tubes were completely degraded. Small differences in dose distribution were observed between bare iodine-125 seeds and iodine-125 seed strands. CONCLUSIONS: Our results suggest that these novel iodine-125 seed strands connected using magnesium alloy AZ31 are promising anti-cancer drug for brachytherapy due to the rapid degradation of connective materials and even distribution of seed doses in tumors. Some recent patents are also outlined in this article. PMID- 24483349 TI - Comment on "Coherence and uncertainty in nanostructured organic photovoltaics". PMID- 24483346 TI - Staging and prognostication of multiple myeloma. AB - Multiple myeloma (MM) is a heterogeneous disease that, over the past 15 years, has seen an increased understanding of its biology and of novel therapeutic options. Distinctive subtypes of the disease have been described, each with different outcomes and clinic-pathological features. Even though a detailed classification of MM into at least seven or eight major subtypes is possible, a more practical clinical approach can classify the disease into high-risk and non high-risk MM. Such classification has permitted a more personalized approach to the management of the disease. Additionally, risk stratification should be included in outcome discussions with patients, as survival differs significantly by high-risk status. Nowadays, test for risk stratification are widely available and can be routinely used in the clinic. A greater understanding of the genetic abnormalities underlying the biology of MM will allow for the development of novel targeted therapies and better prognostic markers of the disease. PMID- 24483350 TI - Extensive experience in the management of macroprolactinomas. AB - OBJECTIVES: Macroprolactinomas are pituitary tumours that can be managed with dopamine agonists (DA), surgery and radiotherapy. We aimed to assess the outcomes of these treatment modalities. DESIGN: Retrospective case-note study of patients managed in a single tertiary referral centre. PATIENTS: One hundred patients (68 male) diagnosed with macroprolactinoma between 1971 and 2009. MEASUREMENTS: We assessed the response to first-line treatment in terms of reduction in serum prolactin, endocrine status, symptomatic improvement and tumour shrinkage. Patients were divided into a group that received only DA therapy and a group that received surgery, radiotherapy or both, with or without a DA. We compared pituitary function at baseline and at last clinic visit between the two groups. RESULTS: In total, there were 1170 patient years of follow-up. Pituitary surgery was performed in 29/100 patients. Fourteen patients received pituitary radiotherapy (8/14 surgery also). At last clinic visit, the nonmedical therapy group had a higher risk of gonadotrophin deficiency (77.4% vs 44.8%, P = 0.0037), TSH deficiency (54.8% vs 25.4%, P = 0.0009) and ACTH deficiency (56.2% vs 17.2%, P = 0.0001). When last reviewed, 23/29 (79.3%) patients who underwent surgery and 10/14 (71.4%) patients who received radiotherapy were taking a DA. CONCLUSIONS: Treatment with a DA alone is associated with better outcomes in terms of pituitary function and as such represents the optimal first-line therapy for macroprolactinomas. Surgery and radiotherapy should be reserved for patients who are either intolerant of or resistant to DAs. Following surgery and/or radiotherapy, the majority of patients still require a DA for control of prolactin hypersecretion. PMID- 24483351 TI - The flowers report: three views. PMID- 24483352 TI - How to ... :use games in medical education. AB - There is tremendous scope for greater use of games in medical education. In this introductory article, the authors explain what sets games apart from other learning activities, discuss the place of games in the curriculum, and list sources of information for interested teachers. This paper will be followed, in the next issue, by a detailed description of three examples of learning through games in biochemistry, physiology and pharmacology. PMID- 24483353 TI - Assessment of problem-solving skills, 2. AB - Techniques of assessing simultaneously all components of the problem-solving process are described and illustrated. The relative merits of each are examined. Methods of summarizing, scoring, and reporting performance on such exercises are considered and specific examples are given. PMID- 24483354 TI - The problems of separating education from practice. AB - In the next few issues we shall be highlighting some controversial topics in nurse education. Here, Dr Dorothy Kergin discusses the problems for learners and teachers created by the organizational separation of nurse education and nurse practice in Canada. Methods of bridging the gap at McMaster University include the establishment of communication channels, informal sharing of responsibilities and the funding of joint appointments. PMID- 24483355 TI - The anatomy of the peritoneum. AB - The author describes two educational strategies for helping students to understand the complex three-dimensional structure of the peritoneal cavity and the developmental changes by which that structure arises. The first strategy consists of a series of conducted circular tours round the peritoneal lining of the postnatal abdomen. The second is a demonstration of the developmental history of the placing of the gut and its peritoneum using a model. PMID- 24483356 TI - Teaching interpersonal skills in physician assistant programmes. AB - Increasing awareness that the technical competence of health professionals must be complemented by a well developed set of interpersonal skills (IPS) has resulted in the rapid growth of the formal teaching of IPS in training programmes for an important group of new health professionals in the United States-physician assistants (PAs). This is a report of a national survey which was part of a study designed to determine the extent and characteristics of IPS teaching. Most PA programmes have a specific course or a section of a large course for the teaching of IPS. Psychologists, physician assistants, and psychiatrists serve as teachers for most of these programmes. The majority of programmes teach process skills (for example, listening, responding), information-gathering skills, and psychological intervention skills (for example, demonstrating empathy). Less than half the programmes report the provision of instruction in one-to-one patient education, team membership skills, sexual and family counselling and self-care for health professionals. Most of the programmes which responded to the survey use videotechnology in teaching or assessing IPS. PMID- 24483357 TI - Lessons from BLAT. AB - As acronyms go, BLAT has little to commend it. It has been likened to the sort of expletive beloved by children's comics and can be roughly translated into Polish. The latter, with its allusion to a lady of the streets, is not totally inaccurate, as BLAT is at the service of the medical and health professions. BLAT actually stands for The British Life Assurance Trust, and it represents the coming together in 1966 of the British Medical Association and the British Life Offices, for the purpose of establishing a charitable trust to promote innovation in health and medical education. BMA requires no explanation; BLO is the professional organization of the companies who make up the life assurance industry in the UK. Health is the obvious common ground between the two parent bodies, with the facetious claiming that both have a common financial interest in keeping people alive: the one to maintain the patient list, the other to maintain the premium paying list.(1.) PMID- 24483360 TI - The MCQ Controversy: The Issue is Content, not Form. PMID- 24483362 TI - Jottings. PMID- 24483361 TI - Association for medical education in europe-annual conference 2-5 september, nijmegen, the Netherlands. PMID- 24483363 TI - Computers in the life sciences-applications in research and education. PMID- 24483364 TI - Comparison of film-coated retarded release pellets manufactured by layering technique or by bed rotor pelletization. AB - In order to investigate the influence of coatings for controlled active pharmaceutical ingredient (API) release, two types of pellets were used. Microcrystalline pellets were coated with a model API using the Wurster fluidized bed technique in laboratory scale (layered Cellets). Another type of pellets consisting of microcrystalline cellulose and model API was manufactured by fluidized bed rotor pelletization (matrix pellets (MP)). Both kinds of pellets were coated in a Wurster fluidized bed process with a polymer mixture of ethylcellulose to achieve retarded API release. With layered Cellets and an increased thickness of the ethylcellulose layer, the lag-time was increased and the release rate was decreased. In the case of MP, retardation was less pronounced probable due to inhomogeneous polymer film formation as a result of the porous particle surface. To reduce the surface roughness, the MP were coated with polyvinylpyrrolidone (PVP) as an intermediate smoothing layer, in a first trial step by step. In a second trial, pelletization and the coating steps were performed in an uninterrupted process. Intermediate PVP coating improved the ethylcellulose film formation and led to a more pronounced retardation of API release. The uninterrupted process of matrix pellet manufacturing and coating results in a product with only low retarded release. PMID- 24483365 TI - Unsaturated macrocyclic dihydroxamic acid siderophores produced by Shewanella putrefaciens using precursor-directed biosynthesis. AB - To acquire iron essential for growth, the bacterium Shewanella putrefaciens produces the macrocyclic dihydroxamic acid putrebactin (pbH2; [M + H(+)](+), m/zcalc 373.2) as its native siderophore. The assembly of pbH2 requires endogenous 1,4-diaminobutane (DB), which is produced from the ornithine decarboxylase (ODC)-catalyzed decarboxylation of l-ornithine. In this work, levels of endogenous DB were attenuated in S. putrefaciens cultures by augmenting the medium with the ODC inhibitor 1,4-diamino-2-butanone (DBO). The presence in the medium of DBO together with alternative exogenous non-native diamine substrates, (15)N2-1,4-diaminobutane ((15)N2-DB) or 1,4-diamino-2(E)-butene (E DBE), resulted in the respective biosynthesis of (15)N-labeled pbH2 ((15)N4-pbH2; [M + H(+)](+), m/zcalc 377.2, m/zobs 377.2) or the unsaturated pbH2 variant, named here: E,E-putrebactene (E,E-pbeH2; [M + H(+)](+), m/zcalc 369.2, m/zobs 369.2). In the latter system, remaining endogenous DB resulted in the parallel biosynthesis of the monounsaturated DB-E-DBE hybrid, E-putrebactene (E-pbxH2; [M + H(+)](+), m/zcalc 371.2, m/zobs 371.2). These are the first identified unsaturated macrocyclic dihydroxamic acid siderophores. LC-MS measurements showed 1:1 complexes formed between Fe(III) and pbH2 ([Fe(pb)](+); [M](+), m/zcalc 426.1, m/zobs 426.2), (15)N4-pbH2 ([Fe((15)N4-pb)](+); [M](+), m/zcalc 430.1, m/zobs 430.1), E,E-pbeH2 ([Fe(E,E-pbe)](+); [M](+), m/zcalc 422.1, m/zobs 422.0), or E-pbxH2 ([Fe(E-pbx)](+); [M](+), m/zcalc 424.1, m/zobs 424.2). The order of the gain in siderophore-mediated Fe(III) solubility, as defined by the difference in retention time between the free ligand and the Fe(III)-loaded complex, was pbH2 (DeltatR = 8.77 min) > E-pbxH2 (DeltatR = 6.95 min) > E,E-pbeH2 (DeltatR = 6.16 min), which suggests one possible reason why nature has selected for saturated rather than unsaturated siderophores as Fe(III) solubilization agents. The potential to conduct multiple types of ex situ chemical conversions across the double bond(s) of the unsaturated macrocycles provides a new route to increased molecular diversity in this class of siderophore. PMID- 24483366 TI - Relationship between brain volumetric changes and interim drinking at six months in alcohol-dependent patients. AB - BACKGROUND: Chronic alcohol consumption results in brain damage potentially reversible with abstinence. It is however difficult to gauge the degree of recovery of brain tissues with abstinence since changes are subtle and a significant portion of patients relapse. State-of-the-art morphometric methods are increasingly used in neuroimaging studies to detect subtle brain changes at a voxel level. Our aim was to use the most refined morphometric methods to observe in alcohol dependence the relationship between volumetric changes and interim drinking over a 6-month follow-up. METHODS: Overall, 19 patients with alcohol dependence received volumetric T1-weighted magnetic resonance imaging (MRI) after detoxification. A 6-month follow-up study was then conducted, during which 11 of them received a second MRI scan. First, correlations were conducted between gray matter (GM) and white matter (WM) volumes of patients at alcohol treatment entry and the amount of alcohol consumed between treatment entry and follow-up. Second, longitudinal analyses were performed from pairs of MRI scans using tensor-based morphometry in the 11 patients, and correlations were computed between the resultant Jacobian maps of GM and WM and interim drinking. RESULTS: Our preliminary results showed that, among others, alcoholics with smaller thalamus at alcohol treatment entry tended to resume with heavy alcohol consumption (p < 0.005 uncorrected [unc.]). Our longitudinal study revealed an overall inverse relationship between recovery of brain structures like the cerebellum, striatum, and cingulate gyrus, and the amount of alcohol consumed over the 6-month follow up (p < 0.005 unc.). The recovery could be observed not only with strict abstinence but also in cases of moderate resumption of alcohol consumption, when there had been no drastic relapse into alcohol dependence. CONCLUSIONS: Those preliminary findings indicate that the volume of the thalamus at treatment entry may have an influence on subsequent interim drinking. There is recovery of certain brain regions even when patients resume with moderate, but not drastic, alcohol consumption. PMID- 24483368 TI - Classical density functional theory for associating fluids in orienting external fields. AB - We develop a classical density functional theory (DFT) for two-site associating fluids in spatially homogeneous external fields which exhibit orientational inhomogeneities. The Helmholtz free-energy functional is obtained using Wertheim's thermodynamic perturbation theory and the orientational distribution function is obtained using DFT in the canonical ensemble. It is shown that an orientating field significantly enhances association by ordering the molecules, thereby reducing the entropic penalty of association. It is also shown that association enhances the orientational order for fixed field strength. PMID- 24483369 TI - Dynamical arrest in adhesive hard-sphere dispersions driven by rigidity percolation. AB - One major goal in condensed matter is identifying the physical mechanisms that lead to arrested states of matter, especially gels and glasses. The complex nature and microscopic details of each particular system are relevant. However, from both scientific and technological viewpoints, a general, consistent and unified definition is of paramount importance. Through Monte Carlo computer simulations of states identified in experiments, we demonstrate that dynamical arrest in adhesive hard-sphere dispersions is the result of rigidity percolation with coordination number equal to 2.4. This corresponds to an established mechanism leading to mechanical transitions in network-forming materials [Phys. Rev. Lett. 54, 2107 (1985)]. Our findings connect the concept of critical gel formation in colloidal suspensions with short-range attractive interactions to the universal concept of rigidity percolation. Furthermore, the bond, angular, and local distributions along the gelation line are explicitly studied in order to determine the topology of the structure at the critical gel state. PMID- 24483370 TI - Fractographic aspects of crack branching instability using a phase-field model. AB - A phase-field model of a crack front propagating in a three-dimensional brittle material is used to study the fractographic patterns induced by the branching instability. The numerical results of this model give rise to crack surfaces that are similar to those obtained in various experimental situations. Depending on applied loading configurations and initial conditions, we show that the branching instability is either restricted to a portion of the crack front or revealed through quasi-two-dimensional branches. For the former, the crack front leaves on the main broken surface either aligned or disordered parabolic marks. For the latter, fractography reveals the so called echelon cracks showing that branching instability can also induce crack front fragmentation. PMID- 24483371 TI - Self-organized defect strings in two-dimensional crystals. AB - Using experiments with single-particle resolution and computer simulations we study the collective behavior of multiple vacancies injected into two-dimensional crystals. We find that the defects assemble into linear strings, terminated by dislocations with antiparallel Burgers vectors. We show that these defect strings propagate through the crystal in a succession of rapid one-dimensional gliding and rare rotations. While the rotation rate decreases exponentially with the number of defects in the string, the diffusion constant is constant for large strings. By monitoring the separation of the dislocations at the end points, we measure their effective interactions with high precision beyond their spontaneous formation and annihilation, and we explain the double-well form of the dislocation interaction in terms of continuum elasticity theory. PMID- 24483367 TI - Enzyme recruitment and its role in metabolic expansion. AB - Although more than 10(9) years have passed since the existence of the last universal common ancestor, proteins have yet to reach the limits of divergence. As a result, metabolic complexity is ever expanding. Identifying and understanding the mechanisms that drive and limit the divergence of protein sequence space impact not only evolutionary biologists investigating molecular evolution but also synthetic biologists seeking to design useful catalysts and engineer novel metabolic pathways. Investigations over the past 50 years indicate that the recruitment of enzymes for new functions is a key event in the acquisition of new metabolic capacity. In this review, we outline the genetic mechanisms that enable recruitment and summarize the present state of knowledge regarding the functional characteristics of extant catalysts that facilitate recruitment. We also highlight recent examples of enzyme recruitment, both from the historical record provided by phylogenetics and from enzyme evolution experiments. We conclude with a look to the future, which promises fruitful consequences from the convergence of molecular evolutionary theory, laboratory directed evolution, and synthetic biology. PMID- 24483372 TI - Instabilities at frictional interfaces: creep patches, nucleation, and rupture fronts. AB - The strength and stability of frictional interfaces, ranging from tribological systems to earthquake faults, are intimately related to the underlying spatially extended dynamics. Here we provide a comprehensive theoretical account, both analytic and numeric, of spatiotemporal interfacial dynamics in a realistic rate and-state friction model, featuring both velocity-weakening and velocity strengthening behaviors. Slowly extending, loading-rate-dependent creep patches undergo a linear instability at a critical nucleation size, which is nearly independent of interfacial history, initial stress conditions, and velocity strengthening friction. Nonlinear propagating rupture fronts-the outcome of instability-depend sensitively on the stress state and velocity-strengthening friction. Rupture fronts span a wide range of propagation velocities and are related to steady-state-front solutions. PMID- 24483373 TI - Moving contact line of a volatile fluid. AB - Interfacial flows close to a moving contact line are inherently multiscale. The shape of the interface and the flow at meso- and macroscopic scales inherit an apparent interface slope and a regularization length, both named after Voinov, from the microscopic inner region. Here, we solve the inner problem associated with the contact line motion for a volatile fluid at equilibrium with its vapor. The evaporation or condensation flux is then controlled by the dependence of the saturation temperature on interface curvature-the so-called Kelvin effect. We derive the dependencies of the Voinov angle and of the Voinov length as functions of the parameters of the problem. We then identify the conditions under which the Kelvin effect is indeed the mechanism regularizing the contact line motion. PMID- 24483374 TI - Stochastic fluctuations and the detectability limit of network communities. AB - We have analyzed the detectability limits of network communities in the framework of the popular Girvan and Newman benchmark. By carefully taking into account the inevitable stochastic fluctuations that affect the construction of each and every instance of the benchmark, we come to the conclusion that the native, putative partition of the network is completely lost even before the in-degree/out-degree ratio becomes equal to that of a structureless Erdos-Renyi network. We develop a simple iterative scheme, analytically well described by an infinite branching process, to provide an estimate of the true detectability limit. Using various algorithms based on modularity optimization, we show that all of them behave (semiquantitatively) in the same way, with the same functional form of the detectability threshold as a function of the network parameters. Because the same behavior has also been found by further modularity-optimization methods and for methods based on different heuristics implementations, we conclude that indeed a correct definition of the detectability limit must take into account the stochastic fluctuations of the network construction. PMID- 24483375 TI - Classification of transport backbones of complex networks. AB - Transport properties in random and scale-free (SF) networks are studied by analyzing the betweenness centrality (BC) distribution P(B) in the minimum spanning trees (MSTs) and infinite incipient percolation clusters (IIPCs) of the networks. It is found that P(B) in MSTs scales as P(B)~B(-delta). The obtained values of delta are classified into two different categories, delta?1.6 and delta?2.0. Using the mapping between BC and the branch size of tree structures, it is proved that delta in MSTs which are close to critical trees is 1.6. In contrast, delta in MSTs which are supercritical trees is shown to be 2.0. We also find delta=1.5 in IIPCs, which is a natural result because IIPC is physically critical. Based on the results in MSTs, a physical reason why delta>=2 in the original networks is suggested. PMID- 24483377 TI - Random-matrix spectra as a time series. AB - Spectra of ordered eigenvalues of finite random matrices are interpreted as a time series. Data-adaptive techniques from signal analysis are applied to decompose the spectrum in clearly differentiated trend and fluctuation modes, avoiding possible artifacts introduced by standard unfolding techniques. The fluctuation modes are scale invariant and follow different power laws for Poisson and Gaussian ensembles, which already during the unfolding allows one to distinguish the two cases. PMID- 24483376 TI - Stabilizing saddles. AB - A synergetic control technique for stabilizing a priori unknown saddle steady states of dynamical systems is described. The method involves an unstable filter technique combined with a derivative feedback. The cut-off frequency of the filter is not limited by the damping of the system, and therefore can be set relatively high. This essentially increases the rate of convergence to the steady state. The synergetic technique is robust to the influence of unknown external forces, which change the coordinates of the steady state in the phase space. PMID- 24483379 TI - Monte Carlo simulation with aspect-ratio optimization: anomalous anisotropic scaling in dimerized antiferromagnets. AB - We present a method that optimizes the aspect ratio of a spatially anisotropic quantum lattice model during the quantum Monte Carlo simulation, and realizes the virtually isotropic lattice automatically. The anisotropy is removed by using the Robbins-Monro algorithm based on the correlation length in each direction. The method allows for comparing directly the value of the critical amplitude among different anisotropic models, and identifying the universality more precisely. We apply our method to the staggered dimer antiferromagnetic Heisenberg model and demonstrate that the apparent nonuniversal behavior is attributed mainly to the strong size correction of the effective aspect ratio due to the existence of the cubic interaction. PMID- 24483378 TI - Contraction of an air disk caught between two different liquids. AB - When a drop impacts a pool of liquid it entraps a thin disk of air under its center. This disk contracts rapidly into a bubble to minimize surface energy. Herein we use ultra-high-speed imaging to measure the contraction speed of this disk when the drop and pool are of different liquids. For miscible liquids the contraction rate is governed by the weaker of the two surface tensions. Some undulations are observed on the edge of the disk for a water drop impacting a pool of water, but not on a pool of lower surface tension. Similar results are observed for a pair of immiscible liquids. PMID- 24483380 TI - Biased and greedy random walks on two-dimensional lattices with quenched randomness: the greedy ant within a disordered environment. AB - The main characteristics of biased greedy random walks (BGRWs) on two-dimensional lattices with real-valued quenched disorder on the lattice edges are studied. Here the disorder allows for negative edge weights. In previous studies, considering the negative-weight percolation (NWP) problem, this was shown to change the universality class of the existing, static percolation transition. In the presented study, four different types of BGRWs and an algorithm based on the ant colony optimization heuristic were considered. Regarding the BGRWs, the precise configurations of the lattice walks constructed during the numerical simulations were influenced by two parameters: a disorder parameter rho that controls the amount of negative edge weights on the lattice and a bias strength B that governs the drift of the walkers along a certain lattice direction. The random walks are "greedy" in the sense that the local optimal choice of the walker is to preferentially traverse edges with a negative weight (associated with a net gain of "energy" for the walker). Here, the pivotal observable is the probability that, after termination, a lattice walk exhibits a total negative weight, which is here considered as percolating. The behavior of this observable as function of rho for different bias strengths B is put under scrutiny. Upon tuning rho, the probability to find such a feasible lattice walk increases from zero to 1. This is the key feature of the percolation transition in the NWP model. Here, we address the question how well the transition point rho(c), resulting from numerically exact and "static" simulations in terms of the NWP model, can be resolved using simple dynamic algorithms that have only local information available, one of the basic questions in the physics of glassy systems. PMID- 24483381 TI - Work fluctuations in a time-dependent harmonic potential: rigorous results beyond the overdamped limit. AB - We investigate the stochastic motion of a Brownian particle in the harmonic potential with a time-dependent force constant. It may describe the motion of a colloidal particle in an optical trap where the potential well is formed by a time-dependent field. We use the path integral formalism to solve the Langevin equation and the associated Fokker-Planck (Kramers) equation. Rigorous relations are derived to generate the probability density function for the time-dependent nonequilibrium work production beyond the overdamped limit. We find that the work distribution exhibits an exponential tail with a power-law prefactor, accompanied by an interesting oscillatory feature (multiple pseudo-locking-unlocking transitions) due to the inertial effect. Some exactly solvable cases are discussed in the overdamped limit. PMID- 24483382 TI - Criticality and scaling behavior of percolation with multiple giant clusters under an Achlioptas process. AB - Achlioptas processes, a class of percolation models which can lead to rich critical phenomena, including the well-known explosive percolation, have attracted much attention in recent years. In this paper, we show that, in a three vertex Achlioptas process, two giant clusters emerge after the percolation transition with size fluctuations in different realizations, and the choice of the connecting vertex in the smaller cluster depends on a probability parameter p, the increase of which can make the transition sharper. Using finite-size scaling analysis, we can determine the critical point r(c) and critical exponents eta, 1/nu, and beta through Monte Carlo simulations. Comparison of such exponents for different giant clusters indicates that their critical nature is always the same. However, when link choice is strongly biased, it is surprising that the scaling relation eta=beta/nu is violated, and the data collapse for scaling function diverges. Furthermore, by inspecting the variance of exponents with p, three distinct scaling phases are classified for different parameter intervals according to the divergence scaling function, which suggests an inconsistent scaling form in the critical window with the supercritical region. The study on the criticality and scaling behavior of multiple giant clusters in an Achlioptas process, in particular, the discovery of three scaling phases that depend on the parameter p, may help us in finding a complete scaling theory for the Achlioptas process percolation and give insight into understanding the accelerating nature of the phase transition for Achlioptas processes once reaching criticality. PMID- 24483383 TI - Pattern formation in individual-based systems with time-varying parameters. AB - We study the patterns generated in finite-time sweeps across symmetry-breaking bifurcations in individual-based models. Similar to the well-known Kibble-Zurek scenario of defect formation, large-scale patterns are generated when model parameters are varied slowly, whereas fast sweeps produce a large number of small domains. The symmetry breaking is triggered by intrinsic noise, originating from the discrete dynamics at the microlevel. Based on a linear-noise approximation, we calculate the characteristic length scale of these patterns. We demonstrate the applicability of this approach in a simple model of opinion dynamics, a model in evolutionary game theory with a time-dependent fitness structure, and a model of cell differentiation. Our theoretical estimates are confirmed in simulations. In further numerical work, we observe a similar phenomenon when the symmetry breaking bifurcation is triggered by population growth. PMID- 24483384 TI - Transport and diffusion of overdamped Brownian particles in random potentials. AB - We present a numerical study of the anomalies in transport and diffusion of overdamped Brownian particles in totally disordered potential landscapes in one and in two dimensions. We characterize and analyze the effects of three different disordered potentials. The anomalous regimes are characterized by the time exponents that exhibit the statistical moments of the ensemble of particle trajectories. The anomaly in the transport is always of the subtransport type, but diffusion presents a greater variety of anomalies: Both subdiffusion and superdiffusion are possible. In two dimensions we present a mixed anomaly: subdiffusion in the direction perpendicular to the force and superdiffusion in the parallel direction. PMID- 24483385 TI - Renewal and memory origin of anomalous diffusion: a discussion of their joint action. AB - The adoption of the formalism of fractional calculus is an elegant way to simulate either subdiffusion or superdiffusion from within a renewal perspective where the occurrence of an event at a given time t does not have any memory of the events occurring at earlier times. We illustrate a physical model to assign infinite memory to renewal anomalous diffusion and we find (i) a condition where the simultaneous action of a renewal and a memory source of subdiffusion generates localization and (ii) a condition where they make subdiffusion weaker and superdiffusion emerge. We argue that our approach may provide important contributions to the current search to distinguish the renewal from the memory source of subdiffusion. PMID- 24483386 TI - Thermodynamics of quantum-jump-conditioned feedback control. AB - We consider open quantum systems weakly coupled to thermal reservoirs and subjected to quantum feedback operations triggered with or without delay by monitored quantum jumps. We establish a thermodynamic description of such systems and analyze how the first and second law of thermodynamics are modified by the feedback. We apply our formalism to study the efficiency of a qubit subjected to a quantum feedback control and operating as a heat pump between two reservoirs. We also demonstrate that quantum feedbacks can be used to stabilize coherences in nonequilibrium stationary states which in some cases may even become pure quantum states. PMID- 24483387 TI - Analytical calculation of four-point correlations for a simple model of cages involving numerous particles. AB - Dynamics of a one-dimensional system of Brownian particles with short-range repulsive interaction (diameter sigma) is studied with a liquid-theoretical approach. The mean square displacement, the two-particle displacement correlation, and the overlap-density-based generalized susceptibility are calculated analytically by way of the Lagrangian correlation of the interparticulate space, instead of the Eulerian correlation of density that is commonly used in the standard mode-coupling theory. In regard to the mean square displacement, the linear analysis reproduces the established result on the asymptotic subdiffusive behavior of the system. A finite-time correction is given by incorporating the effect of entropic nonlinearity with a Lagrangian version of mode-coupling theory. The notorious difficulty in derivation of the mode-coupling theory concerning violation of the fluctuation-dissipation theorem is found to disappear by virtue of the Lagrangian description. The Lagrangian description also facilitates analytical calculation of four-point correlations in the space time, such as the two-particle displacement correlation. The two-particle displacement correlation, which is asymptotically self-similar in the space-time, illustrates how the cage effect confines each particle within a short radius on one hand and creates collective motion of numerous particles on the other hand. As the time elapses, the correlation length grows unlimitedly, and the generalized susceptibility based on the overlap density converges to a finite value which is an increasing function of the density. The distribution function behind these dynamical four-point correlations and its extension to three dimensional cases, respecting the tensorial character of the two-particle displacement correlation, are also discussed. PMID- 24483388 TI - Stability of earthquake clustering models: criticality and branching ratios. AB - We study the stability conditions of a class of branching processes prominent in the analysis and modeling of seismicity. This class includes the epidemic-type aftershock sequence (ETAS) model as a special case, but more generally comprises models in which the magnitude distribution of direct offspring depends on the magnitude of the progenitor, such as the branching aftershock sequence (BASS) model and another recently proposed branching model based on a dynamic scaling hypothesis. These stability conditions are closely related to the concepts of the criticality parameter and the branching ratio. The criticality parameter summarizes the asymptotic behavior of the population after sufficiently many generations, determined by the maximum eigenvalue of the transition equations. The branching ratio is defined by the proportion of triggered events in all the events. Based on the results for the generalized case, we show that the branching ratio of the ETAS model is identical to its criticality parameter because its magnitude density is separable from the full intensity. More generally, however, these two values differ and thus place separate conditions on model stability. As an illustration of the difference and of the importance of the stability conditions, we employ a version of the BASS model, reformulated to ensure the possibility of stationarity. In addition, we analyze the magnitude distributions of successive generations of the BASS model via analytical and numerical methods, and find that the compound density differs substantially from a Gutenberg-Richter distribution, unless the process is essentially subcritical (branching ratio less than 1) or the magnitude dependence between the parent event and the direct offspring is weak. PMID- 24483390 TI - Persistence of Brownian motion in a shear flow. AB - The persistence of a Brownian particle in a shear flow is investigated. The persistence probability P(t), which is the probability that the particle does not return to its initial position up to time t, is known to obey a power law P(t)?t( theta). Since the displacement of a particle along the flow direction due to convection is much larger than that due to Brownian motion, we define an alternative displacement in which the convection effect is removed. We derive theoretically the two-time correlation function and the persistence exponent theta of this displacement. The exponent has different values at short and long times. The theoretical results are compared with experiment and a good agreement is found. PMID- 24483389 TI - Evanescent continuous-time random walks. AB - We study how an evanescence process affects the number of distinct sites visited by a continuous-time random walker in one dimension. We distinguish two very different cases, namely, when evanescence can only occur concurrently with a jump, and when evanescence can occur at any time. The first is characteristic of trapping processes on a lattice, whereas the second is associated with spontaneous death processes such as radioactive decay. In both of these situations we consider three different forms of the waiting time distribution between jumps, namely, exponential, long tailed, and ultraslow. PMID- 24483391 TI - Kinetics of deposition of oriented superdisks. AB - We use numerical Monte Carlo simulation to study the kinetics of the deposition of oriented superdisks, bounded by the Lame curves of the form |x|(2p)+|y|(2p)=1 on a regular planar substrate. Recently, it was shown that the maximum packing density as well as jamming density rho(J) exhibit a discontinuous derivative at p=0.5 when the shape changes from convex to concave form. By careful examination of the late-stage approach to the jamming limit, we find that the leading term in the temporal development is also nonanalytic at p=0.5 and offer heuristic excluded-area arguments for this behavior. PMID- 24483392 TI - Counting metastable states in a kinetically constrained model using a patch repetition analysis. AB - We analyze metastable states in the East model, using a recently proposed patch repetition analysis based on time-averaged density profiles. The results reveal a hierarchy of states of varying lifetimes, consistent with previous studies in which the metastable states were identified and used to explain the glassy dynamics of the model. We establish a mapping between these states and configurations of systems of hard rods, which allows us to analyze both typical and atypical metastable states. We discuss connections between the complexity of metastable states and large-deviation functions of dynamical quantities, both in the context of the East model and more generally in glassy systems. PMID- 24483393 TI - Conciliating synchronicity with spatial discretization, exclusion, interactions, and detailed balance. AB - The construction of a discrete stochastic system of interacting particles that evolves through a fully synchronous evolution rule while satisfying detailed balance is a highly demanding task. As a consequence, the presence of nontrivial interaction fields can make synchronicity and thermodynamic equilibrium look as two conflicting counterparts. We show that, with the proper prescriptions, the process of migration of particles in a lattice of mutually exclusive nodes can be simulated with a fully synchronous algorithm, which we call parallel Kawasaki dynamics (PKD), that incorporates site exclusion, local interactions, and detailed balance without the need of system partitioning schemes. We show that the underlying pseudo-Hamiltonian (which is derived from the PKD dynamics instead of being assumed a priori as usual in a sequential Monte Carlo scheme) is temperature dependent and causes the resulting equilibrium properties to differ substantially from the conventional hopping model when the system is near critical conditions. PMID- 24483394 TI - Coefficient of performance for a low-dissipation Carnot-like refrigerator with nonadiabatic dissipation. AB - We study the coefficient of performance (COP) and its bounds for a Carnot-like refrigerator working between two heat reservoirs at constant temperatures T(h) and T(c), under two optimization criteria chi and Omega. In view of the fact that an "adiabatic" process usually takes finite time and is nonisentropic, the nonadiabatic dissipation and the finite time required for the adiabatic processes are taken into account by assuming low dissipation. For given optimization criteria, we find that the lower and upper bounds of the COP are the same as the corresponding ones obtained from the previous idealized models where any adiabatic process is undergone instantaneously with constant entropy. To describe some particular models with very fast adiabatic transitions, we also consider the influence of the nonadiabatic dissipation on the bounds of the COP, under the assumption that the irreversible entropy production in the adiabatic process is constant and independent of time. Our theoretical predictions match the observed COPs of real refrigerators more closely than the ones derived in the previous models, providing a strong argument in favor of our approach. PMID- 24483395 TI - Local immobilization of particles in mass transfer described by a Jeffreys-type equation. AB - We consider the Jeffreys-type equation as the foundation in three different models of mass transfer, namely, the Jeffreys-type and two-phase models and the D(1) approximation to the linear Boltzmann equation. We study two classic (1+1) dimensional problems in the framework of each model. The first problem is the transfer of a substance initially confined at a point. The second problem is the transfer of a substance from a stationary point source. We calculate the mean square displacement (MSD) for the solutions of the first problem. The temporal behavior of the MSD in the framework of the first and third models is found to be the same as that in the Brownian motion described by the standard Langevin equation. In addition, we find a remarkable phenomenon when a portion of the substance does not move. PMID- 24483396 TI - Scaling behavior of the Heisenberg model in three dimensions. AB - We report on extensive numerical simulations of the three-dimensional Heisenberg model and its analysis through finite-size scaling of Lee-Yang zeros. Besides the critical regime, we also investigate scaling in the ferromagnetic phase. We show that, in this case of broken symmetry, the corrections to scaling contain information on the Goldstone modes. We present a comprehensive Lee-Yang analysis, including the density of zeros, and confirm recent numerical estimates for critical exponents. PMID- 24483397 TI - Driven isotropic Heisenberg spin chain with arbitrary boundary twisting angle: exact results. AB - We consider an open isotropic Heisenberg quantum spin chain, coupled at the ends to boundary reservoirs polarized in different directions, which sets up a twisting gradient across the chain. Using a matrix product ansatz, we calculate the exact magnetization profiles and magnetization currents in the nonequilibrium steady state of a chain with N sites. The magnetization profiles are harmonic functions with a frequency proportional to the twisting angle theta. The currents of the magnetization components lying in the twisting plane and in the orthogonal direction behave qualitatively differently: In-plane steady-state currents scale as 1/N^{2} for fixed and sufficiently large boundary coupling, and vanish as the coupling increases, while the transversal current increases with the coupling and saturates to 2theta/N. PMID- 24483398 TI - Chloride ions induce order-disorder transition at water-oxide interfaces. AB - Water can form quasi-two-dimensional ordered layers near a solid interface. The solvation dynamics and ionic transport phenomena through this ordered water structure is of direct relevance to a variety of problems in interface science. Molecular dynamics simulations are used to study the impact of local fluctuation of the chloride ion density in the vicinity of an oxide surface on the structure and dynamics of water layers. We demonstrate that local increase in chloride ions beyond a threshold concentration near the water-MgO (100) interface introduces an order-disorder transition of this two-dimensional layered network into bulklike water, leading to increased diffusional characteristics and reduced hydrogen bonding lifetimes. We find that the extent of this order-disorder transition can be tuned by modifying the defect chemistry and nature of the underlying substrate. The kinetic fluidity resulting from order-disorder transition at high chloride ion concentration has significance for a broad range of phenomena, ranging from freezing point depression of brine to onset of aqueous corrosion. PMID- 24483399 TI - Performance characteristics and optimal analysis of a nanosized quantum dot photoelectric refrigerator. AB - We study the thermodynamic performance of a nanosized photoelectric refrigerator consisting of three coupled single-level quantum dots embedded between two reservoirs at different temperatures. Based on the quantum master equation, we derive expressions for the cooling power and coefficient of performance (COP) of the refrigerator and plot the characteristic curves between the cooling power and the COP. We analyze the optimal performance parameters under conditions of maximum cooling power and maximum COP, and we discuss the influence of the energy level difference and the temperature ratio on the optimal performance parameters in detail. PMID- 24483400 TI - Two rigidity-percolation transitions on binary Bethe networks and the intermediate phase in glass. AB - Rigidity percolation is studied analytically on randomly bonded networks with two types of nodes, respectively, with coordination numbers z(1) and z(2), and with g(1) and g(2) degrees of freedom each. For certain cases that model chalcogenide glass networks, two transitions, both of first order, are found, with the first transition usually rather weak. The ensuing intermediate pase, although not isostatic in its entirety, has very low self-stress. Our results suggest a possible mechanism for the appearance of intermediate phases in glass that does not depend on a self-organization principle. PMID- 24483401 TI - Boosting work characteristics and overall heat-engine performance via shortcuts to adiabaticity: quantum and classical systems. AB - Under a general framework, shortcuts to adiabatic processes are shown to be possible in classical systems. We study the distribution function of the work done on a small system initially prepared at thermal equilibrium. We find that the work fluctuations can be significantly reduced via shortcuts to adiabatic processes. For example, in the classical case, probabilities of having very large or almost zero work values are suppressed. In the quantum case, negative work may be totally removed from the otherwise non-positive-definite work values. We also apply our findings to a micro Otto-cycle-based heat engine. It is shown that the use of shortcuts, which directly enhances the engine output power, can also increase the heat-engine efficiency substantially, in both quantum and classical regimes. PMID- 24483402 TI - Thermodynamic cost of acquiring information. AB - Connections between information theory and thermodynamics have proven to be very useful to establish bounding limits for physical processes. Ideas such as Landauer's erasure principle and information-assisted work extraction have greatly contributed not only to broadening our understanding about the fundamental limits imposed by nature, but also paving the way for practical implementations of information-processing devices. The intricate information thermodynamics relation also entails a fundamental limit on parameter estimation, establishing a thermodynamic cost for information acquisition. We show that the amount of information that can be encoded in a physical system by means of a unitary process is limited by the dissipated work during the implementation of the process. This includes a thermodynamic tradeoff for information acquisition. Likewise, the information acquisition process is ultimately limited by the second law of thermodynamics. This tradeoff for information acquisition may find applications in several areas of knowledge. PMID- 24483403 TI - Transient aging in fractional Brownian and Langevin-equation motion. AB - Stochastic processes driven by stationary fractional Gaussian noise, that is, fractional Brownian motion and fractional Langevin-equation motion, are usually considered to be ergodic in the sense that, after an algebraic relaxation, time and ensemble averages of physical observables coincide. Recently it was demonstrated that fractional Brownian motion and fractional Langevin-equation motion under external confinement are transiently nonergodic-time and ensemble averages behave differently-from the moment when the particle starts to sense the confinement. Here we show that these processes also exhibit transient aging, that is, physical observables such as the time-averaged mean-squared displacement depend on the time lag between the initiation of the system at time t=0 and the start of the measurement at the aging time t(a). In particular, it turns out that for fractional Langevin-equation motion the aging dependence on t(a) is different between the cases of free and confined motion. We obtain explicit analytical expressions for the aged moments of the particle position as well as the time averaged mean-squared displacement and present a numerical analysis of this transient aging phenomenon. PMID- 24483404 TI - Dependence of asymptotic decay exponents on initial condition and the resulting scaling violation. AB - There are several examples which show that the critical exponents can be dependent on the initial condition of the system. In such situations, there are many systems where various issues related to the universal behavior, e.g., the existence of universality, the splitting of the universality class, scaling violations, whether the initial dependence should persist even after a sufficiently long time or is a transient effect, the reasons for such features, etc. are not yet quite clear. In this article, with the simple example of the conserved lattice gas model (CLG), we investigate such issues and clearly show that under certain situations the asymptotic decay exponents are, in fact, dependent on the initial condition of the system. We show that such an effect arises because of the existence of two competing time scales and identify the initial conditions which capture the universal features of the system. PMID- 24483405 TI - Geometrical aspects of quantum walks on random two-dimensional structures. AB - We study the transport properties of continuous-time quantum walks (CTQWs) over finite two-dimensional structures with a given number of randomly placed bonds and with different aspect ratios (ARs). Here, we focus on the transport from, say, the left side to the right side of the structure where absorbing sites are placed. We do so by analyzing the long-time average of the survival probability of CTQWs. We compare the results to the classical continuous-time random walk case (CTRW). For small ARs (landscape configurations) we observe only small differences between the quantum and the classical transport properties, i.e., roughly the same number of bonds is needed to facilitate the transport. However, with increasing ARs (portrait configurations) a much larger number of bonds is needed in the CTQW case than in the CTRW case. While for CTRWs the number of bonds needed decreases when going from small ARs to large ARs, for CTQWs this number is large for small ARs, has a minimum for the square configuration, and increases again for increasing ARs. We explain our findings by analyzing the average eigenstates of the corresponding structures: The participation ratios allow us to distinguish between localized and nonlocalized (average) eigenstates. In particular, for large ARs we find for CTQWs that the eigenstates are localized for bond numbers exceeding the bond numbers needed to facilitate transport in the CTRW case. Thus, a rather large number of bonds is needed in order for quantum transport to be efficient for large ARs. PMID- 24483406 TI - Design and characterization of nonlinear functions for the transmission of a small signal with non-Gaussian noise. AB - We design nonlinear functions for the transmission of a small signal with non Gaussian noise and perform experiments to characterize their responses. Using statistical design theory [A. Ichiki and Y. Tadokoro, Phys. Rev. E 87, 012124 (2013)], a static nonlinear function is estimated from the probability density function of the given noise in order to maximize the signal-to-noise ratio of the output. Using an electronic system that implements the optimized nonlinear function, we confirm the recovery of a small signal from a signal with non Gaussian noise. In our experiment, the non-Gaussian noise is a mixture of Gaussian noises. A similar technique is also applied to the optimization of the threshold value of the function. We find that, for non-Gaussian noise, the response of the optimized nonlinear systems is better than that of the linear system. PMID- 24483407 TI - Information-driven current in a quantum Maxwell demon. AB - We describe a minimal model of a quantum Maxwell demon obeying Hamiltonian dynamics. The model is solved exactly, and we analyze its steady-state behavior. We find that writing information to a quantum memory induces a probability current through the demon, which is the quantum analog of the classical Maxwell demon's action. Our model offers a simple and pedagogical paradigm for investigating the thermodynamics of quantum information processing. PMID- 24483408 TI - Rectification and diffusion of self-propelled particles in a two-dimensional corrugated channel. AB - Rectification and diffusion of noninteracting self-propelled particles is numerically investigated in a two-dimensional corrugated channel. From numerical simulations, we obtain the average velocity and the effective diffusion coefficient. It is found that the self-propelled particles can be rectified by the self-propelled velocity. There exist optimal values of the parameters (the self-propelled velocity, the translational diffusion constant, and the height of the potential) at which the average velocity takes its maximal value. There exists an optimal translational diffusion at which the effective diffusion constant is maximal. The self-propelled velocity can strongly increase the effective diffusion, while the large rotational diffusion rate can strongly suppress the effective diffusion. PMID- 24483409 TI - Jamming graphs: a local approach to global mechanical rigidity. AB - We revisit the concept of minimal rigidity as applied to frictionless, repulsive soft sphere packings in two dimensions with the introduction of the jamming graph. Minimal rigidity is a purely combinatorial property encoded via Laman's theorem in two dimensions. It constrains the global, average coordination number of the graph, for example. However, minimal rigidity does not address the geometry of local mechanical stability. The jamming graph contains both properties of global mechanical stability at the onset of jamming and local mechanical stability. We demonstrate how jamming graphs can be constructed using local moves via the Henneberg construction such that these graphs fall under the jurisdiction of correlated percolation. We then probe how jamming graphs destabilize, or become unjammed, by deleting a bond and computing the resulting rigid cluster distribution. We also study how the system restabilizes with the addition of new contacts and how a jamming graph with extra (redundant) contacts destabilizes. The latter endeavor allows us to probe a disk packing in the rigid phase and uncover a potentially new diverging length scale associated with the random deletion of contacts as compared to the study of cut-out (or frozen-in) subsystems. PMID- 24483410 TI - Method to describe stochastic dynamics using an optimal coordinate. AB - A general method to describe the stochastic dynamics of Markov processes is suggested. The method aims to solve three related problems: the determination of an optimal coordinate for the description of stochastic dynamics; the reconstruction of time from an ensemble of stochastic trajectories; and the decomposition of stationary stochastic dynamics into eigenmodes which do not decay exponentially with time. The problems are solved by introducing additive eigenvectors which are transformed by a stochastic matrix in a simple way - every component is translated by a constant distance. Such solutions have peculiar properties. For example, an optimal coordinate for stochastic dynamics with detailed balance is a multivalued function. An optimal coordinate for a random walk on a line corresponds to the conventional eigenvector of the one-dimensional Dirac equation. The equation for the optimal coordinate in a slowly varying potential reduces to the Hamilton-Jacobi equation for the action function. PMID- 24483411 TI - Statistics of the duration time of a random walk given its present position: dating a random walk. AB - We consider the distribution of the duration time, the time elapsed since it began, of a diffusion process given its present position, under the assumption that the process began at the origin. For unbiased diffusion, the distribution does not exist (it is identically zero) for one- and two-dimensional systems. We find the explicit expression for the distribution for three and higher dimensions and discuss the behavior of the duration time statistics: we find that the expected duration time exists only for dimensions five and higher, whereas the variance becomes finite for seven dimensions and above. We then turn to the case of biased diffusion. The drift velocity introduces a new time scale and the resulting statistics arise from the interplay of the diffusive time scale and the drift time scale. For these systems all the moments exist and explicit expressions are presented and discussed for the expected duration time and its variance for all dimensions. PMID- 24483412 TI - Brownian particles on rough substrates: relation between intermediate subdiffusion and asymptotic long-time diffusion. AB - Brownian particles in random potentials show an extended regime of subdiffusive dynamics at intermediate times. The asymptotic diffusive behavior is often established at very long times and thus cannot be accessed in experiments or simulations. For the case of one-dimensional random potentials with Gaussian distributed energies, we present a detailed analysis of experimental and simulation data. It is shown that the asymptotic long-time diffusion coefficient can be related to the behavior at intermediate times, namely, the minimum of the exponent that characterizes subdiffusion and hence corresponds to the maximum degree of subdiffusion. As a consequence, investigating only the dynamics at intermediate times is sufficient to predict the order of magnitude of the long time diffusion coefficient and the time scale at which the crossover from subdiffusion to diffusion occurs, i.e., when the long-time diffusive regime and hence thermal equilibrium is established. Inversely, theoretical predictions derived for the asymptotic long-time behavior can be used to quantitatively characterize the intermediate behavior, which hardly has been studied so far. PMID- 24483413 TI - Memory decay and loss of criticality in quorum percolation. AB - In this paper, we present the effects of memory decay on a bootstrap percolation model applied to random directed graphs (quorum percolation). The addition of decay was motivated by its natural occurrence in physical systems previously described by percolation theory, such as cultured neuronal networks, where decay originates from ionic leakage through the membrane of neurons and/or synaptic depression. Surprisingly, this feature alone appears to change the critical behavior of the percolation transition, where discontinuities are replaced by steep but finite slopes. Using different numerical approaches, we show evidence for this qualitative change even for very small decay values. In experiments where the steepest slopes can not be resolved and still appear as discontinuities, decay produces nonetheless a quantitative difference on the location of the apparent critical point. We discuss how this shift impacts network connectivity previously estimated without considering decay. In addition to this particular example, we believe that other percolation models are worth reinvestigating, taking into account similar sorts of memory decay. PMID- 24483414 TI - Nonequilibrium heat capacity. AB - Development of steady state thermodynamics and statistical mechanics depends crucially on our ability to extend the notions of equilibrium thermodynamics to nonequilibrium steady states (NESS). The present paper considers the extension of heat capacity. A modified definition is proposed which continues to maintain the same relation to steady state Shannon entropy as in equilibrium, thus providing a thermodynamically consistent treatment of NESS heat capacity. PMID- 24483415 TI - Thermal fluctuation statistics in a molecular motor described by a multidimensional master equation. AB - We present a theoretical investigation of thermal fluctuation statistics in a molecular motor. Energy transfer in the motor is described using a multidimensional discrete master equation with nearest-neighbor hopping. In this theory, energy transfer leads to statistical correlations between thermal fluctuations in different degrees of freedom. For long times, the energy transfer is a multivariate diffusion process with constant drift and diffusion. The fluctuations and drift align in the strong-coupling limit enabling a one dimensional description along the coupled coordinate. We derive formal expressions for the probability distribution and simulate single trajectories of the system in the near- and far-from-equilibrium limits both for strong and weak coupling. Our results show that the hopping statistics provide an opportunity to distinguish different operating regimes. PMID- 24483416 TI - Accelerated transport and growth with symmetrized dynamics. AB - In this paper we consider a model of accelerated dynamics with the rules modified from those of the recently proposed [Dong et al., Phys. Rev. Lett. 109, 130602 (2012)] accelerated exclusion process (AEP) such that particle-vacancy symmetry is restored to facilitate a mapping to a solid-on-solid growth model in 1+1 dimensions. In addition to kicking a particle ahead of the moving particle, as in the AEP, in our model another particle from behind is drawn, provided it is within the "distance of interaction" denoted by l(max). We call our model the doubly accelerated exclusion process (DAEP). We observe accelerated transport and interface growth and widening of the cluster size distribution for cluster sizes above l(max), when compared with the ordinary totally asymmetric exclusion process (TASEP). We also characterize the difference between the TASEP, AEP, and DAEP by computing a "staggered" order parameter, which reveals the local order in the steady state. This order in part explains the behavior of the particle current as a function of density. The differences of the steady states are also reflected by the behavior of the temporal and spatial correlation functions in the interface picture. PMID- 24483417 TI - Information flow and optimal protocol for a Maxwell-demon single-electron pump. AB - We study the entropy and information flow in a Maxwell-demon device based on a single-electron transistor with controlled gate potentials. We construct the protocols for measuring the charge states and manipulating the gate voltages, which minimizes irreversibility for (i) constant input power from the environment or (ii) given energy gain. Charge measurement is modeled by a series of detector readouts for time-dependent gate potentials, and the amount of information obtained is determined. The protocols optimize irreversibility that arises due to (i) enlargement of the configuration space on opening the barriers, and (ii) finite rate of operation. These optimal protocols are general and apply to all systems in which barriers between different regions can be manipulated. PMID- 24483418 TI - Nematic phase in stripe-forming systems within the self-consistent screening approximation. AB - We show that in order to describe the isotropic-nematic transition in stripe forming systems with isotropic competing interactions of the Brazovskii class it is necessary to consider the next to leading order in a 1/N approximation for the effective Hamiltonian. This can be conveniently accomplished within the self consistent screening approximation. We solve the relevant equations and show that the self-energy in this approximation is able to generate the essential wave vector dependence to account for the anisotropic character of a two-point correlation function characteristic of a nematic phase. PMID- 24483419 TI - Nonequilibrium steady state and induced currents of a mesoscopically glassy system: interplay of resistor-network theory and Sinai physics. AB - We introduce an explicit solution for the nonequilibrium steady state (NESS) of a ring that is coupled to a thermal bath, and is driven by an external hot source with log-wide distribution of couplings. Having time scales that stretch over several decades is similar to glassy systems. Consequently there is a wide range of driving intensities where the NESS is like that of a random walker in a biased Brownian landscape. We investigate the resulting statistics of the induced current I. For a single ring we discuss how sign of I fluctuates as the intensity of the driving is increased, while for an ensemble of rings we highlight the fingerprints of Sinai physics on the distribution of the absolute value of I. PMID- 24483420 TI - Reaction-diffusion theory in the presence of an attractive harmonic potential. AB - Problems involving the capture of a moving entity by a trap occur in a variety of physical situations, the moving entity being an electron, an excitation, an atom, a molecule, a biological object such as a receptor cluster, a cell, or even an animal such as a mouse carrying an epidemic. Theoretical considerations have almost always assumed that the particle motion is translationally invariant. We study here the case when that assumption is relaxed, in that the particle is additionally subjected to a harmonic potential. This tethering to a center modifies the reaction-diffusion phenomenon. Using a Smoluchowski equation to describe the system, we carry out a study which is explicit in one dimension but can be easily extended for arbitrary dimensions. Interesting features emerge depending on the relative location of the trap, the attractive center, and the initial placement of the diffusing particle. PMID- 24483421 TI - Normal-to-anomalous diffusion transition in disordered correlated potentials: from the central limit theorem to stable laws. AB - We study the diffusion of an ensemble of overdamped particles sliding over a tilted random potential (produced by the interaction of a particle with a random polymer) with long-range correlations. We found that the diffusion properties of such a system are closely related to the correlation function of the corresponding potential. We model the substrate as a symbolic trajectory of a shift space which enables us to obtain a general formula for the diffusion coefficient when normal diffusion occurs. The total time that the particle takes to travel through n monomers can be seen as an ergodic sum to which we can apply the central limit theorem. The latter can be implemented if the correlations decay fast enough in order for the central limit theorem to be valid. On the other hand, we presume that when the central limit theorem breaks down the system give rise to anomalous diffusion. We give two examples exhibiting a transition from normal to anomalous diffusion due to this mechanism. We also give analytical expressions for the diffusion exponents in both cases by assuming convergence to a stable law. Finally we test our predictions by means of numerical simulations. PMID- 24483422 TI - Tricritical behavior of soft nematic elastomers. AB - We propose a lattice statistical model to investigate the phase diagrams and the soft responses of nematic liquid-crystal elastomers. Using suitably scaled infinite-range interactions, we obtain exact self-consistent equations for the tensor components of the nematic order parameter in terms of temperature, the distortion and stress tensors, and the initial nematic order. These equations are amenable to simple numerical calculations, which are used to characterize the low temperature soft regime. We find a peculiar phase diagram, in terms of temperature and the diagonal component of the distortion tensor along the stretching direction, with first- and second-order transitions to the soft phase, and the prediction of tricritical points. This behavior is not qualitatively changed if we use different values of the initial nematic order parameter. PMID- 24483423 TI - First-principles calculation of entropy for liquid metals. AB - We demonstrate the accurate calculation of entropies and free energies for a variety of liquid metals using an extension of the two-phase thermodynamic (2PT) model based on a decomposition of the velocity autocorrelation function into gas like (hard sphere) and solid-like (harmonic) subsystems. The hard sphere model for the gas-like component is shown to give systematically high entropies for liquid metals as a direct result of the unphysical Lorentzian high-frequency tail. Using a memory function framework we derive a generally applicable velocity autocorrelation and frequency spectrum for the diffusive component which recovers the low-frequency (long-time) behavior of the hard sphere model while providing for realistic short-time coherence and high-frequency tails to the spectrum. This approach provides a significant increase in the accuracy of the calculated entropies for liquid metals and is compared to ambient pressure data for liquid sodium, aluminum, gallium, tin, and iron. The use of this method for the determination of melt boundaries is demonstrated with a calculation of the high pressure bcc melt boundary for sodium. With the significantly improved accuracy available with the memory function treatment for softer interatomic potentials, the 2PT model for entropy calculations should find broader application in high energy density science, warm dense matter, planetary science, geophysics, and material science. PMID- 24483424 TI - Generalized information entropies depending only on the probability distribution. AB - In the framework of superstatistics it has been shown that one can calculate the entropy of nonextensive statistical mechanics. We follow a similar procedure; we assume a Gamma(chi(2)) distribution depending on beta that also depends on a parameter p(l). From it we calculate the Boltzmann factor and show that it is possible to obtain the information entropy S=k?(l=1)(Omega)s(p(l)), where s(p(l))=1-p(l)(p(l)). By maximizing this information measure, p(l) is calculated as function of betaE(l) and, at this stage of the procedure, p(l) can be identified with the probability distribution. We show the validity of the saddle point approximation and we also briefly discuss the generalization of one of the four Khinchin axioms. The modified axioms are then in accordance with the proposed entropy. As further possibilities, we also propose other entropies depending on p(l) that resemble the Kaniakadis and two possible Sharma-Mittal entropies. By expanding in series all entropies in this work we have as a first term the Shannon entropy. PMID- 24483425 TI - Equilibration of quantum chaotic systems. AB - The quantum ergordic theorem for a large class of quantum systems was proved by von Neumann [Z. Phys. 57, 30 (1929)] and again by Reimann [Phys. Rev. Lett. 101, 190403 (2008)] in a more practical and well-defined form. However, it is not clear whether the theorem applies to quantum chaotic systems. With a rigorous proof still elusive, we illustrate and verify this theorem for quantum chaotic systems with examples. Our numerical results show that a quantum chaotic system with an initial low-entropy state will dynamically relax to a high-entropy state and reach equilibrium. The quantum equilibrium state reached after dynamical relaxation bears a remarkable resemblance to the classical microcanonical ensemble. However, the fluctuations around equilibrium are distinct: The quantum fluctuations are exponential while the classical fluctuations are Gaussian. PMID- 24483426 TI - Full-counting statistics of random transition-rate matrices. AB - We study the full-counting statistics of current of large open systems through the application of random-matrix theory to transition-rate matrices. We develop a method for calculating the ensemble-averaged current-cumulant generating functions based on an expansion in terms of the inverse system size. We investigate how different symmetry properties and different counting schemes affect the results. PMID- 24483427 TI - Influence of stochastic perturbation of both action updating and strategy updating in mixed-strategy 2*2 games on evolution of cooperation. AB - In a mixed-strategy game framework, each agent's strategy is defined by a real number; on the other hand, in a discrete strategy game framework, only binary strategies, either cooperation or defection, are allowed. In a spatial mixed strategy game, with respect to the process for updating action (offer), either a synchronous or an asynchronous strategy update should be presumed. This study elucidates how stochastic perturbation that results from a synchronous or an asynchronous process for updating action significantly affects the enhancement of cooperation in an evolutionary process. Especially, when a synchronous process for updating action is assumed, the extent of cooperation increases with an increase in degree. PMID- 24483428 TI - White-noise limit of nonwhite nonequilibrium processes. AB - The asymptotic behavior of a stochastic process subject to a colored noise is considered in the limit of vanishing correlation time of the noise. The interpretation of the multiplicative noise of the effective equation is investigated. The mathematically consistent formulation of the stochastic calculus for the limiting process is given. It differs in general from the Stratonovich one which is recovered when the colored noise obeys detailed balance or is a one-dimensional process. PMID- 24483429 TI - Jammed lattice sphere packings. AB - We generate and study an ensemble of isostatic jammed hard-sphere lattices. These lattices are obtained by compression of a periodic system with an adaptive unit cell containing a single sphere until the point of mechanical stability. We present detailed numerical data about the densities, pair correlations, force distributions, and structure factors of such lattices. We show that this model retains many of the crucial structural features of the classical hard-sphere model and propose it as a model for the jamming and glass transitions that enables exploration of much higher dimensions than are usually accessible. PMID- 24483430 TI - Analog of surface melting in a macroscopic nonequilibrium system. AB - Agitated wet granular matter can be considered as a nonequilibrium model system for phase transitions, where the macroscopic particles replace the molecules and the capillary bridges replace molecular bonds. It is demonstrated experimentally that a two-dimensional wet granular crystal driven far from thermal equilibrium melts from its free surface, preceded by an amorphous state. The transition into the surface melting state, as revealed by the bond orientational order parameters, behaves like a first order phase transition, with a threshold being traceable to the rupture energy of a single capillary bridge. The observation of such a transition in the macroscopic nonequilibrium system triggers the question of the universality of surface melting. PMID- 24483431 TI - Simulations of granular gravitational collapse. AB - A freely cooling granular gas in a gravitational field undergoes a collapse to a multicontact state in a finite time. Previous theoretical [D. Volfson et al., Phys. Rev. E 73, 061305 (2006)] and experimental work [R. Son et al., Phys. Rev. E 78, 041302 (2008)] have obtained contradictory results about the rate of energy loss before the gravitational collapse. Here we use a molecular dynamics simulation in an attempt to recreate the experimental and theoretical results to resolve the discrepancy. We are able to nearly match the experimental results, and find that to reproduce the power law predicted in the theory we need a nearly elastic system with a constant coefficient of restitution greater than 0.993. For the more realistic velocity-dependent coefficient of restitution, there does not appear to be a power-law decay and the transition from granular gas to granular solid is smooth, making it difficult to define a time of collapse. PMID- 24483432 TI - Drag force on a spherical intruder in a granular bed at low Froude number. AB - The drag force on an object, or "intruder," in a granular material arises from interparticle friction, as well as the cyclic creation and buckling of force chains within the material. In contrast to fluids, for which drag forces are well understood, there is no straightforward relationship between speed and mean drag force in granular materials. We investigate spherical intruder particles of varying radii moving at low speeds through granular beds. The system can be parametrized using the dimensionless Froude number Fr=2v/?[gR], for intruders of radius R moving at a speed v. For frictional systems, we find the drag force obeys a linear relationship with Fr for low Froude numbers above Fr>1. For Fr<1 we observe a deviation from this linear trend. This transition can be explained by considering the characteristic inertial and gravitational granular time scales of the system. We show that a suitably normalized measure of dissipated power obeys a linear relationship with the imposed intruder velocity, independent of the intruder dimensions. This is found to hold even for particles with no friction, identifying a relationship between the imposed motion of the intruder and the resistance of the granular material to purely geometric rearrangements. PMID- 24483433 TI - Collision dynamics of particle clusters in a two-dimensional granular gas. AB - In a granular gas, inelastic collisions produce an instability in which the constituent particles cluster heterogeneously. These clusters then interact with each other, further decreasing their kinetic energy. We report experiments of the free collisions of dense clusters of particles in a two-dimensional geometry. The particles are composed of solid CO(2), which float nearly frictionlessly on a hot surface due to sublimated vapor. After two dense clusters of ~100 particles collide, there are two distinct stages of evolution. First, the translational kinetic energy rapidly decreases by over 90% as a "jamming front" sweeps across each cluster. Subsequently, the kinetic energy decreases more slowly as the particles approach the container boundaries. In this regime, the measured velocity distributions are non-Gaussian with long tails. Finally, we compare our experiments to computer simulations of colliding, two-dimensional, granular clusters composed of circular, viscoelastic particles with friction. PMID- 24483434 TI - Homogeneous steady state of a confined granular gas. AB - The nonequilibrium statistical mechanics and kinetic theory for a model of a confined quasi-two-dimensional gas of inelastic hard spheres is presented. The dynamics of the particles includes an effective mechanism to transfer the energy injected in the vertical direction to the horizontal degrees of freedom. The Enskog approximation is formulated and used as the basis to investigate the temperature and the distribution function of the steady state eventually reached by the system. An exact scaling of the distribution function of the system having implications on the form of its moments is pointed out. The theoretical predictions are compared with numerical results obtained by a particle simulation method, and a good agreement is found. PMID- 24483435 TI - Effect of inertia on sheared disordered solids: critical scaling of avalanches in two and three dimensions. AB - Molecular dynamics simulations with varying damping are used to examine the effects of inertia and spatial dimension on sheared disordered solids in the athermal quasistatic limit. In all cases the distribution of avalanche sizes follows a power law over at least three orders of magnitude in dissipated energy or stress drop. Scaling exponents are determined using finite-size scaling for systems with 10(3)-10(6) particles. Three distinct universality classes are identified corresponding to overdamped and underdamped limits, as well as a crossover damping that separates the two regimes. For each universality class, the exponent describing the avalanche distributions is the same in two and three dimensions. The spatial extent of plastic deformation is proportional to the energy dissipated in an avalanche. Both rise much more rapidly with system size in the underdamped limit where inertia is important. Inertia also lowers the mean energy of configurations sampled by the system and leads to an excess of large events like that seen in earthquake distributions for individual faults. The distribution of stress values during shear narrows to zero with increasing system size and may provide useful information about the size of elemental events in experimental systems. For overdamped and crossover systems the stress variation scales inversely with the square root of the system size. For underdamped systems the variation is determined by the size of the largest events. PMID- 24483436 TI - Approach to failure in porous granular materials under compression. AB - We investigate the approach to catastrophic failure in a model porous granular material undergoing uniaxial compression. A discrete element computational model is used to simulate both the microstructure of the material and the complex dynamics and feedbacks involved in local fracturing and the production of crackling noise. Under strain-controlled loading, microcracks initially nucleate in an uncorrelated way all over the sample. As loading proceeds the damage localizes into a narrow damage band inclined at 30 degrees -45 degrees to the load direction. Inside the damage band the material is crushed into a poorly sorted mixture of mainly fine powder hosting some larger fragments. The mass probability density distribution of particles in the damage zone is a power law of exponent 2.1, similar to a value of 1.87 inferred from observations of the length distribution of wear products (gouge) in natural and laboratory faults. Dynamic bursts of radiated energy, analogous to acoustic emissions observed in laboratory experiments on porous sedimentary rocks, are identified as correlated trails or cascades of local ruptures that emerge from the stress redistribution process. As the system approaches macroscopic failure consecutive bursts become progressively more correlated. Their size distribution is also a power law, with an equivalent Gutenberg-Richter b value of 1.22 averaged over the whole test, ranging from 3 to 0.5 at the time of failure, all similar to those observed in laboratory tests on granular sandstone samples. The formation of the damage band itself is marked by a decrease in the average distance between consecutive bursts and an emergent power-law correlation integral of event locations with a correlation dimension of 2.55, also similar to those observed in the laboratory (between 2.75 and 2.25). PMID- 24483437 TI - Detailed characterization of rattlers in exactly isostatic, strictly jammed sphere packings. AB - We generate jammed disordered packings of 100<=N<=2000 monodisperse hard spheres in three dimensions whose strictly jammed backbones are demonstrated to be exactly isostatic with unprecedented numerical accuracy. This is accomplished by using the Torquato-Jiao (TJ) packing algorithm as a means of studying the maximally random jammed (MRJ) state. The rattler fraction of these packings converges towards 0.015 in the infinite-system limit, which is markedly lower than previous estimates for the MRJ state using the Lubachevsky-Stillinger protocol. This is because the packings that the TJ algorithm creates are closer to the true MRJ state, as shown using bond-orientational and translational order metrics. The rattler pair correlation statistics exhibit strongly correlated behavior contrary to the conventional understanding that they be randomly (Poisson) distributed. Dynamically interacting "polyrattlers" may be found imprisoned in shared cages as well as interacting through "bottlenecks" in the backbone and these clusters are mainly responsible for the sharp increase in the rattler pair correlation function near contact. We discover the surprising existence of polyrattlers with cluster sizes of up to five rattlers (which is expected to increase with system size) and present a distribution of polyrattler occurrence as a function of cluster size and system size. We also enumerate all of the rattler interaction topologies we observe and present images of several examples, showing that MRJ packings of monodisperse spheres can contain large rattler cages while still obeying the strict jamming criterion. The backbone spheres that encage the rattlers are significantly hypostatic, implying that correspondingly hyperstatic regions must exist elsewhere in these isostatic packings. We also observe that rattlers in hard-sphere packings share an apparent connection with the low-temperature two-level system anomalies that appear in real amorphous insulators and semiconductors. PMID- 24483438 TI - Dynamic regimes for driven colloidal particles on a periodic substrate at commensurate and incommensurate fillings. AB - We numerically examine colloidal particles driven over a muffin tin substrate. Previous studies of this model identified a variety of commensurate and incommensurate static phases in which topological defects can form domain walls, ordered stripes, superlattices, or disordered patchy regimes as a function of the filling fraction. Here, we show that the addition of an external drive to these static phases can produce distinct dynamical responses. At incommensurate fillings the flow occurs in the form of localized pulses or solitons correlated with topological defect structures. Transitions between different modes of motion can occur as a function of increasing drive. We measure the average particle velocity for specific ranges of external drive and show that changes in the velocity response correlate with changes in the topological defect arrangements. We also demonstrate that in the different dynamic phases, the particles have distinct trajectories and velocity distributions. Dynamic transitions between ordered and disordered flows exhibit hysteresis, while in strongly disordered regimes there is no hysteresis and the velocity-force curves are smooth. When stripe patterns are present, transport can occur at an angle to the driving direction. PMID- 24483439 TI - Structure and coarsening at the surface of a dry three-dimensional aqueous foam. AB - We utilize total-internal reflection to isolate the two-dimensional surface foam formed at the planar boundary of a three-dimensional sample. The resulting images of surface Plateau borders are consistent with Plateau's laws for a truly two dimensional foam. Samples are allowed to coarsen into a self-similar scaling state where statistical distributions appear independent of time, except for an overall scale factor. There we find that statistical measures of side number distributions, size-topology correlations, and bubble shapes are all very similar to those for two-dimensional foams. However, the size number distribution is slightly broader, and the shapes are slightly more elongated. A more obvious difference is that T2 processes now include the creation of surface bubbles, due to rearrangement in the bulk, and von Neumann's law is dramatically violated for individual bubbles. But nevertheless, our most striking finding is that von Neumann's law appears to holds on average, namely, the average rate of area change for surface bubbles appears to be proportional to the number of sides minus six, but with individual bubbles showing a wide distribution of deviations from this average behavior. PMID- 24483440 TI - Liquid-liquid phase transition in a two-dimensional system with anomalous liquid properties. AB - The phase diagram of the two-dimensional particles interacting through a smooth version of Stell-Hemmer interaction was studied using Monte Carlo computer simulations. By evaluating the pressure-volume isotherms, we observed liquid liquid, liquid-gas phase transitions and three stable crystal phases. The model shows the liquid-liquid critical point in stable liquid phase and is confirmed by observing properties of other thermodynamic functions such as heat capacity and isothermal compressibility, for example. The liquid-gas and the liquid-liquid critical points were estimated within the thermodynamic limit. PMID- 24483441 TI - Structure and dynamics of self-assembling colloidal monolayers in oscillating magnetic fields. AB - Many fascinating phenomena such as large-scale collective flows, enhanced fluid mixing, and pattern formation have been observed in so-called active fluids, which are composed of particles that can absorb energy and dissipate it into the fluid medium. For active particles immersed in liquids, fluid-mediated viscous stresses can play an important role on the emergence of collective behavior. Here, we experimentally investigate their role in the dynamics of self-assembling magnetically driven colloidal particles which can rapidly form organized hexagonal structures. We find that viscous stresses reduce hexagonal ordering, generate smaller clusters, and significantly decrease the rate of cluster formation, all while holding the system at constant number density. Furthermore, we show that time and length scales of cluster formation depend on the Mason number (Mn), or ratio of viscous to magnetic forces, scaling as t?Mn and L?Mn( 1/2). Our results suggest that viscous stresses hinder collective behavior in a self-assembling colloidal system. PMID- 24483442 TI - Fluctuations of orientational order and clustering in a two-dimensional colloidal system under quenched disorder. AB - Using both video microscopy of superparamagnetic colloidal particles confined in two dimensions and corresponding computer simulations of repulsive parallel dipoles, we study the formation of fluctuating orientational clusters and topological defects in the context of the KTHNY-like melting scenario under quenched disorder. We analyze cluster densities, average cluster sizes, and the population of noncluster particles, as well as the development of defects, as a function of the system temperature and disorder strength. In addition, the probability distribution of clustering and orientational order is presented. We find that the well-known disorder-induced widening of the hexatic phase can be traced back to the distinct development characteristics of clusters and defects along the melting transitions from the solid phase to the hexatic phase to the isotropic fluid. PMID- 24483443 TI - Magnetic wire-based sensors for the microrheology of complex fluids. AB - We propose a simple microrheology technique to evaluate the viscoelastic properties of complex fluids. The method is based on the use of magnetic wires of a few microns in length submitted to a rotational magnetic field. In this work, the method is implemented on a surfactant wormlike micellar solution that behaves as an ideal Maxwell fluid. With increasing frequency, the wires undergo a transition between a steady and a hindered rotation regime. The study shows that the average rotational velocity and the amplitudes of the oscillations obey scaling laws with well-defined exponents. From a comparison between model predictions and experiments, the rheological parameters of the fluid are determined. PMID- 24483444 TI - Nonequilibrium interfaces in colloidal fluids. AB - The time-dependent structure, interfacial tension, and evaporation of an oversaturated colloid-rich (liquid) phase in contact with an undersaturated colloid-poor (vapor) phase of a colloidal dispersion is investigated theoretically during the early-stage relaxation, where the interface is relaxing towards a local equilibrium state while the bulk phases are still out of equilibrium. Since systems of this type exhibit a clear separation of colloidal and solvent relaxation time scales with typical times of interfacial tension measurements in between, they can be expected to be suitable for analogous experimental studies, too. The major finding is that, irrespective of how much the bulk phases differ from two-phase coexistence, the interfacial structure and the interfacial tension approach those at two-phase coexistence during the early stage relaxation process. This is a surprising observation since it implies that the relaxation towards global equilibrium of the interface is not following but preceding that of the bulk phases. Scaling forms for the local chemical potential, the flux, and the dissipation rate exhibit qualitatively different leading order contributions depending on whether an equilibrium or a nonequilibrium system is considered. The degree of nonquilibrium between the bulk phases is found to not influence the qualitative relaxation behavior (i.e., the values of power-law exponents), but to determine the quantitative deviation of the observed quantities from their values at two-phase coexistence. Whereas the underlying dynamics differs between colloidal and molecular fluids, the behavior of quantities such as the interfacial tension approaching the equilibrium values during the early-stage relaxation process, during which nonequilibrium conditions of the bulk phases are not changed, can be expected to occur for both types of systems. PMID- 24483445 TI - Connecting the random organization transition and jamming within a unifying model system. AB - While the random organization transition describes the change from reversible to irreversible dynamics in a nonequilibrium system, the athermal jamming transition at zero shear rate occurs when particles can no longer avoid overlaps. Despite the obvious differences between these two transitions, we show that they both occur within the same model packing problem. In this unifying model system the particles are first randomly distributed and then displaced in each step if they overlap. For random displacements we obtain a random organization transition, while jamming occurs in the case of deterministic shifts. We also analyze the critical behavior of random organization. Our results show that random organization and jamming are opposite limits of random sphere packings, and we expect that various equilibrium and nonequilibrium transitions can be formulated as related intermediate packing problems. PMID- 24483446 TI - Far-from-equilibrium sheared colloidal liquids: disentangling relaxation, advection, and shear-induced diffusion. AB - Using high-speed confocal microscopy, we measure the particle positions in a colloidal suspension under large-amplitude oscillatory shear. Using the particle positions, we quantify the in situ anisotropy of the pair-correlation function, a measure of the Brownian stress. From these data we find two distinct types of responses as the system crosses over from equilibrium to far-from-equilibrium states. The first is a nonlinear amplitude saturation that arises from shear induced advection, while the second is a linear frequency saturation due to competition between suspension relaxation and shear rate. In spite of their different underlying mechanisms, we show that all the data can be scaled onto a master curve that spans the equilibrium and far-from-equilibrium regimes, linking small-amplitude oscillatory to continuous shear. This observation illustrates a colloidal analog of the Cox-Merz rule and its microscopic underpinning. Brownian dynamics simulations show that interparticle interactions are sufficient for generating both experimentally observed saturations. PMID- 24483447 TI - Active matter ratchets with an external drift. AB - When active matter particles such as swimming bacteria are placed in an asymmetric array of funnels, it has been shown that a ratchet effect can occur even in the absence of an external drive. Here we examine active ratchets for two dimensional arrays of funnels or L shapes where there is also an externally applied dc drive or drift. We show that for certain conditions the ratchet effect can be strongly enhanced and it is possible to have conditions under which run and-tumble particles with one run length move in the opposite direction from particles with a different run length. For the arrays of L shapes, we find that the application of a drift force can enhance a transverse rectification in the direction perpendicular to the drift. When particle-particle steric interactions are included, we find that the ratchet effects can be either enhanced or suppressed depending on barrier geometry, particle run length, and particle density. PMID- 24483448 TI - Faraday waves on nematic liquid crystals: effect of Marangoni flow and thermal phase transition. AB - The parametric instability in nematic liquid crystal layers has been studied using linear stability theory. Using material parameters of typical nematics, the neutral stability curve and dispersion relation of a system that presents critical subharmonic waves is obtained. The critical acceleration and wave number of the unstable stationary waves are discontinuous at the nematic-isotropic transition temperature and conform to similar sharp changes experienced by the viscosities and surface tension as a function of temperature. Due to Marangoni flow the curve of the critical acceleration as a function of excitation frequency exhibits a minimum. If the Marangoni flow is neglected and the dynamical viscosity is increased, a monotonously increasing dependence of the acceleration in terms of oscillation frequency is observed. A bicritical instability is reached for a layer thickness of a few millimeters. A well-defined subharmonic wave is attained when the thickness of the layer is further increased. The dispersion relation of these waves displays a discontinuous shift at high frequencies due to alternating secondary thresholds of Faraday waves. At negligible external forcing we determined the dispersion relationship of thermal surface waves. PMID- 24483449 TI - NaCl crystallization in apolar nanometer-sized confinement studied by atomistic simulations. AB - The structure and growth of molecular NaCl crystals in bulk and in a narrow, nanometer-sized apolar confinement are examined by explicit-water molecular dynamics computer simulations. It is demonstrated that fast crystallization and subsequent diffusion-controlled cluster growth in bulk is triggered by supersaturations that exceed a certain threshold value. In confinement, simulated in a pseudo grand canonical setup, salt is shown to be expelled from the narrow apolar slab region, and the effective ion concentration inside the nanoconfinement is always considerably lower than the reservoir salt concentration so that no fast crystallization takes place. For very small slab widths (d<1.5 nm) salt is almost entirely expelled while water remains in the slab, indicating a capillary evaporation phenomenon for the polar ions. If forced into the apolar confinement by simulating in a strictly canonical setup, we find stable crystals only if at least three crystalline planes fit into the slab, which happens above a 2-nm slab width. In this case the (100) plane of the bulk crystal is oriented parallel to the apolar surface delimited by a subnanometer thin hydration layer. This work presents molecular-level insight of salt crystallization in apolar confinements of a nanometer scale with possible implications in double-layer supercapacitor physics and geological salt weathering. PMID- 24483450 TI - Frequency dependence of dielectric saturation. AB - Dielectric saturation originates from the upper bound to dipole orientation, reached when all dipoles are aligned "perfectly" with respect to the electric field. For Debye-type dynamics, it is well established that the saturation effect is diminished at high frequencies relative to its steady-state value. Here, it is argued that a similar frequency dependence of this nonlinear dielectric effect is expected also for dispersive dynamics, provided that the system is dynamically homogeneous. By contrast, more realistic relaxation time dispersions based upon heterogeneous dynamics display a strongly reduced frequency dependence of dielectric saturation. Calculations demonstrate this effect in terms of both the fundamental and the third harmonic frequency susceptibilities. The relations of signatures of nonlinearity in different Fourier components of the response are briefly discussed. PMID- 24483452 TI - Three-dimensional dynamics of a particle with a finite energy of magnetic anisotropy in a rotating magnetic field. AB - A model of a single ferromagnetic particle with a finite coupling energy of the magnetic moment with the body of the particle is formulated, and regimes of its motion in a rotating magnetic field are investigated. Regimes are possible that are synchronous and asynchronous with the field. In a synchronous regime the easy axis of the particle is in the plane of the rotating magnetic field at low frequencies (a planar regime) and on the cone at high frequencies (a precession regime). The stability of these regimes is investigated, and it is shown that the precession regime is stable for field strengths below the critical value. In a particular range of field strength value, irreversible jumps of the magnetic moment take place in the asynchronous planar regime. The stability of this regime is investigated, and it is shown that it is stable for field strengths above the critical value, which depends on the frequency. The implications of these results for the energy dissipation in a rotating field are analyzed, and it is shown that the maximum of the heat production near the transition to the synchronous regime is flattened out by the transition to the precession regime. PMID- 24483453 TI - Crystallization induced by multiple seeds: dynamical density functional approach. AB - Using microscopic dynamical density functional theory, we calculate the dynamical formation of polycrystals by following the crystal growth around multiple crystalline seeds imposed to an undercooled fluid. Depending on the undercooling and the size ratio as well as the relative crystal orientation of two neighboring seeds, three possibilities of the final state emerge, namely no crystallization at all, formation of a monocrystal, or two crystallites separated by a curved grain boundary. Our results, which are obtained for two-dimensional hard disk systems using a fundamental-measure density functional, shed new light on the particle-resolved structure and growth of polycrystalline material in general. PMID- 24483451 TI - Collective behavior of penetrable self-propelled rods in two dimensions. AB - Collective behavior of self-propelled particles is observed on a microscale for swimmers such as sperm and bacteria as well as for protein filaments in motility assays. The properties of such systems depend both on their dimensionality and the interactions between their particles. We introduce a model for self-propelled rods in two dimensions that interact via a separation-shifted Lennard-Jones potential. Due to the finite potential barrier, the rods are able to cross. This model allows us to efficiently simulate systems of self-propelled rods that effectively move in two dimensions but can occasionally escape to the third dimension in order to pass each other. Our quasi-two-dimensional self-propelled particles describe a class of active systems that encompasses microswimmers close to a wall and filaments propelled on a substrate. Using Monte Carlo simulations, we first determine the isotropic-nematic transition for passive rods. Using Brownian dynamics simulations, we characterize cluster formation of self propelled rods as a function of propulsion strength, noise, and energy barrier. Contrary to rods with an infinite potential barrier, an increase of the propulsion strength does not only favor alignment but also effectively decreases the potential barrier that prevents crossing of rods. We thus find a clustering window with a maximum cluster size at medium propulsion strengths. PMID- 24483454 TI - Nanomotor mechanisms and motive force distributions from nanorotor trajectories. AB - Nanomotors convert chemical energy into mechanical motion. For a given motor type, the underlying chemical reaction that enables motility is typically well known, but the detailed, quantitative mechanism by which this reaction breaks symmetry and converts chemical energy to mechanical motion is often less clear, since it is difficult experimentally to measure important parameters such as the spatial distribution of chemical species around the nanorotor during operation. Without this information on how motor geometry affects motor function, it is difficult to control and optimize nanomotor behavior. Here we demonstrate how one easily observable characteristic of nanomotor operation-the visible trajectory of a nanorotor-can provide quantitative information about the role of asymmetry in nanomotor operation, as well as insights into the spatial distribution of motive force along the surface of the nanomotor, the motive torques, and the effective diffusional motion. PMID- 24483455 TI - Onset of irreversibility and chaos in amorphous solids under periodic shear. AB - A fundamental problem in the physics of amorphous materials is understanding the transition from reversible to irreversible plastic behavior and its connection to yield. Currently, continuum material modeling relies on phenomenological yield thresholds, however in many cases the transition from elastic to plastic behavior is gradual, which makes it difficult to identify an exact yield criterion. Here we show that under periodic shear, amorphous solids undergo a transition from repetitive, predictable behavior to chaotic, irregular behavior as a function of the strain amplitude. In both the periodic and chaotic regimes, localized particle rearrangements are observed. We associate the point of transition from repetitive to chaotic behavior with the yield strain and suggest that at least for oscillatory shear, yield in amorphous solids is a result of a "transition to chaos." PMID- 24483456 TI - Effects of initial height on the steady-state persistence probability of linear growth models. AB - The effects of the initial height on the temporal persistence probability of steady-state height fluctuations in up-down symmetric linear models of surface growth are investigated. We study the (1+1)-dimensional Family model and the (1+1)- and (2+1)-dimensional larger curvature (LC) model. Both the Family and LC models have up-down symmetry, so the positive and negative persistence probabilities in the steady state, averaged over all values of the initial height h(0), are equal to each other. However, these two probabilities are not equal if one considers a fixed nonzero value of h(0). Plots of the positive persistence probability for negative initial height versus time exhibit power-law behavior if the magnitude of the initial height is larger than the interface width at saturation. By symmetry, the negative persistence probability for positive initial height also exhibits the same behavior. The persistence exponent that describes this power-law decay decreases as the magnitude of the initial height is increased. The dependence of the persistence probability on the initial height, the system size, and the discrete sampling time is found to exhibit scaling behavior. PMID- 24483457 TI - Avalanche localization and crossover scaling in amorphous plasticity. AB - We perform large-scale simulations of a two-dimensional lattice model for amorphous plasticity with random local yield stresses and long-range quadrupolar elastic interactions. We show that as the external stress increases towards the yielding phase transition, the scaling behavior of the avalanches crosses over from mean-field theory to a different universality class. This behavior is associated with strain localization, which significantly depends on the short range properties of the interaction kernel. PMID- 24483458 TI - Minimization of instabilities in growing interfaces: a variational approach. AB - The Mullins-Sekerka and the electric breakdown instabilities are well known to lead to the spontaneous formation of a variety of complex spatial structures, among them dendritic crystal shapes, and treelike electric discharge patterns. Controlling such systems by suppressing predominantly excited solutions offers the opportunity to manipulate and stabilize these patterns in a defined way for a wide range of technological applications. In this work, we employ a variational approach which enables one to systematically search for the ideal conditions under which the patterns grow, but where interfacial deformations are efficiently minimized. The effectiveness of our variational control method is illustrated via linear stability calculations on both two-dimensional and three-dimensional contour-dynamics models for crystal growth and electric discharge phenomena. PMID- 24483459 TI - Effects of interface sliding on the formation of telephone cord buckles. AB - Sliding at interface during thin film buckling was reported by recent atomistic simulations. A stability analysis under the Foppl-von Karman plate theory is performed to investigate the effect of interface sliding on the transition of a straight-sided blister to the telephone cord buckle in biaxially compressed thin films on rigid substrates. It is shown that the critical stress and the wavelength of the telephone cord buckle significantly increase as the interface sliding is noticeable in comparison with the constant values derived from previous classic analysis without interface sliding. Our theoretic analysis is further validated by results from numerical simulations based on our recently developed continuum model of nonlinear buckling. The results indicate that the wavelength variation in the telephone cord buckle observed in experiments may be due to interface sliding. PMID- 24483460 TI - Droplet spreading on a two-dimensional wicking surface. AB - The dynamics of droplet spreading on two-dimensional wicking surfaces were studied using square arrays of Si nanopillars. It was observed that the wicking film always precedes the droplet edge during the spreading process causing the droplet to effectively spread on a Cassie-Baxter surface composed of solid and liquid phases. Unlike the continual spreading of the wicking film, however, the droplet will eventually reach a shape where further spreading becomes energetically unfavorable. In addition, we found that the displacement-time relationship for droplet spreading follows a power law that is different from that of the wicking film. A quantitative model was put forth to derive this displacement-time relationship and predict the contact angle at which the droplet will stop spreading. The predictions of our model were validated with experimental data and results published in the literature. PMID- 24483461 TI - Computer simulation and detailed mean-field approximation applied to adsorption on nanoparticles. AB - Adsorption thermodynamics of interacting particles adsorbed on icosahedral and truncated octahedral nanoparticles was studied by a detailed mean-field approximation and Monte Carlo simulations. The nanoparticle is tackled as a multivariate surface, where different types of adsorption sites occur according to coordination with nearest neighbors. In addition, lateral couplings between the adsorbed particles are considered. The analysis covers a wide range of interactions, extending from physical to strong chemical bonds, and different sizes and shapes of nanoparticles. PMID- 24483462 TI - Generalized Onsager theory of liquid crystals. AB - The Onsager theory is known to be inaccurate in its prediction of the critical transition density for small aspect ratio hard rods. In this paper we generalize the Onsager theory in two dimensions by taking into account the short-range order as well as the higher-order virial coefficients, up to the fourth order. By carrying out molecular dynamics (MD) simulations on "molecules" comprising linked hard disks with an aspect ratio l ranging from 5 to 13, we show that the generalized theory is much improved as compared to the traditional theory, with its predictions of the transition density agreeing well with the simulation results. This indicates the importance of short-range order considerations (in conjunction with steric repulsion) for molecules with l<=10, a group which includes the most commonly encountered thermotropic liquid crystals. MD simulations further yield evidence for hexagonal order for molecules with l<=8, indicating an intermediate hexagonal phase before solidifying at higher densities. PMID- 24483463 TI - Formation of the smectic-B crystal from a simple monatomic liquid. AB - We report a molecular dynamics simulation demonstrating that the smectic-B crystalline phase (Cry-B), commonly observed in mesogenic systems of anisotropic molecules, can be formed by a system of identical particles interacting via a spherically symmetric potential. The Cry-B phase forms as a result of a first order transition from an isotropic liquid phase upon isochoric cooling at appropriate number density. Its structure, determined by the design of the pair potential, corresponds to the Cry-B structure formed by elongated particles with the aspect ratio 1.8. The diffraction pattern and the real-space structure inspection demonstrate dominance of the ABC-type of axial layer stacking. This result opens a general possibility of producing smectic phases using isotropic interparticle interaction both in simulations and in colloidal systems. PMID- 24483464 TI - Polarity sensitive electric responses in a twisted smectic-C liquid crystal. AB - The observation of two polarity-sensitive electrical responses found in the low frequency (<1 Hz) regime of a square wave field is reported for an achiral rodlike smectic-C liquid crystal with negative dielectric and conductivity anisotropies and in the 90 degrees -twisted configuration. The first involves a transient director modulation appearing at each polarity reversal and vanishing under steady field conditions. The instability is polarity sensitive, with the maximum distortion localized near the negative electrode instead of the sample midplane. This is inferred from the wave-vector orientation alternating in the two halves of the driving cycle between the alignment directions at the two substrates. Various electro-optic characteristics of this temporal phenomenon are also described. Following a similar observation in nematic liquid crystals, we associate the transient periodic order with the Carr-Helfrich mechanism assisted by quadrupolar flexoelectric polarization obtaining under electric field gradients. The second polarity-sensitive effect manifests in the relative shift of the periodic Freedericksz pattern upon field reversal. The shift, which is linear in field for low fields, tends to saturate for large fields. It is interpreted as due to flexoelectric polarization associated primarily with the c director twist about the layer normal. A model involving a periodic wedgelike band, which has the twist localized within it and is flanked by two uniformly and transversely aligned regions, accounts for the flexoelectric shift of the optical pattern. PMID- 24483465 TI - Generalized Langevin-Debye model of the field dependence of tilt, birefringence, and polarization current near the de Vries smectic-A* to smectic-C* liquid crystal phase transition. AB - In chiral smectic-A (Sm-A) liquid crystals, an applied electric field induces a tilt of the optic axis from the layer normal. When these materials are of the de Vries type, the electroclinic tilt susceptibility is unusually large, with the field-induced director reorientation accompanied by a substantial increase in optical birefringence with essentially no change in the smectic layer spacing. In order to account for the observed electro-optic behavior, we assume that the molecular orientation distribution in the Sm-A has two degrees of freedom: azimuthal orientation and tilt of the molecular long axis from the layer normal, with the tilt confined to a narrow range of angles. We present a generalized Langevin-Debye model of the response of this orientational distribution to applied field that gives a field-induced optic axis tilt, birefringence, and polarization dependence that agrees well with experimental measurements and reproduces the double-peaked polarization current response characteristic of a first-order Sm-A(*)-Sm-C(*) transition. Additionally, we find that the measured field-induced polarization and the Langevin-Debye model predictions can be quantitatively described as pre-transitional behavior near the tricritical point of a recently published generalized 3D XY model of interacting hard rods confined to reorient on a cone in the presence of an applied field. PMID- 24483466 TI - Bilayers in nanoparticle-doped polar mesogens. AB - Structures of the mesophases of five members of the 4-n-alkyl-4'-cyanobiphenyl homologous series (4-n-butyl-4'-cyanobiphenyl to 4-n-octyl-4'-cyanobiphenyl) doped with milled BaTiO_{3} nanoparticles were investigated by x-ray scattering. Clear solutions of each of the 4-n-alkyl-4'-cyanobiphenyls were first prepared in n-heptane and then doped with an n-heptane/nanoparticle dispersion, which led to gelation. The nanogels were found to be one-dimensional, multilayered, smectic nanostructures in each case. Surprisingly, a characteristic layer spacing of 4.5 nm was observed in all five homologues. Synchrotron x-ray scattering study of the multilayer structures of doped 4-n-pentyl-4'-cyanobiphenyl and 4-n-octyl-4' cyanobiphenyl revealed nine orders of the primary Bragg reflection which were used to calculate the electron density profiles of the multilayers by Fourier analysis. The multilayers were found to consist of molecular bilayers wherein the mesogens were arranged in a head-to-head assembly of the polar head groups. The alkyl tails of the mesogenic molecules were freely movable and the tail-to-tail assembly was stabilized by heptane. The dissolved nanoparticles clearly induced a new self-assembled nanostructure in which the rigid aromatic part, and not the overall length, of the molecules defined the layer spacing. PMID- 24483467 TI - Biaxiality-induced magnetic field effects in bent-core nematics: molecular-field and Landau theory. AB - Nematic liquid crystals composed of bent-core molecules exhibit unusual properties, including an enhanced Cotton-Mouton effect and an increasing isotropic (paranematic)-nematic phase transition temperature as a function of magnetic field. These systems are thought to be good candidate biaxial liquid crystals. Prompted by these experiments, we investigate theoretically the effect of molecular biaxiality on magnetic-field-induced phenomena for nematic liquid crystals, using both molecular field and Landau theory. The geometric mean approximation is used in order to specify the degree of molecular biaxiality using a single parameter. We reproduce experimental field-induced phenomena and predict also an experimentally accessible magnetic critical point. The Cotton Mouton effect and temperature dependence of the paranematic-nematic phase transition are more pronounced with increased molecular biaxiality. We compare our theoretical approaches and make contact with recent relevant experimental results on bent-core molecular systems. PMID- 24483468 TI - Rotational and translational diffusion of anisotropic gold nanoparticles in liquid crystals controlled by varying surface anchoring. AB - We study translational and rotational diffusion of anisotropic gold nanoparticles (NPs) dispersed in the bulk of a nematic liquid crystal fluid host. Experimental data reveal strong anisotropy of translational diffusion with respect to the uniform far-field director, which is dependent on shape and surface functionalization of colloids as well as on their ground-state alignment. For example, elongated NPs aligned parallel to the far-field director translationally diffuse more rapidly along the director whereas diffusion of NPs oriented normal to the director is faster in the direction perpendicular to it while they are also undergoing elasticity-constrained rotational diffusion. To understand physical origins of these rich diffusion properties of anisotropic nanocolloids in uniaxially anisotropic nematic fluid media, we compare them to diffusion of prolate and oblate ellipsoidal particles in isotropic fluids as well as to diffusion of shape-isotropic particles in nematic fluids. We also show that surface functionalization of NPs with photosensitive azobenzene groups allows for in situ control of their diffusivity through trans-cis isomerization that changes surface anchoring. PMID- 24483469 TI - Supramolecular nature of the nematic-nematic phase transitions of hard boardlike molecules. AB - The phase behavior of hard boardlike biaxial particles of relative dimensions close to the clamitic to discotic crossover is explored by means of Monte Carlo molecular simulations. Transitions between two distinct biaxial nematic phases as well as transitions from a biaxial nematic to a uniaxial Sm-A phase are obtained. The formation of anisotropic supramolecular assemblies is demonstrated and is quantified by means of rotationally invariant pair correlation functions. PMID- 24483470 TI - Feedback control of flow alignment in sheared liquid crystals. AB - Based on a continuum theory, we investigate the manipulation of the nonequilibrium behavior of a sheared liquid crystal via closed-loop feedback control. Our goal is to stabilize a specific dynamical state, that is, the stationary "flow alignment," under conditions where the uncontrolled system displays oscillatory director dynamics with in-plane symmetry. To this end we employ time-delayed feedback control (TDFC), where the equation of motion for the ith component q(i)(t) of the order parameter tensor is supplemented by a control term involving the difference q(i)(t)-q(i)(t-tau). In this diagonal scheme, tau is the delay time. We demonstrate that the TDFC method successfully stabilizes flow alignment for suitable values of the control strength K and tau; these values are determined by solving an exact eigenvalue equation. Moreover, our results show that only small values of K are needed when the system is sheared from an isotropic equilibrium state, contrary to the case where the equilibrium state is nematic. PMID- 24483471 TI - Polymer-disordered liquid crystals: susceptibility to an electric field. AB - When nematic liquid crystals are embedded in random polymer networks, the disordered environment disrupts the long-range order, producing a glassy state. If an electric field is applied, it induces large and fairly temperature independent orientational order. To understand the experiments, we simulate a liquid crystal in a disordered polymer network, visualize the domain structure, and calculate the response to a field. Furthermore, using an Imry-Ma-like approach we predict the domain size and estimate the field-induced order. The simulations and analytic results agree with each other, and suggest how the materials can be optimized for electro-optic applications. PMID- 24483472 TI - Unusual temperature dependence of the splay elastic constant of a rodlike nematic liquid crystal doped with a highly kinked bent-core molecule. AB - We report an unusual temperature dependence of the elastic constants of a rodlike nematic liquid crystal (RLC) mixed with a highly kinked bent-core liquid crystal (BLC). On cooling through the nematic phase, the splay elastic constant (K(11)) of the RLC-BLC mixture increased below the nematic-isotropic phase transition temperature, but started to decrease midway through the nematic phase. The decrease of K(11) was more prominent with a greater concentration of BLC. On the other hand, the bend elastic constant (K(33)) of the RLC-BLC mixture monotonically increased through the nematic phase with decreasing temperature. PMID- 24483473 TI - Labyrinthine instability in freely suspended films of a polarization-modulated smectic phase. AB - We report on fingering and labyrinthine instabilities of the layer dislocation lines in freely suspended polar liquid-crystalline films. These polar fingerlike and labyrinth structures reversibly form upon a transition into a modulated phase. External electric fields of several kV/m applied in the film plane can reversibly influence the formation of the finger textures. We show that the labyrinthine pattern is intrinsically related to regular splay deformations of the polarization. PMID- 24483474 TI - Planar anchoring strength and pitch measurements in achiral and chiral chromonic liquid crystals using 90-degree twist cells. AB - Chromonic liquid crystals are formed by molecules that spontaneously assemble into anisotropic structures in water. The ordering unit is therefore a molecular assembly instead of a molecule as in thermotropic liquid crystals. Although it has been known for a long time that certain dyes, drugs, and nucleic acids form chromonic liquid crystals, only recently has enough knowledge been gained on how to control their alignment so that studies of their fundamental liquid crystal properties can be performed. In this article, a simple method for producing planar alignment of the nematic phase in chromonic liquid crystals is described, and this in turn is used to create twisted nematic structures of both achiral and chiral chromonic liquid crystals. The optics of 90-degree twist cells allows the anchoring strength to be measured in achiral systems, which for this alignment technique is quite weak, about 3*10(-7) J/m(2) for both disodium cromoglycate and Sunset Yellow FCF. The addition of a chiral amino acid to the system causes the chiral nematic phase to form, and similar optical measurements in 90-degree twist cells produce a measurement of the intrinsic pitch of the chiral nematic phase. From these measurements, the helical twisting power for L-alanine is found to be (1.1+/-0.4)*10(-2) MUm(-1) wt%(-1) for 15 wt% disodium cromoglycate. PMID- 24483475 TI - Volume phase transition of N-isopropylacrylamide gels crosslinked by a crosslinker with six hands. AB - Crosslinkers play an essential role in determining the physical properties of gels. We synthesized a new type of crosslinker with three vinyl groups [trisacrylaminomethan (TRI), which joins six polymer chains per single molecule]. We found that N-isopropylacrylamide (NIPA) gels crosslinked with the new crosslinker gel at a much lower fraction of crosslinker than the gel crosslinked with popular N,N'-methylenebisacrylamide (BIS). We also found that the NIPA gels with TRI crosslinker displayed larger discrete volume changes at the volume phase transition. We discuss the effects of the average length of NIPA chains between two crosslinkers on the volume phase transition as well as the effects of inhomogeneity in gels caused by a low fraction of crosslinker. PMID- 24483476 TI - Free-evolution kinetics in a high-swelling polymeric hydrogel. AB - We employ nuclear magnetic resonance microimaging to study the kinetics of a high swelling ionic polymer gel. This includes the time evolution of the sphere diameter and also the evolution of the swollen-unswollen boundary. The experimental results for spherical ionic polyacrylamide gels are compared with the predictions of a nonlinear poroelastic theory by numerically solving the equations for the evolution. PMID- 24483477 TI - Electrical impedance controls mechanical sensing in ionic polymer metal composites. AB - Ionic polymer metal composites (IPMCs) are a class of soft electroactive materials that are recently finding extensive application as mechanical sensors and energy harvesters in liquids. In their most fundamental form, IPMCs are composed of a hydrated ionomeric membrane that is sandwiched between two electrochemically deposited metal electrodes. Ionomer swelling, counterion diffusion, and the formation of electric double layers are some of the physical phenomena underpinning energy transduction in IPMCs; however, a thorough understanding of the relative influence of such phenomena is yet to be established. Here, we propose a physics-based modeling framework, based on the Poisson-Nernst-Planck system, to describe IPMC chemoelectrical response to an imposed time-varying flexural deformation. We utilize the method of matched asymptotic expansions to compute a closed-form solution for the electric potential and counterion concentration in the IPMC. The model predicts that IPMC sensing is independent of the time rate of deformation and linearly correlated to the mechanical curvature, with a coefficient of proportionality that is a function of the ionomer thickness and the temperature. Thus, our results demonstrate that the characterization of IPMC electrical impedance suffices to identify all the parameters that are relevant to sensing, in contrast with the current state of knowledge. Theoretical results are validated through experiments on patterned in-house fabricated IPMC samples that are subject to time-varying flexural deformations. PMID- 24483478 TI - Writhe and mutual entanglement combine to give the entanglement length. AB - We propose a method to estimate N(e), the entanglement length, that incorporates both local and global topological characteristics of chains in a melt under equilibrium conditions. This estimate uses the writhe of the chains, the writhe of the primitive paths, and the number of kinks in the chains in a melt. An advantage of this method is that it works for both linear and ring chains, works under all periodic boundary conditions, does not require knowing the contour length of the primitive paths, and does not rely on a smooth set of data. We apply this method to linear finitely extendable nonlinear elastic chains and we observe that our estimates are consistent with those from other studies. PMID- 24483479 TI - Creep anomaly in electrospun fibers made of globular proteins. AB - The anomalous responses of electrospun nanofibers and film fabricated of unfolded bovine serum albumin (BSA) under constant stress (creep) is observed. In contrast to typical creep behavior of viscoelastic materials demonstrating (after immediate elastic response) a time-dependent elongation, in case of low applied stresses (<1 MPa) the immediate elastic response of BSA samples is followed by gradual contraction up to 2%. Under higher stresses (2-6 MPa) the contraction phase changes into elongation; and in case of stresses above 7 MPa only elongation was observed, with no initial contraction. The anomalous creep behavior was not observed when the BSA samples were subjected to additional creep cycles independently on the stress level. The above anomaly, which was not observed before either for viscoelastic solids or for polymers, is related to specific protein features, namely, to the ability to fold. We hypothesize that the phenomenon is caused by folding of BSA macromolecules into dry molten globule states, feasible after cross-linked bonds break up, resulting from the applied external force. PMID- 24483481 TI - Squirmer dynamics near a boundary. AB - The boundary behavior of axisymmetric microswimming squirmers is theoretically explored within an inertialess Newtonian fluid for a no-slip interface and also a free surface in the small capillary number limit, preventing leading-order surface deformation. Such squirmers are commonly presented as abridged models of ciliates, colonial algae, and Janus particles and we investigate the case of low mode axisymmetric tangential surface deformations with, in addition, the consideration of a rotlet dipole to represent torque-motor swimmers such as flagellated bacteria. The resulting boundary dynamics reduces to a phase plane in the angle of attack and distance from the boundary, with a simplifying time reversal duality. Stable swimming adjacent to a no-slip boundary is demonstrated via the presence of stable fixed points and, more generally, all types of fixed points as well as stable and unstable limit cycles occur adjacent to a no-slip boundary with variations in the tangential deformations. Nonetheless, there are constraints on swimmer behavior-for instance, swimmers characterized as pushers are never observed to exhibit stable limit cycles. All such generalities for no slip boundaries are consistent with observations and more geometrically faithful simulations to date, suggesting the tangential squirmer is a relatively simple framework to enable predications and classifications for the complexities associated with axisymmetric boundary swimming. However, in the presence of a free surface, with asymptotically small capillary number, and thus negligible leading-order surface deformation, no stable surface swimming is predicted across the parameter space considered. While this is in contrast to experimental observations, for example, the free-surface accumulation of sterlet sperm, extensive surfactants are present, most likely invalidating the low capillary number assumption. In turn, this suggests the necessity of surface deformation for stable free-surface three-dimensional finite-size microswimming, as previously highlighted in a two-dimensional mathematical study of singularity swimmers [Crowdy et al., J. Fluid Mech. 681, 24 (2011)]. PMID- 24483480 TI - Teardrop shapes minimize bending energy of fusion pores connecting planar bilayers. AB - A numerical gradient flow procedure was devised to characterize minimal energy shapes of fusion pores connecting two parallel planar bilayer membranes. Pore energy, composed of splay, tilt, and stretching, was obtained by modeling each bilayer as two monolayers and treating each monolayer of a bilayer membrane as a freely deformable surface described with a mean lipid orientation field. Voids between the two monolayers were prevented by a steric penalty formulation. Pore shapes were assumed to possess both axial and reflectional symmetry. For fixed pore radius and bilayer separation, the gradient flow procedure was applied to initially toroidal pore shapes. Using initially elliptical pore shapes yielded the same final shape. The resulting minimal pore shapes and energies were analyzed as a function of pore dimension and lipid composition. Previous studies either assumed or confined pore shapes, thereby tacitly supplying an unspecified amount of energy to maintain shape. The shapes derived in the present study were outputs of calculations and an externally provided energy was not supplied. Our procedure therefore yielded energy minima significantly lower than those reported in prior studies. The membrane of minimal energy pores bowed outward near the pore lumen, yielding a pore length that exceeded the distance between the two fusing membranes. PMID- 24483482 TI - Initiation and dynamics of a spiral wave around an ionic heterogeneity in a model for human cardiac tissue. AB - In relation to cardiac arrhythmias, heterogeneity of cardiac tissue is one of the most important factors underlying the onset of spiral waves and determining their type. In this paper, we numerically model heterogeneity of realistic size and value and study formation and dynamics of spiral waves around such heterogeneity. We find that the only sustained pattern obtained is a single spiral wave anchored around the heterogeneity. Dynamics of an anchored spiral wave depend on the extent of heterogeneity, and for certain heterogeneity size, we find abrupt regional increase in the period of excitation occurring as a bifurcation. We study factors determining spatial distribution of excitation periods of anchored spiral waves and discuss consequences of such dynamics for cardiac arrhythmias and possibilities for experimental testings of our predictions. PMID- 24483483 TI - Transient domain formation in membrane-bound organelles undergoing maturation. AB - The membrane components of cellular organelles have been shown to segregate into domains as the result of biochemical maturation. We propose that the dynamical competition between maturation and lateral segregation of membrane components regulates domain formation. We study a two-component fluid membrane in which enzymatic reaction irreversibly converts one component into another and phase separation triggers the formation of transient membrane domains. The maximum domain size is shown to depend on the maturation rate as a power law similar to the one observed for domain growth with time in the absence of maturation, despite this time dependence not being verified in the case of irreversible maturation. This control of domain size by enzymatic activity could play a critical role in regulating exchange between organelles or within compartmentalized organelles such as the Golgi apparatus. PMID- 24483484 TI - Spin models inferred from patient-derived viral sequence data faithfully describe HIV fitness landscapes. AB - Mutational escape from vaccine-induced immune responses has thwarted the development of a successful vaccine against AIDS, whose causative agent is HIV, a highly mutable virus. Knowing the virus' fitness as a function of its proteomic sequence can enable rational design of potent vaccines, as this information can focus vaccine-induced immune responses to target mutational vulnerabilities of the virus. Spin models have been proposed as a means to infer intrinsic fitness landscapes of HIV proteins from patient-derived viral protein sequences. These sequences are the product of nonequilibrium viral evolution driven by patient specific immune responses and are subject to phylogenetic constraints. How can such sequence data allow inference of intrinsic fitness landscapes? We combined computer simulations and variational theory a la Feynman to show that, in most circumstances, spin models inferred from patient-derived viral sequences reflect the correct rank order of the fitness of mutant viral strains. Our findings are relevant for diverse viruses. PMID- 24483485 TI - Principle for performing attractor transits with single control in Boolean networks. AB - We present an algebraic approach to reveal attractor transitions in Boolean networks under single control based on the recently developed matrix semitensor product theory. In this setting, the reachability of attractors is estimated by the state transition matrices. We then propose procedures that compute the shortest control sequence and the result of each step of input (control) exactly. The general derivation is exemplified by numerical simulations for two kinds of gene regulation networks, the protein-nucleic acid interactions network and the cAMP receptor of Dictyostelium discoideum network. PMID- 24483486 TI - Rheology of a vesicle suspension with finite concentration: a numerical study. AB - Vesicles, closed membranes made of a bilayer of phospholipids, are considered as a biomimetic system for the mechanics of red blood cells. The understanding of their dynamics under flow and their rheology is expected to help the understanding of the behavior of blood flow. We conduct numerical simulations of a suspension of vesicles in two dimensions at a finite concentration in a shear flow imposed by countertranslating rigid bounding walls by using an appropriate Green's function. We study the dynamics of vesicles, their spatial configurations, and their rheology, namely, the effective viscosity eta(eff). A key parameter is the viscosity contrast lambda (the ratio between the viscosity of the encapsulated fluid over that of the suspending fluid). For small enough lambda, vesicles are known to exhibit tank treading (TT), while at higher lambda they exhibit tumbling (TB). We find that eta(eff) decreases in the TT regime, passes a minimum at a critical lambda=lambda(c), and increases in the TB regime. This result confirms previous theoretical and numerical works performed in the extremely dilute regime, pointing to the robustness of the picture even in the presence of hydrodynamic interactions. Our results agree also with very recent numerical simulations performed in three dimensions both in the dilute and more concentrated regime. This points to the fact that dimensionality does not alter the qualitative features of eta(eff). However, they disagree with recent simulations in two dimensions. We provide arguments about the possible sources of this disagreement. PMID- 24483487 TI - Forces due to curving protofilaments in microtubules. AB - Microtubules consist of 13 protofilaments arranged in the form of a cylinder. The protofilaments are composed of longitudinally attached tubulin dimers that can exist in either a less curved state [GTP-bound tubulin (T)] or a more curved state [GDP-bound tubulin (D)]. Hydrolysis of T into D leaves the straight and laterally attached protofilaments of the microtubule in a mechanically stressed state, thus leading to their unzipping. The elastic energy in the unzipping protofilaments can be harnessed by a force transducer such as the Dam1 kinetochore ring complex in order to exert pulling force on chromosomes during cell division. In the present paper we develop a simple continuum model to obtain this pulling force as a function of the mechanical properties of protofilaments and the size of the Dam1-kinetochore ring. We also extend this model to investigate the role played by the T subunits found at the plus end of the microtubule (the T cap) on the mechanical stability of microtubules. PMID- 24483488 TI - Stochastic model for protein flexibility analysis. AB - Protein flexibility is an intrinsic property and plays a fundamental role in protein functions. Computational analysis of protein flexibility is crucial to protein function prediction, macromolecular flexible docking, and rational drug design. Most current approaches for protein flexibility analysis are based on Hamiltonian mechanics. We introduce a stochastic model to study protein flexibility. The essential idea is to analyze the free induction decay of a perturbed protein structural probability, which satisfies the master equation. The transition probability matrix is constructed by using probability density estimators including monotonically decreasing radial basis functions. We show that the proposed stochastic model gives rise to some of the best predictions of Debye-Waller factors or B factors for three sets of protein data introduced in the literature. PMID- 24483489 TI - Cell-to-cell coordination for the spontaneous cAMP oscillation in Dictyostelium. AB - We propose a new cellular dynamics scheme for the spontaneous cAMP oscillations in Dictyostelium discoideum. Our scheme seamlessly integrates both receptor dynamics and G-protein dynamics into our previously developed cellular dynamics scheme. Extensive computer simulation studies based on our new cellular dynamics scheme were conducted in mutant cells to evaluate the molecular network. The validity of our proposed molecular network as well as the controversial PKA dependent negative feedback mechanism was supported by our simulation studies. Spontaneous cAMP oscillations were not observed in a single mutant cell. However, multicellular states of various mutant cells consistently initiated spontaneous cAMP oscillations. Therefore, cell-to-cell coordination via the cAMP receptor is essential for the robust initiation of spontaneous cAMP oscillations. PMID- 24483490 TI - Mathematical modeling of human brain physiological data. AB - Recently, a mathematical model of the basic physiological processes regulating the cerebral perfusion and oxygen supply was introduced [Jung et al., J. Math. Biol. 51, 491 (2005)]. Although this model correctly describes the interdependence of arterial blood pressure (ABP) and intracranial pressure (ICP), it fails badly when it comes to explaining certain abnormal correlations seen in about 80% of the recordings of ABP together with ICP and the partial oxygen pressure (TiPO(2)) of the neuronal tissue, taken at an intensive care unit during neuromonitoring of patients with a severe brain trauma. Such recordings occasionally show segments, where the mean arterial blood pressure is correlated with the partial oxygen pressure in tissue but anticorrelated with the intracranial pressure. The origin of such abnormal correlations has not been fully understood yet. Here, two extensions to the previous approach are proposed which can reproduce such abnormal correlations in simulations quantitatively. Furthermore, as the simulations are based on a mathematical model, additional insight into the physiological mechanisms from which such abnormal correlations originate can be gained. PMID- 24483491 TI - Potassium ions in the cavity of a KcsA channel model. AB - The high rate of ion flux and selectivity of potassium channels has been attributed to the conformation and dynamics of the ions in the filter which connects the channel cavity and the extracellular environment. The cavity serves as the reservoir for potassium ions diffusing from the intracellular medium. The cavity is believed to decrease the dielectric barrier for the ions to enter the filter. We study here the equilibrium and dynamic properties of potassium ions entering the water-filled cavity of a KcsA channel model. Atomistic molecular dynamics simulations that are supplemented by electrostatic calculations reveal the important role of water molecules and the partially charged protein helices at the bottom of the cavity in overcoming the energy barrier and stabilizing the potassium ion in the cavity. We further show that the average time for a potassium ion to enter the cavity is much shorter than the conduction rate of a potassium passing through the filter, and this time duration is insensitive over a wide range of the membrane potential. The conclusions drawn from the study of the channel model are applicable in generalized contexts, including the entry of ions in artificial ion channels and other confined geometries. PMID- 24483493 TI - Trend and fluctuations: analysis and design of population dynamics measurements in replicate ecosystems. AB - The dynamical evolution of complex systems is often intrinsically stochastic and subject to external random forces. In order to study the resulting variability in dynamics, it is essential to make measurements on replicate systems and to separate arbitrary variation of the average dynamics of these replicates from fluctuations around the average dynamics. Here we do so for population time series data from replicate ecosystems sharing a common average dynamics or common trend. We explain how model parameters, including the effective interactions between species and dynamical noise, can be estimated from the data and how replication reduces errors in these estimates. For this, it is essential that the model can fit a variety of average dynamics. We then show how one can judge the quality of a model, compare alternate models, and determine which combinations of parameters are poorly determined by the data. In addition we show how replicate population dynamics experiments could be designed to optimize the acquired information of interest about the systems. Our approach is illustrated on a set of time series gathered from replicate microbial closed ecosystems. PMID- 24483492 TI - Model-independent decomposition of two-state data. AB - Two-state models often provide a reasonable approximation of protein behaviors such as partner binding, folding, and conformational changes. Many different techniques have been developed to determine the population ratio between two states as a function of different experimental conditions. Data analysis is accomplished either by fitting individual measured spectra to a linear combination of known basis spectra or alternatively by decomposing the entire set of spectra into two components using a least-squares optimization of free parameters within an assumed population model. Here we demonstrate that it is possible to determine the population ratio in a two-state system directly from data without an a priori model for basis spectra or populations by applying physical constraints iteratively to a singular value decomposition of optical fluorescence, x-ray-scattering, and electron paramagnetic resonance data. PMID- 24483494 TI - Electromechanics of a membrane with spatially distributed fixed charges: flexoelectricity and elastic parameters. AB - We investigate the electrostatic contribution to the lipid membrane mechanical parameters: tension, bending rigidity, spontaneous curvature, and flexocoefficient, using an approach where stress in the membrane is explicitly balanced. Our model includes an applied electrostatic potential as well as a charge distribution in the membrane. We apply our theory to membranes having surface charges and electric dipoles at the surface. PMID- 24483495 TI - Potentiation decay of synapses and length distributions of synfire chains self organized in recurrent neural networks. AB - Synfire chains are thought to underlie precisely timed sequences of spikes observed in various brain regions and across species. How they are formed is not understood. Here we analyze self-organization of synfire chains through the spike timing dependent plasticity (STDP) of the synapses, axon remodeling, and potentiation decay of synaptic weights in networks of neurons driven by noisy external inputs and subject to dominant feedback inhibition. Potentiation decay is the gradual, activity-independent reduction of synaptic weights over time. We show that potentiation decay enables a dynamic and statistically stable network connectivity when neurons spike spontaneously. Periodic stimulation of a subset of neurons leads to formation of synfire chains through a random recruitment process, which terminates when the chain connects to itself and forms a loop. We demonstrate that chain length distributions depend on the potentiation decay. Fast potentiation decay leads to long chains with wide distributions, while slow potentiation decay leads to short chains with narrow distributions. We suggest that the potentiation decay, which corresponds to the decay of early long-term potentiation of synapses, is an important synaptic plasticity rule in regulating formation of neural circuity through STDP. PMID- 24483496 TI - Self-organized criticality in single-neuron excitability. AB - We present experimental and theoretical arguments, at the single-neuron level, suggesting that neuronal response fluctuations reflect a process that positions the neuron near a transition point that separates excitable and unexcitable phases. This view is supported by the dynamical properties of the system as observed in experiments on isolated cultured cortical neurons, as well as by a theoretical mapping between the constructs of self-organized criticality and membrane excitability biophysics. PMID- 24483497 TI - Dendritic signal transmission induced by intracellular charge inhomogeneities. AB - Signal propagation in neuronal dendrites represents the basis for interneuron communication and information processing in the brain. Here we take into account charge inhomogeneities arising in the vicinity of ion channels in cytoplasm and obtain a modified cable equation. We show that charge inhomogeneities acting on a millisecond time scale can lead to the appearance of propagating waves with wavelengths of hundreds of micrometers. They correspond to a certain frequency band predicting the appearance of resonant properties in brain neuron signaling. We also show that membrane potential in spiny dendrites obeys the modified cable equation suggesting a crucial role of the spines in dendritic subthreshold resonance. PMID- 24483498 TI - Quantification of non-Markovian effects in the Fenna-Matthews-Olson complex. AB - The excitation energy transfer dynamics in the Fenna-Matthews-Olson complex is quantified in terms of a non-Markovianity measure based on the time evolution of the trace distance of two quantum states. We use a system description derived from experiments and different environmental fluctuation spectral functions, which are obtained either from experimental data or from molecular dynamics simulations. These exhibit, in all cases, a nontrivial structure with several peaks attributed to vibrational modes of the pigment-protein complex. Such a structured environmental spectrum can, in principle, give rise to strong non Markovian effects. We present numerically exact real-time path-integral calculations for the transfer dynamics and find, in all cases, a monotonic decrease of the trace distance with increasing time which renders a Markovian description valid. PMID- 24483499 TI - Lattice-free descriptions of collective motion with crowding and adhesion. AB - Cell-to-cell adhesion is an important aspect of malignant spreading that is often observed in images from the experimental cell biology literature. Since cell-to cell adhesion plays an important role in controlling the movement of individual malignant cells, it is likely that cell-to-cell adhesion also influences the spatial spreading of populations of such cells. Therefore, it is important for us to develop biologically realistic simulation tools that can mimic the key features of such collective spreading processes to improve our understanding of how cell-to-cell adhesion influences the spreading of cell populations. Previous models of collective cell spreading with adhesion have used lattice-based random walk frameworks which may lead to unrealistic results, since the agents in the random walk simulations always move across an artificial underlying lattice structure. This is particularly problematic in high-density regions where it is clear that agents in the random walk align along the underlying lattice, whereas no such regular alignment is ever observed experimentally. To address these limitations, we present a lattice-free model of collective cell migration that explicitly incorporates crowding and adhesion. We derive a partial differential equation description of the discrete process and show that averaged simulation results compare very well with numerical solutions of the partial differential equation. PMID- 24483500 TI - Stable coexistence in a Lotka-Volterra model with heterogeneous resources and intraguild predation. AB - In this study we model population dynamics in a three-species food web with heterogeneous resources and intraguild predation by using a nonspatial Lotka Volterra system with a density-dependent interaction of resource items. The model consists of two predators with an intraguild predation (IGP) relation competing for a common resource. The resource is subdivided into subpopulations of different quality that are distinguished by grazing rates of the two predators, contact rates between subpopulations and mortality rates. The proposed system describes an exchange of traits between species from distinct subpopulations by using a species interaction term. In particular, we examine the percentage of stable coexistence solutions versus resource carrying capacity and contact rates between distinct resource pools. We also present a numerical comparison of the percentage of stable food webs found for different numbers of subpopulations. While at high enrichment no stable coexistence was found in the IGP system with a single resource, our model predicts a stable coexistence of two IGP-related predators and resources at high and intermediate enrichment already at a low contact rate between subpopulations. PMID- 24483501 TI - Global force-torque phase diagram for the DNA double helix: structural transitions, triple points, and collapsed plectonemes. AB - We present a free energy model for structural transitions of the DNA double helix driven by tensile and torsional stress. Our model is coarse grained and is based on semiflexible polymer descriptions of B-DNA, underwound L-DNA, and highly overwound P-DNA. The statistical-mechanical model of plectonemic supercoiling previously developed for B-DNA is applied to semiflexible polymer models of P- and L-DNA to obtain a model of DNA structural transitions in quantitative accord with experiment. We identify two distinct plectonemic states, one "inflated" by electrostatic repulsion and thermal fluctuations and the other "collapsed," with the two double helices inside the supercoils driven to close contact. We find that supercoiled B and L are stable only in the inflated form, while supercoiled P is always collapsed. We also predict the behavior and experimental signatures of highly underwound "Q"-DNA, the left-handed analog of P-DNA; as for P, supercoiled Q is always collapsed. Overstretched "S"-DNA and strand-separated "stress-melted" DNA are also included in our model, allowing prediction of a global phase diagram for forces up to 1000 pN and torques between +/-60 pN nm, or, in terms of linking number density, from sigma=-5 to +3. PMID- 24483503 TI - Collective behavior and predation success in a predator-prey model inspired by hunting bats. AB - We establish an agent-based model to study the impact of prey behavior on the hunting success of predators. The predators and prey are modeled as self propelled particles moving in a three-dimensional domain and subject to specific sensing abilities and behavioral rules inspired by bat hunting. The predators randomly search for prey. The prey either align velocity directions with peers, defined as "interacting" prey, or swarm "independently" of peer presence; both types of prey are subject to additive noise. In a simulation study, we find that interacting prey using low noise have the maximum predation avoidance because they form localized large groups, while they suffer high predation as noise increases due to the formation of broadly dispersed small groups. Independent prey, which are likely to be uniformly distributed in the domain, have higher predation risk under a low noise regime as they traverse larger spatial extents. These effects are enhanced in large prey populations, which exhibit more ordered collective behavior or more uniform spatial distribution as they are interacting or independent, respectively. PMID- 24483504 TI - Partial mixing phase of binary cells in finite systems. AB - We study the self-organization of binary cell mixtures in finite cubic lattices. Depending on the relative attractions between cell types, the binary mixture model generates four distinct cellular associations: complete sorting, shell-core sorting, partial mixing, and complete mixing of heterotypic cells. At the boundaries between these four phases, the cellular associations show large variations, representing phase transitions. We find that the partial mixing phase is highly tolerant to thermal fluctuations. Interestingly, human pancreatic islets, the micro-organs for glucose homeostasis, adapt the partial mixing phase consisting of alpha and beta cells. PMID- 24483505 TI - Network growth with arbitrary initial conditions: degree dynamics for uniform and preferential attachment. AB - This paper provides time-dependent expressions for the expected degree distribution of a given network that is subject to growth. We consider both uniform attachment, where incoming nodes form links to existing nodes selected uniformly at random, and preferential attachment, where probabilities are assigned proportional to the degrees of the existing nodes. We consider the cases of single and multiple links being formed by each newly introduced node. The initial conditions are arbitrary, that is, the solution depends on the degree distribution of the initial graph which is the substrate of the growth. Previous work in the literature focuses on the asymptotic state, that is, when the number of nodes added to the initial graph tends to infinity, rendering the effect of the initial graph negligible. Our contribution provides a solution for the expected degree distribution as a function of time, for arbitrary initial condition. Previous results match our results in the asymptotic limit. The results are discrete in the degree domain and continuous in the time domain, where the addition of new nodes to the graph are approximated by a continuous arrival rate. PMID- 24483502 TI - Biophysical significance of the inner mitochondrial membrane structure on the electrochemical potential of mitochondria. AB - The available literature supports the hypothesis that the morphology of the inner mitochondrial membrane is regulated by different energy states, that the three dimensional morphology of cristae is dynamic, and that both are related to biochemical function. Examination of the correlation between the inner mitochondrial membrane (IMM) structure and mitochondrial energetic function is critical to an understanding of the links between mesoscale morphology and function in progressive mitochondrial dysfunction such as aging, neurodegeneration, and disease. To investigate this relationship, we develop a model to examine the effects of three-dimensional IMM morphology on the electrochemical potential of mitochondria. The two-dimensional axisymmetric finite element method is used to simulate mitochondrial electric potential and proton concentration distribution. This simulation model demonstrates that the proton motive force (Deltap) produced on the membranes of cristae can be higher than that on the inner boundary membrane. The model also shows that high proton concentration in cristae can be induced by the morphology-dependent electric potential gradient along the outer side of the IMM. Furthermore, simulation results show that a high Deltap is induced by the large surface-to-volume ratio of an individual crista, whereas a high capacity for ATP synthesis can primarily be achieved by increasing the surface area of an individual crista. The mathematical model presented here provides compelling support for the idea that morphology at the mesoscale is a significant driver of mitochondrial function. PMID- 24483506 TI - Epidemic threshold in directed networks. AB - Epidemics have so far been mostly studied in undirected networks. However, many real-world networks, such as the online social network Twitter and the world wide web, on which information, emotion, or malware spreads, are directed networks, composed of both unidirectional links and bidirectional links. We define the directionality xi as the percentage of unidirectional links. The epidemic threshold tau(c) for the susceptible-infected-susceptible (SIS) epidemic is lower bounded by 1/lambda(1) in directed networks, where lambda(1), also called the spectral radius, is the largest eigenvalue of the adjacency matrix. In this work, we propose two algorithms to generate directed networks with a given directionality xi. The effect of xi on the spectral radius lambda(1), principal eigenvector x(1), spectral gap (lambda(1)-|lambda(2)|), and algebraic connectivity MU(N-1) is studied. Important findings are that the spectral radius lambda(1) decreases with the directionality xi, whereas the spectral gap and the algebraic connectivity increase with the directionality xi. The extent of the decrease of the spectral radius depends on both the degree distribution and the degree-degree correlation rho(D). Hence, in directed networks, the epidemic threshold is larger and a random walk converges to its steady state faster than that in undirected networks with the same degree distribution. PMID- 24483507 TI - Laser-filament-induced snow formation in a subsaturated zone in a cloud chamber: experimental and theoretical study. AB - 1 kHz, 2 mJ, 45 fs, 800 nm laser pulses were fired into a laboratory diffusion cloud chamber through a subsaturated zone (relative humidity ~73%, T ~ 4.3 degrees C). After 60 min of laser irradiation, an oval-shaped snow pile was observed right below the filament center and weighed ~12.0 mg. The air current velocity at the edge of the vortices was estimated to be ~16.5 cm/s. Scattering scenes recorded from the side show that filament-induced turbulence were formed inside the cloud chamber with two vortices below the filament. Two-dimensional simulations of the air flow motion in two cross sections of the cloud chamber confirm that the turbulent vortices exist below the filament. Based upon this simulation, we deduce that the vortices indeed have a three-dimensional elliptical shape. Hence, we propose that inside vortices where the humidity was supersaturated or saturated the condensation nuclei, namely, HNO(3), N(2)(+), O(2)(+) and other aerosols and impurities, were activated and grew in size. Large sized particles would eventually be spun out along the fast moving direction towards the cold plate and formed an oval-shaped snow pile at the end. PMID- 24483508 TI - Explaining Zipf's law via a mental lexicon. AB - Zipf's law is the major regularity of statistical linguistics that has served as a prototype for rank-frequency relations and scaling laws in natural sciences. Here we show that Zipf's law-together with its applicability for a single text and its generalizations to high and low frequencies including hapax legomena-can be derived from assuming that the words are drawn into the text with random probabilities. Their a priori density relates, via the Bayesian statistics, to the mental lexicon of the author who produced the text. PMID- 24483509 TI - Behavior of susceptible-vaccinated-infected-recovered epidemics with diversity in the infection rate of individuals. AB - We study a susceptible-vaccinated-infected-recovered (SVIR) epidemic-spreading model with diversity of infection rate of the individuals. By means of analytical arguments as well as extensive computer simulations, we demonstrate that the heterogeneity in infection rate can either impede or accelerate the epidemic spreading, which depends on the amount of vaccinated individuals introduced in the population as well as the contact pattern among the individuals. Remarkably, as long as the individuals with different capability of acquiring the disease interact with unequal frequency, there always exist a cross point for the fraction of vaccinated, below which the diversity of infection rate hinders the epidemic spreading and above which expedites it. The overall results are robust to the SVIR dynamics defined on different population models; the possible applications of the results are discussed. PMID- 24483510 TI - Statistical mechanics of multiedge networks. AB - Statistical properties of binary complex networks are well understood and recently many attempts have been made to extend this knowledge to weighted ones. There are, however, subtle yet important considerations to be made regarding the nature of the weights used in this generalization. Weights can be either continuous or discrete magnitudes, and in the latter case, they can additionally have undistinguishable or distinguishable nature. This fact has not been addressed in the literature insofar and has deep implications on the network statistics. In this work we face this problem introducing multiedge networks as graphs where multiple (distinguishable) connections between nodes are considered. We develop a statistical mechanics framework where it is possible to get information about the most relevant observables given a large spectrum of linear and nonlinear constraints including those depending both on the number of multiedges per link and their binary projection. The latter case is particularly interesting as we show that binary projections can be understood from multiedge processes. The implications of these results are important as many real-agent based problems mapped onto graphs require this treatment for a proper characterization of their collective behavior. PMID- 24483511 TI - Hierarchical scale-free network is fragile against random failure. AB - We investigate site percolation in a hierarchical scale-free network known as the Dorogovtsev-Goltsev-Mendes network. We use the generating function method to show that the percolation threshold is 1, i.e., the system is not in the percolating phase when the occupation probability is less than 1. The present result is contrasted to bond percolation in the same network of which the percolation threshold is zero. We also show that the percolation threshold of intentional attacks is 1. Our results suggest that this hierarchical scale-free network is very fragile against both random failure and intentional attacks. Such a structural defect is common in many hierarchical network models. PMID- 24483512 TI - Scaling symmetry, renormalization, and time series modeling: the case of financial assets dynamics. AB - We present and discuss a stochastic model of financial assets dynamics based on the idea of an inverse renormalization group strategy. With this strategy we construct the multivariate distributions of elementary returns based on the scaling with time of the probability density of their aggregates. In its simplest version the model is the product of an endogenous autoregressive component and a random rescaling factor designed to embody also exogenous influences. Mathematical properties like increments' stationarity and ergodicity can be proven. Thanks to the relatively low number of parameters, model calibration can be conveniently based on a method of moments, as exemplified in the case of historical data of the S&P500 index. The calibrated model accounts very well for many stylized facts, like volatility clustering, power-law decay of the volatility autocorrelation function, and multiscaling with time of the aggregated return distribution. In agreement with empirical evidence in finance, the dynamics is not invariant under time reversal, and, with suitable generalizations, skewness of the return distribution and leverage effects can be included. The analytical tractability of the model opens interesting perspectives for applications, for instance, in terms of obtaining closed formulas for derivative pricing. Further important features are the possibility of making contact, in certain limits, with autoregressive models widely used in finance and the possibility of partially resolving the long- and short-memory components of the volatility, with consistent results when applied to historical series. PMID- 24483513 TI - Asymmetric coevolutionary voter dynamics. AB - We consider a modification of the adaptive contact process that, interpreted in the context of opinion dynamics, breaks the symmetry of the coevolutionary voter model by assigning to each node type a different strategy to promote consensus: Orthodox opinion holders spread their opinion via social pressure and rewire their connections following a segregationist strategy; heterodox opinion holders adopt a proselytic strategy, converting their neighbors through personal interactions, and relax to the orthodox opinion according to its representation in the population. We give a full description of the phase diagram of this asymmetric model, using the standard pair approximation equations and assessing their performance by comparison with stochastic simulations. We find that although global consensus is favored with regard to the symmetric case, the asymmetric model also features an active phase. We study the stochastic properties of the corresponding metastable state in finite-size networks, discussing the applicability of the analytic approximations developed for the coevolutionary voter model. We find that, in contrast to the symmetric case, the final consensus state is predetermined by the system's parameters and independent of initial conditions for sufficiently large system sizes. We also find that rewiring always favors consensus, both by significantly reducing convergence times and by changing their scaling with system size. PMID- 24483515 TI - Calculation of mean spectral density for statistically uniform treelike random models. AB - For random matrices with treelike structure there exists a recursive relation for the local Green functions whose solution permits us to find directly many important quantities in the limit of infinite matrix dimensions. The purpose of this article is to investigate and compare expressions for the spectral density of random regular graphs, based on easy approximations for real solutions of the recursive relation valid for trees with large coordination number. The obtained formulas are in a good agreement with the results of numerical calculations even for small coordination number. PMID- 24483514 TI - Collective dynamics of pedestrians interacting with attractions. AB - In order to investigate collective effects of interactions between pedestrians and attractions, this study extends the social force model. Such interactions lead pedestrians to form stable clusters around attractions, or even to rush into attractions if the interaction becomes stronger. It is also found that for high pedestrian density and intermediate interaction strength, some pedestrians rush into attractions while others move to neighboring attractions. These collective patterns of pedestrian movements or phases and transitions between them are systematically presented in a phase diagram. The results suggest that safe and efficient use of pedestrian areas can be achieved by moderating the pedestrian density and the strength of attractive interaction, for example, in order to avoid situations involving extreme desire for limited resources. PMID- 24483516 TI - Robustness of network measures to link errors. AB - In various applications involving complex networks, network measures are employed to assess the relative importance of network nodes. However, the robustness of such measures in the presence of link inaccuracies has not been well characterized. Here we present two simple stochastic models of false and missing links and study the effect of link errors on three commonly used node centrality measures: degree centrality, betweenness centrality, and dynamical importance. We perform numerical simulations to assess robustness of these three centrality measures. We also develop an analytical theory, which we compare with our simulations, obtaining very good agreement. PMID- 24483517 TI - Universal size effects for populations in group-outcome decision-making problems. AB - Elections constitute a paradigm of decision-making problems that have puzzled experts of different disciplines for decades. We study two decision-making problems, where groups make decisions that impact only themselves as a group. In both studied cases, participation in local elections and the number of democratic representatives at different scales (from local to national), we observe a universal scaling with the constituency size. These results may be interpreted as constituencies having a hierarchical structure, where each group of N agents, at each level of the hierarchy, is divided in about N(delta) subgroups with delta~1/3. Following this interpretation, we propose a phenomenological model of vote participation where abstention is related to the perceived link of an agent to the rest of the constituency and which reproduces quantitatively the observed data. PMID- 24483518 TI - Reducing financial avalanches by random investments. AB - Building on similarities between earthquakes and extreme financial events, we use a self-organized criticality-generating model to study herding and avalanche dynamics in financial markets. We consider a community of interacting investors, distributed in a small-world network, who bet on the bullish (increasing) or bearish (decreasing) behavior of the market which has been specified according to the S&P 500 historical time series. Remarkably, we find that the size of herding related avalanches in the community can be strongly reduced by the presence of a relatively small percentage of traders, randomly distributed inside the network, who adopt a random investment strategy. Our findings suggest a promising strategy to limit the size of financial bubbles and crashes. We also obtain that the resulting wealth distribution of all traders corresponds to the well-known Pareto power law, while that of random traders is exponential. In other words, for technical traders, the risk of losses is much greater than the probability of gains compared to those of random traders. PMID- 24483519 TI - Effects of variable-state neighborhoods for spreading synergystic processes on lattices. AB - A theoretical framework for the description of susceptible-infected-removed (SIR) spreading processes with synergistic transmission of infection on a lattice is developed. The model incorporates explicitly the effects of time-dependence of the state of the hosts in the neighborhood of transmission events. Exact solution of the model shows that time-dependence of the state of nearest neighbors of recipient hosts is a key factor for synergistic spreading processes. It is demonstrated that the higher the connectivity of a lattice, the more prominent is the effect of synergy on spread. PMID- 24483520 TI - Percolation of a general network of networks. AB - Percolation theory is an approach to study the vulnerability of a system. We develop an analytical framework and analyze the percolation properties of a network composed of interdependent networks (NetONet). Typically, percolation of a single network shows that the damage in the network due to a failure is a continuous function of the size of the failure, i.e., the fraction of failed nodes. In sharp contrast, in NetONet, due to the cascading failures, the percolation transition may be discontinuous and even a single node failure may lead to an abrupt collapse of the system. We demonstrate our general framework for a NetONet composed of n classic Erdos-Renyi (ER) networks, where each network depends on the same number m of other networks, i.e., for a random regular network (RR) formed of interdependent ER networks. The dependency between nodes of different networks is taken as one-to-one correspondence, i.e., a node in one network can depend only on one node in the other network (no-feedback condition). In contrast to a treelike NetONet in which the size of the largest connected cluster (mutual component) depends on n, the loops in the RR NetONet cause the largest connected cluster to depend only on m and the topology of each network but not on n. We also analyzed the extremely vulnerable feedback condition of coupling, where the coupling between nodes of different networks is not one-to one correspondence. In the case of NetONet formed of ER networks, percolation only exhibits two phases, a second order phase transition and collapse, and no first order percolation transition regime is found in the case of the no-feedback condition. In the case of NetONet composed of RR networks, there exists a first order phase transition when the coupling strength q (fraction of interdependency links) is large and a second order phase transition when q is small. Our insight on the resilience of coupled networks might help in designing robust interdependent systems. PMID- 24483521 TI - Critical properties of a dissipative sandpile model on small-world networks. AB - A dissipative sandpile model is constructed and studied on small-world networks (SWNs). SWNs are generated by adding extra links between two arbitrary sites of a two-dimensional square lattice with different shortcut densities phi. Three regimes are identified: regular lattice (RL) for phi?2(-12), SWN for 2( 12)=0.1. In the RL regime, the sandpile dynamics is characterized by the usual Bak, Tang, and Weisenfeld (BTW)-type correlated scaling, whereas in the RN regime it is characterized by mean-field scaling. On SWNs, both scaling behaviors are found to coexist. Small compact avalanches below a certain characteristic size s(c) are found to belong to the BTW universality class, whereas large, sparse avalanches above s(c) are found to belong to the mean-field universality class. A scaling theory for the coexistence of two scaling forms on a SWN is developed and numerically verified. Though finite-size scaling is not valid for the dissipative sandpile model on RLs or on SWNs, it is found to be valid on RNs for the same model. Finite-size scaling on RNs appears to be an outcome of super diffusive sand transport and uncorrelated toppling waves. PMID- 24483522 TI - Multiopinion coevolving voter model with infinitely many phase transitions. AB - We consider an idealized model in which individuals' changing opinions and their social network coevolve, with disagreements between neighbors in the network resolved either through one imitating the opinion of the other or by reassignment of the discordant edge. Specifically, an interaction between x and one of its neighbors y leads to x imitating y with probability (1-alpha) and otherwise (i.e., with probability alpha) x cutting its tie to y in order to instead connect to a randomly chosen individual. Building on previous work about the two-opinion case, we study the multiple-opinion situation, finding that the model has infinitely many phase transitions (in the large graph limit with infinitely many initial opinions). Moreover, the formulas describing the end states of these processes are remarkably simple when expressed as a function of beta=alpha/(1 alpha). PMID- 24483523 TI - s-core network decomposition: a generalization of k-core analysis to weighted networks. AB - A broad range of systems spanning biology, technology, and social phenomena may be represented and analyzed as complex networks. Recent studies of such networks using k-core decomposition have uncovered groups of nodes that play important roles. Here, we present s-core analysis, a generalization of k-core (or k-shell) analysis to complex networks where the links have different strengths or weights. We demonstrate the s-core decomposition approach on two random networks (ER and configuration model with scale-free degree distribution) where the link weights are (i) random, (ii) correlated, and (iii) anticorrelated with the node degrees. Finally, we apply the s-core decomposition approach to the protein-interaction network of the yeast Saccharomyces cerevisiae in the context of two gene expression experiments: oxidative stress in response to cumene hydroperoxide (CHP), and fermentation stress response (FSR). We find that the innermost s-cores are (i) different from innermost k-cores, (ii) different for the two stress conditions CHP and FSR, and (iii) enriched with proteins whose biological functions give insight into how yeast manages these specific stresses. PMID- 24483524 TI - Percolation on random networks with arbitrary k-core structure. AB - The k-core decomposition of a network has thus far mainly served as a powerful tool for the empirical study of complex networks. We now propose its explicit integration in a theoretical model. We introduce a hard-core random network (HRN) model that generates maximally random networks with arbitrary degree distribution and arbitrary k-core structure. We then solve exactly the bond percolation problem on the HRN model and produce fast and precise analytical estimates for the corresponding real networks. Extensive comparison with real databases reveals that our approach performs better than existing models, while requiring less input information. PMID- 24483525 TI - Integrable approximation of regular islands: the iterative canonical transformation method. AB - Generic Hamiltonian systems have a mixed phase space, where classically disjoint regions of regular and chaotic motion coexist. We present an iterative method to construct an integrable approximation H(reg), which resembles the regular dynamics of a given mixed system H and extends it into the chaotic region. The method is based on the construction of an integrable approximation in action representation which is then improved in phase space by iterative applications of canonical transformations. This method works for strongly perturbed systems and arbitrary degrees of freedom. We apply it to the standard map and the cosine billiard. PMID- 24483526 TI - Metastable dynamical patterns and their stabilization in arrays of bidirectionally coupled sigmoidal neurons. AB - Transient patterns in a bistable ring of bidirectionally coupled sigmoidal neurons were studied. When the system had a pair of spatially uniform steady solutions, the instability of unstable spatially nonuniform steady solutions decreased exponentially with the number of neurons because of the symmetry of the system. As a result, transient spatially nonuniform patterns showed dynamical metastability: Their duration increased exponentially with the number of neurons and the duration of randomly generated patterns obeyed a power-law distribution. However, these metastable dynamical patterns were easily stabilized in the presence of small variations in coupling strength. Metastable rotating waves and their pinning in the presence of asymmetry in the direction of coupling and the disappearance of metastable dynamical patterns due to asymmetry in the output function of a neuron were also examined. Further, in a two-dimensional array of neurons with nearest-neighbor coupling, intrinsically one-dimensional patterns were dominant in transients, and self-excitation in these neurons affected the metastable dynamical patterns. PMID- 24483527 TI - Optical rogue waves for the inhomogeneous generalized nonlinear Schrodinger equation. AB - We present optical rogue wave solutions for a generalized nonlinear Schrodinger equation by using similarity transformation. We have predicted the propagation of rogue waves through a nonlinear optical fiber for three cases: (i) dispersion increasing (decreasing) fiber, (ii) periodic dispersion parameter, and (iii) hyperbolic dispersion parameter. We found that the rogue waves and their interactions can be tuned by properly choosing the parameters. We expect that our results can be used to realize improved signal transmission through optical rogue waves. PMID- 24483528 TI - Stability boundary and collisions of two-dimensional solitons in PT-symmetric couplers with the cubic-quintic nonlinearity. AB - We introduce one- and two-dimensional (1D and 2D) models of parity-time (PT) symmetric couplers with the mutually balanced linear gain and loss applied to the two cores and cubic-quintic (CQ) nonlinearity acting in each one. The 2D and 1D models may be realized in dual-core optical wave guides in the spatiotemporal and spatial domains, respectively. Stationary solutions for PT-symmetric solitons in these systems reduce to their counterparts in the usual coupler. The most essential problem is the stability of the solitons, which become unstable against symmetry breaking with the increase of the energy (norm) and retrieve the stability at still larger energies. The boundary value of the intercore-coupling constant, above which the solitons are completely stable, is found by means of an analytical approximation, based on the cw (zero-dimensional) counterpart of the system. The approximation demonstrates good agreement with numerical findings for the 1D and 2D solitons. Numerical results for the stability limits of the 2D solitons are obtained by means of the computation of eigenvalues for small perturbations, and verified in direct simulations. Although large parts of the soliton families are unstable, the instability is quite weak. Collisions between 2D solitons in the PT-symmetric coupler are studied by means of simulations. Outcomes of the collisions are inelastic but not destructive, as they do not break the PT symmetry. PMID- 24483529 TI - Semiclassical theory of speckle correlations. AB - Coherent wave propagation in random media results in a characteristic speckle pattern, with spatial intensity correlations with short-range and long-range behavior. Here, we show how the speckle correlation function can be obtained from a ray picture for two representative geometries, namely a chaotic cavity and a random waveguide. Our calculation allows us to study the crossover between a "ray limit" and a "wave limit," in which the Ehrenfest time tau(E) is larger or smaller than the typical transmission time tau(D), respectively. Remarkably, long range speckle correlations persist in the ray limit tau(E)?tau(D). PMID- 24483531 TI - Effective dynamics of twisted and curved scroll waves using virtual filaments. AB - Scroll waves are three-dimensional excitation patterns that rotate around a central filament curve; they occur in many physical, biological, and chemical systems. We explicitly derive the equations of motion for scroll wave filaments in reaction-diffusion systems with isotropic diffusion up to third order in the filament's twist and curvature. The net drift components define at every instance of time a virtual filament which lies close to the instantaneous filament. Importantly, virtual filaments obey simpler, time-independent laws of motion which we analytically derive here and illustrate with numerical examples. Stability analysis of scroll waves is performed using virtual filaments, showing that filament curvature and twist add as quadratic terms to the nominal filament tension. Applications to oscillating chemical reactions and cardiac tissue are discussed. PMID- 24483530 TI - Experimental observation of localized modes in a dielectric square resonator. AB - We investigated the frequency spectra and field distributions of a dielectric square resonator in a microwave experiment. Since such systems cannot be treated analytically, the experimental studies of their properties are indispensable. The momentum representation of the measured field distributions shows that all resonant modes are localized on specific classical tori of the square billiard. Based on these observations a semiclassical model was developed. It shows excellent agreement with all but a single class of measured field distributions that will be treated separately. PMID- 24483532 TI - Complex mode dynamics of coupled wave oscillators. AB - We explore how nonlinear coherent waves localized in a few wells of a periodic potential can act analogously to a chain of coupled oscillators. We identify the small-amplitude oscillation modes of these "coupled wave oscillators" and find that they can be extended into the large amplitude regime, where some "ring" for long times. We also reveal the appearance of complex behavior such as the breakdown of Josephson-like oscillations, the destabilization of fundamental oscillation modes, and the emergence of chaotic oscillations for large amplitude excitations. We show that the dynamics may be accurately described by a discrete model with nearest-neighbor coupling, in which the lattice oscillators bear an effective mass. PMID- 24483533 TI - Synchronization of chemical noise-sustained structures in asymmetrically coupled differential-flow reactors. AB - The differential-flow-induced chemical instability is investigated in the context of two coupled reactors with cubic autocatalytic kinetics (the Gray-Scott model). Previous results for master-slave arrangement [Izus, Deza, and Sanchez, J. Chem. Phys. 132, 234112 (2010)] are extended in this study to include bidirectional coupling between reactions. Numerical simulations in the convectively unstable regime show that synchronized noise-sustained structures are developed in both reactors due to the selective amplification of noise. A theoretical analysis shows that the nature of the synchronization and the stability of the synchronized manifold are related with the properties of the critical modes. PMID- 24483534 TI - Nonlinear time reversal of classical waves: experiment and model. AB - We consider time reversal of electromagnetic waves in a closed, wave-chaotic system containing a discrete, passive, harmonic-generating nonlinearity. An experimental system is constructed as a time-reversal mirror, in which excitations generated by the nonlinearity are gathered, time-reversed, transmitted, and directed exclusively to the location of the nonlinearity. Here we show that such nonlinear objects can be purely passive (as opposed to the active nonlinearities used in previous work), and we develop a higher data rate exclusive communication system based on nonlinear time reversal. A model of the experimental system is developed, using a star-graph network of transmission lines, with one of the lines terminated by a model diode. The model simulates time reversal of linear and nonlinear signals, demonstrates features seen in the experimental system, and supports our interpretation of the experimental results. PMID- 24483535 TI - Synchronization of electrochemical oscillators with differential coupling. AB - Experiments are presented to describe the effect of capacitive coupling of two electrochemical oscillators during Ni dissolution in sulfuric acid solution. Equivalent circuit analysis shows that the coupling between the oscillators occurs through the difference between the differentials of the electrode potentials. The differential nature of the coupling introduces strong negative nonisochronicity (i.e., phase shear, strong dependence of the period on the amplitude) in the coupling mechanism with smooth oscillators (under conditions just above a Hopf bifurcation point). Because of the negative nonisochronicity, asymmetrically coupled oscillators exhibit anomalous phase synchronization in the form of frequency difference enhancement. At strong coupling bistability is observed between in-phase and antiphase synchronized states. With relaxation oscillators, in contrast to the resistive coupling where antiphase synchronization can occur, the typical system response with weak coupling is out of-phase synchronization. When the capacitance is applied on the individual resistors attached to the electrodes the oscillators exhibit weak positive nonisochronicity; this is in contrast with the strong negative nonisochronicity obtained with cross coupling. The proposed coupling configurations reveal the importance of the nonisochronicity level of oscillations for the experimentally observed synchronization patterns and also provide efficient ways of tuning the nonisochronicity level of the oscillations. This latter feature can be exploited to design synchronization features with a combination of resistive (difference) and capacitive (differential) coupling. PMID- 24483536 TI - Empirical method to measure stochasticity and multifractality in nonlinear time series. AB - An empirical algorithm is used here to study the stochastic and multifractal nature of nonlinear time series. A parameter can be defined to quantitatively measure the deviation of the time series from a Wiener process so that the stochasticity of different time series can be compared. The local volatility of the time series under study can be constructed using this algorithm, and the multifractal structure of the time series can be analyzed by using this local volatility. As an example, we employ this method to analyze financial time series from different stock markets. The result shows that while developed markets evolve very much like an Ito process, the emergent markets are far from efficient. Differences about the multifractal structures and leverage effects between developed and emergent markets are discussed. The algorithm used here can be applied in a similar fashion to study time series of other complex systems. PMID- 24483537 TI - Preferred frequency responses to oscillatory inputs in an electrochemical cell model: linear amplitude and phase resonance. AB - We investigate the dynamic mechanisms of generation of amplitude and phase resonance in a phenomenological electrochemical cell model in response to sinusoidal inputs. We describe how the attributes of the impedance and phase profiles change as the participating physicochemical parameters vary within a range corresponding to the existence of stable nodes and foci in the corresponding autonomous system, thus extending previous work that considered systems close to limit cycle regimes. The method we use permits us to understand how changes in these parameters generate amplifications of the cell's response at the resonant frequency band and captures some important nonlinear effects. PMID- 24483538 TI - Topological bifurcations in a model society of reasonable contrarians. AB - People are often divided into conformists and contrarians, the former tending to align to the majority opinion in their neighborhood and the latter tending to disagree with that majority. In practice, however, the contrarian tendency is rarely followed when there is an overwhelming majority with a given opinion, which denotes a social norm. Such reasonable contrarian behavior is often considered a mark of independent thought and can be a useful strategy in financial markets. We present the opinion dynamics of a society of reasonable contrarian agents. The model is a cellular automaton of Ising type, with antiferromagnetic pair interactions modeling contrarianism and plaquette terms modeling social norms. We introduce the entropy of the collective variable as a way of comparing deterministic (mean-field) and probabilistic (simulations) bifurcation diagrams. In the mean-field approximation the model exhibits bifurcations and a chaotic phase, interpreted as coherent oscillations of the whole society. However, in a one-dimensional spatial arrangement one observes incoherent oscillations and a constant average. In simulations on Watts-Strogatz networks with a small-world effect the mean-field behavior is recovered, with a bifurcation diagram that resembles the mean-field one but where the rewiring probability is used as the control parameter. Similar bifurcation diagrams are found for scale-free networks, and we are able to compute an effective connectivity for such networks. PMID- 24483540 TI - Transfer of dipolar gas through the discrete localized mode. AB - By considering the discrete nonlinear Schrodinger model with dipole-dipole interactions for dipolar condensate, the existence, the types, the stability, and the dynamics of the localized modes in a nonlinear lattice are discussed. It is found that the contact interaction and the dipole-dipole interactions play important roles in determining the existence, the type, and the stability of the localized modes. Because of the coupled effects of the contact interaction and the dipole-dipole interactions, rich localized modes and their stability nature can exist: when the contact interaction is larger and the dipole-dipole interactions is smaller, a discrete bright breather occurs. In this case, while the on-site interaction can stabilize the discrete breather, the dipole-dipole interactions will destabilize the discrete breather; when both the contact interaction and the dipole-dipole interactions are larger, a discrete kink appears. In this case, both the on-site interaction and the dipole-dipole interactions can stabilize the discrete kink, but the discrete kink is more unstable than the ordinary discrete breather. The predicted results provide a deep insight into the dynamics of blocking, filtering, and transfer of the norm in nonlinear lattices for dipolar condensates. PMID- 24483539 TI - Clustering in delay-coupled smooth and relaxational chemical oscillators. AB - We investigate cluster synchronization in networks of nonlinear systems with time delayed coupling. Using a generic model for a system close to the Hopf bifurcation, we predict the order of appearance of different cluster states and their corresponding common frequencies depending upon coupling delay. We may tune the delay time in order to ensure the existence and stability of a specific cluster state. We qualitatively and quantitatively confirm these results in experiments with chemical oscillators. The experiments also exhibit strongly nonlinear relaxation oscillations as we increase the voltage, i.e., go further away from the Hopf bifurcation. In this regime, we find secondary cluster states with delay-dependent phase lags. These cluster states appear in addition to primary states with delay-independent phase lags observed near the Hopf bifurcation. Extending the theory on Hopf normal-form oscillators, we are able to account for realistic interaction functions, yielding good agreement with experimental findings. PMID- 24483541 TI - Stabilization of a scroll ring by a cylindrical Neumann boundary. AB - We study the interaction of phase singularities with homogeneous Neumann boundaries in one, two, and three spatial dimensions for the complex Ginzburg Landau equation. The existence of a boundary-induced drift attractor, well known for spiral waves in two spatial dimensions, is demonstrated for scroll waves in three spatial dimensions. We find that a cylindrical Neumann boundary can lock a scroll ring, thus preventing the collapse of its closed filament. PMID- 24483542 TI - Quasiperiodic graphs at the onset of chaos. AB - We examine the connectivity fluctuations across networks obtained when the horizontal visibility (HV) algorithm is used on trajectories generated by nonlinear circle maps at the quasiperiodic transition to chaos. The resultant HV graph is highly anomalous as the degrees fluctuate at all scales with amplitude that increases with the size of the network. We determine families of Pesin-like identities between entropy growth rates and generalized graph-theoretical Lyapunov exponents. An irrational winding number with pure periodic continued fraction characterizes each family. We illustrate our results for the so-called golden, silver, and bronze numbers. PMID- 24483543 TI - Universal asymptotic behavior in nonlinear systems driven by a two-frequency forcing. AB - We examine the time-dependent behavior of a nonlinear system driven by a two frequency forcing. By using a nonperturbative approach, we are able to derive an asymptotic expression, valid in the long-time limit, for the time average of the output variable which describes the response of the system. We identify several universal features of the asymptotic response of the system, which are independent of the details of the model. In particular, we determine an asymptotic expression for the width of the resonance observed by keeping one frequency fixed and varying the other one. We show that this width is smaller than the usually assumed Fourier width by a factor determined by the two driving frequencies, and independent of the model system parameters. Additional general features can also be identified depending on the specific symmetry properties of the system. Our results find direct application in the study of sub-Fourier signal processing with nonlinear systems. PMID- 24483544 TI - Nucleation in bistable dynamical systems with long delay. AB - In an asymmetric bistable dynamical system with delayed feedback, one of the stable states is usually "stronger" than the other one: The system relaxes to it not only from close initial conditions, but also from oscillatory initial configurations which contain epochs of stay near both attractors. However, if the initial nucleus of the stronger phase is shorter than a certain critical value, it shrinks, and the weaker state is established instead. We observe this effect in a paradigmatic model and in an experiment based on a bistable semiconductor laser and characterize it in terms of scaling laws governing its asymptotic properties. PMID- 24483545 TI - General multicomponent Yajima-Oikawa system: Painleve analysis, soliton solutions, and energy-sharing collisions. AB - We consider the multicomponent Yajima-Oikawa (YO) system and show that the two component YO system can be derived in a physical setting of a three-coupled nonlinear Schrodinger (3-CNLS) type system by the asymptotic reduction method. The derivation is further generalized to the multicomponent case. This set of equations describes the dynamics of nonlinear resonant interaction between a one dimensional long wave and multiple short waves. The Painleve analysis of the general multicomponent YO system shows that the underlying set of evolution equations is integrable for arbitrary nonlinearity coefficients which will result in three different sets of equations corresponding to positive, negative, and mixed nonlinearity coefficients. We obtain the general bright N-soliton solution of the multicomponent YO system in the Gram determinant form by using Hirota's bilinearization method and explicitly analyze the one- and two-soliton solutions of the multicomponent YO system for the above mentioned three choices of nonlinearity coefficients. We also point out that the 3-CNLS system admits special asymptotic solitons of bright, dark, anti-dark, and gray types, when the long-wave-short-wave resonance takes place. The short-wave component solitons undergo two types of energy-sharing collisions. Specifically, in the two component YO system, we demonstrate that two types of energy-sharing collisions (i) energy switching with opposite nature for a particular soliton in two components and (ii) similar kind of energy switching for a given soliton in both components-result for two different choices of nonlinearity coefficients. The solitons appearing in the long-wave component always exhibit elastic collision whereas those of short-wave components exhibit standard elastic collisions only for a specific choice of parameters. We have also investigated the collision dynamics of asymptotic solitons in the original 3-CNLS system. For completeness, we explore the three-soliton interaction and demonstrate the pairwise nature of collisions and unravel the fascinating state restoration property. PMID- 24483547 TI - Dependence of scroll-wave dynamics on the orientation of a gradient of excitability. AB - The dynamics of scroll waves with a variable orientation to a vertically oriented gradient of excitability is studied by optical tomography in the ferroin catalyzed Belousov-Zhabotinsky reaction. An almost perpendicular orientation between the scroll wave and gradient induces a pair of twists of opposite handedness on the scroll wave. The position of the nodal plane formed between the twists is governed by the time delay of the twist formation and therefore leads to a symmetric or asymmetric twisted scroll wave. Larger inclinations between scroll wave and gradient cause a drift of the filament along the reactor wall until it reaches the bottom of the reaction container. In this case, the scroll wave does not twist, suggesting that a drift acts as an alternative mechanism of responding to the gradient. PMID- 24483546 TI - Phase noise of oscillators with unsaturated amplifiers. AB - We study the role of amplifier saturation in eliminating feedback noise in self sustained oscillators. We extend previous works that use a saturated amplifier to quench fluctuations in the feedback magnitude, while simultaneously tuning the oscillator to an operating point at which the resonator nonlinearity cancels fluctuations in the feedback phase. We consider a generalized model which features an amplitude-dependent amplifier gain function. This allows us to determine the total oscillator phase noise in realistic configurations due to noise in both quadratures of the feedback, and to show that it is not necessary to drive the resonator to large oscillation amplitudes in order to eliminate noise in the phase of the feedback. PMID- 24483548 TI - Limits to detection of generalized synchronization in delay-coupled chaotic oscillators. AB - We study how reliably generalized synchronization can be detected and characterized from time-series analysis. To that end, we analyze synchronization in a generalized sense of delay-coupled chaotic oscillators in unidirectional ring configurations. The generalized synchronization condition can be verified via the auxiliary system approach; however, in practice, this might not always be possible. Therefore, in this study, widely used indicators to directly quantify generalized and phase synchronization from noise-free time series of two oscillators are employed complementarily to the auxiliary system approach. In our analysis, none of the indices provide the consistent results of the auxiliary system approach. Our findings indicate that it is a major challenge to directly detect synchronization in a generalized sense between two oscillators that are connected via a chain of other oscillators, even if the oscillators are identical. This has major consequences for the interpretation of the dynamics of coupled systems and applications thereof. PMID- 24483549 TI - Circularly polarized few-cycle optical rogue waves: rotating reduced Maxwell Bloch equations. AB - The rotating reduced Maxwell-Bloch (RMB) equations, which describe the propagation of few-cycle optical pulses in a transparent media with two isotropic polarized electronic field components, are derived from a system of complete Maxwell-Bloch equations without using the slowly varying envelope approximations. Two hierarchies of the obtained rational solutions, including rogue waves, which are also called few-cycle optical rogue waves, of the rotating RMB equations are constructed explicitly through degenerate Darboux transformation. In addition to the above, the dynamical evolution of the first-, second-, and third-order few cycle optical rogue waves are constructed with different patterns. For an electric field E in the three lower-order rogue waves, we find that rogue waves correspond to localized large amplitude oscillations of the polarized electric fields. Further a complementary relationship of two electric field components of rogue waves is discussed in terms of analytical formulas as well as numerical figures. PMID- 24483550 TI - Semiclassical initial-value representation of the transfer operator. AB - The ability of semiclassical initial-value representation (IVR) methods to determine approximate energy levels for bound systems is limited due to problems associated with long classical trajectories. These difficulties become especially severe for large or classically chaotic systems. This work attempts to overcome such problems by developing an IVR expression that is classically equivalent to Bogomolny's formula for the transfer matrix [E. B. Bogomolny, Nonlinearity 5, 805 (1992); Chaos 2, 5 (1992)] and can be used to determine semiclassical energy levels. The method is adapted to levels associated with states of desired symmetries and applied to two two-dimensional quartic oscillator systems, one integrable and one mostly chaotic. For both cases, the technique is found to resolve all energy levels in the ranges investigated. The IVR method does not require a search for special trajectories obeying boundary conditions on the Poincare surface of section and leads to more rapid convergence of Monte Carlo phase space integrations than a previously developed IVR technique. It is found that semiclassical energies can be extracted from the eigenvalues of transfer matrices of dimension close to the theoretical minimum determined by Bogomolny's theory. The results support the assertion that the present IVR theory provides a different semiclassical approximation to the transfer matrix than that of Bogomolny for h?0. For the chaotic system investigated the IVR energies are found to be generally more accurate than those predicted by Bogomolny's theory. PMID- 24483551 TI - Statistics of turbulent fluctuations in counter-rotating Taylor-Couette flows. AB - The statistics of velocity fluctuations of turbulent Taylor-Couette flow are examined. The rotation rates of the inner and outer cylinders are varied while keeping the Taylor number fixed to 1.49*10(12) [O(Re)=10(6)]. The azimuthal velocity component of the flow is measured using laser Doppler anemometry. For each experiment 5*10(6) data points are acquired and carefully analyzed. Using extended self-similarity [Benzi et al., Phys. Rev. E 48, R29 (1993)] the longitudinal structure function exponents are extracted and are found to weakly depend on the ratio of the rotation rates. For the case where only the inner cylinder rotates the results are in good agreement with results measured by Lewis and Swinney [Phys. Rev. E 59, 5457 (1999)] using hot-film anemometry. The power spectra show clear -5/3 scaling for the intermediate angular velocity ratios omega(o)/omega(i)?{0.6,0.8,1.0}, roughly -5/3 scaling for omega(o)/omega(i)?{0.2,0.3,0.4,2.0}, and no clear scaling law can be found for omega(0)/omega(i)=0 (inner cylinder rotation only); the local scaling exponent of the spectra has a strong frequency dependence. We relate these observations to the shape of the probability density function of the azimuthal velocity and the presence of a neutral line. PMID- 24483552 TI - Dual role of gravity on the Faraday threshold for immiscible viscous layers. AB - This work discusses the role of gravity on the Faraday instability, and the differences one can expect to observe in a low-gravity experiment when compared to an earth-based system. These differences are discussed in the context of the viscous linear theory for laterally infinite systems, and a surprising result of the analysis is the existence of a crossover frequency where an interface in low gravity switches from being less to more stable than an earth-based system. We propose this crossover exists in all Faraday systems, and the frequency at which it occurs is shown to be strongly influenced by layer height. In presenting these results physical explanations are provided for the behavior of the predicted forcing amplitude thresholds and wave number selection. PMID- 24483553 TI - Stretch flow of confined non-Newtonian fluids: nonlinear fingering dynamics. AB - We employ a weakly nonlinear perturbative scheme to investigate the stretch flow of a non-Newtonian fluid confined in Hele-Shaw cell for which the upper plate is lifted. A generalized Darcy's law is utilized to model interfacial fingering formation in both the weak shear-thinning and weak shear-thickening limits. Within this context, we analyze how the interfacial finger shapes and the nonlinear competition dynamics among fingers are affected by the non-Newtonian nature of the stretched fluid. PMID- 24483554 TI - Fractal continuum model for tracer transport in a porous medium. AB - A model based on the fractal continuum approach is proposed to describe tracer transport in fractal porous media. The original approach has been extended to treat tracer transport and to include systems with radial and uniform flow, which are cases of interest in geoscience. The models involve advection due to the fluid motion in the fractal continuum and dispersion whose mathematical expression is taken from percolation theory. The resulting advective-dispersive equations are numerically solved for continuous and for pulse tracer injection. The tracer profile and the tracer breakthrough curve are evaluated and analyzed in terms of the fractal parameters. It has been found in this work that anomalous transport frequently appears, and a condition on the fractal parameter values to predict when sub- or superdiffusion might be expected has been obtained. The fingerprints of fractality on the tracer breakthrough curve in the explored parameter window consist of an early tracer breakthrough and long tail curves for the spherical and uniform flow cases, and symmetric short tailed curves for the radial flow case. PMID- 24483556 TI - Dynamics of finite-symmetry and general-shaped objects under shear and shear alignment of uniaxial objects at finite temperatures. AB - We prove that, for an object with a finitefold rotational symmetry (except for a twofold one) around an axis and mirror symmetries (such as a square rod or pentagonal slab, etc.), dynamics of the symmetry axis in low Reynolds number shear flow exactly follows the same form as that of a uniaxial object (e.g., a circular rod or symmetric ellipsoid) as the so-called Jeffery orbits. We use the formulation in which the dynamics of the rigid body follows first-order ordinary differential equations in time [Phys. Rev. E 84, 056309 (2011)]. Interaction between the object and the shear flow enters through a set of scalar coefficients, and the flow field does not need to be solved dynamically. Results of numerical simulations for general-shaped objects also are discussed. In the second part, Brownian dynamics of a uniaxial object is studied numerically. With D as the rotational diffusion constant, alpha as a parameter characterizing the aspect ratio, and gamma as the shear rate, the object starts to align with the flow when the value of D/(gammaalpha) decreases near 1. At large alpha (the long object limit), the results suggest much lower flow alignment when D/(gammaalpha)>1. PMID- 24483555 TI - Flow of a thin liquid film coating a horizontal stationary cylinder. AB - An experimental and theoretical study of the flow of liquid films around a stationary horizontal cylinder is reported. The film presents two different behaviors: The flow is stable in the upper zone (up to ~150 degrees with the vertical) and Rayleigh-Taylor-like instabilities appear in the lower zone. For the stable region, film thickness evolution could be described by numerically integrating an evolution equation obtained using a lubrication approximation. For the unstable region, a linear stability analysis allows us to determine the maximum growth wavelength for the Rayleigh-Taylor instability. Approximate analytical solutions were obtained for generatrices at an angle with the vertical theta=0 (stable region) and theta=pi (where the instability appears). PMID- 24483557 TI - Viscous-fingering minimization in uniform three-dimensional porous media. AB - In this paper, we consider a radial displacement of a viscous fluid by another one of much lower viscosity through a three-dimensional uniform porous medium. It is well known that when a less viscous fluid is pumped at a constant injection rate, very complex interfacial patterns are formed. The control and eventual suppression of these instabilities are relevant to a large number of areas in science and technology. Here, we use a variational approach to search for an analytical form of an optimal flow rate so that the interface between two almost neutrally buoyant fluids grows, but the emergence of interfacial disturbances is minimized. We find a closed analytical solution for the ideal flow rate which surprisingly does not depend on either the properties of the fluids or the permeability of the porous medium. PMID- 24483558 TI - Multiple collisions in turbulent flows. AB - In turbulent suspensions, collision rates determine how rapidly particles coalesce or react with each other. To determine the collision rate, many numerical studies rely on the ghost collision approximation (GCA), which simply records how often pairs of point particles come within a threshold distance. In many applications, the suspended particles stick (or in the case of liquid droplets, coalesce) upon collision, and it is the frequency of first contact which is of interest. If a pair of "ghost" particles undergoes multiple collisions, the GCA may overestimate the true collision rate. Here, using fully resolved direct numerical simulations of turbulent flows at moderate Reynolds number (Re(lambda)=130), we investigate the prevalence and properties of multiple collisions. We find the probability P(N(c)) for a given pair of ghost particles to collide N(c) times to be of the form P(N(c))=betaalpha(N(c)) for N(c)>1, where alpha and beta are coefficients which depend upon the particle inertia. We also investigate the statistics of the times that ghost particles remain in contact. We show that the probability density function of the contact time is different for the first collision. The difference is explained by the effect of caustics in the phase space of the suspended particles. We demonstrate that, as a result of multiple collisions, the GCA leads to a small, but systematic overestimate of the collision rate, which is of the order of ~15% when the particle inertia is small, and slowly decreases when inertia increases. PMID- 24483559 TI - Capillary channel flow experiments aboard the International Space Station. AB - In the near-weightless environment of orbiting spacecraft capillary forces dominate interfacial flow phenomena over unearthly large length scales. In current experiments aboard the International Space Station, partially open channels are being investigated to determine critical flow rate-limiting conditions above which the free surface collapses ingesting bubbles. Without the natural passive phase separating qualities of buoyancy, such ingested bubbles can in turn wreak havoc on the fluid transport systems of spacecraft. The flow channels under investigation represent geometric families of conduits with applications to liquid propellant acquisition, thermal fluids circulation, and water processing for life support. Present and near future experiments focus on transient phenomena and conduit asymmetries allowing capillary forces to replace the role of gravity to perform passive phase separations. Terrestrial applications are noted where enhanced transport via direct liquid-gas contact is desired. PMID- 24483560 TI - Approach and coalescence of liquid drops in air. AB - The coalescence of liquid drops has conventionally been thought to have just two regimes when the drops are brought together slowly in vacuum or air: a viscous regime corresponding to the Stokes-flow limit and a later inertially dominated regime. Recent work [Proc. Natl. Acad. Sci. 109, 6857 (2012)] found that the Stokes-flow limit cannot be reached in the early moments of coalescence, because the inertia of the drops cannot be neglected then. Instead, the drops are described by an "inertially limited viscous" regime, where surface tension, inertia, and viscous forces all balance. The dynamics continue in this regime until either viscosity or inertia dominate on their own. I use an ultrafast electrical method and high-speed imaging to provide a detailed description of coalescence near the moment of contact for drops that approach at low speed and coalesce as undeformed spheres. These measurements support a description of coalescence having three regimes. Signatures both before and after contact identify a threshold approach speed for deformation of the drops by the ambient gas. PMID- 24483561 TI - Solid-particle jet formation under shock-wave acceleration. AB - When solid particles are impulsively dispersed by a shock wave, they develop a spatial distribution which takes the form of particle jets whose selection mechanism is still unidentified. The aim of the present experimental work is to study particle dispersal with fingering effects in an original quasi-two dimensional experiment facility in order to accurately extract information. Shock and blast waves are generated in the carrier gas at the center of a granular medium ring initially confined inside a Hele-Shaw cell and impulsively accelerated. With the present experimental setup, the particle jet formation is clearly observed. From fast flow visualizations, we notice, in all instances, that the jets are initially generated inside the particle ring and thereafter expelled outward. This point has not been observed in three-dimensional experiments. We highlight that the number of jets is unsteady and decreases with time. For a fixed configuration, considering the very early times following the initial acceleration, the jet size selection is independent of the particle diameter. Moreover, the influence of the initial overpressure and the material density on the particle jet formation have been studied. It is shown that the wave number of particle jets increases with the overpressure and with the decrease of the material density. The normalized number of jets as a function of the initial ring acceleration shows a power law valid for all studied configurations involving various initial pressure ratios, particle sizes, and particle materials. PMID- 24483562 TI - Instabilities of a free bilayer flowing on an inclined porous medium. AB - The instabilities of a free bilayer flowing on an inclined Darcy-Brinkman porous layer have been explored. The bilayer is composed of a pair of immiscible liquid films with a deformable liquid-liquid interface and a liquid-air free surface. An Orr-Sommerfeld analysis of the governing equations and boundary conditions uncovers that this configuration can be unstable by a pair of long-wave interfacial modes at the free surface and at the interface together with a couple of finite wave-number shear modes originating from the inertial influences at the liquid layers. In particular, one of the shear modes originates beyond a threshold flow rate owing to the slippage at the porous-liquid interface and is found to be the dominant one even when the porous medium is moderately thin, porous, and permeable. The strength of the porous media mediated mode (a) grows with increase in porosity, (b) grows and then remains invariant with increase in thickness, and (c) initially grows and then decays with increase in the permeability of the porous layer. Further, the presence of a lower layer with smaller viscosity and a thicker upper layer is found to facilitate the growth of this newly identified porous media mode. Importantly, beyond a threshold upper to lower thickness and viscosity ratios and the angle of inclination the porous media mode dominates over all the other interfacial or shear modes, highlighting its importance in the bilayer flows down an inclined porous medium. The study showcases the importance of a porous layer in destabilizing a free bilayer flow down an inclined plane, which can be of importance to improve mixing, emulsification, and heat and mass transfer characteristics in the microscale devices. PMID- 24483563 TI - Scalings for unsteady natural convection boundary layers on an evenly heated plate with time-dependent heating flux. AB - It is of fundamental significance, especially with regard to application, to fully understand the flow behavior of unsteady natural convection boundary layers on a vertical plate heated by a time-dependent heat flux. Such an understanding is currently scarce. In this paper, the scaling analysis by Lin et al. [Phys. Rev. E 79, 066313 (2009)] using a simple three-region structure for the unsteady natural convection boundary layer of a homogeneous Newtonian fluid with Pr>1 under isothermal heating was substantially extended for the case when the heating is due to a time-varying sinusoidal heat flux. A series of scalings was developed for the thermal boundary thickness, the plate temperature, the viscous boundary thicknesses, and the maximum vertical velocity within the boundary layer, which are the major parameters representing the flow behavior, in terms of the governing parameters of the flow, i.e., the Rayleigh number Ra, the Prandtl number Pr, and the dimensionless natural frequency f(n) of the time-varying sinusoidal heat flux, at the start-up stage, at the transition time scale which represents the ending of the start-up stage and the beginning of the transitional stage of the boundary-layer development, and at the quasi-steady stage. These scalings were validated by comparison to 10 full numerical solutions of the governing equations with Ra, Pr, and f(n) in the ranges 10(6)<=Ra<=10(9), 3<=Pr<=100, and 0.01<=f_{n}<=0.1 and were shown in general to provide an accurate description of the flow at different development stages, except for high-Pr runs in which a further, although weak, Pr dependence is present, which cannot be accurately predicted by the current scaling analysis using the simple three region structure, attributed to the non-boundary-layer nature of the velocity field with high-Pr fluids. Some scalings at the transition time scale and at the quasi-steady stage also produce noticeable deviations from the numerical results when f(n) is reduced, indicating that there may be a further f(n) dependence of the scalings which also cannot be accurately predicted by the current scaling analysis. PMID- 24483564 TI - Hyperbolic regions in flows through three-dimensional pore structures. AB - Finite time Lyapunov exponents are used to determine expanding, contracting, and hyperbolic regions in computational simulations of laminar steady-state fluid flows within realistic three dimensional pore structures embedded within an impermeable matrix. These regions correspond approximately to pores where flow converges (contraction) or diverges (expansion), and to throats between pores where the flow mixes (hyperbolic). The regions are sparse and disjoint from one another, occupying only a small percentage of the pore space. Nonetheless, nearly every percolating fluid particle trajectory passes through several hyperbolic regions indicating that the effects of in-pore mixing are distributed throughout an entire pore structure. Furthermore, the observed range of fluid dynamics evidences two scales of heterogeneity within each of these flow fields. There is a larger scale that affects dispersion of fluid particle trajectories across the connected network of pores and a relatively small scale of nonuniform distributions of velocities within an individual pore. PMID- 24483565 TI - Turbulent plane Poiseuille-Couette flow as a model for fluid slip over superhydrophobic surfaces. AB - In this study, plane Poiseuille-Couette flow is simulated as a model for specified streamwise slip on one of the channel walls. The relative velocity between the two walls is set to be 1, 2, and 4 in viscous wall units. This is equivalent to the presence of a superhydrophobic surface at one of the channel walls that causes fluid to slip on the boundary. The results show that the streamwise slip forces turbulence in the near-wall region to tend towards a limiting one-component state. This leads to the suppression of small scale turbulence and laminarization close to the wall and then to drag reduction. The selective weakening of the streamwise vorticity close the wall and the observed decrease of turbulence kinetic energy production can then be considered as a consequence of this effect. Changes in the coherent structures, including a decrease of sweep events and increase of ejection events close to the wall where slip occurs, are also observed. PMID- 24483567 TI - Symmetry breaking of decaying magnetohydrodynamic Taylor-Green flows and consequences for universality. AB - We investigate the evolution and stability of a decaying magnetohydrodynamic Taylor-Green flow, using pseudospectral simulations with resolutions up to 2048(3). The chosen flow has been shown to result in a steep total energy spectrum with power law behavior k(-2). We study the symmetry breaking of this flow by exciting perturbations of different amplitudes. It is shown that for any finite amplitude perturbation there is a high enough Reynolds number for which the perturbation will grow enough at the peak of dissipation rate resulting in a nonlinear feedback into the flow and subsequently break the Taylor-Green symmetries. In particular, we show that symmetry breaking at large scales occurs if the amplitude of the perturbation is sigma(crit)~Re(-1) and at small scales occurs if sigma(crit)~Re(-3/2). This symmetry breaking modifies the scaling laws of the energy spectra at the peak of dissipation rate away from the k(-2) scaling and towards the classical k(-5/3) and k(-3/2) power laws. PMID- 24483566 TI - Instability of subharmonic resonances in magnetogravity shear waves. AB - We study analytically the instability of the subharmonic resonances in magnetogravity waves excited by a (vertical) time-periodic shear for an inviscid and nondiffusive unbounded conducting fluid. Due to the fact that the magnetic potential induction is a Lagrangian invariant for magnetohydrodynamic Euler Boussinesq equations, we show that plane-wave disturbances are governed by a four dimensional Floquet system in which appears, among others, the parameter E representing the ratio of the periodic shear amplitude to the vertical Brunt Vaisala frequency N(3). For sufficiently small E and when the magnetic field is horizontal, we perform an asymptotic analysis of the Floquet system following the method of Lebovitz and Zweibel [Astrophys. J. 609, 301 (2004)]. We determine the width and the maximal growth rate of the instability bands associated with subharmonic resonances. We show that the instability of subharmonic resonance occurring in gravity shear waves has a maximal growth rate of the form Delta(m)=(3?[3]/16)E. This instability persists in the presence of magnetic fields, but its growth rate decreases as the magnetic strength increases. We also find a second instability involving a mixing of hydrodynamic and magnetic modes that occurs for all magnetic field strengths. We also elucidate the similarity between the effect of a vertical magnetic field and the effect of a vertical Coriolis force on the gravity shear waves considering axisymmetric disturbances. For both cases, plane waves are governed by a Hill equation, and, when E is sufficiently small, the subharmonic instability band is determined by a Mathieu equation. We find that, when the Coriolis parameter (or the magnetic strength) exceeds N(3)/2, the instability of the subharmonic resonance vanishes. PMID- 24483568 TI - Electro-orientation and electrorotation of metal nanowires. AB - The physical mechanisms responsible for the electrical orientation and electrical rotation of metal nanowires suspended in an electrolyte as a function of frequency of the applied ac electric field are examined theoretically and experimentally. The alignment of a nanowire in an ac field with a fixed direction is called electro-orientation. The induced constant rotation of a nanowire in a rotating electric field is called electrorotation. In both situations, the applied electric field interacts with the induced charge in the electrical double layer at the metal-electrolyte interface, causing rotation due to the torque on the induced dipole, and also from induced-charge electro-osmotic flow around the particle. First, we describe the dipole theory that describes electro-orientation and electrorotation of perfectly polarizable metal rods. Second, based on a slender approximation, an analytical theory that describes induced-charge electro orientation and electrorotation of metal nanowires is provided. Finally, experimental measurements of the electro-orientation and electrorotation of metal nanowires are presented and compared with theory, providing a comprehensive study of the relative importance between induced-dipole rotation and induced-charge electro-osmotic rotation. PMID- 24483569 TI - Flame front speed and onset of instability in the burning of inclined thin solid fuel samples. AB - We focus on the front propagation of diffusive flames obtained from the downward burning of inclined thermally thin solid fuels. This process consists of a pyrolysis reaction in the solid-phase and a combustion reaction in the gas phase. The solid-phase model is based on two coupled one-dimensional equations of temperature and solid density. We reduce the system into a single one-dimensional equation from which we obtain an analytical expression for the flame front speed. This expression may be understood as an upper bound of the burning spread rate in inclined samples. The gas-phase model is based on four coupled two-dimensional equations. These are employed to derive a criterion for determining the critical inclination angle beyond which the flame behavior becomes unstable. The comparison with the experiments confirms the validity of our predictions. PMID- 24483570 TI - Convection patterns in a liquid metal under an imposed horizontal magnetic field. AB - We performed laboratory experiments of Rayleigh-Benard convection with liquid gallium under various intensities of a uniform imposed horizontal magnetic field. An ultrasonic velocity profiling method was used to visualize the spatiotemporal structure of the flows with simultaneous monitoring of the temperature fluctuations in the liquid gallium layer. The explored Rayleigh numbers Ra range from the critical value for onset of convection to 10(5); the Chandrasekhar number Q covers values up to 1100. A regime diagram of the convection patterns was established in relation to the Ra and Q values for a square vessel with aspect ratio 5. We identified five flow regimes: (I) a fluctuating large-scale pattern without rolls, (II) weakly constrained rolls with fluctuations, (III) a continuous oscillation of rolls, (IV) repeated roll number transitions with random reversals of the flow direction, and (V) steady two-dimensional (2D) rolls. These flow regimes are classified by the Ra/Q values, the ratio of the buoyancy to the Lorentz force. Power spectra from the temperature time series indicate that regimes I and II have the features of developed turbulence, while the other regimes do not. The region of steady 2D rolls (Busse balloon) extends to high Ra values in the present setting by a horizontal magnetic field and regime V is located inside the Busse balloon. Concerning the instabilities of the steady 2D rolls, regime III is the traveling wave convection developed from the oscillatory instability. Regime IV can be regarded as a state of phase turbulence, which is induced by intermittent occurrences of the skewed-varicose instability. PMID- 24483571 TI - Analytical model for the radio-frequency sheath. AB - A simple analytical model for the planar radio-frequency (rf) sheath in capacitive discharges is developed that is based on the assumptions of a step profile for the electron front, charge exchange collisions with constant cross sections, negligible ionization within the sheath, and negligible ion dynamics. The continuity, momentum conservation, and Poisson equations are combined in a single integro-differential equation for the square of the ion drift velocity, the so called sheath equation. Starting from the kinetic Boltzmann equation, special attention is paid to the derivation and the validity of the approximate fluid equation for momentum balance. The integrals in the sheath equation appear in the screening function which considers the relative contribution of the temporal mean of the electron density to the space charge in the sheath. It is shown that the screening function is quite insensitive to variations of the effective sheath parameters. The two parameters defining the solution are the ratios of the maximum sheath extension to the ion mean free path and the Debye length, respectively. A simple general analytic expression for the screening function is introduced. By means of this expression approximate analytical solutions are obtained for the collisionless as well as the highly collisional case that compare well with the exact numerical solution. A simple transition formula allows application to all degrees of collisionality. In addition, the solutions are used to calculate all static and dynamic quantities of the sheath, e.g., the ion density, fields, and currents. Further, the rf Child-Langmuir laws for the collisionless as well as the collisional case are derived. An essential part of the model is the a priori knowledge of the wave form of the sheath voltage. This wave form is derived on the basis of a cubic charge-voltage relation for individual sheaths, considering both sheaths and the self-consistent self-bias in a discharge with arbitrary symmetry. The externally applied rf voltage is assumed to be sinusoidal, although the model can be extended to arbitrary wave forms, e.g., for dual-frequency discharges. The model calculates explicitly the cubic correction parameter in the charge-voltage relation for the case of highly asymmetric discharges. It is shown that the cubic correction is generally moderate but more pronounced in the collisionless case. The analytical results are compared to experimental data from the literature obtained by laser electric field measurements of the mean and dynamic fields in the capacitive sheath for various gases and pressures. Very good agreement is found throughout. PMID- 24483572 TI - Quantum theory of terahertz emission due to ultrashort pulse ionization of gases. AB - A microscopic model is developed to analyze terahertz (THz) emission after ultrashort one- and two-color laser-pulse excitations of an atomic gas. Optical Bloch equations are derived to describe the pulse-induced ionization in the many atom system including the Coulombic scattering of the ionized electrons. The model captures the continuous transition between the tunneling and the multiphoton ionization regimes. Numerical evaluations for a wide range of pulse configurations identify optimized excitation conditions for strong THz emission. PMID- 24483573 TI - Collisional and collisionless expansion of Yukawa balls. AB - The expansion of Yukawa balls is studied by means of molecular dynamics simulations of collisionless and collisional situations. High computation speed was achieved by using the parallel computing power of graphics processing units. When the radius of the Yukawa ball is large compared to the shielding length, the expansion process starts with the blow-off of the outermost layer. A rarefactive wave subsequently propagates radially inward at the speed of longitudinal phonons. This mechanism is fundamentally different from Coulomb explosions, which employ a self-similar expansion of the entire system. In the collisionless limit, the outer layers carry away most of the available energy. The simulations are compared with analytical estimates. In the collisional case, the expansion process can be described by a nonlinear diffusion equation that is a special case of the porous medium equation. PMID- 24483574 TI - Fast multidimensional model for the simulation of Raman amplification in plasma. AB - We present Leap, a simulation model for Raman amplification in plasma, combining an envelope treatment of the laser fields with an electrostatic particle-in-cell solver. The code is fully two dimensional, with the model readily extendible to three dimensions, and includes dispersive and refractive effects. Simulations carried out for Raman amplification in a plasma channel show that guiding of both the pump and the probe contribute to the evolution of the probe, resulting in a shorter, more intense pulse. PMID- 24483575 TI - Exchange effects in plasmas: the case of low-frequency dynamics. AB - Recently, there has been a surge of interest in nonequilibrium collective quantum models, where particle dispersion and spin are examples of effects taken into account. Here, we derive a kinetic plasma model containing fermion exchange effects. Exchange interactions are of great importance in many systems and have no classical analogy. Our model therefore constitutes a possible probe of collective quantum phenomena in other regimes. As an example, we consider the influence of the exchange effect on low-frequency dynamics, in particular ion acoustic waves. Comparisons to related computational techniques are given and the differences are highlighted. Furthermore, we discuss the applicability of our model, its limitations, and possible extensions. PMID- 24483576 TI - Thomas-Fermi Z-scaling laws and coupling stabilization for plasmas. AB - Extending the well-known Thomas-Fermi Z-scaling laws to the Coulomb coupling parameter, we investigate the stabilization of the ionic coupling in isochoric heating [Clerouin et al., Phys. Rev. E 87, 061101 (2013)]. This stabilization is restricted to a domain in atomic number Z, temperature, and density, including strong limitations on high couplings, that can only be obtained for high-Z elements. Contact is made with recent isochoric heating experiments. The consequences for corresponding states with respect to ionic coupling are also quantified via orbital free molecular dynamics simulations. This opens avenues for future isochoric heating experiments. PMID- 24483577 TI - Cancellation properties in Hall magnetohydrodynamics with a strong guide magnetic field. AB - We present a signed measure analysis of compressible Hall magnetohydrodynamic turbulence with an external guide field. Signed measure analysis allows us to characterize the scaling behavior of the sign-oscillating flow structures and their geometrical properties (fractal dimensions of structures). A reduced numerical model, valid when a strong guide magnetic field is present, is used here. In order to discuss the effect of the Hall term, different values for the ion skin depth are considered in the simulations. Results show that as the Hall term is increased, the fractal dimension of the current and vorticity sheets decreases. This observation, together with previous analysis of the same fields, provides a comprehensive description of the effect of the Hall force on the formation of structures. Two main processes are identified, namely, the widening and unraveling of the sheets. PMID- 24483578 TI - Kinetic solvers with adaptive mesh in phase space. AB - An adaptive mesh in phase space (AMPS) methodology has been developed for solving multidimensional kinetic equations by the discrete velocity method. A Cartesian mesh for both configuration (r) and velocity (v) spaces is produced using a "tree of trees" (ToT) data structure. The r mesh is automatically generated around embedded boundaries, and is dynamically adapted to local solution properties. The v mesh is created on-the-fly in each r cell. Mappings between neighboring v-space trees is implemented for the advection operator in r space. We have developed algorithms for solving the full Boltzmann and linear Boltzmann equations with AMPS. Several recent innovations were used to calculate the discrete Boltzmann collision integral with dynamically adaptive v mesh: the importance sampling, multipoint projection, and variance reduction methods. We have developed an efficient algorithm for calculating the linear Boltzmann collision integral for elastic and inelastic collisions of hot light particles in a Lorentz gas. Our AMPS technique has been demonstrated for simulations of hypersonic rarefied gas flows, ion and electron kinetics in weakly ionized plasma, radiation and light particle transport through thin films, and electron streaming in semiconductors. We have shown that AMPS allows minimizing the number of cells in phase space to reduce the computational cost and memory usage for solving challenging kinetic problems. PMID- 24483579 TI - Compression algorithm for discrete light-cone quantization. AB - We adapt the compression algorithm of Weinstein, Auerbach, and Chandra from eigenvectors of spin lattice Hamiltonians to eigenvectors of light-front field theoretic Hamiltonians. The latter are approximated by the standard discrete light-cone quantization technique, which provides a matrix representation of the Hamiltonian eigenvalue problem. The eigenvectors are represented as singular value decompositions of two-dimensional arrays, indexed by transverse and longitudinal momenta, and compressed by truncation of the decomposition. The Hamiltonian is represented by a rank-four tensor that is decomposed as a sum of contributions factorized into direct products of separate matrices for transverse and longitudinal interactions. The algorithm is applied to a model theory to illustrate its use. PMID- 24483580 TI - Discrete dipole approximation in time domain through the Laplace transform. AB - We present a form of the discrete dipole approximation for electromagnetic scattering computations in time domain. We show that the introduction of complex frequencies, through the Laplace transform, significantly improves the computation time. We also show that the Laplace transform and its inverse can be combined to extract the field inside a scatterer at a real resonance frequency. PMID- 24483581 TI - Minimal model for acoustic forces on Brownian particles. AB - We present a generalization of inertial coupling (IC) [Balboa Usabiaga et al., J. Comput. Phys. 235, 701 (2013)], which permits the resolution of radiation forces on small particles with arbitrary acoustic contrast factor. The IC method is based on a Eulerian-Lagrangian approach: particles move in continuum space while the fluid equations are solved in a regular mesh (here we use the finite volume method). Thermal fluctuations in the fluid stress, important below the micron scale, are also taken into account following the Landau-Lifshitz fluid description. Each particle is described by a minimal cost resolution which consists of a single small kernel (bell-shaped function) concomitant to the particle. The main role of the particle kernel is to interpolate fluid properties and spread particle forces. Here, we extend the kernel functionality to allow for an arbitrary particle compressibility. The particle-fluid force is obtained from an imposed "no-slip" constraint which enforces similar particle and kernel fluid velocities. This coupling is instantaneous and permits the capture of the fast, nonlinear effects underlying the radiation forces on particles. Acoustic forces arise because of an excess either in particle compressibility (monopolar term) or in mass (dipolar contribution) over the fluid values. Comparison with theoretical expressions shows that the present generalization of the IC method correctly reproduces both contributions. Due to its low computational cost, the present method allows for simulations with many [O(10(4))] particles using a standard graphical processor unit. PMID- 24483582 TI - Multicomponent lattice Boltzmann equation method with a discontinuous hydrodynamic interface. AB - In the multicomponent lattice Boltzmann equation simulation method (MCLB), applied to the continuum regime of fluid flow, the finite width of the fluid fluid interface introduces unphysical scales. We present a practical, robust, computationally efficient, and easy to implement solution to this problem which needs only low order interpolation to be stable and accurate and is applicable to any MCLB variant which uses a continuous phase field to distinguish between immiscible fluids with arrested coalescence. Our method extends the ideas of Kim and Pitsch, [Phys. Fluids 19, 108101 (2007)] and uses no external force distribution whatsoever to generate continuum interfacial physics, i.e., the Laplace law and no traction conditions on interfacial stresses. As such, it is amenable to the simplest form of Chapman-Enskog analysis used for lattice Boltzmann models. We assess our method and proceed to compare key results obtained with it against other equivalent data, obtained using the established continuum regime MCLB technique based upon the work of Lishchuk, Care, and Halliday, [Phys. Rev. E 67, 036701 (2003)] and Halliday, Hollis, and Care, [Phys. Rev. E 76, 026708 (2007)], quantifying performance in terms of the minimum feasible capillary available to simulation using that technique. PMID- 24483583 TI - Mean-field embedding of the dual-fermion approach for correlated electron systems. AB - To reduce the rapidly growing computational cost of the dual-fermion lattice calculation with increasing system size, we introduce two embedding schemes. One is the real fermion embedding, and the other is the dual-fermion embedding. Our numerical tests show that the real fermion and dual-fermion embedding approaches converge to essentially the same result. The application on the Anderson disorder and Hubbard models shows that these embedding algorithms converge more quickly with system size as compared to the conventional dual-fermion method, for the calculation of both single- and two-particle quantities. PMID- 24483584 TI - Symmetric multivariate polynomials as a basis for three-boson light-front wave functions. AB - We develop a polynomial basis to be used in numerical calculations of light-front Fock-space wave functions. Such wave functions typically depend on longitudinal momentum fractions that sum to unity. For three particles, this constraint limits the two remaining independent momentum fractions to a triangle, for which the three momentum fractions act as barycentric coordinates. For three identical bosons, the wave function must be symmetric with respect to all three momentum fractions. Therefore, as a basis, we construct polynomials in two variables on a triangle that are symmetric with respect to the interchange of any two barycentric coordinates. We find that, through the fifth order, the polynomial is unique at each order, and, in general, these polynomials can be constructed from products of powers of the second- and third-order polynomials. The use of such a basis is illustrated in a calculation of a light-front wave function in two dimensional phi(4) theory; the polynomial basis performs much better than the plane-wave basis used in discrete light-cone quantization. PMID- 24483586 TI - Statistical topology of three-dimensional Poisson-Voronoi cells and cell boundary networks. AB - Voronoi tessellations of Poisson point processes are widely used for modeling many types of physical and biological systems. In this paper, we analyze simulated Poisson-Voronoi structures containing a total of 250000000 cells to provide topological and geometrical statistics of this important class of networks. We also report correlations between some of these topological and geometrical measures. Using these results, we are able to corroborate several conjectures regarding the properties of three-dimensional Poisson-Voronoi networks and refute others. In many cases, we provide accurate fits to these data to aid further analysis. We also demonstrate that topological measures represent powerful tools for describing cellular networks and for distinguishing among different types of networks. PMID- 24483585 TI - Comparison of scalable fast methods for long-range interactions. AB - Based on a parallel scalable library for Coulomb interactions in particle systems, a comparison between the fast multipole method (FMM), multigrid-based methods, fast Fourier transform (FFT)-based methods, and a Maxwell solver is provided for the case of three-dimensional periodic boundary conditions. These methods are directly compared with respect to complexity, scalability, performance, and accuracy. To ensure comparable conditions for all methods and to cover typical applications, we tested all methods on the same set of computers using identical benchmark systems. Our findings suggest that, depending on system size and desired accuracy, the FMM- and FFT-based methods are most efficient in performance and stability. PMID- 24483587 TI - Consistent two-population lattice Boltzmann model for thermal flows. AB - Theory of two-population lattice Boltzmann equations for thermal flow simulations is revisited. The present approach makes use of a consistent division of the conservation laws between the two lattices, where mass and the momentum are conserved quantities on the first lattice, and the energy is conserved quantity of the second lattice. The theory of such a division is developed, and the advantage of energy conservation in the model construction is demonstrated in detail. The present fully local lattice Boltzmann theory is specified on the standard lattices for the simulation of thermal flows. Extension to the subgrid entropic lattice Boltzmann formulation is also given. The theory is validated with a set of standard two-dimensional simulations including planar Couette flow and natural convection in two dimensions. PMID- 24483588 TI - Evolution of the force distributions in jammed packings of soft particles. AB - The evolution of the force distributions during the isotropic compression of two dimensional packings of soft frictional particles is investigated numerically. Regardless of the applied deformation, the normal contact force distribution P(f(n)) can be fitted by the product of a power law, and a stretched exponential, while the tangential force distribution P(f(t)) is fitted well by a Gaussian. With increasing strain, the asymptotic behavior at large forces does not change, but both P(f(n)) and P(f(t)) exhibit a broadening, even though, when scaled with the average forces, their widths decrease. Furthermore, the distribution of friction mobilization P(eta) is a decreasing function of eta=|f(t)|/(MUf(n)), except for an increased probability of fully mobilized contacts (eta=1). The excess coordination number of the packings increases with the applied strain, indicating that the more a packing is compressed the more stable it becomes. PMID- 24483589 TI - Onsagerian formula for the excluded volume of spherodisks. AB - By a formal analytic argument based on Minkowski's expression for the isotropic average of the excluded volume of convex bodies, we reproduce the exact formula for the excluded volume of two spherorods-also known by the more traditional name of spherocylinders, which is classically derived through a geometric construction. By applying the same argument to spherodisks, which represent discotic platelets, we obtain a simple explicit formula for their excluded volume, whose validity is corroborated by a shape-reconstruction algorithm. PMID- 24483590 TI - Calculation of the nematic entropy using digital images. AB - In this work we will use digital images to compute the entropy dependence on temperature of a nematic lyotropic sample. The set of images comprehend the entire temperature range between a reentrant nematic isotropic phase transition, at a low temperature, and a usual nematic isotropic phase transition at a higher temperature. We will show that, inside the nematic phase, the image entropy profile agrees accurately with the entropy given by the Maier-Saupe model. As far as we know, this is the first time that the entropy of a lyotropic nematic phase is evaluated by this method, which introduces a way to measure their macroscopic variables. Namely, being that the entropy is a thermodynamical potential, this result implies that digital images can be used to compute mean values of nematic random variables. PMID- 24483591 TI - Physical aspects of the initial phase of endocytosis. AB - The endocytotic mechanism of entry of virions into cells includes wrapping of a virion by the host membrane with subsequent formation of a vesicle covering a virion. The energy along this pathway depends on the ligand-receptor interaction and deformation of the cell membrane and underlying actin cytoskeleton. The available models describe the cytoskeleton deformation by using the conventional continuum theory of elasticity and predict that this factor often controls the repulsive part of the virion-cell interaction. This approach is, however, debatable because the size of virions is smaller than or comparable to the length scale characterizing the cytoskeleton structure. The author shows that the continuum theory appreciably (up to one order of magnitude) overestimates the cytoskeleton-deformation energy and that the scale of this energy is comparable to that of cell membrane bending. PMID- 24483592 TI - Alternate islands of multiple isochronous chains in wave-particle interactions. AB - We analyze the dynamics of a relativistic particle moving in a uniform magnetic field and perturbed by a standing electrostatic wave. We show that a pulsed wave produces an infinite number of perturbative terms with the same winding number, which may generate islands in the same region of phase space. As a consequence, the number of isochronous island chains varies as a function of the wave parameters. We observe that in all the resonances, the number of chains is related to the amplitude of the various resonant terms. We determine analytically the position of the periodic points and the number of island chains as a function of the wave number and wave period. Such information is very important when one is concerned with regular particle acceleration, since it is necessary to adjust the initial conditions of the particle to obtain the maximum acceleration. PMID- 24483593 TI - Comment on "Ratchet universality in the presence of thermal noise". AB - A recent paper [P. J. Martinez and R. Chacon, Phys. Rev. E 87, 062114 (2013)] presents numerical simulations on a system exhibiting directed ratchet transport of a driven overdamped Brownian particle subjected to a spatially periodic, symmetric potential. The authors claim that their simulations prove the existence of a universal waveform of the external force that optimally enhances directed transport, hence confirming the validity of a previous conjecture put forth by one of them in the limit of vanishing noise intensity. With minor corrections due to noise, the conjecture holds even in the presence of noise, according to the authors. On the basis of their results the authors claim that all previous theories, which predict a different optimal force waveform, are incorrect. In this Comment we provide sufficient numerical evidence showing that there is no such universal force waveform and that the evidence obtained by the authors otherwise is due to their particular choice of parameters. Our simulations also suggest that previous theories correctly predict the shape of the optimal waveform within their validity regime, namely, when the forcing is weak. On the contrary, the aforementioned conjecture does not hold. PMID- 24483594 TI - Reply to "Comment on 'Ratchet universality in the presence of thermal noise' ". AB - The Comment by Quintero et al. [preceding Comment, Phys. Rev. E 88, 066101 (2013)] does not dispute the central result of our paper [Martinez and Chacon, Phys. Rev. E 87, 062114 (2013)], which is a theory explaining the interplay between thermal noise and symmetry breaking in the ratchet transport of a Brownian particle moving on a periodic substrate subjected to a temporal biharmonic excitation gamma[etasin(omegat)+alpha(1-eta)sin(2omegat+phi)]. In the Comment, the authors claim, on the sole basis of their numerical simulations for the particular case alpha=2, that "there is no such universal force waveform and that the evidence obtained by the authors otherwise is due to their particular choice of parameters." Here we demonstrate by means of theoretical arguments and additional numerical simulations that all the conclusions of our original article are preserved. PMID- 24483595 TI - Antioxidative activities of algal keto carotenoids acting as antioxidative protectants in the chloroplast. AB - Very diverse carotenoid structures exist in the photosynthesis apparatus of different algae. Among them, the keto derivatives are regarded the most antioxidative. Therefore, four different keto carotenoids, peridinin, fucoxanthin, siphonaxanthin and astaxanthin fatty acid monoesters, were isolated and purified from Amphidinium carterae, Phaeodactylum tricornutum, Caulerpa taxifolia and Haematococcus pluvialis, respectively. The carotenoids were assayed as inhibitors of photosensitizer initiated reactions or scavengers of radicals in the early events generating reactive oxygen species as starters for peroxidation and as protectants against the whole reaction chain finally leading to lipid peroxidation. These in vitro studies demonstrated the substantial antioxidative properties as indicated by the IC(50) values of all four keto carotenoids with superior protection by astaxanthin fatty acid monoesters which were as effective as free astaxanthin and of peridinin against radicals. As an example, the in vivo relevance of fucoxanthin for protection of photosynthesis from excess light and from peroxidative agents was evaluated with intact cells. Cultures of P. tricornutum with decreased fucoxanthin content generated by inhibitor treatment were exposed to strong light or cumene hydroperoxyde. In each case, oxidation of chlorophyll as marker for damaging of the photosynthesis apparatus was less severe when the fucoxanthin was at maximum level. PMID- 24483596 TI - T-cell/histiocyte-rich large B-cell lymphoma--transformation of nodular lymphocyte predominant Hodgkin lymphoma in the bone marrow. PMID- 24483597 TI - Parasitic pedunculated fibroid. Is laparoscopic management the best approach? PMID- 24483598 TI - Degradation of caffeic acid in subcritical water and online HPLC-DPPH assay of degradation products. AB - Caffeic acid was subjected to degradation under subcritical water conditions within 160-240 degrees C and at a constant pressure of 5 MPa in a continuous tubular reactor. Caffeic acid degraded quickly at these temperatures; the main products identified by liquid chromatography-diode array detection/mass spectrometry were hydroxytyrosol, protocatechuic aldehyde, and 4-vinylcatechol. The reaction rates for the degradation of caffeic acid and the formation of products were evaluated. Online high-performance liquid chromatography/2,2 diphenyl-1-picryhydrazyl assay was used to determine the antioxidant activity of each product in the solution. It was found that the overall antioxidant activity of the treated solution did not change during the degradation process. This study showed a potential of formation of antioxidants from natural phenolic compounds under these subcritical water conditions, and this may lead to a discovering of novel antioxidants compounds during the extraction by this technique. PMID- 24483599 TI - Hematopoietic stem cell transplantation effects on spinal cord compression in Hurler. AB - Hurler syndrome type 1 (MPS-1) is an autosomal recessive lysosomal disorder due to the deficiency of the enzyme alpha-L-iduronidase which is necessary for the degradation of dermatan and heparan sulfate. It is characterized by deposit of glycosaminoglycans in tissues, progressive multisystem dysfunction, and early death. HSCT for children with MPS-I is effective, resulting in increased life expectancy and improvement of clinical parameters. The spinal MRI performed on a female 10 yr old undergoing HSCT at the age of 18 months and receiving ERT revealed a considerable decrease in soft tissue around the tip of odontoid causing a significant reduction in spinal cord compression. In light of this result, we suppose that combined ERT and HSCT are successful in Hurler I disease. PMID- 24483600 TI - The thioredoxin superfamily in oxidative protein folding. AB - SIGNIFICANCE: The thioredoxin (Trx) superfamily proteins, including protein disulfide isomerases (PDI) and Dsb protein family, are major players in oxidative protein folding, which involves native disulfide bond formation. These proteins contain Trx folds with CXXC active sites and fulfill their physiological functions in oxidative cellular compartments such as the endoplasmic reticulum (ER) or the bacterial periplasm. RECENT ADVANCES: The structure of the Trx superfamily protein PDI has been solved by X-ray crystallography and shown to be a flexible molecule, having a horseshoe shape with a closed reduced and an open oxidized conformation, which is important for exerting its catalytic activity. Atomic force microscopy revealed that PDI works as a placeholder to prevent early non-native disulfide bond formation and further misfolding. S-nitrosylation of the active site of PDI inhibits the PDI activity and links protein misfolding to neurodegenerative diseases like Alzheimer's and Parkinson's diseases. CRITICAL ISSUES: Electron transfer pathways of the oxidative protein folding show conserved Trx-like thiol-disulfide chemistry. Overall, mammalian cells have a large number of disulfide-containing proteins, the folding of which involves non native disulfide bond isomerization. The process is sensitive to oxidative stress and ER stress. FUTURE DIRECTIONS: The correct oxidative protein folding is critical for the substrate protein stability and function, and protein misfolding is linked to, for example, neurodegenerative diseases. Further understanding on the mechanisms and specific roles of Trx superfamily proteins in oxidative protein folding may lead to drug development for the treatment of bacterial infection and various human diseases in aging and neurodegeneration. PMID- 24483601 TI - Differences in alcohol brand consumption between underage youth and adults-United States, 2012. AB - BACKGROUND: The alcohol brand preferences of US underage drinkers have recently been identified, but it is not known whether youth are simply mimicking adult brand choices or whether other factors are impacting their preferences. This study is the first to compare the alcohol brand preferences of underage drinkers and adults. METHODS: The authors conducted a cross-sectional assessment of youth and adult alcohol brand preferences. A 2012 Internet-based survey of a nationally representative sample of 1032 underage drinkers, ages 13-20, was used to determine the prevalence of past-30-day consumption for each of 898 alcohol brands, and each brand's youth market share, based on the total number of standard drinks consumed. Data on the brand-specific prevalence of past-30-day or past-7-day consumption among older youth (ages 18-20), adults (ages 21+), and young adults (ages 21-34) was obtained from Gfk MRI's Survey of the Adult Consumer for the years 2010-2012. Overall market shares for each brand, also measured by the total number of standard drinks consumed, were estimated from national data compiled by Impact Databank for the year 2010. RESULTS: Although most alcohol brands popular among underage drinkers were also popular among adult drinkers, there were several brands that appeared to be disproportionately consumed by youth. CONCLUSIONS: This article provides preliminary evidence that youth do not merely mimic the alcohol brand choices of adults. Further research using data derived from fully comparable data sources is necessary to confirm this finding. PMID- 24483602 TI - Orally delivered water soluble Coenzyme Q10 (Ubisol-Q10) blocks on-going neurodegeneration in rats exposed to paraquat: potential for therapeutic application in Parkinson's disease. AB - BACKGROUND: Paraquat, still used as an herbicide in some parts of the world, is now regarded as a dangerous environmental neurotoxin and is linked to the development Parkinson's disease (PD). Paraquat interacts with cellular redox systems and causes mitochondrial dysfunction and the formation of reactive oxygen species, which in turn, plays a crucial role in the pathophysiology of PD. Various antioxidant therapies have been explored with the expectations that they deliver health benefits to the PD patients, however, no such therapies were effective. Here we have tested the neuroprotective efficacy of a novel water soluble CoQ10 (Ubisol-Q10), in a rat model of paraquat-induced neurodegeneration in order to evaluate its potential application in the management of PD. RESULTS: We have developed a rat model of progressive nigrostriatal degeneration by giving rats five intraperitoneal injections of paraquat (10 mg/kg/injection), once every five days. Neuronal death occurred over a period of 8 weeks with close to 50% reduction in the number of tyrosine hydroxylase-positive cells. Ubisol-Q10, at 6 mg CoQ10/kg body weight/day, was delivered as a supplement in drinking water. The intervention begun after the completion of paraquat injections when the neurodegenerative process had already began and about 20% of TH-positive neurons were lost. Ubisol-Q10 treatment halted the progression of neurodegeneration and remaining neurons were protected. The outcomes were evaluated based on the number of surviving tyrosine hydroxylase-positive neurons in the substantia nigra region and improved motor skills in response to the Ubisol-Q10 intervention. To maintain this neuroprotection, however, continuous Ubisol- Q10 supplementation was required, if withdrawn, the neuronal death pathway resumed, suggesting that the presence of CoQ10 was essential for blocking the pathway. CONCLUSION: The CoQ10, given orally as Ubisol-Q10 in drinking solution, was effective in blocking the progression of neurodegeneration when administered therapeutically (post-toxin injection), at a much lower concentration than other previously tested oil soluble formulations and well within the acceptable daily intake of 12 mg/kg/day. Such unprecedented neuroprotection has never been reported before. These results are very encouraging and suggest that Ubisol-Q10 should be further tested and developed as a therapy for halting the progression of PD. PMID- 24483603 TI - A new flavonoid glycoside from the rhizomes and roots of Smilax scobinicaulis. AB - A new flavonoid glycoside, hesperetin-7-O-[beta-D-glucopyranosyl-(1 -> 3)]-beta-D glucopyranosyl (1), was isolated from the n-BuOH extract of Smilax scobinicaulis, together with four known flavonoid glycosides, clematine (2), ononin (3), daidzin (4) and puerarin (5). All of the five compounds were reported from this material for the first time. Their structures were determined on the basis of spectroscopic and spectrometric methods. PMID- 24483604 TI - Concepts, challenges, and opportunities in allo-head and body reconstruction (AHBR). PMID- 24483605 TI - Heterosexual Seduction in the Urban Night Context: Behaviors and Meanings. AB - This article presents an anthropological analysis of heterosexual seduction behaviors of men and women (from 18 to 65 years old, with varying civil status) who attended nightclubs located in the movida areas of Lisbon, Portugal. These behaviors were analyzed according to structure versus communitas theories. Nighttime seduction behaviors were observed and recorded in a field diary, and in depth semistructured interviews with 60 men and 60 women were conducted. Interviews were analyzed using the thematic content analysis model. Results suggested that the communitas domain was evinced in the various seduction strategies. These courtship behaviors tended to follow a specific pattern: nonverbal seduction, visual seduction, verbal seduction, and acting-consisting of caresses, touches, and kisses. When this escalation process evoked positive responses, it generally culminated in the complete synchrony of movements between the two bodies. The seduction process encompassed both masculine and feminine initiatives: Women engaged primarily in nonverbal and visual seduction, while men appeared to orchestrate verbal courtship and acting. However, sometimes men and women did not want to seduce or be seduced because they were married (especially women) or were with their partners (especially young men) and did not want to endanger the structure domain. PMID- 24483606 TI - Reply to "Comment on 'Coherence and uncertainty in nanostructured organic photovoltaics'". PMID- 24483608 TI - Phase 0 and phase III transport in various organs: combined concept of phases in xenobiotic transport and metabolism. AB - The historical phasing concept of drug metabolism and elimination was introduced to comprise the two phases of metabolism: phase I metabolism for oxidations, reductions and hydrolyses, and phase II metabolism for synthesis. With this concept, biological membrane barriers obstructing the accessibility of metabolism sites in the cells for drugs were not considered. The concept of two phases was extended to a concept of four phases when drug transporters were detected that guided drugs and drug metabolites in and out of the cells. In particular, water soluble or charged drugs are virtually not able to overcome the phospholipid membrane barrier. Drug transporters belong to two main clusters of transporter families: the solute carrier (SLC) families and the ATP binding cassette (ABC) carriers. The ABC transporters comprise seven families with about 20 carriers involved in drug transport. All of them operate as pumps at the expense of ATP splitting. Embedded in the former phase concept, the term "phase III" was introduced by Ishikawa in 1992 for drug export by ABC efflux pumps. SLC comprise 52 families, from which many carriers are drug uptake transporters. Later on, this uptake process was referred to as the "phase 0 transport" of drugs. Transporters for xenobiotics in man and animal are most expressed in liver, but they are also present in extra-hepatic tissues such as in the kidney, the adrenal gland and lung. This review deals with the function of drug carriers in various organs and their impact on drug metabolism and elimination. PMID- 24483607 TI - Reversible dimers of the atypical antipsychotic quetiapine inhibit p-glycoprotein mediated efflux in vitro with increased binding affinity and in situ at the blood brain barrier. AB - The multidrug resistance transporter P-glycoprotein (P-gp) is highly expressed in the capillary endothelial cells of the blood-brain barrier (BBB) where it functions to limit the brain penetration of many drugs, including antipsychotic agents used to treat schizophrenia. Therefore, in an effort to inhibit the transporter, we designed dimers of the antipsychotic drug and P-gp substrate quetiapine (QT), linked by variable length tethers. In P-gp overexpressing cells and in human brain capillary endothelial hCMEC/D3 cells, the dimer with the shortest tether length (QT2C2) (1) was the most potent inhibitor showing >80-fold better inhibition of P-gp-mediated transport than monomeric QT. The dimers, which are linked via ester moieties, are designed to revert to the therapeutic monomer once inside the target cells. We demonstrated that the addition of two sterically blocking methyl groups to the linker (QT2C2Me2, 8) increased the half-life of the molecule in plasma 10-fold as compared to the dimer lacking methyl groups (QT2C2, 1), while retaining inhibitory potency for P-gp transport and sensitivity to cellular esterases. Experiments with purified P-gp demonstrated that QT2C2 (1) and QT2C2Me2 (8) interacted with both the H- and R-binding sites of the transporter with binding affinities 20- to 30-fold higher than that of monomeric QT. Using isolated rat brain capillaries, QT2C2Me2 (8) was a more potent inhibitor of P-gp transport than QT. Lastly, we showed that QT2C2Me2 (8) increased the accumulation of the P-gp substrate verapamil in rat brain in situ three times more than QT. Together, these results indicate that the QT dimer QT2C2Me2 (8) strongly inhibited P-gp transport activity in human brain capillary endothelial cells, in rat brain capillaries, and at the BBB in an animal model. PMID- 24483609 TI - Task force on graduate medical education. PMID- 24483610 TI - How To...: Use Prepared TV Material and Films in Medical Education. AB - The use of educational television requires special skills on the part of both teacher and student. The experience and research results of the Open University are used as a basis to describe some functions and associated pedagogical considerations of the use of television in medical education. Emphasis is placed on pre-prepared materials and films. Interactive and live television and other uses particular to this medium will be considered in future issues. PMID- 24483611 TI - The way we teach...: students to care for patients. AB - This article describes several techniques used at the University of New Mexico School of Medicine in an attempt to overcome the problem of dehumanization of young physicians in training. Finding the use of questionnaires, interview evaluators and simulated patients insufficient, the authors developed a caring skills curriculum. Practical skills in communication, understanding, listening and awareness are developed through a study programme utilizing videotapes, work books, interrupted audiotapes and simulated patients. PMID- 24483612 TI - Original research: programme evaluation: an anthropological look at the clerkship. AB - Members of the Departments of Medical Education and Medicine sought to design a study that would produce an accurate, detailed description of the nine-week medicine clerkship. An anthropological research approach was adopted to develop a richly detailed, composite picture of the clerkship experience from the student's perspective. The results indicate the value of this approach under selected conditions, as discussed in the article. While it is impossible to prove a direct causal relationship, several problems identified during the study have since been alleviated. PMID- 24483613 TI - Case studies: games: three examples from biochemistry, physiology and pharmacology. AB - In the last issue Anthony Short and David Tomlinson (1980) gave an introductory discussion of the use of games in medical education. Here, with Michael Billet and Judyth Aarons, they give a detailed description of three games which currently form part of the curriculum at the University of Nottingham Medical School. PMID- 24483614 TI - Personal view: the myth of educational dominance. AB - A new theory is presented regarding the nature of the medical practice dilemma and its relation to medical education. The main thrust is that there is an innately structured and accepted form in which the healing service needs to be provided in order to be effective and ensure patient satisfaction. Without a return to this form, it is argued, elaborate devices to modify the curriculum are a waste of money, since education cannot transform practice. PMID- 24483615 TI - Educational organizations: the Australian and new zealand association for medical education. AB - The Australasian and New Zealand Association for Medical Education (ANZAME) was conceived in Sydney between 1969 and 1971. During this period medical educators from the Universities of Sydney and New South Wales met to discuss topics of mutual interest. The meetings were so successful that the idea of an Australia wide association for medical education was raised. A questionnaire circulated to all medical schools in 1971 found considerable support for such a move, and a national conference was organized in Canberra in 1972. A steering committee presented a draft constitution to the conference and the Association was born on 11 August 1972. PMID- 24483618 TI - Letters: training for paramedical personnel. PMID- 24483620 TI - Epilepsy-related brain networks in ring chromosome 20 syndrome: an EEG-fMRI study. AB - OBJECTIVE: To identify the brain networks that are involved in the different electroencephalography (EEG) abnormalities in patients with ring chromosome 20 [r(20)] syndrome. We hypothesize the existence of both distinctive and common brain circuits for the paroxysmal high voltage sharp waves (hSWs), the seizures, and the slow-wave 3-7 Hz rhythm that characterize this condition. METHODS: Thirteen patients with [r(20)] syndrome were studied by means of EEG simultaneously recorded with functional magnetic resonance imaging (EEG-fMRI). EEG traces were reviewed in order to detect the pathologic interictal (hSWs) and ictal activities; the 3-7 Hz theta-delta power was derived using a fast Fourier transform. A group-level analysis was performed for each type of EEG abnormality separately using a fixed-effect model and a conjunction analysis. Finally, a second-level random-effect model was applied considering together the different EEG abnormalities, without distinction between hSW, seizures, or theta-delta rhythms. RESULTS: Subcontinuous theta-delta rhythm was recorded in seven patients, seizures in two, and hSWs in three patients. The main results are the following: (1) the slow-wave rhythm was related to blood oxygen level-dependent (BOLD) increases in the premotor, sensory-motor, and temporoparietal cortex, and to BOLD decrements involving the default mode (DMN) and the dorsal attention networks (DANs); (2) the ictal-related BOLD changes showed an early involvement of the prefrontal lobe; (3) increases in BOLD signal over the basal ganglia, either for interictal and ictal activities, were observed; (4) a common pattern of positive BOLD changes in the bilateral perisylvian regions was found across the different EEG abnormalities. SIGNIFICANCE: The BOLD increment in the perisylvian network and the decrease of the DMN and DAN could be the expression of the [r(20)] syndrome-related cognitive and behavioral deficits. The observed BOLD patterns are similar to the ones detected in other epileptic encephalopathies, suggesting that different epileptic disorders characterized by neurobehavioral regression are associated with dysfunction in similar brain networks. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here. PMID- 24483621 TI - Enantioselective biotransformation of hexabromocyclododecane by in vitro rat and trout hepatic sub-cellular fractions. AB - alpha-, beta-, and gamma-Hexabromocyclododecanes (HBCDs) were subjected to in vitro biotransformation experiments with rat and trout liver S9 fractions for different incubation times (10, 30, and 60 min) at 2 concentration levels (1 and 10 MUM). The metabolic degradation of target HBCDs followed first order kinetics. Whereas beta-HBCD undergoes rapid biotransformation (t0.5 = 6.4 and 38.1 min in rat and trout, respectively), alpha-HBCD appears the most resistant to metabolic degradation (t0.5 = 17.1 and 134.9 min). The biotransformation rate in trout was slower than in rat. Investigation of HBCD degradation profiles revealed the presence of at least 3 pentabromocyclododecene (PBCD) and 2 tetrabromocyclododecadiene (TBCD) isomers indicating reductive debromination as a metabolic pathway for HBCDs. Both mono- and di- hydroxyl metabolites were identified for parent HBCDs, while only mono hydroxyl metabolites were detected for PBCDs and TBCDs. Interestingly, delta-HBCD was detected only in trout S9 fraction assays indicating metabolic interconversion of test HBCD diastereomers during biotransformation in trout. Finally, enantioselective analysis showed significant enrichment of the (-)-alpha-HBCD enantiomer (EF = 0.321 and 0.419 after 60 min incubation in rat and trout, respectively). The greater enrichment of (-)-alpha-HBCD in rat than in trout underlines the species-specific differences in HBCD metabolism and the need for caution when extending similar results from animal studies to humans. PMID- 24483622 TI - Gold nanorod linking to control plasmonic properties in solution and polymer nanocomposites. AB - A novel, solution-based method is presented to prepare bifunctional gold nanorods (B-NRs), assemble B-NRs end-to-end in various solvents, and disperse linked B-NRs in a polymer matrix. The B-NRs have poly(ethylene glycol) grafted along its long axis and cysteine adsorbed to its ends. By controlling cysteine coverage, bifunctional ligands or polymer can be end-grafted to the AuNRs. Here, two dithiol ligands (C6DT and C9DT) are used to link the B-NRs in organic solvents. With increasing incubation time, the nanorod chain length increases linearly as the longitudinal surface plasmon resonance shifts toward lower adsorption wavelengths (i.e., red shift). Analogous to step-growth polymerization, the polydispersity in chain length also increases. Upon adding poly(ethylene glycol) or poly(methyl methacrylate) to chloroform solution with linked B-NR, the nanorod chains are shown to retain end-to-end linking upon spin-casting into PEO or PMMA films. Using quartz crystal microbalance with dissipation (QCM-D), the mechanism of nanorod linking is investigated on planar gold surfaces. At submonolayer coverage of cysteine, C6DT molecules can insert between cysteines and reach an areal density of 3.4 molecules per nm(2). To mimic the linking of Au NRs, this planar surface is exposed to cysteine-coated Au nanoparticles, which graft at 7 NPs per MUm(2). This solution-based method to prepare, assemble, and disperse Au nanorods is applicable to other nanorod systems (e.g., CdSe) and presents a new strategy to assemble anisotropic particles in organic solvents and polymer coatings. PMID- 24483623 TI - Transvaginal ultrasound-guided aspiration of benign ovarian cysts. AB - In our study, we evaluate the diagnostic and therapeutic efficacy of transvaginal ultrasound-guided aspiration of benign ovarian cysts in selected patients. A total of 46 women with benign ovarian cysts were referred to our outpatient clinic. The aspirated fluid was collected and sent for cytological analysis. All women were re-evaluated at 1, 3 and 6 months after the procedure. The cytological analysis was negative for malignancy in all cases. Our study showed an overall recurrence rate for ovarian cysts of 39.1%. Women with endometriotic ovarian cysts have an increased incidence of recurrence, 62.5% (n = 5), in comparison with serous cysts, 35.2% (n = 12) and serous-haemorrhagic cysts, 15% (n = 1), chi(2) = 9.913, df = 2, p = 0.007. The results of our study reveal that transvaginal ultrasound-guided aspiration of benign ovarian cysts is a simple, safe and effective procedure. PMID- 24483626 TI - The prevalence of thyroglossal tract thyroid tissue on SPECT/CT following (131) I ablation therapy after total thyroidectomy for thyroid cancer. AB - OBJECTIVE: To determine the prevalence of thyroglossal tract thyroid tissue on SPECT/CT and to assess the contribution of this tissue to total neck radioactive iodine (RAI) activity in patients given (131) I ablation therapy after total thyroidectomy for thyroid cancer. PATIENTS AND METHODS: Eighty-three consecutive patients with thyroid cancer treated with total thyroidectomy underwent whole body planar and SPECT/CT imaging of the neck following initial RAI ablation. On SPECT/CT, thyroglossal tract thyroid tissue was defined as RAI in the anterior neck, superior to the thyroid bed in close proximity to the midline without evidence of localization to lymph nodes. Quantification was performed using region of interest analysis on planar imaging following localization on SPECT/CT. SPECT/CT, and planar images were classified by two reviewers as positive, negative or equivocal with interobserver agreement quantified using a Kappa score. Disagreement was resolved using a third reviewer. RESULTS: Thyroglossal tract thyroid tissue was present in 39/83 (47%; 95%CI: 36-58%) patients on SPECT/CT. In these 39 patients, this tissue contributed to a significant amount of total neck activity (median = 50%; IQR 19-74%). Interobserver agreement for the presence of thyroglossal tract thyroid tissue was substantial on SPECT/CT (Kappa = 0.73) and fair on planar imaging (Kappa = 0.31). CONCLUSION: Thyroglossal tract thyroid tissue was present in one half of our study population and contributed to a significant amount of total neck RAI activity. Given the high prevalence of this tissue, our results suggest that total neck RAI activity on planar imaging may not be suitable to assess the completeness of thyroid bed surgery. PMID- 24483628 TI - Effects of white light-emitting diode (LED) light exposure with different correlated color temperatures (CCTs) on human lens epithelial cells in culture. AB - Cataract is the major cause for legal blindness in the world. Oxidative stress on the lens epithelial cells (hLECs) is the most important factor in cataract formation. Cumulative light-exposure from widely used light-emitting diodes (LEDs) may pose a potential oxidative threat to the lens epithelium, due to the high-energy blue light component in the white-light emission from diodes. In the interest of perfecting biosafety standards for LED domestic lighting, this study analyzed the photobiological effect of white LED light with different correlated color temperatures (CCTs) on cultured hLECs. The hLECs were cultured and cumulatively exposed to multichromatic white LED light with CCTs of 2954, 5624, and 7378 K. Cell viability of hLECs was measured by Cell Counting Kit-8 (CCK-8) assay. DNA damage was determined by alkaline comet assay. Intracellular reactive oxygen species (ROS) generation, cell cycle, and apoptosis were quantified by flow cytometry. Compared with 2954 and 5624 K LED light, LED light having a CCT of 7378 K caused overproduction of intracellular ROS and severe DNA damage, which triggered G2 /M arrest and apoptosis. These results indicate that white LEDs with a high CCT could cause significant photobiological damage to hLECs. PMID- 24483624 TI - Framing ethnic variations in alcohol outcomes from biological pathways to neighborhood context. AB - BACKGROUND: Health disparities research seeks to eliminate disproportionate negative health outcomes experienced in some racial/ethnic minority groups. This brief review presents findings on factors associated with drinking and alcohol related problems in racial/ethnic groups. METHODS: Those discussed are as follows: (i) biological pathways to alcohol problems, (ii) gene * stress interactions, (iii) neighborhood disadvantage, stress, and access to alcohol, and (iv) drinking cultures and contexts. RESULTS: These factors and their interrelationships are complex, requiring a multilevel perspective. CONCLUSIONS: The use of interdisciplinary teams and an epigenetic focus are suggested to move the research forward. The application of multilevel research to policy, prevention, and intervention programs may help prioritize combinations of the most promising intervention targets. PMID- 24483627 TI - Automated modular synthesis of aptamer-drug conjugates for targeted drug delivery. AB - Aptamer-drug conjugates (ApDCs) are promising targeted drug delivery systems for reducing toxicity while increasing the efficacy of chemotherapy. However, current ApDC technologies suffer from problems caused by the complicated preparation and low controllability of drug-aptamer conjugation. To solve such problems, we have designed and synthesized a therapeutic module for solid phase synthesis, which is a phosphoramdite containing an anticancer drug moiety and a photocleavable linker. Using this module, we have realized automated and modular synthesis of ApDCs, and multiple drugs were efficiently incorporated into ApDCs at predesigned positions. The ApDCs not only recognize target cancer cells specifically, but also release drugs in a photocontrollable manner. We demonstrated the potential of automated and modular ApDC technology for applications in targeted cancer therapy. PMID- 24483629 TI - Entanglement generation is not necessary for optimal work extraction. AB - We consider reversible work extraction from identical quantum systems. From an ensemble of individually passive states, work can be produced only via global unitary (and thus entangling) operations. However, we show here that there always exists a method to extract all possible work without creating any entanglement, at the price of generically requiring more operations (i.e., additional time). We then study faster methods to extract work and provide a quantitative relation between the amount of generated multipartite entanglement and extractable work. Our results suggest a general relation between entanglement generation and the power of work extraction. PMID- 24483630 TI - Asking photons where they have been. AB - We present surprising experimental evidence regarding the past of photons passing through an interferometer. The information about the positions through which the photons pass in the interferometer is retrieved from modulations of the detected signal at the vibration frequencies of mirrors the photons bounce off. From the analysis we conclude that the past of the photons is not represented by continuous trajectories, although a "common sense" analysis adopted in various welcher weg measurements, delayed-choice which-path experiments, and counterfactual communication demonstrations yields a single trajectory. The experimental results have a simple explanation in the framework of the two-state vector formalism of quantum theory. PMID- 24483631 TI - Compact surface Fano states embedded in the continuum of waveguide arrays. AB - We describe theoretically and observe experimentally the formation of a surface state in a semi-infinite waveguide array with a side-coupled waveguide, designed to simultaneously achieve Fano and Fabry-Perot resonances. We demonstrate that the surface mode is compact, with all energy concentrated in a few waveguides at the edge and no field penetration beyond the side-coupled waveguide position. Furthermore, we show that by broadening the spectral band in the rest of the waveguide array it is possible to suppress exponentially localized modes, while the Fano state having the eigenvalue embedded in the continuum is preserved. PMID- 24483632 TI - Designing bell inequalities from a Tsirelson bound. AB - We present a simple analytic bound on the quantum value of general correlation type Bell inequalities, similar to Tsirelson's bound. It is based on the maximal singular value of the coefficient matrix associated with the inequality. We provide a criterion for tightness of the bound and show that the class of inequalities where our bound is tight covers many famous examples from the literature. We describe how this bound helps to construct Bell inequalities, in particular inequalities that witness the dimension of the measured observables. PMID- 24483633 TI - Generalized Bose-Einstein condensation into multiple states in driven-dissipative systems. AB - Bose-Einstein condensation, the macroscopic occupation of a single quantum state, appears in equilibrium quantum statistical mechanics and persists also in the hydrodynamic regime close to equilibrium. Here we show that even when a degenerate Bose gas is driven into a steady state far from equilibrium, where the notion of a single-particle ground state becomes meaningless, Bose-Einstein condensation survives in a generalized form: the unambiguous selection of an odd number of states acquiring large occupations. Within mean-field theory we derive a criterion for when a single state and when multiple states are Bose selected in a noninteracting gas. We study the effect in several driven-dissipative model systems, and propose a quantum switch for heat conductivity based on shifting between one and three selected states. PMID- 24483634 TI - Precision measurement of electronic ion-ion interactions between neighboring Eu3+ optical centers. AB - We report measurements of discrete excitation-induced frequency shifts on the 7F0 >5D0 transition of the Eu+ center in La:Lu:EuCl3.6D2O resulting from the optical excitation of neighboring Eu3+ ions. Shifts of up to 46.081+/-0.005 MHz were observed. The magnitude of the interaction between neighboring ions was found to be significantly larger than expected from the electric dipole-dipole mechanism often observed in rare earth systems. We show that a large network of interacting and individually addressable centers can be created by lightly doping crystals otherwise stoichiometric in the optically active rare earth ion, and that this network could be used to implement a quantum processor with more than ten qubits. PMID- 24483635 TI - Embedding quantum simulators for quantum computation of entanglement. AB - We introduce the concept of embedding quantum simulators, a paradigm allowing the efficient quantum computation of a class of bipartite and multipartite entanglement monotones. It consists in the suitable encoding of a simulated quantum dynamics in the enlarged Hilbert space of an embedding quantum simulator. In this manner, entanglement monotones are conveniently mapped onto physical observables, overcoming the necessity of full tomography and reducing drastically the experimental requirements. Furthermore, this method is directly applicable to pure states and, assisted by classical algorithms, to the mixed-state case. Finally, we expect that the proposed embedding framework paves the way for a general theory of enhanced one-to-one quantum simulators. PMID- 24483637 TI - Ultrafast quantum random access memory utilizing single Rydberg atoms in a Bose Einstein condensate. AB - We propose a long-lived and rapidly accessible quantum memory unit, for which the operational Hilbert space is spanned by states involving the two macroscopically occupied hyperfine levels of a miscible binary atomic Bose-Einstein condensate and the Rydberg state of a single atom. It is shown that an arbitrary qubit state, initially prepared using a flux qubit, can be rapidly transferred to and from the trapped atomic ensemble in approximately 10 ns and with a large fidelity of 97%, via an effective two-photon process using an external laser for the transition to the Rydberg level. The achievable ultrafast transfer of quantum information therefore enables a large number of storage and retrieval cycles from the highly controllable quantum optics setup of a dilute ultracold gas, even within the typically very short flux qubit lifetimes of the order of microseconds. PMID- 24483636 TI - Long lifetime and high-fidelity quantum memory of photonic polarization qubit by lifting zeeman degeneracy. AB - Long-lived and high-fidelity memory for a photonic polarization qubit (PPQ) is crucial for constructing quantum networks. We present a millisecond storage system based on electromagnetically induced transparency, in which a moderate magnetic field is applied on a cold-atom cloud to lift Zeeman degeneracy and, thus, the PPQ states are stored as two magnetic-field-insensitive spin waves. Especially, the influence of magnetic-field-sensitive spin waves on the storage performances is almost totally avoided. The measured average fidelities of the polarization states are 98.6% at 200 MUs and 78.4% at 4.5 ms, respectively. PMID- 24483638 TI - Near-extreme statistics of Brownian motion. AB - We study the statistics of near-extreme events of Brownian motion (BM) on the time interval [0,t]. We focus on the density of states near the maximum, rho(r,t), which is the amount of time spent by the process at a distance r from the maximum. We develop a path integral approach to study functionals of the maximum of BM, which allows us to study the full probability density function of rho(r,t) and obtain an explicit expression for the moments <[rho(r,t)]k> for arbitrary integer k. We also study near extremes of constrained BM, like the Brownian bridge. Finally we also present numerical simulations to check our analytical results. PMID- 24483639 TI - Collisional thermalization of hydrogen and helium in solar-wind plasma. AB - In situ observations of the solar wind frequently show the temperature of alpha particles (fully ionized helium) Talpha to significantly differ from that of protons (ionized hydrogen) Tp. Many heating processes in the plasma act preferentially on alpha particles, even as collisions among ions act to gradually establish thermal equilibrium. Measurements from the Wind spacecraft's Faraday cups reveal that, at r=1.0 AU from the Sun, the observed values of the alpha proton temperature ratio, thetaalphap=Talpha/Tp, has a complex, bimodal distribution. This study applied a simple model for the radial evolution of thetaalphap to these data to compute expected values of thetaalphap at r=0.1 AU. These inferred thetaalphap values have no trace of the bimodality seen in the thetaalphap values measured at r=1.0 AU but are instead consistent with the actions of the known mechanisms for alpha-particle preferential heating. This result underscores the importance of collisional processes in the dynamics of the solar wind and suggests that similar mechanisms may lead to preferential alpha particle heating in both slow and fast wind. PMID- 24483640 TI - Forecasting neutron star temperatures: predictability and variability. AB - It is now possible to model thermal relaxation of neutron stars after bouts of accretion during which the star is heated out of equilibrium by nuclear reactions in its crust. Major uncertainties in these models can be encapsulated in modest variations of a handful of control parameters that change the fiducial crustal thermal conductivity, specific heat, and heating rates. Observations of thermal relaxation constrain these parameters and allow us to predict longer term variability in terms of the neutron star core temperature. We demonstrate this explicitly by modeling ongoing thermal relaxation in the neutron star XTE J1701 462. Its future cooling, over the next 5 to 30 years, is strongly constrained and depends mostly on its core temperature, uncertainties in crust physics having essentially been pinned down by fitting to the first three years of observations. PMID- 24483641 TI - Topology and dark energy: testing gravity in voids. AB - Modified gravity has garnered interest as a backstop against dark matter and dark energy (DE). As one possible modification, the graviton can become massive, which introduces a new scalar field--here with a Galileon-type symmetry. The field can lead to a nontrivial equation of state of DE which is density and scale dependent. Tension between type Ia supernovae and Planck could be reduced. In voids, the scalar field dramatically alters the equation of state of DE, induces a soon-observable gravitational slip between the two metric potentials, and develops a topological defect (domain wall) due to a nontrivial vacuum structure for the field. PMID- 24483643 TI - Bootstrapping conformal field theories with the extremal functional method. AB - The existence of a positive linear functional acting on the space of (differences between) conformal blocks has been shown to rule out regions in the parameter space of conformal field theories (CFTs). We argue that at the boundary of the allowed region the extremal functional contains, in principle, enough information to determine the dimensions and operator product expansion (OPE) coefficients of an infinite number of operators appearing in the correlator under analysis. Based on this idea we develop the extremal functional method (EFM), a numerical procedure for deriving the spectrum and OPE coefficients of CFTs lying on the boundary (of solution space). We test the EFM by using it to rederive the low lying spectrum and OPE coefficients of the two-dimensional Ising model based solely on the dimension of a single scalar quasiprimary--no Virasoro algebra required. Our work serves as a benchmark for applications to more interesting, less known CFTs in the near future. PMID- 24483644 TI - Stability, Higgs boson mass, and new physics. AB - Assuming that the particle with mass ~126 GeV discovered at LHC is the standard model Higgs boson, we find that the stability of the electroweak (EW) vacuum strongly depends on new physics interaction at the Planck scale MP, despite of the fact that they are higher-dimensional interactions, apparently suppressed by inverse powers of MP. In particular, for the present experimental values of the top and Higgs boson masses, if tau is the lifetime of the EW vacuum, new physics can turn tau from tau?TU to tau?TU, where TU is the age of the Universe, thus, weakening the conclusions of the so called metastability scenario. PMID- 24483642 TI - Catalog of 174 binary black hole simulations for gravitational wave astronomy. AB - This Letter presents a publicly available catalog of 174 numerical binary black hole simulations following up to 35 orbits. The catalog includes 91 precessing binaries, mass ratios up to 8?1, orbital eccentricities from a few percent to 10( 5), black hole spins up to 98% of the theoretical maximum, and radiated energies up to 11.1% of the initial mass. We establish remarkably good agreement with post Newtonian precession of orbital and spin directions for two new precessing simulations, and we discuss other applications of this catalog. Formidable challenges remain: e.g., precession complicates the connection of numerical and approximate analytical waveforms, and vast regions of the parameter space remain unexplored. PMID- 24483646 TI - Study of the 14Be continuum: identification and structure of its second 2+ state. AB - The coupling between bound quantum states and those in the continuum is of high theoretical interest. Experimental studies of bound drip-line nuclei provide ideal testing grounds for such investigations since they, due to the feeble binding energy of their valence particles, are easy to excite into the continuum. In this Letter, continuum states in the heaviest particle-stable Be isotope, 14Be, are studied by employing the method of inelastic proton scattering in inverse kinematics. New continuum states are found at excitation energies E*=3.54(16) MeV and E*=5.25(19) MeV. The structure of the earlier known 2(1)+ state at 1.54(13) MeV was confirmed with a predominantly (0d5/2)2 configuration while there is very clear evidence that the 2(2)+ state has a predominant (1s1/2, 0d5/2) structure with a preferential three-body decay mechanism. The region at about 7 MeV excitation shows distinct features of sequential neutron decay via intermediate states in 13Be. This demonstrates that the increasing availability of energetic beams of exotic nuclei opens up new vistas for experiments leading towards a new understanding of the interplay between bound and continuum states. PMID- 24483647 TI - New fission fragment distributions and r-process origin of the rare-earth elements. AB - Neutron star (NS) merger ejecta offer a viable site for the production of heavy r process elements with nuclear mass numbers A?140. The crucial role of fission recycling is responsible for the robustness of this site against many astrophysical uncertainties, but calculations sensitively depend on nuclear physics. In particular, the fission fragment yields determine the creation of 110?A?170 nuclei. Here, we apply a new scission-point model, called SPY, to derive the fission fragment distribution (FFD) of all relevant neutron-rich, fissioning nuclei. The model predicts a doubly asymmetric FFD in the abundant A?278 mass region that is responsible for the final recycling of the fissioning material. Using ejecta conditions based on relativistic NS merger calculations, we show that this specific FFD leads to a production of the A?165 rare-earth peak that is nicely compatible with the abundance patterns in the Sun and metal-poor stars. This new finding further strengthens the case of NS mergers as possible dominant origin of r nuclei with A?140. PMID- 24483649 TI - Evidence for the dipole nature of the low-energy gamma enhancement in 56Fe. AB - The gamma-ray strength function of 56Fe has been measured from proton-gamma coincidences for excitation energies up to ~11 MeV. The low-energy enhancement in the gamma-ray strength function, which was first discovered in the (3He,alphagamma)56Fe reaction, is confirmed with the (p,p'gamma)56Fe experiment reported here. Angular distributions of the gamma rays give for the first time evidence that the enhancement is dominated by dipole transitions. PMID- 24483650 TI - Ground state hyperfine splitting in 6,7Li atoms and the nuclear structure. AB - Relativistic and QED corrections are calculated for a hyperfine splitting of the 2S1/2 ground state in 6,7Li atoms with a numerically exact account for electronic correlations. The resulting theoretical predictions achieve such a precision level that, by comparison with experimental values, they enable determination of the nuclear properties. In particular, the obtained results show that the 7Li nucleus, having a charge radius smaller than 6Li, has about a 40% larger Zemach radius. Together with known differences in the electric quadrupole and magnetic dipole moments, this calls for a deeper understanding of the Li nuclear structure. PMID- 24483648 TI - Measurement of the dipole polarizability of the unstable neutron-rich nucleus 68Ni. AB - The E1 strength distribution in 68Ni has been investigated using Coulomb excitation in inverse kinematics at the R3B-LAND setup and by measuring the invariant mass in the one- and two-neutron decay channels. The giant dipole resonance and a low-lying peak (pygmy dipole resonance) have been observed at 17.1(2) and 9.55(17) MeV, respectively. The measured dipole polarizability is compared to relativistic random phase approximation calculations yielding a neutron-skin thickness of 0.17(2) fm. A method and analysis applicable to neutron rich nuclei has been developed, allowing for a precise determination of neutron skins in nuclei as a function of neutron excess. PMID- 24483651 TI - Isotopically resolved photoelectron imaging unravels complex atomic autoionization dynamics by two-color resonant ionization. AB - Angle-resolved electron spectroscopy in coincidence with high-resolution mass spectroscopy has been applied to study two-color resonant photoionization in atomic xenon. Separation of different isotopes enabled us to extract results for the electronic dynamics free from depolarization effects, which are generally introduced by the coupling of the electronic and nuclear angular momenta. The concerted experimental and theoretical analysis of the photoelectron angular distributions in the region of an autoionizing resonance emphasizes the strong sensitivity of the observed structures to the fine details of the treatment of the underlying dynamics. PMID- 24483652 TI - Nonadiabatic effects in ultracold molecules via anomalous linear and quadratic Zeeman shifts. AB - Anomalously large linear and quadratic Zeeman shifts are measured for weakly bound ultracold 88Sr2 molecules near the intercombination-line asymptote. Nonadiabatic Coriolis coupling and the nature of long-range molecular potentials explain how this effect arises and scales roughly cubically with the size of the molecule. The linear shifts yield nonadiabatic mixing angles of the molecular states. The quadratic shifts are sensitive to nearby opposite f-parity states and exhibit fourth-order corrections, providing a stringent test of a state-of-the art ab initio model. PMID- 24483653 TI - Magic polarization for optical trapping of atoms without Stark-induced dephasing. AB - We demonstrate that the differential ac-Stark shift of a Zeeman-sensitive ground hyperfine transition in an optical trap can be eliminated by using properly polarized trapping light. We use the vector polarizability of an alkali-metal atom to produce a polarization-dependent ac-Stark shift that resembles a Zeeman shift. We study a transition from the |2S1/2,F=2,mF=-2> to the |2S1/2,F=1,mF=-1> state of 7Li to observe 0.59+/-0.02 Hz linewidth with interrogation time of 2 s and 0.82+/-0.06 s coherence time of a superposition state. Implications of the narrow linewidth and the long coherence time for precision spectroscopy and quantum information processing using atoms in an optical lattice are discussed. PMID- 24483654 TI - High-harmonic probing of electronic coherence in dynamically aligned molecules. AB - We introduce and demonstrate a new approach to measuring coherent electron wave packets using high-harmonic spectroscopy. By preparing a molecule in a coherent superposition of electronic states, we show that electronic coherence opens previously unobserved high-harmonic-generation channels that connect distinct but coherently related electronic states. Performing the measurements in dynamically aligned nitric oxide molecules we observe the complex temporal evolution of the electronic coherence under coupling to nuclear motion. Choosing a weakly allowed transition to prepare the wave packet, we demonstrate an unprecedented sensitivity that arises from optical interference between coherent and incoherent pathways. This mechanism converts a 0.1% excitation fraction into a ~20% signal modulation. PMID- 24483655 TI - Absolute polarization measurement using a vector light shift. AB - We have measured the vector light shift due to a cavity built-up optical lattice by using a variation of the Hanle effect with trapped Cs atoms, where the time evolving population of all magnetic sublevels is measured in situ. The measurement is linearly sensitive to the electric field of the nonlinearly polarized light, which allows unprecedented sensitivity to absolute linear polarization quality, to the level of 10(-10) in fractional intensity. Our approach to measuring and improving linear polarization can be applied to electron electric dipole moment searches, optical lattice clocks, magnetometery, and quantum computing. PMID- 24483656 TI - Imaging cold molecules on a chip. AB - We present the integrated imaging of cold molecules in a microchip environment. The on-chip detection is based on resonance-enhanced multiphoton ionization, which is quantum state selective and generally applicable. We demonstrate and characterize time-resolved spatial imaging and subsequently use it to analyze the effect of a phase-space manipulation sequence aimed at compressing the velocity distribution of a molecular ensemble with a view to future high-resolution spectroscopic studies. The realization of such on-chip measurements adds the final fundamental component to the molecule chip, offering a new and promising route for investigating cold molecules. PMID- 24483657 TI - Observation of 2p3d(1Po)->1s3d(1De) radiative transition in He-like Si, S, and Cl ions. AB - We present an experimental determination of the 2p3d(1Po)->1s3d(1De) x-ray line emitted from He-like Si, S, and Cl projectile ions, excited in collisions with thin carbon foils, using a high-resolution bent-crystal spectrometer. A good agreement between the observation and state-of-the-art relativistic calculations using the multiconfiguration Dirac-Fock formalism including the Breit interaction and QED effects implies the dominance of fluorescent decay over the autoionization process for the 2p3d(^{1}P^{o}) state of He-like heavy ions. This is the first observation of the fluorescence-active doubly excited states in He like Si, S, and Cl ions. PMID- 24483658 TI - From photons to phonons and back: a THz optical memory in diamond. AB - Optical quantum memories are vital for the scalability of future quantum technologies, enabling long-distance secure communication and local synchronization of quantum components. We demonstrate a THz-bandwidth memory for light using the optical phonon modes of a room temperature diamond. This large bandwidth makes the memory compatible with down-conversion-type photon sources. We demonstrate that four-wave mixing noise in this system is suppressed by material dispersion. The resulting noise floor is just 7*10(-3) photons per pulse, which establishes that the memory is capable of storing single quanta. We investigate the principle sources of noise in this system and demonstrate that high material dispersion can be used to suppress four-wave mixing noise in Lambda type systems. PMID- 24483659 TI - Nonequilibrium and nonperturbative dynamics of ultrastrong coupling in open lines. AB - The time and space resolved dynamics of a qubit with an Ohmic coupling to propagating 1D photons is studied, from weak coupling to the ultrastrong coupling regime. A nonperturbative study based on matrix product states shows the following results, (i) The ground state of the combined systems contains excitations of both the qubit and the surrounding bosonic field. (ii) An initially excited qubit equilibrates through spontaneous emission to a state, which under certain conditions is locally close to that ground state, both in the qubit and the field. (iii) The resonances of the combined qubit-photon system match those of the spontaneous emission process and also the predictions of the adiabatic renormalization [A. J. Leggett et al., Rev. Mod. Phys. 59, 1 (1987)]. Finally, nonperturbative ab initio calculations show that this physics can be studied using a flux qubit galvanically coupled to a superconducting transmission line. PMID- 24483660 TI - Photon counting as a probe of superfluidity in a two-band Bose-Hubbard system coupled to a cavity field. AB - We show that photon number measurement can be used to detect superfluidity for a two-band Bose-Hubbard model coupled to a cavity field. The atom-photon coupling induces transitions between the two internal atomic levels and results in entangled polaritonic states. In the presence of a cavity field, we find different photon numbers in the Mott-insulating versus superfluid phases, providing a method of distinguishing the atomic phases by photon counting. Furthermore, we examine the dynamics of the photon field after a rapid quench to zero atomic hopping by increasing the well depth. We find a robust correlation between the field's quench dynamics and the initial superfluid order parameter, thereby providing a novel and accurate method of determining the order parameter. PMID- 24483662 TI - Observation of the Dyakonov-Tamm wave. AB - A surface electromagnetic wave called the Dyakonov-Tamm wave has been theoretically predicted to exist at the interface of two dielectric materials at least one of which is both anisotropic and periodically nonhomogeneous. For experimental confirmation, a prism-coupled configuration was used to excite Dyakonov-Tamm waves guided by the interface of a dense thin film of magnesium fluoride and a chiral sculptured thin film of zinc selenide. The excitation was indicated by a reflection dip (with respect to the angle of incidence in the prism-coupled configuration) that is independent of the polarization state of the incident light as well as the thicknesses of both partnering materials beyond some thresholds. Applications to optical sensing and long-range on-chip communication are expected. PMID- 24483661 TI - Measurement of the time-resolved reflection matrix for enhancing light energy delivery into a scattering medium. AB - Multiple scatterings occurring in a turbid medium attenuate the intensity of propagating waves. Here, we propose a method to efficiently deliver light energy to the desired target depth in a scattering medium. We measure the time-resolved reflection matrix of a scattering medium using coherent time-gated detection. From this matrix, we derive and experimentally implement an incident wave pattern that optimizes the detected signal corresponding to a specific arrival time. This leads to enhanced light delivery at the target depth. The proposed method will lay a foundation for efficient phototherapy and deep-tissue in vivo imaging in the near future. PMID- 24483663 TI - Spatiotemporal rogue events in optical multiple filamentation. AB - The transient appearance of bright spots in the beam profile of optical filaments formed in xenon is experimentally investigated. Fluence profiles are recorded with high-speed optical cameras at the kilohertz repetition rate of the laser source. A statistical analysis reveals a thresholdlike appearance of heavy-tailed fluence distributions together with the transition from single to multiple filamentation. The multifilament scenario exhibits near-exponential probability density functions, with extreme events exceeding the significant wave height by more than a factor of 10. The extreme events are isolated in space and in time. The macroscopic origin of these experimentally observed heavy-tail statistics is shown to be local refractive index variations inside the nonlinear medium, induced by multiphoton absorption and subsequent plasma thermalization. Microscopically, mergers between filament strings appear to play a decisive role in the observed rogue wave statistics. PMID- 24483645 TI - Observation of a charged charmoniumlike structure Zc(4020) and search for the Zc(3900) in e+e-->pi+pi-hc. AB - We study e+e-->pi+pi-hc at center-of-mass energies from 3.90 to 4.42 GeV by using data samples collected with the BESIII detector operating at the Beijing Electron Positron Collider. The Born cross sections are measured at 13 energies and are found to be of the same order of magnitude as those of e+e-->pi+pi-J/psi but with a different line shape. In the pi+/-hc mass spectrum, a distinct structure, referred to as Zc(4020), is observed at 4.02 GeV/c2. The Zc(4020) carries an electric charge and couples to charmonium. A fit to the pi+/-hc invariant mass spectrum, neglecting possible interferences, results in a mass of (4022.9+/-0.8+/ 2.7) MeV/c2 and a width of (7.9+/-2.7+/-2.6) MeV for the Zc(4020), where the first errors are statistical and the second systematic. The difference between the parameters of this structure and the Zc(4025) observed in the D*D[over -]* final state is within 1.5sigma, but whether they are the same state needs further investigation. No significant Zc(3900) signal is observed, and upper limits on the Zc(3900) production cross sections in pi+/-hc at center-of-mass energies of 4.23 and 4.26 GeV are set. PMID- 24483664 TI - Full-polarized tomographic diffraction microscopy achieves a resolution about one fourth of the wavelength. AB - We present a marker-free microscope that records the phase, amplitude, and polarization state of the field diffracted by the sample for different illumination directions. The data are processed with an appropriate inversion method to yield the sample permittivity map. We observe that the full-polarized information ameliorates significantly the three-dimensional image of weakly scattering subdiffraction objects. A resolution about one-fourth of the illumination wavelength is experimentally demonstrated on complex samples. PMID- 24483665 TI - Self-localized states in photonic topological insulators. AB - We propose solitons in a photonic topological insulator: self-localized wave packets forming topological edge states residing in the bulk of a nonlinear photonic topological insulator. These self-forming entities exhibit, despite being in the bulk, the property of unidirectional transport, similar to the transport their linear counterparts display on the edge of a topological insulator. In the concrete case of a Floquet topological insulator, such a soliton forms when a wave packet induces, through nonlinearity, a defect region in a honeycomb lattice of helical optical waveguides, and at the same time the wave packet populates a continuously rotating outer (or inner) edge state of that region. The concept is universal and applicable to topological systems with nonlinear response or mean-field interactions. PMID- 24483666 TI - Nanofluidic osmotic diodes: theory and molecular dynamics simulations. AB - Osmosis describes the flow of water across semipermeable membranes powered by the chemical free energy extracted from salinity gradients. While osmosis can be expressed in simple terms via the van 't Hoff ideal gas formula for the osmotic pressure, it is a complex phenomenon taking its roots in the subtle interactions occurring at the scale of the membrane nanopores. Here we use new opportunities offered by nanofluidic systems to create an osmotic diode exhibiting asymmetric water flow under reversal of osmotic driving. We show that a surface charge asymmetry built on a nanochannel surface leads to nonlinear couplings between water flow and the ion dynamics, which are capable of water flow rectification. This phenomenon opens new opportunities for water purification and complex flow control in nanochannels. PMID- 24483667 TI - Viscoelastic flows in simple liquids generated by vibrating nanostructures. AB - Newtonian fluid mechanics, in which the shear stress is proportional to the strain rate, is synonymous with the flow of simple liquids such as water. We report the measurement and theoretical verification of non-Newtonian, viscoelastic flow phenomena produced by the high-frequency (20 GHz) vibration of gold nanoparticles immersed in water-glycerol mixtures. The observed viscoelasticity is not due to molecular confinement, but is a bulk continuum effect arising from the short time scale of vibration. This represents the first direct mechanical measurement of the intrinsic viscoelastic properties of simple bulk liquids, and opens a new paradigm for understanding extremely high frequency fluid mechanics, nanoscale sensing technologies, and biophysical processes. PMID- 24483669 TI - Simulations of collisionless perpendicular shocks in partially ionized plasmas. AB - Perpendicular collisionless shocks propagating into partially ionized plasmas are investigated by two-dimensional hybrid particle simulations. It is shown that some neutral particles leak into the upstream region from the downstream region, the leaking neutral particles become pickup ions in the upstream region and modify the shock structure, the pickup ions are preferentially accelerated, and plasma instabilities are excited by the pickup ions in the upstream and downstream regions. PMID- 24483668 TI - Deflection of MeV electrons by self-generated magnetic fields in intense laser solid interactions. AB - We show that the interaction of relativistic-intensity, picosecond laser pulses with solid targets is affected by the reflected light through the strong currents and 10(4) T magnetic fields it produces. Three-dimensional particle-in-cell simulations, with the axisymmetry broken by a small angle of incidence, show that these magnetic fields deflect the laser-accelerated electrons away from the incident laser axis. This directly impacts the interpretation of electron divergence and directionality in applications such as laser-driven ion acceleration or fast-ignition inertial fusion. PMID- 24483670 TI - High-quality electron beams from beam-driven plasma accelerators by wakefield induced ionization injection. AB - We propose a new and simple strategy for controlled ionization-induced trapping of electrons in a beam-driven plasma accelerator. The presented method directly exploits electric wakefields to ionize electrons from a dopant gas and capture them into a well-defined volume of the accelerating and focusing wake phase, leading to high-quality witness bunches. This injection principle is explained by example of three-dimensional particle-in-cell calculations using the code OSIRIS. In these simulations a high-current-density electron-beam driver excites plasma waves in the blowout regime inside a fully ionized hydrogen plasma of density 5*10(17)cm-3. Within an embedded 100 MUm long plasma column contaminated with neutral helium gas, the wakefields trigger ionization, trapping of a defined fraction of the released electrons, and subsequent acceleration. The hereby generated electron beam features a 1.5 kA peak current, 1.5 MUm transverse normalized emittance, an uncorrelated energy spread of 0.3% on a GeV-energy scale, and few femtosecond bunch length. PMID- 24483671 TI - Ultrafast short-range disordering of femtosecond-laser-heated warm dense aluminum. AB - We have probed, with time-resolved x-ray absorption near-edge spectroscopy (XANES), a femtosecond-laser-heated aluminum foil with fluences up to 1 J/cm2. The spectra reveal a loss of the short-range order in a few picoseconds. This time scale is compared with the electron-ion equilibration time, calculated with a two-temperature model. Hydrodynamic simulations shed light on complex features that affect the foil dynamics, including progressive density change from solid to liquid (~10 ps). In this density range, quantum molecular dynamics simulations indicate that XANES is a relevant probe of the ionic temperature. PMID- 24483672 TI - Demonstration of the improved rocket efficiency in direct-drive implosions using different ablator materials. AB - The success of direct-drive implosions depends critically on the ability to create high ablation pressures (~100 Mbar) and accelerating the imploding shell to ignition-relevant velocities (>3.7*10(7 ) cm/s) using direct laser illumination. This Letter reports on an experimental study of the conversion of absorbed laser energy into kinetic energy of the shell (rocket efficiency) where different ablators were used to vary the ratio of the atomic number to the atomic mass. The implosion velocity of Be shells is increased by 20% compared to C and CH shells in direct-drive implosions when a constant initial target mass is maintained. These measurements are consistent with the predicted increase in the rocket efficiency of 28% for Be and 5% for C compared to a CH ablator. PMID- 24483673 TI - Observation of a geometric Hall effect in a spinor Bose-Einstein condensate with a Skyrmion spin texture. AB - For a spin-carrying particle moving in a spatially varying magnetic field, effective electromagnetic forces can arise due to the geometric phase associated with adiabatic spin rotation of the particle. We report the observation of a geometric Hall effect in a spinor Bose-Einstein condensate with a Skyrmion spin texture. Under translational oscillations of the spin texture, the condensate resonantly develops a circular motion in a harmonic trap, demonstrating the existence of an effective Lorentz force. When the condensate circulates, quantized vortices are nucleated in the boundary region of the condensate and the vortex number increases over 100 without significant heating. We attribute the vortex nucleation to the shearing effect of the effective Lorentz force from the inhomogeneous effective magnetic field. PMID- 24483674 TI - Waveform-dependent absorbing metasurfaces. AB - We present the first use of a waveform-dependent absorbing metasurface for high power pulsed surface currents. The new type of nonlinear metasurface, composed of circuit elements including diodes, is capable of storing high-power pulse energy to dissipate it between pulses, while allowing propagation of small signals. Interestingly, the absorbing performance varies for high-power pulses but not for high-power continuous waves (CW's), since the capacitors used are fully charged up. Thus, the waveform dependence enables us to distinguish various signal types (i.e., CW or pulse) even at the same frequency, which potentially creates new kinds of microwave technologies and applications. PMID- 24483675 TI - Influence of packing on low energy vibrations of densified glasses. AB - A comparative study of Raman scattering and low temperature specific heat capacity has been performed on samples of B2O3, which have been high-pressure quenched to go through different glassy phases having growing density to the crystalline state. It has revealed that the excess volume characterizing the glassy networks favors the formation of specific glassy structural units, the boroxol rings, which produce the boson peak, a broad band of low energy vibrational states. The decrease of boroxol rings with increasing pressure of synthesis is associated with the progressive depression of the excess low energy vibrations until their full disappearance in the crystalline phase, where the rings are missing. These observations prove that the additional soft vibrations in glasses arise from specific units whose formation is made possible by the poor atomic packing of the network. PMID- 24483676 TI - Classical topological order in Abelian and non-Abelian generalized height models. AB - We present Monte Carlo simulations on a new class of lattice models in which the degrees of freedom are elements of an Abelian or non-Abelian finite symmetry group G, placed on directed edges of a two-dimensional lattice. The plaquette group product is constrained to be the group identity. In contrast to discrete gauge models (but similar to past work on height models), only elements of symmetry-related subsets S?G are allowed on edges. These models have topological sectors labeled by group products along topologically nontrivial loops. Measurement of relative sector probabilities and the distribution of distance between defect pairs are done to characterize the types of order (topological or quasi-long-range order) exhibited by these models. We present particular models in which fully local non-Abelian constraints lead to global topological liquid properties. PMID- 24483677 TI - Living clusters and crystals from low-density suspensions of active colloids. AB - Recent studies aimed at investigating artificial analogs of bacterial colonies have shown that low-density suspensions of self-propelled particles confined in two dimensions can assemble into finite aggregates that merge and split, but have a typical size that remains constant (living clusters). In this Letter, we address the problem of the formation of living clusters and crystals of active particles in three dimensions. We study two systems: self-propelled particles interacting via a generic attractive potential and colloids that can move toward each other as a result of active agents (e.g., by molecular motors). In both cases, fluidlike "living" clusters form. We explain this general feature in terms of the balance between active forces and regression to thermodynamic equilibrium. This balance can be quantified in terms of a dimensionless number that allows us to collapse the observed clustering behavior onto a universal curve. We also discuss how active motion affects the kinetics of crystal formation. PMID- 24483678 TI - Thermally and vibrationally induced tautomerization of single porphycene molecules on a Cu(110) surface. AB - We report the direct observation of intramolecular hydrogen atom transfer reactions (tautomerization) within a single porphycene molecule on a Cu(110) surface by scanning tunneling microscopy. It is found that the tautomerization can be induced via inelastic electron tunneling at 5 K. By measuring the bias dependent tautomerization rate of isotope-substituted molecules, we can assign the scanning tunneling microscopy-induced tautomerization to the excitation of specific molecular vibrations. Furthermore, these vibrations appear as characteristic features in the dI/dV spectra measured over individual molecules. The vibrational modes that are associated with the tautomerization are identified by density functional theory calculations. At higher temperatures above ~75 K, tautomerization is induced thermally and an activation barrier of about 168 meV is determined from an Arrhenius plot. PMID- 24483679 TI - Unified stress tensor of the hydration water layer. AB - We present the general stress tensor of the ubiquitous hydration water layer (HWL), based on the empirical hydration force, by combining the elasticity and hydrodynamics theories. The tapping and shear component of the tensor describe the elastic and damping properties of the HWL, respectively, in good agreement with experiments. In particular, a unified understanding of HWL dynamics provides the otherwise unavailable intrinsic parameters of the HWL, which offer additional but unexplored aspects to the supercooled liquidity of the confined HWL. Our results may allow deeper insight on systems where the HWL is critical. PMID- 24483680 TI - Phenomenological model for the normal-state angle-resolved photoemission spectroscopy line shapes of high-temperature superconductors. AB - Providing a full theoretical description of the single-particle spectral function observed for high-temperature superconductors in the normal state is an important goal, yet unrealized. Here, we present a phenomenological model approaching towards this goal. The model results from implementing key phenomenological improvement in the so-called extremely correlated Fermi-liquid model. The model successfully describes the dichotomy of the spectral function as functions of momentum and energy and fits data for different materials (Bi2Sr2CaCu2O8+delta and La2-xSrxCuO4), with an identical set of intrinsic parameters. The current analysis goes well beyond the prevalent analysis of the spectral function as a function of momentum alone. PMID- 24483681 TI - Effective J=1/2 insulating state in Ruddlesden-Popper iridates: an LDA+DMFT study. AB - Using ab initio methods for correlated electrons in solids, we investigate the metal-insulator transition across the Ruddlesden-Popper (RP) series of iridates and explore the robustness of the Jeff=1/2 state against band effects due to itineracy, tetragonal distortion, octahedral rotation, and Coulomb interaction. We predict the effects of epitaxial strain on the optical conductivity, magnetic moments, and Jeff=1/2 ground-state wave functions in the RP series. To describe the solution of the many-body problem in an intuitive picture, we introduce a concept of energy-dependent atomic states, which strongly resemble the atomic Jeff=1/2 states but with coefficients that are energy or time dependent. We demonstrate that the deviation from the ideal Jeff=1/2 state is negligible at short time scales for both single- and double-layer iridates, while it becomes quite significant for Sr3Ir2O7 at long times and low energy. Interestingly, Sr2IrO4 is positioned very close to the SU(2) limit, with only ~3% deviation from the ideal Jeff=1/2 situation. PMID- 24483682 TI - Effect of Pauli blockade on spin-dependent diffusion in a degenerate electron gas. AB - Spin-polarized transport of photoelectrons in bulk, p-type GaAs is investigated in the Pauli blockade regime. In contrast to usual spin diffusion processes in which the spin polarization decreases with distance traveled due to spin relaxation, images of the polarized photoluminescence reveal a spin-filter effect in which the spin polarization increases during transport over the first 2 MUm from 26% to 38%. This is shown to be a direct consequence of the Pauli principle and the associated quantum degeneracy pressure which results in a spin-dependent increase in the minority carrier diffusion constants and mobilities. The central role played by the quantum degeneracy pressure is confirmed via the observation of a spin-dependent increase in the photoelectron volume and a spin-charge coupling description of this is presented. PMID- 24483683 TI - Spin-orbit torques in Co/Pd multilayer nanowires. AB - Current induced spin-orbit torques have been studied in ferromagnetic nanowires made of 20 nm thick Co/Pd multilayers with perpendicular magnetic anisotropy. Using Hall voltage and lock-in measurements, it is found that upon injection of an electric current both in-plane (Slonczewski-like) and perpendicular (fieldlike) torques build up in the nanowire. The torque efficiencies are found to be as large as 1.17 and 5 kOe at 10(8) A/cm2 for the in-plane and perpendicular components, respectively, which is surprisingly comparable to previous studies in ultrathin (~1 nm) magnetic bilayers. We show that this result cannot be explained solely by spin Hall effect induced torque at the outer interfaces, indicating a probable contribution of the bulk of the Co/Pd multilayer. PMID- 24483684 TI - Dirac versus Weyl fermions in topological insulators: Adler-Bell-Jackiw anomaly in transport phenomena. AB - Dirac metals (gapless semiconductors) are believed to turn into Weyl metals when perturbations, which break either time reversal symmetry or inversion symmetry, are employed. However, no experimental evidence has been reported for the existence of Weyl fermions in three dimensions. Applying magnetic fields near the topological phase transition from a topological insulator to a band insulator in Bi1-xSbx we observe not only the weak antilocalization phenomenon in magnetoconductivity near zero magnetic fields (B<0.4 T), but also its upturn above 0.4 T only for E//B. This "incompatible" coexistence between weak antilocalization and "negative" magnetoresistivity is attributed to the Adler Bell-Jackiw anomaly ("topological" E.B term) in the presence of weak antilocalization corrections. PMID- 24483685 TI - Strain-engineered surface transport in Si(001): complete isolation of the surface state via tensile strain. AB - By combining density functional theory, nonequilibrium Green's function formulism and effective-Hamiltonian approaches, we demonstrate strain-engineered surface transport in Si(001), with the complete isolation of the Si surface states from the bulk bands. Our results show that sufficient tensile strain can effectively remove the overlap between the surface valence state and the bulk valence band, because of the drastically different deformation potentials. Isolation of the surface valence state is possible with a tensile strain of ~1.5%, a value that is accessible experimentally. Quantum transport simulations of a chemical sensing device based on strained Si(001) surface confirm the dominating surface conductance, giving rise to an enhanced molecular sensitivity. Our results show promise for using strain engineering to further our ability to manipulate surface states for quantum information processing and surface state-based devices. PMID- 24483686 TI - Steady-state entanglement in the nuclear spin dynamics of a double quantum dot. AB - We propose a scheme for the deterministic generation of steady-state entanglement between the two nuclear spin ensembles in an electrically defined double quantum dot. Because of quantum interference in the collective coupling to the electronic degrees of freedom, the nuclear system is actively driven into a two-mode squeezedlike target state. The entanglement buildup is accompanied by a self polarization of the nuclear spins towards large Overhauser field gradients. Moreover, the feedback between the electronic and nuclear dynamics leads to multistability and criticality in the steady-state solutions. PMID- 24483687 TI - Edge reconstruction in the nu=2/3 fractional quantum Hall state. AB - The edge structure of the nu=2/3 fractional quantum Hall state has been studied for several decades, but recent experiments, exhibiting upstream neutral mode(s), a plateau at a Hall conductance of 1/3(e2/h) through a quantum point contact, and a crossover of the effective charge, from e/3 at high temperature to 2e/3 at low temperature, could not be explained by a single theory. Here we develop such a theory, based on edge reconstruction due to a confining potential with finite slope, that admits an additional nu=1/3 incompressible strip near the edge. Renormalization group analysis of the effective edge theory due to disorder and interactions explains the experimental observations. PMID- 24483688 TI - Quantifying many-body effects by high-resolution Fourier transform scanning tunneling spectroscopy. AB - High-resolution Fourier transform scanning tunneling spectroscopy (FT-STS) is used to study many-body effects on the surface state of Ag(111). Our results reveal a kink in the otherwise parabolic band dispersion of the surface electrons and an increase in the quasiparticle lifetime near the Fermi energy Ef. The experimental data are accurately modeled with the T-matrix formalism for scattering from a single impurity, assuming that the surface electrons are dressed by the electron-electron and electron-phonon interactions. We confirm the latter as the interaction responsible for the deviations from bare dispersion. We further show how FT-STS can be used to simultaneously extract real and imaginary parts of the self-energy for both occupied and unoccupied states with a momentum and energy resolution competitive with angle-resolved photoemission spectroscopy. From our quantitative analysis of the data we extract a Debye energy of hOmegaD=14+/-1 meV and an electron-phonon coupling strength of lambda=0.13+/ 0.02, consistent with previous results. This proof-of-principle measurement advances FT-STS as a method for probing many body effects, which give rise to a rich array of material properties. PMID- 24483689 TI - Induced superconductivity in graphene grown on rhenium. AB - We report a new way to strongly couple graphene to a superconductor. The graphene monolayer has been grown directly on top of a superconducting Re(0001) thin film and characterized by scanning tunneling microscopy and spectroscopy. We observed a moire pattern due to the mismatch between Re and graphene lattice parameters that we have simulated with ab initio calculations. The density of states around the Fermi energy appears to be position dependent on this moire pattern. Tunneling spectroscopy performed at 50 mK shows that the superconducting behavior of graphene on Re is well described by the Bardeen-Cooper-Schrieffer theory and stands for a very good interface between the graphene and its metallic substrate. PMID- 24483690 TI - Rotation and anisotropic molecular orbital effect in a single H2TPP molecule transistor. AB - Electron transport through a single molecule is determined not only by the intrinsic properties of the molecule but also by the configuration of the molecule with respect to the lead electrodes. Here, we show how electron transport through a single H2TPP molecule is modulated by changes in the configuration. The Coulomb stability diagram of a single H2TPP molecule transistor exhibited a few different patterns in different measurement scans. Furthermore, the sample exhibited negative differential resistance, the magnitude of which changed with the pattern in the Coulomb stability diagram. Such behavior can be explained by the rotation of the molecule with anisotropic molecular orbitals in the gap electrodes induced by electrical stress. Moreover, we find that the energy separations between molecular orbitals are also affected by the rotation, confirming that the metal-molecule interface configuration renormalizes the electronic levels in the molecule. PMID- 24483691 TI - Inducing spin correlations and entanglement in a double quantum dot through nonequilibrium transport. AB - For a double quantum dot system in a parallel geometry, we demonstrate that by combining the effects of a flux and driving an electrical current through the structure, the spin correlations between electrons localized in the dots can be controlled at will. In particular, a current can induce spin correlations even if the spins are uncorrelated in the initial equilibrium state. Therefore, we are able to engineer an entangled state in this double-dot structure. We take many body correlations fully into account by simulating the real-time dynamics using the time-dependent density matrix renormalization group method. Using a canonical transformation, we provide an intuitive explanation for our results, related to Ruderman-Kittel-Kasuya-Yoshida physics driven by the bias. PMID- 24483692 TI - Universal quantum fluctuations of a cavity mode driven by a Josephson junction. AB - We analyze the quantum dynamics of a superconducting cavity coupled to a voltage biased Josephson junction. The cavity is strongly excited at resonances where the voltage energy lost by a Cooper pair traversing the circuit is a multiple of the cavity photon energy. We find that the resonances are accompanied by substantial squeezing of the quantum fluctuations of the cavity over a broad range of parameters and are able to identify regimes where the fluctuations in the system take on universal values. PMID- 24483693 TI - From Coulomb-blockade to nonlinear quantum dynamics in a superconducting circuit with a resonator. AB - Motivated by recent experiments on superconducting circuits consisting of a dc voltage-biased Josephson junction in series with a resonator, quantum properties of these devices far from equilibrium are studied. This includes a crossover from a domain of incoherent to a domain of coherent Cooper pair tunneling, where the circuit realizes a driven nonlinear oscillator. Equivalently, weak photon-charge coupling turns into strong correlations captured by a single degree of freedom. Radiated photons offer a new tool to monitor charge flow and current noise gives access to nonlinear dynamics, which allows us to analyze quantum-classical boundaries. PMID- 24483694 TI - Triangular antiferromagnet with nonmagnetic impurities. AB - The effect of nonmagnetic impurities on the phase diagram of the classical Heisenberg antiferromagnet on a triangular lattice is investigated. We present analytical arguments confirmed by numerical calculations that at zero temperature vacancies stabilize a conical state providing an example of "order by quenched disorder" effect. Competition between thermal fluctuations and the site disorder leads to a complicated H-T phase diagram, which is deduced from the classical Monte Carlo simulations for a representative vacancy concentration. For the XY triangular-lattice antiferromagnet with an in-plane external field, nonmagnetic impurities stabilize the fanlike spin structure. We also briefly discuss the effect of quantum fluctuations. PMID- 24483695 TI - Probing the spin pumping mechanism: exchange coupling with exponential decay in Y3Fe5O12/barrier/Pt heterostructures. AB - It is widely believed that the mechanism for spin pumping in ferromagnet nonmagnet bilayers is the exchange interaction between the ferromagnet and nonmagnetic material. We observe 1000-fold exponential decay of spin pumping from thin Y3Fe5O12 films to Pt across insulating barriers, from which exponential decay lengths of 0.16, 0.19, and 0.23 nm are extracted for oxide barriers having band gaps of 4.91, 3.40, and 2.36 eV, respectively. This archetypal signature of quantum tunneling through a barrier underscores the importance of exchange coupling for spin pumping and reveals its dependence on the characteristics of the barrier material. PMID- 24483696 TI - Emergent spin filter at the interface between ferromagnetic and insulating layered oxides. AB - We report a strong effect of interface-induced magnetization on the transport properties of magnetic tunnel junctions consisting of ferromagnetic manganite La0.7Ca0.3MnO3 and insulating cuprate PrBa2Cu3O7. Contrary to the typically observed steady increase of the tunnel magnetoresistance with decreasing temperature, this system exhibits a sudden anomalous decrease at low temperatures. Interestingly, this anomalous behavior can be attributed to the competition between the positive spin polarization of the manganite contacts and the negative spin-filter effect from the interface-induced Cu magnetization. PMID- 24483697 TI - Single-photon nonlinear optics with graphene plasmons. AB - We show that it is possible to realize significant nonlinear optical interactions at the few photon level in graphene nanostructures. Our approach takes advantage of the electric field enhancement associated with the strong confinement of graphene plasmons and the large intrinsic nonlinearity of graphene. Such a system could provide a powerful platform for quantum nonlinear optical control of light. As an example, we consider an integrated optical device that exploits this large nonlinearity to realize a single photon switch. PMID- 24483698 TI - Probing the anharmonicity of the potential well for a magnetic vortex core in a nanodot. AB - The anharmonicity of the potential well confining a magnetic vortex core in a nanodot is measured dynamically with a magnetic resonance force microscope (MRFM). The stray field of the MRFM tip is used to displace the equilibrium core position away from the nanodot center. The anharmonicity is then inferred from the relative frequency shift induced on the eigenfrequency of the vortex core translational mode. An analytical framework is proposed to extract the anharmonic coefficient from this variational approach. Traces of these shifts are recorded while scanning the tip above an isolated nanodot, patterned out of a single crystal FeV film. We observe a +10% increase of the eigenfrequency when the equilibrium position of the vortex core is displaced to about one-third of its radius. This calibrates the tunability of the gyrotropic mode by external magnetic fields. PMID- 24483699 TI - Properties of epitaxial films made of relaxor ferroelectrics. AB - Finite-temperature properties of epitaxial films made of Ba(Zr,Ti)O3 relaxor ferroelectrics are determined as a function of misfit strain, via the use of a first-principles-based effective Hamiltonian. These films are macroscopically paraelectric at any temperature, for any strain ranging between ?-3% and ?+3%. However, original temperature-versus-misfit strain phase diagrams are obtained for the Burns temperature (Tb) and for the critical temperatures (Tm,z and Tm,IP) at which the out-of-plane and in-plane dielectric response peak, respectively, which allow the identification of three different regions. These latter differ from their evolution of Tb, Tm,z, and/or Tm,IP with strain, which are the fingerprints of a remarkable strain-induced microscopic change: each of these regions is associated with its own characteristic behavior of polar nanoregions at low temperature, such as strain-induced rotation or strain-driven elongation of their dipoles or even increase in the average size of the polar nanoregions when the strength of the strain grows. PMID- 24483700 TI - Domains within domains and walls within walls: evidence for polar domains in cryogenic SrTiO3. AB - Resonant piezoelectric spectroscopy shows polar resonances in paraelectric SrTiO3 at temperatures below 80 K. These resonances become strong at T<40 K. The resonances are induced by weak electric fields and lead to standing mechanical waves in the sample. This piezoelectric response does not exist in paraelastic SrTiO3 nor at temperatures just below the ferroelastic phase transition. The interpretation of the resonances is related to ferroelastic twin walls which become polar at low temperatures in close analogy with the known behavior of CaTiO3. SrTiO3 is different from CaTiO3, however, because the wall polarity is thermally induced; i.e., there exists a small temperature range well below the ferroelastic transition point at 105 K where polarity appears on cooling. As the walls are atomistically thin, this transition has the hallmarks of a two dimensional phase transition restrained to the twin boundaries rather than a classic bulk phase transition. PMID- 24483702 TI - Observation of enhanced diffusivity in magnetically powered reciprocal swimmers. AB - We report on the development of a system of micron-sized reciprocal swimmers that can be powered with small homogeneous magnetic fields, and whose motion resembles that of a helical flagellum moving back and forth. We have measured the diffusivities of the swimmers to be higher compared to nonactuated objects of identical dimensions at long time scales, in accordance with the theoretical predictions made by Lauga [Phys. Rev. Lett. 106, 178101 (2011)]. Randomness in the reciprocity of the actuation strokes was found to have a strong influence on the enhancement of the diffusivity, which has been investigated with numerical calculations. PMID- 24483701 TI - Domain wall roughness in stripe phase BiFeO3 thin films. AB - Using the model system of ferroelectric domain walls, we explore the effects of long-range dipolar interactions and periodic ordering on the behavior of pinned elastic interfaces. In piezoresponse force microscopy studies of the characteristic roughening of intrinsic 71 degrees stripe domains in BiFeO3 thin films, we find unexpectedly high values of the roughness exponent zeta=0.74+/ 0.10, significantly different from those obtained for artificially written domain walls in this and other ferroelectric materials. The large value of the exponent suggests that a random field-dominated pinning, combined with stronger disorder and strain effects due to the step-bunching morphology of the samples, could be the dominant source of pinning in the system. PMID- 24483703 TI - Bidirectional bacterial gliding motility powered by the collective transport of cell surface proteins. AB - The gliding motility of Flavobacterium johnsoniae is driven by moving surface adhesive proteins. Recently, these motility components were observed to travel along a closed loop on the cell surface. The mechanism by which such moving surface adhesins give rise to cell motion remains unknown. On the basis of the unique motility properties of F. johnsoniae, we present a generic model for bidirectional motion of rigidly coupled adhesins, which are propelled in opposite directions. Using analytical and numerical methods, we demonstrate that, for a sufficiently large adhesin speed, bidirectional motion arises from spontaneous symmetry breaking. The model also predicts that, close to the bifurcation point, a weak asymmetry in the binding dynamics is sufficient to facilitate directed motility, indicating that the direction of motion could be sensitively regulated internally in response to inhomogeneity of the environment. PMID- 24483704 TI - Escape of DNA from a weakly biased thin nanopore: experimental evidence for a universal diffusive behavior. AB - We report experimental escape time distributions of double-stranded DNA molecules initially threaded halfway through a thin solid-state nanopore. We find a universal behavior of the escape time distributions consistent with a one dimensional first passage formulation notwithstanding the geometry of the experiment and the potential role of complex molecule-liquid-pore interactions. Diffusion constants that depend on the molecule length and pore size are determined. Also discussed are the practical implications of long time diffusive molecule trapping in the nanopore. PMID- 24483705 TI - Comment on "Vacuum Rabi splitting in a semiconductor circuit QED system". PMID- 24483706 TI - Three approaches to one problem: protein folding in the periplasm, the endoplasmic reticulum, and the intermembrane space. AB - SIGNIFICANCE: The bacterial periplasm, the endoplasmic reticulum (ER), and the intermembrane space (IMS) of mitochondria contain dedicated machineries for the incorporation of disulfide bonds into polypeptides, which cooperate with chaperones, proteases, and assembly factors during protein biogenesis. RECENT ADVANCES: The mitochondrial disulfide relay was identified only very recently. The current knowledge of the protein folding machinery of the IMS will be described in detail in this review and compared with the "more established" systems of the periplasm and the ER. CRITICAL ISSUES: While the disulfide relays of all three compartments adhere to the same principle, the specific designs and functions of these systems differ considerably. In particular, the cooperation with other folding systems makes the situation in each compartment unique. FUTURE DIRECTIONS: The biochemical properties of the oxidation machineries are relatively well understood. However, it still remains largely unclear as to how the quality control systems of "oxidizing" compartments orchestrate the activities of oxidoreductases, chaperones, proteases, and signaling molecules to ensure protein homeostasis. PMID- 24483707 TI - Decrease in 3-nitrotyrosine in the amniotic fluid of women with cytomegalovirus infection. AB - The aim of this study was to assess oxidative stress in pregnant women infected with cytomegalovirus on the basis of 3-nitrotyrosine levels in amniotic fluid (AF). The 3-nitrotyrosine (3-NT) level in AF was measured using the competitive ELISA method. The study groups were as follows: group I consisted of women with IgM and/or IgA; group II were women with only IgG anti-CMV antibodies and group III were seronegative women, used as the control group. Age, gestational age and socioeconomic status were also assessed. The average level of 3-nitrotyrosine in group II and the control group was similar: 53.14 nM 3-NT and 49.78 nM 3-NT, respectively. However, in group I, the lowest level 3-NT in AF was observed - 39.17 nM 3-NT and statistical analysis showed significant differences in levels of 3-NT between group I and the control group (p < 0.01). We conclude that significantly lower levels of 3-nitrotyrosine in pregnant women with CMV infection may indicate an increase in the antioxidant defence mechanisms in these patients. PMID- 24483708 TI - Acquired pseudo-Pelger-Huet anomaly under maintenance therapy with rituximab in follicular lymphoma. PMID- 24483709 TI - Self-assembly of Archimedean tilings with enthalpically and entropically patchy polygons. AB - Considerable progress in the synthesis of anisotropic patchy nanoplates (nanoplatelets) promises a rich variety of highly ordered two-dimensional superlattices. Recent experiments of superlattices assembled from nanoplates confirm the accessibility of exotic phases and motivate the need for a better understanding of the underlying self-assembly mechanisms. Here, we present experimentally accessible, rational design rules for the self-assembly of the Archimedean tilings from polygonal nanoplates. The Archimedean tilings represent a model set of target patterns that (i) contain both simple and complex patterns, (ii) are comprised of simple regular shapes, and (iii) contain patterns with potentially interesting materials properties. Via Monte Carlo simulations, we propose a set of design rules with general applicability to one- and two component systems of polygons. These design rules, specified by increasing levels of patchiness, correspond to a reduced set of anisotropy dimensions for robust self-assembly of the Archimedean tilings. We show for which tilings entropic patches alone are sufficient for assembly and when short-range enthalpic interactions are required. For the latter, we show how patchy these interactions should be for optimal yield. This study provides a minimal set of guidelines for the design of anisostropic patchy particles that can self-assemble all 11 Archimedean tilings. PMID- 24483710 TI - A new method for evaluating the dissolution of orodispersible films. AB - The aim of this research was to develop and assess a new dissolution apparatus for orodispersible films (ODFs). The new apparatus was based on a flow-through cell design which requires only a limited amount of dissolution medium and can automatically collect samples in short-time intervals. Compared with the dissolution method in Chinese Pharmacopeia, our method simulated the flow condition of the oral cavity and resulted in reproducible dissolution data and remarkably discriminating capability. Therefore, we concluded that the proposed dissolution method was particularly suitable for evaluating the dissolution of ODFs and should also be applicable to other fast-dissolving solid dosage forms. PMID- 24483711 TI - Recent advances in the treatment of neurogenic erectile dysfunction. AB - Neurogenic erectile dysfunction (ED) can be broadly defined as an inability to sustain or maintain a penile erection owing to a neurological impairment, either centrally or peripherally or both. Although significant advances in the pharmacological treatment of ED have occurred in recent years, especially after the introduction of oral selective phosphodiesterase type 5 inhibitor, the treatment of neurological patients with ED may be challenging for prescribers, given poor data available on this topic and the variety of etiologic factors (iatrogenic, endocrine, psychiatric and psychosocial) to consider. At the same time, several, new oral, local and surgical treatments are available and their efficacy and safety depend on the specific cases. This review provides a comprehensive and updated description of current and future ED therapies, including assigned patents, with a special focus on the treatment of neurogenic erectile dysfunction. PMID- 24483712 TI - Two patterns of cannabis use among adolescents: results of a 10-year prospective study using a growth mixture model. AB - BACKGROUND: The present study aimed to distinguish cannabis consumption patterns among adolescents and to relate these to life satisfaction, academic achievement, and the use of other psychoactive substances. METHODS: This study used a prospective design. Cannabis use was measured 14 times over the course of 10 years. Participants were 318 adolescents aged 14 to 15 at the beginning of the study. RESULTS: Growth mixture modeling identified 2 latent classes. Class 1 was defined by phases of high-frequency cannabis use, and Class 2 was defined by low frequency use or nonuse. Class 1 reported decreased satisfaction with life and one's own academic and professional achievement at the age of 24 as well as higher use of tobacco and illicit substances. CONCLUSIONS: High-frequency use of cannabis predicts a decreased satisfaction with life and one's own academic and professional achievement as well as an increased use of other substances. PMID- 24483713 TI - Thyroid remnant ablation following administration of a diagnostic dose of iodine 131 under thyrogen stimulation. PMID- 24483714 TI - LeMYC2 acts as a negative regulator of blue light mediated photomorphogenic growth, and promotes the growth of adult tomato plants. AB - BACKGROUND: Arabidopsis ZBF1/MYC2bHLH transcription factor is a repressor of photomorphogenesis, and acts as a point of cross talk in light, abscisic acid (ABA) and jasmonic acid (JA) signaling pathways. MYC2 also functions as a positive regulator of lateral root development and flowering time under long day conditions. However, the function of MYC2 in growth and development remains unknown in crop plants. RESULTS: Here, we report the functional analyses of LeMYC2 in tomato (Lycopersicon esculentum). The amino acid sequence of LeMYC2 showed extensive homology with Arabidopsis MYC2, containing the conserved bHLH domain. To study the function of LeMYC2 in tomato, overexpression and RNA interference (RNAi) LeMYC2 tomato transgenic plants were generated. Examination of seedling morphology, physiological responses and light regulated gene expression has revealed that LeMYC2 works as a negative regulator of blue light mediated photomorphogenesis. Furthermore, LeMYC2 specifically binds to the G-box of LeRBCS-3A promoter. Overexpression of LeMYC2 has led to increased root length with more number of lateral roots. The tomato plants overexpressing LeMYC2 have reduced internode distance with more branches, and display the opposite morphology to RNAi transgenic lines. Furthermore, this study shows that LeMYC2 promotes ABA and JA responsiveness. CONCLUSIONS: Collectively, this study highlights that working in light, ABA and JA signaling pathways LeMYC2 works as an important regulator for growth and development in tomato plants. PMID- 24483716 TI - Postgraduate training in clinical oncology. PMID- 24483715 TI - Predictors of prejudice against lesbians and gay men in Jamaica. AB - Jamaica has acquired an international reputation for strong antigay prejudice, incidents of antigay violence, and outspoken, antigay public figures. In recent years, national and international gay rights groups have attempted to improve this situation. However, these efforts have not been based on an empirical analysis of the factors underlying Jamaican antigay bias, which is essential for developing effective prejudice-reducing strategies. Using data collected in two large-scale national surveys in 2011 and 2012 (N 2011 = 997, N 2012 = 945), we investigated predictors of Jamaican antigay prejudice, including age, gender, religious affiliation, education, income, and a preference for dancehall music. We also examined changes in reported antigay bias between 2011 and 2012 after accounting for other predictors. All proposed variables predicted some aspect of antigay prejudice, though sometimes in unexpected ways. Male gender emerged as a particularly important predictor. We discuss the strengths and limitations of our design and the implications of our findings for prejudice-reduction strategies in Jamaica. PMID- 24483717 TI - Organize and conduct demonstrations. AB - Demonstrations have come to assume a very different role from the one they played earlier this century when they were the mainstay of formal medical education. Today, the activities encompassed by demonstration are increasingly being incorporated into other teaching methods. This article considers those contexts in which demonstrations may most profitably be used and the steps involved in planning them so as to ensure students' participation. PMID- 24483718 TI - The cardiovascular system. AB - In the last issue of this journal an approach to the construction of integrated, multidisciplinary course units was described (Neame 1981). This approach is illustrated in relation to the cardiovascular system course unit developed for use early in the second year of the five-year curriculum at the Faculty of Medicine, The University of Newcastle, New South Wales. PMID- 24483719 TI - Teaching general practitioners to teach. PMID- 24483720 TI - Teaching residents through consultation. AB - Some patients present problems which exceed a junior doctor's ability to analyse and synthesize information on which management decisions must be made. As a result, he or she often consults with an attending physician or consultant. In this article four types of consultation are identified and analysed, each of which has potential for use as a teaching strategy. PMID- 24483721 TI - The MCQ Controversy-A Review. PMID- 24483724 TI - Relative eccentric distance sum/product indices for QSAR/QSPR: development, evaluation, and application. PMID- 24483723 TI - Stable pediatric kidney transplant recipients run higher urine indoleamine 2, 3 dioxygenase (IDO) levels than healthy children. AB - Immune cells utilize the IDO enzymatic conversion of trp to kyn to determine T cell activation vs. anergy/apoptosis. In prior studies, urine IDO levels were higher in rejecting renal allografts than in stable state. However, urine IDO levels in healthy subjects or children are unknown. As a corollary to a larger longitudinal and prospective study of serum and urine IDO levels for transplant immune monitoring, here, we analyzed the difference between urine IDO levels in stable post-transplant vs. healthy children. IDO levels were measured by tandem mass spectrometry and expressed as kyn/trp ratios. We compared one-time urine samples, from 34 well children at general pediatric clinics, to the first-month post-transplant urine samples from 18 children, while in stable state (no acute rejection or major infection event in next 30 days). Urine kyn/trp ratios were significantly higher in stable children in first-month post-kidney transplant (median 16.6, range 3.9-44.0) vs. healthy children (median 9.2, range 3.51-17.0; p = 0.0057 by nonparametric Mann-Whitney test). Higher urine IDO levels even with stable transplant suggest a continuous ongoing low-grade allorecognition/inflammatory process. Our data also provide baseline urine IDO levels in healthy subjects for use in future studies. PMID- 24483726 TI - Quantitation of chlorophylls and 22 of their colored degradation products in culinary aromatic herbs by HPLC-DAD-MS and correlation with color changes during the dehydration process. AB - Chlorophylls and their green and olive-brown derivatives were successfully separated from culinary herb extracts by HPLC with photodiode-array and mass spectrometry detection. The method involved a ternary gradient elution and reverse-phase separation conditions capable of resolving 24 different pigments (2 chlorophylls and 22 of their derivatives) of different polarities within 28 min. The method was applied to monitor color changes in 50 samples of culinary aromatic herbs subjected to five different drying treatments. Of the 24 pigments, 14 were key to understanding the differences between the primary degradation pathways of chlorophyll a and chlorophyll b in culinary herbs during drying processes. A color degradation ladder based on the total molar percentage of all the remaining green pigments was also proposed as a tool to measure the impact of drying treatments on aromatic herb visual aspects. PMID- 24483725 TI - Isolation and structural characterisation of acid- and pepsin-soluble collagen from the skin of squid Sepioteuthis lessoniana (Lesson, 1830). AB - Acid-solubilised collagen (ASC) and pepsin-solubilised collagen (PSC) were effectively isolated from squid skin with good yield and total protein content. ASC and PSC consist of two alpha-chains with an imino acid content of 182.6 and 184 imino acid residues/1000 residues. The molecular weight was determined to be between 73 and 107 kDa by using SDS-PAGE. For peptide mapping, collagens were digested with achromo endopeptidase, and all components, including alpha, beta chains, were markedly hydrolysed. Degradation peptides with molecular weights between 106.9 and 15.47 kDa were obtained. UV-vis absorption spectrum revealed distinct absorption at 220-240 nm. FT-IR spectra of collagens were almost similar when compared with standard. In differential scanning calorimetry profile, ASC and PSC exhibited a To of 59.10, 62.18 degrees C and TP of 104.91, 98.10 degrees C, respectively. This investigation indicates that the collagen isolated from the squid skin, which is thrown as waste in the seafood-processing plant, might supplement the vertebrate collagen in industrial applications. PMID- 24483727 TI - Biologically inspired stealth peptide-capped gold nanoparticles. AB - Introduction into the human body makes most nanoparticle systems susceptible to aggregation via nonspecific protein binding. Here, we developed a peptide-capped gold nanoparticle platform that withstands aggregation in undiluted human serum at 37 degrees C for 24 h. This biocompatible and natural system is based on mimicking human proteins which are enriched in negatively charged glutamic acid and positively charged lysine residues on their surface. The multifunctional EKEKEKE-PPPPC-Am peptide sequence consists of a stealth glutamic acid/lysine portion combined with a surface anchoring linker containing four prolines and a cysteine. Particle stability was measured via optical spectroscopy and dynamic light scattering in single protein, high salt, and undiluted human serum solutions. In vitro cell experiments demonstrate EKEKEKE-PPPPC-Am capped gold nanoparticles effectively minimize nonspecific cell uptake by nonphagocytic bovine aortic endothelial cells and phagocytic murine macrophage RAW 264.7 cells. Cytotoxicity studies show that peptide-capped gold nanoparticles do not affect cell viability. Finally, the peptide EKEKEKE-PPPPC-Am was extended with cyclic RGD to demonstrate specific cell targeting and stealth without using poly(ethylene glycol). Adding the functional peptide via peptide sequence extension avoids complex conjugation chemistries that are used for connection to synthetic materials. Inductively coupled plasma mass spectroscopy results indicate high aortic bovine endothelial cell uptake of c[RGDfE(SGG-KEKEKE-PPPPC Am)] capped gold nanoparticles and low uptake of the control scrambled sequence c[RDGfE(SGG-KEKEKE-PPPPC-Am)] capped gold nanoparticles. PMID- 24483728 TI - First-principles calculations and electron density topological analysis of covellite (CuS). AB - Covellite (CuS) is an important mineral sulfide that can be used in many technological applications. It has a simple formula but a complex structure consisting of alternating layers of planar CuS3 triangles and CuS4 tetrahedrons with S-S bonds. Accurate first-principles calculations are performed for covellite structure (CuS), aiming to provide insights about its structural, mechanical and electronic properties and to unveil the nature of its chemical bonding. DFT and DFT+U methods have been used and showed to be sensitive to the correlation treatment (U value). Although it is not possible to extract a universal value of the U, this study indicates that U = 5 eV is an adequate value. The electronic structure analysis shows a significant metallic character due to p(S)-d(Cu) orbital interactions up to Fermi level. The projected density of states indicates that most of the contribution comes from the atomic orbitals in the [001] plane of the covellite, explaining the conductivity anisotropy observed experimentally. Topological analysis of the electron density was performed by means of quantum theory of atoms in molecules (QTAIM). Two different topological charges in Cu and S were calculated, confirming an ionic model with mix-charges. This mineral presents ionic degree of ~ 32%. On the basis of the QTAIM analysis, the covalent character of S-S bond is confirmed, and the favored cleavage of CuS at the [001] surface might be at the Cu-S bond. The S atoms occupy most of the cell volume, and their contributions dominate the crystal compressibility: kappa(S) ~ kappa(CuS). PMID- 24483729 TI - Exploring the experience of psychological morbidity and service access in community dwelling stroke survivors: a follow-up study. AB - PURPOSE: Post-stroke depression occurs in one-third of stroke survivors with a similar risk of development across short, intermediate and long-term recovery stages. Knowledge of factors influencing psychological morbidity beyond the first year post-stroke can inform long-term interventions and improve community service access for stroke survivors. This paper aimed to identify the physical and psycho social functioning status of stroke survivors beyond 12 months post-stroke. Qualitative processes explored the longer term experiences of psychological morbidity and service access needs. METHOD: A cross-sectional follow-up of participants from a prospective cohort study. In that study, patients and were followed for 12 months post-stroke. In this study, participants from that cohort study were interviewed up to five years post-stroke. Data generation and analysis were concurrent and were analysed thematically, employing a process of constant comparison. RESULTS: Our sample included 14 participants, aged 58-89 years at an average of three years post-stroke (range 18 months to five years). Our qualitative key themes emerged as follows: physical impacts on post-stroke psychological morbidity, the experience of psychological distress, factors attenuating distress and service delivery implications. CONCLUSIONS: The experience of psychological morbidity persists beyond 12 months post-stroke, having a profound impact on community access, and social participation. Clinical implications are a need for long-term psychological monitoring post-stroke and for ongoing rehabilitation that addresses disability, community participation and social support. PMID- 24483730 TI - Time until first dental caries for young children first seen in Federally Qualified Health Centers: a retrospective cohort study. AB - OBJECTIVES: The study assessed the time until first dental caries for young children seen at five Federally Qualified Health Centers (FQHC) in Iowa and the relationship with the frequency and gaps (in months) of dental episodes, the number of topical fluoride treatments, and the number of dentists caring for the subject. METHODS: Forty children were randomly selected at each FQHC (n = 200). All children were continuously enrolled in the Medicaid program and had their first dental visit prior to age 6. Dental chart findings, claims data for the child and family, and birth certificate information were merged into one dataset. Dental visits were followed for a minimum of 36 months, including dental visits external to the FQHCs. Using time until first caries as the dependent variable, the data were subject to left, interval, and right censoring and were analyzed via Weibull regression. RESULTS: Slightly more than half of the 200 children experienced caries. Regression analysis indicated that the hazard of first dental caries increased by approximately 2% with each additional month that transpired between preventive recall examinations. In addition, children with older siblings who had a dental visit at the same center during the previous year prior to the subject's first visit were more likely to have a longer time until first dental caries. CONCLUSIONS: Timing of dental care episodes was associated with caries experience in young children from low income families. Dental professionals should focus on regularity of dental care to prevent or delay caries experience in young children. PMID- 24483731 TI - Observation of environment-induced double sudden transitions in geometric quantum correlations. AB - Correlations in quantum systems exhibit a rich phenomenology under the effect of various sources of noise. We investigate theoretically and experimentally the dynamics of quantum correlations and their classical counterparts in two nuclear magnetic resonance setups, as measured by geometric quantifiers based on trace norm. We consider two-qubit systems prepared in Bell diagonal states, and perform the experiments in real decohering environments resulting from Markovian local noise which preserves the Bell diagonal form of the states. We then report the first observation of environment-induced double sudden transitions in the geometric quantum correlations, a genuinely nonclassical effect not observable in classical correlations. The evolution of classical correlations in our physical implementation reveals in turn the finite-time relaxation to a pointer basis under nondissipative decoherence, which we characterize geometrically in full analogy with predictions based on entropic measures. PMID- 24483732 TI - Superfluidity and space-time translation symmetry breaking. AB - I present a simple model that exhibits a temporal analogue of superconducting crystalline (Larkin-Ovchinnikov-Ferrell-Fulde) ordering, with a time-dependent order parameter. I sketch designs for minimally dissipative ac circuits, all based on time translation symmetry (tau) invariant dynamics, exploiting weak links (Josephson effects). These systems violate tau spontaneously. I also discuss effective theories of that phenomenon, and space-time generalizations. PMID- 24483733 TI - Genuine multipartite Einstein-Podolsky-Rosen steering. AB - We develop the concept of genuine N-partite Einstein-Podolsky-Rosen (EPR) steering. This nonlocality is the natural multipartite extension of the original EPR paradox. Useful properties emerge that are not guaranteed for genuine multipartite entangled states. In particular, there is a close link with the task of one-sided, device-independent quantum secret sharing. We derive inequalities to demonstrate multipartite EPR steering for Greenberger-Horne-Zeilinger and Gaussian continuous variable states in loophole-free scenarios. PMID- 24483734 TI - Resource theory of quantum states out of thermal equilibrium. AB - The ideas of thermodynamics have proved fruitful in the setting of quantum information theory, in particular the notion that when the allowed transformations of a system are restricted, certain states of the system become useful resources with which one can prepare previously inaccessible states. The theory of entanglement is perhaps the best-known and most well-understood resource theory in this sense. Here, we return to the basic questions of thermodynamics using the formalism of resource theories developed in quantum information theory and show that the free energy of thermodynamics emerges naturally from the resource theory of energy-preserving transformations. Specifically, the free energy quantifies the amount of useful work which can be extracted from asymptotically many copies of a quantum system when using only reversible energy-preserving transformations and a thermal bath at fixed temperature. The free energy also quantifies the rate at which resource states can be reversibly interconverted asymptotically, provided that a sublinear amount of coherent superposition over energy levels is available, a situation analogous to the sublinear amount of classical communication required for entanglement dilution. PMID- 24483736 TI - Stringent restriction from the growth of large-scale structure on apparent acceleration in inhomogeneous cosmological models. AB - Probes of cosmic expansion constitute the main basis for arguments to support or refute a possible apparent acceleration due to different expansion rates in the Universe as described by inhomogeneous cosmological models. We present in this Letter a separate argument based on results from an analysis of the growth rate of large-scale structure in the Universe as modeled by the inhomogeneous cosmological models of Szekeres. We use the models with no assumptions of spherical or axial symmetries. We find that while the Szekeres models can fit very well the observed expansion history without a Lambda, they fail to produce the observed late-time suppression in the growth unless Lambda is added to the dynamics. A simultaneous fit to the supernova and growth factor data shows that the cold dark matter model with a cosmological constant (LambdaCDM) provides consistency with the data at a confidence level of 99.65%, while the Szekeres model without Lambda achieves only a 60.46% level. When the data sets are considered separately, the Szekeres with no Lambda fits the supernova data as well as the LambdaCDM does, but provides a very poor fit to the growth data with only 31.31% consistency level compared to 99.99% for the LambdaCDM. This absence of late-time growth suppression in inhomogeneous models without a Lambda is consolidated by a physical explanation. PMID- 24483737 TI - New class of N=1 no-scale supergravity models. AB - We introduce a new N=1 no-scale supergravity model with F- and D-term breaking. It contains a single chiral supermultiplet T and a single U(1) vector multiplet U, gauging a nonanomalous axionic shift symmetry. Both supersymmetry and the gauge symmetry are spontaneously broken, with the spin-3/2, spin-1, and spin-1/2 masses sliding along a classical flat direction, with a single real massless scalar in the spectrum. The other degrees of freedom are absorbed by the massive gravitino and vector. We extend our model, under very mild conditions, to general gauge groups and matter content. PMID- 24483735 TI - Silicon detector dark matter results from the final exposure of CDMS II. AB - We report results of a search for weakly interacting massive particles (WIMPS) with the silicon detectors of the CDMS II experiment. This blind analysis of 140.2 kg day of data taken between July 2007 and September 2008 revealed three WIMP-candidate events with a surface-event background estimate of 0.41( 0.08)(+0.20)(stat)(-0.24)(+0.28)(syst). Other known backgrounds from neutrons and 206Pb are limited to <0.13 and <0.08 events at the 90% confidence level, respectively. The exposure of this analysis is equivalent to 23.4 kg day for a recoil energy range of 7-100 keV for a WIMP of mass 10 GeV/c2. The probability that the known backgrounds would produce three or more events in the signal region is 5.4%. A profile likelihood ratio test of the three events that includes the measured recoil energies gives a 0.19% probability for the known-background only hypothesis when tested against the alternative WIMP+background hypothesis. The highest likelihood occurs for a WIMP mass of 8.6 GeV/c2 and WIMP-nucleon cross section of 1.9*10(-41) cm2. PMID- 24483739 TI - Isospin splittings in the light-baryon octet from lattice QCD and QED. AB - While electromagnetic and up-down quark mass difference effects on octet baryon masses are very small, they have important consequences. The stability of the hydrogen atom against beta decay is a prominent example. Here, we include these effects by adding them to valence quarks in a lattice QCD calculation based on Nf=2+1 simulations with five lattice spacings down to 0.054 fm, lattice sizes up to 6 fm, and average up-down quark masses all the way down to their physical value. This allows us to gain control over all systematic errors, except for the one associated with neglecting electromagnetism in the sea. We compute the octet baryon isomultiplet mass splittings, as well as the individual contributions from electromagnetism and the up-down quark mass difference. Our results for the total splittings are in good agreement with experiment. PMID- 24483740 TI - Collective modes in light nuclei from first principles. AB - Results for ab initio no-core shell model calculations in a symmetry-adapted SU(3)-based coupling scheme demonstrate that collective modes in light nuclei emerge from first principles. The low-lying states of 6Li, 8Be, and 6He are shown to exhibit orderly patterns that favor spatial configurations with strong quadrupole deformation and complementary low intrinsic spin values, a picture that is consistent with the nuclear symplectic model. The results also suggest a pragmatic path forward to accommodate deformation-driven collective features in ab initio analyses when they dominate the nuclear landscape. PMID- 24483742 TI - Chemical state of complex uranium oxides. AB - We report here the first direct observation of U(V) in uranium binary oxides and analyze the gradual conversion of the U oxidation state in the mixed uranium systems. Our finding clarifies previous contradicting results and provides important input for the geological disposal of spent fuel, recycling applications, and chemistry of uranium species. PMID- 24483741 TI - Accurate atom counting in mesoscopic ensembles. AB - Many cold atom experiments rely on precise atom number detection, especially in the context of quantum-enhanced metrology where effects at the single particle level are important. Here, we investigate the limits of atom number counting via resonant fluorescence detection for mesoscopic samples of trapped atoms. We characterize the precision of these fluorescence measurements beginning from the single-atom level up to more than one thousand. By investigating the primary noise sources, we obtain single-atom resolution for atom numbers as high as 1200. This capability is an essential prerequisite for future experiments with highly entangled states of mesoscopic atomic ensembles. PMID- 24483743 TI - Threshold alignment reversal and circularly polarized fluorescence in rotationally resolved H2. AB - Using H2 and D2 targets, we have measured the polarization of Fulcher-band fluorescence resulting from spin-polarized electron-impact excitation of vibrationally and rotationally resolved d 3Pi(u) -> a 3Sigma(g)+ transitions for incident electron energies from 14.3 to 28.5 eV. Near threshold, the linear polarization P1 descends from positive values through zero to negative values, indicating a dynamic production of M(N)=0 states. The circular polarization P3 is measured to be nonzero, indicating the orientation of rotationally resolved molecular states. For Q-branch transitions, P3 is consistent with theory based on Hund's case (b) coupling. The R-branch P3 values do not agree with theory equally well, indicating the effect of Sigma-symmetry perturbation of the parent d 3Pi(u)+ state. PMID- 24483744 TI - Efficient biologically inspired photocell enhanced by delocalized quantum states. AB - Artificially implementing the biological light reactions responsible for the remarkably efficient photon-to-charge conversion in photosynthetic complexes represents a new direction for the future development of photovoltaic devices. Here, we develop such a paradigm and present a model photocell based on the nanoscale architecture and molecular elements of photosynthetic reaction centers. Quantum interference of photon absorption and emission induced by the dipole dipole interaction between molecular excited states guarantees an enhanced light to-current conversion and power generation for a wide range of electronic, thermal, and optical parameters for optimized dipolar geometries. This result opens a promising new route for designing artificial light-harvesting devices inspired by biological photosynthesis and quantum technologies. PMID- 24483745 TI - High-Q hybrid plasmon-photon modes in a bottle resonator realized with a silver coated glass fiber with a varying diameter. AB - We experimentally demonstrate that hybrid plasmon-photon modes exist in a silver coated glass bottle resonator. The bottle resonator is realized in a glass fiber with a smoothly varying diameter, which is subsequently coated with a rhodamine 800-dye doped acryl-glass layer and a 30 nm thick silver layer. We show by means of photoluminescence experiments supported by electromagnetic simulations that the rhodamine 800 photoluminescence excites hybrid plasmon-photon modes in such a bottle resonator, which provide a plasmon-type field enhancement at the outer silver surface and exhibit quality factors as high as 1000. PMID- 24483746 TI - Electric field in a plasma channel in a high-pressure nanosecond discharge in hydrogen: a coherent anti-stokes Raman scattering study. AB - Experimental results of a study of the electric field in a plasma channel produced during nanosecond discharge at a H2 gas pressure of (2-3)*10(5) Pa by the coherent anti-Stokes scattering method are reported. The discharge was ignited by applying a voltage pulse with an amplitude of ~100 kV and a duration of ~5 ns to a blade cathode placed at a distance of 10 and 20 mm from the anode. It was shown that this type of gas discharge is characterized by the presence of an electric field in the plasma channel with root-mean-square intensities of up to 30 kV/cm. Using polarization measurements, it was found that the direction of the electric field is along the cathode-anode axis. PMID- 24483747 TI - Probing the complex ion structure in liquid carbon at 100 GPa. AB - We present the first direct experimental test of the complex ion structure in liquid carbon at pressures around 100 GPa, using spectrally resolved x-ray scattering from shock-compressed graphite samples. Our results confirm the structure predicted by ab initio quantum simulations and demonstrate the importance of chemical bonds at extreme conditions similar to those found in the interiors of giant planets. The evidence presented here thus provides a firmer ground for modeling the evolution and current structure of carbon-bearing icy giants like Neptune, Uranus, and a number of extrasolar planets. PMID- 24483748 TI - Broad and intense radiation accompanying multiple volume reflection of ultrarelativistic electrons in a bent crystal. AB - The radiation emitted by 120 GeV/c electrons traversing a single bent crystal under multiple volume reflection orientation is investigated. Multiple volume reflection in one crystal occurs as a charged particle impacts on a bent crystal at several axial channeling angles with respect to a crystal axis. The resulting energy-loss spectrum of electrons was very intense over the full energy range up to the nominal energy of the beam. As compared to the radiation emission by an individual volume reflection, the energy-loss spectrum is more intense and peaks at an energy 3 times greater. Experimental results are compared to a theoretical approach based on the direct integration of the quasiclassical Baier and Katkov formula. In this way, it is possible to determine the mean number of photons emitted by each electron and, thus, to extract the single-photon spectrum, which is broad and intense. The soft part of the radiation spectrum is due to the contribution of coherent interaction between electrons and several reflecting planes intersecting the same crystal axis, whereas the hard part is mainly connected to coherent bremsstrahlung induced by correlated scattering of electrons by atomic strings (string of strings scattering and radiation). The radiation generation by multiple volume reflection takes place over a broad angular range of the incident beam with respect to coherent bremsstrahlung and channeling radiation in straight crystals. Therefore, this type of radiation can be exploited for applications, such as beam dump and collimation devices for future linear colliders. PMID- 24483749 TI - Interfacial structure and chemistry of GaN on Ge(111). AB - The interface of GaN grown on Ge(111) by plasma-assisted molecular beam epitaxy is resolved by aberration corrected scanning transmission electron microscopy. A novel interfacial structure with a 5?4 closely spaced atomic bilayer is observed that explains why the interface is flat, crystalline, and free of GeN(x). Density functional theory based total energy calculations show that the interface bilayer contains Ge and Ga atoms, with no N atoms. The 5?4 bilayer at the interface has a lower energy than a direct stacking of GaN on Ge(111) and enables the 5?4 lattice matching growth of GaN. PMID- 24483750 TI - Decay of fermionic quasiparticles in one-dimensional quantum liquids. AB - The low-energy properties of one-dimensional quantum liquids are commonly described in terms of the Tomonaga-Luttinger liquid theory, in which the elementary excitations are free bosons. To this approximation, the theory can be alternatively recast in terms of free fermions. In both approaches, small perturbations give rise to finite lifetimes of excitations. We evaluate the decay rate of fermionic excitations and show that it scales as the eighth power of energy, in contrast to the much faster decay of bosonic excitations. Our results can be tested experimentally by measuring the broadening of power-law features in the density structure factor or spectral functions. PMID- 24483751 TI - Theory of the quantum breathing mode in harmonic traps and its use as a diagnostic tool. AB - An analytical expression for the quantum breathing frequency omegab of harmonically trapped quantum particles with inverse power-law repulsion is derived. It is verified by ab initio numerical calculations for electrons confined in a lateral (2D) quantum dot. We show how this relation can be used to express the ground state properties of harmonically trapped quantum particles as functions of the breathing frequency by presenting analytical results for the kinetic, trap, and repulsive energy and for the linear entropy. Measurement of omegab together with these analytical relations represents a tool to characterize the state of harmonically trapped interacting particles--from the Fermi gas to the Wigner crystal regime. PMID- 24483752 TI - Unexpected z-direction Ising antiferromagnetic order in a frustrated spin-1/2 J1 J2 XY model on the honeycomb lattice. AB - Using the density matrix renormalization group on wide cylinders, we study the phase diagram of the spin-1/2 XY model on the honeycomb lattice, with first neighbor (J1=1) and frustrating second-neighbor (J2>0) interactions. For the intermediate frustration regime 0.22?J2?0.36, we find a surprising antiferromagnetic Ising phase, with ordered moments pointing along the z axis, despite the absence of any S(z)S(z) interactions in the Hamiltonian. Surrounding this phase as a function of J2 are antiferromagnetic phases with the moments pointing in the x-y plane for small J2 and a close competition between an x-y plane magnetic collinear phase and a dimer phase for large values of J2. We do not find any spin-liquid phases in this model. PMID- 24483753 TI - Magnon breakdown in a two dimensional triangular lattice Heisenberg antiferromagnet of multiferroic LuMnO3. AB - The breakdown of magnons, the quasiparticles of magnetic systems, has rarely been seen. By using an inelastic neutron scattering technique, we report the observation of spontaneous magnon decay in multiferroic LuMnO3, a simple two dimensional Heisenberg triangular lattice antiferromagnet, with large spin S=2. The origin of this rare phenomenon lies in the nonvanishing cubic interaction between magnons in the spin Hamiltonian arising from the noncollinear 120 degrees spin structure. We observed all three key features of the nonlinear effects as theoretically predicted: a rotonlike minimum, a flat mode, and a linewidth broadening, in our inelastic neutron scattering measurements of single crystal LuMnO3. Our results show that quasiparticles in a system hitherto thought of as "classical" can indeed break down. PMID- 24483754 TI - Double exchange via t(2g) orbitals and the Jahn-Teller effect in ferromagnetic La0.7Sr0.3CoO3 probed by epitaxial strain. AB - The magnetic exchange in hole-doped ferromagnetic cobaltates is investigated by studying the magnetic and electronic properties of La0.7Sr0.3CoO3 films as a function of epitaxial strain. We found a strong-coupling double exchange mechanism between Co3+ (4t(2g) 2e(g)) and Co4+ (3t(2g) 2e(g)) high-spin states mediated by t(2g) electrons--in contrast to the moderate coupling provided by the e(g) exchange in manganites. The strong sensitivity of the Curie temperature TC to the bulk compression can be explained by the small bandwidth of the t(2g)-derived states. A strain-induced Jahn-Teller effect is likewise observed. The experimental results clarify the magnetic exchange mechanism in the cobaltates. PMID- 24483755 TI - Anisotropy-driven spin relaxation in germanium. AB - A unique spin depolarization mechanism, induced by the presence of g-factor anisotropy and intervalley scattering, is revealed by spin-transport measurements on long-distance germanium devices in a magnetic field longitudinal to the initial spin orientation. The confluence of electron-phonon scattering (leading to Elliott-Yafet spin flips) and this previously unobserved physics enables the extraction of spin lifetime solely from spin-valve measurements, without spin precession, and in a regime of substantial electric-field-generated carrier heating. We find spin lifetimes in Ge up to several hundreds of nanoseconds at low temperature, far beyond any other available experimental results. PMID- 24483756 TI - Theory of wave propagation in magnetized near-zero-epsilon metamaterials: evidence for one-way photonic states and magnetically switched transparency and opacity. AB - We study propagation of transverse-magnetic electromagnetic waves in the bulk and at the surface of a magnetized epsilon-near-zero (ENZ) medium in a Voigt configuration. We reveal that in a certain range of material parameters novel regimes of wave propagation emerge; we show that the transparency of the medium can be altered with the magnetization leading either to magnetically induced Hall opacity or Hall transparency of the ENZ. In our theoretical study, we demonstrate that surface waves at the interface between either a transparent or an opaque Hall medium and a homogeneous medium may, under certain conditions, be predominantly one way. Moreover, we predict that one-way photonic surface states may exist at the interface of an opaque Hall ENZ and a regular metal, giving rise to the possibility for backscattering immune wave propagation and isolation. PMID- 24483757 TI - Comparison of nifedipine and progesterone for maintenance tocolysis after arrested preterm labour. AB - The aim of our study was to compare the efficacy and safety of nifedipine and progesterone for maintenance tocolysis after arrested preterm labour, in prolonging pregnancy and preventing recurrence of preterm labour. This study was a randomised comparative study conducted on 110 pregnant women with arrested preterm labour, randomised to receive either nifedipine 20 mg Q 8-hourly or progesterone 400 mg daily for maintenance tocolysis. Other than demographic parameters, obstetric parameters like previous history of abortions or preterm deliveries, gestational age, cervical dilatation and effacement, ultrasound measured cervical length at admission, were noted. Outcome measures studied were mean prolongation of pregnancy, mode of delivery, neonatal outcome and side effects of both the drugs. We found that there was no significant difference in the demographic profile, parity, number of abortions, previous preterm deliveries, gestational age, cervical dilatation and effacement at admission between the two groups. A total of 10% of the patients in the nifedipine group and 61% of the patients in the progesterone group delivered at term (p value 0.000). The mean prolongation of pregnancy in the nifedipine group was 16.63 days and 40.14 days in the progesterone group which was significant (p = 0.000). Neonates in the progesterone group had better birth weight, better Apgar scores at 1 and 5 min, lesser need for ventilation and significantly lesser composite morbidity. Nifedipine was associated significantly with side-effects. We conclude that when compared with nifedipine, progesterone significantly prolongs pregnancy in women with arrested preterm labour with better neonatal outcomes and fewer side-effects. PMID- 24483758 TI - Severe early onset hydramnios in a singleton pregnancy due to antenatal Bartter syndrome. PMID- 24483760 TI - Lymphocele: prevalence and management in gynecological malignancies. AB - A lymphocele is a cystic mass that may occur in the retroperitoneum following a systematic pelvic and/or para-aortic lymphadenectomy. Lymphoceles may be the cause of severe morbidity, or rarely mortality. Symptomatic lymphoceles manifest with pain, compression of adjacent structures, lymphoedema, deep vein thrombosis or inflammation. The morbidity associated with a symptomatic lymphocele may reduce the quality of life of a patient, as well as delay subsequent cancer treatment. The number and positivity of removed lymph nodes, surgical approach, type of tumor, radiotherapy and BMI rate are among the most discussed risk factors of lymphocele formation. The incidence of postoperative lymphocele is reported in the broad range of 1-58%; 5-18% of those who are symptomatic. Only symptomatic lymphoceles should be treated. Mini-invasive methods involving catheter drainage and sclerotization tend to prevail. Surgery either via laparoscopy or laparotomy remains an option in recurring, poorly accessible or inflammatory lymphoceles. PMID- 24483761 TI - Occupational hazards in medical education. PMID- 24483759 TI - Autonomous portable solar ultraviolet spectroradiometer (APSUS) - a new CCD spectrometer system for localized, real-time solar ultraviolet (280-400 nm) radiation measurement. AB - Terrestrial solar ultraviolet (UV) radiation has significant implications for human health and increasing levels are a key concern regarding the impact of climate change. Monitoring solar UV radiation at the earth's surface is therefore of increasing importance. A new prototype portable CCD (charge-coupled device) spectrometer-based system has been developed that monitors UV radiation (280-400 nm) levels at the earth's surface. It has the ability to deliver this information to the public in real time. Since the instrument can operate autonomously, it is called the Autonomous Portable Solar Ultraviolet Spectroradiometer (APSUS). This instrument incorporates an Ocean Optics QE65000 spectrometer which is contained within a robust environmental housing. The APSUS system can gather reliable solar UV spectral data from approximately April to October inclusive (depending on ambient temperature) in the UK. In this study the new APSUS unit and APSUS system are presented. Example solar UV spectra and diurnal UV Index values as measured by the APSUS system in London and Weymouth in the UK in summer 2012 are shown. PMID- 24483762 TI - Continuing Education-the Old Shibboleths Still Abound. PMID- 24483763 TI - Anatomy. AB - At Southampton, gross anatomy is allocated 165 hours as part of a 254-hour course which includes microscopic and developmental anatomy and geriatrics. The 130 students work from prosected material, supplemented by written material and illustrations. They do not dissect for themselves. Since the introduction of the new course there has been no indication of any deterioration in the examination performance of students. PMID- 24483764 TI - Prepare graduate students for teaching responsibilities. AB - During graduate training, students often undertake some teaching responsibilities, which provides useful experience for a future career in academia. However, they receive little guidance to prepare them for this role. This article describes some of the attempts that have been made to overcome this deficiency, with emphasis on the specially developed teaching course offered to graduate students at the University of Kentucky; this provides instruction on planning, implementing and evaluating instruction, and classroom training in instructional skills. Evaluation suggests that the programme is relevant and effective, and provides a useful model for other medical schools. PMID- 24483765 TI - An evaluation of medical students' practical experience upon qualification. AB - The acquisition of many practical skills-including competence to take initial responsibility for managing serious or life-threatening situations-is rarely assessed in formal medical qualifying examinations in the UK. This paper reports an investigation of two groups of graduands' experiences of practical procedures and acute conditions. Similar patterns of experience were reported by students undertaking their clinical work in different medical schools, including the lack of opportunity to practise certain procedures. A large proportion felt incompetent to manage emergencies. The study demonstrates how a simple self reporting technique can provide useful data and identify problems of continuity between two stages of medical education-the undergraduate period and the pre registration year. PMID- 24483766 TI - Evaluation and validation of a course in practice management for senior residents. AB - Many doctors reach the end of their specialist training to find that they need to cope well and efficiently with the business aspects of setting up and managing a medical practice-yet this has frequently been ignored in their education. This article describes the design and evaluation of a course in practice management offered to doctors near the end of their specialist training. PMID- 24483767 TI - The society of teachers of family medicine. PMID- 24483768 TI - Clinical Supervisor's Report. AB - In this series, we print evaluation instruments, questionnaires, rating scales and similar resource materials useful to teachers, evaluators and planners. You may wish to adapt such instruments for your own purposes. The feature in this issue has been prepared by Nicholas A. Saunders, Charles E. Engel, and Grahame I. Feletti from whom further information is available. PMID- 24483772 TI - A strong metal-to-metal interaction in an edge-sharing bioctahedral compound that leads to a very short tungsten-tungsten double bond. AB - An ionic edge-sharing bioctahedral (ESBO) species has been prepared having a tetramethylated bicyclic guanidinate with two fused six-membered rings characterized by a fairly flat N-C(N)-N skeleton and abbreviated as TMhpp. The anion has two W(IV) atoms bridged by two oxo groups; the metal atoms are also spanned by two bridging guanidinate ligands, and each has two monodentate chlorine atoms. The complex formulated as (H2TMhpp)2[W(MU-O)(MU-TMhpp)Cl2]2 has the shortest W-W distance (2.3318(8) A) of any species with a sigma(2)pi(2) electronic configuration. The anion and cations are connected by hydrogen bonds. To unambiguously ascertain the existence of the double-bonded W2(MU-O)2 entity, density functional theory calculations and natural bond orbital analyses were done on an analogous but hypothetical species with a W2(MU-OH)2 core having trivalent tungsten atoms and a possible sigma(2)pi(2)delta(2) electronic configuration. The calculations decidedly support the presence of tungsten-oxo instead of tungsten-hydroxo groups and thus the existence of the double-bonded W2(MU-O)2 core. The strong bonding interaction between metal atoms is a clear indication that under certain circumstances the two octahedra in ESBO species do not behave as the sum of two mononuclear compounds. PMID- 24483771 TI - Meningeal spread of blastic plasmacytoid dendritic cell neoplasm. PMID- 24483774 TI - Follicular variant of papillary thyroid carcinoma: distinct biologic behavior based on ultrasonographic features. PMID- 24483773 TI - PKCepsilon contributes to chronic ethanol-induced steatosis in mice but not inflammation and necrosis. AB - BACKGROUND: Protein kinase C epsilon (PKCepsilon) has been shown to play a role in experimental steatosis by acute alcohol. The "two-hit" hypothesis implies that preventing steatosis should blunt more advanced liver damage (e.g., inflammation and necrosis). However, the role of PKCepsilon in these pathologies is not yet known. The goal of this current work was to address this question in a model of chronic alcohol exposure using antisense oligonucleotides (ASO) against PKCepsilon. METHODS: Accordingly, PKCepsilon ASO- and saline-treated mice were fed high-fat control or ethanol (EtOH)-containing enteral diets for 4 weeks. RESULTS: Chronic EtOH exposure significantly elevated hepatic lipid pools as well as activated PKCepsilon. The PKCepsilon ASO partially blunted the increases in hepatic lipids caused by EtOH. Administration of PKCepsilon ASO also completely prevented the increase in the expression of fatty acid synthase, and tumor necrosis factor alpha caused by EtOH. Despite these protective effects, the PKCepsilon ASO was unable to prevent the increases in inflammation and necrosis caused by chronic EtOH. These latter results correlated with an inability of the PKCepsilon ASO to blunt the up-regulation of plasminogen activator inhibitor-1 (PAI-1) and the accumulation of fibrin. Importantly, PAI-1 has been previously shown to more robustly mediate inflammation and necrosis (vs. steatosis) after chronic EtOH exposure. CONCLUSIONS: This study identifies a novel potential mechanism where EtOH, independent of steatosis, can contribute to liver damage. These results also suggest that PAI-1 and fibrin accumulation may be at the center of this PKCepsilon-independent pathway. PMID- 24483738 TI - Measurement of D0-D0 mixing parameters and search for CP violation using D0 -> K+ pi- decays. AB - Measurements of charm mixing parameters from the decay-time-dependent ratio of D0 -> K+ pi- to D0 -> K- pi+ rates and the charge-conjugate ratio are reported. The analysis uses data, corresponding to 3 fb(-1) of integrated luminosity, from proton-proton collisions at 7 and 8 TeV center-of-mass energies recorded by the LHCb experiment. In the limit of charge-parity (CP ) symmetry, the mixing parameters are determined to be x'2=(5.5+/-4.9)*10(-5), y'=(4.8+/-1.0)*10(-3), and RD=(3.568+/-0.066)*10(-3). Allowing for CP violation, the measurement is performed separately for D0 and D0 mesons yielding AD=(-0.7+/-1.9)%, for the direct CP-violating asymmetry, and 0.75<|q/p|<1.24 at the 68.3% confidence level, for the parameter describing CP violation in mixing. This is the most precise determination of these parameters from a single experiment and shows no evidence for CP violation. PMID- 24483775 TI - Specific hydrolysis and accumulation of antiproliferative lignans in the fruit of Leuzea carthamoides (Willd.) DC. AB - Dibenzylbutyrolactone-type lignan glycosides (tracheloside and carthamoside), their aglycones (trachelogenin and carthamogenin) and feruloyl-serotonin isomers were determined in the fruits of Leuzea carthamoides by using LC-UV, LC-MS/MS and GC-MS techniques. The composition of the embryo and wall parts of the fruits was analysed before and after their hydrolysis. As a result of these studies, fruit part-specific accumulation of lignan glycosides and feruloyl-serotonins were confirmed, demonstrating that the embryo contains a high amount of lignan glycosides (tracheloside 32.9 mg/g, carthamoside 45.3 mg/g), while the wall part of the fruit accumulates feruloyl-serotonins (63.0 mg/g). Enzymatic hydrolysis of the embryo resulted in the quantitative transformation of lignan glycosides into their corresponding aglycones, allowing selective isolation of trachelogenin and carthamogenin. These aglycones were subjected to an antiproliferative study against the SW480 colon adenocarcinoma cell line. In this test, moderate activity of carthamogenin and a significant effect of trachelogenin were demonstrated in a concentration range of 22-185 MUM. PMID- 24483776 TI - Self-reported recall and daily diary-recorded measures of weight monitoring adherence: associations with heart failure-related hospitalization. AB - BACKGROUND: Weight monitoring is an important element of HF self-care, yet the most clinically meaningful way to evaluate weight monitoring adherence is uncertain. We conducted this study to evaluate the association of (1) self reported recall and (2) daily diary-recorded weight monitoring adherence with heart failure-related (HF-related) hospitalization. METHODS: We conducted a prospective cohort study among 216 patients within a randomized trial of HF self care training. All patients had an initial self-care training session followed by 15 calls (median) to reinforce educational material; patients were also given digital scales, instructed to weigh daily, record weights in a diary, and mail diaries back monthly. Weight monitoring adherence was assessed with a self reported recall question administered at 12 months and dichotomized into at least daily versus less frequent weighing. Diary-recorded weight monitoring was evaluated over 12 months and dichotomized into >=80% and <80% adherence. HF related hospitalizations were ascertained through patient report and confirmed through record review. RESULTS: Over 12 months in 216 patients, we identified 50 HF-related hospitalizations. Patients self-reporting daily or more frequent weight monitoring had an incidence rate ratio of 1.34 (95% CI 0.24-7.32) for HF related hospitalizations compared to those reporting less frequent weight monitoring. Patients who completed >=80% of weight diaries had an IRR of 0.37 (95% CI 0.18-0.75) for HF-related hospitalizations compared to patients who completed <80% of weight diaries. CONCLUSIONS: Self-reported recall of weight monitoring adherence was not associated with fewer HF hospitalizations. In contrast, diary-recorded adherence >=80% of days was associated with fewer HF related hospitalizations. Incorporating diary-based measures of weight monitoring adherence into HF self-care training programs may help to identify patients at risk for HF-related hospitalizations. PMID- 24483777 TI - PLGA micro and nanoparticles in delivery of peptides and proteins; problems and approaches. AB - During the last decades, many of the poorly controlled diseases were treated using newly developed peptide and proteins. Although the majority of such therapeutic moieties have undesirable pharmacokinetic properties and there is still need for administration in relatively short intervals, new formulation strategies allow us to select appropriate carriers in the development of these compounds. Polyesters such as polylactide-co-glycolide were used to stabilize and control the release rate of peptide and proteins. Besides many appropriate characteristics, these polymers, however, have some limitations and drawbacks which limit their extensive use in formulation. In this review, the factors affecting the loading, release behavior, particle size distribution and burst effect were evaluated and appropriate suggestions to optimize the formulation with these polymers were proposed. PMID- 24483779 TI - Lower the electron affinity by halogenation: an unusual strategy to design superalkali cations. AB - A new kind of cationic superatom compounds (M-F)(+) (M = OLi4, NLi5, CLi6, BLi7, and Al14) with low vertical electron affinities (VEA) has been designed based on the distinctive electronic structure of superalkaline-earth atom. The stability of the studied superatom architectures is guaranteed by strong M-fluorine interactions, considerable HOMO-LUMO gaps, as well as large dissociation energies. What is extraordinary is that fluorination plays an important role in lowering the VEA value of M(+) and enables the resulting (M-F)(+) fluorides to join the superalkali family. However, the same strategy does not work as well for the alkaline-earth atoms whose valence electrons are more tightly bound. The comparative study on (OLi4-X)(+) (X = F, Cl, Br) reveals that fluorination is more effective than chlorination and bromination to reduce the VEA value of the OLi4(+) cation. As for the (Al14-X)(+) species, there is no obvious dependence of VEA values on halogen atomic number. PMID- 24483778 TI - Sexual assault risks among gay and bisexual men. AB - The goal of this study was to examine lifetime patterns of sexual assault and associated risks among a purposive sample of gay and bisexual men (N = 183; 18 to 35 years old, M = 24.3). Cross-sectional data were collected via written, self administered questionnaires and face-to-face, event-based qualitative interviews. Alcohol severity scores indicated high rates of hazardous drinking (53.0%) and possible dependence (14.2%) among participants. One-half of men (50.8%) reported childhood sexual abuse (CSA), and 67.2% reported adult sexual assault (ASA). Average age at most recent ASA was 21 years. Most perpetrators (83.9%) of recent ASA incidents were male; 67.0% of participants reported consuming alcohol and/or drugs prior to the most recent incident. Regression findings indicated more severe CSA experiences and past alcohol-related problems predicted recent severe ASA. Although we found similarities between gay and bisexual men in lifetime sexual assault history, we found some distinct differences in ASA risk factors. Bisexual men reported higher alcohol severity scores, more female ASA perpetrators, higher internalized homophobia scores, and fewer male sexual partners than gay men. Findings suggest the need for interventions that reduce ASA risk among sexual minority men-and the potential benefits of focusing on alcohol consumption in risk reduction efforts. PMID- 24483781 TI - Plant cyclopropylsterol-cycloisomerase: key amino acids affecting activity and substrate specificity. AB - The enzyme CPI (cyclopropylsterol-cycloisomerase) from the plant sterol pathway catalyses the cleavage of the 9beta,19-cyclopropane ring of the 4alpha-methyl cyclopropylsterol cycloeucalenol to produce the Delta8-sterol obtusifoliol. Randomly mutated plasmids carrying the Arabidopsis thaliana cpi gene were screened for inactive CPI mutant enzymes on the basis of their ability to genetically complement a Saccharomyces cerevisiae erg7 (defective in oxidosqualene cyclase) ergosterol auxotroph grown in the presence of exogenous cycloeucalenol, and led to the identification of four catalytically important residues. Site-directed mutagenesis experiments confirmed the role of the identified residues, and demonstrated the importance of selected acidic residues and a conserved G108NYFWTHYFF117 motif. The mutated isomerases were assayed both in vivo by quantification of cycloeucalenol conversion into ergosterol in erg7 cells, and in vitro by examination of activities of recombinant AtCPI (A. thaliana CPI) mutants. These studies show that Gly28, Glu29, Gly108 and Asp260 are crucial for CPI activity and that an hydroxy function at residue 113 is needed for maximal substrate affinity and CPI activity. CPI is inactive on upstream 4alpha,beta-dimethyl-cyclopropylsterol precursors of phytosterols. The single mutation W112L generates a CPI with an extended substrate specificity, that is able to convert 4alpha,beta-dimethyl-cyclopropylsterols into the corresponding Delta8 products. These findings provide insights into the molecular basis of CPI activity and substrate specificity. PMID- 24483780 TI - ESCMID and ECMM joint clinical guidelines for the diagnosis and management of systemic phaeohyphomycosis: diseases caused by black fungi. AB - The aetiological agents of many invasive fungal infections are saprobes and opportunistic pathogens. Some of these fungi are darkly pigmented due to melanin production and traditionally have been named 'dematiaceous'. The melanized fungi cause a wide array of clinical syndromes ranging from superficial to deep-seated infections. Diagnosis relies on histopathological examination of clinical specimens and on examination of cultures. Sequencing is recommended for accurate species identification, especially for unusual or newly described pathogens. In cases of mycetoma and chromoblastomycosis, pathognomonic histological findings are useful and the Fontana-Masson stain, specific for melanin, usually confirms the diagnosis. There are no standardized therapies but voriconazole, posaconazole and itraconazole demonstrate the most consistent in vitro activity against this group of fungi. Oral itraconazole has been considered the drug of choice, given the extensive clinical experience with this drug. However, voriconazole may presumably be superior for central nervous system infections because of its ability to achieve good levels in the cerebrospinal fluid. Posaconazole is a well tolerated alternative drug, backed by less clinical experience but with excellent salvage treatment results after failure of other antifungals. Amphotericin B has been useful as alternative therapy in some cases. Combination antifungal therapy is recommended for cerebral abscesses when surgery is not possible and for disseminated infections in immunocompromised patients. PMID- 24483782 TI - New Insights into the Connection Between Histone Deacetylases, Cell Metabolism, and Cancer. AB - SIGNIFICANCE: Histone deacetylases (HDACs) activity and cell metabolism are considered important targets for cancer therapy, as both are deregulated and associated with the onset and maintenance of tumors. RECENT ADVANCES: Besides the classical function of HDACs as HDAC enzymes controlling the transcription, it is becoming increasingly evident that these proteins are involved in the regulation of several other cellular processes by their ability to deacetylate hundreds of proteins with different functions in both the cytoplasm and the nucleus. Importantly, recent high-throughput studies have identified as important target proteins several enzymes involved in different metabolic pathways. Conversely, it has been also shown that metabolic intermediates may control HDACs activity. Consequently, the acetylation/deacetylation of metabolic enzymes and the ability of metabolic intermediates to modulate HDACs may represent a cross-talk connecting cell metabolism, transcription, and other HDACs-controlled processes in physiological and pathological conditions. CRITICAL ISSUES: Since metabolic alterations and HDACs deregulation are important cancer hallmarks, disclosing connections among them may improve our understanding on cancer mechanisms and reveal novel therapeutic protocols against this disease. FUTURE DIRECTIONS: High throughput metabolic studies performed by using more sophisticated technologies applied to the available models of conditional deletion of HDACs in cell lines or in mice will fill the gap in the current understanding and open directions for future research. PMID- 24483783 TI - Behavioral health parity and the Affordable Care Act. AB - Prior to the passage of the Mental Health Parity and Addiction Equity Act (MHPAEA) and the Patient Protection and Affordable Care Act (ACA), about 49 million Americans were uninsured. Among those with employer-sponsored health insurance, 2% had coverage that entirely excluded mental health benefits and 7% had coverage that entirely excluded substance use treatment benefits. The rates of noncoverage for mental and substance use disorder care in the individual health insurance markets are considerably higher. Private health insurance generally limits the extent of these benefits. The combination of MHPEA and ACA extended overall health insurance coverage to more people and expanded the scope of coverage to include mental health and substance abuse benefits. PMID- 24483786 TI - Driving at the quantum speed limit: optimal control of a two-level system. AB - A remarkably simple result is derived for the minimal time Tmin required to drive a general initial state to a final target state by a Landau-Zener-type Hamiltonian or, equivalently, by time-dependent laser driving. The associated protocol is also derived. A surprise arises for some states when the interaction strength is bounded by a constant c. Then, for large c, the optimal driving is of type bang-off-bang and for increasing c one recovers the unconstrained result. However, for smaller c the optimal driving can suddenly switch to bang-bang type. We discuss the notion of quantum speed limit time. PMID- 24483785 TI - Breakdown of quasilocality in long-range quantum lattice models. AB - We study the nonequilibrium dynamics of correlations in quantum lattice models in the presence of long-range interactions decaying asymptotically as a power law. For exponents larger than the lattice dimensionality, a Lieb-Robinson-type bound effectively restricts the spreading of correlations to a causal region, but allows supersonic propagation. We show that this decay is not only sufficient but also necessary. Using tools of quantum metrology, for any exponents smaller than the lattice dimension, we construct Hamiltonians giving rise to quantum channels with capacities not restricted to a causal region. An analytical analysis of long range Ising models illustrates the disappearance of the causal region and the creation of correlations becoming distance independent. Numerical results obtained using matrix product state methods for the XXZ spin chain reveal the presence of a sound cone for large exponents and supersonic propagation for small ones. In all models we analyzed, the fast spreading of correlations follows a power law, but not the exponential increase of the long-range Lieb-Robinson bound. PMID- 24483784 TI - Legionella pneumophila subversion of host vesicular transport by SidC effector proteins. AB - Tethering proteins play a key role in vesicular transport, ensuring that cargo arrives at a specific destination. The bacterial effector protein SidC and its paralog SdcA have been described as tethering factors encoded by the intracellular pathogen Legionella pneumophila. Here, we demonstrate that SidC proteins are important for early events unique to maturation of vacuoles containing Legionella and discover monoubiquitination of Rab1 as a new SidC dependent activity. The crystal structure of the SidC N-terminus revealed a novel fold that is important for function and could be involved in Legionella adaptations to evolutionarily divergent host cells it encounters in natural environments. PMID- 24483787 TI - Geometry-induced superdiffusion in driven crowded systems. AB - Recent molecular dynamics simulations of glass-forming liquids revealed superdiffusive fluctuations associated with the position of a tracer particle (TP) driven by an external force. Such an anomalous response, whose mechanism remains elusive, has been observed up to now only in systems close to their glass transition, suggesting that this could be one of its hallmarks. Here, we show that the presence of superdiffusion is in actual fact much more general, provided that the system is crowded and geometrically confined. We present and solve analytically a minimal model consisting of a driven TP in a dense, crowded medium in which the motion of particles is mediated by the diffusion of packing defects, called vacancies. For such nonglass-forming systems, our analysis predicts a long lived superdiffusion which ultimately crosses over to giant diffusive behavior. We find that this trait is present in confined geometries, for example long capillaries and stripes, and emerges as a universal response of crowded environments to an external force. These findings are confirmed by numerical simulations of systems as varied as lattice gases, dense liquids, and granular fluids. PMID- 24483788 TI - Large scale anomalies in the microwave background: causation and correlation. AB - Most treatments of large scale anomalies in the microwave sky are a posteriori, with unquantified look-elsewhere effects. We contrast these with physical models of specific inhomogeneities in the early Universe which can generate these apparent anomalies. Physical models predict correlations between candidate anomalies and the corresponding signals in polarization and large scale structure, reducing the impact of cosmic variance. We compute the apparent spatial curvature associated with large-scale inhomogeneities and show that it is typically small, allowing for a self-consistent analysis. As an illustrative example we show that a single large plane wave inhomogeneity can contribute to low-l mode alignment and odd-even asymmetry in the power spectra and the best-fit model accounts for a significant part of the claimed odd-even asymmetry. We argue that this approach can be generalized to provide a more quantitative assessment of potential large scale anomalies in the Universe. PMID- 24483789 TI - Action and entanglement in gravity and field theory. AB - In nongravitational quantum field theory, the entanglement entropy across a surface depends on the short-distance regularization. Quantum gravity should not require such regularization, and it has been conjectured that the entanglement entropy there is always given by the black hole entropy formula evaluated on the entangling surface. We show that these statements have precise classical counterparts at the level of the action. Specifically, we point out that the action can have a nonadditive imaginary part. In gravity, the latter is fixed by the black hole entropy formula, while in nongravitating theories it is arbitrary. From these classical facts, the entanglement entropy conjecture follows by heuristically applying the relation between actions and wave functions. PMID- 24483790 TI - Anomaly nucleation constrains SU(2) gauge theories. AB - We argue for the existence of additional constraints on SU(2) gauge theories in four dimensions when realized in ultraviolet completions admitting an analog of D brane nucleation. In type II string compactifications these constraints are necessary and sufficient for the absence of cubic non-Abelian anomalies in certain nucleated SU(N>2) theories. It is argued that they appear quite broadly in the string landscape. Implications for particle physics are discussed; most realizations of the standard model in this context are inconsistent, unless extra electroweak fermions are added. PMID- 24483792 TI - Split isobaric analog state in 55Ni: case of strong isospin mixing. AB - Study of beta+ decay of the exotic Tz=-3/2 nucleus 55Cu, via delayed gamma rays, has revealed a strongly isospin mixed doublet (4599-4579 keV) in 55Ni, which represents the fragmented and previously unknown isobaric analog of the ground state of 55Cu. The observed small log ft values to both states in the doublet confirm the superallowed Fermi beta decay. The near degeneracy of a pair of 3/2- levels in 55Ni results in the strong isospin mixing. The isospin mixing matrix element between the T=3/2 and T=1/2 levels is inferred from the experiment to be 9(1) keV, which agrees well with the matrix element of the charge symmetry breaking shell model Hamiltonian of Ormand and Brown. A precise value of the half life of 55Cu at 57(3) ms was also obtained. PMID- 24483794 TI - Role of rotational wave packets in strong field experiments. AB - Complex revival features of rotational wave packets are obtained from the interplay of a molecular rotational distribution and a measured physical observable. The analysis of the measured temporal behavior can be used to retrieve either one or both quantities. We show here the first observation of high order fractional revival (up to 1/12 in CO2) using time-of-flight measurements of ion yields leading to the information required for full reconstruction of the rotational wave packet. We further show via an analysis of higher order fractional revivals in high harmonic generation that new information on the participating ionic channels can be clearly identified, showing the general implication of our results. PMID- 24483793 TI - Unified approach to probing Coulomb effects in tunnel ionization for any ellipticity of laser light. AB - We present experimental data that show significant deviations from theoretical predictions for the location of the center of the electron momenta distribution at low values of ellipticity epsilon of laser light. We show that these deviations are caused by significant Coulomb focusing along the minor axis of polarization, something that is normally neglected in the analysis of electron dynamics, even in cases where the Coulomb correction is otherwise taken into account. By investigating ellipticity-resolved electron momenta distributions in the plane of polarization, we show that Coulomb focusing predominates at lower values of ellipticity of laser light, while Coulomb asymmetry becomes important at higher values, showing that these two complementary phenomena can be used to probe long-range Coulomb interaction at all polarizations of laser light. Our results suggest that both the breakdown of Coulomb focusing and the onset of Coulomb asymmetry are linked to the disappearance of Rydberg states with increasing ellipticity. PMID- 24483795 TI - Nonlinearly induced PT transition in photonic systems. AB - We study the effect of nonlinearity on systems with periodic parity-time (PT) symmetry, and show that nonlinearity can transform the system from broken to full PT symmetry and vice versa. Furthermore, we show that even when the nonlinearity is insufficient to induce a transition from broken to full PT symmetry, still, the wave functions neither decay nor diverge, despite the fact that the system has a complex eigenvalue spectrum. Rather, the amplitudes of the wavefunctions oscillate around the transition point. Our results apply to a wide variety of systems in optics and beyond. PMID- 24483791 TI - Double diffractive cross-section measurement in the forward region at the LHC. AB - The first double diffractive cross-section measurement in the very forward region has been carried out by the TOTEM experiment at the LHC with a center-of-mass energy of sqrt[s]=7 TeV. By utilizing the very forward TOTEM tracking detectors T1 and T2, which extend up to |eta|=6.5, a clean sample of double diffractive pp events was extracted. From these events, we determined the cross section sigmaDD=(116+/-25) MUb for events where both diffractive systems have 4.7<|eta|min<6.5. PMID- 24483796 TI - Phase winding a two-component Bose-Einstein condensate in an elongated trap: experimental observation of moving magnetic orders and dark-bright solitons. AB - We investigate the phase winding dynamics of a harmonically trapped two-component BEC subject to inhomogeneous Rabi oscillations between two pseudospin components. While the single-particle dynamics can be explained by mapping the system to a two-component Bose-Hubbard model, nonlinearities due to the interatomic repulsion lead to new effects observed in the experiments: In the presence of a linear magnetic field gradient, a qualitatively stable moving magnetic order that is similar to antiferromagnetic order is observed after critical winding is achieved. We also demonstrate how the phase winding can be used to generate copious dark-bright solitons in a two-component BEC, opening the door for new experimental studies of these nonlinear features. PMID- 24483797 TI - Tuning Mie scattering resonances in soft materials with magnetic fields. AB - An original approach is proposed here to reversibly tune Mie scattering resonances occurring in random media by means of external low induction magnetic fields. This approach is valid for both electromagnetic and acoustic waves. The experimental demonstration is supported by ultrasound experiments performed on emulsions made of fluorinated ferrofluid spherical droplets dispersed in a Bingham fluid. We show that the electromagnet-induced change of droplet shape into prolate spheroids, with a moderate aspect ratio of 2.5, drastically affects the effective properties of the disordered medium. Its effective acoustic attenuation coefficient is shown to vary by a factor of 5, by controlling both the flux density and orientation of the applied magnetic field. PMID- 24483798 TI - Anomalous k?(-8/3) spectrum in electron magnetohydrodynamic turbulence. AB - Electron magnetohydrodynamic turbulence is investigated under the presence of a relatively strong external magnetic field b0e? and through three-dimensional direct numerical simulations. Our study reveals the emergence of a k?(-8/3) scaling for the magnetic energy spectrum at scales k?(D)<=k?<=k?(D), where k?(D) and k?(D) are, respectively, the typical largest dissipative scales along and transverse to the b0 direction. Unlike standard magnetohydrodynamic, this turbulence regime is characterized by filaments of electric currents parallel to b0. The anomalous scaling is in agreement with a heuristic model in which the transfer in the parallel direction is negligible. Implications for solar wind turbulence are discussed. PMID- 24483799 TI - Two color free-electron laser and frequency beating. AB - We review the theory of two color high gain free-electron laser emission, derive the integral equation characterizing the evolution of the optical intensities, and provide a description of the relevant dynamics. The characteristic feature of this regime is the existence of a mutual bunching, whose origin and role are discussed. PMID- 24483800 TI - Convective velocity reversal caused by turbulence transition in tokamak plasma. AB - Particle transport has been studied in the Tore Supra tokamak by using modulated ion cyclotron resonance heating to generate perturbations of density and temperature. For the first time, a reversal of the particle convective velocity and a strong increase in the turbulent particle flux have been clearly observed. When the mixed critical gradient zetac=R/L(T)+4(R/L(n))=22 is exceeded, the particle flux increases sharply and the convective velocity reverses from inward to outward. These observations are in agreement with quasilinear, gyrokinetic calculations. The critical gradient corresponds to a transition from an instability driven by the ion temperature gradient to the onset of another instability caused by trapped electrons. PMID- 24483801 TI - Pair correlations in the two-dimensional Fermi gas. AB - We consider the two-dimensional Fermi gas at finite temperature with attractive short-range interactions. Using the virial expansion, which provides a controlled approach at high temperatures, we determine the spectral function and contact for the normal state. Our calculated spectra are in qualitative agreement with recent photoemission measurements [M. Feld et al., Nature (London) 480, 75 (2011).], thus suggesting that the observed pairing gap is a feature of the high temperature gas rather than being evidence of a pseudogap regime just above the superfluid transition temperature. We further argue that the strong pair correlations result from the fact that the crossover to bosonic dimers occurs at weaker interactions than previously assumed. PMID- 24483802 TI - Dissipative dynamics of a driven quantum spin coupled to a bath of ultracold fermions. AB - We explore the dynamics and the steady state of a driven quantum spin coupled to a bath of fermions, which can be realized with a strongly imbalanced mixture of ultracold atoms using currently available experimental tools. Radio-frequency driving can be used to induce tunneling between the spin states. The Rabi oscillations are modified due to the coupling of the quantum spin to the environment, which causes frequency renormalization and damping. The spin-bath coupling can be widely tuned by adjusting the scattering length through a Feshbach resonance. When the scattering potential creates a bound state, by tuning the driving frequency it is possible to populate either the ground state, in which the bound state is filled, or a metastable state in which the bound state is empty. In the latter case, we predict an emergent inversion of the steady-state magnetization. Our work shows that different regimes of dissipative dynamics can be explored with a quantum spin coupled to a bath of ultracold fermions. PMID- 24483803 TI - Strain-induced formation of fourfold symmetric SiGe quantum dot molecules. AB - The strain field distribution at the surface of a multilayer structure with disklike SiGe nanomounds formed by heteroepitaxy is exploited to arrange the symmetric quantum dot molecules typically consisting of four elongated quantum dots ordered along the [010] and [100] directions. The morphological transition from fourfold quantum dot molecules to continuous fortresslike quantum rings with an increasing amount of deposited Ge is revealed. We examine key mechanisms underlying the formation of lateral quantum dot molecules by using scanning tunneling microscopy and numerical calculations of the strain energy distribution on the top of disklike SiGe nanomounds. Experimental data are well described by a simple thermodynamic model based on the accurate evaluation of the strain dependent part of the surface chemical potential. The spatial arrangement of quantum dots inside molecules is attributed to the effect of elastic property anisotropy. PMID- 24483804 TI - Competing thermodynamic and dynamic factors select molecular assemblies on a gold surface. AB - Controlling the self-assembly of surface-adsorbed molecules into nanostructures requires understanding physical mechanisms that act across multiple length and time scales. By combining scanning tunneling microscopy with hierarchical ab initio and statistical mechanical modeling of 1,4-substituted benzenediamine (BDA) molecules adsorbed on a gold (111) surface, we demonstrate that apparently simple nanostructures are selected by a subtle competition of thermodynamics and dynamics. Of the collection of possible BDA nanostructures mechanically stabilized by hydrogen bonding, the interplay of intermolecular forces, surface modulation, and assembly dynamics select at low temperature a particular subset: low free energy oriented linear chains of monomers and high free energy branched chains. PMID- 24483805 TI - Three-dimensional imaging of individual dopant atoms in SrTiO3. AB - We report on three-dimensional (3D) imaging of individual Gd dopant atoms in a thin (~2.3 nm) foil of SrTiO3, using quantitative scanning transmission electron microscopy. Uncertainties in the depth positions of individual dopants are less than 1 unit cell. The overall dopant concentration measured from atom column intensities agrees quantitatively with electrical measurements. The method is applied to analyze the 3D arrangement of dopants within small clusters containing 4-5 Gd atoms. PMID- 24483806 TI - Ion depletion near a solution surface: is image-charge repulsion sufficient? AB - Grazing-incidence Rutherford backscattering and angle-resolved x-ray photoelectron spectrometry are used to determine the ion-concentration profiles near the surface of a solution consisting of a salt (TEABr) in a weakly polar organic liquid (polyethylene glycol) with atomic-layer depth resolution. The predictions of a model, in which ions in solution are repelled from the surface due to a screened Coulomb interaction with their image charge, are in good agreement with measured ion profiles. This contrasts with the behavior of salts in aqueous and highly polar organic solutions. PMID- 24483807 TI - Hysteretic melting transition of a soliton lattice in a commensurate charge modulation. AB - We report on the observation of the hysteretic transition of a commensurate charge modulation in IrTe2 from transport and scanning tunneling microscopy (STM) studies. Below the transition (TC~275 K on cooling), a q=1/5 charge modulation was observed, which is consistent with previous studies. Additional modulations [qn=(3n+2)(-1)] appear below a second transition at TS~180 K on cooling. The coexistence of various modulations persists up to TC on warming. The atomic structures of charge modulations and the temperature-dependent STM studies suggest that 1/5 modulation is a periodic soliton lattice that partially melts below TS on cooling. Our results provide compelling evidence that the ground state of IrTe2 is a commensurate 1/6 charge modulation, which originates from the periodic dimerization of Te atoms visualized by atomically resolved STM images. PMID- 24483808 TI - Electron interactions and gap opening in graphene superlattices. AB - We develop a theory of interaction effects in graphene superlattices, where tunable superlattice periodicity can be used as a knob to control the gap at the Dirac point. Applied to graphene on hexa-boron-nitride (G/h-BN), our theory predicts substantial many-body enhancement of this gap. Tunable by the moire superlattice periodicity, a few orders of magnitude enhancement is reachable under optimal conditions. The Dirac point gap enhancement can be much larger than that of the minigaps opened by Bragg scattering at principal superlattice harmonics. This naturally explains the conundrum of large Dirac point gaps recently observed in G/h-BN heterostructures and their tunability by the G/h-BN twist angle. PMID- 24483809 TI - Effect of Coulomb interaction on microwave-induced magnetoconductivity oscillations of surface electrons on liquid helium. AB - The experimental observation of the strong Coulombic effect on magneto oscillations of the photoconductivity of surface electrons in liquid helium is reported. The observed broadening of the oscillations and shifts in positions of conductivity extrema with increasing electron density are in good agreement with the linear transport theory, which takes into account an internal electric field of fluctuational origin. These results provide important evidence for identification of the mechanism of the oscillations and zero-resistance states developed in their minima. PMID- 24483810 TI - Observation of incipient charge nematicity in Ba(Fe(1-x)Co(x))2As2. AB - Using electronic Raman spectroscopy, we report direct measurements of charge nematic fluctuations in the tetragonal phase of strain-free Ba(Fe(1-x)Co(x))2As2 single crystals. The strong enhancement of the Raman response at low temperatures unveils an underlying charge nematic state that extends to superconducting compositions and which has hitherto remained unnoticed. Comparison between the extracted charge nematic susceptibility and the elastic modulus allows us to disentangle the charge contribution to the nematic instability, and to show that charge nematic fluctuations are weakly coupled to the lattice. PMID- 24483811 TI - A-type antiferro-orbital ordering with I4(1)/a symmetry and geometrical frustration in the spinel vanadate MgV2O4. AB - We conduct a detailed structural analysis of the S=1 pyrochlore antiferromagnet MgV2O4, which exhibits an antiferromagnetic ordering marginally at TN=40 K, triggered by a structural transition from cubic to tetragonal symmetry at TS=62 K, using high resolution synchrotron x-ray diffraction and convergent beam electron diffraction. We reveal that the tetragonal phase below TS has the symmetry of I4(1)/a and that the distortion pattern of VO6 octahedra is consistent with A-type antiferro-orbital ordering with alternating stacking of layers with yz/xy orbital chains and zx/xy orbital chains along the tetragonal c axis. This implies that an anisotropic coupling of V moments produced by the orbital ordering below TS primarily brings about the antiferromagnetic ordering. PMID- 24483812 TI - Unraveling orbital hybridization of triplet emitters at the metal-organic interface. AB - We have investigated the structural and electronic properties of phosphorescent planar platinum(II) complexes at the interface of Au(111) with submolecular resolution using combined scanning tunneling microscopy and spectroscopy as well as density functional theory. Our analysis shows that molecule-substrate coupling and lateral intermolecular interactions are weak. While the ligand orbitals remain essentially unchanged upon contact with the substrate, we found modified electronic behavior at the Pt atom due to local hybridization and charge transfer to the substrate. Thus, this novel class of phosphorescent molecules exhibits well-defined and tunable interaction with its local environment. PMID- 24483813 TI - Terahertz electron-hole recollisions in GaAs/AlGaAs quantum wells: robustness to scattering by optical phonons and thermal fluctuations. AB - Electron-hole recollisions are induced by resonantly injecting excitons with a near-IR laser at frequency fNIR into quantum wells driven by a 10 kV/cm field oscillating at fTHz=0.57 THz. At T=12 K, up to 18 sidebands are observed at frequencies fsideband=fNIR+2nfTHz, with -8<=2n<=28. Electrons and holes recollide with total kinetic energies up to 57 meV, well above the ELO=36 meV threshold for longitudinal optical (LO) phonon emission. Sidebands with order up to 2n=22 persist up to room temperature. A simple model shows that LO phonon scattering suppresses but does not eliminate sidebands associated with kinetic energies above ELO. PMID- 24483814 TI - Directing the self-assembly of block copolymers into a metastable complex network phase via a deep and rapid quench. AB - The free-energy landscape of self-assembling block copolymer systems is characterized by a multitude of metastable minima. Using particle-based simulations of a soft, coarse-grained model, we explore opportunities to reproducibly direct the spontaneous ordering of these self-assembling systems into a metastable complex network morphology--specifically, Schoen's I-WP periodic minimal surface--starting from a highly unstable state that is generated by a rapid expansion. This process-directed self-assembly provides an alternative to fine-tuning molecular architecture or blending for fabricating complex network structures. Comparing our particle-based simulation results to recently developed free-energy techniques, we critically assess their ability to predict spontaneous formation and highlight the importance of nonequilibrium molecular conformations in the starting state and the local conservation of density. PMID- 24483815 TI - Nonequilibrium collective dynamics in photoexcited lipid multilayers by time resolved diffuse x-ray scattering. AB - We study the nonequilibrium shape fluctuations in fluorescence labeled phospholipid multibilayers composed of the model lipid DOPC and the well-known lipid dye Texas red, driven out of equilibrium by short laser pulses. The temporal evolution of the lipid bilayer undulations after excitation was recorded by time resolved x-ray diffraction. Already at moderate peak intensities (Pp<=10(5) W/cm2), pulsed laser illumination leads to significant changes of the undulation modes in a well-defined lateral wavelength band. The observed phenomena evolve on nano- to microsecond time scales after optical excitation, and can be described in terms of a modulation instability in the lipid multilamellar stack. PMID- 24483816 TI - Microscopic origin of internal stresses in jammed soft particle suspensions. AB - The long time persistence of mechanical stresses is a generic property of glassy materials. Here we identify the microscopic mechanisms that control internal stresses in highly concentrated suspensions of soft particles brought to rest from steady flow. The persistence of the asymmetric angular distortions which characterize the pair distribution function during flow is at the origin of the internal stresses. Their long time evolution is driven by in-cage rearrangements of the elastic contacts between particles. The trapped macroscopic stress is related to the solvent viscosity, particle elasticity and volume fraction through a universal scaling derived from simulations and experiments. PMID- 24483817 TI - Elasticity-based mechanism for the collective motion of self-propelled particles with springlike interactions: a model system for natural and artificial swarms. AB - We introduce an elasticity-based mechanism that drives active particles to self organize by cascading self-propulsion energy towards lower-energy modes. We illustrate it on a simple model of self-propelled agents linked by linear springs that reach a collectively rotating or translating state without requiring aligning interactions. We develop an active elastic sheet theory, complementary to the prevailing active fluid theories, and find analytical stability conditions for the ordered state. Given its ubiquity, this mechanism could play a relevant role in various natural and artificial swarms. PMID- 24483818 TI - Drought response of mesophyll conductance in forest understory species--impacts on water-use efficiency and interactions with leaf water movement. AB - Regulation of stomatal (gs ) and mesophyll conductance (gm ) is an efficient means for optimizing the relationship between water loss and carbon uptake in plants. We assessed water-use efficiency (WUE)-based drought adaptation strategies with respect to mesophyll conductance of different functional plant groups of the forest understory. Moreover we aimed at assessing the mechanisms of and interactions between water and CO2 conductance in the mesophyll. The facts that an increase in WUE was observed only in the two species that increased gm in response to moderate drought, and that over all five species examined, changes in mesophyll conductance were significantly correlated with the drought-induced change in WUE, proves the importance of gm in optimizing resource use under water restriction. There was no clear correlation of mesophyll CO2 conductance and the tortuosity of water movement in the leaf across the five species in the control and drought treatments. This points either to different main pathways for CO2 and water in the mesophyll either to different regulation of a common pathway. PMID- 24483820 TI - Too many applicants for postgraduate training. PMID- 24483819 TI - Long-term survival rate of teeth receiving multidisciplinary endodontic, periodontal and prosthodontic treatments. AB - Deciding whether to replace or preserve a compromised tooth, even with emerging trends in implant dentistry, is still a common dilemma for practitioners. This study sought to determine the 3- to more than 10-year survival rate of teeth that had undergone endodontic, periodontal and prosthodontic treatments. A total of 245 teeth in 87 patients were clinically and radiographically evaluated. All the teeth had received crown lengthening surgery by a single periodontist. Root canal therapy and prosthodontic procedures were rendered either by specialists or by experienced general dentists. Numbers of lost teeth were recorded and the criteria for hopeless teeth were defined. Survival rate was determined using the Kaplan-Meier estimator. Clinical indices including pocket depth (PD), bleeding index (BI), C/R ratio, position of the restoration margin relative to the gingival margin (RM-GM) and the presence of intra-canal post were compared between different survival groups (<3, 3-5, 5-10 and >10 years) using one-way analysis of variance (anova). Potential predictors of failure were determined using the Cox regression model. The mean +/- s.d. of 3-, 5-, 10- and 13-year survival rates was 98 +/- 1%, 96 +/- 1.6%, 83.1 +/- 4.5% and 51.9 +/- 14.5%, respectively. The mean PD (P < 0.013), as well as C/R ratio in the mesial (P = 0.003) and distal (P = 0.007) surfaces, was significantly higher in the >10-year survived teeth. Bleeding index and RM-GM showed no significant differences between the groups. C/R ratio and RM-GM position appeared to be the major determinants of tooth loss. The long-term survival rate of multidisciplinary treated teeth was 83-98% in this specific sample. PMID- 24483821 TI - How to... Organize Rotational Training Schemes in Medicine. AB - In this article, the author describes the trials, tribulations and rewards of organizing and running rotational training schemes based on his experience at Newcastle, England, where he was until recently Professor of Medicine. Dr Kerr offers advice on how to encourage consultant colleagues to participate in senior house officer/registrar rotations for general professional training, and discusses the advantages and disadvantages of 2-year and 3-year schemes. Important questions such as who should appoint SHOs, when should posts be advertised, how to organize study leave and how to fill gaps left by early departure from 3-year schemes are also discussed. Senior registrar rotations are even more difficult to organize. Dr Kerr describes their advantages and related problems-especially that of rotation to district general hospitals, with hints on how to bend the rules to help trainees. PMID- 24483822 TI - The way we teach... haematology to undergraduates. AB - In this article the author describes the integrated undergraduate haematology course at McMaster University. A novel feature is the 'Triple-Jump Exercise' three-step form of evaluation, which offers an opportunity to assess problem solving, history taking, and data acquisition and formulation in a reasonably standardized way. An account of how haematology is taught at postgraduate level will be published in the next issue of Medical Teacher. PMID- 24483823 TI - Medical students' perceptions of teachers' attitudes towards psychology and sociology. AB - The social and behavioural sciences are increasingly being recognized by educational planners as having a place of considerable importance in undergraduate medical education, yet discussions with teachers of the subjects suggest that many do not feel an integral part of the school as a whole. This study reports upon the views of nearly 4,000 medical students of their teachers' attitudes towards the topics. It suggests that medical schools vary considerably in the way medical teachers perceive these subjects as having a rightful place in the course. In one new 'integrated' medical school, however, the social and behavioural sciences appear to have gained acceptance by teachers throughout the five-year course. The implications for teachers of psychology and sociology are considered. PMID- 24483824 TI - Helping Those Who Fail the MRCGP Examination. PMID- 24483826 TI - Course evaluation questionnaire. AB - In this series we print evaluation instruments, questionnaires, rating scales and similar resource material useful to teachers, evaluators and planners. You may wish to use or adapt such instruments for your own purposes. The feature in this issue is taken from WHO Off-set publication No. 68 Self-assessment for teachers of health workers: how to be a better teacher by Arie Rotem and Fred R. Abbatt. PMID- 24483825 TI - Practical tips. PMID- 24483828 TI - Jottings. PMID- 24483830 TI - Programme evaluation. PMID- 24483831 TI - Endometrial carcinoma development in an endometrial polyp with early metaplastic bone formation in a young female patient. PMID- 24483833 TI - Predictors for thyroid carcinoma in Israel: a national cohort of 1,624,310 adolescents followed for up to 40 years. AB - INTRODUCTION: Data on adolescent precursors of thyroid cancer in adulthood are scant. METHODS: In order to evaluate potential risk factors for thyroid cancer, we linked two national data sources: the military recruitment health examinations and the Israel National Cancer Register. The study population (1,624,310 participants) included 1,145,865 Jewish males aged 16-19 years when examined between 1967 and 2005, and 478,445 Jewish females aged 16-19 years when examined between 1989 and 2005. The cancer follow-up extended up to 2006. Multivariable Cox proportional hazards modeling was used. RESULTS: During 24,389,502 person years of follow-up, 760 incidence cases of thyroid cancer were identified. The mean age at diagnosis was 25.2+/-4.2 years for women and 37.2+/-10.0 years for men. Women had a substantially higher incidence (birth cohort-adjusted hazard ratio (HR)=5.70 [95% CI 4.45-7.31]; p<0.001). Height predicted incidence in both sexes, with birth cohort-adjusted HRs of 1.03 (p<0.001) in males and 1.04 (p<0.001) in females, per 1 cm increment in height. In males, but not in females, there was a graded association between education, as measured by years of schooling, and incidence of thyroid cancer. Body mass index was not associated with incidence. In a multivariable analysis of 617,613 males and 469,185 females examined from 1989 onwards, which included sex, birth year, height, and education, the excess risk in females persisted strongly (HR=5.67 [CI 4.30 7.13]), as did the association with height. CONCLUSIONS: Female sex, measured height in adolescence, and later birth cohorts were independent predictors of thyroid cancer in young and middle-aged adults in Israel. Further study is needed to unravel the mechanisms whereby height is associated with thyroid cancer. PMID- 24483832 TI - Multifunctional nanoparticles as nanocarrier for vincristine sulfate delivery to overcome tumor multidrug resistance. AB - Multifunctional nanoparticles, Fol/R7 NPs, based on pH-sensitive PLGA-PEG-folate and cell penetrating peptide R7-conjugated PLGA-PEG, were constructed for targeting vincristine sulfate (VCR) to tumor and overcoming multidrug resistance (MDR). In this study, the pH-triggered VCR release was 65.6% during 8 h in pH 5.0, but only 35.8% in pH 7.4, demonstrating that a large amount of VCR released rapidly at weak acidic environment. The VCR-Fol/R7 NPs could significantly enhance cellular uptake and cytotoxicity in MCF-7 and MCF-7/Adr cells when compared to the nanoparticles solely modified by folate or R7. With folate receptor-mediated endocytosis and strong intracellular penetration, VCR-Fol/R7 NPs increased drug accumulation in resistant tumor cells by escaping P glycoprotein mediated drug efflux. In vivo imaging suggested the active targeting attributed to pH sensitivity and folate receptor-mediated effect could improve tumor targeting efficacy. Indeed, VCR-Fol/R7 NPs exhibited the stongest antitumor efficacy in vivo. Therefore, Fol/R7 NPs are an effective nanocarrier for delivering antitumor drug and overcoming multidrug resistance. PMID- 24483834 TI - Cu-free 1,3-dipolar cycloaddition click reactions to form isoxazole linkers in chelating ligands for fac-[M(I)(CO)3]+ centers (M = Re, 99mTc). AB - Isoxazole ring formation was examined as a potential Cu-free alternative click reaction to Cu(I)-catalyzed alkyne/azide cycloaddition. The isoxazole reaction was explored at macroscopic and radiotracer concentrations with the fac [M(I)(CO)3](+) (M = Re, (99m)Tc) core for use as a noncoordinating linker strategy between covalently linked molecules. Two click assembly methods (click, then chelate and chelate, then click) were examined to determine the feasibility of isoxazole ring formation with either alkyne-functionalized tridentate chelates or their respective fac-[M(I)(CO)3](+) complexes with a model nitrile oxide generator. Macroscale experiments, alkyne-functionalized chelates, or Re complexes indicate facile formation of the isoxazole ring. (99m)Tc experiments demonstrate efficient radiolabeling with click, then chelate; however, the chelate, then click approach led to faster product formation, but lower yields compared to the Re analogues. PMID- 24483835 TI - Spontaneous septostomy in monochorionic diamniotic twins: difficult diagnosis, difficult management. PMID- 24483837 TI - Rate constant calculations of H-atom abstraction reactions from ethers by HO2 radicals. AB - In this work, we detail hydrogen atom abstraction reactions from six ethers by the hydroperoxyl radical, including dimethyl ether, ethyl methyl ether, propyl methyl ether, isopropyl methyl ether, butyl methyl ether, and isobutyl methyl ether, in order to test the effect of the functional group on the rate constant calculations. The Moller-Plesset (MP2) method with the 6-311G(d,p) basis set has been employed in the geometry optimizations and frequency calculations of all of the species involved in the above reaction systems. The connections between each transition state and the corresponding local minima have been determined by intrinsic reaction coordinate calculations. Energies are reported at the CCSD(T)/cc-pVTZ level of theory and include the zero-point energy corrections. As a benchmark in the electronic energy calculations, the CCSD(T)/CBS extrapolation was used for the reactions of dimethyl ether + HO2 radicals. A systematic calculation of the high-pressure limit rate constants has been performed using conventional transition-state theory, including asymmetric Eckart tunneling corrections, in the temperature range of 500-2000 K. The one dimensional hindrance potentials obtained at MP2/6-311G(d,p) for the reactants and transition states have been used to describe the low frequency torsional modes. Herein, we report the calculated individual, average, and total rate constants. A branching ratio analysis for every reaction site has also been performed. PMID- 24483836 TI - Pacing at rates slower than the lower rate limit: function or malfunction? PMID- 24483838 TI - Progressive jugular vein thrombosis in cutaneous extramedullary plasmacytoma. PMID- 24483840 TI - Reduction of physical activity in daily life and its determinants in smokers without airflow obstruction. AB - BACKGROUND AND OBJECTIVE: In smokers without airflow obstruction, detailed, objective and controlled quantification of the level of physical inactivity in daily life has never been performed. This study aimed to objectively assess the level of physical activity in daily life in adult smokers without airflow obstruction in comparison with matched non-smokers, and to investigate the determinants for daily physical activity in smokers. METHODS: Sixty smokers (aged 50 (39-54) years) and 50 non-smokers (aged 48 (40-53) years) matched for gender, age, anthropometric characteristics, educational level, employment status and seasons of the year assessment period were cross-sectionally assessed regarding their daily physical activity with a step counter, besides assessment of lung function, functional exercise capacity, quality of life, anxiety, depression, self-reported comorbidities carbon monoxide level, nicotine dependence and smoking habits. RESULTS: When compared with non-smokers, smokers walked less in daily life (7923 +/- 3558 vs 9553 +/- 3637 steps/day, respectively), presented worse lung function, functional exercise capacity, quality of life, anxiety and depression. Multiple regression analyses identified functional exercise capacity, Borg fatigue, self-reported motivation/physical activity behaviour and cardiac disease as significant determinants of number of steps/day in smokers (partial r(2) = 0.10, 0.12, 0.16 and 0.05; b = 15, -997, 1207 and -2330 steps/day, respectively; overall fit of the model R(2) = 0.38; P < 0.001). CONCLUSIONS: Adult smokers without airflow obstruction presented reduced level of daily physical activity. Functional exercise capacity, extended fatigue sensation, aspects of motivation/physical activity behaviour and self-reported cardiac disease are significant determinants of physical activity in daily life in smokers. PMID- 24483839 TI - Lactococcus garvieae endocarditis presenting with subdural haematoma. AB - BACKGROUND: Lactococcus garvieae is a rare cause of infective endocarditis (IE) in humans and the bacterium can easily be misidentified. Intracranial haemorrhage often occurs in conjunction with IE, but subdural haemorrhage (SDH) is very rarely encountered. CASE PRESENTATION: The patient was an 81-year-old male with a history of cardiovascular disease and a prosthetic biologic aortic valve. He presented with fatigue and an acute onset of headache. Computed tomography (CT) revealed a left-sided fronto-temporal subdural haematoma. Low-grade fever was noted and blood cultures yielded growth of L. garvieae. Transesophageal echocardiography (TEE) revealed small vegetations on the native mitral valve and on the prosthetic aortic valve. Treatment with penicillin and tobramycin was initiated and the recovery was slow but uneventful. CONCLUSION: This is the first report of a case where SDH was the sole presenting neurological sign of IE. The case demonstrates that IE should be considered in patients with SDH where a history of trauma is absent, especially if the patient has fever or predisposing conditions such as a prosthetic heart valve. PMID- 24483841 TI - Serum angiogenin level in sickle cell disease and beta thalassemia patients. AB - INTRODUCTION: Angiogenesis has been investigated in different kinds of anemia. However, its role as a marker of angiogenesis has not been investigated in thalassemia or sickle cell disease (SCD). OBJECTIVES: We aimed to investigate serum angiogenin level in children and adolescents with beta thalassemia or SCD and its relation to possible risk factors of angiogenesis. MATERIALS AND METHODS: This study included; 32 beta-thalassemia major (beta-TM) patients aged 14.2 +/- 3.8 years, 20 beta-thalassemia intermedia (beta-TI) patients aged 14.3 +/- 4.8 years, 20 SCD patients aged 14.1 +/- 2.4 years; 8 with (HbSS) and 12 with sickle thalassemia (HbS/beta-thalassemia) and 35 age and sex-matched controls. Data collected regarding; age, sex, disease duration, blood transfusion frequency, transfusion index, chelation type and duration, CBC, Hb electrophoresis, serum ferritin and serum angiogenin level (by ELISA). RESULTS: Angiogenin level was significantly higher in patients with SCD [250 (100-300) pg/mL] compared to beta TM [180 (140-230) pg/mL] and controls [89 (80-103) pg/mL] (P < .001) especially those with HbSS (P = .06). There was a significant negative correlation between serum angiogenin and age of patients, age of onset and duration of chelation in beta-TM (P < .01, P < .001, P = .003) and beta-TI (P = .009, P = .03, P < .001) and with serum ferritin in beta-TI group (r = -0.573, P = .008). In SCD, angiogenin level was negatively correlated with both frequency of blood transfusion (r = -0.731, P < .001) and duration of hydroxyurea therapy (P = .017). CONCLUSIONS: High angiogenin level detected among patients with SCD may be negatively influenced by regular blood transfusion and hydroxyurea therapy, while; early onset of chelation therapy may decrease angiogenin level in beta-TM. PMID- 24483842 TI - Why does the Iranian national program of screening newborns for G6PD enzyme deficiency miss a large number of affected infants? AB - PURPOSE: G6PD enzyme deficiency is one of the most prevalent genetic disorders worldwide and it has high incidence rate in Northern provinces of Iran. It was observed that national neonatal screening for G6PD enzyme deficiency fails to detect all affected infants. In order to clarify the cause, this study has been done in Thalassemia Research Center, Sari, Iran. MATERIALS AND METHODS: This was a diagnostic study. The newborns with parents of Mazandarani origin were enrolled. Cord blood from the placental side was collected and used for decolorization test, quantitative enzyme assay (QEA) and DNA study. A heel-prick sample collected on day 3-5 after birth was used for fluorescent spot test (FST). In male cases, QEA was considered as the gold standard. For females, DNA study was considered as the gold standard. Based on QEA test results, neonates with <20% and 20-60% of mean normal enzyme activity were considered as total deficient and partial deficient, respectively. RESULTS: A total of 365 neonates (52.3% females and 47.7% males) were studied. According to FST, 13 male newborns had G6PD deficiency. No deficient female was detected. Decolorization test diagnosed 18 male and one female as G6PD deficient newborns. QEA diagnosed 19 males and 28 females with G6PD enzyme deficiency (26 partial, 2 total deficient cases). DNA analysis detected 14 males as hemizygote and 34 females as heterozygote. CONCLUSION: FST does not have the required sensitivity for newborn screening and QEA is recommended as the preferred method. PMID- 24483844 TI - Concomitant inactivation of foxo3a and fancc or fancd2 reveals a two-tier protection from oxidative stress-induced hydrocephalus. AB - AIMS: This study seeks at investigating the cause of hydrocephalus, and at identifying therapeutic targets for the prevention of hydrocephalus. RESULTS: In this study, we show that inactivation of the Foxo3a gene in two mouse models of Fanconi anemia (FA) leads to the development of hydrocephalus in late embryonic stage and after birth. More than 50% of Foxo3a(-/-) Fancc(-/-) or Foxo3a(-/-) Fancd2(-/-) mice die during embryonic development or within 6 months of life as a result of hydrocephalus characterized by cranial distortion, dilation of the ventricular system, reduced thickness of the cerebral cortex, and disorganization of the ependymal cilia and subcommissural organ. Combined deficiency of Foxo3a and Fancc or Fancd2 not only impairs the self-renewal capacity but also markedly increases the apoptosis of neural stem and progenitor cells (NSPCs), leading to defective neurogenesis. Increased accumulation of reactive oxygen species (ROS) and subsequently de-regulated mitosis and ultimately apoptosis in the neural stem or progenitor cells is identified as one of the potential mechanisms of congenital obstructive hydrocephalus. INNOVATION: The work unravels a two-tier protective mechanism for preventing oxidative stress-induced hydrocephalus. CONCLUSION: The deletion of Foxo3a in FA mice increased the accumulation of ROS and subsequently de-regulated mitosis and ultimately apoptosis in the NSPCs, leading to hydrocephalus development. PMID- 24483846 TI - Oligomeric cationic polymethacrylates: a comparison of methods for determining molecular weight. AB - This study compares three common laboratory methods, size-exclusion chromatography (SEC), (1)H nuclear magnetic resonance (NMR), and matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF), to determine the molecular weight of oligomeric cationic copolymers. The potential bias for each method was examined across a series of polymers that varied in molecular weight and cationic character (both choice of cation (amine versus guanidine) and relative proportion present). SEC was found to be the least accurate, overestimating Mn by an average of 140%, owing to the lack of appropriate cationic standards available, and the complexity involved in estimating the hydrodynamic volume of copolymers. MALDI-TOF approximated Mn well for the highly monodisperse (D < 1.1), low molecular weight (degree of polymerization (DP) <50) species but appeared unsuitable for the largest polymers in the series due to the mass bias associated with the technique. (1)H NMR was found to most accurately estimate Mn in this study, differing to theoretical values by only 5.2%. (1)H NMR end-group analysis is therefore an inexpensive and facile, primary quantitative method to estimate the molecular weight of oliogomeric cationic polymethacrylates if suitably distinct end-groups signals are present in the spectrum. PMID- 24483845 TI - The discovery and development of cyclooxygenase-2 inhibitors as potential anticancer therapies. AB - INTRODUCTION: In the past, clinical studies had demonstrated that aspirin and NSAIDs reduce the risk of colorectal cancer. After the discovery of selective prostaglandin-endoperoxide synthase 2 (PTGS2) inhibitors, the further beneficial effects of celecoxib and some other related structures (coxibs) have been demonstrated in both in vivo and in vitro studies. AREAS COVERED: The authors illustrate the role of prostaglandins following the overexpression of PTGS2 (COX 2) in signaling pathways. The authors elucidate the role of coxibs in cell proliferation, apoptosis, angiogenesis and multi-drug resistance and discuss the molecular mechanisms involved. The authors also present the strong evidence related to the usefulness of coxibs in several cancer cell lines. EXPERT OPINION: There have been a number of PTGS2 (COX-2) selective inhibitors suggested as potential anticancer therapies. In recent years, the development of nanotechnology has also had an impact on chemotherapy. Indeed, nanoparticles of cytotoxic drug carriers have demonstrated potential through their accumulation in cancer cells, and targeting these nanoparticles has been under evaluation. This area could be opened up for coxib development as they are potentially important targets in cancer cells. Further research using celecoxib as a co-drug with PTGS2 overexpressed and PTGS2-independent cancer is still needed. PMID- 24483847 TI - Adjuvant chemotherapy after primary treatments for cervical cancer: a critical point of view and review of the literature. AB - Cervical cancer is the second most frequent female malignancy worldwide. Concurrent chemoradiotherapy represents the standard of care for patients with advanced stage cervical cancer, while radical surgery (RS) and radiotherapy is widely used for treating early stage cervical cancer. However, the poor control of micrometastasis, declining operability, the lack of radiotherapy departments and the high incidence of long-term complications due to radiotherapy have brought about the development of different therapeutic approaches such as neoadjuvant chemotherapy followed by RS. Unfortunately, treatment results are still unsatisfactory due to a high recurrence rate and several authors have studied the possibility to add an adjuvant treatment to primary therapy. We reviewed the literature concerning the role of adjuvant chemotherapy in advanced cervical cancer after neoadjuvant chemotherapy followed by RS and after chemoradiotherapy. PMID- 24483848 TI - Iridium-catalyzed, intermolecular hydroamination of unactivated alkenes with indoles. AB - The addition of an N-H bond to an olefin is the most direct route for the synthesis of alkylamines. Currently, intermolecular hydroamination is limited to reactions of a narrow range of reagents containing N-H bonds or activated alkenes, and all the examples of additions to unactivated alkenes require large excesses of alkene. We report intermolecular hydroamination reactions of indoles with unactivated olefins. The reactions occur with as few as 1.5 equiv of olefin to form N-alkylindoles exclusively and in good yield. Characterizations of the catalyst resting state, kinetic data, labeling studies, and computational data imply that the addition occurs by olefin insertion into the Ir-N bond of an N indolyl complex and that this insertion reaction is faster than insertion of olefin into the Ir-C bond of the isomeric C-2-indolyl complex. PMID- 24483849 TI - Periluminal expression of a secreted transforming growth factor-beta type II receptor inhibits in-stent neointima formation following adenovirus-mediated stent-based intracoronary gene transfer. AB - Transforming growth factor-beta1 (TGF-beta1) has been shown unequivocally to enhance neointima formation in carotid and ileo-femoral arteries. In our previous studies, however, TGF-beta1 expression in coronary arteries actually reduced neointima formation without affecting luminal loss postangioplasty, while expression of a TGF-beta1 antagonist (RIIs) in balloon-injured coronary arteries reduced luminal loss without affecting neointima formation. These observed effects may be a consequence of the mode of coronary artery gene transfer employed, but they may also represent differences in the modes of healing of coronary, carotid, and ileo-femoral arteries after endoluminal injury. To help clarify whether a gene therapy strategy to antagonize TGF-beta might have application within the coronary vasculature, we have investigated the effect of high-level periluminal expression of RIIs using stent-based adenovirus-mediated intracoronary gene transfer. Porcine coronary arteries were randomized to receive a custom-made CoverStent preloaded with saline only, or with 1*10(9) infectious units of adenovirus expressing RIIs or beta-galactosidase (lacZ). Vessels were analyzed 28 days poststenting, at which time angiographic in-stent diameter was significantly greater in RIIs-treated arteries, and in-stent luminal loss significantly reduced. Computerized morphometric minimum in-stent lumen area was ~300% greater in RIIs-exposed vessels than in lacZ or saline-only groups. This was because of significantly reduced neointima formation in the RIIs group. RIIs had no demonstrable effect on cellular proliferation or apoptosis, but greater normalized neointimal/medial collagen content was observed in RIIs-exposed arteries. These data highlight the qualitatively similar effect of TGF-beta antagonism on neointima formation in injured coronary and noncoronary arteries, and suggest that since cellular proliferation is unaffected, TGF-beta1 antagonism might prevent in-stent restenosis without the delayed healing that is associated with drug-eluting stents in current clinical use. PMID- 24483850 TI - Seed oils from non-conventional sources in north-east India: potential feedstock for production of biodiesel. AB - A total of nine oilseeds with more than 15 wt% oil have been investigated for evaluating them as feedstock for biodiesel industries. Fatty acid profiles of all the nine oil samples have been determined by GC-MS analysis. The saponification numbers, gross heats of combustion of the oils and those of corresponding fatty acid methyl esters (FAMEs) as well as cetane indices of the FAMEs have been calculated empirically. Iodine values have been determined experimentally. These values have been used for predicting the quality of the corresponding biodiesels. If prepared from these oils, biodiesels are likely to meet the major specification of biodiesel standards of the USA, Germany and European Standard Organisation. Seed oil from Cucumis sativus is found rich in linoleic acid which is considered an essential fatty acid of biological significance. PMID- 24483851 TI - Related to ABA-Insensitive3(ABI3)/Viviparous1 and AtABI5 transcription factor coexpression in cotton enhances drought stress adaptation. AB - Drought tolerance is an important trait being pursued by the agbiotech industry. Abscisic acid (ABA) is a stress hormone that mediates a multitude of processes in growth and development, water use efficiency (WUE) and gene expression during seed development and in response to environmental stresses. Arabidopsis B3-domain transcription factor Related to ABA-Insensitive3 (ABI3)/Viviparous1 (namely AtRAV2) and basic leucine zipper (bZIPs) AtABI5 or AtABF3 transactivated ABA inducible promoter:GUS reporter expression in a maize mesophyll protoplast transient assay and showed synergies in reporter transactivation when coexpressed. Transgenic cotton (Gossypium hirsutum) expressing AtRAV1/2 and/or AtABI5 showed resistance to imposed drought stress under field and greenhouse conditions and exhibited improved photosynthesis and WUEs associated with absorption through larger root system and greater leaf area. We observed synergy for root biomass accumulation in the greenhouse, intrinsic WUE in the field and drought tolerance in stacked AtRAV and AtABI5 double-transgenic cotton. We assessed AtABI5 and AtRAV1/2 involvement in drought stress adaptations through reactive oxygen species scavenging and osmotic adjustment by marker gene expression in cotton. Deficit irrigation-grown AtRAV1/2 and AtABI5 transgenics had 'less-stressed' molecular and physiological phenotypes under drought, likely due to improved photoassimilation and root and shoot sink strengths and enhanced expression of endogenous GhRAV and genes for antioxidant and osmolyte biosynthesis. Overexpression of bZIP and RAV TFs could impact sustainable cotton agriculture and potentially other crops under limited irrigation conditions. PMID- 24483853 TI - [Bibliometric study of the production and use of the Farmacia Hospitalaria journal (2004-2012)]. AB - OBJECTIVE: To analyze the scientific activity and the production of information of the Farmacia Hospitalaria journal as the Spanish scientific publication of reference in the pharmaceutical area. METHODS: Transversal descriptive study of the results obtained from the bibliometric analysis of the articles published in the journal. Data was obtained from direct queries and Internet access to the scientific literature contained in the electronic version of the journal during the 2004-2012 period. RESULTS: During the period studied 756 articles were published. The number of original articles was 258 (34.12%) with a productivity index of 2.40. The number of institutions identified with published articles was 246. The predominant language was Spanish with 733 (96.96%) articles. We counted 1828 keywords, of which 527 (28.83%) coincided with MeSH. The median calculation of the obsolescence of quoted references was 10, and the Price Index was 8.81%. The percentage of selfquotes was 5.18%. CONCLUSIONS: We confirmed a low proportion of original articles and an adequate percentage of satisfactory quotable articles. The low percentage of keywords that coincide with Medical Subject Headings is noteworthy. The bibliographical references found in the articles come mainly from the English-speaking area and from journals indexed in the Journal Citation Report. The obsolescence analysis of these references produced high results. PMID- 24483852 TI - Mortality in captive baboons (Papio spp.): a-23-year study. AB - BACKGROUND: We report the causes of mortality for 4350 captive baboons that died or were euthanized due to natural causes during a 23 year period at the Southwest National Primate Research Center. METHODS: Necropsy records were retrieved and reviewed to determine a primary cause of death or indication for euthanasia. Data was evaluated for morphological diagnosis, organ system, and etiology. RESULTS: The 20 most common morphologic diagnoses accounted for 76% of the cases, including stillborn (10.8%); colitis (8.6%); hemorrhage (8.4%); ulcer (5.2%); seizures (4.7%); pneumonia (4.2%); inanition (4.1%); dermatitis (3.8%); spondylosis (3.3%); and amyloidosis (3.0%). The digestive system was most frequently involved (21.3%), followed by the urogenital (20.3%), cardiovascular (12.2%), and multisystem disease (10.3%). An etiology was not identified in approximately one-third of cases. The most common etiologies were trauma (14.8%), degenerative (9.5%), viral (8.7%), and neoplastic/proliferative (7.0%). CONCLUSION: This information should be useful for individuals working with baboons. PMID- 24483854 TI - Quality of prescription of high-alert medication and patient safety in pediatric emergency. AB - OBJECTIVE: Verify the importance of compliance by prescribed doses of high-alert medications in unit of pediatric emergency in patient safety. METHOD: This was a cross-sectional descriptive study conducted in a unit of pediatric emergency, for March to April of 2012. This study included all prescriptions that contained at least one high-alert medication, excluding all of others. The data were analyzed using Microsoft Office Excel(r) version 2007, and the study was approved by the Research Ethics Committee of the Hospital. RESULTS: This study included prescriptions for 100 patients with a mean age of 5.2 +/- 4.2 years. Were identified 983 (40.1%) high-alert medications (21 different), with predominance of injectable solutions (834, 84,8%), and of these 727 (73.95%) were electrolytes. The analysis of the dose was possible for 641 electrolytes and 104 non-electrolytes, being the dose inadequacies observed for some medications. Was observed concentration absent to 189 (18.9%) prescribed medications, these with liquid pharmaceutical form or aerosol. Was observed also the absence of maximum dose for 8 (36.3%) prescribed drugs "if necessary". CONCLUSION: The inadequacies of doses of high-alert medications identified in this study may compromise patient safety, demonstrating the importance of knowledge of multidisciplinary health care team by this subject, in this context, it is noteworthy that the acting of a clinical pharmacist together with the health multidisciplined team can contributes with the review of drug prescriptions, reducing potential errors and collaborating with patient safety. PMID- 24483855 TI - [Risk prevention evaluation in the incorporation of new drugs for healthcare practices: a methodological proposal]. AB - OBJECTIVE: Submit a preventive assessment methodology for the risk of medication errors when incorporating new drugs in clinical practice as well as a description of the types of actions arising from such action. MATERIALS AND METHODS: A Standard Operating Procedure was established which defines and plans the process of assessing the risks of new drugs purchased by the Pharmacy Services before being incorporated into the distribution and dispensation channels. The pharmacist responsible for each area fills the Risk Assessment Form, a questionnaire that facilitates the analysis of the product characteristics and provides guidance on safety measures to be taken depending on the results of that assessment. If it is confirmed that the drug requires some additional security measures to be taken, all professionals and technical staff of the Pharmacy Services shall be informed of measures to be taken. RESULTS: Between 2011 and 2013, 64 drugs were assessed. 35 of them (54.6%) required some additional security measure to be applied before being incorporated into clinical practice. CONCLUSIONS: The implementation of the method of preventive risk assessment for new drugs purchased by the Pharmacy Services can be a very useful tool when taking the measures deemed necessary to minimize the likelihood of a medication error occurring before they are incorporated into the distribution/dispensing channels put in place by the Pharmacy Services. PMID- 24483856 TI - [Comparative analysis of the safety of triple therapy with telaprevir between HCV monoinfected and HIV coinfected patients]. AB - PURPOSE: To know the possible differences in the toxicity profile of triple therapy with telaprevir between monoinfected and coinfected patients. METHOD: A retrospective observational study (January 2012- November 2013) of patients with HCV genotype 1, both monoinfected and coinfected with HIV, who had completed 12 weeks of treatment with telaprevir. The necessary variables were collected to characterize patients and the treatment received. The classification was made according to the toxicity criteria of the Division of AIDS v.1.0. A descriptive and comparative statistical analysis using the SPSS v.15.0 software was performed. RESULTS: 100 patients were included, 41% coinfected with HIV. Cirrhosis rate was observed at higher coinfected patients (97.6% vs 52.5%, p <0.001). TOXICITY: increased incidence in coinfected hyperbilirubinemia (51.2% vs 27.1% p = 0.012). TOXICITY grades: no differences in mild-moderate toxicity were observed between the two groups,while severe hyperbilirubinemia was higher in coinfected (26.8% (39.9% vs 12.2% p = 0.003) was observed, and dose adjustment of ribavirin (64.4% vs 26.8% p <0.001) in monoinfected patients. CONCLUSIONS: The study shows a similar toxicity profile between the two groups except for hyperbilirubinemia appears greater in coinfected patients (possibly related to the use of atazanavir) and less use of exogenous erythropoietin and dose reduction of ribavirin in them. PMID- 24483857 TI - [Boceprevir and telaprevir utilization: evaluation for the treatment of chronic hepatitis C]. AB - INTRODUCTION: Protease inhibitors, boceprevir and telaprevir, have changed the treatment paradigm of chronic hepatitis C (CHC). The objective is analyzing the degree of compliance with the recommendations for boceprevir and telaprevir use that have been issued for the Spanish Agency for Medicines and Health Products in patients with CHC on a tertiary hospital. METHOD: All patients who started treatment with triple therapy between March and September 2012 were included. Compliance the initiation criteria were assessed and whether the rules of discontinuation due to ineffectiveness were made. RESULTS: 76 patients, 24 treated with boceprevir and 52 with telaprevir were included. In 11 patients (14.5%) triple therapy was initiated without keeping the Spanish Agency criteria, 6 were monoinfected patients and 4 with liver transplantation. In the group of boceprevir viral load (VL) at 12th week of treatment in 19 patients was measured (79.2%) and in 13 patients at 24th week (61.9 %). For telaprevir VL at week 4 the in 48 patients was determined (92.3%), at week 12 in 45 (91.8%) and at week 24 in 42 patients (93.3%). In all patients that the VL was determined its outcome was linked with the treatment continuation or not. CONCLUSIONS: In most patients (80.3%) start and suspension requirements for triple therapy were kept. There is leeway for action and improvement that requires the involvement of all the acting agents. PMID- 24483858 TI - [Therapeutic drug monitoring of digoxin in cardiac heart failure outpatients: comparisons of two analytical methods]. PMID- 24483859 TI - [Boceprevir and telaprevir safety in routine clinical practice]. AB - PURPOSE: To compare the safety profile of telaprevir (TLV) and boceprevir (BOC) with each other and with those described in clinical trials (CT). MATERIAL AND METHODS: Retrospective multicenter observational study. Variables collected: age, sex, type of patient (naive, nonresponder or recurrent), fibroscan, Hb nadir, neutrophil and platelet count, presence of rash, anorectal discomfort, number of patients treated with erythropoiesis stimulating factors (EPO) and colony stimulating factors granulocyte (G-CSF). RESULTS: BOC vs CT: anemia (56.5% vs. 49%.), Thrombocytopenia (56.5% vs 32%, p = 0.023). neutropenia (17.4% vs. 29.5%). Use of EPO (13% vs 43%;. p = 0.008), pruritus (13% vs. 21.1%), rash (16.1% vs. 8.7%), anorectal discomfort (4.3% vs. 0%, p = 0.0001), dysgeusia (47.8% vs. 37%). TLV vs. CT: anemia (51.2% vs. 32%, p = 0.014), neutropenia (2.3 vs 3.6%), thrombocytopenia (41.9% vs. 27.4%, p = 0.05), pruritus (39.5% vs 47), rash (16.3% vs 55%, P <0.001), anorectal discomfort (39.5% vs 26%), dysgeusia (14% vs. 9.5%). BOC vs TLV: anemia (56.5% vs 51.2%), neutropenia (17.4% vs 2.3%), thrombocytopenia (56.5% vs 41.9%), rash (8.7% vs 16.3%), pruritus (39.5% vs 13%) and anorectal discomfort (4.3% vs 39.5%, P = 0.006), dysgeusia (14% vs 47.8%, P = 0.007), EPO (13% vs. 25.6%). GCSF was used for a patient treated with TLV. CONCLUSIONS: 1. BOC and TLV have shown a worse safety profile for anemia, thrombocytopenia and anorectal discomfort than those described in CT. 2. As in CT, anemia, neutropenia and thrombocytopenia were more common with BOC. Patients treated with TLV experienced more pruritus, rash and anorectal discomfort. PMID- 24483860 TI - [Effectiveness and safety of Very Low Calory Diets in obese patients]. AB - PURPOSE: To evaluate effectiveness, safety and adherence of Very Low Calory Diet (VLCD) in patients with obesity. METHODS: Observational prospective descriptive study. Patients with BMI >30 kg/m2 who started VLCD were included. We arranged 3 pharmacotherapeutical consultations, picking up the variables: age, sex, BMI, side effects and number of VLCD cycles. We defined effectiveness as weight loss in absolute and relative terms and weight loss rate (kg/week); safety as incidence and severity of side effects by the Pharmacovigilance Spanish System (SEFV); and adherence by a SMAQ adapted questionnaire. RESULTS: 29 women and 15 men were included, with a mean of 42 years. 5 patients did not complete the follow-up. Effectiveness: weight loss average was 7kg (IQR 9,5 a 5,3) and relative of 6,7%, (p < 0.0005). The weight loss rate was 1,2kg per week (IQR 1,6 a 0,9). SAFETY: 33% of the patients described side effects. All of them were mild (37% constipation, 16% dizziness, 12% anxiety, 5% headache, 2% gases y 2% epigastrical pain). ADHERENCE: 84% of the patients were adherent by the SMAQ adapted questionnaire: 74% in the first cycle and 92% in the following ones. The relation between the number of cycles and the adherence did not get statistical differences (p = 0,1127). CONCLUSIONS: Effectiveness and adherence to the treatment could improve in obese patients by setting interdisciplinary measures in the daily clinical practice. PMID- 24483861 TI - [Recommendations for the safety preparation of sterile medicines in medical wards]. AB - OBJECTIVE: To develop a recommendations guide about the preparation of sterile medicines in medical wards, and to figure out the current situation of different Spanish hospitals, regarding the preparation of sterile medicines outside the pharmacy. METHODS: The authors reviewed the available international guidelines in order to summarize the main quality recommendations. To know about the current situation in Spanish hospitals, a 30 questions survey was designed and spread to 500 different hospitals. Answers were analysed with SurveyMonkey(r) platform in the period February-July 2012. RESULTS: Based on the literature review, the authors agreed a recommendations list for the safe preparation of sterile medicines in medical wards, which was structured in 8 sections. Regarding the survey results, 8.4% of the hospitals answered, showing a great variability among centres in the quality requirements for sterile compounding outside the pharmacy. It should be pointed out the lack of assigned areas for drug preparation in wards, the lack of protocols to discern which kind of medicines can be compounded in wards as well as the poor recommendations about garment and aseptic technique. CONCLUSIONS: The authors confirm the absence of qualified practice standards to be applied in the preparation of sterile medicines in medical wards, as well as the great variability of diary practice. The implementation of quality and safety recommendations in the preparation of sterile medicines in medical wards may contribute to improve patient safety. PMID- 24483862 TI - [Potentially inappropriate prescribing in hospitalized patients with comparative study between prescription by internist and geriatricians]. AB - OBJECTIVES: To analyze potentially inappropriate prescribing in hospitalized patients and compare the prescription by internists and geriatricians. METHODS: Cross-sectional study in hospitalized patients older than 65 years. We recorded prevalence of potentially inappropriate prescriptions according to the criteria of "Screening Tool of Older Person's Prescriptions". RESULTS: We included 95 hospitalized patients over 65 years with a median age of 79 years (interquartile range: 73-82 years) and 50.5% female. One hundred eighty-three potentially inappropriate prescriptions were detected in 81 patients (85.2% of patients). The most frequent potentially inappropriate prescription were the prolonged use of inhibitors of proton pump high dose (32.6% of patients), the use of benzodiazepines in patients prone to falling (23.2% of patients), the prolonged use of long-acting benzodiazepines (21.1% of patients) and prolonged use of neuroleptic as hypnotics (21.1% of patients). In comparative study between medical specialties, significant differences were found in mean number of drugs (P = 0.0001) and in prolonged use of neuroleptics as hypnotics (P = 0.015). CONCLUSIONS: A high percentage of hospitalized patients older than 65 years receive potentially inappropriate prescribing. Prolonged use of inhibitors of the proton pump at high doses was the most frequent potentially inappropriate prescribing criterion. PMID- 24483863 TI - [Myoclonus in patients treated with etanercept]. PMID- 24483865 TI - [Secondary hemophagocytic syndrome due to Peg-interferon administration]. PMID- 24483864 TI - [Cidofovir dosage in a critically ill patient undergoing continuous veno-venous hemodiafiltration]. PMID- 24483866 TI - [Partial deficiency of ornithine transcarbamylase. A case report]. PMID- 24483867 TI - [Hyperammonemic encephalopathy in a patient treated with 5-fluorouracil]. PMID- 24483871 TI - Theory of genuine tripartite nonlocality of Gaussian states. AB - We investigate the genuine multipartite nonlocality of three-mode Gaussian states of continuous variable systems. For pure states, we present a simplified procedure to obtain the maximum violation of the Svetlichny inequality based on displaced parity measurements, and we analyze its interplay with genuine tripartite entanglement measured via Renyi-2 entropy. The maximum Svetlichny violation admits tight upper and lower bounds at fixed tripartite entanglement. For mixed states, no violation is possible when the purity falls below 0.86. We also explore a set of recently derived weaker inequalities for three-way nonlocality, finding violations for all tested pure states. Our results provide a strong signature for the nonclassical and nonlocal nature of Gaussian states despite their positive Wigner function, and lead to precise recipes for its experimental verification. PMID- 24483872 TI - Coarsening measurement references and the quantum-to-classical transition. AB - We investigate the role of inefficiency in quantum measurements in the quantum-to classical transition, and consistently observe the quantum-to-classical transition by coarsening the references of the measurements (e.g., when and where to measure). Our result suggests that the definition of measurement precision in quantum theory should include the degree of the observer's ability to precisely control the measurement references. PMID- 24483873 TI - Single-slit electron diffraction with Aharonov-Bohm phase: Feynman's thought experiment with quantum point contacts. AB - In a "thought experiment," now a classic in physics pedagogy, Feynman visualizes Young's double-slit interference experiment with electrons in magnetic field. He shows that the addition of an Aharonov-Bohm phase is equivalent to shifting the zero-field wave interference pattern by an angle expected from the Lorentz force calculation for classical particles. We have performed this experiment with one slit, instead of two, where ballistic electrons within two-dimensional electron gas diffract through a small orifice formed by a quantum point contact (QPC). As the QPC width is comparable to the electron wavelength, the observed intensity profile is further modulated by the transverse waveguide modes present at the injector QPC. Our experiments open the way to realizing diffraction-based ideas in mesoscopic physics. PMID- 24483875 TI - Quantum benchmarks for pure single-mode Gaussian states. AB - Teleportation and storage of continuous variable states of light and atoms are essential building blocks for the realization of large-scale quantum networks. Rigorous validation of these implementations require identifying, and surpassing, benchmarks set by the most effective strategies attainable without the use of quantum resources. Such benchmarks have been established for special families of input states, like coherent states and particular subclasses of squeezed states. Here we solve the longstanding problem of defining quantum benchmarks for general pure Gaussian single-mode states with arbitrary phase, displacement, and squeezing, randomly sampled according to a realistic prior distribution. As a special case, we show that the fidelity benchmark for teleporting squeezed states with totally random phase and squeezing degree is 1/2, equal to the corresponding one for coherent states. We discuss the use of entangled resources to beat the benchmarks in experiments. PMID- 24483874 TI - Reaching Fermi degeneracy via universal dipolar scattering. AB - We report on the creation of a degenerate dipolar Fermi gas of erbium atoms. We force evaporative cooling in a fully spin-polarized sample down to temperatures as low as 0.2 times the Fermi temperature. The strong magnetic dipole-dipole interaction enables elastic collisions between identical fermions even in the zero-energy limit. The measured elastic scattering cross section agrees well with the predictions from the dipolar scattering theory, which follow a universal scaling law depending only on the dipole moment and on the atomic mass. Our approach to quantum degeneracy proceeds with very high cooling efficiency and provides large atomic densities, and it may be extended to various dipolar systems. PMID- 24483876 TI - Synchronizing the dynamics of a single nitrogen vacancy spin qubit on a parametrically coupled radio-frequency field through microwave dressing. AB - A hybrid spin-oscillator system in parametric interaction is experimentally emulated using a single nitrogen vacancy (NV) spin qubit immersed in a radio frequency (rf) field and probed with a quasiresonant microwave (MW) field. We report on the MW-mediated locking of the NV spin dynamics onto the rf field, appearing when the MW-driven Rabi precession frequency approaches the rf frequency and for sufficiently large rf amplitudes. These signatures are analogous to a phononic Mollow triplet in the MW rotating frame for the parametric interaction and promise to have impact in spin-dependent force detection strategies. PMID- 24483877 TI - Observation of time-domain Rabi oscillations in the Landau-Zener regime with a single electronic spin. AB - It is theoretically known that the quantum interference of a long sequence of Landau-Zener transitions can result in Rabi oscillations. Because of its stringent requirements, however, this phenomenon has never been experimentally observed in the time domain. Using a nitrogen-vacancy (NV) center spin in isotopically purified diamond, we observed the Rabi oscillations resulting from more than 100 Landau-Zener processes. Our results demonstrate favorable quantum controllability of NV centers, which could find applications in quantum metrology and quantum information processing. PMID- 24483878 TI - Experimental unconditionally secure bit commitment. AB - Quantum physics allows for unconditionally secure communication between parties that trust each other. However, when the parties do not trust each other such as in the bit commitment scenario, quantum physics is not enough to guarantee security unless extra assumptions are made. Unconditionally secure bit commitment only becomes feasible when quantum physics is combined with relativistic causality constraints. Here we experimentally implement a quantum bit commitment protocol with relativistic constraints that offers unconditional security. The commitment is made through quantum measurements in two quantum key distribution systems in which the results are transmitted via free-space optical communication to two agents separated with more than 20 km. The security of the protocol relies on the properties of quantum information and relativity theory. In each run of the experiment, a bit is successfully committed with less than 5.68*10(-2) cheating probability. This demonstrates the experimental feasibility of quantum communication with relativistic constraints. PMID- 24483879 TI - Using concatenated quantum codes for universal fault-tolerant quantum gates. AB - We propose a method for universal fault-tolerant quantum computation using concatenated quantum error correcting codes. The concatenation scheme exploits the transversal properties of two different codes, combining them to provide a means to protect against low-weight arbitrary errors. We give the required properties of the error correcting codes to ensure universal fault tolerance and discuss a particular example using the 7-qubit Steane and 15-qubit Reed-Muller codes. Namely, other than computational basis state preparation as required by the DiVincenzo criteria, our scheme requires no special ancillary state preparation to achieve universality, as opposed to schemes such as magic state distillation. We believe that optimizing the codes used in such a scheme could provide a useful alternative to state distillation schemes that exhibit high overhead costs. PMID- 24483880 TI - Sequences of extremal radially excited rotating black holes. AB - In the Einstein-Maxwell-Chern-Simons theory the extremal Reissner-Nordstrom solution is no longer the single extremal solution with vanishing angular momentum, when the Chern-Simons coupling constant reaches a critical value. Instead a whole sequence of rotating extremal J=0 solutions arises, labeled by the node number of the magnetic U(1) potential. Associated with the same near horizon solution, the mass of these radially excited extremal solutions converges to the mass of the extremal Reissner-Nordstrom solution. On the other hand, not all near horizon solutions are also realized as global solutions. PMID- 24483881 TI - Effect of gravitational focusing on annual modulation in dark-matter direct detection experiments. AB - The scattering rate in dark-matter direct-detection experiments should modulate annually due to Earth's orbit around the Sun. The rate is typically thought to be extremized around June 1, when the relative velocity of Earth with respect to the dark-matter wind is maximal. We point out that gravitational focusing can alter this modulation phase. Unbound dark-matter particles are focused by the Sun's gravitational potential, affecting their phase-space density in the lab frame. Gravitational focusing can result in a significant overall shift in the annual modulation phase, which is most relevant for dark matter with low scattering speeds. The induced phase shift for light O(10) GeV dark matter may also be significant, depending on the threshold energy of the experiment. PMID- 24483882 TI - Multifield inflation after Planck: the case for nonminimal couplings. AB - Multifield models of inflation with nonminimal couplings are in excellent agreement with the recent results from Planck. Across a broad range of couplings and initial conditions, such models evolve along an effectively single-field attractor solution and predict values of the primordial spectral index and its running, the tensor-to-scalar ratio, and non-Gaussianities squarely in the observationally most-favored region. Such models can also amplify isocurvature perturbations, which could account for the low power recently observed in the cosmic microwave background power spectrum at low multipoles. Future measurements of primordial isocurvature perturbations could distinguish between the currently viable possibilities. PMID- 24483883 TI - Universal attractor for inflation at strong coupling. AB - We introduce a novel nonminimal coupling between gravity and the inflaton sector. Remarkably, for large values of this coupling all models asymptote to a universal attractor. This behavior is independent of the original scalar potential and generalizes the attractor in the phi4 theory with nonminimal coupling to gravity. The attractor is located in the "sweet spot" of parameter values that are preferred by Planck's recent results. PMID- 24483884 TI - Entanglement tsunami: universal scaling in holographic thermalization. AB - We consider the time evolution of entanglement entropy after a global quench in a strongly coupled holographic system, whose subsequent equilibration is described in the gravity dual by the gravitational collapse of a thin shell of matter resulting in a black hole. In the limit of large regions of entanglement, the evolution of entanglement entropy is controlled by the geometry around and inside the event horizon of the black hole, resulting in regimes of pre-local equilibration quadratic growth (in time), post-local-equilibration linear growth, a late-time regime in which the evolution does not carry memory of the size and shape of the entangled region, and a saturation regime with critical behavior resembling those in continuous phase transitions. Collectively, these regimes suggest a picture of entanglement growth in which an "entanglement tsunami" carries entanglement inward from the boundary. We also make a conjecture on the maximal rate of entanglement growth in relativistic systems. PMID- 24483885 TI - Quantum spectral curve for planar N=4 super-Yang-Mills theory. AB - We present a new formalism, alternative to the old thermodynamic-Bethe-ansatz like approach, for solution of the spectral problem of planar N=4 super Yang Mills theory. It takes a concise form of a nonlinear matrix Riemann-Hilbert problem in terms of a few Q functions. We demonstrate the formalism for two types of observables--local operators at weak coupling and cusped Wilson lines in a near Bogomol'nyi-Prasad-Sommerfield limit. PMID- 24483887 TI - Fractal dimension of particle showers measured in a highly granular calorimeter. AB - We explore the fractal nature of particle showers using Monte Carlo simulation. We define the fractal dimension of showers measured in a high granularity calorimeter designed for a future lepton collider. The shower fractal dimension reveals detailed information of the spatial configuration of the shower. It is found to be characteristic of the type of interaction and highly sensitive to the nature of the incident particle. Using the shower fractal dimension, we demonstrate a particle identification algorithm that can efficiently separate electromagnetic showers, hadronic showers, and nonshowering tracks. We also find a logarithmic dependence of the shower fractal dimension on the particle energy. PMID- 24483888 TI - Quark-gluon plasma in an external magnetic field. AB - Using numerical simulations of lattice QCD we calculate the effect of an external magnetic field on the equation of state of the quark-gluon plasma. The results are obtained using a Taylor expansion of the pressure with respect to the magnetic field for the first time. The coefficients of the expansion are computed to second order in the magnetic field. Our setup for the external magnetic field avoids complications arising from toroidal boundary conditions, making a Taylor series expansion straightforward. This study is exploratory and is meant to serve as a proof of principle. PMID- 24483890 TI - Elliptic flow splitting as a probe of the QCD phase structure at finite baryon chemical potential. AB - Using a partonic transport model based on the 3-flavor Nambu-Jona-Lasinio model and a relativistic hadronic transport model to describe, respectively, the evolution of the initial partonic and the final hadronic phase of heavy-ion collisions at energies carried out in the beam-energy scan program of the BNL Relativistic Heavy Ion collider, we study the effects of both the partonic and hadronic mean-field potentials on the elliptic flow of particles relative to that of their antiparticles. We find that to reproduce the measured relative elliptic flow differences between nucleons and antinucleons as well as between kaons and antikaons requires a vector coupling constant as large as 0.5-1.1 times the scalar coupling constant in the Nambu-Jona-Lasinio model. Implications of our results in understanding the QCD phase structure at finite baryon chemical potential are discussed. PMID- 24483891 TI - Towards the test of saturation physics beyond leading logarithm. AB - We present results from the first next-to-leading-order (NLO) numerical analysis of forward hadron production in pA and dA collisions in the small-x saturation formalism. Using parton distributions and fragmentation functions at NLO, as well as the dipole amplitude from the solution to the Balitsky-Kovchegov equation with running coupling, together with the NLO corrections to the hard coefficients, we obtain a good description of the available RHIC data in dAu collisions. In the large p? region beyond the saturation scale, we find that the NLO correction becomes dominant and negative, which indicates that other physics beyond NLO becomes important and should also be taken into account. Furthermore, we make predictions for forward hadron production in pPb collisions at the LHC. This analysis not only incorporates the important NLO corrections for all partonic channels, but also reduces the renormalization scale dependence and helps to significantly reduce the theoretical uncertainties. It therefore provides a precise test of saturation physics beyond the leading logarithmic approximation. PMID- 24483892 TI - Continuous centrifuge decelerator for polar molecules. AB - Producing large samples of slow molecules from thermal-velocity ensembles is a formidable challenge. Here we employ a centrifugal force to produce a continuous molecular beam with a high flux at near-zero velocities. We demonstrate deceleration of three electrically guided molecular species, CH3F, CF3H, and CF3CCH, with input velocities of up to 200 m s(-1) to obtain beams with velocities below 15 m s(-1) and intensities of several 10(9) mm(-2) s(-1). The centrifuge decelerator is easy to operate and can, in principle, slow down any guidable particle. It has the potential to become a standard technique for continuous deceleration of molecules. PMID- 24483889 TI - First measurement of the helicity asymmetry for gammap -> ppi0 in the resonance region. AB - The first measurement of the helicity dependence of the photoproduction cross section of single neutral pions off protons is reported for photon energies from 600 to 2300 MeV, covering nearly the full solid angle. The data are compared to predictions from the SAID, MAID, and BnGa partial wave analyses. Strikingly large differences between data and predictions are observed, which are traced to differences in the helicity amplitudes of well-known and established resonances. Precise values for the helicity amplitudes of several resonances are reported. PMID- 24483893 TI - Full counting statistics of laser excited Rydberg aggregates in a one-dimensional geometry. AB - We experimentally study the full counting statistics of few-body Rydberg aggregates excited from a quasi-one-dimensional atomic gas. We measure asymmetric excitation spectra and increased second and third order statistical moments of the Rydberg number distribution, from which we determine the average aggregate size. Estimating rates for different excitation processes we conclude that the aggregates grow sequentially around an initial grain. Direct comparison with numerical simulations confirms this conclusion and reveals the presence of liquidlike spatial correlations. Our findings demonstrate the importance of dephasing in strongly correlated Rydberg gases and introduce a way to study spatial correlations in interacting many-body quantum systems without imaging. PMID- 24483895 TI - Optics of a gas of coherently spinning molecules. AB - We consider the optical properties of a gas of molecules that are brought to fast unidirectional spinning by a pulsed laser field. It is shown that a circularly polarized probe light passing through the medium inverts its polarization handedness and experiences a frequency shift controllable by the sense and the rate of molecular rotation. Our analysis is supported by two recent experiments on the laser-induced rotational Doppler effect in molecular gases and provides a good qualitative and quantitative description of the experimental observations. PMID- 24483894 TI - Strong-field double ionization through sequential release from double excitation with subsequent Coulomb scattering. AB - We perform a triple coincidence study on differential momentum distributions of strong-field double ionization of Ar atoms in linearly polarized fields (795 nm, 45 fs, 7*10(13) W/cm2). Using a three-dimensional two-electron atomic-ensemble semiclassical model including the tunneling effect for both electrons, we retrieve differential momentum distributions and achieve a good agreement with the measurement. Ionization dynamics of the correlated electrons for the side-by side and back-to-back emission is analyzed separately. According to the semiclassical model, we find that the doubly excited states are largely populated after the laser-assisted recollision and large amounts of double ionization dominantly takes place through sequential ionization of doubly excited states at such a low laser intensity. Compared with the Coulomb-free and Coulomb-corrected sequential tunneling models, we verify that electrons can obtain an energy as large as ~6.5U p through Coulomb scattering in the combined laser and doubly charged ionic fields. PMID- 24483896 TI - Universal trimers induced by spin-orbit coupling in ultracold Fermi gases. AB - In this Letter we address the issue of how synthetic spin-orbit (SO) coupling can strongly affect three-body physics in ultracold atomic gases. We consider a system which consists of three fermionic atoms, including two spinless heavy atoms and one spin-1/2 light atom subjected to an isotropic SO coupling. We find that SO coupling can induce universal three-body bound states with a negative s wave scattering length at a smaller mass ratio, where no trimer bound state can exist if in the absence of SO coupling. The energies of these trimers are independent of the high-energy cutoff, and therefore they are universal ones. Moreover, the resulting atom-dimer resonance can be effectively controlled by SO coupling strength. Our results can be applied to systems like a 6Li and 40K mixture. PMID- 24483897 TI - Single-polariton optomechanics. AB - This Letter investigates a hybrid quantum system combining cavity quantum electrodynamics and optomechanics. The Hamiltonian problem of a photon mode coupled to a two-level atom via a Jaynes-Cummings coupling and to a mechanical mode via radiation pressure coupling is solved analytically. The atom-cavity polariton number operator commutes with the total Hamiltonian leading to an exact description in terms of tripartite atom-cavity-mechanics polarons. We demonstrate the possibility to obtain cooling of mechanical motion at the single-polariton level and describe the peculiar quantum statistics of phonons in such an unconventional regime. PMID- 24483898 TI - Optically mediated hybridization between two mechanical modes. AB - In this Letter we study a system consisting of two nearly degenerate mechanical modes that couple to a single mode of an optical cavity. We show that this coupling leads to nearly complete (99.5%) hybridization of the two mechanical modes into a bright mode that experiences strong optomechanical interactions and a dark mode that experiences almost no optomechanical interactions. We use this hybridization to transfer energy between the mechanical modes with 40% efficiency. PMID- 24483899 TI - Phase synchronization of two anharmonic nanomechanical oscillators. AB - We investigate the synchronization of oscillators based on anharmonic nanoelectromechanical resonators. Our experimental implementation allows unprecedented observation and control of parameters governing the dynamics of synchronization. We find close quantitative agreement between experimental data and theory describing reactively coupled Duffing resonators with fully saturated feedback gain. In the synchronized state we demonstrate a significant reduction in the phase noise of the oscillators, which is key for sensor and clock applications. Our work establishes that oscillator networks constructed from nanomechanical resonators form an ideal laboratory to study synchronization- given their high-quality factors, small footprint, and ease of cointegration with modern electronic signal processing technologies. PMID- 24483900 TI - Information gain in tomography--a quantum signature of chaos. AB - We find quantum signatures of chaos in various metrics of information gain in quantum tomography. We employ a quantum state estimator based on weak collective measurements of an ensemble of identically prepared systems. The tomographic measurement record consists of a sequence of expectation values of a Hermitian operator that evolves under repeated application of the Floquet map of the quantum kicked top. We find an increase in information gain and, hence, higher fidelities in the reconstruction algorithm when the chaoticity parameter map increases. The results are well predicted by random matrix theory. PMID- 24483901 TI - Morphogenesis and propagation of complex cracks induced by thermal shocks. AB - We study the genesis and the selective propagation of complex crack networks induced by thermal shock or drying of brittle materials. We use a quasistatic gradient damage model to perform large-scale numerical simulations showing that the propagation of fully developed cracks follows Griffith criterion and depends only on the fracture toughness, while crack morphogenesis is driven by the material's internal length. Our numerical simulations feature networks of parallel cracks and selective arrest in two dimensions and hexagonal columnar joints in three dimensions, without any hypotheses on cracks geometry, and are in good agreement with available experimental results. PMID- 24483903 TI - Tumbling of small axisymmetric particles in random and turbulent flows. AB - We analyze the tumbling of small nonspherical, axisymmetric particles in random and turbulent flows. We compute the orientational dynamics in terms of a perturbation expansion in the Kubo number, and obtain the tumbling rate in terms of Lagrangian correlation functions. These capture preferential sampling of the fluid gradients, which in turn can give rise to differences in the tumbling rates of disks and rods. We show that this is a weak effect in Gaussian random flows. But in turbulent flows persistent regions of high vorticity cause disks to tumble much faster than rods, as observed in direct numerical simulations [S. Parsa, E. Calzavarini, F. Toschi, and G. A. Voth, Phys. Rev. Lett. 109, 134501 (2012)]. For larger particles (at finite Stokes numbers), rotational and translational inertia affects the tumbling rate and the angle at which particles collide, due to the formation of rotational caustics. PMID- 24483902 TI - Photoimprint photoacoustic microscopy for three-dimensional label-free subdiffraction imaging. AB - Subdiffraction optical microscopy allows the imaging of cellular and subcellular structures with a resolution finer than the diffraction limit. Here, combining the absorption-based photoacoustic effect and intensity-dependent photobleaching effect, we demonstrate a simple method for subdiffraction photoacoustic imaging of both fluorescent and nonfluorescent samples. Our method is based on a double excitation process, where the first excitation pulse partially and inhomogeneously bleaches the molecules in the diffraction-limited excitation volume, thus biasing the signal contributions from a second excitation pulse striking the same region. The differential signal between the two excitations preserves the signal contribution mostly from the center of the excitation volume, and dramatically sharpens the lateral resolution. Moreover, due to the nonlinear nature of the signal, our method offers an inherent optical sectioning capability, which is lacking in conventional photoacoustic microscopy. By scanning the excitation beam, we performed three-dimensional subdiffraction imaging of varied fluorescent and nonfluorescent species. As any molecules have absorption, this technique has the potential to enable label-free subdiffraction imaging, and can be transferred to other optical imaging modalities or combined with other subdiffraction methods. PMID- 24483904 TI - Spinodal decomposition in homogeneous and isotropic turbulence. AB - We study the competition between domain coarsening in a symmetric binary mixture below critical temperature and turbulent fluctuations. We find that the coarsening process is arrested in the presence of turbulence. The physics of the process shares remarkable similarities with the behavior of diluted turbulent emulsions and the arrest length scale can be estimated with an argument similar to the one proposed by Kolmogorov and Hinze for the maximal stability diameter of droplets in turbulence. Although, in the absence of flow, the microscopic diffusion constant is negative, turbulence does effectively arrest the inverse cascade of concentration fluctuations by making the low wavelength diffusion constant positive for scales above the Hinze length. PMID- 24483905 TI - Quantum radiation reaction in laser-electron-beam collisions. AB - It is possible using current high-intensity laser facilities to reach the quantum radiation reaction regime for energetic electrons. An experiment using a wakefield accelerator to drive GeV electrons into a counterpropagating laser pulse would demonstrate the increase in the yield of high-energy photons caused by the stochastic nature of quantum synchrotron emission: we show that a beam of 10(9) 1 GeV electrons colliding with a 30 fs laser pulse of intensity 10(22) W cm(-2) will emit 6300 photons with energy greater than 700 MeV, 60* the number predicted by classical theory. PMID- 24483906 TI - Ferromagnetism of a repulsive atomic Fermi gas in an optical lattice: a quantum Monte Carlo study. AB - Using continuous-space quantum Monte Carlo methods, we investigate the zero temperature ferromagnetic behavior of a two-component repulsive Fermi gas under the influence of periodic potentials that describe the effect of a simple-cubic optical lattice. Simulations are performed with balanced and with imbalanced components, including the case of a single impurity immersed in a polarized Fermi sea (repulsive polaron). For an intermediate density below half filling, we locate the transitions between the paramagnetic, and the partially and fully ferromagnetic phases. As the intensity of the optical lattice increases, the ferromagnetic instability takes place at weaker interactions, indicating a possible route to observe ferromagnetism in experiments performed with ultracold atoms. We compare our findings with previous predictions based on the standard computational method used in material science, namely density functional theory, and with results based on tight-binding models. PMID- 24483907 TI - Quantum flutter: signatures and robustness. AB - We investigate the motion of an impurity particle injected with finite velocity into an interacting one-dimensional quantum gas. Using large-scale numerical simulations based on matrix product states, we observe and quantitatively analyze long-lived oscillations of the impurity momentum around a nonzero saturation value, called quantum flutter. We show that the quantum flutter frequency is equal to the energy difference between two branches of collective excitations of the model. We propose an explanation of the finite saturation momentum of the impurity based on the properties of the edge of the excitation spectrum. Our results indicate that quantum flutter exists away from integrability and provide parameter regions in which it could be observed in experiments with ultracold atoms using currently available technology. PMID- 24483908 TI - Dynamic similarity of oscillatory flows induced by nanomechanical resonators. AB - Rarefied gas flows generated by resonating nanomechanical structures pose a significant challenge to theoretical analysis and physical interpretation. The inherent noncontinuum nature of such flows obviates the use of classical theories, such as the Navier-Stokes equations, requiring more sophisticated physical treatments for their characterization. In this Letter, we present a universal dynamic similarity theorem: The quality factor of a nanoscale mechanical resonator at gas pressure P0 is alpha times that of a scaled-up microscale resonator at a reduced pressure alpha P0, where alpha is the ratio of nanoscale and microscale resonator sizes. This holds rigorously for any nanomechanical structure at all degrees of rarefaction, from continuum through to transition and free molecular flows. The theorem is demonstrated for a series of nanomechanical cantilever devices of different size, for which precise universal behavior is observed. This result is of significance for research aimed at probing the fundamental nature of rarefied gas flows and gas-structure interactions at nanometer length scales. PMID- 24483909 TI - Mixed-order phase transition in a one-dimensional model. AB - We introduce and analyze an exactly soluble one-dimensional Ising model with long range interactions that exhibits a mixed-order transition, namely a phase transition in which the order parameter is discontinuous as in first order transitions while the correlation length diverges as in second order transitions. Such transitions are known to appear in a diverse classes of models that are seemingly unrelated. The model we present serves as a link between two classes of models that exhibit a mixed-order transition in one dimension, namely, spin models with a coupling constant that decays as the inverse distance squared and models of depinning transitions, thus making a step towards a unifying framework. PMID- 24483910 TI - Superamphiphobic particles: how small can we go? AB - Water and oil repellent coatings--so-called superamphiphobic coatings--greatly reduce the interaction between a liquid and a solid. So far, only flat or weakly curved superhydrophobic and superamphiphobic surfaces have been designed. This raises the question of whether highly curved structures or microspheres are feasible. Therefore, we coated microspheres with a superamphiphobic layer and measured the force between the spheres and a liquid. A qualitatively different dependence of the adhesion force on the applied load for superamphiphobic and smooth spheres is detected. Furthermore, we demonstrate both experimentally and theoretically that superamphiphobicity fails below a critical particle radius, depending on topological details and type of liquid. Therefore, this study sets a fundamental physical limit to the application of superamphiphobic layers for small objects with high curvature. PMID- 24483911 TI - Light-matter decoupling in the deep strong coupling regime: the breakdown of the Purcell effect. AB - Improvements in both the photonic confinement and the emitter design have led to a steady increase in the strength of the light-matter coupling in cavity quantum electrodynamics experiments. This has allowed us to access interaction-dominated regimes in which the state of the system can only be described in terms of mixed light-matter excitations. Here we show that, when the coupling between light and matter becomes strong enough, this picture breaks down, and light and matter degrees of freedom totally decouple. A striking consequence of such a counterintuitive phenomenon is that the Purcell effect is reversed and the spontaneous emission rate, usually thought to increase with the light-matter coupling strength, plummets instead for large enough couplings. PMID- 24483912 TI - Density of states scaling at the semimetal to metal transition in three dimensional topological insulators. AB - The quantum phase transition between the three dimensional Dirac semimetal and the diffusive metal can be induced by increasing disorder. Taking the system of a disordered Z2 topological insulator as an important example, we compute the single particle density of states by the kernel polynomial method. We focus on three regions: the Dirac semimetal at the phase boundary between two topologically distinct phases, the tricritical point of the two topological insulator phases and the diffusive metal, and the diffusive metal lying at strong disorder. The density of states obeys a novel single parameter scaling, collapsing onto two branches of a universal scaling function, which correspond to the Dirac semimetal and the diffusive metal. The diverging length scale critical exponent nu and the dynamical critical exponent z are estimated, and found to differ significantly from those for the conventional Anderson transition. Critical behavior of experimentally observable quantities near and at the tricritical point is also discussed. PMID- 24483913 TI - Topological crystalline Kondo insulator in mixed valence ytterbium borides. AB - The electronic structures of two mixed valence insulators YbB6 and YbB12 are studied by using the local density approximation supplemented with the Gutzwiller method and dynamic mean field theory. YbB6 is found to be a moderately correlated Z2 topological insulator, similar to SmB6 but having much larger bulk band gap. Notably, YbB12 is revealed to be in a new novel quantum state, strongly correlated topological crystalline Kondo insulator, which is characterized by its nonzero mirror Chern number. The surface calculations find an odd (three) and an even (four) number of Dirac cones for YbB6 and YbB12, respectively. PMID- 24483914 TI - Topological order in a correlated three-dimensional topological insulator. AB - Motivated by experimental progress in the growth of heavy transition metal oxides, we theoretically study a class of lattice models of interacting fermions with strong spin-orbit coupling. Focusing on interactions of intermediate strength, we derive a low-energy effective field theory for a fully gapped, topologically ordered, fractionalized state with an eightfold ground-state degeneracy. This state is a fermionic symmetry-enriched topological phase with particle-number conservation and time-reversal symmetry. The topological terms in the effective field theory describe a quantized magnetoelectric response and nontrivial mutual braiding statistics of dynamical extended vortex loops with emergent fermions in the bulk. We explicitly compute the expected mutual statistics in a specific model on the pyrochlore lattice within a slave-particle mean-field theory. We argue that our model also provides a possible condensed matter realization of oblique confinement. PMID- 24483915 TI - Spin and orbital contributions to magnetically ordered moments in 5d layered perovskite Sr2IrO4. AB - The ratio of orbital (L) and spin (S) contributions to the magnetically ordered moments of a 5d transition metal oxide, Sr2IrO4 was evaluated by nonresonant magnetic x-ray diffraction. We applied an improved experimental setting that minimized the experimental error, in which we varied only the linear polarization of incident x ray at a fixed scattering angle. Strong polarization dependence of the intensity of magnetic diffraction was observed, from which we conclude that the ordered moments contain substantial contribution from the orbital degree of freedom with the ratio of /~5.0, evidencing the pronounced effect of spin orbit coupling. The obtained ratio is close to, but slightly larger than the expected value for the ideal J(eff) = 1/2 moment of a spin-orbital Mott insulator, ||/|| = 4, which cannot be accounted for by the redistribution of orbital components within the t(2g) bands associated with the elongation of the IrO6 octahedra. PMID- 24483916 TI - Enigmatic 4/11 state: a prototype for unconventional fractional quantum Hall effect. AB - The origin of the fractional quantum Hall effect (FQHE) at 4/11 and 5/13 has remained controversial. We make a compelling case that the FQHE is possible here for fully spin polarized composite fermions, but with an unconventional underlying physics. Thanks to a rather unusual interaction between composite fermions, the FQHE here results from the suppression of pairs with a relative angular momentum of three rather than one, confirming the exotic mechanism proposed by Wojs, Yi, and Quinn [Phys. Rev. B 69, 205322 (2004)]. We predict that the 4/11 state reported a decade ago by Pan et al. [Phys. Rev. Lett. 90, 016801 (2003)] is a conventional partially spin polarized FQHE of composite fermions, and we estimate the Zeeman energy where a phase transition into the unconventional fully spin polarized state will occur. PMID- 24483917 TI - Dual topological character of chalcogenides: theory for Bi2Te3. AB - A topological insulator is realized via band inversions driven by the spin-orbit interaction. In the case of Z2 topological phases, the number of band inversions is odd and time-reversal invariance is a further unalterable ingredient. For topological crystalline insulators, the number of band inversions may be even but mirror symmetry is required. Here, we prove that the chalcogenide Bi2Te3 is a dual topological insulator: it is simultaneously in a Z2 topological phase with Z2 invariants (nu0;nu1nu2nu3) = (1;0 0 0) and in a topological crystalline phase with mirror Chern number -1. In our theoretical investigation we show in addition that the Z2 phase can be broken by magnetism while keeping the topological crystalline phase. As a consequence, the Dirac state at the (111) surface is shifted off the time-reversal invariant momentum Gamma; being protected by mirror symmetry, there is no band gap opening. Our observations provide theoretical groundwork for opening the research on magnetic control of topological phases in quantum devices. PMID- 24483918 TI - Spin-polarized surface state in EuO(100). AB - High-quality films of the ferromagnetic semiconductor EuO are grown on epitaxial graphene on Ir(111) and investigated in situ with scanning tunneling microscopy and spectroscopy. Electron scattering at defects leads to standing-wave patterns, manifesting the existence of a surface state in EuO. The surface state is analyzed at different temperatures and energies. We observe a pronounced energy shift of the surface state when cooling down below the Curie temperature TC, which indicates a spin polarization of this state at low temperatures. The experimental results are in agreement with corresponding density functional theory calculations. PMID- 24483919 TI - Identification of the local sources of paramagnetic noise in superconducting qubit devices fabricated on alpha-Al2O3 substrates using density-functional calculations. AB - Effective methods for decoupling superconducting qubits (SQs) from parasitic environmental noise sources are critical for increasing their lifetime and phase fidelity. While considerable progress has been made in this area, the microscopic origin of noise remains largely unknown. In this work, first principles density functional theory calculations are employed to identify the microscopic origins of magnetic noise sources in SQs on an alpha-Al2O3 substrate. The results indicate that it is unlikely that the existence of intrinsic point defects and defect complexes in the substrate are responsible for low frequency noise in these systems. Rather, a comprehensive analysis of extrinsic defects shows that surface aluminum ions interacting with ambient molecules will form a bath of magnetic moments that can couple to the SQ paramagnetically. The microscopic origin of this magnetic noise source is discussed and strategies for ameliorating the effects of these magnetic defects are proposed. PMID- 24483920 TI - Evidence for topologically protected surface states and a superconducting phase in [Tl4](Tl(1-x)Sn(x))Te3 using photoemission, specific heat, and magnetization measurements, and density functional theory. AB - We report the discovery of surface states in the perovskite superconductor [Tl4]TlTe3 (Tl5Te3) and its nonsuperconducting tin-doped derivative [Tl4](Tl0.4Sn0.6)Te3 as observed by angle-resolved photoemission spectroscopy. Density functional theory calculations predict that the surface states are protected by a Z2 topology of the bulk band structure. Specific heat and magnetization measurements show that Tl5Te3 has a superconducting volume fraction in excess of 95%. Thus Tl5Te3 is an ideal material in which to study the interplay of bulk band topology and superconductivity. PMID- 24483921 TI - Domain walls and their experimental signatures in s+is superconductors. AB - Arguments were recently advanced that hole-doped Ba(1-x)K(x)Fe2As2 exhibits the s+is state at certain doping. Spontaneous breaking of time-reversal symmetry in the s+is state dictates that it possess domain wall excitations. Here, we discuss what are the experimentally detectable signatures of domain walls in the s+is state. We find that in this state the domain walls can have a dipolelike magnetic signature (in contrast to the uniform magnetic signature of domain walls p+ip superconductors). We propose experiments where quench-induced domain walls can be stabilized by geometric barriers and observed via their magnetic signature or their influence on the magnetization process, thereby providing an experimental tool to confirm the s+is state. PMID- 24483922 TI - Fermi-liquid computation of the phase diagram of high-Tc cuprate superconductors with an orbital antiferromagnetic pseudogap. AB - A 4-parameter Fermi-liquid calculation of the high-Tc cuprate phase diagram is reported. Simultaneously accounted for are the special doping densities of 5% and 16%, the d-wave functional form of the (orbital antiferromagnetic) pseudogap, the measured Tc, superconducting gap, pseudogap and superfluid density as a function of doping, the particle-hole doping asymmetry and the half-filling spin wave velocity. PMID- 24483923 TI - Size dependence of domain pattern transfer in multiferroic heterostructures. AB - Magnetoelectric coupling in multiferroic heterostructures can produce large lateral modulations of magnetic anisotropy enabling the imprinting of ferroelectric domains into ferromagnetic films. Exchange and magnetostatic interactions within ferromagnetic films oppose the formation of such domains. Using micromagnetic simulations and a one-dimensional model, we demonstrate that competing energies lead to the breakdown of domain pattern transfer below a critical domain size. Moreover, rotation of the magnetic field results in abrupt transitions between two scaling regimes with different magnetic anisotropy. The theoretical predictions are confirmed by experiments on CoFeB/BaTiO3 heterostructures. PMID- 24483886 TI - Measurement of CP violation in the phase space of B+/- -> K+ K- pi+/- and B+/- -> pi+ pi- pi+/- decays. AB - The charmless decays B+/- -> K+ K- pi+/- and B+/- -> pi+ pi- pi+/- are reconstructed in a data set of pp collisions with an integrated luminosity of 1.0 fb(-1) and center-of-mass energy of 7 TeV, collected by LHCb in 2011. The inclusive charge asymmetries of these modes are measured to be A(CP)(B+/- -> K+ K pi+/-) = -0.141+/-0.040 (stat)+/-0.018 (syst)+/-0.007(J/psi K+/-) and A(CP)(B+/ -> pi+ pi- pi+/-) = 0.117+/-0.021 (stat)+/-0.009 (syst)+/-0.007(J/psi K+/-), where the third uncertainty is due to the CP asymmetry of the B+/- -> J/psiK+/- reference mode. In addition to the inclusive CP asymmetries, larger asymmetries are observed in localized regions of phase space. PMID- 24483924 TI - Quantum tunneling of magnetization in a metal-organic framework. AB - Resonant quantum tunneling of magnetization has been observed in a hybrid metal organic framework where an intrinsic magnetic phase separation leads to the coexistence of long-range canted antiferromagnetic order and isolated single-ion quantum magnets. This unusual magnetic phenomenon is well interpreted based on a selective long-distance superexchange model in which the exchange interaction between transition metal ions through an organic linker depends on the position of hydrogen bonds. Our work not only extends the resonant quantum tunneling of magnetization to a new class of materials but also evokes the important role of hydrogen bonding in organic magnetism. PMID- 24483925 TI - Magnetoelastic excitations in the pyrochlore spin liquid Tb2Ti2O7. AB - At low temperatures, Tb2Ti2O7 enters a spin liquid state, despite expectations of magnetic order and/or a structural distortion. Using neutron scattering, we have discovered that in this spin liquid state an excited crystal field level is coupled to a transverse acoustic phonon, forming a hybrid excitation. Magnetic and phononlike branches with identical dispersion relations can be identified, and the hybridization vanishes in the paramagnetic state. We suggest that Tb2Ti2O7 is aptly named a "magnetoelastic spin liquid" and that the hybridization of the excitations suppresses both magnetic ordering and the structural distortion. The spin liquid phase of Tb2Ti2O7 can now be regarded as a Coulomb phase with propagating bosonic spin excitations. PMID- 24483926 TI - Electric-field-induced magnetic anisotropy in a nanomagnet investigated on the atomic scale. AB - Magnetoelectric coupling is studied using the electric field between the tip of a spin-polarized scanning tunneling microscope and a nanomagnet. Our experiments show that a negative (positive) electric field stabilizes (destabilizes) in-plane magnetization against thermal agitation, whereas it destabilizes (stabilizes) out of-plane magnetization. We conclude that the electric field E induces a uniaxial anisotropy that favors in-plane magnetization for E<0 and out-of-plane magnetization for E>0. Our experiments demonstrate magnetic manipulation on the atomic scale without exploiting spin or charge currents. PMID- 24483927 TI - Anomalous Hall effect arising from noncollinear antiferromagnetism. AB - As established in the very early work of Edwin Hall, ferromagnetic conductors have an anomalous Hall conductivity contribution that cannot be attributed to Lorentz forces and therefore survives in the absence of a magnetic field. These anomalous Hall conductivities are normally assumed to be proportional to magnetization. We use symmetry arguments and first-principles electronic structure calculations to counter this assumption and to predict that Mn3Ir, a high-temperature antiferromagnet that is commonly employed in spin-valve devices, has a large anomalous Hall conductivity. PMID- 24483928 TI - Topologically protected magnetic helix for all-spin-based applications. AB - The recent years have witnessed an emergence of the field of all-spin-based devices without any flow of charge. An ultimate goal of this scientific direction is the realization of the full spectrum of spin-based networks as in modern electronics. The concept of energy-storing elements, indispensable for those networks, are so far lacking. Analyzing analytically the size dependent properties of magnetic chains that are coupled via either exchange or long-range dipolar or Ruderman-Kittel-Kasuya-Yosida interactions, we discover a particularly simple law: magnetic configurations corresponding to helices with integer number of twists, which are commensurate with the chain's length, are energetically stable. This finding, supported by simulations and an experimentally benchmarked model, agrees with the study [R. Skomski et al., J. Appl. Phys. 111, 07E116 (2012)] showing that boundaries can topologically stabilize structures that are not stable otherwise. On that basis, an energy-storing element that uses spin at every stage of its operation is proposed. PMID- 24483929 TI - Magnetic field induced transition in vanadium spinels. AB - We study vanadium spinels AV2O4 (A = Cd,Mg) in pulsed magnetic fields up to 65 T. A jump in magnetization at MU0H~40 T is observed in the single-crystal MgV2O4, indicating a field induced quantum phase transition between two distinct magnetic orders. In the multiferroic CdV2O4, the field induced transition is accompanied by a suppression of the electric polarization. By modeling the magnetic properties in the presence of strong spin-orbit coupling characteristic of vanadium spinels, we show that both features of the field induced transition can be successfully explained by including the effects of the local trigonal crystal field. PMID- 24483930 TI - All-semiconductor negative-index plasmonic absorbers. AB - We demonstrate epitaxially grown all-semiconductor thin-film midinfrared plasmonic absorbers and show that absorption in these structures is linked to the excitation of highly confined negative-index surface plasmon polaritons. Strong (>98%) absorption is experimentally observed, and the spectral position and intensity of the absorption resonances are studied by reflection and transmission spectroscopy. Numerical models as well as an analytical description of the excited guided modes in our structures are presented, showing agreement with experiment. The structures investigated demonstrate a wavelength-flexible, all semiconductor, plasmonic architecture with potential for both sensing applications and enhanced interaction of midinfrared radiation with integrated semiconductor optoelectronic elements. PMID- 24483931 TI - Measurement of a saturated emission of optical radiation from gold nanoparticles: application to an ultrahigh resolution microscope. AB - We show that scattering from a single gold nanoparticle is saturable for the first time. Wavelength-dependent study reveals that the saturation behavior is governed by depletion of surface plasmon resonance, not the thermal effect. We observed interesting flattening of the point spread function of scattering from a single nanoparticle due to saturation. By extracting the saturated part of scattering via temporal modulation, we achieve lambda/8 point spread function in far-field imaging with unambiguous separation of adjacent particles. PMID- 24483932 TI - Multiple ordering transitions in a liquid stabilized by low symmetry structures. AB - We present a numerical study of a lattice model of a liquid characterized by a low-symmetry favored local structure. We find that the freezing point is depressed far enough to reveal an exotic liquid-liquid transition characterized by the appearance of an extended chirality, prior to freezing. The ordered liquid can be readily supercooled to zero temperature, as the combination of critical slowing down and competing crystal polymorphs results in a dramatically slow crystallization process. These results provide an explicit scenario by which the ordering of a liquid can proceed via an intermediate liquid-liquid transition, a scenario that may prove helpful in the analysis of low temperature liquids interacting by more realistic interactions. PMID- 24483933 TI - Origin of current blockades in nanopore translocation experiments. AB - We present a detailed investigation of the ionic current in a cylindrical model nanopore in the absence and the presence of a double stranded DNA homopolymer. Our atomistic simulations are capable of reproducing almost exactly the experimental data obtained by Smeets et al., including notably the crossover salt concentration that yields equal current measurements in both situations. We can rule out that the observed current blockade is due to the steric exclusion of charge carriers from the DNA, since for all investigated salt concentrations the charge carrier density is higher when the DNA is present. Calculations using a mean-field electrokinetic model proposed by van Dorp et al. fail quantitatively in predicting this effect. We can relate the shortcomings of the mean-field model to a surface related molecular drag that the ions feel in the presence of the DNA. This drag is independent of the salt concentration and originates from electrostatic, hydrodynamic, and excluded volume interactions. PMID- 24483934 TI - Proposed photosynthesis method for producing hydrogen from dissociated water molecules using incident near-infrared light. AB - Highly efficient solar energy utilization is very desirable in photocatalytic water splitting. However, until now, the infrared part of the solar spectrum, which constitutes almost half of the solar energy, has not been used, resulting in significant loss in the efficiency of solar energy utilization. Here, we propose a new mechanism for water splitting in which near-infrared light can be used to produce hydrogen. This ability is a result of the unique electronic structure of the photocatalyst, in which the valence band and conduction band are distributed on two opposite surfaces with a large electrostatic potential difference produced by the intrinsic dipole of the photocatalyst. This surface potential difference, acting as an auxiliary booster for photoexcited electrons, can effectively reduce the photocatalyst's band gap required for water splitting in the infrared region. Our electronic structure and optical property calculations on a surface-functionalized hexagonal boron-nitride bilayer confirm the existence of such photocatalysts and verify the reaction mechanism. PMID- 24483935 TI - Integrin-linked kinase: a new member of the kinases involved in hypertensive end organ damage? AB - Integrin-linked kinase predominantly localizes at focal adhesions to regulate actin cytoskeletal dynamics, including cell migration and matrix remodelling. Although recent studies have suggested both physiological and pathophysiological roles of integrin-linked kinase in the cardiovascular and renal system, its involvement in hypertensive organ dysfunctions, such as those that occur in kidney, has not been investigated. In the present issue of Clinical Science, Alique and co-workers have demonstrated that angiotensin II-induced renal inflammatory responses were attenuated in mice with conditional deficiency of integrin-linked kinase, which were associated with suppression of nuclear factor kappaB activation and reactive oxygen species generation but not hypertension. The significance, potential mechanisms and future direction are presented and discussed in this Commentary. PMID- 24483936 TI - Toward a rationale for the PTC124 (Ataluren) promoted readthrough of premature stop codons: a computational approach and GFP-reporter cell-based assay. AB - The presence in the mRNA of premature stop codons (PTCs) results in protein truncation responsible for several inherited (genetic) diseases. A well-known example of these diseases is cystic fibrosis (CF), where approximately 10% (worldwide) of patients have nonsense mutations in the CF transmembrane regulator (CFTR) gene. PTC124 (3-(5-(2-fluorophenyl)-1,2,4-oxadiazol-3-yl)-benzoic acid), also known as Ataluren, is a small molecule that has been suggested to allow PTC readthrough even though its target has yet to be identified. In the lack of a general consensus about its mechanism of action, we experimentally tested the ability of PTC124 to promote the readthrough of premature termination codons by using a new reporter. The reporter vector was based on a plasmid harboring the H2B histone coding sequence fused in frame with the green fluorescent protein (GFP) cDNA, and a TGA stop codon was introduced in the H2B-GFP gene by site directed mutagenesis. Additionally, an unprecedented computational study on the putative supramolecular interaction between PTC124 and an 11-codon (33 nucleotides) sequence corresponding to a CFTR mRNA fragment containing a central UGA nonsense mutation showed a specific interaction between PTC124 and the UGA codon. Altogether, the H2B-GFP-opal based assay and the molecular dynamics (MD) simulation support the hypothesis that PTC124 is able to promote the specific readthrough of internal TGA premature stop codons. PMID- 24483937 TI - Factors associated with pain induced by orthodontic separators. AB - Pain resulting from the application of orthodontic forces varies markedly across individuals. The reasons of this variability are still largely unknown. To investigate factors that may be associated with orthodontic pain following the application of orthodontic separators. One hundred and seven participants were screened for pain response over 48 h following placement of orthodontic elastomeric separators. The highest (n = 10) and lowest (n = 10) pain responders were identified, and data collected on tooth pain sensitivity to electrical stimulation in conjunction with using the Pain Catastrophising Scale (PCS), Dental Anxiety Scale (DAS) and cold pressor test (CPT). There were statistically significant differences between high- and low-pain responders in catastrophising score (P <= 0.023). For every PCS magnification score of 1 unit higher, the relative risk of being a high-pain responder was 1.6 (P = 0.002); those scoring higher on helplessness had a lower risk of being so. DAS scores of high-pain responders were twice as high as those of low-pain responder (P = 0.043). During the first 2 min of CPT, the high-pain responders experienced more pain than the low-pain responders (P <= 0.029). Tooth pain thresholds did not differ between the two different pain responder groups. Pain catastrophising, dental anxiety and cold sensitivity appear to modify the pain experienced following placement of orthodontic separators. Further research is needed to determine the validity of screening questions to identify at-risk patients prior to commencing orthodontic treatment. PMID- 24483938 TI - Large-scale synthesis of monodisperse magnesium ferrite via an environmentally friendly molten salt route. AB - Sub-micrometer-sized magnesium ferrite spheres consisting of uniform small particles have been prepared using a facile, large-scale solid-state reaction employing a molten salt technique. Extensive structural characterization of the as-prepared samples has been performed using scanning electron microscope, transmission electron microscopy, high-resolution transmission electron microscopy, selected area electron diffraction, and X-ray diffraction. The yield of the magnesium ferrite sub-micrometer spheres is up to 90%, and these sub micrometer spheres are made up of square and rectangular nanosheets. The magnetic properties of magnesium ferrite sub-micrometer spheres are investigated, and the magnetization saturation value is about 24.96 emu/g. Moreover, the possible growth mechanism is proposed based on the experimental results. PMID- 24483940 TI - Concordant spina bifida in a twin pregnancy. PMID- 24483939 TI - Heart failure patients' perceptions and use of technology to manage disease symptoms. AB - BACKGROUND: Technology use for symptom management is beneficial for both patients and physicians. Widespread acceptance of technology use in healthcare fuels continued development of technology with ever-increasing sophistication. Although acceptance of technology use in healthcare by medical professionals is evident, less is known about the perceptions, preferences, and use of technology by heart failure (HF) patients. This study explores patients' perceptions and current use of technology for managing HF symptoms (MHFS). MATERIALS AND METHODS: A qualitative analysis of in-depth individual interviews using a constant comparative approach for emerging themes was conducted. Fifteen participants (mean age, 64.43 years) with HF were recruited from hospitals, cardiology clinics, and community groups. RESULTS: All study participants reported use of a home monitoring device, such as an ambulatory blood pressure device or bathroom scale. The majority of participants reported not accessing online resources for additional MHFS information. However, several participants stated their belief that technology would be useful for MHFS. Participants reported increased access to care, earlier indication of a worsening condition, increased knowledge, and greater convenience as potential benefits of technology use while managing HF symptoms. For most participants financial cost, access issues, satisfaction with current self-care routine, mistrust of technology, and reliance on routine management by their current healthcare provider precluded their use of technology for MHFS. CONCLUSIONS: Knowledge about HF patients' perceptions of technology use for self-care and better understanding of issues associated with technology access can aid in the development of effective health behavior interventions for individuals who are MHFS and may result in increased compliance, better outcomes, and lower healthcare costs. PMID- 24483942 TI - Laparoscopic treatment of endometriosis and effects on quality of life: a retrospective study using the short form EHP-5 endometriosis specific questionnaire. AB - Complete surgical eradication is considered the mainstay of treatment for endometriosis. The aim of the present study was to investigate patients' own assessment of whether their laparoscopic treatment made a difference to their quality of life, as well as to assess local recurrence rates. We performed a retrospective analysis of 49 women who had laparoscopic treatment for endometriosis at our unit between 1 January 2008 and 1 January 2010. Patients were sent the Short Form EHP-5 questionnaire and asked to score their quality of life in relation to endometriosis symptoms, prior to the surgery and up to 48 months afterwards. Subgroup analysis of stage I/II and stage III/IV disease was performed as well as stratification of the period post-operation into 12-24, 25 36 and 37-48 months for follow-up analysis. Overall, the patients reported improvement in quality of life scores with a significant drop in mean scores from 46.9 pre- to 27.5 post-surgery, signifying benefits from the surgical intervention. All subgroups reported improvement in quality of life scores. The overall symptom recurrence rate was 18.3%. We conclude that patients, post laparoscopic treatment of endometriosis, experience significant improvement in their quality of life, regardless of stage and this can be quantified and qualified. PMID- 24483941 TI - Manganese superoxide dismutase plays an important role in the inflammatory process and predicts disease severity and activity in patients with ulcerative colitis. AB - The aim of this study was to investigate the expression pattern of manganese superoxide dismutase (MnSOD) in relation to inflammatory factors in ulcerative colitis (UC) and characterize this enzyme as a newly identified biomarker potentially linked to disease pathogenesis of UC. MnSOD expression was analyzed immunohistochemically in 48 formalin-fixed and paraffin-embedded specimens from patients with UC who had undergone endoscopical biopsy. MnSOD expression was observed in vascular endothelium, macrophages, and polymorphonuclear leukocytes within lamina propria of inflamed mucosa. The patients who did not express MnSOD tended to have stabilization of symptoms, but accompanied with status of inflammation. The MnSOD expression pattern was strongly correlated with disease type. MnSOD was expressed in polymorphonuclear leukocytes of all disease types, but cases of chronically counting and exacerbation type had particularly high frequency of immunopositive cells. MnSOD expression in macrophages was frequently observed in cases of symptom remaining type. The cases with MnSOD expression in the vascular endothelium showed a tendency to express in relapse-remission and exacerbation of symptoms. Immunohistochemical evaluation for MnSOD expression may be useful for predicting disease severity and activity in patients with UC. PMID- 24483943 TI - ICD recipients' understanding of ethical issues, ICD function, and practical consequences of withdrawing the ICD in the end-of-life. AB - BACKGROUND: The current international expert consensus statements recommend that clinicians should discuss elective implantable cardioverter defibrillator (ICD) deactivation before implantation of the device, and then consistently during the illness trajectory. However, no previous studies have investigated predictors of ICD patients' knowledge about end-of-life issues or whether knowledge influences patients' attitudes about deactivation. METHODS: This nationwide survey study (n = 3,067) had a cross-sectional correlational design of self-reported data. Participants were recruited from the Swedish ICD and Pacemaker Registry and asked to complete a questionnaire about knowledge in relation to the ICD and end-of life. RESULTS: Only 79 respondents (3%) scored correctly on all 11 questions. The mean sample score was 6.6 +/- 2.7 out of a maximum score of 11. A total of 835 participants (29%) had an insufficient knowledge when using the 25th percentile as a cutoff. Younger ICD recipients, those cohabiting, male participants, and those who had received shocks, had a generator replacement, or who had discussed illness trajectory with their physician were more likely to have sufficient knowledge on the end-of-life issues. Insufficient knowledge was associated with indecisiveness to make decisions about ICD deactivation in the end-of-life situations, and with favorable attitudes about replacing the ICD even if seriously ill or have reached an advanced age, and keeping the shock therapy of the ICD even in a terminal phase of life when dying from cancer or other serious chronic illnesses. CONCLUSION: Insufficient knowledge is common among ICD recipients and is associated with attitudes and decisions that may result in a stressful and potentially painful end-of-life situation. PMID- 24483945 TI - Trends in antihypertensive treatment--lessons from the National Acute Stroke Israeli (NASIS) registry. AB - BACKGROUND: Recent guidelines recommended different approaches to hypertension therapy. Our aim was to evaluate trends in blood pressure (BP) management among patients admitted with acute stroke over the past decade. METHODS: The study population comprised 6279 consecutive patients, admitted with an acute stroke, and included in a national registry of three consecutive periods conducted during the years 2004-2010. We compared patients' characteristics and temporal trends of antihypertensive therapy utilization before hospital admission. RESULTS: Among 4727 hypertensive patients, 3940 (83%) patients have taken antihypertensive drug therapy - 1430 (30.2%) a single agent, 1500 (31.7%) two agents and 1010 (21.4%) three or more antihypertensive agents. The most common class used was renin angiotensin system (RAS) blockers (n = 2575; 54%) followed by beta-blockers (n = 2033; 43%). The same pattern was observed in patients treated with monotherapy. The use of RAS blockers and beta-blockers has increased over the years (p < 0.001 for both), whereas the use of diuretics decreased and the use of calcium antagonists remained stable. Among those who were treated with a single agent, the use of diuretics and calcium antagonists decreased and the use of RAS blockers increased, whereas the use of beta-blockers remained unchanged. CONCLUSIONS: RAS blockers and beta-blockers are the most common antihypertensive agents used in Israel. Over time, the use of RAS blockers and beta-blockers has increased, whereas the use of diuretics decreased. PMID- 24483946 TI - Spatial interferences in mental arithmetic: evidence from the motion-arithmetic compatibility effect. AB - Recent research on spatial number representations suggests that the number space is not necessarily horizontally organized and might also be affected by acquired associations between magnitude and sensory experiences in vertical space. Evidence for this claim is, however, controversial. The present study now aims to compare vertical and horizontal spatial associations in mental arithmetic. In Experiment 1, participants solved addition and subtraction problems and indicated the result verbally while moving their outstretched right arm continuously left-, right-, up-, or downwards. The analysis of the problem-solving performances revealed a motion-arithmetic compatibility effect for spatial actions along both the horizontal and the vertical axes. Performances in additions was impaired while making downward compared to upward movements as well as when moving left compared to right and vice versa in subtractions. In Experiment 2, instead of being instructed to perform active body movements, participants calculated while the problems moved in one of the four relative directions on the screen. For visual motions, only the motion-arithmetic compatibility effect for the vertical dimension could be replicated. Taken together, our findings provide first evidence for an impact of spatial processing on mental arithmetic. Moreover, the stronger effect of the vertical dimension supports the idea that mental calculations operate on representations of numerical magnitude that are grounded in a vertically organized mental number space. PMID- 24483944 TI - Amino acid signature enables proteins to recognize modified tRNA. AB - Human tRNA(Lys3)UUU is the primer for HIV replication. The HIV-1 nucleocapsid protein, NCp7, facilitates htRNA(Lys3)UUU recruitment from the host cell by binding to and remodeling the tRNA structure. Human tRNA(Lys3)UUU is post transcriptionally modified, but until recently, the importance of those modifications in tRNA recognition by NCp7 was unknown. Modifications such as the 5-methoxycarbonylmethyl-2-thiouridine at anticodon wobble position-34 and 2 methylthio-N(6)-threonylcarbamoyladenosine, adjacent to the anticodon at position 37, are important to the recognition of htRNA(Lys3)UUU by NCp7. Several short peptides selected from phage display libraries were found to also preferentially recognize these modifications. Evolutionary algorithms (Monte Carlo and self consistent mean field) and assisted model building with energy refinement were used to optimize the peptide sequence in silico, while fluorescence assays were developed and conducted to verify the in silico results and elucidate a 15-amino acid signature sequence (R-W-Q/N-H-X2-F-Pho-X-G/A-W-R-X2-G, where X can be most amino acids, and Pho is hydrophobic) that recognized the tRNA's fully modified anticodon stem and loop domain, hASL(Lys3)UUU. Peptides of this sequence specifically recognized and bound modified htRNA(Lys3)UUU with an affinity 10 fold higher than that of the starting sequence. Thus, this approach provides an effective means of predicting sequences of RNA binding peptides that have better binding properties. Such peptides can be used in cell and molecular biology as well as biochemistry to explore RNA binding proteins and to inhibit those protein functions. PMID- 24483947 TI - Impact of self-management interventions on stable angina symptoms and health related quality of life: a meta-analysis. AB - BACKGROUND: Chronic stable angina (CSA) has a major negative impact on health related quality of life (HRQL) including poor general health status, psychological distress, and inability to self-manage. METHODS: We used meta analysis to assess the effectiveness of self-management interventions for improving stable angina symptoms, HRQL and psychological well-being. Nine trials, involving 1,282 participants in total, were included. We used standard inverse variance random-effects meta-analysis to combine the trials. Heterogeneity between trials was evaluated using chi-square tests for the tau-squared statistic and quantified using the I2 statistic. RESULTS: There was significant improvement in the frequency of angina symptoms (Seattle Angina Questionnaire [SAQ], symptom diary) across trials, standardized mean difference (SMD): 0.30 (95% Confidence interval [CI] 0.14, 0.47), as well as reduction in the use of sublingual (SL) nitrates, SMD: -0.49 (95% CI -0.77, -0.20). Significant improvements for physical limitation (SAQ), SMD: 0.38 (95% CI 0.20, 0.55) and depression scores (Hospital Anxiety and Depression Scale), SMD: -1.38 (95% CI -2.46, -0.30) were also found. The impact of SM on anxiety was uncertain due to statistical heterogeneity across trials for this outcome, I2 = 98%. SM did not improve other HRQL dimensions including angina stability, disease perception, and treatment satisfaction. CONCLUSIONS: SM interventions significantly improve angina frequency and physical limitation; they also decrease the use of SL nitrates and improve depression in some cases. Further work is needed to make definitive conclusions about the impact of SM on cardiac-specific anxiety. PMID- 24483948 TI - A new diterpene from Clinopodium chinense. AB - A new abietane diterpene, named as 3beta-hydroxy-12-O-beta-D-glucopyranosyl 8,11,13-abietatrien-7-one (1), together with four known flavonoids, was isolated from the hot water extract of the aerial parts of Clinopodium chinense. Their structures were determined by analysing the spectroscopic data including 1D, 2D NMR and HR-ESI-MS. Compound 1 tested against HepG-2 and A549 cancer cell lines expressed weak cytotoxicity. Cardioprotective effects of compounds 2-5 against H2O2-induced apoptosis in H9c2 cells were also evaluated; compounds 2 and 3 exhibited moderate cardioprotective effect. PMID- 24483950 TI - Increasing cancer-specific gene expression by targeting overexpressed alpha5beta1 integrin and upregulated transcriptional activity of NF-kappaB. AB - We developed a modular multifunctional nonviral gene delivery system by targeting the overexpressed cancer surface receptor alpha5beta1 integrin and the upregulated transcriptional activity of the cancer resistance mediating transcription factor NF-kappaB, thereby introducing a new form of transcriptional targeting. NF-kappaB regulated therapy can improve specificity of gene expression in cancer tissue and also may offset NF-kappaB mediated cancer resistance. We delivered a luciferase gene under the control of an NF-kappaB responsive element (pNF-kappaB-Luc) encapsulated in a PR_b peptide functionalized stealth liposome that specifically targets the alpha5beta1 integrin and achieved increased gene expression in DLD-1 colorectal cancer cells compared to BJ-fibroblast healthy cells in vitro. The multitargeted system was also able to differentiate between cancer cells and healthy cells better than either of the individually targeted systems. In addition, we constructed a novel cancer therapeutic plasmid by cloning a highly potent diphtheria toxin fragment A (DTA) expressing gene under the control of an NF-kappaB responsive element (pNF-kappaB-DTA). A dose-dependent reduction of cellular protein expression and increased cytotoxicity in cancer cells was seen when transfected with PR_b functionalized stealth liposomes encapsulating the condensed pNF-kappaB-DTA plasmid. Our therapeutic delivery system specifically eradicated close to 70% of a variety of cancer cells while minimally affecting healthy cells in vitro. Furthermore, the modular nature of the nonviral design allows targeting novel pairs of extracellular receptors and upregulated transcription factors for applications beyond cancer gene therapy. PMID- 24483951 TI - Meloxicam pharmacokinetics using nonlinear mixed-effects modeling in ferrets after single subcutaneous administration. AB - This study was designed to investigate the pharmacokinetics of meloxicam, an oxicam class, nonsteroidal anti-inflammatory drug (NSAID), in ferrets. We determined the pharmacokinetic properties of a single subcutaneous dose of meloxicam (0.2 mg/kg) in nine male and nine female ferrets. Blood samples were collected by venipuncture of the cranial vena cava into heparinized syringes. Plasma meloxicam concentrations were determined by high-pressure liquid chromatography (HPLC). Pharmacokinetic variables were calculated using nonlinear mixed-effects modeling to take advantage of the population-based sampling scheme and to minimize sample volume collected per animal. Maximum plasma concentration, volume of distribution per absorption, and elimination half-life were 0.663 MUg/mL, 0.21 L, and 11.4 h, respectively, for females and 0.920 MUg/mL, 0.35 L, and 17.8 h, respectively, for males. Significant differences were found in each of the above parameters between male and female ferrets. Systemic clearance per absorption was not affected by gender and was 13.4 mL/h. Analgesic efficacy was not evaluated, but plasma meloxicam concentrations achieved in these animals are considered effective in other species. Sex differences in the pharmacokinetic behavior of meloxicam should be taken into consideration when treating ferrets. PMID- 24483952 TI - Long-term episomal transgene expression from mitotically stable integration deficient lentiviral vectors. AB - Nonintegrating gene delivery vectors have an improved safety profile compared with integrating vectors, but transgene retention is problematic as nonreplicating episomes are progressively and rapidly diluted out through cell division. We have developed an integration-deficient lentiviral vector (IDLV) system generating mitotically stable episomes capable of long-term transgene expression. We found that a transient cell cycle arrest at the time of transduction with IDLVs resulted in 13-45% of Chinese hamster ovary (CHO) cells expressing the transgene for over 100 cell generations in the absence of selection. The use of a scaffold/matrix attachment region did not result in improved episomal retention in this system, and episomes did not form after transduction with adeno-associated viral or minicircle vectors under the same conditions. Investigations into the episomal status of the vector genome using (1) linear amplification-mediated polymerase chain reaction followed by deep sequencing of vector-genome junctions, (2) Southern blotting, and (3) fluorescent in situ hybridization strongly suggest that the vector is not integrated in the vast majority of cells. In conclusion, we have developed an IDLV procedure generating mitotically stable episomes capable of long-term transgene expression. The application of this approach to stem cell populations could significantly improve the safety profile of a range of stem and progenitor cell gene therapies. PMID- 24483953 TI - Current indications and results of orthotopic ileal neobladder for bladder cancer. AB - During the past three decades, the reconstructive aspects of urologic surgery emerged and became a major component of our surgical specialty, and the most relevant developments have been observed in the field of urinary diversions. Health-related quality of life and self esteem have been improved following orthotopic bladder substitutions, which are actually the preferred method for continent urinary diversion. Patients with neobladders have enhanced cosmesis and the potential for normal voiding function with no abdominal stoma. Patient's selection for orthotopic neobladder formation is mandatory as most of the surgical complications or consequences associated with a neobladder are correlated not only with surgical technique or management after surgery, but also with wrong patient's selection. The principles of intestinal detubularization and reconfiguration to obtain spherical reservoir are the basis of continent urinary diversions and ileum seems to be preferable over any other segment. Nowadays, ileal neobladder is a widely adopted solution after cystectomy with a neobladder rate of 9-19% for population-based data with an increase to 39.1-74% for high volume centers. However, controversies still exist in this urological field about the best candidates for neobladder construction, the best type of neobladder to offer, whether or not an antireflux uretero intestinal anastomosis should be used, the future of minimally invasive approaches, that is, robotic assisted cystectomy plus extracorporeal or intracorporeal neobladder, and last but very important, the functional results and the level of symptoms-induced distress and quality of life in the long term in patients with bladder cancer receiving an orthotopic bladder substitution. All these issues are discussed on the basis of the most recent published data. PMID- 24483954 TI - Influence of changes in physical activity on frequency of hospitalization in chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: To evaluate whether changes in regular physical activity (PA) in patients with chronic obstructive pulmonary disease (COPD) affect the rate of hospitalizations for COPD exacerbation (eCOPD). METHODS: Five hundred forty-three ambulatory clinic patients being treated for COPD were prospectively identified. PA was self-reported by patients, and the level was established by the distance they walked (km/day) at least 3 days per week. Hospitalizations were recorded from hospital databases. All patients with at least a 2-year follow-up after enrollment were included in the analysis. The response variable was the number of hospitalizations for eCOPD within the 3-year period from 2 to 5 years after study enrollment. RESULTS: Three hundred ninety one survivors were studied. Mean forced expiratory volume in 1 s was 52% (+/-14%) of the predicted value. Patients who maintained a lower level of PA had an increased rate of hospitalization (odds ratio 1.901; 95% confidence interval 1.090-3.317). After having had the highest level of PA, those patients who decreased their PA in the follow-up showed an increasing rate of hospitalizations (odds ratio 2.134; 95% confidence interval 1.146-3.977). CONCLUSIONS: Patients with COPD with a low level of PA or who reduced their PA over time were more likely to experience a significant increase in the rate of hospitalization for eCOPD. Changes to a higher level of PA or maintaining a moderate or high level of PA over time, with a low intensity activity such as walking for at least 3-6 km/day, could reduce the rate of hospitalizations for eCOPD. PMID- 24483955 TI - [In process citation]. PMID- 24483949 TI - Chlorinated persistent organic pollutants, obesity, and type 2 diabetes. AB - Persistent organic pollutants (POPs) are lipophilic compounds that travel with lipids and accumulate mainly in adipose tissue. Recent human evidence links low dose POPs to an increased risk of type 2 diabetes (T2D). Because humans are contaminated by POP mixtures and POPs possibly have nonmonotonic dose-response relations with T2D, critical methodological issues arise in evaluating human findings. This review summarizes epidemiological results on chlorinated POPs and T2D, and relevant experimental evidence. It also discusses how features of POPs can affect inferences in humans. The evidence as a whole suggests that, rather than a few individual POPs, background exposure to POP mixtures-including organochlorine pesticides and polychlorinated biphenyls-can increase T2D risk in humans. Inconsistent statistical significance for individual POPs may arise due to distributional differences in POP mixtures among populations. Differences in the observed shape of the dose-response curves among human studies may reflect an inverted U-shaped association secondary to mitochondrial dysfunction or endocrine disruption. Finally, we examine the relationship between POPs and obesity. There is evidence in animal studies that low-dose POP mixtures are obesogenic. However, relationships between POPs and obesity in humans have been inconsistent. Adipose tissue plays a dual role of promoting T2D and providing a relatively safe place to store POPs. Large prospective studies with serial measurements of a broad range of POPs, adiposity, and clinically relevant biomarkers are needed to disentangle the interrelationships among POPs, obesity, and the development of T2D. Also needed are laboratory experiments that more closely mimic real-world POP doses, mixtures, and exposure duration in humans. PMID- 24483956 TI - [Rationalizing versus rationing in the practice of clinical nutrition; fourth Jesus Culebras lecture]. AB - The current economic situation is the reason for this conference that will be split in two main areas: first, we will focus on general concepts on rationalizing versus rationing in health care, and secondly, on rationing in the practice of clinical nutrition. According to the Spanish Royal Academy of the Language, to rationalize is to organize the production or the work in a manner such the yields are increased or the costs are reduced with the least effort. However, to ration is the action and effect of rationing or limiting the consumption of something to prevent negative consequences. In Europe, the percentage of the Gross National Product dedicated to health care progressively decreases whereas the costs of health care are ever increasing. From the economic viewpoint, this would be the main reason why the health care authorities have no other option but rationing. Until what extent the ethical principle of justice is compatible with rationing? Ethically, it seems that in order to accept rationing, not only a fair distribution of the limited resources should be achieved, but also a rational use of them. If we accept that limiting the health care allowances is necessary, we should then answer some questions: is it ethical not to limit? Who decides what is medically necessary? How is it decided? With no coherent answers to these questions it is ethically difficult to accept rationing from a healthcare viewpoint. When dealing with rationing in the practice of clinical nutrition, we should focus on how rationing impacts on hyponutrition, and more particularly on disease-related hyponutrition, since this is the focus of Clinical Nutrition. Given its importance and its implications, in several countries, including Spain, actions integrated in the European Union strategy "Together for health: a Strategic Approach for the EU 2008-2013", are being performed aimed at taking decisions for preventing and managing hyponutrition. However, restrictions persist with the imperative necessity of using all the tools available to prevent hyponutrition in patients at risk, to early detect malnourished patients or patients at risk for hyponutrition, and to establish the most appropriate actions. PMID- 24483957 TI - [Dietary bioactive compounds with potential in preventing pathologies related with overweight and obesity;biologically active peptides]. AB - Overweight and obesity are risk factors for noncommunicable diseases such as cardiovascular diseases, diabetes and some types of cancer. The risk for these noncommunicable diseases increase with the increase in body mass index. Dietary proteins are known to carry a wide range of nutritional, functional and biological properties. Nutritionally, the proteins are a source of energy and amino acids, which are essential for growth and maintenance. Functionally, the proteins contribute to the physicochemical and sensory properties of various protein-rich foods. Furthermore, many dietary proteins possess specific biological properties which make these components potential ingredients of functional or health-promoting foods. Many of these properties are attributed to physiologically active peptides encrypted in protein molecules. This paper reviews antihypertensive, antithrombotic, hypocholesterolemic, hypoglycemic and hypolipidemic peptides originating from different sources and hydrolysis of proteins. PMID- 24483958 TI - From dehydration to hyperhidration isotonic and diuretic drinks and hyperhydratant aids in sport. AB - The needs of water and electrolytes are quite variants, depending on age, physiological or environmental conditions. In most long-term sports, usual weight loss of 3-6%, affect in athletic performance. The effects of a 6% dehydration could be improved with individualized diet-specific nutritional strategies and allow only a 2-3% dehydration, which affect metabolic efficiency but will not risk the health. On the contrary, hyperhydration can be dangerous and is associated with hyponatremia that can cause cerebral edema or respiratory failure. Sports drinks should moisturize, providing minerals and carbohydrates and increase the absorption of water by an ideal combination of salts and sugars. Therefore, it is important to provide correct hydration -protocols before, during and after physical activity, as well as know possible limitations of the sport. PMID- 24483959 TI - Micronutrients influencing the immune response in leprosy. AB - Leprosy is a chronic infectious disease caused by Mycobacterium leprae, an intracellular bacillus of airborne transmission. The disease affects the skin and peripheral nerves and can cause neurological sequelae. The bacillus multiplies slowly in the host and the disease probably occurs due to malfunctioning in host immune response. This review addresses the role of some specific micronutrients in the immune response, such as Vitamins A, D, E, C, Zinc and Selenium, detailing their mechanisms of actions in infectious diseases, and in leprosy. The immune response to pathogens releases harmful substances, which lead to tissue damage. This review discusses how a decreased level of antioxidants may contribute to an increased oxidative stress and complications of infectious diseases and leprosy. As the nutrients have a regulatory effect in the innate and adaptative immune responses, a perfect balance in their concentrations is important to improve the immune response against the pathogens. PMID- 24483960 TI - [Nutrition therapy in enterocutaneous fistula; from physiology to individualized treatment]. AB - Enterocutaneous fistula is the most common of all intestinal fistulas. Is a condition that requires prolonged hospital stay due to complications such as electrolyte imbalance, malnutrition, metabolic disorders and sepsis. Nutritional support is an essential part of the management; it favors intestinal and immune function, promotes wound healing and decreases catabolism. Despite the recognition of the importance of nutrition support, there is no strong evidence on its comprehensive management, which can be limiting when establishing specific strategies. The metabolic imbalance that a fistula causes is unknown. For low output fistulas, energy needs should be based on resting energy expenditure, and provide 1.0 to 1.5 g/kg/d of protein, while in high-output fistulas energy requirement may increase up to 1.5 times, and provide 1.5 to 2.5 g/kg of protein. It is suggested to provide twice the requirement of vitamins and trace elements, and between 5 and 10 times that of Vitamin C and Zinc, especially for high-output fistulas. A complete nutritional assessment, including type and location of the fistula, are factors to consider when selecting nutrition support, whether is enteral or parenteral nutrition. The enteral route should be preferred whenever possible, and combined with parenteral nutrition when the requirements cannot be met. Nutritional treatment strategies in fistulas may include the use of immunomodulators and even stress management. PMID- 24483961 TI - [Adherence and fidelity in patients treated with intragastric balloon]. AB - A correct treatment of obesity needs a program of habits modification regardless of the selected technique, especially if it is minimally invasive as the intragastric balloon (BIG). The adherence of the obese patients with regard to recommended drugs measures to medium- and long-term is less than 50%. Given that the results obtained using the technique of gastric balloon must be seen influenced by adherence to the modification of habits program and its fulfillment, we reviewed series published in attention to the program proposed with the BIG. The series published to date provide few details about the used Therapeutic Programs as well as the adherence of patients to them, and even less concerning the Monitoring Plan and the loyalty of the patient can be seen. We conclude the convenience to agree on a follow-up strategy, at least the 6 months during which the BIG remain in the stomach. PMID- 24483962 TI - Influence of cortisol on zinc metabolism in morbidly obese women. AB - INTRODUCTION: The accumulation of visceral fat affects the metabolism of hormones and some nutrients, but these mechanisms remain unclear. OBJECTIVE: To assess the influence of cortisol on the metabolism of zinc in morbidly obese women. METHOD: Cross-sectional, case-control study involving 80 women aged between 20 and 59 years. The participants were divided into two groups: experimental (morbidly obese, n = 40) and control (normal weight, n = 40). Zinc concentrations were determined by atomic absorption spectroscopy and serum and urinary cortisol by chemiluminescence method. RESULTS: Zinc intake was significantly different between groups. Mean plasma zinc was lower in obese compared to control group. Mean values for erythrocyte zinc were 44.52 +/- 7.84 ug/gHb and 40.17 +/- 6.71 ug/gHb for obese and control groups, respectively. Urinary excretion of this mineral was higher in obese compared to control subjects (p < 0.05). Mean values for plasma cortisol were 9.58 +/- 4.86 ug/dL for obese and 9.89 +/- 5.61 ug/dL for control groups. Mean values for urinary cortisol were 163.00 +/- 100.35 ug/dL and 109.71 +/- 34.88 ug/dL for obese and control groups, respectively (p > 0.05). The correlation analysis between cortisol and zinc was not significant (p > 0.05). CONCLUSIONS: Obese patients have hypozincemia and high erythrocyte zinc levels. The correlation between zinc parameters and cortisol concentration showed no influence of this hormone on zinc metabolism. PMID- 24483963 TI - [Evaluation of a structured program of physical exercise in morbidly obese patients awaiting bariatric surgery]. AB - INTRODUCTION: Obesity is a chronic disease whose prevalence is increasing up to be considered a real epidemic. In the case of morbid obesity, in many cases required to resort to surgery to achieve adequate weight reduction and improvement of comorbidities. There are, however, few studies have evaluated the influence of a structured program of physical exercise in these patients before surgery. OBJECTIVE: To evaluate the influence of a structured program of physical exercise in morbidly obese patients awaiting bariatric surgery. METHOD: Prospective intervention study in 10 patients (6 women and 4 men) morbidly obese bariatric surgery pending of 47.1 +/- 4.6 years. Structured exercise program for 2 months (16 sessions) along with "food education". It was assessed before and after intervention anthropometric and body composition by bioelectrical impedance, fitness, food habits survey, physical activity, quality of life and satisfaction with the program. RESULTS: Weight loss achieved after the program was 5.17 +/- 4.01 kg and BMI of 1.77. There was also a favorable change in body composition with 1.77% increase of muscle mass and decrease of 2.83% and 1.43% in total fat mass and visceral, respectively. The distance traveled as an expression of the physical condition of the subjects improved significantly going from 586.72 +/- 82.8 m to 625.59 +/- 78.2 m. No significant differences in the assessment of quality of life, adherence to the program was 75% and the degree of satisfaction with it was very high. CONCLUSIONS: A structured program of physical exercise in morbidly obese patients awaiting bariatric surgery helps in reducing weight and improving body composition while increasing fitness and is well accepted by patients, so it can be a part of the multidisciplinary approach to this disease. PMID- 24483964 TI - [Micronutrient deficiencies one year after sleeve gastrectomy]. AB - INTRODUCTION: Obesity is one of the largest problems in public health worldwide today. For patients with severe obesity and associated comorbidities, surgical treatment is recommended. OBJECTIVE: To analyze the frequency of micronutrient deficiencies and food intake at least 12 months after sleeve gastrectomy (SG). MATERIALS AND METHODS: This is a cross sectional study carried out between October and December 2009 with measure of serum levels of vitamin B12, vitamin D, folate, calcium, ferritin, zinc, parathyroid hormone and bone mineral density on patients underwent SG at least 12 months before the study. A food intake questionnaire was also performed. For the statistical analysis, the Pearson or Spearman tests was used. RESULTS: Forty patients were evaluated with a mean age of 40 +/- 10 years and mean time post surgery of 26 +/- 6 months. Mean plasma level of 25 OH-vitamin D was 20.9 +/- 10.5 ng/ml. Forty-three percent had low levels of vitamin D (< 20 ng/ml), and 68% showed low levels of calcium (< 1,1 mmol/L) without secondary hyperparathyroidism. Anemia was present in 28% and iron deficiency occurred in 38% of these patients. Deficit of folic acid and vitamin B12 were observed in 13% of the patients. Average daily food intake was 1,256 kcal, 54% of total calories as carbohydrates, 26% as fat and 21% as protein. CONCLUSION: Iron, calcium and vitamin D are the most prevalent micronutrient deficiencies after SG. Long-term vitamin and mineral supplementation should be considered on every patient. Additional long-term studies are needed to establish specific supplementation recommendations after SG. PMID- 24483965 TI - Bacteriological quality and food safety in a Brazilian school food program. AB - INTRODUCTION: Food safety is a critical issue in school food program. OBJECTIVE: This study was conducted to assess the bacteriological quality and food safety practices of a municipal school food program (MSFP) in Jequitinhonha Valley, Brazil. MATERIALS AND METHODS: A checklist based on good manufacturing practices (GMP) for food service was used to evaluate food safety practices. Samples from foods, food contact surfaces, the hands of food handlers, the water supply and the air were collected to assess bacteriological quality in establishments that comprise the MSFP. RESULTS: Nine (81.8%) establishments were classified as poor quality and two (18.2%) as medium quality. Neither Salmonella nor Listeria monocytogenes were detected in food samples. Coliforms, Escherichia coli and Staphylococcus aureus were detected in 36 (52.9%), 1 (1.5%) and 22 (32.4%) of the food samples and in 24 (40.7%), 2 (3.3%) and 13 (22.0%) of the food contact surfaces, respectively. The counts of coliforms and Staphylococcus aureus ranged from 1 to 5.0 and 1 to 5.1 log CFU/g of food, respectively. The mean aerobic mesophilic bacteria count was 3.1 log CFU/100 cm2 of surface area. Coliforms, E. coli and S. aureus were detected on the hands of 33 (73.3%), 1 (2.2%) and 36 (80%) food handlers, respectively. With regard to air quality, all the establishments had an average aerobic mesophilic count above 1.6 log CFU/cm2/week. CONCLUSIONS: The results indicate the need to modify the GMP used in food service in MSFP in relation to food safety, particularly because children served in these establishments are often the most socially vulnerable. PMID- 24483966 TI - Correlation between percentage of body fat measured by the Slaughter equation and bio impedance analysis technique in Mexican schoolchildren. AB - INTRODUCTION: Obesity is considered one of the most serious public health problems of the 21st century in children and adolescents. The percentile or Z score of the body mass index is widely used in children and adolescents to define and assess overweight and obesity, but it does not determine the percentage of total body fat. Other anthropometric measurements that determine total body fat are skinfold thickness and methods of body composition assessment such as bio impedance analysis, both of which are rapid and inexpensive. OBJECTIVE: The aim of the study was to correlate the percentage of body fat determined by the Slaughter equation with the percentage of body fat determined by the bio impedance analysis technique, and the body mass index in schoolchildren. METHODS: The design of the study is cross-sectional and it was performed on a random selection of 74 children (9.47 +/- 1.55 years old) attending a primary school in Colima, Mexico during 2011. The percentage of body fat was measured by the Slaughter equation and bio impedance analysis technique. Body mass index was calculated. Inferential statistics were performed with the non-paired Student's t test, Pearson's correlation for quantitative variables (percentage of body fat by the Slaughter equation and bio impedance analysis) and the Fisher exact test for qualitative variables. RESULTS: A significant correlation (r = 0.74; p < 0.001) was identified between the percentage of fat measured by the Slaughter equation and bio impedance analysis. We also identified a significant correlation between the percentage of fat measured by the Slaughter equation and body mass index (r = 0.85; p < 0.001) and the percentage of fat measured by bio impedance analysis and body mass index (r = 0.78; p < 0.001). CONCLUSION: Given that we identified a significant positive correlation between BIA and STE, we conclude that both are adequate alternatives for measuring the percentage of body fat among schoolchildren in our population. PMID- 24483967 TI - Hypocaloric high-protein diet improves clinical and biochemical markers in patients with nonalcoholic fatty liver disease (NAFLD). AB - OBJECTIVE: To investigate the role of hypocaloric highprotein diet, a prospective clinical study was conducted in NAFLD patients. RESEARCH METHODS AND PROCEDURES: Pre-versus post-interventional data were analyzed in 48 stable NAFLD patients (submitted to a hypocaloric high-protein diet during 75 days. Variables included anthropometrics (body mass index/ BMI and waist circumference/WC), whole-body and segmental bioimpedance analysis and biochemical tests. Diet compliance was assessed by interviews every two weeks. RESULTS: BMI, WC and body fat mass remained relatively stable (-1.3%, -1.8% and -2.5% respectively, no significance). HDL- cholesterol increased (P < 0.05) whereas total, LDL and VLDL cholesterol, triglycerides, aspartate aminotransferase/ AST, gamma glutamyltransferase/GGT, alkaline phosphatase/ AP, fasting blood glucose and glycated hemoglobin/ HbA1c decreased (P < 0.05). When patients were stratified according to increase (22/48, 45.8%) and decrease (21/48, 43.8%) of BMI, association between weight decrease and liver benefit could be elicited in such circumstances for ALT, AP and AST/ALT ratio. No change could be demonstrated in patients who gained weight. Multivariate assessment confirmed that waist circumference, ferritin, triacylglycerol, and markers of glucose homeostasis were the most relevant associated with liver enzymes. DISCUSSION: Ours results are consistent with the literature of calorie restriction in the management of NAFLD. Changes in lifestyle and weight loss are recommended for NAFLD patients. European guidelines also support this recommendation. CONCLUSION: This is the first study that demonstrated that a high protein, hypocaloric diet were associated with improvement of lipid profile, glucose homeostasis and liver enzymes in NAFLD independent on BMI decrease or body fat mass reduction. PMID- 24483968 TI - Development of a tool for quality control audits in hospital enteral nutrition. AB - BACKGROUND AND AIMS: Malnutrition is very prevalent in hospitals, causing physical capacity deterioration, increasing complications and raising mortality. This scenario overloads public health costs enormously. Enteral nutrition (EN) is the first option to fight against malnutrition. Nutrition support teams (NST) work combating such conditions, promoting humanization, but also analyzing the cost benefit of EN therapy. Brazil is one of the first Latin American countries to develop EN laws. Quality control it is in the core of this legal instrument, playing an essential role in NST's task of providing care. Nowadays, tools to access quality control represent a gap in the area. The aim of this study was to develop a quality control tool, according to Brazilian law for EN Therapy regarding multidisciplinary approach, good practices, standard operating procedures, protocol implementation, proper registration and electronic health record. METHODS: A content validation method was utilized in this four stages development process: bibliographic research, expert opinion (subjective), semantic evaluation and expert opinion (objective). In the latter stage ten specialists, expressed their opinion, evaluating the tools by four different attributes: utility, simplicity, objective and low cost on a 5-point Likert scale (1-5). RESULTS: We elaborate three independent tools that together, represent the whole evaluation process, named: NST Activities, EN Preparation and EN Administration. Content Validation Index to the four different attributes ranged form 0,9 to 1. CONCLUSION: This tool had positive approval from experts and is of great value guiding hospital audits, or even serving as checklist to implement a plan on EN therapy. PMID- 24483969 TI - [Habit based consumptions in the mediterranean diet and the relationship with anthropometric parameters in young female kayakers]. AB - INTRODUCTION: Dietary habits and body composition are possibly two of the most modifiable aspects that influence athletic performance in competition and training, especially in individual sports. OBJECTIVE: To determine Mediterranean diet adherence in a group of elite women paddlers and the relationship between these variables with anthropometric parameters and somatotype of the athlete. METHODS: A 90 women cadets who belonged to the national elite canoeing underwent a complete anthropometry according to ISAK instructions; and they selfcompleted KIDMED test to know their adherence to the Mediterranean diet. After that, anthropometric characteristics were compared based on their adherence to the Mediterranean diet. RESULTS AND DISCUSSION: One kayaker had a low adherence to the Mediterranean diet, 38 a medium adherence and 51 an excellent adherence. However, one in every three not eats nuts and one in every five makes sweets more than once a day or industrial pastries for breakfast. When it was dividing paddlers based on their Mediterranean diet adherence it was found that the two groups (low and medium adherence and excellent adherence) did not show differences in most of the anthropometric variables, composition body percentages, somatotype and body mass index. CONCLUSIONS: The paddlers show a medium or excellent Mediterranean diet adherence. There was not clear relationship between anthropometric parameters and the degree of Mediterranean diet adherence in these athletes. It is necessary to continue researching the interaction between these fields in order to indentify possible relationships with health and sport performance in elite kayakers. PMID- 24483970 TI - [Equity and nutritional inequalityin two school centers in Madrid (Spain)]. AB - INTRODUCTION: Health inequality is the difference in incidence, prevalence, mortality, volume of diseases and other adverse sanitary conditions that exist between groups of specific populations. OBJECTIVES: To analyze the possible nutritional inequalities between two educational centers of Madrid to promote healthy habits, to anticipate the obesity and the diseases associated in the children population. METHODS: Observational and transverse study on a sample of 118 students (14 years old/3oESO) of two educational centers of different socioeconomic level. They underwent a survey on lifestyle, anthropometric examinations and measurement of blood pressure and physical activity. RESULTS: In both centers normal weight prevails in both sexes without differences as for the percentage of pupils that are overweight. Major obesity is registered in the public school more than in the private school. The correlation stands out between the percentiles body mass index (BMI) and the blood pressure (BP) (to major BMI, major B.P). The food pattern is similarly independent from the socioeconomic stratum. The fifth part of the pupils (principally women) does not practice any type of physical activity in their free time and they dedicate almost 2 daily hours to sedentary activities. CONCLUSIONS: As a whole, the two educational centers are in the average weight range, even though a tendency has been found in the public school that there is double the rate of obesity. These results can be attributed to the small sample size or that the sociocultural inequality to nutritional level is not so accentuated in the city of Madrid. Prevention and promotion of healthy habits is the way of combating against overweight, juvenile obesity, cardiovascular risk factors and cardiovascular diseases in the adult age. PMID- 24483972 TI - Effect of the "protein diet" and bone tissue. AB - The aim of this study is to evaluate the effect of the hyperproteic diet consumption on bone tissue. METHODS: The study was conducted during sixty days. Twenty eight Wistar albinus rats, adults, originated from Laboratory of Experimental Nutrition were divided in four groups: (n = 7); Control 1 (C1), Control 2 (C2), Hyperproteic 1 (HP1) e Hyperproteic 2 (HP2). The C2 and HP2 groups were submitted to 30% of food restriction. The hyperproteic diet was based on the Atkins diet and prepared to simulate the protein diet. At the end of the study the animals were anesthetized to performer bone densitometry analyses by DEXA and blood and tissue collection. Serum and bone minerals analyses were conducted by colorimetric methods in automated equipment. RESULTS: The total bone mineral density (BMD) of the pelvis and the spine of the food restriction groups (HP2 e C2) were lower (p < 0.05) than C1 e HP1 groups. While the femur BMD of the HP2 was lower (p < 0.05) related to others groups. It had been observed reduction (p < 0.05) in the medium point of the width of femur diaphysis and in bone calcium level in the hyperproteic groups (HP1 e HP2). It was observed similar effect on the osteocalcin level, that presented lower (p < 0.05) in the hyperproteic groups. The insulin level was lower only in HP2 and serum calcium of the HP1 and HP2 groups was lower than C1. CONCLUSION: The protein diet promotes significant bone change on femur and in the hormones levels related to bone synthesis and maintenance of this tissue. PMID- 24483971 TI - The relationship between serum vitamin A and breast cancer staging before and after radiotherapy. AB - INTRODUCTION: Several adverse effects of radiotherapy have been associated with the process of increased oxidative stress in the organism. In this context, vitamin A noteworthy for its important role in combating oxidative stress, in addition to its chemoprotective effect. OBJECTIVE: To assess the serum levels of vitamin A (retinol and beta-carotene) and their relationship to breast cancer staging in patients before and after radiotherapy. METHODS: This is a prospective study of women with breast cancer who were evaluated from October 2011 to September 2012 before (T0) and after radiotherapy (T1-7 days). Serum retinol and beta-carotene levels were analyzed using High Performance Liquid Chromatography. The assignment of breast cancer stages was based on the classification of malignant tumors that has been proposed by the International Union Against Cancer. RESULTS: 230 patients (mean age 63.6 years, SD +/- 9.38) were evaluated. There was a significant reduction in the serum retinol (45.1 +/- 18.2 MUg/dL at T0 to 27.1 +/- 11.7 MUg/dL at T1, p < 0.001) and beta-carotene (209.0 +/- 153.6 MUg/L at T0 to 47.7 +/- 25.5 MUg/L at T1, p < 0.001). There was also a significant difference in serum retinol (p < 0.001) and beta-carotene (p = 0.003) levels based on the disease stage. CONCLUSIONS: It is recommended the early establishment of adequation serum concentrations of retinol and beta-carotene, offering nutritional assistance for those patients with deficiencies, in order to minimize the harmful effects of radiation. PMID- 24483973 TI - [Quality of clinical practice guidelines published in nutrition in hospitalized oncological adult patients]. AB - BACKGROUND: There is a high variability in clinical practice regarding nutritional care which could affect nutritional status of oncological patients. This variability can be diminished following evidence based recommendations from clinical practice guidelines (CPG) with good methodological quality in its development. OBJECTIVE: To review and evaluate the quality of published guidelines in nutrition in hospitalized oncological adult patients. METHODS: A search of CPGs was conducted in MEDLINE, EMBASE, GIN, TripDatabase and pages of recognized guidelines developers. CPGs published between 2003 and 2012 were included. Four independent reviewers assessed the quality of CPGs using the AGREE II instrument. Characteristics of assessed guidelines were extracted and analyzed. RESULTS: 22 CPGs met selection criteria. 90% of guidelines are written in English. There was great variability in quality scores for each domain. Highest rated domain was "clarity of presentation" (median 65.95, range 19.40 to 93.10) while the lowest was "Applicability" (median 21.20, range 0 to 77.10). Sixteen guidelines scored low on "rigour of development" and six had an acceptable or good quality. Only five documents can be considered as "good quality guidelines" because they showed high performance in all domains. CONCLUSION: It was found a wide range of methodological quality scores of evaluated CPGs. Highest rated guidelines are made by agencies that develop guidelines but these are little known in our country. Most of the assessed guidelines have methodological weaknesses, which can affect the quality of the recommendations they make and its validity. PMID- 24483974 TI - [Quality of the diet and lifestyles in health sciences students]. AB - OBJECTIVE: To evaluate the eating habits of the students of the University of Alicante of the degrees of Human Nutrition and Dietetics and Nursing. MATERIAL AND METHODS: The study was carried out to 184 students of both sexes (96 of Human Nutrition and Dietetics and Nursing 88) of the University of Alicante. Were weighed and carved to calculate BMI; food consumption was estimated by the reminder of 24 hours; intake of macro and micronutrients were calculated using the program Easydiet. Comparing the results obtained in both qualifications and according to nutritional status by performing the corresponding statistical analysis. RESULTS: The majority of the students analyzed are normal weight (80%). There were significant differences in the quality of the diet both degrees, being the same characteristics: low in carbohydrates and high in protein. It also shows an imbalance in the type of fat consumed, with a higher consumption of saturated and less from polyunsaturated than recommended. Likewise, analyzed that nutrition students do more exercise than the nurses, although they sleep fewer hours and spend more time in front of the computer and TV. CONCLUSION: While the levels of overweight and obesity among students is less than that of the general population, there are imbalances in your diet, noting that consumption of macronutrients is located away from the recommendations, and that there are deficiencies in the intake of micronutrients. Showing that have knowledge of nutrition, does not affect healthy decision-making to a diet and lifestyle. PMID- 24483975 TI - Supplementation prevalence and adverse effects in physical exercise practitioners. AB - INTRODUCTION: The use of nutritional supplements is prevalent among physical exercise practitioners and some adverse effects have been reported, however not sufficiently substantial, because they originate from isolated cases. OBJECTIVES: Investigate nutritional supplements consumption prevalence and adverse effects of the use of such products. METHODS: An epidemiological, representative and transversal study, with 180 physical exercise practitioners in gyms, who answered questionnaires about sports supplementation, associated factors and self perceived adverse effects. In a subsample of 86 individuals, blood pressure was measured and blood was collected for the evaluation of lipid profile markers, hepatic and renal function. RESULTS: The supplementation prevalence level was 58.3%, whereas the physicians and nutritionists indicated only 21.9%. The reported adverse effects were observed only by supplement users (acne, insomnia, aggressiveness, headaches and tachycardia). Systolic blood pressure was higher in the supplemented group when compared to the control group (p = 0.04), as in the subgroup of thermogenic users (p < 0.0001) and among those who had consumed any type of supplementation for over 2 years (p = 0.005). Serum creatinine levels were higher only in the subgroup of carbohydrates when compared to the control group (p = 0.03). Diastolic blood pressure, lipid profile and hepatic function did not present differences between groups. CONCLUSIONS: The use of nutritional supplements without specialized orientation was elevated among physical exercise practitioners, being associated to adverse effects both by the users themselves and by clinical diagnosis. PMID- 24483976 TI - [Study of two variants of nutritional risk score "NUTRIC" in ventilated critical patients]. AB - INTRODUCTION: The NUTRIC score was proposed to assess the risk of adverse events potentially modifiable through nutritional intervention in critically ill patients. This score uses interleukin-6 (IL-6), a biomarker not always available. OBJECTIVE: To study two variants of the score in patients with assisted mechanical ventilation (AMV): NUTRIC-1 without IL-6 and NUTRIC-2 with CRP as biomarker. METHODS: Observational prospective cohort with 368 patients with AMV >24 hours. The predictive capacity of both NUTRIC scores was studied by binary logistic regression. The significance level was set at 5%. RESULTS: mean age, 52 years; males 68%. Mean APACHE II score: 20.73 points. Death at the ICU: 196 (53%). Mean time on AMV of the survivals: 8.55 days. Mean NUTRIC-1 and NUTRIC-2 in the deceased-survivors: 4.23 - 3.06 (p = 0.000) and 4.68 -3.39 (p = 0.000). The mortality increased in relation to the score (p = 0.000). The calculated AUC for NUTRIC-1 and NUTRIC-2 were 0.671 (CI 0.617-0.726) and 0.679 (CI 0.624- 0.733). The mean CRP was higher in deceased patients: 13.07 mg/dL - 8.97 mg/dL (p = 0.001), the correlation improved with more days on AMV (p = 0.034 and p = 0.010) and the AUC increased in a similar way to IL-6 in the original work (0.008 and 0.007, respectively). CONCLUSION: The two studied variants of the NUTRIC score behaved similarly to the original NUTRIC score. The addition of the CRP improves the score performance and may be an alternative to IL-6, if it is not available. PMID- 24483977 TI - [Relationship among prop phenotype, body mass index, waist circumference, total body fat and food intake]. AB - The PROP phenotype (6-n-propylthiouracil) has been proposed as indicator of body mass index, adiposity and food intake. This relationship among variables is contradictory. No correlation has been found among the PROP phenotype, body indicators and energy consumption in some studies. The aim of this study was to determine the relationship among PROP taster status, body mass index (BMI), waist circumference (WC), total body fat (TBF) and food intake. The PROP taster status was established using two scales: the nine-point scale and the general labeled magnitude scale. Dietary habits of participants were recorded online during 35 days. The classification by PROP phenotype varied according to the scale. No significant differences were observed between PROP tasters and PROP non-tasters, with both scales, in body mass index, waist circumference, total body fat and energy and macronutrient intake. The PROP phenotype was not an indicator factor of body weight, adiposity and energy and macronutrients consumption in young adults. PMID- 24483978 TI - [Trans fatty acid content in foods marketed in the community of Madrid(Spain)]. AB - INTRODUCTION: As a consequence of the scientific evidence which show that the high consumption of trans fatty acids is a risk factor of certain illnesses, sanitary authorities recommend less than 1% intake of trans fatty acids of the total energy intake. Moreover, the European Commission must present, by December 2014, a report about the presence of trans fatty acids in the aliments as well as in the diet of the European Union population. Thus, this study can provide useful information to reach this objective. OBJECTIVES: To determine trans fatty acid presence in some types of foods in the Community of Madrid. METHODS: 170 samples of different foods commonly consumed by children and adolescents were selected and analized. All foods had been purchased in big shopping centers in the Community of Madrid during february of 2010. Results are shown as the percentage of each fatty acid compared to the total amount of fat in the aliment. RESULTS: Only 33 products (19.4%) showed the presence of trans fatty acids over the method detection limit (>= 0.1g per 100g). The highest levels were found in dairy products, with an average content of 0,4%. DISCUSION/CONCLUSIONES: The trans fatty acid content of the analyzed foods can be considered low, compared with the amount reported by other authors in food products marketed in Spain and other countries in the past few years. Further studies should be undertaken to control nutrition security and diet quality of fat intake in the Spanish population, particularly among children and adolescents. PMID- 24483979 TI - [Vitamin K adequacy ina representative sample of Spanish adults. Dietary determinants]. AB - BACKGROUND: Vitamin K is an essential element in the coagulation, which is also involved in gamma-carboxylation reactions of proteins as osteocalcin, which may exert a protective effect against age-dependent bone loss. But there is also evidence that both osteocalcin as vitamin K can have a benefit on the metabolism of glucose, insulin sensitivity and type 2 diabetes mellitus. Therefore, the aim of the present study is to analyse the adequacy of vitamin K intake and food sources in a representative sample of Spanish adults. METHODS: A sample of 1068 adults (521 men and 547 women) with ages ranging from 17 to 60 years, was selected in ten Spanish provinces to constitute a representative sample of the population nationwide. The dietary study was carried out by using a "Food record questionnaire" for 3 consecutive days, including a Sunday. Personal, anthropometric and health data were also collected. RESULTS: The intake of vitamin K (170.2 +/- 14.5 MUg/day) was lower than the established adequate intake for vitamin in the 30.2% of the studied participants. Vitamin intake increases with age (r = 0.201, p < 0.05), in fact, those participants who meet the adequate intake are older (34.5 +/- 12.8 years) than those who do not meet the adequate intake (with a mean age 29.1 +/- 11.9 years) (p < 0.001). Vitamin K intake also increases with weight (r = 0.106, p < 0.05) and height (r = 0.282, p < 0.05), however the participants with overweight/obesity have a significantly lower intake (168.2 +/- 13.5 g/day) than those individuals with normal weight (171.1 +/ 14.9 MUg/day) (p < 0.01). The major food source of vitamin K are vegetables (45.35% of the intake comes from this food group), followed by fats and oils (13.28%), pulses (11.69%), meat (10.62%), cereals (5.33%) and fruits (4.60%). Meeting adequate intake for vitamin K is favoured by the increase in the consumption of vegetables (OR 0.329; CI95%: 0.279, 0.387), dairy (OR 0.815; CI95%: 0.690, 0.963), pulses (OR 0.091; CI95%: 0.054, 0.154) and fruits (OR 0.774; CI95%: 0.677, 0.885) (p < 0.001). A positive correlation was found between vegetable consumption and the intake of vitamin K (r = 0.432, p < 0.001). Adults with an inadequate intake of vitamin K have a lower consumption of vegetables (2.04 +/- 1.16 servings/day) than adults with adequate intake (3.78 +/- 1.65 servings/day) (p < 0.001). CONCLUSIONS: The intake of vitamin K was lower than adequate intake in a significant percentage of the Spanish population (30.2%), which highlights the need to increase the consumption of vegetables, the major source of the vitamin (which are consumed in insufficient amount, by the 49.6% of the studied population), and to improve the diet as a whole, monitoring the intake of vitamin K, in order to obtain a nutritional and health benefit. PMID- 24483980 TI - Cadmium and lead levels consumed by patients with oral hospital diets prescriptions. AB - INTRODUCTION: The levels of cadmium (Cd) and lead (Pb) in foods should be monitored as a function of health risks. OBJECTIVE: To evaluate Cd and Pb levels in oral hospital diets and in an oral food complement (OFC) according to their respective consumption by patients, and to estimate the patient's exposition risk. METHODS: The levels of Cd and Pb were determined by ICP-OES in samples of regular, blend, soft and renal diets and OFC, collected on 6 weekdays. About 14.3% of the diets and OFC served were analyzed. RESULTS AND DISCUSSION: 163 patients participated, with mean weights and ages of 62.7 kg and 56.5 years, respectively, the majority being men (59.5%). The mean Cd content consumed was greater for men fed the regular and blend diets and similar amongst the sexes for the soft diet. The consumption of Cd (max. 21.02 MUg/day) was below the provisional tolerable monthly intake (PTMI). The mean Pb ingested (max. 199.49 MUg/day) was similar amongst the sexes. The soft diet showed the highest Pb content in September/2010, whereas the other showed no variation according to season. In September/2010 and January/2011, the soft and regular diets associated with the OFC offered 207.50 and 210.50 MUg/day of Pb, respectively. CONCLUSIONS: The combination of the diet with the OFC increased the risk of an excessive ingestion of Pb, and the vulnerability of the patients to an excessive exposition to Pb could be greater due to water and medications. It was concluded that whereas the calculated ingestion of Cd conformed to the PTMI, the Pb level and ingestion represented a risk to the health of the patients. PMID- 24483981 TI - Iodine nutrition and thyroid function assessment in childbearing age women from Queretaro, Mexico. AB - OBJECTIVE: To assess iodine nutrition and thyroid function in Mexican childbearing age women. METHODS: 101 childbearing age women (21.7 +/- 3.5 years) randomly selected from the university student population participated in this cross-sectional study. TSH, thyroid hormones, anti-thyroid antibodies, thyroid volume, iodine intake, and urinary iodine concentration (UIC) were assessed. The knowledge about the importance of iodine in nutrition was also evaluated by using questionnaires. RESULTS: TSH median (interquartile range) value was 1.9 (1.4-2.5) mIU/L, while FT4 median value was 9.0 (8.3- 9.6) MUg/dL. The median FT3 and total rT3 values were 3.3 pg/mL and 40.1 ng/dL, respectively. The prevalence of subclinical hypothyroidism (serum TSH >4.5 mIU/L) and of positive anti-thyroid antibodies were 2.9% and <5.9%, respectively. Median thyroid volume was 5.6 mL and none of the subjects were diagnosed with goiter. Median urinary iodine concentration was 146 (104-180) MUg/L. As for the knowledge of iodine nutrition, only 37.6% considered that a pregnant woman needs more dietary iodine than a non pregnant woman, while 43.6% recognized that the lack of iodine can cause mental retardation in children. CONCLUSIONS: Prevalence of thyroid test function abnormalities was low in this population and the median UIC indicates adequate iodine intake. We also found a poor knowledge about the importance iodine nutrition in the studied population. PMID- 24483982 TI - [Biliopancreatic diversion and simultaneous resection of a giant ulcerated fatty mass in a patient with body mass index: 75]. AB - Bariatric Surgery is currently the best treatment option for patients with Morbid Obesity and a Body Mass Index >= 40 kg/m2. Despite its high rate of postoperative and nutritional complications, biliopancreatic diversion (Scopinaro s procedure) has shown best results in terms of excess weight loss and improving obesity associated diseases. This technique was performed on a 52-year-old woman (weight = 174 Kg, height = 152 cm, BMI= 75.3 kg/m2), with a classic open access due to anaesthesiologist's indication. During this procedure it was also performed a resection of a giant fatty mass on the inner side of left lower limb, which was ulcerated and infected. Postoperative period was uneventful, excepting wound dehiscence of the leg, requiring re-suturing. Six months after hospital discharge, the patient's percent excess weight loss was 36.98%. In our bariatric surgery series, with more than 400 patients since 2002, this patient was the one with the highest BMI. PMID- 24483983 TI - Use of a symbiotic supplement in a child with short bowel Syndrome; a case report. AB - The short bowel syndrome (SBS) is due to loss of bowel after surgery. Characterized by generalized nutrients malabsorption, its signs and symptoms include electrolyte imbalance, deficiency of vitamins, minerals and nutrients that can lead to death. Parenteral and enteral nutrition have a key role in its treatment. OBJECTIVE: To describe the clinical course of a patient with SBS during continuous use of enteral nutrition supplemented with symbiotic. CASE REPORT: A seven-year-old male underwent an emergency laparotomy at 18 months old with a massive bowel resection, remaining about 20 cm of the small intestine and the entire colon. He was dependent of exclusive parenteral nutrition for over a year, leading to the occurrence of numerous infectious complications. Due to complications caused by prolonged use of central venous access, was unable to continue to receive the parenteral nutrition. Enteral nutrition by a nasogastric tube and supplemental symbiotic was the nutritional therapy option for him. The assessment of the volume of losses by the colostomy was measured daily. RESULTS: There was a significant reduction of losses by colostomy, especially in the first days after introduction of the enteral nutrition plus symbiotic supplementation, as well as significant decrease in gas production. CONCLUSION: Despite the lack of evidence for a formal recommendation on the use of symbiotic for SBS patients, its use in the nutritional therapy of this patient resulted in reduced electrolyte loss electrolyte and consequent improvement of his clinical and nutritional condition. PMID- 24483984 TI - [Not Available]. PMID- 24483985 TI - [Not Available]. PMID- 24483988 TI - Risk factors for porcine reproductive and respiratory syndrome outbreaks in Vietnamese small stock farms. AB - AIM: To examine risk factors that could have played a role in the 2010 porcine reproductive and respiratory syndrome (PRRS) outbreak in Yenhung district, Quangninh province, North-Vietnam, with the purpose of establishing why existing control measures implemented after previous outbreaks had failed to prevent further outbreaks. METHODS: A case-control study was carried out in Yenhung district. Data were obtained by an interview-based questionnaire survey. The sampling unit was households, which equated to small-scale pig farms. A total of 150 case and 150 control households were selected at communes affected by the 2010 PRRS epidemic during April to June. Risk factors were analysed using binary logistic regression and unconditional multiple logistic regression. RESULTS: Households infected with PRRS were significantly associated with multiple variables belonging to three main groups: (1) location of the farms: i.e. farms positioned <1,000 m from a pig abattoir or within 500 m of local markets or 100 m of main roads; (2) farm management: i.e. where there was non-application of weekly farm disinfection, feeding uncooked swill, new introduction of purchased pigs without isolation, or usage of water from irrigation systems for raising pigs; (3) people and animal contact: i.e. where households kept animals with either no confinement or partial confinement, had visits by family members to other affected farms or had frequent visits by neighbours. The use of water from irrigation systems was found to be the risk factor most strongly associated with infected households in the 2010 outbreak (OR=22; 95% CI=12-42). CONCLUSIONS: The results show that the epidemiology of PRRS in Quangninh province was linked to sociological and cultural practices, and that effective PRRS control needs an integrated approach coupled with behavioural changes in the pig raising practices of the general public. Failure to recognise this could explain why further outbreaks have occurred. PMID- 24483989 TI - Histological subclassification of cirrhosis can predict recurrence after curative resection of hepatocellular carcinoma. AB - BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after curative resection continues to be a major cause of death. This prospective study is designed to investigate whether histological subclassification of cirrhosis using the Laennec system could predict recurrence in patients with hepatitis B virus (HBV)-related HCC after curative resection. METHODS: Patients with HBV-related HCC who underwent curative resection and showed Laennec stage 3 to 4 were enrolled and the cases with stage 4 were subclassified histologically into three groups (stages 4A, 4B and 4C) according to the Laennec system. Between February 2006 and August 2009, 92 patients were recruited. RESULTS: Stage 3, 4A, 4B and 4C were identified in 24 (26.1%), 15 (16.3%), 43 (46.7%) and 10 (10.9%) patients respectively. The cumulative incidence rates of recurrence at 1, 2 and 3 years were 24.2%, 40.5% and 55.1% respectively. On multivariate analysis, serum albumin [hazard ratio (HR), 0.528; 95% confidence interval (CI), 0.312-0.891; P=0.017] and Edmondson-Steiner grade III-IV (HR, 3.456; 95% CI, 1.123-10.517; P=0.031) were significantly correlated with early recurrence (<1 year), whereas stage 4C (HR, 5.426; 95% CI, 1.030-28.598; P=0.046) was the only independent risk factor for late recurrence (>=1 year). CONCLUSIONS: Histological subclassification of cirrhosis using the Laennec system is a significant predictor of late recurrence in patients with HBV-related HCC after curative resection. PMID- 24483991 TI - Impact of Cu doping on the structure and electronic properties of LaCr(1 y)Cu(y)O3. AB - Oxides of the type LaCr(1-y)Cu(y)O3 have been prepared using solid-state methods and their crystal structures refined using synchrotron X-ray powder diffraction. The solubility limit of Cu was found to be around y = 0.2, and such oxides are orthorhombic in space group Pbnm. X-ray absorption spectroscopy measurements at the Cr and Cu L-edges demonstrated that the Cr remains trivalent upon Cu doping, with the Cu being present as Cu(III). The oxides are found to be antiferromagnets, and the Neel temperature, TN, decreases as the Cu content is increased. The crystal and magnetic structures of one example La(Cr0.85Cu0.15)O3 have been investigated between 3 and 350 K by neutron powder diffraction. The samples are semiconductors. PMID- 24483990 TI - Mutational and expressional analysis of SMC2 gene in gastric and colorectal cancers with microsatellite instability. AB - Structural maintenance of chromosomes 2 (SMC2) gene encodes condensin complexes that are required for proper chromosome segregation and maintenance of chromosomal stability. Although cells with defective chromosome segregation become aneuploid and are prone to harbor chromosome instability, pathologic implications of SMC2 gene alterations are largely unknown. In a public database, we found that SMC2 gene had mononucleotide repeats that could be mutated in cancers with microsatellite instability (MSI). In this study, we analyzed these repeats in 32 gastric cancers (GC) with high MSI (MSI-H), 59 GC with low MSI (MSI L)/stable MSI (MSS), 43 colorectal cancers (CRC) with MSI-H and 60 CRC with MSI L/MSS by single-strand conformation polymorphism (SSCP) and DNA sequencing. We also analyzed SMC2 protein expression in GC and CRC tissues using immunohistochemistry. We found SMC2 frameshift mutations in two GC and two CRC that would result in truncation of SMC2. The mutations were detected exclusively in MSI-H cancers, but not in MSI-L/MSS cancers. Loss of SMC2 expression was observed in 22% of GC and 25% of CRC. Of note, all of the cancers with SMC2 frameshift mutations displayed loss of SMC2 expression. Also, both GC and CRC with MSI-H had significantly higher incidences in SMC2 frameshift mutations and loss of SMC2 expression than those with MSI-L/MSS. Our data indicate that SMC2 gene is altered by both frameshift mutation and loss of expression in GC and CRC with MSI-H, and suggest that SMC2 gene alterations might be involved in pathogenesis of these cancers. PMID- 24483992 TI - High sensitivity detection and quantitation of DNA copy number and single nucleotide variants with single color droplet digital PCR. AB - In this study, we present a highly customizable method for quantifying copy number and point mutations utilizing a single-color, droplet digital PCR platform. Droplet digital polymerase chain reaction (ddPCR) is rapidly replacing real-time quantitative PCR (qRT-PCR) as an efficient method of independent DNA quantification. Compared to quantative PCR, ddPCR eliminates the needs for traditional standards; instead, it measures target and reference DNA within the same well. The applications for ddPCR are widespread including targeted quantitation of genetic aberrations, which is commonly achieved with a two-color fluorescent oligonucleotide probe (TaqMan) design. However, the overall cost and need for optimization can be greatly reduced with an alternative method of distinguishing between target and reference products using the nonspecific DNA binding properties of EvaGreen (EG) dye. By manipulating the length of the target and reference amplicons, we can distinguish between their fluorescent signals and quantify each independently. We demonstrate the effectiveness of this method by examining copy number in the proto-oncogene FLT3 and the common V600E point mutation in BRAF. Using a series of well-characterized control samples and cancer cell lines, we confirmed the accuracy of our method in quantifying mutation percentage and integer value copy number changes. As another novel feature, our assay was able to detect a mutation comprising less than 1% of an otherwise wild type sample, as well as copy number changes from cancers even in the context of significant dilution with normal DNA. This flexible and cost-effective method of independent DNA quantification proves to be a robust alternative to the commercialized TaqMan assay. PMID- 24483993 TI - Experimental joint quantum measurements with minimum uncertainty. AB - Quantum physics constrains the accuracy of joint measurements of incompatible observables. Here we test tight measurement-uncertainty relations using single photons. We implement two independent, idealized uncertainty-estimation methods, the three-state method and the weak-measurement method, and adapt them to realistic experimental conditions. Exceptional quantum state fidelities of up to 0.999 98(6) allow us to verge upon the fundamental limits of measurement uncertainty. PMID- 24483994 TI - Experimental test of error-disturbance uncertainty relations by weak measurement. AB - We experimentally test the error-disturbance uncertainty relation (EDR) in generalized, strength-variable measurement of a single photon polarization qubit, making use of weak measurement that keeps the initial signal state practically unchanged. We demonstrate that the Heisenberg EDR is violated, yet the Ozawa and Branciard EDRs are valid throughout the range of our measurement strength. PMID- 24483995 TI - Contextuality in bosonic bunching. AB - In the classical probability theory a sum of probabilities of three pairwise exclusive events is always bounded by one. This is also true in quantum mechanics if these events are represented by pairwise orthogonal projectors. However, this might not be true if the three events refer to a system of indistinguishable particles. We show that one can find three pairwise exclusive events for a system of three bosonic particles whose corresponding probabilities sum to 3/2. This can be done under assumptions of realism and noncontextuality, i.e., that it is possible to assign outcomes to events before measurements are performed and in a way that does not depend on a particular measurement setup. The root of this phenomenon comes from the fact that for indistinguishable particles there are events that can be deduced to be exclusive under the aforementioned assumptions, but at the same time are complementary because the corresponding projectors are not orthogonal. PMID- 24483996 TI - Soliton gyroscopes in media with spatially growing repulsive nonlinearity. AB - We find that the recently introduced model of self-trapping supported by a spatially growing strength of a repulsive nonlinearity gives rise to robust vortex-soliton tori, i.e., three-dimensional vortex solitons, with topological charges S>=1. The family with S=1 is completely stable, while the one with S=2 has alternating regions of stability and instability. The families are nearly exactly reproduced in an analytical form by the Thomas-Fermi approximation. Unstable states with S=2 and 3 split into persistently rotating pairs or triangles of unitary vortices. Application of a moderate torque to the vortex torus initiates a persistent precession mode, with the torus' axle moving along a conical surface. A strong torque heavily deforms the vortex solitons, but, nonetheless, they restore themselves with the axle oriented according to the vectorial addition of angular momenta. PMID- 24483997 TI - Four-coloring model and frustrated superfluidity in the diamond lattice. AB - We propose a novel four-coloring model which describes "frustrated superfluidity" of p-band bosons in the diamond optical lattice. The superfluid phases of the condensate wave functions on the diamond-lattice bonds are mapped to four distinct colors at low temperatures. The fact that a macroscopic number of states satisfy the constraints that four differently colored bonds meet at the same site leads to an extensive degeneracy in the superfluid ground state at the classical level. We demonstrate that the phase of the superfluid wave function as well as the orbital angular momentum correlations exhibit a power-law decay in the degenerate manifold that is described by an emergent magnetostatic theory with three independent flux fields. Our results thus provide a novel example of critical superfluid phase with algebraic order in three dimensions. We further show that quantum fluctuations favor a Neel ordering of orbital angular moments with broken sublattice symmetry through the order-by-disorder mechanism. PMID- 24483998 TI - Constraint-driven condensation in large fluctuations of linear statistics. AB - Condensation is the phenomenon whereby one of a sum of random variables contributes a finite fraction to the sum. It is manifested as an aggregation phenomenon in diverse physical systems such as coalescence in granular media, jamming in traffic, and gelation in networks. We show here that the same condensation scenario, which normally happens only if the underlying probability distribution has tails heavier than exponential, can occur for light-tailed distributions in the presence of additional constraints. We demonstrate this phenomenon on the sample variance, whose probability distribution conditioned on the particular value of the sample mean undergoes a phase transition. The transition is manifested by a change in behavior of the large deviation rate function. PMID- 24483999 TI - Putting water on a lattice: the importance of long wavelength density fluctuations in theories of hydrophobic and interfacial phenomena. AB - The physics of air-water interfaces plays a central role in modern theories of the hydrophobic effect. Implementing these theories, however, has been hampered by the difficulty of addressing fluctuations in the shape of such soft interfaces. We show that this challenge is a fundamental consequence of mapping long wavelength density variations onto discrete degrees of freedom. Drawing from studies of surface roughness in lattice models, we account for the resulting nonlinearities simply but accurately. Simulations show that this approach captures complex solvation behaviors quantitatively. PMID- 24484000 TI - Anomalous anisotropies of cosmic rays from turbulent magnetic fields. AB - The propagation of cosmic rays (CRs) in turbulent interstellar magnetic fields is typically described as a spatial diffusion process. This formalism predicts only a small deviation from an isotropic CR distribution in the form of a dipole in the direction of the CR density gradient or relative background flow. We show that the existence of a global CR dipole moment necessarily generates a spectrum of higher multipole moments in the local CR distribution. These anomalous anisotropies are a direct consequence of Liouville's theorem in the presence of a local turbulent magnetic field. We show that the predictions of this model are in excellent agreement with the observed power spectrum of multi-TeV CRs. PMID- 24484001 TI - Resurgence in quantum field theory: nonperturbative effects in the principal chiral model. AB - We explain the physical role of nonperturbative saddle points of path integrals in theories without instantons, using the example of the asymptotically free two dimensional principal chiral model (PCM). Standard topological arguments based on homotopy considerations suggest no role for nonperturbative saddles in such theories. However, the resurgence theory, which unifies perturbative and nonperturbative physics, predicts the existence of several types of nonperturbative saddles associated with features of the large-order structure of the perturbation theory. These points are illustrated in the PCM, where we find new nonperturbative "fracton" saddle point field configurations, and suggest a quantum interpretation of previously discovered "uniton" unstable classical solutions. The fractons lead to a semiclassical realization of IR renormalons in the circle-compactified theory and yield the microscopic mechanism of the mass gap of the PCM. PMID- 24484005 TI - Magnetic trapping of cold bromine atoms. AB - Magnetic trapping of bromine atoms at temperatures in the millikelvin regime is demonstrated for the first time. The atoms are produced by photodissociation of Br2 molecules in a molecular beam. The lab-frame velocity of Br atoms is controlled by the wavelength and polarization of the photodissociation laser. Careful selection of the wavelength results in one of the pair of atoms having sufficient velocity to exactly cancel that of the parent molecule, and it remains stationary in the lab frame. A trap is formed at the null point between two opposing neodymium permanent magnets. Dissociation of molecules at the field minimum results in the slowest fraction of photofragments remaining trapped. After the ballistic escape of the fastest atoms, the trapped slow atoms are lost only by elastic collisions with the chamber background gas. The measured loss rate is consistent with estimates of the total cross section for only those collisions transferring sufficient kinetic energy to overcome the trapping potential. PMID- 24484004 TI - Angular momentum sensitive two-center interference. AB - In quantum mechanics the Young-type double-slit experiment can be performed with electrons either traveling through a double slit or being coherently emitted from two inversion symmetric molecular sites. In the latter one the valence photoionization cross sections of homonuclear diatomic molecules were predicted to oscillate over kinetic energy almost 50 years ago. Beyond the direct proof of the oscillatory behavior of these photoionization cross sections sigma, we show that the angular distribution of the emitted electrons reveals hitherto unexplored information on the relative phase shift between the corresponding partial waves through two-center interference patterns. PMID- 24484006 TI - Two-center interferences in dielectronic transitions in H2(+) + He collisions. AB - Molecular two-center interferences in a collision induced excitation of H2(+) projectile ions, with simultaneous ionization of helium target atoms, are investigated in a kinematically complete experiment. In the process under investigation, the helium atom is singly ionized and simultaneously the molecular hydrogen ion is dissociated. Different collision mechanisms are identified and interference fringes emerging from a correlated first-order mechanism and from an independent second-order process are observed. PMID- 24484003 TI - Measurement of the 1H(gamma, p)pi0 reaction using a novel nucleon spin polarimeter. AB - We report the first large-acceptance measurement of polarization transfer from a polarized photon beam to a recoiling nucleon. The measurement pioneers a novel polarimetry technique, which can be applied to many other nuclear and hadron physics experiments. The commissioning reaction of 1H(gamma, p)pi0 in the range 0.4 ? l(-4/3). We present experimental measurements of the rotational statistics of neutrally buoyant rods with lengths 2.8 piDD* at sqrt[s] = 4.26 GeV. AB - We report on a study of the process e+ e- -> pi+/- (DD*)? at sqrt[s] = 4.26 GeV using a 525 pb(-1) data sample collected with the BESIII detector at the BEPCII storage ring. A distinct charged structure is observed in the (DD*)? invariant mass distribution. When fitted to a mass-dependent-width Breit-Wigner line shape, the pole mass and width are determined to be Mpole = (3883.9+/-1.5(stat)+/ 4.2(syst)) MeV/c2 and Gammapole = (24.8+/-3.3(stat)+/-11.0(syst)) MeV. The mass and width of the structure, which we refer to as Zc(3885), are 2sigma and 1sigma, respectively, below those of the Zc(3900) -> pi+/- J/psi peak observed by BESIII and Belle in pi+ pi- J/psi final states produced at the same center-of-mass energy. The angular distribution of the piZc(3885) system favors a JP = 1+ quantum number assignment for the structure and disfavors 1- or 0-. The Born cross section times the DD* branching fraction of the Zc(3885) is measured to be sigma(e+ e- -> pi+/- Zc(3885)?)*B(Zc(3885)? -> (DD*)?) = (83.5+/-6.6(stat)+/ 22.0(syst)) pb. Assuming the Zc(3885) -> DD* signal reported here and the Zc(3900) -> piJ/psi signal are from the same source, the partial width ratio (Gamma(Zc(3885) -> DD*)/Gamma(Zc(3900) -> piJ/psi)) = 6.2+/-1.1(stat)+/-2.7(syst) is determined. PMID- 24484022 TI - Quantized superfluid vortex rings in the unitary Fermi gas. AB - In a recent article, Yefsah et al. [Nature (London) 499, 426 (2013)] report the observation of an unusual excitation in an elongated harmonically trapped unitary Fermi gas. After phase imprinting a domain wall, they observe oscillations almost an order of magnitude slower than predicted by any theory of domain walls which they interpret as a "heavy soliton" of inertial mass some 200 times larger than the free fermion mass or 50 times larger than expected for a domain wall. We present compelling evidence that this "soliton" is instead a quantized vortex ring, by showing that the main aspects of the experiment can be naturally explained within the framework of time-dependent superfluid density functional theories. PMID- 24484023 TI - Discontinuities in the first and second sound velocities at the Berezinskii Kosterlitz-Thouless transition. AB - We calculate the temperature dependence of the first and second sound velocities in the superfluid phase of a 2D dilute Bose gas by solving Landau's two fluid hydrodynamic equations. We predict the occurrence of a significant discontinuity in both velocities at the critical temperature, as a consequence of the jump of the superfluid density characterizing the Berezinskii-Kosterlitz-Thouless transition. The key role of the thermal expansion coefficient is discussed. We find that second sound in this dilute Bose gas can be easily excited through a density perturbation, thereby, making the perspective of the measurement of the superfluid density particularly favorable. PMID- 24484024 TI - Quantum and thermal dispersion forces: application to graphene nanoribbons. AB - The van der Waals dispersion force between graphene nanoribbons is investigated. For this purpose, a nonretarded Lifshitz-like formula for parallel 1D systems is presented within the random phase approximation. Using the response properties of the ribbons from a tight binding model, it is found that the qualitative behavior of the force is similar to the one between two insulating 1D systems. On the other hand, the quantum mechanical van der Waals force can become thermal in nature when the nanoribbons have sufficiently strong chemical potential. It is found that this tuning capability is due to the unique dielectric properties of graphene nanoribbons. Results for other typical 1D materials are also presented, which enable building a better understanding of this ubiquitous force at reduced dimensions. PMID- 24484026 TI - Direct evidence for local symmetry breaking during a strain glass transition. AB - Strain glass transition is a unique nanoscale displacive transition with local symmetry breaking while maintaining the macroscopic symmetry or average structure unchanged. It usually occurs in the "nonmartensitic" composition range of a martensitic system. So far, only indirect evidence exists for such a transition, essentially from macroscopic measurements and low-resolution transmission electron microscopy observations, and there is a lack of direct evidence for the speculated local symmetry breaking and the sluggish nature of the glass transition. In this Letter we report in situ high-resolution transmission electron microscopy observations on a Ti50(Pd41Cr9) strain glass alloy and direct evidence for these key issues. Our results show that at temperatures well above the strain glass transition temperature (Tg), the lattice is essentially an undistorted B2 structure. With approaching Tg, the local symmetry breaking gradually occurs with the formation and growth of nanomartensite clusters with a combined stacking period of three and four plane intervals, but the average structure measured by x-ray diffraction remains B2. These nanomartensite clusters become finally frozen below Tg. Our results provide not only a microscopic basis for the macroscopic properties of strain glass, but also new insights into a range of possible applications of this unique class of materials. PMID- 24484021 TI - Measurements of an ablator-gas atomic mix in indirectly driven implosions at the National Ignition Facility. AB - We present the first results from an experimental campaign to measure the atomic ablator-gas mix in the deceleration phase of gas-filled capsule implosions on the National Ignition Facility. Plastic capsules containing CD layers were filled with tritium gas; as the reactants are initially separated, DT fusion yield provides a direct measure of the atomic mix of ablator into the hot spot gas. Capsules were imploded with x rays generated in hohlraums with peak radiation temperatures of ~294 eV. While the TT fusion reaction probes conditions in the central part (core) of the implosion hot spot, the DT reaction probes a mixed region on the outer part of the hot spot near the ablator-hot-spot interface. Experimental data were used to develop and validate the atomic-mix model used in two-dimensional simulations. PMID- 24484027 TI - Encoding of memory in sheared amorphous solids. AB - We show that memory can be encoded in a model amorphous solid subjected to athermal oscillatory shear deformations, and in an analogous spin model with disordered interactions, sharing the feature of a deformable energy landscape. When these systems are subjected to oscillatory shear deformation, they retain memory of the deformation amplitude imposed in the training phase, when the amplitude is below a "localization" threshold. Remarkably, multiple persistent memories can be stored using such an athermal, noise-free, protocol. The possibility of such memory is shown to be linked to the presence of plastic deformations and associated limit cycles traversed by the system, which exhibit avalanche statistics also seen in related contexts. PMID- 24484025 TI - Role of disorder in the thermodynamics and atomic dynamics of glasses. AB - We measured the density of vibrational states (DOS) and the specific heat of various glassy and crystalline polymorphs of SiO2. The typical (ambient) glass shows a well-known excess of specific heat relative to the typical crystal (alpha quartz). This, however, holds when comparing a lower-density glass to a higher density crystal. For glassy and crystalline polymorphs with matched densities, the DOS of the glass appears as the smoothed counterpart of the DOS of the corresponding crystal; it reveals the same number of the excess states relative to the Debye model, the same number of all states in the low-energy region, and it provides the same specific heat. This shows that glasses have higher specific heat than crystals not due to disorder, but because the typical glass has lower density than the typical crystal. PMID- 24484028 TI - Adsorbate electric fields on a cryogenic atom chip. AB - We investigate the behavior of electric fields originating from adsorbates deposited on a cryogenic atom chip as it is cooled from room temperature to cryogenic temperature. Using Rydberg electromagnetically induced transparency, we measure the field strength versus distance from a 1 mm square of yttrium barium copper oxide (YBCO) patterned onto a yttria stabilized zirconia chip substrate. We find a localized and stable dipole field at room temperature and attribute it to a saturated layer of chemically adsorbed rubidium atoms on the YBCO. As the chip is cooled towards 83 K we observe a change in sign of the electric field as well as a transition from a localized to a delocalized dipole density. We relate these changes to the onset of physisorption on the chip surface when the van der Waals attraction overcomes the thermal desorption mechanisms. Our findings suggest that through careful selection of substrate materials, it may be possible to reduce the electric fields caused by atomic adsorption on chips, opening up experiments to controlled Rydberg-surface coupling schemes. PMID- 24484029 TI - Self-doping of ultrathin insulating films by transition metal atoms. AB - Single magnetic Co atoms are deposited on atomically thin NaCl films on Au(111). Two different adsorption sites are revealed by high-resolution scanning tunneling microscopy (STM), i.e., at Na and at Cl locations. Using density functional based simulations of the STM images, we show that the Co atoms substitute with either a Na or Cl atom of the NaCl surface, resulting in cationic and anionic Co dopants with a high thermal stability. The dependence of the magnetic coupling between neighboring Co atoms on their separation is investigated via spatially resolved measurement of the local density of states. PMID- 24484030 TI - Order, criticality, and excitations in the extended Falicov-Kimball model. AB - Using exact numerical techniques, we investigate the nature of excitonic (electron-hole) bound states and the development of exciton coherence in the one dimensional half-filled extended Falicov-Kimball model. The ground-state phase diagram of the model exhibits, besides band-insulator and staggered orbital ordered phases, an excitonic insulator (EI) with power-law correlations. The criticality of the EI state shows up in the von Neumann entropy. The anomalous spectral function and condensation amplitude provide the binding energy and coherence length of the electron-hole pairs which, on their part, point towards a Coulomb interaction driven crossover from BCS-like electron-hole pairing fluctuations to tightly bound excitons. We show that while a mass imbalance between electrons and holes does not affect the location of the BCS-BEC crossover regime, it favors staggered orbital ordering to the disadvantage of the EI. Within the Bose-Einstein condensation (BEC) regime, the quasiparticle dispersion develops a flat valence-band top, in accord with the experimental finding for Ta2NiSe5. PMID- 24484031 TI - From dia- to paramagnetic orbital susceptibility of massless fermions. AB - We study the orbital susceptibility of multiband systems with a pair of Dirac points interpolating between honeycomb and dice lattices. Despite having the same zero-field energy spectrum, these different systems exhibit spectacular differences in their orbital magnetic response, ranging from dia- to paramagnetism at Dirac points. We show that this striking behavior is related to a topological Berry phase varying continuously from pi (graphene) to 0 (dice). The latter strongly constrains interband effects, resulting in an unusual dependence of the magnetic response also at finite doping. PMID- 24484032 TI - Resonant x-ray scattering and the j(eff) = 1/2 electronic ground state in iridate perovskites. AB - The resonant x-ray scattering (magnetic elastic, RXMS, and inelastic, RIXS) of Ir4+ at the L2,3 edges relevant to spin-orbit Mott insulators A(n+1)Ir(n)O(3n+1) (A = Sr, Ba, etc.) are calculated using a single-ion model which treats the spin orbit and tetragonal crystal-field terms on an equal footing. Both RXMS and RIXS in the spin-flip channel are found to display a nontrivial dependence on the direction of the magnetic moment, MU. Crucially, we show that for MU in the ab plane, RXMS in the cross-polarized channel at the L2 edge is zero irrespective of the tetragonal crystal field; spin-flip RIXS, relevant to measurements of magnons, behaves reciprocally, being zero at L2 when MU is perpendicular to the ab plane. Our results have important implications for the assignment of a j(eff) = 1/2 ground state on the basis of resonant x-ray experiments. PMID- 24484033 TI - Stochastic current-induced magnetization switching in a single semiconducting ferromagnetic layer. AB - We show experimental evidence of magnetization switching in a single (Ga,Mn)(As,P) semiconducting ferromagnetic layer, attributed to a strong reduction of the magnetization and the anisotropy due to current injection. The nucleation of magnetization reversal is found to occur even in the absence of a magnetic field and to be both anisotropic and stochastic. Our findings highlight a new mechanism of magnetization manipulation based on spin accumulation in a semiconductor material. PMID- 24484034 TI - Observation of edge transport in the disordered regime of topologically insulating InAs/GaSb quantum wells. AB - We observe edge transport in the topologically insulating InAs/GaSb system in the disordered regime. Using asymmetric current paths we show that conduction occurs exclusively along the device edge, exhibiting a large Hall signal at zero magnetic fields, while for symmetric current paths, the conductance between the two mesoscopicly separated probes is quantized to 2e2/h. Both quantized and self averaged transport show resilience to magnetic fields, and are temperature independent for temperatures between 20 mK and 1 K. PMID- 24484035 TI - Coherent operations and screening in multielectron spin qubits. AB - Multielectron spin qubits are demonstrated, and performance examined by comparing coherent exchange oscillations in coupled single-electron and multielectron quantum dots, measured in the same device. Fast (>1 GHz) exchange oscillations with a quality factor Q~15 are found for the multielectron case, compared to Q~2 for the single-electron case, the latter consistent with experiments in the literature. A model of dephasing that includes voltage and hyperfine noise is developed that is in good agreement with both single- and multielectron data, though in both cases additional exchange-independent dephasing is needed to obtain quantitative agreement across a broad parameter range. PMID- 24484036 TI - Quantum Hall criticality and localization in graphene with short-range impurities at the Dirac point. AB - We explore the longitudinal conductivity of graphene at the Dirac point in a strong magnetic field with two types of short-range scatterers: adatoms that mix the valleys and "scalar" impurities that do not mix them. A scattering theory for the Dirac equation is employed to express the conductance of a graphene sample as a function of impurity coordinates; an averaging over impurity positions is then performed numerically. The conductivity sigma is equal to the ballistic value 4e2/pih for each disorder realization, provided the number of flux quanta considerably exceeds the number of impurities. For weaker fields, the conductivity in the presence of scalar impurities scales to the quantum-Hall critical point with sigma?4*0.4e2/h at half filling or to zero away from half filling due to the onset of Anderson localization. For adatoms, the localization behavior is also obtained at half filling due to splitting of the critical energy by intervalley scattering. Our results reveal a complex scaling flow governed by fixed points of different symmetry classes: remarkably, all key manifestations of Anderson localization and criticality in two dimensions are observed numerically in a single setup. PMID- 24484037 TI - Topologically protected conduction state at carbon foam surfaces: an ab initio study. AB - We report results of ab initio electronic structure and quantum conductance calculations indicating the emergence of conduction at the surface of semiconducting carbon foams. The occurrence of new conduction states is intimately linked to the topology of the surface and not limited to foams of elemental carbon. Our interpretation based on rehybridization theory indicates that conduction in the foam derives from first- and second-neighbor interactions between p? orbitals lying in the surface plane, which are related to p? orbitals of graphene. The topologically protected conducting state occurs on bare and hydrogen-terminated foam surfaces and is thus unrelated to dangling bonds. Our results for carbon foam indicate that the conductance behavior may be further significantly modified by surface patterning. PMID- 24484038 TI - Nature of quasielectrons and the continuum of neutral bulk excitations in Laughlin quantum Hall fluids. AB - We construct model wave functions for a family of single-quasielectron states supported by the nu = 1/3 fractional quantum Hall fluid. The charge e* = e/3 quasielectron state is identified as a composite of a charge-2e* quasiparticle and a -e* quasihole, orbiting around their common center of charge with relative angular momentum nh > 0, and corresponds precisely to the "composite fermion" construction based on a filled n = 0 Landau level plus an extra particle in level n > 0. An effective three-body model (one 2e* quasiparticle and two -e* quasiholes) is introduced to capture the essential physics of the neutral bulk excitations. PMID- 24484039 TI - Counter-propagating edge modes and topological phases of a kicked quantum Hall system. AB - A periodically driven quantum Hall system in a fixed magnetic field is found to exhibit a series of phases featuring anomalous edge modes with the "wrong" chirality. This leads to pairs of counter-propagating chiral edge modes at each edge, in sharp contrast to stationary quantum Hall systems. We show that the pair of Floquet edge modes are protected by the chiral (sublattice) symmetry, and that they are robust against static disorder. The existence of distinctive phases with the same Chern and winding numbers but very different edge state spectra points to the important role played by symmetry in classifying topological properties of driven systems. We further explore the evolution of the edge states with driving using a simplified model, and discuss their experimental signatures. PMID- 24484040 TI - Demonstration of geometric Landau-Zener interferometry in a superconducting qubit. AB - Geometric quantum manipulation and Landau-Zener interferometry have been separately explored in many quantum systems. In this Letter, we combine these two approaches to study the dynamics of a superconducting phase qubit. We experimentally demonstrate Landau-Zener interferometry based on the pure geometric phases in this solid-state qubit. We observe the interference caused by a pure geometric phase accumulated in the evolution between two consecutive Landau-Zener transitions, while the dynamical phase is canceled out by a spin echo pulse. The full controllability of the qubit state as a function of the intrinsically robust geometric phase provides a promising approach for quantum state manipulation. PMID- 24484041 TI - Effect of electron-phonon interactions on orbital fluctuations in iron-based superconductors. AB - To investigate the possibility of whether electron-phonon coupling can enhance orbital fluctuations in iron-based superconductors, we develop an ab initio method to construct the effective low-energy models including the phonon-related terms. With the derived effective electron-phonon interactions and phonon frequencies, we estimate the static part (omega=0) of the phonon-mediated effective on site intra- or interorbital electron-electron attractions as ~-0.4 eV and exchange or pair-hopping terms as ~-0.02 eV. We analyze the model with the derived interactions together with the Coulomb repulsions within the random phase approximation. We find that the enhancement of the orbital fluctuations due to the electron-phonon interactions is small, and that the spin fluctuations enhanced by the Coulomb repulsions dominate. It leads to the superconducting state with the sign reversal in the gap functions (s+/- wave). PMID- 24484042 TI - Cubic Mn2Ga thin films: crossing the spin gap with ruthenium. AB - Cubic Mn2Ga films with the half-Heusler C1b structure are grown on V (001) epitaxial films. The phase is a soft ferrimagnet, with Curie temperature TC = 225 K and magnetization Ms=280 kA m(-1), equivalent to 1.65MUB per formula. Adding ruthenium leads to an increase of TC up to 550 K in cubic Mn2Ru(x)Ga films with x = 0.33 and a collapse of the net magnetization. The anomalous Hall effect changes sign at x = 0.5, where the sign of the magnetization changes and the magnetic easy direction flips from in plane to perpendicular to the film. The Mn2Ru0.5Ga compound with a valence electron count of 21 is identified as a zero-moment ferrimagnet with high spin polarization, which shows evidence of half metallicity. PMID- 24484043 TI - Molecular quantum magnetism in LiZn2Mo3O8. AB - Inelastic neutron scattering at low temperatures T<=30 K from a powder of LiZn2Mo3O8 demonstrates this triangular-lattice antiferromagnet hosts collective magnetic excitations from spin-1/2 Mo3O13 molecules. Apparently gapless (Delta<0.2 meV) and extending at least up to 2.5 meV, the low-energy magnetic scattering cross section is surprisingly broad in momentum space and involves one third of the spins present above 100 K. The data are compatible with the presence of valence bonds involving nearest-neighbor and next-nearest-neighbor spins forming a disordered or dynamic state. PMID- 24484044 TI - Reentrant liquid-liquid phase separation in protein solutions at elevated hydrostatic pressures. AB - We present results from small-angle x-ray scattering data on the effect of high pressure on the phase behavior of dense lysozyme solutions in the liquid-liquid phase separation region, and characterize the underlying intermolecular protein protein interactions as a function of temperature and pressure in this region of phase space. A reentrant liquid-liquid phase separation region has been discovered at elevated pressures, which originates in the pressure dependence of the solvent-mediated protein-protein interactions. PMID- 24484046 TI - Mechanical and microscopic properties of the reversible plastic regime in a 2D jammed material. AB - At the microscopic level, plastic flow of a jammed, disordered material consists of a series of particle rearrangements that cannot be reversed by subsequent deformation. An infinitesimal deformation of the same material has no rearrangements. Yet between these limits, there may be a self-organized plastic regime with rearrangements, but with no net change upon reversing a deformation. We measure the oscillatory response of a jammed interfacial material, and directly observe rearrangements that couple to bulk stress and dissipate energy, but do not always give rise to global irreversibility. PMID- 24484045 TI - Enhanced chemical synthesis at soft interfaces: a universal reaction-adsorption mechanism in microcompartments. AB - A bimolecular synthetic reaction (imine synthesis) was performed compartmentalized in micrometer-diameter emulsion droplets. The apparent equilibrium constant (Keq) and apparent forward rate constant (k1) were both inversely proportional to the droplet radius. The results are explained by a noncatalytic reaction-adsorption model in which reactants adsorb to the droplet interface with relatively low binding energies of a few kBT, react and diffuse back to the bulk. Reaction thermodynamics is therefore modified by compartmentalization at the mesoscale--without confinement on the molecular scale -leading to a universal mechanism for improving unfavorable reactions. PMID- 24484047 TI - Prevalence of dentine hypersensitivity in Chinese rural adults with dental fluorosis. AB - The aim of this study was to estimate the prevalence of dentine hypersensitivity (DH) among residents of rural China with dental fluorosis aged 30-69 years. A village located in northern China in which dental fluorosis was common was selected. Some 1250 residents with fluorosis ranging in age from 30 to 69 years completed a structured questionnaire and underwent clinical examination. Diagnosis of DH was based on the combination of the subject's self-evaluation and clinical examination. Dental fluorosis was evaluated using Dean's index (DI). In the village, the fluoride concentration in drinking water was 1.15-1.50 mg L(-1) . The community fluorosis index was 1.47, and 74 (9.7%) of the participants with dental fluorosis were diagnosed with DH. There was no significant difference between men and women. DH was most commonly observed in the lower incisors, and the most common cause of DH was cold stimulation. Logistic regression analysis showed acid reflux to be the only risk factor for DH in the current study. Among subjects with DH, none took treatment measures, visited a hospital or clinic, or used antisensitivity toothpaste. The prevalence of DH in the selected subjects with dental fluorosis was 9.7%. Acid reflux was found to be a risk factor for DH in the current study. PMID- 24484048 TI - It is about time we put an end to the dehumanisation of the academic world. PMID- 24484049 TI - Not only randomised controlled trials, but also controlled observational studies. PMID- 24484050 TI - Interpretation of randomised clinical trials' results. A reply to J. J. Amy. PMID- 24484051 TI - An "irritating" magnet test. PMID- 24484053 TI - Endosalpingiosis presenting as multiple pelvic masses. PMID- 24484054 TI - Association between neurological disorders, functioning, and mortality in the elderly. AB - OBJECTIVES: In aging populations, the prevalence of neurological disorders increases, which imposes high population burden in terms of mortality, disability, and impaired quality of life. The aim of this study was to assess the prevalence of common neurological disorders and signs and their association with functioning and mortality in an elderly general population. MATERIALS AND METHODS: We used data from the Memory and Morbidity in Augsburg Elderly (MEMO) project, a population-based study of 385 individuals aged >=65. The prevalence of neurological disorders and signs was assessed by physical examination and medical interview. The basic and instrumental activities of daily living were assessed (ADL, IADL). We assessed the association of neurological disorders and signs with everyday functioning and prospectively analyzed their relationship with mortality. RESULTS: We observed considerably impaired functioning for cases with stroke, TIA, PD, and mild motor parkinsonian signs (MMPS). All-cause mortality was significantly increased in participants with stroke and MMPS, even after adjusting for co-variables (HR = 2.71 and 1.80, respectively). CONCLUSIONS: We found that not only specific neurological disorders, but also earlier symptoms are related to impaired functioning and predict mortality in the elderly. These findings have potential clinical relevance for screening and early detection of individuals at risk. PMID- 24484052 TI - Ligand-dependent dynamics of the active-site lid in bacterial dimethylarginine dimethylaminohydrolase. AB - The dimethylarginine dimethylaminohydrolase (DDAH) enzyme family has been the subject of substantial investigation as a potential therapeutic target for the regulation of vascular tension. DDAH enzymes catalyze the conversion of asymmetric N(eta),N(eta)-dimethylarginine (ADMA) to l-citrulline. Here the influence of substrate and product binding on the dynamic flexibility of DDAH from Pseudomonas aeruginosa (PaDDAH) has been assessed. A combination of heteronuclear NMR spectroscopy, static and time-resolved fluorescence measurements, and atomistic molecular dynamics simulations was employed. A monodisperse monomeric variant of the wild-type enzyme binds the reaction product l-citrulline with a low millimolar dissociation constant. A second variant, engineered to be catalytically inactive by substitution of the nucleophilic Cys249 residue with serine, can still convert the substrate ADMA to products very slowly. This PaDDAH variant also binds l-citrulline, but with a low micromolar dissociation constant. NMR and molecular dynamics simulations indicate that the active site "lid", formed by residues Gly17-Asp27, exhibits a high degree of internal motion on the picosecond-to-nanosecond time scale. This suggests that the lid is open in the apo state and allows substrate access to the active site that is otherwise buried. l-Citrulline binding to both protein variants is accompanied by an ordering of the lid. Modification of PaDDAH with a coumarin fluorescence reporter allowed measurement of the kinetic mechanism of the PaDDAH reaction. A combination of NMR and kinetic data shows that the catalytic turnover of the enzyme is not limited by release of the l-citrulline product. The potential to develop the coumarin-PaDDAH adduct as an l-citrulline sensor is discussed. PMID- 24484055 TI - Acetylcholinesterase inhibitory activity of Haplophyton cimicidum. AB - In Oaxaca, Mexico, Haplophyton cimicidum is used in combination with other plants as part of a folk strategy against arthropod pests of crops and cattle. Methanolic and crude alkaloid (acid-base extraction) extracts of H. cimicidum leaves were analysed by thin-layer chromatography (TLC) and assayed in vitro for acetylcholinesterase (AChE) inhibitory activity using Spodoptera frugiperda homogenates as source of enzyme. Derivatised chromatographic plates indicated the presence of indoles and alkaloids in the extracts. The crude alkaloid extract exhibited a higher number of compounds than the methanolic extract as judged by the number of spots on TLC plates. The crude alkaloid extract had a weak inhibition potential of AChE with a lower IC50 (93 MUg mL(-1)) than the methanolic extract (159 MUg mL(-1)). Indole alkaloids may be responsible for the activity, though a subsequent analysis of the extract components is necessary to determine the active alkaloid(s). PMID- 24484056 TI - The importance of contextualization. Anthropological reflections on descriptive analysis, its limitations and implications. AB - This paper regards a concern for the quality of analyses made on the basis of qualitative interviews in some parts of qualitative health research. Starting with discussions departing in discussions on studies exploring 'patient delay' in healthcare seeking, it is argued that an implicit and simplified notion of causality impedes reflexivity on social context, on the nature of verbal statements and on the situatedness of the interview encounter. Further, the authors suggest that in order to improve the quality of descriptive analyses, it is pertinent to discuss the relationship between notions of causality and the need for contextualization in particular. This argument targets several disciplines taking a qualitative approach, including medical anthropology. In particular, researchers working in interdisciplinary fields face the demands of producing knowledge ready to implement, and such demands challenge basic notions of causality and explanatory power. In order to meet these, the authors suggest an analytic focus on process causality linked to contextualization. PMID- 24484058 TI - Fast Switching of CO3(-)(H2O)n and O2(-)(H2O)n reactant ions in dopant-assisted negative photoionization ion mobility spectrometry for explosives detection. AB - Ion mobility spectrometry (IMS) has become the most deployed technique for on site detection of trace explosives, and the reactant ions generated in the ionization source are tightly related to the performances of IMS. Combination of multiform reactant ions would provide more information and is in favor of correct identification of explosives. Fast switchable CO3(-)(H2O)n and O2(-)(H2O)n reactant ions were realized in a dopant-assisted negative photoionization ion mobility spectrometer (DANP-IMS). The switching could be achieved in less than 2 s by simply changing the gas flow direction. Up to 88% of the total reactant ions were CO3(-)(H2O)n in the bidirectional mode, and 89% of that were O2(-)(H2O)n in the unidirectional mode. The characteristics of combination of CO3(-)(H2O)n and O2(-)(H2O)n were demonstrated by the detection of explosives, including 2,4,6 trinitrotoluene (TNT), cyclo-1,3,5-trimethylene-2,4,6-trinitramine (RDX), ammonium nitrate fuel oil (ANFO), and black powder (BP). For TNT, RDX, and BP, product ions with different reduced mobility values (K0) were observed with CO3( )(H2O)n and O2(-)(H2O)n, respectively, which is a benefit for the accurate identification. For ANFO, the same product ions with K0 of 2.07 cm(2) V(-1) s(-1) were generated, but improved peak-to-peak resolution as well as sensitivity were achieved with CO3(-)(H2O)n. Moreover, an improved peak-to-peak resolution was also obtained for BP with CO3(-)(H2O)n, while the better sensitivity was obtained with O2(-)(H2O)n. PMID- 24484057 TI - ECT2 amplification and overexpression as a new prognostic biomarker for early stage lung adenocarcinoma. AB - Genetic abnormality in early-stage lung adenocarcinoma was examined to search for new prognostic biomarkers. Six in situ lung adenocarcinomas and nine small but invasive adenocarcinomas were examined by array-comparative genomic hybridization, and candidate genes of interest were screened. To examine gene abnormalities, 83 cases of various types of lung carcinoma were examined by quantitative real-time genomic PCR and immunohistochemistry. The results were then verified using another set of early-stage adenocarcinomas. Array-comparative genomic hybridization indicated frequent amplification at chromosome 3q26. Of the seven genes located in this region, we focused on the epithelial cell transforming sequence 2 (ECT2) oncogene, as ECT2 amplification was detected only in invasive adenocarcinoma, and not in in situ carcinoma. Quantitative PCR and immunohistochemistry analyses also detected overexpression of ECT2 in invasive adenocarcinoma, and this was correlated with both the Ki-67 labeling index and mitotic index. In addition, it was associated with disease-free survival and overall survival of patients with lung adenocarcinoma. These results were verified using another set of early-stage adenocarcinomas resected at another hospital. Abnormality of the ECT2 gene occurs at a relatively early stage of lung adenocarcinogenesis and would be applicable as a new biomarker for prognostication of patients with lung adenocarcinoma. PMID- 24484059 TI - MR imaging-guided electrophysiological ablation studies in humans with passive catheter tracking: initial results. AB - PURPOSE: To assess if real-time magnetic resonance (MR) imaging-guided radiofrequency (RF) ablation for atrial flutter is feasible in patients. MATERIALS AND METHODS: The study complied with the Declaration of Helsinki and was approved by the local ethics committee. All patients were informed about the investigational nature of the procedures and provided written informed consent. Ten patients (six men; mean age +/- standard deviation, 68 years +/- 10) with symptomatic atrial flutter underwent isthmus ablation. In all patients, two MR imaging conditional steerable diagnostic and ablation catheters were inserted into the coronary sinus via femoral sheaths and into the right atrium with fluoroscopic guidance. The patients were then transferred to a 1.5-T whole-body MR imager for an ablation procedure, in which the catheters were manipulated by an electrophysiologist by using a commercially available interactive real-time steady-state free precession MR imaging sequence. RESULTS: All catheters were placed in standard positions successfully. Furthermore, simple programmed stimulation maneuvers were performed. In one of 10 patients, a complete conduction block was performed with MR imaging guidance. In nine of 10 patients, creating only a small number of additional touch-up lesions was necessary to complete the isthmus block with conventional fluoroscopy (median, three lesions; interquartile range, two to four lesions). CONCLUSION: Real-time MR imaging guided placement of multiple catheters is feasible in patients, with subsequent performance of stimulation maneuvers and occasional complete isthmus ablation. PMID- 24484060 TI - Differentiation of acute osteoporotic and malignant compression fractures of the spine: use of additive qualitative and quantitative axial diffusion-weighted MR imaging to conventional MR imaging at 3.0 T. AB - PURPOSE: To retrospectively determine the value of adding qualitative and quantitative axial diffusion-weighted (DW) imaging to standard spine magnetic resonance (MR) imaging to differentiate between acute osteoporotic and malignant compression fractures at 3.0 T. MATERIALS AND METHODS: The institutional ethics committee approved this retrospective study and waived the requirement to obtain informed consent. The authors retrospectively analyzed 3.0-T MR images, including DW images (b values: 0, 800, and 1400 sec/mm(2)), in 62 patients with acute compression fractures. Three radiologists independently interpreted MR images for the presence of malignancy by using conventional MR images alone and in combination with axial DW images with qualitative and quantitative analysis. Apparent diffusion coefficients (ADCs) were measured within solid portion with careful use of a small region of interest (ROI). The Mann-Whitney U test was performed. RESULTS: There were 30 malignant and 32 acute osteoporotic compression fractures. At qualitative analysis, hyperintensity relative to spinal cord was more frequent in malignant compression fractures than in acute osteoporotic compression fractures (87% vs 22%, respectively; P < .001). Median ADCs of malignant fractures were significantly lower than those of benign fractures (P < .001). With conventional MR imaging alone, sensitivity, specificity, and accuracy were 100%, 94%, and 97%, respectively, for reader 1; 97%, 78%, and 87% for reader 2; and 100%, 84%, and 92% for reader 3. With conventional and DW MR imaging combined, sensitivity, specificity, and accuracy were 100%, 97%, and 98% for all three readers. The addition of DW imaging led to correct changes in diagnosis: Reader 1 improved by 1.6% (one of 62 fractures), reader 2 improved by 11% (seven of 62 fractures), and reader 3 improved by 6.5% (four of 62 fractures). CONCLUSION: The addition of axial DW imaging to a conventional MR imaging protocol improved diagnostic accuracy in the differentiation of acute osteoporotic from malignant compression fractures by measuring ADCs in the solid portion with careful use of a small ROI. PMID- 24484061 TI - Low-risk prostate cancer: the accuracy of multiparametric MR imaging for detection. AB - PURPOSE: To retrospectively determine diagnostic performance with multiparametric magnetic resonance (MR) imaging for detection of cancer of different tumor volumes and Gleason grades in patients with clinically low-risk prostate cancer. MATERIALS AND METHODS: The local ethical committee and institutional review board approved this study. Consecutive patients with clinically determined low-risk cancer (n = 100) were examined with multiparametric MR imaging (T2 weighted, diffusion weighted, and dynamic contrast material enhanced) by using a 3.0-T imager before prostatectomy. Two radiologists independently assessed the likelihood of cancer per sextant. Cancers with a volume of 0.5 cm(3) or more identified at histopathologic examination were compared with multiparametric MR images. Cancer detection with multiparametric MR imaging was assessed for tumors of different volumes and Gleason grades by using a logistic generalized estimating equation model with 95% confidence intervals (CIs) with two optimal dichotomized cutoff scores. RESULTS: For cancers greater than or equal to 0.5 cm(3), with respect to cancer volume and Gleason grade, multiparametric MR imaging showed high diagnostic performance for the detection of cancer. Diagnostic accuracy with multiparametric MR imaging was significantly higher for cancers with a volume greater than 1 cm(3) than for those with a volume of 0.5-1 cm(3) (87.7%; 95% CI: 82.4%, 94.3% vs 82.6%; 95% CI: 79.0%, 88.7%; P = .02) and for cancers with Gleason grades of 7 or more than for those with grades of 6 or less (89.2%; 95% CI: 85.4%, 93.8% vs 80.6%; 95% CI: 71.2%, 89.8%; P = .01). Detection rates for cancers with a volume more than 1 cm(3) and a Gleason grade of 7 or more were significantly higher than for those with a volume of 0.5-1 cm(3) and a Gleason grade of 6 or less(87.8%; 95% CI: 85.3%, 93.7% vs 82.0%; 95% CI: 75.6%, 86.1%; P = .01). CONCLUSION: Detection of prostate cancer in patients with clinically low-risk cancer with multiparametric MR imaging is highly accurate, and larger cancer volume and higher Gleason grade are associated with higher detection accuracy. PMID- 24484062 TI - Aberrant default-mode functional connectivity in patients with end-stage renal disease: a resting-state functional MR imaging study. AB - PURPOSE: To investigate the functional connectivity of the default-mode network (DMN) in patients with end-stage renal disease (ESRD) by using independent component analysis of resting-state functional magnetic resonance (MR) imaging and to correlate these DMN connectivity changes with neuropsychological test results and clinical biomarkers. MATERIALS AND METHODS: Medical research ethics committee approval and written informed consent were obtained. Forty-six patients with ESRD, including 22 with minimal nephrotic encephalopathy (MNE) and 24 without nephrotic encephalopathy, and 23 healthy control subjects underwent resting-state functional MR imaging. All patients were asymptomatic and without history of neurologic or psychiatric disease. Independent component analysis was used to isolate the DMN. To display the voxels that contributed most strongly to an independent component, the intensity values in each spatial map were converted to z scores, which indirectly provided a measurement of functional connectivity in the DMN. Maps of the DMN were compared among the groups. Pearson correlation analysis was performed to correlate abnormal DMN functional connectivity with serum urea, creatinine, duration of dialysis, duration of disease, and neuropsychological test scores. RESULTS: Patients with ESRD showed significantly less functional connectivity in the posterior cingulate cortex, precuneus, and medial prefrontal cortex (MPFC) (P < .01) than did control subjects. Comparison of the two patient groups showed significantly reduced functional connectivity in the superior and MPFC in the MNE group (P < .01). The functional connectivity of the MPFC was positively correlated with digital symbol test score (R = 0.293, P = .048). Serum creatinine level was negatively correlated with functional connectivity of the posterior cingulate cortex and precuneus in patients with ESRD (R = -0.51, P = .002). CONCLUSION: Functional connectivity in the DMN was impaired in patients with ESRD, with further reduction in the MPFC with the development of MNE, which might explain the reduced performance of these patients on neurocognitive tests. Serum creatinine level might be associated with impairment of the DMN in patients with ESRD. PMID- 24484063 TI - Two-view digital breast tomosynthesis screening with synthetically reconstructed projection images: comparison with digital breast tomosynthesis with full-field digital mammographic images. AB - PURPOSE: To compare the performance of two versions of reconstructed two dimensional (2D) images in combination with digital breast tomosynthesis (DBT) versus the performance of standard full-field digital mammography (FFDM) plus DBT. MATERIALS AND METHODS: This trial had ethical committee approval, and all participants gave written informed consent. Examinations (n = 24 901) in women between the ages of 50 and 69 years (mean age, 59.2 years) were interpreted prospectively as part of a screening trial that included independent interpretations of FFDM plus DBT and reconstructed 2D images plus DBT. Reconstructed 2D images do not require radiation exposure. Using analyses for binary data that accounted for correlated interpretations and were adjusted for reader-specific volume, two versions (initial and current) of reconstructed 2D images used during trial periods 1 (from November 22, 2010, to December 21, 2011; 12 631 women) and 2 (from January 20, 2012, to December 19, 2012; 12 270 women) were compared in terms of cancer detection and false-positive rates with the corresponding FFDM plus DBT interpretations. RESULTS: Cancer detection rates were 8.0, 7.4, 7.8, and 7.7 per 1000 screening examinations for FFDM plus DBT in period 1, initial reconstructed 2D images plus DBT in period 1, FFDM plus DBT in period 2, and current reconstructed 2D images plus DBT in period 2, respectively. False-positive scores were 5.3%, 4.6%, 4.6%, and 4.5%, respectively. Corresponding reader-adjusted paired comparisons of false-positive scores revealed significant differences for period 1 (P = .012) but not for period 2 (ratio = 0.99; 95% confidence interval: 0.88, 1.11; P = .85). CONCLUSION: The combination of current reconstructed 2D images and DBT performed comparably to FFDM plus DBT and is adequate for routine clinical use when interpreting screening mammograms. PMID- 24484064 TI - Radiation dose index of renal colic protocol CT studies in the United States: a report from the American College of Radiology National Radiology Data Registry. AB - PURPOSE: To determine radiation dose indexes for computed tomography (CT) performed with renal colic protocols in the United States, including frequency of reduced-dose technique usage and any institutional-level factors associated with high or low dose indexes. MATERIALS AND METHODS: The Dose Imaging Registry (DIR) collects deidentified CT data, including examination type and dose indexes, for CT performed at participating institutions; thus, the DIR portion of the study was exempt from institutional review board approval and was HIPAA compliant. CT dose indexes were examined at the institutional level for CT performed with a renal colic protocol at institutions that contributed at least 10 studies to the registry as of January 2013. Additionally, patients undergoing CT for renal colic at a single institution (with institutional review board approval and informed consent from prospective subjects and waiver of consent from retrospective subjects) were studied to examine individual renal colic CT dose index patterns and explore relationships between patient habitus, demographics, and dose indexes. Descriptive statistics were used to analyze dose indexes, and linear regression and Spearman correlations were used to examine relationships between dose indexes and institutional factors. RESULTS: There were 49 903 renal colic protocol CT examinations conducted at 93 institutions between May 2011 and January 2013. Mean age +/- standard deviation was 49 years +/- 18, and 53.9% of patients were female. Institutions contributed a median of 268 (interquartile range, 77-699) CT studies. Overall mean institutional dose-length product (DLP) was 746 mGy ? cm (effective dose, 11.2 mSv), with a range of 307-1497 mGy ? cm (effective dose, 4.6-22.5 mSv) for mean DLPs. Only 2% of studies were conducted with a DLP of 200 mGy ? cm or lower (a "reduced dose") (effective dose, 3 mSv), and only 10% of institutions kept DLP at 400 mGy ? cm (effective dose, 6 mSv) or less in at least 50% of patients. CONCLUSION: Reduced-dose renal protocol CT is used infrequently in the United States. Mean dose index is higher than reported previously, and institutional variation is substantial. PMID- 24484065 TI - Multiple sclerosis: altered thalamic resting-state functional connectivity and its effect on cognitive function. AB - PURPOSE: To investigate, by using resting-state (RS) functional magnetic resonance (MR) imaging, thalamocortical functional connectivity (FC) and its correlations with cognitive impairment in multiple sclerosis (MS). MATERIALS AND METHODS: All subjects provided written informed consent; the study protocol was approved by the university institutional review board for this HIPAA-compliant study. Forty-eight patients with relapsing-remitting MS and 24 control subjects underwent multimodal MR imaging, including diffusion-tensor imaging, three dimensional (3D) T1-weighted imaging, and functional MR imaging at rest and a neuropsychological examination with the Paced Auditory Serial Addition Test (PASAT). Functional MR imaging data were analyzed with tools from FMRIB Software Library, by using the seed-based method to identify the thalamic RS network (RSN). RESULTS: When compared with control subjects, patients showed gray matter and white matter atrophy, as well as diffusion-tensor imaging abnormalities (P < .01). Patients displayed significantly greater synchronization than control subjects in the cerebellum; basal ganglia; hippocampus; cingulum; and temporo occipital, insular, frontal, and parietal cortices. They also exhibited significantly lower synchronization in the thalamus; cerebellum; cingulum; and insular, prefrontal, and parieto-occipital cortices (cluster level, P < .05, corrected for familywise error [FWE]). In patients, the PASAT score at 3 seconds significantly inversely correlated with the thalamus, cerebellum, and some cortical areas in all cerebral lobes; the PASAT score at 2 seconds significantly correlated, even more strongly, with all the aforementioned regions and, in addition, with the cingulum and the left hippocampus (cluster level, P < .05, corrected for FWE). CONCLUSION: Thalamic RSN is disrupted in MS, and decreased performance in cognitive testing is associated with increased thalamocortical FC, thus suggesting that neuroplasticity changes are unable to compensate for tissue damage and to prevent cognitive dysfunction. PMID- 24484066 TI - Improving effect of Sivelestat on lipopolysaccharide-induced lung injury in rats. AB - Sepsis causes neutrophil sequestration in the lung, which leads to acute lung injury (ALI). Neutrophil elastase (NE) is thought to play an important role in the pathogenesis of ALI. This study investigated whether Sivelestat, a specific NE inhibitor, can attenuate ALI induced by lipopolysaccharide (LPS). In vivo, 30 male Wistar rats were divided into three groups (n = 10 each groups) on the basis of the reagent used, which were subjected to LPS injection with or without Sivelestat treatments to induce ALI model. Lung injury was assessed by pulmonary histology, lung wet-weight to dry-weight (W/D) ratio, immunohistochemical analysis of intercellular adhesion molecule-1 (ICAM-1), the number of myeloperoxidase (MPO)-positive cells, and gene expression of ICAM-1. In vitro, pulmonary microvascular endothelial cells (PMVECs) were stimulated with LPS in the presence and absence of Sivelestat; nuclear factor-kappaB (NF-kappaB) p65 was measured by immunocytochemistry staining and Western blotting. Infusion of LPS induced lung injury, in vivo, as demonstrated by pulmonary edema with infiltration of neutrophils, the increase in lung W/D ratio, the number of MPO positive cells and enhanced expression of ICAM-1 and ICAM-1 gene. In vitro, the significant increased release of NF-kappaB p65 and its subsequent translocation into the nucleus in PMVECs. In contrast, Sivelestat treatment significantly ameliorated the LPS-induced lung injury, as judged by the marked improvement in all these indices. These results indicated that inhibition of NE attenuated LPS induced lung injury through an inhibition of the inflammatory signaling pathway, besides the direct inhibitory effect on NE. PMID- 24484067 TI - Silencing mutant huntingtin by adeno-associated virus-mediated RNA interference ameliorates disease manifestations in the YAC128 mouse model of Huntington's disease. AB - Huntington's disease (HD) is a fatal autosomal dominant neurodegenerative disease caused by an increase in the number of polyglutamine residues in the huntingtin (Htt) protein. With the identification of the underlying basis of HD, therapies are being developed that reduce expression of the causative mutant Htt. RNA interference (RNAi) that seeks to selectively reduce the expression of such disease-causing agents is emerging as a potential therapeutic strategy for this and similar disorders. This study examines the merits of administering a recombinant adeno-associated viral (AAV) vector designed to deliver small interfering RNA (siRNA) that targets the degradation of the Htt transcript. The aim was to lower Htt levels and to correct the behavioral, biochemical, and neuropathological deficits shown to be associated with the YAC128 mouse model of HD. Our data demonstrate that AAV-mediated RNAi is effective at transducing greater than 80% of the cells in the striatum and partially reducing the levels (~40%) of both wild-type and mutant Htt in this region. Concomitant with these reductions are significant improvements in behavioral deficits, reduction of striatal Htt aggregates, and partial correction of the aberrant striatal transcriptional profile observed in YAC128 mice. Importantly, a partial reduction of both the mutant and wild-type Htt levels is not associated with any notable overt neurotoxicity. Collectively, these results support the continued development of AAV-mediated RNAi as a therapeutic strategy for HD. PMID- 24484068 TI - Metabolomic tissue signature in human non-alcoholic fatty liver disease identifies protective candidate metabolites. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is the most common chronic liver disorder in industrialized countries, yet its pathophysiology is incompletely understood. Small-molecule metabolite screens may offer new insights into disease mechanisms and reveal new treatment targets. METHODS: Discovery (N = 33) and replication (N = 66) of liver biopsies spanning the range from normal liver histology to non-alcoholic steatohepatitis (NASH) were ascertained ensuring rapid freezing under 30 s in patients. 252 metabolites were assessed using GC/MS. Replicated metabolites were evaluated in a murine high-fat diet model of NAFLD. RESULTS: In a two-stage metabolic screening, hydroquinone (HQ, p(combined) = 3.0 * 10(-4)) and nicotinic acid (NA, p(combined) = 3.9 * 10(-9)) were inversely correlated with histological NAFLD severity. A murine high-fat diet model of NAFLD demonstrated a protective effect of these two substances against NAFLD: Supplementation with 1% HQ reduced only liver steatosis, whereas 0.6% NA reduced both liver fat content and serum transaminase levels and induced a complex regulatory network of genes linked to NALFD pathogenesis in a global expression pathway analysis. Human nutritional intake of NA equivalent was also consistent with a protective effect of NA against NASH progression. CONCLUSION: This first small-molecular screen of human liver tissue identified two replicated protective metabolites. Either the use of NA or targeting its regulatory pathways might be explored to treat or prevent human NAFLD. PMID- 24484070 TI - Coadministration of protoxin Cry1Ac from Bacillus thuringiensis with metacestode extract confers protective immunity to murine cysticercosis. AB - The Bacillus thuringiensis Cry1Ac protoxin (pCry1Ac) is a promising mucosal immunogen and adjuvant that induces protective immunity against Naegleria fowleri and malaria infection models. We determined whether pCry1Ac acted as a protective adjuvant against infection with Taenia crassiceps. BALB/C mice were thrice i.p. immunized with (i) pCry1Ac, (ii) metacestode extract, (iii) extract + pCry1Ac or (iv) vehicle, challenged with metacestodes on day 26 and then sacrificed 35 days later. Cysticerci in the peritoneal cavity were counted, while the serum antibody response and cytokines were analysed after immunization and during infection. Only immunization with pCry1Ac plus extract conferred a significant protection (up to 47%). This group presented fluctuating antibody peaks during infection and the highest IgG1 and IgM titres. Immunization with extract alone elicited high IgG1 and the highest IgG2a responses after 25 days of infection, while nonimmunized mice presented a poor, mixed-Th1/Th2 response during infection. Sharp peaks of TNFalpha and IFN-gamma occurred immediately after the first immunization with extract, especially in the presence of pCry1Ac, but not after the challenge, while in the control and pCry1Ac-alone groups, cytokines were only detected after the challenge. The data support the protective-adjuvant effect of co-administration of pCry1Ac in cysticercosis. PMID- 24484069 TI - Investigating the impact of alliance-focused training on interpersonal process and therapists' capacity for experiential reflection. AB - OBJECTIVE: In this article we present preliminary findings from a research program designed to investigate the value of alliance-focused training (AFT), a supervision approach designed to enhance therapists' ability to work constructively with negative therapeutic process. METHOD: In the context of a multiple baseline design, all therapists began treating their patients using cognitive therapy and then joined AFT supervision groups at either session 8 or 16 of a 30 session protocol. Study I investigated the impact of AFT on patient and therapist interpersonal process as assessed through the Structural Analysis of Social Behavior (SASB). Study 2 investigated the impact of AFT on therapists' tendency to reflect on their relationships with their patients in an experientially grounded fashion, as assessed via the Experiencing Scale (EXP). Since one of the goals of AFT is to train therapists to use their own emerging feelings as important clues regarding what may be taking place in the therapeutic relationship, we hypothesized that they would show increased levels of EXP after undergoing AFT. RESULTS AND CONCLUSION: The results of both studies 1 and 2 were for the most part consistent with hypotheses. Implications and future research directions are discussed. PMID- 24484071 TI - Li18Na2Ge17--a compound demonstrating cation effects on cluster shapes and crystal packing in ternary Zintl phases. AB - The novel ternary Zintl phase Li18Na2Ge17 was synthesized from a stoichiometric melt and characterized crystallographically. It crystallizes in the trigonal space group P31m (No. 157) with a = 17.0905(4) A, c = 8.0783(2) A, and V = 2043.43(8) A(3) (final R indices R1 = 0.0212 and wR2 = 0.0420 for all data). The structure contains three different Zintl anions in a 1:1:1 ratio: isolated anions Ge(4-), tetrahedra [Ge4](4-), and truncated, Li-centered tetrahedra [Li@Ge12](11 ), whose hexagonal faces are capped by four Li cations, resulting in the Friauf polyhedra [Li@Li4Ge12](7-). According to the Zintl-Klemm concept, Li18Na2Ge17 is an electronically balanced Zintl phase, as experimentally verified by its diamagnetism. The compound is structurally related to Li7RbGe8, which also contains [Ge4](4-) and [Li@Li4Ge12](7-) in its anionic substructure. However, exchanging the heavier alkali metal cation Rb for Na in the mixed-cation germanides leads to drastic changes in stoichiometry and crystal packing, demonstrating the great effects that cations exert on such Zintl phases through optimized cluster sheathing and space filling. PMID- 24484072 TI - Asherman syndrome in a Danish population. AB - Intrauterine adhesions (Asherman syndrome) are rare and mainly seen after delivery or abortion in the presence of retained placental tissue. This descriptive study aimed to identify common risk factors for intrauterine adhesions. In a 10-year period 61 women were identified with intrauterine adhesions. The pathology was suspected from symptoms, ultrasonography or on hysterosalpingography, but a final diagnosis could only be given after hysteroscopy. There was no definite evidence regarding methods for prevention and treatment of the disorder. It seems, however, that a conservative approach to curettage, hysteroscopic removal of retained tissue, and the use of distending media are important, together with gentle tissue handling when such procedures are required. PMID- 24484073 TI - Heterotopic interstitial pregnancy successfully treated with ultrasound-guided potassium chloride injection in the ectopic embryo. PMID- 24484074 TI - Halophytophthora fluviatilis sp. nov. from freshwater in Virginia. AB - Halophytophthora fluviatilis, a novel species from inland freshwater in Virginia, is characterized and described in this study. This homothallic species produced ovoid to globose sporangia, which release zoospores directly through exit pores. It grew well in a relatively wide range of salinity from 1.8 to 19.0 parts per thousand. Sequence analysis of the rRNA internal transcribed spacer region placed this new species in the Halophytophthora sensu stricto clade. Description of this new species expanded the habitat to include geographically distinct inland freshwater ecosystems for the genus Halophytophthora, challenging the notion that this genus is marine or brackish. The need to construct a molecular-based taxonomy for the genus Halophytophthora is also discussed. PMID- 24484075 TI - Compliance with remote monitoring of ICDS/CRTDS in a real-world population. AB - BACKGROUND: Remote monitoring (RM) of defibrillators (implantable cardioverter defibrillators [ICDs]) and cardiac resynchronization therapy devices (CRTDs) has been shown to be cost effective, convenient, and associated with reduced mortality and a reduction in the time to physician intervention for actionable events. However, patient compliance with monitoring over time and what factors might influence such compliance have not been well described. This study sought to identify factors contributing to patient noncompliance with RM of ICDs and CRTDs in a large real-world population. METHODS: Deidentified data on U.S. patients enrolled in the Medtronic CareLink RM system were used to compare patients with no (noncompliant, n = 14,848) and with >= 2 RM transmissions (compliant, n = 103,284) during a 14-month period. RESULTS: Overall noncompliance with RM was 21%. Younger age (<= 40), female sex, wanded device, Medicare Census Division, and small clinic size all predicted patient noncompliance (P < 0.01). Device type (ICD vs CRTD) did not (P = 0.52). Multivariate analysis suggested clinically important predictors of noncompliance to be: age <= 40, odds ratio (OR) 2.64 (95% confidence interval, 2.42-2.88); Medicare Census Division (Mountain vs West North Central), OR 2.15 (1.96-2.37); and small clinic size (1-4 vs >100 patients), OR 4.38 (3.92-4.91). CONCLUSIONS: There is room for improvement in RM usage among enrolled patients. Younger patients, smaller clinics, and certain geographic areas may be targets for research into interventions to further improve the use of RM. PMID- 24484076 TI - An approach to the management of Trypanosoma cruzi infection (Chagas' disease) in immunocompromised patients. AB - The epidemiology of Chagas disease has changed in the last decades due to migration movements, population ageing and the emergence of new transmission routes. In endemic countries, health facilities and access to healthcare are improving and T. cruzi infected patients are also benefiting from medical advances. The HIV epidemic has spread to both endemic and non-endemic areas for T. cruzi, organ transplant rates have increased recently, especially in Latin America, and other medical conditions affecting the immune system are increasing their global burden. The natural course of Chagas disease is mainly determined by the host's cellular immune response. These conditions may therefore overlap with T. cruzi infection and alter the disease's natural history which may present with atypical clinical forms and a higher associated morbidity and mortality in immunocompromised patients. The present review aims to contribute to the management of immunosuppressed patients with T. cruzi infection. PMID- 24484077 TI - Flash nanoprecipitation: prediction and enhancement of particle stability via drug structure. AB - Flash nanoprecipitation (FNP) can generate hydrophobic drug nanoparticles in ~ 100 nm with a much higher drug loading (e.g., > 40 wt %) than traditional nanocarriers (e.g., < 20 wt %). This paper studies the effects of drug molecules on nanoparticle stability made via FNP and demonstrates that chemically bonding a drug compound (e.g., paclitaxel) with a cleavable hydrophobic moiety of organosilicate (e.g., triethoxysilicate) is able to enhance the particle size stability. A nonionic amphiphilic diblock copolymer, poly(lactic-co-glycolic acid)-block-poly(ethylene glycol) (PLGA-b-PEG), is used as a model surfactant to provide steric stabilization. The experiments here show that the lower the drug solubility in the aqueous medium, the more stable the particles in terms of Ostwald ripening, which are consistent with the prediction by the LSW theory. The initial particle size distribution is sufficiently narrow and of insignificance to Ostwald ripening. To correlate the particle stability with hydrophobicity, this study introduces the n-octanol/water partition coefficient (LogP), a hydrophobicity indication, into the FNP technique. A comparison of various drugs and their analogues shows that LogP of a drug is a better hydrophobicity indication than the solubility parameter (delta) and correlates well with the particle stability. Empirically, with ACDLogP > ~ 12, nanoparticles have good stability; with ~ 2 < ACDLogP < ~ 9, nanoparticles show fast Ostwald ripening and interparticle recrystallization; with ACDLogP < ~ 2, the drug is very likely difficult to form nanoparticles. This rule creates a quick way to predict particle stability for a randomly selected drug structure and helps to enable a fast preclinical drug screen. PMID- 24484078 TI - Adverse pregnancy outcomes in hypertensive patients: predictive value of protein concentration versus total protein. AB - OBJECTIVES: To compare the predictive value of protein concentration in a twenty four hour urine collection to the conventional total protein in a twenty-four hour urine collection for adverse pregnancy outcomes in hypertensive patients. STUDY DESIGN: Retrospective cohort study. Hypertensive patients >=20 weeks estimated gestational age (EGA) who completed twenty-four hour urine protein collections were identified; antepartum and delivery data were examined. For study patients who met criteria for adverse pregnancy outcome, multi-variable analysis was performed and summary receiver operating characteristic (ROC) curves were generated for each model (total protein compared to protein concentration). The models were compared by analyzing the area under the curve (AUC). RESULTS: A total of 150 patients were analyzed. Mean gestational age at delivery was 36.7 weeks. Analysis of the ROC curves showed no significant difference between the models (AUCs of 0.668 versus 0.656, p = 0.715). Optimal thresholds were 299.2 mg for total protein and 0.1 mg/ml for protein concentration. CONCLUSION: A protein concentration of 0.1 mg/ml on a twenty-four hour urine collection appears equivalent to the traditional 300 mg total protein. If confirmed by prospective studies, this finding would be clinically important in cases where collections fall short of the 300 mg threshold but exceed the 0.1 mg/ml concentration. PMID- 24484079 TI - Multiple-aetiology enteric infections involving non-O157 Shiga toxin-producing Escherichia coli--FoodNet, 2001-2010. AB - We describe multiple-aetiology infections involving non-O157 Shiga toxin producing Escherichia coli (STEC) identified through laboratory-based surveillance in nine FoodNet sites from 2001 to 2010. A multiple-aetiology infection (MEI) was defined as isolation of non-O157 STEC and laboratory evidence of any of the other nine pathogens under surveillance or isolation of >1 non-O157 STEC serogroup from the same person within a 7-day period. We compared exposures of patients with MEI during 2001-2010 with those of patients with single aetiology non-O157 STEC infections (SEI) during 2008-2009 and with those of the FoodNet population from a survey conducted during 2006-2007. In total, 1870 non O157 STEC infections were reported; 68 (3.6%) were MEI; 60 included pathogens other than non-O157 STEC; and eight involved >1 serogroup of non-O157 STEC. Of the 68 MEI, 21 (31%) were part of six outbreaks. STEC O111 was isolated in 44% of all MEI. Of patients with MEI, 50% had contact with farm animals compared with 29% (P < 0.01) of persons with SEI; this difference was driven by infections involving STEC O111. More patients with non-outbreak-associated MEI reported drinking well water (62%) than respondents in a population survey (19%) (P < 0.01). Drinking well water and having contact with animals may be important exposures for MEI, especially those involving STEC O111. PMID- 24484080 TI - Activity-guided isolation of antioxidants from the leaves of Terminalia arjuna. AB - An activity-guided isolation and purification process was used to identify the l,l-diphenyl-2-picrylhydrazyl (DPPH) free radical-scavenging components of the food plant (Terminalia arjuna) of Antheraea mylitta. Dry leaves of T. arjuna were extracted with different solvents and tested for their antioxidant activity against DPPH(*). The acetone-water (8:2) extract expressed strong DPPH radical scavenging activity, and was subjected to column chromatography over silica gel. Gallic acid, apigenin, luteolin, quercetin, epicatechin, ellagic acid and 1-O beta-galloyl glucose were isolated as active components and characterised by using different spectroscopic techniques. PMID- 24484081 TI - Predictors for delayed encephalopathy following acute carbon monoxide poisoning. AB - BACKGROUND: In Japan, many carbon monoxide (CO) poisoning cases are transported to emergency settings, making treatment and prognostic assessment an urgent task. However, there is currently no reliable means to predict whether "delayed neuropsychiatric sequelae (DNS)" will develop after acute CO poisoning. This study is intended to find out risk factors for the development of DNS and to characterize the clinical course following the development of DNS in acute CO poisoning cases. METHODS: This is a retrospective cohort study of 79 consecutive patients treated at a single institution for CO poisoning. This study included 79 cases of acute CO poisoning admitted to our emergency department after attempted suicide, who were divided into two groups consisting of 13 cases who developed DNS and 66 cases who did not. The two groups were compared and analyzed in terms of clinical symptoms, laboratory findings, etc. RESULTS: Predictors for the development of DNS following acute CO poisoning included: serious consciousness disturbance at emergency admission; head CT findings indicating hypoxic encephalopathy; hematology findings including high creatine kinase, creatine kinase-MB and lactate dehydrogenase levels; and low Global Assessment Scale scores. The clinical course of the DNS-developing cases was characterized by prolonged hospital stay and a larger number of hyperbaric oxygen (HBO) therapy sessions. CONCLUSION: In patients with the characteristics identified in this study, administration of HBO therapy should be proactively considered after informing their family, at initial stage, of the risk of developing DNS, and at least 5 weeks' follow-up to watch for the development of DNS is considered necessary. PMID- 24484084 TI - Get back to work. PMID- 24484082 TI - Crimean-congo haemorrhagic fever in pregnancy and in newborn: a case with a unique clinical course. PMID- 24484085 TI - Off-label prescribing. PMID- 24484086 TI - Reducing off-label prescribing in psychiatry. PMID- 24484089 TI - Guidelines fall short on bariatric surgery. PMID- 24484090 TI - Alcohol and cancer: the urgent need for a new message. PMID- 24484091 TI - Food contaminants capable of causing cancer, pulmonary hypertension and cirrhosis. PMID- 24484092 TI - Double standards in clinical practice ethics. PMID- 24484093 TI - Nutrition in schools - outdated guidelines need updating. PMID- 24484094 TI - The impact of obesity treatment and dietary guidelines on eating disorders. PMID- 24484095 TI - Notifying a doctor of a first hypoglycaemic episode is associated with a lower rate of recurrence among inpatients with diabetes. PMID- 24484096 TI - A computer-based task management system for junior medical officers during after hours shifts. PMID- 24484097 TI - An update of consensus guidelines for warfarin reversal. PMID- 24484098 TI - An update of consensus guidelines for warfarin reversal. PMID- 24484099 TI - Pharmacometrics: an underused resource in Australian clinical research. PMID- 24484100 TI - The after-life of drugs: a responsible care initiative for reducing their environmental impact. PMID- 24484101 TI - A pilot study of an influenza vaccination or mask mandate in an Australian tertiary health service. PMID- 24484102 TI - Unexplained variation in hospital caesarean section rates. PMID- 24484103 TI - Unexplained variation in hospital caesarean section rates. PMID- 24484104 TI - First aid for burns: too little, too late and often wrong. PMID- 24484105 TI - Risk factors for recurrent Mycobacterium ulcerans disease after exclusive surgical treatment in an Australian cohort. PMID- 24484106 TI - Risk factors for recurrent Mycobacterium ulcerans disease after exclusive surgical treatment in an Australian cohort. PMID- 24484107 TI - Comprehensive primary health care and social determinants as top priorities. PMID- 24484108 TI - Comprehensive primary health care and social determinants as top priorities. PMID- 24484109 TI - Climate change and diabetes: averting two linked catastrophes. PMID- 24484110 TI - The scope, funding and publication of musculoskeletal clinical trials performed in Australia. AB - Musculoskeletal conditions are the leading contributors to disability burden globally and account for 27.4% of total disability burden in Australia. Timely research that addresses important questions relevant to consumers, clinicians and policymakers is critical for reducing the burden associated with these conditions. Clinical trials are particularly important for providing information about whether interventions are effective and safe. They are also needed to test strategies for reducing the sizeable delays in translating evidence into practice. A review of the current scope of musculoskeletal clinical trials in Australia found that National Health and Medical Research Council funding is disproportionally low compared with the burden of these conditions (averaging 5.8 new trials per year through the project grant scheme over the past 5 years, representing 0.8% of all project grants and funding, and 5% of NHMRC clinical trial funding). In the past 2 years, 128 Australian-initiated trials were registered in a trial registry, while about one in 20 randomised trials published in 37 leading general medical and musculoskeletal-specific journals was initiated in Australia. None were implementation trials. Relative to the burden of musculoskeletal conditions in Australia, investment in clinical trials is not ideal. While Australian musculoskeletal trialists are productive and internationally competitive, we may not be addressing the most critical issues. There is an urgent need for Australian researchers, clinicians, policymakers and consumers to work collaboratively to prioritise the most important questions, secure appropriate research funding, and undertake well designed trials to ensure we deliver best evidence-informed care and optimal outcomes for people with musculoskeletal conditions. PMID- 24484111 TI - A systematic interim assessment of the Australian Government's Food and Health Dialogue. AB - OBJECTIVE: To evaluate whether the Food and Health Dialogue (the Dialogue), established by the Australian Government in 2009, is having an impact on reducing premature death and disability caused by poor diet in Australia. DESIGN AND SETTING: We used information derived from the Dialogue website, media releases, communiques and e-newsletters to evaluate the Dialogue's achievements from October 2009 to September 2013, using the RE-AIM (reach, efficacy, adoption, implementation and maintenance) framework. Data describing the processed foods marketed in Australia were extracted from an existing food composition database. MAIN OUTCOME MEASURES: Achievements of the Dialogue (goals, targets, actions and health outcomes). RESULTS: The primary goal of the Dialogue was identified as "raising the nutritional profile of foods" to be achieved "through reformulation, consumer education and portion standardisation". Employing a public-private partnership model, the Dialogue has established a framework for collaboration between government, public health groups and industry. In the first 4 years, targets were set for 11 (8.9%) of a total of 124 possible action areas for food reformulation and portion standardisation. None were yet due to have been achieved. There was no evidence that any education programs had been implemented by the Dialogue. There are no indicators of the extent to which population exposure to target nutrients has changed or whether any positive or negative health impacts have ensued. CONCLUSIONS: The Dialogue has highly creditable goals but the mechanism for delivering on them has proved inadequate. Explicit processes and the outcomes to be delivered within defined timelines are required, along with a clear plan for remediation if they are not achieved. PMID- 24484112 TI - Removing the interview for medical school selection is associated with gender bias among enrolled students. AB - OBJECTIVE: To report, and determine reasons for, a change in the gender ratio observed among enrolled medical students after removal of the interview from the selection process. DESIGN, SETTING AND PARTICIPANTS: Cross-sectional study of 4051 students admitted to the medical program at the University of Queensland between 2004 and 2012. Students are enrolled either directly as graduates or via a school-leaver pathway. MAIN OUTCOME MEASURES: Change in proportions of male and female students over time, and gender-specific scores in the three sections of the GAMSAT (Graduate Medical School Admissions Test). RESULTS: Between 2004 and 2008 (when an interview was part of the selection process), 891 enrolled students (51.4%) were male, whereas between 2009 and 2012 (no interview), 1134 (57.7%; P < 0.001) were male. This change in gender ratio was limited to domestic direct graduate-entry students, and the male proportion in this group rose from 50.9% (705 students) before the interview was removed to 64.0% (514 students; P < 0.001) after removal of the interview (reaching 73.8% in 2012). Between 2004 and 2012, male students consistently performed better than female students on GAMSAT section III (mean score, 71.5 v 68.5; P < 0.001). CONCLUSION: The proportion of males enrolled in the medical program at this university increased markedly after removal of the interview from the selection process. This change is limited to domestic direct graduate-entry students, and seems to be due to higher scores by male students in section III of the GAMSAT. The interview may play an important role in ensuring gender equity in selection, and medical schools should carefully monitor the consequences of changes to selection policy. PMID- 24484113 TI - The cost of teaching an intern in New South Wales. AB - OBJECTIVE: To determine the cost of formal and informal teaching specifically provided for interns and to determine how much of an intern's time is spent in these activities. DESIGN, SETTING AND PARTICIPANTS: Costs of formal teaching for 2012 were obtained from the New South Wales Health Education and Training Institute (HETI) and costs of informal teaching by a survey of all interns in a random sample of prevocational networks. MAIN OUTCOME MEASURES: The cost of formal intern education provided by HETI; the number of hours of formal teaching provided to interns in hospital; intern estimates of the amount of non-timetabled teaching received in a typical week. RESULTS: The cost of formal teaching was $11 892 per intern per year and the cost of informal teaching was $2965 per intern per year (survey response rate, 63%) - a total of $14 857. Interns spent 2 hours per week in formal teaching and 28 minutes per week in informal teaching, representing 6.2% of a 40-hour week. CONCLUSION: The time of professionals paid by NSW Health represents most of the expenditure on teaching interns. An increase in time spent on intern teaching beyond the current 6.2% of an intern's 40-hour week would be an investment in better health care. PMID- 24484114 TI - Impact of the Rural Clinical School of Western Australia on work location of medical graduates. AB - OBJECTIVE: To determine whether completing a year of the Rural Clinical School of Western Australia (RCSWA) program is associated with entering the rural medical workforce. DESIGN AND SETTING: Cohort study of graduates from the University of Western Australia who completed Year 5 of medical school between 2002 and 2009, comparing work location (identified from the Australian Health Practitioner Regulation Agency database in March-June 2013) between those who participated in the RCSWA (RCSWA graduates) and those who did not (controls). MAIN OUTCOME MEASURE: Rural or urban work location of graduates. RESULTS: Of 1116 eligible graduates, 1017 (91.1%) could be traced and were included in the study. Of 258 RCSWA graduates, 42 (16.3%) were working rurally compared with 36 of 759 controls (4.7%). Of 195 RCSWA graduates from urban backgrounds, 29 (14.9%) were working rurally compared with 26 of 691 urban-background controls (3.8%). Of 63 rural background RCSWA graduates, 13 (20.6%) were working rurally, compared with 10 of 68 rural-background controls (14.7%). Using logistic regression, RCSWA participation had a strong relationship with working rurally (rural-background RCSWA graduates: odds ratio [OR], 7.5; 95% CI, 3.5-15.8; urban-background RCSWA graduates: OR, 5.1; 95% CI, 2.9-9.1). Rural background without RCSWA participation (OR, 4.2; 95% CI, 1.8-9.2) and older age (age in 2012, 30-39 years: OR, 2.2; 95% CI, 1.3-3.7 v >= 40 years: OR, 6.6; 95% CI, 2.8-15.0) were also significant factors for working rurally. CONCLUSIONS: Participation in the RCSWA is strongly associated with greater likelihood of working rurally. Graduates from urban backgrounds who participated in the RCSWA were much more likely to work in rural areas than those who did not. These data substantiate the RCSWA as an effective rural workforce strategy. PMID- 24484115 TI - headspace - Australia's innovation in youth mental health: who are the clients and why are they presenting? AB - OBJECTIVES: To provide the first national profile of the characteristics of young people (aged 12-25 years) accessing headspace centre services - the Australian Government's innovation in youth mental health service delivery - and investigate whether headspace is providing early service access for adolescents and young adults with emerging mental health problems. DESIGN AND PARTICIPANTS: Census of all young people accessing a headspace centre across the national network of 55 centres comprising a total of 21 274 headspace clients between 1 January and 30 June 2013. MAIN OUTCOME MEASURES: Reason for presentation, Kessler Psychological Distress Scale, stage of illness, diagnosis, functioning. RESULTS: Young people were most likely to present with mood and anxiety symptoms and disorders, self reporting their reason for attendance as problems with how they felt. Client demographic characteristics tended to reflect population-level distributions, although clients from regional areas and of Aboriginal and Torres Strait Islander background were particularly well represented, whereas those who were born outside Australia were underrepresented. CONCLUSION: headspace centres are providing a point of service access for young Australians with high levels of psychological distress and need for care in the early stages of the development of mental disorder. PMID- 24484116 TI - Impact of pneumococcal polysaccharide vaccine in people aged 65 years or older. AB - OBJECTIVE: To evaluate the impact and effectiveness of the 23-valent polysaccharide pneumococcal vaccine (23vPPV) in >= 65-year-old Australians in the context of concurrent 7-valent pneumococcal conjugate vaccine (7vPCV) use in infants. DESIGN, PATIENTS AND SETTING: Ecological analysis of trends in invasive pneumococcal disease (IPD) notification rates and vaccine effectiveness estimation using the screening method, using data on Australians aged >= 65 years (23vPPV funded) and 50-64 years (23vPPV not funded). INTERVENTION: National 23vPPV program for people aged >= 65 years and national 7vPCV program for infants, both commencing in 2005. MAIN OUTCOME MEASURES: IPD incidence rate ratios, 2002-2004 to 2010-2011, and 23vPPV effectiveness against 23vPPV-type IPD. RESULTS: The proportion of people aged >= 65 years who were vaccinated within the previous 5 years in jurisdictions excluding Victoria ranged from 41% to 64% over the study period, with no clear trend over time. Incidence rate ratios in the >= 65-year age group were 0.11 (95% CI, 0.09-0.14) for 7vPCV serotypes, 1.64 (95% CI, 1.41-1.91) for 23vPPV-non-7vPCV serotypes and 2.07 (95% CI, 1.67-2.57) for non-23vPPV serotypes. The incidence rate ratio for total IPD was 0.65 (95% CI, 0.59-0.71) for people aged >= 65 years, and 0.80 (0.71-0.90) for people aged 50 64 years. The estimate of 23vPPV effectiveness was 61.1% (95% CI, 55.1%-66.9%). CONCLUSIONS: The greater reduction in IPD among >= 65-year-olds compared with 50 64-year-olds did not reach statistical significance. However, vaccine effectiveness was significant. Greater reductions in IPD in >= 65-year-olds would be expected from the indirect effects of using 13-valent pneumococcal conjugate vaccine in infants (introduced for Australian infants in 2011) and an increase in 23vPPV coverage. PMID- 24484117 TI - The growing burden of multidrug-resistant infections among returned Australian travellers. PMID- 24484118 TI - Liability in the context of misdiagnosis of melanoma in Australia. AB - Malignant melanoma is a serious and relatively common condition, the diagnosis of which may be difficult. In a recent Supreme Court of New South Wales case, misdiagnosis of melanoma occurred, but there was failure to establish causation of the patient's poor prognosis. Aggressive melanomas may grow quickly, fail to conform to standard and commonly taught diagnostic criteria, and frequently escape early detection. In the event of uncertain diagnosis or failed treatment of a lesion, an appropriate standard of care is full excisional biopsy if not previously performed, or referral of the case to an appropriate specialist or melanoma centre. Clinicians should remain aware of the existence of higher-risk, easily misdiagnosed melanomas with a high mortality rate. Therefore, they should aim to identify these at the earliest opportunity. PMID- 24484119 TI - Sometimes you have to give a man a fish. PMID- 24484122 TI - Observation of grand-canonical number statistics in a photon Bose-Einstein condensate. AB - We report measurements of particle number correlations and fluctuations of a photon Bose-Einstein condensate in a dye microcavity using a Hanbury Brown-Twiss experiment. The photon gas is coupled to a reservoir of molecular excitations, which serve as both heat bath and particle reservoir to realize grand-canonical conditions. For large reservoirs, we observe strong number fluctuations of the order of the total particle number extending deep into the condensed phase. Our results demonstrate that Bose-Einstein condensation under grand-canonical ensemble conditions does not imply second-order coherence. PMID- 24484123 TI - Universal conductivity in a two-dimensional superfluid-to-insulator quantum critical system. AB - We compute the universal conductivity of the (2+1)-dimensional XY universality class, which is realized for a superfluid-to-Mott insulator quantum phase transition at constant density. Based on large-scale Monte Carlo simulations of the classical (2+1)-dimensional J-current model and the two-dimensional Bose Hubbard model, we can precisely determine the conductivity on the quantum critical plateau, sigma(infinity) = 0.359(4)sigmaQ with sigmaQ the conductivity quantum. The universal conductivity curve is the standard example with the lowest number of components where the bottoms-up AdS/CFT correspondence from string theory can be tested and made to use [R. C. Myers, S. Sachdev, and A. Singh, Phys. Rev. D 83, 066017 (2011)]. For the first time, the shape of the sigma(iomega(n)) - sigma(infinity) function in the Matsubara representation is accurate enough for a conclusive comparison and establishes the particlelike nature of charge transport. We find that the holographic gauge-gravity duality theory for transport properties can be made compatible with the data if temperature of the horizon of the black brane is different from the temperature of the conformal field theory. The requirements for measuring the universal conductivity in a cold gas experiment are also determined by our calculation. PMID- 24484124 TI - New dynamical scaling universality for quantum networks across adiabatic quantum phase transitions. AB - We reveal universal dynamical scaling behavior across adiabatic quantum phase transitions in networks ranging from traditional spatial systems (Ising model) to fully connected ones (Dicke and Lipkin-Meshkov-Glick models). Our findings, which lie beyond traditional critical exponent analysis and adiabatic perturbation approximations, are applicable even where excitations have not yet stabilized and, hence, provide a time-resolved understanding of quantum phase transitions encompassing a wide range of adiabatic regimes. We show explicitly that even though two systems may traditionally belong to the same universality class, they can have very different adiabatic evolutions. This implies that more stringent conditions need to be imposed than at present, both for quantum simulations where one system is used to simulate the other and for adiabatic quantum computing schemes. PMID- 24484125 TI - Finding structural anomalies in star graphs using quantum walks. AB - We develop a general theory for a quantum-walk search on a star graph. A star graph has N edges each of which is attached to a central vertex. A graph G is attached to one of these edges, and we would like to find out to which edge it is attached. This is done by means of a quantum walk, a quantum version of a random walk. This walk contains O(sqrt[N]) steps, which represents a speedup over a classical search, which would require O(N) steps. The overall graph, star plus G, is divided into two parts, and we find that for a quantum speedup to occur, the eigenvalues associated with these two parts in the N->infinity limit must be the same. Our theory tells us how the initial state of the walk should be chosen, and how many steps the walk must make in order to find G. PMID- 24484126 TI - Gammalike mass distributions and mass fluctuations in conserved-mass transport processes. AB - We show that, in conserved-mass transport processes, the steady-state distribution of mass in a subsystem is uniquely determined from the functional dependence of variance of the subsystem mass on its mean, provided that the joint mass distribution of subsystems is factorized in the thermodynamic limit. The factorization condition is not too restrictive as it would hold in systems with short-ranged spatial correlations. To demonstrate the result, we revisit a broad class of mass transport models and its generic variants, and show that the variance of the subsystem mass in these models is proportional to the square of its mean. This particular functional form of the variance constrains the subsystem mass distribution to be a gamma distribution irrespective of the dynamical rules. PMID- 24484127 TI - Nanoscale heat engine beyond the Carnot limit. AB - We consider a quantum Otto cycle for a time-dependent harmonic oscillator coupled to a squeezed thermal reservoir. We show that the efficiency at maximum power increases with the degree of squeezing, surpassing the standard Carnot limit and approaching unity exponentially for large squeezing parameters. We further propose an experimental scheme to implement such a model system by using a single trapped ion in a linear Paul trap with special geometry. Our analytical investigations are supported by Monte Carlo simulations that demonstrate the feasibility of our proposal. For realistic trap parameters, an increase of the efficiency at maximum power of up to a factor of 4 is reached, largely exceeding the Carnot bound. PMID- 24484128 TI - Exact nonequilibrium steady state of an open Hubbard chain. AB - We discuss the current carrying nonequilibrium steady state of an open fermionic Hubbard chain that is strongly driven by Markovian incoherent processes localized at the chain ends. An explicit form of an exact many-body density operator for any value of the coupling parameter is presented. The structure of a matrix product form of the solution is encoded in terms of a novel diagrammatic technique that should allow for generalization to other integrable nonequilibrium models. PMID- 24484131 TI - Cosmologically safe eV-scale sterile neutrinos and improved dark matter structure. AB - We show that sterile neutrinos with masses ?1 eV, as motivated by several short baseline oscillation anomalies, can be consistent with cosmological constraints if they are charged under a hidden sector force mediated by a light boson. In this case, sterile neutrinos experience a large thermal potential that suppresses mixing between active and sterile neutrinos in the early Universe, even if vacuum mixing angles are large. Thus, the abundance of sterile neutrinos in the Universe remains very small, and their impact on big bang nucleosynthesis, cosmic microwave background, and large-scale structure formation is negligible. It is conceivable that the new gauge force also couples to dark matter, possibly ameliorating some of the small-scale structure problems associated with cold dark matter. PMID- 24484130 TI - How self-interactions can reconcile sterile neutrinos with cosmology. AB - Short baseline neutrino oscillation experiments have shown hints of the existence of additional sterile neutrinos in the eV mass range. However, such neutrinos seem incompatible with cosmology because they have too large of an impact on cosmic structure formation. Here we show that new interactions in the sterile neutrino sector can prevent their production in the early Universe and reconcile short baseline oscillation experiments with cosmology. PMID- 24484132 TI - Neutrinoless double-beta decay and QCD corrections. AB - We consider one-loop QCD corrections and renormalization group running of the neutrinoless double-beta decay amplitude focusing on the short-range part of the amplitude (without the light neutrino exchange) and find that these corrections can be sizeable. Depending on the operator under consideration, there can be moderate to large cancellations or significant enhancements. We discuss several specific examples in this context. Such large corrections will lead to significant shifts in the half-life estimates, which currently are known to be plagued with the uncertainties due to nuclear physics inputs to the physical matrix elements. PMID- 24484133 TI - Complete next-to-leading-order study on the yield and polarization of Upsilon(1S,2S,3S) at the Tevatron and LHC. AB - Based on the nonrelativistic QCD factorization scheme, we present the first complete next-to-leading-order study on the yield and polarization of Upsilon(1S,2S,3S) hadroproduction. By using the color-octet long-distance matrix elements obtained from fits of the experimental measurements on Upsilon yield and polarization at the Tevatron and LHC, our results can explain the measurements on the yield very well, and for the polarizations of Upsilon(1S,2S,3S), they are in (good, good, bad) agreement with recent CMS measurement, but still have some distance from the CDF measurement. PMID- 24484134 TI - Medium modification of photon-tagged and inclusive jets in high-multiplicity proton-proton collisions. AB - We study modification of the photon-tagged and inclusive jets in pp collisions at sqrt[s]=7 TeV due to mini-quark-gluon plasma which can be produced in high multiplicity events. We show that for underlying events with dN(ch)/deta~20-60 the medium effects lead to a considerable modification of the photon-tagged and inclusive jet fragmentation functions. For inclusive jets, the magnitude of the effect is surprisingly large. The effect is quite strong even for typical underlying events. We find that the spectrum of charged hadrons is suppressed by ~35%-40% at p(T)~5-10 GeV. PMID- 24484136 TI - Ultracold heteronuclear mixture of ground and excited state atoms. AB - We report on the realization of an ultracold mixture of lithium atoms in the ground state and ytterbium atoms in an excited metastable (3P2) state. Such a mixture can support broad magnetic Feshbach resonances which may be utilized for the production of ultracold molecules with an electronic spin degree of freedom, as well as novel Efimov trimers. We investigate the interaction properties of the mixture in the presence of an external magnetic field and find an upper limit for the background interspecies two-body inelastic decay coefficient of K2'<3*10(-12) cm3/s for the 3P2 mJ=-1 substate. We calculate the dynamic polarizabilities of the Yb(3P2) magnetic substates for a range of wavelengths, and find good agreement with our measurements at 1064 nm. Our calculations also allow the identification of magic frequencies where Yb ground and metastable states are identically trapped and the determination of the interspecies van der Waals coefficients. PMID- 24484129 TI - Measurement of the tau-lepton lifetime at Belle. AB - The lifetime of the tau lepton is measured using the process e+ e- -> tau+ tau- , where both tau leptons decay to 3pinu(tau). The result for the mean lifetime, based on 711 fb(-1) of data collected with the Belle detector at the Upsilon(4S) resonance and 60 MeV below, is tau=(290.17+/-0.53(stat)+/-0.33(syst))*10(-15) s. The first measurement of the lifetime difference between tau+ and tau- is performed. The upper limit on the relative lifetime difference between positive and negative tau leptons is |Deltatau|/tau<7.0*10(-3) at 90% C.L. PMID- 24484137 TI - Homodyne tomography of a single photon retrieved on demand from a cavity-enhanced cold atom memory. AB - We experimentally demonstrate that a nonclassical state prepared in an atomic memory can be efficiently transferred to a single mode of free-propagating light. By retrieving on demand a single excitation from a cold atomic gas, we realize an efficient source of single photons prepared in a pure, fully controlled quantum state. We characterize this source using two detection methods, one based on photon-counting analysis and the second using homodyne tomography to reconstruct the density matrix and Wigner function of the state. The latter technique allows us to completely determine the mode of the retrieved photon in its fine phase and amplitude details and demonstrate its nonclassical field statistics by observing a negative Wigner function. We measure a photon retrieval efficiency up to 82% and an atomic memory coherence time of 900 ns. This setup is very well suited to study interactions between atomic excitations and use them in order to create and manipulate more sophisticated quantum states of light with a high degree of experimental control. PMID- 24484138 TI - Seemingly unlimited lifetime data storage in nanostructured glass. AB - We demonstrate recording and retrieval of the digital document with a nearly unlimited lifetime. The recording process of multiplexed digital data was implemented by femtosecond laser nanostructuring of fused quartz. The storage allows unprecedented parameters including hundreds of terabytes per disc data capacity, thermal stability up to 1000 degrees C, and virtually unlimited lifetime at room temperature. We anticipate that this demonstration will open a new era of eternal data archiving. PMID- 24484139 TI - Electric levitation using epsilon-near-zero metamaterials. AB - The ability to manufacture metamaterials with exotic electromagnetic properties has potential for surprising new applications. Here we report how a specific type of metamaterial--one whose permittivity is near zero--exerts a repulsive force on an electric dipole source, resulting in levitation of the dipole. The phenomenon relies on the expulsion of the time-varying electric field from the metamaterial interior, resembling the perfect diamagnetic expulsion of magnetostatic fields. Leveraging this concept, we study some realistic requirements for the levitation or repulsion of a polarized particle radiating at any frequency, from microwave to optics. PMID- 24484140 TI - Disorder induced regular dynamics in oscillating lattices. AB - We explore the impact of weak disorder on the dynamics of classical particles in a periodically oscillating lattice. It is demonstrated that the disorder induces a hopping process from diffusive to regular motion; i.e., we observe the counterintuitive phenomenon that disorder leads to regular behavior. If the disorder is localized in a finite-sized part of the lattice, the described hopping causes initially diffusive particles to even accumulate in regular structures of the corresponding phase space. A hallmark of this accumulation is the emergence of pronounced peaks in the velocity distribution of particles that should be detectable in state of the art experiments, e.g., with cold atoms in optical lattices. PMID- 24484141 TI - Transforming wave propagation in layered media via instability-induced interfacial wrinkling. AB - The ability to control wave propagation in highly deformable layered media with elastic instability-induced wrinkling of interfacial layers is presented. The onset of a wrinkling instability in initially straight interfacial layers occurs when a critical compressive strain is achieved. Further compression beyond the critical strain leads to an increase in the wrinkle amplitude of the interfacial layer. This, in turn, gives rise to the formation of a system of periodic scatterers, which reflect and interfere with wave propagation. We demonstrate that the topology of wrinkling interfacial layers can be controlled by deformation and used to produce band gaps in wave propagation and, hence, to selectively filter frequencies. Remarkably, the mechanism of frequency filtering is effective even for composites with similar or identical densities, such as polymer-polymer composites. Since the microstructure change is reversible, the mechanism can be used for tuning and controlling wave propagation by deformation. PMID- 24484142 TI - Curling edges: a problem that has plagued scrolls for millennia. AB - Qi-Wa refers to the up curl on the lengths of hand scrolls and hanging scrolls, which has troubled Chinese artisans and emperors for as long as the art of painting and calligraphy has existed. This warp is unwelcome not only for aesthetic reasons, but its potential damage to the fiber and ink. Although it is generally treated as a part of the cockling and curling due to moisture, consistency of paste, and defects from the mounting procedures, we demonstrate that the spontaneous extrinsic curvature incurred from the storage is in fact more essential to understanding and curing Qi-Wa. In contrast to the former factors whose effects are less predictable, the plastic deformation and strain distribution on a membrane are a well-defined mechanical problem. We study this phenomenon by experiments, theoretical models, and molecular dynamics simulation, and obtain consistent scaling relations for the Qi-Wa height. This knowledge enables us to propose modifications on the traditional mounting techniques that are tested on real mounted paper to be effective at mitigating Qi-Wa. By experimenting on polymer-based films, we demonstrate the possible relevance of our study to the modern development of flexible electronic paper. PMID- 24484143 TI - Experimental demonstration of energy-chirp control in relativistic electron bunches using a corrugated pipe. AB - The first experimental study is presented of a corrugated wall device that uses wakefields to remove a linear energy correlation in a relativistic electron beam (a "dechirper"). Time-resolved measurements of both longitudinal and transverse wakefields of the device are presented and compared with simulations. This study demonstrates the feasibility to employ a dechirper for precise control of the beam phase space in the next generation of free-electron-lasers. PMID- 24484145 TI - Observation of the optical and spectral characteristics of ball lightning. AB - Ball lightning (BL) has been observed with two slitless spectrographs at a distance of 0.9 km. The BL is generated by a cloud-to-ground lightning strike. It moves horizontally during the luminous duration. The evolution of size, color, and light intensity is reported in detail. The spectral analysis indicates that the radiation from soil elements is present for the entire lifetime of the BL. PMID- 24484146 TI - Higher-order nonlocal effects of a relativistic ponderomotive force in high intensity laser fields. AB - We have developed a new formula for a relativistic ponderomotive force of transversely localized laser fields based on the noncanonical Lie perturbation method by finding proper coordinates and gauges in the variational principle. The formula involves new terms represented by second and third spatial derivatives of the field amplitude, so that the ponderomotive force depends not only on the local field gradient, but also on the curvature and its variation. The formula is then applicable to a regime in which the conventional formula is hardly applied such that nonlocal and/or global extent of the field profile becomes important. The result can provide a theoretical basis for describing nonlinear laser-plasma interaction including such nonlocal effects, which is examined via particle-in cell simulation of laser propagation in a plasma with a super Gaussian transverse field profile. PMID- 24484147 TI - Phase-space dynamics of ionization injection in plasma-based accelerators. AB - The evolution of beam phase space in ionization injection into plasma wakefields is studied using theory and particle-in-cell simulations. The injection process involves both longitudinal and transverse phase mixing, leading initially to a rapid emittance growth followed by oscillation, decay, and a slow growth to saturation. An analytic theory for this evolution is presented and verified through particle-in-cell simulations. This theory includes the effects of injection distance (time), acceleration distance, wakefield structure, and nonlinear space charge forces, and it also shows how ultralow emittance beams can be produced using ionization injection methods. PMID- 24484144 TI - Experimental validation of a novel compact focusing scheme for future energy frontier linear lepton colliders. AB - A novel scheme for the focusing of high-energy leptons in future linear colliders was proposed in 2001 [P. Raimondi and A. Seryi, Phys. Rev. Lett. 86, 3779 (2001)]. This scheme has many advantageous properties over previously studied focusing schemes, including being significantly shorter for a given energy and having a significantly better energy bandwidth. Experimental results from the ATF2 accelerator at KEK are presented that validate the operating principle of such a scheme by demonstrating the demagnification of a 1.3 GeV electron beam down to below 65 nm in height using an energy-scaled version of the compact focusing optics designed for the ILC collider. PMID- 24484149 TI - Scale invariance and universality in a cold gas of indirect excitons. AB - We address, theoretically, the puzzling similarity observed in the thermodynamic behavior of independent clouds of cold dipolar excitons in coupled semiconductor quantum wells. We argue that the condensation of self-trapped exciton gas starts at the same critical temperature in all traps due to the specific scaling rule. As a consequence of the reduced dimensionality of the system, the scaling parameters appear to be insensitive to disorder. PMID- 24484148 TI - Quantum simulation of Landau-Zener model dynamics supporting the Kibble-Zurek mechanism. AB - The Kibble-Zurek mechanism (KZM) captures the key physics of nonequilibrium dynamics in second order phase transitions, and accurately predicts the density of topological defects formed in such processes. However, the central prediction of KZM--i.e., the scaling of the density of defects with the quench rate--still needs further experimental confirmation, particularly for quantum transitions. Here, we perform a quantum simulation of the nonequilibrium dynamics of the Landau-Zener model based on a nine-stage optical interferometer with an overall visibility of 0.975+/-0.008. The results support the adiabatic-impulse approximation, which is the core of Kibble-Zurek theory. Moreover, the developed high-fidelity multistage optical interferometer can support more complex linear optical quantum simulations. PMID- 24484150 TI - Edge theories in projected entangled pair state models. AB - We analyze the low energy excitations of spin lattice systems in two dimensions at zero temperature within the framework of projected entangled pair state models. Perturbations in the bulk give rise to physical excitations located at the edge. We identify the corresponding degrees of freedom, give a procedure to derive the edge Hamiltonian, and illustrate that it can exhibit a rich phase diagram. For topological models, the edge Hamiltonian is constrained by the topological order in the bulk, which gives rise to one-dimensional edge models with unconventional properties; for instance, a topologically ordered bulk can protect a ferromagnetic Ising chain at the edge against spontaneous symmetry breaking. PMID- 24484135 TI - Energy dependence of moments of net-proton multiplicity distributions at RHIC. AB - We report the beam energy (sqrt[sNN]=7.7-200 GeV) and collision centrality dependence of the mean (M), standard deviation (sigma), skewness (S), and kurtosis (kappa) of the net-proton multiplicity distributions in Au+Au collisions. The measurements are carried out by the STAR experiment at midrapidity (|y|<0.5) and within the transverse momentum range 0.44.92 N m. Differences in stiffness and strength in 4 point bending were not statistically significant. CONCLUSIONS: LC-DCP/rod constructs had significantly less permanent angular deformation than CRIF/rod constructs. CRIF/rod constructs became less stiff as torsional load was increased, thus the LC-DCP/rod constructs had significantly greater torsional stiffness and strength under high torsional loads. LC-DCP/rod and CRIF/rod constructs performed similarly under 4-point bend loading conditions. PMID- 24484219 TI - Gamma-irradiated carbon nanotube yarn as substrate for high-performance fiber supercapacitors. AB - As an electrical double layer capacitor, dry-spun carbon nanotube yarn possesses relatively low specific capacitance. This can be significantly increased as a result of the pseudocapacitance of functional groups on the carbon nanotubes developed by oxidation using a gamma irradiation treatment in the presence of air. When coated with high-performance polyaniline nanowires, the gamma irradiated carbon nanotube yarn acts as a high-strength reinforcement and a high efficiency current collector in two-ply yarn supercapacitors for transporting charges generated along the long electrodes. The resulting supercapacitors demonstrate excellent electrochemical performance, cycle stability, and resistance to folding-unfolding that are required in wearable electronic textiles. PMID- 24484215 TI - Point of care diagnostics for sexually transmitted infections: perspectives and advances. AB - Accurate and inexpensive point-of-care (POC) tests are urgently needed to control sexually transmitted infection epidemics, so that patients can receive immediate diagnoses and treatment. Current POC assays for Chlamydia trachomatis and Neisseria gonorrhoeae perform inadequately and require better assays. Diagnostics for Trichomonas vaginalis rely on wet preparation, with some notable advances. Serological POC assays for syphilis can impact resource-poor settings, with many assays available, but only one available in the U.S. HIV POC diagnostics demonstrate the best performance, with excellent assays available. There is a rapid assay for HSV lesion detection; but no POC serological assays are available. Despite the inadequacy of POC assays for treatable bacterial infections, application of technological advances offers the promise of advancing POC diagnostics for all sexually transmitted infections. PMID- 24484220 TI - Our experience of glycopyrrolate 2% cream for axillary hyperhidrosis. PMID- 24484221 TI - Cutaneous pyeloureteral stent for laparoscopic (robot)-assisted pyeloplasty. AB - BACKGROUND AND PURPOSE: In select centers, laparoscopic (robot)-assisted pyeloplasty has emerged as a viable approach for the treatment of ureteropelvic junction obstruction (UPJO). Stent placement for urinary diversion is a common postoperative practice with several potential techniques and respective challenges. Robot-assisted diversion techniques such as indwelling Double-J or nephroureteral stents require either additional anesthesia or costs or they carry bleeding risks. Herein we describe an alternative postpyeloplasty cutaneous pyeloureteral (CPU) stenting technique that minimizes these challenges and achieves effective urinary diversion. PMID- 24484222 TI - Awake mapping for low-grade gliomas involving the left sagittal stratum: anatomofunctional and surgical considerations. AB - OBJECT: Preserving function while optimizing the extent of resection is the main goal in surgery for diffuse low-grade glioma (DLGG). This is particularly relevant for DLGG involving the sagittal stratum (SS), where damage can have severe consequences. Indeed, this structure is a major crossroad in which several important fascicles run. Thus, its complex functional anatomy is still poorly understood. Subcortical electrical stimulation during awake surgery provides a unique opportunity to investigate white matter pathways. This study reports the findings on anatomofunctional correlations evoked by stimulation during resection for gliomas involving the left SS. Surgical outcomes are also detailed. METHODS: The authors performed a review of patients who underwent awake surgery for histopathologically confirmed WHO Grade II glioma involving the left SS in the neurosurgery department between August 2008 and August 2012. Information regarding clinicoradiological features, surgical procedures, and outcomes was collected and analyzed. Intraoperative electrostimulation was used to map the eloquent structures within the SS. RESULTS: Eight consecutive patients were included in this study. There were 6 men and 2 women, whose mean age was 41.7 years (range 32-61 years). Diagnosis was made because of seizures in 7 cases and slight language disorders in 1 case. After cortical mapping, subcortical stimulation detected functional fibers running in the SS in all patients: semantic paraphasia was generated by stimulating the inferior frontooccipital fascicle in 8 cases; alexia was elicited by stimulating the inferior longitudinal fascicle in 3 cases; visual disorders were induced by stimulating the optic radiations in 5 cases. Moreover, in front of the SS, phonemic paraphasia was evoked by stimulating the temporal part of the arcuate fascicle in 5 patients. The resection was stopped according to these functional limits in the 8 patients. After a transient postsurgical worsening, all patients recovered to normal results on examination, except for the persistence of a right superior quadrantanopia in 5 cases, with no consequences for quality of life. The 8 patients returned to a normal social and professional life. Total or subtotal resection was achieved in all cases but one. CONCLUSIONS: The authors suggest that the use of intrasurgical electrical mapping of the white matter pathways in awake patients opens the door to extensive resection of DLGG within the left SS while preserving the quality of life. Further anatomical, clinical, radiological, and electrophysiological studies are needed for a better understanding of the functional anatomy of this complex region. PMID- 24484223 TI - Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations. PMID- 24484224 TI - Increased risk of acute kidney injury associated with higher infusion rate of mannitol in patients with intracranial hemorrhage. AB - OBJECT: Mannitol, an osmotic agent used to decrease intracranial pressure, can cause acute kidney injury (AKI). The objectives of this study were to assess the impact of mannitol on the incidence and severity of AKI and to identify risk factors and outcome for AKI in patients with intracranial hemorrhage (ICH). METHODS: The authors retrospectively evaluated 153 adult patients who received mannitol infusion after ICH between January 2005 and December 2009 in the neurosurgical intensive care unit. Multivariate analysis was used to evaluate the risk factors for AKI after ICH. Based on the odds ratio, weighted scores were assigned to predictors of AKI. RESULTS: The overall incidence of AKI among study participants was 10.5% (n = 16). Acute kidney injury occurred more frequently in patients who received mannitol infusion at a rate >= 1.34 g/kg/day than it did in patients who received mannitol infusion at a rate < 1.34 g/kg/day. A higher mannitol infusion rate was associated with more severe AKI. Independent risk factors for AKI were mannitol infusion rate >= 1.34 g/kg/day, age >= 70 years, diastolic blood pressure (DBP) >= 110 mm Hg, and glomerular filtration rate < 60 ml/min/1.73 m(2). The authors developed a risk model for AKI, wherein patients with a higher risk score showed a graded association with a higher incidence of AKI. CONCLUSIONS: The incidence of AKI following mannitol infusion in patients with ICH was 10.5%. A higher mannitol infusion rate was associated with more frequent and more severe AKI. Additionally, age >= 70 years, DBP >= 110 mm Hg, and established renal dysfunction before starting mannitol therapy were associated with development of AKI. PMID- 24484225 TI - Can helmet design reduce the risk of concussion in football? AB - Of all sports, football accounts for the highest incidence of concussion in the US due to the large number of athletes participating and the nature of the sport. While there is general agreement that concussion incidence can be reduced through rule changes and teaching proper tackling technique, there remains debate as to whether helmet design may also reduce the incidence of concussion. A retrospective analysis was performed of head impact data collected from 1833 collegiate football players who were instrumented with helmet-mounted accelerometer arrays for games and practices. Data were collected between 2005 and 2010 from 8 collegiate football teams: Virginia Tech, University of North Carolina, University of Oklahoma, Dartmouth College, Brown University, University of Minnesota, Indiana University, and University of Illinois. Concussion rates were compared between players wearing Riddell VSR4 and Riddell Revolution helmets while controlling for the head impact exposure of each player. A total of 1,281,444 head impacts were recorded, from which 64 concussions were diagnosed. The relative risk of sustaining a concussion in a Revolution helmet compared with a VSR4 helmet was 46.1% (95% CI 28.1%-75.8%). When controlling for each player's exposure to head impact, a significant difference was found between concussion rates for players in VSR4 and Revolution helmets (chi(2) = 4.68, p = 0.0305). This study illustrates that differences in the ability to reduce concussion risk exist between helmet models in football. Although helmet design may never prevent all concussions from occurring in football, evidence illustrates that it can reduce the incidence of this injury. PMID- 24484226 TI - Fiber tractography of the axonal pathways linking the basal ganglia and cerebellum in Parkinson disease: implications for targeting in deep brain stimulation. AB - OBJECT: Stimulation of white matter pathways near targeted structures may contribute to therapeutic effects of deep brain stimulation (DBS) for patients with Parkinson disease (PD). Two tracts linking the basal ganglia and cerebellum have been described in primates: the subthalamopontocerebellar tract (SPCT) and the dentatothalamic tract (DTT). The authors used fiber tractography to evaluate white matter tracts that connect the cerebellum to the region of the basal ganglia in patients with PD who were candidates for DBS. METHODS: Fourteen patients with advanced PD underwent 3-T MRI, including 30-directional diffusion weighted imaging sequences. Diffusion tensor tractography was performed using 2 regions of interest: ipsilateral subthalamic and red nuclei, and contralateral cerebellar hemisphere. Nine patients underwent subthalamic DBS, and the course of each tract was observed relative to the location of the most effective stimulation contact and the volume of tissue activated. RESULTS: In all patients 2 distinct tracts were identified that corresponded closely to the described anatomical features of the SPCT and DTT, respectively. The mean overall distance from the active contact to the DTT was 2.18 +/- 0.35 mm, and the mean proportional distance relative to the volume of tissue activated was 1.35 +/- 0.48. There was a nonsignificant trend toward better postoperative tremor control in patients with electrodes closer to the DTT. CONCLUSIONS: The SPCT and the DTT may be related to the expression of symptoms in PD, and this may have implications for DBS targeting. The use of tractography to identify the DTT might assist with DBS targeting in the future. PMID- 24484227 TI - Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations. AB - OBJECT: The purpose of this study was to define the outcomes and risks of stereotactic radiosurgery (SRS) for Spetzler-Martin (SM) Grade III arteriovenous malformations (AVMs). METHODS: Between 1987 and 2009, SRS was performed in 474 patients with SM Grade III AVMs. The AVMs were categorized by scoring the size (S), drainage (D), and location (L): IIIa was a small AVM (S1D1L1, N = 282); IIIb was a medium/deep AVM (S2D1L0, N = 44); and IIIc was a medium/eloquent AVM (S2D0L1, N = 148). The median target volume was 3.8 ml (range 0.1-26.3 ml) and the margin dose was 20 Gy (range 13-25 Gy). Eighty-one patients (17%) underwent prior embolization, and 58 (12%) underwent prior resection. RESULTS: At a mean follow-up of 89 months, the total obliteration rates documented by angiography or MRI for all SM Grade III AVMs increased from 48% at 3 years to 69% at 4 years, 72% at 5 years, and 77% at 10 years. The SM Grade IIIa AVMs were more likely to obliterate than other subgroups. The cumulative rate of hemorrhage was 2.3% at 1 year, 4.4% at 2 years, 5.5% at 3 years, 6.4% at 5 years, and 9% at 10 years. The SM Grade IIIb AVMs had a significantly higher cumulative rate of hemorrhage. Symptomatic adverse radiation effects were detected in 6%. CONCLUSIONS: Treatment with SRS was an effective and relatively safe management option for SM Grade III AVMs. Although patients with residual AVMs remained at risk for hemorrhage during the latency interval, the cumulative 10-year 9% hemorrhage risk in this series may represent a significant reduction compared with the expected natural history. PMID- 24484228 TI - Assessment of a noninvasive cerebral oxygenation monitor in patients with severe traumatic brain injury. AB - OBJECT: Development of a noninvasive monitor to assess cerebral oxygenation has long been a goal in neurocritical care. The authors evaluated the feasibility and utility of a noninvasive cerebral oxygenation monitor, the CerOx 3110, which uses near-infrared spectroscopy and ultrasound to measure regional cerebral tissue oxygenation in patients with severe traumatic brain injury (TBI), and compared measurements obtained using this device to those obtained using invasive cerebral monitoring. METHODS: Patients with severe TBI admitted to the intensive care unit at Hadassah-Hebrew University Hospital requiring intracranial pressure (ICP) monitoring and advanced neuromonitoring were included in this study. The authors assessed 18 patients with severe TBI using the CerOx monitor and invasive advanced cerebral monitors. RESULTS: The mean age of the patients was 45.3 +/- 23.7 years and the median Glasgow Coma Scale score on admission was 5 (interquartile range 3-7). Eight patients underwent unilateral decompressive hemicraniectomy and 1 patient underwent craniotomy. Sixteen patients underwent insertion of a jugular bulb venous catheter, and 18 patients underwent insertion of a Licox brain tissue oxygen monitor. The authors found a strong correlation (r = 0.60, p < 0.001) between the jugular bulb venous saturation from the venous blood gas and the CerOx measure of regional cerebral tissue saturation on the side ipsilateral to the catheter. A multivariate analysis revealed that among the physiological parameters of mean arterial blood pressure, ICP, brain tissue oxygen tension, and CerOx measurements on the ipsilateral and contralateral sides, only ipsilateral CerOx measurements were significantly correlated to jugular bulb venous saturation (p < 0.001). CONCLUSIONS: Measuring regional cerebral tissue oxygenation with the CerOx monitor in a noninvasive manner is feasible in patients with severe TBI in the neurointensive care unit. The correlation between the CerOx measurements and the jugular bulb venous measurements of oxygen saturation indicate that the CerOx may be able to provide an estimation of cerebral oxygenation status in a noninvasive manner. PMID- 24484229 TI - Edwin Smith Papyrus Case 8: a reappraisal. AB - There are 3 translations of the Edwin Smith Papyrus: Breasted's (1930), Allen's (2005), and Sanchez and Meltzer's (2012). Case 8 is similarly presented in all 3 translations, although with increasing detail in the later works. The patient in Case 8 had a comminuted skull fracture under intact skin. There were palpable pulsations at the fracture site. There was deviation of the eye on the side of the injury and an ipsilateral spastic hemiparesis in an ambulant patient with bleeding from the nose and ear. Explanations of the paralysis have included a contrecoup lesion and compression of the contralateral cerebral peduncle against the tentorial incisura. Brainstem compression due to herniation is accompanied by loss of consciousness. Extensive contrecoup lesions consistent with the extent of the described paresis would also be associated with probable coma. The paralysis was spastic, but spasticity takes weeks to develop after trauma. Yet this patient's trauma was fresh, as there was still bleeding from the nose and the ear. It is suggested the paresis antedated the trauma, which was not its cause. The reasons for this suggestion are presented in this paper. PMID- 24484230 TI - Effects of cerebral magnetic resonance imaging in outpatients on observed incidence of intracranial tumors and patient survival: a national observational study. AB - OBJECT: It is assumed that the observed increase in brain tumor incidence may at least partially be explained by increased use of MRI. However, to date no direct estimate of this effect is available. The authors undertook this registry-based study to examine whether regional frequencies of cerebral MRI use correlate to regional incidence rates of intracranial tumors and survival of patients with these lesions. METHODS: The authors used Norwegian national population registries from January 2002 through December 2007 to conduct this observational study. They obtained information on outpatient MRI scans in Norwegian counties and examined whether the annual regional rates of cerebral MRI scans correlated to regional age- and sex-adjusted brain tumor incidence rates. They also explored whether differences in cerebral MRI use were associated with survival and examined time trends in the study period. RESULTS: Approximately 50,000 cerebral MRI scans are carried out annually in outpatient settings in Norway, and 6363 primary intracranial tumors were diagnosed in Norway during the study period. There was an overall positive correlation between the annual number of cerebral MRI scans per 100,000 capita and age- and sex-adjusted incidence rates of intracranial tumors in the various Norwegian counties (Spearman's rho = 0.35, p < 0.001). In a linear model, an increase in 1 MRI per 100,000 capita per year results in a 0.004 (95% CI 0.002-0.006) increase in diagnosed intracranial tumors per 100,000 capita per year (p < 0.001). Subgroup analysis showed a correlation between MRI use and the annual age- and sex-adjusted incidence rates of extraaxial tumors (p = 0.04, Spearman's rho = 0.28) but not intraaxial tumors (p = 0.394). Overall survival for unselected patients with intracranial tumors is longer with increasing number of cerebral MRI scans per capita in the county of residence at the time of the diagnosis (log rank, p = 0.029). However, after adjustment for year of diagnosis and catchment region of the Norwegian neurosurgical centers, the association between MRI scans per capita and overall survival was no longer statistically significant (p = 0.076). CONCLUSIONS: Presumably due to the incidental discovery of benign extraaxial tumors, regional differences in the use of cerebral MRI in outpatients affect observed incidence rates of intracranial tumors. PMID- 24484231 TI - Subtle structural change demonstrated on T2-weighted images after clipping of unruptured intracranial aneurysm: negative effects on cognitive performance. AB - OBJECT: The mechanisms underlying neurocognitive changes after surgical clipping of unruptured intracranial aneurysms (UIAs) are poorly understood. The aim of this study was to investigate factors that determine postoperative cognitive decline after UIA surgery. METHODS: Data from 109 patients who underwent surgical clipping of a UIA were retrospectively evaluated. These patients underwent neuropsychological examinations (NPEs), including assessment by the Wechsler Adult Intelligence Scale-Third Edition and the Wechsler Memory Scale-Revised before and 6 months after surgical clipping of the UIA. Results of NPEs were converted into z scores, from which pre- and postoperative cognitive composite scores (CSpre and CSpost) were obtained. The association between the change in CS between pre- and postoperative NPEs (that is, CSpost - CSpre [CSpost - pre]) and various variables was assessed. These latter variables included surgical approach (anterior interhemispheric approach or other approach), structural change evidenced on T2-weighted imaging at 6 months, somatosensory evoked potential amplitude decrease greater than 50% during aneurysm manipulation, preexisting multiple ischemic lesions in the lacunar region detected on preoperative T2 weighted imaging, and total microsurgical time. Paired t-tests of the NPE scores were performed to determine the net effect of these factors on neurocognitive function at 6 months. RESULTS: A significant CSpost - pre decrease was observed in patients with a structural change on postoperative T2-weighted imaging when compared with those without such a change on postoperative T2-weighted imaging ( 0.181 vs 0.043, p = 0.012). Multiple regression analysis demonstrated that postoperative T2-weighted imaging change independently and negatively correlated with CSpost - pre (p = 0.0005). In group-rate analysis, postoperative NPE scores were significantly improved relative to preoperative scores. CONCLUSIONS: Minimal structural damage visualized on T2-weighted images at 6 months as a result of factors such as pial/microvascular injury and excessive retraction during surgical manipulation could cause subtle but significant negative effects on postoperative neurocognitive function after surgical clipping of a UIA. However, this detrimental effect was small, and based on the group-rate analysis, the authors conclude that successful and meticulous surgical clipping of a UIA does not adversely affect postoperative cognitive function. PMID- 24484232 TI - An extent of resection threshold for recurrent glioblastoma and its risk for neurological morbidity. AB - OBJECT: Despite improvements in the medical and surgical management of patients with glioblastoma, tumor recurrence remains inevitable. For recurrent glioblastoma, however, the clinical value of a second resection remains uncertain. Specifically, what proportion of contrast-enhancing recurrent glioblastoma tissue must be removed to improve overall survival and what is the neurological cost of incremental resection beyond this threshold? METHODS: The authors identified 170 consecutive patients with recurrent supratentorial glioblastomas treated at the Barrow Neurological Institute from 2001 to 2011. All patients previously had a de novo glioblastoma and following their initial resection received standard temozolomide and fractionated radiotherapy. RESULTS: The mean clinical follow-up was 22.6 months and no patient was lost to follow-up. At the time of recurrence, the median preoperative tumor volume was 26.1 cm(3). Following re-resection, median postoperative tumor volume was 3.1 cm(3), equating to an 87.4% extent of resection (EOR). The median overall survival was 19.0 months, with a median progression-free survival following re-resection of 5.2 months. Using Cox proportional hazards analysis, the variables of age, Karnofsky Performance Scale (KPS) score, and EOR were predictive of survival following repeat resection (p = 0.0001). Interestingly, a significant survival advantage was noted with as little as 80% EOR. Recursive partitioning analysis validated these findings and provided additional risk stratification at the highest levels of EOR. Overall, at 7 days after surgery, a deterioration in the NIH stroke scale score by 1 point or more was observed in 39.1% of patients with EOR >= 80% as compared with 16.7% for those with EOR < 80% (p = 0.0049). This disparity in neurological morbidity, however, did not endure beyond 30 days postoperatively (p = 0.1279). CONCLUSIONS: For recurrent glioblastomas, an improvement in overall survival can be attained beyond an 80% EOR. This survival benefit must be balanced against the risk of neurological morbidity, which does increase with more aggressive cytoreduction, but only in the early postoperative period. Interestingly, this putative EOR threshold closely approximates that reported for newly diagnosed glioblastomas, suggesting that for a subset of patients, the survival benefit of microsurgical resection does not diminish despite biological progression. PMID- 24484233 TI - Endogenous and exogenous hormone exposure and the risk of meningioma in men. AB - OBJECT: Meningioma is a disease with considerable morbidity and is more commonly diagnosed in females than in males. Hormonally related risk factors have long been postulated to be associated with meningioma risk, but no examination of these factors has been undertaken in males. METHODS: Subjects were male patients with intracranial meningioma (n = 456), ranging in age from 20 to 79 years, who were diagnosed among residents of the states of Connecticut, Massachusetts, and North Carolina, the San Francisco Bay Area, and 8 counties in Texas and matched controls (n = 452). Multivariate logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the association between hormonal factors and meningioma risk in men. RESULTS: Use of soy and tofu products was inversely associated with meningioma risk (OR 0.50 [95% CI 0.37 0.68]). Increased body mass index (BMI) appears to be associated with an approximately 2-fold increased risk of developing meningioma in men. No other single hormone-related exposure was found to be associated with meningioma risk, although the prevalence of exposure to factors such as orchiectomy and vasectomy was very low. CONCLUSIONS: Estrogen-like exogenous exposures, such as soy and tofu, may be associated with reduced risk of meningioma in men. Endogenous estrogen-associated factors such as high BMI may increase risk. Examination of other exposures related to these factors may lead to better understanding of mechanisms and potentially to intervention. PMID- 24484234 TI - Efficacy of local polymer-based and systemic delivery of the anti-glutamatergic agents riluzole and memantine in rat glioma models. AB - OBJECT: The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. METHODS: In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). RESULTS: In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organotypic cultures showed reduced growth of tumors treated with radiation and riluzole in comparison with untreated cultures or cultures treated with radiation or riluzole alone. Three separate efficacy experiments all showed that localized delivery of riluzole or memantine is efficacious against the 9L gliosarcoma tumor in vivo. Systemic riluzole monotherapy was ineffective; however, riluzole given with RT resulted in improved survival. CONCLUSIONS: Riluzole and memantine can be safely and effectively delivered intracranially via polymer in rat glioma models. Both drugs demonstrate efficacy against the 9L gliosarcoma and F98 glioma in vitro and in vivo. Although systemic riluzole proved ineffective in increasing survival, riluzole acted synergistically with radiation and increased survival compared with RT or riluzole alone. PMID- 24484235 TI - Sequential treatment with ipilimumab and BRAF inhibitors in patients with metastatic melanoma: data from the Italian cohort of the ipilimumab expanded access program. AB - Of 93 patients with pretreated, BRAF(V600) mutation-positive advanced melanoma who received vemurafenib or dabrafenib before (n = 45) or after (n = 48) treatment with ipilimumab 3 mg/kg, median overall survival (mOS) from first treatment was 9.9 and 14.5 months, respectively. Among patients treated with a BRAF inhibitor first, mOS from the end of BRAF inhibition was 1.2 months for those who did not complete ipilimumab treatment as per protocol, compared with 12.7 months for those who did (p < .001). Prospective, randomized studies are required to determine the optimal sequencing of ipilimumab and BRAF inhibitors in patients with BRAF-mutated metastatic melanoma. PMID- 24484236 TI - Presence of B cells in tertiary lymphoid structures is associated with a protective immunity in patients with lung cancer. AB - RATIONALE: It is now well established that immune responses can take place outside of primary and secondary lymphoid organs. We previously described the presence of tertiary lymphoid structures (TLS) in patients with non-small cell lung cancer (NSCLC) characterized by clusters of mature dendritic cells (DCs) and T cells surrounded by B-cell follicles. We demonstrated that the density of these mature DCs was associated with favorable clinical outcome. OBJECTIVES: To study the role of follicular B cells in TLS and the potential link with a local humoral immune response in patients with NSCLC. METHODS: The cellular composition of TLS was investigated by immunohistochemistry. Characterization of B-cell subsets was performed by flow cytometry. A retrospective study was conducted in two independent cohorts of patients. Antibody specificity was analyzed by ELISA. MEASUREMENTS AND MAIN RESULTS: Consistent with TLS organization, all stages of B cell differentiation were detectable in most tumors. Germinal center somatic hypermutation and class switch recombination machineries were activated, associated with the generation of plasma cells. Approximately half of the patients showed antibody reactivity against up to 7 out of the 33 tumor antigens tested. A high density of follicular B cells correlated with long-term survival, both in patients with early-stage NSCLC and with advanced-stage NSCLC treated with chemotherapy. The combination of follicular B cell and mature DC densities allowed the identification of patients with the best clinical outcome. CONCLUSIONS: B-cell density represents a new prognostic biomarker for NSCLC patient survival, and makes the link between TLS and a protective B cell-mediated immunity. PMID- 24484237 TI - A new guaianolide sesquiterpene lactone from Curcuma leucorrhiza Roxb. AB - A naturally occurring guaianolide sesquiterpene lactone (1), along with 10 known compounds (2-11), was isolated from the chloroform extract of the dried rhizomes of Curcuma leucorrhiza Roxb. Their structures were elucidated on the basis of spectroscopic studies and X-ray crystallographic analysis. Compound 1 expressed antioxidant activity. The taxonomic status of C. leucorrhiza is briefly discussed based on the chemotaxonomic significance of these findings. PMID- 24484238 TI - Vaccination of sows against type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV) before artificial insemination protects against type 2 PRRSV challenge but does not protect against type 1 PRRSV challenge in late gestation. AB - The objective of the present study was to determine the effects of the commercially available type 2 Porcine Reproductive and Respiratory Syndrome Virus (PRRSV)-based modified live vaccine against type 1 and type 2 PRRSV challenge in pregnant sows. Half of the sows in the study were vaccinated with a type 2 PRRSV based vaccine 4 weeks prior to artificial insemination while the other half remained non-vaccinated. Sows were then challenged intranasally with type 1 or type 2 PRRSV at 93 days of gestation. The sows which received the type 2 PRRSV based vaccine followed by type 2 PRRSV challenge had significantly higher neutralizing antibody titers against type 2 PRRSV than they did against type 1 PRRSV. These same sows had higher frequencies of IFN-gamma-secreting cells when stimulated with type 2 PRRSV compared to those stimulated with type 1 PRRSV. Subsequent virological evaluation demonstrated that the type 2 PRRSV-based vaccine reduced the type 2 PRRSV load but not the type 1 PRRSV load present in the blood of the sows. Additionally, vaccination of pregnant sows with the type 2 PRRSV-based vaccine effectively reduced the level of type 2 PRRSV nucleic acids observed in fetal tissues from type 2 PRRSV-challenged sows but did not reduce the level of type 1 PRRSV nucleic acid observed in fetal tissues from type 1 PRRSV-challenged sows. This study demonstrates that the vaccination of pregnant sows with the type 2 PRRSV-based vaccine protects against type 2 PRRSV challenge but does not protect against type 1 PRRSV challenge. PMID- 24484239 TI - Smoking cessation advice recorded during pregnancy in United Kingdom primary care. AB - BACKGROUND: United Kingdom (UK) national guidelines recommend that all pregnant women who smoke should be advised to quit at every available opportunity, and brief cessation advice is an efficient and cost-effective means to increase quit rates. The Quality and Outcomes Framework (QOF) implemented in 2004 requires general practitioners to document their delivery of smoking cessation advice in patient records. However, no specific targets have been set in QOF for the recording of this advice in pregnant women. We used a large electronic primary care database from the UK to quantify the pregnancies in which women who smoked were recorded to have been given smoking cessation advice, and the associated maternal characteristics. METHODS: Using The Health Improvement Network database we calculated annual proportions of pregnant smokers between 2000 and 2009 with cessation advice documented in their medical records during pregnancy. Logistic regression was used to assess variation in the recording of cessation advice with maternal characteristics. RESULTS: Among 45,296 pregnancies in women who smoked, recorded cessation advice increased from 7% in 2000 to 37% in 2004 when the QOF was introduced and reduced slightly to 30% in 2009. Pregnant smokers from the youngest age group (15-19) were 21% more likely to have a record of cessation advice compared to pregnant smokers aged 25-29 (OR 1.21, 95% CI 1.10-1.35) and pregnant smokers from the most deprived group were 38% more likely to have a record for cessation advice compared to pregnant smokers from the least deprived group (OR 1.38, 95% CI 1.14-1.68). Pregnant smokers with asthma were twice as likely to have documentation of cessation advice in their primary care records compared to pregnant smokers without asthma (OR 1.97, 95% CI 1.80-2.16). Presence of comorbidities such as diabetes, hypertension and mental illness also increased the likelihood of having smoking cessation advice recorded. No marked variations were observed in the recording of cessation advice with body mass index. CONCLUSION: Recorded delivery of smoking cessation advice for pregnant smokers in primary care has increased with some fluctuation over the years, especially after the implementation of the QOF, and varies with maternal characteristics. PMID- 24484240 TI - Activation and inhibition of thermosensitive TRP channels by voacangine, an alkaloid present in Voacanga africana, an African tree. AB - Voacangine (1) is an alkaloid found in the root bark of Voacanga africana. Our previous work has suggested that 1 is a novel transient receptor potential vanilloid type 1 (TRPV1) antagonist. In this study, the agonist and antagonist activities of 1 were examined against thermosensitive TRP channels. Channel activity was evaluated mainly using TRP channel-expressing HEK cells and calcium imaging. Herein, it was shown that 1 acts as an antagonist for TRPV1 and TRPM8 but as an agonist for TRPA1 (EC50, 8 MUM). The compound competitively blocked capsaicin binding to TRPV1 (IC50, 50 MUM). Voacangine (1) competitively inhibited the binding of menthol to TRPM8 (IC50, 9 MUM), but it showed noncompetitive inhibition against icilin (IC50, 7 MUM). Moreover, the compound selectively abrogated chemical agonist-induced TRPM8 activation and did not affect cold induced activation. Among these effects, the TRPM8 inhibition profile is unique and noteworthy, because to date no studies have reported a menthol competitive inhibitor of TRPM8 derived from a natural source. Furthermore, this is the first report of a stimulus-selective TRPM8 antagonist. Accordingly, 1 may contribute to the development of a novel class of stimulus-selective TRPM8 blockers. PMID- 24484242 TI - Methicillin-sensitive Staphylococcus aureus infection causing maternal bacteraemia and fetal death at term gestation: role of bacterial typing and toxin gene profiling. PMID- 24484241 TI - Treatment of submassive pulmonary embolism with tenecteplase or placebo: cardiopulmonary outcomes at 3 months: multicenter double-blind, placebo controlled randomized trial. AB - BACKGROUND: Acute pulmonary embolism (PE) can worsen quality of life due to persistent dyspnea or exercise intolerance. OBJECTIVE: Test if tenecteplase increases the probability of a favorable composite patient-oriented outcome after submassive PE. METHODS: Normotensive patients with PE and right ventricular (RV) strain (by echocardiography or biomarkers) were enrolled from eight hospitals. All patients received low-molecular-weight heparin followed by random assignment to either a single weight-based bolus of tenecteplase or placebo, administered in a double-blinded fashion. The primary composite outcome included: (i) death, circulatory shock, intubation or major bleeding within 5 days or (ii) recurrent PE, poor functional capacity (RV dysfunction with either dyspnea at rest or exercise intolerance) or an SF36((r)) Physical Component Summary (PCS) score < 30 at 90-day follow-up. RESULTS: Eighty-three patients were randomized; 40 to tenecteplase and 43 to placebo. The trial was terminated prematurely. Within 5 days, adverse outcomes occurred in three placebo-treated patients (death in one and intubation in two) and one tenecteplase-treated patient (fatal intracranial hemorrhage). At 90 days, adverse outcomes occurred in 13 unique placebo-treated patients and five unique tenecteplase-treated patients Thus, 16 (37%) placebo treated and six (15%) tenecteplase-treated patients had at least one adverse outcome (exact two-sided P = 0.017). CONCLUSIONS: Treatment of patients with submassive pulmonary embolism with tenecteplase was associated with increased probability of a favorable composite outcome. PMID- 24484243 TI - Probing electronic communication for efficient light-harvesting functionality: dyads containing a common perylene and a porphyrin, chlorin, or bacteriochlorin. AB - The synthesis, photophysical, redox, and molecular-orbital characteristics of three perylene-tetrapyrrole dyads were investigated to probe the efficacy of the arrays for use as light-harvesting constituents. Each dyad contains a common perylene-monoimide that is linked at the N-imide position via an arylethynyl group to the meso-position of the tetrapyrrole. The tetrapyrroles include a porphyrin, chlorin, and bacteriochlorin, which have zero, one, and two reduced pyrrole rings, respectively. The increased pyrrole-ring reduction results in a progressive red shift and intensification of the lowest-energy absorption band, as exemplified by benchmark monomers. The arylethyne linkage affords moderate perylene-tetrapyrrole electronic coupling in the dyads as evidenced by the optical, molecular-orbital, and redox properties of the components of the dyads versus the constituent parts. All three dyads in nonpolar solvents exhibit relatively fast (subpicosecond) energy transfer from the perylene to the tetrapyrrole. Competing charge-transfer processes are also absent in nonpolar solvents, but become active for both the chlorin and bacteriochlorin-containing dyads in polar solvents. Calculations of energy-transfer rates via the Forster, through-space mechanism reveal that these rates are, on average, 3-fold slower than the observed rates. Thus, the Dexter through-bond mechanism contributes more substantially than the through-space mechanism to energy transfer in the dyads. The electronic communication between the perylene and tetrapyrrole falls in a regime intermediate between those operative in other classes of perylene tetrapyrrole dyads that have previously been studied. PMID- 24484244 TI - Photo morphogenesis and photo response of the blue-light receptor gene Cmwc-1 in different strains of Cordyceps militaris. AB - Light is a necessary environmental factor for stroma formation and development of Cordyceps militaris, a well-known edible and medicinal fungus. In this study, photo morphogenesis and the blue-light receptor gene were studied using five representative strains of C. militaris. The results suggest that light was essential for colony pigmentation and could promote conidia production. Cmwc-1, the homologe of the blue-light photoreceptor of Neurospora crassa, was cloned from the genome of C. militaris by Hi-tail PCR. The protein CmWC-1 was characterized by the presence of the LOV and PAS domains and a GATA-type Znf domain. Genetic variation analysis of Cmwc-1 in different strains showed that 15 bp deletions occurred in three strains that resulted in 5-Gln deletions in the transcription activation domain. Phylogenetic analysis based on the Sordariomycetes WC-1-like proteins suggested that the sequence of WC-1 could be used as a candidate marker for phylogenetic analysis in fungi. Cmwc-1 mRNA was light inducible and the expression level increased significantly after irradiation in all tested strains. The sequence of CmWC-1 and the relative expressions responding to irradiation in degenerate and albino strains were similar as the cultivated one. This report will help to open the still-unexplored field of stroma development for this fungus. PMID- 24484246 TI - Cervical pregnancy with placenta percreta diagnosed after pregnancy termination at 10 weeks. PMID- 24484247 TI - Near-infrared imaging of brain tumors using the Tumor Paint BLZ-100 to achieve near-complete resection of brain tumors. AB - OBJECT: The intraoperative clear delineation between brain tumor and normal tissue in real time is required to ensure near-complete resection without damaging the nearby eloquent brain. Tumor Paint BLZ-100, a tumor ligand chlorotoxin (CTX) conjugated to indocyanine green (ICG), has shown potential to be a targeted contrast agent. There are many infrared imaging systems in use, but they are not optimized to the low concentration and amount of ICG. The authors present a novel proof-of-concept near-infrared (NIR) imaging system using a standard charge-coupled device (CCD) camera for visualizing low levels of ICG attached to the tumors. This system is small, inexpensive, and sensitive. The imaging system uses a narrow-band laser at 785 nm and a notch filter in front of the sensor at the band. The camera is a 2-CCD camera, which uses identical CCDs for both visible and NIR light. METHODS: The NIR system is tested with serial dilution of BLZ-100 from 1 MUM to 50 pM in 5% Intralipid solution while the excitation energy is varied from 5 to 40 mW/cm(2). The analog gain of the CCD was changed from 0, 6, and 12 dB to determine the signal-to-noise ratio. In addition to the Intralipid solution, BLZ-100 was injected 48 hours before euthanizing the mice that were implanted with the human glioma cell line. The brain was removed and imaged using the NIR imaging system. RESULTS: The authors' results show that the NIR imaging system using a standard CCD is able to visualize the ICG down to 50 nM of concentration with a high signal-to-noise ratio. The preliminary experiment on human glioma implanted in mouse brains demonstrated that BLZ-100 has a high affinity for glioma compared with normal brain tissue. Additionally, the results show that NIR excitation is able to penetrate deeply and has a potential to visualize metastatic lesions that are separate from the main tumor. CONCLUSIONS: The authors have seen that BLZ-100 has a very high affinity toward human gliomas. They also describe a small, cost-effective, and sensitive NIR system for visualizing brain tumors tagged using BLZ-100. The authors hope that the use of BLZ-100 along with NIR imaging will be useful to delineate the brain tumors in real time and assist surgeons in near-complete tumor removal to increase survival and reduce neurological deficits. PMID- 24484248 TI - Use of fluorescence to guide resection or biopsy of primary brain tumors and brain metastases. AB - OBJECT: The accurate discrimination between tumor and normal tissue is crucial for determining how much to resect and therefore for the clinical outcome of patients with brain tumors. In recent years, guidance with 5-aminolevulinic acid (5-ALA)-induced intraoperative fluorescence has proven to be a useful surgical adjunct for gross-total resection of high-grade gliomas. The clinical utility of 5-ALA in resection of brain tumors other than glioblastomas has not yet been established. The authors assessed the frequency of positive 5-ALA fluorescence in a cohort of patients with primary brain tumors and metastases. METHODS: The authors conducted a single-center retrospective analysis of 531 patients with intracranial tumors treated by 5-ALA-guided resection or biopsy. They analyzed patient characteristics, preoperative and postoperative liver function test results, intraoperative tumor fluorescence, and histological data. They also screened discharge summaries for clinical adverse effects resulting from the administration of 5-ALA. Intraoperative qualitative 5-ALA fluorescence (none, mild, moderate, and strong) was documented by the surgeon and dichotomized into negative and positive fluorescence. RESULTS: A total of 458 cases qualified for final analysis. The highest percentage of 5-ALA-positive fluorescence in open resection was found in glioblastomas (96%, n = 99/103). Among other tumors, 5-ALA positive fluorescence was detected in 88% (n = 21/32) of anaplastic gliomas (WHO Grade III), 40% (n = 8/19) of low-grade gliomas (WHO Grade II), no (n = 0/3) WHO Grade I gliomas, and 77% (n = 85/110) of meningiomas. Among metastases, the highest percentage of 5-ALA-positive fluorescence was detected in adenocarcinomas (48%, n = 13/27). Low rates or absence of positive fluorescence was found among pituitary adenomas (8%, n = 1/12) and schwannomas (0%, n = 0/7). Biopsies of high grade primary brain tumors showed positive rates of fluorescence similar to those recorded for open resection. No clinical adverse effects associated with use of 5 ALA were observed. Only 1 patient had clinically silent transient elevation of liver enzymes. CONCLUSIONS: Study findings suggest that the administration of 5 ALA as a surgical adjunct for resection and biopsy of primary brain tumors and brain metastases is safe. In light of the high rate of positive fluorescence in high-grade gliomas other than glioblastomas, meningiomas, and a variety of metastatic cancers, 5-ALA seems to be a promising tool for enhancing intraoperative identification of neoplastic tissue and optimizing the extent of resection. PMID- 24484249 TI - Analysis of 5-aminolevulinic acid-induced fluorescence in 55 different spinal tumors. AB - OBJECT: Subtotal resection (STR) of spinal tumors can result in tumor recurrence. Currently, no clinically reliable marker is available for intraoperative visualization of spinal tumor tissue. Protoporphyrin IX (PpIX) fluorescence induced by 5-aminolevulinic acid (5-ALA) is capable of visualizing malignant gliomas. Fluorescence-guided resections of malignant cerebral gliomas using 5-ALA have resulted in an increased rate of complete tumor removal. Recently, the application of 5-ALA has also been described in the first cases of spinal tumors. Therefore, the aim of this observational study was to systematically investigate 5-ALA-induced fluorescence characteristics in different spinal tumor entities. METHODS: Three hours before the induction of anesthesia, 5-ALA was administered to patients with different intra- and extradural spinal tumors. In all patients a neurosurgical resection or biopsy of the spinal tumor was performed under conventional white-light microscopy. During each surgery, the presence of PpIX fluorescence was additionally assessed using a modified neurosurgical microscope. At the end of an assumed gross-total resection (GTR) under white-light microscopy, a final inspection of the surgical cavity of fluorescing intramedullary tumors was performed to look for any remaining fluorescing foci. Histopathological tumor diagnosis was established according to the current WHO classification. RESULTS: Fifty-two patients with 55 spinal tumors were included in this study. Resection was performed in 50 of 55 cases, whereas 5 of 55 cases underwent biopsy. Gross-total resection was achieved in 37 cases, STR in 5, and partial resection in 8 cases. Protoporphyrin IX fluorescence was visible in 30 (55%) of 55 cases, but not in 25 (45%) of 55 cases. Positive PpIX fluorescence was mainly detected in ependymomas (12 of 12), meningiomas (12 of 12), hemangiopericytomas (3 of 3), and in drop metastases of primary CNS tumors (2 of 2). In contrast, none of the neurinomas (8 of 8), carcinoma metastases (5 of 5), and primary spinal gliomas (3 of 3; 1 pilocytic astrocytoma, 1 WHO Grade II astrocytoma, 1 WHO Grade III anaplastic oligoastrocytoma) revealed PpIX fluorescence. It is notable that residual fluorescing tumor foci were detected and subsequently resected in 4 of 8 intramedullary ependymomas despite assumed GTR under white-light microscopy. CONCLUSIONS: In this study, 5-ALA-PpIX fluorescence was observed in spinal tumors, especially ependymomas, meningiomas, hemangiopericytomas, and drop metastases of primary CNS tumors. In cases of intramedullary tumors, 5-ALA-induced PpIX fluorescence is a useful tool for the detection of potential residual tumor foci. PMID- 24484250 TI - In vivo visualization of GL261-luc2 mouse glioma cells by use of Alexa Fluor labeled TRP-2 antibodies. AB - OBJECT: For patients with glioblastoma multiforme, median survival time is approximately 14 months. Longer progression-free and overall survival times correlate with gross-total resection of tumor. The ability to identify tumor cells intraoperatively could result in an increased percentage of tumor resected and thus increased patient survival times. Available labeling methods rely on metabolic activity of tumor cells; thus, they are more robust in high-grade tumors, and their utility in low-grade tumors and metastatic tumors is not clear. The authors demonstrate intraoperative identification of tumor cells by using labeled tumor-specific antibodies. METHODS: GL261 mouse glioma cells exhibit high expression of a membrane-bound protein called second tyrosinase-related protein (TRP-2). The authors used these cells to establish an intracranial, immunocompetent model of malignant glioma. Antibodies to TRP-2 were labeled by using Alexa Fluor 488 fluorescent dye and injected into the tail vein of albino C57BL/6 mice. After 24 hours, a craniotomy was performed and the tissue was examined in vivo by using an Optiscan 5.1 handheld portable confocal fiber-optic microscope. Tissue was examined ex vivo by using a Pascal 5 scanning confocal microscope. RESULTS: Labeled tumor cells were visible in vivo and ex vivo under the respective microscopes. CONCLUSIONS: Fluorescently labeled tumor-specific antibodies are capable of binding and identifying tumor cells in vivo, accurately and specifically. The development of labeled markers for the identification of brain tumors will facilitate the use of intraoperative fluorescence microscopy as a tool for increasing the extent of resection of a broad variety of intracranial tumors. PMID- 24484251 TI - Application of indocyanine green video angiography in parasagittal meningioma surgery. AB - OBJECT: There are no doubts about the role that indocyanine green video angiography (ICGVA) can play in current vascular neurosurgery. Conversely, in brain tumor surgery, and particularly in meningioma surgery, this role is still unclear. Vein management is pivotal for approaching parasagittal meningiomas, because venous preservation is strictly connected to both extent of resection and clinical outcome. The authors present the technical traits and the postoperative outcome of the application of ICGVA in patients undergoing parasagittal meningioma surgery. METHODS: The authors retrospectively collected demographic, radiological, intraoperative, and follow-up data in 43 patients with parasagittal meningiomas who underwent surgery with the assistance of ICGVA at Padua Neurosurgical Department between October 2010 and July 2013. Intraoperative ICGVA findings at different stages (before dural opening, after dural opening, during resection, after resection) were reviewed. Additional data on functional monitoring, temporary venous clipping, and flow measurements were also recorded. The overall postoperative outcome was evaluated by assessing both the extent of resection and the clinical outcome data. RESULTS: The ICGVA studies were performed 125 times in 43 patients, providing helpful data for vein management and tumor resection in all stages of surgery. In 16% of meningiomas completely occluding the superior sagittal sinus, the ICGVA data differed from radiological findings and changed the surgical approach. In 20% of cases the intraoperative ICGVA findings directly guided the surgical strategy: venous sacrifice was necessary in 7 cases, without postoperative consequences; temporary clipping with neurophysiological monitoring proved to be predictive of safe venous sacrifice. In 7% of cases the ICGVA data needed to be supplemented with flow measurements. Simpson Grade I-II and Grade III resections were achieved in 86% and 14% of cases, respectively, with a 4.6% rate of overall morbidity. CONCLUSIONS: This study shows that ICGVA can assist the different stages of parasagittal meningiomas surgery, guiding the vein management and tumor resection strategies with a favorable final clinical outcome. However, in the authors' experience the use of other complementary tools was mandatory in selected cases to preserve functional areas. Further studies are needed to confirm that the application of ICGVA in parasagittal meningioma surgery may improve the morbidity rate, as reported in this study. PMID- 24484252 TI - Flow-based evaluation of cerebral revascularization using near-infrared indocyanine green videoangiography. AB - OBJECT: Indocyanine green (ICG) videoangiography has been established as a noninvasive technique to gauge the patency of a bypass graft; however, intraoperative graft patency may not always correlate with graft flow. Altered flow through the bypass graft may directly cause delayed graft occlusion. Here, the authors report on 3 types of flow that were observed through cerebral revascularization procedures. METHODS: Between February 2009 and September 2013, 48 bypass procedures were performed. Excluded from analysis were those cases in which ICG videoangiography was not performed during surgery (whether it was not available or there was a technical issue with the microscope or the quality of ICG angiography) and/or in which angiography or CT angiography was not done within 24-72 hours after surgery. After anastomosis, bypass patency was assessed first using a noninvasive technique and then with ICG videoangiography, and flow through the graft was characterized. Patients who received a vein or radial artery graft were also evaluated with intraoperative angiography. RESULTS: Thirty three patients eligible for analysis were retrospectively analyzed. The patients had undergone extracranial-intracranial (EC-IC) or IC-IC bypass for ischemic stroke (13 patients), moyamoya disease (10 patients), and complex aneurysms (10 patients; 6 giant or large aneurysms, 2 carotid blister-like aneurysms, and 2 dissecting posterior inferior cerebellar artery [PICA] aneurysms). Thirty-six bypasses were performed including 26 superficial temporal artery (STA)-middle cerebral artery (MCA) bypasses (2 bilateral and 1 double-barrel), 6 EC-IC vein grafts, 1 EC-IC radial artery graft, 1 PICA-PICA bypass, 1 MCA-posterior cerebral artery bypass, and 1 occipital artery-PICA bypass. Robust anterograde flow (Type I) was noted in 31 grafts (86%). Delayed but patent graft enhancement and anterograde flow (Type II) was observed in 4 cases (11%); 1 of these cases with an EC-IC vein graft degraded gradually to very delayed flow with no continuity to the bypass site (Type III). Additionally, 1 STA-MCA bypass graft revealed no convincing flow (Type III). The 5 patients with Type II or III grafts were evaluated with a flow probe and reexploration of the bypass site, and in all cases the reason the graft became occluded was believed to be recipient-vessel competitive flow. In no case was there evidence of stenosis or a technical issue at the site of the anastomosis. Three patients with Type II and the 1 patient with Type III flow (11% of procedures) did not have a patent bypass on postoperative imaging. CONCLUSIONS: Indocyanine green videoangiography is reliable for evaluating flow through the EC-IC or IC-IC bypass. The type of flow observed through the graft has a direct relationship with postoperative imaging findings. Despite the possibility of competitive flow, Type III and some Type II flows through the graft indicate the need for graft evaluation and anastomosis exploration. PMID- 24484253 TI - A prospective study of microscope-integrated intraoperative fluorescein videoangiography during arteriovenous malformation surgery: preliminary results. AB - OBJECT: The authors report on the use of a recently developed microscope integrated fluorescent module using low-dose intravenous fluorescein for videoangiography during arteriovenous malformation (AVM) surgery. METHODS: The authors analyzed the application of a low-dose intraoperative fluorescein in 4 consecutive patients undergoing AVM surgery. The ability to distinguish the associated vessels of the AVM from normal vessels and to assess the degree of AVM obliteration based on videoangiography of venous drainage was specifically analyzed. RESULTS: All 4 patients underwent fluorescein angiography without complication. In each case, videoangiography confirmed recognition of feeding arteries and draining veins through the operating oculars under the fluorescent mode. In one case involving a large frontal AVM, videoangiography demonstrated mainly cortical veins on the surface of the AVM and alerted the senior author to first tackle the feeding arteries in the interhemispheric space. While evaluating the flow within the different draining veins after most of the AVM was disconnected, videoangiography also prioritized the order for disconnection of large draining veins to allow mobilization the AVM and exposure of the remaining deep arterial feeders. In the other 3 cases, videoangiography allowed easy recognition of the angioarchitecture of the AVMs, estimated its cortical boundaries, and most importantly, assessed the flow within the draining veins before their disconnection. CONCLUSIONS: The authors found fluorescein videoangiography to be a useful adjunct in resection of AVMs. This technology offers the unique ability to visualize fluorescent vessels and nonfluorescent tissues in near-natural colors simultaneously and permits microsurgical manipulation of relevant structures under the fluorescent mode. Larger-scale studies are needed to establish its efficacy and wider applicability. PMID- 24484254 TI - Potential application of a handheld confocal endomicroscope imaging system using a variety of fluorophores in experimental gliomas and normal brain. AB - OBJECT: The authors sought to assess the feasibility of a handheld visible wavelength confocal endomicroscope imaging system (Optiscan 5.1, Optiscan Pty., Ltd.) using a variety of rapid-acting fluorophores to provide histological information on gliomas, tumor margins, and normal brain in animal models. METHODS: Mice (n = 25) implanted with GL261 cells were used to image fluorescein sodium (FNa), 5-aminolevulinic acid (5-ALA), acridine orange (AO), acriflavine (AF), and cresyl violet (CV). A U251 glioma xenograft model in rats (n = 5) was used to image sulforhodamine 101 (SR101). A swine (n = 3) model with AO was used to identify confocal features of normal brain. Images of normal brain, obvious tumor, and peritumoral zones were collected using the handheld confocal endomicroscope. Histological samples were acquired through biopsies from matched imaging areas. Samples were visualized with a benchtop confocal microscope. Histopathological features in corresponding confocal images and photomicrographs of H & E-stained tissues were reviewed. RESULTS: Fluorescence induced by FNa, 5 ALA, AO, AF, CV, and SR101 and detected with the confocal endomicroscope allowed interpretation of histological features. Confocal endomicroscopy revealed satellite tumor cells within peritumoral tissue, a definitive tumor border, and striking fluorescent cellular and subcellular structures. Fluorescence in various tumor regions correlated with standard histology and known tissue architecture. Characteristic features of different areas of normal brain were identified as well. CONCLUSIONS: Confocal endomicroscopy provided rapid histological information precisely related to the site of microscopic imaging with imaging characteristics of cells related to the unique labeling features of the fluorophores. Although experimental with further clinical trial validation required, these data suggest that intraoperative confocal imaging can help to distinguish normal brain from tumor and tumor margin and may have application in improving intraoperative decisions during resection of brain tumors. PMID- 24484255 TI - Applications of fluorescent technology in neurosurgery. PMID- 24484256 TI - Tumor detection with 5-aminolevulinic acid fluorescence and Gd-DTPA-enhanced intraoperative MRI at the border of contrast-enhancing lesions: a prospective study based on histopathological assessment. AB - OBJECT: High-grade gliomas (HGGs) and metastasis (MET) are the most common intracranial lesions in neurosurgical routine. Both of them show an invasive growth pattern extending into neural tissue beyond the margins of contrast enhancement on MRI. These "undetected" areas might be the origin of early tumor recurrence. The aim of the present study was to evaluate whether 5-aminolevulinic acid (5-ALA) fluorescence provides an additional benefit in detection of invasive tumor compared with intraoperative MRI (iMRI). METHODS: The authors prospectively enrolled 45 patients harboring contrast-enhancing lesions, in whom gross-total resection was intended. All patients had surgery in which iMRI and 5-ALA-guided resection were used following a specific protocol. First, a typical white light tumor resection was performed. Then, spatial location of residual fluorescence was marked. After that, an iMRI was performed and residual uptake of contrast was marked. Navigated biopsy samples were taken from all marked areas and from additional sites according to the surgeon's judgment. Cross tables and receiver operating characteristic curves were calculated, assessing performance of the imaging methods for tumor detection alone and for combined detection of infiltration zone and solid tumor (pathological tissue). Also, correlations of histopathological findings with imaging results were tested using Spearman rho. RESULTS: Thirty-four patients with HGGs and 11 with METs were enrolled. Three patients harboring a MET showed no 5-ALA enhancement and were excluded; 127 histopathological samples were harvested in the remaining patients. In HGG, sensitivity for tumor detection was significantly higher (p < 0.001) in 5-ALA (0.85) than in iMRI (0.41). Specificity was significantly lower (p < 0.001) in 5 ALA (0.43) than in iMRI (0.70). For detection of pathological tissue, 5-ALA significantly exceeded iMRI in specificity (0.80 vs 0.60) and sensitivity (0.91 vs 0.66) (p < 0.001). Imaging results of iMRI and 5-ALA did not correlate significantly; only 5-ALA showed a significant correlation with final histopathological diagnosis of the specimen and with typical histopathological features of HGGs. In METs, sensitivity and specificity for tumor detection were equal in 5-ALA and iMRI. Both techniques showed high values for sensitivity (0.75) and specificity (0.80). The odds ratio for detection of tumor tissue was 12 for both techniques. Concerning pathological tissue, no statistically significant difference was found either. Imaging results of iMRI and 5-ALA correlated significantly (p < 0.022), as with final histopathological diagnosis in METs. CONCLUSIONS: In METs, due to the rate of nonenhancing lesions, the authors found no additional benefit of 5-ALA compared with iMRI. In HGG, imaging results of 5-ALA and iMRI are significantly different at the border zone; 5-ALA has a higher sensitivity and a lower specificity for tumor detection than Gd-DTPA enhanced iMRI. For detection of infiltrating tumor at the border of the resection cavity, 5-ALA is superior to Gd-DTPA-enhanced iMRI concerning both sensitivity and specificity. Thus, use of 5-ALA in addition to iMRI might be beneficial to maximize extent of resection. Clinical synergistic effects will be evaluated in a prospective randomized trial. PMID- 24484257 TI - Use of 5-aminolevulinic acid helps see the way beyond MRI. PMID- 24484258 TI - Is fluorescein-guided technique able to help in resection of high-grade gliomas? AB - OBJECT: Fluorescein, a dye that is widely used as a fluorescent tracer, accumulates in cerebral areas where the blood-brain barrier is damaged. This quality makes it an ideal dye for the intraoperative visualization of high-grade gliomas (HGGs). The authors report their experience with a new fluorescein-guided technique for the resection of HGGs using a dedicated filter on the surgical microscope. METHODS: The authors initiated a prospective Phase II trial (FLUOGLIO) in September 2011 with the objective of evaluating the safety of fluorescein-guided surgery for HGGs and obtaining preliminary evidence regarding its efficacy for this purpose. To be eligible for participation in the study, a patient had to have suspected HGG amenable to complete resection of the contrast enhancing area. The present report is based on the analysis of the short- and long-term results in 20 consecutive patients with HGGs (age range 45-74 years), enrolled in the study since September 2011. In all cases fluorescein (5-10 mg/kg) was injected intravenously after intubation. Tumor resection was performed with microsurgical technique and fluorescence visualization by means of BLUE 400 or YELLOW 560 filters on a Pentero microscope. RESULTS: The median preoperative tumor volume was 30.3 cm(3) (range 2.4-87.8 cm(3)). There were no adverse reactions related to fluorescein administration. Complete removal of contrast enhanced tumor was achieved in 80% of the patients. The median duration of follow up was 10 months. The 6-months progression-free survival rate was 71.4% and the median survival was 11 months. CONCLUSIONS: Analysis of these 20 cases suggested that fluorescein-guided technique with a dedicated filter on the surgical microscope is safe and allows a high rate of complete resection of contrast enhanced tumor as determined on early postoperative MRI. Clinical trial registration no.: 2011-002527-18 (EudraCT). PMID- 24484259 TI - The fluorescein-guided technique. PMID- 24484260 TI - Essentials in intraoperative indocyanine green videoangiography assessment for intracranial aneurysm surgery: conclusions from 295 consecutively clipped aneurysms and review of the literature. AB - OBJECT: Indocyanine green (ICG) videoangiography (VA) in cerebral aneurysm surgery allows confirmation of blood flow in parent, branching, and perforating vessels as well as assessment of remnant aneurysm parts after clip application. A retrospective analysis and review of the literature were conducted to determine the current essential advantages of ICG-VA in aneurysm surgery. METHODS: The authors retrospectively evaluated all aneurysm cases treated with the aid of intraoperative ICG-VA at a single institution between 2007 and 2013. They also analyzed the literature published since the initial description of ICG-VA in 2003. RESULTS: Two hundred forty-six procedures were performed in 232 patients harboring 295 aneurysms. The patients, whose mean age was 54 years, consisted of 159 women and 73 men. One hundred twenty-four surgeries were performed after subarachnoid hemorrhage, and 122 were performed for incidental aneurysms. Single aneurysms were clipped in 185 patients, and multiple aneurysms were clipped in 47 (mean aneurysm diameter 6.9 mm, range 2-40 mm). No complications associated with ICG-VA occurred. Intraoperative microvascular Doppler ultrasonography was performed before ICG-VA in all patients, and postoperative digital subtraction angiography (DSA) studies were available in 121 patients (52.2%) for retrospective comparative analysis. In 22 (9%) of 246 procedures, the clip position was modified intraoperatively as a consequence of ICG-VA. Stenosis of the parent vessels (16 procedures) or occlusion of the perforators (6 procedures), not detected by micro-Doppler ultrasonography, were the most common problems demonstrated on ICG-VA. In another 11 procedures (4.5%), residual perfusion of the aneurysm was observed and one or more additional clips were applied. Vessel stenosis or a compromised perforating artery occurred independent of aneurysm location and was about equally common in middle cerebral artery and anterior communicating artery aneurysms. In 2 procedures (0.8%), aneurysm puncture revealed residual blood flow within the lesion, which had not been detected by the ICG-VA. In the postoperative DSA studies, unexpected small (< 2 mm) aneurysm neck remnants, which had not been detected on intraoperative ICG-VA, were found in 11 (9.1%) of 121 patients. However, these remnants remained without consequence except in 1 patient with a 6-mm residual aneurysm dome, which was subsequently embolized with coils. CONCLUSIONS: In a large cohort of consecutive patients, ICG-VA proved to be a helpful intraoperative tool and led to a significant intraoperative clip modification rate of 15%. However, small, < 2-mm wide neck remnants and a 6-mm residual aneurysm were missed by intraoperative ICG VA in up to 10% of patients. Results in this study confirm that DSA is indispensable for postoperative quality assessment in complex aneurysm surgery. PMID- 24484261 TI - Label-free microscopic assessment of glioblastoma biopsy specimens prior to biobanking [corrected]. AB - Glioblastoma is the most common primary brain tumor with a median 12- to 15-month patient survival. Improving patient survival involves better understanding the biological mechanisms of glioblastoma tumorigenesis and seeking targeted molecular therapies. Central to furthering these advances is the collection and storage of surgical biopsies (biobanking) for research. This paper addresses an imaging modality, confocal reflectance microscopy (CRM), for safely screening glioblastoma biopsy samples prior to biobanking to increase the quality of tissue provided for research and clinical trials. These data indicate that CRM can immediately identify cellularity of tissue biopsies from animal models of glioblastoma. When screening fresh human biopsy samples, CRM can differentiate a cellular glioblastoma biopsy from a necrotic biopsy without altering DNA, RNA, or protein expression of sampled tissue. These data illustrate CRM's potential for rapidly and safely screening clinical biopsy samples prior to biobanking, which demonstrates its potential as an effective screening technique that can improve the quality of tissue biobanked for patients with glioblastoma. PMID- 24484262 TI - Laser scanning confocal endomicroscopy in the neurosurgical operating room: a review and discussion of future applications. AB - Laser scanning confocal endomicroscopy (LSCE) is an emerging technology for examining brain neoplasms in vivo. While great advances have been made in macroscopic fluorescence in recent years, the ability to perform confocal microscopy in vivo expands the potential of fluorescent tumor labeling, can improve intraoperative tissue diagnosis, and provides real-time guidance for tumor resection intraoperatively. In this review, the authors highlight the technical aspects of confocal endomicroscopy and fluorophores relevant to the neurosurgeon, provide a comprehensive summary of LSCE in animal and human neurosurgical studies to date, and discuss the future directions and potential for LSCE in neurosurgery. PMID- 24484263 TI - Evolving applications of fluorescence technology in neurosurgery. PMID- 24484264 TI - Probing the unfolding of myoglobin and domain C of PARP-1 with covalent labeling and top-down ultraviolet photodissociation mass spectrometry. AB - Ultraviolet photodissocation (UVPD) mass spectrometry was used for high mass accuracy top-down characterization of two proteins labeled by the chemical probe, S-ethylacetimidate (SETA), in order to evaluate conformational changes as a function of denaturation. The SETA labeling/UVPD-MS methodology was used to monitor the mild denaturation of horse heart myoglobin by acetonitrile, and the results showed good agreement with known acetonitrile and acid unfolding pathways of myoglobin. UVPD outperformed electron transfer dissociation (ETD) in terms of sequence coverage, allowing the SETA reactivity of greater number of lysine amines to be monitored and thus providing a more detailed map of myoglobin. This strategy was applied to the third zinc-finger binding domain, domain C, of PARP-1 (PARP-C), to evaluate the discrepancies between the NMR and crystal structures which reported monomer and dimer forms of the protein, respectively. The trends reflected from the reactivity of each lysine as a function of acetonitrile denaturation in the present study support that PARP-C exists as a monomer in solution with a close-packed C-terminal alpha helix. Additionally, those lysines for which the SETA reactivity increased under denaturing conditions were found to engage in tertiary polar contacts such as salt bridging and hydrogen bonding, providing evidence that the SETA/UVPD-MS approach offers a versatile means to probe the interactions responsible for conformational changes in proteins. PMID- 24484265 TI - The influences of obesity and age on functional performance during intermittent upper extremity tasks. AB - In this study, the main and interactive effects of obesity and age on functional performance were assessed during intermittent exertions involving the upper extremity. The prevalence of obesity has doubled over the past 30 years and this increase is associated with higher health care costs, rates of workplace injury, and lost workdays. Obesity and aging can modify job demands and affect worker capacity in terms of muscular and psychomotor function. However, there is a lack of empirical studies quantifying the work-relevant (or ergonomic) impacts related to task demands, capacities, and their potential imbalance. Eight obese and eight non-obese participants from each of two age groups (18-25 and 50-65 years) completed three endurance tasks involving fixed levels of task demands: hand grip, shoulder flexion, and a simulated assembly task using the upper extremity. Measures of functional performance including endurance, discomfort, motor control, and task performance were recorded for each of the task conditions. Endurance times were ~60% longer for the non-obese group, and older participants had longer endurance times; however there was no evidence of interactive effects of obesity and age. Obesity also impaired functional performance, as indicated by higher rates of strength loss, increases in discomfort, and declines in task performance. These observed impairments may reflect underlying physiological differences among individuals who are obese, but that are independent of age. Obesity-related impairments may have implications for the design of work duration and demand level to prevent fatigue development for workers who are obese. PMID- 24484266 TI - Toll-like receptor 9 expression in mucoepidermoid salivary gland carcinoma may associate with good prognosis. AB - BACKGROUND: Mucoepidermoid carcinoma (MEC) is the most common salivary gland malignancy. Although several biomarkers have been evaluated, histological grade remains the most valuable prognostic marker. Toll-like receptor 9 (TLR9) is an immune receptor recognizing microbial DNA. Its expression associates with prognosis or cancer properties in several cancers. This study examined the role of TLR9 in MEC. METHODS: Sixty patients with salivary gland MEC were collected from two Finnish university hospitals, and tumor samples were stained for TLR9. Salivary gland high-grade MEC cell line (UT-MUC-1) was cultured to assess TLR9 and MMP-13 expression. The function of TLR9 was studied in vitro using traditional Matrigel((r)) invasion assay and novel human myoma organotypic model. RESULTS: Cancer-specific survival was related with tumor grade (P = 0.01), and there were no deaths in patients with low-grade MEC. TLR9 was expressed in 56 of 60 (93%) tumors. High TLR9 expression indicated better survival in the patient series (P = 0.002) and showed a trend for association with lower disease stage (P = 0.06) and higher differentiation grade (P = 0.068). In multivariate analysis, TLR9 expression was prognostically insignificant due to heavy correlation to disease stage and higher gradus. Treating UT-MUC-1 cells with TLR9 ligand CpG in vitro induced MMP-13 expression and invasion in Matrigel((r)) invasion assay, whereas decreased invasion was seen in myoma organotypic model. CONCLUSION: Functional TLR9 is present in salivary MEC, and high level of expression may indicate good prognosis. However, more studies are needed to evaluate biological consequences of TLR9 interaction in tumor cells. PMID- 24484267 TI - Proposed norms for the Glasgow hearing-aid benefit profile (Ghabp) questionnaire. AB - OBJECTIVE: To form a normative set of responses to the GHABP questionnaire from a large regional dataset. DESIGN: Participants were asked to rate their hearing disability, handicap, hearing-aid (HA) use, HA benefit, HA satisfaction, and residual (aided) disability on a five-point scale for four situations: quiet conversation, television (TV) listening, noisy conversation, and group conversation. A subset of participants also estimated the time spent in these situations. STUDY SAMPLE: A group of 1574 adults with normal to profound hearing thresholds participated. RESULTS: There was a significant relationship between increasing perceived disability and increasing hearing loss as given by the better-ear audiometric average (BEA). Responses for HA measures did not vary greatly with hearing loss: HA use was reported as high, whereas residual disability, HA benefit, and satisfaction were all reported on average as moderate. CONCLUSIONS: The results can be used as a normative dataset with which to evaluate individual responses in the clinic, where the GHABP provides a useful short-form questionnaire to engage the patient. The lack of systematic changes in hearing-aid related responses shows room for improvement in the benefit afforded by amplification. PMID- 24484268 TI - Autologous platelet gel to treat chronic decubital ulcers: a randomized, blind controlled clinical trial in dogs. AB - OBJECTIVE: To determine the efficacy of topical application of the autologous platelet gel (PG) in canine chronic protracted decubital ulcers. STUDY DESIGN: Prospective, randomized, blind controlled clinical trial. ANIMALS: Dogs (n = 18) with bilateral chronic wounds caused by protracted decubitus ulcers. METHODS: For each dog, wound side was randomized to receive either platelet gel (group PG) every 5 days for 5 dressing changes, or paraffin gauzes dressings (group C), as negative control. Wound healing and wound surfaces were compared at admission and then evaluated every 5th day, until day 25. Outcome variables were: open wound area, reduction of open wound surface compared to admission and to each preceding dressing change, time to complete epithelialization. RESULTS: Significant differences in healing process were observed at day 5 and continued throughout the entire study period (P < .00001). At 25 days, mean percent reduction in wound area was 93.5% in group PG and 13.2% in group C (P < .00001). CONCLUSIONS: Appropriately prepared autologous PG, an inexpensive, readily available blood derivative, applied topically results in more rapid healing of chronic non healing decubital ulcers in dogs than those treated by use of paraffin impregnated gauzes. PMID- 24484269 TI - Endobronchial ultrasound-guided transbronchial needle aspiration for non-small cell lung cancer staging. AB - Real-time endobronchial ultrasound-guided transbronchial needle aspiration (EBUS TBNA) is an established technique for invasive mediastinal staging of non-small cell lung cancer (NSCLC). Needle-based techniques are now recommended as a first line diagnostic modality for mediastinal staging. Accurate performance of systematic staging with EBUS-TBNA requires a detailed knowledge of mediastinal anatomy. This examination begins at the N3 lymph nodes, progressing through the N2 and N1 lymph node stations, unless a higher station lymph node is positive for malignant cells by rapid on-site cytologic examination. Objective methods of identifying EBUS-TBNA targets include sampling any lymph node station with a visible lymph node or with a lymph node greater than 5 mm in short axis. Three passes per station or the use of rapid on-site cytologic examination with identification of diagnostic material (tumor or lymphocytes) up to five passes are well-established techniques. Obtaining sufficient tissue for molecular profiling may require performing more than three passes. The operating characteristics of EBUS-TBNA are similar to mediastinoscopy. However, mediastinoscopy should be considered in the setting of a negative EBUS-TBNA and a high posterior probability of N2 or N3 involvement. PMID- 24484270 TI - All that glitters are not flecks: inflammatory choroidal neovascularization in fundus flavimaculatus. PMID- 24484271 TI - Air-stable, nanostructured electronic and plasmonic materials from solution processable, silver nanocrystal building blocks. AB - Herein we describe a room-temperature, chemical process to transform silver nanocrystal solids, deposited from colloidal solutions, into highly conductive, corrosion-resistant, optical and electronic materials with nanometer-scale architectures. After assembling the nanocrystal solids, we treated them with a set of simple, compact, organic and inorganic reagents: ammonium thiocyanate, ammonium chloride, potassium hydrogen sulfide, and ethanedithiol. We find that each reagent induces unique changes in the structure and composition of the resulting solid, giving rise to films that vary from insulating to, in the case of thiocyanate, conducting with a remarkably low resistivity of 8.8*10(-6) Omega.cm, only 6 times that of bulk silver. We show that thiocyanate mediates the spontaneous sintering of nanocrystals into structures with a roughness of less than 1/10th of the wavelength of visible light. We demonstrate that these solution-processed, low-resistivity, optically smooth films can be patterned, using imprint lithography, into conductive electrodes and plasmonic mesostructures with programmable resonances. We observe that thiocyanate-treated solids exhibit significantly retarded atmospheric corrosion, a feature that dramatically increases the feasibility of employing silver for electrical and plasmonic applications. PMID- 24484272 TI - Ultrafast phase transition via catastrophic phonon collapse driven by plasmonic hot-electron injection. AB - Ultrafast photoinduced phase transitions could revolutionize data-storage and telecommunications technologies by modulating signals in integrated nanocircuits at terahertz speeds. In quantum phase-changing materials (PCMs), microscopic charge, lattice, and orbital degrees of freedom interact cooperatively to modify macroscopic electrical and optical properties. Although these interactions are well documented for bulk single crystals and thin films, little is known about the ultrafast dynamics of nanostructured PCMs when interfaced to another class of materials as in this case to active plasmonic elements. Here, we demonstrate how a mesh of gold nanoparticles, acting as a plasmonic photocathode, induces an ultrafast phase transition in nanostructured vanadium dioxide (VO2) when illuminated by a spectrally resonant femtosecond laser pulse. Hot electrons created by optical excitation of the surface-plasmon resonance in the gold nanomesh are injected ballistically across the Au/VO2 interface to induce a subpicosecond phase transformation in VO2. Density functional calculations show that a critical density of injected electrons leads to a catastrophic collapse of the 6 THz phonon mode, which has been linked in different experiments to VO2 phase transition. The demonstration of subpicosecond phase transformations that are triggered by optically induced electron injection opens the possibility of designing hybrid nanostructures with unique nonequilibrium properties as a critical step for all-optical nanophotonic devices with optimizable switching thresholds. PMID- 24484273 TI - Oxidative stress protective effect of Dracocephalum multicaule essential oil against human cancer cell line. AB - In this study, we report the antioxidative and protective effect of essential oil of Dracocephalum multicaule on K562 cells. Our results demonstrated that monoterpenoids, including oxygenated and hydrocarbons, 71.5% and 28.3%, respectively, were the principal essential oils of D. multicaule. Perilla aldehyde (71.5%) and limonene (28.1%) were identified as the main components. Antioxidant studies based on the 2,2-diphenylpicrylhydrazyl assay indicated that the D. multicaule essential oil possesses a marked antioxidant and radical scavenging activity with an IC50 value of 438.2 MUg/mL. Pretreatment with essential oil and main constituents protected K562 cells 49.5% against H2O2 induced oxidative damage throughout increasing the activities of antioxidant enzymes and glutathione content in K562 cells. Collectively, D. multicaule essential oil and its main compounds especially in combinatory condition at a ratio of 7:3 with high antioxidant properties may be able to protect cells against oxidative stress induced by H2O2 through antioxidative mechanisms. PMID- 24484274 TI - Retinal nerve fiber layer thickness is associated with episodic memory deficit in mild cognitive impairment patients. AB - Changes in retinal nerve fiber layer (RNFL) thickness have been reported in patients with mild cognitive impairment (MCI), the pre-dementia stage of Alzheimer's disease (AD). However, whether RNFL thickness is associated with specific cognitive impairment of MCI patients remains unknown. Therefore, we set out to investigate the potential association between RNFL thickness and episodic memory in MCI patients. Seventy five older adults (mean age 74 +/- 3 years, 55% men) were included in the study. Fifty-two participants had normal cognition (NC), and 23 participants were diagnosed with MCI. RNFL thickness was obtained by optical coherence tomography measurement. Cognitive function was evaluated by the Repeatable Battery for the Assessment of Neuropsychological Status on the same day of the optical examination. We found that nasal quadrant RNFL thickness was positively associated with episodic memory scores in the participants with normal cognition: word list learning (r=0.392, p=0.004) and story recall (r=0.307, p=0.027). In the participants with MCI, however, the inferior quadrant RNFL thickness was inversely associated with the episodic memory score: word list learning (r=-0.652, p=0.001), story memory (r=-0.429, p=0.041), and story recall (r=-0.502, p=0.015,). The findings from this pilot study suggest that the inferior quadrant RNFL thickness was associated with specific episodic memory in MCI patients and could serve as a biomarker of MCI and AD. These findings would promote more studies to determine the potential application of RNFL as an AD biomarker. PMID- 24484275 TI - Amygdalar atrophy in early Alzheimer's disease. AB - Current research suggests that amygdalar volumes in patients with Alzheimer's disease (AD) may be a relevant measure for its early diagnosis. However, findings are still inconclusive and controversial, partly because studies did not focus on the earliest stage of the disease. In this study, we measured amygdalar atrophy in 48 AD patients and 82 healthy controls (HC) by using a multi-atlas procedure, MAPER. Both hippocampal and amygdalar volumes, normalized by intracranial volume, were significantly reduced in AD compared with HC. The volume loss in the two structures was of similar magnitude (~24%). Amygdalar volume loss in AD predicted memory impairment after we controlled for age, gender, education, and, more important, hippocampal volume, indicating that memory decline correlates with amygdalar atrophy over and above hippocampal atrophy. Amygdalar volume may thus be as useful as hippocampal volume for the diagnosis of early AD. In addition, it could be an independent marker of cognitive decline. The role of the amygdala in AD should be reconsidered to guide further research and clinical practice. PMID- 24484276 TI - Impaired renal function and biomarkers of vascular disease in Alzheimer's disease. AB - Renal disease is a risk factor for vascular diseases and for dementia, and renal insufficiency can be a feature of Alzheimer's disease (AD). Evidence has suggested that vascular mechanisms mediate the link between renal disease and dementia. Our study sought to test this hypothesis by examining renal and vascular functioning in AD by investigating estimated glomerular filtration rates (eGFR), calculated from serum creatinine concentrations, and established biomarkers of vascular functioning, asymmetrical dimethylarginine (ADMA) and plasma homocysteine (Hcy), in individuals with mild to moderate AD (n = 34) and a group of older adult controls (n = 34). We found significantly reduced eGFR, indicative of impaired renal functioning, in individuals with AD (M = 62.9, SD = 15.2) compared with controls (M = 73.6, SD = 11.8). However, concentrations of ADMA and Hcy did not differ between patient and control groups (ADMA: M = 0.47; M = 0.50; Hcy: M = 17.2; M = 14.9; patients and controls). The criteria for a mediation analysis were not met, as concentrations of ADMA and Hcy did not predict AD, indicating that these biomarkers of vascular functioning did not mediate a relationship between renal functioning and AD. This study indicated that renal insufficiency may independently contribute to AD pathology, and other vascular mechanisms may influence a relationship between renal impairment and AD. PMID- 24484277 TI - Advances of molecular imaging probes for the diagnosis of Alzheimer's disease. AB - Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive decline in multiple cognitive domains and it becomes the most common cause of dementia in the elderly. There is an urgent need for the early diagnosis and treatment of AD to ease caregiver burden and medical costs, as well as improve patients' living activities associated with the dramatic increasing number of affected individuals. Molecular imaging with target-specific probes is contributing to identify the underlying biology in AD, which benefits to the early diagnosis of AD and the evaluation of anti-AD therapy. Molecular imaging probes, such as (11)C-PIB, (11)C-MP4A, (18)F-AV-45, and (11)F-FDG, can selectively bind to special bimolecular of AD or accurately accumulate at the location of damage areas, thus become an edge tool for a better management of the diseases in the clinical practice and new drug development. In the past decades, a large variety of probes is being developed and tested to be useful for the early and accurate diagnosis of Alzheimer's disease, patient selection for disease-modifying therapeutic trials and monitoring the effect of anti-amyloid therapy. Since imaging probes may also help to guide physicians to identify those patients that could best benefit from a given therapeutic regimen, dose, or duration of drug, this paper is to present a perspective of the available imaging probes for AD, classified on different modalities. Meanwhile, recent advances of those probes that have been selected for clinical trials and are at the different stages of the US Food and Drugs Administration (FDA) approval are outlined. Additionally, future directions and specific application of imaging strategies designed for both diagnosis and treatment for AD are discussed. PMID- 24484278 TI - Myelin injury and degraded myelin vesicles in Alzheimer's disease. AB - OBJECTIVE: Myelin disruption is an important feature of Alzheimer's disease (AD) that contributes to impairment of neuronal circuitry and cognition. In this study we characterize myelin degradation in the brains of patients with Alzheimer's disease compared with normal aged controls. METHODS: Myelin from patients with AD (n=13) was compared to matched controls (n=6). Myelin degradation was examined by immunohistochemistry in frontal white matter (WM) for intact myelin basic protein (MBP), degraded MBP, the presence of myelin lipid and for PAS staining. The relationship of myelin degradation and axonal injury was also assessed. RESULTS: Brains from patients with AD had significant loss of intact MBP, and an increase in degraded MBP in periventricular WM adjacent to a denuded ependymal layer. In regions of myelin degradation, vesicles were identified that stained positive for degraded MBP, myelin lipid, and neurofilament but not for intact MBP. Most vesicles stained for PAS, a corpora amylacea marker. The vesicles were significantly more abundant in the periventricular WM of AD patients compared to controls (44.5 +/- 11.0 versus 1.7 +/- 1.1, p=0.02). CONCLUSION: In AD patients degraded MBP is associated in part with vesicles particularly in periventricular WM that is adjacent to areas of ependymal injury. PMID- 24484279 TI - Newly diagnosed dementia and increased risk of hemorrhagic stroke: A nationwide population-based study. AB - BACKGROUND: This retrospective cohort study was designed to assess whether there is an association between newly diagnosed dementia and the risk of stroke. METHODS: From Taiwan's National Health Insurance Research Database of reimbursement claims, we identified 2811 patients with newly diagnosed dementia and 14,055 randomly selected, age-matched patients without dementia. A Cox proportional hazards model was constructed to calculate the development of stroke, including ischemic stroke, and intracerebral, or subarachnoid hemorrhage. RESULTS: During the 3-year follow-up period, 339 patients with dementia (12.06%) and 691 patients without dementia (4.92%) developed stroke. The adjusted HRs of developing stroke among newly diagnosed dementia patients were 2.33-times (range, 2.05-2.66), and the incidence of hemorrhagic stroke was higher than that of other stroke types. Patients who had Alzheimer's disease were at the highest risk of hemorrhagic stroke. CONCLUSION: Individuals with dementia, especially Alzheimer's disease, are at greater risk of developing stroke, especially in intracerebral and subarachnoid hemorrhage than patients without dementia. Early mental screening programs and health education should be initiated for dementia patients. PMID- 24484280 TI - Default mode, executive function, and language functional connectivity networks are compromised in mild Alzheimer's disease. AB - Alzheimer's disease (AD) is characterized by mental and cognitive problems, particularly with memory, language, visuospatial skills (VS), and executive functions (EF). Advances in the neuroimaging of AD have highlighted dysfunctions in functional connectivity networks (FCNs), especially in the memory related default mode network (DMN). However, little is known about the integrity and clinical significance of FNCs that process other cognitive functions than memory. We evaluated 22 patients with mild AD and 26 healthy controls through a resting state functional MRI scan. We aimed to identify different FCNs: the DMN, language, EF, and VS. Seed-based functional connectivity was calculated by placing a seed in the DMN (posterior cingulate cortex), language (Broca's and Wernicke's areas), EF (right and left dorsolateral prefrontal cortex), and VS networks (right and left associative visual cortex). We also performed regression analyses between individual connectivity maps for the different FCNs and the scores on cognitive tests. We found areas with significant decreases in functional connectivity in patients with mild AD in the DMN and Wernicke's area compared with controls. Increased connectivity in patients was observed in the EF network. Regarding multiple linear regression analyses, a significant correlation was only observed between the connectivity of the DMN and episodic memory (delayed recall) scores. In conclusion, functional connectivity alterations in mild AD are not restricted to the DMN. Other FCNs related to language and EF may be altered. However, we only found significant correlations between cognition and functional connectivity in the DMN and episodic memory performance. PMID- 24484281 TI - Cytotoxic clerodane diterpenes from Zuelania guidonia. AB - The leaves of Zuelania guidonia yielded eight new clerodane diterpenes, namely, zuelaguidins A-H (1-8), and the known clerodane diterpene esculentin A (9). Some of these structures contained a 3,6-dihydro-1,2-dioxin moiety. The new compounds were isolated and identified using 1D- and 2D-NMR experiments. All compounds were evaluated for cytotoxicity against the CCRF-CEM (human acute lymphocytic leukemia), CEM-ADR5000 (human acute lymphocytic leukemia resistant to doxorubicin), and MIA-PaCa-2 (human pancreatic carcinoma) cell lines as well as for their selectivity against peripheral blood mononuclear cells from healthy human subjects. Zuelaguidins B, C, and E were the most potent compounds against the CCRF-CEM cell line, with IC50 values ranging from 1.6 to 2.5 MUM. PMID- 24484283 TI - Influence of muscle mass and bone mass on the mobility of elderly women: an observational study. AB - BACKGROUND: The purpose of this study was to investigate the influence of muscle mass and bone mineral density on markers of mobility in dwelling elderly women. METHODS: This cross-sectional study included 99 elderly women, who were 65 years old or above, in Campinas-SP, Brazil. To collect data, we used sociodemographic data, the body mass index (BMI), health status, comorbidities, use of medications, mobility tests (TUG and gait speed) and examinations of the body composition (densitometry with dual-emission X-ray absorptiometry "DXA"). In order to examine the relationship between muscle and bone mass with mobility (gait speed and TUG), we applied the Spearman correlation coefficient.Also was applied the analysis of covariance (ANCOVA) adjusted for age and comorbidities. To identify the factors associated with mobility, we used the univariate and multivariate logistic regression analysis. The level of significance for statistical tests was P < 0.05. RESULTS: The correlation between sarcopenia and bone mineral density with mobility tests showed a significant relationship only between sarcopenia and TUG (r = 0.277, P = 0.006) in Spearman correlation coefficient. The result of the correlation analysis (ANCOVA) showed that sarcopenia was associated with gait speed (r2 = 0.0636, P = 0.0018) and TUG (r2 = 0.0898, P = 0.0027). The results of the multivariate analysis showed that age (P = 0.034, OR = 1.081) was associated with worse performance on gait speed. By highlighting the TUG test, the results of the multivariate analysis showed that the age (P = 0.004, OR = 1.111) and BMI in overweight (P = 0.011, OR = 7.83) and obese (P < 0.001, OR = 7.84) women were associated with lower performance of the functionality of the lower limbs. CONCLUSION: The findings with regard to mobility tests which were analyzed in this study indicate the association of variables related to the aging process that contribute to the decline in physical performance, for example, age, BMI and sarcopenia. PMID- 24484284 TI - Holmium laser enucleation of the prostate and perioperative diagnosis of prostate cancer: an outcomes analysis. AB - OBJECTIVE: Our objective is to assess the outcomes of patients with prostate cancer (PCa) diagnoses undergoing holmium laser enucleation of the prostate (HoLEP). METHODS: From 2009 to 2012, 450 patients underwent HoLEP at our institution. We performed a retrospective review of these patients to identify those with PCa. RESULTS: PCa was diagnosed in 57 (12.7%) HoLEP patients: 11 (19.2%) preoperatively, 43 (75.4%) in the operative specimen, and 3 (5.4%) during follow-up. Mean time to PCa development in the postoperative group was 16 months (9-23). There was no difference in patient characteristics for those diagnosed with PCa at the time of HoLEP or in the postoperative period. There were 5 patients with a Gleason score (GS)>8 and 52 with GS<8 PCa. In the operative group, 39 (91%) elected for active surveillance and 4 (9%) elected to have cancer treatment. In subgroup analysis, men diagnosed with GS>8 intraoperatively or postoperatively had significantly elevated preoperative, postoperative, and percent change prostate-specific antigen (PSA) levels when compared to patients diagnosed GS <= 7 (P=0.01, 0.02, and 0.01, respectively). There were no complications, all voided spontaneously, and one patient had persistent incontinence. CONCLUSION: HoLEP for the treatment of lower urinary tract symptoms (LUTS) in selectively chosen men with known PCa can safely improve urination. Furthermore, PCa is diagnosed at the time of or post HoLEP in nearly 12% of patients. Those patients with persistently elevated post HoLEP PSA levels or low percent change PSA levels should raise suspicion for high GS PCa. Finally, HoLEP does not preclude active surveillance or treatment for PCa when appropriate. PMID- 24484285 TI - Gallic acid tailoring surface functionalities of plasma-polymerized allylamine coated 316L SS to selectively direct vascular endothelial and smooth muscle cell fate for enhanced endothelialization. AB - The creation of a platform for enhanced vascular endothelia cell (VEC) growth while suppressing vascular smooth muscle cell (VSMC) proliferation offers possibility for advanced coatings of vascular stents. Gallic acid (GA), a chemically unique phenolic acid with important biological functions, presents benefits to the cardiovascular disease therapy because of its superior antioxidant effect and a selectivity to support the growth of ECs more than SMCs. In this study, GA was explored to tailor such a multifunctional stent surface combined with plasma polymerization technique. On the basis of the chemical coupling reaction, GA was bound to an amine-group-rich plasma-polymerized allylamine (PPAam) coating. The GA-functionalized PPAam (GA-PPAam) surface created a favorable microenvironment to obtain high ECs and SMCs selectivity. The GA-PPAam coating showed remarkable enhancement in the adhesion, viability, proliferation, migration, and release of nitric oxide (NO) of human umbilical vein endothelial cells (HUVECs). The GA-PPAam coating also resulted in remarkable inhibition effect on human umbilical artery smooth muscle cell (HUASMC) adhesion and proliferation. These striking findings may provide a guide for designing the new generation of multifunctional vascular devices. PMID- 24484282 TI - Adipose tissue-resident regulatory T cells: phenotypic specialization, functions and therapeutic potential. AB - Foxp3(+) CD4(+) regulatory T (Treg) cells, recognized to be one of the most important defences of the human body against an inappropriate immune response, have recently gained attention from those outside immunology thanks to the compelling evidence for their capability to exert non-canonical immune functions in a variety of tissues in health and disease. The recent discovery of the differences between tissue-resident Treg cells and those derived from lymphoid organs is affecting the mindset of many investigators now questioning the broad applicability of observations originally based on peripheral blood/lymphoid organ cells. So far, the best characterized 'Treg flavour' comes from studies focused on their role in suppressing adipose tissue inflammation and obesity-driven insulin resistance. Adipose tissue derived Treg cells are distinct from their counterparts in lymphoid organs based on their transcriptional profile, T-cell receptor repertoire, and cytokine and chemokine receptor expression pattern. These cells are abundant in visceral adipose tissue of lean mice but their number is greatly reduced in insulin-resistant animal models of obesity. Interestingly, peroxisome-proliferator-activated receptor gamma expression by visceral adipose tissue Treg cells is crucial for their accumulation, phenotype and function in the fat and surprisingly necessary for complete restoration of insulin sensitivity in obese mice by the anti-diabetic drug Pioglitazone. This review surveys recent findings relating to the unique phenotype and function of adipose tissue-resident Treg cells, speculates on the nature of their dynamics in lean and obese mouse models, and analyses their potential therapeutic application in the treatment of type 2 diabetes. PMID- 24484286 TI - Microbiopsy a novel sampling technique to early detect dysplastic/malignant alterations in oral mucosal lesions: practicability by general dentists. AB - BACKGROUND: When used in oral medicine clinics, microbiopsy is able to obtain tissue fragments suitable for a highly sensitive first-level diagnosis of dysplastic/malignant alterations in oral mucosal lesions. If feasible by general dentists, this sampling technique could reduce the diagnostic delay for oral malignant and premalignant lesions. This study assesses the adequacy of microbiopsy samples when taken by general dentists. METHODS: Fifty dentists, without specific training on oral medicine, volunteered for enrolment. They were given brief training and asked to prospectively sample any mucosal lesion observed during their routine practice. The sample adequacy features were assessed. RESULTS: The dentists sampled 152 lesions; there were 92.1% of adequate samples (140/152), and the BMZ was visible in 78.6% of these (110/140). Neither the clinical aspect nor lesion site affected either the adequacy or the presence of BMZ. CONCLUSIONS: The high adequacy rate observed and the advantages histological specimens have over cytological ones go to support the feasibility of microbiopsy taken by general dentists for the characterization of oral mucosal lesions and in selecting those requiring further assessment in specialized oral medicine centres. PMID- 24484287 TI - Pneumococcus in Aboriginal and Torres Strait Islanders: the role of Aboriginal Health Workers and implications for nursing practice. AB - Abstract Background: Pneumonia is a common cause of hospitalization in Aboriginal and Torres Strait Islander men and women. Aim: This article seeks to describe the importance of immunizing against pneumonia in Aboriginal Australians and suggest strategies for screening and follow-up. Method: An integrative literature review, using both published and grey literature was undertaken to identify methods of screening and surveillance strategies for pneumococcus. Results: The literature was summarized under the following themes: pneumococcal disease; prevention strategies; access to care; improving access to vaccinations; culturally competent interventions and the role of Aboriginal health professionals. Conclusion: Community controlled conditions and the role of the Aboriginal Health Workers are seen as critical to reducing health disparities. Nurses can play a critical role in bridging the gap between mainstream and community controlled organizations. Working to increase the numbers of Aboriginal health professionals is a critical step in improving health outcomes for Aboriginal and Torres Strait Islander peoples. PMID- 24484289 TI - Short one-pot chemo-enzymatic synthesis of L-lysine and L-alanine diblock co oligopeptides. AB - Amphiphilic diblock co-oligopeptides are interesting and functional macromolecular materials for biomedical applications because of their self assembling properties. Here, we developed a synthesis method for diblock co oligopeptides by using chemo-enzymatic polymerization, which was a relatively short (30 min) and efficient reaction (over 40% yield). Block and random oligo(L lysine-co-L-alanine) [oligo(Lys-co-Ala)] were synthesized using activated papain as enzymatic catalyst. The reaction time was optimized according to kinetic studies of oligo(L-alanine) and oligo(L-lysine). Using (1)H NMR spectroscopy and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, we confirmed that diblock and random co-oligopeptides were synthesized. Optical microscopy further revealed differences in the crystalline morphology between random and block co-oligopeptides. Plate-like, hexagonal, and hollow crystals were formed due to the strong impact of the monomer distribution and pH of the solution. The different crystalline structures open up interesting possibilities to form materials for both tissue engineering and controlled drug/gene delivery systems. PMID- 24484290 TI - Characterization of blaCMY plasmids and their possible role in source attribution of Salmonella enterica serotype Typhimurium infections. AB - Salmonella is an important cause of foodborne illness; however, identifying the source of these infections can be difficult. This is especially true for Salmonella serotype Typhimurium, which is found in diverse agricultural niches. Extended-spectrum cephalosporins (ESC) are one of the primary treatment choices for complicated Salmonella infections. In Salmonella, ESC resistance in the United States is mainly mediated by blaCMY genes carried on various plasmids. In this study, we examined whether the characterization of blaCMY plasmids, along with additional information, can help us identify potential sources of infection by Salmonella, and used serotype Typhimurium as a model. In the United States, monitoring of retail meat, food animals, and ill persons for antimicrobial resistant Salmonella is conducted by the National Antimicrobial Resistance Monitoring System. In 2008, 70 isolates (70/581; 12.0%) (34 isolates from retail meat, 23 food animal, and 13 human) were resistant to ceftriaxone and amoxicillin/clavulanic acid. All were polymerase chain reaction (PCR)-positive for blaCMY and 59/70 (84.3%) of these genes were plasmid encoded. PCR-based replicon typing identified 42/59 (71.2%) IncI1-blaCMY plasmids and 17/59 (28.8%) IncA/C-blaCMY plasmids. Isolates from chickens or chicken products with blaCMY plasmids primarily had IncI1-blaCMY plasmids (37/40; 92.5%), while all isolates from cattle had IncA/C-blaCMY plasmids. Isolates from humans had either IncA/C- blaCMY (n=8/12; [66.7%]) or IncI1- blaCMY (n=4/12 [33.3%]) plasmids. All of the IncI1-blaCMY plasmids were ST12 or were closely related to ST12. Antimicrobial susceptibility patterns (AST) and pulsed-field gel electrophoresis (PFGE) patterns of the isolates were also compared and differences were identified between isolate sources. When the source of a Typhimurium outbreak or sporadic illness is unknown, characterizing the outbreak isolate's blaCMY plasmids, AST, and PFGE patterns may help identify it. PMID- 24484291 TI - Are super-shedder feedlot cattle really super? AB - The objective of this study was to determine the frequency and duration of super shedding in cattle by enumerating Escherichia coli O157:H7 in feces and to compare lineage and pulsed-field gel electrophoresis (PFGE) subtypes from super- and low-shedders. E. coli O157:H7 was enumerated from fecal samples obtained from the rectums of 400 feedlot cattle. Super-shedding steers (N=11) were identified, transported, and penned individually. Freshly voided fecal pats were sampled 2 h before and 6 h after feeding for 7 d, then once daily for an additional 19 d. Isolates (N=126) were subtyped using PFGE, and lineage was typed using a lineage specific polymorphism assay. Of the 11 super-shedders identified at the commercial feedlot, only five were confirmed as super-shedders at the research feedlot, with no super-shedders identified 6 d after sampling at the commercial feedlot. Super-shedding was not consistent in fecal pats collected from the same individual at different times of the day. Isolates exhibited three distinct PFGE subtypes, with most isolates (97.6%) displaying the same subtype, including those obtained from steers that transitioned from super- to low-shedding. The short duration of super-shedding and its lack of continuance suggest that these individuals may not play as great a role in the dissemination of E. coli O157:H7 within the feedlot as previously proposed. PMID- 24484288 TI - Targeting DNA damage response in cancer therapy. AB - Cancer chemotherapy and radiotherapy are designed to kill cancer cells mostly by inducing DNA damage. DNA damage is normally recognized and repaired by the intrinsic DNA damage response machinery. If the damaged lesions are successfully repaired, the cells will survive. In order to specifically and effectively kill cancer cells by therapies that induce DNA damage, it is important to take advantage of specific abnormalities in the DNA damage response machinery that are present in cancer cells but not in normal cells. Such properties of cancer cells can provide biomarkers or targets for sensitization. For example, defects or upregulation of the specific pathways that recognize or repair specific types of DNA damage can serve as biomarkers of favorable or poor response to therapies that induce such types of DNA damage. Inhibition of a DNA damage response pathway may enhance the therapeutic effects in combination with the DNA-damaging agents. Moreover, it may also be useful as a monotherapy when it achieves synthetic lethality, in which inhibition of a complementary DNA damage response pathway selectively kills cancer cells that have a defect in a particular DNA repair pathway. The most striking application of this strategy is the treatment of cancers deficient in homologous recombination by poly(ADP-ribose) polymerase inhibitors. In this review, we describe the impact of targeting the cancer specific aberrations in the DNA damage response by explaining how these treatment strategies are currently being evaluated in preclinical or clinical trials. PMID- 24484292 TI - Effect of porcine circovirus type 2 (PCV2) vaccination on PCV2-viremic piglets after experimental PCV2 challenge. AB - The objective of this study was to evaluate the effect of porcine circovirus type 2 (PCV2) vaccines on PCV2-viremic and -seropositive piglets born from naturally PCV2-infected sows against postnatal PCV2 challenge. The experimental design was aimed at mimicking commercial swine rearing conditions to evaluate the response of the PCV2 vaccine on PCV2-viremic and -seropositive piglets after experimental PCV2 challenge. PCV2a (or 2b)-viremic piglets received a PCV2 vaccine at 21 days of age followed by a PCV2b (or 2a) challenge at 49 days of age (28 days post vaccination). The PCV2 vaccines elicited a high level of humoral (as measured by immunoperoxidase monolayer assay and neutralizing antibody titers) and cellular (as measured by the frequency of PCV2-specific interferon-gamma-secreting cells) immune response in the PCV2-viremic piglets after vaccination even in the presence of maternally derived antibodies (MDA). The initial infection of PCV2 in the pigs was not affected by PCV2 vaccination, however the challenging PCV2 was reduced by PCV2 vaccination on PCV2-viremic pigs. The results from this study demonstrate that the PCV2 vaccine used in this study is effective at reducing PCV2 viremia and lymphoid PCV2 DNA, even for PCV2-viremic pigs with passively acquired MDA at the time of vaccination. PMID- 24484293 TI - Subungual corn: a tender pigmented subungual lesion in older people. AB - BACKGROUND: Heloma durum occurs as a tender mass in the distal nail bed beneath the big toenail in older women. OBJECTIVES: To define and report a variant of heloma durum not referenced in the literature. METHODS: This was a retrospective study whereby records, including photographs, of all cases of subungual corn were reviewed. All patients were seen in an outpatient setting. RESULTS: The records of 16 patients [15 women, one man, mean age 68 years (range 49-87)] were examined; history was between 6 and 30 months, none of the patients had received effective treatment. Mycology was negative. All reported discomfort under the big toe nail; 12 had associated subungual haemorrhage. The right big toenail was involved in 10 of 16 patients. Shared clinical features were of a subungual focus of hyperkeratosis (100%) with haemorrhage admixed in 75% of cases. The lesion was in the midline third of the nail in 11 of 16 patients (69%). The affected distal margin of nail was the uppermost point in the lateral profile of the toe (100%). Hyperextension at the distal interphalangeal joint of the affected toe was demonstrated with the patient standing. Local excision was performed when diagnosis was unclear (eight patients); simple clearance of the keratin plug was performed in the other eight patients. There was no relapse in patients who were followed up for > 6 months (n = 7). CONCLUSIONS: Clinical explanation and paring down should be attempted in order to avoid surgery at this poor healing site in the elderly. PMID- 24484294 TI - Rheumatoid arthritis and genetic variations in cytokine genes: a population-based study in Kashmir Valley. AB - OBJECTIVE: The aim of our study was to determine the genetic associations between polymorphisms of the IL1beta gene (-511C/T and +3953C/T) and IL6 gene (-174G/C) with disease susceptibility and severity in patients with rheumatoid arthritis (RA) in ethnic Kashmiri population. METHODS: Allele and genotype frequencies of IL1beta -511 C/T, IL1beta +3953 C/T and IL6 -174 G/C polymorphisms were compared between 150 RA patients and 200 healthy controls by using PCR-RFLP method. RESULTS: We did not find any significant association between IL1b +3953 C/T and IL6 -174 G/C polymorphism and Rheumatoid Arthritis risk (p>0.05), but IL1beta +3953 CT genotype was associated significantly with increased SJC and ESR and IL6 -174 GG genotype was associated significantly with increased ESR. However IL1b 511C/T polymorphism was significantly associated with rheumatoid arthritis risk and the carriers of IL1beta -511 'C' allele (CC and TC genotypes) appeared to have lower risk for RA development. CONCLUSION: Our findings suggest that the IL1b -511 'C' allele has a protective role from disease development. Furthermore our results suggest a possible role of IL1b +3953 CT and IL6 -174 GG genotypes as disease activity markers of rheumatoid arthritis. PMID- 24484295 TI - Recrudescence of Plasmodium falciparum malaria in a primigravid woman with anaemia as the only sign of disease. PMID- 24484296 TI - Tuning ion transport and selectivity by a salt gradient in a charged nanopore. AB - Inspired by ion channels in biological cells where the intracellular and extracellular ionic concentrations are typically different, a salt concentration gradient through a charged nanopore is proposed to actively regulate its ion transport and selectivity. Results obtained show that, in addition to the ion current rectification phenomenon, a reversed ion selectivity of the nanopore occurs when the concentration gradient is sufficiently large. In addition, if the directions of the applied concentration gradient and electric field are identical, a reversed magnified electric field occurs near the cathode side of the nanopore. This induced field can be used to enhance the capture rate of biomolecules and is therefore capable of improving the performance of single biomolecule sensing using nanopores. PMID- 24484297 TI - Women's satisfaction and symptoms following NovaSure endometrial ablation: a postal questionnaire survey in Lothian, Scotland. AB - Impedance-controlled endometrial ablation (NovaSure) is commonly used to treat premenopausal heavy menstrual bleeding in Lothian, Scotland. Using postal questionnaires, we assessed patient satisfaction, treatment success and post procedure symptoms in a cohort of women who had NovaSure treatment between January 2007 and May 2009. The response rate was 61.2% (115/188): 90.4% (104/115) of women were satisfied and would recommend the procedure; 36.8% (42/114) of women were amenorrhoeic at follow-up (mean = 497 days) and NovaSure significantly improved levels of both menstrual bleeding and pain (p < 0.01). Of the women, 67.0% (77/115) reported symptoms such as discomfort, vaginal discharge and bleeding/spotting within 6 weeks following NovaSure. A total of 13.9% (16/115) required further treatment following NovaSure, including hysterectomy. Patient satisfaction with NovaSure was high. Preoperative counselling needs to include information on character and duration of postoperative symptoms. Future research could compare patient satisfaction and clinical outcomes between NovaSure and the levonorgestrel-releasing intrauterine system. PMID- 24484299 TI - Low temperature aqueous electrodeposited TiO(x) thin films as electron extraction layer for efficient inverted organic solar cells. AB - Organic solar cells based on poly(3-hexylthiophene) and [6,6]-phenyl-C61-butyric acid methyl ester were fabricated with electrodeposited TiOx electron extraction layers 5-180 nm thick. Electrodeposition under ambient conditions is an attractive, facile and viable approach to prepare metal oxide interfacial layers. The TiOx films obtained displayed a linear relationship between thickness and deposition time when fabricated under ambient conditions using an aqueous air stable peroxotitanium precursor. The precursor solution was prepared from titanium isopropoxide using a chelate process, which allowed water to be used as solvent due to considerably decreased sensitivity of the precursor solution towards hydrolysis. Highly conformal TiOx films, typically observed with vacuum deposition techniques, were obtained on the indium tin oxide substrate upon electrogeneration of OH(-) ions using H2O2 additive. Conversely, significantly rougher films with spherical growths were obtained using NO3(-) additives. Low temperature annealing at 200 degrees C in air was found to greatly improve purity and O stoichiometry of the TiOx films, enabling efficient devices incorporating the electrodeposited TiOx to be made. Using MoOx as the hole extraction layer, the maximum power conversion efficiency obtained was 3.8% (Voc = 610 mV; Jsc = 10.6 mA/cm(2); FF = 59%) under simulated 100 mW/cm(2) (AM1.5G) solar irradiation, whereas an efficiency of 3.4% was achieved with fully solution processed interfacial layers comprising the electrodeposited TiOx films and a surfactant-modified PEDOT:PSS hole extraction layer. PMID- 24484300 TI - Electrical tuning of surface plasmon polariton propagation in graphene-nanowire hybrid structure. AB - We demonstrate a dynamic surface plasmonic modulation based on graphene-nanowire (grapheme-NW) hybrid structures in the visible light range. A static modulation depth of as high as 0.07 dB/MUm has been achieved experimentally. Through careful simulation and systematical experimental investigation, we found that the dual confinement effect of charge density and electromagnetic energy around the vicinity of the NW will dramatically enhance the light-matter interaction and increase the Fermi level shifting, which are the key roles for bringing the optical response of the device to the visible range. The carrier concentration near the vicinity of a Ag NW is estimated to reach 0.921*10(14) cm(-2) after applying more than 25 V voltages, which is enough to shift the Fermi level for visible light. Furthermore, the modulation behaviors near the Dirac point of monolayer graphene and the singularity of gap-induced bilayer graphene are investigated. Calculated optical conductivity as a function of Fermi level predicts a minimum value near the Dirac point, which is consistent with the experimental results. PMID- 24484301 TI - Variations in maternal 5-HTTLPR affect observed sensitive parenting. AB - BACKGROUND: Little is known about the genetic determinants of sensitive parenting. Two earlier studies examined the effect of the serotonin transporter polymorphism (5-HTTLPR) on sensitive parenting, but reported opposite results. In a large cohort we further examined whether 5-HTTLPR is a predictor of observed maternal sensitivity and whether observed child social fearfulness moderates the effect of 5-HTTLPR on maternal sensitivity. METHODS: The population-based cohort consisted of 767 mother-child dyads. Maternal sensitivity was repeatedly observed at the child's age of 14 months, 36 months and 48 months. Sensitivity was coded using the Ainsworth's rating scales for sensitivity and cooperation and the revised Erickson rating scales for Supportive presence and Intrusiveness. Child social fearfulness was observed using the Stranger Approach episode of the Laboratory Temperament Assessment Battery at 36 months. RESULTS: Repeated measurement analyses showed a consistent main effect of maternal 5-HTTLPR on sensitivity; mothers carrying the S-allele were more sensitive toward their children (p = .005). This effect was not explained by the child's 5-HTTLPR genotype. We found no evidence that child social fearfulness moderated the effect of 5-HTTLPR on sensitivity. CONCLUSIONS: This study suggests that variations in maternal 5-HTTLPR genotype appear to be involved in the etiology of parenting behavior. The observed effects of this genetic variation are consistent with the notion that parenting may have a genetic component, but large studies are needed to find the specific small molecular effects. PMID- 24484303 TI - Assessment of Postoperative Pain in Cats After Ovariectomy by Laparoscopy, Median Celiotomy, or Flank Laparotomy. AB - OBJECTIVE: To compare postoperative pain, duration of surgery, and duration of anesthesia for 3 methods of ovariectomy in cats: (1) conventional ventral median open approach (Midline), (2) right flank approach (Flank), and (3) median 2 portal laparoscopic procedure (Lap). STUDY DESIGN: Randomized, prospective clinical trial. ANIMALS: Healthy, sexually intact female cats (n = 60). METHODS: Cats were randomly assigned to 1 of 3 groups: Midline (n = 20), Flank (20), and Lap (20) were evaluated 1, 2, 4, 6, and 12 hours after endotracheal extubation. Postoperative pain was scored using the 4A-vet pain scale that combines a subjective numerical pain rating and objective scoring of physiologic and behavioral variables including the response to stimulation of the surgical site. Pain scores (PS) were compared between groups. RESULTS: There was a significant difference in the PS between groups. PS for Midline and Flank were not significantly different but were both significantly higher compared with Lap. Depending on time, 5-20% of the cats had intense postoperative pain in both Midline and Flank groups. None of the Lap cats had intense postoperative pain. CONCLUSIONS: Laparoscopic ovariectomy, although slower, appeared less painful compared with conventional ventral midline and flank ovariectomy. Postoperative pain did not differ significantly between midline and flank groups. PMID- 24484302 TI - Is supramolecular filament chirality the underlying cause of major morphology differences in amyloid fibrils? AB - The unique enhanced sensitivity of vibrational circular dichroism (VCD) to the formation and development of amyloid fibrils in solution is extended to four additional fibril-forming proteins or peptides where it is shown that the sign of the fibril VCD pattern correlates with the sense of supramolecular filament chirality and, without exception, to the dominant fibril morphology as observed in AFM or SEM images. Previously for insulin, it has been demonstrated that the sign of the VCD band pattern from filament chirality can be controlled by adjusting the pH of the incubating solution, above pH 2 for "normal" left-hand helical filaments and below pH 2 for "reversed" right-hand-helical filaments. From AFM or SEM images, left-helical filaments form multifilament braids of left twisted fibrils while the right-helical filaments form parallel filament rows of fibrils with a flat tape-like morphology, the two major classes of fibril morphology that from deep UV resonance Raman scattering exhibit the same cross beta-core secondary structure. Here we investigate whether fibril supramolecular chirality is the underlying cause of the major morphology differences in all amyloid fibrils by showing that the morphology (twisted versus flat) of fibrils of lysozyme, apo-alpha-lactalbumin, HET-s (218-289) prion, and a short polypeptide fragment of transthyretin, TTR (105-115), directly correlates to their supramolecular chirality as revealed by VCD. The result is strong evidence that the chiral supramolecular organization of filaments is the principal underlying cause of the morphological heterogeneity of amyloid fibrils. Because fibril morphology is linked to cell toxicity, the chirality of amyloid aggregates should be explored in the widely used in vitro models of amyloid-associated diseases. PMID- 24484304 TI - Adjacent-segment disease in 511 cases of posterolateral instrumented lumbar arthrodesis: floating fusion versus distal construct including the sacrum. AB - OBJECT: The aim of this study was to study the long-term outcomes of patients undergoing instrumented posterior fusion of the lumbar spine. METHODS: The authors present 511 patients who underwent instrumented arthrodesis for lumbar degenerative disease over a 23-year period at a single institution. Patients underwent follow-up for an average of 39.73 +/- 46.52 months (+/- SD) after the index lumbar arthrodesis procedure. RESULTS: The average patient age was 59.45 +/ 13.48 years. Of the 511 patients, 502 (98.24%) presented with back pain, 379 (74.17%) with radiculopathy, 76 (14.87%) with motor weakness, and 32 (6.26%) with preoperative bowel/bladder dysfunction. An average of 2.04 +/- 1.03 spinal levels were fused. Postoperatively, patients experienced a significant improvement in back pain (p < 0.0001) and radiculopathy (p < 0.0001). Patients with fusions excluding the sacrum (floating fusions) were statistically more likely to develop adjacent-segment disease (ASD) than those with fusion constructs ending at S-1 distally (p = 0.030) but were less likely to develop postoperative radiculopathy (p = 0.030). In the floating fusion cohort, 31 (12.11%) of 256 patients had cephalad ASD, whereas 39 (15.29%) of 255 patients in the lumbosacral cohort had cephalad ASD development; this was not statistically different (p = 0.295). This suggests that caudad ASD development in the floating fusion cohort is due to the added risk of an unfused L5-S1 vertebral level. Because of the elevated risk of symptomatic radiculopathy but lower risk of ASD, patients in the lumbosacral fusion cohort had a reoperation rate similar to those undergoing floating fusions (p = 0.769). CONCLUSIONS: In this paper, the authors present one of the largest cohorts in the Western literature of patients undergoing instrumented fusion for degenerative lumbar spine disease. Patients who had floating lumbar fusions were statistically more likely to develop ASD over time than those who had lumbosacral fusions incorporating the S-1 spinal segment, but were less likely to experience postoperative radicular symptoms. Additional prospective studies may more clearly delineate the long-term risks of instrumented posterolateral fusions of the lumbar spine. PMID- 24484305 TI - Atlantoaxial instability in monozygotic twin sisters: degenerative or congenital disease? AB - The authors report on two 70-year-old monozygotic twin sisters who both suffered severe nontraumatic atlantoaxial instability. If either had been a solitary case, degenerative atlantoaxial instability would have been the most straightforward diagnosis. In this case report the authors attempt to answer the question of whether an underlying congenital predisposition might be involved. PMID- 24484306 TI - In vitro evaluation of a lateral expandable cage and its comparison with a static device for lumbar interbody fusion: a biomechanical investigation. AB - OBJECT: Through in vitro biomechanical testing, the authors compared the performance of a vertically expandable lateral lumbar interbody cage (EC) under two different torque-controlled expansions (1.5 and 3.0 Nm) and with respect to an equivalent lateral lumbar static cage (SC) with and without pedicle screw fixation. METHODS: Eleven cadaveric human L2-3 segments were evaluated under the following conditions: 1) intact; 2) discectomy; 3) EC under 1.50 Nm of torque expansion (EC-1.5Nm); 4) EC under 3.00 Nm of torque expansion (EC-3.0Nm); 5) SC; and 6) SC with a bilateral pedicle screw system (SC+BPSS). Load-displacement behavior was evaluated for each condition using a combination of 100 N of axial preload and 7.5 Nm of torque in flexion and extension (FE), lateral bending (LB), and axial rotation (AR). Range of motion (ROM), neutral zone stiffness (NZS), and elastic zone stiffness (EZS) were statistically compared among conditions using post hoc Wilcoxon signed-rank comparisons after Friedman tests, with a significance level of 0.05. Additionally, any cage height difference between interbody devices was evaluated. When radiographic subsidence was observed, the specimen's data were not considered for the analysis. RESULTS: The final cage height in the EC-1.5Nm condition (12.1 +/- 0.9 mm) was smaller (p < 0.001) than that in the EC-3.0Nm (13.9 +/- 1.1 mm) and SC (13.4 +/- 0.8 mm) conditions. All instrumentation reduced (p < 0.01) ROM with respect to the injury and increased (p <= 0.01) NZS in flexion, extension, and LB as well as EZS in flexion, LB, and AR. When comparing the torque expansions, the EC-3.0Nm condition had smaller (p < 0.01) FE and AR ROM and greater (p <= 0.04) flexion NZS, extension EZS, and AR EZS. The SC condition performed equivalently (p >= 0.10) to both EC conditions in terms of ROM, NZS, and EZS, except for EZS in AR, in which a marginal (p = 0.05) difference was observed with respect to the EC-3.0Nm condition. The SC+BPSS was the most rigid construct in terms of ROM and stiffness, except for 1) LB ROM, in which it was comparable (p = 0.08) with that of the EC-1.5Nm condition; 2) AR NZS, in which it was comparable (p > 0.66, Friedman test) with that of all other constructs; and 3) AR EZS, in which it was comparable with that of the EC-1.5Nm (p = 0.56) and SC (p = 0.08) conditions. CONCLUSIONS: A 3.0-Nm torque expansion of a lateral interbody cage provides greater immediate stability in FE and AR than a 1.5-Nm torque expansion. Moreover, the expandable device provides stability comparable with that of an equivalent (in size, shape, and bone interface material) SC. Specifically, the SC+BPSS construct was the most stable in FE motion. Even though an EC may seem a better option given the minimal tissue disruption during its implantation, there may be a greater chance of endplate collapse by over-distracting the disc space because of the minimal haptic feedback from the expansion. PMID- 24484307 TI - Surgical treatment of double-level isthmic spondylolisthesis. AB - Isthmic spondylolisthesis, which is demonstrated in 4%-6% of the general population, is one of the most common types of spondylolisthesis. However, double level isthmic spondylolisthesis is extremely rare. Only a few reports have examined the outcomes of surgical treatment of double-level spondylolisthesis. The authors present an unusual case of double-level isthmic spondylolisthesis of the lumbar spine. The patient had low-back pain for 20 years and did not respond to conservative treatment. Radiographs revealed bilateral pars defects at L-4 and L-5. Grade 2 isthmic spondylolisthesis was present, both at L4-5 and at L5-S1. The patient underwent decompression, reduction, and posterior lumbar interbody fusion with autogenous bone chips from posterior decompression. At follow-up after 12 months, the patient was free of pain, slippage was corrected, and fusion was achieved. Posterior lumbar interbody fusion with posterior instrumentation and reduction may yield good functional short-term results for double-level spondylolisthesis. PMID- 24484308 TI - Use of accelerometers to measure stress levels in shelter dogs. AB - Stress can compromise welfare in any confined group of nonhuman animals, including those in shelters. However, an objective and practical method for assessing the stress levels of individual dogs housed in a shelter does not exist. Such a method would be useful for monitoring animal welfare and would allow shelters to measure the effectiveness of specific interventions for stress reduction. In this pilot study, activity levels were studied in 13 dogs using accelerometers attached to their collars. Behavioral stress scores as well as urinary and salivary cortisol levels were measured to determine if the dogs' activity levels while confined in the kennel correlated with behavioral and physiological indicators of stress in this population. The results indicated that the accelerometer could be a useful tool to study stress-related activity levels in dogs. Specific findings included a correlation between the salivary cortisol and maximum activity level (r = .62, p = .025) and a correlation between the urine cortisol-to-creatinine ratio and average activity level (r = .61, p = .028) among the study dogs. Further research is needed to better understand the complex relationship between stress and activity level among dogs in a kennel environment. PMID- 24484309 TI - Variations of some physiological and immunological parameters in Siberian sturgeon (Acipenser baerii, Brandt, 1869) subjected to an acute stressor. AB - This study was carried out to investigate the effect of an acute stressor on the variation of some physiological and immunological parameters of Siberian sturgeon (Acipenser baerii) juveniles. Fish, reared in 3 tanks for 10 weeks, were used for this study. The acute stress of fish consisted of 2 min of air exposure stress. Plasma levels of cortisol, glucose, and lactate as well as lysozyme activity in plasma were measured before stress and 1 hr, 3 hr, 6 hr, 9 hr, 12 hr, and 24 hr after stress. The plasma cortisol significantly increased in the highest level 1 hr after stress, yet it gradually declined after 3 hr. The glucose significantly increased only 1 hr after stress. There was no significant difference between plasma lactate prestress and poststress. Moreover, lysozyme activity was enhanced by stress, thus reaching the highest level 9 hr after stress. The results of this study indicate that Siberian sturgeon not only have a rapid response to acute stress, but also a great capacity for recovery from stress, thus returning physiological parameters to prestress levels after 6 hr. PMID- 24484310 TI - Human interaction as environmental enrichment for pair-housed wolves and wolf-dog crosses. AB - Private nonhuman animal sanctuaries are often financially limited in their ability to implement traditional environmental enrichment strategies. One possible solution may be to provide socialized animals with human interaction sessions. However, the merit of human interaction as enrichment has received little empirical attention to date. The present study aimed to evaluate whether human interaction could be enriching for socialized, pair-housed wolves and wolf dog crosses at a private sanctuary. Observations of each subject were conducted in a reversal design to measure species-typical affiliation, activity levels, and aberrant behaviors when caretakers were both present and absent. The results demonstrate significantly higher levels of conspecific-directed affiliation and activity levels and reduced aberrant behavior when human interaction was available. Social play also increased when caregivers were present, supporting the hypothesis that play among conspecifics may be maintained by positive changes in an animal's environment. The potential for human interaction to be established as a scientifically validated, cost-effective enrichment strategy is supported by these findings. PMID- 24484311 TI - Trends in intake and outcome data for animal shelters in a large U.S. Metropolitan area, 1989 to 2010. AB - Trends in nonhuman animal shelter intake and outcomes for dogs and cats in Metro Denver, CO, between 1989 and 2010 were assessed by linear regression analyses of data from 4 of the largest facilities covering 3 counties. The data were analyzed for trends on 3 scales: actual numbers per year, number per 1,000 residents per year, and as a percentage of total intake. Approximately 21,000 dogs and 16,000 cats were taken into the shelters in 2010, representing a 24% decrease for each since 1989. For dogs on a per-1,000-residents basis, intake decreased by 44%, euthanasia by 77%, and adoption by 13%; the live release rate (LRR) increased by 39%. For cats on the same scale, there was a 53% decrease in intake until 1998 followed by an 11% increase through 2010, and an 82% decrease in euthanasia until 2000 followed by a 24% increase through 2010. Adoption of cats per 1,000 residents remained unchanged, but the overall LRR for cats doubled during the study period. Substantially increasing trends in the transfer of dogs and cats from shelters to rescue organizations reflect efforts to optimize adoptions. PMID- 24484312 TI - Time budget and activity patterns of oncilla cats (Leopardus tigrinus) in captivity. AB - Researchers have reported on the diet of Leopardus tigrinus and ecological aspects, but studies of behavior are scarce. The aims of this study were to describe the time budget and activity patterns of 10 captive Leopardus tigrinus individuals. The group had an activity budget of 66% resting, 20.66% moving, 6.08% vigilant, 3.12% feeding, and 4.14% other activities during 720 hr of observations. The activity budgets of the males and females did not differ significantly; however, males ate more than did females. The nonhuman animals spent more time resting during the day than during the night. Moving, socializing, maintenance, and vigilance showed statistically higher mean values at night. Group analysis of the temporal pattern of behavior showed bimodal peaks. Activity levels were high from 5 a.m. to 6 a.m. and decreased through the day only to peak again at 7 p.m. Stereotypic pacing peaked at dawn and at dusk. Patterns of vigilance, feeding, and maintenance were also determined for the group during a 24-hr period. These results may be useful for the development of management plans and effective conservation strategies for captive cats. PMID- 24484313 TI - Quorum vs. diffusion sensing: a quantitative analysis of the relevance of absorbing or reflecting boundaries. AB - The consequences of the boundary conditions (signal reflecting vs. signal adsorbing) on bacterial intercellular communication were addressed by a combined physics and microbiology approach. A predictive biophysical model was devised that considered system size, diffusion from given points, signal molecule decay and boundary properties. The theoretical predictions were tested with two experimental agarose-gel-based set-ups for reflecting or absorbing boundaries. N acyl homoserine lactone (AHL) concentration profiles were measured using the Agrobacterium tumefaciens NTL4 bioassay and found to agree with model predictions. The half-life of AHL was estimated to be 7 days. The absorbing vs. reflecting nature of the boundaries drastically changed AHL concentration profiles. The effect of a single nonreflecting boundary side was equivalent to a 100-fold lower cell concentration. Results suggest that the kinetics of signal accumulation vs. signal removal and their threshold-mediated phenotypic consequences are directly linked to the properties of biofilm boundaries, stressing the relevance of the diffusion sensing component in bacterial communication. PMID- 24484314 TI - Is the Timed Up and Go test a useful predictor of risk of falls in community dwelling older adults: a systematic review and meta-analysis. AB - BACKGROUND: The Timed Up and Go test (TUG) is a commonly used screening tool to assist clinicians to identify patients at risk of falling. The purpose of this systematic review and meta-analysis is to determine the overall predictive value of the TUG in community-dwelling older adults. METHODS: A literature search was performed to identify all studies that validated the TUG test. The methodological quality of the selected studies was assessed using the QUADAS-2 tool, a validated tool for the quality assessment of diagnostic accuracy studies. A TUG score of >=13.5 seconds was used to identify individuals at higher risk of falling. All included studies were combined using a bivariate random effects model to generate pooled estimates of sensitivity and specificity at >=13.5 seconds. Heterogeneity was assessed using the variance of logit transformed sensitivity and specificity. RESULTS: Twenty-five studies were included in the systematic review and 10 studies were included in meta-analysis. The TUG test was found to be more useful at ruling in rather than ruling out falls in individuals classified as high risk (>13.5 sec), with a higher pooled specificity (0.74, 95% CI 0.52-0.88) than sensitivity (0.31, 95% CI 0.13-0.57). Logistic regression analysis indicated that the TUG score is not a significant predictor of falls (OR = 1.01, 95% CI 1.00 1.02, p = 0.05). CONCLUSION: The Timed Up and Go test has limited ability to predict falls in community dwelling elderly and should not be used in isolation to identify individuals at high risk of falls in this setting. PMID- 24484315 TI - Geographical ancestry is a key determinant of epidermal morphology and dermal composition. AB - BACKGROUND: Geographical ancestry plays a key role in determining the susceptibility of human skin to external insults and dermatological disease. Despite this, studies of skin from individuals of diverse geographical ancestry focus primarily on epidermal pigmentation. Few reports characterize the gross morphology and composition of the dermis and dermal-epidermal junction (DEJ). OBJECTIVES: To characterize epidermal morphology and dermal composition in skin from individuals of diverse geographical ancestry. METHODS: Immunohistochemical techniques were used to assess epidermal morphology and protein composition of the DEJ and dermal extracellular matrix in photoprotected skin from young African, Eurasian and Far East Asian individuals (n = 7 per group; age 18-30 years). RESULTS: The epidermis of African skin was thicker, with deeper rete ridges and a more convoluted DEJ than Eurasian and Far East Asian skin. Compared with Eurasians, protein composition of the DEJ was collagen VII poor in African and Far East Asian skin (P < 0.001 and P < 0.01, respectively); the dermis of African skin was enriched in fibrillar collagens (P < 0.05), but was relatively elastin poor (P < 0.05). African dermis was abundant in fibrillin-rich microfibrils and fibulin-5 (P < 0.001 and P < 0.001, respectively) compared with Eurasian and Far East Asian skin. CONCLUSIONS: We demonstrate that fundamental differences exist in skin structure and composition in individuals of diverse geographical ancestry. Disparate environmental pressures encountered by ancestral human populations living at different latitudes may have driven adaptations in skin structure and composition. Further research into the functional significance and clinical consequences of these differences is warranted. PMID- 24484316 TI - Communicating with Assistive Listening Devices and Age-Related Hearing Loss: Perceptions of Older Australians. AB - Abstract Age-related hearing loss can impact adversely on the delivery of primary care and cannot necessarily be remedied by hearing aid technology. A study of 20 older Australians living in a Queensland retirement village and residential hostel complex was undertaken to investigate how communication might be advanced through an assistive listening device (ALD). Most participants were women aged over 85 years; almost all had hearing loss and wore hearing aids. Tests with an ALD found very high levels of satisfaction with understanding speech and sound quality amongst participants. However, few had heard previously of ALDs, all required individualised assistance to fit and use the device and rated ease of use less highly. The findings affirm those of previous studies that ALD technology has a role in communication for older hearing-impaired people and for hearing rehabilitation. Its potential to enhance quality of life can be facilitated and promoted through nursing practice, but requires professional and consumer education so that it is not overlooked as a communication option. PMID- 24484317 TI - Economic and utilization analysis of robot-assisted versus laparoscopic live donor nephrectomy. AB - BACKGROUND: Reports of robot-assisted live donor nephrectomies (LDNs) have been emerging in the literature. We sought to examine the national incidence of robot assisted LDNs and to assess regional use and economic differences in robot assisted versus laparoscopic LDN. METHODS: Data from the Nationwide Inpatient Sample (NIS) were used to identify patients who underwent either laparoscopic or robot-assisted LDN between 2009 and 2011. Descriptive analysis was performed to examine differences between the laparoscopic and robot-assisted groups. RESULTS: A total of 4,163 cases of LDN were performed using robot-assistance or pure laparoscopic surgery between 2009 and 2011. Of these, 142 were classified as robot-assisted nephrectomies; these cases were all from the western United States. There was no difference in the incidence of complications between the laparoscopic and robot-assisted groups (P=0.206). Median (interquartile range [IQR]) total charges for robot-assisted LDN were $48,639 ($42,380-$53,050) vs $37,019 ($28,715-$48,816) for laparoscopic cases (P<0.001). CONCLUSIONS: The role of robotic assistance in LDN remains to be determined; we identified no benefits to robotic assistance in our study. PMID- 24484318 TI - The effect of erythropoietin on bone. PMID- 24484319 TI - TGF-beta favors bone marrow-derived dendritic cells to acquire tolerogenic properties. AB - Dendritic cells (DCs) are the most powerful antigen-presenting cells that have an important role in the immunity and immune tolerance. Transforming growth factor beta (TGF-beta) is a pleiotropic cytokine widely expressing in various tissues and cells, which regulates cellular proliferation, differentiation and apoptosis of several immune cells and is considered to be a key factor in inducing immune tolerance. The effect of TGF-beta on DCs is very complex. In this study, we further investigated the effect of TGF-beta on inducing immune tolerance of DCs. DCs were differentiated from mice bone marrow cells in the absence or presence of TGF-beta. The phenotype as well as function was studied in detail. We found that TGF-beta limited the expression of CD40, CD83, CD86 and MHCII in DCs, increased CD45RB and indoleamine 2, 3-dioxygenase (IDO) expression in DCs, promoted IL-10 and limited IL-12 secretion by DCs. Moreover, TGF-beta increased the endocytosis ability of DCs and limited the ability of DCs in activating T cells. These results suggest that TGF-beta affects the immunity of DCs and enhances their tolerogenicity. PMID- 24484320 TI - The axis inhibition protein 2 polymorphisms and non-syndromic orofacial clefts susceptibility in a Chinese Han population. AB - BACKGROUND: The axis inhibition protein 2 (AXIN2) is an important regulator of beta-catenin degradation in the Wnt pathway, which plays a key role in craniofacial morphogenesis. The goal of this study was to investigate the potential relationship between AXIN2 polymorphisms and the risks of non-syndromic orofacial clefts (NSOC) in a Chinese Han population. METHODS: Four polymorphisms of AXIN2 (rs2240307, rs11867417, rs2240308, and rs7591) were selected to perform a case-control study with 599 NSOC cases and 602 healthy individuals from a Chinese Han population. The single nucleotide polymorphisms (SNPs) were genotyped on basis of double ligation and multiplex fluorescence PCR. RESULTS: Weak associations were found between these four SNPs and the risk of NSOC. Further stratified analysis showed that the overall genotype frequencies of rs2240307 were different between the cleft palate only (CPO) group and the control group (P = 0.048), and GG genotype markedly contributed to the susceptibility to CPO (OR = 3.22, 95% CI = 1.13-9.18). The similar effect was also observed on GA/AA genotype compared with GG homozygote (OR = 0.30, 95% CI = 0.11-0.84). The results of LD analysis between each pair of SNPs revealed that two SNPs (rs11867417 and rs7591) were in a LD block (r(2) > 0.8). But no statistically significant was found between cases and controls from haplotype analysis in these two loci. CONCLUSIONS: The borderline results gave us a hint that rs2240307 contributed to the susceptibility to CPO in a Chinese Han population, which was conductive to improving our awareness of the causes of NSOC. PMID- 24484321 TI - Efficient purification of ginkgolic acids from Ginkgo biloba leaves by selective adsorption on Fe3O4 magnetic nanoparticles. AB - Ginkgolic acids (GAs; anacardic acids; 6-alkylsalicylic acids) are both unwanted constituents in standardized Ginkgo biloba (Ginkgo) extracts and desirable constituents for pharmacological assays. Thus, for the quality control of Ginkgo extracts, the availability of pure GAs is important. In this investigation, inexpensive and easily prepared Fe3O4 magnetic nanoparticles (MNPs) in methanol were used to selectively adsorb GAs from crude petroleum ether extracts of Ginkgo leaves in the presence of various lipids including other alkylphenols (cardanols and cardols). The adsorption capacity of the MNPs is high, at 4-5% (w/w). The moiety responsible for the adsorption is the salicylic acid group, which binds strongly to Fe(III). Desorption with acidified methanol gave an extract with a GA content of 73%. This could be further separated by preparative HPLC on a C8 column. In total, eight different GAs were captured by MNPs. The MNP adsorption step can replace more traditional column chromatography and liquid-liquid extraction steps and is superior in terms of solvent consumption, selectivity, labor, and energy consumption. MNPs might become an efficient separation technique for selected high-value phytochemicals that contain a salicylic acid moiety. PMID- 24484322 TI - Naive T cells in the gut: how to really find them? PMID- 24484323 TI - Inferring clonal evolution of tumors from single nucleotide somatic mutations. AB - BACKGROUND: High-throughput sequencing allows the detection and quantification of frequencies of somatic single nucleotide variants (SNV) in heterogeneous tumor cell populations. In some cases, the evolutionary history and population frequency of the subclonal lineages of tumor cells present in the sample can be reconstructed from these SNV frequency measurements. But automated methods to do this reconstruction are not available and the conditions under which reconstruction is possible have not been described. RESULTS: We describe the conditions under which the evolutionary history can be uniquely reconstructed from SNV frequencies from single or multiple samples from the tumor population and we introduce a new statistical model, PhyloSub, that infers the phylogeny and genotype of the major subclonal lineages represented in the population of cancer cells. It uses a Bayesian nonparametric prior over trees that groups SNVs into major subclonal lineages and automatically estimates the number of lineages and their ancestry. We sample from the joint posterior distribution over trees to identify evolutionary histories and cell population frequencies that have the highest probability of generating the observed SNV frequency data. When multiple phylogenies are consistent with a given set of SNV frequencies, PhyloSub represents the uncertainty in the tumor phylogeny using a "partial order plot". Experiments on a simulated dataset and two real datasets comprising tumor samples from acute myeloid leukemia and chronic lymphocytic leukemia patients demonstrate that PhyloSub can infer both linear (or chain) and branching lineages and its inferences are in good agreement with ground truth, where it is available. CONCLUSIONS: PhyloSub can be applied to frequencies of any "binary" somatic mutation, including SNVs as well as small insertions and deletions. The PhyloSub and partial order plot software is available from https://github.com/morrislab/phylosub/. PMID- 24484324 TI - Epoxy monomers derived from tung oil fatty acids and its regulable thermosets cured in two synergistic ways. AB - A novel biobased epoxy monomer with conjugated double bonds, glycidyl ester of eleostearic acid (GEEA) was synthesized from tung oil fatty acids and characterized by (1)H and (13)C NMR. Differential scanning calorimeter analysis (DSC) and Fourier transform infrared spectroscopy (FT-IR) were utilized to investigate the curing process of GEEA with dienophiles and anhydrides. DSC indicated that GEEA could cross-link with both dienophiles and anhydrides through Diels-Alder reaction and epoxy/anhydride ring-opening reaction. Furthermore, Diels-Alder cross-link was much more active than the ring-opening of epoxy and anhydride in the curing process. FT-IR also revealed that GEEA successively reacted with dienophiles and anhydrides in both cross-linking methods. Dynamic mechanical analysis and mechanical tensile testing were used to study the thermal and mechanical properties of GEEA cured by maleic anhydride, nadic methyl anhydride and 1,1'-(methylenedi-4,1-phenylene)bismaleimide. Due to the independence between the curing agents, dienophile and anhydride, a series of thermosetting polymers with various properties could be obtained by adjusting the composition of these two curing agents. PMID- 24484325 TI - Epigenetics and the unfolded protein response in the lung: emerging role for microRNAs. PMID- 24484326 TI - Weight gain and lung disease: the vagary of body mass index and the dilemma of the obese smoker. PMID- 24484327 TI - Dual inhibition of interleukin-1beta and interleukin-18: a new treatment option for sepsis? PMID- 24484328 TI - Hypoxia-inducible factor-1alpha in pulmonary arterial smooth muscle cells and hypoxia-induced pulmonary hypertension. PMID- 24484329 TI - Fat and cardiotoxicity in hereditary pulmonary hypertension. PMID- 24484331 TI - A pulmonary arteriovenous malformation growing for 35 years comes to an end. PMID- 24484332 TI - Pulmonary embolism diagnosed by contrast-enhanced virtopsy. PMID- 24484333 TI - The intrinsic bias of generalizations. PMID- 24484330 TI - An official American Thoracic Society Statement: pulmonary hypertension phenotypes. AB - BACKGROUND: Current classification of pulmonary hypertension (PH) is based on a relatively simple combination of patient characteristics and hemodynamics. This limits customization of treatment, and lacks the clarity of a more granular identification based on individual patient phenotypes. Rapid advances in mechanistic understanding of the disease, improved imaging methods, and innovative biomarkers now provide an opportunity to define PH phenotypes on the basis of biomarkers, advanced imaging, and pathobiology. This document organizes our current understanding of PH phenotypes and identifies gaps in our knowledge. METHODS: A multidisciplinary committee with expertise in clinical care (pulmonary, cardiology, pediatrics, and pathology), clinical research, and/or basic science in the areas of PH identified important questions and reviewed and synthesized the literature. RESULTS: This document describes selected PH phenotypes and serves as an initial platform to define additional relevant phenotypes as new knowledge is generated. The biggest gaps in our knowledge stem from the fact that our present understanding of PH phenotypes has not come from any particularly organized effort to identify such phenotypes, but rather from reinterpreting studies and reports that were designed and performed for other purposes. CONCLUSIONS: Accurate phenotyping of PH can be used in research studies to increase the homogeneity of study cohorts. Once the ability of the phenotypes to predict outcomes has been validated, phenotyping may also be useful for determining prognosis and guiding treatment. This important next step in PH patient care can optimally be addressed through a consortium of study sites with well-defined goals, tasks, and structure. Planning and support for this could include the National Institutes of Health and the U.S. Food and Drug Administration, with industry and foundation partnerships. PMID- 24484334 TI - Far from "disappointing". PMID- 24484335 TI - Reply: Pharmacological obfuscation of clinical relevance. PMID- 24484336 TI - Reply: "The intrinsic bias of generalizations" and "Far from 'disappointing'". PMID- 24484337 TI - Rationale for anticoagulant therapy of pulmonary fibrosis. PMID- 24484338 TI - Reply: rationale for anticoagulant therapy of pulmonary fibrosis. PMID- 24484339 TI - Mesenchymal stromal (stem) cell therapy: an emerging immunomodulatory strategy for the adjunctive treatment of sepsis. PMID- 24484340 TI - Reply: Mesenchymal stromal (stem) cell therapy: an emerging immunomodulatory strategy for the adjunctive treatment of sepsis. PMID- 24484341 TI - HCAP not busy being born is busy dying. PMID- 24484342 TI - Reply: HCAP not busy being born is busy dying. PMID- 24484343 TI - The continuing search for the peripheral pulmonary nodule and virtual bronchoscopy. PMID- 24484344 TI - Reply: The continuing search for the peripheral pulmonary nodule and virtual bronchoscopy. PMID- 24484345 TI - CXCL13 in tertiary lymphoid tissues: sites of production are different from sites of functional localization. PMID- 24484346 TI - Reply: CXCL13 in tertiary lymphoid tissues: sites of production are different from sites of functional localization. PMID- 24484347 TI - Surgical lung biopsy over bronchoalveolar lavage in chronic hypersensitivity pneumonitis. PMID- 24484348 TI - Reply: Surgical lung biopsy over bronchoalveolar lavage in chronic hypersensitivity pneumonitis. PMID- 24484349 TI - Arousal threshold in obstructive sleep apnea. PMID- 24484350 TI - Reply: Arousal threshold in obstructive sleep apnea. PMID- 24484351 TI - Refractory IgG4-related lung disease with constitutional symptoms and severe inflammation. PMID- 24484352 TI - Reply: Refractory IgG4-related lung disease with constitutional symptoms and severe inflammation. PMID- 24484353 TI - Hemoptysis and hydrocephalus. Follow the lead. PMID- 24484354 TI - Tandem differential mobility spectrometry in purified air for high-speed selective vapor detection. AB - A tandem ion mobility instrument based on differential mobility spectrometry (DMS) was used to demonstrate selectivity in response through differences in field dependence of mobility for ions in purified air at ambient pressure. The concept of chemical selectivity solely from characteristic dispersion curves or from field dependence of ion mobility was experimentally demonstrated in three steps with mixtures of increasing complexity. In a mixture of four alcohols with carbon numbers four and below, distinct pairs of separation voltage and compensation voltage, applied to the first and second DMS stages, permitted isolation of ions from individual substances without detectable levels of other substances. In a three-component mixture of a ketone, alcohol, and organophosphorus compound, the same level of ion isolation was observed using specific and characteristic separation and compensation voltages on each DMS stage. In the last experiment, the isolation of product ions of individual substances from a mixture of 23 volatile organic compounds from four chemical groups was incomplete though the improvement in the ratio of analyte signal to chemical noise was calculated as 31 for DMMP and 106 for 1-hexanol. These findings demonstrate that chemical information available in dispersion curves can be accessed in response times below 100 ms through a tandem DMS measurement. PMID- 24484355 TI - Episiotomy and obstetric perineal wound dehiscence: beyond soreness. AB - Postpartum episiotomy dehiscence is a rare complication of vaginal delivery. Infection rates in episiotomy wounds are surprisingly low; however, it remains the most common cause of wound dehiscence, which may lead to major physical, psychological and social problems if left untreated. Most dehisced perineal wounds are left to heal naturally by secondary intention. This approach often results in a protracted period of significant morbidity for women. There is emerging evidence that early re-suturing closure of broken-down perineal wounds may have a better outcome, but randomised controlled trials are needed to yield evidence-based guidance for this management approach. PMID- 24484357 TI - EPR study of polyaniline synthesized enzymatically in the presence of submicrometer-sized AOT vesicles. AB - EPR spectroscopy was used to examine the magnetic properties of two enzymatically synthesized polyaniline (PANI) samples obtained in the presence of submicrometer sized vesicles formed from sodium bis(2-ethylhexyl)sulfosuccinate (AOT) as templates. PANI-HRPC-AOT was synthesized with horseradish peroxidase isoenzyme C (HRPC) and hydrogen peroxide (H2O2) as oxidant while PANI-TvL-AOT was prepared with Trametes versicolor laccase (TvL) and dioxygen (O2) as oxidant. A commercial conductive sample of the emeraldine salt form of polyaniline (PANI-ES) was also used for comparison in order to correlate the experimental data obtained for PANI HRPC-AOT and PANI-TvL-AOT with the properties of the well-characterized PANI-ES. It was shown that a model based on the concept of correlated polaronic bands could be applied for the interpretation of the EPR spectra of all three examined samples, although PANI-HRPC-AOT and PANI-TvL-AOT were significantly less conductive than PANI-ES. The magnetic properties of the PANI samples could be related to their conductivities, whereby a low conductivity was ascribed to decreased interchain spin interactions which were detectable from a splitting of the triplet spectrum at low temperatures (5-10 K). The obtained effective distance between the polyaniline chains is larger for enzymatically synthesized PANI than for PANI-ES, most likely mainly due to the presence of AOT which could not be removed completely during the work-up. AOT influences the chain conformation and the average chain-chain distance. PMID- 24484358 TI - Apple peel and carboxymethylcellulose-based nanocomposite films containing different nanoclays. AB - Biodegradable packaging films were developed from polymeric blends of apple peel powder (APP) and carboxymethylcellulose (CMC), into which different nanoclays were incorporated to produce a nanocomposite film. After first estimating the barrier and mechanical properties of 4 different biopolymer films (CMC, methylcellulose, gelatin, and polylactide), CMC was chosen as the best film forming solution. Three different nanoclays (Cloisite Na(+) , 30B, and 20A) were subsequently dispersed in a CMC film solution to improve the barrier and physical properties of the final CMC nanocomposite films. The structures of the exfoliated CMC nanocomposite films were characterized using X-ray diffraction (XRD) to determine the most efficient nanoclay type, with Cloisite Na(+) addition being found to demonstrate the greatest improvement in the barrier and mechanical properties of the film. Finally, the CMC and Cloisite Na(+) solution were thoroughly blended with APP using a high-pressure homogenization (HPH) process to develop biopolymer nanocomposite films, which were then characterized using XRD and Fourier transform infrared spectroscopy. The HPH treatment significantly improved the film-forming ability by increasing the dispersity of APP in the CMC nanocomposites, as well as having various other effects on the physical properties. These nanocomposite films can be viewed as an alternative solution for the use of agricultural biomass in developing environmentally friendly packaging materials. PRACTICAL APPLICATION: Cloisite Na(+) nanoclay noticeably improved the barrier and elongation properties of a biopolymer film. High pressure homogenization successfully blended apple peel powder with carboxymethylcellulose to develop a nanocomposite film. The apple peel and CMC based nanocomposite films that were developed could be used as a novel biodegradable packaging material. PMID- 24484359 TI - Graduate medical students' perception of obstetrics and gynaecology as a future career specialty. AB - The aim of this study was to explore the perceptions of graduate-entry medical students of obstetrics and gynaecology as a specialty, in order to understand how to increase its appeal to them, and therefore enhance recruitment to the specialty. A total of 90 questionnaires were returned out of 145 questionnaires distributed to years 2 and 4 graduate-entry medical students (62% response rate). Although fewer than 4% of respondents are considering the specialty as their career choice, more than half of the respondents would consider the specialty as a second option, which shows that there is room to persuade them to have a second look. Gender was the only factor that significantly affected views regarding obstetrics and gynaecology. There is a need for more information about the specialty and its training opportunities and exposure to areas of special interest and subspecialisation, as well as role models, rather than focussing on labour ward in timetables. Areas of apprehension about the specialty, such as the risk of litigation, need to be aired and addressed through career days, as well as formal tutorials within teaching programmes. PMID- 24484356 TI - A hybrid protein-polymer nanoworm potentiates apoptosis better than a monoclonal antibody. AB - B-cell lymphomas continue to occur with a high incidence. The chimeric antibody known as Rituximab (Rituxan) has become a vital therapy for these patients. Rituximab induces cell death via binding and clustering of the CD20 receptor by Fcgamma expressing effector cells. Because of the limited mobility of effector cells, it may be advantageous to cluster CD20 directly using multivalent nanostructures. To explore this strategy, this manuscript introduces a nanoparticle that assembles from a fusion between a single chain antibody and a soluble protein polymer. These hybrid proteins express in Escherichia coli and do not require bioconjugation between the antibody and a substrate. Surprisingly a fusion between an anti-CD20 single chain antibody and a soluble protein polymer assemble worm-like nanostructures, which were characterized using light scattering and cryogenic transmission electron microscopy. These nanoworms competitively bind CD20 on two B-cell lymphoma cell lines, exhibit concentration dependent induction of apoptosis, and induce apoptosis better than Rituximab alone. Similar activity was observed in vivo using a non-Hodgkin lymphoma xenograft model. In comparison to Rituximab, systemic nanoworms significantly slowed tumor growth. These findings suggest that hybrid nanoworms targeted at CD20 may be useful treatments for B-cell related malignancies. Because of the ubiquity of antibody therapeutics, related nanoworms may have uses against other molecular targets. PMID- 24484360 TI - Light-induced bonding and debonding with supramolecular adhesives. AB - Light-responsive supramolecular polymers were applied as reversible adhesives that permit bonding and debonding on demand features. A telechelic poly(ethylene co-butylene) (PEB) was functionalized with either self-complementary hydrogen bonding ureidopyrimidinone (UPy) motifs (UPy-PEB-UPy) or 2,6-bis(1' methylbenzimidazolyl)-pyridine (Mebip) ligands (Mebip-PEB-Mebip), which can coordinate to metal ions (Zn(NTf2)2) and form a metallosupramolecular polymer with the sum formula [Znx(Mebip-PEB-Mebip)](NTf2)2x, with x ~ 1. In the latter case, light-heat conversion is facilitated by the ultraviolet (UV) light absorbing metal-ligand motifs, while in the case of UPy-PEB-UPy a UV absorber was added for this purpose. Single lap joints were prepared by sandwiching films of the supramolecular polymers of a thickness of 80-100 MUm between two glass, quartz, or stainless steel substrates and bonded by exposure to either UV light (320-390 nm, 900 mW/cm(2)) or heat (80 or 200 degrees C for UPy-PEB-UPy and the metallopolymer, respectively). UPy-PEB-UPy and [Zn0.8Mebip-PEB-Mebip](NTf2)1.6 displayed a shear strength of 0.9-1.2 and 1.8-2.5 MPa, respectively. When lap joints were placed under load and exposed to light or heat, the samples debonded within seconds. They could be rebonded through exposure to light or heat, and the original adhesive properties were recovered. PMID- 24484361 TI - Validating a script concordance test for assessing neurological localization and emergencies. AB - BACKGROUND AND PURPOSE: Clinical judgment is the ability to weigh clinical information and make decisions under conditions of uncertainty. Although neurological localization (NL) and neurological emergencies (NE) present such uncertainties, no validated method is reported to assess these decision-making skills. A script concordance test (SCT) was designed and validated to assess clinical judgment in NL and NE. METHODS: Our SCT comprised 14 clinical scenarios (53 questions). Candidates picked the response they considered the best for the questions in each scenario. Undergraduates and internal medicine residents completed the SCT; their responses were scored against the scoring key derived from an expert panel of accredited neurologists. Scores were expressed as a percentage of the maximum score. RESULTS: Mean total scores for undergraduates (n = 52), residents (n = 37) and experts (n = 15) were 61.0 +/- 0.9, 68.3 +/- 1.1 and 76.6 +/- 1.1 (mean +/- standard error of the mean, P < 0.001). Mean scores for undergraduates, residents and experts were 59.3 +/- 1.1, 66.4 +/- 1.4 and 76.1 +/- 1.8 (P < 0.001) for NL, and 62.9 +/- 1.3, 70.4 +/- 1.3 and 77.2 +/- 1.6 (P < 0.001) for NE. Senior residents scored higher than junior residents (postgraduate years 2-5 versus postgraduate year 1, 69.7 +/- 1.4 vs. 65.3 +/- 1.1, P = 0.035). The higher scores with increasing clinical experience supports the construct validity of the SCT. The SCT showed acceptable reliability (G coefficient 0.74 +/- 0.05). CONCLUSIONS: Our SCT is validated to reliably assess NL and NE in undergraduate and postgraduate learners; it is generalizable and feasible. It has potential as a valuable adjunct assessment tool for clinical judgment. Future plans to design SCTs to evaluate other topics in clinical neurology, as a multi-center study, are under way. PMID- 24484362 TI - Occupational epidemiology in the real world: Irving Selikoff, odds ratios, and asbestosis. PMID- 24484364 TI - Estimating occupational beryllium exposure from compliance monitoring data. AB - Occupational exposure to beryllium is widespread and is a health risk. The objectives of this study were to develop plausible models to estimate occupational airborne beryllium exposure. Compliance monitoring data were obtained from the Occupational Safety and Health Administration for 12,148 personal measurements of beryllium exposure from 1979 to 2005. Industry codes were maintained as reported or collapsed based on the number of measurements per cell of a job-exposure matrix (JEM). Probability of exposure was predicted based on year, industry, job, and sampling duration. In these models, probability of exposure decreased over time, was highest in full-shift personal samples, and varied with industry and job. The probability of exposure was calculated using 6 JEMs, each providing similar rankings of the likelihood of non-negligible exposure to beryllium. These statistical models, with expert appraisal, are suitable for the assessment of the probability of elevated occupational exposure to beryllium. PMID- 24484363 TI - Factors associated with self-reported symptoms of acute pesticide poisoning among farmers in northwestern Jamaica. AB - Pesticide poisoning is a major public health concern in developing countries. The authors conducted a population survey among farmers in 3 parishes of northwestern Jamaica to determine the occurrence of acute pesticide poisoning and to identify factors associated with pesticide poisoning. Approximately 16% of 359 farmers who participated in the study reported 1 or more incidents of acute pesticide poisoning within the last 2 years. Only 25% of the farmers reported ever receiving training in pesticide handling or safety. The majority (68%) of farmers who reported pesticide poisoning never sought medical attention for poisoning. The factors found to be associated with pesticide poisoning in this study indicate that implementation of specific intervention strategies and education of farmers is needed in order to improve safe handling, use, and disposal of pesticides and reduce incidents of acute pesticide poisoning. PMID- 24484365 TI - Childhood cancer incidence in proximity to nuclear power plants in Illinois. AB - The objective of this study was to examine childhood cancer incidence in proximity to nuclear power plants in Illinois. Cancer cases diagnosed among Illinois children 0 to 14 years old from 1986 through 2005 were included in the study. Standardized incidence ratio (SIR) was calculated for the geographic zones defined by the proximity to nuclear power plants. The results show that children living within 10 miles of any nuclear power plant did not have significant increase in incidence for leukemia (period 1986-1995: SIR = 0.85 [95% confidence interval, CI: 0.54-1.26]; period 1996-2005: 1.23 [0.91-1.64]), lymphomas [period 1986-1995: 1.38 [0.77-2.27]; period 1996-2005: 0.77 [0.37-1.42]), or other cancer sites. Neither did the children living 10 to 20 miles or 20 to 30 miles from any nuclear power plants. This study did not find any significant childhood cancer excess among children living near nuclear plants and did not observe any dose response patterns. PMID- 24484366 TI - Association of chronic pesticide exposure with serum cholinesterase levels and pulmonary functions. AB - The present study focused on the analysis of serum cholinesterase levels and the pulmonary function tests in seasonal farm workers who were chronically exposed to pesticides, mostly organophosphorus, in comparison with non-farm workers in the farming areas of Cukurova region, Turkey. Serum cholinesterase levels and pulmonary function tests using spyrometer in 50 male seasonal farm workers (study group) were compared to 50 male non-farm workers (control group) in this cross sectional study. The mean serum cholinesterase enzyme level in the farm worker group (7095.5 +/- 1699.4 U/L) was significantly lower than those of the control group (9716.4 +/- 1484.4 U/L) (p < .001). There was no significant difference between pulmonary function tests of 2 groups (p > .05). These results show that chronic environmental organophosphorus exposure caused a decrease in the serum cholinesterase enzyme levels in farm workers, emphasizing the importance of primary prevention. PMID- 24484367 TI - The incidence and risk factors of workplace violence towards female nurses reported via internet in an acute psychiatric hospital. AB - The authors conducted a prospective follow-up study to explore incidence and risk factors related to workplace violence towards nurses. Seventy-seven volunteers were recruited to complete a baseline questionnaire. Participants then used a designated Web site to report violent incidents they encountered during a 6-month period. A generalized estimating equation was used for data analysis. A total of 74 members completed the study; 456 events were reported. The incidence rates of various types of violence are reported in this paper. Risk factors for violence included short duration of employment, marital status, and a high level of anxiety. Strategies to reduce future violence from psychiatric patients include preplacement education that targets this high-risk group of nurses and efforts to reduce the staff anxiety levels. PMID- 24484368 TI - Blood lead levels and risk factors in pregnant women from Durango, Mexico. AB - In this cross-sectional study the authors determined blood lead levels (BLLs) and some risk factors for lead exposure in pregnant women. Two hundred ninety-nine pregnant women receiving medical attention by the Secretary of Health, State of Durango, Mexico, participated in this study between 2007 and 2008. BLLs were evaluated with graphite furnace atomic absorption spectrometry. The authors used Student t test, 1-way analysis of variance (ANOVA), and linear regression as statistical treatments. BLLs ranged from 0.36 to 23.6 MUg/dL (mean = 2.79 MUg/dL, standard deviation = 2.14). Multivariate analysis showed that the main predictors of BLLs were working in a place where lead is used, using lead glazed pottery, and eating soil. PMID- 24484369 TI - Optimism and turbulence in the fifties: the journal becomes an "archive," January 1950. PMID- 24484370 TI - Real world occupational epidemiology, part 1: odds ratios, relative risk, and asbestosis. PMID- 24484371 TI - Neurologic outcome after thoracolumbar partial lateral corpectomy for intervertebral disc disease in 72 dogs. AB - OBJECTIVE: To determine neurologic outcome and factors influencing outcome after thoracolumbar partial lateral corpectomy (PLC) in dogs with intervertebral disc disease (IVDD) causing ventral spinal cord compression. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs with IVDD (n = 72; 87 PLC). METHODS: Dogs with IVDD between T9 and L5 were included if treated by at least 1 PLC. Exclusion criteria were: previous spinal surgery, combination of PLC with another surgical procedure. Neurologic outcome was assessed by: (1) modified Frankel score (MFS) based on neurologic examinations at 4 time points (before surgery, immediately after PLC, at discharge and 4 weeks after PLC); and (2) owner questionnaire. The association of the following factors with neurologic outcome was analyzed: age, body weight, duration of current neurologic dysfunction (acute, chronic), IVDD localization, breed (chondrodystrophic, nonchondrodystrophic), number of PLCs, degree of presurgical spinal cord compression and postsurgical decompression, slot depth, presurgical MFS. Presurgical spinal cord compression was determined by CT myelography (71 dogs) or MRI (1 dog), whereas postsurgical decompression and slot depth were determined on CT myelography (69 dogs). RESULTS: MFS was improved in 18.7%, 31.7%, and 64.2% of dogs at the 3 postsurgical assessments, whereas it was unchanged in 62.6%, 52.8%, and 32.0% at corresponding time points. Based on owner questionnaire, 91.4% of dogs were ambulatory 6 months postsurgically with 74.5% having a normal gait. Most improvement in neurologic function developed within 6 months after surgery. Presurgical MFS was the only variable significantly associated with several neurologic outcome measurements (P < .01). CONCLUSIONS: PLC is an option for decompression in ventrally compressing thoracolumbar IVDD. Prognosis is associated with presurgical neurologic condition. PMID- 24484372 TI - Melatonin treatment induces interplay of apoptosis, autophagy, and senescence in human colorectal cancer cells. AB - In Asia, the incidence of colorectal cancer has been increasing gradually due to a more Westernized lifestyle. The aim of study is to determine the interaction between melatonin-induced cell death and cellular senescence. We treated HCT116 human colorectal adenocarcinoma cells with 10 MUm melatonin and determined the levels of cell death-related proteins and evaluated cell cycle kinetics. The plasma membrane melatonin receptor, MT1, was significantly decreased by melatonin in a time-dependent manner, whereas the nuclear receptor, RORalpha, was increased only after 12 hr treatment. HCT116 cells, which upregulated both pro-apoptotic Bax and anti-apoptotic Bcl-xL in the early response to melatonin treatment, activated autophagic as well as apoptotic machinery within 18 hr. Melatonin decreased the S-phase population of the cells to 57% of the control at 48 hr, which was concomitant with a reduction in BrdU-positive cells in the melatonin treated cell population. We found not only marked attenuation of E- and A-type cyclins, but also increased expression of p16 and p-p21. Compared to the cardiotoxicity of Trichostatin A in vitro, single or cumulative melatonin treatment induced insignificant detrimental effects on neonatal cardiomyocytes. We found that 10 MUm melatonin activated cell death programs early and induced G1 phase arrest at the advanced phase. Therefore, we suggest that melatonin is a potential chemotherapeutic agent for treatment of colon cancer, the effects of which are mediated by regulation of both cell death and senescence in cancerous cells with minimized cardiotoxicity. PMID- 24484374 TI - Influence of TLR-2 in the immune response in the infection induced by fungus Sporothrix schenckii. AB - Toll-like receptors (TLRs) play an important role in immunity, since they bind to pathogen surface antigens and initiate the immune response. However, little is known about the role of TLR-2 in the recognition of S. schenckii and in the subsequent immune response. Therefore, the aim of this study was to evaluate the involvement of TLR-2 in the immune response induced by S. schenckii. C57BL/6 mice (WT) and C57BL/6 TLR-2 knockout (TLR-2-/-) were used to evaluate, over a period of 10 weeks of sporotrichotic infection, the influence of TLR-2 over macrophages production of IL-1beta, IL-12 and TNF-alpha, their stimulation level by NO release and the production of IFN -gamma, IL-6, IL-17 and TGF-beta by spleen cells. The results showed that the production of pro-inflammatory mediators and NO, TLR-2 interference is striking, since its absence completely inhibited it. IL 17 production was independent of TLR-2. The absence of Th1 response in TLR2-/- animals was concomitant with IL-17 production. Therefore, it can be suggested that TLR-2 absence interferes with the course of the infection induced by the fungus S. schenckii. PMID- 24484375 TI - Unequal staffing: A snapshot of nurse staffing in critical care units in New South Wales, Australia. AB - Abstract A growing body of research provides evidence of the link between nurse to-patient ratios and skill mix with adverse patient outcomes. This paper reports an investigation into nurse staffing patterns, skill mix and patient movement in critical care units in New South Wales, Australia. A 'snapshot' of staffing patterns and patient movement over one week in October 2012 was obtained by use of a cross-sectional design using retrospective survey and administrative data. A wide variation was found in nurse-to-patient ratios, skill mix and the number of nursing staff vacancies in coronary care and high dependency units. These variations suggest that the quality of patient care may vary between facilities in New South Wales. PMID- 24484373 TI - Sleep outcomes in youth with chronic pain participating in a randomized controlled trial of online cognitive-behavioral therapy for pain management. AB - Sleep disturbances are commonly reported in youth with chronic pain. We examined whether online cognitive-behavioral therapy (CBT) for pain management would impact youth's sleep. Subjective sleep quality and actigraphic sleep were evaluated in 33 youth (M = 14.8 years; 70% female) with chronic pain participating in a larger randomized controlled trial of online-CBT. The Internet treatment condition (n = 17) received 8-10 weeks of online-CBT + standard care, and the wait-list control condition (n = 16) continued with standard care. Although pain improved with online-CBT, no changes were observed in sleep outcomes. Shorter pretreatment sleep duration was associated with less improvement in posttreatment functioning. Findings underscore the need for further development in psychological therapies to more intensively target sleep loss in youth with chronic pain. PMID- 24484377 TI - Lack of awareness of skin cancer among immunocompromised patients with antineutrophil cytoplasmic antibody-associated vasculitis: a questionnaire survey. PMID- 24484378 TI - Defending honour, keeping face: Interpersonal affordances of anger and shame in Turkey and Japan. AB - In the present study, we tested the idea that emotions are afforded to the extent that they benefit central cultural concerns. We predicted that emotions that are beneficial for the Turkish concern for defending honour (both anger and shame) are afforded frequently in Turkey, whereas emotions that are beneficial for the Japanese concern for keeping face (shame but not anger) are afforded frequently in Japan. N=563 students from Turkey and Japan indicated how frequently people in their culture experience a range of interpersonal anger and shame situations, and how intense their emotions would be. As predicted, participants perceived emotional interactions to occur frequently to the extent that they elicited culturally beneficial emotions. Moreover, the affordance of culturally beneficial emotions differed in predictable ways not only between cultures but also within cultures between situations with close vs. distant others and male vs. female protagonists. PMID- 24484379 TI - Rapid turbidimetric detection of milk powder adulteration with plant proteins. AB - Development of assays to screen milk for economically motivated adulteration with foreign proteins has been stalled since 2008 due to strong international reactions to the melamine poisoning incident in China and the surveillance emphasis placed on low molecular weight nitrogen-rich adulterants. New screening assays are still needed to detect high molecular weight foreign protein adulterants and characterize this understudied potential risk. A rapid turbidimetric method was developed to screen milk powder for adulteration with insoluble plant proteins. Milk powder samples spiked with 0.03-3% by weight of soy, pea, rice, and wheat protein isolates were extracted in 96-well plates, and resuspended pellet solution absorbance was measured. Limits of detection ranged from 100 to 200 MUg, or 0.1-0.2% of the sample weight, and adulterant pellets were visually apparent even at ~0.1%. Extraction recoveries ranged from 25 to 100%. Assay sensitivity and simplicity indicate that it would be ideally suitable to rapidly screen milk samples in resource poor environments where adulteration with plant protein is suspected. PMID- 24484380 TI - Increased alpha-9 human papillomavirus species viral load in human immunodeficiency virus positive women. AB - BACKGROUND: Persistent high-risk (HR) human papillomavirus (HPV) infection and increased HR-HPV viral load are associated with the development of cancer. This study investigated the effect of human immunodeficiency virus (HIV) co-infection, HIV viral load and CD4 count on the HR-HPV viral load; and also investigated the predictors of cervical abnormalities. METHODS: Participants were 292 HIV-negative and 258 HIV-positive women. HR-HPV viral loads in cervical cells were determined by the real-time polymerase chain reaction. RESULTS: HIV-positive women had a significantly higher viral load for combined alpha-9 HPV species compared to HIV negative women (median 3.9 copies per cell compared to 0.63 copies per cell, P = 0.022). This was not observed for individual HPV types. HIV-positive women with CD4 counts >350/MUl had significantly lower viral loads for alpha-7 HPV species (median 0.12 copies per cell) than HIV-positive women with CD4 <=350/MUl (median 1.52 copies per cell, P = 0.008), but low CD4 count was not significantly associated with increased viral load for other HPV species. High viral loads for alpha-6, alpha-7 and alpha-9 HPV species were significant predictors of abnormal cytology in women. CONCLUSION: HIV co-infection significantly increased the combined alpha-9 HPV viral load in women but not viral loads for individual HPV types. High HR-HPV viral load was associated with cervical abnormal cytology. PMID- 24484382 TI - Characterizing psychosocial distress in melanoma patients using the expert rating instrument PO-Bado SF. AB - BACKGROUND: Although psychosocial distress has been evaluated well in cancer entities like breast or prostate cancer, its impact on melanoma patients still needs to be characterized. The objectives of this study were to (i) evaluate psychosocial distress in melanoma patients using an expert rating instrument [basic documentation for psycho-oncology short version (PO-Bado SF)]; (ii) determine associated demographic and clinical variables; and (iii) assess the acceptance of using PO-Bado SF as a routine procedure in a skin cancer unit. METHODS: A cross-sectional group of 696 melanoma patients was recruited. During the routine contact, doctors assessed the patients subjective distress using PO Bado SF. Sociodemographic data, tumour data, treatment and the course of the disease were extracted from the patients' charts. RESULTS: PO-Bado SF was completed in 688 of 696 (99%) participating patients, revealing a high acceptance. In 51 (7%) patients, the PO-Bado SF cut-off score indicated the potential need of psychosocial support. Patients with previous or ongoing radiotherapy, a history of major surgery due to organ metastases, younger age and shorter time since diagnosis were considered significantly more distressed than patients without these criteria. Patients were most distressed by suffering from anxiety/worries and/or tensions. In younger patients emotional variables and other problems like social or family problems were deemed more relevant while functional limitations in daily living were reasons for higher distress in older patients. CONCLUSION: PO-Bado SF is a useful, well-accepted, practical and economic screening tool to identify distressed melanoma patients. Although most melanoma patients seem to cope well with their disease, special attention should be given to young patients in the first years after initial diagnosis and to patients with advanced disease, radiotherapy and major surgery due to their disease. Combination of expert rating tools with self-report screening instruments could further characterize the specific sources of distress to optimize psychosocial support. PMID- 24484383 TI - Molecular machines like myosin use randomness to behave predictably. PMID- 24484381 TI - Biosynthetic potential-based strain prioritization for natural product discovery: a showcase for diterpenoid-producing actinomycetes. AB - Natural products remain the best sources of drugs and drug leads and serve as outstanding small-molecule probes to dissect fundamental biological processes. A great challenge for the natural product community is to discover novel natural products efficiently and cost effectively. Here we report the development of a practical method to survey biosynthetic potential in microorganisms, thereby identifying the most promising strains and prioritizing them for natural product discovery. Central to our approach is the innovative preparation, by a two-tiered PCR method, of a pool of pathway-specific probes, thereby allowing the survey of all variants of the biosynthetic machineries for the targeted class of natural products. The utility of the method was demonstrated by surveying 100 strains, randomly selected from our actinomycete collection, for their biosynthetic potential of four classes of natural products, aromatic polyketides, reduced polyketides, nonribosomal peptides, and diterpenoids, identifying 16 talented strains. One of the talented strains, Streptomyces griseus CB00830, was finally chosen to showcase the discovery of the targeted classes of natural products, resulting in the isolation of three diterpenoids, six nonribosomal peptides and related metabolites, and three polyketides. Variations of this method should be applicable to the discovery of other classes of natural products. PMID- 24484384 TI - Editorial: Perspective of bacterial vaccines. PMID- 24484386 TI - A new dynamic model of the wheelchair propulsion on straight and curvilinear level-ground paths. AB - Independent-roller ergometers (IREs) are commonly used to simulate the behaviour of a wheelchair propelled in a straight line. They cannot, however, simulate curvilinear propulsion. To this effect, a motorised wheelchair ergometer could be used, provided that a dynamic model of the wheelchair-user system propelled on straight and curvilinear paths (WSC) is available. In this article, we present such a WSC model, its parameter identification procedure and its prediction error. Ten healthy subjects propelled an instrumented wheelchair through a controlled path. Both IRE and WSC models estimated the rear wheels' velocities based on the users' propulsive moments. On curvilinear paths, the outward wheel shows root mean square (RMS) errors of 13% in an IRE vs 8% in a WSC. The inward wheel shows RMS errors of 21% in an IRE vs 11% in a WSC. Differences between both models are highly significant (p < 0.001). A wheelchair ergometer based on this new WSC model will be more accurate than a roller ergometer when simulating wheelchair propulsion in tight environments, where many turns are necessary. PMID- 24484385 TI - uPEPperoni: an online tool for upstream open reading frame location and analysis of transcript conservation. AB - BACKGROUND: Several small open reading frames located within the 5' untranslated regions of mRNAs have recently been shown to be translated. In humans, about 50% of mRNAs contain at least one upstream open reading frame representing a large resource of coding potential. We propose that some upstream open reading frames encode peptides that are functional and contribute to proteome complexity in humans and other organisms. We use the term uPEPs to describe peptides encoded by upstream open reading frames. RESULTS: We have developed an online tool, termed uPEPperoni, to facilitate the identification of putative bioactive peptides. uPEPperoni detects conserved upstream open reading frames in eukaryotic transcripts by comparing query nucleotide sequences against mRNA sequences within the NCBI RefSeq database. The algorithm first locates the main coding sequence and then searches for open reading frames 5' to the main start codon which are subsequently analysed for conservation. uPEPperoni also determines the substitution frequency for both the upstream open reading frames and the main coding sequence. In addition, the uPEPperoni tool produces sequence identity heatmaps which allow rapid visual inspection of conserved regions in paired mRNAs. CONCLUSIONS: uPEPperoni features user-nominated settings including, nucleotide match/mismatch, gap penalties, Ka/Ks ratios and output mode. The heatmap output shows levels of identity between any two sequences and provides easy recognition of conserved regions. Furthermore, this web tool allows comparison of evolutionary pressures acting on the upstream open reading frame against other regions of the mRNA. Additionally, the heatmap web applet can also be used to visualise the degree of conservation in any pair of sequences. uPEPperoni is freely available on an interactive web server at http://upep scmb.biosci.uq.edu.au. PMID- 24484387 TI - Reporter-free potentiometric sensing of boronic acids and their reactions by using quaternary ammonium salt-functionalized polymeric liquid membranes. AB - The tremendous applications of boronic acids (BAs) in chemical sensing, medical chemistry, molecular assembly, and organic synthesis lead to an urgent demand for developing effective sensing methods for BAs. This paper reports a facile and sensitive potentiometric sensor scheme for heterogeneous detection of BAs based on their unexpected potential responses on quaternary ammonium salt-doped polymeric liquid membranes. (11)B NMR data reveal that a quaternary ammonium chloride can trigger the hydrolysis of an electrically neutral BA in an aprotic solvent. Using the quaternary ammonium salt as the receptor, the BA molecules can be extracted from the sample solution into the polymeric membrane phase and undergo the concomitant hydrolysis. Such salt-triggered hydrolysis generates H(+) ions, which can be coejected into the aqueous phase with the counterions (e.g., Cl(-)) owing to their high hydrophilicities. The perturbation on the ionic partition at the sample-membrane interface changes the phase boundary potential and thus enables the potentiometric sensing of BAs. In contrast to other transduction methods for BAs, for which labeled or separate reporters are exclusively required, the present heterogeneous sensing scheme allows the direct detection of BAs without using any reporter molecules. This technique shows superior detection limits for BAs (e.g., 1.0 * 10(-6) M for phenylboronic acid) as compared to previously reported methods based on colorimetry, fluorimetry, and mass spectrometry. The proposed sensing strategy has also been successfully applied to potentiometric indication of the BA reactions with hydrogen peroxide and saccharides, which allows indirect and sensitive detection of these important species. PMID- 24484388 TI - High-yield sorting of small-diameter carbon nanotubes for solar cells and transistors. AB - We describe herein a high-yield method to selectively disperse semiconducting CoMoCAT (CO disproportionation on Co-Mo catalysts) single-walled carbon nanotubes (SWNTs) with regioregular poly(3-alkylthiophenes) polymers. We observed that the dispersion yield was directly related to the length of the polymer's alkyl side chains. Molecular dynamics simulations in explicit toluene (real toluene molecules) indicate that polythiophenes with longer alkyl side chains bind strongly to SWNTs, due to the increased overall surface contact area with the nanotube. Furthermore, the sorting process selectively enriches smaller-diameter CoMoCAT SWNTs with larger bandgaps, which is ideal for solar cell applications. Compared to the larger diameter sorted HiPco (High-Pressure CO) SWNTs, solar cells fabricated using our sorted CoMoCAT SWNTs demonstrated higher open-circuit voltage (Voc) and infrared external quantum efficiency (EQE). The Voc achieved is the highest reported for solar cells based on SWNT absorbers under simulated AM1.5 solar illumination. Additionally, we employed the sorted CoMoCAT SWNTs to fabricate thin film transistors with excellent uniformity and device performance. PMID- 24484389 TI - Editorial: Perspective of bacterial vaccines -part II. PMID- 24484390 TI - Nasal ventilation is not continuous positive airway pressure with a rate but mechanical ventilation without a tube. PMID- 24484391 TI - Angiogenic growth factors in maternal and fetal serum in pregnancies complicated with intrauterine growth restriction. AB - The aim of this paper was to study if soluble fms-like tyrosine kinase 1 (sFlt 1), free vascular endothelial growth factor (f-VEGF) and the f-VEGF/sFlt-1 quotient in singleton pregnancies complicated with intrauterine growth restriction (IUGR) are different from controls. This was a case-control study between 18 pregnancies with IUGR and 24 controls. Angiogenic growth factors were measured in maternal serum during pregnancy and in umbilical artery and vein at birth. Results showed that maternal plasma f-VEGF and s-Flt-1 were significantly higher in IUGR compared with controls (p = 0.01 and 0.001, respectively). f VEGF/sFlt-1 quotient was significantly lower in the IUGR group compared with controls. When we analysed umbilical cord angiogenic factors, we found no significant differences in the artery or vein angiogenic growth factors between the IUGR group and controls. It was concluded that mothers of IUGR fetuses have a more anti-angiogenic environment compared to those of controls. PMID- 24484392 TI - Budesonide multi-matrix system formulation for treating ulcerative colitis. AB - Budesonide is a corticosteroid characterized by high topical activity and low systemic effect associated with fewer glucocorticoid-related adverse events than conventional steroids. Differently from Crohn's disease, no evidence suggests that oral budesonide is effective for the induction of remission of ulcerative colitis (UC). Budesonide multi-matrix (MMX) system is a new oral preparation that, by employing a MMX, provides the release of the drug throughout the entire colon. Its efficacy in inducing UC remission, at a dose of 9 mg, is based on some recent trials. However, in two studies the absolute differences between budesonide MMX and placebo were much lower than the rate of success reported in previous trials with mesalazines. In addition, the therapeutic advantage of budesonide MMX 9 mg over 5-aminosalicylic acid (5-ASA) showed by one study, and the advantage of budesonide MMX over budesonide reported in the other study, was only 5.8 and 4.8%, respectively. The evidence supporting the use of budesonide MMX at a dose of 6 mg for maintenance is weak. Therefore, the effective dosage should be 9 mg also in maintenance, but not for > 4 - 6 months, because a prolonged treatment has showed to increase the rate of side effects. PMID- 24484393 TI - Factors associated with young adults delaying and forgoing driving licenses: results from Britain. AB - OBJECTIVE: To identify the reasons that young adults (age 17-29) in Britain delay or forgo driving license acquisition. METHODS: Using year 2010 British National Travel Survey microdata, we first analyze self-reported reasons (including their prioritisation) for not holding a full car driving license and then estimate a logistic regression model for license-holding to investigate additional factors, several of which extend from previous studies. This study also employs a novel segmentation approach to analyze the sets of reasons that individual young adults cite for not driving. RESULTS: These results show that, despite the lack of a graduated driving license system at present, many young adults indicate that issues associated with the driving license acquisition process are the main reason they do not hold a full driving license. About 3 in 10 young adults can be interpreted as not viewing driving as a priority, though half of those without a license are either learning to drive or are deterred principally by the cost of learning. We calculate that after their 17th birthday (the age of eligibility for a full driving license) young adults spend a mean of 1.7 years learning to drive. Young adults citing the costs of insurance or car purchase are likely to cite them as secondary rather than the main reason for not driving, whereas those citing physical/health difficulties are very likely to cite this as the main reason they do not drive. Two distinct groups of young people are identified that both indicate that costs deter them from driving-one group that is less well off financially and that indicates that costs alone are the primary deterrent and one that reports that other reasons also apply and is better off. Status as an international migrant was found to be an important factor, net of confounding variables, for identifying that a young adult in Britain does not hold a driving license. Further research is needed to understand the relative saliency of plausible causal mechanisms for this finding. We also report that both personal income and household income are independently positively associated with license holding but that (intuitively) the relationship of license holding with a young adult's own personal income is the much stronger of the two. CONCLUSIONS: On the basis of these findings, it can be concluded that a number of previously underappreciated factors appear to be linked with young British adults not acquiring a driving license. PMID- 24484394 TI - Superoxide dismutase recombinant Lactobacillus fermentum ameliorates intestinal oxidative stress through inhibiting NF-kappaB activation in a trinitrobenzene sulphonic acid-induced colitis mouse model. AB - AIMS: Superoxide dismutase (SOD) can prevent and cure inflammatory bowel diseases by decreasing the amount of reactive oxygen species. Unfortunately, short half life of SOD in the gastrointestinal tract limited its application in the intestinal tract. This study aimed to investigate the treatment effects of recombinant SOD Lactobacillus fermentum in a colitis mouse model. METHODS AND RESULTS: In this study, we expressed the sodA gene in Lact. fermentum I5007 to obtain the SOD recombinant strain. Then, we determined the therapeutic effects of this SOD recombinant strain in a trinitrobenzene sulphonic acid (TNBS)-induced colitis mouse model. We found that SOD activity in the recombinant Lact. fermentum was increased by almost eightfold compared with that in the wild type. Additionally, both the wild type and the recombinant Lact. fermentum increased the numbers of lactobacilli in the colon of mice (P < 0.05). Colitis mice treated with recombinant Lact. fermentum showed a higher survival rate and lower disease activity index (P < 0.05). Recombinant Lact. fermentum significantly decreased colonic mucosa histological scoring for infiltration of inflammatory cells, lipid peroxidation, the expression of pro-inflammatory cytokines and myeloperoxidase (P < 0.05) and inhibited NF-kappaB activity in colitis mice (P < 0.05). CONCLUSIONS: SOD recombinant Lact. fermentum significantly reduced oxidative stress and inflammation through inhibiting NF-kappaB activation in the TNBS-induced colitis model. SIGNIFICANCE AND IMPACT OF THE STUDY: This study provides insights into the anti-inflammatory effects of SOD recombinant Lact. fermentum, indicating the potential therapeutic effects in preventing and curing intestinal bowel diseases. PMID- 24484398 TI - New Graduate Transition Programs: Relationships With Access to Support and Bullying. AB - Abstract New graduate nurses are often targets of bullying and horizontal violence. The support offered by new graduate nurse transition programs may moderate the effects of bullying and limit its negative impact on new graduate nurse transition. This study examined the relationships between access to support, workplace bullying and new graduate nurse transition within the context of New Graduate Transition programs. As part of a mixed methods study, an online survey was administered to new graduates (n=245) approximately a year from starting employment. Bullied new graduate nurses were less able to access support when needed and had poorer transition experiences than their non-bullied peers. Participation in a formal transition program improved access to support and transition for bullied new graduate nurses. People supports within transition programs positively influenced the new graduate nurse transition experience. Formal transition programs provide support that attenuates the impact of bullying on new graduate nurses and improves transition. PMID- 24484395 TI - Protective effect of esculin on streptozotocin-induced diabetic renal damage in mice. AB - The present study investigated the presence and mechanism of esculin-mediated renoprotection to assess its therapeutic potential. Esculin was orally administered at 20 mg/kg/day for 2 weeks to streptozotocin-induced diabetic mice, and its effects were compared with those of the vehicle in normal and diabetic mice. After oral administration of esculin to mice, the concentrations of esculin and esculetin in blood were 159.5 +/- 29.8 and 9.7 +/- 4.9 ng/mL at 30 min, respectively. Food and water intake were significantly increased in the diabetic mice compared to normal mice but attenuated in mice receiving esculin. The elevated blood glucose level and hepatic glucose-6-phosphatase expression were significantly reduced in esculin-treated diabetic mice, supporting the antidiabetic effect of esculin. Esculin also increased the uptake of glucose and induced the insulin-evoked phosphorylation of insulin receptor, Akt, and glycogen synthase kinase 3beta in C2C12 myotubes, indicating a potential for improvement of insulin sensitivity. In addition, esculin lessened the elevated blood creatinine levels in diabetic mice and ameliorated diabetes-induced renal dysfunction by reducing caspase-3 activation in the kidney. Data support the beneficial effect of esculin against diabetes and oxidative stress-related inflammatory processes in the kidney. PMID- 24484399 TI - Uncontrolled avoidance of threat: Vigilance-avoidance, executive control, inhibition and shifting. AB - It has been argued that anxious individuals orient their attention initially towards and then away from threat; this pattern is known as vigilance-avoidance. While the mechanisms underlying the initial vigilance have been subject to intense speculation and study, mechanisms underlying any subsequent avoidance have been neglected, although it has often been assumed that avoidance is a controlled coping strategy. Using a correlational design, the present study assessed avoidance in a dot-probe task, along with anxiety and two aspects of goal-driven executive control: Shifting and inhibition. Avoidance of threat correlated with state of anxiety; separate from this, avoidance also correlated negatively with shifting performance and was unrelated to inhibition performance. In other words, avoidance appeared to represent a shifting failure in this study. These results suggest that avoidance may occur ballistically in any individual as a consequence of threat exposure and does not necessarily represent a controlled coping response. PMID- 24484400 TI - Mode of delivery in a woman with previous surgery for imperforate anus. PMID- 24484401 TI - Fast screening of ligand-protein interactions based on ligand-induced protein stabilization of gold nanoparticles. AB - High throughput screening of small molecular weight (LMW) ligands for protein and sensitive determination of ligand-induced protein stabilization is an important task in drug discovery and in protein structural and functional genomics studies. In this study, gold nanoparticles (AuNPs) and their aggregation property are used to develop a rapid and less equipment intensive assay for screening the interactions between LMW ligands and transcription factors (TFs) and human serum albumin. The assay is based on the fact that the aggregation/discpersion status of AuNPs is very sensitive to the conformation of surrounding proteins, and when a LMW ligand binds to the proteins, it can enhance proteins' salt and thermal stability, and therefore the protective effect on AuNPs from aggregation. Two TFs, i.e. FoxA1 (Forkhead box A1) and AP-2gamma (activating enhancer binding protein 2 gamma), and 14 compounds from an NCI compounds library and human serum albumin (HSA) and three known ligands (ibuprofen, warfarin, and phenytoin) are involved to demonstrate the concept and to prove its generality and robustness. With this AuNP method, two strong LMW binders are identified for FoxA1 and AP 2gamma; ligand induced protein stabilization is determined. The results have been verified using surface plasmon resonance spectroscopy (SPR) and differential static light scattering (DSLS) techniques. Tryptophan fluorescent measurement is also conducted to provide further information on protein conformational change upon LMW ligand loading as can be observed from AuNPs' UV-vis spectra. FoxA1 and AP-2gamma are pivotal in regulating the transcriptional activity of estrogen receptor alpha and controlling the expression of estrogen-responsive breast cancer cells. Identification of drug candidates targeting these two transcription factors could be an alternative in treating breast cancer, in particular those that have become endocrine resistance. PMID- 24484404 TI - General design strategy for aromatic ketone-based single-component dual-emissive materials. AB - Materials with both fluorescence and room-temperature phosphorescence (RTP) can be useful in the field of optoelectronics. Here we present a general strategy, taking advantage of carbonyl compounds, which have been known to possess efficient intersystem crossing with high triplet state yield, as well as a strongly fluorescent intramolecular charge-transfer (ICT) state, to produce materials with both fluorescence and RTP at the same time, or dual-emission. In the presented model systems, in order to generate a suitable ICT state, Lewis acid binding to aromatic ketone derivatives has been proved to be a viable method. We have selected AlCl3, BCl3, BF3, and GdCl3 as binding Lewis acids, in that they exhibit sufficiently strong binding affinity toward the aromatic ketone derivatives to afford stable complexes and yet do not possess low-lying electronic transitions vs the ligands. We have successfully observed dual emission from these designed complexes in polymers, which act to suppress competitive thermal decay at room temperature. One of the complexes is particularly interesting as it is dual-emissive in the crystalline state. Single crystal XRD reveals that the molecule forms multiple hydrogen bonds with its neighbors in crystals, which may significantly enhance the rigidity of the environment. PMID- 24484403 TI - Satisfaction of treatment with biologics is high in psoriasis: results from the Bio-CAPTURE network. AB - BACKGROUND: Although the effectiveness of biologics for psoriasis has been measured extensively with objective outcome measures, studies based on subjective, patient-reported outcome measures remain scarce. OBJECTIVES: To investigate satisfaction with medication, as measured by the Treatment Satisfaction Questionnaire for Medication (TSQM) for biologics in daily practice psoriasis care in the first 6 months of treatment; and to identify possible differences in satisfaction with medication between patients experienced (biologics-experienced) and inexperienced (biologics-inexperienced) in the use of biologics. METHODS: TSQM baseline measurements were compared using measurements taken after 6 months, using the Wilcoxon signed-rank test for paired comparisons. Intention-to-treat with last observation carried forward (ITT with LOCF) and as treated analyses were performed. The difference between biologics-experienced and biologics-inexperienced patients for TSQM was analysed using ITT with LOCF. At 6 months, outcomes for biologics-experienced and biologics-inexperienced patients were compared using the Mann-Whitney U-test. RESULTS: One hundred and six patients were eligible for analysis, and treated with etanercept (n = 34), adalimumab (n = 49) or ustekinumab (n = 23). Fifty-four per cent of patients were biologics-inexperienced. A statistically significant improvement was seen in all domains of the TSQM ('effectiveness', 'side-effects', 'convenience' and 'global satisfaction') by comparison of months 3 or 6 with baseline (all P <= 0.02). After 6 months, biologics-inexperienced patients scored better on the 'global satisfaction' domain than biologics-experienced patients (P < 0.01). CONCLUSIONS: We provide a prospective, longitudinal analysis of TSQM for biologics in daily practice psoriasis care. High satisfaction rates were achieved. The 'effectiveness' and 'convenience' domains showed the most room for improvement. PMID- 24484405 TI - Combining neural and behavioral indicators in the assessment of internalizing psychopathology in children and adolescents. AB - Anxiety and mood disorders are among the most prevalent mental health problems affecting our youth. We propose that assessment and treatment efforts in this area can benefit from a focus on developmentally sensitive neurobehavioral trait constructs, that is, individual difference constructs with direct referents in both neurobiology and behavior across the lifespan. This approach dovetails with the National Institute of Mental Health's Research Domain Criteria initiative, which aims to improve classification and treatment of psychopathology by delineating dimensions of functioning that transcend measurement domains and traditional diagnostic categories. We highlight two neurobehavioral dimensions with clear relevance for understanding internalizing problems at differing ages: (a) defensive reactivity and (b) cognitive control. Individual differences in defensive reactivity are posited to reflect variations in sensitivity of the brain's negative valence systems, whereas differences in cognitive control are theorized to reflect variations in neural systems dedicated to regulating behavior and affect. Focusing on these target constructs, we illustrate a psychoneurometric approach to assessment of internalizing psychopathology entailing use of neural, self-report, and behavioral indicators. We address the feasibility of the psychoneurometric approach for clinical application and present results from a pilot study demonstrating expected associations for neural, parent-report, and behavioral measures of defensive reactivity and cognitive control with internalizing symptoms in preschoolers. Together, our conceptual and empirical analyses highlight the promise of multimethod, dimensional assessment of internalizing psychopathology in the lab and in the clinic. PMID- 24484402 TI - Chlamydial metabolism revisited: interspecies metabolic variability and developmental stage-specific physiologic activities. AB - Chlamydiae are a group of obligate intracellular bacteria comprising important human and animal pathogens as well as symbionts of ubiquitous protists. They are characterized by a developmental cycle including two main morphologically and physiologically distinct stages, the replicating reticulate body and the infectious nondividing elementary body. In this review, we reconstruct the history of studies that have led to our current perception of chlamydial physiology, focusing on their energy and central carbon metabolism. We then compare the metabolic capabilities of pathogenic and environmental chlamydiae highlighting interspecies variability among the metabolically more flexible environmental strains. We discuss recent findings suggesting that chlamydiae may not live as energy parasites throughout the developmental cycle and that elementary bodies are not metabolically inert but exhibit metabolic activity under appropriate axenic conditions. The observed host-free metabolic activity of elementary bodies may reflect adequate recapitulation of the intracellular environment, but there is evidence that this activity is biologically relevant and required for extracellular survival and maintenance of infectivity. The recent discoveries call for a reconsideration of chlamydial metabolism and future in-depth analyses to better understand how species- and stage-specific differences in chlamydial physiology may affect virulence, tissue tropism, and host adaptation. PMID- 24484407 TI - Combined SAXS/UV-vis/Raman as a diagnostic and structure resolving tool in materials and life sciences applications. AB - In order to diagnose and fully correlate structural, chemical, and functional features of macromolecules and particles in solution, we propose the integration of spectroscopy and scattering on the same measuring volume and at the same time in a dedicated sample environment with multiple probes. Combined SAXS/UV-vis and SAXS/Raman information are employed to study the radiation damage effect in proteins in solution and the scattering from single wall carbon nanotubes (SWNTs) in SDS dispersion, respectively. In the first case, a clear correlation is observed between the time dependence of the radius of gyration (Rg) of the protein determined by SAXS and the turbidity of the protein solution extracted from simultaneous UV-vis measurements. In the second case, the ratio of bundled/isolated carbon nanotubes is obtained unambiguously through proper modeling of the scattering data and cross-validated with the Raman information. The uses of convex constraint analysis (CCA) and two-dimensional correlation analyses (2DCOS and 2DHCOS) are introduced to fully explore the combination of data sets from different techniques and to extract unique insights from the sample. PMID- 24484406 TI - Critical role for the AIM2 inflammasome during acute CNS bacterial infection. AB - Interleukin-1beta (IL-1beta) is essential for eliciting protective immunity during the acute phase of Staphylococcus aureus (S. aureus) infection in the central nervous system (CNS). We previously demonstrated that microglial IL-1beta production in response to live S. aureus is mediated through the Nod-like receptor protein 3 (NLRP3) inflammasome, including the adapter protein ASC (apoptosis-associated speck-like protein containing a caspase-1 recruitment domain), and pro-caspase 1. Here, we utilized NLRP3, ASC, and caspase 1/11 knockout (KO) mice to demonstrate the functional significance of inflammasome activity during CNS S. aureus infection. ASC and caspase 1/11 KO animals were exquisitely sensitive, with approximately 50% of mice succumbing to infection within 24 h. Unexpectedly, the survival of NLRP3 KO mice was similar to wild-type animals, suggesting the involvement of an alternative upstream sensor, which was later identified as absent in melanoma 2 (AIM2) based on the similar disease patterns between AIM2 and ASC KO mice. Besides IL-1beta, other key inflammatory mediators, including IL-6, CXCL1, CXCL10, and CCL2 were significantly reduced in the CNS of AIM2 and ASC KO mice, implicating autocrine/paracrine actions of IL 1beta, as these mediators do not require inflammasome processing for secretion. These studies demonstrate a novel role for the AIM2 inflammasome as a critical molecular platform for regulating IL-1beta release and survival during acute CNS S. aureus infection. PMID- 24484409 TI - Monodisperse antimony nanocrystals for high-rate Li-ion and Na-ion battery anodes: nano versus bulk. AB - We report colloidal synthesis of antimony (Sb) nanocrystals with mean size tunable in the 10-20 nm range and with narrow size distributions of 7-11%. In comparison to microcrystalline Sb, 10 and 20 nm Sb nanocrystals exhibit enhanced rate-capability and higher cycling stability as anode materials in rechargeable Li-ion and Na-ion batteries. All three particle sizes of Sb possess high and similar Li-ion and Na-ion charge storage capacities of 580-640 mAh g(-1) at moderate charging/discharging current densities of 0.5-1C (1C-rate is 660 mA g( 1)). At all C-rates (0.5-20C, e.g. current densities of 0.33-13.2 Ag(1-)), capacities of 20 nm Sb particles are systematically better than for both 10 nm and bulk Sb. At 20C-rates, retention of charge storage capacities by 10 and 20 nm Sb nanocrystals can reach 78-85% of the low-rate value, indicating that rate capability of Sb nanostructures can be comparable to the best Li-ion intercalation anodes and is so far unprecedented for Na-ion storage. PMID- 24484408 TI - Serum complement C4b, fibronectin, and prolidase are associated with the pathological changes of pulmonary tuberculosis. AB - BACKGROUND: Mycobacterium tuberculosis infection can activate the immune system, leading to characteristic pathological changes such as inflammatory granuloma, caseous necrosis, and cavity formation. METHODS: Clinical data of 187 cases of pulmonary tuberculosis (PTB) were analyzed using statistical methods, while serum levels of complement C4b (C4b), fibronectin (FN), and prolidase (PEPD) were detected using the ELISA method among the control, minimal PTB, moderate PTB, and advanced PTB groups. RESULTS: We found significantly higher levels of serum C4b and PEPD (P = 0.018, P = 0.003), and significantly lower levels of serum FN (P < 0.001) in PTB patients. Furthermore, the serum levels of 3 proteins were significantly different among 3 PTB groups. FN level was significantly higher in the moderate PTB group, compared with patients in the minimal and advanced PTB groups (P < 0.05, P < 0.01). PEPD level was significantly higher in the moderate PTB group, compared with the minimal PTB group (P < 0.05). Analysis of clinical data showed that serum albumin, C-reactive protein (CRP), prealbumin, and C4 were significantly higher (P < 0.05), while serum globulin was significantly lower in patients with PTB (P < 0.001). A significant negative correlation was found between C4b and albumin, prealbumin. On the other hand, a significant positive correlation was found between C4b and globulin, CRP, PEPD, as well as between PEPD and CRP (P < 0.05). CONCLUSIONS: Our study showed that C4b, FN, and PEPD are associated with tissue damage, granuloma formation, and cavity formation, respectively, in patients with PTB. The present study provides a new experimental basis to understand the pathogenesis and pathological changes of PTB. PMID- 24484410 TI - Modified inferior oblique transposition considering the equator for primary inferior oblique overaction (IOOA) associated with dissociated vertical deviation (DVD). AB - PURPOSE: Inferior oblique anterior transposition (IOAT) should be done only in patients with inferior oblique overaction (IOOA) and dissociated vertical deviation (DVD) without fusional potential because the procedure can cause anti elevation syndrome. This study reports the results of modified inferior oblique transposition onto the equator in 7 patients diagnosed with infantile exotropia or esotropia associated with IOOA and DVD. METHODS: We performed modified inferior oblique (IO) transposition onto or considering the equator on 7 patients who had infantile exotropia or esotropia associated with IOOA and DVD. Five patients had infantile exotropia, and the other two patients had infantile esotropia. Six patients had undergone bilateral rectus--Bilateral Lateral Rectus (BLR) or Bilateral Medial Rectus (BMR)--recession previously and one patient underwent BLR recession and IO transposition simultaneously. They had more than +1.5 IOOA with DVD in both eyes. IO was transposed vertically onto the equator in this study. The mean distance between the lateral border of the inferior rectus insertion and the equator was 5.6 mm (range: 4.5 to 6.5 mm). Three months after the operation, degree of IOOA and DVD in each eye was evaluated. RESULTS: IOOA and DVD were markedly reduced in all patients (+0.5 ~+1 for IOOA postoperatively). Mild contralateral IOOA was noted but the motility disturbance was successfully corrected in all cases postoperatively. CONCLUSION: Bilateral IO transposition onto the equator could minimize antielevation and corrected IOOA and DVD successfully in patients with infantile exotropia or esotropia. PMID- 24484411 TI - Does one size fit all when it comes to exercise treatment for Achilles tendinopathy? PMID- 24484412 TI - Neck and arm pain: mechanical traction and exercises prove an effective treatment. PMID- 24484413 TI - Fractures through the base of the second and third metacarpals. PMID- 24484414 TI - Integrated shotgun sequencing and bioinformatics pipeline allows ultra-fast mitogenome recovery and confirms substantial gene rearrangements in Australian freshwater crayfishes. AB - BACKGROUND: Although it is possible to recover the complete mitogenome directly from shotgun sequencing data, currently reported methods and pipelines are still relatively time consuming and costly. Using a sample of the Australian freshwater crayfish Engaeus lengana, we demonstrate that it is possible to achieve three-day turnaround time (four hours hands-on time) from tissue sample to NCBI-ready submission file through the integration of MiSeq sequencing platform, Nextera sample preparation protocol, MITObim assembly algorithm and MITOS annotation pipeline. RESULTS: The complete mitochondrial genome of the parastacid freshwater crayfish, Engaeus lengana, was recovered by modest shotgun sequencing (1.2 giga bases) using the Illumina MiSeq benchtop sequencing platform. Genome assembly using the MITObim mitogenome assembler recovered the mitochondrial genome as a single contig with a 97-fold mean coverage (min. = 17; max. = 138). The mitogenome consists of 15,934 base pairs and contains the typical 37 mitochondrial genes and a non-coding AT-rich region. The genome arrangement is similar to the only other published parastacid mitogenome from the Australian genus Cherax. CONCLUSIONS: We infer that the gene order arrangement found in Cherax destructor is common to Australian crayfish and may be a derived feature of the southern hemisphere family Parastacidae. Further, we report to our knowledge, the simplest and fastest protocol for the recovery and assembly of complete mitochondrial genomes using the MiSeq benchtop sequencer. PMID- 24484415 TI - Burden of severe rotavirus disease leading to hospitalization assessed in a prospective cohort study in Sweden. AB - BACKGROUND: The aim of this prospective cohort study was to estimate the burden of severe disease caused by rotavirus-induced gastroenteritis in Swedish children aged < 5 y. METHODS: Rotavirus-positive children admitted to hospitals serving 3 geographical regions with 155,838 children aged < 5 y, were offered inclusion in this 1-year study. Rotavirus strains identified were genotyped using multiplex PCR. Disease progression was documented through interviews and chart reviews. RESULTS: In total, 604 children with rotavirus-induced gastroenteritis were included in the study. Forty-nine of 604 (8.1%) fulfilled the criteria for nosocomial infection. The minimum incidence was 388 per 100,000, with significant variability between study regions, ranging from 280 to 542 per 100,000. In all regions, the peak season occurred in February-April, but the season start varied, with first cases observed in October in the eastern region and December in the northern region. Genotypes identified differed between the regions: G1[P8] was most prevalent in all regions (77%), while the most varied pattern was observed in the western region, with G1[P8] observed in 61%, G4[P8] in 13%, G9[P8] in 10%, G2[P4] in 8%, and G3[P8] in 8% of the children. The median age of hospitalized children was 14 months and the median total duration of diarrhoea was 6.9 days. Sixty-eight percent reported a temperature > 38.5 degrees C upon admission. Complications occurred in > 10% of the children, with hypertonic dehydration (32/604) and seizures (10/604) occurring most frequently. CONCLUSIONS: Rotaviruses may cause severe febrile acute gastroenteritis leading to dehydration requiring acute rehydration in hospital. In addition, further complications occurred in > 10% of hospitalized children. PMID- 24484416 TI - Aspergillus mastoiditis in an immunocompetent patient: a case report and review of the literature. AB - Aspergillus mastoiditis usually occurs in immunocompromised patients. There are a few isolated reports in the literature involving immunocompetent patients. We hereby describe the case of an immunocompetent patient diagnosed with invasive Aspergillus mastoiditis, which was treated successfully, and review the literature pertaining to this condition. The common clinical presentations, putative pathophysiology, and recommended therapy are discussed. PMID- 24484418 TI - Reversible achiral-to-chiral switching of single Mn--phthalocyanine molecules by thermal hydrogenation and inelastic electron tunneling dehydrogenation. AB - Induction of chirality in planar adsorbates by hydrogenation of phthalocyanine molecules on a gold surface is demonstrated. This process merely lowers the molecular symmetry from 4- to 2-fold, but also breaks the mirror symmetry of the entire adsorbate complex (molecule and surface), thus rendering it chiral without any realignment at the surface. Repositioning of single molecules by manipulation with the scanning tunneling microscope (STM) causes interconversion of enantiomers. Dehydrogenation of the adsorbate by means of inelastic electron tunneling restores the mirror symmetry of the adsorbate complex. STM as well as density functional theory (DFT) calculations show that chirality is actually imprinted into the electronic molecular system by the surface, i.e., the lowest unoccupied orbital is devoid of mirror symmetry. PMID- 24484417 TI - Tumor necrosis factor-related apoptosis-inducing ligand regulates hallmark features of airways remodeling in allergic airways disease. AB - Allergic asthma is a complex disease characterized by acute inflammation of the airways that over time leads to the development of significant structural changes termed remodeling. TNF-related apoptosis-inducing ligand (TRAIL) has an important regulatory role in acute allergic airways inflammation through up-regulation of the E3 ubiquitin ligase Midline-1 (MID-1), which limits protein phosphatase 2A (PP2A) activity and downstream dephosphorylation of proinflammatory signaling molecules. The relevance of TRAIL in the development of airways remodeling has yet to be determined. In this study, the lungs of wild-type (WT) BALB/c and Tnfsf10 knockout (TRAIL-/-) mice were chronically exposed to ovalbumin (OVA) for 12 weeks to induce hallmark features of chronic allergic airways disease, including airways hyperreactivity (AHR), subepithelial collagen deposition, goblet cell hyperplasia, and smooth muscle hypertrophy. TRAIL-/- mice were largely protected from the development of AHR and peribronchial eosinophilia and had reduced levels of mast cells in the airways. This correlated with lower levels of cytokines, including IL-4, -5, -10, and -13, and with lower levels of proinflammatory chemokines from cultured cells isolated from the draining lymph nodes. TRAIL-/- mice were also protected from the characteristic features of airways remodeling, including peribronchial fibrosis, smooth muscle hypertrophy, and mucus hypersecretion, which correlated with reduced TGF-beta1 levels in the lungs. MID-1 expression was reduced in TRAIL-/- mice and up-regulated in allergic WT mice. Raising PP2A activity using 2-amino-4-(4-heptyloyphenol)-2-methylbutan-1 ol in allergic WT mice reduced eosinophilia, TGF-beta1, and peribronchial fibrosis. This study shows that TRAIL promotes airways remodeling in an OVA induced model of chronic allergic airways disease. Targeting TRAIL and its downstream proinflammatory signaling pathway involving PP2A may be of therapeutic benefit in reducing the hallmark features of airways remodeling observed in chronic allergic airways inflammation. PMID- 24484419 TI - Radiofrequency catheter ablation can be performed with high success rates and very low complication rates in children and adolescents. AB - AIM: Radiofrequency catheter ablation is a standard treatment for tachyarrhythmia in children. Recently, several centres using cryoenergy for ablation have reported high success and low complication rates, but an increased risk of recurrence of arrhythmia. The aim of this study was to report success, complications and recurrence rates for radiofrequency catheter ablation in children under current conditions. METHODS: A retrospective cohort study of 333 consecutive children undergoing radiofrequency catheter ablation over the last two decades. RESULTS: Radiofrequency catheter ablation was performed successfully in 96.7% of patients, but was significantly less successful in patients with a right anterior or right anterolateral accessory pathway (81.8%). Overall mortality was 0%; there was only one (0.3%) major complication, a pericardial haemorrhage, and only 2.8% of the patients developed minor vascular complications at the puncture site. None of the patients developed a persistent atrioventricular block. Over a median observation time of 4.3 years (0.1; 17.8), recurrence of arrhythmia occurred in 9.3% of all patients, but 50% of children with right lateral accessory pathways. CONCLUSION: Radiofrequency catheter ablation can be performed with high success and very low complication rates in children. Recurrence rates are substantially lower than those reported for cryoablation in the literature. PMID- 24484420 TI - Editorial: Fluorination and fluorinated compounds in medicinal chemistry. PMID- 24484422 TI - Trifluoromethylated heterocycles. AB - This review is a follow-up to the previous chapter, "Monofluorinated Heterocycles" (Topics in Heterocyclic Chemistry, 2012, 33-63), and presents an overview of synthetic chemistry of heterocycles with only one trifluoromethyl group directly attached to the ring (trifluoromethylated heterocycles). Particular attention is given to the modern direct trifluoromethylation methods, including catalytic reactions, organometallic reagents, carbene and hypervalent chemistry, utilization of ionic nucleophilic and electrophilic trifluoromethylating agents, and to other pertinent trends. One of the emphases of the review is compounds with biomedical potential. PMID- 24484421 TI - Decarboxylative fluorination strategies for accessing medicinally- relevant products. AB - Fluorinated organic compounds have a long history in medicinal chemistry, and synthetic methods to access target fluorinated compounds are undergoing a revolution. One powerful strategy for the installation of fluorinecontaining functional groups includes decarboxylative reactions. Benefits of decarboxylative approaches potentially include: 1) readily available substrates or reagents 2) mild reaction conditions; 3) simplified purification. This focus review highlights the applications of decarboxylation strategies for fluorination reactions to access compounds with biomedical potential. The manuscript highlights on two general strategies, fluorination by decarboxylative reagents and by decarboxylation of substrates. Where relevant, examples of medicinally useful compounds that can be accessed using these strategies are highlighted. PMID- 24484423 TI - Trifluoromethyl ethers and -thioethers as tools for medicinal chemistry and drug discovery. AB - The ever-growing number of fluorinated compounds in medicinal and agrochemical applications has led to a remarkable positive emulation in research. The last few years have been the witness of several advances in the search of more effective and user-friendlier methods for the introduction of fluorine as substituent or of fluorinated groups on various structures. In particular, the synthesis of trifluoromethyl ethers and thioethers is receiving increasing attention due to the peculiar properties of the OCF3 and SCF3 groups. This review will cover the different methods for the preparation of trifluoromethyl ethers and thioethers, and will emphasize on the most recent developments, including the use of catalytic methods or of methodologies for trifluoromethylation or trifluoromethanesulfanylation. PMID- 24484424 TI - Recent progress in asymmetric fluorination and trifluoromethylation reactions. AB - All domains of society are impacted by fluorine chemistry. In particular, fluorine plays a key role in medicinal, pharmaceutical and agrochemical sciences in which the synthesis and evaluation of molecules featuring one or more fluorine atoms is nowadays routine in every new discovery and development program. Since the beginning of this century, enantiopure fluorinated molecules are at the forefront of innovation of the tremendous achievements in fluorine chemistry. This review introduces the reader to the recent progress in asymmetric installation of one fluorine and a trifluoromethyl group via nucleophilic, electrophilic and radical diastereo- and enantioselective reactions. PMID- 24484426 TI - Fluorinated mechanism-based inhibitors: common themes and recent developments. AB - Mechanism-based inhibitors are relatively chemically inert compounds that become activated when processed by their target enzyme, leading to covalent enzyme inactivation. Fluorine substitution confers a number of properties that are beneficial to the chemistry of such inhibitors and to their potential use as pharmaceuticals, and indeed several fluorinated mechanism-based inhibitors have made it to clinical usage over the past 50 years. Well-known examples are the 5- fluorouracil metabolite, 5-fluoro-2'-deoxyuridine-5'-monophosphate, which is used in the treatment of cancer, and alpha- difluoromethylornithine for the treatment of African sleeping sickness. As the prevalence of fluorine in medicinal chemistry continues to rise, more and more medically relevant fluorinated mechanism-based inhibitors are being developed with a variety of interesting properties and uses. PMID- 24484427 TI - Fluorinated compounds in medicinal chemistry: recent applications, synthetic advances and matched-pair analyses. AB - In recent years, several new fluorinated functional groups have been employed in medicinal chemistry. This review will highlight some recent developments in this area. We draw attention to useful synthetic advances for the installation of fluorine-containing groups. In addition, we examine the application of some fluorinated functional groups that have recently been gaining popularity in drug discovery. We use matched-pair analysis to assemble aggregate data on the impact on potency of one of these groups, pentafluorosulfanyl, as compared to trifluoromethyl. We further used matchedpair analysis to identify some interesting effects on in vitro ADME properties of replacing H by F on certain moieties. PMID- 24484428 TI - Antibody recognition of fluorinated haptens and antigens. AB - Regarding its many roles for lead optimization and drug development, fluorine will definitely continue to be of major importance in medicinal chemistry. With safe and selective fluorinating agents at hands, the use of fluorinated compounds has become routine in pharmaceutical and material sciences and many of the well appreciated organofluorine inductive effects are now understood. In contrast, our knowledge of how fluorine affects binding affinity and selectivity of proteins and antibodies at the molecular level is by far less advanced. Thus, applications of fluorinated haptens and antigens in the mapping of binding epitopes for various antibodies of diagnostic and therapeutic relevance, as well as for the generation of immune modulating agents and ligands with enhanced T cell affinity are reviewed. Moreover, recent examples of vaccines against cocaine and cancer based on selectively fluorinated antigens with improved antigenic properties are presented. PMID- 24484425 TI - Radiosyntheses using fluorine-18: the art and science of late stage fluorination. AB - Positron (beta(+)) emission tomography (PET) is a powerful, noninvasive tool for the in vivo, three-dimensional imaging of physiological structures and biochemical pathways. The continued growth of PET imaging relies on a corresponding increase in access to radiopharmaceuticals (biologically active molecules labeled with short-lived radionuclides such as fluorine-18). This unique need to incorporate the short-lived fluorine-18 atom (t1/2 = 109.77 min) as late in the synthetic pathway as possible has made development of methodologies that enable rapid and efficient late stage fluorination an area of research within its own right. In this review we describe strategies for radiolabeling with fluorine-18, including classical fluorine-18 radiochemistry and emerging techniques for late stage fluorination reactions, as well as labeling technologies such as microfluidics and solid-phase radiochemistry. The utility of fluorine-18 labeled radiopharmaceuticals is showcased through recent applications of PET imaging in the healthcare, personalized medicine and drug discovery settings. PMID- 24484429 TI - Global overview of the risk linked to the Bacillus cereus group in the egg product industry: identification of food safety and food spoilage markers. AB - AIMS: To evaluate the food safety and spoilage risks associated with psychrotrophic Bacillus cereus group bacteria for the egg product industry and to search for relevant risk markers. METHODS AND RESULTS: A collection of 68 psychrotrophic B. cereus group isolates, coming from pasteurized liquid whole egg products, was analysed through a principal component analysis (PCA) regarding their spoilage and food safety risk potentials. The principal component analysis showed a clear differentiation between two groups within the collection, one half of the isolates representing a safety risk and the other half a spoilage risk. CONCLUSIONS: Relevant risk markers were highlighted by PCA, that is (i) for the food safety risk, the presence of the specific 16S rDNA-1m genetic signature and the ability to grow at 43 degrees C on solid medium and (ii) for the spoilage risk, the presence of the cspA genetic signature. SIGNIFICANCE AND IMPACT OF THE STUDY: This work represents a first step in the development of new diagnostic technologies for the assessment of the microbiological quality of foods likely to be contaminated with psychrotrophic B. cereus group bacteria. PMID- 24484430 TI - Safety system for child pillion riders of underbone motorcycles in Malaysia. AB - OBJECTIVE: Motorcycles are a common mode of transport for most Malaysians. Underbone motorcycles are one of the most common types of motorcycle used in Malaysia due to their affordable price and ease of use, especially in heavy traffic in the major cities. In Malaysia, it is common to see a young or child pillion rider clinging on to an adult at the front of the motorcycle. One of the main issues facing young pillion riders is that their safety is often not taken into account when they are riding on a motorcycle. This article reviews the legally available systems in child safety for underbone motorcycles in Malaysia while putting forth the need for a safety system for child pillion riders. METHOD: Various databases were searched for underbone motorcycle safety systems, related legislation, motorcycle accident data, and types of injuries and these were reviewed to put forth the need for a new safety system. RESULTS: In motorcycle-related accidents, children usually sustain lower limb injuries, which could temporarily or permanently inhibit the child's movements. Accident statistics in Malaysia, especially those involving motorcycles, reflect a pressing need for a reduction in the number of accidents. In Malaysia, the legislation does not go beyond the mandatory use of safety helmets for young pillion users. There is a pressing need for another safety system or mechanism(s) for young pillion riders of underbone motorcycles. Enforcement of laws to enforce the usage of passive safety systems such as helmets and protective gear is difficult in underdeveloped and developing countries. CONCLUSION: The intervention of new technology is inevitable. Therefore, this article highlights the need for a new safety backrest system for child pillion riders to ensure their safety. PMID- 24484431 TI - Next-generation DES: the COMBO dual therapy stent with Genous endothelial progenitor capturing technology and an abluminal sirolimus matrix. AB - In contrast to the use of cytotoxic or cytostatic drugs, a 'pro-healing' approach may have an effect that is beneficial on clinical outcomes. The endothelial progenitor cell capturing stent (ECS) technology accelerates re endothelialization after implantation in animal models and in the human arteriovenous shunt model. Several clinical studies have shown its safety in non complex lesions. However, in the prevention of in-stent restenosis in complex lesions, the ECS is less effective compared with drug-eluting stents. The novel COMBO dual therapy stent is the first stent to combine accelerated endothelial coverage and control of neo-intimal proliferation using a pro-healing technology with an abluminal elution of sirolimus. In the randomized REMEDEE trial, the COMBO dual therapy stent showed similar angiographic and clinical outcomes compared to the paclitaxel-eluting stent. The REMEDEE-OCT study showed equal vascular healing as assessed by optical coherence tomography of the COMBO dual therapy stent compared to the Xience-V stent. PMID- 24484432 TI - Can a brief educational intervention improve sleep and anxiety outcomes for emergency orthopaedic surgical patients? AB - Abstract An educational intervention (EI) is useful in preparing patients for orthopaedic surgery. This quasi-experimental study examined the effect of a brief EI on pain level, anxiety, pain inference on sleep, and sleep satisfaction among Chinese patients undergoing emergency orthopaedic surgery. The intervention group received usual care plus 20-minute EI which comprised a combination of patient education and a breathing relaxation exercise (BRE) whereas the control group received usual care only. The outcomes were evaluated before the EI and at days 2, 4 and 7 post-surgery. One hundred and fifty two participants completed the study. The intervention group had significantly lower pain levels (Brief pain inventory), anxiety levels (The Chinese state Anxiety scale), and lower pain inference scores on mood and better sleep satisfaction. Therefore, a brief EI with a breathing relaxation exercise is a feasible and useful intervention that can improve post-operative outcomes in emergency orthopaedic surgery. PMID- 24484433 TI - Uterine contractility in intrahepatic cholestasis of pregnancy. AB - This study aims to compare uterine activity in intrahepatic cholestasis of pregnancy (ICP) patients vs normal pregnancies, and to determine the relevance of ICP and excessive uterine activity. A total of 59 patients with ICP and 89 with normal pregnancies were selected. Liver function, total bile acids and uterine activity were evaluated; uterine contraction parameters were compared at the specified range of gestational age. Uterine contraction frequency was significantly higher in the third trimester patients with ICP. Aspartate transaminase (AST) appeared to correlate with contraction frequency (r = 0.357, p = 0.006) and Montevideo units (MVUs) (r = 0.349, p = 0.007). For each 50 U/l increase in AST, the hazard ratio of excessive uterine activity was increased by 1.31-fold (95% CI = 1.034-1.663, p = 0.025). The present study demonstrates that third trimester uterine contractility increases in patients with ICP. These findings should be of note, given what is known about obstetric cholestasis, and should prompt further research. PMID- 24484434 TI - Budding yeast as a model organism to study the effects of age. AB - Although a budding yeast culture can be propagated eternally, individual yeast cells age and eventually die. The detailed knowledge of this unicellular eukaryotic species as well as the powerful tools developed to study its physiology makes budding yeast an ideal model organism to study the mechanisms involved in aging. Considering both detrimental and positive aspects of age, we review changes occurring during aging both at the whole-cell level and at the intracellular level. The possible mechanisms allowing old cells to produce rejuvenated progeny are described in terms of accumulation and inheritance of aging factors. Based on the dynamic changes associated with age, we distinguish different stages of age: early age, during which changes do not impair cell growth; intermediate age, during which aging factors start to accumulate; and late age, which corresponds to the last divisions before death. For each aging factor, we examine its asymmetric segregation and whether it plays a causal role in aging. Using the example of caloric restriction, we describe how the aging process can be modulated at different levels and how changes in different organelles might interplay with each other. Finally, we discuss the beneficial aspects that might be associated with age. PMID- 24484435 TI - Running away from unwanted feelings: culture matters. AB - Findings from past research have suggested a link between experiential avoidance and expressive suppression. However, there is emerging evidence showing that the suppression of emotional expression may have different meanings depending on the specific cultural context. Taking a cultural perspective, the present study aimed to examine whether the link between experiential avoidance and expressive suppression is comparable or divergent between two cultural groups [i.e., European Americans (EAs) and Chinese (CH)] with different cultural norms surrounding emotional expression. We hypothesised that the positive association between experiential avoidance and expressive suppression typically found among EAs would be attenuated among CH. Furthermore, the observed cultural group difference in the experiential avoidance-suppression link was hypothesised to be mediated by beliefs in emotional self-control. Data from 224 EA college students and 190 CH college students provided a clear pattern of support for our hypotheses. Implications for current theories on experiential avoidance are discussed. PMID- 24484436 TI - Biotic elicitors effectively increase the glucosinolates content in Brassicaceae sprouts. AB - Several biotic elicitors have been used in Brassicaceae species to enhance their phytochemical quality. However, there is no comparison between elicitors under controlled growth conditions. In order to draw general conclusions about the use of elicitors to enrich ready-to-eat sprouts in health-promoting glucosinolates, the aim of this study was to unveil the effect of the phytohormones methyl jasmonate (25 MUM), jasmonic acid (150 MUM), and salicylic acid (100 MUM), the oligosaccharides glucose (277 mM) and sucrose (146 mM), and the amino acid dl methionine (5 mM) as elicitors over 8-day sprouting Brassica oleraceae (broccoli), Brassica napus (rutabaga cabbage), Brassica rapa (turnip), and Raphanus sativus (China rose radish and red radish), representative species high in glucosinolates previously studied. Results indicated that the phytohormones methyl jasmonate and jasmonic acid and the sugars acted as effective elicitors, increasing the total glucosinolate contents of the sprouts, particularly, glucoraphanin (from 183 to 294 mg.100 g(-1) in MeJA-treated broccoli sprouts), glucoraphenin (from 33 to 124 mg.100 g(-1) and from 167 to 227 mg.100 g(-1) in MeJA-treated China rose radish and red radish, respectively), and glucobrassicin (from 23.4 to 91.0 mg.100 g(-1) and from 29.6 to 186 mg.100 g(-1) in MeJA-treated turnip and rutabaga sprouts, respectively). PMID- 24484437 TI - Female paraphimosis? Management of a large female urethral caruncle, trialling manual reduction. PMID- 24484438 TI - How effective is intralesional injection of triamcinolone acetonide compared with topical treatments in inducing and maintaining hair growth in patients with alopecia areata? A Critically Appraised Topic. PMID- 24484439 TI - Characterization of a novel acetamidobenzoxazolone-based PET ligand for translocator protein (18 kDa) imaging of neuroinflammation in the brain. AB - We developed the novel positron emission tomography (PET) ligand 2-[5-(4 [(11)C]methoxyphenyl)-2-oxo-1,3-benzoxazol-3(2H)-yl]-N-methyl-N-phenylacetamide ([(11)C]MBMP) for translocator protein (18 kDa, TSPO) imaging and evaluated its efficacy in ischemic rat brains. [(11)C]MBMP was synthesized by reacting desmethyl precursor (1) with [(11)C]CH3 I in radiochemical purity of >= 98% and specific activity of 85 +/- 30 GBq/MUmol (n = 18) at the end of synthesis. Biodistribution study on mice showed high accumulation of radioactivity in the TSPO-rich organs, e.g., the lungs, heart, kidneys, and adrenal glands. The metabolite analysis in mice brain homogenate showed 80.1 +/- 2.7% intact [(11)C]MBMP at 60 min after injection. To determine the specific binding of [(11)C]MBMP with TSPO in the brain, in vitro autoradiography and PET studies were performed in an ischemic rat model. In vitro autoradiography indicated significantly increased binding on the ipsilateral side compared with that on the contralateral side of ischemic rat brains. This result was supported firmly by the contrast of radioactivity between the ipsilateral and contralateral sides in PET images. Displacement experiments with unlabelled MBMP or PK11195 minimized the difference in uptake between the two sides. In summary, [(11)C]MBMP is a potential PET imaging agent for TSPO and, consequently, for the up-regulation of microglia during neuroinflammation. PMID- 24484442 TI - Effect of protein environment within cytochrome P450cam evaluated using a polarizable-embedding QM/MM method. AB - Metalloenzymes accommodate cofactors and substrates in their active sites, thereby exerting powerful catalytic effects. Understanding the key elements of the mechanism via which such binding is accomplished using a number of atoms in a protein is a fundamental challenge. To address this issue computationally, here we used mechanical-embedding (ME), electronic-embedding (EE), and polarizable embedding (PE) hybrid quantum mechanics and molecular mechanics (QM/MM) methods and performed an energy decomposition analysis (EDA) of the nonbonding protein environmental effect in the "compound I" intermediate state of cytochrome P450cam. The B3LYP and AMBER99/QP302 methods were used to deal with the QM and MM subsystems, respectively, and the nonbonding interaction energy between these subsystems was decomposed into electrostatic, van der Waals, and polarization contributions. The PE-QM/MM calculation was performed using polarizable force fields that were capable of describing induced dipoles within the MM subsystem, which arose in response to the electric field generated by QM electron density, QM nuclei, and MM point charges. The present QM/MM EDA revealed that the electrostatic term constituted the largest stabilizing interaction between the QM and MM subsystems. When proper adjustment was made for the point charges of the MM atoms located at the QM-MM boundary, EE-QM/MM and PE-QM/MM calculations yielded similar QM electron density distributions, indicating that the MM polarization effect does not have a significant influence on the extent of QM polarization in this particular enzyme system. PMID- 24484440 TI - Persistence of serotonergic enhancement of airway response in a model of childhood asthma. AB - The persistence of airway hyperresponsiveness (AHR) and serotonergic enhancement of airway smooth muscle (ASM) contraction induced by ozone (O3) plus allergen has not been evaluated. If this mechanism persists after a prolonged recovery, it would indicate that early-life exposure to O3 plus allergen induces functional changes predisposing allergic individuals to asthma-related symptoms throughout life, even in the absence of environmental insult. A persistent serotonergic mechanism in asthma exacerbations may offer a novel therapeutic target, widening treatment options for patients with asthma. The objective of this study was to determine if previously documented AHR and serotonin-enhanced ASM contraction in allergic monkeys exposed to O3 plus house dust mite allergen (HDMA) persist after prolonged recovery. Infant rhesus monkeys sensitized to HDMA were exposed to filtered air (FA) (n = 6) or HDMA plus O3 (n = 6) for 5 months. Monkeys were then housed in a FA environment for 30 months. At 3 years, airway responsiveness was assessed. Airway rings were then harvested, and ASM contraction was evaluated using electrical field stimulation with and without exogenous serotonin and serotonin-subtype receptor antagonists. Animals exposed to O3 plus HDMA exhibited persistent AHR. Serotonin exacerbated the ASM contraction in the exposure group but not in the FA group. Serotonin subtype receptors 2, 3, and 4 appear to drive the response. Our study shows that AHR and serotonin-dependent exacerbation of cholinergic-mediated ASM contraction induced by early-life exposure to O3 plus allergen persist for at least 2.5 years and may contribute to a persistent asthma phenotype. PMID- 24484441 TI - A metabolic biosignature of early response to anti-tuberculosis treatment. AB - BACKGROUND: The successful treatment of tuberculosis (TB) requires long-term multidrug chemotherapy. Clinical trials to evaluate new drugs and regimens for TB treatment are protracted due to the slow clearance of Mycobacterium tuberculosis (Mtb) infection and the lack of early biomarkers to predict treatment outcome. Advancements in the field of metabolomics make it possible to identify metabolic profiles that correlate with disease states or successful chemotherapy. However, proof-of-concept of this approach has not been provided for a TB-early treatment response biosignature (TB-ETRB). METHODS: Urine samples collected at baseline and during treatment from 48 Ugandan and 39 South African HIV-seronegative adults with pulmonary TB were divided into discovery and qualification sets, normalized to creatinine concentration, and analyzed by liquid chromatography-mass spectrometry to identify small molecule molecular features (MFs) in individual patient samples. A biosignature that distinguished baseline and 1 month treatment samples was selected by pairwise t-test using data from two discovery sample sets. Hierarchical clustering and repeated measures analysis were applied to additional sample data to down select molecular features that behaved consistently between the two clinical sites and these were evaluated by logistic regression analysis. RESULTS: Analysis of discovery samples identified 45 MFs that significantly changed in abundance at one month of treatment. Down selection using an extended set of discovery samples and qualification samples confirmed 23 MFs that consistently changed in abundance between baseline and 1, 2 and 6 months of therapy, with 12 MFs achieving statistical significance (p < 0.05). Six MFs classified the baseline and 1 month samples with an error rate of 11.8%. CONCLUSIONS: These results define a urine based TB-early treatment response biosignature (TB-ETRB) applicable to different parts of Africa, and provide proof of-concept for further evaluation of this technology in monitoring clinical responses to TB therapy. PMID- 24484443 TI - Preparation of robust biocatalyst based on cross-linked enzyme aggregates entrapped in three-dimensionally ordered macroporous silica. AB - With the aim to provide a highly stable and active biocatalyst, cross-linked enzyme aggregates (CLEAs) of lipase Candida sp. 99-125 were prepared in three dimensionally ordered macroporous silica materials (CLEAs-LP@3DOM-SiO2). Lipase Candida sp. 99-125 was first precipitated in the pores of 3DOM SiO2 (named EAs LP@3DOM-SiO2), and further cross-linked by glutaraldehyde to form CLEAs-LP@3DOM SiO2. Saturated ammonium sulfate was used as a precipitant and glutaraldehyde with a concentration of 0.25% (w/w) was employed as a cross-linker. Compared with EAs-LP@3DOM-SiO2 and native lipase, CLEAs-LP@3DOM-SiO2 exhibited excellent thermal and mechanical stability, and could maintain more than 85% of initial activity after 16 days of shaking in organic and aqueous phase. When CLEAs LP@3DOM-SiO2 was applied in esterification and transesterification reactions, improved activity and reusability were achieved. This method can be used for the immobilization of other enzymes of interest. PMID- 24484444 TI - Defect-dominated doping and contact resistance in MoS2. AB - Achieving low resistance contacts is vital for the realization of nanoelectronic devices based on transition metal dichalcogenides. We find that intrinsic defects in MoS2 dominate the metal/MoS2 contact resistance and provide a low Schottky barrier independent of metal contact work function. Furthermore, we show that MoS2 can exhibit both n-type and p-type conduction at different points on a same sample. We identify these regions independently by complementary characterization techniques and show how the Fermi level can shift by 1 eV over tens of nanometers in spatial resolution. We find that these variations in doping are defect chemistry-related and are independent of contact metal. This raises questions on previous reports of metal-induced doping of MoS2 since the same metal in contact with MoS2 can exhibit both n- and p-type behavior. These results may provide a potential route for achieving low electron and hole Schottky barrier contacts with a single metal deposition. PMID- 24484445 TI - Evaluation of new speed limits in Sweden: a sample survey. AB - OBJECTIVE: The study sought to estimate changes in actual driving speed occurring after new speed limits were introduced in Sweden's rural road network. METHOD: The effects of speed limit changes were estimated for 7 groups of roads of different types and initial speed limits. To study the effects on the entire road network and not only at specific road sites, a sampling survey was conducted in which speed was measured at randomly selected sites before and after the speed limit changes. Systematic sampling was used to select sites that were widely distributed geographically, though the analysis treats the data as if the sites were selected by simple random sampling. The speed of passing vehicles was generally measured using pneumatic tubes stretched across the road. RESULTS: The survey results indicate that the mean car speed increased by 3.5 km/h when the speed limit increased by 10 km/h on motorways and 2 + 1 roads. Reducing the speed limit by 10 km/h on 2 + 1 roads and rural roads with a speed limit of 110 km/h resulted in a 2 km/h decrease in mean speed. On rural roads where the speed limit was lowered from 90 to 80 km/h, the mean speed decreased by 3.3 km/h. These changes are statistically significant. CONCLUSIONS: The present results are in line with previous results indicating an average change in mean speed of approximately 2.5 km/h when the speed limit changes by 10 km/h. The confidence intervals were in most instances fairly small, indicating a sufficiently large number of measurement sites. PMID- 24484450 TI - Antisecretory factor effectively and safely stops childhood diarrhoea: a placebo controlled, randomised study. AB - AIM: We studied the response to high doses of egg yolk containing antisecretory factor (B221(r) , Salovum(r)) in young children with acute diarrhoea, presenting to the Children's Hospital, Lahore, Pakistan. METHODS: In a randomised, placebo controlled trial, 36 children aged 7 to 60 months with acute diarrhoea of unknown aetiology, with mild-to-moderate dehydration, were randomised to the Salovum(r) or placebo groups. Initially, 16 grams of Salovum(r) or ordinary egg yolk (placebo) mixed in oral rehydration salts was given, followed by 8 g every 5 h until recovery. The number and consistency of stools were recorded. RESULTS: The two groups were comparable in age, gender, duration of diarrhoea, hydration and nutritional status, although the proportion with watery stools was higher in the Salovum(r) group (p = 0.04). Reduction in the frequency of stools was seen at 7 versus 18 h (p < 0.0001) and normalising of stool consistency was 10 versus 18 h, p < 0.03) in the Salovum(r) and placebo groups. The overall effect was 35 versus 70 h in the two groups (p = 0.001). No side effects were reported. CONCLUSION: High doses of AF in the form of Salovum(r) effectively and safely reduce childhood diarrhoea of a likely broad aetiology. PMID- 24484451 TI - Biofunctionalized gold nanoparticles for colorimetric sensing of botulinum neurotoxin A light chain. AB - Botulinum neurotoxin is considered as one of the most toxic food-borne substances and is a potential bioweapon accessible to terrorists. The development of an accurate, convenient, and rapid assay for botulinum neurotoxins is therefore highly desirable for addressing biosafety concerns. Herein, novel biotinylated peptide substrates designed to mimic synaptosomal-associated protein 25 (SNAP-25) are utilized in gold nanoparticle-based assays for colorimetric detection of botulinum neurotoxin serotype A light chain (BoLcA). In these proteolytic assays, biotinylated peptides serve as triggers for the aggregation of gold nanoparticles, while the cleavage of these peptides by BoLcA prevents nanoparticle aggregation. Two different assay strategies are described, demonstrating limits of detection ranging from 5 to 0.1 nM of BoLcA with an overall assay time of 4 h. These hybrid enzyme-responsive nanomaterials provide rapid and sensitive detection for one of the most toxic substances known to man. PMID- 24484452 TI - Interstitial pneumonitis caused by everolimus: a case-cohort study in renal transplant recipients. AB - The use of inhibitors of the mammalian target of rapamycin (mTORi) in renal transplantation is associated with many side effects, the potentially most severe being interstitial pneumonitis. Several papers have reported on sirolimus-induced pneumonitis, but less is published on everolimus-induced pneumonitis (EIP). Data on risk factors for contracting EIP are even more scarce. In the present case cohort study in renal transplant recipients (RTR), we aimed to assess the incidence and risk factors of EIP after renal transplantation. This study is a retrospective substudy of a multicenter randomized controlled trial. All patients included in the original trial and treated with prednisolone/everolimus were included in this substudy. RTR who developed EIP were identified as cases. RTR without pulmonary symptoms served as controls. Thirteen of 102 patients (12.7%) developed EIP. We did not find any predisposing factors, especially no correlation with everolimus concentration. On pulmonary CT scan, EIP presented with an organizing pneumonia-like pattern, a nonspecific interstitial pneumonitis like pattern, or both. Median time (range) to the development of EIP after start of everolimus was 162 (38-407) days. In conclusion, EIP is common in RTR, presenting with an organizing pneumonia, a nonspecific interstitial pneumonitis like pattern, or both. No predisposing factors could be identified (Trial registration number: NTR567 (www.trialregister.nl), ISRCTN69188731). PMID- 24484453 TI - Single photons on demand from novel site-controlled GaAsN/GaAsN:H quantum dots. AB - We demonstrate triggered single-photon emission from a novel system of site controlled quantum dots (QDs), fabricated by exploiting the hydrogen-assisted, spatially selective passivation of N atoms in dilute nitride semiconductors. Evidence of this nonclassical behavior is provided by the observation of strong antibunching in the autocorrelation histogram of the QD exciton emission line. This class of site-controlled quantum emitters can be exploited for the fabrication of new hybrid QD-nanocavity systems of interest for future quantum technologies. PMID- 24484454 TI - Genome-wide histone state profiling of fibroblasts from the opossum, Monodelphis domestica, identifies the first marsupial-specific imprinted gene. AB - BACKGROUND: Imprinted genes have been extensively documented in eutherian mammals and found to exhibit significant interspecific variation in the suites of genes that are imprinted and in their regulation between tissues and developmental stages. Much less is known about imprinted loci in metatherian (marsupial) mammals, wherein studies have been limited to a small number of genes previously known to be imprinted in eutherians. We describe the first ab initio search for imprinted marsupial genes, in fibroblasts from the opossum, Monodelphis domestica, based on a genome-wide ChIP-seq strategy to identify promoters that are simultaneously marked by mutually exclusive, transcriptionally opposing histone modifications. RESULTS: We identified a novel imprinted gene (Meis1) and two additional monoallelically expressed genes, one of which (Cstb) showed allele specific, but non-imprinted expression. Imprinted vs. allele-specific expression could not be resolved for the third monoallelically expressed gene (Rpl17). Transcriptionally opposing histone modifications H3K4me3, H3K9Ac, and H3K9me3 were found at the promoters of all three genes, but differential DNA methylation was not detected at CpG islands at any of these promoters. CONCLUSIONS: In generating the first genome-wide histone modification profiles for a marsupial, we identified the first gene that is imprinted in a marsupial but not in eutherian mammals. This outcome demonstrates the practicality of an ab initio discovery strategy and implicates histone modification, but not differential DNA methylation, as a conserved mechanism for marking imprinted genes in all therian mammals. Our findings suggest that marsupials use multiple epigenetic mechanisms for imprinting and support the concept that lineage-specific selective forces can produce sets of imprinted genes that differ between metatherian and eutherian lines. PMID- 24484456 TI - Latent profiles of nonresidential father engagement six years after divorce predict long-term offspring outcomes. AB - This study examined profiles of nonresidential father engagement (i.e., support to the adolescent, contact frequency, remarriage, relocation, and interparental conflict) with their adolescent children (N = 156) 6 to 8 years following divorce and the prospective relation between these profiles and the psychosocial functioning of their offspring, 9 years later. Parental divorce occurred during late childhood to early adolescence; indicators of nonresidential father engagement were assessed during adolescence, and mental health problems and academic achievement of offspring were assessed 9 years later in young adulthood. Three profiles of father engagement were identified in our sample of mainly White, non-Hispanic divorced fathers: Moderate Involvement/Low Conflict, Low Involvement/Moderate Conflict, and High Involvement/High Conflict. Profiles differentially predicted offspring outcomes 9 years later when they were young adults, controlling for quality of the mother-adolescent relationship, mother's remarriage, mother's income, and gender, age, and offspring mental health problems in adolescence. Offspring of fathers characterized as Moderate Involvement/Low Conflict had the highest academic achievement and the lowest number of externalizing problems 9 years later compared to offspring whose fathers had profiles indicating either the highest or lowest levels of involvement but higher levels of conflict. Results indicate that greater paternal psychosocial support and more frequent father-adolescent contact do not outweigh the negative impact of interparental conflict on youth outcomes in the long term. Implications of findings for policy and intervention are discussed. PMID- 24484457 TI - Virulence factors and infection ability of Pseudomonas aeruginosa isolates from a hydropathic facility and respiratory infections. AB - AIMS: To compare the virulence pool and acute infection ability of Pseudomonas aeruginosa isolates from a hydropathic facility, used to treat respiratory conditions by inhalation of untreated natural mineral water, with clinical isolates from respiratory infections. METHODS AND RESULTS: Pseudomonas aeruginosa isolates from a hydropathic facility and from respiratory infections were typed by pulsed-field gel electrophoresis. Nonclonal representatives of each population were selected. 18 virulence-encoding genes were screened by polymerase chain reaction and statistically compared by multiple correspondence analysis. Homogeneous distribution of genes between populations but higher genetic association in aquatic isolates was observed, as well as distinct virulence pool according to location in the water system. Acute infection ability of selected isolates from each population, in Galleria mellonella model, showed lower LD50 of the majority of the hydropathic isolates and significant variations in LD50 of biofilm isolates from different equipments. CONCLUSIONS: Hydrotherapy Ps. aeruginosa isolates present similar virulence to isolates from respiratory infections. Hydrotherapy users may be exposed to different microbiological risks when using different treatment equipments. SIGNIFICANCE AND IMPACT OF THE STUDY: Twenty-one million people use hydropathic facilities in Europe, and the majority present risk factors to pneumonia. This study demonstrates the health risk associated with this practice. Revision of European regulations should be considered. PMID- 24484458 TI - IFN- alpha blocks IL-17 production by peripheral blood mononuclear cells in patients with chronic active hepatitis B Infection. AB - BACKGROUND: IFN-alpha has been used to treat patients with chronic active hepatitis B (CAHB). Recent studies have implicated the IL-23/Th-17 pathway in the pathogenesis of CAHB. In this study, we investigated whether IFN-alpha could affect this pathway. METHODS: Peripheral blood mononuclear cells (PBMCs) obtained from patients with active CAHB (n = 61) and controls (n = 32) were cultured with or without IFN-alpha, and the levels of IL-17 and IL-10 in the supernatants were determined by ELISA, while the frequency of IL-17-expressing cells was measured by FACS. Similar experiments were also conducted with isolated CD4+ T cells from controls. Furthermore, an experiment using an anti-IL-10 antibody was performed to examine the underlying mechanisms of action of IFN-alpha. RESULTS: Both the levels of IL-17 and the frequency of IL-17-expressing cells were significantly higher in the PBMCs from CAHB patients than in the controls. IFN-alpha significantly decreased IL-17 production and the frequency of IL-17-expressing cells in PBMCs from both patients and controls. On the other hand, IFN-alpha increased IL-10 production by PBMCs from patients and controls. Anti-IL-10 antibody was able to neutralize the inhibitory effect of IFN-alpha on IL-17 production by PBMCs. CONCLUSIONS: In vitro experiments showed that IFN-alpha could inhibit IL-17 expression and increase IL-10 production by PBMCs and CD4+ T cells. The inhibitory role of IFN-alpha on IL-17 production was partly mediated by IL-10. PMID- 24484459 TI - Thymol nanoencapsulated by sodium caseinate: physical and antilisterial properties. AB - In this work, thymol was encapsulated in sodium caseinate using high shear homogenization. The transparent dispersion at neutral pH was stable for 30 days at room temperature as determined by dynamic light scattering and atomic force microscopy, which agreed with high zeta potential of nanoparticles. The slightly decreased particle dimension during storage indicates the absence of Ostwald ripening. When molecular binding was studied by fluorescence spectroscopy, thymol was observed to bind with tyrosine and possibly other amino acid residues away from tryptophan of caseins. At pH 4.6 (isoelectric point of caseins), the stabilization of thymol nanoparticles against aggregation was enabled by soluble soybean polysaccharide, resulting from the combined electrostatic and steric repulsions. The encapsulated thymol showed the significantly improved antilisterial activity in milk with different fat levels when compared to thymol crystals, resulting from the quicker mixing and increased solubility in the milk serum. The transparent thymol nanodispersions have promising applications to improve microbiological safety and quality of foods. PMID- 24484460 TI - Editorial: ischemic stroke prevention. PMID- 24484461 TI - Antiplatelets in stroke prevention. AB - Stroke is the second cause of death worldwide and one of the leading cause of disability. Due to the high rate of recurrence, in high risk-patients (eg patients affected by atherosclerotic vascular disease), long-term antiplatelet therapy reduces the risk of vascular events such as non-fatal myocardial infarction, non-fatal stroke, or vascular death. The percentage of reduction of the events can be estimated in approximately 25%. These data justify the directions that are given to us by the current guidelines for prevention of secondary stroke, which recommend the broad use of antiplatelet therapy both for the secondary prevention of stroke in patients with a history of non cardioembolic stroke or TIA. As for the primary prevention indications are less accurate because the absolute benefi ts of aspirin in reducing the happening of vascular events, are generally much lower than in secondary prevention. Although several trials have been investigated use of antiplatelet drugs in ischemic stroke patients, ascertaining the sure benefit, especially in secondary prevention in non-cardioembolic stroke, various issues remains unclarified, and new questions raises with the analysis of the results of available trials. PMID- 24484462 TI - Risk and benefit of statins in stroke secondary prevention. AB - Statin is now recommended in secondary prevention after stroke or transient ischemic attacks to reduce the risk of a new stroke or major cardiovascular events. However, some issues about the extent of the benefit in some stroke patients and the risk of cerebral hemorrhage remain debated. This review shows that statins are significantly effective in decreasing the risk of further strokes despite an increase in the risk of brain hemorrhage. A significant benefit was observed in men and women, in aged patients and possibly to a greater extent in patients with carotid artery stenosis. Intensive statin therapy lowering the LDL-cholesterol beyond the cut-off value of 1.8 mmol/L (70 mg/dl) seems to be more effective than less intensive treatment and without an increased risk of side effects. Overall, statins are well tolerated. Further prospective studies should clarify whether the effect is of the same magnitude in small vessel disease and how to select the patients to reduce the risk of cerebral hemorrhage. PMID- 24484463 TI - Antivitamin K drugs in stroke prevention. AB - Among the different subtypes of ischaemic strokes, almost 20 % are of cardiac origin. Different are the causes of cardioembolic stroke, but the most common is the atrial fibrillation, a supraventricular arrhythmia. Appropriate use of antiplatelet drugs and anticoagulants after transient ischaemic attack (TIA) or ischaemic stroke depends on whether the underlying cause is cardioembolic or of presumed arterial origin. Adequate antiplatelet therapy is recommended for secondary prevention after cerebral ischaemia of presumed arterial origin, whether for patients with TIA and ischaemic stroke of cardiac origin, mainly due to atrial fibrillation. Vitamin K antagonists (VKAs) are highly effective in preventing recurrent ischaemic stroke but have important limitations and are thus underused. Current guidelines still regard Vitamin K Antagonists at INR 2.0-3.0 to be the standard treatment after cerebral ischaemia of cardiac origin for patients who can tolerate them. In this setting antiplatelet therapy provides an alternative when oral anticoagulation is contraindicated or when patient choice or compliance limits choice of therapy, but is much less effective than VKAs. Recent trial data performed with new anticogulants such as the factor Xa and thrombin inhibitors will need to be taken into account, in order to prevent several of the clinical problems actually related to VKAs use. PMID- 24484464 TI - Stroke subtypes and their possible implication in stroke prevention drug strategies. AB - Thrombotic strokes can affect large or small arteries in the brain. Drugs to prevent atherosclerosis complication such as thrombotic strokes, should be drugs able to prevent the accumulation of intravascular fat, reduce vascular proliferation, decrease blood pressure levels with the resulting shear stress, reduce platelet aggregation, and possibly partially or totally reverse carotid plaques. Any of the commonly used antihypertensive drugs lower the incidence of stroke, with larger reductions in BP resulting in larger reductions in risk. Experimental and clinical data suggest that reducing the activity of the renin angiotensin aldosterone system (RAAS) may have beneficial effects beyond the lowering of blood pressure to reduce stroke incidence. In clinical trials, statins consistently reduced the risk of ischemic stroke in patients with or without CHD whereas the data on the effects of other lipid modifying drugs on stroke risk are limited. Approximately 25% of strokes are recurrent. Antiplatelet therapy is indicated for the prevention of recurrent stroke in patients with a history of noncardioembolic minor stroke or transient ischemic attack (TIA). Although clinicians may choose acetylsalicylic acid (ASA) as first-line therapy for secondary prevention, clinical guidelines and evidence from trials suggest that ASA may not be the most effective strategy. A recent review discussed results from clinical trials that have compared the efficacy of ASA monotherapy versus ASA + extended release dipyridamole in secondary stroke prevention. Therefore it is difficult to extrapolate the real benefit of pharmacological prevention strategies against atherothrombotic subtype for excellence in the TOAST classification subtype that is represented by the LAAS and also with regard to lacunar subtype as an expression of lipohyalinosis process which is a further aspect of atherosclerosis. PMID- 24484465 TI - Metabolic syndrome and cardiometabolic risk factors. AB - The metabolic syndrome (MetS) is a cluster of metabolic conditions associated to abdominal obesity, such as elevated blood pressure, impaired glucose tolerance, insulin resistance, elevated triglycerides, and low high-density lipoprotein cholesterol concentrations. Each of the associated conditions has an independent effect, but clustering together they become synergistic, making the risk of developing cardiovascular disease (CVD) greater. There is a big debate as to whether the MetS alone or its associated health conditions are more important for CVD incidence and mortality or whether prevention and/or treatment of the MetS will reduce CVD incidence and mortality. This article reviews the evidence that demonstrates that individuals with the MetS are at increased risk for CVD incidence and mortality and discusses these debated issues. PMID- 24484466 TI - Editorial: atrial fibrillation after coronary surgery: the need for an effective pharmacological prophylaxis. PMID- 24484468 TI - Conjoined twins: experience in an Irish tertiary centre. AB - Conjoined twins are rare, with a reported incidence of 0.19 per 10,000 pregnancies in Europe. We discuss four spontaneous conjoined twin pregnancies presenting to a tertiary referral centre from 2005 to 2011, diagnosed on antenatal dating ultrasound. The cases were monitored closely throughout pregnancy by a multidisciplinary team, with serial surveillance, including ultrasound, fetal echocardiography, magnetic resonance imaging, amniocentesis and further referral to cardiology and paediatric surgery specialists, where indicated. Three female sets were determined antenatally to be not surgically separable; these infants were managed palliatively following a live birth. The male set of conjoined twins was accepted for surgical separation at Great Ormond Street Hospital, London, which was successfully performed electively at 4 months. Of interest, all four parents reside within 20 km of each other, representing a possible cluster of cases. The incidence of conjoined twins in our local population is approximately 0.63 per 10,000 over an 8-year period from 2005 to 2012. This case series highlights a cluster of conjoined twins, managed to viability and delivered in a tertiary referral centre. PMID- 24484467 TI - Parasite clearance following treatment with sulphadoxine-pyrimethamine for intermittent preventive treatment in Burkina-Faso and Mali: 42-day in vivo follow up study. AB - BACKGROUND: Intermittent Preventive Treatment in pregnancy (IPTp) with sulphadoxine-pyrimethamine (SP) is widely used for the control of malaria in pregnancy in Africa. The emergence of resistance to SP is a concern requiring monitoring the effectiveness of SP for IPTp. METHODS: This was an in-vivo efficacy study to determine the parasitological treatment response and the duration of post-treatment prophylaxis among asymptomatic pregnant women receiving SP as part of IPTp in Mali and Burkina-Faso. The primary outcome was the PCR-unadjusted % of patients with parasites recurrence by day 42 defined as a positive diagnostic test by malaria smear at any visit between days 4 and 42. Treatment failure was based on the standard World Health Organization criteria. The therapeutic response was estimated using the Kaplan-Meier curve. RESULTS: A total of 580 women were enrolled in Mali (N=268) and Burkina-Faso (N=312) and followed weekly for 42 days. Among these, 94.3% completed the follow-up. The PCR unadjusted cumulative risk of recurrence by day 42 was 4.9% overall, and 3.2% and 6.5% in Mali and Burkina Faso respectively (Hazard Ratio [HR] =2.14, 95%, CI [0.93-4.90]; P=0.070), and higher among the primi- and secundigravida (6.4%) than multigravida (2.2%, HR=3.01 [1.04-8.69]; P=0.042). The PCR-adjusted failure risk was 1.1% overall (Mali 0.8%, Burkina-Faso 1.4%). The frequencies (95% CI) of the dhfr double and triple mutant and dhps 437 and 540 alleles mutant genotype at enrolment were 24.2% (23.7-25.0), 4.7% (4.4-5.0), and 21.4% (20.8-22.0) and 0.37% (0.29-0.44) in Mali, and 7.1% (6.5-7.7), 44.9% (43.8-46.0) and 75.3% (74.5-76.2) and 0% in Burkina-Faso, respectively. There were no dhfr 164L or dhps 581G mutations. CONCLUSION: SP remains effective at clearing existing infections when provided as IPTp to asymptomatic pregnant women in Mali and Burkina. Continued monitoring of IPTp-SP effectiveness, including of the impact on birth parameters in this region is essential. PMID- 24484469 TI - Prognostic factors for acute myeloid leukaemia in adults--biological significance and clinical use. AB - Acute myeloid leukaemia (AML) is a heterogeneous disease. Prognosis of AML is influenced both by patient-specific as well as disease-specific factors. Age is the most prominent patient-specific risk factor, while chromosomal aberrations are the strongest disease-specific risk factors. For patients with cytogenetically normal AML, prognosis can be specified by mutational status of the genes NPM1, FLT3 and CEBPA. A growing number of recurrent mutations in additional genes have recently been identified, for which the prognostic effect yet has to be determined. Performance status, geriatric assessment, secondary leukaemia following myelodysplastic syndrome or cytotoxic treatment, common laboratory parameters, leukaemic stem cell frequency, bone marrow microenvironment, gene expression levels, epigenetic changes, micro-RNA's as well as kinetics and depth of response to treatment influence prognosis of AML patients. Despite the high number of established risk factors, only few predictive markers exist which can truly aid therapy decisions in patients with AML. PMID- 24484470 TI - Comparative evaluation of three immunochromatographic identification tests for culture confirmation of Mycobacterium tuberculosis complex. AB - BACKGROUND: The rapid identification of acid-fast bacilli recovered from patient specimens as Mycobacterium tuberculosis complex (MTC) is critically important for accurate diagnosis and treatment. A thin-layer immunochromatographic (TLC) assay using anti-MPB64 or anti-MPT64 monoclonal antibodies was developed to discriminate between MTC and non-tuberculosis mycobacteria (NTM). Capilia TB-Neo, which is the improved version of Capilia TB, is recently developed and needs to be evaluated. METHODS: Capilia TB-Neo was evaluated by using reference strains including 96 Mycobacterium species (4 MTC and 92 NTM) and 3 other bacterial genera, and clinical isolates (500 MTC and 90 NTM isolates). M. tuberculosis isolates tested negative by Capilia TB-Neo were sequenced for mpt64 gene. RESULTS: Capilia TB-Neo showed 100% agreement to a subset of reference strains. Non-specific reaction to M. marinum was not observed. The sensitivity and specificity of Capilia TB-Neo to the clinical isolates were 99.4% (99.6% for M. tuberculosis, excluding M. bovis BCG) for clinical MTC isolates and 100% for NTM isolates tested, respectively. Two M. tuberculosis isolates tested negative by Capilia TB-Neo: one harbored a 63-bp deletion in the mpt64 gene and the other possessed a 3,659-bp deletion from Rv1977 to Rv1981c, a region including the entire mpt64 gene. CONCLUSIONS: Capilia TB-Neo is a simple, rapid and highly sensitive test for identifying MTC, and showed better specificity than Capilia TB. However, Capilia TB-Neo still showed false-negative results with mpt64 mutations. The limitation should be recognized for clinical use. PMID- 24484471 TI - Assembly of the bacterial type III secretion machinery. AB - Many bacteria that live in contact with eukaryotic hosts, whether as symbionts or as pathogens, have evolved mechanisms that manipulate host cell behaviour to their benefit. One such mechanism, the type III secretion system, is employed by Gram-negative bacterial species to inject effector proteins into host cells. This function is reflected by the overall shape of the machinery, which resembles a molecular syringe. Despite the simplicity of the concept, the type III secretion system is one of the most complex known bacterial nanomachines, incorporating one to more than hundred copies of up to twenty different proteins into a multi-MDa transmembrane complex. The structural core of the system is the so-called needle complex that spans the bacterial cell envelope as a tripartite ring system and culminates in a needle protruding from the bacterial cell surface. Substrate targeting and translocation are accomplished by an export machinery consisting of various inner membrane embedded and cytoplasmic components. The formation of such a multimembrane-spanning machinery is an intricate task that requires precise orchestration. This review gives an overview of recent findings on the assembly of type III secretion machines, discusses quality control and recycling of the system and proposes an integrated assembly model. PMID- 24484472 TI - Planning for the future: cancer incidence projections in Switzerland up to 2019. AB - BACKGROUND: Projections of the national burden of cancer play a key role in planning cancer control programmes and investments. We present projections of cancer incidence rates and cases for the period up to 2015-2019 in Switzerland. METHODS: Projections were based on cancer incidence data estimated from cancer registries for the 1989-2009 periods and demographic projections of the Federal Statistical Office. Age-specific incidence rates were modelled as a function of age, period-birth cohort using NORDPRED. RESULTS: Up to 2019 the incidence of all cancers combined is expected to decrease slightly for both sexes. Nevertheless, the overall number of cases is predicted to increase. The number of male cancer cases will increase by 30%, from 20005 in 2005-2009 to 25910/year in 2015-2019. For females the number will increase by 20%, from 16913 to 20359/year in 2015 2019. Changes in the population size and structure will be responsible for most of the increase. Among men, the largest increase is observed for melanoma (+54%), thyroid (+45%), non-Hodgkin lymphoma (+43%), and prostate (+37%). Prostate cancer will contribute with 8083 cases, colorectal cancer with 2908 and lung cancer with 2791. For women, cases of lung and oral cavity cancers will increase by +48% and +38%, respectively; those of thyroid by +45% and non-Hodgkin lymphoma by +36%. The sites with the most cancer predicted are breast (5870), colorectal and lung (over 2000 each), melanoma (1341) and corpus uteri (1040). The overall annual cancer burden predicted for 2015-19 is of 46269 new cases in Switzerland. CONCLUSIONS: Substantial investments appear to be needed in Switzerland cancer services to meet and fill absolute increased demand driven by aging population. PMID- 24484474 TI - A novel role of suppressor of cytokine signaling-2 in the regulation of TrkA neurotrophin receptor biology. AB - Suppressor of cytokine signaling-2 (SOCS2) is a regulator of intracellular responses to growth factors and cytokines. Cultured dorsal root ganglia neurons from neonatal mice with increased or decreased SOCS2 expression were examined for altered responsiveness to nerve growth factor (NGF). In the presence of NGF, SOCS2 over-expression increased neurite length and complexity, whereas loss of SOCS2 reduced neurite outgrowth. Neither loss nor gain of SOCS2 expression altered the relative survival of these cells, suggesting that SOCS2 can discriminate between the differentiation and survival responses to NGF. Interaction studies in 293T cells revealed that SOCS2 immunoprecipitates with TrkA and a juxtamembrane motif of TrkA was required for this interaction. SOCS2 also immunoprecipitated with endogenous TrkA in PC12 Tet-On cells. Over expression of SOCS2 in PC12 Tet-On cells increased total and surface TrkA expression. In contrast, dorsal root ganglion neurons which over-expressed SOCS2 did not exhibit significant changes in total levels but an increase in surface TrkA was noted. SOCS2-induced neurite outgrowth in PC12 Tet-On cells correlated with increased and prolonged activation of pAKT and pErk1/2 and required an intact SOCS2 SH2 domain and SOCS box domain. This study highlights a novel role for SOCS2 in the regulation of TrkA signaling and biology. PMID- 24484475 TI - Serous surface papillary adenofibroma of the ovary: impersonator of ovarian malignancy. PMID- 24484473 TI - Modeling organochlorine compounds and the sigma-hole effect using a polarizable multipole force field. AB - The charge distribution of halogen atoms on organochlorine compounds can be highly anisotropic and even display a so-called sigma-hole, which leads to strong halogen bonds with electron donors. In this paper, we have systematically investigated a series of chloromethanes with one to four chloro substituents using a polarizable multipole-based molecular mechanics model. The atomic multipoles accurately reproduced the ab initio electrostatic potential around chloromethanes, including CCl4, which has a prominent sigma-hole on the Cl atom. The van der Waals parameters for Cl were fitted to the experimental density and heat of vaporization. The calculated hydration free energy, solvent reaction fields, and interaction energies of several homo- and heterodimer of chloromethanes are in good agreement with experimental and ab initio data. This study suggests that sophisticated electrostatic models, such as polarizable atomic multipoles, are needed for accurate description of electrostatics in organochlorine compounds and halogen bonds, although further improvement is necessary for better transferability. PMID- 24484476 TI - High-performance adhesives resulting from spontaneous formation of nanogels within miniemulsion particles. AB - Molecular structure plays a crucial role in determining the final properties of pressure-sensitive adhesives. Here, we demonstrate that the molecular structure of polyurethane/(meth)acrylic hybrids synthesized by miniemulsion photopolymerization changes during storage of the dispersion at room temperature because of the spontaneous formation of nanogels by the assembly of polymer chains within the polymer particles. Analysis of the nanogel structure by asymmetric-flow field-flow fractionation allows identification of the molecular structure that provides the unusual combination of high tack adhesion and excellent shear resistance at high temperature [maximum value of the shear adhesion failure temperature (SAFT) test, >210 degrees C]. PMID- 24484477 TI - Identification of Brucella suis from feral swine in selected states in the USA. AB - Serologic tests currently available for brucellosis diagnosis detect antibodies to Brucella but do not distinguish between species of Brucella. Although Brucella suis is known to circulate within various feral swine (Sus scrofa) populations, our objective was to determine the primary species of Brucella circulating in feral swine populations in areas of the US with high brucellosis prevalence. We cultured lymph nodes from 183 feral swine. We identified 22 isolates from 21 animals, and all isolates were genotyped as B. suis. Most isolates were B. suis biovar 1, with the exception of two genetically distinct isolates from one feral swine in Hawaii, which were identified as B. suis biovar 3. Serum from each feral swine was also tested by the fluorescence polarization assay when possible, but only 52% (95% CL = 29.8-74.3) of culture-positive animals were antibody positive. Our results indicate that brucellosis infections in feral swine within the US are typically caused by B. suis. However, improved serologic tests are needed to more accurately determine exposure to Brucella spp. and to monitor disease trends in feral swine populations. PMID- 24484478 TI - The seal tuberculosis agent, Mycobacterium pinnipedii, infects domestic cattle in New Zealand: epidemiologic factors and DNA strain typing. AB - The fur seal (Arctocephalus forsteri), which is abundant in coastal areas of New Zealand, harbors several zoonotic pathogens, including Mycobacterium pinnipedii, a member of the Mycobacterium tuberculosis complex. We describe the microbiology and epidemiology of seven cases of M. pinnipedii infection in beef cattle (Bos primigenius) in coastal areas of New Zealand in 1991-2011. Epidemiologic factors were analyzed on six case farms and a telephone survey of 55 neighboring farms. A DNA-strain typing, using analysis of variable number tandem repeats and the direct repeats (VNTR/DR) of those isolates, was used to compare them to M. bovis isolates commonly found in New Zealand cattle and wildlife. In all cases of M. pinnipedii in cattle, only one animal in the herd was found to be infected. In six of seven cases, the lesions were in the thoracic lymph nodes, indicating a likely aerosol pathway. The lack of multiple cases within a herd suggests that cow-to-cow transmission is uncommon, if it occurs at all. There was no significant difference between case and control farms in distance to sea, herd size, herd type, or farming practice. The odds ratio for access to the beach for cattle on the Chatham Islands was significantly higher than it was for farms on the mainland coastal areas (odds ratio [OR] = 3.6, 95% CI = 1.1-11.4) Likewise, the odds ratio for acquiring tuberculosis was increased when farmers had seen seals on the property (OR = 9, 95% CI = 1.4-56.1 ). In all case farms, cattle had access to seals by beach grazing areas or waterways connecting directly with the ocean. The VNTR/DR typing of the isolates showed some variation in the M. pinnipedii isolates, with only two being identical; all isolates were easily distinguishable from M. bovis isolates. PMID- 24484479 TI - Detection of elephant endotheliotropic herpesvirus infection among healthy Asian elephants (Elephas maximus) in South India. AB - Elephant endotheliotropic herpesviruses (EEHVs) can cause fatal hemorrhagic disease in Asian (Elephas maximus) and African (Loxodonta africana) elephants. Of the seven known EEHV species, EEHV1 is recognized as the most common cause of hemorrhagic disease among Asian elephants in human care worldwide. Recent data collected from ex situ Asian elephants located in multiple North American and European institutions suggest that subclinical EEHV1 infection is common in this population of elephants. Although fatal EEHV1-associated hemorrhagic disease has been reported in range countries, data are lacking regarding the prevalence of subclinical EEHV infections among in situ Asian elephants. We used previously validated EEHV-specific quantitative real-time PCR assays to detect subclinical EEHV infection in three regionally distinct Asian elephant cohorts, totaling 46 in situ elephants in South India, during October and November 2011. Using DNA prepared from trunk washes, we detected EEHV1, EEHV3/4, and EEHV5 at frequencies of 7, 9, and 20% respectively. None of the trunk washes was positive for EEHV2 or 6. At least one EEHV species was detectable in 35% (16/46) of the samples that were screened. These data suggest that subclinical EEHV infection among in situ Asian elephants occurs and that Asian elephants may be natural hosts for EEHV1, EEHV3 or 4, and EEHV5, but not EEHV2 and EEHV6. The methodology described in this study provides a foundation for further studies to determine prevalences of EEHV infection in Asian elephants throughout the world. PMID- 24484480 TI - Patterns of latrine use by raccoons (Procyon lotor) and implication for Baylisascaris procyonis transmission. AB - Mammals often use latrine sites for defecation, yet little is known about patterns of latrine use in many common species such as raccoons (Procyon lotor). Because raccoon latrines are important foci for the transmission of raccoon roundworm (Baylisascaris procyonis), documenting metrics of raccoon latrine use may have public health implications. Although some studies have provided evidence that multiple raccoons visit single latrine sites, exact latrine visitation patterns of raccoons have never been documented. We monitored raccoon latrine usage using proximity-logging collars placed at 15 latrine sites. We found that latrine sites were visited by multiple raccoons (range 1-7), and raccoons visited as many as six latrines during a 2-wk period. No sex differences were found in the number of latrines visited or time spent during visits. We posit that the use of multiple latrine sites by raccoons may lead to the pattern that rates of B. procyonis infection at latrines are greater than infection rates found in individual raccoon fecal samples. This in turn could lead to greater transmission of B. procyonis to paratenic hosts. Our results support the conclusion that raccoon latrines can be major foci for the infection and spread of B. procyonis. PMID- 24484481 TI - Detection of seasonal weight loss and a serologic survey of potential pathogens in wild Pallas' cats (Felis [Otocolobus] manul) of the Daurian Steppe, Russia. AB - We measured seasonal changes in body mass and pathogen exposure in wild Pallas' cats (Felis [Otocolobus] manul) in the Daurian Steppe of Russia in 2010-11. Pallas' cats lost about 30% of body mass over winter. Tests for antibodies to 15 potential pathogens showed that Pallas' cats were exposed to four pathogens. Two of 16 cats had antibodies to Toxoplasma gondii. Two had antibodies to Mycoplasma sp., and one each had antibodies to Influenza A virus and Feline leukemia virus. The percentage of antibody-positive wild Pallas' cats was lower than results reported for other wild felids in the Russian Far East. PMID- 24484482 TI - Phylogenetic comparison of avian haemosporidian parasites from resident and migratory birds in northern Japan. AB - We analyzed blood samples of resident and migratory Japanese birds to evaluate the prevalence and genetic background of avian blood parasites in northern Japan. We used PCR targeting the mitochondrial cytochrome b gene to examine infections of Leucocytozoon, Haemoproteus, and Plasmodium parasites in blood samples from 243 birds of 14 species in three orders (Passeriformes, Columbiformes, and Anseriformes). Sequences were subjected to phylogenetic analysis. The infection rate was 21% in pigeons (Columbiformes) and 17% in Anseriformes. A high infection rate of 93.8% was found in crow species (Passeriformes). Haemoproteus and Plasmodium parasites were detected in only two species. Infected blood samples obtained from seven bird species involved two major clades of Leucocytozoon, which were divided between resident and migratory birds. The parasites, which are genetically distinct from parasites in Japanese resident birds, may have been introduced to Japan by migratory bird species. PMID- 24484483 TI - A rapid field test for sylvatic plague exposure in wild animals. AB - Plague surveillance is routinely conducted to predict future epizootics in wildlife and exposure risk for humans. The most common surveillance method for sylvatic plague is detection of antibodies to Yersinia pestis F1 capsular antigen in sentinel animals, such as coyotes (Canis latrans). Current serologic tests for Y. pestis, hemagglutination (HA) test and enzyme-linked immunosorbent assay (ELISA), are expensive and labor intensive. To address this need, we developed a complete lateral flow device for the detection of specific antibodies to Y. pestis F1 and V antigens. Our test detected anti-F1 and anti-V antibodies in serum and Nobuto filter paper samples from coyotes, and in serum samples from prairie dogs (Cynomys ludovicianus), lynx (Lynx canadensis), and black-footed ferrets (Mustela nigripes). Comparison of cassette results for anti-F1 and anti-V antibodies with results of ELISA or HA tests showed correlations ranging from 0.68 to 0.98. This device provides an affordable, user-friendly tool that may be useful in plague surveillance programs and as a research tool. PMID- 24484484 TI - Health evaluation of free-ranging eastern bettongs (Bettongia gaimardi) during translocation for reintroduction in Australia. AB - Sixty (19 male, 41 female) free-ranging adult eastern bettongs (Bettongia gaimardi) were captured in Tasmania and translocated to the Australian Capital Territory between July 2011 and September 2012 for reintroduction into fenced, predator-proof reserves. The bettongs were anesthetized for physical examination and screened for selected diseases during translocation. Reference ranges for hematologic and biochemical parameters were determined. Two bettongs had detectable antibodies to the alphaherpesviruses macropodid herpesvirus 1 and macropodid herpesvirus 2 by serum neutralization assay. A novel gammaherpesvirus was detected, via PCR, from pooled swabs collected from the nasal, conjunctival, and urogenital tract mucosa of four other bettongs. Sera from 59 bettongs were negative for antibodies to Toxoplasma gondii as assessed by both the modified agglutination test and the direct agglutination test (n = 53) or by the modified agglutination test only (n = 6). Rectal swabs from 14 bettongs were submitted for bacterial culture and all were negative for Salmonella serovars. Ectoparasites identified on the bettongs included fleas (Pygiopsylla zethi, Stephanocircus harrisoni), a louse (Paraheterodoxous sp.), mites (Guntheria cf. pertinax, Haemolaelaps hatteni, a suspected protonymph of Thadeua sp., Cytostethum tasmaniense, Cytostethum intermedium, Cytostethum thetis, Cytostethum wallabia), and ticks (Ixodes cornuatus, Ixodes trichosuri, Ixodes tasmani). An intraerythrocytic organism morphologically consistent with a Theileria species was identified in blood smears from four bettongs. These data provide baseline health and disease information for free-ranging eastern bettongs that can be used for the conservation management of both the source and translocated populations. PMID- 24484486 TI - Sarcocystis canis associated hepatitis in a Steller sea lion (Eumetopias jubatus) from Alaska. AB - Sarcocystis canis infection was associated with hepatitis in a Steller sea lion (Eumetopias jubatus). Intrahepatocellular protozoal schizonts were among areas of necrosis and inflammation. The parasite was genetically identical to S. canis and is the first report in a Steller sea lion, indicating another intermediate host species for S. canis. PMID- 24484485 TI - Dances with anthrax: wolves (Canis lupus) kill anthrax bacteremic plains bison (Bison bison bison) in southwestern Montana. AB - Bacillus anthracis, the cause of anthrax, was recovered from two plains bison (Bison bison bison) cows killed by wolves (Canis lupus) in Montana, USA, without associated wolf mortality in July 2010. This bison herd experienced an epizootic in summer 2008, killing ~ 8% of the herd, the first documented in the region in several decades. No wolf deaths were associated with the 2008 event. Surveillance has continued since 2008, with research, ranch, and wildlife personnel diligent during summer. As part of this, we tested wolf-killed bison and elk (Cervus elaphus) for anthrax during the 2010 summer using lateral flow immunochromatographic assays (LFIA). Two bison cows were positive for protective antigen, confirming active bacteremia. The LFIA results were confirmed with traditional bacteriology recovering viable B. anthracis. No wolf fatalities were associated with the bison deaths, despite consuming the meat. Low-level anthrax occurrence in large, rough terrain landscapes remains difficult to detect, particularly if mortality in the herbivore host is not a consequence of infection. In these instances, surveillance of predators with large home ranges may provide a more sensitive indicator of anthrax emergence or reemergence in such systems. Though speculative, it is also possible that anthrax infection in the bison increased predation risk. These results also suggest B. anthracis remains a threat to wildlife and associated livestock in southwestern Montana. PMID- 24484487 TI - Dermatitis associated with infestation of a trombiculid mite, Leptotrombidium miyajimai, in an Amami rabbit (Pentalagus furnessi). AB - Severe dermatitis caused by trombiculid mite infestation was observed in an Amami rabbit (Pentalagus furnessi). The mite was identified as Leptotrombidium miyajimai. This is the first report of trombiculid mite-associated cutaneous lesions in Amami rabbits and also the first direct evidence of L. miyajimai parasitism of this host species. PMID- 24484488 TI - Assessment of the gastrointestinal helminth fauna of mountain hares (Lepus timidus varronis) from the northwestern Italian Alps, with new records of parasite occurrence. AB - We describe the gastrointestinal parasite community of Lepus timidus varronis, a subspecies of the mountain hare (L. timidus) living in the Alps. Two nematode species are reported for the first time in L. timidus. PMID- 24484489 TI - Molecular evidence for hemotropic Mycoplasma infection in a Japanese badger (Meles meles anakuma) and a raccoon dog (Nyctereutes procyonoides viverrinus). AB - We report detection of hemoplasma in wild Japanese badgers (Meles meles anakuma) and raccoon dogs (Nyctereutes procyonoides viverrinus). Sequence analysis of the entire 16S rRNA genes identified Mycoplasma haemocanis in the raccoon dog sample, and a potential novel Mycoplasma species in the Japanese badger. PMID- 24484490 TI - Season and application rates affect vaccine bait consumption by prairie dogs in Colorado and Utah, USA. AB - Plague, a zoonotic disease caused by the bacterium Yersinia pestis, causes high rates of mortality in prairie dogs (Cynomys spp.). An oral vaccine against plague has been developed for prairie dogs along with a palatable bait to deliver vaccine and a biomarker to track bait consumption. We conducted field trials between September 2009 and September 2012 to develop recommendations for bait distribution to deliver plague vaccine to prairie dogs. The objectives were to evaluate the use of the biomarker, rhodamine B, in field settings to compare bait distribution strategies, to compare uptake of baits distributed at different densities, to assess seasonal effects on bait uptake, and to measure bait uptake by nontarget small mammal species. Rhodamine B effectively marked prairie dogs' whiskers during these field trials. To compare bait distribution strategies, we applied baits around active burrows or along transects at densities of 32, 65, and 130 baits/ha. Distributing baits at active burrows or by transect did not affect uptake by prairie dogs. Distributing baits at rates of >= 65/ha (or >= 1 bait/active burrow) produced optimal uptake, and bait uptake by prairie dogs in the autumn was superior to uptake in the spring. Six other species of small mammals consumed baits during these trials. All four species of tested prairie dogs readily consumed the baits, demonstrating that vaccine uptake will not be an obstacle to plague control via oral vaccination. PMID- 24484491 TI - Mycobacterium pinnipedii in a stranded South American sea lion (Otaria byronia) in Brazil. AB - We report tuberculosis in a stranded South American sea lion (Otaria byronia) in Brazil caused by Mycobacterium pinnipedii, a member of Mycobacterium tuberculosis complex. PMID- 24484492 TI - Evidence of psittacine beak and feather disease virus spillover into wild critically endangered Orange-bellied Parrots (Neophema chrysogaster). AB - We report the recent emergence of a novel beak and feather disease virus (BFDV) genotype in the last remaining wild population of the critically endangered Orange-bellied Parrot (Neophema chrysogaster). This virus poses a significant threat to the recovery of the species and potentially its survival in the wild. We used PCR to detect BFDV in the blood of three psittacine beak and feather disease (PBFD)-affected wild Orange-bellied Parrot fledglings captured as founders for an existing captive breeding recovery program. Complete BFDV genome sequence data from one of these birds demonstrating a 1,993-nucleotide-long read encompass the entire circular genome. Maximum-likelihood (ML) and neighbor joining (NJ) phylogenetic analysis supported the solitary position of this viral isolate in a genetically isolated branch of BFDV. On Rep gene sequencing, a homologous genotype was present in a second wild orange-bellied parrot and the third bird was infected with a distantly related genotype. These viruses have newly appeared in a population that has been intensively monitored for BFDV for the last 13 yr. The detection of two distinct lineages of BFDV in the remnant wild population of Orange-bellied Parrots, consisting of fewer than 50 birds, suggests a role for other parrot species as a reservoir for infection by spillover into this critically endangered species. The potential for such a scenario to contribute to the extinction of a remnant wild animal population is supported by epidemiologic theory. PMID- 24484493 TI - Ljungan virus and an adenovirus in Italian squirrel populations. AB - We report Ljungan virus infection in Eurasian red squirrels (Sciurus vulgaris) for the first time, and extend the known distribution of adenoviruses in both native red squirrels and alien gray squirrels (Sciurus carolinensis) to southern Europe. PMID- 24484495 TI - Chlamydiaceae and Chlamydia-like organisms in free-living small mammals in Europe and Afghanistan. AB - Few data are available on the occurrence of chlamydial infections in wild small mammals. We investigated the significance of free-living small mammals as reservoirs or transmission hosts for microorganisms of the phylum/class Chlamydiae. We obtained 3,664 tissue samples from 911 animals in Switzerland, Germany, Austria, the Czech Republic, and Afghanistan. Samples included internal organs (n = 3,652) and feces (n = 12) from 679 rodents (order Rodentia) and 232 insectivores (order Soricomorpha) and were tested by three TaqMan(r) real-time PCRs specific for members of the family Chlamydiaceae and selected Chlamydia-like organisms such as Parachlamydia spp. and Waddlia spp. Only one of 911 (0.11%) animals exhibited a questionable positive result by Chlamydiaceae-specific real time PCR. Five of 911 animals were positive by specific real-time PCR for Parachlamydia spp. but could not be confirmed by quantitative PCR targeting the Parachlamydia acanthamoebae secY gene (secY qPCR). One of 746 animals (0.13%) was positive by real-time PCR for Waddlia chondrophila. This result was confirmed by Waddlia secY qPCR. This is the first detection of Chlamydia-like organisms in small wildlife in Switzerland. Considering previous negative results for Chlamydiaceae in wild ruminant species from Switzerland, these data suggest that wild small mammals are unlikely to be important carriers or transport hosts for Chamydiaceae and Chlamydia-like organisms. PMID- 24484497 TI - Blood collected on filter paper for wildlife serology: detecting antibodies to Neospora caninum, West Nile virus, and five bovine viruses in reindeer. AB - We compared Nobuto filter paper (FP) whole-blood samples to serum for detecting antibodies to seven pathogens in reindeer (Rangifer tarandus tarandus). Serum and FP samples were collected from captive reindeer in 2008-2009. Sample pairs (serum and FP eluates) were assayed in duplicate at diagnostic laboratories with the use of competitive enzyme-linked immunosorbent assays (cELISAs) for Neospora caninum and West Nile virus (WNV); indirect ELISA (iELISAs) for bovine herpesvirus type 1 (BHV-1), parainfluenza virus type 3 (PI-3), and bovine respiratory syncytial virus (BRSV); and virus neutralization (VN) for bovine viral diarrhea virus (BVDV) types I and II. Assay thresholds were evidence-based values employed by each laboratory. Comparable performance to serum was defined as FP sensitivity and specificity >= 80%. Filter-paper specificity estimates ranged from 92% in the cELISAs for N. caninum and WNV to 98% in the iELISAs for PI-3 and BRSV. Sensitivity was >85% for five tests (most >= 95%) but was insufficient (71-82%) for the PI-3 and BRSV iELISAs. Lowering the threshold for FP samples in these two ELISAs raised sensitivity to >= 87% and reduced specificity slightly (>= 90% in three of the four test runs). Sample size limited the precision of some performance estimates. Based on the criteria of sensitivity and specificity >= 80%, and using adjusted FP thresholds for PI-3 and BRSV, FP sensitivity and specificity were comparable to serum in all seven assays. A potential limitation of FP is reduced sensitivity in tests that require undiluted serum (i.e., N. caninum cELISA and BVDV VNs). Possible toxicity to the assay cell layer in VN requires investigation. Results suggested that cELISA is superior to iELISA for detecting antibodies in FP samples from reindeer and other Rangifer tarandus subspecies. Our findings expand the potential utility of FP sampling from wildlife. PMID- 24484498 TI - Swine infectious agents in Tayassu pecari and Pecari tajacu tissue samples from Brazil. AB - Peccaries and pigs, Tayassuidae and Suidae respectively, diverged approximately one million years ago from a common ancestor. Because these families share some pathogens, peccaries can act as reservoirs of infectious pathogens for domestic and wild swine. We evaluated the presence of swine infectious agents in the spleen and lung tissues of white-lipped peccaries (WLP; Tayassu pecari) and collared peccaries (CP; Pecari tajacu) in Brazil. Samples from 10 adult CP and three WLP, which had been hunted by locals or hit by motor vehicles, were obtained from two free-ranging Brazilian populations. The samples were tested by PCR for Mycoplasma hyopneumoniae, Bordetella bronchiseptica, Pasteurella multocida, porcine circovirus 2 (PCV2), Suid herpesvirus 1 (SuHV-1), and porcine parvovirus (PPV). Positive samples were sequenced. Both species were negative for PPV and B. bronchiseptica and positive for PCV2 and SuHV-1. The lungs of two animals were positive for M. hyopneumoniae and P. multocida. This report is the first demonstration of PCV2 and SuHV-1 swine viruses and of M. hyopneumoniae and P. multocida bacteria in peccaries. One factor contributing to this detection was access to tissue samples, which is uncommon. The role of these infectious agents in peccaries is unknown and further epidemiologic studies should be performed. This study identified several infectious agents in peccaries and highlighted the importance of the tissue type used to detect pathogens. PMID- 24484499 TI - Use of cellulose filter paper to quantify whole-blood mercury in two marine mammals: validation study. AB - Whole blood (WB) is commonly used to assess mercury (Hg) exposure in mammals, but handling and shipping samples collected in remote areas can be difficult. We describe and validate use of cellulose filter paper (FP) for quantifying WB total Hg concentration. Advantec Nobuto(r) FP was soaked with bottlenose dolphin (Tursiops truncatus) or harbor seal (Phoca vitulina) WB (collected between March and July 2012), then air dried. Untreated blood-soaked FPs were analyzed or were eluted with phosphate-buffered saline (PBS) and the eluate and PBS-treated FP Hg concentrations were determined. Total Hg from dried blood-soaked FPs, postelution FPs, and PBS-based eluate were compared with total Hg concentrations from WB. Recovery (on a concentration basis) for soaked FP relative to WB was 0.89 +/- 0.15, for postelution FP was 0.86 +/- 0.13, and for eluate (with a correction factor applied) was 0.96 +/- 0.23. Least-squares linear regressions were fit for soaked papers (y = 1.15x, R(2) = 0.97), postelution FPs (y = 1.22x, R(2) = 0.95), and for eluate with a correction factor applied (y = 0.91x+0.03, R(2) = 0.97) as compared with WB. These data show that FP technology can have a valuable role in monitoring blood Hg concentrations in wildlife populations and FPs have the advantage of being easy to use, store, and transport as compared with WB. PMID- 24484500 TI - Vaccine-induced rabies in a red fox (Vulpes vulpes): isolation of vaccine virus in brain tissue and salivary glands. AB - Oral vaccination campaigns to eliminate fox rabies were initiated in Slovenia in 1995. In May 2012, a young fox (Vulpes vulpes) with typical rabies signs was captured. Its brain and salivary gland tissues were found to contain vaccine strain SAD B19. The Basic Logical Alignment Search Tool alignment of 589 nucleotides determined from the N gene of the virus isolated from the brain and salivary glands of the affected fox was 100% identical to the GenBank reference SAD B19 strain. Sequence analysis of the N and M genes (4,351 nucleotides) showed two nucleotide modifications at position 1335 (N gene) and 3114 (M gene) in the KC522613 isolate identified in the fox compared to SAD B19. PMID- 24484501 TI - Infection of sea lamprey with an unusual strain of Aeromonas salmonicida. AB - The invasion of the Laurentian Great Lakes by the fish-parasitic sea lamprey has led to catastrophic consequences, including the potential introduction of fish pathogens. Aeromonas salmonicida is a bacterial fish pathogen that causes devastating losses worldwide. Currently, there are five accepted subspecies of Aeromonas salmonicida: A. salmonicida subsp. salmonicida, masoucida, smithia, achromogenes, and pectinolytica. We discuss the discovery of an isolate of A. salmonicida that is pathogenic to rainbow trout (Oncorhynchus mykiss) and exhibits unique phenotypic and molecular characteristics. We examined 181 adult sea lamprey (Petromyzon marinus) from the Humber River (Lake Ontario watershed) and 162 adult sea lamprey from Duffins Creek (Lake Ontario watershed) during the spring seasons of 2005-11. Among those, 4/343 (1.2%) sea lamprey were culture positive for A. salmonicida, whereby biochemical and molecular studies identified three of the isolates as A. salmonicida subsp. salmonicida. The remaining isolate (As-SL1) recovered from Humber River sea lamprey was phenotypically more similar to A. salmonicida subsp. salmonicida than to the four other A. salmonicida subspecies. However, unlike A. salmonicida subsp. salmonicida, As-SL1 was sucrose positive, produced an acid-over-acid reaction on triple-sugar iron medium and did not amplify with A. salmonicida subsp. salmonicida specific primers. Phylogenetic analysis based on partial stretches of the 16S rRNA and DNA gyrase subunit B genes further confirmed that the As-SL1 isolate was not A. salmonicida subsp. masoucida, smithia, achromogenes, or pectinolytica. Based on our analyses, the As SL1 isolate is either an unusual strain of A. salmonicida subsp. salmonicida or a novel A. salmonicida subspecies. The four A. salmonicida isolates that were recovered from sea lamprey were pathogenic to rainbow trout in experimental challenge studies. Our study also underscores the potential role of sea lamprey in the ecology of infectious fish diseases. PMID- 24484502 TI - Effects of capture-related injury on postcapture movement of white-tailed deer. AB - Capture-related injuries or deaths of wildlife study subjects pose concerns to researchers, from considerations for animal welfare to inflated project costs and biased data. Capture myopathy (CM) is an injury that can affect an animal's survival <= 30 days postrelease, but is often difficult to detect without close monitoring and immediate necropsy. We evaluated the influence of capture and handling on postcapture movement in an attempt to characterize movement rates of animals suffering from CM. We captured and global positioning system-collared 95 white-tailed deer (Odocoileus virginianus) in central and northern New York during 2006-2008. Six juveniles died within 30 days postrelease, and necropsy reports indicated that two suffered CM (2%). We compared postcapture movement rates for juveniles that survived >30 days with those that died <= 30 days postcapture. Survivor movement rates (43.74 m/hr, SD = 3.53, n = 28) were significantly higher than rates for deer that died within 30 days (17.70 m/hr, SD = 1.57, n = 6) (P<0.01). Additionally, movement rates of juveniles that died of CM (15.1 m/hr) were 5.1 m/hr lower than those for juveniles that died of other causes <= 30 days postcapture (20.2 m/hr), but we were unable to evaluate this statistically because of insufficient sample size. We found no difference in vital rates (temperature, heart rate, respiration rate) during handling between survivors and juveniles that died within 30 days postcapture but observed that survivors were in better body condition at capture. These results suggest that deer likely to die within the 30-day CM window can be identified soon after capture, provided that intensive movement data are collected. Further, even if necropsy reports are unavailable, these animals should be censored from analysis because their behavior is not representative of movements of surviving animals. PMID- 24484503 TI - Locally acquired disseminated histoplasmosis in a northern sea otter (Enhydra lutris kenyoni) in Alaska, USA. AB - Histoplasmosis of local origin has not been reported in humans or wildlife in Alaska, and the disease has never been reported in a free-ranging marine mammal. In 2005 a northern sea otter (Enhydra lutris kenyoni) was found on Kodiak Island, Alaska, at 57 degrees latitude north, far outside the known distribution of Histoplasma capsulatum. The animal died of disseminated histoplasmosis. Microorganisms consistent with Histoplasma sp. were observed on histopathology, and H. capsulatum was identified by PCR and sequencing. We suggest migratory seabirds or aerosol transmission through prevailing winds may have resulted in transmission to the sea otter. PMID- 24484504 TI - Severe hoof disease in free-ranging Roosevelt elk (Cervus elaphus roosevelti) in southwestern Washington, USA. AB - Reports of free-ranging Roosevelt elk (Cervus elaphus roosevelti) with abnormal hooves and lameness increased significantly in southwestern Washington, USA, during winter 2008. In March 2009 we examined five severely affected elk with clinical lameness from this region to characterize hoof lesions, examine the general health of affected elk, and potentially identify etiologies causing hoof disease. Three clinically normal elk from an adjacent but unaffected region were also collected as normal controls. Grossly, affected elk had deformed hooves that were asymmetrical, markedly elongated, and curved or broken, as well as hooves with sloughed horn. Most affected elk had severe sole ulcers with extensive laminar necrosis and pedal osteomyelitis. Histopathology of normal and abnormal hooves identified acute and chronic laminitis in all affected elk and one control elk. Hepatic copper and selenium levels in all affected and control elk were also deficient, and hoof keratin copper levels were low. No significant underlying systemic or musculoskeletal disease was detected in the affected elk, and attempts to isolate bacterial and viral pathogens were unsuccessful. A primary cause of hoof deformity was not definitively identified in this chronically affected group. Studies to identify infectious hoof disease and to characterize acute and subacute lesions are underway. PMID- 24484505 TI - Testing the validity of three submaximal ergometer tests for estimating maximal aerobic capacity in children. AB - AIM: Aerobic capacity in children has been linked to health-related outcomes, but the validity of existing assessment methods is largely unknown. This study evaluated the validity of the Astrand-Rhyming, Woynarowska and Olgun Binyildiz methods. METHODS: Aerobic capacity was estimated from the heart rate response to submaximal ergometer cycling in 62 children aged 11-12 years. Direct measurement of peak oxygen consumption during a graded maximal treadmill test was used as the criterion method. RESULTS: We found low mean bias for age-adjusted Astrand Rhyming data and Woynarowska data, (-14 and 23 mL/min, respectively), low correlation to criterion values (0.81 and 0.74, respectively) and high standard error of estimate (SEE) (340 and 395 mL/min). The Olgun Binyildiz method gave high correlation (0.87) and low SEE (298 mL/min), but large bias (-660 mL/min). All methods underestimated capacity in well-trained children. CONCLUSION: The Olgun Binyildiz method is recommended for following an individual over time, due to its low random error. But for comparing individual data with those obtained using direct measurements, the Woynarowska or Astrand-Rhyming method may be the first choice. However, they all underestimated aerobic capacity in well-trained children. PMID- 24484506 TI - Using the core curriculum on childhood trauma to strengthen clinical knowledge in evidence-based practitioners. AB - The high prevalence of trauma exposure in mental health service-seeking populations, combined with advances in evidence-based practice, competency-based training, common-elements research, and adult learning make this an opportune time to train the mental health workforce in trauma competencies. The Core Curriculum on Childhood Trauma (CCCT) utilizes a five-tiered conceptual framework (comprising Empirical Evidence, Core Trauma Concepts, Intervention Objectives, Practice Elements, and Skills), coupled with problem-based learning, to build foundational trauma knowledge and clinical reasoning skills. We present findings from three studies: Study 1 found that social work graduate students' participation in a CCCT course (N = 1,031) was linked to significant pre-post increases in self-reported confidence in applying core trauma concepts to their clinical work. Study 2 found significant pre-post increases in self-reported conceptual readiness (N = 576) and field readiness (N = 303) among social work graduate students participating in a "Gold Standard Plus" educational model that integrated classroom instruction in core trauma concepts, training in evidence based trauma treatment (EBTT), and implementation of that EBTT in a supervised field placement. Students ranked the core concepts course as an equivalent or greater contributor to field readiness compared to standard EBTT training. Study 3 used qualitative methods to "distill" common elements (35 intervention objectives, 59 practice elements) from 26 manualized trauma interventions. The CCCT is a promising tool for educating "next-generation" evidence-based practitioners who possess competencies needed to implement modularized, individually tailored trauma interventions by strengthening clinical knowledge, clinical reasoning, and familiarity with common elements. PMID- 24484507 TI - Transport measurement of Landau level gaps in bilayer graphene with layer polarization control. AB - Landau level (LL) gaps are important parameters for understanding electronic interactions and symmetry-broken processes in bilayer graphene (BLG). Here we present transport spectroscopy measurements of LL gaps in double-gated suspended BLG with high mobilities in the quantum Hall regime. By using bias as a spectroscopic tool, we measure the gap Delta for the quantum Hall (QH) state at filling factors nu = +/-4 and -2. The single-particle Delta(nu=4) scales linearly with magnetic field B and is independent of the out-of-plane electric field E?. For the symmetry-broken nu = -2 state, the measured values of Delta(nu=-2) are ~1.1 meV/T and 0.17 meV/T for singly gated geometry and dual-gated geometry at E? = 0, respectively. The difference between the two values arises from the E?. dependence of Delta(nu=-2), suggesting that the nu = -2 state is layer polarized. Our studies provide the first measurements of the gaps of the broken symmetry QH states in BLG with well-controlled E? and establish a robust method that can be implemented for studying similar states in other layered materials. PMID- 24484509 TI - Ovarian and hormonal responses to follicular phase administration of investigational metastin/kisspeptin analog, TAK-683, in goats. AB - This study evaluated the effects of follicular phase administration of TAK-683, an investigational metastin/kisspeptin analog, on follicular growth, ovulation, luteal function and reproductive hormones in goats. After confirmation of ovulation by transrectal ultrasonography (Day 0), PGF2alpha (2 mg/head of dinoprost) was administered intramuscularly on Day 10 to induce luteal regression. At 12 h after PGF2alpha administration, intravenous administration of vehicle or 35 nmol (50 MUg)/head of TAK-683 was performed in control (n = 4) and treatment (n = 4) groups, respectively. Blood samples were collected at 6-h intervals for 96 h and then daily until the detection of subsequent ovulation (second ovulation). After the second ovulation, ultrasound examinations and blood sampling were performed every other day or daily until the subsequent ovulation (third ovulation). Mean concentrations of LH and FSH in the treatment group were significantly higher 6 h after TAK-683 treatment than those in the control group (12.0 +/- 10.7 vs 1.0 +/- 0.7 ng/ml for LH, 47.5 +/- 28.2 vs 15.1 +/- 3.4 ng/ml for FSH, p < 0.05), whereas mean concentrations of oestradiol in the treatment group decreased immediately after treatment (p < 0.05) as compared with the control group. Ovulation tended to be delayed (n = 2) or occurred early (n = 1) in the treatment group as compared with the control group. For the second ovulation, ovulatory follicles in the treatment group were significantly smaller in maximal diameter than in the control group (3.8 +/- 0.5 vs 5.4 +/- 0.2 mm, p < 0.05, n = 3). Administration of TAK-683 in the follicular phase stimulates gonadotropin secretion and may have resulted in ovulation of premature follicles in goats. PMID- 24484510 TI - Inhibition of beta-catenin signaling improves alveolarization and reduces pulmonary hypertension in experimental bronchopulmonary dysplasia. AB - Bronchopulmonary dysplasia (BPD) is the most common and serious chronic lung disease of preterm infants. The development of pulmonary hypertension (PH) significantly increases the mortality and morbidity of this disease. beta-Catenin signaling plays an important role in tissue development and remodeling. Aberrant beta-catenin signaling is associated with clinical and experiment models of BPD. To test the hypothesis that inhibition of beta-catenin signaling is beneficial in promoting alveolar and vascular development and preventing PH in experimental BPD, we examined the effects of ICG001, a newly developed pharmacological inhibitor of beta-catenin, in preventing hyperoxia-induced BPD in neonatal rats. Newborn rat pups were randomized at postnatal day (P)2 to room air (RA) + DMSO (placebo), RA + ICG001, 90% FiO2 (O2) + DMSO, or O2 + ICG001. ICG001 (10 mg/kg) or DMSO was given by daily intraperitoneal injection for 14 days during continuous exposure to RA or hyperoxia. Primary human pulmonary arterial smooth muscle cells (PASMCs) were cultured in RA or hyperoxia (95% O2) in the presence of DMSO or ICG001 for 24 to 72 hours. Treatment with ICG001 significantly increased alveolarization and reduced pulmonary vascular remodeling and PH during hyperoxia. Furthermore, administering ICG001 decreased PASMC proliferation and expression of extracellular matrix remodeling molecules in vitro under hyperoxia. Finally, these structural, cellular, and molecular effects of ICG001 were associated with down-regulation of multiple beta-catenin target genes. These data indicate that beta-catenin signaling mediates hyperoxia-induced alveolar impairment and PH in neonatal animals. Targeting beta-catenin may provide a novel strategy to alleviate BPD in preterm infants. PMID- 24484512 TI - Low voltage operating field effect transistors with composite In2O3-ZnO-ZnGa2O4 nanofiber network as active channel layer. AB - Field effect transistors (FETs), incorporating metal-oxide nanofibers as the active conductive channel, have the potential for driving the widespread application of nanowire or nanofiber FETs-based electronics. Here we report on low voltage FETs with integrated electrospun In2O3-ZnO-ZnGa2O4 composite fiber channel layers and high-K dielectric (MgO)0.3-(Bi1.5Zn1.0Nb1.5O7)0.7 gate insulator and compare their performance against FETs utilizing conductive single phase, polycrystalline ZnO or In2O3 channel layers. The polycrystalline In2O3-ZnO ZnGa2O4 composite fibers provide superior performance with high field effect mobility (~7.04 cm2 V(-1) s(-1)), low subthreshold swing (390 mV/dec), and low threshold voltage (1.0 V) combined with excellent saturation, likely resulting from the effective blocking of high current-flow through the In2O3 and ZnO nanocrystallites by the insulating spinel ZnGa2O4 phase. The microstructural evolution of the individual In2O3, ZnO, and ZnGa2O4 phases in composite fibers is clearly observed by high resolution TEM. A systematic examination of channel area coverage, ranging from single fiber to over 90% coverage, demonstrates that low coverage results in relatively low current outputs and reduced reproducibility which we attribute to the difficulty in positioning fibers and fiber length control. On the other hand, those with ~80% coverage exhibited high field effect mobility, high on/off current ratios (>10(5)), and negligible hysteresis following 15 sweep voltage cycles. A special feature of this work is the application of the FETs to modulate the properties of complex polycrystalline nanocomposite channels. PMID- 24484511 TI - Micro-structuring of polycarbonate-urethane surfaces in order to reduce platelet activation and adhesion. AB - In the development of new hemocompatible biomaterials, surface modification appears to be a suitable method in order to reduce the thrombogenetic potential of such materials. In this study, polycarbonate-urethane (PCU) tubes with different surface microstructures to be used for aortic heart valve models were investigated with regard to the thrombogenicity. The surface structures were produced by using a centrifugal casting process for manufacturing PCU tubes with defined casting mold surfaces which are conferred to the PCU surface during the process. Tubes with different structures defined by altering groove widths were cut into films and investigated under dynamic flow conditions in contact with porcine blood. The analysis was carried out by laser scanning microscopy which allowed for counting various morphological types of platelets with regard to the grade of activation. The comparison between plain and shaped PCU samples showed that the surface topography led to a decline of the activation of the coagulation cascade and thus to the reduction of the fibrin synthesis. Comparing different types of structures revealed that smooth structures with a small groove width (d ~ 3 MUm) showed less platelet activation as well as less adhesion in contrast to a distinct wave structure (d ~ 90 MUm). These results prove surface modification of polymer biomaterials to be a suitable method for reducing thrombogenicity and hence give reason for further alterations and improvements. PMID- 24484514 TI - Teaching and learning in implant dentistry: reflecting on achievements and challenges. PMID- 24484513 TI - The development and validation of an LC-MS/MS method for the determination of a new anti-malarial compound (TK900D) in human whole blood and its application to pharmacokinetic studies in mice. AB - BACKGROUND: Malaria is one of the most lethal and life-threatening killer infectious diseases in the world, and account for the deaths of more than half a million people annually. Despite the remarkable achievement made in preventing and eradicating malaria, it still remains a threat to the public health and a burden to the global economy due to the emergence of multiple-drug resistant malaria parasites. Therefore, the need to develop new anti-malarial drugs is crucial. The chemistry department at the University of Cape Town synthesized a number of new CQ-like derivatives (TK-series), and evaluated them for in vitro activity against both CQ-sensitive and -resistant Plasmodium falciparum strains, and for general cytotoxicity against a Chinese Hamster Ovarian (CHO) mammalian cell line. The lead compounds from the TK-series were selected for a comprehensive pharmacokinetic (PK) evaluation in a mouse model. METHODS: A sensitive LC-MS/MS assay was developed for the quantitative determination of TK900D. Multiple reaction monitoring (MRM) in the positive ionization mode was used for detection. The analyte and the internal standard (TK900E) were isolated from blood samples by liquid-liquid extraction with ethyl acetate. Chromatographic separation was achieved with a Phenomenex(r) Kinetex C18 (100 * 2.0 mm id, 2.6 MUm) analytical column, using a mixture of 0.1% formic acid and acetonitrile (50:50; v/v) as the mobile phase. The method was fully validated over concentrations that ranged from 3.910 to 1000 ng/ml, and used to evaluate the PK properties of the lead compounds in a mouse model. RESULTS: The assay was robust, with deviation not exceeding 11% for the intra- and inter-run precision and accuracy. Extraction recovery was consistent and more than 60%. PK evaluation showed that TK900D and TK900E have moderate oral bioavailability of 30.8% and 25.9%, respectively. The apparent half-life ranged between 4 to 6 h for TK900D and 3.6 to 4 h for TK900E. CONCLUSION: The assay was sensitive and able to measure accurately low drug levels from a small sample volume (20 MUl). PK evaluation showed that the oral bioavailability was moderate. Therefore, from a PK perspective, the compounds look promising and can be taken further in the drug development process. PMID- 24484515 TI - Developing implant dentistry education in Europe: the continuum from undergraduate to postgraduate education and continuing professional development. AB - INTRODUCTION: Implant dentistry is a treatment modality which has mainstream clinical practice of comprehensive care, which however is not adequately represented in the undergraduate dental curricula. A consensus workshop organised by ADEE in 2008, set the benchmarks for the knowledge and competences a modern dental practitioner must possess with regard to implant dentistry, as well as defined undergraduate and postgraduate pathways for the acquisition of these competences. Today, 5 years later, there exist several challenges for the implementation of these benchmarks in both undergraduate curricula but also post graduation educational pathways. METHODS: A consensus workshop was organised by ADEE, bringing together 48 opinion leaders, including academic teachers of all disciplines related to implant dentistry, specialists, representatives of relevant scientific and professional associations, as well as industry delegates. The objectives of the workshop were to evaluate the existing scientific literature, reported experience and best practices in order to identify potential and limitations for the implementation of implant dentistry in the undergraduate curriculum, as well produce recommendations for the optimal educational structures for postgraduate programmes and continuing professional development. RESULTS: The scientific committee conducted two European-wide questionnaire surveys to better document the current state of education in implant dentistry. Upon completion of the surveys, reviewers were appointed to produce three scientific review papers, identifying current achievements and future challenges. Finally, during the 3 days of the workshop, all the evidence was reviewed and the main conclusions and recommendations that were adopted by all participants are reported in the present Consensus Paper. CONCLUSIONS: Implementation of implant dentistry in the undergraduate curriculum has improved significantly, but still lags behind the benchmarks set in 2008 and the diversity between institutions remains big. At the post-graduation level, there is currently a wide diversity of courses and pathways towards competences related to implant dentistry and there is at present a great need for quality assurance, as well as standardisation and transparency of the learning outcomes. PMID- 24484516 TI - Contemporary undergraduate implant dentistry education: a systematic review. AB - INTRODUCTION: Consensus reports recommend that students upon graduation should possess a significant level of knowledge and competence in implant dentistry, including basic competences in diagnostics, treatment planning, restorative, straightforward surgical and maintenance procedures. In response, undergraduate curricula need to integrate implant dentistry. This narrative review explores educational programmes in terms of competences, related research and barriers or reflections, regarding implementation in undergraduate curricula. MATERIALS AND METHODS: Publications (2008-2013) were searched systematically in WoS, PubMed and ERIC and screened independently by two authors in four stages: removal of duplicates, title screening, abstract screening and full-text reading. Inclusion criteria encompassed implant dentistry in undergraduate education. RESULTS: Finally, 37 of 420 papers were included. Detailed information regarding programme content, number of participants, staff input, logistics/funding issues is scattered. Theoretical education is predominant, and pre-clinical/clinical training is offered minimally, often carried out in elective programmes. However, selected straightforward cases treated by undergraduates yield positive outcomes with low failure rates, few complications, high patient satisfaction and student appreciation. Barriers to implementing implant dentistry in the undergraduate curriculum include funding issues, limitations in time or staff availability/competence and lack of suitable patients. Overcoming these barriers is worthwhile as experience-based implant education affects future practice as well-informed students propose more restorative alternatives to their patients. CONCLUSION: Although implant dentistry is increasingly integrated in undergraduate curricula, challenges remain in developing strategies to implement existing competence profiles and the extent of experience-based education. To support further advancement, universities should report comprehensively on their implant programmes to allow comparison and reproduction in other environments. PMID- 24484517 TI - Implant dentistry in postgraduate university education. Present conditions, potential, limitations and future trends. AB - INTRODUCTION: In recent years, opportunities for postgraduate university education in implant dentistry have increased significantly, with an increase in both the number but also the complexity of available postgraduate programmes. However, there appears to be a lack of standards directing the learning outcomes of such programmes. METHODS: A scientific literature search was conducted for publications reporting on university programmes within implant dentistry, including description of programmes and evaluation of learning outcomes. A separate Internet search was conducted to collect information on existing university programmes as presented on university websites. RESULTS: Implant dentistry has reached a critical mass of an independent, multidisciplinary and vibrant domain of science, which combines knowledge and discovery from many clinical and basic sciences. Many university programmes conclude with a master's or equivalent degree, but there appears to be a great diversity with regard to duration and learning objectives, as well as targeted skills and competences. The importance of implant dentistry has also increased within established specialist training programmes. There was little indication, however, that the comprehensive aspects of implant dentistry are present in all specialist training programmes where implants are being covered. CONCLUSIONS: Although universities should maintain the options of designing academic programmes as they best see fit, it is imperative for them to introduce some form of transparent and comparable criteria, which will allow the profession and the public to relate the degree and academic credentials to the actual skills and competences of the degree holder. With regard to established specialist training programmes, the interdisciplinary and comprehensive nature of implant dentistry needs to be emphasised, covering both surgical and restorative aspects. Finally, implant dentistry is not, at present, a dental specialty. The profession has not reached a consensus as to whether the introduction of a new recognised specialist field is either necessary or desired. PMID- 24484518 TI - Continuing professional development in implant dentistry in Europe. AB - INTRODUCTION: Training for dental practitioners in implant dentistry ranges from 1- or 2-day short Continuing Professional Development (CPD) courses to certificate/diploma programmes run by universities. In general, the teaching of implant dentistry in Europe lacks structure and standardisation. This paper aims to: (i) identify the current trends in CPD in implant dentistry in Europe; (ii) identify potential and limitations with regards to the design and implementation of CPD activities in implant dentistry; (iii) provide recommendations on the future structure and development of CPD activities in implant dentistry. METHODS: A search of the literature was undertaken in PubMed for manuscripts published in English after 2000 reporting on CPD in dentistry and in implant dentistry in particular. In addition, an electronic survey was conducted, investigating the attitudes towards CPD among a wide group of stakeholders in implant dentistry education. CONCLUSIONS: There is a wide diversity of educational pathways towards achieving competences in implant dentistry through CPD. At present, there is a need for improving the CPD structures in implant dentistry, strengthening the quality assurance and encouraging standardisation and transparency of the learning outcomes. Development of a structured CPD system with clearly defined educational objectives mapped against specific levels of competence is recommended. PMID- 24484519 TI - Implant dentistry education in Europe: 5 years after the Association for Dental Education in Europe consensus report. AB - INTRODUCTION: To promote consensus on implant dentistry university education in Europe, a workshop amongst university teachers and opinion leaders was organised in 2008. As a result, guidelines on both under- and postgraduate education were issued. This study aims to investigate the current status of university teaching of implant dentistry and the impact of the recommendations for teaching and assessment, 5 years after the first consensus. Finally, this report attempts to identify future directions in education within the discipline. MATERIALS AND METHODS: An online survey was distributed amongst 105 academic leaders in implant education in Europe, and 52 questionnaires were returned (response rate 50%). RESULTS: The average amount of implant dentistry in undergraduate curricula has increased to 74 h, compared to 36 h in 2008, and the inclusion of pre-clinical and clinical education has increased. No change occurred with regard to the aimed competence levels. It was suggested that certain implant procedures including surgery should be provided by dentists after attending additional courses, whilst complex treatments will still require specialist training. The 2008 workshop guidelines have been implemented to a varying extent (25-100%) in under- and postgraduate education. Main reported implementation barriers included limited time availability in the curriculum and limited financial/material resources. Future discussions about implant dentistry in Europe should be focused towards integration in current dental curricula, approaches to overcome barriers and the relations with and role of industrial partners. CONCLUSION: Implant dentistry is increasingly integrating in undergraduate dental education. Development of the consensus guidelines in 2008 may have facilitated this process. Nevertheless, further progress is needed on all educational levels to align training of professionals to the growing treatment needs of the population. PMID- 24484520 TI - Current trends and status of continuing professional development in implant dentistry in Europe. AB - INTRODUCTION: Previous surveys have shown that newly graduated dentists, in most European countries, do not obtain adequate theoretical knowledge and, especially, clinical skills in implant dentistry (ID) through their undergraduate education and must therefore acquire knowledge and develop competencies through further postgraduate study. Moreover, clinicians, in general, need to continue to maintain the currency of their competence by undertaking ongoing continuing professional development (CPD). This seems particularly important in ID as techniques, and materials develop rapidly due to advances in biomedical technology. Despite recent developments, CPD in ID remains poorly organised with little standardisation or harmonisation across Europe. The objective of this survey was to explore the current status and trends within CPD education in ID in Europe. MATERIALS AND METHODS: Stakeholders and opinion leaders associated with ID education were invited by email to fill an online questionnaire (closing date: 30th April 2013). Two hundred and forty-seven questionnaires were distributed, and two separate reminders were sent to participants in 38 European countries. The survey contained 14 multiple-choice questions, and the data were collected using SurveyMonkey(c) software, exported in SPSS (Inc, Chicago, IL, USA) format and analysed using descriptive statistics. RESULTS: Two hundred respondents working in 24 countries replied to the survey (response rate of 81% of invitees and 63% of countries surveyed). The results demonstrated a wide divergence in the content and structure of CPD in ID in Europe. CONCLUSIONS: Dentists need CPD to develop their skills and to maintain their competence in ID. There is an urgent need for structured and accredited CPD, which should be readily available to all dentists practising ID. It should have pre-determined learning objectives, delivered by accredited CPD providers and educators, and have assessable outcome measures to ensure the best possible impact on clinical practice and patient safety. PMID- 24484521 TI - Dental implants placed by undergraduate students: clinical outcomes and patients'/students' perceptions. AB - INTRODUCTION: Implant dentistry in undergraduate education is predominantly theoretical or prosthetics oriented. Clinical experience with implant surgery could provide students a better understanding of alternatives for tooth replacements. This study describes an implant dentistry programme for undergraduate students, which included surgical placement of implants. The study presents the clinical outcomes of the programme, patients' satisfaction and students' attitudes/perceptions. It reflects on barriers and problems encountered during implementation and provides suggestions for other institutions. MATERIALS AND METHODS: Thirty-six students placed one implant each for a single tooth replacement after careful radiographic assessment and pre-surgical planning. One stage surgery was performed under one-to-one supervision. Crowns were cemented on individual abutments 3-6 months later. Crestal bone loss was assessed radiographically immediately after surgery, at crown placement and after 1 year of loading. Questionnaires were used to investigate patients' perspectives and students' opinions towards the programme, as well as their perceived level of competence. RESULTS: Thirty-six implants were placed in 27 patients; two (5.6%) failed prior to loading; mean bone loss from time of surgery to crown placement was 1.41 mm and remained unchanged thereafter, reflecting implant success. Overall, patients were satisfied and the majority would repeat the treatment by a student. The students thought it was a valuable experience, although they realised that additional education is necessary to perform implant surgery without supervision. CONCLUSION: Implant placement by undergraduate students resulted in acceptable clinical outcome parameters, patient satisfaction and positive student perceptions. These findings support the further development of clinical implant education in undergraduate dental curricula. PMID- 24484526 TI - Anthropometric specifications, development, and evaluation of EvaRID--a 50th percentile female rear impact finite element dummy model. AB - OBJECTIVES: Whiplash-associated disorders (WADs), or whiplash injuries, due to low-severity vehicle crashes are of great concern in motorized countries and it is well established that the risk of such injuries is higher for females than for males, even in similar crash conditions. Recent protective systems have been shown to be more beneficial for males than for females. Hence, there is a need for improved tools to address female WAD prevention when developing and evaluating the performance of whiplash protection systems. The objective of this study is to develop and evaluate a finite element model of a 50th percentile female rear impact crash test dummy. METHODS: The anthropometry of the 50th percentile female was specified based on literature data. The model, called EvaRID (female rear impact dummy), was based on the same design concept as the existing 50th percentile male rear impact dummy, the BioRID II. A scaling approach was developed and the first version, EvaRID V1.0, was implemented. Its dynamic response was compared to female volunteer data from rear impact sled tests. RESULTS: The EvaRID V1.0 model and the volunteer tests compared well until ~250 ms of the head and T1 forward accelerations and rearward linear displacements and of the head rearward angular displacement. Markedly less T1 rearward angular displacement was found for the EvaRID model compared to the female volunteers. Similar results were received for the BioRID II model when comparing simulated responses with experimental data under volunteer loading conditions. The results indicate that the biofidelity of the EvaRID V1.0 and BioRID II FE models have limitations, predominantly in the T1 rearward angular displacement, at low velocity changes (7 km/h). The BioRID II model was validated against dummy test results in a loading range close to consumer test conditions (EuroNCAP) and lower severity levels of volunteer testing were not considered. CONCLUSIONS: The EvaRID dummy model demonstrated the potential of becoming a valuable tool when evaluating and developing seats and whiplash protection systems. However, updates of the joint stiffness will be required to provide better correlation at lower load levels. Moreover, the seated posture, curvature of the spine, and head position of 50th percentile female occupants needs to be established and implemented in future models. PMID- 24484525 TI - Transcriptomic profiling of TK2 deficient human skeletal muscle suggests a role for the p53 signalling pathway and identifies growth and differentiation factor 15 as a potential novel biomarker for mitochondrial myopathies. AB - BACKGROUND: Mutations in the gene encoding thymidine kinase 2 (TK2) result in the myopathic form of mitochondrial DNA depletion syndrome which is a mitochondrial encephalomyopathy presenting in children. In order to unveil some of the mechanisms involved in this pathology and to identify potential biomarkers and therapeutic targets we have investigated the gene expression profile of human skeletal muscle deficient for TK2 using cDNA microarrays. RESULTS: We have analysed the whole transcriptome of skeletal muscle from patients with TK2 mutations and compared it to normal muscle and to muscle from patients with other mitochondrial myopathies. We have identified a set of over 700 genes which are differentially expressed in TK2 deficient muscle. Bioinformatics analysis reveals important changes in muscle metabolism, in particular, in glucose and glycogen utilisation, and activation of the starvation response which affects aminoacid and lipid metabolism. We have identified those transcriptional regulators which are likely to be responsible for the observed changes in gene expression. CONCLUSION: Our data point towards the tumor suppressor p53 as the regulator at the centre of a network of genes which are responsible for a coordinated response to TK2 mutations which involves inflammation, activation of muscle cell death by apoptosis and induction of growth and differentiation factor 15 (GDF-15) in muscle and serum. We propose that GDF-15 may represent a potential novel biomarker for mitochondrial dysfunction although further studies are required. PMID- 24484527 TI - Temperature-sensitive electrochemical recognition of tryptophan enantiomers based on beta-cyclodextrin self-assembled on poly(L-glutamic acid). AB - A poly(l-glutamic acid)/beta-cyclodextrin (P-l-Glu/beta-CD)-modified glassy carbon electrode (GCE) was prepared by electrochemical polymerization of l glutamic acid on GCE and subsequent self-assembly of beta-CD onto the obtained P l-Glu. Electrochemical recognition of tryptophan (Trp) enantiomers with the P-l Glu/beta-CD was investigated by differential pulse voltammetry (DPV), and the results show that Trp enantiomers can be effectively recognized at the P-l Glu/beta-CD-modified GCE. It is also interesting to find that temperature plays a crucial role in the enantioselective recognition, which is evidenced by the variable-temperature UV spectra of the inclusion complexes of Trp enantiomers and beta-CD. Under optimum conditions, the oxidation peak current ratio of l-Trp to d Trp could reach 2.30, which is attributed to the stereoselectivity of beta-CD to the enantiomeric pair of Trp. PMID- 24484528 TI - The hepatic sinusoid 'classic and contemporary': a report on the 17th international symposium on cells of the hepatic sinusoid (ISCHS). AB - The 17th ISCHS took place in Osaka, Japan, on 23 to 25 September 2013. This symposium focuses on an exchange of views on the structure and function of hepatic sinusoidal cells in addition to their roles in clinical pathophysiology. PMID- 24484529 TI - Physical nature of intermolecular interactions in [BMIM][PF6] ionic liquid. AB - The intermolecular interaction energy in a popular ionic liquid, [BMIM][PF6] is analyzed using the Hybrid Variation-Perturbation Theory approach. The analysis is performed on a sample of configurations from molecular dynamics simulation, instead of minimized structures. The interaction energy components are quantified, showing that the electrostatics is the dominating but not the only important term. It is found that two- and three-body electron delocalization components also contribute to the stabilization of the complexes; however, these interactions vanish beyond the first coordination sphere. The presented study shows a systematic way to obtain the amount of physically meaningful components of the interaction energy, which possibly could be related to macroscopic properties of ionic liquids (e.g., viscosity, melting point) or electron transfer in ionic liquids. PMID- 24484530 TI - Bacterial diversity and antibiotic resistance in water habitats: searching the links with the human microbiome. AB - Water is one of the most important bacterial habitats on Earth. As such, water represents also a major way of dissemination of bacteria between different environmental compartments. Human activities led to the creation of the so-called urban water cycle, comprising different sectors (waste, surface, drinking water), among which bacteria can hypothetically be exchanged. Therefore, bacteria can be mobilized between unclean water habitats (e.g. wastewater) and clean or pristine water environments (e.g. disinfected and spring drinking water) and eventually reach humans. In addition, bacteria can also transfer mobile genetic elements between different water types, other environments (e.g. soil) and humans. These processes may involve antibiotic resistant bacteria and antibiotic resistance genes. In this review, the hypothesis that some bacteria may share different water compartments and be also hosted by humans is discussed based on the comparison of the bacterial diversity in different types of water and with the human-associated microbiome. The role of such bacteria as potential disseminators of antibiotic resistance and the inference that currently only a small fraction of the clinically relevant antibiotic resistome may be known is discussed. PMID- 24484531 TI - 16S rDNA-based metagenomic analysis of dental plaque and lung bacteria in patients with severe acute exacerbations of chronic obstructive pulmonary disease. AB - BACKGROUND AND OBJECTIVE: Acute exacerbations of chronic obstructive pulmonary disease (AE-COPD) are leading causes of mortality in hospital intensive care units. We sought to determine whether dental plaque biofilms might harbor pathogenic bacteria that can eventually cause lung infections in patients with severe AE-COPD. MATERIAL AND METHODS: Paired samples of subgingival plaque biofilm and tracheal aspirate were collected from 53 patients with severe AE COPD. Total bacterial DNA was extracted from each sample individually for polymerase chain reaction amplification and/or generation of bacterial 16S rDNA sequences and cDNA libraries. We used a metagenomic approach, based on bacterial 16S rDNA sequences, to compare the distribution of species present in dental plaque and lung. RESULTS: Analysis of 1060 sequences (20 clones per patient) revealed a wide range of aerobic, anaerobic, pathogenic, opportunistic, novel and uncultivable bacterial species. Species indistinguishable between the paired subgingival plaque and tracheal aspirate samples (97-100% similarity in 16S rDNA sequence) were dental plaque pathogens (Aggregatibacter actinomycetemcomitans, Capnocytophaga sputigena, Porphyromonas gingivalis, Tannerella forsythia and Treponema denticola) and lung pathogens (Acinetobacter baumannii, Klebsiella pneumoniae, Pseudomonas aeruginosa and Streptococcus pneumoniae). Real-time polymerase chain reaction of 16S rDNA indicated lower levels of Pseudomonas aeruginosa and Porphyromonas gingivalis colonizing the dental plaques compared with the paired tracheal aspirate samples. CONCLUSION: These results support the hypothesis that dental bacteria may contribute to the pathology of severe AE COPD. PMID- 24484533 TI - Plasminogen activator inhibitor-1, factor V, factor II and methylenetetrahydrofolate reductase polymorphisms in women with recurrent miscarriage. AB - The present study investigated the association between genetic polymorphisms of selected thrombophilic factors with recurrent miscarriage (RM). The genetic polymorphisms for plasminogen activator inhibitor-1 4G/5G (PAI-1), Factor V Leiden (FVL), Factor II G20210A (FII) and methylenetetrahydrofolate reductase MTHFR C677T were determined in 186 RM women and 129 healthy women. In RM women, the frequency of heterozygosity for PAI-1 5G/4G (31%) was significantly higher than in controls (5G/4G: 22%) whereas no difference was found in the case of homozygosity 4G/4G and 5G/5G. The frequencies of genotype G/A for FVL and FII were significantly higher in RM women (FVL, 10%; FII, 8%) than in controls (FVL, 3%; FII, 2%). No difference was found in the case of MTHFR C677T. The polymorphisms of FVL and FII should be screened in RM women, whereas PAI-1 seems to be weakly associated with RM. The role of MTHFR C677T polymorphisms without hyperhomocysteinemia appears negligible. PMID- 24484532 TI - Influence of sex differences on microRNA gene regulation in disease. AB - Sexual dimorphism is observed in most human diseases. The difference in the physiology and genetics between sexes can contribute tremendously to the disease prevalence, severity, and outcome. Both hormonal and genetic differences between males and females can lead to differences in gene expression patterns that can influence disease risk and course. MicroRNAs have emerged as potential regulatory molecules in all organisms. They can have a broad effect on every aspect of physiology, including embryogenesis, metabolism, and growth and development. Numerous microRNAs have been identified and elucidated to play a key role in cardiovascular diseases, as well as in neurological and autoimmune disorders. This is especially important as microRNA-based tools can be exploited as beneficial therapies for disease treatment and prevention. Sex steroid hormones as well as X-linked genes can have a considerable influence on the regulation of microRNAs. However, there are very few studies highlighting the role of microRNAs in sex biased diseases. This review attempts to summarize differentially regulated microRNAs in males versus females in different diseases and calls for more attention in this underexplored area that should set the basis for more effective therapeutic strategies for sexually dimorphic diseases. PMID- 24484534 TI - NDM-1 Metallo-beta-Lactamase and ArmA 16S rRNA methylase producing Providencia rettgeri clinical isolates in Nepal. AB - BACKGROUND: Drug-resistant Providencia rettgeri producing metallo-beta-lactamase and 16S rRNA methylase has been reported in several countries. We analyzed P. rettgeri clinical isolates with resistance to carbapenems and aminoglycosides in a hospital in Nepal. METHODS: Five clinical isolates of multidrug-resistant P. rettgeri were obtained in a hospital in Nepal. Antimicrobial susceptibilities were determined using the microdilution method and entire genomes were sequenced to determine drug-resistant genes. Epidemiological analysis was performed by pulsed-field gel electrophoresis. RESULTS: Four of the 5 isolates were resistant to carbapenems (imipenem and meropenem), with MICs >=16 mg/L, with the remaining isolate showing intermediate resistance to imipenem, with an MIC of 2 mg/L and susceptibility to meropenem with an MIC <=1 mg/L. All 5 isolates had blaVEB-1. Of the 4 carbapenem-resistant strains, 3 had blaNDM-1 and 1 had blaOXA-72. All isolates were highly resistant to aminoglycosides (MICs >=1,024 mg/L) and harbored armA. As the result of pulsed-field gel electrophoresis pattern analysis in the 5 P. rettgeri isolates, 4 had identical PFGE patterns and the fifth showed 95.7% similarity. CONCLUSIONS: This is the first report describing multidrug resistant P. rettgeri strains harboring blaNDM-1 or blaOXA-72 and armA isolated from patients in Nepal. PMID- 24484535 TI - Voltage-dependent properties of DNA origami nanopores. AB - We show DNA origami nanopores that respond to high voltages by a change in conformation on glass nanocapillaries. Our DNA origami nanopores are voltage sensitive as two distinct states are found as a function of the applied voltage. We suggest that the origin of these states is a mechanical distortion of the DNA origami. A simple model predicts the voltage dependence of the structural change. We show that our responsive DNA origami nanopores can be used to lower the frequency of DNA translocation by 1 order of magnitude. PMID- 24484536 TI - Preparation, characterization and evaluation of novel elastic nano-sized niosomes (ethoniosomes) for ocular delivery of prednisolone. AB - Niosomes embodying ethanol and minimum amount of cholesterol (ethoniosomes) could be promising ocular delivery systems for water soluble and insoluble drugs. This manuscript reports on novel nano-sized elastic niosomes (ethoniosomes) composed of Span 60: cholesterol (7:3 mol/mol) and ethanol, for ocular delivery of prednisolone acetate (Pred A) and prednisolone sodium phosphate (Pred P). These ethoniosomes were prepared with the thin film hydration (TFH) and ethanol injection (EI) methods, characterized for percentage entrapment efficiency (% EE), size, zeta potential, morphology, elasticity, in vitro release and physical stability. Ocular irritation, bioavailability and anti-inflammatory effects were evaluated and compared with the conventional suspension and solution eye drops. The prepared ethoniosomal vesicles (EV) had a Z-average diameter of 267 nm, zeta potential of approximately -40 mV and % change in size after extrusion of 4%. They were physically stable for at least 2 months at 4 degrees C. The prepared EV showed good ocular tolerability using the modified Draize's test and the estimated relative ocular bioavailability for Pred A EV and Pred P EV was 1.54 and 1.75 times greater than that for the suspension and solution eye drops, respectively. The time required for complete healing from the clove oil-induced severe ocular inflammation was reduced to half with Pred A and Pred P EV. More interestingly, the intraocular pressure (IOP) elevation side effect recorded for Pred A and Pred P EV was significantly less than that for the conventional suspension and solution eye drops. PMID- 24484537 TI - STAG2 is a clinically relevant tumor suppressor in pancreatic ductal adenocarcinoma. AB - BACKGROUND: Pancreatic ductal adenocarcinoma (PDA) is a highly lethal cancer characterized by complex aberrant genomes. A fundamental goal of current studies is to identify those somatic events arising in the variable landscape of PDA genomes that can be exploited for improved clinical outcomes. METHODS: We used DNA content flow sorting to identify and purify tumor nuclei of PDA samples from 50 patients. The genome of each sorted sample was profiled by oligonucleotide comparative genomic hybridization and targeted resequencing of STAG2. Transposon insertions within STAG2 in a KRAS (G12D)-driven genetically engineered mouse model of PDA were screened by RT-PCR. We then used a tissue microarray to survey STAG2 protein expression levels in 344 human PDA tumor samples and adjacent tissues. Univariate Kaplan Meier analysis and multivariate Cox Regression analysis were used to assess the association of STAG2 expression relative to overall survival and response to adjuvant therapy. Finally, RNAi-based assays with PDA cell lines were used to assess the potential therapeutic consequence of STAG2 expression in response to 18 therapeutic agents. RESULTS: STAG2 is targeted by somatic aberrations in a subset (4%) of human PDAs. Transposon-mediated disruption of STAG2 in a KRAS (G12D) genetically engineered mouse model promotes the development of PDA and its progression to metastatic disease. There was a statistically significant loss of STAG2 protein expression in human tumor tissue (Wilcoxon-Rank test) with complete absence of STAG2 staining observed in 15 (4.3%) patients. In univariate Kaplan Meier analysis nearly complete STAG2 positive staining (>95% of nuclei positive) was associated with a median survival benefit of 6.41 months (P = 0.031). The survival benefit of adjuvant chemotherapy was only seen in patients with a STAG2 staining of less than 95% (median survival benefit 7.65 months; P = 0.028). Multivariate Cox Regression analysis showed that STAG2 is an independent prognostic factor for survival in pancreatic cancer patients. Finally, we show that RNAi-mediated knockdown of STAG2 selectively sensitizes human PDA cell lines to platinum-based therapy. CONCLUSIONS: Based on these iterative findings we propose that STAG2 is a clinically significant tumor suppressor in PDA. PMID- 24484538 TI - Preclinical drug metabolism and pharmacokinetics, and prediction of human pharmacokinetics and efficacious dose of the investigational Aurora A kinase inhibitor alisertib (MLN8237). AB - Alisertib (MLN8237) is an investigational potent Aurora A kinase inhibitor currently under clinical trials for hematological and nonhematological malignancies. Nonclinical investigation showed that alisertib is a highly permeable compound with high plasma protein binding, low plasma clearance, and moderate volume of distribution in rats, dogs, monkeys and chimpanzees. Consistent with the above properties, the oral bioavailability in animals was greater than 82%. The predicted human oral pharmacokinetic (PK) profile was constructed using allometric scaling of plasma clearance and volume of distribution in the terminal phase from animals. The chimpanzee PK profiles were extremely useful to model absorption rate constant, which was assumed to be similar to that in humans, based on the fact that chimpanzees are phylogenetically closest to humans. The human plasma clearance was projected to be low of 0.12 L/hr/kg, with half-life of approximately 10 hr. For human efficacious dose estimation, the tumor growth inhibition as a measure of efficacy (E) was assessed in HCT116 xenograft mice at several oral QD or BID dose levels. Additionally, subcutaneous mini-pump infusion studies were conducted to assess mitotic index in tumor samples as a pharmacodynamic (PD) marker. PK/PD/E modeling showed that for optimal efficacy and PD in the xenograft mice maintaining a plasma concentration exceeding 1 uM for at least 8-12 hr would be required. These values in conjunction with the projected human PK profile estimated the optimal oral dose of approximately 103 mg QD or 62.4 mg BID in humans. Notably, the recommended Phase 2 dose being pursued in the clinic is close to the projected BID dose. PMID- 24484539 TI - Comparison of catalytic properties of cytochromes P450 3A4 and 3A5 by molecular docking simulation. AB - To investigate the reported differences in catalytic activities of cytochromes P450 (CYP or P450) 3A4 and 3A5, molecular docking studies were conducted of the interactions of 13 compounds with active sites of the reported three-dimensional structure of CYP3A4 and the modeled structure of CYP3A5. The primary sequence of human CYP3A5 was aligned with that of human CYP3A4 (1TQN) using threedimensional modeling software. Docking simulations were carried out after the energy of the CYP3A4 and CYP3A5 structures had been minimized. Kinetic parameters for the substrate oxidations were taken from the literature. Among the substrates that are preferably metabolized by CYP3A4, including carebastine, itraconazole, haloperidol, and fluvastatin, the former three compounds were found to closely dock to the heme region of CYP3A4 but not to that of CYP3A5. The ligand-CYP3A5 interaction energies (U values) for vincristine, R- and S-verapamil, and beta endosulfan were considerably lower than the corresponding ligand-CYP3A4 interaction energies; these substrates also had lower reported Michaelis constants (km) for CYP3A5 than for CYP3A4. Despite higher CYP3A5 km values for alpha-endosulfan and estradiol, the CYP3A5 U value for estradiol was lower than that for CYP3A4. No marked differences of U values between CYP3A4 and CYP3A5 were observed for midazolam and triazolam, and comparable km values for the oxidations of these two substrates have been reported for CYP3A4 and CYP3A5. Molecular docking simulation could partly explain the differences of the affinities (km) of the substrates for CYP3A4 and CYP3A5 based on the accessibility of substrates to the heme moiety of CYP3A molecules. PMID- 24484540 TI - Use of a three-band HRP2/pLDH combination rapid diagnostic test increases diagnostic specificity for falciparum malaria in Ugandan children. AB - BACKGROUND: Rapid diagnostic tests (RDTs) for malaria provide a practical alternative to light microscopy for malaria diagnosis in resource-limited settings. Three-band RDTs incorporating two parasite antigens may have enhanced diagnostic specificity, relative to two-band RDTs with a single parasite antigen (typically histidine-rich protein 2 [HRP2]). METHODS: Phase 1: 2,000 children, two months to five years of age, admitted to a referral hospital in Jinja, Uganda, with acute febrile illness were enrolled. A WHO highly rated three-band RDT was compared to light microscopy of thick peripheral blood films read by local expert microscopists.Phase 2: the three-band RDT was used as a screening tool for inclusion of patients in a clinical trial, and subjects with three positive RDT bands were tested by microscopy using blood samples drawn in parallel. Discordant results were adjudicated by PCR. RESULTS: Phase 1: 1,648 children had both a RDT and peripheral blood smear performed. The specificity of a RDT with all three bands positive was 82% (95% CI: 79-85%) compared to 62% (95% CI: 59-66%) for HRP2 alone. The sensitivity was 88% (95% CI: 85-89%) and 94% (95% CI: 92-95%) for three-band positive RDT and HRP2 antigen, respectively. 119 patients (7.2%) had a positive HRP2 band, but negative parasite lactate dehydrogenase (pLHD) band and negative peripheral smear, and 72 (61%) of these had received pre-treatment with anti-malarials, suggesting a false positive HRP2 result (p = 0.002).Phase 2: the positive predictive value (PPV) of the three-band RDT was 94% (95% CI 89%-97%) using microscopy as the reference standard. However, microscopy-discordant results were shown to be positive for P. falciparum by PCR in all cases, suggesting that the PPV was in fact higher. CONCLUSION: The pLDH antigen on three-band RDTs, used in combination with HRP2, provides added diagnostic specificity for malaria parasitaemia and may be useful to distinguish acute infection from recently treated infection. In situations where diagnostic specificity is desirable (e.g., for selection of malaria-infected participants in clinical trials), a three-band RDT should be considered in a sub-Saharan African setting. PMID- 24484541 TI - Targeted rehabilitation to improve outcome after total knee replacement (TRIO): study protocol for a randomised controlled trial. AB - BACKGROUND: Approximately 20% of patients are not satisfied with the outcome of total knee replacement, great volumes of which are carried out yearly. Physiotherapy is often provided by the NHS to address dysfunction following knee replacement; however the efficacy of this is unknown. Although clinically it is accepted that therapy is useful, provision of physiotherapy to all patients post operatively does not enhance outcomes at one year. No study has previously assessed the effect of targeting therapy to individuals struggling to recover in the early post-operative phase.The aim of the TRIO study is to determine whether stratifying care by targeting physiotherapy to those individuals performing poorly following knee replacement is effective in improving the one year outcomes. We are also investigating whether the structure of the physiotherapy provision itself influences outcomes. METHODS/DESIGN: The study is a multi-centre prospective randomised controlled trial (RCT) of patients undergoing primary total knee replacement, with treatment targeted at those deemed most susceptible to gain from it. Use of the national PROMS programme for pre-operative data collection allows us to screen all patients at initial post-operative clinical review, and recruit only those deemed to be recovering slowly.We aim to recruit 440 patients through various NHS orthopaedic centres who will undergo six weeks of physiotherapy. The intervention will be either 'intensive' involving both hospital and home-based functional exercise rehabilitation, or 'standard of care' consisting of home exercises. Patients will be randomised to either group using a web-based system. Both groups will receive pre and post-intervention physiotherapy review. Patients will be followed-up to one year post-operation. The primary outcome measure is the Oxford Knee Score. Secondary outcomes are patient satisfaction, functional ability, pain scores and cost-effectiveness. TRIAL REGISTRATION: Current Controlled Trials ISRCTN23357609. ClinicalTrials.gov NCT01849445. PMID- 24484542 TI - High response rate but short-term effect of romiplostim in paediatric refractory chronic immune thrombocytopenia. PMID- 24484543 TI - RNA sequencing read depth requirement for optimal transcriptome coverage in Hevea brasiliensis. AB - BACKGROUND: One of the concerns of assembling de novo transcriptomes is determining the amount of read sequences required to ensure a comprehensive coverage of genes expressed in a particular sample. In this report, we describe the use of Illumina paired-end RNA-Seq (PE RNA-Seq) reads from Hevea brasiliensis (rubber tree) bark to devise a transcript mapping approach for the estimation of the read amount needed for deep transcriptome coverage. FINDINGS: We optimized the assembly of a Hevea bark transcriptome based on 16 Gb Illumina PE RNA-Seq reads using the Oases assembler across a range of k-mer sizes. We then assessed assembly quality based on transcript N50 length and transcript mapping statistics in relation to (a) known Hevea cDNAs with complete open reading frames, (b) a set of core eukaryotic genes and (c) Hevea genome scaffolds. This was followed by a systematic transcript mapping process where sub-assemblies from a series of incremental amounts of bark transcripts were aligned to transcripts from the entire bark transcriptome assembly. The exercise served to relate read amounts to the degree of transcript mapping level, the latter being an indicator of the coverage of gene transcripts expressed in the sample. As read amounts or datasize increased toward 16 Gb, the number of transcripts mapped to the entire bark assembly approached saturation. A colour matrix was subsequently generated to illustrate sequencing depth requirement in relation to the degree of coverage of total sample transcripts. CONCLUSIONS: We devised a procedure, the "transcript mapping saturation test", to estimate the amount of RNA-Seq reads needed for deep coverage of transcriptomes. For Hevea de novo assembly, we propose generating between 5-8 Gb reads, whereby around 90% transcript coverage could be achieved with optimized k-mers and transcript N50 length. The principle behind this methodology may also be applied to other non-model plants, or with reads from other second generation sequencing platforms. PMID- 24484544 TI - Oriented covalent immobilization of esterase BioH on hydrophilic-modified Fe3O4 nanoparticles. AB - The esterase BioH from Escherichia coli was covalently immobilized onto the surface of the functional magnetic nanosupport in an oriented manner. The surface of the Fe3O4 nanosupport was modified with acyl azide groups or both acyl azide groups and hydroxyl groups. The protein loading of the support was increased from 55 to 99 mg/g by an improvement in hydrophilicity, and the activity retention of the immobilized esterase on the nanosupport was improved by 40% after hydrophilic modification (30% and 70% of the free BioH, respectively). For the BioH immobilized on the hydrophilic-modified nanosupport, the recovery activity remained 80% of the original activity after 10 times of recycling. The catalytic kinetics and thermo-/pH-stability of the immobilized esterase BioH were also determined and compared with those of the free enzyme. The comparatively high activity retention, improved thermo-/pH-stability, and good reusability of the immobilized enzyme indicate that oriented covalent immobilization is an efficient method for immobilizing esterase BioH. PMID- 24484545 TI - Moderating influences of baseline activity levels in school physical activity programming for children: the Ready for Recess project. AB - BACKGROUND: A limitation of traditional outcome studies from behavioral interventions is the lack of attention given to evaluating the influence of moderating variables. This study examined possible moderation effect of baseline activity levels on physical activity change as a result of the Ready for Recess intervention. METHODS: Ready for Recess (August 2009-September 2010) was a controlled trial with twelve schools randomly assigned to one of four conditions: control group, staff supervision, equipment availability, and the combination of staff supervision and equipment availability. A total of 393 children (181 boys and 212 girls) from grades 3 through 6 (8-11 years old) were asked to wear an Actigraph monitor during school time on 4-5 days of the week. Assessments were conducted at baseline (before intervention) and post intervention (after intervention). RESULTS: Initial MVPA moderated the effect of Staff supervision (beta = -0.47%; p < .05), but not Equipment alone and Staff + Equipment (p > .05). Participants in the Staff condition that were 1 standard deviation (SD) below the mean for baseline MVPA (classified as "low active") had lower MVPA levels at post-intervention when compared with their low active peers in the control condition (Mean diff = -10.8 +/- 2.9%; p = .005). High active individuals (+1SD above the mean) in the Equipment treatment also had lower MVPA values at post-intervention when compared with their highly active peers in the control group (Mean diff = -9.5 +/- 2.9%; p = .009). CONCLUSIONS: These results indicate that changes in MVPA levels at post-intervention were reduced in highly active participants when recess staff supervision was provided. In this study, initial MVPA moderated the effect of Staff supervision on children's MVPA after 6 months of intervention. Staff training should include how to work with inactive youth but also how to assure that active children remain active. PMID- 24484546 TI - The chromatin architectural proteins HMGD1 and H1 bind reciprocally and have opposite effects on chromatin structure and gene regulation. AB - BACKGROUND: Chromatin architectural proteins interact with nucleosomes to modulate chromatin accessibility and higher-order chromatin structure. While these proteins are almost certainly important for gene regulation they have been studied far less than the core histone proteins. RESULTS: Here we describe the genomic distributions and functional roles of two chromatin architectural proteins: histone H1 and the high mobility group protein HMGD1 in Drosophila S2 cells. Using ChIP-seq, biochemical and gene specific approaches, we find that HMGD1 binds to highly accessible regulatory chromatin and active promoters. In contrast, H1 is primarily associated with heterochromatic regions marked with repressive histone marks. We find that the ratio of HMGD1 to H1 binding is a better predictor of gene activity than either protein by itself, which suggests that reciprocal binding between these proteins is important for gene regulation. Using knockdown experiments, we show that HMGD1 and H1 affect the occupancy of the other protein, change nucleosome repeat length and modulate gene expression. CONCLUSION: Collectively, our data suggest that dynamic and mutually exclusive binding of H1 and HMGD1 to nucleosomes and their linker sequences may control the fluid chromatin structure that is required for transcriptional regulation. This study provides a framework to further study the interplay between chromatin architectural proteins and epigenetics in gene regulation. PMID- 24484549 TI - Detection of Huanglongbing disease using differential mobility spectrometry. AB - The viability of the multibillion dollar global citrus industry is threatened by the "green menace", citrus greening disease (Huanglongbing, HLB), caused by the bacterial pathogen Candidatus Liberibacter. The long asymptomatic stage of HLB makes it challenging to detect emerging regional infections early to limit disease spread. We have established a novel method of disease detection based on chemical analysis of released volatile organic compounds (VOCs) that emanate from infected trees. We found that the biomarkers "fingerprint" is specific to the causal pathogen and could be interpreted using analytical methods such as gas chromatography/mass spectrometry (GC/MS) and gas chromatography/differential mobility spectrometry (GC/DMS). This VOC-based disease detection method has a high accuracy of ~90% throughout the year, approaching 100% under optimal testing conditions, even at very early stages of infection where other methods are not adequate. Detecting early infection based on VOCs precedes visual symptoms and DNA-based detection techniques (real-time polymerase chain reaction, RT-PCR) and can be performed at a substantially lower cost and with rapid field deployment. PMID- 24484547 TI - Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. AB - BACKGROUND: Parenterally administered ascorbic acid modulates sepsis-induced inflammation and coagulation in experimental animal models. The objective of this randomized, double-blind, placebo-controlled, phase I trial was to determine the safety of intravenously infused ascorbic acid in patients with severe sepsis. METHODS: Twenty-four patients with severe sepsis in the medical intensive care unit were randomized 1:1:1 to receive intravenous infusions every six hours for four days of ascorbic acid: Lo-AscA (50 mg/kg/24 h, n = 8), or Hi-AscA (200 mg/kg/24 h, n = 8), or Placebo (5% dextrose/water, n = 8). The primary end points were ascorbic acid safety and tolerability, assessed as treatment-related adverse event frequency and severity. Patients were monitored for worsened arterial hypotension, tachycardia, hypernatremia, and nausea or vomiting. In addition Sequential Organ Failure Assessment (SOFA) scores and plasma levels of ascorbic acid, C-reactive protein, procalcitonin, and thrombomodulin were monitored. RESULTS: Mean plasma ascorbic acid levels at entry for the entire cohort were 17.9 +/- 2.4 MUM (normal range 50-70 MUM). Ascorbic acid infusion rapidly and significantly increased plasma ascorbic acid levels. No adverse safety events were observed in ascorbic acid-infused patients. Patients receiving ascorbic acid exhibited prompt reductions in SOFA scores while placebo patients exhibited no such reduction. Ascorbic acid significantly reduced the proinflammatory biomarkers C-reactive protein and procalcitonin. Unlike placebo patients, thrombomodulin in ascorbic acid infused patients exhibited no significant rise, suggesting attenuation of vascular endothelial injury. CONCLUSIONS: Intravenous ascorbic acid infusion was safe and well tolerated in this study and may positively impact the extent of multiple organ failure and biomarkers of inflammation and endothelial injury. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT01434121. PMID- 24484548 TI - Dihydrotestosterone potentiates EGF-induced ERK activation by inducing SRC in fetal lung fibroblasts. AB - Lung maturation is regulated by interactions between mesenchymal and epithelial cells, and is delayed by androgens. Fibroblast-Type II cell communications are dependent on extracellular signal-regulated kinases (ERK) 1/2 activation by the ErbB receptor ligands epidermal growth factor (EGF), transforming growth factor (TGF)-alpha, and neuregulin (Nrg). In other tissues, dihydrotestosterone (DHT) has been shown to activate SRC by a novel nontranscriptional mechanism, which phosphorylates EGF receptors to potentiate EGF-induced ERK1/2 activation. This study sought to determine if DHT potentiates EGFR signaling by a nontranscriptional mechanism. Embryonic day (E)17 fetal lung cells were isolated from dams treated with or without DHT since E12. Cells were exposed to 30 ng/ml DHT for periods of 30 minutes to 3 days before being stimulated with 100 ng/ml EGF, TGF-alpha, or Nrg for up to 30 minutes. Lysates were immunoblotted for ErbB and SRC pathway signaling intermediates. DHT increased ERK1/2 activation by EGF, TGF-alpha, and Nrg in fibroblasts and Type II cells. Characterization in fibroblasts showed that potentiation of the EGF pathway was significant after 60 minutes of DHT exposure and persisted in the presence of the translational inhibitor cycloheximide. SRC and EGF receptor phosphorylation was increased by DHT, as was EGF-induced SHC1 phosphorylation and subsequent association with GRB2. Finally, SRC silencing, SRC inhibition with PP2, and overexpression of a dominant-negative SRC each prevented DHT from increasing EGF-induced ERK1/2 phosphorylation. These results suggest that DHT activates SRC to potentiate the signaling pathway leading from the EGF receptor to ERK activation in primary fetal lung fibroblasts. PMID- 24484550 TI - A sialic acid assay in isolation and purification of bovine k-casein glycomacropeptide: a review. AB - Sialic acid is a carbohydrate moiety of k-casein glycomacropeptide (GMP), which is a 64 amino acid residue C-terminal sialylated phosphorylated glycopeptide released from k-casein by the action of chymosin during cheese making. GMP lacks aromatic amino acids including phenylalanine, tyrosine, and tryptophan. Because of its unique amino acid composition and various biological activities, GMP is thought to be a potential ingredient for dietetic foods (e.g., a food for PKU patients) and pharmaceuticals. Thus, increased attention has been given to the development of techniques to purify GMP. In this review, techniques of GMP purification described in patents and scientific research papers were introduced. A sialic acid assay is the important method to track GMP isolation and purification processes, for which the thiobarbituric acid reaction with 1 propanol as a chromophore extracting solvent is an inexpensive, practical and specific technique. Sephacryl S-200 gel filtration chromatography, cellulose acetate electrophoresis, and sodium dodecyl sulfate polyacrylamide gel electrophoresis are the major techniques to identify sialic acid specific to GMP. Sephacryl S-200 chromatography and cellulose acetate electrophoresis are also used to detect GMP sialic acid in whey pearmeate and whey added commercial margarine samples. Future research includes development of an economical industrial scale method to produce high purity GMP. PMID- 24484551 TI - Immunogenicity of a prophylactic quadrivalent human papillomavirus L1 virus-like particle vaccine in male and female adolescent transplant recipients. AB - Organ TX recipients are at an increased risk of developing cancers of the lower genital tract related to HPV. The quadrivalent HPV vaccine has high efficacy in preventing these diseases, but response to many vaccines is suboptimal after organ transplantation. Liver and kidney TX recipients received quadrivalent HPV vaccine. Serum samples were tested for anti-HPV levels. Of 20 renal transplant recipients screened, 14 received vaccine. Of these, seven completed the vaccine series and seven had incomplete vaccination. Of five liver TX children, three received vaccines (two complete and one incomplete). All eight kidney and liver TX children with complete vaccination and available results were seronegative at baseline and had seroconversion at month 7 for all four HPV types. Six of 14 (42.8%) kidney TX recipients developed AR. During the same time period, eight of 28 (28.5%) non-vaccine renal transplant recipients developed AR (p = ns). Transplant adolescents developed 100% seroconversion to all four HPV serotypes with HPV vaccine with serologic titers similar to historic controls. A non significant increased incidence of AR was noted among kidney transplant vaccine recipients. A much larger study would be needed to evaluate whether HPV vaccination increases AR in transplant adolescents. PMID- 24484552 TI - [Prevalence of self-reported allergy, food hypersensitivity and food intolerance and their influencing factors in 0-36 months old infants in 8 cities in China]. AB - OBJECTIVE: To measure the prevalence, the possible causes and the influencing factors of allergy, food hypersensitivity and food intolerance in 0-36 month old infants in 8 cities in China. METHOD: Totally 2632 infants from the outpatient departments of prevention and health care of two representative hospitals in 8 Chinese cities were randomly selected by applying multistage cluster sampling method from October 2011 to March 2012, and a one-on-one survey to infants' parents was conducted to investigate infants' sensitization status. RESULT: Self reported infant allergy rate was 17.97% (473/2632) ; self-reported food hypersensitivity and food intolerance rates were 6.53% (172/2632) and 4.26% (112/2632) , respectively. The proportion of self-reported food hypersensitivity of 0-12 months old infants was 4.47% (74/1656) and their top five allergens in a descending order were eggs (28.38%) , shrimp (25.68%) , fish (21.62%) , milk (18.92%) and wheat (4.05%) . The proportion of self-reported 13-36 months old infant's food hypersensitivity was 10.05% (98/976) . The top five allergens were shrimp (33.93%) , fish (26.79%) , eggs (23.21%) , milk (12.50%) and soy (3.57%) in 13-24 months group, while fish (38.24%) , shrimp (35.29%) , eggs (20.59%) , milk (20.59%) and peanuts (2.94%) in 25-36 months group. Both 7-12 and 13-24 month old were the highest incidence (both of them were 11.98%, 58/484) of age for developing food hypersensitivity and 7-12-month old was also the highest incidence (8.47%, 41/484) of age for food intolerance. The self-reported food intolerance rate was 3.68% (61/1656) and 5.23% (51/976) in the two age groups, respectively. Age, parental history of allergy and father's educational level (OR was 2.452, 1.482 and 2.598, respectively, P < 0.01) were the risk factors of food hypersensitivity; within two weeks of sickness (OR = 1.267, P < 0.05) was the risk factor of food intolerance. CONCLUSION: Infancy was the most vulnerable period of life of getting allergy, therefore, it is necessary for all infants to prevent allergy through a variety of effective strategies. PMID- 24484553 TI - [Effect of gonadotropin-releasing hormone analog combined with stanazolol on final height in girls with idiopathic central precocious puberty and apparent decrease of linear growth]. AB - OBJECTIVE: To evaluate the effect of combined use of stanazolol (ST) on the final adult height (FAH) in girls with idiopathic central precocious puberty (ICPP) and apparently decreased linear growth during gonadotropin-releasing hormone analog (GnRHa) therapy. METHOD: Sixty-three girls with ICPP and decreased velocity of growth of height (HV<4 cm/yr) during GnRHa therapy were divided into 3 groups based on the following types of interventions:group 1 (n = 20), GnRHa+ST [25-30 ug/(kg.d) every 3-month followed by 3-month discontinuation], group 2 (n = 21), GnRHa+recombinant human growth hormone [rhGH, 1-1.1 U/(kg.w)], group 3 (n = 22), GnRHa alone.HV, the advancement of bone age (BA) for chronological age (CA) (DeltaBA/DeltaCA) and FAH were compared among groups. RESULT: (1)Total duration of ST combination therapy was (12.22 +/- 3.62) months, while total duration of combination of rhGH was (13.22 +/- 6.80) months. (2)HV increased significantly in both group 1 [ (2.79 +/- 0.60) cm/yr vs. (6.27 +/- 1.98) cm/yr, P < 0.01] and in group 2 [(2.80 +/- 0.50) cm/yr vs. (6.25 +/- 1.98) cm/yr, P < 0.01] during combined therapy, but maintained at low levels in group 3 [(3.95 +/- 1.10) cm/yr vs. (3.34 +/- 0.95) cm/yr, P > 0.05].No significant differences of DeltaBA/DeltaCA were found among the three groups [0.25(0.11~0.28), 0.22(0.15~0.31),0.19(0.10~0.32), P > 0.05]. (3)FAH was significantly higher than predicted adult height (PAH) before combined therapy, as well as higher than target height (THt) in both group 1 [(156.25 +/- 2.90) cm vs. (150.78 +/- 3.70) cm, P < 0.01, (156.25 +/- 2.90) cm vs. (153.94 +/- 2.62) cm, P < 0.01], and in group2 [ (157.33 +/- 4.69) cm vs. (152.61 +/- 3.92) cm, P < 0.01, (157.33 +/- 4.69) cm vs. (154.39 +/- 4.72) cm, P = 0.01].In group 3, FAH was similar to PAH [(153.88 +/- 2.6) cm vs. (152.54 +/- 5.86) cm, P > 0.05], and was less than THt [(153.88 +/- 2.6) cm vs. (155.60 +/- 4.52) cm, P = 0.02]. (4)In girls treated with ST, no hirsutism, clitorism or hoarse voice was recorded.No polycystic ovary syndrome was found by B-mode ultrasound. CONCLUSION: Intermittent combined use of low dose ST therapy can increase HV and thus improve FAH in girls with ICPP and apparently decreased linear growth during GnRHa therapy. PMID- 24484554 TI - [Episodic central nervous system symptoms with reversible white matter involvement in Chinese patients with X-linked Charcot-Marie-Tooth disease and literatures review]. AB - OBJECTIVE: To analyze the phenotype and genotype of CMTX1 patients with episodic transient reversible white matter involvement, and delineate the features of brain MRI in the episode and the possible mechanisms. METHOD: Three Chinese probands and their family members were sequenced in the coding regions of GJB1. With the other 16 reported CMTX1 patients with episodic transient reversible white matter involvement, the clinical feature of the episodic central nervous system symptoms and the genotypes were reviewed. RESULT: Missense mutations in GJB1 were identified in all 3 probands. In 19 patients with transient reversible white matter involvement, the episodes were manifested as weakness of the limbs, dysarthria, and dysphagia, without disturbance of consciousness or seizures. The episodes lasted for 13 hours (10 min-72 hours) with complete remission in all patients; There were multiple episodes in 9 patients. During the episode, brain MRI showed symmetrical high signals in T2 weighted, Flair and DWI images in periventricular white matter, with predominance in posterior region including splenium of corpus callosum. These changes in imaging were most prominent during or within 1 week after the clinical episode.Significant improvements occurred within 1 month, with complete remission within 4-6 months.No specific locations of mutant amino acids in GJB1 protein were found in these patients with episodic transient reversible white matter involvement. CONCLUSION: Episodic transient reversible white matter involvement may present in a small number of patients with CMTX1. Transient edema of oligodendrocytes due to the dysfunction of gap junction may be involved in the pathogenesis. There is no correlation between the location of the mutant amino acids in GJB1 and the occurrence of the episodes. PMID- 24484555 TI - [Effects of high volume hemofiltration on hemodynamics and oxygen metabolism at early stage of septic shock in piglet models]. AB - OBJECTIVE: To observe the effects of hemofiltration at early stage of septic shock with different ultrafiltration doses, including hemodynamics, oxygen metabolism, inflammatory mediator in piglet models, and to evaluate the therapeutic effects of HVHF. METHOD: The 18 healthy young piglets (Shanghai species) were divided randomly into three groups:control group (n = 6), conventional volume hemofiltration (CVVH) group [n = 6, ultrafiltration volume = 30 ml/(kg.h)] and high volume hemofiltration (HVHF) group [n = 6, ultrafiltration volume = 50 ml/(kg.h)], the animal model of septic shock was established by injection of lipopolysaccharide (LPS) (150 ug/kg) O111: B4. During the experiment, the following observations were carried out for all groups:1) Changes of hemodynamics [heart rate (HR), mean arterial pressure (MABP), cardiac output (CO), systemic vascular resistance index (SVRI), intrathoracic blood volume (ITBV)] and oxygen metabolism [oxygen delivery (DO2), oxygen consumption (VO2), oxygen extraction rate (O2ER) ] at the time of B0h, 0 h, 2 h, 4 h and 6 h.2) changes of TNF-alpha, IL-6, IL-10 in plasma at different time points (B0h, 0 h, 2 h, 4 h, 6 h). RESULT: Significant difference in circulatory parameters, inflammatory mediators in plasma were found at B0h and 0 h among three groups; the CO in two treatment groups were higher than that in control group at 4 h, 6 h after model establishment (P < 0.05), and SVRI in HVHF groups were higher than that in other two groups at 4 h, 6 h after model was established (P < 0.05). The MABP in HVHF group [4 h (82 +/- 17) mm Hg, 6 h (80 +/- 12) mm Hg](1 mm Hg = 0.133 kPa) were higher than that in CVVH group at 4 h [(67 +/- 12) mm Hg], 6 h [(69 +/- 14) mm Hg] after model was established (P < 0.05). The levels of IL-6, IL-10, TNF alpha in two treatment groups were lower than that in control group at 4 h and 6 h after model was established (P < 0.05), and the IL-6 [(281 +/- 51) pg/ml], TNF alpha [(67 +/- 13) pg/ml] level in HVHF group was lower than that in CVVH group [IL-6(281 +/- 51) pg/ml, TNF-alpha (67 +/- 13) pg/ml] at 6 h (P < 0.05). The DO2 and VO2 in two treatment groups were higher than that in control group at 4 h, 6 h (P < 0.05), the O2ER in HVHF group were higher than that in CVVH group at 4 h (44% +/- 3% vs. 33% +/- 4%), 6 h (43% +/- 5% vs. 31% +/- 3%, P < 0.05). CONCLUSION: High volume hemofiltration (HVHF) at early stage of septic shock piglet models was more effective in improving hemodynamics, oxygen metabolism than conventional CVVH. And HVHF eliminated blood inflammatory mediators more effectively than conventional CVVH. PMID- 24484557 TI - [Efficacy of sublingual immunotherapy with Dermatophagoides farinae drops in preschool and school-age children with allergic asthma and allergic rhinitis]. AB - OBJECTIVE: To evaluate the efficacy of specific sublingual immunotherapy (SLIT) with Dermatophagoides farinae drops on children with allergic asthma and allergic rhinitis of the preschool and school-age groups of children and adolescents. METHOD: This study analyzed the efficacy of SLIT in 122 children (aged 3-14 yr) with house dust mites-induced allergic asthma and allergic rhinitis. According to the age, patients were defined as the preschool group ( <= 6 years old, n = 59) and school-age group (> 6 years old, n = 63). All children were treated with Dermatophagoides farinae drops for at least 2 years. Clinical observation and follow-up study were conducted during the treatment. Before and after SLIT for half a year, 1 year and 2 years, asthma symptom scores (day and night), rhinitis symptom scores and medication scores were evaluated. The adverse events were assessed during the study. RESULT: After SLIT for half a year, 1 year and 2 years, there were no significant differences between the preschool group (0.3 +/- 0.5,0.0 +/- 0.1,0.0 +/- 0.0) and school-age group (0.3 +/- 0.4,0.0 +/- 0.1,0.0 +/ 0.0) in day scores of asthma (Z value was -1.687, -0.613,0.000, all P > 0.05). There were no significant differences between the preschool group (0.2 +/- 0.5,0.1 +/- 0.3,0.0 +/- 0.0) and school-age group (0.2 +/- 0.4,0.1 +/- 0.3, 0.0 +/- 0.0) in night scores of asthma (Z value was -0.496, -0.486,0.000, all P > 0.05). There was no significant differences between the preschool group (1.4 +/- 0.9,0.4 +/- 0.5,0.1 +/- 0.3) and school-age group (1.3 +/- 0.9,0.5 +/- 0.6,0.2 +/ 0.4) in symptom scores of allergic rhinitis (Z value was -0.394, -1.166, -1.075, all P > 0.05). There were no significant differences between the preschool group (1.6 +/- 0.8,0.0 +/- 0.0,0.0 +/- 0.0) and school-age group (1.7 +/- 0.7,0.0 +/- 0.0,0.0 +/- 0.0) in medication scores of allergic rhinitis (Z value was 0.655,0.000,0.000, all P > 0.05). After SLIT for 2 years, most children in the preschool and school-age groups were no longer using asthma controlling medication, with no significant difference between the two groups (Z value was 0.000, P > 0.05). The overall incidence of adverse reactions was only 7%, and there was no significant difference in the incidence of adverse reactions between the two groups (chi(2) = 0.000, P > 0.05). The local adverse events were mild gastrointestinal discomfort and rash, a majority of local adverse events in the preschool group were diarrhea. No severe adverse events happened in the treatment. CONCLUSION: SLIT with Dermatophagoides farinae drops is safe and effective in children with allergic asthma and allergic rhinitis of the preschool and school-age groups of children and adolescents, which provides evidences for early SLIT intervention of the disease. PMID- 24484556 TI - [Effects of niacin on cell adhesion and early atherogenesis: involvement of the p38 mitogen-activated protein kinases pathway]. AB - OBJECTIVE: To examine the effects of niacin on lysophosphatidylcholine (LPC) induced intercellular adhesion molecule-1 (ICAM-1), and gained insight to the mechanisms. METHOD: Human umbilical vein endothelial cell line was cultured using Medium 200 medium in incubator at 37 degrees C and 5% CO2 condition.Experimental groups:(1) the negative control group:medium; (2) LPC different time groups:the medium added with 20 umol/L final concentration of LPC, were cultured for 10 min and 8 h, 24 h; (3) LPC+ p38-mitogen-activated protein kinase (p38MAPK) inhibitor (SB203580) group:the medium added with 10 umol/L p38MAPK inhibitor (SB203580) was cultured for 1 h, then human umbilical vein endothelial cells (HUVECs) added with the LPC were cultured for 10 min, 8 h and 24 h.(4) LPC+different niacin dose group:after separately adding with 0.25, 0.5, 1 mmol/L niacin, the cells were cultured for 18 h, then HUVECs added with the LPC were cultured for 10 min, 8 h and 24 h. Cell concentration in each group was 5*10(5)/ml, inoculated in 6-well plates, each well 1 ml. Detected by Western blot analysis of pp38MAPK, ICAM-1 protein content, real-time quantitative PCR to detect endothelial cell ICAM-1 mRNA expression, cell immunofluorescence to detect LPC-induced ICAM-1 protein expression. RESULT: In LPC 24 h group, the expression of ICAM-1 protein was significantly increased 0.786 +/- 0.02, the LPC+niacin group, ICAM-1 protein levels (0.487 +/- 0.015) was significantly lower than the LPC 24 h group (P < 0.01), in LPC+SB203580 intervention group, ICAM-1 protein levels (0.461 +/- 0.011) was significantly lower than that of the LPC 24 h group (P < 0.01), but did not reach the level of the control group. Adding LPC to culture for 10 min, phosphorylation of p38MAPK (pp38MAPK) reached its peak (0.47 +/- 0.02), niacin could reduce the pp38MAPK (0.07 +/- 0.02), SB203580 could also reduce its activity (0.11 +/- 0.02). Adding LPC to culture for 8 h, ICAM-1 mRNA expression (8.16 +/- 0.15) compared with the control group (1.00 +/- 0.02) had a significant increase (t = 24.34, P < 0.01). Compared with the LPC 8 h, niacin reduced LPC induced ICAM-1 mRNA expression (3.85 +/- 0.14), and showed a dose-dependent manner (F = 8.06, P < 0.01), while SB203580 could not effectively reduce the ICAM 1 mRNA (8.09 +/- 0.11). CONCLUSION: Niacin prevented LPC-induced endothelial dysfunction by reducing expression of ICAM-1. These mechanisms appeared to be at least partly mediated by suppression of the pp38MAPK in endothelial cells. These pleiotropic effects of niacin may potentially contribute to the beneficial effects of risk reduction for atherosclerotic disease. PMID- 24484558 TI - [Clinical characterization and mutation identification for multiple sulfatase deficiency patients in China]. AB - OBJECTIVE: Multiple sulfatase deficiency is a rare autosomal recessively inherited lysosomal storage disorder characterized by the accumulation of sulfated lipids and acid mucopolysaccharides. The aim of this study was to explore the clinical manifestations, enzyme activities and SUMF1 gene mutations in two Chinese patients with multiple sulfatase deficiency. METHOD: One boy and one girl from two families were studied. Both patients presented with mental retardation, mild coarse facial features, a neurodegenerative course of disease with loss of sensory and motor function after 2 years of age, ichthyosis and skeletal abnormalities (kyphosis or/and scoliosis). Clinical characteristics indicate multiple sulfatase deficiency.Sulfatases activities in blood leucocytes, plasma or cultured fibroblast of the patients were measured.Genomic DNAs were extracted from peripheral blood leukocytes from the patients and their parents. All SUMF1 gene exons and intron-exon boundaries were amplified by PCR and subjected for direct sequencing. RESULT: In case 1, five sulfatases activities of blood leucocytes and four sulfatases of cultured skin-fibroblasts were analyzed.In case 2, three sulfatases activities of blood leucocytes were tested.Significantly decreased sulfatases activities confirmed the diagnosis of multiple sulfatase deficiency.On SUMF1 gene, c.793_794 insATG (p. P265X)/ c.1045C>T (p.R349W) in case 1 and c.451A>G (p.K151E)/ c.1046G>C (p.R349Q) in case 2 were detected, respectively. Three novel mutations c.793_794insAGT, c.1046G>C and c.451A>G were identified. CONCLUSIONS: Multiple sulfatase deficiency usually results in multi-organ damage, especially neurologic, skeletal and skin.Sulfatases assay and SUMF1 gene analysis are necessary for the diagnosis. Two Chinese cases with multiple sulfatase deficiency were firstly reported. Three novel mutations were found.It should be considered that the mutation profile of SUMF1 gene in Chinese patients is different from other populations. PMID- 24484559 TI - [Diagnostic and therapeutic methods for perioperative children with congenital heart disease with airway stenosis in pediatric intensive care unit]. AB - OBJECTIVE: To explore the diagnostic and therapeutic methods for perioperative children with congenital heart disease (CHD) with airway stenosis in pediatric intensive care unit (PICU). METHOD: Fiberoptic bronchoscopy was used for the diagnosis of 100 CHD cases in PICU who were clinically considered to have possible airway malformation because of complicated difficult-to-control lung infection, atelectasis and failure with the ventilator after surgery from January 2010 to October 2011. Cases who were confirmed to have severe airway stenosis by bronchoscopy and weaning from the ventilator after surgery were treated with balloon expandable stents into the desired position in the bronchoscopy. RESULT: There were 73 cases (73%) of CHD patients with airway abnormalities, including 31 cases of severe stenosis (31%), moderate stenosis in 29 cases (29%), mild stenosis in 13 cases (13%). Nine of the 10 children in whom the mechanical ventilation was hard to be stopped after surgery because of severe airway stenosis were weaned from mechanical ventilation successfully by fiberoptic bronchoscopy, while one case died from primary disease with severe sepsis after the placement of bronchial stents. CONCLUSION: CHD children with difficult-to control lung infection, atelectasis and failure with ventilator after surgery are often complicated with airway abnormalities. The therapeutic bronchoscopy with airway stent can be used for cases with weaning from the ventilator because of severe airway stenosis. PMID- 24484561 TI - [Diagnosis and prognosis of spontaneous pneumomediastinum in eighteen children]. AB - OBJECTIVE: To analyze the diagnosis, treatment and prognosis of spontaneous pneumomediastinum (SPM) in children. METHOD: A retrospective analysis of the clinical data of 18 children diagnosed with SPM in Yuying Children's Hospital Affiliated to Wenzhou Medical University from December 2007 to February 2013 was performed. Information of the sequelae and recurrence of SPM was obtained by telephone follow-up. SPM was diagnosed according to Versteegh's standard. SPM cases due to mechanical ventilation, trauma, inhaled foreign body or as a result of the underlying disease were not included. Also cases of secondary pneumothorax pneumomediastinum and neonatal mediastinal emphysema were excluded. RESULT: Fifteen of 18 cases were boys and 3 were girls, the range of age was from 9 to 17 years. Predisposing factors included sport activities, severe cough or without a known cause. Clinical manifestations included chest pain, chest tightness, dyspnea, neck pain, back pain, foreign body sensation or pain on swallowing, throat pain of swelling. Chest CT of 18 cases showed pneumomediastinum, 8 cases displayed varied degrees of air in neck, chest; 18 cases of SPM responded well to bed rest, oxygen, antitussive and anti-infection treatment. Fifteen cases received chest CT or X-ray inspection after therapy, showing that the pneumomediastinum disappeared or significantly absorbed, 3 cases improved in clinical symptom. Among 18 patients, telephone follow-up of 14 were successful and 4 cases were lost. An average follow-up time was (24 +/- 17) months. None of the cases had any serious consequences, and recurrence happened in one case. CONCLUSION: Children's spontaneous pneumomediastinum is a benign disease. When a child has chest pain or chest tightness, SPM should be considered after excluding the common diseases. SPM can be diagnosed in association with clinical feature and chest CT examination. Patients respond well to conservative therapy and most of them had no severe sequelae. PMID- 24484560 TI - [Application of electric coagulation treatment via bronchoscopy in the management of congenital vallecular cyst in children]. AB - OBJECTIVE: To discuss the effect of electric coagulation through bronchoscopy in diagnosis and treatment of congenital vallecular cyst in children. METHOD: Ten cases of congenital vallecular cyst in the study with age ranged from 21 days to 4 years and 10 months were treated with electric coagulation through bronchoscopy. The therapeutic effect was evaluated by endoscopic and clinical manifestation. And all the patients were followed-up for 6-12 months. RESULT: All the patients obtained 3-5 times electric coagulation. After the operation, the cyst decreased in size, epiglottis softening was subsided, uplift uncompression, dyspnea and laryngeal stridor were improved obviously. After follow-up periods of 6-12 months, no capsule wall were left, and the activity of the epiglottis resumed.No severe complication was found in any patient. CONCLUSION: Electric coagulation through bronchoscopy is a simple, effective and safe method to treat congenital vallecular cyst in children. PMID- 24484562 TI - [Congenital central hypoventilation syndrome, report of three cases]. AB - OBJECTIVE: To evaluate clinical characteristics and PHOX2B gene mutations in congenital central hypoventilation syndrome (CCHS) and to facilitate the early diagnosis and management of CCHS and reduce the misdiagnosis. METHOD: Clinical data of 3 infants with CCHS who had recurrent respiratory failure episodes and dependent on mechanical ventilation support in 3 from March 2008 to April 2012 were analyzed, and blood gas analysis was performed respectively in the awaken and sleeping status. Gene sequencing was used for detection of PHOX2B gene mutation. RESULT: All the three patients had adequate ventilation during awaken time, but they presented with abnormal frequency and shallow breathing associated with alveolar hypoventilation after falling asleep. Blood gas analysis showed hypercapnia and CO2 partial pressure was consistently over 60 mm Hg (1 mm Hg = 0.133 kPa) after falling asleep, which is in accordance with the clinical features of CCHS. The PHOX2B gene sequencing showed that 6 GCN repeats were inserted at exon3 of PHOX2B in case 1, at same position, 5 GCN repeats were inserted in case 2 and 3. CONCLUSION: Normal ventilation in awaken status while shallow slow breathing accompanied with hypercapnia in sleep are the main clinical characteristics of CCHS, which requires mechanical ventilation. Acquired mutation in exon 3 of PHOX2B gene encoding repeated GCN sequence seems to be the molecular etiology of these three patients. PMID- 24484563 TI - [Guidelines for management of community acquired pneumonia in children(the revised edition of 2013) (II)]. PMID- 24484564 TI - [A case of neonatal intrahepatic cholestasis caused by citrin deficiency complicated with congenital biliary atresia]. PMID- 24484565 TI - [An infant of neurofibromatosis with external genitalia involvement presentation]. PMID- 24484566 TI - [Advances in clinical and molecular genetic research on pyridoxine dependent epilepsy]. PMID- 24484567 TI - [Advance in researches on neonatal humidified high flow nasal cannulae]. PMID- 24484568 TI - [Cardiac sodium channelopathy from bench to bedside]. PMID- 24484569 TI - [Minutes of the 4th national conference on children syncope]. PMID- 24484570 TI - [The Society of Pediatrics, Chinese Medical Association-an intensive training programme for developmental and behavioral pediatrics]. PMID- 24484571 TI - Urinary tract infection syndromes: occurrence, recurrence, bacteriology, risk factors, and disease burden. AB - Urinary tract infection (UTI) is one of the most common bacterial infections, accounting for 0.9% of all ambulatory visits in the United States. This review defines the major UTI syndromes, their occurrence and recurrence, bacteriology, risk factors, and disease burden. PMID- 24484573 TI - Diagnosis and management of urinary tract infection in the emergency department and outpatient settings. AB - Emergency physicians encounter urinary tract infections (UTIs) in a wide spectrum of disease severity and patient populations. The challenges of managing UTIs in an emergency department include limited history, lack of follow-up, and lack of culture and susceptibility results. Most patients do not require an extensive diagnostic evaluation and can be safely managed as outpatients with oral antibiotics. The diagnostic approach to and treatment of adults presenting to emergency departments with UTIs are reviewed. PMID- 24484574 TI - Management of urinary tract infections from multidrug-resistant organisms. AB - Antibiotic resistance worsens clinical outcomes and, in some cases, significantly impacts the clinical management of urinary tract infections in the outpatient setting. This article presents the prevalence and mechanism of relevant antimicrobial resistance patterns encountered among uropathogens, and discusses the efficacy of antibiotic regimens and novel therapies in treating commonly encountered multidrug-resistant organisms. PMID- 24484572 TI - Approach to a positive urine culture in a patient without urinary symptoms. AB - Asymptomatic bacteriuria (ASB) is a condition in which bacteria are present in a noncontaminated urine sample collected from a patient without signs or symptoms related to the urinary tract. ASB must be distinguished from symptomatic urinary tract infection (UTI) by the absence of signs and symptoms compatible with UTI or by clinical determination that a nonurinary cause accounts for the patient's symptoms. The overall purpose of this review is to promote an awareness of ASB as a distinct condition from UTI and to empower clinicians to withhold antibiotics in situations in which antimicrobial treatment of bacteriuria is not indicated. PMID- 24484575 TI - Diagnosis and management of fungal urinary tract infection. AB - When the terms funguria or fungal urinary tract infection are used, most physicians are referring to candiduria and urinary tract infections due to Candida species. Other fungi, including yeasts and molds can involve the kidney during the course of disseminated infection, but rarely cause symptoms referable to the urinary tract. Candida species appear to be unique in their ability to both colonize and cause invasive disease in the urinary tract. This overview focuses only on candiduria and Candida urinary tract infection because they are common and many times present perplexing management issues. PMID- 24484577 TI - Urinary tract infections in special populations: diabetes, renal transplant, HIV infection, and spinal cord injury. AB - Some populations have unique considerations relevant to complicated urinary tract infection. For patients with diabetes, renal transplant, HIV infection, and spinal cord injuries, approaches to management, including diagnosis and treatment, are generally similar to other patients with complicated urinary tract infection. In addition, there is no evidence that treatment of asymptomatic bacteriuria leads to improved outcomes. PMID- 24484576 TI - Diagnosis and management of urinary tract infection in older adults. AB - Urinary tract infection (UTI) is a commonly diagnosed infection in older adults. Despite consensus guidelines developed to assist providers in diagnosing UTI, distinguishing symptomatic UTI from asymptomatic bacteriuria (ASB) in older adults is problematic, as many older adults do not present with localized genitourinary symptoms. This article summarizes the recent literature and guidelines on the diagnosis and management of UTI and ASB in older adults. PMID- 24484578 TI - Diagnosis, management, and prevention of catheter-associated urinary tract infections. AB - Catheter-associated urinary tract infection (CAUTI) is common, costly, and causes significant patient morbidity. CAUTIs are associated with hospital pathogens with a high propensity toward antimicrobial resistance. Treatment of asymptomatic patients with CAUTI accounts for excess antimicrobial use in hospitals and should be avoided. Duration of urinary catheterization is the predominant risk for CAUTI; preventive measures directed at limiting placement and early removal of urinary catheters have an impact on decreasing CAUTI rates. The use of bladder bundles and collaboratives, coupled with the support and active engagement from both hospital leaders and followers, seem to help prevent this common problem. PMID- 24484579 TI - Management of non-catheter-associated complicated urinary tract infection. AB - This article presents an overview of non-catheter-associated complicated urinary tract infection (UTI) from a urologic point of view. Discussion includes the evaluation and workup a complicated UTI through history, physical examination, laboratory analysis, and radiographic studies. Specific types of complicated UTI, such as urinary obstruction and renal abscess, are reviewed. PMID- 24484580 TI - Prevention of recurrent urinary tract infections in women: antimicrobial and nonantimicrobial strategies. AB - Recurrent urinary tract infections (UTIs) are common, especially in women. Low dose daily or postcoital antimicrobial prophylaxis is effective for prevention of recurrent UTIs and women can self-diagnose and self-treat a new UTI with antibiotics. The increasing resistance rates of Escherichia coli to antimicrobial agents has, however, stimulated interest in nonantibiotic methods for the prevention of UTIs. This article reviews the literature on efficacy of different forms of nonantibiotic prophylaxis. Future studies with lactobacilli strains (oral and vaginal) and the oral immunostimulant OM-89 are warranted. PMID- 24484581 TI - Urinary tract infection pathogenesis: host factors. AB - Clinically, host factors in the pathogenesis of urinary tract infection (UTI) may be considered as modifiable (eg, behaviors associated with increased risk of UTI, anatomic and functional problems of the urinary tract) and thus potentially amenable to a change in patient behavior or treatment approach, or as intrinsic and nonmodifiable host factors that neither the patient nor the clinician can influence (eg, gender and genetic influences associated with UTI). Although considering nonmodifiable host factors may be discouraging to patients and clinicians at present, some genetic associations have the potential for future predictive value and may interface with future treatments. PMID- 24484582 TI - Urinary tract infections: diagnostic and management issues. Preface. PMID- 24484583 TI - "No one says 'No' to money" - a mixed methods approach for evaluating conditional cash transfer schemes to improve girl children's status in Haryana, India. AB - INTRODUCTION: Haryana was the first state in India to launch a conditional cash transfer (CCT) scheme in 1994. Initially it targeted all disadvantaged girls but was revised in 2005 to restrict it to second girl children of all groups. The benefit which accrued at girl attaining 18 years and subject to conditionalities of being fully immunized, studying till class 10 and remaining unmarried, was increased from about US$ 500 to US$ 2000. Using a mixed methods approach, we evaluated the implementation and possible impact of these two schemes. METHODS: A survey was conducted among 200 randomly selected respondents of Ballabgarh Block in Haryana to assess their perceptions of girl children and related schemes. A cohort of births during this period was assembled from population database of 28 villages in this block and changes in sex ratio at birth and in immunization coverage at one year of age among boys and girls was measured. Education levels and mean age at marriage of daughters were compared with daughters-in-law from outside Haryana. In-depth interviews were conducted among district level implementers of these schemes to assess their perceptions of programs' implementation and impact. These were analyzed using a thematic approach. RESULTS: The perceptions of girls as a liability and poor (9% to 15%) awareness of the schemes was noted. The cohort analysis showed that while there has been an improvement in the indicators studied, these were similar to those seen among the control groups. Qualitative analysis identified a "conspiracy of silence" - an underplaying of the pervasiveness of the problem coupled with a passive implementation of the program and a clash between political culture of giving subsidies and a bureaucratic approach that imposed many conditionalities and documentary needs for availing of benefits. CONCLUSION: The apparent lack of impact on the societal mindset calls for a revision in the current approach of addressing a social issue by a purely conditional cash transfer program. PMID- 24484584 TI - Exome sequencing identified new mutations in a Marfan syndrome family. AB - Marfan syndrome is a common autosomal dominant hereditary connective tissue disorder. There is no cure for Marfan syndrome currently. Next-generation sequencing (NGS) technology is efficient to identify genetic lesions at the exome level. Here we carried out exome sequencing of two Marfan syndrome patients. Further Sanger sequencing validation in other five members from the same family was also implemented to confirm new variants which may contribute to the pathogenesis of the disease. Two new variants, including one nonsense SNP in the Marfan syndrome gene FBN1 and one missense mutation in exon 15 of LRP1, which may be related to the phenotype of the patients were identified. The exome sequencing analysis provides us a new insight into the molecular events governing pathogenesis of Marfan syndrome. VIRTUAL SLIDE: http://www.diagnosticpathology.diagnomx.eu/vs/1229110069114125. PMID- 24484585 TI - Molecular characteristics of mismatch repair genes in sporadic colorectal tumors in Czech patients. AB - BACKGROUND: Mismatch repair (MMR) genes are known to be frequently altered in colorectal cancer (CRC). Both genetics and epigenetics modifications seems to be relevant in this phenomenon, however it is still not clear how these two aspects are interconnected. The present study aimed at characterizing of epigenetic and gene expression profiles of MMR genes in sporadic CRC patients from the Czech Republic, a country with one of the highest incidences of this cancer all over Europe. METHODS: Expression levels and CpG promoter methylation status of all MMR genes were evaluated in DNA from tumor and adjacent mucosal samples of 53 incident CRC patients. RESULTS: We have found significantly increased transcription levels in EXO1 gene in tumor tissues (P = 0.05) and significant over-expression of MSH3 gene in colon tumors when compared to adjacent mucosal tissues (P = 0.02). Interestingly, almost all MMR genes were differently expressed when localization of tumors was compared. In particular, colon tumors showed an up-regulation of EXO1, MSH2, MSH3, MSH6, and PMS2 genes in comparison to rectal tumors (P = 0.02). Expression levels of all MMR genes positively correlated between each other. The promoter methylation of MLH1 gene was observed in 9% of CRC tissues only. CONCLUSIONS: In our study, we have observed different pattern of MMR genes expression according to tumor localization. However, a lack of association between methylation in MMR genes and their corresponding expressions was noticed in this study, the relationship between these two aspects is worthy to be analyzed in larger population studies and in pre-malignant stages. PMID- 24484586 TI - The complete mitogenome of the crayfish Cherax glaber (Crustacea: Decapoda: Parastacidae). AB - The complete mitochondrial genome of Cherax glaber was sequenced using the HiSeq platform. The mitogenome consists of 15,806 base pairs containing 13 protein coding genes, 2 ribosomal subunit genes, 22 transfer RNAs and a non-coding AT rich region. The Cherax glaber has a base composition of 32.39% for T, 22.42% for C, 33.73% for A and 11.46% for G, with an AT bias of 66.12%. PMID- 24484588 TI - Absence of acquired copy number neutral loss of heterozygosity (CN-LOH) of chromosome 7 in a series of 10 patients with Shwachman-Diamond syndrome. PMID- 24484587 TI - High-throughput screening identifies inhibitors of DUX4-induced myoblast toxicity. AB - BACKGROUND: Facioscapulohumeral muscular dystrophy (FSHD) is caused by epigenetic alterations at the D4Z4 macrosatellite repeat locus on chromosome 4, resulting in inappropriate expression of the DUX4 protein. The DUX4 protein is therefore the primary molecular target for therapeutic intervention. METHODS: We have developed a high-throughput screen based on the toxicity of DUX4 when overexpressed in C2C12 myoblasts, and identified inhibitors of DUX4-induced toxicity from within a diverse set of 44,000 small, drug-like molecules. A total of 1,280 hits were then subjected to secondary screening for activity against DUX4 expressed by 3T3 fibroblasts, for absence of activity against the tet-on system used to conditionally express DUX4, and for potential effects on cellular proliferation rate. RESULTS: This allowed us to define a panel of 52 compounds to use as probes to identify essential pathways of DUX4 activity. We tested these compounds for their ability to protect wild-type cells from other types of cell death-inducing insults. Remarkably, we found that 60% of the DUX4 toxicity inhibitors that we identified also protected cells from tert-butyl hydrogen peroxide, an oxidative stress-inducing compound. Compounds did not protect against death induced by caspase activation, DNA damage, protein misfolding, or ER stress. Encouragingly, many of these compounds are also protective against DUX4 expression in human cells. CONCLUSION: These data suggest that oxidative stress is a dominant pathway through which DUX4-provoked toxicity is mediated in this system, and we speculate that enhancing the oxidative stress response pathway might be clinically beneficial in FSHD. PMID- 24484589 TI - Ethnopharmacology, phytochemistry and pharmacology of Tephrosia purpurea. AB - Tephrosia purpurea (L.) Pers. is popularly known as 'Sarapunkha' in classical Ayurvedic texts. It is a perennial plant belonging to the family Fabaceae, and occurs throughout the Indian subcontinent. T. purpurea is traditionally used to treat splenomegaly, cirrhosis, cough and cold, abdominal swelling and as an antidote in the Ayurvedic system of medicine. Phytochemical investigations indicate the presence of semiglabrin, pongamole, lanceolatins A and B, rutin, lupeol, and beta-sitosterol. Flavonoids including (+)-tephrorin A and B, (+) tephrosone, an isoflavone, 7, 4'-dihydroxy-3', 5'-dimethoxyisoflavone and a chalcone, (+)-tephropurpurin were isolated from the whole plant. Pharmacological activities of different parts of the plant reported include anti-inflammatory, antiulcer, antimicrobial, antioxidant, antiallergic, antidiabetic, hepatoprotective, antitumor and insect repellent activity. In the present review, the literature on the phytochemical and pharmacological investigations of Tephrosia purpurea (L.) Pers. are summarized to August, 2012. PMID- 24484590 TI - Potent anti-angiogenic activity of B19--a mono-carbonyl analogue of curcumin. AB - AIM: The compound B19 (C21H22O5) is a newly synthesized, mono-carbonyl analog of curcumin that has exhibited potential antitumor effects. This present study was performed to identify the anti-angiogenic activity of this compound. METHODS AND RESULTS: B19 inhibited migration and tube formation of human umbilical vein endothelial cells, and arrested microvessel outgrowth from rat aortic rings. In addition, B19 suppressed the neovascularization of chicken chorioallantoic membrane. Mechanistic studies revealed that B19 suppressed the downstream protein kinase activation of vascular endothelial growth factor (VEGF) by decreasing phosphorylated forms of serine/threonine kinase Akt, extracellular signal regulated kinase, and p38 mitogen-activated protein kinase, with or without stimulating vascular endothelial growth factor (VEGF). CONCLUSIONS: B19 exerted anti-angiogenic activity in vitro and ex vivo, which suggests that it merits further investigation as a promising anticancer angiogenesis compound. PMID- 24484591 TI - Ursolic acid induces U937 cells differentiation by PI3K/Akt pathway activation. AB - AIM: Ursolic acid (UA), a pentacyclic triterpenoid, is used as an anti inflammatory and anti-cancer agent. There were few studies on the effects of UA on differentiation, and this is the first time to elucidate the potential effect and molecular mechanism of UA on inducing differentiation in the human leukemia cell line U937. METHODS: Wright-Giemsa staining, nitroblue tetrazolium reduction assay and flow cytometric analysis were utilized to demonstrate the differentiation of U937 cells induced by UA. Western blotting and immunofluorescence assay were used to investigate the possible mechanism. RESULTS: It was found that UA could induce the differentiation of U937cells and Akt-activity was significantly increased during differentiation. Additionally, LY294002, a PI3K-Akt inhibitor, could block the differentiation of U937 cells induced by UA. CONCLUSION: UA could induce the differentiation of U937 cells by activating the PI3K/Akt pathway, and it could be a potential candidate as a differentiation-inducing agent for the therapy of leukemia. PMID- 24484592 TI - Crebanine inhibits voltage-dependent Na+ current in guinea-pig ventricular myocytes. AB - AIM: To study the effects of crebanine on voltage-gated Na(+) channels in cardiac tissues. METHODS: Single ventricular myocytes were enzymatically dissociated from adult guinea-pig heart. Voltage-dependent Na(+) current was recorded using the whole cell voltage-clamp technique. RESULTS: Crebanine reversibly inhibited Na(+) current with an IC50 value of 0.283 mmol.L(-1) (95% confidence range: 0.248-0.318 mmol.L(-1)). Crebanine at 0.262 mmol.L(-1) caused a negative shift (about 12 mV) in the voltage-dependence of steady-state inactivation of Na(+) current, and retarded its recovery from inactivation, but did not affect its activation curve. CONCLUSION: In addition to blocking other voltage-gated ion channels, crebanine blocked Na(+) channels in guinea-pig ventricular myocytes. Crebanine acted as an inactivation stabilizer of Na(+) channels in cardiac tissues. PMID- 24484593 TI - DT-13, a saponin of dwarf lilyturf tuber, exhibits anti-cancer activity by down regulating C-C chemokine receptor type 5 and vascular endothelial growth factor in MDA-MB-435 cells. AB - AIM: To investigate the anticancer activity of DT-13 under normoxia and determine the underlying mechanisms of action. METHODS: MDA-MB-435 cell proliferation, migration, and adhesion were performed to assess the anticancer activity of DT 13, a saponin from Ophiopogon japonicus, in vitro. In addition, the effects of DT 13 on tumor growth and metastasis in vivo were evaluated by orthotopic implantation of MDA-MB-435 cells into nude mice; mRNA levels of vascular endothelial growth factor (VEGF), C-C chemokine receptor type 5 (CCR5) and hypoxia-inducible factor 1alpha (HIF-1alpha) were evaluated by real-time quantitative PCR; and CCR5 protein levels were detected by Western blot assay. RESULTS: At 0.01 to 1 MUmol.L(-1), DT-13 inhibited MDA-MB-435 cell proliferation, migration, and adhesion significantly in vitro. DT-13 reduced VEGF and CCR5 mRNAs, and decreased CCR5 protein expression by down-regulating HIF-1alpha. In addition, DT-13 inhibited MDA-MB-435 cell lung metastasis, and restricted tumor growth slightly in vivo. CONCLUSION: DT-13 inhibited MDA-MB-435 cell proliferation, adhesion, and migration in vitro, and lung metastasis in vivo by reducing VEGF, CCR5, and HIF-1alpha expression. PMID- 24484594 TI - Chemical profiles and anticancer effects of saponin fractions of different polarity from the leaves of Panax notoginseng. AB - AIM: To evaluate the chemical profiles and cytotoxic effects among the total saponin fraction (TSF), 25% ethanol fraction (25EF), 50% ethanol fraction (50EF), and 85% ethanol fraction (85EF) prepared by macroporous resin from the leaves of Panax notoginseng. METHOD: The simultaneous determination of thirteen main saponins, as well as the chemical profiles of saponin fractions of different polarity, was made by HPLC-DAD and LC-ESI-MS(n) analysis. The cytotoxic effects were determined against KP4 cells (human pancreatic cancer), NCI-H727 cells (human lung cancer), HepG2 cells (human hepatocellular cancer), and SGC-7901 cells (human gastric adenocarcinoma). RESULTS: Chemical analysis indicated that 85EF possessed the most abundant cytotoxic protopanaxadiol saponins, including the marker saponins F2, 20(R)-Rg3, 20(S)-Rg3, and Rh2. The MTT assay showed that 85EF also had the strongest cytotoxic effects among the four fractions. 25EF showed no anti-proliferative effects, while 50EF and TSF exhibited weak anti proliferative activity. CONCLUSION: From the aspect of comprehensive utilization of resources, 85EF, enriched with low polarity PPD group saponins, is a new alternative source of anticancer saponins, and a promising botanical preparation for further anticancer studies. PMID- 24484595 TI - Chemical constituents of Euphorbia tibetica and their biological activities. AB - AIM: To investigate the chemical constituents and their biological activities of the aerial parts of Euphorbia tibetica. METHOD: Compounds were isolated and purified by various chromatographic methods, and their structures were elucidated through the use of extensive spectroscopic techniques including 2D-NMR, the structures of compounds 5 and 6 were confirmed by single-crystal X-ray crystallography. Bioactivities of all the isolated compounds were evaluated by the MTT method on A549 and anti-angiogenesis assay. RESULTS: One new compound, methyl 4-epi-shikimate-3-O-gallate (1), together with twenty-three known constituents (2-24) were isolated from the aerial parts of E. tibetica. CONCLUSION: Compound 1 is new, and the other compounds were isolated from this plant for the first time. Compounds 5-7, 9, 11, 17, 18 and 20 exhibited inhibitory effects on the growth of human lung cancer cell A549 and compounds 5, 7, 12, 13, 17 and 19 showed anti-angiogenic effects in a zebrafish model. PMID- 24484596 TI - Triterpenoid saponins from Patrinia scabra. AB - AIM: To study the chemical constituents and bioactivity of the roots of Patrinia scabra Bunge. METHODS: The chemical constituents were isolated using various chromatographic methods, and the structures were elucidated on the basis of spectral analysis and chemical methods. In addition, cytotoxic activities toward HepG2 cells were tested by the MTT method. RESULTS: A new triterpenoid saponin, 3 O-(4'-isovaleryl)-O-beta-D-xylose-12,30-dihydroxy-oleanane-28,13-lactone-22-O- beta-D-glucoside (1), along with two known triterpenoid saponins, acanthopanax saponin CP3 (2) and foetoside C (3), were isolated. CONCLUSION: The aglycone of compound 1 was a new skeleton derivative of oleanolic acid. Compound 2 showed strong cytotoxicity to HePG2 cells (IC50 1.49 MUmol.L(-1)). PMID- 24484597 TI - Structural characterization and identification of major constituents in radix scrophulariae by HPLC coupled with electrospray ionization quadrupole time-of flight tandem mass spectrometry. AB - AIM: To analyze the major constituents in Radix Scrophulariae (Scrophularia ningpoensis). METHOD: Radix Scrophulariae was analyzed by HPLC coupled with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-Q TOF MS/MS). Compounds were separated by HPLC using a C18 column and gradient elution of acetonitrile and 0.1 % (V/V) acetic acid-water. Negative ion mode was employed. RESULTS: A total of thirty-six compounds, including fourteen iridoid glycosides, nineteen phenylpropanoid glycosides, and three organic acids, were identified from Radix Scrophulariae based on the accurate mass measurement of precursor and product ions. Twenty-one of the constituents were identified by comparing their retention times (tR) and ESI-MS/MS data with those of reference standards and/or previous publications, while another fifteen compounds were tentatively identified or deduced according to their Q-TOF MS/MS data which afforded sufficient structural information. CONCLUSION: It is believed that this study is useful for the identification of constituents in Radix Scrophulariae, as well as related plants and complex prescriptions. PMID- 24484598 TI - Pyrolysis characteristics of radix rhizoma rhei, cortex moudan radicis, and radix sanguisorbae and correlations with the carbonizing process of Chinese herbs. AB - AIM: The aim of the work is to study the pyrolysis characteristics of radix rhizoma rhei, cortex moudan radicis, and radix sanguisorbae in an inert atmosphere of argon (Ar), and to investigate the mechanism of the carbonizing process of the three traditional Chinese herbs. METHODS: The pyrolysis characteristics of the crude materials and their extracts were studied by thermogravimetry-mass spectrometry (TG-MS) in a carrier gas of argon, coupled with Fourier transform infrared spectrometry (FTIR) and scanning electron microscopy (SEM) methods. Correlation of the pyrolysis behaviors with the carbonizing process by stir-frying of traditional Chinese medicines was made. RESULTS: Within the temperature range of 200-300 degrees C, which is the testing range for the study of the carbonizing process of Chinese herbs, the temperatures indicated by the maximum weight loss rate peak of the above three extracts were taken as the upper-limit temperatures of the carbonizing process of the herbs, and which were 200, 240 and 247 degrees C for radix rhizoma rhei, cortex moudan radicis, and radix Sanguisorbae, respectively. The ion monitoring signal peaks detected by the TG-MS method corresponded with reports that the level of chemical components of traditional Chinese medicinal materials would decrease after the carbonizing process. It was confirmed by Fourier transform infrared spectrometry (FTIR) and scanning electron microscopy (SEM) methods that better results of "medicinal property preservation" could be obtained by heating at 200 degrees C for radix rhizoma rhei, at about 250 degrees C for cortex moudan radicis, and radix sanguisorbae, as the relative intensity values of the common peaks were among the middle of their three carbonized samples by programmed heating. CONCLUSION: The upper-limit temperatures of the carbonizing process for radix rhizoma rhei, cortex moudan radicis and radix sanguisorbae were 200, 240 and 247 degrees C respectively. It is feasible to research the mechanism and technology of the carbonizing process of traditional Chinese medicinal materials using thermogravimetry, Fourier transform infrared spectrometry, and scanning electron microscopy methods. PMID- 24484599 TI - Mixed nanomicelles loaded with thymopeptides-sodium deoxycholate/phospholipid improve drug absorption. AB - AIM: To improve the absorption of thymopeptides (TH) by preparing sodium deoxycholate/phospholipid-mixed nanomicelles (SDC/PL-MMs). METHODS: TH-SDC/PL-MMs were prepared by a film dispersion method, and then evaluated using photon correlation spectroscopy (PCS), zeta potential measurement, as well as their physical stability after storage for several days. Furthermore, in situ intestinal single-pass perfusion experiments and pharmacodynamics in immunodeficient mice were performed to make a comparison with TH powders and the control drug in absorption properties. RESULTS: A narrow size distribution of nanomicelles, with a mean particle size of (149 +/- 8.32) nm and a zeta potential of (-31.05 +/- 2.52) mV, was obtained. The in situ intestine perfusion experiments demonstrated a significant advantage in absorption characteristics for TH compared to the other formulations, and oral administration of TH-SDC/PL MMs potentiated an equivalent effect with i.h. TH in pharmacodynamic studies in immunodeficient mice. CONCLUSIONS: TH-SDC/PL-MMs prepared by a film dispersion method are able to improve the absorption of TH. SDC/PL-MMs might be a good approach for the more effective delivery of drugs like TH. PMID- 24484600 TI - Characterization and evaluation in vivo of baicalin-nanocrystals prepared by an ultrasonic-homogenization-fluid bed drying method. AB - AIM: To improve the absorption and bioavailability of baicalin using a nanocrystal (or nanosuspension) drug delivery system. METHODS: A tandem, ultrasonic-homogenization-fluid bed drying technology was applied to prepare baicalin-nanocrystal dried powders, and the physicochemical properties of baicalin-nanocrystals were characterized by scanning electron microscopy, photon correlation spectroscopy, powder X-ray diffraction, physical stability, and solubility experiments. Furthermore, in situ intestine single-pass perfusion experiments and pharmacokinetics in rats were performed to make a comparison between the microcrystals of baicalin and pure baicalin in their absorption properties and bioavailability in vivo. RESULTS: The mean particle size of baicalin-nanocrystals was 236 nm, with a polydispersity index of 0.173, and a zeta potential value of -34.8 mV, which provided a guarantee for the stability of the reconstituted nanosuspension. X-Ray diffraction results indicated that the crystallinity of baicalin was decreased through the ultrasonic-homogenization process. Physical stability experiments showed that the prepared baicalin nanocrystals were sufficiently stable. It was shown that the solubility of baicalin in the form of nanocrystals, at 495 MUg.mL(-1), was much higher than the baicalin-microcrystals and the physical mixture (135 and 86.4 MUg.mL(-1), respectively). In situ intestine perfusion experiments demonstrated a clear advantage in the dissolution and absorption characteristics for baicalin nanocrystals compared to the other formulations. In addition, after oral administration to rats, the particle size decrease from the micron to nanometer range exhibited much higher in vivo bioavailability (with the AUC(0-t) value of 206.96 +/- 21.23 and 127.95 +/- 14.41 mg.L(-1).h(-1), respectively). CONCLUSION: The nanocrystal drug delivery system using an ultrasonic-homogenization-fluid bed drying process is able to improve the absorption and in vivo bioavailability of baicalin, compared with pure baicalin coarse powder and micronized baicalin. PMID- 24484601 TI - Urban, semi-urban and rural difference in the prevalence of metabolic syndrome in Shaanxi province, northwestern China: a population-based survey. AB - BACKGROUND: The ongoing rapid urbanization in China offers rural population opportunities not only for economic improvement but also for substantial health risks. Albeit some researches related to rural-urban difference of metabolic syndrome (MS), there lacks studies focusing on this point in undeveloped provinces in China. METHODS: The survey, as part of China National Diabetes and Metabolic disorders Study, was conducted in Shaanxi province from June 2007 to May 2008. A total of 3,297 adults aged 20 years or older were included, of which 1,467 individuals were from urban areas, 839 from semi-urban areas, and 890 from rural areas. The MS was defined according to the 2009 Joint Interim Statement. RESULTS: The age-standardized prevalence of MS was significant higher in rural residents than in urban counterparts (29.0% vs. 25.9%, P = 0.017), in particular among females (30.2% vs. 24.4%, P = 0.003). After adjusted for the listed risk factors, rural residents had a 27.6% increased risk of having MS than urban residents. With respect to MS components, the crude prevalence of raised fasting glucose and raised blood pressure was significantly greater in rural than in urban participants. However, no significant difference in the prevalence of MS was observed between semi-urban and urban participants. CONCLUSIONS: Rural residents in Shaanxi province, northwest China, were at increased risk of MS, which could be partly explained by sociodemographic and lifestyle differences. In addition, the gap between urban and semi-urban areas seemed to be minimized in related to MS prevalence. Much more attention should be paid to and intervention strategies were needed to address the rural-urban disparities in China. PMID- 24484603 TI - Effects of in vitro exposure to titanium dioxide on DNA integrity of bottlenose dolphin (Tursiops truncatus) fibroblasts and leukocytes. AB - In the present study, the genotoxic potential of nanosized TiO2 anatase and micro sized rutile on bottlenose dolphin (Tursiops truncatus) fibroblasts and leukocytes was investigated. Human and mouse cells were also studied in order to compare susceptibility to TiO2 in different mammalian species. Cell lines were exposed for 4, 24, and 48 h to different concentrations of TiO2 (20, 50, 100, 150 MUg/ml) and DNA damage was investigated by single cell gel electrophoresis (Comet assay). Both anatase and rutile induced increased DNA damage, even though statistically significant effects were scattered according to species and cell lines. Bottlenose dolphin leukocytes and murine fibroblasts exhibited increased DNA damage after rutile exposure at some doses/times, while human fibroblasts showed a significant dose-response effect after a 4 h exposure to anatase. Human leukocytes were tolerant to both anatase and rutile. Ultrastructural investigation showed that TiO2 particles entered the cell and were compartmentalized within membrane-bound vesicles. PMID- 24484604 TI - Leishmania braziliensis and Leishmania amazonensis amastigote extracts differ in their enhancement effect on Leishmania infection when injected intradermally. AB - BACKGROUND: It has been reported that repeated intravenous injections of a relatively large amount of Leishmania amazonensis amastigote extract (LaE) in BALB/c mice exacerbates the infection of these mice by Leishmania braziliensis. The identification of the extract active principle(s) through physicochemical purification often involves dilution and losses of protein in the course of successive purification procedures. The large amount of the extract required to induce the phenomenon, therefore, hinders the carrying out of experiments aimed at identifying the active molecule(s) through extract purification. In the present work, a dose-response experiment was done to find out if smaller amounts of LaE than that necessary to be used by the intravenous route would reproduce the phenomenon when injected by the intradermal route. In addition, it was also investigated whether a Leishmania braziliensis amastigote extract (LbE) would exert the same effect and whether the effect would occur in C57BL/6 mice. RESULTS: It was found that a single injection of either LaE or LbE containing 5 MUg of protein was capable of enhancing the infection in BALB/c but not in C57BL/6 mice. In addition, it was observed that the largest tested doses of LbE (containing 30 and 180 MUg of protein) failed to enhance the infection by L. braziliensis, whereas all doses of LaE enhanced equally that infection. CONCLUSIONS: Those results indicate the possible existence in LbE, and not in LaE, of molecules that interfere with the extract infection-enhancing activity when it is injected in large amounts, and that the inoculation of Leishmania extracts through the intravenous and intradermal routes potentiate the infection by L. braziliensis through the same mechanism. PMID- 24484605 TI - Thoughts on a systematic review and meta-analysis of adjuvant chemotherapy in muscle-invasive bladder cancer. PMID- 24484607 TI - Monomeric Abeta1-42 and RAGE: key players in neuronal differentiation. AB - The aggregation of amyloid-beta (Abeta) peptides plays a crucial role in the onset and progression of Alzheimer's disease. Monomeric form of Abeta, indeed, could exert a physiological role. Considering the anti-oligomerization property of all-trans retinoic acid (ATRA), the involvement of monomeric Abeta1-42 in ATRA induced neuronal differentiation has been investigated. Four-day ATRA treatment increases beta-secretase 1 (BACE1) level, Abeta1-42 production, and receptor for advanced glycation end-products (RAGE) expression. RAGE is a well-recognized receptor for Abeta, and the block of both RAGE and Abeta1-42 with specific antibodies strongly impairs neurite formation in ATRA-treated cells. The involvement of Abeta1-42 and RAGE in ATRA-induced morphologic changes has been confirmed treating undifferentiated cells with different molecular assemblies of peptide: 1 MUM monomeric, but not oligomeric, Abeta1-42 increases RAGE expression and favors neurite elongation. The block of RAGE completely prevents this effect. Furthermore, our data underline the involvement of the RAGE-dependent adhesion molecule amphoterin-induced gene and open reading frame-1 as downstream effector of both ATRA and Abeta1-42. In conclusion, our findings identify a novel physiological role for monomeric Abeta1-42 and RAGE in neuronal differentiation. PMID- 24484608 TI - Ethnomedicine use in the war affected region of northwest Pakistan. AB - BACKGROUND: North-West of Pakistan is bestowed with medicinal plant resources due to diverse geographical and habitat conditions. The traditional use of plants for curing various diseases forms an important part of the region's cultural heritage. The study was carried out to document medicinal plants used in Frontier Region (FR) Bannu, an area affected by the "War on Terror". METHODS: Fieldwork was carried out in four different seasons (spring, autumn, summer and winter) from March 2012 to February 2013. Data on medicinal plants was collected using structured and semi-structured questionnaires from 250 respondents. The voucher specimens were collected, processed and identified following standard methods. RESULTS: Of the 107 species of ethnomedicinal plants reported, fifty percent species are herbaceous. The majority of the reported species were wild (55%) but a substantial proportion are cultivated (29%). For most of the plant species (34%), leaves are the most commonly used part in the preparation of ethnomedicines. The most common use of species is for carminative purposes (14 species), with the next most common use being for blood purification (11 species). The main methods used in the preparation of ethnomedicinal recipes involves grinding and boiling, and nearly all the remedies are taken orally along with ingredients such as water, milk or honey for ease of ingestion. Traditional healers prepare plant remedies using one or more plants. There was a significant correlation (r2 = 0.95) between the age of local people and the number of plants known to them, which indicates that in the coming 20 years, an approximate decrease of 75% in the indigenous knowledge may be expected. CONCLUSION: Traditional medicines are important to the livelihoods of rural communities in the region affected by the Global war on Terrorism. The medicinal recipes are indigenous; however, there is a threat to their future use on account of rapid modernization and terrorist activities. Documentation of medicinal plants and recipes may help in the conservation of the regional indigenous medicinal knowledge for future generations and to provide a baseline for further studies. PMID- 24484609 TI - The clinical effectiveness and cost-effectiveness of ablative therapies in the management of liver metastases: systematic review and economic evaluation. AB - BACKGROUND: Many deaths from cancer are caused by metastatic burden. Prognosis and survival rates vary, but survival beyond 5 years of patients with untreated metastatic disease in the liver is rare. Treatment for liver metastases has largely been surgical resection, but this is feasible in only approximately 20 30% of people. Non-surgical alternatives to treat some liver metastases can include various forms of ablative therapies and other targeted treatments. OBJECTIVES: To evaluate the clinical effectiveness and cost-effectiveness of the different ablative and minimally invasive therapies for treating liver metastases. DATA SOURCES: Electronic databases including MEDLINE, EMBASE and The Cochrane Library were searched from 1990 to September 2011. Experts were consulted and bibliographies checked. REVIEW METHODS: Systematic reviews of the literature were undertaken to appraise the clinical effectiveness and cost effectiveness of ablative therapies and minimally invasive therapies used for people with liver metastases. Studies were any prospective study with sample size greater than 100 participants. A probabilistic model was developed for the economic evaluation of the technologies where data permitted. RESULTS: The evidence assessing the clinical effectiveness and cost-effectiveness of ablative and other minimally invasive therapies was limited. Nine studies of ablative therapies were included in the review; each had methodological shortcomings and few had a comparator group. One randomised controlled trial (RCT) of microwave ablation versus surgical resection was identified and showed no improvement in outcomes compared with resection. In two prospective case series studies that investigated the use of laser ablation, mean survival ranged from 41 to 58 months. One cohort study compared radiofrequency ablation with surgical resection and five case series studies also investigated the use of radiofrequency ablation. Across these studies the median survival ranged from 44 to 52 months. Seven studies of minimally invasive therapies were included in the review. Two RCTs compared chemoembolisation with chemotherapy only. Overall survival was not compared between groups and methodological shortcomings mean that conclusions are difficult to make. Two case series studies of laser ablation following chemoembolisation were also included; however, these provide little evidence of the use of these technologies in combination. Three RCTs of radioembolisation were included. Significant improvements in tumour response and time to disease progression were demonstrated; however, benefits in terms of survival were equivocal. An exploratory survival model was developed using data from the review of clinical effectiveness. The model includes separate analyses of microwave ablation compared with surgery and radiofrequency ablation compared with surgery and one of radioembolisation in conjunction with hepatic artery chemotherapy compared with hepatic artery chemotherapy alone. Microwave ablation was associated with an incremental cost-effectiveness ratio (ICER) of L3664 per quality-adjusted life-year (QALY) gained, with microwave ablation being associated with reduced cost but also with poorer outcome than surgery. Radiofrequency ablation compared with surgical resection for solitary metastases < 3 cm was associated with an ICER of -L266,767 per QALY gained, indicating that radiofrequency ablation dominates surgical resection. Radiofrequency ablation compared with surgical resection for solitary metastases >= 3 cm resulted in poorer outcomes at lower costs and a resultant ICER of L2538 per QALY gained. Radioembolisation plus hepatic artery chemotherapy compared with hepatic artery chemotherapy was associated with an ICER of L37,303 per QALY gained. CONCLUSIONS: There is currently limited high-quality research evidence upon which to base any firm decisions regarding ablative therapies for liver metastases. Further trials should compare ablative therapies with surgery, in particular. A RCT would provide the most appropriate design for undertaking any further evaluation and should include a full economic evaluation, but the group to be randomised needs careful selection. SOURCE OF FUNDING: Funding for this study was provided by the Health Technology Assessment programme of the National Institute for Health Research. PMID- 24484610 TI - Personal and social determinants sustaining smoking practices in rural China: a qualitative study. AB - INTRODUCTION: Tobacco use in China is disproportionally distributed among rural and urban populations with rural people smoking more. While there is a wealth of evidence on the association between tobacco use among rural people and their lower socio-economic status (SES), how social structural factors contribute to rural smoking is not well understood. Guided by a socio-ecological model, the objective of this study was to explore the personal and social determinants that play a key role in sustaining smoking practices among Chinese rural people. METHODS: An ethnographic study was conducted in a rural area of Central Jiangsu, China. Participants (n = 29) were recruited from families where there was at least one smoking resident and there were young children. In-depth interviews and unstructured observations were used to collect data, which were then analyzed with an interpretive lens. RESULTS: Although individuals had limited knowledge about the risks of smoking and lack of motivation to quit, social factors were in effect the main barriers to quitting smoking. Cigarette exchange and cigarette gifting permeated every aspect of rural family life, from economic activities to leisure pastimes, in family and wider social interactions. Traditional familism and collectivism interplayed with the pro-smoking environment and supported rural people's smoking practices at the community level. Living in the rural area was also a barrier to quitting smoking because of the lack of information on smoking cessation and the influence of courtyard-based leisure activities that facilitated smoking. CONCLUSION: Development of comprehensive smoking cessation interventions in rural China needs to extend beyond an individual level to take into account the social determinants influencing smoking practices. PMID- 24484611 TI - Variability in fibrosis in tissue samples obtained during diaphragmatic and apical LVAD implantation. AB - BACKGROUND: Histopathologic study of left ventricular (LV) tissue can provide structural data on the heart at the time of left ventricular assist device (LVAD) implantation. We assessed the effect of cannula placement site (apical/diaphragmatic) and cardiomyopathy etiology (ischemic/nonischemic) on cardiac histopathologic changes. METHODS: In 77 heart failure patients, tissue was obtained from the standard apical cannula insertion site or the diaphragmatic surface site during implantation of the HeartMate II (n=53) or HeartWare (n=24) LVAD. Fibrosis and hypertrophy (cytoplasmic and nuclear diameter) were evaluated by computerized morphometry. RESULTS: Thirty-two patients (27 men, 5 women; age, 57+/-15 years) underwent diaphragmatic implantation, and 45 (32 men, 13 women; age, 53+/-12 years) underwent apical implantation. The incidence of ischemic cardiomyopathy in the diaphragmatic and apical groups was 11/32 (34%) vs. 25/45 (56%) (P=.104). Overall, diaphragmatic tissue had less fibrosis than apical tissue (15.7+/-11.7% vs. 22.0+/-17.4%, P=.033), but both showed similar hypertrophic changes (cytoplasmic diameter, 39.0+/-10.3MUm vs. 36.3+/-8.7MUm, P=.141; nuclear diameter, 15.5+/-2.5MUm vs. 14.8+/-3.0MUm, P=.171). Likewise, in ischemic cardiomyopathy, apical samples showed more fibrosis than diaphragmatic samples (26.54+/-19.0% vs. 15.86+/-11.08%, P=.046) but similar hypertrophic changes (cytoplasmic diameter, 34.95+/-6.12MUm vs. 37.48+/-12.07MUm, P=.288; nuclear diameter, 14.66+/-2.69MUm vs. 14.78+/-1.31MUm, P=.451). CONCLUSION: Myocardial histology results at the time of LVAD placement and their prognostic implications may be affected by inlet placement site and cardiomyopathy etiology. In this study, LV samples from apical implantation in ischemic cardiomyopathy patients were the most fibrotic. Thus, sampling site and cardiomyopathy etiology should be considered when interpreting LV samples obtained during LVAD implantation. PMID- 24484612 TI - Nikolai N. Anitschkow and the lipid hypothesis of atherosclerosis. AB - One hundred years ago, Nikolai N. Anitschkow published his seminal observations that rabbits fed a diet with only high-cholesterol developed atheromatous lesions in association with greatly elevated blood cholesterol. For many years, Anitschkow's observations received little recognition. However, eventually a combination of experimental work, autopsy studies, epidemiological investigation and clinical trials has led to the firm establishment of the essential role of lipids in the response to injury theory of atherosclerosis. The twists and turns in the acceptance of the lipid hypothesis of atherosclerosis is briefly reviewed. Today, it is well worth celebrating the 100th anniversary of the seminal insight into human vascular disease of the brilliant experimental pathologist, Nikolai N. Anitschkow. PMID- 24484613 TI - Inter-study reproducibility of arterial spin labelling magnetic resonance imaging for measurement of renal perfusion in healthy volunteers at 3 Tesla. AB - BACKGROUND: Measurement of renal perfusion is a crucial part of measuring kidney function. Arterial spin labelling magnetic resonance imaging (ASL MRI) is a non invasive method of measuring renal perfusion using magnetised blood as endogenous contrast. We studied the reproducibility of ASL MRI in normal volunteers. METHODS: ASL MRI was performed in healthy volunteers on 2 occasions using a 3.0 Tesla MRI scanner with flow-sensitive alternating inversion recovery (FAIR) perfusion preparation with a steady state free precession (True-FISP) pulse sequence. Kidney volume was measured from the scanned images. Routine serum and urine biochemistry were measured prior to MRI scanning. RESULTS: 12 volunteers were recruited yielding 24 kidneys, with a mean participant age of 44.1 +/- 14.6 years, blood pressure of 136/82 mmHg and chronic kidney disease epidemiology formula estimated glomerular filtration rate (CKD EPI eGFR) of 98.3 +/- 15.1 ml/min/1.73 m2. Mean kidney volumes measured using the ellipsoid formula and voxel count method were 123.5 +/- 25.5 cm3, and 156.7 +/- 28.9 cm3 respectively. Mean kidney perfusion was 229 +/- 41 ml/min/100 g and mean cortical perfusion was 327 +/- 63 ml/min/100 g, with no significant differences between ASL MRIs. Mean absolute kidney perfusion calculated from kidney volume measured during the scan was 373 +/- 71 ml/min. Bland Altman plots were constructed of the cortical and whole kidney perfusion measurements made at ASL MRIs 1 and 2. These showed good agreement between measurements, with a random distribution of means plotted against differences observed. The intra class correlation for cortical perfusion was 0.85, whilst the within subject coefficient of variance was 9.2%. The intra class correlation for whole kidney perfusion was 0.86, whilst the within subject coefficient of variance was 7.1%. CONCLUSIONS: ASL MRI at 3.0 Tesla provides a repeatable method of measuring renal perfusion in healthy subjects without the need for administration of exogenous compounds. We have established normal values for renal perfusion using ASL MRI in a cohort of healthy volunteers. PMID- 24484614 TI - Chronic effects of ambient air pollution on respiratory morbidities among Chinese children: a cross-sectional study in Hong Kong. AB - BACKGROUND: The chronic health effects from exposure to ambient air pollution are still unclear. This study primarily aims to examine the relationship between long term exposure to ambient air pollution and respiratory morbidities in Chinese children. METHODS: A cross-sectional study was conducted among 2,203 school children aged 8-10 in three districts with different air pollution levels in Hong Kong. Annual means for ambient PM10, SO2, NO2 and O3 in each district were used to estimate participants' individual exposure. Two questionnaires were used to collect children's respiratory morbidities and other potential risk factors. Multivariable logistic regression was fitted to estimate the risks of air pollution for respiratory morbidities. RESULTS: Compared to those in the low pollution district (LPD), girls in the high-pollution district (HPD) were at significantly higher risk for cough at night (ORadj. = 1.81, 95% CI: 1.71-2.78) and phlegm without colds (ORadj. = 3.84, 95% CI: 1.74-8.47). In addition, marginal significance was reached for elevated risks for asthma, wheezing symptoms, and phlegm without colds among boys in HPD (adjusted ORs: 1.71-2.82), as well as chronic cough among girls in HPD (ORadj. = 2.03, 95% CI: 0.88-4.70). CONCLUSIONS: Results have confirmed certain adverse effects on children's respiratory health from long-term exposure to ambient air pollution. PM10 may be the most relevant pollutant with adverse effects on wheezing and phlegm in boys. Both PM10 and NO2 may be contributing to cough and phlegm in girls. PMID- 24484615 TI - pH-triggered conduction of amine-functionalized single ZnO wire integrated on a customized nanogap electronic platform. AB - The electrical conductance response of single ZnO microwire functionalized with amine-groups was tested upon an acid pH variation of a solution environment after integration on a customized gold electrode array chip. ZnO microwires were easily synthesized by hydrothermal route and chemically functionalized with aminopropyl groups. Single wires were deposited from the solution and then oriented through dielectrophoresis across eight nanogap gold electrodes on a platform single chip. Therefore, eight functionalized ZnO microwire-gold junctions were formed at the same time, and being integrated on an ad hoc electronic platform, they were ready for testing without any further treatment. Experimental and simulation studies confirmed the high pH-responsive behavior of the amine-modified ZnO-gold junctions, obtaining in a simple and reproducible way a ready-to-use device for pH detection in the acidic range. We also compared this performance to bare ZnO wires on the same electronic platform, showing the superiority in pH response of the amine-functionalized material. PMID- 24484617 TI - Serum protein acidic and rich in cysteine (SPARC) as a prognostic marker in soft tissue sarcomas. AB - BACKGROUND: Serum protein acidic and rich in cysteine (SPARC) is a matricellular secreted glycoprotein that performs several cellular functions and has been implicated in tumorigenesis in a variety of tumor types. The chemotherapeutic agent nanoparticle albumin-encapsulated (NAB)-paclitaxel has been postulated to exploit SPARC expression to target neoplastic cells. SPARC's role, and potentially the role of NAB-paclitaxel, in the highly heterogeneous class of soft tissue sarcomas (STS) has not been investigated. Our objective was to explore the pattern of SPARC expression and its prognostic significance in STS. METHODS: 27 tissue specimens representing various STS histologies were stained for SPARC expression by immunohistochemistry (IHC). Staining intensity was scored blindly. Survival was determined from patients' medical records and analyzed using Kaplan Meier and log-rank with respect to SPARC expression level. RESULTS: Elevated SPARC expression was observed in 15/27 (56%) specimens. Overall patient survival segregated strongly based on levels of SPARC expression. Patients who expressed low-to-moderate levels of SPARC exhibited median survival of 22.1 months, while the median survival of patients with moderate-to-high expression levels was 4.4 months (log rank; p = 0.0016). CONCLUSIONS: SPARC expression is elevated in a significant proportion of STS specimens analyzed in this study, but it does not appear to correlate with specific STS histologies. Given our limited sample size, we cannot draw definitive conclusions regarding association of SPARC with STS subtype. Overall survival segregates strongly by degree of SPARC expression, with elevated expression being adverse. If validated in a larger study, our results suggest that trials in STS with agents potentially targeting SPARC, such as NAB paclitaxel, should be stratified by SPARC expression level. PMID- 24484616 TI - Characterization of CTX-M-14 and CTX-M-15 producing Escherichia coli strains causing neonatal sepsis. AB - Neonatal sepsis is a disease affecting newborns <=1 month of age with clinical symptoms and positive blood cultures. The number of Escherichia coli strains causing neonatal sepsis resistant to the antibiotics used in the treatment is increasing. In this study, two E. coli strains causing sepsis in neonates of mothers infected with an E. coli strain harboring extended spectrum beta lactamases were characterized. The bla(CTX-M-15) and the bla(CTX-M-14) genes were found in an IncFIA and nontypeable transferable plasmids, respectively. In addition, these highly virulent strains belonged to ST705 and ST156 clonal groups, respectively. The presence of strains, which are highly virulent and resistant to ampicillin, gentamicin, and cephalosporins, makes a change in empirical treatment necessary as well as an increase in the surveillance of these infections. PMID- 24484618 TI - Consensus-based clinical practice recommendations for the examination and management of falls in patients with Parkinson's disease. AB - Falls in Parkinson's disease (PD) are common and frequently devastating. Falls prevention is an urgent priority, but there is no accepted program that specifically addresses the risk profile in PD. Therefore, we aimed to provide consensus-based clinical practice recommendations that systematically address potential fall risk factors in PD. We developed an overview of both generic (age related) and PD-specific factors. For each factor, we specified: best method of ascertainment; disciplines that should be involved in assessment and treatment; and which interventions could be engaged. Using a web-based tool, we asked 27 clinically active professionals from multiple relevant disciplines to evaluate this overview. The revised version was subsequently reviewed by 12 experts. Risk factors and their associated interventions were included in the final set of recommendations when at least 66% of reviewing experts agreed. These recommendations included 31 risk factors. Nearly all required a multidisciplinary team approach, usually involving a neurologist and PD-nurse specialist. Finally, the expert panel proposed to first identify the specific fall type and to tailor screening and treatment accordingly. A routine evaluation of all risk factors remains reserved for high-risk patients without prior falls, or for patients with seemingly unexplained falls. In conclusion, this project produced a set of consensus-based clinical practice recommendations for the examination and management of falls in PD. These may be used in two ways: for pragmatic use in current clinical practice, pending further evidence; and as the active intervention in clinical trials, aiming to evaluate the effectiveness and cost effectiveness of large scale implementation. PMID- 24484606 TI - Targeted prostate cancer screening in BRCA1 and BRCA2 mutation carriers: results from the initial screening round of the IMPACT study. AB - BACKGROUND: Men with germline breast cancer 1, early onset (BRCA1) or breast cancer 2, early onset (BRCA2) gene mutations have a higher risk of developing prostate cancer (PCa) than noncarriers. IMPACT (Identification of Men with a genetic predisposition to ProstAte Cancer: Targeted screening in BRCA1/2 mutation carriers and controls) is an international consortium of 62 centres in 20 countries evaluating the use of targeted PCa screening in men with BRCA1/2 mutations. OBJECTIVE: To report the first year's screening results for all men at enrollment in the study. DESIGN, SETTING AND PARTICIPANTS: We recruited men aged 40-69 yr with germline BRCA1/2 mutations and a control group of men who have tested negative for a pathogenic BRCA1 or BRCA2 mutation known to be present in their families. All men underwent prostate-specific antigen (PSA) testing at enrollment, and those men with PSA >3 ng/ml were offered prostate biopsy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: PSA levels, PCa incidence, and tumour characteristics were evaluated. The Fisher exact test was used to compare the number of PCa cases among groups and the differences among disease types. RESULTS AND LIMITATIONS: We recruited 2481 men (791 BRCA1 carriers, 531 BRCA1 controls; 731 BRCA2 carriers, 428 BRCA2 controls). A total of 199 men (8%) presented with PSA >3.0 ng/ml, 162 biopsies were performed, and 59 PCas were diagnosed (18 BRCA1 carriers, 10 BRCA1 controls; 24 BRCA2 carriers, 7 BRCA2 controls); 66% of the tumours were classified as intermediate- or high-risk disease. The positive predictive value (PPV) for biopsy using a PSA threshold of 3.0 ng/ml in BRCA2 mutation carriers was 48%-double the PPV reported in population screening studies. A significant difference in detecting intermediate- or high-risk disease was observed in BRCA2 carriers. Ninety-five percent of the men were white, thus the results cannot be generalised to all ethnic groups. CONCLUSIONS: The IMPACT screening network will be useful for targeted PCa screening studies in men with germline genetic risk variants as they are discovered. These preliminary results support the use of targeted PSA screening based on BRCA genotype and show that this screening yields a high proportion of aggressive disease. PATIENT SUMMARY: In this report, we demonstrate that germline genetic markers can be used to identify men at higher risk of prostate cancer. Targeting screening at these men resulted in the identification of tumours that were more likely to require treatment. PMID- 24484619 TI - Expansion of the clinicopathological and mutational spectrum of Perry syndrome. AB - BACKGROUND: Perry syndrome (PS) caused by DCTN1 gene mutation is clinically characterized by autosomal dominant parkinsonism, depression, severe weight loss, and hypoventilation. Previous pathological studies have reported relative sparing of the cerebral cortex in this syndrome. Here, we characterize novel clinical and neuroimaging features in 3 patients with PS. METHODS: (18)F-fluorinated N-3 fluoropropyl-2-beta-carboxymethoxy-3-beta-(4-iodophenyl) nortropane ([(18)F]FP CIT) PET, [(18)F]fluorodeoxyglucose PET, or volumetric MRI was performed in probands, and imaging data were analyzed and compared with those of control subjects. RESULTS: We identified 2 novel mutations of DCTN1. Oculogyric crisis that presented before levodopa treatment was observed in 1 case. One patient had supranuclear gaze palsy. In 2 cases, [(18)F]FP-CIT showed marked loss of dopamine transporter binding with only mild parkinsonism. Areas of hypometabolism or cortical thickness change were observed in dorsolateral frontal, anterior cingulate, lateral temporal, and inferior parietal cortices. CONCLUSION: Oculomotor manifestations are not uncommon in PS. Neuroimaging studies suggest involvement of the frontotemporoparietal cortex, which may be the clinical correlate of apathy and depression, as well as pathological changes in subcortical structures. PMID- 24484620 TI - Switching from aspirin to clopidogrel in patients with aspirin resistance after an ischemic stroke. Is it a good solution? PMID- 24484621 TI - Serum magnesium in postoperative patients admitted to the intensive care unit. PMID- 24484622 TI - Reliability measures in item response theory: manifest versus latent correlation functions. AB - For item response theory (IRT) models, which belong to the class of generalized linear or non-linear mixed models, reliability at the scale of observed scores (i.e., manifest correlation) is more difficult to calculate than latent correlation based reliability, but usually of greater scientific interest. This is not least because it cannot be calculated explicitly when the logit link is used in conjunction with normal random effects. As such, approximations such as Fisher's information coefficient, Cronbach's alpha, or the latent correlation are calculated, allegedly because it is easy to do so. Cronbach's alpha has well known and serious drawbacks, Fisher's information is not meaningful under certain circumstances, and there is an important but often overlooked difference between latent and manifest correlations. Here, manifest correlation refers to correlation between observed scores, while latent correlation refers to correlation between scores at the latent (e.g., logit or probit) scale. Thus, using one in place of the other can lead to erroneous conclusions. Taylor series based reliability measures, which are based on manifest correlation functions, are derived and a careful comparison of reliability measures based on latent correlations, Fisher's information, and exact reliability is carried out. The latent correlations are virtually always considerably higher than their manifest counterparts, Fisher's information measure shows no coherent behaviour (it is even negative in some cases), while the newly introduced Taylor series based approximations reflect the exact reliability very closely. Comparisons among the various types of correlations, for various IRT models, are made using algebraic expressions, Monte Carlo simulations, and data analysis. Given the light computational burden and the performance of Taylor series based reliability measures, their use is recommended. PMID- 24484623 TI - Tension pneumopericardium. PMID- 24484624 TI - Location of the appendix in the gravid patient. AB - BACKGROUND: Several studies have attempted to support or dispel the teaching of appendix movement away from the right lower quadrant (RLQ) during pregnancy with contradictory results. OBJECTIVE: This study investigated the location of the appendix in the gravid patient in an emergency department (ED) setting using computed tomography (CT). METHODS: This was a retrospective chart review of consecutive gravid patients presenting to the ED for trauma who required abdominal CT. The patient population was obtained using the Vidant Medical Center Trauma Registry from January 1, 2000 to December 31, 2006. The abdomen was divided into nine regions using the mid-clavicular lines, superior anterior iliac spine, and umbilicus. A single Board-certified radiologist determined the region location of the appendix. RESULTS: Forty-five patients were identified and 35 were studied. Ten patients were excluded due to appendix not identified, unknown gestational age, or inability to review the CT study. In 21 of 22 third-trimester pregnancies, the appendix was not found in the right lower region (RLR), which corresponded to the RLQ. All 11 patients in the second trimester did not have the appendix in the RLR. Two patients were identified in the first trimester and neither appendix was found in the RLR. CONCLUSIONS: The appendix in the gravid patient was not found in the RLR with increasing frequency as pregnancy progressed. PMID- 24484625 TI - The impact of patient telephone call after discharge on likelihood to recommend in an academic emergency department. AB - BACKGROUND: Patient satisfaction is a common parameter tracked by health care systems, and likely influences patient provider choice and may impact insurer payment. Achieving high satisfaction in an academic emergency department (ED) can be a daunting task due to variable volumes, acuity, and overcrowding. OBJECTIVE: The objective of this study was to assess the impact of a postdischarge telephone call by a staff member after discharge from the ED on patient satisfaction. METHODS: This was a prospective cohort study conducted in the two University of California San Diego Health System EDs. Press Ganey patient satisfaction surveys are mailed to a random sample of 50% of all discharged patients. In August 2010 a program of MD and RN telephone call back 1 to 5 days after the ED visit was initiated. In conjunction with this program, a custom question was added to the standard survey, "Called back after discharge, Yes/No?" All surveys returned between September 22, 2010 and December 7, 2010 were reviewed, and those that chose to self-identify were selected to allow for ED chart review. The key outcome variable "likelihood to recommend score" was dichotomized into the highest category, 5 (very good) and remaining levels, 1-4 (very poor, poor, fair, good). ED records were abstracted for data on waiting time (WT), length of stay (LOS), and triage class (TC). These variables were selected because they have been shown to impact patient satisfaction in prior studies. Likelihood to recommend ratings for those reporting "Yes" to call back were compared to those reporting "No" to call back. Summary statistics were generated for patient characteristics in the "Yes" and "No" groups. Ninety-five percent confidence intervals (CIs) for all counts and proportions were calculated with the "exact" method. A logistic regression model was constructed assessing odds ratio (OR) for likelihood-to-recommend score 5 while controlling for the variables of WT, LOS, and TC. RESULTS: In the study period, about 5000 surveys were mailed, 507 were returned, and 368 self-identified. Of those that self-identified, 136 patients answered "Yes" to the callback question and 232 answered "No." The mean age for those indicating "Yes" was 55.8 years (CI 52.9-58.7), and for those indicating "No," 50.7 years (CI 47.9-53.5). Gender and triage code were similar between the two groups. Among those answering "Yes," 89.0% (CI 82.5-93.7) provided a "5" rating for "likelihood to recommend," compared to 55.6% (CI 49.0-62.1) who replied "No" for call back. The logistic regression model generated an OR of 6.35 (CI 3.4-11.7) for providing a level 5 rating for "likelihood to recommend" for patients reporting "Yes" for call back after controlling for WT, LOS, and TC. CONCLUSION: In the study institution, patients that are called back are much more likely to have a favorable impression of the visit as assessed by likelihood to recommend regardless of WT, LOS, or TC. These data support "call back" as an effective strategy to improve ED patient satisfaction. PMID- 24484626 TI - Infliximab-induced urticaria. PMID- 24484627 TI - Oxycodone insufflation resulting in nasal septal abscess. PMID- 24484628 TI - Arabic-speaking migrants' attitudes, opinions, preferences and past experiences concerning the use of interpreters in healthcare: a postal cross-sectional survey. AB - BACKGROUND: Good communication is an important prerequisite for equal treatment in a healthcare encounter. One way to overcome language barriers when patients and healthcare staff do not share the same language is to use a professional interpreter. Few previous studies have been found investigating the use of interpreters, and just one previous study from the perspective of European migrants, which showed that they perceived interpreters as a communication aid and a guide in the healthcare system as regards information and practical matters. No previous study has gathered quantitative information to focus on non European migrants' attitudes to the use of interpreters in healthcare encounters. Thus, the aim of this study was to investigate Arabic-speaking individuals' attitudes, opinions, preferences and past experiences concerning the use of interpreters in healthcare in order to: (i) understand how persons' expectations and concerns regarding interpreters may vary, both within and across cultural/linguistic populations; (ii) understand the consequences of diverse opinions/expectations for planning responsive services; and (iii) confirm findings from previous qualitative studies. METHOD: A postal cross-sectional study using a structured self-administered 51-item questionnaire was used to describe and document aspects of Arabic-speaking individuals' attitudes to the use of interpreters in healthcare. The sample of 53 Arabic-speaking migrants was recruited from three different places. Participants were mostly born in Iraq and had a high level of education and were almost equally divided between genders. Data were analysed with descriptive statistics. RESULTS: The main findings were that most of the participants perceived the interpreter's role as being a communication aid and a practical aid, interpreting literally and objectively. Trust in the professional interpreter was related to qualification as an interpreter and personal contact with face-to-face interaction. The qualities of the desired professional interpreter were: a good knowledge of languages and medical terminology, translation ability, and sharing the same origin, dialect and gender as the patient. CONCLUSION: This study confirmed previous qualitative findings from European migrant groups with a different cultural and linguistic background. The study supports the importance of planning a good interpretation situation in accordance with individuals' desire, irrespective of the migrant's linguistic and cultural background, and using interpreters who interpret literally and objectively, who are highly trained with language skills in medical terminology, and with a professional attitude to promote communication, thus increasing cost-effective, high-quality individualized healthcare. PMID- 24484629 TI - Phospholipid composition and kinetics in different endobronchial fractions from healthy volunteers. AB - BACKGROUND: Alterations in surfactant phospholipid compositions are a recognized feature of many acute and chronic lung diseases. Investigation of underlying mechanisms requires assessment of surfactant phospholipid molecular composition and kinetics of synthesis and turnover. Such studies have recently become possible in humans due to the development of stable isotope labelling combined with advances in analytical methods in lipidomics. The objectives of this study are to compare phospholipid molecular species composition and phosphatidylcholine synthesis and turnover in surfactant isolated from various endobronchial compartments in healthy adults. METHODS: Healthy adults (N = 10) were infused with methyl-D9-choline chloride and samples of induced sputum, tracheal wash and small volume bronchoalveolar lavage fluid were obtained subsequently at intervals up to 96 hours. Surfactant phospholipid composition and incorporation of stable isotope into surfactant phosphatidylcholine were determined by electrospray ionisation mass spectrometry. RESULTS: While molecular species compositions of phospholipids were similar for all three sample types, dipalmitoylphosphatidylcholine content was highest in lavage, intermediate in tracheal wash and lowest in sputum. Methyl-D9-choline incorporation into surfactant phosphatidylcholine was lower for sputum at 24 hours but reached equilibrium with other sample types by 48 hours. Fractional methyl-D9 dipalmitoylphosphatidylcholine incorporation for all sample types was about 0.5% of the endogenous composition. Lysophosphatidylcholine enrichment was twice than that of phosphatidylcholine. CONCLUSIONS: Tracheal secretions may be of value as a surrogate to assess bronchoalveolar lavage fluid surfactant molecular composition and metabolism in healthy people. Despite minor differences, the phospholipid molecular composition of induced sputum also showed similarities to that of bronchoalveolar lavage fluid. Detailed analysis of newly synthesized individual phosphatidylcholine species provided novel insights into mechanisms of surfactant synthesis and acyl remodelling. Lysophosphatidylcholine methyl-D9 incorporation patterns suggest that these species are secreted together with other surfactant phospholipids and are not generated in the air spaces by hydrolysis of secreted surfactant phosphatidylcholine. Application into patient populations may elucidate potential underlying pathophysiological mechanisms that lead to surfactant alterations in disease states. PMID- 24484630 TI - Paraneoplastic dermatomyositis: a study of 12 cases. AB - INTRODUCTION AND OBJECTIVES: Adult dermatomyositis presents as a paraneoplastic syndrome in up to 25% of cases, but no clinical, histologic, or laboratory markers completely specific for paraneoplastic disease in dermatomyositis have been identified to date. Furthermore, studies on adult dermatomyositis do not usually report the frequency of cutaneous features of dermatomyositis in patients with associated cancer. Our aim was to review the characteristics of paraneoplastic dermatomyositis in patients seen at our hospital. MATERIAL AND METHODS: We studied 12 cases of paraneoplastic dermatomyositis and recorded patient age and sex, associated cancer, time between onset of dermatomyositis and cancer, emergent cutaneous manifestations, muscle involvement, dysphagia, lung disease, and levels of creatine phosphokinase and circulating autoantibodies. RESULTS: The mean age of the patients was 61 years and the 2 most common malignancies were ovarian cancer and bladder cancer. The mean time between the diagnosis of cancer and dermatomyositis was 7 months and in most cases, the cancer was diagnosed first. Seven patients had amyopathic dermatomyositis. The most common cutaneous signs were a violaceous photodistributed rash sparing the interscapular area and a heliotrope rash, followed by Gottron papules and cuticle involvement. Superficial cutaneous necrosis was observed in 3 cases. Myositis specific autoantibodies were not detected in any of the 6 patients who underwent this test. CONCLUSIONS: Paraneoplastic dermatomyositis is often amyopathic. There are no specific cutaneous markers for malignancy in dermatomyositis. Myositis specific antibodies are not associated with paraneoplastic dermatomyositis. PMID- 24484632 TI - Extreme ambient temperatures and cardiorespiratory emergency room visits: assessing risk by comorbid health conditions in a time series study. AB - BACKGROUND: Extreme ambient temperatures are an increasing public health concern. The aim of this study was to assess if persons with comorbid health conditions were at increased risk of adverse cardiorespiratory morbidity during temperature extremes. METHODS: A time series study design was applied to 292,666 and 562,738 emergency room (ER) visits for cardiovascular and respiratory diseases, respectively, that occurred in Toronto area hospitals between April 1st 2002 and March 31st 2010. Subgroups of persons with comorbid health conditions were identified. Relative risks (RRs) and their corresponding 95% confidence intervals (CIs) were estimated using a Poisson regression model with distributed lag non linear model, and were adjusted for the confounding influence of seasonality, relative humidity, day-of-the-week, outdoor air pollutants and daily influenza ER visits. Effect modification by comorbid health conditions was tested using the relative effect modification (REM) index. RESULTS: Stronger associations of cardiovascular disease ER visits were observed for persons with diabetes compared to persons without diabetes (REM = 1.12; 95% CI: 1.01 - 1.27) with exposure to the cumulative short term effect of extreme hot temperatures (i.e. 99th percentile of temperature distribution vs. 75th percentile). Effect modification was also found for comorbid respiratory disease (REM = 1.17; 95% CI: 1.02 - 1.44) and cancer (REM = 1.20; 95% CI: 1.02 - 1.49) on respiratory disease ER visits during short term hot temperature episodes. The effect of extreme cold temperatures (i.e. 1st percentile of temperature distribution vs. 25th percentile) on cardiovascular disease ER visits were stronger for individuals with comorbid cardiac diseases (REM = 1.47; 95% CI: 1.06 - 2.23) and kidney diseases (REM = 2.43; 95% CI: 1.59 - 8.83) compared to those without these conditions when cumulated over a two-week period. CONCLUSIONS: The identification of those most susceptible to temperature extremes is important for public health officials to implement adaptation measures to manage the impact of extreme temperatures on population health. PMID- 24484634 TI - Interleukin-6 is required for cell cycle arrest and activation of DNA repair enzymes after partial hepatectomy in mice. AB - BACKGROUND: Interleukin-6 (IL-6) has been shown to be vital for liver regeneration, however the specific mechanisms and factors involved remain incompletely defined. The present study aimed to investigate whether IL-6 exerts its protective effects via arresting the cell cycle allowing base excision and repair of oxidized DNA after hepatectomy. RESULTS: Following seventy percent partial hepatectomy (PH) in wild type (WT) mice IL-6 serum levels increased reaching peak levels at 3 hours. This was associated with markers of cell cycle arrest as p21 expression was increased and cyclin D1 and proliferating cell nuclear antigen (PCNA) expression decreased. In the absence of IL-6, markers of cell cycle arrest were absent and the number of bromodeoxyuridine (BrdU) positive cells was significantly higher at 28, 32 and 36 hours after PH. The mRNAs for DNA repair enzymes, including Neil-1, 8-oxodGTPase, OGG1, Apex1, and UDG (DNA glycosylase) were increased 2 to 4 fold in WT mice at 6 and/or 12 hours after PH compared to IL-6 knockout (KO) mice. The protein levels of Neil1 and OGG1 were also significantly increased in WT mice compared to KO mice. Pathological changes were far greater and survival was less in IL-6 KO mice than in WT mice. Administration of IL-6 in KO mice restored p21 and DNA repair enzyme expression to wild-type levels and survival was improved. CONCLUSIONS: IL-6 caused cell cycle arrest and delayed proliferation during the first day after PH. This delay was associated with the activation of DNA repair enzymes resulting in accurate replication and restoration of hepatic mass. PMID- 24484633 TI - Resolution of the three dimensional structure of components of the glomerular filtration barrier. AB - BACKGROUND: The human glomerulus is the primary filtration unit of the kidney, and contains the Glomerular Filtration Barrier (GFB). The GFB had been thought to comprise 3 layers - the endothelium, the basement membrane and the podocyte foot processes. However, recent studies have suggested that at least two additional layers contribute to the function of the GFB, the endothelial glycocalyx on the vascular side, and the sub-podocyte space on the urinary side. To investigate the structure of these additional layers is difficult as it requires three dimensional reconstruction of delicate sub-microscopic (<1 MUm) cellular and extracellular elements. METHODS: Here we have combined three different advanced electron microscopic techniques that cover multiple orders of magnitude of volume sampled, with a novel staining methodology (Lanthanum Dysprosium Glycosaminoglycan adhesion, or LaDy GAGa), to determine the structural basis of these two additional layers. Serial Block Face Scanning Electron Microscopy (SBF SEM) was used to generate a 3-D image stack with a volume of a 5.3 x 105 MUm3 volume of a whole kidney glomerulus (13% of glomerular volume). Secondly, Focused Ion Beam milling Scanning Electron Microscopy (FIB-SEM) was used to image a filtration region (48 MUm3 volume). Lastly Transmission Electron Tomography (Tom TEM) was performed on a 0.3 MUm3 volume to identify the fine structure of the glycocalyx. RESULTS: Tom-TEM clearly showed 20 nm fibre spacing in the glycocalyx, within a limited field of view. FIB-SEM demonstrated, in a far greater field of view, how the glycocalyx structure related to fenestrations and the filtration slits, though without the resolution of TomTEM. SBF-SEM was able to determine the extent of the sub-podocyte space and glycocalyx coverage, without additional heavy metal staining. Neither SBF- nor FIB-SEM suffered the anisotropic shrinkage under the electron beam that is seen with Tom-TEM. CONCLUSIONS: These images demonstrate that the three dimensional structure of the GFB can be imaged, and investigated from the whole glomerulus to the fine structure of the glycocalyx using three dimensional electron microscopy techniques. This should allow the identification of structural features regulating physiology, and their disruption in pathological states, aiding the understanding of kidney disease. PMID- 24484635 TI - Estimated incidence rate and distribution of tumours in 4,653 cases of archival submissions derived from the Dutch golden retriever population. AB - BACKGROUND: A genetic predisposition for certain tumour types has been proven for some dog breeds. Some studies have suggested that this may also be true for the Golden retriever breed. The present study aimed to examine a possible existence of a tumour (type) predisposition in the Dutch population of Golden retrievers by evaluating annual estimated incidence rates compared to incidence rates from previous publications. A second aim was to evaluate whether incidences of various tumours differed as related to the diagnostic method chosen, being either cytology or histology. RESULTS: Tumours submitted to Utrecht University during the period 1998-2004 diagnosed either by means of cytology (n = 2,529) or histology (n = 2,124), were related to an average annual Dutch kennel club population of 29,304 Golden retrievers.Combining individual tumours from both the cytological and the histopathological data-set resulted in an annual estimated incidence rate of 2,242 for 100,000 dog-years at risk regarding tumour development in general.The most common cytological tumor diagnoses were 'fat, possibly lipoma' (35%), mast cell tumour (21%) and non-Hodgkin lymphoma (10%). The most commonly diagnosed tumours by histology were mast cell tumour (26%), soft tissue sarcomas (11%) and melanoma (8%). Both the cytological and histopathological data-sets, showed variation; in patient age distribution, age of onset and incidence of various tumours. CONCLUSION: Comparing our data with previous reports in non-breed-specified dog populations, the Golden retriever breed shows an increased risk for the development of tumours in general, as well as an increased risk for the development of specific tumour types, including the group of soft tissue sarcomas. Variations in age, location and incidence of various tumours were observed between the two data-sets, indicating a selection bias for diagnostic procedure. PMID- 24484636 TI - Broadband antireflective silicon nanostructures produced by spin-coated Ag nanoparticles. AB - We report the fabrication of broadband antireflective silicon (Si) nanostructures fabricated using spin-coated silver (Ag) nanoparticles as an etch mask followed by inductively coupled plasma (ICP) etching process. This fabrication technique is a simple, fast, cost-effective, and high-throughput method, making it highly suitable for mass production. Prior to the fabrication of Si nanostructures, theoretical investigations were carried out using a rigorous coupled-wave analysis method in order to determine the effects of variations in the geometrical features of Si nanostructures to obtain antireflection over a broad wavelength range. The Ag ink ratio and ICP etching conditions, which can affect the distribution, distance between the adjacent nanostructures, and height of the resulting Si nanostructures, were carefully adjusted to determine the optimal experimental conditions for obtaining desirable Si nanostructures for practical applications. The Si nanostructures fabricated using the optimal experimental conditions showed a very low average reflectance of 8.3%, which is much lower than that of bulk Si (36.8%), as well as a very low reflectance for a wide range of incident angles and different polarizations over a broad wavelength range of 300 to 1,100 nm. These results indicate that the fabrication technique is highly beneficial to produce antireflective structures for Si-based device applications requiring low light reflection. PMID- 24484637 TI - Detection of tick-borne 'Candidatus Neoehrlichia mikurensis' and Anaplasma phagocytophilum in Spain in 2013. AB - BACKGROUND: 'Candidatus Neoehrlichia mikurensis' is a tick-borne bacteria implicated in human health. To date, 'Ca. Neoehrlichia mikurensis' has been described in different countries from Africa, Asia and Europe, but never in Spain. However, according to the epidemiological features of the main vector in Europe, Ixodes ricinus, its circulation in our country was suspected. METHODS: A total of 200 I. ricinus ticks collected in the North of Spain were analyzed. DNAs were extracted and used as templates for PCRs targeting fragment genes for Anaplasma/Ehrlichia detection. The amplified products were sequenced and analyzed. RESULTS: 'Ca. Neoehrlichia mikurensis' was amplified in two specimens. Furthermore, Anaplasma phagocytophilum was detected in 61 samples analyzed. CONCLUSIONS: The detection of 'Ca. Neoehrlichia mikurensis' in I. ricinus ticks from Spain indicates its circulation and the potential risk of contracting a human infection in this country. PMID- 24484638 TI - Unclamped nephron-sparing surgery with preoperative selective arterial embolization for the management of bilateral giant renal angiomyolipomas. PMID- 24484639 TI - Global Health Action: surviving infancy and taking first steps - the window is open, new challenges for existing niche may enlighten global health. PMID- 24484640 TI - Evaluating the drivers of and obstacles to the willingness to use cognitive enhancement drugs: the influence of drug characteristics, social environment, and personal characteristics. AB - BACKGROUND: The use of cognitive enhancement (CE) by means of pharmaceutical agents has been the subject of intense debate both among scientists and in the media. This study investigates several drivers of and obstacles to the willingness to use prescription drugs non-medically for augmenting brain capacity. METHODS: We conducted a web-based study among 2,877 students from randomly selected disciplines at German universities. Using a factorial survey, respondents expressed their willingness to take various hypothetical CE-drugs; the drugs were described by five experimentally varied characteristics and the social environment by three varied characteristics. Personal characteristics and demographic controls were also measured. RESULTS: We found that 65.3% of the respondents staunchly refused to use CE-drugs. The results of a multivariate negative binomial regression indicated that respondents' willingness to use CE drugs increased if the potential drugs promised a significant augmentation of mental capacity and a high probability of achieving this augmentation. Willingness decreased when there was a high probability of side effects and a high price. Prevalent CE-drug use among peers increased willingness, whereas a social environment that strongly disapproved of these drugs decreased it. Regarding the respondents' characteristics, pronounced academic procrastination, high cognitive test anxiety, low intrinsic motivation, low internalization of social norms against CE-drug use, and past experiences with CE-drugs increased willingness. The potential severity of side effects, social recommendations about using CE-drugs, risk preferences, and competencies had no measured effects upon willingness. CONCLUSIONS: These findings contribute to understanding factors that influence the willingness to use CE-drugs. They support the assumption of instrumental drug use and may contribute to the development of prevention, policy, and educational strategies. PMID- 24484641 TI - Possible role of the alpha7 nicotinic receptors in mediating nicotine's effect on developing lung - implications in unexplained human perinatal death. AB - BACKGROUND: It is well known that maternal smoking during pregnancy is very harmful to the fetus. Prenatal nicotine absorption, in particular, is associated with alterations in lung development and functions at birth and with respiratory disorders in infancy. Many of the pulmonary disorders are mediated by the interaction of nicotine with the nicotinic receptors (nAChRs), above all with the alpha7 nAChR subunits that are widely expressed in the developing lung. To determine whether the lung hypoplasia frequently observed in victims of sudden fetal and neonatal death with a smoker mother may result from nicotine interacting with lung nicotinic receptors, we investigated by immunohistochemistry the possible presence of the alpha7 nAChR subunit overexpression in these pathologies. METHODS: In lung histological sections from 45 subjects who died of sudden intrauterine unexplained death syndrome (SIUDS) and 15 subjects who died of sudden infant death syndrome (SIDS), we applied the radial alveolar count (RAC) to evaluate the degree of lung maturation, and the immunohistochemical technique for nAChRs, in particular for the alpha7 nAChR subunit identification. In the same cases, an in-depth study of the autonomic nervous system was performed to highlight possible developmental alterations of the main vital centers located in the brainstem. RESULTS: We diagnosed a "lung hypoplasia", on the basis of RAC values lower than the normal reference values, in 63% of SIUDS/SIDS cases and 8% of controls. In addition, we observed a significantly higher incidence of strong alpha7 nAChR immunostaining in lung epithelial cells and lung vessel walls in sudden fetal and infant death cases with a smoker mother than in age-matched controls. Hypoplasia of the raphe, the parafacial, the Kolliker-Fuse, the arcuate and the pre-Botzinger nuclei was at the same time present in the brainstem of these victims. CONCLUSIONS: These findings demonstrate that when crossing the placenta, nicotine can interact with nicotinic receptors of both neuronal and non-neuronal cells, leading to lung and nervous system defective development, respectively. This work stresses the importance of implementing preventable measures to decrease the noxious potential of nicotine in pregnancy. PMID- 24484643 TI - The influence of acceleration loading curve characteristics on traumatic brain injury. AB - To prevent brain trauma, understanding the mechanism of injury is essential. Once the mechanism of brain injury has been identified, prevention technologies could then be developed to aid in their prevention. The incidence of brain injury is linked to how the kinematics of a brain injury event affects the internal structures of the brain. As a result it is essential that an attempt be made to describe how the characteristics of the linear and rotational acceleration influence specific traumatic brain injury lesions. As a result, the purpose of this study was to examine the influence of the characteristics of linear and rotational acceleration pulses and how they account for the variance in predicting the outcome of TBI lesions, namely contusion, subdural hematoma (SDH), subarachnoid hemorrhage (SAH), and epidural hematoma (EDH) using a principal components analysis (PCA). Monorail impacts were conducted which simulated falls which caused the TBI lesions. From these reconstructions, the characteristics of the linear and rotational acceleration were determined and used for a PCA analysis. The results indicated that peak resultant acceleration variables did not account for any of the variance in predicting TBI lesions. The majority of the variance was accounted for by duration of the resultant and component linear and rotational acceleration. In addition, the components of linear and rotational acceleration characteristics on the x, y, and z axes accounted for the majority of the remainder of the variance after duration. PMID- 24484642 TI - Informing tendon tissue engineering with embryonic development. AB - Tendon is a strong connective tissue that transduces muscle-generated forces into skeletal motion. In fulfilling this role, tendons are subjected to repeated mechanical loading and high stress, which may result in injury. Tissue engineering with stem cells offers the potential to replace injured/damaged tissue with healthy, new living tissue. Critical to tendon tissue engineering is the induction and guidance of stem cells towards the tendon phenotype. Typical strategies have relied on adult tissue homeostatic and healing factors to influence stem cell differentiation, but have yet to achieve tissue regeneration. A novel paradigm is to use embryonic developmental factors as cues to promote tendon regeneration. Embryonic tendon progenitor cell differentiation in vivo is regulated by a combination of mechanical and chemical factors. We propose that these cues will guide stem cells to recapitulate critical aspects of tenogenesis and effectively direct the cells to differentiate and regenerate new tendon. Here, we review recent efforts to identify mechanical and chemical factors of embryonic tendon development to guide stem/progenitor cell differentiation toward new tendon formation, and discuss the role this work may have in the future of tendon tissue engineering. PMID- 24484645 TI - Force depression decays during shortening in the medial gastrocnemius of the rat. AB - Force depression due to shortening of activated skeletal muscles has previously been described to be long lasting during isometric contractions following the shortening. In the present study, using the medial gastrocnemius of the rat, effects of force depression have been made apparent during shortening by computationally partially compensating for the direct effect of shortening velocity due to the tension-velocity relation. Evidence was found for the decay and complete disappearance of force depression already during continuation of the shortening contraction to short muscle lengths. PMID- 24484644 TI - A mechanistic model on the role of "radially-running" collagen fibers on dissection properties of human ascending thoracic aorta. AB - Aortic dissection (AoD) is a common condition that often leads to life threatening cardiovascular emergency. From a biomechanics viewpoint, AoD involves failure of load-bearing microstructural components of the aortic wall, mainly elastin and collagen fibers. Delamination strength of the aortic wall depends on the load-bearing capacity and local micro-architecture of these fibers, which may vary with age, disease and aortic location. Therefore, quantifying the role of fiber micro-architecture on the delamination strength of the aortic wall may lead to improved understanding of AoD. We present an experimentally-driven modeling paradigm towards this goal. Specifically, we utilize collagen fiber micro architecture, obtained in a parallel study from multi-photon microscopy, in a predictive mechanistic framework to characterize the delamination strength. We then validate our model against peel test experiments on human aortic strips and utilize the model to predict the delamination strength of separate aortic strips and compare with experimental findings. We observe that the number density and failure energy of the radially-running collagen fibers control the peel strength. Furthermore, our model suggests that the lower delamination strength previously found for the circumferential direction in human aorta is related to a lower number density of radially-running collagen fibers in that direction. Our model sets the stage for an expanded future study that could predict AoD propagation in patient-specific aortic geometries and better understand factors that may influence propensity for occurrence. PMID- 24484646 TI - Ultrafast vascular strain compounding using plane wave transmission. AB - Deformations of the atherosclerotic vascular wall induced by the pulsating blood can be estimated using ultrasound strain imaging. Because these deformations indirectly provide information on mechanical plaque composition, strain imaging is a promising technique for differentiating between stable and vulnerable atherosclerotic plaques. This paper first explains 1-D radial strain estimation as applied intravascularly in coronary arteries. Next, recent methods for noninvasive vascular strain estimation in a transverse imaging plane are discussed. Finally, a compounding technique that our group recently developed is explained. This technique combines motion estimates of subsequently acquired focused ultrasound images obtained at various insonification angles. However, because the artery moves and deforms during the multi-angle acquisition, errors are introduced when compounding. Recent advances in computational power have enabled plane wave ultrasound acquisition, which allows 100 times faster image acquisition and thus might resolve the motion artifacts. In this paper the performance of strain imaging using plane wave compounding is investigated using simulations of an artery with a vulnerable plaque and experimental data of a two layered vessel phantom. The results show that plane wave compounding outperforms 0 degrees focused strain imaging. For the simulations, the root mean squared error reduced by 66% and 50% for radial and circumferential strain, respectively. For the experiments, the elastographic signal-to-noise and contrast-to-noise ratio (SNR(e) and CNR(e)) increased with 2.1 dB and 3.7 dB radially, and 5.6 dB and 16.2dB circumferentially. Because of the high frame rate, the plane wave compounding technique can even be further optimized and extended to 3D in future. PMID- 24484647 TI - From the diagnostic investigations of goiter to the diagnosis of lung cancer - case study. AB - Thyroid metastases account for approximately 1.4-3% of all malignancies of the thyroid gland. Thyroid metastases are most common in: clarocellular carcinoma of the kidney, lung cancer, breast cancer, malignant melanoma and cancers of gastrointestinal tract. A rare situation is when thyroid metastasis is diagnosed before detecting primary malignant focus and when it is the first manifestation of underlying disease. We present a case of 64-year-old male with thyroid metastasis being the first manifestation of lung adenocarcinoma.The authors emphasize that patients with the history of malignancy should undergo an ultrasound examination of the thyroid gland in order to exclude a focal lesion, and if such lesion is detected, fine-needle aspiration biopsy is recommended. The authors also point out that establishing final diagnosis of thyroid metastasis of cancer in other organs is only possible on the basis of postoperative histopathology and immunohistochemistry. PMID- 24484649 TI - Enhanced field electron emission properties of hierarchically structured MWCNT based cold cathodes. AB - Hierarchically structured MWCNT (h-MWCNT)-based cold cathodes were successfully achieved by means of a relatively simple and highly effective approach consisting of the appropriate combination of KOH-based pyramidal texturing of Si (100) substrates and PECVD growth of vertically aligned MWCNTs. By controlling the aspect ratio (AR) of the Si pyramids, we were able to tune the field electron emission (FEE) properties of the h-MWCNT cathodes. Indeed, when the AR is increased from 0 (flat Si) to 0.6, not only the emitted current density was found to increase exponentially, but more importantly its associated threshold field (TF) was reduced from 3.52 V/MUm to reach a value as low as 1.95 V/MUm. The analysis of the J-E emission curves in the light of the conventional Fowler Nordheim model revealed the existence of two distinct low-field (LF) and high field (HF) FEE regimes. In both regimes, the hierarchical structuring was found to increase significantly the associated betaLF and betaHF field enhancement factors of the h-MWCNT cathodes (by a factor of 1.7 and 2.2, respectively). Pyramidal texturing of the cathodes is believed to favor vacuum space charge effects, which could be invoked to account for the significant enhancement of the FEE, particularly in the HF regime where a betaHF as high as 6,980 was obtained for the highest AR value of 0.6. PMID- 24484650 TI - Central injection of urocortin-3 but not corticotrophin-releasing hormone influences the ghrelin/GHS-R1a system of the proventriculus and brain in chicks. AB - Ghrelin, the endogenous ligand for growth hormone secretagogue receptor 1a (GHS R1a), stimulates food intake in mammals centrally and peripherally. In contrast, central injection of ghrelin inhibits feeding in neonatal chicks (Gallus gallus), which is thought to be mediated by the corticotrophin-releasing hormone (CRH) system, indicating that the mechanisms underlying ghrelin's action are different in chicks and mammals. However, the interaction between the ghrelin system and the CRH system has not been fully clarified in chicks. In the present study, we examined the effect of intracerebroventricular (ICV) injection of CRH and urocortin-3 (UCN-3), a CRH family peptide and an endogenous ligand for the CRH type-2 receptor (CRH-R2), on synthesis and secretion of ghrelin in chicks. Intracerebroventricular injection of UCN-3 but not CRH increased plasma ghrelin concentration (P < 0.05), diencephalic mRNA expression of ghrelin, and GHS-R1a (P < 0.05) and tended to decrease ghrelin (P = 0.08) and GHS-R1a (P = 0.10) mRNA expression in the proventriculus. Moreover, ICV injection of UCN-3 tended to increase diencephalic mRNA expression of CRH-R2 (P = 0.08) and CRH had no effect on it. In addition, ICV injection of CRH but not UCN-3 increased plasma corticosterone concentration (P < 0.05) and decreased the diencephalic mRNA expression of CRH-R1 (P < 0.05). These results clearly indicate that the roles of the CRH system for the ghrelin system are divided. The present study suggests that UCN-3 is mainly involved in the ghrelin system in chicks perhaps through the CRH-R2. PMID- 24484648 TI - Identification and validation of PROM1 and CRTC2 mutations in lung cancer patients. AB - BACKGROUND: Genetic alterations could be responsible lung cancer, the leading cause of worldwide cancer death. METHODS: This study investigated gene mutations in a Han Chinese family of lung cancer using the whole genome exome sequencing and subsequent Sanger sequencing validation and then confirmed alteration of prominin 1(PROM1) and cyclic AMP-response element binding protein-regulated transcription co-activator2 (CRTC2) in blood samples of 343 sporadic lung cancer patients vs. 280 healthy controls as well as in 200 pairs of lung cancer and the corresponding normal tissues using PCR-restriction fragment length polymorphism and directed DNA sequencing of PCR products. RESULTS: The data showed PROM1 (p. S281R) and CRTC2 (p. R379C) mutations, in 5 and 2 cases of these 343 sporadic lung cancer patients, respectively. Notably, these mutations were absent in the healthy controls. Furthermore, in the 200 lung cancer and the matched normal tissues, PROM1 mutation occurred in 3 patients (i.e., one squamous cell carcinoma and two adenocarcinomas) with a mutation frequency of 1.5%, while CRTC2 mutation occurred in 5 patients (two squamous cell carcinomas and three adenocarcinomas) with a mutation frequency of 2.5%. CONCLUSIONS: The data from the current study demonstrated novel PROM1 and CRTC2 mutations, which could promote lung cancer development. PMID- 24484651 TI - Validation of an interferon stimulatory response element reporter gene assay for quantifying type I interferons. AB - The goal of this work was to develop a virus-free, cell-based interferon (IFN) bioassay and determine the utility of this assay on biological samples that contained IFN-tau, the trophoblast-secreted maternal recognition of pregnancy factor in ruminants. Madin-Darby bovine kidney cells were transduced with lentiviral particles that contained a firefly luciferase reporter construct driven by an IFN stimulatory response element (ISRE). Stably transduced cells were selected with the use of puromycin resistance. A linear, dose-responsive response was detected with human IFN-alpha and ovine IFN-tau. Interferon activity was detected in conditioned media from bovine trophoblast cells and uterine flushes collected from sheep and cattle. Activity also was detected in media collected after individual or small group culture of in vitro-produced bovine blastocysts at day 8 to 10 after fertilization. In summary, this IFN stimulatory response element-reporter assay may be used as an alternative to virus-dependent, cytopathic assays. It contains a similar sensitivity to IFNs and can be completed in a shorter time than cytopathic assays and does not require heightened biosafety conditions after cell transduction. PMID- 24484652 TI - Hypofractionated SBRT versus conventionally fractionated EBRT for prostate cancer: comparison of PSA slope and nadir. AB - BACKGROUND: Patients with early stage prostate cancer have a variety of curative radiotherapy options, including conventionally-fractionated external beam radiotherapy (CF-EBRT) and hypofractionated stereotactic body radiotherapy (SBRT). Although results of CF-EBRT are well known, the use of SBRT for prostate cancer is a more recent development, and long-term follow-up is not yet available. However, rapid post-treatment PSA decline and low PSA nadir have been linked to improved clinical outcomes. The purpose of this study was to compare the PSA kinetics between CF-EBRT and SBRT in newly diagnosed localized prostate cancer. MATERIALS/METHODS: 75 patients with low to low-intermediate risk prostate cancer (T1-T2; GS 3 + 3, PSA < 20 or 3 + 4, PSA < 15) treated without hormones with CF-EBRT (>70.2 Gy, <76 Gy) to the prostate only, were identified from a prospectively collected cohort of patients treated at the University of California, San Francisco (1997-2012). Patients were excluded if they failed therapy by the Phoenix definition or had less than 1 year of follow-up or <3 PSAs. 43 patients who were treated with SBRT to the prostate to 38 Gy in 4 daily fractions also met the same criteria. PSA nadir and rate of change in PSA over time (slope) were calculated from the completion of RT to 1, 2 and 3 years post RT. RESULTS: The median PSA nadir and slope for CF-EBRT was 1.00, 0.72 and 0.60 ng/ml and -0.09, -0.04, -0.02 ng/ml/month, respectively, for durations of 1, 2 and 3 years post RT. Similarly, for SBRT, the median PSA nadirs and slopes were 0.70, 0.40, 0.24 ng and -0.09, -0.06, -0.05 ng/ml/month, respectively. The PSA slope for SBRT was greater than CF-EBRT (p < 0.05) at 2 and 3 years following RT, although similar during the first year. Similarly, PSA nadir was significantly lower for SBRT when compared to EBRT for years 2 and 3 (p < 0.005). CONCLUSION: Patients treated with SBRT experienced a lower PSA nadir and greater rate of decline in PSA 2 and 3 years following completion of RT than with CF-EBRT, consistent with delivery of a higher bioequivalent dose. Although follow-up for SBRT is limited, the improved PSA kinetics over CF-EBRT are promising for improved biochemical control. PMID- 24484653 TI - Nontuberculous mycobacterial (NTM) lung disease: the top ten essentials. AB - This review will utilize essential questions about nontuberculous mycobacterial (NTM) lung disease to succinctly address important new developments in the pathogenesis, diagnosis and management of NTM lung disease with a focus on practical information and "bottom line" answers. 1) What do I tell my patients who ask, "where did I get this infection" and, "should I take showers"? 2) What is the connection between bronchiectasis and the acquisition of NTM lung infection? 3) What other factors are important in the pathogenesis of NTM lung disease? 4) Why does it seem that am I seeing more new NTM lung disease patients? 5) Why is the diagnosis of NTM lung disease so complicated and does the diagnosis of NTM lung infection obligate specific treatment? 6) Unlike traditional tuberculosis, what is behind the irrelevance of most in vitro susceptibility testing reports for NTM infections? 7) Is there anything new for the management of patients with Mycobacterium avium complex lung disease? How does the radiographic appearance influence treatment? 8) Is there anything new for the management of patients with Mycobacterium abscessus lung disease? 9) What about the management of other NTM respiratory pathogens? 10) Is there a role for the use of macrolide monotherapy for non-cystic fibrosis bronchiectasis? PMID- 24484654 TI - Mitotic spindle assembly on chromatin patterns made with deep UV photochemistry. AB - We provide a detailed method to generate arrays of mitotic spindles in vitro. Spindles are formed in extract prepared from unfertilized Xenopus laevis eggs, which contain all the molecular ingredients of mitotic spindles. The method is based on using deep UV photochemistry to attach chromatin-coated beads on a glass surface according to a pattern of interest. The immobilized beads act as artificial chromosomes, and induce the formation of mitotic spindles in their immediate vicinity. To perform the experiment, a chamber is assembled over the chromatin pattern, Xenopus egg extract is flowed in and after incubation the spindles are imaged with a confocal microscope. PMID- 24484655 TI - Geometrical control of actin assembly and contractility. AB - The actin cytoskeleton is a fundamental player in many cellular processes. Ultrastructural studies have revealed its extremely complex organization, where actin filaments self-organize into defined and specialized structures of distinct functions and, yet, are able to selectively recruit biochemical regulators that are available in the entire cell volume. To overcome this extraordinary complexity, simplified reconstituted systems significantly improve our understanding of actin dynamics and self-organization. However, little is known regarding physical rules governing actin networks organization and to which extent network structure may direct and regulate selective interactions with specific regulators. Here, we describe the first method to direct actin filament assembly to specific 2D motifs with a finely tuned geometry and relative distribution. This method enables the study of how geometrical confinement governs actin network structural organization and how, in return, structural cues can control selective contraction by myosin motor. The protocol relies on the use of surface micropatterning and functionalization procedures in order to selectively direct actin filament assembly to specific sites of nucleation. PMID- 24484656 TI - Micropatterning microtubules. AB - The following protocol describes a method to control the orientation and polarity of polymerizing microtubules (MTs). Reconstitution of specific geometries of dynamic MT networks is achieved using a ultraviolet (UV) micropatterning technique in combination with stabilized MT microseeds. The process is described in three main parts. First, the surface is passivated to avoid the non-specific absorption of proteins, using different polyethylene glycol (PEG)-based surface treatment. Second, specific adhesive surfaces (the micropatterns) are imprinted through a photomask using deep UVs. Lastly, MT microseeds are adhered to the micropatterns followed by MT polymerization. PMID- 24484657 TI - Micropatterned, multicomponent supported lipid bilayers for cellular systems. AB - Lipid bilayer membranes are a central structural feature of living cells, providing a wide range of functions including partitioning of organelles, mediating cell interaction with the environment, and modulating intracellular signaling processes. By capturing the fluidity of the natural membranes in a reductionist in vitro model, substrate supported lipid bilayers have emerged as a compelling model system for these structures. Furthermore, the ability to control the composition and mobility of this system at micro- and nanoscales inspired several new routes of biological and biotechnological investigation. Here, we describe key methods used to create multicomponent lipid bilayers, discuss design considerations important to making these systems, and demonstrate this process in the specific context of understanding juxtacrine cell signaling. Different fabrication techniques were combined to first pattern a surface with barriers to lipid diffusion and then spatially control the exposure of this surface to lipid vesicles, leading to local formation of bilayers of different composition. This multicomponent system was used as a platform for to mimic the natural organization of T cells and antigen presenting cells by presenting ligands to the T cell receptor and lymphocyte function-associated antigen-1 that are tethered to separate, closely juxtaposed regions of bilayer. Other technologies like using photochemical polymerization of lipids to pattern bilayers have also been discussed. The information gathered from evaluating membrane interactions in patterned lipid bilayers may lead to the development of membrane-based biomedical devices for conducting novel cell-based assays and potentially high-throughput drug screens targeting membranes or membrane-associated components. PMID- 24484658 TI - Reconstituting functional microtubule-barrier interactions. AB - Local interactions between the tips of microtubules and the cell cortex, or other cellular components such as kinetochores, play an important role in essential cellular processes like establishing cell polarity, distribution of organelles, and microtubule aster and chromosome positioning. Here we present two in vitro assays that specifically mimic microtubule-cortex interactions by employing selectively functionalized microfabricated barriers that allow for the immobilization of proteins with a range of affinities. We describe the microfabrication process to create gold or glass barriers and the subsequent functionalization of these barriers using self-assembled thiol monolayers or polylysine-poly(ethylene glycol), respectively. Near-permanent attachment of proteins is obtained using biotinylated surfaces combined with streptavidin and biotinylated proteins. Lower affinity interactions, further tunable with the addition of imidazole, are obtained using nickel-nitrilotriacetic acid (Ni(II) NTA) functionalization combined with his-tagged proteins. Both mono-NTA and tris NTA compounds are used. We show an assay to reconstitute the "end-on" interaction between dynamic microtubule tips and barrier-attached dynein, mimicking the cellular situation at the cortex and at kinetochores. In a second assay, we reconstitute microtubule-based delivery of end-tracking proteins to functionalized barriers, mimicking the transport of cell-end markers to the cell poles in interphase fission yeast cells. PMID- 24484659 TI - Polyacrylamide hydrogel micropatterning. AB - This chapter describes the production of micropatterns of extracellular matrix proteins on a 2D flat polyacrylamide (PAA) gel. The technique is divided into two parts. First, micropatterns are produced on glass or directly on a photomask using deep UV. Then the micropatterns are transferred on acrylamide gel by polymerization of the gel directly on the template coverslip. This procedure is easy to perform and does not require any expensive equipment. It can be performed in no more than 2h once you get your hands on it. It combines the advantages of other existing techniques: good spatial resolution, suitable for very soft gel, no need for the use of chemical crosslinkers for attachment of the proteins to the acrylamide, no modification of the mechanical properties of the gel by the process, and suitable for multiple protein patterning. We also discuss the storage issues of such substrates and provide a brief review of other existing techniques for micropatterning on PAA. PMID- 24484660 TI - Dynamic photochemical silane micropatterning. AB - This protocol describes a method for dynamic patterning cells on a glass coverslip. The glass substrate is first functionalized with photocleavable silane bearing 2-nitrobenzyl group, thereafter a cell-repellent polymer, poly(ethylene glycol) (PEG), is conjugated. Upon absorption of near-UV light, the PEG is cleaved from the surface, changing the surface from non-cell-adhesive to cell adhesive. The method allows not only for spatially controlling cell attachment on the substrate (conventional patterning), but also inducing cell migration or coculturing heterotypic cells (dynamic patterning). Furthermore, it should be emphasized that the surface is compatible with fluorescence imaging in a high resolution inverted objective setup as it is composed of a normal glass coverslip functionalized with the thin layers. In this chapter, I describe the procedure for the synthesis of the silane molecule, the preparation of the photoactivatable surface, and its application for dynamic cell patterning. PMID- 24484661 TI - Dynamic photochemical lipid micropatterning for manipulation of nonadherent mammalian cells. AB - Cell micropatterning methods with stimuli-responsive dynamic surfaces are getting a lot of attention in a wide variety of research fields, ranging from cell engineering to fundamental studies in cell biology. The surface of a slide coated with photo-cleavable poly(ethylene glycol) (PEG)-lipid can be used to spatiotemporally control cell immobilization and release by light irradiation. On the basis of this surface, it is easy to design simple methods for making a fine micropattern of any kind of cell. Furthermore, target cells can be selectively and rapidly released from this surface by light irradiation. In this review, we first describe how to obtain the photo-cleavable PEG-lipid from commercially available compounds through a facile four-step synthesis. Next, as a cell patterning method, the protocols of coating substrates with the PEG-lipid, irradiating a pattern of light onto the coated substrate, and loading cells onto the irradiated surface are described. These protocols require no expensive equipment and potentially apply to any substrates that can adsorb serum albumin or chemically expose amine moieties on their surfaces. Finally, as an advanced method, cell release from the PEG-lipid surface in microfluidic devices is introduced. We also discuss the advantages and the possible applications of the present dynamic cell-patterning method. PMID- 24484662 TI - Thermosensitive micropatterned substrates. AB - We describe the design of micropatterned surfaces for single cell studies, based on photo-patterned thermoresponsive polymer brushes. Such surfaces allow for spatially controlled cell adhesion at 37 degrees CC and thermal harvesting of the studied cells at T <32 degrees CC. PMID- 24484663 TI - Fabrication of micropatterned arrays of gold nanoparticles for photothermal manipulation of living cells. AB - The fabrication of micro/nanostructured surfaces functionalized with stimulus responsive chemical groups proved to be an interesting approach to simultaneously confine cell adhesion and manipulate cell-substrate interactions down to the single cell level. However, reversibility of stimulus-triggered systems is often not possible or exhibits slow switching kinetics. In contrast to such setups, gold nanoparticles have the properties to efficiently and reversibly generate heat under illumination at their plasmon resonance band. Thus, photo-induced heating could be used to directly and locally interface living cells and dynamically tailor the interactions to their adhesive environment. In the present chapter, we will first detail the preparation of micropatterned and functionalized gold nanoparticles immobilized on glass coverslips, and then report how to reliably characterize the photothermal properties of such substrates that enable the dynamic manipulation of cells. PMID- 24484664 TI - A reagent-based dynamic trigger for cell adhesion, shape change, or cocultures. AB - The described protocol is a simple and easily implemented method for making dynamic micropatterns for cell culture. It is based on the use of a surface coating material (azido-PLL-g-PEG (APP)) that initially repels cells, but which can be made strongly adherent by addition of a small functional peptide (BCN-RGD) to the cell culture medium. The method can be applied to trigger the adhesion, migration, or shape change of single cells or of populations of cells, and it can be used to create patterned cocultures. The entire process can be subdivided into three main parts. The first part describes the creation of patterned APP substrates. The second part describes cell seeding and "click" triggering of cell adhesion; the final part describes variations that allow the overlay of multiple patterns or the creation of patterned cocultures. The APP coating of substrates and the triggering of adhesion only involves treating the surface with aqueous stock solutions, allowing any biology lab to adopt this technique. PMID- 24484665 TI - Cell patterning by micro-pattern projection of UV light through photoinduced enhancement of cell adhesion (PIECA). AB - Here we describe a protocol to prepare cell patterns by immobilizing anchor dependent cells onto the desired area of an unpatterned culture substrate by micro-patterned light projection with high precision to the size of one single cell. The method is based on the phenomenon that the Ca(2+)-dependent adhesion of anchor-dependent cells becomes insensitive temporarily to the removal of Ca(2+) due to the influence of the less-invasive in situ UV irradiation. By repeating the process, a patterned coculture system can be fabricated. In clear contrast to conventional cell patterning that uses fixed-patterned substrates, the cell retaining area is defined after cell seeding. Therefore, the cell separation on a substrate based on imaging cytometry can be implemented by combining this method with a computer-controlled microprojection coupled with a microscope. Because the cells thus patterned can continue to grow and migrate freely afterward from their initial positions, the method is expected to provide a useful cell manipulating tool, especially in cases where spontaneous development of the cells after patterning is necessary and important, such as an analysis of cell migration. PMID- 24484666 TI - Preparing substrates encoding cell patterning and localized intracellular magnetic particle stimulus for high-throughput experimentation. AB - Magnetic particles, beyond the simple cell sorting and drug delivery applications for which they are typically known, have become a powerful tool in permitting remote control of biological activity. While this functionality is traditionally accomplished by linking particles to extracellular, membrane localized moieties (such as ion channels and integrins), the intracellular stimulation of cells via magnetic nanoparticles has recently shown to be a unique and powerful method by which to spatially polarize cell behavior. More traditional magnetic stimulation approaches, whereby single magnetic tweezers or permanent magnets are placed in proximity to cells growing on substrates lack resolution, control, and scalability. Conventional single cell-patterning approaches, while having large precision and scalability, typically allow the evaluation of the response of cells to only their immediate extracellular, protein environment. Here, we detail the protocol combining the above approaches to resolve the problems hampering many biomagnetic studies. By integrating the scalability and resolution of traditional silicon microfabrication with modern surface patterning capabilities, we demonstrate a method of conducting thousands of biomagnetic experiments in parallel, whereby individual cells with designed, patterned matrix are subjected to controlled, repetitive magnetic stimulus introduced by electroplated, micromagnetic elements. PMID- 24484667 TI - Microfabricated chambers as force sensors for probing forces of fungal growth. AB - The mechanical properties of fungal cells influence their growth, division, morphogenesis, and invasiveness. These cells are characterized by high internal turgor pressure contained by a stiff but elastic cell wall. In here, we describe simple and versatile methods to measure forces of fungal growth, turgor pressure, and elastic moduli of fungi cell wall, using microfabricated polydimethylsiloxane wells of varying stiffness as single cell force sensors. We demonstrate the strength of this method with the rod-shape fission yeast Schizosaccaromyces pombe and highlight how it may be implemented for studying mechanical properties of other walled cells. PMID- 24484668 TI - Visualizing single rod-shaped fission yeast vertically in micro-sized holes on agarose pad made by soft lithography. AB - Fission yeast cells are rod-shaped unicellular organism that is normally imaged horizontally with its long axis parallel to image plane. This orientation, while practical, limits the imaging resolution of biological structures which are oriented perpendicular to the long axis of the cell. We present here a method to prepare agarose pads with micro-sized holes to load single fission yeast cell vertically and image cell with its long axis perpendicular to the image plane. As a demonstration, actomyosin ring contraction is shown with this new imaging device. PMID- 24484669 TI - Microfabricated environments to study collective cell behaviors. AB - Coordinated cell movements in epithelial layers are essential for proper tissue morphogenesis and homeostasis. Microfabrication techniques have proven to be very useful for studies of collective cell migration in vitro. In this chapter, we briefly review the use of microfabricated substrates in providing new insights into collective cell behaviors. We first describe the development of micropatterned substrates to study the influence of geometrical constraints on cell migration and coordinated movements. Then, we present an alternative method based on microfabricated pillar substrates to create well-defined gaps within cell sheets and study gap closure. We also provide a discussion that presents possible pitfalls and sheds light onto the important parameters that allow the study of long-term cell culture on substrates of well-defined geometries. PMID- 24484670 TI - Methods in Cell Biology. Micropatterning in cell biology part B. Preface. PMID- 24484671 TI - Lumbar tactile acuity is near identical between sides in healthy pain-free participants. AB - A growing body of literature suggests that alterations in brain structure and function are a feature of chronic back pain. Tactile acuity is considered a clinical signature of primary somatosensory representation and offers a simple measure of cortical reorganisation. Clinical interpretation of test scores from an individual patient is hampered by variance in published normative values and less than ideal inter-rater reliability. These problems might be mitigated in people with unilateral back pain by using the patient as their own control and comparing tactile acuity at the painful site to performance at the corresponding position on the non-painful side. The first step in exploring this approach is to quantify the normal side-to-side difference in healthy populations. We pooled data from three previous studies that measured lumbar tactile acuity bilaterally in healthy controls using similar protocols. We calculated the mean and variance of the absolute error between sides, the standard error of measurement and the reliable change index (RCI). The mean difference between sides was 3.2 mm (+/ 5.2) when assessed vertically and 1.9 mm (+/-3.2) when assessed horizontally. The standard error of measurement was 4.2 mm when assessed vertically and 2.7 mm when assessed horizontally. The RCI suggests that differences of greater than 13 mm when assessed horizontally and 17 mm when assessed vertically equate to 95% confidence that a difference truly exists. Several assumptions related to the application of this approach need to be investigated further. PMID- 24484672 TI - Validation of Chinese version of the Morisky medication adherence scale in patients with epilepsy. AB - PURPOSE: This study aimed to validate a Chinese version of the Morisky Medication Adherence Scale (MMAS-8) in patients with epilepsy. The relationships between adherence, seizure frequency, and adverse effects were assessed using this method. METHODS: Data from patients diagnosed with epilepsy at the Department of Neurology of Huashan Hospital were collected between January and June 2013. To validate the MMAS-8, internal consistency, test-retest reliability, and factor analysis were calculated. Relationships between adherence, seizure frequency, and adverse effects were assessed using Pearson's correlation. RESULTS: One hundred and eleven patients were recruited. The MMAS-8 had moderate internal consistency (Cronbach's alpha=0.556) and good test-retest reliability (intraclass correlation coefficient=0.729). The MMAS-8 adherence rate was 79.2%. MMAS-8 adherence was negatively correlated with seizure frequency and adverse effects (r = -0.708, p<0.001; r = -0.484, p<0.001). CONCLUSION: The MMAS-8 scale can be used as a tool to assess medication adherence in Chinese patients with epilepsy. Better seizure control and lower rates of adverse effects were significantly correlated with higher adherence scores. PMID- 24484673 TI - Monitoring the VEGF level in aqueous humor of patients with ophthalmologically relevant diseases via ultrahigh sensitive paper-based ELISA. AB - The vascular endothelial growth factor (VEGF) level in aqueous humor has been used as an indicator to monitor specific diseases in the retinal ischemic condition. For clinical diagnosis, only about 200 MUL of aqueous humor can be collected from the anterior chamber before the threat of anterior chamber collapse. It is necessary to develop an inexpensive diagnostic approach with the characteristics of highly sensitive, short operation duration, and requires small clinical sample quantities. To achieve the main objective of this study, we first prepared bevacizumab to be conjugated with HRP. We then deposited 2 MUL aqueous humor from patients with different diseases onto each test zone of paper-based 96 well plates. After the colorimetric results were performed via ELISA protocol, the output signals were recorded using a commercial desktop scanner for analysis. In this study, only 2 MUL from the aqueous humor of each patient was required for paper-based ELISA. The mean aqueous VEGF level was 14.4 pg/mL from thirteen patients (N = 13) with senile cataract as the control. However, the mean aqueous VEGF level from other patients with proliferative diabetic retinopathy (N = 14), age-related macular degeneration (N = 17), and retinal vein occlusion (N = 10) showed VEGF increases to 740.1 pg/mL, 383 pg/mL, and 219.4 pg/mL, respectively. PMID- 24484674 TI - Quantitative characterization of mineralized silk film remodeling during long term osteoblast-osteoclast co-culture. AB - The goal of this study was to explore quantitative assessments of mineralized silk protein biomaterial films by co-cultures of human mesenchymal stem cell derived osteoblasts and human acute monocytic leukemia cell line-derived osteoclasts during long-term culture (8-32 weeks). The remodeled films were quantitatively assessed using three different techniques during this extended cultivation to provide more comprehensive insight into the impact of co-cultures on surface remodeling. Scanning electron microscopy (SEM) with three dimensional surface reconstructions was used to quantitatively determine various surface morphological features and measures of roughness indicative of remodeling by the cells. Additionally, reconstructed surfaces were converted to depth images for Fourier analysis to quantify the potential fractal organization of biomineralization. The long-term remodeled films were also imaged using confocal reflectance microscopy and micro-computed tomography (micro-CT) to further quantify morphological changes. Films remodeled in co-culture demonstrated increased roughness parameters, fractal organization, and volume compared to films remodeled by osteoblasts alone. The combination of these techniques to quantify remodeling of mineralized protein films shows promise for quantifying processes related to mineralized surfaces. PMID- 24484675 TI - A tunable silk-alginate hydrogel scaffold for stem cell culture and transplantation. AB - One of the major challenges in regenerative medicine is the ability to recreate the stem cell niche, which is defined by its signaling molecules, the creation of cytokine gradients, and the modulation of matrix stiffness. A wide range of scaffolds has been developed in order to recapitulate the stem cell niche, among them hydrogels. This paper reports the development of a new silk-alginate based hydrogel with a focus on stem cell culture. This biocomposite allows to fine tune its elasticity during cell culture, addressing the importance of mechanotransduction during stem cell differentiation. The silk-alginate scaffold promotes adherence of mouse embryonic stem cells and cell survival upon transplantation. In addition, it has tunable stiffness as function of the silk alginate ratio and the concentration of crosslinker--a characteristic that is very hard to accomplish in current hydrogels. The hydrogel and the presented results represents key steps on the way of creating artificial stem cell niche, opening up new paths in regenerative medicine. PMID- 24484676 TI - An in vitro spinal cord injury model to screen neuroregenerative materials. AB - Implantable 'structural bridges' based on nanofabricated polymer scaffolds have great promise to aid spinal cord regeneration. Their development (optimal formulations, surface functionalizations, safety, topographical influences and degradation profiles) is heavily reliant on live animal injury models. These have several disadvantages including invasive surgical procedures, ethical issues, high animal usage, technical complexity and expense. In vitro 3-D organotypic slice arrays could offer a solution to overcome these challenges, but their utility for nanomaterials testing is undetermined. We have developed an in vitro model of spinal cord injury that replicates stereotypical cellular responses to neurological injury in vivo, viz. reactive gliosis, microglial infiltration and limited nerve fibre outgrowth. We describe a facile method to safely incorporate aligned, poly-lactic acid nanofibre meshes (+/-poly-lysine + laminin coating) within injury sites using a lightweight construct. Patterns of nanotopography induced outgrowth/alignment of astrocytes and neurons in the in vitro model were strikingly similar to that induced by comparable materials in related studies in vivo. This highlights the value of our model in providing biologically-relevant readouts of the regeneration-promoting capacity of synthetic bridges within the complex environment of spinal cord lesions. Our approach can serve as a prototype to develop versatile bio-screening systems to identify materials/combinatorial strategies for regenerative medicine, whilst reducing live animal experimentation. PMID- 24484677 TI - Disability in patients with multiple sclerosis: influence of insulin resistance, adiposity, and oxidative stress. AB - OBJECTIVE: The aims of the present study were to report the prevalence of insulin resistance (IR) in patients with multiple sclerosis (MS); to verify differences in metabolic and inflammatory biomarkers, and oxidative stress in patients with MS with or without IR; and to assess if IR and adiposity are associated with disability in these patients. METHODS: The study enrolled 110 patients with MS and 175 healthy individuals. Patients with MS were divided in those with IR (n = 44) and those without (n = 66). Metabolic and inflammatory markers, oxidative stress, and disability were evaluated by the Extended Disability Status Scale (EDSS). RESULTS: IR prevalence was verified in 40% of the patients with MS and in 21.1% of the control group (odds ratio, 2.48; 95% confidence interval, 1.469 4.210; P = 0.0006). Patients with the disease and IR showed higher EDSS (P = 0.031), interleukin (IL)-6 (P = 0.028), IL-17 (P = 0.006), oxidative stress evaluated by tert-butyl hydroperoxide-initiated chemiluminescence (P = 0.029), and advanced oxidation protein products (P = 0.025) than those patients without IR. The multivariate analysis showed that disability was associated with IR evaluated by homeostasis model assessment of insulin resistance (P = 0.030) and adiposity evaluated by waist circumference (P = 0.0179) and body mass index (P = 0.0033). CONCLUSION: This is the first study to demonstrate an increase IR prevalence and the association between IR and adiposity with disability assessed by EDSS in patients with MS. IR seems to be associated with chronic inflammatory process and oxidative stress in patients with MS. More studies are warranted to elucidate the mechanisms by which IR and adiposity could contribute to the progression and disability in patients with MS. PMID- 24484678 TI - Effect of folic acid on appetite in children: ordinal logistic and fuzzy logistic regressions. AB - OBJECTIVE: Reduced appetite and low food intake are often a concern in preschool children, since it can lead to malnutrition, a leading cause of impaired growth and mortality in childhood. It is occasionally considered that folic acid has a positive effect on appetite enhancement and consequently growth in children. The aim of this study was to assess the effect of folic acid on the appetite of preschool children 3 to 6 y old. METHODS: The study sample included 127 children ages 3 to 6 who were randomly selected from 20 preschools in the city of Tehran in 2011. Since appetite was measured by linguistic terms, a fuzzy logistic regression was applied for modeling. The obtained results were compared with a statistical ordinal logistic model. RESULTS: After controlling for the potential confounders, in a statistical ordinal logistic model, serum folate showed a significantly positive effect on appetite. A small but positive effect of folate was detected by fuzzy logistic regression. Based on fuzzy regression, the risk for poor appetite in preschool children was related to the employment status of their mothers. CONCLUSIONS: In this study, a positive association was detected between the levels of serum folate and improved appetite. For further investigation, a randomized controlled, double-blind clinical trial could be helpful to address causality. PMID- 24484679 TI - Iron status of pregnant Indian women from an area of active iron supplementation. AB - OBJECTIVE: The aim of this study was to investigate the iron status of pregnant tribal women from Ramtek, Nagpur, Maharashtra, India using a combination of indices. METHODS: A community-based observational study was conducted to assess iron status using a convenience sample of pregnant Indian tribal women from Ramtek. Pregnant women were recruited at 13 to 22 wk gestation (first visit; n = 211) and followed to 29 to 42 wk gestation (second visit; n = 177) of pregnancy. Sociodemographic and anthropometric data; iron supplement intake; and blood samples for estimating hemoglobin (Hb), serum ferritin (SF), soluble transferrin receptor (sTfR), and C-reactive protein (CRP) were obtained. RESULTS: The mean (SD) Hb concentration at recruitment was 106 (15) g/L and 106 (14) g/L at the second visit; 41% of the women at recruitment and 55% at second visit were anemic (14% higher, P < 0.001). No women at recruitment and 3.7% at second visit had SF concentration < 15 ng/mL; and 3.3% at recruitment and 3.9% at the second visit had sTfR > 4.4 ng/mL (0.6% higher, P = 0.179). Almost 62% and 71% of pregnant women used iron supplements at both visits, respectively. Iron supplement intake > 7 d in the preceding month improved the Hb concentration by 3.23 g/L and reduced sTfR concentration by 13%; women who were breastfeeding at the time of recruitment had 11% higher SF concentration. CONCLUSIONS: The iron indices suggest that pregnant tribal women of central India, although anemic, had good iron status. Use of iron supplements > 7 d in the preceding month improved iron status; however, non-iron-deficiency anemia persisted in this group. PMID- 24484681 TI - The four-compartment model of body composition in obese Chilean schoolchildren, by pubertal stage: comparison with simpler models. AB - OBJECTIVES: We assessed the agreement of body fat and fat-free mass measured by simpler methods against the four-compartment model (4C). METHODS: In 60 obese schoolchildren (body mass index >=95th percentile) between the ages of 8 and 13 y who were recruited from one school in Chile, multicompartmental body composition was estimated with the use of isotopic dilution, plethysmography (BodPod), radiographic absorptiometry (DEXA), and anthropometric equations. These results were compared to those of the 4C model, which is considered the gold standard. RESULTS: For body fat, the 4C model showed the best agreement with DEXA for boys in Tanner stages I and II (r = 0.971) and with isotopic dilution for boys in Tanner stages III and IV (r = 0.984). The best agreement in girls occurred with isotopic dilution, regardless of pubertal stage (r = 0.948 for Tanner stages I and II; r = 0.978 for Tanner stages III and IV). Both isotopic dilution and the Huang, Ellis, and Deurenberg anthropometric equations underestimated body fat in boys; by contrast, DEXA, BodPod, and the Slaughter equation overestimated body fat in boys. All of the equations underestimated body fat in girls. For fat-free mass in both boys and girls, the 4C model showed the best agreement with isotopic dilution, regardless of pubertal stage. The Huang equation showed the best agreement for boys (r = 0.730 for Tanner stages I and II; r = 0.695 for Tanner stages III and IV) and for girls in Tanner stages I and II (r = 0.884). The Ellis equation had the best agreement for girls in Tanner stages III and IV (r = 0.917). CONCLUSIONS: For obese Chilean children of both sexes, isotopic dilution and DEXA were the two-compartment methods that had the best agreement with the gold-standard 4C model for both body fat and fat-free mass; these were followed by the Huang and Ellis anthropometric equations. PMID- 24484680 TI - Longitudinal changes in bioimpedance phase angle reflect inverse changes in serum IL-6 levels in maintenance hemodialysis patients. AB - OBJECTIVE: We hypothesize that longitudinal changes in phase angle (PA) have independent associations with changes in inflammatory parameters over time and consequently with long-term survival in patients on maintenance hemodialysis (MHD). The aim of the present study was to determine the effect of change in nutritional and inflammatory parameters over time on change in PA and on subsequent mortality in patients on MHD. METHODS: A 2-y prospective longitudinal study was performed on 91 prevalent HD patients (57 men and 34 women), followed by an additional 3 y of clinical observations. Dietary intake, biochemical markers of nutrition, body composition, and interleukin (IL)-6 levels were measured at baseline and at 6, 12, 18, and 24 mo following enrollment. RESULTS: In a linear mixed-effect model adjusted for baseline demographic and clinical parameters, each pg/mL increase in IL-6 over time was associated with a decrease in PA levels of 0.001 degrees /2-y (P = 0.003 for IL-6 * time interaction). PA remained associated with the rate of change in IL-6 even after controlling for extracellular water and fat mass. Changes in PA over time were associated with inverse linear changes in IL-6 (adjusted r = -0.32; P = 0.005) and consequently with mortality risk. For each 1 degrees increase in PA, the crude and adjusted mortality hazard ratios using Cox models with effect of time-varying risk were 0.62 (95% confidence interval [CI], 0.54-0.71) and 0.61 (95% CI, 0.53-0.71), respectively. Additionally, longitudinal changes in PA exhibited significant associations with slopes of changes over time in main nutritional markers. CONCLUSIONS: Longitudinal changes in PA appear to be reliable in detecting changes in nutritional and inflammatory parameters over time, a combination that may contribute to the understanding of its prognostic utility. PMID- 24484682 TI - Effect of maternal diabetes and hypercholesterolemia on fetal liver of albino Wistar rats. AB - OBJECTIVE: The aim of this study was to predict the development of hepatic lesions and impairment of function during the development of fetuses (13-, 15-, 17-, and 19-d-old embryos) of diabetic and hypercholesterolemic mothers. METHODS: Eighty virgin and fertile male rats (one male/three females) of Wistar strain with an average body weight of 150 to 180 g were used. Mating was carried out, and pregnancy was determined by examining sperm in vaginal smears. Pregnant rats were arranged into three groups; control, diabetic (single intraperitoneal injection [i.p.] of 60 mg streptozotocin/kg) and hypercholesterolemic groups (fed on a diet containing 3% cholesterol for 6 wk before conception and throughout gestation) (n = 20). Pregnant rats were sacrificed and 13-, 15-, 17-, and 19-d old embryos and livers were incised and subjected to histological and transmission electronic microscopical (TEM) investigations, assessments of alkaline phosphatase (Al-Pase) isoenzymes electrophoresis, DNA fragmentation, and comet assay. Flow cytometric analysis of apoptosis and caspases 3 and 9 in the livers of mother rats and their 19-d-old fetuses was determined. RESULTS: Histologic findings of diabetic and hypercholesterolemic mothers revealed apparent damage of hepatocytes, accumulation of lipid-laden cells, and vascular steatosis, while the 13-, 15-, 17- or 19-d-old fetuses of either diabetic or hypercholesterolemic mothers revealed disorganized hepatic architecture and massive cell damage. TEM of diseased mothers and their fetuses possessed increased incidence of pyknotic hepatocytes with massive vesicuolation of rough endoplasmic reticulum and degeneration of mitochondria. Al-Pase isoenzymes were altered and genomic DNA of both double and single helical structures were markedly damaged, especially in fetuses of maternally diabetic and hypercholesterolemic mothers. Flow cytometry revealed an increase in apoptosis and caspases 3 and 9 in diabetic and hypercholesterolemic mothers and their 19-d old fetuses. CONCLUSION: These results suggested that maternal diabetes and hypercholesterolemia predicted early hepatitis and increased apoptosis in mothers and their fetuses as a result of oxidative stress and elevated apoptic markers caspases 3 and 9. PMID- 24484683 TI - Green tea polyphenols protect against okadaic acid-induced acute learning and memory impairments in rats. AB - OBJECTIVE: Green tea polyphenols (GTPs) are now being considered possible protective agents in neurodegenerative diseases such as Alzheimer's disease (AD). Previous studies suggested that GTPs could inhibit amyloid fibril formation and protect neurons from toxicity induced by beta-amyloid. However, whether GTPs can ameliorate learning and memory impairments and also reduce tau hyperphosphorylation induced by okadaic acid (OA) in rats remains unclear. The aim of this study was to determine if GTPs have neuroprotection against OA induced neurotoxicity. METHODS: In this work, rats were pretreated with GTPs by intragastric administration for 4 wk. Then OA was microinjected into the right dorsal hippocampus. Morris water maze tests were used to test the ethologic changes in all groups, and tau protein hyperphosphorylation was detected both in vivo and in vitro. RESULTS: The ethologic test indicated that the staying time and swimming distance in the target quadrant were significantly decreased after OA treatment, whereas rats pretreated with GTPs stayed longer in the target quadrant. Methyl thiazolyl tetrazolium assay and lactate dehydrogenase leakage showed that GTPs greatly ameliorated primary hippocampal neurons damage induced by OA. Furthermore, reduced hyperphosphorylated tau protein was detected with GTPs pretreatment. CONCLUSION: Taken together, our results suggest that GTPs have neuroprotection against OA-induced neurotoxicity. PMID- 24484684 TI - Regulation of corticosterone function during early weaning and effects on gastric cell proliferation. AB - OBJECTIVES: The development of the gastrointestinal tract depends on many elements, including glucocorticoids. In the current study, we evaluated the effects of early weaning on corticosterone function and the growth of rat gastric mucosa. METHODS: By using Wistar rats submitted to early weaning at 15 d, we analyzed plasma corticosterone, corticosteroid-binding globulin (CBG), and glucocorticoid receptor (GR) distribution in the gastric epithelium. RESULTS: With the use of radioimmunoassay, we found that early weaning increased corticosterone concentration at day 16 and 17 in test subjects as compared with controls, whereas it was equivalent between groups at day 18. CBG binding capacity decreased during treatment, and it was significantly lower at day 18. At this age, GR levels and distribution in the gastric mucosa were also reduced as compared with suckling counterparts. To reduce corticosterone activity during early weaning and to explore cell proliferation responses, we administered RU486 to 15-d-old pups. We found that cytoplasmic GR reached a peak after 48 h, whereas nuclear levels remained constant, thereby confirming the inhibition of receptor function. Next, by checking gastric proliferative responses, we observed that RU486 induced higher DNA synthesis and mitotic indices in test subjects as compared with control groups. CONCLUSIONS: We demonstrated that early weaning changed corticosterone activity by increasing hormone levels, reducing CBG binding capacity, and decreasing GR distribution in the gastric epithelium. These modifications seem to be important to the reorganization of gastric growth after the abrupt interruption of suckling. PMID- 24484685 TI - Brazil's staple food and incident diabetes. AB - OBJECTIVE: The aim of this study was to investigate the association of Brazil's staple food, rice, beans and manioc, and the incidence of type 2 diabetes mellitus type 2 (T2DM) in adults assisted by a Brazilian Family Doctor Program (FDP). METHODS: The baseline information was collected on visits to 13 units of the FDP from July 2006 to December 2007 (CAMELIA Study). The units were revisited by trained researchers between July and December 2011, who reviewed medical records of all participants of the baseline. Biochemical, anthropometrical and blood pressure measurements, new diagnoses, and medical prescriptions were collected. Individuals ages >=20 y, who were non-diabetic at baseline were included (N = 409). Food consumption was estimated using a validated semi quantitative food frequency questionnaire. Incident of diabetes was classified according to fasting serum glucose (>=126 mg/dL), individual's use of antidiabetic drugs, and/or diagnosis of diabetes described in the medical record. Individuals who were negative at baseline and also were negative for the above conditions were classified as non-diabetics. RESULTS: Individuals who developed T2DM (N = 30) reported higher consumption of red meat and beans and less consumption of cassava flour, independent of the interval between visits and other potential confounding variables. The cassava flour showed a protective effect (relative risk, 0.910; 95% confidence interval, 0.842-0.982). CONCLUSIONS: The consumption of cassava flour, a low-cost product, could be considered in diets for the prevention and control of diabetes. The hypothesis must be investigated in cohorts from different populations and tested in randomized controlled trials. PMID- 24484686 TI - Pressure ulcers and malnutrition: a devastating and common association. PMID- 24484687 TI - Oil body-associated hazelnut allergens including oleosins are underrepresented in diagnostic extracts but associated with severe symptoms. AB - BACKGROUND: Oil body-associated allergens such as oleosins have been reported for important allergenic foods such as peanut, sesame and hazelnut. Here we investigate whether oil body associated proteins (OAPs) are linked with specific clinical phenotypes and whether they are represented in skin prick test (SPT) reagents. METHODS: A hazelnut OAP fraction was characterized by mass-spectrometry (MS) to identify its major constituents. Polyclonal rabbit antibodies were generated against hazelnut OAPs. The presence of OAPs in commercially available hazelnut SPTs was studied by immunoblot and spiking experiments. OAP-specific IgE antibodies were measured in sera from patients with a convincing history of hazelnut allergy by RAST (n = 91), immunoblot (n = 22) and basophil histamine release (BHR; n = 14). RESULTS: Hazelnut OAPs were analysed by MS and found to be dominated by oleosins at ~14 and ~17 kDa, and a 27 kDa band containing oleosin dimers and unidentified protein. In 36/91 sera specific IgE against hazelnut OAPs was detected, and confirmed to be biologically active by BHR (n = 14). The majority (21/22) recognized the oleosin bands at 17 kDa on immunoblot, of which 11 exclusively. These OAP-specific IgE responses dominated by oleosin were associated with systemic reactions to hazelnut (OR 4.24; p = 0.015) and negative SPT (chi2 6.3, p = 0.012). Immunoblot analysis using OAP-specific rabbit antiserum demonstrated that commercial SPT reagents are virtually devoid of OAPs, sometimes (3/9) resulting in false-negative SPT. Spiking of SPT reagents with OAP restored serum IgE binding of these false-negative patients on immunoblot at mainly 17 kDa. CONCLUSION: Hazelnut allergens found in oil bodies dominated by oleosin are associated with more severe systemic reactions and negative SPT. Defatted diagnostic extracts are virtually devoid of these allergens, resulting in poor sensitivity for detection of IgE antibodies against these clinically relevant molecules. PMID- 24484689 TI - Two-dimensional countercurrent chromatography * high performance liquid chromatography for preparative isolation of toad venom. AB - In this work, a new on-line two-dimensional chromatography coupling of flow programming counter-current chromatography and high-performance liquid chromatography (2D CCC*HPLC) was developed for preparative separation of complicated natural products. The CCC column was used as the first dimensional isolation and a preparative ODS column operated in reversed-phase (RP) mode as the second dimension. The CCC was operated at a controlled flow rate to ensure that each fraction eluted within one hour, corresponding to the isolation time of the 2nd dimensional preparative HPLC. The eluent from the 1st dimensional CCC was diluted using a makeup pump and trapped onto holding column, before been eluted and transferred to the 2nd dimensional HPLC. The performance of the holding column was evaluated, in terms of column size, dilution ratio and diameter-height ratio, as well as system pressure, for the solution to the issue of online trapping of low pressure eluent from a CCC column. Satisfactory trapping efficiency and tolerable CCC pressure can be achieved using a commercially available 15mm*30mm i.d. ODS pre-column. The present integrated system was successfully applied in a one-step preparative separation of 12 compounds, from the crude methanol extract of venom of Bufo bufo gargarizans. Compounds 1-12 were isolated in overall yield of 1.0%, 0.8%, 2.0%, 1.3%, 2.0%, 1.5%, 1.9%, 3.6%, 6.1%, 4.8%, 3.5% and 4.1%, with HPLC purity of 99.9%, 99.7%, 90.6%, 99.9%, 77.0%, 99.9%, 90.4%, 99.9%, 52.0%, 99.9%, 99.3%, and 85.0%, respectively. All the results demonstrate that the flow programming CCC*HPLC method is an efficient and convenient way for the separation of compounds from toad venom and it can also be applied to isolate other complex multi-component natural products. PMID- 24484688 TI - [Efficacy of the subcutaneous route compared to intravenous hydration in the elderly hospitalised patient: a randomised controlled study]. AB - INTRODUCTION: The subcutaneous (SC) route has recently emerged as a rehydration method with potential advantages in the geriatric population. Nevertheless, little is known about its application during hospitalization. The objective of the present study is to evaluate the subcutaneous non-inferiority efficacy in hydration against the intravenous (IV) route in elderly patients with dehydration. MATERIAL AND METHODS: A prospective, randomized and controlled interventional trial of patients 65 years and older admitted to an Acute Geriatric Unit with mild to moderate dehydration and oral intolerance, evaluating the non-inferiority of subcutaneous fluid therapy versus the intravenous route. The intervention consisted of the administration of up to 1.5 l/day/route for 72 hours subcutaneous vs. intravenous, evaluating the variations in biochemical parameters (urea, creatinine, osmolarity), clinical outcome, and route related complications. RESULTS: Sixty seven patients completed the study (34 SC, age 86.4 +/- 8.5 years, 41% women, vs. 33 IV, 84.3 +/- 6.6, 54.5% women, with no significant differences). The amount of fluid administered per day by route was 1.320 ml +/- 400 SC vs. 1.480 ml +/- 340 IV, P = .092. During follow similar reductions were observed between groups without any statistical significance, with mean differences pre-postintervention of urea (49.6 +/- 52.3 SC vs. 50.3 +/- 52.3 IV, P=.96); creatinine (0.68 +/- 0.66 SC vs. 0.60 +/- 0.49 IV, P=.58), and osmolarity (15.6 +/- 24.4 SC vs. 21.1 +/- 31 IV, P=.43). Fewer catheter extraction episodes were observed in the SC group, which also was the group most prone to peri-clysis edema. CONCLUSIONS: The efficacy of subcutaneous rehydration in elderly hospitalized patients with mild-moderate dehydration is not inferior to that obtained intravenously, and may even have additional advantages. PMID- 24484690 TI - New perspectives on diastereoselective determination of hexabromocyclododecane traces in fish by ultra high performance liquid chromatography-high resolution orbitrap mass spectrometry. AB - A new analytical method is presented for diastereoisomer-specific identification and quantitation of hexabromocyclododecanes (HBCD) in fish samples. The method is based on extraction of the target analytes from samples with a mixture of organic solvents, with further three-stage clean-up including destructive removal of matrix components with sulphuric acid and acid-impregnated silica gel, and Florisil adsorption column chromatography. Ultra high performance liquid chromatography (UPLC) coupled with high resolution (HR) Orbitrap mass spectrometry featuring heated electrospray ionization (HESI-II) interface operated in negative ion mode was employed for the identification/quantitation of contaminants. The developed methodology was robustly validated in terms of recovery, repeatability, intermediate precision, linear calibration ranges, limits of detection and quantitation, and used for analysis of twenty five Baltic wild salmon (Salmo salar) samples. Under the optimized conditions, recoveries for selected analytes were within the range of 91.4-103.6%, and the repeatability and intermediate precision in terms of relative standard deviations (RSDs) were in the ranges 1.6-8.3% and 1.6-12.5%, respectively, for all three validation levels. The elaborated method achieved instrumental limits of quantification (i-LOQ) of 1.3-3.0pg on column for three HBCD diastereoisomers corresponding to the method LOQ of 0.005-0.012ngg(-1) wet weight (w.w.) The presence of HBCD diastereoisomers was confirmed in all the analyzed Baltic salmon samples in the concentration range of 0.39-3.82ngg(-1) w.w. with an average of 1.59ngg(-1) w.w. for total HBCD. The diastereomer pattern typical for aquatic biota was observed with strong predominance of alpha-HBCD. The newly developed methodology could be employed for a regular diastereomer-specific monitoring of HBCD content in fish samples, representing a good alternative to existing LC-MS/MS methods in terms of sensitivity and accuracy, and providing further possibilities for inclusion of other contaminants in the scope of analysis. PMID- 24484691 TI - Introducing the concept of centergram. A new tool to squeeze data from separation techniques-mass spectrometry couplings. AB - In separation techniques hyphenated to mass spectrometry (MS) the bulk from the separation step is continuously flowing into the mass spectrometer where the compounds, arriving at each separation time, are ionized and further separated based on their m/z ratio. An MS detector is recognized as being a universal detector, although it can also be a very selective instrument. In spite of these advantages, classical two dimensional representations from these hyphenated systems, such as those based on the base peak of electropherogram/chromatogram or on the total ion of electropherogram/chromatogram, usually hide a large number of features that if correctly assessed will show the presence of co-migrating species and/or the low abundant ones. The uses of peak picking algorithms to detect and measure as many peaks as possible from a dataset allow extracting much more information. However, a single migrating compound usually produces a multiplicity of ions, making difficult to differentiate peaks generated by the same compound from other peaks due e.g., to closely co-migrating/eluting species. In this work, a new representation is proposed and its usefulness demonstrated with experimental data from capillary electrophoresis-hyphenated to a time of flight mass spectrometer via an electrospray interface. This representation, called centergram, is obtained after using a peak picking methodology that detects electrophoretic peaks of single ions and measure their positions. The centergram is the histogram (i.e. the count of the number of observations that fall into each one of the intervals, known as bins, as determined by the user) of the measured positions. The intensity of the bars in this histogram will indicate the amount of peaks in the whole dataset whose centers are within each interval. As a compound that has been separated and has entered the MS instrument will produce multiple images at the same position along the m/z dimension, the centergram will exhibit a series of intense bars around the migration time. Those bars will allow defining a centergram peak whose area will be proportional to the number of different types of ions that have been generated in the ionization chamber, the position will be equal to the migration/retention time of the parent compounds and the width will depend on the precision in the measurement of the peak positions. The efficiency of this peak is determined to be up to thirty times higher than the equivalent peak in the classical base peak electropherogram allowing detecting easily co-migrating peaks or the presence of compounds at very low abundance. The number of peaks detected by using this new tool called centergram was increased by more than a factor of 3 compared to the standard representations. PMID- 24484692 TI - Study of surface-bonded dicationic ionic liquids as stationary phases for hydrophilic interaction chromatography. AB - In the present study, several geminal dicationic ionic liquids based on 1,4-bis(3 allylimidazolium)butane and 1,8-bis(3-allylimidazolium)octane in combination with different anions bromide and bis(trifluoromethanesulphonyl)imide were prepared and then bonded to the surface of 3-mercaptopropyl modified silica materials through the "thiol-ene" click chemistry as stationary phases for hydrophilic interaction chromatography (HILIC). Compared with their monocationic analogues, the dicationic ionic liquids stationary phases presented effective retention and good selectivity for typical hydrophilic compounds under HILIC mode with the column efficiency as high as 130,000 plates/m. Moreover, the influence of different alkyl chain spacer between dications and combined anions on the retention behavior and selectivity of the dicationic ionic liquids stationary phases under HILIC mode was displayed. The results indicated that the longer linkage chain would decrease the hydrophilicity and retention on the dicationic ionic liquid stationary phase, and while differently combined anions had no difference due to the exchangeability under the common HILIC mobile phase with buffer salt. Finally, the retention mechanism was investigated by evaluating the effect of chromatographic factors on retention, including the water content in the mobile phase, the mobile phase pH and buffer salt concentration. The results showed that the dicationic ionic liquids stationary phases presented a mixed-mode retention behavior with HILIC mechanism and anion exchange. PMID- 24484693 TI - A standardized method for the calibration of thermodynamic data for the prediction of gas chromatographic retention times. AB - A new method for calibrating thermodynamic data to be used in the prediction of analyte retention times is presented. The method allows thermodynamic data collected on one column to be used in making predictions across columns of the same stationary phase but with varying geometries. This calibration is essential as slight variances in the column inner diameter and stationary phase film thickness between columns or as a column ages will adversely affect the accuracy of predictions. The calibration technique uses a Grob standard mixture along with a Nelder-Mead simplex algorithm and a previously developed model of GC retention times based on a three-parameter thermodynamic model to estimate both inner diameter and stationary phase film thickness. The calibration method is highly successful with the predicted retention times for a set of alkanes, ketones and alcohols having an average error of 1.6s across three columns. PMID- 24484695 TI - Outcomes of non-vertex second twins, following vertex vaginal delivery of first twin: a secondary analysis of the WHO Global Survey on maternal and perinatal health. AB - BACKGROUND: Mode of delivery remains a topic of debate in vertex/non-vertex twin pregnancies. We used the WHO Global Survey dataset to determine the risk of adverse maternal/perinatal outcomes associated with presentation of the second twin, following vaginal delivery of a vertex first twin. METHODS: We analysed a derived dataset of twin pregnancies >= 32 weeks gestation where the first twin was vertex and delivered vaginally. Maternal, delivery and neonatal characteristics and adverse outcomes were reported by presentation of the second twin. Logistic regression models (adjusted for maternal and perinatal confounders, mode of delivery and region) were developed to determine odds of adverse outcomes associated with presentation. RESULTS: 1,424 twin pregnancies were included, 25.9% of these had a non-vertex second twin and Caesarean was more common in non-vertex presentations (6.2% vs 0.9%, p < 0.001). While the odds of Apgar < 7 at 5 minutes were higher in non-vertex presenting second twins (16.0% vs 11.4%, AOR 1.42 95% CI 1.01-2.00), the odds of maternal ICU admission (4.6% vs 1.7%, AOR 1.30, 95% CI 0.88-1.94), blood transfusion (6.0% vs 3.4%, AOR 1.23, 95% CI 0.67-2.25), stillbirth (7.6% vs 4.7%, AOR 1.15, 95% CI 0.72-1.73), early neonatal death (3.8% vs 2.1%, AOR 1.68, 95% CI 0.96-2.94), and NICU admission (26.6% vs 23.2%, AOR 0.93, 95% CI 0.62-1.39) were not. CONCLUSION: After a vaginal delivery of a vertex first twin, non-vertex presentation of the second twin is associated with increased odds of Apgar <7 at 5 minutes, but not of other maternal/perinatal outcomes. Presentation of the second twin is not as important a consideration in planning twin vaginal birth as previously considered. PMID- 24484696 TI - Memory deficits in aging and neurological diseases. AB - Memory is central to our ability to perform daily life activities and correctly function in society. Improvements in public health and medical treatment for a variety of diseases have resulted in longer life spans; however, age-related memory impairments have been significant sources of morbidity. Loss in memory function is not only associated with aging population but is also a feature of neurodegenerative diseases such as Alzheimer's disease and other psychiatric and neurological disorders. Here, we focus on current understanding of the impact of normal aging on memory and what is known about its mechanisms, and further review pathological mechanisms behind the cause of dementia in Alzheimer's disease. Finally, we discuss schizophrenia and look into abnormalities in circuit function and neurotransmitter systems that contribute to memory impairment in this illness. PMID- 24484697 TI - The "memory kinases": roles of PKC isoforms in signal processing and memory formation. AB - The protein kinase C (PKC) isoforms, which play an essential role in transmembrane signal conduction, can be viewed as a family of "memory kinases." Evidence is emerging that they are critically involved in memory acquisition and maintenance, in addition to their involvement in other functions of cells. Deficits in PKC signal cascades in neurons are one of the earliest abnormalities in the brains of patients suffering from Alzheimer's disease. Their dysfunction is also involved in several other types of memory impairments, including those related to emotion, mental retardation, brain injury, and vascular dementia/ischemic stroke. Inhibition of PKC activity leads to a reduced capacity of many types of learning and memory, but may have therapeutic values in treating substance abuse or aversive memories. PKC activators, on the other hand, have been shown to possess memory-enhancing and antidementia actions. PKC pharmacology may, therefore, represent an attractive area for developing effective cognitive drugs for the treatment of many types of memory disorders and dementias. PMID- 24484698 TI - CaMKII: a molecular substrate for synaptic plasticity and memory. AB - Learning and memory is widely believed to result from changes in connectivity within neuronal circuits due to synaptic plasticity. Work over the past two decades has shown that Ca(2+) influx during LTP induction triggers the activation of CaMKII in dendritic spines. CaMKII activation results in autophosphorylation of the kinase rendering it constitutively active long after the Ca(2+) dissipates within the spine. This "molecular switch"(1) mechanism is essential for LTP and learning and memory. Here, we discuss this key regulatory mechanism and the diversity of downstream targets that can be modulated by CaMKII to exert dynamic control of synaptic structure and function. PMID- 24484699 TI - The transcription factor Zif268/Egr1, brain plasticity, and memory. AB - The capacity to remember our past experiences and organize our future draws on a number of cognitive processes that allow our brain to form and store neural representations that can be recalled and updated at will. In the brain, these processes require mechanisms of neural plasticity in the activated circuits, brought about by cellular and molecular changes within the neurons activated during learning. At the cellular level, a wealth of experimental data accumulated in recent years provides evidence that signaling from synapses to nucleus and the rapid regulation of the expression of immediate early genes encoding inducible, regulatory transcription factors is a key step in the mechanisms underlying synaptic plasticity and the modification of neural networks required for the laying down of memories. In the activated neurons, these transcriptional events are thought to mediate the activation of selective gene programs and subsequent synthesis of proteins, leading to stable functional and structural remodeling of the activated networks, so that the memory can later be reactivated upon recall. Over the past few decades, novel insights have been gained in identifying key transcriptional regulators that can control the genomic response of synaptically activated neurons. Here, as an example of this approach, we focus on one such activity-dependent transcription factor, Zif268, known to be implicated in neuronal plasticity and memory formation. We summarize current knowledge about the regulation and function of Zif268 in different types of brain plasticity and memory processes. PMID- 24484701 TI - BDNF-TrkB receptor regulation of distributed adult neural plasticity, memory formation, and psychiatric disorders. AB - Brain-derived neurotrophic factor (BDNF) and its single transmembrane receptor, tropomysin-related kinase B (TrkB), are essential for adult synaptic plasticity and the formation of memories. However, there are regional and task-dependent differences underlying differential mechanisms of BDNF-TrkB function in the formation of these memories. Additionally, the BDNF pathway has been implicated in several psychiatric disorders including posttraumatic stress disorder, phobia, and panic disorder. Gaining a better understanding of this pathway and the neurobiology of memory through fundamental research may be helpful to identify effective prevention and treatment approaches both for diseases of memory deficit as well as in cases of enhanced aversive memory, such as in anxiety disorders. PMID- 24484702 TI - Mechanisms of synaptic plasticity and recognition memory in the perirhinal cortex. AB - Learning is widely believed to involve synaptic plasticity, employing mechanisms such as those used in long-term potentiation (LTP) and long-term depression (LTD). In this chapter, we will review work on mechanisms of synaptic plasticity in perirhinal cortex in vitro and relate these findings to studies underlying recognition memory in vivo. We describe how antagonism of different glutamate and acetylcholine receptors, inhibition of nitric oxide synthase, inhibition of CREB phosphorylation, and interfering with glutamate AMPA receptor internalization can produce deficits in synaptic plasticity in vitro. Inhibition of each of these different mechanisms in vivo also results in recognition memory deficits. Therefore, we provide strong evidence that synaptic plastic mechanisms are necessary for the information processing and storage that underlies object recognition memory. PMID- 24484703 TI - Molecular influences on working memory circuits in dorsolateral prefrontal cortex. AB - The working memory circuits of the primate dorsolateral prefrontal cortex (dlPFC) are modulated in a unique manner, often opposite to the molecular mechanisms needed for long-term memory consolidation. Working memory, our "mental sketch pad" is an ephemeral process, whereby transient, mental representations form the foundation for abstract thought. The microcircuits that generate mental representations are found in deep layer III of the dlPFC, where pyramidal cells excite each other to keep information "in mind" through NMDA receptor synapses on spines. The catecholaminergic and cholinergic arousal systems have rapid and flexible influences on the strength of these connections, thus allowing coordination between arousal and cognitive states. These modulators can rapidly weaken connectivity, for example, as occurs during uncontrollable stress, via feedforward calcium-cAMP signaling opening potassium (K(+)) channels near synapses on spines. Lower levels of calcium-cAMP-K(+) channel signaling provide negative feedback within recurrent excitatory circuits, and help to gate inputs to shape the contents of working memory. There are also explicit mechanisms to inhibit calcium-cAMP signaling and strengthen connectivity, for example, postsynaptic alpha2A-adrenoceptors on spines. This work has led to the development of the alpha2A agonist, guanfacine, for the treatment of a variety of dlPFC disorders. In mental illness, there are a variety of genetic insults to the molecules that normally serve to inhibit calcium-cAMP signaling in spines, thus explaining why so many genetic insults can lead to the same phenotype of impaired dlPFC cognitive function. Thus, the molecular mechanisms that provide mental flexibility may also confer vulnerability when dysregulated in cognitive disorders. PMID- 24484700 TI - Mechanisms of translation control underlying long-lasting synaptic plasticity and the consolidation of long-term memory. AB - The complexity of memory formation and its persistence is a phenomenon that has been studied intensely for centuries. Memory exists in many forms and is stored in various brain regions. Generally speaking, memories are reorganized into broadly distributed cortical networks over time through systems level consolidation. At the cellular level, storage of information is believed to initially occur via altered synaptic strength by processes such as long-term potentiation. New protein synthesis is required for long-lasting synaptic plasticity as well as for the formation of long-term memory. The mammalian target of rapamycin complex 1 (mTORC1) is a critical regulator of cap-dependent protein synthesis and is required for numerous forms of long-lasting synaptic plasticity and long-term memory. As such, the study of mTORC1 and protein factors that control translation initiation and elongation has enhanced our understanding of how the process of protein synthesis is regulated during memory formation. Herein we discuss the molecular mechanisms that regulate protein synthesis as well as pharmacological and genetic manipulations that demonstrate the requirement for proper translational control in long-lasting synaptic plasticity and long-term memory formation. PMID- 24484704 TI - Cost-benefit decision circuitry: proposed modulatory role for acetylcholine. AB - In order to select which action should be taken, an animal must weigh the costs and benefits of possible outcomes associate with each action. Such decisions, called cost-benefit decisions, likely involve several cognitive processes (including memory) and a vast neural circuitry. Rodent models have allowed research to begin to probe the neural basis of three forms of cost-benefit decision making: effort-, delay-, and risk-based decision making. In this review, we detail the current understanding of the functional circuits that subserve each form of decision making. We highlight the extensive literature by detailing the ability of dopamine to influence decisions by modulating structures within these circuits. Since acetylcholine projects to all of the same important structures, we propose several ways in which the cholinergic system may play a local modulatory role that will allow it to shape these behaviors. A greater understanding of the contribution of the cholinergic system to cost-benefit decisions will permit us to better link the decision and memory processes, and this will help us to better understand and/or treat individuals with deficits in a number of higher cognitive functions including decision making, learning, memory, and language. PMID- 24484705 TI - Molecular mechanisms of threat learning in the lateral nucleus of the amygdala. AB - Pavlovian threat conditioning is a behavioral paradigm that has been successfully utilized to define the mechanisms underlying threat (fear) memory formation. The amygdala is a temporal lobe structure required for the acquisition, consolidation, and expression of threat (fear) memories. In particular, the lateral nucleus of the amygdala (LA) is the major input structure of the amygdala and is required for all aspects of threat learning and memory. The LA expresses many neurotransmitter and neuromodulator receptors. This chapter covers the molecular mechanisms that occur downstream of these receptors and how they influence LA-dependent Pavlovian threat learning. PMID- 24484706 TI - Epigenetics of memory and plasticity. AB - Although all neurons carry the same genetic information, they vary considerably in morphology and functions and respond differently to environmental conditions. Such variability results mostly from differences in gene expression. Among the processes that regulate gene activity, epigenetic mechanisms play a key role and provide an additional layer of complexity to the genome. They allow the dynamic modulation of gene expression in a locus- and cell-specific manner. These mechanisms primarily involve DNA methylation, posttranslational modifications (PTMs) of histones and noncoding RNAs that together remodel chromatin and facilitate or suppress gene expression. Through these mechanisms, the brain gains high plasticity in response to experience and can integrate and store new information to shape future neuronal and behavioral responses. Dynamic epigenetic footprints underlying the plasticity of brain cells and circuits contribute to the persistent impact of life experiences on an individual's behavior and physiology ranging from the formation of long-term memory to the sequelae of traumatic events or of drug addiction. They also contribute to the way lifestyle, life events, or exposure to environmental toxins can predispose an individual to disease. This chapter describes the most prominent examples of epigenetic marks associated with long-lasting changes in the brain induced by experience. It discusses the role of epigenetic processes in behavioral plasticity triggered by environmental experiences. A particular focus is placed on learning and memory where the importance of epigenetic modifications in brain circuits is best understood. The relevance of epigenetics in memory disorders such as dementia and Alzheimer's disease is also addressed, and promising perspectives for potential epigenetic drug treatment discussed. PMID- 24484707 TI - Deciphering memory function with optogenetics. AB - Optogenetics has accelerated the field of neuroscience by overcoming many of the spatial, genetic, and temporal limitations of previous techniques to control neural activity. The study of learning and memory has profoundly benefited from these tools mainly from their use in rodents. New insights have been made regarding the involvement of specific cell types or populations of synapses in the acquisition, consolidation, and retrieval of memories. The cellular specificity and temporal precision of optogenetic manipulations have also shown to be useful to study synaptic mechanisms supporting learning and memory including long-term synaptic plasticity. Recently, new light-sensitive molecules have been developed to control intracellular pathways or gene expression, which promise to enhance our understanding of the molecular mechanism of memory function. PMID- 24484709 TI - Preface. Molecular basis of memory. PMID- 24484708 TI - The tagging and capture hypothesis from synapse to memory. AB - The synaptic tagging and capture theory (STC) was postulated by Frey and Morris in 1997 and provided a strong framework to explain how to achieve synaptic specificity and persistence of electrophysiological-induced plasticity changes. Ten years later, the same argument was applied on learning and memory models to explain the formation of long-term memories, resulting in the behavioral tagging hypothesis (BT). These hypotheses are able to explain how a weak event that induces transient changes in the brain can establish long-lasting phenomena through a tagging and capture process. In this framework, it was postulated that the weak event sets a tag that captures plasticity-related proteins/products (PRPs) synthesized by an independent strong event. The tagging and capture processes exhibit symmetry, and therefore, PRPs can be captured if they are synthesized either before or after the setting of the tag. In summary, the hypothesis provides a wide framework that gives a solid explanation of how lasting changes occur and how the interaction between different events leads to promotion, reinforcement, or impairment of such changes. In this chapter, we will summarize the postulates of STC hypothesis, the common features between synaptic plasticity and memory, as well as a detailed compilation of the findings supporting the existence of BT process. At the end, we pose some questions related to BT mechanism and LTM formation, which probably will be answered in the near future. PMID- 24484710 TI - Young adults with co-occurring disorders: substance use disorder treatment response and outcomes. AB - Compared to other life stages, young adulthood (ages 18-24) is characterized by qualitative differences including the highest rates of co-occurring substance use and psychiatric disorders (COD). Little is known, however, regarding young adults' response to substance use disorder (SUD) treatment, especially those with COD. Greater knowledge in this area could inform and enhance the effectiveness and efficiency of SUD care for this patient population. The current study investigated differences between 141 COD and 159 SUD-only young adults attending psychiatrically-integrated residential SUD treatment on intake characteristics, during-treatment changes on clinical targets (e.g., coping skills; abstinence self-efficacy), and outcomes during the year post-discharge. Contrary to expectations, despite more severe clinical profiles at intake, COD patients showed similar during-treatment improvements on clinical target variables, and comparable post-treatment abstinence rates and psychiatric symptoms. Clinicians referring young adults with COD to specialized care may wish to consider residential SUD treatment programs that integrate evidence-based psychiatric services. PMID- 24484711 TI - Managing metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer in the older patient. AB - Treating older patients with metastatic human epidermal growth factor receptor 2 (HER2)-positive breast cancer is often challenging. This is largely due to the issues providers face in making decisions in the setting of limited efficacy and toxicity data specific to older women in addition to the competing challenges of managing comorbidity and preserving functional status. Here, we discuss currently available treatment regimens and other important issues to consider when treating older patients with metastatic, HER2-positive disease. PMID- 24484712 TI - Getting beyond screening for frailty in older patients with cancer. PMID- 24484713 TI - Accuracy of the G-8 geriatric-oncology screening tool for identifying vulnerable elderly patients with cancer according to tumour site: the ELCAPA-02 study. AB - BACKGROUND/OBJECTIVE: G-8 screening tool showed good screening properties for identifying vulnerable elderly patients with cancer who would benefit from a comprehensive geriatric assessment (CGA). We investigated whether tumour site and metastatic status affected its accuracy. MATERIALS AND METHODS: DESIGN: Cross sectional analysis of a prospective cohort study. SETTING: Geriatric-oncology clinics of two teaching hospitals in the urban area of Paris. PARTICIPANTS: Patients aged 70 or over (n = 518) with breast ( n= 113), colorectal (n = 108), urinary-tract (n = 89), upper gastrointestinal/liver (n = 85), prostate (n = 69), or other cancers (n = 54). MEASUREMENTS: Reference standard for diagnosing vulnerability was the presence of at least one abnormal test among the Activities of Daily Living (ADLs), Instrumental ADL, Mini-Mental State Examination, Mini Nutritional Assessment, Cumulative Illness Rating Scale-Geriatrics, Timed Get-Up and-Go, and Mini-Geriatric Depression Scale. Sensitivity, specificity and likelihood ratios of G-8 scores <= 14 were compared according to tumour site and patient characteristics. RESULTS: Median age was 80; 48.2% had metastases. Prevalence of vulnerability and abnormal G-8 score was 84.2% (95% confidence interval [95% CI], 81-87.3) and 79.5% (95% CI, 76-83). The G-8 was 86.9% sensitive (95% CI, 83.4-89.9) and 59.8% specific (95% CI, 48.3-70.4). G-8 performance varied significantly (all p values < 0.001) across tumour sites (sensitivity, 65.2% in prostate cancer to 95.1% in upper gastrointestinal/liver cancer; and specificity, 23.1% in colorectal cancer to 95.7% in prostate cancer) and metastatic status (sensitivity and specificity, 93.8% and 53.3% in patients with metastases vs. 79.5% and 63.3% in those without, respectively). Differences remained significant after adjustment on age and performance status. CONCLUSION: These G-8 accuracy variations across tumour sites should be considered when using G-8 to identify elderly patients with cancer who could benefit from CGA. PMID- 24484714 TI - Completion of radiotherapy is associated with the Vulnerable Elders Survey-13 score in elderly patients with cancer. AB - OBJECTIVES: Vulnerability assessment of geriatric patients with cancer may contribute to improved anti-cancer treatment with maximal results and minimal side effects. The aim of the present study was to evaluate whether the Vulnerable Elders Survey-13 (VES-13) score is associated with completion of radiotherapy among elderly patients with cancer. MATERIALS AND METHODS: This was a prospective observational study that included patients greater than age 75 with histologically confirmed cancer disease, referred to the Department of Radiation Oncology to receive radical or palliative radiotherapy, from 2010 to 2012. VES-13 forms were filled in before the initiation of radiotherapy and scores were assigned according to a standardized scoring procedure. RESULTS: Of a total of 230 participants (median age 78.5 years), 41 (17.8%) did not complete radiotherapy. These patients had higher VES-13 scores (median with interquartile range: 5 [2-8.5]) compared to those who completed the treatment (3 [1-7]; P = 0.008). A VES-13 score >3 was associated with 2.14 times higher probability of not completing radiotherapy, whereas in patients with scores >7 this probability was 3.34 times higher. The association between higher VES-13 scores and non completion of radiotherapy was independent of other factors, such as age, sex, comorbidities, type of radiotherapy, and presence of side effects. CONCLUSION: Patients with higher VES-13 scores had increased probability of not completing radiotherapy in our study, and this effect was independent of other factors that might affect radiotherapy completion. PMID- 24484715 TI - Frailty indicators and functional status in older patients after colorectal cancer surgery. AB - OBJECTIVES: The number of older survivors from colorectal cancer is increasing, but little is known regarding long-term consequences of cancer treatment in this patient group. Physical function is an important outcome for older patients, affecting both autonomy and quality of life. We aimed to investigate physical function in older patients with colorectal cancer before and after surgery, and to examine the role of individual frailty indicators as predictors of functional decline. MATERIAL AND METHODS: We present 16-28 months follow-up data of older patients after elective surgery for colorectal cancer. During a home-visit, physical function was evaluated by activities of daily living (ADL), instrumental activities of daily living (IADL), the timed up-and-go (TUG) test, and grip strength. Measurements were compared with those obtained preoperatively using the Wilcoxon signed rank test. Frailty indicators were dichotomized and implemented in logistic regression models to explore their associations to a decline in the physical function scores. RESULTS: Eighty-four patients were included and the median age was 82 years. There was a significant decrease in ADL (p = 0.04) and IADL scores (p <= 0.001) at follow-up. We found no associations between frailty indicators and the risk of decline in physical functioning. CONCLUSION: In our population of older patients with surgically treated colorectal cancer, there was a significant decline in ADL- and IADL-scores at follow-up. No change was found in TUG or grip strength, and frailty indicators did not predict decline in physical function. PMID- 24484716 TI - The association of resilience and age in individuals with colorectal cancer: an exploratory cross-sectional study. AB - BACKGROUND: Studies generally report lower emotional distress in older patients with cancer than in younger patients with cancer. The personality construct of resilience was previously found to be higher with age, but has not been assessed in relation to emotional distress in older patients with cancer. OBJECTIVE: To assess the mediating effect of resilience on the associations between age and emotional distress in patients with colorectal cancer (CRC). PATIENTS AND METHODS: An exploratory cross-sectional study of 92 individuals, aged 27-87 years, diagnosed with CRC stage II-III, 1-5 years prior to enrollment in the study. They completed the Wagnild and Young's resilience scale and Brief Symptoms Inventory-18, cancer-related problem list, and demographic and disease-related details. RESULTS: Older age, male gender, and less cancer-related problems were associated with higher resilience and lower emotional distress. A Structural Equation Modeling (SEM) analysis and mediation tests showed that, while controlling for cancer-related problems, resilience mediated the effects of age and gender on emotional distress. CONCLUSIONS: The study enlarges the explanation for the consistent previous findings on the better adjustment of older patients with cancer. Increased professional support should be provided for patients with low resilience levels. PMID- 24484717 TI - Metabolic syndrome and colorectal cancer: is hyperinsulinemia/insulin receptor mediated angiogenesis a critical process? AB - OBJECTIVE: Components of metabolic syndrome (MS) have been individually linked to colorectal cancer risk and prognosis; however, an understanding of the dominant mechanisms is lacking. MATERIALS AND METHODS: Twenty-one patients (10 MS; 11 non MS) with resectable colorectal cancer were prospectively enrolled. Patients were classified for MS by the World Health Organization criteria and tested for circulating vascular endothelial growth factor (VEGF), interleukin-6 (IL-6), insulin-like growth factor-1 (IGF-1), fasting insulin, and tumor expression of IGF-1 receptor (IGF-1R), insulin-receptor (IR) and receptor for advanced glycation end-products (RAGE). Circulating markers were re-tested 6 months after surgery. RESULTS: The MS group had significantly higher baseline and post operative fasting insulin levels (p < 0.001 and 0.003). No differences were observed in circulating IL-6, VEGF, IGF-1 and free IGF-1. By immunohistochemistry (IHC), IGF-1R expression was significantly higher in tumor vs. normal tissues (p < 0.001) while IR expression showed no difference. Interestingly, 64% of tumors demonstrated high IR positivity in the vessels within or surrounding the tumor stroma, but not in the vessels away from the tumor. By reverse transcription polymerase chain reaction (RT-PCR), tumor IGF-1R over-expression (80%) was confirmed, but there was no difference between MS and non-MS patients. Tumor RAGE over-expression was found in 67% of patients and was equally distributed between the two groups. CONCLUSIONS: Hyperinsulinemia was the only significant factor distinguishing patients with colorectal cancer who have MS. The preferential over expression of IR in the peri-tumoral microvessels suggests that hyperinsulinemia might contribute to colorectal cancer growth by enhancing angiogenesis. PMID- 24484718 TI - Patients over 65 years are assigned lower ECOG PS scores than younger patients, although objectively measured physical activity is no different. AB - OBJECTIVES: The Eastern Cooperative Group Performance Status (ECOG PS) is a widely used standard functional classification in oncology practice, the verbal descriptors of which refer to physical activity (PA). Little is known about the cut-off points of this scale and measured PA levels. This research investigated the relationship between PS assigned, objectively measured PA, and patient age. MATERIALS AND METHODS: One hundred ambulatory patients with treatment-naive cancer wore an accelerometer (RT3) for a mean (SD) of 5.6 (1.1) days before initial oncology evaluation and ECOG PS assignment. RESULTS: Seventy five participants (75%) were <65 years and 25 were >=65 years. Eighty nine (89%) were assigned an ECOG PS of 0 or 1 and 11% a PS of 2 or 3. A weak but significant inverse association was found between objectively measured PA and PS (rho = 0.26, p = 0.01). Seventy one participants (80%) with a PS of 0 or 1 spent more than 50% of waking hours resting. Participants assigned a PS of 2-3 spent significantly more time resting than those assigned a PS of 0 (p = 0.01). Age >=65 years was significantly related to PS assigned (p = 0.04), although the older cohort were no less sedentary than younger patients. CONCLUSION: PA levels were low, but PS scoring reflected relative PA levels and differentiated between patients of PS 0 and 2-3. Chronological age was not predictive of activity levels, but older patients were assigned lower PS scores. Incorporation of objective PA measures may merit further investigation especially in the geriatric oncology setting. PMID- 24484719 TI - Fall-related injuries in elderly cancer patients treated with neurotoxic chemotherapy: a retrospective cohort study. AB - BACKGROUND: Fall-related injuries are a well-described cause of morbidity and mortality in the community-dwelling elderly population, but have not been well described in patients with cancer. Cancer treatment with chemotherapy can result in many unwanted side effects, including peripheral neuropathy if the drugs are potentially neurotoxic. Peripheral neuropathy and other side effects of chemotherapy may lead to an increased risk of fall-related injuries. METHODS: We conducted a retrospective cohort analysis using the records of 65,311 patients with breast, colon, lung, or prostate cancer treated with chemotherapy in the SEER-Medicare database from 1994 to 2007. The primary outcome was any fall related injury defined as a traumatic fracture, dislocation, or head injury within 12 months of the first dose of chemotherapy. The sample population was divided into 3 cohorts based on whether they most frequently received a neurotoxic doublet, single agent, or a non-neurotoxic chemotherapy. Cox proportional-hazards analyses were adjusted for baseline characteristics to determine the risk of fall-related injuries among the 3 cohorts. RESULTS: The rate of fall-related injuries for patients receiving a doublet of neurotoxic chemotherapy (9.15 per 1000 person-months) was significantly higher than for those receiving a single neurotoxic agent (7.76 per 1000 person-months) or a non neurotoxic agent (5.19 per 1000 person-months). Based on the Cox proportional hazards model risk of fall-related injuries was highest for the cohort receiving a neurotoxic doublet after the model was adjusted for baseline characteristics. CONCLUSIONS: Among elderly patients with cancer, use of neurotoxic chemotherapy is associated with an increased risk of fall-related injuries. PMID- 24484721 TI - Tolerance and benefits of treatment for elderly patients with limited small-cell lung cancer. AB - OBJECTIVES: Over 20% of all newly diagnosed Dutch patients with small-cell lung cancer (SCLC) are aged >=75 years. Uncertainties still exist about safety and efficacy of chemotherapy and chemoradiation in elderly patients. We evaluated the association between patient characteristics and (completion of) treatment and also evaluated toxicity, response and survival in elderly patients with SCLC. MATERIALS AND METHODS: Population-based data from patients aged 75 years or older and diagnosed with limited SCLC in 1997-2004 in The Netherlands were used (N = 368). Additional data on co-morbidity, motive for deviating from guidelines, grades 3-5 toxicity, response and survival were gathered from medical records. RESULTS: Although only relatively fit elderly were selected for chemotherapy, almost 70% developed toxicity, leading to early termination of chemotherapy in over half of all patients. Median survival time was 6.7 months, but differed strongly according to type and completion of treatment (13.5 months for chemoradiation, 7.1 months for chemotherapy, 2.9 months for best supportive care, 11.5 months for patients receiving at least 4 cycles of chemotherapy and 3.6 months for less than 4 cycles). CONCLUSION: Although toxicity rate was high and many patients could not complete the full chemotherapy, those who received chemotherapy or chemoradiation had a significantly better survival. We hypothesize that a better selection by proper geriatric assessments is needed to achieve a more favourable balance between benefit and harm. PMID- 24484720 TI - An evaluation of elderly patients (>=70 years old) enrolled in Phase I clinical trials at University of Texas Health Science Center at San Antonio-Cancer Therapy Research Center from 2009 to 2011. AB - OBJECTIVE: Elderly patients with cancer are under-represented in clinical trials, and there is especially scant data on their participation in early-phase trials. In an effort to provide more data, we reviewed our Phase I experience. METHODS: We conducted a retrospective analysis of 461 patients enrolled in Phase I clinical trials at the Cancer Therapy Research Center (CTRC) from 2009 to 2011 to determine the rate of completion of at least 12 weeks of treatment, incidence of adverse events, prevalence of co-morbidities, functional status, and survival. Elderly (E) was defined as >=70 years; non-elderly (NE) was defined as <=69 years. RESULTS: The elderly represented 15% (69/461) of enrolled patients. The most common malignancies were colon (20%), hematologic (18%), lung (15%), and breast (8%). The median age of E was 72 years (range 70-85, SD 3.15), and 49% of the E was female. Co-morbidities (E vs. NE) include diabetes (28% vs. 23%), hypertension (65% vs. 44%), and chronic kidney disease (91% vs. 48%). Thirty-two percent of E vs. 37% of NE completed at least 12 weeks of treatment. Reasons for not completing in E vs. NE respectively were progression of disease (43% vs. 61%), toxicity (28% vs. 9%), and self-withdrawal (11% vs. 7%). Reasons for not completing the protocol was significantly associated with being elderly (p = 0.005). There were non-significant differences in toxicity in E vs. NE CONCLUSION: Elderly patients have a higher likelihood of not completing trials for reasons including toxicity. This highlights the need for better Phase I trial designs incorporating ideal geriatric assessment tools. PMID- 24484722 TI - Bevacizumab in elderly patients with metastatic colorectal cancer. AB - The progressively ageing population combined with an increased availability of antitumoural agents has created a new, challenging therapeutic scenario for oncologists. Due to the lack of evidence-based data on elderly patients it is uncertain whether the criteria for assessing the risk/benefit ratio of treatment strategies in these patients coincide with those classically used for the general population. A critical reevaluation of the role and potential options of systemic chemotherapy in elderly patients with metastatic colorectal cancer (mCRC) is warranted as the historical conservative approach of oncologists may have resulted in undertreatment of this patient population. Bevacizumab was demonstrated to improve the outcome of mCRC patients when used in combination with standard first and second line chemotherapy. However, its toxicity profile including hypertension, thromboembolic events, haemorrhage and proteinuria may raise important concerns when this anti-angiogenic agent is used in elderly patients with comorbidities. In this review article we analyse the available evidence on the safety and effectiveness of bevacizumab in elderly mCRC patients. Based on the data from subgroup or pooled analysis of prospective trials, observational cohort studies, retrospective population-based studies and a single recent randomised phase III trial, we conclude that the clinical benefit and safety profile of bevacizumab in elderly patients are not significantly different from those reported in younger patients, with the exception of an increased risk of arterial thromboembolic events. Bevacizumab should therefore be considered as a potential therapeutic option for elderly patients with mCRC. PMID- 24484723 TI - The role of hypomethylating agents in the treatment of elderly patients with AML. AB - There is a major unmet medical need for treatment options in elderly patients with acute myeloid leukemia (AML) who are deemed ineligible for intensive treatment. The recent approval of decitabine in the European Union for the treatment of patients with AML>= 65 years old highlights the potential for hypomethylating agents in this setting. Here, we review evidence to support the use of hypomethylating agents in elderly patients and emphasize the importance of tolerability and quality of life considerations. We focus on the rationale for the continued clinical development of the ribonucleoside analog azacitidine in this setting. We discuss potential differences in the activity of azacitidine and decitabine in different patient subgroups that could possibly be explained by important differences in mechanism of action. Finally, we assess practical challenges that will be faced when integrating hypomethylating agents into clinical practice, such as how to define ineligibility for intensive treatment. PMID- 24484724 TI - Perceptions, attitudes, and experiences of hematology/oncology fellows toward incorporating geriatrics in their training. AB - The aging of the U.S. population continues to highlight emerging issues in providing care generally for older adults and specifically for older adults with cancer. The majority of patients with cancer in the U.S. are currently 65 years of age or older; therefore, training and research in geriatrics and geriatric oncology are viewed to be integral in meeting the needs of this vulnerable population. Yet, the ways to develop and integrate best geriatrics training within the context of hematology/oncology fellowship remain unclear. Toward this end, the current study seeks to evaluate the prior and current geriatric experiences and perspectives of hematology/oncology fellows. To gain insight into these experiences, focus groups of hematology/oncology fellows were conducted. Emergent themes included: 1) perceived lack of formal geriatric oncology didactics among fellows; 2) a considerable amount of variability exists in pre fellowship geriatric experiences; 3) shared desire to participate in a geriatric oncology-based clinic; 4) differences across training levels in confidence in managing older adults with cancer; and 5) identification of specific criteria on how best to approach older adults with cancer in a particular clinical scenario. The present findings will help guide future studies in evaluating geriatrics among hematology/oncology fellows across institutions. They will also have implications in the development of geriatrics curricula and competencies specific to hematology/oncology training. PMID- 24484725 TI - Complicated and complex: helping the older patient with cancer to exit the labyrinth. PMID- 24484726 TI - Implementing lessons learned from previous bronchial biopsy trials in a new randomized controlled COPD biopsy trial with roflumilast. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a chronic inflammatory disease mediated by an array of inflammatory cells and mediators, but above all, CD8+ T-lymphocytes, macrophages and neutrophils are important players in disease pathogenesis. Roflumilast, a first-in-class, potent and selective phosphodiesterase 4 (PDE4) inhibitor, reduces the rate of exacerbations in patients with a high risk of future exacerbations and has been shown to reduce inflammatory cells and mediators in induced sputum, a surrogate of airway inflammation. However, these anti-inflammatory effects are yet to be confirmed in another robust study directly assessing inflammatory markers in bronchial sub mucosa. METHODS/DESIGN: An international, 16-week, randomized, double-blind, placebo-controlled, parallel-group study investigating the effects of roflumilast 500 MUg once-daily versus placebo on inflammatory parameters in bronchial biopsy tissue specimens, sputum and blood serum. One hundred and fifty patients with COPD and chronic bronchitis for at least 12 months will be recruited into the study and randomized in a 1:1 ratio to receive either roflumilast or placebo. The primary endpoint will be the number of CD8+ cells (cell counts per mm2) in bronchial biopsy tissue specimens (sub-mucosa) and the key secondary endpoint will be the number of CD68+ cells (cell counts per mm2), assessed by indirect immunohistochemistry. DISCUSSION: It is hypothesized that treatment with roflumilast reduces the characteristic inflammation found in the airways of patients with moderate-to-severe COPD, compared with placebo. The design of the present study has built on the work of previous bronchial biopsy studies available in the literature. It is hoped that it will reveal the cellular mechanisms underlying the anti-inflammatory effects of roflumilast and identify potentially important biomarkers and other surrogate endpoints in patients with COPD. The design and rationale for this trial are described herein. PMID- 24484727 TI - Assessment of maxillofacial trauma in emergency department. AB - INTRODUCTION: The incidence and epidemiological causes of maxillofacial (MF) trauma varies widely. The objective of this study is to point out maxillofacial trauma patients' epidemiological properties and trauma patterns with simultaneous injuries in different areas of the body that may help emergency physicians to deliver more accurate diagnosis and decisions. METHODS: In this study we analyze etiology and pattern of MF trauma and coexisting injuries if any, in patients whose maxillofacial CT scans was obtained in a three year period, retrospectively. RESULTS: 754 patients included in the study consisting of 73.7% male and 26.3% female, and the male-to-female ratio was 2.8:1. Mean age was 40.3 +/- 17.2 years with a range of 18 to 97. 57.4% of the patients were between the ages of 18-39 years and predominantly male. Above 60 years of age, referrals were mostly woman. The most common cause of injuries were violence, accounting for 39.7% of the sample, followed by falls 27.9% and road traffic accidents 27.2%. The primary cause of injuries were violence between ages 20 and 49 and falls after 50. Bone fractures found in 56,0% of individuals. Of the total of 701 fractured bones in 422 patients the most frequent was maxillary bone 28,0% followed by nasal bone 25,3%, zygoma 20,2%, mandible 8,4%, frontal bone 8,1% and nasoethmoidoorbital bone 3,1%. Fractures to maxillary bone were uppermost in each age group.8, 9% of the patients had brain injury and only frontal fractures is significantly associated to TBI (p < 0.05) if coexisting facial bone fracture occurred. Male gender has statistically stronger association for suffering TBI than female (p < 0, 05). Most common cause of TBI in MF trauma patients was violence (47, 8%).158 of the 754 patients had consumed alcohol before trauma. No statistically significant data were revealed between alcohol consumption gender and presence of fracture. Violence is statistically significant (p < 0.05) in these patients. CONCLUSION: Studies subjected maxillofacial traumas yield various etiologic factors, demographic properties and fracture patterns probably due to social, cultural and governmental differences. Young males subjected to maxillofacial trauma more commonly as a result of interpersonal violence. PMID- 24484728 TI - Research on placebo analgesia is relevant to clinical practice. AB - Over the decades, research into placebo responses has shed light onto several endogenous (i.e. produced from within) mechanisms underlying modulation of pain perception initiated after the administration of inert substances (i.e. placebos). Chiropractors and manual therapists should embrace analgesic-placebo research in an attempt to maximize clinical benefit. Historical views that placebo responses are fake, passive, undesirable, and require deception and therefore should be minimized and avoided in clinical practice are outdated. Further, statements that contend the placebo response represents a single mechanism are overly simplistic. This commentary will discuss research that shows that there are several active biological processes underlying modulation of pain perception involved in placebo analgesia and its counterpart nocebo hyperalgesia. We contend that it is highly likely that, to some extent, all of these biological processes are engaged, in varying degrees, following all interventions and represent endogenous pain modulating processes. Failure, of chiropractors and manual therapists, to embrace a more contemporary view of analgesic-placebo research serves as a barrier to transferring knowledge into clinical practice and represents a missed opportunity to improve the delivery of current treatments. PMID- 24484729 TI - Vertical nanowire probes for intracellular signaling of living cells. AB - The single living cell action potential was measured in an intracellular mode by using a vertical nanoelectrode. For intracellular interfacing, Si nanowires were vertically grown in a controlled manner, and optimum conditions, such as diameter, length, and nanowire density, were determined by culturing cells on the nanowires. Vertical nanowire probes were then fabricated with a complimentary metal-oxide-semiconductor (CMOS) process including sequential deposition of the passivation and electrode layers on the nanowires, and a subsequent partial etching process. The fabricated nanowire probes had an approximately 60-nm diameter and were intracellular. These probes interfaced with a GH3 cell and measured the spontaneous action potential. It successfully measured the action potential, which rapidly reached a steady state with average peak amplitude of approximately 10 mV, duration of approximately 140 ms, and period of 0.9 Hz. PMID- 24484730 TI - Portal vein resection in borderline resectable pancreatic cancer: a United Kingdom multicenter study. AB - BACKGROUND: Until recently, in the United Kingdom, borderline resectable pancreatic cancer with invasion into the portomesenteric veins often resulted in surgical bypass because of the presumed high risk for complications and the uncertainty of a survival benefit associated with a vascular resection. Portomesenteric vein resection has therefore remained controversial. We present the second largest published cohort of patients undergoing portal vein resection for borderline resectable (T3) adenocarcinoma of the head of the pancreas. STUDY DESIGN: This is a UK multicenter retrospective cohort study comparing pancreaticoduodenectomy with vein resection (PDVR), standard pancreaticoduodenectomy (PD), and surgical bypass (SB). Nine high-volume UK centers contributed. All consecutive patients with T3 (stage IIA to III) adenocarcinoma of the head of the pancreas undergoing surgery between December 1998 and June 2011 were included. The primary outcomes measures are overall survival and in-hospital mortality. Secondary outcomes measure is operative morbidity. RESULTS: One thousand five hundred and eighty-eight patients underwent surgery for borderline resectable pancreatic cancer; 840 PD, 230 PDVR, and 518 SB. Of 230 PDVR patients, 129 had primary closure (56%), 65 had end to end anastomosis (28%), and 36 had interposition grafts (16%). Both resection groups had greater complication rates than the bypass group, but with no difference between PD and PDVR. In-hospital mortality was similar across all 3 surgical groups. Median survival was 18 months for PD, 18.2 months for PDVR, and 8 months for SB (p = 0.0001). CONCLUSIONS: This study, the second largest to date on borderline resectable pancreatic cancer, demonstrates no significant difference in perioperative mortality in the 3 groups and a similar overall survival between PD and PDVR; significantly better compared with SB. PMID- 24484731 TI - Stress hormone epinephrine increases IgA transport across respiratory epithelial surfaces. AB - BACKGROUND: Secretory immunoglobulin A (sIgA) is the principle antibody produced at the respiratory surface. Respiratory sIgA levels are increased early after injury in both human and laboratory animals; the mechanisms are uncertain. Stress hormones, including epinephrine (Epi) and norepinephrine (NE), increase early after injury. In addition, respiratory epithelial cells are known to be responsive to beta2-agonists. We therefore studied the effect of Epi, NE, and albuterol on IgA transport in vitro. STUDY DESIGN: Calu-3 respiratory epithelial cell monolayers grown in a 2-chamber cell culture system were treated for 24 hours with Epi, NE, or albuterol (10(-6)M). Dimeric IgA was added to the basal chamber of Calu-3 cells and IgA transcellular transport was indexed by recovery of SIgA in the apical chamber by enzyme-linked immunosorbent assay. In separate experiments, Klebsiella pneumoniae (10(5) colony-forming units/mL) was added to the apical chamber of treated Calu-3 cell monolayers and bacterial passage across Calu-3 cells was determined by bacterial recovery from basal chamber media. Calu 3 cells not treated with Epi, NE, or albuterol served as control. Cell monolayer integrity was confirmed by transepithelial electrical resistance. RESULTS: Calu-3 cells treated with Epi led to a significant increase in sIgA transport, this was associated with an increase in polyimmunoglobulin receptor expression. Calu-3 cells treated with NE or albuterol showed no statistical difference compared with control. Only cells treated with Epi led to a significant increase in pro inflammatory cytokine expression and decrease in bacterial passage. CONCLUSIONS: Epinephrine is likely an early upstream signal in the enhanced IgA response at respiratory surfaces after injury. PMID- 24484732 TI - An examination of places where African American men who have sex with men (MSM) use drugs/drink alcohol: a focus on social and spatial characteristics. AB - BACKGROUND: Drug and alcohol use are risk factors for HIV transmission. Much of the HIV behavioural research has focused on risk without consideration of the social and spatial context of the behaviour. Yet, risk may be specific or unique to place. The purpose of this study was to examine the social and spatial characteristics of places where African American men who have sex with men (AA MSM) use drugs and/or alcohol. Specifically, we examined spatial intensity and clustering of drug/alcohol places and characteristics of their social networks at these places. METHODS: Participants were recruited using outreach, on-line advertisements and word-of-mouth referrals. Inclusion criteria were: age 18 or older and sex with a man in the prior 90 days. Participants (n=51) completed a socio-spatial inventory in which they provided addresses of n=187 places where they most recently used drugs and/or drank alcohol. Participants described characteristics of people who were at these places. RESULTS: The mean age of participants was 36.5 years (SD=10.9). Half (51%) identified as gay, 31% bisexual, 4% heterosexual and 10% as not sure/questioning and 27% self-reported HIV positive status. Drug/alcohol places were spatially concentrated in the inner part of the city and evidence of clustering by participant characteristics was present. Of n=187 places named where the participant drank alcohol or used drugs, 68% were described as a residence (participants or "someone one else's house"), 20% were bars/clubs or restaurants, 8% were outside places and 4% were miscellaneous (e.g. on the bus/car). There were differences in the characteristics of social network members by place-type. At residential places, a greater proportion of networks listed were sex partners or kin, compared to other place-types. A greater proportion of networks listed at bars/clubs/restaurants were gay, knew that the participant had sex with men, and were younger compared to other place-types. CONCLUSION: AA MSM drink alcohol and use drugs in a variety of place-types and with various social network members. Little research has been done on factors that shape the geography of AA MSM substance use. Future research is needed to explore these complex associations. PMID- 24484734 TI - Ensuring information integrity in the electronic health record: the crisis and the challenge. PMID- 24484733 TI - [Consensus statement on monitoring of HIV: pregnancy, birth, and prevention of mother-to-child transmission]. AB - OBJECTIVE: The main objective in the management of HIV-infected pregnant women is prevention of mother-to-child transmission; therefore, it is essential to provide universal antiretroviral treatment, regardless of CD4 count. All pregnant women must receive adequate information and undergo HIV serology testing at the first visit. METHODS: We assembled a panel of experts appointed by the Secretariat of the National AIDS Plan (SPNS) and the other participating Scientific Societies, which included internal medicine physicians with expertise in the field of HIV infection, gynecologists, pediatricians and psychologists. Four panel members acted as coordinators. Scientific information was reviewed in publications and conference reports up to November 2012. In keeping with the criteria of the Infectious Diseases Society of America, 2levels of evidence were applied to support the proposed recommendations: the strength of the recommendation according to expert opinion (A, B, C), and the level of empirical evidence (I, II, III). This approach has already been used in previous documents from SPNS. RESULTS AND CONCLUSIONS: The aim of this paper was to review current scientific knowledge, and, accordingly, develop a set of recommendations regarding antiretroviral therapy (ART), regarding the health of the mother, and from the perspective of minimizing mother-to-child transmission (MTCT), also taking into account the rest of the health care of pregnant women with HIV infection. We also discuss and evaluate other strategies to reduce the MTCT (elective Cesarean, child's treatment...), and different aspects of the topic (ARV regimens, their toxicity, monitoring during pregnancy and postpartum, etc.). PMID- 24484735 TI - Publishing systematic reviews in ophthalmology: new guidance for authors. PMID- 24484736 TI - Cell-specific and context-dependent effects of GITR in cancer, autoimmunity, and infection. AB - A breadth of studies have demonstrated the importance of GITR-GITRL in diverse immune processes. However, only a limited number of studies to date have attributed the effects of GITR/GITRL to specific cell types. Moreover, the context-dependent role of GITR/GITRL in different models makes the consequences of GITR ligation difficult to generalize. There is a significant interest in the therapeutic application of GITR agonists and antagonists in human disease. Thus, the field must come to a consensus regarding the cell type-specific and physiological effects of GITR in different disease states. Here we attempt to summarize the extensive literature on GITR, to synthesize a more cohesive picture of the role of GITR/GITRL in immunity, and to identify areas that require clarification. PMID- 24484738 TI - Transparency in medical error disclosure: the need for formal teaching in undergraduate medical education curriculum. PMID- 24484737 TI - Single-base resolution of mouse offspring brain methylome reveals epigenome modifications caused by gestational folic acid. AB - BACKGROUND: Epigenetic modifications, such as cytosine methylation in CpG-rich regions, regulate multiple functions in mammalian development. Maternal nutrients affecting one-carbon metabolism during gestation can exert long-term effects on the health of the progeny. Using C57BL/6 J mice, we investigated whether the amount of ingested maternal folic acid (FA) during gestation impacted DNA methylation in the offspring's cerebral hemispheres. Reduced representation bisulfite sequencing at single-base resolution was performed to analyze genome wide DNA methylation profiles. RESULTS: We identified widespread differences in the methylation patterns of CpG and non-CpG sites of key developmental genes, including imprinted and candidate autism susceptibility genes (P <0.05). Such differential methylation of the CpG and non-CpG sites may use different mechanisms to alter gene expressions. Quantitative real time reverse transcription-polymerase chain reaction confirmed altered expression of several genes. CONCLUSIONS: These finding demonstrate that high maternal FA during gestation induces substantial alteration in methylation pattern and gene expression of several genes in the cerebral hemispheres of the offspring, and such changes may influence the overall development. Our findings provide a foundation for future studies to explore the influence of gestational FA on genetic/epigenetic susceptibility to altered development and disease in offspring. PMID- 24484739 TI - Maternal obesity is associated with a lipotoxic placental environment. AB - Maternal obesity is associated with placental lipotoxicity, oxidative stress, and inflammation, where MAPK activity may play a central role. Accordingly, we have previously shown that placenta from obese women have increased activation of MAPK JNK. Here, we performed RNA-sequencing on term placenta from twenty-two subjects who were dichotomized based on pre-pregnancy BMI into lean (BMI 19-24 kg/m(2); n = 12) and obese groups (BMI, 32-43 kg/m(2); n = 12). RNA-seq revealed 288 genes to be significantly different in placenta from obese women by >= 1.4-fold. GO analysis identified genes related to lipid metabolism, angiogenesis, hormone activity, and cytokine activity to be altered in placenta from obese women. Indicative of a lipotoxic environment, increased placental lipid and CIDEA protein were associated with decreased AMPK and increased activation of NF-kappaB (p65) in placenta from obese women. Furthermore, we observed a 25% decrease in total antioxidant capacity and increased nuclear FOXO4 localization in placenta from obese women that was significantly associated with JNK activation, suggesting that maternal obesity may also be associated with increased oxidative stress in placenta. Maternal obesity was also associated with decreased HIF 1alpha protein expression, suggesting a potential link between increased inflammation/oxidative stress and decreased angiogenic factors. Together, these findings indicate that maternal obesity leads to a lipotoxic placental environment that is associated with decreased regulators of angiogenesis and increased markers of inflammation and oxidative stress. PMID- 24484740 TI - Relationship between vitamin D status and the inflammatory state in patients with chronic spontaneous urticaria. AB - BACKGROUND: Chronic spontaneous urticaria (CSU) is an immune-inflammatory disease, characterized by acute phase response (APR) and immune activation. There has been increasing evidence showing that vitamin D deficiency/insufficiency is associated with increased incidence and/or severity of immune-inflammatory disorders. AIM: To assess relationship between vitamin D status and C-reactive protein (CRP), a nonspecific inflammatory marker of CSU activity. METHODS: Concentrations of CRP and 25-hydroxyvitamin D [25(OH)D], a biomarker of vitamin D status were measured in serum of CSU patients and compared with the healthy controls. RESULTS: Serum 25(OH)D concentration was significantly lower in CSU group as compared with the normal subjects. The prevalence of vitamin D deficiency (< 20 ng/ml) was significantly higher in patients with CSU than among normal population. There were no significant differences in prevalence of 25(OH)D insufficiency between the groups. Serum CRP concentrations were significantly higher in CSU patients as compared with the healthy subjects. There were no significant correlations between CRP and 25(OH)D concentrations in CSU patients. CONCLUSIONS: CSU is associated with lower serum 25(OH)D concentration and higher prevalence of its deficiency. The results failed to show any effect of vitamin D status on circulating CRP concentrations in CSU. A potential role of vitamin D in pathogenesis and/or additive therapy of CSU needs to be examined in other cohorts of CSU patients as well as in larger studies. PMID- 24484742 TI - Reduction of meckelin leads to general loss of cilia, ciliary microtubule misalignment and distorted cell surface organization. AB - BACKGROUND: Meckelin (MKS3), a conserved protein linked to Meckel Syndrome, assists in the migration of centrioles to the cell surface for ciliogenesis. We explored for additional functions of MKS3p using RNA interference (RNAi) and expression of FLAG epitope tagged protein in the ciliated protozoan Paramecium tetraurelia. This cell has a highly organized cell surface with thousands of cilia and basal bodies that are grouped into one or two basal body units delineated by ridges. The highly systematized nature of the P. tetraurelia cell surface provides a research model of MKS and other ciliopathies where changes in ciliary structure, subcellular organization and overall arrangement of the cell surface can be easily observed. We used cells reduced in IFT88 for comparison, as the involvement of this gene's product with cilia maintenance and growth is well understood. RESULTS: FLAG-MKS3p was found above the plane of the distal basal body in the transition zone. Approximately 95% of those basal bodies observed had staining for FLAG-MKS3. The RNAi phenotype for MKS3 depleted cells included global shortening and loss of cilia. Basal body structure appeared unaffected. On the dorsal surface, the basal bodies and their associated rootlets appeared rotated out of alignment from the normal anterior-posterior rows. Likewise, cortical units were abnormal in shape and out of alignment from normal rows. A GST pull down using the MKS3 coiled-coil domain suggests previously unidentified interacting partners. CONCLUSIONS: Reduction of MKS3p shows that this protein affects development and maintenance of cilia over the entire cell surface. Reduction of MKS3p is most visible on the dorsal surface. The anterior basal body is attached to and moves along the striated rootlet of the posterior basal body in preparation for duplication. We propose that with reduced MKS3p, this attachment and guidance of the basal body is lost. The basal body veers off course, causing basal body rows to be misaligned and units to be misshapen. Rootlets form normally on these misaligned basal bodies but are rotated out of their correct orientation. Our hypothesis is further supported by the identification of novel interacting partners of MKS3p including a kinetodesmal fiber protein, KdB2. PMID- 24484743 TI - Emergency surgeon: " last of the mohicans" 2014-2016 editorial policy WSES- WJES: position papers, guidelines, courses, books and original research; from WJES impact factor to WSES congress impact factor. PMID- 24484741 TI - Maternal morbidity and preterm birth in 22 low- and middle-income countries: a secondary analysis of the WHO Global Survey dataset. AB - BACKGROUND: Preterm birth (PTB) (<37weeks) complicates approximately 15 million deliveries annually, 60% occurring in low- and middle-income countries (LMICs). Several maternal morbidities increase the risk of spontaneous (spPTB) and provider-initiated (piPTB) preterm birth, but there is little data from LMICs. METHOD: We used the WHO Global Survey to analyze data from 172,461 singleton deliveries in 145 facilities across 22 LMICs. PTB and six maternal morbidities (height <145 cm, malaria, HIV/AIDS, pyelonephritis/UTI, diabetes and pre eclampsia) were investigated. We described associated characteristics and developed multilevel models for the risk of spPTB/piPTB associated with maternal morbidities. Adverse perinatal outcomes (Apgar <7 at 5 minutes, NICU admission, stillbirth, early neonatal death and low birthweight) were determined. RESULTS: 8.2% of deliveries were PTB; one-quarter of these were piPTB. 14.2% of piPTBs were not medically indicated. Maternal height <145 cm (AOR 1.30, 95% CI 1.10 1.52), pyelonephritis/UTI (AOR 1.16, 95% CI 1.01-1.33), pre-gestational diabetes (AOR 1.41, 95% CI 1.09-1.82) and pre-eclampsia (AOR 1.25, 95% CI 1.05-1.49) increased odds of spPTB, as did malaria in Africa (AOR 1.67, 95%CI 1.32-2.11) but not HIV/AIDS (AOR 1.17, 95% CI 0.79-1.73). Odds of piPTB were higher with maternal height <145 cm (AOR 1.47, 95% CI 1.23-1.77), pre-gestational diabetes (AOR 2.51, 95% CI 1.81-3.47) and pre-eclampsia (AOR 8.17, 95% CI 6.80-9.83). CONCLUSIONS: Maternal height <145 cm, diabetes and pre-eclampsia significantly increased odds of spPTB and piPTB, while pyelonephritis/UTI and malaria increased odds of spPTB only. Strategies to reduce PTB and associated newborn morbidity/mortality in LMICs must prioritize antenatal screening/treatment of these common conditions and reducing non-medically indicated piPTBs where appropriate. PMID- 24484744 TI - Seminars in nuclear medicine. PMID- 24484745 TI - The garden city. PMID- 24484746 TI - Comparison of magnetic resonance imaging with radionuclide methods of evaluating the kidney. AB - Nuclear medicine and MRI provide information about renal perfusion, function (glomerular filtration rate), and drainage. Some tracers that are used in nuclear medicine (technetium-diethylene triamine pentaacetic acid ([(99m)Tc-DTPA] and (51)chromium-EDTA) and some contrast media (CM) that are used for MRI (gadolinium DTPA for instance) share the same pharmacokinetic properties, though, detection techniques are different (low-spatial resolution 2-dimensional projection with a good concentration-to-signal linearity for nuclear medicine and high-resolution 3 dimensional localization with nonlinear behavior for MRI). Thus, though based on the same principles, the methods are not the same and they provide somewhat different information. Many MRI perfusion studies have been conducted; some of them were compared with nuclear medicine with no good agreement. Phase contrast can reliably assess global renal blood flow but not perfusion at a tissular level. Arterial spin labeling has not proven to be a reliable tool to measure renal perfusion. Techniques using CM theoretically can assess perfusion at the tissular level, but they have not proven to be precise. To assess renal function, many models have been proposed. Some MRI techniques using CM, both semiquantitative (Patlak) and quantitative, have shown ability to roughly assess relative function. Some quantitative methods (Annet's and Lee's methods) have even showed that they could roughly estimate absolute renal function, with better results than estimated glomerular filtration rate. Quantification of drainage has not been much studied using MRI. PMID- 24484748 TI - Clinical problems in renovascular disease and the role of nuclear medicine. AB - Although renovascular disease remains defined as a stenosis of the main renal artery or its proximal branches (renal artery stenosis [RAS]), its clinical overview has changed dramatically over the last 15-20 years and its management is more controversial than ever before. The clinical problems, not only diagnosis and treatment but also the relative contribution of different pathophysiological mechanisms involved in the progression of kidney disease, have shifted dramatically. This presentation aims to emphasize the paradigm change revisiting the (recent) past focused on renovascular hypertension (RVH) to the current context of preservation or recovery of threatened renal function in patients with progressive atherosclerotic renovascular disease until its last stage of irreversible "ischemic nephropathy." In the past, the foreground was occupied by RVH, a very rare disease, where the activation of the renin-angiotensin aldosterone system (RAAS) was supposed to play the major, if not only, role in RVH issues. The retrospective RVH diagnosis was established either on the improvement or, more rarely, on the cure of hypertension after revascularization by, most often, a percutaneous transluminal renal angioplasty with or without a stent placement. At this time, captoptril radionuclide renography was an efficient diagnostic tool, because it was a functional (angiotensin-converting enzyme inhibition), noninvasive test aiming to evidence both the RAAS activation and the lateralization (or asymmetry) of renin secretion by the kidney affected by a "hemodynamically significant" RAS. At present, even if captoptril radionuclide renography could be looked upon as the most efficient (and cost effective in selected high-risk patients) noninvasive, functional test to predict the improvement of hypertension after RAS correction, its clinical usefulness is questioned as the randomized, prospective trials failed to demonstrate any significant benefits (either on blood pressure control or on renal function protection) of the revascularization over current antihypertensive therapy. Today many patients with RVH remain undetected for years because they are treated successfully and at low expense with these new blockers of RAAS. In addition to its well-known role in hemodynamics, angiotensin II promotes activations of profibrogenic and inflammatory factors and cells and stimulates reactive oxygen species generation. The "atherosclerotic milieu" itself plays a role in the loss of renal microvessels and defective angiogenesis. After an "adaptative" phase, ischemia eventually develops and induces hypoxia, the substratum of ischemic nephropathy. Because blood oxygen level-dependent MRI may provide an index of oxygen content in vivo, it may be useful to predict renal function outcome after percutaneous transluminal renal angioplasty. New PET tracers, dedicated to assess RAAS receptors, inflammatory cell infiltrates, angiogenesis, and apoptose, would be tested in this context of atherosclerotic renovascular disease. PMID- 24484749 TI - Febrile urinary tract infections: clinical and laboratory diagnosis, imaging, and prognosis. AB - According to the literature, febrile urinary tract infections (UTIs) are among the most common severe bacterial infections occurring in childhood, with potential serious long-term consequences. In recent years, there have been significant developments in our understanding of the pathophysiology and clinical and laboratory issues of febrile UTIs. Studies are focusing on the role of predisposing host factors related to genes regulating immune response, inflammation and fibrosis in the development of acute renal damage and subsequent processes leading to renal scars. All the available guidelines underline the importance of a correct diagnosis of febrile UTI to allow a more rational use of antibiotics and imaging. As a consequence, a shift from aggressive imaging studies to a more restrictive and targeted approach has been recently observed. Regarding the prognosis of febrile UTI, the introduction of prenatal ultrasound studies revealed that a great portion of the alterations at imaging (and thus of the clinical complications), previously attributed to postinfection scarring, were because of congenital kidney and urinary tract abnormalities. Although the long-term consequences of febrile UTIs are difficult to ascertain, it seems that children with febrile UTI, normal renal function and normal kidneys at start present a very low risk of developing decreased renal function or hypertension during follow-up. However, high body temperature and high procalcitonin levels during the acute phase of disease, which are indicative of severe inflammation, and the finding of renal scarring on imaging with DMSA scintigraphy 6 months after febrile UTI, together with the detection of congenital kidney and urinary tract abnormalities, indicate "kidney at risk" in UTI. PMID- 24484750 TI - Transplanted kidney function evaluation. AB - The best option for the treatment of end-stage renal disease is kidney transplantation. Prompt diagnosis and management of early posttransplantation complications is of utmost importance for graft survival. Biochemical markers, allograft biopsies, and imaging modalities are used for the timely recognition and management of graft dysfunction. Among several other factors, improvements in imaging modalities have been regarded as one of the factors contributing to increased short-term graft survival. Each imaging procedure has its own unique contribution to the evaluation of renal transplant dysfunction. In the era of multimodality imaging and emerging clinical considerations for the improvement of graft survival, evaluating an imaging modality in its own right may not be relevant and may fall short of expectation. Recognized as being mainly a functional imaging procedure, radionuclide imaging provides valuable information on renal function that cannot be obtained with other imaging modalities. For evaluating and establishing the current place, indications, and potential applications of radionuclide renal transplant imaging, a classification of renal allograft complications based on renal allograft dysfunction is essential. The major factor affecting long-term graft loss is chronic allograft nephropathy. Its association with early posttransplantation delayed graft function and repeated acute rejection episodes is well documented. Long-term graft survival rate have not improve significantly over the years. Imaging procedures are most commonly performed during the early period after transplantation. There seems to be a need for performing more frequent late posttransplantation imaging for the evaluation of acute allograft dysfunction, subclinical pathology, and chronic allograft changes; for understanding their contribution to patient management; and for identification of pathophysiological mechanisms leading to proteinuria and hypertension. With its unique advantage of relating perfusion to function, the potential for radionuclide imaging to replace late protocol biopsies needs to be investigated. PMID- 24484747 TI - Molecular imaging of urogenital diseases. AB - There is an expanding and exciting repertoire of PET imaging radiotracers for urogenital diseases, particularly in prostate cancer, renal cell cancer, and renal function. Prostate cancer is the most commonly diagnosed cancer in men. With growing therapeutic options for the treatment of metastatic and advanced prostate cancer, improved functional imaging of prostate cancer beyond the limitations of conventional CT and bone scan is becoming increasingly important for both clinical management and drug development. PET radiotracers, apart from 18F-FDG, for prostate cancer are 18F-sodium fluoride, 11C-choline, and 18F fluorocholine, and (11C-acetate. Other emerging and promising PET radiotracers include a synthetic l-leucine amino acid analogue (anti-18F-fluorocyclobutane-1 carboxylic acid), dihydrotestosterone analogue (18F-fluoro-5alpha dihydrotestosterone), and prostate-specific membrane antigen-based PET radiotracers (eg, N-[N-[(S)-1,3-dicarboxypropyl]carbamoyl]-4-18F-fluorobenzyl-l cysteine, 89Zr-DFO-J591, and 68Ga [HBED-CC]). Larger prospective and comparison trials of these PET radiotracers are needed to establish the role of PET/CT in prostate cancer. Although renal cell cancer imaging with FDG-PET/CT is available, it can be limited, especially for detection of the primary tumor. Improved renal cell cancer detection with carbonic anhydrase IX (CAIX)-based antibody (124I girentuximab) and radioimmunotherapy targeting with 177Lu-cG250 appear promising. Evaluation of renal injury by imaging renal perfusion and function with novel PET radiotracers include p-18F-fluorohippurate, hippurate m-cyano-p-18F fluorohippurate, and rubidium-82 chloride (typically used for myocardial perfusion imaging). Renal receptor imaging of the renal renin-angiotensin system with a variety of selective PET radioligands is also becoming available for clinical translation. PMID- 24484752 TI - Efficient extraction of proteins from formalin-fixed paraffin-embedded tissues requires higher concentration of tris(hydroxymethyl)aminomethane. AB - BACKGROUND: Numerous formaldehyde-fixed and paraffin-embedded clinical tissues have been created in the past decades and stored in pathological depositories at hospitals as well as in clinical laboratories worldwide. In addition to the archived tissues, formaldehyde-fixation is also mandatory for preparing proteomics samples from diseased patients or animal models in order to inactivate contagious agents. Protein extraction from formaldehyde-fixed tissues is hampered by the Schiff base formation between the amino groups of proteins and formaldehyde. Although achievement of the highest extraction efficiency of proteins from the formaldehyde-fixed tissues is essential for obtaining maximum proteomics information, no attention has been paid to the concentration dependence of tris(hydroxymethyl)aminomethane on the extraction efficacy. We suspected that the concentration of tris(hydroxymethyl)aminomethane affects the protein extraction efficiency because of its property as a primary amine that reverses the Schiff base formation between the primary amines of proteins and formaldehyde. Thus we pursued optimization of the component and protocol of protein extraction buffer to achieve better extraction efficiency of proteins from formaldehyde-fixed and paraffin-embedded tissues. RESULTS: In order to simulate protein extraction from diseased tissues we made formaldehyde-fixed and paraffin-embedded samples from mouse liver slices and investigated the protein extraction efficiency and speed by changing the concentration of the protein extraction buffer component tris(hydroxymethyl)aminomethane under various extraction conditions. We find, as expected, that tris(hydroxymethyl)aminomethane significantly affects the performance of protein extraction from the formaldehyde fixed and paraffin-embedded samples both in the extraction yield and in the extraction speed. CONCLUSIONS: We recommend the concentration of tris(hydroxymethyl)aminomethane in protein extraction buffer to be higher than 300 mM when extraction is conducted for 90 min at 90 degrees C to achieve the most efficient protein extraction in a shorter time. The information will be essential for performing the most efficient protein extraction from formaldehyde fixed and paraffin-embedded tissue samples for proteomics analysis. PMID- 24484751 TI - Computer-assisted diagnosis in renal nuclear medicine: rationale, methodology, and interpretative criteria for diuretic renography. AB - The goal of artificial intelligence, expert systems, decision support systems, and computer-assisted diagnosis (CAD) in imaging is the development and implementation of software to assist in the detection and evaluation of abnormalities, to alert physicians to cognitive biases, to reduce intraobserver and interobserver variability, and to facilitate the interpretation of studies at a faster rate and with a higher level of accuracy. These developments are needed to meet the challenges resulting from a rapid increase in the volume of diagnostic imaging studies coupled with a concurrent increase in the number and complexity of images in each patient data. The convergence of an expanding knowledge base and escalating time constraints increases the likelihood of physician errors. Errors are even more likely when physicians interpret low volume studies such as technetium-99m-mercaptoacetyltriglycine diuretic scans where imagers may have had limited training or experience. Decision support systems include neural networks, case-based reasoning, expert systems, and statistical systems. iRENEX (renal expert) is an expert system for diuretic renography that uses a set of rules obtained from human experts to analyze a knowledge base of both clinical parameters and quantitative parameters derived from the renogram. Initial studies have shown that the interpretations provided by iRENEX are comparable to the interpretations of a panel of experts. iRENEX provides immediate patient-specific feedback at the time of scan interpretation, can be queried to provide the reasons for its conclusions, and can be used as an educational tool to teach trainees to better interpret renal scans. It also has the capacity to populate a structured reporting module and generate a clear and concise impression based on the elements contained in the report; adherence to the procedural and data entry components of the structured reporting module ensures and documents procedural competency. Finally, although the focus is CAD applied to diuretic renography, this review offers a window into the rationale, methodology, and broader applications of computer-assisted diagnosis in medical imaging. PMID- 24484753 TI - Design process of cementless femoral stem using a nonlinear three dimensional finite element analysis. AB - BACKGROUND: Minimal available information concerning hip morphology is the motivation for several researchers to study the difference between Asian and Western populations. Current use of a universal hip stem of variable size is not the best option for all femur types. This present study proposed a new design process of the cementless femoral stem using a three dimensional model which provided more information and accurate analysis compared to conventional methods. METHODS: This complete design cycle began with morphological analysis, followed by femoral stem design, fit and fill analysis, and nonlinear finite element analysis (FEA). Various femur parameters for periosteal and endosteal canal diameters are measured from the osteotomy level to 150 mm below to determine the isthmus position. RESULTS: The results showed better total fit (53.7%) and fill (76.7%) canal, with more load distributed proximally to prevent stress shielding at calcar region. The stem demonstrated lower displacement and micromotion (less than 40 MUm) promoting osseointegration between the stem-bone and providing primary fixation stability. CONCLUSION: This new design process could be used as a preclinical assessment tool and will shorten the design cycle by identifying the major steps which must be taken while designing the femoral stem. PMID- 24484754 TI - Creation of an iliac arteriovenous shunt lowers blood pressure in chronic obstructive pulmonary disease patients with hypertension. AB - OBJECTIVE: Vasodilators are used with caution in patients with chronic obstructive pulmonary disease (COPD). We have developed a device for percutaneous arteriovenous shunt creation in the iliac region to increase cardiac output and oxygen delivery for patients with COPD. Although this device does not cause significant blood pressure changes in normotensive patients with COPD, we hypothesized that arteriovenous shunt creation might cause vasodilator effects in hypertensive patients because of a reduction in vascular resistance. METHODS: Twenty-four patients with COPD and hypertension enrolled in an open label study of arteriovenous shunt creation for COPD. We performed cardiac catheterization at baseline and again 3 to 6 months after the procedure. As a safety measure we also recorded office blood pressure at baseline and again after 3, 6, 9, and 12 months. RESULTS: The procedure increased oxygen delivery (1.1-1.4 L.min(-1)) and cardiac output (6-8.2 L.min(-1)) (P < .001) and lowered both the systemic vascular resistance (P < .001) and the pulmonary vascular resistance (P < .01). After 12 months, however, the average systolic blood pressure was reduced from 145 to 132 mm Hg (P < .0001), and the average diastolic blood pressure was reduced from 86 to 67 mm Hg (P < .0001). CONCLUSIONS: Percutaneous iliac arteriovenous fistula creation for COPD causes a significant and persistent lowering of blood pressure in patients with co-existing hypertension. PMID- 24484755 TI - On the 60th anniversary of carotid surgery for the prevention of stroke. PMID- 24484756 TI - Therapeutic compliance of first line disease-modifying therapies in patients with multiple sclerosis. COMPLIANCE Study. AB - INTRODUCTION: Non-adherence to disease-modifying therapies (DMTs) in multiple sclerosis may be associated with reduced efficacy. We assessed compliance, the reasons for non-compliance, treatment satisfaction, and quality of life (QoL) of patients treated with first-line therapies. METHODS: A cross-sectional, multicenter study was conducted that included relapsing multiple sclerosis patients. Compliance in the past month was assessed using Morisky-Green test. Seasonal compliance and reasons for non-compliance were assessed by an ad-hoc questionnaire. Treatment satisfaction and QoL were evaluated by means of TSQM and PRIMUS questionnaires. RESULTS: A total of 220 patients were evaluated (91% relapsing-remitting); the mean age was 39.1 years, 70% were female, and the average time under treatment was 5.4 years. Subcutaneous interferon (IFN) beta-1b was used in 23% of the patients, intramuscular IFN beta-1a in 21%, subcutaneous IFN beta-1a in 37%, and with glatiramer acetate in 19%. The overall compliance was 75%, with no significant differences related to the therapy, and 81% did not report any seasonal variation. Compliant patients had significantly lower disability scores and time of diagnosis, and greater satisfaction with treatment and its effectiveness. Discomfort and flu-like symptoms were the most frequent reasons for non-compliance. The satisfaction and QoL were associated with less disability and number of therapeutic switches. CONCLUSIONS: The rate of compliance, satisfaction and QoL in multiple sclerosis patients under DMTs is high, especially for those newly diagnosed, less disabled, and with fewer therapeutic switches. Discomfort and flu-like symptoms associated with injected therapies significantly affect adherence. PMID- 24484758 TI - Words of wisdom: Re: Autonomic nerve development contributes to prostate cancer progression. PMID- 24484757 TI - Psychometric properties of a new short version of the State-Trait Anxiety Inventory (STAI) for the assessment of anxiety in the elderly. AB - INTRODUCTION: Anxiety has negative effects on the cognitive performance and psychosocial adjustment of elderly people. Given the high prevalence of anxiety symptoms in patients suffering from cognitive impairment, it has been suggested that these symptoms may be an early marker of dementia. The State-Trait Anxiety Inventory (STAI) is one of the most widely-used scales for evaluating anxiety in elderly people. However, inasmuch as the STAI may be difficult to apply to older people, having a short form of it would be desirable. METHODS: The participants comprised 489 community-dwelling individuals aged 68 years and over. All of them were volunteers in a longitudinal study for early detection of Alzheimer' Disease (Proyecto Vallecas). The full sample was divided in two homogeneous subgroups: Group A, used to reduce the number of items and response options, and Group B, the group used to determine the psychometric properties of the new short form (STAIr). RESULTS: A dichotomous Rasch model was used to obtain the STAIr. No statistically significant differences for STAIr scores were found with respect to sociodemographic variables. Psychometric properties and normative data were obtained for the new short version. CONCLUSIONS: The STAIr is composed of 13 items and data fits the model well. Since it is short and easy to apply to elderly people, STAIr will be very useful in clinical and research settings. PMID- 24484759 TI - Words of wisdom: Re: Men with low preoperative sexual function may benefit from nerve-sparing radical prostatectomy. PMID- 24484760 TI - Words of wisdom: Re: Punctuated evolution of prostate cancer genomes. PMID- 24484762 TI - Words of wisdom: Re: Micropercutaneous nephrolithotomy (Microperc) vs retrograde intrarenal surgery for the management of small renal calculi: a randomized controlled trial. PMID- 24484761 TI - Words of wisdom: Re: Pazopanib versus sunitinib in metastatic renal-cell carcinoma. PMID- 24484763 TI - Words of wisdom: Re: Refractory chronic pelvic pain syndrome in men: can transcutaneous electrical nerve stimulation help? PMID- 24484764 TI - Dissociating the ability and propensity for empathy. AB - Neuroimaging suggests psychopaths have reduced vicarious activations when simply witnessing pain but less so when asked to empathize. This inspired us to distinguish the ability from the propensity to empathize. We argue that (i) this ability-propensity distinction is crucial to characterizing empathy in psychiatric disorders such as psychopathy and autism, (ii) that costly helping might be best predicted by the propensity for empathy, and (iii) suggest how social neuroscientists can start exploring this distinction. PMID- 24484765 TI - Environmental impact assessment of a WtE plant after structural upgrade measures. AB - The study focuses on analysing the evolution of environmental impacts caused by a medium-large Italian WtE plant before and after revamping and maintenance operations, with the aim of providing an evaluation of how much these structural upgrade measures may affect the total environmental performance. LCA methodology was applied for the modelling and comparison of six WtE scenarios, each describing the main structural upgrades carried out in the plant over the years 1996-2011. The comparison was conducted by adopting 1ton of MSW as the functional unit, and the net contribution from energy recovery to power generation was distinguished by defining consistent national grid electricity mixes for every year considered. The Ecoindicator99 2.09 impact assessment method was used to evaluate the contribution to midpoint and endpoint categories (e.g. carcinogens, respiratory inorganics and organics, climate change, damage to human health). Lastly, the "Pedigree quality matrix" was applied to verify the reliability and robustness of the model created. As expected, the results showed better environmental scores after both the implementation of new procedures and the integration of operations. However, while a net reduction of air emissions seems to be achievable through dedicated flue gas treatment technologies, outcomes underscored potentials for improving the management of bottom ash through the adoption of alternative options aimed to use that solid residue mainly as filler, and to decrease risks from its current disposal in landfill. If the same effort that is put into flue gas treatment were devoted to energy recovery, the targets for the WtE plant could be easily met, achieving a higher sustainability. This aspect is even more complex: national policies for implementing greener and renewable energy sources would result in a lower impact of the national energy mix and, hence, in a lower net avoided burden from energy recovery. The study confirmed the expected improvements, indicating quantitatively the lower environmental impact resulting from structural upgrade operations in a WtE plant. Furthermore, the work highlights the importance of considering the evolution of the national energy mix in LCA studies, especially during the present years of transition from fossil fuels to renewable sources. PMID- 24484766 TI - On the understanding and control of the spontaneous heating of dried tannery wastewater sludge. AB - We studied the spontaneous heating of dried sludge produced by treating wastewater mainly originating from tanneries. Heating up to burning has been observed in the presence of air and moisture, starting at ambient temperature. To understand and prevent the process we combined chemical and morphological analyses (ESEM) with thermal activity monitoring in insulated vessels. Selective additions of chemicals, either to amplify or depress the reactivity, have been used to investigate and identify both the chemical mechanism causing the sludge self-heating, and a prevention or a mitigation strategy. FeS additions accelerate the onset of reactivity, while S sustains it over time. On the contrary, Ca(OH)2, Na2CO3, NaHCO3, FeCl2, EDTA, NaClO can limit, up to completely preventing, the exothermic activity. All the experimental evidences show that the reactions supporting the dried sludge self-heating involve the Fe/S/O system. The total suppression of the reactivity requires amounts of additives that are industrially incompatible with waste reduction and economics. The best prevention requires reduction or removal of S and Fe from the dried solid matrix. PMID- 24484767 TI - Real time PCR to detect the environmental faecal contamination by Echinococcus multilocularis from red fox stools. AB - The oncosphere stage of Echinococcus multilocularis in red fox stools can lead, after ingestion, to the development of alveolar echinococcosis in the intermediate hosts, commonly small mammals and occasionally humans. Monitoring animal infection and environmental contamination is a key issue in public health surveillance. We developed a quantitative real-time PCR technique (qPCR) to detect and quantify E. multilocularis DNA released in fox faeces. A qPCR technique using a hydrolysis probe targeting part of the mitochondrial gene rrnL was assessed on (i) a reference collection of stools from 57 necropsied foxes simultaneously investigated using the segmental sedimentation and counting technique (SSCT) (29 positive for E. multilocularis worms and 28 negative animals for the parasite); (ii) a collection of 114 fox stools sampled in the field: two sets of 50 samples from contrasted endemic regions in France and 14 from an E. multilocularis-free area (Greenland). Of the negative SSCT controls, 26/28 were qPCR-negative and two were weakly positive. Of the positive SSCT foxes, 25/29 samples were found to be positive by qPCR. Of the field samples, qPCR was positive in 21/50 (42%) and 5/48 (10.4%) stools (2 samples inhibited), originating respectively from high and low endemic areas. In faeces, averages of 0.1 pg/MUl of DNA in the Jura area and 0.7 pg/MUl in the Saone-et-Loire area were detected. All qPCR-positive samples were confirmed by sequencing. The qPCR technique developed here allowed us to quantify environmental E. multilocularis contamination by fox faeces by studying the infectious agent directly. No previous study had performed this test in a one-step reaction. PMID- 24484768 TI - WITHDRAWN: Corrigendum to "World Association for the Advancement of Veterinary Parasitology (WAAVP): The 50th anniversary in 2013-History, achievements, and future perspectives" [Vet. Parasitol. 195 (2013) 206-217]. AB - The Publisher regrets that this article is an accidental duplication of an article that has already been published, http://dx.doi.org/10.1016/j.vetpar.2013.12.026. The duplicate article has therefore been withdrawn. PMID- 24484769 TI - Peripheral pain-sensing neurons: from molecular diversity to functional specialization. AB - Recent work in Cell Reports by Minett et al. and Yang et al. highlights the complexity of pain pathways and points to new ways of thinking about chronic and disease-related pain. PMID- 24484770 TI - Should infants presenting with an apparent life-threatening event undergo evaluation for serious bacterial infections and respiratory pathogens? AB - We sought to identify which patients with an apparent life-threatening event require infectious evaluation through an analysis of infants aged <=12 months brought to an emergency department with an apparent life-threatening event. Among the 533 children evaluated, there were no cases of meningitis, 1 case of bacteremia, 17 cases of urinary tract infection, 22 cases of bacterial pneumonia, 22 cases of respiratory syncytial virus, and 2 cases of influenza virus identified in respiratory specimens. PMID- 24484771 TI - Hypotension in preterm neonates: low blood pressure alone does not affect neurodevelopmental outcome. AB - OBJECTIVE: To compare neurodevelopmental outcome, mean arterial blood pressure (MABP), and regional cerebral oxygenation (rSco2) between preterm neonates treated for hypotension and controls. STUDY DESIGN: Preterm neonates (N = 66) with a gestational age (GA) <=32 weeks, without a patent ductus arteriosus, treated for hypotension (dopamine >=5 MUg/kg/min) were included. Neonates were matched to controls for GA, birth weight, sex, and year of birth. The rSco2 was determined by using near-infrared spectroscopy. Monitoring of MABP, rSco2, and arterial saturation was started at admission and continued for at least 72 hours. Neurodevelopmental outcome was assessed at 18 and 24 months' corrected age by using the Griffiths Mental Development Scales or the Bayley Scales of Infant and Toddler Development, Third Edition. RESULTS: Infants treated for hypotension spent more time with an MABP less than GA (median 9% vs 0%, P < .001) and time with an MABP/rSco2 correlation >0.5 (27% vs 17%, P < .001). Time spent with an rSco2 <50% and neurodevelopmental outcome at 18 and 24 months' corrected age were not significantly different between infants treated for hypotension and controls. The 26 neonates with an rSco2 <50% for >10% of time had a lower neurodevelopmental outcome at 18 months (median 99 vs 104, P = .02). CONCLUSION: An MABP less than GA (in weeks) was not associated with lower rSco2 or with lower neurodevelopmental outcome scores. However, regardless of MABP, low rSco2 was associated with lower neurodevelopmental outcome scores. Perfusion/oxygenation variables could be of additional value in neonatal intensive care. PMID- 24484772 TI - Spatiotemporal calcium dynamics in single astrocytes and its modulation by neuronal activity. AB - Astrocytes produce a complex repertoire of Ca2+ events that coordinate their major functions. The principle of Ca2+ events integration in astrocytes, however, is unknown. Here we analyze whole Ca2+ events, which were defined as spatiotemporally interconnected transient Ca2+ increases. Using such analysis in single hippocampal astrocytes in culture and in slices we found that spreads and durations of Ca2+ events follow power law distributions, a fingerprint of scale free systems. A mathematical model demonstrated that such Ca2+ dynamics can arise from intracellular inositol-3-phosphate diffusion. The power law exponent (alpha) was decreased by activation of metabotropic glutamate receptors (mGluRs) either by specific receptor agonist or by low frequency stimulation of glutamatergic fibers in hippocampal slices. Decrease in alpha indicated an increase in proportion of large Ca2+ events. Notably, mGluRs activation did not increase the frequency of whole Ca2+ events. This result suggests that neuronal activity does not trigger new Ca2+ events in astrocytes (detectable by our methods), but modulates the properties of existing ones. Thus, our results provide a new perspective on how astrocyte responds to neuronal activity by changing its Ca2+ dynamics, which might further affect local network by triggering release of gliotransmitters and by modulating local blood flow. PMID- 24484773 TI - Fast fixing and comprehensive identification to help improve real-time ligands discovery based on formaldehyde crosslinking, immunoprecipitation and SDS-PAGE separation. AB - BACKGROUND: Fast Fixation is necessary to study real-time protein-protein interactions under physiological conditions. Fast formaldehyde cross-linking can fix transient and weak protein interactions, thereby reducing the number of false negatives but producing great complexity. To reduce this complexity, immunoaffinity purification can Fish out complexes that include particular target proteins, but affinity-based co-purification has a limited capacity to eliminate nonspecific binding to beads and/or antibodies. To Filter out these complexes, SDS-PAGE is used to disrupt non-covalent bonds, thereby eliminating uncross linked complexes and simultaneously providing molecular weight information for identification. RESULTS: We described a 4 F strategy to help improve real-time ligands discovery based on formaldehyde crosslinking, immunoprecipitation and SDS PAGE separation: Fast Fix, Fish, and Filter, using albumin interactome as an example. The use of gel excision without staining makes this strategy comprehensive and sensitive. The target protein must be identified in the same slice as its ligands. The ligands must be identified in slices for the experimental group but not in the corresponding control slices. Only proteins that appear in the range of molecular weights equal to or greater than the sum of the proteins' theoretical molecular weights, together with the target, are considered ligands. In this study, 5 s of cross-linking with 10% formaldehyde was achieved in human blood. The use of this strategy identified 35 ligands for albumin. Comparison with four major previous studies of the albuminome revealed that 68.57% of the 35 ligands identified in our study were identified in these other studies. CONCLUSIONS: Fast cross-linking was achieved. The 4 F strategy can be used to identify real-time in situ interactions without prior intervention and to comprehensively identify ligands of particular target proteins with fewer false positives. PMID- 24484774 TI - Prevention of mother-to-child transmission (PMTCT) of HIV services in Adama town, Ethiopia: clients' satisfaction and challenges experienced by service providers. AB - BACKGROUND: The coverage and uptake of prevention of mother-to-child transmission (PMTCT) of HIV services has remained very low in Ethiopia. One of the pillars of improving quality of health services is measuring and addressing client satisfaction. In Ethiopia, information about the quality of PMTCT services regarding client satisfaction is meager. METHODS: A facility-based cross sectional study using quantitative methods was conducted in Adama town. We interviewed 423 pregnant women and 31 health providers from eight health facilities. Satisfaction of clients was measured using a standard questionnaire adapted from the UNAIDS best practices collection on HIV/AIDS. Bivariate and multivariate logistic regression analyses were used to identify factors associated with clients' satisfaction. RESULTS: About three-fourth (74.7%) of clients reported that they were satisfied with the PMTCT services provided by the health facilities. However, a much lower proportion (39%) of the total respondents (pregnant women who underwent an ANC follow-up session), said they received and understood the messages related to mother-to-child transmission (MTCT) of HIV and PMTCT. The main challenges reported by service providers were lack of training, lack of feedback on job performance and inadequate pay. Clients' satisfaction with PMTCT service was found to be associated with liking the discussion they had with their counselor, non-preference to a different counselor with regards to sex and/or age and not seeing the same ANC counselor before and after HIV test. CONCLUSION: Although 74.7% of clients were satisfied, the majority did not have a good understanding of the counseling on MTCT and PMTCT. We recommend more efforts to be exerted on improving provider-client communication, devising ways of increasing clients' satisfaction and designing an effective motivation strategy for service providers to enhance the status of PMTCT services. PMID- 24484775 TI - Proteogenomic analysis of pathogenic yeast Cryptococcus neoformans using high resolution mass spectrometry. AB - BACKGROUND: Cryptococcus neoformans, a basidiomycetous fungus of universal occurrence, is a significant opportunistic human pathogen causing meningitis. Owing to an increase in the number of immunosuppressed individuals along with emergence of drug-resistant strains, C. neoformans is gaining importance as a pathogen. Although, whole genome sequencing of three varieties of C. neoformans has been completed recently, no global proteomic studies have yet been reported. RESULTS: We performed a comprehensive proteomic analysis of C. neoformans var. grubii (Serotype A), which is the most virulent variety, in order to provide protein-level evidence for computationally predicted gene models and to refine the existing annotations. We confirmed the protein-coding potential of 3,674 genes from a total of 6,980 predicted protein-coding genes. We also identified 4 novel genes and corrected 104 predicted gene models. In addition, our studies led to the correction of translational start site, splice junctions and reading frame used for translation in a number of proteins. Finally, we validated a subset of our novel findings by RT-PCR and sequencing. CONCLUSIONS: Proteogenomic investigation described here facilitated the validation and refinement of computationally derived gene models in the intron-rich genome of C. neoformans, an important fungal pathogen in humans. PMID- 24484777 TI - A cross-sectional study of differences in 6-min walk distance in healthy adults residing at high altitude versus sea level. AB - BACKGROUND: We sought to determine if adult residents living at high altitude have developed sufficient adaptation to a hypoxic environment to match the functional capacity of a similar population at sea level. To test this hypothesis, we compared the 6-min walk test distance (6MWD) in 334 residents living at sea level vs. at high altitude. METHODS: We enrolled 168 healthy adults aged >=35 years residing at sea level in Lima and 166 individuals residing at 3,825 m above sea level in Puno, Peru. Participants completed a 6-min walk test, answered a sociodemographics and clinical questionnaire, underwent spirometry, and a blood test. RESULTS: Average age was 54.0 vs. 53.8 years, 48% vs. 43% were male, average height was 155 vs. 158 cm, average blood oxygen saturation was 98% vs. 90%, and average resting heart rate was 67 vs. 72 beats/min in Lima vs. Puno. In multivariable regression, participants in Puno walked 47.6 m less (95% CI 81.7 to -13.6 m; p < 0.01) than those in Lima. Other variables besides age and height that were associated with 6MWD include change in heart rate (4.0 m per beats/min increase above resting heart rate; p < 0.001) and percent body fat ( 1.4 m per % increase; p = 0.02). CONCLUSIONS: The 6-min walk test predicted a lowered functional capacity among Andean high altitude vs. sea level natives at their altitude of residence, which could be explained by an incomplete adaptation or a protective mechanism favoring neuro- and cardioprotection over psychomotor activity. PMID- 24484779 TI - Hospital of diagnosis and probability to receive a curative treatment for oesophageal cancer. AB - BACKGROUND: Surgical treatment of oesophageal cancer in the Netherland is performed in high volume centres. However, the decision to refer patients for curative surgery is made in the referring hospital of diagnosis. The objective of this study was to determine the influence of hospital of diagnosis on the probability of receiving a curative treatment and survival. MATERIAL AND METHOD: All patients with resectable oesophageal cancer (cT1-3, cN0-3, cM0-1A) diagnosed between 2003 and 2010 (n = 849) were selected from the population-based Eindhoven Cancer Registry, an area with ten non-academic hospitals. Multivariate logistic regression analysis was conducted to examine the independent influence of hospital of diagnosis on the probability to receive curative treatment. Furthermore, the effect of hospital of diagnosis on overall survival was examined using multivariate Cox regression analysis. RESULTS: 849 patients were included in the study. A difference in proportion of patients referred for surgery was observed ranging from 33% to 67% (p = 0.002) between hospitals of diagnosis. Multivariate logistic regression analysis confirmed the effect of hospital of diagnosis on the chance of undergo curative treatment (OR 0.1, 95% CI 0.1-0.4). Multivariate Cox regression analysis showed that hospital of diagnosis also had an effect on overall survival, up to hazard ratio (HR) 2.2 (95% CI 1.3-3.7). CONCLUSION: There is a strong relation between hospital of diagnosis and the chance of referring patients with oesophageal cancer for a curative treatment as well as overall survival. Patients diagnosed with oesophageal cancer should be discussed within a regional multidisciplinary expert panel. PMID- 24484780 TI - Three heads are better than one: a mixed methods study examining collaborative versus traditional test-taking with nursing students. AB - Patient care requires a collaborative teamwork approach; therefore, nursing programs must provide students with ample opportunities to hone teamwork skills. Although collaborative testing (CT) has been utilized in higher education for decades, its uptake in nursing education has only recently surfaced. The purpose of this mixed methods study was to examine CT versus traditional test-taking with undergraduate nursing students in a Western Canadian university. Using a cross over design, surveys, and focus groups, nursing students' experiences of learning, retention of course content, and teamwork were explored. A convenience sample of 70 students was recruited. In this paper, we present the results along with recommendations for future research. The treatment effect was highly significant with CT scores being an average of 7.99 units higher than traditional test-taking scores when the test was allocated a total score of 100. However, the two formative tests were weighted minimally resulting in participating students' overall grades being increased by an average of 1.2 out of 100. Of practical significance, students perceived that CT helped them understand the course material better and they appreciated the opportunity to practice effective communication within a group to prepare for future practice. PMID- 24484781 TI - What, if all alerts were specific - estimating the potential impact on drug interaction alert burden. AB - PURPOSE: Clinical decision support systems (CDSS) may potentially improve prescribing quality, but are subject to poor user acceptance. Reasons for alert overriding have been identified and counterstrategies have been suggested; however, poor alert specificity, a prominent reason of alert overriding, has not been well addressed. This paper aims at structuring modulators that determine alert specificity and estimating their quantitative impact on alert burden. METHODS: We developed and summarized optimizing strategies to guarantee the specificity of alerts and applied them to a set of 100 critical and frequent drug interaction (DDI) alerts. Hence, DDI alerts were classified as dynamic, i.e. potentially sensitive to prescription-, co-medication-, or patient-related factors that would change alert severity or render the alert inappropriate compared to static, i.e. always applicable alerts not modulated by cofactors. RESULTS: Within the subset of 100 critical DDI alerts, only 10 alerts were considered as static and for 7 alerts, relevant factors are not generally available in today's patient charts or their consideration would not impact alert severity. The vast majority, i.e. 83 alerts, might require a decrease in alert severity due to factors related to the prescription (N=13), the co-medication (N=11), individual patient data (N=36), or combinations of them (N=23). Patient related factors consisted mainly of three lab values, i.e. renal function, potassium, and therapeutic drug monitoring results. CONCLUSION: This paper outlines how promising the refinement of knowledge bases is in order to increase specificity and decrease alert burden and suggests how to structure knowledge bases to refine DDI alerting. PMID- 24484783 TI - Invited commentary. PMID- 24484784 TI - Invited commentary. PMID- 24484785 TI - Invited commentary. PMID- 24484786 TI - Invited commentary. PMID- 24484787 TI - Invited commentary. PMID- 24484788 TI - Invited commentary. PMID- 24484789 TI - Invited commentary. PMID- 24484790 TI - Invited commentary. PMID- 24484791 TI - Invited commentary. PMID- 24484792 TI - Invited commentary. PMID- 24484793 TI - Invited commentary. PMID- 24484794 TI - Invited commentary. PMID- 24484795 TI - Invited commentary. PMID- 24484796 TI - Invited commentary. PMID- 24484797 TI - Invited commentary. PMID- 24484798 TI - Invited commentary. PMID- 24484799 TI - Invited commentary. PMID- 24484800 TI - Invited commentary. PMID- 24484801 TI - Invited commentary. PMID- 24484802 TI - Invited commentary. PMID- 24484803 TI - Invited commentary. PMID- 24484804 TI - Epicardial ablation performance of a novel radiofrequency device on the beating heart in pigs. AB - PURPOSE: Only bipolar clamps create reliable transmural lesions on the beating heart. This study evaluated the performance of a new radiofrequency (RF) device on the beating heart in an acute porcine model. DESCRIPTION: Six domestic pigs were ablated with a novel bipolar RF linear device on the beating heart (ablation time of 40 s, 3 each on right and left atria and 1 each on superior and inferior vena cavae). The heart was stained with 2, 3, 5-triphenyl-tetrazolium chloride, and each lesion was cross-sectioned for lesion depth and transmurality. EVALUATION: Transmurality was documented in 89% of the cross-sections. Sixty three percent of lesions were transmural along the entire lesion length. Overall, 85% of the nontransmural cross-sections were located on the right atrium, and half of the nontransmural sections were in the superior or inferior vena cavae lesions. CONCLUSIONS: This novel device was able to create transmural lesions on the beating heart, more effectively in the left atrium than in the right atrium. PMID- 24484805 TI - Invited commentary. PMID- 24484806 TI - Reconstruction of a complex tracheal injury using an intercostal muscle flap. AB - Blunt tracheobronchial injuries occur rarely but can be life threatening. These injuries require accurate preoperative diagnosis and potentially complex reconstruction. We present the case of a 15-year-old boy who was transferred to the University of Washington with a complex tracheobronchial injury after rolling over in a sand-rail dune buggy. The injury was repaired successfully using an intercostal muscle flap and cardiopulmonary bypass. PMID- 24484807 TI - Aortic valve replacement 10 years after lung transplantation. AB - Age-related native pathologic conditions are an inevitable sequela in long-term survivors of solid organ transplantation. A sexagenarian presented with severe aortic valve stenosis 10 years after lung transplantation (LTx). Despite overwhelming concerns of infection because of long-term immunosuppression and the risk of postoperative deterioration of function in transplanted lungs, an open heart surgical procedure with appropriate perioperative management was undertaken, and a successful aortic valve replacement (AVR) was performed. PMID- 24484808 TI - Radiologically indeterminate pulmonary cysts in Birt-Hogg-Dube syndrome. AB - Birt-Hogg-Dube (BHD) syndrome is an inherited disease characterized by recurrent pneumothorax. We report some unusual clinicopathologic features of the lung in a Japanese family with this syndrome presenting with recurrent pneumothorax. Radiologic imaging did not show detectable lesions; however, at video-assisted thoracic surgery (VATS), multiple diffusely distributed microcysts were visible on the pleura. This characteristic morphologic feature was common to all affected family members. The proband underwent genetic testing and BHD syndrome was diagnosed. Although many patients with BHD syndrome with pneumothorax show obvious pulmonary cysts, this case suggests that radiologically indeterminate cysts have the potential to cause pneumothorax. PMID- 24484809 TI - Two unusual cases of adult onset congenital bronchoesophageal fistulas treated with fistula division. AB - Adult onset congenital bronchoesophageal fistula is a very rare entity. We report 2 cases of adult onset type II congenital bronchoesophageal fistula between the distal thoracic esophagus and the lower lobe superior segmental bronchi surgically treated through a right and left thoracotomy, respectively. In both cases the fistula was transected and sutured with no parenchyma resection. Both patients had an uneventful recovery. Resection of the underlying parenchyma during surgery for bronchoesophageal fistula is not always necessary as the lung can heal in time after performing just fistulectomy. PMID- 24484810 TI - Cardiac cavernous hemangioma and multiple pulmonary cavernous hemangiomas. AB - We describe for the first time a rare coexistence of a cardiac cavernous hemangioma with multiple pulmonary cavernous hemangiomas. Computed tomography revealed bilateral pulmonary nodules, left pleural effusion, and pericardial effusion. Positron emission tomography showed a pericardial neoplasm. Pathologically, multiple large dilated vascular spaces, lined by a single layer of endothelial cells and filled with blood, were revealed in both the cardiac tumor and the pulmonary nodules. Immunohistochemical examination of the lining cells showed positivity for CD31, FLI1, FVIII, and CD34. Taken together, these findings led to the diagnosis of cardiac cavernous hemangioma and multiple pulmonary cavernous hemangiomas. PMID- 24484811 TI - Spontaneous rupture of a cystic mediastinal teratoma complicated by superior vena cava syndrome. AB - Spontaneous rupture of cystic mediastinal teratomas is rare but may cause serious complications. Here we report an unusual case of a cystic teratoma, which ruptured into the mediastinal and pleural cavities resulting in superior vena cava syndrome, acute mediastinitis, and pleural effusion. Early diagnosis and prompt surgical treatment of ruptured mediastinal teratomas are essential to preventing life-threatening complications. PMID- 24484812 TI - Left posterolateral thoracotomy: an alternative approach for pulmonary valve replacement. AB - Pulmonary valve replacement in adults who have a repaired tetralogy of Fallot is realized through a redo median sternotomy. A dilated ascending aorta is often present and adherent to the sternum and can be injured during sternum reentry, with dramatic consequences. We report on an adult patient with a corrected tetralogy of Fallot who underwent pulmonary valve replacement, thick transannular patch excision, and left pulmonary artery enlargement. Surgery was performed through a left posterolateral thoracotomy. This surgical approach was safe and efficient and, compared with the left anterior thoracotomy approach, offered many more possibilities. PMID- 24484813 TI - The "TEVAR-first" approach to DeBakey I aortic dissection with mesenteric malperfusion. AB - Acute DeBakey type 1 aortic dissection presenting with mesenteric malperfusion is a lethal variant of all dissection-related malperfusion syndromes with reported mortality rates of 38% to 75%. Conventional surgical treatment involves proximal aortic replacement to restore true lumen perfusion, followed by mesenteric revascularization if malperfusion persists. In an attempt to improve the dismal outcomes associated with this malperfusion syndrome, we have instituted a [thoracic endovascular aortic repair] "TEVAR-First" approach in hemodynamically stable patients, which allows for earlier true lumen expansion and resolution of the malperfusion syndrome. PMID- 24484814 TI - Combined transaortic transcatheter valve replacement and thoracic endografting. AB - Direct transaortic (TAo) approach for transcatheter aortic valve replacement (TAVR) in patients with symptomatic, severe aortic stenosis (AS) with prohibitive transfemoral access is being increasingly performed. Furthermore, concomitant catheter-based procedures such as percutaneous coronary intervention (PCI) are also being increasingly performed during TAVR. We report a single-stage, catheter based treatment of both critical AS and descending thoracic aortic aneurysm (DTA) by performing TAVR with concomitant thoracic aortic endovascular repair (TEVAR) through direct TAo access via a minimally invasive partial sternotomy approach. To our knowledge, this is the first report of a "hybrid" TAVR+TEVAR. PMID- 24484815 TI - Intimal intussusception in aortic dissection and coexisting coronary artery disease. AB - Intimal tear is rarely circumferential in aortic dissection. In such an instance, intimal intussusception may occur. This exposes the patient to the additional risk of severe aortic regurgitation, blockage of the left main coronary artery ostium, or both in proximal intimal intussusception in ascending aortic dissection. Here we present a 61-year-old patient with ascending aortic dissection, aortic regurgitation caused by an intussuscepted proximal intimal flap, and coexisting coronary artery disease. The presenting symptoms and electrocardiographic findings simulated an acute coronary syndrome. Among other diagnostic measures, only transesophageal echocardiography clearly defined the pathologic condition. The patient underwent a successful aortic root replacement and coronary artery bypass grafting. PMID- 24484816 TI - Endovascular repair of acute ascending aortic disruption via the right axillary artery. AB - Endovascular repair of emergent syndromes involving the ascending aorta is uncommon. We describe an acute disruption of the ascending aorta during stenting of the pulmonary artery, resulting in an acute aortopulmonary artery defect and severe pulmonary edema. The disruption was treated successfully using an endovascular approach, with rapid resolution of the patient's pulmonary edema. PMID- 24484817 TI - Valve-sparing root replacement surgery for the truncal valve in an adult: report of the initial successful case. AB - We describe here an initial successful case of valve-sparing surgery using reimplantation technique in a 24-year-old male with aortic root dilatation with truncal valve insufficiency after common arterial trunk repair. Concomitant right ventricular outflow tract reconstruction with expanded polytetrafluoroethylene was also successfully performed. He was discharged home on postoperative day 10 without stenosis or regurgitation of repaired valves. He is in New York Heart Association class I condition without any anticoagulant agents 6 months after operation. Of course, careful follow-up will be needed though our early result is acceptable. PMID- 24484818 TI - Safe sternal reentry in patients with large thoracic aortic pseudoaneurysms. AB - Sternal reentry for ascending aorta pseudoaneurysm repair presents a formidable challenge because of the risk of aneurysm rupture and hemorrhage. We describe two cases of large pseudoaneurysms at high risk for rupture during sternal reentry in which the chest was safely entered by use of an anterior sternal retraction technique. Several other methods for sternal reentry have been reported; however, the reliability and efficiency of the described technique make it the preferred method for sternal reentry for pseudoaneurysms at our institution. PMID- 24484819 TI - Anomalous origin of the left coronary artery from the pulmonary artery, scimitar syndrome, and aortic coarctation. AB - Anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA) represents one of the most common causes of myocardial ischemia in infants and if left untreated results in a high mortality rate. When ALCAPA coexists with other congenital malformations, particularly those associated with pulmonary hypertension, the initial presentation can be quite confusing and is often misinterpreted. We report an infant with ALCAPA associated with scimitar syndrome and aortic coarctation whose clinical course illustrates the complexities and difficulties of management with a successful outcome. PMID- 24484820 TI - Case of congenital aneurysm of sinus of Valsalva with common arterial trunk. AB - We describe an unusual case of a patient with common arterial trunk and interrupted aortic arch, complicated by congenital aneurysm of the sinus of Valsalva, who underwent successful repair. To our knowledge, no such case has been reported in the English literature. The combination of common arterial trunk and congenital aneurysm of the sinus of Valsalva may yield insights into the morphogenesis of congenital aneurysm of the sinus of Valsalva. PMID- 24484821 TI - Bronchogenic cyst with milk of calcium. PMID- 24484822 TI - Obstructing endobronchial lipoma. PMID- 24484823 TI - A pulmonary vascular variation to be considered in resective lung surgical procedures. PMID- 24484824 TI - Coronary artery fistula to pulmonary artery: coronary-dependent pulmonary circulation. PMID- 24484825 TI - Intramyocardial left anterior descending artery as cause of myocardial ischemia. PMID- 24484826 TI - Single-incision subxiphoid approach for bilateral metastasectomy. AB - We report a case of single-incision bilateral partial lung resection using the subxiphoid approach. This approach requires a 3-cm incision in the abdomen, making it aesthetically favorable. In addition, it does not cause postoperative intercostal neuropathy, and postoperative pain is minimal because the intercostal space is bypassed. Moreover, this technique enables exposure to both lungs through a single incision and has potential for widespread use if maneuverability can be increased by improving the instruments used. PMID- 24484827 TI - The performance of high-volume bronchoalveolar lavage for the evaluation and diagnosis of interstitial lung disease. AB - Although high-volume bronchoalveolar lavage (BAL) is an excellent research tool, its use in the evaluation of interstitial lung disease remains controversial, particularly in the age of lung biopsy in video-assisted thoracic surgery. Recently, a new practice guideline made several important recommendations for the performance of the procedure and the handling, processing, and analysis of samples. Here we describe this recommended technique, our experience performing BAL in 42 patients, and the usefulness of our differential cell count results. We demonstrate that BAL is straightforward and safe to perform and conclude that it may offer valuable data in evaluating interstitial lung disease, particularly in patients with an acute presentation or who are not fit for lung biopsy. PMID- 24484828 TI - Transthoracic esophagectomy using endobronchial blocker after previous pneumonectomy. AB - Esophagectomy after pneumonectomy is very rare. We present a case of esophagectomy for esophageal cancer after left pneumonectomy. By application of an endobronchial blocker, satisfactory results were achieved and the disadvantages of extracorporeal membrane oxygenation, cardiopulmonary bypass, and other ventilation methods were avoided. PMID- 24484829 TI - Constructive remarks concerning visceral pleural surface invasion in non-small cell lung cancer patients. PMID- 24484830 TI - Could difference of smoking rate between men and women affect the risk difference of acute kidney injury according to sex? PMID- 24484831 TI - Sternal wound infection and bilateral internal mammary artery harvest: there's more to it than the harvesting technique. PMID- 24484832 TI - Reply: To PMID 23673070. PMID- 24484833 TI - Reply: To PMID 23453745. PMID- 24484834 TI - An adolescent with aortic regurgitation caused by Behcet's disease. PMID- 24484835 TI - Semirigid band annuloplasty. PMID- 24484836 TI - Surgical treatment of retroperitoneal tumors with cavoatrial extension. PMID- 24484837 TI - Reply: To PMID 23706466. PMID- 24484838 TI - Tracheal diverticulum: a rare cause of hoarseness of the voice. AB - Tracheal diverticulum is a rare benign disease also known as paratracheal air cyst. Mostly these are asymptomatic and are discovered incidentally on radiologic examination of the chest. Common symptoms are cough, recurrent respiratory tract infections, and sometimes dysphagia. Herein we report a rare case of hoarseness of voice caused by tracheal diverticulum. Computed tomography scan of neck revealed a large tracheal diverticulum, probably compressing the recurrent laryngeal nerve as bronchoscopy showed impaired right vocal cord movement. Two weeks after diverticulectomy, the patient's voice returned to normal. PMID- 24484839 TI - Idiopathic bilateral segmental pulmonary artery aneurysm. AB - Aneurysms of segmental pulmonary arteries are rare. They can be potentially fatal, but remain undetected in the majority of cases. A young person reported with massive hemoptysis, and a ruptured large segmental pulmonary artery aneurysm of the left lung was identified as the cause. Incidentally a smaller aneurysm on the segmental artery of the right lung was noticed. The case is of rare occurrence, and the urgency of intervention on the left lung with consideration of an aneurysm on the right lung makes this case challenging. The clinical decision making for the choice of procedure for this rare and emergent situation is presented. PMID- 24484840 TI - Pneumomediastinum after percutaneous endoscopic gastrostomy tube placement. AB - The incidence of esophageal perforation or confounding mechanisms of pneumomediastinum specifically introduced by the addition of percutaneous endoscopic gastrostomy (PEG) tube insertion to esophagogastroduodenoscopy have not been described, and pneumomediastinum in the absence of esophageal perforation after PEG has not been reported. Typically, pneumomediastinum is an ominous finding, although benign causes exist. We present two cases of post-PEG pneumomediastinum not correlated with esophageal perforation on follow-up imaging. When pneumomediastinum is detected after PEG, appropriate studies should be undertaken to confirm its cause and to determine treatment plans. Further investigation may be warranted to ascertain the true incidence, causes, and clinical significance of post-PEG pneumomediastinum. PMID- 24484841 TI - Transcatheter aortic valve implantation and left ventricular assist device: a word of caution. AB - Aortic valve disease in the setting of a left ventricular assist device presents unique challenges. We present the case of a patient who underwent transcatheter aortic valve implantation to replace a stenotic aortic valve to facilitate left ventricular assist device explantation. Thirty-three days later, the porcine pericardial valve cusps were fused and a thick pseudomembrane had occluded the left ventricular outflow tract, forcing the explant to be aborted. PMID- 24484842 TI - Double aortic arch with ascending aortic aneurysm and aortic valve regurgitation. AB - Double aortic arch is a rare congenital great vessel anomaly. We report a 21-year old man who was diagnosed with a double aortic arch combining with ascending aortic aneurysm and aortic valve regurgitation. Computerized tomographic angiography and echocardiogram confirmed the diagnosis before operation. The patient underwent aortic root replacement and artificial vessel construction. At 3 years' follow-up, the patient continues to have a good surgical recovery, although long-term results need observing. A review of the literature shows no double aortic arch combination with ascending aortic aneurysm and aortic regurgitation has been reported so far. PMID- 24484843 TI - Mitral leaflet restoration using a billowing leaflet in active infective endocarditis. AB - A key to the success of mitral valve repair in patients with infective endocarditis is the technique used for reconstruction of the missing leaflet. We report the case of a 47-year-old man with active mitral infective endocarditis. After dissection of the infected segments of P3 and the posteromedial commissure, the defect was reconstructed using tissue from a billowing A2 medial and A3 segment. Chordal transfer with an anterior chord was performed to correct the A3 mild prolapse. Follow-up echocardiography showed recovery of mitral valve morphology and function without regurgitation. PMID- 24484844 TI - The left atrial "Medusa myxoma". AB - Although myxomas are the most commonly seen primary cardiac tumors, encompassing 30% to 50% of all primary tumors of the heart, they remain a rare finding with an annual reported incidence of 0.5 per million. The presenting symptoms of an atrial myxoma are widely varied as are the clinical consequences. Regardless of presentation, once a diagnosis is made prompt surgical excision is recommended to minimize the potential complications of obstruction or embolization. We present the "Medusa myxoma," an arborizing 4-fingered left atrial myxoma extending from the fossa ovalis across the left atrium. PMID- 24484845 TI - Diagnosis of esophageal lung combined with pulmonary sling using multidetector computed tomography. PMID- 24484846 TI - Sternal dehiscence after clamshell incision in lung transplantation treated with the STRAsbourg Thoracic Osteosyntheses System (STRATOS). AB - Clamshell incision with transverse sternotomy is the approach of choice for bilateral lung transplantation when cardiopulmonary bypass becomes necessary or to improve exposure. Sternal dehiscence is a well-known complication of this approach. This results in chronic thoracic pain and contributes to a delayed pulmonary rehabilitation. Sternal dehiscence can be treated with conservative therapy, but severe dehiscence requires secondary surgical closure. Several techniques of osteosynthesis have been reported with conflicting results. We describe the first use of the STRAsbourg Thoracic Osteosyntheses System (STRATOS) devices in three cases of secondary sternal closure without infection after bilateral lung transplantation. PMID- 24484849 TI - Contamination of hypertonic saline solutions in use by cystic fibrosis patients in Israel. AB - BACKGROUND: Treatment of cystic fibrosis (CF) patients with inhaled hypertonic saline (HS) solutions is safe, beneficial and reduces exacerbation rates. We studied contamination of solutions used by Israeli CF patients for prolonged periods. METHODS: The study addressed whether daily opening of previously unopened solutions caused contamination, survival of 6 CF-associated bacteria in artificially inoculated solutions, in-use contamination of solutions and patterns of their use by patients. RESULTS: Repeated opening did not contaminate solutions and survival of indicator bacteria was variable. Mycobacterium abscessus survived in 3% HS solution for 6 weeks and Burkholderia cenocepacia and Pseudomonas aeruginosa were longer. In 30/76 (39.5%) of used solutions 49 contaminants were found, none being common CF-associated pathogens. CONCLUSIONS: Most CF-related bacteria survived to some degree in HS. Approximately 40% of solutions used by patients were contaminated by organisms of uncertain significance. Our findings highlight the potential risk posed by contamination of HS solutions and support recommendations to use sterile unit-dose formulations. PMID- 24484847 TI - Validity and reliability of the Spanish version of the 10-item CD-RISC in patients with fibromyalgia. AB - BACKGROUND: No resilience scale has been validated in Spanish patients with fibromyalgia. The aim of this study was to evaluate the validity and reliability of the 10-item CD-RISC in a sample of Spanish patients with fibromyalgia. METHODS: DESIGN: Observational prospective multicenter study. SAMPLE: Patients with diagnoses of fibromyalgia recruited from primary care settings (N = 208). INSTRUMENTS: In addition to sociodemographic data, the following questionnaires were administered: Pain Visual Analogue Scale (PVAS), the 10-item Connor-Davidson Resilience scale (10-item CD-RISC), the Fibromyalgia Impact Questionnaire (FIQ), the Hospital Anxiety and Depression Scale (HADS), the Pain Catastrophizing Scale (PCS), the Chronic Pain Acceptance Questionnaire (CPAQ), and the Mindful Attention Awareness Scale (MAAS). RESULTS: Regarding construct validity, the factor solution in the Principal Component Analysis (PCA) was considered adequate, so the KMO test had a value of 0.91, and the Barlett's test of sphericity was significant (chi2 = 852.8; gl = 45; p < 0.001). Only one factor showed an eigenvalue greater than 1, and it explained 50.4% of the variance. PCA and Confirmatory Factor Analysis (CFA) results did not show significant differences between groups. The 10-item CD-RISC scale demonstrated good internal consistency (Cronbach's alpha = 0.88) and test-retest reliability (r = 0.89 for a six-week interval). The 10-item CD-RISC score was significantly correlated with all of the other psychometric instruments in the expected direction, except for the PVAS (-0.115; p = 0.113). CONCLUSIONS: Our study confirms that the Spanish version of the 10-item CD-RISC shows, in patients with fibromyalgia, acceptable psychometric properties, with a high level of reliability and validity. PMID- 24484850 TI - Impact of allergic rhinitis and specific subcutaneous immunotherapy on peripheral blood basophils of patients sensitized to Dermatophagoides pteronyssinus. AB - BACKGROUND: Basophils are important effectors cells in allergic rhinitis (AR) since they are involved in immunoglobulin (Ig) E - mediated inflammation and in the release of pro-inflammatory mediators. Specific subcutaneous immunotherapy (SCIT) provides clear immunologic modulation in some immune cells, however its systemic effects on basophils are not well known. METHODS: Peripheral blood (PB) samples from 43 patients with allergic rhinitis mono-sensitized to Dermatophagoides pteronyssinus (Dpt) [33 of them under SCIT with allergoid Dpt extract, in maintenance dose (SCIT), with evaluation just before SCIT injection (SCIT-T0) and 4 hours later (SCIT-T4) and the other 10 Dpt allergic patients never having, in the past, undergone specific immunotherapy treatment (NSIT)], and 15 healthy age- and gender-matched controls (HG), were analyzed. For each sample, the total (t-IgE) and specific IgE (s-IgE) was performed, as well as, the relative frequency and absolute number of PB basophils and receptor-bound IgE and IgG expression were evaluated by flow cytometry and the Histamine N methyltransferase (HNMT) and tryptase alpha/beta1 (TPSAB1) gene expression was assessed by real-time PCR. RESULTS: Higher levels of receptor-bound IgE were observed in SCIT patients, which are correlated with the levels of serum t-IgE and s-IgE, whereas no significant differences were observed for receptor-bound IgG. Regarding HNMT mRNA expression, significantly lower expression levels were detected in AR patients compared to HG, independently of type of therapy. Moreover a negative correlation was found between HNMT gene expression and time under SCIT. Conversely, tryptase gene expression was significantly up-regulated in NSIT when compared to HG; however in SCIT patients, tryptase gene expression was significantly decreased than in NSIT patients. No differences were found for any parameter between SCIT-T0 and SCIT-T4 with exception of a transient increased expression of tryptase in SCIT-T4. CONCLUSION: PB basophils from patients with AR show altered functional features, which seems to be influenced by SCIT, suggesting that these cells could be useful to clarify the SCIT triggered mechanisms at a systemic level. PMID- 24484851 TI - Box-Behnken methodology for Cr (VI) and leather dyes removal by an eco-friendly biosorbent: F. vesiculosus. AB - This study focused on leather industrial effluents treatment by biosorption using Fucus vesiculosus as low-cost adsorbent. These effluents are yellowish-brown color and high concentration of Cr (VI). Therefore, biosorption process was optimized using response surface methodology based on Box-Behnken design operating with a simulated leather effluent obtained by mixture of Cr (VI) solution and four leather dyes. The key variables selected were initial solution pH, biomass dosage and CaCl2 concentration in the pretreatment stage. The statistical analysis shows that pH has a negligible effect, being the biomass dosage and CaCl2 concentration the most significant variables. At optimal conditions, 98% of Cr (VI) and 88% of dyes removal can be achieved. Freundlich fitted better to the obtained equilibrium data for all studied systems than Temkin, Langmuir or D-R models. In addition, the use of the final biosorbent as support-substrate to grown of enzyme producer fungi, Pleurotus ostreatus, was also demonstrated. PMID- 24484852 TI - Adsorption removal of cesium from drinking waters: a mini review on use of biosorbents and other adsorbents. AB - Radiocesium (Cs) removal from waters becomes an emerging issue after the Fukushima Daiichi Nuclear Power Plant Disaster, during which a total of approximately 3.3*10(16) Bq Cs was released to contaminate the environment. This mini-review provided a summary on literature works to develop efficient adsorbent for removing Cs from waters. Adsorbent made of raw and modified minerals, composites particles, and biosorbents that are highly specific to Cs in the presence of other alkali and alkali earth metals were summarized. Development of Prussian blue (PB) nanoparticles on Cs removal and its potential use in drinking waterworks was discussed. This review is a unique report for adsorption removal of Cs from contaminated waters. PMID- 24484854 TI - Rhinolith in right nasal cavity. PMID- 24484855 TI - [Latanoprost and sweating episodes]. PMID- 24484856 TI - Use of the Airtraq(r) device for airway management in the prehospital setting--a retrospective study. AB - BACKGROUND: Difficulties with prehospital intubations have encouraged the development of indirect laryngoscopy techniques, facilitating laryngeal visualization. Airtraq(r) is a relatively new single-use indirect laryngoscope. The Airtraq(r) has been evaluated in several prehospital mannequin intubation trials. However, prehospital clinical experience with the device is limited. METHODS: A retrospective medical chart review was performed for patients who underwent prehospital endotracheal intubation in the Stockholm County between January 2008 and December 2012. Both anaesthesiologists and nurse anaesthetists performed prehospital intubations during the study period. All Airtraq(r) intubations during this period were included in the analysis. The objective was to estimate the success rate of Airtraq(r) used in a prehospital setting. RESULTS: During the 5-year period (January 2008- December 2012), 2453 tracheal intubations were performed. Airtraq(r) was used in 28 cases (1%). The overall Airtraq(r) intubation success rate was 68%. Among patients with anticipated or unexpected difficult airway (23/28) the Airtraq(r) success rate was 61% (14/23). Among patients who underwent drug facilitated or rapid-sequence intubation protocols 4/5 (80%) were successfully intubated with Airtraq(r). CONCLUSION: In conclusion, this retrospective study showed a higher Airtraq(r) success rate than previous prospective prehospital trials. However, compared to other prehospital direct and indirect intubation methods the Airtraq success rate is low. Further clinical trials are necessary to evaluate the role of Airtraq(r) in the prehospital airway management. PMID- 24484857 TI - Correlation of surface texture with the stainability of ceramics. AB - STATEMENT OF PROBLEM: Stainability is an important factor in the long-term clinical success of ceramic restorations. Contour adjustments on restoration surfaces cause differences in ceramic texture that may be affected differently by the staining agent. PURPOSE: The purpose of this study was to evaluate the surface texture obtained by different surface treatments relevant to the stainability of heat-pressed leucite-reinforced ceramic disk-shaped specimens. MATERIAL AND METHODS: Sixty-six ceramic disks (IPS Empress Esthetic) (15 * 2 mm) were prepared, glazed, and then assigned to 6 groups. All disks were abraded with a diamond rotary cutting instrument except group GG (control), which was not subjected to any procedure. Group R (rotary diamond cutting instrument) was left untreated after abrasion. Group PB was polished with an abrasive stone, a round polishing brush, and paste with felt wheels. Group PU was polished with 1.0- to 0.5-MUm polishing pastes with a goat-hair brush. Group PS was polished with abrasive stone, silicon carbide polishers, and polishing paste with polishing disks. Group GR was reglazed. Surface roughness was measured with a profilometer and evaluated with scanning electron microscopy. A spectrophotometer was used before and after 12 days of immersion in a coffee solution to assess color difference. Data were analyzed by 1-way ANOVA, the Tukey honestly significant difference test, and the Pearson rank correlation tests (alpha=.05). RESULTS: Ra values of groups from highest to lowest were, in order, R, PB, PU, PS, GR, and GG (P<.01). Scanning electron microscope images and Ra values were compatible. The color difference (DeltaE) values of groups from highest to lowest were, in order, R, PB, PU, PS, GR, and GG. A positive significant relationship of 65.6% between the Ra and DeltaE values was found (P<.01). CONCLUSIONS: Ceramic staining may be related to surface texture. The use of appropriate polishing materials with compatible porcelain may reduce stainability. PMID- 24484853 TI - The composition and stability of the vaginal microbiota of normal pregnant women is different from that of non-pregnant women. AB - BACKGROUND: This study was undertaken to characterize the vaginal microbiota throughout normal human pregnancy using sequence-based techniques. We compared the vaginal microbial composition of non-pregnant patients with a group of pregnant women who delivered at term. RESULTS: A retrospective case-control longitudinal study was designed and included non-pregnant women (n = 32) and pregnant women who delivered at term (38 to 42 weeks) without complications (n = 22). Serial samples of vaginal fluid were collected from both non-pregnant and pregnant patients. A 16S rRNA gene sequence-based survey was conducted using pyrosequencing to characterize the structure and stability of the vaginal microbiota. Linear mixed effects models and generalized estimating equations were used to identify the phylotypes whose relative abundance was different between the two study groups. The vaginal microbiota of normal pregnant women was different from that of non-pregnant women (higher abundance of Lactobacillus vaginalis, L. crispatus, L. gasseri and L. jensenii and lower abundance of 22 other phylotypes in pregnant women). Bacterial community state type (CST) IV-B or CST IV-A characterized by high relative abundance of species of genus Atopobium as well as the presence of Prevotella, Sneathia, Gardnerella, Ruminococcaceae, Parvimonas, Mobiluncus and other taxa previously shown to be associated with bacterial vaginosis were less frequent in normal pregnancy. The stability of the vaginal microbiota of pregnant women was higher than that of non-pregnant women; however, during normal pregnancy, bacterial communities shift almost exclusively from one CST dominated by Lactobacillus spp. to another CST dominated by Lactobacillus spp. CONCLUSION: We report the first longitudinal study of the vaginal microbiota in normal pregnancy. Differences in the composition and stability of the microbial community between pregnant and non-pregnant women were observed. Lactobacillus spp. were the predominant members of the microbial community in normal pregnancy. These results can serve as the basis to study the relationship between the vaginal microbiome and adverse pregnancy outcomes. PMID- 24484858 TI - A consecutive case series experience with [18 F] florbetapir PET imaging in an urban dementia center: impact on quality of life, decision making, and disposition. AB - BACKGROUND: Identification and quantification of fibrillar amyloid in brain using positron emission tomography (PET) imaging and AmyvidTM ([18 F] Amyvid, [18 F] florbetapir, 18 F-AV-45) was recently approved by the US Food and Drug Administration as a clinical tool to estimate brain amyloid burden in patients being evaluated for cognitive impairment or dementia. Imaging with [18 F] florbetapir offers in vivo confirmation of the presence of cerebral amyloidosis and may increase the accuracy of the diagnosis and likely cause of cognitive impairment (CI) or dementia. Most importantly, amyloid imaging may improve certainty of etiology in situations where the differential diagnosis cannot be resolved on the basis of standard clinical and laboratory criteria. RESULTS: A consecutive case series of 30 patients (age 50-89; 16 M/14 F) were clinically evaluated at a cognitive evaluation center of urban dementia center and referred for [18 F] florbetapir PET imaging as part of a comprehensive dementia workup. Evaluation included neurological examination and neuropsychological assessment by dementia experts. [18 F] florbetapir PET scans were read by trained nuclear medicine physicians using the qualitative binary approach. Scans were rated as either positive or negative for the presence of cerebral amyloidosis. In addition to a comprehensive dementia evaluation, post [18 F] florbetapir PET imaging results caused diagnoses to be changed in 10 patients and clarified in 9 patients. Four patients presenting with SCI were negative for amyloidosis. These results show that [18 F] florbetapir PET imaging added diagnostic clarification and discrimination in over half of the patients evaluated. CONCLUSIONS: Amyloid imaging provided novel and essential data that: (1) caused diagnosis to be revised; and/or (2) prevented the initiation of incorrect or suboptimal treatment; and/or (3) avoided inappropriate referral to an anti-amyloid clinical trial. PMID- 24484859 TI - Febrile seizures. AB - INTRODUCTION: Simple febrile seizures are generalised in onset and have a brief duration. The American Academy of Pediatrics defines this brief duration to be <15 minutes; whereas, in the UK, a maximum duration of 10 minutes is used. Simple febrile seizures do not occur more than once in 24 hours and resolve spontaneously. Complex febrile seizures are longer lasting, have focal symptoms (at onset or during the seizure), and can recur within 24 hours or within the same febrile illness. This review only deals with simple febrile seizures. About 2% to 5% of children in the US and Western Europe, and 6% to 9% of infants and children in Japan, will have experienced at least one febrile seizure by the age of 5 years. A very small number of children with simple febrile seizures may develop afebrile seizures, but simple febrile seizures are not associated with any permanent neurological deficits. METHODS AND OUTCOMES: We conducted a systematic review and aimed to answer the following clinical question: What are the effects of treatments given during episodes of fever in children (aged 6 months to 5 years) with one or more previous simple febrile seizures? We searched: Medline, Embase, The Cochrane Library, and other important databases up to July 2013 (Clinical Evidence reviews are updated periodically, please check our website for the most up-to-date version of this review). We included harms alerts from relevant organisations such as the US Food and Drug Administration (FDA) and the UK Medicines and Healthcare products Regulatory Agency (MHRA). RESULTS: We found 4 RCTs or systematic reviews of RCTs that met our inclusion criteria. We performed a GRADE evaluation of the quality of evidence for interventions. CONCLUSIONS: In this systematic review, we present information relating to the effectiveness and safety of the following interventions: intermittent anticonvulsants (clobazam, diazepam, lorazepam), antipyretic drug treatments (paracetamol, ibuprofen), and conservative measures (watchful waiting, physical antipyretic measures [tepid sponging, removing clothes, cooling room, direct fanning of child]). PMID- 24484860 TI - Relation of ST-segment elevation before and after percutaneous transluminal coronary angioplasty to left ventricular area at risk, myocardial infarct size, and systolic function. AB - Electrocardiography is an excellent tool for decision making in patients with ST elevation myocardial infarction (STEMI). However, little is known on the correlation between its dynamic changes during primary percutaneous coronary intervention (PCI) and the anatomic information provided by cardiovascular magnetic resonance. The study aimed to assess the predictive value of dynamic ST segment changes before and after PCI on myocardial area at risk (AAR), infarct size, and left ventricular function in patients with STEMI. Eighty-five consecutive patients with a first STEMI were included. An electrocardiogram was recorded before and after PCI at 1, 24, 48, 72, and 120 hours. Sum of ST elevation (sumSTE), the number of STE, and STE resolution (resSTE) were determined. Complete resSTE was defined as >=70% resolution, and patients were classified into 3 groups: group 1 (resSTE 1 hour after PCI) n = 39; group 2 (resSTE 120 hour after PCI) n = 27; and group 3, without resSTE (n = 19). Cardiovascular magnetic resonance was performed during hospitalization and at 6 months. Left ventricular volumes, ejection fraction, AAR, infarct size, myocardial salvage index, and microvascular obstruction were determined. Before PCI, the number of STE and sumSTE were best associated with AAR (p <0.001). After PCI, lack of resSTE (group 3) was associated with larger infarct size, MVO, and lower myocardial salvage index. However, sumSTE at 120 hours after PCI best discriminated patients with larger infarct size, ventricular volumes, and lower ejection fraction during hospitalization and at follow-up. In conclusion, admission sumSTE best correlates with AAR, whereas sumSTE at 120 hours rather than early resSTE best correlates with infarct size and left ventricular volumes during hospitalization and at 6 months. PMID- 24484861 TI - Assessment of dabigatran utilization and prescribing patterns for atrial fibrillation in a physician group practice setting. AB - For years, warfarin and aspirin have been standard therapies for prophylaxis of stroke in atrial fibrillation. In late 2010, dabigatran, an oral direct thrombin inhibitor, became available for use in nonvalvular atrial fibrillation. We sought to evaluate utilization and prescribing patterns of dabigatran in a physician group practice setting. We retrospectively collected prescription data from October 2010 to December 2011 including indication of use, dose, renal function, drug interactions, history of warfarin therapy, and risk assessment scores (CHADS2 and HAS-BLED). Off-label use (history of valve disease or no diagnosis of atrial fibrillation) occurred in 20% (n = 34) of 174 patients. Renal function assessed by Cockcroft-Gault equation identified 1 case of contraindicated use and the need for initial renal dose adjustment in approximately 1/2 of the patients with reduced renal function (15-30 ml/min). Review of anticoagulant use revealed 68% of patients (n = 119) previously received warfarin and ultimately 20% of all patients on dabigatran resumed warfarin therapy. A significant increase in the use of permeability glycoprotein inhibitors and proton pump inhibitors after initiating dabigatran was observed. Nearly 10% of patients had a CHADS2 score of 0. For patients receiving novel oral anticoagulants, prospective inclusion in anticoagulation services and guidance from specific "place in therapy" statements have potential to play a large role in maximizing safety while aiding in continued research. PMID- 24484862 TI - Comparison of characteristics and outcomes of patients with heart failure preserved ejection fraction versus reduced left ventricular ejection fraction in an urban cohort. AB - Despite significant advances in therapies for patients with heart failure with reduced ejection fraction (HFrEF), there are no evidence-based therapies for heart failure with preserved ejection fraction (HFpEF), also known as diastolic heart failure (HF). Differences in pathophysiologic mechanisms are touted as to why patients with HFpEF purportedly do not derive similar therapeutic benefits compared with HFrEF. Similarly, the relative frequencies of HFpEF and HFrEF may differ between hospitalized and ambulatory settings. There are limited data on the prevalence, characteristics, treatment, and short-term outcomes of patients hospitalized with HFpEF. We sought to investigate these in patients hospitalized with HFpEF in an urban, hospitalized setting using the Get With The Guidelines registry. We retrospectively reviewed all consecutive discharges (n = 1,701) with a diagnosis of acute decompensated HF from December 1, 2006 to September 30, 2008. Patients with HFpEF (n = 499) were older, overweight, predominantly women, and had underlying hypertension and dyslipidemia. Presenting blood pressure and levels of creatinine were higher, with lower brain natriuretic peptide levels compared with patients with HFrEF (n = 598). Length of stay and 30-day mortality were comparable between patients with HFpEF and HFrEF. Thirty-day readmission was initially lower in patients with HFpEF. However 30-day mortality from any cause after the index HF hospitalization and survival curve at 1-year was no different between patients with HFpEF and HFrEF. In conclusion, lower 30-day readmissions do not translate into improved long-term outcome in patients with HFpEF. PMID- 24484863 TI - Utility of the Penn classification in predicting outcomes of surgery for acute type a aortic dissection. AB - The Penn classification, a risk assessment system for acute type A aortic dissection (AAAD), is based on preoperative ischemic conditions. We investigated whether Penn classes predict outcomes after surgery for AAAD. Three hundred fifty one patients with DeBakey type I AAAD treated surgically, January 1997 to January 2011, were divided into 4 groups per Penn class: Aa (no ischemia, n = 187), Ab (localized ischemia with branch malperfusion, n = 67), Ac (generalized ischemia with circulatory collapse, n = 46), and Abc (localized and generalized ischemia, n = 51). Early and late outcomes were compared between groups. In-hospital mortality was 3% (6 of 187) for Penn Aa, 6% (4 of 67) for Penn Ab, 17% (8 of 46) for Penn Ac, and 22% (11 of 51) for Penn Abc. Multivariate logistic regression analysis showed Penn classes Ac and Abc, operation time >6 hours, and entry in the descending thoracic aorta to be risk factors for in-hospital mortality. Incidences of neurologic, respiratory, and hepatic complications differed between groups. Five-year cumulative survival was 85% in the Penn Aa group, 74% in the Penn Ab group (p = 0.027 vs Penn Aa), 78% in the Penn Ac group, and 67% in the Penn Abc group (p <0.001 vs Penn Aa). In conclusion, morbidity and mortality are high in patients with generalized ischemia. The Penn classification appears to be a useful risk assessment system for AAAD, predictive of outcomes. PMID- 24484864 TI - Recognition of hypertrophic cardiomyopathy as a contemporary, relatively common, and treatable disease (from the International Summit V). PMID- 24484865 TI - Growth of the aorta in childhood. PMID- 24484866 TI - Value of EuroSCORE II in predicting total and cardiac mortality in patients undergoing percutaneous coronary interventions. PMID- 24484867 TI - Risk of myocardial infarction with oral direct thrombin inhibitors: trial sequential analysis based on two published data sets. PMID- 24484868 TI - Reply: To PMID 24075284. PMID- 24484869 TI - The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies. AB - BACKGROUND: Not all obese subjects have an adverse metabolic profile predisposing them to developing type 2 diabetes or cardiovascular disease. The BioSHaRE-EU Healthy Obese Project aims to gain insights into the consequences of (healthy) obesity using data on risk factors and phenotypes across several large-scale cohort studies. Aim of this study was to describe the prevalence of obesity, metabolic syndrome (MetS) and metabolically healthy obesity (MHO) in ten participating studies. METHODS: Ten different cohorts in seven countries were combined, using data transformed into a harmonized format. All participants were of European origin, with age 18-80 years. They had participated in a clinical examination for anthropometric and blood pressure measurements. Blood samples had been drawn for analysis of lipids and glucose. Presence of MetS was assessed in those with obesity (BMI >= 30 kg/m2) based on the 2001 NCEP ATP III criteria, as well as an adapted set of less strict criteria. MHO was defined as obesity, having none of the MetS components, and no previous diagnosis of cardiovascular disease. RESULTS: Data for 163,517 individuals were available; 17% were obese (11,465 men and 16,612 women). The prevalence of obesity varied from 11.6% in the Italian CHRIS cohort to 26.3% in the German KORA cohort. The age-standardized percentage of obese subjects with MetS ranged in women from 24% in CHRIS to 65% in the Finnish Health2000 cohort, and in men from 43% in CHRIS to 78% in the Finnish DILGOM cohort, with elevated blood pressure the most frequently occurring factor contributing to the prevalence of the metabolic syndrome. The age standardized prevalence of MHO varied in women from 7% in Health2000 to 28% in NCDS, and in men from 2% in DILGOM to 19% in CHRIS. MHO was more prevalent in women than in men, and decreased with age in both sexes. CONCLUSIONS: Through a rigorous harmonization process, the BioSHaRE-EU consortium was able to compare key characteristics defining the metabolically healthy obese phenotype across ten cohort studies. There is considerable variability in the prevalence of healthy obesity across the different European populations studied, even when unified criteria were used to classify this phenotype. PMID- 24484871 TI - Low and high-frequency somatosensory evoked potentials recorded from the human pedunculopontine nucleus. AB - OBJECTIVE: To investigate the generators of the somatosensory evoked potential (SEP) components recorded from the Pedunculopontine Tegmental nucleus (PPTg). METHODS: Twenty-two patients, suffering from Parkinson's disease (PD), underwent electrode implantation in the PPTg area for deep brain stimulation (DBS). SEPs were recorded from the DBS electrode contacts to median nerve stimulation. RESULTS: SEPs recorded from the PPTg electrode contacts could be classified in 3 types, according to their waveforms. (1) The biphasic potential showed a positive peak (P16) whose latency (16.05 +/- 0.61 ms) shifted of 0.18 +/- 0.07 ms from the lower to the upper contact of the electrode. (2) The triphasic potential showed an initial positive peak (P15) whose latency (15.4 +/- 0.2 ms) did not change across the DBS electrode contacts. (3) In the last SEP configuration (mixed biphasic and triphasic waveform), the positive peak was bifid including both the P15 and P16 potentials. CONCLUSION: While the P16 potential is probably generated by the somatosensory volley travelling along the medial lemniscus, the P15 response represents a far-field potential probably generated at the cuneate nucleus level. SIGNIFICANCE: Our results show the physiological meaning of the somatosensory responses recorded from the PPTg nucleus area. PMID- 24484870 TI - miR-125a regulates cell cycle, proliferation, and apoptosis by targeting the ErbB pathway in acute myeloid leukemia. AB - microRNA profiling of acute myeloid leukemia patient samples identified miR-125a as being decreased. Current literature has investigated miR-125a's role in normal hematopoiesis but not within acute myeloid leukemia. Analysis of the upstream region of miR-125a identified several CpG islands. Both precursor and mature miR 125a increased in response to a de-methylating agent, Decitabine. Profiling revealed the ErbB pathway as significantly decreased with ectopic miR-125a. Either ectopic expression of miR-125a or inhibition of ErbB via Mubritinib resulted in inhibition of cell cycle proliferation and progression with enhanced apoptosis revealing ErbB inhibitors as potential novel therapeutic agents for treating miR-125a-low AML. PMID- 24484872 TI - Oscillatory neural activity of anteromedial globus pallidus internus in Tourette syndrome. PMID- 24484874 TI - Recent advances and new strategies in the NMR-based identification of natural products. AB - Nature comprises an untapped pool of unique compounds with high structural uniqueness and exceptional properties. At the core of natural products (NPs) discovery is the identification procedure and NMR remains the most efficient method. Technical improvements such as miniaturized and crycogenic NMR probes along with hyphenation capabilities and computational support are at the center of evolution. Concepts such as dereplication and metabolomics are increasingly adopted in NPs using the power of databases, currently fragmented. The introduction and utilization of these technical and computational implements could lead NPs research to more comprehensive structure identification and new holistic perspectives. PMID- 24484875 TI - Computational imaging, sensing and diagnostics for global health applications. AB - In this review, we summarize some of the recent work in emerging computational imaging, sensing and diagnostics techniques, along with some of the complementary non-computational modalities that can potentially transform the delivery of health care globally. As computational resources are becoming more and more powerful, while also getting cheaper and more widely available, traditional imaging, sensing and diagnostic tools will continue to experience a revolution through simplification of their designs, making them compact, light-weight, cost effective, and yet quite powerful in terms of their performance when compared to their bench-top counterparts. PMID- 24484876 TI - Novel fermentation processes for manufacturing plant natural products. AB - Microbial production of plant natural products (PNPs), such as terpenoids, flavonoids from renewable carbohydrate feedstocks offers sustainable and economically attractive alternatives to their petroleum-based production. Rapid development of metabolic engineering and synthetic biology of microorganisms shows many advantages to replace the current extraction of these useful high price chemicals from plants. Although few of them were actually applied on a large scale for PNPs production, continuous research on these high-price chemicals and the rapid growing global market of them, show the promising future for the production of these PNPs by microorganisms with a more economic and environmental friendly way. Introduction of novel pathways and optimization of the native cellular processes by metabolic engineering of microorganisms for PNPs production are rapidly expanding its range of cell-factory applications. Here we review recent progress in metabolic engineering of microorganisms for the production of PNPs. Besides, factors restricting the yield improvement and application of lab-scale achievements to industrial applications have also been discussed. PMID- 24484877 TI - Animal microsurgery using microfluidics. AB - Small multicellular genetic organisms form a central part of modern biological research. Using these small organisms provides significant advantages in genetic tractability, manipulation, lifespan and cost. Although the small size is generally advantageous, it can make procedures such as surgeries both time consuming and labor intensive. Over the past few years there have been dramatic improvements in microfluidic technologies that enable significant improvements in microsurgery and interrogation of small multicellular model organisms. PMID- 24484878 TI - Fluidic and microfluidic tools for quantitative systems biology. AB - Understanding genes and their functions is a daunting task due to the level of complexity in biological organisms. For discovering how genotype and phenotype are linked to each other, it is essential to carry out systematic studies with maximum sensitivity and high-throughput. Recent developments in fluid-handling technologies, both at the macro and micro scale, are now allowing us to apply engineering approaches to achieve this goal. With these newly developed tools, it is now possible to identify genetic factors that are responsible for particular phenotypes, perturb and monitor cells at the single-cell level, evaluate cell-to cell variability, detect very rare phenotypes, and construct faithful in vitro disease models. PMID- 24484879 TI - Use of in vitro bioassays for assessing botanicals. AB - In vitro bio assays can play a vital role in evaluating botanicals ranging from comparative screening, interaction studies, bio-activity guided fractionation, biological characterization, assisting in stability studies to studying mechanism of actions. In this review, we present some challenges and common pitfalls of using bioassays for assessing botanicals including guidance to overcome them. The overall objective of this review is to improve the success of botanicals products by incorporating robust bioassays during various stages of research and development. PMID- 24484880 TI - Human-on-chip for therapy development and fundamental science. AB - Organ-on-chip systems integrate microfluidic technology and living cells to study human physiology and pathophysiology. These human in vitro models are promising substitutes for animal testing, and their small scale enables precise control of culture conditions and high-throughput experiments, which would not be economically sustainable on a macroscopic level. Multiple sources of biological material are used in the development of organ-on-chips, from biopsies to stem cells. Each source has its own peculiarities and technical requirements for integration into microfluidic chips, and is suitable for specific applications. While a biopsy is the tissue of choice for the biomimetic response to ageing, induced pluripotent stem cells hold great promise for the study of genetic related disease pathogenesis, and primary cultures can fill the gap. PMID- 24484882 TI - Recent developments in microfluidic large scale integration. AB - In 2002, Thorsen et al. integrated thousands of micromechanical valves on a single microfluidic chip and demonstrated that the control of the fluidic networks can be simplified through multiplexors [1]. This enabled realization of highly parallel and automated fluidic processes with substantial sample economy advantage. Moreover, the fabrication of these devices by multilayer soft lithography was easy and reliable hence contributed to the power of the technology; microfluidic large scale integration (mLSI). Since then, mLSI has found use in wide variety of applications in biology and chemistry. In the meantime, efforts to improve the technology have been ongoing. These efforts mostly focus on; novel materials, components, micromechanical valve actuation methods, and chip architectures for mLSI. In this review, these technological advances are discussed and, recent examples of the mLSI applications are summarized. PMID- 24484881 TI - Universal quantitative NMR analysis of complex natural samples. AB - Nuclear Magnetic Resonance (NMR) is a universal and quantitative analytical technique. Being a unique structural tool, NMR also competes with metrological techniques for purity determination and reference material analysis. In pharmaceutical research, applications of quantitative NMR (qNMR) cover mostly the identification and quantification of drug and biological metabolites. Offering an unbiased view of the sample composition, and the possibility to simultaneously quantify multiple compounds, qNMR has become the method of choice for metabolomic studies and quality control of complex natural samples such as foods, plants or herbal remedies, and biofluids. In this regard, NMR-based metabolomic studies, dedicated to both the characterization of herbal remedies and clinical diagnosis, have increased considerably. PMID- 24484883 TI - Microfluidics for biological measurements with single-molecule resolution. AB - Single-molecule approaches in biology have been critical in studies ranging from the examination of physical properties of biological macromolecules to the extraction of genetic information from DNA. The variation intrinsic to many biological processes necessitates measurements with single-molecule resolution in order to accurately recapitulate population distributions. Microfluidic technology has proven to be useful in the facilitation and even enhancement of single-molecule studies because of the precise liquid handling, small volume manipulation, and high throughput capabilities of microfluidic devices. In this review we survey the microfluidic "toolbox" available to the single-molecule specialist and summarize some recent biological applications of single-molecule detection on chip. PMID- 24484884 TI - New materials for microfluidics in biology. AB - With its continuous progress, microfluidics has become a key enabling technology in biological research. During the past few years, the major growth of microfluidics shifted to the introduction of new materials in making microfluidic chips, primarily driven by the demand of versatile strategies to interface microfluidics with biological cell studies. Although polydimethylsiloxane is still used as primary frame material, hydrogels have been increasingly employed in cell-culture related applications. Moreover, plastics and paper are attracting more attention in commercial device fabrication. Aiming to reflect this trend, current review focuses on the progress of microfluidic chip materials over the time span of January 2011 through June 2013, and provides critical discussion of the resulting major new tools in biological research. PMID- 24484885 TI - Biochemical strategies for enhancing the in vivo production of natural products with pharmaceutical potential. AB - Natural products have been associated with significant health benefits in preventing and treating various chronic human diseases such as cancer, cardiovascular diseases, diabetes, Alzheimer's disease, and pathogenic infections. However, the isolation, characterization and evaluation of natural products remain a challenge, mainly due to their limited bioavailability. Metabolic engineering and fermentation technology have emerged as alternative approaches for generating natural products under controlled conditions that can be optimized to maximize yields. Optimization of these processes includes the evaluation of factors such as host selection, product biosynthesis interaction with the cell's central metabolism, product degradation, and byproduct formation. This review summarizes the most recent biochemical strategies and advances in expanding and diversifying natural compounds as well as maximizing their production in microbial and plants cells. PMID- 24484886 TI - Microfluidic cell culture. AB - Microfluidic techniques allow precise control of fluids and particles at the nanoliter scale and facilitate simultaneous manipulation and analysis of cultured cells, starting from a single cell to larger populations and to intact tissues. The use of integrated microfluidic devices has considerably advanced the fields of quantitative and systems biology. In this review, we survey the recent developments in microfluidic cell culture, and discuss not only the advantages but also limitations of using such systems, and give an outlook on potential future developments. PMID- 24484887 TI - DNA barcoding of medicinal plant material for identification. AB - Because of the increasing demand for herbal remedies and for authentication of the source material, it is vital to provide a single database containing information about authentic plant materials and their potential adulterants. The database should provide DNA barcodes for data retrieval and similarity search. In order to obtain such barcodes, several molecular methods have been applied to develop markers that aid with the authentication and identification of medicinal plant materials. In this review, we discuss the genomic regions and molecular methods selected to provide barcodes, available databases and the potential future of barcoding using next generation sequencing. PMID- 24484888 TI - Preparative chromatography and natural products discovery. AB - Methodology is reviewed which significantly enhances the economics and efficiency of larger scale preparative normal phase chromatography. Maintenance of hydration of the silica media and regeneration and re-equilibration of the column after each separation is demonstrated to allow repeated use of the column without loss of performance or requirement of repacking. PMID- 24484890 TI - Current initiatives for the validation of analytical methods for botanicals. AB - The demand for validated analytical methods for botanicals has grown in response to the increasing consumer market for botanical supplements. Government initiatives to increase the availability of validated analytical methods and botanical reference material have led to the publication of numerous validation studies in scientific journals. Single laboratory validation and collaborative validation studies are structured to confirm a method's ruggedness and fit for purpose. The performance characteristics and statistical protocols followed throughout a validation study vary with the source of guidelines. Analytical techniques and priority methods are influenced by the need for fast-screening techniques, the limited availability of reference material, market value, and the prevalence of contaminants in botanical supplements. PMID- 24484891 TI - Recent progress in the physics of microfluidics and related biotechnological applications. AB - Since the mid-nineties, the physical understanding of microfluidic flows has reached a level sufficiently elaborate for envisaging applications in all sorts of domains. As the domain expanded, the existence of new situations where fluid dynamics at small or moderate Reynolds numbers combines with confinement, interfaces, transport, particles along with disordered substrates raised new challenges. The present review is restricted to three domains in which progress in the physical description has been made recently (droplet-based, inertial and paper-based microfluidics) and for which biotechnological applications are foreseeable. PMID- 24484889 TI - Advances in high-throughput single-cell microtechnologies. AB - Micro-scale biological tools that have allowed probing of individual cells--from the genetic, to proteomic, to phenotypic level--have revealed important contributions of single cells to direct normal and diseased body processes. In analyzing single cells, sample heterogeneity between and within specific cell types drives the need for high-throughput and quantitative measurement of cellular parameters. In recent years, high-throughput single-cell analysis platforms have revealed rare genetic subpopulations in growing tumors, begun to uncover the mechanisms of antibiotic resistance in bacteria, and described the cell-to-cell variations in stem cell differentiation and immune cell response to activation by pathogens. This review surveys these recent technologies, presenting their strengths and contributions to the field, and identifies needs still unmet toward the development of high-throughput single-cell analysis tools to benefit life science research and clinical diagnostics. PMID- 24484892 TI - Quantitative metabolic profiling of grape, apple and raspberry volatile compounds (VOCs) using a GC/MS/MS method. AB - Nowadays the trend in analytical chemistry is clearly towards the creation of multiple methods with extended coverage, enabling the determination of many different classes of compounds in a single analysis in which virtually all classes of different compounds are included in a single run. The aim of this study was to develop and validate a versatile and selective GC/MS/MS method for metabolite profiling of volatile compounds in apples, raspberries and grapes. Validation of the method was performed in terms of the limit of detection, limit of quantification, linearity range, and inter and intraday precision. Confirmation of the identity of the compounds in samples was carried out by checking compliance of the q/Q ratio of samples and reference standards. The multiple reaction monitoring with selection of two transition ions, one for quantification and one for confirmation, provided excellent selectivity and sensitivity, using the q/Q ratio as a confirmatory parameter. A multi target method was developed and validated for the simultaneous quantification and confirmation of 160 volatile compounds of raspberries, apples and grapes. The main classes were esters (42), alcohols (32), monoterpenes (31), aldehydes (17), ketones (12), norisoprenoids (8), acids (8), sesquiterpenes (7), pyrazines (3) and ethers (1) allowing the detection and quantification of 69 compounds in apples, 122 in grapes and 42 in raspberries. Moreover, the method developed can be easily extended to volatile compounds in other fruits and can therefore be widely used for quantification/profiling studies in the field of fruit aroma. PMID- 24484893 TI - Elective stent-graft treatment for the management of thoracic aorta mural thrombus. AB - BACKGROUND: Optimal management of aorta mural thrombus (AMT) continues to be controversial. The aim of this study was to describe the management of AMT in the thoracic aorta with either conservative or stent-graft treatment and to analyze the role of morphological characteristics of thrombus in the selection of suitable candidates for intervention. METHODS: A retrospective review was conducted of all patients admitted for thoracic AMT. Clinical data, treatment used, and outcomes were recorded. Patients were divided in two groups according to the treatment used: either conservative or stent-graft. Morphological features of thrombus, including size, sessile or pedunculated aspect and mobility, were compared between the two groups. RESULTS: From January 2006 to March 2013, 13 consecutive patients (nine male, mean age 53, range 37-76) were admitted for symptomatic (n = 8) or asymptomatic AMT (n = 5). All patients received unfractionated heparin. Management of primary aortic thrombus required stent graft in seven patients, aortic thrombectomy in one, and anticoagulation therapy alone in five. Indications for intervention were recurrent embolism (n = 4), occurrence of embolism under heparin (n = 1), or persistent thrombus (n = 2). Endovascular exclusion of AMT was successful in all cases, with no complications or deaths at 30 days and no recurrence at midterm. Analysis of the morphological features of the thrombus identified solely the high degree mobility as associated with adverse outcome (p = .048). CONCLUSION: In our experience, stent-graft exclusion of AMT is an effective approach. Systematic evaluation of thrombus mobility by a real-time imaging study can be helpful to better define the indications for radical treatment of the aortic lesion. PMID- 24484894 TI - Genetic diversity and insecticide resistance during the growing season in the green peach aphid (Hemiptera: Aphididae) on primary and secondary hosts: a farm scale study in Central Chile. AB - The seasonal dynamics of neutral genetic diversity and the insecticide resistance mechanisms of insect pests at the farm scale are still poorly documented. Here this was addressed in the green peach aphid Myzus persicae (Sulzer) (Hemiptera: Aphididae) in Central Chile. Samples were collected from an insecticide sprayed peach (Prunus persica L.) orchard (primary host), and a sweet-pepper (Capsicum annum var. grossum L.) field (secondary host). In addition, aphids from weeds (secondary hosts) growing among these crops were also sampled. Many unique multilocus genotypes were found on peach trees, while secondary hosts were colonized mostly by the six most common genotypes, which were predominantly sensitive to insecticides. In both fields, a small but significant genetic differentiation was found between aphids on the crops vs. their weeds. Within season comparisons showed genetic differentiation between early and late season samples from peach, as well as for weeds in the peach orchard. The knock-down resistance (kdr) mutation was detected mostly in the heterozygote state, often associated with modified acetylcholinesterase throughout the season for both crops. This mutation was found in high frequency, mainly in the peach orchard. The super-kdr mutation was found in very low frequencies in both crops. This study provides farm-scale evidence that the aphid M. persicae can be composed of slightly different genetic groups between contiguous populations of primary and secondary hosts exhibiting different dynamics of insecticide resistance through the growing season. PMID- 24484896 TI - Durability and integrity studies of environmentally conditioned interfaces in fibrous polymeric composites: critical concepts and comments. AB - Fibre reinforced polymer (FRP) composites are the most promising and elegant material of the present century. Their durability and integrity in various service environments can be altered by the response of its constituent i.e. fibre, polymer matrix, and the existing interface/interphase between the fibre and polymer matrix, in that particular environment. The interphase is generally manifested by chemical bonding, molecular segregation and also by van der Waals bonding. The sizing of fibres generally influences the chemistry and character of the interface/interphase and might generate structural gradient in the polymer matrix. Their susceptibilities to degradation are dependent of the nature of environments and each of the constituents' responds differently and uniquely. Amongst the three constituents, the interface/interphase has a very critical role to play on the performance and reliability of FRP composites. The reduced glass transition temperature of the interphase may induce low modulus area, which subsequently affects fracture toughness and local stresses of the composite. These result in high fracture toughness at ambient temperatures, but significantly reduced performance at high temperatures. PMID- 24484897 TI - Click chemistry inspired facile synthesis and bioevaluation of novel triazolyl analogs of Ludartin. AB - A convenient and modular synthesis involving diastereoselective Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction was carried out to furnish 1,4-disubstituted-1,2,3-triazoles of Ludartin. This reaction scheme involving Michael addition followed by regioselective Huisgen 1,3-dipolar cycloaddition reaction leading to the formation of triazolyl analogs is being reported for the first time. All the triazolyl products were characterised using spectral data analysis. Sulphorhodamine B cytotoxicity screening of the resulting products against a panel of five human cancerous cell-lines revealed that few of the analogs display promising broad spectrum cytotoxic effect. Among all the synthesized compounds, only 3q displayed the best cytotoxic effect with IC50 values of 12, 11, 38, 39 and 8.5 MUM but less than the standard Ludartin (1) with IC50 values of 6.3, 7.4, 7.5, 6.9 and 0.5 MUM against human neuroblastoma (T98G), lung (A-549), prostate (PC-3), colon (HCT-116) and breast (MCF-7) cancer cell lines, respectively. The present synthesis was designed based on the previous literature reports of Ludartin as an aromatase inhibitor. Our work provides an initial study on structure-activity relationship of triazolyl analogs of sesquiterpene lactones in general and Ludartin (1) in particular. PMID- 24484898 TI - A simple and efficient dispersion correction to the Hartree-Fock theory. AB - One of the most challenging problems in computational chemistry and in drug discovery is the accurate prediction of the binding energy between a ligand and a protein receptor. It is well known that the binding energy calculated with the Hartree-Fock molecular orbital theory (HF) lacks the dispersion interaction energy that significantly affects the accuracy of the total binding energy of a large molecular system. We propose a simple and efficient dispersion energy correction to the HF theory (HF-Dtq). The performance of HF-Dtq was compared with those of several recently proposed dispersion corrected density functional theory methods (DFT-Ds) as to the binding energies of 68 small non-covalent complexes. The overall performance of HF-Dtq was found to be nearly equivalent to that of more sophisticated B3LYP-D3. HF-Dtq will thus be a useful and powerful method for accurately predicting the binding energy between a ligand and a protein, albeit it is a simple correction procedure based on HF. PMID- 24484895 TI - A bottom-up approach to understanding protein layer formation at solid-liquid interfaces. AB - A common goal across different fields (e.g. separations, biosensors, biomaterials, pharmaceuticals) is to understand how protein behavior at solid liquid interfaces is affected by environmental conditions. Temperature, pH, ionic strength, and the chemical and physical properties of the solid surface, among many factors, can control microscopic protein dynamics (e.g. adsorption, desorption, diffusion, aggregation) that contribute to macroscopic properties like time-dependent total protein surface coverage and protein structure. These relationships are typically studied through a top-down approach in which macroscopic observations are explained using analytical models that are based upon reasonable, but not universally true, simplifying assumptions about microscopic protein dynamics. Conclusions connecting microscopic dynamics to environmental factors can be heavily biased by potentially incorrect assumptions. In contrast, more complicated models avoid several of the common assumptions but require many parameters that have overlapping effects on predictions of macroscopic, average protein properties. Consequently, these models are poorly suited for the top-down approach. Because the sophistication incorporated into these models may ultimately prove essential to understanding interfacial protein behavior, this article proposes a bottom-up approach in which direct observations of microscopic protein dynamics specify parameters in complicated models, which then generate macroscopic predictions to compare with experiment. In this framework, single-molecule tracking has proven capable of making direct measurements of microscopic protein dynamics, but must be complemented by modeling to combine and extrapolate many independent microscopic observations to the macro-scale. The bottom-up approach is expected to better connect environmental factors to macroscopic protein behavior, thereby guiding rational choices that promote desirable protein behaviors. PMID- 24484899 TI - gamma-Alkylidene-gamma-lactones and isobutylpyrrol-2(5H)-ones analogues to rubrolides as inhibitors of biofilm formation by gram-positive and gram-negative bacteria. AB - Several molecules have been discovered that interfere with formation of bacterial biofilms, opening a new strategy for the development of more efficient treatments in case of antibiotic resistant bacteria. Amongst the most active compounds are some natural brominated furanones from marine algae Delisea pulchra that have proven to be able to control pathogenic biofilms. We have recently reported that some rubrolide analogues are able to inhibit biofilm formation of Enterococcus faecalis. In the present Letter we describe results of the biological evaluation of a small library of 28 compounds including brominated furanones and the corresponding lactams against biofilm formation of Staphylococcus aureus, Pseudomonas aeruginosa, Staphylococcus epidermidis and Streptococcus mutans. Our results showed that in general these compounds were more active against biofilms of S. epidermidis and P. aeruginosa, with little or no inhibition of planktonic bacterial growth. In some cases they were able to prevent biofilm formation of P. aeruginosa at concentrations as low as 0.6 MUg/mL (1.3 MUM, compound 3d) and 0.7 MUg/mL (1.3 MUM, 3f). Results also indicate that, in general, lactams are more active against biofilms than their precursors, thus designating this class of molecules as good candidates for the development of a new generation of antimicrobial drugs targeted to biofilm inhibition. PMID- 24484900 TI - The insulin secretory action of novel polycyclic guanidines: discovery through open innovation phenotypic screening, and exploration of structure-activity relationships. AB - We report the discovery of the glucose-dependent insulin secretogogue activity of a novel class of polycyclic guanidines through phenotypic screening as part of the Lilly Open Innovation Drug Discovery platform. Three compounds from the University of California, Irvine, 1-3, having the 3-arylhexahydropyrrolo[1,2 c]pyrimidin-1-amine scaffold acted as insulin secretagogues under high, but not low, glucose conditions. Exploration of the structure-activity relationship around the scaffold demonstrated the key role of the guanidine moiety, as well as the importance of two lipophilic regions, and led to the identification of 9h, which stimulated insulin secretion in isolated rat pancreatic islets in a glucose dependent manner. PMID- 24484902 TI - Mechanical ventilation and clinical practice heterogeneity in intensive care units: a multicenter case-vignette study. AB - BACKGROUND: Observational studies on mechanical ventilation (MV) show practice variations across ICUs. We sought to determine, with a case-vignette study, the heterogeneity of processes of care in ICUs focusing on mechanical ventilation procedures, and whether organizational patterns or physician characteristics influence practice variations. METHODS: We conducted a cross-sectional multicenter study using the case-vignette methodology. Descriptive analyses were calculated for each organizational pattern and respondent characteristics. An Index of Qualitative Variation (IQV, from 0, no heterogeneity, to a maximum of 1) was calculated. RESULTS: Forty ICUs from France (N = 33) and Switzerland (N = 7) participated; 396 physicians answered our case-vignettes. There was major heterogeneity of management processes related to MV within and across centers (mean IQV per center 0.51, SD 0.09). We observed the lowest variability (mean IQV per question < 0.4) for questions related to intubation procedure, ventilation of acute respiratory distress syndrome and the use of the semirecumbent position. We observed a high variability (mean IQV per question > 0.6) for questions related to management of endotracheal tube or suctioning, management of sedation and analgesia, and respect of autonomy. Heterogeneity was independent of respondent characteristics and of the presence of written procedures. There was a correlation between the processes associated with the highest variability (mean IQV per question > 0.6) and the annual volume of ICU admission (r = 0.32 (0.01 to 0.58)) and MV (r = 0.38 (0.07 to 0.63)). Within ICUs there was a large heterogeneity regarding knowledge of a local written procedure. CONCLUSIONS: Large clinical practice variations were found among ICUs. High volume centers were more likely to have heterogeneous practices. The presence of a local written procedure or respondent characteristics did not influence practice variation. PMID- 24484903 TI - Open questions: a rose is a rose is a rose--or not? PMID- 24484904 TI - Antioxidant Vitamin C attenuates experimental abdominal aortic aneurysm development in an elastase-induced rat model. AB - BACKGROUND: We investigated the hypothesis that an antioxidant, Vitamin C, could attenuate abdominal aortic aneurysm (AAA) development in a rat model. METHODS: An AAA model induced by intraluminal infusion was created in 36 male Sprague Dawley rats, which were randomly distributed into three groups: Sham (saline infused, placebo treated), Control (elastase infused, placebo treated), and Vitamin C (elastase infused, vitamin C treated). Vitamin C and placebo were intraperitoneally injected, initiating 1 wk before the infusion and continuing throughout the study. The aortic dilatation ratio was measured, and aortic tissues were further examined using biochemical and histologic techniques. RESULTS: Vitamin C attenuated the development of AAA, decreasing maximal aortic diameter by 25.8% (P < 0.05) and preserving elastin lamellae (P < 0.05). Vitamin C also decreased 8-hydroxyguanine (a marker of oxidative damage to DNA) and 8 isoprostane content (a marker of oxidative stress) in aortic tissues (P < 0.05, respectively). The proteins of matrix metalloproteinase (MMP)-2, MMP-9, and interleukin 6 were markedly downregulated (P < 0.05, respectively), accompanied with notably reduced messenger RNA expression of tumor necrosis factor-alpha, MMP 2/9, and interleukin 1beta (P < 0.05, respectively). However, messenger RNA of tissue inhibitors of metalloproteinase-1 and tissue inhibitors of metalloproteinase-2 were both significantly upregulated in Vitamin C group. Vitamin C treatment had no significant effect on systolic blood pressure (P > 0.05). CONCLUSIONS: Vitamin C attenuated AAA development in an elastase-induced rat model via crucial protective effect, which was mediated by an increased level of antioxidant in cooperation with preserving elastin lamellae, inhibiting matrix degrading proteinases and suppressing inflammatory responses. PMID- 24484905 TI - Protective effect of leflunomide against oxidative intestinal injury in a rodent model of sepsis. AB - BACKGROUND: Sepsis is defined as an uncontrolled inflammatory response in a host. The process may lead to severe sepsis, multisystem organ failure and even death. Leflunomide has important immunomodulatory and anti-inflammatory effects, which may mitigate host response to bacterial translocation. The goal of our study was to measure the effects leflunomide administration had on a variety of biochemical markers upregulated in systemic inflammatory response syndrome, sepsis, and multiple organ failure syndrome. MATERIALS AND METHODS: Wistar albino type rats were randomly divided into five groups: control, sham, leflunomide, sepsis, and sepsis + leflunomide. Sepsis was achieved by means of the cecal ligation and puncture method. Leflunomide 2 * 10 mg/kg/d was administered before the experiment. At the end of 24 h, the tissue levels of superoxide dismutase, catalase activity, malondialdehyde, nitric oxide, and protein carbonyl were measured. RESULTS: The level of the bowel superoxide dismutase and catalase levels of the sepsis group is significantly lower than those of the control, sham, and leflunomide groups (P < 0.05). Malondialdehyde, nitric oxide, and protein carbonyl levels are significantly higher in sepsis compared with other groups (P < 0.05). CONCLUSIONS: Leflunomide's prevention of protein and lipid peroxidation was observed in septic bowel tissue. Use of leflunomide could have protective effects against both the onset and the progressive stages of sepsis. PMID- 24484906 TI - Prehospital triage of trauma patients using the Random Forest computer algorithm. AB - BACKGROUND: Overtriage not only wastes resources but also displaces the patient from their community and causes delay of treatment for the more seriously injured. This study aimed to validate the Random Forest computer model (RFM) as means of better triaging trauma patients to level 1 trauma centers. METHODS: Adult trauma patients with "medium activation" presenting via helicopter to a level 1 trauma center from May 2007 to May 2009 were included. The "medium activation" trauma patient is alert and hemodynamically stable on scene but has either subnormal vital signs or accumulation of risk factors that may indicate a potentially serious injury. Variables included in the RFM analysis were demographics, mechanism of injury, prehospital fluid, medications, vitals, and disposition. Statistical analysis was performed via the Random Forest algorithm to compare our institutional triage rate to rates determined by the RFM. RESULTS: A total of 1653 patients were included in this study, of which 496 were used in the testing set of the RFM. In our testing set, 33.8% of patients brought to our level 1 trauma center could have been managed at a level 3 trauma center, and 88% of patients who required a level 1 trauma center were identified correctly. In the testing set, there was an overtriage rate of 66%, whereas using the RFM, we decreased the overtriage rate to 42% (P < 0.001). There was an undertriage rate of 8.3%. The RFM predicted patient disposition with a sensitivity of 89%, specificity of 42%, negative predictive value of 92%, and positive predictive value of 34%. CONCLUSIONS: Although prospective validation is required, it appears that computer modeling potentially could be used to guide triage decisions, allowing both more accurate triage and more efficient use of the trauma system. PMID- 24484907 TI - Possible nitric oxide modulation in the protective effects of rutin against experimental head trauma-induced cognitive deficits: behavioral, biochemical, and molecular correlates. AB - BACKGROUND: Traumatic head injury is turning out to be a major cause of disability and death. Nitric oxide (NO), an intercellular messenger plays a crucial role in the pathophysiology of several neurologic disorders. Therefore, the present study was designed to investigate the effects of rutin, a well-known flavonoid against cognitive deficits and neuroinflammation associated with traumatic head injury and the probable role of NO pathway in this effect. MATERIALS AND METHODS: Wistar rats were exposed to head trauma using weight drop method and kept for a postsurgical rehabilitation period of 2 wk. Later, animals were administered with rutin (20, 40, and 80 mg/kg; per oral) alone and in combination with NO modulators such as N(G)-nitro-L-arginine methyl ester and L arginine, daily for another 2 wk. RESULTS: Head injury caused impaired spatial navigation in Morris water maze test and poor retention in elevated plus maze task. Furthermore, there was a significant rise in acetylcholinesterase activity, oxidative stress, neuroinflammation (tumor necrosis factor alpha), and neuronal apoptosis (caspase-3) in both cortex and hippocampal regions of traumatized rat brain. Rutin significantly attenuated these behavioral, biochemical, and molecular alterations associated with head trauma. Furthermore, pretreatment of N(G)-nitro-L-arginine methyl ester (10 mg/kg, intraperitoneally), a nonspecific nitric oxide synthase inhibitor, with subeffective dose of rutin (40 mg/kg) potentiated the protective effects; however, pretreatment of L-arginine (100 mg/kg; intraperitoneally), an NO donor, reversed the effects of rutin. CONCLUSIONS: The present study suggests that NO modulation could possibly be involved in the neuroprotective effects of rutin against head trauma-induced cognitive deficits, neuroinflammation, and apoptotic signaling cascade. PMID- 24484908 TI - Curcumin inhibits the increase of labile zinc and the expression of inflammatory cytokines after traumatic spinal cord injury in rats. AB - BACKGROUND: The present study aimed to investigate the effects of curcumin on the levels of spinal cord labile zinc (Zn) and inflammatory cytokines in rats after traumatic spinal cord injury (SCI). METHODS: Adult male Sprague-Dawley rats were subjected to laminectomy at T8-T9 and compression with a vascular clip. There were three groups: (a) sham group; (b) SCI group; and (c) SCI + curcumin group. We measured spinal labile Zn by N-(6-methoxy-8-quinolinyl)-4 methylbenzenesulfonamide (TSQ) fluorescence staining, inflammatory cytokines such as interleukin 1beta, interleukin-6, and tumor necrosis factor alpha by enzyme linked immunosorbent assay, hindlimb locomotion function by Basso, Beattie, and Bresnahan rating, spinal cord edema by wet dry weight method, and apoptosis by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling analysis. RESULTS: The results showed that SCI caused a significant increase in labile Zn and inflammatory cytokines in the injured rat spinal cord. Treatment with curcumin after SCI markedly downregulated the levels of these agents and ameliorated SCI-induced hindlimb locomotion deficits, spinal cord edema, and apoptosis. CONCLUSIONS: Curcumin treatment attenuates the increase of labile Zn and the expression of inflammatory cytokines in the injured spinal cord, and this may be a mechanism whereby curcumin improves the outcome after SCI. PMID- 24484909 TI - Metformin anti-tumor effect via disruption of the MID1 translational regulator complex and AR downregulation in prostate cancer cells. AB - BACKGROUND: Metformin is an approved drug prescribed for diabetes. Its role as an anti-cancer agent has drawn significant attention because of its minimal side effects and low cost. However, its mechanism of anti-tumour action has not yet been fully clarified. METHODS: The effect on cell growth was assessed by cell counting. Western blot was used for analysis of protein levels, Boyden chamber assays for analyses of cell migration and co-immunoprecipitation (CoIP) followed by western blot, PCR or qPCR for analysis of protein-protein and protein-mRNA interactions. RESULTS: Metformin showed an anti-proliferative effect on a wide range of prostate cancer cells. It disrupted the AR translational MID1 regulator complex leading to release of the associated AR mRNA and subsequently to downregulation of AR protein in AR positive cell lines. Inhibition of AR positive and negative prostate cancer cells by metformin suggests involvement of additional targets. The inhibitory effect of metformin was mimicked by disruption of the MID1-alpha4/PP2A protein complex by siRNA knockdown of MID1 or alpha4 whereas AMPK activation was not required. CONCLUSIONS: Findings reported herein uncover a mechanism for the anti-tumor activity of metformin in prostate cancer, which is independent of its anti-diabetic effects. These data provide a rationale for the use of metformin in the treatment of hormone naive and castration resistant prostate cancer and suggest AR is an important indirect target of metformin. PMID- 24484910 TI - Biosynthesis of poly(3-hydroxybutyrate-co-3-hydroxy-4-methylvalerate) by recombinant Escherichia coli expressing leucine metabolism-related enzymes derived from Clostridium difficile. AB - An obligate anaerobic bacterium Clostridium difficile has a unique metabolic pathway to convert leucine to 4-methylvalerate, in which 4-methyl-2-pentenoyl-CoA (4M2PE-CoA) is an intermediate of this pathway. 4M2PE-CoA is also able to be converted to 3-hydroxy-4-methylvalerate (3H4MV), a branched side chain monomer unit, for synthesis of polyhydroxyalkanoate (PHA) copolymer. In this study, to synthesize 3H4MV-containing PHA copolymer from leucine, the leucine metabolism related enzymes (LdhA and HadAIBC) derived from C. difficile and PHA biosynthesis enzymes (PhaPCJAc and PhaABRe) derived from Aeromonas caviae and Ralstonia eutropha were co-expressed in the codon usage-improved Escherichia coli. Under microaerobic culture conditions, this E. coli was able to synthesize P(3HB-co 12.2 mol% 3H4MV) from glucose with the supplementation of 1 g/L leucine. This strain also produced P(3HB-co-12.6 mol% 3H4MV) using the culture supernatant of leucine overproducer E. coli strain NS1391 as the medium for PHA production, achieving 3H4MV copolymer synthesis only from glucose. Furthermore, we tested the feasibility of the 3H4MV copolymer synthesis in E. coli strain NS1391 from glucose. The recombinant E. coli NS1391 was able to synthesize P(3HB-co-3.0 mol% 3H4MV) from glucose without any leucine supplementation. This study demonstrates the potential of the new metabolic pathway for 3H4MV synthesis using leucine metabolism-related enzymes from C. difficile. PMID- 24484911 TI - Growth differentiation factor-15 is a useful prognostic marker in patients with heart failure with preserved ejection fraction. AB - BACKGROUND: Circulating growth differentiation factor 15 (GDF-15) levels correlate with heart mass and fibrosis; however, little is known about its value in predicting the prognosis of patients with heart failure with preserved ejection fraction (HFpEF). METHODS: We measured serum GDF-15 levels in 149 consecutive patients with left ventricular diastolic dysfunction (LVDD) and normal LV ejection fraction (>50%) and followed them for cardiovascular events. LVDD was defined according to the European Society of Cardiology guidelines. RESULTS: The New York Heart Association functional class and circulating B-type natriuretic peptide (BNP) levels were significantly higher in the high-GDF-15 group (n = 75; greater than or equal to the median value [3694 pg/mL]) than in the low-GDF-15 group (n = 74). Patients were divided into HFpEF and LVDD groups according to the presence or absence of HF. Serum GDF-15 levels were significantly higher in the HFpEF group (n = 73) than in the LVDD group (n = 76) (median, 4215 [interquartile range, 3382-5287] vs 3091 [interquartile range, 2487 4217 pg/mL]; P < 0.0001). Kaplan-Meier curve analysis showed a significantly higher probability of cardiovascular events in the high-GDF-15 group than in the low-GDF-15 group for data of all patients (log-rank test P = 0.006) and data of patients in the HFpEF group only (P = 0.014). Multivariate Cox hazard analysis identified age (hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.87-0.98; P = 0.008), atrial fibrillation (HR, 7.95; 95% CI, 1.98-31.85, P = 0.003), lnBNP (HR, 3.37; 95% CI, 1.73-6.55; P < 0.0001), and GDF-15 (ln[GDF-15]) (HR, 4.74; 95% CI, 1.26-17.88, P = 0.022) as independent predictors of primary end points. CONCLUSIONS: GDF-15 is a potentially useful prognostic biomarker in patients with HFpEF. PMID- 24484912 TI - Effects of the metabolic syndrome on right heart mechanics and function. AB - BACKGROUND: We sought to investigate right ventricular (RV) and right atrial (RA) deformation obtained using 3-dimensional echocardiography (3DE) and 2-dimensional (2DE) strain in subjects with the metabolic syndrome (MS). METHODS: This cross sectional study included 108 untreated subjects with the MS and 75 control subjects similar according to sex and age. The MS was defined by the presence >= 3 American Heart Association/National Heart, Lung, and Blood Institute criteria. All the subjects underwent adequate laboratory analyses and complete 2DE and 3DE examination. RESULTS: 2DE global longitudinal strain of the RV was significantly decreased in the MS group compared with the control subjects (-24 +/- 5 vs -27 +/ 5%; P < 0.001). Similar results were obtained for the RA longitudinal strain (40 +/- 5 vs 44 +/- 7%; P < 0.001). Systolic and early diastolic RV and RA strain rates were decreased, whereas late diastolic strain rates were increased among the MS participants compared with the control subjects. 3DE RV ejection fraction was significantly decreased in the MS subjects (55 +/- 4 vs 58 +/- 4%; P < 0.001). The multivariate analysis of MS criteria showed that systolic blood pressure, waist circumference, and fasting glucose were independently associated with RV and/or RA myocardial function and deformation. CONCLUSIONS: RV mechanics and RA mechanics, assessed using 3DE and 2DE strain, were significantly deteriorated in the MS subjects. Among all MS risk factors, systolic blood pressure, abdominal circumference, and fasting glucose were the most responsible for the right heart remodelling. PMID- 24484913 TI - QRS widening rates and genetic polymorphisms of matrix metalloproteinases in a cohort of patients with chronic heart failure. AB - BACKGROUND: QRS duration is considered to be an indicator of adverse outcome in patients with heart failure (HF), and genetic polymorphisms may be involved in this conductivity impairment. We studied the prognostic impact of the QRS widening rate (QRS-WR) on patients with HF and the influence of the matrix metalloproteinases gene polymorphisms on the QRS-WR. METHODS: This prospective cohort study included 184 patients with left ventricular (LV) systolic dysfunction (LV ejection fraction [LVEF] < 45%). The QRS-WR was calculated as the difference between 2 electrocardiogram assessments (in ms) divided by the time elapsed between each evaluation (months). The MMP-1 -1607 1G/2G, MMP-2 -790G/T and -1575G/A, MMP-3 -1171 5A/6A, MMP-9 -1562 C/T and R279Q, and MMP-12 -82A/G polymorphisms were genotyped using polymerase chain reaction-restriction fragment length polymorphism. RESULTS: Patients were predominantly white (68%) men (67%) in New York Heart Association functional classes I and II (77%). Patients with HF with a QRS-WR >= 0.5 ms/month had more HF-related deaths and more combined clinical events than those with a QRS-WR < 0.5 ms/month (P = 0.03 and P = 0.01, respectively). After adjusting for other covariates, the QRS-WR remained an independent predictor of combined clinical events (hazard ratio, 1.6; 95% confidence interval, 1.1-2.5; P = 0.02). The MMP-1 2G2G genotype was associated with nearly a 2-fold increase in QRS-WR (P = 0.03). Conversely, patients with the MMP-3 5A5A genotype and a nonischemic cause of HF were protected against QRS enlargement (P = 0.03). CONCLUSIONS: QRS-WR retains prognostic value in patients with chronic HF receiving guideline-based pharmacologic treatment. MMP gene polymorphisms can influence the rate of QRS enlargement over time. PMID- 24484914 TI - An approach to the rational use of revascularization in heart failure patients. AB - The most common cause of heart failure with reduced ejection fraction (HFrEF) is coronary artery disease. A multitude of factors come into play when deciding whether a patient with HFrEF and coronary artery disease should have coronary artery bypass graft (CABG) surgery, percutaneous coronary intervention, or medical therapy alone. For candidates for percutaneous coronary intervention and CABG, evidence from large registries would suggest that patients with 2-vessel coronary artery diseases and proximal left anterior descending disease and all patients with 3-vessel coronary artery disease do better with CABG. For patients that are candidates for medical therapy with or without CABG, the results of the Surgical Treatment for Ischemic Heart Failure (STICH) trial indicate that with CABG, the reduction of mortality is not statistically significant (hazard ratio [HR], 0.86; P = 0.12). However, CABG is superior in reducing cardiovascular deaths (HR, 0.81; P = 0.05), and the combination of cardiovascular deaths and cardiovascular hospitalizations (HR, 0.74; P < 0.001). Patients undergoing CABG have an upfront risk that is eliminated by 2 years and thereafter do better. The assessment of cardiac viability or reversible ischemia does not appear to be helpful in determining which individuals will improve more with CABG. Patients with severe mitral regurgitation who undergo CABG appear to benefit from simultaneous valve repair but not from the addition of surgical ventricular reconstruction of the left ventricle, although in specific patients this might be considered. The totality of evidence would thus suggest that patients with HFrEF should be evaluated for the possibility of coronary revascularization if they are candidates for CABG. PMID- 24484915 TI - Congenital absence of nitric oxide synthase 3 potentiates cardiac dysfunction and reduces survival in doxorubicin- and trastuzumab-mediated cardiomyopathy. AB - BACKGROUND: Doxorubicin (DOX) and trastuzumab (TRZ) are highly effective chemotherapeutic agents in the breast cancer setting, limited by their cardiotoxic side effects. Among the potential mechanisms for this drug-induced cardiomyopathy, increased production of oxidative stress (OS) through a nitric oxide synthase 3 (NOS3)-dependent pathway has gained recent attention. The objective of the study was to determine the role of NOS3 and OS in a clinically relevant female murine model of DOX- and TRZ-induced heart failure. METHODS: A total of 120 female mice (60 wild-type [WT] and 60 NOS3 knockout [NOS3(-/-)]) were treated with either 0.9% saline, DOX, TRZ, or DOX with TRZ (DOX+TRZ). Serial echocardiography was performed for a total of 10 days, after which the mice were euthanized for histological and biochemical analyses. RESULTS: In WT female mice receiving DOX+TRZ, left ventricular ejection fraction (LVEF) decreased from 75 +/ 3% at baseline to 46 +/- 2% at day 10 (P < 0.05). In the NOS3(-/-) group, LVEF decreased from 72 +/- 3% at baseline to 35 +/- 2% at day 10 (P < 0.05). LVEF was significantly lower in NOS3(-/-) female mice receiving DOX+TRZ than WT mice at day 10 (P < 0.05). Compared with WT, NOS3(-/-) female mice also demonstrated increased mortality after treatment with DOX+TRZ, corroborating the echocardiographic findings. Histological analysis demonstrated increased myofibrillar degradation and loss of cell integrity in NOS3(-/-) female mice treated with DOX+TRZ. There was increased generation of oxidized phosphatidylcholine, a marker of OS, in NOS3(-/-) female mice receiving DOX+TRZ compared with control mice. CONCLUSIONS: Congenital absence of NOS3 potentiates the cardiotoxic side effects of DOX+TRZ in an acute female murine model of chemotherapy-induced cardiomyopathy. PMID- 24484916 TI - Reversed Z-plasty and its variations to release wide-scar contraction. AB - BACKGROUND AND AIM: Z-plasty is one of the most widely used techniques in plastic and reconstructive surgery. It is useful especially to release linear-scar contractures, yet difficult to use for wide scars. The aim of this study was to report on a new technique for the effective release of contractures for wide scars using reversed Z-plasty and its variations. METHODS: This report describes a novel technique to release contractures effectively for wide scars using reversed Z-plasty and its variation. The design is a reverse style of conventional Z-plasty. In our case series, the reversed three-flap, four-flap Z plasty or its variation was chosen depending on the width of the contracted scar. RESULTS: We performed this technique on 28 patients. All wounds healed well and the scar contracture was satisfactorily released. CONCLUSION: This procedure is useful and practical for wide-scar contractures. PMID- 24484917 TI - Data model, dictionaries, and desiderata for biomolecular simulation data indexing and sharing. AB - BACKGROUND: Few environments have been developed or deployed to widely share biomolecular simulation data or to enable collaborative networks to facilitate data exploration and reuse. As the amount and complexity of data generated by these simulations is dramatically increasing and the methods are being more widely applied, the need for new tools to manage and share this data has become obvious. In this paper we present the results of a process aimed at assessing the needs of the community for data representation standards to guide the implementation of future repositories for biomolecular simulations. RESULTS: We introduce a list of common data elements, inspired by previous work, and updated according to feedback from the community collected through a survey and personal interviews. These data elements integrate the concepts for multiple types of computational methods, including quantum chemistry and molecular dynamics. The identified core data elements were organized into a logical model to guide the design of new databases and application programming interfaces. Finally a set of dictionaries was implemented to be used via SQL queries or locally via a Java API built upon the Apache Lucene text-search engine. CONCLUSIONS: The model and its associated dictionaries provide a simple yet rich representation of the concepts related to biomolecular simulations, which should guide future developments of repositories and more complex terminologies and ontologies. The model still remains extensible through the decomposition of virtual experiments into tasks and parameter sets, and via the use of extended attributes. The benefits of a common logical model for biomolecular simulations was illustrated through various use cases, including data storage, indexing, and presentation. All the models and dictionaries introduced in this paper are available for download at http://ibiomes.chpc.utah.edu/mediawiki/index.php/Downloads. PMID- 24484918 TI - The epidemiology of acute and critical illness in older adults. AB - The world and US population continues to increase with an extended lifespan. Disability rates in older adults have not changed, however; they are living longer with disabilities that affect quality of life and complicate acute and critical illness. Because increasing numbers of older adults will live with disabilities and chronic disease, new strategies are needed to improve both quality of life and end-of-life decision making. PMID- 24484919 TI - The impact of aging physiology in critical care. AB - Aging physiology greatly impacts care delivery in the geriatric patient population. Consideration should be given to addressing the patient-specific needs regarding the systemic changes seen in the aging patient. Each major body system presents its own unique challenges to the critical care practitioner, and a comprehensive understanding of these changes is necessary to effectively care for this patient population. This article summarizes these changes and provides key points for the practitioner to consider when caring for the aging patient in the critical care arena. PMID- 24484920 TI - Focused assessment in the care of the older adult. AB - This article presents an overview of the focused subjective and objective assessment of the older adult for the critical care nurse. Discussion includes the distinguishing features inherent to older adults, and relevant evidence-based screening tools that the nurse can use in assessing the critically ill older adult. PMID- 24484921 TI - Ethnogeriatrics in critical care. AB - This article discusses the increased diversity of older adults expected to be treated in intensive care units over the next 10 years. The importance of the integration of an ethnogeriatric assessment to include ethnicity, level of acculturation, religion/spirituality, preferred interaction pattern, facilitation of communication, and physical examination constraints due to ethnicity are discussed. PMID- 24484922 TI - Nutrition and hydration in older adults in critical care. AB - Nutrition and hydration are vital components of critical care nursing. However, meeting the nutrition and hydration needs of the critically ill older adult is often complex, because of preexisting risk factors (malnutrition, unintentional weight loss, frailty, and dehydration); as well as intensive care unit-related challenges (catabolism, eating and feeding, end-of-life care). This article highlights the challenges of managing nutrition and hydration in the critically ill older adult, reviews assessment principles, and offers strategies for optimizing nutrition and hydration. PMID- 24484923 TI - Infection, sepsis, and immune function in the older adult receiving critical care. AB - The elderly are vulnerable to developing sepsis due to functional and immune changes, and frequent instrumentation and contact with the health care system. Those infected often present with nonspecific complaints and are at risk for underrecognition and undertreatment, with greater likelihood of rapid progression to severe sepsis and septic shock; however, often respond well to early, organized, and aggressive interventions. Survivors may not return to baseline level of function and may require long-term care facilities after discharge from the hospital. Patient and family preferences for goals of care should be explored as early as possible and incorporated into treatment plans. PMID- 24484924 TI - Cardiovascular issues in older adults. AB - This article discusses selected cardiovascular conditions that nurses encounter when caring for elders hospitalized in the intensive care unit. Physiologic changes that predispose elders to these conditions, typical signs and symptoms, common diagnostic tests, and evidence-based treatment for this population are included. The implications for nursing care of critically ill elders who have these conditions are also discussed. PMID- 24484925 TI - Pulmonary issues in the older adult. AB - This article elicits why critical care nurses need to become aware of the pulmonary issues of older adults. The population of older adults is increasing. Older adults undergo anatomic and physiologic changes of the protective mechanisms of the pulmonary system. These changes alter the rate and effort of breathing. Speech is slowed because of expiratory strength effort. Cognition changes may be the only indication of impaired oxygenation. Bedside nursing care provides protection from pulmonary complications. Health behaviors of smoking cessation, oral hygiene, and exercise promote pulmonary health even in older adults. PMID- 24484926 TI - Renal issues in older adults in critical care. AB - Renal issues are among the most commonly encountered complications in the intensive care unit, increasing mortality, morbidity, and health care costs. Older adult patients face an increased risk because of several factors, including the normal effects of aging and a higher rate of comorbid conditions that may affect kidney function. This article describes the classification of renal dysfunction, the effects of aging on kidney function, as well as additional risk factors, management strategies, and outcomes in the older adult population. PMID- 24484927 TI - Aging muscles and joints: mobilization. AB - Critical illness can impose immobility in older patients, resulting in loss of strength and functional ability. Many factors contribute to immobility, including patients' medical conditions, medical devices and equipment, nutrition, use of restraint, and staff priorities. Early mobilization reduces the impact of immobility and improves outcomes for older patients. Several important components make up successful mobility programs, including good patient assessment, a core set of interventions, and use of the interprofessional health care team. Nurses can lead in improving the mobilization of older critical care patients, thus reducing clinical risk in this vulnerable population. PMID- 24484928 TI - Psychiatric disorders impacting critical illness. AB - An astounding 30% to 50% of older patients who are hospitalized for a medical condition also have a psychiatric disorder. The intent of this article is to prepare acute care nurses to meet the mental health needs of older adults with a critical illness and prevent untoward sequelae of medical events. The authors discuss the importance of baseline assessment data, issues related to informed consent, manifestations of common psychiatric disorders that may be seen in older adults in the acute care setting, as well as strategies to improve patient outcomes. PMID- 24484929 TI - Delirium in the elderly adult in critical care. AB - Several neurologic conditions are commonly seen with elderly adults in the critical care area. This article addresses a common neurologic condition commonly seen in elderly adults: delirium. PMID- 24484930 TI - Oncologic issues in the older adult in critical care. AB - This article describes the pathophysiologic changes that occur with aging as they relate to cancer and cytotoxic therapies, implications related to drug therapy, and complications of treatment modalities as they relate to older persons with cancer who may potentially be admitted to the intensive care unit. Knowledge of these issues is essential for health care providers, so that they can face the complex challenges and optimize the outcomes of critically ill older persons with cancer. PMID- 24484931 TI - Nursing practice of palliative care with critically ill older adults. AB - Palliative care is emerging as an alternative care paradigm for critically ill older patients in the critical care setting. Critical care nurses are well positioned to take on a leadership role in reconceptualizing care in the critical care unit, and creating the space and opportunity for palliative care. This article provides information on the practice of palliative care with critically ill older adults along with evidence-based content and resources, allowing critical care nurses to advocate for palliative care in their own work environments accompanied by the necessary resources that will support efficient implementation. PMID- 24484932 TI - Caring for older adults in critical care. PMID- 24484933 TI - Factors associated with the utilisation of postnatal care services among the mothers of Nepal: analysis of Nepal demographic and health survey 2011. AB - BACKGROUND: Postnatal care is essential to save the life of the mother and newborn. Knowledge on the determinants of postnatal care assists the policy makers to design, justify and implement appropriate interventions. The current study aimed to analyse the factors associated with utilisation of postnatal care services by mothers in Nepal based on the data from Nepal Demographic and Health Survey (NDHS) 2011. METHODS: This study utilised the data from NDHS 2011. The association between utilisation of at least one postnatal care visit (within 6 weeks of delivery) and immediate postnatal care (within 24 hours of delivery) with selected factors was examined by using Chi-square test (chi(2)), followed by multiple logistic regression. RESULT: Of the 4079 mothers, 43.2% reported attending postnatal care within the first six weeks of birth, while 40.9% reported attending immediate postnatal care. Mothers who were from urban areas, from rich families, who were educated, whose partners were educated, who delivered in a health facility, who had attended a four or more antenatal visits, and whose delivery was attended by a skilled attendant were more likely to report attending at least one postnatal care visit. On the other hand, mothers who reported agricultural occupation, and whose partners performed agricultural occupation were less likely to have attended at least one postnatal care visit. Similarly, mothers who were from the urban areas, from rich families, who were educated, whose partners were educated, who had attended four or more antenatal visits, who delivered in a health facility and had delivered in the presence of a skilled birth attendant were more likely to report attending immediate postnatal care. Mothers who reported agricultural occupation, and whose partners performed agricultural occupation were less likely to attend immediate postnatal care. CONCLUSION: The majority of postnatal mothers in Nepal did not seek postnatal care. Increasing utilisation of the recommended four or more antenatal visits, delivery at health facility and increasing awareness and access to services through community-based programs especially for the rural, poor, and less educated mothers may increase postnatal care attendance in Nepal. PMID- 24484934 TI - DNA damage response in adult stem cells. AB - This review discusses the processes of DNA-damage-response and DNA-damage repair in stem and progenitor cells of several tissues. The long life-span of stem cells suggests that they may respond differently to DNA damage than their downstream progeny and, indeed, studies have begun to elucidate the unique stem cell response mechanisms to DNA damage. Because the DNA damage responses in stem cells and progenitor cells are distinctly different, stem and progenitor cells should be considered as two different entities from this point of view. Hematopoietic and mammary stem cells display a unique DNA-damage response, which involves active inhibition of apoptosis, entry into the cell-cycle, symmetric division, partial DNA repair and maintenance of self-renewal. Each of these biological events depends on the up-regulation of the cell-cycle inhibitor p21. Moreover, inhibition of apoptosis and symmetric stem cell division are the consequence of the down-regulation of the tumor suppressor p53, as a direct result of p21 up regulation. A deeper understanding of these processes is required before these findings can be translated into human anti-aging and anti-cancer therapies. One needs to clarify and dissect the pathways that control p21 regulation in normal and cancer stem cells and define (a) how p21 blocks p53 functions in stem cells and (b) how p21 promotes DNA repair in stem cells. Is this effect dependent on p21s ability to inhibit p53? Such molecular knowledge may pave the way to methods for maintaining short-term tissue reconstitution while retaining long-term cellular and genomic integrity. PMID- 24484935 TI - The role of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in the primary staging of rectal cancer. AB - BACKGROUND: In this study we aimed to determine the need for 18F flourodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in the preoperative staging of rectal carcinoma in our large patient group according to level and location of tumor. METHOD: Totally, 97 patients diagnosed with primary rectal adenocarcinoma between May 2009 and July 2011 were included in the study. Preoperative staging was performed by evaluating contrast enhanced thoracic, abdominal, and pelvic computed tomographies. After staging by conventional methods, all patients underwent an 18F-FDG PET/CT. In all cases, the relationship between 18F-FDG uptake and gender, tumor height at the anal canal, localization in the rectal wall, plasma carcinoembryonic antigen levels, histopathological tumor type, and tumor stage were examined. RESULTS: While the ceCT was normal in 4 (4%) patients, it was positive for the rectum in 93 (95%), pelvic lymph nodes in 22 (22%), and distant metastases in 14 (14%) (liver (8), lung (8), bone (2), distant lymph nodes (6), and uterus (1)). Using computed tomography, disease stages were determined as stage 0, 1, 2, 3, and 4 in 4, 8, 48, 23, and 14 patients, respectively; 18F-FDG PET/CT was normal in two (2%) patients. The mean SUVmax of FDG-positive rectal tumors was calculated as 17.31 +/- 9.37. Additionally, 18F-FDG uptake was seen in pelvic lymph nodes in 15 (15%) patients and in distant organs in 24 (24%) patients (liver (9), lung (12), bone (5), distant lymph nodes (11), uterus (1), and sigmoid colon (1)). According to an 18F-FDG PET/CT, 2, 7, 47, 20, and 21 patients were staged as stage 0, 1, 2, 3, and 4, respectively. In 14 patients (14.4%), the stage of the disease was either changed, and there was a need to make adjustments to the patient's treatment strategy (n = 10), or the type of operation was changed (n = 4). In seven patients (0.7%), findings from 18F-FDG PET/CT images did not require any changes of the treatment plan. CONCLUSION: F-FDG PET/CT provides new findings in addition to conventional techniques in the staging of primary rectal cancer. These findings could change the patients' treatment strategies. PMID- 24484936 TI - Sequential Cdk1 and Plk1 phosphorylation of caspase-8 triggers apoptotic cell death during mitosis. AB - Caspase-8 is crucial for cell death induction, especially via the death receptor pathway. The dysregulated expression or function of caspase-8 can promote tumor formation, progression and treatment resistance in different human cancers. Here, we show procaspase-8 is regulated during the cell cycle through the concerted inhibitory action of Cdk1/cyclin B1 and polo-like kinase 1 (Plk1). By phosphorylating S387 in procaspase-8 Cdk1/cyclin B1 generates a phospho-epitope for the binding of the PBD of Plk1. Subsequently, S305 in procaspase-8 is phosphorylated by Plk1 during mitosis. Using an RNAi-based strategy we could demonstrate that the extrinsic cell death is increased upon Fas-stimulation when endogenous caspase-8 is replaced by a mutant (S305A) mimicking the non phosphorylated form. Together, our data show that sequential phosphorylation by Cdk1/cyclin B1 and Plk1 decreases the sensitivity of cells toward stimuli of the extrinsic pathway during mitosis. Thus, the clinical Plk1 inhibitor BI 2536 decreases the threshold of different cancer cell types toward Fas-induced cell death. PMID- 24484938 TI - Antioxidants in food: content, measurement, significance, action, cautions, caveats, and research needs. AB - There are a multitude of antioxidants in foods, especially in foods of plant origin. Higher intake of antioxidant-rich foods is clearly associated with better health and functional longevity. The specific agents and mechanisms responsible are not yet clear, but there is convincing evidence that including more plant based, antioxidant-rich foods, herbs, and beverages in the diet is effective in promoting health and lowering risk of various age-related diseases. The content of some individual antioxidants, such as vitamin C, in food can be measured, but it is not feasible to attempt to measure each antioxidant separately, and methods have been developed to assess the "total antioxidant content" of foods. One of the most widely used methods is the ferric reducing/antioxidant power (FRAP) assay, which is relatively simple, quick, sensitive, and inexpensive to perform. There are many published studies that have used the FRAP assay, and these have generated a very large database of total antioxidant content of foods that can help guide food choices for increased antioxidant intake. The FRAP assay has also been used to assess the bioavailability of antioxidants in foods and to investigate the effects of growing conditions, storage, processing, and cooking method on the total antioxidant content of food. The test can be employed as a quality control check device, and to detect adulteration of food. Furthermore, in a modified form (FRASC), the assay can measure ascorbic acid content almost simultaneously with the total antioxidant content of the sample. In this chapter, basic concepts of oxidation and the role of antioxidants, as well as the types and action of different antioxidants in foods will be reviewed briefly, and the underpinning concepts and evidence for health benefits of increased intake of dietary antioxidants will be discussed, with some focus on vitamin C, and also in the context of our evolutionary development. The basic concepts and limitations of measuring "total antioxidant content" of food will be presented. The FRAP assay and the modified version FRASC will be described, and the total antioxidant content (as the FRAP value) of a range of foods will be presented. Finally, issues of bioavailability and redox balance will be discussed in relation to the biological significance and molecular action of antioxidants in foods, some caution and caveats are presented about overcoming biological barriers to absorption of antioxidant phytochemicals, and research needs to further our understanding in the important area of food, antioxidants, and health will be highlighted. PMID- 24484939 TI - Micronutrient status in type 2 diabetes: a review. AB - Type 2 diabetes is characterized by significant losses of important micronutrients due to metabolic basis of the disease and its complications. Evidence of changes in trace mineral and vitamin metabolism as a consequence of type 2 diabetes is reviewed in this chapter. This review is not a meta-analysis but an overview of the micronutrient status, metabolic needs, and potential micronutrient requirements in type 2 diabetics. This chapter will not concentrate on vitamin D and type 2 diabetes as this is a topic that has been extensively reviewed before. The less well-known micronutrients notably zinc, magnesium, chromium, copper, manganese, iron, selenium, vanadium, B-group vitamins, and certain antioxidants are assessed. While some evidence is available to demonstrate the positive influence of micronutrient supplementation on glycemic control, much remains to be investigated. Additional research is necessary to characterize better biomarkers of micronutrient status and requirements in type 2 diabetics. The optimal level of micronutrient supplementation to achieve glucose homeostasis in type 2 diabetics remains a challenge. PMID- 24484937 TI - miR181b is induced by the chemopreventive polyphenol curcumin and inhibits breast cancer metastasis via down-regulation of the inflammatory cytokines CXCL1 and -2. AB - Chronic inflammation is a major risk factor for the development and metastatic progression of cancer. We have previously reported that the chemopreventive polyphenol Curcumin inhibits the expression of the proinflammatory cytokines CXCL1 and -2 leading to diminished formation of breast and prostate cancer metastases. In the present study, we have analyzed the effects of Curcumin on miRNA expression and its correlation to the anti-tumorigenic properties of this natural occurring polyphenol. Using microarray miRNA expression analyses, we show here that Curcumin modulates the expression of a series of miRNAs, including miR181b, in metastatic breast cancer cells. Interestingly, we found that miR181b down-modulates CXCL1 and -2 through a direct binding to their 3'-UTR. Overexpression or inhibition of miR181b in metastatic breast cancer cells has a significant impact on CXCL1 and -2 and is required for the effect of Curcumin on these two cytokines. miR181b also mediates the effects of Curcumin on inhibition of proliferation and invasion as well as induction of apoptosis. Importantly, over-expression of miR181b in metastatic breast cancer cells inhibits metastasis formation in vivo in immunodeficient mice. Finally, we demonstrated that Curcumin up-regulates miR181b and down-regulates CXCL1 and -2 in cells isolated from several primary human breast cancers. Taken together, these data show that Curcumin provides a simple bridge to bring metastamir modulation into the clinic, placing it in a primary and tertiary preventive, as well as a therapeutic, setting. PMID- 24484940 TI - Sarcopenia and nutrition. AB - Preserving or restoring adequate nutritional status is a key factor to delay the onset of chronic diseases and to accelerate recovery from acute illnesses. In particular, consistent and robust data show the loss of muscle mass, that is, sarcopenia, is clinically relevant since it is closely related to increased morbidity and mortality in healthy individuals and patients. Sarcopenia is defined as the age-related loss of muscle mass and function. International study groups have recently proposed separate definitions and diagnostic criteria for sarcopenia. Unfortunately, the rate of agreement in assessing the prevalence of sarcopenia is just fair, which highlights the need for a common effort to harmonize definitions and diagnostic criteria. Sarcopenia should be distinct from myopenia, which is the disease-associated loss of muscle mass, although in clinical practice it may be impossible to separate them (i.e., in old cancer patients). The pathogenesis of sarcopenia is complex and multifactorial. Consequently, its treatment should target the different factors involved, including quantitatively and qualitatively inappropriate food intake and reduced physical activity. PMID- 24484941 TI - Current evidence on dietary pattern and cognitive function. AB - With global aging population, age-related cognitive decline becomes epidemic. Lifestyle-related factor is one of the key preventative measures. Dietary pattern analysis which considers dietary complexity has recently used to examine the linkage between nutrition and cognitive function. A priori approach defines dietary pattern based on existing knowledge. Results of several dietary pattern scores were summarized. The heterogeneity of assessment methods and outcome measurements lead to inconsistent results. Posteriori approach derives a dietary pattern independently of the existing nutrition-disease knowledge. It showed a dietary pattern abundant with plant-based food, oily fish, lower consumption of processed food, saturated fat, and simple sugar which appears to be beneficial to cognitive health. Despite inconclusive evidence from both approaches, diet and exercise, beneficial for other diseases, remains to be the two key modifiable factors for cognitive function. Large-scale prospective studies in multiethics population are required to provide stronger evidence in the future. PMID- 24484943 TI - Radiotherapy induced xerostomia: mechanisms, diagnostics, prevention and treatment--evidence based up to 2013. AB - Definition and prevalence of xerostomia were shortly presented. Radiosensitivity of the salivary glands, mechanism, diagnostics, and possible prediction methods of the intensity of xerostomia in the pre-radiotherapy period are widely discussed. Prevention of xerostomia: salivary gland sparing radiotherapy, cytoprotective agents, preservation by stimulation with cholinergic muscarinic agonists, surgical transfer of submandibular glands according to ASCO Management Guidelines and Quality of Life Recommendations were cited. Oral Care Study Group (2010) therapeutic approaches for relieving xerostomia are referred. Current therapies, restricted to symptom relief such as oral hygiene with fluoride agents, antimicrobials to prevent dental caries, saliva substitutes to relieve symptoms, and sialogenic agents to stimulate saliva were also discussed. PMID- 24484944 TI - The role of balloon sinuplasty in the treatment of sinus headache. AB - INTRODUCTION: Headache attributed to rhinosinusitis, commonly called sinus headache (SH), is probably one of the most prevalent secondary headaches. The purpose of our study was to examine further sinus headache comparing the effect of conventional functional endoscopic sinus surgery and the balloon sinuplasty. MATERIAL AND METHODS: Eighty-three consecutive patients were enrolled from 2009 to 2012, who were diagnosed sinus headache according the diagnostic criteria of AAO-HNS and of HIS. 40 patients were randomized to Conventional Endoscopy Sinus Surgery for frontal sinus (ESS Group), 35 to balloon sinuplasty of frontal sinus (BS Group). RESULTS: The mean operative time was 65 +/- 15 min for ESS group patients and 32 +/- 7 min for 23 patients (BS1 Group) and 55 +/- 18 min for 12 treated with hybrid technique (BS2 Group). The preoperative mean of SNOT-22 scores improved from 28.6 +/- 1.2 in ESS group and 27.3 +/- 0.8 in BS group to a 1-month postoperative scores of 14.5 +/- 0.6 in ESS group and 10.3 +/- 0.5 in BS group and to a 6-month postoperative scores of 7.8 +/- 0.6 and 5.3 +/- 0.3, respectively (p<0.0001). The headache scores base on analog visual scale improved from a preoperative mean of 6.5 +/- 0.3 in ESS group and 7.1 +/- 0.4 in Bs group to a 1-month postoperative scores of 5.4 +/- 0.4 in ESS group and 5.5 +/- 0.4 in BS group and to a 6-month postoperative scores of 2.7 +/- 0.5 and 1.2 +/- 0.1, respectively, representing a statistically significant reduction in headache score in both group. CONCLUSION: Our data prove that improvement in headache can be expected in patients treated with balloon catheter. PMID- 24484945 TI - The activity of N-acetyl-beta-d-hexosaminidase A and B and beta-glucuronidase in nasal polyps and hypertrophic nasal concha. AB - Nasal polyps and hypertrophic lower nasal conchae are common disorders of nasal cavity. The majority of etiopathogenetic theories indicate inflammatory background of polyps and hypertrophic concha. N-acetyl-beta-D-hexosaminidase and beta-glucuronidase are lysosomal exoglycosidases revealing accelerated activity in inflammatory processes. AIM: The aim of the study was to evaluate the catabolism of glycoconjugates in nasal polyps and hypertrophic nasal concha basing on the activity of N-acetyl-beta-D-hexosaminidase (HEX) and beta glucuronidase (GLU). MATERIAL AND METHODS: Material consisted of nasal polyps taken from 40 patients during polypectomy in patients with chronic rhinosinusitis with nasal polyps (CRSwNP) and hypertrophic lower nasal conchae taken from 20 patients during mucotomy. The activity of HEX, HEX A, HEX B and GLU in supernatant of homogenates of nasal polyps and hypertrophic lower nasal concha tissues has been estimated using colorimetric method. RESULTS: Statistically significant decrease has been observed in concentration of the activity (per 1mg of tissue) of HEX (p<0.05), HEX B (p<0.001) and specific activity (per 1mg of protein) of HEX B (p<0.001) in nasal polyps tissue in comparison to hypertrophic lower nasal conchae tissue. CONCLUSIONS: Decrease in the activity and specific activity concentration of the majority of examined lysosomal exoglycosidases (increasing in inflammations) in comparison to hypertrophic lower nasal conchae suggests electrolytes disorders and questions the inflammatory background of nasal polyps. PMID- 24484946 TI - [The assessment of hearing impairment in patients over 60 years of age using hearing aids]. AB - OBJECTIVE: To assess the hearing impairment in people over 60 years old using hearing aids. This was a single-center study, but it is planned to extend it further to the whole country. MATERIALS AND METHODS: The study was focused on patients with hearing aids. During the assessment 57 people were included in the observation in order to control the status of their hearing loss and benefit from traditional hearing aids as well as the possibility to apply the auditory implants in case of a little benefit from hearing aids. The otoscopy and pure tone audiometry were performed as well as the questionnaires on demographic and epidemiological data of patients were collected as well as the quality of their life with hearing aids was subjectively assessed. RESULTS: The results show that 91% of patients have sensorineural hearing loss (SHL), the remaining 9%--severe mixed hearing loss. Severe SHL was found in 22 patients, the moderate hearing loss was observed in 37%, and the profound SHL was the case in 5 patients. Minimal SHL was observed in 7% of patients (n=4). More than 73% of the study subjects were male (n=38). The average age of the patients who completed the survey was 74 years old. Thirty-five patients used their hearing aid over 3 years and less than 70% of them used it every day all day. Hearing aid was not actively used by 10 patients. Over the last year 51.92% of the patients underwent a hearing examination. CONCLUSIONS: The bone anchored hearing aid was suggested to 2% of subjects and the cochlear implant was offered to 10 patients. The data analysis shows the need to educate and inform the elderly about alternative methods of hearing loss treatment. PMID- 24484947 TI - [The results of myringoplasty using underlay technique]. AB - INTRODUCTION: The method of tympanic membrane repairing is called myringoplasty. AIM OF THE STUDY: We analysed the reasons of failure of this procedure. MATERIAL AND METHODS: The structural results were observed among 36 patients under restricted criteria with diagnosed chronic otitis media. The unsuccessful procedure was one with reperforation. We studied Eustachian tube function and also localisation and size of the perforation. RESULTS: The failure rate was 25%, which was mainly observed among individuals with incorrect Eustachian tube function - 70% and margin perforations - 50%. The localisation and the size of the perforation did not matter. CONCLUSIONS: The main reasons of myringoplasty failure were incorrect Eustachian tube function and margin perforations of tympanic membrane. PMID- 24484948 TI - [The usefulness of evaluation of: ferritin, ultrasensitive CRP and tissue specific polypeptide 18th (TPS) in assessment of therapy efficacy in patients with nasal polyps]. AB - BACKGROUND: Chronic rhinosinusitis with nasal polyps is social, clinical and cost effective problem, by reason of bothersome symptoms, chronic nature of the disease, tendency to recur and lack of satisfying treatment. AIM: The aim of this study is assessment of suitability of hsCRP, ferritin and blood levels in nasal polyps patients in evaluation of treatment efficacy. METHODS: The study enrolled 38 patients between 20 and 68 years of age. Patients were divided into 2 groups. Levels of ultrasensitive CRP ferritin and TPS have been measured in all patients. The ultrasensitive CRP levels have been measured by chemiluminescence method. Ferritin levels have been measured by MEIA method. The TPS levels have been measured by chemiluminescence method. RESULTS: Comparison of mean ferritin levels in both study groups in each stage of observation shows the significant difference of mean values in only 6 weeks after surgery. Mean ferritin level is significantly lower in group I than in group II (p<0.05). Mean hsCRP levels vary from one corresponding to ferritin levels. Statistically significant difference between study groups in 2nd and 6th week after surgery has been ascertained (p<0.05). Similarly, like in ferritin levels, the TPS levels are significantly different in 6th week after surgery. CONCLUSIONS: Analysis of ferritin, hsCRP and TPS serum levels indicates that these may be useful in assessment of treatment efficacy in patients with nasal polyps. Rise of the chosen inflammatory state parameter level in the postoperative monitoring and anti-inflammatory treatment introduction in nasal polyps patients may inhibit the recurrence of the disease. PMID- 24484949 TI - Leiomyosarcoma of the external ear--case report. AB - In head and neck region leiomyosarcoma is a very rare finding. This tumor is usually located in abdominal cavity. We report a case of 78-year-old man with tumor of the auricle that was resected with 0.7 cm margin. Histological and immunohistochemical analysis revealed the leiomyosarcoma. Adjuvant therapy was not advised. During 3 years of follow-up there are no signs of recurrence. Review of the literature shows that the survival of patients with leiomyosarcoma in head and neck region seems to be similar to other kinds of sarcomas in this localization. It is not clear, how large surgical margins should be to achieve satisfactory local control. PMID- 24484950 TI - Intralaryngeal ectopic thyroid. AB - Lingual thyroid is the most common presentation of ectopic thyroid tissue. In contrast, to that laryngeal location is extremely rare. We report a case of 59 years old woman with a history of progressive dyspnea and nodular thyroid goiter. Endoscopic examination revealed subglottic smooth tumor of the right side of the larynx. CT scans revealed mass localized in infraglottic part of the larynx, causing infraglottic stenosis. The biopsy of the tumor revealed: Struma nodosa. Reviewing the literature we found only seven cases described. We present development of the thyroid gland and origins causing ectopy. PMID- 24484951 TI - Mycorrhizal symbiosis effects on growth of chalk false-brome (Brachypodium pinnatum) are dependent on the environmental light regime. AB - AMF (arbuscular mycorrhizal fungi) colonization of the grass chalk false-brome (Brachypodium pinnatum (L.) P. B.) was studied in selected habitats under spatially different light regimes: (a) shade condition under oak trees, (b) half shade in a shrubby area and (c) full-sun conditions on unshaded grassland. This study assessed the variations in AMF colonization of the grass dependent on the light supply in field habitats. Soil, root and shoot samples were collected four times during the vegetation period (in June, July, September and October). Root colonization, root and shoot biomass as well as soil water content were determined. The highest rate of AMF colonization was detected in June under half sun and full-sun conditions, where about 50% of the roots were colonized. The average amount of arbuscules was less than 20% in the roots at the three sites, with the highest number of arbuscules in June, under half-sun and full-sun conditions, however, not under the trees. Overall, best mycorrhizal colonization occurred during summer, and its rate decreased in autumn. This tendency inversely correlated with the amount of precipitation, and thus with the water content of soils. The high colonization rate of the examined root samples, and also its seasonal fluctuation, might reflect the importance of the symbiosis where inorganic nutrients and water are the growth-limiting factors. The marginal AMF colonization of chalk false-brome under shade conditions indicates that plants do not use AMF under all stress conditions. When low light limits photosynthesis and thus growth of the plants, they dispense with the colonization of AMF in order to save the expenditure of organic carbon. PMID- 24484952 TI - Light and nitrogen nutrition regulate apical control in Rosa hybrida L. AB - Apical control is defined as the inhibition of basal axillary bud outgrowth by an upper actively growing axillary axis, whose regulation is poorly understood yet differs markedly from the better-known apical dominance. We studied the regulation of apical control by environmental factors in decapitated Rosa hybrida in order to remove the apical hormonal influence and nutrient sink. In this plant model, all the buds along the main axis have a similar morphology and are able to burst in vitro. We concentrated on the involvement of light intensity and nitrate nutrition on bud break and axillary bud elongation in the primary axis pruned above the fifth leaf of each rose bush. We observed that apical control took place in low light (92 MUmol m(-2)s(-1)), where only the 2-apical buds grew out, both in low (0.25 mM) and high (12.25 mM) nitrate. In contrast, in high light (453 MUmol m(-2)s(-1)), the apical control only operates in low nitrate while all the buds along the stem grew out when the plant was supplied with a high level of nitrate. We found a decreasing photosynthetic activity from the top to the base of the plant concomitant with a light gradient along the stem. The quantity of sucrose, fructose, glucose and starch are higher in high light conditions in leaves and stem. The expression of the sucrose transporter RhSUC2 was higher in internodes and buds in this lighting condition, suggesting an increased capacity for sucrose transport. We propose that light intensity and nitrogen availability both contribute to the establishment of apical control. PMID- 24484953 TI - GIP1 may act as a coactivator that enhances transcriptional activity of LBD18 in Arabidopsis. AB - The LATERAL ORGAN BOUNDARIES DOMAIN/ASYMMETRIC LEAVES2-LIKE (LBD/ASL) gene family encodes a class of transcription factors harboring a conserved plant-specific lateral organ boundaries domain and plays a key role in lateral organ development of plants. Recent studies have revealed developmental functions of some LBD genes in Arabidopsis, rice, and maize. We have shown previously that LBD18/ASL20 promotes the emergence of lateral roots in Arabidopsis. LBD18 induces EXPANSIN14 (EXP14) expression by binding to a specific region of the EXP14 promoter. To further understand the molecular mechanism of LBD18 acting as a transcription factor, we isolated a protein interacting with LBD18 by screening an Arabidopsis cDNA library using the yeast two-hybrid system with LBD18 as bait. We found that GBF INTERACTING PROTEIN1 (GIP1) interacts with LBD18 in yeast and Arabidopsis protoplasts. Reverse-transcription-polymerase chain reaction analysis showed overlapping expression of GIP1 and LBD18 in various tissues of Arabidopsis such as roots, aerial parts, and rosette leaves. Transient gene expression assay results with Arabidopsis protoplasts indicated that GIP1 enhances transcriptional activity of LBD18 in the EXP14 promoter fused to the GUS reporter gene. These results show that GIP1 may act as a transcriptional coactivator of LBD18. PMID- 24484954 TI - Phosphoenolpyruvate carboxylase, NADP-malic enzyme, and pyruvate, phosphate dikinase are involved in the acclimation of Nicotiana tabacum L. to drought stress. AB - Drought stress is one of the most frequent forms of abiotic stresses, which occurs under condition of limited water availability. In this work, the possible participation of phosphoenolpyruvate carboxylase (EC 4.1.1.31; PEPC), NADP-malic enzyme (EC 1.1.1.40; NADP-ME), and pyruvate, phosphate dikinase (EC 2.7.9.1; PPDK) in response to drought of tobacco plants (Nicotiana tabacum L., cv. W38) was investigated. Enzyme specific activities in tobacco leaves of drought stressed plants were significantly increased after 11 days of stress, PEPC 2.3 fold, NADP-ME 3.9-fold, and PPDK 2.7-fold compared to control plants. The regulation of PEPC and NADP-ME activities were studied on transcriptional level by the quantitative RT PCR and on translational level - immunochemically. The amount of NADP-ME protein and transcription of mRNA for chloroplastic NADP-ME isoform were increased indicating their enhanced synthesis de novo. On the other hand, mRNA for cytosolic isoform of NADP-ME was decreased. The changes in PEPC protein and PEPC mRNA were not substantial. Therefore regulation of PEPC activity by phosphorylation was evaluated and found to be involved in the stress response. During recovery, activities of the tested enzymes returned close to their basal levels. PMID- 24484955 TI - Mitogen-activated protein kinase 6 controls root growth in Arabidopsis by modulating Ca2+ -based Na+ flux in root cell under salt stress. AB - Little is known about the role of mitogen-activated protein kinase 6 (MPK6) in Na(+) toxicity and inhibition of root growth in Arabidopsis under NaCl stress. In this study, we found that root elongation in seedlings of the loss-of-function mutants mpk6-2 and mpk6-3 was less sensitive to NaCl or Na-glutamate, but not to KCl or mannitol, as compared with that of wild-type (WT) seedlings. The less sensitive characteristic was eliminated by adding the Ca(2+) chelator EGTA or the Ca(2+) channel inhibitor LaCl3, but not the Ca(2+) ionophore A23187. This suggested that the tolerance of mpk6 to Na(+) toxicity was Ca(2+)-dependent. We measured plasma membrane (PM) Na(+)-conducted currents (NCCs) in root cells. Increased concentrations of NaCl increased the inward NCCs while decreased the outward NCCs in WT root cells, attended by a positive shift in membrane potential. In mpk6 root cells, NaCl significantly increased outward but not inward NCCs, accompanied by a negative shift in membrane potential. That is, mpk6 decreased NaCl-induced the Na(+) accumulation by modifying PM Na(+) flux in root cells. Observations of aequorin luminescence revealed a NaCl-induced increase of cytosolic Ca(2+) in mpk6 root cells, resulting from PM Ca(2+) influx. An increase of cytosolic Ca(2+) was required to alleviate the NaCl-increased Na(+) content and Na(+)/K(+) ratio in mpk6 roots. Together, these results show that mpk6 accumulated less Na(+) in response to NaCl because of the increased cytosolic Ca(2+) level in root cells; thus, its root elongation was less inhibited than that of WT by NaCl. PMID- 24484956 TI - How do background ozone concentrations affect the biosynthesis of rosmarinic acid in Melissa officinalis? AB - Lemon balm (Melissa officinalis; Lamiaceae) plants were exposed to background ozone (O3) dosages (80ppb for 5h), because high background levels of O3 are considered to be as harmful as episodic O3 peaks. Immediately at the end of fumigation the plants appeared visually symptomless, but necrotic lesions were observed later. The biosynthesis of rosmarinic acid (RA) comprises eight enzymes, among them phenylalanine ammonia-lyase (PAL), 4-coumarate:coenzyme A ligase (4CL), tyrosine aminotransferase (TAT) and rosmarinic acid synthase (RAS). The transcript levels of these genes have been investigated by quantitative RT-PCR. There was a quick up-regulation of all genes at 3h of O3 exposure, but at 24h from beginning of exposure (FBE) only RAS and PAL were up-regulated. The specific activity of RAS was closely correlated with a decrease of RA concentration in lemon balm leaves. The specific activity of PAL increased at 12h FBE to 163% in comparison to control levels. This work provides insight into the effect of O3 stress on the formation of the main phenolic ingredient of the pharmaceutically important plant M. officinalis. PMID- 24484957 TI - The inter-monomer interface of the major light-harvesting chlorophyll a/b complexes of photosystem II (LHCII) influences the chlorophyll triplet distribution. AB - Under strong light conditions, long-lived chlorophyll triplets ((3)Chls) are formed, which can sensitize singlet oxygen, a species harmful to the photosynthetic apparatus of plants. Plants have developed multiple photoprotective mechanisms to quench (3)Chl and scavenge singlet oxygen in order to sustain the photosynthetic activities. The lumenal loop of light-harvesting chlorophyll a/b complex of photosystem II (LHCII) plays important roles in regulating the pigment conformation and energy dissipation. In this study, site directed mutagenesis analysis was applied to investigate triplet-triplet energy transfer and quenching of (3)Chl in LHCII. We mutated the amino acid at site 123 located in this region to Gly, Pro, Gln, Thr and Tyr, respectively, and recorded fluorescence excitation spectra, triplet-minus-singlet (TmS) spectra and kinetics of carotenoid triplet decay for wild type and all the mutants. A red-shift was evident in the TmS spectra of the mutants S123T and S123P, and all of the mutants except S123Y showed a decrease in the triplet energy transfer efficiency. We propose, on the basis of the available structural information, that these phenomena are related to the involvement, due to conformational changes in the lumenal region, of a long-wavelength lutein (Lut2) involved in quenching (3)Chl. PMID- 24484958 TI - Root phosphoenolpyruvate carboxylase and NAD-malic enzymes activity increase the ammonium-assimilating capacity in tomato. AB - Plant ammonium tolerance has been associated with the capacity to accumulate large amounts of ammonium in the root vacuoles, to maintain carbohydrate synthesis and especially with the capacity of maintaining high levels of inorganic nitrogen assimilation in the roots. The tricarboxylic acid cycle (TCA) is considered a cornerstone in nitrogen metabolism, since it provides carbon skeletons for nitrogen assimilation. The hypothesis of this work was that the induction of anaplerotic routes of phosphoenolpyruvate carboxylase (PEPC), malate dehydrogenase (MDH) and malic enzyme (NAD-ME) would enhance tolerance to ammonium nutrition. An experiment was established with tomato plants (Agora Hybrid F1) grown under different ammonium concentrations. Growth parameters, metabolite contents and enzymatic activities related to nitrogen and carbon metabolism were determined. Unlike other tomato cultivars, tomato Agora Hybrid F1 proved to be tolerant to ammonium nutrition. Ammonium was assimilated as a biochemical detoxification mechanism, thus leading to the accumulation of Gln and Asn as free amino acids in both leaves and roots as an innocuous and transitory store of nitrogen, in addition to protein synthesis. When the concentration of ammonium in the nutrient solution was high, the cyclic operation of the TCA cycle seemed to be interrupted and would operate in two interconnected branches to provide alpha ketoglutarate for ammonium assimilation: one branch supported by malate accumulation and by the induction of anaplerotic PEPC and NAD-ME in roots and MDH in leaves, and the other branch supported by stored citrate in the precedent dark period. PMID- 24484959 TI - Intrinsic water use efficiency controls the adaptation to high salinity in a semi arid adapted plant, henna (Lawsonia inermis L.). AB - Adaptation to salinity of a semi-arid inhabitant plant, henna, is studied. The salt tolerance mechanisms are evaluated in the belief that gas exchange (water vapor and CO2) should play a key role on its adaptation to salt stress because of the strong evaporation conditions and soil water deficit in its natural area of distribution. We grow henna plants hydroponically under controlled climate conditions and expose them to control (0mM NaCl), and two levels of salinity; medium (75mM NaCl) and high (150mM NaCl). Relative growth rate (RGR), biomass production, whole plant and leaf structure and ultrastructure adaptation, gas exchange, chlorophyll fluorescence, nutrients location in leaf tissue and its balance in the plant are studied. RGR and total biomass decreased as NaCl concentration increased in the nutrient solution. At 75mM NaCl root biomass was not affected by salinity and RGR reached similar values to control plants at the end of the experiment. At this salinity level henna plant responded to salinity decreasing shoot to root ratio, increasing leaf specific mass (LSM) and intrinsic water use efficiency (iWUE), and accumulating high concentrations of Na(+) and Cl(-) in leaves and root. At 150mM NaCl growth was severely reduced but plants reached the reproductive phase. At this salinity level, no further decrease in shoot to root ratio or increase in LSM was observed, but plants increased iWUE, maintaining water status and leaf and root Na(+) and Cl(-) concentrations were lower than expected. Moreover, plants at 150mM NaCl reallocated carbon to the root at the expense of the shoot. The effective PSII quantum yield [Y(II)] and the quantum yield of non-regulated energy dissipation [Y(NO)] were recovered over time of exposure to salinity. Overall, iWUE seems to be determinant in the adaptation of henna plant to high salinity level, when morphological adaptation fails. PMID- 24484960 TI - The phenolic content and its involvement in the graft incompatibility process of various pear rootstocks (Pyrus communis L.). AB - This study investigates the influence of various rootstocks for pear on the phytochemical composition in the phloem above and below the graft union and the role of phenols in pear graft incompatibility. Assays of phloem with cambium from 4-year-old 'Conference', 'Abate Fetel' and 'Williams' pear trees grafted on different rootstocks: Quince MA, Quince BA 29, Fox 11, Farold 40 (Daygon), seedling Pyrus communis L. and own rooted (P. communis L.) were analyzed with HPLC-MS. The most abundant phenolic compound in phloem above and below the graft union was arbutin, followed by procyanidin B1 and chlorogenic acid. In 'Conference' and 'Abate Fetel', higher arbutin content levels were measured above the graft union, while in the incompatible scion of 'Williams' on quince MA higher arbutin content levels were measured below the graft union. In all three observed cultivars (in 'Conference' the difference was not significant) grafted on Fox 11 rootstock, the highest content of arbutin was measured below the graft union. The results indicate that not only catechin and procyanidin B1, but also arbutin and several flavonols could be involved in graft incompatibility. All cultivars grafted on quince rootstocks had higher levels of epicatechin and procyanidin B2 below the graft union, even though some differences were not significant. It seems that those phenols do not affect pear incompatibility. A severe incompatibility between Fox 11 rootstock and 'Williams' was detected. PMID- 24484961 TI - Selenium alleviates cadmium toxicity by preventing oxidative stress in sunflower (Helianthus annuus) seedlings. AB - The present study investigated the possible mediatory role of selenium (Se) in protecting plants from cadmium (Cd) toxicity. The exposure of sunflower seedlings to 20MUM Cd inhibited biomass production, decreased chlorophyll and carotenoid concentrations and strongly increased accumulation of Cd in both roots and shoots. Similarly, Cd enhanced hydrogen peroxides content and lipid peroxidation as indicated by malondialdehyde accumulation. Pre-soaking seeds with Se (5, 10 and 20MUM) alleviated the negative effect of Cd on growth and led to a decrease in oxidative injuries caused by Cd. Furthermore, Se enhanced the activities of catalase, ascorbate peroxidase and glutathione reductase, but lowered that of superoxide dismutase and guaiacol peroxidase. As important antioxidants, ascorbate and glutathione contents in sunflower leaves exposed to Cd were significantly decreased by Se treatment. The data suggest that the beneficial effect of Se during an earlier growth period could be related to avoidance of cumulative damage upon exposure to Cd, thus reducing the negative consequences of oxidative stress caused by heavy metal toxicity. PMID- 24484962 TI - The circadian clock gene regulatory module enantioselectively mediates imazethapyr-induced early flowering in Arabidopsis thaliana. AB - Plant growth and development are strongly affected by environmental pollutants, such as herbicides. Widely used herbicides can remain in soil or aquatic systems for long periods of time. Herbicide pollutants have been reported to heavily affect global plant growth and pose a significant challenge to agriculture. However, it is unclear whether herbicides affect plant flowering. Here, we demonstrated that imazethapyr (IM), a chiral herbicide, can enantioselectively promote flowering in Arabidopsis thaliana. We clarified the possible mechanism by which IM promotes flowering and found that the photoperiod pathway may play an important role in propagating the IM stress signal. IM enantiomers decreased the amplitude of core oscillators (CIRCADIAN CLOCK ASSOCIATED 1 and LATE ELONGATED HYPOCOTYL) and utilized the up-regulation of the GIGANTEA-(CONSTANS)-FLOWERING LOCUS T pathway to induce floral gene, APETALA1 over-expression enantioselectively; this treatment ultimately caused early flowering. Our findings provide new insight into the method by which plants control reproductive timing in response to herbicide stress. Flowering time is an important trait in crops and affects the life cycles of pollinator species. The persistence of herbicides in the biosphere will alter plant life cycles and diversity. PMID- 24484963 TI - Modification of catalase and MAPK in Vicia faba cultivated in soil with high natural radioactivity and treated with a static magnetic field. AB - The effects of a static magnetic field (SMF) and high natural radioactivity (HR) on catalase and MAPK genes in Vicia faba were investigated. Soil samples with high natural radioactivity were collected from Ramsar in north Iran where the annual radiation absorbed dose from background radiation is higher than 20mSv/year. The specific activity of the radionuclides of (232)Th, (236)Ra, and (40)K was measured using gamma spectrometry. The seeds were planted either in the soil with high natural radioactivity or in the control soils and were then exposed to a SMF of 30mT for 8 days; 8h/day. Levels of expression of catalase and MAPK genes, catalase activity and H2O2 content were evaluated. The results demonstrated significant differences in the expression of catalase and MAPK genes in SMF- and HR-treated plants compared to the controls. An increase in catalase activity was accompanied by increased expression of its gene and accumulation of H2O2. Relative expression of the MAPK gene in treated plants, however, was lower than those of the controls. The results suggest that the response of V. faba plants to SMF and HR may be mediated by modification of catalase and MAPK. PMID- 24484964 TI - Glutamine synthetase I-deficiency in Mesorhizobium loti differentially affects nodule development and activity in Lotus japonicus. AB - In this study, we focused on the effect of glutamine synthetase (GSI) activity in Mesorhizobium loti on the symbiosis between the host plant, Lotus japonicus, and the bacteroids. We used a signature-tagged mutant of M. loti (STM30) with a transposon inserted into the GSI (mll0343) gene. The L. japonicus plants inoculated with STM30 had significantly more nodules, and the occurrence of senesced nodules was much higher than in plants inoculated with the wild-type. The acetylene reduction activity (ARA) per nodule inoculated with STM30 was lowered compared to the control. Also, the concentration of chlorophyll, glutamine, and asparagine in leaves of STM30-infected plants was found to be reduced. Taken together, these data demonstrate that a GSI deficiency in M. loti differentially affects legume-rhizobia symbiosis by modifying nodule development and metabolic processes. PMID- 24484966 TI - Three strains of Wolbachia pipientis and high rates of infection in Iranian sandfly species. AB - Individual wild-caught sandflies from Iran were examined for infections of Wolbachia pipientis by targeting the major surface protein gene wsp of this intracellular alpha-proteobacterium. In total, 638 male and female sandflies were screened, of which 241 were found to be positive for one of three wsp haplotypes. Regardless of geographical origins and habitats, Phlebotomus (Phlebotomus) papatasi and other sandfly species were found to be infected with one common, widespread strain of A-group W. pipientis (Turk 54, GenBank accession EU780683; AY288297). In addition, a new A-group haplotype (Turk07, GenBank accession KC576916) was isolated from Phlebotomus (Paraphlebotomus) mongolensis and Phlebotomus (Pa.) caucasicus, and a new B-group haplotype (AZ2331, GenBank accession JX488735) was isolated from Phlebotomus (Larroussius) perfiliewi. Therefore, Wolbachia was found to occur in at least three of the incriminated vectors of zoonotic cutaneous leishmaniasis and zoonotic visceral leishmaniasis in different geographical regions of Iran. It may provide a new tool for the future control of leishmaniasis. PMID- 24484965 TI - Exploring necrotizing autoimmune myopathies with a novel immunoassay for anti-3 hydroxy-3-methyl-glutaryl-CoA reductase autoantibodies. AB - INTRODUCTION: Necrotizing autoimmune myopathies (NAM) have recently been defined as a distinct group of severe acquired myopathies, characterized by prominent myofiber necrosis without significant muscle inflammation. Because of the lack of appropriate biomarkers, these diseases have been long misdiagnosed as atypical forms of myositis. NAM may be associated to autoantibodies directed against signal recognition particle (SRP) or 3-hydroxy-3-methyl-glutaryl-CoA reductase (HMGCR). The objective of this work was to quantify anti-HMGCR autoantibodies in patients with suspicion of NAM through the development of a new addressable laser bead immunoassay (ALBIA). METHODS: Recombinant HMGCR C-domain was bound to fluorescent beads. After incubation with serum, autoantibodies were revealed using class- or subclass-specific anti-human immunoglobulin G (IgG) antibodies. Anti-HMGCR levels were assayed in 150 patients with suspicion of NAM, 142 controls with different inflammatory/autoimmune diseases and 100 healthy donors. Inhibition with free recombinant HMGCR and immunoprecipitation experiments confirmed test specificity. Reproducibility and repeatability were determined from sera with various levels of anti-HMGCR autoantibodies. A multiplex assay (ALBIA-NAM) was also developed to permit the simultaneous quantification of anti HMGCR and anti-signal recognition particle autoantibodies. RESULTS: No controls scored positive. Of 150 patients with suspicion of NAM, 24% were positive for anti-HMGCR autoantibodies with levels ranging from 24 to 2,656 AU/mL. Anti-HMGCR positivity could be associated to a cytoplasmic pattern in immunofluorescence assay on HEp-2 cells. Anti-HMGCR-positive patients had high creatine kinase (CK) levels (mean 6,630 IU/L) and only 40% of them had been exposed to statins. Multiplex ALBIA-NAM was equally as effective as monoplex anti-HMGCR and anti-SRP ALBIA. CONCLUSIONS: Both monoplex ALBIA-HMGCR and multiplex ALBIA-NAM reliably detect and quantify anti-HMGCR autoantibodies. A positive result allows ascribing patients with a necrotizing myopathy to an autoimmune form. Anti-HMGCR autoantibodies may be found in patients who have not taken statins. PMID- 24484967 TI - The Central-European SentiMag study: sentinel lymph node biopsy with superparamagnetic iron oxide (SPIO) vs. radioisotope. AB - Sentinel lymph node biopsy (SLNB) is the standard surgical procedure for the axilla in early node-negative breast cancer. To date, the "gold standard" to localize the sentinel lymph node (SLN) is the radiotracer (99m)Tc with or without blue dye. The aim of this study was to evaluate potential equivalency of the new SentiMag((r)) technique in comparison to the "gold standard". Within this prospective, multicentric and multinational non-inferiority study including 150 patients (99m)Tc was compared with the magnetic technique, using superparamagnetic iron oxide particles (SPIOs, Sienna+((r))) for localization of SLNs. The results showed a detection rate per patient of 97.3% (146/150) for (99m)Tc vs. 98.0% (147/150) for Sienna+((r)) with a similar average number of removed SLNs per patient and a higher per patient malignancy detection rate for the SPIO tracer. We obtained convincing results that magnetic SLNB can be performed easily, safely and equivalently well in comparison to the radiotracer method. PMID- 24484968 TI - Cancer, metabolism, fructose, artificial sweeteners, and going cold turkey on sugar. PMID- 24484969 TI - Correction: Dispelling myths about rare disease registry system development. PMID- 24484970 TI - Dedifferentiated gastrointestinal stromal tumor arising de novo from the small intestine. AB - Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract and usually display monotonous cytologic features and immunoactivity for CD117. Anaplastic GIST, with pleomorphic cells and loss of CD117, until recently have only been reported in patients with chronic imatinib mesylate treatment. Dedifferentiated GISTs arising de novo is a newly identified entity that may prove to be difficult to diagnose. We present the case of a 52 year-old female found to have a dedifferentiated GIST without prior imatinib mesylate therapy. This case is the first reported dedifferentiated GIST arising de novo from the small bowel, and at 30cm in greatest diameter, the largest reported to date. Additionally, we demonstrate for the first time the loss of DOG1 in the anaplastic component of the tumor. De novo dedifferentiated GIST is a rare and diagnostically challenging tumor that may be mischaracterized unless considered in the differential diagnosis. PMID- 24484971 TI - Impermeable dust mite covers in the primary and tertiary prevention of allergic disease: a meta-analysis. AB - BACKGROUND: Up to 40% of the world's population has been diagnosed with an allergic disease. The most prevalent allergy is to house dust mites. Impermeable mattress covers are often the first treatment in the prevention and decrease of symptoms of allergic disease. OBJECTIVE: To perform a meta-analysis evaluating the effectiveness of impermeable mattress covers in the primary prevention of allergic disease and as a single intervention in the tertiary prevention of allergic disease symptoms. METHODS: MEDLINE, Embase, Web of Science, and CINAHL were systematically searched for relevant publications. Seven primary prevention trials (n = 3,461) and 17 tertiary prevention trials (n = 1,671) met the inclusion criteria and were included in the review. All article reviews and abstractions were performed in duplicate. RESULTS: No significant pooled relative risks were found for the prevention of allergic disease. The pooled relative risks were 0.97 (95% confidence interval [CI] 0.62-1.51) for house dust mite sensitization, 0.92 (95% CI 0.81-1.05) for wheeze, 0.85 (95% CI 0.70-1.02) for asthma, 1.03 (95% CI 0.90-1.19) for allergic rhinitis, and 1.05 (95% CI 0.84 1.32) for allergic dermatitis. Likewise, no significant pooled standardized mean differences were found in the tertiary prevention of symptoms. The pooled standardized mean differences were -0.03 (95% CI -0.15 to 0.09) for peak flow, 0.06 (95% CI -0.32 to 0.20) for asthma symptom score, and -0.39 (95% CI -0.88 to 0.11) for nasal symptom score. A significant effect was seen in the decrease of house mite dust level in the mattress (-0.79, 95% CI -0.98 to -0.60). CONCLUSION: No evidence was found to support the use of impermeable mattress covers in the primary prevention of allergic disease or in the tertiary prevention of allergic disease symptoms. PMID- 24484972 TI - Current update on cellular and molecular mechanisms of hereditary angioedema. AB - OBJECTIVE: To provide an update on the molecular mechanisms of hereditary angioedema (HAE). DATA SOURCES: MEDLINE and PubMed databases were searched to identify pertinent articles using the following key terms: hereditary angioedema, angioedema, C1 inhibitor, bradykinin, contact system, factor XII, mechanism, pathophysiology, severity, permeability, and estrogen. STUDY SELECTIONS: Articles were selected based on their relevance to the subject matter. RESULTS: Although the biochemical basis of "classic" HAE is known to result from C1 esterase inhibitor (C1INH) deficiency, a new form, HAE with normal C1INH, has been identified. HAE types I and II are caused by mutations in the SERPING1 gene that result in decreased plasma levels of functional C1INH. In HAE with normal C1INH, mutations in the F12 gene have been identified in a subset of individuals, but the genetic defect remains unknown in most patients. The primary mediator of swelling in HAE is bradykinin, a product of the plasma contact system that increases vascular permeability. HAE disease severity is highly variable and may be influenced by polymorphisms in other genes and other factors, such as hormones, trauma, stress, and infection. CONCLUSION: Hereditary angioedema is a heterogeneous disorder with a complex pathophysiology. Implicated genes include SERPING1 and FXII in patients with HAE from C1INH deficiency and HAE with normal C1INH levels, respectively. Disease severity is highly variable. PMID- 24484973 TI - Primary vision and facial emotion recognition in early Parkinson's disease. AB - BACKGROUND: In early stages of idiopathic Parkinson's disease (IPD), lower order vision (LOV) deficits including reduced colour and contrast discrimination have been consistently reported. Data are less conclusive concerning higher order vision (HOV) deficits, especially for facial emotion recognition (FER). However, a link between both visual levels has been hypothesized. OBJECTIVE: To screen for both levels of visual impairment in early IPD. METHODS: We prospectively recruited 28 IPD patients with disease duration of 1.4+/-0.8 years and 25 healthy controls. LOV was evaluated by Farnsworth-Munsell 100 Hue Test, Vis-Tech and Pelli-Robson test. HOV was examined by the Ekman 60 Faces Test and part A of the Visual Object and Space recognition test. RESULTS: IPD patients performed worse than controls on almost all LOV tests. The most prominent difference was seen for contrast perception at the lowest spatial frequency (p=0.0002). Concerning FER IPD patients showed reduced recognition of "sadness" (p=0.01). "Fear" perception was correlated with perception of low contrast sensitivity in IPD patients within the lowest performance quartile. Controls showed a much stronger link between "fear" perception" and low contrast detection. CONCLUSION: At the early IPD stage there are marked deficits of LOV performances, while HOV performances are still intact, with the exception of reduced recognition of "sadness". At this stage, IPD patients seem still to compensate the deficient input of low contrast sensitivity, known to be pivotal for appreciation of negative facial emotions and confirmed as such for healthy controls in this study. PMID- 24484975 TI - The vesicular monoamine transporter-2: an important pharmacological target for the discovery of novel therapeutics to treat methamphetamine abuse. AB - Methamphetamine abuse escalates, but no approved therapeutics are available to treat addicted individuals. Methamphetamine increases extracellular dopamine in reward-relevant pathways by interacting at vesicular monoamine transporter-2 (VMAT2) to inhibit dopamine uptake and promote dopamine release from synaptic vesicles, increasing cytosolic dopamine available for reverse transport by the dopamine transporter (DAT). VMAT2 is the target of our iterative drug discovery efforts to identify pharmacotherapeutics for methamphetamine addiction. Lobeline, the major alkaloid in Lobelia inflata, potently inhibited VMAT2, methamphetamine evoked striatal dopamine release, and methamphetamine self-administration in rats but exhibited high affinity for nicotinic acetylcholine receptors (nAChRs). Defunctionalized, unsaturated lobeline analog, meso-transdiene (MTD), exhibited lobeline-like in vitro pharmacology, lacked nAChR affinity, but exhibited high affinity for DAT, suggesting potential abuse liability. The 2,4-dicholorophenyl MTD analog, UKMH-106, exhibited selectivity for VMAT2 over DAT, inhibited methamphetamine-evoked dopamine release, but required a difficult synthetic approach. Lobelane, a saturated, defunctionalized lobeline analog, inhibited the neurochemical and behavioral effects of methamphetamine; tolerance developed to the lobelane-induced decrease in methamphetamine self-administration. Improved drug-likeness was afforded by the incorporation of a chiral N-1,2-dihydroxypropyl moiety into lobelane to afford GZ-793A, which inhibited the neurochemical and behavioral effects of methamphetamine, without tolerance. From a series of 2,5 disubstituted pyrrolidine analogs, AV-2-192 emerged as a lead, exhibiting high affinity for VMAT2 and inhibiting methamphetamine-evoked dopamine release. Current results support the hypothesis that potent, selective VMAT2 inhibitors provide the requisite preclinical behavioral profile for evaluation as pharmacotherapeutics for methamphetamine abuse and emphasize selectivity for VMAT2 relative to DAT as a criterion for reducing abuse liability of the therapeutic. PMID- 24484976 TI - Customizing monoclonal antibodies for the treatment of methamphetamine abuse: current and future applications. AB - Monoclonal antibody-based medications designed to bind (+)-methamphetamine (METH) with high affinity are among the newest approaches to the treatment of METH abuse and the associated medical complications. The potential clinical indications for these medications include treatment of overdose, reduction of drug dependence, and protection of vulnerable populations from METH-related complications. Research designed to discover and conduct preclinical and clinical testing of these antibodies suggests a scientific vision for how intact monoclonal antibody (mAb) (singular and plural) or small antigen-binding fragments of mAb could be engineered to optimize the proteins for specific therapeutic applications. In this review, we discuss keys to success in this development process including choosing predictors of specificity, efficacy, duration of action, and safety of the medications in disease models of acute and chronic drug abuse. We consider important aspects of METH-like hapten design and how hapten structural features influence specificity and affinity, with an example of a high-resolution X-ray crystal structure of a high-affinity antibody to demonstrate this structural relationship. Additionally, several prototype anti-METH mAb forms such as antigen binding fragments and single-chain variable fragments are under development. Unique, customizable aspects of these fragments are presented with specific possible clinical indications. Finally, we discuss clinical trial progress of the first in kind anti-METH mAb, for which METH is the disease target instead of vulnerable central nervous system networks of receptors, binding sites, and neuronal connections. PMID- 24484978 TI - Bupropion and bupropion analogs as treatments for CNS disorders. AB - Bupropion, introduced as an antidepressant in the 1980s, is also effective as a smoking cessation aid and is beneficial in the treatment of methamphetamine addiction, cocaine dependence, addictive behaviors such as pathological gambling, and attention deficit hyperactivity disorder. (2S,3S)-hydroxybupropion is an active metabolite of bupropion produced in humans that contributes to antidepressant and smoking cessation efficacy and perhaps benefits in other CNS disorders. Mechanisms underlying its antidepressant and smoking abstinence remain elusive. However, it seems likely that efficacy is due to a combination of the effects of bupropion and/or its active metabolite (2S,3S)-hydroxybupropion involving the inhibition of reuptake of dopamine (DA) and NE in reward centers of the brain and the noncompetitive antagonism of alpha4beta2- and alpha3beta4* nAChRs. These combined effects of bupropion and its active metabolite may be responsible for its ability to decrease nicotine reward and withdrawal. Studies directed toward development of a bupropion analog for treatment of cocaine addiction led to compounds, typified by 2-(N-cyclopropylamino)-3' chloropropiophenone (RTI-6037-39), thought to act as indirect DA agonists. In addition, (2S,3S)-hydroxybupropion analogs were developed, which had varying degrees of DA and NE uptake inhibition and antagonism of nAChRs. These compounds will be valuable tools for animal behavioral studies and as clinical candidates. Here, we review the (1) early studies leading to the development of bupropion, (2) bupropion metabolism and the identification of (2S,3R)-hydroxybupropion as an active metabolite, (3) mechanisms of bupropion and metabolite action, (4) effects in animal behavioral studies, (5) results of clinical studies, and (6) development of bupropion analogs as potential pharmacotherapies for treating nicotine and cocaine addiction. PMID- 24484974 TI - Glial modulators as potential treatments of psychostimulant abuse. AB - Glia (including astrocytes, microglia, and oligodendrocytes), which constitute the majority of cells in the brain, have many of the same receptors as neurons, secrete neurotransmitters and neurotrophic and neuroinflammatory factors, control clearance of neurotransmitters from synaptic clefts, and are intimately involved in synaptic plasticity. Despite their prevalence and spectrum of functions, appreciation of their potential general importance has been elusive since their identification in the mid-1800s, and only relatively recently have they been gaining their due respect. This development of appreciation has been nurtured by the growing awareness that drugs of abuse, including the psychostimulants, affect glial activity, and glial activity, in turn, has been found to modulate the effects of the psychostimulants. This developing awareness has begun to illuminate novel pharmacotherapeutic targets for treating psychostimulant abuse, for which targeting more conventional neuronal targets has not yet resulted in a single, approved medication. In this chapter, we discuss the molecular pharmacology, physiology, and functional relationships that the glia have especially in the light in which they present themselves as targets for pharmacotherapeutics intended to treat psychostimulant abuse disorders. We then review a cross section of preclinical studies that have manipulated glial processes whose behavioral effects have been supportive of considering the glia as drug targets for psychostimulant-abuse medications. We then close with comments regarding the current clinical evaluation of relevant compounds for treating psychostimulant abuse, as well as the likelihood of future prospects. PMID- 24484977 TI - Monoamine transporter inhibitors and substrates as treatments for stimulant abuse. AB - The acute and chronic effects of abused psychostimulants on monoamine transporters and associated neurobiology have encouraged development of candidate medications that target these transporters. Monoamine transporters, in general, and dopamine transporters, in particular, are critical molecular targets that mediate abuse-related effects of psychostimulants such as cocaine and amphetamine. Moreover, chronic administration of psychostimulants can cause enduring changes in neurobiology reflected in dysregulation of monoamine neurochemistry and behavior. The current review will evaluate evidence for the efficacy of monoamine transporter inhibitors and substrates to reduce abuse related effects of stimulants in preclinical assays of stimulant self administration, drug discrimination, and reinstatement. In considering deployment of monoamine transport inhibitors and substrates as agonist-type medications to treat stimulant abuse, the safety and abuse liability of the medications are an obvious concern, and this will also be addressed. Future directions in drug discovery should identify novel medications that retain efficacy to decrease stimulant use but possess lower abuse liability and evaluate the degree to which efficacious medications can attenuate or reverse neurobiological effects of chronic stimulant use. PMID- 24484982 TI - Sigma (sigma) receptors as potential therapeutic targets to mitigate psychostimulant effects. AB - Many psychostimulants, including cocaine and methamphetamine, interact with sigma (sigma) receptors at physiologically relevant concentrations. The potential therapeutic relevance of this interaction is underscored by the ability to selectively target sigma receptors to mitigate many behavioral and physiological effects of psychostimulants in animal and cell-based model systems. This chapter begins with an overview of these enigmatic proteins. Provocative preclinical data showing that sigma ligands modulate an array of cocaine and methamphetamine effects are summarized, along with emerging areas of research. Together, the literature suggests targeting of sigma receptors as an innovative option for combating undesired actions of psychostimulants through both neuronal and glial mechanisms. PMID- 24484980 TI - Beyond small-molecule SAR: using the dopamine D3 receptor crystal structure to guide drug design. AB - The dopamine D3 receptor is a target of pharmacotherapeutic interest in a variety of neurological disorders including schizophrenia, restless leg syndrome, and drug addiction. The high protein sequence homology between the D3 and D2 receptors has posed a challenge to developing D3 receptor-selective ligands whose behavioral actions can be attributed to D3 receptor engagement, in vivo. However, through primarily small-molecule structure-activity relationship (SAR) studies, a variety of chemical scaffolds have been discovered over the past two decades that have resulted in several D3 receptor-selective ligands with high affinity and in vivo activity. Nevertheless, viable clinical candidates remain limited. The recent determination of the high-resolution crystal structure of the D3 receptor has invigorated structure-based drug design, providing refinements to the molecular dynamic models and testable predictions about receptor-ligand interactions. This chapter will highlight recent preclinical and clinical studies demonstrating potential utility of D3 receptor-selective ligands in the treatment of addiction. In addition, new structure-based rational drug design strategies for D3 receptor-selective ligands that complement traditional small-molecule SAR to improve the selectivity and directed efficacy profiles are examined. PMID- 24484983 TI - Mixed kappa/MU partial opioid agonists as potential treatments for cocaine dependence. AB - Cocaine use activates the dopamine reward pathway, leading to the reinforcing effects of dopamine. There is no FDA-approved medication for treating cocaine dependence. Opioid agonists and antagonists have been approved for treating opioid and alcohol dependence. Agonists that activate the MU opioid receptor increase dopamine levels in the nucleus accumbens, while MU receptor antagonists decrease dopamine levels by blocking the effects of endogenous opioid peptides. Activation of the kappa opioid receptor decreases dopamine levels and leads to dysphoria. In contrast, inhibition of the kappa opioid receptor decreases dopamine levels in the nucleus accumbens. Antagonists acting at the kappa receptor reduce stress-mediated behaviors and anxiety. Mixed partial MU/kappa agonists have the potential of striking a balance between dopamine levels and attenuating relapse to cocaine. The pharmacological properties of mixed MU/kappa opioid receptor agonists will be discussed and results from clinical and preclinical studies will be presented. Results from studies with some of the classical benzomorphans and morphinans will be presented as they lay the foundation for structure-activity relationships. Recent results with other partial opioid agonists, including buprenorphine derivatives and the mixed MU/kappa peptide CJ-15,208, will be discussed. The behavioral effects of the mixed MU/kappa MCL-741, an aminothiazolomorphinan, in attenuating cocaine-induced locomotor activity will be presented. While not a mixed MU/kappa opioid, results obtained with GSK1521498, a MU receptor inverse agonist, will be discussed. Preclinical strategies and successes will lay the groundwork for the further development of mixed MU/kappa opioid receptor agonists to treat cocaine dependence. PMID- 24484981 TI - Dopamine D4 receptors in psychostimulant addiction. AB - Since the cloning of the D4 receptor in the 1990s, interest has been building in the role of this receptor in drug addiction, given the importance of dopamine in addiction. Like the D3 receptor, the D4 receptor has limited distribution within the brain, suggesting it may have a unique role in drug abuse. However, compared to the D3 receptor, few studies have evaluated the importance of the D4 receptor. This may be due, in part, to the relative lack of compounds selective for the D4 receptor; the early studies were mainly conducted in mice lacking the D4 receptor. In this review, we summarize the literature on the structure and localization of the D4 receptor before reviewing the data from D4 knockout mice that used behavioral models relevant to the understanding of stimulant use. We also present evidence from more recent pharmacological studies using selective D4 agonists and antagonists and animal models of drug-seeking and drug-taking. The data summarized here suggest a role for D4 receptors in relapse to stimulant use. Therefore, treatments based on antagonism of the D4 receptor may be useful treatments for relapse to nicotine, cocaine, and amphetamine use. PMID- 24484984 TI - The combination of metyrapone and oxazepam for the treatment of cocaine and other drug addictions. AB - Although scientists have been investigating the neurobiology of psychomotor stimulant reward for many decades, there is still no FDA-approved treatment for cocaine or methamphetamine abuse. Research in our laboratory has focused on the relationship between stress, the subsequent activation of the hypothalamic pituitary-adrenal (HPA) axis, and psychomotor stimulant reinforcement for almost 30 years. This research has led to the development of a combination of low doses of the cortisol synthesis inhibitor, metyrapone, and the benzodiazepine, oxazepam, as a potential pharmacological treatment for cocaine and other substance use disorders. In fact, we have conducted a pilot clinical trial that demonstrated that this combination can reduce cocaine craving and cocaine use. Our initial hypothesis underlying this effect was that the combination of metyrapone and oxazepam reduced cocaine seeking and taking by decreasing activity within the HPA axis. Even so, doses of the metyrapone and oxazepam combination that consistently reduced cocaine taking and seeking did not reliably alter plasma corticosterone (or cortisol in the pilot clinical trial). Furthermore, subsequent research has demonstrated that this drug combination is effective in adrenalectomized rats, suggesting that these effects must be mediated above the level of the adrenal gland. Our evolving hypothesis is that the combination of metyrapone and oxazepam produces its effects by increasing the levels of neuroactive steroids, most notably tetrahydrodeoxycorticosterone, in the medial prefrontal cortex and amygdala. Additional research will be necessary to confirm this hypothesis and may lead to the development of improved and specific pharmacotherapies for the treatment of psychomotor stimulant use. PMID- 24484979 TI - The role of guanfacine as a therapeutic agent to address stress-related pathophysiology in cocaine-dependent individuals. AB - The pathophysiology of cocaine addiction is linked to changes within neural systems and brain regions that are critical mediators of stress system sensitivity and behavioral processes associated with the regulation of adaptive goal-directed behavior. This is characterized by the upregulation of core adrenergic and corticotropin-releasing factor mechanisms that subserve negative affect and anxiety and impinge upon intracellular pathways in the prefrontal cortex underlying cognitive regulation of stress and negative emotional state. Not only are these mechanisms essential to the severity of cocaine withdrawal symptoms, and hence the trajectory of clinical outcome, but also they may be particularly pertinent to the demography of cocaine dependence. The ability of guanfacine to target overlapping stress, reward, and anxiety pathophysiology suggests that it may be a useful agent for attenuating the stress- and cue induced craving state not only in women but also in men. This is supported by recent research findings from our own laboratory. Additionally, the ability of guanfacine to improve regulatory mechanisms that are key to exerting cognitive and emotional control over drug-seeking behavior also suggests that guanfacine may be an effective medication for reducing craving and relapse vulnerability in many drugs of abuse. As cocaine-dependent individuals are typically polydrug abusers and women may be at a greater disadvantage for compulsive drug use than men, it is plausible that medications that target catecholaminergic frontostriatal inhibitory circuits and simultaneously reduce stress system arousal may provide added benefits for attenuating cocaine dependence. PMID- 24484985 TI - Salvinorin A analogs and other kappa-opioid receptor compounds as treatments for cocaine abuse. AB - Acute activation of kappa-opioid receptors produces anti-addictive effects by regulating dopamine levels in the brain. Unfortunately, classic kappa-opioid agonists have undesired side effects such as sedation, aversion, and depression, which restrict their clinical use. Salvinorin A (Sal A), a novel kappa-opioid receptor agonist extracted from the plant Salvia divinorum, has been identified as a potential therapy for drug abuse and addiction. Here, we review the preclinical effects of Sal A in comparison with traditional kappa-opioid agonists and several new analogs. Sal A retains the anti-addictive properties of traditional kappa-opioid receptor agonists with several improvements including reduced side effects. However, the rapid metabolism of Sal A makes it undesirable for clinical development. In an effort to improve the pharmacokinetics and tolerability of this compound, kappa-opioid receptor agonists based on the structure of Sal A have been synthesized. While work in this field is still in progress, several analogs with improved pharmacokinetic profiles have been shown to have anti-addictive effects. While in its infancy, it is clear that these compounds hold promise for the future development of anti-addictive therapeutics. PMID- 24484986 TI - Nicotinic receptor antagonists as treatments for nicotine abuse. AB - Despite the proven efficacy of current pharmacotherapies for tobacco dependence, relapse rates continue to be high, indicating that novel medications are needed. Currently, several smoking cessation agents are available, including varenicline (Chantix(r)), bupropion (Zyban(r)), and cytisine (Tabex(r)). Varenicline and cytisine are partial agonists at the alpha4beta2* nicotinic acetylcholine receptor (nAChR). Bupropion is an antidepressant but is also an antagonist at alpha3beta2* ganglionic nAChRs. The rewarding effects of nicotine are mediated, in part, by nicotine-evoked dopamine (DA) release leading to sensitization, which is associated with repeated nicotine administration and nicotine addiction. Receptor antagonists that selectivity target central nAChR subtypes mediating nicotine-evoked DA release should have efficacy as tobacco use cessation agents with the therapeutic advantage of a limited side-effect profile. While alpha conotoxin MII (alpha-CtxMII)-insensitive nAChRs (e.g., alpha4beta2*) contribute to nicotine-evoked DA release, these nAChRs are widely distributed in the brain, and inhibition of these receptors may lead to nonselective and untoward effects. In contrast, alpha-CtxMII-sensitive nAChRs mediating nicotine-evoked DA release offer an advantage as targets for smoking cessation, due to their more restricted localization primarily to dopaminergic neurons. Small drug-like molecules that are selective antagonists at alpha-CtxMII-sensitive nAChR subtypes that contain alpha6 and beta2 subunits have now been identified. Early research identified a variety of quaternary ammonium analogs that were potent and selective antagonists at nAChRs mediating nicotine-evoked DA release. More recent data have shown that novel, nonquaternary bis-1,2,5,6-tetrahydropyridine analogs potently inhibit (IC50<1nM) nicotine-evoked DA release in vitro by acting as antagonists at alpha CtxMII-sensitive nAChR subtypes; these compounds also decrease NIC self administration in rats. PMID- 24484989 TI - Preface. Emerging targets and therapeutics in the treatment of psychostimulant abuse. PMID- 24484987 TI - New directions in nicotine vaccine design and use. AB - Clinical trials of nicotine vaccines suggest that they can enhance smoking cessation rates but do not reliably produce the consistently high serum antibody concentrations required. A wide array of next-generation strategies are being evaluated to enhance vaccine efficacy or provide antibody through other mechanisms. Protein conjugate vaccines may be improved by modifications of hapten or linker design or by optimizing hapten density. Conjugating hapten to viruslike particles or disrupted virus may allow exploitation of naturally occurring viral features associated with high immunogenicity. Conjugates that utilize different linker positions on nicotine can function as independent immunogens, so that using them in combination generates higher antibody concentrations than can be produced by a single immunogen. Nanoparticle vaccines, consisting of hapten, T cell help peptides, and adjuvants attached to a liposome or synthetic scaffold, are in the early stages of development. Nanoparticle vaccines offer the possibility of obtaining precise and consistent control of vaccine component stoichiometry and spacing and immunogen size and shape. Passive transfer of nicotine-specific monoclonal antibodies offers a greater control of antibody dose, the ability to give very high doses, and an immediate onset of action but is expensive and has a shorter duration of action than vaccines. Viral vector mediated transfer of genes for antibody production can elicit high levels of antibody expression in animals and may present an alternative to vaccination or passive immunization if the long-term safety of this approach is confirmed. Next generation immunotherapies are likely to be substantially more effective than first-generation vaccines. PMID- 24484988 TI - Bath salts, mephedrone, and methylenedioxypyrovalerone as emerging illicit drugs that will need targeted therapeutic intervention. AB - The term "synthetic cathinones" is fairly new, but, although the abuse of synthetic cathinones is a recent problem, research on cathinone analogs dates back >100 years. One structural element cathinone analogs have in common is an alpha-aminophenone moiety. Introduction of amine and/or aryl substituents affords a large number of agents. Today, >40 synthetic cathinones have been identified on the clandestine market and many have multiple "street names." Many cathinone analogs, although not referred to as such until the late 1970s, were initially prepared as intermediates in the synthesis of ephedrine analogs. The cathinones do not represent a pharmacologically or mechanistically homogeneous class of agents. Currently abused synthetic cathinones are derived from earlier agents and seem to produce their actions primarily via the dopamine, norepinephrine, and/or serotonin transporter; that is, they either release and/or inhibit the reuptake of one or more of these neurotransmitters. The actions of these agents can resemble those of central stimulants such as methamphetamine, cocaine, and/or empathogens such as 1-(3,4-methylenedioxyphenyl)-2-aminopropane (Ecstasy) and/or produce other effects. Side effects are primarily of a neurological and/or cardiovascular nature. The use of the "and/or" term is emphasized because synthetic cathinones represent a broad class of agents that produce a variety of actions; the agents cannot be viewed as being pharmacologically equivalent. Until valid structure-activity relationships are formulated for each behavioral/mechanistic action, individual synthetic cathinones remain to be evaluated on a case-by-case basis. Treatment of synthetic cathinone intoxication requires more "basic science" research. At this time, treatment is mostly palliative. PMID- 24484990 TI - Re: Gore et al.: Peripheral hypertrophic subepithelial corneal degeneration: nomenclature, phenotypes, and long-term outcomes (Ophthalmology 2013;120:892-8). PMID- 24484991 TI - LAPTOP study: a 24-month trial of verteporfin versus ranibizumab for polypoidal choroidal vasculopathy. PMID- 24484992 TI - Author reply: To PMID 23474249. PMID- 24484993 TI - Maternal characteristics and pregnancy outcomes after assisted reproductive technology by infertility diagnosis: ovulatory dysfunction versus tubal obstruction. AB - OBJECTIVE: To examine differences in maternal characteristics and pregnancy outcomes between women with ovulatory dysfunction (OD) and women with tubal obstruction (TO) who underwent assisted reproductive technology (ART). DESIGN: Retrospective cohort study. SETTING: Centers for Disease Control and Prevention. PATIENT(S): Exposed and nonexposed groups were selected from the 2000-2006 National ART Surveillance System linked with live-birth certificates from three states: Florida, Massachusetts, and Michigan. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Maternal characteristics and pregnancy outcomes, including newborn's health status right after delivery (Apgar score, <7 vs. >= 7) as the study outcome of interest, were assessed among women with OD/polycystic ovary syndrome (PCOS) and TO who used ART. RESULT(S): A significantly higher prevalence of women with OD/PCOS were younger (<35 years of age; 65.7% vs. 48.9%), were white (85.4% vs. 74.4%), had higher education (29.4% vs. 15.6%), and experienced diabetes (8.8% vs. 5.3%) compared with those having TO. The odds of having a lower (<7) Apgar score at 5 minutes were almost twice as high among newborns of women with OD/PCOS compared with those with TO (crude odds ratio, 1.86; 95% confidence interval [CI], 1.31, 2.64; adjusted odds ratio, 1.90; 95% CI, 1.30, 2.77). CONCLUSION(S): Women with OD/PCOS who underwent ART have different characteristics and health issues (higher prevalence of diabetes) and infant outcomes (lower Apgar score) compared with women with TO. PMID- 24484994 TI - Assisted reproductive technologies impair the expression and methylation of insulin-induced gene 1 and sterol regulatory element-binding factor 1 in the fetus and placenta. AB - OBJECTIVE: To evaluate the cholesterol metabolism linked to assisted reproductive technology (ART) by analyzing the expression levels and DNA methylation patterns of the insulin-induced gene (INSIG), sterol regulatory element-binding protein (SREBP), and SREBP cleavage-activating protein in the fetus and placenta. DESIGN: Experimental research study. SETTING: An IVF center, university-affiliated teaching hospital. PATIENT(S): Four patients groups were recruited: pregnancies after IVF/intracytoplasmic sperm injection (ICSI) (n = 55), natural pregnancies (n = 40), multifetal reduction after IVF/ICSI (n = 56), and multifetal reduction after controlled ovarian hyperstimulation (COH) (n = 42). INTERVENTION(S): Expression and DNA methylation of INSIG-SREBP- SREBP cleavage-activating protein in the fetus and placenta samples were determined. MAIN OUTCOME MEASURE(S): The expression and DNA methylation patterns were tested by real-time quantitative polymerase chain reaction (PCR) and pyrosequencing. RESULT(S): In the ICSI treatment group, significantly higher levels of triglycerides and apolipoprotein B were observed in cord blood compared with controls. Meanwhile, in ICSI conceived fetuses, the expression of INSIG1 was significantly higher, and methylation rates were lower, than in the IVF and control groups. Furthermore, in the placenta, the INSIG1 and SREBF1 transcripts were also significantly higher with lower methylation rates in the ICSI group than in the IVF and control groups. CONCLUSION(S): Our results indicated that the dysregulation of INSIG1 and SREBF1 caused by ART were observed not only in the fetus but also in the placenta, primarily in the ICSI group. However, the long-term sequelae of this dysregulation should be closely followed. PMID- 24484995 TI - Knowledge, attitudes, and practices regarding conception and fertility: a population-based survey among reproductive-age United States women. AB - OBJECTIVE: To assess overall knowledge, attitudes, and practices related to conception and fertility among reproductive-age women in the United States. DESIGN: Online survey of a cross-sectional sample of 1,000 women. SETTING: United States, March 2013. PATIENT(S): Women aged 18-40 years. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Knowledge, attitudes, and practices regarding selected topics in reproductive health. RESULT(S): Forty percent of women across all age groups expressed concerns about their ability to conceive. Yet one-third of women were unaware of adverse implications of sexually transmitted infections, obesity, or irregular menses for procreative success, and one-fifth were unaware of the effects of aging. Approximately 40% were unfamiliar with the ovulatory cycle. Overall, younger women (18-24 years) demonstrated less knowledge regarding conception, fertility, and ovulation, whereas older women tended to believe in common myths and misconceptions. Respondents in all age groups identified women's health care providers (75%) and Web sites (40%) as top sources of reproductive health-related information; however, engagement with providers on specific factors affecting fertility is sparse. CONCLUSION(S): Knowledge regarding ovulation, fertility, and conception is limited among this sample of reproductive age US women. Future initiatives should prioritize improved provider engagement and accurate information dissemination in Web-based venues. PMID- 24484996 TI - Prevalence of the Aurora kinase C c.144delC mutation in infertile Moroccan men. AB - OBJECTIVE: To evaluate the carrier frequency of the pathogenic c.144delC mutation in AURKC gene and the contribution of this mutation in male infertility in a Moroccan population. DESIGN: Sanger sequencing of exon 3 in AURKC gene in infertile and control patients in Morocco. SETTING: Research institute. PATIENT(S): A total of 326 idiopathic infertile patients, and 450 age-related men. INTERVENTION(S): The incidence of AURKC c.144delC mutation was determined in men with unexplained spermatogenic failure and a control cohort of normospermic fertile men. MAIN OUTCOME MEASURE(S): Genomic DNA was extracted from peripheral blood lymphocytes and the screening of the c.144delC mutation in AURKC gene performed by polymerase chain reaction and sequencing. RESULT(S): The c.144delC mutation in AURKC gene was found in patients at homozygous and heterozygous states, with an allelic frequency of 2.14%, whereas in controls this mutation was found only in the heterozygous state, with lower frequency (1%). Homozygous patients were characterized by macrocephalic and multiflagellar spermatozoa. CONCLUSION(S): Our data indicate that the AURKC c.144delC mutation has a relatively high carrier frequency in the Moroccan population; thus, we recommend screening for this deletion in infertile men with a high percentage of large headed and multiflagellar spermatozoa. PMID- 24484997 TI - Rural-urban differences in the long-term risk of colorectal cancer after adenoma removal: a population-based study. AB - BACKGROUND: We investigated the impact of municipality of residence on colonoscopic surveillance and colorectal cancer risk after adenoma resection in a French well-defined administrative area. METHODS: This registry-based study included all patients residing in Cote d'Or (n=5769) first diagnosed with colorectal adenomas between January 1, 1990, and December 31, 1999. Information about colonoscopic surveillance and colorectal cancer incidence was collected until December 31, 2003. RESULTS: A rural place of residence reduced the probability of colonoscopic surveillance in men [HR=0.89 (95%CI: 0.79-0.99), p=0.041] and in patients without family history of colorectal cancer [HR=0.91(0.82-0.99), p=0.044]. After a median follow-up of 7.7 years, 87 patients developed invasive colorectal cancer. After advanced adenoma removal, the standardized incidence ratio for colorectal cancer was 3.03 (95%CI: 1.92-4.54) for rural patients and 1.87 (95%CI: 1.26-2.66) for urban patients compared with the general population. The risk of colorectal cancer was higher in rural patients than in urban ones only after removal of the initial advanced adenoma [HR=1.73 (95%CI: 1.01-3.00, p=0.048)]. Further adjustment for surveillance colonoscopy, physician location, and other confounders had little impact on these results. CONCLUSION: The increased risk of subsequent colorectal cancer after advanced adenoma removal in French rural patients was not explained by a lower rate of colonoscopic surveillance. The role of socio-economic and environmental factors requires further exploration. PMID- 24484998 TI - Changing prevalence patterns in endoscopic and histological diagnosis of gastritis? Data from a cross-sectional Central European multicentre study. AB - BACKGROUND AND AIMS: Traditionally, Helicobacter infection is considered to be the most common cause of gastritis. In the cross-sectional Central European histoGERD trial, we assessed the prevalence of different types of gastritis, correlating histological and endoscopic diagnoses. METHODS: A total of 1123 individuals participated in an observational multicentre study. Endoscopists classified individuals as positive or negative for gastritis and rendered the putative cause. Pathologists evaluated biopsy specimens based upon the Updated Sydney System. RESULTS: Histological diagnosis of gastritis was made in 639 (56.9%) participants. In all, 210 (18.7%) individuals were diagnosed with Helicobacter gastritis, 215 (19.1%) with post Helicobacter gastritis, 234 (20.8%) with reactive gastropathy, 26 (2.3%) with autoimmune gastritis, and 6 (0.5%) with focally enhanced gastritis related to Crohn's disease. In 46 out of 639 (7.2%) individuals diagnosed with gastritis, combinations of different histological subtypes were noted the most common being reactive gastropathy and post Helicobacter gastritis. Endoscopic diagnosis of gastritis was made in 534 (47.6%) individuals. CONCLUSIONS: Reactive gastropathy was more common than active Helicobacter gastritis, and the majority of cases attributable to Helicobacter infection were no longer ongoing, i.e. post Helicobacter gastritis. Agreement between histological and endoscopic diagnoses was better in reactive gastropathy than in Helicobacter gastritis. PMID- 24485001 TI - Multimodal interventions including nutrition in the prevention and management of disease-related malnutrition in adults: a systematic review of randomised control trials. AB - BACKGROUND & AIMS: There has been a move to improve nutritional status in malnourished patients through the use of multimodal interventions (MI). There are currently no systematic reviews that have examined their effectiveness. This analysis aimed to examine the effects on nutritional, clinical, functional and patient-centred outcomes. METHODS: A systematic review and meta-analysis using Cochrane methodology. RESULTS: 15 studies were included in the analysis, 13 comparing MI with usual care and 2 comparing MI with a nutrition intervention alone. Quality of studies varied and studies reported few relevant outcomes. Only 3 outcomes were compatible with meta-analysis; weight, mortality and length of stay (LOS). No statistically significant differences between groups were found. Narrative review was inconclusive. There was no evidence of benefit in the intervention groups in relation to body composition, functional status or quality of life (QoL). Intervention groups appeared to show a trend towards increased energy and protein intake however data was provided by only 2 studies (301 participants). CONCLUSIONS: No conclusive evidence of benefit for MI on any of the reviewed outcomes was found. Well designed, high quality trials addressing the impact of MI on relevant nutritional, functional and clinical outcomes are required. PMID- 24484999 TI - Prevention and treatment of acute radiation-induced skin reactions: a systematic review and meta-analysis of randomized controlled trials. AB - BACKGROUND: Radiation-induced skin reaction (RISR) is a common side effect that affects the majority of cancer patients receiving radiation treatment. RISR is often characterised by swelling, redness, pigmentation, fibrosis, and ulceration, pain, warmth, burning, and itching of the skin. The aim of this systematic review was to assess the effects of interventions which aim to prevent or manage RISR in people with cancer. METHODS: We searched the following databases up to November 2012: Cochrane Skin Group Specialised Register, CENTRAL (2012, Issue 11), MEDLINE (from 1946), EMBASE (from 1974), PsycINFO (from 1806), CINAHL (from 1981) and LILACS (from 1982). Randomized controlled trials evaluating interventions for preventing or managing RISR in cancer patients were included. The primary outcomes were development of RISR, and levels of RISR and symptom severity. Secondary outcomes were time taken to develop erythema or dry desquamation; quality of life; time taken to heal, a number of skin reaction and symptom severity measures; cost, participant satisfaction; ease of use and adverse effects. Where appropriate, we pooled results of randomized controlled trials using mean differences (MD) or odd ratios (OR) with 95% confidence intervals (CI). RESULTS: Forty-seven studies were included in this review. These evaluated six types of interventions (oral systemic medications; skin care practices; steroidal topical therapies; non-steroidal topical therapies; dressings and other). Findings from two meta-analyses demonstrated significant benefits of oral Wobe-Mugos E for preventing RISR (OR 0.13 (95% CI 0.05 to 0.38)) and limiting the maximal level of RISR (MD -0.92 (95% CI -1.36 to -0.48)). Another meta-analysis reported that wearing deodorant does not influence the development of RISR (OR 0.80 (95% CI 0.47 to 1.37)). CONCLUSIONS: Despite the high number of trials in this area, there is limited good, comparative research that provides definitive results suggesting the effectiveness of any single intervention for reducing RISR. More research is required to demonstrate the usefulness of a wide range of products that are being used for reducing RISR. Future efforts for reducing RISR severity should focus on promising interventions, such as Wobe-Mugos E and oral zinc. PMID- 24485000 TI - Omentectomy in addition to gastric bypass surgery and influence on insulin sensitivity: a randomized double blind controlled trial. AB - BACKGROUND & AIMS: Accumulation of visceral adipose tissue is associated with insulin resistance and cardio-vascular disease. The aim of this study was to elucidate whether removal of a large amount of visceral fat by omentectomy in conjunction with Roux en-Y gastric bypass operation (RYGB) results in enhanced improvement of insulin sensitivity compared to gastric bypass surgery alone. METHODS: Eighty-one obese women scheduled for RYGB were included in the study. They were randomized to RYGB or RYGB in conjunction with omentectomy. Insulin sensitivity was measured by hyperinsulinemic euglycemic clamp before operation and sixty-two women were also reexamined 2 years post-operatively. The primary outcome measure was insulin sensitivity and secondary outcome measures included cardio-metabolic risk factors. RESULTS: Two-year weight loss was profound but unaffected by omentectomy. Before intervention, there were no clinical or metabolic differences between the two groups. The difference in primary outcome measure, insulin sensitivity, was not significant between the non-omentectomy (6.7 +/- 1.6 mg/kg body weight/minute) and omentectomy groups (6.6 +/- 1.5 mg/kg body weight/minute) after 2 years. Nor did any of the cardio-metabolic risk factors that were secondary outcome measures differ significantly. CONCLUSION: Addition of omentectomy to gastric bypass operation does not give an incremental effect on long term insulin sensitivity or cardio-metabolic risk factors. The clinical usefulness of omentectomy in addition to gastric bypass operation is highly questionable. CLINICAL TRIAL REGISTRATION NUMBER: NCT01785134. PMID- 24485002 TI - The use of 2D fingerprint methods to support the assessment of structural similarity in orphan drug legislation. AB - BACKGROUND: In the European Union, medicines are authorised for some rare disease only if they are judged to be dissimilar to authorised orphan drugs for that disease. This paper describes the use of 2D fingerprints to show the extent of the relationship between computed levels of structural similarity for pairs of molecules and expert judgments of the similarities of those pairs. The resulting relationship can be used to provide input to the assessment of new active compounds for which orphan drug authorisation is being sought. RESULTS: 143 experts provided judgments of the similarity or dissimilarity of 100 pairs of drug-like molecules from the DrugBank 3.0 database. The similarities of these pairs were also computed using BCI, Daylight, ECFC4, ECFP4, MDL and Unity 2D fingerprints. Logistic regression analyses demonstrated a strong relationship between the human and computed similarity assessments, with the resulting regression models having significant predictive power in experiments using data from submissions of orphan drug medicines to the European Medicines Agency. The BCI fingerprints performed best overall on the DrugBank dataset while the BCI, Daylight, ECFP4 and Unity fingerprints performed comparably on the European Medicines Agency dataset. CONCLUSIONS: Measures of structural similarity based on 2D fingerprints can provide a useful source of information for the assessment of orphan drug status by regulatory authorities. PMID- 24485004 TI - Dominance of an invasive fruit fly species, Bactrocera invadens, along an altitudinal transect in Morogoro, Eastern Central Tanzania. AB - Bactrocera invadens, a fruit fly from Asia, is an invasive pest species across Africa. It appears to continue spreading, not only in latitude but also in altitude. To assess its capacity to infest a large variety of hosts and its competition with other fruit fly species, a study along an altitudinal gradient was conducted. At low altitudes, the high abundance in the field and high infestation of B. invadens in different fruit species make it a serious pest. At high altitudes, colonization has started and B. invadens occurs in low numbers by reproducing successfully in high altitude fruits. Overall the abundance and infestation of B. invadens is influenced by its direct competitor Ceratitis rosa and the presence of its preferred host species. C. rosa is still the dominant species in temperate fruits grown at high altitude. Ceratitis cosyra, however, is negatively affected by B. invadens, this species seems to have shifted hosts to avoid competition. The broad host range and competitive potential of B. invadens increase the risk for further spread not only to higher areas, but also to subtropical regions. PMID- 24485003 TI - Protective effect of S-adenosylmethionine on hepatic ischemia-reperfusion injury during hepatectomy in HCC patients with chronic HBV infection. AB - BACKGROUND: Although hepatectomy is often performed with the Pringle maneuver, the problem of hepatic ischemia-reperfusion injury (HIRI) can also be serious. Thus, the present study was designed to investigate the protective effect of S adenosylmethionine (SAMe) on HIRI, especially for patients with hepatocellular carcinoma (HCC) associated with chronic hepatitis B virus (HBV) infection and cirrhosis. METHODS: Eighty-one HCC patients with chronic HBV infection, undergoing partial hepatectomy with inflow occlusion, were divided into three groups. In the pretreatment group (PR group, n = 26), patients were given SAMe two hours before surgery. In the post-treatment group (PO group, n = 25), patients were given SAMe six hours after surgery. And in the control group (control group, n = 30), patients received partial hepatectomy without any SAMe. All pre-, intra- and postoperative blood samples were collected to measure the plasma levels of transaminases, bilirubin and cytokines. The results were compared among the three groups. RESULTS: There were no statistically significant intergroup differences observed in age, gender, hepatic inflow occlusion time and the results of liver function tests. Preoperative administration of SAMe (PR group) significantly reduced the plasma levels of alanine transaminase (ALT), aspartate transferase (AST), total bilirubin (TBIL) and direct bilirubin (DBIL) as compared to the other two groups. In the PO group, TBIL and DBIL were significantly lower than in the control group. Significant differences were also seen in IL-6 and TNF-alpha between the PR group and the other groups. In all groups, postoperative liver reserve function in the PR group as revealed by ICGR15 (Post ICGR15) was at its best before abdominal closure. Compared to the control group, the risk of complications and the hospital stay after surgery were significantly meliorated in the PR group. Additionally, patients with cirrhosis had a more acute rate of change in ALT and AST than non-cirrhotic patients. CONCLUSIONS: Taken together, our preliminary findings suggest that preoperative administration of SAMe is useful and safe for reducing the HIRI in partial hepatectomy, especially for HCC patients whose disease is associated with chronic HBV infection and cirrhosis. PMID- 24485005 TI - Educating novice practitioners to detect elder financial abuse: a randomised controlled trial. AB - BACKGROUND: Health and social care professionals are well positioned to identify and intervene in cases of elder financial abuse. An evidence-based educational intervention was developed to advance practitioners' decision-making in this domain. The objective was to test the effectiveness of a decision-training educational intervention on novices' ability to detect elder financial abuse. The research was funded by an E.S.R.C. grant reference RES-189-25-0334. METHODS: A parallel-group, randomised controlled trial was conducted using a judgement analysis approach. Each participant used the World Wide Web to judge case sets at pre-test and post-test. The intervention group was provided with training after pre-test testing, whereas the control group were purely given instructions to continue with the task. 154 pre-registration health and social care practitioners were randomly allocated to intervention (n78) or control (n76). The intervention comprised of written and graphical descriptions of an expert consensus standard explaining how case information should be used to identify elder financial abuse. Participants' ratings of certainty of abuse occurring (detection) were correlated with the experts' ratings of the same cases at both stages of testing. RESULTS: At pre-test, no differences were found between control and intervention on rating capacity. Comparison of mean scores for the control and intervention group at pre test compared to immediate post-test, showed a statistically significant result. The intervention was shown to have had a positive moderate effect; at immediate post-test, the intervention group's ratings had become more similar to those of the experts, whereas the control's capacity did not improve. The results of this study indicate that the decision-training intervention had a positive effect on detection ability. CONCLUSIONS: This freely available, web-based decision training aid is an effective evidence-based educational resource. Health and social care professionals can use the resource to enhance their ability to detect elder financial abuse. It has been embedded in a web resource at http://www.elderfinancialabuse.co.uk. PMID- 24485006 TI - Hiding behind the mycobacterial cell wall. AB - A recent study has found that pathogenic mycobacteria employ two structurally related cell wall lipids to coordinately recruit macrophages permissive to infection and intracellular replication, all the while inhibiting the recruitment of macrophages with enhanced bactericidal activity. These findings suggest a novel mechanism of immune evasion. PMID- 24485007 TI - Clinical disease activity and acute phase reactant levels are discordant among patients with active rheumatoid arthritis: acute phase reactant levels contribute separately to predicting outcome at one year. AB - INTRODUCTION: Clinical trials of new treatments for rheumatoid arthritis (RA) typically require subjects to have an elevated acute phase reactant (APR), in addition to tender and swollen joints. However, despite the elevation of individual components of the Clinical Disease Activity Index (CDAI) (tender and swollen joint counts and patient and physician global assessment), some patients with active RA may have normal erythrocyte sedimentation rate (ESR) and/or C reactive protein (CRP) levels and thus fail to meet entry criteria for clinical trials. We assessed the relationship between CDAI and APRs in the Consortium of Rheumatology Researchers of North America (CORRONA) registry by comparing baseline characteristics and one-year clinical outcomes of patients with active RA, grouped by baseline APR levels. METHODS: This was an observational study of 9,135 RA patients who had both ESR and CRP drawn and a visit at which CDAI was >2.8 (not in remission). RESULTS: Of 9,135 patients with active RA, 58% had neither elevated ESR nor CRP; only 16% had both elevated ESR and CRP and 26% had either ESR or CRP elevated. Among the 4,228 patients who had a one-year follow-up visit, both baseline and one-year follow-up modified Health Assessment Questionnaire (mHAQ) and CDAI scores were lowest for patients with active RA but with neither APR elevated; both mHAQ and CDAI scores increased sequentially with the increase in number of elevated APR levels at baseline. Each individual component of the CDAI followed the same trend, both at baseline and at one-year follow-up. The magnitude of improvement in both CDAI and mHAQ scores at one year was associated positively with the number of APRs elevated at baseline. CONCLUSIONS: In a large United States registry of RA patients, APR levels often do not correlate with disease activity as measured by joint counts and global assessments. These data strongly suggest that it is appropriate to obtain both ESR and CRP from RA patients at the initial visit. Requiring an elevation in APR levels as a criterion for inclusion of RA patients in studies of experimental agents may exclude some patients with active disease. PMID- 24485008 TI - Consequences of increased use of computed tomography imaging for trauma patients in rural referring hospitals prior to transfer to a regional trauma centre. AB - BACKGROUND: Computed tomography (CT) plays an integral role in the evaluation and management of trauma patients. As the number of referring hospital (RH)-based CT scanners increased, so has their utilization in trauma patients before transfer. We hypothesized that this has resulted in increased time at RH, image duplication, and radiation dose. METHODS: A retrospective chart review was completed for trauma activations transferred to an ACS-verified Level II Trauma Centre (TC) during two time periods: 2002-2004 (Group 1) and 2006-2008 (Group 2). 2005 data were excluded as this marked the transition period for acquisition of hospital-based CT scanners in RH. Statistical analysis included t test and chi(2) analysis. P<0.05 was considered significant. RESULTS: 1017 patients met study criteria: 503 in group 1 and 514 in group 2. Mean age was greater in group 2 compared to group 1 (40.3 versus 37.4, respectively; P=0.028). There were 115 patients in group 1 versus 202 patients in group 2 who underwent CT imaging at RH (P<0.001). Conversely, 326 patients in group 1 had CT scans performed at the TC versus 258 patients in group 2 (P<0.001). Mean time at the RH was similar between the groups (117.1 and 112.3min for group 1 and 2, respectively; P=0.561). However, when comparing patients with and without a pretransfer CT at the RH, the median time at RH was 140 versus 67min, respectively (P<0.001). The number of patients with duplicate CT imaging (n=34 in group 1 and n=42 in group 2) was not significantly different between the two time periods (P=0.392). Head CTs comprised the majority of duplicate CT imaging in both time periods (82.4% in group 1 and 90.5% in group 2). Mean total estimated radiation dose per patient was not significantly different between the two groups (group 1=8.4mSv versus group 2=7.8mSv; P=0.192). CONCLUSIONS: A significant increase in CT imaging at the RH prior to transfer to the TC was observed over the study periods. No associated increases in mean time at the RH, image duplication at TC, total estimated radiation dose per patient, and mortality rate were observed. PMID- 24485009 TI - How plants sense ethylene gas--the ethylene receptors. AB - Ethylene is a hormone that affects many processes important for plant growth, development, and responses to stresses. The first step in ethylene signal transduction is when ethylene binds to its receptors. Numerous studies have examined how these receptors function. In this review we summarize many of these studies and present our current understanding about how ethylene binds to the receptors. The biochemical output of the receptors is not known but current models predict that when ethylene binds to the receptors, the activity of the associated protein kinase, CTR1 (constitutive triple response1), is reduced. This results in downstream transcriptional changes leading to ethylene responses. We present a model where a copper cofactor is required and the binding of ethylene causes the receptor to pass through a transition state to become non-signaling leading to lower CTR1 activity. PMID- 24485011 TI - A validated stability-indicating HPLC method for the simultaneous determination of pheniramine maleate and naphazoline hydrochloride in pharmaceutical formulations. AB - BACKGROUND: A simple, rapid, and accurate stability-indicating reverse phase liquid chromatographic method was developed and validated for the simultaneous determination of pheniramine maleate and naphazoline hydrochloride in bulk drugs and pharmaceutical formulations. RESULTS: Optimum chromatographic separations among pheniramine maleate, naphazoline hydrochloride and stress-induced degradation products have been achieved within 10 minutes by using an Agilent zorbax eclipse XDB C18 column (150 mm * 4.6 mm, 5 MUm) as the stationary phase with a mobile phase consisted of 10 mM phosphate buffer pH 2.8 containing 0.5% triethlamine and methanol (68:32, v/v) at a flow rate of 1 mL min-1. Detection was performed at 280 nm using a diode array detector. Theoretical plates for pheniramine maleate and naphazoline hydrochloride were calculated to be 6762 and 6475, respectively. The method was validated in accordance with ICH guidelines with respect to linearity, accuracy, precision, robustness, specificity, limit of detection and quantitation. Regression analysis showed good correlations (R2 > 0.999) for pheniramine maleate in the concentration range of 150-1200 MUg mL-1 and naphazoline hydrochloride in 12.5-100 MUg mL-1. The method results in excellent separation of both the analytes and degradation products. The peak purity factor is >=980 for both analytes after all types of stress, indicating complete separation of both analyte peaks from the stress induced degradation products. CONCLUSIONS: Overall, the proposed stability-indicating method was suitable for routine quality control and drug analysis of pheniramine maleate and naphazoline hydrochloride in pharmaceutical formulations. PMID- 24485010 TI - Regulation of iron transport systems in Enterobacteriaceae in response to oxygen and iron availability. AB - Iron is an essential nutrient for most bacteria. Depending on the oxygen available in the surrounding environment, iron is found in two distinct forms: ferrous (Fe(II)) or ferric (Fe(III)). Bacteria utilize different transport systems for the uptake of the two different forms of iron. In oxic growth conditions, iron is found in its insoluble, ferric form, and in anoxic growth conditions iron is found in its soluble, ferrous form. Enterobacteriaceae have adapted to transporting the two forms of iron by utilizing the global, oxygen sensing regulators, ArcA and Fnr to regulate iron transport genes in response to oxygen. PMID- 24485013 TI - Physical activity intensity and health status perception of breast cancer patients undergoing adjuvant chemotherapy. AB - PURPOSE: The aim was to evaluate the physical activity intensity (PAI) of patients receiving adjuvant chemotherapy and investigate the relationship between health status perception and PAI in Japan. METHODS: Consenting participants of this prospective, descriptive, repeated measures design were 28 women aged 20-64 with stage I-IIIA initial breast cancer whose regimen included anthracycline. Participants wore a triaxial accelerometer and their PAI was measured for a 14 day period at the beginning of chemotherapy. The SF-36 Survey and Cancer Fatigue Scale were administered. The accelerometer was used to calculate the number of steps, physical activity level (PAL) and total minutes of PAI levels of under 1.5 Mets, 1.5-2.9 Mets, and more than 3.0 Mets during the first half (FH; days 2-7) and second half (SH; days 8-14) of the study. Data were analyzed using Pearson's correlation coefficient and multiple regression analysis. RESULTS: During FH, the mean number of steps was 3841.1 steps/day and mean PAL was 1.43; during SH, the mean number of steps was 4058.4 steps/day, mean PAL was 1.43; participants spent over 70% of the day working quietly in a sitting position. PAL during SH was significantly associated with mean time spent during activities of 1.5-2.9 Mets (beta = 0.880, p < 0.0001) and 3.0 Mets (beta = 0.268, p < 0.0001). CONCLUSION: Patients receiving adjuvant chemotherapy had extremely low physical activity. They should be provided useful information of appropriate physical movement and be supported in resolving physical and psychological distress. PMID- 24485012 TI - Identification of patient subgroups and risk factors for persistent arm/shoulder pain following breast cancer surgery. AB - PURPOSE: In this prospective, longitudinal study, we extend our findings on persistent breast pain in patients (n = 398) following breast cancer surgery and evaluate the prevalence and characteristics of persistent pain in the arm/shoulder. In addition, differences in the severity of common symptoms and quality of life outcomes measured prior to surgery, among the arm pain classes, were evaluated. METHODS AND SAMPLE: Patients were recruited from Breast Care Centers located in a Comprehensive Cancer Center, two public hospitals, and four community practices. Patients were assessed prior to and monthly for six months following breast cancer surgery. RESULTS: Using growth mixture modeling, patients were classified into no (41.6%), mild (23.6%), and moderate (34.8%) arm pain classes based on ratings of worst arm/shoulder pain. Compared to the no pain class, patients in the moderate pain class were significantly younger, had a higher body mass index, and were more likely to report preoperative breast pain and swelling in the affected breast. In addition, patients in the moderate pain class reported higher levels of depression, anxiety, and sleep disturbance than the no pain class. CONCLUSIONS: Findings suggest that approximately 35% of women experience persistent levels of moderate arm/shoulder pain in the first six months following breast cancer surgery. Moderate arm/shoulder pain is associated with clinically meaningful decrements in functional status and quality of life. PMID- 24485014 TI - The influence of symptom clusters and the most distressing concerns regarding quality of life among patients with inoperable lung cancer. AB - PURPOSE: To explore the influence of symptom clusters and the most distressing concerns on global rating of quality of life (QoL) among patients with inoperable lung cancer (LC) over a three-month period following diagnosis. METHODS: Data were derived from a longitudinal study dealing with the symptom experiences of 400 patients with LC at three time points: close to diagnosis and one and three months later. The symptom clusters were derived from a QoL questionnaire using factor analysis, which resulted in three clusters: the Respiratory cluster, the Pain cluster and the Mood cluster. The most distressing concerns were derived from responses to a free listing question ('What is most distressing at present') and were categorised under three dimensions: Bodily distress, Life situation with LC and Iatrogenic distress. Cross-sectional, multivariate regression analyses with QoL as a dependent variable were used to determine predictors (symptom clusters and most distressing concerns) at the three time points. RESULTS: All three symptom clusters predicted QoL at each time point. Close to diagnosis, none of the dimensions of most distressing concerns predicted QoL, while the dimension Bodily distress was a significant predictor of QoL after one month. The Life situation with LC dimension was a significant predictor of QoL three months after diagnosis. CONCLUSIONS: Symptom clusters are important to LC patients' QoL and need to be acknowledged by healthcare professionals. The present study shows the importance of patients' descriptions of key concerns, which vary from diagnosis onwards, and urges healthcare professionals to be vigilant to such changes. PMID- 24485015 TI - Unexpected plateauing of childhood obesity rates in developed countries. AB - Surveys performed in the past 10 to 15 years show a yet unexplained stabilization or decline in prevalence rates of childhood obesity in developed countries. The projected continuous increase in obesity prevalence throughout future decades seems not to occur at present. Apparently, saturation has been reached, which might be related to societal adjustments. Hence, we postulate a cumulative effect of public health programs for obesity prevention resulting, for example, in an increase in physical activity, and a decline in television viewing and in the consumption of sugar-sweetened soft drinks by children. Effective public health programs are urgently needed for developing countries, where obesity rates in children still continued to increase during the past decade. PMID- 24485016 TI - Dispersion durations of P-wave and QT interval in children treated with a ketogenic diet. AB - BACKGROUND: Limited data are available on the effects of a ketogenic diet on dispersion duration of P-wave and QT-interval measures in children. We searched for the changes in these measures with serial electrocardiograms in patients treated with a ketogenic diet. METHODS: Twenty-five drug-resistant patients with epilepsy treated with a ketogenic diet were enrolled in this study. Electrocardiography was performed in all patients before the beginning and at the sixth month after implementation of the ketogenic diet. Heart rate, maximum and minimum P-wave duration, P-wave dispersion, and maximum and minimum corrected QT interval and QT dispersion were manually measured from the 12-lead surface electrocardiogram. RESULTS: Minimum and maximum corrected QT and QT dispersion measurements showed nonsignificant increase at month 6 compared with baseline values. Other previously mentioned electrocardiogram parameters also showed no significant changes. CONCLUSIONS: A ketogenic diet of 6 months' duration has no significant effect on electrocardiogram parameters in children. Further studies with larger samples and longer duration of follow-up are needed to clarify the effects of ketogenic diet on P-wave dispersion and corrected QT and QT dispersion. PMID- 24485017 TI - Calcifying fibrous tumor presenting as rectal submucosal tumor: first case reported in rectum. AB - Calcifying fibrous tumor (CFT) is a recently recognized rare benign lesion characterized by dense hyalinized collagenous tissue with interspersed spindle cells and a lymphoplasmocytic infiltrate. Calcification is the hallmark of CFT and may present in the form of psammomatous bodies or dystrophic calcifications. CFT of the intestinal tract is uncommon and rectal CFT has never been reported. Recently, we experienced a case of CFT found in the rectum of a 36-year-old man. In this study, we described the characteristic histopathological findings with a review of the relevant literature. Although CFT of the intestinal tract as an intrinsic visceral lesion is unusual and clinically unexpected, CFT should be considered in the differential diagnosis of rectal submucosal tumor. PMID- 24485018 TI - Reprint of: A review of cellular therapies for chronic lymphocytic leukemia. PMID- 24485019 TI - Reprint of: Back to the future! The evolving role of maintenance therapy after hematopoietic stem cell transplantation. AB - Relapse is a devastating event for patients with hematologic cancers treated with hematopoietic stem cell transplantation. In most situations, relapse treatment options are limited. Maintenance therapy offers the possibility of delaying or avoiding disease recurrence, but its role remains unclear in most conditions that we treat with transplantation. Here, Dr. Hourigan presents an overview of minimal residual disease (MRD) measurement in hematologic malignancies and the applicability of MRD-based post-transplantation interventions. Dr. McCarthy reviews current knowledge of maintenance therapy in the autologous transplantation context, with emphasis on immunologic interventions and immune modulation strategies designed to prevent relapse. Dr. de Lima discusses current lines of investigation in disease recurrence prevention after allogeneic transplantation, focusing on acute myeloid leukemia and myelodysplastic syndrome. PMID- 24485020 TI - Link between insulin resistance and hypertension: What is the evidence from evolutionary biology? AB - Insulin resistance and hypertension are considered as prototypical "diseases of civilization" that are manifested in the modern environment as plentiful food and sedentary life. The human propensity for insulin resistance and hypertension is a product, at least in part, of our evolutionary history. Adaptation to ancient lifestyle characterized by a low sodium, low-calorie food supply and physical stress to injury response has driven our evolution to shape and preserve a thrifty genotype, which is favorite with energy-saving and sodium conservation. As our civilization evolved, a sedentary lifestyle and sodium- and energy-rich diet, the thrifty genotype is no longer advantageous, and may be maladaptive to disease phenotype, such as hypertension, obesity and insulin resistance syndrome. This article reviews human evolution and the impact of the modern environment on hypertension and insulin resistance. PMID- 24485021 TI - A panel of genes methylated with high frequency in colorectal cancer. AB - BACKGROUND: The development of colorectal cancer (CRC) is accompanied by extensive epigenetic changes, including frequent regional hypermethylation particularly of gene promoter regions. Specific genes, including SEPT9, VIM1 and TMEFF2 become methylated in a high fraction of cancers and diagnostic assays for detection of cancer-derived methylated DNA sequences in blood and/or fecal samples are being developed. There is considerable potential for the development of new DNA methylation biomarkers or panels to improve the sensitivity and specificity of current cancer detection tests. METHODS: Combined epigenomic methods - activation of gene expression in CRC cell lines following DNA demethylating treatment, and two novel methods of genome-wide methylation assessment - were used to identify candidate genes methylated in a high fraction of CRCs. Multiplexed amplicon sequencing of PCR products from bisulfite-treated DNA of matched CRC and non-neoplastic tissue as well as healthy donor peripheral blood was performed using Roche 454 sequencing. Levels of DNA methylation in colorectal tissues and blood were determined by quantitative methylation specific PCR (qMSP). RESULTS: Combined analyses identified 42 candidate genes for evaluation as DNA methylation biomarkers. DNA methylation profiles of 24 of these genes were characterised by multiplexed bisulfite-sequencing in ten matched tumor/normal tissue samples; differential methylation in CRC was confirmed for 23 of these genes. qMSP assays were developed for 32 genes, including 15 of the sequenced genes, and used to quantify methylation in tumor, adenoma and non neoplastic colorectal tissue and from healthy donor peripheral blood. 24 of the 32 genes were methylated in >50% of neoplastic samples, including 11 genes that were methylated in 80% or more CRCs and a similar fraction of adenomas. CONCLUSIONS: This study has characterised a panel of 23 genes that show elevated DNA methylation in >50% of CRC tissue relative to non-neoplastic tissue. Six of these genes (SOX21, SLC6A15, NPY, GRASP, ST8SIA1 and ZSCAN18) show very low methylation in non-neoplastic colorectal tissue and are candidate biomarkers for stool-based assays, while 11 genes (BCAT1, COL4A2, DLX5, FGF5, FOXF1, FOXI2, GRASP, IKZF1, IRF4, SDC2 and SOX21) have very low methylation in peripheral blood DNA and are suitable for further evaluation as blood-based diagnostic markers. PMID- 24485022 TI - Economic evaluation of intravenous iodinated contrast media in Italy. AB - BACKGROUND: Contrast-induced acute kidney injury (CI-AKI) is defined as a deterioration in renal function after administration of radiologic iodinated contrast media (CM). Iodixanol, showed a lower CI-AKI incidence than low-osmolar contrast media (LOCM). A cost-effectiveness analysis was performed comparing iodixanol and LOCM in intravenous (IV) setting in Italy. METHODS: A Markov model was developed. Patients moved across four health states: CI-AKI free, CI-AKI, myocardial infarction, and death. The simulation horizon was lifetime with 1 month cycles. Costs and outcomes were discounted at 3.5 percent rate. CI-AKI incidence was considered from published literature across different definitions. Cost-effectiveness of iodixanol was assessed in terms of incremental cost per life-year gained. Net monetary benefit (NMB) was also calculated. Both deterministic and probabilistic sensitivity analyses were performed. RESULTS: Base-case results showed an average survival increase of 0.51 life-years and a savings of ?7.25 for iodixanol versus LOCM. The cost-effectiveness of iodixanol was confirmed when other scenarios were explored, such as varying CI-AKI definition, sub-populations with specified risk factors, CM hospital bids prices, and inclusion of adverse drug reactions of allergic nature. An NMB ranging between ?6,007.25 and ?30,007.25 was calculated. CONCLUSION: Base-case results show that IV iodixanol is cost-effective compared with LOCM in the Italian clinical setting of a hospital computed tomography radiology practice. However, some caution is due, mainly linked to inherent limitations of the modeling technique and to the lack of agreement on CI-AKI incidence data in the clinical literature. PMID- 24485023 TI - Introduction: autophagy in kidneys. PMID- 24485025 TI - Autophagy: emerging therapeutic target for diabetic nephropathy. AB - Autophagy is a major catabolic pathway by which mammalian cells degrade and recycle macromolecules and organelles. It plays a critical role in removing protein aggregates, as well as damaged or excess organelles, to maintain intracellular homeostasis and to keep cells healthy. The accumulation of damaged proteins and organelles induced by hyperglycemia and other metabolic alterations is strongly associated with the development of diabetic nephropathy. Autophagy is up-regulated under conditions of calorie restriction and environmental stress, such as oxidative stress and hypoxia in proximal tubular cells, and occurs even under normal conditions in podocytes. These findings have led to our hypothesis that autophagy is involved in the pathogenesis of diabetic nephropathy, a hypothesis increasingly supported by experimental evidence. To date, however, the exact role of autophagy in diabetic nephropathy has not been fully revealed. This article therefore reviews recent findings and provides perspectives on the involvement of autophagy in diabetic nephropathy. PMID- 24485024 TI - mTOR signaling in autophagy regulation in the kidney. AB - Cells possess adaptive biosynthetic systems to maintain cellular energy levels for survival under adverse environmental conditions. Autophagy is an evolutionarily conserved cellular catabolic process that breaks down and recycles cytosolic material including macromolecules and organelles through lysosomal degradation. This catabolic process, represented by macroautophagy, is induced by a variety of cellular stresses such as nutrient starvation, which causes a shortage of cellular energy for cells to maintain cellular homeostasis and essential biological activities. In contrast, upon nutrient availability, cells stimulate anabolic processes. The mechanistic/mammalian target of rapamycin, a serine/threonine protein kinase, is a key player in stimulating cellular anabolism in response to nutrients and growth factors, and plays a crucial role in suppressing autophagy activity. Growing evidence has suggested that autophagy activity is required for the maintenance and physiological functions of renal cells including proximal tubular cells and podocytes. In this article, we discuss recent progress in the regulation of autophagy by mechanistic/mammalian target of rapamycin signaling. PMID- 24485027 TI - Polycystic kidney disease: a case of suppressed autophagy? AB - Autosomal-dominant polycystic kidney disease is the most common form of polycystic kidney disease in adults and is caused by a mutation in the polycystic kidney disease 1 or 2 genes, which encode, respectively, polycystin-1 and polycystin-2. Autophagy is present in polycystic kidneys in rat and mouse models of polycystic kidney disease. Autophagy has yet to be shown in human polycystic kidney disease kidneys. The mechanism of cyst growth has been studied extensively in vitro and in vivo. Multiple molecules and signaling pathways have been implicated in cyst growth including mammalian target of rapamycin, the renin angiotensin-aldosterone system, vasopressin and cyclic adenosine monophosphate, epidermal growth factor and insulin-like growth factor tyrosine kinases, vascular endothelial growth factor, extracellular signal-related kinase, tumor necrosis factor-alpha, cyclin-dependent kinases, caspases and apoptosis, and cyclic adenosine monophosphate-activated protein kinases. Many of the agents that inhibit these signaling pathways and slow cyst growth are also autophagy inducers such as mammalian target of rapamycin inhibitors, cyclin-dependent kinase inhibitors, caspase inhibitors, tyrosine kinase inhibitors, metformin, curcumin, and triptolide. There are reasons to believe that suppression of autophagy may play a role in cyst formation and growth. This review presents the hypothesis that suppression of autophagy may play a role in cyst formation and growth, based on the following: (1) many of the agents that protect against polycystic kidney disease also induce autophagy, (2) suppression of autophagy in polycystic kidney disease 1 knockout cells, (3) a defect in autophagy in congenital polycystic kidney mice with polycystic kidney disease, (4) how suppressed autophagy may relate to apoptosis in polycystic kidney disease, and (5) conditions with defective cilia, the ciliopathies, are associated with decreased autophagy. PMID- 24485026 TI - Autophagy in acute kidney injury. AB - Acute kidney injury is a major kidney disease associated with poor clinical outcomes. The pathogenesis of acute kidney injury is multifactorial and is characterized by tubular cell injury and death. Recent studies have shown autophagy induction in proximal tubular cells during acute kidney injury. The regulatory mechanisms of tubular cell autophagy are poorly understood; however, some recent findings have set up a foundation for further investigation. Although autophagy may promote cell death under certain experimental conditions, pharmacologic and autophagy-related gene knockout studies have established a renoprotective role for autophagy in acute kidney injury. The mechanisms by which autophagy protects cells from injury and how, possibly, its pro-survival role switches to pro-death under certain conditions are discussed. Further research is expected to help us understand the regulatory network of tubular cell autophagy, define its precise roles in the specific context of acute kidney injury, and identify autophagy-targeting strategies for the prevention and treatment of acute kidney injury. PMID- 24485028 TI - Emerging roles of autophagy in the stressed kidney allograft. AB - The transplanted kidney integrates a considerable number of tissular stress that challenge cell viability and promote inflammation and fibrogenesis. These injuries ultimately may lead to structural deterioration (ie, interstitial fibrosis and tubular atrophy) and to loss of function. In response to ischemic, toxic, or immunologic insults, which are the most frequent injuries encountered by transplanted kidneys, cells must adapt to maintain vital metabolic functions and to avoid death. Among the adaptive responses activated, autophagy has emerged as an important integrator of various extracellular and intracellular triggers (often related to nutrient availability or immunologic stimuli), which may in turn regulate cell viability and both innate and adaptive immune functions. This review provides an overview of the recent literature on the implications of autophagy in the field of kidney transplantation and discusses future directions for research. PMID- 24485029 TI - Autophagy in glomerular health and disease. AB - Glomerular filtration coupled to tubular reabsorption was the prerequisite for one of the most important milestones in evolution, when animals made their way from water onto land. To fulfill the enormous filtration task the filter is composed of the most sophisticated postmitotic epithelial cells--the podocytes, which have only a very limited ability to regenerate. Podocyte injury and loss owing to genetic, toxic, immunologic, or metabolic insults underlie the most common glomerular diseases. Thus, the understanding of the factors and mechanisms that help to maintain podocytes are of major clinical importance. Recently, autophagy emerged as a key mechanism to eliminate unwanted cytoplasmic materials, thereby preventing cellular damage and stress to safeguard long-lived podocytes. Here, we highlight the accumulating evidence suggesting that autophagy plays a critical role in the homeostasis of podocytes during glomerular disease and aging. PMID- 24485030 TI - Autophagy and immune response in kidneys. AB - Autophagy is a ubiquitous intracellular catabolic process that contributes to homeostatic maintenance and regulates the balance between health and disease. Emerging evidence from both the immunology and renal literature suggests that important relationships exist between the immune system and renal autophagy that may have significant implications for our understanding of the pathogenesis of kidney diseases. Autophagic flux in renal parenchymal cells can protect against acute and chronic kidney injury and can be stimulated via activation of innate immune receptors, cytokine secretion, and/or direct contact by immune cells. Conversely, modulation of autophagy in renal cells may influence both adaptive and innate immune cell responses. Autophagy can promote the ability of renal epithelial cells, which can act as antigen-presenting cells, to process and present self-antigen to immune cells. In addition, autophagic control of inflammasome function can modify the intrarenal inflammatory milieu, thereby preventing immune cell infiltration. Because autophagy and immune responses may promote or protect against kidney injury, further research is needed to better understand how interactions between renal parenchymal cells and the immune system are altered by autophagy. Novel agents are being developed that promote or inhibit various steps of the autophagy pathway, and it is likely that whether such agents are beneficial or harmful in the context of kidney disease will depend, at least in part, on whether and how they influence the relationship between autophagy and the immune response in the kidney. PMID- 24485031 TI - Regulation of autophagy by TGF-beta: emerging role in kidney fibrosis. AB - Autophagy is a highly conserved homoeostatic mechanism for cell survival under conditions of stress, and is widely implicated as an important pathway in many biological processes and diseases. In progressive kidney diseases, fibrosis represents the common pathway to end-stage kidney failure. Transforming growth factor-beta1 (TGF-beta1) is a pleiotropic cytokine that has been established as a central mediator of kidney fibrosis. A recently emerging body of evidence from studies in renal cells in culture and experimental animal models suggests that TGF-beta1 regulates autophagy and that autophagy regulates many critical aspects of normal and disease conditions associated with kidney fibrosis, such as tubulointerstitial fibrosis, glomerulosclerosis, and diabetic nephropathy. Here, we review the recent advances exploring the process of autophagy, its regulation by TGF-beta1, and the implication in the pathogenesis of progressive kidney fibrosis and injury responses. Understanding the cellular and molecular bases of this process is crucial for identifying potential new diagnostic and therapeutic targets of kidney fibrosis. PMID- 24485033 TI - Three-dimensional brain surface visualization for epilepsy surgery of focal cortical dysplasia. AB - Focal cortical dysplasia (FCD) causes medically intractable seizures in 5-10% of adult epilepsy patients, but patients can become seizure free through surgical resection. The authors present the utility of three-dimensional surface visualization (3DSV) that expands on existing imaging datasets to highlight surface vasculature as a tool for achieving more successful resections in patients with FCD. In this prospective series of six patients, preoperative 3DSV was performed for planning the surgical approach to the lesion and for intraoperative guidance. Reconstructions involved volume rendering of a contrast enhanced dataset to visualize surface venous vasculature. Postoperatively, five of the six patients had complete resections, with one patient having a subtotal resection due to proximity to crucial vasculature. We report that 3DSV is a useful tool for surgical planning, since topographical relationships between lesion location and surface vasculature landmarks are less likely to change with surgical progress. PMID- 24485032 TI - Chaperone-mediated autophagy in the kidney: the road more traveled. AB - Chaperone-mediated autophagy (CMA) is a lysosomal proteolytic pathway in which cytosolic substrate proteins contain specific chaperone recognition sequences required for degradation and are translocated directly across the lysosomal membrane for destruction. CMA proteolytic activity has a reciprocal relationship with macroautophagy: CMA is most active in cells in which macroautophagy is least active. Normal renal proximal tubular cells have low levels of macroautophagy, but high basal levels of CMA activity. CMA activity is regulated by starvation, growth factors, oxidative stress, lipids, aging, and retinoic acid signaling. The physiological consequences of changes in CMA activity depend on the substrate proteins present in a given cell type. In the proximal tubule, increased CMA results from protein or calorie starvation and from oxidative stress. Overactivity of CMA can be associated with tubular lysosomal pathology and certain cancers. Reduced CMA activity contributes to protein accumulation in renal tubular hypertrophy, but may contribute to oxidative tissue damage in diabetes and aging. Although there are more questions than answers about the role of high basal CMA activity, this remarkable feature of tubular protein metabolism appears to influence a variety of chronic diseases. PMID- 24485034 TI - Uptake and sorption of aluminium and fluoride by four green algal species. AB - BACKGROUND: We examined the uptake and sorption of aluminium (Al) and fluoride (F) by green algae under conditions similar to those found in the effluents of the aluminium industry. We took into account the speciation of Al in the medium since Al can form stable complexes with F and these complexes may play a role in the uptake and sorption of Al. We compared the capacity of four species of green algae (i.e. Chlamydomonas reinhardtii, Pseudokirchneriella subcapitata, Chlorella vulgaris, and Scenedesmus obliquus) to accumulate and adsorb Al and F. The selected algae were exposed during 4 days, covering all growth phases of algae, to a synthetic medium containing Al and F at pH 7.0. During this period, dissolved Al as well as cellular growth were followed closely. At the end of the exposure period, the solutions were filtered in order to harvest the algal cells. The cells were then rinsed with enough ethylene diaminetetraacetic acid to remove loosely bound ions from the algal surface, determined from the filtrates. Finally, the filters were digested in order to quantify cellular uptake. RESULTS: Little difference in Al removal was observed between species. Aluminium sorption (15%) and uptake (26%) were highest in P. subcapitata, followed by C. reinhardtii (7% and 17% respectively), S. obliquus (13% and 5%), and C. vulgaris (7% and 2%). However, none of these species showed significant uptake or sorption of F. We also studied the influence of pH on the uptake and sorption of Al and F by P. subcapitata. We measured a combined uptake and sorption of Al of 50% at pH 7.5, of 41% at pH 7.0, and of 4% at pH 5.5. Thus, accumulation was reduced with acidification of the medium as expected by the increased competition with protons and possibly by a reduced bioavailability of the Al-F complexes which dominated the solution at low pH. CONCLUSION: Out of the four tested species, P. subcapitata showed the highest sorption of aluminium and fluoride under our test conditions. These results provide key information on the development of an environmental biotechnology which can be applied to industrial effluents. PMID- 24485035 TI - Failure to find evidence for deletion of LCE3C and LCE3B genes at PSORS4 contributing to psoriasis susceptibility in Tunisian families. AB - BACKGROUND: Recently, it has been shown that a deletion in the late cornified envelope (LCE) gene cluster (LCE3C_LCE3B-del) is associated with susceptibility to psoriasis in European and Asian populations. However, no study of this deletion has been performed in the North African population. The aim of the present study was to investigate whether this deletion is associated with familial psoriasis in Tunisian population. METHODS: A total of 34 patients and 55 healthy individuals were recruited from 7 multiplex families and a PCR assay was used to determine the association of this deletion. Its effect on susceptibility to psoriasis was assessed using the PDT program. RESULTS: We failed to detect any evidence of association between LCE3C_LCE3B-del and psoriasis in Tunisian families. No epistasic effect was found between the deletion and PSORS1 locus. CONCLUSIONS: These findings indicate that the LCE3C_LCE3B-del does not contribute in a major way to psoriasis susceptibility in Tunisian families. PMID- 24485036 TI - Characterization and evaluation of the novel agarose-nickel composite matrix for possible use in expanded bed adsorption of bio-products. AB - Agarose-nickel (Ag-Ni) composite matrix was evaluated for its use in expanded bed adsorption (EBA). Bovine serum albumin (BSA) and lysozyme were used as model proteins in batch and column adsorption studies. Accordingly, Reactive Green 19 (RG19) dye-ligand was covalently immobilized onto the support matrix to prepare affinity adsorbent for protein adsorption. Results were then compared with data obtained from Streamline commercial matrix. In batch experiments RG19 derivatives of Ag-Ni (RG19-Ag-Ni) exhibited high adsorption rate; and also a higher binding capacity of BSA (31.4mg/ml adsorbent) was observed for Ag-Ni compared to the commercial adsorbent. More than 70% of the adsorption capacity was achieved within 30min which is a reasonable contact time for EBA operations. The equilibrium adsorption data well agreed with Langmuir isotherm model. The expanded bed adsorption studies showed a reasonable breakthrough behavior at high flow rates and a higher dynamic binding capacity (DBC) was obtained for novel matrix in compare to streamline at the same fluid velocity. DBC at 10% breakthrough reached 66% of the saturated adsorption capacity at the high flow velocity of 450cm/h which indicates the favorable column efficiency. Additionally, two different Ag-Ni size fractions (75-150 and 150-300MUm) were examined to investigate the expanded bed performance dependency on the adsorbent particle size with respect to the hydrodynamic stability and adsorption properties using lysozyme as model protein. Interestingly, the small ones showed less axial dispersion coefficient (<1.0*10(-5)m(2)/s) which resulted in higher bed stability in high fluid viscosities. Overall, the adsorption experiments results demonstrated that small size fraction of Ag-Ni matrices acts more effectively for expanded bed adsorption of bio-molecules. PMID- 24485037 TI - Improving stability of virus-like particles by ion-exchange chromatographic supports with large pore size: advantages of gigaporous media beyond enhanced binding capacity. AB - Limited binding capacity and low recovery of large size multi-subunits virus-like particles (VLPs) in conventional agarose-gel based chromatographic supports with small pores have long been a bottleneck limiting the large scale purification and application of VLPs. In this study, four anion exchange media including DEAE Sepharose FF (DEAE-FF), DEAE-Capto, gigaporous DEAE-AP-120nm and DEAE-AP-280nm with average pore diameters of 32nm, 20nm, 120nm and 280nm, respectively, were applied for purification of hepatitis B virus surface antigen (HBsAg) VLPs. Pore size effects of media on the VLPs adsorption equilibrium, adsorption kinetics, dynamic binding capacity (DBC), and recovery were investigated in detail. According to the confocal laser scanning microscopy observation, adsorption of the VLPs in DEAE-FF and DEAE-Capto was mostly confined to a thin shell on the outer surface of the beads, leaving the underlying pore space and the binding sites inaccessibly, while the large pores in gigaporous media enabled the VLPs to access to the interior pore spaces by diffusion transport efficiently. Compared to the most widely used DEAE-FF, gigaporous media DEAE-AP-280nm gained about 12.9 times increase in static adsorption capacity, 8.0 times increase in DBC, and 11.4 times increase in effective pore diffusivity. Beyond increasing the binding capacity and enhancing the mass transfer, the gigaporous structure also significantly improved the stability of the VLPs during intensive adsorption desorption process by lowing the multi-point interaction between the VLPs and binding sites in the pores. At 2.0mg/mL-media loading quantity, about 85.5% VLPs were correctly self-assembled after the chromatography with DEAE-AP-280nm media; oppositely about 85.2% VLPs lost their normal assembly with DEAE-FF due to irreversible disassembly. Comparative investigation was made to study the purifying performance of these four chromatographic media for actual VLPs purification from recombinant Hansenula polymorpha. DEAE-AP-280nm media were demonstrated the best results showing the highest recovery of 68.33% and purification fold of 3.47, at 2.98mg protein/mL-media loading quantity and a flow rate of 240cm/h. PMID- 24485038 TI - An automated solid-phase microextraction method based on magnetic molecularly imprinted polymer as fiber coating for detection of trace estrogens in milk powder. AB - A new automated solid-phase micro extraction (SPME) sampling method was developed for quantitative enrichment of estrogens (ES) from milk powder, using magnetic molecularly imprinted polymer (MMIP) as fiber coating. The method (MMIP-SPME) was built with several electromagnetic stainless steel fibers, placed in parallel for simultaneously extraction. The MMIP was synthesized using core-shell Fe3O4@SiO2 nanoparticles (NPs) as magnetic support. Estradiol (E2) was employed as the template molecule, acrylamide (AA) as functional monomer, and ethylene glycol dimethacrylate (EGDMA) as cross-linker. MMIP can be easily absorbed or desorbed from fibers when the current is turned on or off, creating magnetism. Compared to traditional MIP-SPME, the prepared procedure of MMIP-SPME is time-saving and organic solvent-free. The proposed device significantly improved the efficiency of separation and enrichment of estrogens from complex matrices thereby and facilitating the pretreatment steps by electromagnetically controlled extraction fibers to achieve full automation. Several experimental parameters were studied, including extraction and desorption kinetics, solution pH, desorption solution, ratio, and shuttle rate. The newly developed MMIP-SPME showed good sensitivity and high binding capacity, fast adsorption kinetics and desorption kinetics for estrone (E1), estradiol (E2), estriol (E3) and diethylstilbestrol (DES) under optimized conditions. The detection limits for the four estrogens were 1.5 5.5ngg(-1) with excellent reproducibility (RSD values less than 7.1%) when milk powder samples spiked with analytes at 20, 100 and 250ngg(-1) were studied. PMID- 24485039 TI - A trial of intracranial pressure monitoring in traumatic brain injury. AB - BACKGROUND: Intracranial pressure (ICP) monitoring is considered the standard of care for severe traumatic brain injury (TBI) and is used frequently, but the efficacy of treatment based on monitoring in improving the outcome has not been rigorously assessed. METHODS: OBJECTIVE: The objective was to compare efficacy of guideline-based management in which a protocol for monitoring intraparenchymal ICP was used (ICP group) or a protocol in which treatment was based on imaging and clinical examination (exam group). DESIGN: A multicenter randomized controlled trial was conducted. SETTING: The trial was set in ICUs in Bolivia or Ecuador. SUBJECTS: Patients had severe TBI (n = 324) and were 13 years of age or older. INTERVENTIONS: Patients were randomly allocated to ICP monitoring or clinical exam-based monitoring. OUTCOMES: The primary outcome was a composite of survival time, impaired consciousness, functional status at 3 and 6 months, and neuropsychological status at 6 months; neuropsychological status was assessed by an examiner who was unaware of the protocol assignment. This composite measure was based on performance across 21 measures of functional and cognitive status and was calculated as a percentile (with 0 indicating the worst performance, and 100 the best performance). RESULTS: There was no significant between-group difference in the primary outcome, a composite measure based on percentile performance across 21 measures of functional and cognitive status (score 56 in the pressure-monitoring group versus 53 in the imaging-clinical examination group; P = 0.49). Six-month mortality rates were 39% in the pressure-monitoring group and 41% in the imaging-clinical examination group (P = 0.60). The median lengths of stay in the ICU were similar in the two groups (12 days in the pressure-monitoring group and 9 days in the imaging-clinical examination group; P = 0.25), although the number of days of brain-specific treatments (for example, administration of hyperosmolar fluids and the use of hyperventilation) in the ICU was higher in the imaging-clinical examination group than in the pressure monitoring group (4.8 versus 3.4, P = 0.002). The distributions of serious adverse events were similar in the two groups. CONCLUSIONS: For patients with severe TBI, care focused on maintaining monitored ICP at 20 mmHg or less was not shown to be superior to care based on imaging and clinical examination. PMID- 24485040 TI - High ALDH1A1 expression correlates with poor survival in papillary thyroid carcinoma. AB - BACKGROUND: High expression of aldehyde dehydrogenase 1 (ALDH1) has been confirmed in many tumors. This enzyme plays an important role in tumor proliferation, metastasis, and drug resistance. However, in the case of papillary thyroid carcinoma (PTC), the relationship between ALDH1 expression and prognosis remains unknown. METHOD: We used tissue microarrays to evaluate ALDH1A1 expression in 247 surgically resected PTC specimens by immunochemistry, and correlated the findings with the clinicopathological parameters. RESULT: ALDH1A1 levels were significantly higher than in normal thyroid tissues. Moreover, ALDH1A1 overexpression was significantly associated with extrathyroid extension (P = 0.001), pT status (P < 0.001), pN status (P = 0.016) and TNM stage (P < 0.001). The Kaplan-Meier survival analysis suggested that high ALDH1A1 expression reflects a poorer lymph node recurrence-free survival (LN-RFS) and distant recurrence-free survival (DRFS) in PTC patients, as compared with patients having low ALDH1A1 expression. Multivariate analysis confirmed the ALDH1A1 expression was an independent prognostic factor for LN-RFS and DRFS in PTC patients. CONCLUSION: In conclusion, high ALDH1A1 expression correlates with poor survival in PTC patients. PMID- 24485042 TI - Transaminase elevation secondary to the use of adalimumab. PMID- 24485041 TI - Repetitive hypoxic preconditioning induces an immunosuppressed B cell phenotype during endogenous protection from stroke. AB - BACKGROUND: Repetitive hypoxic preconditioning (RHP) creates an anti-inflammatory phenotype that protects from stroke-induced injury for months after a 2-week treatment. The mechanisms underlying long-term tolerance are unknown, though one exposure to hypoxia significantly increased peripheral B cell representation. For this study, we sought to determine if RHP specifically recruited B cells into the protected ischemic hemisphere, and whether RHP could phenotypically alter B cells prior to stroke onset. METHODS: Adult, male SW/ND4 mice received RHP (nine exposures over 2 weeks; 8 to 11 % O2; 2 to 4 hours) or identical exposures to 21 % O2 as control. Two weeks following RHP, a 60-minute transient middle cerebral artery occlusion was induced. Standard techniques quantified CXCL13 mRNA and protein expression. Two days after stroke, leukocytes were isolated from brain tissue (70:30 discontinuous Percoll gradient) and profiled on a BD-FACS Aria flow cytometer. In a separate cohort without stroke, sorted splenic CD19+ B cells were isolated 2 weeks after RHP and analyzed on an Illumina MouseWG-6 V2 Bead Chip. Final gene pathways were determined using Ingenuity Pathway Analysis. Student's t test or one-way analysis of variance determined significance (P < 0.05). RESULTS: CXCL13, a B cell-specific chemokine, was upregulated in post-stroke cortical vessels of both groups. In the ischemic hemisphere, RHP increased B cell representation by attenuating the diapedesis of monocyte, macrophage, neutrophil and T cells, to quantities indistinguishable from the uninjured, contralateral hemisphere. Pre-stroke splenic B cells isolated from RHP-treated mice had >1,900 genes differentially expressed by microarray analysis. Genes related to B-T cell interactions, including antigen presentation, B cell differentiation and antibody production, were profoundly downregulated. Maturation and activation were arrested in a cohort of B cells from pre-stroke RHP-treated mice while regulatory B cells, a subset implicated in neurovascular protection from stroke, were upregulated. CONCLUSIONS: Collectively, our data characterize an endogenous neuroprotective phenotype that utilizes adaptive immune mechanisms pre-stroke to protect the brain from injury post-stroke. Future studies to validate the role of B cells in minimizing injury and promoting central nervous system recovery, and to determine whether B cells mediate an adaptive immunity to systemic hypoxia that protects from subsequent stroke, are needed. PMID- 24485044 TI - What makes a great radiology review course lecture: the Ottawa radiology resident review course experience. AB - BACKGROUND: Little objective evidence exists regarding what makes a good lecture. Our purpose was to determine qualities of radiology review course lectures that are associated with positive audience evaluation. METHODS: 57 presentations from the Ottawa Resident Review Course (2012) were analyzed by a PGY4 radiology resident blinded to the result of audience evaluation. Objective data extracted were: slides per minute, lines of text per text slide, words per text slide, cases per minute, images per minute, images per case, number of audience laughs, number of questions posed to the audience, number of summaries, inclusion of learning objectives, ending on time, use of pre/post-test and use of special effects. Mean audience evaluation scores for each talk from daily audience evaluations (up to 60 per talk) were standardized out of 100. Correlation coefficient was calculated between continuous variables and audience evaluation scores. Student T test was performed on categorical variables and audience evaluation scores. RESULTS: Strongest positive association with audience evaluation scores was for image quality (r = 0.57) and number of times the audience laughed (r = 0.3). Strongest negative association was between images per case and audience scores (r = -0.25). Talks with special effects were rated better (mean score 94.3 vs. 87.1, p < 0.001). Talks with the highest image quality were rated better (mean score 94.1 vs. 87.5, p < 0.001). Talks which contained a pre/post-test were rated better (mean score 92 vs. 87.8, p = 0.004). CONCLUSION: Many factors go into making a great review course lecture. At the University of Ottawa Resident Review Course, high quality images, use of special effects, use of pre/post-test and humor were most strongly associated with high audience evaluation scores. High image volume per case may be negatively associated with audience evaluation scores. PMID- 24485043 TI - Persistent pulmonary arterial hypertension in the newborn (PPHN): a frequent manifestation of TMEM70 defective patients. AB - INTRODUCTION: Mutations in the TMEM70 are the most common cause of nuclear ATP synthase deficiency resulting in a distinctive phenotype characterized by severe neonatal hypotonia, hypertrophic cardiomyopathy (HCMP), facial dysmorphism, severe lactic acidosis, hyperammonemia and 3-methylglutaconic aciduria (3-MGA). METHODS AND RESULTS: We collected 9 patients with genetically confirmed TMEM70 defect from 8 different families. Six were homozygous for the c.317-2A>G mutation, 2 were compound heterozygous for mutations c.317-2A>G and c.628A>C and 1 was homozygous for the novel c.701A>C mutation. Generalized hypotonia, lactic acidosis, hyperammonemia and 3-MGA were present in all since birth. Five patients presented acute respiratory distress at birth requiring intubation and ventilatory support. HCMP was detected in 5 newborns and appeared a few months later in 3 additional children. Five patients showed a severe and persistent neonatal pulmonary hypertension (PPHN) requiring Nitric Oxide (NO) and/or sildenafil administration combined in 2 cases with high-frequency oscillatory (HFO) ventilation. In 3 of these patients, echocardiography detected signs of HCMP at birth. CONCLUSIONS: PPHN is a life-threatening poorly understood condition with bad prognosis if untreated. Pulmonary hypertension has rarely been reported in mitochondrial disorders and, so far, it has been described in association with TMEM70 deficiency only in one patient. This report further expands the clinical and genetic spectrum of the syndrome indicating PPHN as a frequent and life-threatening complication regardless of the type of mutation. Moreover, in these children PPHN appears even in the absence of an overt cardiomyopathy, thus representing an early sign and a clue for diagnosis. PMID- 24485045 TI - Optimizing bioluminescence imaging to study protozoan parasite infections. AB - Bioluminescence imaging is a non-invasive technique which can be used to monitor infections in real-time. However, its utility is restricted by difficulties in detecting pathogens in deep tissue. 'Red-shifted' luciferases, which emit light of longer wavelength than standard bioluminescence-generating proteins, greatly enhance sensitivity, and have wide applicability for studying parasite infections. PMID- 24485047 TI - Acute toxicity of definitive chemoradiation in patients with inoperable or irresectable esophageal carcinoma. AB - BACKGROUND: Definitive chemoradiation (dCRT) is considered curative intent treatment for patients with inoperable or irresectable esophageal cancer. Acute toxicity data focussing on dCRT are lacking. METHODS: A retrospective analysis of patients treated with dCRT consisting of 6 cycles of paclitaxel 50 mg/m2 and carboplatin AUC2 concomitant with radiotherapy (50.4 Gy?1.8Gy) from 2006 through 2011 at a single tertiary center was performed. Toxicity, hospital admissions and survival were analysed. RESULTS: 127 patients were treated with definitive chemoradiation. 33 patients were medically inoperable, 94 patients were irresectable, Despite of a significantly smaller tumor length in inoperable patients grade >=3 toxicity was significantly recorded more often in the inoperable patients (44%) than in irresectable patients (20%) (p < 0.05) Hospital admission occurred more often in the inoperable patients (39%) than in the irresectable patients (22%) (p < 0.05) Median number of cycles of chemotherapy was five for inoperable patients (p = 0.01), while six cycles could be administered to patients with irresectable disease. Recurrence and survival were not significantly different. The odds ratio for developing toxicity >= grade 3 was 2.6 (95% CI 1.0-6.4 p < 0.05) for being an inoperable patient and 1.2 (95% CI 1.0-1.4 p = 0.02) per 10 extra micromol/l creatinine. CONCLUSIONS: Our data show that acute toxicity of definitive chemoradiation is worse in patients with medically inoperable esophageal carcinoma compared to patients with irresectable esophageal cancer and mainly occurs in the 5th cycle of treatment. Improvement of supportive care should be undertaken in this more fragile group. PMID- 24485046 TI - How might flukes and tapeworms maintain genome integrity without a canonical piRNA pathway? AB - Surveillance by RNA interference is central to controlling the mobilization of transposable elements (TEs). In stem cells, Piwi argonaute (Ago) proteins and associated proteins repress mobilization of TEs to maintain genome integrity. This defense mechanism targeting TEs is termed the Piwi-interacting RNA (piRNA) pathway. In this opinion article, we draw attention to the situation that the genomes of cestodes and trematodes have lost the piwi and vasa genes that are hallmark characters of the germline multipotency program. This absence of Piwi like Agos and Vasa helicases prompts the question: how does the germline of these flatworms withstand mobilization of TEs? Here, we present an interpretation of mechanisms likely to defend the germline integrity of parasitic flatworms. PMID- 24485050 TI - Enhanced bone mass and physical fitness in prepubescent basketball players. AB - The aim of this study was to examine the effect of basketball practice on bone acquisition in the prepubertal age. In total, 48 prepubescent male basketball players aged 11.1 +/- 0.8 yr, Tanner stage 1, were compared with 50 controls matched for age and pubertal stage. Areal bone mineral density, bone mineral content (BMC), and bone area (BA) in deferent sites associated with anthropometric parameters were measured by dual-energy X-ray absorptiometry. Running and jumping tests were performed. Analysis of Student's impaired t-test revealed that basketball players attained better results in all physical fitness tests (p < 0.05). They also exhibited significantly greater BMC and BA in whole body, upper and lower extremities, trochanter, total hip, and whole right and left radius (p < 0.001) compared with the controls. No significant differences were observed between groups in right and left ultradistal and third distal radius and spinal regions, BMC, and BA, whereas a significant positive correlation was reported between lean mass, BMC, and BA of lower limbs. In summary, basketball practice in prepubertal age is associated with improved physical fitness and enhanced lean and bone mass in loaded sites. PMID- 24485048 TI - Influence of type 2 diabetes on symbolic analysis and complexity of heart rate variability in men. AB - BACKGROUND: Individuals with diabetes may develop cardiac autonomic dysfunction that may be evaluated by heart rate variability (HRV). The aim was evaluated heart rate variability (HRV) of individuals with type 2 diabetes, without cardiovascular autonomic neuropathy (CAN), in response to active postural maneuver by means of nonlinear analysis (symbolic analysis, Shannon and conditional entropy) and correlate HRV parameters between them, glycated hemoglobin and diabetes duration. METHODS: Nineteen men with type 2 diabetes without CAN (T2D) and nineteen healthy men (CG), age-range from 40 to 60 years were studied. We assessed HRV in supine and orthostatic position using symbolic analysis (0V%, 1V%, 2LV% and 2UV%), Shannon and conditional entropy (SE and NCI). RESULTS: In supine position T2D presented higher sympathetic modulation (0V%) than CG. However, there was not any difference between groups for indexes of complexity (SE and NCI). Furthermore, T2D presented a preserved response of cardiac autonomic modulation after active postural maneuver. CONCLUSIONS: The present study showed that individuals with type 2 diabetes without CAN presented higher cardiac sympathetic modulation. However, the complexity of HRV was not influenced by imbalance of the autonomic modulation in individuals with type 2 diabetes. In addition, the response of autonomic nervous system in the heart remains preserved after active postural maneuver in individuals with type 2 diabetes, possibly due to the lack of CAN in this group. PMID- 24485051 TI - Morphometric study of the scapular free flap and the free rib osteomyocutaneous flap. AB - The scapula free flap is often the first choice for reconstruction of bony defects of the facial skeleton. However, the vascularised rib as part of a free rib osteomyocutaneous flap may be a suitable second choice. We have investigated the morphology and clinical dimensions of the 7th rib and the scapula, and the ability of the available bone to carry dental implants. The age and sex of the cadaver, and the donor side, were also recorded. The dimensions of the scapulas and 7th ribs (n=130 of each) from 65 cadavers were measured at 4 different points using osteometric methods. Examination showed that bone from the scapula and 7th rib were sufficient for placement of implants. The 7th rib gave reliable measurements for both height and width, and a consistent relation between compact and cancellous bone. Although the scapula provided adequate compact and cancellous bone, there were variations depending on the segment of bone chosen. Bones from male cadavers were more suitable for implantation. In both the scapula and the 7th rib ageing had a significant adverse effect in only one dimension. Most points of measurement have satisfactory bony dimensions for insertion of dental implants. PMID- 24485052 TI - The stability following advancement genioplasty with biodegradable screw fixation. AB - The purpose of this study was to compare postoperative stability using biodegradable screws with that of metal plates for fixation of advancement genioplasty. We studied patients who had advancement genioplasty alone or at the same time as other orthognathic surgery including mandibular setback. We assessed the lateral cephalographs at different time points (preoperatively, and 7 days, 3 months, 6 months, and 12 months postoperatively). A total of 54 patients were enrolled and 27 patients were assigned to each group. The position of pogonion was stable 12 months postoperatively, and the amount of skeletal advancement was reflected in soft tissue close to 100%. There were no clinical differences between biodegradable screws and conventional metal plates used for fixation. Biodegradable fixation for advancement genioplasty is a good option for patients who would require a second operation for removal of the plates. PMID- 24485053 TI - An analytical method to calculate equivalent fields to irregular symmetric and asymmetric photon fields. AB - Equivalent field is frequently used for central axis depth-dose calculations of rectangular- and irregular-shaped photon beams. As most of the proposed models to calculate the equivalent square field are dosimetry based, a simple physical based method to calculate the equivalent square field size was used as the basis of this study. The table of the sides of the equivalent square or rectangular fields was constructed and then compared with the well-known tables by BJR and Venselaar, et al. with the average relative error percentage of 2.5 +/- 2.5% and 1.5 +/- 1.5%, respectively. To evaluate the accuracy of this method, the percentage depth doses (PDDs) were measured for some special irregular symmetric and asymmetric treatment fields and their equivalent squares for Siemens Primus Plus linear accelerator for both energies, 6 and 18MV. The mean relative differences of PDDs measurement for these fields and their equivalent square was approximately 1% or less. As a result, this method can be employed to calculate equivalent field not only for rectangular fields but also for any irregular symmetric or asymmetric field. PMID- 24485054 TI - Correlating planned radiation dose to the cochlea with primary site and tumor stage in patients with head and neck cancer treated with intensity-modulated radiation therapy. AB - The aim of the study was to determine tumor characteristics that predict higher planned radiation (RT) dose to the cochlea in patients with head and neck cancer (HNC) treated with intensity-modulated radiotherapy (IMRT). From 2004 to 2012, 99 patients with HNC underwent definitive IMRT to a median dose of 69.96Gy in 33 fractions, with the right and left cochlea-vestibular apparatus contoured for IMRT optimization as avoidance structures. If disease involvement was adjacent to the cochlea, preference was given to tumor coverage by prescription dose. Descriptive statistics were calculated for dose-volume histogram planning data, and mean planning dose to the cochlea (from left or right cochlea, receiving the greater amount of RT dose) was correlated to primary site and tumor stage. Mean (standard deviation) cochlear volume was 1.0 (0.60)cm(3) with maximum and mean planned doses of 31.9 (17.5)Gy and 22.1 (13.7)Gy, respectively. Mean planned dose (Gy) to cochlea by tumor site was as follows: oral cavity (18.6, 14.4), oropharynx (21.7, 9.1), nasopharynx (36.3, 10.4), hypopharynx (14.9, 7.1), larynx (2.1, 0.62), others including the parotid gland, temporal bone, and paranasal sinus (33.6, 24.0), and unknown primary (25.6, 6.7). Average mean planned dose (Gy) to the cochlea in T0-T2 and T3-T4 disease was 22.0 and 29.2Gy, respectively (p = 0.019). By site, a significant difference was noted for nasopharynx and others (31.6 and 50.7, p = 0.012) but not for oropharynx, oral cavity, and hypopharynx. Advanced T category predicted for higher mean cochlear dose, particularly for nasopharyngeal, parotid gland, temporal bone, and paranasal sinus HNC sites. PMID- 24485055 TI - Use of proton beams with breast prostheses and tissue expanders. AB - Since the early 2000s, a small but rapidly increasing number of patients with breast cancer have been treated with proton beams. Some of these patients have had breast prostheses or tissue expanders in place during their courses of treatment. Procedures must be implemented to plan the treatments of these patients. The density, kilovoltage x-ray computed tomography numbers (kVXCTNs), and proton relative linear stopping powers (pRLSPs) were calculated and measured for several test sample devices. The calculated and measured kVXCTNs of saline were 1% and 2.4% higher than the values for distilled water while the calculated RLSP for saline was within 0.2% of the value for distilled water. The measured kVXCTN and pRLSP of the silicone filling material for the test samples were approximately 1120 and 0.935, respectively. The conversion of kVXCTNs to pRLSPs by the treatment planning system standard tissue conversion function is adequate for saline-filled devices but for silicone-filled devices manual reassignment of the pRLSPs is required. PMID- 24485056 TI - Dosimetric effects of rotational offsets in stereotactic body radiation therapy (SBRT) for lung cancer. AB - To quantitatively evaluate dosimetric effects of rotational offsets in stereotactic body radiation therapy (SBRT) for lung cancer. Overall, 11 lung SBRT patients (8 female and 3 male; mean age: 75.0 years) with medially located tumors were included. Treatment plans with simulated rotational offsets of 1 degrees , 3 degrees , and 5 degrees in roll, yaw, and pitch were generated and compared with the original plans. Both clockwise and counterclockwise rotations were investigated. The following dosimetric metrics were quantitatively evaluated: planning target volume coverage (PTV V100%), max PTV dose (PTV Dmax), percentage prescription dose to 0.35cc of cord (cord D0.35cc), percentage prescription dose to 0.35cc and 5cc of esophagus (esophagus D0.35cc and D5cc), and volume of the lungs receiving at least 20Gy (lung V20). Statistical significance was tested using Wilcoxon signed rank test at the significance level of 0.05. Overall, small differences were found in all dosimetric matrices at all rotational offsets: 95.6% of differences were < 1% or < 1Gy. Of all rotational offsets, largest change in PTV V100%, PTV Dmax, cord D0.35cc, esophagus D0.35cc, esophagus D5cc, and lung V20 was - 8.36%, - 6.06%, 11.96%, 8.66%, 6.02%, and - 0.69%, respectively. No significant correlation was found between any dosimetric change and tumor-to-cord/esophagus distances (R(2) range: 0 to 0.44). Larger dosimetric changes and intersubject variations were observed at larger rotational offsets. Small dosimetric differences were found owing to rotational offsets up to 5 degrees in lung SBRT for medially located tumors. Larger intersubject variations were observed at larger rotational offsets. PMID- 24485057 TI - Update on romiplostim and eltrombopag indirect comparison. PMID- 24485059 TI - Tandem Aldol-Michael reactions in aqueous diethylamine medium: a greener and efficient approach to dimedone-barbituric acid derivatives. AB - BACKGROUND: Green chemistry is a rapidly developing new field that provides us with a proactive avenue for the sustainable development of future science and technologies. Green chemistry uses highly efficient and environmentally benign synthetic protocols to deliver lifesaving medicines, accelerating lead optimization processes in drug discovery, with reduced unnecessary environmental impact. From this view point, it is desirable to use water instead of organic solvents as a reaction medium, since water is safe, abundant and an environmentally benign solvent. RESULTS: A convenient one-pot method for the efficient synthesis of the novel Zwitterion derivatives 4a-pvia a three-component condensation reaction of barbituric acid derivatives 1a,b, dimedone 2, and various aldehydes 3 in the presence of aqueous diethylamine media is described. This new approach is environmentally benign, with clean synthetic procedure, short reaction times and easy work-up procedure which proceeded smoothly to provide excellent yield (88-98%). The synthesized products were characterized by elemental analysis, IR, MS, NMR and CHN analysis. The structure of 4a was further confirmed by single crystal X-ray diffraction. The compound crystallizes in the orthorhombic space group Pbca with alpha = 14.6669 (5) A, b = 18.3084 (6) A, c = 19.0294 (6) A, alpha = 90 degrees , beta = 90 degrees , = 90 degrees , V = 5109.9 (3) A3, and Z = 8. The molecules are packed in crystal structure by weak intermolecular C-H? ? ?O hydrogen bonding interactions. CONCLUSIONS: An environmentally benign Aldol-Michael protocol for the synthesis of dimedone barbituric derivatives using aqueous diethylamine medium is achieved. PMID- 24485058 TI - Selenium and selenocysteine: roles in cancer, health, and development. AB - The many biological and biomedical effects of selenium are relatively unknown outside the selenium field. This fascinating element, initially described as a toxin, was subsequently shown to be essential for health and development. By the mid-1990s selenium emerged as one of the most promising cancer chemopreventive agents, but subsequent human clinical trials yielded contradictory results. However, basic research on selenium continued to move at a rapid pace, elucidating its many roles in health, development, and in cancer prevention and promotion. Dietary selenium acts principally through selenoproteins, most of which are oxidoreductases involved in diverse cellular functions. PMID- 24485060 TI - Comparison of categorical alcohol dependence versus a dimensional measure for predicting weekly alcohol use in heavy drinkers. AB - BACKGROUND: The DSM specifies categorical criteria for psychiatric disorders. In contrast, a dimensional approach considers variability in symptom severity and can significantly improve statistical power. The current study tested whether a categorical, DSM-defined diagnosis of Alcohol Dependence (AD) was a better fit than a dimensional dependence measure for predicting change in alcohol consumption among heavy drinkers following a brief alcohol intervention (BI). DSM IV and DSM-5 alcohol use disorder (AUD) measures were also evaluated. METHODS: Participants (N=246) underwent a diagnostic interview after receiving a BI, then reported daily alcohol consumption using an Interactive Voice Response system. Dimensional AD was calculated by summing the dependence criteria (mean=4.0; SD=1.8). The dimensional AUD measure was a summation of positive Alcohol Abuse plus AD criteria (mean=5.8; SD=2.5). A multi-model inference technique was used to determine whether the DSM-IV categorical diagnosis or dimensional approach would provide a more accurate prediction of first week consumption and change in weekly alcohol consumption following a BI. RESULTS: The Akaike information criterion (AIC) for the dimensional AD model (AIC=7625.09) was 3.42 points lower than the categorical model (AIC=7628.51) and weight of evidence calculations indicated there was 85% likelihood that the dimensional model was the better approximating model. Dimensional AUD models fit similarly to the dimensional AD model. All AUD models significantly predicted change in alcohol consumption (p's=.05). CONCLUSION: A dimensional AUD diagnosis was superior for detecting treatment effects that were not apparent with categorical and dimensional AD models. PMID- 24485061 TI - Temporal trends in the survival of drug and alcohol abusers according to the primary drug of admission to treatment in Spain. AB - BACKGROUND: Mortality of alcohol and drug abusers is much higher than the general population. We aimed to characterize the role of the primary substance of abuse on the survival of patients admitted to treatment and to analyze changes in mortality over time. METHODS: Longitudinal study analyzing demographic, drug use, and biological data of 5023 patients admitted to three hospital-based treatment units in Barcelona, Spain, between 1985 and 2006. Vital status and causes of death were ascertained from clinical charts and the mortality register. Piecewise regression models were used to analyze changes in mortality. RESULTS: The primary substances of dependence were heroin, cocaine, and alcohol in 3388 (67.5%), 945 (18.8%), and 690 patients (13.7%), respectively. The median follow-up after admission to treatment was 11.6 years (IQR: 6.6-16.1), 6.5 years (IQR: 3.9-10.6), and 4.8 years (IQR: 3.1-7.8) for the heroin-, cocaine-, and alcohol-dependent patients, respectively. For heroin-dependent patients, mortality rate decreased from 7.3*100person-years (p-y) in 1985 to 1.8*100p-y in 2008. For cocaine dependent patients, mortality rate decreased from 10.7*100p-y in 1985 to <2.5*100p-y after 2004. The annual average decrease was 2% for alcohol-dependent patients, with the lowest mortality rate (3.3*100p-y) in 2008. CONCLUSIONS: Significant reductions in mortality of alcohol and drug dependent patients are observed in recent years in Spain. Preventive interventions, treatment of substance dependence and antiretroviral therapy may have contributed to improve survival in this population. PMID- 24485062 TI - Enhanced sensitivity and response bias for male anger in women with borderline personality disorder. AB - Interpersonal difficulties, which are characteristic of Borderline personality disorder (BPD), may be related to problems with social cognition. We explored facial emotion recognition in 44 women (15 with BPD, 15 healthy controls, and 14 with a history of childhood trauma but no BPD) examining the role of BPD and abuse history in the ability to detect fearful, angry and happy cues in emotional faces. In Task 1, participants viewed pictures of morphed faces containing different percentages of specific emotions and reported the emotion they saw. In Task 2, participants were asked to increase the intensity of a specific emotion on an initially neutral face until they could detect that emotion in the face. Across both tasks, BPD predicted the earlier detection of anger in male faces. BPD symptoms also predicted the misidentification of anger in male faces containing no anger cues. Although participants with BPD were slower to recognize happiness in male faces, their overall ability to recognize happiness was unimpaired. Abuse history did predict problems with happiness recognition. Finally, recognition of fear was unrelated to abuse history and BPD. Findings suggest that BPD is associated with a bias toward seeing anger in males and that this is independent of abuse history. PMID- 24485063 TI - No matter of etiology: biogenetic, psychosocial and vulnerability-stress causal explanations fail to improve attitudes towards schizophrenia. AB - Many anti-stigma campaigns emphasize biogenetic causes to convey that schizophrenia is an "illness like others". A growing body of studies shows that although biogenetic explanations reduce blame, they tend to reinforce prognostic pessimism and harsher treatment of people with schizophrenia. In contrast, psychosocial explanations attenuate prognostic pessimism and perceived otherness, but seem less suitable to reduce blame. We hypothesized that a vulnerability stress model that combines biogenetic and psychosocial explanations would yield clearer stigma-reducing effects than the mono-causal models. In an online experiment, 416 participants from the general population randomly received either a vulnerability-stress, biogenetic, psychosocial or control-intervention, which consisted of information text and video presentation of a case-example. Causal beliefs, stereotypes and desired social distance were assessed by self-report. Baseline causal beliefs were weakly associated with stereotypes. The vulnerability-stress intervention did not reduce stigma more effectively than the biogenetic or psychosocial intervention and was less effective in reducing perceived blame than the biogenetic intervention. Compared to the control intervention, no intervention showed significant stigma-reducing effects, but the psychosocial and vulnerability-stress conditions both increased blame. We found no evidence for vulnerability-stress explanations as a mean to reduce stigma. We propose further research to identify more effective ways to tackle stigma. PMID- 24485064 TI - Gender differences in characteristics and outcomes of smokers diagnosed with psychosis participating in a smoking cessation intervention. AB - While research has identified gender differences in characteristics and outcomes of smokers in the general population, no studies have examined this among smokers with psychosis. This study aimed to explore gender differences among 298 smokers with psychosis (schizophrenia, schizoaffective and bipolar affective disorder) participating in a smoking intervention study. Results revealed a general lack of gender differences on a range of variables for smokers with psychosis including reasons for smoking/quitting, readiness and motivation to quit, use of nicotine replacement therapy, and smoking outcomes including point prevalence or continuous abstinence, and there were no significant predictors of smoking reduction status according to gender at any of the follow-up time-points. The current study did find that female smokers with psychosis were significantly more likely than males to report that they smoked to prevent weight gain. Furthermore, the females reported significantly more reasons for quitting smoking and were more likely to be driven by extrinsic motivators to quit such as immediate reinforcement and social influence, compared to the male smokers with psychosis. Clinical implications include specifically focussing on weight issues and enhancing intrinsic motivation to quit smoking for female smokers with psychosis; and strengthening reasons for quitting among males with psychosis. PMID- 24485065 TI - Agreement between ST elevation and late enhancement evaluated by MRI in patients with acute myocarditis. AB - BACKGROUND: ECG is widely used in the evaluation of patients with acute myocarditis. Magnetic resonance imaging (MRI) has emerged as the most important imaging tool in the diagnosis of myocarditis. The objective of this study is to determine the agreement between ECG and MRI findings in patients with acute myocarditis. METHODS: This is a retrospective cohort that includes 32 consecutive patients with acute myocarditis. ST elevation (STE) in mm was registered in every ECG lead. In every myocardial segment the presence of late enhancement (LE) was registered. RESULTS: STE was found in 75% of the patients, with the inferolateral region being the most frequently affected (46.9%). LE was found in most of the patients (87.5%); the inferolateral wall was also the most frequently affected (50%). There was a moderate agreement between the inferolateral localization of STE and LE in patients with acute myocarditis, k = 0.43, p = 0.01. There was no agreement for the other localizations. CONCLUSION: There was a moderate agreement between the localization of STE and LE only in the inferolateral localization. LE localization based on the STE localization cannot be inferred, neither vice versa in another localization different from the inferolateral. PMID- 24485066 TI - Back to basics in sepsis treatment: critically ill patients need intensive care. PMID- 24485067 TI - [Professional communication in long term health care quality]. AB - OBJECTIVE: To Identify aspects of professional communication that affect the quality of long-term care for patients with chronic illness or disabilities and their families, in the experience of health professionals, as input for the development of an assessment tool. MATERIAL AND METHOD: Descriptive qualitative.The data was processed by performing an interpretative analysis from grounded theory. The participants included 12 health professionals (three doctors, three nurses, three therapists and three psychologists), who work at the Hospital of the Universidad de La Sabana, Chia, and other institutions in Bogota, Colombia,with more than five years experience in programs treating chronic disease or disability in hospital therapeutic contexts. Semi-structured interviews and a Delphi survey were used. Validation strategies included, theoretical sampling, script evaluation by judges, triangulation of data collection techniques, and interviewers. RESULTS: We defined specific aspects of professional communication that could optimize the quality of health care, in information management as well as in the relationships with patients and families. From these aspects, an explanatory matrix was designed with axes, categories, and codes as a support for the construction of tools. CONCLUSIONS: Health communication, in order to become a therapeutic support element, requires professional training in communication skills to give information in an understandable way, with emotional support and coping possibilities. It should include and involve the family in decision making. PMID- 24485068 TI - The rare case of cervical rib fusion to the second rib. AB - This article reports on 3 patients who presented with arterial thoracic outlet syndrome and were found to have a rare clinical entity. All 3 patients presented with a rare cervical rib, which was also found to be fused to the second rib, with no first rib at all. All underwent transaxillary cervical and second rib resections and anterior scalenectomy. After transaxillary thoracic outlet decompression, all completed physical therapy with complete resolution of symptoms. PMID- 24485069 TI - Immunohistochemical expression of MMP-14 and MMP-2, and MMP-2 activity during human ovarian follicular development. AB - BACKGROUND: The aim of this study was to investigate the presence of MMP-14 and MMP-2 during human ovarian follicular development using immunohistochemistry, and the activity of MMP-2 in follicular fluid using zymography. METHODS: Ovarian tissue collected from the archives of the Department of Pathology was examined and medical records and histopathology were reviewed. Follicular fluids were collected at the IVF-department and analyzed using zymography. RESULTS: MMP-14 and MMP-2 were increasingly found in the growing follicles and MMP-2 was highly expressed in the corpus luteum. Pro-MMP-2 was present in follicular fluid of IVF patients. CONCLUSIONS: The presence of MMP-14 and MMP-2 during human ovarian follicular development from the primordial follicle to the tertiary follicle and corpus luteum is confirmed, as was indicated by earlier animal studies following stimulation with gonadotrophins. PMID- 24485070 TI - Macrophages migrate in an activation-dependent manner to chemokines involved in neuroinflammation. AB - BACKGROUND: In neuroinflammatory diseases, macrophages can play a dual role in the process of tissue damage, depending on their activation status (M1 / M2). M1 macrophages are considered to exert damaging effects to neurons, whereas M2 macrophages are reported to aid regeneration and repair of neurons. Their migration within the central nervous system may be of critical importance in the final outcome of neurodegeneration in neuroinflammatory diseases e.g. multiple sclerosis (MS). To provide insight into this process, we examined the migratory capacity of human monocyte-derived M1 and M2 polarised macrophages towards chemoattractants, relevant for neuroinflammatory diseases like MS. METHODS: Primary cultures of human monocyte-derived macrophages were exposed to interferon gamma and lipopolysaccharide (LPS) to evoke proinflammatory (M1) activation or IL 4 to evoke anti-inflammatory (M2) activation. In a TAXIScan assay, migration of M0, M1 and M2 towards chemoattractants was measured and quantified. Furthermore the adhesion capacity and the expression levels of integrins as well as chemokine receptors of M0, M1 and M2 were assessed. Alterations in cell morphology were analysed using fluorescent labelling of the cytoskeleton. RESULTS: Significant differences were observed between M1 and M2 macrophages in the migration towards chemoattractants. We show that M2 macrophages migrated over longer distances towards CCL2, CCL5, CXCL10, CXCL12 and C1q compared to non-activated (M0) and M1 macrophages. No differences were observed in the adhesion of M0, M1 and M2 macrophages to multiple matrix components, nor in the expression of integrins and chemokine receptors. Significant changes were observed in the cytoskeleton organization upon stimulation with CCL2, M0, M1 and M2 macrophages adopt a spherical morphology and the cytoskeleton is rapidly rearranged. M0 and M2 macrophages are able to form filopodia, whereas M1 macrophages only adapt a spherical morphology. CONCLUSIONS: Together our results indicate that the alternative activation status of macrophages promotes their migratory properties to chemoattractants relevant for neuroinflammatory diseases like MS. Conversely, classically activated, proinflammatory macrophages have reduced migratory properties. Based on our results, we postulate that the activation status of the macrophage influences the capacity of the macrophages to rearrange their cytoskeleton. This is the first step in understanding how modulation of macrophage activation affects macrophage migration in neuroinflammatory diseases like MS. PMID- 24485071 TI - Anti S enigma in a pregnant patient. AB - Among the antibodies of the MNS blood group system, anti S antibody is generally IgG antibody reacting at 37 degrees C. It is rarely implicated in hemolytic transfusion reaction; however, it can lead to potentially severe transfusion reactions. Anti S is also capable of causing mild to severe fatal hemolytic disease of newborn. We report a case of anti S antibody in a pregnant patient with complicated falciparum malaria. PMID- 24485076 TI - [Management of nocturia: a nosological entity within lower urinary tract symptoms in men]. AB - AIM: To review the definition, pathophysiology, impact and management of nocturia in men METHODS: We conducted a literature review using Medline and Embase with the following keywords: nocturia or nocturnal polyuria. RESULTS: Nocturia in men is a multifactorial condition that may results from prostate but also kidney, bladder, heart, or lung diseases. It affects up to 60 % of men over 70 years and is responsible for major morbidity (sleep disorders, depression, falls, fractures), especially in the elderly. Pathophysiologically, we distinguish nocturia related to excessive urine production from those resulting from a reduction in the maximum voided volume. Thus, the first and most important workup is a frequency-volume chart conducted on a 72-hour-period. The initial assessment should then be continued to clearly identify the factors contributing to polyuria (disturbance of the pattern of endogenous production of arginine vasopressin, obstructive sleep apnea...) or to a reduction in the maximum voided volume (benign prostatic hyperplasia, overactive bladder). Treatment is then targeted: treatment of benign prostatic hyperplasia, antimuscarinic in case of overactive bladder, analogue of arginin vasopressin (demopressine) if nocturnal polyuria is involved, or continuous positive airway pressure in case of a sleep apnea syndrome. CONCLUSION: Nocturia is a common and serious condition due to its morbidity. Its understanding and management have evolved significantly in recent years and are now based on a multimodal approach. PMID- 24485072 TI - Improving the transition from medical school to internship - evaluation of a preparation for internship course. AB - BACKGROUND: This study evaluates the impact of a new 'Preparation for Internship' (PRINT) course, which was developed to facilitate the transition of University of New South Wales (UNSW) medical graduates from Medical School to Internship. METHODS: During a period of major curricular reform, the 2007 (old program) and 2009 (new program) cohorts of UNSW final year students completed the Clinical Capability Questionnaire (CCQ) prior to and after undertaking the PRINT course. Clinical supervisors' ratings and self-ratings of UNSW 2009 medical graduates were obtained from the Hospital-based Prevocational Progress Review Form. RESULTS: Prior to PRINT, students from both cohorts perceived they had good clinical skills, with lower ratings for capability in procedural skills, operational management, and administrative tasks. After completing PRINT, students from both cohorts perceived significant improvement in their capability in procedural skills, operational management, and administrative tasks. Although PRINT also improved student-perceived capability in confidence, interpersonal skills and collaboration in both cohorts, curriculum reform to a new outcomes based program was far more influential in improving self-perceptions in these facets of preparedness for hospital practice than PRINT. CONCLUSIONS: The PRINT course was most effective in improving students' perceptions of their capability in procedural skills, operational management and administrative tasks, indicating that student-to-intern transition courses should be clinically orientated, address relevant skills, use experiential learning, and focus on practical tasks. Other aspects that are important in preparation of medical students for hospital practice cannot be addressed in a PRINT course, but major improvements are achievable by program-wide curriculum reform. PMID- 24485075 TI - [Renin-angiotensin system and urological cancers]. AB - INTRODUCTION: A controversy animates the literature on the potential role of the renin-angiotensin system (RAS) in tumorogenesis. The objective of this review was to determine the involvement of this pathway in cancer, and more specifically in urological cancers. MATERIAL AND METHOD: We made a systematic review of articles referenced in Pubmed, using the following keywords alone or combined: cancer, renin, angiotensin, VEGF, AT1R, antagonists of angiotensin-2 receptors, inhibitors of angiotensinogen converting. RESULTS: Many types of cancers overexpress AT1-R in their tumoral tissues (breast, stomach, bladder, astrocytoma, glioblastoma, ovary, uterus, pancreas, kidney, prostate, adrenal gland). Ang-II can induce VEGF-A expression and promote neoangiogenesis, but also can trigger different molecular pathways involved in cell proliferation or inhibit apoptosis. Several xenograft murin models demonstrated anti-tumoral efficacy of RAS blockers, alone or using combined therapies, targeting angiogenesis and slowing down tumor growth. Retrospective studies in patients have also revealed a better progression-free survival and a better response to therapies in those treated with RAS blockers. CONCLUSION: Many data seem to demonstrate the involvement of the RAS in carcinogenesis, as well as anti-tumoral effect of RAS blockers in addition to anti-cancer treatments. Clinical data are now expected to confirm these experimental findings. PMID- 24485077 TI - [Ipsilateral dual kidney transplantation: a monocentric experience about 15 cases and literature review]. AB - OBJECTIVE: Our study aimed to support the viability of the concept of Ipsilateral Dual Kidney Transplantation (DKT) by presenting our initial experience and proposing a review of the literature in this subject. METHODS: Fifteen ipsilateral DKT were performed at Nice University Hospital between August 2010 and March 2012. We have described our skin incision preferences, the vascular anastomoses, and the uretero-vesical reimplantation. We have analyzed the operative duration, the cold ischemia time (CIT) of both transplants, the blood transfusion volume, the intraoperative and postoperative complications, the time to diuresis recovery, the hospital stay, and the kinetics of the creatinine clearance until the third postoperative month. We have compared our results with those of the literature. RESULTS: The average CIT of the first transplant (T1) was 17.5 +/- 3.3 hours, and that of the second (T2) was 18.4 +/- 3.3 hours. The mean operating time was 234 +/- 67 minutes. Patients received an average of 2 units of blood during surgery [0-4] and 1.8 units in the postoperative period [0 15]. The complications rate was 26.7% and included an intraoperative T2 artery thrombosis and 3 postoperative complications consistent with a hematoma, a T2 ureteric necrosis and a T2 venous thrombosis. Two transplants were lost (6.7%) and one death (6.7%) was reported on day 40. The average length of hospital stay was 20.9 +/- 7.8 days. The mean creatinine clearance values were 12.6 mL/min at D2, 35.6 mL/min at D7, 44.9 mL/min on discharge, and 48.2 mL/min at D90. CONCLUSION: Our results supported the viability of the dual kidney transplantation concept. Furthermore the ipsilateral approach shortened the procedure and limited the surgical trauma by preserving the contralateral iliac fossa, without compromising renal function recovery or increasing morbidity. PMID- 24485078 TI - [Management of the bladder cuff removal by open excision versus transurethral resection of the ureteral orifice after laparoscopic radical nephroureterectomy in upper urinary tract--urothelial carcinoma]. AB - OBJECTIVES: To assess treatment-related complication outcomes in the management of the bladder cuff removal by open excision (OE) or transurethral resection of the ureteral orifice (TURUO) after laparoscopic radical nephroureterectomy (LNU) in upper urinary tract urothelial carcinoma (UUT-UC). PATIENTS AND METHODS: We did a retrospective study involving patients having UUT-UC who underwent LNU from 2004 to 2012 in two references center. Flexible ureteroscopy was carried out for multiple biopsies. Patients were assigned to one of two different surgical groups consisting of LNU with OE versus TURUO for the bladder cuff removal. Perioperative characteristics, complication related treatment and oncological outcomes were collected during the follow-up. RESULTS: Overall, 29 patients underwent LNU over-time including 16 using LNU with OE and 13 LNU with TURUO. LNU+OE were older (66.5 years [48-87] [P<0.01]). Operative time was shorter (180 min vs. 240 min [P=0.01]) with a longer hospital stay (7 days vs. 5 days [P<0.01]) than TURUO technic. No difference in the complication rate was reported. LNU +OE was associated with higher grade (81.3% vs. 38.5% [P=0.026]) and more invasive tumor (37.5% vs. 24.1% [P=0.03]). Regardless the technic, the cancer-specific survival rate was 63.7 years without significant differences between technics. CONCLUSION: TURUO was shorter in hospital stay but had a longer operative time with no impact on the treatment-related complication. Oncological control not highlighted any difference between technics however longer follow up is expected for recommendations. PMID- 24485079 TI - [Value of MRI in detection of extracapsular extension in prostate cancer: a prospective study comparing imaging and histology]. AB - OBJECTIVE: To establish MRI's performances for the detection of extracapsular progression of prostate carcinoma, in a single center, analyzing the correlation between MRI imaging and histological analysis of prostate specimen. METHODS: From February 2008 to June 2012, all the patients selected for prostatectomy had a pre operative MRI. Diffusion, T2 and dynamic T1 with gadolinium injection sequences were realized on a 1.5T-MRI with external antenna. All imaging data was analyzed by a specialized radiologist. Prostate specimens were histologically analyzed throughout large blades for utmost topographic comparison. The histological TNM was compared to the MRI data. MRI's capacity in determining the existence and the size of extracapsular progression was studied. RESULTS: One hundred and fifty eight patients (median age 62 years old, mean PSA 8.6 ng/mL) were included, among which 45% of d'Amico low risk and 55% of intermediate and high risk. Histological results were 63% of pT2 and 37% of pT3. MRI's sensibility and specificity for detecting extracapsular progression were 0.30 and 0.85 respectively (PPV 0.54; NPV 0.67), with a 65% accuracy. In the low risk group, sensibility equaled to 0.16. CONCLUSION: In our experience, MRI results were not reliable to influence the choice of treatment. It should be executed by expert radiologists, who are still very few. PMID- 24485080 TI - [The local anesthesia for the prostatic biopsies echo-guided: forward-looking randomized study comparing two methods]. AB - INTRODUCTION: The realization of the prostatic biopsies is a painful act. The objective of our work was to compare the analgesic efficiency of the injection of the lidocaine at the level of periprostatics laterals and apical areas compared with the use of gel of lidocaine intrarectal associated with the taking of oral tramadol. PATIENTS AND METHODS: Between November 2007 and December 2009, 60 patients admitted in the service of urology of the university hospital Mohammed VI of Marrakesh for prostatic biopsies were randomized in two groups. The group 1 (30 patients) received two tablets from tramadol 50mg with 10 mL of gel of lidocaine 2% intrarectal while 30 patients of the group 2 received 10 mL from lidocaine 2% injected at the level of periprostatics laterals and apicales. The pain was estimated by a visual analog scale (AVS) at the introduction of the probe of echography (AVS 1), at the time of the biopsy (AVS 2) and 20 minutes later (AVS 3). RESULTS: There was no significant difference between both groups concerning AVS 1 means. The average score of the pain was significantly lower in the group 2 for the AVS 2 and AVS 3. CONCLUSION: The periprostatics anesthesia assured a better control of the pain at the time of the prostatic biopsy and 20 minutes later, without increase of the complications. We recommend it to decrease the pain and the discomfort related to this technique. PMID- 24485081 TI - [Comparison of the morbidity between limited and extended pelvic lymphadenectomy during laparoscopic radical prostatectomy]. AB - OBJECTIVE: To compare the morbidity of limited pelvic lymphadenectomy to extended lymphadenectomy in patients undergoing LRP (Laparoscopic Radical Prostatectomy) for clinically localized prostate cancer. PATIENTS AND METHODS: We performed a prospective monocentric study focused on 303 consecutive patients having a pelvic lymphadenectomy during LRP from June 2000 to April 2010. One hundred and seventy six patients had a limited pelvic lymphadenectomy (June 2000-June 2006, group 1). One hundred and twenty seven patients had an extended pelvis lymphadenectomy (June 2006-April 2010, group 2) including two sub-groups according to the lateral limit of the procedure i.e. with (group 2a, 60 patients) or without dissection of the lateral side of the iliac artery (group 2b, 67 patients). RESULTS: Preoperative data (age, BMI, cTNM, Gleason score and PSA) were comparable between the groups. The number of lymph nodes and the incidence of metastatic lymph nodes were lower in group 1 (6,7 lymph nodes and 5,7%) compared to group 2 (a+b) (15.6 lymph nodes and 18.9%) (P=0.001 and P=0.0004). However, there was no difference between groups 2a and 2b (15.4 and 16.7% vs 15,8 and 20.8% P=0.65 respectively). There were more complications in the extended lymphadenectomy group compared to the limited procedure (35.4% vs 14.2%, P=0.0001), in particular more lymphatic complications (27.5% vs 10.2% P=0.0001) and lymphoedema (LO) (15.7% vs 0.6% P=0.00001). However the lymphorhea (LR) and lymphocele (LC) rate was not different (P=0.11 and P=0.17). All complications were mainly of low Clavien's classification grade (1+2) whatever the group of lymphadenectomy. The hospital stay was not increased in group 2a or 2b in regard to group 1. The rate of LR and LC was higher in group 2a than in group 1 (P=0.02 and P=0.05) but not between group 2b and 1 (P=0.81 and P=0.47). CONCLUSION: Our study showed a higher rate of complications after extended pelvic lymphadenectomy but of low grade in most cases. Moreover the lateral dissection sparing the lateral side of the iliac artery reduced the risk of lymphatic complications without decreasing the number of lymph nodes removed and the rate of metastasis. PMID- 24485082 TI - [Bipolar versus monopolar transurethral resection of the prostate: a prospective randomized study]. AB - PURPOSE: To compare bipolar with standard monopolar transurethral resection of the prostate (TURP). MATERIAL AND METHODS: A prospectively randomized study was conducted between January 2010 and September 2011. Primary end points studied were efficacy (maximum flow rate [Qmax], International Prostate Symptom Score) and safety (adverse events, decline in postoperative serum sodium [Na+] and haemoglobin [Hb] levels). Secondary end points were operation time and duration of irrigation, catheterization, and hospitalization. RESULTS: Sixty consecutive patients were randomized and completed the study, with 29 patients in the monopolar TURP group and 31 in the TURIS group. At baseline, the two groups were comparable in age, prostate volume, mean prostate-specific antigen value, International Prostate Symptom Score, and they had at least 12 months of follow up. Declines in the mean postoperative serum Na+ for bipolar and monopolar TURP groups were 1.2 and 8.7 mmol/L, respectively. However, there was no statistical difference in the decline in postoperative Hb between the two groups. The mean catheterization time was 26.6 and 52 hours in the bipolar and standard groups, respectively. This difference was statistically significant as was the difference in the time to hospital discharge. The IPSS and Qmax improvements were comparable between the two groups at 12 months of follow-up. CONCLUSION: No clinically relevant differences in short-term efficacy are existed between the two techniques, but bipolar TURP is preferable due to a more favorable safety profile and shorter catheterization duration. PMID- 24485083 TI - [Postoperative male stress urinary incontinence: outcomes of treatment by I-STOP TOMS(r) transobturator sling]. AB - OBJECTIVE: To evaluate the outcome of postoperative male stress urinary incontinence surgery using the I-STOP TOMS((r)) sub-urethral sling. MATERIAL AND METHOD: Between April 2007 and August 2012, 29 patients had been treated by sub urethral sling. Stress urinary incontinence was classified as mild, moderate or severe according to the number of pads per day. Patients were also assessed thanks to IQOL, MHU and Ditrovie self-administered questionnaires. RESULTS: Before surgery, 16 patients (55.2%) had mild incontinence, 12 (41.4%) had moderate incontinence and one (3.4%) had severe incontinence. Preoperative median MHU was 9 (5-12); median IQOL was 73 (58-88); and median Ditrovie was 2.7 (2.1 3.3). Three months after surgery, median MHU was 7 (4-9); median IQOL was 85 (75 99); and median Ditrovie was 2.1 (1.6-2.4). Pre- and postoperative questionnaires scores show a significant improvement for IQOL (P=0.014) and Ditrovie (P<0.001). After 3 months, six patients were dry (20.7%), 19 patients had mild incontinence (65.5%) and four had moderate incontinence (13.8%); in resume 17 patients (58.6%) showed a significant improvement in the number of pads (20.7% dry, 37.9% improved). After a mean follow-up of 24 +/- 19.9 months, five patients were dry (17.2%), 20 patients (69%) had mild incontinence and four had moderate incontinence (13.8%). CONCLUSION: I-STOP TOMS((r)) sub-urethral sling improved the level of postoperative stress urinary incontinence. However, the continence rate was weak. PMID- 24485084 TI - [Andrological description of a population of azoospermic men with agenesis of the vas deferens]. AB - CONTEXT: In the 1990's, congenital agenesis of the vas deferens was identified as a minor form of cystic fibrosis in relation to the frequency of mutations of the CFTR gene associated. It is responsible for masculine infertility by obstructive azoospermia; which is not accessible to a surgical treatment. However, surgical sperm retrieval and injection de spermatozoide en intracytopasmique (ICSI) allow fatherhood for these patients. PATIENTS AND METHODS: A retrospective analysis of 104 consecutive patients from 1996 to 2006. A comprehensive clinical, spermiologic, hormonal, imaging and genetic workup was carried on. The data from the surgical extractions and the attempts of ICSI were collected. RESULTS: Seventy-five percent of the patients had a mutation of the CFTR gene; ultrasound imaging revealed a renal or a seminal vesicle abnormality in 20% and 84.5% of the patients, respectively. The association of a semen volume less than 2 mL with a pH less than 7.2, a fructose less than 2 and mean sudoral chlore greater than 60 mmol/L enabled an immediate identification of 30% of patients carrier of the mutation and without renal abnormality. The sperm extraction rate was 98%. CONCLUSION: A search for the CFTR gene mutations and an ultrasound imaging of the genito-urinary system are essential to the workup of these patients. The association of a semen volume less than 2 mL, a semen pH less than 7.2 and a fructose less than 2 must point towards a minor form of cystic fibrosis and prompt the workup of genetic abnormalities and sudoral chlore testing. The results of the sperm extraction combined to the technical advances of IVF/ICSI allow excellent pregnancy rates of 66% for the companions of these patients. PMID- 24485085 TI - [Renal unilateral oncocytis: case report]. AB - The renal oncocytoma tumors are rare (5% of renal tumors). These benign tumors are incidentally diagnosed most often in an asymptomatic form. Sometimes it is multiple bilateral tumors affecting the renal parenchyma and forming a renal oncocytosis. We report the case of a unilateral right renal oncocytosis, very rare situation, characterized by a right renal parenchymal nodules with oncocytoma and a normal left kidney. PMID- 24485086 TI - [Penile gangrene: a rare complication of systemic calciphylaxis, to be screened]. AB - Gangrene of the penis is a rare and serious complication of end stage renal disease, being an expression of systemic calciphylaxis. We report the case of a 58-year-old patient with chronic renal failure and diabetes, who presented with a necrosis of the gland. MRI defined the limits of necrosis. The treatment consisted in partial amputation of the penis. Histological examination found a calciphylaxis. PMID- 24485087 TI - Downregulation of Smurf2, a tumor-suppressive ubiquitin ligase, in triple negative breast cancers: involvement of the RB-microRNA axis. AB - BACKGROUND: The HECT family ubiquitin ligase Smurf2 regulates cell polarity, migration, division, differentiation and death, by targeting diverse substrates that are critical for receptor signaling, cytoskeleton, chromatin remodeling and transcription. Recent studies suggest that Smurf2 functions as a tumor suppressor in mice. However, no inactivating mutation of SMURF2 has been reported in human, and information about Smurf2 expression in human cancer remains limited or complicated. Here we demonstrate that Smurf2 expression is downregulated in human breast cancer tissues, especially of the triple-negative subtype, and address the mechanism of Smurf2 downregulation in triple-negative breast cancer cells. METHODS: Human breast cancer tissues (47 samples expressing estrogen receptor (ER) and 43 samples with triple-negative status) were examined by immunohistochemistry for the expression of Smurf2. Ten widely-studied human breast cancer cell lines were examined for the expression of Smurf2. Furthermore, microRNA-mediated regulation of Smurf2 was investigated in triple-negative cancer cell lines. RESULTS: Immunohistochemical analysis showed that benign mammary epithelial cells expressed high levels of Smurf2, so did cells in ductal carcinomas in situ. In contrast, invasive ductal carcinomas showed focal or diffuse decrease in Smurf2 expression, which was observed more frequently in triple-negative tumors than in ER-positive tumors. Consistently, human triple negative breast cancer cell lines such as BT549, MDA-MB-436, DU-4475 and MDA-MB 468 cells showed significantly lower expression of Smurf2 protein, compared to ER + or HER2+ cell lines. Studies using quantitative PCR and specific microRNA inhibitors indicated that increased expression of miR-15a, miR-15b, miR-16 and miR-128 was involved in Smurf2 downregulation in those triple-negative cancer cell lines, which have mutations in the retinoblastoma (RB) gene. Forced expression of RB increased levels of Smurf2 protein with concomitant decreases in the expression of the microRNAs. CONCLUSIONS: This study provides evidence of posttranscriptional downregulation of Smurf2 in triple-negative breast cancers, and demonstrates that the loss of RB function is involved in microRNA-mediated interference with Smurf2 translation. The new link from RB inactivation to Smurf2 downregulation is likely to play a role in malignant phenotypes of triple negative breast cancer cells. PMID- 24485088 TI - Italian guidelines for management and treatment of hyperbilirubinaemia of newborn infants >= 35 weeks' gestational age. AB - Hyperbilirubinaemia is one of the most frequent problems in otherwise healthy newborn infants. Early discharge of the healthy newborn infants, particularly those in whom breastfeeding is not fully established, may be associated with delayed diagnosis of significant hyperbilirubinaemia that has the potential for causing severe neurological impairments. We present the shared Italian guidelines for management and treatment of jaundice established by the Task Force on Hyperbilirubinaemia of the Italian Society of Neonatology.The overall aim of the present guidelines is to provide an useful tool for neonatologists and family paediatricians for managing hyperbilirubinaemia. PMID- 24485089 TI - Geometrical adaptation in ulna and radius of cerebral palsy patients: measures and consequences. AB - BACKGROUND: The presence of significant forearm bone torsion might affect planning and evaluating treatment regimes in cerebral palsy patients. We aimed to evaluate the influence of longstanding wrist flexion, ulnar deviation, and forearm pronation due to spasticity on the bone geometries of radius and ulna. Furthermore, we aimed to model the hypothetical influence of these deformities on potential maximal moment balance for forearm rotation. METHODS: Geometrical measures were determined in hemiplegic cerebral palsy patients (n=5) and healthy controls (n=5). Bilateral differences between the spastic arm and the unaffected side were compared to bilateral differences between the dominant and non-dominant side in the healthy controls. Hypothetical effects of bone torsion on potential maximal forearm rotation moment were calculated using an existing anatomical muscle model. FINDINGS: Patients showed significantly smaller (radius: 41.6%; ulna: 32.9%) and shorter (radius: 9.1%; ulna: 8.4%) forearm bones in the non dominant arm than in the dominant arm compared to controls (radius: 2.4%; ulna 2.5% and radius: 1.5%; ulna: 1.0% respectively). Furthermore, patients showed a significantly higher torsion angle difference (radius: 24.1 degrees ; ulna: 26.2 degrees ) in both forearm bones between arms than controls (radius: 2.0 degrees ; ulna 1.0 degrees ). The model predicted an approximate decrease of 30% of potential maximal supination moment as a consequence of bone torsion. INTERPRETATION: Torsion in the bones of the spastic forearm is likely to influence potential maximal moment balance and thus forearm rotation function. In clinical practice, bone torsion should be considered when evaluating movement limitations especially in children with longstanding spasticity of the upper extremity. PMID- 24485090 TI - Rapid chondrolysis of the knee after partial lateral meniscectomy in professional athletes. AB - BACKGROUND: Postoperative knee joint chondrolysis is a rare but serious complication. The aim of our study is to report the clinical presentation, the early, mid and long-term outcomes of rapid chondrolysis after a partial lateral meniscectomy in elite athletes. METHODS: Clinical records of 10 consecutive cases of rapid chondrolysis after partial lateral meniscectomy in eight professional athletes were retrospectively reviewed. There were seven males and one female with a mean age of 25.2 years (range 20-32 years) at index procedure. An initial conservative approach to its treatment was attempted in all cases. Arthroscopic lavage was advocated in two cases. Patients were clinically reviewed at last follow-up with comparative X-rays, a subjective IKDC, a Lysholm and Tegner scale. RESULTS: All patients resumed their pre-injury level of activity at a mean 8 (+/ 2.45) months after the index procedure. At a mean of 82 (+/-36) months of follow up, the mean subjective IKDC, Lyshom and Tegner scale were respectively 82.64 (+/ 8.61), 86.6 (+/-6.44), 9 (+/-1.41). All knees demonstrated joint space narrowing scored Kellgren and Lawrence II (n=1) III (n=4) or IV (n=5) on conventional radiographs. CONCLUSION: By reviewing the common factors in each of these cases we believe that rapid chondrolysis occurs primarily due to the excessive loading of the articular cartilage in the lateral compartment of the knee. In this series, although the results in the medium term were good, the long-term outcome must be guarded due to the high rate of radiographic osteoarthritis of the lateral compartment seen in this population. STUDY DESIGN: Retrospective case series, Level IV. PMID- 24485091 TI - Sugar-sweetened carbonated beverage consumption and childhood/adolescent obesity: a case-control study. AB - OBJECTIVE: To assess the association between the consumption of sugar-sweetened carbonated beverages (SSCB) and obesity in children and adolescents from Navarra (Spain). DESIGN: We used a matched case-control study design. The exposure, SSCB consumption (1 serving: 200 ml), was measured with a previously validated FFQ. Anthropometrical measures were taken using standardized protocols. The outcome, obesity, was defined as BMI above the age- and sex-specific 97th percentile according to the Spanish reference charts. In the analysis we used conditional logistic regression. Potential confounders were controlled using a multivariable model. SETTING: Subjects were recruited in the paediatric departments of the Universidad de Navarra Clinic and the Navarra Hospital Complex, and in three primary health centres of Navarra. Controls were recruited when attending for a routine medical examination or vaccination. SUBJECTS: One hundred and seventy four obese children and 174 individually sex- and age-matched controls, 52.87% boys, with a mean age of 11.6 years. Exclusion criteria were dietary interventions, exposure to hormone treatment, development of secondary obesity due to endocrinopathy and serious intercurrent illness. RESULTS: Independently of other factors, high consumption of SSCB (>4 servings/week) was significantly associated with obesity (OR = 3.46; 95% CI 1.24, 9.62; P = 0.01). Besides, each additional daily serving of SSCB was associated with a 69% relative increase in the risk of obesity (OR = 1.69; 95% CI 1.04, 2.73; P = 0.03). CONCLUSIONS: We found a strong and significant association between SSCB consumption and obesity risk. Our results suggest a monotonic dose-response linear shape for this association in children and adolescents (P for trend = 0.02). PMID- 24485093 TI - Family networks to improve outcomes in children with intellectual and developmental disorders: a qualitative study. AB - BACKGROUND: There are at least 50 million children with an intellectual or developmental disorder in South Asia. The vast majority of these children have no access to any service and there are no resources to develop such services. We aimed to explore a model of care-delivery for such children, whereby volunteer family members of affected individuals could be organized and trained to form an active, empowered group within the community that, a) using a task-sharing approach, are trained by specialists to provide evidence-based interventions to their children; b) support each other, with the more experienced FaNs i.e. family networks, providing peer-supervision and training to new family members who join the group; and c) works to reduce the stigma associated with the condition. METHODS: We used qualitative methods to explore carers' perspectives about such a care-delivery model. RESULTS: The key findings of this research are that there is a huge gap between the needs of the carers and available services. Carers would welcome a volunteer-led service, and some community members would have time to volunteer. Raising community awareness in a culturally sensitive manner prior to launching such a service and linking it to the community health workers programme would increase the likelihood of success. Gender-matching would be important. It would be possible to form family networks around the more motivated volunteers, with support from local non-governmental organizations. The carers were receptive to the use of technology to assist the work of the volunteers as well as for networking. CONCLUSIONS: We conclude that family volunteers delivering evidence based packages of care after appropriate training is a feasible system that can help reduce the treatment gap for childhood intellectual and developmental disorders in under-served populations. PMID- 24485094 TI - Gestodene: a review of its pharmacology, potency and tolerability in combined contraceptive preparations. AB - Combined progestin-estrogen pills are an established and reliable contraceptive option used by women worldwide. Combined oral contraceptives (COCs) containing the progestins--gestodene, desogestrel or norgestimate--were developed to minimize androgenic side effects and are considered an effective, well-tolerated contraceptive option. Gestodene achieves contraceptive efficacy with the lowest dose of any progestin in a COC, and has an established and favorable short- and long-term tolerability profile. In this review we present an overview of the pharmacology, potency and tolerability of gestodene. PMID- 24485092 TI - Characterization of CD4+ subpopulations and CD25+ cells in ileal lymphatic tissue of weaned piglets infected with Salmonella Typhimurium with or without Enterococus faecium feeding. AB - The aim of the present study was to test the effect of Enterococcus faecium NCIMB 10415 (E. faecium) on CD4+ T helper immune cell subpopulations and CD25+ cells in ileal lymphatic tissue after challenge with Salmonella (S.) Typhimurium DT 104. German Landrace piglets treated with E. faecium (n=16) as a feed additive and untreated controls (n=16) were challenged with S. Typhimurium 10 days after weaning. The expression of lineage specific T helper cell subtype master transcription factors on mRNA level was measured in the whole tissue of the gut associated lymphoid tissues (ileocecal mesenteric lymph node, ileum with Peyer's patches and papilla ilealis) and in magnetically sorted T helper cells from blood and ileocecal mesenteric lymph nodes at two and 28 days post infection. CD25 protein expression of T helper cells was studied by flow cytometry in ileal Peyer's patches, lymph nodes and blood. Distribution and morphology of CD25+ cells was demonstrated in situ by immunohistochemistry in paraffin embedded specimens of the ileum and the ileocecal mesenteric lymph nodes. The data provide evidence for a higher T helper 2 cell driven immune response in the control group compared to the E. faecium treated group (P<0.05) in CD4+ magnetically sorted lymphocytes from the ileocecal mesenteric lymph nodes at two and 28 days post infection. We did not observe differences for CD25+ cells in immunohistochemistry and flow cytometry between E. faecium fed pigs and the control group, but provided a detailed description of the occurrence and morphology of these cells in the gut associate lymphoid tissues of piglets. In conclusion we suggest that (i) prolonged feeding with E. faecium can result in changes of the T helper cell response leading to a stronger infection with S. Typhimurium and (ii) that it is important to examine purified immune cells to be able to detect effects on T helper cell subpopulations. PMID- 24485096 TI - Intrauterine contraception: attitudes, practice, and knowledge among Swedish health care providers. AB - OBJECTIVES: Intrauterine contraception (IUC) is safe and highly effective, but its use remains low. Previous studies have shown that knowledge of IUC among health care providers (HCPs) is poor and that IUC is recommended to a very limited group of women. This study sought to investigate attitudes, practices and knowledge regarding IUC among Swedish HCPs. STUDY DESIGN: A pretested, national Web survey was emailed to 1157 HCPs who provide contraceptive counseling in Sweden. The collected data were transferred to IBM SPSS Statistics 20 and analyzed using chi(2) test, Fisher's Exact Test, Student's t test, and Kendall's tau-b, as appropriate. RESULTS: A total of 692 individuals (471 midwives and 221 gynecologists) answered the survey, resulting in a response rate of 60%. Younger HCPs and HCPs who performed a large number of IUC insertions considered the method applicable for a broad spectrum of women. Fewer than 30% considered IUC an option for younger women, women with a previous ectopic pregnancy or women with pelvic inflammatory disease. During insertion, 24% of the gynecologists and 15% of the midwives used analgesia in the form of paracetamol or nonsteroidal anti inflammatory drug, transcutaneous electrical nerve stimulation, hot water bottles or misoprostol for cervical ripening. HCPs at workplaces with guidelines for the insertion procedure were more likely to use analgesia and misoprostol. HCPs who performed a large number of insertions per month reported a greater use of analgesia and misoprostol (p<.01). CONCLUSION: Swedish gynecologists and midwives do not always adhere to scientific evidence and follow existing guidelines with regard to IUC. Efforts are needed to increase the number of HCPs offering IUC, especially to young and nulliparous women. IMPLICATIONS: Greater educational efforts are needed to counter reluctance among HCPs toward using IUC, especially in young and nulliparous women. PMID- 24485095 TI - Injectable and oral contraception and the incidence and progression of cervical disease in HIV-infected women in South Africa. AB - BACKGROUND: Few data exist regarding the effect of hormonal contraception (HC) on incidence and progression of cervical disease (e.g., cervical dysplasia, squamous intraepithelial lesions, cervical intraepithelial neoplasia) in HIV-infected African women. STUDY DESIGN: We conducted an observational study of HIV seropositive women in Johannesburg, South Africa. The effect of individual HC types on the incidence and progression of cervical disease was determined using Poisson regression to obtain adjusted incidence rate ratios. RESULTS: We evaluated 594 HIV-infected women, with median follow-up time of 445 days; 75 of these women were receiving some form of HC (largely DMPA, NET-EN, or COCs) at baseline. Risks of incidence and progression of cervical disease were similar comparing women not receiving HCs to women receiving DMPA, NET-EN, or COCs both individually by HC-type and considering all HC together. CONCLUSIONS: There was no statistically significant effect of particular HC methods or of HC use in general on rates of incidence or progression of cervical disease in this study. These results should reassure us that use of HC is unlikely to substantially increase risks of cervical disease among HIV-positive women. PMID- 24485097 TI - Comparison of human ventral frontal cortex areas for cognitive control and language with areas in monkey frontal cortex. AB - Human ventrolateral frontal cortex (vlFC) is identified with cognitive processes such as language and cognitive flexibility. The relationship between it and the vlFC of other primates has therefore been the subject of particular speculation. We used a combination of structural and functional neuroimaging methods to identify key components of human vlFC. We compared how vlFC areas interacted with other brain areas in 25 humans and 25 macaques using the same methods. We identified a core set of 11 vlFC components that interacted in similar ways with similar distributed circuits in both species and, in addition, one distinctively human component in ventrolateral frontal pole. Fundamental differences in interactions with posterior auditory association areas in the two species were also present-these were ubiquitous throughout posterior human vlFC but channeled to different frontal regions in monkeys. Finally, there were some differences in interregional interactions within vlFC in the two species. PMID- 24485098 TI - RNAmotifs: prediction of multivalent RNA motifs that control alternative splicing. AB - RNA-binding proteins (RBPs) regulate splicing according to position-dependent principles, which can be exploited for analysis of regulatory motifs. Here we present RNAmotifs, a method that evaluates the sequence around differentially regulated alternative exons to identify clusters of short and degenerate sequences, referred to as multivalent RNA motifs. We show that diverse RBPs share basic positional principles, but differ in their propensity to enhance or repress exon inclusion. We assess exons differentially spliced between brain and heart, identifying known and new regulatory motifs, and predict the expression pattern of RBPs that bind these motifs. RNAmotifs is available at https://bitbucket.org/rogrro/rna_motifs. PMID- 24485099 TI - Three dimensional simulation of transport and fate of oil spill under wave induced circulation. AB - An oil spill model is developed and coupled to a current-wave model to simulate oil spill transport in aquatic environments where waves are present. The oil spill model incorporates physical-chemical processes of oil spill, and simulates oil slick transport by a circulation-driven Lagrangian Parcel model. Using the coupled oil spill model and the current-wave model CH3D-SWAN, a laboratory observed wave induced circulation and oil slick evolution are successfully simulated, while different current-wave coupling schemes generate different flow patterns and oil slick evolution. The modeling system is also shown to simulate Langmuir circulation and resulting oil slicks. Hypothetical scenarios of oil spill near Virginia coast during Hurricane Isabel and Irene are simulated using the oil spill model and the CH3D-Storm Surge Modeling System to assess the role of storm waves during oil spill. The spill area is significantly larger when storm waves are considered, implying waves significantly increase oil spill dispersion. PMID- 24485100 TI - Effects of pre-deployment loperamide provision on use and travelers' diarrhea outcomes among U.S. military personnel deployed to Turkey. AB - OBJECTIVE: This study assessed the efficacy of education and self-treatment with loperamide on diarrhea morbidity and healthcare utilization in a deployed military setting. METHOD: In this prospective, controlled study, volunteers from military personnel deployed to Incirlik Air Base received either travelers' diarrhea education (non-loperamide group) or education plus a supply of loperamide (loperamide group). Volunteers were surveyed to determine frequency and outcomes of diarrheal illness. RESULTS: 109 deployed personnel were enrolled with 48 assigned to the loperamide group, and 61 to the non-loperamide group. Overall, 41 (38%) service members had at least one diarrheal episode. Only 10 (9%) service members sought treatment from a healthcare provider and the distribution was similar in both groups. Loperamide use for self-treatment was more common in the loperamide group (85%) vs. (57%), [p = 0.02]) but use of antibiotics was similar in both groups (loperamide (30%) vs. non-loperamide (20%). CONCLUSIONS: Provision of loperamide and education did not significantly affect healthcare utilization or antibiotic use to manage diarrheal episodes, when compared to education alone. Further prospective studies will either need a very large patient population to power them or should use other primary end points such a functional assessment in addition to seeking care. PMID- 24485102 TI - Degloving injury of the abdomen and external genitalia successfully treated with full-thickness degloved skin graft in a child: a 10-year follow-up. PMID- 24485101 TI - Regulatory role of TRIM21 in the type-I interferon pathway in Japanese encephalitis virus-infected human microglial cells. AB - BACKGROUND: Japanese encephalitis virus (JEV) infection leads to Japanese encephalitis (JE) in humans. JEV is transmitted through mosquitoes and maintained in a zoonotic cycle. This cycle involves pigs as the major reservoir, water birds as carriers and mosquitoes as vectors. JEV invasion into the central nervous system (CNS) may occur via antipodal transport of virions or through the vascular endothelial cells. Microglial cells get activated in response to pathogenic insults. JEV infection induces the innate immune response and triggers the production of type I interferons. The signaling pathway of type I interferon production is regulated by a number of molecules. TRIM proteins are known to regulate the expression of interferons; however, the involvement of TRIM genes and their underlying mechanism during JEV infection are not known. METHODS: Human microglial cells (CHME3) were infected with JEV to understand the role of TRIM21 in JEV infection and its effect on type I interferon (IFN-beta) production. Cells were infected in presence and absence of exogenous TRIM21 as well as after knocking down the TRIM21 mRNA. Levels of activated IRF3 expression were measured through Western blot analyses of anti-p-IRF3 antibody, and IFN-beta production was measured by using IFN-beta real-time PCR and luciferase activity analyses. RESULTS: JEV infection increased expression of TRIM21 in CHME3 cells. JEV induced an innate immune response by increasing production of IFN-beta via IRF3 activation and phosphorylation. Overexpression of TRIM21 resulted in downregulation of p-IRF3 and IFN-beta, while silencing led to increased production of p-IRF3 and IFN-beta in JEV-infected CHME3 cells. CONCLUSION: This report demonstrates TRIM21 as a negative regulator of interferon-beta (IFN-beta) production mediated by IRF-3 during JEV infection in human microglial cells. PMID- 24485104 TI - Knee, shoulder, ankle features, level I shoulder evidence, and ultrasonography expert opinion. PMID- 24485105 TI - The role of fluoroscopically guided intra-articular hip injections in potential candidates for hip arthroscopy: experience at a UK tertiary referral center over 34 months. PMID- 24485107 TI - Regarding "surgical dislocation of the hip versus arthroscopic treatment of femoroacetabular impingement: a prospective matched-pair study with average 2 year follow-up". PMID- 24485106 TI - Authors' reply. PMID- 24485108 TI - Authors' reply. PMID- 24485109 TI - Warmed irrigation fluid does not decrease perioperative hypothermia during arthroscopic shoulder surgery. AB - PURPOSE: To compare the clinical efficacy of warmed irrigation fluid and room temperature fluid in decreasing perioperative hypothermia during arthroscopic rotator cuff surgery. METHODS: In this prospective, randomized, comparative study, warmed (36 degrees C) arthroscopic irrigation fluid (group W, n = 36) or room-temperature irrigation fluid (group RT, n = 36) was used without intraoperative warming devices during arthroscopic shoulder surgery in 72 patients. The serial core body temperature and the last and lowest core body temperatures were measured by use of an esophageal stethoscope with a thermometer and a digital tympanic thermometer at 15-minute intervals during the operation and recovery period, respectively. When patients arrived in the postanesthesia care unit (PACU) after surgery, they were warmed immediately and monitored thereafter for body temperature and development of hypothermia-related adverse effects such as postoperative shivering and cardiac events. We evaluated the changes in the patients' weight and prothrombin time on postoperative day 1 and the hemoglobin level and visual analog scale pain score immediately after the operation and on postoperative day 1. RESULTS: The 2 groups did not differ in demographic and surgical data and incidence of intraoperative hypothermia (33 of 36 [91.6%] in group RT and 34 of 36 [94.4%] in group W, P = .276). The core body temperatures decreased throughout the surgery and increased linearly in the PACU, without any intergroup differences (P > .05). All patients were normothermic within 1 hour of arrival in the PACU. The 2 groups did not differ in postoperative weight change, prothrombin time, hemoglobin level, or postoperative visual analog scale pain score (all P > .05). Postoperative shivering occurred in 3 patients and 1 patient in group RT and group W, respectively. No cardiac events occurred in either group. CONCLUSIONS: Warmed irrigation fluid was not superior to room-temperature irrigation fluid in reducing the occurrence of perioperative hypothermia during arthroscopic shoulder surgery. LEVEL OF EVIDENCE: Level I, randomized controlled trial. PMID- 24485110 TI - Outcomes after bankart repair in a military population: predictors for surgical revision and long-term disability. AB - PURPOSE: To quantify the rate of surgical failure after anterior shoulder stabilization procedures, as well as to identify demographic and surgical risk factors associated with poor outcomes. METHODS: All Army patients undergoing arthroscopic or open Bankart repair for shoulder instability were isolated from the Military Health System Management Analysis and Reporting Tool between 2003 and 2010. Demographic variables (age, gender) and surgical variables (treatment facility volume, admission status, surgical technique) were extracted. Rates of surgical failure, defined as subsequent revision surgery or medical discharge with persistent shoulder complaints, were recorded from the electronic medical record and US Army Physical Disability Agency database. Risk factor analysis was performed with univariate t tests, chi(2) tests, and a multivariable logistic regression model with failure as the outcome. RESULTS: A total of 3,854 patients underwent Bankart repair during the study period, with most procedures having been performed arthroscopically (n = 3,230, 84%) and on an outpatient basis (n = 3,255, 84%). Patients were predominately men (n = 3,531, 92%), and the mean age was 28.0 years (SD, 7.5 years). A total of 193 patients (5.0%) underwent revision stabilization whereas 339 patients (8.8%) were medically discharged with complaints of shoulder instability, for a total combined failure rate of 13.8% (n = 532). Univariate analyses showed no significant effect for gender; however, younger age, higher facility volume, open repair, and inpatient status were significant factors associated with subsequent surgical failure. Multivariable analyses confirmed that young age (odds ratio [OR], 0.93; 95% confidence interval [CI], 0.91 to 0.96; P < .001), open repair (OR, 0.52; 95% CI, 0.36 to 0.75; P = .001), and inpatient status (OR, 0.58; 95% CI, 0.40 to 0.84; P = .004) were independently associated with failure by revision surgery. CONCLUSIONS: Young age remains a significant risk factor for surgical failure after Bankart repair. Patients who underwent arthroscopic Bankart repair had a significantly lower surgical failure rate (4.5%) than patients who underwent open anterior stabilization (7.7%). Despite advances in surgical technique, 1 in 20 military service members required revision surgery after failed primary stabilization in this study. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24485111 TI - Does footprint preparation influence tendon-to-bone healing after rotator cuff repair in an animal model? AB - PURPOSE: The aim of this study was to investigate the influence of footprint spongialization and radiofrequency ablation on rotator cuff repair outcomes compared with an untreated group in a rat model. METHODS: We randomly assigned 189 Sprague-Dawley rats to either a spongialization, radiofrequency ablation, or untreated group. After separation of the supraspinatus tendon from the greater tubercle, the footprint was prepared by removing the cortical bone with a burr (spongialization), was prepared by ablating soft tissue with a radiofrequency ablation device, or was left unaltered (untreated). Biomechanical testing (after 7 weeks, n = 165) and histologic analysis after 1 and 7 weeks (n = 24) followed reinsertion. RESULTS: The mean load to failure was 17.51 +/- 4.46 N/mm(2) in the spongialization group, 15.56 +/- 4.85 N/mm(2) in the radiofrequency ablation group, and 19.21 +/- 5.19 N/mm(2) in the untreated group. A significant difference was found between the spongialization and radiofrequency ablation groups (P = .0409), as well as between the untreated and radiofrequency ablation groups (P = .0014). There was no significant difference between the spongialization and untreated groups (P = .2456). The mean area of fibrocartilage transition, characterized by the presence of type II collagen, was larger after 1 and 7 weeks in the spongialization group (0.57 +/- 0.1 mm(2) and 0.58 +/- 0.1 mm(2), respectively) and untreated group (0.51 +/- 0.1 mm(2) and 0.51 +/- 0.2 mm(2), respectively) than in the radiofrequency ablation group (0.11 +/- 0.1 mm(2) and 0.4 +/- 0.1 mm(2), respectively) with P < .05 and P < .01. CONCLUSIONS: The results of this study show that radiofrequency ablation of the footprint results in a poor biomechanical and histologic outcome in an animal model. No preparation of the footprint has the same effect as spongialization. CLINICAL RELEVANCE: Different techniques of footprint preparation in rotator cuff repair may influence tendon-to-bone healing. PMID- 24485112 TI - Psychological distress in hip arthroscopy patients affects postoperative pain control. AB - PURPOSE: To determine whether patients with higher levels of preoperative psychological distress more frequently use a postoperative fascia iliaca nerve block for pain control after hip arthroscopy, and to determine whether a fascia iliaca nerve block is an effective adjunct to multimodal oral and intravenous analgesia after hip arthroscopy. METHODS: One hundred seven patients undergoing hip arthroscopy were prospectively enrolled. Before surgery, patients were administered the Distress Risk Assessment Method questionnaire to quantify their level of preoperative psychological distress. Postoperatively, patients with pain inadequately controlled by multimodal oral and intravenous analgesics could request and receive a fascia iliaca nerve block. Pain scores, opioid consumption, time in the post-anesthesia care unit (PACU), and postoperative complications were recorded for all patients. RESULTS: Patients with normal Distress Risk Assessment Method scores requested fascia iliaca nerve blocks approximately half as frequently (18 of 50 [36%]) as patients in the at-risk category (28 of 47 [60%]) or distressed category (7 of 10 [70%]) (P = .02). Patients with high levels of distress also received 40% more intraoperative opioid than patients with normal scores (P = .04). In the study population as a whole, patients who received a fascia iliaca nerve block (n = 53) had a higher initial visual analog scale (VAS) pain score in the PACU (7.2 +/- 0.3 v 5.5 +/- 0.4, P = .001) and showed greater improvement in the VAS pain score by PACU discharge (-4.3 +/- 0.2 v -2.1 +/- 0.3, P <= .0001) compared with patients who did not receive a block (n = 54). CONCLUSIONS: Patients with higher levels of preoperative psychological distress more frequently requested a postoperative nerve block to achieve adequate pain control after hip arthroscopy. Patients receiving a block had greater improvement in VAS pain scores compared with patients managed with oral and intravenous analgesics alone. LEVEL OF EVIDENCE: Level IV, case series. PMID- 24485113 TI - Symptoms of nerve dysfunction after hip arthroscopy: an under-reported complication? AB - PURPOSE: The primary purpose of this study was to analyze the rate, pattern, and severity of symptoms of nerve dysfunction after hip arthroscopy (HA) by reviewing prospectively collected data. The secondary purpose was to study whether symptoms of nerve dysfunction were related to traction time. METHODS: From March to October 2010, 52 consecutive patients-27 male patients (mean age, 40 years; range, 21 to 63 years) and 25 female patients (mean age, 37 years; range, 15 to 60 years), underwent HA with labral repair, rim trimming, and osteoplasty. The patients received a follow-up questionnaire 1 year after HA concerning symptoms of nerve dysfunction, possible localization, and erectile dysfunction. Fifty patients participated and returned fully completed questionnaires. Patients reporting symptoms of nerve dysfunction 1 year after HA were re-examined. RESULTS: Twenty-three of 50 patients (46%) reported symptoms of nerve dysfunction during the first week after HA; this was reduced to 14 patients (28%) after 6 weeks, 11 patients (22%) after 26 weeks, and 9 patients (18%) after 1 year. One patient experienced temporary erectile dysfunction. No difference in traction time between patients with symptoms of nerve dysfunction (n = 23) and patients without (n = 27) was found (98 minutes v 100 minutes; P = .88). CONCLUSIONS: Forty-six percent of patients undergoing HA reported symptoms of nerve dysfunction within the first 6 weeks after surgery. One year postoperatively, these symptoms remained in only 18% of all patients. Traction time during surgery was not different in patients with and those without symptoms of nerve dysfunction. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24485114 TI - Arthroscopic labral base repair in the hip: clinical results of a described technique. AB - PURPOSE: The purpose of this study was to evaluate the clinical outcomes of a cohort of patients who underwent labral repair by use of a previously published labral base repair suture technique for the treatment of acetabular labral tears and pincer-type femoroacetabular impingement (FAI). METHODS: Patients who received hip arthroscopy for symptomatic intra-articular hip disorders and underwent the previously described labral base repair technique were included in the study group. Patients who had Tonnis arthritis grade 2 or greater, had Legg Calves-Perthes disease, or underwent simple looped stitch repair were excluded. The patient-reported outcome scores included the modified Harris Hip Score, the Non-Arthritic Hip Score, the Hip Outcome Score-Activities of Daily Living, and the Hip Outcome Score-Sport-Specific Subscale obtained preoperatively and at 2 years' and 3 years' follow-up. Any complications, revision surgeries, and conversions to total hip arthroplasty were noted. RESULTS: Of the patients, 54 (82%) were available for follow-up. The mean length of follow-up for this cohort was 2.4 years (range, 1.7 to 4.1 years). At final follow-up, there was significant improvement in all 4 patient-reported outcome scores (modified Harris Hip Score, 63.7 to 89.9; Non-Arthritic Hip Score, 60.9 to 87.9; Hip Outcome Score Activities of Daily Living, 66.9 to 91.0; and Hip Outcome Score-Sport-Specific Subscale, 46.5 to 79.2) (P < .0001). A good or excellent result was achieved in 46 patients (85.2%). There was significant improvement in pain as measured by the change in visual analog scale score from 6.5 to 2.3 (P < .0001), and the patient satisfaction rating was 8.56 +/- 2.01. There were no perioperative complications. Revision surgery was required in 3 patients (5.6%), and 2 patients (3.7%) required conversion to total hip arthroplasty. CONCLUSIONS: The clinical results of this labral base repair technique showed favorable clinical improvements based on 4 patient-reported outcome questionnaires, visual analog scale, and patient satisfaction. More clinical, biomechanical, and histologic studies are needed to determine the optimal repair technique. LEVEL OF EVIDENCE: Level IV, therapeutic case series. PMID- 24485115 TI - Trends in the surgical treatment of articular cartilage lesions in the United States: an analysis of a large private-payer database over a period of 8 years. AB - PURPOSE: The purpose of this study was to quantify the current trends in knee cartilage surgical techniques performed in the United States from 2004 through 2011 using a large private-payer database. A secondary objective was to identify salient demographic factors associated with these procedures. METHODS: We performed a retrospective database review using a large private-payer medical record database within the PearlDiver database. The PearlDiver database is a publicly available, Health Insurance Portability and Accountability Act-compliant national database compiled from a collection of private insurer records. A search was performed for surgical techniques in cartilage palliation (chondroplasty), repair (microfracture/drilling), and restoration (arthroscopic osteochondral autograft, arthroscopic osteochondral allograft, autologous chondrocyte implantation, open osteochondral allograft, and open osteochondral autograft). The incidence, growth, and demographic factors associated with the surgical procedures were assessed. RESULTS: From 2004 through 2011, 198,876,000 patients were analyzed. A surgical procedure addressing a cartilage defect was performed in 1,959,007 patients, for a mean annual incidence of 90 surgeries per 10,000 patients. Across all cartilage procedures, there was a 5.0% annual incidence growth (palliative, 3.7%; repair, 0%; and restorative, 3.1%) (P = .027). Palliative techniques (chondroplasty) were more common (>2:1 ratio for repair [marrow-stimulation techniques] and 50:1 ratio for restoration [autologous chondrocyte implantation and osteochondral autograft and allograft]). Palliative surgical approaches were the most common technique, regardless of age, sex, or region. CONCLUSIONS: Articular cartilage surgical procedures in the knee are common in the United States, with an annual incidence growth of 5%. Surgical techniques aimed at palliation are more common than cartilage repair and restoration techniques regardless of age, sex, or region. LEVEL OF EVIDENCE: Level IV, retrospective database analysis. PMID- 24485116 TI - The outcomes and surgical techniques of the latarjet procedure. AB - PURPOSE: To determine the optimal position and orientation of the coracoid bone graft for the Latarjet procedure for recurrent instability in patients with recurrent anterior instability and high degrees of glenoid bone loss. METHODS: A systematic review of the literature including the Cochrane Database of Systematic Reviews, the Cochrane Central Register of Controlled Trials, PubMed (1980-2012), and Medline (1980-2012) was conducted. The following search teams were used: glenoid bone graft, coracoid transfer, glenoid rim fracture, osseous glenoid defect, and Latarjet. Studies deemed appropriate for inclusion were then analyzed. Study data collected included level of evidence, patient demographic characteristics, preoperative variables, intraoperative findings, technique details, and postoperative recovery and complications where available. RESULTS: The original search provided a total of 344 studies. A total of 334 studies were subsequently excluded because they were on an irrelevant topic, used an arthroscopic technique, or were not published in English or because they were review articles, leaving 10 studies eligible for inclusion. Given the different methods used in each of the studies included in the review, descriptive analysis was performed. The duration of follow-up ranged from 6 months to 14.3 years postoperatively. With the exception of 2 studies, all authors reported on recurrent shoulder instability after Latarjet reconstruction; the rate of recurrent anterior shoulder instability ranged from 0% to 8%. Overall patient satisfaction was listed in 4 studies, each of which reported good to excellent satisfaction rates of more than 90% at final follow-up. CONCLUSIONS: As noted in this review, the current literature on Latarjet outcomes consists mostly of retrospective Level IV case series. Although promising outcomes with regard to a low rate of recurrent instability have been seen with these reports, it should be noted that subtle variations in surgical technique, among other factors, may drastically impact the likelihood of glenohumeral degenerative changes arising in these patients. LEVEL OF EVIDENCE: Level IV, systematic review of Level IV studies. PMID- 24485117 TI - Management of the contaminated anterior cruciate ligament graft. AB - PURPOSE: This systematic review explores management strategies for intraoperative anterior cruciate ligament (ACL) graft contamination. METHODS: Two databases (Medline and EMBASE) were screened for studies involving ACL graft contamination published between 1946 and April 2013. We included studies evaluating the management of a contaminated graft and excluded small case-series studies. We conducted a full-text review of eligible studies, and the references were searched for additional eligible studies. Inclusion and exclusion criteria were applied to the searched studies. RESULTS: Our search yielded 6 laboratory investigations with a total of 495 graft samples used. These samples were contaminated and cleansed by various methods. The most successful sterilization protocols used chlorhexidine or mechanical agitation with a polymyxin B bacitracin solution to achieve sterility in 100% of their respective experimental graft tissues. A chlorhexidine soak and plain bacitracin soak were also effective, at 97.5% and 97%, respectively. Povidone-iodine and an antibiotic soak of polymyxin-bacitracin were the least effective, with sterility rates of 48% and 57%, respectively. CONCLUSIONS: The results of this review suggest that the optimal agent for sterilizing a dropped graft is chlorhexidine. A protocol of mechanical agitation and serial dilution with a polymyxin B-bacitracin solution was also highly effective; however, the sample size was too small to realistically recommend its use. Bacitracin alone was also found to be an effective sterilization agent, as was a combined solution of neomycin and polymyxin B. Pooled results showed that normal saline solution, povidone-iodine, and a polymyxin B-bacitracin solution all yielded suboptimal sterilization. The available evidence, however, is laboratory based and may not accurately reflect clinical conditions; moreover, there is a lack of biomechanical studies evaluating sterilized grafts. As a result, the findings should be interpreted with caution. LEVEL OF EVIDENCE: Level IV, systematic review of basic science studies. PMID- 24485118 TI - Use of ultrasonography as a diagnostic and therapeutic tool in sports medicine. AB - Ultrasonography has many important advantages over other imaging modalities and many important applications in sports medicine. This article presents an evidence based discussion of the use of ultrasound technology to diagnose and treat common musculoskeletal disorders, with emphasis on the shoulder, elbow, hip, knee, and foot and ankle. Topics include basic principles, scan artifacts, the appearance of musculoskeletal structure characteristics and pathologies, and various diagnostic and therapeutic applications in sports medicine. PMID- 24485119 TI - ISAKOS upper extremity committee consensus statement on the need for diversification of the Rockwood classification for acromioclavicular joint injuries. AB - Optimal treatment for the unstable acromioclavicular (AC) joint remains a highly debated topic in the field of orthopaedic medicine. In particular, no consensus exists regarding treatment of grade III injuries, which are classified according to the Rockwood classification by disruption of both the coracoclavicular and AC ligaments. The ISAKOS Upper Extremity Committee has provided a more specific classification of shoulder pathologies to enhance the knowledge on and clinical approach to these injuries. We suggest the addition of grade IIIA and grade IIIB injuries to a modified Rockwood classification. Grade IIIA injuries would be defined by a stable AC joint without overriding of the clavicle on the cross-body adduction view and without significant scapular dysfunction. The unstable grade IIIB injury would be further defined by therapy-resistant scapular dysfunction and an overriding clavicle on the cross-body adduction view. PMID- 24485120 TI - Severe clinical outcome is uncommon in Clostridium difficile infection in children: a retrospective cohort study. AB - BACKGROUND: Clostridium difficile infection (CDI) is the most common cause of health care-associated diarrhea in children and adults. Although serious complications of CDI have been reported to be increasing in adults, this trend has not yet been demonstrated in children. The purpose of this study was to examine the features of CDI in a pediatric population, with special attention to the occurrence of CDI-related severe outcomes. METHODS: A chart review was conducted for patients with C. difficile infection detected by cytotoxin assay between August, 2008 and July, 2012. Basic demographics, mode of acquisition (nosocomial versus community), laboratory and clinical features, treatment, and outcome data were collected. Pulsed-field gel electrophoresis and polymerase chain reaction detection of toxin A (tcdA), toxin B (tcdB), binary toxin (cdtB) and tcdC genes were performed on isolates from nosocomial cases by the National Microbiology Laboratory, Winnipeg, Manitoba. RESULTS: Ninety percent of children with CDI experienced resolution of symptoms by 30 days after disease onset and 2% experienced a severe outcome. There were no cases where colectomy was performed for CDI, and only one case where CDI contributed to death. Various combinations of clinical and laboratory features were not predictive of a severe outcome. Seventy-four percent of cases were nosocomial-associated. Among all cultured strains, the NAP4 strain occurred most frequently (24%), followed by NAP1 (11%). There was no association between strain type and clinical outcome; however, relapses were significantly more frequent in NAP4-infected children. CONCLUSIONS: Severe outcomes due to CDI are uncommon in children compared to adults. Further prospective pediatric studies on CDI in community and hospital settings are required to better understand risk factors, optimal treatment and the significance of NAP4 in pediatric CDI. PMID- 24485121 TI - A perylene derivative regulates HIF-1alpha and Stat3 signaling pathways. AB - It is becoming increasingly evident that improving the cure rate of many cancers will require treatment regimens hit more than one validated tumor targets. Developing an anti-cancer agent that targets two oncoproteins simultaneously is a promising strategy for accomplishing this goal. It would be expected to promote drug efficacy, reduce therapy-resistant without introducing additional toxic side effects. HIF-1alpha is a key regulator of the cellular response to hypoxia and is involved in tumor angiogenesis and cancer cell survival, glucose metabolism, and invasion. Stat3 has several oncogenic functions, including suppression of anti tumor immune responses and promotion of inflammation. Recently, we have identified the perylene derivative, TEL03, as a dual inhibitor that targets both HIF-1alpha and Stat3. TEL03 blocks the expression of both HIF-1alpha and Stat3, regulated oncogenes (e.g., Bcl-2, VEGF, Glut1, and others) in cancer cells, and induces cancer cell apoptosis. The results demonstrated that: (i) TEL03 blocks Stat3 phosphorylation, and inhibits Stat3 transcriptional activity; and (ii) interferes the binding of HIF-1alpha to p300/CBP inducing its degradation by proteasomes under hypoxic conditions. Our in vivo tests showed that as a dual inhibitor, TEL03 dramatically inhibited tumor growth, and provided the evidence that targeting both HIF-1alpha and Stat3 simultaneously could be a promising strategy for breast and pancreatic cancer therapies. PMID- 24485122 TI - Synthesis of aminoalkyl-substituted coumarin derivatives as acetylcholinesterase inhibitors. AB - Alzheimer's disease, one of the most common forms of dementia, is a progressive neurodegenerative disorder symptomatically characterized by declines in memory and cognitive abilities. To date, the successful therapeutic strategy to treat AD is maintaining levels of acetylcholine by inhibiting acetylcholinesterase (AChE). In the present study, coumarin derivatives were designed and synthesized as AChE inhibitors based on the lead structure of scopoletin. Of those synthesized, pyrrolidine-substituted coumarins 3b and 3f showed ca. 160-fold higher AChE inhibitory activities than scopoletin. These compounds also ameliorated scopolamine-induced memory deficit in mice when administered orally at the dose of 1 and 2 mg/kg. PMID- 24485123 TI - Discovery of novel 6,7-disubstituted-4-phenoxyquinoline derivatives bearing 5 (aminomethylene)pyrimidine-2,4,6-trione moiety as c-Met kinase inhibitors. AB - A series of novel quinoline derivatives bearing 5-(aminomethylene)pyrimidine 2,4,6-trione moiety were designed, synthesized, and evaluated for their c-Met kinase inhibitory activities and antiproliferative activities against 5 cancer cell lines (HT-29, H460, MKN-45, A549, and U87MG) in vitro. Most compounds showed moderate to excellent potency, with the most promising analogue 45 (c-Met half maximal inhibitory concentration [IC50]=1.15 nM) showing high selectivity versus 5 other tyrosine kinases, VEGFR-2, Flt-3, PDGFR-beta, c-Kit, and EGFR. Structure activity relationship studies indicated that electron-donating groups on the phenyl ring at the 3-position of pyrimidine-2,4,6-trione were required to increase the electron density on the 5-(aminomethylene)pyrimidine-2,4,6-trione moiety. PMID- 24485124 TI - Bicyclic brominated furanones: a new class of quorum sensing modulators that inhibit bacterial biofilm formation. AB - Both natural and synthetic brominated furanones are known to inhibit biofilm formation by bacteria, but their toxicity to mammalian cells is often not reported. Here, we designed and synthesized a new class of brominated furanones (BBFs) that contained a bicyclic structure having one bromide group with well defined regiochemistry. This class of molecules exhibited reduction in the toxicity to mammalian cells (human neuroblastoma SK-N-SH) and did not inhibit bacteria (Pseudomonas aeruginosa and Escherichia coli) growth, but retained the inhibitory activity towards biofilm formation of bacteria. In addition, all the BBFs inhibited the production of virulence factor elastase B in P. aeruginosa. To explore the effect of BBFs on quorum sensing, we used a reporter gene assay and found that 6-BBF and 7-BBF exhibited antagonistic activities for LasR protein in the lasI quorum sensing circuit, while 5-BBF showed agonistic activity for the rhlI quorum sensing circuit. This study suggests that structural variation of brominated furanones can be designed for targeted functions to control biofilm formation. PMID- 24485125 TI - Pneumonia associated with inhaled corticosteroid use in chronic obstructive pulmonary disease: another perspective. PMID- 24485126 TI - Traumatic brain injury and stroke. PMID- 24485127 TI - The enduring culture of Mayo Clinic. PMID- 24485128 TI - Exercise biology and medicine: innovative research to improve global health. PMID- 24485130 TI - Stroke risk and outcomes in patients with traumatic brain injury: 2 nationwide studies. AB - OBJECTIVE: To investigate whether patients with traumatic brain injury (TBI) have an increased risk of stroke or poststroke mortality. PARTICIPANTS AND METHODS: Using Taiwan's National Health Insurance Research Database, we conducted a retrospective cohort study of 30,165 patients with new TBI and 120,660 persons without TBI between January 1, 2000, and December 31, 2004. The risk of stroke was compared between 2 cohorts through December 31, 2008. To investigate the association between in-hospital mortality after stroke and history of TBI, we conducted a case-control study of 7751 patients with newly diagnosed stroke between January 1, 2005, and December 31, 2008. RESULTS: The TBI cohort had an increased stroke risk (hazard ratio [HR], 1.98; 95% CI, 1.86-2.11). Among patients with stroke, those with a history of TBI had a higher risk of poststroke mortality compared with those without TBI (odds ratio, 1.57; 95% CI, 1.13-2.19). In the TBI cohort, factors associated with stroke were history of TBI hospitalization (HR, 3.14; 95% CI, 2.77-3.56), emergency care for TBI (HR, 3.37; 95% CI, 2.88-3.95), brain hemorrhage (HR, 2.69; 95% CI, 2.43-2.99), skull fracture (HR, 3.00; 95% CI, 2.42-3.71), low income (HR, 2.65; 95% CI, 2.16-3.25), and high medical expenditure for TBI care (HR, 2.26; 95% CI, 2.09-2.43). The severity of TBI was also correlated with poststroke mortality. CONCLUSIONS: Traumatic brain injury was associated with risk of stroke and poststroke mortality. The relationship between TBI and poststroke mortality does not seem to transcend all age groups. This research shows the importance of prevention, early recognition, and treatment of stroke in this vulnerable population. PMID- 24485132 TI - Physical activity and dietary behavior in US adults and their combined influence on health. AB - OBJECTIVE: To examine the association between objectively measured physical activity and dietary behavior and their combined effect on health. PATIENTS AND METHODS: Data for this study were obtained from the 2003-2006 National Health and Nutrition Examination Survey cycles. The data were evaluated between September 9, 2012, and August 14, 2013. As part of the national survey, participants wore an accelerometer for 4 or more days to assess physical activity, blood samples were obtained to assess various biological markers, and interviews were conducted to assess dietary behavior. We selected a sample of 5211 participants and categorized them into 4 groups: (1) healthy diet and active, (2) unhealthy diet and active, (3) healthy diet and inactive, and (4) unhealthy diet and inactive. RESULTS: A total of 16.5% of participants (weighted proportions) were classified as consuming a healthy diet and being sufficiently active. After adjustments, participants were 32% more likely to consume a healthy diet if they met physical activity guidelines. For nearly all biomarkers, those who consumed a healthy diet and were sufficiently active had the most favorable biomarker levels. Compared with those who consumed a healthy diet and were active, participants who consumed an unhealthy diet and were inactive were 2.4 times more likely to have metabolic syndrome. CONCLUSION: Our findings indicate a relationship between objectively measured physical activity and dietary behavior and that participating in regular physical activity and eating a healthy diet are associated with better health outcomes when compared with diet or physical activity alone. PMID- 24485133 TI - Relation of age with symptom severity and quality of life in patients with fibromyalgia. AB - OBJECTIVE: To examine the relation of age with symptom severity and quality of life (QOL) in patients with fibromyalgia, and to compare physical and mental health of our female patients with those of the US female general population. PATIENTS AND METHODS: We studied 978 patients with fibromyalgia from May 1, 2001 through April 30, 2004, and divided them into age groups of young (<=39 years), middle-aged (40-59 years), and older (>=60 years). They completed the Fibromyalgia Impact Questionnaire and the Short Form-36 Health Status Questionnaire (SF-36). Standardized SF-36 physical and mental health summary scores were compared with those of the US female general population of similar age. One-way analysis of variance and post hoc paired t test analyses were performed to detect differences across age groups. RESULTS: Pairwise comparison found young and middle-aged patients having worse fibromyalgia symptoms in all subscales except the anxiety subscale compared with older patients (P<=.01). Similarly, these young and middle-aged patients had worse QOL in the SF-36 mental component summary, as well as SF-36 general health perceptions, vitality, social functioning, and mental health index, compared with older patients (all P<.001). When the QOL of our female patients was compared with that of the US female general population of similar age with standardized SF-36 scores, all age groups had lower QOL in physical, as well as mental, health, with more reduction in physical health, particularly in young patients. CONCLUSION: Our study shows that symptom severity and QOL differ across age groups in patients with fibromyalgia, with young and middle-aged patients having poorer QOL and worse fibromyalgia symptoms than do older patients. QOL in physical health was reduced more than in mental health, particularly in young patients, compared with the general population. PMID- 24485134 TI - Clinical characteristics, etiologic associations, laboratory findings, treatment, and proposal of diagnostic criteria of pernio (chilblains) in a series of 104 patients at Mayo Clinic, 2000 to 2011. AB - OBJECTIVE: To further characterize the clinical features, etiologic associations, laboratory findings, and treatment of pernio. PATIENTS AND METHODS: This is a retrospective review of patients with pernio seen at our institution between January 1, 2000, and December 31, 2011. RESULTS: Of 104 patients with pernio (mean age at diagnosis, 38.3 years), 82 (79%) were women. Pernio affected the toes in 85 patients (82%) and the fingers in 31 (30%). Thirty-eight patients (37%) had at least 1 abnormal laboratory test result, and test results were positive for cold agglutinins in 11 (55%) of 20 tested patients. Results were negative for cryoglobulins in all tested patients (n=53). Four patients (4%) had connective tissue disease (nonlupus) associated with pernio; 3 patients (3%) had an associated hematologic malignant disease. Conservative treatments (eg, warming, drying, and smoking cessation) provided complete response in 23 (82%) of 28 patients with follow-up data. CONCLUSION: To our knowledge, this study represents one of the largest single-center case series of pernio to date. Most of the patients did not have an underlying systemic association with pernio, although a few patients had pernio in association with connective tissue disease or hematologic malignant disease. PMID- 24485129 TI - Prehospital use of inhaled corticosteroids and point prevalence of pneumonia at the time of hospital admission: secondary analysis of a multicenter cohort study. AB - OBJECTIVE: To address clinical concern regarding the use of inhaled corticosteroids (ICSs) and the risk for pneumonia, particularly among patients with chronic obstructive pulmonary disease (COPD) and asthma. PATIENTS AND METHODS: A multicentered prospective cohort of patients admitted to the hospital from March 1, 2009, through August 31, 2009, with pneumonia or another risk factor for acute respiratory distress syndrome was analyzed to determine the risk for pneumonia requiring hospitalization among patients taking ICSs. The adjusted risk (odds ratio [OR]) for developing pneumonia because of ICSs was determined in a multiple logistic regression model. RESULTS: Of the 5584 patients in the cohort, 495 (9%) were taking ICSs and 1234 (22%) had pneumonia requiring hospitalization. In univariate analyses, pneumonia occurred in 222 (45%) of the patients on ICSs vs 1012 (20%) in those who were not (OR, 3.28; 95% CI, 2.71 3.96; P<.001). After adjusting in the logistic regression model, prehospital ICS use was not significantly associated with pneumonia in the whole cohort (OR, 1.20; 95% CI, 0.93-1.53; P=.162), among the subset of 589 patients with COPD (OR, 1.40; 95% CI, 0.95-2.09; P=.093), among the 440 patients with asthma (OR, 1.07; 95% CI, 0.61-1.87; P=.81), nor among the remaining 4629 patients without COPD or asthma (OR, 1.32; 95% CI, 0.88-1.97; P=.179). CONCLUSION: When adjusted for multiple confounding variables, ICS use was not substantially associated with an increased risk for pneumonia requiring admission in our cohort. PMID- 24485131 TI - Postoperative acute respiratory distress syndrome in patients with previous exposure to bleomycin. AB - OBJECTIVE: To determine the incidence and risk factors for postoperative acute respiratory distress syndrome (ARDS) in a large cohort of bleomycin-exposed patients undergoing surgery with general endotracheal anesthesia. PATIENTS AND METHODS: From a Mayo Clinic cancer registry, we identified patients who had received systemic bleomycin and then underwent a major surgical procedure that required more than 1 hour of general anesthesia from January 1, 2000, through August 30, 2012. Heart, lung, and liver transplantations were excluded. Postoperative ARDS (within 7 days after surgery) was defined according to the Berlin criteria. RESULTS: We identified 316 patients who underwent 541 major surgical procedures. Only 7 patients met the criteria for postoperative ARDS; all were white men, and 6 were current or former smokers. On univariate analysis, we observed an increased risk of postoperative ARDS in patients who were current or former smokers. Furthermore, significantly greater crystalloid and colloid administration was found in patients with postoperative ARDS. We also observed a trend toward longer surgical duration and red blood cell transfusion in patients with postoperative ARDS, although this finding was not significant. Intraoperative fraction of inspired oxygen was not associated with postoperative ARDS. In bleomycin-exposed patients, the incidence of postoperative ARDS after major surgery with general anesthesia is approximately 1.3% (95% CI, 0.6%-2.6%). For first major procedures after bleomycin therapy, the incidence is 1.9% (95% CI, 0.9%-4.1%). CONCLUSION: The risk of postoperative ARDS in patients exposed to systemic bleomycin appears to be lower than expected. Smoking status may be an important factor that modifies the risk of postoperative ARDS in these patients. PMID- 24485135 TI - Multiple sclerosis: current and emerging disease-modifying therapies and treatment strategies. AB - Multiple sclerosis (MS) is a chronic inflammatory demyelinating central nervous system disease that typically strikes young adults, especially women. The pathobiology of MS includes inflammatory and neurodegenerative mechanisms that affect both white and gray matter. These mechanisms underlie the relapsing, and often eventually progressive, course of MS, which is heterogeneous; confident prediction of long-term individual prognosis is not yet possible. However, because revised MS diagnostic criteria that incorporate neuroimaging data facilitate early diagnosis, most patients are faced with making important long term treatment decisions, most notably the use and selection of disease-modifying therapy (DMT). Currently, there are 10 approved MS DMTs with varying degrees of efficacy for reducing relapse risk and preserving neurological function, but their long-term benefits remain unclear. Moreover, available DMTs differ with respect to the route and frequency of administration, tolerability and likelihood of treatment adherence, common adverse effects, risk of major toxicity, and pregnancy-related risks. Thorough understanding of the benefit-risk profiles of these therapies is necessary to establish logical and safe treatment plans for individuals with MS. We review the available evidence supporting risk-benefit profiles for available and emerging DMTs. We also assess the place of individual DMTs within the context of several different MS management strategies, including those currently in use (sequential monotherapy, escalation therapy, and induction and maintenance therapy) and others that may soon become feasible (combination approaches and "personalized medicine"). We conducted this review using a comprehensive search of MEDLINE, PubMed, EMBASE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials, from January 1, 1990, to August 31, 2013. The following search terms were used: multiple sclerosis, randomized controlled trials, interferon-beta, glatiramer acetate, mitoxantrone, natalizumab, fingolimod, teriflunomide, dimethyl fumarate, BG-12, alemtuzumab, rituximab, ocrelizumab, daclizumab, neutralizing antibodies, progressive multifocal leukoencephalopathy. PMID- 24485136 TI - 86-year-old man with atrial fibrillation and dyspnea on exertion. PMID- 24485137 TI - Emerging medical devices for minimally invasive cell therapy. AB - The past decade has seen the first wave of cell-based therapeutics undergo clinical trials with varying degrees of success. Although attention is increasingly focused on clinical trial design, owing to spiraling regulatory costs, tools used in delivering cells and sustaining the cells' viability and functions in vivo warrant careful scrutiny. While the clinical administration of cell-based therapeutics often requires additional safeguarding and targeted delivery compared with traditional therapeutics, there is significant opportunity for minimally invasive device-assisted cell therapy to provide the physician with new regenerative options at the point of care. Herein we detail exciting recent advances in medical devices that will aid in the safe and efficacious delivery of cell-based therapeutics. PMID- 24485138 TI - Herpes simplex virus 2 encephalitis in adults. PMID- 24485139 TI - Shared decision making: an alternative view. PMID- 24485140 TI - Brothers with congenital erythropoietic porphyria. PMID- 24485142 TI - Wilberforce J. J. Arnold--"St. Helena's Greatest Friend". PMID- 24485143 TI - Development of population research at Mayo Clinic. PMID- 24485144 TI - The calcium-sensitive Sigma-1 receptor prevents cannabinoids from provoking glutamate NMDA receptor hypofunction: implications in antinociception and psychotic diseases. AB - Through the cannabinoid receptor 1 (CB1), the endocannabinoid system plays a physiological role in maintaining the activity of glutamate N-methyl-D-aspartate (NMDA) receptor within harmless limits. The influence of cannabinoids must be proportional to the stimulus in order to prevent NMDAR overactivation or exaggerated hypofunction that may precipitate symptoms of psychosis. In this framework, the recently reported association of CB1s with NMDARs, which mediates the reduction of cannabinoid analgesia promoted by NMDAR antagonism, could also support the precipitation of schizophrenia brought about by the abuse of smoked cannabis, mostly among vulnerable individuals. Accordingly, we have investigated this possibility using neuroprotection and analgesia as reporters of the CB1 NMDAR connection. We found that the Sigma 1 receptor (sigma1R) acts as a safety switch, releasing NMDARs from the influence of CB1s and thereby avoiding glutamate hypofunction. In sigma1R(-/-) mice the activity of NMDARs increases and cannot be regulated by cannabinoids, and NMDAR antagonism produces no effect on cannabinoid analgesia. In wild-type mice, ligands of the sigma1R did not affect the CB1-NMDAR regulatory association, however, experimental NMDAR hypofunction enabled sigma1R antagonists to release NMDARs from the negative control of CB1s. Of the sigma1R antagonists tested, their order of activity was: S1RA > BD1047 ? NE100 = BD1063, although SKF10047, PRE-084 and (+)pentazocine were inactive yet able to abolish the effect of S1RA in this paradigm. Thus, the sigma1R controls the extent of CB1-NMDAR interaction and its failure might constitute a vulnerability factor for cannabis abuse, potentially precipitating schizophrenia that might otherwise be induced later in time by the endogenous system. PMID- 24485145 TI - Isn't it ironic? Cost-effectiveness and willingness to pay for tolvaptan in the prevention of kidney failure in autosomal dominant polycystic kidney disease. PMID- 24485146 TI - CKD stage at nephrology referral and factors influencing the risks of ESRD and death. AB - BACKGROUND: Patients with chronic kidney disease (CKD) stages 3-5 are at increased risk of progressing to end-stage renal disease (ESRD) or dying prior to the development of ESRD compared with patients with less severe CKD. The magnitude of these risks may vary by stage, which has important implications for therapy. Our objective was to apply a competing risk analysis in order to estimate these risks in a referred cohort of patients with CKD by stage at referral and identify risk factors associated with each outcome. STUDY DESIGN: Retrospective cohort study. SETTING & PARTICIPANTS: 3,273 patients with CKD stages 3-5 who were referred to the nephrology clinic at Sunnybrook Health Sciences Centre, Toronto, prior to December 31, 2008, with follow-up data available prior to December 31,2008. PREDICTORS: CKD stage at time of referral; demographic, laboratory, and clinical characteristics. OUTCOMES: ESRD, defined as the initiation of dialysis therapy or pre-emptive kidney transplantation, and death from any cause prior to ESRD. MEASUREMENTS: Baseline laboratory data. RESULTS: Over a median follow-up of 2.98 years, 459 patients (14%) developed ESRD and 540 (16%) died. Rates per 100 patient-years of ESRD versus death prior to ESRD for CKD stage 3A were 0.6 (95% CI, 0.1-1.0) versus 2.2 (95% CI, 1.2-3.1; P<0.001); for CKD stage 3B, 1.4 (95% CI, 0.8-2.1) versus 4.4 (95% CI, 3.3-5.6; P<0.001); for CKD stage 4, 7.7 (95% CI, 5.9-9.4) versus 8.0 (95% CI, 6.2-9.8; P=0.6); and for CKD stage 5, 41.4 (95% CI, 34.4-48.4) versus 9.4 (95% CI, 5.2 13.4; P<0.001). For those with CKD stage 4, we identified 12 variables associated with higher risk of ESRD and 7 variables associated with higher risk of death prior to ESRD. LIMITATIONS: A cohort analyzed retrospectively. CONCLUSIONS: ESRD and death prior to ESRD incidence was most similar in CKD stage 4. We identified variables easily assessed at the time of referral that could discriminate between these risks. PMID- 24485148 TI - Differences in smoking associated DNA methylation patterns in South Asians and Europeans. AB - BACKGROUND: DNA methylation is strongly associated with smoking status at multiple sites across the genome. Studies have largely been restricted to European origin individuals yet the greatest increase in smoking is occurring in low income countries, such as the Indian subcontinent. We determined whether there are differences between South Asians and Europeans in smoking related loci, and if a smoking score, combining all smoking related DNA methylation scores, could differentiate smokers from non-smokers. RESULTS: Illumina HM450k BeadChip arrays were performed on 192 samples from the Southall And Brent REvisited (SABRE) cohort. Differential methylation in smokers was identified in 29 individual CpG sites at 18 unique loci. Interaction between smoking status and ethnic group was identified at the AHRR locus. Ethnic differences in DNA methylation were identified in non-smokers at two further loci, 6p21.33 and GNG12. With the exception of GFI1 and MYO1G these differences were largely unaffected by adjustment for cell composition. A smoking score based on methylation profile was constructed. Current smokers were identified with 100% sensitivity and 97% specificity in Europeans and with 80% sensitivity and 95% specificity in South Asians. CONCLUSIONS: Differences in ethnic groups were identified in both single CpG sites and combined smoking score. The smoking score is a valuable tool for identification of true current smoking behaviour. Explanations for ethnic differences in DNA methylation in association with smoking may provide valuable clues to disease pathways. PMID- 24485147 TI - GFR estimation: from physiology to public health. AB - Estimating glomerular filtration rate (GFR) is essential for clinical practice, research, and public health. Appropriate interpretation of estimated GFR (eGFR) requires understanding the principles of physiology, laboratory medicine, epidemiology, and biostatistics used in the development and validation of GFR estimating equations. Equations developed in diverse populations are less biased at higher GFRs than equations developed in chronic kidney disease (CKD) populations and are more appropriate for general use. Equations that include multiple endogenous filtration markers are more precise than equations including a single filtration marker. The CKD-EPI (CKD Epidemiology Collaboration) equations are the most accurate GFR estimating equations that have been evaluated in large diverse populations and are applicable for general clinical use. The 2009 CKD-EPI creatinine equation is more accurate in estimating GFR and prognosis than the 2006 MDRD (Modification of Diet in Renal Disease) Study equation and provides lower estimates of prevalence of decreased eGFR. It is useful as a "first test" for decreased eGFR and should replace the MDRD Study equation for routine reporting of serum creatinine-based eGFR by clinical laboratories. The 2012 CKD-EPI cystatin C equation is as accurate as the 2009 CKD-EPI creatinine equation in estimating GFR, does not require specification of race, and may be more accurate in patients with decreased muscle mass. The 2012 CKD-EPI creatinine cystatin C equation is more accurate than the 2009 CKD-EPI creatinine and 2012 CKD-EPI cystatin C equations and is useful as a confirmatory test for decreased eGFR as determined by serum creatinine-based eGFR. Further improvement in GFR estimating equations will require development in more broadly representative populations, including diverse racial and ethnic groups, use of multiple filtration markers, and evaluation using statistical techniques to compare eGFR to "true GFR." PMID- 24485149 TI - The flavonoid-enriched fraction AF4 suppresses neuroinflammation and promotes restorative gene expression in a mouse model of experimental autoimmune encephalomyelitis. AB - The anti-inflammatory and restorative effects of the flavonoid-enriched fraction AF4 were examined in a mouse model of experimental autoimmune encephalomyelitis (EAE). Relative to EAE mice that received vehicle (water, 10 ml/kg/day), oral administration of AF4 (25mg/kg/day) beginning 24h after the onset of clinical signs reduced disease severity from days 19-31 post-immunization. AF4-mediated recovery from EAE was preceded by reduced plasma concentrations of TNFalpha and IL-1beta on day 18 followed by decreased cytokine production and neuropathology in the cerebellum and spinal cord on day 31. Clinical improvement for EAE-AF4 mice from days 18 to 31 was accompanied by the elevated expression of genes that mediate remyelination. These findings suggest that AF4 decreased EAE severity by promoting the resolution of inflammation and improving functional recovery in the CNS. PMID- 24485150 TI - Treatment with atacicept enhances neuronal cell death in a rat model of optic neuritis. AB - We investigated the effect of atacicept, a recombinant fusion protein blocking BLyS and APRIL and acting on B cells, on degeneration of retinal ganglion cells (RGCs) during experimental autoimmune encephalomyelitis (EAE). We used myelin oligodendrocyte glycoprotein in Brown Norway rats to induce a variant of EAE which involves B cells and leads to severe optic neuritis. Intraperitoneal treatment with atacicept at some of the studied dose levels (100 or 200 MUg) resulted in increased apoptosis of retinal ganglion cells whereas at a tenfold lower dose or in vehicle-treated animals no such effect became apparent. Also the extent of inflammation, demyelination, and axonal loss of the optic nerve was more pronounced in rats treated with the higher atacicept dose level. The present study describes observational evidence for adverse effects of atacicept on neuronal survival during EAE. PMID- 24485151 TI - Half-life measurements of chemical inducers for recombinant gene expression. AB - BACKGROUND: Inducible promoters are widely spread genetic tools for triggering, tuning and optimizing the expression of recombinant genes in engineered biological systems. Most of them are controlled by the addition of a specific exogenous chemical inducer that indirectly regulates the promoter transcription rate in a concentration-dependent fashion. In order to have a robust and predictable degree of control on promoter activity, the degradation rate of such chemicals should be considered in many applications like recombinant protein production. RESULTS: In this work, we use whole-cell biosensors to assess the half-life of three commonly used chemical inducers for recombinant Escherichia coli: Isopropyl beta-D-1-thiogalactopyranoside (IPTG), anhydrotetracycline (ATc) and N-(3-oxohexanoyl)-L-homoserine lactone (HSL). A factorial study was conducted to investigate the conditions that significantly contribute to the decay rate of these inducers. Temperature has been found to be the major factor affecting ATc, while medium and pH have been found to highly affect HSL. Finally, no significant degradation was observed for IPTG among the tested conditions. CONCLUSIONS: We have quantified the decay rate of IPTG, ATc and HSL in many conditions, some of which were not previously tested in the literature, and the main effects affecting their degradation were identified via a statistics-based framework. Whole-cell biosensors were successfully used to conduct this study, yielding reproducible measurements via simple multiwell-compatible assays. The knowledge of inducer degradation rate in several contexts has to be considered in the rational design of synthetic biological systems for improving the predictability of induction effects, especially for prolonged experiments. PMID- 24485152 TI - Accordion complication grading predicts short-term outcome after right colectomy. AB - BACKGROUND: The Accordion severity grading system is a novel system to score the severity of postoperative complications in a standardized fashion. This study aims to demonstrate the validity of the Accordion system in colorectal surgery by correlating severity grades with short-term outcomes after right colectomy for colon cancer. METHODS: This is a retrospective cohort review of patients who underwent right colectomy for cancer between January 1, 2002, and January 31, 2007, at a single tertiary care referral center. Complications were categorized according to the Accordion severity grading system: grades 1 (mild), 2 (moderate), 3-5 (severe), and 6 (death). Outcome measures were hospital stay, 30 d readmission rate and 1-y survival. Correlation between Accordion grades and outcome measures is reflected by Spearman rho (rho). One-year survival was obtained per Kaplan-Meier method and compared by logrank test for trend. Significance was set at P <= 0.05. RESULTS: Overall, 235 patients underwent right colectomy for cancer of which 122 (51.9%) had complications. In total, 52 (43%) had an Accordion grade 1 complication; 44 (36%) grade 2; four (3%) grade 3; 11 (9%) grade 4; seven (6%) grade 5; and four (3%) grade 6. There was significant correlation between Accordion grades and hospital stay (rho = 0.495, P < 0.001) and 30-d readmission rate (rho = 0.335, P < 0.001). There was a significant downward trend in 1-y survival as complication severity by Accordion grade increased (P = 0.02). CONCLUSIONS: The Accordion grading system is a useful tool to estimate short-term outcomes after right colectomy for cancer. High-grade Accordion complications are associated with longer hospital stay and increased risk of readmission and mortality. PMID- 24485153 TI - Accelerated functional recovery after skeletal muscle ischemia-reperfusion injury using freshly isolated bone marrow cells. AB - BACKGROUND: Relatively little information exists regarding the usefulness of bone marrow-derived cells for skeletal muscle ischemia-reperfusion injury (I/R), especially when compared with I/R that occurs in other tissues. The objectives of this study were to evaluate the ability of freshly isolated bone marrow cells to home to injured skeletal muscle and to determine their effects on muscle regeneration. MATERIALS AND METHODS: Freshly isolated lineage-depleted bone marrow cells (Lin(-) BMCs) were injected intravenously 2 d after I/R. Bioluminescent imaging was used to evaluate cell localization for up to 28 d after injury. Muscle function, the percentage of fibers with centrally located nuclei, and the capillary-to-fiber ratio were evaluated 14 d after delivery of either saline (Saline) or saline containing Lin(-) BMCs (Lin(-) BMCs). RESULTS: Bioluminescence was higher in the injured leg than the contralateral control leg for up to 7 d after injection (P < 0.05) suggestive of cell homing to the injured skeletal muscle. Fourteen days after injury, there was a significant improvement in maximal tetanic torque (40% versus 22% deficit; P < 0.05), a faster rate of force production (+dP/dt) (123.6 versus 94.5 Nmm/S; P < 0.05), and a reduction in the percentage of fibers containing centrally located nuclei (40 versus 17%; P < 0.05), but no change in the capillary-to-fiber ratio in the Lin(-) BMC as compared with the Saline group. CONCLUSIONS: The homing of freshly isolated BMCs to injured skeletal muscle after I/R is associated with an increase in functional outcomes. PMID- 24485155 TI - Sjogren's syndrome: a forty-year scientific journey. AB - My long scientific journey studying as a disease model Sjogren's syndrome (SS) gave me the opportunity to uncover the mysteries of systemic autoimmune diseases. After an extensive training, under the supervision of the major autoimmune disease investigators, I was able to convey and expand the acquired knowledge through inspiring my students and collaborators. Our research enriches the understanding of the wide clinical spectrum of the syndrome and the clinical, laboratory and molecular events predicting or being responsible for lymphomagenesis. Our molecular and cellular studies indicated that the target of autoimmunity in SS, the activated glandular epithelial cells, play significant role in the initiation and perpetuation of the autoimmune process. Furthermore, discovery of the epitopes on autoantigens where the autoimmune humoral reactivity is directed against, provided us tools to develop specific and sensitive diagnostic assays, to unmask similarities of the epitope sequence with infectious agents and gave us the potential to use them as therapeutic modalities. PMID- 24485154 TI - A/H1N1 antibodies and TRIB2 autoantibodies in narcolepsy patients diagnosed in conjunction with the Pandemrix vaccination campaign in Sweden 2009-2010. AB - Narcolepsy is a lifelong sleep disorder related to hypocretin deficiency resulting from a specific loss of hypocretin-producing neurons in the lateral hypothalamic area. The disease is thought to be autoimmune due to a strong association with HLA-DQB1*06:02. In 2009 the World Health Organization (WHO) declared the H1N1 2009 flu pandemic (A/H1N1PDM09). In response to this, the Swedish vaccination campaign began in October of the same year, using the influenza vaccine Pandemrix((r)). A few months later an excess of narcolepsy cases was observed. It is still unclear to what extent the vaccination campaign affected humoral autoimmunity associated with narcolepsy. We studied 47 patients with narcolepsy (6-69 years of age) and 80 healthy controls (3-61 years of age) selected after the Pandemrix vaccination campaign. The first aim was to determine antibodies against A/H1N1 and autoantibodies to Tribbles homolog 2 (TRIB2), a narcolepsy autoantigen candidate as well as to GAD65 and IA-2 as disease specificity controls. The second aim was to test if levels and frequencies of these antibodies and autoantibodies were associated with HLA-DQB1*06:02. In vitro transcribed and translated [(35)S]-methionine and -cysteine-labeled influenza A virus (A/California/04/2009/(H1N1)) segment 4 hemagglutinin was used to detect antibodies in a radiobinding assay. Autoantibodies to TRIB2, GAD65 and IA-2 were similarly detected in standard radiobinding assays. The narcolepsy patients had higher median levels of A/H1N1 antibodies than the controls (p = 0.006). A/H1N1 antibody levels were higher among the <13 years old (n = 12) compared to patients who were older than 30 years (n = 12, p = 0.014). Being HLA-DQB1*06:02 positive was associated with higher A/H1N1 antibody levels in both patients and controls (p = 0.026). Serum autoantibody levels to TRIB2 were low overall and high binders did not differ between patients and controls. We observed an association between levels of A/H1N1 antibodies and TRIB2 autoantibody levels particularly among the youngest narcolepsy patients (r = 0.819, p < 0.001). In conclusion, following the 2009 influenza pandemic vaccination, A/H1N1 antibody levels were associated with young age-at-onset narcolepsy patients positive for HLA-DQB1*06:02. The possibility that TRIB2 is an autoantigen in narcolepsy remains to be clarified. We could verify autoantibody responses against TRIB2 which needs to be determined in larger patient cohorts and control populations. PMID- 24485156 TI - Diagnosis and classification of Kawasaki disease. AB - Kawasaki disease is an acute systemic vasculitis of unknown etiology. Diagnosis is based on clinical criteria that include fever, exanthema, conjunctivitis, changes in the extremities, erythema of oral mucosa and lips and cervical lymphadenopathy. However, these criteria have low sensitivity and specificity and therefore, other clinical and laboratory features may be helpful in establishing the diagnosis, especially for cases of atypical or incomplete Kawasaki disease. Prognosis depends on the extent of cardiac involvement; coronary aneurysms develop in 20-25% of untreated patients and these may lead to myocardial infarction and sudden death. Treatment with high-dose intravenous immunoglobulin is effective in reducing the risk of coronary aneurysms in most cases and is the treatment of choice for initial Kawasaki disease. PMID- 24485157 TI - Diagnosis and classification of polyarteritis nodosa. AB - Polyarteritis nodosa (PAN) is a systemic necrotizing vasculitis preferentially targeting medium-sized arteries and not associated with glomerulonephritis or small vessel involvement. Anti-neutrophil cytoplasmic antibodies are typically negative. PAN may be triggered by viral infections, particularly hepatitis B virus, but remains idiopathic in most cases. Clinical manifestations of PAN are multisystemic. Peripheral nerve and skin are the most frequently affected tissues. Involvement of the gastrointestinal tract, kidneys, heart, and central nervous system is associated with higher mortality. Laboratory abnormalities reveal a prominent acute phase response but are non-specific. Histologic confirmation of vasculitis in medium sized arteries is desirable and biopsies must be obtained from symptomatic organs if feasible. Skin or muscle and nerve are preferred because of higher diagnostic yield and safety. If biopsies are negative or cannot be obtained, visceral angiography, may reveal multiple micro aneurysms supporting the diagnosis of PAN. Current treatment policy includes high dose corticosteroids, which are combined with immunosuppressive agents when critical organ involvement or life-threatening complications occur. IV pulse cyclophosphamide in the remission induction phase, later switched to a safer immunosuppressant for remission maintenance is a frequently used therapeutic approach. A recent consensus algorithm for the classification of PAN has attempted to overcome some of the caveats of the 1990 American College of Rheumatology (ACR) classification criteria which have proven to be unsatisfactory, and has also confirmed the low prevalence of PAN compared to other systemic necrotizing vasculitides. European league against rheumatic diseases (EULAR)/ACR endorsed international cooperation to establish new diagnostic/classification criteria is currently under way. PMID- 24485158 TI - Diagnosis and classification of granulomatosis with polyangiitis (aka Wegener's granulomatosis). AB - Granulomatosis with polyangiitis (GPA, formerly known as Wegener's Granulomatosis) is an autoimmune small vessel vasculitis which is highly associated with anti-neutrophil cytoplasmic antibodies (ANCA). The hallmarks of this condition are systemic necrotising vasculitis, necrotising granulomatous inflammation, and necrotising glomerulonephritis. The aetiology of granulomatosis with polyangiitis is linked to environmental and infectious triggers inciting onset of disease in genetically predisposed individuals. Anti-neutrophil cytoplasmic antibodies are pathogenic and play an important role in the pathogenesis of this disease, although ANCA positivity is not essential for a clinical diagnosis of granulomatosis with polyangiitis. Granulomatosis with polyangiitis is diagnosed based on clinical manifestations of systemic vasculitis and histological evidence of necrotising vasculitis or granulomatous inflammation. This small vessel vasculitis may present as limited disease of the ears, nose and upper airways or mild, moderate or severe systemic disease. Immunosuppression and adjuvant therapies have contributed to the improved prognosis of granulomatosis with polyangiitis over the past decades. Treatment strategies are tailored to the severity of the disease. They are based on published evidence of the efficacy and safety of the immunosuppressive drugs indicated to manage active vasculitis and maintain clinical remission. This review will summarise the history, aetiology, pathogenesis, classification, diagnosis and management of granulomatosis with polyangiitis. PMID- 24485159 TI - Genome-wide co-localization of Polycomb orthologs and their effects on gene expression in human fibroblasts. AB - BACKGROUND: Polycomb group proteins form multicomponent complexes that are important for establishing lineage-specific patterns of gene expression. Mammalian cells encode multiple permutations of the prototypic Polycomb repressive complex 1 (PRC1) with little evidence for functional specialization. An aim of this study is to determine whether the multiple orthologs that are co expressed in human fibroblasts act on different target genes and whether their genomic location changes during cellular senescence. RESULTS: Deep sequencing of chromatin immunoprecipitated with antibodies against CBX6, CBX7, CBX8, RING1 and RING2 reveals that the orthologs co-localize at multiple sites. PCR-based validation at representative loci suggests that a further six PRC1 proteins have similar binding patterns. Importantly, sequential chromatin immunoprecipitation with antibodies against different orthologs implies that multiple variants of PRC1 associate with the same DNA. At many loci, the binding profiles have a distinctive architecture that is preserved in two different types of fibroblast. Conversely, there are several hundred loci at which PRC1 binding is cell type specific and, contrary to expectations, the presence of PRC1 does not necessarily equate with transcriptional silencing. Interestingly, the PRC1 binding profiles are preserved in senescent cells despite changes in gene expression. CONCLUSIONS: The multiple permutations of PRC1 in human fibroblasts congregate at common rather than specific sites in the genome and with overlapping but distinctive binding profiles in different fibroblasts. The data imply that the effects of PRC1 complexes on gene expression are more subtle than simply repressing the loci at which they bind. PMID- 24485160 TI - LMNA gene mutation as a model of cardiometabolic dysfunction: from genetic analysis to treatment response. AB - AIM: This report highlights the metabolic, endocrine and cardiovascular comorbidities in a case of familial partial lipodystrophy (FPLD), and also evaluates the efficacy and safety of metformin therapy. METHODS: Mutational analysis was carried out of the LMNA gene in a teenage girl with an FPLD phenotype. Insulin resistance, sex hormones and metabolic parameters were also evaluated, and echocardiography, electrocardiography and 24-h blood pressure monitoring were also done. RESULTS: The patient showed atypical fat distribution, insulin resistance and hypertrophic cardiomyopathy. Physical examination revealed muscle hypertrophy with a paucity of fat in the extremities, trunk and gluteal regions, yet excess fat deposits in the face, neck and dorsal cervical region. LMNA sequencing revealed a heterozygous missense mutation (c.1543A>G) in exon 9, leading to substitution of lysine by glutamic acid at position 515 (K515E). Moderate hypertension and secondary polycystic ovary syndrome were also assessed. Treatment with metformin resulted in progressive improvement of metabolic status, while blood pressure values normalized with atenolol therapy. CONCLUSIONS: Very rapid and good results with no side-effects were achieved with metformin therapy for FPLD. The association of an unusual mutation in the LMNA gene was also described. PMID- 24485161 TI - [Benefits and risks of growth hormone in adults with growth hormone deficiency]. AB - Adult growth hormone (GH) deficiency is a well-recognized clinical syndrome with adverse health consequences. Many of these may improve after replacement therapy with recombinant GH. This treatment induces an increase in lean body mass and a decrease in fat mass. In long-term studies, bone mineral density increases and muscle strength improves. Health-related quality of life tends to increase after treatment with GH. Lipid profile and markers of cardiovascular risk also improve with therapy. Nevertheless, GH replacement therapy is not without risk. According to some studies, GH increases blood glucose, body mass index and waist circumference and may promote long-term development of diabetes and metabolic syndrome. Risk of neoplasia does not appear to be increased in adults treated with GH, but there are some high-risk subgroups. Methodological shortcomings and difficulties inherent to long-term studies prevent definitive conclusions about the relationship between GH and survival. Therefore, research in this field should remain active. PMID- 24485162 TI - [Epigenetic heredity (deoxyribonucleic acid methylation): Clinical context in neurodegenerative disorders and ATXN2 gene]. AB - Epigenetics is the group of changes in the phenotype which are related with the process independently of the primary DNA sequence. These changes are intimately related with changes in the gene expression level and its profile across the body. These are mediated by histone tail modifications, DNA methylation, micro RNAs, with chromatin remodeling remaining as the foundation of epigenetic changes. DNA methylation involves the covalent addition of methyl group to cytosine of the DNA, which is mediated by methyltransferases enzymes. DNA methylation regulates gene expression by repressing transcription, while de methylation activates gene transcription. Several human diseases are related with the epigenetic process: cancer, Alzheimer disease, stroke, Parkinson disease, and diabetes. We present here the basis of epigenetic inheritance and show the pathogenic mechanisms relating epigenetics in human diseases, specifically with regard to neurodegeneration. We discuss current concepts aimed at understanding the contribution of epigenetics to human neurodegenerative diseases. We also discuss recent findings obtained in our and other centers regarding the ATXN2 gene that causes spinocerebellar ataxia 2 and amyotrophic lateral sclerosis. Epigenetics play a pivotal role in the pathogenesis of human diseases and in several neurodegenerative disorders, and this knowledge will illuminate the pathways in the diagnostic and therapeutic field, which ultimately will be translated into the clinic context of neurodegenerative diseases. PMID- 24485163 TI - [Use and usefulness of echocardiography performed by "non-cardiologists"]. PMID- 24485164 TI - [Effectiveness of co-management between orthopaedic surgeons and internists for inpatient elders with hip fracture]. AB - BACKGROUND AND OBJECTIVE: Hip fracture is a common injury in elder patients who have comorbidities, and it increases the risk of morbimortality. They could benefit from co-management (CM) between orthopaedic surgeons and internists. The objective was to evaluate the effectiveness of this CM. PATIENTS AND METHOD: Prospective study of 138 patients over 64 years with hip fracture treated with CM care and one-year of follow-up. The control group was a cohort of 153 patients with similar criteria who had been treated with conventional care. Several pre- and postsurgical variables, complications, and potential risk factors for mortality were analyzed. The Charlson index, mental test, Katz and SF-12 quality of life questionnaires, and Merle D'Aubigne hip score were used. RESULTS: Surgical delay was lower in the CM cohort (P=.001). The rates of complications and readmissions were similar in both cohorts. The average stay was lower (P=.001) in the CM cohort. In-hospital and 3-month mortality were similar, but it was lower in the CM cohort at 6 (P=.04) and 12 months (P=.03). In both cohorts, gender, number of comorbidities, ASA score, Charlson index or surgery type were not predictors of mortality. Surgical delay>2 days was a predictor in the CM cohort, whereas age was a predictor in the control cohort. The final functional outcomes were similar in both cohorts. CONCLUSION: Our results show the effectiveness of this CM to reduce surgical delay, hospital stay and mortality at 6 months. PMID- 24485165 TI - [Residential radon and lung cancer. An ecologic study in Galicia, Spain]. AB - BACKGROUND AND OBJECTIVE: Residential radon is the second cause of lung cancer and the first in never smokers. Galicia is a high radon emission area. The objective of this study is to analyze the relationship between municipal lung cancer mortality and residential radon in Galician municipalities. MATERIAL AND METHOD: We performed an ecologic study including 192 municipalities with at least 3 residential radon measurements. The observed number of lung cancer deaths was obtained from the Galician Mortality Registry. Afterwards, we calculated the standardized mortality ratios (SMRs) of lung cancer for males and females for the period comprising 1980-2009. Median municipal residential radon concentrations were correlated with lung cancer SMRs. RESULTS: Median residential radon concentration for the included municipalities was 75 Bq/m(3), with an interquartile range of 40.7 to 154 Bq/m(3). The correlation between lung cancer SMRs and municipal radon concentration was statistically significant for males (P=.023) whereas it did not reach statistical significance for females (P=.087). CONCLUSION: There exists an association between municipal residential radon and lung cancer mortality in Galicia for males, though for women the association is not statistically significant. These results suggest that residential radon could raise the risk of lung cancer in males, though for females no association is evident. PMID- 24485166 TI - Prenatal screening and diagnosis of aneuploidy in multiple pregnancies. AB - Prenatal screening for aneuploidy has changed significantly over the last 30 years, from being age-based to maternal serum and ultrasound based techniques. Multiple pregnancies present particular challenges with regards to screening as serum-based screening techniques are influenced by all feti while ultrasound based techniques can be fetus specific. Tests currently available tend to not perform as well in multiple compared to singleton pregnancies. Considerations must be given to these variations when discussing and performing screening for aneuploidy in this situation. Prenatal invasive diagnosis techniques in multiple pregnancies bring their own challenges from a technical and counselling point of view, in particular with regards to sampling error, mapping and assignment of results and management of abnormal results. This review addresses these particular challenges and provides information to facilitate care. PMID- 24485167 TI - Differences in synovial fluid cytokine levels but not in synovial tissue cell infiltrate between anti-citrullinated peptide/protein antibody-positive and negative rheumatoid arthritis patients. AB - INTRODUCTION: Comparative data on synovial cell infiltrate and cytokine levels in anti citrullinated peptide/protein antibody (ACPA)-positive and ACPA negative rheumatoid arthritis (RA) patients are scarce. Our aim was to analyze synovial cell infiltrate and synovial fluid (SF) levels of cytokines in patients with RA according to the presence or absence of ACPA in serum. METHODS: A cross-sectional study in a single center including consecutive RA patients was performed. Patients were defined as 'ACPA negative' if serum was negative to two different ACPAs [second generation commercial anti-cyclic citrullinated peptide antibodies (CCP2) and chimeric fibrin/filaggrin citrullinated antibodies]. Parallel synovial tissue (ST) biopsies and SF were obtained by knee arthroscopy. Synovial cell infiltrate and endothelial cells were analyzed by immunohistochemistry and SF levels of Th1, Th2, Th17 and pro-inflammatory cytokines by Quantibody(R) Human Array. RESULTS: A total of 83 patients underwent arthroscopy, with a mean age of 55.9 +/- 12 years, and mean disease duration of 45 months (interquartile range, IQR 10.8 to 122). 62% were female and 77% were ACPA positive. No significant differences were found in clinical variables, acute phase reactants, synovial cell infiltrate or lymphoid neogenesis (LN) between ACPA positive and negative patients. However ACPA positive patients had significantly higher levels of IL 1beta, IL-10, IL-17 F and CC chemokine ligand 20 (CCL-20) than ACPA negative patients. CONCLUSIONS: In our cohort of patients with RA no significant differences were found in synovial cell infiltrate or synovial LN according to ACPA status. However, ACPA positive patients had higher levels of T-cell derived and pro-inflammatory cytokines than ACPA negative patients. As systemic and local inflammation was similar in the two groups, these findings support a distinct synovial physiopathology. PMID- 24485168 TI - Vpx rescue of HIV-1 from the antiviral state in mature dendritic cells is independent of the intracellular deoxynucleotide concentration. AB - BACKGROUND: SIVMAC/HIV-2 Vpx recruits the CUL4A-DCAF1 E3 ubiquitin ligase complex to degrade the deoxynucleotide hydrolase SAMHD1. This increases the concentration of deoxynucleotides available for reverse transcription in myeloid cells and resting T cells. Accordingly, transduction of these cells by SIVMAC requires Vpx. Virus-like particles containing SIVMAC Vpx (Vpx-VLPs) also increase the efficiency of HIV-1 transduction in these cells, and rescue transduction by HIV 1, but not SIVMAC, in mature monocyte-derived dendritic cells (MDDCs). Differences in Vpx mechanism noted at that time, along with recent data suggesting that SAMHD1 gains additional restriction capabilities in the presence of type I IFN prompted further examination of the role of Vpx and SAMHD1 in HIV-1 transduction of mature MDDCs. RESULTS: When challenged with Vpx-VLPs, SAMHD1 was degraded in MDDCs even after cells had been matured with LPS, though there was no increase in deoxynucleotide levels. Steady-state levels of HIV-1 late reverse transcription products in mature MDDCs were increased to the same extent by either Vpx-VLPs or exogenous nucleosides. In contrast, only Vpx-VLPs increased the levels of 2-LTR circles and proviral DNA in myeloid cells. These results demonstrate that exogenous nucleosides and Vpx-VLPs both increase the levels of HIV-1 cDNA in myeloid cells, but only Vpx-VLPs rescue 2-LTR circles and proviral DNA in myeloid cells with a previously established antiviral state. Finally, since trans-acting Vpx-VLPs provide long-lasting rescue of HIV-1 vector transduction in the face of the antiviral state, and exogenous nucleosides do not, exogenous nucleosides were used to achieve efficient transduction of MDDCs by vectors that stably encode Vprs and Vpxs from a collection of primate lentiviruses. Vpr from SIVDEB or SIVMUS, Vpx from SIVMAC251 or HIV-2, but not SIVRCM, degraded endogenous SAMHD1, increased steady-state levels of HIV-1 cDNA, and rescued HIV-1 from the antiviral state in MDDCs. CONCLUSION: Inhibition of deoxynucleotide hydrolysis by promoting SAMHD1 degradation is not the only mechanism by which Vpx rescues HIV-1 in MDDCs from the antiviral state. Vpx has an additional effect on HIV-1 transduction of these cells that occurs after completion of reverse transcription and acts independently of deoxynucleotide levels. PMID- 24485169 TI - Umbilical arterial pH in patients with cerebral palsy. AB - BACKGROUND: Umbilical arterial pH (UApH) in severe cerebral palsy (CP) is not fully understood. AIMS: This work aims to determine the relationship between fetal acidemia and clinical features of severe CP. STUDY DESIGN: A retrospective study design is used. SUBJECTS: A review was conducted unti1 April 2013 among 218 infants with CP diagnosed to be caused by antenatal and/or intrapartum conditions determined by the Japan Council for Quality Health Care. After excluding patients in whom the causes of CP were thought to be due to events after delivery, 168 infants born at over 34weeks of gestation that both Apgar score and UApH were measured were selected. OUTCOME MEASURES: Severe fetal acidemia was defined as a pH of less than 7.0. RESULTS: Six major factors were found to be associated with CP: placental abruption (A, n=42), traumatic delivery with an abnormal FHR pattern (B, n=29), an abnormal FHR pattern during labor (C, n=27), chorioamnionitis with an abnormal FHR pattern (D, n=17), an abnormal FHR pattern before labor (E, n=14), and cord prolapse (F, n=10). The UApH was less than 7.0 in 114 cases (67.9%) and more than 7.20 in 20 cases (11.9%). The UApH values were lowest in group A (median 6.7, 6.43-6.99) and highest in group E (7.18, 6.92 7.45). The distribution of the UApH values was significantly different in these groups. CONCLUSION: Placental abruption was a factor most associated with low pH. Even among the infants with severe CP, over 10% of patients exhibited a non acidemic status at birth. PMID- 24485170 TI - Postural complexity differs between infant born full term and preterm during the development of early behaviors. AB - BACKGROUND AND AIMS: Postural control differs between infants born preterm and full term at 1-3weeks of age. It is unclear if differences persist or alter the development of early behaviors. The aim of this longitudinal study was to compare changes in postural control variability during development of head control and reaching in infants born preterm and full term. METHODS: Eighteen infants born preterm (mean gestational age 28.3+/-3.1weeks) were included in this study and compared to existing data from 22 infants born full term. Postural variability was assessed longitudinally using root mean squared displacement and approximate entropy of the center of pressure displacement from birth to 6months as measures of the magnitude of the variability and complexity of postural control. Behavioral coding was used to quantify development of head control and reaching. RESULTS: Group differences were identified in postural complexity during the development of head control and reaching. Infants born preterm used more repetitive and less adaptive postural control strategies than infants born full term. Both groups changed their postural complexity utilized during the development of head control and reaching. DISCUSSION: Early postural complexity was decreased in infants born preterm, compared to infants born full term. Commonly used clinical assessments did not identify these early differences in postural control. Altered postural control in infants born preterm influenced ongoing skill development in the first six months of life. PMID- 24485171 TI - Diabetes knowledge of nurses providing community care for diabetes patients in Auckland, New Zealand. AB - AIMS: To quantify and compare knowledge of diabetes including risk factors for diabetes-related complications among the three main groups of primary health care nurses. METHODS: In a cross-sectional survey of practice, district and specialist nurses (n=1091) in Auckland, New Zealand, 31% were randomly sampled to complete a self-administered questionnaire and telephone interview, designed to ascertain nurses' knowledge of diabetes and best practice, in 2006-2008. RESULTS: All 287 nurses (response rate 86%) completed the telephone interview and 284 the self administered questionnaire. Major risk factors identified by nurses were excess body weight for type 2 diabetes (96%) and elevated plasma glucose levels or glycosylated haemoglobin (86%) for diabetes-related complications. In contrast, major cardiovascular risk factors were less well identified, particularly smoking, although by more specialist nurses (43%) than practice (14%) and district (12%) nurses (p=0.0005). Cardiovascular complications, particularly stroke, were less well known than microvascular complications, and by significantly fewer practice (13%) and district (8%) nurses than specialist nurses (36%, p=0.002). CONCLUSIONS: In general, nurses had better knowledge of overweight as a risk factor for type 2 diabetes mellitus and elevated plasma glucose levels as a risk factor for diabetes-related complications compared with knowledge of cardiovascular risk factors, particularly smoking. PMID- 24485172 TI - Study on detecting spatial distribution of neutrons and gamma rays using a multi imaging plate system. AB - In order to measure the spatial distributions of neutrons and gamma rays separately using the imaging plate, the requirement for the converter to enhance specific component was investigated with the PHITS code. Consequently, enhancing fast neutrons using recoil protons from epoxy resin was not effective due to high sensitivity of the imaging plate to gamma rays. However, the converter of epoxy resin doped with (10)B was found to have potential for thermal and epithermal neutrons, and graphite for gamma rays. PMID- 24485173 TI - Tobacco intervention teachable moments for pediatric otolaryngologists: atopy and second hand smoke exposure among children. AB - OBJECTIVES: Pediatric otolaryngology clinics have tremendous access to children with allergic conditions, yet no research has evaluated in this setting environmental tobacco smoke and the occurrence of atopic diseases. METHODS: Caregivers or parents of 201 consecutive patients in a Hungarian pediatric otolaryngology clinic were queried on otolaryngologic conditions; self-reported diagnoses of atopic diseases; and tobacco smoke exposure. RESULTS: A history of asthma was reported in 10.3% of children; 38.7% had at least one parent who smoked. Fifteen out of the 20 children with asthma (75.0%) had at least one parent who smoked. Having a diagnosis of hay fever and having a parent who smoked greatly increased the odds of having a diagnosis of asthma. CONCLUSIONS: Second hand smoke exposure among children in an otolaryngology clinic was common, and was associated with co-existing atopic conditions. Pediatric otolaryngologists have an important opportunity to address parental smoking as part their care of children. PMID- 24485175 TI - To give or not to give antibiotics in non-severe acute otitis media? The American Academy of Pediatrics Guidelines that do not guide. PMID- 24485174 TI - Understanding minds: early cochlear implantation and the development of theory of mind in children with profound hearing impairment. AB - OBJECTIVE: The present study investigates how auditory stimulation from cochlear implants (CI) is associated with the development of Theory of Mind (ToM) in severely and profoundly hearing impaired children with hearing parents. Previous research has shown that deaf children of hearing parents have a delayed ToM development. This is, however, not always the case with deaf children of deaf parents, who presumably are immersed in a more vivid signing environment. METHODS: Sixteen children with CI (4.25 to 9.5 years of age) were tested on measures of cognitive and emotional ToM, language and cognition. Eight of the children received their first implant relatively early (before 27 months) and half of them late (after 27 months). The two groups did not differ in age, gender, language or cognition at entry of the study. ToM tests included the unexpected location task and a newly developed Swedish social-emotional ToM test. The tests aimed to test both cognitive and emotional ToM. A comparison group of typically developing hearing age matched children was also added (n=18). RESULTS: Compared to the comparison group, the early CI-group did not differ in emotional ToM. The late CI-group differed significantly from the comparison group on both the cognitive and emotional ToM tests. CONCLUSION: The results revealed that children with early cochlear implants solved ToM problems to a significantly higher degree than children with late implants, although the groups did not differ on language or cognitive measures at baseline. The outcome suggests that early cochlear implantation for deaf children in hearing families, in conjunction with early social and communicative stimulation in a language that is native to the parents, can provide a foundation for a more normalized ToM development. PMID- 24485176 TI - Theory-of-mind in adolescents and young adults with Alstrom syndrome. AB - OBJECTIVE: The study focuses on theory-of-mind in adolescents and young adults with Alstrom syndrome (ALMS). ALMS, an autosomal recessive syndrome causes juvenile blindness, sensorineural hearing loss, cardiomyopathy, endocrinological disorders and metabolic dysfunction. Theory-of-mind (ToM) refers to the ability to impute mental states to one self and to others. Clinical observations have revealed an increased occurrence of deviances in mental state understanding in ALMS. In the present study ToM will be examined and related to working memory (WM), verbal ability and sensory loss. METHODS: Twelve young individuals (16-37 years) with ALMS and 24 nondisabled individuals matched on age, gender and educational level participated. ToM was assessed by means of a multiple task that taxes the ability to understand thoughts and feelings of story characters'. WM was examined by means of a reading span task and verbal ability by means of a vocabulary test. RESULTS: The ALMS group performed at significantly lower levels in ToM tasks and displayed a higher variability in performance than the control group. Individuals with ALMS and a relatively poor level performance provided fewer correct mental state inferences in ToM tasks than ALMS individuals with relatively higher performance levels. ALMS individuals with relatively high performance levels made as many correct inferences in ToM tasks as the control group, but their inferences were more often incomplete. Vocabulary skills and educational level, but not WM-capacity predicted ToM performance. Degree of deafblindness did not have an impact on ToM. Age of onset of visual loss but not hearing loss related to ToM. CONCLUSIONS: The individuals with ALMS display a high degree of heterogeneity in terms of ToM, where some individuals reached performance levels comparable to nondisabled individuals. The results are discussed with respect to how cognitive and verbal abilities and factors related to the disability affect ToM. PMID- 24485177 TI - A case-control study of environmental exposures for nonsyndromic cleft of the lip and/or palate in eastern Guangdong, China. AB - OBJECTIVE: To study the relationship between environmental factors and nonsyndromic cleft of the lip and/or palate (NSCLP) in eastern Guangdong for the prevention of NSCLP. METHODS: A 1:1 retrospective case-control study was carried out. Data from 479 children with NSCLP who accepted comprehensive care in our center were recruited as cases from April 2010 to April 2013. An equal number of controls were recruited from pediatrics during the same period. Then we conducted face-to-face interviews with both parents using a structural questionnaire to identify the relationship between NSCLP and environmental risk factors. RESULTS: Univariate Chi-square analysis identified 23 factors (P<0.05) as being significantly related to NSCLP. Stepwise multiple logistic regression analyses demonstrated that there were 16 factors significantly associated with this disease. Being male (OR=0.609), parental childbearing age of 25-29 years (ORfather=0.633; ORmother=0.469), higher parental education level (high school or greater) and folic acid supplementation (OR=0.360) were protective factors against NSCLP. However, positive family history of NSCLP (OR=54.132), positive maternal abortion history (OR=3.698), high or low parental age at time of childbirth, poor maternal education level (primary school) (OR=2.258), maternal common cold during pregnancy (OR=1.464), and drug use during pregnancy (OR=3.364) were significant risk factors for NSCLP. CONCLUSION: The findings are beneficial for researchers to understand the etiology of NSCLP and to lay a solid foundation for the prevention of NSCLP in eastern Guangdong through educational programs to teach parents about the benefits of folic acid supplementation, adequate parental age at childbirth (25-29 years), higher parental education level (high school or higher), and the dangers of common cold and drug use during the first trimester of pregnancy, positive family history and maternal abortion history. PMID- 24485178 TI - An anatomically sound surgical simulation model for myringotomy and tympanostomy tube insertion. AB - OBJECTIVE: Myringotomy and tympanostomy tube insertion (MT) is a common surgical procedure. Although surgical simulation has proven to be an effective training tool, an anatomically sound simulation model for MT is lacking. We developed such a model and assessed its impact on the operating room performance of senior medical students. STUDY DESIGN: Prospective randomized trial. METHODS: A randomized single-blind controlled study of simulation training with the MT model versus no simulation training. Each participant was randomized to either the simulation model group or control group, after performing an initial MT procedure. Within two weeks of the first procedure, the students performed a second MT. All procedures were performed on real patients and rated with a Global Rating Scale by two attending otolaryngologists. Time to complete the MT was also recorded. RESULTS: Twenty-four senior medical students were enrolled. Control and intervention groups did not differ at baseline on their Global Rating Scale score or time to complete the MT procedure. Following simulation training, the study group received significantly higher scores (P=.005) and performed the MT procedure in significantly less time (P=.034). The control group did not improve their performance scores (P>.05) or the time to complete the procedure (P>.05). CONCLUSION: Our surgical simulation model shows promise for being a valuable teaching tool for MT for senior medical students. Such anatomically appropriate physical simulators may benefit teaching of junior trainees. PMID- 24485179 TI - Examining potential barriers to early intervention access in Australian hearing impaired children. AB - OBJECTIVES: Early intervention for children with hearing loss involves assistance in oral speech development, optimal use of hearing devices and fostering a holistic partnership between allied health and the children's families. Adequate access to early intervention has been shown to be vital in the positive development of long term language and social outcomes. However, there has been limited research to identify the factors which may influence access. This study aimed to explore whether access to early intervention by children with hearing loss is affected by: geographical location, socio-economic status and ethnic minority family status. METHODS: A cross-sectional research design was used in this study incorporating a survey of early intervention coordinators and an audit of an organization database. All (N=11) early intervention coordinators at an "Oral Language Centre for Deaf Children" in the state of Victoria, Australia were surveyed on whether child clients (N=133) were accessing an appropriate level of early intervention corresponding to their level of hearing loss. The length of time for each child to enroll for early intervention following diagnosis was obtained from the database of the organization. Potential differences in access between geographical groups, between socio-economic status groups and between ethnic-minority and non-minority groups were analyzed using inferential statistics. RESULTS: Closer geographical proximity to early intervention services was associated with more appropriate (P=.000) and more prompt (P=.005) access. No difference in access to early intervention was detected for different socio economic status groups. Although, ethnic-minority family status was not shown to influence the level of access, it took a significantly longer time for ethnic minority families to enroll for early intervention compared to non-minority families (P=.04). CONCLUSIONS: Findings suggest that geographical proximity and ethnic-minority family status, instead of socio-economic status, are more likely to be potential barriers to early intervention access in children with hearing loss. From the health promotion perspective, attention should be directed towards these potential barriers. PMID- 24485182 TI - A proof-of-concept implementation of a unit-based advanced practice registered nurse (APRN) role: structural empowerment, role clarity and team effectiveness. AB - The quest for decreased cost of care and improved outcomes has created the need for highly effective clinical roles and teams. This article describes the role of a unit-based advanced practice registered nurse (APRN) within a proof-of-concept implementation of a new care delivery model, the Vanderbilt Anticipatory Care Team. Role clarity is central to both structural empowerment of the APRN and team effectiveness. A modified PeaceHealth Team Development Measure tool measured baseline role clarity as a component of overall team effectiveness. A role description for the unit-based APRN based on a comprehensive assessment of the proof-of-concept unit is provided. PMID- 24485181 TI - In silico design and in vivo implementation of yeast gene Boolean gates. AB - In our previous computational work, we showed that gene digital circuits can be automatically designed in an electronic fashion. This demands, first, a conversion of the truth table into Boolean formulas with the Karnaugh map method and, then, the translation of the Boolean formulas into circuit schemes organized into layers of Boolean gates and Pools of signal carriers. In our framework, gene digital circuits that take up to three different input signals (chemicals) arise from the composition of three kinds of basic Boolean gates, namely YES, NOT, and AND. Here we present a library of YES, NOT, and AND gates realized via plasmidic DNA integration into the yeast genome. Boolean behavior is reproduced via the transcriptional control of a synthetic bipartite promoter that contains sequences of the yeast VPH1 and minimal CYC1 promoters together with operator binding sites for bacterial (i.e. orthogonal) repressor proteins. Moreover, model-driven considerations permitted us to pinpoint a strategy for re-designing gates when a better digital performance is required. Our library of well-characterized Boolean gates is the basis for the assembly of more complex gene digital circuits. As a proof of concepts, we engineered two 2-input OR gates, designed by our software, by combining YES and NOT gates present in our library. PMID- 24485183 TI - Measuring endoscopic performance for colorectal cancer prevention quality improvement in a gastroenterology practice. AB - A gastroenterology practice lacked quality measures to evaluate the practice's colorectal cancer prevention efforts. Colonoscopy performance data were gathered from a retrospective review of 90 charts using a modified Colorectal Cancer Prevention Data Collection Form. Practice stakeholders and project leader reviewed the data, identified practice deficiencies, conducted root cause analysis, and developed practice changes. Implementing the prioritized recommendations and routinely benchmarking care were warranted to ensure effective practice to improve outcomes for colorectal cancer prevention. Achieving higher-value care has led to increased efforts to improve systems for measuring care, using these measures for quality improvement and directly linking quality outcomes to reimbursement. PMID- 24485184 TI - Evidence-based protocol: diagnosis and treatment of catheter-associated urinary tract infection within adult neurocritical care patient population. AB - Evidence exists that patients requiring neurologic ICU admission have concomitant immunosuppression that makes them more prone to acquiring nosocomial infections. The risk of infection is highest in the acute phase after stroke, which may be attributed to stroke-induced immunodepression syndrome. Significant numbers of patients are being diagnosed inappropriately with catheter-associated urinary tract infection, for which they receive treatment that is not recommended. Protocol-based care enables providers to translate evidence into practice. PMID- 24485185 TI - Using dedicated nurses to improve core measures compliance. AB - To ensure The Joint Commission and Centers of Medicare and Medicaid Services core measures were being met, University of Kentucky Health Care created a team to explore the issues and create solutions. Six nurses were placed in the role of core measure nurse, who were responsible for identification of Core Measure patients, standard work, concurrent review, and working with the informaticist team to increase core measure performance. Building strong relationships with the bedside staff was also a key step to the success of these nurses. After the pilot, the compliance perfection scores were sustained as the roles were adopted by administration and made permanent. PMID- 24485186 TI - Pain, perceptions, and perceived conflicts: improving the patient's experience. AB - Pain is the number 1 reason patients seek care in an emergency department (ED). A limiting factor for effective pain management may be clinical staff attitudes about pain and pain management. Analysis of data from an investigation into pain, perceptions, and perceived conflicts of ED staff pain management revealed a need for change. Operation Pain and ED pain champions created an environment that promoted enhanced pain management resulting in measurable outcomes. Emergency nurses participating in Operation Pain placed a higher priority on pain management for their patients. PMID- 24485187 TI - Reducing skin breakdown in patients receiving extracorporeal membranous oxygenation. AB - This article describes three strategies a cardiovascular-thoracic intensive care unit implemented to decrease the rate of hospital-acquired pressure ulcers in patients on extracorporeal membranous oxygenation support. These strategies include increased staff awareness of physiologic factors placing a critically ill patient on extracorporeal support at increased risk for development of pressure ulcers, development of a turning guideline and a skin care bundle, and use of coaching by a clinical nurse specialist to promote pressure ulcer prevention. PMID- 24485188 TI - Engaging the learner by bridging the gap between theory and clinical competence: the impact of concept mapping and simulation as innovative strategies for nurse sensitive outcome indicators. AB - Concept mapping and simulation provide professional nurses in the academic and practice environment with an opportunity for experiential learning. This integral combination allows for learning to be congruent with the national clinical practice guidelines that support and promote nurse-sensitive indicators. Implications for practice are forthcoming as data are collected on the impact on health outcomes when using concept mapping and simulation. PMID- 24485189 TI - A nursing focus on EMR usability enhancing documentation of patient outcomes. AB - Achieving the healthcare reform goals of broad electronic medical record (EMR) adoption and meaningful use will require that usability of EMR's be addressed. A usability checklist was implemented in a process improvement redesign of nursing documentation in an academic medical center to ensure optimal design of the user interface in the EMR. The outcomes of this framework were based on metrics of usability: efficiency, effectiveness and satisfaction. Implementation of a usability checklist as standard work ensures a focus on the user interface design to enhance use of the EMR by nursing in clinical care and improve patient outcomes. PMID- 24485190 TI - Using a web-based patient-provider messaging system to enhance patient satisfaction among active duty sailors and Marines seen in the psychiatric outpatient clinic: a pilot study. AB - Patient satisfaction is imperative in providing safe, effective, and quality patient care. Several articles have examined the effect of a secure on-line communication system in the primary care setting to improve the delivery of patient care. This article describes the use of an asynchronous Web-based messaging system in the psychiatric outpatient setting to enhance patient satisfaction among active duty military service members. PMID- 24485191 TI - A critical analysis and adaptation of a clinical practice guideline for the management of behavioral problems in residents with dementia in long-term care. AB - The purpose of this project was to analyze the clinical practice guidelines for management of long-term care residents with dementia and draft an adaptation for implementation. The adaptation focused on individualizing interventions derived from evidence-based research and included strategies to maximize staff buy-in and implementation. The overall goal of the guideline is to decrease psychotropic medication use, particularly antipsychotics. PMID- 24485192 TI - Nurse-sensitive outcomes: indicators of quality care? PMID- 24485193 TI - Nursing-sensitive innovations influencing outcomes. PMID- 24485194 TI - Factors underlying inadequate parents' awareness regarding pediatrics immunization: findings of cross-sectional study in Mosul- Iraq. AB - BACKGROUND: Since last 100 years, immunization rate is one of the best public health outcome and service indicators. However, the immunization system is still imperfect; there are many countries that still have unvaccinated children. Parental decisions regarding immunization are very important to improve immunization rate. The aim of this study is to evaluate the association between parental knowledge-practice (KP) regarding immunization with family and immunization providers' factors. METHODS: This is a prospective cross-sectional study design. Immunization knowledge and practices among 528 Iraqi parents were evaluated through validated questionnaire. Familial data and immunization provider's characteristics were collected from parents through interview. RESULTS: More than half of respondents/study population (66.1%) have adequate knowledge- practice scores. Significant associations were noted for knowledge practice groups with father's education level, mother's education level, mother's age at delivery, number of preschool children, parents gender, family income, provider types, and birth place (p < 0.05). CONCLUSION: Immunization campaigns and awareness are required to improve parents' knowledge and practice regarding immunization. The study results reinforce recommendations for use of educational programmes to improve the immunization knowledge and practice. PMID- 24485195 TI - Degree, duration, and causes of visual impairment in eyes affected with ocular tuberculosis. AB - BACKGROUND: Ocular tuberculosis (TB) can affect nearly every ocular tissue, leading to a variety of vision-threatening clinical manifestations. The goal of this study is to estimate the degree, duration, and causes of visual impairment in eyes affected by ocular TB. RESULTS: This was a retrospective study of patients diagnosed as ocular TB based on polymerase chain reaction (PCR) for Mycobacterium tuberculosis complex. We applied the World Health Organization definition of visual impairment (VI) to affected eye(s), instead of better-seeing eye. Best-corrected visual acuity (BCVA) of <6/18 and >=6/60 in the affected eye was classified as moderate VI and <6/60 and >=3/60 as severe VI. Data collected included presenting and final BCVA of affected eyes and the worst BCVA during the study period. Sixty-one eyes of 40 patients were analyzed. Twenty-five patients (52.1%) had bilateral disease. The mean worst BCVA and mean final BCVA (logMAR) were 1.26 +/- 0.87 and 0.61 +/- 0.85, respectively, and their difference was highly significant (p < 0.0001, Friedman test). The median worst and final BCVA results were 1.30 (range 0.0 to 3.0) and 0.20 (range 0.0 to 3.0), respectively. The mean duration of follow-up was 98.34 +/- 81.81 weeks. Moderate and severe VIs were seen in 14 (22.9%) and 12 (19.7%) eyes, respectively, during the course of follow up. Twenty eyes (32.8%) had BCVA of <3/60. Moderate VI or worse was most commonly seen in eyes with multifocal serpiginoid choroiditis (n = 6; 100%), retinal vasculitis (n = 25; 80.6%), and panuveitis (n = 12; 80%). The mean duration of visual loss was 25.2 +/- 42.37 weeks (median 6.43 weeks, range 0 to 206.42 weeks). Vitreous hemorrhage, complicated cataract, and macular scarring were the common causes of VI. CONCLUSION: Ocular TB can result in prolonged visual impairment, more commonly in patients with posterior uveitis or panuveitis. PMID- 24485196 TI - Alu elements shape the primate transcriptome by cis-regulation of RNA editing. AB - BACKGROUND: RNA editing by adenosine to inosine deamination is a widespread phenomenon, particularly frequent in the human transcriptome, largely due to the presence of inverted Alu repeats and their ability to form double-stranded structures--a requisite for ADAR editing. While several hundred thousand editing sites have been identified within these primate-specific repeats, the function of Alu-editing has yet to be elucidated. RESULTS: We show that inverted Alu repeats, expressed in the primate brain, can induce site-selective editing in cis on sites located several hundred nucleotides from the Alu elements. Furthermore, a computational analysis, based on available RNA-seq data, finds that site selective editing occurs significantly closer to edited Alu elements than expected. These targets are poorly edited upon deletion of the editing inducers, as well as in homologous transcripts from organisms lacking Alus. Sequences surrounding sites near edited Alus in UTRs, have been subjected to a lesser extent of evolutionary selection than those far from edited Alus, indicating that their editing generally depends on cis-acting Alus. Interestingly, we find an enrichment of primate-specific editing within encoded sequence or the UTRs of zinc finger-containing transcription factors. CONCLUSIONS: We propose a model whereby primate-specific editing is induced by adjacent Alu elements that function as recruitment elements for the ADAR editing enzymes. The enrichment of site-selective editing with potentially functional consequences on the expression of transcription factors indicates that editing contributes more profoundly to the transcriptomic regulation and repertoire in primates than previously thought. PMID- 24485197 TI - Quality of life in stable schizophrenia: the relative contributions of disorganization and cognitive dysfunction. AB - OBJECTIVE: The purpose of this study was to examine the relative contributions of disorganization and cognitive dysfunction to quality of life (QOL) in patients with stable schizophrenia. METHODS: A total of 276 consecutive outpatients with stable schizophrenia were enrolled in a cross-sectional study. We performed a mediation analysis to assess the specific effect of disorganization on QOL, as assessed by the Heinrichs-Carpenter Quality of Life Scale (QLS), and the possible mediating role of cognitive dysfunction. RESULTS: Our findings were as follows: (i) disorganization was negatively related to the total QLS score; (ii) disorganization was negatively related to two of the four QLS domains, namely the role-functioning domain (occupational/educational) and the intrapsychic functioning domain (e.g., motivation, curiosity, and empathy); and (iii) verbal memory was a partial mediator of the relationship between disorganization and QLS (the total score and the two above-mentioned domains). CONCLUSIONS: Disorganization demonstrated direct and indirect effects via verbal memory on two domains of functioning, as measured by the QLS. These results highlight the importance of improving disorganization and cognition (particularly verbal memory) to improve the functional outcomes of patients with schizophrenia. PMID- 24485198 TI - The sensitivity and specificity of frozen-section histopathology in the management of benign oral and maxillofacial lesions. AB - PURPOSE: The management of odontogenic cysts and tumors typically requires a biopsy, which may present significant challenges and prompt an additional visit to the operating room before definitive treatment. The aim of this study was to determine the validity of frozen-section diagnosis in the management of benign oral and maxillofacial lesions, allowing intraoperative diagnosis followed by definitive treatment under the same general anesthetic. MATERIALS AND METHODS: A retrospective chart review of patients treated at the University of Michigan Health System was performed. Patients of all ages who had a diagnosis of a benign maxillofacial lesion by frozen-section and permanent histopathology reports were included for analysis. Patients were identified using the Current Procedural Terminology code for enucleation and curettage and International Classification of Diseases, Ninth Revision codes for benign cysts or tumors of skull, face, or lower jaw. RESULTS: Of 450 patients reviewed, 214 had intraoperative frozen section examination available for comparison with permanent histopathology. There were 121 men (56.5%) and 93 women (43.5%), with a mean age of 41 years. Compared with final permanent histopathology, the overall sensitivity of frozen sections was 92.1%. Frozen-section histopathology had a sensitivity greater than 90% and a specificity greater than 95% for the diagnosis of dentigerous cyst and keratocyst odontogenic tumor. CONCLUSIONS: In this study of 214 patients with benign maxillofacial lesions, frozen-section histopathology was found to be a valid diagnostic modality with high sensitivity, specificity, and positive and negative predictive values. These results and analysis support the use of frozen-section histopathology for the treatment of benign maxillofacial lesions and underscore its value in the management of these lesions. PMID- 24485199 TI - Fetal demise and associated factors following umbilical cord prolapse in Mulago hospital, Uganda: a retrospective study. AB - BACKGROUND: Umbilical cord prolapse is an obstetric complication associated with high perinatal morbidity and mortality. A few interventions may improve fetal outcome. In developed countries these have advanced to giving intrauterine fetal resuscitation. Conditions in low resource settings do not allow for some of these advanced techniques. Putting the mother in knee chest position and immediate delivery may be the only options possible.We set out to determine the incidence of fetal demise and associated factors following umbilical cord prolapsed (UCP) in Mulago Hospital, Uganda. METHODS: In a retrospective study conducted in Mulago hospital, Uganda, file records of mothers who delivered between 1st January 2000 to 31st December 2009 and had pregnancies complicated by umbilical cord prolapse with live fetus were selected. We collected information on referral status, cord position, cervical dilatation, fetal heart state at the time of diagnosis of UCP, diagnosis to delivery interval, use of knee chest position, mode of delivery, birth weight and fetal outcome.We computed incidence of fetal demise following UCP and determined factors associated with fetal demise in pregnancies complicated by UCP. RESULTS: Of 438 cases with prolapsed cord, 101(23%) lost their babies within 24 hours after birth or were delivered dead. This gave annual cumulative incidence of fetal death following UCP of 23/1000 live UCP cases delivered /year.The major factors associated with fetal outcome in pregnancies complicated by UCP included; diagnosis to delivery interval <30 min, RR 0.79 (CI 0.74-0.85), mode of delivery, RR 1.14 (CI 1.02-1.28), knee chest position, RR 0.81 (CI 0.70-0.95). CONCLUSIONS: The annual cumulative incidence of fetal death in our study was 23/1000 live UCP cases delivery per year for the period of 10 years studied. Cesarean section reduced perinatal mortality by a factor of 2. Diagnosis to delivery interval <30 minutes and putting mother in knee chest position were protective against fetal death. PMID- 24485202 TI - Snapshots of diabetes care in Canada. PMID- 24485200 TI - Acrylic splint Herbst and Hanks telescoping Herbst: a retrospective study of emergencies, retreatments, treatment times and failures. AB - INTRODUCTION: The Herbst appliance has been reported to be one of the most efficient for the correction of class II malocclusions. However, there are many complications that make its use difficult for clinicians and patients (splint loosening, telescope breakage, splint breakage, low comfort). The aim of this study was to evaluate and compare emergencies, retreatments, failures and overall treatment time of two types of Herbst appliances: the HT Herbst and the acrylic splint Herbst. MATERIALS AND METHODS: Two hundred and eight patients with Class II malocclusion were selected consecutively in a private practice. They were treated either with an acrylic splint Herbst (155 pt, mean age 10.3 +/- 3.7) or with a HT Herbst (53 pt, mean age 11.3 +/- 4.2 years). Tables were used for each patient to record the following complications, if present: detached Herbst, broken and repaired Herbst, broken and rebuilt Herbst (emergencies), Herbst that had to be re-made for lack of patient cooperation (retreatments) and appliances that had to be removed (failed treatment). RESULTS: Results showed that the HT Herbst and the acrylic splint Herbst have the same retreatment probability and the same treatment time. Moreover, the HTH has a lower risk of functional impairment: the acrylic splint Herbst has an emergency probability that is twice as high as the HTH. On the other hand, the HTH has a failure frequency that is nearly 6 times higher than the traditional Herbst although the statistical analysis could not provide any certain conclusion about it. CONCLUSION: In cases where a higher relative risk of failure for the traditional Herbst was confirmed, the HTH proved to be a better appliance than the traditional Herbst. PMID- 24485203 TI - Regarding "cardiovascular complications of diabetes" editorial article Can J Diabetes; 37(5); (2013), 279-281. PMID- 24485204 TI - Letter to the editor. PMID- 24485206 TI - Are sugar-sweetened beverage taxes a cost-effective means of reducing weight? PMID- 24485205 TI - Platelet rich plasma for treatment of nonhealing diabetic foot ulcers: a case report. AB - Diabetic foot ulcers are one of the most important causes of lower limb amputations worldwide. The conventional treatments of diabetic foot ulcers are costly and often require patients to be hospitalized for long periods of time, thus representing a huge burden on any health care system. The use of autologous platelet-rich plasma (PRP), which is rich in multiple growth factors, may bear some similarities to the natural wound healing process. Nonetheless, few studies on human subjects have so far addressed the efficacy of PRP as a novel and minimally invasive treatment. Today, there is only 1 approved and available system to separate PRP from a patient's own blood in order to be used in diabetic ulcers. This system incorporates bovine thrombin for activation of PRP gel and may be applied by many healthcare providers without the need for extensive special training. In this report, a patient with extensive diabetic foot ulcers, non-responsive to other treatment modalities, was successfully treated by PRP. PMID- 24485207 TI - Quality of diabetes care in the Canadian forces. AB - BACKGROUND: Published data on quality of care indicators from various countries indicate the challenges of providing high-quality diabetes care. The objective of this study was to evaluate the quality of care provided to members of the Canadian Forces (CF) who have diabetes, by determining the extent to which healthcare providers adhere to recommendations outlined in the 2008 Canadian Diabetes Association (CDA) clinical practice guidelines. METHODS: All 14 CF bases meeting eligibility criteria were included in the evaluation. Cases of diabetes were ascertained based on laboratory criteria. Adherence to 21 CDA guideline recommendations was evaluated following a review of patient medical records. RESULTS: The CF demonstrated high adherence (>75%) with 9 recommendations, moderate adherence (50% to 75%) with 7 recommendations and low adherence (<50%) with 5 recommendations. Most notably, there were 4 recommendations for which adherence was greater than 90%. The mean rate of adherence with all applicable recommendations per patient was 60.3% (95% Confidence Interval [CI], 59.0% to 61.6%). CF adherence rates were generally similar to or better than comparable rates in the civilian population within Canada and other industrialized countries. CONCLUSIONS: It is unclear what accounts for the favourable quality of diabetes care in the CF Health Services, but this highly structured practice setting has a number of features that distinguish it from provincial healthcare systems. Several strategies can be considered to improve diabetes care even further, including providing feedback to physicians about their performance, promoting the use of diabetes care flow sheets and creating a diabetes registry. PMID- 24485208 TI - Impact of patient use of an online patient portal on diabetes outcomes. AB - OBJECTIVE: To assess the effect of patient use of an online patient portal on diabetes outcomes. METHODS: Patients included were those with diabetes who were newly referred to a Vancouver-based tertiary care diabetologist between April 2008 and October 2012. Each patient was assessed by the diabetologist, received initial diabetes education and was referred, as necessary, for further education and self-management training. All patients who provided an e-mail address at registration were invited to open an online patient portal account. The portal provided access to diabetes education material, personal laboratory values and a messaging system allowing communication with the diabetologist and staff. Patients who logged in 1 or more times were defined as portal users (n=50); patients who never logged in to the portal were defined as non-users (n=107). A1C was measured at 2 time points: at baseline (i.e. initial, in-clinic visit) and at last follow up (visit no less than 6 months and no more than 2 years after the initial visit). Because usership is self-selected, propensity score matching was used to create comparable user/non-user groups based on available baseline covariates. RESULTS: Compared to non-users, a higher proportion of users achieved A1C <=7% at follow up (56% vs. 32%) (p=0.031). CONCLUSION: Accessing an online patient portal is associated with improved glycemic control. PMID- 24485209 TI - Association of diabetic autonomic neuropathy with red blood cell aldose reductase activity. AB - OBJECTIVE: Activation of polyol pathway based on increased activity of aldose reductase (AR) has been implicated in the development of diabetic complications including diabetic autonomic neuropathy (DAN). The relationship between DAN and hyperglycemia-induced activation of polyol pathway is still uncertain. In the present study, we investigate the association between aldose reductase activity and diabetic autonomic neuropathy by measuring AR level in red blood cells (RBC). METHOD: In this study, 145 subjects with diabetes with or without DAN and 32 subjects without diabetes have been included. All subjects have been investigated for autonomic function tests and RBC aldose reductase activity. DAN was defined if results of any 2 of the tests of parasympathetic function were abnormal. RBC aldose reductase level was determined spectrophotometrically and expressed as unit/g of hemoglobin. The values were expressed as mean +/- standard deviation, and ANOVA test has been applied for comparison between groups. RESULTS: RBC aldose reductase activity was found to be significantly higher in people with diabetes with autonomic neuropathy in comparison to people with diabetes without autonomic neuropathy and healthy individuals without diabetes. Aldose reductase (AR) level ranges from 0.8 units/g Hb to 14.2 units/g Hb. The mean AR level was 8.6+/-2.95 units in subjects of DM with autonomic neuropathy, while mean AR level was 4.1+/-1.78 units and 2.0+/-0.89 units in people with diabetes without neuropathy and normal healthy individuals, respectively (p<0.001). CONCLUSIONS: High aldose reductase activity is associated with the presence of autonomic neuropathy in subjects of type 2 DM. PMID- 24485210 TI - Food choice decision-making by women with gestational diabetes. AB - OBJECTIVE: To enhance the dietary education presented to women with gestational diabetes (GDM) by exploring the reasons and experiences that women with GDM reported in making their food-choice decisions after receipt of dietary education from a healthcare professional. METHODS: Food Choice Map (FCM) semi-structured in depth interviews were conducted with 30 women with GDM living in the Winnipeg area during their pregnancies. Verbatim transcripts were generated from the interviews. A constant comparative method was used to generate common themes to answer research inquiries. RESULTS: Personal food preferences, hunger and cravings were the main factors affecting food choice decision-making in women with GDM. Although the information from healthcare professionals was 1 factor that affected food choice decision-making for most of the participants, more than half of the women, including all the women who were on insulin, reported difficulties in quick adaptation to dietary management in a limited time period. Information from other sources such as family members, friends, and internet were used to cope with the adaptation. These difficulties led to a sense of decreased control of GDM and were accompanied by frustration, especially for women taking insulin. CONCLUSIONS: Food choice decision-making varied for this group of women with GDM. Knowledge and information aided in making healthy food choices and in portion control. However, balancing individual needs and blood glucose control in a short time period was felt to be difficult and created frustration. The findings suggested that dietary consultation needs to be personalized and to be time sensitive to promote confidence in self-control. PMID- 24485211 TI - Self-management, health service use and information seeking for diabetes care among Black Caribbean immigrants in Toronto. AB - OBJECTIVE: The objective of this research was to explore self-management practices and the use of diabetes information and care among Black-Caribbean immigrants with type 2 diabetes. METHOD: The study population included Black Caribbean immigrants and Canadian-born participants between the ages of 35 to 64 years with type 2 diabetes. Study participants were recruited from community health centres (CHCs), diabetes education centres, hospital-based diabetes clinics, the Canadian Diabetes Association and immigrant-serving organizations. A structured questionnaire was used to collect demographics and information related to diabetes status, self-management practices and the use of diabetes information and care. RESULTS: Interviews were conducted with 48 Black-Caribbean immigrants and 54 Canadian-born participants with type 2 diabetes. Black-Caribbean immigrants were significantly more likely than the Canadian-born group to engage in recommended diabetes self-management practices (i.e. reduced fat diet, reduced carbohydrate diet, non-smoking and regular physical activity) and receive regular A1C and eye screening by a health professional. Black-Caribbean immigrant participants were significantly more likely to report receiving diabetes information and care through a community health centre (CHC) and nurses and dieticians than their Canadian-born counterparts. CONCLUSIONS: CHCs and allied health professionals play an important role in the management of diabetes in the Black-Caribbean immigrant community and may contribute to this group's favourable diabetes self-management profile and access to information and care. Additional research is necessary to confirm whether these findings are generalizable to the Black-Caribbean community in general (i.e. immigrant and non-immigrant) and to determine whether the use of CHCs and/or allied health professionals is associated with favourable outcomes in the Black-Caribbean immigrant community as well as others. PMID- 24485212 TI - Dosing irregularities and self-treated hypoglycemia in type 2 diabetes: results from the Canadian cohort of an international survey of patients and healthcare professionals. AB - OBJECTIVE: Despite their importance in achieving good glycemic control, few real world data on insulin dosing irregularities and hypoglycemia are available. The multinational, online Global Attitude of Patients and Physicians (GAPP2) survey was conducted to address this situation. METHODS: Insulin-treated patients with type 2 diabetes and healthcare professionals (HCPs) who treat such patients were surveyed in an online cross-sectional study. This article summarizes findings from a sample of the online population in a Canadian cohort of 156 patients and 202 HCPs. RESULTS: A total of 156 patients completed the questionnaires; 26% reported experiencing a dosing irregularity (missed, mistimed or reduced a basal insulin dose) in the previous 30 days. Up to 60% reported risk for hypoglycemia as the reason for intentional dosing irregularities. Of all patients, 80% reported experiencing a self-treated hypoglycemic event, and 33% recalled having at least 1 event in the previous month. HCPs recorded similar levels of patient reported dosing irregularities. Over 90% indicated they recommended patients to temporarily reduce their insulin doses to deal with hypoglycemia. CONCLUSIONS: A sizeable minority of patients experienced dosing irregularities and self-treated hypoglycemia in this Canadian cohort. The data suggest that HCPs who completed the survey are aware of this and of the need to provide education and support for patients who regularly miss, mistime or reduce insulin doses. Although the desire to prevent hypoglycemic events is understandable and important, HCPs need to ensure fear of hypoglycemia does not compromise optimal diabetes management. PMID- 24485213 TI - The effect of hypoglycemia on health-related quality of life: Canadian results from a multinational time trade-off survey. AB - OBJECTIVE: The aim of this study was to investigate the impact of hypoglycemia according to severity and time of onset on health-related quality of life (HRQoL) in a Canadian population. METHODS: Time trade-off (TTO) methodology was used to estimate health utilities associated with hypoglycemic events in a representative sample of the Canadian population. A global analysis conducted in the United Kingdom, Canada, Germany and Sweden has been published. The present Canadian analysis focuses on 3 populations: general, type 1 and type 2 diabetes. Using a web-based survey, participants (>18 years) assessed the utility of 13 different health states (severe, non-severe, daytime and nocturnal hypoglycemia at different frequencies) using a scale from 1 (perfect health) to 0 (death). The average disutility value for each type of event was calculated. RESULTS: Of 2258 participants, 1696 completers were included in the analysis. A non-severe nocturnal hypoglycemic event was associated with a significantly greater disutility than a non-severe daytime event (-0.0076 vs. -0.0056, respectively; p=0.05), while there was no statistically significant difference between severe nocturnal and severe daytime events (-0.0616 vs. -0.0592; p=0.76). Severe hypoglycemia was associated with greater disutility than non-severe hypoglycemia (p<0.0001). Similar trends were reported in participants with diabetes. CONCLUSIONS: The findings presented here show that any form of hypoglycemia had a negative impact on HRQoL in a Canadian population. Nocturnal and/or severe hypoglycemia had a greater negative impact on HRQoL compared with daytime and/or non-severe events. This highlights the importance of preventing the development and nocturnal manifestation of hypoglycemia in patients with diabetes. PMID- 24485214 TI - Sedentary behaviour as an emerging risk factor for cardiometabolic diseases in children and youth. AB - Sedentary behaviour (e.g. TV viewing, seated video game playing, prolonged sitting) has recently emerged as a distinct risk factor for cardiometabolic diseases in children and youth. This narrative review provides an overview of recent evidence in this area and highlights research gaps. Current evidence suggests that North American children and youth spend between 40% and 60% of their waking hours engaging in sedentary pursuits. Although data are lacking concerning temporal trends of objectively measured sedentary time, self-reported sedentary behaviours have increased over the past half century, with a rapid increase since the late 1990s. Excessive sedentary behaviour has been found to have independent and deleterious associations with markers of adiposity and cardiometabolic disease risk. These associations are especially consistent for screen-based sedentary behaviours (TV viewing, computer games, etc), with more conflicting findings observed for overall sedentary time. The above associations are possibly mediated by the influence of screen-based sedentary behaviours on energy intake. Although excessive sitting has been reported to have adverse acute and chronic metabolic impacts in adults, research on children is lacking. Research is particularly needed to investigate the impact of characteristics of sedentary behaviour (i.e. type/context, sedentary bout length, breaks in sedentary time, etc), as well as interventions that examine the health and behavioural impacts of sitting per se. PMID- 24485215 TI - Lifestyle and cardiometabolic risk in adults with type 1 diabetes: a review. AB - Over the past decades, there has been a major upward shift in the prevalence of cardiometabolic risk (CMR) factors (central obesity, insulin resistance, hypertension and dyslipidemia) in patients with type 1 diabetes, which could have either an additive or a synergistic effect on risk for cardiovascular disease. These metabolic changes are occurring in parallel to the worldwide obesity epidemic and the widespread use of intensive insulin therapy. Poor lifestyle habits (poor diet quality, sedentary behaviours and smoking) are known to be driving factors for increased CMR factors in the general population. The objective of this review is to explore the lifestyle habits of adults with type 1 diabetes and its potential association with CMR factors. Evidence suggests that adherence to dietary guidelines is low in subjects with type 1 diabetes with a high prevalence of patients consuming an atherogenic diet. Sedentary habits are also more prevalent than in the general population, possibly because of the additional contribution of exercise-induced hypoglycemic fear. Moreover, the prevalence of smokers is still significant in the population with type 1 diabetes. All of these behaviours could trigger a cascade of metabolic anomalies that may contribute to increased CMR factors in patients with type 1 diabetes. The intensification of insulin treatment leading to new daily challenges (e.g. carbohydrates counting, increase of hypoglycemia) could contribute to the adoption of poor lifestyle habits. Preventive measures, such as identification of patients at high risk and promotion of lifestyle changes, should be encouraged. The most appropriate therapeutic measures remain to be established. PMID- 24485217 TI - The cytochrome b6f complex at the crossroad of photosynthetic electron transport pathways. AB - Regulation of photosynthetic electron transport at the level of the cytochrome b6f complex provides efficient performance of the chloroplast electron transport chain (ETC). In this review, after brief overview of the structural organization of the chloroplast ETC, the consideration of the problem of electron transport control is focused on the plastoquinone (PQ) turnover and its interaction with the b6f complex. The data available show that the rates of plastoquinol (PQH2) formation in PSII and its diffusion to the b6f complex do not limit the overall rate of electron transfer between photosystem II (PSII) and photosystem I (PSI). Analysis of experimental and theoretical data demonstrates that the rate-limiting step in the intersystem chain of electron transport is determined by PQH2 oxidation at the Qo-site of the b6f complex, which is accompanied by the proton release into the thylakoid lumen. The acidification of the lumen causes deceleration of PQH2 oxidation, thus impeding the intersystem electron transport. Two other mechanisms of regulation of the intersystem electron transport have been considered: (i) "state transitions" associated with the light-induced redistribution of solar energy between PSI and PSII, and (ii) redistribution of electron fluxes between alternative pathways (noncyclic electron transport and cyclic electron flow around PSI). PMID- 24485216 TI - Cortical bone loss at the tibia in postmenopausal women with osteoporosis is associated with incident non-vertebral fractures: results of a randomized controlled ancillary study of HORIZON. AB - BACKGROUND: In postmenopausal women, yearly intravenous zoledronate (ZOL) compared to placebo (PLB) significantly increased bone mineral density (BMD) at lumbar spine (LS), femoral neck (FN), and total hip (TH) and decreased fracture risk. The effects of ZOL on BMD at the tibial epiphysis (T-EPI) and diaphysis (T DIA) are unknown. METHODS: A randomized controlled ancillary study of the HORIZON trial was conducted at the Department of Osteoporosis of the University Hospital of Berne, Switzerland. Women with >=1 follow-up DXA measurement who had received >=1 dose of either ZOL (n=55) or PLB (n=55) were included. BMD was measured at LS, FN, TH, T-EPI, and T-DIA at baseline, 6, 12, 24, and 36 months. Morphometric vertebral fractures were assessed. Incident clinical fractures were recorded as adverse events. RESULTS: Baseline characteristics were comparable with those in HORIZON and between groups. After 36 months, BMD was significantly higher in women treated with ZOL vs. PLB at LS, FN, TH, and T-EPI (+7.6%, +3.7%, +5.6%, and +5.5%, respectively, p<0.01 for all) but not T-DIA (+1.1%). The number of patients with >=1 incident non-vertebral or morphometric fracture did not differ between groups (9 ZOL/11 PLB). Mean changes in BMD did not differ between groups with and without incident fracture, except that women with an incident non vertebral fracture had significantly higher bone loss at predominantly cortical T DIA (p=0.005). CONCLUSION: ZOL was significantly superior to PLB at T-EPI but not at T-DIA. Women with an incident non-vertebral fracture experienced bone loss at T-DIA. PMID- 24485218 TI - Fluorescence quenching in the lichen Peltigera aphthosa due to desiccation. AB - Photoprotective mechanisms were studied on the tripartite lichen Peltigera aphthosa that exhibits external cephalodia. Using the methods of steady-state and time-resolved fluorescence microscopy, we studied the dynamics of the rehydration process in different parts of the lichen thalli. It was found that apical, medial and basal parts of the thallus are not only morphologically different, but also show completely different chlorophyll induction curves and other spectral characteristics. In dry state, significant contribution to the fluorescence spectrum of lichen gives a green fluorescence of hyphae forming the upper crust, which is rapidly and almost completely quenched during the rehydration process. Probably this is one of the protective mechanisms that reduce the amount of light reaching the PS II reaction centers in the dry state. In the process of rehydration, we observed an increase in the intensity of the chlorophyll fluorescence of the photobiont at 680 nm, with significant changes of the fluorescence lifetimes and the amplitude ratios of fast and slow components of fluorescence decay kinetics. While in dry state, chlorophyll fluorescence is strongly quenched (opposite to the fluorescence of the hyphae), and the fluorescence time constants recover to the typical decay times of active photosynthetic organisms during rehydration. The quantitative behavior of these changes differs largely between the apical, medial and basal parts of the thallus, probably due to the complex interactions of the fungus, algae and cyanobacteria. PMID- 24485219 TI - [Assessment of quality of pre- and postoperative information documents about carpal tunnel syndrome]. AB - Before surgery for carpal tunnel syndrome, oral patient information is partially understood and accepted. The objective of this study was to perform a documentation for patients, as recommended by the High Authority in Healthcare (HAS), then to compare the effectiveness of oral information. Our series included 37 patients who received the same information: preoperative shower, pathophysiology, and postoperative instructions. The first 18 (group 1) received only oral information. The following 19 (group 2) received oral, written and visual information. The information in Group 2 followed the methodology of McClune: promoter (Department of Hand Surgery), organizing committee (two teachers from the School of Decorative Arts, two teachers of the School of Medicine), group work (five art students, five medical students), panel of experts (three surgeons, two occupational therapists, one physiotherapist). Four documents were developed: a booklet, a diagram, an animation, a poster. Satisfaction was higher in group 2. Understanding and memorization were better in group 2. Fifty-six percent of patients in group 1 would have liked a paper, 12.5% videos, none went on the Internet. Twelve and a half percent of the patients in group 2 went on the Internet, 18.8% would have liked videos. Our results show that in terms of carpal tunnel syndrome, the written and visual information materials for patients significantly improve the efficacy of oral information. These documents may be extended to other pathologies in Hand Surgery. PMID- 24485221 TI - Cost-effectiveness of a universal strategy of brief dietary intervention for primary prevention in primary care: population-based cohort study and Markov model. AB - BACKGROUND: A healthy diet is associated with reduced risk of diabetes, cardiovascular disease and cancer. The study aimed to evaluate the cost effectiveness of a universal strategy to promote healthy diet through brief intervention in primary care. METHODS: The research was informed by a systematic review of randomised trials which found that brief interventions in primary care may be associated with a 0.5 portion per day increase in fruit and vegetable consumption. A Markov model that included five long-term conditions (diabetes, coronary heart disease, stroke, colorectal cancer and depression) was developed. Empirical data from a large cohort of United Kingdom-based participants sampled from the Clinical Practice Research Datalink populated the model. Simulations compared an intervention promoting healthy diet over 5 years in healthy adults, and standard care in which there was no intervention. The annual cost of intervention, in the base case, was one family practice consultation per participant year. Health service costs were included and the model adopted a lifetime perspective. The primary outcome was net health benefit in quality adjusted life years (QALYs). RESULTS: A cohort of 262,704 healthy participants entered the model. Intervention was associated with an increase in life years lived free from physical disease of 41.9 (95% confidence interval -17.4 to 101.0) per 1,000 participants entering the model (probability of increase 88.0%). New incidences of disease states were reduced by 28.4 (18.7 to 75.8) per 1,000, probability reduced 84.6%. Discounted incremental QALYs were 4.3 (-8.8 to 18.0) per 1,000, while incremental costs were L139,755 (L60,466 to 220,059) per 1,000. Net health benefits at L30,000 per QALY were -0.32 (-13.8 to 13.5) QALYs per 1,000 participants (probability cost-effective 47.9%). When the intervention was restricted to adults aged 50 to 74 years, net health benefits were 2.94 (-21.3 to 26.4) QALYs per 1000, probability increased 59.0%. CONCLUSIONS: A universal strategy to promote healthy diet through brief intervention in primary care is unlikely to be cost-effective, even when delivered at low unit cost. A targeted strategy aimed at older individuals at higher risk of disease might be more cost effective. More effective dietary change interventions are needed. PMID- 24485220 TI - Policy recommendations for addressing privacy challenges associated with cell based research and interventions. AB - BACKGROUND: The increased use of human biological material for cell-based research and clinical interventions poses risks to the privacy of patients and donors, including the possibility of re-identification of individuals from anonymized cell lines and associated genetic data. These risks will increase as technologies and databases used for re-identification become affordable and more sophisticated. Policies that require ongoing linkage of cell lines to donors' clinical information for research and regulatory purposes, and existing practices that limit research participants' ability to control what is done with their genetic data, amplify the privacy concerns. DISCUSSION: To date, the privacy issues associated with cell-based research and interventions have not received much attention in the academic and policymaking contexts. This paper, arising out of a multi-disciplinary workshop, aims to rectify this by outlining the issues, proposing novel governance strategies and policy recommendations, and identifying areas where further evidence is required to make sound policy decisions. The authors of this paper take the position that existing rules and norms can be reasonably extended to address privacy risks in this context without compromising emerging developments in the research environment, and that exceptions from such rules should be justified using a case-by-case approach. In developing new policies, the broader framework of regulations governing cell-based research and related areas must be taken into account, as well as the views of impacted groups, including scientists, research participants and the general public. SUMMARY: This paper outlines deliberations at a policy development workshop focusing on privacy challenges associated with cell-based research and interventions. The paper provides an overview of these challenges, followed by a discussion of key themes and recommendations that emerged from discussions at the workshop. The paper concludes that privacy risks associated with cell-based research and interventions should be addressed through evidence-based policy reforms that account for both well-established legal and ethical norms and current knowledge about actual or anticipated harms. The authors also call for research studies that identify and address gaps in understanding of privacy risks. PMID- 24485222 TI - Comprehensive metagenomic approach for detecting causative microorganisms in culture-negative infective endocarditis. PMID- 24485223 TI - Long-term cost-effectiveness of transcatheter versus surgical closure of secundum atrial septal defect in adults. AB - BACKGROUND: The most common congenital anomaly in adults is secundum, which can be closed using a surgical or transcatheter approach. Despite the growing use of transcatheter ASD closure, few studies have examined the cost-effectiveness of this strategy. We sought to compare the long-term cost effectiveness of transcatheter and surgical closure of secundum in adults. METHODS: A decision analytic model was used with all clinical outcome parameter estimates obtained from the province-wide Quebec Congenital Heart Disease Database. Costs were obtained from a single academic centre (Canadian dollars). A cost-effectiveness analysis using a discrete event Monte Carlo simulation model from the perspective of a single third party payer and multiple sensitivity analyses were performed. Patients were followed for a maximum of 5 years after ASD closure. RESULTS: Between l998 and 2005, we identified 718 adults (n=335 transcatheter; n=383 surgical) who underwent ASD closure in Quebec. The 5-year cost of surgical closure was $15,304 SD $4581 versus $11,060 SD $5169 for the transcatheter alternative. At 5 years, transcatheter closure was marginally more effective than surgery (4.683 SD 0.379 life-years versus 4.618 SD 0.638 life-years). Probabilistic sensitivity analyses demonstrated that transcatheter ASD closure was a dominant strategy with an 80% probability of cost savings and equal or greater efficacy compared to surgical treatment. CONCLUSION: Although definitive conclusions are limited given the observational nature of the primary data sources, transcatheter ASD closure appeared to be a cost-effective strategy associated with slightly improved clinical outcomes and reduced costs compared to surgical closure at 5-years follow-up. PMID- 24485224 TI - The case for the reservoir-wave approach. AB - The Reservoir-Wave Approach is an alternative, time-domain approach to arterial hemodynamics that is based on the assertion that measured pressure and flow can be resolved into their volume-related (i.e., reservoir) and wave-related (i.e., excess) components. The change in reservoir pressure is assumed to be proportional to the difference between measured inflow and calculated outflow. Wave intensity analysis of the excess components yields a pattern of aortic wave propagation and reflection in the dog that is novel and physiologically plausible: waves are reflected positively from a site in the femoral circulation and negatively from a site below the diaphragm, where the total "daughter-vessel" cross-sectional area exceeds the "mother-vessel" area. With vasodilatation, the negative reflection is augmented and with vasoconstriction, it is virtually eliminated. On the other hand, conventional hemodynamic analysis has been shown to yield a paradoxical "forward-going backward wave" and the impedance minimum, previously assumed to be an indicator of the source of wave reflection according to quarter-wave-length theory, has been shown to be due to the reservoir component. Clinical studies employing the Reservoir-Wave Approach should be undertaken to verify experimental observations and, perhaps, to gain new diagnostic and therapeutic insights. PMID- 24485225 TI - Left ventricular synchronization and systolic function estimated by speckle tracking echocardiography pre-and post-radiofrequency ablation in patients with atrial fibrillation. PMID- 24485226 TI - Insulin resistance and short-term mortality in patients with acute myocardial infarction. PMID- 24485227 TI - Assessment of the effects of 174G/C polymorphism on interleukin 6 gene on macrovascular complications in patients with type 2 diabetes mellitus. PMID- 24485228 TI - Assessing vulnerable plaque: is shear stress enough? PMID- 24485229 TI - Brazilian Portuguese translation and cross-cultural adaptation of the "Caregiver Priorities and Child Health Index of Life with Disabilities" (CPCHILD) questionnaire. AB - BACKGROUND: Consideration of the quality of life in relation to individual health status is crucial for planning and maintaining a system of patient-centered care. Until recently, there have been no suitable instruments to assess health-related quality of life (HRQoL,) of children and adolescents with severe, non-ambulant cerebral palsy (GMFCS functional levels IV and V). The "Caregiver Priorities and Child Health Index of Life with Disabilities Questionnaire" (CPCHILD) was developed in English specifically for this population, and has been validated in Canada. The aim of this study was to translate and adapt the CPCHILD Questionnaire into Brazilian Portuguese, thus permitting researchers in Brazil to access this important tool for measuring HRQoL in this population, as well as the possibility of making comparisons with other studies that use the same questionnaire in other languages. METHOD: The cross-cultural adaptation included two forward translations by independent translators, their synthesis, two back translations by independent translators, an assessment of the versions by an expert committee and the development of a pre-final version, which was tested on 30 caregivers of children (5 -18) with severe cerebral palsy (GMFCS IV & V). RESULTS: Despite the relative equivalence between the two translations, some items required adaptations for the synthesized version. Certain modifications were necessary in the pre-final version to achieve idiomatic equivalence. The modifications were required to account for the socioeconomic and cultural levels of the target population. CONCLUSION: The translation and cross-cultural adaptation of the CPCHILD questionnaire provides a Brazilian Portuguese equivalent to measure the HRQoL of children with severe developmental disabilities, with the potential to measure the benefits of various procedures that are indicated for these patients. This adaptation exhibited a satisfactory level of semantic equivalence between the Portuguese target and the original English source versions. The validity of the Brazilian version of the instrument must be established in the future by assessing its psychometric properties on Brazilian epidemiological samples. PMID- 24485230 TI - Is inhibitory control a 'no-go' in adolescents with autism spectrum disorder? AB - BACKGROUND: Autism spectrum disorder (ASD) refers to a range of neurodevelopmental conditions characterized by social communication deficits, repetitive behaviours, and restrictive interests. Impaired inhibition has been suggested to exacerbate the core symptoms of ASD. This is particularly critical during adolescence when social skills are maturing to adult levels. Using magnetoencephalography (MEG), we identified the location and timing pattern of neural activity associated with inhibition in adolescents with autism, compared to typically developing adolescents. METHODS: The MEG data from 15 adolescents with ASD and 15 age-matched controls (13 to 17 years) were collected during a go/no-go task with inverse ratios of go/no-go trials in two conditions: an inhibition condition (1:2) and a baseline condition (2:1). No-go trials from the two conditions were analyzed using beamformer source localizations from 200 ms to 400 ms post-stimulus onset. Significant activations were determined using permutation testing. RESULTS: Adolescents with ASD recruited first the right middle frontal gyrus (200 to 250 ms) followed by the left postcentral gyrus (250 to 300 ms) and finally the left middle frontal and right medial frontal gyri (300 to 400 ms). Typically developing adolescents recruited first the left middle frontal gyrus (200 to 250 ms), followed by the left superior and inferior frontal gyri (250 to 300 ms), then the right middle temporal gyrus (300 to 350 ms), and finally the superior and precentral gyri and right inferior lobule (300 to 400 ms). CONCLUSIONS: Adolescents with ASD showed recruitment limited largely to the frontal cortex unlike typically developing adolescents who recruited parietal and temporal regions as well. These findings support the presence of an atypical, restricted inhibitory network in adolescents with ASD compared to controls. PMID- 24485231 TI - Clinical trial design in small cell lung cancer: surrogate end points and statistical evolution. AB - BACKGROUND: Small-cell lung cancer (SCLC) is a disease for which few recent therapeutic advances have been achieved. SCLC trial design and reporting may have an impact on the interpretation of studies. Furthermore, the use of surrogate end points in SCLC has not been explored. MATERIAL AND METHODS: Through examining SCLC trials published in the Journal of Clinical Oncology (JCO) (8471 patients from 66 trials between 1983 and 2010), we examined how SCLC trial reporting and design has evolved, determining if the type I error, power, and sample size calculations were provided. We assessed primary end points for all trials and sought to discover surrogate end points for overall survival (OS). RESULTS: There was increased reporting of statistical design in power (16.7% in 1986-1996 to 77.8% in 2006-2010; P = .001) and type I error (22.2% in 1986-1996 to 72.2% in 2006-2010; P = .005). Of trials published in 1986 to 1996, 72.2% failed to report a primary end point, whereas only 5.56% of trials conducted in 2006 to 2010 failed to do so (P = .004). Of phase II trials, primary end points were identified as response rate (RR) in 65%, OS in 25%, and progression-free survival (PFS) in 10%. CONCLUSION: There is a strong correlation between RR and both PFS (P = .013) and OS (P = .012) in extensive disease (ED). RR (P = .029) exhibits a negative trend over time, with a dramatic and significant decrease in RR across all studies starting in 2005. A strong correlation exists between PFS and OS for limited disease (LD) (P = .036) and ED (P = .058). We found no change in OS (P = .383) over time. PMID- 24485232 TI - Thymic epithelial neoplasms: a 12-year Canadian regional cancer program experience. AB - BACKGROUND: Thymic epithelial neoplasms are rare, with little prospective research to guide management. Surgery is the primary treatment modality for localized disease, but chemotherapy may be indicated in advanced disease. We performed a retrospective chart review of all cases over a 12-year period at our institution. PATIENTS AND METHODS: With ethics approval, data collected included patient characteristics, histologic type (World Health Organization [WHO] criteria), staging (Masaoka system), paraneoplastic syndromes, treatment details, and outcomes. The primary analysis is descriptive. RESULTS: Thymic epithelial neoplasms were identified in 76 patients: 46% women with a median age 60 years (range, 25-89 years), 93% with Eastern Cooperative Oncology Group performance status of 0 to 1. Myasthenia gravis was present in 21%. The distribution by WHO histologic classification was A, 15%; AB, 30%; B1, 16%; B2, 13%; B3, 17%; C, 7%; neuroendocrine thymic tumor (NETT), 1%; and unclassified, 1%. Of 64 patients who underwent operation, 53 underwent R0 resection. Eleven surgical patients received chemotherapy (induction, n = 6; adjuvant, n = 4; both, n = 1) and 27 received radiotherapy (induction, n = 2; adjuvant, n = 25). Twelve patients were not considered for surgery, and 3 patients received no therapy at all. Chemotherapy was received at some point in the disease course in 14 patients. Common first line regimens were platinum/etoposide (n = 8), carboplatin/paclitaxel (n = 3), and CAP (cyclophosphamide, doxorubicin [Adriamycin], cisplatin [n = 2]). The first-line response rate (Response Evaluation in Solid Tumors [RECIST]) was 55%. After a median follow-up of 45 months, 59 (78%) patients remain alive. Thymoma was associated with superior overall survival compared with thymic carcinoma (P < .0001). CONCLUSION: Although surgical resection is the mainstay of treatment for thymic epithelial neoplasms, it remains clear that these are chemosensitive diseases. PMID- 24485234 TI - Patient safety. PMID- 24485235 TI - Psychological health and safety in Canadian healthcare settings. AB - Psychological health and safety are growing priorities in Canadian workplaces, including Canadian healthcare settings. The workplace has a key role to play in promoting mental health. The Canadian Healthcare Association recently adopted a position statement strongly encouraging members and all health stakeholders to adopt and take action to implement the new voluntary standard, outlined in Psychological Health and Safety in the Workplace. PMID- 24485233 TI - Prognostic implications of tumoral expression of insulin like growth factors 1 and 2 in patients with non-small-cell lung cancer. AB - INTRODUCTION: The currently available systemic therapies for non-small-cell lung cancer (NSCLC) have limited efficacy. Previous studies indicated an association of elevated insulinlike growth factor (IGF)-1 receptor (IGF-1R) and insulin receptor expression levels with poor survival in patients with NSCLC. To better understand the molecular biomarkers involved in the IGF signaling pathway in NSCLC, the expression levels of IGF-1 and IGF-2 are characterized and evaluated for their association with IGF-1R and phosphorylated IGF-1R (pIGF-1R) expression in NSCLC. MATERIALS AND METHODS: A total of 352 patients who underwent NSCLC resection with curative intent were studied. The expression patterns of the IGF 1, IGF-2, IGF-1R, and pIGF-1R proteins were assessed immunohistochemically using tissue microarrays. RESULTS: The IGF-1 expression was higher in patients with adenocarcinoma (ADC) than in those with squamous cell carcinoma (SCC), whereas the IGF-2 score was higher in patients with SCC than those with ADC. Likewise, the IGF-1 score was higher in patients with mutated epidermal growth factor receptor (mtEGFR) than in those with wild type EGFR (wtEGFR), whereas the IGF-2 score was higher in patients with wtEGFR than in those with mtEGFR. Patients with low levels of IGF-1 expression had longer overall survival (OS) than those with high IGF-1 expression, and subgroup analyses found a significant difference in OS only in patients with ADC. CONCLUSION: The overexpression of IGF-1 predicts poor survival among patients with NSCLC, especially those with ADC. These results might serve as a future guide for clinical trials involving IGF-1R-targeting agents. PMID- 24485236 TI - Medication reconciliation: a prescription for safer care. AB - Four national healthcare organizations - Accreditation Canada, the Canadian Institute for Health Information, the Canadian Patient Safety Institute and the Institute for Safe Medication Practices Canada - recently collaborated to better understand and share comprehensive information about medication reconciliation in Canada. This article summarizes the key findings of their joint report titled Medication Reconciliation in Canada: Raising the Bar and profiles innovative approaches and tools for healthcare organizations across Canada. PMID- 24485237 TI - Diabetes in visible minority populations in Ontario. AB - Most published data on ethnic variations in diabetes care and outcomes come from the United States, and their generalizability to inform clinical care and policy making in Canada is limited. As a result, the Institute for Clinical Evaluative Sciences (ICES) has conducted several studies examining the burden of diabetes for and the quality of care received by visible minority populations in Ontario compared with the general population. PMID- 24485238 TI - In conversation with Janet M. Davidson. PMID- 24485239 TI - Safety for all: bringing together patient and employee safety. AB - The safety of patients and of employees in healthcare have historically been separately managed and regulated. Despite efforts to reduce injury rates for employees and adverse events for patients, healthcare organizations continue to see less-than-optimal outcomes in both domains. This article challenges readers to consider how the traditional siloed approach to patient and employee safety can lead to duplication of effort, confusion, missed opportunities and unintended consequences. The authors propose that only through integrating patient and employee safety activities and challenging the paradigms that juxtapose the two will healthcare organizations experience sustained and improved safety practice and outcomes. PMID- 24485240 TI - Engaging patients and family members in better hand hygiene practices: a teaching hospital's challenge. AB - It is universally agreed that healthcare workers need to wash their hands in order to help control the spread of hospital-acquired infections. However, we have to be mindful that patients and family members are a significant part of the contamination equation as well. This article details the efforts by University Health Network (UHN) to develop hand hygiene resources for use with patients and family members at all of UHN's sites. PMID- 24485241 TI - Medication reconciliation: the priority that isn't. AB - Medication reconciliation is a crucial step in safe care, but it is often done inconsistently or inadequately, or missed altogether. This can be dangerous and even deadly for patients, and expensive for the system. In this article, the authors discuss the current status of medication reconciliation in Canada, barriers to its implementation and steps healthcare organizations across the country are taking to introduce medication reconciliation. They conclude by outlining ways that provincial and territorial governments could re-energize work on medication reconciliation. PMID- 24485242 TI - Measuring quality at a system level: an impossible task? The Toronto Central LHIN Experience. AB - Quality is being measured and reported across healthcare organizations and sectors, but efforts are rarely made to connect the activity in one organization to quality experienced by patients and clients in another part of the healthcare system. This article describes one regional health organization's journey to measuring health quality at a system level. The authors describe a highly consultative and iterative process used to measure quality across the continuum of care, and the challenges experienced in approaching this type of measurement, and they highlight some of the early findings. PMID- 24485243 TI - Managing access and flow through appropriate discharge: preventing common errors and improving processes. AB - Increased pressure on acute care hospitals to move patients seamlessly through the healthcare system has resulted in more attention to the process of discharging patients, particularly seniors, from hospitals. When alignment with the Health Care Consent Act is lacking, errors can occur in the process. Examples of mistakes by healthcare professionals include these: taking direction from the wrong substitute decision-maker (SDM); taking direction from a family member when the patient is capable; allowing an SDM to make an advance directive on behalf of a patient; being aware of a known prior expressed wish but ignoring that wish when considering a placement plan; waiting for an SDM who is not available, willing and capable instead of proceeding down the hierarchy of decision-makers; or permitting families to propose discharge plans. Such errors have the potential to compromise quality of care, but they also work to prevent timely and appropriate discharge. In order to minimize these common errors in the consent process for placements, we have proposed a checklist to help meet ethical and legal obligations in the discharge process. We suggest the checklist may minimize avoidable conflict and misunderstanding and promote a seamless discharge process. PMID- 24485244 TI - Activity-based funding model provides foundation for province-wide best practices in renal care. AB - British Columbia has a unique funding model for renal care in Canada. Patient care is delivered through six health authorities, while funding is administered by the Provincial Renal Agency using an activity-based funding model. The model allocates funding based on a schedule of costs for every element of renal care, excluding physician fees. Accountability, transparency of allocation and tracking of outcomes are key features that ensure successful implementation. The model supports province-wide best practices and equitable care and fosters innovation. Since its introduction, the outpatient renal services budget has grown less than the population, while maintaining or improving clinical outcomes. PMID- 24485245 TI - Evaluating the adoption of e-prescribing in primary care. AB - The purpose of this study was to examine the adoption of e-prescribing by primary care physicians in Central Vancouver Island. To accomplish this, a multi-method study design was used to compare the ideal state of e-prescribing (desired e prescribing features in an electronic medical record [EMR]) with the possible state (what the EMR offers) and current state (what physicians are using in practice). The authors found that recruited physicians are using most of the e prescribing and EMR features available. However, there are several gaps between the ideal, possible and current states of e-prescribing. The authors address the identified gaps through physician-level, policy-related and technology-related recommendations to improve the adoption, design and development of e-prescribing features. PMID- 24485246 TI - Pilot testing of a questionnaire for the evaluation of mental health services in family health team clinics in Ontario. AB - Family health teams (FHTs), regarded today as a premier model of provision of primary care services in North America, were introduced in 2004 to improve traditionally fragmented primary healthcare in Ontario. Physicians and healthcare providers from various disciplines team up under the same roof in FHTs to provide and coordinate care and to ensure adequate access to and continuity of care. Because many Canadians with mental health problems consult family physicians in primary care, routine evaluation of the delivery of primary mental health care services in FHTs is becoming important. The authors' goal was to develop and test an evaluation tool (containing a questionnaire for patients and a questionnaire for providers) for mental health services provided in FHTs with a focus on accessibility, availability, quality, continuity of care and coordination of services. They developed and pilot tested an English-French tailored evaluation instrument in several FHTs in South East, Champlain and North East Local Health Integration Networks across Ontario. A convenience sample of English- and French speaking healthcare providers and patients using mental health services was recruited. Provider and patient questionnaires were developed and pilot-tested with 12 providers and 10 clients. Patient reviewers rated the patient questionnaire consistently as "good" or "very good." Provider reviewers found the provider questionnaire to be important and timely and the questions to be adequate and interesting. This instrument evaluates, from both the patient and provider perspectives, whether mental health services are structured to meet expectations set for FHTs, and enables healthcare providers, administrators and policy makers to learn about the benefits and the deficiencies of mental health care delivered through these clinics. This instrument can also be used to enhance future research and evaluation of FHTs. Further validation effort will be required to establish its validity and reliability. PMID- 24485247 TI - Ischemic stroke risk in a southeastern Chinese population: Insights from 5 lipoxygenase activating protein and phosphodiesterase 4D single-nucleotide polymorphisms. AB - BACKGROUND/PURPOSE: Through a genome-wide linkage scan, an Icelandic genetic research group identified two new genes associated with ischemic stroke: the 5 lipoxygenase activating protein (ALOX5AP) gene and the phosphodiesterase 4D (PDE4D) gene. Because they regulate arterial inflammation and are closely related to atherosclerosis and plaque instability, these two mutated genes have become a research hotspot. The purpose of this study was to investigate the association between the risk of ischemic stroke and single-nucleotide polymorphisms (SNPs) in the ALOX5AP and PDE4D genes in a southeastern Chinese population. METHODS: A total of 459 patients with stroke and 462 control individuals were recruited in the study. Four ALOX5AP SNPs (SG13S32, SG13S42, SG13S89, and SG13S114), and three PDE4D SNPs (SNP83, SNP87, and SNP45) were studied. SNP genotypes were determined by polymerase chain reaction amplification followed by allele-specific primer extension, with detection by matrix-assisted laser desorption/ionization time-of flight. Data were coded and entered in SPSS Windows (version 16.0). Odds ratios and 95% confidence intervals were calculated using multivariate logistic regression analysis. Generalized multifactor dimensionality reduction (GMDR) analysis was applied to detect gene-gene interactions. RESULTS: No statistically significant differences were found in the SNP genotype frequencies between cases and controls for the seven SNPs studied. GMDR analysis revealed no evidence of interactions between these seven polymorphic sites and an increased stroke risk. In addition, no association between different stroke types and the control group was detected. Results showed that only the ALOX5AP gene, and specifically the rs9551963 and rs4769060 genotypes, exhibited significantly different distributions between the stroke and control groups in female participants. CONCLUSION: No association was found between SNPs of ALOX5AP or PDE4D and the risk of overall ischemic stroke in a southeastern Chinese population. Interactions between these two genes were not risk factors for cerebral infarction. In atherothrombotic and small-artery disease subtypes, none of the seven SNPs was associated with any stroke risk; however, the ALOX5AP gene might be related to ischemic stroke incidence in females. PMID- 24485248 TI - Close relationship of a novel Flavobacteriaceae alpha-amylase with archaeal alpha amylases and good potentials for industrial applications. AB - BACKGROUND: Bioethanol production from various starchy materials has received much attention in recent years. alpha-Amylases are key enzymes in the bioconversion process of starchy biomass to biofuels, food or other products. The properties of thermostability, pH stability, and Ca-independency are important in the development of such fermentation process. RESULTS: A novel Flavobacteriaceae Sinomicrobium alpha-amylase (FSA) was identified and characterized from genomic analysis of a novel Flavobacteriaceae species. It is closely related with archaeal alpha-amylases in the GH13_7 subfamily, but is evolutionary distant with other bacterial alpha-amylases. Based on the conserved sequence alignment and homology modeling, with minor variation, the Zn2+- and Ca2+-binding sites of FSA were predicated to be the same as those of the archaeal thermophilic alpha amylases. The recombinant alpha-amylase was highly expressed and biochemically characterized. It showed optimum activity at pH 6.0, high enzyme stability at pH 6.0 to 11.0, but weak thermostability. A disulfide bond was introduced by site directed mutagenesis in domain C and resulted in the apparent improvement of the enzyme activity at high temperature and broad pH range. Moreover, about 50% of the enzyme activity was detected under 100 degrees C condition, whereas no activity was observed for the wild type enzyme. Its thermostability was also enhanced to some extent, with the half-life time increasing from 25 to 55 minutes at 50 degrees C. In addition, after the introduction of the disulfide bond, the protein became a Ca-independent enzyme. CONCLUSIONS: The improved stability of FSA suggested that the domain C contributes to the overall stability of the enzyme under extreme conditions. In addition, successfully directed modification and special evolutionary status of FSA imply its directional reconstruction potentials for bioethanol production, as well as for other industrial applications. PMID- 24485249 TI - voom: Precision weights unlock linear model analysis tools for RNA-seq read counts. AB - New normal linear modeling strategies are presented for analyzing read counts from RNA-seq experiments. The voom method estimates the mean-variance relationship of the log-counts, generates a precision weight for each observation and enters these into the limma empirical Bayes analysis pipeline. This opens access for RNA-seq analysts to a large body of methodology developed for microarrays. Simulation studies show that voom performs as well or better than count-based RNA-seq methods even when the data are generated according to the assumptions of the earlier methods. Two case studies illustrate the use of linear modeling and gene set testing methods. PMID- 24485250 TI - Implementation of laparoscopy in abdominal surgery: Mission accomplished? PMID- 24485251 TI - Laparoscopy in the acute abdomen. AB - Laparoscopy has become a routine procedure in the management of acute abdominal disease and can be considered both an excellent therapeutic and additional diagnostic tool in selected cases. However, a high level of expertise in laparoscopic and emergency surgery is required. Hemodynamic instability, huge abdominal distension, fecal peritonitis and perforated cancer are relative contraindications for the laparoscopic approach. In recent years, abdominal emergencies have increasingly been managed successfully by laparoscopy. In acute appendicitis, acute cholecystitis and perforated peptic ulcer, randomized controlled trials have proven that the laparoscopic approach is as safe and as effective as open surgery, with fewer complications and a quicker postoperative recovery. Other indications such as blunt and penetrating trauma to the abdomen, small bowel occlusion and perforated diverticular disease are under debate, indicating that more randomized controlled trials comparing laparoscopic and open surgery are still necessary. PMID- 24485252 TI - The potential benefits and disadvantages of laparoscopic surgery for ulcerative colitis: A review of current evidence. AB - Up to 35% of patients with ulcerative colitis will require surgery during the course of their disease. Nowadays, a total colectomy with ileal pouch-anal anastomosis is the preferred procedure, which can be performed open or via laparoscopic approach. Since the early '90s, minimally invasive techniques have gained popularity, but the extend of restorative procedures in these patients has restricted the use of laparoscopic approaches mainly to elective procedures in specialised centres. This review discusses the benefits and disadvantages of laparoscopic surgery when compared to open surgery. It presents the current evidence on short-term and long-term post-operative results, functional outcome, fecundity, and costs, for both elective and emergency indications. In addition, the value of new techniques (including single port surgery) and alternative laparoscopic approaches (e.g. ileo-rectal anastomosis, Kock-pouch and appendectomy) will be discussed. PMID- 24485253 TI - Laparoscopy for colorectal cancer. AB - The laparoscopic approach for colorectal cancer resection has been evolved from an experimental procedure with oncological concerns to routine daily practice within a period of two decades. Numerous randomized controlled trials and meta analyses have shown that laparoscopic resection results in faster recovery with similar oncological outcome compared to an open approach, both for colon and rectal cancer. Besides improved cosmesis, other long-term advantages seem to be less adhesion related small bowel obstruction and reduced incisional hernia rate. Adequate patient selection and surgical experience are of crucial importance. Experience can be gradually expanded step by step, by increasing the complexity of the procedure. A decision to convert should be made early in the procedure, because the outcome after a reactive conversion is worse than initial open resection or strategic conversion. The additive value of new techniques such as robotic surgery has to be proven in randomized studies including a cost effectiveness assessment. PMID- 24485254 TI - Minimally invasive surgery for oesophageal cancer. AB - Worldwide an increasing part of oncologic oesophagectomies is performed in a minimally invasive way. Over the past decades multiple reports have addressed the perioperative outcomes and oncologic safety of minimally invasive oesophageal surgery. Although many of these (retrospective) case-control studies identified minimally invasive oesophagectomy as a safe alternative to open techniques, the clear benefit remained subject to debate. Recently, this controversy has partially resolved due to the results of the first randomized controlled trial that compared both techniques. In this trial short-term benefits of minimally invasive oesophagectomy were demonstrated in terms of lower incidence of pulmonary infections, shorter hospital stay and better postoperative quality of life. However, the current lack of long-term data on recurrence rate and overall survival precludes a comprehensive comparison of minimally invasive and open oesophagectomy. Proclaiming minimally invasive oesophagectomy as the standard of care for patients with resectable oesophageal cancer would therefore be a premature decision. PMID- 24485255 TI - Multidisciplinary laparoscopic treatment for bowel endometriosis. AB - Endometriosis is a handicapping disease affecting young females in the reproductive period. It mainly occurs in the pelvis and affects the bowel in 3 37%. Endometriosis can cause menstrual and non-menstrual pelvic pain and infertility. Colorectal involvement results in alterations of bowel habit such as constipation, diarrhoea, tenesmus, and rarely rectal bleeding. A precise diagnosis about the presence, location and extent is necessary. Based on clinical examination, the diagnosis of bowel endometriosis can be made by transvaginal ultrasound, barium enema examination and magnetic resonance imaging. Multidisciplinary laparoscopic treatment has become the standard of care and depending on size of the lesion and site of involvement full-thickness disc excision or bowel resection is performed by an experienced colorectal surgeon. Anastomotic complications occur around 1%. Long-term outcome after bowel resection for severe endometriosis is good with a pregnancy rate of 50%. PMID- 24485256 TI - Laparoscopy for pelvic floor disorders. AB - Surgical treatment of pelvic floor disorders has significantly evolved during the last decade, with increasing understanding of anatomy, pathophysiology and the minimally-invasive 'revolution' of laparoscopic surgery. Laparoscopic pelvic floor repair requires a thorough knowledge of pelvic floor anatomy and its supportive components before repair of defective anatomy is possible. Several surgical procedures have been introduced and applied to treat rectal prolapse syndromes. Transabdominal procedures include a variety of rectopexies with the use of sutures or prosthesis and with or without resection of redundant sigmoid colon. Unfortunately there is lack of one generally accepted standard treatment technique. This article will focus on recent advances in the management of pelvic floor disorders affecting defecation, with a brief overview of contemporary concepts in pelvic floor anatomy and different laparoscopic treatment options. PMID- 24485257 TI - Advanced laparoscopic surgery for colorectal disease: NOTES/NOSE or single port? AB - Laparoscopic surgery for colorectal disease is an evolving, dynamic subject undergoing constant adaptation. Hence there are significant ongoing advances in technique and technology as has been seen with the emergence of single port and Natural Orifice Transluminal Endoscopic operations with already considerable ramifications for many aspects of minimal access surgery. Most recently single port technologies and expertise have synergized with Transanal Endoscopic (TEM/TEO) experience to allow their convergence out of their respective niches so that pelvic surgery can be laparoendoscopically performed from both its abdominal and perineal aspects. Distinct from wound-related benefits, such capacity for high resolution and multi-dimensional imaging relates significant benefit to the operating team and patient. This state of the art review demonstrates the crucial perspective that advanced practices and performance capabilities are intrinsically complimentary rather than competitive. All surgeons need therefore to participate in adapting their practice styles to allow technical step-advance across the discipline. PMID- 24485258 TI - Laparoscopic surgery for gastro-esophageal acid reflux disease. AB - Gastro-esophageal reflux disease is a troublesome disease for many patients, severely affecting their quality of life. Choice of treatment depends on a combination of patient characteristics and preferences, esophageal motility and damage of reflux, symptom severity and symptom correlation to acid reflux and physician preferences. Success of treatment depends on tailoring treatment modalities to the individual patient and adequate selection of treatment choice. PubMed, Embase, The Cochrane Database of Systematic Reviews, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched for systematic reviews with an abstract, publication date within the last five years, in humans only, on key terms (laparosc* OR laparoscopy*) AND (fundoplication OR reflux* OR GORD OR GERD OR nissen OR toupet) NOT (achal* OR pediat*). Last search was performed on July 23nd and in total 54 articles were evaluated as relevant from this search. The laparoscopic Toupet fundoplication is the therapy of choice for normal-weight GERD patients qualifying for laparoscopic surgery. No better pharmaceutical, endoluminal or surgical alternatives are present to date. No firm conclusion can be stated on its cost-effectiveness. Results have to be awaited comparing the laparoscopic 180-degree anterior fundoplication with the Toupet fundoplication to be a possible better surgical alternative. Division of the short gastric vessels is not to be recommended, nor is the use of a bougie or a mesh in the vast majority of GERD patients undergoing surgery. The use of a robot is not recommended. Anti-reflux surgery is to be considered expert surgery, but there is no clear consensus what is to be called an 'expert surgeon'. As for setting, ambulatory settings seem promising although high-level evidence is lacking. PMID- 24485259 TI - Laparoscopic liver surgery: An overview of the literature and experiences of a single centre. AB - In the past two decades there has been an enormous increase in laparoscopic liver surgery. There is a trend from limited to laparoscopic major resections and more centres are adopting laparoscopic liver surgery as a standard of care. Although no randomized clinical trials are published, different reports on minor and major hepatectomies and meta-analyses suggest (at least) equal outcomes and cost effectiveness compared to open procedures. PMID- 24485260 TI - Laparoscopic pancreatic surgery: An overview of the literature and experiences of a single center. AB - Pancreatic surgery was reported as early as 1898. Since then significant developments have been made in the field of pancreatic resections. In addition, advances in laparoscopic surgery in general have seen the description of this approach in pancreatic surgery with increasing frequency. Although there are no randomized controlled trials, several large series and comparative studies have reported on the short and long term outcome of laparoscopic pancreatic surgery. Furthermore, in the last decade published systematic reviews and meta-analyses have reported on cost effectiveness and outcomes of these procedures. PMID- 24485261 TI - Laparoscopy in the era of enhanced recovery. AB - Laparoscopy is one of the cornerstones in the surgical revolution and transformed outcome and recovery for various surgical procedures. Even if these changes were widely accepted for basic interventions, like appendectomies and cholecystectomies, laparoscopy still remains challenged for more advanced operations in many aspects. Despite these discussion, there is an overwhelming acceptance in the surgical community that laparoscopy did transform the recovery for several abdominal procedures. The importance of improved peri-operative patient management and its influence on outcome started to become a focus of attention 20 years ago and is now increasingly spreading, as shown by the incoming volume of data on this topic. The enhanced recovery after surgery (ERAS) concept incorporates simple measures of general management, and requires multidisciplinary collaboration from hospital staff as well as the patient and the relatives. Several studies have demonstrated a significant decrease in postoperative complication rate, length of hospital stay and reduced overall cost. The key elements of success are fluid restriction, a functioning epidural and preoperative carbohydrate intake. With the expansion of laparoscopic techniques, ERAS increasingly incorporates laparoscopic patients, especially in colorectal surgery. However, the precise impact of laparoscopy on ERAS is still not clearly defined. Increasing evidence suggests that laparoscopy itself is an additional ERAS item that should be considered as routine where feasible in order to obtain the best surgical outcomes. PMID- 24485262 TI - Transanal endoscopic microsurgery. AB - Transanal endoscopic microsurgery (TEMS) is a well established method of accurate resection of specimens from the rectum under binocular vision. This review examines its role in the treatment of benign conditions of the rectum and the evidence to support its use and compliment existing endoscopic treatments. The evolution of TEMS in early rectal cancer and the concepts and outcomes of how it has been utilised to treat patients so far are presented. The bespoke nature of early rectal cancer treatment is changing the standard algorithms of rectal cancer care. The future of TEMS in the organ preserving treatment of early rectal cancer is discussed and how as clinicians we are able to select the correct patients for neoadjuvant or radical treatments accurately. The role of radiotherapy and outcomes from combination treatment using TEMS are presented with suggestions for areas of future research. PMID- 24485263 TI - Laparoscopy for primary and secondary bariatric procedures. AB - Recently obesity has been defined as a disease and has turned bariatric surgery into a part of a chronic illness management. Obesity induces several comorbidities leading to cardiovascular disease and mortality. The effects of bariatric surgery on these comorbidities used to be classified as weight-loss induced. However bariatric surgery has recently been termed metabolic surgery because of the suspected direct, weight loss independent effect of bariatric procedures on the physiopathological mechanisms causing excess fat storage and insulin resistance. This review describes the standard procedures commonly performed and their specific outcomes on metabolic diseases in order to work towards more patient tailored treatment of obesity and to reduce side effects. Furthermore this review focuses on gaps in understanding the pathogenesis of obesity and its treatment with bariatric surgery. Surgery failures as well as new techniques are discussed and evaluated. PMID- 24485264 TI - Laparoscopy in diverticular disease: Controversies. AB - A minimally invasive approach to the management of diverticular disease has gained acceptance over the last number of years. Certainly, in the elective setting, laparoscopic sigmoid resection compares favourably with open surgery. The use of laparoscopy in the context of emergency surgery for complicated diverticular disease remains controversial however recent studies have demonstrated a defined role for laparoscopy in the acute setting. PMID- 24485265 TI - Laparoscopy in Crohn's disease. AB - In Crohn's disease (CD) surgical management, laparoscopic approach offers several theoretical advantages over the open approach. However, the importance of inflammatory lesions associated with CD, and the frequent presence of adhesions from previous surgery have initially questioned its feasibility and safety. In the present review article we will discuss the role of laparoscopic approach for Crohn's disease surgical management, along with its potential benefits as compared to the open approach. PMID- 24485266 TI - Laparoscopy in cholecysto-choledocholithiasis. AB - Gallstone disease is one of the most common problems in the gastroenterology and is associated with significant morbidity. It may present as stones in the gallbladder (cholecystolithiasis) or in the common bile duct (choledocholithiasis). At the end of the 1980s laparoscopy was introduced and first laparoscopic cholecystectomy was performed in 1985. The laparoscopic technique for removing the gallbladder is the current treatment of choice, although indications for open surgery exist. To perform laparoscopic cholecystectomy as safe as possible multiple safety measures were developed. The gold standard for diagnosing and removing common bile duct stones is Endoscopic Retrograde Cholangiopancreatography (ERCP). The surgical treatment option for choledocholithiasis is laparoscopic cholecystectomy with common bile duct exploration. If experience is not available, than ERCP followed by elective cholecystectomy is by far the best therapeutic modality. The present review will discuss the use, benefits and drawbacks of laparoscopy in patients with cholecystolithiasis and choledocholithiasis. PMID- 24485267 TI - Laparoscopic appendectomy: State of the art. Tailored approach to the application of laparoscopic appendectomy? AB - Acute appendicitis is the most common surgical emergency in developed countries. The treatment of acute appendicitis is either open or laparoscopic appendectomy. The latter has gained wide acceptance in the past years, although the debate on the true merits of laparoscopic appendectomy is still on going. Some authors prefer this approach as the gold standard for all patients, but in our opinion a tailored approach is warranted for specific patient groups. In addition, a standardised guideline on the technical aspects is still lacking. In the current article, open versus laparoscopic appendectomy and several technical aspects, such as stump closure, appendix extraction and single incision are discussed laparoscopic appendectomy are being addressed. In the future perspectives we will briefly discuss the third 'newly' introduced antibiotic treatment. PMID- 24485268 TI - Robotics: The next step? AB - Robotic systems were introduced 15 years ago to support complex endoscopic procedures. The technology is increasingly used in gastro-intestinal surgery. In this article, literature on experimental- and clinical research is reviewed and ergonomic issues are discussed. METHODS: literature review was based on Medline search using a large variety of search terms, including e.g. robot(ic), randomized, rectal, oesophageal, ergonomics. Review articles on relevant topics are discussed with preference. RESULTS: There is abundant evidence of supremacy in performing complex endoscopic surgery tasks when using the robot in an experimental setting. There is little high-level evidence so far on translation of these merits to clinical practice. DISCUSSION: Robotic systems may appear helpful in complex gastro-intestinal surgery. Moreover, dedicated computer based technology integrated in telepresence systems opens the way to integration of planning, diagnostics and therapy. The first high tech add-ons such as near infrared technology are under clinical evaluation. PMID- 24485269 TI - The first endemic West African vertebrate family - a new anuran family highlighting the uniqueness of the Upper Guinean biodiversity hotspot. AB - BACKGROUND: Higher-level systematics in amphibians is relatively stable. However, recent phylogenetic studies of African torrent-frogs have uncovered high divergence in these phenotypically and ecologically similar frogs, in particular between West African torrent-frogs versus Central (Petropedetes) and East African (Arthroleptides and Ericabatrachus) lineages. Because of the considerable molecular divergence, and external morphology of the single West African torrent frog species a new genus was erected (Odontobatrachus). In this study we aim to clarify the systematic position of West African torrent-frogs (Odontobatrachus). We determine the relationships of torrent-frogs using a multi-locus, nuclear and mitochondrial, dataset and include genera of all African and Asian ranoid families. Using micro-tomographic scanning we examine osteology and external morphological features of West African torrent-frogs to compare them with other ranoids. RESULTS: Our analyses reveal Petropedetidae (Arthroleptides, Ericabatrachus, Petropedetes) as the sister taxon of the Pyxicephalidae. The phylogenetic position of Odontobatrachus is clearly outside Petropedetidae, and not closely related to any other ranoid family. According to our time-tree estimation Odontobatrachus has been separated from other frog lineages since the Cretaceous (90.1 Ma; confidence interval: 84.2-97.1 Ma). Along with this molecular evidence, osteological and external diagnostic characters recognize West African torrent-frogs as distinct from other ranoids and provide strong support for the necessity of the recognition of a new family of frogs. This is the only endemic vertebrate family occurring in the Upper Guinea biodiversity hotspot. CONCLUSION: Based on molecular and morphological distinctiveness, the West African torrent-frog Odontobatrachus natator is allocated to a newly described anuran family. The discovery of an endemic vertebrate family in West Africa highlights the Upper Guinean forests as an outstanding, but highly endangered biodiversity hotspot. PMID- 24485270 TI - The use of TriCalcium Phosphate (TCP) and stem cells for the regeneration of osteoperiosteal critical-size mandibular bony defects, an in vitro and preclinical study. AB - The investigation aims to assess the reconstruction of critical-size mandibular bone defects in rabbits using beta-Tricalcium Phosphate (beta-TCP) scaffolding loaded with stem cells. A 20 mm-long mandibular osteoperiosteal continuity defect was created in 8 New Zealand rabbits and filled with beta-TCP scaffolding. In 6 cases bone marrow stem cells (BMSCs) harvested, and enriched, from the posterior iliac crest of the same rabbit were seeded into the scaffolding, while a scaffold was used alone in two cases chosen at random. Radiographic analysis was carried out immediately following surgery and 4, 8 and 12 weeks postoperatively. Cone Beam CT (CBCT) scanning, biomechanical testing and histology assessments were carried out on the explanted mandibles three months postoperatively. The radiography showed minimal new bone formation in all the cases, with significant amounts of undegraded scaffold material visible. Sporadic areas of bone formation were seen, these did not bridge the gap of the created surgical defect. The mechanical properties of the regenerated bone were of an inferior quality when compared with that of the contralateral non-operated side. The addition of BMSCs to the biodegradable beta-TCP scaffold did not improve reconstruction of the created mandibular defect. Despite successful aspiration and culture of BMSCs, the survival of these cells in vivo was questionable. PMID- 24485271 TI - Epidemiology and treatment outcome of surgically treated mandibular condyle fractures. A five years retrospective study. AB - Surgical management of mandibular condyle fractures is still controversial. Although it provides better outcome than closed treatment questions still remain about the surgical approach and the osteosynthesis devices to be used. Between 2005 and 2010, we managed 168 mandibular condyle fractures with open treatment. Two surgical approaches were used in this study, a pre-auricular and a high submandibular approach (one or the other or as a combined approach). Internal fixation was performed using TCP((r)) plates (Medartis, Basel, Switzerland) or with two lag screws (15 and 17 mm). Delta plates were used in 15 cases (8.9%). We report the epidemiology of these fractures and the outcomes of the surgical treatment. We assessed the complications related to the surgical procedure and those related to the osteosynthesis material. The facial nerve related complication rate was very low and the osteosynthesis materials used proved to be strong enough to realize a stable fixation. The two approaches used in this study appeared to be safe with good aesthetic results. Most of the surgical procedure failures occurred in high subcondylar fractures especially when bilateral. PMID- 24485272 TI - Health literacy assessment and patient satisfaction in surgical practice. AB - BACKGROUND: Individuals with limited health literacy have barriers to patient physician communication. Problems in communication are known to contribute to malpractice litigation. Concern exists, however, about the feasibility and patient acceptance of a health literacy assessment. This study was performed to determine the feasibility of health literacy assessment in surgical practice and its effect on patient satisfaction. STUDY DESIGN: Every patient seen in a Breast Surgery Clinic during a 2-year period was asked to undergo a health literacy assessment with the Newest Vital Sign (NVS) as part of the routine history and physical examination. During the year before routine NVS assessments and during the 2-year study period, all patients were asked to rate their "overall satisfaction with clinic visit" on a 5-point scale. RESULTS: A total of 2,026 of 2,097 patients (96.6%) seen during the study were eligible for the health literacy assessment. Of those, no patients refused assessment, and only one patient was missed. Therefore, 2,025 of 2,026 eligible patients (99.9%) underwent the assessment. The average time for NVS assessment was 2:02 minutes. Only 19% of patients had adequate health literacy. Patient satisfaction ratings were slightly greater during the first year of the health literacy assessment (3.8 vs 3.7, P = .049) compared with the year prior to health literacy assessment and greater during the second year of health literacy assessment (4.1 vs 3.7, P < .0001). CONCLUSION: Routine health literacy assessment is feasible in surgical practice and results in no decrease in patient satisfaction. In fact, satisfaction was greater during the years when health literacy assessments were performed. PMID- 24485274 TI - The application of knowledge synthesis methods in agri-food public health: recent advancements, challenges and opportunities. AB - Knowledge synthesis refers to the integration of findings from individual research studies on a given topic or question into the global knowledge base. The application of knowledge synthesis methods, particularly systematic reviews and meta-analysis, has increased considerably in the agri-food public health sector over the past decade and this trend is expected to continue. The objectives of our review were: (1) to describe the most promising knowledge synthesis methods and their applicability in agri-food public health, and (2) to summarize the recent advancements, challenges, and opportunities in the use of systematic review and meta-analysis methods in this sector. We performed a structured review of knowledge synthesis literature from various disciplines to address the first objective, and used comprehensive insights and experiences in applying these methods in the agri-food public health sector to inform the second objective. We describe five knowledge synthesis methods that can be used to address various agri-food public health questions or topics under different conditions and contexts. Scoping reviews describe the main characteristics and knowledge gaps in a broad research field and can be used to evaluate opportunities for prioritizing focused questions for related systematic reviews. Structured rapid reviews are streamlined systematic reviews conducted within a short timeframe to inform urgent decision-making. Mixed-method and qualitative reviews synthesize diverse sources of contextual knowledge (e.g. socio-cognitive, economic, and feasibility considerations). Systematic reviews are a structured and transparent method used to summarize and synthesize literature on a clearly-defined question, and meta analysis is the statistical combination of data from multiple individual studies. We briefly describe and discuss key advancements in the use of systematic reviews and meta-analysis, including: risk-of-bias assessments; an overall quality-of evidence approach; engagement of stakeholders; Bayesian, multivariate, and network meta-analysis; and synthesis of diagnostic test accuracy studies. We also highlight several challenges and opportunities in the conduct of systematic reviews (e.g. inclusion of grey literature, minimizing language bias, and optimizing search strategies) and meta-analysis (e.g. inclusion of observational studies and approaches to address the insufficient reporting of data and significant heterogeneity). Many of these developments have yet to be comprehensively applied and evaluated in an agri-food public health context, and more research is needed in this area. There is a need to strengthen knowledge synthesis capacity and infrastructure at the regional, national, and international levels in this sector to ensure that the best available knowledge is used to inform future decision-making about agri-food public health issues. PMID- 24485273 TI - Longitudinal study of striatal activation to reward and loss anticipation from mid-adolescence into late adolescence/early adulthood. AB - Adolescent risk-taking behavior has been associated with age-related changes in striatal activation to incentives. Previous cross-sectional studies have shown both increased and decreased striatal activation to incentives for adolescents compared to adults. The monetary incentive delay (MID) task, designed to assess functional brain activation in anticipation of reward, has been used extensively to examine striatal activation in both adult and adolescent populations. The current study used this task with a longitudinal approach across mid-adolescence and late adolescence/early adulthood. Twenty-two participants (13 male) were studied using the MID task at two time-points, once in mid-adolescence (mean age=16.11; SD=1.44) and a second time in late adolescence/early adulthood (mean age=20.14; SD=.67). Results revealed greater striatal activation with increased age in high- compared to low-incentive contexts (incentive magnitude), for gain as well as for loss trials (incentive valence). Results extend cross-sectional findings and show reduced striatal engagement in adolescence compared to adulthood during preparation for action in an incentive context. PMID- 24485275 TI - Cost-effectiveness of diagnostic strategies using quantitative real-time PCR and bacterial culture to identify contagious mastitis cases in large dairy herds. AB - Diagnostic strategies to detect contagious mastitis caused by Mycoplasma bovis, Staphylococcus aureus, and Streptococcus agalactiae in dairy herds during an outbreak have been minimally studied with regard to cost and diagnostic sensitivity. The objective of this cross-sectional study was to compare the cost effectiveness of diagnostic strategies for identification of infected cows in two California dairy herds during contagious mastitis outbreaks. M. bovis was investigated in a subset of a herd (n=1210 cows) with an estimated prevalence of 2.8% (95% CI=1.9, 3.7), whereas Staph. aureus and Strep. agalactiae were studied in a second herd (n=351 cows) with an estimated prevalence of 3.4% (95% CI=1.5, 5.3) and 16.8% (95% CI=12.9, 20.7), respectively. Diagnostic strategies involved a combination of testing stages that utilized bacterial culture, quantitative real-time PCR (qPCR), or both. Strategies were applied to individual or pooled samples of 5, 10, 50 or 100 samples. Culture was considered the gold standard for sensitivity estimation of each strategy. The reference strategy was the strategy with the lowest cost per culture-positive cow which for both M. bovis and Strep. agalactiae consisted of 2 stages, culture of samples in pools of 5 followed by culture of individual samples in positive pools with a sensitivity of 73.5% (95% CI: 55.6, 87.1) and 96.6% (95% CI: 27.7, 84.8), respectively. The reference strategy for Staph. aureus consisted of 3 stages, culture of individual samples in pools of 100 (stage 1), culture constituents of those positive from stage 1 in pools of 5 (stage 2), culture constituents of those positive from stage 2 individually (stage 3) which resulted in a sensitivity of 58.3% (95% CI: 88.3, 99.6). The most cost-effective alternative to the reference strategy was whole herd milk culture for all 3 pathogens. QPCR testing was a component of the second most cost-effective alternative for M. bovis and the third most cost-effective alternatives for the 3 pathogens. A stochastic model was used to assess the effect of prevalence or herd size on the cost-effectiveness of diagnostic strategies. In the current study, increasing the prevalence of mastitis did not alter the ranking of strategies by cost-effectiveness. However, larger herds could benefit from testing larger pools such as 50 or 100 samples to improve cost effectiveness. Several diagnostic strategy options exist to identify contagious mastitis in herds, decisions should be based on cost and sensitivity of the strategies available. PMID- 24485276 TI - The spread of highly pathogenic avian influenza (subtype H5N1) clades in Bangladesh, 2010 and 2011. AB - Since the global spread of highly pathogenic avian influenza H5N1 during 2005 2006, control programs have been successfully implemented in most affected countries. HPAI H5N1 was first reported in Bangladesh in 2007, and since then 546 outbreaks have been reported to the OIE. The disease has apparently become endemic in Bangladesh. Spatio-temporal information on 177 outbreaks of HPAI H5N1 occurring between February 2010 and April 2011 in Bangladesh, and 37 of these outbreaks in which isolated H5N1 viruses were phylogenetically characterized to clade, were analyzed. Three clades were identified, 2.2 (21 cases), 2.3.4 (2 cases) and 2.3.2.1 (14 cases). Clade 2.2 was identified throughout the time period and was widely distributed in a southeast-northwest orientation. Clade 2.3.2.1 appeared later and was generally confined to central Bangladesh in a north-south orientation. Based on a direction test, clade 2.2 viruses spread in a southeast-to-northwest direction, whereas clade 2.3.2.1 spread west-to-east. The magnitude of spread of clade 2.3.2.1 was greater relative to clade 2.2 (angular concentration 0.2765 versus 0.1860). In both cases, the first outbreak(s) were identified as early outliers, but in addition, early outbreaks (one each) of clade 2.2 were also identified in central Bangladesh and in northwest Bangladesh, a considerable distance apart. The spread of highly pathogenic avian influenza H5N1 in Bangladesh is characterized by reported long-distance translocation events. This poses a challenge to disease control efforts. Increased enforcement of biosecurity and stronger control of movements between affected farms and susceptible farms, and better surveillance and reporting, is needed. Although the movement of poultry and equipment appears to be a more likely explanation for the patterns identified, the relative contribution of trade and the market chain versus wild birds in spreading the disease needs further investigation. PMID- 24485277 TI - Rabies in the Dutch East Indies a century ago - a spatio-temporal case study in disease emergence. AB - Rabies continues to spread through the Indonesian archipelago. During the past 20 years, several islands - including Flores, Ambon and Bali - that had historically been free of rabies have become infected. However, the Dutch East Indies (a Dutch colony that became modern Indonesia following World War II) had been infected since the 1880s. The spread of rabies is a lesson in the emergence of an infectious disease. Reports of human cases treated for rabies and livestock rabies cases from the 1880s to 1917 were compiled. The spatial and temporal distribution of these cases was analyzed using maps, spatial statistics and time series techniques. The first confirmed case of rabies was reported in 1889 from the Batavia [Jakarta] district (although disease suspicion was reported as early as 1884). During the 1890s rabies was already commonly reported from Java and the east coast of Sumatra, and by the late 1890s, from Celebes [Sulawesi]. Between 1900 and 1916, cases were reported from other parts of Java, Sumatra and Sulawesi, and from Borneo, the Moluccas and other outlying islands. Between 1897 and 1916, a total of 8826 human cases treated for rabies were reported and between 1908 and 1917, 1033 livestock cases were reported. Most (97.5%) human cases treated were attributed to rabid dogs. Increasing numbers of reports were observed during the period. Between 1908 and 1916 the correlation between human and livestock case reports was 64.2%, and at the district level it was 75.9%. Moderate correlations (>40%) were found between human cases and livestock cases reported up to six months previously. Based on year of first report from each district, human cases were strongly clustered (Moran's autocorrelation 0.47, P=0.005). The most likely spatio-temporal cluster of reported cases of humans treated for rabies originated from the west coast of Sumatra between 1899 and 1905, and other clusters were identified in west Java (1898-1899), the district of Batavia and in east Java (1910-1911), Nusa Tengarra Barat (1912), Borneo (1914) and the east coast of Sumatra (1903-1906). Rabies was probably first introduced to the colonial capital of the Dutch Indies, Batavia [Jakarta] in the 1880s. It then spread rapidly throughout most of the archipelago during the next two to three decades because of the movement of dogs via the military forces, for trade and as pets, despite government regulations designed to control the epidemic. Such a history suggests that further emergence and reemergence of rabies in rabies-free islands will occur based on an island's location and position within the complex social, trade and transport network that represents the Indonesian archipelago. Targeted surveillance and enforcement of quarantine regulations remain critical, to prevent history repeating itself. PMID- 24485278 TI - A multi-analysis approach for space-time and economic evaluation of risks related with livestock diseases: the example of FMD in Peru. AB - This study presents a multi-disciplinary decision-support tool, which integrates geo-statistics, social network analysis (SNA), spatial-stochastic spread model, economic analysis and mapping/visualization capabilities for the evaluation of the sanitary and socio-economic impact of livestock diseases under diverse epidemiologic scenarios. We illustrate the applicability of this tool using foot and-mouth disease (FMD) in Peru as an example. The approach consisted on a flexible, multistep process that may be easily adapted based on data availability. The first module (mI) uses a geo-statistical approach for the estimation (if needed) of the distribution and abundance of susceptible population (in the example here, cattle, swine, sheep, goats, and camelids) at farm-level in the region or country of interest (Peru). The second module (mII) applies SNA for evaluating the farm-to-farm contact patterns and for exploring the structure and frequency of between-farm animal movements as a proxy for potential disease introduction or spread. The third module (mIII) integrates mI II outputs into a spatial-stochastic model that simulates within- and between farm FMD-transmission. The economic module (mIV) connects outputs from mI-III to provide an estimate of associated direct and indirect costs. A visualization module (mV) is also implemented to graph and map the outputs of module I-IV. After 1000 simulated epidemics, the mean (95% probability interval) number of outbreaks, infected animals, epidemic duration, and direct costs were 37 (1, 1164), 2152 (1, 13, 250), 63 days (0, 442), and US$ 1.2 million (1072, 9.5 million), respectively. Spread of disease was primarily local (<4.5km), but geolocation and type of index farm strongly influenced the extent and spatial patterns of an epidemic. The approach is intended to support decisions in the last phase of the FMD eradication program in Peru, in particular to inform and support the implementation of risk-based surveillance and livestock insurance systems that may help to prevent and control potential FMD virus incursions into Peru. PMID- 24485279 TI - [Polycystic ovary syndrome: what are the obstetrical risks?]. AB - Polycystic ovary syndrome (PCOS) is the most common endocrine disorder in women of reproductive age and the leading cause of female infertility. This condition is frequently associated with significant metabolic disorders, including obesity and hyperinsulinemia. Therefore, it seems essential to focus on the pregnancy of these patients and possible obstetric complications. Many studies suggest an increase in the risk of obstetric pathology: early miscarriage, gestational hypertension, preeclampsia, gestational diabetes mellitus diagnosed during early pregnancy, prematurity, low birthweight or macrosomia, neonatal complications and cesarean sections. However, it is difficult to conclude clearly about it, because of the heterogeneity of definition of PCOS in different studies. In addition, many confounding factors inherent in PCOS including obesity are not always taken into account and generate a problem of interpretation. However it seems possible to conclude that PCOS does not increase the risk of placental abruption, HELLP syndrome, liver disease, postpartum hemorrhage, late miscarriage and stillbirth. PMID- 24485280 TI - The contribution of Saharan dust in PM(10) concentration levels in Anatolian Peninsula of Turkey. AB - Sahara-originated dust is the most significant natural source of particulate matter; however, this contribution is still unclear in the Eastern Mediterranean especially in Western Turkey, where significant industrial sources and metropolitan areas are located. The Real-time Air Quality Modeling System (RAQMS) is utilized to explore the possible effects of Saharan dust on high levels of PM10 measured in Turkey. RAQMS model is compared with 118-air quality stations distributed throughout Turkey (81 cities) for April 2008. MODIS aerosol product (MOD04 for Terra and MYD04 for Aqua) is used to see columnar aerosol loading of the atmosphere at 550 nm (Aerosol optical depth (AOD) values found to be between 0.6 and 0.8 during the episode). High-resolution vertical profiles of clouds and aerosols are provided from CALIOP, on board of CALISPO satellite. The results suggest a significant contribution of Sahara dust to high levels of PM10 in Turkey with RAQMS and in situ time series showing similar patterns. The two data sets are found to be in agreement with a correlation of 0.87. PMID- 24485281 TI - A passive sampling method for detecting analgesics, psycholeptics, antidepressants and illicit drugs in aquatic environments in the Czech Republic. AB - The goal of this study was to assess the bioavailable concentrations of analgesics, psycholeptics, antidepressants and illicit drugs in the surface waters of the Czech Republic. All of the sampling sites are located within the most important water quality monitoring profiles at the Czech Hydrometeorological Institute. The total concentrations of the compounds ranged from 463 to 6,447 ng POCIS(-1) (Polar Organic Chemical Integrative Sampler). Carbamazepine (196-2,690 ng POCIS(-1)) and tramadol (160-2,250 ng POCIS(-1)) were the most abundant compounds at every site. The most polluted sites were those that received communal wastewater effluent and had a low dilution factor (ratio of wastewater effluent and river flow). The aqueous concentrations of the target compounds were estimated using sampling rate values obtained during a field calibration experiment. Patterns in the aqueous concentrations of the compounds (after back calculation from POCIS extracts) and the POCIS concentrations are different, possibly leading to discrepancies between the toxicity assessments conducted using POCIS extracts and those conducted using grab samples of water from the same location. PMID- 24485282 TI - Reducing bottlenecks: professionals' and adolescents' experiences with transitional care delivery. AB - BACKGROUND: The purpose of this study was to describe the interventions implemented in a quality improvement programme to improve transitional care and evaluate its effectiveness in reducing bottlenecks as perceived by professionals and improving chronically ill adolescents' experiences with care delivery. METHODS: This longitudinal study was undertaken with adolescents and professionals who participated in the Dutch 'On Your Own Feet Ahead!' quality improvement programme. This programme followed the Breakthrough Series improvement and implementation strategy.A total of 102/128 (79.7%) professionals from 21 hospital teams filled out a questionnaire at the start of the programme (T0), and 79/123 (64.2%; five respondents had changed jobs) professionals completed the same questionnaire 1 year later (T1). Seventy-two (58.5%) professionals from 21 teams returned questionnaires at both time points. Of 389 and 430 participating adolescents, 36% and 41% returned questionnaires at T0 and T1, respectively. We used descriptive statistics and two-tailed, paired t-tests to investigate improvements in bottlenecks in transitional care (perceived by professionals) and care delivery (perceived by adolescents). RESULTS: Professionals observed improvement in all bottlenecks at T1 (vs. T0; p < 0.05), especially in the organisation of care, such as the presence of a joint mission between paediatric and adult care, coordination of care, and availability of more resources for joint care services. Within a 1-year period, the transition programme improved some aspects of patients' experiences with care delivery, such as the provision of opportunities for adolescents to visit the clinic alone (p < 0.001) and to decide who should be present during consultations (p < 0.05). CONCLUSIONS: This study demonstrated that transitional care interventions may improve the organisation and coordination of transitional care and better prepare adolescents for the transition to adult care within a 1-year period. By setting specific goals based on experiences with bottlenecks, the breakthrough approach helped to improve transitional care delivery for adolescents with chronic conditions. PMID- 24485283 TI - Evaluating the efficacy and cost-effectiveness of web-based indicated prevention of major depression: design of a randomised controlled trial. AB - BACKGROUND: Major depressive disorder (MDD) imposes a considerable disease burden on individuals and societies. Web-based interventions have shown to be effective in reducing depressive symptom severity. However, it is not known whether web based interventions may also be effective in preventing the onset of MDD. The aim of this study is to evaluate the (cost-) effectiveness of an indicated web-based guided self-help intervention (GET.ON Mood Enhancer Prevention) on the onset of MDD. METHODS/DESIGN: A randomised controlled trial (RCT) will be conducted to compare the (cost-) effectiveness of the GET.ON Mood Enhancer Prevention training with a control condition exclusively receiving online-based psychoeducation on depression. Adults with subthreshold depression (N = 406) will be recruited from the general population and randomised to one of the two conditions. The primary outcome is time to onset of MDD within a 12-months follow-up period. MDD will be assessed according to DSM-IV criteria as assessed by the telephone-administered Structured Clinical Interview for DSM-IV (SCID). Time to onset of MDD will be assessed using life charts. Secondary outcomes include changes on various indicators of depressive symptom severity, anxiety and quality of life from baseline to post-treatment, to a 6-month and a 12-month follow up. Additionally, an economic evaluation using a societal perspective will be conducted to examine the intervention's cost-effectiveness. DISCUSSION: This is one of the first randomised controlled trials that examines the effect of an indicated guided self help web-based intervention on the incidence of major depression. If shown to be effective, the intervention will contribute to reducing the disease burden due to MDD in the general population. TRIAL REGISTRATION: German Clinical Trial Registration DRKS00004709. PMID- 24485284 TI - Do we need a new vaccine to control the re-emergence of pertussis? AB - Bordetella pertussis causes whooping cough and is re-emerging in developed countries despite widespread immunization with acellular pertussis vaccines (Pa), which are less effective than the whole cell vaccines that they replaced. Efficacy of Pa could be improved by switching from alum to alternative adjuvants that generate more potent cell mediated immunity. PMID- 24485286 TI - [CCAFU Recommendations 2013: Bladder carcinoma]. AB - INTRODUCTION: The objective was to update the guidelines of the French Urological Association Cancer Committee for non invasive (NMIBC) and invasive bladder cancer (MIBC). METHODS: A Medline search was performed between 2010 and 2013, as regards diagnosis, options of treatment and follow-up of bladder cancer, to evaluate different references with levels of evidence. RESULTS: Diagnosis of NMIBC (Ta, T1, CIS) depends on cystoscopy and complete deep resection of the tumour. The use of fluorescence and a second-look indication are essential to improve initial diagnosis. Risks of both recurrence and progression can be estimated using the EORTC score. A stratification of patients into low, intermediate and high groups is pivotal for recommending adjuvant treatment: instillation of chemotherapy (immediate post-operative, standard schedule) or intravesical BCG (standard schedule and maintenance). Cystectomy is recommended in BCG-refractory patients. Extension evaluation of MIBC is based on pelvic-abdominal and thoracic CT-scan, MRI and FDGPET remain optional. Cystectomy associated with extensive lymph nodes resection is considered the gold standard for non metastatic MIBC. An orthotopic bladder substitution should be proposed to both male and female patients lacking any contraindications and in cases of negative frozen urethral samples, otherwise trans-ileal ureterostomy is recommended as urinary diversion. The interest of neoadjuvant chemotherapy is well known for advanced MIBC as T3-T4 and/or N1-3. As regards metastatic MIBC, first-line chemotherapy using platin is recommended (GC or MVAC), when status (PS<1) and renal function (creatinine clearance > 60 ml/min) permits (only in 50% of cases). In second line treatment, only chemotherapy using vinfluvine has been validated to date. Conclusion.-These new guidelines will hopefully contribute not only to improve patient management, but also diagnosis and treatment for NMIBC and MIBC. PMID- 24485287 TI - [CCAFU Recommendations 2013: Upper urinary tract carcinoma]. AB - INTRODUCTION: The objective was to update the guidelines of the French Urological Association Cancer Committee for upper tract urothelial carcinoma (UTUC). METHODS: A Medline search was performed between 2010 and 2013, as regards diagnosis, options of treatment and follow-up of UTUC, to evaluate different references with levels of evidence. RESULTS: The diagnosis of this rare pathology is based on CT-scan acquisition during excretion and ureteroscopy with histological biopsies. Total nephro-urectomy remains the gold standard for surgical treatment, nevertheless a conservative endoscopic approach can be proposed : unifocal tumour and diameter < 1 cm and low grade and absence of invasion on CT-scan. Close monitoring with endoscopic follow-up (flexible ureteroscope) in compliant patients is therefore necessary. CONCLUSION: These new guidelines will hopefully contribute not only to improve patient management, but also diagnosis and treatment for UTUC. PMID- 24485285 TI - Association between the oxytocin receptor (OXTR) gene and mesolimbic responses to rewards. AB - BACKGROUND: There has been significant progress in identifying genes that confer risk for autism spectrum disorders (ASDs). However, the heterogeneity of symptom presentation in ASDs impedes the detection of ASD risk genes. One approach to understanding genetic influences on ASD symptom expression is to evaluate relations between variants of ASD candidate genes and neural endophenotypes in unaffected samples. Allelic variations in the oxytocin receptor (OXTR) gene confer small but significant risk for ASDs for which the underlying mechanisms may involve associations between variability in oxytocin signaling pathways and neural response to rewards. The purpose of this preliminary study was to investigate the influence of allelic variability in the OXTR gene on neural responses to monetary rewards in healthy adults using functional magnetic resonance imaging (fMRI). METHODS: The moderating effects of three single nucleotide polymorphisms (SNPs) (rs1042778, rs2268493 and rs237887) of the OXTR gene on mesolimbic responses to rewards were evaluated using a monetary incentive delay fMRI task. RESULTS: T homozygotes of the rs2268493 SNP demonstrated relatively decreased activation in mesolimbic reward circuitry (including the nucleus accumbens, amygdala, insula, thalamus and prefrontal cortical regions) during the anticipation of rewards but not during the outcome phase of the task. Allelic variation of the rs1042778 and rs237887 SNPs did not moderate mesolimbic activation during either reward anticipation or outcomes. CONCLUSIONS: This preliminary study suggests that the OXTR SNP rs2268493, which has been previously identified as an ASD risk gene, moderates mesolimbic responses during reward anticipation. Given previous findings of decreased mesolimbic activation during reward anticipation in ASD, the present results suggest that OXTR may confer ASD risk via influences on the neural systems that support reward anticipation. PMID- 24485288 TI - [CCAFU Recommendations 2013: Penile cancer]. AB - INTRODUCTION: Malignant tumours of the penis are rare tumours. The objective of this article is to propose guidelines for the management of these tumours. MATERIAL AND METHODS: A review of the literature was performed by selecting articles on penile cancer published in PUBMED. RESULTS: The most common histological type is squamous cell carcinoma. Clinical examination of the penis is usually sufficient to assess local extension of the primary tumour, but it can be completed by MRI to assess deeper extension. Inguinal lymph nodes must be systematically palpated on both sides to assess regional extension. In the presence of palpable lymph nodes, aspiration cytology is recommended in combination with abdomen and pelvis computed tomography and (18)F-FDG PET-CT. Sentinel lymph node biopsy is recommended in the case of penile cancer at high risk of lymph node extension with no palpable lymph nodes. Treatment of the primary tumour is usually surgical. It must be as conservative as possible while ensuring negative surgical margins. Brachytherapy or local treatment (laser, cytotoxic cream, etc.) can be proposed in some cases. Bilateral lymph node chains must be systematically treated at the time of diagnosis of the disease. Inguinal lymphadenectomy alone has a curative role in patients with metastatic invasion of a single lymph node (stage pN1). In the case of more extensive lymph node involvement, multimodal management combining chemotherapy, surgery and possibly radiotherapy, must be considered. CONCLUSION: The treatment of penile cancer is usually surgical possibly in combination with chemotherapy in the presence of lymph node extension. The main prognostic factor is lymph node involvement, requiring appropriate management right from the time of diagnosis. PMID- 24485289 TI - [CCAFU Recommendations 2013: Testicular germ cell cancer]. AB - INTRODUCTION: The objective of this article is to establish guidelines proposed by the external genital organ group of the CCAFU for the diagnosis, treatment and follow-up of the germ cell tumours of the testis. MATERIAL AND METHODS: The multidisciplinary working party studied previous guidelines, exhaustively reviewed the literature, and evaluated references and their level of proof in order to attribute grades of recommendation. RESULTS: The initial work-up of testicular cancer is based on clinical, laboratory (AFP, total hCG, LDH) and imaging assessment (scrotal ultrasound and chest, abdomen and pelvis computed tomography). Inguinal orchidectomy is the first-line treatment allowing characterization of the histological type, local staging and identification of risk factors for micrometastases. The management of stage I tumours must be adapted to the risk by explaining to the patient the benefits/disadvantages of active treatment or watchful waiting as a function of the risk of relapse. Treatment options for stage 1 seminomas comprise : watchful waiting, chemotherapy (1 cycle of carboplatin) or para-aortic radiotherapy. Treatment options for stage 1 nonseminomatous germ cell tumours comprise : watchful waiting, chemotherapy (2 cycles of BEP) or staging retroperitoneal lymphadenectomy. The management of metastatic tumours essentially comprises chemotherapy with 3 or 4 cycles of BEP according to the prognostic group. Radiotherapy may be indicated in seminomas with lymph node metastasis < 3 cm. Review 3 to 4 weeks post-chemotherapy is essentially based on tumour marker assays and chest, abdomen and pelvis computed tomography. Surgical retroperitoneal lymph node dissection is indicated for all residual NSGCT masses > 1 cm and for persistent residual seminoma masses > 3 cm with (18)F-FDG PET-CT uptake. CONCLUSIONS: Germ cell tumours have an excellent survival rate based on precise initial staging, adapted and strictly defined treatment and close surveillance. PMID- 24485290 TI - [CCAFU's contribution to the French National Cancer Institute's reference frame: Retroperitoneal sarcomas]. AB - INTRODUCTION: Retroperitoneal sarcomas are rare tumours. The objective of this article is to propose management guidelines. MATERIAL AND METHODS: A review of the literature was performed using the PubMed search engine (1985-2013) with the key words: retroperitoneal sarcoma, prognosis, recurrence, surgery, radiation therapy, chemotherapy. RESULTS: Chest, abdomen and pelvis computed tomography is the reference examination. Other examinations are optional. PET scan is not indicated for the primary diagnosis. CT-guided retroperitoneal biopsy is recommended and must be systematically performed before any management of a suspicious retroperitoneal mass. All retroperitoneal sarcomas must be registered and presented to a multidisciplinary consultation meeting devoted to the management of sarcomas (regional meetings) prior to any therapeutic intervention. Treatment is essentially surgical and is primarily designed to achieve negative surgical margins (R0). Neoadjuvant or adjuvant radiotherapy and chemotherapy can be proposed depending on the risk of progression and the resectability. The recurrence rate is related to tumour grade and surgical margins. The final prognosis is intimately related to the quality of initial management and the number of cases treated by each centre. CONCLUSION: Retroperitoneal sarcomas have a poor prognosis. The quality of initial management directly impacts recurrence free survival and overall survival. The prognosis is improved by multidisciplinary management conducted in a reference centre. PMID- 24485291 TI - [CCAFU's contribution to the French National Cancer Institute's reference frame: Adrenal malignant tumors]. AB - INTRODUCTION: Malignant tumours of the adrenal gland are adrenocortical carcinomas (ACC), malignant phaeochromocytomas (MPC) or metastatic tumours. The objective of this article is to propose guidelines for the management of these tumours. MATERIAL AND METHODS: A review of the literature was performed by selecting articles on malignant tumours of the adrenal gland published in PUBMED. RESULTS: Abdominal computed tomography is the reference first-line examination. A diameter > 6 cm, a heterogeneous appearance, irregular margins, spontaneous high density (> 20 HU) and delayed wash-out are radiological signs of malignancy. MRI can be used to characterize the tumour with a sensitivity of 89% and a specificity of 99%. Hormone assays and an endocrinology consultation are recommended before any management. When ACC is suspected, (18)FDG-PET is the reference scintigraphic examination, while the isotope of choice for MPC is (18)F DOPA, which is more sensitive than MIBG. These scintigraphic examinations have a sensitivity close to 100% and allow staging of distant metastases. Percutaneous biopsy has a limited place in the diagnostic work-up. It is only indicated in the case of suspected adrenal metastasis after having excluded phaeochromocytoma and must not be performed in the case of suspected adrenocortical carcinoma. Surgery is first-line treatment for localized and resectable tumours, but is rarely curative due to the high recurrence rate. For ACC, adjuvant therapy by mitotane or adjuvant radiotherapy can be proposed. Metabolic radiotherapy with (131)I-MIBG can be proposed for the treatment of MPC. First-line chemotherapy is indicated in the case of advanced disease or unresectable tumour. Surgical treatment of adrenal metastasis by adrenalectomy is recommended depending on the type and prognosis of the primary cancer. CONCLUSION: Preoperative laboratory, morphological and scintigraphic assessment is essential before any management. First-line treatment is surgical when the tumour is resectable, but must be completed by adjuvant therapy to limit the risk of recurrence. PMID- 24485292 TI - [CCAFU Recommendations 2013: Renal cancer]. AB - INTRODUCTION: The renal sub Committee of the CCAFU established guidelines for diagnosis, treatment, evaluation and standard of care for renal cell carcinoma. METHODS: 2010 Guidelines were updated based on systematic literature search performed by the sub-Committee in Medline and PubMed databases to evaluate references, levels of evidence and grade of recommendation. RESULTS: Multiphasic CT is the standard imaging technique for renal tumors diagnosis. Percutaneous renal biopsies are increasingly important for the management of localized RCC. Partial Nephrectomy is the first option when technically feasible for cT1 tumours. Open surgery remains the standard approach for locally advanced RCCs. New drugs are available for the treatment of metastatic RCC while the role of nephrectomy needs to be established by the Carmena trial. CONCLUSIONS: Conservative and mini-invasive therapies are increasingly important for the management of localized RCC. Therapeutic armamentarium continues to increase in mRCC. PMID- 24485293 TI - [CCAFU Recommendations 2013: Diagnosis, treatment, follow up of urological cancers]. AB - INTRODUCTION: The objective of the 2013 recommendations performed by the different committees of CCAFU is to improve the management of urological cancers regarding diagnosis, clinical assessment and treatments in men and women. MATERIAL AND METHODS: 2010 clinical guidelines were updated based on international AUA and EAU guidelines and on systematic literature search performed by each sub-Committee in Medline and PubMed databases to evaluate references, levels of evidence and grade of recommendation. RESULTS: CCAFU clinical guidelines reply to the main clinical questions on management of urological cancers. CONCLUSION: French clinical guidelines are updated every three years by CCAFU in accordance with the main international guidelines in onco urology. PMID- 24485294 TI - [Incidence and mortality of urological cancers in 2012 in France]. AB - OBJECTIVES: Present national estimations of the incidence and mortality trends in urological cancers in France between 1980 and 2012. MATERIAL AND METHODS: Francim database and French Register of Cancers. RESULTS: Analysis of the current data shows a regular increase of the incidence of renal cancer in men and women (7,781 cases in men and 3,792 in women in 2012). For bladder cancer, trends are divergent. There is a small reduction in incidence for men and an increase for women (9,549 cases in men and 2,416 in women in 2012). Testicular cancer is still increasing slightly (2,317 incidental cases in 2012). The incidence of prostate cancer experienced a huge increase up until 2005, and thereafter it decreased sharply, though it is difficult to discern whether this drop (which was observed up until 2008) continued at the same rate after that point (56,841 incidences in 2012 based on the rates calculated for 2009). CONCLUSION: The analyses by organ database show that there are significant variations in the incidence of urological cancers, particularly for prostate cancer, which shows that both the natural history of urological tumours and the methods of detection have an impact on incidence. PMID- 24485295 TI - [CCAFU Recommendations 2013: Prostate cancer]. AB - INTRODUCTION: The sub Comittee prostate of the CCAFU established guidelines for diagnostic, treatment, evaluation and standart of care of prostate cancer. METHODS: Guidelines 2010 were updated based on systematic literature search performed by the sub-Comittee in Medline and PubMed databases to evaluate references, levels of evidence and grade of recommandation. RESULTS: Pathological examination of the tissue specimens was defined specifically for Gleason score according to ISP 2005 recommandations. Prostate and pelvis RMN became the reference in terms of radiological exam. Individual and early diagnosis of prostate cancer was defined and role of PSA was precised. Active surveillance became one of the standart of care of low-risk tumors, radical prostatectomy remained one of the options for all risk group tumors, length of hormonotherapy in association with radiotherapy was precised according to the risk group. Side effects of hormonotherapy treament needed specific supervision ; hormonotherapy had no indication in case of non metastatic tumors and intermittent hormonotherapy in metastatic tumors. New hormonal drugs in pre and post chemotherapy and bone target drugs opened new therapeutics pathways. CONCLUSION: From 2010 to 2013, standarts of care of prostate cancer were modified because of results of prospective studies and new therapeutics. They allowed precise treatments for each specific clinical situation. In the future, multidisciplinary treatments for high risk tumors, time of adjuvant treatment and sequencies of new hormonal treatment had to be defined. PMID- 24485297 TI - Enrichment, distribution and sources of heavy metals in the sediments of Deception Bay, Queensland, Australia. AB - Sediment samples from 13 sampling sites in Deception Bay, Australia were analysed for the presence of heavy metals. Enrichment factors, modified contamination indices and Nemerow pollution indices were calculated for each sampling site to determine sediment quality. The results indicate significant pollution of most sites by lead (average enrichment factor (EF) of 13), but there is also enrichment of arsenic (average EF 2.3), zinc (average EF 2.7) and other heavy metals. The modified degree of contamination indices (average 1.0) suggests that there is little contamination. By contrast, the Nemerow pollution index (average 5.8) suggests that Deception Bay is heavily contaminated. Cluster analysis was undertaken to identify groups of elements. Strong correlation between some elements and two distinct clusters of sampling sites based on sediment type was evident. These results have implications for pollution in complex marine environments where there is significant influx of sand and sediment into an estuarine environment. PMID- 24485296 TI - Efficacy and safety of balugrastim compared with pegfilgrastim in patients with breast cancer receiving chemotherapy. AB - BACKGROUND: Recombinant granulocyte colony-stimulating factors (G-CSFs) reduce the incidence and duration of chemotherapy-induced neutropenia and febrile neutropenia when given as adjunct therapy to patients receiving myelosuppressive chemotherapy. Balugrastim is a long-acting G-CSF composed of a genetic fusion between recombinant human serum albumin and G-CSF. We compared the efficacy and safety of balugrastim and pegfilgrastim, a long-acting pegylated recombinant G CSF, in patients with breast cancer who were scheduled to receive chemotherapy. PATIENTS AND METHODS: In this double-blind randomized phase III trial, patients with >= 1.5 * 10(9) neutrophils/L were randomly assigned to subcutaneous injections of balugrastim 40 mg (n = 153) or pegfilgrastim 6 mg (n = 151). The primary efficacy end point was the duration of severe neutropenia (DSN) (days with an absolute neutrophil count [ANC] < 0.5 * 10(9) cells/L) during cycle 1. Efficacy analyses were performed in the per-protocol (PP) population. In a separate open-label single-arm study, newly recruited patients (n = 77) received balugrastim 40 mg and were included in the safety analysis. RESULTS: The mean DSN in cycle 1 was 1.1 days in the balugrastim group and 1.0 days in the pegfilgrastim group (95% confidence interval [CI], -0.13-0.37). Two and 4 patients, respectively, had febrile neutropenia during cycle 1. Twenty percent of patients in the balugrastim group and 19% in the pegfilgrastim group had adverse events (AEs) considered to be related to study medication; 3.9% and 4.7% of patients, respectively, experienced serious AEs. CONCLUSIONS: This study demonstrates the comparable safety and efficacy profile of balugrastim and pegfilgrastim and the noninferiority of balugrastim for reduction in DSN. There were no unexpected safety events. PMID- 24485299 TI - Improving xylose utilization by recombinant Zymomonas mobilis strain 8b through adaptation using 2-deoxyglucose. AB - BACKGROUND: Numerous attempts have been made to improve xylose utilization in Z. mobilis including adaptive approaches. However, no one has yet found a way to overcome the reduced xylose utilization observed in fermentations carried out in the presence of glucose as well as the inhibitory compounds found within pretreated and saccharified biomass. Our goal was to generate Z. mobilis strains that are more robust than the wildtype strain with increased productivity in fermenting the glucose and xylose present in PCS. Through adaptation in the presence of 2-deoxyglucose, we have generated Zymomonas mobilis strain #7, which is better suited to utilizing xylose in pretreated corn stover (PCS) fermentations in the presence of both glucose and model inhibitory compounds of acetate and furfural. Strain #7 over performed the parent strain 8b both on simultaneous saccharification and fermentation (SFF) of PCS and fermentation of saccharified PCS slurry. At 65% neutralized PCS liquor level, strain #7 used 86% of the xylose present in the liquor while strain 8b was not able to ferment the liquor under similar conditions. Similarly, under SSF process conditions with 20% total solids loading of PCS, strain #7 used more than 50% of the xylose present, while strain 8b did not utilize any xylose under this condition. We have further identified genetic alterations in strain #7 in relation to the parental strain 8b that may be responsible for these phenotypic enhancements. RESULTS: We performed an extended lab-directed evolution of Z. mobilis strain 8b in the presence of acetate and a non-hydrolyzable glucose analogue 2-deoxyglucose. Following the adaptation, we identified and characterized numerous candidate strains and found a dramatic increase in xylose usage not only in shake flask, but also in a controlled PCS fermentation. We re-sequenced the genomes of evolved strains to identify genetic alterations responsible for these improved phenotypes, and identified two mutations that may be key to the improved xylose usage in these strains. CONCLUSION: We have generated Z. mobilis strain #7, which can ferment xylose efficiently in the presence of toxins present in pretreated corn stover. Genetic alterations responsible for the improvement have been identified. PMID- 24485298 TI - The RBPome: where the brains meet the brawn. PMID- 24485300 TI - Annual ryegrass-associated bacteria with potential for plant growth promotion. AB - Annual ryegrass is a fast-growing cool-season grass broadly present in the Portuguese "montado", a typically Mediterranean agro-forestry-pastoral ecosystem. A culture-dependent approach was used to investigate natural associations of this crop with potentially beneficial bacteria, aiming to identify strains suitable for biofertilization purposes. Annual ryegrass seedlings were used to trap bacteria from three different soils in laboratory conditions. Using a nitrogen free microaerophilic medium, 147 isolates were recovered from the rhizosphere, rhizoplane, and surface-sterilized plant tissues, which were assigned to 12 genera in classes Alphaproteobacteria, Betaproteobacteria, Gammaproteobacteria, Bacilli and Actinobacteria. All isolates were able to grow in the absence of nitrogen and several of them were able to perform in vitro activities related to plant growth promotion. Isolates of the genera Sphingomonas and Achromobacter were found to be the most effective stimulators of annual ryegrass growth under nitrogen limitation (47-92% biomass increases). Major enhancements were obtained with isolates G3Dc4 (Achromobacter sp.) and G2Ac10 (Sphingomonas sp.). The latest isolate was also able to increment plant growth in nitrogen-supplemented medium, as well as the phosphate solubilizer and siderophore producer, G1Dc10 (Pseudomonas sp.), and the cellulose/pectin hydrolyser, G3Ac9 (Paenibacillus sp.). This study represents the first survey of annual ryegrass-associated bacteria in the "montado" ecosystem and unveiled a set of strains with potential for use as inoculants. PMID- 24485301 TI - Estimating age at death using the sternal end of the fourth ribs from Mexican males. AB - The indicators proposed by Iscan et al. (1984) are said to reflect age changes that occur in the sternal end of the fourth rib. These indicators have been used to estimate age-at-death in adult skeletal samples. However, Iscan et al. developed their methods using a forensic sample from Florida (U.S.A.). In order to test the reproducibility of those methods we evaluate its accuracy for the fourth ribs by applying it to a sample of known age and sex but of different biological affinity: modern males from Mexico City. We found that the method developed by Iscan et al. underestimates age-at-death in the Mexican sample. PMID- 24485302 TI - Phylogeny, regeneration, ageing and cancer: role of microenvironment and possibility of its therapeutic manipulation. AB - Data about the possible correlation between reduction of the regeneration capacity in the course of phylogeny and formation of malignant tumours have been summarized from invertebrates to mammals. The evolutionarily increasing complexity of body building plane and expectancy of longevity in the course of phylogeny seems to be grossly negatively correlated with diminished regeneration capacity, but positively with increased occurrence of malignant tumours. A certain evolution-based switch-off mechanism reducing the extent of regeneration in developmentally complicated and long-living animals such as mammals and birds can be hypothesized and benefits of loss of this ability are discussed. This high incidence of malignancies seems to be related, in addition to other factors, to prolonged and cumulative exposure to cancerogenic stimuli in the course of lifetime. Longevity, supported by the progress and availability of medical care to the population, has been unveiling this phenomenon during recent decades. From this point of view, ageing represents the main risk for cancer acquisition. The probable role of microenvironment in all the discussed phenomena such as healing/regeneration, inflammation, and cancer is discussed and targeting of microenvironment is consequently predicted as a possible therapeutic target where controlled manipulation may represent a new approach to the treatment of cancer patients. PMID- 24485303 TI - Correlated increase of omentin-1 and adiponectin by exenatide, avandamet and dietary change in diet-induced obese rats. AB - Adipokines omentin-1 and adiponectin have been reported to improve insulin resistance. It is known that insulin sensitizers exenatide, avandamet, or diet change from high-fat to normal chow ameliorate metabolic disorders. However, whether these treatments increase omentin-1 levels in high fat-diet animals and the relationship between omentin- 1 and adiponectin remain largely unknown. We investigated the effect of insulin sensitizers exenatide and avandamet, and of dietary change on these adipokine levels, body weight, and insulin sensitivity in diet-induced obese rats. Obesity was induced in rats by high-fat diet feeding for 8 weeks, and then the rats were given exenatide, avandamet and diet change to normal chow, respectively, for additional 8 weeks. Compared to the high-fat control group, exenatide and avandamet treatment significantly induced adipose gene expression and elevated the circulation levels of omentin-1 and adiponectin, whereas they decreased the leptin gene expression and circulation level, which is associated with improvement of systemic insulin sensitivity and the glucose and lipid profile. Notably, there was a significant positive correlation between omentin-1 and adiponectin in the above regimens, suggesting that omentin-1 and adiponectin may contribute to the insulin-sensitizing effect of exenatide and avandamet. PMID- 24485304 TI - Protective effect of the nitric oxide pathway in L-citrulline renal ischaemia reperfusion injury in rats. AB - To observe the protective effects of L-citrulline on the renal I/R injury and elucidate the mechanisms involved, 48 rats were randomized into eight groups: Group 1: sham operated; Group 2: I/R (45 min renal ischaemia and 24 h reperfusion); Group 3: I/R + L-citrulline (300 mg/kg, i.g.); Group 4: I/R + L citrulline (600 mg/kg, i.g.); Group 5: I/R + L-citrulline (900 mg/kg, i.g.); Group 6: I/R + normal saline (NS, i.g.); Group 7: I/R + N sup omega nitro-L arginine ester (L-NAME, 20 mg/kg, i.p.); Group 8: I/R + L-citrulline (900 mg/kg, i.g.) + L-NAME (20 mg/ kg, i.p.). At the end of the reperfusion period, serum was collected and the kidneys underwent histological and biochemical examinations. Our results showed that pre-treatment with L-citrulline (300, 600, and 900 mg/kg) significantly ameliorated the renal injury caused by I/R. Moreover, L-citrulline prevented induction of lipid peroxidation and increased the activity of superoxide dismutase and the levels of glutathione and nitric oxide. The I/R induced decreases in total nitric oxide synthase activity, inducible nitric oxide activity, constitutive nitric oxide activity and endothelial nitric oxide protein expression in the renal cortex were significantly prevented. However, the L citrulline-mediated protection was significantly antagonized by co-administration of L-NAME. These results suggested that L-citrulline administration exhibited significant protection against renal I/R injury. This protective effect, at least in part, via up-regulation of the endothelial nitric oxide protein expression and constitutive nitric oxide synthase activity, maintained production of nitric oxide at the basal level. PMID- 24485305 TI - Stress perception and (GT)n repeat polymorphism in haem oxygenase 1 promoter are both risk factors in development of eating disorders. AB - Haem oxygenase 1 (HO-1) plays a pivotal role in metabolic stress protecting cells in dependence on reactive oxygen species. This study investigated a potential gene environment interaction between the (GT)n repeat HO1 polymorphism and the stress perception in patients with eating disorder and in controls. Stress perception and (GT)n polymorphism were measured in 127 patients with eating disorders and in 78 healthy controls using Stress and Coping Inventory and genotyping. Based on the inventory, overall, specific and weighted stress scores were defined. Clinical stress score was generated according to the patient's history and interviews. According to our hypothesis, 1) all stress scores describing subjective stress perception were significantly higher in patients compared to controls (P <= 0.001; P <= 0.002; P <= 0.001), 2) the L/L genotype of GT promoter repeats (L < 25 GT repeats, S < 25 GT repeats) in the patients was associated with higher overall (P <= 0.001), specific (P <= 0.010) and weighted stress score (P <= 0.005) compared to the L/S variant, and 3) Pearson's correlation of clinical versus objective stress scores showed not very tight relationship (0.198; 0.287; 0.224, respectively). We assume potential risk of the L allele of HO1 promoter polymorphism for the stress response and contribution of the subjective stress perception together with the L/L genotype to the development of eating disorder. Decreased HO1 expression in the presence of L/L genotype plus more intensive stress perception in the patients can lead to secondary stress, with increasing severity of the symptoms and aggravation of the disease. PMID- 24485306 TI - Hypermethylation of RAD51L3 and XRCC2 genes to predict late toxicity in chemoradiotherapy-treated cervical cancer patients. AB - Cervical cancer affects women worldwide, especially in developing countries. Approximately 500,000 cases of this disease are diagnosed per year. The method of choice in the treatment of advanced cervical cancers (in accordance with the International Federation of Gynecology and Obstetrics staging system (FIGO) starting from stage IIB) is combined radiotherapy with concomitant chemotherapy. This treatment provides good tumour control, but it carries a risk of late complications in the irradiated area in 10-15 % of cases. Methylation is one of the methods of epigenetic control, which has an important role in gene expression. Aberrant methylation of normal CpG islands in promoters of tumour suppressor genes such as RB, p53 or DNA reparation genes ATM, BRCA1,2, and RAD51 gene family causes silencing of their function and cell cycle deregulation, which is one of the efficient ways of neoplastic transformation. The significantly decreased expression of molecules involved in DNA response may cause facilitated radiosensitivity in predisposed individuals. We looked for the relationship between hypermethylation of 18 DNA reparation genes and late toxicity occurrence in cervical cancer patients treated by chemoradiotherapy using methylation specific multiplex ligation-dependent probe amplification (MS-MLPA). The cut-off value for the hypermethylation was set at 10 %. We confirmed significant association between promoter hypermethylation in the XRCC2 gene and occurrence of late grade III-IV toxicity in cervical cancer patients (P = 0.0357). This finding could be useful in the late toxicity prediction in radiotherapy-treated patients. PMID- 24485307 TI - Association of Gln223Arg polymorphism of the leptin receptor with hypertensive left ventricular hypertrophy. AB - This study was aimed to determine whether the leptin receptor Gln223Arg polymorphism has an effect on plasma leptin levels and left ventricular hypertrophy in hypertension. The genotypes and allelic frequencies of the leptin receptor Gln223Arg were examined using the polymerase chain reaction and restriction fragment length polymorphism in 190 hypertensive patients and 88 healthy controls. Logarithmic (log) transformation of the plasma leptin level was carried out before performing comparison and regression analysis. The values of log(plasma leptin levels) in the hypertensive patients were higher than those of controls and they were higher in hypertensive patients with left ventricular hypertrophy than those without it (P < 0.05). The genotype (AA, AG, and GG) distribution of Gln223Arg polymorphism was 6.8, 33.8, and 59.4% in hypertensive patients with left ventricular hypertrophy, 4.3, 27.6, and 68.1% in patients without left ventricular hypertrophy, and 2.3, 26.1, and 71.6% in the controls, respectively. A significant difference was found among these three groups (P < 0.05). The frequency of allele A was higher in patients with left ventricular hypertrophy than in patients without it (23.6 vs. 18.1%; P < 0.05). Log(plasma leptin levels) and left ventricular mass index were higher in patients with the AA genotype than those with the AG or GG genotype in hypertensive patients (P < 0.05). In multivariate regression analysis, the AA genotype as an independent predictor had statistically significant effects on the left ventricular mass index. Our results suggest that the Gln223Arg polymorphism of the leptin receptor is significantly associated with plasma leptin levels and left ventricular hypertrophy in hypertension. PMID- 24485308 TI - Target-site resistance to pyrethroid insecticides in German populations of the cabbage stem flea beetle, Psylliodes chrysocephala L. (Coleoptera: Chrysomelidae). AB - Cabbage stem flea beetle, Psylliodes chrysocephala L. (Coleoptera: Chrysomelidae) is a major pest of winter oilseed rape in several European countries particularly attacking young emerging plants in autumn. Over the last several decades, pyrethroid insecticides have been foliarly applied to control flea beetle outbreaks. Recent control failures in northern Germany suggested pyrethroid resistance development in cabbage stem flea beetles, which were confirmed by resistance monitoring bioassays using lambda-cyhalothrin in an adult vial test. The purpose of this study was to investigate the presence of polymorphisms in the para-type voltage-gated sodium channel gene of P. chrysocephala known to be involved in knock-down resistance (kdr). By using a degenerate primer approach we PCR amplified part of the para-type sodium channel gene and identified in resistant flea beetles a single nucleotide polymorphism resulting in an L1014F (kdr) mutation within domain IIS6 of the channel protein, known as one of the chief pyrethroid target-site resistance mechanisms in several other pest insects. Twenty populations including four archived museum samples collected between 1945 and 1958 were analyzed using a newly developed pyrosequencing diagnostic assay. The assay revealed a kdr allele frequency of 90-100% in those flea beetle populations expressing high-level cross-resistance in discriminating dose bioassays against different pyrethroids such as lambda-cyhalothrin, tau fluvalinate, etofenprox and bifenthrin. The presence of target-site resistance to pyrethroids in cabbage stem flea beetle is extremely worrying considering the lack of effective alternative modes of action to control this pest in Germany and other European countries, and is likely to result in major control problems once it expands to other geographies. The striking fact that cabbage stem flea beetle is next to pollen beetle, Meligethes aeneus the second coleopteran pest in European winter oilseed rape resisting pyrethroid treatments by expressing a target-site mutation, underpins the importance of diversity in available chemistry for resistance management tactics based on mode of action rotation in order to guarantee sustainable winter oilseed rape cultivation in Europe. PMID- 24485309 TI - Antioxidant, phase II and III responses induced by lipoic acid in the fish Jenynsia multidentata (Anablapidae) and its influence on endolsulfan accumulation and toxicity. AB - Antioxidants like lipoic acid (LA) are known to trigger augmented antioxidant and phase II and III responses. This study aimed to evaluate the effect of LA in P glycoprotein (Pgp) expression, glutathione-S-transferase (GST) activity, total antioxidant competence, levels of lipid peroxides (TBARS) and accumulation of the organochlorine insecticide endosulfan (Endo: alpha-, beta-isomers and sulfate metabolite) in different organs of the fish Jenynsia multidentata. One hundred and twenty females (1.55+/-0.07 g) were fed during 8 days with (n=60) or without (n=60) a LA enriched ration (6000 mg/kg). Four experimental groups were defined: LA/-Endo; +LA/-Endo; -LA/+Endo; and +LA/+Endo. Endo groups were exposed during 24 h to 1.4 MUg of insecticide/L. Results showed that only LA induced a significant increment in liver Pgp expression. GST activity was augmented in liver after exposure to LA or Endo. TBARS levels were lowered in liver and gills after LA pre treatment. Total antioxidant capacity was lowered in liver of Endo exposed fish, a result that was reversed by LA pre-treatment. It is concluded that LA induced the expected effects in terms of Pgp expression, GST activity and reduced TBARS levels although favored alpha-Endo accumulation in brain. However, the Endo metabolism to the more persistent endosulfan sulfate was not facilitated by LA pre-treatment. PMID- 24485310 TI - Resistance to ACCase-inhibiting herbicides in an Asia minor bluegrass (Polypogon fugax) population in China. AB - Asia minor bluegrass (Polypogon fugax) is a common annual grass weed of winter crops distributed across China. We conducted a study on the resistance level and the mechanism of resistance to ACCase-inhibiting herbicides in a P. fugax population from China. Whole-plant dose-response experiments in greenhouse showed that the resistant P. fugax population was 1991, 364, 269, 157, and 8-fold resistant to clodinafop-propargyl, fluazifop-p-butyl, haloxyfop-R-methyl, quizalofop-p-ethyl and fenoxaprop-p-ethyl relative to the reference susceptible population, which was susceptible to all the five AOPP herbicides. Much lower R/S values of 3.5, 2.4 and 3.5, respectively, were detected for clethodim, sethoxydim and pinoxaden. Molecular analysis of resistance confirmed that the Ile2041 to Asn mutation in the resistant population conferred resistance to AOPP herbicides, but not to CHD and DEN herbicides. This is the first report of a target site mutation that corresponded to resistance to AOPP herbicides in P. fugax. Proper resistance management practices are necessary to prevent ACCase-inhibiting herbicides from becoming ineffective over wide areas. PMID- 24485311 TI - Inhibition of Fusarium graminearum growth and mycotoxin production by phenolic extract from Spirulina sp. AB - Fusarium graminearum is a fungal species complex pathogenic occurring worldwide, mainly associated with cereal crops. The most important Fusarium mycotoxins are fumonisins, zearalenone and trichothecenes. The availability of efficient control measures that are less harmful to both the environment and the consumers is urgent. For such, phenolic acids (PAs) from natural sources are known to reduce fungal contaminations. This work aimed to identify the PAs present in a culture extract of Spirulina algae (strain LEB-18) and evaluate its effect on mycelial growth rate, glucosamine level, amylase activity and mycotoxin production by four strains of two lineages of F. graminearum. Results showed that amendment of potato dextrose media with LEB-18 extract (3% w/v), which was mainly composed by gallic acid, greatly reduced radial growth of fungal colonies compared to media containing a single PA and the control. Also, average reductions of 40% and 62% in the glucosamine levels and the amylase activity were observed. In general, the LEB-18 extract and the PAs reduced mycotoxin concentration, with an average reduction of 68% for the trichothecene mycotoxins deoxynivalenol and nivalenol. PMID- 24485312 TI - CPPU elevates photosynthetic abilities, growth performances and yield traits in salt stressed rice (Oryza sativa L. spp. indica) via free proline and sugar accumulation. AB - Application of N-2-(chloro-4-pyridyl)-N-phenyl urea (CPPU) to salt susceptible cultivar of indica rice (cv. PTT1) effected on free proline and soluble sugar accumulation and regulated the physio-morphological responses when subjected to salt stress condition was firstly demonstrated in this study. Soluble sugars, including sucrose, glucose and fructose, in leaf blade and leaf sheath were enriched in 0.1 mM CPPU pretreated plants subsequently exposed to 16.6 dS m(-1) NaCl for 10 days. In the long period (15 days) salt stress, free proline content in the leaf blade and leaf sheath were evidently peaked to act as osmotic adjustment in the salt-stressed plants. In addition, the photosynthetic pigments, including chlorophyll a, chlorophyll b, total chlorophyll and total carotenoids, were maintained by the functional regulation of soluble sugar and free proline in the cellular levels, thereby leading to higher net photosynthetic rate. Further, the stomatal closure and transpiration rate in CPPU pretreated plants were retained under salt stress, thereby resulting in alleviation of growth performance and yield traits. This study suggested that exogenous application of CPPU may alternatively play effective role to improve the salt tolerant abilities of salt susceptible rice crop. PMID- 24485313 TI - Stereoselective degradation and toxic effects of benalaxyl on blood and liver of the Chinese lizard Eremias argus. AB - Benalaxyl as a xylem-systemic fungicide is usually direct sprayed on the soil surface, which is potential harm to the animals lived in the soil. However, the stereoselectivity of benalaxyl in reptiles have rarely been studied. In this study, Chinese lizards (Eremias argus) were firstly used to evaluate the stereoselectivity in biodegradation and toxicity of racemate and individual enantiomers of benalaxyl. A method for determining residues of the two enantiomers of benalaxyl in lizard blood and liver by high-performance liquid chromatography coupled with triple quadrupole mass spectrometry (HPLC-MS/MS) was developed. The degradation followed pseudo first-order kinetics and the degradation of the (S)-(+)-benalaxyl was faster than its antipode in blood and liver (Half-time t1/2 of (R)-(-)-benalaxyl and (S)-(+)-benalaxyl were 5.08 h and 3.75 h in blood, 6.21 h and 4.45 h in liver, separately). Moreover, antioxidant defenses consisting of activities of superoxide dismutase (SOD), catalase (CAT), glutathione S-transferase (GST) and lipid peroxide malondialdehyde (MDA) were determined in 24h acute exposure. Enantioselectivity of acute toxicity depended on the concentration and form of benalaxyl. In addition, cellular degeneration, decrease of cell number, clustering phenomena of cell nuclei and preliminary liver fibrosis were observed in pathological detection at the termination of 21-d subchronic exposure (20 mg/kg(-bw) of racemate and individual enantiomers of benalaxyl). The enantiomer fractions (EFs) in racemate and individual enantiomer groups were approached both in blood and liver caused by the chiral conversion. The chiral conversion from (R)-(-)-benalaxyl to (S)-(+)-benalaxyl and (S)-(+) benalaxyl to (R)-(-)-benalaxyl were the primary cause for no remarkable differences in toxicity between the enantiomers of benalaxyl. PMID- 24485314 TI - Combined effects of temperature and avermectins on life history and stress response of the western flower thrips, Frankliniella occidentalis. AB - Temperature and pesticide are two important factors that affect survival, reproduction and other physiological processes of insects. To determine interactions of elevated temperature and avermectins treatment on the western flower thrips, Frankliniella occidentalis, newly emerged adults were exposed to combinations of three temperatures (21, 26 and 33 degrees C) and two avermectins concentrations (0, 45 ppm), and survival rate, reproduction, longevity, antioxidant enzymes activities and heat shock proteins (hsps) induction were analyzed. The results showed that the survival, longevity and reproduction of F. occidentalis decreased with increased temperature and avermectins treatment. While elevated temperature and avermectins treatment significantly decreased activity of SOD, activities of POD and GST significantly increased after exposure to elevated temperature, avermectins or their combination. Elevated temperature had no effect on activity of CAT, but it was obviously improved by the combination of temperature and avermectins treatment. Expression analysis of hsps showed that four heat shock proteins (hsp90, hsc702, hsp60 and hop) were up regulated by the induction of elevated temperature with small fold changes. After treatment with avermectins, expression levels of hsp90, hsc701, hsc702 and hop were significantly up-regulated with increased temperature and higher than those of their respective control at higher temperature. Surprisingly, expression level of hps60 was down-regulated with increased temperature, but the expression level at 21 or 26 degrees C remained higher than that of control. Overall, our studies suggest that elevated temperature enhance toxicity of avermectins and their combination induced acute oxidative damage to F. occidentalis. Therefore, consideration of temperature in evaluating avermectins toxicity is necessary to make accurate prediction of its effect on F. occidentalis and other insects. PMID- 24485315 TI - Molecular mechanisms of herbicide-inducible gene expression of tobacco CYP71AH11 metabolizing the herbicide chlorotoluron. AB - Tobacco cytochrome P450 (CYP) 71AH11 metabolized the herbicide chlorotoluron, and its mRNA level was increased in tobacco culture cells by the treatment of 2,4-D. In order to clarify molecular mechanisms of induced gene expression of CYP71AH11 by herbicide treatment, a 1574-bp 5'-flanking region of CYP71AH11 was cloned, ligated to the reporter beta-glucuronidase (GUS) gene, and then transformed into tobacco plants. The GUS activity in the transgenic tobacco plants was highly induced by bromoxynil treatment, followed by 2,4-D. Chlorotoluron was slightly increased the GUS activity. The bromoxynil-increased GUS activity was partially repressed by the antioxidants, suggesting that reactive oxygen species may be involved in activation of the 5'-flanking region of CYP71AH11 by bromoxynil treatment. Deletion and mutation assays showed that the region CD (-1281 to 770bp from the start codon of CYP71AH11) was important, but not sufficient, for response to bromoxynil. Electrophoretic mobility shift assays and southwestern blotting revealed that the sequences AAAAAG, and GAACAAAC and GAAAATTC in the CD region were important for interaction to the nuclear proteins of <30 and ~75 kDa, respectively. Particularly, interaction between AAAAAG and <30 kDa proteins was increased by bromoxynil treatment. These results gave a cue for understanding the bromoxynil-induced gene expression of CYP71AH11, which may contribute to herbicide tolerance and selectivity in crop plants. PMID- 24485316 TI - RNAi mediated knockdown of the ryanodine receptor gene decreases chlorantraniliprole susceptibility in Sogatella furcifera. AB - The diamide insecticides activate ryanodine receptors (RyRs) to release and deplete intracellular calcium stores from the sarcoplasmic reticulum of muscles and the endoplasmic reticulum of many types of cells. They rapidly interrupt feeding of the target pest and eventually kill the pest due to starvation. However, information about the structure and function of insect RyRs is still limited. In this study, we isolated a 15,985bp full-length cDNA (named SfRyR) from Sogatella furcifera, a serious rice planthopper pest throughout Asia. SfRyR encodes a 5140-amino acid protein, which shares 78-97% sequence identities with other insect homologues, and less than 50% identities with Homo sapiens RyR1-3. All hallmarks of the RyR proteins are conserved in SfRyR. In the N-terminus, SfRyR has a MIR domain, two RIH domains, three SPRY domains, four copies of RyR repeated domain and a RIH-associated domain. In the C-terminus, SfRyR possesses two consensus calcium ion-binding EF-hand motifs, and six transmembrane helices. Temporal and spatial expression analysis showed that SfRyR was widely found in all development stages including egg, first through fifth instar nymphs, macropterous adult females and males. On day 2 fifth-instar nymphs, SfRyR was ubiquitously expressed in the head, thorax and abdomen. Dietary ingestion of dsSfRyR1 and dsSfRyR2 significantly reduced the mRNA level of SfRyR in the treated nymphs by 77.9% and 81.8% respectively, and greatly decreased chlorantraniliprole-induced mortality. Thus, our results suggested that SfRyR gene encoded a functional RyR that mediates chlorantraniliprole toxicity to S. furcifera. PMID- 24485317 TI - Interaction of prometryn to human serum albumin: insights from spectroscopic and molecular docking studies. AB - Prometryn possesses much potential hazard to environment because of its chemical stability and biological toxicity. Here, the binding properties of prometryn with human serum albumin (HSA) and the protein structural changes were determined under simulative physiological conditions (pH 7.4) by multispectroscopic methods including fluorescence, UV-vis absorption, Fourier transform infrared (FT-IR) and circular dichroism (CD) spectroscopy, coupled with molecular modeling technique. The result of fluorescence titration suggested that the fluorescence quenching of HSA by prometryn was considered as a static quenching procedure. The negative enthalpy change (DeltaH(?)) and positive entropy change (DeltaS(?)) values indicated that the binding process was governed mainly by hydrophobic interactions and hydrogen bonds. The site marker displacement experiments suggested the location of prometryn binding to HSA was Sudlow's site I in subdomain IIA. Furthermore, molecular docking studies revealed prometryn can bind in the large hydrophobic activity of subdomain IIA. Analysis of UV-vis absorption, synchronous fluorescence, CD and FT-IR spectra demonstrated that the addition of prometryn resulted in rearrangement and conformational alteration of HSA with reduction in alpha-helix and increases in beta-sheet, beta-turn and random coil structures. This work provided reasonable model helping us further understand the transportation, distribution and toxicity effect of prometryn when it spreads into human blood serum. PMID- 24485318 TI - The trypsin inhibitor from Entada acaciifolia seeds affects negatively the development of Mediterranean flour moth, Anagasta kuehniella. AB - The Mediterranean flour moth (Anagasta kuehniella) is a pest insect that attacks stored foods. The difficulty in controlling this kind of pest promotes the development of alternatives for pest control, among them the use of proteins with insecticide effect. In this work, we evaluated the role of a trypsin inhibitor purified from Entada acaciifolia seeds (EATI) on the A. kuehniella development. Different concentrations of inhibitor were added to a diet to determine its effects on insect performance. At 0.4%, the EATI decreases the larval weight and survival rates by 54.6% and 15%, respectively; in addition to the extension of the life cycle of insect. The biochemical analysis showed that the inhibitor is refractory to the digestion by midgut proteases, and led to a reduction of 32% in general proteolytic activity. A detailed analysis of the enzymatic activity revealed a decrease of 50% in trypsin activity as the chymotrypsin activity increased by 12%; possibly to compensate the commitment of the digestive process. The trypsins from the EATI-fed group stayed sensitive to the inhibition by EATI, and based on kinetic assays no new trypsin enzymes were produced as adaptation attempt. The insecticides effects observed for the EATI against this pest encourage a more in depth study of its possible long-term use as a biotechnological tool. PMID- 24485319 TI - Genomic analyses of sodium channel alpha-subunit genes from strains of melon thrips, Thrips palmi, with different sensitivities to cypermethrin. AB - We examined the genomic organization of the sodium channel alpha-subunit gene in two strains of melon thrips, Thrips palmi, having differing sensitivity to cypermethrin. The nucleotide sequences of the strains included 18 or 16 putative exons which covered the entire coding region of the gene producing 2039 amino acid residues. Deduced amino acid sequences of both strains showed 80% homology with those of Periplaneta americana and Cimex lectularius. Comparison of deduced amino acid sequences of both strains showed no consistent amino acid difference. In addition to the previously reported resistant amino acid (Ile) at the T929I site, both strains encoded another resistant amino acids at two positions which are involved in pyrethroid resistance in other arthropods. These amino acids might also involve in the basal levels of resistance to pyrethroids of both strains. PMID- 24485320 TI - Effects of a protease inhibitor protein from Xenorhabdus bovienii on physiology of pea aphid (Acyrthosiphon pisum). AB - The effects of a protease inhibitor protein from Xenorhabdus bovienii strain xbi1 (Xbpi-1) on biochemistry and physiology of pea aphid (Acyrthosiphon pisum) were studied, and the effects of Xbpi-1 on the activities of aphid aminopeptidase and the concentrations of carbohydrates, free amino acids and lipids in A. pisum were determined. The results showed that the activity of aminopeptidase was reduced 18.30% by Xbpi-1 in vitro assays. In addition, the total sugar, glycogen, and lipid concentrations per aphid fed on an artificial diet with Xbpi-1 were reduced by 39.41%, 24.61% and 26.25%, respectively, compared to the controls. The total free amino acids in the aphids on the diet with Xbpi-1 was significantly decreased by 20.78% compared to the control. The mortalities of A. pisum were significantly higher when the concentrations of Xbpi-1 were 400 and 800 MUg/ml in the artificial diet. The results from this study indicated that Xbpi-1 had adverse effects on the physiology and biochemistry of A. pisum. PMID- 24485321 TI - Evidence for photochemical and microbial debromination of polybrominated diphenyl ether flame retardants in San Francisco Bay sediment. AB - Brominated diphenyl ethers (BDEs) are flame retardant compounds that have been classified as persistent organic pollutants under the Stockholm Convention and targeted for phase-out. Despite their classification as persistent, PBDEs undergo debromination in the environment, via both microbial and photochemical pathways. We examined concentrations of 24 PBDE congeners in 233 sediment samples from San Francisco Bay using Positive Matrix Factorization (PMF). PMF analysis revealed five factors, two of which contained high proportions of congeners with two or three bromines, indicating that they are related to debromination processes. One of the factors included PBDE 15 (4,4'-dibromo diphenyl ether, comprising 20% of the factor); the other included PBDE 7 (2,4-dibromo diphenyl ether; 12%) and PBDE 17 (2,2',4-tribromo diphenyl ether; 16%). The debromination processes that produce these congeners are probably photochemical debromination and anaerobic microbial debromination, although other processes could also be responsible. Together, these two debromination factors represent about 8% of the mass and 13% of the moles of PBDEs in the data matrix, suggesting that PBDEs undergo measurable degradation in the environment. PMID- 24485323 TI - Utilizing an observational learning paradigm to examine associative changes in pain-related fear. PMID- 24485322 TI - Greater impact of dietary fat manipulation than apolipoprotein E genotype on ex vivo cytokine production - insights from the SATgenepsilon study. AB - Apolipoprotein E (APOE) genotype is believed to play an important role in cardiovascular risk. APOE4 carriers have been associated with higher blood lipid levels and a more pro-inflammatory state compared with APOE3/E3 individuals. Although dietary fat composition has been considered to modulate the inflammatory state in humans, very little is known about how APOE genotype can impact on this response. In a follow-up to the main SATgenepsilon study, we aimed to explore the effects of APOE genotype, as well as, dietary fat manipulation on ex vivo cytokine production. Blood samples were collected from a subset of SATgenepsilon participants (n=52/88), prospectively recruited according to APOE genotype (n=26 E3/E3 and n=26 E3/E4) after low-fat (LF), high saturated fat (HSF) and HSF with 3.45g docosahexaenoic acid (DHA) dietary periods (each diet eight weeks in duration assigned in the same order) for the measurement of ex vivo cytokine production using whole blood culture (WBC). Concentrations of IL-1beta, IL-6, IL 8, IL-10 and TNF-alpha were measured in WBC supernatant samples after stimulation for 24h with either 0.05 or 1MUg/ml of bacterial lipopolysaccharide (LPS). Cytokine levels were not influenced by genotype, whereas, dietary fat manipulation had a significant impact on TNF-alpha and IL-10 production; TNF alpha concentration was higher after consumption of the HSF diet compared with baseline and the LF diet (P<0.05), whereas, IL-10 concentration was higher after the LF diet compared with baseline (P<0.05). In conclusion, our study has revealed the amount and type of dietary fat can significantly modulate the production of TNF-alpha and IL-10 by ex vivo LPS-stimulated WBC samples obtained from normolipidaemic subjects. PMID- 24485324 TI - Clinical characteristics of acute kidney injury in patients with scrub typhus- RIFLE criteria validation. AB - There are limited data available on the validity of the RIFLE classification for AKI in patients with scrub typhus. We investigated the incidence and clinical characteristics of scrub typhus associated AKI using the RIFLE criteria. From 2010 to 2012, 238 patients were diagnosed with scrub typhus. Of these, we included 223 patients who were followed up until renal recovery or for at least three months. We evaluated the incidence, clinical characteristics, and severity of AKI based on the RIFLE classification. Of the 223 patients, 47 (21%) had scrub typhus-associated AKI. The incidence of AKI was 21.1%; of which, 10.7%, 9.4% and 1% were classified as Risk, Injury and Failure, respectively. In comparison with patients in the non-AKI group, the patients in the AKI group were older (70 +/- 9 vs 61 +/- 14 year, P = 0.01) and had one or more comorbidities such as hypertension, diabetes, and chronic kidney disease (77% vs 22%, p = 0.01). In the AKI group, forty-four patients had AKI prior to admission, and three patients experienced AKI during their hospitalization. By multivariate logistic regression analysis, age and comorbidity were significant predictors of AKI. All patients recovered baseline renal function without renal replacement therapy following antibiotics therapy and supportive care. The incidence of AKI in patient with scrub typhus is 21%. Age and co-morbidity are significant predictors of AKI in scrub typhus. In cases of scrub typhus-associated AKI, anti-rickettsia agent and supportive care are very important. PMID- 24485325 TI - Direct hemoperfusion using polymyxin-B immobilized fiber for severe septic patients with hematological disorders: a single-center analysis. AB - The benefit of endotoxin absorption therapy (direct hemoperfusion with polymyxin B-immobilized fiber: PMX-DHP) for severe septic patients is still controversial. There are limited data on the clinical experience and efficacy of PMX-DHP for septic patients with hematological disorders. At our institution, 16 patients with hematological diseases underwent PMX-DHP therapy for gram-negative septic shock from February 2006 to March 2012. Most of the patients had severe neutropenia (median neutrophil counts: 7/MUL) due to intensive chemotherapy for their hematological diseases. After the PMX-DHP therapy, six patients recovered from the shock status (favorable group) and ten died of the sepsis (unfavorable group). We analyzed the differences between the two groups based on clinical characteristics just before PMX-DHP therapy. Regarding sequential organ failure assessment (SOFA) score, which is a scoring system to determine the degree of organ dysfunction, all patients in the favorable group scored less than 11. The sensitivity and specificity of SOFA score less than 11 for the therapeutic efficacy were 100% and 80%, respectively. Our results suggest that septic patients with hematological diseases may not be a candidate for PMX-DHP therapy when they have already developed serious organ dysfunction. PMID- 24485326 TI - Immunogenicity of single-dose Vero cell-derived Japanese encephalitis vaccine in Japanese adults. AB - In Japan, intensive immunization against Japanese encephalitis (JE) was performed from 1967 to 1976, and regular JE immunization was performed thereafter. However, for Japanese adults facing JE risk, dates of vaccination with new inactivated Vero cell-derived JE vaccine are unavailable. This study investigated how a single dose of Vero cell-derived JE vaccine affects Japanese adults. Neutralizing antibodies were measured pre- and post-JE vaccination in 79 participants (age 40.7 +/- 9.4 years), enrolled between October 2009 and March 2011, whose JE vaccination data were gathered from vaccination records and history taking. Before vaccination, the participants' seroprotection rate (SPR) was 51.9%, whereas SPR after vaccination was 93.7%. The seroconversion rate (SCR), which measures seronegative cases that turn seropositive after vaccination, was 86.8%. The geometric mean titer (GMT) was 14.7 before vaccination and 70.1 after vaccination. Age was a significant difference between seroprotected (42.8 years) and non-seroprotected (38.7 years) groups before vaccination. Then the difference of age, SCR, pre-vaccination GMT, post-vaccination GMT and sex ratio were also significant in participants aged 25-39 years and >=40 years, who represent generations born when Japan's JE-vaccination policy changed. SCR was 100% in participants aged 25-39 years with a vaccination recorded 55.6% in participants aged 25-39 without a vaccination record, and 96.0% in participants aged >=40 years. Thus, more participants aged 25-39 years were seroprotected before vaccination, but SCR was higher in those aged >=40 years. Most Japanese adults can be protected after one-dose vaccination, but this may be insufficient for people aged 25-39 years without recorded JE vaccination. PMID- 24485327 TI - A smartphone intervention for adolescent obesity: study protocol for a randomised controlled non-inferiority trial. AB - BACKGROUND: There are few evidence-based mobile health solutions for treating adolescent obesity. The primary aim of this parallel non-inferiority trial is to assess the effectiveness of an experimental smartphone application in reducing obesity at 12 months, compared to the Temple Street W82GO Healthy Lifestyles intervention. METHODS/DESIGN: The primary outcome measure is change in body mass index standardised deviation score at 12 months. The secondary aim is to compare the effect of treatment on secondary outcomes, including waist circumference, insulin sensitivity, quality of life, physical activity and psychosocial health. Adolescents with a body mass index at or above the 98th percentile (12 to 17 years) will be recruited from the Obesity clinic at Temple Street Children's University Hospital in Dublin, Ireland. W82GO is a family-based lifestyle change intervention delivered in two phases over 12 months. In the current study, participants will be randomised for phase two of treatment to either usual care or care delivered via smartphone application. One hundred and thirty-four participants will be randomised between the two study arms. An intention-to-treat analysis will be used to compare treatment differences between the groups at 12 months. DISCUSSION: The results of this study will be disseminated via open access publication and will provide important information for clinicians, patients and policy makers regarding the use of mobile health interventions in the management of adolescent obesity. TRIAL REGISTRATION: Clinicaltrials.gov NCT01804855. PMID- 24485328 TI - [Can one harvest a long bone stick in the radial forearm flap? Original radioanatomical and NanoSPECT-CT Bioscan microvascular study]. AB - OBJECTIVES: The composite radial forearm flap is a surgical option in the reconstruction of large traumatic or oncologic orofacial defects. Nevertheless, it has been criticized for its poor bone transport faculties that would make this flap insufficient in large osseous mandibular reconstructions, or for oral prosthetic rehabilitation with dental implants. What is more, the morbidity of the donor site has often been pointed. The aim of this radioanatomic study was to revisit the vascularization of the composite radial forearm flap, focusing on the bone stick. METHODS: A radioanatomic study was performed on seven upper limbs taken from fresh cadavers. First, the vessels were washed with a 40 degrees C solution of potassium acetate. Then an intra-arterial injection of a mixture of lead oxide and agar-agar was performed. 3D-CT-scan examinations of the anatomical pieces were performed. In a second step, the flaps were harvested and analyzed with a Microscan examination (NanoSPECT-CT Bioscan((r)), voxel 220 microns). Collateral branches of the radial artery to the bone and the skin were counted and classified. RESULTS: One radial diaphyseal artery was present in all the cases. The nutrient foramen took place at the anteromedial aspect of the diaphysis, between 45 and 65 % of the length of the bone. A dense anastomotic periosteal network was highlightened, supplied by one to four musculoperiosteal branches, and one to six fascio-periosteal arteries arising from the radial artery. A total of mean five osseous branches, and 12 cutaneous branches have been observed. CONCLUSIONS: The results of the present preclinical study suggested that a 16-cm bone stick could be harvested with an optimal vascular safety, without consideration for the morbidity at the donor site. The original approach in this study, relating anatomy to the preclinical imaging, allowed a precise visualization of the microvascularization of the soft and hard tissues. It opened a field of innovative research in plastic and reconstructive surgery. PMID- 24485329 TI - From fingerprinting to kinetics in evaluating food quality changes. AB - Historically, the study of food quality changes during processing, preservation, and storage has evolved from targeted, single-response studies towards studies relying on both targeted and untargeted approaches analyzing multiple responses. In our opinion, future studies should be based on a zoom-in approach in which fingerprinting is used as a multivariate, hypothesis-free starting point to screen for key quality differences in food extracts of differently processed, preserved, and stored foods. By interpreting the identity of selected fingerprint markers in terms of their relevance and consequences for application or connecting the markers to particular food reactions, in a subsequent kinetic study mechanistic as well as quantitative insight into the effect of extrinsic processing variables on quality changes can be obtained. PMID- 24485331 TI - Time to act: the challenges of working during and after cancer, initiatives in research and practice. PMID- 24485330 TI - Impact of a fixed price system on the supply of institutional long-term care: a comparative study of Japanese and German metropolitan areas. AB - BACKGROUND: The need for institutional long-term care is increasing as the population ages and the pool of informal care givers declines. Care services are often limited when funding is controlled publicly. Fees for Japanese institutional care are publicly fixed and supply is short, particularly in expensive metropolitan areas. Those insured by universal long-term care insurance (LTCI) are faced with geographically inequitable access. The aim of this study was to examine the impact of a fixed price system on the supply of institutional care in terms of equity. METHODS: The data were derived from official statistics sources in both Japan and Germany, and a self-administered questionnaire was used in Japan in 2011. Cross-sectional multiple regression analyses were used to examine factors affecting bed supply of institutional/residential care in fixed price and free prices systems in Tokyo (Japan), and an individually-bargained price system in North Rhine-Westphalia (Germany). Variables relating to costs and needs were used to test hypotheses of cost-dependency and need-orientation of bed supply in each price system. Analyses were conducted using data both before and after the introduction of LTCI, and the results of each system were qualitatively compared. RESULTS: Total supply of institutional care in Tokyo under fixed pricing was found to be cost-dependent regarding capital costs and scale economies, and negatively related to need. These relationships have however weakened in recent years, possibly caused by political interventions under LTCI. Supply of residential care in Tokyo under free pricing was need-oriented and cost dependent only regarding scale economies. Supply in North Rhine-Westphalia under individually bargained pricing was cost-independent and not negatively related to need. CONCLUSIONS: Findings suggest that publicly funded fixed prices have a negative impact on geographically equitable supply of institutional care. The contrasting results of the non-fixed-price systems for Japanese residential care and German institutional care provide further theoretical supports for this and indicate possible solutions against inequitable supply. PMID- 24485332 TI - Matrix metalloproteinases and E-cadherin immunoreactivity in different basal cell carcinoma histological types. AB - The immunohistochemical staining of matrix metalloproteinases (MMPs) and E cadherin in tumor epithelial and stromal cells was analyzed in a group of solid, superficial spreading and cystic tumors and in a group of morpheaform and recurrent basal cell carcinomas (BCC) in order to determine whether any of these factors possibly contribute to tumor therapy resistance. Tumor tissues of 64 patients were obtained by complete excisional or curettage biopsy of BCC and these were immunohistochemically stained for MMP-1, MMP-2, MMP-9, MMP-13 and E cadherin. In the morpheaform and recurrent BCC, MMP-9 expression significantly increased in the stroma, while E-cadherin expression was negative in epithelial cells. Odds ratio for development of morpheaform and recurrent BCC was 6.2 for positive MMP-1 immunostaining in epithelial tumor cells, 5.8 for positive MMP-9 immunostaining in tumor stroma, 3.2 for positive MMP-13 immunostaining in tumor stroma, and 4.5 for negative E-cadherin in epithelial tumor cells. Our results suggest that MMP-1 immunostaining in tumor cells, MMP-9 expression in stromal cells, and absence of E-cadherin expression are associated with morpheaform and recurrent BCC. PMID- 24485333 TI - Soy extract-dependent changes in morphofunctional parameters of the pituitary corticotropes in adult rats. AB - Numerous studies have established a link between estrogen levels and activity of the hypothalamic pituitary adrenal (HPA) system. Considering the "weak estrogenic" effect of soy isoflavones, this study was designed to evaluate the influence of soy extract treatment on some morphofunctional parameters of rat pituitary corticotropes in vivo. Adult male orchidectomized Wistar rats received estradiol-dipropionate or soy extract in oil/ethanol solvent subcutaneously for 3 weeks. Both controls, sham-operated (So) and orchidectomized (Orx) rats, were injected with solvent, in the same regime. Changes in pituitary volume, total volume, total number and volume of individual corticotropes were evaluated stereologically, while ACTH levels were determined biochemically. In comparison with So rats, estradiol treatment provoked increases (p<0.05) of: ACTH level (166%), pituitary weight (167%) and volume (102%), total volume (20%) and total number of corticotropes (18%). In comparison to Orx, following estradiol treatment elevation (p<0.05) of: ACTH level (69%), pituitary weight (131%) and volume (82%), total (30%) and individual volume (29%) of corticotropes was observed. Soy extract treatment led to enhancement (p<0.05) of: ACTH level (28%), total (25%) and individual volume (20%) of corticotropes. It can be concluded that soy extract acts in a similar way to estradiol, but the increased activity of corticotropes was weaker. PMID- 24485334 TI - The use of biochip immunofluorescence microscopy for the diagnosis of Pemphigus vulgaris. AB - Pemphigus vulgaris is an autoimmune intraepithelial blistering skin disease characterized by the presence of circulating autoantibodies directed against surfaces of keratinocytes. Diagnosis is generally based on clinical features, histology, direct and indirect immunofluorescence and ELISA. This study describes a new BIOCHIP mosaic-based indirect immunofluorescence technique based on recombinant antigenic substrates and transfected cells. We investigated the diagnostic use of BIOCHIP for the serological diagnosis of Pemphigus vulgaris. Autoantibodies against desmoglein 3 were detected in 97.62% of patients (41/42) with P. vulgaris. There were no positive results in the negative control group. Our study revealed that BIOCHIP has high sensitivity and specificity comparable to that of the ELISA assays. Therefore the BIOCHIP technique seems to be an appropriate method for the diagnosis of P. vulgaris as it has been shown to be a simple, standardized and readily available novel tool, which could facilitate the diagnosis of this autoimmune bullous disease. We suggest that it could be used as an initial screening test to identify patients with P. vulgaris before using the ELISA approach. PMID- 24485335 TI - TRIM29 as a novel prostate basal cell marker for diagnosis of prostate cancer. AB - Tripartite motif protein 29 (TRIM29) is one of the TRIM family proteins, some of which function as E3 ubiquitin ligases. In this study, we investigated the usefulness of TRIM29 for diagnosis of prostate cancer. Prostate tissues including carcinoma and non-carcinoma tissues obtained by needle biopsy and radical prostatectomy were used. Immunohistochemistry was performed according to standard procedures using an antibody against TRIM29. Immunohistochemical staining with an antibody against 34betaE12, which recognizes cytokeratins 1, 5, 10 and 14, was performed as a control. Basal cells of normal prostatic glands were stained with anti-TRIM29 antibody in all cases, whereas prostate cancer tissues had no or little staining with anti-TRIM29 antibody. TRIM29 is selectively expressed in basal cells of the normal prostate gland, and immunohistochemical staining with anti-TRIM29 antibody showed the same expression pattern as that with 34betaE12 in prostate cancer and its benign mimics. Our data indicate that TRIM29 may be useful for distinguishing prostate cancers from benign tissues. PMID- 24485337 TI - Pregnane xenobiotic receptors and their effect on drug elimination from the organism. AB - Nuclear receptors are intracellular proteins which, having been activated by their more or less specific ligands, regulate (usually increase) the transcription of target genes. They thus participate in a regulation of a number of physiologic functions. Some of them - especially pregnane xenobiotic receptors - serve primarily as protection of the organism from the xenobiotic intoxication. This is because many xenobiotics activate their function which consists in increasing the gene expression of enzymes involved in the metabolism of xenobiotics and detoxication drug transporters. Clarification of these mechanisms enabled the understanding of the substance of many drug-drug interactions observed in the clinical practice. Polymorphism of the nuclear receptors appears to be one of the causes of the interindividual variability in response to drug administration. PMID- 24485336 TI - A cleavage clock regulates features of lineage-specific differentiation in the development of a basal branching metazoan, the ctenophore Mnemiopsis leidyi. AB - BACKGROUND: An important question in experimental embryology is to understand how the developmental potential responsible for the generation of distinct cell types is spatially segregated over developmental time. Classical embryological work showed that ctenophores, a group of gelatinous marine invertebrates that arose early in animal evolution, display a highly stereotyped pattern of early development and a precocious specification of blastomere fates. Here we investigate the role of autonomous cell specification and the developmental timing of two distinct ctenophore cell types (motile compound comb-plate-like cilia and light-emitting photocytes) in embryos of the lobate ctenophore, Mnemiopsis leidyi. RESULTS: In Mnemiopsis, 9 h after fertilization, comb plate cilia differentiate into derivatives of the E lineage, while the bioluminescent capability begins in derivatives of the M lineage. Arresting cleavage with cytochalasin B at the 1-, 2- or 4-cell stage does not result in blastomere death; however, no visible differentiation of the comb-plate-like cilia or bioluminescence was observed. Cleavage arrest at the 8- or 16-cell stage, in contrast, results in the expression of both differentiation products. Fate mapping experiments indicate that only the lineages of cells that normally express these markers in an autonomous fashion during normal development express these traits in cleavage-arrested 8- and 16-cell stage embryos. Lineages that form comb plates in a non-autonomous fashion (derivatives of the M lineage) do not. Timed actinomycin D and puromycin treatments show that transcription and translation are required for comb formation and suggest that the segregated material might be necessary for activation of the appropriate genes. Interestingly, even in the absence of cytokinesis, differentiation markers appear to be activated at the correct times. Treatments with a DNA synthesis inhibitor, aphidicolin, show that the number of nuclear divisions, and perhaps the DNA to cytoplasmic ratio, are critical for the appearance of lineage-specific differentiation. CONCLUSION: Our work corroborates previous studies demonstrating that the cleavage program is causally involved in the spatial segregation and/or activation of factors that give rise to distinct cell types in ctenophore development. These factors are segregated independently to the appropriate lineage at the 8- and the 16-cell stages and have features of a clock, such that comb-plate-like cilia and light-emitting photoproteins appear at roughly the same developmental time in cleavage-arrested embryos as they do in untreated embryos. Nuclear division, which possibly affects DNA-cytoplasmic ratios, appears to be important in the timing of differentiation markers. Evidence suggests that the 60 cell stage, just prior to gastrulation, is the time of zygotic gene activation. Such cleavage-clock-regulated phenomena appear to be widespread amongst the Metazoa and these cellular and molecular developmental mechanisms probably evolved early in metazoan evolution. PMID- 24485338 TI - The effect of postoperative pain treatment on the incidence of anastomotic insufficiency after rectal and rectosigmoideal surgery. AB - The aim of prospective study was to evaluate the pain relief in the postoperative period and consumption of opioid and non-opioid analgesics as a risk factor of the anastomotic insufficiency after rectal and rectosigmoideal resection for carcinoma. Anastomotic insufficiency is one of the most feared and life threatening early complications. No articles about the effect of the response to opioid therapy in the postoperative period on the risk of this major clinical problem have been published. We compared the effect of opioid and non-opioid analgesics in 109 patients who underwent rectal and rectosigmoideal resection in a prospective study. We evaluated the appearance of anastomotic insufficiency and clinical conditions in the relationship with the pain relief in the postoperative period and consumption of opioid and non-opioid analgesics. The pain intensity and the consumption of analgesics were significantly increased in the group of nonresponders. The rate of PONV (postoperative nausea and vomiting) in the responders and nonresponders groups was 69% and 78%, respectively. However, the differences did not reach significant level. Other clinical conditions were not significantly different between the both groups, too. The difference in the incidence of anastomotic insufficiency between both groups was highly significant, 6% cases of anastomotic insufficiency in the responders group and 19% in nonresponders group (chi2 = 7.73; p=0.0054). Nonrespoders to opioid therapy and their high consumption of second-line analgesics is a high risk factor for anastomotic insufficiency. PMID- 24485339 TI - The role of taste in cephalic phase of insulin secretion. AB - The effect of a short gustatory signal of a sweet solution was tested on 15 young male volunteers. The experiment consisted of mouth rinsing with either a sucrose or aspartate solution or pure water as a placebo. Blood was then taken in short intervals of 0, 5, 10, 15 and 20 min. Blood glucose, C-peptide, insulin and cortisol were determined. While C-peptide and glucose were unaffected, a short term increase in insulin was observed after the sucrose, but not after the aspartate or placebo. The increase in insulin was significant, though it amounted to only 0.5 mIU/l and lasted approx. 15 min reaching then the starting value. The decline of cortisol level within 20 min of the experiment was approx. 40 nmol/l, although it was also observed after aspartate or placebo mouth rinsing and was probably caused by stress factors or anticipation. In conclusion, the contribution of taste to the cephalic phase of insulin secretion is small yet significant, and mouth rinsing with 5% sucrose causes an insulin increase of just under 1 IU/l, which returns to starting level within 15 min. PMID- 24485340 TI - Self-gripping CovidienTM ProGripTM mesh versus polypropylene mesh in open inguinal hernia repair: multicenter short term results. AB - The purpose of this study was to compare clinical outcomes following sutureless ProGripTM mesh repair to traditional Lichtenstein repair with polypropylene mesh secured with sutures. Data were collected prospectively and were analyzed for 57 male and 3 female patients with 60 inguinal hernias. All patients included underwent open surgical repair for inguinal hernia with polypropylene mesh or ProGrip mesh. In our two centres study sixty patients were operated; 30 were treated with Lichtenstein repair with polypropylene mesh (L group) and 30 with ProGrip mesh (P group) with or without fixation. The primary parameter measured was intensity of postoperative pain using visual analogue scale (VAS); other outcomes included assessment of early and late complication. VAS was assessed in 7 days and 4 months of the postoperative period. Our results show that VAS scored at the 7th postoperative day was 1.5 for the ProGrip mesh versus 4.4 in Lichtenstein repair group. The difference between groups was statistically significant (P=0.001). Surgery duration was significantly shorter in the P group (24.9 vs. 58.3 min; P=0.001). No recurrence was observed at 3 months in both groups. The 3-months follow-up has shown that time necessary to return to daily routine activity was significantly lower in the P group during the (P=0.001). Surgery duration, early and late postoperative, pain and return to daily routine activity rates were significantly reduced with self-gripping ProGrip mesh compared to Lichtenstein repair with polypropylene mesh. PMID- 24485341 TI - Evaluation of Tp-e interval and Tp-e/QT ratio in patients with chronic hepatitis B. AB - Chronic hepatitis B (CHB) is a chronic inflammatory viral disorder. Several studies have suggested that the interval from the peak to the end of the electrocardiographic T wave (Tp-e) may correspond to the transmural dispersion of repolarisation and that increased Tp-e interval and Tp-e/QT ratio are associated with malignant ventricular arrhythmias. Impaired autonomic function has been described in patients with CHB. The aim of this study was to evaluate ventricular repolarisation by using Tp-e interval and Tp-e/QT ratio in patients with CHB, and to assess the relation with inflammation. Fifty-five patients with CHB and 50 controls were included. Tp-e interval and Tp-e/QT ratio were measured from the 12 lead electrocardiogram, and Tp-e interval corrected for heart rate. These parameters were compared between groups. In electrocardiographic parameters analysis, QT dispersion (QTd) and corrected QTd were significantly increased in CHB patients compared to the controls (38.3 +/- 10.9 vs. 28.5 +/- 7.3 milliseconds and 39.5 +/- 11.2 vs. 29.6 +/- 7.6 milliseconds, P=0.01 and P<0.001, respectively). cTp-e interval and Tp-e/QT ratio were also significantly higher in CHB patients (85.3 +/- 8.2 vs. 74.5 +/- 7.4 milliseconds and 0.24 +/- 0.02 vs. 0.18 +/- 0.02, all P-value < 0.001). Our study revealed that Tp-e interval and Tp e/QT ratio were increased in CHB patients. PMID- 24485342 TI - Presence of hypogammaglobulinemia - a risk factor of mortality in patients with severe sepsis, septic shock, and SIRS. AB - In this retrospective study we assessed the frequency of hypogammaglobulinemia in 708 patients with SIRS, severe sepsis and septic shock. We evaluated the relationship between hypogammaglobulinemia IgG, IgM and 28 day mortality. Total of 708 patients and 1,513 samples were analyzed. In the three subgroups we investigated, patients met the criteria of SIRS, severe sepsis and septic shock. IgG hypogammaglobulinemia was demonstrated in 114 patients with severe sepsis (25.2%), 11 septic shock patients (24.4%), and in 29 SIRS patients (13.9%). IgM hypogammaglobulinemia was documented in 55 patients with severe sepsis (12.2%), 6 septic shock patients (13.3%), and in 17 SIRS patients (8.1%). Mortality of patients with severe sepsis and normal IgG levels was significantly lower (111 patients; 32.8%) compared with those with IgG hypogammaglobulinemia (49 patients; 43.0%; p=0.001). Mortality of patients with septic shock and IgG hypogammaglobulinemia (n=5) was significantly higher compared with those with normal IgG levels (45.5% vs. 38.2%; p=0.001). Mortality of patients with severe sepsis and IgM hypogammaglobulinemia did not differ from that of patients with normal IgM levels (37.0 vs. 41.8%). Mortality of patients with septic shock and IgM hypogammaglobulinemia was significantly higher compared with those with normal IgM levels (50% vs. 38.5%; p=0.0001). This study documented relatively high incidence of hypogammaglobulinemia IgG and IgM in patients with severe sepsis, septic shock and SIRS respectively. The presence of IgG hypogammaglobulinemia in patients with severe sepsis is independent factor of mortality. PMID- 24485343 TI - Accelerated bilateral cataract formation as a first manifestation of diabetes mellitus. AB - There is a proved relationship between diabetes mellitus and the cataract formation. The incidence of this is usually related to the duration of diabetes. In this manuscript we report a 15 years old female presented to the emergency room with a 4 hour history of rapid bilateral diminished vision, initially diagnosed with idiopathic cataracts, but after more laboratory evaluations revealed new-onset type 1 diabetes mellitus without ketosis. PMID- 24485344 TI - Cohort study of diabetes in HIV-infected adult patients: evaluating the effect of diabetes mellitus on immune reconstitution. AB - We conducted a retrospective cohort study assessing the association between diabetes mellitus (DM) and immune recovery in HIV-infected adults. Immune reconstitution after initiating antiretroviral therapy was more rapid in DM patients (120.4 cells/year) compared to non-DM patients (94.2 cells/year, p<0.023). Metformin use was associated with improved CD4 recovery (p=0.034). PMID- 24485345 TI - Glucagon-like peptide-1 receptor agonists and pancreatitis: a meta-analysis of randomized clinical trials. AB - AIMS: Several randomized trials with metabolic outcomes have reported that glucagon like peptide-1 receptor agonists (GLP-1 RA) could be associated with an increased risk of pancreatitis. The present meta-analysis aimed to examine this hypothesis. METHODS: An extensive Medline, Embase, and Cochrane Database search for "exenatide", "liraglutide", "albiglutide", "taspoglutide", "dulaglutide", "lixisenatide", and "semaglutide" was performed up to March 31st, 2013. INCLUSION CRITERIA: (i) randomized trials, (ii) duration >=12 weeks; (iii) on type 2 diabetes; and (iv) comparison of GLP-1RA with placebo or active drugs. Mantel Haenszel odds ratio with 95% confidence interval (MH-OR) was calculated for pancreatitis. RESULTS: 80 eligible trials were identified. Of these, 39 had not disclosed their findings or did not report any information on pancreatitis. The remaining 41 trials enrolled 14,972 patients, with a total exposure of 14,333 patient * years (8353 and 5980 patient * years for GLP-1 receptor agonists and comparators, respectively). The overall risk of pancreatitis was not different between GLP-1RA and comparators (MH-OR: 1.01[0.37; 2.76]; p = 0.99). CONCLUSIONS: The present meta-analysis does not suggest any increase in the risk of pancreatitis with the use of GLP-1RA. However, it should be recognized that the number of observed cases of incident pancreatitis is very small and the confidence intervals of risk estimates are wide. PMID- 24485346 TI - Glycaemic threshold for diabetes-specific retinopathy among individuals from Saudi Arabia, Algeria and Portugal. AB - We studied the glycaemic threshold and prevalence of diabetic retinopathy in screen-detected diabetes in Saudi Arabia, Algeria and Portugal. The prevalence of diabetes-specific retinopathy started to increase at an HbA1c level of 6-6.4% (42 47 mmol/mol) and in individuals with HbA(1c) >7.0% the prevalence was 6.0%. PMID- 24485347 TI - Multidimensional family therapy decreases the rate of externalising behavioural disorder symptoms in cannabis abusing adolescents: outcomes of the INCANT trial. AB - BACKGROUND: US-based trials have shown that Multidimensional Family Therapy (MDFT) not only reduces substance abuse among adolescents, but also decreases mental and behavioural disorder symptoms, most notably externalising symptoms. In the INCANT trial, MDFT decreased the rate of cannabis dependence among Western European youth. We now focus on other INCANT outcomes, i.e., lessening of co morbidity symptoms and improvement of family functioning. METHODS: INCANT was a randomised controlled trial comparing MDFT with individual therapy (IP) at and across sites in Berlin, Brussels, Geneva, The Hague, and Paris. We recruited 450 boys and girls aged 13 up to 18 years with a cannabis use disorder, and their parent(s), and followed them for 12 months. Mental and behavioural characteristics (classified as 'externalising' or 'internalising') and family conflict and cohesion were assessed. RESULTS: From intake through 12 months, MDFT and IP groups improved on all outcome measures. Models including treatment, site, and referral source showed that MDFT outperformed IP in reducing externalising symptoms.Adolescents were either self-referred to treatment (mostly on the initiative from people close to the teen) or referred under some measure of coercion by an external authority. These two groups reacted equally well to treatment. CONCLUSIONS: Both MDFT and IP reduced the rate of externalising and internalising symptoms and improved family functioning among adolescents with a cannabis use disorder. MDFT outperformed IP in decreasing the rate of externalising symptoms. Contrary to common beliefs among therapists in parts of Western Europe, the 'coerced' adolescents did at least as well in treatment as the self-referred adolescents.MDFT shows promise as a treatment for both substance use disorders and externalising symptoms. TRIAL REGISTRATION ISRNCT: ISRCTN51014277. PMID- 24485348 TI - 'Oming in on RNA-protein interactions. PMID- 24485349 TI - Luminescence dating and palaeomagnetic age constraint on hominins from Sima de los Huesos, Atapuerca, Spain. AB - Establishing a reliable chronology on the extensive hominin remains at Sima de los Huesos is critical for an improved understanding of the complex evolutionary histories and phylogenetic relationships of the European Middle Pleistocene hominin record. In this study, we use a combination of 'extended-range' luminescence dating techniques and palaeomagnetism to provide new age constraint on sedimentary infills that are unambiguously associated with the Sima fossil assemblage. Post-infrared-infrared stimulated luminescence (pIR-IR) dating of K feldspars and thermally transferred optically stimulated luminescence (TT-OSL) dating of individual quartz grains provide weighted mean ages of 433 +/- 15 ka (thousands of years) and 416 +/- 19 ka, respectively, for allochthonous sedimentary horizons overlying the hominin-bearing clay breccia. The six replicate luminescence ages obtained for this deposit are reproducible and provide a combined minimum age estimate of 427 +/- 12 ka for the underlying hominin fossils. Palaeomagnetic directions for the luminescence dated sediment horizon and underlying fossiliferous clays display exclusively normal polarities. These findings are consistent with the luminescence dating results and confirm that the hominin fossil horizon accumulated during the Brunhes Chron, i.e., within the last 780 ka. The new bracketing age constraint for the Sima hominins is in broad agreement with radiometrically dated Homo heidelbergensis fossil sites, such as Mauer and Arago, and suggests that the split of the H. neanderthalensis and H. sapiens lineages took place during the early Middle Pleistocene. More widespread numerical dating of key Early and Middle Pleistocene fossil sites across Europe is needed to test and refine competing models of hominin evolution. The new luminescence chronologies presented in this study demonstrate the versatility of TT-OSL and pIR-IR techniques and the potential role they could play in helping to refine evolutionary histories over Middle Pleistocene timescales. PMID- 24485350 TI - Influence of lower limb configuration on walking cost in Late Pleistocene humans. AB - It has been proposed that Neandertals had about 30% higher gross cost of transport than anatomically modern humans (AMH) and that such difference implies higher daily energy demands and reduced foraging ranges in Neandertals. Thus, reduced walking economy could be among the factors contributing to the Neandertals' loss in competition with their anatomically modern successors. Previously, Neandertal walking cost had been estimated from just two parameters and based upon a pooled-sex sample. In the present study, we estimate sex specific walking cost of Neandertals using a model accounting for body mass, lower limb length, lower limb proportions, and other features of lower limb configuration. Our results suggest that Neandertals needed more energy to walk a given distance than did AMH but the difference was less than half of that previously estimated in males and even far less pronounced in females. In contrast, comparison of the estimated walking cost adjusted to body mass indicates that Neandertals spent less energy per kilogram of body mass than AMH thanks to their lower limb configuration, males having 1-5% lower and females 1 3% lower mass-specific net cost of transport than AMH of the same sex. The primary cause of high cost of transport in Neandertal males is thus their great body mass, possibly a consequence of adaptation to cold, which was not fully offset by their cost-moderating lower limb configuration. The estimated differences in absolute energy spent for locomotion between Neandertal and AMH males would account for about 1% of previously estimated daily energy expenditure of Neandertal or AMH males. PMID- 24485351 TI - Applying biologic therapies to the management of patients with rheumatoid arthritis. AB - The challenge of providing uniformly effective rheumatoid arthritis care has thus far defied a simple solution. Variations in care range from the appropriate adjustment or switching of therapy subsequent to increased disease activity to the selection of therapeutic agent chosen following failure. This program is designed to improve the understanding of advances in immunopathologic discoveries that provide valuable aid in individualized treatment plans and the appropriate patient selection of available DMARDS and biologic therapeutics. Also, expert rheumatologists will discuss the latest data of head-to-head trials and recommendations for clinical effectiveness. This CME program will bring rheumatologists and other health care professionals up to date in managing their patients with rheumatoid arthritis. PMID- 24485352 TI - Endobronchial tuberculosis simulating lung cancer. PMID- 24485353 TI - Recombinant human thyrotropin-aided versus thyroid hormone withdrawal-aided radioiodine treatment for differentiated thyroid cancer after total thyroidectomy: a meta-analysis. AB - BACKGROUND AND PURPOSE: We conducted a meta-analysis of randomized controlled trials (RCTs) to compare the effects of recombinant human thyrotropin (rhTSH) and thyroid hormone withdrawal (THW) on thyrotropin stimulation prior to remnant ablation of differentiated thyroid cancer (DTC). MATERIAL AND METHODS: A comprehensive search was conducted for articles discussing rhTSH and THW prior to December 2012. After applying the inclusion criteria, all the available data were summarized to analyze the efficacy of rhTSH and THW for stimulating TSH. RESULTS: Seven RCTs that involved a total of 1535 patients, were included in the analysis. The ablation rates of the rhTSH group and the THW group were not significantly different (RR=0.97, 95% CI: 0.94-1.01, p=0.1). Patients in the rhTSH group had a better quality of life (QoL) than those in the THW group on the day of ablation (RR=3.92, 95% CI: 3.44-5.40, p<0.00001). However, there was no difference in the QoL 3 months after ablation (RR=-0.9, 95% CI: -2.20-0.39, p=0.17). Additionally, there were no significant differences in serum thyroglobulin (Tg) levels measured just before radioiodine remnant ablation (preablation thyroglobulin levels) (RR= 0.14, 95% CI: -0.73-0.45, p=0.65), or in days of hospital isolation (RR=-10.51, 95% CI: -32.79-11.73, p=0.35) CONCLUSIONS: Our findings indicate that the administration of rhTSH had resulted in an ablation rate similar to that of THW for DTC patients, but rhTSH provided a better QoL at the time of ablation. PMID- 24485355 TI - The JSLM 'Guidelines for Notification of Unnatural Death': comparison with the systems of reporting death in other countries. AB - 'Guidelines for Notification of Unnatural Death', published by the Japanese Society of Legal Medicine (JSLM) in 1994, has been sometimes criticised by many doctors and lawyers. In various countries, laws specify the type of deaths that should undergo post-mortem examination. The centralized system of reporting death deals with treatment-related deaths. Although the JSLM Guidelines are based on such international norms, the dispute over reporting unnatural deaths in Japan goes against the dominant global trend. One way of solving these issues is to ensure that the police transform their own death investigation apparatus to delink it from criminal investigations. And we need to press for a system that can give the information obtained in investigations back to society, such as to the medical world or other public organisations. PMID- 24485354 TI - Suggestion for the prostatic fossa clinical target volume in adjuvant or salvage radiotherapy after a radical prostatectomy. AB - BACKGROUND AND PURPOSE: To assess the location of recurrent tumors and suggest the optimal target volume in adjuvant or salvage radiotherapy (RT) after a radical prostatectomy (RP). MATERIAL AND METHODS: From January 2000 to December 2012, 113 patients had been diagnosed with suspected recurrent prostate cancer by MRI scan and received salvage RT in the Samsung Medical Center. This study assessed the location of the suspected tumor recurrences and used the inferior border of the pubic symphysis as a point of reference. RESULTS: There were 118 suspect tumor recurrences. The most common site of recurrence was the anastomotic site (78.8%), followed by the bladder neck (15.3%) and retrovesical area (5.9%). In the cranial direction, 106 (87.3%) lesions were located within 30 mm of the reference point. In the caudal direction, 12 lesions (10.2%) were located below the reference point. In the transverse plane, 112 lesions (94.9%) were located within 10mm of the midline. CONCLUSIONS: A MRI scan acquired before salvage RT is useful for the localization of recurrent tumors and the delineation of the target volume. We suggest the optimal target volume in adjuvant or salvage RT after RP, which includes 97% of suspected tumor recurrences. PMID- 24485357 TI - Facial scar assessment and challenges for the future. PMID- 24485356 TI - Azilsartan, an angiotensin II type 1 receptor blocker, restores endothelial function by reducing vascular inflammation and by increasing the phosphorylation ratio Ser(1177)/Thr(497) of endothelial nitric oxide synthase in diabetic mice. AB - BACKGROUND: Azilsartan, an angiotensin II type 1 (AT1) receptor blocker (ARB), has a higher affinity for and slower dissociation from AT1 receptors and shows stronger inverse agonism compared to other ARBs. Possible benefits of azilsartan in diabetic vascular dysfunction have not been established. METHODS: We measured vascular reactivity of aortic rings in male KKAy diabetic mice treated with vehicle, 0.005% azilsartan, or 0.005% candesartan cilexetil for 3 weeks. Expression of markers of inflammation and oxidative stress was measured using semiquantitative RT-PCR in the vascular wall, perivascular fat, and skeletal muscle. Phosphorylation of endothelial nitric oxide synthase (eNOS) at Ser1177 and Thr495 was measured using Western blotting, and the ratio of phosphorylation at Ser1177 to phosphorylation at Thr495 was used as a putative indicator of vascular eNOS activity. RESULTS: (1) Vascular endothelium-dependent relaxation with acetylcholine in KKAy mice was improved by azilsartan treatment compared to candesartan cilexetil; (2) the ratio of Ser1177/Thr495 phosphorylation of eNOS was impaired in KKAy and was effectively restored by azilsartan; (3) anomalies in the expression levels of monocyte chemotactic protein 1 (MCP1), F4/80, NAD(P)H oxidase (Nox) 2, and Nox4 of the aortic wall and in the expression of TNFalpha in the perivascular fat were strongly attenuated by azilsartan compared to candesartan cilexetil. CONCLUSIONS: These results provide evidence that azilsartan prevents endothelial dysfunction in diabetic mice, more potently than does candesartan cilexetil. Azilsartan's higher affinity for and slower dissociation from AT1 receptors may underlie its efficacy in diabetic vascular dysfunction via a dual effect on uncoupled eNOS and on Nox. PMID- 24485358 TI - Effect of hydrogel grafting, water and surfactant wetting on the adherence of PET wound dressings. AB - Traditional wound dressings, including cotton gauze, absorbent pads and bandages, can cause trauma and pain to wounds during dressing changes, leading to a variety of physical and psychosocial sequelae. The aim of this study was to adapt an in vitro model of adherence to evaluate the effects of various methods to theoretically reduce the adherence of wound dressings. Gelatin in liquid form was cast onto poly(ethylene terephthalate) (PET) fabric and allowed to solidify and progressively dry to simulate wound desiccation in the clinical setting. A 180 degrees peel test of PET from the gelatin slab yielded adherence data of peeling energy. The peeling energy of PET increased with the drying time. It was possible to reduce the force by drying at 75% relative humidity (RH). After drying for 24h, either 500MUL of water or surfactant solution was added onto the PET surface (16*60mm(2)). The peeling energy decreased dramatically with wetting and there was no significant difference between water and surfactant. As a long-term strategy for decreasing adherence, a thin layer of polyacrylamide (PAM) hydrogel was deposited onto PET fabric via UV irradiation. This resulted in a much lower peeling energy without severely compromising fabric flexibility. This hydrogel layer could also serve as a reservoir for bioactive and antimicrobial agents which could be sustainably released to create a microbe-free microenvironment for optimized wound healing. PMID- 24485359 TI - Editorial comment. PMID- 24485360 TI - In vitro comparisons of retropulsion and fragmentation efficacy of 2 cordless, handheld pneumatic and electromechanical lithotripsy devices. AB - OBJECTIVE: To compare, in vitro, probe velocity/displacement, retropulsion, and fragmentation capacity of the cordless electromechanical (LithoBreaker) (hard vs soft probe guide) and pneumatic (StoneBreaker). MATERIALS AND METHODS: Probe velocities/displacements were measured using high-speed resolution camera (100.000 frames/s). The lithotripsy probes were projected through a 7.5F ureteroscope against a nonfrangible led ball placed in a 15F horizontally mounted silicone tube immersed in water bath as an in vitro ureter model. Retropulsion is considered as displacement distance of led ball. Fragmentation efficiency was quantified as number of shots required to break Bego-stone phantoms (hard [15:3] and soft [15:6], average size 7.5 * 5.5 mm) placed on metal mesh into <3-mm fragments. Mean and standard deviation of repetitive measurements were statistically analyzed. RESULTS: StoneBreaker yielded higher probe velocity (22 +/- 1.9 m/s) compared with LithoBreaker with hard (14.2 +/- 0.5 m/s) and soft (11.5 +/- 0.5 m/s) probe. Maximum probe displacement for StoneBreaker was 1.04 mm vs 0.9 mm and 1.1 mm (hard vs soft LithoBreaker-probe, respectively). Retropulsion using 1-mm probes showed no statistical differences. Using harder 2 mm probe decreased Lithobreaker retropulsion significantly compared with Stonebreaker. The amount of shots (1-mm probe) to fragment soft Bego stones was significantly higher for LithoBreaker with soft (mean 31.5 +/- 11.31) and hard (mean 21.5 +/- 5.29) probe guide vs StoneBreaker (mean 11.2 +/- 2.65). Fragmentation efficiency for hard Bego stones showed similar statistically significant outcome. Comparison of the 2 probe guides showed higher velocity linked to harder-probe that improved LithoBreaker fragmentation performance and reduce propulsion. CONCLUSION: Both examined lithotripters are effective in cracking stone phantoms with relatively low pulse number. They produce comparable retropulsions. Fragmentation improved substantially using LithoBreaker with hard probe guide. More tests are required to assess differences in stone clearance time. PMID- 24485361 TI - Complete primary repair of bladder exstrophy is associated with detrusor underactivity type of neurogenic bladder. AB - OBJECTIVE: To test the hypothesis that complete primary repair of bladder exstrophy (CPRE) is associated with detrussor underactivity. For this purpose, we review (1) our experience, (2) the results of the published literature as it pertains to bladder function, and (3) the known anatomic basis on which the mechanism of the observed outcome can be understood. METHODS: The medical records of all patients who underwent CPRE by the author between 2004 and 2010 were reviewed. Attention was focused on the clinical, imaging, and urodynamic findings. RESULTS: Four men and 2 women underwent CPRE. Follow-up ranges from 2 to 8 years. Four underwent bilateral ureteral reimplantation combined with bladder neck repair in 3. Detrusor activity (or overactivity) was not recorded in the 5 patients who underwent urodynamic studies. Four patients achieved short periods of urinary continence. The percent predicted bladder capacity, adjusted for age, ranged from 25 to 70, with a median of 60. Of the 68 publications on CPRE since 1999, none reports the presence of detrusor activity. A description of the pelvic plexus anatomy by Walsh and Donker provides a basis for the mechanism of injury resulting in the previously mentioned results: (1) complete penile disassembly eliminates the distal fixation point of the bladder-urethral plate, (2) the subsequent dissection and mobilization result in shearing injury to the microscopic pelvic plexus branches to the bladder, external sphincter, and prostatic urethra. CONCLUSION: CPRE results in disruption of the branches of the pelvic plexus and a neurogenic bladder (detrussor underactivity). PMID- 24485362 TI - Reply: To PMID 24485359. PMID- 24485363 TI - Seminal-sparing cystectomy: technical evolution and results over a 20-year period. AB - OBJECTIVE: To demonstrate the oncologic and functional results of seminal-sparing cystectomy (SSC) in patients with bladder cancer (BC) and to describe the evolution of our surgical technique over a 20-year period. METHODS: From 1990 to 2009 we performed SSC in 88 patients with non-muscle-invasive BC and in 10 patients with muscle-invasive BC away from the bladder neck. Sixty-one of the 98 patients (1990-2002) underwent cystoadenomectomy with ileocapsuloplasty (ICP), consisting of the anastomosis between the Camey II ileal reservoir and the upper edge of the prostatic capsule. This technique was affected by a relevant percentage of anastomotic stricture (11%). From 2003 to 2009, we performed the endocapsular ileourethral anastomosis (EIUA) in 30 patients, on the basis of the direct anastomosis between the ileal reservoir and the urethral stump inside the prostatic apex. Seven patients were lost to follow-up. RESULTS: After a mean follow-up of 102 months, 81 patients (89%) were alive, and 10 patients (11%) had died (8 of disease progression). Early and late complication rates were 25% and 24%, respectively. Complete daytime continence was obtained in 87 patients (95.6%), and nighttime continence was achieved in 34 patients (37%). In the ICP group, stricture of the prostatic fossa affected 7 patients (11%), whereas no neobladder-urethral anastomosis stricture was noticed in the EIUA group. Normal erectile function was preserved in 87 patients (95.6%). CONCLUSION: SSC offers good oncologic and functional results in carefully selected patients. EIUA represents an evolution from ICP because EIUA reduces the risk of stenosis. PMID- 24485364 TI - Start planning for APIC education opportunities in 2014. PMID- 24485365 TI - State of infection prevention in US hospitals enrolled in the National Health and Safety Network. AB - BACKGROUND: This report provides a national cross-sectional snapshot of infection prevention and control programs and clinician compliance with the implementation of processes to prevent health care-associated infections (HAIs) in intensive care units (ICUs). METHODS: All hospitals, except Veterans Affairs hospitals, enrolled in the National Healthcare Safety Network (NHSN) were eligible to participate. Participation involved completing a survey assessing the presence of evidence-based prevention policies and clinician adherence and joining our NHSN research group. Descriptive statistics were computed. Facility characteristics and HAI rates by ICU type were compared between respondents and nonrespondents. RESULTS: Of the 3,374 eligible hospitals, 975 provided data (29% response rate) on 1,653 ICUs, and there were complete data on the presence of policies in 1,534 ICUs. The average number of infection preventionists (IPs) per 100 beds was 1.2. Certification of IP staff varied across institutions, and the average hours per week devoted to data management and secretarial support were generally low. There was variation in the presence of policies and clinician adherence to these policies. There were no differences in HAI rates between respondents and nonrespondents. CONCLUSIONS: Guidelines for IP staffing in acute care hospitals need to be updated. In future work, we will analyze the associations between HAI rates and infection prevention and control program characteristics, as well as the inplementation of and clinician adherence to evidence-based policies. PMID- 24485366 TI - Longitudinal evaluation of a World Wide Web-based antimicrobial stewardship program: assessing factors associated with approval patterns and trends over time. AB - BACKGROUND: The Johns Hopkins Children's Medical and Surgery Center developed a Web-based Antimicrobial Stewardship Program (ASP) in 2005. The present study aimed to assess longitudinal antimicrobial request and approval patterns for this ASP. METHODS: We analyzed a total of 16,229 antimicrobial requests for 3,542 patients between June 1, 2005, and June 30, 2009. Antimicrobial approval was the outcome of interest. We assessed gaming by studying trends in automatically approved requests. Nonparametric tests for trend were performed to detect changes in approval patterns. Multiple logistic regression was used to identify factors associated with approval. RESULTS: The vast majority (91.3%) of antimicrobial requests were approved, with an increase of 6.1% over time (P < .01). Renewal requests were more likely than primary requests (adjusted odds ratio [aOR], 1.72; 95% confidence interval [CI], 1.45-2.04) to be approved. Antiviral requests had higher odds of approval than antibiotic requests (aOR, 1.27; 95% CI, 1.04-1.56). Compared with requests by medical services, requests by surgical services had lower odds of approval (aOR, 0.70; 95% CI, 0.59-0.83), whereas pediatric intensive care requests had higher odds of approval (aOR, 1.18; 95% CI, 1.00 1.40). The number of auto-approved requests remained consistent. CONCLUSIONS: The Web-based ASP allows management of a large number of antimicrobial requests, without apparent gaming. Observed differences in approval patterns based on patient, requestor, and antimicrobial factors may inform the development of ASPs and evaluation of provider education and training. PMID- 24485367 TI - Assessing the impact of an educational intervention on ventilator-associated pneumonia in a pediatric critical care unit. AB - BACKGROUND: Ongoing educational programs targeting health care professionals have shown positive outcomes by reducing the morbidity and mortality associated with health care-associated infections (HAIs). We undertook this study to measure the impact of such a program in a pediatric critical care unit of a developing country. METHODS: This prospective study was conducted in 2 time periods of 6 months each, with an educational intervention for resident doctors and nurses in between. The rates of ventilator-associated pneumonia (VAP) during the preintervention and postintervention periods were estimated by active surveillance. RESULTS: The incidence density of VAP was reduced by 28% (20.2 vs 14.6 per 1,000 ventilator-days; P = .21, Z test) despite a significant increase in the ventilator utilization ratio during the postintervention period (0.64 vs 0.88; P < .0001, Pearson's chi2 test). There was a statistically significant reduction in mortality among patients who received mechanical ventilation for >=48 hours in the postintervention period (49.3% vs 31.4%; P = .029, Pearson's chi2 test). CONCLUSIONS: Educational programs have a positive impact on reducing the morbidity and mortality associated with HAIs. Incidence rates based on device days should be compared by keeping the variations in device utilization ratio in mind. PMID- 24485368 TI - Effectiveness of infection prevention measures featuring advanced source control and environmental cleaning to limit transmission of extremely-drug resistant Acinetobacter baumannii in a Thai intensive care unit: An analysis before and after extensive flooding. AB - BACKGROUND: Advanced source control (once-daily bathing and 4-times daily oral care with chlorhexidine aqueous solution) and thorough environmental cleaning were implemented in response to an increased incidence of colonization and infection with extremely drug-resistant (XDR) Acinetobacter baumannii in a Thai medical intensive care unit (MICU). METHODS: During the 12-month baseline period (P1), contact isolation, active surveillance for XDR A baumannii, cohorting of XDR A baumannii patients, twice-daily environmental cleaning with detergent disinfectant, and antibiotic stewardship were implemented. In the 5.5-month intervention period (P2), additional measures were introduced. Sodium hypochlorite was substituted for detergent-disinfectant, and advanced source control was implemented. All interventions except cleaning with sodium hypochlorite were continued during the 12.5-month follow-up period (P3). Extensive flooding necessitating closure of the hospital for 2 months occurred between P2 and P3. RESULTS: A total of 1,365 patients were studied. Compared with P1 (11.1 cases/1,000 patient-days), the rate of XDR A baumannii clinical isolates declined in P2 (1.74 cases/1,000 patient-days; P < .001) and further in P3 (0.69 cases/1,000 patient-days; P < .001). Compared with P1 (12.15 cases/1,000 patient days), the rate of XDR A baumannii surveillance isolates also declined in P2 (2.11 cases/1,000 patient-days; P < .001) and P3 (0.98 cases/1,000 patient-days; P < .001). Incidence of nosocomial infections remained stable. Six patients developed chlorhexidine-induced rash (1.4/1,000 patient-days); 31 patients developed mucositis (17.1/1,000 patient-days). CONCLUSIONS: These results support advanced source control and thorough environmental cleaning to limit colonization and infection with XDR A baumannii in MICUs in resource-limited settings. PMID- 24485369 TI - Sustained low incidence of central venous catheter-related infections over six years in a Swedish hospital with an active central venous catheter team. AB - BACKGROUND: There are limited data on the long-term effects of implementing a central venous catheter (CVC) program for prevention of CVC infections. The aims of this study were to evaluate the incidence of CVC colonization, catheter related infections (CRI), catheter-related bloodstream infections (CRBSI), and their risk factors over a 6-year period in a hospital with an active CVC team. METHODS: We conducted a continuous prospective study aiming to include all CVCs used at our hospital during the years 2004 to 2009, evaluating colonization, CRI, CRBSI, and possible risk factors. RESULTS: A total of 2,772 CVCs was used during the study period. Data on culture results and catheterization time were available for 2,045 CVCs used in 1,674 patients. The incidences of colonization, CRI, and CRBSI were 7.0, 2.2, and 0.6 per 1,000 CVC-days, respectively. Analysis of quarterly incidences revealed 1 occasion with increasing infection rates. Catheterization time was a risk factor for CRI but not for CRBSI. Other risk factors for CRI were hemodialysis and CVC use in the internal jugular vein compared with the subclavian vein. Hemodialysis was the only risk factor for CRBSI. CONCLUSION: We found that a CRI prevention program led by an active CVC team and adhered to by the entire staff at a county hospital is successful in keeping CVC infections at a low rate over a long period of time. PMID- 24485370 TI - Hospital-acquired infections and thermally injured patients: chlorhexidine gluconate baths work. AB - BACKGROUND: Thermally injured patients are at high risk for infections, including hospital acquired infections (HAIs). We modeled a twice-daily chlorhexidine gluconate (CHG) bath protocol aimed at decreasing HAIs. METHODS: Bathing with a 0.9% CHG solution in sterile water was provided twice daily as part of routine care. Institutional HAI prevention bundles were in place and did not change during the study. Baseline HAI rates were collected for 12 months before the quality study implementation. Centers for Disease Control and Prevention definitions for HAIs were used; our blinded Infection Control physician made each determination. This was an Institutional Review Board-exempt protocol. RESULTS: The study cohort included 203 patients before the quality trial and 277 patients after the quality trial. The median burn area was 25% of total body surface area. Baseline HAI rates were as follows: ventilator-associated pneumonia, 2.2 cases/1,000 ventilator-days; cathether-associated urinary tract infection, 2.7 cases/1,000 catheter-days; central line-associated bloodstream infection, 1.4 cases/1,000 device-days. With implementation of this protocol, the rates dropped to zero and have stayed at that level with the exception of 1 cathether associated urinary tract infection. There were no untoward effects or observed delays in wound healing with this protocol. All of these changes were clinically significant, although not statistically significant; the study was not powered for statistical significance. CONCLUSIONS: Using this nurse-driven protocol, we decreased, in a sustainable manner, the HAI rate in our intensive care unit to zero. No integumentary difficulties or wound healing delays were related to this protocol. PMID- 24485371 TI - Use of hand-held computers to determine the relative contribution of different cognitive, attitudinal, social, and organizational factors on health care workers' decision to decontaminate hands. AB - BACKGROUND: Observational and survey methods have limitations in measuring hand hygiene behavior. The ability of a personal digital assistant to anonymously gather data at the point of decision making could potentially address these. METHODS: Participants were provided with a personal digital assistant to be used for three 2-hour periods and asked to rate influential factors of the Health Belief Model (HBM). Participants were also required to enter what they thought they should do and what they actually did. RESULTS: A total of 741 hand hygiene opportunities was recorded. All HBM constructs were higher for hand hygiene opportunities where there was compliance versus noncompliance, with a significant difference for patient pressure, my risk, perceived benefits, perceived seriousness, and availability of good facilities. Only 20% of doctors, 28% of nurses, and 66% of physiotherapists always did what they thought they should. There was no correlation between self-reported and actual compliance. CONCLUSION: The HBM appeared to be a useful theoretical framework. Surprisingly, participants rated their compliance as high despite having recorded instances where they did not do what they thought they should do. This suggests that staff may have a different definition of compliance than strict observation of the guidelines. PMID- 24485372 TI - Recurrence of Clostridium difficile infection among veterans with spinal cord injury and disorder. AB - BACKGROUND: Recurrent Clostridium difficile (CDI) infection is a growing concern; however, there are little data on impact of recurrent CDI on those with spinal cord injury and disorder (SCI/D). Therefore, the objective of this study was to identify risk factors associated with recurrence of CDI among Veterans with SCI/D. METHODS: This was a retrospective cohort study with data from outpatient, inpatient, and extended care settings at 83 Department of Veterans Affairs facilities from 2002 to 2009. RESULTS: Of 1,464 cases of CDI analyzed, 315 cases (21.5%) had a first recurrence of CDI. Multivariable regression demonstrated that risk factors significantly associated with increased recurrence were concomitant fluoroquinolone use (odds ratio [OR], 1.39; 95% confidence interval [CI]: 1.08 1.80), whereas concomitant tetracycline use (OR, 0.35; 95% CI: 0.14-0.90), and cerebrovascular accident (OR, 0.46; 95% CI: 0.25-0.85) were associated with decreased recurrence. A subanalysis in those with health care facility-onset CDI showed that increased length of stay postinitial CDI was a significant risk factor for recurrence as was concomitant use of fluoroquinolones and that tetracycline remained protective for recurrence. CONCLUSION: Concomitant fluoroquinolone use was a risk factor for the recurrence of CDI. In contrast, tetracyclines and cerebrovascular accident were protective. Length of stay greater than 90 days from the initial CDI episode was also a risk factor for recurrence among those with health care facility-onset CDI. Future studies should focus on effective strategies to prevent these risk factors among the SCI/D population. PMID- 24485373 TI - Incidence of nosocomial hemodialysis-associated bloodstream infections at a county teaching hospital. AB - BACKGROUND: Infections are an important cause of morbidity and mortality in patients undergoing hemodialysis. Limited information is to be found regarding nosocomial hemodialysis-associated bloodstream infections (HABSI). METHODS: We sought to determine the rate of nosocomial HABSI and its associated risk factors at Riverside County Regional Medical Center. Inpatients who received hemodialysis during 2011 and 2012 were included, and outcomes were recorded along with risk factors. Data was analyzed with SPSS Inc software. RESULTS: A total of 619 patients was included. Fourteen HABSI were detected, with a rate of 3.33/1,000 hemodialysis sessions and 1.03/1,000 patient-days. An association was detected between HABSI and vascular access type (highest risk with nontunneled catheters), length of hospital stay, number of hemodialysis sessions, and hemoglobin A1c level. A correlation was also noted between HABSI because of MRSA and colonization of nares with MRSA. A predominance of staphylococci infections was detected. CONCLUSION: The rate of HABSI observed at Riverside County Regional Medical Center was lower than similar studies (2.5 per 1,000 patient-days and 3.95 per 1,000 hemodialysis sessions). The most important risk factors were determined to be nontunneled catheters, hemoglobin A1c greater than 7%, and nares colonization for HABSI because of MRSA. Infection prevention efforts in the inpatient hemodialysis population should focus on control of hyperglycemia and decolonization of nares from MRSA. PMID- 24485374 TI - Development of a standardized process improvement protocol to address elevated health care-associated infection rates on an incented quality scorecard. AB - This practice forum report details a standardized improvement process that was created both to improve patient outcomes related to various hospital-acquired infections and to address leadership concerns related to incented quality metrics. A 3-year retrospective review identified common issues to guide future interventions and confirmed that this methodology reduced the rate of recurrent infections across the health care system. Process tool samples are provided. PMID- 24485375 TI - Improving infection prevention methods in hemodialysis units: a multicenter survey. AB - The aim of this cross-sectional study was to investigate the implementation of and compliance with international infection control standards by patients and staff in dialysis centers in Shiraz, Iran. The results indicate negligence in various aspects of infection control. Providing staff education and training programs, establishing effective surveillance systems, and enforcing regulations in the hospitals should help improve infection prevention. PMID- 24485376 TI - Direct feedback with the ATP luminometer as a process improvement tool for terminal cleaning of patient rooms. AB - We assessed the adenosine triphosphate luminometer as a tool for point-of cleaning education. Following a terminal cleaning, infection preventionists met with cleaning staff and used the luminometer to evaluate multiple surfaces; 820 surfaces in 210 rooms were sampled. The mean proportion of clean surfaces improved significantly over the study period, P = .012. These findings suggest that direct measurement and education at the point of cleaning with an objective tool is useful for improving terminal cleaning. PMID- 24485377 TI - Knowledge and attitudes of visitors to patients in contact isolation. AB - In this study, conducted at a tertiary care center, we surveyed visitors to patients in contact isolation to assess their knowledge and attitudes about contact isolation. Although response rates were low, we found that visitors had an overall positive perception and understanding of contact isolation. We think this is likely attributable to the communication and education provided by health care providers to the visitors. PMID- 24485378 TI - Ventilator-associated pneumonia due to extensive drug-resistant Acinetobacter baumannii: risk factors, clinical features, and outcomes. AB - Acinetobacter baumannii is characterized by a rapid development of resistance to the commonly used antimicrobial agents. We investigated the risk factors, clinical features, and outcomes in ventilator-associated pneumonia (VAP) caused by extensive drug-resistant Acinetobacter baumannii (XDRAB). Clinical parameters and overall in-hospital mortality rates were compared between the VAP with and without XDRAB infection groups. This study showed that VAP caused by XDRAB was not associated with in-hospital mortality. However, it was related to high Simplified Acute Physiology Score II scores and increasing durations of hospital stays. PMID- 24485379 TI - The first case of avian influenza A (H7N9) virus occurring in the autumn season, China. PMID- 24485380 TI - Incidence of needlestick and other sharp object injuries in a Chinese hospital. PMID- 24485381 TI - Evaluation of a new rapid readout biological indicator for use in 132 degrees C and 135 degrees C vacuum-assisted steam sterilization cycles. AB - BACKGROUND: Sterilization is a process that cannot be inspected or tested in a practical manner to assure that all microorganisms have been inactivated. The process must therefore be validated for all of the specific items processed or monitored on a per cycle basis. METHODS: A new, faster rapid readout biological indicator (RRBI) has been developed for use in 132 degrees C and 135 degrees C vacuum-assisted steam sterilization cycles. The aim of this study was to evaluate the performance of this new 1-hour readout RRBI at 132 degrees C in side-by-side testing with an existing 3-hour readout RRBI and also evaluate the performance of the new RRBI in 135 degrees C cycles. Readout responses of 1 hour (fluorescent) and 48 hours and 7 days (growth) of the new RRBI were compared with 3-hour, 48 hour, and 7-day readouts of the 3-hour RRBI following exposures in 132 degrees C cycles using a highly controlled test vessel, ie, a steam resistometer. Additional testing of the 1-hour RRBIs was also performed in 135 degrees C cycles. RESULTS: The number and percentage of fluorescent-positive 1-hour RRBIs were virtually identical to those of the 3-hour RRBIs after 1 and 3 hours of incubation, respectively. Testing of the 1-hour RRBI in 135 degrees C cycles paralleled the results of the testing at 132 degrees C but with the expected shorter exposure times. CONCLUSION: The results of this study suggest that the 1 hour RRBI is equivalent to the 3-hour RRBI and would be suitable for use in monitoring dynamic air removal steam sterilization cycles at both 132 degrees C and 135 degrees C per recommended practice guidelines. PMID- 24485382 TI - Comparison of washer-disinfector cleaning indicators: impact of temperature and cleaning cycle parameters. AB - BACKGROUND: Because automated instrument washer-disinfectors (WD) are widely used in health care to reprocess a variety of medical instruments, we developed a study to compare 3 cleaning indicators to determine whether they detected suboptimal temperature, time, enzymatic detergent, and fluid action in a washer disinfector. METHODS: The Miele WD was used for this comparison. One optimal cycle and 14 cycles with suboptimal enzymatic detergent, cleaning time, temperature, or inactive spray arms were evaluated. The cleaning indicators evaluated included the following: Pinnacle Monitor for Automated Enzymatic Cleaning Process (PNCL), Wash-Checks (WC), and TOSI. The scoring system for all 3 indicators was harmonized to a common scale. Soiled tweezers were included in each cycle evaluated. RESULTS: The PNCL, TOSI, and WC cleaning indicators showed significantly more failures at 40 degrees C compared with 60 degrees C (100% vs 0% for PNCL, 17% vs 0% for TOSI, and 60% vs 22% for WC, respectively). There were significantly more failures at suboptimal temperatures with a 2- versus 4-minute cycle (100% vs 0% for PNCL, 17% vs 0% for TOSI, and 17% vs 0% for WC, respectively, for 40 degrees C cycles). Despite suboptimal cleaning cycles, all soiled tweezers looked clean. CONCLUSION: All 3 cleaning indicators responded to suboptimal WD conditions; however, the PNCL was the most affected by alterations in the cycle conditions evaluated. In simulated use testing, cleaning indicators provided a more sensitive audit tool compared with visual inspection of soiled instruments after automated cleaning. PMID- 24485383 TI - Hand hygiene among neurologists attending a congress. AB - Hand hygiene is effective in preventing health care-associated infections, but hand hygiene compliance is low among health care workers in different hospital settings. Less is known about hand hygiene among physicians in a nonhospital setting. We evaluated handwashing behavior among 200 neurologists (100 males and 100 females) attending a world congress. Overall, 74.0% performed proper hand hygiene using soap and water, and there were significant differences between sex and handwashing behavior. PMID- 24485384 TI - Robustness of nanofiltration for increasing the viral safety margin of biological products. AB - In this study, the virus-removal capacity of nanofiltration was assessed using validated laboratory scale models on a wide range of viruses (pseudorabies virus; human immunodeficiency virus; bovine viral diarrhea virus; West Nile virus; hepatitis A virus; murine encephalomyocarditis virus; and porcine parvovirus) with sizes from 18 nm to 200 nm and applying the different process conditions existing in a number of Grifols' plasma-derived manufacturing processes (thrombin, alpha1-proteinase inhibitor, Factor IX, antithrombin, plasmin, intravenous immunoglobulin, and fibrinogen). Spiking experiments (n = 133) were performed in process intermediate products, and removal was subsequently determined by infectivity titration. Reduction Factor (RF) was calculated by comparing the virus load before and after nanofiltration under each product purification condition. In all experiments, the RFs were close to or greater than 4 log10 (>99.99% of virus elimination). RF values were not significantly affected by the process conditions within the limits assayed (pH, ionic strength, temperature, filtration ratio, and protein concentration). The virus-removal capacity of nanofiltration correlated only with the size of the removed agent. In conclusion, nanofiltration, as used in the manufacturing of several Grifols' products, is consistent, robust, and not significantly affected by process conditions. PMID- 24485385 TI - A sideways step... PMID- 24485386 TI - Enhanced corticobulbar excitability in chronic smokers during visual exposure to cigarette smoking cues. AB - BACKGROUND: Neuroimaging studies of chronic smokers report altered activity of several neural regions involved in the processing of rewarding outcomes. Neuroanatomical evidence suggests that these regions are directly connected to the tongue muscle through the corticobulbar pathways. Accordingly, we examined whether corticobulbar excitability might be considered a somatic marker for nicotine craving. METHODS: We compared motor-evoked potential (MEP) amplitudes recorded from the tongue and the extensor carpi radialis (control muscle) of chronic smokers under drug withdrawal and intake conditions as well as a nonsmoker group. All participants were tested during passive exposure to pictures showing a smoking cue or a meaningless stimulus. In the intake condition, chronic smokers were asked to smoke a real cigarette (CSn: group 1) or a placebo (CSp: group 2). RESULTS: Results show that MEP amplitudes recorded from the tongues of participants in the CSn and CSp groups under the withdrawal condition were selectively enhanced during exposure to a smoking cue. However, this effect on tongue MEP amplitudes disappeared in the intake condition for both the CSn and CSp groups. LIMITATIONS: Limitations include the fact that the study was conducted in 2 different laboratories, the small sample size, the absence of data on chronic smoker craving strength and the different tastes of the real and placebo cigarettes. CONCLUSION: These results suggest that, in chronic smokers, tongue muscle MEP amplitudes are sensitive to neural processes active under the physiological status of nicotine craving. This finding implicates a possible functional link between neural excitability of the corticobulbar pathway and the reward system in chronic smokers. PMID- 24485387 TI - Oxidation and nitration in dopaminergic areas of the prefrontal cortex from patients with bipolar disorder and schizophrenia. AB - BACKGROUND: Increased oxidative stress is strongly implicated in bipolar disorder (BD), where protein oxidation, lipid peroxidation and oxidative damage to DNA have been consistently reported. High levels of dopamine (DA) in mania are also well-recognized in patients with BD, and DA produces reactive oxygen species and electron-deficient quinones that can oxidize proteins when it is metabolized. METHODS: Using immunohistochemistry and acceptor photobleaching Forster resonance energy transfer (FRET), we examined oxidation and nitration of areas immunoreactive for the DA transporter (DAT) and tyrosine hydroxylase (TH) in the postmortem prefrontal cortex from patients with BD, schizophrenia and major depression as well as nonpsychiatric controls. RESULTS: We found increased oxidation of DAT-immunoreactive regions in patients with BD (F3,48 = 6.76, p = 0.001; Dunnett post hoc test p = 0.001) and decreased nitration of TH immunoreactive regions in both patients with BD (F3,45 = 3.10, p = 0.036; Dunnett post hoc test p = 0.011) and schizophrenia (p = 0.027). On the other hand, we found increased global levels of oxidation in patients with BD (F3,44 = 6.74, p = 0.001; Dunnett post hoc test p = 0.001) and schizophrenia (p = 0.020), although nitration levels did not differ between the groups (F3,46 = 1.75; p = 0.17). LIMITATIONS: Limitations of this study include the use of postmortem brain sections, which may have been affected by factors such as postmortem interval and antemortem agonal states, although demographic factors and postmortem interval were accounted for in our statistical analysis. CONCLUSION: These findings suggest alterations in levels of protein oxidation and nitration in DA-rich regions of the prefrontal cortex in patients with BD and schizophrenia, but more markedly in those with BD. PMID- 24485388 TI - The role of inflammatory and anti-inflammatory cytokines in the pathogenesis of human tegumentary leishmaniasis. AB - In tegumentary leishmaniasis caused by Leishmania braziliensis, there is evidence that increased production of IFN-gamma, TNF-alpha and absence of IL-10 is associated with strong inflammatory reaction and with tissue destruction and development of the lesions observed in cutaneous leishmaniasis (CL) and mucosal leishmaniasis (ML). We evaluate the role of regulatory cytokines and cytokine antagonists in the downregulation of immune response in L. braziliensis infection. Peripheral blood mononuclear cells from CL and ML were stimulated with soluble Leishmania antigen in the presence or absence of regulatory cytokines (IL 10, IL-27 and TGF-beta) or antagonists of cytokines (alpha-TNF-alpha and alpha IFN-gamma). Cytokines production (IL-10, IL-17, TNF-alpha and IFN-gamma) was measured by ELISA. IL-10 and TGF-beta downmodulate TNF-alpha and IL-17 production, whereas IL-27 had no effect in the production of TNF-alpha, IFN-gamma and IL-17 in these patients. Neutralization of TNF-alpha decreased IFN-gamma level and the neutralization of IFN-gamma decreased TNF-alpha level and increased IL-10 production. This study demonstrate that IL-10 and TGF-beta are cytokines that appear to be more involved in modulation of immune response in CL and ML patients. IL-10 might have a protective role, since the neutralization of IFN gamma decreases the production of TNF-alpha in an IL-10-dependent manner. PMID- 24485389 TI - Formative research to develop a community-based intervention for chronic disease prevention in Guatemalan school-age children. AB - BACKGROUND: Noncommunicable diseases (NCD) are the most common causes of morbidity and mortality worldwide, even in low- and middle-income countries (LMIC). Recent trends in health promotion emphasize community-based interventions as an important strategy for improving health outcomes. The aim of this study was to conduct formative research regarding the perceptions of NCD risk factors, their influencing factors, and community resources available to aid the development and implementation of a community-based intervention with school-age children. METHODS: Focus group discussions (n = 18), home visits (n = 30), and individual semi-structured interviews (n = 26) were conducted in three urban communities in Guatemala with school-age children (10-12 years of age), teachers, parents, and local community members (i.e., school principals, school food kiosk vendors, religious leaders, authority representatives). All focus groups and interviews were transcribed verbatim for thematic analysis. RESULTS: Children, parents, and teachers have general knowledge about modifiable risk factors. Adults worried more about tobacco use, as compared to unhealthy diet and physical inactivity in children. Participants identified features at the intrapersonal (e.g., negative emotional state), interpersonal (e.g., peers as role models), and organizational and community levels (e.g., high levels of crime) that influence these risk factors in children. School committees, religious leaders, and government programs and activities were among the positive community resources identified. CONCLUSIONS: These findings should help researchers in Guatemala and similar LMIC to develop community-based interventions for NCD prevention in school-age children that are effective, feasible, and culturally acceptable. PMID- 24485390 TI - A new hybrid intelligent system for accurate detection of Parkinson's disease. AB - Elderly people are commonly affected by Parkinson's disease (PD) which is one of the most common neurodegenerative disorders due to the loss of dopamine-producing brain cells. People with PD's (PWP) may have difficulty in walking, talking or completing other simple tasks. Variety of medications is available to treat PD. Recently, researchers have found that voice signals recorded from the PWP is becoming a useful tool to differentiate them from healthy controls. Several dysphonia features, feature reduction/selection techniques and classification algorithms were proposed by researchers in the literature to detect PD. In this paper, hybrid intelligent system is proposed which includes feature pre processing using Model-based clustering (Gaussian mixture model), feature reduction/selection using principal component analysis (PCA), linear discriminant analysis (LDA), sequential forward selection (SFS) and sequential backward selection (SBS), and classification using three supervised classifiers such as least-square support vector machine (LS-SVM), probabilistic neural network (PNN) and general regression neural network (GRNN). PD dataset was used from University of California-Irvine (UCI) machine learning database. The strength of the proposed method has been evaluated through several performance measures. The experimental results show that the combination of feature pre-processing, feature reduction/selection methods and classification gives a maximum classification accuracy of 100% for the Parkinson's dataset. PMID- 24485392 TI - MCT1 A1470T: a novel polymorphism for sprint performance? AB - OBJECTIVES: The A1470T polymorphism (rs1049434) in the monocarboxylate (lactate/pyruvate) transporter 1 gene (MCT1) has been suggested to influence athletic performance in the general population. We compared genotype distributions and allele frequencies of the MCT1 gene A1470T polymorphism between endurance athletes, sprint/power athletes and matched controls. We also examined the association between the MCT1 A1470T and the athletes' competition level ('elite' and 'national' level). DESIGN: The study involved endurance athletes (n=112), sprint/power athletes (n=100), and unrelated sedentary controls (n=621), all Caucasians. METHODS: Genomic DNA was extracted from buccal epithelium using a standard protocol. We conducted Fisher's exact tests and multinomial logistic regression analyses to assess the association between MCT1 genotype and athletic status/competition level. RESULTS: Sprint/power athletes were more likely than controls to possess the minor T allele (TT genotype compared to the AA [p<0.001]; TT or AT compared to the AA [p=0.007]; TT compared to both AA and AT genotypes [p<0.001]). Likewise, sprint/power athletes were more likely than endurance athletes to have the TT genotype compared to the AA (p=0.029) and the TT compared to both AA and AT genotypes (p=0.027). Furthermore, elite sprint/power athletes were more likely than national-level athletes to have the TT genotype compared to the AA (p=0.044), and more likely to have the TT genotype compared to both AA and AT genotypes (recessive model) (p=0.045). CONCLUSIONS: The MCT1 TT genotype is associated with elite sprint/power athletic status. Future studies are encouraged to replicate these findings in other elite athlete cohorts. PMID- 24485393 TI - Guidelines for safety in the gastrointestinal endoscopy unit. PMID- 24485394 TI - Design parameters for the separation of fat from natural whole milk in an ultrasonic litre-scale vessel. AB - The separation of milk fat from natural whole milk has been achieved by applying ultrasonic standing waves (1 MHz and/or 2 MHz) in a litre-scale (5L capacity) batch system. Various design parameters were tested such as power input level, process time, specific energy, transducer-reflector distance and the use of single and dual transducer set-ups. It was found that the efficacy of the treatment depended on the specific energy density input into the system. In this case, a plateau in fat concentration of ~20% w/v was achieved in the creamed top layer after applying a minimum specific energy of 200 kJ/kg. In addition, the fat separation was enhanced by reducing the transducer reflector distance in the vessel, operating two transducers in a parallel set-up, or by increasing the duration of insonation, resulting in skimmed milk with a fat concentration as low as 1.7% (w/v) using raw milk after 20 min insonation. Dual mode operation with both transducers in parallel as close as 30 mm apart resulted in the fastest creaming and skimming in this study at ~1.6 g fat/min. PMID- 24485395 TI - Role of H2O2 in the fluctuating patterns of COD (chemical oxygen demand) during the treatment of palm oil mill effluent (POME) using pilot scale triple frequency ultrasound cavitation reactor. AB - Palm oil mill effluent (POME) is a highly contaminating wastewater due to its high chemical oxygen demand (COD) and biochemical oxygen demand (BOD). Conventional treatment methods require longer residence time (10-15 days) and higher operating cost. Owing to this, finding a suitable and efficient method for the treatment of POME is crucial. In this investigation, ultrasound cavitation technology has been used as an alternative technique to treat POME. Cavitation is the phenomenon of formation, growth and collapse of bubbles in a liquid. The end process of collapse leads to intense conditions of temperature and pressure and shock waves which assist various physical and chemical transformations. Two different ultrasound systems i.e. ultrasonic bath (37 kHz) and a hexagonal triple frequency ultrasonic reactor (28, 40 and 70 kHz) of 15 L have been used. The results showed a fluctuating COD pattern (in between 45,000 and 60,000 mg/L) while using ultrasound bath alone, whereas a non-fluctuating COD pattern with a final COD of 27,000 mg/L was achieved when hydrogen peroxide was introduced. Similarly for the triple frequency ultrasound reactor, coupling all the three frequencies resulted into a final COD of 41,300 mg/L compared to any other individual or combination of two frequencies. With the possibility of larger and continuous ultrasonic cavitational reactors, it is believed that this could be a promising and a fruitful green process engineering technique for the treatment of POME. PMID- 24485396 TI - Effective ultrasound electrochemical degradation of methylene blue wastewater using a nanocoated electrode. AB - A novel sonoelectrochemical catalytic oxidation-driven process using a nanocoated electrode to treat methylene blue (MB) wastewater was developed. The nano-scale (nanocoated) electrode generated more hydroxyl radicals than non-nano-scale (non nanocoated) electrodes did. However, hydroxyl radicals were easily adsorbed by the nanomaterial and thus were not able to enter the solution. Supersonic waves were found to enhance the mass-transfer effect on the nanocoated electrode surface, resulting in rapid diffusion of the generated hydroxyl radicals into the solution. In solution, the hydroxyl radicals then reacted with organic pollutants in the presence of ultrasonic waves. The effect of the nanocoated electrode on the MB wastewater treatment process was enhanced by ultrasound when compared to the non-nanocoated electrode used under the same conditions. The synergy of the nanocoated electrode and ultrasonic waves towards MB degradation was then studied. The optimum operating conditions resulted in a 92% removal efficiency for TOC and consisted of a current of 600 mA, an ultrasound frequency of 45 kHz, and a supersonic power of 250 W. The mechanism of ultrasound enhancement of the nanocoated electrode activity with respect to MB treatment is discussed. The reaction intermediates of the sonoelectrochemical catalytic oxidation process were monitored, and degradation pathways were proposed. The sonoelectrochemical catalytic oxidation-driven process using nanocoated electrodes was found to be a very efficient method for the treatment of non-biodegradable wastewater. PMID- 24485397 TI - The dipeptidyl peptidase-4 inhibitor vildagliptin does not affect ex vivo cytokine response and lymphocyte function in patients with type 2 diabetes mellitus. AB - AIMS: The enzyme dipeptidyl peptidase-4 (DPP-4) is a key player in the degradation of incretin hormones that are involved in glucose metabolism. DPP-4 is also expressed on immune cells and is associated with several immunological functions. Some studies have reported increased rates of infections in patients treated with DPP-4 inhibitors. We therefore assessed whether treatment with the DPP-4 inhibitor vildagliptin affected cytokine production and T-cell differentiation. METHODS: Patients with type 2 diabetes were treated with vildagliptin or an active comparator, acarbose, for four weeks, in a randomized cross-over trial. Blood was sampled at the end of each treatment period and peripheral blood mononuclear cells were isolated and stimulated with a broad spectrum of pattern recognition receptor agonists. RESULTS: Serum cytokine concentrations and ex vivo cytokine production (both monocyte and T-cell derived) did not differ during treatment with vildagliptin compared to acarbose. Similarly, ex vivo relative upregulation of mRNA transcription of T-cell lineage specific transcription factors was unaffected by vildagliptin treatment. CONCLUSIONS: These data show that a four-week treatment with vildagliptin in patients with type 2 diabetes mellitus does not result in a significant modulation of cytokine responses. This observation suggests that inhibition of DDP-4 does not lead to an increased risk of infection by diminishing cytokine production. PMID- 24485398 TI - Adding glimepiride to insulin+metformin in type 2 diabetes of more than 10 years' duration--a randomised, double-blind, placebo-controlled, cross-over study. AB - AIMS: To investigate the effect on glycaemic control of adding glimepiride to on going treatment with metformin and insulin in patients with known diabetes more than 10 years. METHODS: Glimepiride 4 mg or placebo was added in randomised order for three months with a washout period of 6 weeks. All insulin regimens were allowed. Insulin doses were reduced if considered necessary. Continuous glucose monitoring was performed at the end of each period. RESULTS: Forty-three patients, median age 66 years (46-74), diabetes duration 16 (10-30), BMI 30 kg/m(2) (25-37) and mean HbA1c 7.1% NGSP, (64 mmol/mol IFCC) were randomised. With placebo there was no change in HbA1c while a decrease of 0.6%, (7 mmol/mol IFCC) (P < 0.001), was observed with glimepiride even though insulin doses had to be reduced in 23 patients (median change 29%, range 2-100%). Minor hypoglycaemia was reported but no severe hypoglycaemic event was observed. The ratio between C peptide/glucose increased significantly (P < 0.001) with glimepiride, both fasting and postprandially and, in a stepwise multiple regression analysis of possible predictive factors for response, a more pronounced decrease in HbA1c was associated with the magnitude of the increment in C-peptide/glucose. Older age was associated with a smaller response. Twenty-nine patients (67%) were defined as responders if this was defined as an HbA1c decrease >=0.5% (5 mmol/mol IFCC) or an insulin dose reduction >=20%. CONCLUSIONS: Even after long duration of diabetes, addition of glimepiride to insulin and metformin can be effective in lowering HbA1c and/or reducing the need for exogenous insulin. PMID- 24485399 TI - Gender-dependent associations of CDKN2A/2B, KCNJ11, POLI, SLC30A8, and TCF7L2 variants with type 2 diabetes in (North African) Tunisian Arabs. AB - We investigated the impact of gender on T2DM association with confirmed susceptibility loci. CDKN2A/2B rs10811661, KCNJ11 rs5219, and TCF7L2 rs7903146 were associated with T2DM in females, while POLI rs488846 was associated with T2DM among males; the association of SLC30A8 rs13266634 and TCF7L2 rs4506565, rs12243326, and rs12255372 with T2DM was gender-independent. PMID- 24485401 TI - The extrinsic coagulation cascade and tissue factor pathway inhibitor in macrophages: a potential therapeutic opportunity for atherosclerotic thrombosis. AB - OBJECTIVES: The coagulation protease cascade plays the central requisite role in initiation of arterial atherothrombosis. However, the relative participation of the extrinsic as compared to the intrinsic pathway is incompletely resolved. We have investigated in vivo the relative importance of the extrinsic and intrinsic pathways to define which is more essential to atherothrombosis and therefore the preferable prophylactic therapeutic target. We further addressed which type of plaque associated macrophage population is associated with the thrombotic propensity of atherosclerotic plaques. METHODS: Both photochemical injury and ferric chloride vascular injury models demonstrated arterial thrombosis formation in ApoE deficient mice. We found that direct interference with the extrinsic pathway, but not the intrinsic pathway, markedly diminished the rate of thrombus formation and occlusion of atherosclerotic carotid arteries following experimental challenge. To explore which plaque macrophage subtype may participate in plaque thrombosis in regard to expression tissue factor pathway inhibitor (TFPI), bone marrow derived macrophages of both M and GM phenotypes expressed tissue factor (TF), but the level of TFPI was much greater in M- type macrophages, which exhibited diminished thrombogenic activity, compared to type GM-macrophages. RESULTS AND CONCLUSIONS: Our works support the hypothesis that the TF-initiated and direct extrinsic pathway provides the more significant contribution to arterial plaque thrombogenesis. Activation of the TF driven extrinsic pathway can be influenced by differing colony-stimulating factor influenced macrophage TFPI-1 expression. These results advance our understanding of atherothrombosis and identify potential therapeutic targets associated with the extrinsic pathway and with macrophages populating arterial atherosclerotic plaques. PMID- 24485400 TI - Influence of factor 5 rs6025 and factor 2 rs1799963 mutation on inhibitor development in patients with hemophilia A--an Israeli-German multicenter database study. AB - OBJECTIVE: The present cohort study was performed to investigate the impact of the factor 5 rs6025 [F5] and the factor 2 rs1799963 [F2] mutations on high-titer inhibitor development [HRI] in patients with severe/moderate-severe hemophilia A [HA]. PATIENTS AND METHODS: 216 patients with F8<2% born between 1980 and 2011 were followed after initial HA diagnosis over the first 200 exposure days. The first HA patient per family who presented for diagnosis was included in the present study. RESULTS: 32 of 216 children [14.8%] tested for F5/F2 carried either the F5 or the F2 variant. HRI occurred in 14 out of 32F5/F2-carriers compared with 40 of 184 without F5/F2. Multivariate analysis adjusted for F8 genotype, treatment intensity, first-line use of plasma derived FVIII versus recombinant FVIII concentrates revealed that the presence of F5/F2 independently increases the risk of HRI development to odds [OR] of 3.4. Large deletions in the F8 gene [OR: 5.10], patients from Israel [OR: 4.0], the increase of FVIII per one IU/kgbw [OR: 1.05] and birth year [OR: 1.12] were significantly associated with the risk to develop HRI. CONCLUSION: Data presented here suggest that HRI development is of multifactorial origin and that F5 and F2 mutations may contribute to this risk. PMID- 24485402 TI - Residual vein thrombosis and onset of post-thrombotic syndrome: influence of the 4G/5G polymorphism of plasminogen activator inhibitor-1 gene. AB - BACKGROUND: Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades. In this prospective cohort analytic study, we investigated the role of this single nucleotide polymorphism in the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. PATIENTS/METHODS: In a group of 168 patients with post-surgical deep vein thrombosis of the legs, we analyzed the 4G/5G polymorphism in the promoter of PAI-1 gene and plasmatic PAI-1 activity. Enrolled patients were divided in two groups: patients with 4G/5G polymorphism and increased PAI-1 activity (n=85) and patients without 4G/5G polymorphism and normal PAI-1 activity (n=83). All patients were treated according to current protocols and re-examined after 3, 12 and 36 months in order to evaluate the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. RESULTS: We found a significantly increased PAI activity in carrier of the 4G allele, who experienced much more frequently a persistence of thrombosis after 3, 12 and 36 months and/or the development of post-thrombosis syndrome, in spite of the anticoagulant treatment. CONCLUSIONS: These data not only confirm the role played by PAI-1 activity and by the 4G/5G SNP of the PAI-1 gene, but also suggest that current therapeutic protocols, recommending the administration of low weight molecular heparin and oral anticoagulant for the treatment of deep vein thrombosis, could be non sufficient for patients genetically predisposed to a less efficient clot lysis. PMID- 24485403 TI - Modified cIg-FISH protocol for multiple myeloma in routine cytogenetic laboratory practice. AB - The International Myeloma Working Group recommends that fluorescence in situ hybridization (FISH) be performed on specifically identified plasma cells (PC). This is because chromosomal abnormalities are not frequently detected by traditional karyotyping due to the low proliferative rate of PC in multiple myeloma (MM). Conventional FISH enhances the sensitivity but lacks the specificity, as it does not distinguish PC from other hematopoetic cells. To fulfill this recommendation, PC need to be selected either by flow cytometry or immunomagnetic bead-based PC sorting or by concomitant labeling of the cytoplasmic immunoglobulin light chain, which allows for unambiguous identification. These techniques require expertise, time, and funding and are not easily incorporated into the routine workflow of the cytogenetic laboratory. We have modified and refined the technique using fixed cell pellets to achieve nicely separated and easily identifiable PC. With immunostaining and subsequent FISH (i.e., cytoplasmic immunoglobulin FISH, cIg-FISH), this technique can be easily incorporated into every cytogenetic laboratory. Twenty samples from patients with MM were subjected to routine FISH, cIg-FISH, and chromosomal karyotyping and the results were compared. Three FISH probes, which enabled detection of the t(4;14), t(14;16) and deletion of TP53, were used to validate this modified technique successfully. PMID- 24485405 TI - Mean platelet volume in children with attention deficit hyperactivity disorder. AB - The mean platelet volume (MPV), the accurate measure of platelet size, is considered a marker and determinant of platelet function. MPV can be a potentially useful prognostic biomarker in patients with cardiovascular disease. After reviewing literature, we hypothesized that attention deficit hyperactivity disorder (ADHD) in childhood may be a risk factor for coronary heart disease (CHD) in adulthood. The aim of this study was investigation of MPV and platelet count (PLT) in children with ADHD and healthy subjects. The MPV and the PLT were measured in 70 children with ADHD (aged 6-16 years), and compared with 41 healthy controls. The MPV was found to be significantly increased in ADHD group compared to control group (p=.006). There was no significant difference in the PLT between groups (p>.05). To our knowledge, this was the first study of investigating the levels of MPV and PLT in children with ADHD. Although significance and cause of increased MPV level in ADHD remain unclear in present study, further studies are warranted to investigate relationships among MPV, ADHD in childhood and CHD in adulthood. PMID- 24485404 TI - Single nucleotide polymorphism at alcohol dehydrogenase-1B is associated with risk of esophageal squamous cell carcinoma. AB - BACKGROUND: Esophageal squamous incidence in many developed countries has increased dramatically over last decades, while the underlying mechanism of the biogenesis of ES was still unknown. METHODS: Here, we investigate 1001 subjects with esophageal cancer recruited from the affiliated hospital of Shanghai Jiao Tong University from Jan. 1, 2001 to Feb. 2, 2004. Single nucleotide polymorphism (SNP) of alcohol dehydrogenase-1B (ADH1B) was performed, and the recombinant plasimd containing ADH1B was constructed. Then, the ADH1B was purified and the enzymatic activity was assayed according to the methodology of Quayle. Furthermore, the effect of ADH1B on proliferation of human esophageal squamous cell lines was determined and the underlying mechanism of ADH1B was investigated. RESULTS: Logistic regression analyses revealed that subjects carrying the GG variant homozygote had a significant 2.81-fold (adjusted OR = 2.81; 95% CI = 2.18 3.62) increased risk of esophageal cancer. We found that SNP of ADH1B (GG) significantly promotes cell proliferation in ESGG. ADH1B (GG) could down-regulate endogenous ADH1B expression at posttranscriptional level. Moreover, re-expression of ADH1B in cells transfected with ADH1B (AA) significantly inhibits cell proliferation. CONCLUSIONS: Our data implied that ADH1B (GG) could promote cell proliferation in human ESGG through regulating the enzyme activity of ADH1B. Therefore, we propose that ADH1B might be used as a therapeutic agent for human ESGG. PMID- 24485407 TI - Low birth-weight and risk for major depression: a community-based longitudinal study. AB - The current study examines the association between low birth weight and risk for major depression from early adolescence to early adulthood. It accounts for eight documented confounders, and depression within families. Data were analyzed from the National Longitudinal Survey of Youth 1979 on mothers and offspring. Major depression was assessed with the Center for Epidemiologic Studies Depression Scale Short-Form (CES-D-SF) among offspring (N=3398) biannually, from 2000 to 2010 (aged 14-25). Competing models were examined with survival analysis and Generalized Estimated Equations (GEE). CES-D-SF based major depression was reported by 33.46% (n=1137) of participants. Among persons with very low birth weight (<1500 g), 47.5% (n=19/40) were classified with CES-D-SF depression (OR=1.81, 95% CI=0.97, 3.39). Similar results were found with survival analysis (HR=1.97, 95% CI=0.97, 4.01). Among multiple offspring families, GEE modeling showed a similar trend. On aggregate (unadjusted OR=2.46, 95% CI=1.07, 5.63; adjusted OR=2.43, 95% CI=0.94, 6.23), and within families of mothers with CES-D SF depression (unadjusted OR=2.54, 95% CI=0.55, 11.66; adjusted OR=1.79, 95% CI=0.28, 11.42). Compelling evidence is lacking in favor of an association between very low birth weight (<1500 g), and suspected major depression from early adolescence to early adulthood after accounting for documented confounders. PMID- 24485406 TI - N-acetyl cysteine and selenium protects mercuric chloride-induced oxidative stress and antioxidant defense system in liver and kidney of rats: a histopathological approach. AB - Mercury exposure is second-most common cause of metal poisoning which is quite stable and biotransformed to highly toxic metabolites thus eliciting biochemical alterations and oxidative stress. The aim of present study describes the protective effect of selenium either alone or in combination with N-acetyl cysteine (NAC) against acute mercuric chloride poisoning. The experiment was carried out in male albino Sprague Dawley rats (n=30) which was divided into five groups. Group 1 served as control. Groups 2-5 were administered mercuric chloride (HgCl2: 12mol/kg, i.p.) once only, group 2 served as experimental control. Animals of groups 3, 4 and 5 were received N-acetyl cysteine (NAC: 0.6mg/kg, i.p.) and selenium (Se: 0.5mg/kg, p.o.) and NAC with Se in combination. Acute HgCl2 toxicity caused significant rise in serum alanine aminotransferase, aspartate aminotransferase, alkaline phosphatase, lactate dehydrogenase, albumin, bilirubin, gamma-glutamyl transpeptidase, cholesterol, triglycerides, protein, urea, creatinine, uric acid and blood urea nitrogen content. Animals also showed significantly higher mercury content in liver and kidney, significant rise in lipid peroxidation level with concomitant decrease in reduced glutathione content and the antioxidant enzyme activities of superoxide dismutase and catalase after HgCl2 exposure. Results of the present investigation clearly showed that combination therapy with NAC+Se provide maximum protection against mercury toxicity than monotherapy (alone treated groups) by preventing oxidative degradation of biological membrane from metal mediated free radical attacks. PMID- 24485408 TI - Is elevated norepinephrine an etiological factor in some cases of schizophrenia? AB - A number of hypotheses have been put forth regarding the etiology of schizophrenia, including the dopamine hypothesis, NMDA receptor hypofunction hypothesis, and others. A lesser known theory is that elevated noradrenergic signaling plays a causative role in the disease. This paper briefly re-examines the merits of this hypothesis, including as it relates to some recently published studies. Several lines of evidence are investigated, including: endogenous level studies of norepinephrine (NE); modulation of the disease by noradrenergic drugs; association of the disease with bipolar disorder and hypertension, since these latter two conditions may involve elevated NE transmission; and effects of psychological stress on the disease, since stress can produce elevated release of NE. For many of these lines of evidence, their relationship with prepulse inhibition of startle is examined. A number of these studies support the hypothesis, and several suggest that elevated NE signaling plays a particularly prominent role in the paranoid subtype of schizophrenia. If the hypothesis is correct for some persons, conventional pharmaceutical treatment options, such as use of atypical antipsychotics (which may themselves modulate noradrenergic signaling), may be improved if selective NE transmission modulating agents are added to or even substituted for these conventional drugs. PMID- 24485409 TI - Oman: a case for a sink of begomoviruses of geographically diverse origins. AB - Oman is a trading nation and intensive agriculture is only a recent phenomenon. Exotic geminiviruses have recently emerged as a constraint to horticultural crops, and can be traced to trade and human migration. Greater phytosanitary precautions need to be implemented to limit future problems and prevent their outward spread. PMID- 24485410 TI - Diabetes predicts long-term disability in an elderly urban cohort: the Northern Manhattan Study. AB - PURPOSE: There are limited data on vascular predictors of long-term disability in Hispanics. We hypothesized that (1) functional status declines over time and (2) vascular risk factors predict functional decline. METHODS: The Northern Manhattan Study contains a population-based study of 3298 stroke-free individuals aged 40 years or older, followed for median 11 years. The Barthel Index (BI) was assessed annually. Generalized estimating equations and Cox models were adjusted for demographic, medical, and social risk factors. Stroke and myocardial infarction occurring during follow-up were censored in sensitivity analysis. Secondarily, motor and nonmotor domains of the BI were analyzed. RESULTS: Mean age (standard deviation) of the cohort (n = 3298) was 69.2 (10) years, 37% were male, 52% Hispanic, 22% diabetic, and 74% hypertensive. There was a mean annual decline of 1.02 BI points (P < .0001). Predictors of decline in BI included age, female sex, diabetes, depression, and normocholesterolemia. Results did not change with censoring. We found similar predictors of BI for motor and nonmotor domains. CONCLUSION: In this large, population-based, multiethnic study with long-term follow-up, we found a 1% mean decline in function per year that did not change when vascular events were censored. Diabetes predicted functional decline in the absence of clinical vascular events. PMID- 24485411 TI - Parricide: a forensic approach. AB - Parricide is the act of murdering one's father (patricide), mother (matricide) or other close relative, but usually not children (infanticide). It is a rare event and little information is available on this topic. This study aims to increase knowledge about this phenomenon, promoting the timely detection of problematic cases and avoiding fatalities. A retrospective study based on the autopsy reports of parricide victims performed by the North Services of the National Institute of Legal Medicine and Forensic Sciences of Portugal between 2003 and 2011, as well as on the judicial outcome of each case, was performed. Seven cases of parricide were found, corresponding to 1.7% of all the homicides undergoing forensic evaluated. Victims and perpetrators were typically males. The assaults occurred all at home, in the presence of witnesses, and the perpetrator remained at the scene after the crime. The main alleged reasons were untreated psychiatric illness and financial conflicts in the cases of adult parricide, and attempts to protect the mother from intimate partner violence in younger ones. The judicial outcomes ranged from acquittal for nonimputability to conviction for murder, manslaughter or involuntary manslaughter. This study was carried out on a forensic sample and it is useful to implement strategies to prevent parricide. PMID- 24485412 TI - The clavicle bone as an alternative matrix in forensic toxicological analysis. AB - Although human blood is the reference medium in the field of forensic toxicology, alternative matrices may be required when traditional specimens are not available, especially in the investigation of cases involving decomposing remains. Clavicle bone may provide an appropriate sample of choice since it can easily be obtained at autopsy after the removal of the breastplate for the inspection of the thoracic viscera. To the author's knowledge, this is the first time that clavicle bone is used as an alternative matrix for the detection of drugs. The present study aimed to investigate the suitability of clavicle bone as an alternative matrix for the detection of opiates. Opiates were assayed using a gas chromatography-mass spectrometry in the selected ion monitoring mode. Morphine-d6, codeine-d6 and 6-MAM-d3 were used as internal standards for the determination of morphine, codeine and 6-MAM, respectively. A GC/MS method was developed and validated for the determination of opiates in clavicle samples. Morphine, codeine and 6-MAM were successfully separated in spiked samples allowing for their detection at low levels without interferences from the matrix. Chromatographic run time was 11 min and the tested linearity ranged from 5 to 500 ng/g (r2 > 0.99) for all analytes. The method was further applied in clavicle samples of drug-related cases. Its validation parameters and the application of the developed method in clavicle samples from drug addicts, prove its suitability for the detection of opiates and potentially other drugs. PMID- 24485413 TI - Estimation of stature from lengths of index and ring fingers in a North-eastern Indian population. AB - Forensic anthropology involves identification of human remains in a legal situation. Along with the other three parameters of forensic anthropology, i.e., age, sex and ethnicity, stature estimation is an essential element of medico legal investigations when identifications of unknown dismembered remains are involved. The present study was conducted with an aim to find the correlation between stature and the lengths of the index and ring fingers and to derive linear and multiple regression models for estimation of adult stature from the index finger and ring finger measurements. The subjects chosen for the study were composed of adult individuals belonging to the "Rajbanshi", an ethnic community of North-eastern India. A total of 500 adults (250 males and 250 females) aged between 18 years and 60 years took part in the study. All the measurements were taken using standard techniques. Stature, index finger length and ring finger length were significantly longer in the males than the females. The correlation coefficient (r) between stature and finger lengths was observed to be positive and statistically significant. Linear and multiple regression models were derived for estimation of stature from a length of index and ring fingers. The predictive accuracy of stature estimation was higher for the females than the males. It was observed that the values of the correlation coefficient (r) and the coefficient of determination (R(2)) increased in multiple regression models when compared to the linear regression models. The study also focuses on the usability of sex specific regression models in forensic casework. The study concludes that such regression models, as those derived in the present work, can be of significant utility in the estimation of stature. PMID- 24485414 TI - Patterns of suicide in Brunei Darussalam and comparison with neighbouring countries in South East Asia. AB - A retrospective study of suicides in Brunei Darussalam (Brunei) over a 20 year period from 1991-2010 was conducted by analysing the post-mortem examination and external examination reports and other relevant records. The suicide rate in Brunei is very low (1.9 deaths per 100,000 per year). The majority of the victims were expatriates 82(66%) and hanging was the commonest mode of suicide both in expatriate and local population. The study showed that the suicide rate among the Bruneian Malays was the lowest (0.5 deaths per 100,000 per year) among the different nationalities. The study highlights the demographics and socio-economic background of the victims, methods used in committing suicide, suicide rates in different ethnic groups and predisposing factors. The results of this study would be of use for taking preventive measures to minimize the incidence of suicide. PMID- 24485415 TI - Inmate-to-inmate violence as a marker of suicide attempt risk during imprisonment. AB - OBJECTIVES: To estimate the incidence of suicide attempts during imprisonment in a French prison and to determine factors associated with them. METHODS: All male inmates of a prison for prisoners awaiting trial or serving a short sentence (Bordeaux, France) were eligible for this cross-sectional study. They were face to-face interviewed by an experienced psychologist (n = 369; mean age = 36 years). Socio-demographic data, imprisonment conditions, health status, healthcare utilization, mental health, impulsiveness, inmate-to-inmate violence (victim and perpetrator status) and suicidal behaviours were documented. RESULTS: The incidence of suicidal attempts during imprisonment was 13.4 per 100 person years. Having made at least one suicide attempt during imprisonment was associated with: being a victim of physical or sexual violence without perpetrating it (adjusted OR = 5.4; 95%CI [2.4-12]), suffering from depressive and anxious symptoms (adjusted OR = 3.3; 95%CI [1.5-7.7]), having children (adjusted OR = 3.0; 95%CI [1.2-7.7]) and having a poor perceived health status (OR = 2.5; 95%CI [1.1-5.4]). A history of suicide attempt before imprisonment was not associated with the risk of suicide attempts while imprisoned. CONCLUSION: Our results suggest that violence plays a major role in the suicidal process in prison. The inclusion of inmate-to-inmate violence in the screening checklists of inmate suicide risk should be explored. PMID- 24485416 TI - The applicability of Greulich and Pyle atlas to assess skeletal age for four ethnic groups. AB - BACKGROUND: Recently, determination of skeletal age, defined as the assessment of bone age, has rapidly become an important task between forensic experts and radiologists. The Greulich-Pyle (GP) atlas is one of the most frequently used methods for the assessment of skeletal age around the world. After presentation of the GP approach for the estimation of the bone age, much research has been conducted to examine the usability of this method in various geographic or ethnic categories. This study investigates on a small-scale and compares the reliability of the GP atlas for assessment of the bone age for four ethnic groups - Asian, African/American, Caucasian and Hispanic - for a different range of ages. MATERIALS AND METHODS: Plain radiographs of 184 left hands and wrists for males from the healthy sample between 1 to 18 years of age for four ethnic groups were taken. The skeletal age (SA) was estimated by a radiologist using the GP atlas. The blind method was utilized. The mean (SA) results were compared with mean chronological ages (CA) for the separate ethnic groups. SPSS was used to conduct the analysis and the paired t-test was applied to show the difference between the mean CA and mean SA achieved from the GP atlas. RESULTS: The results from the GP atlas were compared to the CA of the samples. In Asian subjects the mean difference was 0.873 years. The GP atlas showed delayed bone age at 2-7 ages (from 0.2 to 2.3 year) and then advanced bone age for age 8. In the African/American subjects the difference between CA and SA was statistically significant (P-value = 0.048). The mean difference in the Caucasian and Hispanic subjects reflects no considerable distinction with a standard deviation (SD) of 0.3088 and 0.3766, respectively, (P-value >0.05 for both groups). CONCLUSION: According to the present study, it is concluded that although the GP atlas is reliable for Caucasian and Hispanic ethnic groups it is not applicable for other ethnic groups for different ranges of age, especially in the sample of the male African/American group from 8 years to 15 years and Asian during childhood. Although it is not clear whether the other references are more useful than this standard, we believe that some enhancement is vital for the GP atlas to obtain more consistent results. PMID- 24485417 TI - Issues in the diagnosis of hypothermia: a comparison of two geographically separate populations. AB - A review of hypothermic deaths was undertaken using cases from the Charite University, Berlin, Germany and Forensic Science South Australia, Australia. There were 16 cases from Berlin (age range 38-96 years; average 68 years; M:F = 13:3) Wischnewski spots were present in all 16 cases (100%), skin discolouration in nine (56%), and acute pancreatitis and muscle haemorrhage in one case each (6%). There were 62 Australian cases (age range 30-89 years; average 67 years; M:F = 13:18). Wischnewski spots were present in 57 (92%), skin discolouration in seven (11%), vacuolization of renal cells in six (10%), and acute pancreatitis in one (2%). Reporting of the pathological findings in hypothermia may vary among jurisdictions influenced by the location and nature of these deaths and also by reliance on particular features to make the diagnosis. In addition, it is possible that the aetiology of these markers is quite complex and involves not only a significant reduction in core temperature, but the variable and poorly understood interaction of a number of other factors. PMID- 24485418 TI - Autopsy practice in forensic pathology - evidence-based or experience-based? a review of autopsies performed on victims of traumatic asphyxia in a mass disaster. AB - Current autopsy practice in forensic pathology is to a large extent based on experience and individual customary practices as opposed to evidence and consensus based practices. As a result there is the potential for substantial variation in how knowledge is applied in each case. In the present case series, we describe the variation observed in autopsy reports by five different pathologists of eight victims who died simultaneously from traumatic asphyxia due to compression during a human stampede. We observed that there was no mention of the availability of medical charts in five of the reports, of potentially confounding resuscitation efforts in three reports, of cardinal signs in seven reports and of associated injuries to a various degree in all reports. Further, there was mention of supplemental histological examination in two reports and of pre-autopsy radiograph in six reports. We inferred that reliance on experience and individual customary practices led to disparities between the autopsy reports as well as omissions of important information such as cardinal signs, and conclude that such reliance increases the potential for error in autopsy practice. We suggest that pre-autopsy data-gathering and the use of check lists specific to certain injury causes are likely to result in less deviation from evidence-based practices in forensic pathology. Pre-autopsy data-gathering and check lists will help ensure a higher degree of standardization in autopsy reports thus enhancing the quality and accuracy of the report as a legal document as well as rendering it more useful for data-gathering efforts. PMID- 24485419 TI - Suicide of physicians in the special wards of Tokyo Metropolitan area. AB - Numerous studies on physician suicide in various countries have been reported but no data from Japan on the issue can be found to date. In this study, physician suicides in the special wards of Tokyo Metropolitan area in 1996-2010 were investigated retrospectively. A total of 87 cases were enrolled. The results suggested that physician suicide has been linked to pre-existing psychiatric illnesses and occupational problems, and that psychiatrists have a relatively higher suicide risk compared to those majoring in other specialities of medicine. A distinctive feature was that 19 cases had used either drugs or devices which were accessible due to their profession some time during the process of committing suicide. Another notable feature was that 4 out of 5 anaesthesiologists enrolled in the study had chosen poisoning for their suicide method, with the drugs frequently used in their speciality. The findings advocate strongly for efficient suicide prevention measures for physicians including an early detection and treatment of psychiatric illnesses, as well as an urgent need for a more effective pharmacy management in applicable institutions together with the implementation of self discipline on each physician. This is the first broad academic study on physician suicide in Japan. PMID- 24485420 TI - A fatal iatrogenic right vertebral injury after transoral odontoidectomy and posterior cervical stabilization for a type II odontoid fracture. AB - The authors present a singular case of an iatrogenic right vertebral artery injury, involving a 67 year-old man, who reported a type II odontoid fracture (Anderson and D'Alonzo Classification) and posterior atlantoaxial dislocation following a road traffic accident. A small injury involving the right vertebral artery occurred as a consequence of transoral odontoidectomy and posterior cervical stabilization. It was caused by bone spicules of spinal origin and their presence was confirmed by the histological section of the right vertebral artery at the level of C1-C2. The case confirms how iatrogenic vertebral artery injuries during cervical spine surgery may be potentially lethal, especially where complications arise some days after surgery. PMID- 24485421 TI - Role of oral fluids in DNA investigations. AB - The assay of oral fluid (OF), a biofluid historically well-studied biochemically and physiologically, is a growing area of research with implications for basic and clinical purposes. In the last decade, it has gained considerable attention and lately, the use of OF has provided a substantial addition as an investigative tool in forensic and/or legal procedures. This article is an appraisal of various applications of OF sourced DNA in the field of forensic analysis. We have discussed the significance of different collection methods and their variations along with the application of specific analytical methods based on the condition of the sample. It is likely that the germaneness of OF assays will continue to expand thus providing a new instrument for investigation in criminal/legal proceedings. PMID- 24485422 TI - Perceptions and practices of medical practitioners towards ethics in medical practice - a study from coastal South India. AB - Ethics is the application of values and moral rules to human activities. Medical practitioners are expected to not only have the skills and knowledge relevant to their field but also with the ethical and legal expectations that arise out of the standard practices. The present research was conducted with an aim to study the perceptions and practices of medical practitioners towards healthcare ethics in Indian scenario and to strengthen the evidence in the field of ethics training. A cross-sectional study was carried out in three associate hospitals of a Medical College in Southern India. Medical practitioners included in the study were administered a pre-tested, semi-structured questionnaire. Data was collected based on their responses on a 5 point Likert scale and analyzed using SPSS version 11.5. The majority of the participants mentioned that their perceptions of ethics in medical practice were based on information obtained during their undergraduate training, followed by experience at work. The medical practitioners had a positive perception on issues relating to consent in medical practice. However, the same degree of perception was not observed for issues related to confidentiality and their dealing with patients during emergency conditions. The majority of the medical practitioners agreed that ethical conduct is important to avoid legal and disciplinary actions. Among the medical practitioners, the responses of specialists and non-specialists were mostly similar with major differences of opinion for a few issues. A highest level of knowledge, awareness and understanding of ethics are expected in medical practice as it is the foundation of sound healthcare delivery system. PMID- 24485423 TI - Pesticide poisoning trend analysis of 13 years: a retrospective study based on telephone calls at the National Poisons Information Centre, All India Institute of Medical Sciences, New Delhi. AB - The study was designed to analyze the incidence and pattern of pesticide poisoning calls reported to the National Poisons Information Centre (NPIC), AIIMS, New Delhi and highlight the common classes of pesticides involved in poisoning. The telephone calls received by the Centre during the thirteen year period (1999-2012) were entered into a preset proforma and then into a retrievable database. A total of 4929 calls of pesticide poisoning were recorded. The data was analyzed with respect to age, gender, mode and type of poisoning. The age ranged from 1 to 65 years with the preponderance of males (M = 62.19%, F = 37.80%). The age group mainly involved in poisoning was 18-35 years. While 59.38% calls pertained to household pesticides, 40.61% calls related to agricultural pesticides. The common mode of poisoning was intentional (64.60%) followed by accidental (34.40%) and unknown (1%). Amongst the household pesticides, the highest number of calls were due to pyrethroids (26.23%) followed by rodenticides (17.06%), organophosphates (6.26%), carbamates (4.95%) and others (4.86%). In agricultural pesticides group, the organophosphates (9.79%) ranked the first followed by, aluminium phosphide (9.65%), organochlorines (9.31%), pyrethroids (3.87%), herbicides, weedicides and fungicides (3.20%), ethylene dibromide (2.82%), and others (1.70%). The data analysis shows a high incidence of poisoning due to household pesticides as compared to agricultural pesticides, clearly emphasizing the need for creating awareness and education about proper use and implementation of prevention programmes. PMID- 24485424 TI - Determination of clozapine in hair and nail: the role of keratinous biological materials in the identification of a bloated cadaver case. AB - Keratinous biological materials, such as hair and nails, offer a substantially longer retrospective window of detection compared to other body fluids. Little research on drug analysis in nails is currently being conducted. In this study, the hair and nails from a bloated cadaver was analyzed. The study showed that the forensic toxicology results of keratinous biological materials could provide valuable clues for solving cases. In this study, a method was developed for the extraction and analysis of clozapine from hair and nails. The keratinous bio samples were washed and then pulverized using a freeze mill. After ultrasonic bath extraction, the supernatants were analyzed by ultra-performance liquid chromatography tandem mass spectrometer (UPLC-MS/MS). The method presented in this study proved to be reliable, specific, selective and sensitive with high precision and accuracy. Clozapine was found in both hair and nails from a long term user's remains, even after serious decomposition. The mean concentration of clozapine in the hair was 322.9 pg/mg and 138.3 pg/mg in the nails. Toxicological results helped police narrow the scope of the investigation and improved the efficiency of the breaking of the case. The findings of the present study demonstrated that the method can be used in forensic investigation. Toxicological results increased the efficiency of cadaver identification and the solving of the case. The study demonstrated that hair and nail analysis could provide vital clues for solving cases and showed the value of keratinous biological materials in the forensics field. PMID- 24485425 TI - Forensic age estimation in living subjects based on ultrasound examination of the ossification of the olecranon. AB - Radiation-free imaging procedures for the purposes of forensic age diagnosis are highly desirable, especially for children. With this in mind, the stage of ossification of the olecranon was prospectively determined in 309 male and 307 female healthy volunteers aged between 10 and 25 years, based on ultrasound. A four-stage classification system was used for this purpose. This stage classification system takes into account whether an isolated secondary ossification centre, an epiphyseal cartilage or an epiphysis which is completely fused with the diaphysis can be detected. The earliest observation of stage 2 was at 10.0 years in males and 10.1 years in females. Both findings are determined by the lower age limit of the sample and are thus not representative of the minimum age for ossification stage 2. Stage 3 was first noticed at age 13.5 years in males and 10.6 years in females. Stage 4 was first reached at age 13.7 years in males and 12.3 years in females. Hence, in our sample, ossification stage 3 can be seen as evidence that females have reached the age of 10 years and males the age of 13 years. In our sample, stage 4 provides evidence that a female individual has reached the age of 12 years. It was concluded that the results of our study should be validated using other samples. PMID- 24485426 TI - Heat-related deaths in Adelaide, South Australia: review of the literature and case findings - an Australian perspective. AB - Heat waves are not uncommon in Australia, but the event of 2009 was particularly severe and ranks third of the 21 recorded heat wave events in south-eastern Australia in terms of the resulting mortality and morbidity. This is a review of Coronial autopsy findings in South Australia (which has an area of nearly 1 million square kilometres with a population of 1.6 million that predominantly resides within the region of the capital: Adelaide) during the period of the 2009 heat wave. Fifty-four post-mortem examinations were performed on cases in which exposure to high ambient temperature was regarded as having caused or significantly contributed to the death. The findings (including results of toxicological and biochemical analyses, where available) are reviewed and compared with the post-mortem examination findings in 22 deaths over the same period not attributed to the effects of heat. There were no specific autopsy findings that distinguished heat-related from non heat-related deaths. The lack of specific post-mortem findings increases the reliance on scene investigation in order to be able to categorise a death as being heat-related. A checklist for scene investigators is proposed in order to assist with collection of relevant data to assist the Coronial investigation process. PMID- 24485427 TI - A multidisciplinary approach to fatal dog attacks. PMID- 24485428 TI - Injuries over neck in hanging deaths and its relation with ligature material: is it vital? AB - Hanging is a common suicidal means adopted. Careful inspection and noting of ligature mark is a vital factor during medico-legal postmortem. Ligature material used by the deceased is an important factor causing ligature mark in hanging. Apart from the ligature mark there are other injuries over neck surrounding it, which are called as 'peri-ligature injuries'. Peri-ligature injuries such as blisters, bruise, abrasion, etc. are influenced by different types of ligature material involved. These peri-ligature injuries are important for commenting on the antemortem nature of hanging in addition to other factors. Thus the present study on hanging deaths was carried out to see the relation of ligature material and different injuries occurring over the neck. PMID- 24485429 TI - Homicide in Brescia County (Northern Italy): a thirty-year review. AB - This retrospective study analyses post-mortem examination data of 251 homicide victims recorded by the Brescia Institute of Forensic Medicine between the years 1982 and 2012. The following variables were considered: year, month and day of death; gender, age and nationality of the victim; type of injurious mean; cause of death; homicide-suicides events; multiple murders; scene of death; toxicological data. Victims were usually young (30% was in the 21-30 years class) and males (64%). Although the victims were mostly Italians (73%), from 1990's more and more foreign victims appeared, following the migratory flow that affected Brescia County. The offenders frequently used firearms to kill their victims (41%), in particular for multiple murders. Sharp instruments were used mostly by foreigners. The study also emphasized 20 homicide-suicide events, mostly committed between intimates and family members. PMID- 24485430 TI - Subarachnoid hemorrhage caused by a traffic accident: de novo aneurysm ruptured 30 years after surgical neck clipping. AB - A man, who had a medical history of surgical neck clipping 30 years previously, died of traffic accident. The medico-legal autopsy showed subarachnoid hemorrhage and ruptured aneurysm on the lateral side of the clip. Microscopic examination showed the aneurysm was not to be regeneration, but a new de novo aneurysm. We diagnosed the cause of death was traumatic aneurysmal rupture. In addition, we discussed the cause of a newly formed de novo aneurysm which may be affected by past surgical neck clipping. PMID- 24485431 TI - Forensic physicians and written evidence: witness statements v. expert reports. AB - When assisting the courts in criminal proceedings, the work of forensic physicians are leaning more towards the preparation of written evidence rather than the giving of oral evidence in person. For this, they may be asked to serve either as professional witnesses or expert witnesses. These 2 roles have nevertheless been a constant source of confusion among forensic physicians. In view of this, the article aims to highlight the similarities and differences between these 2 roles particularly in relation to the preparation of written evidence. It will take a close look at the forms of written evidence which forensic physicians are expected to produce in those distinct capacities and the attending duties, evidentiary rules and legal liabilities. Through this, the work aspires to assist forensic physicians undertake those responsibilities on a more informed footing. PMID- 24485432 TI - Evaluation of the morphological changes of gastric mucosa induced by a low concentration of acetic acid using a rat model. AB - Oral ingestion of concentrated acetic acid causes corrosive injury of the gastrointestinal tract. To assess the effects of a low concentration of acetic acid on gastric mucosa, we examined the gastric mucosal changes in rats at 1 and 3 days after the injection of 5% or 25% acetic acid into the gastric lumen. The area of the gastric ulcerative lesions in the 25% acetic acid group was significantly larger than that in the 5% acetic acid group. The lesion area was reduced significantly at 3 days after injection in the 5% acetic acid group, whereas no significant difference in lesion area was observed at 1 and 3 days in the 25% acetic acid group. Histologically, corrosive necrosis was limited to the mucosal layer in the 5% acetic acid group, whereas necrosis extended throughout the gastric wall in the 25% acetic acid group. At 3 days post-injection, the 25% acetic acid group showed widespread persistent inflammation, whereas the 5% acetic acid group showed widespread appearance of fibroblasts indicative of a healing process. These results indicate that a low concentration of acetic acid damages the gastric mucosa and that the degree of mucosal damage depends on the concentration of acetic acid. PMID- 24485433 TI - Sudden death due to ruptured pseudoaneurysm of femoral artery in injected drug abusers - report of four cases at autopsy and review of literature. AB - Pseudoaneurysm in injected drug abusers occurs due to traumatic damage by the repeated injections and infections. It most commonly involves the femoral artery that requires intensive management. When medical attention is delayed, the victim is prone to have massive bleeding from the ruptured artery, resulting in death. Although pseudoaneurysms in injected drug abusers are known, there is paucity of autopsy study on sudden deaths due to its rupture. We report four such cases with different presentations of the pseudoaneurysm that had ruptured spontaneously. The paper highlights the case history and autopsy findings of these cases with review of literature of this catastrophic event in injected drug abusers. PMID- 24485434 TI - Fatal aorto-esophageal fistula in child: a case report. AB - Esophageal foreign body ingestion is especially frequent in childhood and may cause fatal complications in case of late diagnosis and delayed treatment. We present a case of 2-year old girl who was admitted to emergency department with massive bleeding. However, she died due to an unrecognized foreign body resulted an aorto-esophageal fistula. At autopsy an aorto-esophageal fistula was detected by gross examination. Tissue samples were obtained from the organs and fistula region. In histopathological examination, a calcified body with multinucleated giant cell and surrounding granulation tissue was detected at the bleeding site. An ulcerated fistula tract ran from the intima to the adventitia, passing through layers of esophageal wall was also noticed. The mortality rate for foreign body ingestion is less than 1%, except in cases of perforation. Therefore the presented case is among rare examples of fatal foreign body ingestions. PMID- 24485435 TI - Soft tissue thickness in young north eastern Brazilian individuals with different skeletal classes. AB - The aim of this study was to evaluate the variation in facial soft tissue thickness in young north eastern Brazilian individuals according to gender and skeletal class. Measurements were obtained from digitized teleradiographs of 300 children, aged from 8 to 12 years, using the Sidexis Xg program. Data of mean, standard deviation, maximum and minimum soft tissue thickness values of the faces of Angle's Class I, II and III individuals, were evaluated. The results demonstrated that there was no difference in soft tissue thickness among the skeletal classes for most of anthropological points. For the Class I, statistical differences were found (P < 0.05) between the genders in the rhinion point, subnasal and upper lip. It was concluded that there was no difference in soft tissue thickness among the skeletal classes, except between Class II and III for the points: Stomion, Bottom lip and Pogonion, allowing definition of parameters of this population for the purpose of facial reconstruction. PMID- 24485436 TI - Analysis of complaints lodged by patients attending a university hospital: a 4 year analysis. AB - OBJECTIVE: Health practitioners often regard complaints concerning the quality of patient care in a negative light. However, complaints by patients and their relatives are an important source of information when considering ways in which to improve care. In the present study, we evaluated the complaints of patients and their relatives with regard to our hospital, such that we could take adequate remedial measures. METHOD: Records of all patient complaints made between June 2008 and June 2012 were retrieved from the archives of the Quality Improvement Unit. The socio-demographic profiles of complainants, and their reasons for complaining, were analyzed using the SPSS statistical package. RESULTS: The results revealed that 453 complaints, relating to medical care, the attitude of staff, waiting times, and financial issues, were made against our hospital over 4 years. Of the complainants, 68.9% (n = 312) were male, and 31.1% (n = 141) were female. The majority (16.3% and 20.4%, respectively) of the complaints were due to medical care and staff attitude problems. The unit about which most patients complained was hospital administration (22.1%), and one hundred fifty-three (33.8%) complaints were about physicians. Complaint frequency was 0.22 per 1.000 visits. CONCLUSION: Complaints may be potentially useful quality assurance tools, and can identify system flaws. The primary causes of complaints were medical care, attitude of the staff, and waiting time, and many of these issues may be remedied. PMID- 24485437 TI - Elbow dislocation secondary to fall during police arrest. AB - A case of total elbow dislocation with significant swelling and loss of distal pulses during police arrest is described. To date, this specific injury in relation to police arrest has not been described in the literature. Whilst attempting to remove the detainee from a public transport vehicle, the patient and the officers involved fell to the ground with his arm slightly flexed. He was handcuffed to the rear and taken to the police office. Whilst there, it was noted that his left elbow was swelling dramatically and he complained of pain. The detainee and officers attended the emergency room and he was found to have a total dislocation of the left elbow and vascular compromise of the limb. The elbow was promptly reduced with sedation and a post reduction angiogram demonstrated injury to the tissues surrounding the brachial artery. PMID- 24485438 TI - A method of calculating human deciduous crown formation times and of estimating the chronological ages of stressful events occurring during deciduous enamel formation. AB - Knowledge of deciduous crown formation times is useful in forensic anthropology and when aging juvenile remains from an archaeological context. Until now, histological techniques for calculating enamel formation times in deciduous teeth have been completely dependent on being able to visualise clear daily incremental markings. In the first part of this study we took twenty deciduous teeth where daily incremental markings were easily visible on both aspects of the crown and used these as the basis for generating regression equations to predict enamel formation times. We were then able to use these regression equations to calculate deciduous crown formation times in a further fifty deciduous teeth where it was not possible to see daily increments. We present here new data for deciduous crown formation times based on these regression equations. In the second part of this study these regression formulae were applied blind to teeth from two individuals with known medical histories. The formulae were able to successfully determine the times of prenatal and postnatal enamel formation relative to the neonatal line and also to correctly estimate the ages at which accentuated 'stress lines' occurred during the period of deciduous crown formation. PMID- 24485440 TI - Response to "significance of descriptive statistics in forensic anthropology research", published in the November 2013 issue of the Journal of Forensic and Legal Medicine. PMID- 24485439 TI - A case of atypical chronic subdural hematoma: a spontaneous rupture of dural lymphoma nodule. AB - In forensic medicine, a chronic subdural hematoma (SDH) usually results from trauma, sometimes minimal for elderly people. The case reported here is a forensic medical description of an atypical chronic subdural hematoma. A woman aged of 40-year-old died following a coma. The autopsy and histological analyses revealed the hemorrhagic disintegration of a lymphoid nodule, a metastasis from generalized lymphoma. The combination of chronic symptomatic SDH and a tumor of the dura mater have been described, but are very rare. The possibility of trauma, even minimal, has never been excluded in these cases. In fact, the clinical picture of these patients suggested a significant movement of the brain within the cranial cavity due to the physiological decrease in brain volume. In the reported case, this particular process was excluded since the spontaneous hemorrhagic effusion produced by the meningeal lymphoid nodule was the cause of the chronic SDH. This pathophysiological explanation was possible because the entire brain and meninges were removed for histological analysis. Trauma, even minimal trauma, is not always involved in the formation of a chronic SDH. PMID- 24485441 TI - Sex determination using mandibular anthropometric parameters in subadult Iranian samples. AB - INTRODUCTION: Sex determination is the first step in the identification of corpses and skeletal remains. The mandible is the largest and strongest bone of the face and has high durability. It is known that skeletal features vary by population, thus the need to establish population-specific standards. In this study, for the first time, we investigated mandibular anthropometric parameters for sex determination in subadult Iranian cadavers. METHODS: Eight mandibular anthropometric parameters were measured in 45 Iranian cadavers below the age of 20 (23 males and 22 females corpses), and the relationships of these variables with gender were determined. Collected data were analyzed using descriptive analysis, ROC curve, cross tabulation and discriminant analysis in SPSS 13. RESULTS: No significant statistical difference was seen in the mandibular anthropometric values between the two genders in samples below the age of 12. In the 12-19 age group, accuracy of symphysial height and bigonial breadth in differentiation of gender was 69% and 86.2% respectively. CONCLUSION: Although mandibular anthropometric parameters are not helpful in sex determination below the age of 12, if for some reasons such as explosions, air disasters and other accidents, only the mandible is available, symphysial height and mandibular bigonial breadth could be used to determine the gender with high accuracy. PMID- 24485442 TI - Stability of lip-print patterns: a longitudinal study of Saudi females. AB - Lip-print groove patterns have recently been verified as a unique parameter for identification. This study investigated the stability of lip-print patterns over time to validate their secure use in civil and criminal investigations. One hundred and sixteen female lip prints were analyzed and compared with the prints of the same subjects taken 3 years earlier. The old and new lower lip prints of each subject were examined for similarities in the groove patterns in different areas of the lip (lower right, lower middle and lower left), and a score for similarity was developed for the statistical analysis of the lower lip stability data. No significant difference in the frequency of pattern types was detected between old and new prints (P > 0.05). Statistically, 89.6% of subjects showed characteristic typical groove(s) in the lip area(s) of the old and corresponding new prints: 24.1% in the three areas, 48.3% in two areas and 17.2% in one area. This study proves the lasting stability of lip-print patterns over the years in Saudi females and recommends paying attention to the presence of characteristic typical grooves in these prints. Further studies on larger samples, including male prints, should be performed to validate the lip prints for criminal use. PMID- 24485443 TI - Lumbar disc herniation and cauda equina syndrome following spinal manipulative therapy: a review of six court decisions in Canada. AB - The purpose of this review is to expand practitioners' knowledge on areas of liability when treating low back pain patients. Six cases where chiropractors in Canada were sued for allegedly causing or aggravating lumbar disc herniation after spinal manipulative therapy were retrieved using the CANLII search database. The case series involves 4 men and 2 women with an average age of 37.3 years (range, 31-48 years). Trial courts' decisions were rendered between 2000 and 2011. This study highlights the following conclusions from Canadian courts: 1) informed consent is an ongoing process that cannot be entirely delegated to office personnel; 2) when the patient's history reveals risk factors for lumbar disc herniation the chiropractor has the duty to rule out disc pathology as an etiology for the symptoms presented by the patients before beginning anything but conservative palliative treatment; 3) lumbar disc herniation may be triggered by spinal manipulative therapy on vertebral segments distant from the involved herniated disc such as the thoracic spine. PMID- 24485444 TI - Long-distance migration and colonization of transplanted neural stem cells. PMID- 24485445 TI - Neural stem cell dissemination after grafting to CNS injury sites. PMID- 24485446 TI - Golgi feels DNA's pain. AB - The Golgi apparatus consists of disc-like cisternae, stretching around the nucleus through forces exerted by F-actin and the Golgi membrane protein GOLPH3. Farber-Katz et al. now report that DNA damage triggers Golgi dispersal and inhibits vesicular transport through DNA-PK-mediated GOLPH3 phosphorylation, thereby linking the DNA damage response to Golgi regulation. PMID- 24485447 TI - The changing lipidome during cell division. AB - Cell division entails dramatic membrane rearrangements, but what is the role of lipids in the process? Eggert et al. explore the dynamics of the lipidome during cell division and provide new insights on the functions of specific lipids in cytokinesis. PMID- 24485448 TI - Mom's milk molds neural wiring for metabolism. AB - Vogt et al. demonstrate that, in mice, maternal high-fat feeding during lactation is sufficient to program the offspring for impaired energy and glucose homeostasis throughout their lifetime. They reveal that the resulting abnormal insulin signaling in the offspring interferes with the formation of hypothalamic neural circuits that contribute to metabolic status. PMID- 24485449 TI - Sex-specific aging in flies, worms, and missing great-granddads. AB - Two recent studies identify how sex-specific pheromonal factors in flies and worms alter lifespan through metabolic pathways that are shared with mammals. Sex differences in human lifespans imply nonautonomous effects modulated by sex specific gene-environment interactions that could still include pheromonal mechanisms. PMID- 24485450 TI - Progeria: a paradigm for translational medicine. AB - Rare diseases are powerful windows into biological processes and can serve as models for the development of therapeutic strategies. The progress made on the premature aging disorder Progeria is a shining example of the impact that studies of rare diseases can have. PMID- 24485451 TI - You are what you host: microbiome modulation of the aging process. AB - The critical impact that microbiota have on health and disease makes the interaction between host and microbiome increasingly important as we evaluate therapeutics. Here, we highlight growing evidence that, beyond disease, microbes also affect the most fundamental of host physiological phenotypes, the rate of aging itself. PMID- 24485452 TI - DNA damage triggers Golgi dispersal via DNA-PK and GOLPH3. AB - The response to DNA damage, which regulates nuclear processes such as DNA repair, transcription, and cell cycle, has been studied thoroughly. However, the cytoplasmic response to DNA damage is poorly understood. Here, we demonstrate that DNA damage triggers dramatic reorganization of the Golgi, resulting in its dispersal throughout the cytoplasm. We further show that DNA-damage-induced Golgi dispersal requires GOLPH3/MYO18A/F-actin and the DNA damage protein kinase, DNA PK. In response to DNA damage, DNA-PK phosphorylates GOLPH3, resulting in increased interaction with MYO18A, which applies a tensile force to the Golgi. Interference with the Golgi DNA damage response by depletion of DNA-PK, GOLPH3, or MYO18A reduces survival after DNA damage, whereas overexpression of GOLPH3, as is observed frequently in human cancers, confers resistance to killing by DNA damaging agents. Identification of the DNA-damage-induced Golgi response reveals an unexpected pathway through DNA-PK, GOLPH3, and MYO18A that regulates cell survival following DNA damage. PMID- 24485453 TI - Lung stem cell differentiation in mice directed by endothelial cells via a BMP4 NFATc1-thrombospondin-1 axis. AB - Lung stem cells are instructed to produce lineage-specific progeny through unknown factors in their microenvironment. We used clonal 3D cocultures of endothelial cells and distal lung stem cells, bronchioalveolar stem cells (BASCs), to probe the instructive mechanisms. Single BASCs had bronchiolar and alveolar differentiation potential in lung endothelial cell cocultures. Gain- and loss-of-function experiments showed that BMP4-Bmpr1a signaling triggers calcineurin/NFATc1-dependent expression of thrombospondin-1 (Tsp1) in lung endothelial cells to drive alveolar lineage-specific BASC differentiation. Tsp1 null mice exhibited defective alveolar injury repair, confirming a crucial role for the BMP4-NFATc1-TSP1 axis in lung epithelial differentiation and regeneration in vivo. Discovery of this pathway points to methods to direct the derivation of specific lung epithelial lineages from multipotent cells. These findings elucidate a pathway that may be a critical target in lung diseases and provide tools to understand the mechanisms of respiratory diseases at the single-cell level. PMID- 24485455 TI - Molecular mechanism of autophagic membrane-scaffold assembly and disassembly. AB - Autophagy is a catabolic pathway that sequesters undesired cellular material into autophagosomes for delivery to lysosomes for degradation. A key step in the pathway is the covalent conjugation of the ubiquitin-related protein Atg8 to phosphatidylethanolamine (Atg8-PE) in autophagic membranes by a complex consisting of Atg16 and the Atg12-Atg5 conjugate. Atg8 controls the expansion of autophagic precursor membranes, but the underlying mechanism remains unclear. Here, we reconstitute Atg8 conjugation on giant unilamellar vesicles and supported lipid bilayers. We found that Atg8-PE associates with Atg12-Atg5-Atg16 into a membrane scaffold. By contrast, scaffold formation is counteracted by the mitochondrial cargo adaptor Atg32 through competition with Atg12-Atg5 for Atg8 binding. Atg4, previously known to recycle Atg8 from membranes, disassembles the scaffold. Importantly, mutants of Atg12 and Atg16 deficient in scaffold formation in vitro impair autophagy in vivo. This suggests that autophagic scaffolds are critical for phagophore biogenesis and thus autophagy. PMID- 24485454 TI - Crosstalk between sentinel and helper macrophages permits neutrophil migration into infected uroepithelium. AB - The phagocytes of the innate immune system, macrophages and neutrophils, contribute to antibacterial defense, but their functional specialization and cooperation is unclear. Here, we report that three distinct phagocyte subsets play highly coordinated roles in bacterial urinary tract infection. Ly6C(-) macrophages acted as tissue-resident sentinels that attracted circulating neutrophils and Ly6C(+) macrophages. Such Ly6C(+) macrophages played a previously undescribed helper role: once recruited to the site of infection, they produced the cytokine TNF, which caused Ly6C(-) macrophages to secrete CXCL2. This chemokine activated matrix metalloproteinase-9 in neutrophils, allowing their entry into the uroepithelium to combat the bacteria. In summary, the sentinel macrophages elicit the powerful antibacterial functions of neutrophils only after confirmation by the helper macrophages, reminiscent of the licensing role of helper T cells in antiviral adaptive immunity. These findings identify helper macrophages and TNF as critical regulators in innate immunity against bacterial infections in epithelia. PMID- 24485456 TI - Extracellular architecture of the SYG-1/SYG-2 adhesion complex instructs synaptogenesis. AB - SYG-1 and SYG-2 are multipurpose cell adhesion molecules (CAMs) that have evolved across all major animal taxa to participate in diverse physiological functions, ranging from synapse formation to formation of the kidney filtration barrier. In the crystal structures of several SYG-1 and SYG-2 orthologs and their complexes, we find that SYG-1 orthologs homodimerize through a common, bispecific interface that similarly mediates an unusual orthogonal docking geometry in the heterophilic SYG-1/SYG-2 complex. C. elegans SYG-1's specification of proper synapse formation in vivo closely correlates with the heterophilic complex affinity, which appears to be tuned for optimal function. Furthermore, replacement of the interacting domains of SYG-1 and SYG-2 with those from CAM complexes that assume alternative docking geometries or the introduction of segmental flexibility compromised synaptic function. These results suggest that SYG extracellular complexes do not simply act as "molecular velcro" and that their distinct structural features are important in instructing synaptogenesis. PAPERFLICK: PMID- 24485457 TI - Sensing of amino acids in a dopaminergic circuitry promotes rejection of an incomplete diet in Drosophila. AB - The brain is the central organizer of food intake, matching the quality and quantity of the food sources with organismal needs. To ensure appropriate amino acid balance, many species reject a diet lacking one or several essential amino acids (EAAs) and seek out a better food source. Here, we show that, in Drosophila larvae, this behavior relies on innate sensing of amino acids in dopaminergic (DA) neurons of the brain. We demonstrate that the amino acid sensor GCN2 acts upstream of GABA signaling in DA neurons to promote avoidance of the EAA deficient diet. Using real-time calcium imaging in larval brains, we show that amino acid imbalance induces a rapid and reversible activation of three DA neurons that are necessary and sufficient for food rejection. Taken together, these data identify a central amino-acid-sensing mechanism operating in specific DA neurons and controlling food intake. PMID- 24485459 TI - Motor-circuit communication matrix from spinal cord to brainstem neurons revealed by developmental origin. AB - Accurate motor-task execution relies on continuous comparison of planned and performed actions. Motor-output pathways establish internal circuit collaterals for this purpose. Here we focus on motor collateral organization between spinal cord and upstream neurons in the brainstem. We used a newly developed mouse genetic tool intersectionally with viruses to uncover the connectivity rules of these ascending pathways by capturing the transient expression of neuronal subpopulation determinants. We reveal a widespread and diverse network of spinal dual-axon neurons, with coincident input to forelimb motor neurons and the lateral reticular nucleus (LRN) in the brainstem. Spinal information to the LRN is not segregated by motor pool or neurotransmitter identity. Instead, it is organized according to the developmental domain origin of the progenitor cells. Thus, excerpts of most spinal information destined for action are relayed to supraspinal centers through exquisitely organized ascending connectivity modules, enabling precise communication between command and execution centers of movement. PMID- 24485458 TI - Control of stress-induced persistent anxiety by an extra-amygdala septohypothalamic circuit. AB - The extended amygdala has dominated research on the neural circuitry of fear and anxiety, but the septohippocampal axis also plays an important role. The lateral septum (LS) is thought to suppress fear and anxiety through its outputs to the hypothalamus. However, this structure has not yet been dissected using modern tools. The type 2 CRF receptor (Crfr2) marks a subset of LS neurons whose functional connectivity we have investigated using optogenetics. Crfr2(+) cells include GABAergic projection neurons that connect with the anterior hypothalamus. Surprisingly, we find that these LS outputs enhance stress-induced behavioral measures of anxiety. Furthermore, transient activation of Crfr2(+) neurons promotes, while inhibition suppresses, persistent anxious behaviors. LS Crfr2(+) outputs also positively regulate circulating corticosteroid levels. These data identify a subset of LS projection neurons that promote, rather than suppress, stress-induced behavioral and endocrinological dimensions of persistent anxiety states and provide a cellular point of entry to LS circuitry. PMID- 24485460 TI - Progesterone receptor in the vascular endothelium triggers physiological uterine permeability preimplantation. AB - Vascular permeability is frequently associated with inflammation and is triggered by a cohort of secreted permeability factors such as vascular endothelial growth factor (VEGF). Here, we show that the physiological vascular permeability that precedes implantation is directly controlled by progesterone receptor (PR) and is independent of VEGF. Global or endothelial-specific deletion of PR blocks physiological vascular permeability in the uterus, whereas misexpression of PR in the endothelium of other organs results in ectopic vascular leakage. Integration of an endothelial genome-wide transcriptional profile with chromatin immunoprecipitation sequencing revealed that PR induces an NR4A1 (Nur77/TR3) dependent transcriptional program that broadly regulates vascular permeability in response to progesterone. Silencing of NR4A1 blocks PR-mediated permeability responses, indicating a direct link between PR and NR4A1. This program triggers concurrent suppression of several junctional proteins and leads to an effective, timely, and venous-specific regulation of vascular barrier function that is critical for embryo implantation. PMID- 24485461 TI - Structural basis for DNA binding specificity by the auxin-dependent ARF transcription factors. AB - Auxin regulates numerous plant developmental processes by controlling gene expression via a family of functionally distinct DNA-binding auxin response factors (ARFs), yet the mechanistic basis for generating specificity in auxin response is unknown. Here, we address this question by solving high-resolution crystal structures of the pivotal Arabidopsis developmental regulator ARF5/MONOPTEROS (MP), its divergent paralog ARF1, and a complex of ARF1 and a generic auxin response DNA element (AuxRE). We show that ARF DNA-binding domains also homodimerize to generate cooperative DNA binding, which is critical for in vivo ARF5/MP function. Strikingly, DNA-contacting residues are conserved between ARFs, and we discover that monomers have the same intrinsic specificity. ARF1 and ARF5 homodimers, however, differ in spacing tolerated between binding sites. Our data identify the DNA-binding domain as an ARF dimerization domain, suggest that ARF dimers bind complex sites as molecular calipers with ARF-specific spacing preference, and provide an atomic-scale mechanistic model for specificity in auxin response. PMID- 24485462 TI - Sensitizing protective tumor microenvironments to antibody-mediated therapy. AB - Therapy-resistant microenvironments represent a major barrier toward effective elimination of disseminated malignancies. Here, we show that select microenvironments can underlie resistance to antibody-based therapy. Using a humanized model of treatment refractory B cell leukemia, we find that infiltration of leukemia cells into the bone marrow rewires the tumor microenvironment to inhibit engulfment of antibody-targeted tumor cells. Resistance to macrophage-mediated killing can be overcome by combination regimens involving therapeutic antibodies and chemotherapy. Specifically, the nitrogen mustard cyclophosphamide induces an acute secretory activating phenotype (ASAP), releasing CCL4, IL8, VEGF, and TNFalpha from treated tumor cells. These factors induce macrophage infiltration and phagocytic activity in the bone marrow. Thus, the acute induction of stress-related cytokines can effectively target cancer cells for removal by the innate immune system. This synergistic chemoimmunotherapeutic regimen represents a potent strategy for using conventional anticancer agents to alter the tumor microenvironment and promote the efficacy of targeted therapeutics. PMID- 24485465 TI - "There won't' be anything else...it's over": perceptions of women referred to palliative care only. AB - BACKGROUND: It is not well-known how women with advanced breast and gynecological cancers cope with the transition to palliative care (PC) only, but we anticipate that this is a challenging situation for them. OBJECTIVE: To investigate women's understanding on the reasons of anticancer treatment withdrawal, their ideas about PC, and also perceptions of the communication of bad news. METHOD: Twenty women were interviewed by a single researcher after being informed that their antineoplastic treatment would be discontinued and they would be exclusively monitored by PC staff. The interviews were audiotaped, transcribed verbatim, and analyzed according to content analysis. RESULTS: Three categories were identified in the participants' narratives: (1) an understanding of the meaning of PC; (2) a lack of understanding of the shift in treatment and follow-up; (3) differing perspectives about hope. The PC Unit was stigmatized as a place to die, resulting in a "place to die" subcategory. The narratives of the participants who previously had experienced PC converged on a subcategory that reveals better recognition of the importance of the PC Unit as "a place that enhances the quality of life". CONCLUSION: The participants manifested little knowledge about PC and the forthcoming strategies for their clinical follow-up. In addition, the PC Unit was patently stigmatized as a place to die. Early referral to PC seems to be associated with a less painful therapeutic transition, based on more accurate knowledge of the importance of PC. PMID- 24485463 TI - Mathematical modeling of PDGF-driven glioblastoma reveals optimized radiation dosing schedules. AB - Glioblastomas (GBMs) are the most common and malignant primary brain tumors and are aggressively treated with surgery, chemotherapy, and radiotherapy. Despite this treatment, recurrence is inevitable and survival has improved minimally over the last 50 years. Recent studies have suggested that GBMs exhibit both heterogeneity and instability of differentiation states and varying sensitivities of these states to radiation. Here, we employed an iterative combined theoretical and experimental strategy that takes into account tumor cellular heterogeneity and dynamically acquired radioresistance to predict the effectiveness of different radiation schedules. Using this model, we identified two delivery schedules predicted to significantly improve efficacy by taking advantage of the dynamic instability of radioresistance. These schedules led to superior survival in mice. Our interdisciplinary approach may also be applicable to other human cancer types treated with radiotherapy and, hence, may lay the foundation for significantly increasing the effectiveness of a mainstay of oncologic therapy. PAPERCLIP: PMID- 24485467 TI - 1-Hz repetitive transcranial magnetic stimulation increases cerebral vasomotor reactivity: a possible autonomic nervous system modulation. AB - BACKGROUND: Neuromodulation techniques, i.e. repetitive transcranial magnetic stimulation (rTMS) and transcranial direct current stimulation (tDCS), can modify cerebral hemodynamics. High frequency rTMS appeared to decrease cerebral vasomotor reactivity (VMR), while there is still poor evidence about the effect of low frequency (LF) rTMS on cerebral blood flow (CBF) and VMR. HYPOTHESIS: The present study aimed to test if LF rTMS decreases CBF and increases cerebral VMR. Monolateral or bilateral hemispheric involvement and duration of the effect were considered. A possible role of autonomic nervous system in CBF and VMR modulation was also investigated. METHODS: Twenty-four right-handed healthy subjects underwent randomly real (12) or sham (12) 20-min 1-Hz rTMS on left primary motor cortex. Mean flow velocity and VMR of middle cerebral arteries were evaluated by means of transcranial Doppler before (T0), after 10 min (T1) and after 2 (T2), 5 (T3) and 24 h (T4) from rTMS. Heart rate variability (HRV) was studied within the same timing interval, assessing low frequency/high frequency (LF/HF) ratio as index of autonomic balance. RESULTS: After real rTMS compared with sham stimulation, MFV decreased bilaterally at T1 (F = 3.240, P = .030) while VMR increased bilaterally (F = 5.116, P = .002) for at least 5 h (T3). LF/HF ratio decreased early after real rTMS (F = 2.881, P = .040). CONCLUSION: 1-Hz rTMS may induce a bilateral long-lasting increase of VMR, while its effect on MFV is short lasting. Moreover, HRV changes induced by rTMS suggest a possible autonomic nervous system modulation. PMID- 24485468 TI - Epithelial-myoepthelial carcinoma of the tracheobronchial tree: the prognostic role of myoepithelial cells. AB - OBJECTIVES: Epithelial myoepithelial carcinoma (EMC) of the lung is a very rare tumor that is characterized by biphasic differentiation of epithelial and myoepithelial cells. Current discussion about this entity focuses on the malignant potential of the tumor and the role of myoepithelial cells in diagnosis and patient prognosis. This study reports five EMC cases in the lung and discusses issues related to EMC prognosis. MATERIALS AND METHODS: The five EMC cases were diagnosed and collected at the Samsung Medical Center (Seoul, Korea) from 1998 to 2012. Four patients with EMC were received a lobectomy and one patient was given a bronchoscopy to excise the tumor. All cases were evaluated with hematoxylin and eosin and immunohistochemical staining, which included S-100 protein, smooth muscle actin, TTF-1, cytokeratin, vimentin, and p27 analysis. RESULTS AND CONCLUSION: All cases revealed biphasic differentiation of epithelial and myoepithelial tumor cells with various stromal patterns. One of the cases contained predominantly myoepithelial and focal epithelial differentiation, and the tumor showed recurrence and metastasized to the chest wall. This was the first case of metastatic pulmonary EMC. Therefore, we suggest that EMC of the lung has a malignant potential, and that myoepithelial tumor cells may be associated with a pulmonary EMC prognosis. PMID- 24485469 TI - The developmental health of children of parents with intellectual disabilities: cross sectional study. AB - In a representative population-based sample of 46,025 families caring for a young child, parental intellectual disability (identified in 588 families) was associated with increased risk of child developmental delay, child speech and language problems, child behaviour problems and frequent child accidents and injuries. Parental intellectual disability was also associated with increased risk of exposure to a wide range of environmental adversities such as poverty, poor housing and social isolation. Adjusting for between-group differences in exposure to low socio-economic position reduced the risk of adverse child outcomes by over 50% on each of the four measures of child developmental health. In the final fully adjusted model parental intellectual disability was associated with increased risk of child developmental delay and child speech and language problems. However, there were no significant associations between parental intellectual disability and child behaviour problems or frequent accidents and injuries. PMID- 24485466 TI - Task-dependent activity and connectivity predict episodic memory network-based responses to brain stimulation in healthy aging. AB - BACKGROUND: Transcranial magnetic stimulation (TMS) can affect episodic memory, one of the main cognitive hallmarks of aging, but the mechanisms of action remain unclear. OBJECTIVES: To evaluate the behavioral and functional impact of excitatory TMS in a group of healthy elders. METHODS: We applied a paradigm of repetitive TMS - intermittent theta-burst stimulation - over left inferior frontal gyrus in healthy elders (n = 24) and evaluated its impact on the performance of an episodic memory task with two levels of processing and the associated brain activity as captured by a pre and post fMRI scans. RESULTS: In the post-TMS fMRI we found TMS-related activity increases in left prefrontal and cerebellum-occipital areas specifically during deep encoding but not during shallow encoding or at rest. Furthermore, we found a task-dependent change in connectivity during the encoding task between cerebellum-occipital areas and the TMS-targeted left inferior frontal region. This connectivity change correlated with the TMS effects over brain networks. CONCLUSIONS: The results suggest that the aged brain responds to brain stimulation in a state-dependent manner as engaged by different tasks components and that TMS effect is related to inter individual connectivity changes measures. These findings reveal fundamental insights into brain network dynamics in aging and the capacity to probe them with combined behavioral and stimulation approaches. PMID- 24485471 TI - Dissecting the impact of sleep and stress on the cortisol awakening response in young adults. AB - Cortisol rises precipitously upon awakening, in what has been called the cortisol awakening response (CAR). Atypical CARs have been linked to a number of negative health outcomes. Yet, our understanding of the possible mechanisms creating these associations remains unclear. Both stress and sleep can influence CAR, and may potentially explain its links to health. However, these factors also impact each other, and their influence on CAR has rarely been studied simultaneously. In order to differentiate their effects, this study examined the impact of daily life hassles, anticipatory stress, and subjectively reported sleep on CAR among 58 college students. Self-reported stress and sleep, as well as salivary cortisol (collected during the first hour after awakening) were obtained across two consecutive days. Total sleep time predicted CAR magnitude, but daily hassles and anticipatory stress did not after accounting for the effect of sleep. Lower total sleep time was associated with lower awakening cortisol and greater CAR. These results provide further evidence for the impact of sleep insufficiency on CAR, and suggest future efforts to use CAR as a stress biomarker should take the impact of sleep into consideration. PMID- 24485470 TI - Sex-specific associations between placental leptin promoter DNA methylation and infant neurobehavior. AB - BACKGROUND: Leptin (LEP) is a hormone central for energy homeostasis and has been implicated in neurodevelopment. This adipokine is produced by the placenta and is epigenetically regulated by promoter DNA methylation. Recent evidence has suggested a role for LEP in behavioral development. In this study, we investigated associations between profiles of human newborn neurobehavior and placental LEP DNA methylation. METHODS: We determined LEP promoter methylation in 444 placental samples from healthy term infants and measured LEP gene expression in a random subset of these samples. Infant neurobehavior was assessed with the NICU Network Neurobehavioral Scales (NNNS) and we examined the relationship between LEP promoter methylation and profiles of infant neurobehavior derived from these scores generated using a hierarchical model-based clustering method. RESULTS: LEP methylation is negatively correlated with gene expression only in placentas from male infants (r=-0.6, P=0.006). A 10% increase in LEP DNA methylation was associated with membership in a profile of infant neurobehavior marked by increased lethargy and hypotonicity (OR=1.9; 95% CI: 1.07-3.4), and consistently with reduced risk of membership in a profile characterized by decreased lethargy and hypotonicity (OR=0.54; 95% CI: 0.3-0.94) only in male infants (n=223). No statistically significant associations were observed amongst female infants. DISCUSSION: These results suggest that increased placental LEP DNA methylation, related to reduced expression, may play a role in human newborn neurodevelopment, particularly in reactivity to various stimuli, but that these effects may be sexually dimorphic. PMID- 24485473 TI - Burnout symptom sub-types and cortisol profiles: what's burning most? AB - The current study assessed which specific burnout symptoms were most predictive of distinct diurnal cortisol profiles. Participants included 401 day-shift workers employed in a random sampling of 34 Canadian workplaces. The 16-item Maslach Burnout Inventory was used to extract burnout sub-scales that included emotional exhaustion, cynicism, professional inefficacy, as well as a global burnout average. Consenting workers provided five saliva samples a day (awaking, 30 min after awaking, 1,400 h, 1,600 h, and bedtime) repeated three times over the course of a week (Saturday, Tuesday, Thursday) to capture workday and non workday variations. Multilevel regression models were estimated from cortisol measurements at each occasion within a day at level-1, workers at level-2, and workplaces at level-3. Multilevel regression analyses found that emotional exhaustion and a global burnout showed the strongest and consistent negative associations to cortisol in the afternoon and evening. In a separate analysis using regression coefficients, emotional exhaustion and a global burnout average were associated with low cortisol levels 30 min upon awakening. By contrast, professional inefficacy was associated only with lower bedtime cortisol. No associations were detected for cynicism and sex did not emerge as a moderator in secondary analyses. Our findings are discussed in a theoretical framework postulating different pathophysiological stages of burnout development. Specifically, professional inefficacy may be the earliest warning signal culminating with emotional exhaustion that may dampen diurnal cortisol levels. PMID- 24485472 TI - Anxiolytic function of the orexin 2/hypocretin A receptor in the basolateral amygdala. AB - The orexin/hypocretin system interacts with many of the same circuitries contributing to stress-associated disorders like depression and anxiety. These include potentially reciprocal connections with corticotropin releasing factor (CRF) neurons which drive the hypothalamic-pituitary-adrenal (HPA) endocrine response in addition to having an anxiogenic effect in the central amygdala (CeA). Antagonism of the orexin type 1 receptor (Orx1) in the hypothalamus has also been shown to block panic attacks. However, few studies have investigated the effect of orexinergic signaling in the basolateral amygdala (BLA) which is responsible for contextual fear, and modulates the activity of the CeA. To this end, we chronically stressed c57bl/6 mice with social defeat and examined the gene expression of the orexin receptors in the BLA. We found that the transcripts for the Orx1 and Orx2 receptors diverged in the BLA with Orx1 increasing and Orx2 decreasing in animals that were susceptible to the chronic defeat. These changes were not seen in the prelimbic cortex (PrL) which sends efferents to the BLA. We then tried to recapitulate these expression patterns in the BLA using short hairpin interfering sequences delivered by adeno-associated viruses to knock down the orexin receptors. While the Orx1 knockdown did reduce locomotor activity, it did not decrease depressive or anxious behaviors. Knocking down the Orx2 receptors in the BLA increased anxious behavior as measured by reduced social preference and reduced time spent in the center of an open field. Due to the divergent expression patterns of the two receptors in response to chronic stress, orexinergic activity in the BLA may be responsible for bidirectional modulation of anxious behavior. Furthermore, these data raise the possibility that an Orx2 agonist may serve as an effective means to treat anxiety disorders. PMID- 24485474 TI - Photoperiodic responses of depression-like behavior, the brain serotonergic system, and peripheral metabolism in laboratory mice. AB - Seasonal affective disorder (SAD) is characterized by depression during specific seasons, generally winter. The pathophysiological mechanisms underlying SAD remain elusive due to a limited number of animal models with high availability and validity. Here we show that laboratory C57BL/6J mice display photoperiodic changes in depression-like behavior and brain serotonin content. C57BL/6J mice maintained under short-day conditions, as compared to those under long-day conditions, demonstrated prolonged immobility times in the forced swimming test with lower brain levels of serotonin and its precursor l-tryptophan. Furthermore, photoperiod altered multiple parameters reflective of peripheral metabolism, including the ratio of plasma l-tryptophan to the sum of other large neutral amino acids that compete for transport across the blood-brain barrier, responses of circulating glucose and insulin to glucose load, sucrose intake under restricted feeding condition, and sensitivity of the brain serotonergic system to peripherally administered glucose. These data suggest that the mechanisms underlying SAD involve the brain-peripheral tissue network, and C57BL/6J mice can serve as a powerful tool for investigating the link between seasons and mood. PMID- 24485475 TI - Lipopolysaccharide-induced brain activation of the indoleamine 2,3-dioxygenase and depressive-like behavior are impaired in a mouse model of metabolic syndrome. AB - Although peripheral low-grade inflammation has been associated with a high incidence of mood symptoms in patients with metabolic syndrome (MetS), much less is known about the potential involvement of brain activation of cytokines in that context. Recently we showed in a mouse model of MetS, namely the db/db mice, an enhanced hippocampal inflammation associated with increased anxiety-like behavior (Dinel et al., 2011). However, depressive-like behavior was not affected in db/db mice. Based on the strong association between depressive-like behavior and cytokine-induced brain activation of indoleamine 2,3-dioxygenase (IDO), the enzyme that metabolizes tryptophan along the kynurenine pathway, these results may suggest an impairment of brain IDO activation in db/db mice. To test this hypothesis, we measured the ability of db/db mice and their healthy db/+ littermates to enhance brain IDO activity and depressive-like behavior after a systemic immune challenge with lipopolysaccharide (LPS). Here we show that LPS (5 MUg/mouse) significantly increased depressive-like behavior (increased immobility time in a forced-swim test, FST) 24h after treatment in db/+ mice, but not in db/db mice. Interestingly, db/db mice also displayed after LPS treatment blunted increase of brain kynurenine/tryptophan ratio compared to their db/+ counterparts, despite enhanced induction of hippocampal cytokine expression (interleukin-1beta, tumor necrosis factor-alpha). Moreover, this was associated with an impaired effect of LPS on hippocampal expression of the brain-derived neurotrophic factor (BDNF) that contributes to mood regulation, including under inflammatory conditions. Collectively, these data indicate that the rise in brain tryptophan catabolism and depressive-like behavior induced by innate immune system activation is impaired in db/db mice. These findings could have relevance in improving the management and treatment of inflammation-related complications in MetS. PMID- 24485476 TI - Oxytocin does not make a face appear more trustworthy but improves the accuracy of trustworthiness judgments. AB - Previous research on the relation between oxytocin and trustworthiness evaluations has yielded inconsistent results. The current study reports an experiment using artificial faces which allows manipulating the dimension of trustworthiness without changing factors like emotions or face symmetry. We investigate whether (1) oxytocin increases the average trustworthiness evaluation of faces (level effect), and/or whether (2) oxytocin improves the discriminatory ability of trustworthiness perception so that people become more accurate in distinguishing faces that vary along a gradient of trustworthiness. In a double blind oxytocin/placebo experiment (N=106) participants conducted two judgement tasks. First they evaluated the trustworthiness of a series of pictures of artificially generated faces, neutral in the trustworthiness dimension. Next they compared neutral faces with artificially generated faces that were manipulated to vary in trustworthiness. The results indicate that oxytocin (relative to a placebo) does not affect the evaluation of trustworthiness in the first task. However, in the second task, misclassification of untrustworthy faces as trustworthy occurred significantly less in the oxytocin group. Furthermore, oxytocin improved the discriminatory ability of untrustworthy, but not trustworthy faces. We conclude that oxytocin does not increase trustworthiness judgments on average, but that it helps people to more accurately recognize an untrustworthy face. PMID- 24485477 TI - Sampling compliance for cortisol upon awakening in children and adolescents. AB - Compliance with awakening salivary sampling is important for precise measurement of the diurnal cortisol profile. During childhood and adolescence, developmental factors influence sampling upon awakening (awake0) due to school routine, sleep/wake patterns, and age related cortisol changes. In the present study, children and adolescents' sampling compliance of awakening cortisol was evaluated using accelerometry. Children and adolescents (N=201; 45.3% female; 8-18 years; Mage=12.68 years, SD=2.03) participating in the Healthy Heart Project collected saliva samples, wore a tri-axle accelerometer, and completed demographic questionnaires. Intra-class correlations derived to examine awake0 sampling compliance indicated children and adolescents were highly compliant (ICC=.98). In children, a delay in awake0 sampling was associated with a steeper diurnal slope (beta=-.23, p=.037) and greater awake0 cortisol (beta=.24, p=.024); this was not observed in adolescents. In summary, children and adolescents are compliant with awakening salivary sampling. Sampling delay, particularly in children, and time of awakening influenced measures of the diurnal cortisol profile. These findings inform future studies assessing the diurnal cortisol profile in children and adolescents. PMID- 24485478 TI - Is very high C-reactive protein in young adults associated with indicators of chronic disease risk? AB - BACKGROUND: Cases with very high C-reactive protein (CRP>10mg/L) are often dropped from analytic samples in research on risk for chronic physical and mental illness, but this convention could inadvertently result in excluding those most at risk. We tested whether young adults with very high CRP scored high on indicators of chronic disease risk. We also tested intergenerational pathways to and sex-differentiated correlates of very high CRP. METHODS: Data came from Waves I (ages 11-19) and IV (ages 24-34) of the National Longitudinal Study of Adolescent Health (N=13,257). At Wave I, participants' parents reported their own education and health behaviors/health. At Wave IV, young adults reported their socioeconomic status, psychological characteristics, reproductive/health behaviors and health; trained fieldworkers assessed BMI, waist circumference, blood-pressure, and medication use, and collected bloodspots from which high sensitivity CRP (hs-CRP) was assayed. RESULTS: Logistic regression analyses revealed that many common indicators of chronic disease risk - including parental health/health behaviors reported 14 years earlier - were associated with very high CRP in young adults. Several of these associations attenuated with the inclusion of BMI. More than 75% of young adults with very high CRP were female. Sex differences in associations of some covariates and very high CRP were observed. CONCLUSION: Especially among females, the exclusion of cases with very high CRP could result in an underestimation of "true" associations of CRP with both, chronic disease risk indicators and morbidity/mortality. In many instances, very high CRP could represent an extension of the lower CRP range when it comes to chronic disease risk. PMID- 24485479 TI - Noradrenergic blockade and memory in patients with major depression and healthy participants. AB - OBJECTIVE: Patients with major depressive disorder (MDD) often suffer from impaired declarative, episodic and working memory. Further, MDD is associated with alterations in the noradrenergic system. There is evidence that presynaptic alpha2 receptors that inhibit release of noradrenaline are upregulated in MDD. Results from our recent study demonstrated that increasing noradrenergic activity by blocking the alpha2 receptor with yohimbine leads to stronger memory consolidation in MDD patients. In the current study, we further examined the role of noradrenaline on memory in MDD by administering clonidine that activates presynaptic alpha2 receptors and thereby globally suppresses the noradrenergic output. METHODS: In a placebo-controlled, within-subject crossover design, 20 patients with MDD and 20 healthy controls received either 0.15 mg of clonidine or placebo orally before memory testing. A word list paradigm (memory consolidation), an autobiographical memory test (retrieval) and a working memory test were applied. Salivary alpha-amylase and blood pressure were measured. RESULTS: Across groups, clonidine decreased blood pressure and alpha-amylase. Clonidine impaired memory consolidation (word list learning) in depressed patients and controls. Memory retrieval and working memory were not affected by clonidine. CONCLUSIONS: Reducing noradrenergic activity had a specific effect on memory consolidation in patients with MDD and healthy controls. The underlying mechanisms need further scrutiny. PMID- 24485480 TI - Effects of acute social stress on emotion processing in children. AB - The current study investigates the effect of a single episode of acute social stress on healthy children's processing of facial expressions of emotion. Healthy nine- and ten-year-old boys (N=39) underwent either a standardized psychosocial laboratory stressor (the Trier Social Stress Test for Children) or a control condition without exposure to socio-evaluative stress. Immediately thereafter, they classified pictures of faces displaying ambiguous facial expressions. Boys who had undergone the stress procedure were more likely to categorize ambiguously angry-fearful faces as fearful (and simultaneously less likely to categorize them as angry) relative to boys who had undergone the control condition. We suggest (i) that decreased sensitivity to anger cues following a stressful experience may represent an adaptive coping mechanism in healthy children, and/or (ii) that a heightened sensitivity to fearful cues may indicate the influence of children's own emotional states on their interpretations of others' emotional states. PMID- 24485481 TI - Rapid changes in histone deacetylases and inflammatory gene expression in expert meditators. AB - BACKGROUND: A growing body of research shows that mindfulness meditation can alter neural, behavioral and biochemical processes. However, the mechanisms responsible for such clinically relevant effects remain elusive. METHODS: Here we explored the impact of a day of intensive practice of mindfulness meditation in experienced subjects (n=19) on the expression of circadian, chromatin modulatory and inflammatory genes in peripheral blood mononuclear cells (PBMC). In parallel, we analyzed a control group of subjects with no meditation experience who engaged in leisure activities in the same environment (n=21). PBMC from all participants were obtained before (t1) and after (t2) the intervention (t2-t1=8h) and gene expression was analyzed using custom pathway focused quantitative-real time PCR assays. Both groups were also presented with the Trier Social Stress Test (TSST). RESULTS: Core clock gene expression at baseline (t1) was similar between groups and their rhythmicity was not influenced in meditators by the intensive day of practice. Similarly, we found that all the epigenetic regulatory enzymes and inflammatory genes analyzed exhibited similar basal expression levels in the two groups. In contrast, after the brief intervention we detected reduced expression of histone deacetylase genes (HDAC 2, 3 and 9), alterations in global modification of histones (H4ac; H3K4me3) and decreased expression of pro inflammatory genes (RIPK2 and COX2) in meditators compared with controls. We found that the expression of RIPK2 and HDAC2 genes was associated with a faster cortisol recovery to the TSST in both groups. CONCLUSIONS: The regulation of HDACs and inflammatory pathways may represent some of the mechanisms underlying the therapeutic potential of mindfulness-based interventions. Our findings set the foundation for future studies to further assess meditation strategies for the treatment of chronic inflammatory conditions. PMID- 24485482 TI - Markers of low-grade inflammation and endothelial dysfunction are related to reduced information processing speed and executive functioning in an older population - the Hoorn Study. AB - Low-grade inflammation and endothelial dysfunction are related to cognitive decline and dementia, in a complex interplay with vascular factors and aging. We investigated, in an older population, low-grade inflammation and endothelial dysfunction in relation to detailed assessment of cognitive functioning. Furthermore, we explored this association within the context of vascular factors. 377 participants (73 +/- 6 years) of the population-based Hoorn Study were included. In plasma samples of 2000-2001 (n=363) and/or 2005-2008 (n=323), biomarkers were determined of low-grade inflammation (CRP, TNF-alpha, IL-6, IL-8, SAA, MPO, and sICAM-1) and endothelial dysfunction (vWF, sICAM-1, sVCAM-1, sTM, sE-selectin). In 2005-2008, all participants underwent neuropsychological examination. Composite z-scores were computed for low-grade inflammation and endothelial dysfunction at both time points, and for six domains of cognitive functioning (abstract reasoning, memory, information processing speed, attention and executive functioning, visuoconstruction, and language). The association between low-grade inflammation and endothelial dysfunction, and cognitive functioning was evaluated with linear regression analysis. In secondary analyses, we explored the relation with vascular risk factors and cardiovascular disease. Low-grade inflammation and endothelial dysfunction were associated with worse performance on information processing speed and attention and executive functioning, in prospective and cross-sectional analyses (standardized betas ranging from -0.20 to -0.10). No significant relation with other cognitive domains was observed. Adjusting for vascular factors slightly attenuated the associations. Low-grade inflammation and endothelial dysfunction accounted for only 2.6% explained variance in cognitive functioning, on top of related vascular risk factors and cardiovascular disease. Bootstrapping analyses show that low grade inflammation and endothelial dysfunction mediate the relation between vascular risk factors and cognitive functioning. This study shows that low-grade inflammation and endothelial dysfunction contribute to reduced information processing speed and executive functioning in an older population. PMID- 24485483 TI - Ketamine prevents stress-induced cognitive inflexibility in rats. AB - Chronic stress produces both morphological and functional alternations of the rat medial prefrontal cortex (mPFC). N-methyl-d-aspartic acid (NMDA) glutamate receptor inhibition may alleviate such stress-induced dendritic reorganization in the mPFC. However, it is unknown whether administration of a NMDAR antagonist would also prevent alterations in PFC-mediated cognitive functions. Here, we investigated whether administration of ketamine, the noncompetitive antagonist of NMDA receptors before each stress session would prevent cognitive impairments in a rat model of prefrontal cortex (PFC)-dependent attentional set-shifting task (ASST), a measure of cognitive flexibility. Repeated restraint stress (1h daily for 7 days) significantly and specifically impaired extra-dimensional (ED) set shifting ability of rats. Pretreatment with ketamine (10mg/kg, IP) completely and specifically prevented this stress-induced cognitive inflexibility. The present study demonstrates procognitive efficacy of ketamine in an animal stress model, which confirms and extends the role of the NMDA receptors in mediating stress evoked prefrontal dysfunctions. PMID- 24485484 TI - Sex differences in response to chronic mild stress and congenital serotonin deficiency. AB - Women exhibit a nearly twofold increased risk of developing depression and anxiety disorders when compared to men, a fact that has been hypothesized to result in part from increased stress susceptibility. Here, we used the tryptophan hydroxylase-2 R439H knock-in mouse (Tph2KI) and the chronic unpredictable mild stress (CMS) model to examine sex differences in response to congenital 5-HT deficiency and chronic stress. Our results demonstrate that female mice, but not 5-HT-deficient animals, exhibit significantly increased susceptibility to CMS induced despair-like behavior in the forced swim test. In addition, female 5-HT deficient mice exhibit anhedonia-like behavior in the sucrose preference test, whereas male 5-HT-deficient animals do not, suggesting that females exhibit increased sensitivity to at least some of the effects of congenital 5-HT deficiency. Although CMS did not reduce cell proliferation in the hippocampus, low levels of brain 5-HT were associated with increased hippocampal cell proliferation, an effect that was predominantly observed in females. Overall, these results highlight the importance of interactions between psychiatric disease risk factors such as sex, chronic stress and congenital 5-HT deficiency in the development of aberrant emotional behavior. PMID- 24485485 TI - Effects of inhibition of gonadotropin releasing hormone secretion on the response to novel objects in young male and female sheep. AB - This study investigated the actions of blocking the GnRH receptor using a specific agonist on the response of male and female sheep to a novel object placed in their pen. The study is part of a series performed on 46 same sex twin animals. One of the pair received a subcutaneous implant of the GnRH agonist Goserelin acetate every four weeks while the other remained untreated. Implantation began immediately prior to puberty; at 8 weeks in the males and 28 weeks in the females (as timing of puberty is sex specific). To determine the effects of agonist treatment on the reproductive axis blood samples were collected for measurement of testosterone in the males and progesterone in the females. In addition the volume of the scrotum was determined. The present study aimed to determine whether there are sexually differentiated behavioural responses to a novel object at different stages of brain development (8, 28 and 48 weeks of age) and whether these responses are altered by GnRHa treatment. Approach behaviour towards and interactions with the novel object were monitored as was the number of vocalisations per unit time during the test period. GnRHa treatment suppressed testosterone concentrations and testicular growth in the males and progesterone release in the females. Sheep vocalised significantly more prior to weaning (8 weeks of age) than post weaning (28 and 48 weeks of age) suggesting stress on separation from their dams. Our current study shows that males are more likely to leave their conspecifics to approach a novel object than females. As this behaviour was not altered by suppression of the reproductive axis we suggest that, although sex differences are more obviously expressed in the phenotype after puberty, these may be developed during adolescence but not primarily altered during puberty by sex hormones. PMID- 24485486 TI - An elevated pro-inflammatory cytokine profile in multiple chemical sensitivity. AB - BACKGROUND: Multiple chemical sensitivity (MCS) is a medically unexplained condition characterized by reports of recurrent unspecific symptoms attributed to exposure to low levels of common volatile chemicals. The etiology of MCS is poorly understood, but dysregulation of the immune system has been proposed as part of the pathophysiology. OBJECTIVE: To compare plasma levels of cytokines in Danish MCS individuals with a healthy, sex- and age-matched control group. METHOD: Blood samples were obtained from 150 un-exposed MCS individuals and from 148 age- and sex-matched healthy controls. Plasma concentrations of 14 cytokines, chemokines and growth and allergen-specific IgE were measured. All participants completed a questionnaire including questions on MCS, psychological distress, morbidities and medication use at the time of the study. RESULTS: Plasma levels of interleukin-1beta, -2, -4, and -6 were significantly (P<0.001) increased in the MCS group compared with controls, tumor necrosis factor-alpha was borderline significantly (P=0.05) increased and interleukin-13 was significantly decreased (P<0.001). CONCLUSION: MCS individuals displayed a distinct systemic immune mediator profile with increased levels of pro-inflammatory cytokines and interleukin-2 and inverse regulation of Th2 associated cytokines interleukin-4 and interleukin-13 suggestive of low-grade systemic inflammation, along with a deviating Th2-associated cytokine response not involving IgE-mediated mechanisms. PMID- 24485487 TI - Cortisol response to cosyntropin administration in military veterans with or without posttraumatic stress disorder. AB - Studies have demonstrated altered sensitivity of the hypothalamic-pituitary adrenal (HPA) axis to its direct regulators in veterans with posttraumatic stress disorder (PTSD), but little is known about the adrenal response to hormonal stimulation in PTSD. An increased cortisol response to synthetic corticotropin releasing factor (CRF) was recently found to be associated with war-zone deployment and not PTSD specifically. To more accurately assess whether there is altered adrenocortical responsivity to hormonal stimulation in relation to war zone deployment or PTSD, we performed the low-dose cosyntropin stimulation test in a sample of 45 male veterans: 13 war-zone exposed veterans with chronic PTSD (PTSD+), 22 war-zone exposed veterans without chronic PTSD (PTSD-), and 10 veterans not exposed to a war-zone and without chronic PTSD (non-exposed). Plasma cortisol and ACTH were measured at baseline and at intervals over a one hour period following intravenous administration of 1MUg of cosyntropin. A significant main effect of group (PTSD+, PTSD-, non-exposed) on the cortisol response to cosyntropin was observed. Cosyntropin-stimulated plasma cortisol levels were significantly higher in the PTSD+ and PTSD- groups compared to the non-exposed group. A significant main effect of group was also observed on peak cortisol levels. These findings suggest that war-zone exposure itself has persistent effects on adrenocortical activity. PMID- 24485488 TI - Evidence for alterations in stimulatory G proteins and oxytocin levels in children with autism. AB - The neurotransmitter oxytocin plays an important role in social affiliation. Low oxytocin levels and defects in the oxytocin receptor have been reported in childhood autism. However, little is known about oxytocin's post-receptor signaling pathways in autism. Oxytocin signals via stimulatory and inhibitory G proteins. c-fos mRNA expression has been used as a marker of OT signaling as well as of G protein signaling. Herein, we hypothesized that oxytocin and its signaling pathways would be altered in children with autism. We measured plasma oxytocin levels by ELISA, G-protein and c-fos mRNA by PCR, and G proteins by immunoblot in cultured peripheral blood mononuclear cells (PBMCs) in children with autism and in age-matched controls. Males with autism displayed elevated oxytocin levels compared to controls (p<0.05). Children with autism displayed significantly higher mRNA for stimulatory G proteins compared to controls (p<0.05). Oxytocin levels correlated strongly positively with c-fos mRNA levels, but only in control participants (p<0.01). Oxytocin, G-protein, and c-fos mRNA levels correlated inversely with measures of social and emotional behaviors, but only in control participants. These data suggest that children with autism may exhibit a dysregulation in oxytocin and/or its signaling pathways. PMID- 24485489 TI - Child diurnal cortisol rhythms, parenting quality, and externalizing behaviors in preadolescence. AB - This study examined a neurobiologically informed model of the emergence of child externalizing behaviors in an ethnically diverse community sample of 232 9-12 year old children. Replicating extensive prior research, our analyses revealed that parents' inconsistent discipline and poor quality monitoring were predictive of child externalizing behavior. In addition, poor parental monitoring, but not inconsistent discipline, was associated with children having a significantly flatter morning-to-evening cortisol slope, which was in turn, related to higher levels of externalizing behaviors. An indirect effect of parental monitoring on externalizing behaviors, through child diurnal cortisol rhythms, was also supported. These findings highlight the role of the hypothalamic-pituitary adrenal (HPA) axis and its hormonal end product, cortisol, in the relationship between the caregiving environment and the development of externalizing behaviors. PMID- 24485490 TI - Linking genetic variants of the mineralocorticoid receptor and negative memory bias: interaction with prior life adversity. AB - Substantial research has been conducted investigating the association between life adversity and genetic vulnerability for depression, but clear mechanistic links are rarely identified and investigation often focused on single genetic variants. Complex phenotypes like depression, however, are likely determined by multiple variants in interaction with environmental factors. As variations in the mineralocorticoid receptor gene (NR3C2) have been related to a higher risk for depression, we investigated whether NR3C2 variance is related to negative memory bias, an established endophenotype for depression, in healthy participants. Furthermore, we explored the influence of life adversity on this association. We used a set-based analysis to simultaneously test all measured variation in NR3C2 for an association with negative memory bias in 483 participants and an interaction with life adversity. To further specify this interaction, we split the sample into low and high live adversity groups and repeated the analyses in both groups separately. NR3C2 variance was associated with negative memory bias, especially in the high life adversity group. Additionally, we identified a functional polymorphism (rs5534) related to negative memory bias and demonstrating a gene*life adversity interaction. Variations in NR3C2 are associated with negative memory bias and this relationship appears to be influenced by life adversity. As negative memory bias is implicated in the susceptibility to depression, our findings provide mechanistic support for the notion that variations in NR3C2 - which could compromise the proper function of this receptor - are a risk factor for the development of mood disorders. PMID- 24485491 TI - Chronic exposure to exogenous glucocorticoids primes microglia to pro inflammatory stimuli and induces NLRP3 mRNA in the hippocampus. AB - Chronic stress as well as chronic treatment with glucocorticoids (GCs) primes the neuroinflammatory response to a subsequent pro-inflammatory challenge. However, it remains unclear whether chronic GCs sensitize the response of key CNS immune substrates (i.e. microglia) to pro-inflammatory stimuli. In the present set of studies, male Sprague-Dawley rats underwent sham surgery or were adrenalectomized and then treated with varying concentrations of corticosterone (CORT; 0, 25, 50, and 75 MUg/ml) administered in their drinking water. After 10 days of CORT exposure, whole hippocampus was collected and expression of glial activation markers measured or hippocampal microglia were isolated and challenged with LPS to probe for CORT-induced sensitization of pro-inflammatory responses. Chronic CORT exposure increased the gene expression of NLRP3, Iba-1, MHCII, and NF kappaBIalpha in a concentration dependent manner. Chronic CORT (75 MUg/ml) exposure potentiated the microglial proinflammatory response (TNFalpha, IL-1beta, IL-6 and NLRP3) to LPS compared to the microglial response of sham surgery animals treated with vehicle. The present set of results demonstrate that chronic exposure to GCs primes microglia to pro-inflammatory stimuli and add to a growing body of evidence suggesting that a permissive function of GCs is that of an endogenous danger signal or alarmin. PMID- 24485492 TI - Testosterone enhances risk tolerance without altering motor impulsivity in male rats. AB - Anabolic-androgenic steroids (AAS) increase impulsive and uncontrolled aggressive ('roid rage) in humans and enhance agonistic behavior in animals. However, the underlying mechanisms for AAS-induced aggression remain unclear. Potential contributing elements include an increase risk-taking and/or motor impulsivity due to AAS. This study addressed the effects of chronic high-dose testosterone on risk tolerance using a risky decision-making task (RDT) and motor impulsivity with a go/no-go task in operant chambers. Male Long-Evans rats were treated for at least 4 weeks with testosterone (7.5mg/kg) or vehicle beginning in late adolescence. Testosterone was used because it is popular among human AAS users. In RDT testing, one lever was paired with delivery of a small "safe" food reward, while the other was paired with a large "risky" reward associated with an increasing risk of footshock (0%, 25%, 50%, 75%, 100%) in successive test blocks. Three shock intensities were used: 1.0, 1.2, and 1.4mA/kg. As shock intensity and risk of shock increased, preference for the lever signifying a large reward significantly declined for both vehicle- and testosterone-treated rats (p<0.05). There was also a significant effect of drug (p<0.05), where testosterone-treated rats showed greater preference for the large reward, compared to vehicle-treated controls. Increased preference for the large reward, despite risk of footshock, is consistent with increased risk tolerance. In go/no-go testing, rats were trained to press a single lever if the go cue was presented (stimulus light) or to refrain from pressing during the no-go cue (tone). There was no effect of testosterone on pre-cue responses, or performance in go and no-go trials. These results suggest that AAS may increase risk-tolerance without altering motor impulsivity. PMID- 24485494 TI - Glutamate receptor antibodies directed against AMPA receptors subunit 3 peptide B (GluR3B) associate with some cognitive/psychiatric/behavioral abnormalities in epilepsy patients. AB - Antibodies (Ab's) to glutamate receptors, directed specifically against AMPA receptors subunit 3 peptide B (i.e. GluR3 amino acids 372-395), named GluR3B Ab's, can by themselves activate GluR3-containing glutamate/AMPA receptors, evoke ion currents via the receptor's ion channel, kill neurons and damage the brain. Herein we first tested 14 consecutive epilepsy patients and 10 healthy controls, and found that 7 (50%) patients had GluR3B Ab's. Second, in 71 other consecutive epilepsy patients (20 generalized epilepsy, 51 partial epilepsy) and 49 controls, we found that 17 (24%) patients had GluR3B Ab's, of which 8 had generalized and 9 partial epilepsy. We then studied 41 epilepsy patients: 21 patients with GluR3B Ab's and 20 without such Ab's (pooled of both tests without biased selection), for possible association of GluR3B Ab's with disease severity and/or neurobehavioral/cognitive comorbidities. Of the 21 patients with GluR3B Ab's, 6 had symptomatic, 7 cryptogenic, and 8 idiopathic epilepsy. Of the 20 patients without GluR3B Ab's, 16 had idiopathic etiology, and 4 nonidiopathic epilepsy. We found that among the 21 patients with GluR3B Ab's, 19 patients (90%) had learning problems, 16 (76%) attention problems, and 15 (71%) psychiatric problems. In contrast, among the 20 patients without GluR3B Ab's, only 6 (30%) had learning problems (p<0.0001), 5 (25%) attention problems (p=0.0017), and 2 (10%) psychiatric problems (p<0.0001). These findings suggest either that neurobehavioral abnormalities occur more frequently in epilepsy patients already having GluR3B Ab's, and may be due to them, or that GluR3B Ab's are more frequent in patients already having neurobehavioral abnormalities. PMID- 24485495 TI - Sex differences in serotonin (5-HT) 1A receptor regulation of HPA axis and dorsal raphe responses to acute restraint. AB - The serotonin (5-HT) 1A receptor subtype has been implicated as an important mediator for the stimulatory influence of serotonin on stress hypothalamic pituitary-adrenal (HPA) activity, at least in males. Females show greater HPA axis responses to stress compared to males. To determine the nature by which the 5-HT 1A receptor contributes to the sex difference in stress, we examined neuroendocrine and cellular (Fos) responses in male and female rats receiving systemic injections of the 5-HT 1A receptor antagonist, WAY 100635, prior to acute restraint exposure. WAY decreased the corticosterone response in males, but not in females. In the paraventricular nucleus of the hypothalamus (PVH), WAY produced similar decrements in the restraint-induced activation (Fos) of neuroendocrine neurons in males and females. In contrast to the PVH, WAY administration increased total Fos activation in the dorsal raphe nucleus, but only in males. WAY also provoked higher Fos responses within subsets of dorsal raphe cells identified as serotonergic (tryptophan hydroxylase-, TPH-ir) in both males and females. These data provide evidence to suggest a differential influence of presynaptic 5-HT 1A receptors to regulate the stress-induced recruitment of non-serotonergic dorsal raphe neurons in males and females. At present, we cannot rule out a possible role for estrogen in females to alter 5-HT outflow to the HPA axis. There was a negative correlation between estrogen and Fos responses within TPH-positive cells in the dorsal raphe of WAY-administered females, whereas a positive correlation was found between estrogen and 5-HT 1A mRNA expression localized to the region of the zona incerta in close proximity to the PVH. As the raphe complex and 5-HT system impinge on several central autonomic, behavioral and neuroendocrine control systems, the current findings provide an important framework for future studies directed at sex differences in adaptive homeostatic responses. PMID- 24485496 TI - Intranasal oxytocin as strategy for medication-enhanced psychotherapy of PTSD: salience processing and fear inhibition processes. AB - About ten percent of people experiencing a traumatic event will subsequently develop post-traumatic stress disorder (PTSD). PTSD is characterized by an exaggerated fear response which fails to extinguish over time and cannot be inhibited in safe contexts. The neurobiological correlates of PTSD involve enhanced salience processing (i.e. amygdala, dorsal anterior cingulate cortex (dACC) and anterior insula (AI) hyperactivity), and reduced top-down inhibitory control over this fear response (i.e. dorsal and ventromedial prefrontal cortex (vmPFC) hypoactivity and diminished structural and functional connectivity between the vmPFC, hippocampus and amygdala). Therefore, dampening the exaggerated fear response (i.e. by reducing amygdala hyperactivity) and enhancing top-down inhibitory control (i.e. by promoting prefrontal control over the amygdala) during psychotherapy is an important target for medication-enhanced psychotherapy (MEP) in PTSD patients. Since the neuropeptide oxytocin (OT) has been found to act on these two processes, we propose that OT is a promising pharmacological agent to boost treatment response in PTSD. Human fMRI studies indicate that intranasal OT attenuates amygdala (hyper)activity and enhances connectivity of the amygdala with the vmPFC and hippocampus, resulting in increased top-down control over the fear response. In addition, intranasal OT was found to attenuate amygdala-brainstem connectivity and to change activity and connectivity in nodes of the salience network (i.e. AI and dACC). Furthermore, OT administration may modulate hypothalamus-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS) function and may enhance social behaviour, which could be beneficial in the therapeutic alliance. We also discuss contextual and interindividual factors (e.g. gender and social context) which may influence the effectiveness of OT in MEP. In all, we propose that intranasal OT given prior to each psychotherapy session may be an effective additive treatment to boost treatment response in PTSD. PMID- 24485493 TI - Maternal PTSD associates with greater glucocorticoid sensitivity in offspring of Holocaust survivors. AB - Intergenerational effects of trauma have been observed clinically in a wide range of populations, and parental PTSD has been associated with an increased risk for psychopathology in offspring. In studies of Holocaust survivor offspring, parental PTSD, and particularly maternal PTSD, has been associated with increased risk for PTSD, low basal urinary cortisol excretion and enhanced cortisol suppression in response to dexamethasone. Such findings implicate maternally derived glucocorticoid programming in the intergenerational transmission of trauma-related consequences, potentially resulting from in utero influences or early life experiences. This study investigated the relative influence of Holocaust exposure and PTSD in mothers and fathers on glucocorticoid sensitivity in offspring. Eighty Holocaust offspring and 15 offspring of non-exposed Jewish parents completed evaluations and provided blood and urine samples. Glucocorticoid sensitivity was evaluated using the lysozyme suppression test (LST), an in vitro measure of glucocorticoid receptor sensitivity in a peripheral tissue, the dexamethasone suppression test (DST), and 24-h urinary cortisol excretion. Maternal PTSD was associated with greater glucocorticoid sensitivity in offspring across all three measures of glucocorticoid function. An interaction of maternal and paternal PTSD on the DST and 24-h urinary cortisol showed an effect of decreased glucocorticoid sensitivity in offspring with paternal, but not maternal, PTSD. Although indirect, these findings are consistent with the hypothesis that epigenetic programming may be involved in the intergenerational transmission of trauma-related effects on glucocorticoid regulation. PMID- 24485497 TI - Delayed effects of cortisol enhance fear memory of trace conditioning. AB - Corticosteroids induce rapid non-genomic effects followed by slower genomic effects that are thought to modulate cognitive function in opposite and complementary ways. It is presently unknown how these time-dependent effects of cortisol affect fear memory of delay and trace conditioning. This distinction is of special interest because the neural substrates underlying these types of conditioning may be differently affected by time-dependent cortisol effects. Delay conditioning is predominantly amygdala-dependent, while trace conditioning additionally requires the hippocampus. Here, we manipulated the timing of cortisol action during acquisition of delay and trace fear conditioning, by randomly assigning 63 men to one of three possible groups: (1) receiving 10mg hydrocortisone 240 min (slow cort) or (2) 60 min (rapid cort) before delay and trace acquisition, or (3) placebo at both times, in a double-blind design. The next day, we tested memory for trace and delay conditioning. Fear potentiated startle responses, skin conductance responses and unconditioned stimulus expectancy scores were measured throughout the experiment. The fear potentiated startle data show that cortisol intake 240 min before actual fear acquisition (slow cort) uniquely strengthened subsequent trace conditioned memory. No effects of cortisol delivery 60 min prior to fear acquisition were found on any measure of fear memory. Our findings emphasize that slow, presumably genomic, but not more rapid effects of corticosteroids enhance hippocampal-dependent fear memories. On a broader level, our findings underline that basic experimental research and clinically relevant pharmacological treatments employing corticosteroids should acknowledge the timing of corticosteroid administration relative to the learning phase, or therapeutic intervention. PMID- 24485498 TI - Depression but not anxiety is associated with metabolic syndrome in primary care based community sample. AB - INTRODUCTION: Metabolic syndrome (MetS) and depression are considered important risk factors for diabetes and cardiovascular disease. Recent evidence suggests that depression can be an important predictor of MetS. Data on the association between anxiety and MetS remain mixed. In a large primary care based community sample we investigated an association of depressive and anxiety disorders and symptoms with MetS. METHODS: A total of 1115 (51% men, mean age 62.0 +/- 9.6 years) randomly selected individuals of 45 years and older were evaluated for: (i) MetS using the World Health Organization (WHO), National Cholesterol Education Program Adult Treatment Panel III (NCEP/ATP III) and International Diabetes Federation (IDF) criteria; (ii) current major depressive episode (MDE) and current generalized anxiety disorder (GAD), the Mini International Neuropsychiatric interview; (iii) lifetime MDE; and (iv) symptoms of depression and anxiety, the Hospital Anxiety and Depression scale (HADS). Socio-demographic characteristics (education, residence, marital status and social status) and medical histories (physical activity, smoking status, alcohol consumption and histories of myocardial infarction and stroke) were also evaluated. RESULTS: After adjusting for socio-demographic status, medical histories and current GAD, current MDE and lifetime MDE were associated with greater prevalence of MetS according to the WHO criteria (OR=1.7, 95%CI [1.1-2.7] and OR=3.7, 95%CI [2.4 5.7], respectively, p <= 0.001). Lifetime MDE was also associated with MetS according to the IDF and NCEP/ATP III criteria. On the other hand, current GAD was not associated with MetS in multivariate regression models when adjusted for current MDE. Similar results were obtained when evaluating an association between depression/anxiety symptoms and MetS, since elevated depressive, but not anxiety, symptoms were independently associated with MetS. CONCLUSIONS: Depressive, but not anxiety, disorders and symptoms are associated with greater prevalence rate of MetS. Assessment and management of MetS risk factors should be considered in depressed individuals. PMID- 24485499 TI - Cerebrospinal fluid neuropeptide Y in combat veterans with and without posttraumatic stress disorder. AB - Accruing evidence indicates that neuropeptide Y (NPY), a peptide neurotransmitter, is a resilience-to-stress factor in humans. We previously reported reduced cerebrospinal fluid (CSF) NPY concentrations in combat-related posttraumatic stress disorder (PTSD) subjects as compared with healthy, non combat-exposed volunteers. Here we report CSF NPY in combat-exposed veterans with and without PTSD. We quantified NPY concentrations in morning CSF from 11 male subjects with PTSD from combat in Iraq and/or Afghanistan and from 14 combat exposed subjects without PTSD. NPY-like immunoreactivity (NPY-LI) was measured by EIA. The relationship between CSF NPY and clinical symptoms, as measured by the Clinician-Administered PTSD Scale (CAPS) and Beck Depression Inventory (BDI), was assessed, as was the relationship between combat exposure scale (CES) scores and CSF NPY. As compared with the combat-exposed comparison subjects without PTSD, individuals with PTSD had significantly lower concentrations of CSF NPY [mean CSF NPY was 258. 6 +/- 21.64 pg/mL in the combat trauma-no PTSD group but only 180.5 +/- 12.62 pg/mL in PTSD patients (p=0.008)]. After adjusting for CES and BDI scores the two groups were still significantly different with respect to NPY. Importantly, CSF NPY was negatively correlated with composite CAPS score and intrusive (re-experiencing) subscale scores, but did not significantly correlate with CES or BDI scores. Our current findings further suggest that NPY may regulate the manifestation of PTSD symptomatology, and extend previous observations of low CSF NPY concentrations in the disorder. Central nervous system NPY may be a clinically important pharmacotherapeutic target, and/or diagnostic measure, for PTSD. PMID- 24485500 TI - Suitability of commercial barometric pressure sensors to distinguish sitting and standing activities for wearable monitoring. AB - Despite its medical relevance, accurate recognition of sedentary (sitting and lying) and dynamic activities (e.g. standing and walking) remains challenging using a single wearable device. Currently, trunk-worn wearable systems can differentiate sitting from standing with moderate success, as activity classifiers often rely on inertial signals at the transition period (e.g. from sitting to standing) which contains limited information. Discriminating sitting from standing thus requires additional sources of information such as elevation change. The aim of this study is to demonstrate the suitability of barometric pressure, providing an absolute estimate of elevation, for evaluating sitting and standing periods during daily activities. Three sensors were evaluated in both calm laboratory conditions and a pilot study involving seven healthy subjects performing 322 sitting and standing transitions, both indoor and outdoor, in real world conditions. The MS5611-BA01 barometric pressure sensor (Measurement Specialties, USA) demonstrated superior performance to counterparts. It discriminates actual sitting and standing transitions from stationary postures with 99.5% accuracy and is also capable to completely dissociate Sit-to-Stand from Stand-to-Sit transitions. PMID- 24485501 TI - Introduction. Fertility in the face of genetically determined steroidogenic dysfunction. AB - The functional compromise attributable to disordered steroidogenesis, gonadal as well as extragonadal, has a profound impact on human fertility. In this installment of Views and Reviews, we present the latest insights as they apply to the disordered function of various enzymes. PMID- 24485502 TI - Fertility in patients with genetic deficiencies of cytochrome P450c17 (CYP17A1): combined 17-hydroxylase/17,20-lyase deficiency and isolated 17,20-lyase deficiency. AB - CYP17A1 catalyzes the 17-hydroxylase and 17,20-lyase reactions, regulating the steroid hormones produced by the adrenal glands and gonads. Mutations that compromise all CYP17A1 activities are extremely rare and cause combined 17 hydroxylase/17,20-lyase deficiency. Clinically, combined 17-hydroxylase/17,20 lyase deficiency presents with hypertension, hypokalemia, primary amenorrhea, and sexual infantilism. A few mutations selectively impair 17,20-lyase activity, and some mutations in cofactor proteins cytochrome P450-oxidoreductase and cytochrome b5 also selectively disrupt 17,20-lyase activity. The defect in sex steroid synthesis impairs fertility in both male and female patients when the deficiency is severe. This paper reviews the genetics, steroidogenesis, and fertility impairments associated with these disorders. PMID- 24485503 TI - Aromatase and estrogen receptor alpha deficiency. AB - Studies on the phenotypes of women and men with mutations disrupting estrogen biosynthesis and action have significantly advanced our knowledge of the physiologic roles of estrogen in humans. Aromatase deficiency results from autosomal recessive inheritance of mutations in the CYP19A1 gene. It gives rise to ambiguous genitalia in 46,XX fetuses. At puberty, affected girls have hypergonadotropic hypogonadism, do not develop secondary sexual characteristics, and exhibit progressive virilization. The affected 46,XY men have normal male sexual differentiation and pubertal maturation. These men, however, are extremely tall and have eunucoid proportions with continued linear growth into adulthood, severely delayed epiphyseal closure, and osteoporosis due to estrogen deficiency. Although estrogen has been shown to be essential for normal sperm production and function in mice, its role in fertility is not clear in men. Thus far, one man and an unrelated woman with estrogen resistance due to mutations in the estrogen receptor alpha (ESR1) gene have been described. Their clinical presentations are similar to that of aromatase-deficient men and women. PMID- 24485504 TI - In vitro fertilization on the front line: beginning infertility or gonadotropin treatments with in vitro fertilization. PMID- 24485505 TI - Methotrexate for assisted reproductive technology (ART) ectopic pregnancy. PMID- 24485506 TI - Use of fresh versus cryopreserved sperm. PMID- 24485507 TI - Base excision DNA repair levels in mitochondrial lysates of Alzheimer's disease. AB - Alzheimer's disease (AD) is a senile dementia with increased incidence in older subjects (age >65 years). One of the earliest markers of AD is oxidative DNA damage. Recently, it has been reported that preclinical AD patient brains show elevated levels of oxidative damage in both nuclear and mitochondrial nucleic acids. Moreover, different oxidative lesions in mitochondrial DNA are between 5- and 10-fold higher than in nuclear DNA in both control and AD postmortem brains. We previously showed that there is a significant loss of base excision repair (BER) components in whole tissue extracts of AD and mild cognitive impairment subjects relative to matched control subjects. However, comprehensive analysis of specific steps in BER levels in mitochondrial extracts of AD patient brains is not available. In this study, we mainly investigated various components of BER in mitochondrial extracts of AD and matched control postmortem brain samples. We found that the 5-hydroxyuracil incision and ligase activities are significantly lower in AD brains, whereas the uracil incision, abasic site cleavage, and deoxyribonucleotide triphosphate incorporation activities are normal in these samples. PMID- 24485509 TI - Position control of an electro-pneumatic system based on PWM technique and FLC. AB - In this paper, modeling and PWM based control of an electro-pneumatic system, including the four 2-2 valves and a double acting cylinder are studied. Dynamic nonlinear behavior of the system, containing fast switching solenoid valves and a pneumatic cylinder, as well as electrical, magnetic, mechanical, and fluid subsystems are modeled. A DC-DC power converter is employed to improve solenoid valve performance and suppress system delay. Among different position control methods, a proportional integrator derivative (PID) controller and fuzzy logic controller (FLC) are evaluated. An experimental setup, using an AVR microcontroller is implemented. Simulation and experimental results verify the effectiveness of the proposed control strategies. PMID- 24485510 TI - Authors' reply regarding "A general three dimensional parametric geometry of the native aortic valve and root for biomechanical modeling". PMID- 24485508 TI - Migration of neutrophils targeting amyloid plaques in Alzheimer's disease mouse model. AB - Immune responses in the brain are thought to play a role in disorders of the central nervous system, but an understanding of the process underlying how immune cells get into the brain and their fate there remains unclear. In this study, we used a 2-photon microscopy to reveal that neutrophils infiltrate brain and migrate toward amyloid plaques in a mouse model of Alzheimer's disease. These findings suggest a new molecular process underlying the pathophysiology of Alzheimer's disease. PMID- 24485511 TI - Quantifying lumbar-pelvis coordination during gait using a modified vector coding technique. AB - The complexity of human gait patterns has become a topic of major interest in motor control and biomechanics. Range of motion is still the preferred method to quantify movement impairment, however, within these traditional linear measures, the inter-segmental coordination and movement variability is normally ignored. A dynamical systems approach using vector coding and circular statistics provides non-linear techniques to quantify coordination and variability. This study provides comprehensive vector coding and circular statistics calculations. Additionally, pelvis-lumbar coordination and coordination variability data obtained from ten healthy young male participants during five walking trials using an optoelectronic system is provided. This novel data can form the baseline information for future studies in this area of research. Finally, a new illustration to present coordination and coordination variability information of gait kinematics, combining the output from the modified vector coding technique with traditional time-series segmental angle data is presented. This technique, when applied to single patients can be beneficial to assess the effect of an intervention on the patient-specific inter-segmental coordination pattern with implications to the clinical setting. PMID- 24485512 TI - Patellar mechanics during simulated kneeling in the natural and implanted knee. AB - Kneeling is required during daily living for many patients after total knee replacement (TKR), yet many patients have reported that they cannot kneel due to pain, or avoid kneeling due to discomfort, which critically impacts quality of life and perceived success of the TKR procedure. The objective of this study was to evaluate the effect of component design on patellofemoral (PF) mechanics during a kneeling activity. A computational model to predict natural and implanted PF kinematics and bone strains after kneeling was developed and kinematics were validated with experimental cadaveric studies. PF joint kinematics and patellar bone strains were compared for implants with dome, medialized dome, and anatomic components. Due to the less conforming nature of the designs, change in sagittal plane tilt as a result of kneeling at 90 degrees knee flexion was approximately twice as large for the medialized-dome and dome implants as the natural case or anatomic implant, which may result in additional stretching of the quadriceps. All implanted cases resulted in substantial increases in bone strains compared with the natural knee, but increased strains in different regions. The anatomic patella demonstrated increased strains inferiorly, while the dome and medialized dome showed increases centrally. An understanding of the effect of implant design on patellar mechanics during kneeling may ultimately provide guidance to component designs that reduces the likelihood of knee pain and patellar fracture during kneeling. PMID- 24485513 TI - Prediction bands and intervals for the scapulo-humeral coordination based on the Bootstrap and two Gaussian methods. AB - Quantitative motion analysis protocols have been developed to assess the coordination between scapula and humerus. However, the application of these protocols to test whether a subject's scapula resting position or pattern of coordination is "normal", is precluded by the unavailability of reference prediction intervals and bands, respectively. The aim of this study was to present such references for the "ISEO" protocol, by using the non-parametric Bootstrap approach and two parametric Gaussian methods (based on Student's T and Normal distributions). One hundred and eleven asymptomatic subjects were divided into three groups based on their age (18-30, 31-50, and 51-70). For each group, "monolateral" prediction bands and intervals were computed for the scapulo humeral patterns and the scapula resting orientation, respectively. A fourth group included the 36 subjects (42 +/- 13 year-old) for whom the scapulo-humeral coordination was measured bilaterally, and "differential" prediction bands and intervals were computed, which describe right-to-left side differences. Bootstrap and Gaussian methods were compared using cross-validation analyses, by evaluating the coverage probability in comparison to a 90% target. Results showed a mean coverage for Bootstrap from 86% to 90%, compared to 67-70% for parametric bands and 87-88% for parametric intervals. Bootstrap prediction bands showed a distinctive change in amplitude and mean pattern related to age, with an increase toward scapula retraction, lateral rotation and posterior tilt. In conclusion, Bootstrap ensures an optimal coverage and should be preferred over parametric methods. Moreover, the stratification of "monolateral" prediction bands and intervals by age appears relevant for the correct classification of patients. PMID- 24485515 TI - Letter to the Editor regarding "A general three-dimensional parametric geometry of the native aortic valve and root for biomechanical modeling". PMID- 24485516 TI - Impact of fatty acids on brain circulation, structure and function. AB - The use of dietary intervention has evolved into a promising approach to prevent the onset and progression of brain diseases. The positive relationship between intake of omega-3 long chain polyunsaturated fatty acids (omega3-LCPUFAs) and decreased onset of disease- and aging-related deterioration of brain health is increasingly endorsed across epidemiological and diet-interventional studies. Promising results are found regarding to the protection of proper brain circulation, structure and functionality in healthy and diseased humans and animal models. These include enhanced cerebral blood flow (CBF), white and gray matter integrity, and improved cognitive functioning, and are possibly mediated through increased neurovascular coupling, neuroprotection and neuronal plasticity, respectively. Contrary, studies investigating diets high in saturated fats provide opposite results, which may eventually lead to irreversible damage. Studies like these are of great importance given the high incidence of obesity caused by the increased and decreased consumption of respectively saturated fats and omega3-LCPUFAs in the Western civilization. This paper will review in vivo research conducted on the effects of omega3-LCPUFAs and saturated fatty acids on integrity (circulation, structure and function) of the young, aging and diseased brain. PMID- 24485514 TI - Plaque hemorrhage in carotid artery disease: pathogenesis, clinical and biomechanical considerations. AB - Stroke remains the most prevalent disabling illness today, with internal carotid artery luminal stenosis due to atheroma formation responsible for the majority of ischemic cerebrovascular events. Severity of luminal stenosis continues to dictate both patient risk stratification and the likelihood of surgical intervention. But there is growing evidence to suggest that plaque morphology may help improve pre-existing risk stratification criteria. Plaque components such a fibrous tissue, lipid rich necrotic core and calcium have been well investigated but plaque hemorrhage (PH) has been somewhat overlooked. In this review we discuss the pathogenesis of PH, its role in dictating plaque vulnerability, PH imaging techniques, marterial properties of atherosclerotic tissues, in particular, those obtained based on in vivo measurements and effect of PH in modulating local biomechanics. PMID- 24485518 TI - Duplication cyst with esophageal mucosa at the floor of the mouth: a case report. AB - Intraoral localization of alimentary tract duplication is extremely rare. We report a duplication cyst at the floor of the mouth, lined by esophageal epithelium and treated successfully by surgical excision. To our knowledge, this is the third case of intraoral enteric duplication cysts lined with esophageal epithelium reported in the literature. PMID- 24485517 TI - What do grid cells contribute to place cell firing? AB - The unitary firing fields of hippocampal place cells are commonly assumed to be generated by input from entorhinal grid cell modules with differing spatial scales. Here, we review recent research that brings this assumption into doubt. Instead, we propose that place cell spatial firing patterns are determined by environmental sensory inputs, including those representing the distance and direction to environmental boundaries, while grid cells provide a complementary self-motion related input that contributes to maintaining place cell firing. In this view, grid and place cell firing patterns are not successive stages of a processing hierarchy, but complementary and interacting representations that work in combination to support the reliable coding of large-scale space. PMID- 24485523 TI - Orchestrating immune check-point blockade for cancer immunotherapy in combinations. AB - Inhibitory receptors on immune system cells respond to membrane-bound and soluble ligands to abort or mitigate the intensity of immune responses by raising thresholds of activation, halting proliferation, favoring apoptosis or inhibiting/deviating effector function differentiation. Such evolutionarily selected inhibitory mechanisms are termed check-points and therefore check-point inhibitors empower any ongoing anti-cancer immune response that might have been too weak or exhausted. Monoclonal antibodies (mAb) interfering with CTLA-4 CD80/86, PD-1 - PD-L1, TIM-3-GAL9 and LAG3-MHC-II belong to this category of check-point inhibitors. The anti-CTLA-4 mAb ipilimumab has been approved for metastatic melanoma. Anti-PD-1 and anti-PD-L1 mAbs have shown extremely encouraging clinical activity. The potential of combination strategies with these agents has recently been highlighted by clinical observations on CTLA-4+PD-1 combined blockade in melanoma patients. PMID- 24485524 TI - [Bilateral endogenous ophthalmitis due to Candida glabrata after complicated bariatric surgery]. AB - CASE REPORT: A 43 year-old female presented with decreased visual acuity in the right eye. "Snowball-like" retinal lesions were found in both eyes on examination. Due to a lack of improvement with intravitreal antifungal empirical treatment, vitreous culture was performed and Candida glabrata was isolated. The patient then received intravitreal amphotericin B, as well as systemic treatment with caspofungin and amphotericin B lipid complex. DISCUSSION: Endogenous fungal endophthalmitis is a sight-threatening condition. There are few reports of Candida glabrata endogenous endophthalmitis. Treatment regimens for Candida endophthalmitis include combinations of systemic and/or intravitreal antifungals, as well as vitrectomy. PMID- 24485525 TI - Norwegian Red Cross--80 years in service for blood donors. AB - The voluntary, non-remunerated blood donation organization is the important part of the International Red Cross movement. Historically the Red Cross Blood Program was established in Oslo with the main objectives to recruit new donors, support the blood banks with recruiting materials and to support in recruiting efforts made by local Red Cross branches. Currently the continual education of the recruited skilled personals, at all levels, is considered to be an essential part of such a program. The 2013 coincide with the 12th anniversary of Norwegian educational program in Quality in Transfusion Medicine. This report focuses on the historical background on the Red Cross Quality Course in Transfusion Medicine, as well as the progress made so far and looking into future perspectives. PMID- 24485526 TI - Interleukin-23 receptor single nucleotide polymorphisms in ulcerative colitis. A study in Iranian populations. AB - BACKGROUND/OBJECTIVE: Genetic factors seem to play an important role in the pathogenesis of ulcerative colitis (UC). Genome wide association studies showed a highly significant association between interleukin 23 receptor (IL23R) single nucleotide polymorphisms (SNPs) and Crohn's disease; however, there are contrary results regarding the disease-modifying effects of IL23R variants in UC. This study was performed in a group of patients with UC to test the possible role of IL23R SNPs in conferring susceptibility or protection against the disease. METHODS: The study was performed on 67 Iranian adult patients with UC and 78 healthy controls. Eight IL23R SNPs were genotyped, using real-time polymerase chain reaction (RT-PCR). The frequencies of alleles and genotype at each position were determined and compared between two groups of patients and controls. RESULTS: The frequency of the T allele at position rs1343151 was significantly higher in the patient group, compared to the controls (P=0.018). The TT genotype at the same position was also significantly overrepresented in the patient group (P=0.02). There was no significant difference in alleles and genotype frequencies of other SNPs between patients and controls. CONCLUSIONS: This study identified a new susceptibility locus associated with UC. Our findings provide further insight into the genetics of UC, which might be amenable to future therapeutic intervention. PMID- 24485527 TI - Lethal effect of a hyperthermic CO2 pneumoperitoneum on gastric cancer cells. AB - OBJECTIVES: We investigated the lethal effect of a hyperthermic CO2 pneumoperitoneum on gastric cancer cells. This could form the theoretical basis for further studies of the feasibility and safety of inflating hyperthermic CO2 in the abdominal cavity of gastric cancer patients during laparoscopy. METHODS: An in vitro hyperthermic CO2 pneumoperitoneum experimental model was built, where gastric cancer cell line SGC-7901 cells were grouped according to temperature. Cytotoxicity was detected using a cell counting kit; apoptosis was detected by Annexin V-FITC/PI flow cytometry and Hoechst 33342/PI fluorescent microscopy. Morphological alterations were observed by transmission electron microscopy. Invasion and migration were detected by a scratch test and by transwell migration, respectively. RESULTS: Cytotoxicity assays showed that a hyperthermic CO2 pneumoperitoneum significantly inhibited the proliferation of SGC-7901 cells (P<0.05); it also significantly induced apoptosis of SGC-7901 cells (P<0.05). Morphological observations showed that the cell membrane and nucleus had an apoptotic phenotype. The invasiveness and migration ability of the gastric cancer cells subjected to hyperthermic CO2 were significantly reduced. CONCLUSIONS: A hyperthermic CO2 pneumoperitoneum had a lethal effect on gastric cancer SGC-7901 cells by inhibiting their invasion and migration, and by inducing apoptosis. PMID- 24485528 TI - Is imaging the extremities with PEM feasible? A novel application for a high resolution positron emission scanner. AB - INTRODUCTION: Positron emission mammography (PEM) has better spatial resolution than positron emission tomography/computed tomography (PET/CT), or PET/CT. We evaluated the feasibility of extremity imaging with PEM using PET as a standard. METHODS/MATERIALS: Fourteen patients underwent sequential PET/CT and PEM. RESULTS/DISCUSSION: PEM visualized with equal or improved resolution all of the lesions identified on PET/CT. It often provided additional information such improved uptake localization and also visualized activity in an adjacent structures that was not seen on PET/CT or magnetic resonance imaging. We believe PEM can image the extremities in diseases like melanoma, arthritis and osteomyelitis and patients with metallic hardware. PMID- 24485529 TI - Five-year malignancy incidence in patients with chronic pruritus: a population based cohort study aimed at limiting unnecessary screening practices. AB - BACKGROUND: The incidence of malignancy in patients with chronic pruritus and nondiseased skin is unknown. OBJECTIVE: We sought to assess the hazard ratio (HR) of incident overall malignancy and incident malignancy by subtype in patients with chronic pruritus during the 5 years after diagnosis. METHODS: A population based cohort study was performed in the Health Improvement Network. In all, 8744 patients with chronic pruritus were matched with 31,580 patients without chronic pruritus based on sex, age, and practice. Primary outcomes were HR of incident malignancy and HR of malignancy subtypes. RESULTS: The fully adjusted HR for incident malignancy in patients with chronic pruritus was 1.14 (95% confidence interval 0.98-1.33). The fully adjusted HR for incident hematologic malignancy and incident bile duct malignancy in patients with chronic pruritus was 2.02 (95% confidence interval 1.48-2.75) and 3.73 (95% confidence interval 1.55-8.97), respectively. The incidence of hematologic malignancy and cholangiocarcinoma in patients with chronic pruritus was 0.0016 and 0.0003 per person-year, respectively. LIMITATIONS: Potential for misclassification and detection biases is a limitation. CONCLUSIONS: Chronic pruritus without concomitant skin changes is a risk factor for having undiagnosed hematologic and bile duct malignancies, but not other malignancies. The overall incidence of these malignancies in patients with chronic pruritus is very low. PMID- 24485530 TI - Skin cancer and photoprotection in people of color: a review and recommendations for physicians and the public. AB - Skin cancer is less prevalent in people of color than in the white population. However, when skin cancer occurs in non-whites, it often presents at a more advanced stage, and thus the prognosis is worse compared with white patients. The increased morbidity and mortality associated with skin cancer in patients of color compared with white patients may be because of the lack of awareness, diagnoses at a more advanced stage, and socioeconomic factors such as access to care barriers. Physician promotion of skin cancer prevention strategies for all patients, regardless of ethnic background and socioeconomic status, can lead to timely diagnosis and treatment. Public education campaigns should be expanded to target communities of color to promote self-skin examination and stress importance of photoprotection, avoidance of tanning bed use, and early skin cancer detection and treatment. These measures should result in reduction or earlier detection of cutaneous malignancies in all communities. Furthermore, promotion of photoprotection practices may reduce other adverse effects of ultraviolet exposure including photoaging and ultraviolet-related disorders of pigmentation. PMID- 24485531 TI - Individualized positive end-expiratory pressure application in patients with acute respiratory distress syndrome. AB - Current treatment of acute respiratory distress syndrome is based on ventilatory support with a lung protective strategy, avoiding the development of iatrogenic injury, including ventilator-induced lung injury. One of the mechanisms underlying such injury is atelectrauma, and positive end-expiratory pressure (PEEP) is advocated in order to avoid it. The indicated PEEP level has not been defined, and in many cases is based on the patient oxygen requirements for maintaining adequate oxygenation. However, this strategy does not consider the mechanics of the respiratory system, which varies in each patient and depends on many factors-including particularly the duration of acute respiratory distress syndrome. A review is therefore made of the different methods for adjusting PEEP, focusing on the benefits of individualized application. PMID- 24485532 TI - [Pneumocystis jiroveci pneumonia: Clinical characteristics and mortality risk factors in an Intensive Care Unit]. AB - OBJECTIVE: To describe the epidemiological characteristics of the population with Pneumocystis jiroveci (P. jiroveci) pneumonia, analyzing risk factors associated with the disease, predisposing factors for admission to an intensive care unit (ICU), and prognostic factors of mortality. DESIGN AND PATIENTS: A retrospective observational study was carried out, involving a cohort of patients consecutively admitted to a hospital in Spain from 1 January 2007 to 31 December 2011, with a final diagnosis of P. jiroveci pneumonia. SETTING: The ICU and hospitalization service of Hospital del Mar, Barcelona (Spain). RESULTS: We included 36 patients with pneumonia due to P. jiroveci. Of these subjects, 16 required ICU admission (44.4%). The average age of the patients was 41.3 +/- 12 years, and 23 were men (63.9%). A total of 86.1% had a history of human immunodeficiency virus (HIV) infection, and the remaining 13.9% presented immune-based disease subjected to immunosuppressive therapy. Risk factors associated to hospital mortality were age (51.8 vs. 37.3 years, P=.002), a higher APACHE score upon admission (17 vs. 13 points, P=.009), the need for invasive mechanical ventilation (27.8% vs. 11.1%, P=.000), requirement of vasoactive drugs (25.0% vs. 11.1%, P=.000), fungal coinfection (22.2% vs. 11.1%, P=.001), pneumothorax (16.7% vs. 83.3%, P=.000) and admission to the ICU (27.8% vs. 72.2% P=.000). CONCLUSIONS: The high requirement of mechanical ventilation and vasoactive drugs associated with fungal coinfection and pneumothorax in patients admitted to the ICU remain as risk factors associated with mortality in patients with P. jiroveci pneumonia. PMID- 24485533 TI - [Teaching basic life support to the general population. Alumni intervention analysis]. AB - OBJECTIVES: The aim of this study was to investigate the rate at which the alumni of basic life support courses witnessed and intervened in out-of-hospital emergency situations, and to identify the variables characterizing those alumni associated with a greater number of witnessing events and interventions. An analysis of the efficiency of the courses was also carried out. DESIGN: A descriptive, cross-sectional study was made. SETTING: A district in the province of Almeria (Spain). PATIENTS: Alumni of a mass basic life support training program targeted to the general population "Plan Salvavidas" conducted between 2003-2009. INTERVENTIONS: In 2010 the alumni were administered a telephone survey asking whether they had witnessed an emergency situation since attending the program, with the collection of information related to this emergency situation. MAIN VARIABLES OF INTEREST: Rate of out-of-hospital emergencies witnessed by the alumni. Rate of intervention of the alumni in emergency situations. Variables characterizing alumni with a greater likelihood of witnessing an emergency situation. RESULTS: A total of 3,864 trained alumni were contacted by telephone. Of 1,098 respondents, 63.9% were women, and the mean age was 26.61+/-10.6 years. Of these alumni, 11.75% had witnessed emergency situations, an average of three years after completing the course. Of these emergencies, 23.3% were identified as cardiac arrest. The alumni intervened in 98% of the possible cases. In 63% of the cases, there was no connection between the alumni and the victim. The majority of the emergency situations occurred in the street and in public spaces. A greater likelihood of witnessing an emergency situation was associated with being a healthcare worker and with being over 18 years of age. CONCLUSIONS: The rate of out-of-hospital emergencies witnessed by these alumni after the course was 11.75%. The level of intervention among the alumni was high. The most efficient target population consisted of healthcare workers. PMID- 24485534 TI - [Further clarifications on the limitation of life-sustaining treatment and organ donation]. PMID- 24485535 TI - [Lactic acid as a prognostic marker in obstetric postpartum hemorrhage]. PMID- 24485536 TI - Parapharyngeal ectopic thyroid: A clinical case report. PMID- 24485537 TI - Unexpected dimerization of isoprene in a gas chromatography inlet. A study by gas chromatography/mass spectrometry coupling. AB - During analysis of pure isoprene by gas chromatography/mass spectrometry (GC-MS) using a programmed temperature vaporization (PTV) inlet, the presence of several isoprene dimers was detected in the total ion chromatograms (TICs). This study intends to determine the part of the instrument where dimerization occurs and the relative importance of the dimer amounts under different experimental conditions. The reference thermal dimerization of isoprene gives four six-membered cyclic dimers and two eight-membered ones. In all samples containing different amounts of freshly distilled isoprene, only peaks corresponding to the former appeared in TICs. For the same temperature, their amounts increase as the concentration of injected isoprene increases. The main products are diprene (from 80 to 100%) of the total dimers and dipentene (from 1 to 14%). The sum of the two other dimers is never higher than 6%. In conclusion, isomeric dimers are produced through a dimerization in the inlet. No dimerization of isoprene occurs in the mass spectrometer source. Then care is needed when analyzing terpenic compounds in the presence of isoprene by GC-MS because structures, retention times and mass spectra of diprene and dipentene are close. PMID- 24485538 TI - Molecular theory of size exclusion chromatography for wide pore size distributions. AB - Chromatographic processes can conveniently be modeled at a microscopic level using the molecular theory of chromatography. This molecular or microscopic theory is completely general; therefore it can be used for any chromatographic process such as adsorption, partition, ion-exchange or size exclusion chromatography. The molecular theory of chromatography allows taking into account the kinetics of the pore ingress and egress processes, the heterogeneity of the pore sizes and polymer polydispersion. In this work, we assume that the pore size in the stationary phase of chromatographic columns is governed by a wide lognormal distribution. This property is integrated into the molecular model of size exclusion chromatography and the moments of the elution profiles were calculated for several kinds of pore structure. Our results demonstrate that wide pore size distributions have strong influence on the retention properties (retention time, peak width, and peak shape) of macromolecules. The novel model allows us to estimate the real pore size distribution of commonly used HPLC stationary phases, and the effect of this distribution on the size exclusion process. PMID- 24485540 TI - An injection molded microchip for nucleic acid purification from 25 microliter samples using isotachophoresis. AB - We present a novel microchip device for purification of nucleic acids from 25MUL biological samples using isotachophoresis (ITP). The device design incorporates a custom capillary barrier structure to facilitate robust sample loading. The chip uses a 2mm channel width and 0.15mm depth to reduce processing time, mitigate Joule heating, and achieve high extraction efficiency. To reduce pH changes in the device due to electrolysis, we incorporated a buffering reservoir physically separated from the sample output reservoir. To reduce dispersion of the ITP focused zone, we used optimized turn geometries. The chip was fabricated by injection molding PMMA and COC plastics through a commercial microfluidic foundry. The extraction efficiency of nucleic acids from the device was measured using fluorescent quantification, and an average recovery efficiency of 81% was achieved for nucleic acid masses between 250pg and 250ng. The devices were also used to purify DNA from whole blood, and the extracted DNA was amplified using qPCR to show the PCR compatibility of the purified sample. PMID- 24485541 TI - A critical overview of non-aqueous capillary electrophoresis. Part II: separation efficiency and analysis time. AB - A survey of the literature on non-aqueous capillary zone electrophoresis leaves one with the impression of a prevailing notion that non-aqueous conditions are principally more favorable than conventional aqueous media. Specifically, the application of organic solvents in capillary zone electrophoresis (CZE) is believed to provide the general advantages of superior separation efficiency, higher applicable electric field strength, and shorter analysis time. These advantages, however, are often claimed without providing any experimental evidence, or based on rather uncritical comparisons of limited sets of arbitrarily selected separation results. Therefore, the performance characteristics of non-aqueous vs. aqueous CZE certainly deserve closer scrutiny. The primary intention of Part II of this review is to give a critical survey of the literature on non-aqueous capillary electrophoresis (NACE) that has emerged over the last five years. Emphasis is mainly placed on those studies that are concerned with the aspects of plate height, plate number, and the crucial mechanisms contributing to zone broadening, both in organic and aqueous conditions. To facilitate a deeper understanding, this treatment covers also the theoretical fundamentals of peak dispersion phenomena arising from wall adsorption; concentration overload (electromigration dispersion); longitudinal diffusion; and thermal gradients. Theoretically achievable plate numbers are discussed, both under limiting (at zero ionic strength) and application-relevant conditions (at finite ionic strength). In addition, the impact of the superimposed electroosmotic flow contributions to overall CZE performance is addressed, both for aqueous and non-aqueous media. It was concluded that for peak dispersion due to wall adsorption and due to concentration overload (electromigration dispersion, leading to peak triangulation) no general conjunction with the solvent can be deduced. This is in contrast to longitudinal diffusion: the plate height (and the plate number) obtainable under limiting conditions (at zero ionic strength) has the same ultimate value for all solvents. However, in background electrolytes with finite ionic strength, the maximum reachable plate number depends on the solvent, and in water it is higher than in the most commonly used organic solvents: methanol and acetonitrile. Thermal peak broadening is also larger in the organic solvents if compared to aqueous solutions under comparable conditions. However, its influence on the plate height is negligible under conditions established with commercial instrumentation. From the laws of electric and thermal conductance, it follows that no general conclusion can be drawn that with organic solvents higher field strength can be applied and shorter analysis time can be reached; the contrary is more evident: under comparable conditions aqueous solutions lead to more favorable results. This comprehensive analysis provides strong evidence that the broadly held notion of non-aqueous CZE being principally superior to aqueous CZE is a myth rather than a fact. However, several studies in which the employment of non-aqueous conditions has been instrumental to solve challenging analytical problems demonstrate that the intelligent use of non-aqueous CE has and will continue having its place in modern separation science. PMID- 24485539 TI - Polyamines in biological samples: rapid and robust quantification by solid-phase extraction online-coupled to liquid chromatography-tandem mass spectrometry. AB - Polyamines are ubiquitous active biogenic amines which contribute to basic cellular functions. Hence, their quantification in samples of diverse biological origins is essential for understanding how they function, especially in disease relevant conditions. We present here a robust, high-throughput solid-phase extraction online coupled to a liquid chromatography-tandem mass spectrometry (SPE-LC/MS/MS) approach for the simultaneous quantification of eight polyamines in various biological samples. The polyamines include 1,3-diaminopropane, putrescine, cadaverin, N-acetyl-putrescine, spermidine, spermine, N(1)-acetyl spermine, and l-ornithine. The novelty of the work is the use of two SPE columns online coupled to LC/MS/MS, which minimizes the sample pretreatment to a single derivatization step. The analysis is complete within 4min, making the method highly suitable for routine clinical analysis and high throughput screenings. The method was fully validated with serum samples. Dynamic ranges were 0.03 to 15MUg/ml for ornithine and 1 to 500ng/ml for other polyamines, which cover physiological concentrations in serum samples. Lower limits of quantification (LLoQ) were found to be between 0.1 and 5ng/ml. As a proof of concept, we investigated gender differences in polyamine levels by analyzing the serum levels of 102 subjects. PMID- 24485542 TI - New approach for purification of pre-miR-29 using lysine-affinity chromatography. AB - miRNA-based gene therapy applications require microRNA with high purity degree, good quality and biologically active. Owing to the commercial interest in these approaches, there is a growing interest in the development of innovative procedures to easily and efficiently purify the RNA. Thus, several chromatographic and non-chromatographic methods have been reported to accomplish this purpose, but not all of these strategies allow the efficient separation of miRNAs. The present study describes a new strategy that uses a lysine ligand in affinity chromatography to efficiently separate pre-miR-29 from a small RNAs mixture. The interest on this biomolecule is related to the fact that pre-miR-29 deficiencies or excesses have been associated to a number of clinically important diseases. The retention behaviour of pre-miR-29 was characterized and adjusted to achieve higher specificity in this chromatographic operation, using an ammonium sulfate stepwise gradient. Overall, it was verified that lysine-agarose support can promote a specific interaction with the pre-miR-29 favouring its total separation. The results also suggest that the underlying mechanism involves biorecognition of pre-miR-29 by the lysine ligands, resulting from the occurrence of different elementary interactions, including hydrogen and hydrophobic interactions. PMID- 24485543 TI - Systolic dysfunction and diastolic dysfunction do not influence medium-term prognosis in patients with cirrhosis. AB - OBJECTIVE: Myocardial dysfunction has been described in patients with cirrhosis and may contribute to haemodynamic disturbances in advanced disease states. However, the prognostic impact of cardiac systolic and diastolic dysfunction in cirrhosis is controversial. We aimed to evaluate the performance of echocardiographic parameters of cardiac function as medium-term prognostic markers, in a cohort of cirrhotic patients. METHODS: Ninety-eight patients (52 discharged after hospitalization for decompensated cirrhosis and 46 ambulatory) were prospectively evaluated. A comprehensive echocardiographic study, including tissue-Doppler and speckle tracking analysis, was performed at baseline. Patients were followed-up for 6 months for the occurrence of death. RESULTS: Twenty patients died during the follow-up. None of the echocardiographic parameters were associated with the occurrence of death. A Child score>10 points (HR 13.1, 95% CI 3.79-45.0, p<0.001) and a mean arterial pressure below the median (HR 3.2, 95% CI 1.14-8.80, p=0.028) were the only independent predictors of mortality in Cox regression multivariate analysis. In previously hospitalized patients, cardiac output, C-reactive protein and albumin levels were associated with 6-month mortality in univariate analysis; this association was lost after adjusting for Child score. CONCLUSIONS: Medium-term mortality in cirrhosis seems to be mainly determined by liver disease severity rather than by myocardial dysfunction. Modern echocardiographic indices of systolic and diastolic function do not seem to be useful in identifying patients at increased risk of dying. PMID- 24485544 TI - Characteristics of patients admitted to internal medicine departments with high serum cobalamin levels: results from a prospective cohort study. PMID- 24485545 TI - Stroke severity and outcome in women and men in the Lecco area, Italy. PMID- 24485546 TI - "Go4Life" exercise counseling, accelerometer feedback, and activity levels in older people. AB - Older people are more sedentary than other age groups. We sought to determine if providing an accelerometer with feedback about activity and counseling older subjects using Go4Life educational material would increase activity levels. Participants were recruited from independent living areas within assisted living facilities and the general public in the Rochester, MN area. 49 persons aged 65 95 (79.5+/-7.0 years) who were ambulatory but sedentary and overweight participated in this randomized controlled crossover trial for one year. After a baseline period of 2 weeks, group 1 received an accelerometer and counseling using Go4Life educational material (www.Go4Life.nia.nih.gov) for 24 weeks and accelerometer alone for the next 24 weeks. Group 2 had no intervention for the first 24 weeks and then received an accelerometer and Go4Life based counseling for 24 weeks. There were no significant baseline differences between the two groups. The intervention was not associated with a significant change in activity, body weight, % body fat, or blood parameters (p>0.05). Older (80-93) subjects were less active than younger (65-79) subjects (p=0.003). Over the course of the 48 week study, an increase in activity level was associated with a decline in % body fat (p=0.008). Increasing activity levels benefits older patients. However, providing an accelerometer and a Go4Life based exercise counseling program did not result in a 15% improvement in activity levels in this elderly population. Alternate approaches to exercise counseling may be needed in elderly people of this age range. PMID- 24485547 TI - Prevention of varicella: time for two-dose vaccination. PMID- 24485548 TI - Protection against varicella with two doses of combined measles-mumps-rubella varicella vaccine versus one dose of monovalent varicella vaccine: a multicentre, observer-blind, randomised, controlled trial. AB - BACKGROUND: Rates of varicella have decreased substantially in countries implementing routine varicella vaccination. Immunisation is possible with monovalent varicella vaccine or a combined measles-mumps-rubella-varicella vaccine (MMRV). We assessed protection against varicella in naive children administered one dose of varicella vaccine or two doses of MMRV. METHODS: This study was done in ten European countries with endemic varicella. Healthy children aged 12-22 months were randomised (3:3:1 ratio, by computer-generated randomisation list, with block size seven) to receive 42 days apart (1) two doses of MMRV (MMRV group), or (2) MMR at dose one and monovalent varicella vaccine at dose two (MMR+V group), or (3) two doses of MMR (MMR group; control). Participants and their parents or guardians, individuals involved in assessment of any outcome, and sponsor staff involved in review or analysis of data were masked to treatment assignment. The primary efficacy endpoint was occurrence of confirmed varicella (by detection of varicella zoster virus DNA or epidemiological link) from 42 days after the second vaccine dose to the end of the first phase of the trial. Cases were graded for severity. Efficacy analyses were per protocol. Safety analyses included all participants who received at least one vaccine dose. This trial is registered with ClinicalTrials.gov, number NCT00226499. FINDINGS: Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14.2 months, SD 2.5) were vaccinated. In the efficacy cohort of 5285 children, the mean duration of follow-up in the MMRV group was 36 months (SD 8.8), in the MMR+V group was 36 months (8.5) and in the MMR group was 35 months (8.9). Varicella cases were confirmed for 37 participants in the MMRV group (two moderate to severe), 243 in the MMR+V group, and 201 in the MMR group. Second cases occurred for three participants (all in the MMR+V group). Varicella cases were moderate to severe for two participants in the MMRV group, 37 in the MMR+V group (one being a second case that followed a mild first case); and 117 in the MMR group. Efficacy of two-dose MMRV against all varicella was 94.9% (97.5% CI 92.4-96.6), and against moderate to severe varicella was 99.5% (97.5-99.9). Efficacy of one-dose varicella vaccine against all varicella was 65.4% (57.2 72.1), and against moderate to severe varicella (post hoc) was 90.7% (85.9-93.9). The most common adverse event in all groups was injection-site redness (up to 25% of participants). Within 15 days after dose one, 57.4% (95% CI 53.9-60.9) of participants in the MMRV group reported fever of 38 degrees C or more, by contrast with 44.5% (41.0-48.1) with MMR+V, and 39.8% (33.8-46.1) with MMR. Eight serious adverse events were deemed related to vaccination (three MMRV, four MMR+V, one MMR). All resolved within the study period. INTERPRETATION: These results support the implementation of two-dose varicella vaccination on a short course, to ensure optimum protection from all forms of varicella disease. FUNDING: GlaxoSmithKline Vaccines. PMID- 24485549 TI - Prospective randomised controlled trial of nanocrystalline silver dressing versus plain gauze as the initial post-debridement management of military wounds on wound microbiology and healing. AB - INTRODUCTION: Recent conflicts have been characterised by the use of improvised explosive devices causing devastating injuries, including heavily contaminated wounds requiring meticulous surgical debridement. After being rendered surgical clean, these wounds are dressed and the patient transferred back to the UK for on going treatment. A dressing that would prevent wounds from becoming colonised during transit would be desirable. The aim of this study was to establish whether using nanocrystalline silver dressings, as an adjunct to the initial debridement, would positively affect wound microbiology and wound healing compared to standard plain gauze dressings. METHODS: Patients were prospectively randomised to receive either silver dressings, in a nanocrystalline preparation (ActicoatTM), or standard of care dressings (plain gauze) following their initial debridement in the field hospital. On repatriation to the UK microbiological swabs were taken from the dressing and the wound, and an odour score recorded. Wounds were followed prospectively and time to wound healing was recorded. Additionally, patient demographic data were recorded, as well as the mechanism of injury and Injury Severity Score. RESULTS: 76 patients were recruited to the trial between February 2010 and February 2012. 39 received current dressings and 37 received the trial dressings. Eleven patients were not swabbed. There was no difference (p=0.1384, Fishers) in the primary outcome measure of wound colonisation between the treatment arm (14/33) and the control arm (20/32). Similarly time to wound healing was not statistically different (p=0.5009, Mann-Whitney). Wounds in the control group were scored as being significantly more malodorous (p=0.002, Mann Whitney) than those in the treatment arm. CONCLUSIONS: This is the first randomised controlled trial to report results from an active theatre of war. Performing research under these conditions poses additional challenges to military clinicians. Meticulous debridement of wounds remains the critical determinant in wound healing and infection and this study did not demonstrate a benefit of nanocrystaline silver dressing in respect to preventing wound colonisation or promoting healing, these dressings do however seem to significantly reduce the unpleasant odour commonly associated with battlefield wounds. PMID- 24485550 TI - Lower genitourinary trauma in modern warfare: the experience from civil violence in Iraq. AB - BACKGROUND: Reports on genitourinary (GU) trauma during the Iraqi conflict have been limited to battlefield injuries. We sought to characterise the incidence, mechanism of injury, wounding pattern, and management of lower GU injuries sustained in civil violence during the Iraqi war. PATIENTS AND METHODS: A total of 2800 casualties with penetrating trauma to the abdomen and pelvis were treated at the Yarmouk Hospital, Baghdad from January 2004 to June 2008. Of the casualties 504 (18%) had GU trauma including 217 (43%) with one or more injuries to the lower GU organs. RESULTS: Among the 217 patients there were 262 lower GU injuries involving the bladder in 128 (48.8%) patients, bulbo-prostatic urethra in 21 (8%), penis in 24 (9.2%), and scrotum in 89 (34%). Injuries to the anterior urethra and genitals were inflicted by Improvised Explosive Devices (IEDs) in 53 67% of cases and by individual firearms in 33-47%, while injuries to the posterior urethra and bladder were inflicted by IEDs in 17-22% of cases and by firearms in 78-83%. All penile wounds were repaired save 3 (12.5%) patients who underwent total penectomy. Of 63 injured testicles 54 (86%) could be salvaged and 9 (14%) required unilateral orchiectomy. The leading cause of death was an associated injury to major blood vessels in 26 (84%) of 31 patients who died. CONCLUSIONS: Injuries to the anterior urethra and genitals were commonly caused by IEDs, while injuries to the posterior urethra and bladder were usually caused by individual firearms. Testis injury was almost always salvageable. Associated trauma to major blood vessels was the leading cause of death in these casualties. PMID- 24485552 TI - Consensus of the Orthopedic Anesthesia, Pain, and Rehabilitation Society on the use of peripheral nerve blocks in patients receiving thromboprophylaxis. AB - Evidence supports the concept that patients undergoing major orthopedic surgery benefit from either thromboprophylaxis or peripheral nerve blocks, especially continuous techniques. A group of anesthesiologists with significant experience in orthopedic anesthesia and peripheral nerve blocks reviewed the literature related to thromboprophylaxis and peripheral nerve blocks and their combination in orthopedics. Major bleeding, including retroperitoneal hematoma, is an established complication of thromboprophylaxis. Major bleeding, including retroperitoneal hematoma, is also an established complication of peripheral nerve blocks. Between 1997 and 2012, only 4 case reports of major bleeding were reported in patients receiving thromboprophylaxis and peripheral nerve blocks. Evidence supports the safety of the combination of thromboprophylaxis and peripheral nerve blocks. This group of experts concluded that currently there is no evidence that the combination of thromboprophylaxis and peripheral nerve block increases the risk of major bleeding compared to either of the treatments alone. PMID- 24485553 TI - Considerations for the use of short-acting opioids in general anesthesia. AB - Anesthesiologists play a critical role in facilitating a positive perioperative experience and early recovery for patients. Depending on the kind of procedure or surgery, a wide variety of agents and techniques are currently available to anesthesiologists to administer safe and efficacious anesthesia. Notably, the fast-track or ambulatory surgery environment requires the use of agents that enable rapid induction, maintenance, and emergence combined with minimal adverse effects. Short-acting opioids demonstrate a safe and rapid onset/offset of effect; that short effect is both predictable and precise. It also ensures easier titration and reduced or rapidly reversed side effects. Due to their distinct pharmacokinetic and pharmacodynamic properties, and, in one case, rapid extra hepatic clearance of remifentanil, these agents have several applications in general anesthesia. PMID- 24485551 TI - Prevalence and clinical significance of night eating syndrome in university students. AB - PURPOSE: Most studies of night eating syndrome (NES) fail to control for binge eating, despite moderate overlap between the two conditions. Establishing the independent clinical significance of NES is imperative for it to be considered worthy of clinical attention. We compared students with and without NES on eating disorder symptomatology, quality of life, and mental health, while exploring the role of binge eating in associations. METHODS: Students (N = 1,636) ages 18-26 years (M = 20.9) recruited from 10 U.S. universities completed an online survey including the Night Eating Questionnaire (NEQ), Eating Disorder Examination Questionnaire (EDE-Q), Project Eating Among Teens, and the Health-Related Quality of Life-4. NES was diagnosed according to endorsement of proposed diagnostic criteria on the NEQ. Groups (NES vs. non-NES) were compared on all dependent variables and stratified by binge eating status in secondary analyses. RESULTS: The prevalence of NES in our sample was 4.2%; it decreased to 2.9% after excluding those with binge eating. Body mass index did not differ between groups, but students with NES were significantly more likely to have histories of underweight and anorexia nervosa. In students with NES, EDE-Q scores were significantly higher; purging, laxative use, and compulsive exercise were more frequent; quality of life was reduced; and histories of depression, attention deficit/hyperactivity disorder, and self-injury were more common. Binge eating did not account for all of these differences; the presence of it and NES was associated with additive risk for psychopathology on some items. CONCLUSIONS: NES may be a distinct clinical entity from other DSM-5 eating disorders. PMID- 24485555 TI - Effect of the first GnRH and two doses of PGF2alpha in a 5-day progesterone-based CO-Synch protocol on heifer pregnancy. AB - The objectives were (1) to determine the effects of gonadorelin hydrochloride (GnRH) injection at controlled internal drug release (CIDR) insertion on Day 0 and the number of PGF2alpha doses at CIDR removal on Day 5 in a 5-day CO-Synch + CIDR program on pregnancy rate (PR) to artificial insemination (AI) in heifers; (2) to examine how the effect of systemic concentration of progesterone and size of follicles influenced treatment outcome. Angus cross beef heifers (n = 1018) at eight locations and Holstein dairy heifers (n = 1137) at 15 locations were included in this study. On Day 0, heifers were body condition scored (BCS), and received a CIDR. Within farms, heifers were randomly divided into two groups: at the time of CIDR insertion, the GnRH group received 100 MUg of GnRH and No-GnRH group received none. On Day 5, all heifers received 25 mg of PGF2alpha at the time of CIDR insert removal. The GnRH and No-GnRH groups were further divided into 1PGF and 2PGF groups. The heifers in 2PGF group received a second dose of PGF2alpha 6 hours after the administration of the first dose. Beef heifers underwent AI at 56 hours and dairy heifers at 72 hours after CIDR removal and received 100 MUg of GnRH at the time of AI. Pregnancy was determined approximately at 35 and/or 70 days after AI. Controlling for herd effect (P < 0.06), the treatments had significant effect on AI pregnancy in beef heifers (P = 0.03). The AI-PRs were 50.3%, 50.2%, 59.7%, and 58.3% for No-GnRH + PGF + GnRH, No-GnRH + 2PGF + GnRH, GnRH + PGF + GnRH, and GnRH + 2PGF + GnRH groups, respectively. The AI-PRs were ranged from 50% to 62.4% between herds. Controlling for herd effects (P < 0.01) and for BCS (P < 0.05), the AI pregnancy was not different among the treatment groups in dairy heifers (P > 0.05). The AI-PRs were 51.2%, 51.9%, 53.9%, and 54.5% for No-GnRH + PGF + GnRH, No-GnRH + 2PGF + GnRH, GnRH + PGF + GnRH, and GnRH + 2PGF + GnRH groups, respectively. The AI-PR varied among locations from 48.3% to 75.0%. The AI-PR was 43.5%, 50.4%, and 64.2% for 2.5 or less, 2.75 to 3.5, and greater than 3.5 BCS categories. Numerically higher AI-PRs were observed in beef and dairy heifers that exhibited high progesterone concentrations at the time of CIDR insertion (>1 ng/mL, with a CL). In addition, numerically higher AI-PRs were also observed in heifers receiving CIDR + GnRH with both high and low progesterone concentration (<1 ng/mL) initially compared with heifers receiving a CIDR only with low progesterone. In dairy heifers, there were no differences in the pregnancy loss between 35 and 70 days post-AI among the treatment groups (P > 0.1). In conclusion, GnRH administration at the time of CIDR insertion is advantageous in beef heifers, but not in dairy heifers, to improve AI-PR in the 5-day CIDR + CO-Synch protocol. In addition, in this study, both dairy heifers that received either one or two PGF2alpha doses at CIDR removal resulted in similar AI-PR in this study regardless of whether they received GnRH at CIDR insertion. PMID- 24485554 TI - Avoidance of cigarette pack health warnings among regular cigarette smokers. AB - BACKGROUND: Previous research with adults and adolescents indicates that plain cigarette packs increase visual attention to health warnings among non-smokers and non-regular smokers, but not among regular smokers. This may be because regular smokers: (1) are familiar with the health warnings, (2) preferentially attend to branding, or (3) actively avoid health warnings. We sought to distinguish between these explanations using eye-tracking technology. METHOD: A convenience sample of 30 adult dependent smokers participated in an eye-tracking study. Participants viewed branded, plain and blank packs of cigarettes with familiar and unfamiliar health warnings. The number of fixations to health warnings and branding on the different pack types were recorded. RESULTS: Analysis of variance indicated that regular smokers were biased towards fixating the branding rather than the health warning on all three pack types. This bias was smaller, but still evident, for blank packs, where smokers preferentially attended the blank region over the health warnings. Time-course analysis showed that for branded and plain packs, attention was preferentially directed to the branding location for the entire 10s of the stimulus presentation, while for blank packs this occurred for the last 8s of the stimulus presentation. Familiarity with health warnings had no effect on eye gaze location. CONCLUSION: Smokers actively avoid cigarette pack health warnings, and this remains the case even in the absence of salient branding information. Smokers may have learned to divert their attention away from cigarette pack health warnings. These findings have implications for cigarette packaging and health warning policy. PMID- 24485556 TI - Cervical changes in estrogen receptor alpha, oxytocin receptor, LH receptor, and cyclooxygenase-2 depending on the histologic compartment, longitudinal axis, and day of the ovine estrous cycle. AB - The aim was to investigate the histologic distribution of estrogen receptor alpha (ERalpha), oxytocin receptor (OxR), LH receptor (LHR), and cyclooxygenase-2 (COX 2) in the cervix of the ewe during the estrous cycle. Immunohistochemistry was performed in the cranial and caudal cervix of Corriedale ewes on Day 1 (n = 6), 6 (n = 5), or 13 (n = 6) after estrous detection (Day 0). The ERalpha proportional score (%ERalpha nuclei) was lower in the cranial cervix than in the caudal cervix, whereas the OxR and COX-2 immunostaining areas (%areas) were greater in the cranial cervix than in the caudal cervix (P < 0.04). The %ERalpha nuclei decreased from Days 1 to 13 in luminal epithelia, but increased from Days 1 to 6 or remained unchanged in stromata (P < 0.003). The %OxR area was higher on Day 6 than on Days 1 and 13 in the superficial glandular epithelium, and increased from Days 1 to 13 in the deep glandular epithelium (P < 0.04). The %LHR area increased during the estrous cycle in luminal epithelia and fold stroma (P < 0.004). The %COX-2 area was restricted to epithelia, and it was lower on Day 1 than on Days 6 and 13 in luminal epithelia (P < 0.05). Differences in ERalpha, OxR, LHR, and COX 2 between cranial and caudal cervical zones indicate different physiological functions, and their cyclic variations in the cervical epithelia, in contrast to little or no variations in the stroma, suggest a hormone-responsive driving role of epithelia in cervical function. PMID- 24485557 TI - Effect of conditioning contraction intensity on postactivation potentiation is muscle dependent. AB - We aimed to examine whether the influence of conditioning contraction intensity on the extent of postactivation potentiation (PAP) is muscle dependent. Eleven healthy males performed both thumb adduction and plantar flexion as a conditioning contraction. The conditioning contraction intensities were set at 20%, 40%, 60%, 80%, or 100% of the maximal voluntary isometric contraction (MVC). Before and after the conditioning contraction, twitch torque was measured for the respective joint to calculate the extent of PAP. In plantar flexion, the extent of PAP became significantly larger as the conditioning contraction intensity increased up to 80% MVC (p<0.05). In contrast, the extent of PAP in thumb adduction increased significantly only up to 60% MVC (p<0.05), but not at higher intensities. These results indicate that the influence of the conditioning contraction intensity on the extent of PAP is muscle dependent. Our results suggest that a conditioning contraction with submaximal intensity can sufficiently evoke sizable PAP in the muscle where most of muscle fibers are recruited at submaximal intensities, thereby attenuating muscle fatigue induced by the conditioning contraction. PMID- 24485558 TI - Low-frequency accelerations over-estimate impact-related shock during walking. AB - During gait, a failure to acknowledge the low-frequency component of a segmental acceleration signal will result in an overestimation of impact-related shock and may lead to inappropriately drawn conclusions. The present study was undertaken to investigate the significance of this low-frequency component in two distinctly different modalities of gait: barefoot (BF) and shod (SHOD) walking. Twenty-seven participants performed five walking trials at self-selected speed in each condition. Peak positive accelerations (PPA) at the shank and spine were first derived from the time-domain signal. The raw acceleration signals were then resolved in the frequency-domain and the active (low-frequency) and impact related components of the power spectrum density (PSD) were quantified. PPA was significantly higher at the shank (P<0.0001) and spine (P=0.0007) in the BF condition. In contrast, no significant differences were apparent between conditions for shank (P=0.979) or spine (P=0.178) impact-related PSD when the low frequency component was considered. This disparity between approaches was due to a significantly higher active PSD in both signals in the BF condition (P<0.0001; P=0.008, respectively), due to kinematic differences between conditions (P<0.05). These results indicate that the amplitude of the low-frequency component of an acceleration signal during gait is dependent on knee and ankle joint coordination behaviour, and highlight that impact-related shock is more accurately quantified in the frequency-domain following subtraction of this component. PMID- 24485559 TI - Stretch-shortening cycle characteristics during vertical jumps carried out with small and large range of motion. AB - In the present study we investigated kinematical characteristics of the knee and ankle extensors to estimate the length change properties of the contractile and the passive elements in countermovement jumps (CMJ) and drop jumps (DJ) performed with small (40 degrees ) and large (80 degrees ) range of joint motion (SRM and LRM). At SRM the accelerations at maximal muscle lengths compared with the last phase of joint flexion were greater for the gastrocnemius and the soleus (124.9% and 79.4%) and also were greater than at the beginning of joint extension, while no difference was measured at LRM. The differences suggest that at LRM the length change of the serial passive elements from the end of joint flexion to the beginning of joint extension is minimal and simultaneously the length change of the contractile elements is significant, but at SRM - especially in the plantar flexors - the length change of the contractile elements is minimal while in the passive elements significant. It can be presumed that for SRM at the end of joint flexion significant elastic energy is stored and at the beginning of joint extension reused, while for LRM elastic energy storage is not dominant. PMID- 24485560 TI - Validity of fascicle length estimation in the vastus lateralis and vastus intermedius using ultrasonography. AB - The purpose of this study was to determine the validity of fascicle length estimation in the vastus lateralis (VL) and vastus intermedius (VI) using ultrasonography. The fascicle lengths of the VL and VI muscles were measured directly (dFL) using calipers, and were estimated (estmFL) using ultrasonography, in 10 legs from five Thiel's embalmed cadavers. To determine the validity of the estmFLs, FL was estimated using five previously published models and compared with dFL. The intraclass correlation coefficients (ICCs) of two of the five models were>0.75, indicating that these estimates were valid. Both of these models combined measurement of the length of the visible part of the fascicle with linear extrapolation of the length of the part of the fascicle that was not visible on the sonographic image. The ICCs and absolute% difference were best in models that used appropriate pennation angles. These results suggest that two of the five previously published models are valid for obtaining estmFL of the VL and VI using ultrasonography. PMID- 24485561 TI - Naming and framing in genomic testing. AB - What's in a name? Terminology has the power to shape the ethical and regulatory debate surrounding commercially offered genomic testing. This article discusses the normative effects of naming and framing, and proposes that the medical frame, with its focus on the reduction of harm, should be used in the evaluation and regulation of predictive genomic testing. PMID- 24485562 TI - The echocardiographic evaluation of a bicuspid aortic valve: the effect of jet eccentricity and left ventricular outflow tract geometry on the effective orifice area. PMID- 24485563 TI - Lung reperfusion injury in patients after balloon angioplasty for pulmonary artery stenosis. AB - OBJECTIVES: To determine the incidence and degree of acute lung reperfusion injury (ARI) in patients undergoing balloon angioplasty of branch pulmonary artery stenosis and to evaluate the correlation and efficacy of an oxygenation index in confirming the clinical diagnosis. DESIGN: Retrospective, single-center observational study. SETTING: Cardiac catheterization laboratory at a tertiary care children's hospital. PATIENTS: Patients with congenital heart disease undergoing pulmonary artery balloon angioplasty. INTERVENTION: Review of patient medical and catheterization records. MEASUREMENTS AND MAIN RESULTS: The records of all patients with biventricular physiology undergoing balloon angioplasty of branch pulmonary artery stenosis over a period of 2 years (12/2006-12/2008) were reviewed. Data collection included demographics, details of pulmonary artery intervention, right ventricle/femoral artery systolic pressure (RV/FA) ratio, and post-procedure recovery condition. Markers of ARI, including clinical, radiographic, and blood gas analysis, were examined. Criteria for ARI were based on the International Society of Heart and Lung Transplantation (ISHLT) grading system, in which a PaO2/FIO2 of 200 to 300 indicates ARI. The distribution of PaO2/FIO2 after pulmonary artery intervention, the relation of clinical to laboratory manifestation of ARI, and the correlation among different oxygenation indices were examined. During the study period, 46 patients with congenital heart disease and branch pulmonary artery stenosis were identified. Patient age ranged from 2 months to 25 years (mean 6.2+/-6 years) and weight ranged from 5 to 86 kg (mean 23+/-18 kg). ARI was identified in 10 of 46 patients (22%) using clinical criteria and correlated with ISHLT gas exchange criteria. Analysis of RV/FA ratio before (0.82+/-0.34) and after (0.71+/-0.22) balloon angioplasty revealed statistically significant decrease (p<0.004). The degree of ARI was graded using ISHLT criteria and correlated with the presence of clinical symptoms (p<0.002). As anticipated, the PaO2/FIO2 ratio had a strong correlation with A-aDO2 (r = 0.75) and SpO2/FIO2 (r = 0.7) and a strong specificity (0.78) to identify patients with clinical ARI. CONCLUSION: ARI often can occur after pulmonary artery interventions. The PaO2/FIO2 is a valuable test for identifying patients at risk of developing ARI and can help guide the care of these patients in the postintervention period. PMID- 24485564 TI - Molecular identification of Anisakis species (Nematoda: Anisakidae) from marine fishes collected in Turkish waters. AB - Anisakid nematodes are important etiological agents for zoonotic human anisakiasis (or anisakidosis). These parasites in the Turkish waters still remain unexplored. This study aims the molecular identification of Anisakis species in Turkey's coast from Black, Aegean and Mediterranean Sea and specifically to screen for zoonotic species in commonly commercialized a total of 1145 fish belonging to 31 different species using both polymerase chain reaction restriction fragment length polymorphism analysis (PCR-RFLP) and sequencing of the ribosomal internal transcribed spacer (ITS) regions and the mitochondrial cytochrome C oxidase subunit II (cox2) gene. A total of 776 Anisakis type I larvae were isolated in 56/1145 (4.8%) fish of 7 species from Turkish waters. The combining all of our results, e.g., morphology, PCR-RFLP, ITS region, and the cox2 gene, conclusively supported the identification of 3 Anisakis spp. taken from marine fish hosts, namely Anisakis pegreffii, Anisakis typica and Anisakis simplex sensu stricto (s.str.)/A. pegreffii hybrid genotype. No Anisakis larvae were isolated from the Black Sea whereas A. pegreffii, A. typica and A. simplex s.str./A. pegreffii hybrid genotype was found in the Aegean Sea and A. pegreffii was only isolated from the Mediterranean Sea. This study represents the first identification of A. typica and A. simplex s.str./A. pegreffii hybrid genotypes from Turkish waters. Moreover, in the present study first record of the presence of A. pegreffii is also reported from Turkish coasts of Aegean and Mediterranean Sea. No zoonotic Anisakis species were found in commonly commercialized 1025 fish belonging to 16 different species from the Black Sea, thus Turkish populations who consume captured fish from the Black Sea may have a less risk of human anisakiasis or allergies. However, the prevalence of larvae were 47.1% and 46% and recognized zoonotic A. pegreffii were identified from the Aegean and Mediterranean Sea coast, suggesting a high threat of anisakiasis or allergies for Turkish populations who consume fish originating in these regions. PMID- 24485565 TI - Anthelmintic resistance in important parasites of horses: does it really matter? AB - Parascaris equorum and cyathostomins are currently considered the most important parasites of horses and have traditionally been controlled with anthelmintics belonging to three drug classes: benzimidazoles, the tetrahydropyrimidine pyrantel, and macrocyclic lactones. Unfortunately, resistance to benzimidazoles, and to a lesser extent pyrantel, is widespread in cyathostomins around the world. Furthermore, resistance to macrocyclic lactones appears to be in the early stages of development in cyathostomins in multiple locations. In contrast, P. equorum populations have remained susceptible to the three anthelmintic drug classes for a considerably longer period of time. However, over the last 10 years, resistance to macrocyclic lactones has been described in multiple countries. In contrast, resistance to pyrantel has only been described in the USA; resistance to benzimidazoles has yet to be reported. Despite the large number of reports of anthelmintic resistance in both cyathostomins and P. equorum, there are presently no reports that definitively link anthelmintic resistance with clinical problems in horses. However, that generally appears to be due to a publication bias toward well managed horse farms and the lack of appropriate diagnostic methods for rapidly quantifying anthelmintic resistance in these parasites. Management-based, and other, reasons likely responsible for this apparent anomaly are also discussed. Finally, future research priorities in this area, identified from a discussion at the 9th International Conference on Equine Infectious Diseases, are summarized. PMID- 24485566 TI - Human papillomavirus (HPV) status of non-tobacco related squamous cell carcinomas of the lateral tongue. AB - OBJECTIVES: The human papillomavirus (HPV) is an important cause of some head and neck squamous cell carcinomas (HNSCCs), but its role in cancer of the lateral tongue is debatable. Suspicion of HPV causation is heightened when these lateral tongue carcinomas arise in patients that are young and/or have never smoked. The purpose of this study was to determine the incidence of transcriptionally active high risk HPV in these tumors, with a particular emphasis on non-smoking patients who are often presumed to have HPV-positive tumors. METHODS: We evaluated 78 HNSCCs of the lateral tongue for the presence of HPV using p16 immunohistochemistry and an RNA in situ hybridization assay targeting HPV E6/E7 mRNA. The study population was enriched for patients without traditional risk factors such as smoking and drinking. RESULTS: P16 overexpression was detected in 9 (11.5%) of 78 cases, but HPV E6/E7 mRNA transcripts were detected in only 1 (1.3%) case (positive predictive value of p16 staining for the presence of transcriptionally active HPV=0.12). HPV mRNA transcripts were not detected in any patient under 40 (n=11), or in patients who had never smoked (n=44), had quit smoking (n=15), and/or were only light consumers of alcohol (n=57). CONCLUSIONS: HPV is not detected in the vast majority of lateral tongue carcinomas. In light of the observation that HPV plays little if any role in the development of these cancers, routine HPV testing is unwarranted , even for patients without traditional risk factors. P16 staining is not a reliable marker for the presence of transcriptionally active HPV at this particular anatomic site. PMID- 24485567 TI - [Myoepithelioma of the nose]. PMID- 24485568 TI - Response to "re: cloacal exstrophy: a single centre experience". PMID- 24485569 TI - The war on Syrian civilians. PMID- 24485570 TI - Suicide: who should know? PMID- 24485571 TI - Tobacco control in the USA: an end to political mythology. PMID- 24485572 TI - Next steps for adolescent health: a Lancet Commission. PMID- 24485573 TI - Intimate partner violence and HIV: unwelcome accomplices. PMID- 24485575 TI - Keertan Dheda: rising star of pulmonary medicine. PMID- 24485576 TI - Electronic cigarettes and smoking cessation: a quandary? PMID- 24485577 TI - Electronic cigarettes and smoking cessation: a quandary? PMID- 24485578 TI - Electronic cigarettes and smoking cessation: a quandary? PMID- 24485579 TI - Electronic cigarettes and smoking cessation: a quandary? - Authors' reply. PMID- 24485580 TI - Management of acute myocardial infarction. PMID- 24485581 TI - Management of acute myocardial infarction - Authors' reply. PMID- 24485582 TI - Management of acute myocardial infarction. PMID- 24485584 TI - The Earth-Heart sign: a new diagnostic finding in a patient with tension pneumomediastinum. PMID- 24485585 TI - Balsacones D-I, dihydrocinnamoyl flavans from Populus balsamifera buds. AB - A phytochemical investigation of an ethanolic extract from Populus balsamifera L. buds resulted in the isolation and characterization of twelve new flavan derivatives consisting of six pairs of enantiomers. Structures of (+) and (-) balsacones D-I were elucidated based on spectroscopic data (1D and 2D NMR, MS) and their absolute configurations were established using X-ray single crystal diffraction analysis and ECD computational calculations. Antibacterial activity and cytotoxicity of all purified enantiomers were evaluated in vitro against Staphylococcus aureus and human skin fibroblast cells, respectively. PMID- 24485586 TI - White matter pathway organization of the reward system is related to positive and negative symptoms in schizophrenia. AB - The reward system in schizophrenia has been linked to the emergence of delusions on the one hand and to negative symptoms such as affective flattening on the other hand. Previous Diffusion Tensor Imaging (DTI) studies reported white matter microstructure alterations of regions related to the reward system. The present study aimed at extending these findings by specifically investigating connection pathways of the reward system in schizophrenia. Therefore, 24 patients with schizophrenia and 22 healthy controls matched for age and gender underwent DTI scans. Using a probabilistic fiber tracking approach we bilaterally extracted pathways connecting the ventral tegmental area (VTA) with the nucleus accumbens (NAcc), the medial and lateral orbitofrontal cortices (mOFC, lOFC), the dorsolateral prefrontal cortex (dlPFC) and the amygdala; as well as pathways connecting NAcc with mOFC, lOFC, dlPFC and amygdala resulting in a total of 18 connections. Probability indices forming part of a bundle of interest (PIBI) were compared between groups using independent t-tests. In 6 connection pathways PIBI values were increased in schizophrenia. In 3 of these pathways the spatial extension of connection pathways was decreased. In schizophrenia patients, there was a negative correlation of PIBI-values and PANSS negative scores in the left VTA-amygdala and in the left NAcc-mOFC connection. A sum score of delusions and hallucinations correlated positively with PIBI-values of the left amygdala-NAcc connection. Structural organization of specific segments of white matter pathways of the reward system in schizophrenia may contribute to the emergence of delusions and negative symptoms in schizophrenia. PMID- 24485588 TI - Detection of Leishmania infantum in 4 different dog samples by real-time PCR and ITS-1 nested PCR. AB - The canine visceral leishmaniasis (CVL) diagnosis is an important step of visceral leishmaniasis control program in Brazil, which involves the elimination of infected dogs, the main animal reservoir host of the disease. The aim of the present study was to evaluate a sensitive real-time PCR method for Leishmania infantum detection in 4 different clinical samples of dogs, including the noninvasive conjunctival swab (CS) sample. The results of real-time PCR were compared with those obtained using internal transcribed spacer 1 nested PCR. Animals were divided into 2 groups based on the absence or presence of CVL clinical sings. The CS associated with real-time PCR, using primers addressed to kinetoplast DNA minicircles, was able to detect L. infantum infection in 96.7% of dogs without clinical signs and in 100% of the symptomatic animals, demonstrating the importance of these procedures for diagnosing CVL. PMID- 24485590 TI - [Alpha genes triplication-associated E-Saskatoon hemoglobinopathy]. PMID- 24485589 TI - Diagnosis of American cutaneous leishmaniasis by enzyme immunoassay using membrane antigens of Leishmania (Viannia) braziliensis. AB - This study evaluated the reactivity of membrane antigens of Leishmania (Viannia) braziliensis for the diagnosis of ACL by enzyme immunoassay (EIA). Promastigotes of L. (V.) braziliensis were grown in medium 199 and lysed in a sonicator. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) and Western blotting showed that specific proteins of L. (V.) braziliensis (apparent molecular weights 36 kDa and 48-56 kDa) were recognized by sera from ACL patients. These proteins were eluted from the SDS-PAGE and tested in EIA-IgG with sera from ACL patients, healthy individuals, patients with toxoplasmosis, paracoccidioidomycosis, syphilis, tuberculosis, leprosy, and Chagas disease. The EIA-IgG with membrane antigens allowed us to distinguish patients with ACL from healthy individuals and patients with other diseases (P < 0.0001), and showed a sensitivity of 93.3% and specificity of 90.8%, not including Chagas disease patients. 2D-SDS-PAGE followed by Western blotting was performed to improve the characterization of the antigens, and showed a component with isoelectric points near the acid pH side and apparent molecular weights of 48-56 kDa. The results showed good sensitivity and specificity of EIA-IgG with membrane antigens, indicating their potential use for diagnosis of ACL, as well as seroepidemiological surveys and follow-up of clinically cured patients. PMID- 24485587 TI - d-Cycloserine augmentation of cognitive remediation in schizophrenia. AB - d-Cycloserine (DCS) has been shown to enhance memory and, in a previous trial, once-weekly DCS improved negative symptoms in schizophrenia subjects. We hypothesized that DCS combined with a cognitive remediation (CR) program would improve memory of a practiced auditory discrimination task and that gains would generalize to performance on unpracticed cognitive tasks. Stable, medicated adult schizophrenia outpatients participated in the Brain Fitness CR program 3-5 times per week for 8weeks. Subjects were randomly assigned to once-weekly adjunctive treatment with DCS (50mg) or placebo administered before the first session each week. Primary outcomes were performance on an auditory discrimination task, the MATRICS cognitive battery composite score and the Scale for the Assessment of Negative Symptoms (SANS) total score. 36 subjects received study drug and 32 completed the trial (average number of CR sessions=26.1). Performance on the practiced auditory discrimination task significantly improved in the DCS group compared to the placebo group. DCS was also associated with significantly greater negative symptom improvement for subjects symptomatic at baseline (SANS score >=20). However, improvement on the MATRICS battery was observed only in the placebo group. Considered with previous results, these findings suggest that DCS augments CR and alleviates negative symptoms in schizophrenia patients. However, further work is needed to evaluate whether CR gains achieved with DCS can generalize to other unpracticed cognitive tasks. PMID- 24485591 TI - Polyradiculoneuritis, cryopyrin-associated periodic syndromes, and familial Mediterranean fever. PMID- 24485593 TI - Adoption of an integrated radiology reading room within a urologic oncology clinic: initial experience in facilitating clinician consultations. AB - PURPOSE: The authors describe their initial experience in implementing an integrated radiology reading room within a urologic oncology clinic, including the frequency and nature of clinician consultations and the perceived impact on patient management by clinicians. METHODS: A radiology reading room was established within an office-based urologic oncology clinic in proximity to the surgeon's work area. A radiologist was present in this reading room for a 3-hour shift each day. The frequency and nature of consultations during these shifts were recorded. Also, the clinic's staff completed a survey assessing perceptions of the impact of the integrated reading room on patient management. RESULTS: One hundred two consultations occurred during 57 included dates (average, 1.8 consultations per shift): 52% for review of external cases brought in by patients on discs, 43% for review of internal cases, and 5% for direct review by the radiologist of imaging with patients. The maximum number of consultations during a single shift was 8. All of the clinic's urologists indicated that >90% of consultations benefited patient care. The clinicians indicated tendencies to view consultations as affecting management in the majority of cases, to be more likely to seek consultation for outside imaging when the radiologist was on site, and to be less likely to repeat outside imaging when the radiologist was on site. CONCLUSIONS: The integrated reading room within the clinic has potential to improve the quality of care, for instance by facilitating increased review of outside imaging studies and thereby potentially reducing duplicate ordering and by enabling occasional direct image review with patients by radiologists. PMID- 24485592 TI - ACR appropriateness criteria right upper quadrant pain. AB - Acute right upper quadrant pain is a common presenting symptom in patients with acute cholecystitis. When acute cholecystitis is suspected in patients with right upper quadrant pain, in most clinical scenarios, the initial imaging modality of choice is ultrasound. Although cholescintigraphy has been shown to have slightly higher sensitivity and specificity for diagnosis, ultrasound is preferred as the initial study for a variety of reasons, including greater availability, shorter examination time, lack of ionizing radiation, morphologic evaluation, confirmation of the presence or absence of gallstones, evaluation of bile ducts, and identification or exclusion of alternative diagnoses. CT or MRI may be helpful in equivocal cases and may identify complications of acute cholecystitis. When ultrasound findings are inconclusive, MRI is the preferred imaging test in pregnant patients who present with right upper quadrant pain. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 2 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application of a well established consensus methodology (modified Delphi) to rate the appropriateness of imaging and treatment procedures by the panel. In those instances in which evidence is lacking or not definitive, expert opinion may be used to recommend imaging or treatment. PMID- 24485594 TI - From terpyridine-based assemblies to metallo-supramolecular polyelectrolytes (MEPEs). AB - Introducing metal ion coordination as bonding motive into polymer architectures provides new structures and properties for polymeric materials. The metal ions can be part of the backbone or of the side-chains. In the case of linear metallo polymers the repeat unit bears at least two metal ion receptors in order to facilitate metal-ion induced self-assembly. If the binding constants are sufficiently high, macromolecular assemblies will form in a solution. Likewise, polymeric networks can be formed by metal ion induced crosslinking. The metal ion coordination sites introduce dynamic features, e.g. for self-healing or responsive materials, as well as additional functional properties including spin crossover, electro-chromism, and reactivity. Terpyridines have attracted attention as receptors in metallo-polymers due to their favorable properties. It is well suited to assemble linear rigid-rod like metallo-polymers in case of rigid ditopic ligands. Terpyridine binds a large number of metal ions and are readily functionalized giving rise to a plethora of available ligands as components in metallo-polymers. By the judicious choice of the metal ions, the design of the ligands, the counter ions and the boundary conditions of self assembly, the final structure and properties of the resulting metallo-polymers can be tailored at all length scales. Here, we review recent activities in the area of metallo-polymers based on terpyridines as central metal ion receptors. PMID- 24485595 TI - Lipid membranes in external electric fields: kinetics of large pore formation causing rupture. AB - About 40 years ago, Helfrich introduced an elastic model to explain shapes and shape transitions of cells (Z Naturforsch C, 1973; 28:693). This seminal article stimulated numerous theoretical as well as experimental investigations and created new research fields. In particular, the predictive power of his approach was demonstrated in a large variety of lipid model system. Here in this review, we focus on the development with respect to planar lipid membranes in external electric fields. Stimulated by the early work of Helfrich on electric field forces acting on liposomes, we extended his early approach to understand the kinetics of lipid membrane rupture. First, we revisit the main forces determining the kinetics of membrane rupture followed by an overview on various experiments. Knowledge on the kinetics of defect formation may help to design stable membranes or serve for novel mechanism for controlled release. PMID- 24485596 TI - Impact of metabolic syndrome on oncologic outcome after radical gastrectomy for gastric cancer. AB - BACKGROUND: Few studies have reported the relationship between MS and the prognosis of gastric cancer. METHODS: Data were collected from 505 patients who underwent radical gastrectomy for gastric cancer between January 2006 and December 2007. After exclusion, remaining 204 patients were divided into two groups based on the presence of MS. RESULTS: No significant differences were observed in tumor stage and grade between the MS (n=60) and non-MS (n=144) groups. The median follow-up periods were 53.2+/-23.5 and 54.7+/-22.1 months in for the MS and non-MS groups, respectively (P=0.677). Seventeen (28.3%) and 21 (14.6%) patients showed tumor recurrence in the MS and non-MS groups, respectively (P=0.022). In addition, disease-free survival of patients in the MS group was less than in non-MS group (P=0.036). The Cox regression hazard model demonstrated that advanced tumor stage (stage III or IV, HR=17.8, 95% CI=5.3 to 59.4) and presence of MS (HR=2.8, 95% CI=1.3 to 5.8) were independent risk factors for recurrence. CONCLUSION: MS may be an important prognostic factor for gastric cancer. Control of MS could improve the therapeutic efficacy of gastric cancer. PMID- 24485597 TI - Traumatic bile duct neuroma after resection of hilar cholangiocarcinoma. PMID- 24485598 TI - Integration of literacy into speech-language therapy: a descriptive analysis of treatment practices. AB - PURPOSE: The purpose of the present study was: (a) to examine the extent to which speech-language therapy provided to children with language disorders in the schools targets code-based literacy skills (e.g., alphabet knowledge and phonological awareness) during business-as-usual treatment sessions, and (b) to determine whether literacy-focused therapy time was associated with factors specific to children and/or speech-language pathologists (SLPs). METHOD: Participants were 151 kindergarten and first-grade children and 40 SLPs. Video recorded therapy sessions were coded to determine the amount of time that addressed literacy. Assessments of children's literacy skills were administered as well as questionnaires regarding characteristics of SLPs (e.g., service delivery, professional development). RESULTS: Results showed that time spent addressing code-related literacy across therapy sessions was variable. Significant predictors included SLP years of experience, therapy location, and therapy session duration, such that children receiving services from SLPs with more years of experience, and/or who utilized the classroom for therapy, received more literacy-focused time. Additionally, children in longer therapy sessions received more therapy time on literacy skills. CONCLUSIONS: There is considerable variability in the extent to which children received literacy-focused time in therapy; however, SLP-level factors predict time spent in literacy more than child-level factors. Further research is needed to understand the nature of literacy-focused therapy in the public schools. LEARNING OUTCOMES: Readers will be able to: (a) define code-based literacy skills, (b) discuss the role that speech-language pathologists have in fostering children's literacy development, and (c) identify key factors that may currently influence the inclusion of literacy targets in school-based speech-language therapy. PMID- 24485599 TI - Utility of B-cell epitopes based peptides of RD1 and RD2 antigens for immunodiagnosis of pulmonary tuberculosis. AB - Tuberculosis (TB) continues to be a major health problem due to lack of accurate, rapid, and cost-effective diagnostic tests. Serodiagnostic tests incorporating highly specific region of difference (RD) antigens (early secretory antigenic target 6 [ESAT-6], culture filtrate protein 10 [CFP-10], culture filtrate protein 21 [CFP-21], and mycobacterial protein from species tuberculosis 64 [MPT-64]) have recently been shown to be promising for specific diagnosis of TB in our lab. However, only few studies have reported the use of synthetic peptides of RD antigens, and none has used them to differentiate TB from sarcoidosis, a close mimic of smear-negative pulmonary TB (PTB) with entirely different management. The present study was conducted with an aim to study the utility of B-cell epitopes based peptides of RD1 (ESAT-6, CFP-10) and RD2 (CFP-21, MPT-64) antigens for immunodiagnosis of PTB for which sputum smear-positive PTB patients, sputum smear-negative PTB patients, sarcoidosis patients, and healthy controls (n = 24/group) were recruited. Bioinformatic software Bcepred was used to predict linear B-cell epitopes, using physico-chemical properties on a non-redundant dataset. Seven peptides as representative B-cell epitopes of ESAT-6, CFP-10, CFP 21, and MPT-64 were evaluated as targets of the antibody responses in TB patients and controls by enzyme-linked immunosorbent assay (ELISA). The current study showed sensitivity with individual peptides ranging from 37.5% to 83.3% for smear positive, 25% to 58.3% for smear negative as compared to 4.16% to 20.8% for sarcoidosis. Four out of 7 peptides that showed higher reactivity with TB patients and better discrimination from sarcoidosis patients representing ESAT-6, CFP-10, CFP-21, and MPT-64 were selected for multiepitope ELISA. The combination of peptides yielded 83.3% sensitivity for smear positive, 62.5% for smear negative, and only 4.16% for sarcoidosis. The specificity, however, for all the peptides/combination was 100%. Combination of peptides has proven to be better than individual peptides as per the latest criteria of the World Health Organization according to which a test that can replace smear microscopy with sensitivity of >90% for smear-positive patients and >65% for smear-negative TB patients with a specificity >95%, and thus, the present study suggests that a test based on combination of peptides selected from mycobacterial RD1 and RD2 antigens could be important for promoting an early diagnosis and management of otherwise difficult to diagnose smear-negative PTB patients. Moreover, it can also be used to discriminate sarcoidosis from PTB, thus preventing the misdiagnosis and mismanagement. PMID- 24485601 TI - Blood pressure of general and abdominal obese children and adolescents in Shandong, China. PMID- 24485600 TI - Copper and lactational hormones influence the CTR1 copper transporter in PMC42-LA mammary epithelial cell culture models. AB - Adequate amounts of copper in milk are critical for normal neonatal development, however the mechanisms regulating copper supply to milk have not been clearly defined. PMC42-LA cell cultures representative of resting, lactating and suckled mammary epithelia were used to investigate the regulation of the copper uptake protein, CTR1. Both the degree of mammary epithelial differentiation (functionality) and extracellular copper concentration greatly impacted upon CTR1 expression and its plasma membrane association. In all three models (resting, lactating and suckling) there was an inverse correlation between extracellular copper concentration and the level of CTR1. Cell surface biotinylation studies demonstrated that as extracellular copper concentration increased membrane associated CTR1 was reduced. There was a significant increase in CTR1 expression (total and membrane associated) in the suckled gland model in comparison to the resting gland model, across all copper concentrations investigated (0-50 MUM). Regulation of CTR1 expression was entirely post-translational, as quantitative real-time PCR analyses showed no change to CTR1 mRNA between all models and culture conditions. X-ray fluorescence microscopy on the differentiated PMC42-LA models revealed that organoid structures distinctively accumulated copper. Furthermore, as PMC42-LA cell cultures became progressively more specialised, successively more copper accumulated in organoids (resting= 0.3mg/dL), and length of stay (LOS) were also assessed. The urinary output at 2, 4, 6, 8, and 24h was not significantly different in the three groups. Neither the ACM at day 60 (4.0%, 7.1%, and 7.2%; P=0.74) or at one year (38.1%, 33.9% and 32.7%, P=0.84) nor the HHF at day 60 (22.0%, 21.4%, and 14.5%, P=0.55) or one year (60.0%, 50.0%, and 47%, P=0.40) differed between HDF, LDFD, and LDF groups, respectively. No differences in the Borg index or LOS were noted. WRF was higher in the HDF than in LDFD and LDF groups at day 1 (24% vs. 11% vs. 7%, P<0.0001) but not at sCr peak (44% vs. 38% vs. 29%, P=0.27). No significant differences in adverse events were noted. CONCLUSIONS: In ADHF patients, there were no significant differences in the in-hospital and post discharge outcomes between high- vs. low-dose furosemide infusion; the addition of low-dose dopamine infusion was not associated with any beneficial effects. PMID- 24485634 TI - Autophagy: a potential novel mechanistic contributor to atrial fibrillation. PMID- 24485635 TI - Infiltrated atrial fat characterizes underlying atrial fibrillation substrate in patients at risk as defined by the ARIC atrial fibrillation risk score. AB - BACKGROUND: It is known that expanded epicardial fat is associated with atrial fibrillation (AF). However, infiltrated intraatrial fat has not been previously quantified in individuals at risk as determined by the ARIC AF risk score. METHODS: Patients in sinus rhythm (N=90, age 57 +/- 10 years; 55 men [63.2%]), in 3 groups at risk of AF as determined by the ARIC AF risk score [low (<= 11 points; n=15), moderate (12-18 points; n=40), high (>= 19 points; n=23) risk of AF], and paroxysmal AF (n=12) underwent cardiac magnetic resonance study. Intraatrial and epicardial fat was analyzed with a Dark-blood DIR-prepared Fat Water-separated sequence in the horizontal longitudinal axis. OsiriX DICOM viewer (Geneva, Switzerland) was used to quantify the intraatrial fat area. Width of the cephalad portion of the interatrial septum was measured at the level of the fossa ovalis. RESULTS: Intraatrial fat monotonically increased with growing AF risk in study groups (low AF risk 16 +/- 4 vs. moderate AF risk 32 +/- 18 vs. high AF risk 81 +/- 83 mm(2); ANOVA P=0.012). Log-transformed intraatrial fat predicted ARIC AF risk score in multivariate ordered probit regression after adjustment for sex, race, left and right atrial area indices, and body mass index (beta coefficient 0.50 [95% CI 0.03-0.97]; P=0.037), whereas epicardial fat did not. Interatrial septum width showed similar association (3.0 +/- 1.4 vs. 5.0 +/- 1.8 vs. 7.1 +/- 2.7 mm; ANOVA P<0.001; adjusted beta-coefficient 2.80 [95% CI 1.19 4.41]; P=0.001). CONCLUSIONS: Infiltrated intraatrial fat characterizes evolving substrate in individuals at risk of AF. PMID- 24485636 TI - Inhibition of high-mobility group box 1 improves myocardial fibrosis and dysfunction in diabetic cardiomyopathy. AB - BACKGROUND: High-mobility group box 1 (HMGB1) is an important mediator of the inflammatory response. Its expression is increased in diabetic cardiomyopathy (DCM), but its role is unclear. We investigated the potential role and mechanism of HMGB1 in diabetes-induced myocardial fibrosis and dysfunction in mice. METHODS: In vivo, type 1 diabetes was induced by streptozotocin (STZ) in mice. HMGB1 expression was knocked down by lentivirus-mediated short-hairpin RNA (shRNA). Cardiac function was assessed by echocardiography. Total collagen deposition was assessed by Masson's trichrome and Picrosirius red staining. HMGB1, collagen I and III, and transforming growth factor beta1 (TGF-beta1) expression was quantified by immunostaining and western bolt analysis. In vitro, isolated neonatal cardiac fibroblasts were treated with high glucose (HG) or recombinant HMGB1 (rHMGB1). Pharmacologic (neutralizing anti-HMGB1 antibody) or genetic (shRNA-HMGB1) inhibition of HMGB1 was used to investigate the role of HMGB1 in HG-induced functional changes of cardiac fibroblasts. RESULTS: In vivo, HMGB1 was diffusely expressed in the myocardium of diabetic mice. HMGB1 silencing ameliorated left ventricular dysfunction and remodeling and decreased collagen deposition in diabetic mice. In vitro, HG induced HMGB1 translocation and secretion in both viable cardiomyocytes and fibroblasts. Administration of rHMGB1 dose-dependently increased the expression of collagens I and III and TGF-beta1 in cardiac fibroblasts. HMGB1 inhibition reduced HG-induced collagen production, matrix metalloproteinase (MMP) activities, proliferation, and activated mitogen activated protein kinase signaling in cardiac fibroblasts. CONCLUSIONS: HMGB1 inhibition could alleviate cardiac fibrosis and remodeling in diabetic cardiomyopathy. Inhibition of HMGB1 might have therapeutic potential in the treatment of the disease. PMID- 24485637 TI - Fulfilling current criteria of bidirectional mitral isthmus linear block is necessary but not sufficient for prevention of recurrent peri-mitral atrial tachycardia. PMID- 24485638 TI - The origins of the theory of capillary circulation. PMID- 24485639 TI - Effects of renal denervation on the development of post-myocardial infarction heart failure and cardiac autonomic nervous system in rats. PMID- 24485640 TI - Amiodarone toxicity showing high liver density on CT scan with normal liver function and plasma amiodarone levels in a long-term amiodarone user. PMID- 24485641 TI - Atrial mass reduction in radiofrequency catheter ablation for long-standing persistent atrial fibrillation: do we really ablate the sick or the healthy tissue? PMID- 24485642 TI - First-degree relatives of bicuspid aortic valve patients with normal aortic dimensions do not carry an increased risk of aortic dilatation. PMID- 24485643 TI - Interleukin-8 as a predictor of acute idiopathic pericarditis recurrences. A pilot study. PMID- 24485644 TI - A night in the emergency department: a nursing narrative. PMID- 24485645 TI - Aortic valve replacement: clinical context or discordant data? PMID- 24485646 TI - Evolutionary clues to dengue neuropathogenesis. PMID- 24485647 TI - Compliance with long-term malaria prophylaxis in British expatriates. AB - BACKGROUND: There were 219 million cases of malaria with 600,000 deaths in 2010. Current UK guidance recommends malaria chemoprophylaxis for travellers to malaria endemic areas. Despite proven efficacy, compliance amongst long-term travellers with prophylaxis and personal protective strategies is sub-optimal. This survey assesses compliance rates amongst Foreign and Commonwealth Office employees on placement in malaria endemic areas and establishes the rationale for their decisions. METHODS: A Survey Monkey questionnaire was circulated to Foreign and Commonwealth Office employees on long-term placement in endemic areas. This ascertained background knowledge of malaria, compliance with prevention strategies and the rationale for decisions made. RESULTS: The response rate was 56.5% (327 of 579); responses showed a good knowledge of malaria. 59% of respondents continued their prophylaxis for 0-3 months only. No pregnant women reported compliance of greater than 95%. More than half of the individuals with a compliance of <25% cited concerns about long term safety. 39.5% of respondents reported significant side-effects to chemoprophylaxis. 12.8% reported contracting malaria. CONCLUSION: Despite being well informed, poor adherence was reported, especially amongst pregnant respondents. The majority of individuals ceased medication within three months. Concern regarding the safety of long-term medication was the major barrier. Suggestions are made regarding optimisation of compliance or alternative strategies. PMID- 24485648 TI - The current role of targeted therapies to induce radioiodine uptake in thyroid cancer. AB - Targeted therapy pinpointing specific alteration in cancer cells has gained an important role in the treatment of cancer. Compounds that re-induce thyroid specific functions could be particularly useful in differentiated thyroid cancers by rendering them susceptible to radioiodine treatment, which is relatively specific and has few adverse effects. This review describes the rationale for radioiodine treatment, considering the targets of compounds with differentiation inducing effects, and the impact of these drugs on the expression of thyroid specific proteins and on iodine-uptake. We survey the results from the clinical trials thus far performed. We conclude that although retinoids, thiazolidinediones, histone deacetylase inhibitors and DNA methyltransferase inhibitors do increase the expression of thyroid-specific proteins, their clinical efficacy is limited. The relatively low rate of remissions in clinical trials with re-differentiating compounds could be due to low levels of the target, heterogeneity of iodine uptake into the tumor, poor correlation of radioiodine uptake and clinical remission, and/or the slow onset of the therapeutic effect. Although the mode of action is not clear, the combination of tyrosine kinase inhibitors and RAI treatment could improve clinical responses in non-radioiodine avid metastatic thyroid carcinoma. PMID- 24485649 TI - Validity of the clinical and content scales of the Multiphasic Personality Inventory Minnesota 2 for the diagnosis of psychogenic non-epileptic seizures. AB - INTRODUCTION: The use of the Multiphasic Personality Inventory Minnesota 2 (MMPI 2) for the diagnosis of psychogenic non-epileptic seizures (PNES) is controversial. This study examines the validity of the clinical scales and, unlike previous works, the content scales. METHODS: Cross-sectional study of 209 patients treated in the epilepsy unit. We performed a logistic regression analysis, taking video-electroencephalography as the reference test, and as predictor variables age, sex, IQ and clinical (model A) or content scales (model B) of the MMPI-2. The models were selected according to the Aikake index and compared using the DeLong test. RESULTS: We analyzed 37 patients with PNES alone, or combined with seizures, and 172 patients with seizures only. The model consisting of sex, Hs (hypochondriasis) and Pa (paranoia) showed a sensitivity of 77.1%, a specificity of 76.8%, a percentage of correct classification of 76.8%, and an area under the curve (AUC) of 0.836 for diagnosing CNEP. Model B, consisting of sex, HEA (health concerns) and FRS (fears), showed a sensitivity of 65.7%, a specificity of 78.0%, a percentage of correct classification of 75.9% and an AUC of 0.840. DeLong's test did not detect significant differences. CONCLUSIONS: The MMPI-2 has a moderate validity for the diagnosis of PNES in patients referred to an epilepsy unit. Using content scales does not significantly improve results from the clinical scales. PMID- 24485650 TI - Characteristics of the first 2,000 patients registered in a specialist headache clinic. AB - OBJECTIVES: Headache is a common cause of medical consultations. We aim to analyze demographic characteristics of first two thousand patients in our register, and the incidence of their different headaches coded according to the International Classification of Headache Disorders, ii edition (ICHD-II). PATIENTS AND METHODS: On January 2008 a headache outpatient clinic was established in a tertiary hospital. Patients could be referred by general practitioners according to previously consensused criteria, as well as by general neurology or other specialities clinics. The following variables were prospectively collected on all patients; age, sex, referral source, complementary tests required, and the previously prescribed symptomatic or prophylactic therapies. All headaches were classified accordingly to ICHD-II. When a patient fulfilled criteria for more than one type of headache, all of them were diagnosed and classified. RESULTS: In October 2012, 2000 patients (ratio women/men 2.59/1) had been seen in our headache clinic. The median age was 42 years (range: 11-94), 55.3% were referred from primary care, and 68.1% did not require complementary tests. A total of 3095 headaches were recorded in these 2000 patients, of which 2222 (71.8%) were considered primary headaches, 382 (12.3%) secondary headaches, with 117 (3.8%) corresponding to cranial neuralgias, 136 (4.3%) were unclassified headaches, and 238 (7.7%) were included in the research Appendix of the ICHD-II. The most represented group was 1 (migraine) with 53% of all headaches. CONCLUSIONS: The characteristics of first 2000 patients in our register were comparable to those previously described in other types of headache outpatient clinics. Migraine was the most frequent diagnosis, and secondary headaches were not as frequent in our series. Most headaches could be coded according to ICHD-II criteria. PMID- 24485651 TI - Clinical spectrum and diagnostic value of antibodies against the potassium channel related protein complex. AB - INTRODUCTION: Antibodies against a protein complex that includes voltage-gated potassium channels (VGKC) have been reported in patients with limbic encephalitis, peripheral nerve hyperexcitability, Morvan's syndrome, and a large variety of neurological syndromes. REVIEW SUMMARY: In this article, a review is presented of the syndromes associated with antibodies against VGKC-related proteins and the main antigens of this protein complex, the proteins LGI1 (leucine rich glioma inactivated protein 1) and Caspr2 (contactin-associated protein-like 2). The conceptual problems and clinical implications of the description of antibodies against VGKC-related proteins other than LGI1 and Caspr2 are also discussed. Although initial studies indicated the occurrence of antibodies against VGKC, recent investigations have shown that the main antigens are a neuronal secreted protein known as LGI1 which modulates synaptic excitability, and a protein called Caspr2 located on the cell surface and processes of neurons of different brain regions, and at the juxtaparanodal region of myelinated axons. While antibodies against LGI1 preferentially associate with classical limbic encephalitis, antibodies against Caspr2 associate with a wider spectrum of symptoms, including Morvan's syndrome, peripheral nerve hyperexcitability or neuromyotonia, and limbic or more extensive encephalitis. In addition there are reports of patients with antibodies against VGKC-related proteins that are different from LGI1 or Caspr2. In these cases, the identity and location of the antigens are unknown, the syndrome association is not specific, and the response to treatment uncertain. CONCLUSIONS: The discovery of antigens such as LGI1 and Caspr2 has resulted in a clinical and molecular definition of the broad group of diseases previously attributed to antibodies against VGKC. Considering the literature that describes the presence of antibodies against VGKC other than LGI1 and Caspr2 proteins, we propose a practical algorithm for the diagnosis and treatment of these patients. PMID- 24485652 TI - [The study of social inequalities in child and adolescent health in Spain]. AB - OBJECTIVE: To identify and describe studies on social inequalities in child and adolescent health conducted in Spain with special emphasis on social determinants. METHODS: In July 2012, we conducted a systematic review in the PubMed, MEDES, SCOPUS and COCHRANE databases. We included studies on social inequalities in child and adolescent health in Spain published between 2000 and 2012. A total of 2147 abstracts were reviewed by two researchers and 80 manuscripts were fully reviewed by three researchers. Risk of bias was assessed. Seventy-two articles were finally included. RESULTS: A total of 83% of the studies were cross-sectional and the most frequently studied age group consisted of 13-15-year-olds. More than 20 individual or group determinants were identified. The most frequently analyzed determinants were the most advantaged educational level and occupation of the mother or the father. In 38% of the studies analyzing education and occupation, there was no definition of the determinant. Social inequalities were detected in dental health with all determinants and in all age groups (9% of studies with a high risk of bias). Social inequalities were also detected in obesity, physical activity and mental health with some determinants. Specific data were missing for younger children. No social inequalities were found in the use of health services, excluding dental care. Few studies analyzed immigration and 42% of them had a high risk of bias. CONCLUSION: Wide diversity was found in the measurement of social determinants, with a lack of studies in preschoolers and of studies with longitudinal designs. The results of this study confirm social inequalities in some aspects of health. PMID- 24485653 TI - [Evaluation of the Health Observatory of Asturias (Spain): web and social network metrics and health professionals' opinions]. AB - OBJECTIVE: To evaluate the Health Observatory of Asturias (Observatorio de Salud de Asturias [OBSA]), which collects and disseminates health data from Asturias through a website and social networks. METHOD: A cross-sectional study was conducted between 2012 and 2013. The study included a process evaluation that analyzed the reach of the OBSA's website, Facebook and Twitter accounts through web metrics and the use made by health professionals in Asturias of these media. Satisfaction was assessed through an online questionnaire. To estimate the potential effects of the OBSA, the study also included an evaluation of the results with a non-experimental design. RESULTS: The total number of visits to the website increased in 2012, with more than 37,000 visits. The questionnaire (n=43) showed that 72.1% of the health professionals knew of the OBSA and that 81.5% of them had used it. Most health professionals reported they were satisfied with the OBSA and believed that it encouraged cooperation among professionals (51.6%). CONCLUSION: The OBSA is known and consulted by most health professionals and is achieving some of its main objectives: to inform health staff and stimulate discussion. According to the results, information and communication technologies could play an important role in the presentation of health data in a more interactive and accessible way. PMID- 24485654 TI - Image quality evaluation of a portable handheld ultrasound machine for the focused assessment with sonography for trauma examination. PMID- 24485655 TI - [Cystic adenomatoid malformation: presenting late in a young adult and debuting with pneumothorax]. PMID- 24485656 TI - Breast cancer proteins PALB2 and BRCA2 stimulate polymerase eta in recombination associated DNA synthesis at blocked replication forks. AB - One envisioned function of homologous recombination (HR) is to find a template for DNA synthesis from the resected 3'-OH molecules that occur during double strand break (DSB) repair at collapsed replication forks. However, the interplay between DNA synthesis and HR remains poorly understood in higher eukaryotic cells. Here, we reveal functions for the breast cancer proteins BRCA2 and PALB2 at blocked replication forks and show a role for these proteins in stimulating polymerase eta (Poleta) to initiate DNA synthesis. PALB2, BRCA2, and Poleta colocalize at stalled or collapsed replication forks after hydroxyurea treatment. Moreover, PALB2 and BRCA2 interact with Poleta and are required to sustain the recruitment of Poleta at blocked replication forks. PALB2 and BRCA2 stimulate Poleta-dependent DNA synthesis on D loop substrates. We conclude that PALB2 and BRCA2, in addition to their functions in D loop formation, play crucial roles in the initiation of recombination-associated DNA synthesis by Poleta-mediated DNA repair. PMID- 24485657 TI - Hypothalamic eIF2alpha signaling regulates food intake. AB - The reversible phosphorylation of the alpha subunit of eukaryotic initiation factor 2 (eIF2alpha) is a highly conserved signal implicated in the cellular adaptation to numerous stresses such as the one caused by amino acid limitation. In response to dietary amino acid deficiency, the brain-specific activation of the eIF2alpha kinase GCN2 leads to food intake inhibition. We report here that GCN2 is rapidly activated in the mediobasal hypothalamus (MBH) after consumption of a leucine-deficient diet. Furthermore, knockdown of GCN2 in this particular area shows that MBH GCN2 activity controls the onset of the aversive response. Importantly, pharmacological experiments demonstrate that the sole phosphorylation of eIF2alpha in the MBH is sufficient to regulate food intake. eIF2alpha signaling being at the crossroad of stress pathways activated in several pathological states, our study indicates that hypothalamic eIF2alpha phosphorylation could play a critical role in the onset of anorexia associated with certain diseases. PMID- 24485658 TI - Wnt/beta-catenin signaling defines organizing centers that orchestrate growth and differentiation of the regenerating zebrafish caudal fin. AB - Zebrafish regenerate their fins via the formation of a population of progenitor cells, the blastema. Wnt/beta-catenin signaling is essential for blastemal cell proliferation and patterning of the overlying epidermis. Yet, we find that beta catenin signaling is neither active in the epidermis nor the majority of the proliferative blastemal cells. Rather, tissue-specific pathway interference indicates that Wnt signaling in the nonproliferative distal blastema is required for cell proliferation in the proximal blastema, and signaling in cells lining the osteoblasts directs osteoblast differentiation. Thus, Wnt signaling regulates epidermal patterning, blastemal cell proliferation, and osteoblast maturation indirectly via secondary signals. Gene expression profiling, chromatin immunoprecipitation, and functional rescue experiments suggest that Wnt/beta catenin signaling acts through Fgf and Bmp signaling to control epidermal patterning, whereas retinoic acid and Hedgehog signals mediate its effects on blastemal cell proliferation. We propose that Wnt signaling orchestrates fin regeneration by defining organizing centers that instruct cellular behaviors of adjacent tissues. PMID- 24485659 TI - Sequential and opposing activities of Wnt and BMP coordinate zebrafish bone regeneration. AB - Zebrafish fully regenerate lost bone, including after fin amputation, through a process mediated by dedifferentiated, lineage-restricted osteoblasts. Mechanisms controlling the osteoblast regenerative program from its initiation through reossification are poorly understood. We show that fin amputation induces a Wnt/beta-catenin-dependent epithelial to mesenchymal transformation (EMT) of osteoblasts in order to generate proliferative Runx2(+) preosteoblasts. Localized Wnt/beta-catenin signaling maintains this progenitor population toward the distal tip of the regenerative blastema. As they become proximally displaced, preosteoblasts upregulate sp7 and subsequently mature into re-epithelialized Runx2(-)/sp7(+) osteoblasts that extend preexisting bone. Autocrine bone morphogenetic protein (BMP) signaling promotes osteoblast differentiation by activating sp7 expression and counters Wnt by inducing Dickkopf-related Wnt antagonists. As such, opposing activities of Wnt and BMP coordinate the simultaneous demand for growth and differentiation during bone regeneration. This hierarchical signaling network model provides a conceptual framework for understanding innate bone repair and regeneration mechanisms and rationally designing regenerative therapeutics. PMID- 24485660 TI - Autonomous CaMKII mediates both LTP and LTD using a mechanism for differential substrate site selection. AB - Traditionally, hippocampal long-term potentiation (LTP) of synaptic strength requires Ca(2+)/calmodulin (CaM)-dependent protein kinase II (CaMKII) and other kinases, whereas long-term depression (LTD) requires phosphatases. Here, we found that LTD also requires CaMKII and its phospho-T286-induced "autonomous" (Ca(2+) independent) activity. However, whereas LTP is known to induce phosphorylation of the AMPA-type glutamate receptor (AMPAR) subunit GluA1 at S831, LTD instead induced CaMKII-mediated phosphorylation at S567, a site known to reduce synaptic GluA1 localization. GluA1 S831 phosphorylation by "autonomous" CaMKII was further stimulated by Ca(2+)/CaM, as expected for traditional substrates. By contrast, GluA1 S567 represents a distinct substrate class that is unaffected by such stimulation. This differential regulation caused GluA1 S831 to be favored by LTP type stimuli (strong but brief), whereas GluA1 S567 was favored by LTD-type stimuli (weak but prolonged). Thus, requirement of autonomous CaMKII in opposing forms of plasticity involves distinct substrate classes that are differentially regulated to enable stimulus-dependent substrate-site preference. PMID- 24485661 TI - Pol II docking and pausing at growth and stress genes in C. elegans. AB - Fluctuations in nutrient availability profoundly impact gene expression. Previous work revealed postrecruitment regulation of RNA polymerase II (Pol II) during starvation and recovery in Caenorhabditis elegans, suggesting that promoter proximal pausing promotes rapid response to feeding. To test this hypothesis, we measured Pol II elongation genome wide by two complementary approaches and analyzed elongation in conjunction with Pol II binding and expression. We confirmed bona fide pausing during starvation and also discovered Pol II docking. Pausing occurs at active stress-response genes that become downregulated in response to feeding. In contrast, "docked" Pol II accumulates without initiating upstream of inactive growth genes that become rapidly upregulated upon feeding. Beyond differences in function and expression, these two sets of genes have different core promoter motifs, suggesting alternative transcriptional machinery. Our work suggests that growth and stress genes are both regulated postrecruitment during starvation but at initiation and elongation, respectively, coordinating gene expression with nutrient availability. PMID- 24485663 TI - VEGF-A promotes IL-17A-producing gammadelta T cell accumulation in mouse skin and serves as a chemotactic factor for plasmacytoid dendritic cells. AB - BACKGROUND: IL-17-producing CD4(+) T (Th17) cells and their cytokines, IL-17A and IL-22, are deeply involved in the pathogenesis of psoriasis by stimulating epidermal keratinocytes to proliferate and to produce cytokines/chemokines and vascular endothelial growth factor (VEGF)-A. Plasmacytoid dendritic cells (pDCs), infiltrating in psoriatic lesions, are known to exacerbate the Th17-mediated pathogenesis of psoriasis. OBJECTIVE: To address the initiative role of VEGF-A in the development of psoriasis and the pDC accumulation. METHODS: Numerical changes and VEGF receptor 1 (VEGFR1) and VEGFR2 expressions were investigated in skin infiltrating T cells and pDCs of K14-VEGF-A transgenic (Tg) and wild type (WT) mice. The chemotactic properties of VEGF-A for purified splenic pDCs were also evaluated by real-time chemotaxis assay. RESULTS: By flow cytometry and immunohistochemistry, we observed that the number of dermal IL-17A(+) gammadelta T cells, but not CD4(+) T cells, was increased in VEGF-A Tg mice, suggesting that the main source of IL-17A was gammadelta T cells. Moreover, we identified pDCs as 440c(+) cells by immunohistochemistry and as PDCA-1(+)B220(+) cells by flow cytometry, and found that pDCs infiltrated at a higher frequency in VEGF-A Tg than WT mice. pDCs, but not gammadelta T cells, isolated from the skin expressed VEGFR1 and VEGFR2. Freshly isolated splenic pDCs expressed both receptors after 48-h cultivation. pDCs did not produce cytokines in response to VEGF-A, however, they had a strong velocity of chemotaxis toward VEGF-A at a comparable level to chemerin. CONCLUSIONS: These findings suggest that VEGF-A functions as not only a downstream enhancer but also an upstream initiator by chemoattracting pDCs in psoriatic lesions. PMID- 24485662 TI - ZFX controls propagation and prevents differentiation of acute T-lymphoblastic and myeloid leukemia. AB - Tumor-propagating cells in acute leukemia maintain a stem/progenitor-like immature phenotype and proliferative capacity. Acute myeloid leukemia (AML) and acute T-lymphoblastic leukemia (T-ALL) originate from different lineages through distinct oncogenic events such as MLL fusions and Notch signaling, respectively. We found that Zfx, a transcription factor that controls hematopoietic stem cell self-renewal, controls the initiation and maintenance of AML caused by MLL-AF9 fusion and of T-ALL caused by Notch1 activation. In both leukemia types, Zfx prevents differentiation and activates gene sets characteristic of immature cells of the respective lineages. In addition, endogenous Zfx contributes to gene induction and transformation by Myc overexpression in myeloid progenitors. Key Zfx target genes include the mitochondrial enzymes Ptpmt1 and Idh2, whose overexpression partially rescues the propagation of Zfx-deficient AML. These results show that distinct leukemia types maintain their undifferentiated phenotype and self-renewal by exploiting a common stem-cell-related genetic regulator. PMID- 24485664 TI - Safety of cabazitaxel in senior adults with metastatic castration-resistant prostate cancer: results of the European compassionate-use programme. AB - BACKGROUND: Cabazitaxel/prednisone has been shown to prolong survival versus mitoxantrone/prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) that has progressed during or after docetaxel. Subsequently, compassionate-use programmes (CUPs) and expanded-access programmes (EAPs) were established worldwide, allowing access to cabazitaxel before its commercial availability. Preliminary results of the European CUP/EAP, focusing on the elderly population (aged > or =70 years), are reported. PATIENTS AND METHODS: Enrolled patients with progressive mCRPC received cabazitaxel (25 mg/m2) plus 10mg oral prednisone/prednisolone every 3 weeks until disease progression, death, unacceptable toxicity or physician/patient decision. Safety was analysed by age group (<70, 70-74 and > or =75 years). The influence of selected variables on grade > or =3 neutropenia and/or neutropenic complications was analysed in multivariate analysis. RESULTS: 746 men were enrolled (<70 years, n=421; 70-74, n=180, > or =75 years, n=145). Number of cabazitaxel cycles, dose reductions for any cause, dose delays possibly related to cabazitaxel adverse events, and tolerability were similar in the three age groups. Prophylactic granulocyte colony-stimulating factor (G-CSF) use was more common in men aged > or =0 years. In multivariate analysis, age > or =75 years, treatment cycle 1, and neutrophil count <4000/mm3 before cabazitaxel injection were associated with increased risk of developing grade > or =3 neutropenia and/or neutropenic complications. Prophylactic use of G-CSF at a given cycle significantly reduced this risk by 30% (odds ratio 0.70, p=0.04). CONCLUSION: The results suggest that cabazitaxel has a manageable safety profile in everyday clinical practice. Prophylactic use of G CSF, especially at cycle 1 and in men aged > or =75 years, is important and improves tolerability in senior adults treated with cabazitaxel. PMID- 24485665 TI - Randomised phase II trial of photodynamic therapy plus oral fluoropyrimidine, S 1, versus photodynamic therapy alone for unresectable hilar cholangiocarcinoma. AB - BACKGROUND: Hilar cholangiocarcinoma is an uncommon cancer and its overall incidence is increasing. Photodynamic therapy (PDT) has been proposed as palliative management for unresectable hilar cholangiocarcinoma (UHC). To date, little is known about the role of the addition of systemic chemotherapy to PDT for UHC. We performed a prospective, randomised, phase II trial to compare PDT plus S-1 and PDT alone for UHC. METHODS: Patients with UHC were randomly assigned (in a 1:1 ratio) to PDT plus S-1 or PDT alone. The primary end-point was overall survival. The secondary end-points were progression-free survival, complications, re-intervention rate and quality of life. This trial is registered with clinicalTrials.gov, number NCT00869635. FINDINGS: Between February 2009 and May 2012, we randomly assigned 21 patients to receive PDT plus S-1 and 22 to receive PDT alone. The UHC patients treated with PDT plus S-1 showed higher 1-year survival rate compared with the patients treated with PDT alone (76.2% versus 32%, P=0.003) and prolonged overall survival (median 17 months, 95% confidence interval [CI]: 12.6-21.4, versus 8 months, 95% CI: 6-10, P=0.005, hazard ratio [HR], 0.36; 95% CI: 0.17-0.75). Regarding the secondary end-points, PDT plus S-1 was associated with prolonged progression-free survival compared with PDT alone (median 10 months [95% CI: 4.1-16] versus 2 months [95% CI: 0.4-3.5], P=0.009 (HR for progression 0.39, 95% CI: 0.19-0.83). There were no differences in the number of PDT sessions, the frequency of cholangitis, overall adverse events or the quality of life in either group. INTERPRETATIONS: PDT plus S-1 was well tolerated and was associated with a significant improvement of overall survival and progression-free survival compared with PDT alone in patients with UHC. These findings warrant further clinical investigation of PDT plus S-1 in patients with UHC. PMID- 24485666 TI - Malnutrition and clinical outcome in gynecologic patients. AB - OBJECTIVES: An association between malnutrition and poor patient outcome has been established in various medical fields, but there is a general lack of data on the prevalence of malnutrition among gynecologic patients. Therefore an assessment of malnutrition is needed to detect malnourished patients in gynecology and initiate nutritional therapy if needed. STUDY DESIGN: Between 2011 and 2012 at our Gynecologic Department of a German University Hospital, 397 patients were evaluated regarding the risk of malnutrition and occurrence of complications during the time of hospitalization. The Nutritional Risk Screening (NRS) 2002 system was used to estimate the risk level for malnutrition. Of the 397 patients, 336 received surgery and 61 were treated conservatively. Patients were included independently of surgical intervention or age. The parameters for the clinical outcome were complications and time of hospitalization. RESULTS: A severe risk of malnutrition was diagnosed in 142 patients (35.8%) according to an NRS score of >=3. Furthermore, a significantly higher complication rate among those patients who were at risk for malnutrition (NRS 1-2) (7.8%) or who were malnourished (NRS >=3) (22.8%) was found (p<0.001 chi(2)). Regarding the length of stay (LOS) in hospital, the medial hospitalization time increased from 7 to 10 days when patients were malnourished (NRS score >=3) (p<0.001). CONCLUSIONS: Malnutrition occurs frequently among gynecologic patients. Adequate perioperative nutritional supportive therapy should be considered in malnourished patients to improve their clinical outcome. PMID- 24485667 TI - Pregnancy outcomes in a university hospital after legal requirement for single embryo transfer. AB - OBJECTIVE: To present our in vitro fertilization outcomes after implementation of the Turkish government policy limiting the number of transferred embryos to one, in women under the age of 35, and two, in women over age 35; and to demonstrate the feasibility of this policy. STUDY DESIGN: We retrospectively reviewed the records of 423 patients who underwent ovarian stimulation, oocyte pick-up, intracytoplasmic sperm injection and embryo transfer due to primary or secondary infertility over a 22-month time interval. Clinical pregnancy was defined as a fetal heartbeat in the seventh gestational week. Embryo transfers were carried out on day 3 or 5. Descriptive statistics are given as the number of subjects and percentages. RESULTS: A total of 353 embryo transfers were performed: 261 (73.9%) were single-embryo transfer (244 (69.1%) elective and 17 (4.8%) non-elective) and 92 (26.1%) were double-embryo transfer. Of the 244 elective single-embryo transfers, 6.6% (n=16) were performed using frozen-thawed embryos. The average patient age was 29.6+/-4.5 years in the single-embryo group and 36.5+/-2.4 years in the double-embryo group. The cumulative pregnancy rates per oocyte pick-up were similar in both groups: 41% (n=107) in the single-embryo group and 43.4% (n=40) in the double-embryo group (p=0.678). The cumulative live birth rate of the single-embryo group (32.1%) was not statistically different from the double embryo group (35.8%) (p=0.518). The twin pregnancy rate after single-embro transfer was significantly lower than with double-embryo transfer (2.8% (n=3) vs. 32.5% (n=13); p<0.001) and 62.5% of the twin pregnancies occurred in women 35 years or older who underwent double-embryo transfer. No significant difference in the spontaneous abortion rates was recorded between the single- and double-embryo transfer groups (16 (6.1%) vs. 6 (6.5%); p=0.894). CONCLUSION: Single-embryo transfer results in a pregnancy rate comparable to double-embryo transfer, with a significantly reduced multiple pregnancy rate. Double-embryo transfer in patients over age 35 should be reconsidered because of the resulting high rate of multiple pregnancy. PMID- 24485668 TI - Differential response to lipopolysaccharide by JEG-3 and BeWo human choriocarcinoma cell lines. AB - OBJECTIVE: To determine the effect of lipopolysaccharide (LPS) on NF-kappaB gene expression and proinflammatory cytokine release from trophoblast cell models, JEG 3 and BeWo human choriocarcinoma cells. STUDY DESIGN: Serum-starved JEG-3 and BeWo cells were treated with LPS (from Escherichia coli serotype 0111:B4) for 24 or 48h. Cell culture medium was collected and assayed for interleukin (IL)-1beta, IL-6, IL-8, and transforming necrosis factor (TNF)-alpha cytokine release using enzyme-linked immunosorbent assays. RNA was extracted from the cells and real time PCR was performed to measure NF-kappaB mRNA expression. All results were analyzed by one-way analysis of variance tests followed by Sidak's post hoc analysis. p<0.05 was considered statistically significant. RESULTS: LPS triggered an inflammatory response in JEG-3 cells by inducing a 1.5-fold increase in NF kappaB mRNA expression and TNF-alpha release (0MUg/mL: 15.13+/-2.14, 1MUg/mL: 14.94+/-0.75, 10MUg/mL: 23.05+/-4.50, p<0.05) and a 2-fold elevation in IL-6 secretion (0MUg/mL: 12.54+/-5.44, 1MUg/mL: 25.54+/-0.91, 10MUg/mL: 24.28+/-4.43, p<0.05). In contrast, BeWo cells were not as sensitive to LPS exposure; NF-kappaB mRNA expression was unchanged between LPS-treated and control cells, whereas a small but significant 1.3-fold increase in TNF-alpha release was found (TNF alpha: 15.45+/-1.53pg/mL, control: 12.24+/-1.00pg/mL, p<0.05). The inflammatory pathways in BeWo cells were found to be active given that treatment of these cells with IL-1beta and TNF-alpha induced IL-6 secretion. Interestingly, 1MUg/mL LPS appeared to decrease IL-6 and TNF-alpha release from BeWo cells. IL-1beta and IL-8 secretion were not detected from either cell lines. CONCLUSION: LPS activates the NF-kappaB pathway in JEG-3 but not BeWo human choriocarcinoma cells and this may be the reason for their differential inflammatory response to LPS exposure. PMID- 24485669 TI - Biomarkers of endothelial dysfunction in preeclampsia and neonatal morbidity: a case-control study. AB - OBJECTIVE: To investigate the association of preeclampsia with angiogenic imbalance, and the correlation of levels of angiogenic and anti-angiogenic factors to complications in mother and fetus. STUDY DESIGN: Serum samples were obtained from 40 women with established preeclampsia (study group) and from 40 normotensive women (control group). Epidemiological characteristics of the two groups were analyzed. The levels of the angiogenic (VEGF and PlGF) and anti angiogenic (sFlt-1) factors of the two study groups were determined in serum using ELISA. Neonatal adverse outcomes (late preterm, early term, low birth weight (LBW), very LBW (VLBW), intrauterine growth restriction (IUGR), and neonatal intensive care unit (NICU) admission) between the groups of the study were analyzed, as well as the association between the biomarkers of the study and neonatal adverse outcomes of the preeclamptic group of patients. RESULTS: sFlt-1 levels were significantly higher in the preeclamptic women compared to normotensive women (median (range): 21297 (690-32637)pg/ml vs. 846.45 (363 2867)pg/ml, respectively), whereas there was a significant decrease in the levels of VEGF (90 (90-211)pg/ml vs. 90.55 (90-521)pg/ml, respectively), as well as in the levels of PlGF (13.62 (8-532)pg/ml vs. 239.86 (61-685)pg/ml, respectively). The increased serum values of the anti-angiogenic sFlt-1 were associated with increased rates of late preterm and early term births and VLBW. CONCLUSION: An imbalance between angiogenic and anti-angiogenic factors exists in preeclampsia and is associated with adverse maternal and neonatal outcomes. PMID- 24485670 TI - Comment on: Fasting blood glycemia: a good predictor of weight loss after Roux-en Y gastric bypass. PMID- 24485671 TI - Association between somatic cell count during the first lactation and the cumulative milk yield of cows in Irish dairy herds. AB - Reduced potential milk yield is an important component of mastitis costs in dairy cows. The first aim of this study was to assess associations between somatic cell count (SCC) during the first lactation, and cumulative milk yield over the first lactation and subsequent lifetime of cows in Irish dairy herds. The second aim was to assess the association between SCC at 5 to 30d in milk during parity 1 (SCC1), and SCC over the entire first lactation for cows in Irish dairy herds. The data set studied included records from 51,483 cows in 5,900 herds. Somatic cell count throughout the first lactation was summarized using the geometric mean and variance of SCC. Data were analyzed using linear models that included random effects to account for the lack of independence between observations, and herd level variation in coefficients. Models were developed in a Bayesian framework and parameters were estimated from 10,000 Markov chain Monte Carlo simulations. The final models were a good fit to the data. A 1-unit increase in mean natural logarithm SCC over the first lactation was associated with a median decrease in first lactation and lifetime milk yield of 135 and 1,663kg, respectively. A 1 unit increase in the variance of natural logarithm SCC over the first lactation was associated with a median decrease in lifetime milk yield of 719kg. To demonstrate the context of lifetime milk yield results, microsimulation was used to model the trajectory of individual cows and evaluate the expected outcomes for particular changes in herd-level geometric mean SCC over the first lactation. A 75% certainty of savings of at least ?199/heifer in the herd was detected if herd level geometric mean SCC over the first lactation was reduced from >=120,000 to <=72,000cells/mL. The association between SCC1 and SCC over the remainder of the first lactation was highly herd dependent, indicating that control measures for heifer mastitis should be preferentially targeted on an individual-herd basis toward either the pre- and peripartum period, or the lactating period, to optimize the lifetime milk yield of dairy cows. PMID- 24485672 TI - Production, fertility, survival, and body measurements of Montbeliarde-sired crossbreds compared with pure Holsteins during their first 5 lactations. AB - Two-breed crossbreds of Montbeliarde and Holstein (MO * HO) as well as 3-breed crossbreds of Montbeliarde and Jersey/Holstein (MO * JH) were compared with pure Holstein (HO) cows for production, somatic cell score (SCS), fertility, survival to subsequent calving, mortality, and body measurements during their first 5 lactations. Cows calved for the first time between 2005 and 2010 and were housed in either a confinement herd or a herd that had access to pasture for 165d of the year in the north central region of the United States. Body, hoof, and udder measurements of cows were also objectively measured. The MO * HO crossbred cows were not different from pure HO cows for fat-plus-protein production during any lactation. However, the MO * JH crossbred cows had 5% lower fat-plus-protein production compared with pure HO cows in the confinement herd. On the other hand, the MO * JH crossbred cows were not different for fat-plus-protein production in the third to fifth lactation compared with pure HO cows in the seasonal pasture herd. Across the 2 herds, the MO * HO and MO * JH crossbred cows had 21% higher first-service conception rate, 41 fewer days open, and 12% higher pregnancy rate compared with the pure HO cows. Furthermore, the MO * HO (5%) and MO * JH (12%) crossbred cows had lower mortality rates than the pure HO cows (18%). Because of superior fertility and lower mortality rates, the MO * HO and MO * JH crossbred cows, combined, had greater survival to second (+13%), third (+24%), fourth (+25%), and fifth (+17%) lactation compared with pure HO cows. For body measurements, MO * HO were similar to pure HO cows for hip height and heart girth, but MO * HO cows had more body condition and greater body weight (+39kg) across the first 5 lactations. The MO * JH cows had more body condition but 5cm shorter hip height and 28kg less body weight than pure HO cows across the first 5 lactations. Foot angle was steeper and hoof length was shorter for MO * HO cows, but MO * JH cows were similar to pure HO cows for hoof measurements. PMID- 24485673 TI - Short communication: validation of somatic cell score-associated loci identified in a genome-wide association study in German Holstein cattle. AB - Recently, we identified 6 genomic loci affecting daughter yield deviations (DYD) for somatic cell score (SCS) in a genome-wide association study (GWAS) performed with German Holstein bulls. In the current study, we tested if these loci were associated with SCS in cows using their own performance data. The study was performed with 1,412 German Holstein cows, of which 483 were daughters of 71 bulls that had been used in the GWAS. We tested 10 single nucleotide polymorphisms (SNP) representing 6 genomic regions that were associated with DYD for SCS in bulls. All tested SNP were significant in cows. Seven of them, located on Bos taurus autosomes (BTA) 6, 13, and 19, had the same direction of effect as those previously reported in the bull population. The most significant associations were detected on BTA6 and BTA19, accounting for 1.8% of the total genetic variance. The major allele of the 2 SNP on BTA6 and the minor allele of the 2 SNP on BTA19 were favorable for lower SCS. The differences between the homozygous genotype classes were up to 15,000 cells/mL. The verification of SNP associated with SCS in this study provides further evidence for the functional role of the linked genomic regions for immune response and contributes to identification of causative mutations. In particular, SNP with minor frequency of the favorable allele possess high potential to reduce SCS in German Holstein cattle by selection. PMID- 24485675 TI - Association of total mixed ration particle fractions retained on the Penn State Particle Separator with milk, fat, and protein yield lactation curves at the cow level. AB - As part of a larger project aiming to develop management evaluation tools based on results from test-day (TD) models, the objective of this study was to examine the effect of physical composition of total mixed rations (TMR) tested quarterly from March 2006 through December 2008 on milk, fat, and protein yield curves for 25 herds in Ragusa, Sicily. A random regression sire-maternal grandsire model was used to estimate variance components for milk, fat, and protein yields fitted on a full data set, including 241,153 TD records from 9,809 animals in 42 herds recorded from 1995 through 2008. The model included parity, age at calving, year at calving, and stage of pregnancy as fixed effects. Random effects were herd * test date, sire and maternal grandsire additive genetic effect, and permanent environmental effect modeled using third-order Legendre polynomials. Model fitting was carried out using ASREML. Afterward, for the 25 herds involved in the study, 9 particle size classes were defined based on the proportions of TMR particles on the top (19-mm) and middle (8-mm) screen of the Penn State Particle Separator. Subsequently, the model with estimated variance components was used to examine the influence of TMR particle size class on milk, fat, and protein yield curves. An interaction was included with the particle size class and days in milk. The effect of the TMR particle size class was modeled using a ninth-order Legendre polynomial. Lactation curves were predicted from the model while controlling for TMR chemical composition (crude protein content of 15.5%, neutral detergent fiber of 40.7%, and starch of 19.7% for all classes), to have pure estimates of particle distribution not confounded by nutrient content of TMR. We found little effect of class of particle proportions on milk yield and fat yield curves. Protein yield was greater for sieve classes with 10.4 to 17.4% of TMR particles retained on the top (19-mm) sieve. Optimal distributions different from those recommended may reflect regional differences based on climate and types and quality of forages fed. PMID- 24485674 TI - Effect of dietary N-carbamoylglutamate on milk production and nitrogen utilization in high-yielding dairy cows. AB - The objective of the current study was to investigate the effect of N carbamoylglutamate (NCG) supplementation on milk production and nitrogen (N) utilization in Chinese Holstein dairy cows. Sixty multiparous cows (78+/-17.3 d in milk, 635+/-61.00kg of body weight, and 41.9+/-7.9kg/d milk yield; mean +/- SD) were blocked by parity, days in milk, and milk yield and randomly allocated to 1 of 4 groups, each of which was fed a dietary treatment containing 0 (control), 10, 20, or 30g of NCG/d. Milk yield was recorded weekly. Dry matter intake, milk composition, plasma variables, and urea N contents in plasma, urine, and milk were determined every other week. Blood samples were collected from the coccygeal vein. Rumen microbial protein synthesis was estimated based on the purine derivatives in the urine. Dry matter intake was found to be similar between the treatments. Addition of 20g of NCG/d tended to increase milk yield (40.2 vs. 38.1kg/d) and increased the content (2.83 vs. 2.74%) and yield (1.12 vs. 1.02kg/d) of milk protein compared with the control. The yield and content of milk fat were similar between the treatments, whereas the contents of lactose and total solids increased linearly with an increase in NCG. Dietary supplementation of NCG linearly increased the plasma nitric oxide level and decreased the plasma ammonia N level. Compared with the control, the plasma Arg concentration in cows fed 10, 20, and 30g of NCG/d was increased by 1.1, 10.4, and 16.0%, respectively. The urea N concentrations in the milk, plasma, and urine decreased with the addition of NCG, although the lowest urea N concentrations were observed with the addition of 20g of NCG/d. The conversion of dietary crude protein to milk protein exhibited quadratic trends of improvement by NCG supplementation, with a peak at 20g of NCG/d. The rumen microbial protein synthesis was not altered by NCG supplementation, but the metabolizable protein tended to show a quadratic increase in cows fed 20g of NCG/d. In conclusion, supplementation of 20g of NVG/d may alter the plasma metabolites, optimize the AA profile, increase the metabolizable protein utilization, and thereby improve the lactation performance and N utilization of high-yielding dairy cows. PMID- 24485676 TI - Short communication: survival of the characteristic microbiota in probiotic fermented camel, cow, goat, and sheep milks during refrigerated storage. AB - The objective of this study was to monitor the viability during storage of Lactobacillus acidophilus LA-5 (A), Bifidobacterium animalis ssp. lactis BB-12 (B), and Streptococcus thermophilus CHCC 742/2130 (T) in probiotic cultured dairy foods made from pasteurized camel, cow, goat, and sheep milks fermented by an ABT type culture. The products manufactured were stored at 4 degrees C for 42d. Microbiological analyses were performed at weekly intervals. Streptococcus thermophilus CHCC 742/2130 was the most numerous culture component in all 4 products both at the beginning and at the end of storage. The viable counts of streptococci showed no significant decline in fermented camel milk throughout the entire storage period. The initial numbers of Lb. acidophilus LA-5 were over 2 orders of magnitude lower than those of Strep. thermophilus CHCC 742/2130. With the progress of time, a slow and constant decrease was observed in lactobacilli counts; however, the final viability percentages of this organism did not differ significantly in the probiotic fermented milks tested. The cultured dairy foods made from cow, sheep, and goat milks had comparable B. animalis ssp. lactis BB-12 counts on d 0, exceeding by approximately 0.5 log10 cycle those in the camel milk based product. No significant losses occurred in viability of bifidobacteria in fermented camel, cow, and sheep milks during 6wk of refrigerated storage. In conclusion, all 4 varieties of milk proved to be suitable raw materials for the manufacture of ABT-type fermented dairy products that were microbiologically safe and beneficial for human consumption. It was suggested that milk from small ruminants be increasingly used to produce probiotic fermented dairy foods. The development of camel milk-based probiotic cultured milks appears to be even more promising because new markets could thus be conquered. It must be emphasized, however, that further microbiological and sensory studies, technology development activities, and market research are needed before such food products can be successfully commercialized. PMID- 24485677 TI - Manufacture and sensory analysis of reduced- and low-sodium Cheddar and Mozzarella cheeses. AB - High sodium intake negatively affects consumer health, thus there is active interest in lowering sodium levels in dairy foods. Cheddar and low-moisture, part skim Mozzarella cheeses were made with total salt levels of 0.7, 1.0, 1.25, 1.35, and 1.8% (wt/wt) in triplicate, thus reducing sodium by 25 to 60%. Multiple manufacturing protocols for salt reduction were used to produce cheeses with similar postpress moisture and pH, independent of the final salt levels in cheese, in order to study the role of salt in cheese acceptability. Cheese flavor was evaluated by a descriptive taste panel on a 15-point intensity scale. Consumer acceptance was evaluated by a consumer panel on a 9-point hedonic scale. Taste panels conducted with cubed Cheddar cheese (at 3 and 6mo) and cold shredded Mozzarella cheese (at 3wk) showed that consumer liking for cheese was low at 0.7 and 0.9% salt, but all cheeses containing higher salt levels (1.25, 1.35, and 1.8% salt) were comparably preferred. The cheeses had acceptable liking scores (>=6) when served as quesadilla or pizza toppings, and consumers were able to differentiate cheeses at alternate salt levels; for example, 1.8 and 1.5% salt cheeses scored similarly, as did cheeses with 1.5% and 1.35% salt, but 1.35% salt cheese scored lower than and was discernible from 1.8% salt cheese. Descriptive panelists perceived salty, sour, umami, bitter, brothy, lactone/fatty acid, and sulfur attributes as different across Mozzarella cheeses, with the perception of each significantly increasing along with salt level. Salty and buttery attributes were perceived more with increasing salt levels of Cheddar cheese by the descriptive panel at 3mo, whereas bitter, brothy, and umami attributes were perceived less at the higher salt levels. However, this trend reversed at 6mo, when perception of salty, sour, bitter, buttery, lactone/fatty acid, and umami attributes increased with salt level. We conclude that consumers can distinguish even a 30% salt reduction and a gradually phased sodium reduction is needed to improve acceptability of lower sodium cheeses. PMID- 24485678 TI - Effect of a tea tree oil and organic acid footbath solution on digital dermatitis in dairy cows. AB - Copper sulfate is the industry gold standard footbath ingredient for controlling dairy cow digital dermatitis. However, when used footbath solutions are deposited on soil, high levels of copper in the soil may result, which can have toxic and negative effects on plant growth. An alternative to copper sulfate is Provita Hoofsure Endurance (Provita Eurotech Ltd., Omagh, UK), which is a biodegradable solution containing organic acids, tea tree oil, and wetting agents. The objective of this study was to quantify changes in digital dermatitis frequency when using Provita Hoofsure Endurance and copper sulfate in a split footbath in 3 commercial dairy herds. This study was conducted from January 5, 2012, to March 19, 2012, in 3 commercial Kentucky dairies with 120, 170, and 200 milking Holstein cows. None of the herds was using a footbath for digital dermatitis control before the study. Footbath solutions were delivered using a split footbath. During the study, a 3% Hoofsure Endurance solution for the left hooves and a 5% copper sulfate solution for the right hooves was used. Digital dermatitis was scored every 3wk using the M0 to M4 system, where M0=a claw free of signs of digital dermatitis; M1=a lesion <2cm that is not painful; M2=the ulcerative stage, with lesion diameter of >2cm, and painful to the touch; M3=the healing stage and covered by a scab; and M4=the chronic stage and characterized by dyskeratosis or proliferation of the surface that is generally not painful. McNemar's test statistic suggested that a statistically significant difference existed in the proportions of M1 and M2 lesions between the beginning and end of the study for both treatments. This indicates that each solution was effective in decreasing the proportion of M1 or M2 lesions from baseline to the last time point. A chi-square test calculated using PROC FREQUENCY of SAS (SAS Institute Inc., Cary, NC) indicated that no statistically significant relationship existed between the treatments among changes in digital dermatitis frequency from the baseline to the end of the study. Performance of the 2 footbath solutions was comparable throughout the study. No significant differences were observed between the copper sulfate and Provita Hoofsure Endurance. PMID- 24485679 TI - Short communication: effect of homogenization on heat inactivation of Mycobacterium avium subspecies paratuberculosis in milk. AB - Mycobacterium avium ssp. paratuberculosis (MAP) can be present in cow milk and low numbers may survive high-temperature, short-time (HTST) pasteurization. Although HTST treatment leads to inactivation of at least 5 log10 cycles, it might become necessary to enhance the efficacy of HTST by additional treatments such as homogenization if the debate about the role of MAP in Crohn's disease of humans concludes that MAP is a zoonotic agent. This study aimed to determine whether disrupting the clumps of MAP in milk by homogenization during the heat treatment process would enhance the inactivation of MAP. We used HTST pasteurization in a continuous-flow pilot-plant pasteurizer and evaluated the effect of upstream, downstream, and in-hold homogenization on inactivation of MAP. Reduction of MAP at 72 degrees C with a holding time of 28s was between 3.7 and 6.9 log10 cycles, with an overall mean of 5.5 log10 cycles. None of the 3 homogenization modes applied showed a statistically significant additional effect on the inactivation of MAP during HTST treatment. PMID- 24485680 TI - Effects of folic acid and vitamin B12 supplementation on culling rate, diseases, and reproduction in commercial dairy herds. AB - This study was undertaken to determine the effect of a combined folic acid and vitamin B12 supplement given in early lactation on culling rate, metabolic disorders and other diseases, and reproduction in commercial dairy herds. A total of 805 cows (271 primiparous and 534 multiparous cows) in 15 commercial dairy herds were involved. Every 2mo from February to December 2010 and within each herd, cows were assigned according to parity, previous 305-d milk production, and calving interval to 5mL of either (1) saline 0.9% NaCl (control group) or (2) 320mg of folic acid + 10mg of vitamin B12 (vitamin group). Treatments were administered weekly by intramuscular injections starting 3wk before the expected calving date until 8wk after parturition. A total of 221 cows were culled before the next dry period. Culling rate was not affected by treatment and was 27.5%; culling rate was greater for multiparous (32.2%) than for primiparous cows (18.8%). Within the first 60d in milk (DIM), 47 cows were culled, representing 21.3% of total culling, and no treatment effect was noted. Ketosis incidence based on a threshold >=100umol/L of beta-hydroxybutyrate in milk was 38.3+/-2.9% for the vitamin group and 41.8+/-3.0% for the control group and was not affected by treatment. The combined supplement of folic acid and vitamin B12 did not decrease incidence of retained placenta, displaced abomasum, milk fever, metritis, or mastitis. However, the incidence of dystocia decreased by 50% in multiparous cows receiving the vitamin supplement, although no effect was observed in primiparous cows. The first breeding postpartum for multiparous cows occurred 3.8d earlier with the vitamin supplement compared with controls, whereas no treatment effect was seen for primiparous cows. Days open, first- and second breeding conception rates, number of breedings per conception, and percentage of cows pregnant at 150 DIM were not affected by treatment. The reduced percentage of dystocia combined with the earlier DIM at first breeding for multiparous cows receiving the combined supplementation in folic acid and vitamin B12 indicates that the vitamin supplement had a positive effect in older cows. PMID- 24485681 TI - The effect of prebiotics on adherence of probiotics. AB - Prebiotics are generally considered to promote the function or viability of probiotics via their fermentation, but their effect on the adherence of probiotics is still unclear. In this study, we examined the effect of 4 commercially available prebiotics [Orafti GR, Orafti P95, and Orafti Synergy (Beneo GmbH, Mannheim, Germany), and Vivinal (Friesland Foods Domo, Amersfoort, the Netherlands)] and 3 simple saccharides (glucose, galactose, and lactose) on the adherence of 5 probiotic type strains, 2 lactococci starter cultures, and 5 potential dairy probiotic strains from the Culture Collection of Dairy Microorganisms (Tabor, Czech Republic). Adherence was tested in microtiter plates on the following types of substrate: polystyrene alone and polystyrene coated with either porcine mucus or cocultures of the human colon cell lines Caco2 and HT29-MXT (1:9 ratio of HT29-MXT:Caco2). Adherence was evaluated as a change in fluorescence in the well of a microtiter plate. The most commonly observed effect (with a few exceptions) of prebiotics was decreased adherence of the tested strains observed on all types of substrate. The tested saccharides, which are part of the residual compounds of the used prebiotics, had a very similar effect eliciting a decrease in adherence ability in the majority of the probiotic strains. PMID- 24485682 TI - Short communication: plasma concentration of glucose-dependent insulinotropic polypeptide may regulate milk energy production in lactating dairy cows. AB - In dairy cows, an increase in plasma concentration of glucose-dependent insulinotropic polypeptide (GIP) is associated with an increase in metabolizable energy intake, but the role of GIP in energy partitioning of dairy cattle is not certain. The objective of this study was to examine the relationship between plasma GIP concentrations and energy partitioning toward milk production. Four mid-lactation, primiparous, rumen-fistulated Holstein-Friesian cows were fed a control diet of 55% forage and 45% concentrate [dry matter (DM) basis] in a 4*4 Latin square design with 4-wk periods. The 4 treatments were (1) control diet fed at 1000 and 1600h, and (2) once-daily (1000h) feeding, (3) twice-daily (1000 and 1600h) feeding, and (4) 4 times/d (1000, 1600, 2200 and 0400h) feeding of the control diet plus 1 dose (1.75kg on a DM basis at 0955h) into the rumen of supplemental vegetable proteins (Amino Green; SCA NuTec Ltd., Thirsk, UK). Measurements of respiratory exchange and energy balance were obtained over 4d during the last week of each period while cows were housed in open-circuit respiration chambers. Blood was collected from the jugular vein every 30min for 12h, using indwelling catheters, starting at 0800h on d 20 of each period. Plasma GIP concentration was measured in samples pooled over each 5 consecutive blood samplings. The relationships between plasma GIP, DM intake, heat production, respiratory quotient (RQ), milk yield, and milk energy output were analyzed using linear correlation procedures, with metabolizable intake as a partial variant. Plasma GIP concentration was not correlated with heat production, or milk yield, but was positively correlated with milk energy yield (correlation coefficient=0.67) and negatively correlated with RQ (correlation coefficient= 0.72). The correlations between GIP with RQ and milk energy output do not imply causality, but support a role for GIP in the regulation of energy metabolism in dairy cows. PMID- 24485683 TI - Associations between herd-level factors and lying behavior of freestall-housed dairy cows. AB - Our objective was to investigate the associations between herd-level factors and lying behavior of high-producing dairy cows housed in freestall barns. Lying behavior of approximately 40 focal cows in one high-producing pen was monitored on each of 40 farms in the northeastern United States (NE) and 39 farms in California (CA). All cows within the pen were gait scored using a 1-to-5 scale to calculate the prevalence of clinical lameness (score >=3) and severe lameness (score >=4). Facility and management measures, including stall design, bedding, and flooring type within the pen, were collected. Herd-level factors associated with daily lying time, standard deviation (SD) of daily lying time, frequency of lying bouts, and lying bout duration at the univariate level were submitted to multivariable general linear models. In the NE, daily lying time increased with the use of deep bedding (estimate = 0.80+/-0.31h/d) and as average days in milk (DIM) of the focal cows increased (estimate = 0.08+/-0.04h/d for a 10-d increase in DIM). The SD of daily lying time decreased as stall stocking density increased (estimate = -0.08+/-0.03h/d for a 10% increase), and increased with the presence of rubber flooring in the pen (estimate = 0.16+/-0.08h/d) and percentage of stalls with fecal contamination (estimate = 0.04+/-0.01h/d for a 10% increase). Frequency of lying bouts decreased (estimate = -1.90+/-0.63 bouts/d) and average bout duration increased (estimate = 15.44+/-3.02 min) with the use of deep bedding. In CA, where all farms used deep bedding, daily lying time increased as average DIM of the focal cows increased (estimate = 0.08+/-0.03h/d for a 10-d increase). The SD of daily lying time decreased when feed was delivered more than once per day (estimate = -0.24+/-0.08h/d). The percentage of lame cows was correlated with the percentage of stalls with fecal contamination (r=0.45), which in turn was associated with fewer (estimate = -0.25+/-0.06 bouts/d) and longer lying bouts (estimate = 1.85+/-0.39 min/d). These findings suggest that lying time be interpreted in conjunction with variability in lying time and bout structure and in context with lameness prevalence, production parameters, and facility characteristics. PMID- 24485684 TI - Immunoglobulin E epitope mapping by microarray immunoassay reveals differences in immune response to genetic variants of caseins from different ruminant species. AB - The allergenicity of the caseins (CN), one of the major allergens in cow milk, is well characterized and their immunoglobulin E (IgE)-binding epitopes have been identified. However, investigations about the allergenic potential of the genetic variants occurring in the caseins are lacking. Therefore, this study determined the influence of the genetic polymorphism on IgE binding to epitopes of bovine casein variants. Furthermore, differences in IgE binding between epitopes of goats and water buffaloes were analyzed. A set of 187 peptides, covering the previously identified sequential IgE-binding epitopes of alphaS1-, alphaS2-, beta , and kappa-CN variants from cows and the corresponding homologous peptides of water buffaloes and goats, were synthesized and tested by means of peptide microarray for IgE binding, using sera from 16 cow milk-sensitized individuals. Seven of the 16 sera samples showed positive signals on microarrays and were included in this study. In 5 alphaS1-CN variants (A, B, C, E, and I), the AA substitution or deletion affected the immunoreactivity of epitopes AA 4 to 23, AA 17 to 36, AA 83 to 102, AA 173 to 192, and AA 175 to 194, as well as of the variant-specific peptides AA 184 to 196, AA 187 to 199, AA 174 to 193, and AA 179 to 198, which were found to resist gastrointestinal digestion. Variation in IgE binding was further detected for peptides AA 103 to 123 and AA 108 to 129 of 3 beta-CN variants (A(1), A(2), and B). The majority of sera showed IgE binding to alphaS1-CN peptides of cows and the homologous counterpart of goats and water buffaloes. However, alphaS1- and beta-CN epitopes from goats and water buffaloes had lower immunoreactivity than those of cows, but, in some cases, higher or exclusive IgE binding was observed. The results of this study indicate that genetic variants of the caseins differ in their allergenicity. This might be useful in the search for a suitable protein source for cow milk-allergic patients. In addition, milk from water buffaloes and goats harbor an allergenic potential due to cross-reactivity of IgE antibodies with cow milk caseins and are, therefore, not an acceptable alternative in the nutrition of cow milk allergic patients. PMID- 24485685 TI - Surface roughness and packaging tightness affect calcium lactate crystallization on Cheddar cheese. AB - Calcium lactate crystals that sometimes form on Cheddar cheese surfaces are a significant expense to manufacturers. Researchers have identified several postmanufacture conditions such as storage temperature and packaging tightness that contribute to crystal formation. Anecdotal reports suggest that physical characteristics at the cheese surface, such as roughness, cracks, and irregularities, may also affect crystallization. The aim of this study was to evaluate the combined effects of surface roughness and packaging tightness on crystal formation in smoked Cheddar cheese. Four 20-mm-thick cross-section slices were cut perpendicular to the long axis of a retail block (~300g) of smoked Cheddar cheese using a wire cutting device. One cut surface of each slice was lightly etched with a cheese grater to create a rough, grooved surface; the opposite cut surface was left undisturbed (smooth). The 4 slices were vacuum packaged at 1, 10, 50, and 90kPa (very tight, moderately tight, loose, very loose, respectively) and stored at 1 degrees C. Digital images were taken at 1, 4, and 8 wk following the first appearance of crystals. The area occupied by crystals and number of discrete crystal regions (DCR) were quantified by image analysis. The experiment was conducted in triplicate. Effects of storage time, packaging tightness, surface roughness, and their interactions were evaluated by repeated-measures ANOVA. Surface roughness, packaging tightness, storage time, and their 2-way interactions significantly affected crystal area and DCR number. Extremely heavy crystallization occurred on both rough and smooth surfaces when slices were packaged loosely or very loosely and on rough surfaces with moderately tight packaging. In contrast, the combination of rough surface plus very tight packaging resulted in dramatic decreases in crystal area and DCR number. The combination of smooth surface plus very tight packaging virtually eliminated crystal formation, presumably by eliminating available sites for nucleation. Cut-and-wrap operations may significantly influence the crystallization behavior of Cheddar cheeses that are saturated with respect to calcium lactate and thus predisposed to form crystals. PMID- 24485686 TI - Milk production during the colostral period is not related to the later lactational performance in dairy cows. AB - In dairy cows, milk yield increases rapidly after parturition until a peak at around wk 6 of lactation. However, the description of the shape of the lactation curve is commonly based on weekly average milk yields. For a more detailed analysis of the milk production curve from the very beginning of lactation including the colostral period and the effect of colostrum yield on further lactational performance, the first 10 milkings after parturition, daily milk yields from d 1 to 28 of lactation, and the cumulative milk production on d 100 to 305 of lactation were investigated in 17 primiparous and 39 multiparous cows milked twice daily. Milk yield at the first milking after parturition (colostrum) ranged from 1.3 to 20.7kg (Delta=19.4kg) in multiparous and from 1.8 to 10.9kg in primiparous animals (Delta=9.1kg). At the tenth milking, milk production ranged from 9.2 to 21.5kg (Delta=12.3kg) in multiparous and from 7.0 to 15.2kg (Delta=8.2kg) in primiparous animals. Immediately after parturition, daily milk production increased rapidly, but after approximately 1wk in lactation, the slope of the daily milk production curve flattened and continued more linear. A nonlinear regression equation was used to determine this timely change, which occurred earlier in primiparous (d 6.9+/-0.3) than in multiparous cows (d 8.2+/ 0.2). The correlation between the amount of first colostrum and milk production during further lactation decreased already from 0.47 on d 5 to 0.32 on d 14. In multiparous cows, the correlation between total milk production of the previous 305d standard lactation and the amount of first colostrum was not significant (correlation=0.29), whereas the correlation with the daily production increased from 0.45 on d 5 to 0.69 on d 14. However, in primiparous animals, correlations between first-colostrum yield and daily milk yields up to d 28 of lactation were not significant, possibly due to the smaller sample size compared with multiparous animals. First-colostrum yield and cumulative milk production of 100, 200, and 305 lactation days were not significantly correlated in multiparous and primiparous cows. In conclusion, the milk production during the first few milkings is widely independent from the overall production level of a cow. Potentially, genetic selection toward lower milk yield during the very first days after parturition at a simultaneously high lactational performance may be a tool to ensure sufficient colostrum quality and to reduce the metabolic load around parturition. PMID- 24485687 TI - Strategy for the simulation and analysis of longitudinal phenotypic and genomic data in the context of a temperature * humidity-dependent covariate. AB - A simulation study was conducted to evaluate the performance of genomic random regression models for the continuous environmental descriptor temperature humidity index (THI). Statistically innovative aspects of the study included the combined simulation of both longitudinal phenotypic data representing the same trait in the course of THI and genomic data. The longitudinal trait was simulated (phenotypically expressed) at 5 different values of THI. For a moderate heritability trait, heritabilities were 0.30, 0.35, 0.40, 0.40, and 0.35 for THI of 15, 30, 45, 60 and 75, respectively. In a consecutive run, low heritabilities of 0.05, 0.1, 0.15, 0.15, and 0.10 were simulated, respectively. On the genomic level, simulation combined high and low linkage disequilibrium with 5,000-, 15,000-, and 50,000-SNP chip applications to simulate different scenarios of genomic architecture. With regard to data analyses, 2 strategies were applied to evaluate the accuracy of genomic predictions across THI, with special focus on the extreme ends of the environmental scale. In the first strategy, 100, 80, 50, or 20% of phenotypes at THI 75 were deleted randomly and the remaining data set was used to predict the breeding value at THI 75 for non-phenotyped, but genotyped cows. In the second strategy, 1,600 cows had complete information (genotypes and phenotypes) and 400 cows were genotyped, but with missing phenotypes for all THI. For the first strategy and without phenotypic observations at THI 75, accuracies of genomic predictions were lower than 0.34. When only 20% of cows had phenotypic records at THI 75, accuracies increased (~0.60). Such a small proportion of phenotyped cows was sufficient to predict reliable genomic breeding values for cows without phenotypes for extreme THI. For the second strategy, also for low linkage disequilibrium combined with a low density 5,000-SNP chip, the average accuracy of genomic predictions was 0.52, which is substantially higher than accuracies based on pedigree relationships. From a practical perspective, genomic random regression models can be used to predict genomic breeding values for scarce phenotypes (e.g., novel traits) traits measured in extreme environments, or traits measured late in life, such as longevity. PMID- 24485688 TI - Factors influencing the chance of cows being pregnant 30 days after the herd voluntary waiting period. AB - The objective of this study was to study factors affecting a reproductive performance indicator at the cow level adjusted for herd management strategy. Associations between the outcome variable, pregnant or not at the herd voluntary waiting period (VWP) plus 30d (pregnant at VWP+30), and the predictor variables were analyzed using a multivariable, generalized estimation equations model that adjusted for clustering of the data at the herd level. The statistical analysis was stratified on parity. In total, 132,721 cows were retained for analyses, of which 29,113 (22%) were pregnant at VWP+30d. Of the nonpregnant cows, 81,483 cows had records of artificial inseminations (AI) and 22,125 cows had no records of AI. The chance of pregnancy was higher for cows of the Swedish Red and for other/crossbreeds compared with Swedish Holstein, for cows from herds with high heat detection efficiency compared with cows from herds with medium and low heat detection efficiency, for cows from herds with long VWP (i.e., >51d) compared with cows from herds with short VWP (<51d), and for cows in freestalls compared with cows in tiestalls. The chance for pregnancy was lower for cows with severe problems at claw trimming compared with cows with no problems at trimming (only for second- and higher-parity cows), for cows that had a record of reproduction related disease, for cows that had a record of any other disease compared with cows without record, for second- and higher-parity cows with records of dystocia compared with cows with no record of dystocia, for first-parity cows in the group with the highest milk yield compared with first-parity cows in the group with the lowest milk yield, for cows of third and higher parity in the group with the lowest milk yield compared with cows in higher yielding groups, for cows bred in summer compared with those bred in winter-spring (not significant for first parity cows), and for cows with a twin birth had compared with cows with a single birth. We observed associations of the dose-response type, such that when the milk fat-to-protein ratio increased, the chance for pregnancy decreased, and as the somatic cell count increased, the chance for pregnancy decreased. In conclusion, factors that are known to affect reproductive efficiency also affect the chance of cows being pregnant at the herd VWP plus 30d. PMID- 24485689 TI - Lactobacillus casei MYL01 modulates the proinflammatory state induced by ethanol in an in vitro model. AB - Accumulating studies have suggested that probiotics have beneficial effects on liver injury but the underlying mechanism has remained unclear. Toll-like receptors (TLR) expressed on immune cells and hepatocytes recognize bacterial components that are translocated from the gut into the portal vein. To date, it has been demonstrated that ethanol alone, without microbial components, is able to activate TLR, leading to promotion of proinflammatory cytokine production. Because the enhanced signaling of TLR triggers persistent inflammation, we hypothesized that development of hepatocyte TLR tolerance to repetitive stimulation plays an important role in protecting the liver from hypergeneration of proinflammatory cytokines. In this study, we showed that Lactobacillus casei MYL01 modulated the proinflammatory state induced by ethanol and investigated in detail the mechanism underlying the observation that L. casei MYL01 gave rise to TLR tolerance toward ethanol stimulation. The effects of L. casei MYL01 in the attenuation of ethanol-induced liver damage were due to enhancement of IL-10 production, which limited the proinflammatory process. Furthermore, better defense of hepatocytes against ethanol challenge by treatment of L. casei MYL01 was attributed to previous induction of toll interacting protein (TOLLIP) and suppressor of cytokine signaling (SOCS)1 and SOCS3 expression via activation of TLR1, TLR2, TLR6, and TLR9, an action that cross-regulated ethanol-TLR4-nuclear factor kappaB signal transduction events. This finding might help establish an in vitro platform for selecting hepatoprotective probiotic strains in terms of ethanol-induced liver damage. PMID- 24485690 TI - Cost-effectiveness of feeding strategies to reduce greenhouse gas emissions from dairy farming. AB - The objective of this paper was to evaluate the cost-effectiveness of 3 feeding strategies to reduce enteric CH4 production in dairy cows by calculating the effect on labor income at the farm level and on greenhouse gas (GHG) emissions at the chain level (i.e., from production of farm inputs to the farm gate). Strategies included were (1) dietary supplementation of an extruded linseed product (56% linseed; 1kg/cow per day in summer and 2kg/cow per day in winter), (2) dietary supplementation of a nitrate source (75% nitrate; 1% of dry matter intake), and (3) reducing the maturity stage of grass and grass silage (grazing at 1,400 instead of 1,700kg of dry matter/ha and harvesting at 3,000 instead of 3,500kg of dry matter/ha). A dairy farm linear programing model was used to define an average Dutch dairy farm on sandy soil without a predefined feeding strategy (reference situation). Subsequently, 1 of the 3 feeding strategies was implemented and the model was optimized again to determine the new economically optimal farm situation. Enteric CH4 production in the reference situation and after implementing the strategies was calculated based on a mechanistic model for enteric CH4 and empirical formulas explaining the effect of fat and nitrate supplementation on enteric CH4 production. Other GHG emissions along the chain were calculated using life cycle assessment. Total GHG emissions in the reference situation added up to 840kg of CO2 equivalents (CO2e) per t of fat- and protein corrected milk (FPCM) and yearly labor income of ?42,605. Supplementation of the extruded linseed product reduced emissions by 9kg of CO2e/t of FPCM and labor income by ?16,041; supplementation of the dietary nitrate source reduced emissions by 32kg of CO2e/t of FPCM and labor income by ?5,463; reducing the maturity stage of grass and grass silage reduced emissions by 11kg of CO2e/t of FPCM and labor income by ?463. Of the 3 strategies, reducing grass maturity was the most cost-effective (?57/t of CO2e compared with ?241/t of CO2e for nitrate supplementation and ?2,594/t of CO2e for linseed supplementation) and had the greatest potential to be used in practice because the additional costs were low. PMID- 24485691 TI - The effect of butter grains on physical properties of butter-like emulsions. AB - Milk fat exists as globules in its natural state in milk. The potential of using globular fat to modulate the rheological properties and crystallization behavior in butter-like emulsions was studied in the present work. We conducted a comparative study of butter-like emulsions, with a fat phase consisting of 0, 10, 25, 50, or 100% anhydrous milk fat (AMF), the remaining fat being butter grains, and all samples containing 20% water, to obtain systematic variation in the ratio of globular fat. All emulsions were studied over 4wk of storage at 5 degrees C. By combining small and large deformation rheology, we conducted a detailed characterization of the rheological behavior of butter-like emulsions. We applied differential scanning calorimetry to monitor thermal behavior, confocal laser scanning microscopy for microstructural analysis, and low-field pulsed nuclear magnetic resonance spectrometry to measure solid fat content. By combining these techniques, we determined that increasing the fraction of globular fat (by mixing with butter grains) decreases the hardness of butter-like emulsions up to an order of magnitude at d 1. However, no difference was observed in thermal behavior as a function of butter grain content, as all emulsions containing butter grains revealed 2 endothermal peaks corresponding to the high (32.7 degrees C +/- 0.6) and medium (14.6 degrees C +/- 0.1) melting fractions of fatty acids. In terms of microstructure, decreasing the amount of butter grains in the emulsions resulted in formation of a denser fat crystal network, corresponding to increased hardness. Moreover, microstructural analysis revealed that the presence of butter grains resulted in faster formation of a continuous fat crystal network compared with the 100% AMF sample, which was dominated by crystal clusters surrounded by liquid oil. During storage, hardness remained stable and no changes in thermal behavior were observed, despite an increase in solid fat content of up to 5%. After 28d of storage, we observed no difference in either microstructural or rheological properties, indicating that formation of primary bonds occurs primarily within the first day of storage. The rheological behavior of butter like emulsions is not determined solely by hardness, but also by stiffness related to secondary bonds within the fat crystal network. The complex rheological behavior of milk fat-based emulsions is better characterized using multiple parameters. PMID- 24485692 TI - Efficacy of 5-day parenteral versus intramammary benzylpenicillin for treatment of clinical mastitis caused by gram-positive bacteria susceptible to penicillin in vitro. AB - The efficacy of parenteral (intramuscular) or intramammary (IMM) benzylpenicillin treatment for clinical mastitis caused by gram-positive bacteria susceptible to penicillin in vitro was investigated. Cows with clinical mastitis in 1 udder quarter were randomly placed into 2 treatment groups. The preliminary bacteriological diagnosis of intramammary infection (IMI) was based on on-farm culturing, and the bacteriological diagnoses were later confirmed by a quantitative PCR assay. Clinical mastitis caused by gram-positive bacteria susceptible to benzylpenicillin was treated with penicillin via either the parenteral route (20mg/kg) or IMM route (600mg) once per day for 5d. The outcome of the treatment was evaluated 3 to 4wk after the onset of the treatment. The affected quarter was examined to assess the clinical cure, and milk samples were collected from the affected quarter to determine the bacteriological cure and milk N-acetyl-beta-d-glucosaminidase activity. The survival and the composite milk somatic cell counts of the treated cows were followed up for 6 and 3mo after treatment, respectively. A total of 140 cows with clinical mastitis were included in the study, 61 being treated with benzylpenicillin parenterally and 79 via the IMM route. From all quarters treated, 108 of 140 (77.1%) were cured clinically and 77 of 140 (55.0%) were cured bacteriologically. The route of treatment did not significantly affect the outcome of the treatment; 80.3% of the quarters with parenteral treatment and 74.7% of the quarters with IMM treatment showed a clinical cure, and 54.1 and 55.7% a bacteriological cure, respectively. The milk N-acetyl-beta-d-glucosaminidase activity was significantly lower in the quarters with a clinical or bacteriological cure than in the quarters with no cure. The 6 mo survival and the proportion of cows with composite milk somatic cell counts <200,000/mL among the treated cows during the 3-mo follow-up period did not significantly differ between the treatment groups. In conclusion, the outcome of either parenteral or IMM benzylpenicillin treatment of clinical mastitis caused by penicillin-susceptible bacteria was similar. PMID- 24485693 TI - Comparison of supplementation of n-3 fatty acids from fish and flax oil on cytokine gene expression and growth of milk-fed Holstein calves. AB - The ability to reduce incidence of disease in calves and improve early vaccination strategies is of particular interest for dairy producers. The n-3 fatty acids have been reported to reduce inflammatory diseases in humans but limited research has been done in calves. The objective of this study was to compare supplementation of n-3 fatty acids from fish and flax oil on gene expression of whole blood cells and growth of milk-fed Holstein calves. Forty eight Holstein bull calves from a commercial dairy were randomly assigned to 1 of 3 diets beginning at 4d old: (1) control milk replacer (MR) with all pork fat, (2) MR with 2% flax oil, and (3) MR with 2% fish oil. All MR were 17% fat, 27% crude protein on a dry matter (DM) basis, with all protein from whey sources. Calves were each fed 654g DM of MR daily for the first 25d and then 327g/d for d26, 27, and 28. On d28, calves were challenged with a Pasteurella vaccine and the temperature response to the vaccine was recorded. Milk and feed intake and fecal scores were recorded daily, and body weight and hip width were recorded weekly. Blood was collected from all calves on d25. One tube of collected blood was incubated with endotoxin (lipopolysaccharide; LPS) for 2h and frozen with a second tube of control blood. Quantitative real-time PCR was used to assess the effects of LPS stimulation on cytokine gene expression. During the 28 d, calves supplemented with flax oil had a greater growth rate and feed efficiency than calves fed fish oil (0.52+/-0.02 vs. 0.48+/-0.02g of gain:g of feed). Fish oil tended to decrease LPS stimulation of tumor necrosis factor-alpha expression. Flax oil, but not fish oil, decreased the expression of IL-4 and tended to decrease expression of osteopontin and IL-8. Flax oil tended to reduce the increase in rectal temperature in response to a Pasteurella vaccine. In conclusion, our data support the idea that supplementation with n-3 fatty acids affects cytokine gene expression. PMID- 24485694 TI - Evaluation of dairy powder products implicates thermophilic sporeformers as the primary organisms of interest. AB - Dairy powder products (e.g., sweet whey, nonfat dry milk, acid whey, and whey protein concentrate-80) are of economic interest to the dairy industry. According to the US Dairy Export Council, customers have set strict tolerances (<500 to <1,000/g) for thermophilic and mesophilic spores in dairy powders; therefore, understanding proliferation and survival of sporeforming organisms within dairy powder processing plants is necessary to control and reduce sporeformer counts. Raw, work-in-process, and finished product samples were collected from 4 dairy powder processing facilities in the northeastern United States over a 1-yr period. Two separate spore treatments: (1) 80 degrees C for 12min (to detect sporeformers) and (2) 100 degrees C for 30min (to detect highly heat resistant sporeformers) were applied to samples before microbiological analyses. Raw material, work-in-process, and finished product samples were analyzed for thermophilic, mesophilic, and psychrotolerant sporeformers, with 77.5, 71.0, and 4.6% of samples being positive for those organisms, respectively. Work-in-process and finished product samples were also analyzed for highly heat resistant thermophilic and mesophilic sporeformers, with 63.7 and 42.6% of samples being positive, respectively. Sporeformer prevalence and counts varied considerably by product and plant; sweet whey and nonfat dry milk showed a higher prevalence of thermophilic and mesophilic sporeformers compared with acid whey and whey protein concentrate-80. Unlike previous reports, we found limited evidence for increased spore counts toward the end of processing runs. Our data provide important insight into spore contamination patterns associated with production of different types of dairy powders and support that thermophilic sporeformers are the primary organism of concern in dairy powders. PMID- 24485695 TI - Effect of ambient temperature and sodium bicarbonate supplementation on water and electrolyte balances in dry and lactating Holstein cows. AB - The aim of this study was to quantify the effect of the interaction between 2 constant ambient temperatures [thermoneutrality (TN; 15 degrees C) and high temperature (HT; 28 degrees C)] and 2 levels of Na bicarbonate supplementation [calculated to provide diet Na contents of 0.20%DM (Na-) and 0.50%DM (Na+)] on water partitioning in dairy cows. Treatments were compared on 4 dry and 4mid lactation Holstein cows according to 2 Latin squares (1 for each physiological stage) over the course of 4 periods of 15d. Diets consisted of a total mixed ration based on maize silage. Dry cows were restricted to their protein and energy requirements, whereas lactating cows were fed ad libitum. The daily average temperature-humidity index was 59.4 for TN and 73.2 for HT. Lactating and dry cows had higher vaginal temperatures at HT than at TN, but the increase was more pronounced in lactating cows (+1.05 vs. +0.12 degrees C for vaginal temperature, respectively). Dry matter intake (DMI) of lactating cows decreased by 2.3kg/d at HT. Free water intake (FWI) and estimated volume of water lost to evaporation increased at HT in both lactating and dry cows; no interactions were observed between temperature and physiological stage. When expressed as a proportion of DMI, the increase in evaporation that occurred with increasing temperature was completely compensated for by an increase in FWI for both physiological stages. The urinary water excretion increased slightly at HT in lactating cows but not in dry cows, which may be related to the low chloride content of the offered diet. High Na supplementation increased DMI slightly in lactating cows, but milk yield was not affected. Sodium supplementation did not limit the decrease in DMI observed in lactating cows at HT; this observation is likely due to the high diet electrolyte balance of the offered diets. Sodium supplementation increased FWI in lactating cows and urinary flow in both physiological states. The interaction between ambient temperature and Na supplementation did not affect either water intake or water evaporation. This study demonstrates that the development of predictive models for water intake that include environmental variables could be based on mechanistic models of evaporation. PMID- 24485696 TI - Variation in the incidence of hospital-acquired anemia during hospitalization with acute myocardial infarction (data from 57 US hospitals). AB - Development of hospital-acquired anemia (HAA) during acute myocardial infarction may be related to processes of care and is associated with poor outcomes. Little is known about variation in the incidence of HAA across hospitals or the hospital characteristics associated with HAA. We studied 17,676 patients with acute myocardial infarction without anemia at admission, defining HAA as a hemoglobin decline below anemia diagnostic thresholds and moderate-to-severe HAA as a hemoglobin decline to <11 g/dl. We calculated median rate ratios (MRRs), the median value of the relative risk (RR) for HAA for 2 patients with identical characteristics presenting to 2 randomly selected hospitals, to identify variation in HAA adjusting for patient characteristics. Separate models were fit to test the association between hospital characteristics and HAA. HAA (57.5%) and moderate-to-severe HAA (20.1%) were common. The incidence of HAA varied substantially across hospitals and remained significant after multivariable adjustment (any HAA: MRR 1.09, 95% confidence interval (CI) 1.07 to 1.13; moderate-to-severe HAA: MRR 1.27, 95% CI 1.19 to 1.39). Adjusting for patient characteristics, teaching status (RR 0.91, 95% CI 0.84 to 0.97 vs nonteaching status), and region (Northeast vs Midwest: RR 1.10, 95% CI 1.01 to 1.19; West vs Midwest: RR 1.19, 95% CI 1.06 to 1.33, respectively) was associated with risk of HAA. Teaching status (RR 0.7, 95% CI 0.6 to 0.9 vs nonteaching status) and region (South vs Midwest: RR 1.3, 95% CI 1.0 to 1.5) were independently associated with moderate-to-severe HAA. In conclusion, we observed significant variability in the incidence of HAA across hospitals and found a lower risk of HAA at teaching centers, suggesting that qualitative studies of the relation between HAA and processes of care are needed to identify targets for quality improvement. PMID- 24485697 TI - Incidence and predictors of early left ventricular thrombus after ST-elevation myocardial infarction in the contemporary era of primary percutaneous coronary intervention. AB - The aim of this study was to define the incidence of left ventricular thrombus (LVT) and its predictors in the contemporary era of primary percutaneous intervention (pPCI) and contrast echocardiography. We retrospectively analyzed 1,059 patients presenting with ST-elevation myocardial infarction (STEMI) to our tertiary cardiac center and treated with pPCI. Preprocedural pharmacology and procedural technique (including access route, the use of drug-eluting stents, and thrombectomy) were at the operators' discretion. Transthoracic echocardiography was performed before discharge; echo contrast agent was used when appropriate. LVT was detected in 42 subjects (4%). There were no significant differences in baseline demographics or pre-PCI clinical features between the 2 groups. Post treatment, mean ejection fraction (EF) in patients with LVT was 35+/-8.4% and in those without LVT was 47+/-10%, p<0.001. Thirty-seven patients (88%) in the LVT group presented with an anterior STEMI versus 471 patients (42%) in the without LVT group (p<0.001). Apical akinesis was noted in all patients with LVT irrespective of the principal location of the MI. Multivariate analysis predictors of LVT were reduced EF, anterior site of MI, and the use of platelet glycoprotein IIb/IIIa inhibitors. After diagnosis of LVT, patients were treated with warfarin for 3 to 6 months. No significant difference in mortality was detectable at discharge between the 2 groups. In conclusion, in the contemporary era of pPCI, the incidence of LVT in patients with STEMI is significantly lower than that of the previous (thrombolysis) literature. The early presence of LVT is more likely in patients with anterior STEMI (involving the apex) and reduced EF. PMID- 24485698 TI - Preventing the collapse of a peripheral vein during cannulation: an evaluation of various tourniquet techniques on vein compressibility. AB - BACKGROUND: Venous access can occasionally be difficult to obtain secondary to near-complete compressibility of peripheral veins in some patients. OBJECTIVE: This study utilizes ultrasound to assess vein compressibility with different tourniquet techniques commonly available in the emergency department. METHODS: After approval by the Institutional Review Board, a prospective single-center study was conducted assessing the compressibility of basilic veins with ultrasound. Compressibility was assessed at baseline, use of one proximal tourniquet, two tourniquets (one distal and one proximal), and a proximal blood pressure cuff inflated to 150 mm Hg. Vein compressibility was rated as complete, moderate, or mild after light pressure was applied with the ultrasound probe. RESULTS: One hundred healthy patients were recruited into the study. Ninety-eight subjects had completely compressible basilic veins at baseline. When one tourniquet and two tourniquets were applied, 62 and 31 participants, respectively, demonstrated completely compressible veins. Fisher's exact test comparing one vs. two tourniquets revealed no difference between these two techniques (p = 0.4614). Only two participants continued to have a completely compressible vein after application of the blood pressure cuff with statistical significance by Fisher's exact test compared to both tourniquet groups (p < 0.0001). CONCLUSIONS: Both tourniquets and blood pressure cuffs can decrease the compressibility of peripheral veins. Although no difference was identified between one and two tourniquets, utilization of blood pressure cuffs significantly decreased compressibility. The findings of this study can be utilized in the emergency department when attempting to obtain peripheral venous access, specifically supporting the use of blood pressure cuffs to decrease compressibility. PMID- 24485699 TI - Cerebellar astrocytoma presenting with headache and nystagmus in a 20-year-old male. PMID- 24485700 TI - No association between hyponatremia and rhabdomyolysis in rats. AB - BACKGROUND: Rhabdomyolysis is an uncommon complication of hyponatremia, reported previously only in case reports and small retrospective studies, and its underlying mechanism is controversial. Some studies support the hypothesis that the rapid correction of hyponatremia is responsible for rhabdomyolysis, whereas others emphasize the severity of the hyponatremia as a predisposing factor for rhabdomyolysis. OBJECTIVES: To test the association between hyponatremia and rhabdomyolysis and to demonstrate a causal association. METHODS: Hyponatremia was induced by administration of water and desmopressin acetate in rats during 3 days, followed by its rapid correction, using animal models established for the evaluation of central pontine myelinolysis. The plasma creatine phosphokinase levels, a marker for rhabdomyolysis, were monitored, and hematoxylin and eosin sections of the quadriceps and gastrocnemius muscles were evaluated for signs of rhabdomyolysis. RESULTS: The induction of hyponatremia and its correction were accompanied by the previously reported neurological sequelae, including signs of central pontine myelinolysis. However, no increase in plasma creatine phosphokinase levels was found, and histopathological examination of the quadriceps and gastrocnemius muscles revealed no sign of rhabdomyolysis. CONCLUSIONS: The present study, which is the first to test the association between hyponatremia and rhabdomyolysis in an animal model, does not support any causal association between hyponatremia and rhabdomyolysis. Thus, other factors might be necessary for an association between hyponatremia and rhabdomyolysis, such as genetic factors or convulsions that are known to be associated with both hyponatremia and rhabdomyolysis. Further research in this important physiologic and clinical question is needed. PMID- 24485701 TI - Low maternal progesterone may contribute to both obstetrical complications and autism. AB - Studies show increased autism risk among children born to mothers experiencing obstetrical complications. Although this is usually interpreted as suggesting that the obstetrical complications could be causing autism, it is possible that a single factor could be responsible for both complications and autism. We hypothesized that low levels of the hormone progesterone is responsible since it is supplied to the fetus maternally and does not only support pregnancy but also promotes brain development. Following a review of the literature, we report findings from a survey of mothers of autistic children (n=86) compared to mothers of typically-developing children (n=88) regarding obstetrical histories, including five obstetrical risk factors indicative of low progesterone. Using this analysis, the ASD group had significantly more risk factors than controls (1.21 +/- 0.09 vs. 0.76 +/- 0.08, p<.0001), suggesting low progesterone. Thus, results suggest that low progesterone may be responsible for both obstetrical complications and brain changes associated with autism and that progesterone levels should be routinely monitored in at-risk pregnancies. Our hypothesis also suggests that ensuring adequate levels of progesterone may decrease the likelihood of autism. PMID- 24485702 TI - Clinical outcome of isolated locoregional recurrence in patients with breast cancer according to their primary local treatment. AB - INTRODUCTION: This study assessed the clinical outcome and prognostic factors in patients with breast cancer who presented with isolated locoregional recurrence (ILRR) as a first event. MATERIALS AND METHODS: Between 1970 and 2008, 2960 patients with pT1-2, N0-3, M0 primary invasive breast cancer had either breast conserving therapy (BCT) using lumpectomy and radiation therapy (RT) (group A = 1849 patients) or mastectomy without RT (group B = 1111 patients). Out of groups A and B, 117 and 103 patients, respectively, developed ILRR as a first event. Those 220 patients served as the basis for this study. A multivariate analysis was performed to estimate the clinical outcome of both groups, taking into account clinically relevant variables for the primary tumor and ILRR. RESULTS: The median follow-up after ILRR was 83 months. The median disease-free interval (DFI) was 79 and 38 months for groups A and B, respectively. The overall survival (OS) for group A was 81% and 69% at 5 and 8 years, respectively. For group B, it was 61% and 46%, respectively. The distant metastasis-free survival (DMFS) for group A was 84% at 5 years and remained 84% at 8 years. The DMFS for group B was 60% at 5 years and 52% at 8 years. In multivariate analysis, initial local treatment (BCT vs. mastectomy without RT), pathologic T stage, locoregional recurrence site (local vs. regional), and DFI (<= 4 years vs. > 4 years) were significant prognostic variables for both OS and DMFS. CONCLUSION: Patients with breast cancer who developed ILRR after BCT as their initial local treatment have better clinical outcome compared with those who had mastectomy without RT. PMID- 24485703 TI - Population-based reference for birth weight for gestational age in northern China. AB - BACKGROUND: Localized birth weight references for gestational age serve as an essential tool in accurate evaluation of atypical birth outcomes (e.g. small for gestational age) in clinical diagnosis and region-specific epidemiological studies. Such standards are currently not available in Mainland China. AIMS: To construct up-to-date, sex- and parity-specific birth weight references based on 231,937 births in Taiyuan, China during years 2005-2011. STUDY DESIGN: Population based, cross-sectional. SUBJECTS: Hospital-registered, healthy infants with births dated between 11/01/2005 and 12/31/2011 within Taiyuan area. OUTCOME MEASURES: Birth weight in grams, and gestational age in complete weeks were calculated using a combination of last-menstrual-date-based estimation and ultrasound examination. RESULTS: Separate birth weight references are constructed for male and female infants born from primiparous and multiparous mothers. Male infants are found to weigh more than female infants in later gestational ages (appr. weeks 33-42), and infants born to multiparous mother are found to weigh more than infants born to primiparous mothers in later gestational ages (appr. weeks 36-42). CONCLUSIONS: The Taiyuan birth weight reference curves display similar trends of growth as reference curves from other countries worldwide (Netherlands, Scotland, Australia, Canada, Hong Kong, Korea and Kuwait). However, growth of birth weight for Taiyuan infants tends to be slower compared to European and North American infants regardless of gender, but similar to infants from other Asian countries. PMID- 24485704 TI - The role of fish movements and the spread of infectious salmon anemia virus (ISAV) in Chile, 2007-2009. AB - Infectious salmon anemia virus (ISAV) infection is a constant major threat to farmed and wild Atlantic salmon worldwide. Many epidemics have recently been reported in the most important salmon farming regions of the world, including Chile (2007-2009), where ISAV generated the most important disease and economic crisis in history of the salmon industry of the country. The spread of ISAV within a region is most likely by local or neighborhood spread from an infected farm; however, there is evidence that anthropogenic activities, such as movement of live or harvested fish or their byproduct, may have played a more important role than environmental or passive transmission in the 2007-2009 outbreak. Atlantic salmon farms (n=421) were retrospectively followed from stocking to harvesting in southern Chile at the time of the ISAV epidemic (2007-2009). The effect of husbandry and spatial risk factors, in addition to contact-network risk factors, which were obtained from the social network analyses, on time to first ISAV infection was estimated using a multivariable Cox proportional hazards model. Five variables were retained in the final fitted model: co-existing multiple generations on a farm (hazard ratio [HR]=2.585), mean smolt weight at stocking greater than 120g (HR=1.165), farm area (perkm(2)) (HR=1.005), and increased number of shipments entering a farm, i.e. the farm input degree (HR=1.876) were associated with reduced time to infection; whereas time-to infection was longer for farms located farther from an ongoing ISAV outbreak (HR=0.943). It was demonstrated that movements of latently infected fish resulted in approximately 7 outbreaks, and potentially explain about 6% of the total number of cases during the epidemic. Results from this study provide new information about the mechanisms of spread of ISAV in one the largest documented ISAV epidemics in the world. Findings may be used to support the design and implementation of risk-based surveillance and control programs that may help to prevent, detect and control future ISAV outbreaks. PMID- 24485705 TI - Occurrence and severity of lung lesions in slaughter pigs vaccinated against Mycoplasma hyopneumoniae with different strategies. AB - Different vaccination strategies against Mycoplasma hyopneumoniae have been adopted worldwide. Reports from the field indicate varying levels of protection among currently available vaccines. The goal of the present study was to compare the efficacies of three widespread commercial vaccination strategies against M. hyopneumoniae under field conditions. 20 farms were included. 14 farms used different single dose vaccines (vaccine 1 [V1], 8 herds; vaccine 2 [V2], 6 herds); another 6 farms (V3) used a two dose vaccination strategy. Gross lesions of 854 lungs and histopathology from 140 lungs were quantified, and a quantitative PCR was applied to detect M. hyopneumoniae and porcine circovirus 2 (PCV2) DNA in lung tissue (n=140). In addition, porcine reproductive and respiratory disease virus (PRRSV), swine influenza virus (SIV), Actinobacillus pleuropneumoniae, Haemophilus parasuis and Pasteurella multocida were tested by qualitative PCR. 53% of lungs were positive for M. hyopneumoniae. 55.9% of lungs showed macroscopic enzootic pneumonia (EP)-like lesions. Lung lesion scores (P<0.001) and M. hyopneumoniae-loads (P<0.008) differed significantly among the vaccination groups, with the most severe cases and highest amounts occurring in V1. Histological alterations differed (P<0.001) between V1 and V3. Lung lesion scores and histopathological changes were significantly correlated, with prevalence and load of M. hyopneumoniae indicating that the applied diagnostic tools are valuable in confirming the prevalence and severity of M. hyopneumoniae infections. Comparing different vaccination strategies against M. hyopneumoniae indicates varying levels of protection. M. hyopneumoniae is still a major problem despite the widely applied vaccination. PMID- 24485706 TI - Prevalence and risk factors of Coxiella burnetii seropositivity in Danish beef and dairy cattle at slaughter adjusted for test uncertainty. AB - Antibodies to Coxiella burnetii have been found in the Danish dairy cattle population with high levels of herd and within herd seroprevalences. However, the prevalence of antibodies to C. burnetii in Danish beef cattle remains unknown. The objectives of this study were to (1) estimate the prevalence and (2) identify risk factors associated with C. burnetii seropositivity in Danish beef and dairy cattle based on sampling at slaughter. Eight hundred blood samples from slaughtered cattle were collected from six Danish slaughter houses from August to October 2012 following a random sampling procedure. Blood samples were tested by a commercially available C. burnetii antibody ELISA kit. A sample was defined positive if the sample-to-positive ratio was greater than or equal to 40. Animal and herd information were extracted from the Danish Cattle Database. Apparent (AP) and true prevalences (TPs) specific for breed, breed groups, gender and herd type; and breed-specific true prevalences with a random effect of breed was estimated in a Bayesian framework. A Bayesian logistic regression model was used to identify risk factors of C. burnetii seropositivity. Test sensitivity and specificity estimates from a previous study involving Danish dairy cattle were used to generate prior information. The prevalence was significantly higher in dairy breeds (AP=9.11%; TP=9.45%) than in beef breeds (AP=4.32%; TP=3.54%), in females (AP=9.10%; TP=9.40%) than in males (AP=3.62%; TP=2.61%) and in dairy herds (AP=15.10%; TP=16.67%) compared to beef herds (AP=4.54%; TP=3.66%). The Bayesian logistic regression model identified breed group along with age, and number of movements as contributors for C. burnetii seropositivity. The risk of seropositivity increased with age and increasing number of movements between herds. Results indicate that seroprevalence of C. burnetii is lower in cattle sent for slaughter than in Danish dairy cows in production units. A greater proportion of this prevalence is attributed to slaughtered cattle of dairy breeds or cattle raised in dairy herds rather than beef breeds. PMID- 24485707 TI - An integrated web system to support veterinary activities in Italy for the management of information in epidemic emergencies. AB - The management of public health emergencies is improved by quick, exhaustive and standardized flow of data on disease outbreaks, by using specific tools for data collection, registration and analysis. In this context, the National Information System for the Notification of Outbreaks of Animal Diseases (SIMAN) has been developed in Italy to collect and share data on the notifications of outbreaks of animal diseases. SIMAN is connected through web services to the national database of animals and holdings (BDN) and has been integrated with tools for the management of epidemic emergencies. The website has been updated with a section dedicated to the contingency planning in case of epidemic emergency. EpiTrace is one such useful tool also integrated in the BDN and based on the Social Network Analysis (SNA) and on network epidemiological models. This tool gives the possibility of assessing the risk associated to holdings and animals on the basis of their trade, in order to support the veterinary services in tracing back and forward the animals in case of outbreaks of infectious diseases. PMID- 24485708 TI - Mining free-text medical records for companion animal enteric syndrome surveillance. AB - Large amounts of animal health care data are present in veterinary electronic medical records (EMR) and they present an opportunity for companion animal disease surveillance. Veterinary patient records are largely in free-text without clinical coding or fixed vocabulary. Text-mining, a computer and information technology application, is needed to identify cases of interest and to add structure to the otherwise unstructured data. In this study EMR's were extracted from veterinary management programs of 12 participating veterinary practices and stored in a data warehouse. Using commercially available text-mining software (WordStatTM), we developed a categorization dictionary that could be used to automatically classify and extract enteric syndrome cases from the warehoused electronic medical records. The diagnostic accuracy of the text-miner for retrieving cases of enteric syndrome was measured against human reviewers who independently categorized a random sample of 2500 cases as enteric syndrome positive or negative. Compared to the reviewers, the text-miner retrieved cases with enteric signs with a sensitivity of 87.6% (95%CI, 80.4-92.9%) and a specificity of 99.3% (95%CI, 98.9-99.6%). Automatic and accurate detection of enteric syndrome cases provides an opportunity for community surveillance of enteric pathogens in companion animals. PMID- 24485710 TI - STOPping peanut allergy: the saga of food oral immunotherapy. PMID- 24485709 TI - Assessing the efficacy of oral immunotherapy for the desensitisation of peanut allergy in children (STOP II): a phase 2 randomised controlled trial. AB - BACKGROUND: Small studies suggest peanut oral immunotherapy (OIT) might be effective in the treatment of peanut allergy. We aimed to establish the efficacy of OIT for the desensitisation of children with allergy to peanuts. METHODS: We did a randomised controlled crossover trial to compare the efficacy of active OIT (using characterised peanut flour; protein doses of 2-800 mg/day) with control (peanut avoidance, the present standard of care) at the NIHR/Wellcome Trust Cambridge Clinical Research Facility (Cambridge, UK). Randomisation (1:1) was by use of an audited online system; group allocation was not masked. Eligible participants were aged 7-16 years with an immediate hypersensitivity reaction after peanut ingestion, positive skin prick test to peanuts, and positive by double-blind placebo-controlled food challenge (DBPCFC). We excluded participants if they had a major chronic illness, if the care provider or a present household member had suspected or diagnosed allergy to peanuts, or if there was an unwillingness or inability to comply with study procedures. Our primary outcome was desensitisation, defined as negative peanut challenge (1400 mg protein in DBPCFC) at 6 months (first phase). Control participants underwent OIT during the second phase, with subsequent DBPCFC. Immunological parameters and disease specific quality-of-life scores were measured. Analysis was by intention to treat. Fisher's exact test was used to compare the proportion of those with desensitisation to peanut after 6 months between the active and control group at the end of the first phase. This trial is registered with Current Controlled Trials, number ISRCTN62416244. FINDINGS: The primary outcome, desensitisation, was recorded for 62% (24 of 39 participants; 95% CI 45-78) in the active group and none of the control group after the first phase (0 of 46; 95% CI 0-9; p<0.001). 84% (95% CI 70-93) of the active group tolerated daily ingestion of 800 mg protein (equivalent to roughly five peanuts). Median increase in peanut threshold after OIT was 1345 mg (range 45-1400; p<0.001) or 25.5 times (range 1.82-280; p<0.001). After the second phase, 54% (95% CI 35-72) tolerated 1400 mg challenge (equivalent to roughly ten peanuts) and 91% (79-98) tolerated daily ingestion of 800 mg protein. Quality-of-life scores improved (decreased) after OIT (median change -1.61; p<0.001). Side-effects were mild in most participants. Gastrointestinal symptoms were, collectively, most common (31 participants with nausea, 31 with vomiting, and one with diarrhoea), then oral pruritus after 6.3% of doses (76 participants) and wheeze after 0.41% of doses (21 participants). Intramuscular adrenaline was used after 0.01% of doses (one participant). INTERPRETATION: OIT successfully induced desensitisation in most children within the study population with peanut allergy of any severity, with a clinically meaningful increase in peanut threshold. Quality of life improved after intervention and there was a good safety profile. Immunological changes corresponded with clinical desensitisation. Further studies in wider populations are recommended; peanut OIT should not be done in non-specialist settings, but it is effective and well tolerated in the studied age group. FUNDING: MRC-NIHR partnership. PMID- 24485711 TI - [Healthcare administration and the economic crisis: apropos of a case]. PMID- 24485712 TI - The ADHF/NT-proBNP risk score to predict 1-year mortality in hospitalized patients with advanced decompensated heart failure. AB - BACKGROUND: The acute decompensated heart failure/N-terminal pro-B-type natriuretic peptide (ADHF/NT-proBNP) score is a validated risk scoring system that predicts mortality in hospitalized heart failure patients with a wide range of left ventricular ejection fractions (LVEFs). We sought to assess discrimination and calibration of the score when applied to patients with advanced decompensated heart failure (AHF). METHODS: We studied 445 patients hospitalized for AHF, defined by the presence of severe symptoms of worsening HF at admission, severely depressed LVEF, and the need for intravenous diuretic and/or inotropic drugs. The primary outcome was cumulative (in-hospital and post discharge) mortality and post-discharge 1-year mortality. Separate analyses were performed for patients aged <= 70 years. A Seattle Heart Failure Score (SHFS) was calculated for each patient discharged alive. RESULTS: During follow-up, 144 patients (32.4%) died, and 69 (15.5%) underwent heart transplantation (HT) or ventricular assist device (VAD) implantation. After accounting for the competing events (VAD/HT), the ADHF/NT-proBNP score's C-statistic for cumulative mortality was 0.738 in the overall cohort and 0.771 in patients aged <= 70 years. The C statistic for post-discharge mortality was 0.741 and 0.751, respectively. Adding prior (<=6 months) hospitalizations for HF to the score increased the C-statistic for post-discharge mortality to 0.759 in the overall cohort and to 0.774 in patients aged <= 70 years. Predicted and observed mortality rates by quartiles of score were highly correlated. The SHFS demonstrated adequate discrimination but underestimated the risk. The ADHF/NT-proBNP risk calculator is available at http://www.fsm.it/fsm/file/NTproBNPscore.zip. CONCLUSIONS: Our data suggest that the ADHF/NT-proBNP score may efficiently predict mortality in patients hospitalized with AHF. PMID- 24485713 TI - Towards a values-based person specification for recruitment of compassionate nursing and midwifery candidates: a study of registered and student nurses' and midwives' perceptions of prerequisite attributes and key skills. AB - Selection and retention of preregistration nursing and midwifery students are issues that exercise educators, universities and commissioning bodies both nationally and internationally. It has recently become an expectation that a values-based approach is used within recruitment and selection activities in the UK. The desirability of a person specification to support transparent recruitment and selection is well recognised. An online survey of registered and student nurses and midwives found consensus around the desirability of several personal attributes and key skills. There was consensus in the top seven ranked attributes which were honesty and trustworthiness, communication skills, being a good listener, patience and tactfulness, sensitivity and compassion, the ability to seek and act on guidance and being a good team worker; this was between registered and unregistered nurses and midwives and also between participants representing all fields of nursing and midwifery practice. Some of the responses from Practice Education Facilitators (PEFs) (n=5) and senior managers (n=15) differed from those of other registrants surveyed. The attribute 'Able to draw on knowledge and experience' was considered more important by PEFs and 'Observant and able to act on your own initiative within your level of responsibility' and 'Able to draw on knowledge and experience' were ranked more highly by senior managers. PMID- 24485714 TI - Situation awareness in undergraduate nursing students managing simulated patient deterioration. AB - BACKGROUND: Nursing work often occurs in complex and potentially hazardous settings. Awareness of patient and practice environments is an imperative for nurses in practice. OBJECTIVES: To explore nursing students' situation awareness while engaging in simulated patient deterioration scenarios. DESIGN: The educational process of FIRST(2)ACT was the model for the nurse intervention. Situation awareness was measured quantitatively using the Situation Awareness Global Assessment tool. Four domains were measured: physiological perception (patient parameters), global perception (surroundings), comprehension (interpretation of information), and projection (forecasting outcomes). SETTINGS: Clinical laboratories at each of three participating universities. PARTICIPANTS: Ninety-seven nursing students from three Australian universities. METHODS: Between March and July 2012, students participated in three video-recorded simulation events, in which a trained actor played patient roles and groups of three students worked as teams. To measure situation awareness, following the simulation each team leader was taken to a separate room and asked to report on a question set regarding the patient's vital signs, bedside setting and medical diagnosis. RESULTS AND CONCLUSIONS: Overall, situation awareness was low (41%). Of the four domains, physiological perceptions scored the lowest (26%) and projection the highest (59%). Final year nursing students may not have well developed situation awareness skills, especially when dealing with these types of scenarios. Education providers need to consider ways to assist students to fully develop this attribute. Findings suggest that this is an aspect of undergraduate nursing education that requires significant consideration by curriculum developers. PMID- 24485716 TI - [Metformin-associated lactic acidosis in the Intensive Care Unit]. PMID- 24485715 TI - Developmental expression profiles of axon guidance signaling and the immune system in the marmoset cortex: potential molecular mechanisms of pruning of dendritic spines during primate synapse formation in late infancy and prepuberty (I). AB - The synapse number and the related dendritic spine number in the cerebral cortex of primates shows a rapid increase after birth. Depending on the brain region and species, the number of synapses reaches a peak before adulthood, and pruning takes place after this peak (overshoot-type synaptic formation). Human mental disorders, such as autism and schizophrenia, are hypothesized to be a result of either too weak or excessive pruning after the peak is reached. Thus, it is important to study the molecular mechanisms underlying overshoot-type synaptic formation, particularly the pruning phase. To examine the molecular mechanisms, we used common marmosets (Callithrix jacchus). Microarray analysis of the marmoset cortex was performed in the ventrolateral prefrontal, inferior temporal, and primary visual cortices, where changes in the number of dendritic spines have been observed. The spine number of all the brain regions above showed a peak at 3 months (3 M) after birth and gradually decreased (e.g., at 6 M and in adults). In this study, we focused on genes that showed differential expression between ages of 3 M and 6 M and on the differences whose fold change (FC) was greater than 1.2. The selected genes were subjected to canonical pathway analysis, and in this study, we describe axon guidance signaling, which had high plausibility. The results showed a large number of genes belonging to subsystems within the axon guidance signaling pathway, macrophages/immune system, glutamate system, and others. We divided the data and discussion of these results into 2 papers, and this is the first paper, which deals with the axon guidance signaling and macrophage/immune system. Other systems will be described in the next paper. Many components of subsystems within the axon guidance signaling underwent changes in gene expression from 3 M to 6 M so that the synapse/dendritic spine number would decrease at 6 M. Thus, axon guidance signaling probably contributes to the decrease in synapse/dendritic spine number at 6 M, the phenomenon that fits the overshoot-type synaptic formation in primates. Microglial activity (evaluated by quantifying AIF1 expression) and gene expression of molecules that modulate microglia, decreased at 6 M, just like the synapse/dendritic spine number. Thus, although microglial activity is believed to be related to phagocytosis of synapses/dendritic spines, microglial activity alone cannot explain how pruning was accelerated in the pruning phase. On the other hand, expression of molecules that tag synapses/dendritic spines as a target of phagocytosis by microglia (e.g., complement components) increased at 6 M, suggesting that these tagging proteins may be involved in the acceleration of pruning during the pruning phase. PMID- 24485717 TI - Rolf G. Behrents selected as the next Editor-in-Chief. PMID- 24485718 TI - Adult and pediatric cone-beam computed tomography dosimetries. PMID- 24485719 TI - Authors' response. PMID- 24485720 TI - Authors' response. PMID- 24485721 TI - Condylar position. PMID- 24485722 TI - An evidence iceberg. PMID- 24485723 TI - The fear of scientific publishing. PMID- 24485724 TI - Editor-in-Chief's response. PMID- 24485726 TI - Early cleft management: the case for nasoalveolar molding. PMID- 24485727 TI - Early cleft management: in search of evidence. PMID- 24485728 TI - Evaluation of cone-beam computed tomography in the diagnosis of simulated small osseous defects in the mandibular condyle. AB - INTRODUCTION: In this study, we investigated the impact of defect size and scan voxel size on the accuracy of cone-beam computed tomography (CBCT) diagnoses of simulated condylar defects and assessed the value of orthodontic CBCT images typically scanned at lower settings (0.4-mm voxel size and full-size field of view) in diagnosing condylar erosion defects. METHODS: Cylindrical holes simulating condylar defects with varied diameters (<=2, 2-3, and >3 mm) and depths (<=2 and >2 mm) were created in 22 fresh pig mandibular condyles, with defect number and size per condyle and quadrant randomly determined. With the soft tissues repositioned, 2 CBCT scans (voxel sizes, 0.4 and 0.2 mm) of the pig heads were obtained from an i-CAT unit (Imaging Science International, Hatfield, Pa). Reconstructed CBCT data were analyzed independently by 2 calibrated, blinded raters using Dolphin-3D (Dolphin Imaging and Management Solutions, Chatsworth, Calif) for defect identification and localization and defect diameter and depth measurements, which were compared with physical diagnoses obtained from polyvinyl siloxane impressions. RESULTS: Identification and localization of simulated defects demonstrated moderate interrater reliability and excellent specificity and sensitivity, except for extremely small defects (both diameter and depth <=2 mm) viewed with 0.4-mm scans, which had a significantly lower sensitivity (67.3%). Geometric measurements of simulated defects demonstrated good but not excellent interrater reliability and submillimeter inaccuracy for all defects. Receiver operating characteristic analyses demonstrated that the overall accuracy of diagnosing simulated condylar defects based on CBCT geometric measurements was fair and good for the 0.4-mm and 0.2-mm voxel-size scans, respectively. With the prevalence of condylar erosion defects in the patients considered, the positive predictive values of diagnoses based on 0.5-mm size (diameter or depth) cutoff points were near 15% and 50% for asymptomatic and symptomatic temporomandibular joints, respectively; the negative predictive values were near 95% and 90%, respectively. CONCLUSIONS: When using orthodontic CBCT images for diagnosing condylar osseous defects, extremely small (<2 mm) defects can be difficult to detect; caution is also needed for the diagnostic accuracy of positive diagnoses, especially those from asymptomatic temporomandibular joints. PMID- 24485730 TI - Comparison of cephalometric measurements and cone-beam computed tomography-based measurements of palatal bone thickness. AB - INTRODUCTION: The purpose of this study was to determine the relationships between cephalometric measurements and cone-beam computed tomography-based measurements of the palatal bone thickness. METHODS: Thirty sets of cone-beam computed tomography images and lateral cephalograms were used. Palatal bone thicknesses were measured anteroposteriorly from between the first and second premolars to between the first and second molars using both imaging methods, and also laterally from 1.5 mm off-center to 10 mm off-center in the cone-beam computed tomography images. Repeated-measures analysis of variance was used to examine the differences between the measurements. RESULTS: Bland-Altman plots showed that the 95% limits of agreement were smallest at 5 mm off-center (-0.2 +/ 1.7 mm). The 5-mm off-center measurements were the only ones for which there were no statistically significant differences compared with the cephalometric measurements in all anteroposterior areas. The measurements at 1.5 mm off-center were significantly thicker than the cephalometric measurements only from the area between the second premolar and the first molar to the area between the first and second molars. CONCLUSIONS: Among the areas measured, the bone at 5 mm off-center is most likely to be depicted in cephalograms as palatal bone contours. PMID- 24485729 TI - Accuracy, reproducibility, and time efficiency of dental measurements using different technologies. AB - INTRODUCTION: Historically, orthodontists have taken dental measurements on plaster models. Technological advances now allow orthodontists to take these measurements on digital models. In this study, we aimed to assess the accuracy, reproducibility, and time efficiency of dental measurements taken on 3 types of digital models. METHODS: emodels (GeoDigm, Falcon Heights, Minn), SureSmile models (OraMetrix, Richardson, Tex), and AnatoModels (Anatomage, San Jose, Calif) were made for 30 patients. Mesiodistal tooth-width measurements taken on these digital models were timed and compared with those on the corresponding plaster models, which were used as the gold standard. Accuracy and reproducibility were assessed using the Bland-Altman method. Differences in time efficiency were tested for statistical significance with 1-way analysis of variance. RESULTS: Measurements on SureSmile models were the most accurate, followed by those on emodels and AnatoModels. Measurements taken on SureSmile models were also the most reproducible. Measurements taken on SureSmile models and emodels were significantly faster than those taken on AnatoModels and plaster models. CONCLUSIONS: Tooth-width measurements on digital models can be as accurate as, and might be more reproducible and significantly faster than, those taken on plaster models. Of the models studied, the SureSmile models provided the best combination of accuracy, reproducibility, and time efficiency of measurement. PMID- 24485731 TI - Long-term occlusal changes assessed by the American Board of Orthodontics' model grading system. AB - INTRODUCTION: The purpose of this study was to assess the long-term posttreatment changes in all criteria of the American Board of Orthodontics' (ABO) model grading system. METHODS: We used plaster models from patients' final and posttreatment records. Thirty patients treated by 1 orthodontist using 1 bracket prescription were selected. An initial discrepancy index for each subject was performed to determine the complexity of each case. The final models were then graded using the ABO's model grading system immediately at posttreatment and postretention. Statistical analysis was performed on the 8 criteria of the model grading system, including paired t tests and Pearson correlations. An alpha of 0.05 was considered statistically significant. RESULTS: The average length of time between the posttreatment and postretention records was 12.7 +/- 4.4 years. It was shown that alignment and rotations worsened by postretention (P = 0.014), and a weak statistically significant correlation at posttreatment and postretention was found (0.44; P = 0.016). Both marginal ridges and occlusal contacts scored less well at posttreatment. These criteria showed a significant decrease in scores between posttreatment and postretention (P <0.001), but the correlations were not statistically significant. The average total score showed a significant decrease between posttreatment and postretention (P <0.001), partly because of the large decrease in the previous 2 criteria. CONCLUSIONS: Higher scores for occlusal contacts and marginal ridges were found at the end of treatment; however, those scores and the overall scores for the 30 subjects improved in the postretention phase. PMID- 24485732 TI - Dimensions and morphologic variations of sella turcica in type 1 diabetic patients. AB - INTRODUCTION: Some chronic diseases are associated with changes in the morphology of sella turcica, and type 1 diabetes is the most common chronic disease in children and adolescents. Therefore, the aim of this study was to evaluate the size and morphology of sella turcica in patients with type 1 diabetes compared with a healthy control group. METHODS: The study included 76 type 1 diabetic patients (38 boys, 38 girls; ages, 14.16 +/- 2.46 years) and 76 controls (38 boys, 38 girls; ages, 14 +/- 2.08 years). The groups were categorized as pubertal and postpubertal according to bone age. The length, height, and diameter of sella turcica were measured. Then the morphology of sella turcica was analyzed and categorized as normal, oblique anterior wall, bridging, double contour of the floor, irregularity in the posterior part of dorsum sellae, or pyramidal shape of the dorsum sellae. All measurements were made on tracings of cephalometric radiographs. Differences between the groups were tested with the Mann-Whitney U test. Categorical data were evaluated with the Fisher exact test, and the Bonferroni correction was made. The significance level was assigned as P <0.05. RESULTS: There was no statistically significant difference in the dimensions of sella between the diabetic patients (diameter, 12.20 +/- 1.49 mm; length, 10.49 +/- 1.55 mm; height, 8.07 +/- 1.25 mm) and the controls (diameter, 12.45 +/- 1.43 mm; length, 10.90 +/- 1.73 mm; height, 8.29 +/- 1.66 mm). However, diameter and length increased with age in the overall assessment. Length was greater in the postpubertal controls (11.39 +/- 1.69 mm) compared with the pubertal controls (10.41 +/- 1.64 mm). Diameter was greater in the postpubertal diabetic patients (1.283 +/- 1.55 mm) than in the pubertal diabetic patients (11.56 +/- 1.12 mm) and was specifically higher in postpubertal boys. Normal sella morphology was less common in general in the diabetic patients, particularly in the diabetic boys and diabetic pubertal boys (P <0.05). CONCLUSIONS: The measurements concerning sella were similar in the type 1 diabetic and control subjects, but dysmorphologic types were more common in diabetic patients. PMID- 24485733 TI - Reliability of upper airway linear, area, and volumetric measurements in cone beam computed tomography. AB - INTRODUCTION: Our objective was to assess the intraexaminer and interexaminer reliabilities of upper airway linear, area, and volumetric measurements in cone beam computed tomography. METHODS: Cone-beam computed tomography scans of 12 subjects were randomly selected from a pool of 132 orthodontic patients. An undergraduate student, an orthodontist, and a dental radiologist independently made linear, area, and volumetric measurements. Linear anteroposterior and transversal measurements, cross-sectional area, sagittal area, minimum axial area, and volume measurements were made. The intraclass correlation coefficient (ICC) was used to assess intraexaminer and interexaminer reliabilities, and measurement errors were assessed. Agreement was further assessed with the Bland Altman method and 95% limits of agreement. RESULTS: Overall, the ICC values indicated good reliability for the measurements assessed. The ICC values were greater than 0.9 (excellent) for 93% of intraexaminer and 73% of interexaminer assessments. Transversal width measurements and cross-sectional area at the level of the vallecula, however, had only moderate reliability (minimum ICC, 0.63), large 95% limits of agreement, and the greatest mean measurement errors (as high as 16% and 13% of the mean measurements, respectively). Linear anteroposterior measurements; cross-sectional areas at the levels of the palatal plane, soft palate, and tongue; and sagittal area and volume were reliable measurements, with a minimum ICC of 0.93 and more restricted limits of agreement. CONCLUSIONS: Based on these results, airway assessments by examiners with different backgrounds might have reliable anteroposterior linear measurements; cross-sectional areas at the levels of the palatal plane, soft palate, and tongue; and sagittal area and volume. The unreliable measurements were linear width, cross-sectional area at the level of the vallecula, and minimum axial area. PMID- 24485734 TI - Antimicrobial effect of Melaleuca alternifolia dental gel in orthodontic patients. AB - The aim of this study was to evaluate the antimicrobial effect and sensorial analysis of the gel developed with the essential oil of Melaleuca alternifolia. Thirty-four volunteers, divided into 2 groups, were monitored for 4 weeks. Initially, clinical biofilm (plaque index) and saliva samples (bacteria count) were collected, from which the standard values for each patient were obtained. For 7 days, group 1 used the melaleuca gel (Petite Marie/All Chemistry, Sao Paulo, Brazil), and group 2 used Colgate Total (S.B. Campo, Sao Paulo, Brazil). After 7 days, the plaque index was performed again, as well as the bacteria count and the sensorial analysis (appearance, color, odor, brightness, viscosity, and first taste sensation). The volunteers were instructed to return to their usual dental hygiene habits for 15 days. After this, group 1 started using Colgate Total, and group 2 started using the melaleuca gel, with the same evaluation procedures as the first week. The data were analyzed statistically with a significance level of 5%. In the bacteria count and clinical disclosure, the melaleuca gel was more effective in decreasing the dental biofilm and the numbers of bacteria colonies. According to the data from the sensory evaluation, Colgate Total (the control) showed better results regarding flavor and first sensation (P <0.05). We concluded that melaleuca gel is efficient in bacteria control but needs improvement in taste and first sensation. PMID- 24485735 TI - Impact of metal and ceramic fixed orthodontic appliances on judgments of beauty and other face-related attributes. AB - INTRODUCTION: Physical attributes, behavior, and personal ornaments exert a direct influence on how a person's beauty and personality are judged. The aim of this study was to investigate how people who wear a fixed orthodontic appliance see themselves and are seen by others in social settings. METHODS: A total of 60 adults evaluated their own smiling faces in 3 different scenarios: without a fixed orthodontic appliance, wearing a metal fixed orthodontic appliance, and wearing an esthetic fixed orthodontic appliance. Furthermore, 15 adult raters randomly assessed the same faces in standardized front-view facial photographs. Both the subjects and the raters answered a questionnaire in which they evaluated criteria on a numbered scale ranging from 0 to 10. The models judged their own beauty, and the raters assigned scores to beauty, age, intelligence, ridiculousness, extroversion, and success. RESULTS: The self-evaluations showed decreased beauty scores (P <0.0001) when a fixed orthodontic appliance, especially a metal one, was being worn. There was no statistically significant difference between the 3 situations in the 6 criteria analyzed. CONCLUSIONS: A fixed orthodontic appliance did not affect how personal attributes are assessed. However, fixed orthodontic appliances apparently changed the subjects' self perceptions when they looked in the mirror. PMID- 24485736 TI - Maxillary arch width and buccal corridor changes with orthodontic treatment. Part 1: differences between premolar extraction and nonextraction treatment outcomes. AB - INTRODUCTION: In this retrospective study, we examined and compared the pretreatment and posttreatment arch widths and buccal corridor changes in subjects who had received orthodontic treatment either with or without premolar extractions. METHODS: Pretreatment and posttreatment casts, frontal smiling photographs, and lateral cephalograms of 30 extraction and 27 nonextraction patients were analyzed to determine any significant differences in arch widths, buccopalatal inclinations of the teeth, and buccal corridor widths and areas, both within and between the 2 groups. Relationships between buccal corridor measurements and corresponding arch widths and buccopalatal inclinations of the teeth were also examined. RESULTS: There was a significant increase in the posttreatment maxillary intercanine width in the extraction group but not in the nonextraction group. Both the pretreatment and posttreatment arch widths between the maxillary first molars and at the level of the posterior rugae were greater in the nonextraction group than in the extraction group. There were no significant differences in any buccal corridor widths or areas measured between the extraction and nonextraction subjects. CONCLUSIONS: Because they reflect different morphologies, there are likely to be significant differences in average maxillary anterior and posterior posttreatment arch widths in those treated with or without extractions. However, these arch width differences are not likely to be discernible in extraction and nonextraction patients as differences in the buccal corridor widths and areas. PMID- 24485737 TI - Cephalometric investigation of craniomaxillofacial structures during the prenatal period: a cadaver study. AB - INTRODUCTION: We aimed to investigate the morphometric development of the cranial base and its related structures, and their growth rate changes from the ninth gestational week to full term in a large group of human fetuses. METHODS: We selected 203 (109 male, 94 female) fetuses between 9 and 40 weeks of gestation and without any external anomalies. From each fetus, standard lateral and posteroanterior cephalometric images were taken using a dental digital panoramic and cephalometric x-ray machine. Fourteen linear and 9 angular parameters were measured. RESULTS: The cranial base angle showed a statistically significant increase between the groups from only the second to the third trimester periods. The sagittal translation of the maxilla increased during the prenatal period, whereas the mandibular sagittal relation grew at a steady rate. The vertical plane angles of the maxilla and the mandible did not show any significant changes. The maxillary length to mandibular length ratio remained stable. CONCLUSIONS: The cranial base angle increased, especially in the second through the third trimesters. The maxilla and the mandible demonstrated different growth patterns in the sagittal direction. The findings of this study could be a guide for interpreting the relationships among the craniofacial structures. PMID- 24485738 TI - Timely relocation of subapically impacted maxillary canines and replacement of an ankylosed mandibular molar are the keys to eruption disturbances in a prepubertal patient. AB - Eruption disturbances such as impaction and ankylosis complicate orthodontic treatment because soft-tissue and hard-tissue considerations must be taken into account. Treatment is further complicated when such eruption disturbances occur in a growing patient. Extraction of impacted or ankylosed teeth can be an option that carries the weight of additional prostheses and bony defects, whereas exposure or luxation followed by orthodontic traction can preserve the patient's teeth and bony structure with improved esthetics. Therefore, an accurate diagnosis is needed in establishing an efficient and effective force system to achieve the desired tooth movements with few unwanted sequelae. This case report describes the process of differential diagnosis with the aid of 3-dimensional imaging in constructing a force-driven system, using the centers of resistance as reference points, to successfully bring a pair of impacted maxillary canines into alignment and protract a mandibular molar to achieve an acceptable occlusion in an adolescent girl. PMID- 24485739 TI - Interdisciplinary treatment of a periodontally compromised adult patient with multiple missing posterior teeth. AB - This article reports the comprehensive, interdisciplinary treatment of a 50-year old periodontally compromised adult patient with multiple missing posterior teeth. After initial periodontal treatment, the maxillary first molars and right central incisor were intruded orthodontically. Miniscrews were used to intrude the maxillary first molars by 3 mm. The mandibular arch was restored with a tooth supported overdenture. Root coverage of the maxillary right central incisor was performed using Alloderm (Biohorizons, Birmingham, Ala). At the end of the interdisciplinary therapy, the results were esthetically pleasing, with the patient's oral functions restored to the optimum. The emphasis of this report is to highlight the importance of integrating various specialties such as periodontics, orthodontics, endodontics, and restorative dentistry toward a common goal of improving the patient's oral health, function, and esthetics. PMID- 24485740 TI - Perceptions of midline deviations among different facial types. AB - INTRODUCTION: The correction of a deviated midline can involve complicated mechanics and a protracted treatment. The threshold below which midline deviations are considered acceptable might depend on multiple factors. The objective of this study was to evaluate the effect of facial type on laypersons' perceptions of various degrees of midline deviation. METHODS: Smiling photographs of male and female subjects were altered to create 3 facial type variations (euryprosopic, mesoprosopic, and leptoprosopic) and deviations in the midline ranging from 0.0 to 4.0 mm. Evaluators rated the overall attractiveness and acceptability of each photograph. RESULTS: Data were collected from 160 raters. The overall threshold for the acceptability of a midline deviation was 2.92 +/- 1.10 mm, with the threshold for the male subject significantly lower than that for the female subject. The euryprosopic facial type showed no decrease in mean attractiveness until the deviations were 2 mm or more. All other facial types were rated as decreasingly attractive from 1 mm onward. Among all facial types, the attractiveness of the male subject was only affected at deviations of 2 mm or greater; for the female subject, the attractiveness scores were significantly decreased at 1 mm. The mesoprosopic facial type was most attractive for the male subject but was the least attractive for the female subject. CONCLUSIONS: Facial type and sex may affect the thresholds at which a midline deviation is detected and above which a midline deviation is considered unacceptable. Both the euryprosopic facial type and male sex were associated with higher levels of attractiveness at relatively small levels of deviations. PMID- 24485741 TI - Accurate registration of cone-beam computed tomography scans to 3-dimensional facial photographs. AB - INTRODUCTION: Registering a 3-dimensional (3D) facial surface scan to a cone-beam computed tomography (CBCT) scan has various advantages. One major advantage is to compensate for the inaccuracy of the CBCT surface data. However, when registering CBCT and 3D facial scans, changes in facial expression, spatial soft-tissue changes, and differences in the patient's positioning can decrease the accuracy of the registration. In this study, we introduce a new 3D facial scanner that is combined with a CBCT apparatus. Our goal was to evaluate the registration accuracy of CBCT and 3D facial scans, which were taken with the shortest possible time between them. METHODS: The experiment was performed with 4 subjects. Each patient was instructed to hold as still as possible while the CBCT scan was taken, followed immediately by the 3D facial surface scan. The images were automatically registered with software. The accuracy was measured by determining the degree of agreement between the soft-tissue surfaces of the CBCT and the 3D facial images. RESULTS: The average surface discrepancy between the CBCT facial surface and 3D facial surface was 0.60 mm (SD, 0.12 mm). Registration accuracy was also visually verified by toggling between the images of the CBCT and 3D facial surface scans while rotating the registered images. CONCLUSIONS: Registration of consecutively taken CBCT and 3D facial images resulted in reliable accuracy. PMID- 24485742 TI - Litigation and legislation. Macadamias, pistachios, and filberts. PMID- 24485743 TI - Introduction to observational studies: part 2. PMID- 24485744 TI - Rakkyo fructan as a cryoprotectant for serum-free cryopreservation of mammalian cells. AB - Cryopreservation refers to the long-term storage of mammalian cells. Mammalian serum is generally used as a cryoprotectant, but is associated with problems including the risk of contamination by pathogens and quality control issues. Therefore, a serum-free cryopreservation method needs to be established. In this study, we focused on rakkyo fructan, a fructose polymer, derived from the Japanese shallot as an alternative factor to serum. Fructan contributes to tolerance to frost and dehydration in plants by stabilizing the plant membrane. However, whether fructan protects mammalian cells against freezing stress remains unknown. The ability of rakkyo fructan to be an alternative cryoprotectant to fetal bovine serum (FBS) was examined in the present study. 2E3-O, a mouse hybridoma, was preserved in rakkyo fructan, was highly viable after being defrosted, and then proliferated rapidly. When rakkyo fructan was combined with dimethylsulfoxide (DMSO), its ability to protect the hybridoma against freezing stress was improved. The rakkyo fructan and DMSO mixture was used in the cryopreservation of the mammalian cell lines CHO-DP12, a producer of recombinant antibodies, and HepG2, human hepatoma cells frequently tested in bio-artificial livers. Following the freezing and thawing processes, CHO-DP12 cells retained their ability to produce recombinant antibodies and as did HepG2 cells for albumin and mRNA expression of cytochrome P450 enzymes. These results indicate that rakkyo fructan is a promising cryoprotectant that prevents mammalian cells from freezing stress similar to FBS. PMID- 24485745 TI - Bio-imaging of hydroxyl radicals in plant cells using the fluorescent molecular probe rhodamine B hydrazide, without any pretreatment. AB - Rhodamine B hydrazide can be used to detect hydroxyl radicals in plant cells. RBH was easily inserted into plant cells without any pretreatment, and specifically reacted with intracellular hydroxyl radicals produced by antimycin A. RBH will be a powerful tool for detecting hydroxyl radicals in plant cells. PMID- 24485746 TI - Band gap structures in underwater screens of periodically spaced porous plates. AB - Acoustic properties of different periodic structures composed of alternating fluid and fluid-saturated porous layers obeying Biot's theory are investigated. At first, the network of modes and the transmission coefficients of finite structures of six plates are studied in the frequency-angle of incidence plane. It is shown that the network of modes concentrates in localized domains of the plane where the transmission coefficients will take the greatest values. With this minimum of six plates, the structures exhibit the main features as for structures containing more plates, especially those with an infinite number of plates. Then, considering infinite structures the band gap calculations are led using the Bloch-Floquet theorem. The evanescent and propagative zones in the frequency-angle of incidence plane are determined. What is proposed here is a class of underwater porous screens that exhibits band gaps extending over great angular domains and enlarging in the frequency domain when the pores at the interfaces of the porous plates are sealed. The effect of porosity on the band gaps is also investigated. PMID- 24485747 TI - Stable bubble oscillations beyond Blake's critical threshold. AB - The equilibrium radius of a single spherical bubble containing both non condensable gas and vapor is determined by the mechanical balance at the bubble interface. This expression highlights the fact that decreasing the ambient pressure below the so called Blake's critical threshold, the bubble has no equilibrium state at all. In the last decade many authors have tried to find evidence for the existence of stable bubble oscillation under harmonic forcing in this regime, that is, they have tried to stabilize the bubble motion applying ultrasonic radiation on the bubble. The available numerical results provide only partial proof for the existence as they are usually based on linearized or weakly nonlinear (higher order approximation) bubble models. Here, based on numerical techniques of the modern nonlinear and bifurcation theory, the existence of stable bubble motion has been proven without any restrictions in nonlinearities. Although the model, applied in this paper, is the rather simple Rayleigh-Plesset equation, the presented technique can be extended to more complex bubble models easily. PMID- 24485748 TI - Elastic characterization of platinum/rhodium alloy at high temperature by combined laser heating and laser ultrasonic techniques. AB - We demonstrate an innovative pump-probe technique combined with laser heating to determine the velocity of a surface Rayleigh wave at high temperature. Laser ultrasonics in a point-source-point-receiver configuration was combined with laser heating to evaluate the elastic properties of micron size specimens. The measurements of the velocity of the surface Rayleigh wave (SRW) were conducted at 1070K. PMID- 24485749 TI - Investigation of quasi lateral-field-excitation on (yxl)-17 degrees LiNbO3 single crystal. AB - Quasi lateral-field-excitation (LFE) on LiNbO3 crystal is investigated both theoretically and experimentally. It is found that when the driving electric field direction is parallel to the crystallographic X-axis of the piezoelectric substrate, (yxl)-17 degrees LiNbO3 LFE bulk acoustic wave devices work on quasi LFE mode. The experimental results agreed with the theoretical prediction well. The results provide the cut of LiNbO3 crystal for quasi-LFE bulk acoustic wave devices, which is important for designing high performance LFE sensors on LiNbO3 substrates. PMID- 24485750 TI - Biosorption of Cr (VI) by Typha angustifolia: mechanism and responses to heavy metal stress. AB - In this study, Typha angustifolia was proven to have an excellent accumulation ability in high concentrations of wastewater solutions having Cr (VI) concentrations up to 30 mg L(-1) for 20 days (74% of removal efficiency). Synchrotron microfocus micro X-ray fluorescence (MU-XRF) mapping showed that the uptaken Cr was mainly enriched in the outer layer of the roots and a small portion of it was uniformly distributed in the fronds. The total proteins, soluble sugars, and malondialdehyde in T. angustifolia increased when the concentration of Cr (VI) increased from 9 to 30 mg L(-1). Transmission electron microscope (TEM) assay showed that no lignifications were observed when Cr was absorbed by T. angustifolia. It was concluded that T. angustifolia can uptake Cr by means of surface layer absorption and transportation, and alleviate stresses associated with the sorption of Cr (VI) by thickening of cell walls or secretion of chemical substances. PMID- 24485752 TI - A single-institution study of 117 pregnancy-associated breast cancers (PABC): Presentation, imaging, clinicopathological data and outcome. AB - BACKGROUND: This retrospective single-institution study was designed to describe the main clinical, radiological and histological features, as well as the outcome of pregnancy-associated breast cancer (PABC), with a special emphasis on imaging and diagnostic difficulties. MATERIAL AND METHODS: We reviewed all breast cancers diagnosed during pregnancy or during the 12 months following delivery at our institution, between 1993 and 2009. Out of a total of 16,555 new cases of breast cancer observed during this period, 117 PABC (0.7%) were diagnosed. RESULTS: Mean age at diagnosis was 33.7 years. Most cancers (81.2%) were diagnosed after delivery. Intermediate or high family risk was frequent (27.5%). The most common mode of presentation was a palpable mass (89.7%). Mean time to diagnosis was 5.8 months. Sensitivity for mammography was 80.9% and for ultrasound 77%. Most prognostic factors were unfavourable: frequent lymph node involvement (51.8%), high-grade tumours, hormone receptor negativity (45.9%) and HER2 positivity (38.7%). Treatments generally included surgery (61.7% mastectomies), radiotherapy (96%) and chemotherapy (79.6%). Overall 5-year survival was 81.8%. CONCLUSION: PABC is an uncommon but aggressive form of breast cancer and must be considered in the presence of any breast abnormality during pregnancy or the months following delivery. Mammography and ultrasound should both be performed at the slightest clinical suspicion. Radiologists must be aware that masses may lack typical malignant ultrasound characteristics. Biopsies should be largely performed. PMID- 24485751 TI - PDGF mediates derivation of human embryonic germ cells. AB - Human embryonic germ cells (hEGCs) are a valuable and underutilized source of pluripotent stem cells. Unlike embryonic stem cells, which have been extensively studied, little is known about the factors that regulate hEGC derivation and maintenance. This study demonstrates for the first time a central role for selective activation of PDGFR signaling in the derivation and maintenance of pluripotency in hEGCs. In the study, hEGCs were found to express PDGF receptor alpha at high levels compared to human embryonic stem cells (hESCs). PDGF significantly improved formation of alkaline phosphatase (AP) positive hEGC colonies. We subsequently determined that PDGF activates the phosphatidylinositol 3-kinase (PI3K) pathway as phosphorylation of AKT was up-regulated in response to PDGF. Furthermore, inhibition of PI3K signaling using small molecular inhibitor LY294002 led to significantly decreased AP positive hEGC colony formation whereas inhibition of MAPK pathway using U0126 had a negligible effect. We established a primary mechanism for PDGF mediated derivation and maintenance of hEGCs by demonstrating that OCT4 was upregulated and PTEN was suppressed in a dose dependent manner in response to PDGF. PMID- 24485753 TI - EPA guidance on tobacco dependence and strategies for smoking cessation in people with mental illness. AB - Tobacco dependence is the most common substance use disorder in adults with mental illness. The prevalence rates for tobacco dependence are two to four times higher in these patients than in the general population. Smoking has a strong, negative influence on the life expectancy and quality of life of mental health patients, and remains the leading preventable cause of death in this group. Despite these statistics, in some countries smokers with mental illness are disadvantaged in receiving intervention and support for their tobacco dependence, which is often overlooked or even tolerated. This statement from the European Psychiatric Association (EPA) systematically reviews the current evidence on tobacco dependence and withdrawal in patients with mental illness and their treatment. It provides seven recommendations for the core components of diagnostics and treatment in this patient group. These recommendations concern: (1) the recording process, (2) the timing of the intervention, (3) counselling specificities, (4) proposed treatments, (5) frequency of contact after stopping, (6) follow-up visits and (7) relapse prevention. They aim to help clinicians improve the care, health and well-being of patients suffering from mental illness. PMID- 24485754 TI - The relationships among work stress, strain and self-reported errors in UK community pharmacy. AB - BACKGROUND: Changes in the UK community pharmacy profession including new contractual frameworks, expansion of services, and increasing levels of workload have prompted concerns about rising levels of workplace stress and overload. This has implications for pharmacist health and well-being and the occurrence of errors that pose a risk to patient safety. Despite these concerns being voiced in the profession, few studies have explored work stress in the community pharmacy context. OBJECTIVES: To investigate work-related stress among UK community pharmacists and to explore its relationships with pharmacists' psychological and physical well-being, and the occurrence of self-reported dispensing errors and detection of prescribing errors. METHOD: A cross-sectional postal survey of a random sample of practicing community pharmacists (n = 903) used ASSET (A Shortened Stress Evaluation Tool) and questions relating to self-reported involvement in errors. Stress data were compared to general working population norms, and regressed on well-being and self-reported errors. RESULTS: Analysis of the data revealed that pharmacists reported significantly higher levels of workplace stressors than the general working population, with concerns about work life balance, the nature of the job, and work relationships being the most influential on health and well-being. Despite this, pharmacists were not found to report worse health than the general working population. Self-reported error involvement was linked to both high dispensing volume and being troubled by perceived overload (dispensing errors), and resources and communication (detection of prescribing errors). CONCLUSIONS: This study contributes to the literature by benchmarking community pharmacists' health and well-being, and investigating sources of stress using a quantitative approach. A further important contribution to the literature is the identification of a quantitative link between high workload and self-reported dispensing errors. PMID- 24485755 TI - Early sensitivity to arguments: how preschoolers weight circular arguments. AB - Observational studies suggest that children as young as 2 years can evaluate some of the arguments people offer them. However, experimental studies of sensitivity to different arguments have not yet targeted children younger than 5 years. The current study aimed at bridging this gap by testing the ability of preschoolers (3-, 4-, and 5-year-olds) to weight arguments. To do so, it focused on a common type of fallacy-circularity-to which 5-year-olds are sensitive. The current experiment asked children-and, as a group control, adults-to choose between the contradictory opinions of two speakers. In the first task, participants of all age groups favored an opinion supported by a strong argument over an opinion supported by a circular argument. In the second task, 4- and 5-year-olds, but not 3-year-olds or adults, favored the opinion supported by a circular argument over an unsupported opinion. We suggest that the results of these tasks in 3- to 5 year-olds are best interpreted as resulting from the combination of two mechanisms: (a) basic skills of argument evaluations that process the content of arguments, allowing children as young as 3 years to favor non-circular arguments over circular arguments, and (b) a heuristic that leads older children (4- and 5 year-olds) to give some weight to circular arguments, possibly by interpreting these arguments as a cue to speaker dominance. PMID- 24485756 TI - The effectiveness of psychosocial interventions for stroke family caregivers and stroke survivors: a systematic review and meta-analysis. AB - OBJECTIVE: To evaluate the effectiveness of psychosocial interventions for family caregivers on their psychosocial and physical wellbeing, quality of life, and the use of healthcare resources by stroke survivors. METHODS: Electronic English and Chinese bibliographic databases were searched (inception to January 2012) for clinical trials. Two reviewers independently selected and appraised study quality. When possible, data from randomized controlled trials (RCTs) were statistically pooled. Otherwise, a narrative summary was used. RESULTS: Eighteen studies (psychoeducation and social support group) were included. Pooled analysis of two individual psychoeducation programs showed a small effect on improving family functioning (SMD: -0.12; 95% CI: -0.23 to -0.01; p=0.03). Caregivers receiving psychoeducation that aimed at equipping caregivers with the skills of problem-solving, caregiving, and stress-coping appeared to have a more positive influence on the caregivers' psychosocial wellbeing and a reduced use of healthcare resources by stroke survivors. CONCLUSION: Evidence on the effects of psychosocial interventions was limited. More RCTs of multifaceted psychoeducation programs are needed to further examine the optimal dose and format. PRACTICAL IMPLICATIONS: To support caregivers across the stroke trajectory, the core skills of problem-solving and stress-coping should be included in the psychosocial interventions. PMID- 24485757 TI - Clear cell papillary renal cell carcinoma: Incidence, morphological features, immunohistochemical profile, and biologic behavior: A single institution study. AB - This study was undertaken to determine the incidence and the clinicopathologic characteristics of those tumors that qualify as clear cell papillary renal cell carcinoma (CCPRCC) by the current definitions. From January 1, 2003 to April 30, 2013, a total of twenty-eight CCPRCC were identified (28/648, 4.3%). CCPRCC showed variable architectural patterns including cystic, papillary, tubular, and acinar. Irrespective of the architecture, the tumors were composed of cuboidal or columnar cells with clear cytoplasm, small vesicular, round or oval nuclei, and inconspicuous nucleoli. Variably thick bundles of smooth muscle actin-positive soft tissue encircled the whole tumors, forming a continuous pseudocapsule. CCPRCC strongly expressed PAX8, CA-IX, CK7, cytokeratin 34betaE12, and vimentin, and were negative for RCC, P504s/AMACR, and TFE3. On ultrastructural examination, CCPRCC showed short microvilli, cytoplasmic interdigitations, nuclear pseudoinclusions, and stromal myofibroblasts. To the best of our knowledge, this is first comprehensive ultrastructural study of CCPRCC in the literature. The major differential diagnostic considerations are clear cell renal cell carcinoma, multilocular cystic renal cell carcinoma, papillary renal cell carcinoma with clear cell changes, and Xp11.2 translocation renal cell carcinoma. CCPRCC seems to have a favorable prognosis. In the current series, none of the patients had local recurrence or metastatic disease. PMID- 24485758 TI - Expression of selected cytochrome P450 isoforms and of cooperating enzymes in colorectal tissues in selected pathological conditions. AB - The current interest in CYP expression in the colon results from its uniqueness as a target organ for cancer. To date, the CYP expression profiles in the colon have not yet been subject of comprehensive research. In this study, we investigated 40 patients with Crohn's disease, 40 with ulcerative colitis, and 40 healthy subjects as a control group. Colon tissues were fixed, dehydrated, cleared in xylene and embedded in paraffin. Sections were prepared from paraffin blocks for immunohistochemical staining with specific antibodies. We used antibodies to the human CYP1A1, CYP2B6, CYP2C9, CYP2E1 and CYP3A4 isoforms, as well as antibodies to the human glycoprotein P, glutathione-S transferase and antibody to the UDP-glucuronosyltransferase. The sections were stained immunohistochemically and examined using light microscopy. Cellular localization was determined, and computer image analysis was used. In all cases with Crohn's disease, the proteins studied showed at least a twofold expression. Ulcerative colitis showed a much weaker influence regarding the expression of the proteins studied but in case of CYP2C9 and UDP-glucuronosyltransferase, a decrease of expression was observed. PMID- 24485759 TI - Actionable findings and the role of IT support: report of the ACR Actionable Reporting Work Group. AB - The ACR formed the Actionable Reporting Work Group to address the potential role of IT in the communication of imaging findings, especially in cases that require nonroutine communication because of the urgency of the findings or their unexpected nature. These findings that require special communication with referring clinicians are classified as "actionable findings." The work group defines 3 categories of actionable findings that require, respectively, communication and clinical decision within minutes (category 1), hours (category 2), or days (category 3). Although the work group does not believe that there can be definitive lists of such findings, it developed lists in each category that would apply in most general hospital settings. For each category, the work group discusses ways in which IT can assist interpreting radiologists in successfully communicating to the relevant clinicians to ensure optimal patient care. IT systems can also help document the communication and facilitate auditing of the documentation. The work group recommends that vendors develop platforms that can be customized on the basis of local preferences and needs. Whatever system is used, it should be highly reliable and fit seamlessly into radiologists' workflow. PMID- 24485760 TI - Driving change: taking ownership of our profession and its future. AB - The open-microphone sessions at the AMCLC provide a forum for the ACR's membership to be heard. The topics in 2013 included a review of the annual radiology workforce survey, the impact of teleradiology services, and the rationale for the new Imaging 3.0 initiative. Comments from members at the 2013 AMCLC unequivocally illustrated a single overarching theme: anxiety-anxiety about the future of our practices and anxiety about our profession. In light of recent and anticipated changes in health care, radiologists, radiation oncologists, interventional radiologists, nuclear medicine physicians, and medical physicists members of the ACR-must continue to establish a leadership role in the health care system and serve as a cornerstone for all patient-care delivery models. ACR commissions, networks, institutes, and initiatives will position us for smoother transitions in the persistently altering health care landscape and will ensure that we have the expertise and tools to serve as leaders in health care systems and advocates for our patients in current and future health care systems. PMID- 24485762 TI - Synthesis of L-2,3-diaminopropionic acid, a siderophore and antibiotic precursor. AB - L-2,3-diaminopropionic acid (L-Dap) is an amino acid that is a precursor of antibiotics and staphyloferrin B a siderophore produced by Staphylococcus aureus. SbnA and SbnB are encoded by the staphyloferrin B biosynthetic gene cluster and are implicated in L-Dap biosynthesis. We demonstrate here that SbnA uses PLP and substrates O-phospho-L-serine and L-glutamate to produce a metabolite N-(1-amino 1-carboxyl-2-ethyl)-glutamic acid (ACEGA). SbnB is shown to use NAD(+) to oxidatively hydrolyze ACEGA to yield alpha-ketoglutarate and L-Dap. Also, we describe crystal structures of SbnB in complex with NADH and ACEGA as well as with NAD(+) and alpha-ketoglutarate to reveal the residues required for substrate binding, oxidation, and hydrolysis. SbnA and SbnB contribute to the iron sparing response of S. aureus that enables staphyloferrin B biosynthesis in the absence of an active tricarboxylic acid cycle. PMID- 24485761 TI - Genetically encoded fluorescent biosensors for live-cell visualization of protein phosphorylation. AB - Fluorescence-based, genetically encodable biosensors are widely used tools for real-time analysis of biological processes. Over the last few decades, the number of available genetically encodable biosensors and the types of processes they can monitor have increased rapidly. Here, we aim to introduce the reader to general principles and practices in biosensor development and highlight ways in which biosensors can be used to illuminate outstanding questions of biological function. Specifically, we focus on sensors developed for monitoring kinase activity and use them to illustrate some common considerations for biosensor design. We describe several uses to which kinase and second-messenger biosensors have been put, and conclude with considerations for the use of biosensors once they are developed. Overall, as fluorescence-based biosensors continue to diversify and improve, we expect them to continue to be widely used as reliable and fruitful tools for gaining deeper insights into cellular and organismal function. PMID- 24485764 TI - Removal of bacteria from stallion semen by colloid centrifugation. AB - Bacteria (environmental contaminants and occasionally potential pathogens) are found in most stallion ejaculates and may negatively affect sperm quality during storage. Since the use of antibiotics can lead to the development of resistance, an alternative means of microbial control is desirable. The removal of bacteria from stallion semen using Single Layer Centrifugation through Androcoll-E was investigated. Known doses of cultured bacteria were added to freshly collected ejaculates (15mL aliquots) before processing by Single Layer Centrifugation. The resulting sperm pellets and controls (not processed by Single Layer Centrifugation) were cultured and the bacteria identified. In experiment 1, doses of E. coli from 2*10(2) to 2*10(7) colony forming units were added to aliquots of semen. In experiment 2, Taylorella equigenitalis or a mix of E. coli, Klebsiella pneumoniae and Streptococcus equi subsp. zooepidemicus (approximately 7*10(6), 5*10(6), and 6*10(6)cfu, respectively) were added to 15mL aliquots of semen. In experiment 1, more than 90% of the bacteria were removed where loading doses were >*10(4)cfu/mL. In experiment 2, varying proportions of different bacteria were removed, ranging from 68% for naturally occurring Corynebacterium spp. to >97% for added cultured E. coli. Thus, Single Layer Centrifugation can separate spermatozoa from many, but not all bacteria in stallion ejaculates and could be a useful alternative to adding antibiotics to semen extenders to control bacterial contamination. However, further research is needed to determine the effect of small numbers of bacteria on sperm quality. PMID- 24485763 TI - Distinct prion strains are defined by amyloid core structure and chaperone binding site dynamics. AB - Yeast prions are self-templating protein-based mechanisms of inheritance whose conformational changes lead to the acquisition of diverse new phenotypes. The best studied of these is the prion domain (NM) of Sup35, which forms an amyloid that can adopt several distinct conformations (strains) that produce distinct phenotypes. Using magic-angle spinning nuclear magnetic resonance spectroscopy, we provide a detailed look at the dynamic properties of these forms over a broad range of timescales. We establish that different prion strains have distinct amyloid structures, with many side chains in different chemical environments. Surprisingly, the prion strain with a larger fraction of rigid residues also has a larger fraction of highly mobile residues. Differences in mobility correlate with differences in interaction with the prion-partitioning factor Hsp104 in vivo, perhaps explaining strain-specific differences in inheritance. PMID- 24485765 TI - Second primary cancers after radiation for prostate cancer: a systematic review of the clinical data and impact of treatment technique. AB - The development of a radiation induced second primary cancer (SPC) is one the most serious long term consequences of successful cancer treatment. This review aims to evaluate SPC in prostate cancer (PCa) patients treated with radiotherapy, and assess whether radiation technique influences SPC. A systematic review of the literature was performed to identify studies examining SPC in irradiated PCa patients. This identified 19 registry publications, 21 institutional series and 7 other studies. There is marked heterogeneity in published studies. An increased risk of radiation-induced SPC has been identified in several studies, particularly those with longer durations of follow-up. The risk of radiation induced SPC appears small, in the range of 1 in 220 to 1 in 290 over all durations of follow-up, and may increase to 1 in 70 for patients followed up for more than 10 years, based on studies which include patients treated with older radiation techniques (i.e. non-conformal, large field). To date there are insufficient clinical data to draw firm conclusions about the impact of more modern techniques such as IMRT and brachytherapy on SPC risk, although limited evidence is encouraging. In conclusion, despite heterogeneity between studies, an increased risk of SPC following radiation for PCa has been identified in several studies, and this risk appears to increase over time. This must be borne in mind when considering which patients to irradiate and which techniques to employ. PMID- 24485766 TI - Conventional margins not sufficient for post-prostatectomy prostate bed coverage: an analysis of 477 cone-beam computed tomography scans. AB - PURPOSE: To study prostate bed deformation, and compare coverage by 5 mm and 10mm posterior expansion PTV margins. METHOD: Fifty patients who completed post prostatectomy radiotherapy had two expansion margins applied to the planning CT CTV: PTV10 (10 mm isometrically) and PTV5 (5 mm posteriorly, 10 mm all other directions). The CTV was then contoured on 477 pre-treatment CBCTs, and PTV5 and PTV10 coverage of each CBCT-CTVs was assessed. The maximum distance from the planning CT CTV to the combined CTV of all CBCTs including the planning CT CTV was measured for the superior part of the prostate bed, and the inferior part of the prostate bed, for every patient. RESULTS: The mean difference between largest and smallest CBCT-CTVs per patient was 18.7 cm(3) (range 6.3-34.2 cm(3)). Out of 477 CBCTs, there were 43 anterior geometric geographical misses for either PTV with a mean volume of 2.25 cm(3) (range 0.01-18.88 cm(3)). For PTV10, there were 26 posterior geometric geographical misses with a mean volume of 1.37 cm(3) (0.01 11.02 cm(3)). For PTV5, there were 46 posterior geometric geographical misses with a mean volume of 3.22 cm(3) (0.01-19.82 cm(3)). The maximum edge-to-edge distance for the superior prostate bed was anterior 19 mm, posterior 16 mm, left and right 7 mm. The maximum edge-to-edge distance for the inferior prostate bed was anterior 4mm, posterior 12 mm, left and right 7 mm. CONCLUSION: This study supports differential margins for the superior and inferior portions of the prostate bed. Because of the large deformation of CTV volume seen, adaptive radiotherapy solutions should be investigated further. PMID- 24485767 TI - The mutation of DBC2 in breast cancer patients from the Han ethnic group in Eastern China. AB - OBJECTIVE: To investigate DBC2 mutations in breast cancer patients and evaluate the relationship between gene mutations and breast cancer susceptibility in an Eastern China population. METHODS: Mutation analyses of 285bp promoter sequence, coding exon 7 and its exon/intron boundaries of DBC2 were performed in 32 breast cancer specimens by polymerase chain reaction and direct sequencing. Eighteen benign breast tumor specimens were also analyzed as control. RESULTS: No mutation in the promoter or exon 7 was found in either group. An intronic alteration (IVS7+53C>G) was detected in 13 specimens. There was no significant difference in the rate of IVS7+53C>G alteration between the study and control groups (8/32 vs 5/18, respectively, P>0.05). The G allele of IVS7+53 was correlated with HER2 and p53 expression (P<0.05), but not with age, tumor size, lymph node metastasis, ER or PR expression (P>0.05). CONCLUSION: Mutation in the promoter and exon 7 of DBC2 gene is not common in the Chinese population and may not contribute to the susceptibility for breast cancer in China. The intronic alteration IVS7+53C>G is a common polymorphism in the Chinese Han ethnic group. Further research is warranted to evaluate the relationship between IVS7+53C>G and the susceptibility for breast cancer. PMID- 24485768 TI - Environmental hypoxia but not minor shell damage affects scope for growth and body condition in the blue mussel Mytilus edulis (L.). AB - The effects of short-term (7 d) exposure to environmental hypoxia (2.11 mg O2 L 1; control: 6.96 mg O2 L-1) and varying degrees of shell damage (1 or 2, 1 mm diameter holes; control: no holes) on respiration rate, clearance rate, ammonia excretion rate, scope for growth (SFG) and body condition index were investigated in adult blue mussels (Mytilus edulis). There was a significant hypoxia-related reduction in SFG (>6.70 to 0.92 J g-1 h-1) primarily due to a reduction in energy acquisition as a result of reduced clearance rates during hypoxia. Shell damage had no significant affect on any of the physiological processes measured or the SFG calculated. Body condition was unaffected by hypoxia or shell damage. In conclusion, minor physical damage to mussels had no effect on physiological energetics but environmental hypoxia compromised growth, respiration and energy acquisition presumably by reducing feeding rates. PMID- 24485769 TI - Immunohistochemical localization of Toll-like receptor 2 in skin Langerhans' cells of striped dolphin (Stenella coeruleoalba). AB - The skin is the primary interface between the body and the environment, and has a central role in host defence. In the epidermis, Langerhans' cells form an interconnecting network of dendritic cells, that play a central role within inflammatory and immune responses of terrestrial and aquatic mammals, but few studies aimed at their characterization have been carried out in cetaceans, so far. Toll-like receptors are crucial players in the innate immune response to microbial invaders. These receptors are expressed on immune cells, such as monocytes, macrophages, dendritic cells, and granulocytes. The aim of this preliminary study was to describe the expression of Toll-like receptor 2 in a stranded striped dolphin (Stenella coeruleoalba) skin. Immunoreactive cells were predominantly found within the stratified squamous epithelium. Other Toll-like receptor 2 positive cells of varying morphology, were found, and may help to increase the knowledge on the interaction occurring between dolphins and the environment in which they live at their most crucial interface: the skin. PMID- 24485770 TI - Recurrent catheter related bloodstream infections by Candida glabrata: successful treatment with taurolidine. PMID- 24485771 TI - Response to the letter to the editor - practical considerations in choosing a taurolidine containing catheter lock solution. PMID- 24485772 TI - Reply of letter to the editor - nutritional risk screening and its clinical significance in hospitalized children. PMID- 24485773 TI - Evaluation of three indirect calorimetry devices in mechanically ventilated patients: which device compares best with the Deltatrac II((r))? A prospective observational study. AB - BACKGROUND & AIMS: Indirect calorimetry (IC) is the gold standard to measure energy expenditure (EE) in hospitalized patients. The popular 30 year-old Deltatrac II((r)) (Datex) IC is no more commercialized, but other manufacturers have developed new devices. This study aims at comparing for the first time simultaneously, two new IC, the CCM express((r)) (Medgraphics) and the Quark RMR((r)) (Cosmed) with the Deltatrac II((r)) to assess their potential use in intensive care unit (ICU) patients. METHODS: ICU patients on mechanical ventilation, with positive end-expiratory pressure <9 cm H2O and fraction of inspired oxygen <60%, underwent measurements by the three IC simultaneously connected during 20 min to the ventilator (Evita XL((r)), Drager). Patients' characteristics, VO2 consumption, VCO2 production, respiratory quotient and EE were recorded. Data were presented as mean (SD) and compared by linear regression, repeated measure one-way ANOVA and Bland & Altman diagrams. RESULTS: Forty patients (23 males, 60(17) yrs, BMI 25.4(7.0) kg/m(2)) were included. For the Deltatrac II((r)), VO2 was 227(61) ml/min, VCO2 189(52) ml/min and EE 1562(412) kcal/d. VO2, VCO2, and EE differed significantly between Deltatrac II((r)) and CCM express((r)) (p < 0.001), but not between Deltatrac II((r)) and Quark RMR((r)). For EE, diagrams showed a mean difference (2SD) of 25.2(441) kcal between Deltatrac II((r)) vs. the Quark RMR((r)), and -273 (532) kcal between Deltatrac II((r)) vs CCM express((r)). CONCLUSION: Quark RMR((r)) compares better with Deltatrac II((r)) than CCM express((r)), but it suffers an EE variance of 441 kcal, which is not acceptable for clinical practice. New indirect IC should be further improved before recommending their clinical use in ICU. PMID- 24485774 TI - Socio-demographic influences on epilepsy outcomes in an inner-city population. AB - PURPOSE: Previous studies show anti-epileptic drug compliance and seizure control in people with epilepsy (PWE) to be lower among low-income groups and African Americans. We examined how socio-demographic factors influence seizure control in an inner-city population. METHODS: The clinic records of 193 PWE were analyzed. Good seizure control was defined as no seizures in the previous year. Bivariate and multivariate analyses were performed to examine the effects of race, age, gender, median household income, medication cost, and insurance status on good seizure control. RESULTS: There were 69 Caucasians and 124 African-Americans (age 47.8+/-16.5 years) in the study. African Americans had a significantly lower income than Caucasians (p<0.001); but did not have inferior seizure control (p=0.18). Seizure control was also not affected by gender (p=0.82), AED costs (p=0.06), insurance type (p=0.20), or race-independent household income (p=0.75). CONCLUSION: Contrary to prior literature, we find that in our population of PWE there were no significant effects of race or family income on seizure outcomes. Our findings add to the existing literature on socio-demographic disparities in PWE and merit further exploration by other groups. PMID- 24485775 TI - Anatomic characteristics of aortic transection: centerline analysis to facilitate graft selection. AB - BACKGROUND: Traumatic transection of the thoracic aorta is a life-threatening complication that most commonly occurs after high-speed motor vehicle collisions. Although such injuries were previously treated with open surgical reconstruction, they are now more commonly being treated with endovascularly placed stent grafts. Unfortunately, most stent grafts are designed for treating aortic aneurysmal disease instead of traumatic injury. Further refinements in stent graft technology depend on a thorough anatomic understanding of the transection injury process. METHODS: All patients with computed tomography (CT) evidence of blunt aortic injury (BAI) between 2006 and 2012 at a Level 1 trauma center were queried. Their initial CT scans were imported into the Intuition (Terarecon, Inc.) viewing program, and off-line centerline reconstruction was performed. Standard demographic data were collected in addition to anatomic characteristics, including aortic diameters and the relationship of the injury to the arch vessels. RESULTS: Thirty-five patients were identified. Three patients were injured proximal to the left subclavian artery. The average length from the left subclavian artery to the proximal site of injury was 16.2 mm (range 2-31 mm). Most patients had >15 mm of landing zone beyond the left subclavian artery. The range of proximal diameters ranged from 17 to 32 mm, with an average aortic diameter of 23.9 mm. The average length of injured aortic segment was 27 mm. CONCLUSIONS: In this contemporary series from a large trauma center, 91% of patients are anatomically able to be treated with a stent graft that does not require coverage of the left common carotid artery. Most patients have an aortic diameter that falls between 21 and 26 mm in diameter, as well as a short segment of injured artery. Centers interested in emergently treating aortic transections are able to do so while maintaining a limited stock of stent grafts that can be used to treat the majority of the population. PMID- 24485776 TI - Effect of conditioning on visceral organs during indirect ischemia/reperfusion injury. AB - BACKGROUND: The mortality and morbidity rates of even extensive thoracoabdominal replacement have improved markedly in recent years. We investigated the effects of a temporary occlusion of the aorta as a direct precondition and temporary occlusion of the axillary artery for remote preconditioning to determine any effects that preconditioning may have on indirect (nonischemic) injuries to visceral organs (indirect effects of remote ischemia/reperfusion injury). METHODS: Thirty-seven New Zealand white rabbits were divided into five groups: controls (sham-operated; group 1); direct ischemia to the infrarenal aorta without preconditioning (group 2); direct ischemic preconditioning to the infrarenal aorta (group 3); remote ischemic preconditioning before clamping the infrarenal aorta (group 4); and simultaneous direct aortic and remote ischemic preconditioning before the clamping and during clamping of the infrarenal aorta (group 5). We used a 30-minute ischemia period for aortic occlusion for spinal cord ischemia/reperfusion. The axillary artery was used for remote preconditioning. After 24 hours, tissue specimens of the internal organs were obtained. RESULTS: Myocardial congestion was the main pathology detected in all groups. Histopathologic evaluation of tissue samples taken from the hearts showed no significant differences in terms of the degree of polymorphonuclear leukocyte (PMNL) infiltration and edema between the groups. Lung congestion and pneumonic cell infiltration were detected in all the groups. Pneumonic cell infiltration was significantly high in groups 2 and 3. Cell infiltration was lowest in group 4 at 71.4% of normal values, which differed from the normal values of 25-33.3% in the other groups (P < 0.05). Although there is a difference between the groups in case of renal congestion, there is not any difference as tubular damage and PMN. There was a significant difference with regard to renal congestion between groups 2 and 3. Renal congestion was normal in 80% of the kidneys in group 3. This differed from the normal values observed in the other groups (14.3-57.1%, P < 0.05). Liver congestion was detected in all groups. CONCLUSIONS: Different preconditioning methods may play an important role in distinct organ injuries during aortic cross-clamping. The visceral organs that exhibited positive and constructive results with direct and remote preconditioning included the lungs and kidneys during indirect ischemia/reperfusion injury. Remote ischemic conditioning was determined to be especially advantageous as a protection method, due to the fact that it is easy to use and effective for indirect ischemia/reperfusion injury. PMID- 24485777 TI - A randomized, controlled animal trial demonstrating the feasibility and safety of the MagellanTM endovascular robotic system. AB - BACKGROUND: The success of remotely steerable catheters designed for cardiac ablation procedures in the peripheral vasculature (in the laboratory and in highly select live cases) has led to the development of a vascular robotic system designed specifically for use in the arterial and venous systems. Limited bench top and animal testing has been successful, but no randomized, controlled study of the system's safety has been performed. METHODS: In a 3-phase study, we performed a randomized, controlled trial comparing standard manual catheterization and balloon angioplasty of visceral, renal, and contralateral lower extremity vessels in a porcine model. We also demonstrated feasibility of standard device deployment through the system. RESULTS: There was 100% technical success in test (robotic) and control (manual) arm cannulation and balloon angioplasty of all target vessels, without complications. Pathologic analysis at 7 days revealed significantly fewer traumatic lesions in the test animal arm as compared with the control arm (P < 0.001) and, by 30 days, all lesions had healed in both groups. There was 100% success in delivery of standard devices (balloons and stents) without complications. CONCLUSIONS: Remotely steerable robotic catheters are at least as safe as manual catheter techniques, and may prove less traumatic to peripheral vessels. Standard devices can be deployed through the system, and the stability of the platform may aid in ease of device delivery in difficult vascular segments. PMID- 24485778 TI - Effects of cilostazol on oxidative stress, systemic cytokine release, and spinal cord injury in a rat model of transient aortic occlusion. AB - BACKGROUND: Cilostazol is a phosphodiesterase inhibitor that has anti inflammatory potential in addition to vasodilator and antiplatelet effects. The aim of this study was to determine the influence of cilostazol on biochemical markers of oxidative damage, proinflammatory cytokine release, and spinal cord injury after transient aortic occlusion in rats. METHODS: Animals were randomized into 3 groups. Sham group rats were subjected to laparotomy without aortic occlusion. Control group rats were pretreated with intraperitoneal dimethyl sulfoxide, and cilostazol group rats received intraperitoneal cilostazol (20 mg/kg/day) for 3 days before the induction of ischemia. Ischemia was induced by clamping of the infrarenal aorta, and 48 hours after reperfusion, Tarlov grades were assessed and spinal cord conduction velocities (SCCVs) were measured using epidural electrical stimulation. Erythrocyte superoxide dismutase (SOD) and catalase activities and plasma malondialdehyde, serum tumor necrosis factor alpha, interleukin-1beta, and interleukin-6 levels were analyzed. Spinal cord histopathology was examined to determine neuronal damage and tissue inflammation. RESULTS: Aortic occlusion caused significant increases in SOD, catalase activities, and malondialdehyde and cytokine levels accompanied by spinal cord injury. Cilostazol significantly reduced malondialdehyde levels but did not significantly alter the activations of antioxidant enzymes, levels of proinflammatory cytokines, or histologic severity of inflammation. The differences regarding the results of Tarlov grading, SCCVs, and neuronal viability between the ischemic and cilostazol pretreated groups were statistically nonsignificant. CONCLUSION: The present experimental study indicated that cilostazol pretreatment used in this study before aortic occlusion decreased lipid peroxidation, which may be related to the reduction of reactive oxygen species. Cilostazol did not significantly suppress systemic cytokine release and prevent spinal cord inflammation and injury; however, it did show some benefit. Additional investigations might be needed to determine the critical dose of cilostazol for clarifying the protective role of this drug in spinal cord ischemia/reperfusion injury. PMID- 24485779 TI - Sarcomas of the aorta: a systematic review and pooled analysis of published reports. AB - BACKGROUND: Aortic sarcomas are rare and aggressive tumors with a propensity for arterial embolization, disseminated metastases, and rapid clinical deterioration. Overall, little is known about the evaluation and management of this disease. METHODS: A systematic review and pooled analysis were performed from a comprehensive search of the MEDLINE database for reports of primary aortic sarcomas published in the English language. RESULTS: One hundred sixty-five cases were analyzed. The median age was 60 years, and the male:female ratio was 1.5:1. High tumor grade (87.3%), arterial embolization (46.7%), and metastatic disease at diagnosis (44.8%) were common. Typical histologies were undifferentiated (39.4%), angiosarcomatous (37%), leiomyosarcomatous (13.3%), and fibroblastic (7.3%). Management was diverse and included combinations of surgical resection (46.7%), palliative vascular surgeries (37.7%), chemotherapy (28.7%), and radiotherapy (14.7%). The median survival was 11 months, and the 1-, 3-, and 5 year survival rates were 46.7%, 17.1%, and 8.8%, respectively. On univariate analyses, metastatic disease at diagnoses, surgical resection, and chemotherapy were associated with survival. On multivariate analysis, only metastatic disease remained significant (P < 0.001). CONCLUSIONS: Aortic tumors are devastating malignancies with distinct clinical features from sarcomas at other sites. Although prognosis is poor overall, long-term survivors have been reported, and aggressive management with surgical resection and adjuvant therapy should be considered in medically suitable patients. High embolic rates suggest a potential role for prophylactic anticoagulation. PMID- 24485780 TI - [Lesions of the fingers]. PMID- 24485781 TI - Identification of a methoxynaphthalene scaffold as a core replacement in quinolizidinone amide M(1) positive allosteric modulators. AB - A series of methoxynaphthalene amides were prepared and evaluated as alternatives to quinolizidinone amide M1 positive allosteric modulators. A methoxy group was optimal for M1 activity and addressed key P-gp issues present in the aforementioned quinolizidinone amide series. PMID- 24485782 TI - Identification and biological evaluation of flavonoids from the fruits of Prunus mume. AB - This Letter describes the identification of potent antioxidant and anti osteoporosis agents from the fruits of Prunus mume. From the methanol extract, a novel flavan dimer, characterized as 2beta,3beta-epoxy-5,7,4'-trihydroxyflavan (4alpha->8)-epicatechin (1), was isolated along with five known flavonoids (2-6). Their structures were determined based on extensive spectroscopic analysis, including IR, HRESIMS, 1D- and 2D-NMR, and CD spectra. The antioxidant activities of compounds 1-6 were evaluated in terms of their peroxyl radical-scavenging (Trolox equivalent) and reducing capacities. All isolates showed potent peroxyl radical-scavenging and reducing activities at concentrations of 1-10 MUM. Among them, compounds 1 and 2 were the most active at 1 MUM. Anti-osteoporosis activities were investigated using both murine osteoblastic MC3T3-E1 cells and osteoclastic RAW 264.7 cells. Compounds 2, 3, and 6 significantly stimulated the differentiation of osteoblastic MC3T3-E1 cells to increase collagen synthesis or mineralization functions of osteoblasts. Compounds 1, 3, 4, and 6 significantly suppressed tartrate-resistant acid phosphatase (TRAP) activity in receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclastic RAW 264.7 macrophage cells. PMID- 24485783 TI - Antifungal ether diglycosides from Matayba guianensis Aublet. AB - Since the 1960s, fungal infections have become a major worldwide public health problem. Antifungal treatments have many limitations, such as toxicity and resistance. Matayba guianensis Aublet (Sapindaceae) was chemically investigated as part of our ongoing search for lead molecules against fungi in the Brazilian Cerrado biome. The ethanolic extract of M. guianensis root bark revealed the presence of two previously unreported ether diglycosides: matayoside E (1) and F (2) with anti Candida activity, along with two known compounds: cupanioside (3) and stigmasterol (4). PMID- 24485784 TI - 4'-Substituted pyrimidine nucleosides lacking 5'-hydroxyl function as potential anti-HCV agents. AB - Hepatitis C virus (HCV) infection is one of the major health problems worldwide. If left untreated, it leads to liver cirrhosis, liver cancer and death. Herein, we report synthesis and anti-HCV activity of a new class of pyrimidine nucleosides possessing a 4'-carboxymethyl (9-16, 21 and 23) or 4'-carboxamide function (17-19 and 24). Among these, 10-12 (EC50=33.1-42.4 MUM), 14 and 21 (EC50=43.4-59.5 MUM) exhibited potent activity in HCV-1a replicon cells without any toxicity to parent Huh-7 cells (CC50=>829-1055 MUM). The anti-HCV activities demonstrated by this unusual class of compounds were superior to that of ribavirin (EC50=81.9 MUM). Further, the most active analog, 12, was found to interact synergistically with ribavirin to inhibit HCV RNA replication. PMID- 24485785 TI - A new topical vasoconstrictor-based strategy for prevention of oral mucositis. AB - OBJECTIVE: In a new strategy, we sought to determine whether vasoconstriction and transient hypoxia of the mucosa during irradiation would prevent or suppress radiation-induced oral mucositis. STUDY DESIGN: Topical vasoconstrictor was applied once to the oral cavity; 20 minutes later hamsters or mice received 19 to 30 Gy to the mucosa. Oral mucositis was scored using functional assay, gross morphology, and histology of mucosal tissue over the next 12 to 16 days. RESULTS: A single application of phenylephrine (14 mM to 136 mM) 20 minutes before irradiation conferred highly significant (P < .001), dose-dependent suppression of weight loss, oral secretion, and histopathology of mucosa seen in mice treated with 0 mM phenylephrine + 19-Gy irradiation. Epinephrine, norepinephrine, and phenylephrine showed up to 100% radioprotective efficacy at concentrations that reflected their rank-ordered affinities for the alpha1-adrenergic receptor. CONCLUSIONS: Phenylephrine swish-and-spit application before radiotherapy, or multiple applications during chemotherapy, may provide a simple, cost-effective strategy for suppression of oral mucositis in patients undergoing radiotherapy, chemotherapy, or bone marrow transplant. PMID- 24485786 TI - Platelet-rich fibrin has a healing effect on chemotherapy-induced mucositis in hamsters. AB - OBJECTIVE: The aim of this study was to evaluate the healing effect of topically applied platelet-rich fibrin (PRF) on experimental oral mucositis induced by chemotherapy in hamsters. STUDY DESIGN: Oral mucositis was induced in 93 Syrian golden hamsters by an intraperitoneal injection of 5-fluorouracil, which was followed by light scratching of the cheek pouch. The hamsters were randomly divided into a PRF group, a fibrin group, and an untreated control group. The recovery stage of oral mucositis was evaluated through daily weighing, measurements of the ulcer area, histopathologic analysis, and a myeloperoxidase activity assay. RESULTS: The PRF group exhibited significant improvements in the size and histologic features of the ulcer and in the myeloperoxidase activity compared with the control group (P < .05). CONCLUSIONS: The current findings suggest the consideration for future clinical trials in humans. PMID- 24485788 TI - ? PMID- 24485789 TI - Retinitis pigmentosa sine pigmenti. Debut with macular oedema. AB - CASE REPORT: A 25-year-old woman, with metamorphopsia in her left eye of one year onset. The examination revealed a bilateral cystoid macular oedema (CME) and vascular attenuation. We describe the diagnostic tests, as well as differential diagnosis and treatment response with carbonic anhydrase inhibitors. DISCUSSION: The retinitis pigmentosa sine pigment is a subtype of atypical retinitis pigmentosa characterised by the absence of pigment deposits. The night blindness is milder, and perimetric and electroretinographic impairment is lower. CME is an important cause of central vision loss, and responds to anhydrase carbonic inhibitors. PMID- 24485787 TI - DNA cleavage enzymes for treatment of persistent viral infections: recent advances and the pathway forward. AB - Treatment for most persistent viral infections consists of palliative drug options rather than curative approaches. This is often because long-lasting viral DNA in infected cells is not affected by current antivirals, providing a source for viral persistence and reactivation. Targeting latent viral DNA itself could therefore provide a basis for novel curative strategies. DNA cleavage enzymes can be used to induce targeted mutagenesis of specific genes, including those of exogenous viruses. Although initial in vitro and even in vivo studies have been carried out using DNA cleavage enzymes targeting various viruses, many questions still remain concerning the feasibility of these strategies as they transition into preclinical research. Here, we review the most recent findings on DNA cleavage enzymes for human viral infections, consider the most relevant animal models for several human viral infections, and address issues regarding safety and enzyme delivery. Results from well-designed in vivo studies will ideally provide answers to the most urgent remaining questions, and allow continued progress toward clinical application. PMID- 24485791 TI - A biocleavable pullulan-based vector via ATRP for liver cell-targeting gene delivery. AB - Pullulan due to its specificity for liver has been widely exploited for biomedical applications. In this work, a tailor-made biocleavable pullulan-based gene vector (PuPGEA) with good hemocompatibility was successfully proposed via atom transfer radical polymerization (ATRP) for efficient liver cell-targeting gene delivery. A two-step method involving the reaction of hydroxyl groups of pullulan with cystamine was developed to introduce reduction-sensitive disulfide linked initiation sites of ATRP onto pullulan. The poly(glycidyl methacrylate) (PGMA) side chains prepared subsequently via ATRP were functionalized with ethanolamine (EA) to produce the resultant biocleavable comb-shaped PuPGEA vectors consisting of nonionic pullulan backbones and disulfide-linked cationic EA-functionalized PGMA (PGEA) side chains with plentiful secondary amine and nonionic hydroxyl units. The cationic PGEA side chains can be readily cleavable from the pullulan backbones of PuPGEA under reducible conditions. Due to the liver targeting performance of pullulan backbones, such PuPGEA vectors exhibited much higher gene transfection efficiency and cellular uptake rates in HepG2 cell lines than in Hella cell lines. In addition, in vitro transfection efficiency and uptake mechanism of polyplex in HepG2 cells were evaluated in the presence of different endocytosis inhibitors, indicating that the asialoglycoprotein receptor was involved in transfection process of hepatocytes. More importantly, in comparison with gold standard polyethylenimine (PEI, ~25 kDa), PuPGEA vectors possessed excellent hemocompatibility without causing undesirable hemolysis. Properly grafting short bioreducible PGEA polycation side chains from a liver cell-targeting pullulan backbone is an effective means to produce new hemocompatible polysaccharide-based gene delivery vectors. PMID- 24485790 TI - Spatial patterning of BMP-2 and BMP-7 on biopolymeric films and the guidance of muscle cell fate. AB - In the cellular microenvironment, growth factor gradients are crucial in dictating cell fate. Towards developing materials that capture the native microenvironment we engineered biomimetic films that present gradients of matrix bound bone morphogenetic proteins (BMP-2 and BMP-7). To this end layer-by-layer films composed of poly(L-lysine) and hyaluronan were combined in a simple microfluidic device enabling spatially controlled growth factor diffusion along the film. Linear long-range gradients of both BMPs induced the trans differentiation of C2C12 myoblasts towards the osteogenic lineage in a dose dependent manner with a different signature for each BMP. The osteogenic marker alkaline phosphatase (ALP) increased in a linear manner for BMP-7 and non linearly for BMP-2. Moreover, an increased expression of the myogenic marker troponin T was observed with decreasing matrix-bound BMP concentration, providing a substrate that it is both osteo- and myo-inductive. Lastly, dual parallel matrix-bound gradients of BMP-2 and -7 revealed a complete saturation of the ALP signal. This suggested an additive or synergistic effect of the two BMPs. This simple technology allows for determining quickly and efficiently the optimal concentration of matrix-bound growth factors, as well as for investigating the presentation of multiple growth factors in their solid-phase and in a spatially controlled manner. PMID- 24485792 TI - The effect of retinal pigment epithelial cell patch size on growth factor expression. AB - The spatial organization of retinal pigment epithelial (RPE) cells grown in culture was controlled using micropatterning techniques in order to examine the effect of patch size on cell health and differentiation. Understanding this effect is a critical step in the development of multiplexed high throughput fluidic assays and provides a model for replicating disease states associated with the deterioration of retinal tissue during age-related macular degeneration (AMD). Microcontact printing of fibronectin on polystyrene and glass substrates was used to promote cell attachment, forming RPE patches of controlled size and shape. These colonies mimic the effect of atrophy and loss-of-function that occurs in the retina during degenerative diseases such as AMD. After 72 h of cell growth, levels of vascular endothelial growth factor (VEGF), an important biomarker of AMD, were measured. Cells were counted and morphological indicators of cell viability and tight junction formation were assessed via fluorescence microscopy. Up to a twofold increase of VEGF expression per cell was measured as colony size decreased, suggesting that the local microenvironment of, and connections between, RPE cells influences growth factor expression leading to the initiation and progression of diseases such as AMD. PMID- 24485794 TI - The role of fucosylation in the promotion of endothelial progenitor cells in neovascularization and bone repair. AB - Bone marrow-derived endothelial progenitor cells (EPCs) are being tested as a therapy to treat a variety of ischemic diseases. Poor homing to targeted tissues is one of the major factors limiting the therapeutic efficacy of EPCs. Here, we show that human cord blood-derived EPCs expressed little sialyl Lewis X (sLe(x)) antigen that is necessary for selectin-mediated cell-cell interactions. Expression of alpha1,3-fucosyltransferase VI (FucT VI) in the EPCs enhanced sLe(x) synthesis, E- and P-selectin-binding, and EPC adhesion to tumor necrosis factor-alpha-stimulated human umbilical vein endothelial cells in culture. In a mouse model of hind limb ischemia, in which EPCs were injected intravenously, FucT VI expression increased EPC homing, neovascularization, and blood flow in ischemic muscles. In another mouse model of femoral fracture, FucT VI-expressing EPCs were more efficient than control EPCs in targeting to peri-fracture tissues to enhance angiogenesis, blood flow and bone repair. These results indicate that fucosylated EPCs may be used to as an improved cellular source to treat ischemic diseases. PMID- 24485793 TI - The influence of a spatiotemporal 3D environment on endothelial cell differentiation of human induced pluripotent stem cells. AB - Current EC differentiation protocols are inefficient, and the phenotypes of the differentiated ECs are only briefly stable, which significantly inhibits their utility for basic science research. Here, a remarkably more efficient hiPSC-EC differentiation protocol that incorporates a three-dimensional (3D) fibrin scaffold is presented. With this protocol, up to 45% of the differentiated hiPSCs assumed an EC phenotype, and after purification, greater than 95% of the cells displayed the EC phenotype (based on CD31 expression). The hiPSC-ECs continued to display EC characteristics for 4 weeks in vitro. Gene and protein expression levels of CD31, CD144 and von Willebrand factor-8 (vWF-8) were significantly up regulated in differentiated hiPSC-ECs. hiPSC-ECs also have biological function to up-take Dil-conjugated acetylated LDL (Dil-ac-LDL) and form tubular structures on Matrigel. Collectively, these data demonstrate that a 3D differentiation protocol can efficiently generate ECs from hiPSCs and, furthermore, the differentiated hiPSC-ECs are functional and can maintain EC fate up to 4 weeks in vitro. PMID- 24485795 TI - Osseointegration of machined, injection moulded and oxygen plasma modified PEEK implants in a sheep model. AB - Machined and injection moulded polyetheretherketone (PEEK) implants with and without an oxygen plasma modification were prepared and implanted in sheep cancellous and cortical bone. After 4, 12 and 26 weeks, osseointegration was evaluated through mechanical push-out tests and histomorphometry. In the cancellous bone, push-out force increased with time, a trend toward higher force was observed for machined compared to moulded, and oxygen plasma modified compared to unmodified. On-going remodelling of the bone was detected in the periphery of the implants at 4 weeks. Minimal or no inflammation was observed with all the implants at all locations and time-points. Bone-implant contact (BIC) was quantified at all-time points and locations for all the four PEEK implant surfaces. The BIC values ranged from 15 to 75% with an average of 29 +/- 13% in the cancellous bone and 25-65% with an average of 50 +/- 12% in the cortical bone. In the cortical bone the BIC increased significantly from 4 to 26 weeks. This in vivo study has identified that surface topography of PEEK implants influences osseointegration. In addition, oxygen plasma has the potential to increase bone-implant interface stability. This study provides a unique reference for further modifications and in vivo assessment of PEEK implants. PMID- 24485796 TI - Progestogens in postmenopausal hormone therapy and the risk of breast cancer. AB - Hormone therapy is the treatment of choice for the alleviation of menopausal symptoms and the treatment of urogenital atrophy. In women with an intact uterus a progestogen must be added to estrogen therapy to prevent endometrial hyperplasia and cancer. There is a wide variety of marketed progestogens which differ in their pharmacological properties according to their structure. Convincing evidence from both clinical trials and epidemiological studies indicates that combined estrogen-progestogen therapy confers a higher risk of breast cancer compared to estrogen monotherapy. Concerning the different types of progestogens, data from large observational studies suggest that natural progesterone and dydrogesterone are associated with a lower risk of breast cancer compared with the other progestins. Observational studies, furthermore, indicate that sequential estrogen-progestogen regimens may lead to a lower risk elevation compared to continuous regimens. The effect of tibolone on breast cancer is unclear. Concluding, both the type of the progestogen and the mode of HT administration may have an impact on breast cancer risk. PMID- 24485797 TI - Austerity and health. PMID- 24485798 TI - Gene expression signatures of primary and metastatic uterine leiomyosarcoma. AB - Leiomyosarcoma (LMS) is the most common uterine sarcoma. Although the disease is relatively rare, it is responsible for considerable mortality due to frequent metastasis and chemoresistance. The molecular events related to LMS metastasis are unknown to date. The present study compared the global gene expression patterns of primary uterine LMSs and LMS metastases. Gene expression profiles of 13 primary and 15 metastatic uterine LMSs were analyzed using the HumanRef-8 BeadChip from Illumina. Differentially expressed candidate genes were validated using quantitative real-time polymerase chain reaction (PCR) and immunohistochemistry. To identify differently expressed genes between primary and metastatic tumors, we performed one-way analysis of variance with Benjamini Hochberg correction. This led to identification of 203 unique probes that were significantly differentially expressed in the 2 tumor groups by greater than 1.58 fold with P < .01, of which 94 and 109 were overexpressed in primary and metastatic LMSs, respectively. Genes overexpressed in primary uterine LMSs included OSTN, NLGN4X, NLGN1, SLITRK4, MASP1, XRN2, ASS1, RORB, HRASLS, and TSPAN7. Genes overexpressed in LMS metastases included TNNT1, FOLR3, TDO2, CRYM, GJA1, TSPAN10, THBS1, SGK1, SHMT1, EGR2, and AGT. Quantitative real-time PCR confirmed significant anatomical site-related differences in FOLR3, OSTN, and NLGN4X levels; and immunohistochemistry showed significant differences in TDO2 expression. Gene expression profiling differentiates primary uterine LMSs from LMS metastases. The molecular signatures unique to primary and metastatic LMSs may aid in understanding tumor progression in this cancer and in providing a molecular basis for prognostic studies and therapeutic target discovery. PMID- 24485799 TI - Romidepsin induces cell cycle arrest, apoptosis, histone hyperacetylation and reduces matrix metalloproteinases 2 and 9 expression in bortezomib sensitized non small cell lung cancer cells. AB - Histone deacetylase (HDAC) inhibitors have been proven to be effective therapeutic agents to kill cancer cells through inhibiting HDAC activity or altering the structure of chromatin. We recently reported that chemotherapy by the HDAC inhibitor, romidepsin activates the anti- apoptotic transcription factor NF-kappaB in A549 non-small cell lung cancer (NSCLC) cells and fails to induce significant levels of apoptosis. We also demonstrated that NF-kappaB inhibition with proteasome inhibitor bortezomib enhanced HDAC inhibitor induced mitochondrial injury and sensitize A549 NSCLC cells to apoptosis through the generation of reactive oxygen species. In this study, we investigate whether combined treatment with romidepsin and bortezomib would induce apoptosis in A549 NSCLC cells by activating cell cycle arrest, enhanced generation of p21 and p53, down-regulation of matrix metalloproteinases (MMPs) 2,9 also altering the acetylation status of histone proteins. Our data show that combination of romidepsin and bortezomib caused cell cycle arrest at Sub G0-G1 transition, up regulation of cell cycle protein p21 and tumour suppressor protein p53. In addition, romidepsin down-regulated the expression of MMP-2,9 and hyperacetylation of histone H3 and H4 in bortezomib sensitised A549 NSCLC cells. From this study we concluded that romidepsin and bortezomib cooperatively inhibit A549 NSCLC cell proliferation by altering the histone acetylation status, expression of cell cycle regulators and MMPs. Romidepsin along with bortezomib might be an effective treatment approach for A549 NSCLC cells. PMID- 24485800 TI - Modafinil combined with cognitive training is associated with improved learning in healthy volunteers--a randomised controlled trial. AB - Improving cognition in people with neuropsychiatric disorders remains a major clinical target. By themselves pharmacological and non-pharmacological approaches have shown only modest effects in improving cognition. In the present study we tested a recently-proposed methodology to combine CT with a 'cognitive-enhancing' drug to improve cognitive test scores and expanded on previous approaches by delivering combination drug and CT, over a long intervention of repeated sessions, and used multiple tasks to reveal the cognitive processes being enhanced. We also aimed to determine whether gains from this combination approach generalised to untrained tests. In this proof of principle randomised-controlled trial thirty-three healthy volunteers were randomised to receive either modafinil or placebo combined with daily cognitive training over two weeks. Volunteers were trained on tasks of new-language learning, working memory and verbal learning following 200 mg modafinil or placebo for ten days. Improvements in trained and untrained tasks were measured. Rate of new-language learning was significantly enhanced with modafinil, and effects were greatest over the first five sessions. Modafinil improved within-day learning rather than between-day retention. No enhancement of gains with modafinil was observed in working memory nor rate of verbal learning. Gains in all tasks were retained post drug-administration, but transfer effects to broad cognitive abilities were not seen. This study shows that combining CT with modafinil specifically elevates learning over early training sessions compared to CT with placebo and provides a proof of principle experimental paradigm for pharmacological enhancement of cognitive remediation. PMID- 24485801 TI - A population-based overview of sequences of targeted therapy in metastatic renal cell carcinoma. AB - BACKGROUND: Several TTs are available to treat mRCC; however, the optimal sequence of therapy remains unknown. PATIENTS AND METHODS: Consecutive population based samples of patients with mRCC treated with TT were collected from 12 cancer centers via the International Metastatic Renal Cell Carcinoma Database Consortium. Patient characteristics, first-line and second-line progression-free survival rates and overall survival data were collected based on sequencing of TT. Multivariable analysis was performed when there were significant differences on univariable analysis. RESULTS: A total of 2106 patients were included with a median follow-up of 36 months; 907 (43%) and 318 (15%) patients received subsequent second-line and third-line TT, respectively. Baseline characteristics were well matched among different sequences apart from more patients with non clear-cell histology in the vascular endothelial growth factor (VEGF) to mammalian target of rapamycin (mTOR) group compared with the VEGF to VEGF group sequence. When adjusting for the Heng risk criteria and non-clear-cell histology, the hazard ratio for death for the VEGF to mTOR group versus the VEGF to VEGF group was 0.833 (95% confidence interval [CI], 0.669-1.037; P = .1016). More specifically, the adjusted hazard ratio for death for the sunitinib to everolimus versus sunitinib to temsirolimus sequences was 0.774 (95% CI, 0.52-1.153; P = .2086). CONCLUSION: In this large multicenter analysis evaluating different sequences of TT in mRCC, no substantial effect on outcome based on sequence of TT was identified. PMID- 24485803 TI - Face validity and reliability of a pictorial instrument for assessing fundamental movement skill perceived competence in young children. AB - OBJECTIVES: To determine reliability and face validity of an instrument to assess young children's perceived fundamental movement skill competence. DESIGN: Validation and reliability study. METHODS: A pictorial instrument based on the Test Gross Motor Development-2 assessed perceived locomotor (six skills) and object control (six skills) competence using the format and item structure from the physical competence subscale of the Pictorial Scale of Perceived Competence and Acceptance for Young Children. Sample 1 completed object control items in May (n=32) and locomotor items in October 2012 (n=23) at two time points seven days apart. Children were asked at the end of the test-retest their understanding of what was happening in each picture to determine face validity. Sample 2 (n=58) completed 12 items in November 2012 on a single occasion to test internal reliability only. RESULTS: Sample 1 children were aged 5-7 years (M=6.0, SD=0.8) at object control assessment and 5-8 years at locomotor assessment (M=6.5, SD=0.9). Sample 2 children were aged 6-8 years (M=7.2, SD=0.73). Intra-class correlations assessed in Sample 1 children were excellent for object control (intra-class correlation=0.78), locomotor (intra-class correlation=0.82) and all 12 skills (intra-class correlations=0.83). Face validity was acceptable. Internal consistency was adequate in both samples for each subscale and all 12 skills (alpha range 0.60-0.81). CONCLUSIONS: This study has provided preliminary evidence for instrument reliability and face validity. This enables future alignment between the measurement of perceived and actual fundamental movement skill competence in young children. PMID- 24485802 TI - Different biological and prognostic breast cancer populations identified by FDG PET in sentinel node-positive patients: results and clinical implications after eight-years follow-up. AB - BACKGROUND: Sentinel node (SN) biopsy is the standard method to evaluate axillary node involvement in breast cancer (BC). Positron emission tomography with 2 (fluorine-18)-fluoro-2-deoxy-D-glucose (FDG-PET) provides a non-invasive tool to evaluate regional nodes in BC in a metabolic-dependent, biomolecular-related way. In 1999, we initiated a prospective non-randomized study to compare these two methods and to test the hypothesis that FDG-PET results reflect biomolecular characteristics of the primary tumor, thereby yielding valuable prognostic information. PATIENTS AND METHODS: A total of 145 cT1N0 BC patients, aged 24-70 years, underwent FDG-PET and lymphoscintigraphy before surgery. SN biopsy was followed in all cases by complete axillary dissection. Pathologic evaluation in tissue sections for involvement of the SN and other non-SN nodes served as the basis of the comparison between FDG-PET imaging and SN biopsy. RESULTS: FDG-PET and SN biopsy sensitivity was 72.6% and 88.7%, respectively, and negative predictive values were 80.5% and 92.2%, respectively. A subgroup of more aggressive tumors (ER-GIII, Her2+) was found mainly in the FDG-PET true-positive (FDG-PET+) patients, whereas LuminalA, Mib1 low-rate BCs were significantly undetected (p = 0.009) in FDG-PET false-negative (FDG-PET-) patients. Kaplan Meier survival estimates after a median follow-up of more than 8 years showed significantly worse overall survival for FDG-PET+ patients in node-positive (N+) patients (p = 0.035) as compared to N+/FDG-PET- patients, which overlapped with survival curves of N- and FDG-PET+ or - patients. CONCLUSIONS: Our findings suggest that FDG-PET results reflect intrinsic biologic features of primary BC tumors and have prognostic value with respect to nodal metastases. FDG-PET false negative cases appear to identify less aggressive indolent metastases. The possibility to identify a subgroup of N+ BC patients with an outcome comparable with N- BC patients could reduce the surgical and adjuvant therapeutic intervention. PMID- 24485805 TI - Comparison of percutaneous cryoablation with microwave ablation in a porcine liver model. AB - We compared imaging and pathological changes between argon-helium cryosurgical (AH) and microwave (MW) ablation in a porcine liver model. Immediately after ablation, computed tomography (CT) imaging showed that the area affected by MW ablation was considerably greater than that affected by AH ablation; moreover, the surface area of necrotic tissue was considerably greater in the AH group, whereas the depth of the necrotic area was similar. Seven days after ablation, the affected area had not changed much in the AH group, but it had significantly increased in the MW group; similarly, the surface and depth of the necrotic areas had not changed much in the AH group, but they had increased significantly in the MW group. The pathological findings showed similar definitive areas for both groups at both time points. The findings indicated that long time after both therapies, complete tissue necrosis can be achieved, but the extent and depth of necrosis differ: necrosis foci after AH ablation could be predicted by ice ball under CT image, and necrosis foci after MW ablation will increase obviously. MW ablation might therefore be suitable for tumors with a larger volume and simple anatomical structures, and AH ablation might be suitable for tumors with complex anatomical structures or those located near important organs. These two methods could therefore be used in combination in clinical settings, but details of the procedure need to be studied. PMID- 24485806 TI - [What is new about obstetrical interventions during labor and normal delivery?]. AB - This systematic review of the literature reports studies published over the last five years (2008-2013) about interventions during labor and normal delivery. The points made concerning active management of labor, interventions aimed at improving maternal comfort, management of occiput posterior fetal presentations, management of second stage of labor and prevention techniques for perineal lesions. Although obstetrics remains an "art" to which training is mainly based on experience and clinical expertise, this "art" at present cannot live without the evidence-based medicine. Numerous randomized trials published and in process, demonstrate awareness of this reality in our specialty. PMID- 24485804 TI - The transcription factor IRF8 activates integrin-mediated TGF-beta signaling and promotes neuroinflammation. AB - Recent epidemiological studies have identified interferon regulatory factor 8 (IRF8) as a susceptibility factor for multiple sclerosis (MS). However, how IRF8 influences the neuroinflammatory disease has remained unknown. By studying the role of IRF8 in experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we found that Irf8(-/-) mice are resistant to EAE. Furthermore, expression of IRF8 in antigen-presenting cells (APCs, such as macrophages, dendritic cells, and microglia), but not in T cells, facilitated disease onset and progression through multiple pathways. IRF8 enhanced alphavbeta8 integrin expression in APCs and activated TGF-beta signaling leading to T helper 17 (Th17) cell differentiation. IRF8 induced a cytokine milieu that favored growth and maintenance of Th1 and Th17 cells, by stimulating interleukin-12 (IL-12) and IL-23 production, but inhibiting IL-27 during EAE. Finally, IRF8 activated microglia and exacerbated neuroinflammation. Together, this work provides mechanistic bases by which IRF8 contributes to the pathogenesis of MS. PMID- 24485807 TI - [Reliability of endocervical curettage after conservative treatment of intraepithelial neoplasia of the cervix]. AB - OBJECTIVE: To evaluate the reliability of endocervical curettage (ECC) in patients previously treated for CIN. PATIENTS AND METHODS: Retrospective analysis of data from 85 patients between January 1985 and December 2011 who received an ECC during monitoring after treatment of CIN. The reliability of the ECC was evaluated by comparison with the final histological analysis of the surgical specimen or the data for subsequent cyto-colpo-histological follow-up. RESULTS: Patients were referred to colposcopy either within the immediate post-treatment monitoring (n=42), meanly 9.7+/-5.3 months after treatment, or if cytological abnormalities were detected during long-term monitoring, meanly 78.6+/-52.4 months after treatment. Colposcopy was unsatisfactory in 75.3% of patients and normal colposcopic findings were found in 80% of patients. A perfect agreement between the ECC and the endocervical final diagnosis was noted in 68 patients (80%). For the diagnosis of severe cervical lesions (CIN 2+) ECC had a sensitivity of 86.2% (68.3-96.1), a specificity of 94.6% (85.1-98.9) and positive and negative predictive values of 61.4% (47.6-74.0) and 93% (83.0-98.1), respectively. CONCLUSION: The high sensitivity and negative predictive value of ECC for the diagnosis of severe post-therapeutic endocervical lesions avoid iterative treatment without increasing the risk of progression of a lesion to cancer. PMID- 24485808 TI - Contribution of V/Q SPECT to planar scintigraphy in the diagnosis of pulmonary embolism. AB - AIM: To evaluate the feasibility of V/Q SPECT and analyze its contribution to planar V/Q lung scintigraphy in the diagnosis of pulmonary embolism (PE). MATERIAL AND METHODS: A total of 109 patients with suspected PE showing Wells score>2 and elevated D-dimer were studied. The V/Q could not be completed in 7 patients, so they were excluded. Ventilation and perfusion scans were done using Technegas and (99m)Tc-MAA. Planar study included 8 projections on a 256*256 matrix and 128 projections on a 128*128 matrix were acquired for the SPECT study, applying an iterative method. Planar images were interpreted according to modified PIOPED criteria, and SPECT by the guidelines of the EANMMI. The results with both techniques were compared. RESULTS: V/Q planar scintigraphy and SPECT could be performed in 102 patients. V/Q planar scintigraphy was considered "diagnostic" in 39 of the 102 patients, and "non-diagnostic" in 63. Of the 39 "diagnostic" studies, 31 were reported as high probability of PE and 8 as normal. Of the 63 "non-diagnostic", 26 corresponded to intermediate, 29 to low, and 8 to very low probability. The SPECT study was "diagnostic" in 97 and indeterminate in only 5. All patients with a high probability planar scintigraphy had a positive SPECT. In the 8 patients with a normal planar scintigraphy SPECT was negative in 5 and positive in 3. In the 63 patients with a "non-diagnostic" planar scintigraphy SPECT was "diagnostic" in 58 of them, positive in 17 and negative in 41. CONCLUSION: V/Q SPECT is a feasible technique as it was performed in 102 of the 109 patients who were enrolled in the study (94%). The addition of V/Q SPECT to planar V/Q decreases the number of "non-diagnostic" reports from 62% in planar scintigraphy to 4.9% in SPECT. Therefore, V/Q SPECT should be included in the diagnosis approach of PE due to its high diagnostic yield. PMID- 24485809 TI - A retrospective study of temporomandibular joint ankylosis secondary to surgical treatment of mandibular condylar fractures. AB - We investigated the incidence of ankylosis of the temporomandibular joint (TMJ) after open operations for fractures of the mandibular condyle, and analysed possible risk factors in a total of 385 patients with 492 condylar fractures who had been operated on in our department from 2001 to 2010. Sixteen patients developed postoperative ankylosis of the TMJ with 26 joints (5%) affected during a follow-up of 6 months-10 years. Of the 492 condylar fractures, the most common ones that were associated with postoperative ankylosis were those of the condylar head (20/248), followed by the condylar neck (6/193). Subcondylar fractures did not cause postoperative ankylosis (0/51). Among the 16 patients with postoperative ankylosis, 13 had associated anterior mandibular fractures. Long screw (bicortical screw) fixation of fractures of the condylar head seemed to be associated with a lower incidence of postoperative ankylosis than fixation by miniplate and wire or removal of the fractured fragment. The articular discs were damaged in all ankylosed joints, and the remaining fractured fragment was found in 10 ankylosed joints after fractures of the condylar head. The results suggest that fractures of the condylar head are more prone to lead to postoperative ankylosis of the TMJ, and that the possible risk factors seem to include the technique used for fixation and damage to the disc, together with an anterior mandibular fracture with the fractured fragment remaining. PMID- 24485810 TI - Risk of bleeding after dentoalveolar surgery in patients taking anticoagulants. AB - To avoid increasing the risk of thromboembolic events, it is recommended that treatment with anticoagulants should be continued during dentoalveolar operations. We have evaluated the incidence of bleeding after dentoalveolar operations in a prospective study of 206 patients, 103 who were, and 103 who were not, taking anticoagulants. Seventy-one were taking thrombocyte aggregation inhibitors and 32 vitamin K antagonists. Patients were treated according to guidelines developed at the Academic Centre for Dentistry Amsterdam (ACTA), The Netherlands. The operations studied included surgical extraction (when the surgeon had to incise the gingiva before extraction), non-surgical extraction, apicectomy, and placement of implants. Patients were given standard postoperative care and those taking vitamin K antagonists used tranexamic acid mouthwash postoperatively. No patient developed a severe bleed that required intervention. Seven patients (7%) taking anticoagulants developed mild postoperative bleeds. Patients taking vitamin K antagonists reported 3 episodes (9%) compared with 4 (6%) in the group taking thrombocyte aggregation inhibitors. Among patients not taking anticoagulants, two (2%) developed mild bleeding. The differences between the groups were not significant. All bleeding was controlled by the patients themselves with compression with gauze. We conclude that dentoalveolar surgery is safe in patients being treated with anticoagulants provided that the conditions described in the ACTA guidelines are met. PMID- 24485811 TI - Influence of gamma irradiation on uranium determination by Arsenazo III in the presence of Fe(II)/Fe(III). AB - Arsenazo III is a widely used reagent for the concentration measurement of uranium and other actinides in aqueous samples. This study indicates that, for routine aqueous samples, due to the strong complexing ability with Arsenazo III, Fe(III) can significantly decrease the UV-Vis absorbance of the U(VI)-Arsenazo III complex, whereas the influence of Fe(II) on the absorbance is negligible. However, when Fe(II) is present in a gamma-irradiated U(VI) aqueous sample, it can give rise to the Fenton reaction, which produces oxidizing radicals that decompose the subsequently added Arsenazo III, leading to a sharp decrease in the absorbance of the U(VI)-Arsenazo III complex. The decrease in absorbance depends on the iron content and irradiation dose. Furthermore, the oxidizing radicals from the Fenton reaction induced by gamma irradiation can be continually produced. Even if the irradiated solution has been aged for more than one month in the absence of light at room temperature and without the exclusion of oxygen, the reactivity of the radicals did not decrease toward the subsequently added Arsenazo III. This finding demonstrates that the presence of Fe(II) in gamma irradiated U(VI) aqueous samples can lead to incorrect U(VI) measurement using the Arsenazo III method, and a new method needs to be developed for the quantitative determination of U(VI) in the presence of gamma radiation and ferrous iron. PMID- 24485812 TI - Differential toxicity and uptake of Diazinon on embryo-larval development of Rhinella arenarum. AB - Diazinon, an anti-cholinesterase organophosphate, is an extensively used pesticide. The main objective of this work was to assess the lethal and sublethal effects of Diazinon and its comparison with the uptake by embryos and larvae of the common South American toad Rhinella arenarum by means of standardized bioassays during acute (96 h), short-term chronic (168 h) and chronic (504 h) exposures. Toxicity resulted time- and stage-dependent, thus the lethal concentration 50 for 96 h, 168 h and 504 h were 27.2; 20.1 and 6.8 mg Diazinon L( 1) for embryos and 8, 6.7 and 1.9 mg Diazinon L(-1) for larvae. It is noteworthy the remarkable differences found in the concentration which caused lethality with those causing adverse effects on development such as malformations (teratogenic effects). Therefore, the teratogenic index from 144 h was greater than two; the main adverse effects were axial flexures, irregular borders, wavy tail, microcephaly, malformed mouth and adhesive structures, gut miscoiling, underdeveloped gills, cloacal edema, desquamation and severe hydropsy. Moreover, the characteristic sublethal effect of Diazinon on larvae was abnormal behavior related to neurotoxicity with a NOEC-168 h of 4.5 mg Diazinon L(-1). Diazinon contents in R. arenarum were time-dependent and significantly related to exposure concentration for both embryos and larvae. Diazinon contents were also stage dependent, as it was up to 27 times higher for organisms exposed from blastula stage onwards than early larvae. These facts and the Hazard Quotients, a numerical expression of ecological risk, of 2.73, which is above USEPA's Level of Concern, showed the threat that Diazinon represents for R. arenarum populations. PMID- 24485813 TI - Influence of swine manure on growth, P uptake and activities of acid phosphatase and phytase of Polygonum hydropiper. AB - Excessive application of animal manure to the farmland results in enrichment of P in the soil. Phytoremediation is a promising strategy for extracting excess P from manure impacted soil. P uptake characteristics of a mining ecotype (ME) and a non-mining ecotype (NME) of Polygonum hydropiper were investigated in this study by adopting soil culture containing various concentrations of swine manure (0-200 g swine manure kg(-1) soil). A peak value in the biomass of P. hydropiper was determined in 100 g kg(-1) soil. Significant increase of P content in tissues of two ecotypes was noticed with an increase in swine manure concentration. Maximum P accumulation in shoots and roots was observed at the concentration of 100 g kg(-1) soil, however, the ME accumulated more P as compared to the NME. The ME showed a lower plant effective number and a higher P extraction ratio compared to the NME. Both acid phosphatase and phytase activities of P. hydropiper were obviously enhanced under swine manure impacted soil compared with control, while those of ME higher than the NMEs. Therefore, the two ecotypes of P. hydropiper can accumulate P from soil amended with swine manure and establishes the foundation for phytoremediation. PMID- 24485814 TI - Flame retardant associations between children's handwipes and house dust. AB - Polybrominated diphenyl ether (PBDE), flame retardants (FRs) have been ubiquitously detected at high concentrations in indoor environments; however, with their recent phase-out, more attention is being focused on measurements of exposure to alternative FRs such as organophosphate FRs (OPFRs). In our previous research, we found that PBDE residues measured on children's handwipes were a strong predictor of serum PBDE levels. Here we build upon this research to examine longitudinal changes in PBDEs in indoor dust and children's handwipes, and explore the associations between handwipes and dust for alternative FRs. Children from our previous study were re-contacted after approximately two years and new samples of indoor dust and handwipes were collected. PBDE dust-levels were significantly correlated between two different sampling rounds separated by two years; however, PBDE levels in handwipes were not correlated, perhaps suggesting that the sources of PBDEs remained relatively constant in the home, but that behavioral differences in children are changing with age and influencing handwipe levels. OPFRs [i.e. tris(1,3-dichloroisopropyl) phosphate (TDCPP), tris(2-chloroethyl) phosphate (TCEP), tris(2-chloroisopropyl) phosphate (TCIPP)], 2-ethylhexyl-2,3,4,5-tetrabromobenzoate (EH-TBB, also known as TBB), di(2 ethylhexyl) tetrabromophthalate (BEH-TEBP, also known as TBPH), and 1,2,5,6,9,10 hexabromocyclododecane (HBCD) were also ubiquitously detected in house dust samples and geometric mean levels were similar to PBDE levels, or higher in the case of the OPFRs. Significant associations between handwipes and house dust were observed for these alternative FRs, particularly for EH-TBB (rs=0.54; p<0.001). Increasing house dust levels and age were associated with higher levels of FRs in handwipes, and high hand washing frequency (>5 times d(-1)) was associated with lower FR levels in handwipes. Overall these data suggest that exposure to these alternative FRs will be similar to PBDE exposure, and the influence of hand-to mouth behavior in children's exposure needs to be further examined to better estimate exposure potential. PMID- 24485815 TI - Removal of endocrine-disrupting chemicals and conventional pollutants in a continuous-operating activated sludge process integrated with ozonation for excess sludge reduction. AB - Sludge ozonation is considered as a promising technology to achieve a complete reduction of excess sludge, but as yet its effects on the removal of endocrine disrupting chemicals (EDCs) and conventional pollutants (i.e., COD, N and P) in the activated sludge process are still unclear. In this study, two lab-scale continuous-operating activated sludge treatment systems were established: one was operated in conjunction with ozonation for excess sludge reduction, and the other was operated under normal conditions as control. The results indicate that an ozone dose of 100 mg O3 g(-1)SS led to a zero yield of excess sludge in the sludge-reduction system during a continuous-operating period of 45d. Although ozonation gave a relatively lower specific oxygen uptake rate of activated sludge, it had little effect on the system's removal performance of COD and nitrogen substances. As a plus, sludge ozonation contributed a little more removal of target EDCs (estrone, 17beta-estrodiol, estriol, 17alpha ethinylestradiol, bisphenol A, and 4-nonylphenol). However, the total phosphorus removal declined notably due to its accumulation in the sludge-reduction system, which necessitates phosphorus recovery for the activated sludge process. PMID- 24485816 TI - Assessment of Envi-CarbTM as a passive sampler binding phase for acid herbicides without pH adjustment. AB - The graphitised carbon solid phase extraction (SPE) sorbent Envi-Carb has been used to fabricate glass fibre filter- Envi-Carb "sandwich" disks for use as a passive sampler for acid herbicides. Passive sampler uptake of a suite of herbicides, including the phenoxyacetic acid herbicides 4-chloro-o-tolyloxyacetic acid (MCPA), 2,4-dichlorophenoxyacetic acid (2,4-D) and 3,6-dichloro-2 methoxybenzoic acid (Dicamba), was achieved without pH adjustment, demonstrating for the first time a suitable binding phase for passive sampling of acid herbicides at neutral pH. Passive sampling experiments with Duck River (Tasmania, Australia) water spiked at 0.5 MUg L(-1) herbicide concentration over a 7 d deployment period showed that sampling rates in Duck River water decreased for seven out of eight herbicides, and in the cases of 3,6-dichloro-2 pyridinecarboxylic acid (Clopyralid) and Dicamba no accumulation of the herbicides occurred in the Envi-Carb over the deployment period. Sampling rates for 4-amino-3,5,6-trichloro-2-pyridinecarboxylic acid (Picloram), 2,4-D and MCPA decreased to approximately 30% of the sampling rates in ultrapure water, whilst sampling rates for 2-(4,6-dimethylpyrimidin-2-ylcarbamoylsulfamoyl) benzoic acid, methyl ester (Sulfometuron-methyl) and 3,5,6-Trichloro-2-pyridinyloxyacetic acid (Triclopyr) were approximately 60% of the ultrapure water sampling rate. For methyl N-(2,6-dimethylphenyl)-N-(methoxyacetyl)-D-alaninate (Metalaxyl-M) there was little variation in sampling rate between passive sampling experiments in ultrapure water and Duck River water. SPE experiments undertaken with Envi-Carb disks using ultrapure water and filtered and unfiltered Duck River water showed that not only is adsorption onto particulate matter in Duck River water responsible for a reduction in herbicide sampling rate, but interactions of herbicides with dissolved or colloidal matter (matter able to pass through a 0.2 MUm membrane filter) also reduces the herbicide sampling rate. PMID- 24485818 TI - Subtypes of irritable bowel syndrome in children: prevalence at diagnosis and at follow-up. AB - OBJECTIVES: To assess the prevalence of irritable bowel syndrome (IBS) subtypes in childhood at diagnosis and their changes over 1 year. STUDY DESIGN: This is an observational, prospective, multicenter study. Consecutive pediatric patients with IBS, according to Rome III criteria, were enrolled over a 1-year period. Parents recorded weekly stool frequency and consistency and gastrointestinal and extraintestinal symptoms in a diary. Stool consistency was scored according to the Bristol Stool Form Scale. Children were evaluated after 2, 3, 6, and 12 months. RESULTS: We enrolled 100 children with IBS (median age 9.9 years, range 4.2-16.7 years, 52 girls and 48 boys). At time of enrollment, constipation-IBS was the prevalent subtype (45%), with a prevalence of girls at 62% (P < .005); diarrhea-IBS was reported in 26% of children, with a prevalence of boys at 69% (P < .005); and alternating-IBS was described in 29% of children, without a difference between sexes. During the follow-up, 10% of patients changed their IBS subtypes at 2 months, 9% at 3 months, 7% at 6 months, and 6.3% at 12 months. Twenty-four percent of patients changed IBS subtype between the time of enrollment and 12 months. CONCLUSIONS: Constipation-IBS is the prevalent subtype in children, with a higher frequency in girls. In boys, diarrhea-IBS is the most common subtype. It is important to acquire knowledge about IBS subtypes to design clinical trials that may eventually shed new light on suptype-specific approaches to this condition. PMID- 24485817 TI - Selected persistent organic pollutants in human placental tissue from the United States. AB - Emerging and legacy environmental pollutants such as polybrominated diphenyl ethers (PBDEs), polychlorinated biphenyls (PCBs) and organochlorine pesticide metabolite DDE are found in human placenta, indicating prenatal exposure, but data from the United States are sparse. We sought to determine concentrations of these compounds in human placentae as part of a formative research project conducted by the National Children's Study Placenta Consortium. A total of 169 tissue specimens were collected at different time points post delivery from 43 human placentae at three U.S. locations, and analyzed by gas chromatography coupled with mass spectrometry following extraction using matrix solid phase dispersion. PBDEs, PCBs, and DDE were detected in all specimens. The concentrations of 10 PBDEs (Sigma10PBDEs), 32 PCBs (Sigma32PCBs) and p,p'-DDE were 43-1723, 76-856 and 10-1968pgg(-1) wet weight, respectively, in specimens collected shortly after delivery. Significant geographic differences in PBDEs were observed, with higher concentrations in placentae collected in Davis, CA than in those from Rochester, NY or Milwaukee, WI. We combined these with other published data and noted first-order declining trends for placental PCB and DDE concentrations over the past decades, with half-lives of about 5 and 8years, respectively. The effect of time to tissue collection from refrigerated placentae on measured concentrations of these three classes of persistent organic pollutants was additionally examined, with no significant effect observed up to 120h. The results of this work indicate that widespread prenatal exposure to persistent organic pollutants in the United States continues. PMID- 24485819 TI - Longitudinal tracking of dual-energy X-ray absorptiometry bone measures over 6 years in children and adolescents: persistence of low bone mass to maturity. AB - OBJECTIVES: Early assessment of bone mass may be useful for predicting future osteoporosis risk if bone measures "track" during growth. This prospective longitudinal multicenter study examined tracking of bone measures in children and adolescents over 6 years to sexual and skeletal maturity. STUDY DESIGN: A total of 240 healthy male and 293 healthy female patients, ages 6-17 years, underwent yearly evaluations of height, weight, body mass index, skeletal age, Tanner stage, and dual-energy x-ray absorptiometry (DXA) bone measurements of the whole body, spine, hip, and forearm for 6 years. All subjects were sexually and skeletally mature at final follow-up. Correlation was performed between baseline and 6-year follow-up measures, and change in DXA Z-scores was examined for subjects who had baseline Z < -1.5. RESULTS: DXA Z-scores (r = 0.66-0.87) had similar tracking to anthropometric measures (r = 0.64-0.74). Tracking was stronger for bone mineral density compared with bone mineral content and for girls compared with boys. Tracking was weakest during mid- to late puberty but improved when Z-scores were adjusted for height. Almost all subjects with baseline Z < -1.5 had final Z-scores below average, with the majority remaining less than -1.0. CONCLUSIONS: Bone status during childhood is a strong predictor of bone status in young adulthood, when peak bone mass is achieved. This suggests that bone mass measurements in children and adolescents may be useful for early identification of individuals at risk for osteoporosis later in life. PMID- 24485821 TI - Neurocognitive evidence for revision of treatment targets and guidelines for phenylketonuria. AB - OBJECTIVES: To compare the neurocognitive outcomes of patients with phenylketonuria (PKU) to determine whether decreasing phenylalanine (Phe) levels to <240 is preferable to the use of 360 MUmol/L as an upper-target Phe level. An additional aim was to establish the influence of biochemical indices other than Phe on neurocognitive outcomes. STUDY DESIGN: Patients with PKU (n = 63; mean age 10.8 +/- 2.3 years) and healthy controls (n = 73; mean age 10.9 +/- 2.2 years) performed computerized tasks measuring neurocognitive functions (inhibitory control, cognitive flexibility, and motor control). Lifetime and concurrent blood Phe levels, Phe-to-tyrosine ratio (Phe:Tyr), and Phe variations were examined in relation to neurocognitive outcomes using nonparametric tests and regression analyses. RESULTS: Patients with PKU with Phe levels <=240 MUmol/L and healthy controls performed equally well. Patients with Phe levels between 240 and 360 MUmol/L and >=360 MUmol/L performed more poorly than did controls across tasks. Patients with Phe levels <=240 MUmol/L performed significantly better than patients with levels between 240 and 360 MUmol/L on tasks measuring inhibitory control and cognitive flexibility. Absolute Phe levels and Phe variation were the best predictors of motor control, whereas Phe:Tyr were the best predictors of inhibitory control. CONCLUSIONS: The results of this study suggest that upper Phe targets should be lowered to optimize neurocognitive outcomes. Moreover, Phe variation and Phe:Tyr appear to be of additional value in treatment monitoring. PMID- 24485820 TI - Significant hepatic involvement in patients with ornithine transcarbamylase deficiency. AB - OBJECTIVE: To determine the frequency of significant liver injury and acute liver failure (ALF) in patients with ornithine transcarbamylase deficiency (OTCD), the most common urea cycle defect. STUDY DESIGN: In this historical cohort study, charts of 71 patients with OTCD at 2 centers were reviewed to assess the prevalence of ALF (international normalized ratio [INR] >=2.0), liver dysfunction (INR 1.5-1.99), and hepatocellular injury (aspartate aminotransferase/alanine aminotransferase >=250 IU/L). RESULTS: More than one-half (57%) of the 49 patients with symptomatic OTCD had liver involvement; 29% met the criteria for ALF, 20% had liver dysfunction, and 8% had isolated hepatocellular injury. The prevalence of ALF was highest in the patients with more severe OTCD, including those with markedly elevated ammonia levels (>1000 MUmol/L). Some patients with severe liver involvement (INR >=2.0 and aspartate aminotransferase/alanine aminotransferase >1000 IU/L) had only moderate hyperammonemia (ammonia 100-400 MUmol/L). ALF was the initial presenting symptom of OTCD in at least 3 of 49 symptomatic patients with OTCD. CONCLUSION: Episodes of hepatocellular injury, liver dysfunction, and ALF were identified in a high proportion of children with symptomatic OTCD. The more severely affected patients had a higher likelihood of ALF. The diagnosis of a urea cycle defect should be considered in patients with unexplained ALF, liver dysfunction, or hepatocellular injury. PMID- 24485822 TI - Electroencephalographic characteristics in preterm infants born with intrauterine growth restriction. AB - OBJECTIVE: To determine the impact of fetal growth on postnatal amplitude integrated electroencephalography (aEEG) and power spectrum electroencephalography (EEG) data in preterm infants born with intrauterine growth restriction (IUGR). STUDY DESIGN: We defined IUGR as birth weight <10th percentile, and control as birth weight appropriate for gestational age (GA). We performed single-channel (C3-C4) EEG during the first 48 hours of life and measured the upper and lower margins of the aEEG trace width. EEG readings were analyzed by spectral analysis, and the relative power of the frequency bands was calculated. The Lacey Assessment of the Preterm Infant was administered before discharge. RESULTS: We enrolled 14 infants with IUGR (mean GA, 34.3 +/- 1.8 weeks; mean birth weight 1486 +/- 304 g) and 16 appropriate for GA controls (mean GA, 33.7 +/- 2 weeks; mean birth weight, 1978 +/- 488 g). There were no significant between-group differences in perinatal complications. The mean aEEG trace width was 20.8 +/- 1.4 MUv in the infants with IUGR versus 17.3 +/- 1.6 MUv in controls (P < .001). The infants with IUGR also had significantly greater delta frequency activity and decreased theta, alpha, and beta frequency activities compared with controls. Delta frequency activity decreased with increasing GA (r = -0.8; P = .001 for infants with IUGR and r = -0.9; P < .001 for controls). The Lacey Assessment of the Preterm Infant developmental score was significantly lower in the infants with IUGR (P < .02) and was correlated with aEEG trace width (r = -0.6; P = .002) and with delta activity (r = -0.5; P = .02). CONCLUSION: Preterm infants with IUGR have delayed EEG maturation associated with delayed neuromotor development. The predictive value of these alterations regarding developmental deficits associated with IUGR remains undetermined, however. PMID- 24485823 TI - Algorithm-based cholesterol monitoring in children with type 1 diabetes. AB - OBJECTIVE: To facilitate child-specific and diabetes-related cholesterol control, we developed a monitoring algorithm derived from population-based reference values. STUDY DESIGN: Low-density lipoprotein (LDL)-, non-high-density lipoprotein (HDL)-, and HDL cholesterol percentile values were calculated for children with type 1 diabetes (T1D) and their peers without T1D within algorithm based categories of sex, age: 1-10 vs >10-<18 years, body mass index: <90th vs >=90th percentile, and hemoglobin A1c <6%, 6%-<7.5%, 7.5%-9%, >9%. Analyses included 26 147 patients sampled from a German/Austrian population-based registry for T1D (Diabetes Documentation and Quality Management System) and 14 057 peers without diabetes participating in the national Health Interview and Examination Survey for Children and Adolescents in Germany. RESULTS: Reference percentile values for cholesterol were derived as a diagnostic algorithm aimed at supporting long-term cholesterol control. Taking account of a patient's sex, age-group, weight-, and hemoglobin A1c-category, the flowcharts of the algorithm developed separately for LDL-, non-HDL-, and HDL cholesterol allow comparing his/her cholesterol levels with population-based reference percentile values of peers without T1D. CONCLUSIONS: The population-based algorithmic approach applied to LDL-, non-HDL-, and HDL cholesterol allows referencing children with T1D with regard to their peers without T1D and, if necessary, suggests corrections of glycemic control to optimize long-term cholesterol levels. PMID- 24485824 TI - [Intermediate term outcome in 70 patients with Tako-Tsubo syndromes]. AB - BACKGROUND: Tako-Tsubo syndrome is a reversible left ventricular myocardial dysfunction. There are few publications on its evolution and the purpose of this study is to describe the medium-term outcome of patients who presented this pathology. METHODS: This retrospective study included 70 patients presenting with Tako-Tsubo syndrome who were referred to Haut-Leveque hospital between November 2003 and January 2012. The parameters included in follow-up were: number of cardiovascular events, recurrence, electrocardiographic and echocardiographic evolution. RESULTS: Sixty-eight patients had a mean follow-up of 4.8+/-2.4 years. The survival rate was 92%, 39 patients (57%) showed no cardiovascular symptoms, 12 (18%) had one or more new episodes of chest pain and 4 (6%) had stage II dyspnoea on the NYHA classification scale. One patient had a recurrence 6.5 years later, triggered by the same stress as the first instance. Forty-five patients (64%) had ECGs which evolved in the early days to diffuse T-wave inversion. In the medium term, 32 (54%) patients had a normal ECG, 19 (32%) had inverted T waves in precordial leads and 2 (3%) had Q-waves. In terms of echocardiography, left ventricular ejection fraction was normal in all with variable delays. Four patients continued to have apical hypokinesia. CONCLUSION: This study shows that the medium-term outlook is favourable in terms of cardiovascular mortality and that recurrence is rare. It highlights, however, the persistence of electrocardiographic and echocardiographic abnormalities. PMID- 24485825 TI - [Palliative care for patients with heart failure]. AB - PURPOSE: Heart failure is a common disease and its progression to end-stage heart failure is responsible of high mortality. The aim of this retrospective study was to assess the access to integrated palliative care to the usual management, 6 months prior to their death, and especially during the last hospitalization. PATIENTS AND METHODS: A retrospective study was performed in patients who died of heart failure in 2009 in two hospitals. The analysis was performed on 20 cases of each institution. The records of consecutive patients were included in an anti chronological order from 31st December 2009. RESULTS: For their last hospitalization, 37 patients (93%) were hospitalized in emergency. Within 3 days prior to death, the most frequent symptoms were dyspnea (n=33, 82%), and pain (n=30, 75%). Therapeutic most frequently used were oxygen (n=31, 77%) and analgesics (n=30, 75%). No patient was seen by a psychologist. The decision to limit treatment for comfort care was reported for 24 patients (60%) and the median of the average time between the decision and death was 2 days (Q1-Q3, 1-5 days). CONCLUSION: Patients with terminal heart failure have many symptoms often requiring multidisciplinary care. This type of study relating practices shows that there is still a lot to do to integrate palliative care in the usual management of patients with heart failure. PMID- 24485826 TI - [Prevalence and predictors of obstructive sleep apnea in patients admitted for acute myocardial infarction]. AB - BACKGROUND: Obstructive sleep apnea has been implicated in the pathogenesis and aggravation of coronary atherosclerosis. However, it remains underdiagnosed in cardiology practice. AIM: The aim of this study was to determine the prevalence of obstructive sleep apnea and the predictors of severe sleep apnea in patients admitted for ST elevation myocardial infarction. METHODS: This was a prospective study which has included 120 patients hospitalized for ST elevation myocardial infarction, from April 2011 to March 2012. All patients have undergone an overnight sleep study using a portable polygraphy device, in the 15 days following the acute coronary syndrome. The diagnostic of obstructive sleep apnea was considered as apnea-hypopnea index of >= 5 events per hour, severe sleep apnea was defined as apnea -hypopnea index of >= 30. Subjective daytime sleepiness was assessed by the Epworth sleepiness scale. All patients have had an oxygen saturation monitoring in the coronary care unit using a pulse oxymeter, before undergoing the sleep study. RESULTS: The study population was made up of 102 men and 18 women. The mean age was 58 +/- 12 years. Smoking was the major cardiovascular risk factor found in 72% of all patients, diabetes and hypertension were represented in 40% and 44% of the population, respectively. Eighty-seven percent of patients were admitted in the first 24 hours of symptom onset. A primary percutaneous coronary intervention was performed in 60% of cases while fibrinolysis was done in 10% of patients. The prevalence of obstructive sleep apnea was 79%. Mean apnea-hypopnea index was 15.76 +/- 14.93 and severe form was diagnosed in 16% of all patients. Multivariate analysis showed that Epworth sleepiness score of >= 4 and nocturnal desaturation below 82% were independent predictive factors for severe obstructive sleep apnea. CONCLUSION: Prevalence of obstructive sleep apnea was very high in patients admitted for acute myocardial infarction. Epworth sleepiness score of >= 4 and nocturnal desaturation below 82% were independent predictive factors for severe form of sleep apnea. PMID- 24485827 TI - [Using transient elastography as a screening tool for liver fibrosis in addiction service]. AB - BACKGROUND: Most addictive behaviors are risk factors for chronic hepatitis. The level of liver fibrosis is the main prognostic factor of chronic hepatitis. Transient elastography is a valid and accessible tool for measuring the level of liver fibrosis. Its routine use in addiction service is however poorly documented. AIMS OF THE STUDY: To test the feasibility of a systematic use of transient elastography as a tool for screening and diagnosis of liver fibrosis in patients hospitalized in an addiction medicine ward and to determine the prevalence of hepatic fibrosis, its predictive factors and etiologies and appreciate its evolution during alcohol detoxification. PATIENTS AND METHODS: Two hundred and twenty-seven patients were included, hepatic elastography was measured by two operators according to the standards. Threshold of fibrosis (F1) was 8 kPa, threshold cirrhosis (F4) was 13 kPa. RESULTS: Hepatic elastography was performed in 208 (92%) patients. A body mass index greater than 30 was associated with the non-feasibility of transient elastography, anti-HCV positive serology was associated with a lower reproductibility of transient elastography. Of the 208 patients, 61 had liver stiffness >= 8 kPa (prevalence of fibrosis of 29%), 25 had liver stiffness >= 13 kPa, fibrosis was not known for 46 (75%) of the 61 patients with fibrosis. A fibrosis was independently associated with the following variables: time between last alcohol ingestion and transient elastography measurement< 8 days, GGT>65 UI/L and serum concentration of platelets< 150 * 10(9)/L. Thirty patients had a second transient elastography in a median of 21 days after the first measurement. The decrease in liver stiffness during detoxification was significant only for patients whose alcohol ingestion was recent. CONCLUSION: Our study confirmed that the measurement of liver stiffness by transient elastography was an efficient tool for the diagnosis and detection of liver fibrosis in patients with addictive behavior. The decrease in hepatic elastography during alcohol detoxification may serve as a motivational tool. PMID- 24485828 TI - [Higher, faster, stronger]. PMID- 24485829 TI - [Hemorrhoidal surgery: new trends for day-case surgery]. AB - Despite recommendations and encouragements, day-case hemorrhoidal surgery is incompletely developed. The incidence of postoperative pain, urinary retention and the risk of bleeding vary according to the surgical procedure but they are considered as the main impediments to ambulatory management. Consequently, besides the use of good clinical practice concerning ambulatory surgery, hemorrhoidal surgery requires an effective control of postoperative pain based on the use of pudendal block, an adaptation of the anesthetic technique and a careful postoperative follow-up. PMID- 24485830 TI - Ambulatory thyroid surgery: do the risks overcome the benefits? AB - With appropriate selection, ambulatory thyroid surgery is feasible. Thyroid surgery is unique amongst ambulatory procedures in that it is associated with a small but unpredictable risk of rapid onset compromising cervical haematoma that may require immediate treatment. Reports of "safety" are frequently from series which are too small to give complete assurance. Postoperative haemorrhage is the only issue that makes day case surgery questionable because other risks (hypocalcaemia, nerve injury) can be mitigated. Studies suggest 20-60% bleed will occur after 6 hours but the clinical severity of later bleeds is unclear. The reliability of more specific data from complications occurring at home is liable to under-reporting. The need for a tracheostomy is considerably higher when there is a delay in the recognition of symptoms (as it could be at home) and re intervention; this underlies the increased morbidity with laryngeal and supraglottic oedema that may accompany a delay in the treatment of post thyroidectomy bleeds. The estimated cost savings from ambulatory thyroid surgery may be an over-estimate given that true costs may be reduced by optimisation of ward staffing. PMID- 24485831 TI - Methotrexate enhances 5-aminolevulinic acid-mediated photodynamic therapy-induced killing of human SCC4 cells by upregulation of coproporphyrinogen oxidase. AB - BACKGROUND/PURPOSE: Topical 5-aminolevulinic acid-mediated photodynamic therapy (ALA-PDT) is effective for treatment of oral precancerous and cancerous lesions. This in vitro study tried to examine whether the SCC4 cell killing by ALA-PDT was enhanced by pretreatment of methotrexate (MTX). METHODS: To measure the SCC4 cell killing abilities by MTX-pretreated ALA-PDT (MTX-ALA-PDT), the SCC4 cells were pretreated with 0 mg/L, 0.001 mg/L, 0.01 mg/L, 0.1 mg/L, or 1 mg/L of MTX for 72 hours, then incubated with 0 mM, 0.0625 mM, 0.125 mM, 0.187 mM, 0.25 mM, or 0.375 mM ALA for 4 hours, and subsequently illuminated with a 640-nm light-emitting diode array at a light dose of 10 J/cm(2). The 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide assay was conducted at 24 hours to quantify SCC4 cell survival rates after MTX-ALA-PDT treatment. Western blot analyses were used to examine the MTX-mediated enhancement in the expressions of the heme production related enzymes, coproporphyrinogen oxidase (CPOX), protoporphyrinogen oxidase (PPOX), and ferrochelatase, in the MTX-preconditioned SCC4 cells. RESULTS: Pretreatment of SCC4 cells by 0.001 mg/L MTX for 72 hours resulted in a significant augmentation in MTX-ALA-PDT-induced killing of SCC4 cells (p < 0.05). The SCC4 cells treated with 0.001 mg/L MTX for 72 hours showed a significant and 1.65-fold increase in CPOX expression compared with the control SCC4 cells without MTX treatment (p < 0.05). However, no significant changes in the expressions of PPOX and ferrochelatase were observed in the SCC4 cells pretreated with different concentrations of MTX. CONCLUSION: MTX enhances ALA-PDT-induced SCC4 cell killing through upregulation of CPOX expression and subsequent increase in intracellular protoporphyrin IX production in SCC4 cells. PMID- 24485832 TI - FOXL2 is a female sex-determining gene in the goat. AB - The origin of sex reversal in XX goats homozygous for the polled intersex syndrome (PIS) mutation was unclear because of the complexity of the mutation that affects the transcription of both FOXL2 and several long noncoding RNAs (lncRNAs). Accumulating evidence suggested that FOXL2 could be the sole gene of the PIS locus responsible for XX sex reversal, the lncRNAs being involved in transcriptional regulation of FOXL2. In this study, using zinc-finger nuclease directed mutagenesis, we generated several fetuses, of which one XX individual bears biallelic mutations of FOXL2. Our analysis demonstrates that FOXL2 loss of function dissociated from loss of lncRNA expression is sufficient to cause an XX female-to-male sex reversal in the goat model and, as in the mouse model, an agenesis of eyelids. Both developmental defects were reproduced in two newborn animals cloned from the XX FOXL2(-/-) fibroblasts. These results therefore identify FOXL2 as a bona fide female sex-determining gene in the goat. They also highlight a stage-dependent role of FOXL2 in the ovary, different between goats and mice, being important for fetal development in the former but for postnatal maintenance in the latter. PMID- 24485833 TI - Pds5 prevents the PolySUMO-dependent separation of sister chromatids. AB - BACKGROUND: The establishment, maintenance, and dissolution of sister chromatid cohesion are sequentially coordinated during the cell cycle to ensure faithful chromosome transmission. This cell-cycle-dependent regulation of cohesion is mediated, in part, by distinct posttranslational modifications of cohesin, a protein complex consisting of the Smc1-Smc3 ATPase, the Mcd1/Scc1 alpha-kleisin, and Scc3. Although cohesion is established in S phase, cohesins are not sufficient to maintain cohesion as cells progress from G2 to the metaphase-to anaphase transition. Rather, the cohesin-associated factor Pds5 is also required to keep sisters paired until anaphase onset. How Pds5 maintains cohesion at the molecular level and whether this maintenance involves the regulation of cohesin modifications remains to be defined. RESULTS: In pds5 mutants, we find that Mcd1 is extensively SUMOylated and that premature sister separation requires Siz2 dependent polySUMOylation. Moreover, abrogation of Pds5 function promotes the proteasome-dependent degradation of Mcd1 and a significant loss of cohesin from chromatin independently of anaphase onset. We further demonstrate that inactivation of the Slx5-Slx8 SUMO-targeted ubiquitin ligase, required for targeting polySUMOylated factors for proteasome-mediated destruction, limits Mcd1 turnover and restores both cell growth and cohesion in metaphase cells defective for Pds5 function. CONCLUSIONS: We propose that Pds5 maintains cohesion, at least in part, by antagonizing the polySUMO-dependent degradation of cohesin. PMID- 24485834 TI - STIL microcephaly mutations interfere with APC/C-mediated degradation and cause centriole amplification. AB - BACKGROUND: STIL is a centriole duplication factor that localizes to the procentriolar cartwheel region, and mutations in STIL are associated with autosomal recessive primary microcephaly (MCPH). Excess STIL triggers centriole amplification, raising the question of how STIL levels are regulated. RESULTS: Using fluorescence time-lapse imaging, we identified a two-step process that culminates in the elimination of STIL at the end of mitosis. First, at nuclear envelope breakdown, Cdk1 triggers the translocation of STIL from centrosomes to the cytoplasm. Subsequently, the cytoplasmic bulk of STIL is degraded via the anaphase-promoting complex/cyclosome (APC/C)-proteasome pathway. We identify a C terminal KEN box as critical for STIL degradation. Remarkably, this KEN box is deleted in MCPH mutants of STIL, rendering STIL resistant to proteasomal degradation and causing centriole amplification. CONCLUSIONS: Our results reveal a role for Cdk1 in STIL dissociation from centrosomes during early mitosis, with implications for the timing of cartwheel disassembly. Additionally, we propose that centriole amplification triggered by STIL stabilization is the underlying cause of microcephaly in human patients with corresponding STIL mutations. PMID- 24485835 TI - A PIP5 kinase essential for efficient chemotactic signaling. AB - In neutrophils and Dictyostelium, chemoattractant gradients generate directed cell migration by eliciting signaling events that bias intrinsic motility and favor the production and retention of upgradient pseudopods. Phosphoinositides are actively regulated during chemotaxis in these cells, most iconically in the production of PI(3,4,5)P3 gradients within the plasma membrane. Although it is now known that PI(3,4,5)P3 signaling is nonessential for gradient sensing, the role of the related phosphoinositide PI(4,5)P2 is little understood, despite its clear importance in many cell biological processes. We describe here a PIP5 kinase, PikI, which produces PI(4,5)P2 and is essential for efficient chemotaxis of Dictyostelium cells. Without PikI, PI(4,5)P2 levels are reduced by 90%, and while pikI(-) cells move at normal speeds, they are highly disorientated in cAMP gradients. Following chemotactic stimulation, Ras is efficiently activated in pikI(-) cells, yet Ras-dependent responses (including activation of PKB) are severely impaired. PikI is phosphorylated by PKB, and in vitro studies of a phosphomimic mutant suggest that this phosphorylation increases PikI activity. We propose that adequate PI(4,5)P2 levels are required to couple activated Ras to its downstream effectors and that these levels are regulated by PikI, making it a crucial player in gradient sensing. PMID- 24485836 TI - Mitochondria and melanosomes establish physical contacts modulated by Mfn2 and involved in organelle biogenesis. AB - BACKGROUND: To efficiently supply ATP to sites of high-energy demand and finely regulate calcium signaling, mitochondria adapt their metabolism, shape, and distribution within the cells, including relative positioning with respect to other organelles. However, physical contacts between mitochondria and the secretory/endocytic pathway have been demonstrated so far only with the ER, through structural and functional interorganellar connections. RESULTS: Here we show by electron tomography that mitochondria physically contact melanosomes, specialized lysosome-related organelles of pigment cells, through fibrillar bridges resembling the protein tethers linking mitochondria and the ER. Mitofusin (Mfn) 2, which bridges ER to mitochondria, specifically localizes also to melanosome-mitochondrion contacts, and its knockdown significantly reduces the interorganellar connections. Contacts are associated to the melanogenesis process, as indicated by the fact that they are reduced in a model of aberrant melanogenesis whereas they are enhanced both where melanosome biogenesis takes place in the perinuclear area and when it is actively stimulated by OA1, a G protein-coupled receptor implicated in ocular albinism and organellogenesis. Consistently, Mfn2 knockdown prevents melanogenesis activation by OA1, and the pharmacological inhibition of mitochondrial ATP synthesis severely reduces contact formation and impairs melanosome biogenesis, by affecting in particular the developing organelles showing the highest frequency of contacts. CONCLUSIONS: Altogether, our findings reveal the presence of an unprecedented physical and functional connection between mitochondria and the secretory/endocytic pathway that goes beyond the ER-mitochondria linkage and is spatially and timely associated to secretory organelle biogenesis. PMID- 24485838 TI - Increasing breastfeeding rates to six months among nulliparous women: a quasi experimental study. AB - OBJECTIVE: the aim of this study was to evaluate the effectiveness of a multiphased midwifery intervention called the 'Milky Way' on any breastfeeding rates until six months. DESIGN: a quasi-experimental study with two groups: standard care and intervention. SETTING: a tertiary, metropolitan hospital in Sydney, Australia. PARTICIPANTS: eligible participants were nulliparous women aged 19 years and above who planned to breast feed and had basic English literacy (n=420). On the basis of inclusion criteria, women remained in the study if they intended to breast feed prior to birth and had a live, term birth where the infant could breast feed (n=366). INTERVENTION: the Milky Way program was informed from theories in midwifery and psychology. The program started in early second trimester. It included three antenatal breastfeeding classes and take home learning activities followed by two postnatal lactation consultation phone calls. MEASUREMENTS AND FINDINGS: antenatal baseline information was collected on the recruitment day and postnatal data were collected via phone interviews at one, four and six month post partum. Breast feeding rates were analysed based on intention to treat. There were no significant differences in the antenatal baseline data between the groups. Compared to standard care, women in the Milky Way group had higher rates of breast feeding at one (83.7%, n=144 versus 61.3%, n=119, p<0.001), four (64.5%, n=111 versus 37.1%, n=72, p<0.001) and six months (54.3%, n=94 versus 31.4%, n=61 p<0.001). KEY CONCLUSION: assignment to the Milky Way intervention was associated with significantly higher rates of breastfeeding compared with assignment to standard care only. IMPLICATIONS FOR PRACTICE: the Milky Way program is a feasible intervention which we recommend to be available to all women who want to breastfeed for the first time. PMID- 24485837 TI - A role for myosin II in mammalian mitochondrial fission. AB - Mitochondria are dynamic organelles, undergoing both fission and fusion regularly in interphase cells. Mitochondrial fission is thought to be part of a quality control mechanism whereby damaged mitochondrial components are segregated from healthy components in an individual mitochondrion, followed by mitochondrial fission and degradation of the damaged daughter mitochondrion. Fission also plays a role in apoptosis. Defects in mitochondrial dynamics can lead to neurodegenerative diseases such as Alzheimer's disease. Mitochondrial fission requires the dynamin GTPase Drp1, which assembles in a ring around the mitochondrion and appears to constrict both outer and inner mitochondrial membranes. However, mechanisms controlling Drp1 assembly on mammalian mitochondria are unclear. Recent results show that actin polymerization, driven by the endoplasmic reticulum-bound formin protein INF2, stimulates Drp1 assembly at fission sites. Here, we show that myosin II also plays a role in fission. Chemical inhibition by blebbistatin or small interfering RNA (siRNA)-mediated suppression of myosin IIA or myosin IIB causes an increase in mitochondrial length in both control cells and cells expressing constitutively active INF2. Active myosin II accumulates in puncta on mitochondria in an actin- and INF2 dependent manner. In addition, myosin II inhibition decreases Drp1 association with mitochondria. Based on these results, we propose a mechanistic model in which INF2-mediated actin polymerization leads to myosin II recruitment and constriction at the fission site, enhancing subsequent Drp1 accumulation and fission. PMID- 24485839 TI - Infective endocarditis with multiple septic emboli due to Streptococcus mitis: a wolf in sheep's clothing. PMID- 24485840 TI - Blood borne hormones in a cross-talk between peripheral and brain mechanisms regulating blood pressure, the role of circumventricular organs. AB - Accumulating evidence suggests that blood borne hormones modulate brain mechanisms regulating blood pressure. This appears to be mediated by the circumventricular organs which are located in the walls of the brain ventricular system and lack the blood-brain barrier. Recent evidence shows that neurons of the circumventricular organs express receptors for the majority of cardiovascular hormones. Intracerebroventricular infusions of hormones and their antagonists is one approach to evaluate the influence of blood borne hormones on the neural mechanisms regulating arterial blood pressure. Interestingly, there is no clear correlation between peripheral and central effects of cardiovascular hormones. For example, angiotensin II increases blood pressure acting peripherally and centrally, whereas peripherally acting pressor catecholamines decrease blood pressure when infused intracerebroventricularly. The physiological role of such dual hemodynamic responses has not yet been clarified. In the paper we review studies on hemodynamic effects of catecholamines, neuropeptide Y, angiotensin II, aldosterone, natriuretic peptides, endothelins, histamine and bradykinin in the context of their role in a cross-talk between peripheral and brain mechanisms involved in the regulation of arterial blood pressure. PMID- 24485841 TI - Screening for abdominal aortic aneurysm in 65-year-old men remains cost-effective with contemporary epidemiology and management. AB - OBJECTIVES: The epidemiology and management of abdominal aortic aneurysms (AAA) has changed significantly, with lower prevalence, increased longevity of patients, increased use of endovascular aneurysm repair (EVAR), and improved outcome. The clinical and health economic effectiveness of one-time screening of 65-year-old men was assessed within this context. METHODS: One-time ultrasound screening of 65-year-old men (invited) versus no screening (control) was analysed in a Markov model. Data on the natural course of AAA (risk of repair and rupture) was based on randomised controlled trials. Screening detected AAA prevalence (1.7%), surgical management (50% EVAR), repair outcome, costs, and long-term survival were based on contemporary population-based data. Incremental cost efficiency ratios (ICER), absolute and relative risk reduction for death from AAA (ARR, RRR), numbers needed to screen (NNS), and life-years gained were calculated. Annual discounting was 3.5%. RESULTS: In base case at 13-years follow up the ICER was ?14,706 per incremental quality-adjusted life-year (QALY); ARR was 15.1 per 10,000 invited, NNS was 530, and QALYs gained were 56.5 per 10,000 invited. RRR was 42% (from 0.36% in control to 0.21% in invited). In a lifetime analysis the ICER of screening decreased to ?7,570/QALY. The parameters with highest impact on the cost-efficiency of screening in the sensitivity analysis were the prevalence of AAA (threshold value <0.5%) and degree of incidental detection in the control cohort. CONCLUSIONS: In the face of recent changes in the management and epidemiology of AAA, screening men for AAA remains cost effective and delivers significant clinical impact. PMID- 24485842 TI - Association of total white cell count with mortality and major adverse events in patients with peripheral arterial disease: a systematic review. AB - OBJECTIVES: Peripheral arterial disease (PAD) is principally caused by atherosclerosis, an established inflammatory disease. Total white cell count (TWCC) is a marker of inflammation and has been associated with outcomes for patients with inflammatory diseases. The aim of this systematic review was to assess the association of TWCC with mortality and major adverse events (MAEs) in PAD patients. METHODS: Studies investigating the association of TWCC with outcome in patients with PAD were identified by a literature search using the Medline and Cochrane databases. To be eligible for inclusion, studies needed to investigate the association of TWCC with mortality or a composite endpoint that included mortality in patients with PAD. Studies were excluded when the primary focus was carotid artery disease, aortic aneurysmal disease, intracranial vascular disease, or rheumatoid arthritis and treatment with chemotherapy or transplantation of stem cells. Secondary searching of reference lists and relevant reviews was performed. RESULTS: Ten studies including 8,490 patients with PAD met the inclusion criteria. All studies investigated more than 100 patients with four studies assessing more than 1,000 patients. Study quality varied with well established risk factors of outcome such as age, smoking, diabetes, and the ankle brachial index being adjusted for inconsistently. The study populations were also disparate. Few studies reported relative risk and 95% confidence intervals for the association of TWCC with mortality or MAE. TWCC was positively and significantly associated with death alone in four of five studies investigating 3,387 patients. TWCC was positively and significantly associated with MAE in five of six studies investigating a total of 6,846 patients. CONCLUSIONS: Current evidence suggests a positive association of TWCC with mortality and MAEs in patients with PAD. Further well-designed prospective studies are required with high-quality analysis and more complete reporting of outcomes. PMID- 24485843 TI - An endovascular strategy for suspected ruptured abdominal aortic aneurysm brings earlier home discharge but not early survival or cost benefits. PMID- 24485844 TI - Outcomes after open repair for ruptured abdominal aortic aneurysms in patients with friendly versus hostile aortoiliac anatomy. AB - OBJECTIVES: In patients with a ruptured abdominal aortic aneurysm (RAAA), anatomic suitability for endovascular aneurysm repair (EVAR) depends on aortic neck and iliac artery characteristics. If the aortoiliac anatomy is unsuitable for EVAR ("hostile anatomy"), open repair (OR) is the next option. We hypothesized that the death rate for OR is higher in patients with hostile anatomy than in patients with friendly anatomy. METHODS: We conducted an observational cohort study in 279 consecutive patients with an RAAA treated with OR between 2004 and 2011. The primary endpoint was 30-day or in-hospital death. Aortoiliac anatomy (friendly vs. hostile) was determined prospectively by the vascular surgeon and the interventional radiologist treating the patient. A multivariable logistic regression analysis was done to assess the risk of dying in patients with hostile anatomy after adjustment for age, sex, comorbidity, and hemodynamic stability. RESULTS: Aortoiliac anatomy was friendly in 71 patients and hostile in 208 patients. Death rate was 38% (95% confidence interval (CI): 28 to 50%) in patients with friendly anatomy and 30% (95% CI: 24 to 37%) in patients with hostile anatomy (p = .23). After multivariable adjustment, the risk of dying was not higher in patients with hostile anatomy (adjusted odds ratio 0.744, 95% CI 0.394 to 1.404). CONCLUSION: The death rate after open repair for an RAAA is comparable in patients with friendly and hostile aortoiliac anatomy. PMID- 24485845 TI - Ovarian mucinous tumors arising from mature cystic teratomas--a molecular genetic approach for understanding the cellular origin. AB - Mucinous tumors of the ovary are frequently associated with mature cystic teratomas, and it has been speculated that the mucinous tumors arise from teratoma components. The cellular origins of mature cystic teratomas are believed to be post-meiotic ovarian germ cells, and the analysis of microsatellite markers such as short tandem repeats is suitable for determining the cellular origin of tumors. In this study, we analyzed 3 ovarian mature cystic teratomas, all of which were associated with simultaneous ovarian mucinous tumors within the same ovary. Two of the 3 mucinous tumors were intestinal-type and the other was endocervical type. A laser capture microdissection technique was used to separate the epithelial component of the mucinous tumor, the components of the mature cystic teratoma, and control ovarian somatic tissue. Using short tandem repeat analysis based on 6 markers (D20S480, D6S2439, D6S1056, D9S1118, D4S2639, and D17S1290), we could distinguish the germ cell (homozygous) or somatic (heterozygous) origin of a given component in each sample. The epithelial components of the intestinal-type mucinous tumors in cases 1 and 2 were homozygous, and the epithelial component in case 3 (endocervical type) was heterozygous. All teratomatous components were homozygous, and the control components were heterozygous. In addition, we analyzed 3 mature cystic teratomas without mucinous tumors, and all 3 were homozygous in the tumor component. Our data suggest that the origin of mucinous tumors in the ovary may differ among histological subtypes, and intestinal-type mucinous tumors may arise from mature cystic teratomas, although endocervical-type mucinous tumors may not. PMID- 24485846 TI - At last, Burkholderia spp. is one of the inclusion criteria--a negative (but published) randomised controlled trial. PMID- 24485847 TI - Combination antidepressant therapy for major depressive disorder: speed and probability of remission. AB - INTRODUCTION: Only about a third of patients with an episode of major depressive disorder remit with a given treatment and few remissions occur within the first weeks of treatment. This study tested whether combining escitalopram and bupropion as initial treatment would result in quicker remission and a higher remission rate than monotherapy with either drug. METHOD: Two hundred forty-five outpatients aged 18-65 having non-psychotic, non-bipolar major depression were randomly assigned to double-blind treatment with bupropion or escitalopram or the combination dosed to a maximum of bupropion 450 mg/d and/or escitalopram 40 mg/d for 12 weeks. A Montgomery-Asberg Depression Rating Scale score of 22 was required for randomization, while a Hamilton Rating Scale for Depression score <= 7 defined remission. We hypothesized that bupropion plus escitalopram would outperform both monotherapies in both earlier onset of remission and higher rate of remission. RESULTS: Primary analyses did not demonstrate that dual therapy outperformed both monotherapies in either timing of remission or remission rate. All three treatments were well tolerated. DISCUSSION: These results do not support initial use of bupropion plus escitalopram to speed or enhance antidepressant response. CLINICAL TRIALS REGISTRATION: NCT00519428. PMID- 24485848 TI - Resilience characteristics mitigate tendency for harmful alcohol and illicit drug use in adults with a history of childhood abuse: a cross-sectional study of 2024 inner-city men and women. AB - Resilience refers to abilities to cope adaptively with adversity or trauma. A common psychological sequella of childhood abuse or other traumatic experiences is substance use problems. There are, however, very limited data on relationships among resilience traits, childhood abuse, and alcohol or drug use problems. Hence, we aimed to examine associations between resilience characteristics and lifetime alcohol and illicit drug use in 2024 inner-city adults with high rates of childhood abuse and other trauma exposure. In this cross-sectional study, resilience was assessed with the Connor-Davidson Resilience Scale, childhood abuse with the Childhood Trauma Questionnaire, lifetime alcohol and illicit drug use with the Alcohol Use Disorder Identification Test and Drug Abuse Screening Test. Associations between resilience and substance use were examined with linear regression models, adjusting for trauma load, age, and sex. We found that resilience characteristics mitigated tendency for lifetime alcohol use problems both as a main effect (beta = -0.11; p = 0.0014) and an interaction with severity of childhood abuse (beta = -0.06; p = 0.0115) after trauma severity, age, and sex were controlled for. Similarly, resilience reduced lifetime illicit drug use both as a main effect (beta = -0.03; p = 0.0008) and as an interaction with severity of childhood abuse (beta = -0.01; p = 0.0256) after trauma load, age, and sex were adjusted for. Our findings add to a nascent body of literature suggesting that resilience characteristics mitigate risks not only for PTSD, major depression, and suicidality, but also for substance use problems in adults exposed to childhood abuse or other traumatic experiences. PMID- 24485849 TI - Involvement of neutrophils in thrombus formation in living mice. AB - Thrombosis is one of the major causes of human death worldwide. Identification of the cellular and molecular mechanisms leading to thrombus formation is thus crucial for the understanding of the thrombotic process. To examine thrombus formation in a living mouse, new technologies have been developed. Digital intravital microscopy allows to visualize the development of thrombosis and generation of fibrin in real-time within living animal in a physiological context. This specific system allowed the identification of new cellular partners involved in platelet adhesion and activation. Furthermore, it improved, especially, the knowledge of the early phase of thrombus formation and fibrin generation in vivo. Until now, platelets used to be considered the sole central player in thrombus generation. However, recently, it has been demonstrated that leukocytes, particularly neutrophils, play a crucial role in the activation of the blood coagulation cascade leading to thrombosis. In this review, we summarized the mechanisms leading to thrombus formation in the microcirculation according to the method of injury in mice with a special focus on the new identified roles of neutrophils in this process. PMID- 24485850 TI - CTA with fluoroscopy image fusion guidance in endovascular complex aortic aneurysm repair. AB - OBJECTIVES: To evaluate the effect of intraoperative guidance by means of live fluoroscopy image fusion with computed tomography angiography (CTA) on iodinated contrast material volume, procedure time, and fluoroscopy time in endovascular thoraco-abdominal aortic repair. METHODS: CTA with fluoroscopy image fusion road mapping was prospectively evaluated in patients with complex aortic aneurysms who underwent fenestrated and/or branched endovascular repair (FEVAR/BEVAR). Total iodinated contrast material volume, overall procedure time, and fluoroscopy time were compared between the fusion group (n = 31) and case controls (n = 31). Reasons for potential fusion image inaccuracy were analyzed. RESULTS: Fusion imaging was feasible in all patients. Fusion image road-mapping was used for navigation and positioning of the devices and catheter guidance during access to target vessels. Iodinated contrast material volume and procedure time were significantly lower in the fusion group than in case controls (159 mL [95% CI 132 186 mL] vs. 199 mL [95% CI 170-229 mL], p = .037 and 5.2 hours [95% CI 4.5-5.9 hours] vs. 6.3 hours (95% CI 5.4-7.2 hours), p = .022). No significant differences in fluoroscopy time were observed (p = .38). Respiration-related vessel displacement, vessel elongation, and displacement by stiff devices as well as patient movement were identified as reasons for fusion image inaccuracy. CONCLUSION: Image fusion guidance provides added value in complex endovascular interventions. The technology significantly reduces iodinated contrast material dose and procedure time. PMID- 24485851 TI - Parkin and mitochondrial quality control: toward assembling the puzzle. AB - Parkin is an E3 ubiquitin ligase associated with autosomal-recessive Parkinsonism. Moreover, parkin inactivation has been found in sporadic Parkinson's disease (PD), suggesting a wider pathogenic impact than initially predicted. Beyond its role in PD, parkin has also been implicated in innate immune responses. Since its discovery, mounting evidence indicates that parkin can mediate degradative as well as nondegradative ubiquitination. Here we review recent insights into the structure of parkin, the mechanism of its E3 ligase activity, and its functional versatility in an attempt to merge controversial aspects into a more comprehensive picture of this multifaceted E3 ubiquitin ligase. PMID- 24485852 TI - Epigenetic regulation of oogenesis and germ stem cell maintenance by the Drosophila histone methyltransferase Eggless/dSetDB1. AB - The Drosophila melanogaster histone lysine methyltransferase (HKMT) Eggless (Egg/dSETDB1) catalyzes methylation of Histone H3 lysine 9 (H3K9), a signature of repressive heterochromatin. Our previous studies showed that H3K9 methylation by Egg is required for oogenesis. Here we analyze a set of EMS-induced mutations in the egg gene, identify the molecular lesions of these mutations, and compare the effects on oogenesis of both strong loss-of-function and weak hypomorphic alleles. These studies show that H3K9 methylation by Egg is required for multiple stages of oogenesis. Mosaic expression experiments show that the egg gene is not required intrinsically in the germ cells for their early differentiation, but is required in the germ cells for their survival past stage 5 of oogenesis. egg is also required in germ stem cells for their maintenance, since egg- germ stem cells initially survive but are not maintained as females age. Mosaic analysis also reveals that the early egg chamber budding defects in egg- ovaries are due to an intrinsic requirement for egg in follicle stem cells and their descendents, and that egg plays a non-autonomous role in somatic cells in the germarium to influence the differentiation of early germ cells. PMID- 24485853 TI - Development of the hemochorial maternal vascular spaces in the placenta through endothelial and vasculogenic mimicry. AB - The maternal vasculature within the placenta in primates and rodents is unique because it is lined by fetal cells of the trophoblast lineage and not by maternal endothelial cells. In addition to trophoblast cells that invade the uterine spiral arteries that bring blood into the placenta, other trophoblast subtypes sit at different levels of the vascular space. In mice, at least five distinct subtypes of trophoblast cells have been identified which engage maternal endothelial cells on the arterial and venous frontiers of the placenta, but which also form the channel-like spaces within it through a process analogous to formation of blood vessels (vasculogenic mimicry). These cells are all large, post-mitotic trophoblast giant cells. In addition to assuming endothelial cell like characteristics (endothelial mimicry), they produce dozens of different hormones that are thought to regulate local and systemic maternal adaptations to pregnancy. Recent work has identified distinct molecular pathways in mice that regulate the morphogenesis of trophoblast cells on the arterial and venous sides of the vascular circuit that may be analogous to specification of arterial and venous endothelial cells. PMID- 24485854 TI - The effect of hyperinsulinemia and hyperglycemia on endothelial function in pregnant patients with type-2 diabetes. AB - We studied endothelial function (flow mediated vasodilation, FMD) during hyperinsulinemia and hyperglycemia in pregnant women with type-2 diabetes, in the second and third trimester. We found that hyperglycemia reduces FMD in late pregnancy. PMID- 24485855 TI - Novel insights into metabolic sequelae of obstructive sleep apnoea: a link between hypoxic stress and chronic diabetes complications. AB - An increasing body of evidence suggests that obstructive sleep apnoea (OSA) is independently associated with an increased risk of cardiovascular disease, glucose intolerance, and deteriorations in glycaemic control. Despite the knowledge of a multifactorial pathogenesis of long-term diabetes complications, there is a paucity of information on impact of comorbidities associated with chronic intermittent hypoxemia on development and progression of chronic diabetes complications. This review explores the clinical and scientific overlap of OSA and type 2 diabetes mellitus (T2DM) and its possible impact on the development and progression of diabetes macrovascular and microvascular complications. Multiple prospective observational cohort studies have demonstrated that OSA significantly increases the risk of cardiovascular disease independent of potential confounding risk factors. The current evidence further suggests that OSA with concurrent T2DM is associated with an increased risk of oxidative stress induced damage of vulnerable endothelial and mesangial cells and peripheral nerves. Further studies are needed to validate the impact of OSA treatment on diabetes micro- and macrovascular complications. Since it is presently still unknown whether OSA treatment may provide a diabetes-modifying intervention that could delay or halt the progression of chronic diabetes complications, the emphasis is on early diagnosis and satisfactory treatment of both OSA and T2DM. PMID- 24485856 TI - Liver disease and diabetes: association, pathophysiology, and management. AB - Diabetes is associated with a spectrum of liver diseases including nonalcoholic liver disease, steatohepatitis, and liver cirrhosis with their increased complications and mortality. Hepatitis C virus (HCV) and its associated liver cirrhosis has been associated with diabetes through insulin resistance. Cryptogenic diabetes occurs as a consequence of liver cirrhosis with the pathophysiology being complex, but mostly attributed to the increased insulin resistance in muscle, liver, and adipose tissue. As for the management of diabetes in patients with liver disease, lifestyle modification plays an important role. Oral diabetic medications are contraindicated in patients with advanced liver diseases with associated cirrhosis, ascites, or encephalopathy. As for stable liver disease, metformin and thiazolenediones have shown mixed results, with some showing them to be effective in improving liver transaminases in addition to histological improvement in steatosis and inflammation. alpha glucosidase inhibitors may be helpful in decreasing hepatic encephalopathy. Upregulation of Dipeptidyl peptidase-4 (DPP-4) has been suggested as a possible pathogenetic mechanism for HCV-related insulin resistance, and treatment with DPP 4 inhibitors could improve insulin sensitivity in diabetic patients with liver disease. Patients with impaired liver function with associated insulin resistance may need increased insulin requirements. On the other hand patients with altered liver metabolism might need decreased insulin requirements. PMID- 24485857 TI - A retrospective multi-institutional study of treatment for mild gestational diabetes in Japan. AB - AIMS: To determine whether treating mild gestational diabetes mellitus (GDM) is associated with improvement of pregnancy outcomes in Japan. METHODS: In a multi institutional retrospective study, we examined pregnant women meeting the criteria for mild GDM (i.e., only one abnormal value [OAV] for 75-g OGTT; fasting glucose >=100 mg/dL, 1-h postprandial glucose >=180 mg/dL, and 2-h postprandial glucose >=150 mg/dL), receiving either routine prenatal care (non-treatment group) or dietary intervention alone or dietary intervention with self-monitoring of blood glucose and/or insulin therapy, if necessary (treatment group). Pregnancy outcomes were compared between these groups. RESULTS: Data from 893 eligible women were collected from 30 institutions. Participants included 542 untreated and 351 treated women. Although there were no significant differences in baseline clinical characteristics or maternal and perinatal outcomes between these groups, the incidence of large-for-gestational-age (LGA) infants was lower in the treatment group (P=0.07). Multiple logistic regression analysis (MLRA) revealed that pre-pregnancy BMI and gestational weight gain were associated with LGA infants, while 75-g OGTT results were unrelated to LGA. When overweight and obese women were the subjects, the number of LGA infants was significantly lower in the intervention than in the control group, and gestational weight gain was significantly lower in the treatment than in the control group. MLRA showed that intervention was significantly related to a lower incidence of LGA infants. CONCLUSIONS: Our study suggests that maternal BMI impacts fetal growth and that treatment for overweight or obese mothers with OAV is associated with a lower frequency of LGA infants. PMID- 24485859 TI - How diabetes risk assessment tools are implemented in practice: a systematic review. AB - This review aimed to explore the extent of the use of diabetes risk assessment tools and to determine influential variables associated with the implementation of these tools. CINAHL, Google Scholar, ISI Citation Indexes, PubMed, and Scopus were searched from inception to January 2013. Studies that reported the use of diabetes risk assessment tools to identify individuals at risk of diabetes were included. Of the 1719 articles identified, 24 were included. Follow-up of high risk individuals for diagnosis of diabetes was conducted in 5 studies. Barriers to the uptake of diabetes risk assessment tools by healthcare practitioners included (1) attitudes toward the tools; (2) impracticality of using the tools and (3) lack of reimbursement and regulatory support. Individuals were reluctant to undertake self-assessment of diabetes risk due to (1) lack of perceived severity of type 2 diabetes; (2) impracticality of the tools; and (3) concerns related to finding out the results. The current use of non-invasive diabetes risk assessment scores as screening tools appears to be limited. Practical follow up systems as well as strategies to address other barriers to the implementation of diabetes risk assessment tools are essential and need to be developed. PMID- 24485858 TI - Depression and type 2 diabetes in low- and middle-income countries: a systematic review. AB - Eighty percent of people with type 2 diabetes reside in low- and middle-income countries (LMICs). Yet much of the research around depression among people with diabetes has been conducted in high-income countries (HICs). In this systematic review we searched Ovid Medline, PubMed, and PsychINFO for studies that assessed depression among people with type 2 diabetes in LMICs. Our focus on quantitative studies provided a prevalence of comorbid depression among those with diabetes. We reviewed 48 studies from 1,091 references. We found that this research has been conducted primarily in middle-income countries, including India (n = 8), Mexico (n = 8), Brazil (n = 5), and China (n = 5). There was variation in prevalence of comorbid depression across studies, but these differences did not reveal regional differences and seemed to result from study sample (e.g., urban vs rural and clinical vs population-based samples). Fifteen depression inventories were administered across the studies. We concluded that despite substantial diabetes burden in LMICs, few studies have reviewed comorbid depression and diabetes. Our review suggests depression among people with diabetes in LMICs may be higher than in HICs. Evidence from these 48 studies underscores the need for comprehensive mental health care that can be integrated into diabetes care within LMIC health systems. PMID- 24485860 TI - Opaque bubble layer: incidence, risk factors, and clinical relevance. AB - PURPOSE: To assess the incidence, risk factors, and impact on visual outcomes of an opaque bubble layer (OBL) produced by an Intralase femtosecond laser (60 kHz) during laser in situ keratomileusis (LASIK). SETTING: Laser Vision Center, Chang Gung Memorial Hospital, Keelung, Taiwan. DESIGN: Case series. METHODS: Patients had femtosecond laser-assisted LASIK surgery. The surgical procedures were videotaped, and the patterns and sizes of the OBLs noted during the operations were analyzed. Preoperative and postoperative data included patient demographics, visual acuity, contrast sensitivity, refractive status, keratometry, and intraoperative data (eg, flap size, flap thickness, and docking times). RESULTS: The study analyzed 23 patients (40 eyes). Twenty-one eyes (52.5%) developed an OBL, 40.0% with a hard pattern and 12.5% with a soft pattern. The hard OBLs covered a mean area of 28.6% +/- 10.1% (SD) and the soft OBLs, of 7.4% +/- 5.6% (P = .002). The preoperative central cornea was significantly thicker in eyes that developed an OBL (P = .045). The visual outcomes 1 month postoperatively were comparable between the 2 groups except that eyes with an OBL had slightly decreased contrast sensitivity under scotopic conditions. CONCLUSIONS: Thicker corneas tended to develop an OBL during femtosecond laser-assisted LASIK surgery. An OBL did not affect postoperative visual acuity except for a mild decrease in scotopic contrast sensitivity. PMID- 24485861 TI - Cataract surgery in ancient Egypt. AB - Ophthalmology was one of the most important specialties in Egyptian medicine, and more specialists are known in this field than in any other. This specialization seems, however, to have been of a purely noninvasive nature. Even though it has been claimed that cataract surgery was performed in pharaonic Egypt, careful analysis of the sources does not support the claim. No example of cataract surgery or of any other invasive ophthalmologic procedure can be found in the original sources. PMID- 24485862 TI - Endothelial cell loss with ultrashort-pulse laser and manually generated full thickness clear corneal incisions. AB - PURPOSE: To compare the extent of corneal endothelial cell loss resulting from creating full-thickness clear corneal incisions manually using a diamond blade with that resulting from use of an ultrashort-pulse laser. SETTING: Lensar, Inc., Orlando, Florida, USA. DESIGN: Experimental study. METHODS: Ex vivo porcine globes were randomly assigned to groups for manual or laser-generated full thickness CCIs. Standard 3-plane manual or laser incisions were made in freshly excised porcine globes. Two laser incision geometries were tested: with the exit incision perpendicular or 45 degrees to the posterior corneal surface. Corneas excised from the globe were measured immediately and after storage for 48 hours in Dulbecco modified Eagle media. Cell loss was assessed by measuring the area of damaged endothelial cells with a fluorescent microscope after cornea staining with a 3-component fluorescent live cell-dead cell assay. The percentage cell loss was expressed as the damaged area divided by the total area of a typical human corneal endothelium. RESULTS: Endothelial cell losses caused by manual and laser full-thickness CCIs were in the range of 0.8% to 1.4%. Although the mean endothelial cell loss percentages were lower for laser than for manual full thickness CCIs, the measurements showed no statistically significant differences in the endothelial cell loss percentage between manual full-thickness CCIs and laser full-thickness CCIs with a perpendicular exit incision or 45-degree exit incision geometry. CONCLUSION: Ultrashort-pulse laser-generated full-thickness CCIs resulted in the statistically equivalent levels of corneal endothelial cell loss as full-thickness CCIs created by standard manual methods. PMID- 24485863 TI - [Chest computed tomography in children: indications, efficiency and effective dose]. AB - INTRODUCTION: New multidetector row computed tomography (CT) has made the imaging of younger children more feasible and extending CT indications to a wide range of pediatric respiratory diseases in the last few years. However, CT is a source of radiation exposure. The aim of this study was to evaluate the main indications and the contribution of chest CT in pediatric pulmonology as well as induced radiation. METHODS: This was an observational, prospective study. Children whose chest CTs were analyzed during multidisciplinary meetings (radiologist, pulmonary pediatrician) were included from November 2009 to April 2010. We collected demographic data, CT results, contribution of CT to diagnosis and management, and radiation doses (dose-length product [DLP] and effective dose). Radiation doses were compared according to the CT scans (Lille University Hospital with 128-slice dual-source CT or Lille University Hospital single-source 64-slice CT, or CT performed outside the university hospital). RESULTS: One hundred thirty-five patients were included. The mean age was 6.4 years old. The main indications were analysis of bronchial disease (44%), infectious disease (16%), interstitial disease (14%), or a malformation (9%). The aim of CT was diagnosis (61%) or follow-up of previous lung diseases (39%). Diagnosis chest-CT directly contributed to diagnosis in 48% of cases and to treatment in 24%. Follow-up CT contributed to diagnosis in 38% and treatment in 19% of cases. DLP and effective doses were significantly lower for CT performed in the university hospital, especially with the 128-slice CT compared to the others (P<0.001). The effective doses were: 128-slice CT, 0.61 mSv +/- 0.32; 64-slice CT, 1.24 mSv +/- 0.97; outside university hospital, 2.56 mSv +/- 1.98. CONCLUSION: This study confirms the role played by chest CT in children, which contributes to diagnosis and management of lung diseases. The main concern of CT application, especially in children, is the radiation burden. Children are more susceptible to the effects of radiation than adults and have a longer life expectancy to develop complications. Both radiologists and pediatricians should be aware of a potential risk and have to conjugate their efforts in reducing this risk. The wide range of radiation doses in this study for the same CT procedures underlines the extensive efforts still needed to limit radiation exposure in children. PMID- 24485864 TI - [Impact of corticosteroids in the immediate management of invasive meningococcal disease associated with hyperinvasive strains of the ST-11 clonal complex in children]. AB - OBJECTIVES: We used data from the Groupe de pathologie infectieuse pediatrique and Association clinique et therapeutique infantile du Val-de-Marne (GPIP/ACTIV) National Survey of Bacterial Meningitis in children and the National Reference Center for Meningococci (CNRM) microbiological data to assess the potential impact of corticosteroids on the immediate management of invasive meningococcal disease (IMD) associated with different genotypes, including highly pro inflammatory strains of the ST-11 clonal complex (genotype ST-11). METHODS: From 2001 to 2009, 259 pediatric wards and 168 microbiology laboratories distributed throughout France prospectively included all under-18-year-old patients with IMD (meningitis or purpura fulminans). The strains were sent to the CNRM for genotyping. We linked the ACTIV clinical data of IMD cases, where information on corticosteroid therapy was available, to strains isolated by the CRNM. RESULTS: A total of 1981 IMD cases were identified during the 8-year study, 805 cases (712 [88.5%] bacterial meningitis and 93 [11.5%] purpura fulminans) had steroid treatment data (33.8% received corticosteroids). The genotype of the strains was available for 410 patients (24.4% related to genotype ST-11; 100 patients). For all cases and regardless of the corticosteroids, mortality was significantly associated with the genotype ST-11 (OR=2.39, 95% CI [1.29; 4.42], P=0.004). For all cases and regardless of the genotypes of the isolates, mortality was also significantly higher for children with than without corticosteroid therapy (12.7% versus 4.5%, P<0.001). However, this treatment had been prescribed more frequently in severe cases, including shock, PF, coma and/or mechanical ventilation. For children who did not receive corticosteroids, the mortality rate was significantly higher with genotype ST-11 compared to other genotypes (OR=4.68 [1.91, 11.46], P=0.001). This difference disappeared in children who received corticosteroids. CONCLUSION: This study indicates that in the absence of corticosteroids, higher mortality in invasive meningococcal disease is associated with the ST-11 clonal complex strains. This suggests a possible positive effect of corticosteroid therapy depending on the genotype of the strain involved. PMID- 24485865 TI - How accurately can we predict the fracture load of the proximal femur using finite element models? AB - BACKGROUND: Current clinical methods for fracture prediction rely on two dimensional imaging methods such as dual-energy X-ray absorptiometry and have limited predictive value. Several researchers have tried to integrate three dimensional imaging techniques with the finite element (FE) method to improve the accuracy of fracture predictions. Before FE models could be used in clinical settings, a thorough validation of their accuracy is required. In this paper, we try to evaluate the current state of accuracy of subject-specific FE models that are used for prediction of the fracture load of proximal femora. METHODS: All the studies that have used FE for prediction of fracture load and have compared the predicted fracture load with experimentally measured fracture loads in vitro are identified through a systematic search of the literature. A quantitative analysis of the results of those studies has been carried out to determine the absolute prediction error, percentage error, and linear correlations between predicted and measured fracture loads. FINDINGS: The reported coefficients of determination (R(2)) vary between 0.773 and 0.96 while the percentage error in prediction of fracture load varies between 5 and 46% with most studies reporting percentage errors between 10 and 20%. INTERPRETATION: We conclude that FE models, which are currently used only experimentally, are in general more accurate than clinically used fracture risk assessment techniques. However, the accuracy of FE models depends on the details of their modeling methodologies. Therefore, modeling procedures need to be optimized and standardized before FE could be used in clinical settings. PMID- 24485866 TI - Temporary inactivation of the rodent hippocampus: an evaluation of the current methodology. AB - Temporary cellular inactivation is a useful and increasingly popular approach in examining brain function. In general the methods allow for fast-acting manipulations that have the advantage of being reversible. However, there is significant variation in detailed procedures across experiments and most authors show very little evidence about the extent or duration of inactivation. Here we investigate a commonly used method of temporarily inactivating the hippocampus in rats. Using immediate early gene activation after electroconvulsive shock we measure the extent of inactivation using different lengths of infusion needles and one vs. two bilateral infusion sites. Our methods allowed us to uncover some possible confounding factors. We suggest specific variations in the procedures which decrease or eliminate these problems. We also investigate the properties of the sodium channel blocker ropivacaine and recommend this drug based on its functional profile and established low level of toxicity. PMID- 24485867 TI - Validation of an enzyme-linked immunoassay (ELISA) for plasma oxytocin in a novel mammal species reveals potential errors induced by sampling procedure. AB - BACKGROUND: The neuropeptide oxytocin is increasingly the focus of many studies investigating human and animal social behaviours and diseases. However, interpretation and comparison of results is made difficult by a lack of consistent methodological approaches towards analysing this hormone. NEW METHOD: This study determined the sample collection and analysis protocols that cause the least amounts of protocol dependant variation in plasma oxytocin concentrations detected by ELISA. The effect of vacutainer type, sample extraction prior to analysis and capture and restraint protocol were investigated while validating an assay protocol for two novel species, grey seals (Halichoerus grypus) and harbour seals (Phoca vitulina). RESULTS: Where samples are extracted prior to analysis, vacutainer type (EDTA mean: 8.25+/-0.56 pg/ml, heparin mean: 8.25+/-0.62 pg/ml, p=0.82), time taken to obtain a sample and restraint protocol did not affect the concentration of oxytocin detected. However, concentrations of oxytocin detected in raw plasma samples were significantly higher than those in extracted samples, and varied significantly with vacutainer type (EDTA mean: 534.4+/-43.7 pg/ml, heparin mean: 300.9+/-19.6 pg/ml, p<0.001) and capture and restraint methodology. There was no relationship between oxytocin concentrations detected in raw and extracted plasma (p=0.25). COMPARISON WITH EXISTING METHOD(S): Over half the reviewed published studies analysing plasma oxytocin use raw plasma and different vacutainer types are used without consistency or justification through-out the literature. CONCLUSIONS: We caution that studies using raw plasma are likely to over estimate oxytocin concentrations, cannot be used to accurately infer true values via correlations and are susceptible to variation according vacutainer type. PMID- 24485868 TI - Applying EEG phase synchronization measures to non-linearly coupled neural mass models. AB - BACKGROUND: Recent neuroimaging analyses aim to understand how information is integrated across brain regions that have traditionally been studied in isolation; however, detecting functional connectivity networks in experimental EEG recordings is a non-trivial task. NEW METHOD: We use neural mass models to simulate 10-s trials with coupling between 1-3 and 5-8s and compare how well three phase-based connectivity measures recover this connectivity pattern across a set of experimentally relevant conditions: variable oscillation frequency and power spectrum, feed forward connections with or without feedback, and simulated signals with and without volume conduction. RESULTS: Overall, the results highlight successful detection of the onset and offset of significant synchronizations for a majority of the 28 simulated configurations; however, the tested phase measures sometimes differ in their sensitivity and specificity to the underlying connectivity. COMPARISON WITH EXISTING METHODS: Prior work has shown that these phase measures perform well on signals generated by a computational model of coupled oscillators. In this work we extend previous studies by exploring the performance of these measures on a different class of computational models, and we compare the methods on 28 variations that capture a set of experimentally relevant conditions. CONCLUSIONS: Our results underscore that no single phase synchronization measure is substantially better than all others, and experimental investigations will likely benefit from combining a set of measures together that are chosen based on both the experimental question of interest, the signal to noise ratio in the EEG data, and the approach used for statistical significance. PMID- 24485869 TI - A multi-digit tactile motion stimulator. AB - BACKGROUND: One of the hallmarks of haptic exploration is that it typically involves movement between skin and object. Explored objects may contact multiple digits simultaneously so information about motion must be integrated across digits, a process about which little is known. NEW METHOD: To fill this gap, we have developed a stimulator that allows for the simultaneous and independent delivery of motion stimuli to multiple digits. The stimulator consists of individual units that deliver motion with three degrees of freedom: rotation (to produce motion), vertical excursion (to control depth of indentation into the skin) and arm orientation (to control the direction of motion). Each degree of freedom is controlled by a single motor. The compact design of the simulator allows for the side-by-side arrangement of the stimulator units such that they impinge upon adjacent fingers. RESULTS: To demonstrate the functionality of the stimulator, we performed a series of psychophysical experiments that investigate the perception of motion on multiple fingers. We find that, while the sensitivity to changes in motion direction is equivalent whether stimuli are presented to the same or to different fingers, the perceived direction of motion depends on the relative configuration of the digits. COMPARISON WITH EXISTING METHODS: We replicated the results of previous experiments investigating motion discrimination with a single digit and were able to extend these findings by investigating motion perception across multiple digits. CONCLUSION: The novel motion stimulator will be an invaluable tool to investigate how motion information is integrated across multiple digits. PMID- 24485870 TI - In vitro electrophoresis and in vivo electrophysiology of peripheral nerve using DC field stimulation. AB - BACKGROUND: Given the movement of molecules within tissue that occurs naturally by endogenous electric fields, we examined the possibility of using a low-voltage DC field to move charged substances in rodent peripheral nerve in vitro. NEW METHOD: Labeled sugar- and protein-based markers were applied to a rodent peroneal nerve and then a 5-10 V/cm field was used to move the molecules within the extra- and intraneural compartments. Physiological and anatomical nerve properties were also assessed using the same stimulation in vivo. RESULTS: We demonstrate in vitro that charged and labeled compounds are capable of moving in a DC field along a nerve, and that the same field applied in vivo changes the excitability of the nerve, but without damage. CONCLUSIONS: The results suggest that low-voltage electrophoresis could be used to move charged molecules, perhaps therapeutically, safely along peripheral nerves. PMID- 24485871 TI - Sholl analysis: a quantitative comparison of semi-automated methods. AB - BACKGROUND: Sholl analysis remains one of the most commonly used methods to quantify neuronal dendritic complexity and is therefore a key analysis tool in neurobiology. While initially proposed when the quantification of neuronal structure was undertaken manually, the advent of software packages allowing automated analysis has resulted in the introduction of several semi and fully automated methods to quantify dendritic complexity. Unfortunately results from these methods have not in all cases been consistent. We therefore compared the results of five commonly used methods (Simple Neurite Tracer, manual, Fast Sholl, Bitmap, and Ghosh lab) using manual analysis as a ground truth. NEW METHOD: Comparison of four semi-automated methods to the manual method using diolistically labelled mouse retinal ganglion cells. RESULTS: We report consistency across a range of published techniques. While the majority perform well (Simple Neurite Tracer and Fast Sholl profiles have areas under the curve within 4.5% of the profile derived using the manual method), we highlight two areas in two of the methods (Bitmap and Ghosh lab methods) where errors may occur, namely undercounting (>20% relative to the manual profile) and a second peak. COMPARISON WITH EXISTING METHODS: Our results support published validation of the Fast Sholl method. CONCLUSIONS: Our study highlights the importance of manual calibration of automated analysis software. PMID- 24485872 TI - Cladribine in the treatment of acute myeloid leukemia. PMID- 24485873 TI - An Australian national panel study of diurnal temperature range and children's respiratory health. AB - BACKGROUND: It is still uncertain whether diurnal temperature range (DTR) affects children's respiratory function. OBJECTIVE: To examine the effects of DTR on lung function and respiratory symptoms for school children with asthma in Australia. METHODS: A panel of 270 children (ages 7-12 years) with asthma living in 6 Australian cities was recruited. They were asked to perform 3 successive forced expiratory maneuvers using a portable electronic peak flow meter twice daily for 4 weeks. The highest values for peak expiratory flow (PEF) were stored for each session. At the same time, they were asked to record their respiratory symptoms (eg, cough and/or phlegm and wheeze and/or chest tightness) every day in the morning (for nighttime symptoms) and evening (for daytime symptoms). Daily data on different metrics of ambient temperature and air pollution were obtained from fixed monitors nearby. Relative humidity data were downloaded from the Weather Underground website. Mixed models, adjusting for children's individual characteristics and air pollution, were used to examine the effects of DTR on PEF and respiratory symptoms. RESULTS: DTR had linear effects on PEF and respiratory symptoms. An increase in DTR induced a reduction in PEF and increased the occurrence of respiratory symptoms. In general, the effects lasted for 3 days (lag, 0-2 days). The effects occurred for both boys and girls. CONCLUSION: Our findings provide evidence that DTR had significant effects on lung function and respiratory symptoms for children with asthma. These results indicate that it is important and necessary to protect children with asthma from the effect of unstable weather. PMID- 24485874 TI - Sweat conductivity: an accurate diagnostic test for cystic fibrosis? AB - BACKGROUND: Sweat chloride test is the gold standard test for cystic fibrosis (CF) diagnosis. Sweat conductivity is widely used although still considered a screening test. METHODS: This was a prospective, cross-sectional, diagnostic research conducted at the laboratory of the Instituto da Crianca of the Hospital das Clinicas, Sao Paulo, Brazil. Sweat chloride (quantitative pilocarpine iontophoresis) and sweat conductivity tests were simultaneously performed in patients referred for a sweat test between March 2007 and October 2008. Conductivity and chloride cut-off values used to rule out or diagnose CF were <75 and >=90 mmol/L and <60 and >=60 mmol/L, respectively. The ROC curve method was used to calculate the sensitivity, specificity, positive (PPV) and negative predictive value (NPV), as well as the respective 95% confidence intervals and to calculate the area under the curve for both tests. The kappa coefficient was used to evaluate agreement between the tests. RESULTS: Both tests were performed in 738 children, and CF was ruled out in 714 subjects; the median sweat chloride and conductivity values were 11 and 25 mmol/L in these populations, respectively. Twenty-four patients who had received a diagnosis of CF presented median sweat chloride and conductivity values of 87 and 103 mmol/L, respectively. Conductivity values above 90 mmol/L had 83.3% sensitivity, 99.7% specificity, 90.9% PPV and 99.4% NPV to diagnose CF. The best conductivity cut-off value to exclude CF was <75 mmol/L. Good agreement was observed between the tests (kappa: 0.934). CONCLUSIONS: The sweat conductivity test yielded a high degree of diagnostic accuracy and it showed good agreement with sweat chloride. We suggest that it should play a role as a diagnostic test for CF in the near future. PMID- 24485875 TI - Impact of single immunosuppressive drug withdrawal on lymphocyte immunoreactivity. AB - BACKGROUND: Chronic rejection is a major cause of graft loss in kidney transplant recipients. Nonadherence to drug therapy is a well-recognized cause of chronic rejection leading to long-term graft dysfunction and failure for transplant recipients. Immunosuppressive medications with short half-lives that require frequent dosing, such as tacrolimus, complicate transplant regimens and may increase noncompliance. Regimens could be simplified using drugs with long half lives requiring once-daily administration, such as sirolimus. The impact of missing doses of single agents has not been studied extensively. Erratic compliance or temporary discontinuation of immunosuppressive drugs may have significant implications for chronic rejection. METHODS: Our study evaluated the impact of single drug withdrawal of commonly used immunosuppressive agents (sirolimus and tacrolimus) on lymphocyte responses. We analyzed lymphocyte proliferation, cytokine secretion, and adenosine triphosphate generation using a crossover study design with normal healthy patients. Lymphocyte proliferation was assessed using 5-bromo-2-deoxyuridine incorporation, and T cell function was analyzed by examining adenosine triphosphate generation. RESULTS: Our results indicate that sirolimus exerts prolonged suppression of lymphocyte proliferation and decreased interleukin 17A that lasts up to 48 h after drug withdrawal. In comparison, tacrolimus did not have a similar effect on lymphocyte proliferation or interleukin 17A secretion. CONCLUSION: Future analysis of sirolimus in diverse transplantation populations merits investigation. PMID- 24485876 TI - Immunotherapy for solid tumors--a review for surgeons. AB - Immunotherapy has evolved considerably in the last decade and is becoming an integral component of the armamentarium for the treatment of patients with advanced solid tumors. It is important for clinicians, especially surgeons, to understand the basic principles of novel immunotherapies and the immune system. This review summarizes the evolution of the most relevant immunotherapies, their mechanisms of action, the data supporting their clinical use, and integration of immunotherapy into multidisciplinary management of solid tumors. This review should serve as a primer for clinicians and surgeons to understand the rapidly evolving field of immunotherapy. PMID- 24485877 TI - Real time shear waves elastography monitoring of thermal ablation: in vivo evaluation in pig livers. AB - BACKGROUND: Thermal ablation is a widely used minimally invasive treatment modality for different cancers. However, lack of a real-time imaging system for accurate evaluation of the procedure is one of the reasons of local recurrences. Shear waves elastography (SWE) is a new ultrasound (US) imaging modality to quantify tissue stiffness. The aim of the study was to assess the feasibility and accuracy of US elastography for quantitative monitoring of thermal ablation and to determine the elasticity threshold predictive of coagulation necrosis. METHODS: A total of 29 in vivo thermal lesions were performed in pig livers with radiofrequency system. SWE and B-mode images were acquired simultaneously. Liver elasticity was quantified by using SWE data and expressed in kilopascal. After the procedure, pathologic analysis of treated tissues was compared with US images. The sensitivity and positive predictive value of the SWE maps of tissue elasticity were calculated and compared with the boundaries of the pale coagulation necrosis areas found at pathology. RESULTS: The liver mean elasticity values before and after thermal therapy were 6.4 +/- 0.3 and 38.1 +/- 2.5 kPa, respectively (P < 0.0001). For a threshold of 20 kPa, sensitivity (i.e., the rate of pixels correctly detected as necrosed tissue) was 0.8, and the positive predictive value (i.e., the rate of pixels in the elastographic map >20 kPa that actually developed coagulation necrosis) was 0.83. CONCLUSIONS: Tissue areas with coagulation necrosis are significantly stiffer than the surrounding tissue. SWE permits the real-time detection of coagulation necrosis produced by radiofrequency and could potentially be used to monitor US-guided thermal ablation. PMID- 24485878 TI - PFS as a surrogate for overall survival in metastatic melanoma. PMID- 24485879 TI - Surrogate endpoints for overall survival in metastatic melanoma: a meta-analysis of randomised controlled trials. AB - BACKGROUND: Recent phase 3 trials have shown an overall survival benefit in metastatic melanoma. We aimed to assess whether progression-free survival (PFS) could be regarded as a reliable surrogate for overall survival through a meta analysis of randomised trials. METHODS: We systematically reviewed randomised trials comparing treatment regimens in metastatic melanoma that included dacarbazine as the control arm, and which reported both PFS and overall survival with a standard hazard ratio (HR). We correlated HRs for overall survival and PFS, weighted by sample size or by precision of the HR estimate, assuming fixed and random effects. We did sensitivity analyses according to presence of crossover, trial size, and dacarbazine dose. FINDINGS: After screening 1649 reports and meeting abstracts published before Sept 8, 2013, we identified 12 eligible randomised trials that enrolled 4416 patients with metastatic melanoma. Irrespective of weighting strategy, we noted a strong correlation between the treatment effects for PFS and overall survival, which seemed independent of treatment type. Pearson correlation coefficients were 0.71 (95% CI 0.29-0.90) with a random-effects assumption, 0.85 (0.59-0.95) with a fixed-effects assumption, and 0.89 (0.68-0.97) with sample-size weighting. For nine trials without crossover, the correlation coefficient was 0.96 (0.81-0.99), which decreased to 0.93 (0.74-0.98) when two additional trials with less than 50% crossover were included. Inclusion of mature follow-up data after at least 50% crossover (in vemurafenib and dabrafenib phase 3 trials) weakened the PFS to overall survival correlation (0.55, 0.03-0.84). Inclusion of trials with no or little crossover with the random-effects assumption yielded a conservative statement of the PFS to overall survival correlation of 0.85 (0.51-0.96). INTERPRETATION: PFS can be regarded as a robust surrogate for overall survival in dacarbazine-controlled randomised trials of metastatic melanoma; we postulate that this association will hold as treatment standards evolve and are adopted as the control arm in future trials. FUNDING: None. PMID- 24485880 TI - The influence of discrimination on smoking cessation among Latinos. AB - BACKGROUND: Although studies have shown a cross-sectional link between discrimination and smoking, the prospective influence of discrimination on smoking cessation has yet to be evaluated. Thus, the purpose of the current study was to determine the influence of everyday and major discrimination on smoking cessation among Latinos making a quit attempt. METHODS: Participants were 190 Spanish speaking smokers of Mexican Heritage recruited from the Houston, TX metropolitan area who participated in the study between 2009 and 2012. Logistic regression analyses were conducted to evaluate the associations of everyday and major discrimination with smoking abstinence at 26 weeks post-quit. RESULTS: Most participants reported at least some everyday discrimination (64.4%), and at least one major discrimination event (56%) in their lifetimes. Race/ethnicity/nationality was the most commonly perceived reason for both everyday and major discrimination. Everyday discrimination was not associated with post-quit smoking status. However, experiencing a greater number of major discrimination events was associated with a reduced likelihood of achieving 7-day point prevalence smoking abstinence, OR=.51, p=.004, and continuous smoking abstinence, OR=.29, p=.018, at 26 weeks post-quit. CONCLUSIONS: Findings highlight the high frequency of exposure to discrimination among Latinos, and demonstrate the negative impact of major discrimination events on a smoking cessation attempt. Efforts are needed to attenuate the detrimental effects of major discrimination events on smoking cessation outcomes. PMID- 24485881 TI - Behavioral disinhibition in mice bred for high drinking in the dark (HDID) and HS controls increases following ethanol. AB - BACKGROUND: Alcohol consumption and behavioral inhibition share some common underlying genetic mechanisms. The current study examined whether lines of mice selected for high blood ethanol concentrations, attained by heavy drinking in the dark period (DID) of the light-dark cycle that models binge drinking, also exhibit higher levels of drug-naive inhibition. It also examined whether the administration of ethanol would result in higher levels of disinhibition in these selected lines compared to the founder stock (HS). METHODS: A Go/No-Go task was used to assess baseline inhibition and the effects of acute ethanol on disinhibition (response to a No-Go cue) in the HS line and in mice selected for high levels of DID (HDID-1 and HDID-2). RESULTS: Lines did not differ in inhibition at baseline and all lines showed increased disinhibition following moderate doses of ethanol. Ethanol decreased responding to Go cues for HDID-2 and HS lines at high doses but not HDID-1 mice. CONCLUSIONS: These data corroborate previous work showing ethanol-induced increases in behavioral disinhibition. The selection paradigm did not result in differential sensitivity to the disinhibiting effects of ethanol, but did result in differential sensitivity to the suppressant effects of ethanol on operant behavior between the two HDID lines. PMID- 24485882 TI - Muscle and fascicle excursion in children with cerebral palsy. AB - BACKGROUND: Fascicle length and fascicle excursion measurements in children with cerebral palsy have yielded inconsistent results. The purpose of this study was to measure in vivo passive fascicle lengths and fascicle excursions in the Medial Gastrocnemius muscle of children with cerebral palsy and typically developing controls. METHODS: We measured 11 children with spastic cerebral palsy and 14 controls between the ages of 9 and 16years. Ultrasound imaging was used to measure fascicle lengths while a dynamometer moved the ankle joint through the range of motion. A common range of motion for all subjects was used for analysis of fascicle excursion. FINDINGS: Fascicle lengths in children with cerebral palsy were 43% smaller than those for control subjects throughout the range of motion. The relative fascicle excursion was 92% greater on average for the cerebral palsy compared to the control group children. The muscle excursion for the control group children was greater than for the cerebral palsy group children. INTERPRETATION: Since the fascicles in children with spastic cerebral palsy are shorter, but they go through the same excursion as fascicles in typically developing children, sarcomeres within the medial gastrocnemius muscle must be working over a larger range of sarcomere lengths. Combined with findings of overstretched sarcomeres in spastic muscles reported in the literature, our results suggest that the increased passive forces and the weakness found in spastic muscles may be caused by a decrease in contractile filament overlap as sarcomeres are pulled to extreme lengths in children with cerebral palsy. PMID- 24485883 TI - Impaired control of weight bearing ankle inversion in subjects with chronic ankle instability. AB - BACKGROUND: Previous studies have proposed that evertor muscle weakness represents an important factor affecting chronic ankle instability. For research purposes, ankle evertor strength is assessed by means of isokinetic evaluations. However, this methodology is constraining for daily clinical use. The present study proposes to assess ankle evertor muscle weakness using a new procedure, one that is easily accessible for rehabilitation specialists. To do so, we compared weight bearing ankle inversion control between patients suffering from chronic ankle instability and healthy subjects. METHODS: 12 healthy subjects and 11 patients suffering from chronic ankle instability conducted repetitions of one leg weight bearing ankle inversion on a specific ankle destabilization device equipped with a gyroscope. Ankle inversion control was performed by means of an eccentric recruitment of evertor muscles. Instructions were to perform, as slow as possible, the ankle inversion while resisting against full body weight applied on the tested ankle. RESULTS: Data clearly showed higher angular inversion velocity peaks in patients suffering from chronic ankle instability. This illustrates an impaired control of weight bearing ankle inversion and, by extension, an eccentric weakness of evertor muscles. INTERPRETATION: The present study supports the hypothesis of a link between the decrease of ankle joint stability and evertor muscle weakness. Moreover, it appears that the new parameter is of use in a clinical setting. PMID- 24485884 TI - Mandard tumour regression grade, perineural invasion, circumferential resection margin and post-chemoradiation nodal status strongly predict outcome in locally advanced rectal cancer treated with preoperative chemoradiotherapy. AB - AIMS: The pathology of tumours after chemo/radiotherapy for locally advanced rectal cancer can be difficult to interpret. The ypTNM staging does not accurately predict outcomes. Therefore, we developed a new prognostic index for this purpose. MATERIALS AND METHODS: The Nottingham Rectal Cancer Prognostic Index (NRPI) is based on a study of 158 patients with locally advanced rectal cancer treated with preoperative chemo/radiotherapy at Nottingham University Hospital between April 2001 and December 2008. Patients were treated with radiotherapy to a dose of 50 Gy in 25 fractions over 5 weeks with/without concurrent capecitabine chemotherapy. Surgery was carried out after an interval of 6-10 weeks. Factors found to be significant on univariate analysis to predict for disease-free (DFS) and overall survival were further explored in multivariate analysis. The significant factors (Mandard tumour regression grade, perineural invasion, circumferential resection margin status and nodal status) were weighted to establish a score for the index. The median follow-up was 40 months (range 3 90 months). RESULTS: On survival analysis, four distinct prognostic groups were found: Score 0 = excellent prognosis, 1-3 = good prognosis, 4-8 = moderate prognosis, 9-14 = poor prognosis. The NRPI significantly predicted both DFS and overall survival (P < 0.0001). DFS at 5 years was 95, 63, 25 and 0% for the four groups. On multivariate analysis the NRPI was found to be the strongest predictor of DFS including nodal and circumferential resection margin status (P < 0.0001). It was a stronger predictor of overall survival than the American Joint Committee on Cancer/Dukes staging (P < 0.0001). CONCLUSIONS: The NRPI allocates patients into distinct prognostic categories. This seems to be a much stronger predictive factor than the American Joint Committee on Cancer/Dukes staging. This requires further validation, but seems to be a useful clinical index for future studies. PMID- 24485885 TI - Radical radiotherapy for bladder cancer - contemporary outcomes from a UK centre. PMID- 24485886 TI - Unique pharmacology of heteromeric alpha7beta2 nicotinic acetylcholine receptors expressed in Xenopus laevis oocytes. AB - alpha7beta2 is a novel type of nicotinic acetylcholine receptor shown to be uniquely expressed in cholinergic neurons of the basal forebrain and in hippocampal interneurons. We have compared the pharmacological properties of recombinant homomeric alpha7 and heteromeric alpha7beta2 nicotinic acetylcholine receptors in order to reveal the pharmacological consequences of beta2 subunit incorporation into the pentamer. The non-selective agonist epibatidine did not distinguish alpha7beta2 from alpha7 nicotinic acetylcholine receptors, but three other non-selective agonists (nicotine, cytisine and varenicline) were less efficacious on alpha7beta2 than on alpha7. A more dramatic change in efficacy was seen with eight different selective alpha7 agonists. Because of their very low intrinsic efficacy, some compounds became very efficacious functional antagonists at alpha7beta2 receptors. Three alpha4beta2 nicotinic receptor selective agonists that were not active on alpha7, were also inactive on alpha7beta2, and dihydro beta-erythroidine, an alpha4beta2 receptor-preferring antagonist, inhibited alpha7 and alpha7beta2 in a similar manner. These results reveal significant effects of beta2 incorporation in determining the relative efficacy of several non-selective and alpha7 selective agonists, and also show that incorporation of beta2 subunits does not cause a shift to a more "beta2-like" pharmacology of alpha7 nicotinic acetylcholine receptors. PMID- 24485887 TI - Effects of clonidine in the isolated rat testicular capsule. AB - The testicular capsule contracts in response to noradrenaline and adrenaline, but the effects of adrenoceptor agonists, as for instance clonidine, had not yet been thoroughly evaluated. The testicular capsule from adult male Wistar rats was isolated and mounted in organ bath and cumulative concentration curves were performed for clonidine and other adrenergic agonists in the absence or presence of alpha-adrenoceptors antagonists. The order of potency for agonists (pD2) was clonidine=adrenaline>UK 14,304>noradrenaline>phenylephrine>methoxamine. The consecutive curves for clonidine showed desensitization with 3-fold rightward shift and Emax reduction of 40%. The noradrenaline curves were 4.5, 19 and 190 fold less potent after clonidine pretreatment at 10-5, 10-4 or 10-3 M for 10 min, respectively, added to Emax decrease by about 20%. Clonidine (10-5 M for 10 min) was unable to alter the noradrenaline curves if the treatment was made in the presence of idazoxan (alpha2-adrenoceptor antagonist) whereas prazosin (alpha1 adrenoceptor antagonist) was ineffective. The effect of idazoxan 3*10-7 M on noradrenaline curves was decreased by 50% after clonidine pretreatment, as reflected by the concentration ratio of 5.2+/-1.2 (treated tissue) and 10.1+/-1.0 (untreated tissue). However, the concentration ratio for prazosin 3*10-8 M was unchanged. After phenoxybenzamine (irreversible antagonist of alpha1 adrenoceptor) pretreatment, the residual noradrenaline contraction was antagonized by idazoxan or prazosin with pKB values of 7.8 and 5.1, respectively. The results indicate the presence of alpha2-adrenoceptors in testicular capsule. Furthermore, these receptors may be desensitized by clonidine, causing a decreased potency of noradrenaline. PMID- 24485888 TI - Functional activation of Galphaq via serotonin2A (5-HT2A) and muscarinic acetylcholine M1 receptors assessed by guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding/immunoprecipitation in rat brain membranes. AB - Functional coupling between serotonin2A (5-HT2A) receptors and Galphaq proteins in native brain membranes has been sparsely reported thus far. In the present study, the guanosine-5'-O-(3-[35S]thio)triphosphate ([35S]GTPgammaS) binding assay combined with immunoprecipitation using magnetic beads (Dynabeads Protein A) coated with anti-Galphaq antibody was developed. Under experimental conditions optimised for assay constituents (GDP, MgCl2, and NaCl), for contents of membrane protein, anti-Galphaq antibody, and Dynabeads Protein A, and for the incubation period, 5-HT stimulated specific [35S]GTPgammaS binding to Galphaq in rat cerebral cortical membranes in a concentration-dependent and saturable manner, with a signal/noise ratio that was sufficiently high for further detailed pharmacological characterisation. This characterisation revealed an involvement of 5-HT2A receptors. Activation of Galphaq proteins was also detectable by the addition of carbachol via muscarinic acetylcholine M1 receptors, (-)-epinephrine, and dopamine, but not by L-glutamate or (+/-)-baclofen. When 5-HT2A receptors and M1 receptors were stimulated simultaneously, there were non-additive effects, indicating that the two receptors were coupled to the same components of Galphaq proteins in the rat cerebral cortex. This method will serve as an efficacious strategy for neurobiological investigations aimed at elucidating the physiological and pathological implications of signal transduction systems mediated via Galphaq proteins coupled with 5-HT2A receptors and muscarinic acetylcholine M1 receptors. PMID- 24485889 TI - Analgesic effect of minocycline in rat model of inflammation-induced visceral pain. AB - The present study investigates the analgesic effect of minocycline, a semi synthetic tetracycline antibiotic, in a rat model of inflammation-induced visceral pain. Inflammation was induced in male rats by intracolonic administration of tri-nitrobenzenesulphonic acid (TNBS). Visceral hyperalgesia was assessed by comparing the viscero-motor response (VMR) to graded colorectal distension (CRD) prior and post 7 days after TNBS treatment. Electrophysiology recordings from CRD-sensitive pelvic nerve afferents (PNA) and lumbo-sacral (LS) spinal neurons were performed in naive and inflamed rats. Colonic inflammation produced visceral hyperalgesia characterized by increase in the VMRs to CRD accompanied with simultaneous activation of microglia in the spinal cord and satellite glial cells (SGCs) in the dorsal root ganglions (DRGs). Selectively inhibiting the glial activation following inflammation by araC (Arabinofuranosyl Cytidine) prevented the development of visceral hyperalgesia. Intrathecal minocycline significantly attenuated the VMR to CRD in inflamed rats, whereas systemic minocycline produced a delayed effect. In electrophysiology experiments, minocycline significantly attenuated the mechanotransduction of CRD-sensitive PNAs and the responses of CRD-sensitive LS spinal neurons in TNBS-treated rats. While the spinal effect of minocycline was observed within 5min of administration, systemic injection of the drug produced a delayed effect (60min) in inflamed rats. Interestingly, minocycline did not exhibit analgesic effect in naive, non-inflamed rats. The results demonstrate that intrathecal injection of minocycline can effectively attenuate inflammation-induced visceral hyperalgesia. Minocycline might as well act on neuronal targets in the spinal cord of inflamed rats, in addition to the widely reported glial inhibitory action to produce analgesia. PMID- 24485890 TI - Saxagliptin affects long-bone microarchitecture and decreases the osteogenic potential of bone marrow stromal cells. AB - Diabetes mellitus is associated with a decrease in bone quality and an increase in fracture incidence. Additionally, treatment with anti-diabetic drugs can either adversely or positively affect bone metabolism. In this study we evaluated: the effect of a 3-week oral treatment with saxagliptin on femoral microarchitecture in young male non-type-2-diabetic Sprague Dawley rats; and the in vitro effect of saxagliptin and/or fetal bovine serum (FBS), insulin or insulin-like growth factor-1 (IGF1), on the proliferation, differentiation (Runx2 and PPAR-gamma expression, type-1 collagen production, osteocalcin expression, mineralization) and extracellular-regulated kinase (ERK) activation, in bone marrow stromal cells (MSC) obtained from control (untreated) rats and in MC3T3E1 osteoblast-like cells. In vivo, oral saxagliptin treatment induced a significant decrease in the femoral osteocytic and osteoblastic density of metaphyseal trabecular bone and in the average height of the proximal cartilage growth plate; and an increase in osteoclastic tartrate-resistant acid phosphatase (TRAP) activity of the primary spongiosa. In vitro, saxagliptin inhibited FBS-, insulin- and IGF1-induced ERK phosphorylation and cell proliferation, in both MSC and MC3T3E1 preosteoblasts. In the absence of growth factors, saxagliptin had no effect on ERK activation or cell proliferation. In both MSC and MC3T3E1 cells, saxagliptin in the presence of FBS inhibited Runx2 and osteocalcin expression, type-1 collagen production and mineralization, while increasing PPAR-gamma expression. In conclusion, orally administered saxagliptin induced alterations in long-bone microarchitecture that could be related to its in vitro down-regulation of the ERK signaling pathway for insulin and IGF1 in MSC, thus decreasing the osteogenic potential of these cells. PMID- 24485891 TI - Activation of PPARgamma attenuates LPS-induced acute lung injury by inhibition of HMGB1-RAGE levels. AB - HMGB1-RAGE signaling pathway is involved in the development of ALI/ARDS. At the same time, activation of PPARgamma has been shown to inhibit the occurrence of ALI/ARDS. However, it is unknown whether activation of PPARgamma benefits ALI/ARDS by regulation of HMGB1-RAGE signaling. This study aims to address these issues. We found in this study that LPS induced dramatic pathological changes of ALI in mice; these were accompanied with elevated expression of HMGB1 and RAGE. Prior treatment of mice with PPARgamma agonist rosiglitazone significantly suppressed LPS-induced ALI and reversed the elevation of HMGB1 and RAGE; these were accompanied with the induction of HO-1. The presence of selective HO-1 inhibitor Znpp abolished the protective effects of rosiglitazone on LPS-induced ALI. This study suggests that activation of PPARgamma inhibits the development of LPS-induced ALI by negative modulation of HMGB1-RAGE pathway, and has a potential value in the clinical treatment of such conditions. PMID- 24485892 TI - Arylbenzofuran isolated from Dalbergia odorifera suppresses lipopolysaccharide induced mouse BV2 microglial cell activation, which protects mouse hippocampal HT22 cells death from neuroinflammation-mediated toxicity. AB - Neuroinflammation is a key mechanism against infection, injury, and trauma in the central nervous system (CNS). The heartwood of Dalbergia odorifera T. Chen is an important source of traditional Korean and Chinese medicines. (2R, 3R) Obtusafuran (1) and isoparvifuran (2) are arylbenzofuran compounds isolated from D. odorifera. This study determined the efficacy of (1) and (2) in modulating the regulation of anti-inflammatory activity through the upregulation of heme oxygenase (HO)-1 in BV2 microglia. Compound (1) inhibited the protein expression of inducible nitric oxide synthase (iNOS), iNOS-derived nitric oxide (NO), cyclooxygenase (COX)-2, and COX-2-derived prostaglandin E2 (PGE2) in lipopolysaccharide (LPS)-stimulated mouse BV2 microglia. (2R, 3R)-Obtusafuran (1) also reduced tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL 1beta) production, and these anti-neuroinflammatory effects were shown to be correlated with the suppression of the phosphorylation and degradation of inhibitor of nuclear factor kappa B-alpha (IkappaB-alpha), and nuclear factor kappa B nuclear (NF-kappaB) translocation and DNA binding activity. In addition, (1) upregulated HO-1 expression via nuclear translocation of nuclear factor E2 related factor 2 (Nrf2) in mouse BV2 microglia. Using tin protoporphyrin (SnPP), an HO activity inhibitor, we verified that the inhibitory effects of (1) on the proinflammatory mediators and proteins were associated with the induction of HO-1 expression. Activated microglia-mediated cell death of mouse hippocampal HT22 cells was significantly repressed by (1). Our data suggest that (2R, 3R) obtusafuran (1) has therapeutic potential against neurodegenerative diseases caused by neuroinflammation. PMID- 24485893 TI - Modes of direct modulation by taurine of the glutamate NMDA receptor in rat cortex. AB - Taurine is an endogenous brain substance with robust neuromodulatory and possible neuroprotective properties. Though other mechanisms of action have been reported, its interaction with the NMDA (N-methyl-D-aspartic acid) receptor is undocumented. We investigated taurine's interaction with the NMDA receptor using electrophysiological and receptor binding approaches. The effects of taurine on field potential responses in layer-5 of prelimbic cortex in rat brain slices evoked by single-pulse electrical stimulation of ventral medial cortex were determined. Picrotoxin (80 uM) was present in all control and drug solutions to block the Cl(-) channels associated with the GABA-, taurine-, and strychnine sensitive glycine- receptors. A typical response consisted of an NBQX (2,3-dioxo 6-nitro-1,2,3,4-tetrahydrobenzo-[f]-quinoxaline-7-sulfonamide)-sensitive negative wave (N1) followed by a positive wave (P1) and a broad negativity (N2), both sensitive to dl-AP5 (dl-2-amino-5-phosphonopentanoic acid) inhibition. Taurine exerted a 41.5 +/- 8.3% (n = 9) voltage reduction within the late phase of N2. This taurine action was prevented by 100 uM AP5, but not by 10 uM nifedipine, supporting a direct modulation of NMDA receptor function by taurine, without requiring the involvement of the L-type Ca(2+) channel. Taurine did not alter specific [(3)H] MK-801 binding to rat cortical membranes in the presence of glycine or glutamate; but inhibited spermine-potentiated specific [(3)H] MK-801 binding to NMDA receptors by 15-20% in the presence of glycine. In addition, taurine reduced the apparent affinity of the NMDA receptor for glycine (in the presence of spermine) by 10-fold. These results show that taurine interacts directly with the NMDA receptor by multiple mechanisms. PMID- 24485894 TI - Altered energy production, lowered antioxidant potential, and inflammatory processes mediate CNS damage associated with abuse of the psychostimulants MDMA and methamphetamine. AB - Central nervous system (CNS) damage associated with psychostimulant dependence may be an ongoing, degenerative process with adverse effects on neuropsychiatric function. However, the molecular mechanisms regarding how altered energy regulation affects immune response in the context of substance use disorders are not fully understood. This review summarizes the current evidence regarding the effects of psychostimulant [particularly 3,4-methylenedioxy-N-methylamphetamine (MDMA) and methamphetamine] exposure on brain energy regulation, immune response, and neuropsychiatric function. Importantly, the neuropsychiatric impairments (e.g., cognitive deficits, depression, and anxiety) that persist following abstinence are associated with poorer treatment outcomes - increased relapse rates, lower treatment retention rates, and reduced daily functioning. Qualifying the molecular changes within the CNS according to the exposure and use patterns of specifically abused substances should inform the development of new therapeutic approaches for addiction treatment. PMID- 24485895 TI - A recombinant adenovirus bicistronically expressing porcine interferon-alpha and interferon-gamma enhances antiviral effects against foot-and-mouth disease virus. AB - Foot-and-mouth disease (FMD) is a virulent and economically costly disease in domestic livestock. Since the current vaccine available against FMD provides no protection until 7days postvaccination, the only alternative method to halt the spread of the FMD virus (FMDV) during outbreaks is by the application of anti viral agents. The combination of recombinant adenovirus expressing type I interferon (IFN-alpha) and adenovirus expressing type II IFN (IFN-gamma) has been reported to be an effective anti-viral treatment strategy against FMDV. Nevertheless, the recombinant adenovirus mixture may be inefficient because of the low anti-viral efficiency of IFN-gamma compared to that of IFN-alpha. In this study, we generated a recombinant adenovirus co-expressing porcine IFN-alpha and IFN-gamma in tandem using an FMDV 2A sequence to mediate effective cleavage of the two proteins (referred to as Ad-porcine IFN-alphagamma). We demonstrated that both recombinant porcine IFN-alpha and IFN-gamma were expressed and interferon stimulated gene (ISG)s related with IFN-alpha and IFN-gamma were induced in porcine kidney (IBRS-2) cells infected with Ad-porcine IFN-alphagamma. Additionally, the anti-viral effects of Ad-porcine IFN-alphagamma against FMDV were enhanced both in IBRS-2 cells and in CD-1 (ICR) suckling mice compared to that of adenovirus expressing only a single protein. We propose that Ad-porcine IFN-alphagamma could be a rapid, highly efficient, convenient anti-viral agent against FMDV. PMID- 24485896 TI - Coxsackievirus B3 VLPs purified by ion exchange chromatography elicit strong immune responses in mice. AB - Coxsackievirus B3 (CVB3) is an important cause of acute and chronic viral myocarditis, and dilated cardiomyopathy (DCM). Although vaccination against CVB3 could significantly reduce the incidence of serious or fatal viral myocarditis and various other diseases associated with CVB3 infection, there is currently no vaccine or therapeutic reagent in clinical use. In this study, we contributed towards the development of a CVB3 vaccine by establishing an efficient and scalable ion exchange chromatography-based purification method for CVB3 virus and baculovirus-insect cell-expressed CVB3 virus-like particles (VLPs). This purification system is especially relevant for vaccine development and production on an industrial scale. The produced VLPs were characterized using a number of biophysical methods and exhibited excellent quality and high purity. Immunization of mice with VLPs elicited a strong immune response, demonstrating the excellent vaccine potential of these VLPs. PMID- 24485897 TI - Educational attainment and hippocampal atrophy in the Alzheimer's disease neuroimaging initiative cohort. AB - INTRODUCTION: Subjects with higher cognitive reserve (CR) may be at a lower risk for Alzheimer's disease (AD), but the neural mechanisms underlying this are not known. Hippocampal volume loss is an early event in AD that triggers cognitive decline. MATERIALS AND METHODS: Regression analyses of the effects of education on MRI-measured baseline HV in 675 subjects (201 normal, 329 with mild cognitive impairment (MCI), and 146 subjects with mild AD), adjusting for age, gender, APOE E4 status and intracranial volume (ICV). Subjects were derived from the Alzheimer's Disease Neuroimaging Initiative (ADNI), a large US national biomarker study. RESULTS: The association between higher education and larger HV was significant in AD (P=0.014) but not in cognitively normal or MCI subjects. In AD, HV was about 8% larger in a person with 20 years of education relative to someone with 6 years of education. There was also a trend for the interaction between education and APOE E4 to be significant in AD (P=0.056). CONCLUSION: A potential protective association between higher education and lower hippocampal atrophy in patients with AD appears consistent with prior epidemiologic data linking higher education levels with lower rates of incident dementia. Longitudinal studies are warranted to confirm these findings. PMID- 24485898 TI - MRI abnormality of the pulvinar in patients with status epilepticus. AB - OBJECTIVE: Recently, magnetic resonance imaging (MRI) abnormalities of the pulvinar in patients with epilepsy have received greater attention, but their occurrence and features have not been fully elucidated. Therefore, we investigated the clinical and radiological features of patients with epilepsy who presented MRI abnormalities of the pulvinar. PATIENTS AND METHODS: We retrospectively investigated 225 consecutive patients who came to our institute because of seizures and underwent an MRI within 24h. The patients who exhibited pulvinar MRI abnormalities, their profile, seizure type, efficacy of medication, and chronological changes of MRI findings were examined. RESULTS: Out of the 225 patients who underwent MRI within 24h of seizure, 17 exhibited MRI abnormalities of the pulvinar. All of these 17 patients presented status epilepticus. Bilateral pulvinar diffusion-weighted imaging (DWI) hyperintensity was observed in 3 patients and unilateral pulvinar DWI hyperintensity in the other 14. Out of these 14 patients, 7 exhibited DWI hyperintensity in the ipsilateral cerebral cortex, and 10 patients presented an old lesion due to stroke or trauma. CONCLUSIONS: Our results demonstrated that the involvement of the pulvinar in status epilepticus is more frequent than expected and consisted of unilateral or bilateral DWI hyperintensities that may completely normalize. These pulvinar MRI abnormalities possibly reflect the epileptogenic hyperexcitation of different cortical areas through their connections with the pulvinar. PMID- 24485899 TI - Anti-KANNO: a novel alloantibody against a red cell antigen of high frequency. AB - We encountered a broadly reactive red cell alloantibody in 1991, reacting unlike any other known antibody, and named it anti-KANNO after the first patient. A total of 28 cases of anti-KANNO in the Japanese literature were reviewed. To distinguish KANNO from other antibodies against high-frequency antigens, including anti-JMH, anti-Ch/Rg, and anti-Jr(a), we conducted serologic studies with proteolytic enzyme and chemical treatments, complement sensitization against red cells, and serum neutralization techniques. Reactivity of anti-KANNO against red cells lacking high-frequency antigens and antisera to high-frequency antigens against KANNO cells were tested. Among the 28 patients, 26 were female, of whom 25 had a history of pregnancy. Red cells from patient KANNO were reactive with antisera against antigens of high frequency. Anti-KANNO reacted weakly with all cells known to lack high-frequency antigens. It reacted with 2 aminoethylisothiouronium bromide, so it can be distinguished from anti-JMH. Differences among anti-KANNO, anti-Ch/Rg, and anti-Jr(a) emerged with enzyme treated cells, complement-sensitized cells, and the addition of normal serum. As yet, there are no reports of hemolytic transfusion reaction or hemolytic disease of the fetus and newborn attributable to anti-KANNO. It appears that anti-KANNO is a newly characterized antibody more likely stimulated by pregnancy than by transfusion and with little or no clinical significance. Further surveillance and investigation of anti-KANNO, its antigen biochemistry, and its genetics are warranted. PMID- 24485900 TI - Widespread pH abnormalities in patients with malformations of cortical development and epilepsy: a phosphorus-31 brain MR spectroscopy study. AB - INTRODUCTION: Neuroimaging studies demonstrate that not only the lesions of malformations of cortical development (MCD) but also the normal-appearing parenchyma (NAP) present metabolic impairments, as revealed with (1)H-MRS. We have previously detected biochemical disturbances in MCD lesions with phosphorus 31 magnetic resonance spectroscopy (31P-MRS). Our hypothesis is that pH abnormalities extend beyond the visible lesions. METHODS: Three-dimensional 31P MRS at 3.0 T was performed in 37 patients with epilepsy and MCD, and in 31 matched-control subjects. The patients were assigned into three main MCD subgroups: cortical dysplasia (n=10); heterotopia (n=14); schizencephaly/polymicrogyria (n=13). Voxels (12.5 cm3) were selected in five homologous regions containing NAP: right putamen; left putamen; frontoparietal parasagittal cortex; right centrum semiovale; and left centrum semiovale. Robust methods of quantification were applied, and the intracellular pH was calculated with the chemical shifts of inorganic phosphate (Pi) relative to phosphocreatine (PCr). RESULTS: In comparison to controls and considering a Bonferroni adjusted p value <0.01, MCD patients presented significant reduction in intracellular pH in the frontoparietal parasagittal cortex (6.985+/-0.022), right centrum semiovale (7.004+/-0.029), and left centrum semiovale (6.995+/-0.030), compared to controls (mean values+/-standard deviations of 7.087+/-0.048, 7.096+/-0.042, 7.088+/ 0.045, respectively). Dunnet and Dunn tests demonstrated that the differences in pH values remained statistically significant in all MCD subgroups. No significant differences were found for the putamina. CONCLUSION: The present study demonstrates widespread acidosis in the NAP, and reinforces the idea that MCD visible lesions are only the tip of the iceberg. PMID- 24485902 TI - Treating the whole not the hole: necessary coupling of technologies for diabetic foot ulcer treatment. AB - Type 2 diabetes is the epidemic of our generation, and diabetic foot ulcers (DFUs) are a major complication. Although DFU formation itself can indicate disease progression, the failure to effectively treat ulcers contributes further to a decay in patient quality of life and increased mortality. Herein we discuss the development of next-generation DFU therapies including: (i) topical growth factors, (ii) scaffolds, and (iii) cellular therapies. Individually these therapies have yielded measurable but modest improvements in DFU repair. Because DFUs arise as a result of multiple biochemical deficiencies, a singular treatment modality is unlikely to be effective. Next-generation DFU technologies must be combined to address effectively the complex underlying pathology and enable reliable DFU repair. PMID- 24485901 TI - The new normal: immunomodulatory agents against sepsis immune suppression. AB - Sepsis is the leading cause of death among critically ill patients in intensive care units, and treatment options are limited. Therapies developed against the proinflammatory stage have failed clinically; therefore, new approaches that target the host immune response in sepsis are necessary. Increasing evidence suggests that a major pathophysiological event in sepsis is immune suppression, often resulting in secondary fungal, bacterial, or viral infections. Recent studies from animal sepsis models and patient samples suggest that cytokines such as interleukin-7 (IL-7), IL-15, granulocyte macrophage colony-stimulating factor (GM-CSF), as well as co-inhibitory molecule blockade, such as anti-programmed cell death receptor-1 (anti-PD-1) and anti-B and T lymphocyte attenuator (anti BTLA), may have utility in alleviating the clinical morbidity associated with sustained sepsis. This review discusses some of these novel immunomodulatory agents and evaluates their potential use as therapeutics. PMID- 24485903 TI - The outer membrane protein P2 (OmpP2) of Haemophilus parasuis induces proinflammatory cytokine mRNA expression in porcine alveolar macrophages. AB - Porins, expressed by Gram-negative bacteria, have several biological effects on host tissues or cells. The outer membrane protein P2 (OmpP2), a member of the porin family, has been identified as a multifunctional protein involved in the pathogenicity of Haemophilus parasuis. In the present study, it was shown that OmpP2 (0.5-10 MUg/mL) from H. parasuis Nagasaki strain up-regulated mRNA expression of interleukin (IL)-1alpha, IL-1beta, IL-6 and IL-8 in porcine alveolar macrophages (PAM, 3D4/31) in vitro, in a dose-dependent manner. Moreover, OmpP2 porin induced a more prolonged cytokine response in PAM than that of the lipooligosaccharide (LOS) from this microorganism. The data demonstrate that H. parasuis OmpP2 can stimulate proinflammatory cytokine mRNA expression, suggesting that this particular porin might play an important role in the pathogenesis of disease caused by H. parasuis. PMID- 24485904 TI - Respiratory disease and particulate air pollution in Santiago Chile: contribution of erosion particles from fine sediments. AB - Air pollution in Santiago is a serious problem every winter, causing thousands of cases of breathing problems within the population. With more than 6 million people and almost two million vehicles, this large city receives rainfall only during winters. Depending on the frequency of storms, statistics show that every time it rains, air quality improves for a couple of days, followed by extreme levels of air pollution. Current regulations focus mostly on PM10 and PM2.5, due to its strong influence on respiratory diseases. Though more than 50% of the ambient PM10s in Santiago is represented by soil particles, most of the efforts have been focused on the remaining 50%, i.e. particulate material originating from fossil and wood fuel combustion, among others. This document emphasizes the need for the creation of erosion/sediment control regulations in Chile, to decrease respiratory diseases on Chilean polluted cities. PMID- 24485905 TI - Can ammonia tolerance amongst lichen functional groups be explained by physiological responses? AB - Ammonia (NH3) empirical critical levels for Europe were re-evaluated in 2009, based mainly on the ecological responses of lichen communities without acknowledging the physiological differences between oligotrophic and nitrophytic species. Here, we compare a nitrogen sensitive lichen (Evernia prunastri) with a nitrogen tolerant one (Xanthoria parietina), focussing on their physiological response (Fv/Fm) to short-term NH3 exposure and their frequency of occurrence along an NH3 field gradient. Both frequency and Fv/Fm of E. prunastri decreased abruptly above 3 MUg m(-3) NH3 suggesting direct adverse effects of NH3 on its photosynthetic performance. By contrast, X. parietina increased its frequency with NH3, despite showing decreased capacity of photosystem II above 50 MUg m(-3) NH3, suggesting that the ecological success of X. parietina at ammonia-rich sites might be related to indirect effects of increased nitrogen (NH3) availability. These results highlight the need to establish NH3 critical levels based on oligotrophic lichen species. PMID- 24485906 TI - Height, aging and cognitive abilities across Europe. AB - Previous research has found that as a marker of childhood circumstances, height is correlated with cognitive functioning at older ages. Using data from the Survey of Health, Ageing, and Retirement in Europe (SHARE) and about 17,000 respondents from 11 countries, we find that height is positively and significantly associated with cognitive functioning in later life despite controlling for a myriad of possible confounding factors. A 10 cm increase in height is associated with a 0.04 standard deviation increase in a summary cognitive score (mean 0.02, std. dev. 0.77). We find that being born in a country where the infant mortality rate at the time of birth is high has a negative and significant influence on cognitive functioning in later life. A 10% increase in the infant mortality rate is associated with a 0.1 standard deviation decrease in the summary cognitive score. We also find some evidence that height serves as a protective factor against age related deterioration in cognitive functioning. For persons of average stature, age related decreases in cognition scores are 3-5 percentage points smaller if they move up a quartile in the height distribution. Our results also suggest that there is a significant positive association between height and cognitive abilities across countries for this pre-1950 birth cohort of respondents, with correlations ranging from 0.4 to 0.8. PMID- 24485908 TI - Effects of storm runoff on the thermal regime and water quality of a deep, stratified reservoir in a temperate monsoon zone, in Northwest China. AB - Jinpen Reservoir is a deep, stratified reservoir in Shaanxi province, located in a warm temperate zone of Northwest China. Influenced by a temperate monsoon climate, more than 60% of the annual precipitation is concentrated from late summer to autumn (July-September). In recent years, extreme rainfall events occurred more frequently and strongly affected the thermal structure, mixing layer depth and evolution of stratification of Jinpen Reservoir. The reservoir's inflow volume increased sharply after heavy rainfall during the flooding season. Large volumes of inflow induced mixing of stratified water zones in early autumn and disturbed the stratification significantly. A temporary positive effect of such disturbance was the oxygenation of the water close to the bottom of the reservoir, leading to inhibition of the release of nutrients from sediments, especially phosphate. However, the massive inflow induced by storm runoff with increased oxygen-consuming substances led to an increase of the oxygen consumption rate. After the bottom water became anaerobic again, the bottom water quality would deteriorate due to the release of pollutants from sediments. Heavy rainfall events could lead to very high nutrient input into the reservoir due to massive erosion from the surrounding uninhabited steep mountains, and the particulate matter contributed to most nutrient inputs. Reasonably releasing density flow is an effective way to reduce the amounts of particulate associated pollutants entering the reservoir. Significant turbid density flow always followed high rainfall events in Jinpen Reservoir, which not only affected the reservoir water quality but also increased costs of the drinking water treatment plant. Understanding the effects of the storm runoff on the vertical distributions of water quality indicators could help water managers to select the proper position of the intake for the water plant in order to avoid high turbidity outflow. PMID- 24485909 TI - Application of a sewage-based approach to assess the use of ten illicit drugs in four Chinese megacities. AB - Sewage-based epidemiology was applied for the first time to a number of mainland Chinese megacities. The application monitored influents to 9 sewage treatment plants (STPs) to estimate the use of illicit drugs in Beijing, Guangzhou, Shenzhen, and Shanghai. Altogether, 11.4 million inhabitants were covered during September-October 2012. 24-h composite raw sewage samples were collected for 4 consecutive days at each STP. Each collected sample was analyzed for cocaine, benzoylecgonine, ecgonine methylester, methadone, 2-ethylidene-1,5-dimethyl-3,3 diphenylpyrrolidine, 6-monoacetylmorphine, amphetamine, methamphetamine, ecstasy, mephedrone, methylenedioxypyrovalerone, 11-nor-9-carboxy-delta-9 tetrahydrocannabinol, ketamine, and norketamine. Through the analysis of these chemical residues, the use of amphetamine, cannabis, cocaine, ecstasy, heroin, mephedrone, methadone, methamphetamine, methylenedioxypyrovalerone and ketamine among Chinese urban inhabitants was monitored. The results obtained demonstrated in a quantitative way that the drug use patterns of Chinese are different from their European counterparts. Abuse of methamphetamine and ketamine was particularly noteworthy in China, while consumption of cocaine and ecstasy, the most popular drugs in Europe, was very low among the sampled Chinese inhabitants. Further, the use of most drugs demonstrated a geographical trend, since their use was much higher in the southern cities of Shenzhen and Guangzhou than it was in Beijing and Shanghai. Interestingly, the exclusive, but minor, metabolite of heroin, 6-monoacetylmorphine, was detected only sporadically. This would suggest that the use of heroin among Chinese urban users sampled in the study was low. Further, the patterns of drug use observed during the study are largely consistent with trends reported by the United Nations Office on Drugs and Crime. Overall, our study suggests that sewage-based epidemiology can readily be used to monitor the use of illicit drugs in those countries/regions where traditional means to monitor drug use patterns have only yielded limited or information of questionable reliability. PMID- 24485910 TI - Does measuring the median nerve at the carpal tunnel outlet improve ultrasound CTS diagnosis? AB - INTRODUCTION: Nerve conduction is often regarded as more sensitive than ultrasonography (US) for diagnosing carpal tunnel syndrome (CTS). The diagnostic value of US derives from median nerve enlargement occurring at both ends of the carpal tunnel resulting in a dumbbell-like swelling from carpal tunnel pressure. An important reason for the inferior sensitivity of US may be because measurements are restricted to the carpal tunnel inlet. We investigate the value of including median nerve enlargement at the carpal tunnel outlet for diagnosing CTS. METHODS: Retrospective cohort study of nerve conduction verified CTS, determining sensitivity, specificity, and positive and negative predictive values of carpal tunnel inlet and outlet median nerve cross sectional area as determined by US for the diagnosis of CTS. Nerve conduction graded CTS severity. RESULTS: 127 hands from 77 patients with CTS and 35 control healthy hands were assessed. US sensitivity for diagnosing CTS increased from 65% to 84% by including outlet enlargement of the median nerve. Specificity changed from 94% to 86%, positive predictive value from 98% to 96% and the negative predictive value from 43% to 60%. 25 hands out of the 127 from CTS patients showed enlargement restricted to the outlet and mainly occurred in moderate CTS. CONCLUSION: In our population, the use of carpal tunnel outlet median nerve enlargement in addition to inlet median nerve size increases sensitivity for diagnosing CTS by 19%. PMID- 24485911 TI - A novel SCARB2 mutation in progressive myoclonus epilepsy indicated by reduced beta-glucocerebrosidase activity. AB - Action myoclonus renal failure (AMRF) syndrome is a rare form of progressive myoclonus epilepsy with renal dysfunction related to mutations in the SCARB2 gene. This gene is involved in lysosomal mannose-6-phosphate-independent trafficking of beta-glucocerebrosidase (GC), an enzyme deficient in Gaucher disease. We report a family with myoclonic epilepsy, ataxia and skeletal muscle atrophy but without cognitive impairment or overt renal disease. A novel SCARB2 mutation was indicated by a striking discrepancy between lymphocyte and fibroblast GC activity in the proband evaluated for possible Gaucher disease. Our findings expand the genetic and phenotypic diversity of AMRF and suggest that low GC activity may present an important biochemical clue to the diagnosis of AMRF. PMID- 24485912 TI - Molecular characterization of collaborator of ARF (CARF) as a DNA damage response and cell cycle checkpoint regulatory protein. AB - CARF is an ARF-binding protein that has been shown to regulate the p53-p21-HDM2 pathway. CARF overexpression was shown to cause growth arrest of human cancer cells and premature senescence of normal cells through activation of the p53 pathway. Because replicative senescence involves permanent withdrawal from the cell cycle in response to DNA damage response-mediated signaling, in the present study we investigated the relationship between CARF and the cell cycle and whether it is involved in the DNA damage response. We demonstrate that the half life of CARF protein is less than 60 min, and that in cycling cells CARF levels are highest in G2 and early prophase. Serially passaged normal human skin and stromal fibroblasts showed upregulation of CARF during replicative senescence. Induction of G1 growth arrest and senescence by a variety of drugs was associated with increase in CARF expression at the transcriptional and translational level and was seen to correlate with increase in DNA damage response and checkpoint proteins, ATM, ATR, CHK1, CHK2, gammaH2AX, p53 and p21. Induction of growth arrest by oncogenic RAS and shRNA-mediated knockdown of TRF2 in cancer cells also caused upregulation of CARF. We conclude that CARF is associated with DNA damage response and checkpoint signaling pathways. PMID- 24485914 TI - A review of health governance: definitions, dimensions and tools to govern. AB - BACKGROUND: The premise that good governance will ultimately lead to better health outcomes has been central to the proliferation of work in this area over the past decade. OBJECTIVE: To consolidate and align literature on governance by presenting an overview of efforts to define, describe and operationalize the health governance function. METHODS: A targeted review of governance literature. RESULTS: (1) A variety of terms have been assigned to precede health governance definitions. These terms commonly describe governance ideals (e.g. good, democratic) or characteristics of the organization of actors in governance arrangements (e.g. hierarchical, networked). (2) Dimensions of governance are defined from different perspectives and in varied combinations, capturing values, sub-functions and/or outcomes of governance. (3) Tools used to govern remain to be cataloged, however, measures can be aligned according to dimensions of governance or their ability to create specific relationships between actors. DISCUSSION: Resolving the conceptual confusion around health governance requires recognition for the differences in the premise and approaches taken to defining governance, as well as specifying core dimensions and aligning applicable tools. CONCLUSION: Despite a growing literature base, a concerted effort is needed for a more accessible understanding of health governance that is both practical at present and actionable for policy-makers. PMID- 24485913 TI - [Unusual location of molluscum contagiosum]. PMID- 24485915 TI - [The rectal prolapse dilemma: abundance of adjectives]. PMID- 24485916 TI - Diverse effect of different odor stimuli on behavior and Fos protein production in the olfactory system neurogenic region of adult rats. AB - Previously it has been demonstrated that processes of postnatal neurogenesis in the olfactory system neurogenic region-the subventricular zone (SVZ), rostral migratory stream (RMS), and olfactory bulb (OB) can be significantly altered by different factors of an environment. However, the mechanisms involved in regulation of neurogenesis by exogenous factors in the olfactory system remain unclear. The purpose of the present study was to contribute to the understanding of these mechanisms by immunohistochemical assessment of Fos protein induction in areas of adult neurogenesis. To evaluate the coordinate activation of Fos production in neurons of the olfactory system neurogenic region, a brief exposure to artificial odor (eau de Cologne) or naturalistic odor (cat odor) has been used in alert rats. Our results revealed that the effects of these odors are easily distinguishable at both the behavioral and the morphological level. Cat odor induced greater changes in anxiety level, and produced typical pattern of Fos activation in the accessory olfactory bulb (AOB), a brain region associated with defensive behavior. An important finding is, that next to distinct Fos expression in the OB and the AOB, Fos positive cells have been found also within the SVZ/RMS of the odor stimulated rats. Interestingly, Fos expression in the RMS was detected only after exposure to artificial odor stimulus. These results provide new evidence that some SVZ/RMS cells have complete prerequisites necessary for the Fos signal transduction cascade. PMID- 24485917 TI - The putative pigeon homologue to song bird LMAN does not modulate behavioral variability. AB - The active generation of behavioral variability is thought to be a pivotal element in reinforcement based learning. One example for this principle is song learning in oscine birds. Oscines possess a highly specialized set of brain areas that compose the song system. It is yet unclear how the song system evolved. One important hypothesis assumes a motor origin of the song system, i.e. the song system may have developed from motor pathways that were present in an early ancestor of extant birds. Indeed, in pigeons neural pathways are present that parallel the song system. We examined whether one component of these pathways, a forebrain area termed nidopallium intermedium medialis pars laterale (NIML), is functionally comparable to its putative homologue, the lateral magnocellular nucleus of the anterior nidopallium (LMAN) of the song system. LMAN conveys variability into the motor output during singing; a function crucial for song learning and maintenance. We tested if NIML is likewise associated with the generation of variability. We used a behavioral paradigm in which pigeons had to find hidden target areas on a touch screen to gain food rewards. Alterations in pecking variability would result in changes of performance levels in this search paradigm. We found that pharmacological inactivation of NIML did not reduce pecking variability contrasting increases of song stereotypy observed after LMAN inactivation. PMID- 24485918 TI - Doping control analyses in horseracing: a clinician's guide. AB - Doping(1) in sports is highly detrimental, not only to the athletes involved but to the sport itself as well as to the confidence of the spectators and other participants. To protect the integrity of any sport, there must be in place an effective doping control program. In human sports, a 'top-down' and generally unified approach is taken where the rules and regulations against doping for the majority of elite sport events held in any country are governed by the World Anti Doping Agency (WADA). However, in horseracing, there is no single organisation regulating this form of equestrian sport; instead, the rules and regulations are provided by individual racing authorities and so huge variations exist in the doping control programs currently in force around the world. This review summarises the current status of doping control analyses in horseracing, from sample collection, to the analyses of the samples, and to the need for harmonisation as well as exploring some of the difficulties currently faced by racing authorities, racing chemists and regulatory veterinarians worldwide. PMID- 24485919 TI - Stiff-knee gait in cerebral palsy: how do patients adapt to uneven ground? AB - Patients with cerebral palsy frequently experience foot dragging and tripping during walking due to reduced toe clearance mostly caused by a lack of adequate knee flexion in swing (stiff-knee gait). The aim of this study was to investigate adaptive mechanism to an uneven surface in stiff-knee walkers with cerebral palsy. Sixteen patients with bilateral cerebral palsy, GMFCS I-II and stiff-knee gait, mean age 14.1 (SD=6.2) years, were compared to 13 healthy controls with mean age 13.5 (SD=4.8) years. Gait analysis including EMG was performed under even and uneven surface conditions. Similar strategies to improve leg clearance were found in patients as well as in controls. Both adapted with significantly reduced speed and cadence, increased outward foot rotation, knee and hip flexion as well as anterior pelvic tilt. Therefore cerebral palsy and stiff-knee gait did not affect the adaptation capacity on the uneven surface. On the uneven surface an average increase in knee flexion of 7 degrees (SD=3 degrees ) and 12 degrees (SD=5 degrees ) was observed in controls and patients with cerebral palsy, respectively. Although rectus femoris activity was increased in patients with cerebral palsy, they were able to increase their knee flexion during swing. The results of this study suggest that walking on uneven surface has the potential to improve knee flexion in stiff-knee walkers. Therefore training on uneven surface could be used as a conservative treatment regime alone, in combination with Botulinum neurotoxin or in the rehabilitation of surgery. PMID- 24485920 TI - Differential diagnosis of parkinsonism with visual inspection of posture and gait in the early stage. AB - BACKGROUND: Parkinson's disease (PD) differs from atypical parkinsonism in many clinical aspects. Principally, posture and gait are distinct features in the early stages of the disease; thus, these differences can be helpful in differential diagnosis. METHODS: We analyzed videos of patients with PD or atypical parkinsonism. A total of 76 patients with early PD (n=56) or atypical parkinsonism (n=20) were included. Items related to posture and gait were classified into three categories (standing, gait and associated symptoms) and each sub-item was analyzed. RESULTS: Asymmetric arm-swing (p=0.004) and accompanying tremor (p=0.016) were significant indicators of early-stage PD. Staggering gait (p=0.007) and en-bloc turning (p=0.026) were more common in atypical parkinsonism. Characteristics with a high odds-ratio for atypical parkinsonism were en-bloc turning (beta=8.475, p=0.032) and normal arm-swing (beta=14.6084, p=0.036). CONCLUSIONS: Visual inspection of gait and posture provides reliable clues in the differential diagnosis of parkinsonism. PMID- 24485921 TI - Detecting glaucoma using automated pupillography. AB - OBJECTIVE: To evaluate the ability of a binocular automated pupillograph to discriminate healthy subjects from those with glaucoma. DESIGN: Cross-sectional observational study. PARTICIPANTS: Both eyes of 116 subjects, including 66 patients with glaucoma in at least 1 eye and 50 healthy subjects from the Diagnostic Innovations in Glaucoma Study. Eyes were classified as glaucomatous by repeatable abnormal standard automated perimetry (SAP) or progressive glaucomatous changes on stereophotographs. METHODS: All subjects underwent automated pupillography using the RAPDx pupillograph (Konan Medical USA, Inc., Irvine, CA). MAIN OUTCOME MEASURES: Receiver operating characteristic (ROC) curves were constructed to assess the diagnostic ability of pupil response parameters to white, red, green, yellow, and blue full-field and regional stimuli. A ROC regression model was used to investigate the influence of disease severity and asymmetry on diagnostic ability. RESULTS: The largest area under the ROC curve (AUC) for any single parameter was 0.75. Disease asymmetry (P <0.001), but not disease severity (P = 0.058), had a significant effect on diagnostic ability. At the sample mean age (60.9 years), AUCs for arbitrary values of intereye difference in SAP mean deviation (MD) of 0, 5, 10, and 15 dB were 0.58, 0.71, 0.82, and 0.90, respectively. The mean intereye difference in MD was 2.2+/ 3.1 dB. The best combination of parameters had an AUC of 0.85; however, the cross validated bias-corrected AUC for these parameters was only 0.74. CONCLUSIONS: Although the pupillograph had a good ability to detect glaucoma in the presence of asymmetric disease, it performed poorly in those with symmetric disease. PMID- 24485922 TI - Regulation of renal fibrosis by Smad3 Thr388 phosphorylation. AB - Transforming growth factor-beta (TGF-beta) promotes tissue fibrosis via receptor mediated phosphorylation of the receptor-activated Smad2/3, together with Smad4. Of these, Smad3 plays a major profibrotic role in mouse models of tissue fibrosis. Transcriptional activity of the Smad3 protein is regulated by phosphorylation of residues in the C-terminal domain and the linker region. Herein, we examined the role of a novel phosphorylation site within the MH2 domain (T388) in the regulation of Smad3 activity. Confocal microscopy using an Smad3 phosphorylated T388-specific antibody identified phosphorylation of Smad3 T388 in myofibroblasts and tubular epithelial cells in human focal and segmental glomerulosclerosis and mouse models of unilateral ureteric obstruction and diabetic nephropathy, whereas phosphorylated T388 was largely absent in normal kidney. In vitro, TGF-beta1 induced phosphorylation of Smad3 T388 in a biphasic pattern. A point mutation of T388/V in an Smad3 construct demonstrated that phosphorylation of T388 promotes Smad3 binding to Smad4 and CDK8, but was not necessary for nuclear translocation. Furthermore, T388 phosphorylation was required for TGF-beta-induced collagen I gene promoter activity and extracellular matrix production in cultured fibroblasts. In conclusion, our study identifies phosphorylation of T388 in the Smad3 MH2 domain as an important mechanism that regulates the profibrotic TGF-beta/Smad3 signaling pathway, which has direct relevance to human and experimental fibrotic kidney disease. PMID- 24485924 TI - [Current trends and proposals on emerging infectious diseases, proceedings of the seminar of Val de Grace, December 7, 2012]. PMID- 24485925 TI - Integrating psychology with interpersonal communication skills in undergraduate nursing education: addressing the challenges. AB - The inclusion of the social, behavioural and bio-sciences is acknowledged as essential to the development of the art and science of nursing. Nonetheless, the literature highlights on-going debate about the content and delivery of these subject areas in undergraduate nursing education. The bio-sciences and social sciences in particular have received much attention but more recently the inclusion of psychology in nursing curricula is gaining momentum. Studies conducted on nursing students' views of these supporting sciences have also highlighted problems with their understanding, relevance and application to nursing practice. Although broad guidelines are given as to what should be included, no detail is given as to how much detail or at what level these subjects should be taught. Subsequently, approved institutions are responsible for their own course content. This has resulted in inconsistent and varied approaches to integrating the sciences in undergraduate nursing curricula. Following a recent review of the undergraduate nursing curriculum in one university in the Republic of Ireland a decision was made to combine the teaching, learning and assessment of Applied Psychology with Interpersonal Communication skills. This paper will describe the developmental process and evaluation of the integrated module. PMID- 24485923 TI - Elevated YAP and its downstream targets CCN1 and CCN2 in basal cell carcinoma: impact on keratinocyte proliferation and stromal cell activation. AB - Yes-associated protein (YAP) is a transcriptional co-activator of hippo signaling pathway, which plays an important role in organ size control and tumorigenesis. Here we report that YAP and its downstream transcriptional targets CCN1 and CCN2 are markedly elevated in keratinocytes in human skin basal cell carcinoma tumor islands. In human keratinocytes, knockdown of YAP significantly reduced expression of CCN1 and CCN2, and repressed proliferation and survival. This inhibition of proliferation and survival was rescued by restoration of CCN1 expression, but not by CCN2 expression. In basal cell carcinoma stroma, CCN2 regulated genes type I collagen, fibronectin, and alpha-smooth muscle actin were highly expressed. Furthermore, atomic force microscopy revealed increased tissue stiffness in basal cell carcinoma stroma compared to normal dermis. These data provide evidence that up-regulation of YAP in basal cell carcinoma impacts both aberrant keratinocyte proliferation, via CCN1, and tumor stroma cell activation and stroma remodeling, via CCN2. Targeting YAP and/or CCN1 and CCN2 may provide clinical benefit in basal cell carcinoma. PMID- 24485926 TI - Using the Apple iPad to facilitate student-led group work and seminar presentation. AB - Mobile technology has become progressively more visible within the Higher Education learning environment, and is, in the author's experience, often used casually by students to support their learning. The project outlined within this paper examines the efficacy of using such technology (Apple iPad) more formally in facilitating increased levels of interaction and group cohesion within a series of tutorial sessions involving undergraduate nursing students (n = 24). For the purposes of the project, a tutorial group was created and facilitated in which the students undertook and fed back upon a series of specific iPad supported activities. Data was collected at the mid point and cessation of the project. The outcomes were most encouraging, and indicated that mobile computing platforms of this type may indeed help students to engage more fully with learning activities and materials, and as a corollary, increase student confidence with peer presentation and feedback. PMID- 24485927 TI - Primary cerebellar paraganglioma: a pediatric case report and review of the literature. AB - BACKGROUND: Only four cases of primary intracerebellar paragangliomas have been reported in the literature to date. Because of its rarity, primary intracerebellar paraganglioma still presents a diagnostic challenge for both radiologists and neurosurgeons, and the optimal therapeutic modality is still debatable for its hypervascularity and location. PATIENTS: We report a 16-year old boy with pathology-proven primary intracerebellar paraganglioma who presented with dull headache, dizziness, and gait disturbance, and underwent gross total resection. Further, we review all reported cases of primary intracerebellar paraganglioma in the English literature and discuss its clinical profile, neuroradiological features, and treatment modalities. RESULTS: His symptoms improved following tumor removal without radiotherapy, and postoperative neuroimaging thirteenth months after surgery showed no recurrence. In the literature, all four patients were stable in the follow-up period including three with complete resection and one with partial resection plus adjuvant radiotherapy. CONCLUSION: Surgical resection is the treatment modality most often used for primary intracerebellar paraganglioma; radiation therapy may be used when there is residual tumor or recurrence. Angiography may help to clarify the vessel architecture for reducing intraoperative bleeding when primary intracerebellar paraganglioma is considered. PMID- 24485928 TI - Occipital and craniocervical pain and brain MRI in children with migraine. AB - BACKGROUND: Both cervical and occipital pain has been reported in pediatric patients with migraine. There are no descriptions of anatomical changes on conventional brain magnetic resonance imaging that can explain the pathophysiology of headache with cervical and occipital pain in this age group. Our aim was to evaluate the frequency of cervical and occipital pain in children and adolescents with migraine as opposed to other types of headache and to seek corresponding anatomic abnormalities on brain magnetic resonance imaging. METHODS: The cohort included 194 patients with headache attending the ambulatory headache clinic of a pediatric tertiary medical center. Data were collected by medical file review and revision of conventional magnetic resonance scans. RESULTS: Patients were divided into two groups: migraine headache (n = 125) and other types of headache (n = 69). Occipital pain was reported by 16.4% of the patients and cervical pain by 4.1%; neither type of pain was characteristic of migraine headache in particular. Brain magnetic resonance imaging did not show any anatomic changes specific to migraine or other headache types, regardless of the presence of occipital or cervical pain. CONCLUSIONS: Occipital and cervical pain are not characteristic symptoms of any headache group in the pediatric age group, and their presence or absence does not correspond to changes on conventional brain magnetic resonance imaging. PMID- 24485929 TI - Genetic testing in infantile spasms identifies a chromosome 13q deletion and retinoblastoma. AB - BACKGROUND: Infantile spasms is an epileptic encephalopathy and the common final manifestation of numerous disparate insults to the developing brain during infancy. The varied etiologies may be structural, metabolic, genetic, or unknown. Etiological diagnosis is important as it may lead to specific therapy, which may affect developmental outcome. PATIENT: We report a case of infantile spasms of unknown etiology with dysmorphic features, in which genetic copy number variation microarray testing was included in the investigation of the cause of the disease. RESULTS: A large deletion of chromosome 13 was identified in the region 13q13 to 13q21.3 encompassing the retinoblastoma gene (13q14.2). Urgent ophthalmological evaluation revealed an asymptomatic retinoblastoma of the left eye, leading to early treatment. CONCLUSION: This is the first case report of infantile spasms specifically associated with a chromosome 13q deletion. Chromosomal region 13q13 to 13q21.3 may contain one or more genes whose hemizygous loss leads to infantile spasms. Copy number variation testing for cryptogenic infantile spasms led to the discovery of a mutation responsible for retinoblastoma, enabling early diagnosis and treatment of a potentially life-threatening cancer. High-sensitivity molecular diagnosis improves health care and substantially reduces expenses. This shift in diagnostic evaluation is broadly relevant to health care. PMID- 24485930 TI - Granulomatous herpes simplex encephalitis in an infant with multicystic encephalopathy: a distinct clinicopathologic entity? AB - BACKGROUND: Herpes simplex virus encephalitis can manifest as a range of clinical presentations including classic adult, neonatal, and biphasic chronic granulomatous herpes encephalitis. METHOD: We report an infant with granulomatous herpes simplex virus type 2 encephalitis with a subacute course and multicystic encephalopathy. CASE: A 2-month-old girl presented with lethargy and hypothermia. Computed tomography scan of the head showed multicystic encephalopathy and calcifications. Cerebrospinal fluid analysis by polymerase chain reaction testing for herpes simplex virus 1 and 2, enterovirus, and cytomegalovirus was negative. Normal cerebrospinal fluid interferon-alpha levels argued against Aicardi Goutieres syndrome. The patient died 2 weeks after presentation. At autopsy, multicystic encephalopathy was confirmed with bilateral gliosis, granulomatous inflammation with multinucleated giant cells, and calcifications. Bilateral healing necrotizing retinitis suggested a viral etiology, but retina and brain were free of viral inclusions and immunohistochemically negative for herpes simplex virus-2 and cytomegalovirus. However, polymerase chain reaction analysis showed herpes simplex virus-2 DNA in four cerebral paraffin blocks. Subsequent repeat testing of the initial cerebrospinal fluid sample using a different polymerase chain reaction assay was weakly positive for herpes simplex virus-2 DNA. CONCLUSION: Granulomatous herpes simplex virus encephalitis in infants can present with subacute course and result in multicystic encephalopathy with mineralization and minimal cerebrospinal fluid herpes simplex virus DNA load. Infectious etiologies should be carefully investigated in the differential diagnosis of multicystic encephalopathy with mineralization, in particular if multinucleated giant cells are present. PMID- 24485931 TI - Cerebral salt wasting in status epilepticus: two cases and review of the literature. AB - BACKGROUND: Cerebral salt wasting is a hypovolemic hyponatremia state, caused by natriuresis and diuresis. The most important element of treatment is to replace the volume and sodium loss and improve the current clinic. PATIENTS: We present two children who were treated in the intensive care unit who subsequently developed cerebral salt wasting. Diagnosis was based on hyponatremia associated with high urinary sodium excretion and inappropriately high urine output in the presence of dehydration. As part of the treatment, one patient was given fluid and sodium replacement, measures that were insufficient in the other patient, who also required fludrocortisone treatment. CONCLUSION: The status epilepticus may be involved in the etiology of cerebral salt wasting. In both patients, cerebral salt wasting was detected in the posttreatment follow-up evaluations. Cerebral salt wasting is particularly likely to occur in individuals with status epilepticus, and the electrolyte and hydration status of these patients should be monitored closely, even after the convulsions are taken under control. PMID- 24485932 TI - The distribution of Aspergillus spp. opportunistic parasites in hives and their pathogenicity to honey bees. AB - Stonebrood is a disease of honey bee larvae caused by fungi from the genus Aspergillus. As very few studies have focused on the epidemiological aspects of stonebrood and diseased brood may be rapidly discarded by worker bees, it is possible that a high number of cases go undetected. Aspergillus spp. fungi are ubiquitous and associated with disease in many insects, plants, animals and man. They are regarded as opportunistic pathogens that require immunocompromised hosts to establish infection. Microbiological studies have shown high prevalences of Aspergillus spp. in apiaries which occur saprophytically on hive substrates. However, the specific conditions required for pathogenicity to develop remain unknown. In this study, an apiary was screened to determine the prevalence and diversity of Aspergillus spp. fungi. A series of dose-response tests were then conducted using laboratory reared larvae to determine the pathogenicity and virulence of frequently occurring isolates. The susceptibility of adult worker bees to Aspergillus flavus was also tested. Three isolates (A. flavus, Aspergillus nomius and Aspergillus phoenicis) of the ten species identified were pathogenic to honey bee larvae. Moreover, adult honey bees were also confirmed to be highly susceptible to A. flavus infection when they ingested conidia. Neither of the two Aspergillus fumigatus strains used in dose-response tests induced mortality in larvae and were the least pathogenic of the isolates tested. These results confirm the ubiquity of Aspergillus spp. in the apiary environment and highlight their potential to infect both larvae and adult bees. PMID- 24485933 TI - Multidrug-resistant Escherichia coli from canine urinary tract infections tend to have commensal phylotypes, lower prevalence of virulence determinants and ampC replicons. AB - Multidrug-resistant Escherichia coli is an emerging clinical challenge in domestic species. Treatment options in many cases are limited. This study characterized MDR E. coli isolates from urinary tract infections in dogs, collected between 2002 and 2011. Isolates were evaluated in terms of beta lactamase production, phylogenetic group, ST type, replicon type and virulence marker profile. Comparisons were made with antibiotic susceptible isolates also collected from dogs with urinary tract infections. AmpC beta-lactamase was produced in 67% of the MDR isolates (12/18). Of these, 8 could be specifically attributed to the CMY-2 gene. None of the isolates tested in either group expressed ESBLs. Phylo-group distribution was as expected in the susceptible isolates, with an over representation of the pathogenic B2 phylo-group (67%). In contrast, the phylogenetic background for the MDR group was mixed, with representation of commensal phylo-groups A and B1. The B2 phylo-group represented the smallest proportion (A, B1, B2 or D was 28%, 22%, 11% and 33%, respectively). Virulence marker profiles, evaluated using Identibac((r)) microarray, discriminated between the two groups. Marker sequences for a core panel of virulence determinants were identified in most of the susceptible isolates, but not in most of the MDR isolates. These findings indicate that for MDR isolates, plasmid-mediated AmpC is an important resistance mechanism, and while still capable of causing clinical disease, there is evidence for a shift towards phylogenetic groups of reduced inferred virulence potential. There was no evidence of zoonotic potential in either the susceptible or MDR urinary tract isolates in this study. PMID- 24485934 TI - Single nucleotide repeat analysis of B. anthracis isolates in Canada through comparison of pyrosequencing and Sanger sequencing. AB - Several technology platforms have been developed to resolve the phylogenetic placement of B. anthracis. However, these methods lack the resolution to identify differences between closely related strains within an outbreak due to the highly clonal nature of B. anthracis. Single Nucleotide Repeats (SNRs) are a type of rapidly evolving genetic marker that can be used to track epidemiological distribution in the event of an outbreak. Four SNR targets were used to detect and type 35 B. anthracis isolates in our collection; 18 from across Canada obtained between 1972 and 2005 and 17 from the 2006 Anthrax outbreak in north eastern Saskatchewan. A control sequence was developed for pyrosequencing which yielded consistent and accurate reads of SNRs. However, when DNA from the isolates was tested using pyrosequencing the results were inconsistent and did not reflect the number of SNRs obtained by Sanger sequencing. The SNR numbers derived from the Sanger sequencing show two of the four SNR loci could provide information on subtype, whereas the other two were not discriminatory. There is variation in SNRs between strains isolated from different outbreaks, the subset of 2006 outbreak strains showed very little difference in SNR number, and thus suggests low diversity among the strains sampled from the same outbreak. PMID- 24485935 TI - Sample and data sharing barriers in biobanking: consent, committees, and compromises. AB - The ability to exchange samples and data is crucial for the rapidly growth of biobanking. However, sharing is based on the assumption that the donor has given consent to a given use of her or his sample. Biobanking stakeholders, therefore, must choose 1 of 3 options: obtain general consent enabling multiple future uses before taking a sample from the donor, try to obtain consent again before sharing a previously obtained sample, or look for a legally endorsed way to share a sample without the donor's consent. In this study, we present the results of 36 semistructured qualitative interviews with Swiss biobanking stakeholders regarding these options and the role of ethics committees in the process of authorizing sharing. Our results show that despite a lack of legal or guideline based barriers to general consent, some stakeholders and ethics committees have reservations about this method of consent. In most cases, however, a general consent form is already in use. Many interviewees describe processes involving the ethics committees as time-consuming and cumbersome and their requirements as too demanding for donors/patients. Greater awareness of donors' opinions and preferences and the content of guidelines and recommendations could therefore be helpful for a better justified perspective of biobanking stakeholders and ethical committee members, equally. Finally, it may be necessary to differentiate between procedures governing future samples, where general consent is clearly desirable, and the use of old yet still relevant samples, where the option of using them without consent can be highly beneficial for research. PMID- 24485936 TI - Urban-rural differences in asthma prevalence among young adolescents: The role of behavioural and environmental factors. AB - BACKGROUND: Asthma prevalence has been reported to be lower in rural areas compared to urban areas, although this has been inconsistent. This study aims to identify the influence of urban-rural residence on asthma prevalence in adolescents in the Republic of Macedonia and to investigate characteristics that may explain observed associations. METHODS: Following International Study of Asthma and Allergies in Childhood protocol, a national sample of Macedonian urban and rural dwelling adolescents (12-16 years) was recruited in 2006. Self completed questionnaires were used to collect data on wheeze and asthma as well as personal, environmental and dietary characteristics. Following descriptive and multiple logistic regression analyses, a mediation analysis approach was performed to help explain observed associations. RESULTS: A lower prevalence of current wheeze and ever-diagnosed asthma was observed in rural compared to urban dwelling adolescents (4.9% vs. 7.2% and 1.2% vs. 1.9%, respectively). After adjustment for potential confounders, the associations, although still protective, were not statistically significant (wheeze: OR=0.74, 95%CI=0.46-1.21; asthma: OR=0.97, 95%CI=0.38-2.46). The associations between urban-rural status with current wheeze and asthma were mediated by region of the country (wheeze 9%; asthma 19%) and by diet (>5% change for both wheeze and asthma). Having a dog resulted in a strengthening of the association between urban-rural status and current wheeze by 11.9%. CONCLUSIONS: The prevalence of asthma and wheeze was lower in rural dwelling Macedonian adolescents and the association was mediated by the region of the country with diet likely to be part of the reason for this mediating effect. PMID- 24485937 TI - Allergy medical care network: a new model of care for specialties. AB - In 2005 the Althaia Foundation Allergy Department performed its daily activity in the Hospital Sant Joan de Deu of Manresa. Given the increasing demand for allergy care, the department's performance was analysed and a strategic plan (SP) for 2005-2010 was designed. The main objective of the study was to assess the impact of the application of the SP on the department's operations and organisational level in terms of profitability, productivity and quality of care. MATERIAL AND METHODS: Descriptive, retrospective study which evaluated the operation of the allergy department. The baseline situation was analysed and the SP was designed. Indicators were set to perform a comparative analysis after application of the SP. RESULTS: The indicators showed an increase in medical care activity (first visits, 34%; successive visits, 29%; day hospital treatments, 51%), high rates of resolution, reduced waiting lists. Economic analysis indicated an increase in direct costs justified by increased activity and territory attended. Cost optimisation was explained by improved patient accessibility, minimised absenteeism in the workplace and improved cost per visit. CONCLUSIONS: After application of the SP a networking system was established for the allergy speciality that has expanded the territory for which it provides care, increased total activity and the ability to resolve patients, optimised human resources, improved quality of care and streamlined medical costs. PMID- 24485938 TI - Bronchial hyperreactivity in children with antibody deficiencies. AB - BACKGROUND: Antibody deficiency comprises a heterogeneous group of disorders characterised by the body's inability to mount an effective antibody response to pathogens. Although it has been reported that asthma and allergic disease are frequent in antibody deficiencies, there are no data that evaluate and compare bronchial hyperreactivity (BHR) in all groups of antibody deficiencies. In this study, we aimed to evaluate and compare the frequency of BHR in patients with different antibody deficiencies. METHODS: The study was carried out on 113 patients between ages 5 and 18 diagnosed with antibody deficiencies. The patients and their families were questioned on their history of asthma and allergic diseases. Allergic skin prick tests and non-specific bronchial provocation test with methacholine was done for all patients. Complete blood count and serum total IgE levels were measured. RESULTS: The mean age of the patients was 10.8 +/- 3.8 years and 66.4% were male. Within the study group 41.6% of the patients had selective IgA deficiency, 24.8% had IgG subclass deficiency, 14.2% had partial IgA deficiency, 10.6% had common variable immunodeficiency, 6.2% had transient hypogammaglobulinaemia and 2.7% X-linked agammaglobulinaemia. In total group, 42.5% had bronchial hyperreactivity with methacholine challenge test. BHR was more significant in both patients with selective IgA deficiency and partial IgA deficiency compared to those with IgG subclass deficiency (P=0.041 and P=0.038, respectively). CONCLUSION: BHR was high in antibody deficiencies, especially selective IgA deficiency compared to IgG subclass deficiency. PMID- 24485939 TI - Mortality and morbidity in patients with X-linked agammaglobulinaemia. AB - BACKGROUND: X-linked agammaglobulinaemia (XLA) is a genetic disorder characterised by a defect in the generation of mature B cells, lack of antibodies production, and susceptibility to recurrent bacterial infections. Understanding of the risk factors responsible for morbidity and mortality in these patients can help in a better management of this disorder. However, there is a lack of specific studies in the literature regarding the morbidity and mortality of XLA patients. This study is designed to evaluate morbidities and mortality and survival rates in Iranian patients with XLA diagnosis during the past 20 years. METHODS: We have registered the clinical data of the XLA patients and followed them up until 2010. At the time of diagnosis, a four-page questionnaire including complete medical information was filled out for all patients. Follow-up information was gathered either by reviewing the patients' hospital records or regularly visiting the patients. RESULTS: Among 41 patients, 26.8% died during the follow up period. All of the complications before the initiation of treatment such as pneumonia, otitis media and diarrhoea were reduced after immunoglobulin replacement, except sinusitis and conjunctivitis. There were significant associations between some immunological and clinical characteristics such as lymphocyte subsets, consanguinity marriage and mortality. CONCLUSION: Despite recent advances in the treatment of XLA, these patients still suffer from severe complications. Associations between poor prognosis and clinical and some immunological characteristics of the patients may help physicians to select poor prognoses patients at higher risk of mortality to develop prevention strategies for them. PMID- 24485940 TI - Are skin prick tests really safe? A case of anaphylaxis caused by skin prick testing with inhalant allergens. PMID- 24485941 TI - Establishing a cut-off for the serum levels of specific IgE to milk and its components for cow's milk allergy: results from a specific population. AB - BACKGROUND: Cow's milk allergy diagnosis many times requires double-blind placebo controlled food challenge (DBPCFC), which presents high accuracy but involves risks, specifically in infants and anaphylactic patients. The identification of the cut-off values for specific IgE to milk or its components would contribute to cow's milk allergy (CMA) diagnosis. The aim of this study was to compare discriminating concentration of a cow's milk specific IgE and its fractions (alpha-lactoalbumin, beta-lactoglobulin, casein) in children for the CMA diagnosis. METHODS: this study included 123 patients (M:F=1.3:1) median age at diagnosis=1.91 years, (3.5m to 13.21y) with CMA diagnosis via DBPCFC (n=26), proven anaphylaxis due to cow's milk (n=46) or a suggestive clinical history associated with a positive skin prick test (n=51) and open oral food challenge. The control group included 61 patients (1 male:1.1 female) ages ranging from 0.66 to 16.7 years (median=6.83 years). Receiver operator characteristics (ROC) curves were constructed to determine the best cut-offs that guarantees high specificity (>95%) for cow's milk and its components. RESULTS: considering 98% specificity, cut-off points were: 3.06 kU/L for cow's milk, 2.06 kU/L for alpha-lactalbumin, 1.85 kU/L for beta-lactoglobulin and 1.47kU/L for casein. The best ROC curve (area under the curve=0.929) was obtained evaluating cow's milk. CONCLUSION: this study showed that the cut-off point detected for whole cow's milk revealed a better discriminatory capacity for CMA diagnosis without the necessity of the milk components testing. PMID- 24485942 TI - Optimization of the rodent model of polymicrobial sepsis. PMID- 24485943 TI - Community building and mental health in mid-life and older life: evidence from China. AB - The Chinese government has adopted a "community building" strategy nationwide to build community capacity by expanding community-based services since the mid 1980s. This study empirically examines whether the mental health among middle aged and older Chinese adults is associated with the spearhead of this strategy, measured by the number of the amenities and organizations set within the community, and the years the community residents' committee has been in existence. Multilevel mixed regression analyses in SAS 9.2 of the data from The Chinese Health and Retirement Longitudinal Study (CHARLS) 2008 Pilot Survey indicated that these two community-level variables explained the variances in mental health among middle-aged and older Chinese adults. Additionally, the number of amenities and organizations within the community was significantly associated with the mental health in midlife and later life, even after controlling for the individual-level socioeconomic and social ties and for support predictors. The empirical evidence from this study indicates that developing the community capacity by establishing the community-based grassroots organizations and semi-public spaces will benefit an individual's mental health in current China. PMID- 24485944 TI - Are Hsp70 protein expression and genetic polymorphism implicated in multiple sclerosis inflammation? AB - Genetic and environmental factors contribute to disease Multiple Sclerosis (MS) susceptibility, the most prevalent neurological pathology affecting young individuals in Western countries. We focused our attention on HSP70-2, an inducible chaperon induced under stress conditions. Genotype analysis of HSP70-2 (+1267 A/G) polymorphism revealed a significant association between the minor allele G and presence of MS (OR:1.31, 95% CI: 1.02-1.69, P = 0.039). In addition, Hsp70-2 protein content in vitro from PBMC was significantly lower in MS patients with GG genotype compared to AA genotype, indicating an implication of the G allele of HSP70-2 gene polymorphism in the development of MS. PMID- 24485945 TI - Cultured primary human fetal retinal pigment epithelium (hfRPE) as a model for evaluating RPE metabolism. AB - Mitochondrial dysfunction has been shown to contribute to age-related and proliferative retinal diseases. Over the past decade, the primary human fetal RPE (hfRPE) culture model has emerged as an effective tool for studying RPE function and mechanisms of retinal diseases. This model system has been rigorously characterized and shown to closely resemble native RPE cells at the genomic and protein level, and that they are capable of accomplishing the characteristic functions of a healthy native RPE (e.g., rod phagocytosis, ion and fluid transport, and retinoid cycle). In this review, we demonstrated that the metabolic activity of the RPE is an indicator of its health and state of differentiation, and present the hfRPE culture model as a valuable in vitro system for evaluating RPE metabolism in the context of RPE differentiation and retinal disease. PMID- 24485946 TI - Ectopic peripontine arcuate fibres, a novel finding in pontine tegmental cap dysplasia. AB - BACKGROUND: Pontine Tegmental Cap Dysplasia (PTCD) is a recently described hindbrain malformation presenting hypoplasia of the ventral pons, and a "pontine tegmental cap". Previous DTI studies identified ectopic transversely oriented nerve fibres in the cap, and absence of transverse fibre bundles in the ventral pons, characterizing PTCD as an embryonic axon guidance defect. A new case with relatively mild symptoms was investigated to identify fibre tracts in the tegmental cap by tracking their connections. In the process a new bilateral ectopic fibre tract was found. METHODS: Routine T1- and T2 weighted images and Diffusion Tensor Imaging (DTI) data were obtained on a 3 T MR scanner. Fractional Anisotropy maps colour coded for orientation were generated. High Angular Resolution Diffusion Imaging (HARDI) data were used for reconstructing maps denoting multiple fibre orientations (i.e. fibre crossings) per voxel through which accurate fibre tracking was performed. RESULTS INTERPRETATION: Peripontine arcuate fibres were identified, representing a second structural abnormality not previously recorded in PTCD. PMID- 24485948 TI - Standardization of Tc-99 by two methods and participation at the CCRI(II)-K2. Tc 99 comparison. AB - The work accomplished within the participation at the 2012 key comparison of Tc 99 is presented. The solution was standardized for the first time in IFIN-HH by two methods: LSC-TDCR and 4pi(PC)beta-gamma efficiency tracer. The methods are described and the results are compared. For the LSC-TDCR method, the program TDCR07c, written and provided by P. Cassette, was used for processing the measurement data. The results are 2.1% higher than when applying the TDCR06b program; the higher value, calculated with the software TDCR07c, was used for reporting the final result in the comparison. The tracer used for the 4pi(PC)beta gamma efficiency tracer method was a standard (60)Co solution. The sources were prepared from the mixture (60)Co+(99)Tc solution and a general extrapolation curve, type: N(betaTc-99)/(M)(Tc-99)=f [1-epsilon(Co-60)], was drawn. This value was not used for the final result of the comparison. The difference between the values of activity concentration obtained by the two methods was within the limit of the combined standard uncertainty of the difference of these two results. PMID- 24485947 TI - The power of clinicians' affective communication: how reassurance about non abandonment can reduce patients' physiological arousal and increase information recall in bad news consultations. An experimental study using analogue patients. AB - OBJECTIVE: The diagnosis of incurable cancer may evoke physiological arousal in patients. Physiological arousal can negatively impact patients' recall of information provided in the medical consultation. We aim to investigate whether clinicians' affective communication during a bad news consultation will decrease patients' physiological arousal and will improve recall. METHODS: Healthy women (N=50), acting as analogue patients, were randomly assigned to watch one out of the two versions of a scripted video-vignette of a bad news consultation in which clinician's communication differed: standard vs. affective communication. Participants' skin conductance levels were obtained during video-watching, and afterwards their recall was assessed. RESULTS: While the diagnosis increased skin conductance levels in all analogue patients, skin conductance levels during the remainder of the consultation decreased more in the affective communication condition than in the standard condition. Analogue patients' recall was significantly higher in the affective condition. CONCLUSION: Breaking bad news evokes physiological arousal. Affective communication can decrease this evoked physiological arousal and might be partly responsible for analogue patients' enhanced information recall. PRACTICE IMPLICATIONS: Although our findings need to be translated to clinical patients, they suggest that clinicians need to deal with patients' emotions before providing additional medical information. PMID- 24485949 TI - Effects of l-DOPA pre-loading on the uptake of boronophenylalanine using the F98 glioma and B16 melanoma models. AB - The present study was undertaken to evaluate the effects of l-DOPA pre-loading on the uptake of BPA using the F98 rat glioma and the murine B16 melanoma models. In vitro pretreatments of F98 glioma and B16 melanoma cells with l-DOPA, followed by exposure to BPA increased boron uptake, as determined by inductively coupled plasma-optical emission spectroscopy (ICP-OES). Based on this, in vivo studies were initiated in F98 glioma bearing rats. Initially, the l-DOPA dosing paradigm was evaluated. Maximum tumor boron uptake was observed following i.p. administration of l-DOPA (50mg/kg) followed 24h later by BPA (31.8+/-8.9 vs. 17.2+/-6.3ug/g for BPA alone). Next, the effect of l-DOPA pre-loading as a function of the route of administration of BPA was evaluated in F98 glioma bearing rats. The greatest increase in uptake was seen following i.v. administration of BPA, while in contrast no significant increase was seen following intracarotid (i.c.) administration (38.6+/-12.4 vs. 34.2+/-10.9). Cellular localization of the F98 glioma, as determined by secondary ion mass spectrometry (SIMS) boron imaging revealed equivalent tumor boron concentrations following l-DOPA pre-loading. In vivo studies in B16 melanoma bearing mice showed equivalent tumor boron values in treated and untreated mice, suggesting that the effects of l-DOPA pre-loading may depend both on the histologic type of tumor and its anatomic site. PMID- 24485950 TI - The relationship between Helicobacter pylori and cancer risk. AB - OBJECTIVES: This study investigated the correlation between Helicobacter pylori (HP) and cancer risk. We compared the age, sex, and comorbidity of cancer patients both infected and not infected by HP. METHODS: In this study, we compared a comparison cohort (N=24,088) and an HP cohort (N=6022), both taken from the NHI database. We performed a statistical analysis with the multivariable Cox proportional model to estimate the risk of developing cancer for a comparison and the HP cohort. RESULTS: Our results showed that the proportion of peptic ulcers in the HP cohort was nearly 4 times higher than that in the comparison cohort. The HP cohort was significantly associated with increased colorectal (HR=1.73, 95% CI=1.08-2.77), stomach (HR=5.21, 95% CI=2.46-11.05) and pancreatic (HR=2.77, 95% CI=1.04-7.39) cancer risks compared to the comparison cohort. In addition, the cancer risk in the HP cohort was considerably higher than that in the comparison cohort when hypertension was absent in both cohorts. CONCLUSIONS: In this study, we proposed a method to investigate the correlation between HP infection and cancer risk. We found that HP infection is associated with the development of colorectal, stomach, and pancreatic cancers, and could thus be an independent carcinogenic risk factor. PMID- 24485951 TI - Rapid exclusion of the diagnosis of immune HIT by AcuStar HIT and heparin-induced multiple electrode aggregometry. AB - BACKGROUND: Accurate diagnosis of heparin-induced thrombocytopenia (HIT) is essential but remains challenging. We have previously demonstrated, in a retrospective study, the usefulness of the combination of the 4Ts score, AcuStar HIT and heparin-induced multiple electrode aggregometry (HIMEA) with optimized thresholds. OBJECTIVES: We aimed at exploring prospectively the performances of our optimized diagnostic algorithm on suspected HIT patients. The secondary objective is to evaluate performances of AcuStar HIT-Ab (PF4-H) in comparison with the clinical outcome. METHODS: 116 inpatients with clinically suspected immune HIT were included. Our optimized diagnostic algorithm was applied to each patient. Sensitivity, specificity, negative predictive value (NPV), positive predictive value (PPV) of the overall diagnostic strategy as well as AcuStar HIT Ab (at manufacturer's thresholds and at our thresholds) were calculated using clinical diagnosis as the reference. RESULTS: Among 116 patients, 2 patients had clinically-diagnosed HIT. These 2 patients were positive on AcuStar HIT-Ab, AcuStar HIT-IgG and HIMEA. Using our optimized algorithm, all patients were correctly diagnosed. AcuStar HIT-Ab at our cut-off (>9.41 U/mL) and at manufacturer's cut-off (>1.00 U/mL) showed both a sensitivity of 100.0% and a specificity of 99.1% and 90.4%, respectively. CONCLUSION: The combination of the 4Ts score, the HemosIL(r) AcuStar HIT and HIMEA with optimized thresholds may be useful for the rapid and accurate exclusion of the diagnosis of immune HIT. PMID- 24485952 TI - Transfusion related anaphylaxis during orthotopic liver transplantation. AB - Acute non-hemolytic transfusion reactions, consisting of both allergic and febrile reactions, are common occurring in up to 10.2% of transfused blood products, however anaphylaxis, or severe allergic reactions, are rare following transfusion. The incidence of anaphylaxis is more common after the transfusion of plasma containing products with estimations from 1:10,000-33,000 units of platelets and 1:29,000-50,000 units of fresh frozen plasma (FFP) compared with 1:50,000-200,000 units of red blood cells. Despite the rare occurrence, the clinical significance of transfusion related anaphylaxis can be severe with 12 reported fatalities over a 5-year span. We report a case of FFP related anaphylaxis in a patient anticipating orthotopic liver transplant (OLT) with a unique peri-operative treatment plan. PMID- 24485953 TI - Blood group O patients require more blood transfusion in orthotopic liver transplantation. PMID- 24485954 TI - Influenza vaccine and false-positive HBsAg results. PMID- 24485955 TI - Red cell alloimmunization in thalassemia patients in a developing country - what can be done? PMID- 24485956 TI - A1A2BO and Rh gene frequencies among six populations of Jammu and Kashmir, India. AB - A study was undertaken to record gene frequencies of ABO blood groups, their subtypes and Rh antigen for six different endogamous groups including a tribal population. The ABO phenotypic frequency varies among six different populations showing significant difference (p<0.0005). Gujjar and Bakarwal (a tribal population) shows highest (42.29%) of B blood phenotypes. A1 is the highest among Syeds (39.31%), O blood group frequency highest among Mughals (43.23%) and A1B and A2B are rare phenotypes showing very low frequency among all populations. The pattern of allele frequencies (p<0.025) is in order of I(O)>I(B)>I(A1)>I(A2), except Syeds (I(O)>I(A1)>I(B)>I(A2)). The rhesus protein (Rh) phenotypic frequency (p<0.01) shows significant increase in Rh(D) positive (87.86% in Syed to 96.03% in Khan) among all populations. The Rh allele (p<0.05) and genotype (p<0.02) frequencies shows a significant difference. Heterozygosity for Rh protein is less than homozygosity among six populations. The result from this study provides information on the genetic variation in blood antigens and rhesus protein among human populations inhabiting Jammu and Kashmir. PMID- 24485957 TI - Association of Merkel cell polyomavirus infection with EGFR mutation status in Chinese non-small cell lung cancer patients. AB - OBJECTIVES: Female lung cancer patients with no smoking habit and non-mucinous adenocarcinoma have a higher rate of epidermal growth factor receptor (EGFR) gene mutations, which is related to tyrosine kinase inhibitors (TKIs) sensitivity. Unfortunately the cause of EGFR gene mutations is still elusive. In this study, we search for the association between Merkel cell polyomavirus (MCPyV) infection and EGFR gene mutations. MATERIALS AND METHODS: We studied 189 non-small cell lung cancer (NSCLC) samples for the presence of MCPyV large T (LT) DNA, LT antigen and EGFR hotspot mutations. Clinicopathological parameters of this cohort were also analyzed. RESULTS: Thirty out of 163 adenocarcinoma and 2 out of 18 squamous cell carcinoma were found to have MCPyV LT DNA by PCR. Immunostaining also showed LT protein expression in most of the DNA positive samples. EGFR mutations were more frequently detected in female (P=0.009) and non-smoking patients (P=0.0001). Furthermore, a significant association between MCPyV infection and EGFR mutations was found (P=0.001). CONCLUSION: Our study shows that MCPyV LT DNA is present in a subgroup of NSCLC, which is significantly correlated with EGFR mutations. To the best of our knowledge, this is the first study to find an association between MCPyV infection and EGFR hotspot mutations. These results support the possibility that MCPyV has a partial role in the carcinogenesis of NSCLC in a subgroup of patients. PMID- 24485958 TI - Use of virtual assisted lung mapping (VAL-MAP), a bronchoscopic multispot dye marking technique using virtual images, for precise navigation of thoracoscopic sublobar lung resection. AB - OBJECTIVE: We have developed a novel bronchoscopic multiple marking technique to assist resection of hardly palpable lung tumors. Because 3-dimensional virtual images were used and multiple markings made on the lung surface to provide "geometric" information, we termed this technique "virtual assisted lung mapping" (VAL-MAP). The safety and efficacy of VAL-MAP were evaluated. METHODS: Virtual bronchoscopy was used to select 2 to 4 appropriate bronchial branches for marking. Bronchoscopy was conducted with the patient under local anesthesia. A metal-tip catheter was inserted into a selected bronchus and advanced to the pleura. The location of the catheter tip was fluoroscopically confirmed, and 1 mL of indigo carmine was injected. This procedure was repeated to complete all the planned markings. Post-VAL-MAP computed tomography was used to visualize the localization of the multiple markings on 3-dimensional virtual images, which were used as references in the subsequent operation. RESULTS: Of the 95 marking attempts made for 37 tumors in 30 patients, 88 (92.6%) were identified and contributed to the surgery. No clinically evident complications were associated with the procedure. A total of 15 wedge resections and 18 segmentectomies were thoracoscopically conducted, with a successful resection rate of 100%. Multiple markings of the VAL-MAP were complementary, enabling us to achieve complete resection even when 1 of the markings failed. The markings were visible even on interlobar fissures, at the apex, and on the diaphragm, which conventional percutaneous marking can hardly reach. CONCLUSIONS: VAL-MAP was safely conducted with satisfactory outcomes in our early experience. Additional confirmation of its safety and efficacy is necessary. PMID- 24485959 TI - Use of argatroban: experiences in continuous renal replacement therapy in critically ill patients after cardiac surgery. AB - OBJECTIVES: Acute kidney injury requiring renal replacement therapy (RRT) is a common complication after cardiac surgery, complicated by suspected or proven heparin-induced thrombocytopenia (type II). The present study evaluated the use of argatroban as an anticoagulant during continuous RRT in the early period after cardiac surgery. Argatroban was compared with unfractionated heparin (UH) with respect to bleeding complications and the effectiveness of anticoagulation. METHODS: Patients requiring RRT after cardiac surgery from March 2007 to June 2009 were identified. The effectiveness of anticoagulation was measured indirectly by the duration of dialysis filter use. Bleeding was defined as clinical signs of blood loss or the need for transfusion. RESULTS: Of 94 patients, 41 received argatroban, 27 UH, and 26 required conversion from UH to argatroban. In all 3 subgroups, RRT was begun within a median postoperative period of 2.0 days. Similar levels of anticoagulation were achieved with the duration of the circuit and filter changed an average of 1.1 times daily during RRT. Liver function was comparable in all patients. Neither clinically relevant signs of bleeding nor significant differences in the hemoglobin levels or a requirement for transfusion were noted. However, the Simplified Acute Physiology Score II values during dialysis and mortality were significantly greater in the patients initially receiving argatroban compared with those who received UH alone (54 +/- 2 vs 43 +/- 3, P < .001; 71% vs 44%, P = .04). CONCLUSIONS: Argatroban can provide effective anticoagulation in postoperative cardiac patients receiving continuous RRT. Close monitoring and dose titration resulted in a comparable risk of bleeding for anticoagulation with both argatroban and heparin, regardless of the disease severity or impaired hepatic function. PMID- 24485960 TI - Prolonged QTc affects short-term and long-term outcomes in patients with normal left ventricular function undergoing cardiac surgery. AB - OBJECTIVE: Although it is known that preoperative decreased left ventricular ejection fraction (LVEF) is a risk for morbidity and mortality after cardiac surgery, there are no reliable markers of risk in patients with preserved LVEF. This study examines whether a prolonged QTc interval is associated with adverse outcomes in patients with preoperative LVEF greater than 40% undergoing cardiac surgery. METHODS: A retrospective chart review of patients who had cardiac surgery at St. Paul's Hospital in Vancouver, Canada, between 2004 and 2009, who had a preoperative LVEF greater than 40%, was undertaken. We tested for association of preoperative prolonged QTc interval with mortality and morbidity using unadjusted and adjusted analyses. RESULTS: Five-hundred and fifty-five patients with a preoperative LVEF greater than 40% were included in the study; 496 (89.4%) had cardiopulmonary bypass and the remainder were off pump. Preoperative prolonged QTc was associated with increased mortality at 30 days (P < .01), 90 days (P < .01), and 8 years (P < .01), and these results remained significant after adjusting for the clinical variables significantly associated with mortality (8-year odds ratio, 2.42; 95% confidence interval, 1.34-4.34; P = .003). Similar results were found when the analysis was restricted to the more homogeneous group of patients undergoing on-pump coronary artery bypass (CABG, n = 408). Prolonged QTc was also associated with prolonged intensive care unit stay (P = .02), prolonged hospital stay (P < .01), development of atrial arrhythmias (P = .02), and low cardiac output syndrome (on-pump CABG, P = .02). CONCLUSIONS: In patients undergoing cardiac surgery and a preoperative LVEF greater than 40%, a prolonged QTc interval is associated with increased short-term and long-term mortality and increased perioperative morbidity, and therefore should be considered when assessing risk preoperatively. PMID- 24485961 TI - Historical perspectives of The American Association for Thoracic Surgery: G. Alexander Patterson. PMID- 24485962 TI - The way we talk is the way we teach. PMID- 24485964 TI - Spontaneous giant right coronary artery pseudoaneurysm. PMID- 24485965 TI - Thoracic aortic endografting facilitates the resection of tumors infiltrating the aorta. AB - OBJECTIVES: We and others have reported the early experience with off-label use of thoracic aortic endografts to facilitate the resection of tumors infiltrating the aorta. We describe our extended experience and long-term outcome using this innovative approach. METHODS: Patients with preoperative suspected thoracic aortic infiltration who underwent endografting followed by en bloc tumor resection including the aortic wall were retrospectively reviewed and data were analyzed. RESULTS: Between 2008 and 2012, 5 patients (4 female) with a median age of 52 years (34-63 years) were included. Tumors infiltrating the aorta were non small cell lung carcinomas (n = 3) and sarcomas (n = 2). Both patients with sarcoma had neoadjuvant radiation, whereas patients with non-small cell lung carcinomas had neoadjuvant (n = 2) or adjuvant chemoradiation (n = 1). Aortic endografting was performed 1 to 17 days before resection of the tumor. The proximal end of the stent-graft was deployed in the aortic arch (n = 2) or the descending aorta (n = 3). The tumor was resected en bloc in all patients and combined with chest wall and 2 to 3 levels of spinal resection in 4 of the 5 patients. Two patients with full-thickness aortic wall resection had additional buttressing of the defect. Cardiopulmonary bypass was never required. One patient had an empyema requiring debridements and thoracic window. After a median follow up of 39 months (range, 9-62 months), all patients were alive and disease-free. None of them had overt endograft-related complications. CONCLUSIONS: Thoracic aortic endografting allowed safe en bloc resection of tumors invading the aortic wall. Therefore, the indication for thoracic aortic endografts could be extended to specific oncologic cases. PMID- 24485966 TI - A technique for repair of partial anomalous pulmonary vein connection to the superior vena cava. PMID- 24485967 TI - Neonatal intensive care and late preterm infants: health and family functioning at three years. AB - BACKGROUND: Late preterm infants (LPIs), born at 34+0 to 36+6 weeks of gestation contribute a significant proportion of all neonatal intensive care (NIC) admissions and are regarded as being at risk of adverse outcomes compared to term born infants. AIM: To explore the health outcomes and family functioning of LPIs who required neonatal intensive care, at three years of age. STUDY DESIGN AND SUBJECTS: This cohort study included 225 children born late preterm, between 1 January and 31 December 2006 in Northern Ireland. Children admitted for NIC (study group, n=103) were compared with children who did not require NIC or who required special care only for up to three days (comparison group, n=122). OUTCOME MEASURES: Health outcomes were measured using the Health Status Questionnaire, health service usage by parent report and family functioning using the PedsQLTM Family Impact Module. RESULTS: LPIs who required NIC revealed similar health outcomes at three years in comparison to those who did not. Despite this, more parents of LPIs who required NIC reported visiting their GP and medical specialists during their child's third year of life. Differences in family functioning were also observed with mothers of LPIs who required NIC reporting, significantly lower levels of social and physical functioning, increased difficulties with communication and increased levels of worry. CONCLUSIONS: LPIs were observed to have similar health outcomes at three years of age regardless of NIC requirement. The increase in GP and medical specialist visits and family functioning difficulties observed among those infants who required NIC merits further investigation. PMID- 24485968 TI - [Diabetic patient satisfaction in primary care: a comparison of Spain vs. Europe]. PMID- 24485969 TI - [Use of resources and associated costs of chronic obstructive pulmonary disease exacerbations: A population based retrospective study]. AB - OBJECTIVE: Exacerbations are a clinical characteristic of chronic obstructive pulmonary disease (COPD). The objective of the study was to estimate the resource use and costs associated with COPD exacerbations PATIENTS AND METHODS: Observational study performed by retrospective review of patient clinical charts of a Hospital and 6 associated Primary Care Centers. COPD patients >40years old who were followed-up during 2010-2011, and who fulfilled inclusion/exclusion criteria were included in the study. Healthcare resource use and costs associated to COPD exacerbations (moderate/severe) were estimated. Healthcare resource use, loss of productivity and costs associated to the follow-up of COPD patients (with/without exacerbations) were also estimated. STATISTICAL ANALYSIS: regression model and ANCOVA, P<.05. RESULTS: A total of 1,210patients were included in the study, of whom 51.2% experienced an exacerbation, and with an average of 4exacerbations/patient. Presence of exacerbations was associated with age, COPD severity, presence of comorbidities, and time from diagnosis. The average healthcare cost of an exacerbation was ?481 (moderate: ?375; severe: ?863). Patients who experienced an exacerbation had a higher resource use and costs (P<.001). Thus, the follow-up cost of patients without exacerbations was ?1,392 versus ?3,175 for patients with exacerbations. CONCLUSION: The presence of exacerbations in COPD patients was associated with an increase in resource use and associated costs. PMID- 24485970 TI - [Relationship between antihypertensive drug use and development of atrial fibrillation in hypertensive patients in a Primary Care center]. AB - INTRODUCTION: Although antihypertensive treatment can reduce the risk of cardiovascular morbimortality, studies aimed at evaluating the association between antihypertensive drug use and incidence of atrial fibrillation (AF) yield mixed results. This study aimed to determine the possible relationship between antihypertensive drug use and development of AF. MATERIAL AND METHODS: Case control study. CASES: Hypertensive patients with AF diagnosed at least one year after the start of drug treatment for hypertension. CONTROLS: Hypertensive patients without AF with pharmacological antihypertensive treatment for at least one year, matching by sex, age and duration of antihypertensive therapy at diagnosis of AF cases. The study included 136 cases and 132 controls. VARIABLES: AF, antihypertensive drugs, control of hypertension, duration of treatment with antihypertensive drugs, number of antihypertensive drugs. ANALYSIS: Crude OR were calculated, with logistic regression being used to calculate the adjusted odds ratios. RESULTS: Overall, diuretics was close to statistical significance: OR 0.616 (95% CI 0.365 to 1.040), as a protective factor for development of AF. Calcium channel blockers behaved as a protective factor against development of AF at 75 years or older (OR 0.366; 95% CI 0.173 to 0.772), and within this age in women (OR 0.343; 95% CI 0.145-0.811). CONCLUSIONS: Calcium channel blockers in the group of 75 years or more, especially in women, worked statistically significant as a drug protecting against the appearance of AF. Diuretics may have a protective role in AF incidence in all hypertensive patients. PMID- 24485971 TI - [Electrocardiographic anomalies after acute alcohol intoxication]. PMID- 24485972 TI - Benefits of ultrasound vs. computed tomography in the diagnosis of pediatric lateral neck abscesses. AB - OBJECTIVE: There are no studies comparing the accuracy of ultrasound and computed tomography in the same population of pediatric patients with lateral neck abscesses. This case series assesses the accuracy of the two imaging techniques. METHODS: One hundred and forty imaging studies (ultrasound n=39 or CT n=101) that were performed from 2005 to 2011 prior to incision and drainage of a lateral neck mass at a tertiary care academic institution were retrospectively reviewed. All children 0-18 years of age with lateral neck abscesses who underwent CT or ultrasound imaging prior to drainage were included. Sensitivity, specificity, and positive and negative predictive values of ultrasound and CT were determined as compared to the gold standard, incision and drainage of the suspected abscess. RESULTS: In children undergoing incision and drainage, the prevalence of an abscess was 89%. Ultrasound has a high specificity (100%) but a low sensitivity (53%). The positive predictive value (96%) is high while the negative predictive value is low (16%), assuming a positive abscess prevalence of 0.9. In contrast, CT has low specificity (18%) but slightly higher sensitivity (68%) compared to ultrasound. Similar to ultrasound, CT had low negative (6%) and high positive (88%) predictive values. CONCLUSIONS: This study demonstrates that ultrasound may be an equivalently sensitive and more specific diagnostic tool when compared to CT in the work-up of lateral neck abscesses in children. It is safe and effective in diagnosis when there is an undetermined probability of an abscess. PMID- 24485973 TI - Cochlear implants in children deafened by congenital cytomegalovirus and matched Connexin 26 peers. AB - OBJECTIVE: To compare the long-term speech perception and production outcomes after cochlear implantation (CI) in children deafened by congenital cytomegalovirus (cCMV) with a matched group of Cx26-CI children by controlling for chronological age and magnetic resonance imaging (MRI) findings. METHODS: Retrospective review of 12 cCMV-CI children and matched Cx26-CI children for speech perception and speech production outcomes. RESULTS: Two trends were seen in our data. First, cCMV-CI children with normal MRI scans perform equally or even slightly better on speech perception tests compared to their Cx26-CI peers during the first three years. The majority of cCMV-CI children with normal MRI scans (5 out of 7), suffered from a delayed-onset SNHL. Their mean age at first implantation (2y9m, range 15-82m) was higher compared to their matched Cx26 peers (9m, range 7-12m). Before being implanted, the majority of these delayed-onset hearing impaired children had benefited from a certain period of normal hearing (with or without amplification of a hearing aid). Possibly, this input might have led to an advantage the first three years after CI. Second, results between cCMV CI children with and cCMV-CI children without MRI abnormalities and their matched Cx26-CI counterparts tentatively suggest that, over a 5-yr follow-up period, cCMV CI children with abnormalities on MRI scans catch up for speech perception, but lag behind for speech production. CONCLUSION: cCMV-CI children with normal MRI scans perform equally or even slightly better on speech perception tests compared to their Cx26-CI peers during the first three years, whereas results between cCMV CI children with and cCMV-CI children without MRI abnormalities and their matched Cx26-CI counterparts tentatively suggest that, over a 5-yr follow-up period, cCMV CI children with abnormal MRI scans catch up for speech perception, but lag behind for speech production. In future, the inclusion of MRI results may assist in improved counseling of parents with cCMV deafened children seeking CI. PMID- 24485974 TI - Periodic botulinum toxin injections for paradoxical vocal fold motion in a child with cerebral palsy: a case study. AB - We describe an unusual case of paradoxical vocal fold motion in a child with cerebral palsy. Clinically, the child presented with mild stridor, which worsened over months, eventually requiring emergency intubation. After an unsuccessful trial of medical management, microlaryngoscopy revealed abnormal adduction of the vocal folds during inspiration. This was successfully treated with periodic type A botulinum toxin injections to the vocal folds, sparing the child from tracheostomy. PMID- 24485975 TI - Is bone turnover of jawbone and its possible over suppression by bisphosphonates of etiologic importance in pathogenesis of bisphosphonate-related osteonecrosis? AB - PURPOSE: The pathogenesis of bisphosphonate-related osteonecrosis of the jaw (BRONJ) is not completely understood. The most popular hypothesis has suggested that the bone turnover (BT) in the jawbone is greater than that in other sites and that this turnover will be overly suppressed by bisphosphonates. Using bone scintigraphy, a simple tool for the quantitative evaluation of bone metabolism and blood flow, the goals of the present study were to determine whether the rate of bone remodeling is greater in the jaw and whether the bone BT in the jaw is differentially altered after bisphosphonate intake compared with that in other skeletal sites. MATERIALS AND METHODS: The bone scintigraphies of 90 female patients with breast cancer were retrospectively analyzed (n = 45 with bisphosphonate intake; n = 45 without bisphosphonate intake [control group]). All patients in the study group had undergone bone scintigraphy before therapy and during the treatment (course after 12 and 24 months). The data were quantitatively analyzed using 6 predetermined regions of interest. RESULTS: The bone BT of the mandible was similar to that of the femur and significantly reduced compared with that of the maxilla (P < .01). None of the investigated bone regions (including the mandible and maxilla) were significantly altered after bisphosphonate administration (P > .05). CONCLUSIONS: The finding that the mandible had significantly lower bone BT than that of the maxilla and that two thirds of BRONJ cases occur in the mandible were inconsistent with the investigated hypothesis. Furthermore, the bone BT in the jawbone was not overly suppressed by bisphosphonates. Thus, it is unlikely that over suppression of bone BT is the exclusive causation playing a role in the pathomechanism of BRONJ. PMID- 24485976 TI - Application of anteromedial thigh flap for the reconstruction of oral and maxillofacial defects. AB - PURPOSE: To discuss the vascular anatomy of the anteromedial thigh (AMT) flap and to evaluate the feasibility of the AMT flap for the reconstruction of oral and maxillofacial defects. PATIENTS AND METHODS: A retrospective review was performed of 18 patients who underwent reconstruction of oral and maxillofacial defects with AMT flaps from January 2009 through December 2011 in the Second Xiangya Hospital. Eleven unifoliate AMT flaps were elevated to reconstruct defects of the tongue, soft palate, and floor of the mouth and 7 chimeric anterolateral thigh (ALT) and AMT flaps were harvested to reconstruct through-and-through cheek defects. RESULTS: The flaps were 4 * 6 to 9 * 11 cm(2). All the AMT flaps were nourished by the descending branch (DB) of the lateral circumflex femoral artery. The cutaneous perforators were derived from the rectus femoris branch of the DB in 15 cases and directly from the DB in the other 3 cases. Postoperatively, all flaps survived completely, without major complications. Of the 18 donor sites, 14 were closed directly, leaving only linear scars, and 4 were closed using full thickness skin grafts owing to larger defects. All patients were followed for approximately 6 to 30 months, and they were satisfied with the esthetic and functional results of the donor and recipient sites after the reconstruction. CONCLUSIONS: Because of easy perforator dissection, the AMT flap can be used as an alternative to the ALT flap or harvested with the ALT flap as chimeric ALT and AMT flaps for the reconstruction of oral and maxillofacial defects. PMID- 24485977 TI - Flow-through flap for salvage of fibula osseocutaneous vascular variations: a surgical approach and proposed modification of its classification. AB - The osseocutaneous fibula free flap is commonly used in mandibular reconstruction. Clinically important anatomic variants of the donor vessels have been reported. The authors describe a rare variant encountered while raising an osseocutaneous fibula flap. The fibula was supplied by the peroneal vessels and the overlying skin paddle was supplied by musculocutaneous perforators arising from the posterior tibial vessels. By raising 2 separate free flaps and configuring them in microvascular series with the fibula acting as a flow-through flap, the reconstruction was successful. Although the anatomic variant has been described, the authors' approach to it has not. The benefits of this method over other options include preservation of a skin paddle for monitoring and watertight oral closure and a long pedicle to the skin paddle permitting a wide arc of movement. The authors suggest a modification to the existing classification of perforators to the lateral leg skin to guide intraoperative decision making. PMID- 24485978 TI - Short-term evaluation of grafts fixed with either N-butyl-2-cyanocrylate or screws. AB - PURPOSE: N-butyl-2-cyanoacrylate (NB-Cn) is an alternative method for onlay graft fixation and might be efficient for preserving the graft volume. Our aim was to analyze the gene expression and mineralized tissue variations of calvarial bone grafting fixed in the mandible with either NB-Cn or a titanium screw (TiS). MATERIALS AND METHODS: New Zealand rabbits had bilateral calvarial grafts fixed at both sides of the mandible with either NB-Cn or a TiS. The rabbits were sacrificed at 4 and 8 days, and micro-computed tomography analysis was performed. For molecular analysis, the gene expression of interleukin-6, interleukin-10, and tumor necrosis factor-alpha was assessed. Quantification using real-time polymerase chain reaction was performed. Statistical analysis was performed using the paired Student t test (P < .05). RESULTS: Bone graft fixation with NB-Cn promoted superior volume and density preservation. The percentage of mineralized tissue at the center portion and border of the graft was very similar (NB-Cn, 50.6% +/- 8.3% and 50.3% +/- 10.6%, respectively) and superior than in the TiS group (32.5% +/- 3.5% and 33.8% +/- 6%, respectively). Genes from the NB-Cn group were upregulated compared with those in the TiS group at the initial phases of bone healing (4 days), with the profile reversed at the 8-day point. At day 8, the osteoclastogenesis-related genes were upregulated in the TiS group. CONCLUSIONS: Onlay bone grafts fixed with screws induced more inflammation during the initial remodeling process than did NB-Cn. The differences in the incorporation into the host bed suggest that the use of adhesives for graft fixation will promote superior volume and density preservation. PMID- 24485979 TI - Identification of proteins with increased levels in ameloblastic carcinoma. AB - PURPOSE: The comparative proteomic approach by a combination of 2-dimensional electrophoresis and matrix-assisted laser desorption-ionization-time of flight mass spectrometry (MS) analysis is an attractive strategy for the discovery of cancer biomarkers and therapeutic targets. The identification of protein biomarkers associated with ameloblastic carcinoma (AC), a malignant epithelial odontogenic tumor, will potentially improve the diagnostic and prognostic accuracy for this malignant neoplasm. The aim of the present study was to identify highly expressed proteins in AC that could be considered as potential biomarkers. MATERIALS AND METHODS: The protein profile of an AC was compared with the protein profiles of 3 cases of benign ameloblastoma. Proteins that showed increased levels in AC were identified using MS, and the augmented amount of some of these proteins in the malignant lesion was confirmed by Western blot or immunohistochemistry. RESULTS: We detected a total of 782 spots in the protein profile of AC, and 19 of them, showing elevated levels compared with benign ameloblastoma, were identified using MS. These proteins have been implicated in several cellular functions, such as cell structure, metabolism, stress response, and signal transduction. CONCLUSIONS: The increased expression of the identified proteins and the minor expression of some proteins that might inhibit tumor progression could be involved in the evolution from a benign lesion to carcinoma. PMID- 24485980 TI - Stress analysis of temporomandibular joint disc during maintained clenching using a viscohyperelastic finite element model. AB - PURPOSE: People with bruxism exert parafunctional grinding and clenching activities. Those habits are suspected to be associated with temporomandibular disorder development. The aim of this study was to analyze the behavior of the temporomandibular joint disc under maintained clenching. MATERIALS AND METHODS: For this analysis, a viscohyperelastic finite element model was used. The model included half the mandible, the left disc, and the left temporal bone and used muscular efforts as loading conditions. The viscohyperelastic properties of the disc were based on literature data from asymptomatic human cadaveric disc specimens. RESULTS: Stresses in the disc decreased slightly (<15%) after 10 seconds of maintained clenching. In contrast, strains increased in nearly all disc regions, with the maximum (33%) in the lateral part of the disc. The greatest creep strain (-0.1) also was found in the lateral part. CONCLUSION: Results suggest that maintained clenching leads to an increase in strains in the entire disc and to greater creep strain in the lateral part. This may be related to disc damage. PMID- 24485981 TI - Velopharyngeal anatomy in patients with obstructive sleep apnea versus normal subjects. AB - PURPOSE: Obesity can cause disturbed breathing and is one of the most significant risk factors for obstructive sleep apnea (OSA). However, the anatomic basis of OSA and, specifically, the anatomic mechanisms leading from obesity to OSA are still unclear. We examined the anatomic features of the velopharynx in patients with OSA versus those without in correlation with the body mass index (BMI), age, history of snoring, and OSA severity and re-evaluated the contribution of adding a frontal view to the cephalometric analysis of patients with OSA. MATERIALS AND METHODS: Lateral and frontal cephalometric measurements were taken to assess the velopharyngeal anatomic features of 306 men with various degrees of OSA and 64 men without OSA and without a history of snoring. The demographic, polysomnographic, and cephalometric features were compared. RESULTS: The patients with OSA had an increased pharyngeal length, thicker velum, a thicker posterior pharyngeal wall, a reduced pharyngeal width, and a consequent narrowing of the pharyngeal lumen. As the BMI increased, the OSA severity increased. Also, in parallel, the velum and posterior pharyngeal wall thickness increased and the pharyngeal width decreased. Three types of velopharyngeal narrowing, with an increased occurrence in severe degrees of OSA, were identified: bottle shape, hourglass shape, and tube shape. These aerodynamically unfavorable changes might cause increased upper airway resistance, explaining the development of both OSA and hypoventilation syndrome in obese patients. CONCLUSIONS: Velopharyngeal thickening and lumen narrowing were shown to be features of obese men with OSA. However, these features developed only above a threshold BMI value. The combination of frontal and lateral cephalometry is important for comprehensive evaluation of patients with OSA. PMID- 24485982 TI - Psychopathy and facial emotion recognition ability in patients with bipolar affective disorder with or without delinquent behaviors. AB - BACKGROUND: It is well known that patients with bipolar disorder are more prone to violence and have more criminal behaviors than general population. A strong relationship between criminal behavior and inability to empathize and imperceptions to other person's feelings and facial expressions increases the risk of delinquent behaviors. In this study, we aimed to investigate the deficits of facial emotion recognition ability in euthymic bipolar patients who committed an offense and compare with non-delinquent euthymic patients with bipolar disorder. METHOD: Fifty-five euthymic patients with delinquent behaviors and 54 non-delinquent euthymic bipolar patients as a control group were included in the study. Ekman's Facial Emotion Recognition Test, sociodemographic data, Hare Psychopathy Checklist, Hamilton Depression Rating Scale and Young Mania Rating Scale were applied to both groups. RESULTS: There were no significant differences between case and control groups in the meaning of average age, gender, level of education, mean age onset of disease and suicide attempt (p>0.05). The three types of most committed delinquent behaviors in patients with euthymic bipolar disorder were as follows: injury (30.8%), threat or insult (20%) and homicide (12.7%). The best accurate percentage of identified facial emotion was "happy" (>99%, for both) while the worst misidentified facial emotion was "fear" in both groups (<50%, for both). The total accuracy rate of recognition toward facial emotions was significantly impaired in patients with delinquent behaviors than non-delinquent ones (p<0.05). The accuracy rate of recognizing the fear expressions was significantly worse in the case group than in the control group (p<0.05). In addition, it tended to be worse toward angry facial expressions in criminal euthymic bipolar patients. The response times toward happy, fear, disgusted and angry expressions had been significantly longer in the case group than in the control group (p<0.05). CONCLUSION: This study is the first, searching the ability of facial emotion recognition in euthymic patients with bipolar disorder who had delinquent behaviors. We have shown that patients with bipolar disorder who had delinquent behaviors may have some social interaction problems i.e., misrecognizing fearful and modestly anger facial emotions and need some more time to response facial emotions even in remission. PMID- 24485983 TI - Third trimester NG2-positive amniotic fluid cells are effective in improving repair in spinal cord injury. AB - Spinal cord injury presents a significant therapeutic challenge since the treatments available are mostly vain. The use of stem cells to treat this condition represents a promising new therapeutic strategy; therefore, a variety of stem cell treatments have been recently examined in animal models of CNS trauma. In this work, we analyzed the effects of third trimester amniotic fluid cells in a mouse model of spinal cord injury. Among the different cultures used for transplantation, some were able to induce a significant improvement in motor recovery (cultures #3.5, #3.6 and #7.30), evaluated by means of open field free locomotion. All effective cell cultures expressed the surface marker nerve/glial antigen 2, ortholog of the human chondroitin sulfate proteoglycan 4, which is present on several types of immature progenitor cells. The improved motor functional recovery was correlated with higher myelin preservation in the ventral horn white matter and an increased vascularization in the peri-lesion area. Real Time PCR analysis showed higher expression levels of vascular endothelial growth factor and hypoxia-inducible factor-1alpha mRNA two days after cells transplantation compared to PBS-treated animals, indicating that an angiogenic pathway might have been activated by these cells, possibly through the production of hepatocyte growth factor. This cytokine appears to be produced mostly in filtering organs, such as the lung, of the transplanted animals and is likely released in the blood suggesting an endocrine role of hepatocyte growth factor in targeting the injury site. PMID- 24485984 TI - DNA repair signalling pathway genes are overexpressed in poor-quality pre implantation human embryos with complex aneuploidy. AB - OBJECTIVE: Chromosomal abnormalities and poor quality are correlated with DNA damage in the pre-implantation stage in humans. This study aimed to explore the altered expression of DNA damage signalling pathways - including apoptosis, cell cycle and DNA repair pathways - in poor-quality pre-implantation human embryos with complex aneuploidy. STUDY DESIGN: Surplus Day 4 embryos from candidates undergoing pre-implantation genetic screening were pooled into two groups. Group 1 included good-quality embryos that had simple aneuploidy, a single chromosome [according to fluorescence in situ hybridization-based pre-implantation genetic diagnosis (PGD) on Day 3], a normal rate of cell division, and graded as A or B (excellent to good). Group 2 included embryos with more than one aneuploid chromosome on PGD on Day 3, an abnormal rate of cell division, and graded as C or D (fair to poor). Gene expression of DNA damage signalling pathways was analysed using a real-time polymerase chain reaction-based array, which included 84 genes after specific pre-amplification of cDNA by a primer mix, including all array genes. RESULTS: In Group 2, five of the 84 genes studied showed significant overexpression (p<0.05): MSH3, XRCC1, RAD50, LIG1 and CDK7. Alterations were in agreement with genetic relationships in pathway analyses on DAVID. CONCLUSIONS: The five overexpressed genes are involved in DNA repair. Therefore, in comparison with cell cycle control and apoptotic pathways, DNA repair pathways are more activated in poor-quality pre-implantation human embryos with complex aneuploidy. This suggests that the dominant response to DNA damage in such embryos is DNA repair rather than cell division or apoptosis. PMID- 24485985 TI - Proteomic investigation of cultivated fibroblasts from patients with mitochondrial short-chain acyl-CoA dehydrogenase deficiency. AB - Short-chain acyl-CoA dehydrogenase (SCAD) deficiency is a rare inherited autosomal recessive disorder with not yet well established mechanisms of disease. In the present study, the mitochondrial proteome of five symptomatic patients homozygous for missense variations in the SCAD gene ACADS was investigated in an extensive large-scale proteomic study to map protein perturbations linked to the disease. Fibroblast cultures of patient cells homozygous for either c.319C>T/p.Arg107Cys (n=2) or c.1138C>T/p.Arg380Trp (n=3) in ACADS, and healthy controls (normal human dermal fibroblasts), were studied. The mitochondrial proteome derived from these cultures was analyzed by label free proteomics using high mass accuracy nanoliquid chromatography tandem mass spectrometry (nanoLC MS/MS). More than 300 mitochondrial proteins were identified and quantified. Thirteen proteins had significant alteration in protein levels in patients carrying variation c.319C>T in ACADS compared to controls and they belonged to various pathways, such as the antioxidant system and amino acid metabolism. Twenty-two proteins were found significantly altered in patients carrying variation c.1138C>T which included proteins associated with fatty acid beta oxidation, amino acid metabolism and protein quality control system. Three proteins were found significantly regulated in both patient groups: adenylate kinase 4 (AK4), nucleoside diphosphate kinase A (NME1) and aldehyde dehydrogenase family 4 member A1 (ALDH4A1). Proteins AK4 and NME1 deserve further investigation because of their involvement in energy reprogramming, cell survival and proliferation with relevance for SCAD deficiency and related metabolic disorders. PMID- 24485986 TI - Multi-detector computed tomography of an aortic dissection in a cat. AB - Contrast enhanced, multi-detector computed tomography (MDCT) is a useful diagnostic imaging modality that has become increasingly available in veterinary medicine. Multi-planar and three-dimensional reconstructions allow accurate and comprehensive assessment of cardiac and vascular lesions with short image acquisition times. ECG-gated, contrast enhanced MDCT was used to assess the lesion extent and therapeutic options in a case of aortic dissection diagnosed in a hypertensive cat. PMID- 24485987 TI - Advanced multimodality imaging of an anomalous vessel between the ascending aorta and main pulmonary artery in a dog. AB - A 1-year-old male German shorthaired pointer was referred for evaluation of tachypnea and hemoptysis. A grade VI/VI left basilar continuous murmur was ausculted. Multimodality imaging consisting of thoracic radiographs, transthoracic and transesophageal echocardiography, fluoroscopy-guided selective angiography, computed tomography angiogram (CTA) and magnetic resonance angiogram (MRA), was performed on this patient. The defect included a left-to-right shunting anomalous vessel between the ascending aorta and main pulmonary artery, along with a dissecting aneurysm of the main and right pulmonary artery. An MRA post-processing technique (PC VIPR) was used to allow for high resolution angiographic images and further assessment of the patient's hemodynamics prior to surgical correction. This case report describes the clinical course of a canine patient with a rare form of congenital cardiac disease, and the multiple imaging modalities that were used to aid in diagnosis and treatment. PMID- 24485988 TI - Acute intake of a high-fructose diet alters the balance of adipokine concentrations and induces neutrophil influx in the liver. AB - The postprandial state is a period of metabolic fluxes, biosynthesis and oxidative metabolism. A considerable amount is known about the inflammatory response to the chronic consumption of fructose, but little is known about its effects in the postprandial state. The aim of the present study was to investigate the inflammatory effects of a single meal containing fructose on healthy mice. Male BALB/c and LysM-eGFP mice at 12-14 weeks were divided into three groups: fasted, control (mice fed with a sucrose-containing diet) and fructose (mice fed with a fructose-containing diet). One, 2 or 4 h postprandial, the BALB/c mice were killed, and samples were collected. LysM-eGFP mice were submitted to intravital microscopy. The fed mice showed a low-grade inflammatory response apart from dietary composition, which was characterized by increased numbers of leukocytes and high serum concentrations of pentraxin 3, leptin and resistin. TNF-alpha and CCL2 concentrations rose in the liver after the meal. IL 6 concentration increased and IL-10 decreased in the adipose tissue of the fed mice. Mice fed with the fructose-containing diet showed an intensification of the inflammatory response. Furthermore, the adiponectin concentration dropped, and the liver influx of neutrophils increased after fructose intake. Overall, this study showed a rapid increase in the systemic and tissue-specific immune response after a balanced meal. The study also showed an increased neutrophil influx in liver associated with an imbalance of adipokine concentrations and an increase of cytokine in the liver and adipose tissue following a fructose-containing meal. PMID- 24485989 TI - (232)Th(d,4n)(230)Pa cross-section measurements at ARRONAX facility for the production of (230)U. AB - INTRODUCTION: (226)Th (T1/2=31 min) is a promising therapeutic radionuclide since results, published in 2009, showed that it induces leukemia cells death and activates apoptosis pathways with higher efficiencies than (213)Bi. (226)Th can be obtained via the (230)U alpha decay. This study focuses on the (230)U production using the (232)Th(d,4n)(230)Pa(beta-)(230)U reaction. METHODS: Experimental cross sections for deuteron-induced reactions on (232)Th were measured from 30 down to 19 MeV using the stacked-foil technique with beams provided by the ARRONAX cyclotron. After irradiation, all foils (targets as well as monitors) were measured using a high-purity germanium detector. RESULTS: Our new (230)Pa cross-section values, as well as those of (232)Pa and (233)Pa contaminants created during the irradiation, were compared with previous measurements and with results given by the TALYS code. Experimentally, same trends were observed with slight differences in orders of magnitude mainly due to the nuclear data change. Improvements are ongoing about the TALYS code to better reproduce the data for deuteron-induced reactions on (232)Th. CONCLUSIONS: Using our cross-section data points from the (232)Th(d,4n)(230)Pa reaction, we have calculated the thick-target yield of (230)U, in Bq/MUA.h. This value allows now to a full comparison between the different production routes, showing that the proton routes must be preferred. PMID- 24485990 TI - Influence of pegylation and hapten location at the surface of radiolabelled liposomes on tumour immunotargeting using bispecific antibody. AB - INTRODUCTION: This paper proposes liposomes as a potential new tool for radioimmunotherapy in solid tumours with a two step targeting system. Tumour pretargeting is obtained by using a monoclonal bispecific antibody (BsmAb, anti CEA x anti-DTPA-In) and pegylated liposomes containing lipid-hapten (DSPE-DTPA-In or DSPE-PEG-DTPA-In). To optimise at the same time in vivo behaviour and specific targeting, the study focuses on the liposome formulation in order to determine more precisely the role of pegylation on both the blood half-life and the specific recognition with the BsmAb. METHODS: Different liposome formulations containing two PEG length (1000 and 2000) in varying amount (1.5-6 mol%) were prepared with DTPA directly coupled to DSPE or at the end of the PEG chain (DSPE DTPA or DSPE-PEG-DTPA). Liposomes were immobilized on an L1 chip to measure by SPR (Surface Plasmon Resonance) the effect of pegylation on the BsmAb recognition of the DTPA-In hapten. Pharmacokinetic studies were performed in mice. Tumour targeting was studied in nude mice xenografted with human colorectal adenocarcinoma cells that express CEA, and doubly radiolabelled liposomes (with (111)In and (125)I) injected 24h after the BsmAb. RESULTS: The best in vitro apparent dissociation constant was obtained with liposomes bearing DTPA at the end of the PEG chain (KD=6.3 nM), which showed significant specific tumour uptake after BsmAb injection (8.6 +/- 2.4% ID/g at 24h versus 4.5 +/- 0.5%ID/g for passive targeting, alpha=0.01). All tumour/organ ratios were superior to 1 at 24h for this formulation, except for the spleen. CONCLUSION: The feasibility of specific tumour targeting in mice with a BsmAb and radiolabelled liposomes was demonstrated and the interest of SPR to predict their targeting performance in vivo was highlighted. This original and new approach provides promising prospects for the radioimmunotherapy of solid tumours. PMID- 24485992 TI - Surveillance of hand, foot, and mouth disease for a vaccine. PMID- 24485994 TI - Editorial comment. PMID- 24485991 TI - Hand, foot, and mouth disease in China, 2008-12: an epidemiological study. AB - BACKGROUND: Hand, foot, and mouth disease is a common childhood illness caused by enteroviruses. Increasingly, the disease has a substantial burden throughout east and southeast Asia. To better inform vaccine and other interventions, we characterised the epidemiology of hand, foot, and mouth disease in China on the basis of enhanced surveillance. METHODS: We extracted epidemiological, clinical, and laboratory data from cases of hand, foot, and mouth disease reported to the Chinese Center for Disease Control and Prevention between Jan 1, 2008, and Dec 31, 2012. We then compiled climatic, geographical, and demographic information. All analyses were stratified by age, disease severity, laboratory confirmation status, and enterovirus serotype. FINDINGS: The surveillance registry included 7,200,092 probable cases of hand, foot, and mouth disease (annual incidence, 1.2 per 1000 person-years from 2010-12), of which 267,942 (3.7%) were laboratory confirmed and 2457 (0.03%) were fatal. Incidence and mortality were highest in children aged 12-23 months (38.2 cases per 1000 person-years and 1.5 deaths per 100,000 person-years in 2012). Median duration from onset to diagnosis was 1.5 days (IQR 0.5-2.5) and median duration from onset to death was 3.5 days (2.5 4.5). The absolute number of patients with cardiopulmonary or neurological complications was 82,486 (case-severity rate 1.1%), and 2457 of 82486 patients with severe disease died (fatality rate 3.0%); 1617 of 1737 laboratory confirmed deaths (93%) were associated with enterovirus 71. Every year in June, hand, foot, and mouth disease peaked in north China, whereas southern China had semiannual outbreaks in May and September-October. Geographical differences in seasonal patterns were weakly associated with climate and demographic factors (variance explained 8-23% and 3-19%, respectively). INTERPRETATION: This is the largest population-based study up to now of the epidemiology of hand, foot, and mouth disease. Future mitigation policies should take into account the heterogeneities of disease burden identified. Additional epidemiological and serological studies are warranted to elucidate the dynamics and immunity patterns of local hand, foot, and mouth disease and to optimise interventions. FUNDING: China-US Collaborative Program on Emerging and Re-emerging Infectious Diseases, WHO, The Li Ka Shing Oxford Global Health Programme and Wellcome Trust, Harvard Center for Communicable Disease Dynamics, and Health and Medical Research Fund, Government of Hong Kong Special Administrative Region. PMID- 24485993 TI - Female gender is associated with a worse survival after radical cystectomy for urothelial carcinoma of the bladder: a competing risk analysis. AB - OBJECTIVE: To determine the association of gender with outcome after radical cystectomy for patients with bladder cancer. METHODS: An observational cohort study was conducted using retrospectively collected data from 11 centers on patients with advanced bladder cancer treated with radical cystectomy. The association of gender with disease recurrence and cancer-specific mortality was examined using a competing risk analysis. RESULTS: The study comprised 4296 patients, including 890 women (21%). The median follow-up duration was 31.5 months for all patients. Disease recurred in 1430 patients (33.9%) (36.8% of women and 33.1% of men) at a median of 11 months after surgery. Death from any cause was observed in 46.0% of men and 50.1% of women. Cancer-specific death was observed in 33.0% of women and 27.2% of men. Multivariable regression with competing risk found that female gender was associated with an increased risk for disease recurrence and cancer-specific mortality (hazard ratio, 1.27; 95% confidence interval, 1.108-1.465; P = .007) compared with male gender. Important limitations include the inability to account for additional potential confounders, such as differences in environmental exposures, treatment selection, and histologic subtypes between men and women. CONCLUSION: Our analysis identified female gender as a poor-risk feature for patients undergoing radical cystectomy. This adverse prognostic factor was independent of standard clinical and pathologic features and competing risk from non-cancer-related death. PMID- 24485995 TI - Editorial comment. PMID- 24485996 TI - Can computed tomography--assisted virtual endoscopy be an innovative tool for detecting urethral tissue pathologies? AB - OBJECTIVE: To test if virtual endoscopy (VE) enabled by 3-dimensional computed tomographic (CT) scanner with supporting software allows for practical clinical interrogation and evaluation of the urethral lumen and anatomy in an animal model. METHODS: Assessment of urethral anatomy and repair results was performed in 18 male beagles using conventional retrograde urethrography, CT-assisted retrograde urethography, and voiding urethrocystography. The image slices from these studies were processed using TeraRecon software to create a virtual representation of the urethra and compared with conventional urethrography and postmortem analysis of retrieved urethras for diagnostic assessment and correlation. RESULTS: CT-assisted VE showed the orientation, size, and gross morphology of urethral anatomy, including the lesions in all the 18 animals studied. The VE showed patent urethra in 12 dogs, stenosed urethra in 3 dogs, urethral diverticulum with stricture in 2 animals, and fistula in one. These findings correlated with those of conventional diagnostic methods. The findings of the voiding and retrograde virtual urethrocystoscopy studies were also comparable. CONCLUSION: These results demonstrate that CT-assisted VE is able to identify the anatomic landmarks in an animal model. This allows for detection of the site of different pathologies and their relations to important structures such as urethral sphincters and the bladder neck. Digital imaging might be used to identify urethral pathologies with greater details and characterization of the lesions when compared with the conventional urethrocystography. PMID- 24485997 TI - Perineal anastomotic urethroplasty in a pediatric cohort with posterior urethral strictures: critical analysis of outcomes in a contemporary series. AB - OBJECTIVE: To evaluate the long-term outcomes of perineal anastomotic urethroplasty for post-traumatic pediatric posterior urethral strictures. METHODS: We retrospectively reviewed the medical records of 65 boys who had a perineal anastomotic urethroplasty for post-traumatic posterior urethral strictures between 1991 and 2010. Patients were followed up for a mean (range) of 78 (13-210) months by a history, urinary flow rate estimate, retrograde urethrography, and voiding cystourethrography. Regression analysis was done to assess the predictors of success after urethroplasty. RESULTS: The mean (range) age of the patients was 9.3 (3-16) years. The estimated radiographic stricture length before surgery was 2.4 (1-5) cm. All patients presented with a suprapubic cystostomy tube and scheduled for delayed or repeated correction of a urethral stricture. Twenty boys (30%) had failed previous attempts of repair elsewhere. Mean interval between the original trauma and repair in new cases, and since the last repair in recurrent cases, was 7 months. The perineal anastomotic repair was successful in 58 of 65 (89%) patients. All treatment failures were at the anastomosis and were within the first year. Failed repairs were successfully managed endoscopically in 5 patients and by repeat perineal anastomotic repair in the remaining 2. All boys are continent. There was no chordee or urethral diverticula during the follow-up. CONCLUSION: One-stage perineal anastomotic repair of post-traumatic urethral strictures in boys is feasible with minimal morbidity. Denovo cases and surgeon experience are the predictors of success after urethroplasty. PMID- 24485998 TI - Prospective randomized comparison of retroperitoneoscopic vs open pyeloplasty with minimal incision: subjective and objective assessment in adults. AB - OBJECTIVE: To determine the subjective and objective outcomes of retroperitoneoscopic vs open pyeloplasty with minimal incision in a prospective randomized comparison study. METHODS: In this study between August 2011 to July 2013, 30 patients underwent retroperitoneal laparoscopic pyeloplasty and 30 open pyeloplasty with minimal incision (incision length <10 cm) after randomization. The 2 groups were compared for the visual pain score on the first and second postoperative days as the primary end point of the study. Complications were recorded and graded using Dindo-modified Clavien classification of surgical complications. Success rates were evaluated by improvement in pain score and objectively by diethylene triamine penta-acetic acid renal scan and other parameters. Statistical analysis was performed with SPSS version 16.0 (IBM) with P <.05 considered statistically significant. RESULTS: The difference in the visual pain score (5.6 vs 3.2 on day 1; 3.8 vs 1.5 on day 2) and the diclofenac requirements (333.3 vs 178.75 mg) were statistically significant and more in the open pyeloplasty. The hospital stay and convalescence were significantly lower in retroperitoneoscopic group. Success rate was found to be 96.67% with 1 failure in each group. Two patients in retroperitoneoscopic group required conversion. Both groups showed significant improvement in pain score and drainage pattern on diethylene triamine penta-acetic acid scan with decrease in hydronephrosis on ultrasound evaluation. CONCLUSION: Although subjective and objective outcomes are equivalent in both the groups, the retroperitoneoscopic approach is associated with significantly less pain, less analgesic requirement, shorter hospital stay and short convalescence in comparison with open pyeloplasty. PMID- 24485999 TI - The characteristics of the stone and urine composition in Chinese stone formers: primary report of a single-center results. AB - OBJECTIVE: To assess urine composition in Chinese patients with urolithiasis. METHODS: Five hundred seven Chinese patients with urolithiasis from our center in southern China were included in this study. Analysis of stone composition was performed using infrared spectrometry. From all patients, 24-hour urine samples were collected for analysis of urinary variables. Some ion activity product risk indices were also calculated. RESULTS: The major stone constituents in the 507 analyzed stones were as follows: calcium oxalate (78.3%), infection stone components (14.6%), uric acid (3.6%), and calcium phosphate (3.4%). Only 1 stone was composed of cystine (0.2%). Of all patients, 504 (99.4%) had 1 or several urinary metabolic abnormalities. Hypocitraturia was recorded in 93.9%, high sodium excretion in 58.6%, small urine volume in 45.6%, hyperoxaluria in 31.0%, hypercalciuria in 26.0%, hyperuricosuria in 19.3%, and hyperphosphaturia in 2.8%. Moreover, high sodium excretion was more frequent in men than women (59.2% vs 49.3%, P = .027), whereas hypercalciuria was more common in women (34.5% vs 20.4%, P <.001). High levels of urine sodium (187.7 +/- 86.9 vs 179.8 +/- 107.7 mmol/24h, P = .038) and phosphate (18.26 +/- 8.36 vs 15.69 +/- 11.14 mmol/24h, P <.001) were found in men than in women. Infection stones were significantly (P <.004) more common in women. Compared with noninfection stone formers, the occurrence of hypomagnesuria (P = .040) was more common in patients with infection stones. CONCLUSION: The results of urinary risk factors for stone formation in this study might serve as a basis for design of recurrence prevention. It is of interest to note that some of the demonstrated abnormalities differ from that in reports from other countries. PMID- 24486000 TI - Determinants of holmium:yttrium-aluminum-garnet laser time and energy during ureteroscopic laser lithotripsy. AB - OBJECTIVE: To evaluate the association of preoperative noncontrast computed tomography stone characteristics, laser settings, and stone composition with cumulative holmium:yttrium-aluminum-garnet (Ho:YAG) laser time/energy. MATERIALS AND METHODS: We retrospectively reviewed patients who underwent semirigid/flexible ureteroscopy and Ho:YAG laser lithotripsy (200 or 365 MUm laser fiber; 0.8-1.0 J energy; and 8-10 Hz rate) at 2 tertiary care centers (April 2010-May 2012). Studied parameters were as follows: patient's characteristics; stone characteristics (location, burden, hardness, and composition); total laser time and energy; and surgical outcomes. RESULTS: One hundred patients met our inclusion criteria. Mean stone size was 1.01 +/- 0.42 cm and volume 0.33 +/- 0.04 cm(3). Mean stone radiodensity was 990 +/- 296 HU, and Hounsfield units density 13.8 +/- 6.0 HU/mm. All patients were considered stone free. Stone size and volume had a significant positive correlation with laser energy (R = 0.516, P <.001; R = 0.621, P <.001) and laser time (R = 0.477, P <.001; R = 0.567, P <.001). When controlling for stone size, only the correlation between HU and laser time was significant (R = 0.262, P = .011). In the multivariate analysis, with exception of stone composition (P = .103), all parameters significantly increased laser energy (R(2) = 0.524). Multivariate analysis revealed a positive significant association of laser time with stone volume (P <.001) and Hounsfield units density (P <.001; R(2) = 0.512). In multivariate analysis for laser energy, only calcium phosphate stones required less energy to fragment compared with uric acid stones. No significant differences were found in the multivariate laser time model. CONCLUSION: Ho:YAG laser cumulative energy and total time are significantly affected by stone dimensions, hardness location, fiber size, and power. Kidney location, laser fiber size, and laser power have more influence on the final laser energy than on the total laser time. Calcium phosphate stones require less laser energy to fragment. PMID- 24486001 TI - Frequent truncating mutations of STAG2 in bladder cancer. PMID- 24486002 TI - Activation of the CXCL12/CXCR4 signaling axis may drive vascularization of the ovine placenta. AB - Early pregnancy, when most embryonic losses occur, is a critical period in which vital placental vascularization is established. Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis, and factors that regulate VEGF function, expression, or both may ultimately affect vascularization. Activation of the C-X-C chemokine receptor type 4 (CXCR4) by its cognate ligand, C-X-C chemokine ligand 12 (CXCL12), increases VEGF synthesis and secretion, which in turn stimulates CXCL12 and CXCR4 production and this synergistic regulation may influence placental vascularization. We hypothesized that expression of CXCL12, CXCR4, select angiogenic factors, and their receptors would increase in placental tissues during early pregnancy and that treatment of ovine trophectoderm cells with CXCL12 would increase production of angiogenic factors. To test this hypothesis, maternal caruncle (CAR) and fetal extraembryonic membrane (FM) tissues were collected on days 18, 20, 22, 25, 26, and 30 of pregnancy and on day 10 of the estrous cycle (control, NP) to determine relative mRNA or protein expression of CXCL12 and CXCR4 and selected angiogenic factors. In CAR, expression of mRNA for CXCR4 increased on day 18, 20, 22, and 25 and CXCL12 increased on day 18 and 20 compared with NP ewes. CXCL12 protein followed a similar pattern in CAR tissue, with greater levels on day 20 than in NP tissue. Greater levels of fibroblast growth factor 2 (FGF2) mRNA was observed in CAR on day 20 of gestation than on day 30. In FM, CXCL12, CXCR4, angiopoietin 1, VEGF, and VEGF receptor 1 were enhanced with advancing pregnancy, whereas FGF2 and kinase insert domain receptor (or VEGF receptor 2) peaked on day 25. An increase in protein levels occurred on day 25 compared with day 20 in FM for CXCL12 and CXCR4, as well as a similar tendency for FGF2 protein. Both CXCL12 and CXCR4 are specifically localized to trophoblast cells and to the uterine luminal and glandular epithelium. Treatment of ovine trophectoderm cells with CXCL12 increased mRNA expression for VEGF and FGF2. The relationship between VEGF, FGF2, and the CXCL12/CXCR4 signaling underscores the potential role for this chemokine axis in driving placentation. PMID- 24486003 TI - Biomolecular dynamics and binding studies in the living cell. AB - Isolation and preparation of proteins of higher organisms often is a tedious task. In the case of success, the properties of these proteins and their interactions with other proteins can be studied in vitro. If however, these proteins are modified in the cell in order to gain or change function, this is non-trivial to correctly realise in vitro. When, furthermore, the cellular function requires the interplay of more than one or two proteins, in vitro experiments for the analysis of this situation soon become complex. Instead, we thus try to obtain information on the molecular properties of proteins in the living cell. Then, the cell takes care of correct protein folding and modification. A series of molecular techniques are, and new ones become, available which allow for measuring molecular protein properties in the living cell, offering information on concentration (FCS), dynamics (FCS, RICS, FRAP), location (PALM, STED), interactions (F3H, FCCS) and protein proximities (FRET, BRET, FLIM, BiFC). Here, these techniques are presented with their advantages and drawbacks, with examples from our current kinetochore research. The review is supposed to give orientation to researchers planning to enter the field, and inform which techniques help us to gain molecular information on a multi-protein complex. We show that the field of cellular imaging is in a phase of transition: in the future, an increasing amount of physico-chemical data can be determined in the living cell. PMID- 24486004 TI - Understanding the origins of language: An interactive stance: Comment on "Modelling language evolution: Examples and predictions" by Gong, Shuai and Zhang. PMID- 24486005 TI - Climate change, sea-level rise, and conservation: keeping island biodiversity afloat. AB - Island conservation programs have been spectacularly successful over the past five decades, yet they generally do not account for impacts of climate change. Here, we argue that the full spectrum of climate change, especially sea-level rise and loss of suitable climatic conditions, should be rapidly integrated into island biodiversity research and management. PMID- 24486006 TI - Surgical and endovascular treatment of extracranial carotid artery aneurysms: early and long-term results of a single center. AB - PURPOSE: To evaluate early and long-term results of surgical and endovascular therapy of extracranial carotid artery aneurysms. PATIENTS AND METHODS: A retrospective study was conducted of 26 aneurysms in 25 patients (19 men and 6 women) who underwent surgery between 1993 and 2010: 18 were atherosclerotic, 3 were from arteritis, 1 was a relapsing mycotic aneurysm from previous carotid surgery, and 4 were posttraumatic. A neurologic event was the presenting symptom in 10 cases (7 transient ischemic attacks, 3 strokes); 13 patients were asymptomatic and a cranial nerve dysfunction (hoarseness) was present in 2; fever was present in 1. A total of 15 aneurysms, located on the carotid bifurcation (CB), were resected and an end-to-end carotid anastomosis was performed. In 6 patients with CB aneurysms, a vein graft was applied in 5, and a polytetrafluoroethylene graft in the other. Aneurysmorrhaphy and a vein patch was the procedure in 2 patients with an aneurysm of the CB. One of these 2 patients had a relapsing mycotic pseudoaneurysm and was treated initially with a vein patch, subsequently with a vein graft, and lastly with a carotid artery ligation. Three common carotid artery aneurysms from arteritis were treated under local anesthesia through implantation of a Viabahn endoprosthesis. RESULTS: A perioperative minor stroke occurred in 1 patient (3.8%) because of intentional ligation of the internal carotid artery from a relapsing mycotic aneurysm, already treated with a vein patch and subsequently with a vein bypass. No permanent cranial nerve injuries were recorded; transient cranial nerve injuries were observed in 2 patients. CONCLUSIONS: Surgical treatment is feasible, with an acceptable rate of stroke and cranial nerve injuries, especially when the aneurysm is located on the common carotid artery and carotid bulb. Endovascular therapy is a fascinating option, with satisfactory early and long-term results, and should always be considered when treating aneurysms located in the distal internal carotid artery and when the patient is not a good candidate for open surgery. PMID- 24486007 TI - Postpartum contraceptive choices among ethnically diverse women in New Mexico. AB - OBJECTIVE: The objective of the study was to determine if postpartum contraceptive choices by primiparous women differ by ethnicity. STUDY DESIGN: Retrospective nested cohort study analyzing women's characteristics and contraceptive choice. RESULTS: Of 652 participants, 312 (47.8%) were Hispanic, 287 (44.0%) were non-Hispanic white, and 53 (8.1%) were American Indian (AI). In multivariate analysis, depot medroxyprogesterone acetate (DMPA) and intrauterine device (IUD)/implant choice was related to AI [DMPA: odds ratio (OR) 15.28, confidence interval (CI) 4.49-52.04; IUD/implant: OR 0.46, CI 0.22-0.92] and Hispanic (DMPA: OR 3.44, CI 1.12-10.58) ethnicity. CONCLUSION: DMPA use was higher among Hispanic and AI women and IUD/implant use lower in AI women compared to non-Hispanic white women. PMID- 24486008 TI - Contraceptive method selection by women with inflammatory bowel diseases: a cross sectional survey. AB - OBJECTIVE: Women with inflammatory bowel diseases (IBDs) utilize contraception at a lower rate than the general population. We sought to identify factors associated with contraceptive use and selection of more effective methods in IBD patients at risk for unintended pregnancy. STUDY DESIGN: An online survey was distributed to women with IBD in January 2013. Contraceptive methods were categorized by effectiveness and associations with use explored by demographics, disease characteristics and reproductive goals. RESULTS: A total of 162 respondents were analyzed: 62% had Crohn's disease and 38% ulcerative colitis. Mean age was 31 (range 20-45), 97% identified as White, and 53% were nulliparas. Seventy-four percent were currently using IBD medications. A quarter of participants (23%) used no contraception, 17% used highly effective methods, 41% used short-term hormonal methods, and 19% chose barrier/behavioral methods. Prior IBD-related surgery, biologic therapy use and low education attainment were associated with no contraception use. Of contraceptive users, age, parity, insurance status, IBD surgery and prior immunomodulator use were associated with highly effective method selection. CONCLUSIONS: A quarter of women with IBD at risk for pregnancy in this study population reported no contraceptive method use. Higher levels of IBD activity influence contraceptive use and method selection, which could guide future patient and provider educational interventions. IMPLICATIONS: Pregnancy planning is important for women with inflammatory bowel diseases to avoid adverse outcomes in a disease-poor state. Use of contraception assists in avoidance of unintended pregnancy. IBD characteristics are targets for educational interventions to improve uptake of highly effective contraceptive methods. PMID- 24486009 TI - Ideal body condition improves reproductive performance and influences genetic health in female mink. AB - Selection for large body size in mink (Neovison vison) can result in obesity, which is associated with poor reproduction and metabolic disorders. Caloric restriction is effective in diminishing oxidative stress and delaying aging related diseases. This study investigated the effects of moderate diet restriction on body condition, health, and reproductive success of mink breeder females. One-hundred control females were fed according to conventional feeding practice, while the feed allowance of their 100 sister-pair females was restricted in order to maintain an ideal body condition during the fall and eliminate the need for drastic slimming prior to breeding. Repeated measures analyses revealed that body weight gain during the fall and weight loss prior to breeding was significantly less for the restricted females. The restricted females had significantly larger live litters (5.88 kits) than the control dams (4.62 kits; P<0.05). They were also able to maintain their body weight and condition during early lactation and were able to regain weight and condition post-lactation, unlike their control sisters. Based on their comet scores (restricted: 88; control: 116), the restricted primiparous females experienced less DNA damage (P<0.05), while no significant differences were apparent for the multiparous females (restricted: 170; control: 153). No changes in telomere length were observed among the dams. Moderate diet restriction of mink breeder females during the fall eliminated extreme fluctuations in body weight and condition throughout the seasonal production cycle and improved their litter size, and in primiparous females, lessened DNA damage. PMID- 24486010 TI - Crenactin from Pyrobaculum calidifontis is closely related to actin in structure and forms steep helical filaments. AB - Polymerising proteins of the actin family are nearly ubiquitous. Crenactins, restricted to Crenarchaea, are more closely related to actin than bacterial MreB. Crenactins occur in gene clusters hinting at an unknown, but conserved function. We solved the crystal structure of crenactin at 3.2 A resolution. The protein crystallises as a continuous right-handed helix with 8 subunits per complete turn, spanning 419 A. The structure of crenactin shows several loops that are longer than in actin, but overall, crenactin is closely related to eukaryotic actin, with an RMSD of 1.6 A. Crenactin filaments imaged by electron microscopy showed polymers with very similar helical parameters. PMID- 24486011 TI - Regulation of pannexin channels by post-translational modifications. AB - The large-pore channels formed by the pannexin family of proteins have been implicated in many physiological and pathophysiological functions, mainly through their ATP release function. However, a tight regulation of channel opening is necessary to modulate their function in vivo. Post-translational modifications have been postulated as some of the regulating mechanisms for Panx1, while Panx2 and Panx3 have not been as well characterized. Positive regulators include caspase cleavage to open Panx1 channels in apoptotic cells, and activation by Src family kinases via ionotropic receptors in neurons and macrophages. S nitrosylation of cysteines has been shown to both inhibit and activate the Panx1 channel in different cell types. All three pannexins are N-glycosylated but to different levels of modification. Their diverse glycosylation appears to regulate cellular localization, intermixing, and may restrict their ability to function as inter-cellular channels. It is clear that our understanding of pannexin post translational modification and their role in channel function regulation is still in its infancy even a decade after their discovery. PMID- 24486012 TI - Old cogs, new tricks: a scaffolding role for connexin43 and a junctional role for sodium channels? AB - Cardiac conduction is the process by which electrical excitation is communicated from cell to cell within the heart, triggering synchronous contraction of the myocardium. The role of conduction defects in precipitating life-threatening arrhythmias in various disease states has spurred scientific interest in the phenomenon. While the understanding of conduction has evolved greatly over the last century, the process has largely been thought to occur via movement of charge between cells via gap junctions. However, it has long been hypothesized that electrical coupling between cardiac myocytes could also occur ephaptically, without direct transfer of ions between cells. This review will focus on recent insights into cardiac myocyte intercalated disk ultrastructure and their implications for conduction research, particularly the ephaptic coupling hypothesis. PMID- 24486013 TI - Role of connexin/pannexin containing channels in infectious diseases. AB - In recent years it has become evident that gap junctions and hemichannels, in concert with extracellular ATP and purinergic receptors, play key roles in several physiological processes and pathological conditions. However, only recently has their importance in infectious diseases been explored, likely because early reports indicated that connexin containing channels were completely inactivated under inflammatory conditions, and therefore no further research was performed. However, recent evidence indicates that several infectious agents take advantage of these communication systems to enhance inflammation and apoptosis, as well as to participate in the infectious cycle of several pathogens. In the current review, we will discuss the role of these channels/receptors in the pathogenesis of several infectious diseases and the possibilities of generating novel therapeutic approaches to reduce or prevent these diseases. PMID- 24486015 TI - The role of the gap junction protein connexin43 in B lymphocyte motility and migration. AB - The gap junction family of proteins is widely expressed in mammalian cells and form intercellular channels between adjacent cells, as well as hemichannels, for transport of molecules between the cell and the surrounding environment. In addition, gap junction proteins have recently been implicated as important for the regulation of cell adhesion and migration in a variety of cell types. The gap junction protein connexin43 (Cx43) regulates B lymphocyte adhesion, BCR- and LFA 1-mediated activation of the GTPase Rap1, and cytoskeletal rearrangements resulting in changes to cell shape and membrane spreading. We demonstrate here that the actin cytoskeleton is important for the distribution of Cx43 in the B cell plasma membrane and for other cell processes involving the cytoskeleton. Using shRNA knockdown of Cx43 in B lymphoma cells we show that Cx43 is also necessary for chemokine-mediated Rap 1 activation, motility, CXCL12-directed migration, and movement across an endothelial cell monolayer. These results demonstrate that in addition to its role in B cell spreading, Cx43 is an important regulator of B-cell motility and migration, processes essential for normal B-cell development and immune responses. PMID- 24486014 TI - Gap junctional regulation of signal transduction in bone cells. AB - The role of gap junctions, particularly that of connexin43 (Cx43), has become an area of increasing interest in bone physiology. An abundance of studies have shown that Cx43 influences the function of osteoblasts and osteocytes, which ultimately impacts bone mass acquisition and skeletal homeostasis. However, the molecular details underlying how Cx43 regulates bone are only coming into focus and have proven to be more complex than originally thought. In this review, we focus on the diverse molecular mechanisms by which Cx43 gap junctions and hemichannels regulate cell signaling pathways, gene expression, mechanotransduction and cell survival in bone cells. This review will highlight key signaling factors that have been identified as downstream effectors of Cx43 and the impact of these pathways on distinct osteoblast and osteocyte functions. PMID- 24486016 TI - Extra-articular fractures of the digital metacarpals and phalanges of the long fingers. AB - Metacarpal and phalangeal fractures of the long fingers are the result of trauma occurring under extremely varied circumstances. As a consequence, the clinical presentation varies greatly, with every bone and joint potentially being involved. Each step of their treatment is crucial, although the benign appearance of these injuries can lead to steps being missed: diagnostic phase with clinical examination and radiographs; therapeutic phase where the most suitable treatment is chosen, which combines mobilization of the digital chains as soon as possible and in every patient; follow-up phase with regular monitoring to detect any complications, especially secondary displacement, and verify that good progress is being made during rehabilitation. The goal of any fracture treatment is to preserve or restore the anatomy, with the emphasis here being on the stability and mobility of the digital chains. The potential progression towards serious functional sequelae (pain, instability or stiffness in hand) and the resulting significant socio-economic repercussions must be at the forefront of a surgeon's mind early on during the initial care of any finger or hand trauma. PMID- 24486017 TI - Tyr phosphorylation of PDP1 toggles recruitment between ACAT1 and SIRT3 to regulate the pyruvate dehydrogenase complex. AB - Mitochondrial pyruvate dehydrogenase complex (PDC) is crucial for glucose homeostasis in mammalian cells. The current understanding of PDC regulation involves inhibitory serine phosphorylation of pyruvate dehydrogenase (PDH) by PDH kinase (PDK), whereas dephosphorylation of PDH by PDH phosphatase (PDP) activates PDC. Here, we report that lysine acetylation of PDHA1 and PDP1 is common in epidermal growth factor (EGF)-stimulated cells and diverse human cancer cells. K321 acetylation inhibits PDHA1 by recruiting PDK1, and K202 acetylation inhibits PDP1 by dissociating its substrate PDHA1, both of which are important in promoting glycolysis in cancer cells and consequent tumor growth. Moreover, we identified mitochondrial ACAT1 and SIRT3 as the upstream acetyltransferase and deacetylase, respectively, of PDHA1 and PDP1, while knockdown of ACAT1 attenuates tumor growth. Furthermore, Y381 phosphorylation of PDP1 dissociates SIRT3 and recruits ACAT1 to PDC. Together, hierarchical, distinct posttranslational modifications act in concert to control molecular composition of PDC and contribute to the Warburg effect. PMID- 24486018 TI - A phosphate-binding pocket within the platform-PAZ-connector helix cassette of human Dicer. AB - We have solved two families of crystal structures of the human Dicer "platform PAZ-connector helix" cassette in complex with small interfering RNAs (siRNAs). The structures possess two adjacently positioned pockets: a 2 nt 3'-overhang binding pocket within the PAZ domain (3' pocket) and a phosphate-binding pocket within the platform domain (phosphate pocket). One family of complexes contains a knob-like alpha-helical protrusion, designated "hDicer-specific helix," that separates the two pockets and orients the bound siRNA away from the surface of Dicer, which could be indicative of a product release/transfer state. In the second complex, the helical protrusion is melted/disordered and the bound siRNA is aligned toward the surface of Dicer, suggestive of a cleavage-competent state. These structures allow us to propose that the transition from the cleavage competent to the postulated product release/transfer state may involve release of the 5'-phosphate from the phosphate pocket while retaining the 3' overhang in the 3' pocket. PMID- 24486019 TI - Optimal translational termination requires C4 lysyl hydroxylation of eRF1. AB - Efficient stop codon recognition and peptidyl-tRNA hydrolysis are essential in order to terminate translational elongation and maintain protein sequence fidelity. Eukaryotic translational termination is mediated by a release factor complex that includes eukaryotic release factor 1 (eRF1) and eRF3. The N terminus of eRF1 contains highly conserved sequence motifs that couple stop codon recognition at the ribosomal A site to peptidyl-tRNA hydrolysis. We reveal that Jumonji domain-containing 4 (Jmjd4), a 2-oxoglutarate- and Fe(II)-dependent oxygenase, catalyzes carbon 4 (C4) lysyl hydroxylation of eRF1. This posttranslational modification takes place at an invariant lysine within the eRF1 NIKS motif and is required for optimal translational termination efficiency. These findings further highlight the role of 2-oxoglutarate/Fe(II) oxygenases in fundamental cellular processes and provide additional evidence that ensuring fidelity of protein translation is a major role of hydroxylation. PMID- 24486022 TI - The rate of overdiagnosis inextricably linked to prostate-specific antigen-based screening for prostate cancer can be quantified in several ways, but what is the practicable message? PMID- 24486021 TI - Chromatin immunoprecipitation indirect peaks highlight long-range interactions of insulator proteins and Pol II pausing. AB - Eukaryotic chromosomes are partitioned into topologically associating domains (TADs) that are demarcated by distinct insulator-binding proteins (IBPs) in Drosophila. Whether IBPs regulate specific long-range contacts and how this may impact gene expression remains unclear. Here we identify "indirect peaks" of multiple IBPs that represent their distant sites of interactions through long range contacts. Indirect peaks depend on protein-protein interactions among multiple IBPs and their common cofactors, including CP190, as confirmed by high resolution analyses of long-range contacts. Mutant IBPs unable to interact with CP190 impair long-range contacts as well as the expression of hundreds of distant genes that are specifically flanked by indirect peaks. Regulation of distant genes strongly correlates with RNAPII pausing, highlighting how this key transcriptional stage may trap insulator-based long-range interactions. Our data illustrate how indirect peaks may decipher gene regulatory networks through specific long-range interactions. PMID- 24486020 TI - Rad54 functions as a heteroduplex DNA pump modulated by its DNA substrates and Rad51 during D loop formation. AB - The displacement loop (D loop) is the product of homology search and DNA strand invasion, constituting a central intermediate in homologous recombination (HR). In eukaryotes, the Rad51 DNA strand exchange protein is assisted in D loop formation by the Rad54 motor protein. Curiously, Rad54 also disrupts D loops. How these opposing activities are coordinated toward productive recombination is unknown. Moreover, a seemingly disparate function of Rad54 is removal of Rad51 from heteroduplex DNA (hDNA) to allow HR-associated DNA synthesis. Here, we uncover features of D loop formation/dissociation dynamics, employing Rad51 filaments formed on ssDNAs that mimic the physiological length and structure of in vivo substrates. The Rad54 motor is activated by Rad51 bound to synapsed DNAs and guided by a ssDNA-binding domain. We present a unified model wherein Rad54 acts as an hDNA pump that drives D loop formation while simultaneously removing Rad51 from hDNA, consolidating both ATP-dependent activities of Rad54 into a single mechanistic step. PMID- 24486023 TI - Re: James E. Thompson, Sam Egger, Maret Bohm, et al. Superior quality of life and improved surgical margins are achievable with robotic radical prostatectomy after a long learning curve: a prospective single-surgeon study of 1552 consecutive cases. Eur Urol 2014;65:521-31. PMID- 24486024 TI - The effect of neoadjuvant chemotherapy on perioperative outcomes in patients who have bladder cancer treated with radical cystectomy: a population-based study. AB - BACKGROUND: Although therapeutic guidelines recommend the use of neoadjuvant chemotherapy before radical cystectomy (RC) in patients who have muscle-invasive bladder cancer (MIBC), this approach remains largely underused. One of the main reasons for this phenomenon might reside in concerns regarding the risk of morbidity and mortality associated with neoadjuvant chemotherapy. OBJECTIVE: To compare perioperative outcomes between patients receiving neoadjuvant chemotherapy and those treated with RC alone. DESIGN, SETTING, AND PARTICIPANTS: Relying on the Surveillance Epidemiology and End Results-Medicare-linked database, 3760 patients diagnosed with MIBC between 2000 and 2009 were evaluated. INTERVENTION: RC alone or RC plus neoadjuvant chemotherapy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Complications occurred within 30 and 90 d after surgery. Heterologous blood transfusions (HBTs), length of stay (LoS), readmission, and perioperative mortality were compared. To decrease the effect of unmeasured confounders associated with treatment selection, propensity score matched analyses were performed. RESULTS AND LIMITATIONS: Overall, 416 (11.1%) of patients received neoadjuvant chemotherapy. Following propensity score matching, 416 (20%) and 1664 (80%) patients treated with RC plus neoadjuvant chemotherapy and RC alone remained, respectively. The 30-d complication, readmission, and mortality rates were 66.0%, 32.2%, and 5.3%, respectively. The 90-d complication, readmission, and mortality rates were 72.5%, 46.6%, and 8.2%, respectively. When patients were stratified according to neoadjuvant chemotherapy status, no significant differences were observed in the rates of complications, HBT, prolonged LoS, readmission, and mortality between the two groups (all p >= 0.1). These results were confirmed in multivariate analyses, where the use of neoadjuvant chemotherapy was not associated with higher risk of 30- and 90-d complications, HBT, prolonged LoS, readmission, and mortality (all p >= 0.1). Our study is limited by its retrospective nature. CONCLUSIONS: The use of neoadjuvant chemotherapy is not associated with higher perioperative morbidity or mortality. These results should encourage wider use of neoadjuvant chemotherapy when clinically indicated. PATIENT SUMMARY: Chemotherapy before radical cystectomy in patients with muscle-invasive bladder cancer does not increase the risk of complications or death. The use of chemotherapy should be strongly encouraged, as recommended by clinical guidelines, given its benefits. PMID- 24486025 TI - Developmental roles of brain histamine. AB - Histamine appears early during brain development, has been shown to regulate fetal and adult brain-derived stem cells in a receptor type-dependent manner, and has widespread actions on systems involved in arousal and movement. Developmental studies in both rodents and zebrafish have elucidated the spatiotemporal patterning of the histaminergic system and, in zebrafish, have revealed the mechanisms whereby histamine regulates the number of hypocretin/orexin (hcrt) neurons, which in turn may regulate the number of histaminergic cells. Recent demonstrations of increased numbers of histaminergic neurons in patients with narcolepsy highlight the importance, for our understanding of both normal and pathological brain function, of understanding these interactions. Here, we review recent research into the developmental roles of histamine and suggest key areas for future research. PMID- 24486026 TI - Support for midwives - a model of professional supervision based on the recertification programme for midwives in New Zealand. AB - Following a traumatic practice experience the physiological and psychological effects experienced by midwives are exacerbated as a result of dysfunctional health organisations and the counterproductive behaviours therein. It is suggested the stress experienced would have been reduced if support in the form of professional supervision had been available. The aim of this article is to demonstrate that professional supervision should be viewed as a competency requirement by the Midwifery Council of New Zealand and incorporated into the midwifery recertification programme. A model of professional supervision for midwives based on the recertification programme is introduced and the importance of reflection on practice emphasised. Providing support by means of professional supervision in the midwifery recertification programme, has the potential to make midwives feel valued, improve their job satisfaction, reduce violence in the workplace, aid in the attrition rate and improve the care for the childbearing woman. PMID- 24486027 TI - Heterogeneity of baseline neural marker expression by undifferentiated mesenchymal stem cells may be correlated to donor age. AB - Previous studies reported much heterogeneity in baseline neural marker expression by undifferentiated mesenchymal stem cells (MSCs) of animal and human origin, which could confound reproducibility of neural differentiation experiments with MSCs. Nevertheless, basic donor characteristics such as age and gender were unspecified in these previous studies; and relative levels of baseline neural marker expression amongst primary MSCs of different tissue and donor origin have not been compared by quantitative real-time polymerase chain reaction (qRT-PCR) analysis, which is the focus of this study. The results showed that amongst a mixed group of primary adipose and bone marrow-derived MSCs (12-50 years), the observed variability in baseline neural marker expression may be correlated to donor age. Adipose-derived MSCs from the youngest donor (male, 12 years old) displayed the highest expression of all four early neural markers (Pax6, Nestin, Musashi 1 and betaIII-tubulin), and three out of four mature neural markers (NCAM, NSE and NFM) analyzed by qRT-PCR. Conversely, adipose MSCs of the oldest donor (female, 50 years old) displayed the lowest expression of three out of four early neural markers (Pax6, Musashi 1 and betaIII-tubulin), and three out of four mature neural markers (MAP2, NCAM and NSE) analyzed by qRT-PCR. PMID- 24486029 TI - Polycistronic expression of a beta-carotene biosynthetic pathway in Saccharomyces cerevisiae coupled to beta-ionone production. AB - The flavour and fragrance compound beta-ionone, which naturally occurs in raspberry and many other fruits and flowers, is currently produced by synthetic chemistry. This study describes a synthetic biology approach for beta-ionone production from glucose by Saccharomyces cerevisiae that is partially based on polycistronic expression. Experiments with model proteins showed that the T2A sequence of the Thosea asigna virus mediated efficient production of individual proteins from a single transcript in S. cerevisiae. Subsequently, three beta carotene biosynthesis genes from the carotenoid-producing ascomycete Xanthophyllomyces dendrorhous (crtI, crtE and crtYB) were expressed in S. cerevisiae from a single polycistronic construct. In this construct, the individual crt proteins were separated by T2A sequences. Production of the individual proteins from the polycistronic construct was confirmed by Western blot analysis and by measuring the production of beta-carotene. To enable beta ionone production, a carotenoid-cleavage dioxygenase from raspberry (RiCCD1) was co-expressed in the beta-carotene producing strain. In glucose-grown cultures with a second phase of dodecane, beta-ionone and geranylacetone accumulated in the organic phase. Thus, by introducing a polycistronic construct encoding a fungal carotenoid pathway and an expression cassette encoding a plant dioxygenase, a novel microbial production system has been established for a fruit flavour compound. PMID- 24486028 TI - Analysis of microRNA transcription and post-transcriptional processing by Dicer in the context of CHO cell proliferation. AB - CHO cells are the mammalian cell line of choice for recombinant production of therapeutic proteins. However, their low rate of proliferation limits obtainable space-time yields due to inefficient biomass accumulation. We set out to correlate microRNA transcription to cell-specific growth-rate by microarray analysis of 5 CHO suspension cell lines with low to high specific growth rates. Global microRNA expression analysis and Pearson correlation studies showed that mature microRNA transcript levels are predominately up-regulated in a state of fast proliferation (46 positively correlated, 17 negatively correlated). To further validate this observation, the expression of three genes that are central to microRNA biogenesis (Dicer, Drosha and Dgcr8) was analyzed. The expression of Dicer, which mediates the final step in microRNA maturation, was found to be strongly correlated to growth rate. Accordingly, knockdown of Dicer impaired cell growth by reducing growth-correlating microRNA transcripts. Moderate ectopic overexpression of Dicer positively affected cell growth, while strong overexpression impaired growth, presumably due to the concomitant increase of microRNAs that inhibit cell growth. Our data therefore suggest that Dicer dependent microRNAs regulate CHO cell proliferation and that Dicer could serve as a potential surrogate marker for cellular proliferation. PMID- 24486031 TI - Research priorities for children's nursing in Ireland: a Delphi study. AB - This paper is a report of a study which identified research priorities for children's nursing in an acute care setting in Ireland. A limited number of studies have examined research priorities for children's nursing. This study was undertaken against the backdrop of significant proposed changes to the delivery of children's healthcare. A three round Delphi survey design was used to identify and rate the importance of research priorities for children's nursing. In round I participants were asked to identify five of the most important research priorities for children's nursing. Participants in round II were asked to rate the importance of each research priority on a 7-point Likert scale. In round III participants were presented with the mean score of each research priority from the second questionnaire, and again asked to consider the importance of each topic on a 7-point Likert scale. The aim was to reach consensus on the priorities. The top three priorities identified were recognition and care of the deteriorating child, safe transfer of the critically ill child between acute health care facilities, and the child and family's perceptions of care at end-of life. The wide variation of priorities reflects the scope of care delivery of children's nurses and mirrors many global care concerns in caring for children. PMID- 24486032 TI - Multipolar radiofrequency ablation for colorectal liver metastases close to major hepatic vessels. AB - BACKGROUND: Resection of colorectal liver metastases (CRLM) is often hindered by their location close to the major hepatic vessels. So far, radiofrequency ablation for perivascular tumours was thought to be ineffective and unsafe due to either the heat sink effect or vascular thrombosis. The aim of this study was to examine whether RFA using multipolar probes could be a safe and effective option for CRLM adjacent to major hepatic vessels. METHODS: Patients were treated with multipolar RFA during an open procedure using 3 simultaneously placed electrodes. In 52 consecutive patients with CRLM, 144 tumours were ablated with RFA. In 16 out of 52 (31%) patients, metastases were abutting major hepatic vessels. We examined whether perivascular location was a risk factor for local tumour progression. The relation between perivascular location and time to local tumour progression and recurrence free survival was assessed using cox-regression analysis. RESULTS: All patients were followed for at least 3 years after RFA unless they deceased before this time. Local tumour progression following RFA occurred in 17 out of 144 tumours (12%), of which 4 out of 21 were perivascular tumours. Tumour size was the only risk factor for local tumour progression in this study. Proximity to large vessels was neither a risk factor for local local tumour progression, nor for time to local tumour progression or recurrence free survival. DISCUSSION: This study indicates that patients with CRLM abutting any of the large hepatic vessels can be safe and effectively treated with RFA when using a multipolar system. PMID- 24486033 TI - 3-D based minimally invasive one-stage lateral sinus elevation - a prospective randomized clinical pilot study with blinded assessment of postoperative visible facial soft tissue volume changes. AB - OBJECTIVE: The purpose of this prospective and randomized clinical study was to assess differences in patient morbidity between minimally invasive lateral sinus elevation (study group, n = 14) and conventional one-stage lateral sinus elevation (control group, n = 12). It was hypothesized that trauma to soft tissue was reduced in the study group. MATERIALS AND METHODS: Optical 3-D imaging was assessed blinded on days 1 and 7 after surgery to determine the visible soft tissue swelling of the upper lip and cheeks. Postoperative pain and discomfort were evaluated by a visual analogue scale (VAS; scale 0-10). RESULTS: Immediately and on day 1 after surgery, the study group patients rated pain and discomfort as 2.4 [SD 1.7] and 3.1 [SD 2.1], respectively, on the VAS; while, the controls rated 4 [SD 1.6] and 5.6 [SD 1.7], respectively. The mean facial soft tissue volume change, assessed on day 1 after surgery, was 5.0 cm(3) [range: 0.2-9.2] for the study group and 15.5 cm(3) (9.3-21.55) for the controls (p = 0.00). CONCLUSIONS: Despite the small number of patients in this prospective study, 3-D based minimally invasive one-stage lateral sinus elevation resulted in favourable patient morbidity with less postoperative visible facial soft tissue volume changes. PMID- 24486034 TI - Mutations in SNF1 complex genes affect yeast cell wall strength. AB - The trimeric SNF1 complex from Saccharomyces cerevisiae, a homolog of mammalian AMP-activated kinase, has been primarily implicated in signaling for the utilization of alternative carbon sources to glucose. We here find that snf1 deletion mutants are hypersensitive to different cell wall stresses, such as the presence of Calcofluor white, Congo red, Zymolyase or the glucan synthase inhibitor Caspofungin in the growth medium. They also have a thinner cell wall. Caspofungin treatment triggers the phosphorylation of the catalytic Snf1 kinase subunit at Thr210 and removal of this phosphorylation site by mutagenesis (Snf1 T210A) abolishes the function of Snf1 in cell wall integrity. Deletion of the PFK1 gene encoding the alpha-subunit of the heterooctameric yeast phosphofructokinase suppresses the cell wall phenotypes of a snf1 deletion, which suggests a compensatory effect of central carbohydrate metabolism. Epistasis analyses with mutants in cell wall integrity (CWI) signaling confirm that the SNF1 complex and the CWI pathway independently affect yeast cell integrity. PMID- 24486035 TI - [Analysis of knowledge about healthy breakfast and its relation to life style habits and academic performance in compulsory secondary students]. AB - OBJECTIVES: The main objective of the study is to analyze whether students of Compulsory Secondary Education (ESO) of Badajoz city known foods that are part of a healthy breakfast. It also intends to see the relationship of this knowledge with lifestyle habits and academic performance. MATERIALS AND METHOD: A representative sample of 1197 secondary students in the city of Badajoz (Spain) (50.1% female) was calculated their Body Mass Index (BMI) and were asked to fill in a questionnaire, previously validated in a pilot study, which included sociodemographic items as well as others related with life style habits. They were also asked to choose among a series of food, which of them were a part of a healthy breakfast. RESULTS: 49.2% of adolescents know foods which are a part of a healthy breakfast. Very low correlations were obtained between all the variables analyzed and knowledge of foods that make up a healthy breakfast. However, within a few variables are significant differences (P<.05) between subgroups, such as families of students with low cultural level of aided schools, repeaters, without reading habit, passing lot of time with friends, who have been on a diet, make less than 3 meals a day and spend less than 10minutes for breakfast and know the amount of fruit that should be consumed daily. CONCLUSIONS: Life style habits of adolescents are not related to the knowledge about the foods that are part of a healthy breakfast. PMID- 24486036 TI - Late rescue of proximal endograft failure using fenestrated and branched devices. AB - OBJECTIVE: Endovascular aneurysm repair (EVAR) will fail over time in a percentage of patients. Mechanical failure of the device, progression of aortic disease, or interface complications between the device and the native vasculature may contribute. Our aim was to evaluate the role of fenestrated and branched endografts as treatment options for failed devices. METHODS: Between January 2001 and June 2013, 970 patients were enrolled into a physician-sponsored investigational device exemption (PSIDE) study and treated with a fenestrated/branched endograft. All patients treated for nonurgent proximal neck failure of an infrarenal endoprosthesis previously implanted during EVAR comprised the study group. Patients treated for a primary aneurysm within the PSIDE were evaluated as a comparison group to identify preoperative risk factors for failure. A retrospective review was undertaken to determine the details of the initial EVAR, whereas the prospective PSIDE database was used to assess outcomes of secondary treatment. Three-dimensional imaging techniques were used to define all morphologic measurements. Statistical analysis included comparisons between categoric variables with the chi(2) test and between continuous variables with the Wilcoxon rank sum test between patients with late failures and those with native aortic repair. Kaplan-Meier curves were used to analyze overall survival. RESULTS: Of 970 patients enrolled in the PSIDE, 54 (5.6%) had late failure of a prior endograft. Fenestrated/branched devices were used to address the failure in each patient. The etiology of failure was related to a proximal neck issue in all patients: type Ia endoleak in 38, stent migration in 18, neck degeneration in 28, or some combination of these factors. The endovascular rescue procedure took place a mean of 61 months after the primary procedure. The mean aneurysm diameter at reintervention was 67 mm. Patients requiring a secondary fenestrated procedure were younger at the time of their primary intervention (P = .039) and were more likely to have a history of chronic renal insufficiency (P = .05) compared with other patients in the PSIDE. Technical success rate in the study group was 85% (44 of 52). Successful stenting was achieved in 71 of 77 (92%) target vessels. Thirty-day mortality was 3.8% (two of 52). Fluoroscopy dose and operating time were longer in the rescue group (P = .07) than in the control group (P = .008). Secondary interventions were required in 36.5% (19 of 52) of patients. CONCLUSIONS: Our series demonstrates the risk for late failure after EVAR is greater in patients who are younger and have chronic renal impairment at the time of implantation. Branched and fenestrated repair after failed EVAR is more complex than repair in the native aorta. More research is needed to identify patients at higher risk of failure after EVAR to prevent the need for rescue in the future. PMID- 24486037 TI - Geometrical consequences of kissing stents and the Covered Endovascular Reconstruction of the Aortic Bifurcation configuration in an in vitro model for endovascular reconstruction of aortic bifurcation. AB - OBJECTIVE: Kissing stents (KS) are commonly used to treat aortoiliac occlusive disease, but patency results are often lower than those of isolated stents. The Covered Endovascular Reconstruction of the Aortic Bifurcation (CERAB) technique was recently introduced to reconstruct the aortic bifurcation in a more anatomical and physiological fashion. The aim of this study is to compare the geometrical consequences of various stent configurations in vitro. METHODS: Anatomic vessel phantoms of the aortoiliac bifurcation were created to accommodate stent configurations. Self-expandable nitinol KS, balloon-expandable covered KS, and two versions of the CERAB configuration were deployed, one with the iliac legs positioned inside the tapered part of the aortic cuff (1) and one with the legs deployed above this level (2). Computed tomography data were obtained to assess the geometry. The conformation ratio (D-ratio) was calculated by use of the ratio of the major and minor axes. The proximal mismatch area, mean mismatch area, and total mismatch volume were calculated. RESULTS: The highest D ratios were observed in the nitinol KS and the CERAB configuration, implying an ideal "double-D" shape. The proximal and mean mismatch areas were four- to sixfold lower in the CERAB (1) configuration when compared with nitinol KS and CERAB (2), respectively, whereas the covered KS had the highest mismatch area. Nitinol and covered KS had the largest mismatch volume, whereas the mismatch volume was the lowest in the CERAB (1) configuration. CONCLUSIONS: Although nitinol self-expandable stents have a high stent conformation, the lowest radial mismatch was found in the CERAB (1) configuration, supporting the hypothesis that the CERAB configuration is the most anatomical and physiological reconstruction of the aortic bifurcation. Within the CERAB configuration, the two limbs are ideally positioned inside the tapering portion of the cuff, minimizing mismatch. PMID- 24486038 TI - Community change and evidence for variable warm-water temperature adaptation of corals in Northern Male Atoll, Maldives. AB - This study provides a descriptive analysis of the North Male, Maldives seven years after the 1998 bleaching disturbance to determine the state of the coral community composition, the recruitment community, evidence for recovery, and adaptation to thermal stress. Overall, hard coral cover recovered at a rate commonly reported in the literature but with high spatial variability and shifts in taxonomic composition. Massive Porites, Pavona, Synarea, and Goniopora were unusually common in both the recruit and adult communities. Coral recruitment was low and some coral taxa, namely Tubipora, Seriatopora, and Stylophora, were rarer than expected. A study of the bleaching response to a thermal anomaly in 2005 indicated that some taxa, including Leptoria, Platygyra, Favites, Fungia, Hydnophora, and Galaxea astreata, bleached as predicted while others, including Acropora, Pocillopora, branching Porites, Montipora, Stylophora, and Alveopora, bleached less than predicted. This indicates variable-adaptation potentials among the taxa and considerable potential for ecological reorganization of the coral community. PMID- 24486039 TI - Metal pollution status in Zhelin Bay surface sediments inferred from a sequential extraction technique, South China Sea. AB - Surface sediments collected from Zhelin Bay, the largest mariculture base of eastern Guangdong Province, were analyzed for total metal concentrations and chemical speciation. The results demonstrated that the average total concentration (mg/kg) ranges were 36.7-65.8 (Pb), 53.8-98.8 (Cr), 39.0-87.1 (Ni), 50.9-144.5 (Cu), and 175.0-251.2 (Zn), which were clearly higher with respect to their corresponding benchmark values. The predominant speciation of Pb was reducible and comprised a residual fraction, whereas a major portion (57.6-95.4%) of Cr, Ni, Cu, and Zn was strongly associated with the residual fractions. Taking as a whole, surface sediments of Zhelin Bay had a 21% probability of toxicity based on the mean effects range-median quotient. PMID- 24486040 TI - Meteorologically-driven circulation and flushing times of the Bay of Algeciras, Strait of Gibraltar. AB - A primitive-equation model has been used to investigate the meteorologically driven circulation of the Bay of Algeciras. It is shown that the mean circulation of Atlantic Water (AW) is characterized by an anticyclonic cell, while Mediterranean Water (MW) follows a preferred cyclonic pathway. Meteorological forcing distorts substantially the AW mean circulation pattern, and only modulates that of the MW. Winds drive a vertical circulation cell in the Atlantic layer consistent with Ekman dynamics, whereas the horizontal circulation pattern is markedly dependent on the swift Atlantic jet entering the Mediterranean and changes from clearly anticyclonic to cyclonic as the jet separates or approaches the strait's northern shoreline. This occurs through atmospheric pressure-driven acceleration/deceleration of the jet, in agreement with internal hydraulics theory predictions. It is also found that the renewal of AW is largely modulated by tides, with meteorological forcing playing a secondary role. The opposite applies to the renewal of MW. PMID- 24486041 TI - Tracking anthropogenic influences on the continental shelf of China with sedimentary linear alkylbenzenes (LABs). AB - Surface sediments collected along the entire continental shelf of China, including Yellow Sea, the East China Sea (ECS) inner shelf and the South China Sea (SCS), were analyzed for linear alkylbenzenes (LABs), from which regional anthropogenic influences on the marine environment were assessed. The occurrence of LABs (5.6-77 ng/g; mean: 25 ng/g; median: 20 ng/g) implied light sewage contamination in coast sediment off China. Specifically, the SCS had higher sedimentary LAB levels than Yellow Sea and the ECS inner shelf, which was mainly related to the intensity of domestic wastewater discharge and marine fishing activities. Values of L/S and C13/C12 (defined in the main text) suggested certain degradation while I/E indicated limited degradation of LABs. Also, additional input sources and congener inter-conversions may have contributed to the inconsistent results for degradation of LABs in offshore sediments. Atmospheric inputs and wastewater discharge from marine fishing vessels predominantly contributed to sedimentary LABs in Yellow Sea and the SCS, while riverine input was mainly responsible for LABs along the ECS inner shelf. PMID- 24486042 TI - Perylene as an indicator of land-based plant biomarkers in the southwest Caspian Sea. AB - In this study, 84 surface sediment samples, from 28 Iranian rivers, 45 surface sediment samples and 31 samples from one core in the southwest of the Caspian Sea were collected and analyzed for polycyclic aromatic hydrocarbons (PAHs). The results showed high variability of perylene in coastal surface sediments (1.3 123.6 ng g-1 dw) and river sediments (0.5-111.1 ng g-1 dw). Core samples revealed high levels of perylene which increased with depth. Three diagnostic ratios (DRs) for source identification of perylene (Per/TPAH, Per/PAI and Py/Per) revealed a dominance of biogenic inputs to the surface layers (coasts and rivers) and diagenetic production of perylene in the sediment core. Hyrcanian forests with humid climates favor wood-degrading fungi and the production of perylene and its precursors. Biogenic production of perylene as a land plant derived biomarker can be used for the reconstruction of paleoclimatic conditions of the southwest Caspian Sea. PMID- 24486043 TI - Variability of the dissolved nutrient (N, P, Si) concentrations in the Bay of Annaba in relation to the inputs of the Seybouse and Mafragh estuaries. AB - Dissolved inorganic nitrogen (DIN), phosphate (PO4) and silicic acid (Si(OH)4) loads from the Seybouse and the Mafragh estuaries into the Bay of Annaba, Algeria, were assessed at three stations of the Bay over three years. The Seybouse inputs had high levels of DIN and PO4, in contrast to the Mafragh estuary's near-pristine inputs; Si(OH)4 levels were low in both estuaries. The DIN:PO4 molar ratios were over 30 in most samples and the Si(OH)4:DIN ratio was less than 0.5 in the Seybouse waters, but nearly balanced in the Mafragh. The specific fluxes of Si-Si(OH)4 (400-540 kg Si km-2 yr-1) were comparable in the two catchments, but those of DIN were several-fold higher in the Seybouse (373 kg N km-2 yr-1). The inner Bay affected by the Seybouse inputs had high levels of all nutrients, while the Mafragh plume and the outer marine station were less enriched. PMID- 24486044 TI - Coral reef baselines: how much macroalgae is natural? AB - Identifying the baseline or natural state of an ecosystem is a critical step in effective conservation and restoration. Like most marine ecosystems, coral reefs are being degraded by human activities: corals and fish have declined in abundance and seaweeds, or macroalgae, have become more prevalent. The challenge for resource managers is to reverse these trends, but by how much? Based on surveys of Caribbean reefs in the 1970s, some reef scientists believe that the average cover of seaweed was very low in the natural state: perhaps less than 3%. On the other hand, evidence from remote Pacific reefs, ecological theory, and impacts of over-harvesting in other systems all suggest that, historically, macroalgal biomass may have been higher than assumed. Uncertainties about the natural state of coral reefs illustrate the difficulty of determining the baseline condition of even well studied systems. PMID- 24486045 TI - Littering dynamics in a coastal industrial setting: the influence of non-resident populations. AB - We examined if there is truth to the preconceptions that non-resident workers (including FIFO/DIDO's) detract from communities. We used marine debris to test this, specifically focussing on littering behaviour and evidence of awareness of local environmental programs that focus on marine debris. Littering was most common at recreational areas, then beaches and whilst boating. Twenty-five percent of respondents that admit to littering, reported no associated guilt with their actions. Younger respondents litter more frequently. Thus, non-resident workers litter at the same rate as permanent residents, visitors and tourists in this region, within this study. Few respondents are aware of the environmental programs that operate in their local region. Awareness was influenced by a respondent's residency (non-residents are less aware), age, and level of education. To address this failure we recommend that industries, that use non resident workers, should develop inductions that expose new workers to the environmental programs in their region. PMID- 24486047 TI - Prevalence of genital mycoplasmas in asymptomatic male partners of women diagnosed as having chlamydial infections. AB - We examined 209 asymptomatic male partners of women diagnosed as having chlamydial infections for the prevalence of Neisseria gonorrhoeae, Chlamydia trachomatis, Mycoplasma genitalium, Mycoplasma hominis, Ureaplasma urealyticum, and Ureaplasma parvum in their first-voided urine (FVU) by nucleic acid amplification tests. Quantification of leukocytes in FVU was performed by automated urine particle analyzers. Two (1.0%) men were positive for N. gonorrhoeae, and 92 (44.0%) were positive for C. trachomatis. In men negative for these pathogens, prevalences of M. genitalium, M. hominis, U. urealyticum, and U. parvum were 0.9%, 29.6%, 27.8%, and 20.1%, respectively, and 58.3% were positive for at least one species of the genital mycoplasmas. Leukocyte counts in FVU from 92 men positive for C. trachomatis were significantly greater than those from 115 men negative for C. trachomatis (p < 0.0001). However, there was no significant difference in leukocyte counts between 66 men positive for at least one species of M. hominis, U. urealyticum, and U. parvum and 48 men negative for all the species (p = 0.1657). The present population of asymptomatic male partners of women diagnosed as having chlamydial infections showed a low prevalence of M. genitalium infections but would be at high risk of being infected by the other genital mycoplasmas. However, it was still unclear whether these genital mycoplasmas would contribute to the development of inflammation of the male urethra. When these partners are negative for C. trachomatis and N. gonorrhoeae, the recommendation to presumptively treat them to disrupt transmission networks of the genital mycoplasmas would seem premature. PMID- 24486046 TI - Phytoestrogens and cognitive function: a review. AB - Neuroprotective effects of phytoestrogen compounds (found in soy) have been demonstrated in animal research and cell culture studies. In particular, phytoestrogens have been shown to reduce Alzheimer's Disease (AD) related pathology, potentially alleviating risk of AD progression. In addition to their antioxidant properties, soy products also have the ability to affect cognition via interaction with estrogen receptors. However, observational studies and randomised controlled trials in humans have resulted in inconclusive findings within this domain. There are several possible reasons for these discrepant data. Studies which report no effect of phytoestrogens on cognition have mainly been carried out in European cohorts, with an average low dietary consumption. In contrast, investigation of Asian populations, with a higher general intake of tofu (a non-fermented soy product) have shown negative associations with cognitive function in those over the age of 65. Consideration of type of soy product is important, as in the latter sample, protective effects of tempe (fermented soy) were also observed. Limited data provide evidence that effects of phytoestrogens on cognition may be modified by dosage, duration of consumption and cognitive test used. Additionally, characteristics of the study population including age, gender, ethnicity and menopausal status appear to be mediating variables. Phytoestrogen treatment interventions have also shown time-limited positive effects on cognition. These findings are consistent with estrogen treatment studies, where initial positive short-term cognitive effects may occur, which reverse with long-term continuous use in elderly women. Well controlled, large scale studies are needed to assess the effects of phytoestrogens on the aging brain and provide further understanding of this association. PMID- 24486048 TI - Mucoepidermoid carcinoma in a bone marrow transplant patient. PMID- 24486049 TI - An endoplasmic reticulum trafficking signal regulates surface expression of beta4 subunit of a voltage- and Ca2+-activated K+ channel. AB - Voltage-dependent and calcium-activated K+ (MaxiK, BK) channels are widely expressed in many tissues and organs where they play various physiological roles. Here we report discovery of a functional trafficking signal in MaxiK channel accessory beta4 subunit that could regulate activity of MaxiK alpha subunit (hSlo) on the plasma membrane. We demonstrate that beta4 is mostly retained within the cell and removal or mutation of beta4 trafficking signal significantly enhances its surface expression in HEK293T expression system. In hippocampal slices and cultured neurons we also observed significant beta4 expressions within the neurons. Finally, we show that unlike SV1 and beta1 subunits, beta4 shows no dominant-negative effect on MaxiK channel alpha subunit. Taken together, we propose beta4 subunit of MaxiK channel is mostly retained within the cells without interfering with other subunits. Removal of beta4 retention signal increases its surface expression that may lead to reduction of the MaxiK channel activity and neuronal excitability. PMID- 24486050 TI - Compositional and functional features of the gastrointestinal microbiome and their effects on human health. AB - The human gastrointestinal tract contains distinct microbial communities that differ in composition and function based on their location, as well as age, sex, race/ethnicity, and diet of their host. We describe the bacterial taxa present in different locations of the GI tract, and their specific metabolic features. The distinct features of these specific microbial communities might affect human health and disease. Several bacterial taxa and metabolic modules (biochemical functions) have been associated with human health and the absence of disease. Core features of the healthy microbiome might be defined and targeted to prevent disease and optimize human health. PMID- 24486051 TI - Manipulation of the microbiota for treatment of IBS and IBD-challenges and controversies. AB - There is compelling rationale for manipulating the microbiota to treat inflammatory bowel diseases (IBDs). Although studies of animal models of intestinal inflammation produced promising results, trials in humans have been disappointing. In contrast to IBD, the role of the microbiota in the development of irritable bowel syndrome (IBS) only recently has been considered, but early stage results have been encouraging. As pharmaceutical companies develop fewer truly novel agents for treatment of these disorders, consumers seek safer, long term strategies to deal with chronic symptoms. We assess the rationale for modulating the microbiota for treatment of IBD and IBS, and discuss whether current concepts are simplistic and overstated or simply under-researched. Are claims exaggerated and expectations unrealistic? Difficulties with microbiota terminology and technologies, as well as differences among patients and the heterogeneity of these diseases, pose additional challenges in developing microbiota-based therapies for IBD and IBS. PMID- 24486053 TI - Meta'omic analytic techniques for studying the intestinal microbiome. AB - Nucleotide sequencing has become increasingly common and affordable, and is now a vital tool for studies of the human microbiome. Comprehensive microbial community surveys such as MetaHit and the Human Microbiome Project have described the composition and molecular functional profile of the healthy (normal) intestinal microbiome. This knowledge will increase our ability to analyze host and microbial DNA (genome) and RNA (transcriptome) sequences. Bioinformatic and statistical tools then can be used to identify dysbioses that might cause disease, and potential treatments. Analyses that identify perturbations in specific molecules can leverage thousands of culture-based isolate genomes to contextualize culture-independent sequences, or may integrate sequence data with whole-community functional assays such as metaproteomic or metabolomic analyses. We review the state of available systems-level models for studies of the intestinal microbiome, along with analytic techniques and tools that can be used to determine its functional capabilities in healthy and unhealthy individuals. PMID- 24486054 TI - [Analysis of stay and mortality in an intensive care unit]. PMID- 24486052 TI - T-helper 2 cytokines, transforming growth factor beta1, and eosinophil products induce fibrogenesis and alter muscle motility in patients with eosinophilic esophagitis. AB - BACKGROUND & AIMS: Patients with eosinophilic esophagitis (EoE) often become dysphagic from the combination of organ fibrosis and motor abnormalities. We investigated mechanisms of dysphagia, assessing the response of human esophageal fibroblasts (HEFs), human esophageal muscle cells (HEMCs), and esophageal muscle strips to eosinophil-derived products. METHODS: Biopsy specimens were collected via endoscopy from the upper, middle, and lower thirds of the esophagus of 18 patients with EoE and 21 individuals undergoing endoscopy for other reasons (controls). Primary cultures of esophageal fibroblasts and muscle cells were derived from 12 freshly resected human esophagectomy specimens. Eosinophil distribution was investigated by histologic analyses of full-thickness esophageal tissue. Active secretion of EoE-related mediators was assessed from medium underlying mucosal biopsy cultures. We quantified production of fibronectin and collagen I by HEF and HEMC in response to eosinophil products. We also measured the expression of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 by, and adhesion of human eosinophils to, HEFs and HEMCs. Eosinophil products were tested in an esophageal muscle contraction assay. RESULTS: Activated eosinophils were present in all esophageal layers. Significantly higher concentrations of eosinophil-related mediators were secreted spontaneously in mucosal biopsy specimens from patients with EoE than controls. Exposure of HEFs and HEMCs to increasing concentrations of eosinophil products or co-culture with eosinophils caused HEFs and HEMCs to increase secretion of fibronectin and collagen I; this was inhibited by blocking transforming growth factor beta1 and p38 mitogen-activated protein kinase signaling. Eosinophil binding to HEFs and HEMCs increased after incubation of mesenchymal cells with eosinophil-derived products, and decreased after blockade of transforming growth factor beta1 and p38 mitogen-activated protein kinase blockade. Eosinophil products reduced electrical field-induced contraction of esophageal muscle strips, but not acetylcholine-induced contraction. CONCLUSIONS: In an analysis of tissues samples from patients with EoE, we linked the presence and activation state of eosinophils in EoE with altered fibrogenesis and motility of esophageal fibroblasts and muscle cells. This process might contribute to the development of dysphagia. PMID- 24486055 TI - Quantification of nanoparticle uptake into hair follicles in pig ear and human forearm. AB - Drug delivery via the hair follicle (HF) especially with nanoparticles (NP) recently gained attention due to a depot effect and facilitated absorption conditions within the lower HF. With the prospect of transdermal drug delivery, it is of interest to optimize the follicular uptake of NP. In this study, a method was developed to quantify NP uptake into HF and applied in vitro in a pig ear model and in vivo in human volunteers. The influence of NP material on HF uptake was investigated using fluorescence-labeled NP based on poly(D,L-lactide co-glycolide) (PLGA). All NP had similar hydrodynamic sizes (163-170 nm) but different surface modifications: (i) plain PLGA, (ii) chitosan-coated PLGA (Chit. PLGA), and (iii) Chit.-PLGA coated with different phospholipids (PL) (DPPC (100), DPPC:Chol (85:15), and DPPC:DOTAP (92:8). Differential stripping was performed, including complete mass balance. The samples were extracted for fluorescence quantification. An effect of the PL coating on follicular uptake was observed as DPPC (100) and DPPC:DOTAP (92:8) penetrated into HF to a higher extent than the other tested NP. The effect was observed both in the pig ear model as well as in human volunteers, although it was statistically significant only in the in vitro model. An excellent in vitro-in vivo correlation (IVIVC, r(2)=0.987) between both models was demonstrated, further supporting the suitability of the pig ear model as a surrogate for the in vivo situation in humans for quantifying NP uptake into HF. These findings may help to optimize NP for targeting the HF and to improve transdermal delivery. PMID- 24486058 TI - Treatment of advanced non-small-cell lung cancer with epidermal growth factor receptor (EGFR) mutation or ALK gene rearrangement: results of an international expert panel meeting of the Italian Association of Thoracic Oncology. AB - The availability of targeted drugs has made the assessment of the EGFR mutation and ALK rearrangement critical in choosing the optimal treatment for patients with advanced non-small-cell lung cancer (NSCLC). In May 2013, the Italian Association of Thoracic Oncology (AIOT) organized an International Experts Panel Meeting to review strengths and limitations of the available evidence for the diagnosis and treatment of advanced NSCLC with EGFR or anaplastic lymphoma kinase (ALK) alterations and to discuss implications for clinical practice and future clinical research. All patients with advanced NSCLC, with the exclusion of pure squamous cell carcinoma in former or current smokers, should be tested for EGFR mutations and ALK rearrangements before decisions are made on first-line treatment. First-line treatment of EGFR-mutated cases should be with an EGFR tyrosine kinase inhibitor (TKI). Any available agent (gefitinib, erlotinib, or afatinib) can be used, until further data from comparative studies may better guide TKI selection. As general rule, and when clinically feasible, results of EGFR mutational status should be awaited before starting first-line treatment. Panelists agreed that the use of crizotinib is justified in any line of treatment. Although solid evidence supporting the continuation of EGFR TKIs or crizotinib beyond progression is lacking, in some cases (minimal, asymptomatic progression, or oligoprogression manageable by local therapy), treatment continuation beyond progression could be justified. Experimental strategies to target tumor heterogeneity and to treat patients after failure of EGFR TKIs or crizotinib are considered high-priority areas of research. A number of relevant research priorities were identified to optimize available treatment options. PMID- 24486059 TI - Tissue microarrays in non-small-cell lung cancer: reliability of immunohistochemically-determined biomarkers. AB - BACKGROUND: The reliability of immunohistochemically-determined biomarkers using tissue microarrays (TMAs) of clinical specimens has long been open to question. Heterogeneity related to tumor biology might compromise determination of accurate biomarker expression in tumors, especially in small core biopsies. We evaluated the reliability of immunohistochemical staining scoring in small core biopsies using 11 biomarkers in non-small-cell lung cancer (NSCLC). MATERIALS AND METHODS: Four 1-mm tumor cores from 178 NSCLCs, 2 representing peripheral areas close to the border of normal lung tissue and 2 representing central areas, were examined. The biomarkers analyzed included p63, p40, cytokeratin 1/5/10/14, cytokeratin 7, thyroid transcription factor-1, napsin A, cyclin-D1, p53, Ki-67, integrin beta-1, and thymidylate synthase. RESULTS: Using a random intercept logistic regression model, immunohistochemical marker expression of TMAs had a moderate to high reliability measured using the intraclass correlation coefficient (0.67-0.99) between cores within the same tumor. Reliability was dependent on the selected biomarker, with lineage-specific biomarkers being less heterogeneously expressed than functional biomarkers. Expressions of most biomarkers showed no significant difference between central versus peripheral tumor cores. CONCLUSION: Our results demonstrated that biomarkers involved in clinical tumor classification (cell lineage markers) of NSCLC can be adequately assessed using 1 or 2 biopsy samples. However, the optimal number of cores required for biomarkers with functional properties varied from 1 to > 4 cores. The results indicate that the optimal number of biopsies required to compensate for potential biomarker heterogeneity should be determined individually for each biomarker used in clinical settings. PMID- 24486060 TI - Atypical (mid-ventricular) Takotsubo syndrome in a survival of out-of-hospital ventricular fibrillation: cause or consequence? PMID- 24486057 TI - Divergent neuroendocrine responses to localized and systemic inflammation. AB - The sympathetic nervous system (SNS) is part of an integrative network that functions to restore homeostasis following injury and infection. The SNS can provide negative feedback control over inflammation through the secretion of catecholamines from postganglionic sympathetic neurons and adrenal chromaffin cells (ACCs). Central autonomic structures receive information regarding the inflammatory status of the body and reflexively modulate SNS activity. However, inflammation and infection can also directly regulate SNS function by peripheral actions on postganglionic cells. The present review discusses how inflammation activates autonomic reflex pathways and compares the effect of localized and systemic inflammation on ACCs and postganglionic sympathetic neurons. Systemic inflammation significantly enhanced catecholamine secretion through an increase in Ca(2+) release from the endoplasmic reticulum. In contrast, acute and chronic GI inflammation reduced voltage-gated Ca(2+) current. Thus it appears that the mechanisms underlying the effects of peripheral and systemic inflammation neuroendocrine function converge on the modulation of intracellular Ca(2+) signaling. PMID- 24486056 TI - Neuroendocrine regulation of inflammation. AB - The interaction between the sympathetic nervous system and the immune system has been documented over the last several decades. In this review, the neuroanatomical, cellular, and molecular evidence for neuroimmune regulation in the maintenance of immune homeostasis will be discussed, as well as the potential impact of neuroimmune dysregulation in health and disease. PMID- 24486061 TI - Choline prevents cardiac hypertrophy by inhibiting protein kinase C-delta dependent transient receptor potential canonical 6 channel. PMID- 24486062 TI - International RCT-based guidelines for use of preoperative stress testing and perioperative beta-blockers and statins in non-cardiac surgery. AB - BACKGROUND: Cardiologists frequently advise on perioperative care for non-cardiac surgery and require guidance based on randomised controlled trials that are not discredited by misconduct or misreporting. Regional political bodies currently do not provide this. We therefore examined the credible randomised controlled trial (RCT) evidence on key cardiac perioperative questions which currently have 14 recommendations. METHODS: Three aspects of perioperative measures were considered: perioperative statins, preoperative stress-testing and perioperative beta-blockade. One author searched PubMed for RCTs considering these topics. All authors independently assessed the RCTs and then collaboratively composed guidelines. RESULTS: Perioperative statin therapy has been examined by three RCTs, DECREASE III and IV, which are discredited and a third containing serious inconsistencies undermining its validity. Preoperative stress testing has been examined by two RCTs: one discredited trial, DECREASE II, and a second which found no benefit. Perioperative beta-blockade has been examined by eleven RCTs, two of which are discredited. The nine remaining trials together suggest that perioperative beta-blockade increases mortality. CONCLUSIONS: When the non credible RCTs are omitted, the evidence base on these three subjects is much smaller than previously believed: 14 recommendations can be replaced by 3. Current guideline arrangements collectively paralyse the numerous signatories from making urgent amendments after initial publication, even when important new information comes to light. Clinicians simply have to wait for the routine five year expiry. We present a concise scientifically based guideline and commit to updating it responsibly. PMID- 24486063 TI - Change in serum PEDF level after pioglitazone treatment is independently correlated with that in HOMA-IR. PMID- 24486064 TI - Al-Akhawayni's views on stroke. PMID- 24486065 TI - The clinical impact of ajmaline challenge in elderly patients with suspected atrioventricular conduction disease. AB - BACKGROUND: The effects and the safety of ajmaline challenge in elderly patients with suspected atrioventricular (AV) conduction disease have not been systematically investigated. The purpose of this study was to assess the response of intravenous administration of ajmaline in patients older than 75 years suspected to be affected by AV conduction disease with respect to unmask high degree His-Purkinje block or the typical Brugada ECG pattern. METHODS: Consecutive patients older than 75 years having undergone in our centre an electrophysiologic study with intravenous ajmaline administration were eligible for this study. RESULTS: A total of 162 consecutive patients older than 75 years (84 males; mean age: 78+/-4 years) were included. Ajmaline induced prolongation of the H-V interval up to 100 ms or more in 25 patients (15%). High degree His Purkinje block was produced in 5 patients (3%). Moreover, ajmaline challenge unmasked a Brugada type 1 ECG in 12 patients (7%). No ventricular tachyarrhythmia was observed during the pharmacologic challenge and no severe side effects occurred. Among the study population, 56 (34%) and 6 patients (4%) underwent a PM and ICD implantation, respectively. For the patients with BS, a family screening was performed in a total of 37 individuals. Eighteen family members (48%) presented a positive ajmaline test and 1 (3%) a spontaneous Brugada type 1 ECG. CONCLUSIONS: Ajmaline challenge in the elderly is a safe procedure to unmask AV conduction disease and can lead to an unexpected diagnosis of BS. Although the clinical impact is obvious, the therapeutic management remains controversial. PMID- 24486066 TI - All patients with a postdural puncture headache should receive an epidural blood patch. AB - Postdural puncture headache (PDPH) is an important complication of obstetric epidural anaesthesia and analgesia. Though often self-limiting, PDPH is unpleasant, at times incapacitating, and associated with complications, some of which are serious. Despite this, treatment options are few and of limited efficacy. The epidural blood patch (EBP) has been used for PDPH treatment for over 50 years.(1) It is probably the most efficacious of therapies, although this is unproven, and plays an important part in the management of this condition.(2) However, PDPH is often complex, of variable severity and duration, and merits a cautious and individualized approach to its diagnosis and treatment. An EBP may be part of that treatment but administering it to all women with PDPH is not the optimal management approach. PMID- 24486067 TI - The transcription factor Etv5 controls TH17 cell development and allergic airway inflammation. AB - BACKGROUND: The differentiation of TH17 cells, which promote pulmonary inflammation, requires the cooperation of a network of transcription factors. OBJECTIVES: We sought to define the role of Etv5, an Ets-family transcription factor, in TH17 cell development and function. METHODS: TH17 development was examined in primary mouse T cells wherein Etv5 expression was altered by retroviral transduction, small interfering RNA targeting a specific gene, and mice with a conditional deletion of Etv5 in T cells. The direct function of Etv5 on the Il17 locus was tested with chromatin immunoprecipitation and reporter assays. The house dust mite-induced allergic inflammation model was used to test the requirement for Etv5-dependent TH17 functions in vivo. RESULTS: We identify Etv5 as a signal transducer and activator of transcription 3-induced positive regulator of TH17 development. Etv5 controls TH17 differentiation by directly promoting Il17a and Il17f expression. Etv5 recruits histone-modifying enzymes to the Il17a-Il17f locus, resulting in increased active histone marks and decreased repressive histone marks. In a model of allergic airway inflammation, mice with Etv5-deficient T cells have reduced airway inflammation and IL-17A/F production in the lung and bronchoalveolar lavage fluid compared with wild-type mice, without changes in TH2 cytokine production. CONCLUSIONS: These data define signal transducer and activator of transcription 3-dependent feed-forward control of TH17 cytokine production and a novel role for Etv5 in promoting T cell-dependent airway inflammation. PMID- 24486068 TI - IgE-mediated mast cell responses are inhibited by thymol-mediated, activation induced cell death in skin inflammation. AB - BACKGROUND: Mast cells play a critical role in inflammatory skin diseases through releasing proinflammatory mediators; however, few therapies directly target these cells. In 1878, the use of topical thymol, a now recognized potent agonist for transient receptor potential channels, was first described to treat eczema and psoriasis. OBJECTIVE: We sought to determine the mechanisms through which thymol can alter skin inflammation. METHODS: We examined the effect of topical thymol on IgE-dependent responses using a mast cell-dependent passive cutaneous anaphylaxis (PCA) model, as well as in vitro-cultured mast cells. RESULTS: Thymol dose dependently inhibited PCA when administered topically 24 hours before antigen challenge but provoked an ear-swelling response directly on application. This direct effect was associated with local mast cell degranulation and was absent in histamine-deficient mice. However, unlike with PCA responses, there was no late phase swelling. In vitro thymol directly triggered calcium flux in mast cells through transient receptor potential channel activation, along with degranulation and cytokine transcription. However, no cytokine protein was produced. Instead, thymol induced a significant increase in apoptotic cell death that was seen both in vitro and in vivo. CONCLUSIONS: We propose that the efficacy of thymol in reducing IgE-dependent responses is through promotion of activation-induced apoptotic cell death of mast cells and that this likely explains the clinical benefits observed in early clinical reports. PMID- 24486069 TI - Genetic predictors associated with improvement of asthma symptoms in response to inhaled corticosteroids. AB - BACKGROUND: To date, genome-wide association studies (GWASs) of inhaled corticosteroid (ICS) response in asthmatic patients have focused primarily on lung function and exacerbations. OBJECTIVE: We hypothesized that GWAS analysis could identify novel genetic markers predicting a symptomatic response to ICSs. METHODS: We analyzed differences in asthma symptoms in response to ICSs in 124 white children from the Childhood Asthma Management Program (CAMP) trial using scores from diary cards. Of the 440,862 single nucleotide polymorphisms (SNPs) analyzed, the top 100 ranked SNPs were pursued for replication initially in subjects from the pediatric Childhood Asthma Research and Education trials (77 white children) and then in subjects from the adult Asthma Clinical Research Network (110 white adults) and Leukotriene Modifier or Corticosteroid or Corticosteroid-Salmeterol trials (110 white adults). RESULTS: The lowest P value for GWAS analysis in the CAMP trial was 8.94 * 10(-8) (rs2388639). Of the 60 SNPs available in the Childhood Asthma Research and Education Network trials, rs1558726 (combined P = 1.02 * 10(-5)), rs2388639 (combined P = 8.56 * 10(-9)), and rs10044254 (combined P = 9.16 * 10(-8)) independently replicated. However, these 3 SNPs were not additionally replicated in the adult asthmatic patients of the remaining trials. rs10044254 lies in the intronic region of F-box and leucine rich repeat protein 7 (FBXL7) and is associated with decreased expression in immortalized B cells derived from CAMP participants. CONCLUSIONS: We have identified a novel SNP, rs10044254, associated with both decreased expression of FBXL7 and improved symptomatic response to ICSs in 2 independent pediatric cohorts. Our results suggest that there might be a specific genetic mechanism regulating symptomatic response to ICSs in children that does not carry over to adults. PMID- 24486070 TI - The expression of cannabinoid receptor 1 is significantly increased in atopic patients. PMID- 24486072 TI - [An iris metastasis revealed a bronchopulmonary cancer]. AB - We report the case of a 53-year-old patient referred by his ophthalmologist for a red, painful eye. On exam, he demonstrated findings of granulomatous uveitis with ocular hypertension (38 mm Hg) and a whitish, vascularized iris tumor with invasion of the irido-corneal angle. As our first hypothesis was an iris metastasis, a systemic work-up was carried out, which revealed moderately differentiated broncho-pulmonary carcinoma with multiple metastases (brain, cerebellum and adrenal). Emergency radio-chemotherapy was initiated, and the outcome was good, with rapid regression of the iris metastasis and good efficacy against the primary cancer. After one year of follow-up, the patient developed a metastasis at a new site, and his general condition deteriorated. PMID- 24486071 TI - Prostaglandin E2 resistance in granulocytes from patients with aspirin exacerbated respiratory disease. AB - BACKGROUND: Aspirin-exacerbated respiratory disease (AERD) is an inflammatory condition of the respiratory tract and is characterized by overproduction of leukotrienes (LT) and large numbers of circulating granulocyte-platelet complexes. LT production can be suppressed by prostaglandin E(2) (PGE(2)) and the cyclic AMP-dependent protein kinase A (PKA). OBJECTIVE: To determine if PGE(2) dependent control of LT production by granulocytes is dysregulated in AERD. METHODS: Granulocytes from well-characterized patients with and without AERD were activated ex vivo and subjected to a range of functional and biochemical analyses. RESULTS: Granulocytes from subjects with AERD generated more LTB4 and cysteinyl LTs than did granulocytes from controls with aspirin-tolerant asthma and controls without asthma. When compared with controls, granulocytes from subjects with AERD had comparable levels of EP(2) protein expression and PGE(2) mediated cAMP accumulation, yet were resistant to PGE(2)-mediated suppression of LT generation. Percentages of platelet-adherent neutrophils correlated positively with LTB4 generation and inversely with responsiveness to PGE(2)-mediated suppression of LTB(4). The PKA inhibitor H89 potentiated LTB4 generation by control granulocytes but was inactive in granulocytes from individuals with AERD and had no effect on platelet P-selectin induction. Both tonic PKA activity and levels of PKA catalytic gamma subunit protein were significantly lower in granulocytes from individuals with AERD relative to those from controls. CONCLUSIONS: Impaired granulocyte PKA function in AERD may lead to dysregulated control of 5-lipoxygenase activity by PGE(2), whereas adherent platelets lead to increased production of LTs, which contributes to the features of persistent respiratory tract inflammation and LT overproduction. PMID- 24486073 TI - [Factors linked to foveoschisis in high myopia]. AB - PURPOSE: To investigate the factors linked to foveoschisis in high myopia. METHODS: Retrospective study of 113 patients (200 eyes) with high myopia was conducted between January 2010 and June 2012. Subjects underwent a complete ophthalmic examination, spectral domain optical coherence tomography (OCT TOPCON 2000) and ocular echography. RESULTS: Of the 200 eyes, 22 (11%) had foveoschisis on OCT examination. On the basis of univariate analysis, five variables were associated with the pathologic changes, including spherical equivalent over 10 diopters (P=0.044), axial length over 30 mm (P=0.0028), macular chorioretinal atrophy (P=0.0009), posterior staphyloma (P=0.0007) and vitreoretinal interface factors (P=0.0002). In the multivariate analysis, three factors were independently associated with foveoschisis in high myopia: axial length (adjusted OR, 16.7; IC 95% 1.4-219.7, P=0.036), macular chorioretinal atrophy (adjusted OR, 13.2; IC 95%, 1.3-133.1, P=0.044), and vitreoretinal interface factors (adjusted OR, 36.1; IC 95%, 3.5-376.9, P=0.002). CONCLUSIONS: In our study, axial length, macular chorioretinal atrophy, and vitreoretinal interface factors were independently associated foveoschisis in highly myopic eyes. PMID- 24486074 TI - [Clinical study and risk factors for recurrence of basal cell carcinoma of the eyelid: results of a Tunisian series and review of the literature]. AB - PURPOSE: To report our results of treatment of eyelid basal cell carcinomas and evaluate risk factors for recurrence. PATIENTS AND METHODS: We carried out a retrospective study of 172 basal cell carcinomas in 168 patients, treated in the Ophthalmology department of Sousse University Medical Center (Tunisia), from January 1987 to July 2012. Initial treatment was surgical excision with a standard margin of 4mm or a single radiation treatment. When excision was incomplete, we had the choice between further excision, radiotherapy or a "wait and see" approach. Mean follow-up in our study was 11.5 months with range from 1 month to 14 years. RESULTS: We treated 169 tumors in 165 patients, with three patients out of 168 having refused the proposed treatment. Primary radiotherapy was performed in 4 cases in patients presenting with large tumors and refusing disfiguring surgery. For the 165 other tumors (95.9%), surgical excision was performed. Surgical margins were clear in 106 cases (64.2%) and positive in 37 cases (22.4%). No residual tumor was noted in 2 cases for which biopsy was initially performed, and margins could not be visualized in 20 cases (12.1%) due to the small size or fragmentation of the specimen. For the incompletely excised tumors, we performed a second excision in three cases (8%), radiotherapy in 11 cases (29.7%) and a "wait and see" approach in 22 cases (59.4%). The recurrence rate was 6.9%, with a mean time of 32.8 months until recurrence. CONCLUSION: Basal cell carcinoma represents the most frequent malignant tumor of the eyelids. Surgery remains the standard treatment. The "wait and see" approach offers an interesting option for the management of incompletely excised basal cell carcinoma, especially with low risk lesions. PMID- 24486075 TI - On the reliability of mitotic count on biopsy samples of gastrointestinal stromal tumors. PMID- 24486076 TI - On the reliability of mitotic count on biopsy samples of gastrointestinal stromal tumors. PMID- 24486077 TI - Prostate cancer Ki-67 (MIB-1) expression, perineural invasion, and gleason score as biopsy-based predictors of prostate cancer mortality: the Mayo model. AB - OBJECTIVE: To determine the role of cellular proliferation and other biopsy-based features in the prediction of prostate cancer mortality. PATIENTS AND METHODS: Between 1993 and 2012, our institution has performed quantitation of prostate cancer DNA ploidy and Ki-67 (MIB-1) on most prostate cancer needle biopsy specimens. The outcomes of 451 consecutive patients with biopsy-proven cancer treated by radical prostatectomy between January 24, 1995, and December 29, 1998, without neoadjuvant hormonal therapy were assessed. Clinical and biopsy information obtained before radical prostatectomy was placed in multivariate Cox proportional hazards regression models to predict local or systemic progression and cancer-specific death. Predictive ability was evaluated using a concordance index. RESULTS: With a median follow-up of 12.9 years, 46 patients experienced local or systemic progression, and 18 patients died of prostate cancer. On multivariate analysis, the biopsy features of Ki-67 expression, perineural invasion, and Gleason score were associated with local or systemic progression. Ki-67 expression, perineural invasion, and Gleason score were associated with cancer-specific death with a concordance index of 0.892. After adjusting for perineural invasion and Gleason score, each 1% increase in Ki-67 expression was associated with a 12% increased risk of cancer-specific death (P<.001). Ki-67 expression alone was a strong predictor of cancer-specific outcomes and improved the predictive ability of currently used algorithms. CONCLUSION: This study documents that long-term prostate cancer outcomes are best estimated with a combination of Gleason score, perineural invasion, and Ki-67 expression. Given its low cost, rapid assessment, and strong predictive power, we believe that adding Ki-67 expression to perineural invasion and Gleason score at biopsy should be considered a standard by which all new biomarkers are compared before introducing them into clinical practice. PMID- 24486078 TI - Leadership models in health care - a case for servant leadership. AB - Our current health care system is broken and unsustainable. Patients desire the highest quality care, and it needs to cost less. To regain public trust, the health care system must change and adapt to the current needs of patients. The diverse group of stakeholders in the health care system creates challenges for improving the value of care. Health care providers are in the best position to determine effective ways of improving the value of care. To create change, health care providers must learn how to effectively lead patients, those within health care organizations, and other stakeholders. This article presents servant leadership as the best model for health care organizations because it focuses on the strength of the team, developing trust and serving the needs of patients. As servant leaders, health care providers may be best equipped to make changes in the organization and in the provider-patient relationship to improve the value of care for patients. PMID- 24486079 TI - Influence of ultrasonication times on the tunable colour emission of ZnO nanophosphors for lighting applications. AB - This paper reports on the sonochemical synthesis of zinc oxide (ZnO) nanophosphors (NPr) at different ultrasonication times (5 min, 30 min, 1h, 5h, 10h and 15 h) for near white light emission applications. X-ray photoelectron spectroscopy indicated that the O1s peak consists of two components. These were O1 (ZnO) and O2 (deficient oxygen; OH groups) centred at 529.7+/-0.3 eV and 531.1+/-0.3 eV, respectively. All samples showed UV and defect level emission (DLE). The DLE enhancement was due to the increase in oxygen related defects such as oxygen vacancies/interstitials. Due to the combination of near UV and DLE near white light emission in ZnO NPr was obtained. The emission could be tuned with different ultrasonic times. It was found that the ultrasonication time influenced the growth mechanism and luminescence properties of the ZnO NPr. PMID- 24486080 TI - Synthesis and sonocatalytic property of rod-shape Sr(OH)2.8H2O. AB - A novel rod-shape sonocatalyst Sr(OH)2.8H2O was prepared by a facile precipitation method, and characterized by X-ray powder diffraction, transmission electron microscopy, Fourier transform infrared spectroscopy and UV-vis absorption spectroscopy. Comparative sonocatalytic degradation experiments were carried out in different conditions under ultrasonic irradiation by using rhodamine B (RhB) as the model substrate, indicating that Sr(OH)2.8H2O was highly sonocatalytic. Total organic carbon experiment demonstrated Sr(OH)2.8H2O with mass mineralization of organic carbon. The effects of catalyst amount, initial RhB concentration and ultrasonic energy of degradation were investigated, and the sonocatalyst could be reused 5 times without significant loss of activity. Furthermore, the potent degrading capability was ascribed to ultrasonic cavitation producing flash light/energy which generated radicals (e.g., OH) with high oxidation activity. PMID- 24486081 TI - Maple Syrup Urine Disease Complicated with Kyphoscoliosis and Myelopathy. AB - Maple syrup urine disease (MSUD) is an autosomal recessive aminoacidopathy secondary to an enzyme defect in the catabolic pathway of the branched-chain amino acids (BCAAs: leucine, isoleucine, and valine). Accumulation of their corresponding keto-acids leads to encephalopathy if not treated in time. A newborn male patient was suspected to have MSUD after tandem mass study when he presented symptoms and signs suggestive neonatal sepsis, anemia, and diarrhea. Food restriction of BCAAs was started; however, acrodermatitis enteropathica-like skin eruptions occurred at age 2 months. The skin rashes resolved after adding BCAAs and adjusting the infant formula. At age 7 months, he suffered from recurrent skin lesions, zinc deficiency, osteoporosis, and kyphosis of the thoracic spine with acute angulation over the T11-T12 level associated with spinal compression and myelopathy. After supplementation of zinc products and pamidronate, skin lesions and osteopenia improved gradually. Direct sequencing of the DBT gene showed a compound heterozygous mutation [4.7 kb deletion and c.650 651insT (L217F or L217fsX223)]. It is unusual that neurodegeneration still developed in this patient despite diet restriction. Additionally, brain and spinal magnetic resonance imaging, bone mineral density study, and monitoring of zinc status are suggested in MSUD patients. PMID- 24486085 TI - Green tea (-)-epigallocatechin gallate suppresses IGF-I and IGF-II stimulation of 3T3-L1 adipocyte glucose uptake via the glucose transporter 4, but not glucose transporter 1 pathway. AB - This study investigated the pathways involved in EGCG modulation of insulin-like growth factor (IGF)-stimulated glucose uptake in 3T3-L1 adipocytes. EGCG inhibited IGF-I and IGF-II stimulation of adipocyte glucose uptake with dose and time dependencies. EGCG at 20MUM for 2h decreased IGF-I- and IGF-II-stimulated glucose uptake by 59% and 64%, respectively. Pretreatment of adipocytes with antibody against the EGCG receptor (also known as the 67-kDa laminin receptor; 67LR), prevented the effects of EGCG on IGF-increased glucose uptake, but pretreatment with normal rabbit immunoglobulin did not. This suggests that the 67LR mediates the anti-IGF effect of EGCG on adipocyte glucose uptake. Further analysis indicated EGCG, IGF-I, and IGF-II did not alter total levels of GLUT1 or GLUT4 protein. However, EGCG prevented the IGF-increased GLUT4 levels in the plasma membrane and blocked the IGF-decreased GLUT4 levels in low-density microsomes. Neither EGCG nor its combination with IGF altered GLUT1 protein levels in the plasma membrane and low-density microsomes. EGCG also suppressed the IGF-stimulated phosphorylation of IGF signaling molecules, PKCzeta/lambda, but not AKT and ERK1/2, proteins. This study suggests that EGCG suppresses IGF stimulation of 3T3-L1 adipocyte glucose uptake through inhibition of the GLUT4 translocation, but not through alterations of the GLUT1 pathway. PMID- 24486086 TI - Membrane lipids tune synaptic transmission by direct modulation of presynaptic potassium channels. AB - Voltage-gated potassium (Kv) channels are involved in action potential (AP) repolarization in excitable cells. Exogenous application of membrane-derived lipids, such as arachidonic acid (AA), regulates the gating of Kv channels. Whether membrane-derived lipids released under physiological conditions have an impact on neuronal coding through this mechanism is unknown. We show that AA released in an activity-dependent manner from postsynaptic hippocampal CA3 pyramidal cells acts as retrograde messenger, inducing a robust facilitation of mossy fiber (Mf) synaptic transmission over several minutes. AA acts by broadening presynaptic APs through the direct modulation of Kv channels. This form of short-term plasticity can be triggered when postsynaptic cell fires with physiologically relevant patterns and sets the threshold for the induction of the presynaptic form of long-term potentiation (LTP) at hippocampal Mf synapses. Hence, direct modulation of presynaptic Kv channels by activity-dependent release of lipids serves as a physiological mechanism for tuning synaptic transmission. PMID- 24486087 TI - Mapping sensory circuits by anterograde transsynaptic transfer of recombinant rabies virus. AB - Primary sensory neurons convey information from the external world to relay circuits within the CNS, but the identity and organization of the neurons that process incoming sensory information remains sketchy. Within the CNS, viral tracing techniques that rely on retrograde transsynaptic transfer provide a powerful tool for delineating circuit organization. Viral tracing of the circuits engaged by primary sensory neurons has, however, been hampered by the absence of a genetically tractable anterograde transfer system. In this study, we demonstrate that rabies virus can infect sensory neurons in the somatosensory system, is subject to anterograde transsynaptic transfer from primary sensory to spinal target neurons, and can delineate output connectivity with third-order neurons. Anterograde transsynaptic transfer is a feature shared by other classes of primary sensory neurons, permitting the identification and potentially the manipulation of neural circuits processing sensory feedback within the mammalian CNS. PMID- 24486088 TI - Clinical significance of the best response during repeated transarterial chemoembolization in the treatment of hepatocellular carcinoma. AB - BACKGROUND & AIMS: We assessed the clinical implications of the best response compared with the initial response during repeated transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC). METHODS: We evaluated 332 patients with intermediate-stage HCC and preserved liver function initially treated with repeated TACE. All had >=1 lesion measuring >=1 cm, and the response measured after each session was based on EASL and mRECIST criteria. We performed survival analyses according to response kinetics, and identified clinical factors associated with the need for repeated TACE to achieve the best response. RESULTS: An objective response, either a complete response (CR) or a partial response (PR), after the first TACE was seen in about 50% of patients by both EASL and mRECIST. In terms of the best response during serial TACE, 250 patients (75.3%) by EASL and 278 (83.7%) by mRECIST were overall responders. The sizes of the largest and second largest tumors were the only parameters positively correlated with the number of TACE sessions required to achieve the best response (p<0.05). Multivariate Cox analysis showed that achieving a CR or PR as the best response was the best predictor of survival following TACE with a hazard ratio of 0.45 by EASL and 0.24 by mRECIST, and more than 0.69 and 0.71, respectively for initial responders (p<0.05). CONCLUSIONS: The best response observed during serial TACE, rather than the initial response, most strongly predicts the survival of patients with intermediate-stage HCC. The number of TACE sessions needed to achieve a best response is a function of tumor size. PMID- 24486090 TI - Reply by authors. PMID- 24486089 TI - Risk factors predictive of anemia development during telaprevir plus peginterferon/ribavirin therapy in treatment-experienced patients. AB - BACKGROUND & AIMS: Anemia is a common adverse event associated with telaprevir based triple therapy of chronic, genotype 1 hepatitis C. Identification of patients at risk of developing anemia could allow evaluation of suitability for therapy, and aid in determining frequency of anemia monitoring and treatment management. METHODS: This post-hoc analysis utilized data from the no lead-in telaprevir, peginterferon and ribavirin arm of the REALIZE study. Anemia was defined as a single occurrence of hemoglobin <10 g/dl at any point during treatment. Pre-treatment factors with potential to act as prognostic indicators of anemia including age, sex, BMI, and baseline hemoglobin were analysed by univariate and multivariate logistic regression analyses. Nomograms (graphical representations of risk factors) were developed to predict the likelihood of developing anemia. RESULTS: Among the 265 patients, 102 (38%) had anemia, with 78/102 (77%) developing anemia on or before week 12. Most patients developed anemia after week 2 and an inverse correlation was found between week 2 hemoglobin and the likelihood of developing anemia. Overall, 60% of patients (60/100) with week 2 hemoglobin <13 g/dl subsequently developed anemia. The multivariate analysis revealed older age (>45 years), lower BMI (<=25 mg/m(2)) and baseline hemoglobin (continuous variable) were significantly associated with the probability of developing anemia during telaprevir treatment. CONCLUSIONS: These analyses indicate the potential of using predictive risk factors such as low baseline and on-treatment hemoglobin to identify patients at risk of developing anemia on telaprevir-based triple therapy, which may increase the potential for treatment success by careful patient monitoring. PMID- 24486092 TI - Editorial comment. PMID- 24486093 TI - Risk factors for foot-and-mouth disease in Zambia, 1981-2012. AB - The aim of this study was to describe the spatial distribution of foot-and-mouth disease (FMD) outbreaks in Zambia for the period January 1981-December 2012 and to quantify the association between geographical features (proximity to roads, national parks, wetland areas) and the spatial distribution of FMD using a Poisson point process model. Details of FMD outbreaks retrieved from the Zambian Department of Veterinary and Livestock Development included the date of onset of clinical signs and the name of the ward in which the index case enterprise was located. A total of 62 FMD outbreaks occurred throughout the study period. Outbreaks occurred in the south of the Southern province along the border with Namibia and Botswana (n=5), in the Western province (n=2), in the Southern and Central provinces on the Kafue flood plains (n=44), and in the north east of the country close to the border with Tanzania (n=11). Increases in distance to the nearest major international border crossing, distance to the nearest major road, distance to the wetland area of the Kafue flood plain, wetness index and elevation were all associated with a decrease in FMD-outbreak ward intensity. Our analyses support the hypothesis that in drier areas of the country cattle are more likely to aggregate around communal drinking pools. Aggregation of cattle provides conditions suitable for FMD spread and detection. PMID- 24486094 TI - Modeling and mitigating winter hay bale damage by elk in a low prevalence bovine tuberculosis endemic zone. AB - Wildlife causes extensive crop damage throughout much of North America and these shared feeds are a key risk factor in the transmission of diseases between wildlife and livestock, including bovine tuberculosis (TB). Predicting wildlife use of agricultural crops can provide insight directed toward targeted disease mitigation at areas of potential indirect interaction. In this study, we quantified use of hay bales by elk (Cervus canadensis) during the winter in southwestern Manitoba, Canada using a database of 952 damage claims paid compensation from 1994 to 2012. We evaluated environmental factors predicted to determine risk of hay bale damage on each quarter section by elk using a Resource Selection Probability Function (RSPF) model. The most important variables (as measured for each quarter section and based on cumulative Akaike weights that scale from 0 to 1) were distance to protected areas (1.00), forest including a buffer around the quarter section (1.00), forage crop including a buffer around the quarter section (1.00), distance from streams (0.99), forage crop (0.92), cereal and oilseed crop cover including a buffer (0.85), and forest cover (0.82). We then developed an RSPF-based predictive map of damage to hay bales by elk that identified key areas with high probability of damage (RSPF>=0.6), accounting for 3.5% of the study area. We then multiplied the RSPF values by the inverse of the proximity to known cases of TB positive elk and determined that 0.51% of the study area had an overall high combined probability of hay bale damage and proximity to TB positive elk (i.e. adjusted probability of >=0.6). In the southern half of the study area where 164 hay yard barrier fences have been implemented since 2002, there has been a significant decrease in the number of annual claims. Barrier fencing around Riding Mountain National Park has been successful at reducing elk damage where it has been implemented. In our study area, prevalence of TB in both cattle (0.003%) and elk (0.89%) is very low, precluding conventional epidemiological analyses. In the absence of clear evidence of specific routes of TB transmission, we advocate that on-farm risk assessments and mitigation efforts should continue to address areas where elk cause damage to hay bales in winter using barrier fencing. Mitigation effort should especially focus on areas where TB positive elk have been identified, as these sites provide potential for indirect interaction between cattle and elk. PMID- 24486095 TI - It takes a system to treat a pneumothorax. PMID- 24486096 TI - Extending our reach: use of mHealth to support patients after emergency care. PMID- 24486097 TI - Does this patient have acute mesenteric ischemia? PMID- 24486098 TI - Maintenance of certification: a work in progress. PMID- 24486099 TI - The expert witness in emergency medicine. PMID- 24486100 TI - A new toolkit for behavioral health. PMID- 24486101 TI - Further results on global state feedback stabilization of nonlinear high-order feedforward systems. AB - In this paper, by introducing a combined method of sign function, homogeneous domination and adding a power integrator, and overcoming several troublesome obstacles in the design and analysis, the problem of state feedback control for a class of nonlinear high-order feedforward systems with the nonlinearity's order being relaxed to an interval rather than a fixed point is solved. PMID- 24486102 TI - The sorption of heavy metals on thermally treated sediments with high organic matter content. AB - A sediment sample with organic matter higher than 60% was thermally treated and the sorption of Cu(II), Cd(II), and Pb(II) was investigated and compared to evaluate the potential use of sediments with high organic matter content to produce biochar. Cu(II) and Cd(II) sorption generally decreased with increasing pyrolysis temperature, concurred with decreased oxygen-containing functional groups of the adsorbents. Sediment particles pyrolyzed at 400 and 500 degrees C showed higher sorption to Pb(II) than other temperatures. The small hydrated ionic radius of Pb(II) may enable its close contact with solid particles and thus facilitated the diffusion of Pb(II) into the pores and the formation of cation-pi bond with aromatic structures generated by pyrolysis. The sorption of heavy metals in thermally treated sediment showed comparable sorption to or higher sorption than natural adsorbents and biochars from biomass, suggesting their possible significant impact on the transport and risk of heavy metals. PMID- 24486103 TI - Morphometry to identify subtypes of leukocytes. AB - INTRODUCTION: Recent studies in image cytometry evaluated the replacement of specific markers by morphological parameters. The aim of this study was to develop and evaluate a method to identify subtypes of leukocytes using morphometric data of the nuclei. METHOD: The analyzed images were generated with a laser scanning cytometer. Two free programs were used for image analysis and statistical evaluation: Cellprofiler and Tanagra respectively. A sample of leukocytes with 200 sets of images (DAPI, CD45 and CD14) was analyzed. Using feature selection, the 20 best parameters were chosen to conduct cross validation. RESULTS: The morphometric data identified the subpopulations of the analyzed leukocytes with a sensitivity and specificity of 0.95 per sample. CONCLUSION: The present study is the first that identifies subpopulations of leukocytes by nuclear morphology. PMID- 24486104 TI - Generation of gene-modified cynomolgus monkey via Cas9/RNA-mediated gene targeting in one-cell embryos. AB - Monkeys serve as important model species for studying human diseases and developing therapeutic strategies, yet the application of monkeys in biomedical researches has been significantly hindered by the difficulties in producing animals genetically modified at the desired target sites. Here, we first applied the CRISPR/Cas9 system, a versatile tool for editing the genes of different organisms, to target monkey genomes. By coinjection of Cas9 mRNA and sgRNAs into one-cell-stage embryos, we successfully achieve precise gene targeting in cynomolgus monkeys. We also show that this system enables simultaneous disruption of two target genes (Ppar-gamma and Rag1) in one step, and no off-target mutagenesis was detected by comprehensive analysis. Thus, coinjection of one-cell stage embryos with Cas9 mRNA and sgRNAs is an efficient and reliable approach for gene-modified cynomolgus monkey generation. PMID- 24486106 TI - Treatment outcome of HAART-treated patients in a resource-limited setting: the Belgrade Cohort Study. AB - INTRODUCTION: We evaluated the effects of highly-active-antiretroviral-therapy (HAART) in a resource-limited settings. METHODS: A cross-sectional study was performed in patients who had initiated HAART at the HIV/AIDS-Center, Belgrade, Serbia. Treatment response was considered favorable in case of the achievement of undetectable HIVRNA plasma-viral-load (pVL<50 copies/MUL), and with the CD4+ T cell counts increased above 350cells/MUL. The treatment failure was defined as pVL over 1.7 log10 copies/mL, regardless of immunological improvement. RESULTS: Eight hundred and forty HIV infected patients were followed-up for 8.2+/ 3.4years. Out of 697 patients available for follow-up, 113 (16.2%) patients died, 44 (6.3%) experienced treatment failure, while 540 (77.5%) had sustained undetectable viremia. In 419 (60.1%) favorable treatment response was achieved, while the dissociation between immunological and virological responses to HAART occurred in 121 (14.4%). A baseline CD4+ T-cell counts above 200 cells/MUL was the single independent predictor of a favorable treatment response (HR=2, 95%CI=1.69-2.61, P=0.001), while pre-treatment with ART, HCV co-infection and AIDS at the time of treatment initiation, were all factors preventing a favorable response (HR=0.27, 95%CI=0.19-0.36, P=0.001; HR=0.75, 95%CI=0.56-0.95, P=0.02; HR=0.73, 95%CI=0.17-0.95, P=0.018, respectively). A sustained viral suppression was an independent predictor of survival (HR=0.2, 95% CI 0.07-0.61, P=0.004). HAART treated HIV-infected patients who reach and maintain undetectable viremia, have an 80% probability of a 14-years survival (P=0.08, log-rank). CONCLUSION: If patient with advanced HIV-related immunodeficiency reach and maintain optimal viral suppression during HAART, regardless of the level of immune recovery, and if they continue to maintain this, their prognosis may be fairly good even in the resource-limited settings. PMID- 24486105 TI - Nonstochastic reprogramming from a privileged somatic cell state. AB - Reprogramming somatic cells to induced pluripotency by Yamanaka factors is usually slow and inefficient and is thought to be a stochastic process. We identified a privileged somatic cell state, from which acquisition of pluripotency could occur in a nonstochastic manner. Subsets of murine hematopoietic progenitors are privileged whose progeny cells predominantly adopt the pluripotent fate with activation of endogenous Oct4 locus after four to five divisions in reprogramming conditions. Privileged cells display an ultrafast cell cycle of ~8 hr. In fibroblasts, a subpopulation cycling at a similar ultrafast speed is observed after 6 days of factor expression and is increased by p53 knockdown. This ultrafast cycling population accounts for >99% of the bulk reprogramming activity in wild-type or p53 knockdown fibroblasts. Our data demonstrate that the stochastic nature of reprogramming can be overcome in a privileged somatic cell state and suggest that cell-cycle acceleration toward a critical threshold is an important bottleneck for reprogramming. PAPERCLIP: PMID- 24486107 TI - MiR-1 targets PIK3CA and inhibits tumorigenic properties of A549 cells. AB - MicroRNAs are small endogenous RNAs that play important roles in the pathogenesis of human diseases, including malignancy. MicroRNA-1 (miR-1) is downregulated in non-small cell lung cancer (NSCLC); however, the underlying mechanisms by which it suppresses tumorigenesis in NSCLC are largely unknown. We investigated whether phosphoinositide-3-kinase catalytic subunit alpha (PIK3CA) was a novel target of miR-1 in the NSCLC cell line A549, and the mechanism of miR-1 inhibition of the tumorigenic properties of A549 cells is discussed. The influence of miR-1 on A549 cells was studied by transfection with miR-1 mimics or inhibitor. MiR-1 overexpression led to downregulation of PIK3CA protein, but not mRNA by western blot and quantitative real-time PCR, respectively. The dual-luciferase reporter assay confirmed that miR-1 targeted PIK3CA directly. PIK3CA downregulation by miR 1 mimics led to a significant reduction of phosphorylated Akt and survivin protein, the downstream targets of the PI3K/Akt pathway. Cell proliferation was studied using a cell counting kit. Migration and invasion were evaluated by Transwell and Matrigel assays, respectively. Cell cycle and apoptosis were detected by flow cytometry. The results were that miR-1 upregulation inhibited A549 cell proliferation, migration, and invasion. These findings indicate that miR-1 may play an important role in the pathogenesis of NSCLC by regulating PIK3CA through the PI3K/Akt pathway. Increasing miR-1 expression may provide a novel approach for NSCLC treatment. PMID- 24486108 TI - Performance of FDG PET/ceCT in the evaluation of patients with lung cancer. AB - AIM: The aim of this study was to assess the performance of FDG PET/ceCT simultaneously acquired, contemporary read and finally discussed by the radiologist and the nuclear medicine physician for staging and restaging lung cancer patients. METHODS: We analysed 17 consecutive patients (7F; 10M; mean age 68). Six patients were in staging, 8 patients were in restaging (1 during therapy, 2 after therapy and 5 during the follow-up) and 2 patients needed to characterise a suspect pulmonary mass. All the patients underwent combined FDG PET/CT and ceCT acquired simultaneously on the same tomograph. The images were read and reported together by the nuclear medicine physician and the radiologist. RESULTS: None of the patients had adverse reactions nor complained about the procedure. Thirteen FDG PET/ceCT turned out positive, while 4 were completely negative. Among positive patients, a significant SUV max was detected in all the cases (range 1.8-17.5). In the end, 9 patients had a true positive result, 4 true negative, 3 false positive and 1 false negative. Sensitivity, specificity and accuracy of the combined procedure were 90%, 57% and 76% respectively. In 7/17 patients FDG PET/CT and ceCT were completely concordant. FDG PET/CT provided a significant impact on the final interpretation in 7/17 patients while ceCT had a major impact in 3/17 patients. DISCUSSION: This preliminary study shows that FDG PET/ceCT is a feasible technique for lung cancer patients, providing an optimal sensitivity (90%). From our results it is advisable not to include patients without an histological diagnosis of cancer due to possible false positivity of the two methods, significantly reducing specificity. However, a proper patient selection is not easy and the future of this combined test relies essentially on the capacity to early identify only the subjects who would really benefit from both the procedures. PMID- 24486109 TI - Molecular docking study, synthesis and biological evaluation of Schiff bases as Hsp90 inhibitors. AB - Heat shock protein 90 (Hsp90) is an emerging attractive target for the discovery of novel cancer therapeutic agents. Docking methods are powerful in silico tools for lead generation and optimization. In our mission to rationally develop novel effective small molecules against Hsp90, we predicted the potency of our designed compounds by Sybyl surflex Geom X docking method. The results of the above studies revealed that Schiff bases derived from 2,4-dihydroxy benzaldehyde/5 chloro-2,4-dihydroxy benzaldehyde demonstrated effective binding with the protein. Subsequently, a few of them were synthesized (1-10) and characterized by IR, (1)HNMR and mass spectral analysis. The synthesized molecules were evaluated for their potential to suppress Hsp90 ATPase activity by Malachite green assay. The anticancer studies were performed by 3-(4,5-dimethythiazol- 2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay method. The software generated results was in satisfactory agreement with the evaluated biological activity. PMID- 24486110 TI - Effect of concurrent radiochemotherapy and chemotherapy on serum proteins for prospective predictors of patients with HPV induced cervical cancer. AB - OBJECTIVES: To evaluate the effectiveness of radiochemotherapy and chemotherapy on human papilloma virus induced cervical cancer patients by the estimation of serum proteins and magnetic resonance imaging. METHODS: HPV 16/18 viral DNA was detected in the plasma of cervical cancer patients (n=50) by PCR using HPV consensus primers. Of the 50 cervical cancer patients, 25 cases undergoing radiation with chemotherapy and another 25 cases undergoing chemotherapy. Levels of pre- and post-treated serum squamous cell carcinoma antigen, soluble CD44, cancer antigen-125 were measured and evaluated the tumour size at pre- and post radiation based on magnetic resonance images. The effectiveness of treatment was evaluated in terms of protein levels and represented as whisker line graphs. RESULTS: Of the amplified 50 samples, HPV 16 and 18 strains were identified as 48 and 44%, respectively. Serum protein levels were significantly increased in both pre-treated groups when compared to healthy group. Post-treated (radiotherapy) cervical cancer patients' shows decreased tumour size when compared to pre treated groups. Taking consideration of proteins, squamous cell carcinoma antigen, soluble CD44, cancer antigen-125 levels are more decreased in patients treated with radiochemotherapy than chemotherapy alone. The decreased levels of proteins were significantly higher in early stage of the cervical cancer than the advanced stage of cancer patients. CONCLUSION: Serum levels of protein markers are more improved in patients treated with radiochemotherapy than chemotherapy hence, radiochemotherapy may be the best choice of treatment with reference to proteins at early stage of cervical cancer when compared to chemotherapy alone. PMID- 24486111 TI - Acute and sub-chronic toxicity studies of the extract of Thunberg Fritillary Bulb. AB - The aim of this study was to investigate the acute and sub-chronic toxicity of extract of Thunberg Fritillary Bulb. For the acute toxicity tests, graded doses of the extract were administered orally to mice. The animals were observed for toxic symptoms and mortality daily for 14days. In the sub-chronic toxicity study, rats were orally administered the extract at doses of 1 and 3mg/kg body weight (BW) for 26weeks. After 26weeks, the rats were sacrificed for hematological, biochemical and histological examination. In the acute toxicity tests, the estimated median lethal dosage (LD50) was 52.2mg/kg body weight in the mice. In the sub-chronic toxicity tests, a dose of 1mg/kg body weight presented no toxicity. Above the 1mg/kg dose, the main adverse signs observed in male rats were body or head tremor and spontaneous motor activity reduction. There were no other significant changes observed in hematology, blood biochemistry, organ weight and organ histology. The overall findings of this study indicate that the extract of Thunberg Fritillary Bulb is non-toxic up to 1mg/kg body weight, which can be considered a safe application dose. PMID- 24486112 TI - Characteristics and treatment options of elderly Chinese patients with cancer as determined by Comprehensive Geriatric Assessment (CGA). AB - OBJECTIVE: China is experiencing a rapid increase in cancer incidence in elderly patients. In order to better understand this group, a large study of patients from multiple tertiary centers in the Beijing area was designed. This study was designed to provide insight into their unique treatment preferences, including the use of traditional Chinese medicine (TCM). MATERIALS AND METHODS: 803 patients from nine hospitals in the Beijing area were enrolled into this study. The inclusion criteria were patients who were 65 years or older and had a diagnosis of cancer at any stage. The CGA questionnaire used with these patients included the Chinese translation of the Gero-Oncology Health and Quality of Life Assessment tool. The questionnaire was provided to patients by a research nurse and was administered in Mandarin. RESULTS: The mean age of the patients was 72 years (range 65-94). The patients were mainly male (59.8%) and of Han ethnicity (95.4%). About 45% of these patients also had concurrent TCM in addition to their other cancer treatments. About 70% were able to manage their activities of daily living without assistance. Patients on TCM were more likely to have higher number of co-morbidities compared to their counterparts. CONCLUSION: This is the largest prospective study of CGA assessments done on elderly patients with cancer in Asia. The study demonstrates that CGA provides insights into understanding the needs of elderly Chinese patients with cancer. TCM is used frequently in China, and its impact on quality of life needs further investigation. PMID- 24486113 TI - [Sarcoid pleural effusion]. AB - Pleural effusion (PE) is a very uncommon manifestation of sarcoidosis. It is equally observed in men and women, can appear at any age and in all radiologic stages, though it is more common in stages i and ii. Effusions have usually a mild or medium size and mainly involve the right side. Various mechanisms can be implicated. PE will be a serous exudate if there is an increase in the capillary permeability due to direct involvement of the pleural membrane, a chylothorax if mediastinum lymph nodes compress the thoracic duct and/or the lymphatic drainage from the pleural cavity, an hemothorax if granuloma compress or invade pleural small vessels or capillaries, and even a transudate if there is compression of the inferior vena cava, atelectasis due to complete bronchial obstruction or when the resolution of the PE is incomplete with chronic thickening of visceral pleura (trapped lung). It manifests biochemically as a pauci-cellular exudate with a predominance of lymphocytes, though there can be a preponderance of eosinophils or neutrophils. Protein concentrations are usually proportionately higher than lactate dehidrogenase, adenosine deaminase is normally low and it is possible to find increased levels of CA-125 in women. The tuberculin test is negative and pleural or lung biopsies yield the diagnosis by confirming the presence of non caseating granulomata. These PE can have a favorable self-limited outcome, even though in most cases treatment with corticosteroids is needed, while surgery is required in a few cases. PMID- 24486114 TI - [Intestinal microbiota in the critical patient. a positive approach through the contribution of symbiotics]. PMID- 24486115 TI - [Maternal autoimmune thyroid disease: relevance for the newborn]. AB - BACKGROUND AND OBJECTIVE: Autoimmune thyroid disease is amongst the most frequent endocrine disorders during pregnancy. It is associated with an increase in perinatal morbidity, congenital defects, neurological damage, fetal and neonatal thyroid dysfunction. Maternal thyroid hormones play a key role in child neurodevelopment. We aimed to evaluate the thyroid function and the clinical course of neonates born from mothers with autoimmune thyroid disease during the first months of life in order to define the follow-up. PATIENTS AND METHOD: We monitored thyroid function and clinical status during the first months in 81 newborns of mothers with autoimmune thyroid disease; 16 had Graves disease and 65 autoimmune thyroiditis. RESULTS: A percentage of 4.93 newborns had congenital defects, and 8.64% neonates showed an increase in thyrotropin (TSH) (>9.5 MUUI/mL 2 times) and required thyroxin within the first month of life. A 85.7% of these showed a negative newborn screening (due to a later increase of TSH). A higher TSH value in the newborn was related to an older age of the mother, higher levels of thyroid peroxidase (TPO) antibody during pregnancy and lower birth weight. A higher free thyroxine (FT4) value in the newborn was related to fewer days of life and mothers with Graves disease. CONCLUSIONS: We recommend the evaluation of TSH, T4 and TPO antibodies before 10 weeks in all pregnant women with follow-up if maternal thyroid autoimmunity or disorders is detected. It is also recommended to test children's serum TSH and FT4 at 48 h of life in newborns of mothers with autoimmune thyroid disease and repeat them between the 2nd and 4th week in children with TSH>6 MUUI/mL. Careful endocrine follow-up is advised in pregnant women and children if hyperthyroidism is detected. PMID- 24486116 TI - An alternative approach to histopathological validation of PET imaging for radiation therapy image-guidance: a proof of concept. AB - PURPOSE: In radiotherapy, PET images can be used to guide the delivery of selectively escalated doses to biologically relevant tumour subvolumes. Validation of PET for such applications requires demonstration of spatial coincidence between PET tracer uptake pattern and the histopathologically confirmed target. This study introduces a novel approach to histopathological validation of PET image segmentation for radiotherapy guidance. METHODS AND MATERIALS: Sequential tissue sections from surgically excised whole-tumour specimens were used to acquire full 3D-sets of both histopathological images (microscopy) and PET tracer distribution images (autoradiography). After these datasets were accurately registered, a full 3D autoradiographic distribution of PET tracer was reconstructed and used to obtain synthetic PET images (sPET) by simulating the image deterioration induced by processes involved in PET image formation. To illustrate the method, sPET images were used in this study to investigate spatial coincidence between high FDG uptake areas and the distribution of viable tissue in two small animal tumour models. RESULTS: The reconstructed 3D autoradiographic distribution of the PET tracer was spatially coherent, as indicated by the high average value of the normalised pixel-by-pixel correlation of intensities between successive slices (0.84 +/- 0.05 and 0.94 +/- 0.02). The loss of detail in the sPET images versus the 3D autoradiography was significant as indicated by Dice coefficient values corresponding to the two tumours (0 and 0.1 at 70% threshold). The maximum overlap between the FDG segmented volumes and the extent of the viable tissue as indicated by Dice coefficient values, was 0.8 for one tumour (for the image thresholded at 22% of max intensity) and 0.88 for the other (threshold of 14% of max intensity). CONCLUSION: It was demonstrated that the use of synthetic PET images for histopathological validation allows for bypassing a technically challenging and error-prone step of registering non-invasive PET images with histopathology. PMID- 24486117 TI - Prophylactic use of Mepitel Film prevents radiation-induced moist desquamation in an intra-patient randomised controlled clinical trial of 78 breast cancer patients. AB - PURPOSE: Safetac-based soft silicone dressings used in a management setting decrease the severity of radiation-induced acute skin reactions but do not affect moist desquamation rates. Here we investigate the prophylactic use of another Safetac product, Mepitel Film, on moist desquamation rates. MATERIAL AND METHODS: A total of 80 breast cancer patients receiving radiation therapy were recruited between October 2012 and April 2013; 78 participants contributed data for analysis. Lateral and medial halves of the skin areas to be irradiated were randomised to Mepitel Film or aqueous cream; skin dose was measured using thermoluminescent dosimeters; skin reaction severity was assessed using RISRAS and RTOG scales. RESULTS: Overall skin reaction severity was reduced by 92% (p<0.0001) in favour of Mepitel Film (RISRAS). All patients developed some form of reaction in cream-treated skin which progressed to moist desquamation in 26% of patients (RTOG grades I: 28%; IIA: 46%; IIB: 18%; III: 8%). Only 44% of patients had a skin reaction under the Film, which did not progress to moist desquamation in any of the patients (RTOG grades I: 36%; IIA: 8%). CONCLUSIONS: Mepitel Film completely prevented moist desquamation and reduced skin reaction severity by 92% when used prophylactically in our cohort. PMID- 24486118 TI - Social support attenuates the adverse consequences of social deprivation stress in domestic piglets. AB - Social deprivation is a severe stressor affecting a number of behavioral and physiological functions of gregarious species. It is assumed that, dependent upon the level of familiarity, social support given by a conspecific may attenuate the adverse consequences of stress. We investigated the effects of a 4h maternal and littermate deprivation on behavioral reactions, stress hormone responses and brain corticosteroid receptor expression in 7-, 21- and 35-day-old domestic piglets (Sus scrofa) that were left alone or in the presence either of a familiar or unfamiliar age-matched piglet. Compared to control animals, all of the socially deprived piglets showed significant stress responses, such as impaired habituation in repeated open-field/novel-object tests, enhanced ACTH and cortisol release, and altered corticosteroid receptor expression in the hypothalamus. In addition, our results demonstrated that younger piglets had more difficulty coping with stress. The presence of an age-matched conspecific had a direct calming effect on the deprived piglet during the deprivation procedure, which was revealed by diminished stress-induced HPA activity and altered reactions in the behavioral test situations (e.g., activity, escape, and vocalization). Furthermore, because the presence of a familiar piglet causes a more pronounced buffering effect, we have shown for the first time that the degree of familiarity between the piglets may influence the effectiveness of social support. Our study emphasizes the benefits of social partners on positive welfare and the ability for pigs to cope with stress; therefore, our results should be taken into account during handling practices such as weaning and mixing. PMID- 24486119 TI - Diagnosis and classification of adult Still's disease. AB - The cornerstone of adult onset Still's disease is the triad of daily fever, arthritis and rash. This syndrome remains enigmatic and most often a disease of exclusion. There are both musculoskeletal as well as systemic features. More importantly, reactive hemophagocytic syndrome may occur in patients. In this review we attempt to place this syndrome in perspective, including data on geoepidemiology, clinical and laboratory features. PMID- 24486120 TI - The classification and diagnosis of cutaneous lupus erythematosus. AB - Lupus erythematosus (LE) is an inflammatory connective tissue disease of generalized autoimmunity characterized by pathogenic autoantibodies and immune complexes, attributed to loss of immune tolerance. Cutaneous involvement, which appears in the majority of patients with the disease, can present as LE-specific or LE-nonspecific manifestations. The LE-nonspecific manifestations include e.g. vascular skin changes and may be associated with systemic organ manifestations or other autoimmune diseases. In contrast, the LE-specific manifestations encompass the various subtypes of cutaneous lupus erythematosus (CLE), which are classified as separate entities without or with less severe systemic organ involvement. In the "Duesseldorf Classification", CLE is subdivided into four different categories: acute CLE (ACLE), subacute CLE (SCLE), chronic CLE (CCLE), and intermittent CLE (ICLE). Differentiation between these subtypes is based on clinical features and average duration of the cutaneous lesions, but can also consider histological changes of skin biopsy specimens and laboratory abnormalities. In addition, direct immunofluorescence and photoprovocation may be applied to confirm the diagnosis in specific cases. Further investigations should be considered dependent on the clinical symptoms of the CLE patient and the results of the laboratory tests. A revised scoring system, the Cutaneous Lupus Erythematosus Disease Area and Severity Index (RCLASI) has recently been validated to assess disease activity and damage in CLE. In this review, we focus on the classification of CLE and the diagnostic procedures to identify and confirm the different subtypes of the disease. PMID- 24486121 TI - Impact of oncotype DX recurrence score in the management of breast cancer cases. AB - BACKGROUND: Oncologists have used clinicopathologic features to guide treatment decisions for their breast cancer patients; however, more recently, results of multigene assays are also being considered. A popular assay, Oncotype DX (Genomic Health), stratifies node-negative breast cancer patients into groups that are at low, intermediate, or high risk for distant recurrence and guides decisions about adjuvant chemotherapy utilization. OBJECTIVE: We studied the impact of Oncotype DX recurrence score (ODxRS) compared with that of clinicopathologic features on adjuvant chemotherapy utilization in node-negative breast cancer patients and in node-positive breast cancer patients, and we evaluated whether clinicopathologic features impact the decision for adjuvant chemotherapy utilization in a subset of node-negative breast cancer patients with an intermediate-risk ODxRS. METHODS: A retrospective study from a single academic institution was performed on 425 patients with invasive breast carcinoma. RESULTS: Adjuvant chemotherapy utilization most significantly correlated with a high-risk ODxRS (P < .0001) and, to a lesser degree, patient's age and tumor size. No statistically significant association was found between ODxRS and adjuvant chemotherapy utilization in a subset of patients. In the 156 node-negative breast cancer patients with intermediate-risk ODxRS, high tumor grade most significantly correlated with adjuvant chemotherapy utilization (P < .0001). CONCLUSION: ODxRS, if available, heavily impacts adjuvant chemotherapy utilization and more so than any clinicopathologic factor in node-negative breast cancer patients. Node-negative breast cancer patients in the intermediate-risk group whose tumors were high grade were more likely to receive adjuvant chemotherapy. PMID- 24486122 TI - Ultrasonography mapping combined with mammography before breast-conserving surgery for primary breast cancer with microcalcifications: a novel approach. AB - INTRODUCTION: Evaluation for the spread of breast cancer with microcalcifications is challenging, because the microcalcifications sometimes spread beyond the lesions detectable by ultrasonography (US). An original method for preoperative mapping was performed for such lesions, using US in combination with mammography (MG) (US + MG mapping) before breast-conserving surgery (BCS). MATERIALS AND METHODS: A total of 885 consecutive patients underwent BCS for primary breast cancer. Of the 885 patients, 154 (17.4%) with ductal carcinoma in situ or invasive carcinoma having microcalcifications underwent US + MG mapping preoperatively. Five patients who received neoadjuvant chemotherapy and 17 patients who were lost to follow-up were excluded. Accordingly, 133 lesions in 132 patients were retrospectively evaluated. The associations among this method, surgical margin (positive, close, or negative), pathologic characteristics, the area of the lesion within the specimen, and local recurrence rate during 5 years of follow-up were analyzed. RESULTS: The median age and follow-up duration were 51.3 years (range, 28-80 years) and 71.4 months (range, 60-79 months), respectively. The surgical margin was negative in 96 lesions (72.2%), close in 27 lesions (20.3%), and positive in 10 lesions (7.5%). Local recurrence was noted in 1 patient (0.8%). There was no significant association between surgical margin status and the presence of invasive carcinoma. Larger lesion area was significantly associated with positive or close margin (P = .027). CONCLUSION: US + MG mapping is useful and results in a high complete-resection rate and an extremely low 5-year local recurrence rate. PMID- 24486123 TI - Midline versus transverse incision for cesarean delivery in low-income countries. AB - While transverse incision is the recommended entry technique for cesarean delivery in high-income countries, it is our experience that midline incision is still used routinely in many low-income settings. Accordingly, international guidelines lack uniformity on this matter. Although evidence is limited, the literature suggests important advantages of the transverse incision, with lower risk of long-term disabilities such as wound disruption and hernia. Also, potential extra time spent on this incision appears not to impact neonatal outcome. Therefore, we suggest that it is time for a change in guidelines for low income settings in which resources are limited for treating complications that may be life threatening. PMID- 24486124 TI - Safety, efficacy, and prognostic factors in endovascular treatment of pelvic congestion syndrome. AB - OBJECTIVE: To evaluate the safety and effectiveness of transcatheter embolization using coils for treatment of pelvic congestion syndrome (PCS) and to elucidate prognostic factors for clinical success. METHODS: Data were retrospectively analyzed from 113 women with PCS who underwent endovascular embolization of ovarian and pelvic varicose veins at Hospital Clinico Universitario, Zaragoza, Spain between January 2001 and January 2011. Pain score was evaluated before and after the procedure via a visual analog scale (VAS). Associated symptoms (dysmenorrhea, dyspareunia, urinary urgency, and lower limb symptoms) were also evaluated. Patients were followed up for 12 months. RESULTS: The technical and clinical success was 100%. At 12 months, 53% of patients had no pelvic pain and 47% reported a reduction in pelvic pain. The average VAS was 7.34 before the procedure and 0.47 at 12 months. Complete relief of pain and associated symptoms was achieved for 37% of patients. Urinary urgency, lower limb symptoms, and vulvar and lower limbs varicosities were prognostic factors related to incomplete treatment success. The global complication rate was low (5/113, 4.4%). CONCLUSION: Transcatheter embolization was a safe and effective treatment for PCS. Lower limb symptoms, urinary urgency, and varicosities were associated with incomplete clinical success. PMID- 24486125 TI - Prevalence and knowledge of heavy menstrual bleeding among African American women. AB - OBJECTIVE: To assess self-reported prevalence, knowledge, and health literacy regarding heavy menstrual bleeding (HMB) among African American women. METHODS: A quantitative cross-sectional survey study was conducted. An original survey was developed and distributed to a convenience sample of African American women aged 18-60 years at a community fair in a large city in the Midwestern region of the USA. RESULTS: Of the 274 surveys distributed, 247 were returned, 193 of which met the inclusion criteria. Overall, 163 (84.5%) participants demonstrated adequate health literacy; however, 168 (87.0%) answered fewer than 8 of 15 knowledge questions correctly. Although 75 (38.9%) women reported seeing a clinician for HMB, 89 (46.1%) believed that there was nothing that they could do to prevent it from occurring. CONCLUSION: The present study found that the proportion of HMB among participants was higher than the nationwide prevalence. However, a gap existed in knowledge of HMB among the women surveyed. The study findings indicate an opportunity for community-based education to raise awareness of HMB, its associated clinical presentations, and available treatment modalities. PMID- 24486126 TI - Blastomycosis of the head and neck. AB - BACKGROUND: Blastomyces dermatitidis infection of head and neck structures is a rare clinical entity. However, the potential for significant morbidity warrants clinical consideration and timely diagnosis. OBJECTIVE OF REVIEW: To describe the clinical presentations, diagnostic challenges, and outcomes of otolaryngologic blastomycosis. SEARCH STRATEGY: A literature search of the Pubmed and Ovid databases with the terms "blastomycosis AND. . . " followed by all terms related to anatomical regions of the head and neck. EVALUATION METHOD: All publications which discussed pertinent otolaryngologic involvement from blastomycotic infections were evaluated. RESULTS AND CONCLUSION: The larynx was the most commonly reported site of infection, followed by the oral cavity, neck, ear, nasal cavity/paranasal sinuses, and skull base/orbit/calvarium. Diagnosis of blastomycosis was almost universally delayed due to the resemblance of presentation to more common clinical entities, most notably squamous cell carcinoma. A substantial portion of cases (42%) presented without clinical or radiographic evidence of pulmonary infection. The initial diagnostic confusion often resulted in disease progression and trials of invasive therapies. Most patients experienced complete resolution of symptoms and lesions within months of initiation of proper antifungal medications. Permanent sequelae were relatively uncommon and related to the structures involved in the primary infection. PMID- 24486127 TI - Parents' sense of coherence and the adolescent's health and emotional and behavioral adjustment: the case of adolescents with diabetes. AB - INTRODUCTION: This study examines parental sense of coherence (SOC) as a resource to health and well-being among adolescents with diabetes. METHOD: Participants were recruited by the Juvenile Diabetes Research Foundation and a major pediatric diabetes clinic. Parents of 75 adolescents with type 1 diabetes completed the SOC Questionnaire. Parents and adolescents completed questionnaires regarding the child's physical health, disease self-management, and behavioral problems. Parents and physicians reported adolescent's HbA1c level. RESULTS: Results showed that parents' SOC was positively correlated to adolescents' physical health and negatively to internalizing problems. CONCLUSIONS: Findings highlight the place of parents in the wellness of adolescents with disease and provide a basis for interventions that enhance adolescents' health and psychological adjustment. PMID- 24486128 TI - Integration versus disintegration: a grounded theory study of adolescent and young adult development in the context of perinatally-acquired HIV infection. AB - Adolescents/young adults with perinatally-acquired HIV infection experience a number of issues that impact developmental tasks. No study to date has described the process by which this occurs. The purpose of this grounded theory study was to describe the process by which HIV infection impacts adolescent/young adult development. Interviews were conducted and analyzed with 25 participants age 18 to 24. Six core categories emerged that were used to generate a theory, integration versus disintegration, that describes how perinatal HIV impacts participants' development. The results of this study provide unique clinical considerations for pediatric and adult clinicians providing care for this population. PMID- 24486129 TI - Mitochondrial homeostasis: the interplay between mitophagy and mitochondrial biogenesis. AB - Mitochondria are highly dynamic organelles and their proper function is crucial for the maintenance of cellular homeostasis. Mitochondrial biogenesis and mitophagy are two pathways that regulate mitochondrial content and metabolism preserving homeostasis. The tight regulation between these opposing processes is essential for cellular adaptation in response to cellular metabolic state, stress and other intracellular or environmental signals. Interestingly, imbalance between mitochondrial proliferation and degradation process results in progressive development of numerous pathologic conditions. Here we review recent studies that highlight the intricate interplay between mitochondrial biogenesis and mitophagy, mainly focusing on the molecular mechanisms that govern the coordination of these processes and their involvement in age-related pathologies and ageing. PMID- 24486131 TI - Synthesis and receptor binding studies of some new arylcarboxamide derivatives as sigma-1 ligands. AB - We describe here the synthesis and the binding interaction with sigma1 and sigma2 receptors of a series of new arylcarboxamide derivatives variously substituted on the aromatic portions. Maintaining a partial scaffold of a series of compounds previously synthesized by us, we evaluate the effect of the substitution on sigma binding. The synthesized compounds have been tested to estimate their affinity and selectivity toward sigma1 and sigma2 receptors. Two out of 16 derivatives showed an interesting sigma1 affinity (21.2 and 13.6 nM-compounds 2m and 2p) and a good selectivity (Ki(sigma2)/Ki(sigma1) >140 and >40, respectively). PMID- 24486130 TI - Joint inhibition of TOR and JNK pathways interacts to extend the lifespan of Brachionus manjavacas (Rotifera). AB - The TOR kinase pathway is central in modulating aging in a variety of animal models. The target of rapamycin (TOR) integrates a complex network of signals from growth conditions, nutrient availability, energy status, and physiological stresses and matches an organism's growth rate to the resource environment. Important remaining problems are the identification of the pathways that interact with TOR and their characterization as additive or synergistic. One of the most versatile stress sensors in metazoans is the Jun-N-terminal kinase (JNK) signaling pathway. JNK is an evolutionarily conserved stress-activated protein kinase that is induced by a range of stressors, including UV irradiation, reactive oxygen species, DNA damage, heat, and bacterial antigens. JNK is thought to interact with the TOR pathway, but its effects on TOR are poorly understood. We used the rotifer Brachionus manjavacas as a model animal to probe the regulation of TOR and JNK pathways and explore their interaction. The effect of various chemical inhibitors was examined in life table and stressor challenge experiments. A survey of 12 inhibitors revealed two, rapamycin and JNK inhibitor, that significantly extended lifespan of B. manjavacas. At 1 MUM concentration, exposure to rapamycin or JNK inhibitor extended mean rotifer lifespan by 35% and maximum lifespan by 37%. Exposure to both rapamycin and JNK inhibitor simultaneously extended mean rotifer lifespan by 65% more than either alone. Exposure to a combination of rapamycin and JNK inhibitors conveyed greater protection to starvation, UV and osmotic stress than either inhibitor alone. RNAi knockdown of TOR and JNK gene expression was investigated for its ability to extend rotifer lifespan. RNAi knockdown of the TOR gene resulted in 29% extension of the mean lifespan compared to control and knockdown of the JNK gene resulted in 51% mean lifespan extension. In addition to the lifespan, we quantified mitochondria activity using the fluorescent marker MitoTracker and lysosome activity using LysoTracker. Treatment of rotifers with JNK inhibitor enhanced mitochondria activity nearly 3-fold, whereas rapamycin treatment had no significant effect. Treatment of rotifers with rapamycin or JNK inhibitor reduced lysosome activity in 1, 3 and 8 day old animals, but treatment with both inhibitors did not produce any additive effect. We conclude that inhibition of TOR and JNK pathways significantly extends the lifespan of B. manjavacas. These pathways interact so that inhibition of both simultaneously acts additively to extend rotifer lifespan more than the inhibition of either alone. PMID- 24486132 TI - IV. Discovery of CXCR3 antagonists substituted with heterocycles as amide surrogates: improved PK, hERG and metabolic profiles. AB - The structure-human CXCR3 binding affinity relationship of a series of pyridyl/pyrazinyl-piperazinyl-piperidine derivatives were explored with a focus to improve PK, hERG and metabolic profiles. Several small heterocycles were identified as amide surrogates, which minimized many potential metabolite issues. During the course of SAR development, we have observed the additive effect of desirable functional groups to improve hERG and PK profiles which lead to the discovery of many clinically developable CXCR3 antagonists with excellent overall profile. PMID- 24486133 TI - A click chemistry approach to pleuromutilin derivatives. Part 3: extended footprinting analysis and excellent MRSA inhibition for a derivative with an adenine phenyl side chain. AB - Five promising pleuromutilin derivatives from our former studies, all containing adenine on various linkers, were supplemented with two new compounds. The binding to Escherichia coli ribosomes was verified by extensive chemical footprinting analysis. The ability to inhibit bacterial growth was investigated on two Staphylococcus aureus strains and compared to the pleuromutilin drugs tiamulin and valnemulin. Three of the compounds show an effect similar to tiamulin and one compound shows an excellent effect similar to valnemulin. PMID- 24486134 TI - Substituted piperidines as HDM2 inhibitors. AB - Novel small molecule HDM2 inhibitor, substituted piperidine, was identified. Initial SAR study indicated potential for several position optimizations. Additional potency enhancement was achieved by introducing a sidechain off the aromatic ring. DMPK study of one of the active compounds has shown a moderate oral PK and reasonable bioavailability. PMID- 24486135 TI - Whole-organ bioengineering: current tales of modern alchemy. AB - End-stage organ disease affects millions of people around the world, to whom organ transplantation is the only definitive cure available. However, persistent organ shortage and the resulting widespread transplant backlog are part of a disturbing reality and a common burden felt by thousands of patients on waiting lists in almost every country where organ transplants are performed. Several alternatives and potential solutions to this problem have been sought in past decades, but one seems particularly promising now: whole-organ bioengineering. This review describes briefly the evolution of organ transplantation and the development of decellularized organ scaffolds and their application to organ bioengineering. This modern alchemy of generating whole-organ scaffolds and recellularizing them with multiple cell types in perfusion bioreactors is paving the way for a new revolution in transplantation medicine. Furthermore, although the first generation of bioengineered organs still lacks true clinical value, it has created a number of novel tissue and organ model platforms with direct application in other areas of science (eg, developmental biology and stem cell biology, drug discovery, physiology and metabolism). In this review, we describe the current status and numerous applications of whole-organ bioengineering, focusing also on the multiple challenges that researchers have to overcome to translate these novel technologies fully into transplantation medicine. PMID- 24486136 TI - Renal glucuronidation and multidrug resistance protein 2-/ multidrug resistance protein 4-mediated efflux of mycophenolic acid: interaction with cyclosporine and tacrolimus. AB - Mycophenolic acid (MPA) is an immunosuppressant used in transplant rejection, often in combination with cyclosporine (CsA) and tacrolimus (Tac). The drug is cleared predominantly via the kidneys, and 95% of the administered dose appears in urine as 7-hydroxy mycophenolic acid glucuronide (MPAG). The current study was designed to unravel the renal excretory pathway of MPA and MPAG, and their potential drug-drug interactions. The role of multidrug resistance protein (MRP) 2 and MRP4 in MPA disposition was studied using human embryonic kidney 293 (HEK293) cells overexpressing the human transporters, and in isolated, perfused kidneys of Mrp2-deficient rats and Mrp4-deficient mice. Using these models, we identified MPA as substrate of MRP2 and MRP4, whereas its MPAG appeared to be a substrate of MRP2 only. CsA inhibited MPAG transport via MRP2 for 50% at 8 MUM (P < 0.05), whereas Tac had no effect. This was confirmed by cell survival assays, showing a 10-fold increase in MPA cytotoxicity (50% reduction in cell survival changed from 12.2 +/- 0.3 MUM to 1.33 +/- 0.01 MUM by MPA + CsA; P < 0.001) and in perfused kidneys, showing a 50% reduction in MPAG excretion (P < 0.05). The latter effect was observed in Mrp2-deficient animals as well, supporting the importance of Mrp2 in MPAG excretion. CsA, but not Tac, inhibited MPA glucuronidation by rat kidney homogenate and human uridine 5'-diphospho glucuronosyltransferase-glucuronosyltransferase 1A9 (P < 0.05 and P < 0.01, respectively). We conclude that MPA is a substrate of both MRP2 and MRP4, but MRP2 is the main transporter involved in renal MPAG excretion. In conclusion, CsA, but not Tac, influences MPA clearance by inhibiting renal MPA glucuronidation and MRP2-mediated MPAG secretion. PMID- 24486137 TI - 30 Hz theta-burst stimulation over primary somatosensory cortex modulates corticospinal output to the hand. AB - BACKGROUND: The primary somatosensory cortex (SI) is important for hand function and has direct connectivity with the primary motor cortex (M1). Much of our present knowledge of this connectivity and its relevance to hand function is based on animal research. In humans, less is known about the neural mechanisms by which SI influences motor circuitry that outputs to the muscles controlling the hand. OBJECTIVE: The present study investigated the influence of SI on corticospinal excitability, and inhibitory and excitatory intracortical neural circuitry within M1 before and after continuous theta-burst stimulation (cTBS). Motor-evoked potentials (MEPs), short-latency intracortical inhibition (SICI) and intracortical facilitation (ICF) were recorded from the first dorsal interosseous (RFDI) muscle of the right hand following 30 Hz cTBS over left-hemisphere SI and M1 delivered in separate sessions. RESULTS: cTBS over SI facilitated MEPs and did not alter ICF or SICI. cTBS delivered over M1 suppressed MEPs and ICF and did not alter SICI. CONCLUSIONS: These findings indicate that SI influences corticospinal output to the hand, possibly via corticocortical projections, and may be one mechanism by which somatosensory information influences hand control. PMID- 24486138 TI - Afferent inhibition of infraspinatus primary motor cortex by stimulation of the suprascapular nerve. PMID- 24486139 TI - Multiple pathways are involved in palmitic acid-induced toxicity. AB - In this study, we identified the toxic mechanism following the accumulation of palmitic acid (PA), a saturated fatty acid, in human Chang liver cells. After PA exposure for 24 h, the mitochondria and the endoplasmic reticulum (ER) became dilated, and lipid droplets and organelles were observed within autophagosomes. Cell viability decreased with an ATP reduction and the G2/M phase arrest. The expression of SOD-2, but not of SOD-1, markedly increased after PA exposure, which also elevated the number of cells generating ROS. PA enhanced the levels of proteins related to apoptosis, necroptosis, autophagy, and ER stress. Moreover, the inhibition of caspases, p53, necroptosis, or ER stress substantially rescued PA-induced cytotoxicity and, similarly, the inhibition of caspases and ER stress counteracted PA-induced changes in the cell cycle. Conversely, the inhibition of necroptosis and p53 signaling accelerated the changes in the cell cycle triggered by PA exposure. Blocking autophagy exacerbated PA-induced cytotoxicity and alterations in the cell cycle and caused disappearance of cellular components. These results suggest that PA induces apoptosis accompanied by autophagy through mitochondrial dysfunction and ER stress, which are triggered by oxidative stress in Chang liver cells and that blocking autophagy accelerates cell damage following PA exposure. PMID- 24486140 TI - An impedance-based cytotoxicity assay for real-time and label-free assessment of T-cell-mediated killing of adherent cells. AB - The in vitro assessment of T-cell-mediated cytotoxicity plays an important and increasingly relevant role both in preclinical target evaluation and during immunomonitoring to accompany clinical trials employing targeted immunotherapies. For a long time, the gold standard for this purpose has been the chromium release assay (CRA). This end point assay, however, shows several disadvantages including the inevitable use of radioactivity. Based on electrical impedance measurements (using the xCELLigence system), we have established a label-free assay, facilitating the real-time monitoring of T-cell-mediated cytotoxicity. The coculture of peptide-specific T-cell lines with peptide-loaded target cells reproducibly led to a decrease in impedance due to induced apoptosis and detachment of target cells. Comparing our results to the standard CRA assay, we could demonstrate that impedance-based measurements show comparable results after short incubation periods (6h) but outperform the CRA both in reproducibility and sensitivity after prolonged incubation (24h), enabling the detection of target cell lysis with an effector to target ratio as low as 0.05:1. The impedance-based assay represents a valuable and highly sensitive tool for label-free real-time high throughput analysis of T-cell-mediated cytotoxicity. PMID- 24486141 TI - Beyond a motor disorder: a prospective evaluation of sleep quality in cervical dystonia. AB - BACKGROUND: Little is known about sleep disturbances in cervical dystonia (CD), particularly the relationship to motoric symptoms. It is critical to clarify these points given the impact on quality of life. METHODS: Primary CD patients receiving botulinum toxin (BoNT) injections and age- and gender- matched healthy controls were included. In both groups, sleep quality and daytime sleepiness were assessed. In CD, these assessments were repeated following BoNT injections. CD severity, mood symptoms, and health impact of CD were also assessed. RESULTS: 54 CD patients and 55 controls were included. Impaired sleep quality was more frequent in CD compared to controls (t = 4.82, p < 0.0005), even when controlling for the effects of depression, anxiety, and benzodiazepineuse (F = 5.62, p = 0.020). Excessive daytime sleepiness was not significantly different between groups (t = 1.67, p = 0.1). 48 patients received BoNT and returned for follow-up. There was no improvement in sleep quality (t = 0.834, p = 0.41) or daytime somnolence (t = 1.77, p = 0.083) despite improvement in CD severity (t = 4.77, p < 0.0005) with BoNT. There was a small improvement in health impact (t = 2.10, p = 0.04). CONCLUSION: Sleep quality was more impaired in CD patients, compared to healthy subjects, and did not improve following BoNT treatment, despite a robust improvement in CD severity. This dichotomy suggests that sleep aberrations in CD require separate focus for effective treatment and cannot be viewed as secondary complications of the motor elements of this condition. PMID- 24486142 TI - Alcohol consumption and mortality: a dose-response analysis in terms of time. AB - PURPOSE: Low-to-moderate alcohol consumption is associated with decreased mortality. However, many aspects of this association are still debated. Our aim was to complement available information by conducting a dose-response analysis of the association between alcohol consumption and survival time. METHODS: In a Swedish population-based cohort of 67,706 middle-aged and elderly men and women, frequency and amount of drinking were assessed through a self-administrated questionnaire. During 15 years of follow-up, 13,323 participants died. Differences in survival (10th percentile differences, PDs) according to levels of alcohol consumption were estimated using Laplace regression. RESULTS: We found evidence of nonlinearity between alcohol consumption and survival. Among women, we observed a rapid increase in survival up to 6 g/d of alcohol consumption (0.5 drinks/d) where survival was 17 months longer (PD = 17 months, 95% confidence interval, 10 to 24). After this peak, higher alcohol consumption was progressively associated with shorter survival. Among men, survival improved up to 15 g/d (1.5 drinks/d) where we observed a PD of 15 months (95% confidence interval, 8 to 22). CONCLUSIONS: Low alcohol consumption was associated with improved survival up to 1.5 years for women with an average consumption of 0.5 drinks per day and to 1.3 years for men with an average consumption of 1.5 drinks per day. PMID- 24486143 TI - Glucose metabolic gene expression in growth hormone transgenic coho salmon. AB - Salmonids are generally known to be glucose intolerant. However, previous studies have shown that growth hormone (GH) transgenic coho salmon display modified nutritional regulation of glycolysis and lipogenesis compared to non-transgenic fish, suggesting the potential for better use of glucose in GH transgenic fish. To examine this in detail, GH transgenic and non-transgenic coho salmon were subjected to glucose tolerance test and subsequent metabolic assessments. After intra-peritoneal injection of 250mg/kg glucose, we analysed post-injection kinetics of glycaemia and expression of several key target genes highly involved in glucose homeostasis in muscle and liver tissues. Our data show no significant differences in plasma glucose levels during peak hyperglycaemia (3-6h after injection), demonstrating a similar glucose tolerance between transgenic and non transgenic. However, and unrelated to the hyperglycaemic episode, GH transgenic fish return to a slightly lower basal glycaemia values 24h after injection. Correspondingly, GH transgenic fish exhibited higher mRNA levels of glucokinase (GK) and glucose-6-phosphate dehydrogenase (G6PDH) in liver, and glucose transporter (GLUT4) in muscle. These data suggest that these metabolic actors may be involved in different glucose use in GH transgenic fish, which would be expected to influence the glucose challenge response. Overall, our data demonstrate that GH transgenic coho salmon may be a pertinent animal model for further study of glucose metabolism in carnivorous fish. PMID- 24486145 TI - Adiponectin: A multitasking player in the field of liver diseases. AB - Adiponectin is the most abundant adipokine synthesized by adipose tissue and has been shown to be a key component in the relationship between adiposity, insulin resistance and inflammation. It circulates in plasma at physiological concentrations that represent 0.05% of all plasma proteins. Adiponectin has trimeric, hexameric and multimeric forms that bind to receptors AdipoR1, AdipoR2 and T-cadherin especially in liver, muscle and endothelial cells. Adiponectin is considered a potent modulator of lipid and glucose metabolism with antidiabetic, antiatherogenic and anti-inflammatory properties, and plays an important role in the pathogenesis of metabolic diseases. The hepatoprotective effects of adiponectin, especially in non-alcoholic fatty liver disease (NAFLD), have been widely investigated, and its antisteatotic, anti-inflammatory and antifibrogenic effects have already been described. Adiponectin levels are reduced in individuals with fatty liver disease independently of body mass index, insulin resistance and other adipokines, and are inversely related to the severity of steatosis and necroinflammation, suggesting an important role in the relationship between adipose tissue, the liver and insulin sensitivity. Adiponectin has also been found to be reduced in cases of hepatitis B and C infection, and in cholestatic and autoimmune diseases, but is increased in patients with cirrhosis of different aetiologies. In addition, an important role for the liver in the regulation of adiponectin secretion by adipocytes, mediated by bile acids, has recently been proposed. The present report describes the importance of adiponectin in hepatic diseases as well as some future perspectives of the role of adiponectin as a biomarker and therapeutic target in liver diseases. PMID- 24486144 TI - Resting EEG in psychosis and at-risk populations--a possible endophenotype? AB - BACKGROUND: Finding reliable endophenotypes for psychosis could lead to an improved understanding of aetiology, and provide useful alternative phenotypes for genetic association studies. Resting quantitative electroencephalography (QEEG) activity has been shown to be heritable and reliable over time. However, QEEG research in patients with psychosis has shown inconsistent and even contradictory findings, and studies of at-risk populations are scarce. Hence, this study aimed to investigate whether resting QEEG activity represents a candidate endophenotype for psychosis. METHOD: QEEG activity at rest was compared in four frequency bands (delta, theta, alpha, and beta), between chronic patients with psychosis (N=48), first episode patients (N=46), at-risk populations ("at risk mental state", N=33; healthy relatives of patients, N=45), and healthy controls (N=107). RESULTS: Results showed that chronic patients had significantly increased resting QEEG amplitudes in delta and theta frequencies compared to healthy controls. However, first episode patients and at-risk populations did not differ from controls in these frequency bands. There were no group differences in alpha or beta frequency bands. CONCLUSION: Since no abnormalities were found in first episode patients, ARMS, or healthy relatives, resting QEEG activity in the frequency bands examined is unlikely to be related to genetic predisposition to psychosis. Rather than endophenotypes, the low frequency abnormalities observed in chronic patients are probably related to illness progression and/or to the long-term effects of treatments. PMID- 24486146 TI - [Lupus vulgaris tumor nickname of the forearm]. PMID- 24486147 TI - Des-acyl ghrelin protects microvascular endothelial cells from oxidative stress induced apoptosis through sirtuin 1 signaling pathway. AB - OBJECTIVE: Ghrelin is a stomach-derived hormone. Acylation of ghrelin has been essential for its biological activities such as stimulating appetite. On the other hand, the function of des-acyl ghrelin (Des-G) has not been fully elucidated. The aim of the present study is to examine the anti-apoptotic effect of Des-G on endothelial cells. MATERIALS/METHODS: After human retinal microvascular endothelial cells (RMECs) were pretreated with or without 100nmol/L Des-G, apoptosis was induced with 0.1mmol/L hydrogen peroxide (H2O2). For pharmacological inhibition of surtuin 1 (SIRT1) catalytic activity, the cells were treated with 10MUmol/L Ex-527. Inhibition of SIRT1 with siRNA was also performed. The quantitative estimation of DNA fragmentation was used as a marker of apoptosis. Furthermore, total SIRT activity in nuclear extracts, mRNA and protein levels of SIRT1, manganese superoxide dismutase (MnSOD) and catalase were determined. RESULTS: Des-G pretreatment protected RMECs from oxidative stress induced apoptosis and increased SIRTs deacetylase activity in nuclear extracts. On the other hand, both pharmacological and siRNA mediated inhibition of SIRT1 attenuated the anti-apoptotic effect of Des-G. Moreover, Des-G increased mRNA and protein levels of SIRT1 and antioxidant enzymes such as MnSOD and CAT, which are downstream targets of SIRT1. Although the treatment of Ex-527 did not alter mRNA expression levels of SIRT1, it decreased mRNA expression levels of antioxidant enzymes in the cells with Des-G pretreatment. CONCLUSIONS: Our results suggest that SIRT1 signaling pathway contributes to protective effect of Des-G against oxidative stress-induced apoptosis. PMID- 24486148 TI - The periosteal pulley technique for orbital fat realignment and correction of nasojugal groove in lower lid blepharoplasty. AB - BACKGROUND: Removal of orbital fat in lower lid blepharoplasty has been widely replaced by fat realignment over the orbital rim. However, incomplete correction or recurrence of fat bulging is still common compared to a simple fat removal procedure due to improper transfer and fixation of fat over the orbital rim. The authors present a novel technique of orbital fat transfer under the periosteal strip to secure the fat along the orbital rim and prevent recurrence of fat bulging from reherniation. METHODS: Of the patients who underwent lower blepharoplasties using the periosteal pulley technique during January 2010 to September 2012, 115 were included in this prospective uncontrolled clinical trial. There were 107 females and eight males. The follow-up period ranged from 6 months to 2 years (average 1 year). The results on the last follow-up were categorised into four grades: excellent, good, fair and poor. RESULT: Of the 115 patients, 10, 81 and 24 patients achieved excellent, good and fair results, respectively. We have three cases of temporary lower lid retraction or ectropion that developed 1 month after surgery and were resolved within 3-4 months. No revision surgery is needed. CONCLUSION: We propose the periosteal pulley technique as an alternative way of orbital fat transfer in lower lid blepharoplasty. This technique can provide a secure fixation of fat that not only corrects the nasojugal groove but also prevents further herniation of the remaining fat. PMID- 24486149 TI - The reduced work hours debate in general plastic surgery journals. PMID- 24486150 TI - Pinnaplasty: a porcine training model. PMID- 24486151 TI - Patient-centred decision making in breast reconstruction utilising the delayed immediate algorithm. AB - Delayed-immediate reconstruction is an increasingly valuable algorithm for patients anticipating post-mastectomy radiation therapy. Despite the cosmetic and long-term advantages of autologous tissue repair, a subset of patients choose implant-based reconstruction after their initial preference for autologous reconstruction. A critical evaluation of patients who initially planned to undergo delayed-immediate reconstruction but later chose to continue with implant based reconstruction has not been previously reported. A retrospective analysis of the senior author's (M.Y.N.) patients who initially intended to undergo delayed-immediate autologous breast reconstruction following mastectomy and chose to abandon autologous reconstruction in favour of prosthetic reconstruction was completed from 2005 to 2011. Seven patients (10 breasts) met inclusion criteria. The mean patient age and body mass index were 50.2 years and 32.1 kg m(-2), respectively. Expansion required an average of 4.4 office visits to achieve adequate expansion volume, mean 483 ml (240-600 ml). The mean time from expander placement to definitive reconstruction was 14.6 months. Mean follow-up time was 20.4 months. Complications included infection (1/7), incisional dehiscence (1/7) and capsular contracture (2/7), and late revision surgery was performed in two patients. Successful reconstruction was achieved in 100% of patients (7/7) with a patient-reported satisfaction of 100%. Patient motivations for changing the reconstructive algorithm included a faster post-operative recovery in four patients (4/7) and potential donor-site morbidity in three patients (3/7). Depression or cancer-related fatigue symptoms were self-reported in 4/7. Avoiding donor-site morbidity and a simpler recovery are the main factors that influence patients to change their desire for autologous reconstruction to an implant-based reconstruction. Cancer-related fatigue and depression are prevalent in this population and may be implicated in a patient's desire to undergo less extensive reconstructive surgery. Allowing for the choice of definitive implant-based reconstruction in select patients is safe and is likely to result in high patient satisfaction with satisfactory aesthetic outcomes. PMID- 24486152 TI - A single-centre cost comparison analysis of collagenase injection versus surgical fasciectomy for Dupuytren's contracture of the hand. AB - BACKGROUND AND AIM: The options for treating patients with Dupuytren's contracture have broadened with the introduction of collagenase. Although the literature would suggest that collagenase treatment is effective, has few complications and is popular with patients, it has not been widely commissioned by the National Health Services of the United Kingdom and other European countries due to concerns about cost. The aim of this study was to compare the cost of surgical fasciectomy to collagenase injections for the treatment of Dupuytren's contracture in a single centre. METHOD: Prospective data on 40 patients undergoing fasciectomy or collagenase injection (20 patients in each group) were collected between January and March 2013. Financial data on the costs of the procedures, equipment, theatre time and follow-up appointments were calculated. RESULTS: The average cost of an open partial fasciectomy pathway was L 7115.34 and that of a collagenase pathway was L 2110.62. Eight collagenase patients had physician-led follow-up appointments and only three had hand physiotherapy appointments. By contrast, every fasciectomy patient had at least one physician and one physiotherapist follow-up appointment routinely. CONCLUSION: The results of this study demonstrate that collagenase treatment for Dupuytren's contracture of a single digit in selected patients is just over L 5000 less than treatment for the same condition using surgical fasciectomy. Collagenase-treated patients require much less physician- and physiotherapist-led postoperative follow-up. PMID- 24486153 TI - Microtubule minus-end stabilization by polymerization-driven CAMSAP deposition. AB - Microtubules are cytoskeletal polymers with two structurally and functionally distinct ends, the plus- and the minus-end. Here, we focus on the mechanisms underlying the regulation of microtubule minus-ends by the CAMSAP/Nezha/Patronin protein family. We show that CAMSAP2 is required for the proper organization and stabilization of interphase microtubules and directional cell migration. By combining live-cell imaging and in vitro reconstitution of microtubule assembly from purified components with laser microsurgery, we demonstrate that CAMSAPs regulate microtubule minus-end growth and are specifically deposited on the lattice formed by microtubule minus-end polymerization. This process leads to the formation of CAMSAP-decorated microtubule stretches, which are stabilized from both ends and serve as sites of noncentrosomal microtubule outgrowth. The length of the stretches is regulated by the microtubule-severing protein katanin, which interacts with CAMSAPs. Our data thus indicate that microtubule minus-end assembly drives the stabilization of noncentrosomal microtubules and that katanin regulates this process. PMID- 24486154 TI - Mitochondrial ROS regulates cytoskeletal and mitochondrial remodeling to tune cell and tissue dynamics in a model for wound healing. AB - How cues that trigger the wound response result in tissue healing is a question of immense biological and medical importance. Here we uncover roles for mitochondrial reactive oxygen species (mtROS) during Drosophila dorsal closure, a model for wound healing. By using real-time visualization of ROS activity and single-cell perturbation strategies, we demonstrate that stochasticities in ROS generation in the amnioserosa are necessary and sufficient to trigger cell delamination. We identify dose-dependent effects of mtROS on actomyosin and mitochondrial architecture, dynamics, and activity that mediate both stochasticities in cell behavior and the phases of tissue dynamics accompanying dorsal closure. Our results establish that ROS levels tune cell behavior and tissue dynamics qualitatively and quantitatively. They identify a pathway triggered by ROS and mediated by the Rho effector ROCK and its substrates that influences tissue patterning and homeostasis through the coordinate regulation of both mitochondrial morphology and tissue tension. PMID- 24486156 TI - Posterior interosseus nerve palsy resulting from inflammatory myofibroblastic pseudotumor: case presentation. AB - Local compression by a mass lesion is a potential cause of posterior interosseous nerve (PIN) palsy. Reported cases of PIN pathology do not include inflammatory myofibroblastic pseudotumor. We report the case of a 44-year-old woman with a 3 month history of progressive weakness of the left finger extensors. Sonographic imaging identified a mass compressing the PIN, and histologic examination of the specimen revealed an inflammatory myofibroblastic pseudotumor. Complete resection of the mass while sparing the nerve was possible, and the patient has regained functional use of the left hand. The differential diagnosis of PIN palsy should include inflammatory myofibroblastic pseudotumor. PMID- 24486155 TI - Oxidative stress resulting from exposure of a human salivary gland cells to paraoxon: an in vitro model for organophosphate oral exposure. AB - Organophosphate (OP) compounds are used as insecticides, acaricides, and chemical agents and share a common neurotoxic mechanism of action. The biochemical alterations leading to many of the deleterious effects have been studied in neuronal cell lines, however, non-neuronal toxic effects of OPs are far less well characterized in vitro, and specifically in cell lines representing oral routes of exposure. To address this void, the human salivary gland (HSG) cell line, representing likely interactions in the oral cavity, was exposed to the representative OP paraoxon (PX; O,O-diethyl-p-nitrophenoxy phosphate) over a range of concentrations (0.01-100 MUM) and analyzed for cytotoxicity. PX induced cytotoxicity in HSG cells at most of the exposure concentrations as revealed by MTT assay, however, the release of LDH only occurred at the highest concentration of PX tested (100 MUM) at 48 h. Slight increases in cellular ATP levels were measured in PX-exposed (10 MUM) HSG cells at 24 h. Exposing HSG cells to 10 MUM PX also led to an increase in DNA fragmentation prior to loss of cellular membrane integrity implicating reactive oxygen species (ROS) as a trigger of toxicity. The ROS genes gss, gstm2, gstt2 and sod2 were upregulated, and the presence of superoxide following 10 MUM PX exposure was determined via dihydroethidium fluorescence studies further implicating PX-induced oxidative stress in HSG cells. PMID- 24486157 TI - Septic bursitis after ultrasound-guided percutaneous treatment of rotator cuff calcific tendinopathy. AB - Calcific tendinopathy of the rotator cuff is a common condition. Ultrasound guided percutaneous aspiration is one of several options to treat this condition. The main advantages of this procedure are short duration, good outcome, and low cost. Furthermore, only minor complications have been reported in the literature, namely, vagal reactions during the procedure and mild postprocedural pain. We report the first case of septic bursitis after ultrasound-guided percutaneous treatment of calcific tendinopathy. Although this is generally considered a very safe procedure, a risk of infection should be taken into account. PMID- 24486159 TI - Three-dimensional prediction of the nose for facial reconstruction using cone beam computed tomography. AB - The identification of interrelationship between the hard and soft tissues of the face is mandatory for facial reconstruction. The aim of this study was to investigate the relationship between the hard and soft dimensions of the nose and to predict the position of the nose using cone-beam computed tomography (CBCT) scans obtained from 60 adults. Three-dimensional placements of the nasal soft structures (pronasale, subnasale, ala) from the nasal hard structures (nasal bone, nasal cavity) were measured in order to compute the regression equations to find the most probable position of the pronasale, subnasale, and ala. The positions of the pronasale, subnasale, and ala can be predicted using the regression models. These results suggest that hard and soft tissue relation data from CBCT can be useful for predicting the position of nose. PMID- 24486160 TI - Nurses perceptions of sleep in the intensive care unit environment: a literature review. AB - OBJECTIVES: Sleep deprivation within intensive care units (ICU) remains a recurring norm despite the extensive research highlighting a crucial need for sleep promotion. However, the degree to which sleep deprivation can be associated with the nurses' provision of care remains unclear. Therefore, this critical literature review aims to explore the nurses' knowledge and prioritisation of sleep whilst examining the nurses' use of sleep assessment skills and tools. The nurses' awareness and prioritisation of sleep promoting interventions and complimentary therapies will also be analysed. METHODS: The online databases Cochrane, CINAHL and Science Direct were searched for English language articles, published between 2003 and 2013 which were downloadable in full text format. A total of 378 articles were identified and 25 papers met all the inclusion criteria. CONCLUSIONS: It appears that ICU nurses lack a complex understanding of the importance of sleep and the interventions needed to promote it. Indeed, studies suggest that inattention to sufficient training and a lack of structured protocol within practice makes the provision of sleep for the ICU patient impossible. Therefore, whilst further empirical research is required it may be noted that evidence informed education programmes and sleep assessment tools require development within the ICU environment. PMID- 24486158 TI - Developmental cigarette smoke exposure: hippocampus proteome and metabolome profiles in low birth weight pups. AB - Exposure to cigarette smoke during development is linked to neurodevelopmental delays and cognitive impairment including impulsivity, attention deficit disorder, and lower IQ. However, brain region specific biomolecular alterations induced by developmental cigarette smoke exposure (CSE) remain largely unexplored. In the current molecular phenotyping study, a mouse model of 'active' developmental CSE (serum cotinine > 50 ng/mL) spanning pre-implantation through third trimester-equivalent brain development (gestational day (GD) 1 through postnatal day (PD) 21) was utilized. Hippocampus tissue collected at the time of cessation of exposure was processed for gel-based proteomic and non-targeted metabolomic profiling with partial least squares-discriminant analysis (PLS-DA) for selection of features of interest. Ingenuity pathway analysis was utilized to identify candidate molecular and metabolic pathways impacted within the hippocampus. CSE impacted glycolysis, oxidative phosphorylation, fatty acid metabolism, and neurodevelopment pathways within the developing hippocampus. PMID- 24486161 TI - RANKL/RANK - from bone physiology to breast cancer. AB - RANK and its ligand RANKL are key molecules in bone metabolism and are critically involved in pathologic bone disorders. Deregulation of the RANK/RANKL system is for example a main reason for the development of postmenopausal osteoporosis, which affects millions of women worldwide. Another essential function of RANK and RANKL is the development of a functional lactating mammary gland during pregnancy. Sex hormones, in particular progesterone, induce RANKL expression resulting in proliferation of mammary epithelial cells. Moreover, RANK and RANKL have been shown to regulate mammary epithelial stem cells. RANK and RANKL were also identified as critical mechanism in the development of hormone-induced breast cancer and metastatic spread to bone. In this review, we will focus on the various RANK/RANKL functions ranging from bone physiology, immune regulation, and initiation of breast cancer. PMID- 24486162 TI - First evidence of the use of olfaction in Odonata behaviour. AB - Dragonflies and damselflies are among the most ancient winged insects. Adults belonging to this order are visually oriented and are considered anosmic on the basis of neuroanatomical investigations. As a consequence, the chemical ecology of these predatory insects has long been neglected. Morphological and electrophysiological data demonstrated that dragonfly antennae possess olfactory sensilla. Additionally, a neuroanatomical study revealed the presence of spherical knots in the aglomerular antennal lobe that could allow for the perception of odour. However, the biological role of the antennal olfactory sensilla remains unknown, and no bioassay showing the use of olfaction in Odonata has been performed thus far. Here, we demonstrate through behavioural assays that adults of Ischnura elegans are attracted by olfactory cues emitted by prey; furthermore, using electrophysiological single-cell recordings, we prove that the antennal olfactory sensilla of I. elegans respond to prey odour. Our results clearly demonstrate the involvement of antennal olfactory sensilla in Odonata predation, thus showing, for the first time, the use of olfaction in Odonata biology. This finding indicates that the nervous system of Odonata is able to receive and process olfactory information, suggesting that the simple organisation of the antennal lobe does not prevent the use of olfaction in insects. PMID- 24486163 TI - Informal caregiver strain, preference and satisfaction in hospital-at-home and usual hospital care for COPD exacerbations: results of a randomised controlled trial. AB - BACKGROUND: Informal caregivers play an important role in hospital-at-home schemes. However they may increase their burden, especially chronic diseases, like COPD. In the absence of clear differences in effectiveness and cost effectiveness between hospital-at-home and usual hospital care, informal caregiver preferences play an important role. This study investigated informal caregiver strain, satisfaction and preferences for place of treatment with a community-based hospital-at-homes scheme for COPD exacerbations. METHOD: The study was part of a larger randomised controlled trial. By randomisation, patients were allocated to usual hospital care or hospital-at-home, which included discharge at day 4 of admission, followed by home treatment with homes visits by community nurses until day 7 of treatment. Patients allocated to usual hospital care received care as usual in the hospital and were discharged at day 7. Patients were asked if they had an informal caregiver and who this was. Patients and their caregivers were followed for 90 days. Informal caregiver strain was assessed with the caregiver strain index. Satisfaction and preference were assessed using questionnaires. All measurements were performed at the end of the 7-day treatment and the end of the 90-days follow-up. FINDINGS: Of the 139 patients, 124 had an informal caregiver, of whom three-quarter was the patients' spouse. There was no significant difference in caregiver strain between hospital at-home and usual hospital care at both time points (mean difference at T+4 days 0.47 95% CI -0.96 to 1.91, p=0.514; mean difference at T+90 days 0.36 95% CI 1.85 to 1.35, p=0.634). At the end of the 7-day treatment, 33% (N=15) of caregivers of patients allocated to hospital treatment and 71% (N=37) of caregivers of patients allocated to home treatment preferred home treatment, if they could choose. Caregivers were satisfied with the treatment the patient received within hospital-at-home. CONCLUSION: There were no differences in caregiver strain between the community-based hospital-at-home scheme and usual hospital care. Most caregivers were satisfied with the treatment. In addition to other outcomes, our results support the wider implementation of hospital-at-home for COPD exacerbations. PMID- 24486164 TI - Exploring new graduate nurse confidence in interprofessional collaboration: a mixed methods study. AB - BACKGROUND: Confidence is required for effective engagement in interprofessional collaboration. New graduate nurses often lack confidence in interprofessional interactions, and this may compromise the delivery of safe and effective healthcare. OBJECTIVES: The overall objective of this study was to explore new graduate nurse confidence in interprofessional collaboration. DESIGN: An explanatory sequential mixed methods design was used. METHODS: New graduate nurses from Ontario, Canada (N=514) completed a cross-sectional descriptive survey in 2012. The survey measured perceived confidence in interprofessional collaboration, and it included items that were proposed to have a relationship with new graduate nurse confidence in interprofessional collaboration. Follow-up qualitative telephone interviews were conducted with 16 new graduate nurses. RESULTS: The quantitative findings suggested that several factors have a positive relationship with new graduate nurse confidence in interprofessional collaboration: availability and accessibility of manager, availability and accessibility of educator, number of different disciplines worked with daily, number of team strategies, and satisfaction with team. The qualitative phase supported the quantitative findings and also provided new information about factors that facilitated and challenged new graduate nurse confidence when engaging in interprofessional collaboration. The facilitators were: experience, knowledge, respect, supportive relationships, and opportunities to collaborate. Challenges included: lack of experience, lack of knowledge, communication challenges, and balancing practice expectations. The overall findings relate to team and organizational support, and new graduate nurse development. CONCLUSION: Interventions that provide support for interprofessional collaboration at the team and organizational levels, and develop new graduate nurse knowledge and experiences regarding collaborative practice, are essential for enhancing new graduate nurse confidence in interprofessional collaboration. PMID- 24486165 TI - Frailty and outcomes after implantation of left ventricular assist device as destination therapy. AB - BACKGROUND: Frailty is recognized as a major prognostic indicator in heart failure. There has been interest in understanding whether pre-operative frailty is associated with worse outcomes after implantation of a left ventricular assist device (LVAD) as destination therapy. METHODS: Patients undergoing LVAD implantation as destination therapy at the Mayo Clinic, Rochester, Minnesota, from February 2007 to June 2012, were included in this study. Frailty was assessed using the deficit index (31 impairments, disabilities and comorbidities) and defined as the proportion of deficits present. We divided patients based on tertiles of the deficit index (>0.32 = frail, 0.23 to 0.32 = intermediate frail, <0.23 = not frail). Cox proportional hazard regression models were used to examine the association between frailty and death. Patients were censored at death or last follow-up through October 2013. RESULTS: Among 99 patients (mean age 65 years, 18% female, 55% with ischemic heart failure), the deficit index ranged from 0.10 to 0.65 (mean 0.29). After a mean follow-up of 1.9 +/- 1.6 years, 79% of the patients had been rehospitalized (range 0 to 17 hospitalizations, median 1 per person) and 45% had died. Compared with those who were not frail, patients who were intermediate frail (adjusted HR 1.70, 95% CI 0.71 to 4.31) and frail (HR 3.08, 95% CI 1.40 to 7.48) were at increased risk for death (p for trend = 0.004). The mean (SD) number of days alive out of hospital the first year after LVAD was 293 (107) for not frail, 266 (134) for intermediate frail and 250 (132) for frail patients. CONCLUSIONS: Frailty before destination LVAD implantation is associated with increased risk of death and may represent a significant patient selection consideration. PMID- 24486166 TI - Corynebacterium propinquum as the first cause of infective endocarditis in childhood. AB - We here present a 7-year-old girl with ventricular septum defect and ventriculoatrial communication, who developed infective endocarditis (IE) due to Corynebacterium propinquum in the tricuspid valve. The patient was admitted because of an 8-day history of fever. Transthoracic echocardiogram showed non pedunculated vegetation on the septal leaflet of the tricuspid valve. Gram positive coryneform bacteria grew from three consecutive sets of blood cultures taken on admission. C. propinquum was confirmed by 3 microbiological approaches; (i) biochemical testing using API Coryne panels, (ii) a sequence-based method using the 16S rRNA gene and partial rpoB sequencing, and (iii) matrix-assisted laser desorption ionization-time of flight mass spectrometry. The isolates were susceptible to a wide variety of beta-lactams and vancomycin. The patient was successfully treated with antimicrobial agents without surgical intervention. There have only been available of clinical details of two adult cases of invasive C. propinquum infections; one of which was presented as IE, and the other was pleuritis in a patient with lung cancer. To the best of our knowledge, this is the first report to describe C. propinquum as a cause of IE as well as that of invasive infections in a pediatric population. Multiple methods that reliably differentiated related species helped us to establish this rare organism. Our report expanded the clinical spectrum of C. propinquum infections. PMID- 24486167 TI - The duration of fever and other symptoms after the initiation of laninamivir octanoate hydrate in the Japanese 2011-2012 influenza season. AB - Laninamivir octanoate hydrate (laninamivir) is a long-acting, single inhalation neuraminidase inhibitor that was approved in Japan in 2010 for the treatment of influenza A and B virus infection. We investigated the duration of fever and other symptoms after the initiation of laninamivir in the Japanese 2011-2012 influenza season. Virus isolation was done and the 50% inhibitory concentration (IC50) was measured for the virus isolates at days 1 and 5. For 211 patients (A(H3N2): 190, B: 21), the median durations of fever of A(H3N2) and B patients were 33.0 and 50.0 h, respectively (p = 0.0989). Fever was resolved within 72 h after inhalation by 89.7% of the A(H3N2) patients and by 81.0% of the patients with B. The median durations of symptoms for A(H3N2) and B patients were 89.0 and 94.0 h, respectively (p = 0.5809). On day 5, the influenza virus-positive rates for A(H3N2) and B patients were significantly different: 25.8% (40/155) and 70.6% (12/17), respectively (p < 0.0001). No significant change in IC50 value was found between day 1 and day 5 for any of the four tested neuraminidase inhibitors, and no IC50 value exceeded 50 nM. The incidence of adverse drug reactions was 1.3% (3/234), with no serious reactions reported. These results show that laninamivir was effective for the treatment of both influenza A(H3N2) and B in this study, with no safety issues. The clinical effectiveness of laninamivir for A(H3N2) was superior to that for B. PMID- 24486168 TI - Clinical practice guidelines for therapeutic drug monitoring of arbekacin: a consensus review of the Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring. AB - Arbekacin (ABK) was approved and widely used in Japan for treatment of patients infected with MRSA, and TDM was introduced in clinical practice. The Japanese Society of Chemotherapy and the Japanese Society of Therapeutic Drug Monitoring decided to develop a clinical practice guidelines for TDM of ABK for the following reasons. First, although the daily dose of 150-200 mg was approved in Japan, recent PK-PD studies revealed that higher serum concentration is required to achieve better clinical efficacy and several findings concerning the usefulness of higher dosage regimen have obtained recently. Second, although maximal concentrations that obtained immediately after the end of administration (Cmax) was generally adopted, the serum concentration at 1 h after initiation of administration [peak serum concentration (Cpeak)] proved to be more suitable as an efficacy indicator of aminoglycosides. Lastly, as ABK is approved only in Japan, no international practice guideline for TDM has not been available in ABK to date. This guideline evaluated the scientific data associated with serum ABK monitoring and provided recommendations based on the available evidence. Potential limitations of this guideline, however, include the findings that few prospective clinical trials of TDM of ABK are available in the treatment of MRSA infections and that most of the published literature describes observational studies. PMID- 24486169 TI - Desulfovibrio desulfuricans bacteremia in a patient hospitalized with acute cerebral infarction: case report and review. AB - Desulfovibrio spp. can be found in soil, water, and sewage, as well as in the digestive tracts of animals and humans. We report a case of Desulfovibrio desulfuricans bacteremia during hospitalization with acute cerebral infarction following aspiration bronchopneumonia and severe diarrhea, and the case strongly suggests that Desulfovibrio spp. bacteremia can occur as an infection due to disturbance of endogenous gut flora including antibiotic administration. Because Desulfovibrio spp. is difficult to detect in short-time incubation, its bacteremia is possibly overlooked in hospitalized patients. A few clinical cases of D. desulfuricans bacteremia have been reported in Japan, and they are reviewed briefly in this article. PMID- 24486170 TI - Leptospirosis in a Japanese urban area: a case report and literature review. AB - Leptospirosis is not a major disease in urban areas of Japan. We describe a 49 year-old man with leptospirosis, who lived in an urban area and had no history of living in endemic area of leptospirosis. As he worked at a fish market infested with rats, he was suspected of having contracted leptospirosis and received antimicrobial agent treatment. Serum and urinary tests confirmed the diagnosis of leptospirosis. Although it took six days from the onset until treatment initiation, the patient improved in response to receiving ceftriaxone for seven days. Analyzing past reports of Japanese patients with leptospirosis who had no history of overseas travel, we identified 90 patients with courses similar to that of our patient, and the period from onset to treatment initiation was about six days on average (described in 46 cases). Health care providers as well as patients need to recognize that even people with no history of being in an endemic area of leptospirosis may still be at risk of developing this disease depending on occupations and activities. PMID- 24486171 TI - Thoracic empyema in children: clinical presentation, microbiology analysis and therapeutic options. AB - Thoracic empyema is an accumulation of purulent fluid in the pleural space presenting as a complication of bacterial pneumonia. The aims of the study were to present the incidence, demographic results, clinical presentation, laboratory and microbiology results, imaging and the therapeutic options. From January 1992 until December 2009 we collected data of children hospitalized with empyema in our medical center in north of Israel. Empyema was found in 53 pediatric patients. The median age of the patients was 3 years and 31 (58%) were male. Forty one (77%) of the cases were diagnosed in the last nine years. Fever, cough and respiratory distress were the most frequent clinical signs. In 29 (55%) patients pleural effusion was found at admission. Chest ultrasound was performed in 44 (83%) of the patients. Causative organisms were confirmed by culture in 35 patients. Positive culture was found in 17 (32%) patients in the pleural fluid. Streptococcus pneumoniae was the leading pathogen. The drugs the patients received at admission were penicillin in 21 cases, cefuroxime in19 cases and ceftriaxone in 11 cases. During hospitalization a change of antibiotic therapy was required, using mainly ceftriaxone and clindamycin. The pleural purulent fluid was drained by video assisted thoracoscopy surgery in 34 (64%) patients. All the children recovered. The incidence of empyema as a complication of community acquired pneumonia had increased in the last decade in our region. Streptococcus pneumoniae is the most common pathogen. Third generation cephalosprins and clindamycin can be suggested as a good empiric treatment. PMID- 24486172 TI - Effectiveness of antibiotic combination therapy as evaluated by the Break-point Checkerboard Plate method for multidrug-resistant Pseudomonas aeruginosa in clinical use. AB - Multidrug-resistant Pseudomonas aeruginosa (MDRP) strains are defined as having resistance to the following 3 groups of antibiotics: carbapenems, aminoglycosides, and fluoroquinolones. Antibiotic combinations have demonstrated increased activity in vitro compared with a single agent. As an in vitro method of determining the combination activity of antibiotics, the Break-point Checkerboard Plate (BC-plate) can be used routinely in clinical microbiology laboratories. We evaluated the effectiveness of the BC-plate for MDRP infections in clinical settings. We retrospectively selected cases of MDRP infection treated with combination therapy of antibiotics in Tokyo Medical University Hospital (1015 beds), Tokyo, Japan, from November 2010 to October 2012. A total of 28 MDRP strains were clinically isolated from 28 patients during the study period. This study design is a case series of MDRP infection. Six infections among the 28 patients were treated based on the results of the BC-plate assay, and the 6 strains tested positive for MBL. One patient had pneumonia, 3 had urinary tract infections, 1 had vertebral osteomyelitis, and 1 had nasal abscess. The combination of aztreonam with amikacin demonstrated the most frequently recognized in vitro effect (5 patients). Next, aztreonam with ciprofloxacin and piperacillin with amikacin revealed equivalent in vitro effects (3 patients, respectively). The clinical cure rate was 83.3% (5/6 patients). Antibiotic combination therapy based on the results of the BC-plate assay might indicate the effective therapy against MDRP infection in clinical settings. PMID- 24486173 TI - Management of refractory Mycoplasma pneumoniae pneumonia: utility of measuring serum lactate dehydrogenase level. AB - It has been suggested that cytokines are associated with refractory Mycoplasma pneumoniae pneumonia, and steroid administration is reported to be effective in this situation. In order to elucidate the characteristics of refractory M. pneumoniae pneumonia, we analyzed five pediatric patients with refractory M. pneumoniae pneumonia, which was defined as showing prolonged fever and deterioration of clinical and radiological findings despite administration of appropriate antibiotics, compared with 15 pediatric patients with M. pneumoniae pneumonia who responded to treatment promptly (control group). Serum lactate dehydrogenase (LDH), alanine aminotransferase (ALT), aspartate aminotransferase (AST), and interleukin (IL)-18 levels were significantly higher in the refractory group than in the control group at the initiation of corticosteroid use (LDH: 571 vs 292 IU/L, p = 0.0129; ALT: 25 vs 11 IU/L, p = 0.0143; AST: 41 vs 26 IU/L, p = 0.0404; IL-18: 579 vs 365 pg/mL, p = 0.0402). Significant correlation was found between serum values of IL-18 and LDH (r(2) = 0.504, p = 0.0433). The administration of corticosteroids to patients in the refractory group resulted in the rapid improvement of symptoms and decrease in serum LDH levels in all patients. A serum LDH level of >=410 IU/L, which was calculated from receiver operating characteristic curve analysis, seemed to be an appropriate criterion for the initiation of steroid therapy. In conclusion, serum IL-18 and LDH levels can be used as parameters to determine which patients are candidates for corticosteroid therapy. In addition, serum LDH levels seem to be a useful marker for the evaluation of therapeutic efficacy in refractory M. pneumoniae pneumonia. PMID- 24486175 TI - Standardizing family education in a pediatric respiratory care unit. PMID- 24486174 TI - Exploring sleep-wake experiences of mothers during maintenance therapy for their child's acute lymphoblastic leukemia. AB - A qualitative study was designed to explore sleep-wake experience of mothers of children in maintenance treatment for Acute Lymphoblastic Leukemia. Interviews were conducted with 20 participants using open-ended, semi-structured questions and were transcribed verbatim. Two main themes emerged: "It's a whole new cancer world" and "I don't remember what it's like to have sleep." Mothers experience difficulty sleeping during their children's treatment, and expressed several serious issues. Although the mothers were able to employ various mechanisms to address sleep deprivation and disruption, interventions such as social support, journaling, spiritual guidance, and/or self-talk may be most beneficial. PMID- 24486176 TI - Methaemoglobinaemia and renal failure following mesalazine for treatment of inflammatory bowel disease. PMID- 24486177 TI - Iron treatment and inflammatory bowel disease: what happens in real practice? AB - BACKGROUND AND AIMS: Iron deficiency anaemia (IDA), the most common extra intestinal complication of inflammatory bowel disease (IBD), negatively impacts quality of life. We audited the recent practice of anaemia treatment in an unselected IBD population. METHODS: A questionnaire was distributed to adult IBD outpatients in a university hospital to assess the form and frequency of iron prescribed, duration of use, side effects, and completion of therapy. The efficacy of treatment was determined by the resolution of anaemia and change in haemoglobin from baseline. RESULTS: Of 87 IBD patients (60 patients with Crohn's disease, 25 with ulcerative colitis, 2 with microscopic colitis), 85 received various dosing regimens of iron tablets; 15 patients also received IV iron. Side effects were reported in 43 (51%) patients, with no clear relationship to dose prescribed and 26 (32%) patients were unable to complete the intended course. Only 36 (42%) patients completed the course of oral iron without side effects and in these patients, haemoglobin normalised in about 30%. Their median haemoglobin change was 12.5 (5.3-23.5)g/l. The median duration of treatment in those without side effects was 4.5months, and in those with adverse effects was 2months. Only one adverse effect was reported for IV iron. CONCLUSIONS: Treatment with oral iron results in failure to control anaemia in 2 out of 3 IBD patients, which is likely in part to be due to the side effects reported by over half of patients. Patients failing to tolerate or adequately respond to therapy should be offered alternative treatment. PMID- 24486178 TI - Trough s-infliximab and antibodies towards infliximab in a cohort of 79 IBD patients with maintenance infliximab treatment. AB - BACKGROUND AND AIMS: The anti-TNF antibody infliximab is effective in inducing remission in Crohn's disease as well as in ulcerative colitis and many patients are treated for several years with sustained clinical remission. However, the role of monitoring s-infliximab and antibodies towards infliximab during maintenance treatment remains unclear. Our aim was to correlate serum drug levels and antibodies to clinical activity, CRP, albumin and concomitant immunosuppression in a cohort on maintenance infliximab treatment. METHODS: We included 79 patients with Crohn's disease or ulcerative colitis who had responded to infliximab and received maintenance treatment (4-69 infusions) in this retrospective study. Infliximab levels and antibodies towards the drug were analyzed with in-house-developed ELISA assays. RESULTS: The mean s-infliximab was significantly higher in patients in remission (4.1MUg/mL) as compared with disease flare (mean 1.8MUg/mL); p<0.001. The s-infliximab showed a significant negative correlation with Harvey-Bradshaw index (r=-0.21; p<0.05). Serum infliximab progressively decreased with the number of accumulated infusions (p<0.05). In patients with undetectable trough levels, 55% of the patients with concomitant immunosuppressive were positive for antibodies against infliximab, as compared with 94% of patients on monotherapy. Patients with undetectable serum infliximab were in clinical remission at 25% of the visits. CONCLUSIONS: The trough level 4.1MUg/mL may serve as cut-off for clinical remission. Drug trough levels decreased during treatment and almost all patients with undetectable s infliximab and monotherapy had developed antibodies against the drug. PMID- 24486179 TI - Severe inflammatory bowel disease associated with congenital alteration of transforming growth factor beta signaling. AB - Transforming growth factor beta is a pleiotropic cytokine which plays a central role in the homeostasis of the immune system. A complex dysregulation of its signaling occurs in Loeys-Dietz syndrome, a monogenic disorder caused by mutations of transforming growth factor beta receptors type 1 or type 2, characterized by skeletal involvement, craniofacial abnormalities, and arterial tortuosity with a strong predisposition for aneurysm and dissection. In addition, several immunologic abnormalities have been described in these patients, including an increased risk of allergic disorders as well as eosinophilic gastrointestinal disorders. The occurrence of inflammatory bowel disorders has been also reported, but it is poorly documented. We describe two unrelated children with Loeys-Dietz syndrome affected by severe chronic inflammatory colitis appearing at an early age. The intestinal disease presented similar features in both patients, including a histopathological picture of non eosinophilic chronic ulcerative colitis, striking elevation of inflammatory markers, and a distinctly severe clinical course leading to failure to thrive, with resistance to multiple immunosuppressive treatments. One of the patients also presented autoimmune thyroiditis. Our report confirms that chronic ulcerative colitis may be associated with Loeys-Dietz syndrome. This finding suggests that an alteration of transforming growth factor beta signaling may by itself predispose to inflammatory colitis in humans, and represent an invaluable model to understand inflammatory bowel diseases. PMID- 24486180 TI - Laparoscopic ventral rectopexy for the treatment of outlet obstruction associated with recto-anal intussusception and rectocele: a valid alternative to STARR procedure in patients with anal sphincter weakness. AB - OBJECTIVE: This study was designed to assess the safety and outcomes achieved with Stapled Trans-Anal Rectal Resection (STARR) vs laparoscopic ventral rectopexy (LVR) in obstructed defecation patients. METHOD: From 2002 to 2011, 52 patients (females) had a rectocele with outlet obstruction. After clinical assessment by an Obstructed Defecation Syndrome score (ODS), an anorectal manometry, a defecography and an endoanal ultrasound, the patients underwent either a STARR (n=25) or a LVR (n=27) according to the existence of an asymptomatic anal sphincter injury. Functional results were evaluated clinically and by the preoperative and 18 months postoperative ODS score and by an 18 months postoperative score of satisfaction. RESULTS: Average ages were 56 +/- 10 years in the STARR and 60 +/- 9 years in LVR. The 1-month postoperative complication rates were comparable for the 2 groups (25%). Mean length of stay was shorter for STARR than for LVR (5.6 +/- 2.1 vs. 7.1 +/- 2.9, P=0.009). After treatment, the ODS was lowered by 56% in LVR and 59% in the STARR (P=0.0001) but with no difference between the 2 groups. Eighty percent of patients were very or moderately satisfied after LVR, versus 84% after STARR. CONCLUSIONS: The 2 surgical procedures obtain good results with 80% of satisfied patients with a length of stay a little shorter in the STARR. BRIEF SUMMARY: In our retrospective study, Stapled Trans-Anal Rectal Resection (STARR) and laparoscopic ventral rectopexy improved the outlet obstruction associated with recto-anal intussusception and rectocele. PMID- 24486181 TI - UHRF1 overexpression drives DNA hypomethylation and hepatocellular carcinoma. AB - Ubiquitin-like with PHD and RING finger domains 1 (UHRF1) is an essential regulator of DNA methylation that is highly expressed in many cancers. Here, we use transgenic zebrafish, cultured cells, and human tumors to demonstrate that UHRF1 is an oncogene. UHRF1 overexpression in zebrafish hepatocytes destabilizes and delocalizes Dnmt1 and causes DNA hypomethylation and Tp53-mediated senescence. Hepatocellular carcinoma (HCC) emerges when senescence is bypassed. tp53 mutation both alleviates senescence and accelerates tumor onset. Human HCCs recapitulate this paradigm, as UHRF1 overexpression defines a subclass of aggressive HCCs characterized by genomic instability, TP53 mutation, and abrogation of the TP53-mediated senescence program. We propose that UHRF1 overexpression is a mechanism underlying DNA hypomethylation in cancer cells and that senescence is a primary means of restricting tumorigenesis due to epigenetic disruption. PMID- 24486183 TI - Association between GSK3beta gene and increased impulsivity in bipolar disorder. AB - Bipolar patients present increased levels of impulsivity even during remission periods. It is known that this dimensional trait negatively impacts on the course of illness and worsens their prognosis and outcome. Evidence from both basic and clinical researches supports that Lithium (Li) may decrease impulsivity. Owing to the fact that Li inhibits both glycogen synthetase kinase-3 (GSK3) isoenzimes, our aim was to analyze the potential impact of genetic variants located at the GSK3 alpha and beta genes on impulsivity levels in a bipolar sample. Our sample consisted of 199 unrelated Caucasian bipolar outpatients who were recruited from the Bipolar Disorder Unit of the Hospital Clinic of Barcelona and from primary care settings from Oviedo. Four polymorphisms at the GSK3 alpha and beta genes were genotyped in order to analyze the impact of genetic variability on impulsivity as measured by the BIS-11 scale. Single SNP analysis showed that patients carrying T and G alleles at the rs1732170-GSK3beta and the rs334558 GSK3beta, respectively, presented increased levels of attentional impulsivity compared to non-carriers. These results were also confirmed by haplotype analysis. Our results suggest that genetic variability at GSK3beta gene is associated to increased impulsivity in bipolar patients. PMID- 24486182 TI - The serotonin transporter 5-HTTLPR polymorphism in the association between sleep quality and affect. AB - A link between sleep and affect is well-known. Serotonin (5-HT) is associated with the regulation of affective as well as sleep-related processes. A functional polymorphism in the serotonin transporter gene (5-HTTLPR) has been associated with serotonergic functioning. The present study investigated whether allelic variation of this gene moderates the association between nighttime subjective sleep quality and affect the following day. A population-based sample of 361 ethnically homogenous adult female twins underwent a five day protocol based on the experience sampling method (ESM), assessing momentary negative affect, positive affect, and subjective sleep quality repeatedly and prospectively. There was a significant interaction between sleep quality and genotype in predicting positive affect the next day: carriers of one (n=167) or two S-alleles (n=78) had a significantly steeper slope compared to LL carriers (n=116) (chi(2)=4.16, p=.042 and chi(2)=3.90, p=.048 respectively). The association between subjective sleep quality and positive affect the next day varied as a function of 5-HTTLPR: it was stronger in carriers of at least one copy of the S-allele compared to homozygous L-carriers, supporting a link between sleep and affect regulation, in which serotonin may play a role. However, these results are preliminary and require replication. PMID- 24486184 TI - Trypanosoma cruzi infection results in an increase in intracellular cholesterol. AB - Chagasic cardiomyopathy caused by Trypanosoma cruzi is a major health concern in Latin America and among immigrant populations in non-endemic areas. T. cruzi has a high affinity for host lipoproteins and uses the low density lipoprotein receptor (LDLr) for invasion. Herein, we report that T. cruzi infection is associated with an accumulation of LDL and cholesterol in tissues in both acute and chronic murine Chagas disease. Similar findings were observed in tissue samples from a human case of Chagasic cardiomyopathy. T. cruzi infection of cultured cells displayed increased invasion with increasing cholesterol levels in the medium. Studies of infected host cells demonstrated alterations in their cholesterol regulation. T. cruzi invasion/infection via LDLr appears to be involved in changes in intracellular cholesterol homeostasis. The observed changes in intracellular lipids and associated oxidative stress due to these elevated lipids may contribute to the development of Chagasic cardiomyopathy. PMID- 24486186 TI - Russia: lessons for alcohol epidemiology and alcohol policy. PMID- 24486185 TI - Molecular characterization of hepatitis A outbreak in the province of Rome, Lazio region, Italy, January-July 2013. AB - Reduced circulation of hepatitis A virus lead to an increase of susceptible individuals, and outbreaks occurred recently. In Northern Italy an outbreak is ongoing, attributed to a monophyletic genotype IA strain, with mixed frozen berries as probable source. From 01/01/2013 to 07/15/2013, 30 cases were diagnosed at National Institute for Infectious Diseases, Rome, Italy, representing about twice the number of cases in whole 2012. Phylogenetic analysis indicated that most, although not all, infections were attributable to the same monophyletic genotype IA strain identified in the contemporary Northern Italy outbreak. This strain is also very similar to previous isolates from Venezuela. PMID- 24486187 TI - Alcohol and mortality in Russia: prospective observational study of 151,000 adults. AB - BACKGROUND: Russian adults have extraordinarily high rates of premature death. Retrospective enquiries to the families of about 50,000 deceased Russians had found excess vodka use among those dying from external causes (accident, suicide, violence) and eight particular disease groupings. We now seek prospective evidence of these associations. METHODS: In three Russian cities (Barnaul, Byisk, and Tomsk), we interviewed 200,000 adults during 1999-2008 (with 12,000 re interviewed some years later) and followed them until 2010 for cause-specific mortality. In 151,000 with no previous disease and some follow-up at ages 35-74 years, Poisson regression (adjusted for age at risk, amount smoked, education, and city) was used to calculate the relative risks associating vodka consumption with mortality. We have combined these relative risks with age-specific death rates to get 20-year absolute risks. FINDINGS: Among 57,361 male smokers with no previous disease, the estimated 20-year risks of death at ages 35-54 years were 16% (95% CI 15-17) for those who reported consuming less than a bottle of vodka per week at baseline, 20% (18-22) for those consuming 1-2.9 bottles per week, and 35% (31-39) for those consuming three or more bottles per week; trend p<0.0001. The corresponding risks of death at ages 55-74 years were 50% (48-52) for those who reported consuming less than a bottle of vodka per week at baseline, 54% (51 57) for those consuming 1-2.9 bottles per week, and 64% (59-69) for those consuming three or more bottles per week; trend p<0.0001. In both age ranges most of the excess mortality in heavier drinkers was from external causes or the eight disease groupings strongly associated with alcohol in the retrospective enquiries. Self-reported drinking fluctuated; of the men who reported drinking three or more bottles of vodka per week who were reinterviewed a few years later, about half (185 of 321) then reported drinking less than one bottle per week. Such fluctuations must have substantially attenuated the apparent hazards of heavy drinking in this study, yet self-reported vodka use at baseline still strongly predicted risk. Among male non-smokers and among females, self-reported heavy drinking was uncommon, but seemed to involve similar absolute excess risks. INTERPRETATION: This large prospective study strongly reinforces other evidence that vodka is a major cause of the high risk of premature death in Russian adults. FUNDING: UK Medical Research Council, British Heart Foundation, Cancer Research UK, European Union, WHO International Agency for Research on Cancer. PMID- 24486188 TI - Data, children's rights, and the new development agenda. PMID- 24486189 TI - The effect of iron overload on red blood cell morphology. PMID- 24486190 TI - Wetland assessment, monitoring and management in India using geospatial techniques. AB - Satellite remote sensing and GIS have emerged as the most powerful tools for inventorying, monitoring and management of natural resources and environment. In the special context of wetland ecosystems, remotely sensed data from orbital platforms have been extensively used in India for the inventory, monitoring and preparation of action plans for conservation and management. First scientific inventory of wetlands in India was carried out in 1998 by Space Applications Centre (ISRO), Ahmedabad using indigenous IRS (Indian Remote Sensing Satellite) data of 1992-93 timeframe, which stimulated extensive use of geospatial techniques for wetland conservation and management. Subsequently, with advances in GIS, studies were carried out for development of Wetland Information System for a state (West Bengal) and for Loktak lake wetland (a Ramsar site) as a prelude to National Wetland Information System. Research has also been carried out for preparation of action plans especially for Ramsar sites in the country. In a novel research, use of the geospatial technology has also been demonstrated for biodiversity conservation using landscape ecological metrics. A country-wide estimate of emission of methane, a Green House Gas, from wetlands has also been made using MODIS data. Present article critically reviews the work carried out in India for wetland conservation and management using geospatial techniques. PMID- 24486191 TI - Differential regulation of the multiple insulin and insulin receptor mRNAs by somatostatin. AB - We used rainbow trout as a model to study the regulation of the multiple and distinct insulin (INS) and insulin receptor (IR) mRNAs by somatostatin (SS). Implantation of SS reduced growth of animals without affecting food intake. SS decreased INS1 and INS2 expression in Brockmann bodies, but increased INS1 and INS2 expression in adipose and INS1 expression in brain. SS reduced mRNA levels of IR 2 and IR 3 in adipose tissue; of IR1 and IR 4 in Brockmann bodies; of IR1, IR2, IR3, and IR4 in cardiac muscle; of IR2 and IR4 in liver; of IR 3 and IR 4 in gill; and of IR4 in skeletal muscle. The direct effects of SS were examined in Brockmann bodies and liver in vitro. SS decreased INS and IR mRNAs in both tissues in a concentration-, time-, and isoform/subtype-dependent manner. These results indicate that SS regulates the expression of INS- and IR-encoding mRNAs and that independent mechanisms may serve to regulate the various INS isoforms and IR subtypes. PMID- 24486192 TI - Leptin signaling regulates hypothalamic expression of nescient helix-loop-helix 2 (Nhlh2) through signal transducer and activator 3 (Stat3). AB - Mice with a deletion of the hypothalamic basic helix-loop-helix transcription factor Nhlh2 display adult onset obesity. We have previously shown that Nhlh2 expression is induced by leptin. In this study, we identify a small proximal leptin-responsive promoter region in the Nhlh2 gene. This 163bp promoter contains five putative binding sites for the leptin-activated Stat3 transcription factor, and two putative binding sites for the NFkappaB transcription factor. Results of mutagenesis studies reveal that deletion of the NFkappaB sites have little effect, mutagenesis of the third Stat3 site eliminates both leptin-induced and basal expression of Nhlh2. Mutagenesis of the 4th and 5th sites eliminates leptin induced expression, and increases basal expression above the WT promoter. Stat3 can be preferentially pulled down from leptin-treated mouse hypothalamic chromatin extracts. This study identifies leptin-induced Stat3 transcription factor as the major transcriptional regulator of Nhlh2. As Nhlh2 transcriptionally regulates genes within the melanocortin pathway, these findings have implications for human body weight control. PMID- 24486193 TI - The feasibility of volunteers facilitating personalized activities for nursing home residents with dementia and agitation. AB - BACKGROUND: Nursing home residents' behavioral and psychological symptoms of dementia are often exacerbated by a lack of social contact and meaningful activity. Volunteers might assist in addressing this deficiency but they are often discouraged by staff from engaging with residents with challenging behaviors. As a result, some of the neediest residents receive the least social and psychological support. AIM: This project explored the implementation of personalized, one-to-one activities by nursing home volunteers to determine if volunteers were able and willing to complete a training program and undertake activities with residents with dementia and challenging behaviors. METHODS: 19 nursing home volunteers in Melbourne, Australia, were trained to apply Montessori type personalized activities with a selected resident whose dementia was complicated by a frequent, non-aggressive agitated behavior. The volunteers were asked to attend a workshop and pay six 30-min visits to the resident over a three week period. They completed knowledge and attitude rating scales before and after the intervention and were interviewed afterward regarding their experiences and perceptions. RESULTS: 16 volunteers completed the program and eight met or exceeded every study requirement. Most of them derived satisfaction from engaging residents' interest and were pleased to learn new skills. The scores on the dementia knowledge and attitude rating scale of those who completed the visits were higher at the study's outset than the scores of those who failed to make any visits. CONCLUSIONS: It is certainly feasible to train volunteers to work with residents who might otherwise be isolated. It is important to demonstrate activities to volunteers at the outset and to provide them with careful, ongoing supervision and support. Notwithstanding some difficulties and challenges, volunteers represent a growing and hitherto untapped pool of support for people with dementia and complex needs. PMID- 24486194 TI - Low dystrophin levels in heart can delay heart failure in mdx mice. AB - Duchenne muscular dystrophy is caused by mutations that prevent synthesis of functional dystrophin. All patients develop dilated cardiomyopathy. Promising therapeutic approaches are underway that successfully restore dystrophin expression in skeletal muscle. However, their efficiency in the heart is limited. Improved quality and function of only skeletal muscle potentially accelerate the development of cardiomyopathy. Our study aimed to elucidate which dystrophin levels in the heart are required to prevent or delay cardiomyopathy in mice. Heart function and pathology assessed with magnetic resonance imaging and histopathological analysis were compared between 2, 6 and 10-month-old female mdx Xist(Deltahs) mice, expressing low dystrophin levels (3-15%) in a mosaic manner based on skewed X-inactivation, dystrophin-negative mdx mice, and wild type mice of corresponding genetic backgrounds and gender. With age mdx mice developed dilated cardiomyopathy and hypertrophy, whereas the onset of heart pathology was delayed and function improved in mdx-Xist(Deltahs) mice. The ejection fraction, the most severely affected parameter for both ventricles, correlated to dystrophin expression and the percentage of fibrosis. Fibrosis was partly reduced from 9.8% in mdx to 5.4% in 10 month old mdx-Xist(Deltahs) mice. These data suggest that mosaic expression of 4-15% dystrophin in the heart is sufficient to delay the onset and ameliorate cardiomyopathy in mice. PMID- 24486195 TI - Oleuropein prevents doxorubicin-induced cardiomyopathy interfering with signaling molecules and cardiomyocyte metabolism. AB - Oleuropein, a natural phenolic compound, prevents acute doxorubicin (DXR)-induced cardiotoxicity but there is no evidence regarding its role in chronic DXR-induced cardiomyopathy (DXR-CM). In the present study, we investigated the role of oleuropein in DXR-CM by addressing cardiac geometry and function (transthoracic echocardiography), cardiac histopathology, nitro-oxidative stress (MDA, PCs, NT), inflammatory cytokines (IL-6, Big ET-1), NO homeostasis (iNOS and eNOS expressions), kinases involved in apoptosis and metabolism (Akt, AMPK) and myocardial metabonomics. Rats were randomly divided into 6 groups: Control, OLEU 1 and OLEU-2 [oleuropein at 1000 and 2000 mg/kg in total, respectively, intraperitoneally (i.p.) for 14 days], DXR (18 mg/kg, i.p. divided into 6 equal doses for 2 weeks), DXR-OLEU-1 and DXR-OLEU-2 (both oleuropein and DXR as previously described). Impaired left ventricular contractility and inflammatory and degenerative pathology lesions were encountered only in the DXR group. The DXR group also had higher MDA, PCs, NT, IL-6 and Big ET-1 levels, higher iNOS and lower eNOS, Akt and AMPK activation compared to controls and the oleuropein treated groups. Metabonomics depicted significant metabolite alterations in the DXR group suggesting perturbed energy metabolism and protein biosynthesis. The effectiveness of DXR in inhibiting cell proliferation is not compromised when oleuropein is present. We documented an imbalance between iNOS and eNOS expressions and a disturbed protein biosynthesis and metabolism in DXR-CM; these newly recognized pathways in DXR cardiotoxicity may help identifying novel therapeutic targets. Activation of AMPK and suppression of iNOS by oleuropein seem to prevent the structural, functional and histopathological cardiac effects of chronic DXR toxicity. PMID- 24486196 TI - HASF, a PKC-epsilon activator with novel features for cardiomyocyte protection. PMID- 24486197 TI - Nitrite reduction and cardiovascular protection. AB - Inorganic nitrite, a metabolite of endogenously produced nitric oxide (NO) from NO synthases (NOS), provides the largest endocrine source of directly bioavailable NO. The conversion of nitrite to NO occurs mainly through enzymatic reduction, mediated by a range of proteins, including haem-globins, molybdo flavoproteins, mitochondrial proteins, cytochrome P450 enzymes, and NOS. Such nitrite reduction is particularly favoured under hypoxia, when endogenous formation of NO from NOS is impaired. Under normoxic conditions, the majority of these nitrite reductases also scavenge NO, or diminish its bioavailability via reactive oxygen species (ROS) production, suggesting an intricate balance. Moreover, nitrite, whether produced endogenously, or derived from exogenous nitrite or nitrate administration (including dietary sources via the Nitrate Nitrite-NO pathway) beneficially modulates many key cardiovascular pathological processes. In this review, we highlight the landmark studies which revealed nitrite's function in biological systems, and inspect its evolving role in cardiovascular protection. Whilst these effects have mainly been ascribed to the activity of one or more nitrite reductases, we also discuss newly-identified mechanisms, including nitrite anhydration, the involvement of s-nitrosothiols, nitro-fatty acids, and direct nitrite normoxic signalling, involving modification of mitochondrial structure and function, and ROS production. This article is part of a Special Issue entitled "Redox Signalling in the Cardiovascular System". PMID- 24486198 TI - Three-component aza-Diels-Alder reactions using Yb(OTf)3 catalyst under conventional/ultrasonic techniques. AB - The Yb(OTf)3 catalyzed formal aza-Diels-Alder (or Povarov) reaction of cyclopentadiene and 1,3-cyclohexadiene with in situ-generated N-arylimines under conventional/ultrasonic techniques is herein described. This kind of three component Povarov reaction results in quinoline and phenanthridine derivatives, which are important biological compounds. PMID- 24486199 TI - Simultaneous ultrasound-assisted removal of sunset yellow and erythrosine by ZnS:Ni nanoparticles loaded on activated carbon: optimization by central composite design. AB - The present study focused on the simultaneous ultrasound-assisted removal of sunset yellow and erythrosine dyes from aqueous solutions using ZnS:Ni nanoparticles loaded on activated carbon (ZnS:Ni-NP-AC) as an adsorbent. ZnS:Ni nanoparticles were synthesized and characterized using different techniques such as FESEM, XRD and TEM. The effects of various parameters such as sonication time, pH, initial dye concentrations and adsorbent dose on the percentage of dye removal were investigated. Parameters were optimized by central composite design (CCD) combined with response surface methodology (RSM) and desirability function (DF). A good agreement between experimental and predicted values was observed. The ultrasound-assisted adsorbent (0.04 g) was capable of high percentage removal (98.7% and 99.6%) of sunset yellow and erythrosine in short time (3.8 min). PMID- 24486200 TI - Multiple transformation with the crtYB gene of the limiting enzyme increased carotenoid synthesis and generated novel derivatives in Xanthophyllomyces dendrorhous. AB - Xanthophyllomces dendrorhous (in asexual state named as Phaffia rhodozyma) is a fungus which produces astaxanthin, a high value carotenoid used in aquafarming. Genetic pathway engineering is one of several steps to increase the astaxanthin yield. The limiting enzyme of the carotenoid pathway is phytoene synthase. Integration plasmids were constructed for transformation with up to three copies of the crtYB gene. Upon stepwise transformation, the copy numbers of crtYB was continuously increased leading to an almost saturated level of phytoene synthase as indicated by total carotenoid content. Several carotenoid intermediates accumulated which were absent in the wild type. Some of them are substrates and intermediates of astaxanthin synthase. They could be further converted into astaxanthin by additional transformation with the astaxanthin synthase gene. However, three intermediates exhibited an unusual optical absorbance spectrum not found before. These novel keto carotenoid were identified by HPLC co chromatography with reference compounds generated in Escherichia coli and one of them 3-HO-4-keto-7',8'-dihydro-beta-carotene additionally by NMR spectroscopy. The others were 4-keto-beta-zeacarotene and 4-keto-7',8'-dihydro-beta-carotene. A biosynthesis pathway with their origin from neurosporene and the reason for their synthesis especially in our transformants has been discussed. PMID- 24486202 TI - [EPI-CLIN 7: a turning point!]. PMID- 24486201 TI - Dynamic fluid flow stimulation on cortical bone and alterations of the gene expressions of osteogenic growth factors and transcription factors in a rat functional disuse model. AB - Recently we have developed a dynamic hydraulic stimulation (DHS) as a loading modality to induce anabolic responses in bone. To further study the functional process of DHS regulated bone metabolism, the objective of this study was to evaluate the effects of DHS on cortical bone and its alterations on gene expressions of osteogenic growth factors and transcription factors as a function of time. Using a model system of 5-month-old hindlimb suspended (HLS) female Sprague-Dawley rats, DHS was applied to the right tibiae of the stimulated rats with a loading frequency of 2Hz with 30mmHg (p-p) dynamic pressure, 5days/week, for a total of 28days. Midshafts of the tibiae were analyzed using MUCT and histology. Total RNA was analyzed using RT-PCR on selected osteogenic genes (RUNX2, beta-catenin, osteopontin, VEGF, BMP2, IGF-1, and TGF-beta) on 3-, 7-, 14 , and 21-day. Results showed increased Cort.Th and Ct.BV/TV as well as a time dependent fashion of gradual changes in mRNA levels upon DHS. While DHS-driven fold changes of the mRNA levels remained low before Day-7, its fold changes started to elevate by Day-14 and then dropped by Day-21. This study further delineates the underlying molecular mechanism of DHS-derived mechanical signals, and its time-dependent optimization. PMID- 24486203 TI - Design, synthesis, and evaluation of pyrrolo[2,1-f][1,2,4]triazine derivatives as novel hedgehog signaling pathway inhibitors. AB - A novel series of Hh signaling pathway inhibitors were designed by replacing the pyrimidine skeleton of our earlier reported lead compound 1 with pyrrolo[2,1 f][1,2,4]triazine scaffold. Starting from this new scaffold, SAR exploration was investigated based on structural modification on A-ring, C-ring and D-ring. And several much potent compounds were studies in vivo to profile their pharmacokinetic properties. Finally, optimization leads to the identification of compound 19a, a potent Hh signaling pathway inhibitor with superior potency in vitro and satisfactory pharmacokinetic properties in vivo. PMID- 24486204 TI - Design and synthesis of peptide-MCA substrates for a novel assay of histone methyltransferases and their inhibitors. AB - Histone methyltransferases (HMTs) play an important role in controlling gene expression through site-specific methylation of lysines in core and linker histones within chromatin. As the typical HMTs, G9a and Set7/9 have been intensively studied that G9a is specific to the methylation at H3K9 and H3K27 and represses transcription, while Set7/9 methylates at H3K4. In this report we prepared various peptide-MCAs (4-methylcoumaryl-7-amides) related to histone tail and protein-substrates such as p53 and estrogen receptor-alpha. The fluorogenic substrates are applied for the assay of HMTs and an inhibitor, for example. The most sensitive and specific MCA-substrates to G9a and Set7/9 are discovered. The peptide-MCAs corresponding to the methylation sequences are promising for screening of HMT inhibitors. PMID- 24486205 TI - Synthesis and structure-activity relationship of p-carborane-based non secosteroidal vitamin D analogs. AB - 1alpha,25-Dihydroxyvitamin D3 [1alpha,25(OH)2D3: 1] is a specific modulator of nuclear vitamin D receptor (VDR), and novel vitamin D analogs are therapeutic candidates for multiple clinical applications. We recently developed non secosteroidal VDR agonists bearing a p-carborane cage (a carbon-containing boron cluster) as a hydrophobic core structure. These carborane derivatives are structurally quite different from classical secosteroidal vitamin D analogs. Here, we report systematic synthesis and activity evaluation of carborane-based non-secosteroidal vitamin D analogs. The structure-activity relationships of carborane derivatives are different from those of secosteroidal vitamin D derivatives, and in particular, the length and the substituent position of the dihydroxylated side chain are rather flexible in carborane derivatives. The structure-activity relationships presented here should be helpful in development of non-secosteroidal vitamin D analogs for clinical applications. PMID- 24486206 TI - Vertically transmitted nasopharyngeal infection of the human papillomavirus: does it play an aetiological role in nasopharyngeal cancer? AB - OBJECTIVES: Despite identification of important risk factors, aetiology of nasopharyngeal cancer (NPC) remained enigmatic. Oncogenic Human Papillomavirus (HPV), a cause of cervical and genital tract epithelial cancers, has recently been isolated from NPC tumour tissues, raising the question of whether HPV may play a role in NPC. Accumulating evidence showed that perinatal HPV transmission to newborns can occur through exposures to genital tract secretions, amniotic fluid, or blood during vaginal delivery in mothers with cervical HPV infection, with viral DNA fingerprint showing maternal-foetal concordance. Persistence of perinatally acquired oncogenic HPV infection presents clear biological plausibility as an aetiological agent. Co-infection of HPV and EBV may also co operatively impact on neoplastic transformation. Our findings also suggest that regional disease burdens of oncogenic HPV strains have strong type-specific associations with regional risk of NPC. If true, this hypothesis presents immense potentials for preventive interventions through community control of HPV infection and newborn vaccination. PMID- 24486207 TI - A new class of synthetic anti-lipopolysaccharide peptides inhibits influenza A virus replication by blocking cellular attachment. AB - Influenza A viruses are a continuous threat to human health as illustrated by the 2009 H1N1 pandemic. Since circulating influenza virus strains become increasingly resistant against currently available drugs, the development of novel antivirals is urgently needed. Here, we have evaluated a recently described new class of broad-spectrum antiviral peptides (synthetic anti-lipopolysaccharide peptides; SALPs) for their potential to inhibit influenza virus replication in vitro and in vivo. We found that particularly SALP PEP 19-2.5 shows high binding affinities for the influenza virus receptor molecule, N-Acetylneuraminic acid, leading to impaired viral attachment and cellular entry. As a result, replication of several influenza virus subtypes (H7N7, H3N2 and 2009 pandemic H1N1) was strongly reduced. Furthermore, mice co-treated with PEP 19-2.5 were protected against an otherwise 100% lethal H7N7 influenza virus infection. These findings show that SALPs exhibit antiviral activity against influenza viruses by blocking virus attachment and entry into host cells. Thus, SALPs present a new class of broad spectrum antiviral peptides for further development for influenza virus therapy. PMID- 24486208 TI - The effect of Chaihu-Shugan-San and its components on the expression of ERK5 in the hippocampus of depressed rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chaihu-Shugan-San (CSS) is a well-known, Chinese traditional medicine used to treat depression. Little is known about the antidepressant mechanism of CSS. The main aims of the this study were to evaluate the antidepressant-like effects of CSS and its components and further explore the CSS's effect upon signal transduction of extracellular signal-regulated kinase 5 (ERK5) expressions in the hippocampus of rats with depression induced by chronic unpredicted mild stress. MATERIALS AND METHODS: SD rats were randomly divided into six groups: Normal; Model; CSS; Component I; Component II; and Fluoxetine. Antidepressant-like effects of CSS and two of its constituents, Components I and II in aqueous extract, were assessed using rats exposed to chronic unpredictable mild stress (CUMS) by measuring weight change, observing the open-field test and measuring sucrose water consumption. Antidepressant mechanism were examined by measuring the effect of CSS, and two of its constituents, on extracellular signal regulated kinase 5 (ERK5) expression, phosphorylation-ERK5 (p-ERK5), and ERK5 mRNA in the hippocampus by using western blotting and Real-time Polymerase Chain Reaction (PCR). Three preparations were prepared: (1) an aqueous extract of CSS (5.9 g/kg.d); (2) Component I (3.3 g/kg.d); and (3) Component II (2.6 g/kg.d). During the 28-day CUMS, the three preparations were intragastrically administered all three preparations. Simultaneously a parallel positive fluoxetine control group was given fluoxetine hydrochloride (1.8mg/kg.d). Normal and Model groups were intragastrically administered with a isovolumic distilled water (4.5 ml/kg.d). RESULTS: Depressed rats had decreased weight gain; decreased locomotor activity as measured by the open field test; and reduced sucrose consumption. The rats' hippocampus ERK5 activation was significantly suppressed. CSS reduced the incidence of depressive-like behaviors and increased ERK5 activation in depressed rats at the same rate as fluoxetine. Component I, and II, each had only a partial effect on the depression indicators measured. CONCLUSIONS: CSS aqueous extract has antidepressant-like effects on CUMS-induced depression model rats. The antidepressant effect of CSS is greater than that of either the two separate components measured. CSS's antidepressant mechanism may be mediated by reversing the stress-induced disruption of ERK5 activity. PMID- 24486209 TI - Schisandrin B suppresses TGFbeta1-induced stress fiber formation by inhibiting myosin light chain phosphorylation. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Schisandra chinensis fruit extract (SCE) has been used as a traditional oriental medicine for treating vascular diseases. However, the pharmacologic effects and mechanisms of SCE on vascular fibrosis are still largely unknown. Transforming growth factor beta1 (TGFbeta1)-mediated cellular changes are closely associated with the pathogenesis of vascular fibrotic diseases. Particularly, TGFbeta1 induces actin stress fiber formation that is a crucial mechanism underlying vascular smooth muscle cell (VSMC) migration in response to vascular injury. In this study, we investigated the effect of SCE and its active ingredients on TGFbeta1-induced stress fiber assembly in A7r5 VSMCs. MATERIALS AND METHODS: To investigate pharmacological actions of SCE and its ingredients on TGFbeta1-treated VSMCs, we have employed molecular and cell biological technologies, such as confocal microscopy, fluorescence resonance energy transfer, western blotting, and radiometric enzyme analyses. RESULTS: We found that SCE inhibited TGFbeta1-induced stress fiber formation and cell migration. Schisandrin B (SchB) showed the most prominent effect among the active ingredients of SCE tested. SchB reduced TGFbeta1-mediated phosphorylation of myosin light chain, and this effect was independent of RhoA/Rho-associated kinase pathway. Fluorescence resonance energy transfer and radiometric enzyme assays confirmed that SchB inhibited myosin light chain kinase activity. We also showed that SchB decreased TGFbeta1-mediated induction of alpha-smooth muscle actin by inhibiting Smad signaling. CONCLUSIONS: The present study demonstrates that SCE and its active ingredient SchB suppressed TGFbeta1-induced stress fiber formation at the molecular level. Therefore, our findings may help future investigations to develop multi-targeted therapeutic strategies that attenuate VSMC migration and vascular fibrosis. PMID- 24486212 TI - Good practice in ethnopharmacology and other sciences relying on taxonomic nomenclature. PMID- 24486210 TI - Subchronic toxicity study of Coptidis rhizoma in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Coptidis Rhizoma (CR) is a medical herb from the family Ranunculacease that has been used to treat gastroenteritis, dysentery, diabetes mellitus, and severe skin diseases. AIM OF THE STUDY: To evaluate the no observed-adverse-effect level (NOAEL) and the toxicity of CR, following repeat oral administration to rats for 13 weeks. MATERIALS AND METHODS: CR was administered by oral gavage to groups of rats (n=10/group, each sex) at dose levels of 0 (control), 25, 74, 222, 667 or 2000 mg/kg/day 5 times per week for 13 weeks. Mortality, clinical signs, body weights, food consumption, hematology, serum chemistry, urinalysis, vaginal cytology and sperm morphology, organ weights, gross and histopathological findings were compared between control and CR groups. RESULTS: Urinalysis showed a significant increase in N-acety1-beta glucosaminidase in males in the 2000 mg/kg/day group (P<0.01). However, no mortality or remarkable clinical signs were observed during this 13-week study. No adverse effects on body weight, food consumption, hematology, serum chemistry, organ weights, gross lesion, histopathology, vaginal cytology, sperm motility, or deformity were observed in the males or female rats treated with CR. CONCLUSIONS: On the basis of these results, the NOAEL of CR is determined to be 667 mg/kg/day for males and 2000 mg/kg/day for females. PMID- 24486211 TI - Glycyrrhizin accelerates the metabolism of triptolide through induction of CYP3A in rats. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Triptolide (TP), a major active component of Tripterygium wilfordii, possesses various pharmacological activities with narrow therapeutic window and severe toxicities. Glycyrrhizin (GL), the principal bioactive ingredient of licorice root extract, has been reported to be concomitantly administered with TP in treatment of rheumatoid arthritis with the aim of potentiated efficacy and reduced toxicity. The aim of the study is to investigate the effect of GL on the pharmacokinetic profiles of TP and related mechanisms. MATERIALS AND METHODS: Male and female Wistar rats were randomly divided into two groups: Control group and GL group (pretreated with GL at 100 mg/kg/day for seven consecutive days). After oral administration of TP at a single dose of 450 MUg/kg, plasma concentrations of TP were determined using HPLC MS/MS and pharmacokinetic parameters were calculated by non-compartmental analysis using Phoenix WinNonlin 6.3 software. Since CYP3A is the primary isoform of cytochrome P450s responsible for the metabolism of TP, we further determined to what extent ketoconazole (KCZ), a potent CYP3A inhibitor, could influence the effect of GL on the pharmacokinetics of TP by comparing the pharmacokinetic profiles of TP in GL group (pretreated with GL) and GL+KCZ group (pretreated with both GL and KCZ), as well as verified whether pretreatment of GL could induce the activity of hepatic CYP3A by comparing the AUC parameters after intravenous administration of midazolam (MDZ), a typical probe drug for CYP3A, in rats pretreated with vehicle or GL. RESULTS: Our study revealed marked differences in pharmacokinetic profiling patterns of TP between male and female rats in the Control group; the plasma level of TP in males was far lower than that in females. After pretreatment with GL, the pharmacokinetic profiles of TP were significantly altered in both male and female rats; a remarkable decrease was found in the value of AUCinfinity, MRTinfinity and t1/2 in the GL group, compared with the Control group. But such a decrease was reversed by KCZ; compared with the GL group, the values of AUCinfinity, MRTinfinity and t1/2 were significantly increased in the GL+KCZ group. Pretreatment with GL notably increased the AUCinfinity of 1'-hydroxymidazolam (OH-MDZ) and the ratio of AUCinfinity of OH MDZ to MDZ, demonstrating induction of the activity of CYP3A by GL. CONCLUSION: Pretreatment with GL significantly accelerates the metabolic elimination of TP from the body mainly through induction of hepatic CYP3A activity. These results may help explain why toxicity of TP may be attenuated with concomitant use of GL. PMID- 24486213 TI - Protective effects of puerariae radix extract and its single compounds on methylglyoxal-induced apoptosis in human retinal pigment epithelial cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: In Korea, Puerariae radix is a medicinal plant traditionally used to treat various diseases including diabetes mellitus. To provide pharmacological basis for Puerariae radix in the treatment of diabetes, we investigated the protective effects of the ethanolic extract and its single compounds on apoptosis associated with glycation in human retinal pigment epithelial (RPE) cells. MATERIALS AND METHODS: In the present work, a quantified ethanolic extract or single compounds of Puerariae radix were selected to determine its anti-apoptotic effect in human RPE cells cultured with methylglyoxal (MG), which is a stimulator of glycation. To assess the protective effect of the extract or single compounds, the cytotoxicity assessment was performed using an MTT assay in the human RPE cells. Selected active compounds or extracts were tested by FACS analysis with annexin V staining for apoptosis. RESULTS: Daidzein (1), daidzin (2), puerarin (3), 3'-hydroxy-daidzein 8-C-apiosyl (1->6) glucoside (4), and daidzein 8-C-apiosyl (1->6) glucoside (5), and pueroside B (6) were isolated from an ethanolic extract of Puerariae radix. MG induced apoptosis was completely inhibited by Puerariae radix, ethanolic extract, and single compounds. Of the six major compounds, daidzin (2) and 3'-hydroxy daidzein 8-C-apiosyl (1->6) glucoside (4) significantly inhibited MG-induced apoptosis. CONCLUSION: Our results provide the first evidence that, due to its anti-glycation effect, Puerariae radix extract could inhibit MG-induced apoptosis in the cultured human RPE cells. These data suggest that Puerariae radix extract, especially its single compounds daidzin and 3'-hydroxy-daidzein 8-C-apiosyl (1 >6) glucoside, has potential utility as a preventive agent for glycation-related diabetic retinopathy. PMID- 24486214 TI - Nucleolin-targeting liposomes guided by aptamer AS1411 for the delivery of siRNA for the treatment of malignant melanomas. AB - BRAF gene mutation is found in more than 60% of malignant melanomas, which are difficult to treat. In this study, a new tumor-targeting liposome was developed to deliver anti-BRAF siRNA (siBraf) for the treatment of melanomas. Nucleolin is overexpressed on the surface of cancer cells. AS1411, an aptamer showing specific binding to nucleolin, was conjugated to PEGylated cationic liposome as the targeting probe ASLP (AS1411-PEG-liposome). The ASLP/siRNA complex was formed through electrostatic interaction between ASLP and siRNA. The binding of AS1411 to the surface of PEGylated liposomes was confirmed by gel electrophoresis and capillary electrophoresis. Real-time PCR and Western blot analysis showed that ASLP/siBraf exhibited strong silencing activity of BRAF gene. The much higher accumulation of the siRNA in tumor cells comparing with normal cells indicated that ASLP displayed excellent tumor-targeting capability. Notably, ASLP/siBraf showed significant silencing activity in A375 tumor xenograft mice and inhibited the melanoma growth. These results suggested that the new nucleolin-targeted siRNA delivery system by AS1411 may have the potential for the treatment of melanoma. PMID- 24486215 TI - Star-shaped cyclodextrin-poly(l-lysine) derivative co-delivering docetaxel and MMP-9 siRNA plasmid in cancer therapy. AB - A new cyclodextrin derivative (CD-PLLD) consisting of a beta-cyclodextrin core and poly(l-lysine) dendron arms was prepared by the click conjugation of per-6 azido-b-cyclodextrin with propargyl focal point poly(l-lysine) dendron of third generation, and then used for docetaxel (DOC) and the best siRNA plasmid targeting MMP-9 (pMR3) co-delivery. Different from commonly used amphiphilic copolymers with cationic character, the as obtained cyclodextrin derivative may be used directly for the combinatorial delivery of nucleic acid and lipophilic anticancer drugs without a complicated micellization process. It was found that CD-PLLD/pMR3 nanocomplex showed a good gene transfection efficiency in vitro, and could mediate the reduce of MMP-9 protein in HNE-1 cells. For co-delivery analysis, the obtained CD-PLLD/DOC/pMR3 complexes could induce a more significant apoptosis than DOC or pMR3 used only, and decreased invasive capacity of HNE-1 cells. Moreover, the star-shaped copolymer exhibited better blood compatibility and lower cytotoxicity compared to PEI-25k in the hemolysis and MTT assays, which should be encouraged in nasopharyngeal cancer therapy. PMID- 24486216 TI - Silicate bioceramics enhanced vascularization and osteogenesis through stimulating interactions between endothelia cells and bone marrow stromal cells. AB - The facts that biomaterials affect the behavior of single type of cells have been widely accepted. However, the effects of biomaterials on cell-cell interactions have rarely been reported. Bone tissue engineering involves osteoblastic cells (OCs), endothelial cells (ECs) and the interactions between OCs and ECs. It has been reported that silicate biomaterials can stimulate osteogenic differentiation of OCs and vascularization of ECs. However, the effects of silicate biomaterials on the interactions between ECs and OCs during vascularization and osteogenesis have not been reported, which are critical for bone tissue regeneration in vivo. Therefore, this study aimed to investigate the effects of calcium silicate (CS) bioceramics on interactions between human umbilical vein endothelial cells (HUVECs) and human bone marrow stromal cells (HBMSCs) and on stimulation of vascularization and osteogenesis in vivo through combining co-cultures with CS containing scaffolds. Specifically, the effects of CS on the angiogenic growth factor VEGF, osteogenic growth factor BMP-2 and the cross-talks between VEGF and BMP-2 in the co-culture system were elucidated. Results showed that CS stimulated co-cultured HBMSCs (co-HBMSCs) to express VEGF and the VEGF activated its receptor KDR on co-cultured HUVECs (co-HUVECs), which was also up-regulated by CS. Then, BMP-2 and nitric oxide expression from the co-HUVECs were stimulated by CS and the former stimulated osteogenic differentiation of co-HBMSCs while the latter stimulated vascularization of co-HVUECs. Finally, the poly(lactic-co glycolic acid)/CS composite scaffolds with the co-cultured HBMSCs and HUVECs significantly enhanced vascularization and osteogenic differentiation in vitro and in vivo, which indicates that it is a promising way to enhance bone regeneration by combining scaffolds containing silicate bioceramics and co cultures of ECs and OCs. PMID- 24486218 TI - MicroRNA-195 inhibits non-small cell lung cancer cell proliferation, migration and invasion by targeting MYB. AB - MicroRNA-195 (miR-195) has been implicated in several other cancers; however, its role in non-small cell lung cancer (NSCLC) remains unclear. In this study, we demonstrated that miR-195 was significantly down-regulated in NSCLC samples and cell lines compared with corresponding normal counterparts. In vitro and in vivo functional assays demonstrated that modulation of miR-195 expression affected NSCLC cell proliferation, migration and invasion. Using miRNA target prediction algorithms and reporter assays, we demonstrated that miR-195 suppressed the expression of MYB both at the mRNA and protein level, and was directly bound to the 3'untranslated region of MYB mRNA. Overexpression of MYB in NSCLC cells using an ectopic expression vector restored the decreased cell proliferation, migration and invasion effects induced by miR-195. Finally, we observed an inverse correlation between MYB and miR-195 in NSCLC. Taken together, our findings indicated that miR-195 functions as tumour suppressor in NSCLC, and the miR 195/MYB axis might represent a potential therapeutic target for NSCLC intervention. PMID- 24486217 TI - Nucleotide metabolism, oncogene-induced senescence and cancer. AB - Senescence is defined as a stable cell growth arrest. Oncogene-induced senescence (OIS) occurs when an activated oncogene is expressed in a normal cell. OIS acts as a bona fide tumor suppressor mechanism by driving stable growth arrest of cancer progenitor cells harboring the initial oncogenic hit. OIS is often characterized by aberrant DNA replication and the associated DNA damage response. Nucleotides, in particular deoxyribonucleotide triphosphates (dNTPs), are necessary for both DNA replication and repair. Imbalanced dNTP pools play a role in a number of human diseases, including during the early stages of cancer development. This review will highlight what is currently known about the role of decreased nucleotide metabolism in OIS, how nucleotide metabolism leads to transformation and tumor progression, and how this pathway can be targeted as a cancer therapeutic by inducing senescence of cancer cells. PMID- 24486219 TI - The AMP-activated protein kinase (AMPK) and cancer: many faces of a metabolic regulator. AB - The AMP-activated protein kinase (AMPK) is a central regulator of cellular metabolism and energy homeostasis in mammalian tissues. Pertinent to cancer biology is the fact that AMPK is situated in the center of a signaling network involving established tumor suppressors including LKB1, TSC2 and p53. However, recent research suggests that AMPK can exert pro- or anti-tumorigenic roles in cancer depending on context. Loss of AMPK activity has been observed in several tumor types, and can cooperate with oncogenic drivers to reprogram tumor cell metabolism and enhance cell growth and proliferation. However, AMPK activation can also provide a growth advantage to tumor cells by regulating cellular metabolic plasticity, thus providing tumor cells the flexibility to adapt to metabolic stress. Here we discuss the contextual nature of the "two faces" of AMPK in cancer, and discuss the rationale and context for employing AMPK activators versus inhibitors for cancer therapy. PMID- 24486222 TI - Setleis syndrome: genetic and clinical findings in a new case with epilepsy. AB - BACKGROUND: Focal facial dermal dysplasias are a group of inherited ectodermal disorders characterized by congenital bitemporal or periauricular scar-like depressions as well as other facial and nonfacial developmental defects. Four subtypes have been delineated, and mutations in the TWIST2 gene have been identified in type III focal facial dermal dysplasia (Setleis syndrome). PATIENTS: We describe a sporadic patient with the hallmark bitemporal scar-like lesions, severe intellectual disability, and focal epilepsy. RESULTS: The boy has typical features of Setleis syndrome, and he developed focal epilepsy, a previously unreported feature of this syndrome. No mutations in the TWIST2 gene were found, and there were no pathologic copy number abnormalities. CONCLUSIONS: Epilepsy could represent a new manifestation, and the patient described broadens the spectrum of clinical features associated with Setleis syndrome, including central nervous system involvement. PMID- 24486221 TI - Mechanism-based treatment in tuberous sclerosis complex. AB - BACKGROUND: Tuberous sclerosis complex (TSC) is a genetic multisystem disorder that affects the brain in almost every patient. It is caused by a mutation in the TSC1 or TSC2 genes, which regulate mammalian target of rapamycin (mTOR), a key player in control of cellular growth and protein synthesis. The most frequent neurological symptoms are seizures, which occur in up to 90% of patients and often are intractable, followed by autism spectrum disorders, intellectual disability, attention deficit-hyperactivity disorder, and sleep problems. Conventional treatment has frequently proven insufficient for neurological and behavioral symptoms, particularly seizure control. This review focuses on the role of TSC/mTOR in neuronal development and network formation and recent mechanism-based treatment approaches. METHODS: We performed a literature review to identify ongoing therapeutic challenges and novel strategies. RESULTS: To achieve a better quality of life for many patients, current therapy approaches are directed at restoring dysregulated mTOR signaling. Studies in animals have provided insight into aberrant neuronal network formation caused by constitutive activation of the mTOR pathway, and initial studies in TSC patients using magnetic resonance diffusion tensor imaging and electroencephalogram support a model of impaired neuronal connectivity in TSC. Rapamycin, an mTOR inhibitor, has been used successfully in Tsc-deficient mice to prevent and treat seizures and behavioral abnormalities. There is recent evidence in humans of improved seizure control with mTOR inhibitors. CONCLUSIONS: Current research provides insight into aberrant neuronal connectivity in TSC and the role of mTOR inhibitors as a promising therapeutic approach. PMID- 24486220 TI - Anti-tumor activity of non-steroidal anti-inflammatory drugs: cyclooxygenase independent targets. AB - Non-steroidal anti-inflammatory drugs (NSAIDs) are used extensively for analgesic and antipyretic treatments. In addition, NSAIDs reduce the risk and mortality to several cancers. Their mechanisms in anti-tumorigenesis are not fully understood, but both cyclooxygenase (COX)-dependent and -independent pathways play a role. We and others have been interested in elucidating molecular targets of NSAID-induced apoptosis. In this review, we summarize updated literature regarding cellular and molecular targets modulated by NSAIDs. Among those NSAIDs, sulindac sulfide and tolfenamic acid are emphasized in this review because these two drugs have been well investigated for their anti-tumorigenic activity in many different types of cancer. PMID- 24486223 TI - Atlas shrugged: cervical myelopathy caused by congenital atlantoaxial dislocation aggravated by child labor. AB - BACKGROUND: Symptomatic atlantoaxial dislocation is common in predisposing genetic or acquired disorders. However, an isolated atlantoaxial dislocation frequently is congenital and silent unless discovered during course of evaluation for neurological symptoms of cervical spinal cord injury attributed to minor or chronic, repetitive trauma. PATIENT: A 12-year-old girl working as a farm laborer developed calf pain provoked by walking, which increased in severity and progressed to involve the upper limbs. It was followed by progressive ascending quadriplegia. The illness resembled acute inflammatory demyelinating polyneuropathy with respiratory involvement. Presence of "claw" hands bilaterally and wasting of intrinsic muscles of the hands led to the suspicion of a cervical myelopathy. RESULT: Neuroimaging confirmed a congenital atlantoaxial dislocation with basilar invagination. The absence of abnormal signals in the cervical spinal cord was unusual. The symptomatic congenital atlantoaxial dislocation was postulated to be precipitated by chronic trauma suffered while habitually carrying heavy loads on the head and leading to spinal cord injury without radiographic abnormalities. Correction via surgery was successful. CONCLUSIONS: Congenital atlantoaxial dislocation should be suspected in a clinical setting of neurological symptoms of cervical spinal cord injury without obvious trauma or predisposing primary diseases. Prompt cervical spine imaging reveals the correct diagnosis. Physicians in countries in which child labor is rampant should be aware of the potential complications of cervical cord injuries from child labor. PMID- 24486224 TI - Probiotic Lactobacillus rhamnosus GR-1 supernatant prevents lipopolysaccharide induced preterm birth and reduces inflammation in pregnant CD-1 mice. AB - OBJECTIVE: The objective of this study was to determine the effect of probiotic Lactobacillus rhamnosus GR-1 supernatant (GR-1 SN) on lipopolysaccharide-induced preterm birth (PTB) and outputs of cytokines, chemokines, and progesterone in pregnant CD-1 mice. STUDY DESIGN: We compared PTB rates after intrauterine injection of lipopolysaccharide with and without previous GR-1 SN treatment. Cytokines and chemokines in the maternal plasma, myometrium, placenta, and amniotic fluid were examined with multiplex assay, and circulating maternal progesterone was measured with enzyme-linked immunoassay. Statistical significance was assessed with 2-tailed 1-way analysis of variance or analysis of variance on ranks. Fetal sex ratios in mice that delivered preterm were compared with those that delivered at term after lipopolysaccharide and GR-1 SN treatments. RESULTS: GR-1 SN reduced lipopolysaccharide-induced PTB by 43%. GR-1 SN significantly decreased the lipopolysaccharide-induced production of interleukin (IL)-1beta, -6, and -12p40, tumor necrosis factor-alpha, CCL4, and CCL5 in maternal plasma; IL-6, -12p70, -17, and -13 and tumor necrosis factor alpha in myometrium; IL-6, -12p70, and -17 in placenta; and IL-6, tumor necrosis factor-alpha, CCL3, and CCL4 in amniotic fluid. Maternal plasma progesterone was reduced significantly after lipopolysaccharide injection with and without GR-1 SN pretreatment. There was no difference in fetal sex ratios between mice that delivered preterm and those that did not after lipopolysaccharide and GR-1 SN treatments. CONCLUSION: The supernatant of probiotic L rhamnosus GR-1 attenuated lipopolysaccharide-induced inflammation and PTB in vivo. GR-1 SN may confer therapeutic benefits in the prevention of infection-associated PTB by controlling systemic and intrauterine inflammation. PMID- 24486225 TI - Lifetime physical activity and pelvic organ prolapse in middle-aged women. AB - OBJECTIVE: To determine, in a case-control study, whether pelvic organ prolapse (POP) is associated with overall lifetime physical activity (combined leisure, outdoor, household, occupational), and lifetime leisure, lifetime strenuous, and teen years strenuous activity. STUDY DESIGN: One hundred ninety-one POP cases (defined as maximal vaginal descent >=1 cm below the hymen) and 191 age and recruitment-site matched controls (defined as maximal vaginal descent <=1 cm above the hymen) between 39-65 years with no or mild urinary incontinence, were recruited chiefly from primary care clinics. Participants completed Lifetime Physical Activity and Occupation Questionnaires, recalling activities during 4 age epochs. We performed separate logistic regression models for physical activity measures. RESULTS: Compared with controls, POP cases had greater body mass index and parity. Median overall lifetime activity, expressed in metabolic equivalents-hours/week, did not differ significantly between cases and controls. In adjusted analyses, we observed no associations between odds of POP and overall lifetime physical activity, lifetime leisure activity, or lifetime strenuous activity. There was a marginally significant nonlinear relationship between teen strenuous activity and POP with an increase in the log-odds of POP for women reporting >=21 hours/week of strenuous activity (P = .046). CONCLUSION: Lifetime physical activity does not increase the odds of anatomic POP in middle-aged women not seeking care for POP. Strenuous activity during teenage years may confer higher odds of POP. This relationship and the potential role of physical activity and POP incidence should be evaluated prospectively. PMID- 24486226 TI - Risk of cesarean in obese nulliparous women with unfavorable cervix: elective induction vs expectant management at term. AB - OBJECTIVE: The objective of the study was to examine maternal and neonatal outcomes in obese nulliparous women with an unfavorable cervix undergoing elective induction of labor compared with expectant management after 39.0 weeks. STUDY DESIGN: This was a retrospective analysis of a cohort of nulliparous women with a vertex singleton gestation who delivered at MedStar Washington Hospital Center from 2007 to 2012. Patients with unfavorable cervix between 38.0 and 38.9 weeks (modified Bishop <5) and a body mass index of 30.0 kg/m(2) or greater at the time of delivery were included. Women undergoing elective induction between 39.0 and 40.9 weeks' gestation were compared with those who were expectantly managed beyond 39.0 weeks. Outcomes were analyzed using chi(2), Student t, or Wilcoxon rank sum tests as appropriate with a significance set at P < .05. RESULTS: Sixty patients meeting inclusion criteria underwent elective induction of labor and were compared with 410 patients expectantly managed beyond 39.0 weeks. The rate of cesarean delivery was significantly higher in the electively induced group (40.0% vs 25.9%, respectively, P = .022). Other maternal outcomes, including operative vaginal delivery, rate of third- or fourth-degree lacerations, chorioamnionitis, postpartum hemorrhage, and a need for a blood transfusion were similar. The neonatal intensive care unit admission rate was higher in the electively induced group (18.3% vs 6.3%, P = .001). Birthweight, umbilical artery pH less than 7.0, and Apgar less than 7 at 5 minutes were similar. CONCLUSION: Elective labor induction at term in obese nulliparous parturients carries an increased risk of cesarean delivery and higher neonatal intensive care unit admission rate as compared with expectant management. PMID- 24486228 TI - Evolution of division of labor: emergence of different activities among group members. AB - The division of labor is an important component of the organization of human society. However, why this division evolved in hominids requires further investigation. Archeological evidence suggests that it appeared after the emergence of Homo sapiens and contributed to the great success of our species. We develop a mathematical model to investigate under what conditions division of labor should evolve. We assume two types of resources the acquisition of which demands different skills, and study the evolution of the strategy that an individual should use to divide its lifetime into learning and using each skill. We show that division of labor likely evolves when group size is large, skill learning is important for acquiring resources, and there is food sharing within a group. We also investigate division of labor by gender under the assumption that the genders have different efficiencies in acquiring each resource. We show that division of labor by gender likely evolves when skill learning is important and the difference in efficiencies between genders in acquiring resources is large. We discuss how the results of our analysis might apply to the evolution of division of labor in hominids. PMID- 24486227 TI - Complications related to pubic hair removal. AB - OBJECTIVE: We investigated the prevalence and correlates of complications related to pubic hair removal among a diverse clinical sample of women attending a public clinic. STUDY DESIGN: Women (aged 16-40 years) who received care from April to June 2012 at 2 publicly funded clinics completed an anonymous, self-administered questionnaire (n = 369). After excluding women with missing data, analyses were conducted on 333 women. Additional measures were retrieved through a medical chart review. A chi(2) and a multivariable logistic regression were used to analyze participant characteristics, pubic hair removal behaviors, and complications related to pubic hair removal. RESULTS: Most women (87%) admitted to current removal of at least some pubic hair, whereas the remainder responded that they had removed pubic hair in the past. Under- or normal-weight women were more likely to report total pubic hair removal than overweight or obese women. The majority (60%) had experienced at least 1 health complication because of the removal, of which the most common were epidermal abrasion and ingrown hairs. Black and Hispanic women were less likely than white women to report complications. Overweight or obese women were almost twice as likely to report a complication and almost 3 times as likely if they also had total hair removal. Only 4% had seen a health care provider for a complication related to hair removal and only 4% discussed safe removal practices with their doctor. CONCLUSION: Minor complications commonly occur as a result of pubic hair removal. Gynecological visits could provide a safe environment for women to discuss pubic hair removal practices. PMID- 24486229 TI - Viral genome phylogeny based on Lempel-Ziv complexity and Hausdorff distance. AB - In this paper, we develop a novel method to study the viral genome phylogeny. We apply Lempel-Ziv complexity to define the distance between two nucleic acid sequences. Then, based on this distance we use the Hausdorff distance (HD) and a modified Hausdorff distance (MHD) to make the phylogenetic analysis for multi segmented viral genomes. The results show the MHD can provide more accurate phylogenetic relationship. Our method can have global comparison of all multi segmented genomes simultaneously, that is, we treat the multi-segmented viral genome as an entirety to make the comparative analysis. Our method is not affected by the number or order of segments, and each segment can make contribution for the phylogeny of whole genomes. We have analyzed several groups of real multi-segmented genomes from different viral families. The results show that our method will provide a new powerful tool for studying the classification of viral genomes and their phylogenetic relationships. PMID- 24486230 TI - Residue interaction network analysis of Dronpa and a DNA clamp. AB - Topology is an essential aspect of protein structure. The network paradigm is increasingly used to describe the topology and dynamics of proteins. In this paper, the effect of topology on residue interaction network was investigated for two different proteins: Dronpa and a DNA clamp, which have cylindrical and toroidal topologies, respectively. Network metrics including characteristic path lengths, clustering coefficients, and diameters were calculated to investigate their global topology parameters such as small-world properties and packing density. Measures of centrality including betweenness, closeness, and residue centrality were computed to predict residues critical to function. Additionally, the detailed topology of the hydrophobic pocket in Dronpa, and communication pathways across the interface in the DNA clamp, were investigated using the network. The results are presented and discussed with regard to existing residue interaction network properties of globular proteins and elastic network models on Dronpa and the DNA clamp. The topological principle underlying residue interaction networks provided insight into the architectural organization of proteins. PMID- 24486231 TI - Simulation of swimming of a flexible filament using the generalized lattice spring lattice-Boltzmann method. AB - A generalized lattice-spring lattice-Boltzmann model (GLLM) is introduced by adding a three-body force in the traditional lattice-spring model. This method is able to deal with bending deformation of flexible biological bodies in fluids. The interactions between elastic solids and fluid are treated with the immersed boundary-lattice Boltzmann method. GLLM is validated by comparing the present results with the existing theoretical and simulation results. As an application of GLLM, swimming of flagellum in fluid is simulated and propulsive force as a function of driven frequency and fluid structures at various Reynolds numbers 0.15-5.1 are presented in this paper. PMID- 24486232 TI - The importance of liver microcirculation in promoting autoimmune hepatitis via maintaining an inflammatory cytokine milieu--a mathematical model study. AB - In autoimmune diseases, inflammatory cytokine concentrations are important for initiating and maintaining the status of autoimmunity. Autoimmune hepatitis (AIH) is an inflammatory liver disease characterized by a loss of immune tolerance against specific antigens located in hepatocytes. During the progression of the disease, antigen-presenting cells and different classes of T-helper cells secrete specific cytokines important for maintaining the disease. As these cytokines are secreted into the local liver environment, the blood flow in liver sinusoids might influence the local cytokine concentration. Considering the liver tissue as a porous medium, based on Darcy's law, the microcirculation within a liver lobule was modelled. Using realistic physiological pressure differences and tissue permeabilities, the blood velocity inside the sinusoids could be calculated and validated with blood velocity data obtained via Orthogonal Polarization Spectral Imaging (OPSI). Furthermore, oxygen consumption is modelled to obtain Rappaport's acinus model. Finally, steady state spatial distributions of secreted cytokines within the liver lobule could be estimated for specified realistic production rates of T-helper cells. It could be demonstrated that the characteristics of the liver microcirculation have an important impact on establishing inflammatory cytokine levels within the portal fields and the vascular septa promoting the occurrence of interface hepatitis. PMID- 24486233 TI - Insights into the mechanisms of thymus involution and regeneration by modeling the glucocorticoid-induced perturbation of thymocyte populations dynamics. AB - T-cells develop in the thymus and based on CD4 and CD8 expressions there are four main thymocyte populations in a normal mouse thymus. Currently, there are several mathematical models that describe the dynamics of thymocyte populations in a normal thymus, but only a few of them model the transient perturbation of their homeostasis. Our aim is to model the perturbation in the dynamics of each thymocyte population which is induced by the administration of a glucocorticoid, i.e. dexamethasone. The proposed approach relies on extending a four compartment thymus model based on differential equations by adding perturbation terms either globally (at the level of each equation) or locally (at the level of proliferation, death, and transfer rates). By fitting the perturbed model with experimental data on mice thymi collected before and after the administration of dexamethasone, it was possible to estimate the relevant parameters using a population-based stochastic search method. The fitted model is further used to conduct a quantitative analysis on the differentiated impact of dexamethasone on each T-cell population and on proliferation, death, and transfer processes. The obtained quantitative information on the perturbation could be used to explore and modify the flow of thymocytes between thymus compartments in order to elucidate the mechanisms of thymus involution and its subsequent regeneration. Since glucocorticoids are raised in many pathological situations, such a model could be useful in evaluating the impact of diseases on thymocyte dynamics in the thymus. PMID- 24486234 TI - Dynamic flight stability of a hovering model dragonfly. AB - The longitudinal dynamic flight stability of a model dragonfly at hovering flight is studied, using the method of computational fluid dynamics to compute the stability derivatives and the techniques of eigenvalue and eigenvector analysis for solving the equations of motion. Three natural modes of motion are identified for the hovering flight: one unstable oscillatory mode, one stable fast subsidence mode and one stable slow subsidence mode. The flight is dynamically unstable owing to the unstable oscillatory mode. The instability is caused by a pitch-moment derivative with respect to horizontal velocity. The damping force and moment derivatives (with respect to horizontal and vertical velocities and pitch-rotational velocity, respectively) weaken the instability considerably. The aerodynamic interaction between the forewing and the hindwing does not have significant effect on the stability properties. The dragonfly has similar stability derivatives, hence stability properties, to that of a one-wing-pair insect at normal hovering, but there are differences in how the derivatives are produced because of the highly inclined stroke plane of the dragonfly. PMID- 24486235 TI - Chromatin structure and radiation-induced DNA damage: from structural biology to radiobiology. AB - Genomic DNA in eukaryotic cells is basically divided into chromosomes, each consisting of a single huge nucleosomal fiber. It is now clear that chromatin structure and dynamics play a critical role in all processes involved in DNA metabolism, e.g. replication, transcription, repair and recombination. Radiation is a useful tool to study the biological effects of chromatin alterations. Conversely, radiotherapy and radiodiagnosis raise questions about the influence of chromatin integrity on clinical features and secondary effects. This review focuses on the link between DNA damage and chromatin structure at different scales, showing how a comprehensive multiscale vision is required to understand better the effect of radiations on DNA. Clinical aspects related to high- and low dose of radiation and chromosomal instability will be discussed. At the same time, we will show that the analysis of the radiation-induced DNA damage distribution provides good insight on chromatin structure. Hence, we argue that chromatin "structuralists" and radiobiological "clinicians" would each benefit from more collaboration with the other. We hope that this focused review will help in this regard. PMID- 24486236 TI - Characterization of the dynamic activities of a population of microbubbles driven by pulsed ultrasound exposure in sonoporation. AB - Ultrasound-driven microbubble activities have been exploited to transiently disrupt the cell membrane (sonoporation) for non-viral intracellular drug delivery and gene transfection both in vivo and in vitro. In this study, we investigated the dynamic behaviors of a population of microbubbles exposed to pulsed ultrasound and their impact on adherent cells in terms of intracellular delivery and cell viability. By systematically analyzing the bubble activities at time scales relevant to pulsed ultrasound exposure, we identified two quantification parameters that categorize the diverse bubble activities subjected to various ultrasound conditions into three characteristic behaviors: stable cavitation/aggregation (type I), growth/coalescence and translation (type II) and localized inertial cavitation/collapse (type III). Correlation of the bubble activities with sonoporation outcome suggested that type III behavior resulted in intracellular delivery, whereas type II behavior caused the death of a large number of cells. These results provide useful insights for rational selection of ultrasound parameters to optimize outcomes of sonoporation and other applications that exploit the use of ultrasound-driven bubble activities. PMID- 24486237 TI - Ultrasound analysis of diaphragm kinetics and the diagnosis of airway obstruction: the role of the M-mode index of obstruction. AB - Diaphragm motion in forced expiration can be analyzed using M-mode ultrasound in an anterior subcostal approach. Maximum expiratory diaphragmatic excursion (EDEMax) and forced expiratory diaphragmatic excursion in the first second (FEDE1) are considered the physiopathological analogues of vital capacity (VC) and forced expiratory volume in the first second (FEV1). As the FEV1/VC % ratio is used as a marker of obstruction, our aim was to determine if the ratio FEDE1/EDEMax (M-mode index of obstruction [MIO]) differs between healthy subjects and patients with airway obstruction. One hundred twenty-four outpatients were examined by diaphragm ultrasound after spirometry. The MIO, expressed as the mean +/- standard deviation (range), was 87.08 +/- 6.64 (72.84-100) in the healthy group (N = 61) and 67.09 +/- 12.49 (33.33-91.30) in the group with obstructed airways (N = 63). The difference between the two groups was significant (p < 0.0001), and MIO was significantly correlated with FEV1/VC (p < 0.0001). A MIO <77 was identified as a possibile cutoff for suspecting an obstructive spirometric pattern with a 95.5% positive predictive value. The MIO can be interpreted as a speed index of diaphragmatic relaxation that seems to be slower in obstructed patients and could be used to screen for obstructed airway diseases. PMID- 24486238 TI - Completely reversed flow in the vertebral artery does not always indicate subclavian steal phenomenon. AB - We evaluated the causes, differential diagnosis and clinical significance of completely reversed flow (CRF) in the vertebral artery (VA). Twenty-three patients diagnosed with CRF in the VA by Doppler ultrasound were studied retrospectively. CRF was divided into intermittent CRF and continuous CRF. The peak reversed velocity (PRV) and ratio of time in intermittent CRF to one cardiac cycle (tICRF/CC) were calculated. Causes of CRF were determined on the basis of previous angiography results. The results indicated that subclavian steal phenomenon (SSP) caused all cases of continuous CRF (n = 8). Intermittent CRF was caused by SSP (n = 6) or proximal VA occlusion (n = 9). PRV and tICRF/CC were increased in SSP as compared with VA occlusion (p < 0.05). Using a cutoff of tICRF/CC = 0.30, we achieved excellent accuracy in predicting the cause of intermittent CRF (100%) and posterior circulatory infarction (91%). Thus, analysis of CRF patterns and measurements of VA parameters can be used in differential diagnosis of the causes of CRF and in prediction of posterior circulatory infarction. PMID- 24486239 TI - Modeling of femoral neck cortical bone for the numerical simulation of ultrasound propagation. AB - Quantitative ultrasound assessment of the cortical compartment of the femur neck (FN) is investigated with the goal of achieving enhanced fracture risk prediction. Measurements at the FN are influenced by bone size, shape and material properties. The work described here was aimed at determining which FN material properties have a significant impact on ultrasound propagation around 0.5 MHz and assessing the relevancy of different models. A methodology for the modeling of ultrasound propagation in the FN, with a focus on the modeling of bone elastic properties based on scanning acoustic microscopy data, is introduced. It is found that the first-arriving ultrasound signal measured in through-transmission at the FN is not influenced by trabecular bone properties or by the heterogeneities of the cortical bone mineralized matrix. In contrast, the signal is sensitive to variations in cortical porosity, which can, to a certain extent, be accounted for by effective properties calculated with the Mori-Tanaka method. PMID- 24486240 TI - 21st century challenges to the provision of health care to adults with spina bifida: a rehabilitation approach. PMID- 24486241 TI - Validation of a body-worn accelerometer to measure activity patterns in octogenarians. AB - OBJECTIVE: To determine the validity of a triaxial body-worn accelerometer for detection of gait and postures in people aged >80 years. DESIGN: Participants performed a range of activities (sitting, lying, walking, standing) in both a controlled and a home setting while wearing the accelerometer. Activities in the controlled setting were performed in a scripted sequence. Activities in the home setting were performed in an unscripted manner. Analyzed accelerometer data were compared against video observation as the reference measure. SETTING: Independent living and long-term-care retirement village. PARTICIPANTS: Older people (N=22; mean age +/- SD, 88.1+/-5y) residing in long-term-care and independent-living retirement facilities. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: The level of agreement between video observation and the accelerometer for the total duration of each activity, and second-by-second correspondence between video observation and the accelerometer for each activity. RESULTS: The median absolute percentage errors between video observation and the accelerometer were <1% for locomotion and lying. The absolute percentage errors were higher for sitting (median, -22.3%; interquartile range [IQR], -62.8% to 10.7%) and standing (median, 24.7%; IQR, -7.3% to 39.6%). A second-by-second analysis between video observation and the accelerometer found an overall agreement of >=85% for all activities except standing (median, 56.1%; IQR, 34.8%-81.2%). CONCLUSIONS: This single-device accelerometer provides a valid measure of lying and locomotion in people aged >80 years. There is an error of approximately 25% when discriminating sitting from standing postures, which needs to be taken into account when monitoring longer-term habitual activity in this age group. PMID- 24486242 TI - Comparing multicomponent interventions to improve skin care behaviors and prevent recurrence in veterans hospitalized for severe pressure ulcers. AB - OBJECTIVE: To compare a multicomponent motivational interviewing (MI)/self management (SM) intervention with a multicomponent education intervention to improve skin-protective behaviors and prevent skin worsening in veterans with spinal cord injury (SCI) hospitalized for severe pressure ulcers (PrUs). DESIGN: Single-blinded, prospective, randomized controlled trial. SETTING: Six Veterans Affairs SCI centers. PARTICIPANTS: Veterans admitted for a severe (stage III/IV) PrU were followed up to 6 months postdischarge. INTERVENTION: Telephone-based individual MI counseling plus SM skills group (SM+MI; n=71) versus an active control group of telephone-based individual educational counseling plus group education (n=72). MAIN OUTCOME MEASURES: Self-reported skin-protective behaviors, objective skin worsening. RESULTS: Intention-to-treat analyses found nonsignificant increases in skin behaviors in the SM+MI versus education control intervention arms at 3 and 6 months. The difference in behaviors used between SM+MI and education control intervention participants was 4.6% (95% confidence interval [CI], -11.3 to 2.7) (0-3mo) and 3.0% (95% CI, -8.7 to 3.9) (0-6mo). High rates of skin worsening were observed (n=74, 51.7%), usually within 3 months postdischarge and most frequently within the month postdischarge. Skin worsening, skin-related visits, and readmissions did not differ by study arm. Study limitations are presented. CONCLUSIONS: For persons with chronic SCI and severe PrUs, complicated by multiple comorbidities, a primary focus on improving patient behavior is likely insufficient to address the complex problem of PrUs in SCI. More health care systems-level changes such as collaborative care may be needed to reduce PrU recurrence, especially in this era in which many people are discharged from the hospital unhealed or with little sitting tolerance. PMID- 24486243 TI - Parkinsonism may be part of the symptom complex of DOOR syndrome. PMID- 24486244 TI - Effect of estrogen on Th1, Th2 and Th17 cytokines production by proteolipid protein and PHA activated peripheral blood mononuclear cells isolated from multiple sclerosis patients. AB - BACKGROUND AND AIMS: A large body of studies has shown that 17-beta estradiol (E2) has a protective effect on susceptibility to experimental autoimmune encephalomyelitis (EAE). Clinical improvement in multiple sclerosis and its animal model, EAE, during pregnancy, when estrogen levels are high, suggests an immunomodulatory role for estrogens. The immune basis for this protection is poorly understood. In this study we evaluated the effect of E2 on the synthesis of inflammatory, antiinflammatory and regulatory cytokines. METHODS: We analyzed the effect of E2 on IL-4, IL-10, IL-17, TNF-alpha and IFN-gamma cytokines produced by proteolipid protein (PLP) or mitogen phytohemagglutinin (PHA) activated peripheral blood mononuclear cells isolated from multiple sclerosis patients in comparison to healthy control group. We used RT-PCR and ELISA to detect the level of cytokines. RESULTS: We found that E2 significantly increased IL-10 expression and secretion and decreased expression of TNF-alpha in both groups and IL-4 in patients in cells stimulated with PLP or PHA (p <0.0001). CONCLUSION: These data indicated that E2 could affect expression and secretion of inflammatory and anti-inflammatory cytokines and could regulate immune responses especially in the differentiation towards regulatory responses, and this finding might have therapeutic value in multiple sclerosis. PMID- 24486245 TI - Estrogen receptor beta and CXCR4/CXCL12 expression: differences by sex and hormonal status in lung adenocarcinoma. AB - BACKGROUND AND AIMS: Studies have reported differences in lung cancer behavior between sex and hormonal status that suggest a role of estrogens and estrogen receptor beta (ERbeta) in lung carcinogenesis. In some types of hormone-dependent cancer, estrogens may regulate CXCL12/CXCR4 expression through ERbeta signaling. High expression of CXCL12/CXCR4 is associated with poor prognosis in lung cancer because it promotes tumor growth and metastasis. Therefore, in this study we investigated whether lung adenocarcinoma tissues from pre- and postmenopausal women and from men exhibit different ERbeta, CXCR4/CXCL12 expression and whether this expression is associated with clinicopathological features. METHODS: Sixty primary tumor samples of lung adenocarcinoma from pre- and postmenopausal women and from men were collected for this study. Thirty samples of healthy lung tissue adjacent to the tumor site were used as controls. ERbeta and CXCL12/CXCR4 expression was analyzed by immunohistochemistry. Expression of these proteins was measured by digital image software and compared between sex and hormonal status. RESULTS: Lung adenocarcinomas overexpressed ERbeta, CXCR4 and CXCL12 compared to normal lung. Moreover, lung adenocarcinomas from premenopausal women exhibited higher signals for ERbeta, CXCL12 and CXCR4 compared to postmenopausal women and to men, who showed lower signals for these proteins. A multivariate analysis revealed a strong association between the immunoreactivity level of ERbeta, CXCL12/CXCR4 and both sex and hormonal status, but not with tumor stage and smoking. CONCLUSION: These results demonstrated that ERbeta and CXCL12/CXCR4 expression in lung adenocarcinoma depends on sex and hormonal status, which may partly explain the sex and hormonal differences in lung cancer behavior. PMID- 24486246 TI - Detection of common chromosomal translocations in small round blue cell pediatric tumors. AB - BACKGROUND AND AIMS: Recurrent and specific chromosomal translocations have been described in four pediatric sarcomas belonging to the small round blue cell (SRBC) group of tumors. Identification of mRNA chimeras using RT-PCR discriminates among alveolar rhabdomyosarcoma (ARMS), Ewing's sarcoma (ES/pPNET), synovial sarcoma (SS) and desmoplastic small round cell tumor (DSRCT); however, frequencies of these translocations are variable. We present a retrospective study comparing histological examination and occurrence of major chromosomal translocations to validate the diagnosis and to assess the frequency of these molecular markers in a group of 92 small round blue cell (SRBC) tumor samples from Hospital Infantil de Mexico. METHODS: We tested a panel of RT-PCR assays to each RNA tumor sample from formalin-fixed, paraffin-embedded tumors to detect specific mRNA chimeras in 47 ES/pPNET, 19 ARMS, four SS, three DSRCT, and 19 other SRBC tumors. RESULTS: After excluding poor RNA quality samples, we found translocations in 17/31 ES/pPNET (54.8%), 10/19 ARMS (52.6%), 4/4 SS (100%) and 4/4 DSRCT (100%). We found disagreement in only three samples: one ES/pPNET and one embryonal rhabdomyosarcoma harbor a PAX3-FOXO1 translocation (for ARMS), and one neuroepithelioma harboring a EWS-WT1 (for DSRCT). Unsuitable RNA was found in 20/92 samples (21.7%) and was related to necrosis, small amount of tumor tissue, and use of nitric acid in bone biopsies, but was not related to age of the block. CONCLUSIONS: We found a significantly lower occurrence of chromosomal translocations in ES/pPNET compared to reports from other groups. Differences may exist in the frequencies of these molecular markers among different populations. PMID- 24486247 TI - Cyclic pamidronate infusion for neonatal-onset osteogenesis imperfecta. AB - BACKGROUND: Patients with severe osteogenesis imperfecta (OI; MIM number 259420) suffer from low bone mass, fractures, and bone pain since birth, and have poor prognosis. This study assessed the outcome of patients with severe OI who were treated with cyclic pamidronate prior to the age of 1 year. METHODS: The six patients, who had bone fractures either in utero or in their 1st month of life, were treated with cyclic pamidronate from a mean age of 2.8 months. RESULTS: All the patients tolerated the infusion, except for having transient hypocalcemia at the first infusion. Decreases in irritability and improvements in feeding were observed 2-3 months after the first infusion. All patients showed a rapid increase in bone mineral density over the first 2 years. Fractures occurred at a rate of 0.6/year. At a mean age of 6.4 years, five patients with no interruption in treatment had normal ambulatory function, but they were short in height. CONCLUSION: Patients with neonatal OI can have a favorable outcome when treated with cyclic pamidronate infusions early in life. PMID- 24486248 TI - Continuous-time models of group selection, and the dynamical insufficiency of kin selection models. AB - Traditionally, the process of group selection has been described mathematically by discrete-time models, and analyzed using tools like the Price equation. This approach makes implicit assumptions about the process that are not valid in general, like the central role of synchronized mass-dispersion and group re formation events. In many important examples (like hunter-gatherer tribes) there are no mass-dispersion events, and the group-level events that do occur, like fission, fusion, and extinction, occur asynchronously. Examples like these can be fully analyzed by the equations of two-level population dynamics (described here) so their models are dynamically sufficient. However, it will be shown that examples like these cannot be fully analyzed by kin selection (inclusive fitness) methods because kin selection versions of group selection models are not dynamically sufficient. This is a critical mathematical difference between group selection and kin selection models, which implies that the two theories are not mathematically equivalent. PMID- 24486249 TI - Compliant ankle function results in landing-take off asymmetry in legged locomotion. AB - The spring loaded inverted pendulum (SLIP) model is widely used to predict and explain basic characteristics of human walking and running. Its periodic running solutions can be mirrored at the instant of the vertical orientation of the leg and thus are symmetric between landing and take-off. In contrast, human running shows asymmetries between touchdown and take-off (e.g. shorter brake than push duration, greater mean ground reaction force during braking phase). Yet it is not fully understood whether these asymmetries are caused by asymmetric muscle properties (e.g. velocity-dependent force generation) or the asymmetric lever arm system in the human leg. We extend the SLIP model by a foot segment and a compliant ankle joint. This represents the extended foot contact and the displacement of the center of pressure during contact. With this model we investigate to which extent the landing-take off asymmetry in legged locomotion is caused by this asymmetric lever arm system. We find similar landing-take off asymmetries as in human running suggesting that the asymmetric lever arm system contributes to the asymmetry. PMID- 24486250 TI - Sequence-based prediction of protein-protein interaction sites with L1-logreg classifier. AB - Protein-protein interactions are of central importance for virtually every process in a living cell. Information about the interaction sites in proteins improves our understanding of disease mechanisms and can provide the basis for new therapeutic approaches. Since a multitude of unique residue-residue contacts facilitate the interactions, protein-protein interaction sites prediction has become one of the most important and challenging problems of computational biology. Although much progress in this field has been reported, this problem is yet to be satisfactorily solved. Here, a novel method (LORIS: L1-regularized LOgistic Regression based protein-protein Interaction Sites predictor) is proposed, that identifies interaction residues, using sequence features and is implemented via the L1-logreg classifier. Results show that LORIS is not only quite effective, but also, performs better than existing state-of-the art methods. LORIS, available as standalone package, can be useful for facilitating drug-design and targeted mutation related studies, which require a deeper knowledge of protein interactions sites. PMID- 24486251 TI - Modelling cell division and endoreduplication in tomato fruit pericarp. AB - In many developing plant tissues and organs, differentiating cells switch from the classical cell cycle to an alternative partial cycle. This partial cycle bypasses mitosis and allows for multiple rounds of genome duplication without cell division, giving rise to cells with high ploidy numbers. This partial cycle is referred to as endoreduplication. Cell division and endoreduplication are important processes for biomass allocation and yield in tomato. Quantitative trait loci for tomato fruit size or weight are frequently associated with variations in the pericarp cell number, and due to the tight connection between endoreduplication and cell expansion and the prevalence of polyploidy in storage tissues, a functional correlation between nuclear ploidy number and cell growth has also been implicated (karyoplasmic ratio theory). In this paper, we assess the applicability of putative mechanisms for the onset of endoreduplication in tomato pericarp cells via development of a mathematical model for the cell cycle gene regulatory network. We focus on targets for regulation of the transition to endoreduplication by the phytohormone auxin, which is known to play a vital role in the onset of cell expansion and differentiation in developing tomato fruit. We show that several putative mechanisms are capable of inducing the onset of endoreduplication. This redundancy in explanatory mechanisms is explained by analysing system behaviour as a function of their combined action. Namely, when all these routes to endoreduplication are used in a combined fashion, robustness of the regulation of the transition to endoreduplication is greatly improved. PMID- 24486252 TI - Post-international adoption medical follow-up at the Angers university hospital between 2009 and 2012. AB - OBJECTIVE: The authors had for aim to describe infectious diseases in internationally adopted child at arrival in France. PATIENTS AND METHODS: We made a retrospective descriptive study of the children's files having undergone medical check-ups between 2009 and 2012. RESULTS: One hundred and eighty-two files were included: 80% of the children came from Africa, 15% from South America and the Caribbean, 3% from Asia, and 2% from Europe. Forty-three percent were diagnosed with tinea. HIV, hepatitis C, and syphilis blood tests were all negative. Six children presented with acute or chronic hepatitis B, another 5 children with acute hepatitis A. One blood test for cysticercosis was positive. Two children presented with malaria. 58% of the children carried an intestinal parasite; the most prevalent was Giardia duodenalis. Bacteriological stool culture was positive for 17 children, for 9 with an antibiotic resistant bacterium. Twenty-seven children had a positive virological stool culture, 2 for a poliovirus. CONCLUSION: A systematic infectious check-up should be performed for a child adopted internationally when he/she arrives in France. This allows diagnosing diseases requiring an emergency treatment, or asymptomatic but severe diseases when chronic. Some blood tests must be double-checked when the child arrives, because of possible false negative initial tests results in the country of origin. Screening, early treatment, and implementing prophylaxis can decrease the risk of transmission to relatives. It also allows monitoring the antimicrobial resistance of some pathogens and the reintroduction of the poliovirus in France. PMID- 24486253 TI - Association between gray matter volume in the caudate nucleus and financial extravagance: findings from voxel-based morphometry. AB - Consumer behavior differs among individuals; one such common individual difference is financial extravagance. Recent research suggests that the activation of the caudate nucleus plays an important role in consumer behavior. However, to the best of our knowledge, no study has investigated the specific relationship between the caudate nucleus and consumer financial extravagance. Therefore, in this study, we investigated the association between individual differences in financial extravagance and regional gray matter volume in the caudate nucleus by using voxel-based morphometry (VBM). We recruited 776 healthy, right-handed individuals (432 men and 344 women; mean age=20.7 +/- 1.8) and used voxel-based morphometry and a financial extravagance questionnaire to determine the association between financial extravagance and gray matter structure in the caudate nucleus. Our measure of financial extravagance was based on the novelty seeking subscales of the Japanese version of the Temperament and Character Inventory. A multiple regression analysis including financial extravagance, age, sex, Raven's Advanced Progressive Matrix score, total intracranial volume, and novelty seeking subscales was conducted to examine what variables were related to regional gray matter volume in the region of interest within the caudate nucleus. A significant positive correlation was found between the obtained financial extravagance score and regional gray matter volume in the caudate nucleus. We found that structural variations in the caudate nucleus contributed to individual differences in financial extravagance. This finding may provide a new neuroscientific approach to understanding individual characteristics of consumers. PMID- 24486254 TI - Gender and gonadectomy influence on neurons in superior cervical ganglia of sexually mature rats. AB - Gonadal hormones have a significant influence on both the number of neurons and the density of synapses in the superior cervical ganglion (SCG) during the early postnatal period. There are no studies reporting influence of the absence of these factors in sexually mature animals, although changes in SCG-neurons of the rat were observed up to 6 months of age. Hence, we investigated whether gonadectomy of sexually mature rats influences morphological properties of neurons in the SCG of the rat and if so, would it have a specific effect on neurochemically distinct subpopulations. Male and female Sprague-Dawley rats were gonadectomized at the age of two months. After 30 days, they were sacrificed and SCGs were harvested and processed immunohistochemically. The mean diameter of NPY neurons was greater in male rats, in comparison to all other groups (p<0.05). The number of NPY+, NPY- and total neurons per section area was significantly higher in female than in male, orchidectomized or the ovariectomized animals (p<0.05). The share of the different neuronal populations in the SCG that were encircled with calretinin-positive baskets (c.b+) or c.b.- (NPY+ or NPY-) was significantly influenced by the gender of the animals and gonadectomy, with significantly more c.b.+ in male animals (p<0.05). Results of the present study indicate that substantial changes in the SCG neurons of the rat occur after reaching sexual maturity, and are influenced by the gonadectomy. PMID- 24486255 TI - Melatonin treatment during early life interacts with restraint to alter neuronal morphology and provoke depressive-like responses. AB - Stressors during early life induce anxiety- and depressive-like responses in adult rodents. Siberian hamsters (Phodopus sungorus) exposed to short days post weaning also increase adult anxiety- and depressive-like behaviors. To test the hypothesis that melatonin and exposure to stressors early in life interact to alter adult affective responses, we administered melatonin either during the perinatal (gestational day 7 to postnatal day 14) or postnatal (day 15-56) periods and also exposed a subset of dams to restraint during gestation (1 h 2*/day for 4 days). During the final week of injections, depressive-like behaviors were assessed using the sucrose anhedonia and forced swim tests. Hamsters exposed to prenatal restraint and treated with melatonin only during the postnatal period increased depressive-like responses in the forced swim test relative to all other groups. Offspring from restrained dams increased the number of fecal boli produced during the forced swim test, an anxiety-like response. In the present study, prenatal restraint reduced CA1 dendritic branching overall and perinatal melatonin protected hamsters from this restraint-induced reduction. These results suggest that the photoperiodic conditions coincident with birth and early life stressors are important in the development of adult affective responses. PMID- 24486257 TI - Working memory and visuospatial deficits correlate with oculomotor control in children with fetal alcohol spectrum disorder. AB - Previous studies have demonstrated that children with Fetal Alcohol Spectrum Disorder (FASD) exhibit deficits in measures of eye movement control that probe aspects of visuospatial processing and working memory. The goal of the present study was to examine, in a large cohort of children with FASD, prenatal alcohol exposure (PAE) but not FASD, and typically developing control children, the relationship between performance in eye movement tasks and standardized psychometric tests that assess visuospatial processing and working memory. Participants for this dataset were drawn from a large, multi-site investigation, and included children and adolescents aged 5-17 years diagnosed with an FASD (n=71), those with PAE but no clinical FASD diagnosis (n=20), and typically developing controls (n=111). Participants completed a neurobehavioral test battery and a series of saccadic eye movement tasks. The FASD group performed worse than controls on the psychometric and eye movement measures of working memory and visuospatial skills. Within the FASD group, digit recall, block recall, and animal sorting were negatively correlated with sequence errors on the memory-guided task, and arrows was negatively correlated with prosaccade endpoint error. There were no significant correlations in the control group. These data suggest that psychometric tests and eye movement control tasks may assess similar domains of cognitive function, and these assessment tools may be measuring overlapping brain regions damaged due to prenatal alcohol exposure. The results of this study demonstrate that eye movement control tasks directly relate to outcome measures obtained with psychometric tests and are able to assess multiple domains of cognition simultaneously, thereby allowing for an efficient and accurate assessment. PMID- 24486256 TI - The rat retrosplenial cortex is required when visual cues are used flexibly to determine location. AB - The present study examined the consequences of retrosplenial cortex lesions in rats on two novel spatial tasks. In the first experiment, rats discriminated opposing room views from the same general location, along with their opposing directions of travel ('Perspective' task). Rats were trained with food rewards using a go/no-go design. Extensive retrosplenial cortex lesions involving both the granular and dysgranular areas impaired acquisition of this discrimination, which relied on distal visual cues. The same rats were then trained on a non spatial go/no-go discrimination between different digging media. No lesion effect was apparent. In the final experiment, rats discriminated between two locations within a room ('Location' task) such that direction of travel at each location would be of less help in solving the problem. Both extensive retrosplenial lesions and selective dysgranular retrosplenial lesions impaired this Location task. These results highlight the importance of the retrosplenial cortex (areas 29 and 30), including the dysgranular cortex (area 30), for the effective use of distal visual cues to solve spatial problems. The findings, which help to explain the bias away from visual allocentric solutions that is shown by rats with retrosplenial cortex lesions when performing spatial tasks, also support the notion that the region assists the integration of different categories of visuospatial information. PMID- 24486258 TI - Beneficial effects of early environmental enrichment on motor development and spinal cord plasticity in a rat model of cerebral palsy. AB - Cerebral palsy (CP) results from nonprogressive lesions in the immature brain generating changes on the neuromuscular system. Environmental enrichment (EE) is a combination of stimuli that provides greater motivation and interest in novel movement exploration through the provision of various devices associated to enhanced social stimulation that would mimic the physiotherapy approach. The aim of this study was to verify whether EE is able to prevent the establishment of motor impairment in a CP rat model. The animals were divided in two groups: control animals (healthy) and animals submitted to a CP model. After this, the pups were exposed to two environments: enriched or standard, totaling four groups: Control group (without CP in a standard environment), CP group (CP model in a standard environment), EE group (without CP in an enriched environment) and CP-EE (CP model in an enriched environment). The experimental model was induced in pregnant Wistar rats by the association of maternal exposure to bacterial endotoxin, perinatal anoxia and sensorimotor restriction of the pups. The assessment of motor skills was held using the following tests: open field, rotarod, horizontal ladder, narrow suspended bar and stride length. The histological analysis evaluated the mean cross-sectional area (CSA) of the soleus muscle fibers, the mean CSA of motoneuronal somata and expression of synaptophysin in the ventral horn of the spinal cord. EE was able to prevent the motor deficits, however, it did not reverse the muscle atrophy observed in CP animals. Furthermore, there was an average increase in the mean area of motoneurons and an increase in the expression of synaptophysin in the ventral horn of the spinal cord of the CP-EE group in relation to CP animals reared in a standard environment. Hereupon, the stimulus increment provided by EE can prevent the onset of motor deficits and histological changes in a CP rat model. PMID- 24486260 TI - Targeting a rare amyloidotic disease through rationally designed polymer conjugates. AB - Saraiva et al. discovered in 2006 a RAGE-based peptide sequence capable of preventing transthyretin (TTR) aggregate-induced cytotoxicity, hallmark of initial stages of an inherited rare amyloidosis known as Familial Amyloidotic Polyneuropathy (FAP). To allow clinical progression of this peptidic sequence as FAP treatment, a family of polymer conjugates has been designed, synthesised and fully characterised. This approach fulfils the strategies defined in the Polymer Therapeutics area as an exhaustive physico-chemical characterisation fitting activity output towards a novel molecular target that is described here. RAGE peptide acts extracellularly, therefore, no intracellular drug delivery was necessary. PEG was selected as carrier and polymer-drug linker optimisation was then carried out by means of biodegradable (disulphide) and non-biodegradable (amide) covalent bonds. Conjugate size in solution, stability under in vitro and in vivo scenarios and TTR binding affinity through surface plasmon resonance (SPR) was also performed with all synthesised conjugates. In their in vitro evaluation by monitoring the activation of caspase-3 in Schwann cells, peptide derivatives demonstrated retention of peptide activity reducing TTR aggregates (TTRagg) cytotoxicity upon conjugation and a greater plasma stability than the parent free peptide. The results also confirmed that a more stable polymer peptide linker (amide) is required to secure therapeutic efficiency. PMID- 24486261 TI - Reply: Carvedilol versus metoprolol, but which metoprolol? Effect on inappropriate cardioverter-defibrillator therapy. PMID- 24486259 TI - Neurochemical alterations in frontal cortex of the rat after one week of hypobaric hypoxia. AB - Residing at high altitude may lead to reduced blood oxygen saturation in the brain and altered metabolism in frontal cortical brain areas, probably due to chronic hypobaric hypoxia. These changes may underlie the increased rates of depression and suicidal behavior that have been associated with life at higher altitudes. To test the hypothesis that hypobaric hypoxia is responsible for development of mood disorders due to alterations in neurochemistry, we assessed depression-like behavior in parallel to levels of brain metabolites in rats housed at simulated altitude. 32 female Sprague Dawley rats were housed either in a hypobaric hypoxia chamber at 10,000 ft of simulated altitude for 1 week or at local conditions (4500 ft of elevation in Salt Lake City, Utah). Depression-like behavior was assessed using the forced swim test (FST) and levels of neurometabolites were estimated by in vivo proton magnetic resonance spectroscopy in the frontal cortex, the striatum and the hippocampus at baseline and after a week of exposure to hypobaric hypoxia. After hypoxia exposure the animals demonstrated increased immobility behavior and shortened latency to immobility in the FST. Elevated ratios of myo-inositol, glutamate, and the sum of myo-inositol and glycine to total creatine were observed in the frontal cortex of hypoxia treated rats. A decrease in the ratio of alanine to total creatine was also noted. This study shows that hypoxia induced alterations in frontal lobe brain metabolites, aggravated depression-like behavior and might be a factor in increased rates of psychiatric disorders observed in populations living at high altitudes. PMID- 24486262 TI - Erdheim-Chester disease involving the brain and the heart. PMID- 24486263 TI - Ablation of the epicardial substrate in ventricular tachycardia associated with structural heart disease: outside in or inside out? PMID- 24486264 TI - New-onset atrial fibrillation after aortic valve replacement: comparison of transfemoral, transapical, transaortic, and surgical approaches. AB - OBJECTIVES: This study sought to determine the incidence of new-onset atrial fibrillation (AF) associated with different methods of isolated aortic valve replacement (AVR)-transfemoral (TF), transapical (TA), and transaortic (TAo) catheter-based valve replacement and conventional surgical approaches. BACKGROUND: The relative incidences of AF associated with the various access routes for AVR have not been well characterized. METHODS: In this single-center, retrospective cohort study, we evaluated a total of 231 consecutive patients who underwent AVR for degenerative aortic stenosis (AS) between March 2010 and September 2012. Patients with a history of paroxysmal, persistent, or chronic AF, with bicuspid aortic valves, and patients who died within 48 h after AVR were excluded. A total of 123 patients (53% of total group) qualified for inclusion. Data on documented episodes of new-onset AF, along with all clinical, echocardiographic, procedural, and 30-day follow-up data, were collated. RESULTS: AF occurred in 52 patients (42.3%). AF incidence varied according to the procedural method. AF occurred in 60% of patients who underwent surgical AVR (SAVR), in 53% after TA-TAVR, in 33% after TAo-TAVR cases, and 14% after TF-TAVR. The episodes occurred at a median time interval of 53 (25th to 75th percentile, 41 to 87) h after completion of the procedure. Procedures without pericardiotomy had an 82% risk reduction of AF compared with those with pericardiotomy (adjusted odds ratio: 0.18; 95% confidence interval: 0.05 to 0.59). CONCLUSIONS: AF was a common complication of AVR with a cumulative incidence of >40% in elderly patients with degenerative AS who underwent either SAVR or TAVR. AF was most common with SAVR and least common with TF-TAVR. Procedures without pericardiotomy were associated with a lower incidence of AF. PMID- 24486265 TI - Reply: Sudden death in adolescent athletes. PMID- 24486267 TI - Sudden death in adolescent athletes. PMID- 24486266 TI - Diagnostic performance of noninvasive fractional flow reserve derived from coronary computed tomography angiography in suspected coronary artery disease: the NXT trial (Analysis of Coronary Blood Flow Using CT Angiography: Next Steps). AB - OBJECTIVES: The goal of this study was to determine the diagnostic performance of noninvasive fractional flow reserve (FFR) derived from standard acquired coronary computed tomography angiography (CTA) datasets (FFR(CT)) for the diagnosis of myocardial ischemia in patients with suspected stable coronary artery disease (CAD). BACKGROUND: FFR measured during invasive coronary angiography (ICA) is the gold standard for lesion-specific coronary revascularization decisions in patients with stable CAD. The potential for FFR(CT) to noninvasively identify ischemia in patients with suspected CAD has not been sufficiently investigated. METHODS: This prospective multicenter trial included 254 patients scheduled to undergo clinically indicated ICA for suspected CAD. Coronary CTA was performed before ICA. Evaluation of stenosis (>50% lumen reduction) in coronary CTA was performed by local investigators and in ICA by an independent core laboratory. FFR(CT) was calculated and interpreted in a blinded fashion by an independent core laboratory. Results were compared with invasively measured FFR, with ischemia defined as FFR(CT) or FFR <=0.80. RESULTS: The area under the receiver operating characteristic curve for FFR(CT) was 0.90 (95% confidence interval [CI]: 0.87 to 0.94) versus 0.81 (95% CI: 0.76 to 0.87) for coronary CTA (p = 0.0008). Per-patient sensitivity and specificity (95% CI) to identify myocardial ischemia were 86% (95% CI: 77% to 92%) and 79% (95% CI: 72% to 84%) for FFR(CT) versus 94% (86 to 97) and 34% (95% CI: 27% to 41%) for coronary CTA, and 64% (95% CI: 53% to 74%) and 83% (95% CI: 77% to 88%) for ICA, respectively. In patients (n = 235) with intermediate stenosis (95% CI: 30% to 70%), the diagnostic accuracy of FFR(CT) remained high. CONCLUSIONS: FFR(CT) provides high diagnostic accuracy and discrimination for the diagnosis of hemodynamically significant CAD with invasive FFR as the reference standard. When compared with anatomic testing by using coronary CTA, FFR(CT) led to a marked increase in specificity. (HeartFlowNXT-HeartFlow Analysis of Coronary Blood Flow Using Coronary CT Angiography [HFNXT]; NCT01757678). PMID- 24486268 TI - Heart transplant allocation: in desperate need of revision. PMID- 24486269 TI - Endocardial ablation to eliminate epicardial arrhythmia substrate in scar-related ventricular tachycardia. AB - OBJECTIVES: We evaluated the feasibility and safety of epicardial substrate elimination with endocardial radiofrequency (RF) delivery in patients with scar related ventricular tachycardia (VT). BACKGROUND: Epicardial RF delivery is limited by fat or associated with bleeding, extra-cardiac damages, coronary vessels and phrenic nerve injury. Alternative ablation approaches might be desirable. METHODS: Forty-six patients (18 ischemic cardiomyopathy [ICM], 13 nonischemic dilated cardiomyopathy [NICM], 15 arrhythmogenic right ventricular cardiomyopathy [ARVC]) with sustained VT underwent combined endo- and epicardial mapping. All patients received endocardial ablation targeting local abnormal ventricular activities in the endocardium (Endo-LAVA) and epicardium (Epi-LAVA), followed by epicardial ablation if needed. RESULTS: From a total of 173 endocardial ablations targeting Epi-LAVA at the facing site, 48 (28%) applications (ICM: 20 of 71 [28%], NICM: 3 of 39 [8%], ARVC: 25 of 63 [40%]) successfully eliminated the Epi-LAVA. Presence of Endo-LAVA, the most delayed and low bipolar amplitude of Epi-LAVA, low unipolar amplitude in the facing endocardium, and Epi-LAVA within a wall thinning area at computed tomography scan were associated with successful ablation. Endocardial ablation could abolish all Epi-LAVA in 4 ICM and 2 ARVC patients, whereas all patients with NICM required epicardial ablation. Endocardial ablation was able to eliminate Epi-LAVA at least partially in 15 (83%) ICM, 2 (13%) NICM, and 11 (73%) ARVC patients, contributing to a potential reduction in epicardial RF applications. Pericardial bleeding occurred in 4 patients with epicardial ablation. CONCLUSIONS: Elimination of Epi LAVA with endocardial RF delivery is feasible and might be used first to reduce the risk of epicardial ablation. PMID- 24486270 TI - Atrial fibrillation genomics: time to take the next step. PMID- 24486272 TI - Reply: Sudden death in adolescent athletes. PMID- 24486273 TI - The game changer? PMID- 24486274 TI - Pericardial invasion: lessons learned from surgical and transcatheter aortic valve replacement. PMID- 24486271 TI - Novel genetic markers associate with atrial fibrillation risk in Europeans and Japanese. AB - OBJECTIVES: This study sought to identify nonredundant atrial fibrillation (AF) genetic susceptibility signals and examine their cumulative relations with AF risk. BACKGROUND: AF-associated loci span broad genomic regions that may contain multiple susceptibility signals. Whether multiple signals exist at AF loci has not been systematically explored. METHODS: We performed association testing conditioned on the most significant, independently associated genetic markers at 9 established AF loci using 2 complementary techniques in 64,683 individuals of European ancestry (3,869 incident and 3,302 prevalent AF cases). Genetic risk scores were created and tested for association with AF in Europeans and an independent sample of 11,309 individuals of Japanese ancestry (7,916 prevalent AF cases). RESULTS: We observed at least 4 distinct AF susceptibility signals on chromosome 4q25 upstream of PITX2, but not at the remaining 8 AF loci. A multilocus score comprised 12 genetic markers demonstrated an estimated 5-fold gradient in AF risk. We observed a similar spectrum of risk associated with these markers in Japanese. Regions containing AF signals on chromosome 4q25 displayed a greater degree of evolutionary conservation than the remainder of the locus, suggesting that they may tag regulatory elements. CONCLUSIONS: The chromosome 4q25 AF locus is architecturally complex and harbors at least 4 AF susceptibility signals in individuals of European ancestry. Similar polygenic AF susceptibility exists between Europeans and Japanese. Future work is necessary to identify causal variants, determine mechanisms by which associated loci predispose to AF, and explore whether AF susceptibility signals classify individuals at risk for AF and related morbidity. PMID- 24486275 TI - Early post-discharge bleeding and antiplatelet therapy discontinuation among acute myocardial infarction patients treated with percutaneous coronary intervention. PMID- 24486276 TI - Smarter deployment of implantable cardioverter-defibrillators in nonischemic cardiomyopathy: feasible or mythical? PMID- 24486277 TI - Autoimmunity and atrioventricular block of unknown etiology in adults: the role of anti-Ro/SSA antibodies. PMID- 24486279 TI - Is cardiac magnetic resonance one of cardiology's magic crystal balls? PMID- 24486278 TI - Trends in the use and outcomes of ventricular assist devices among medicare beneficiaries, 2006 through 2011. AB - OBJECTIVES: This study sought to examine trends in mortality, readmission, and costs among Medicare beneficiaries receiving ventricular assist devices (VADs) and associations between hospital-level procedure volume and outcomes. BACKGROUND: VADs are an option for patients with advanced heart failure, but temporal changes in outcomes and associations between facility-level volume and outcomes are poorly understood. METHODS: This is a population-based, retrospective cohort study of all fee-for-service Medicare beneficiaries with heart failure who received an implantable VAD between 2006 and 2011. We used Cox proportional hazards models to examine temporal changes in mortality, readmission, and hospital-level procedure volume. RESULTS: Among 2,507 patients who received a VAD at 103 centers during the study period, the in-hospital mortality decreased from 30% to 10% (p < 0.001), the 1-year mortality decreased from 42% to 26% (p < 0.001), and the all-cause readmission was frequent (82% and 81%; p = 0.70). After covariate adjustment, in-hospital and 1-year mortality decreased (p < 0.001 for both), but the all-cause readmission did not change (p = 0.82). Hospitals with a low procedure volume had higher risks of in-hospital mortality (risk ratio: 1.72; 95% confidence interval [CI]: 1.28 to 2.33) and 1 year mortality (risk ratio: 1.55; 95% CI: 1.24 to 1.93) than high-volume hospitals. Procedure volume was not associated with risk of readmission. The greatest cost was from the index hospitalization and remained unchanged ($204,020 in 2006 and $201,026 in 2011; p = 0.21). CONCLUSIONS: Short- and long-term mortality after VAD implantation among Medicare beneficiaries improved, but readmission remained similar over time. A higher volume of VAD implants was associated with lower risk of mortality but not readmission. Costs to Medicare have not changed in recent years. PMID- 24486280 TI - Cardiac magnetic resonance imaging findings and the risk of cardiovascular events in patients with recent myocardial infarction or suspected or known coronary artery disease: a systematic review of prognostic studies. AB - The goal of this study was to review the prognostic value of cardiac magnetic resonance (CMR) imaging findings for future cardiovascular events in patients with a recent myocardial infarction (MI) and patients with suspected or known coronary artery disease (CAD). Although the diagnostic value of CMR findings is established, the independent prognostic association with future cardiovascular events remains largely unclear. Studies published by February 2013, identified by systematic MEDLINE and EMBASE searches, were reviewed for associations between CMR findings (left ventricular ejection fraction [LVEF], wall motion abnormalities [WMA], abnormal myocardial perfusion, microvascular obstruction, late gadolinium enhancement, edema, and intramyocardial hemorrhage) and hard events (all-cause mortality, cardiac death, cardiac transplantation, and MI) or major adverse cardiovascular events (MACE) (hard events and other cardiovascular events defined by the authors of the evaluated papers). Fifty-six studies (n = 25,497) were evaluated. For patients with recent MI, too few patients were evaluated to establish associations between CMR findings and hard events. LVEF (range of adjusted hazard ratios [HRs]: 1.03 to 1.05 per % decrease) was independently associated with MACE. In patients with suspected or known CAD, WMA (adjusted HRs: 1.87 to 2.99), inducible perfusion defects (adjusted HRs: 3.02 to 7.77), LVEF (adjusted HRs: 0.72 to 0.82 per 10% increase), and infarction (adjusted HRs: 2.82 to 9.43) were independently associated with hard events, and the presence of inducible perfusion defects was associated with MACE (adjusted HRs: 1.76 to 3.21). The independent predictor of future cardiovascular events for patients with a recent MI was LVEF, and the predictors for patients with suspected or known CAD were WMA, inducible perfusion defects, LVEF, and presence of infarction. PMID- 24486281 TI - Optimizing P2Y12 receptor inhibition in patients with acute coronary syndrome on the basis of platelet function testing: impact of prasugrel and high-dose clopidogrel. AB - OBJECTIVES: This study sought to evaluate the impact of treatment with prasugrel and high-dose clopidogrel on the basis of platelet function testing in patients with acute coronary syndrome (ACS) who are undergoing percutaneous coronary intervention (PCI). BACKGROUND: The clinical impact of treatment with prasugrel in patients with ACS who have high platelet reactivity (HPR) is unknown. METHODS: Patients with ACS who were pre-treated with clopidogrel and undergoing successful PCI were enrolled in a single-center, prospective registry. Platelet function was measured 12 to 36 h after PCI with the Multiplate device (Roche Diagnostics GmbH, Mannheim, Germany). Patients with HPR (>46 U) were switched to prasugrel or treated with high-dose clopidogrel, and those without HPR continued treatment with 75 mg of clopidogrel. RESULTS: A total of 741 consecutive patients were enrolled in the study between September 2011 and August 2012, and 219 of these patients (29.5%) had HPR. Although platelet reactivity decreased after treatment adjustments in those with HPR, prasugrel provided significantly more potent platelet inhibition compared with high-dose clopidogrel (p < 0.0001). Compared with patients without HPR, the risk of all-cause death, myocardial infarction, stent thrombosis, or stroke at 1 year was significantly higher in the high-dose clopidogrel group (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.45 to 3.55; p < 0.0001), and patients who were switched to prasugrel had similar outcomes (HR: 0.90; 95% CI: 0.44 to 1.81; p = 0.76). Bleeding Academic Research Consortium (BARC) type 3/5 bleeding was also more frequent in patients treated with high-dose clopidogrel (HR: 2.09; 95% CI: 1.05 to 4.17; p = 0.04) than in patients switched to prasugrel (HR: 0.45; 95% CI: 0.11 to 1.91; p = 0.28). In a multivariate model, HPR with high-dose clopidogrel, but not with prasugrel, was an independent predictor of the composite ischemic endpoint (HR: 1.90; 95% CI: 1.17 to 3.08; p = 0.01). CONCLUSIONS: Switching patients with ACS who have HPR to treatment with prasugrel reduces thrombotic and bleeding events to a level similar to that of those without HPR; however, there is a higher risk of both thrombotic and bleeding complications with high-dose clopidogrel. PMID- 24486282 TI - Mammoth right atrium. PMID- 24486283 TI - Carvedilol versus metoprolol, but which metoprolol? Effect on inappropriate cardioverter-defibrillator therapy. PMID- 24486284 TI - 'Real-world' antithrombotic treatment in atrial fibrillation: The EORP-AF pilot survey. AB - BACKGROUND: Current guidelines strongly recommend that oral anticoagulation should be offered to patients with atrial fibrillation and >=1 stroke risk factors. The guidelines also recommend that oral anticoagulation still should be used in the presence of stroke risk factors irrespective of rate or rhythm control. METHODS: In an analysis from the dataset of the EURObservational Research Programme on Atrial Fibrillation Pilot Survey (n = 3119), we examined antithrombotic therapy prescribing, with particular focus on the risk factors determining oral anticoagulation or antiplatelet therapy use. RESULTS: When oral anticoagulation was used among admitted patients in whom no pharmacologic cardioversion, electrical cardioversion, or catheter ablation was performed or planned, vitamin K antagonist therapy was prescribed in the majority (72.2%), whereas novel oral anticoagulants were used in the minority (7.7%). There was no significant difference in bleeding risk factors among the patients treated with the different types of antithrombotic therapies, except for those with chronic kidney disease, in whom oral anticoagulation was less commonly used (P = .0318). Antiplatelet therapy was more commonly used in patients with a high Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile international normalized ratio, Elderly (>65 years), Drugs/alcohol concomitantly score (>=2) (P < .0001). More oral anticoagulation use was associated with female gender (P = .0245). Less novel oral anticoagulant use was associated with valvular heart disease (P < .0001), chronic heart failure (P = .0010), coronary artery disease (P < .0001), and peripheral artery disease (P = .0092). Coronary artery disease was the strongest reason for combination therapy with oral anticoagulation plus antiplatelet drug (odds ratio, 8.54; P < .0001). When the Congestive heart failure, Hypertension, Age >=75 [Doubled], Diabetes, Stroke [Doubled]-Vascular disease, Age 65-74, and Sex category [female] score was used, 95.6% of patients with a score >=1 received antithrombotic therapy, with 80.5% of patients with a score >=1 receiving oral anticoagulation. Of note, 83.7% of those with a score >=2 received antithrombotic therapy. Of the latter, 70.9% of those with a score >=2 received oral anticoagulation, vitamin K antagonists were used in 64.1%, and novel oral anticoagulants were used in 6.9%. CONCLUSIONS: The EURObservational Research Programme on Atrial Fibrillation Pilot Survey provides contemporary data on oral anticoagulation prescribing by European cardiologists for atrial fibrillation. Although the uptake of oral anticoagulation (mostly vitamin K antagonist therapy) has improved since the Euro Heart Survey a decade ago, antiplatelet therapy is still commonly prescribed, with or without oral anticoagulation, whereas elderly patients are commonly undertreated with oral anticoagulation. PMID- 24486285 TI - Pinched: superior mesenteric artery syndrome. PMID- 24486287 TI - B-type natriuretic peptide and clinical judgment in the detection of exercise induced myocardial ischemia. AB - BACKGROUND: Myocardial ischemia has been shown to be associated with increased levels of B-type natriuretic peptide (BNP). However, it remains unclear whether and how BNP levels could be used clinically in patients with suspected exercise induced myocardial ischemia. METHODS: We enrolled 274 consecutive patients with suspected exercise-induced myocardial ischemia referred for evaluation by rest/bicycle myocardial perfusion single-photon emission computed tomography (SPECT). All clinical information available to the treating cardiologist was used to quantify the clinical judgment regarding the presence of myocardial ischemia using a visual analogue scale twice: once before and once after bicycle exercise stress testing. BNP measurements were obtained before, immediately after, and 2 hours after stress testing in a blinded manner. The presence of myocardial ischemia was adjudicated on the basis of perfusion SPECT combined with coronary angiography findings. RESULTS: Exercise-induced myocardial ischemia was adjudicated to be present in 103 patients (38%). BNP levels were significantly higher at all time points in patients with myocardial ischemia compared with those without (P < .01 for all). The accuracy of BNP levels as quantified by the area under the receiver operating characteristic curve (AUC) was similar among the time points evaluated (AUC, 0.677-0.697). Combining clinical judgment before exercise testing with BNP levels at rest increased diagnostic accuracy from AUC 0.708 to 0.754 (P = .018). When combining clinical judgment after exercise testing with BNP levels, AUC increased from 0.741 to 0.771 (P = .055). CONCLUSIONS: Combining clinical judgment with BNP levels increased the diagnostic accuracy regarding the presence of myocardial ischemia. PMID- 24486286 TI - Survival after community diagnosis of early-stage non-small cell lung cancer. AB - BACKGROUND: "Rush to surgery" among patients with worse symptoms, delays related to morbidity, and inclusion of patients with advanced disease in study populations have produced a mixed picture of importance of time to treatment to survival of non-small cell lung cancer. Our objective was to assess the contribution of diagnosis to first surgery interval to survival among patients diagnosed in the community with early-stage non-small cell lung cancer. METHODS: Patients with early-stage lung cancer (N = 174) at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins who were diagnosed and treated from 2003 to 2009 and followed through 2011 made up a prospective study of overall survival. Diagnosis to first surgery interval was examined overall, as 2 segments (referral interval and treatment interval), as short and longer intervals, and as a continuous variable. RESULTS: The majority of patients were female (55%) and aged more than 65 years (61%). The average mean referral and treatment delays were 61.2 and 5.9 days, respectively. Cox method hazard analysis revealed that older age (years) at diagnosis (hazard ratio [HR], 1.02; 95% confidence interval [CI], 1.00-1.05), stage IIB (HR, 2.17; 95% CI, 1.12-4.21), large (>4 cm) (HR, 3.68; 95% CI, 1.05-12.93) or unknown tumor size (HR, 4.45; 95% CI, 1.21-16.38), and weeks from diagnosis to first surgery interval (HR, 1.04; 95% CI, 1.00-1.09) predicted worse overall survival. The threshold period of less than 42 days from diagnosis to surgery did not reach statistical significance. CONCLUSIONS: Patients seem to benefit from rapid reduction of tumor burden with surgery. Reasons for delay were not available. Nevertheless, referral delay experienced in the community is unduly long. In addition to patient choices, an unconscious patient or physician bias that lung cancer is untreatable or an inevitable consequence of smoking may be operating and needs further investigation. PMID- 24486288 TI - Hepatitis C screening trends in a large integrated health system. AB - BACKGROUND: As new hepatitis C virus (HCV) therapies emerge, only 1%-12% of individuals are screened in the US for HCV infection. Presently, HCV screening trends are unknown. METHODS: We utilized the Kaiser Permanente Mid-Atlantic States' (KPMAS) data repository to investigate HCV antibody screening between January 1, 2003 and December 31, 2012. We identified the proportion screened for HCV and 5-year cumulative incidence of screening, the screening positivity rate, the provider types performing HCV screening, patient-level factors associated with being screened, and trends in screening over time. RESULTS: There were 444,594 patients who met the inclusion criteria. Overall, 15.8% of the cohort was ever screened for HCV. Adult primary care and obstetrics and gynecology providers performed 75.9% of all screening. The overall test positivity rate was 3.8%. Screening was more frequent in younger age groups (P <.0001) and those with a documented history of illicit drug use (P <.0001). Patients with missing drug use history (46.7%) were least likely to be screened (P <.0001). While the rate of HCV screening increased in the later years of the study among those enrolled in KPMAS 2009-2012, only 11.8% were screened by the end of follow-up. CONCLUSION: Screening for HCV is increasing but remains incomplete. Targeting screening to those with a history of injection drug will not likely expand screening, as nearly half of patients have no documented drug use history. Routine screening is likely the most effective approach to expand HCV screening. PMID- 24486289 TI - Individual and composite study endpoints: separating the wheat from the chaff. AB - We provide an overview of the individual and combined clinical endpoints and patient-reported outcomes typically used in clinical trials and prospective epidemiological investigations. We discuss the strengths and limitations associated with the utilization of aggregated study endpoints and surrogate measures of important clinical endpoints and patient-centered outcomes. We hope that the points raised in this overview will lead to the collection of clinically rich, relevant, measurable, and cost-efficient study outcomes. PMID- 24486290 TI - Variation in the intensity of hematuria evaluation: a target for primary care quality improvement. AB - BACKGROUND: Hematuria is a common clinical finding and represents the most frequent presenting sign of bladder cancer. The American Urological Association recommends cystoscopy and abdomino-pelvic imaging for patients aged more than 35 years. Nonetheless, less than half of patients presenting with hematuria undergo proper evaluation. We sought to identify clinical and nonclinical factors associated with evaluation of persons with newly diagnosed hematuria. METHODS: We performed a retrospective cohort study, using claims data and laboratory values. The primary exposure was practice site, as a surrogate for nonclinical, potentially modifiable sources of variation. Primary outcomes were cystoscopy or abdomino-pelvic imaging within 180 days after hematuria diagnosis. We modeled the association between clinical and nonclinical factors and appropriate hematuria evaluation. RESULTS: We identified 2455 primary care patients aged 40 years or more and diagnosed with hematuria between 2004 and 2012 in the absence of other explanatory diagnosis; 13.7% of patients underwent cystoscopy within 180 days. Multivariate logistic regression revealed significant variation between those who did and did not undergo evaluation in age, gender, and anticoagulant use (P < .001, P = .036, P = .028, respectively). Addition of practice site improved the predictive discrimination of each model (P < .001). Evaluation was associated with a higher rates of genitourinary neoplasia diagnosis. CONCLUSIONS: Patients with hematuria rarely underwent complete evaluation. Although established risk factors for malignancy were associated with increasing use of diagnostic testing, factors unassociated with risk, such as practice site, also accounted for significant variation. Inconsistency across practice sites is undesirable and may be amenable to quality improvement interventions. PMID- 24486291 TI - Crizotinib (PF-2341066) induces apoptosis due to downregulation of pSTAT3 and BCL 2 family proteins in NPM-ALK(+) anaplastic large cell lymphoma. AB - Nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) is an aberrant fusion gene product with tyrosine kinase activity and is expressed in substantial subset of anaplastic large cell lymphomas (ALCL). It has been shown that NPM-ALK binds to and activates signal transducer and activator of transcription 3 (STAT3). Although NPM-ALK(+) ALCL overall shows a better prognosis, there is a sub-group of patients who relapses and is resistant to conventional chemotherapeutic regimens. NPM-ALK is a potential target for small molecule kinase inhibitors. Crizotinib (PF-2341066) is a small, orally bioavailable molecule that inhibits growth of tumors with ALK activity as shown in a subgroup of non-small lung cancer patients with EML4-ALK expression. In this study, we have investigated the in vitro effects of Crizotinib in ALCL cell line with NPM-ALK fusion. Crizotinib induced marked downregulation of STAT3 phosphorylation, which was associated with significant apoptotic cell death. Apoptosis induction was attributed to caspase-3 cleavage and marked downregulation of the Bcl-2 family of proteins including MCL 1. These findings implicate that Crizotinib has excellent potential to treat patients with NPM-ALK(+) ALCL through induction of apoptotic cell death and downregulation of major oncogenic proteins in this aggressive lymphoma. PMID- 24486292 TI - Transcriptional regulation of cuticle biosynthesis. AB - Plant cuticle is the hydrophobic protection layer that covers aerial plant organs and plays a pivotal role during plant development and interactions of plants with the environment. The mechanical structure and chemical composition of cuticle lipids and other secondary metabolites vary considerably between plant species, and in response to environmental stimuli and stresses. As the cuticle plays an important role in responses of plants to major abiotic stresses such as drought and high salinity, close attention has been paid to molecular processes underlying the stress-induced biosynthesis of cuticle components. This review addresses the genetic networks responsible for cuticle formation and in particular highlights the role of transcription factors that regulate cuticle formation in response to abiotic stresses. PMID- 24486293 TI - Effect of optical coherence tomography scan pattern and density on the detection of full-thickness macular holes. AB - PURPOSE: To evaluate the impact of different scan patterns and scan densities on small full-thickness macular hole (MH) detection. DESIGN: Retrospective cross sectional analysis. METHODS: Analysis was performed on 25 eyes from 24 patients with full-thickness MHs imaged with the Heidelberg Spectralis HRA+OCT. Included eyes underwent concurrent imaging with a standard (61-line) raster volume and a 24-line radial pattern. A 6-line radial scan pattern was extrapolated from the higher-density radial pattern. Comparisons of the missed hole rate as well as the proportion of individual B-scans demonstrating a full-thickness defect (termed "full-thickness detection index") were carried out for the 3 scan patterns. Additionally, qualitative and quantitative hole parameters were evaluated to identify factors associated with "missed" holes. RESULTS: Full-thickness defects were missed at substantially higher rates using both standard raster volume (20.0%, 90% confidence interval [CI] 8.2%-37.5%) and 6-line radial scanning (12.0%, 90% CI 3.7%-30.4%) when compared to 24-line radial scanning (0% for both comparisons). Full-thickness detection indices were significantly higher for both radial scan patterns when compared to raster scanning (P < .001 for both comparisons). Missed holes were smaller and commonly associated with prehole flaps. CONCLUSION: High-density radial scanning demonstrated superior detection rates of small full-thickness MHs compared to standard raster volume scanning. This finding may be attributable to the greater foveolar scan density attained with radial scan patterns. Failure to utilize radial scanning in the setting of suspected macular holes may lead to a delay in surgical treatment, with attendant worse anatomic and visual outcomes. PMID- 24486294 TI - A lower haemoglobin level predicts a worse survival of patients with advanced gastric cancer. PMID- 24486295 TI - Collaborative practices for medicinal chemistry research across the big pharma and not-for-profit interface. AB - In response to the dual challenges of increasingly risky target portfolios and realignment of traditional pharmaceutical company resources away from early-phase research and development (R&D), research groups have sought to engage across the industrial and not-for-profit divide, resulting in the emergence of many different collaborative models. Here, we describe two successful collaborations based upon shared commitment and risk. The risks and complexities of external collaboration can be mitigated by appropriate agreements and tools, but we found that it remains essential that the collaborating scientists adopt a collaborative mindset and embrace the diverse ways of working of partner organizations. PMID- 24486296 TI - Reprint of "GELFrEE fractionation combined with mass spectrometry for proteome analysis of secreted toxins from Enteropathogenic Escherichia coli (EPEC)". AB - Enteropathogenic Escherichia coli, or EPEC, is a human pathogen associated with gastroenteritis and diarrheal disease whose pathogenicity is related to the secretion of effector proteins (exotoxins). Determining exotoxin expression level is of considerable interest to those studying toxin function and pathological phenotypes. Mass spectrometry (MS) provides an ideal platform for detection and quantification of proteins from complex mixtures. Here, we apply a solution-phase electrophoretic platform (GELFrEE) followed by MS to characterize the secreted proteome of a wild type and mutant strain of EPEC (DeltasepD), exhibiting enhanced secretion of effector proteins. Through peptide-level analysis, a total of 363 and 155 proteins were identified from the wild type and mutant strains, respectively. Semi-quantitative analysis of the MS data reveals the effector proteins EspB, EspC, and EspD appear in a relatively greater abundance from wild type EPEC, while two major virulence factors in EPEC, Tir and NleA appear in greater abundance from the secreted proteome of the mutant strain. Additionally, intact proteins may further be characterized following GELFrEE with MS to improve throughput of analysis. This study demonstrates the application of GELFrEE-MS to differentiate wild type and mutant strains of EPEC. This platform is therefore a powerful tool to study exotoxin secretion from pathogenic bacteria. PMID- 24486297 TI - Reprint of "Identification of staphylococcal species based on variations in protein sequences (mass spectrometry) and DNA sequence (sodA microarray)". AB - This report is among the first using sequence variation in newly discovered protein markers for staphylococcal (or indeed any other bacterial) speciation. Variation, at the DNA sequence level, in the sodA gene (commonly used for staphylococcal speciation) provided excellent correlation. Relatedness among strains was also assessed using protein profiling using microcapillary electrophoresis and pulsed field electrophoresis. A total of 64 strains were analyzed including reference strains representing the 11 staphylococcal species most commonly isolated from man (Staphylococcus aureus and 10 coagulase negative species [CoNS]). Matrix assisted time of flight ionization/ionization mass spectrometry (MALDI TOF MS) and liquid chromatography-electrospray ionization tandem mass spectrometry (LC ESI MS/MS) were used for peptide analysis of proteins isolated from gel bands. Comparison of experimental spectra of unknowns versus spectra of peptides derived from reference strains allowed bacterial identification after MALDI TOF MS analysis. After LC-MS/MS analysis of gel bands bacterial speciation was performed by comparing experimental spectra versus virtual spectra using the software X!Tandem. Finally LC-MS/MS was performed on whole proteomes and data analysis also employing X!tandem. Aconitate hydratase and oxoglutarate dehydrogenase served as marker proteins on focused analysis after gel separation. Alternatively on full proteomics analysis elongation factor Tu generally provided the highest confidence in staphylococcal speciation. PMID- 24486298 TI - Reprint of "Which metaproteome? The impact of protein extraction bias on metaproteomic analyses". AB - Culture-independent techniques such as LC-MS/MS-based metaproteomic analyses are being increasingly utilized for the study of microbial composition and function in complex environmental samples. Although several studies have documented the many challenges and sources of bias that must be considered in these types of analyses, none have systematically characterized the effect of protein extraction bias on the biological interpretation of true environmental biofilm metaproteomes. In this study, we compared three protein extraction methods commonly used in the analyses of environmental samples [guanidine hydrochloride (GuHCl), B-PER, sequential citrate-phenol (SCP)] using nano-LC-MS/MS and an environmental marine biofilm to determine the unique biases introduced by each method and their effect on the interpretation of the derived metaproteomes. While the protein extraction efficiencies of the three methods ranged from 2.0 to 4.3%, there was little overlap in the sequence (1.9%), function (8.3% of total assigned protein families) and origin of the identified proteins from each extract. Each extraction method enriched for different protein families (GuHCl--photosynthesis, carbohydrate metabolism; B-PER--membrane transport, oxidative stress; SCP- calcium binding, structural) while 23.7-45.4% of the identified proteins lacked SwissProt annotations. Taken together, the results demonstrated that even the most basic interpretations of this complex microbial assemblage (species composition, ratio of prokaryotic to eukaryotic proteins, predominant functions) varied with little overlap based on the protein extraction method employed. These findings demonstrate the heavy influence of protein extraction on biofilm metaproteomics and provide caveats for the interpretation of such data sets when utilizing single protein extraction methods for the description of complex microbial assemblages. PMID- 24486299 TI - Trichostatin A increases the levels of plasma gelsolin and amyloid beta-protein in a transgenic mouse model of Alzheimer's disease. AB - AIMS: Gelsolin (GSN), a multifunctional protein, binds to amyloid beta-protein (Abeta), inhibits its fibrillization, solubilizes preformed Abeta fibrils, and helps in its clearance from the brain. Trichostatin A (TSA), a histone deacetylase (HDAC) inhibitor, induces the protein expression of gelsolin. In the present study, we investigated how TSA-treatment of APPswe/PS1deltaE9 transgenic (Tg) mice of Alzheimer's disease (AD) will affect the plasma levels of gelsolin and Abeta. MAIN METHODS: TSA (5mg/kg body weight on alternate days for two months) was intraperitoneally injected to AD Tg mice. Gelsolin was measured by Western blotting and Abeta was measured by enzyme-linked immunosorbent assay. KEY FINDINGS: TSA-treatment significantly increased the levels of plasma gelsolin by 1.79-fold as compared with vehicle-treated control mice (p<0.01). The levels of Abeta 1-40 and Abeta 1-42 in the plasma were also higher in TSA-treated mice in comparison with vehicle-treated mice. The treatment of transgenic AD mice with TSA did not affect the body weight in both male and female groups as compared to vehicle-treated animals. A positive correlation was observed between the plasma levels of gelsolin and Abeta 1-40 (r=0.594, p=0.042) or Abeta 1-42 (r=0.616, p=0.033) in AD Tg mice. SIGNIFICANCE: These results suggest that TSA increases the levels of plasma gelsolin and Abeta in AD Tg mice, which may have implications in gelsolin-mediated clearance of Abeta. PMID- 24486300 TI - Radioprotective efficacy of delta-tocotrienol, a vitamin E isoform, is mediated through granulocyte colony-stimulating factor. AB - AIMS: The objectives of this study were to determine the cytokine induction by delta tocotrienol (DT3, a promising radiation countermeasure) and to investigate the role of granulocyte colony-stimulating factor (G-CSF) in its radioprotective efficacy against ionizing radiation in mice. MAIN METHODS: Multiplex Luminex was used to analyze cytokines induced by DT3 and other tocols (gamma-tocotrienol and tocopherol succinate) in CD2F1 mice. Mice were injected with an optimal dose of DT3 and a G-CSF antibody, and their 30-day survival against cobalt-60 gamma irradiation was monitored. The neutralization of G-CSF by the administration of a G-CSF-specific antibody in DT3-injected mice was investigated by multiplex Luminex. KEY FINDINGS: Our data demonstrate that DT3 induced high levels of various cytokines comparable to other tocols being developed as radiation countermeasures. DT3 significantly protected mice against ionizing radiation, and the administration of a G-CSF neutralizing antibody to DT3-treated animals resulted in the complete abrogation of DT3's radioprotective efficacy and neutralization of G-CSF in peripheral blood. SIGNIFICANCE: Our study findings suggest that G-CSF induced by DT3 mediates its radioprotective efficacy against ionizing radiation in mice. PMID- 24486301 TI - The roles of p53R2 in cancer progression based on the new function of mutant p53 and cytoplasmic p21. AB - Although the deregulated expression of p53R2, a p53-inducible protein and homologue of the R2 subunit of ribonucleotide reductase, has been detected in several human cancers, p53R2 roles in cancer progression and malignancy still remains controversial. In this article, we present a viable hypothesis about the roles of p53R2 in cancer progression and therapy resistance based on the roles of cytoplasmic p21 and mutant p53. Since p53R2 can up-regulate p21 and p21, it in turn has a dual role in cell cycle. Hence, p53R2 can play a dual role in cell cycle progression. In addition, because p53 is the main regulator of p53R2, the mutant p53 may induce the expression of p53R2 in some cancer cells based on the "keep of function" phenomenon. Therefore, depending on the locations of p21 and the new abilities of mutant p53, p53R2 has dual role in cell cycle progression. Since the DNA damaging therapies induce p53R2 expression through the induction of p53, p53R2 can be the main therapy resistance mediator in cancers with cytoplasmic p21. PMID- 24486302 TI - Suppressive effects of 17beta-estradiol on tributyltin-induced neuronal injury via Akt activation and subsequent attenuation of oxidative stress. AB - AIMS: Neuroactive steroids are reported to protect neurons from various harmful compounds; however, the protective mechanisms remain largely unclear. In this study, we examined the suppressive effects of 17beta-estradiol (E2) on tributyltin (TBT)-induced neurotoxicity. MAIN METHODS: Organotypic hippocampal slices were prepared from neonatal rats and then cultured. Cell death was assayed by propidium iodide uptake. Levels of reactive oxygen species (ROS) were determined by dihydroethidium staining. Protein phosphorylation was evaluated by immunoblotting. KEY FINDINGS: Pretreatment of the slices with E2 dose-dependently attenuated the neuronal injury induced by TBT. An estrogen receptor antagonist, ICI182,780 abrogated these neuroprotective effects. The de novo protein synthesis inhibitors actinomycin D and cycloheximide showed no effects on the neuroprotective mechanism, indicating that a nongenomic pathway acting via the estrogen receptor may be involved in the neuroprotection conferred by E2. E2 suppressed the ROS production and lipid peroxidation induced by TBT, and these effects were almost completely canceled by ICI182,780. TBT decreased Akt phosphorylation, and this reduction was suppressed by E2. An Akt inhibitor, triciribine, attenuated the decreases in both the ROS production and neuronal injury mediated by E2. SIGNIFICANCE: E2 enhances the phosphorylation of Akt, thereby attenuating the oxidative stress and subsequent neuronal injury induced by TBT. PMID- 24486303 TI - Ventricular tachyarrhythmias during acute myocardial infarction: the role of endothelin-1. AB - Ventricular arrhythmogenesis during acute coronary syndromes is a common cause of sudden cardiac death, but the underlying mechanisms remain incompletely understood. Recent evidence indicates an emerging pathophysiologic role of endothelin-1 during myocardial ischaemia and evolving infarction. At the early stages post-coronary occlusion, endothelin-1 enhances sympathetic activation, an effect mediated via the ETA receptor, whereas the ETB receptor exerts protective actions. The importance of this interaction is clearly decreased during subsequent stages, during which endothelin-1 may participate in the genesis of ventricular tachycardia or fibrillation via other mechanisms; of these, the effects of endothelin-1 on repolarizing potassium currents and electrical conduction via gap junctions merit further research. The relative roles of ETA and ETB receptors during this phase are unclear. Evaluation of the arrhythmogenic effects of endothelin-1 during acute coronary syndromes may provide the tools towards lowering sudden cardiac death rates. PMID- 24486304 TI - Carotenoids inhibit lipid peroxidation and hemoglobin oxidation, but not the depletion of glutathione induced by ROS in human erythrocytes. AB - AIMS: Despite the presence of endogenous antioxidants in erythrocytes, these cells are highly susceptible to oxidative damage and some exogenous antioxidants, such as carotenoids, are able to inhibit the pro-oxidant effect provided by reactive oxygen species. In this study, we evaluated the potential of carotenoids usually detected in human blood plasma (beta-carotene, zeaxanthin, lutein, beta cryptoxanthin and lycopene) to prevent the oxidative damage in erythrocytes. MAIN METHODS: Human erythrocytes were subjected to induced oxidative damage and the following biomarkers of oxidative stress were monitored: lipid peroxidation [induced by tert-butyl hydroperoxide (tBHP) or by 2,2'-azobis (2 methylpropionamidine) dihydrochloride (AAPH)] and AAPH-induced oxidation of hemoglobin and depletion of glutathione. KEY FINDINGS: When tBHP was used to induce lipid peroxidation, lycopene was the most efficient carotenoid (IC50=2.2 +/- 0.4 MUM), while lutein was the most efficient (IC50=2.5 +/- 0.7 MUM) when peroxyl radicals (ROO) were generated by AAPH. In relation to the hemoglobin oxidation induced by AAPH, beta-carotene and zeaxanthin were the most efficient antioxidants (IC50=2.9 +/- 0.3 MUM and 2.9 +/- 0.1 MUM, respectively). Surprisingly beta-cryptoxanthin and lycopene did not inhibit hemoglobin oxidation or lipid peroxidation when induced by AAPH, even at the highest tested concentration (3 MUM). Additionally, the tested carotenoids did not prevent ROO mediated GSH depletion and GSSG formation probably due to the lack of interaction between carotenoids (apolar) and glutathione (polar). SIGNIFICANCE: Our study contributes with important insights that carotenoids may exert therapeutical potential to act as a natural antioxidant to prevent ROO-induced toxicity in human erythrocytes. PMID- 24486306 TI - Robotic partial nephrectomy with superselective versus main artery clamping: a retrospective comparison. AB - BACKGROUND: Concerns have been raised regarding partial nephrectomy (PN) techniques that do not occlude the main renal artery. OBJECTIVE: Compare the perioperative outcomes of superselective versus main renal artery control during robotic PN. DESIGN, SETTING, AND PARTICIPANTS: A retrospective analysis of 121 consecutive patients undergoing robotic PN using superselective control (group 1, n=58) or main artery clamping (group 2, n=63). INTERVENTION: Group 1 underwent tumor-specific devascularization, maintaining ongoing arterial perfusion to the renal remnant at all times. Group 2 underwent main renal artery clamping, creating global renal ischemia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Perioperative and functional data were evaluated. The Pearson chi-square or Fisher exact and Wilcoxon rank sum tests were used. RESULTS AND LIMITATIONS: All robotic procedures were successful, all surgical margins were negative, and no kidneys were lost. Compared with group 2 tumors, group 1 tumors were larger (3.4 vs 2.6cm, p=0.004), more commonly hilar (24% vs 6%, p=0.009), and more complex (PADUA 10 vs 8, p=0.009). Group 1 patients had longer median operative time (p<0.001) and transfusion rates (24% vs 6%, p<0.01) but similar estimated blood loss (200 vs 150ml), perioperative complications (15% vs 13%), and hospital stay. Group 1 patients had less decrease in estimated glomerular filtration rate at discharge (0% vs 11%, p=0.01) and at last follow-up (11% vs 17%, p=0.03). On computed tomography volumetrics, group 1 patients trended toward greater parenchymal preservation (95% vs 90%, p=0.07) despite larger tumor size and volume (19 vs 8ml, p=0.002). Main limitations are the retrospective study design, small cohort, and short follow-up. CONCLUSIONS: Robotic PN with superselective vascular control enables tumor excision without any global renal ischemia. Blood loss, complications, and positive margin rates were low and similar to main artery clamping. In this initial developmental phase, limitations included more perioperative transfusions and longer operative time. The advantage of superselective clamping for better renal function preservation requires validation by prospective randomized studies. PATIENT SUMMARY: Preserving global blood flow to the kidney during robotic partial nephrectomy (PN) does not lead to a higher complication rate and may lead to better postoperative renal function compared with clamped PN techniques. PMID- 24486305 TI - Innate immunity and cardiomyocytes in ischemic heart disease. AB - Myocardial ischemia/reperfusion (I/R) is the most common cause of myocardial inflammation, which is primarily a manifestation of the innate immune responses. Innate immunity is activated when pattern recognition receptors (PRRs) respond to molecular patterns common to microbes and to danger signals expressed by injured or infected cells, so called pathogen-associated molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs). The expression of various PRRs in cardiomyocytes and the release of DAMPs from cardiomyocytes subjected to I/R injury, through active mechanisms as well as passive processes, enable cardiomyocytes to generate innate immune responses. Studies in isolated heart and cardiomyocytes have confirmed the inflammatory and functional effects of cardiac PRRs especially Toll-like receptors in response to I/R-derived DAMPs, such as heat shock proteins. This review addresses the active role of cardiomyocytes in mediating innate inflammatory responses to myocardial I/R. We propose that cardiomyocytes act as innate immune cells in myocardial I/R injury. PMID- 24486307 TI - Stratification of high-risk prostate cancer into prognostic categories: a European multi-institutional study. AB - BACKGROUND: High-risk prostate cancer (PCa) is an extremely heterogeneous disease. A clear definition of prognostic subgroups is mandatory. OBJECTIVE: To develop a pretreatment prognostic model for PCa-specific survival (PCSS) in high risk PCa based on combinations of unfavorable risk factors. DESIGN, SETTING, AND PARTICIPANTS: We conducted a retrospective multicenter cohort study including 1360 consecutive patients with high-risk PCa treated at eight European high volume centers. INTERVENTION: Retropubic radical prostatectomy with pelvic lymphadenectomy. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Two Cox multivariable regression models were constructed to predict PCSS as a function of dichotomization of clinical stage (< cT3 vs cT3-4), Gleason score (GS) (2-7 vs 8 10), and prostate-specific antigen (PSA; <= 20 ng/ml vs > 20 ng/ml). The first "extended" model includes all seven possible combinations; the second "simplified" model includes three subgroups: a good prognosis subgroup (one single high-risk factor); an intermediate prognosis subgroup (PSA >20 ng/ml and stage cT3-4); and a poor prognosis subgroup (GS 8-10 in combination with at least one other high-risk factor). The predictive accuracy of the models was summarized and compared. Survival estimates and clinical and pathologic outcomes were compared between the three subgroups. RESULTS AND LIMITATIONS: The simplified model yielded an R(2) of 33% with a 5-yr area under the curve (AUC) of 0.70 with no significant loss of predictive accuracy compared with the extended model (R(2): 34%; AUC: 0.71). The 5- and 10-yr PCSS rates were 98.7% and 95.4%, 96.5% and 88.3%, 88.8% and 79.7%, for the good, intermediate, and poor prognosis subgroups, respectively (p = 0.0003). Overall survival, clinical progression-free survival, and histopathologic outcomes significantly worsened in a stepwise fashion from the good to the poor prognosis subgroups. Limitations of the study are the retrospective design and the long study period. CONCLUSIONS: This study presents an intuitive and easy-to-use stratification of high-risk PCa into three prognostic subgroups. The model is useful for counseling and decision making in the pretreatment setting. PMID- 24486309 TI - A reassortment vaccine candidate as the improved formulation to induce protection against very virulent infectious bursal disease virus. AB - Infectious bursal disease (IBD) is a highly contagious immunosuppressive disease affecting all major poultry producing areas of the world. Infectious bursal disease virus (IBDV) is genetically prone to mutation so that vaccines have to be changed accordingly. However, the traditional method of vaccine development with blind passage could not fit the style of the emergency prevention of IBDV. In this study, for the first time, a segment-reassortment attenuated IBDV rXATB, consisting of modified segment A of a prevalent strain and segment B of an attenuated strain, was designed and rescued; rXATB was stable and could induce good humoral and cellular immune responses which resulted in excellent protection against the lethal challenge of vvIBDV without obvious immunosuppression in chicken. This study revolutionarily provides a new formulation based on reverse genetics to develop new vaccine against prevalent IBDV. PMID- 24486308 TI - What is the most bothersome lower urinary tract symptom? Individual- and population-level perspectives for both men and women. AB - BACKGROUND: No study has compared the bothersomeness of all lower urinary tract symptoms (LUTS) using a population-based sample of adults. Despite this lack of evidence, investigators have often cited their LUTS of interest as the "most bothersome" or "one of the most bothersome." OBJECTIVE: To compare the population and individual-level burden of LUTS in men and women. DESIGN, SETTING, AND PARTICIPANTS: In this population-based cross-sectional study, questionnaires were mailed to 6000 individuals (18-79 yr of age) randomly identified from the Finnish Population Register. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The validated Danish Prostatic Symptom Score questionnaire was used for assessment of bother of 12 different LUTS. The age-standardized prevalence of at least moderate bother was calculated for each symptom (population-level burden). Among symptomatic individuals, the proportion of affected individuals with at least moderate bother was calculated for each symptom (individual-level bother). RESULTS AND LIMITATIONS: A total of 3727 individuals (62.4%) participated (53.7% female). The LUTS with the greatest population-level burden were urgency (7.9% with at least moderate bother), stress urinary incontinence (SUI) (6.5%), nocturia (6.0%), postmicturition dribble (5.8%), and urgency urinary incontinence (UUI) (5.0%). Burden from incontinence symptoms was higher in women than men, and the opposite was true for voiding and postmicturition symptoms. At the individual level, UUI was the most bothersome for both genders. Although the response proportion was high, approximately a third did not participate. CONCLUSIONS: Both men and women with UUI report moderate or major bother more frequently than individuals with other LUTS. At the population level, the most prevalent bothersome symptoms are urgency, SUI, and nocturia. PATIENT SUMMARY: Urinary urgency was the most common troubling symptom in a large population-based study; however, for individuals, urgency incontinence was the most likely to be rated as bothersome. PMID- 24486310 TI - Recombinant Ag85B vaccine by taking advantage of characteristics of human parainfluenza type 2 virus vector showed Mycobacteria-specific immune responses by intranasal immunization. AB - Viral vectors are promising vaccine candidates for eliciting suitable Ag-specific immune response. Since Mycobacterium tuberculosis (Mtb) normally enters hosts via the mucosal surface of the lung, the best defense against Mtb is mucosal vaccines that are capable of inducing both systemic and mucosal immunity. Although Mycobacterium bovis bacille Calmette-Guerin is the only licensed tuberculosis (TB) vaccine, its efficacy against adult pulmonary forms of TB is variable. In this study, we assessed the effectiveness of a novel mucosal TB vaccine using recombinant human parainfluenza type 2 virus (rhPIV2) as a vaccine vector in BALB/c mice. Replication-incompetent rhPIV2 (M gene-eliminated) expressing Ag85B (rhPIV2-Ag85B) was constructed by reverse genetics technology. Intranasal administration of rhPIV2-Ag85B induced Mtb-specific immune responses, and the vaccinated mice showed a substantial reduction in the number of CFU of Mtb in lungs and spleens. Unlike other viral vaccine vectors, the immune responses against Ag85B induced by rhPIV2-Ag85B immunization had an advantage over that against the viral vector. In addition, it was revealed that rhPIV2-Ag85B in itself has an adjuvant activity through the retinoic acid-inducible gene I receptor. These findings provide further evidence for the possibility of rhPIV2 Ag85B as a novel TB vaccine. PMID- 24486311 TI - Recombinant lipidated dengue-4 envelope protein domain III elicits protective immunity. AB - The combination of recombinant protein antigens with an immunostimulator has the potential to greatly increase the immunogenicity of recombinant protein antigens. In the present study, we selected the dengue-4 envelope protein domain III as a dengue vaccine candidate and expressed the protein in lipidated form using an Escherichia coli-based system. The recombinant lipidated dengue-4 envelope protein domain III folded into the proper conformation and competed with the dengue-4 virus for cellular binding sites. Mice immunized with lipidated dengue-4 envelope protein domain III without exogenous adjuvant had higher frequencies of dengue-4 envelope protein domain III-specific B cells secreting antibodies than mice immunized with the nonlipidated form. Importantly, lipidated dengue-4 envelope protein domain III-immunized mice demonstrated a durable neutralizing antibody response and had reduced viremia levels after challenge. The study demonstrates that lipidated dengue-4 envelope protein domain III is immunogenic and may be a potential dengue vaccine candidate. Furthermore, the lipidation strategy can be applied to other serotypes of dengue virus. PMID- 24486312 TI - Evaluation of efficacy, biodistribution and safety of antibiotic-free plasmid encoding somatostatin genes delivered by attenuated Salmonella enterica serovar Choleraesuis. AB - We describe here a balanced-lethal system using an Asd(+) expression plasmid pVGS/2SS-asd encoding two copies of somatostatin (SS) genes carried by Deltaasd/Deltacrp double mutant Salmonella enterica serovar Choleraesuis (named C501). The advantage of this novel system is the use of asd (aspartate semialdehyde dehydrogenase) gene as selection marker to replace the antibiotic resistance markers, thus eliminating the industrial cultivation and environmental problems. We then evaluated the efficacy, biodistribution and safety of antibiotic-free plasmid delivered by strains C501. Mice orally immunized with C501 (pVGS/2SS-asd) had significantly higher levels of anti-SS total IgG and IgA antibodies than control mice and demonstrated a bias toward Th2-associated responses (IgG1/IgG2a ratio>1). Safety evaluation indicated that vaccinated mice displayed no abnormal clinical signs and histological changes. Biodistribution result revealed that the GS/2SS message was detected in several examined tissues with the exception of ovary and brain, but was rapidly cleared from the body (approximately 10 days). Furthermore, the risk of integration of plasmid pVGS/2SS asd into the host cellular genome was considered to be negligible. These results may have important implications for the use of vaccine strain C501 (pVGS/2SS-asd) in domestic animals and prompt new perspectives on the safety of DNA vaccines delivered by attenuated bacteria. PMID- 24486313 TI - Metabolites in vertebrate Hedgehog signaling. AB - The Hedgehog (HH) signaling pathway is critical in embryonic development, stem cell biology, tissue homeostasis, chemoattraction and synapse formation. Irregular HH signaling is associated with a number of disease conditions including congenital disorders and cancer. In particular, deregulation of HH signaling has been linked to skin, brain, lung, colon and pancreatic cancers. Key mediators of the HH signaling pathway are the 12-pass membrane protein Patched (PTC), the 7-pass membrane protein Smoothened (SMO) and the GLI transcription factors. PTC shares homology with the RND family of small-molecule transporters and it has been proposed that it interferes with SMO through metabolites. Although a conclusive picture is lacking, substantial efforts are made to identify and understand natural metabolites/sterols, including cholesterol, vitamin D3, oxysterols and glucocorticoides, that may be affected by, or influence the HH signaling cascade at the level of PTC and SMO. In this review we will elaborate the role of metabolites in HH signaling with a focus on oxysterols, and discuss advancements in modern analytical approaches in the field. PMID- 24486314 TI - The phenotype and tissue-specific nature of multipotent cells derived from human mature adipocytes. AB - Dedifferentiated fat (DFAT) cells derived from mature adipocytes have been considered to be a homogeneous group of multipotent cells, which present to be an alternative source of adult stem cells for regenerative medicine. However, many aspects of the cellular nature about DFAT cells remained unclarified. This study aimed to elucidate the basic characteristics of DFAT cells underlying their functions and differentiation potentials. By modified ceiling culture technique, DFAT cells were converted from human mature adipocytes from the human buccal fat pads. Flow cytometry analysis revealed that those derived cells were a homogeneous population of CD13(+) CD29(+) CD105(+) CD44(+) CD31(-) CD34(-) CD309( ) alpha-SMA(-) cells. DFAT cells in this study demonstrated tissue-specific differentiation properties with strong adipogenic but much weaker osteogenic capacity. Neither did they express endothelial markers under angiogenic induction. PMID- 24486315 TI - Studies on the analysis of 25-hydroxyvitamin D(3) by isotope-dilution liquid chromatography-tandem mass spectrometry using enzyme-assisted derivatisation. AB - The total serum concentration of 25-hydroxyvitamins D (25-hydroxyvitamin D3 and 25-hydroxyvitamin D2) is currently used as an indicator of vitamins D status. Vitamins D insufficiency is claimed to be associated with multiple diseases, thus accurate and precise reference methods for the quantification of 25 hydroxyvitamins D are needed. Here we present a novel enzyme-assisted derivatisation method for the analysis of vitamins D metabolites in adult serum utilising 25-[26,26,26,27,27,27-(2)H6]hydroxyvitamin D3 as the internal standard. Extraction of 25-hydroxyvitamins D from serum is performed with acetonitrile, which is shown to be more efficient than ethanol. Cholesterol oxidase is used to oxidize the 3beta-hydroxy group in the vitamins D metabolites followed by derivatisation of the newly formed 3-oxo group with Girard P reagent. 17beta Hydroxysteroid dehydrogenase type 10 is shown to oxidize selectively the 3alpha hydroxy group in the 3alpha-hydroxy epimer of 25-hydroxyvitamin D3. Quantification is achieved by isotope-dilution liquid chromatography-tandem mass spectrometry. Recovery experiments for 25-hydroxyvitamin D3 performed on adult human serum give recovery of 102-106%. Furthermore in addition to 25 hydroxyvitamin D3, 24,25-dihydroxyvitamin D3 and other uncharacterised dihydroxy metabolites, were detected in adult human serum. PMID- 24486317 TI - Orchestration of plant defense systems: genes to populations. AB - Research over the past decades has made immense progress in identifying some genes and mechanisms underlying plant defense against biotic organisms. The recent movement towards systems biology approaches has increased mechanistic knowledge, revealing a need for understanding how all the genes and mechanisms integrate to create a response to any given biotic interaction. This begins with evidence that diverse molecular patterns converge, suggesting that the plant perceives signals not the interacting species. These signals then coordinate across regulatory networks via molecular interactions and cause non-cell autonomous responses in neighboring and systemic cells. Finally, the identification of transporters is showing that plant defenses are harmonized across tissues and even show the potential for coordination across individuals within a population. PMID- 24486316 TI - Methylation of yeast ribosomal protein S2 is elevated during stationary phase growth conditions. AB - Ribosomes, as the center of protein translation in the cell, require careful regulation via multiple pathways. While regulation of ribosomal synthesis and function has been widely studied on the transcriptional and translational "levels," the biological roles of ribosomal post-translational modifications (PTMs) are largely not understood. Here, we explore this matter by using quantitative mass spectrometry to compare the prevalence of ribosomal methylation and acetylation for yeast in the log phase and the stationary phase of growth. We find that of the 27 modified peptides identified, two peptides experience statistically significant changes in abundance: a 1.9-fold decrease in methylation for k(Me)VSGFKDEVLETV of ribosomal protein S1B (RPS1B), and a 10-fold increase in dimethylation for r(DiMe)GGFGGR of ribosomal protein S2 (RPS2). While the biological role of RPS1B methylation has largely been unexplored, RPS2 methylation is a modification known to have a role in processing and export of ribosomal RNA. This suggests that yeast in the stationary phase increase methylation of RPS2 in order to regulate ribosomal synthesis. These results demonstrate the utility of mass spectrometry for quantifying dynamic changes in ribosomal PTMs. PMID- 24486318 TI - Determination of phosphorus impurity that directly affects quantification of microbial genomic DNA using inductively coupled plasma optical emission spectrometry. AB - We prepared genomic DNA from human placenta, Escherichia coli, and Bacillus subtilis using various DNA extraction methods and quantified the genomic DNA using ultraviolet (UV) spectrophotometry, capillary electrophoresis (CE), and inductively coupled plasma optical emission spectrometry (ICP-OES). Application of ICP-OES unexpectedly led to a serious overestimation of phosphorus in B. subtilis genomic DNA prepared using cetyltrimethyl ammonium bromide (CTAB). Further investigations using reversed-phase high-performance liquid chromatography (RP-HPLC), ultra-performance liquid chromatography electrospray ionization tandem mass spectrometry (UPLC-ESI-MS/MS), and (31)P nuclear magnetic resonance (NMR) identified the phosphorus impurity as lipoteichoic acid (LTA). PMID- 24486319 TI - Nanoparticle imaging and diagnostic of Caenorhabditis elegans intracellular pH. AB - A novel diagnostic tool has been developed for the characterization of intracellular pH (pHi) in the model organism Caenorhabditis elegans. This tool exploits the chemical stability of colloidal silica and the pH sensitivity of certain fluorescent dyes. Once ingested, the fluorescent colloidal dispersion yields a reliable visual indication of pH without the use of chemical fixatives or damaging the nematode. The pH-sensitive silica nanoparticles were visualized by confocal microscopy, and the fluorescence spectra from the internally referenced colloidal particulates were measured. By comparing the fluorescence profile of colloids in wild-type (N2) and mutant (eat-3) C. elegans against a calibration series, the intestinal pHi could be established in each population. The rapid characterization of pHi using this inexpensive nonintrusive technique has significant implications for disease research where C. elegans is used as a model organism. PMID- 24486320 TI - Label-free fluorescent sensor for lead ion detection based on lead(II)-stabilized G-quadruplex formation. AB - A label-free fluorescent DNA sensor for the detection of lead ions (Pb(2+)) based on lead(II)-stabilized G-quadruplex formation is proposed in this article. A guanine (G)-rich oligonucleotide, T30695, was used as a recognition probe, and a DNA intercalator, SYBR Green I (SG), was used as a signal reporter. In the absence of Pb(2+), the SG intercalated with the single-stranded random-coil T30695 and emitted strong fluorescence. While in the presence of Pb(2+), the random-coil T30695 would fold into a G-quadruplex structure and the SG could barely show weak fluorescence, and the fluorescence intensity was inversely proportional to the involving amount of Pb(2+). Based on this, a selective lead ion sensor with a limit of detection of 3.79 ppb (parts per billion) and a detection range from 0 to 600 ppb was constructed. Because detection for real samples was also demonstrated to be reliable, this simple, low-cost, sensitive, and selective sensor holds good potential for Pb(2+) detection in real environmental samples. PMID- 24486322 TI - Mesenchymal stem cells rescue injured endothelial cells in an in vitro ischemia reperfusion model via tunneling nanotube like structure-mediated mitochondrial transfer. AB - Mesenchymal stem cells can be used as a novel treatment of ischemic vascular disease; however, their therapeutic effect and mechanism of action require further evaluation. Mitochondrial dysfunction has core functions in ischemia reperfusion injury of the microvascular network. A recent discovery has shown that intercellular communication using tunneling nanotubes can transfer mitochondria between adjacent cells. This study aimed to investigate the tunneling nanotube mechanisms that might be involved in stem cell-mediated mitochondrial rescue of injured vascular endothelial cells. Using laser scanning confocal microscopy, mitochondrial transfer via a tunneling nanotube-like structure was detected between mesenchymal stem cells and human umbilical vein endothelial cells. Oxygen glucose deprivation and reoxygenation were performed on human umbilical vein endothelial cells, which induced mitochondrial transfer through tunneling nanotube-like structures to become frequent and almost unidirectional from mesenchymal stem cells to injured endothelial cells, thereby resulting in the rescue of aerobic respiration and protection of endothelial cells from apoptosis. We found that the formation of tunneling nanotube-like structures might represent a defense and rescue mechanism through phosphatidylserines exposed on the surface of apoptotic endothelial cells and stem cell recognition. Our data provided evidence that stem cells can rescue damaged vascular endothelial cells through a mechanism that has not yet been identified. PMID- 24486321 TI - Redox properties of human hemoglobin in complex with fractionated dimeric and polymeric human haptoglobin. AB - Haptoglobin (Hp) is an abundant and conserved plasma glycoprotein, which binds acellular adult hemoglobin (Hb) dimers with high affinity and facilitates their rapid clearance from circulation after hemolysis. Humans possess three main phenotypes of Hp, designated Hp 1-1, Hp 2-1, and Hp 2-2. These variants exhibit diverse structural configurations and have been reported to be functionally nonequivalent. We have investigated the functional and redox properties of Hb-Hp complexes prepared using commercially fractionated Hp and found that all forms exhibit similar behavior. The rate of Hb dimer binding to Hp occurs with bimolecular rate constants of ~0.9 MUM(-1) s(-1), irrespective of the type of Hp assayed. Although Hp binding does accelerate the observed rate of HbO2 autoxidation by dissociating Hb tetramers into dimers, the rate observed for these bound dimers is three- to fourfold slower than that of Hb dimers free in solution. Co-incubation of ferric Hb with any form of Hp inhibits heme loss to below detectable levels. Intrinsic redox potentials (E1/2) of the ferric/ferrous pair of each Hb-Hp complex are similar, varying from +54 to +59 mV (vs NHE), and are essentially the same as reported by us previously for Hb-Hp complexes prepared from unfractionated Hp. All Hb-Hp complexes generate similar high amounts of ferryl Hb after exposure to hydrogen peroxide. Electron paramagnetic resonance data indicate that the yields of protein-based radicals during this process are approximately 4 to 5% and are unaffected by the variant of Hp assayed. These data indicate that the Hp fractions examined are equivalent to one another with respect to Hb binding and associated stability and redox properties and that this result should be taken into account in the design of phenotype specific Hp therapeutics aimed at countering Hb-mediated vascular disease. PMID- 24486324 TI - Recent progress in development of new sonosensitizers for sonodynamic cancer therapy. AB - Developing an effective treatment for cancer is still a challenge. Despite great success with traditional cancer therapies, there are numerous disadvantages for conventional treatments such as systemic toxicity, low selectivity, drug resistance and potential long-term side effects. Recently, photodynamic therapy (PDT) has been widely applied in clinical settings. However, this approach suffers from the major shortcoming derived from the limited penetrability of visible light. Sonodynamic therapy (SDT) utilizing ultrasound combined with a sonosensitizer represents a novel noninvasive approach for cancer therapy, which is deemed to overcome the disadvantage of PDT. In this review, we extensively summarize the recent progress in the discovery of new sonosensitizers for SDT and discuss the future directions for the development of novel sonosensitizers. PMID- 24486323 TI - Mouse model of intrauterine inflammation: sex-specific differences in long-term neurologic and immune sequelae. AB - Preterm infants, especially those that are exposed to prenatal intrauterine infection or inflammation, are at a major risk for adverse neurological outcomes, including cognitive, motor and behavioral disabilities. We have previously shown in a mouse model that there is an acute fetal brain insult associated with intrauterine inflammation. The objectives of this study were: (1) to elucidate long-term (into adolescence and adulthood) neurological outcomes by assessing neurobehavioral development, MRI, immunohistochemistry and flow cytometry of cells of immune origin and (2) to determine whether there are any sex-specific differences in brain development associated with intrauterine inflammation. Our results have shown that prenatal exposure appeared to lead to changes in MRI and behavior patterns throughout the neonatal period and during adulthood. Furthermore, we observed chronic brain inflammation in the offspring, with persistence of microglial activation and increased numbers of macrophages in the brain, ultimately resulting in neuronal loss. Moreover, our study highlights the sex-specific differences in long-term sequelae. This study, while extending the growing literature of adverse neurologic outcomes following exposure to inflammation during early development, presents novel findings in the context of intrauterine inflammation. PMID- 24486325 TI - A novel feed-forward loop between ARIH2 E3-ligase and PABPN1 regulates aging associated muscle degeneration. AB - Alanine expansion mutations in poly(A)-binding protein nuclear 1 (PABPN1) cause muscle weakness in the late-onset disorder oculopharyngeal muscular dystrophy. In affected muscles, expanded PABPN1 forms nuclear aggregates, depleting levels of soluble PABPN1 and inducing a genome-wide shift from distal to proximal polyadenylation site usage. PABPN1 protein accumulation is regulated by the ubiquitin proteasome system, which is highly dysregulated in oculopharyngeal muscular dystrophy. We show that ARIH2 E3-ligase regulates PABPN1 protein accumulation and aggregation. Levels of ARIH2 mRNA are regulated by PABPN1 via proximal polyadenylation site usage. We demonstrate that masking the proximal polyadenylation site in ARIH2 3' untranslated region by antisense oligonucleotides elevates the expression of ARIH2 and PABPN1 and restores myogenic defects that are induced by ARIH2 or PABPN1 down-regulation in cell culture. In vivo ARIH2 mRNA levels significantly decrease from midlife in vastus lateralis muscles and highly correlate with muscle degeneration. We suggest that the expression of both genes is maintained by a feed-forward loop between mRNA stability regulated by PABPN1 and protein turnover regulated by ARIH2. PMID- 24486326 TI - Discordant biological and toxicological species responses to TLR3 activation. AB - Toll-like receptors (TLRs) are highly conserved type 1 membrane proteins that initiate a multiplicity of transient gene transcriptions, resulting in innate and adaptive immune responses. These essential immune responses are triggered by common TLR pattern recognition receptors of microbial products expressed through the cytoplasmic carboxy-terminal Toll/IL-1 domain. Toll/IL-1 adapter protein cascades are induced by an activated Toll/IL-1 to induce transient transcription responses. All TLRs, with the exception of TLR3, use an MyD88 adapter to Toll/IL 1 to initiate a proinflammatory cascade. TLR3 uses the toll receptor 3/4 induction factor adapter to initiate a different cytosolic adapter cascade with double-stranded RNA agonists. This non-MyD88 pathway induces both NF-kappaB and type 1 interferon responses. By using a TLR3-restricted double-stranded RNA agonist, rintatolimod, we demonstrate significant unexpected differences in toxic responses between rats and primates. The mechanism of this differential response is consistent with a relative down-regulation of the NF-kappaB inflammatory cytokine induction pathway in the cynomolgus monkey and humans, but not observed systemically in rat. Our findings suggest evaluation of TLR3 agonists in drug therapy. PMID- 24486328 TI - Synergistic interaction between ketamine and magnesium in lowering body temperature in rats. AB - A large body of evidence supports the existence of an endogenous glutamate system that tonically modulates body temperature via N-methyl-d-aspartate (NMDA) receptors. Ketamine and magnesium, both NMDA receptor antagonists, are known for their anesthetic, analgesic and anti-shivering properties. This study is aimed at evaluating the effects of ketamine and magnesium sulfate on body temperature in rats, and to determine the type of interaction between them. The body temperature was measured by insertion of a thermometer probe 5cm into the colon of unrestrained male Wistar rats (200-250g). Magnesium sulfate (5 and 60mg/kg, sc) showed influence neither on baseline, nor on morphine-evoked hyperthermic response. Subanesthetic doses of ketamine (5-30mg/kg, ip) given alone, produced significant dose-dependent reduction in both baseline colonic temperature and morphine-induced hyperthermia. Analysis of the log dose-response curves for the effects of ketamine and ketamine-magnesium sulfate combination on the baseline body temperature revealed synergistic interaction, and about 5.3 fold reduction in dosage of ketamine when the drugs were applied in fixed ratio (1:1) combinations. In addition, fixed low dose of magnesium sulfate (5mg/kg, sc) enhanced the temperature lowering effect of ketamine (1.25-10mg/kg, ip) on baseline body temperature and morphine-induced hyperthermia by factors of about 2.5 and 5.3, respectively. This study is the first to demonstrate the synergistic interaction between magnesium sulfate and ketamine in a whole animal study and its statistical confirmation. It is possible that the synergy between ketamine and magnesium may have clinical relevance. PMID- 24486327 TI - Cocaine enhances HIV-1-induced CD4(+) T-cell apoptosis: implications in disease progression in cocaine-abusing HIV-1 patients. AB - Substance abuse is a major barrier in eradication of the HIV epidemic because it serves as a powerful cofactor for viral transmission, disease progression, and AIDS-related mortality. Cocaine, one of the commonly abused drugs among HIV-1 patients, has been suggested to accelerate HIV disease progression. However, the underlying mechanism remains largely unknown. Therefore, we tested whether cocaine augments HIV-1-associated CD4(+) T-cell decline, a predictor of HIV disease progression. We examined apoptosis of resting CD4(+) T cells from HIV-1 negative and HIV-1-positive donors in our study, because decline of uninfected cells plays a major role in HIV-1 disease progression. Treatment of resting CD4(+) T cells with cocaine (up to 100 MUmol/L concentrations) did not induce apoptosis, but 200 to 1000 MUmol/L cocaine induced apoptosis in a dose-dependent manner. Notably, treatment of CD4(+) T cells isolated from healthy donors with both HIV-1 virions and cocaine significantly increased apoptosis compared with the apoptosis induced by cocaine or virions alone. Most important, our biochemical data suggest that cocaine induces CD4(+) T-cell apoptosis by increasing intracellular reactive oxygen species levels and inducing mitochondrial depolarization. Collectively, our results provide evidence of a synergy between cocaine and HIV-1 on CD4(+) T-cell apoptosis that may, in part, explain the accelerated disease observed in HIV-1-infected drug abusers. PMID- 24486329 TI - The effects of social isolation on wound healing mechanisms in female mice. AB - Various stressors impair wound healing in humans and rodents. For example, social isolation delays wound closure in rodents, but the healing mechanisms that underlie this delay have yet to be identified. Here, the effects of three weeks of social isolation on hypothalamic-pituitary-adrenal axis responses and healing factors involved in the inflammatory and proliferative phases of wound healing were assessed in adult female hairless mice. Social isolation reduced basal circulating corticosterone concentrations and increased body and thymus weights compared with group-housed controls. Isolation impaired dermal wound closure by up to 30% and reduced initial total wound bacterial load relative to controls. Inflammatory gene expression in the wounds was not affected by the observed differences in wound bacterial load. However, isolation reduced wound gene expression of keratinocyte growth factor and vascular endothelial growth factor, which are involved in keratinocyte proliferation/migration and angiogenesis during the proliferative phase of healing. These data indicate that social isolation induces healing impairments that may be attributed to reductions in growth factors necessary for proper skin cell proliferation and blood vessel growth during healing. This healing impairment occurred in the absence of both high wound bacterial load and elevated circulating glucocorticoids, which have previously been hypothesized to be required for stress-impaired healing in mice. PMID- 24486330 TI - Getting closer to a point-of-care diagnostic assessment in patients with chronic liver disease: controlled attenuation parameter for steatosis. PMID- 24486331 TI - Replacing a crystal ball with a calculator in predicting liver disease outcomes. PMID- 24486332 TI - Nucleocytoplasmic shuttling of the Duchenne muscular dystrophy gene product dystrophin Dp71d is dependent on the importin alpha/beta and CRM1 nuclear transporters and microtubule motor dynein. AB - Even though the Duchenne muscular dystrophy (DMD) gene product Dystrophin Dp71d is involved in various key cellular processes through its role as a scaffold for structural and signalling proteins at the plasma membrane as well as the nuclear envelope, its subcellular trafficking is poorly understood. Here we map the nuclear import and export signals of Dp71d by truncation and point mutant analysis, showing for the first time that Dp71d shuttles between the nucleus and cytoplasm mediated by the conventional nuclear transporters, importin (IMP) alpha/beta and the exportin CRM1. Binding was confirmed in cells using pull downs, while in vitro binding assays showed direct, high affinity (apparent dissociation coefficient of c. 0.25nM) binding of Dp71d to IMPalpha/beta. Interestingly, treatment of cells with the microtubule depolymerizing reagent nocodazole or the dynein inhibitor EHNA both decreased Dp71d nuclear localization, implying that Dp71d nuclear import may be facilitated by microtubules and the motor protein dynein. The role of Dp71d in the nucleus appears to relate in part to interaction with the nuclear envelope protein emerin, and maintenance of the integrity of the nuclear architecture. The clear implication is that Dp71d's previously unrecognised nuclear transport properties likely contribute to various, important physiological roles. PMID- 24486333 TI - Cell-line-specific high background in the Proteasome-Glo assay of proteasome trypsin-like activity. AB - Proteasome-Glo is a homogeneous cell-based assay of proteasomal chymotrypsin like, trypsin-like, and caspase-like activities using luminogenic substrates, commercially available from Promega. Here we report that the background activity from cleavage of the substrate of the trypsin-like sites by nonproteasomal proteases in multiple breast and lung cancer cell lines exceeds the activity of the proteasome. We also observed substantial background chymotrypsin-like activity in some cell lines. Thus, Proteasome-Glo assay must be used with caution, and it is necessary to include a specific proteasome inhibitor to determine the background for each proteasome activity. PMID- 24486334 TI - Assessment of dronedarone utilization using US claims databases. AB - BACKGROUND: A dronedarone utilization study using US MarketScan and InVision Data Mart databases was conducted to estimate the prevalence of the following: (1) dronedarone use in contraindicated patients with worsening heart failure (HF) or hospitalization for HF within 1 month before dronedarone prescription; (2) concomitant prescribing of contraindicated drugs; and (3) recommended creatinine testing after dronedarone initiation among dronedarone users. METHODS: In this retrospective cohort study, data in the MarketScan database between July 20, 2009, and December 31, 2011, and in the InVision Data Mart database between July 20, 2009, and March 31, 2012, were analyzed. The study population included patients who received >=1 dronedarone prescription during the study period. The following variables were reported: worsening of or hospitalization for HF, concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors or QT prolonging drugs, and creatinine testing. RESULTS: There were 31,408 and 7025 dronedarone users identified in the MarketScan and InVision Data Mart databases, respectively. Approximately 86% to 90% of patients had a diagnosis of atrial fibrillation in each database. In the MarketScan database, 40% were women and 54% were aged >=65 years. In the InVision Data Mart database, 31% were women and 32% were aged >=65 years. The corresponding prevalence of worsening or hospitalization for HF was 6.4% (95% CI, 6.2-6.7) and 4.7% (95% CI, 4.2-5.2) in each database, respectively. The corresponding estimates of concomitant prescribing of potent cytochrome P450 CYP 3A4 inhibitors and QT-prolonging drugs within 30 days before initiation or refilling of dronedarone were 2.0% (95% CI, 1.8-2.1) and 10.0% (95% CI, 9.7-10.4), respectively, in the MarketScan database, and 2.3% (95% CI, 2.0-2.7) and 11.2% (95% CI, 10.5-12.0) in the InVision Data Mart database. More than 50% of patients in each database had serum creatinine tests conducted after dronedarone initiation. CONCLUSIONS: The results of the present analysis based on a long-term follow-up (nearly 3 years) were consistent with the previous findings that dronedarone has mostly been used appropriately in compliance with US prescribing in the target populations. PMID- 24486335 TI - Tolerability and pharmacokinetic properties of ondansetron administered subcutaneously with recombinant human hyaluronidase in minipigs and healthy volunteers. AB - BACKGROUND: Subcutaneous ondansetron facilitated by recombinant human hyaluronidase PH20 (rHuPH20) is an alternative for treating nausea/vomiting in patients who cannot receive ondansetron by other routes of administration. OBJECTIVE: Based on preclinical results in minipigs, a Phase I study was designed to assess the tolerability and pharmacokinetic properties of subcutaneous ondansetron + rHuPH20 compared with intramuscular, intravenous, or oral ondansetron monotherapy in healthy volunteers. METHODS: In a crossover design, 3 minipigs were dosed with subcutaneous ondansetron 0.08 mg/kg + rHuPH20, or as intramuscular or intravenous monotherapy, for the evaluation of plasma ondansetron concentrations and local tolerability. In a randomized, open-label, 4 way crossover study, subjects received a randomized sequence of SC ondansetron 4 mg + rHuPH20, or ondansetron monotherapy IM (4 mg), IV (4 mg), or PO (8 mg), over 4 daily visits. Study participants included healthy volunteers aged 19 to 65 years with adequate venous access in both upper extremities and no history of QT interval prolongation. Primary tolerability end points (administration-site observations, systemic adverse events [AEs], and subject-assessed pain) were assessed, and pharmacokinetic parameters (AUC, Cmax, Tmax, t1/2) were computed to compare relative rate and extent of systemic exposure. Results were described using summary statistics, and bioequivalence was determined with a linear mixed effects model. RESULTS: In the preclinical study, no adverse events or significant local reactions were observed. The Cmax (45.8 ng/mL at 0.08 hour) with subcutaneous administration + rHuPH20 was 83% greater and was achieved 68% faster than with intramuscular administration (Cmax = 25 ng/mL at 0.25 hour). In the clinical study, a total of 12 subjects (7 women, 5 men; white majority; mean age, 44.8) were randomized. The majority of AEs were at the injection site, mild in severity, and transient. After subcutaneous administration of ondansetron + rHuPH20, geometric mean Cmax was 35% higher than with intramuscular ondansetron, 43% lower than with intravenous ondansetron, and 126% higher than with oral ondansetron (corrected for dose). Bioequivalence tests demonstrated that systemic exposure after subcutaneous administration was similar to that after intramuscular or intravenous administration and significantly greater than that after oral administration. CONCLUSIONS: Subcutaneous ondansetron + rHuPH20 was generally well-tolerated. Subcutaneous dosing resulted in an extent of systemic exposure similar to that with intramuscular or intravenous dosing and greater than that with oral administration, and may be an option for clinical administration of ondansetron. ClinicalTrials.gov identifier: NCT01572012. PMID- 24486336 TI - Treatment of peripheral arterial disease in diabetes: a consensus of the Italian Societies of Diabetes (SID, AMD), Radiology (SIRM) and Vascular Endovascular Surgery (SICVE). AB - Diabetic foot (DF) is a chronic and highly disabling complication of diabetes. The prevalence of peripheral arterial disease (PAD) is high in diabetic patients and, associated or not with peripheral neuropathy (PN), can be found in 50% of cases of DF. It is worth pointing out that the number of major amputations in diabetic patients is still very high. Many PAD diabetic patients are not revascularised due to lack of technical expertise or, even worse, negative beliefs because of poor experience. This despite the progress obtained in the techniques of distal revascularisation that nowadays allow to reopen distal arteries of the leg and foot. Italy has one of the lowest prevalence rates of major amputations in Europe, and has a long tradition in the field of limb salvage by means of an aggressive approach in debridement, antibiotic therapy and distal revascularisation. Therefore, we believe it is appropriate to produce a consensus document concerning the treatment of PAD and limb salvage in diabetic patients, based on the Italian experience in this field, to share with the scientific community. PMID- 24486337 TI - The effects of menstrual-related pain on attentional interference. AB - Pain-related attentional interference has been found in both chronic pain and laboratory-inducted pain settings. However, few studies have examined such interference effects during common everyday painful episodes. Menstrual cycle related pain is a common pain that affects a large number of women on a regular basis. The purpose of the current study was, therefore, to examine the effects of menstrual pain on attentional interference. Fifty-two healthy adult women were tested during 2 different phases of their menstrual cycles: once during a nonpain phase (mid follicular), and once while experiencing menstrual pain (late luteal/early follicular). On each testing session, participants received a battery of 4 attentional interference tasks that included selective attention (flanker task), attention span (n-back task), attentional switching (switching task), and divided attention (dual task). Greater attentional interference effects were found to occur during the menstrual pain phase compared to the nonpain phase. Interestingly, the nature of this effect was a general worsening in performance (e.g., slowing, less accurate), rather than a specific attentional deficit. These results add to a growing literature that generally indicates that attentional interference occurs across a range of different types of pain, including common painful episodes. However, they also highlight that the specific nature of this interference effect may depend on the type pain under consideration. Implications of these findings are also considered. PMID- 24486338 TI - Absence of MGST1 mRNA and protein expression in human neuroblastoma cell lines and primary tissue. AB - A recent study identified a haplotype on a small region of chromosome 12, between markers D12S1725 and D12S1596, shared by all patients with familial neuroblastoma (NB). We previously localized the human MGST1 gene, whose gene product protects against oxidative stress, to this very same chromosomal region (12p112.1-p13.33). Owing to the chromosomal location of MGST1; its roles in tumorigenesis, drug resistance, and oxidative stress; and the known sensitivity of NB cell lines to oxidative stress, we considered a role for MGST1 in NB development. Surprisingly there was no detectable MGST1 mRNA or protein in either NB cell lines or NB primary tumor tissue, although all other human tissues, cell lines, and primary tumor tissue examined to date express MGST1 at high levels. The mechanism behind the failure of NB cells and tissue to express MGST1 mRNA is unknown and involves the failure of MGST1 pre-mRNA expression, but does not involve chromosomal rearrangement or nucleotide variation in the promoter, exons, or 3' untranslated region of MGST1. MGST1 provides significant protection against oxidative stress and constitutes 4 to 6% of all protein in the outer membrane of the mitochondria. As NB cells are extremely sensitive to oxidative stress, and often used as a model system to investigate mitochondrial response to endogenous and exogenous stress, these findings may be due to the lack of expression MGST1 protein in NB. The significance of this finding to the development of neuroblastoma (familial or otherwise), however, is unknown and may even be incidental. Although our studies provide a molecular basis for previous work on the sensitivity of NB cells to oxidative stress, and possibly marked variations in NB mitochondrial homeostasis, they also imply that the results of these earlier studies using NB cells are not transferable to other tumor and cell types that express MGST1 at high concentrations. PMID- 24486339 TI - P2Y(2)R activation by nucleotides released from oxLDL-treated endothelial cells (ECs) mediates the interaction between ECs and immune cells through RAGE expression and reactive oxygen species production. AB - Lipoprotein oxidation, inflammation, and immune responses involving the vascular endothelium and immune cells contribute to the pathogenesis of atherosclerosis. In an atherosclerotic animal model, P2Y2 receptor (P2Y2R) upregulation and stimulation were previously shown to induce intimal hyperplasia and increased intimal monocyte infiltration. Thus, we investigated the role of P2Y2R in oxidized low-density lipoprotein (oxLDL)-mediated oxidative stress and the subsequent interaction between endothelial cells (ECs) and immune cells. The treatment of human ECs with oxLDL caused the rapid release of ATP (maximum after 5 min). ECs treated with oxLDL or the P2Y2R agonists ATP/UTP for 1h exhibited significant reactive oxygen species (ROS) production, but this effect was not observed in P2Y2R siRNA-transfected ECs. In addition, oxLDL and ATP/UTP both induced RAGE expression, which was P2Y2R dependent. Oxidized LDL- and ATP/UTP mediated ROS production was diminished in RAGE siRNA-transfected ECs, suggesting that RAGE is an important mediator in P2Y2R-mediated ROS production. Treatment with oxLDL for 24h induced P2Y2R expression in the human monocyte cell line THP-1 and increased THP-1 cell migration toward ECs. The addition of apyrase, an enzyme that hydrolyzes nucleotides, or diphenyleneiodonium (DPI), a well-known inhibitor of NADPH oxidase, significantly inhibited the increase in cell migration caused by oxLDL. P2Y2R siRNA-transfected THP-1 cells did not migrate in response to oxLDL or ATP/UTP treatment, indicating a critical role for P2Y2R and nucleotide release in oxLDL-induced monocyte migration. Last, oxLDL and ATP/UTP effectively increased ICAM-1 and VCAM-1 expression and the subsequent binding of THP-1 cells to ECs, which was inhibited by pretreatment with DPI or by siRNA against P2Y2R or RAGE, suggesting that P2Y2R is an important mediator in oxLDL-mediated monocyte adhesion to ECs through the regulation of ROS-dependent adhesion molecule expression in ECs. Taken together, our findings suggest that P2Y2R could be a therapeutic target for the prevention of vascular disorders, including atherosclerosis. PMID- 24486340 TI - Glutamate triggers neurosecretion and apoptosis in bovine chromaffin cells through a mechanism involving NO production by neuronal NO synthase activation. AB - Previous work from our group stated that nitric oxide (NO), via cytokines, induces apoptosis in chromaffin cells by a mechanism involving iNOS, nNOS, and NF kappaB. In this paper the involvement of glutamate as a possible intracellular trigger of neurosecretion and NO-mediated apoptosis has been evaluated. We show that chromaffin cells express different ionotropic and metabotropic glutamate receptors, this exerting different effects on the regulation of basal and glutamate-induced catecholamine secretion, via NO/cGMP. In addition, we studied the effects of endogenously generated NO, both basal and glutamate-stimulated, on apoptosis of chromaffin cells. Our results show that glutamate agonists are able to induce cell death and apoptosis in bovine chromaffin cells, parallel to an increase in NO production. Such effects were reversed by NOS inhibitors and glutamate receptor antagonists. Under basal conditions, iNOS inhibitors did not have any effect on apoptosis, whereas nNOS inhibitors induced apoptosis, indicating a neuroprotective effect of constitutive nNOS-generated NO. In contrast, glutamate-induced apoptosis was strongly reversed by nNOS inhibitors and weakly by iNOS inhibitors, thus indicating nNOS involvement in glutamate mediated apoptosis. These results were confirmed by the fact that nNOS expression, but not iNOS, is specifically activated by glutamate. Finally, our results suggest the participation of PKG, PKA, PKC, and MAPK pathways in glutamate-mediated nNOS activation in chromaffin cells and point out the involvement of both PKA and PKC signaling pathways in the apoptotic effect of glutamate. PMID- 24486341 TI - Rutin decreases lipopolysaccharide-induced acute lung injury via inhibition of oxidative stress and the MAPK-NF-kappaB pathway. AB - Acute lung injury (ALI) is a serious disease with unacceptably high mortality and morbidity rates. Up to now, no effective therapeutic strategy for ALI has been established. Rutin, quercetin-3-rhamnosyl glucoside, expresses a wide range of biological activities and pharmacological effects, such as anti-inflammatory, antihypertensive, anticarcinogenic, vasoprotective, and cardioprotective activities. Pretreatment with rutin inhibited not only histopathological changes in lung tissues but also infiltration of polymorphonuclear granulocytes into bronchoalveolar lavage fluid in lipopolysaccharide (LPS)-induced ALI. In addition, LPS-induced inflammatory responses, including increased secretion of proinflammatory cytokines and lipid peroxidation, were inhibited by rutin in a concentration-dependent manner. Furthermore, rutin suppressed phosphorylation of NF-kappaB and MAPK and degradation of IkappaB, an NF-kappaB inhibitor. Decreased activities of antioxidative enzymes such as superoxide dismutase, catalase, glutathione peroxidase, and heme oxygenase-1 caused by LPS were reversed by rutin. At the same time, we found that ALI amelioration by chelation of extracellular metal ions with rutin is more efficacious than with deferoxamine. These results indicate that the protective mechanism of rutin is through inhibition of MAPK-NF-kappaB activation and upregulation of antioxidative enzymes. PMID- 24486342 TI - Glucosamine attenuates cigarette smoke-induced lung inflammation by inhibiting ROS-sensitive inflammatory signaling. AB - Cigarette smoking causes persistent lung inflammation that is mainly regulated by redox-sensitive pathways. We have reported that cigarette smoke (CS) activates a NADPH oxidase-dependent reactive oxygen species (ROS)-sensitive AMP-activated protein kinase (AMPK) signaling pathway leading to induction of lung inflammation. Glucosamine, a dietary supplement used to treat osteoarthritis, has antioxidant and anti-inflammatory properties. However, whether glucosamine has similar beneficial effects against CS-induced lung inflammation remains unclear. Using a murine model we show that chronic CS exposure for 4 weeks increased lung levels of 4-hydroxynonenal (an oxidative stress biomarker), phospho-AMPK, and macrophage inflammatory protein 2 and induced lung inflammation; all of these CS induced events were suppressed by chronic treatment with glucosamine. Using human bronchial epithelial cells, we demonstrate that cigarette smoke extract (CSE) sequentially activated NADPH oxidase; increased intracellular levels of ROS; activated AMPK, mitogen-activated protein kinases (MAPKs), nuclear factor-kappaB (NF-kappaB), and signal transducer and activator of transcription proteins 3 (STAT3); and induced interleukin-8 (IL-8). Additionally, using a ROS scavenger, a siRNA that targets AMPK, and various pharmacological inhibitors, we identified the signaling cascade that leads to induction of IL-8 by CSE. All these CSE induced events were inhibited by glucosamine pretreatment. Our findings suggest a novel role for glucosamine in alleviating the oxidative stress and lung inflammation induced by chronic CS exposure in vivo and in suppressing the CSE induced IL-8 in vitro by inhibiting both the ROS-sensitive NADPH oxidase/AMPK/MAPK signaling pathway and the downstream transcriptional factors NF kappaB and STAT3. PMID- 24486343 TI - Cross-linking methionine and amine residues with reactive halogen species. AB - Irreversible cross-links are increasingly being recognized as important posttranslational oxidative protein modifications that contribute to tissue injury during oxidative stress and inflammation. They also have a structural function in extracellular matrix proteins such as collagen IV. Likely contenders for forming such cross-links are the reactive halogen species that are generated by neutrophils and eosinophils, including hypochlorous acid, hypobromous acid, and their related haloamines. Methionine residues are kinetically preferred targets for these oxidants and oxidation can potentially result in sulfilimine (>S=N-) bonds with amines. Therefore, we investigated whether oxidation of methionine in the model peptide formyl-Met-Leu-Phe-Lys (fMLFK) produces cross links with lysine residues, using mass spectrometry to characterize the products. As expected, the sulfoxide was the major product with each reactive halogen species. However, intra- and intermolecular cross-linked products were also formed. Isomers of an intramolecular sulfilimine were readily produced by hypobromous acid and bromamines, with hypochlorous acid forming lesser amounts. The predominant cross-link with chloramines was an intermolecular bond between the sulfur of fMLFK and the amine derived from the chloramine. Reactive halogen species also formed these sulfilimine cross-links in other peptides that contain methionine. We propose that protein cross-links involving methionine and amine residues will form via this mechanism when granulocytes are activated at sites of inflammation. Our results also support the proposal that reactive halogen species generated by the peroxidase peroxidasin could be responsible for the sulfilimine bonds that are integral to the structure of collagen IV. PMID- 24486344 TI - Salvianolic acid A protects RPE cells against oxidative stress through activation of Nrf2/HO-1 signaling. AB - Reactive oxygen species (ROS) impair the physiological functions of retinal pigment epithelial (RPE) cells, which is known as one major cause of age-related macular degeneration. Salvianolic acid A (Sal A) is the main effective aqueous extract of Salvia miltiorrhiza. The aim of this study was to test the potential role of Sal A against oxidative stress in cultured RPE cells and to investigate the underlying mechanistic signaling pathways. We observed that Sal A significantly inhibited hydrogen peroxide (H2O2)-induced primary and transformed RPE cell death and apoptosis. H2O2-stimulated mitogen-activated protein kinase activation, ROS production, and subsequent proapoptotic AMP-activated protein kinase activation were largely inhibited by Sal A. Further, Sal A stimulation resulted in a fast and dramatic activation of Akt/mammalian target of rapamycin complex 1 (mTORC1) signaling, followed by phosphorylation, accumulation, and nuclear translocation of the NF-E2-related factor 2 (Nrf2), along with increased expression of the antioxidant-response element-dependent gene heme oxygenase-1 (HO-1). Both Nrf2 and HO-1 were required for Sal A-mediated cytoprotective effect, as Nrf2/HO-1 inhibition abolished Sal A-induced beneficial effects against H2O2. Meanwhile, the PI3K/Akt/mTORC1 chemical inhibitors not only suppressed Sal A-induced Nrf2/HO-1 activation, but also eliminated its cytoprotective effect in RPE cells. These observations suggest that Sal A activates the Nrf2/HO-1 axis in RPE cells and protects against oxidative stress via activation of Akt/mTORC1 signaling. PMID- 24486345 TI - Neutralizing antibodies and broad, functional T cell immune response following immunization with hepatitis C virus proteins-based vaccine formulation. AB - HCV is a worldwide health problem despite the recent advances in the development of more effective therapies. No preventive vaccine is available against this pathogen. However, non-sterilizing immunity has been demonstrated and supports the potential success of HCV vaccines. Induction of cross-neutralizing antibodies and T cell responses targeting several conserved epitopes, have been related to hepatitis C virus (HCV) clearance. Therefore, in this work, the immunogenicity of a preparation (MixprotHC) based on protein variants of HCV Core, E1, E2 and NS3 was evaluated in mice and monkeys. IgG from MixprotHC immunized mice and monkeys neutralized the infectivity of heterologous HCVcc. Moreover, strong CD4+ and CD8+ T cells proliferative and IFN-gamma secretion responses were elicited against HCV proteins. Remarkably, immunization with MixprotHC induced control of viremia in a surrogate challenge model in mice. These results suggest that MixprotHC might constitute an effective immunogen against HCV in humans with potential for reducing the likelihood of immune escape and viral persistence. PMID- 24486346 TI - Impact of 2+1 pneumococcal conjugate vaccine program in the province of Quebec, Canada. AB - BACKGROUND: Quebec was the first jurisdiction in the world to recommend a 3-dose (2+1) pneumococcal conjugate vaccine (PCV) schedule. The program was implemented in December 2004 with a catch-up for children <5 years. PCV-7 was first used and replaced, respectively, by PCV-10 in 2009 and by PCV-13 in 2011. METHODS: Cases of invasive pneumococcal disease (IPD) notified to public health authorities and isolates submitted to the provincial reference laboratory during the period 2000 2011 were analyzed. RESULTS: IPD incidence in children <5 years was 67/100,000 in 2001-2004, and decreased to 32/100,000 in 2007-2009 following PCV-7 implementation (p<0.01). A further decrease to 24/100,000 was observed in 2010 2011 following PCV-10 introduction (p<0.01). PCV-7 serotypes represented 82% of the total IPD cases in 2000-2004 and elimination was achieved in 2011. Main emerging serotypes were 19A and 7F. Children exposed to the PCV-10 experienced lower IPD rates and all serotypes contributed to the decline, mainly 7F and 19A. In adults, a decrease of low magnitude was observed in 2005-2006 but rates in 2007-2009 were higher than in the prevaccination period. CONCLUSIONS: A 3-dose PCV schedule with high uptake is highly effective and should be recommended worldwide. Serotype replacement eroded benefits especially in adults. PCV-10 introduction had an effect and the impact of PCV-13 use remains to be evaluated. PMID- 24486347 TI - Surface display of Clonorchis sinensis enolase on Bacillus subtilis spores potentializes an oral vaccine candidate. AB - Clonorchis sinensis (C. sinensis) infections remain the common public health problem in freshwater fish consumption areas. New effective prevention strategies are still the urgent challenges to control this kind of foodborne infectious disease. The biochemical importance and biological relevance render C. sinensis enolase (Csenolase) as a potential vaccine candidate. In the present study, we constructed Escherichia coli/Bacillus subtilis shuttle genetic engineering system and investigated the potential of Csenolase as an oral vaccine candidate for C. sinensis prevention in different immunization routes. Our results showed that, compared with control groups, both recombinant Csenolase protein and nucleic acid could induce a mixed IgG1/IgG2a immune response when administrated subcutaneously (P<0.001), intraperitoneally (P<0.01) and intramuscularly (P<0.001) with worm reduction rate of 56.29%, 15.38% and 37.42%, respectively. More importantly, Csenolase could be successfully expressed as a fusion protein (55kDa) on B. subtilis spore indicated by immunoblot and immunofluorescence assays. Killed spores triggered reactive Th1/Th2 immune response and exhibited protective efficacy against C. sinensis infection. Csenolase derived oral vaccine conferred worm reduction rate and egg reduction rate at 60.07% (P<0.001) and 80.67% (P<0.001), respectively. The shuttle genetic engineering system facilitated the development of oral vaccine with B. subtilis stably overexpressing target protein. Comparably vaccinal trails with Csenolase in different immunization routes potentialize Csenolase an oral vaccine candidate in C. sinensis prevention. PMID- 24486348 TI - Safety and immunogenicity of booster immunization with 7-valent pneumococcal conjugate vaccine in children with idiopathic nephrotic syndrome. AB - Safety and immunogenicity of a booster dose of 7-valent pneumococcal conjugate vaccine (PCV7) were evaluated in 29 patients with idiopathic nephrotic syndrome (INS), who had been primed 12 months earlier with one dose of PCV7. PCV7 was not associated with increased risk of INS relapse (RR=0.77, p=0.8) and serotype specific antibodies increased in all subjects at 1 month (p<0.01). The quantitative characteristics of immune response and the effect of treatment with mycophenolate mofetil and/or cyclosporine A following booster PCV7 were similar with primary response. Additional PCV7 doses could be safely given in children with INS to increase circulating antibodies above the protective threshold. PMID- 24486349 TI - Novel in-ovo chimeric recombinant Newcastle disease vaccine protects against both Newcastle disease and infectious bursal disease. AB - Development of a safe and efficient in-ovo vaccine against Newcastle disease (NDV) and very virulent infectious bursal disease virus (vvIBDV) is of great importance. In this study, a chimeric NDV LaSota virus with the L gene of Clone 30 (rLaC30L) was used to generate a recombinant chimeric virus expressing the VP2 protein of vvIBDV (rLaC30L-VP2). The safety and efficacy of rLaC30L-VP2 in-ovo vaccination was then evaluated in 18-day-old special pathogen free (SPF) chicken embryos and commercial broiler embryos for prevention of NDV and vvIBDV. Hatchability and global survival rate of the hatched birds was not affected by in ovo rLaC30L-VP2 vaccination. However, rLaC30L-VP2 in-ovo vaccination induced significant anti-IBDV and anti-NDV antibodies in SPF birds and commercial broilers, and 100% of vaccinated chickens were protected against a lethal NDV challenge. In-ovo rLaC30L-VP2 vaccination also provided resistance against vvIBDV challenge in a significant amount of animals. These results suggest that rLaC30L VP2 is a safe and efficient bivalent live in-ovo vaccine against NDV and vvIBDV. PMID- 24486350 TI - Maternal pneumococcal capsular IgG antibodies and transplacental transfer are low in South Asian HIV-infected mother-infant pairs. AB - BACKGROUND: Our understanding of the mother-to-child transfer of serotype specific pneumococcal antibodies is limited in non-immunized, HIV-positive women. METHODS: We compared geometric mean antibody concentrations (GMCs), geometric mean transplacental cord:maternal ratios (GMRs) and proportions of samples with protective antibody concentration (>=0.35MUg/ml) to serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, 23F between 74 HIV-infected and 98 HIV-uninfected mother-infant pairs who had not received pneumococcal immunization in South Asia. Multivariable analysis was performed to assess the influence of HIV on protective antibody concentrations. RESULTS: HIV-infected mothers and their infants exhibited lower GMCs and GMRs than their uninfected counterparts. This was significant for all serotypes except maternal GMC to serotype 1 and GMR for serotype 6B. In multivariate analysis, HIV was significantly associated with reduced odds of having protective pneumococcal IgG levels; 56-73% reduction for 3 maternal serotypes (4, 5, 23F) and 62-90% reduction for all cord samples except serotype 6B. CONCLUSIONS: Maternal HIV infection is associated with lower levels of maternal pneumococcal antibodies and disproportionately lower cord antibodies, relative to maternal antibodies, suggesting that HIV infection compromises transplacental transfer. Reassessment of maternal and/or infant pneumococcal immunization strategies is needed in HIV-infected women and their infants. PMID- 24486352 TI - Immunogenicity, reactogenicity, and safety of inactivated quadrivalent influenza vaccine candidate versus inactivated trivalent influenza vaccine in healthy adults aged >=18 years: a phase III, randomized trial. AB - BACKGROUND: Two influenza B lineages have been co-circulating since the 1980s, and because inactivated trivalent influenza vaccine (TIV) contains only one B strain, it provides little/no protection against the alternate B-lineage. We assessed a candidate inactivated quadrivalent influenza vaccine (QIV) containing both B lineages versus TIV in healthy adults. METHODS: Subjects received one dose of QIV (lot 1, 2, or 3) or one of two TIVs (B strain from Victoria or Yamagata lineage); randomization was 2:2:2:1:1. Hemagglutination-inhibition assays were performed 21-days post-vaccination; superiority of QIV versus TIV for the alternate B-lineage was demonstrated if the 95% confidence interval (CI) lower limit for the GMT ratio was >=1.5, and non-inferiority against the shared strains was demonstrated if the 95% CI upper limit for the GMT ratio was <=1.5. Reactogenicity and safety were assessed during the post-vaccination period. NCT01196975. RESULTS: Immunogenicity of QIV lots was consistent, QIV was superior to TIV for the alternate B-lineage strain, and QIV was non-inferior versus TIVs for shared strains (A/H1N1, A/H3N2, B-strain). Reactogenicity and safety profile of the QIV was consistent with seasonal influenza vaccines. CONCLUSION: QIV provided superior immunogenicity for the added B strain without affecting the antibody response to the TIV strains, and without compromising safety. PMID- 24486351 TI - Live attenuated influenza vaccine strains elicit a greater innate immune response than antigenically-matched seasonal influenza viruses during infection of human nasal epithelial cell cultures. AB - Influenza viruses are global pathogens that infect approximately 10-20% of the world's population each year. Vaccines, including the live attenuated influenza vaccine (LAIV), are the best defense against influenza infections. The LAIV is a novel vaccine that actively replicates in the human nasal epithelium and elicits both mucosal and systemic protective immune responses. The differences in replication and innate immune responses following infection of human nasal epithelium with influenza seasonal wild type (WT) and LAIV viruses remain unknown. Using a model of primary differentiated human nasal epithelial cell (hNECs) cultures, we compared influenza WT and antigenically-matched cold adapted (CA) LAIV virus replication and the subsequent innate immune response including host cellular pattern recognition protein expression, host innate immune gene expression, secreted pro-inflammatory cytokine production, and intracellular viral RNA levels. Growth curves comparing virus replication between WT and LAIV strains revealed significantly less infectious virus production during LAIV compared with WT infection. Despite this disparity in infectious virus production the LAIV strains elicited a more robust innate immune response with increased expression of RIG-I, TLR-3, IFNbeta, STAT-1, IRF-7, MxA, and IP-10. There were no differences in cytotoxicity between hNEC cultures infected with WT and LAIV strains as measured by basolateral levels of LDH. Elevated levels of intracellular viral RNA during LAIV as compared with WT virus infection of hNEC cultures at 33 degrees C may explain the augmented innate immune response via the up-regulation of pattern recognition receptors and down-stream type I IFN expression. Taken together our results suggest that the decreased replication of LAIV strains in human nasal epithelial cells is associated with a robust innate immune response that differs from infection with seasonal influenza viruses, limits LAIV shedding and plays a role in the silent clinical phenotype seen in human LAIV inoculation. PMID- 24486353 TI - A recombinant bivalent fusion protein rVE confers active and passive protection against Yersinia enterocolitica infection in mice. AB - In the present study, a bivalent chimeric protein rVE comprising immunologically active domains of Yersinia pestis LcrV and YopE was assessed for its prophylactic abilities against Yersinia enterocolitica O:8 infection in murine model. Mice immunized with rVE elicited significantly higher antibody titers with substantial contribution from the rV component (3:1 ratio). Robust and significant resistance to Y. enterocolitica infection with 100% survival (P<0.001) was seen in rVE vaccinated mice when intra peritoneal (I.P.) challenged with 10(8)CFU of Y. enterocolitica O:8 against the 75%, 60% and 75% survival seen in mice immunized with rV, rE, rV+rE, respectively. Macrophage monolayer supplemented with anti-rVE polysera illustrated efficient protection (89.41% survival) against challenge of Y. enterocolitica O:8. In contrast to sera from sham-immunized mice, immunization with anti-rVE polysera provided complete protection to BALB/c mice against I.P. challenge with 10(8)CFU of Y. enterocolitica O:8 and developed no conspicuous signs of infection in necropsy. The histopathological analysis of microtome sections confirmed significantly reduced lesion size or no lesion in liver and intestine upon infection in anti-rVE immunized mice. The findings from this study demonstrated the fusion protein rVE as a potential candidate subunit vaccine and showed the functional role of antibodies in protection against Y. enterocolitica infections. PMID- 24486354 TI - Immuno-proteomic analysis of human immune responses to experimental Neisseria meningitidis outer membrane vesicle vaccines identifies potential cross-reactive antigens. AB - Human volunteers were vaccinated with experimental Neisseria meningitidis serogroup B vaccines based on strain H44/76 detoxified L3 lipooligosaccharide (LOS)-derived outer membrane vesicles (OMV) or the licensed Cuban vaccine, VA MENGOC-BC. Some volunteers were able to elicit cross-bactericidal antibodies against heterologous L2-LOS strain (760676). An immuno-proteomic approach was used to identify potential targets of these cross-bactericidal antibodies using an L2-LOS derived OMV preparation. A total of nine immuno-reactive spots were detected in this proteome: individuals vaccinated with the detoxified OMVs showed an increase in post-vaccination serum reactivity with Spots 2-8, but not with Spots 1 and 9. Vaccination with VA-MENGOC-BC induced sera that showed increased reactivity with all of the protein spots. Vaccinees showed increases in serum bactericidal activity (SBA) against the heterologous L2-LOS expressing strain 760676, which correlated, in general, with immunoblot reactivity. The identities of proteins within the immuno-reactive spots were determined. These included not only well-studied antigens such as Rmp, Opa, PorB and FbpA (NMB0634), but also identified novel antigens such as exopolyphosphatase (NMB1467) and gamma glutamyltranspeptidase (NMB1057) enzymes and a putative cell binding factor (NMB0345) protein. Investigating the biological properties of such novel antigens may provide candidates for the development of second generation meningococcal vaccines. PMID- 24486355 TI - A methodology for interactive mining and visual analysis of clinical event patterns using electronic health record data. AB - Patients' medical conditions often evolve in complex and seemingly unpredictable ways. Even within a relatively narrow and well-defined episode of care, variations between patients in both their progression and eventual outcome can be dramatic. Understanding the patterns of events observed within a population that most correlate with differences in outcome is therefore an important task in many types of studies using retrospective electronic health data. In this paper, we present a method for interactive pattern mining and analysis that supports ad hoc visual exploration of patterns mined from retrospective clinical patient data. Our approach combines (1) visual query capabilities to interactively specify episode definitions, (2) pattern mining techniques to help discover important intermediate events within an episode, and (3) interactive visualization techniques that help uncover event patterns that most impact outcome and how those associations change over time. In addition to presenting our methodology, we describe a prototype implementation and present use cases highlighting the types of insights or hypotheses that our approach can help uncover. PMID- 24486357 TI - Central alpha- and beta-thujone: similar anxiogenic-like effects and differential modulation on GABAA receptors in neonatal chicks. AB - The convulsant effects of alpha-thujone are attributed to inhibitory actions on the GABAA receptor. We investigated, for the first time, the effects of alpha thujone or beta-thujone administrated centrally on the fear/anxiety behaviour of 3-day-old chicks in an Open Field and their modulation on the GABAA receptor. Higher doses were convulsant by eliciting a toxic and excitatory action, with the results showing that a dose of 78 nmol of either of the two diastereoisomers had an anxiogenic-like effect observed as an increased latency to ambulate and a reduced locomotor activity in an Open Field. Nevertheless, only the central administration of alpha-thujone reversed the increase induced by acute stress in the flunitrazepam-sensitive GABAA receptor recruitment. These findings demonstrated that alpha-thujone, when intracerebroventricularly administered, suppressed the GABAA receptor recruitment induced by acute stress, maybe due to alpha-thujone blocking the benzodiazepine binding site or another site of the GABAA complex. However, it should not be discarded that acute stress associated with novelty may have induced the recruitment of a subpopulation of GABAA receptors more sensitive to alpha-thujone than to the constitutive receptors, or that this monoterpene could have inhibited any protein or enzyme trafficking that modulated the phosphorylation of the receptor involved in the turnover of GABAA receptor. beta-Thujone showed behavioural effects similar to its diastereoisomer alpha-thujone. However, its action mechanism may have been mediated by other neurotransmitter systems, such as the serotonergic one or by a different biological effectiveness due to a distinct stereochemistry at the specific site of the GABAA receptor. PMID- 24486356 TI - Oxytocin and vasopressin modulation of the neural correlates of motivation and emotion: results from functional MRI studies in awake rats. AB - Oxytocin and vasopressin modulate a range of species typical behavioral functions that include social recognition, maternal-infant attachment, and modulation of memory, offensive aggression, defensive fear reactions, and reward seeking. We have employed novel functional magnetic resonance mapping techniques in awake rats to explore the roles of these neuropeptides in the maternal and non-maternal brain. Results from the functional neuroimaging studies that are summarized here have directly and indirectly confirmed and supported previous findings. Oxytocin is released within the lactating rat brain during suckling stimulation and activates specific subcortical networks in the maternal brain. Both vasopressin and oxytocin modulate brain regions involved unconditioned fear, processing of social stimuli and the expression of agonistic behaviors. Across studies there are relatively consistent brain networks associated with internal motivational drives and emotional states that are modulated by oxytocin and vasopressin. This article is part of a Special Issue entitled Oxytocin and Social Behav. PMID- 24486358 TI - Is it time to awaken Sleeping Beauty? European psychiatry has been sleeping since 1980. AB - The Diagnostic and Statistical Manual of Mental Disorders (DSM-III), published in 1980, has led to a dead end, the DSM-V. Following the allegory of Sleeping Beauty, the DSM-III put European psychiatry to sleep; it now must wake up to create a 21st century psychiatric language for descriptive psychopathology and psychiatric nosology. Four topics are reviewed. First, the review of descriptive psychopathology focuses on: a) Chaslin's and Jaspers's books, and b) Schneider's transmittal of Jaspers's ideas and involvement with Kraepelin in incorporating neuroscience into psychiatric nosology. Second, US psychiatry's historic steps include: a) the pseudoscience of psychoanalysis, b) the low level of pre-DSM-III diagnostic expertise, c) the neo-Kraepelinian revolution which led to DSM-III, d) the failure to improve diagnostic skills, and e) the reprise of Kraepelin's marketing ("neuroscience will save psychiatry"). Third, the DSM-III devastated European psychiatry by destroying: a) the national textbooks which increased consistency but eliminated creative European thinking; and b) the Arbeitsgemenschaft fur Methodic und Dokumentation in der Psychiatrie, the most reasonable attempt to reach diagnostic agreement: start with symptoms/signs (first level) rather than disorders (second level). Fourth, Berrios elaborated upon Jaspers, who described psychiatry as a hybrid science and heterogeneous. Berrios affirmed that psychiatric symptoms/signs are hybrid. Some symptoms are in the "semantic space" and cannot be "explained" by neuroscience. PMID- 24486359 TI - The cost-effectiveness of influenza vaccination in elderly Australians: an exploratory analysis of the vaccine efficacy required. AB - It is important to consider the value for money offered by existing elderly influenza vaccination programs, particularly as doubts persist about the magnitude of the effectiveness of such programs. An informative approach to explore the value of vaccination is to consider what vaccine efficacy would be required for a program to be considered cost-effective. To estimate the cost effectiveness of the current elderly (65+ years) influenza vaccination program in Australia, we modelled how the hypothetical removal of vaccination would increase current disease burden estimates depending on alternative vaccine efficacy assumptions. The base-case results of the analysis found that the existing elderly vaccination program is likely to be cost-effective (under A$50,000 per quality-adjusted life year gained) if the vaccine efficacy is above ~30%. This study offers reassurance that the influenza vaccination of elderly Australians is likely to offer value for money. PMID- 24486360 TI - Overcoming the knowledge-behavior gap: The effect of evidence-based HPV vaccination leaflets on understanding, intention, and actual vaccination decision. AB - OBJECTIVE: Informed decision making requires transparent and evidence-based (=balanced) information on the potential benefit and harms of medical preventions. An analysis of German HPV vaccination leaflets revealed, however, that none met the standards of balanced risk communication. METHODS: We surveyed a sample of 225 girl-parent pairs in a before-after design on the effects of balanced and unbalanced risk communication on participants' knowledge about cervical cancer and the HPV vaccination, their perceived risk, their intention to have the vaccine, and their actual vaccination decision. RESULTS: The balanced leaflet increased the number of participants who were correctly informed about cervical cancer and the HPV vaccine by 33 to 66 absolute percentage points. In contrast, the unbalanced leaflet decreased the number of participants who were correctly informed about these facts by 0 to 18 absolute percentage points. Whereas the actual uptake of the HPV vaccination 14 months after the initial study did not differ between the two groups (22% balanced leaflet vs. 23% unbalanced leaflet; p=.93, r=.01), the originally stated intention to have the vaccine reliably predicted the actual vaccination decision for the balanced leaflet group only (concordance between intention and actual uptake: 97% in the balanced leaflet group, rs=.92, p=.00; 60% in the unbalanced leaflet group, rs=.37, p=.08). CONCLUSION: In contrast to a unbalanced leaflet, a balanced leaflet increased people's knowledge of the HPV vaccination, improved perceived risk judgments, and led to an actual vaccination uptake, which first was robustly predicted by people's intention and second did not differ from the uptake in the unbalanced leaflet group. These findings suggest that balanced reporting about HPV vaccination increases informed decisions about whether to be vaccinated and does not undermine actual uptake. PMID- 24486362 TI - Comparison of antibody and cell-mediated immune responses of foals and adult horses after vaccination with live Mycobacterium bovis BCG. AB - BACKGROUND: Equine neonates have reduced humoral and cell-mediated immune responses compared to adult horses after administration of killed vaccines. As a basis for this study, we hypothesized that newborn foals can mount strong immune responses after vaccination with live Mycobacterium bovis BCG. METHODS: Healthy 4 day-old foals (n=7), 4-month-old foals (n=7) and adult horses (n=6) were vaccinated once with live M. bovis BCG. Age-matched animals (n=5 per group) were used as unvaccinated controls. Relative vaccine-specific immunoglobulin concentrations and whole blood mRNA expression of IFN-gamma, IL-4, and IL-10 were measured prior to and 2, 4, 6, and 8 weeks after vaccination. Eight weeks after vaccination, delayed type hypersensitivity (DTH) responses were assessed by measuring the increase in double skin thickness after intradermal injection of purified protein derivative. RESULTS: Both groups of foals and adult horses responded with a significant increase in vaccine-specific total IgG, IgGa, IgGc, IgG(T), and IgM concentrations. In contrast, only adult horses mounted significant IgGb responses. Vaccine-specific concentrations of total IgG and IgGa were significantly higher in adult horses than in 4-day-old foals whereas IgGc responses were significantly higher in 4-day-old foals than in the other two age groups. Adult horses had significantly higher basal IFN-gamma and IL-4 mRNA expression than both groups of foals but vaccination with M. bovis BCG did not significantly increase expression of these cytokines, regardless of age group. Immunized horses had significantly higher DTH responses than age-matched unvaccinated controls. DTH responses were significantly greater in both groups of vaccinated foals than in vaccinated adult horses. CONCLUSION: Despite a naive immune system, newborn foals have the ability to mount robust antibody and cell mediated immune responses to M. bovis BCG. PMID- 24486361 TI - Supercritical fluid extraction provides an enhancement to the immune response for orally-delivered hepatitis B surface antigen. AB - The hepatitis B virus continues to be a major pathogen worldwide despite the availability of an effective parenteral vaccine for over 20 years. Orally delivered subunit vaccines produced in maize may help to alleviate the disease burden by providing a low-cost, heat-stable alternative to the parenteral vaccine. Oral subunit vaccination has been an elusive goal due to the large amounts of antigen required to induce an immunologic response when administered through the digestive tract. Here we show that high levels of HBsAg were obtained in maize grain, the grain was formed into edible wafers, and wafers were fed to mice at a concentration of approximately 300 MUg/g. When these wafers were made with supercritical fluid extraction (SFE)-treated maize material, robust IgG and IgA responses in sera were observed that were comparable to the injected commercial vaccine (Recombivax((r))). In addition, all mice administered SFE wafers showed high secretory IgA titers in fecal material whereas Recombivax((r)) treated mice showed no detectable titer. Increased salivary IgA titers were also detected in SFE-fed mice but not in Recombivax((r)) treated mice. Wafers made from hexane-treated or full fat maize material induced immunologic responses, but fecal titers were attenuated relative to those produced by SFE-treated wafers. These responses demonstrate the feasibility of using a two-dose oral vaccine booster in the absence of an adjuvant to induce immunologic responses in both sera and at mucosal surfaces, and highlight the potential limitations of using an exclusively parenteral dosing regime. PMID- 24486363 TI - Development of a multivalent, PrP(Sc)-specific prion vaccine through rational optimization of three disease-specific epitopes. AB - Prion diseases represent a novel form of infectivity caused by the propagated misfolding of a self-protein (PrP(C)) into a pathological, infectious conformation (PrP(Sc)). Efforts to develop a prion vaccine have been complicated by challenges and potential dangers associated with induction of strong immune responses to a self protein. There is considerable value in the development of vaccines that are specifically targeted to the misfolded conformation. Conformation specific immunotherapy depends on identification and optimization of disease-specific epitopes (DSEs)(1) that are uniquely exposed upon misfolding. Previously, we reported development of a PrP(Sc)-specific vaccine through empirical expansions of a YYR DSE. Here we describe optimization of two additional prion DSEs, YML of beta-sheet 1 and a rigid loop (RL) linking beta sheet 2 to alpha-helix 2, through in silico predictions of B cell epitopes and further translation of these epitopes into PrP(Sc)-specific vaccines. The optimized YML and RL vaccines retain their properties of immunogenicity, specificity and safety when delivered individually or in a multivalent format. This investigation supports the utility of combining DSE prediction models with algorithms to infer logical peptide expansions to optimize immunogenicity. Incorporation of optimized DSEs into established vaccine formulation and delivery strategies enables rapid development of peptide-based vaccines for protein misfolding diseases. PMID- 24486365 TI - CD207+ cells recruitment to the vaccination site and draining lymph nodes after the administration of DC-Apo/Nec vaccine in mice. AB - De novo ectopic lymphoid tissue formation is known to occur in certain disease and inflammatory settings. After an effective vaccination with dendritic cells (DC) charged with melanoma apoptotic/necrotic cells (Apo/Nec), a subcutaneous tertiary lymphoid structure was organized, where retained vaccine cells interacted with recruited inflammatory and T cells. In this work we report for the first time the recruitment of two morphologically different CD207(+) cells to vaccination site. The time-course behavior of CD207(+) cells was reciprocal between vaccination site and draining lymph nodes (DLNs). After 6-10 days, CD207(+) cells localized at the paracortical region of DLNs, in close contact with T cell population. DLNs were enriched in a peculiar MHCII(+) CD11c((-)) CD207(+) population, whose role remains to be determined. Whether CD207(+) cells migration to the vaccination site can be associated with a differential anti tumoral response remains as an open and exciting question. PMID- 24486364 TI - Pneumococcal serotype distribution in 1315 nasopharyngeal swabs from a highly vaccinated cohort of Italian children as detected by RT-PCR. AB - The long term impact of 7-valent pneumococcal conjugate vaccine (PCV7) on pneumococcal colonization patterns remains unclear. Carriage and distribution of Streptococcus pneumoniae serotypes as detected by RT-PCR were evaluated in a cohort of 1315 children. S. pneumoniae was identified in the nasopharyngeal swab of 734 children (55.8%); 488/734 (66.5%) children carried more than 1 pneumococcal serotype. As a consequence of co-colonization, a total of 1,728 S. pneumoniae (belonging to 33 serotypes) were identified. As immunogenicity between 2 and 3 doses of PCV7 in the first year of life has been demonstrated to be similar, serotypes distribution was evaluated categorizing vaccination status as 0,1 and 2 or more doses in the first year of life. Among children who started vaccination in the first year of life, PCV7 serotypes were carried in 296 of 1,123 (29.5%) children who had received >=2 PCV7 doses while were carried in 26 of 108 (26.8%) who had received no doses (p=not significant); only 17 children received 1 PCV7 and 3 of them were found positive for PCV7 serotypes. Among those who had received >=2 doses of PCV7 in the first year of life, 47 of 192 (19.7%) carried a PCV7 serotype during the first year after last vaccination, 50 of 125 (28.6%) during the second year, 79 of 224 (35.3%) during the third year, and 65 of 143 (45.5%) during the fourth year (p 0.0001). We did not identify risk factors for PCV7 carriage among children that had received >2 vaccine doses. This study suggests that S. pneumoniae is present in the nasopharynx of the majority of children 0-5 years even if vaccinated, that PCV7 serotypes can be found in nasopharyngeal swabs of PCV7 vaccinated children and that the frequency of PCV7 serotypes increases with the increase of interval from vaccination. PMID- 24486366 TI - Socioecological and message framing factors influencing maternal influenza immunization among minority women. AB - OBJECTIVE: A suboptimal level of seasonal influenza vaccination among pregnant minority women is an intractable public health problem, requiring effective message resonance with this population. We evaluated the effects of randomized exposure to messages which emphasize positive outcomes of vaccination ("gain frame"), or messages which emphasize negative outcomes of forgoing vaccination ("loss-frame"). We also assessed multilevel social and community factors that influence maternal immunization among racially and ethnically diverse populations. STUDY DESIGN: Minority pregnant women in metropolitan Atlanta were enrolled in the longitudinal study and randomized to receive intervention or control messages. A postpartum questionnaire administered 30 days postpartum evaluated immunization outcomes following baseline message exposure among the study population. We evaluated key outcomes using bivariate and multivariate analyses. RESULTS: Neither gain- [OR=0.5176, (95% CI: 0.203,1.322)] nor loss framed [OR=0.5000, 95% CI: (0.192,1.304)] messages were significantly associated with increased likelihood of immunization during pregnancy. Significant correlates of seasonal influenza immunization during pregnancy included healthcare provider recommendation [OR=3.934, 95% CI: (1.331,11.627)], use of hospital-based practices as primary source of prenatal care [OR=2.584, 95% CI: (1.091,6.122)], and perceived interpersonal support for influenza immunization [OR=3.405, 95% CI: (1.412,8.212)]. CONCLUSION: Dissemination of vaccine education messages via healthcare providers, and cultivating support from social networks, will improve seasonal influenza immunization among pregnant minority women. PMID- 24486367 TI - Hyporesponsiveness to the infecting serotype after vaccination of children with seven-valent pneumococcal conjugate vaccine following invasive pneumococcal disease. AB - Antibody responses to the infecting serotype in children who are vaccinated with pneumococcal conjugate vaccine (PCV) after having invasive pneumococcal diseases (IPD) have not been fully investigated. Of 56 children diagnosed with IPD between October 2009 and April 2013 in whom the infecting serotype was confirmed, 17 who were vaccinated with PCV7 following IPD were tested to determine the geometric mean concentration of serotype-specific immunoglobulin G (IgG) and the geometric mean titers of opsonization indices (OIs) using paired sera obtained at the onset of IPD and after PCV doses following the resolution of IPD. The geometric mean concentrations of serotype-specific IgG for all PCV7 serotypes other than serotype 6B were significantly increased after the last PCV7 dose compared with those at the time of IPD onset (P<0.01), as were the geometric mean titers of OIs for all PCV7 serotypes. In 14 children with IPD caused by PCV7 serotypes for whom both IgG and OI results were available, the OIs for the infecting serotype at the time of IPD onset were <8, although the IgG levels varied between from <0.2 to >5.0MUg/ml. After the last PCV7 dose, the OIs for the infecting serotype remained <8 for six (43%) of 14 children. In these six children, hyporesponsiveness to PCV7 was specific for the infecting serotype. Hyporesponsiveness was found for serotypes 6B (n=5) and 23F (n=1). No difference was found between the responders (n=8) and the hyporesponders (n=6) with regard to any clinical characteristics. Our data suggest that hyporesponsiveness to the infecting serotype may occur in children vaccinated with PCV7 following IPD. PMID- 24486368 TI - Immunization with the Leishmania infantum recombinant cyclophilin protein 1 confers partial protection to subsequent parasite infection and generates specific memory T cells. AB - Control of zoonotic visceral leishmaniosis can be achieved using several available drugs. These drugs present high toxicity and require longer treatment regimens which complicate compliance to the treatment. Other control measures directed to the vector or the reservoirs are useful tools to restrain the spreading of this disease but the effects are transitory. A safe, affordable and efficient vaccine conferring long lasting immunity should be the most cost effective way of controlling zoonotic visceral leishmaniosis. The present study aims at characterizing a cyclophilin protein 1 of Leishmania infantum (LiCyP1) and investigating whether recombinant LiCyP1 (LirCyP1) is able to confer protection against infection by evaluating viable parasite load and the generation of specific CD4(+) and CD8(+) effector and central memory T cells in rodent model. LiCyP1 is present in the cytoplasm of L. infantum amastigotes and promastigotes. Immunization of BALB/c mice with LirCyP1 confers high protection to L. infantum infection, causing a marked reduction in parasite replication in the liver and spleen. Furthermore, helper and cytotoxic memory T cell subsets able to specifically recognize parasite antigens expanded in immunized and in challenged mice. CD4(+) T cell subpopulation of intermediate phenotype (CD62L(high)CD127(low)) of challenging mice also presented an accentuated expansion after the recall. This study demonstrated that LirCyP1 confers partial protection to L. infantum infection, promoting the generation of a desired long lasting immunity. LirCyP1 can be considered a potential candidate for the design of a vaccine against zoonotic visceral leishmaniosis. PMID- 24486369 TI - Pandemic A/H1N1 influenza vaccination during pregnancy: a comparative study using the EFEMERIS database. AB - OBJECTIVE: To evaluate the risk of adverse pregnancy outcomes following A/H1N1 vaccination in pregnant women. METHODS: This observational cohort study compared vaccinated and non-vaccinated pregnant women in EFEMERIS, a French prescription database including pregnant women. Women who ended their pregnancy in South Western France between October 21, 2009 and November 30, 2010 (the period of the French vaccination campaign) were included. Two non-vaccinated women were individually matched to each vaccinated woman by month and year of pregnancy onset. Conditional logistic regression and Cox proportional hazards regression were used to evaluate associations between each outcome (all-cause pregnancy loss, preterm delivery, small for gestational age (SGA) and neonatal pathology) and A/H1N1 vaccination during pregnancy. RESULTS: 1645 women of the 12,120 (13.6%) in the database who were administered A/H1N1 vaccine during pregnancy were compared to 3290 non-vaccinated women. Most were vaccinated in December 2009 (61%) with a non-adjuvanted vaccine (93%). The risks of pregnancy loss (adjusted HR=0.56; 95% CI=0.31-1.01), of preterm birth (adjusted HR=0.82; 95% CI=0.64 1.06), and of neonatal pathology (adjusted OR=0.70; 95% CI=0.49-1.02) did not differ between the vaccinated and the non-vaccinated groups. The rate of SGA was lower in the vaccinated group than in the non-vaccinated group (0.5% vs. 1.4%; adjusted OR=0.36; 95% CI=0.17-0.78). CONCLUSION: There was no significant association between adverse pregnancy outcomes and vaccination with a non adjuvanted A/H1N1 vaccine during pregnancy. PMID- 24486370 TI - Influenza and pneumococcal vaccination and risk of stroke or transient ischaemic attack-matched case control study. AB - BACKGROUND: Evidence that respiratory infections trigger stroke suggests that influenza or pneumococcal vaccination might prevent stroke. We aimed to investigate whether influenza or pneumococcal vaccination or both together were associated with reduced risk of stroke or transient ischaemic attack (TIA). METHODS: We used a matched 1:1 case-control design with data from the United Kingdom General Practice Research Database. Cases, aged 18 years or above with stroke (fatal or non-fatal) and TIA during September 2001 to August 2009, were compared with controls matched for age, sex, calendar time and practice, adjusting for cardiovascular risk factors, vaccine risk groups, comorbidity and indicators of functional ability. RESULTS: We included 26,784 cases of stroke and 20,227 cases of TIA with equal numbers of matched controls. Influenza vaccination within-season was associated with 24% reduction in stroke risk (adjusted OR 0.76, 95% CI 0.72 to 0.80) but no reduction in TIA (1.03, 0.98 to 1.09). Stroke risk was significantly lower with early (September to mid-November: 0.74, 0.70 to 0.78) but not later influenza vaccination (mid-November onwards: 0.92, 0.83 to 1.01). Associations persisted after multiple imputation of missing data and sensitivity analysis for unmeasured confounders. Pneumococcal vaccination was not associated with a reduction in risk of stroke (0.98, 0.94 to 1.00) or TIA (1.15, 1.08 to 1.23). CONCLUSIONS: Influenza vaccination was associated with a 24% reduction in risk of stroke but not TIA. Pneumococcal vaccination was not associated with reduced risk of stroke or TIA. This has important implications for potential benefits of influenza vaccine. PMID- 24486371 TI - Facial recognition of heroin vaccine opiates: type 1 cross-reactivities of antibodies induced by hydrolytically stable haptenic surrogates of heroin, 6 acetylmorphine, and morphine. AB - Novel synthetic compounds similar to heroin and its major active metabolites, 6 acetylmorphine and morphine, were examined as potential surrogate haptens for the ability to interface with the immune system for a heroin vaccine. Recent studies have suggested that heroin-like haptens must degrade hydrolytically to induce independent immune responses both to heroin and to the metabolites, resulting in antisera containing mixtures of antibodies (type 2 cross-reactivity). To test this concept, two unique hydrolytically stable haptens were created based on presumed structural facial similarities to heroin or to its active metabolites. After conjugation of a heroin-like hapten (DiAmHap) to tetanus toxoid and mixing with liposomes containing monophosphoryl lipid A, high titers of antibodies after two injections in mice had complementary binding sites that exhibited strong type 1 ("true") specific cross-reactivity with heroin and with both of its physiologically active metabolites. Mice immunized with each surrogate hapten exhibited reduced antinociceptive effects caused by injection of heroin. This approach obviates the need to create hydrolytically unstable synthetic heroin like compounds to induce independent immune responses to heroin and its active metabolites for vaccine development. Facial recognition of hydrolytically stable surrogate haptens by antibodies together with type 1 cross-reactivities with heroin and its metabolites can help to guide synthetic chemical strategies for efficient development of a heroin vaccine. PMID- 24486372 TI - A review of successful flavivirus vaccines and the problems with those flaviviruses for which vaccines are not yet available. AB - Genus flavivirus comprises many important human pathogens causing public health problems worldwide. Some flavivirus infections are characterized by a relatively high mortality rate and/or high sequelae rate in survivors. Because most flavivirus life cycles are maintained between arthropod vectors and amplifying/reservoir hosts in the absence of humans, eradication of flaviviruses might be extremely difficult. Flavivirus vaccine development is considered a reasonable method to prevent flavivirus infections. Some vaccines have been successfully developed, but others have not, regardless of much effort. This review article describes currently available flavivirus vaccines against yellow fever, Japanese encephalitis, and tick-borne encephalitis. In addition, the current status of dengue and West Nile virus vaccine development is reviewed and problems regarding their development are discussed. PMID- 24486373 TI - Random myosin loss along thick-filaments increases myosin attachment time and the proportion of bound myosin heads to mitigate force decline in skeletal muscle. AB - Diminished skeletal muscle performance with aging, disuse, and disease may be partially attributed to the loss of myofilament proteins. Several laboratories have found a disproportionate loss of myosin protein content relative to other myofilament proteins, but due to methodological limitations, the structural manifestation of this protein loss is unknown. To investigate how variations in myosin content affect ensemble cross-bridge behavior and force production we simulated muscle contraction in the half-sarcomere as myosin was removed either (i) uniformly, from the Z-line end of thick-filaments, or (ii) randomly, along the length of thick-filaments. Uniform myosin removal decreased force production, showing a slightly steeper force-to-myosin content relationship than the 1:1 relationship that would be expected from the loss of cross-bridges. Random myosin removal also decreased force production, but this decrease was less than observed with uniform myosin loss, largely due to increased myosin attachment time (ton) and fractional cross-bridge binding with random myosin loss. These findings support our prior observations that prolonged ton may augment force production in single fibers with randomly reduced myosin content from chronic heart failure patients. These simulations also illustrate that the pattern of myosin loss along thick-filaments influences ensemble cross-bridge behavior and maintenance of force throughout the sarcomere. PMID- 24486374 TI - Glycyl radical activating enzymes: structure, mechanism, and substrate interactions. AB - The glycyl radical enzyme activating enzymes (GRE-AEs) are a group of enzymes that belong to the radical S-adenosylmethionine (SAM) superfamily and utilize a [4Fe-4S] cluster and SAM to catalyze H-atom abstraction from their substrate proteins. GRE-AEs activate homodimeric proteins known as glycyl radical enzymes (GREs) through the production of a glycyl radical. After activation, these GREs catalyze diverse reactions through the production of their own substrate radicals. The GRE-AE pyruvate formate lyase activating enzyme (PFL-AE) is extensively characterized and has provided insights into the active site structure of radical SAM enzymes including GRE-AEs, illustrating the nature of the interactions with their corresponding substrate GREs and external electron donors. This review will highlight research on PFL-AE and will also discuss a few GREs and their respective activating enzymes. PMID- 24486375 TI - Response to the Letter to the Editor entitled, "Optimization of the rodent model of polymicrobial sepsis" from Maddison Griffin, B. Biomed. Sci., Hayley L. Letson, MSc, and Geoffrey P. Dobson, PhD. PMID- 24486377 TI - Mode of action of the positive modulator PNU-120596 on alpha7 nicotinic acetylcholine receptors. AB - We investigated the mode of action of PNU-120596, a type II positive allosteric modulator of the rat alpha7 nicotinic acetylcholine receptor expressed by GH4C1 cells, using patch-clamp and fast solution exchange. We made two important observations: first, while PNU-120596 rapidly associated to desensitized receptors, it had at least hundredfold lower affinity to resting conformation, therefore at 10 MUM concentration it dissociated from resting receptors; and second, binding of PNU-120596 slowed down dissociation of choline molecules from the receptor radically. We propose that when agonist concentration is transiently elevated in the continuous presence of the modulator (as upon the neuronal release of acetylcholine in a modulator-treated animal) these two elements together cause occurrence of a cycle of events: Binding of the modulator is limited in the absence of the agonist. When the agonist is released, it binds to the receptor, and induces desensitization, thereby enabling modulator binding. Modulator binding in turn traps the agonist within its binding site for a prolonged period of time. Once the agonist finally dissociated, the modulator can also dissociate without re-binding, and the receptor assumes its original resting conformation. In kinetic simulations this "trapped agonist cycle" mechanism did not require that the orthosteric and allosteric ligands symmetrically modify each other's affinity, only the modulator must decrease agonist accessibility, and the agonist must induce a conformation that is accessible to the modulator. This mechanism effectively prolongs and amplifies the effect of the agonist. PMID- 24486378 TI - Role of ERK signaling in activity-dependent modifications of histone proteins. AB - It is well-established that neuronal intracellular signaling governed by the extracellular signal-regulated kinase (ERK/MAPK) plays a crucial role in long term adaptive changes that occur during cognitive processes. ERK is a downstream component of a conserved signaling module that is activated by the serine/threonine kinase, Raf, which activates the MAPK/ERK kinase (MEK)1/2 protein kinases, which, in turn, activate ERK1/2. This signaling pathway has been reported to be activated in numerous physiological conditions due to a variety of stimuli, ranging from the activation of ionotropic glutamatergic receptors to metabotropic dopaminergic receptors and neurotrophin receptors. Interestingly, activated ERK can have early and late downstream effects at both the nuclear and synaptic levels. Locally, ERK signaling results in transient changes in the efficacy of synaptic transmission by modifying both pre- and post-synaptic targets. Once translocated into the nucleus, ERK signaling may control transcription by targeting several different regulators of gene expression such as transcription factors and histone proteins. ERK function is considered fundamental in processes such as long-term memory storage and drug addiction, by means of its role in activity-dependent epigenetic modifications that occur in the brain. In this review, we summarize the current understanding of ERK action in the neuroepigenetic processes underlying physiological responses, cognitive processes and drug addiction. PMID- 24486379 TI - Kinetic properties and open probability of alpha7 nicotinic acetylcholine receptors. AB - The alpha7 nicotinic acetylcholine receptor (nAChR) has some peculiar kinetic properties. From the literature of alpha7 nAChR-mediated currents we concluded that experimentally measured kinetic properties reflected properties of the solution exchange system, rather than genuine kinetic properties of the receptors. We also concluded that all experimentally measured EC50 values for agonists must inherently be inaccurate. The aim of this study was to assess the undistorted kinetic properties of alpha7 nAChRs, and to construct an improved kinetic model, which can also serve as a basis of modeling the effect of the positive allosteric modulator PNU-120596, as it is described in the accompanying paper. Agonist-evoked currents were recorded from GH4C1 cells stably transfected with pCEP4/rat alpha7 nAChR using patch-clamp and fast solution exchange. We used two approaches to circumvent the problem of insufficient solution exchange rate: extrapolation and kinetic modeling. First, using different solution exchange rates we recorded evoked currents, and extrapolated their amplitude and kinetics to instantaneous solution exchange. Second, we constructed a kinetic model that reproduced concentration-dependence and solution exchange rate-dependence of receptors, and then we simulated receptor behavior at experimentally unattainably fast solution exchange. We also determined open probabilities during choline evoked unmodulated and modulated currents using nonstationary fluctuation analysis. The peak open probability of 10 mM choline-evoked currents was 0.033 +/ 0.006, while in the presence of choline (10 mM) and PNU-120596 (10 MUM), it was increased to 0.599 +/- 0.058. Our kinetic model could adequately reproduce low open probability, fast kinetics, fast recovery and solution exchange rate dependent kinetics. PMID- 24486380 TI - Physical exercise improves synaptic dysfunction and recovers the loss of survival factors in 3xTg-AD mouse brain. AB - Physical exercise has become a potentially beneficial therapy for reducing neurodegeneration symptoms in Alzheimer's disease. Previous studies have shown that cognitive deterioration, anxiety and the startle response observed in 7 month-old 3xTg-AD mice were ameliorated after 6 months of free access to a running wheel. Also, alterations in synaptic response to paired-pulse stimulation were improved. The present study further investigated some molecular mechanisms underlying the beneficial effects of 6 months of voluntary exercise on synaptic plasticity in 7-month-old 3xTg-AD mice. Changes in binding parameters of [(3)H] flunitrazepam to GABAA receptor and of [(3)H]-MK-801 to NMDA receptor in cerebral cortex of 3xTgAD mice were restored by voluntary exercise. In addition, reduced expression levels of NMDA receptor NR2B subunit were reestablished. The synaptic proteins synaptophysin and PSD-95 and the neuroprotective proteins GDNF and SIRT1 were downregulated in 3xTgAD mice and were recovered by exercise treatment. Overall, in this paper we highlight the fact that different interrelated mechanisms are involved in the beneficial effects of exercise on synaptic plasticity alterations in the 3xTg-AD mouse model. PMID- 24486376 TI - Crosstalk between telomere maintenance and radiation effects: A key player in the process of radiation-induced carcinogenesis. AB - It is well established that ionizing radiation induces chromosomal damage, both following direct radiation exposure and via non-targeted (bystander) effects, activating DNA damage repair pathways, of which the proteins are closely linked to telomeric proteins and telomere maintenance. Long-term propagation of this radiation-induced chromosomal damage during cell proliferation results in chromosomal instability. Many studies have shown the link between radiation exposure and radiation-induced changes in oxidative stress and DNA damage repair in both targeted and non-targeted cells. However, the effect of these factors on telomeres, long established as guardians of the genome, still remains to be clarified. In this review, we will focus on what is known about how telomeres are affected by exposure to low- and high-LET ionizing radiation and during proliferation, and will discuss how telomeres may be a key player in the process of radiation-induced carcinogenesis. PMID- 24486381 TI - Broad spectrum and prolonged efficacy of dimiracetam in models of neuropathic pain. AB - Dimiracetam, a bicyclic 2-pyrrolidinone derivative originally developed as cognition enhancer, is a member of the nootropic family for which anecdotal efficacy in models of neuropathic pain has been reported. Its antineuropathic activity was evaluated in established models of neuropathic pain induced by nerve injury, chemotherapy or MIA-induced osteoarthritis. Acutely, dimiracetam was very effective in models of antiretroviral drug induced painful neuropathy, oxaliplatin-induced hyperalgesia and in the MIA-osteoarthritis. Chronic dimiracetam dosing in the MIA and ART- induced models completely reverted hyperalgesia back to the level of healthy controls. Once reached, the maximal effect was maintained despite dose diminution and increased inter-dose interval. The effect of the last dose outlasted dimiracetam half-life longer than 12 times. In synaptosomal preparations, dimiracetam counteracted the NMDA-induced release of glutamate with highest potency in the spinal cord, possibly via NMDA receptor isoforms containing pH-sensitive GluN1 and GluN2A subunits. Dimiracetam appears to be a promising and safe treatment for neuropathic pain conditions for which there are very limited therapeutic options. PMID- 24486382 TI - TRR469, a potent A(1) adenosine receptor allosteric modulator, exhibits anti nociceptive properties in acute and neuropathic pain models in mice. AB - A(1) adenosine receptors (ARs) have been identified as a potential target for the development of anti-nociceptive compounds. The present study explores the analgesic effects of a novel A(1)AR positive allosteric modulator, TRR469, in different models of acute and chronic pain in mice. To evaluate the allosteric enhancement, in vitro binding experiments were performed. The anti-nociceptive properties were investigated in formalin and writhing tests, and in the streptozotocin-induced diabetic neuropathic pain model. Rotarod and catalepsy tests were used to identify potential side effects, while the functional effect of TRR469 was studied using [(3)H]-d-aspartate release from synaptosomes. TRR469 effectively inhibited nociceptive responses in the formalin and writhing tests, with effects comparable to those of the reference analgesic morphine. Isobolographic analysis of the combination of TRR469 and morphine revealed an additive interaction. TRR469 was anti-allodynic in the neuropathic pain model and did not display locomotor or cataleptic side effects. TRR469 enhanced the binding of the agonist radioligand [(3)H]-CCPA and induced a 33-fold increase of adenosine affinity in spinal cord membranes. In mouse spinal cord synaptosomes, TRR469 enhanced the inhibitory effect of A(1)AR activation on [(3)H]-d-aspartate release, a non-metabolizable analogue of glutamate. In conclusion, this research demonstrates the anti-nociceptive effect of the novel compound TRR469, one of the most potent and effective A(1)AR positive allosteric modulators so far synthesized. The use of TRR469 allows for the possibility of exploiting analgesic properties of endogenous adenosine, with a minor potential to develop the various side effects often associated with the use of direct receptor agonists. PMID- 24486383 TI - Aqueous extract of Gardenia jasminoides targeting oxidative stress to reduce polyQ aggregation in cell models of spinocerebellar ataxia 3. AB - Spinocerebellar ataxias (SCAs), caused by expanded CAG repeats encoding a long polyglutamine (polyQ) tract in the respective proteins, are characterized by the accumulation of intranuclear and cytoplasmic misfolded polyQ aggregation that leads to cell death. Suppression of aggregate formation can inhibit a wide range of downstream pathogenic events and is expected to be a therapeutic strategy for SCAs. Here we show the anti-aggregation potential of Gardenia jasminoides (G. jasminoides) and its components/metabolite geniposide, crocin, and genipin, in ATXN3/Q75-GFP 293 cells, a putative SCA3 cell model. We found the aggregation can be significantly prohibited by G. jasminoides, genipin, geniposide and crocin. Meanwhile, G. jasminoides, genipin, geniposide, and crocin up-regulated anti oxidative markers NFE2L2, NQO1, GCLC and GSTP1, and reduced the production of reactive oxidative species (ROS) in the same cell models. All of them further inhibited the aggregation in neurally differentiated SH-SY5Y ATXN3/Q75-GFP cells. Our results demonstrate that G. jasminoides, genipin, geniposide and crocin work on polyQ-aggregation reduction by suppressing ROS. These findings indicate the therapeutic applications of G. jasminoides in treating SCAs. Furthermore, oxidative stress inhibition could be a good target for drug development of anti polyQ aggregation. PMID- 24486385 TI - Targeting histone-modifications in Alzheimer's disease. What is the evidence that this is a promising therapeutic avenue? AB - Alzheimer' s disease (AD) is the most common form of dementia causing an increasing emotional and economical burden to our societies. Although much progress has been made regarding the molecular mechanisms that underlie AD pathogenesis effective therapies are not available yet. The emerging field of neuroepigenetics has provided evidence that de-regulation of epigenetic processes play a role in AD. In this article we will critically review the primary research data that led to the hypothesis that targeting histone-modifying enzymes could be used to treat AD pathogenesis and address the question if the field is ready to translate such findings into clinical application. PMID- 24486384 TI - The recovery of acetylcholinesterase activity and the progression of neuropathological and pathophysiological alterations in the rat basolateral amygdala after soman-induced status epilepticus: relation to anxiety-like behavior. AB - Organophosphorus nerve agents are powerful neurotoxins that irreversibly inhibit acetylcholinesterase (AChE) activity. One of the consequences of AChE inhibition is the generation of seizures and status epilepticus (SE), which cause brain damage, resulting in long-term neurological and behavioral deficits. Increased anxiety is the most common behavioral abnormality after nerve agent exposure. This is not surprising considering that the amygdala, and the basolateral nucleus of the amygdala (BLA) in particular, plays a central role in anxiety, and this structure suffers severe damage by nerve agent-induced seizures. In the present study, we exposed male rats to the nerve agent soman, at a dose that induce SE, and determined the time course of recovery of AChE activity, along with the progression of neuropathological and pathophysiological alterations in the BLA, during a 30-day period after exposure. Measurements were taken at 24 h, 7 days, 14 days, and 30 days after exposure, and at 14 and 30 days, anxiety-like behavior was also evaluated. We found that more than 90% of AChE is inhibited at the onset of SE, and AChE inhibition remains at this level 24 h later, in the BLA, as well as in the hippocampus, piriform cortex, and prelimbic cortex, which we analyzed for comparison. AChE activity recovered by day 7 in the BLA and day 14 in the other three regions. Significant neuronal loss and neurodegeneration were present in the BLA at 24 h and throughout the 30-day period. There was no significant loss of GABAergic interneurons in the BLA at 24 h post-exposure. However, by day 7, the number of GABAergic interneurons in the BLA was reduced, and at 14 and 30 days after soman, the ratio of GABAergic interneurons to the total number of neurons was lower compared to controls. Anxiety-like behavior in the open-field and the acoustic startle response tests was increased at 14 and 30 days post exposure. Accompanying pathophysiological alterations in the BLA - studied in in vitro brain slices - included a reduction in the amplitude of field potentials evoked by stimulation of the external capsule, along with prolongation of their time course and an increase in the paired-pulse ratio. Long-term potentiation was impaired at 24 h, 7 days, and 14 days post-exposure. The loss of GABAergic interneurons in the BLA and the decreased interneuron to total number of neurons ratio may be the primary cause of the development of anxiety after nerve agent exposure. PMID- 24486386 TI - Change in intraindividual variability over time as a key metric for defining performance-based cognitive fatigability. AB - Cognitive fatigability is conventionally quantified as the increase over time in either mean reaction time (RT) or error rate from two or more time periods during sustained performance of a prolonged cognitive task. There is evidence indicating that these mean performance measures may not sufficiently reflect the response characteristics of cognitive fatigue. We hypothesized that changes in intraindividual variability over time would be a more sensitive and ecologically meaningful metric for investigations of fatigability of cognitive performance. To test the hypothesis fifteen young adults were recruited. Trait fatigue perceptions in various domains were assessed with the Multidimensional Fatigue Index (MFI). Behavioral data were then recorded during performance of a three hour continuous cued Stroop task. Results showed that intraindividual variability, as quantified by the coefficient of variation of RT, increased linearly over the course of three hours and demonstrated a significantly greater effect size than mean RT or accuracy. Change in intraindividual RT variability over time was significantly correlated with relevant subscores of the MFI including reduced activity, reduced motivation and mental fatigue. While change in mean RT over time was also correlated with reduced motivation and mental fatigue, these correlations were significantly smaller than those associated with intraindividual RT variability. RT distribution analysis using an ex-Gaussian model further revealed that change in intraindividual variability over time reflects an increase in the exponential component of variance and may reflect attentional lapses or other breakdowns in cognitive control. These results suggest that intraindividual variability and its change over time provide important metrics for measuring cognitive fatigability and may prove useful for inferring the underlying neuronal mechanisms of both perceptions of fatigue and objective changes in performance. PMID- 24486387 TI - A model of curved saccade trajectories: spike rate adaptation in the brainstem as the cause of deviation away. AB - The trajectory of saccades to a target is often affected whenever there is a distractor in the visual field. Distractors can cause a saccade to deviate towards their location or away from it. The oculomotor mechanisms that produce deviation towards distractors have been thoroughly explored in behavioral, neurophysiological and computational studies. The mechanisms underlying deviation away, on the other hand, remain unclear. Behavioral findings suggest a mechanism of spatially focused, top-down inhibition in a saccade map, and deviation away has become a tool to investigate such inhibition. However, this inhibition hypothesis has little neuroanatomical or neurophysiological support, and recent findings go against it. Here, we propose that deviation away results from an unbalanced saccade drive from the brainstem, caused by spike rate adaptation in brainstem long-lead burst neurons. Adaptation to stimulation in the direction of the distractor results in an unbalanced drive away from it. An existing model of the saccade system was extended with this theory. The resulting model simulates a wide range of findings on saccade trajectories, including findings that have classically been interpreted to support inhibition views. Furthermore, the model replicated the effect of saccade latency on deviation away, but predicted this effect would be absent with large (400 ms) distractor-target onset asynchrony. This prediction was confirmed in an experiment, which demonstrates that the theory both explains classical findings on saccade trajectories and predicts new findings. PMID- 24486389 TI - Markovian approximation to the finite loci coalescent with recombination along multiple sequences. AB - The coalescent with recombination process has initially been formulated backwards in time, but simulation algorithms and inference procedures often apply along sequences. Therefore it is of major interest to approximate the coalescent with recombination process by a Markov chain along sequences. We consider the finite loci case and two or more sequences. We formulate a natural Markovian approximation for the tree building process along the sequences, and derive simple and analytically tractable formulae for the distribution of the tree at the next locus conditioned on the tree at the present locus. We compare our Markov approximation to other sequential Markov chains and discuss various applications. PMID- 24486388 TI - Nucleic acid delivery with microbubbles and ultrasound. AB - Nucleic acid-based therapy is a growing field of drug delivery research. Although ultrasound has been suggested to enhance transfection decades ago, it took a combination of ultrasound with nucleic acid carrier systems (microbubbles, liposomes, polyplexes, and viral carriers) to achieve reasonable nucleic acid delivery efficacy. Microbubbles serve as foci for local deposition of ultrasound energy near the target cell, and greatly enhance sonoporation. The major advantage of this approach is in the minimal transfection in the non-insonated non-target tissues. Microbubbles can be simply co-administered with the nucleic acid carrier or can be modified to carry nucleic acid themselves. Liposomes with embedded gas or gas precursor particles can also be used to carry nucleic acid, release and deliver it by the ultrasound trigger. Successful testing in a wide variety of animal models (myocardium, solid tumors, skeletal muscle, and pancreas) proves the potential usefulness of this technique for nucleic acid drug delivery. PMID- 24486390 TI - Blockade of endothelin ET(A), but not thromboxane, receptors offsets the cyclosporine-evoked hypertension and interrelated baroreflex and vascular dysfunctions. AB - The impairment of arterial baroreceptor and vasodilator functions are two major contributors to the hypertensive action of cyclosporine (CSA). In this study, in vivo and in vitro pharmacological studies were performed to investigate whether these effects of CSA are differentially modulated by endothelin and thromboxane signaling. The treatment of rats with CSA (25mg/kg/day i.p.) for 7 consecutive days caused significant increases in blood pressure (BP), attenuated reflex heart rate (HR) responses to vasopressor (phenylephrine, PE) and vasodepressor (sodium nitroprusside, SNP) agents, and reduced cumulative vasorelaxant responses elicited by acetylcholine (Ach, 1*10(-9)-1*10(-5)M) in PE-precontracted isolated aortas. These effects of CSA were blunted after concurrent i.p. administration of atrasentan (selective ETA blocker, 10mg/kg/day), but not terutroban (thromboxane receptor blocker, 10mg/kg/day). Moreover, atrasentan reversed the reductions in aortic protein expression of eNOS caused by CSA whereas terutroban was without effect. We also report that the favorable effect of atrasentan on CSA-evoked impairment in aortic Ach responsiveness disappeared in rats treated simultaneously with L-NAME (NOS inhibitor, 10mg/kg/day) but not BQ 788 (ETB receptor blocker, 0.1mg/kg/day) or indomethacin (cycloxygenase inhibitor, 5mg/kg/day). Together, the data implicate endothelin ETA receptors in baroreflex and vascular derangements which predispose to the hypertensive effect of CSA. Moreover, the facilitation of NOS, but not ETB receptors or cycloxygenase-derived prostanoids, signaling is pivotal for advantageous effect of atrasentan on the aortic CSA-Ach interaction. PMID- 24486391 TI - mGlu(2) receptor-mediated modulation of conditioned avoidance behavior in rats. AB - Inhibition of conditioned avoidance behavior in rats is generally considered predictive for antipsychotic activity in man. The present study investigated the mGlu2-mediated modulation of conditioned avoidance and compared mGlu2 agonists with available antipsychotics for their relative effects on conditioned avoidance behavior and locomotion. The mGlu2/3 orthosteric agonist 4-amino-2 thiabicyclo[3.1.0]hexane-4,6-dicarboxylic acid 2,2-dioxide (LY-404039) and mGlu2 positive allosteric modulator (PAM) 3-(cyclopropylmethyl)-7-(4-phenylpiperidin-1 yl)-8-(trifluoromethyl)[1,2,4]triazolo[4,3-a]pyridine (JNJ-42153605) inhibited avoidance and blocked escape behavior. The mGlu2/3 negative allosteric modulators (NAMs) 7-(dimethylamino)-4-(3-pyridin-3-ylphenyl)-8-(trifluoromethyl)-1,3-dihydro 2 H-1,5-benzodiazepin-2-one (JNJ-42112265) and 4-[3-(2,6-dimethylpyridin-4 yl)phenyl]-7-methyl-8-(trifluoromethyl)-1,3-dihydro-2H-1,5-benzodiazepin-2-one (RO-4491533) reversed the LY-404039-induced impairment of avoidance and escape. JNJ-42112265 also reversed the impairment of avoidance and escape induced by the mGlu2-specific PAM JNJ-42153605, suggesting that the effects on conditioned avoidance are specifically mGlu2-mediated. The mGlu2/3 antagonist (2-(2 carboxycyclopropyl)-3-(9H-xanthen-9-yl)-d-alanine (LY-341495; s.c.) reversed the LY-404039-induced escape impairment but failed to restore avoidance, suggesting interfering side effects. Like the tested antipsychotics, mGlu2/3 orthosteric and allosteric agonists inhibited avoidance behavior and locomotion at similar doses. Hence no clear-cut differences between mGlu2 modulators and currently available antipsychotics in the way they interfere with avoidance behavior in relation to inhibition of locomotion could be established. PMID- 24486392 TI - Piromelatine, a novel melatonin receptor agonist, stabilizes metabolic profiles and ameliorates insulin resistance in chronic sleep restricted rats. AB - Chronic sleep deprivation may speed the onset or increase the severity of age related conditions such as Type 2 diabetes, high blood pressure and obesity. Piromelatine (Neu-P11) is a novel melatonin agonist, which has been developed for the treatment of insomnia. Animal studies have suggested possible efficacy of piromelatine in sleep maintenance, anxiety and depression. In addition, piromelatine has been shown to inhibit weight gain and improve insulin sensitivity in high-fat/high-sucrose-fed (HFSD) rats. The objective of this study was to investigate the effects of piromelatine on insulin sensitivity in sleep restricted rats. Sleep restriction was established by rotating cages intermittently for 20h thereby sleeping time of rats was limited to 4h per day. During 8 days of sleep restriction, rats were injected intraperitoneally with piromelatine (20mg/kg), melatonin (5mg/kg) or a vehicle. The results showed that sleep restriction increased plasma glucose, fasting insulin, total cholesterol (TC), triglycerides (TG) and oxidative stress markers while HDL-cholesterol (HDL C) level and glucose tolerance were decreased. However, under piromelatine or melatonin treatment, the levels of plasma glucose, TG, TC decreased and HDL-C, glucose tolerance and antioxidative potency increased when compared with the vehicle-treated group. These data suggest that chronic sleep restriction in rats induce metabolic dysfunction, oxidative stress and insulin resistance, and these symptoms were improved by treatment with piromelatine or melatonin. We conclude that piromelatine could regulate metabolic profiles and insulin sensitivity, and attenuate insulin resistance induced by sleep restriction. PMID- 24486393 TI - SGLT2 selective inhibitor ipragliflozin reduces body fat mass by increasing fatty acid oxidation in high-fat diet-induced obese rats. AB - Ipragliflozin is a novel and selective sodium-glucose cotransporter 2 (SGLT2) inhibitor that induces sustained increases in urinary glucose excretion by inhibiting renal glucose reabsorption and thereby exerting a subsequent antihyperglycemic effect. Here, we examined the effect of ipragliflozin on body weight in high-fat diet-induced (HFD) obese rats. Treatment of ipragliflozin (10mg/kg once daily) reduced body weight despite a slight increase in food intake. Dual-energy X-ray absorptiometry and computed tomography demonstrated that the reduction in body weight was accompanied by reduced visceral and subcutaneous fat masses but not lean mass or bone mineral content. Analysis of plasma and urinary parameters suggested the possibility that ipragliflozin enhanced lipolysis and fatty acid oxidation, and indirect calorimetry showed that ipragliflozin decreased the heat production rate from glucose but increased the rate from fat and lowered the respiratory exchange ratio. In conclusion, these data demonstrate that ipragliflozin-induced urinary glucose excretion specifically reduces fat mass with steady calorie loss by promoting the use of fatty acids instead of glucose as an energy source in HFD rats. By improving hyperglycemia and promoting weight reduction, ipragliflozin may prove useful in treating type 2 diabetes in obese individuals. PMID- 24486394 TI - Insights in the mechanism underlying the protective effect of alpha-lipoic acid against acetaminophen-hepatotoxicity. AB - Acetaminophen (APAP) is one of the most widely used analgesic antipyretic drugs and is a major cause of acute liver failure at overdose. The aim of this study is to investigate the possible protective effect of alpha-lipoic acid (alpha-LA, 20 or 100 mg/kg administered simultaneously or after 1.5 h) against APAP-induced hepatotoxicity in rats. Administration of APAP (1.5 g/kg i.p.) resulted in elevation of serum ALT and hepatic malondialdehyde (MDA) content, as well as decrease in hepatic glutathione (GSH) content. In addition, elevation in hepatic hemeoxygenase-1 (HO-1) and NADPH oxidase expression was observed accompanied with a significant reduction in glutathione synthase and cystathionine-beta-synthase (CbetaS) expression. Furthermore, nuclear factor kappa-B (NF-kappaB) activity was enhanced in APAP-treated rats. Administration of the standard APAP antidote; N acetylcysteine (NAC, 1200 mg/kg) or alpha-LA (20 mg/kg), simultaneously or 1.5 h after APAP, ameliorated APAP-induced alterations in liver function, oxidant and inflammatory markers. Importantly, simultaneous administration of NAC or alpha-LA (20 mg/kg) was more protective than their later administration. However, the beneficial effect of alpha-LA was lost at higher dose level (100 mg/kg). Taken together, the beneficial effects of alpha-lipoic acid (20 mg/kg) were comparable to those of NAC which provides a new possible treatment for APAP-induced hepatotoxicity in patients who cannot tolerate NAC. However, careful dose selection is warranted since the beneficial effects of alpha-LA were lost at higher doses. PMID- 24486395 TI - Silymarin ameliorates fructose induced insulin resistance syndrome by reducing de novo hepatic lipogenesis in the rat. AB - High dietary fructose causes insulin resistance syndrome (IRS), primarily due to simultaneous induction of genes involved in glucose, lipid and mitochondrial oxidative metabolism. The present study evaluates effect of a hepatoprotective agent, silymarin (SYM) on fructose-induced metabolic abnormalities in the rat and also assessed the associated thrombotic complications. Wistar rats were kept on high fructose (HFr) diet throughout the 12-week study duration (9 weeks of HFr feeding and subsequently 3 weeks of HFr plus SYM oral administration [once daily]). SYM treatment significantly reduced the HFr diet-induced increase expression of peroxisome proliferator-activated receptor gamma coactivator (PGC) 1alpha/beta, peroxisome proliferator-activated receptor (PPAR)-alpha, forkhead box protein O1 (FOXO1), sterol regulatory element binding protein (SREBP)-1c, liver X receptor (LXR)-beta, fatty acid synthase (FAS) and PPARgamma genes in rat liver. SYM also reduced HFr diet mediated increase in plasma triglycerides (TG), non-esterified fatty acids (NEFA), uric acid, malondialdehyde (MDA), total nitrite and pro-inflammatory cytokines (C-reactive protein [CRP], interleukin-6 [IL-6], interferon-gamma [IFN-gamma] and tumor necrosis factor [TNF]) levels. Moreover, SYM ameliorated HFr diet induced reduction in glucose utilization and endothelial dysfunction. Additionally, SYM significantly reduced platelet activation (adhesion and aggregation), prolonged ferric chloride-induced blood vessel occlusion time and protected against exacerbated myocardial ischemia reperfusion (MI-RP) injury. SYM treatment prevented HFr induced mRNA expression of hepatic PGC-1alpha/beta and also its target transcription factors which was accompanied with recovery in insulin sensitivity and reduced propensity towards thrombotic complications and aggravated MI-RP injury. PMID- 24486396 TI - Antinociceptive esters of N-methylanthranilic acid: Mechanism of action in heat mediated pain. AB - Recently, we identified a new natural antinociceptive alkaloid ternanthranin, isopropyl N-methylanthranilate (ISOAN), from the plant species Choisya ternata Kunth (Rutaceae). In this work we concentrated on the elucidation of its mechanism of action in comparison with two other esters of this acid (methyl (MAN) and propyl (PAN)). Mice orally pre-treated with ISOAN, MAN or PAN (at 0.3, 1 and 3mg/kg) were less sensitive to chemical or thermal stimuli in different nociception models (formalin-, capsaicin- and glutamate-induced licking response, tail flick and hot plate). All compounds (1 and 3mg/kg) showed significant activity in the peripheral nociception models, as well as a dose-dependent spinal antinociceptive effect in the tail flick model. We observed that glibenclamide was able to reverse the antinociceptive effect of ISOAN in the hot plate model suggesting the involvement of K(+)ATP channels. The antinociceptive effect of MAN and PAN may be related to adrenergic, nitrergic and serotoninergic pathways. In addition, the antinociception of PAN was reverted by naloxone implying that the opioid pathway participates in its activity. The cholinergic and cannabinoid systems were found not be involved in the onset of the antinociceptive effects of any of the esters. In conclusion, isopropyl, methyl and propyl N methylanthranilates produced significant peripheral and central antinociception at doses lower than that of morphine, the classical opioid analgesic drug, without causing toxicity. PMID- 24486397 TI - Eplerenone mimics features of the alternative activation in macrophages obtained from patients with heart failure and healthy volunteers. AB - Alternative activation of macrophages plays protective role in cardiac remodelling in heart failure and the activity of mineralocorticoid receptor may determine the phenotype of these cells. We examined the influence of eplerenone, aldosterone, and IL-4 on descriptors of alternative activation in blood monocytes collected from 19 patients with heart-failure and 20 healthy volunteers. "Heart failure" macrophages in comparison with "healthy" macrophages had increased mineralocorticoid activity, NO and reactive oxygen species production, expression of iNOS mRNA and protein, but decreased expression of arginase I and mannose receptor proteins, and activity of MnSOD and CuZnSOD. Aldosterone increased mineralocorticoid activity, NO and reactive oxygen species production, iNOS mRNA and protein expression, MnSOD and CuZnSOD activity. Eplerenone attenuated the effects of aldosterone on all but MnSOD and CuZnSOD variables. Eplerenone alone increased the production of NO, MnSOD and CuZnSOD activity, arginase I gene and protein expression, and mannose receptor gene and protein expression, but decreased mineralocorticoid activity only in "heart failure" macrophages. The latter suggests altered function of mineralocorticoid receptor in heart failure. Increased mineralocorticoid activity accounts for increased NO production, iNOS gene and protein expression but does not explain the increased basal reactive oxygen species production and decreased markers of alternative activation in "heart failure" macrophages. In the lack of change in basal mineralocorticoid activity, eplerenone increases markers of alternative activation in a mineralocorticoid receptor-independent manner. Because of changes in iNOS and NO variable, eplerenone induced qualitatively different activation of macrophages from that obtained with IL-4. PMID- 24486398 TI - Identification of a novel GPR81-selective agonist that suppresses lipolysis in mice without cutaneous flushing. AB - GPR81, which exhibits a high degree of homology with GPR109a, has been recently identified as a lactate receptor. Similar to GPR109a, the activation of GPR81 by lactate suppresses lipolysis, suggesting that GPR81 may be a potential drug target for treating dyslipidemia. In addition, the fact that GPR81 is expressed only in adipocytes, whereas GPR109a is expressed in various tissues and cells, including Langerhans cells, which are considered responsible for flushing, indicates that targeting GPR81 could lead to the development of antidyslipidemia agents with a reduced risk of this side effect. However, the pharmacological role of GPR81 remains largely unclear, mainly because of the lack of potent and selective surrogate GPR81 agonists suitable for in vivo studies. In the present study, we showed that lactate-induced suppression of lipolysis in explants of white adipose tissue (WAT) depends on the presence of GPR81. We also performed high-throughput screening (HTS) and identified four novel chemical clusters as GPR81 agonists. Chemical optimization of aminothiazole derivatives led to the discovery of a lead compound with improved potency. The compound inhibited lipolysis in differentiated 3T3-L1 adipocytes. Finally, intraperitoneal administration of this compound suppressed lipolysis in mice at doses that did not cause cutaneous flushing. This is the first description of a 50nM GPR81 selective agonist with in vivo efficacy, without the side effect, i.e., flushing. These results suggest that GPR81 is an attractive drug target for treating dyslipidemia without the risk of flushing. PMID- 24486399 TI - Modulation of peripheral Na(+) channels and neuronal firing by n-butyl-p aminobenzoate. AB - n-butyl-p-aminobenzoate (BAB), a local anesthetic, is administered epidurally in cancer patients to treat pain that is poorly controlled by other drugs that have a number of adverse effects. The purpose of the study was to unravel the mechanisms underlying the apparent selective pain suppressant effect of BAB. We used the whole-cell patch-clamp technique to record Na(+) currents and action potentials (APs) in dissociated, nociceptive dorsal root ganglion (DRG) cells from rats, two types of peripheral sensory neuron Na(+) channels (Nav1.7 and Nav1.8), and the motor neuron-specific Na(+) channel (Nav1.6) expressed in HEK293 cells. BAB (1-100MUM) inhibited, in a concentration-dependent manner, the depolarization evoked repetitive firing in DRG cells, the three types of Na(+) current expressed in HEK293 cells, and the TTXr Na(+) current of the DRG neurons. BAB induced a use-dependent block that caused a shift of the inactivation curve in the hyperpolarizing direction. BAB enhanced the onset of slow inactivation of Nav1.7 and Nav1.8 currents but not of Nav1.6 currents. At clinically relevant concentrations (1-100MUM), BAB is thus a more potent inhibitor of peripheral TTX sensitive TTXs, Nav1.7 and TTX-resistant NaV1.8 Na(+) channels than of motor neuron axonal Nav1.6 Na(+) channels. BAB had similar effects on the TTXr Na(+) channels of rat DRG neurons and Nav1.8 channels expressed in HEK293 cells. The observed selectivity of BAB in treating cancer pain may be due to an enhanced and selective responsiveness of Na(+) channels in nociceptive neurons to this local anesthetic. PMID- 24486400 TI - Pericyte function in the physiological central nervous system. AB - Damage to the central nervous system (CNS) leads to disruption of the vascular network, causing vascular dysfunction. Vascular dysfunction is the major event in the pathogenesis of CNS diseases and is closely associated with the severity of neuronal dysfunction. The suppression of vascular dysfunction has been considered a promising avenue to limit damage to the CNS, leading to efforts to clarify the cellular and molecular basis of vascular homeostasis maintenance. A reduction of trophic support and oxygen delivery due to circulatory insufficiency has long been regarded as a major cause of vascular damage. Moreover, recent studies provide a new perspective on the importance of the structural stability of blood vessels in CNS diseases. This updated article discusses emerging information on the key role of vascular integrity in CNS diseases, specially focusing on pericyte function. PMID- 24486401 TI - Sphingosine kinase 2 prevents the nuclear translocation of sphingosine 1 phosphate receptor-2 and tyrosine 416 phosphorylated c-Src and increases estrogen receptor negative MDA-MB-231 breast cancer cell growth: The role of sphingosine 1 phosphate receptor-4. AB - We demonstrate that pre-treatment of estrogen receptor negative MDA-MB-231 breast cancer cells containing ectopically expressed HA-tagged sphingosine 1-phosphate receptor-2 (S1P2) with the sphingosine kinase 1/2 inhibitor SKi (2-(p hydroxyanilino)-4-(p-chlorophenyl)thiazole) or the sphingosine kinase 2 selective inhibitor (R)-FTY720 methyl ether (ROMe) or sphingosine kinase 2 siRNA induced the translocation of HA-tagged S1P2 and Y416 phosphorylated c-Src to the nucleus of these cells. This is associated with reduced growth of HA-tagged S1P2 over expressing MDA-MB-231 cells. Treatment of HA-S1P2 over-expressing MDA-MB-231 cells with the sphingosine 1-phosphate receptor-4 (S1P4) antagonist CYM50367 or with S1P4 siRNA also promoted nuclear translocation of HA-tagged S1P2. These findings identify for the first time a signaling pathway in which sphingosine 1 phosphate formed by sphingosine kinase 2 binds to S1P4 to prevent nuclear translocation of S1P2 and thereby promote the growth of estrogen receptor negative breast cancer cells. PMID- 24486402 TI - PTEN inhibits the invasion and metastasis of gastric cancer via downregulation of FAK expression. AB - The tumor suppressor gene phosphatase and tensin homolog (PTEN) is essential in inhibiting tumor growth and metastasis. However, the mechanism by which PTEN restricts gastric cancer progression and metastasis remains largely elusive. Here we demonstrated that PTEN overexpression or knockdown in gastric cancer cells led to the downregulation or upregulation of focal adhesion kinase (FAK), and decreased or increased cell invasion, respectively. Moreover, FAK overexpression could rescue the inhibition of cell invasion by PTEN. These results were further confirmed in orthotropic gastric cancer nude mice model. In addition, in human gastric cancer tissues, PTEN protein level was conversely correlated with FAK protein level. Mechanistically, we found that PTEN inhibited PI3K/NF-kappaB pathway and inhibited the DNA binding of NF-kappaB on FAK promoter. Taken together, our data reveal a novel mechanism that PTEN inhibits the growth and invasion of gastric cancer via the downregulation of FAK expression and suggest that exploiting PTEN/PI3K/NF-kappaB/FAK axis is a promising approach to treat gastric cancer metastasis. PMID- 24486403 TI - NF-kappaB enhances hypoxia-driven T-cell immunosuppression via upregulation of adenosine A(2A) receptors. AB - Hypoxia affects inflammation by modulating T-cell activation via the adenosinergic system. We supposed that, in turn, inflammation influences cell hypoxic behavior and that stimulation of T-cells in inflammatory conditions involves the concerted action of the nuclear factor kappaB (NF-kappaB) and the related hypoxia-inducible factor 1alpha (HIF-1alpha) on the adenosinergic system. We addressed this hypothesis by monitoring both transcription factors and four adenosinergic signaling parameters - namely adenosine, adenosine deaminase (ADA), adenosine A2A receptor (A2AR) and cAMP - in T-cells stimulated using phorbol myristate acetate and phytohemagglutinin and submitted to hypoxic conditions which were mimicked using CoCl2 treatment. We found that cell viability was more altered in stimulated than in resting cells under hypoxia. Detailed analysis showed that: i) NF-kappaB activation remained at basal level in resting hypoxic cells but greatly increased following stimulation, stimulated hypoxic cells exhibiting the higher level; ii) HIF-1alpha production induced by hypoxia was boosted via NF-kappaB activation in stimulated cells whereas hypoxia increased HIF-1alpha production in resting cells without further activating NF-kappaB; iii) A2AR expression and cAMP production increased in stimulated hypoxic cells whereas adenosine level remained unchanged due to ADA regulation; and iv) the presence of H2S, an endogenous signaling molecule in inflammation, reversed the effect of stimulation on cell viability by down-regulating the activity of transcription factors and adenosinergic immunosuppression. We also found that: i) the specific A2AR agonist CGS-21680 increased the suppressive effect of hypoxia on stimulated T-cells, the antagonist ZM-241385 exhibiting the opposite effect; and ii) Rolipram, a selective inhibitor of cAMP-specific phosphodiesterase 4, and 8-Br cAMP, a cAMP analog which preferentially activates cAMP-dependent protein kinase A (PKA), increased T-cell immunosuppression whereas H-89, a potent and selective inhibitor of cAMP-dependent PKA, restored cell viability. Together, these data indicate that inflammation enhances T-cell sensitivity to hypoxia via NF-kappaB activation. This process upregulates A2AR expression and enhances cAMP production and PKA activation, resulting in adenosinergic T-cell immunosuppression that can be modulated via H2S. PMID- 24486404 TI - Non-thermal atmospheric pressure plasma induces apoptosis in oral cavity squamous cell carcinoma: Involvement of DNA-damage-triggering sub-G(1) arrest via the ATM/p53 pathway. AB - Recent advances in physics have made possible the use of non-thermal atmospheric pressure plasma (NTP) in cancer research. Although increasing evidence suggests that NTP induces death of various cancer cell types, thus offering a promising alternative treatment, the mechanism of its therapeutic effect is little understood. In this study, we report for the first time that NTP led to apoptotic cell death in oral cavity squamous cell carcinoma (OSCC). Interestingly, NTP induced a sub-G(1) arrest in p53 wild-type OSCCs, but not in p53-mutated OSCCs. In addition, NTP increased the expression levels of ATM, p53 (Ser 15, 20 and 46), p21, and cyclin D1. A comet assay, Western blotting and immunocytochemistry of gammaH2AX suggested that NTP-induced apoptosis and sub-G(1) arrest were associated with DNA damage and the ATM/p53 signaling pathway in SCC25 cells. Moreover, ATM knockdown using siRNA attenuated the effect of NTP on cell death, sub-G(1) arrest and related signals. Taken together, these results indicate that NTP induced apoptotic cell death in p53 wild-type OSCCs through a novel mechanism involving DNA damage and triggering of sub-G(1) arrest via the ATM/p53 pathway. These findings show the therapeutic potential of NTP in OSCC. PMID- 24486405 TI - Having excess levels of PCSK9 is not sufficient to induce complex formation between PCSK9 and the LDL receptor. AB - Proprotein convertase subtilisin/kexin-9 (PCSK9) acts mainly by forming complexes with the LDL receptor at the cell surface, which are then degraded in the lysosome. Studies were performed to determine whether excess levels of PCSK9 was sufficient to induce PCSK9/LDL receptor complex formation in human hepatocyte like C3A cells. It was demonstrated using ELISA that instead of considering the overall levels of PCSK9 protein that is produced in response to certain treatment, what is critical is how much PCSK9 is actually capable of forming complexes. Despite the high levels, most of the PCSK9 produced as a result of incubating cells with a medium supplemented with BDTM MITO+ serum extender (MITO+ medium) appeared to be inhibited by a secreted factor. Having lower levels of PCSK9/LDL receptor complexes did not prevent an increase in the degradation rate of LDL receptors in MITO+ medium as compared to fetal bovine serum (FBS) containing medium (Regular medium), an effect that did not correlate with an increase in protein levels of the inducible degrader of LDL receptors (IDOL), as demonstrated using Western blotting analysis. Additional studies are required to determine the exact mechanism(s) for the degradation of the LDL receptor and/or to identify the secreted inhibitor of PCSK9. PMID- 24486406 TI - Subtypes of irritable bowel syndrome in children and adolescents. AB - BACKGROUND & AIMS: Pharmacologic treatments for irritable bowel syndrome (IBS) and medical management of symptoms are increasingly based on IBS subtype, so it is important to accurately differentiate patients. Few studies have classified subtypes of pediatric IBS, and conclusions have been challenged by methodologic limitations. We performed a prospective study to investigate the distribution of IBS subtypes among children and adolescents based on stool diary information, and compared subtypes according to demographic and pain characteristics. METHODS: We studied 129 subjects, ages 7 to 18 years (mean age, 11.4 +/- 2.8 y; 60.5% female; 69.0% white) who met Pediatric Rome III IBS criteria and were part of larger studies of children with functional gastrointestinal disorders, recruited from primary and tertiary care centers. Children completed daily pain and stool diaries for 2 weeks. Participants were assigned IBS subtypes based on their reported stool information per adult Rome III criteria. IBS subtypes were compared for demographic variables and pain characteristics. RESULTS: IBS with constipation was the most common subtype of the disorder (58.1% of subjects), whereas mixed IBS was the least common (2.3% of subjects); 34.1% of subjects were unsubtyped IBS and 5.4% had IBS with diarrhea. The groups of different IBS subtypes did not differ significantly by sex, age, ethnicity, or pain characteristics. CONCLUSIONS: In contrast to adults, in children, IBS with constipation and unsubtyped IBS are the most common subtypes, whereas IBS with diarrhea and mixed IBS are less common. Demographic and pain characteristics cannot distinguish subtypes. PMID- 24486407 TI - Sodium phosphate does not increase risk for acute kidney injury after routine colonoscopy, compared with polyethylene glycol. AB - BACKGROUND & AIMS: Oral sodium phosphate (OSP) is a common bowel purgative administered before colonoscopy; the Food and Drug Administration has warned against its use because of concerns about acute kidney injury (AKI) from the absorbed phosphate and dystrophic calcification. However, it is not clear if OSP is associated with AKI in the general population or in high-risk subgroups undergoing colonoscopy. We estimated the risk of AKI among patients undergoing a screening colonoscopy using OSP vs polyethylene glycol (PEG) for bowel cleansing in a large, US-based claims database. METHODS: We used an insurance database to identify a cohort of patients ages 50 to 75 years who underwent screening colonoscopies as outpatients from January 2000 through November 2008 (before the Food and Drug Administration warning), receiving OSP (n = 121,266) or PEG (n = 429,430) within 30 days beforehand, without prior use of either drug. We collected data from patients for 6 months afterward to identify those who developed AKI or renal failure, or received dialysis. Adjusted and propensity score-matched hazard ratios (HR) and 95% confidence intervals (CI) were estimated using Cox proportional hazards models. We investigated the effects in subgroups with higher AKI risk (patients with chronic kidney disease, kidney stones, hypertension, or diabetes, or using antihypertensive or nonsteroidal anti inflammatory drugs). RESULTS: AKI occurred in 0.2% of OSP users and in 0.3% of PEG users (adjusted HR, 0.86; 95% CI, 0.75-0.99). OSP users matched well with PEG users, producing similar estimates (HR, 0.85; 95% CI, 0.72-1.01). We did not observe a consistent increase in the risk of AKI or other outcomes in any subgroups analyzed. CONCLUSIONS: In a large database analysis, we did not associate administration of OSP before colonoscopy with increased risk of postprocedure AKI, even in high-risk clinical subgroups. PMID- 24486408 TI - Early trough levels and antibodies to infliximab predict safety and success of reinitiation of infliximab therapy. AB - BACKGROUND & AIMS: Few agents are available for the treatment of inflammatory bowel diseases, and patients frequently become unresponsive to biologics. We investigated the feasibility of reinitiating infliximab therapy for patients who previously received only episodic therapy with, lost response to, or had infusion reactions to infliximab. We also aimed to identify factors associated with the success and safety of restarting infliximab, such as antibodies to infliximab and trough levels of the drug. METHODS: From the inflammatory bowel disease biobank, we identified 128 consecutive patients (105 patients with Crohn's disease, 23 patients with ulcerative colitis) who restarted infliximab after a median 15 month discontinuation (range, 6-125 mo; 28 patients for loss of response or infusion reactions, 100 patients for remission or pregnancy). We also analyzed serum samples that had been collected during the first period of infliximab therapy (T-1), when therapy was reinitiated (T0), and at later time points (T+1, T+2) for trough levels and antibodies to infliximab. We investigated correlations among response to treatment, infusion reactions, treatment modalities, trough levels, and antibodies to infliximab. RESULTS: Reinitiation of infliximab therapy produced a response in 84.5% of patients at week 14, 70% of patients at 1 year, and in 61% of patients at more than 4 years. Fifteen patients had acute infusion reactions and 10 patients had delayed infusion reactions. The absence of antibodies to infliximab at T+1 (hazard ratio [HR], 0.14; 95% confidence interval [CI], 0.026-0.74; P = .021) and reinitiation with concomitant immunomodulator therapy were associated with short-term responses (HR, 6.0; 95% CI, 1.3-27; P = .019). Pregnancy or remission as reason for discontinuation (HR, 2.70; 95% CI, 1.09-6.67; P = .033) and higher trough levels at T+1 (HR, 2.94; 95% CI, 1.18 7.69; P = .021) were associated with long-term response. Undetectable antibodies to infliximab at T+1 were associated with the safety of reinitiating therapy (HR for infusion reaction with detectable antibodies to infliximab, 7.7; 95% CI, 1.88 31.3; P = .004). CONCLUSIONS: Reinitiating infliximab therapy can be safe and effective for patients with Crohn's disease or ulcerative colitis after a median 15-month discontinuation period. PMID- 24486409 TI - Detection of serrated lesions: we are still in the teething stage. PMID- 24486410 TI - Heparan sulfate proteoglycans and heparin regulate melanoma cell functions. AB - BACKGROUND: The solid melanoma tumor consists of transformed melanoma cells, and the associated stromal cells including fibroblasts, endothelial cells, immune cells, as well as, soluble macro- and micro-molecules of the extracellular matrix (ECM) forming the complex network of the tumor microenvironment. Heparan sulfate proteoglycans (HSPGs) are an important component of the melanoma tumor ECM. Importantly, there appears to be both a quantitative and a qualitative shift in the content of HSPGs, in parallel to the nevi-radial growth phase-vertical growth phase melanoma progression. Moreover, these changes in HSPG expression are correlated to modulations of key melanoma cell functions. SCOPE OF REVIEW: This review will critically discuss the roles of HSPGs/heparin in melanoma development and progression. MAJOR CONCLUSIONS: We have correlated HSPGs' expression and distribution with melanoma cell signaling and functions as well as angiogenesis. GENERAL SIGNIFICANCE: The current knowledge of HSPGs/heparin biology in melanoma provides a foundation we can utilize in the ongoing search for new approaches in designing anti-tumor therapy. This article is part of a Special Issue entitled Matrix-mediated cell behaviour and properties. PMID- 24486411 TI - Yap1 mediates tolerance to cobalt toxicity in the yeast Saccharomyces cerevisiae. AB - BACKGROUND: Cobalt has a rare occurrence in nature, but may accumulate in cells to toxic levels. In the present study, we have investigated how the transcription factor Yap1 mediates tolerance to cobalt toxicity. METHODS: Fluorescence microscopy was used to address how cobalt activates Yap1. Using microarray analysis, we compared the transcriptional profile of a strain lacking Yap1 to that of its parental strain. To evaluate the extent of the oxidative damage caused by cobalt, GSH was quantified by HPLC and protein carbonylation levels were assessed. RESULTS: Cobalt activates Yap1 under aerobiosis and anaerobiosis growth conditions. This metal generates a severe oxidative damage in the absence of Yap1. However, when challenged with high concentrations of cobalt, yap1 mutant cells accumulate lower levels of this metal. Accordingly, microarray analysis revealed that the expression of the high affinity phosphate transporter, PHO84, a well-known cobalt transporter, is compromised in the yap1 mutant. Moreover, we show that Yap1 is a repressor of the low affinity iron transporter, FET4, which is also known to transport cobalt. CONCLUSIONS: Cobalt activates Yap1 that alleviates the oxidative damage caused by this metal. Yap1 partially controls cobalt cellular uptake via the regulation of PHO84. Although FET4 repression by Yap1 has no effect on cobalt uptake, it may be its first line of defense against other toxic metals. GENERAL SIGNIFICANCE: Our results emphasize the important role of Yap1 in mediating cobalt-induced oxidative damages and reveal new routes for cell protection provided by this regulator. PMID- 24486412 TI - Upregulation of HIF-2alpha induced by sorafenib contributes to the resistance by activating the TGF-alpha/EGFR pathway in hepatocellular carcinoma cells. AB - Sorafenib, the first-line systemic drug for advanced hepatocellular carcinoma (HCC), has demonstrated limited benefits with very low response rates. Thus it is essential to investigate the underlying mechanisms for the resistance to sorafenib and seek potential strategy to enhance its efficacy. Hypoxic cells inside solid tumors are extremely resistant to therapies as their survival ability is increased due to the cellular adaptive response to hypoxia, which is controlled by hypoxia-inducible factor (HIF)-1 and HIF-2. Sorafenib inhibits HIF 1alpha synthesis, making the hypoxic response switch from HIF-1alpha- to HIF 2alpha-dependent pathways and providing a mechanism for more aggressive growth of tumors. The present study has demonstrated that upregulation of HIF-2alpha induced by sorafenib contributes to the resistance of hypoxic HCC cells by activating the transforming growth factor (TGF)-alpha/epidermal growth factor receptor (EGFR) pathway. Blocking the TGF-alpha/EGFR pathway by gefitinib, a specific EGFR inhibitor, reduced the activation of STAT (signal transducer and activator of transcription) 3, AKT and ERK (extracellular signal-regulated kinase), and synergized with sorafenib to inhibit proliferation and induce apoptosis of hypoxic HCC cells. Transfection of HIF-2alpha siRNA into HCC cells downregulated the expression of VEGF (vascular endothelial growth factor), cyclin D1, HIF-2alpha and TGF-alpha, and inhibited the activation of EGFR. HIF-2alpha siRNA inhibited the proliferation and promoted the apoptosis of HCC cells in vitro, and synergized with sorafenib to suppress the growth of HCC tumors in vivo. The results indicate that targeting HIF-2alpha-mediated activation of the TGF-alpha/EGFR pathway warrants further investigation as a potential strategy to enhance the efficacy of sorafenib for treating HCC. PMID- 24486413 TI - Synthesis of a new class of pyrrolo[3,4-h]quinazolines with antimitotic activity. AB - A new series of pyrrolo[3,4-h]quinazolines was conveniently prepared with a broad substitution pattern. A large number of derivatives was obtained and the cellular cytotoxicity was evaluated in vitro against 5 different human tumor cell lines with GI50 values reaching the low micromolar level (1.3-19.8 MUM). These compounds were able to induce cell death mainly by apoptosis through a mitochondrial dependent pathway. Selected compounds showed antimitotic activity and a reduction of tubulin polymerization in a concentration-dependent manner. Moreover, they showed anti-angiogenic properties since reduced in vitro endothelial cell migration and disrupted HUVEC capillary-like tube network in Matrigel. PMID- 24486414 TI - Synthesis and in vitro urease inhibitory activity of N,N'-disubstituted thioureas. AB - Thiourea derivatives (1-38) were synthesized and evaluated for their urease inhibition potential. The synthetic compounds showed a varying degree of in vitro urease inhibition with IC50 values 5.53 +/- 0.02-91.50 +/- 0.08 MUM, most of which are superior to the standard thiourea (IC50 = 21.00 +/- 0.11 MUM). In order to ensure the mode of inhibition of these compounds, the kinetic study of the most active compounds has been carried out. Most of these inhibitors were found to be mixed-type of inhibitors, except compounds 13 and 30 which were competitive, while compound 19 was identified as non-competitive inhibitor with Ki values between 8.6 and 19.29 MUM. PMID- 24486415 TI - Click chemistry approach: regioselective one-pot synthesis of some new 8 trifluoromethylquinoline based 1,2,3-triazoles as potent antimicrobial agents. AB - Three series of 8-trifluoromethylquinoline based 1,2,3-triazoles derivatives (5a c, 6a-d and 7a-c) were synthesized by multi-step reactions by click chemistry approach. Synthesized compounds were characterized by spectral studies and X-ray analysis. The final compounds were screened for their in-vitro antimicrobial activity by well plate method (zone of inhibition). Compounds 5c, 6b, 8b, 11 and 12 were found to be active against tested microbial strains. The results are summarized in Tables 5 and 6. PMID- 24486417 TI - Design, synthesis, pharmacological evaluation and computational studies of 1 (biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1-yl]ethanones as potential antipsychotics. AB - This article describes the design of biphenyl moiety linked with aryl piperazine and syntheses of fourteen 1-(biphenyl-4-yl)-2-[4-(substituted phenyl)-piperazin-1 yl]ethanone derivatives along with their pharmacological evaluation for antipsychotic activity and computational studies including quantitative structure activity relationship (QSAR) and descriptor based similarity study. All compounds were found to exhibit considerable anti-dopaminergic and anti-serotonergic activity in behavioural models. Among all derivatives, compound 1-(biphenyl-4-yl) 2-[4-(2-methoxyphenyl)-piperazin-1-yl]ethanone (3c) and 1-(biphenyl-4-yl)-2-[4 (2,3-dichlorophenyl)-piperazin-1-yl]ethanone (3k) showed impressive antipsychotic profile with lower potency for catalepsy induction. These results were found to be sturdily matching with docking study in designing of compounds with homology model of human dopamine D2 receptor. Also the QSAR study strongly supports the obtained results. PMID- 24486416 TI - Synthesis and evaluation of anti-tubercular activity of 6-(4-substitutedpiperazin 1-yl) phenanthridine analogues. AB - A series of seventeen new 6-(4-substitutedpiperazin-1-yl)phenanthridine derivatives were designed, synthesized, and evaluated for their anti-tubercular activity against Mycobacterium tuberculosis H37Rv by Microplate Alamar Blue Assay and most active compounds were tested for cytotoxicity studies against mouse macrophage cell lines (RAW264.7). Among the tested compounds, ten compounds exhibited significant activity against the growth of M. tuberculosis (MIC ranging from 1.56 to 6.25 MUg/mL). In particular, compounds 5e, 5j and 5k displayed excellent activity against the growth of M. tuberculosis (MIC 1.56 MUg/mL). The selectivity index values were found to be >25, indicating compounds likeliness in drug development for tuberculosis. The structure of 5k is substantiated by X-ray crystallographic study. Structure-activity correlation indicates the importance of substituent at 4th position of piperazinyl phenanthridine ring. PMID- 24486418 TI - Synthesis and 3D-QSAR study of 1,4-dihydropyridine derivatives as MDR cancer reverters. AB - A series of symmetrical and unsymmetrical 1,4-dihydropyridines were synthesized by a rapid, single pot microwave irradiation (MWI) based protocol along with conventional approach and characterized by NMR, IR and mass spectroscopic techniques. The compounds were evaluated for their tumor cell cytotoxicity in HL 60 tumor cells. A 3D-QSAR study using CoMFA and CoMSIA was carried out to decipher the factors governing MDR reversing ability in cancer. The resulting contour maps derived by the best 3D-QSAR models provide a good insight into the molecular features relevant to the biological activity in this series of analogs. 3D contour maps as a result of 3D-QSAR were utilized to identify some novel features that can be incorporated into the 1,4-dihydropyridine framework to enhance the activity. PMID- 24486419 TI - Synthesis and biological evaluation of 2-oxonicotinonitriles and 2 oxonicotinonitrile based nucleoside analogues. AB - Drug resistance and emergence of new pathogens highlight the need for developing new therapeutic agents. We focused on 2-oxonicotinonitrile (2-ONN) as derivative of the natural product 2-pyridinone.(1) Herein, we describe the synthesis of 2 ONNs bearing two aryl groups, which we coupled with organohalides, including three glycosyl bromides, to prepare the nucleoside analogues. Coupling occurred mostly at the 2-ONN ring nitrogen to give the aimed targets, and in a few cases, it happened at the 2-oxo position giving O-alkylation products. Free 2-ONNs and their acetylated nucleosides were tested against a number of viruses. The nucleoside analogue 2a(Ac) showed good anti SARS-CoV and anti influenza A (H5N1) activities. Additionally, 7b had good activity against Gram positive bacterium, Bacillis subtilis. PMID- 24486420 TI - GABAergic cell type diversity in the basolateral amygdala. AB - Here I review the diversity of GABAergic neurons in the rodent basolateral amygdala (BLA). In spite of the recent identification of the role played by certain neurons of BLA in learning and memory of fear, the diversity of GABAergic neurons has not been fully explored. I describe analogies and differences between GABAergic neurons in BLA and cerebral cortex. Emphasis is given to a comprehensive functional, neurochemical and anatomical classification of GABAergic neuron types. PMID- 24486421 TI - Chemical structure analyses of phosphorylated chitosan. AB - Chemical modification of chitosan to generate new bio-functional materials can bring more desirable properties depending on the nature of the groups introduced. Phosphorylated chitosan has attracted interests in recent years. The literature has reported that the phosphorylation of chitosan could be achieved through three different reaction routes, namely, in the presence of H3PO4/urea, H3PO4/Et3PO4/P2O5, or P2O5/CH3SO3H. However, the exact chemical structure of phosphorylated chitosan synthesized by different reaction routes has not been systematically studied and compared. Meanwhile, the most common opinion is that the hydroxyl group in chitosan is the main substitution site. In this work, phosphorylated chitosan was synthesized using three different reaction routes, and the chemical structures of the products were studied by infrared, X-ray photoelectron and (13)C NMR spectroscopic characterization. It was observed that in the reaction routes using H3PO4/urea and H3PO4/Et3PO4/P2O5, the amino groups were substituted instead of the hydroxyl groups. In the reaction route using P2O5/CH3SO3H, the amino groups were shielded by the ionic binding with CH3SO3H, and the C-6 hydroxyl groups were phosphorylated. Different structures of the phosphorylated chitosan were proposed based on the characterization results. PMID- 24486422 TI - Influence of methylphenidate on spatial attention asymmetry in adolescents with attention deficit hyperactivity disorder (ADHD): preliminary findings. AB - Atypical asymmetries of spatial attention have been reported in children with attention deficit hyperactivity disorder (ADHD) and may be exacerbated by non spatial factors such as attentional capacity. Although preliminary evidence suggests that asymmetries of attention in ADHD may be modifiable by the psychostimulant, methylphenidate, further placebo-controlled studies are required. This study first aimed to confirm recent evidence that increasing non spatial processing load at fixation can unmask a spatial gradient of target detection in children with ADHD but not Controls. Second, we used placebo controlled randomised trial methodology to ask whether 20mg of methylphenidate (MPH) could remediate any load-dependent asymmetry of spatial attention in adolescents with ADHD. Twelve male adolescents with ADHD were assessed twice in a double-blind, randomized design, under either placebo or an acute dose of methylphenidate. Thirteen typically developing adolescent Controls completed a single session under placebo. Participants completed a computer-based task in which they monitored a centrally presented rapid serial visual presentation stream for a probe stimulus, while also responding to brief peripheral events. The attentional load of the central task was manipulated by varying the target instructions but not the physical stimuli or the frequency of targets. Between group analyses under placebo conditions indicated that increased attentional load induced a spatial gradient for target detection in the ADHD but not Controls, such that load slowed response times for left, but not, right hemi-field targets. This load-dependent spatial asymmetry in the adolescents with ADHD was abolished by administration of methylphenidate. Methylphenidate may "normalise" target detection between the hemi-fields in ADHD via enhancement of the right lateralised ventral attention networks that support non-spatial attention. PMID- 24486423 TI - Mapping nociceptive stimuli in a peripersonal frame of reference: evidence from a temporal order judgment task. AB - The ability to localize nociceptive stimuli on the body surface is essential for an organism to respond appropriately to potential physical threats. This ability not only requires a representation of the space of the observer's body, but also of the external space with respect to their body. Therefore, localizing nociceptive stimuli requires coordinating multiple senses into an integrated frame of reference. The peripersonal frame of reference allows for the coding of the position of somatosensory stimuli on the body surface and the position of stimuli occurring close to the body (e.g., visual stimuli). Intensively studied for touch, this topic has been largely ignored when it comes to nociception. Here, we investigated, using a temporal order judgment task, whether the spatial perception of nociceptive stimuli is coordinated with that of proximal visual stimuli into an integrated representation of peripersonal space. Participants judged which of two nociceptive stimuli, one presented to either hand, had been presented first. Each pair of nociceptive stimuli was preceded by lateralized visual cues presented either unilaterally or bilaterally, and either close to, or far from, the participant's body. The perception of nociceptive stimuli was biased in favor of the stimulus delivered on the hand adjacent to the unilateral visual cue, especially when the cue was presented near the participant's hand. These results therefore suggest that a peripersonal frame of reference is used to map the position of nociceptive stimuli in multisensory space. We propose that peripersonal space constitutes a kind of margin of safety around the body to alert an organism to possible threats. PMID- 24486424 TI - Review of the effectiveness of transcranial magnetic stimulation for post traumatic stress disorder. AB - BACKGROUND: Post-traumatic stress disorder (PTSD) is a psychiatric condition with significant morbidity and limited treatment options. Transcranial magnetic stimulation (TMS) has been shown to be an effective treatment for mental illnesses including major depressive disorder. OBJECTIVE: Review effectiveness of TMS for PTSD. METHODS: Literature review with descriptions of primary studies as well as meta-analysis of studies with a control group. RESULTS: Eight primary studies were identified and three studies met criteria for meta-analysis. All studies suggest effectiveness of TMS for PTSD. Additionally, right-sided may be more effective than left-sided treatment, there is no clear advantage in high versus low frequency, and the treatment is generally well tolerated. Meta analysis shows significant effect size on PTSD symptoms that may be correlated with total number of stimulations. CONCLUSIONS: TMS for PTSD appears to be an effective and well-tolerated treatment that warrants additional study to further define treatment parameters, course, and side effects. PMID- 24486425 TI - Concurrent cognitive control training augments the antidepressant efficacy of tDCS: a pilot study. AB - BACKGROUND: Major depressive disorder (MDD) is frequently associated with underactivity of the dorsolateral prefrontal cortex (DLPFC) which has led to this brain region being identified as an important target for the development of neurobiological treatments. Transcranial direct current stimulation (tDCS) administered to the DLPFC has antidepressant efficacy, however the magnitude of antidepressant outcomes are limited. Concurrent cognitive activity has been shown to enhance tDCS induced stimulation effects. Cognitive control training (CCT) is a new cognitive therapy for MDD that aims to enhance DLPFC activity via behavioral methods. HYPOTHESIS: We tested the hypothesis that co-administration of DLPFC tDCS and CCT would result in a greater reduction in depressive symptomology than administration of tDCS or CCT alone. METHODS: 27 adult participants with MDD were randomized into a three-arm sham-controlled between groups pilot study comparing the efficacy of 2 mA tDCS + CCT, sham tDCS + CCT and sham CCT + 2 mA tDCS (5 sessions administered on consecutive working days). Blinded assessments of depression severity and cognitive control were conducted at baseline, end of treatment and a three week follow up review. RESULTS: All three treatment conditions were associated with a reduction in depression severity at the end of five treatment sessions. However, only administration of tDCS + CCT resulted in sustained antidepressant response at follow up, the magnitude of which was greater than that observed immediately following conclusion of the treatment course. CONCLUSIONS: The results provide preliminary evidence that concurrent CCT enhances antidepressant outcomes from tDCS. In the current sample, participants receiving concurrent tDCS and CCT continued to improve following cessation of treatment. The clinical superiority of a combined therapeutic approach was apparent even in a small sample and following a relatively short treatment course. PMID- 24486426 TI - Cost-effectiveness of supported employment for veterans with spinal cord injuries. AB - OBJECTIVE: To estimate the cost-effectiveness of a supported employment (SE) intervention that had been previously found effective in veterans with spinal cord injuries (SCIs). DESIGN: Cost-effectiveness analysis, using cost and quality of-life data gathered in a trial of SE for veterans with SCI. SETTING: SCI centers in the Veterans Health Administration. PARTICIPANTS: Subjects (N=157) who completed a study of SE in 6 SCI centers. Subjects were randomly assigned to the intervention of SE (n=81) or treatment as usual (n=76). INTERVENTION: A vocational rehabilitation program of SE for veterans with SCI. MAIN OUTCOME MEASURES: Costs and quality-adjusted life years, which were estimated from the Veterans Rand 36-Item Health Survey, extrapolated to Veterans Rand 6 Dimension utilities. RESULTS: Average cost for the SE intervention was $1821. In 1 year of follow-up, estimated total costs, including health care utilization and travel expenses, and average quality-adjusted life years were not significantly different between groups, suggesting the Spinal Cord Injury Vocational Integration Program intervention was not cost-effective compared with usual care. CONCLUSIONS: An intensive program of SE for veterans with SCI, which is more effective in achieving competitive employment, is not cost-effective after 1 year of follow-up. Longer follow-up and a larger study sample will be necessary to determine whether SE yields benefits and is cost-effective in the long run for a population with SCI. PMID- 24486427 TI - GLP-1 amidation efficiency along the length of the intestine in mice, rats and pigs and in GLP-1 secreting cell lines. AB - XXX: Measurements of plasma concentrations of the incretin hormone GLP-1 are complex because of extensive molecular heterogeneity. This is partly due to a varying and incompletely known degree of C-terminal amidation. Given that virtually all GLP-1 assays rely on a C-terminal antibody, it is essential to know whether or not the molecule one wants to measure is amidated. We performed a detailed analysis of extractable GLP-1 from duodenum, proximal jejunum, distal ileum, caecum, proximal colon and distal colon of mice (n=9), rats (n=9) and pigs (n=8) and determined the degree of amidation and whether this varied with the six different locations. We also analyzed the amidation in 3 GLP-1 secreting cell lines (GLUTag, NCI-H716 and STC-1). To our surprise there were marked differences between the 3 species with respect to the concentration of GLP-1 in gut. In the mouse, concentrations increased continuously along the intestine all the way to the rectum, but were highest in the distal ileum and proximal colon of the rat. In the pig, very little or no GLP-1 was present before the distal ileum with similar levels from ileum to distal colon. In the mouse, GLP-1 was extensively amidated at all sampling sites, whereas rats and pigs on average had around 2.5 and 4 times higher levels of amidated compared to non-amidated GLP-1, although the ratio varied depending upon the location. GLUTag, NCI-H716 and STC-1 cells all exhibited partial amidation with 2-4 times higher levels of amidated compared to non-amidated GLP-1. PMID- 24486428 TI - Opiorphin increases blood pressure of conscious rats through renin-angiotensin system (RAS). AB - Human opiorphin is a recently identified endogenous pentapeptide, encoded by ProL1 multigenes family that contributes to cardiovascular modulation. The aim of this study was to evaluate the effect of opiorphin through intravenous injection (i.v.) on mean arterial pressure (MAP) regulation. To investigate the bioactivity of opiorphin, a rat cannulation model was developed for MAP measurement and blood sampling. In our present study, opiorphin (200-700 nmol/kg) increased MAP in dose related and time-dependent manner in conscious rats, which associated highly with the elevation of angiotensin II (AngII) levels in serum. Furthermore, the MAP elevation induced by opiorphin was completely blocked by AngII receptor antagonist valsartan and partially attenuated by angiotensin-converting enzyme inhibitor captopril. Finally, we tested the effect of opiorphin in hypoxia condition, which exhibited that opiorphin reversed hypoxia induced hypotension in conscious rats. Taken together, these results indicated that opiorphin may play an important role in the modulation of blood pressure through AngII dependent pathway, which may help future development of potent clinical therapeutics for emergency treatment. PMID- 24486429 TI - Properties of apolipoprotein E derived peptide modulate their lipid-binding capacity and influence their anti-inflammatory function. AB - Apolipoprotein-derived peptides are promising candidates for the treatment of various inflammatory conditions. The beneficial effects of these peptides are based on multiple mechanisms; prominent among them being high-affinity binding to pro-inflammatory oxidized phospholipids (Ox-PLs) and facilitating their sequestration/metabolism/clearance in the body. This indicates that peptides which can bind exclusively to Ox-PLs without recognizing normal, non-oxidized phospholipids (non-Ox-PLs) will be more potent anti-inflammatory agent than that of the peptides that bind to both Ox-PLs and non-Ox-PLs. In order to develop such Ox-PL-specific peptides, the knowledge about the properties (molecular determinants) of peptides that govern their Ox-PL preference is a must. In this study we have synthesized eleven peptides corresponding to the conserved regions of human apolipoprotein E and compared their biochemical properties, lipid binding specificities, and anti-inflammatory properties. Our results show that these peptides exhibit considerably different specificities towards non-Ox-PL and different species of Ox-PLs. Some of these peptides bind exclusively to the Ox PLs and inhibit the pro-inflammatory function of Ox-PLs in human blood. Biochemical characterization revealed that the peptides possess substantially different properties. Our results suggest that physicochemical properties of peptides play an important role in their lipid-binding specificity. PMID- 24486431 TI - WITHDRAWN: Successful bipolar catheter ablation of ventricular premature complex from the posterior papillary muscle. AB - This article has been withdrawn at the request of the author(s) and/or editor. The Publisher apologizes for any inconvenience this may cause. The full Elsevier Policy on Article Withdrawal can be found at http://www.elsevier.com/locate/withdrawalpolicy. PMID- 24486430 TI - A unique co-culture model for fundamental and applied studies of human fetoplacental steroidogenesis and interference by environmental chemicals. AB - BACKGROUND: Experimental tools for studying the complex steroidogenic interactions that occur between placenta and fetus during human pregnancy are extremely limited. OBJECTIVES: We aimed to develop a co-culture model to study steroidogenesis by the human fetoplacental unit and its disruption by exposure to environmental contaminants. METHODS: We cultured BeWo human choriocarcinoma cells, representing the villous cytotrophoblast, and H295R human adrenocortical carcinoma cells, representing the fetal unit, in a carefully adapted co-culture medium. We placed H295R cells in 24-well plates and BeWo cells on transwell inserts with or without pesticide treatment (atrazine or prochloraz) and assessed CYP19 activity and hormonal production after 24 hr of co-culture. RESULTS: The co culture exhibited the steroidogenic profile of the fetoplacental unit, allowing a synergistic production of estradiol and estriol (but not of estrone) of 133.3 +/- 11.3 pg/mL and 440.8 +/- 44.0 pg/mL, respectively. Atrazine and prochloraz had cell-type specific effects on CYP19 activity and estrogen production in co culture. Atrazine induced CYP19 activity and estrogen production in H295R cells only, but did not affect overall estrogen production in co-culture, whereas prochloraz inhibited CYP19 activity exclusively in BeWo cells and reduced estrogen production in co-culture by almost 90%. In contrast, prochloraz did not affect estradiol or estrone production in BeWo cells in monoculture. These differential effects underline the relevance of our co-culture approach to model fetoplacental steroidogenesis. CONCLUSIONS: The co-culture of H295R and BeWo cells creates a unique in vitro model to reproduce the steroidogenic cooperation between fetus and placenta during pregnancy and can be used to study the endocrine-disrupting effects of environmental chemicals. PMID- 24486432 TI - Mid-term follow up of thromboembolic complications in left ventricular endocardial cardiac resynchronization therapy. AB - BACKGROUND: Endocardial left ventricular (LV) pacing for cardiac resynchronization therapy (CRT) has been proposed as an alternative to traditional LV transvenous epicardial pacing with equal or superior cardiac performance. The risks of cerebral thromboembolism and possible interference with mitral valve function moderate its clinical application. OBJECTIVE: The purpose of this study was to investigate cerebral thromboembolic complications after LV endocardial lead placement. Mitral regurgitation (MR) was the secondary outcome measure. METHODS: CRT candidates with a failed coronary sinus approach or nonresponders to conventional CRT underwent endocardial LV lead implantation (45 atrial transseptal, 6 transapical). Coumarin was prescribed with a targeted international normalized ratio between 3.5 and 4.5. Patient records were checked and general practitioners were contacted regarding cerebral thromboembolic complications. MR was evaluated by echocardiography at baseline and after 6 months. RESULTS: In 7 patients, 6 ischemic strokes and 2 transient ischemic attacks occurred, corresponding to 6.1 thromboembolic events per 100 patient years (95% confidence interval 3.4-15.8). One patient refused hospital admission; all other patients had a subtherapeutic anticoagulation level at the time of the event. No major bleeding complications occurred. There was no change in the grade of MR (grade 2, P = .727) after 6 months. CONCLUSION: Endocardial LV lead placement in patients with advanced heart failure is associated with thromboembolic risk. However, all but 1 patient had a subtherapeutic level of anticoagulation. Endocardial LV lead placement is not associated with aggravation of MR. PMID- 24486433 TI - Force-dependent melting of supercoiled DNA at thermophilic temperatures. AB - Local DNA opening plays an important role in DNA metabolism as the double-helix must be melted before the information contained within may be accessed. Cells finely tune the torsional state of their genomes to strike a balance between stability and accessibility. For example, while mesophilic life forms maintain negatively superhelical genomes, thermophilic life forms use unique mechanisms to maintain relaxed or even positively supercoiled genomes. Here, we use a single molecule magnetic tweezers approach to quantify the force-dependent equilibrium between DNA melting and supercoiling at high temperatures populated by Thermophiles. We show that negatively supercoiled DNA denatures at 0.5 pN lower tension at thermophilic vs. mesophilic temperatures. This work demonstrates the ability to monitor DNA supercoiling at high temperature and opens the possibility to perform magnetic tweezers assays on thermophilic systems. The data allow for an estimation of the relative energies of base-pairing and DNA bending as a function of temperature and support speculation as to different general mechanisms of DNA opening in different environments. Lastly, our results imply that average in vivo DNA tensions range between 0.3 and 1.1 pN. PMID- 24486434 TI - Sesquiterpene dimmer (DSF-27) inhibits the release of neuroinflammatory mediators from microglia by targeting spleen tyrosine kinase (Syk) and Janus kinase 2 (Jak2): Two major non-receptor tyrosine signaling proteins involved in inflammatory events. AB - Non-receptor protein tyrosine kinases (NRPTKs)-dependent inflammatory signal transduction cascades play key roles in immunoregulation. However, drug intervention through NRPTKs-involved immunoregulation mechanism in microglia (the major immune cells of the central nervous system) has not been widely investigated. A main aim of the present study is to elucidate the contribution of two major NRPTKs (Syk and Jak2) in neuroinflammation suppression by a bioactive sesquiterpene dimmer (DSF-27). We found that LPS-stimulated BV-2 cells activated Syk and further initiated Akt/NF-kappaB inflammatory pathway. This Syk-dependent Akt/NF-kappaB inflammatory pathway can be effectively ameliorated by DSF-27. Moreover, Jak2 was activated by LPS, which was followed by transcriptional factor Stat3 activation. The Jak2/Stat3 signal was suppressed by DSF-27 through inhibition of Jak2 and Stat3 phosphorylation, promotion of Jak/Stat3 inhibitory factors PIAS3 expression, and down-regulation of ERK and p38 MAPK phosphorylation. Furthermore, DSF-27 protected cortical and mesencephalic dopaminergic neurons against neuroinflammatory injury. Taken together, our findings indicate NRPTK signaling pathways including Syk/NF-kappaB and Jak2/Stat3 cascades are potential anti-neuroinflammatory targets in microglia, and may also set the basis for the use of sesquiterpene dimmer as a therapeutic approach for neuroinflammation via interruption of these pathways. PMID- 24486436 TI - Oxidative stress/reactive metabolite gene expression signature in rat liver detects idiosyncratic hepatotoxicants. AB - Previously we reported a gene expression signature in rat liver for detecting a specific type of oxidative stress (OS) related to reactive metabolites (RM). High doses of the drugs disulfiram, ethinyl estradiol and nimesulide were used with another dozen paradigm OS/RM compounds, and three other drugs flutamide, phenacetin and sulindac were identified by this signature. In a second study, antiepileptic drugs were compared for covalent binding and their effects on OS/RM; felbamate, carbamazepine, and phenobarbital produced robust OS/RM gene expression. In the present study, liver RNA samples from drug-treated rats from more recent experiments were examined for statistical fit to the OS/RM signature. Of all 97 drugs examined, in addition to the nine drugs noted above, 19 more were identified as OS/RM-producing compounds-chlorpromazine, clozapine, cyproterone acetate, dantrolene, dipyridamole, glibenclamide, isoniazid, ketoconazole, methapyrilene, naltrexone, nifedipine, sulfamethoxazole, tamoxifen, coumarin, ritonavir, amitriptyline, valproic acid, enalapril, and chloramphenicol. Importantly, all of the OS/RM drugs listed above have been linked to idiosyncratic hepatotoxicity, excepting chloramphenicol, which does not have a package label for hepatotoxicity, but does have a black box warning for idiosyncratic bone marrow suppression. Most of these drugs are not acutely toxic in the rat. The OS/RM signature should be useful to avoid idiosyncratic hepatotoxicity of drug candidates. PMID- 24486435 TI - Association between arsenic exposure from drinking water and hematuria: results from the Health Effects of Arsenic Longitudinal Study. AB - Arsenic (As) exposure has been associated with both urologic malignancy and renal dysfunction; however, its association with hematuria is unknown. We evaluated the association between drinking water As exposure and hematuria in 7843 men enrolled in the Health Effects of Arsenic Longitudinal Study (HEALS). Cross-sectional analysis of baseline data was conducted with As exposure assessed in both well water and urinary As measurements, while hematuria was measured using urine dipstick. Prospective analyses with Cox proportional regression models were based on urinary As and dipstick measurements obtained biannually since baseline up to six years. At baseline, urinary As was significantly related to prevalence of hematuria (P-trend<0.01), with increasing quintiles of exposure corresponding with respective prevalence odds ratios of 1.00 (reference), 1.29 (95% CI: 1.04 1.59), 1.41 (95% CI: 1.15-1.74), 1.46 (95% CI: 1.19-1.79), and 1.56 (95% CI: 1.27 1.91). Compared to those with relatively little absolute urinary As change during follow-up (-10.40 to 41.17 MUg/l), hazard ratios for hematuria were 0.99 (95% CI: 0.80-1.22) and 0.80 (95% CI: 0.65-0.99) for those whose urinary As decreased by >47.49 MUg/l and 10.87 to 47.49 MUg/l since last visit, respectively, and 1.17 (95% CI: 0.94-1.45) and 1.36 (95% CI: 1.10-1.66) for those with between-visit increases of 10.40 to 41.17 MUg/l and >41.17 MUg/l, respectively. These data indicate a positive association of As exposure with both prevalence and incidence of dipstick hematuria. This exposure effect appears modifiable by relatively short-term changes in drinking water As. PMID- 24486437 TI - Small synthetic hyaluronan disaccharides afford neuroprotection in brain ischemia related models. AB - High molecular weight (HMW) glycosaminoglycanes of the extracellular matrix have been implicated in tissue repair. The aim of this study was to evaluate if small synthetic hyaluronan disaccharides with different degrees of sulfation (methyl 2 acetamido-2-deoxy-3-O-(beta-d-glucopyranosyluronic acid)-O-sulfo-alpha-d glucopyranoside, sodium salt (di0S), methyl 2-acetamido-2-deoxy-3-O-(beta-d glucopyranosyluronic acid)-6-di-O-sulfo-alpha-d-glucopyranoside, disodium salt (di6S) and methyl 2-acetamido-2-deoxy-3-O-(beta-d-glucopyranosyluronic acid)-4,6 di-O-sulfo-alpha-d-glucopyranoside, trisodium salt (di4,6S)) could improve cell survival in in vitro and in vivo brain ischemia-related models. Rat hippocampal slices subjected to oxygen and glucose deprivation and a photothrombotic stroke model in mice were used. The three hyaluran disaccharides, incubated during the oxygen and glucose deprivation (15min) and re-oxygenation periods (120min), reduced cell death of hippocampal slices measured as 3-(4,5-dimethylthiazol-2-yl) 2,5-diphenyltetrazolium bromide reduction, being the most potent di4,6S; in contrast, high molecular hyaluronan was ineffective. The protective actions of di4,6S against oxygen and glucose deprivation were related to activation of the PI3K/Akt survival pathway, reduction of p65 translocation to the nucleus, inhibition of inducible nitric oxide oxidase induction and reactive oxygen species production, and to an increase in glutathione levels. Administered 1h post-stroke, di4,6S reduced cerebral infarct size and improved motor activity in the beam walk test. In conclusion, di4,6S affords neuroprotection in in vitro and in vivo models of ischemic neuronal damage. Our results suggest that its neuroprotective effect could be exerted through its capability to reduce oxidative stress during ischemia. Its small molecular size makes it a more potential druggable drug to target the brain as compared with its HMW parent compound hyaluronan. PMID- 24486438 TI - Inter-hemispheric functional connectivity changes with corpus callosum morphology in multiple sclerosis. AB - Multiple sclerosis (MS) affects myelin sheaths within the central nervous system, concurring to cause brain atrophy and neurodegeneration as well as gradual functional disconnections. To explore early signs of altered connectivity in MS from a structural and functional perspective, the morphology of corpus callosum (CC) was correlated with a dynamic inter-hemispheric connectivity index. Twenty mildly disabled patients affected by a relapsing-remitting (RR) form of MS (EDSS?3.5) and 15 healthy subjects underwent structural MRI to measure CC thickness over 100 sections and electroencephalography to assess a spectral coherence index between primary regions devoted to hand control, at rest and during an isometric handgrip. In patients, an overall CC atrophy was associated with increased lesion load. A less efficacious inter-hemispheric coherence (IHCoh) during movement was associated with CC atrophy in sections interconnecting homologous primary motor areas (anterior mid-body). In healthy controls, less efficacious IHCoh at rest was associated with a thinner CC splenium. Our data suggest that in mildly disabled RR-MS patients a covert impairment may be detected in the correlation between the structural (CC thickness) and functional (IHCoh) measures of homologous networks, whereas these two counterparts do not yet differ individually from controls. PMID- 24486439 TI - Loss of duplexmiR-223 (5p and 3p) aggravates myocardial depression and mortality in polymicrobial sepsis. AB - Sepsis is the leading cause of death in critically ill patients. While myocardial dysfunction has been recognized as a major manifestation in severe sepsis, the underlying molecular mechanisms associated with septic cardiomyopathy remain unclear. In this study, we performed a miRNA array analysis in hearts collected from a severe septic mouse model induced by cecal ligation and puncture (CLP). Among the 19 miRNAs that were dys-regulated in CLP-mouse hearts, miR-223(3p) and miR-223*(5p) were most significantly downregulated, compared with sham-operated mouse hearts. To test whether a drop of miR-223 duplex plays any roles in sepsis induced cardiac dysfunction and inflammation, a knockout (KO) mouse model with a deletion of the miR-223 gene locus and wild-type (WT) mice were subjected to CLP or sham surgery. We observed that sepsis-induced cardiac dysfunction, inflammatory response and mortality were remarkably aggravated in CLP-treated KO mice, compared with control WTs. Using Western-blotting and luciferase reporter assays, we identified Sema3A, an activator of cytokine storm and a neural chemorepellent for sympathetic axons, as an authentic target of miR-223* in the myocardium. In addition, we validated that miR-223 negatively regulated the expression of STAT-3 and IL-6 in mouse hearts. Furthermore, injection of Sema3A protein into WT mice revealed an exacerbation of sepsis-triggered inflammatory response and myocardial depression, compared with control IgG1 protein-treated WT mice following CLP surgery. Taken together, these data indicate that loss of miR 223/-223* causes an aggravation of sepsis-induced inflammation, myocardial dysfunction and mortality. Our study uncovers a previously unrecognized mechanism underlying septic cardiomyopathy and thereby, may provide a new strategy to treat sepsis. PMID- 24486440 TI - Engineering biotin prototrophic Corynebacterium glutamicum strains for amino acid, diamine and carotenoid production. AB - The Gram-positive Corynebacterium glutamicum is auxotrophic for biotin. Besides the biotin uptake system BioYMN and the transcriptional regulator BioQ, this bacterium possesses functional enzymes for the last three reactions of biotin synthesis starting from pimeloyl-CoA. Heterologous expression of bioF from the Gram-negative Escherichia coli enabled biotin synthesis from pimelic acid added to the medium, but expression of bioF together with bioC and bioH from E. coli did not entail biotin prototrophy. Heterologous expression of bioWAFDBI from Bacillus subtilis encoding another biotin synthesis pathway in C. glutamicum allowed for growth in biotin-depleted media. Stable growth of the recombinant was observed without biotin addition for eight transfers to biotin-depleted medium while the empty vector control stopped growth after the first transfer. Expression of bioWAFDBI from B. subtilis in C. glutamicum strains overproducing the amino acids l-lysine and l-arginine, the diamine putrescine, and the carotenoid lycopene, respectively, enabled formation of these products under biotin-depleted conditions. Thus, biotin-prototrophic growth and production by recombinant C. glutamicum were achieved. PMID- 24486441 TI - The pyruvate dehydrogenase complex of Corynebacterium glutamicum: an attractive target for metabolic engineering. AB - The pyruvate dehydrogenase complex (PDHC) catalyzes the oxidative thiamine pyrophosphate-dependent decarboxylation of pyruvate to acetyl-CoA and CO2. Since pyruvate is a key metabolite of the central metabolism and also the precursor for several relevant biotechnological products, metabolic engineering of this multienzyme complex is a promising strategy to improve microbial production processes. This review summarizes the current knowledge and achievements on metabolic engineering approaches to tailor the PDHC of Corynebacterium glutamicum for the bio-based production of l-valine, 2-ketosiovalerate, pyruvate, succinate and isobutanol and to improve l-lysine production. PMID- 24486442 TI - Metabolic engineering of Corynebacterium glutamicum for glycolate production. AB - Corynebacterium glutamicum - a well-known industrial amino acid producer - has recently been engineered for the production of a variety of new products including diamines, alcohols, carotenoids and organic acids. Glycolic acid was shown here not to serve as sole or combined carbon source for C. glutamicum. Glycolate affected growth of C. glutamicum only at high concentrations (460mM) and in a comparable manner as other salts (480mM potassium chloride and 490mM sodium chloride). A transcriptome analysis of cells grown in the presence of glycolate or potassium chloride revealed nine glycolate-specific gene expression changes including increased levels of a putative l-lactate permease gene when glycolate was present in medium. Subsequently, glycolate was shown to interfere with l-lactate utilization but not with growth with acetate or pyruvate. Heterologous expression of the glyoxylate reductase gene ycdW from Escherchia coli resulted in a titer of 0.4g/L glycolate in minimal medium with glucose and acetate. Deletion of the malate synthase gene aceB improved glycolate titer by about tenfold. Reducing isocitrate dehydrogenase activity by replacing the translational start codon (ATG to GTG) further increased glycolate titer by more than 30%. The production of 5.3+/-0.1g/L glycolate with a yield of 0.18g/g and a volumetric productivity of about 0.1gL(-1)h(-1) is the first report of a C. glutamicum strain capable of glycolate production. PMID- 24486443 TI - Novel type of red-shifted chlorophyll a antenna complex from Chromera velia: II. Biochemistry and spectroscopy. AB - A novel chlorophyll a containing pigment-protein complex expressed by cells of Chromera velia adapted to growth under red/far-red illumination [1]. Purification of the complex was achieved by means of anion-exchange chromatography and gel filtration. The antenna is shown to be an aggregate of ~20kDa proteins of the light-harvesting complex (LHC) family, unstable in the isolated form. The complex possesses an absorption maximum at 705nm at room temperature in addition to the main chlorophyll a maximum at 677nm producing the major emission band at 714nm at room temperature. The far-red absorption is shown to be the property of the isolated aggregate in the intact form and lost upon dissociation. The purified complex was further characterized by circular dichroism spectroscopy and fluorescence spectroscopy. This work thus identified the third different class of antenna complex in C. velia after the recently described FCP-like and LHCr-like antennas. Possible candidates for red antennas are identified in other taxonomic groups, such as eustigmatophytes and the relevance of the present results to other known examples of red-shifted antenna from other organisms is discussed. This work appears to be the first successful isolation of a chlorophyll a-based far-red antenna complex absorbing above 700nm unrelated to LHCI. PMID- 24486444 TI - Electrochemically produced hydrogen peroxide affects Joliot-type oxygen-evolution measurements of photosystem II. AB - The main technique employed to characterize the efficiency of water-splitting in photosynthetic preparations in terms of miss and double hit parameters and for the determination of Si (i=2,3,0) state lifetimes is the measurement of flash induced oxygen oscillation pattern on bare platinum (Joliot-type) electrodes. We demonstrate here that this technique is not innocent. Polarization of the electrode against an Ag/AgCl electrode leads to a time-dependent formation of hydrogen peroxide by two-electron reduction of dissolved oxygen continuously supplied by the flow buffer. While the miss and double hit parameters are almost unaffected by H2O2, a time dependent reduction of S1 to S-1 occurs over a time period of 20 min. The S1 reduction can be largely prevented by adding catalase or by removing O2 from the flow buffer with N2. Importantly, we demonstrate that even at the shortest possible polarization times (40s in our set up) the S2 and S0 decays are significantly accelerated by the side reaction with H2O2. The removal of hydrogen peroxide leads to unperturbed S2 state data that reveal three instead of the traditionally reported two phases of decay. In addition, even under the best conditions (catalase+N2; 40s polarization) about 4% of S-1 state is observed in well dark-adapted samples, likely indicating limitations of the equal fit approach. This article is part of a special issue entitled: photosynthesis research for sustainability: keys to produce clean energy. PMID- 24486445 TI - Epigallocatechin gallate counteracts oxidative stress in docosahexaenoxic acid treated myocytes. AB - Skeletal muscle is a key organ of mammalian energy metabolism, and its mitochondria are multifunction organelles that are targets of dietary bioactive compounds. The goal of this work was to examine the regulation of mitochondrial dynamics, functionality and cell energy parameters using docosahexaenoic acid (DHA), epigallocatechin gallate (EGCG) and a combination of both in L6 myocytes. Compounds (at 25MUM) were incubated for 4h. Cells cultured with DHA displayed less oxygen consumption with higher ADP/ATP ratio levels concomitant with downregulation of Cox and Ant1 gene expression. The disruption of energetic homeostasis by DHA, increases intracellular reactive oxygen species (ROS) levels and decreases mitochondrial membrane potential. The defence mechanism to counteract the excess of ROS production was by the upregulation of Ucp2, Ucp3 and MnSod gene expression. Moreover myocytes cultured with DHA had a higher mitochondrial mass with a higher proportion of large and elongated mitochondria, whereas the fission genes Drp1 and Fiss1 and the fusion gene Mfn2 were downregulated. In myocytes co-incubated with DHA and EGCG, ROS levels and the adenosine diphosphate (ADP)/adenosine triphosphate (ATP) ratio were similar to untreated myocytes and the decrease of oxygen consumption, higher mitochondrial mass and the overexpression of Ucp2 and Ucp3 genes were similar to the DHA treated cells with also a higher amount of mitochondrial deoxyribonucleic acid (DNA), and reduced Drp1 and Fiss1 gene expression levels. In conclusion the addition of EGCG to DHA returned the cells to the control conditions in terms of mitochondrial morphology, energy and redox status, which were unbalanced in the DHA-treated myocytes. PMID- 24486447 TI - SQSTM1 mutations--bridging Paget disease of bone and ALS/FTLD. AB - Paget disease of bone (PDB) is a skeletal disorder common in Western Europe but extremely rare in the Indian subcontinent and Far East. The condition has a strong genetic element with mutations affecting the SQSTM1 gene, encoding the p62 protein, frequently identified. Recently SQSTM1 mutations have also been reported in a small number of patients with amyotrophic lateral sclerosis (ALS) and frontotemporal lobar degeneration (FTLD), neurodegenerative disorders in which significant coexistence with PDB has not been previously recognized. Although several SQSTM1 mutations are common to both ALS/FTLD and PDB, many are ALS/FTLD specific. The p62 protein regulates various cellular processes including NF kappaB signaling and autophagy pathways. Here we consider how knowledge of the impact of PDB-associated SQSTM1 mutations (several of which are now known to be relevant for ALS/FTLD) on these pathways, as well as the locations of the mutations within the p62 primary sequence, may provide new insights into ALS/FTLD disease mechanisms. PMID- 24486446 TI - Multifunctional ECM proteins in bone and teeth. AB - The extracellular matrix (ECM) of all tissues and organs is a highly organized and complex structure unique to the specific organ type. The ECM contains structural and functional proteins that define cellular function, organization, behavior and ultimately organ characteristics and function. The ECM was initially thought to contain only a specific set of secretory proteins. However, our group and several other groups have shown that the ECM contains functional proteins that have been previously defined as solely intracellular. In the present review, we have focused on the ECM of mineralized tissues namely bone and dentin. We provide here, a brief review of some non-classical ECM proteins that have been shown to possess both intra and extracellular roles in the formation of these mineralized matrices. PMID- 24486449 TI - Characterization of the anisotropic mechanical behaviour of colonic tissues: experimental activity and constitutive formulation. AB - The aim was to investigate the biomechanical behaviour of colonic tissues by a coupled experimental and numerical approach. The wall of the colon is composed of different tissue layers. Within each layer, different fibre families are distributed according to specific spatial orientations, which lead to a strongly anisotropic configuration. Accounting for the complex histology of the tissues, mechanical tests must be planned and designed to evaluate the behaviour of the colonic wall in different directions. Uni-axial tensile tests were performed on tissue specimens from 15 fresh pig colons, accounting for six different loading directions (five specimens for each loading direction). The next step of the investigation was to define an appropriate constitutive framework and develop a procedure for identification of the constitutive parameters. A specific hyperelastic formulation was developed that accounted for the multilayered conformation of the colonic wall and the fibre-reinforced configuration of the tissues. The parameters were identified by inverse analyses of the mechanical tests. The comparison of model results with experimental data, together with the evaluation of satisfaction of material thermomechanics principles, confirmed the reliability of the analysis developed. This work forms the basis for more comprehensive activities that aim to provide computational tools for the interpretation of surgical procedures that involve the gastrointestinal tract, considering the specific biomedical devices adopted. PMID- 24486448 TI - The dynamic metabolism of hyaluronan regulates the cytosolic concentration of UDP GlcNAc. AB - Hyaluronan, a macromolecular glycosaminoglycan, is normally synthesized by hyaluronan synthases at the plasma membrane using cytosolic UDP-GlcUA and UDP GlcNAc substrates and extruding the elongating chain into the extracellular space. The cellular metabolism (synthesis and catabolism) of hyaluronan is dynamic. UDP-GlcNAc is also the substrate for O-GlcNAc transferase, which is central to the control of many cytosolic pathways. This Perspective outlines recent data for regulation of hyaluronan synthesis and catabolism that support a model that hyaluronan metabolism can be a rheostat for controlling an acceptable normal range of cytosolic UDP-GlcNAc concentrations in order to maintain normal cell functions. PMID- 24486450 TI - Six hospitals are named as "outliers" for mortality rates. PMID- 24486451 TI - Obama challenges Republicans to offer alternatives to health act. PMID- 24486452 TI - Peers vote to legislate against smoking in cars with children. PMID- 24486453 TI - Inhibitory effects of mitotane on viability and secretory activity in mouse gonadotroph cell lines. AB - Mitotane represents the mainstay medical treatment for metastatic, inoperable or recurrent adrenocortical carcinoma. Besides the well-known adverse events, mitotane therapy is associated also with endocrinological effects, including sexual and reproductive dysfunction. The majority of male patients undergoing adjuvant mitotane therapy show a picture of hypogonadism, characterized by low free testosterone and high sex hormone binding globulin levels and unmodified LH concentrations. Since mitotane has been shown to have direct pituitary effects, we investigated whether mitotane may influence both cell viability and function of gonadotroph cells in the settings of two pituitary cell lines. We found that mitotane reduces cell viability, induces apoptosis, modifies cell cycle phase distribution and secretion of gonadotroph cells. The present data strengthen previous evidence showing a direct mitotane effect at pituitary level and represent a possible explanation of the lack of LH increase following decrease in free testosterone in patients undergoing adjuvant mitotane therapy. PMID- 24486454 TI - Characteristics of 17beta-hydroxysteroid dehydrogenase 8 and its potential role in gonad of Zhikong scallop Chlamys farreri. AB - 17beta-Hydroxysteroid dehydrogenases (17beta-HSDs) are important enzymes catalyzing steroids biosynthesis and metabolism in vertebrates. Although studies indicate steroids play a potential role in reproduction of molluscs, little is known about the presence and function of 17beta-HSDs in molluscs. In the present study, a full-length cDNA encoding 17beta-HSD type 8 (17beta-HSD8) was identified in the Zhikong scallop Chlamys farreri, which is 1104bp in length with an open reading frame of 759bp encoding a protein of 252 amino acids. Phylogenetic analysis revealed that the C. farreri 17beta-HSD8 (Cf-17beta-HSD8) belongs to the short chain dehydrogenase/reductase family (SDR) and shares high homology with other 17beta-HSD8 homologues. Catalytic activity assay in vitro demonstrated that the refolded Cf-17beta-HSD8 expressed in Escherichia coli could effectively convert estradiol-17beta (E2) to estrone (E1), and weakly catalyze the conversion of testosterone (T) to androstenedione (A) in the presence of NAD(+). The Cf 17beta-HSD8 mRNA was ubiquitously expressed in all tissues analyzed, including gonads. The expression levels of Cf-17beta-HSD8 mRNA and protein increased with gametogenesis in both ovary and testis, and were significantly higher in testis than in ovary at growing stage and mature stage. Moreover, results of in situ hybridization and immunohistochemistry revealed that the mRNA and protein of Cf 17beta-HSD8 were expressed in follicle cells and gametes at all stages except spermatozoa. Our findings suggest that Cf-17beta-HSD8 may play an important role in regulating gametogenesis through modulating E2 levels in gonad of C. farreri. PMID- 24486455 TI - Ginsenoside-mediated blockade of 1alpha,25-dihydroxyvitamin D3 inactivation in human liver and intestine in vitro. AB - The beneficial effects of vitamin D3 are exerted through 1alpha,25 dihydroxyvitamin D3 [1alpha,25(OH)2D3], the dihydroxy metabolite of vitamin D3. Hepatic and intestinal biotransformation of 1alpha,25(OH)2D3 and modifiers of metabolic capacity could be important determinants of bioavailability in serum and tissues. Ginsenosides and their aglycones, mainly 20(S)-protopanaxadiol (aPPD) and 20(S)-protopanaxatriol (aPPT), are routinely ingested as health supplements. The purpose of the present study was to investigate the potential of ginsenosides and their aglycones to block hepatic and intestinal inactivation of 1alpha,25(OH)2D3, which is the most potent ligand of vitamin D receptor. In vitro biotransformation reactions were initiated with NADPH regenerating solutions following initial preincubation of pooled human hepatic or intestinal microsomal protein or human recombinant CYP3A4 supersomes with 1alpha,25(OH)2D3 or midazolam. Formation of hydroxylated metabolites of 1alpha,25(OH)2D3 or midazolam was analyzed using liquid chromatography-mass spectrometry. Co-incubation of 1alpha,25(OH)2D3 with various ginsenosides (Rg1, Rh2, aPPD, aPPT and total ginsenosides) led to differential inhibition (30-100%) of its hydroxylation. Results suggest that aPPD, aPPT and Rh2 strongly attenuated the hydroxylation of 1alpha,25(OH)2D3. Follow up inhibition studies with aPPD and aPPT at varying concentrations (0.5-100MUM) led to up to 91-100% inhibition of formation of hydroxylated metabolites of 1alpha,25(OH)2D3 thus preventing inactivation of active vitamin D3. The IC50 values of aPPD or aPPT for the most abundant hydroxylated metabolites of 1alpha,25(OH)2D3 ranged from 3.3 to 9.0MUM in human microsomes. The inhibitory mechanism of aPPD or aPPT for CYP3A4-mediated biotransformation of 1alpha,25(OH)2D3 was competitive in nature (apparent Ki: 1.7 2.9MUM). Similar inhibitory effects were also observed upon addition of aPPD or aPPT into midazolam hydroxylation assay. In summary, our results suggest that ginsenosides, specifically aPPD and aPPT, inhibit the CYP3A4-mediated catabolism of active vitamin D3 in human liver and intestine, potentially providing additional vitamin D-related benefits to patients with cancer, neurodegenerative and metabolic diseases. PMID- 24486456 TI - A potential link between bacterial pathogens and allergic conjunctivitis by dendritic cells. AB - The association and mechanism of bacteria linking to the allergic inflammation have not been well elucidated. This study was to explore a potential link between bacterial pathogens and allergic conjunctivitis by dendritic cells (DCs). Bone marrow-derived DCs from BALB/c and MyD88 knockout mice were treated with or without bacterial pathogens or thymic stromal lymphopoietin (TSLP). Two murine models of the topical challenge with LPS or flagellin and experimental allergic conjunctivitis (EAC) were used for in vivo study. The mRNA expression was determined by reverse transcription and real time PCR, and protein production was evaluated by ELISA, Western blotting, immunofluorescent staining and flow cytometry. TSLP mRNA and protein were found to be largely induced by DCs challenged with microbial pathogens, highly by lipopolysaccharide (LPS) and flagellin. The expression of MyD88, NFkappaB1, NFkappaB2 and RelA accompanied by NFkappaB p65 nuclear translocation and TSLP induction were significantly stimulated by flagellin, but blocked by TLR5 antibody or NFkappaB inhibitor in DCs from MyD88(+/+) but not MyD88(-/-) mice. TSLP promoted the expression of CD40, CD80, OX40 ligand (OX40L), IL-13 and CCL17 by DCs. TSLP-producing DCs were identified in vivo in ocular surface conjunctiva and draining cervical lymph nodes from two murine models of topical challenge with LPS or flagellin, and EAC in BALB/c mice. TSLP/TSLPR/OX40L signaling was observed in DCs of EAC mice. Our findings demonstrate that DCs not only respond to TSLP, but also produce TSLP via TLR/MyD88/NFkappaB pathways in response to bacterial pathogens, suggesting a potential link between bacteria and allergic disease. PMID- 24486457 TI - Effects of vitamin B12 on the corneal nerve regeneration in rats. AB - The study was designed to investigate the effects of a new ophthalmic solution containing 0.05% vitamin B12 0.05% on corneal nerve regeneration in rats after corneal injury. Eyes of anesthetized male Wistar rats were subjected to corneal injury by removing the corneal epithelium with corneal brush (Algerbrush). After the epithelial debridement, the right eye of each animal received the instillation of one drop of the ophthalmic solution containing vitamin B12 0.05% plus taurine 0.5% and sodium hyaluronate 0.5% four time per day for 10 or 30 days. Left eyes were used as control and treated with solution containing taurine 0.5% and sodium hyaluronate 0.5% alone following the same regimen. Fluorescein staining by slit-lamp and morphological analysis was used to determine corneal wound healing. Immunohistochemistry, immunoblot and confocal microscopy were used to examine corneal re-innervation. Slit-lamp and histological analyses showed that re-epithelization of the corneas was accelerated in rats treated with vitamin B12. A clear-cut difference between the two groups of rats was seen after 10 days of treatment, whereas a near-to-complete re-epithelization was observed in both groups at 30 days. Vitamin B12 treatment had also a remarkable effect on corneal re-innervation, as shown by substantial increased in the expression of neurofilament 160 and beta-III tubulin at both 10 and 30 days. The presence of SV2A-positive nerve endings suggests the presence of synapse-like specialized structures in corneal epithelium of the eye treated with vitamin B12. Our findings suggest that vitamin B12 treatment represents a powerful strategy to accelerate not only re-epithelization but also corneal re-innervation after mechanical injury. PMID- 24486458 TI - P2X4 receptors expressed on microglial cells in post-ischemic inflammation of brain ischemic injury. AB - Post-ischemic inflammation is an essential step in the progression of brain ischemia injury. P2X4 receptors are the predominant purinergic P2X receptor subtypes expressed on immune and neural cells. The subtype traffic between intracellular compartments and the plasma membrane form protein interactions with each other to regulate ATP-dependent signaling. The P2X4 receptors expressed on microglial cells have been reported to be involved in the inflammatory response of many central nervous system diseases. However, the mechanism that activates microglial cells and the role of P2X4 receptor expressed in microglial cells in the ischemic brain remains to be clarified. Here we provide a review for understanding and exploring converging lines of evidence for involvement of P2X4 receptors expressed on microglial cells in the post-ischemic inflammation in the brain ischemic injury. PMID- 24486459 TI - Potential chemoprevention of LPS-stimulated nitric oxide and prostaglandin E2 production by alpha-L-rhamnopyranosyl-(1->6)-beta-D-glucopyranosyl-3 indolecarbonate in BV2 microglial cells through suppression of the ROS/PI3K/Akt/NF-kappaB pathway. AB - alpha-l-Rhamnopyranosyl-(1->6)-beta-d-glucopyranosyl-3-indolecarbonate (RG3I) is a chemical constituent isolated from the commonly used Asian traditional medicinal plant, Clematis mandshurica; however, no studies have been reported on its anti-inflammatory properties. In the present study, we found that RG3I attenuates the lipopolysaccharide (LPS)-induced DNA-binding activity of nuclear factor-kappaB (NF-kappaB) via the dephosphorylation of PI3K/Akt in BV2 microglial cells, leading to a suppression of nitric oxide (NO) and prostaglandin E2 (PGE2) production, along with that of their regulatory genes, inducible NO synthase (iNOS) and cyclooxygenase-2 (Cox-2). Further, the PI3K/Akt inhibitor, LY294002 diminished the expression of LPS-stimulated iNOS and COX-2 genes by suppressing NF-kappaB activity. Moreover, RG3I significantly inhibited LPS-induced reactive oxygen species (ROS) generation similar to the ROS inhibitors, N-acetylcysteine (NAC) and glutathione (GSH). Notably, NAC and GSH abolished the LPS-induced expression of iNOS and Cox-2 in BV2 microglial cells by inhibiting NF-kappaB activity. Taken together, our data indicate that RG3I suppresses the production of proinflammatory mediators such as NO and PGE2 as well as their regulatory genes in LPS-stimulated BV2 microglial cells by inhibiting the PI3K/Akt- and ROS dependent NF-kappaB signaling pathway, suggesting that RG3I may be a good candidate to regulate LPS-induced inflammatory response. PMID- 24486460 TI - Possible determinants and spatial patterns of anaemia among young children in Nigeria: a Bayesian semi-parametric modelling. AB - BACKGROUND: Anaemia is a global public health problem affecting both developing and developed countries with major consequences for human health and socioeconomic development. This paper examines the possible relationship between Hb concentration and severity of anaemia with individual and household characteristics of children aged 6-59 months in Nigeria; and explores possible geographical variations of these outcome variables. METHODS: Data on Hb concentration and severity of anaemia in children aged 6-59 months that participated in the 2010 Nigeria Malaria Indicator Survey were analysed. A semi parametric model using a hierarchical Bayesian approach was adopted to examine the putative relationship of covariates of different types and possible spatial variation. Gaussian, binary and ordinal outcome variables were considered in modelling. RESULTS: Spatial analyses reveal a distinct North-South divide in Hb concentration of the children analysed and that states in Northern Nigeria possess a higher risk of anaemia. Other important risk factors include the household wealth index, sex of the child, whether or not the child had fever or malaria in the 2 weeks preceding the survey, and children under 24 months of age. CONCLUSIONS: There is a need for state level implementation of specific programmes that target vulnerable children as this can help in reversing the existing patterns. PMID- 24486461 TI - The polio eradication campaign: time to shift the goal. AB - The social rejection of the polio eradication campaign in endemic countries challenges an assumption underlying the goal itself: the full compliance of an entire population to a public health programme. The polio campaign, which has been an extraordinary public health enterprise, is at risk of becoming irremediably unpopular if the eradication goal is pursued at all costs. The Global Polio Eradication Initiative (GPEI) should not be driven by the fear of failure, because the greatest benefit of the polio campaign is that it has demonstrated how simple, community-wide actions can contribute to a dramatic decrease in the incidence of a disease. PMID- 24486462 TI - Chemical synthesis, NMR analysis and evaluation on a cancer xenograft model (HL 60) of the aminosteroid derivative RM-133. AB - The aminosteroid derivative RM-133 has been reported to be a promising pro apoptotic agent showing activity on various cancer cell lines. Following the development of solid-phase synthesis that generated a series of libraries of aminosteroid derivatives, we now report the development of a convenient liquid phase chemical synthesis of RM-133, the most promising candidate, in order to obtain sufficient quantities to proceed with the first preclinical assays. A simple and convergent six-step synthesis was designed and allowed the preparation of a gram-quantity scale of RM-133. This aminosteroid derivative was also fully characterized by NMR experiments which revealed an interesting mixture of conformers. Finally, the in vivo potency of RM-133 was evaluated on a xenograft model in nude mice with HL-60 tumors, which has resulted in the blocking of tumor progression by 57%. PMID- 24486463 TI - Electrochemical synthesis of glycoconjugates from activated sterol derivatives. AB - Several derivatives of cholesterol and other 3beta-hydroxy-Delta(5)-steroids were prepared and tested as sterol donors in electrochemical reactions with sugar alcohols. The reactions afforded glycoconjugates with sugar linked to a steroid moiety by an ether bond. Readily available sterol diphenylphosphates yielding up to 54% of the desired glycoconjugate were found to be the best sterol donors. PMID- 24486464 TI - Synthesis of antibacterial TiO2/PLGA composite biofilms. AB - This study developed a TiO2/PLGA [poly(lactic-co-glycolic acid)] composite biomaterial, which possesses antibacterial properties but is biocompatible, for artificial dressing applications. A sol-gel method was used for the preparation of the nano TiO2 powder with anatase phase. Several concentration ratios of TiO2 versus PLGA were analyzed to optimize the disinfection efficiency of the composite biomaterial. The antibacterial activity of the fabricated TiO2/PLGA composite was measured against Staphylococcus aureus and Escherichia coli. To evaluate the feasibility of the biomaterial on wound healing in vitro, human keratinocytes (HaCaTs), fibroblasts (L929s), and bovine carotid artery endothelial cells (BECs) were seeded on the TiO2/PLGA composite biofilms. To investigate the histological effect of the biocompatible biofilm in vivo, a rat subcutaneous implantation was performed. Our results show that TiO2/PLGA composite biofilms containing 10% TiO2 nanoparticles have an effective antibacterial property, a good survival rate on HaCaTs and L929s, and relative safe stability in tissue implantation. FROM THE CLINICAL EDITOR: This study reports the development of titanium dioxide-polylactic-co-glycolic acid composite biofilms, which possess antibacterial properties and are biocompatible for dressing applications, as demonstrated in a model system. PMID- 24486465 TI - Magnetic micelles for DNA delivery to rat brains after mild traumatic brain injury. AB - Traumatic brain injury (TBI) causes significant mortality, long term disability and psychological symptoms. Gene therapy is a promising approach for treatment of different pathological conditions. Here we tested chitosan and polyethyleneimine (PEI)-coated magnetic micelles (CP-mag micelles or CPMMs), a potential MRI contrast agent, to deliver a reporter DNA to the brain after mild TBI (mTBI). CPMM-tomato plasmid (ptd) conjugate expressing a red-fluorescent protein (RFP) was administered intranasally immediately after mTBI or sham surgery in male SD rats. Evans blue extravasation following mTBI suggested CPMM-ptd entry into the brain via the compromised blood-brain barrier. Magnetofection increased the concentration of CPMMs in the brain. RFP expression was observed in the brain (cortex and hippocampus), lung and liver 48 h after mTBI. CPMM did not evoke any inflammatory response by themselves and were excreted from the body. These results indicate the possibility of using intranasally administered CPMM as a theranostic vehicle for mTBI. From the clinical editor: In this study, chitosan and PEI-coated magnetic micelles (CPMM) were demonstrated as potentially useful vehicles in traumatic brain injury in a rodent model. Magnetofection increased the concentration of CPMMs in the brain and, after intranasal delivery, CPMM did not evoke any inflammatory response and were excreted from the body. PMID- 24486466 TI - Perinatal multiple exposure to neurotoxic (lead, methylmercury, ethylmercury, and aluminum) substances and neurodevelopment at six and 24 months of age. AB - We studied neurodevelopment in infants from two communities. Children living in the vicinity of tin-ore kilns and smelters - TOKS; n = 51) were compared to children from a fishing village (Itapua; n = 45). Mean hair-Hg (HHg) concentrations were significantly higher in Itapua children which received significantly (p = 0.0000001) less mean ethylmercury (88.6 MUg) from Thimerosal containing vaccines (TCV) than the TOKS children (120 MUg). Breast-milk Pb concentrations were significantly higher in the TOKS mothers (p = 0.000017; 10.04 vs. 3.9 MUg L(-1)). Bayley mental development index (MDI) and psychomotor development index (PDI) were statistically significant (respectively p < 0.0000001, p = 0.000007) lower for the TOKS children only at 24 months of age. Multivariate regression analysis showed that MDI was negatively affected by breast-milk Pb and by HHg. PDI was positively affected by breastfeeding and negatively affected by ethylmercury. Milestone achievements were negatively affected by breast-milk Pb (age of walking) and by HHg (age of talking). PMID- 24486467 TI - A strategy to potentiate Cd phytoremediation by saltmarsh plants - autochthonous bioaugmentation. AB - The recovery of estuarine environments is in need. Phytoremediation could be a valid option to reduce pollution while preserving natural biodiversity. In this work, estuarine sediments colonized by Juncus maritimus or Phragmites australis were spiked with cadmium in the absence and in the presence of an autochthonous microbial consortium resistant to the metal. The aim of this study was to increase the potential for cadmium phytoremediation that these two halophyte plants have shown. Experiments were carried out in greenhouses with an automatic irrigation system that simulated estuarine tidal cycles. After 2 months, Cd concentration in P. australis stems increased up to 7 times when the rhizosphere was inoculated with the microbial consortium. So, P. australis phytoextraction potential was increased through autochthonous bioaugmentation. As for J. maritimus, up to 48% more Cd (total amount) was observed in its belowground tissues after being subjected to autochthonous bioaugmentation. Therefore, the phytostabilization potential of this plant was promoted. For both plants this increase in cadmium uptake did not cause significant signs of toxicity. Therefore, the addition of autochthonous microorganisms resistant to cadmium seems to be a valuable strategy to potentiate phytoremediation of this metal in saltmarshes, being useful for the recovery of moderately impacted estuaries. This will contribute for an effective management of these areas. Research on this topic regarding estuarine ecosystems, especially saltmarshes, is, to our knowledge, inexistent. PMID- 24486468 TI - Cost-effectiveness analysis of TOC removal from slaughterhouse wastewater using combined anaerobic-aerobic and UV/H2O2 processes. AB - The objective of this study is to evaluate the operating costs of treating slaughterhouse wastewater (SWW) using combined biological and advanced oxidation processes (AOPs). This study compares the performance and the treatment capability of an anaerobic baffled reactor (ABR), an aerated completely mixed activated sludge reactor (AS), and a UV/H2O2 process, as well as their combination for the removal of the total organic carbon (TOC). Overall efficiencies are found to be up to 75.22, 89.47, 94.53, 96.10, 96.36, and 99.98% for the UV/H2O2, ABR, AS, combined AS-ABR, combined ABR-AS, and combined ABR-AS UV/H2O2 processes, respectively. Due to the consumption of electrical energy and reagents, operating costs are calculated at optimal conditions of each process. A cost-effectiveness analysis (CEA) is performed at optimal conditions for the SWW treatment by optimizing the total electricity cost, H2O2 consumption, and hydraulic retention time (HRT). The combined ABR-AS-UV/H2O2 processes have an optimal TOC removal of 92.46% at an HRT of 41 h, a cost of $1.25/kg of TOC removed, and $11.60/m(3) of treated SWW. This process reaches a maximum TOC removal of 99% in 76.5 h with an estimated cost of $2.19/kg TOC removal and $21.65/m(3) treated SWW, equivalent to $6.79/m(3) day. PMID- 24486469 TI - Converting probabilistic tree species range shift projections into meaningful classes for management. AB - The paper deals with the management problem how to decide on tree species suitability under changing environmental conditions. It presents an algorithm that classifies the output of a range shift model for major tree species in Europe into multiple classes that can be linked to qualities characterizing the ecological niche of the species. The classes: i) Core distribution area, ii) Extended distribution area, iii) Occasional occurrence area, and iv) No occurrence area are first theoretically developed and then statistically described. The classes are interpreted from an ecological point of view using criteria like population structure, competitive strength, site spectrum and vulnerability to biotic hazards. The functioning of the algorithm is demonstrated using the example of a generalized linear model that was fitted to a pan-European dataset of presence/absence of major tree species with downscaled climate data from a General Circulation Model (GCM). Applications of the algorithm to tree species suitability classification on a European and regional level are shown. The thresholds that are used by the algorithm are precision-based and include Cohen's Kappa. A validation of the algorithm using an independent dataset of the German National Forest Inventory shows good accordance of the statistically derived classes with ecological traits for Norway spruce, while the differentiation especially between core and extended distribution for European beech that is in the centre of its natural range in this area is less accurate. We hypothesize that for species in the core of their range regional factors like forest history superimpose climatic factors. Problems of uncertainty issued from potentially applying a multitude of modelling approaches and/or climate realizations within the range shift model are discussed and a way to deal with the uncertainty by revealing the underlying attitude towards risk of the decision maker is proposed. PMID- 24486470 TI - The time-dependent effect of ibandronate on bone graft remodeling in an ovariectomized rat spinal arthrodesis model. AB - BACKGROUND CONTEXT: In osteoporotic patients undergoing spinal arthrodesis, the use of bisphosphonates (BPs) remains controversial with regard to bone fusion. There is no consensus about the appropriate time to give BPs to patients with osteoporosis undergoing spinal arthrodesis. PURPOSE: We aimed to study the effect of BPs, given at different times, on the bone response to osteoporotic spinal arthrodesis. STUDY DESIGN/SETTING: Radiological, histologic, and molecular assessments of bone formation after the different administration time of ibandronate in an ovariectomized (OVX) rat spinal fusion model. METHODS: Female Sprague-Dawley rats (n=100) were OVX (n=80) or non-OVX operated (n=20) and randomized into five groups: non-OVX, osteoporosis, and osteoporosis with early, simultaneous, and late BP groups. Eight weeks after ovariectomy, lumbar spinal arthrodesis was performed using autologous tailbones. Animals were killed 4 and 8 weeks after arthrodesis, and bone formation was assessed by measuring bone mineral density (BMD), messenger RNA expression, manual palpation, radiological evaluation, and histomorphometry. RESULTS: Compared with late administration, early administration of ibandronate increased femur BMD in OVX rats and did not hinder bone fusion. Radiological analysis showed that groups given early ibandronate had increased bone volume in the grafted site 8 weeks after surgery. Histomorphometric analysis showed that ibandronate positively affected endochondral and intramembranous ossification. In the OVX groups, ibandronate increased bone turnover to a level similar to that in the non-OVX group. These findings suggested that early administration of ibandronate did not inhibit osteogenesis, including endochondral and intramembranous ossification and fusion rate. CONCLUSIONS: Our results suggest that the early administration of BPs may not hinder the bone fusion of osteoporotic patients undergoing spinal arthrodesis. PMID- 24486471 TI - Occupant and crash characteristics in thoracic and lumbar spine injuries resulting from motor vehicle collisions. AB - BACKGROUND CONTEXT: Motor vehicle collisions (MVC) are a leading cause of thoracic and lumbar (T and L) spine injuries. Mechanisms of injury in vehicular crashes that result in thoracic and lumbar fractures and the spectrum of injury in these occupants have not been extensively studied in the literature. PURPOSE: The objective was to investigate the patterns of T and L spine injuries after MVC; correlate these patterns with restraint use, crash characteristics, and demographic variables; and study the associations of these injuries with general injury morbidity and fatality. STUDY DESIGN/SETTING: The study design is a retrospective study of a prospectively gathered database. PATIENT SAMPLE: Six hundred thirty-one occupants with T and L (T1-L5) spine injuries from 4,572 occupants included in the Crash Injury Research and Engineering Network (CIREN) database between 1996 and 2011 were included in this study. OUTCOME MEASURES: No clinical outcome measures were evaluated in this study. METHODS: The CIREN database includes moderate to severely injured occupants from MVC involving vehicles manufactured recently. Demographic, injury, and crash data from each patient were analyzed for correlations between patterns of T and L spine injuries, associated extraspinal injuries and overall injury severity score (ISS), type and use of seat belts, and other crash characteristics. T and L spine injuries patterns were categorized using a modified Denis' classification to include extension injuries as a separate entity. RESULTS: T and L spine injuries were identified in 631 of 4,572 vehicle occupants, of whom 299 sustained major injuries (including 21 extension injuries) and 332 sustained minor injuries. Flexion-distraction injuries were more prevalent in children and young adults and extension injuries in older adults (mean age, 65.7 years). Occupants with extension injuries had a mean body mass index of 36.0 and a fatality rate of 23.8%, much higher than the fatality rate for the entire cohort (10.9%). The most frequent extraspinal injuries (Abbreviated Injury Scale Grade 2 or more) associated with T and L spine injuries involved the chest (seen in 65.6% of 631 occupants). In contrast to occupants with major T and L spine injuries, those with minor T and L spine injuries showed a strikingly greater association with pelvic and abdominal injuries. Occupants with minor T and L spine injuries had a higher mean ISS (27.1) than those with major T and L spine injuries (25.6). Among occupants wearing a three-point seat belt, 35.3% sustained T and L spine injuries, whereas only 11.6% of the unbelted occupants sustained T and L spine injuries. Three-point belted individuals were more likely to sustain burst fractures, whereas two-point belted occupants sustained flexion-distraction injuries most often and unbelted occupants had a predilection for fracture dislocations of the T and L spines. Three-point seat belts were protective against neurologic injury, higher ISS, and fatality. CONCLUSIONS: T and L spine fracture patterns are influenced by the age of occupant and type and use of seat belts. Despite a reduction in overall injury severity and mortality, seat belt use is associated with an increased incidence of T and L spine fractures. Minor T and L spine fractures were associated with an increased likelihood of pelvic and abdominal injuries and higher ISSs, demonstrating their importance in predicting overall injury severity. Extension injuries occurred in older obese individuals and were associated with a high fatality rate. Future advancements in automobile safety engineering should address the need to reduce T and L spine injuries in belted occupants. PMID- 24486472 TI - Complications, outcomes, and need for fusion after minimally invasive posterior cervical foraminotomy and microdiscectomy. AB - BACKGROUND CONTEXT: Posterior cervical foraminotomy (PCF) with or without microdiscectomy (posterior cervical discectomy [PCD]) is a frequently used surgical technique for cervical radiculopathy secondary to foraminal stenosis or a laterally located herniated disc. Currently, these procedures are being performed with increasing frequency using advanced minimally invasive techniques. Although the safety and efficacy of minimally invasive PCF/PCD (MI-PCF/PCD) have been established, reports on long-term outcome and need for secondary surgical intervention at the index or adjacent level are lacking. PURPOSE: To determine the rates of complications, long-term outcomes, and need for secondary surgical intervention at the index or adjacent level after MI-PCF and microdiscectomy. STUDY DESIGN: Retrospective analysis of a prospective cohort. PATIENT SAMPLE: Seventy patients treated with MI-PCF and/or MI-PCD for cervical radiculopathy. OUTCOME MEASURES: Visual Analog Scale for neck/arm (VASN/A) pain and Neck Disability Index (NDI). METHODS: Ninety-seven patients underwent MI-PCF with or without MI-PCD between 2002 and 2011. Adequate prospective follow-up was available for 70 patients (95 cervical levels). The primary outcome assessed was need for secondary surgical intervention at the index or adjacent level. The secondary outcomes assessed included complications and improvements in NDI and VASN/A scores. All complications were reviewed. Mixed-model analyses of variance with random subject effects and autoregressive first-order correlation structures were used to test for differences among NDI, VASA, and VASN measurements made over time while accounting for the correlation among repeated observations within a patient. All statistical hypothesis tests were conducted at the 5% level of significance. RESULTS: Patients were followed for a mean of 32.1 months. Of 70 patients operated, there were 3 (4.3%) complications (1 cerebrospinal fluid leak, 1 postoperative wound hematoma, and 1 radiculitis), none of which required a secondary operative intervention. Five patients required an anterior cervical discectomy and fusion (eight total levels fused) on average 44.4 months after the index surgery. Of those, five (5.3%) were at the index level and three (2.1%) were at adjacent levels. Neck Disability Index scores improved significantly (p<.0001) immediately postoperatively and continued to decrease gradually with time. Visual Analog Scale for neck/arm scores improved significantly (p<.0001) from baseline immediately postoperatively but tended to plateau with time. CONCLUSIONS: Minimally invasive PCF with or without MI-PCD is an excellent alternative for cervical radiculopathy secondary to foraminal stenosis or a laterally located herniated disc. There is a low rate (1.1% per index level per year) of future index site fusion and a very low rate (0.9% per adjacent level per year) of adjacent-level disease requiring surgery. PMID- 24486473 TI - Depressive burden is associated with a poorer surgical outcome among lumbar spinal stenosis patients: a 5-year follow-up study. AB - BACKGROUND CONTEXT: In lumbar spinal stenosis (LSS), conservative treatment is usually the first choice of treatment. If conservative treatment fails, surgery is indicated. Psychological factors such as depression and anxiety are known to affect the outcome of surgery. Previous studies on depression and surgery outcome using long follow-up times are scarce. PURPOSE: The purpose of this study was to investigate the effect of depressive symptoms on the surgical outcome during a 5 year follow-up among patients with LSS. STUDY DESIGN: A prospective observational study. PATIENT SAMPLE: Patient sample included 102 LSS patients who needed surgical treatment. OUTCOME MEASURES: The outcome of surgery was evaluated with the Oswestry Disability Index (ODI), visual analog scale pain assessment, and self-reported walking capacity. METHODS: The patients completed a set of questionnaires preoperatively and 3 and 6 months, as well as 1, 2, and 5 years after the surgery. Depressive symptoms were assessed with the Beck Depression Inventory. The depressive burden was estimated by summing all individual Beck Depression Inventory scores. Statistical analyses included cross-sectional group comparisons and linear regression analyses. No conflicts of interest. RESULTS: On 5-year follow-up, a high depressive burden associated with a poorer outcome of surgery when assessed with the ODI. In linear regression analysis, a high depressive burden associated with higher ODI score. CONCLUSIONS: Even slightly elevated long-term depressive symptoms in LSS patients are associated with an increased risk of a poorer functional ability after decompressive surgery. PMID- 24486474 TI - Individual and contextual characteristics as determinants of sagittal standing posture: a population-based study of adults. AB - BACKGROUND CONTEXT: Sagittal standing posture is associated with musculoskeletal symptoms and quality of life. However, the frequency and determinants of suboptimal sagittal alignment outside the clinical context remain to be clarified. PURPOSE: To estimate the association of sociodemographic, anthropometric, and behavioral characteristics with sagittal standing posture among adults from the general population. STUDY DESIGN: Cross-sectional evaluation of a population-based sample. PATIENT SAMPLE: As part of the EPIPorto study, 489 adults were assessed during 2005 to 2008. OUTCOME MEASURES: Individual spinopelvic parameters were measured. Additionally, participants were classified into one of four types of sagittal postural patterns (Roussouly classification: Types 1, 2, and 4 corresponding to nonneutral postures and Type 3 to a neutral posture). METHODS: Spinopelvic parameters were recorded from 36-inch sagittal radiographs obtained in free-standing posture. Age, sex, education, occupation, body mass index (BMI), waist circumference, total physical activity, leisure time physical activity, time spent in sitting position, smoking status, and tobacco cumulative exposure were collected. Individual parameters and patterns of sagittal posture were compared across categories of participants' characteristics. RESULTS: Older age, lower educational level, blue collar occupation, and overall and central obesity were associated with increased sagittal vertical axis and pelvic tilt/pelvic incidence ratio. Taking the neutral postural pattern (Type 3) as reference for the outcome in a multinomial regression model, independently of age, sex, education, total physical activity, and smoking status, overweight adults had higher odds of Type 2 (odds ratio [OR]=1.92; 95% confidence interval [CI]: 1.13-3.27) and Type 4 (OR=2.13; 95% CI: 1.16-3.91) postural patterns in comparison with normal weight subjects. Overall and central obesity were positively related with Type 1 postural pattern (OR=6.10, 95% CI: 1.52-24.57 and OR=3.54, 95% CI: 1.13-11.11, respectively). There was also a weak direct association between female sex and Type 1 postural pattern. Regarding behavioral factors, subjects with total physical activity above the first third exhibited all nonneutral postural patterns less frequently, and current smokers were more likely to present a Type 4 postural pattern. CONCLUSIONS: Higher BMI and central obesity were important potential determinants of nonneutral posture among adults from the general population. Future research should investigate the potential effectiveness of overweight prevention and management in avoiding sagittal misalignment conditions. PMID- 24486475 TI - Evaluation of resorption and biocompatibility of collagen hemostats in the spinal epidural space. AB - BACKGROUND CONTEXT: Collagen hemostats have different characteristics depending on their properties and configuration. In vivo serial evaluation of local reactions because of placement of hemostats in the epidural space has not been reported. PURPOSE: This study compared the resorption and biocompatibility of two types of collagen hemostats placed in the epidural space. STUDY DESIGN: This in vivo study used experimental animals to evaluate collagen hemostats that were placed in the epidural space. METHODS: A ligamentum flavum resection model was created in Japanese white rabbits (n=65). A microfibrillar collagen hemostat (MCH group, n=5), cotton-type collagen hemostat (CCH group, n=5) that was chemically cross-linked, or no hemostat (control group, n=4) was placed in the spinal epidural space. For histologic evaluation, each group was euthanized 1, 2, 4, and 8 weeks postoperatively (PO), and hematoxylin-eosin and immunohistochemical (IHC) staining for inflammatory cytokines (tumor necrosis factor [TNF]-alpha, interleukin [IL]-6), cyclooxygenase (COX)-2, and macrophages (CD68) was performed. To evaluate exudate accumulation and the degree of inflammation in the epidural space, magnetic resonance imaging at 7.04 T was serially performed in each group (n=3) under anesthesia and sedation. RESULTS: The collagen hemostats in both groups were reabsorbed at 4 weeks PO. In the MCH group, there was inflammatory cell infiltration and granuloma formation around the hemostat, TNF alpha-positive cells were seen up to 1 week, and IL-6-, COX-2-, and CD68-positive cells were seen at all evaluation times. In the CCH group, no inflammatory cell infiltration around the hemostat was observed, and IHC staining showed no positive cells at 4 weeks PO and later. T2*-weighted MR images showed significantly higher mean signal intensity of the epidural space in the MCH group than in the CCH group but only at 1 week PO (p<.05). CONCLUSIONS: Resorption of both hemostats was similar. In the MCH group, there was intense tissue inflammation around the hemostatic material, and MR images showed high signal intensity because of exudate accumulation in the epidural space. This indicated a strong foreign-body reaction to the MCH, thus demonstrating a difference in biocompatibility with the CCH. PMID- 24486476 TI - Reducing radiation exposure in early-onset scoliosis surgery patients: novel use of ultrasonography to measure lengthening in magnetically-controlled growing rods. AB - BACKGROUND CONTEXT: Magnetically-controlled growing rod (MCGR) technology has been reported for the treatment of early-onset scoliosis (EOS). Such technology allows for regular and frequent outpatient rod distractions without the need for additional surgery. However, pre- and postdistraction spine radiographs are required to verify the amount of lengthening. This increased exposure to ionizing radiation in developing children significantly increases their risk profile for radiation-induced cancer and noncancerous morbidity. PURPOSE: This study addressed the first and novel application and reliability of the use of ultrasonography, that has no ionizing radiation exposure, as an alternative to plain radiographs in the visualizing and confirming of rod distractions. STUDY DESIGN: A prospective study. PATIENT SAMPLE: Six EOS patients who underwent surgical treatment with MCGRs were prospectively recruited. OUTCOME MEASURES: Imaging measurements based on ultrasound and plain radiographs. METHODS: All patients were imaged via ultrasound, ease of rod identification was established, and the reliability and reproducibility of optimal reference point selection assessed blindly by three individuals. The clinical algorithm, using ultrasound, was subsequently implemented. Plain radiographs served as controls. RESULTS: Assessment of the rod's neck distance on ultrasound demonstrated a high degree of interrater reliability (a=0.99; p<.001). Intrarater reliability remained high on repeat measurements at different time intervals (a=1.00; p<.001). Satisfactory interrater reliability was noted when measuring the rod's neck (a=0.73; p=.010) and high reliability was noted in assessing the housing of the rod (a=0.85; p=.01) on plain radiographs. Under blinded conditions, 2 mm rod distraction measured on radiographs corresponded to 1.7 mm distraction on the ultrasound (standard deviation: 0.24 mm; p<.001). Subsequently, the clinical algorithm using ultrasound, instead of radiographs, has been successfully implemented. CONCLUSIONS: This is the first study to report the use of a novel technique using noninvasive, nonionizing ultrasound to reliably document rod distractions in EOS patients. A high level of inter- and intrarater reliabilities were noted. More importantly, the use of ultrasonography may result in fewer whole spine radiographs from being taken in patients who have had MCGRs implanted for EOS; thereby decreasing their exposure to ionizing radiation and the potential risk of future radiation-induced diseases. PMID- 24486477 TI - Functional aerobic exercise capacity limitation in adolescent idiopathic scoliosis. AB - BACKGROUND CONTEXT: Exercise limitation has been described in patients with adolescent idiopathic scoliosis (AIS); however, whether the walking performance is impaired in these patients should be elucidated. PURPOSE: Thus, we aimed to evaluate the physiologic responses to the incremental shuttle walk test (ISWT) in patients with AIS. STUDY DESIGN/SETTING: Cross-sectional study. PATIENT SAMPLE: Twenty-nine patients with AIS and 20 healthy adolescents aged between 11 and 18 years old. OUTCOME MEASURES: Oxygen uptake (VO2), incremental shuttle walk distance (ISWD), DeltaVO2/Deltawalking velocity, DeltaHR/DeltaVO2, DeltaVE/DeltaVCO2, and linearized Deltatidal volume (VT)/DeltalnVE, forced expiratory volume in the first second of expiration (FEV1), and forced vital capacity (FVC). METHODS: We performed two ISWTs, and the data used were acquired in the second test. We also evaluated the lung function and respiratory muscle strength through spirometry test and manovacuometry, respectively. All authors confirm that there are no conflicts of interest. To compare the means or medians of variables between patients and healthy subjects, we used the unpaired t test or Mann-Whitney U test, respectively. The correlations were assessed by Pearson or Spearman coefficients according to the distribution of the studied variables. The probability of alpha error was set at 5% for all analyses. RESULTS: Adolescent idiopathic scoliosis patients showed significant lower values of ISWD, VO2, and ventilation at the end of the ISWT, as well as lower FEV1 and FVC; they also presented significantly shallower slope of DeltaVT/DeltalnVE, whereas VO2 related significantly with ISWD (r=0.80), FVC (r=0.78), FEV1 (r=0.73), and DeltaVT/DeltalnVE (r=0.58). CONCLUSIONS: Adolescent idiopathic scoliosis correlated to walking limitation and was associated to reduced pulmonary function and worse breathing pattern during exercise. Our results suggest that walking based aerobic exercises should be encouraged in these patients. PMID- 24486478 TI - The effects of a temporarily manipulated dental occlusion on the position of the spine: a comparison during standing and walking. AB - BACKGROUND CONTEXT: The relationship between dental occlusion and body posture or even the spine position is often analyzed and confirmed. However, this relationship has not been systematically investigated for standing and walking. PURPOSE: To examine whether a symmetric or asymmetric dental occlusion block, using 4 mm thick silicon panels, can significantly change the spine position (cervical, thoracic, or lumbar region) during standing and walking. STUDY DESIGN: The following study is a cross-sectional study. PATIENT SAMPLE: This study was carried out with 23 healthy subjects (18 women, 5 men) without discomfort in the temporomandibular system or body movement apparatus. OUTCOME MEASURES: Position changes (millimeter) of the spine (cervical, thoracic, lumbar) in frontal, sagittal, and transverse planes of motion. METHODS: The upper spine position was quantified with an ultrasonic distance measurement system (sonoSens Monitor). Every subject placed the 4 mm thick silicon panel systematically between the left/right premolars or the front teeth. Differences between the habitual and manipulated occlusion positions were determined by the Friedman test, followed by pairwise comparisons with applied Bonferroni-Holm correction. RESULTS: During standing and walking there were significant (p<=.05) differences between the occlusion block conditions and the habitual dental position in all body planes except in the right lumbar region during walking. In addition, differences within the manipulated occlusion position could be detected. Significant differences were also shown between the standing and walking trials in the frontal, sagittal, and transverse planes, particularly with respect to the lumbar region (p<=.001). CONCLUSIONS: Symmetrical and asymmetrical occlusion blocks in the premolar region can be associated with changes in all three spine regions during standing and walking. The results showed highly similar reaction patterns in all spine positions, regardless of the location of the silicon panel. Between standing and walking, the main differences were in the lumbar spine. The results suggest a relationship between the chewing and the movement system. However, it must be stated that this study has no direct clinical impact. The study design cannot determine the causality of the observed associations; also the clinical significance of the small postural changes remains unknown. PMID- 24486480 TI - Retraction: G-protein-coupled receptor 30 and estrogen receptor-alpha are involved in the proliferative effects induced by atrazine in ovarian cancer cells. Environ Health Perspect. 116:1648-55. PMID- 24486479 TI - Lumbar spinal fusion with beta-TCP granules and variable Escherichia coli-derived rhBMP-2 dose. AB - BACKGROUND CONTEXT: The ideal tissue-engineered solution for any bone graft substitute is to assist in the rapid formation of bone and facilitate fusion. PURPOSE: The present study aims to evaluate this E-BMP-2 (Escherichia coli derived human bone morphogenetic protein-2) in ovine posterolateral lumbar fusion (PLF) to examine the influence of dose and overall performance in a model with similar graft size and diffusive challenges to the human. STUDY DESIGN/SETTING: In vivo large animal model study. METHODS: An adult ovine PLF was performed in 30 animals with groups of E-BMP-2 with a beta-tricalcium phosphate (beta-TCP) carrier at three different dosages, beta-TCP alone, and autograft from the iliac crest. The fusions were assessed by radiography (X-ray and microcomputed tomography), mechanical testing, and hard-tissue histology with bone labels at 6, 8, and 10 weeks along with routine paraffin histology at 12 weeks. RESULTS: Results showed increasing new bone and fusion rate with E-BMP-2 dose, whereas beta-TCP alone was largely resorbed and did not achieve fusion in this model at 12 weeks. Autograft showed similar grading for the amount of bone between the transverse processes but a lower fusion rate than beta-TCP/E-BMP-2 groups. Bone labels revealed new bone formation at all time points for the E-BMP2 groups, whereas the autograft group showed active bone formation at 10 weeks. Beta tricalcium phosphate displayed reliable incorporation into the decorticated host bone, whereas limited new bone was found between the transverse processes. At the center of the fusion mass, increased E-BMP-2 dose led to increased incorporation of beta-TCP by new bone. CONCLUSIONS: These results suggest that E-BMP-2 was capable of producing posterolateral fusion in the ovine model that is equal to or superior to autologous graft in terms of fusion rate and mechanical strength. E BMP-2 dose had considerable influence on beta-TCP granule resorption. PMID- 24486481 TI - Pregnane X receptor agonists enhance intestinal epithelial wound healing and repair of the intestinal barrier following the induction of experimental colitis. AB - The intestinal epithelial barrier plays a key role in the maintenance of homeostasis within the gastrointestinal tract. Barrier dysfunction leading to increased epithelial permeability is associated with a number of gastrointestinal disorders including the inflammatory bowel diseases (IBD) - Crohn's disease and ulcerative colitis. It is thought that the increased permeability in patients with IBD may be driven by alterations in the epithelial wound healing response. To this end considerable study has been undertaken to identify signaling pathways that may accelerate intestinal epithelial wound healing and normalize the barrier dysfunction observed in IBD. In the current study we examined the role of the pregnane X receptor (PXR) in modulating the intestinal epithelial wound healing response. Mutations and reduced mucosal expression of the PXR are associated with IBD, and others have reported that PXR agonists can dampen intestinal inflammation. Furthermore, stimulation of the PXR has been associated with increased cell migration and proliferation, two of the key processes involved in wound healing. We hypothesized that PXR agonists would enhance intestinal epithelial repair. Stimulation of Caco-2 intestinal epithelial cells with rifaximin, rifampicin and SR12813, all potent agonists of the PXR, significantly increased wound closure. This effect was driven by p38 MAP kinase-dependent cell migration, and occurred in the absence of cell proliferation. Treating mice with a rodent specific PXR agonist, pregnenolone 16alpha-carbonitrile (PCN), attenuated the intestinal barrier dysfunction observed in the dextran sulphate sodium (DSS) model of experimental colitis, an effect that occurred independent of the known anti-inflammatory effects of PCN. Taken together our data indicate that the activation of the PXR can enhance intestinal epithelial repair and suggest that targeting the PXR may help to normalize intestinal barrier dysfunction observed in patients with IBD. Furthermore, our data provide additional insight into the potential mechanisms through which rifaximin elicits its clinical efficacy in the treatment of IBD. PMID- 24486482 TI - The Biopharmaceutics Classification System: subclasses for in vivo predictive dissolution (IPD) methodology and IVIVC. AB - The Biopharmaceutics Classification System (BCS) has found widespread utility in drug discovery, product development and drug product regulatory sciences. The classification scheme captures the two most significant factors influencing oral drug absorption; solubility and intestinal permeability and it has proven to be a very useful and a widely accepted starting point for drug product development and drug product regulation. The mechanistic base of the BCS approach has, no doubt, contributed to its wide spread acceptance and utility. Nevertheless, underneath the simplicity of BCS are many detailed complexities, both in vitro and in vivo which must be evaluated and investigated for any given drug and drug product. In this manuscript we propose a simple extension of the BCS classes to include sub specification of acid (a), base (b) and neutral (c) for classes II and IV. Sub classification for Classes I and III (high solubility drugs as currently defined) is generally not needed except perhaps in border line solubility cases. It is well known that the , pKa physical property of a drug (API) has a significant impact on the aqueous solubility dissolution of drug from the drug product both in vitro and in vivo for BCS Class II and IV acids and bases, and is the basis, we propose for a sub-classification extension of the original BCS classification. This BCS sub-classification is particularly important for in vivo predictive dissolution methodology development due to the complex and variable in vivo environment in the gastrointestinal tract, with its changing pH, buffer capacity, luminal volume, surfactant luminal conditions, permeability profile along the gastrointestinal tract and variable transit and fasted and fed states. We believe this sub-classification is a step toward developing a more science-based mechanistic in vivo predictive dissolution (IPD) methodology. Such a dissolution methodology can be used by development scientists to assess the likelihood of a formulation and dosage form functioning as desired in humans, can be optimized along with parallel human pharmacokinetic studies to set a dissolution methodology for Quality by Design (QbD) and in vitro-in vivo correlations (IVIVC) and ultimately can be used as a basis for a dissolution standard that will ensure continued in vivo product performance. PMID- 24486483 TI - Evidence for a role of MRCK in mediating HeLa cell elongation induced by the C1 domain ligand HMI-1a3. AB - Diacylglycerol (DAG) is a central mediator of signaling pathways that regulate cell proliferation, survival and apoptosis. Therefore, C1 domain, the DAG binding site within protein kinase C (PKC) and other DAG effector proteins, is considered a potential cancer drug target. Derivatives of 5-(hydroxymethyl)isophthalic acid are a novel group of C1 domain ligands with antiproliferative and differentiation inducing effects. Our previous work showed that these isophthalate derivatives exhibit antiproliferative and elongation-inducing effects in HeLa human cervical cancer cells. In this study we further characterized the effects of bis(3 trifluoromethylbenzyl) 5-(hydroxymethyl)isophthalate (HMI-1a3) on HeLa cell proliferation and morphology. HMI-1a3-induced cell elongation was accompanied with loss of focal adhesions and actin stress fibers, and exposure to HMI-1a3 induced a prominent relocation of cofilin-1 into the nucleus regardless of cell phenotype. The antiproliferative and morphological responses to HMI-1a3 were not modified by pharmacological inhibition or activation of PKC, or by RNAi knock down of specific PKC isoforms, suggesting that the effects of HMI-1a3 were not mediated by PKC. Genome-wide gene expression microarray and gene set enrichment analysis suggested that, among others, HMI-1a3 induces changes in small GTPase mediated signaling pathways. Our experiments revealed that the isophthalates bind also to the C1 domains of beta2-chimaerin, protein kinase D (PKD) and myotonic dystrophy kinase-related Cdc42-binding kinase (MRCK), which are potential mediators of small GTPase signaling and cytoskeletal reorganization. Pharmacological inhibition of MRCK, but not that of PKD attenuated HMI-1a3 induced cell elongation, suggesting that MRCK participates in mediating the effects of HMI-1a3 on HeLa cell morphology. PMID- 24486484 TI - The mammalian orthoreovirus bicistronic M3 mRNA initiates translation using a 5' end-dependent, scanning mechanism that does not require interaction of 5'-3' untranslated regions. AB - Mammalian orthoreovirus mRNAs possess short 5' UTR, lack 3' poly(A) tails, and may lack 5' cap structures at late times post-infection. As such, the mechanisms by which these viral mRNAs recruit ribosomes remain completely unknown. Toward addressing this question, we used bicistronic MRV M3 mRNA to analyze the role of 5' and 3' UTRs during MRV protein synthesis. The 5' UTR was found to be dispensable for translation initiation; however, reducing its length promoted increased downstream initiation. Modifying start site Kozak context altered the ratio of upstream to downstream initiation, whereas mutations in the 3' UTR did not. Moreover, an M3 mRNA lacking a 3' UTR was able to rescue MRV infection to WT levels in an siRNA trans-complementation assay. Together, these data allow us to propose a model in which the MRV M3 mRNA initiates translation using a 5' end dependent, scanning mechanism that does not require the viral mRNA 3' UTR or 5' 3' UTRs interaction. PMID- 24486486 TI - Comparative molecular epidemiology provides new insights into Zucchini yellow mosaic virus occurrence in France. AB - Zucchini yellow mosaic virus (ZYMV, genus Potyvirus) causes important crop losses in cucurbits worldwide. In France, ZYMV epidemics are sporadic but occasionally very severe. This contrasts with Watermelon mosaic virus (WMV, genus Potyvirus) which causes regular and early epidemics. Factors influencing ZYMV epidemiology are still poorly understood. In order to gain new insights on the ecology and epidemiology of this virus, a 5-year multilocation trial was conducted in which ZYMV spread and populations were studied in each of the 20 plot/year combinations and compared with WMV. Search for ZYMV alternative hosts was conducted by testing weeds growing naturally around one plot and also by checking ZYMV natural infections in selected ornamental species. Although similar ZYMV populations were observed occasionally in the same plot in two successive years suggesting the occurrence of overwintering hosts nearby, only two Lamium amplexicaule plants were found to be infected by ZYMV of 3459 weed samples that were tested. The scarcity of ZYMV reservoirs contrasts with the frequent detection of WMV in the same samples. Since ZYMV and WMV have many aphid vectors in common and are transmitted with similar efficiencies, the differences observed in ZYMV and WMV reservoir abundances could be a major explanatory factor for the differences observed in the typology of ZYMV and WMV epidemics in France. Other potential ZYMV alternative hosts have been identified in ornamental species including begonia. Although possible in a few cases, exchanges of populations between different plots located from 500 m to 4 km apart seem uncommon. Therefore, the potential dissemination range of ZYMV by its aphid vectors seems to be rather limited in a fragmented landscape. PMID- 24486485 TI - Selection of an aptamer against rabies virus: a new class of molecules with antiviral activity. AB - Rabies is a fatal central nervous system (CNS) disease caused by the neurotropic rabies virus (RABV). The therapeutic management of RABV infections is still problematic, and novel antiviral strategies are urgently required. We established the RVG-BHK-21 cell line, which expresses RABV glycoprotein on the cell surface, to select aptamers. Through 28 iterative rounds of selection, single-stranded DNA (ssDNA) aptamers were generated by exponential enrichment (SELEX). A virus titer assay and a real-time quantitative reverse transcription PCR (qRT-PCR) assay revealed that four aptamers could inhibit the replication of RABV in cultured baby hamster kidney (BHK)-21 cells. However, the aptamers did not inhibit the replication of other virus, e.g., canine distemper virus (CDV) and canine parvovirus (CPV). In addition, the GE54 aptamer was found to effectively protect mice against lethal RABV challenge. After inoculation with aptamers for 24h or 48h, followed by inoculation with CVS-11, approximately 25-33% of the mice survived. In summary, we selected aptamers that could significantly protect from a lethal dose of RABV in vitro and in vivo. PMID- 24486487 TI - Dihydro-CDDO-trifluoroethyl amide suppresses inflammatory responses in macrophages via activation of Nrf2. AB - Nuclear factor erythroid 2-related factor (Nrf2) is the major regulator of cellular defenses against various pathological stresses in a variety of organ systems, thus Nrf2 has evolved to be an attractive drug target for the treatment and/or prevention of human disease. Several synthetic oleanolic triterpenoids including dihydro-CDDO-trifluoroethyl amide (dh404) appear to be potent activators of Nrf2 and exhibit chemopreventive promises in multiple disease models. While the pharmacological efficacy of Nrf2 activators may be dependent on the nature of Nrf2 activation in specific cell types of target organs, the precise role of Nrf2 in mediating biological effects of Nrf2 activating compounds in various cell types remains to be further explored. Herein we report a unique and Nrf2-dependent anti-inflammatory profile of dh404 in inflamed macrophages. In lipopolysaccharide (LPS)-inflamed RAW264.7 macrophages, dh404 dramatically suppressed the expression of pro-inflammatory cytokines including inducible nitric oxide synthase (iNOS), monocyte chemotactic protein-1 (MCP-1), and macrophage inflammatory protein-1 beta (MIP-1beta), while minimally regulating the expression of interleulin-6 (IL-6), IL-1beta, and tumor necrosis factor alpha (TNFalpha). Dh404 potently activated Nrf2 signaling; however, it did not affect LPS-induced NF-kappaB activity. Dh404 did not interrupt the interaction of Nrf2 with its endogenous inhibitor Kelch-like ECH associating protein 1 (Keap1) in macrophages. Moreover, knockout of Nrf2 blocked the dh404-induced anti inflammatory responses in LPS-inflamed macrophages. These results demonstrated that dh404 suppresses pro-inflammatory responses in macrophages via an activation of Nrf2 independently of Keap1 and NF-kappaB, suggesting a unique therapeutic potential of dh404 for specific targeting a Nrf2-mediated resolution of inflammation. PMID- 24486488 TI - Regulation of cell-matrix adhesion by OLA1, the Obg-like ATPase 1. AB - Attachment of cells to the extracellular matrix induces clustering of membrane receptor integrins which in turn triggers the formation of focal adhesions (FAs). The adaptor/scaffold proteins in FAs provide linkage to actin cytoskeleton, whereas focal adhesion kinase (FAK) and other FA-associated kinases and phosphatases transduce integrin-mediated signaling cascades, promoting actin polymerization and progression of cell spreading. In this study, we explored the role of OLA1, a newly identified member of Obg-like ATPases, in regulating cell adhesion processes. We showed that in multiple human cell lines RNAi-mediated downregulation of OLA1 significantly accelerated cell adhesion and spreading, and conversely overexpression of OLA1 by gene transfection resulted in delayed cell adhesion and spreading. We further found that OLA1-deficient cells had elevated levels of FAK protein and decreased Ser3 phosphorylation of cofilin, an actin binding protein and key regulator of actin filament dynamics, while OLA1 overexpressing cells exhibited the opposite molecular alterations in FAK and cofilin. These findings suggest that OLA1 plays an important negative role in cell adhesion and spreading, in part through the regulation of FAK expression and cofilin phosphorylation, and manipulation of OLA1 may lead to significant changes in cell adhesion and the associated phenotypes. PMID- 24486490 TI - Classification and interaction modes of 40 rice E2 ubiquitin-conjugating enzymes with 17 rice ARM-U-box E3 ubiquitin ligases. AB - Rice, a monocot model crop, contains at least 48 putative E2 ubiquitin (Ub) conjugating enzymes. Based on homology comparisons with 40 Arabidopsis E2 proteins and 35 human E2s, 48 rice E2s were classified into 15 different groups. Yeast two-hybrid analyses using the U-box-domain regions of armadillo (ARM)-U-box E3 Ub-ligases and the Ub-conjugating (UBC) domains of E2s showed that, among 40 rice E2s, 11 E2s accounted for 70% of the interactions with 17 ARM-U-box E3s. Thus, a single E2 could interact with multiple ARM-U-box E3s, suggesting the presence of E2 hubs for E2-E3 interactions in rice. Rice SPL11 ARM-U-box E3 displayed distinct self-ubiquitination patterns, including poly-ubiquitination, mono-ubiquitination, or no ubiquitination, depending on different E2 partners. This suggests that the mode of ubiquitination of SPL11 E3 is critically influenced by individual E2s. PMID- 24486489 TI - Engineering micropatterned surfaces to modulate the function of vascular stem cells. AB - Multipotent vascular stem cells have been implicated in vascular disease and in tissue remodeling post therapeutic intervention. Hyper-proliferation and calcified extracellular matrix deposition of VSC cause blood vessel narrowing and plaque hardening thereby increasing the risk of myocardial infarct. In this study, to optimize the surface design of vascular implants, we determined whether micropatterned polymer surfaces can modulate VSC differentiation and calcified matrix deposition. Undifferentiated rat VSC were cultured on microgrooved surfaces of varied groove widths, and on micropost surfaces. 10MUm microgrooved surfaces elongated VSC and decreased cell proliferation. However, microgrooved surfaces did not attenuate calcified extracellular matrix deposition by VSC cultured in osteogenic media conditions. In contrast, VSC cultured on micropost surfaces assumed a dendritic morphology, were significantly less proliferative, and deposited minimal calcified extracellular matrix. These results have significant implications for optimizing the design of cardiovascular implant surfaces. PMID- 24486491 TI - The RNA recognition motif domains of RBM5 are required for RNA binding and cancer cell proliferation inhibition. AB - RBM5 is a known putative tumor suppressor gene that has been shown to function in cell growth inhibition by modulating apoptosis. RBM5 also plays a critical role in alternative splicing as an RNA binding protein. However, it is still unclear which domains of RBM5 are required for RNA binding and related functional activities. We hypothesized the two putative RNA recognition motif (RRM) domains of RBM5 spanning from amino acids 98-178 and 231-315 are essential for RBM5 mediated cell growth inhibition, apoptosis regulation, and RNA binding. To investigate this hypothesis, we evaluated the activities of the wide-type and mutant RBM5 gene transfer in low-RBM5 expressing A549 cells. We found that, unlike wild-type RBM5 (RBM5-wt), a RBM5 mutant lacking the two RRM domains (RBM5 DeltaRRM), is unable to bind RNA, has compromised caspase-2 alternative splicing activity, lacks cell proliferation inhibition and apoptosis induction function in A549 cells. These data provide direct evidence that the two RRM domains of RBM5 are required for RNA binding and the RNA binding activity of RBM5 contributes to its function on apoptosis induction and cell growth inhibition. PMID- 24486492 TI - Silk sericin-alginate-chitosan microcapsules: hepatocytes encapsulation for enhanced cellular functions. AB - The encapsulation based technology permits long-term delivery of desired therapeutic products in local regions of body without the need of immunosuppressant drugs. In this study microcapsules composed of sericin and alginate micro bead as inner core and with an outer chitosan shell are prepared. This work is proposed for live cell encapsulation for potential therapeutic applications. The sericin protein is obtained from cocoons of non-mulberry silkworm Antheraea mylitta. The sericin-alginate micro beads are prepared via ionotropic gelation under high applied voltage. The beads further coated with chitosan and crosslinked with genipin. The microcapsules developed are nearly spherical in shape with smooth surface morphology. Alamar blue assay and confocal microscopy indicate high cell viability and uniform encapsulated cell distribution within the sericin-alginate-chitosan microcapsules indicating that the microcapsules maintain favourable microenvironment for the cells. The functional analysis of encapsulated cells demonstrates that the glucose consumption, urea secretion rate and intracellular albumin content increased in the microcapsules. The study suggests that the developed sericin-alginate chitosan microcapsule contributes towards the development of cell encapsulation model. It also offers to generate enriched population of metabolically and functionally active cells for the future therapeutics especially for hepatocytes transplantation in acute liver failure. PMID- 24486493 TI - Land use regression models as a tool for short, medium and long term exposure to traffic related air pollution. AB - BACKGROUND AND AIMS: In the HEAPS (Health Effects of Air Pollution in Antwerp Schools) study the importance of traffic-related air pollution on the school and home location on children's health was assessed. 130 children (aged 6 to 12) from two schools participated in a biomonitoring study measuring oxidative stress, inflammation and cardiovascular markers. METHODS: Personal exposure of schoolchildren to black carbon (BC) and nitrogen dioxide (NO2) was assessed using both measured and modeled concentrations. Air quality measurements were done in two seasons at approximately 50 locations, including the schools. The land use regression technique was applied to model concentrations at the children's home address and at the schools. RESULTS: In this paper the results of the exposure analysis are given. Concentrations measured at school 2h before the medical examination were used for assessing health effects of short term exposure. Over two seasons, this short term BC exposure ranged from 514 ng/m(3) to 6285 ng/m(3), and for NO2 from 11 MUg/m(3) to 36 MUg/m(3). An integrated exposure was determined until 10 days before the child's examination, taking into account exposures at home and at school and the time spent in each of these microenvironments. Land use regression estimates were therefore recalculated into daily concentrations by using the temporal trend observed at a fixed monitor of the official air quality network. Concentrations at the children's homes were modeled to estimate long term exposure (from 1457 ng/m(3) to 3874 ng/m(3) for BC; and from 19 MUg/m(3) to 51 MUg/m(3) for NO2). CONCLUSIONS: The land use regression technique proved to be a fast and accurate means for estimating long term and daily BC and NO2 exposure for children living in the Antwerp area. The spatial and temporal resolution was tailored to the needs of the epidemiologists involved in this study. PMID- 24486494 TI - Lower prevalence of antibiotic-resistant Salmonella on large-scale U.S. conventional poultry farms that transitioned to organic practices. AB - As a result of the widespread use of antibiotics in large-scale U.S. poultry production, a significant proportion of Salmonella strains recovered from conventional poultry farms and retail poultry products express antibiotic resistance. We evaluated whether large-scale poultry farms that transitioned from conventional to organic practices and discontinued antibiotic use were characterized by differences in the prevalence of antibiotic-resistant Salmonella compared to farms that maintained conventional practices. We collected poultry litter, water and feed samples from 10 newly organic and 10 conventional poultry houses. Samples were analyzed for Salmonella using standard enrichment methods. Isolates were confirmed using standard biochemical tests and the Vitek(r)2 Compact System. Antimicrobial susceptibility testing was performed by Sensititre(r) microbroth dilution. Data were analyzed using Fisher's exact test and generalized linear mixed models. We detected Salmonella in both conventional and newly organic poultry houses. Salmonella Kentucky was the predominant serovar identified, followed by S. Orion, S. Enteritidis, S. Gostrup and S. Infantis. Among S. Kentucky isolates (n=41), percent resistance was statistically significantly lower among isolates recovered from newly organic versus conventional poultry houses for: amoxicillin-clavulanate (p=0.049), ampicillin (p=0.042), cefoxitin (p=0.042), ceftiofur (p=0.043) and ceftriaxone (p=0.042). Percent multidrug resistance (resistance to >=3 antimicrobial classes) was also statistically significantly lower among S. Kentucky isolates recovered from newly organic poultry houses (6%) compared to those recovered from conventional houses (44%) (p=0.015). To our knowledge, these are the first U.S. data to show immediate, on-farm changes in the prevalence of antibiotic-resistant Salmonella when antibiotics are voluntarily withdrawn from large-scale poultry facilities in the United States. PMID- 24486495 TI - Gas-particle distributions, sources and health effects of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and polychlorinated naphthalenes (PCNs) in Venice aerosols. AB - Air samples were collected in Venice during summer 2009 and 2012 to measure gas and particulate concentrations of polycyclic aromatic hydrocarbons (PAHs), polychlorinated biphenyls (PCBs) and polychlorinated naphthalenes (PCNs). PCB-11, considered a marker for non-Aroclor contamination of the environment, was found for the first time in the Venetian lagoon and in Europe. An investigation on sources has been conducted, evidencing traffic as the major source of PAHs, whereas PCBs have a similar composition to Aroclor 1248 and 1254; in 2009 a release of PCN-42 has been hypothesized. Toxicological evaluation by TCA and TEQ methods, conducted for the first time in Venice air samples, identified BaP, PCB 126 and PCB-169 as the most important contributors to the total carcinogenic activity of PAHs and the total dioxin-like activity of PCBs and PCNs. PMID- 24486496 TI - Sorption and desorption of sulfadimethoxine, sulfaquinoxaline and sulfamethazine antimicrobials in Brazilian soils. AB - Adsorption and desorption are important processes that influence the transport, transformation and bioavailability of antimicrobials in soils. The adsorption desorption characteristics of sulfadimethoxine, sulfaquinoxaline and sulfamethazine in Brazilian soils (sandy, sandy-clay and clay) were evaluated using the batch equilibrium method. The sulfonamides were quantified in the soil solutions by a previously in house validated HPLC-PAD method. The adsorption/desorption data for the sulfonamides in soils fit the Freundlich isotherms well in the logarithmic form. The Freundlich adsorption coefficients ranged from 1.4 to 19.0 MUg(1-1/n)(cm(3))(1/n)g(-1), suggesting that all of the sulfonamides weakly adsorbed on the evaluated soils. The Freundlich desorption coefficients ranged from 0.85 to 24.8 MUg(1-1/n)(cm(3))(1/n)g(-1), indicating that the sulfonamides tend to be leached from soils with high sand and low organic carbon contents, suggesting that there is high potential for surface and groundwater contamination. PMID- 24486497 TI - Overview of technologies for removal of methyl tert-butyl ether (MTBE) from water. AB - Wide use of methyl tert-butyl ether (MTBE) as fuel oxygenates leads to worldwide environment contamination with this compound basically due to fuel leaks from storage or pipelines. Presence of MTBE in drinking water is of high environmental and social concern. Existing methods for MTBE removal from water have a number of limitations which can be possibly overcome in the future with use of emerging technologies. This work aims to provide an updated overview of recent developments in technologies for MTBE removal from water. PMID- 24486499 TI - Assessment of children's exposure to arsenic from CCA-wood staircases at apartment complexes in Florida. AB - Arsenic exposure from wood treated with chromated copper arsenate (CCA) remains a concern due to its presence around homes. This study evaluated children's exposure to As from CCA-treated staircases through determination of bioaccessible soil As and measurements of dislodgeable As on hand railings, steps and surfaces of household objects impacted by CCA-wood leachate. Total As concentrations in 84 soil samples from 4 apartment complexes were elevated at 1.2-66.6 mg/kg with bioaccessible As at 17-84%. Deterministic risk equations were used to estimate daily doses of As in children with estimates ranging from 0.41-54.9 MUg/day from ingestion of dislodgeable As. Lifetime average daily doses from ingestion of dislodgeable As and soil ranged from 8.1*10(-6) to 3.0*10(-5) mg/kg/day, with estimated cancer risks being 1.2-4.5*10(-5). Collectively, these results highlight potential health risks in children who have near-daily exposure to As from CCA-wood and are consistent with estimates generated by USEPA's SHEDS-Wood probabilistic exposure model. PMID- 24486498 TI - Chemical oxidation of hexachlorocyclohexanes (HCHs) in contaminated soils. AB - Chemical oxidation of hexachlorocyclohexanes (HCHs) was evaluated in (i) artificially spiked sand with HCH isomers (alpha, beta, gamma and delta) and (ii) contaminated soil sampled from a former gravel pit backfilled with wastes of lindane (gamma-HCH). Following oxidation treatments were employed: hydrogen peroxide alone (HP), hydrogen peroxide with soluble Fe(II) (Fenton-F), sodium persulfate alone (PS), Fe(II) activated persulfate (AP) and permanganate (PM). GC MS results revealed a significant degradation of all isomers in spiked soil in the order: F>PS>AP>HP>PM. Soluble Fe(II) enhanced the efficiency of H2O2 but decreased the reactivity of persulfate. Similar trend was observed in contaminated soil, but with less degradation probably caused by scavenging effect of organic matter and soil minerals and/or pollutant unavailability. No significant increase in oxidation efficiency was observed after using availability-enhancement agents in contaminated soil. Other limitation factors (oxidant dose, pH, catalyst type etc.) were also addressed. Among all the isomers tested, beta-HCH was the most recalcitrant one which could be explained by higher metabolic and chemical stability. No by-products were observed by GC-MS regardless of the oxidant used. For being the premier study reporting chemical oxidation of HCH isomers in contaminated soils, it will serve as a base for in situ treatments of sites contaminated by HCH isomers and other persistent organic pollutants. PMID- 24486500 TI - Coupling geochemical, mineralogical and microbiological approaches to assess the health of contaminated soil around the Almalyk mining and smelter complex, Uzbekistan. AB - This study describes the impact of airborne pollution resulting from mining and smelting activities on the soils of the Almalyk mining and industrial area (NE Uzbekistan). Samples were collected along a transect downwind of the industrial area. Enriched contents of some metals were found in the upper soil layers near the metallurgical complex (Zn<=3010 mg kg(-1), Pb<=630 mg kg(-1), Cd<=30 mg kg( 1)) which suggests that these metals were derived from local stack emissions. The morphology and internal microstructure of metal-bearing spherical particles found in the heavy mineral fraction suggest that these particles were probably a result of inefficient flue gas cleaning technique of the smelter. The highest metal concentrations were found also in soil solutions and exchangeable solid fractions from the first three locations, and decreased with increasing distance from the pollution source along transect. Thermodynamic equilibrium calculations suggest that the mobile metal pool in the contaminated soil is mainly controlled by dissolution of metal carbonates formed as weathering product of the metalliferous particles. The health of the microbiological soil ecosystem was assessed by measurements of basal respiration, nematode abundance, biomass-related C and N content, and microbial metabolic quotient qCO2. Significant correlations were found between the dissolved metal content and the microbiological health parameters, a negative one for Cmic/Corg ratio, and a positive one for qCO2. A negative correlation was found between the amount of nematodes and the metal contents suggesting that the contaminated soil has significant impact on the functioning of the microbiological community. A better understanding of the spatial variations in the whole ecosystem functioning due to airborne impact could be very useful for establishing suitable land use and best management practices for the polluted areas. PMID- 24486501 TI - An integrated pressure and pathway approach to the spatial analysis of groundwater nitrate: a case study from the southeast of Ireland. AB - Excess nitrogen in soil, aquatic and atmospheric environments is an escalating global problem. Eutrophication is the principal threat to surface water quality in the Republic of Ireland. European Union Water Framework Directive (2000/60/EC) water quality status assessments found that 16% of Irish groundwater bodies were 'at risk' of poor status due to the potential deterioration of associated estuarine and coastal water quality by nitrate from groundwater. This paper presents a methodology for evaluating pressure and pathway parameters affecting the spatial distribution of groundwater nitrate, investigated at a regional scale using existing national spatial datasets. The potential for nitrate transfer to groundwater was rated based on the introduced concepts of Pressure Loading and Pathway Connectivity Rating, each based on a combination of selected pressure and pathway parameters respectively. In the region studied, the South Eastern River Basin District of Ireland, this methodology identified that pathway parameters were more important than pressure parameters in understanding the spatial distribution of groundwater nitrate. Statistical analyses supported these findings and further demonstrated that the proportion of poorly drained soils, arable land, karstic flow regimes, regionally important bedrock aquifers and high vulnerability groundwater within the zones of contribution of the monitoring points are statistically significantly related to groundwater nitrate concentrations. Soil type was found to be the most important parameter. Analysis of variance showed that a number of the pressure and pathway parameters are interrelated. The parameters identified by the presented methodology may provide useful insights into the best way to manage and mitigate the influence of nitrate contamination of groundwater in this region. It is suggested that the identification of critical source areas based on the identified parameters would be an appropriate management tool, enabling planning and enforcement resources to be focussed on areas which will yield most benefit. PMID- 24486502 TI - Factors determining pesticide use practices by farmers in the Sultanate of Oman. AB - In a study of pesticide use on farms in Oman, over 200 respondents were surveyed from amongst owners of and workers on farms that belonged to a Farmers' Association (FA) and those that did not belong to the FA. A questionnaire was used to gauge attitudes to pesticide use whilst inventories of active ingredients were taken for all farms. The age profiles of the respondents were broadly similar, as was the distribution of nationalities amongst the workers. Workers and owners of FA farms were better educated than respondents from non-member farms. A majority of non-FA farm workers reported that they always used pesticides, fewer FA member farm workers and non-FA farm owners reported this behaviour with FA owners showing the lowest proportion of respondents who always used pesticides. Responses amongst farm owners to questions about frequency of pesticide use suggested that this was unaffected by age or education status, but for farm workers younger or less well educated respondents were more likely to respond by indicating that pesticides were always used. When asked to rate pesticides on a scale of 1 (bad) to 10 (good), high responses were most frequent amongst non-FA farm workers followed by FA member farm workers and non-FA farm owners. On average FA farm owners had the lowest average response, and responses by all groups were unaffected by age or education status. Prohibited pesticide use was higher on non-FA farms (4.9% of all pesticides) than on FA farms (1.3%). Pesticide products observed on FA member farms generally contained newer classes of active ingredients and were most frequently from major manufacturing companies in Europe, North America and Japan. Older, off-patent active ingredient containing products were frequently observed on non-FA farms, often from so called 'me-too' producing companies in Asia, the Middle East and North Africa. PMID- 24486503 TI - Cytochrome bd oxidase and bacterial tolerance to oxidative and nitrosative stress. AB - Cytochrome bd is a prokaryotic respiratory quinol:O2 oxidoreductase, phylogenetically unrelated to the extensively studied heme-copper oxidases (HCOs). The enzyme contributes to energy conservation by generating a proton motive force, though working with a lower energetic efficiency as compared to HCOs. Relevant to patho-physiology, members of the bd-family were shown to promote virulence in some pathogenic bacteria, which makes these enzymes of interest also as potential drug targets. Beyond its role in cell bioenergetics, cytochrome bd accomplishes several additional physiological functions, being apparently implicated in the response of the bacterial cell to a number of stress conditions. Compelling experimental evidence suggests that the enzyme enhances bacterial tolerance to oxidative and nitrosative stress conditions, owing to its unusually high nitric oxide (NO) dissociation rate and a notable catalase activity; the latter has been recently documented in one of the two bd-type oxidases of Escherichia coli. Current knowledge on cytochrome bd and its reactivity with O2, NO and H2O2 is summarized in this review in the light of the hypothesis that the preferential (over HCOs) expression of cytochrome bd in pathogenic bacteria may represent a strategy to evade the host immune attack based on production of NO and reactive oxygen species (ROS). This article is part of a Special Issue entitled: 18th European Bioenergetic Conference. PMID- 24486504 TI - Arginine kinase of Litopenaeus vannamei involved in white spot syndrome virus infection. AB - Virus-host interaction is important for virus infection. White spot syndrome virus VP14 contains transmembrane and signal peptides domain, which is considered to be important for virus infection. Until now, the function of this protein remains undefined. In this study, we explored the interaction of VP14 with host cell. A new shrimp protein (arginine kinase of Litopenaeus vannamei, LvAK) is selected and its localization in shrimp cells is also confirmed. Cellular localization of LvAK protein in shrimp hemocytes showed that LvAK was primarily located at the periphery of hemocytes and was scarcely detectable in the nucleus. Tissue distribution indicated that arginine kinase gene was spread commonly in the tissues and was highly present in shrimp muscle tissue. The expression of LvAK mRNA in muscle was significantly up-regulated after WSSV stimulation. Indirect immunofluorescence assay showed that LvAK interacted with VP14 in WSSV infected shrimp. Injection of LvAK protein enhanced the mortality of shrimp infected with white spot syndrome virus (WSSV). These results showed that LvAK is involved in WSSV infection. Future research on this topic will help to reveal the molecular mechanism of WSSV infection. PMID- 24486505 TI - Association of IL-6-174G > C and -572C > G polymorphisms with risk of young ischemic stroke patients. AB - AIM: To investigate the association between interleukin-6 (IL-6) -174G>C and 572C>G polymorphisms and risk for ischemic stroke (IS) in young patients. METHODS: We genotyped IL-6 -174G>C and -572C>G in a case-control study of 430 young IS patients and 461 control subjects. An unconditional multiple logistical regression model was used to calculate the effects of IL-6-174G>C and -572C>G polymorphisms on IS risk. RESULTS: Higher body mass index, diabetes, hypertension, obesity, and smoking were associated with risk of ischemic stroke. Multivariate regression analyses showed that subjects carrying the -174CC genotype (OR=1.69, 95% CI=1.16-2.57) and C allele (OR=1.37, 95% CI=1.09-1.67) had a small but significant increased risk of IS. Similarly, those carrying the 572GG genotype (OR=2.12, 95% CI=1.18-3.82) and G allele (OR=1.43, 95% CI=1.14 1.83) had a moderate increased risk of IS. We found the -174G>C and -572C>G polymorphisms interact with hypertension and obesity. CONCLUSION: Our results suggest that polymorphisms in IL-6-174G>C and -572C>G are associated with IS risk in young patients, and that these polymorphisms interact with hypertension, obesity and etiologic subtypes. These findings could be helpful in identifying individuals at increased risk for developing IS. PMID- 24486506 TI - The effect of XPD/ERCC2 Lys751Gln polymorphism on acute leukemia risk: a systematic review and meta-analysis. AB - AIMS: Epidemiological studies have assessed the association between xeroderma pigmentosum group D (XPD) Lys751Gln and acute leukemia risk with conflicting results. We performed this meta-analysis to derive a more precise estimation of the relationship. Pooled odds ratio (OR) with 95% confidence interval (95% CI) was used to assess the strength of the association. RESULTS: Ten published case control studies including a total of 1494 cases and 2259 controls were identified. Overall, significant risk effects of Lys751Gln genotype was found under the dominant model (OR=1.16; 95% CI=1.01-1.34; P=0.032). When stratified by clinical types, the variant genotype was associated with the acute myeloid leukemia (AML) risk under the heterozygote comparison (OR=1.20; 95% CI=1.00-1.43; P=0.048), the homozygote comparison (OR=1.35; 95% CI=1.05-1.74; P=0.019) and the dominant model (OR=1.23; 95% CI=1.04-1.45; P=0.015), respectively. Furthermore, significantly increased risks were also pronounced in Caucasian AML patients (the homozygote comparison: OR=1.38; 95% CI=1.07-1.78; P=0.013; the dominant model: OR=1.23; 95% CI=1.03-1.46; P=0.020; and the recessive model: OR=1.26; 95% CI=1.00 1.60; P=0.050). No evident heterogeneities were observed for the overall data under all genetic models. In addition, no statistical evidence for publication bias was found using the method of Begg's and Egger's tests. CONCLUSION: This meta-analysis suggested that XPD Lys751Gln polymorphism might be a risk factor for AML and Caucasian acute leukemia patients. PMID- 24486507 TI - Cloning, differential tissue expression of a novel hcApo gene, and its correlation with total carotenoid content in purple and white inner-shell color pearl mussel Hyriopsis cumingii. AB - As a molecular carrier and storage protein, apolipoprotein (Apo) mediates the intracellular uptake of lipids, proteins, vitamins and carotenoids. In this study, we identified a novel Apo gene, designated hcApo, from the freshwater pearl mussel Hyriopsis cumingii. The complete hcApo cDNA consists of 4104 nucleotides with an open reading frame encoding 1155 amino acid residues. The hcApo protein contains a conserved lipoprotein N-terminal domain (LPD-N) that is a characteristic of the large lipid transfer protein (LLTP) superfamily. The hcApo mRNA is constitutively expressed in a wide range of tissues with the highest expression level in the liver. Moreover, differential expression analysis revealed that the hcApo gene is more highly expressed in the liver, kidney, mantle and gill of purple line mussels compared to white line mussels. In situ hybridization investigations of the precise expression site of hcApo mRNA in the mantle showed that hcApo mRNA is specifically expressed in the outer epithelial cells of the middle fold and the inner epithelial cells of the outer fold of the mantle, as well as throughout the outer epithelium of the outer fold and ventral mantle. Another very important finding is that significantly positive correlation existed between the hcApo gene expression level and the total carotenoid content in purple line mussels. These findings may provide a better understanding of the roles of hcApo in the molecular mechanisms of shell formation and coloring of H. cumingii. PMID- 24486508 TI - Impaired left ventricular mechanical and energetic function in mice after cardiomyocyte-specific excision of Serca2. AB - Sarco(endo)plasmic reticulum Ca2+ -ATPase (SERCA)2 transports Ca2+ from the cytosol into the sarcoplasmic reticulum of cardiomyocytes and is essential for maintaining myocardial Ca2+ handling and thus the mechanical function of the heart. SERCA2 is a major ATP consumer in excitation-contraction coupling but is regarded to contribute to energetically efficient Ca2+ handling in the cardiomyocyte. Previous studies using cardiomyocyte-specific SERCA2 knockout (KO) mice have demonstrated that decreased SERCA2 activity reduces the Ca2+ transient amplitude and induces compensatory Ca2+ transport mechanisms that may lead to more inefficient Ca2+ transport. In this study, we examined the relationship between left ventricular (LV) function and myocardial O2 consumption (MVo2) in ex vivo hearts from SERCA2 KO mice to directly measure how SERCA2 elimination influences mechanical and energetic features of the heart. Ex vivo hearts from SERCA2 KO hearts developed mechanical dysfunction at 4 wk and demonstrated virtually no working capacity at 7 wk. In accordance with the reported reduction in Ca2+ transient amplitude in cardiomyocytes from SERCA2 KO mice, work independent MVo2 was decreased due to a reduced energy cost of excitation contraction coupling. As these hearts also showed a marked impairment in the efficiency of chemomechanical energy transduction (contractile efficiency, i.e, work-dependent MVo2), hearts from SERCA2 KO mice were found to be mechanically inefficient. This ex vivo evaluation of mechanical and energetic function in hearts from SERCA2 KO mice brings together findings from previous experimental and mathematical modeling-based studies and demonstrates that reduced SERCA2 activity not only leads to mechanical dysfunction but also to energetic dysfunction. PMID- 24486509 TI - Enhanced p22phox expression impairs vascular function through p38 and ERK1/2 MAP kinase-dependent mechanisms in type 2 diabetic mice. AB - Type 2 diabetes is associated with vascular complication. We hypothesized that increased nicotinamide adenine dinucleotide phosphate (NADPH) oxidase subunit p22(phox) expression impairs vascular endothelium-dependent relaxation (EDR) in type 2 diabetes. Type 2 diabetic (db(-)/db(-)) and control (db(-)/db(+)) mice were treated with reactive oxygen species (ROS) scavenger, polyethylene glycol superoxide dismutase (1,000 U/kg daily ip), or small interfering RNA p22(phox) (p22(phox)-lentivirus-small interfering RNA, 100 MUg iv, 2 times/wk) for 1 mo. EDR was impaired in microvascular bed (coronary arteriole and femoral and mesenteric resistance arteries) from diabetic mice compared with control. Interestingly, ROS scavenger and p22(phox) downregulation did not affect blood glucose level or body weight but significantly improved EDR. Mitogen-activated protein kinases (ERK1/2 and p38) phosphorylation and NADPH oxidase activity were increased in arteries from diabetic mice and were reduced after ROS scavenger or p22(phox) downregulation in db(-)/db(-) mice. The present study showed that enhanced p22(phox) expression causes vascular dysfunction through ERK1/2 and p38 mitogen-activated protein kinase-dependent mechanisms in male type 2 diabetic mice. Therefore, p22(phox) could be an important target to improve vascular function in diabetes. PMID- 24486510 TI - MiRNA-155 targets myosin light chain kinase and modulates actin cytoskeleton organization in endothelial cells. AB - Previously, we identified a microRNA (miRNA) signature for endothelial cells (ECs) subjected to unidirectional shear stress (USS). MiR-155, a multifunctional miRNA that has been implicated in atherosclerosis, was among the shear stress responsive miRNAs. Here, we examined the role of miR-155 in modulating EC phenotype and function. In vitro, increased miR-155 levels in human ECs induced changes in morphology and filamentous (F)-actin organization. In addition, ECs transfected with miR-155 mimic were less migratory and less proliferative and had less apoptosis compared with control ECs. In mouse aorta, miR-155 expression was increased in the intima of thoracic aorta, where blood flow produces steady and unidirectional shear stress, compared with the intima of the lower curvature of the aortic arch, which is associated with oscillatory and low shear stress. These differences in miR-155 expression were associated with distinct changes in EC morphology and F-actin. The effects of miR-155 in vitro were mediated through suppression of two key regulators of the EC cytoskeleton organization: RhoA and myosin light chain kinase (MYLK). A novel direct interaction between miR-155 and the MYLK 3'UTR was verified by luciferase-MYLK 3'UTR reporter assays. Furthermore, the intensity of immunofluorescence staining for RhoA and MYLK in mouse aorta correlated inversely with miR-155 expression. In conclusion, a prominent effect of the multifunctional miR-155 in ECs is modulation of phenotype through alterations in RhoA, MYLK expression, and actin cytoskeleton organization. PMID- 24486512 TI - Type 2 diabetes induces subendocardium-predominant reduction in transient outward K+ current with downregulation of Kv4.2 and KChIP2. AB - In the present study, we examined if and how cardiac ion channels are modified by type 2 diabetes mellitus (T2DM). Subendocardial (Endo) myocytes and subepicardial (Epi) myocytes were isolated from left ventricles of Otsuka-Long-Evans-Tokushima Fatty rats (OLETF) rats, a rat model of T2DM, and Otsuka-Long-Evans-Tokushima (LETO) rats (nondiabetic control rats). Endo and Epi myocytes were used for whole cell patch-clamp recordings and for protein and mRNA analyses. Action potential durations in Endo and Epi myocytes were longer in OLETF rats than in LETO rats, and the difference was larger in Endo myocytes. Steady-state transient outward K+ current (Ito) density was reduced in Endo but not Epi myocytes of OLETF rats compared with LETO rats, although the contribution of the fast component of Ito recovery from inactivation was smaller in both Endo and Epi myocytes of OLETF rats than in LETO rats. Kv4.2 protein was reduced only in Endo myocytes in OLETF rats, although voltage-gated K+ channel-interacting protein 2 (KChIP2) protein levels in both Endo and Epi myocytes were lower in OLETF rats than in LETO rats. Corresponding regional differences in mRNA levels of KChIP2 and Kv4.2 were observed between OLETF and LETO rats. mRNA levels of Iroquois homeobox 5 in Endo myocytes were 53% higher in OLETF rats than in LETO rats. Densities of inward rectifier K+ current and L-type Ca2+ current and mRNA levels of Kv4.3 and Kv1.4 were similar in OLETF and LETO rats. In conclusion, T2DM induces Endo-predominant prolongation of the action potential duration via a reduction of the fast component of Ito recovery from inactivation and reduced steady-state Ito, in which downregulation of Kv4.2 and KChIP2 may be involved. Increased Iroquois homeobox 5 expression may underlie Kv4.2 downregulation in T2DM. PMID- 24486511 TI - Mechanisms of vascular dysfunction in mice with endothelium-specific deletion of the PPAR-delta gene. AB - Peroxisome proliferator-activated receptor (PPAR)-delta is a nuclear hormone receptor that is mainly involved in lipid metabolism. Recent studies have suggested that PPAR-delta agonists exert vascular protective effects. The present study was designed to characterize vascular function in mice with genetic inactivation of PPAR-delta in the endothelium. Mice with vascular endothelial cell-specific deletion of the PPAR-delta gene (ePPARdelta(-/-) mice) were generated using loxP/Cre technology. ePPARdelta(-/-) mice were normotensive and did not display any sign of metabolic syndrome. Endothelium-dependent relaxations to ACh and endothelium-independent relaxations to the nitric oxide (NO) donor diethylammonium (Z)-1-(N,N-diethylamino)diazen-1-ium-1,2-diolate were both significantly impaired in the aorta and carotid arteries of ePPARdelta(-/-) mice (P < 0.05). In ePPARdelta(-/-) mouse aortas, phosphorylation of endothelial NO synthase at Ser(1177) was significantly decreased (P < 0.05). However, basal levels of cGMP were unexpectedly increased (P < 0.05). Enzymatic activity of GTP cyclohydrolase I and tetrahydrobiopterin levels were also enhanced in ePPARdelta( /-) mice (P < 0.05). Most notably, endothelium-specific deletion of the PPAR delta gene significantly decreased protein expressions of catalase and glutathione peroxidase 1 and resulted in increased levels of H2O2 in the aorta (P < 0.05). In contrast, superoxide anion production was unaltered. Moreover, treatment with catalase prevented the endothelial dysfunction and elevation of cGMP detected in aortas of ePPARdelta(-/-) mice. The findings suggest that increased levels of cGMP caused by H2O2 impair vasodilator reactivity to endogenous and exogenous NO. We speculate that chronic elevation of H2O2 predisposes PPAR-delta-deficient arteries to oxidative stress and vascular dysfunction. PMID- 24486514 TI - The effect of hand-arm vibration syndrome on quality of life. AB - BACKGROUND: It is important to determine how hand-arm vibration syndrome (HAVS), a common occupational condition, affects quality of life (QOL). AIMS: To measure the physical (SF12-P) and mental (SF12-M) components of QOL in workers with HAVS, using the SF12 questionnaire, and to determine the effect of the vascular, sensorineural and musculoskeletal components of HAVS on QOL. METHODS: Subjects were recruited consecutively from workers with HAVS attending an occupational medicine clinic. They were assessed to determine the Stockholm vascular and sensorineural scale stages as well as an upper extremity pain score, measured by the Borg scale, as an indication of musculoskeletal problems associated with the use of vibrating tools. The SF12-P and SF12-M were both compared with Canadian population normal values after adjusting for age and sex. Multiple linear regression was used to determine the effect of the various HAVS components on SF12-P and SF12-M as well as the effects of age and carpal tunnel syndrome. RESULTS: One hundred and forty-one subjects were recruited and 139 (99%) agreed to participate, including 134 men and 5 women. The SF12-P and SF12-M scores were significantly below the Canadian population mean values (P < 0.001), indicating lower QOL. In the multiple regression analysis, the predictor with the largest partial R (2) value for both the SF12-P and SF12-M was the upper extremity pain score. CONCLUSIONS: Both the physical and the mental QOL in workers with HAVS were below Canadian population normal values and subjects' upper extremity pain score had the greatest effect on their QOL. PMID- 24486513 TI - Induced overexpression of phospholemman S68E mutant improves cardiac contractility and mortality after ischemia-reperfusion. AB - Phospholemman (PLM), when phosphorylated at Ser(68), inhibits cardiac Na+ / Ca2+ exchanger 1 (NCX1) and relieves its inhibition on Na+ -K+ -ATPase. We have engineered mice in which expression of the phosphomimetic PLM S68E mutant was induced when dietary doxycycline was removed at 5 wk. At 8-10 wk, compared with noninduced or wild-type hearts, S68E expression in induced hearts was ~35-75% that of endogenous PLM, but protein levels of sarco(endo)plasmic reticulum Ca2+ ATPase, alpha1- and alpha2-subunits of Na+ -K+ -ATPase, alpha1c-subunit of L-type Ca2+ channel, and phosphorylated ryanodine receptor were unchanged. The NCX1 protein level was increased by ~47% but the NCX1 current was depressed by ~34% in induced hearts. Isoproterenol had no effect on NCX1 currents but stimulated Na+ K+ -ATPase currents equally in induced and noninduced myocytes. At baseline, systolic intracellular Ca2+ concentrations ([Ca2+]i), sarcoplasmic reticulum Ca2+ contents, and [Ca(2+)]i transient and contraction amplitudes were similar between induced and noninduced myocytes. Isoproterenol stimulation resulted in much higher systolic [Ca2+]i, sarcoplasmic reticulum Ca2+ content, and [Ca2+]i transient and contraction amplitudes in induced myocytes. Echocardiography and in vivo close-chest catheterization demonstrated similar baseline myocardial function, but isoproterenol induced a significantly higher +dP/dt in induced compared with noninduced hearts. In contrast to the 50% mortality observed in mice constitutively overexpressing the S68E mutant, induced mice had similar survival as wild-type and noninduced mice. After ischemia-reperfusion, despite similar areas at risk and left ventricular infarct sizes, induced mice had significantly higher +dP/dt and -dP/dt and lower perioperative mortality compared with noninduced mice. We propose that phosphorylated PLM may be a novel therapeutic target in ischemic heart disease. PMID- 24486515 TI - Efficient visual search for multiple targets among categorical distractors: effects of distractor-distractor similarity across trials. AB - We trained one group of pigeons to search for members of an artificial category among category-unspecified nonmembers. For another group of pigeons, the roles of the targets and of the distractors were reversed. Experiment 1 found that the latter group showed surprisingly efficient search for multiple nonmembers. Search times in this group were generally faster than those in the former group, regardless of the display size. In Experiment 2, search efficiency of the former group decreased with novel, poor, exemplars of the target category, whereas the latter group continued to exhibit efficient search for the nonmembers among novel members of the category. The former group eventually developed efficient search for all the targets through practice, but search time remained longer than in the latter group. These findings suggest that distractor-distractor, not target target, similarity across trials facilitates search for multiple targets, by enhancing target salience relative to global contextual background of search scene. PMID- 24486517 TI - Design and optimization of beta-cell temperature sensor based on 63Ni-Si. AB - A theoretical study of the use of a beta-cell as a temperature sensor using MCNP4C Monte Carlo code is presented in this paper. Nickel-63 and silicon were selected as the beta source and semiconductor material, respectively. The maximum open-circuit voltage (VOC) is equal to 0.445 V with doping concentrations of NA=4 * 10(18)#/cm(3) and ND=8 * 10(19)#/cm(3) in the base and the emitter region, respectively, which, depending on the source activity, enables measurement in a wide range of temperature. The effects of the activity and its change over time on VOC were also studied. The results demonstrated that VOC exhibited smaller changes for higher activities. The temperature sensitivity of this sensor ranges from -2.42 mV/K to -3.41 mV/K for source activities from 100 mCi to 0.001 mCi, respectively, so the optimal activity can be determined according to the desired temperature range and sensitivity. PMID- 24486516 TI - A recombinant fusion protein containing a spider toxin specific for the insect voltage-gated sodium ion channel shows oral toxicity towards insects of different orders. AB - Recombinant fusion protein technology allows specific insecticidal protein and peptide toxins to display activity in orally-delivered biopesticides. The spider venom peptide delta-amaurobitoxin-PI1a, which targets insect voltage-gated sodium channels, was fused to the "carrier" snowdrop lectin (GNA) to confer oral toxicity. The toxin itself (PI1a) and an amaurobitoxin/GNA fusion protein (PI1a/GNA) were produced using the yeast Pichia pastoris as expression host. Although both proteins caused mortality when injected into cabbage moth (Mamestra brassicae) larvae, the PI1a/GNA fusion was approximately 6 times as effective as recombinant PI1a on a molar basis. PI1a alone was not orally active against cabbage moth larvae, but a single 30 MUg dose of the PI1a/GNA fusion protein caused 100% larval mortality within 6 days when fed to 3rd instar larvae, and caused significant reductions in survival, growth and feeding in 4th - 6th instar larvae. Transport of fusion protein from gut contents to the haemolymph of cabbage moth larvae, and binding to the nerve chord, was shown by Western blotting. The PI1a/GNA fusion protein also caused mortality when delivered orally to dipteran (Musca domestica; housefly) and hemipteran (Acyrthosiphon pisum; pea aphid) insects, making it a promising candidate for development as a biopesticide. PMID- 24486518 TI - 99mTc carbonyl DTPA-rituximab: preparation and preliminary bioevaluation. AB - The anti CD20 antibody Rituximab was conjugated with para isothiocyanato benzyl diethylene triamine penta acetic acid (p-NCS-Bz-DTPA) and subsequent radiolabeling with (99m)Tc was carried out via the (99m)Tc carbonyl synthon. The (99m)Tc labeled antibody conjugate exhibited >95% radiochemical purity after purification and retained good in vitro stability when studied up to 24h at room temperature. In vitro cell binding studies carried out in Raji cells expressing CD20 antigen validated the biological efficacy of the preparation. PMID- 24486519 TI - Reprint of "Assessment of marker proteins identified in whole cell extracts for bacterial speciation using liquid chromatography electrospray ionization tandem mass spectrometry". AB - Staphylococcal strains (CoNS) were speciated in this study. Digests of proteins released from whole cells were converted to tryptic peptides for analysis. Liquid chromatography electrospray ionization tandem mass spectrometry (LC-ESI MS/MS, Orbitrap) was employed for peptide analysis. Data analysis was performed employing the open-source software X!Tandem which uses sequenced genomes to generate a virtual peptide database for comparison to experimental data. The search database was modified to include the genomes of the 11 Staphylococcus species most commonly isolated from man. The number of total peptides matching each protein along with the number of peptides specifically matching to the homologue (or homologues) for strains of the same species were assessed. Any peptides not matching to the species examined were considered conflict peptides. The proteins typically identified with the largest percentage of sequence coverage, number of matched peptides and number of peptides corresponding to only the correct species were elongation factor Tu (EF Tu) and enolase (Enol). Additional proteins with consistently observed peptides as well as peptides matching only homologues from the same species were citrate synthase (CS) and 1 pyrroline-5-carboxylate dehydrogenase (1P5CD). Protein markers, previously identified from gel slices, (aconitate hydratase and oxoglutarate dehydrogenase) were found to provide low confidence scores when employing whole cell digests. The methodological approach described here provides a simple yet elegant way of identification of staphylococci. However, perhaps more importantly the technology should be applicable universally for identification of any bacterial species. PMID- 24486520 TI - Etiology of depression comorbidity in combat-related PTSD: a review of the literature. AB - Posttraumatic stress disorder is often diagnosed with other mental health problems, particularly depression. Although PTSD comorbidity has been associated with more severe and chronic symptomology, relationships among commonly co occurring disorders are not well understood. The purpose of this study was to review the literature regarding the development of depression comorbid with combat-related PTSD among military personnel. We summarize results of commonly tested hypotheses about the etiology of PTSD and depression comorbidity, including (1) causal hypotheses, (2) common factor hypotheses, and (3) potential confounds. Evidence suggests that PTSD may be a causal risk factor for subsequent depression; however, associations are likely complex, involving bidirectional causality, common risk factors, and common vulnerabilities. The unique nature of PTSD-depression comorbidity in the context of military deployment and combat exposure is emphasized. Implications of our results for clinical practice and future research are discussed. PMID- 24486521 TI - Changes in attitudes toward seeking mental health services: a 40-year cross temporal meta-analysis. AB - Although rates of treatment seeking for mental health problems are increasing, this increase is driven primarily by antidepressant medication use, and a majority of individuals with mental health problems remain untreated. Helpseeking attitudes are thought to be a key barrier to mental health service use, although little is known about whether such attitudes have changed over time. Research on this topic is mixed with respect to whether helpseeking attitudes have become more or less positive. The aim of the current study was to help clarify this issue using a cross-temporal meta-analysis of scores on Fischer and Turner's (1970) helpseeking attitude measure among university students (N=6796) from 1968 to 2008. Results indicated that attitudes have become increasingly negative over time, r(44)=-0.53, p<0.01, with even stronger negative results when the data are weighted (w) for sample size and study variance, r(44)=-0.63, p<.001. This disconcerting finding may reflect the greater emphasis of Fischer and Turner's scale toward helpseeking for psychotherapy. Such attitudes may be increasingly negative as a result of the unintended negative effects of efforts in recent decades to reduce stigma and market biological therapies by medicalizing mental health problems. PMID- 24486522 TI - Reflective functioning: a review. AB - Reflective functioning offers an empirically grounded framework for the assessment of mentalization. This article briefly outlines the theory of mentalization and the development of the Reflective Functioning (RF) scale (Fonagy, Target, Steele, & Steele, 1998). It then offers a review and discussion of empirical studies of parental RF regarding the role of RF in linking adult and child attachment and parental RF in the context of psychopathology. Furthermore, empirical studies on RF in relation to different psychiatric populations and to the role of RF in psychotherapy process and outcome are reviewed and discussed. Although research on RF is still relatively limited, evidence seems to support the relevance of RF as an empirical measure in the fields of attachment, psychopathology and psychotherapy research. However, the RF scale has certain limitations due to the extensiveness of the measure, which future research should take into account. PMID- 24486523 TI - Depression Anxiety Stress Scales-21: measurement and structural invariance across ratings of men and women. AB - The current study examined the measurement and structural invariance of the Depression Anxiety Stress Scales-21 (DASS-21) across ratings provided by men (N = 227) and women (N = 460). Multiple-group confirmatory factor analysis (CFA) supported full metric invariance and intercepts invariance for 20 of the 21 items. Invariance for all item intercepts was supported by multiple indicators multiple causes (MIMIC) procedure that controlled for the effects of age. Multiple-group CFA supported invariance for all factor variances and covariances. This procedure and the MIMIC analyses found equivalency for all latent mean scores. These findings indicate good support for measurement and structural invariance of the DASS-21 rating across men and women. The psychometric and practical implications of the findings are discussed. PMID- 24486524 TI - p53 inactivation decreases dependence on estrogen/ERK signalling for proliferation but promotes EMT and susceptility to 3-bromopyruvate in ERalpha+ breast cancer MCF-7 cells. AB - BACKGROUND: Most breast cancers express the estrogen receptor alpha (ERalpha(+)), harbor wt TP53, depend on estrogen/ERK signalling for proliferation, and respond to anti-estrogens. However, concomittant activation of the epidermal growth factor receptor (EGFR)/MEK pathway promotes resistance by decreasing estrogen dependence. Previously, we showed that retroviral transduction of mutant p53 R175H into wt TP53 ERalpha(+) MCF-7 cells induces epidermal growth factor (EGF) independent proliferation, activation of the EGF receptor (p-EGFR) and some characteristics of epithelial-mesenchymal transition (EMT). PURPOSE: To investigate whether p53 inactivation augments ERalpha(+) cell proliferation in response to restrictive estradiol, chemical MEK inhibition or metabolic inhibitors. RESULTS: Introduction of mutant p53 R175H lowered expression of p53 dependent PUMA and p21WAF1, decreased E-cadherin and cytokeratin 18 associated with EMT, but increased the % of proliferating ERalpha(+)/Ki67 cells, diminishing estrogen dependence. These cells also exhibited higher proliferation in the presence of MEK-inhibitor UO126, reciprocally correlating with preferential susceptibility to the pyruvate analog 3-bromopyruvate (3-BrPA) without a comparable response to 2-deoxyglucose. p53 siRNA silencing by electroporation in wt TP53 MCF-7 cells also decreased estrogen dependence and response to MEK inhibition, while also conferring susceptibility to 3-BrPA. CONCLUSIONS: (a) ERalpha(+) breast cancer cells dysfunctional for TP53 which proliferate irrespective of low estrogen and chemical MEK inhibition are likely to increase metabolic consumption becoming increasingly susceptible to 3-BrPA; (b) targeting the pyruvate pathway may improve response to endocrine therapy in ERalpha(+) breast cancer with p53 dysfunction. PMID- 24486525 TI - Pharmacological profiles of aminoindanes, piperazines, and pipradrol derivatives. AB - Aminoindanes, piperazines, and pipradrol derivatives are novel psychoactive substances found in "Ecstasy" tablets as replacements for 3,4 methylenedioxymethamphetamine (MDMA) or substances sold as "ivory wave." The pharmacology of these MDMA- and methylphenidate-like substances is poorly known. We characterized the pharmacology of the aminoindanes 5,6-methylenedioxy-2 aminoindane (MDAI), 5-iodoaminoindane (5-IAI), and 2-aminoindane (2-AI), the piperazines meta-chlorophenylpiperazine (m-CPP), trifluoromethylphenylpiperazine (TFMPP), and 1-benzylpiperazine (BZP), and the pipradrol derivatives desoxypipradrol (2-diphenylmethylpiperidine [2-DPMP]), diphenylprolinol (diphenyl 2-pyrrolidinemethanol [D2PM]), and methylphenidate. We investigated norepinephrine (NE), dopamine (DA), and serotonin (5-hydroxytryptamine [5-HT]) uptake inhibition using human embryonic kidney 293 (HEK 293) cells that express the respective human monoamine transporters (NET, DAT, and SERT). We also evaluated the drug-induced efflux of NE, DA, and 5-HT from monoamine-preloaded cells and the binding affinity to monoamine transporters and receptors, including trace amine-associated receptor 1 (TAAR1). 5-IAI and MDAI preferentially inhibited the SERT and NET and released 5-HT. 2-AI interacted with the NET. BZP blocked the NET and released DA. m-CPP and TFMPP interacted with the SERT and serotonergic receptors. The pipradrol derivatives were potent and selective catecholamine transporter blockers without substrate releasing properties. BZP, D2PM, and 2-DPMP lacked serotonergic activity and TAAR1 binding, in contrast to the aminoindanes and phenylpiperazines. In summary, all of the substances were monoamine transporter inhibitors, but marked differences were found in their DAT vs. SERT inhibition profiles, release properties, and receptor interactions. The pharmacological profiles of D2PM and 2-DPMP likely predict a high abuse liability. PMID- 24486526 TI - Differential suppression of the aryl hydrocarbon receptor nuclear translocator dependent function by an aryl hydrocarbon receptor PAS-A-derived inhibitory molecule. AB - The aryl hydrocarbon receptor (AhR) heterodimerizes with the aryl hydrocarbon receptor nuclear translocator (Arnt) for transcriptional regulation. We generated three N-terminal deletion constructs of the human AhR of 12-24 kDa in size- namely D1, D2, and D3--to suppress the Arnt function. We observed that all three deletions interact with the human Arnt with similar affinities. D2, which contains part of the AhR PAS-A domain and interacts with the PAS-A domain of Arnt, inhibits the formation of the AhR gel shift complex. D2 suppresses the 3 methylcholanthrene-induced, dioxin response element (DRE)-driven luciferase activity in Hep3B cells and exogenous Arnt reverses this D2 suppression. D2 suppresses the induction of CYP1A1 at both the message and protein levels in Hep3B cells; however, the CYP1B1 induction is not affected. D2 suppresses the recruitment of Arnt to the cyp1a1 promoter but not to the cyp1b1 promoter, partly because the AhR/Arnt heterodimer binds better to the cyp1b1 DRE than to the cyp1a1 DRE. Interestingly, D2 has no effect on the cobalt chloride-induced, hypoxia inducible factor-1 (HIF-1)-dependent expression of vegf, aldolase c, and ldh-a messages. Our data reveal that the flanking sequences of the DRE contribute to the binding affinity of the AhR/Arnt heterodimer to its endogenous enhancers and the function of AhR and HIF-1 can be differentially suppressed by the D2 inhibitory molecule. PMID- 24486529 TI - Dopant mapping in thin FIB prepared silicon samples by Off-Axis Electron Holography. AB - Modern semiconductor devices function due to accurate dopant distribution. Off Axis Electron Holography (OAEH) in the transmission electron microscope (TEM) can map quantitatively the electrostatic potential in semiconductors with high spatial resolution. For the microelectronics industry, ongoing reduction of device dimensions, 3D device geometry, and failure analysis of specific devices require preparation of thin TEM samples, under 70 nm thick, by focused ion beam (FIB). Such thicknesses, which are considerably thinner than the values reported to date in the literature, are challenging due to FIB induced damage and surface depletion effects. Here, we report on preparation of TEM samples of silicon PN junctions in the FIB completed by low-energy (5 keV) ion milling, which reduced amorphization of the silicon to 10nm thick. Additional perpendicular FIB sectioning enabled a direct measurement of the TEM sample thickness in order to determine accurately the crystalline thickness of the sample. Consequently, we find that the low-energy milling also resulted in a negligible thickness of electrically inactive regions, approximately 4nm thick. The influence of TEM sample thickness, FIB induced damage and doping concentrations on the accuracy of the OAEH measurements were examined by comparison to secondary ion mass spectrometry measurements as well as to 1D and 3D simulations of the electrostatic potentials. We conclude that for TEM samples down to 100 nm thick, OAEH measurements of Si-based PN junctions, for the doping levels examined here, resulted in quantitative mapping of potential variations, within ~0.1 V. For thinner TEM samples, down to 20 nm thick, mapping of potential variations is qualitative, due to a reduced accuracy of ~0.3 V. This article is dedicated to the memory of Zohar Eliyahou. PMID- 24486527 TI - Degradation of connexins and gap junctions. AB - Connexin proteins are short-lived within the cell, whether present in the secretory pathway or in gap junction plaques. Their levels can be modulated by their rate of degradation. Connexins, at different stages of assembly, are degraded through the proteasomal, endo-/lysosomal, and phago-/lysosomal pathways. In this review, we summarize the current knowledge about connexin and gap junction degradation including the signals and protein-protein interactions that participate in their targeting for degradation. PMID- 24486528 TI - Connectivity of vertebrate genomes: Paired-related homeobox (Prrx) genes in spotted gar, basal teleosts, and tetrapods. AB - Teleost fish are important models for human biology, health, and disease. Because genome duplication in a teleost ancestor (TGD) impacts the evolution of teleost genome structure and gene repertoires, we must discriminate gene functions that are shared and ancestral from those that are lineage-specific in teleosts or tetrapods to accurately apply inferences from teleost disease models to human health. Generalizations must account both for the TGD and for divergent evolution between teleosts and tetrapods after the likely two rounds of genome duplication shared by all vertebrates. Progress in sequencing techniques provides new opportunities to generate genomic and transcriptomic information from a broad range of phylogenetically informative taxa that facilitate detailed understanding of gene family and gene function evolution. We illustrate here the use of new sequence resources from spotted gar (Lepisosteus oculatus), a rayfin fish that diverged from teleosts before the TGD, as well as RNA-Seq data from gar and multiple teleost lineages to reconstruct the evolution of the Paired-related homeobox (Prrx) transcription factor gene family, which is involved in the development of mesoderm and neural crest-derived mesenchyme. We show that for Prrx genes, the spotted gar genome and gene expression patterns mimic mammals better than teleosts do. Analyses force the seemingly paradoxical conclusion that regulatory mechanisms for the limb expression domains of Prrx genes existed before the evolution of paired appendages. Detailed evolutionary analyses like those reported here are required to identify fish species most similar to the human genome to optimally connect fish models to human gene functions in health and disease. PMID- 24486530 TI - Identification, by RT-PCR, of eight novel I2-conotoxins from the worm-hunting cone snails Conus brunneus, Conus nux, and Conus princeps from the eastern Pacific (Mexico). AB - Marine snails of the genus Conus (~500 species) are tropical predators that produce venoms for capturing prey, defense and competitive interactions. These venoms contain 50-200 different peptides ("conotoxins") that generally comprise 7 40 amino acid residues (including 0-5 disulfide bridges), and that frequently contain diverse posttranslational modifications, some of which have been demonstrated to be important for folding, stability, and biological activity. Most conotoxins affect voltage- and ligand-gated ion channels, G protein-coupled receptors, and neurotransmitter transporters, generally with high affinity and specificity. Due to these features, several conotoxins are used as molecular tools, diagnostic agents, medicines, and models for drug design. Based on the signal sequence of their precursors, conotoxins have been classified into genetic superfamilies, whereas their molecular targets allow them to be classified into pharmacological families. The objective of this work was to identify and analyze partial cDNAs encoding precursors of conotoxins belonging to I superfamily from three vermivorous species of the Mexican Pacific coast: C. brunneus, C. nux and C. princeps. The precursors identified contain diverse numbers of amino acid residues (C. brunneus, 65 or 71; C. nux, 70; C. princeps, 72 or 73), and all include a highly conserved signal peptide, a C-terminal propeptide, and a mature toxin. All the latter have one of the typical Cys frameworks of the I-conotoxins (C-C-CC-CC-C-C). The prepropeptides belong to the I2-superfamily, and encode eight different hydrophilic and acidic mature toxins, rather similar among them, and some of which have similarity with I2-conotoxins targeting voltage- and voltage-and-calcium-gated potassium channels. PMID- 24486531 TI - Subchronic, reproductive, and maternal toxicity studies with tertiary butyl acetate (TBAC). AB - Tertiary-butyl acetate (TBAC) was tested for subchronic toxicity in rats and mice and reproductive toxicity in rats at inhalation concentrations of 0, 100, 400 or 1600ppm. An oral maternal toxicity study was conducted in rats at dose levels of 0, 400, 800, 1000 and 1600mgkg(-1)d(-1). In the inhalation studies, hematology, clinical chemistry, urinalysis, gross pathology and the majority of body weight and feed consumption values were unaffected. Exposure to TBAC at concentrations of 400ppm and higher caused transient hyperactivity in mice and some evidence of increased motor activity counts in male rats at the 1600ppm exposure level. TBAC caused alpha2u-globulin accumulation in male rat kidneys from all exposure groups and increased liver weights in 1600ppm rats and mice. Levels of thyroxin were decreased in male mice exposed to 1600ppm TBAC for 4weeks but otherwise thyroid endpoints were unaffected in rats and mice at either the 4 or 13weeks time points. There was no evidence or immunotoxicity or reproductive toxicity in rats. Pregnant rats receiving 1000mgkg(-1)d(-1) TBAC exhibited severe signs of acute neurotoxicity and decreased feed consumption and body weight gain. Fetal viability and growth were unaffected. PMID- 24486532 TI - The metrics of MWCNT-induced pulmonary inflammation are dependent on the selected testing regimen. AB - Convincing evidence suggests that high-surface-activity nano-materials, such as MWCNT, exert two modes of action (MoA), in which one appears to be related to surface activity/area and occurs concurrent with deposition, and the other is related to cumulative lung burden. Pulmonary inflammation induced by the latter mode appears to be dependent on cumulative volumetric lung burden and on whether the accumulated particle displacement volume within the pool of alveolar macrophages is above or below the kinetic lung overload threshold. However, the relative importance and effect of each MoA are still controversial. In addition, the test protocol variables, which may predetermine the leading MoA, have not yet received increased attention. This study compares the respective outcome of previously published repeated-exposure inhalation studies with MWCNT (Nanocyl and Baytube) in rats. Modeling procedures were performed to compare post hoc the equivalence of empirical and modeled outcomes, including critical protocol variables. This comparison provided compelling evidence that the accumulated retained particle displacement volume was the most prominent unifying denominator linking the pulmonary retained volumetric particle dose to inflammogenicity and toxicity. However, conventional study designs may not always be appropriate to unequivocally dissociate the surface area/activity-related acute adversity from the cumulative retention volume-related adversity. Thus, in the absence of adequately designed studies, it may become increasingly challenging to differentiate substance-specific deposition-related acute effects from the more chronic retained cumulative dose-related effects. In summary, this analysis of existing data supports the conclusion that both the deposition and retention related effects need to be judiciously dissociated to better understand the MoA of heightened concern. This exercise supports the conclusion that hypothesis based computational study design delivers the highest degree of scientifically important information and may further reduce the number of experimental animals in repeated-exposure inhalation studies with low-toxicity, biopersistent, poorly soluble granular particles. PMID- 24486533 TI - Phytoremediation of dredged marine sediment: monitoring of chemical and biochemical processes contributing to sediment reclamation. AB - In this study, a pilot phytoremediation experiment was performed to treat about 80 m(3) of silty saline sediments contaminated by heavy metals and organic compounds. After preliminary mixing with a sandy soil and green compost application, three different plant treatments [Paspalum vaginatum (P); P. vaginatum + Spartium junceum (P + S); P. vaginatum + Tamarix gallica (P + T)] were compared to each other and to an unplanted control (C) in order to evaluate the plant efficiency in remediating and ameliorating agronomical and functional sediment properties. The experiment was monitored for one year after planting by taking sediment samples at two depths and performing several chemical and biochemical analyses. After one year, the increase in hydrolytic enzyme and dehydrogenase activities indicated the stimulation of sediment functionality. Additionally, the availability of energy sources derived from organic matter application and plant-root activity promoted the formation of a stable organic matter fraction. Finally, P + S and P + T were also effective in decontaminating polluted marine sediments from both organic (total petroleum hydrocarbons, TPH) and inorganic (heavy metal) pollutants. PMID- 24486534 TI - A rhamnose-binding lectin from sea bass (Dicentrarchus labrax) plasma agglutinates and opsonizes pathogenic bacteria. AB - The discovery of rhamnose-binding lectins (RBLs) in teleost fish eggs led to the identification of a novel lectin family characterized by a unique sequence motif and a structural fold, and initially proposed to modulate fertilization. Further studies of the RBL tissue localization and gene organization were also suggestive of role(s) in innate immunity. Here we describe the purification, and biochemical and functional characterization of a novel RBL (DlRBL) from sea bass (Dicentrarchus labrax) serum. The purified DlRBL had electrophoretic mobilities corresponding to 24 kDa and 100 kDa under reducing and non-reducing conditions, respectively, suggesting that in plasma the DlRBL is present as a physiological homotetramer. DlRBL subunit transcripts revealed an open reading frame encoding 212 amino acid residues that included two tandemly-arrayed carbohydrate recognition domains, and an 18-residue signal sequence at the N-terminus. The deduced size of 24.1 kDa for the mature protein was in good agreement with the subunit size of the isolated lectin. Binding activity of DlRBL for rabbit erythrocytes could be inhibited in the presence of rhamnose or galactose, did not require calcium, and was optimal at around 20 degrees C and within the pH 6.5-8.0 range. DlRBL agglutinated Gram positive and Gram negative bacteria, and exposure of formalin-killed Escherichia coli to DlRBL enhanced their phagocytosis by D. labrax peritoneal macrophages relative to the unexposed controls. Taken together, the results suggest that plasma DlRBL may play a role in immune recognition of microbial pathogens and facilitate their clearance by phagocytosis. PMID- 24486535 TI - MAUDE: analysis of robotic-assisted gynecologic surgery. AB - STUDY OBJECTIVE: To evaluate the adverse events encountered during robotic gynecologic surgery, as reported to the FDA MAUDE database from January 2006 to December 2012. DESIGN: Database search (Canadian Task Force classification III). INTERVENTION: A search of the FDA MAUDE database was performed by brand name "da Vinci" and manufacturer "Intuitive Surgical." Reports reflecting gynecologic procedures either by description or procedure name were included. A record of reports was kept to ensure that no duplicates were added. The date and type of event (operator-related error, technical system failure, or surgical injuries attributed to use of the robot) and the clinical outcome were recorded. MEASUREMENTS AND MAIN RESULTS: Twenty-six percent of reported events (n = 73) resulted in injury, and 8.5% (n = 24) resulted in death. Of note, although adnexal procedures were performed in <3% of the cohort, they accounted for 20% of the fatalities. Twenty-one percent of injuries were attributed to operator related error, and 14% to technical system failure; 65% were not directly related to use of the robot. Fifteen deaths were reported during planned hysterectomy. Four of those were due to injury to a major blood vessel (iliac artery in 3, and aorta in 1), although a detailed description of how the injury occurred was absent from the event description. CONCLUSION: It is important to continue to evaluate the occurrence of injuries during robot-assisted surgery in an effort to identify unique challenges associated with this advanced technology. PMID- 24486536 TI - Surface architecture in endometrial tuberculosis. PMID- 24486537 TI - Duplicated renal excretion system in an extraperitoneal laparoscopy for para aortic lymphadenectomy. PMID- 24486538 TI - Villagers in rural India stage anti-superstition march after boy dies from untreated appendicitis. PMID- 24486539 TI - Testosterone therapy is associated with raised risk of myocardial infarction, US study finds. PMID- 24486540 TI - Identification and profiling of sex-biased microRNAs from sea urchin Strongylocentrotus nudus gonad by Solexa deep sequencing. AB - MicroRNAs (miRNAs) are a class of endogenous small non-coding RNAs that regulate gene expression by post-transcriptional repression of messenger RNA. The echinoderm, Strongylocentrotus nudus, is an excellent model organism for studying development and commercially important as a food source. However, to date no miRNAs have been reported to modulate sex gonad differentiation in S. nudus. In this study, we constructed two small RNA libraries from male and female S. nudus gonad respectively for Solexa sequencing. A total of 184 miRNAs including 60 known and 124 novel miRNAs were identified from the two libraries. Furthermore, the nucleotide bias and end variation of the known miRNAs were also analyzed. In addition, 67 differently expressed of the 86 co-expressed and 98 gender-specific (47 male-specific and 51 female-specific) miRNAs that may be involved in sexual differentiation were found by comparing the miRNA expression profiles in the two libraries. This study reveals the first miRNA profile related to the gonad differentiation of the S. nudus. This study gives a first insight into sex differences in miRNA expression of sea urchin which could facilitate studies of the reproductive organ-specific roles of miRNAs. PMID- 24486541 TI - A role for trans-caryophyllene in the moderation of insulin secretion. AB - Glucose-stimulated insulin secretion (GSIS) is essential for the control of metabolic fuel homeostasis and its impairment is a key element in the failure of beta-cells in type 2 diabetes. Trans-caryophyllene (TC), an important constituent of the essential oil of several species of plants, has been reported to activate the type 2 cannabinoid receptor (CB2R). The effects of TC on GSIS are still unknown. Our results demonstrate that administration of TC in MIN6 cells promotes GSIS in a dose dependent manner. However, inhibition of CB2R by a specific inhibitor or specific RNA interference abolished the effects of TC on GSIS, which suggests that the effects of TC on GSIS are dependent on activation of CB2R. Further study demonstrated that treatment with TC leads to the activation of small G protein Arf6 as well as Rac1 and Cdc42. Importantly, Arf6 silencing abolished the effects of TC on GSIS, which suggests that Arf6 participates in mediating the effects of TC on GSIS. We conclude from these data that TC has a novel role in regulating GSIS in pancreatic beta-cells. PMID- 24486542 TI - Lack of anti-tumor activity with the beta-catenin expression inhibitor EZN-3892 in the C57BL/6J Min/+ model of intestinal carcinogenesis. AB - BACKGROUND: Previously, we showed that short-term inhibition of beta-catenin expression and reversal of aberrant beta-catenin subcellular localization by the selective COX-2 inhibitor celecoxib is associated with adenoma regression in the C57BL/6J Min/+ mouse. Conversly, long-term administration resulted in tumor resistance, leading us to investigate alternative methods for selective beta catenin chemoprevention. In this study, we hypothesized that disruption of beta catenin expression by EZN-3892, a selective locked nucleic acid (LNA)-based beta catenin inhibitor, would counteract the tumorigenic effect of Apc loss in Min/+ adenomas while preserving normal intestinal function. MATERIALS AND METHODS: C57BL/6J Apc(+/+) wild-type (WT) and Min/+ mice were treated with the maximum tolerated dose (MTD) of EZN-3892 (30mg/kg). Drug effect on tumor numbers, beta catenin protein expression, and nuclear beta-catenin localization were determined. RESULTS: Although the tumor phenotype and beta-catenin nuclear localization in Min/+ mice did not change following drug administration, we observed a decrease in beta-catenin expression levels in the mature intestinal tissue of treated Min/+ and WT mice, providing proof of principle regarding successful delivery of the LNA-based antisense vehicle. Higher doses of EZN-3892 resulted in fatal outcomes in Min/+ mice, likely due to beta-catenin ablation in the intestinal tissue and loss of function. CONCLUSIONS: Our data support the critical role of Wnt/beta-catenin signaling in maintaining intestinal homeostasis and highlight the challenges of effective drug delivery to target disease without permanent toxicity to normal cellular function. PMID- 24486543 TI - Diacylglycerol kinase gamma is a novel anionic phospholipid binding protein with a selective binding preference. AB - There are ten isozymes of diacylglycerol kinase (DGK), and they regulate diverse patho-physiological functions. Here, we investigated the lipid-binding properties of DGK isozymes using protein-lipid overlay and liposome-binding assays. DGKgamma showed a strong binding activity compared with other DGK isozymes for phosphatidic acid (PA) among the various glycerophospholipids tested. However, DGKgamma failed to interact with DG and lyso-PA. Moreover, the isozyme was capable of binding to ceramide-1-phosphate but not to ceramide or sphingosine-1 phosphate. The isozyme bound more strongly to PA containing unsaturated fatty acid than to PA having only saturated fatty acid. An analysis using a series of deletion mutants of DGKgamma revealed that the N-terminal region, which contains a recoverin homology domain and EF-hand motifs, is responsible for the PA binding activity of DGKgamma. Taken together, these results indicate that DGKgamma is an anionic phospholipid binding protein that preferably interacts with a small highly charged head group that is very close to the glycerol or sphingosine backbone. PMID- 24486544 TI - PITX2 associates with PTIP-containing histone H3 lysine 4 methyltransferase complex. AB - Pituitary homeobox 2 (PITX2), a Paired-like homeodomain transcription factor and a downstream effector of Wnt/beta-catenin signaling, plays substantial roles in embryonic development and human disorders. The mechanism of its functions, however, is not fully understood. In this study, we demonstrated that PITX2 associated with histone H3 lysine 4 (H3K4) methyltransferase (HKMT) mixed-lineage leukemia 4 (MLL4/KMT2D), Pax transactivation domain-interacting protein (PTIP), and other H3K4.HKMT core subunits. This association of PITX2 with H3K4.HKMT complex was dependent on PITX2's homeodomain. Consistently, the PITX2 protein complex was shown to possess H3K4.HKMT activity. Furthermore, the chromatin immunoprecipitation result revealed co-occupancy of PITX2 and PTIP on the promoter of the PITX2's transcriptional target. Taken together, our data provide new mechanistic perspectives on PITX2's functions and its related biological processes. PMID- 24486545 TI - Arabidopsis G-protein beta subunit AGB1 interacts with NPH3 and is involved in phototropism. AB - Heterotrimeric G proteins (Galpha, Gbeta and Ggamma) have pleiotropic roles in plants, but molecular mechanisms underlying them remain to be elucidated. Here we show that Arabidopsis Gbeta (AGB1) interacts with NPH3, a regulator of phototropism. Yeast two-hybrid assays, in vitro pull-down assays and bimolecular fluorescence complementation assays showed that AGB1 and NPH3 physically interact. NPH3-null mutation (nph3) is known to completely abolish hypocotyl phototropism. Loss-of-function mutants of AGB1 (agb1-1 and agb1-2) showed decreased hypocotyl phototropism, and agb1/nph3 double mutants showed no hypocotyl phototropism. These results suggest that AGB1 is involved in the NPH3 mediated regulation of phototropism. PMID- 24486547 TI - De-repression of RaRF-mediated RAR repression by adenovirus E1A in the nucleolus. AB - Transcriptional activity of the retinoic acid receptor (RAR) is regulated by diverse binding partners, including classical corepressors and coactivators, in response to its ligand retinoic acid (RA). Recently, we identified a novel corepressor of RAR called the retinoic acid resistance factor (RaRF) (manuscript submitted). Here, we report how adenovirus E1A stimulates RAR activity by associating with RaRF. Based on immunoprecipitation (IP) assays, E1A interacts with RaRF through the conserved region 2 (CR2), which is also responsible for pRb binding. The first coiled-coil domain of RaRF was sufficient for this interaction. An in vitro glutathione-S-transferase (GST) pull-down assay was used to confirm the direct interaction between E1A and RaRF. Further fluorescence microscopy indicated that E1A and RaRF were located in the nucleoplasm and nucleolus, respectively. However, RaRF overexpression promoted nucleolar translocation of E1A from the nucleoplasm. Both the RA-dependent interaction of RAR with RaRF and RAR translocation to the nucleolus were disrupted by E1A. RaRF mediated RAR repression was impaired by wild-type E1A, but not by the RaRF binding-defective E1A mutant. Taken together, our data suggest that E1A is sequestered to the nucleolus by RaRF through a specific interaction, thereby leaving RAR in the nucleoplasm for transcriptional activation. PMID- 24486546 TI - Diversity of amino acid signaling pathways on autophagy regulation: a novel pathway for arginine. AB - Autophagy is the intracellular bulk degradation process to eliminate damaged cellular machinery and to recycle building blocks, and is crucial for cell survival and cell death. Amino acids modulate autophagy in response to nutrient starvation and oxidative stress. We investigated the relevance of reactive oxygen species (ROS) production on the regulation of autophagy using amino acids, both as a mixture and individually, in rat hepatoma H4-II-E cells. Nutrient starvation elevated ROS production and stimulated autophagy. Treatment with complete (CAA), regulatory (RegAA) and non-regulatory (NonRegAA) amino acid mixtures showed significant suppression of ROS production, whereas only CAA and RegAA exhibited significant suppression of autophagy, suggesting a dissociation of the two responses. The effects of individual amino acids were examined. Leucine from RegAA decreased ROS production and suppressed autophagy. However, methionine and proline from RegAA and arginine, cystine and glutamic acid from NonRegAA suppressed autophagy with an opposite increase in ROS production. Other amino acids from the NonRegAA group showed stimulating effects on ROS production without an autophagic response. Arginine's effect on autophagy suppression was not blocked by rapamycin, indicating an mTOR-independent pathway. Inhibitor studies on arginine-regulated autophagy may indicate the involvement of NO pathway, which is independent from ROS and mTOR pathways. PMID- 24486548 TI - Epigenetic silencing of MicroRNA-503 regulates FANCA expression in non-small cell lung cancer cell. AB - It is reported that MicroRNA-503 (miR-503) regulates cell apoptosis, and thus modulates the resistance of non-small cell lung cancer cells (NSCLC) to cisplatin. However, the exact role of miR-503 in NSCLC remains unknown. In the present study, the level of miR-503 expression in NSCLC was evaluated using realtime PCR, and the DNA methylation status within miR-503 promoter was analyzed by Combined Bisulfite Restriction Analysis (COBRA) or bisulfite-treated DNA sequencing assays (BSP). We found that the expression of miR-503 was significantly decreased in NSCLC tissues compared to normal tissues. A statistically significant inverse association was found between miR-503 methylation status and expression of the miR-503 in tumor tissues (P<0.001), and expression of miR-503 was restored by the demethylating agent 5-aza-2' deoxycytidine, suggesting that methylation was associated with the transcriptional silencing. Then, we show that miR-503 targets a homologous DNA region in the 3'-UTR region of the Fanconi anemia complementation group A protein (FANCA) gene and represses its expression at the transcriptional level. Taken together, our results suggest that miR-503 regulates the resistance of non-small cell lung cancer cells to cisplatin at least in part by targeting FANCA. PMID- 24486549 TI - The microRNA miR-17 regulates lung FoxA1 expression during lipopolysaccharide induced acute lung injury. AB - Acute lung injury (ALI) is a severe pulmonary disease that causes a high number of fatalities worldwide. Studies have shown that FoxA1 expression is upregulated during ALI and may play an important role in ALI by promoting the apoptosis of alveolar type II epithelial cells. However, the mechanism of FoxA1 overexpression in ALI is unclear. In this study, an in vivo murine model of ALI and alveolar type II epithelial cells injury was induced using lipopolysaccharide (LPS). LPS upregulated FoxA1 in the lung tissue of the in vivo ALI model and in LPS challenged type II epithelial cells. In contrast, miR-17 was significantly downregulated in these models. After miR-17 antagomir injection, the expression of FoxA1 was significantly increased in ALI mice. MiR-17 mimics could significantly inhibit FoxA1 mRNA and protein expression, whereas the miR-17 inhibitor could significantly increase FoxA1 mRNA and protein expression in LPS induced type II epithelial cells. Thus, our results suggest that the downregulation of miR-17 expression could lead to FoxA1 overexpression in ALI. PMID- 24486550 TI - The beta-domain of cluster 2b streptokinase is a major determinant for the regulation of its plasminogen activation activity by cellular plasminogen receptors. AB - Cluster 2b streptokinase (SK2b), secreted by invasive skin-trophic strains of Streptococcus pyogenes (GAS), is a human plasminogen (hPg) activator that optimally functions when human plasma hPg is bound, via its kringle-2 domain, to cognizant bacterial cells through the a1a2 domain of the major cellular hPg receptor, Plasminogen-binding group A streptococcal M-like protein (PAM). Another class of streptokinases (SK1), secreted primarily by GAS strains that possess affinity for pharyngeal infections, does not require PAM-bound hPg for optimal activity. We find herein that replacement of the central beta-domain of SK2b with the same module from SK1 reduces the dependency of SK2b on PAM, and the converse is true when the beta-domain of SK1 is replaced with this same region of SK2b. These data suggest that simple evolutionary shuttling of protein domains in GAS can be employed by GAS to rapidly generate strains that differ in tissue tropism and invasive capability and allow the bacteria to survive different challenges by the host. PMID- 24486551 TI - Cell-penetrating peptide-conjugated lipid nanoparticles for siRNA delivery. AB - Lipid nanoparticles (LNP) modified with cell-penetrating peptides (CPP) were prepared for the delivery of small interfering RNA (siRNA) into cells. Lipid derivatives of CPP derived from protamine were newly synthesized and used to prepare CPP-decorated LNP (CPP-LNP). Encapsulation of siRNA into CPP-LNP improved the stability of the siRNA in serum. Fluorescence-labeled siRNA formulated in CPP LNP was efficiently internalized into B16F10 murine melanoma cells in a time dependent manner, although that in LNP without CPP was hardly internalized into these cells. In cells transfected with siRNA in CPP-LNP, most of the siRNA was distributed in the cytoplasm of these cells and did not localize in the lysosomes. Analysis of the endocytotic pathway indicated that CPP-LNP were mainly internalized via macropinocytosis and heparan sulfate-mediated endocytosis. CPP LNP encapsulating siRNA effectively induced RNA interference-mediated silencing of reporter genes in B16F10 cells expressing luciferase and in HT1080 human fibrosarcoma cells expressing enhanced green fluorescent protein. These data suggest that modification of LNP with the protamine-derived CPP was effective to facilitate internalization of siRNA in the cytoplasm and thereby to enhance gene silencing. PMID- 24486552 TI - Human biological sample biobanking to support tissue biomarkers in pharmaceutical research and development. AB - Advances in the understanding of molecular pathology and thereby the mechanisms that could be amenable to therapeutic manipulation are the reason that pharmaceutical research and development is focused increasingly on measurement of molecular biomarkers in human biological samples. Obtaining direct or indirect access to sufficient samples that are fit for research purposes can be a major challenge. A biobanking infrastructure has a significant role in the acquisition, storage and usage of human biological samples and here we review some key requirements for establishing a biobank. These include ensuring; that appropriate governance mechanisms are in place, that samples available are appropriate and fit for the intended research purposes that the infrastructure is sustainable in the future and that use of the biobank assets meets the strategic aims of the host organisation. Finally we present a case study--the STRATUM project which has recently completed and through a collaborative approach involving six industry and public partners drawing on a network of experts, examined biobank policies, public attitudes to biobanking, donor consent, sample and data standards, technical requirements for a register and biobanking financial models, albeit from a UK perspective. PMID- 24486553 TI - S-Nitrosation of monocarboxylate transporter 1: inhibition of pyruvate-fueled respiration and proliferation of breast cancer cells. AB - Energy substrates metabolized through mitochondria (e.g., pyruvate, glutamine) are required for biosynthesis of macromolecules in proliferating cells. Because several mitochondrial proteins are known to be targets of S-nitrosation, we determined whether bioenergetics are modulated by S-nitrosation and defined the subsequent effects on proliferation. The nitrosating agent S-nitroso-L-cysteine (L-CysNO) was used to initiate intracellular S-nitrosation, and treatment decreased mitochondrial function and inhibited proliferation of MCF7 mammary adenocarcinoma cells. Surprisingly, the d-isomer of CysNO (D-CysNO), which is not transported into cells, also caused mitochondrial dysfunction and limited proliferation. Both L- and D-CysNO also inhibited cellular pyruvate uptake and caused S-nitrosation of thiol groups on monocarboxylate transporter 1, a proton linked pyruvate transporter. These data demonstrate the importance of mitochondrial metabolism in proliferative responses in breast cancer and highlight a novel role for inhibition of metabolic substrate uptake through S nitrosation of exofacial protein thiols in cellular responses to nitrosative stress. PMID- 24486554 TI - Dinitrotoluene exposure in the copper mining industry and renal cancer: a case cohort study. AB - OBJECTIVES: To evaluate the association between dinitrotoluene (DNT) exposure and renal cancer in a case-cohort study. METHODS: This case-cohort study was conducted among men born between 1920 and 1974 (n=16 441) who were gainfully employed between 1953 and 1990 in one of two copper mines in Mansfeld, Saxony Anhalt, former German Democratic Republic, and followed up till 31 December 2006. The study included 109 cases with renal cancer identified by record linkage with the Common Cancer Registry of the New Federal States of Germany (GKR) or by a network of pathology institutes. A comparison subcohort of 999 cohort members was selected at random from the total cohort. Duration and intensity of inhalation and dermal exposure to DNT were assessed on the basis of a job exposure matrix. A time-dependent Cox proportional hazards model modified for case-cohort design was used to assess the relationship between cumulative inhalation and dermal DNT exposure and renal cancer. RESULTS: Elevated risks were found for medium (HR=2.73; 95% CI 1.00 to 7.42) and high (HR=1.81; 95% CI 0.75 to 4.33) dermal exposure to DNT. Relative risks for medium inhalation exposure to DNT were not increased (HR=0.93; 95% CI 0.48 to 1.79) while relative risks for high inhalation exposure to DNT were elevated to 1.36 (95% CI 0.84 to 2.21). We found a statistically significant HR of 2.12 (95% CI 1.03 to 4.37) for combined medium or high inhalation and medium or high dermal exposure to DNT. CONCLUSIONS: According to our case-cohort study, dermal and inhalation exposure to DNT is associated with increased renal cancer risk. PMID- 24486555 TI - Nar1 deficiency results in shortened lifespan and sensitivity to paraquat that is rescued by increased expression of mitochondrial superoxide dismutase. AB - Saccharomyces cerevisiae Nar1p is an essential Fe/S protein that exhibits striking similarity to bacterial iron-only hydrogenases. Nar1p is required for the maturation of cytosolic and nuclear, but not of mitochondrial Fe/S proteins, and plays a role in modulating sensitivity to oxygen in both yeast and Caenorhabditis elegans through unknown mechanisms. Here we report that Nar1 deficiency results in shortened lifespan and sensitivity to paraquat that is rescued by increased expression of mitochondrial superoxide dismutase. These data suggest that Nar1p promotes protection against oxidative stress and define a new role for Nar1p in promoting replicative lifespan. PMID- 24486556 TI - Aging effects on oxidative phosphorylation in rat adrenocortical mitochondria. AB - Does aging in itself lead to alteration in adrenocortical mitochondrial oxidative phosphorylation? Mitochondria from Fischer 344 (F344) rats (6 and 24 months old), Brown Norway rats (6 and 32 months old) and F344-Brown Norway hybrid rats (6 and 30 months old) were compared. Mitochondria were isolated from extirpated adrenal cortex. The yields of mitochondria were quantitatively similar in all rat strains irrespective of age. In order to assess the activity of each mitochondrial complex, several different substrates were tested and the rate of oxidative phosphorylation measured. Aging does not affect mitochondrial activity except in the F344 rat adrenal cortex where the maximal ADP-stimulated oxidative phosphorylation decreased with age. We hypothesize that impaired synthesis of steroid hormones by the adrenal cortex with age in F344 rats might be due to decreased adrenocortical mitochondrial oxidative phosphorylation. We conclude that aging results in adrenocortical mitochondria effects that are non-uniform across different rat strains. PMID- 24486558 TI - Hot-melt co-extrusion for the production of fixed-dose combination products with a controlled release ethylcellulose matrix core. AB - In this study, hot-melt co-extrusion was evaluated as a technique for the production of fixed-dose combination products, using ethylcellulose as a core matrix former to control the release of metoprolol tartrate and a polyethylene oxide-based coat formulation to obtain immediate release of hydrochlorothiazide. By lowering the concentration of the hydrophilic additive polyethylene oxide in the plasticized ethylcellulose matrix or by lowering the drug load, the in vitro metoprolol tartrate release from the core was substantially sustained. The in vitro release of hydrochlorothiazide from the polyethylene oxide/polyethylene glycol coat was completed within 45 min for all formulations. Tensile testing of the core/coat mini-matrices revealed an adequate adhesion between the two layers. Raman mapping showed no migration of active substances. Solid state characterization indicated that the crystalline state of metoprolol tartrate was not affected by thermal processing via hot-melt extrusion, while hydrochlorothiazide was amorphous in the coat. These solid state characteristics were confirmed during the stability study. Considering the bioavailability of metoprolol tartrate after oral administration to dogs, the different co-extruded formulations offered a range of sustained release characteristics. Moreover, high metoprolol tartrate plasma concentrations were reached in dogs allowing the administered dose to be halved. PMID- 24486559 TI - Iodine-131 and thyroid function. PMID- 24486557 TI - Nutrition and protein energy homeostasis in elderly. AB - Protein-energy homeostasis is a major determinant of healthy aging. Inadequate nutritional intakes and physical activity, together with endocrine disturbances are associated with of sarcopenia and frailty. Guidelines from scientific societies mainly address the quantitative aspects of protein and energy nutrition in elderly. Besides these quantitative aspects of protein load, perspective strategies to promote muscle protein synthesis and prevent sarcopenia include pulse feeding, the use of fast proteins and the addition of leucine or citrulline to dietary protein. An integrated management of sarcopenia, taking into account the determinants of muscle wasting, i.e. nutrition, physical activity, anabolic factors such as androgens, vitamin D and n-3 polyunsaturated fatty acids status, needs to be tested in the prevention and treatment of sarcopenia. The importance of physical activity, specifically resistance training, is emphasized, not only in order to facilitate muscle protein anabolism but also to increase appetite and food intake in elderly people at risk of malnutrition. According to present data, healthy nutrition in elderly should respect the guidelines for protein and energy requirement, privilege a Mediterranean way of alimentation, and be associated with a regular physical activity. Further issues relate to the identification of the genetics determinants of protein energy wasting in elderly. PMID- 24486560 TI - Association between transforming growth factor beta-1 +869T/C polymorphism and acute rejection of solid organ allograft: A meta-analysis and systematic review. AB - BACKGROUND: Transforming growth factor beta-1(TGFB1) is involved in the acute rejection (AR) episodes of solid organ transplant recipients. However, results from published studies on the association between donor/recipient TGFB1 +869T/C polymorphism and AR risk are conflicting and inconclusive. METHODS: PUBMED, EMBASE, CNKI and Wanfang Database were searched to identify eligible studies investigating the association between donor/recipient TGFB1 +869T/C polymorphism and AR risk. Statistical analysis was performed by using STATA 10.0. RESULTS: A total of 29 studies were included. Overall, the donor TGFB1 +869T/C polymorphism was significantly associated with AR risk in heterozygote comparison (CT vs. TT: OR = 1.67, 95%CI, 1.17-2.39; P heterogeneity=0.285) and dominant model (CC vs. TC/TT: OR = 1.47, 95%CI, 1.05-2.06; P heterogeneity=0.445). In addition, subgroup analysis revealed that CT variant (CT vs. TT: OR = 1.97, 95%CI, 1.20-3.25; P heterogeneity = 0.777) and CC/CT genotype (CC/CT vs. TT: OR = 1.72, 95%CI, 1.07, 2.78; P heterogeneity = 0.619) within donors contributed to higher risk of AR in recipients administrated with CsA or FK506, compared with those applied only CsA. On the other hand, no significant association between recipient TGFB1 +869T/C polymorphism and AR was detected in all genetic models. CONCLUSIONS: This meta analysis and systematic review suggested that donor TGFB1 +869T/C polymorphism was significantly associated with AR of solid organ transplant recipients, and especially among patients in CsA/FK 506 group compared with those in CsA group. PMID- 24486561 TI - Mannose-binding lectin-2 and ficolin-2 gene polymorphisms and clinical risk factors for acute rejection in kidney transplantation. AB - INTRODUCTION: There is growing evidence that the lectin pathway is significantly associated with acute rejection. Rare studies associated both gene polymorphisms of MBL2 and FCN2 with acute rejection after kidney transplantation. The aim of the present study was to investigate the role of the lectin gene profile and clinical risk factors such as PRA level on acute rejection in kidney transplant recipients. METHODS: We prospectively analyzed 157 kidney transplant recipients with and without acute rejection. A total of 6 well-known functional single nucleotide polymorphisms in the MBL2 gene and 5 in the FCN2 gene of the recipients were determined by gene sequencing. MBL2 and FCN2 genotypic variants were analyzed for association with the incidence of acute rejection within the first year after kidney transplantation. RESULTS: After adjusting for variables of P<0.2, we found the differences in the incidence of acute rejection were only according to panel-reactive antibodies (odds ratios (OR) = 6.468, 95% confidence intervals (CI)= 2.017-20.740, P = 0.002) and the HH genotypes of MBL2 promoter 550 (OR = 2.448, 95%CI = 1.026-5.839, P = 0.044). CONCLUSION: Panel-reactive antibodies and the HH genotypes of MBL2 promoter -550 have significant impacts on the risk of developing acute rejection after kidney transplantation. PMID- 24486562 TI - Extracting important information from Chinese Operation Notes with natural language processing methods. AB - Extracting information from unstructured clinical narratives is valuable for many clinical applications. Although natural Language Processing (NLP) methods have been profoundly studied in electronic medical records (EMR), few studies have explored NLP in extracting information from Chinese clinical narratives. In this study, we report the development and evaluation of extracting tumor-related information from operation notes of hepatic carcinomas which were written in Chinese. Using 86 operation notes manually annotated by physicians as the training set, we explored both rule-based and supervised machine-learning approaches. Evaluating on unseen 29 operation notes, our best approach yielded 69.6% in precision, 58.3% in recall and 63.5% F-score. PMID- 24486563 TI - Oxytocin effects on mind-reading are moderated by experiences of maternal love withdrawal: an fMRI study. AB - The neuropeptide oxytocin has been shown to stimulate a range of social behaviors. However, recent studies indicate that the effects of intranasal oxytocin are more nuanced than previously thought and that contextual factors and individual characteristics moderate the beneficiary oxytocin effects. In this randomized-controlled trial we examine the influence of intranasally administered oxytocin on neural activity during mind-reading with fMRI, taking into account harsh caregiving experiences as a potential moderator. Participants were 50 women who received a nasal spray containing either 16 IU of oxytocin or a placebo and had reported how often their mother used love withdrawal as a disciplinary strategy. Participants performed an adapted version of the Reading the Mind in the Eyes Test (RMET), a task which requires individuals to infer mental states by looking at photographs of the eye region of faces. We found that oxytocin enhanced neural activation in the superior temporal gyrus (STG) and insula during the RMET. Moreover, oxytocin increased RMET performance outside the scanner. However, the oxytocin induced changes in STG activation and RMET performance were only brought about in potentially less socially proficient individuals who had low RMET performance, that is, participants reporting higher levels of maternal love withdrawal. PMID- 24486565 TI - The TIM-3 pathway ameliorates Theiler's murine encephalomyelitis virus-induced demyelinating disease. AB - Infection by Theiler's murine encephalomyelitis virus (TMEV) in the central nervous system (CNS) induces an immune-mediated demyelinating disease in susceptible mouse strains and serves as a relevant infection model for human multiple sclerosis. T-cell immunoglobulin and mucin domain-3 (TIM-3) has been demonstrated to play a crucial role in the maintenance of peripheral tolerance. In this study, we examined the regulatory role of the TIM-3 pathway in the development of TMEV-induced demyelinating disease (TMEV-IDD). The expression of TIM-3 was increased at both protein and mRNA levels in the spinal cords of mice with TMEV-IDD compared with naive controls. In addition, by utilizing a blocking mAb, we demonstrate that TIM-3 negatively regulates TMEV-specific ex vivo production of IFN-gamma and IL-10 by CD4(+) T cells and IFN-gamma by CD8(+) T cells from the CNS of mice with TMEV-IDD at 36 days post-infection (dpi). In vivo blockade of TIM-3 by using the anti-TIM-3 mAb resulted in significant exacerbation of the development of TMEV-IDD both clinically and histologically. The number of infiltrating mononuclear cells in the CNS was also increased in mice administered with anti-TIM-3 mAb both at the induction phase (10 dpi) and at the effector phase (36 dpi). Flow cytometric analysis of intracellular cytokines revealed that the number of CD4(+) T cells producing TNF, IL-4, IL-10 and IL-17 was significantly increased at the effector phase in the CNS of anti-TIM-3 mAb treated mice. These results suggest that the TIM-3 pathway plays a critical role in the regulation of TMEV-IDD. PMID- 24486566 TI - A screening-level modeling approach to estimate nitrogen loading and standard exceedance risk, with application to the Tippecanoe River watershed, Indiana. AB - This paper presents a screening-level modeling approach that can be used to rapidly estimate nutrient loading, assess numerical nutrient standard exceedance risk of surface waters leading to potential classification as impaired for designated use, and explore best management practice (BMP) implementation to reduce loading with a relatively low data requirement. The modeling framework uses a hybrid statistical and process based approach to estimate source of pollutants, their transport and decay in the terrestrial and aquatic parts of watersheds. The framework is developed in the ArcGIS environment and is based on the total maximum daily load (TMDL) balance model. Nitrogen (N) is currently addressed in the framework, referred to as WQM-TMDL-N. Loading for each catchment includes non-point sources (NPS) and point sources (PS). The probability of a nutrient load to exceed a target load is evaluated using probabilistic risk assessment, by including the uncertainty associated with export coefficients of various land uses. In an application of this modeling approach to the Tippecanoe River watershed in Indiana, USA, total nitrogen (TN) loading, confidence interval and risk of standard exceedance leading to potential impairment were estimated. Model results suggest that decay coefficients decrease, and delivery fractions increase with increasing stream order. The spatial distribution pattern of delivered incremental TN yield shows a trend similar to that of the delivery fraction in this watershed. The target TN exceedance risk increases considerably when switching from Indiana draft-N benchmark to far lower EPA-proposed TN criteria, suggesting that load reduction to meet the latter criteria may benefit from BMP implementation through source control and delivery reduction. PMID- 24486567 TI - Women's genital sexual arousal to oral versus penetrative heterosexual sex varies with menstrual cycle phase at first exposure. AB - Reproductive-aged women show increased interest in sexual activity during the fertile phase of the menstrual cycle that can motivate sexual behavior and thereby increase the likelihood of conception. We examined whether women demonstrated greater sexual responses (subjective and genital sexual arousal) to penetrative versus oral sexual activities during the fertile versus non-fertile phases of their cycles, and whether women's arousal responses were influenced by the phase during which they were first exposed to these sexual stimuli (e.g., Slob et al., 1991; Wallen and Rupp, 2010). Twenty-two androphilic women completed two identical sexual arousal assessments in which genital responses were measured with a vaginal photoplethysmograph and their feelings of sexual arousal were recorded. Women viewed an array of 90s films varying by couple type (female female, male-male, female-male) and sexual activity type (oral or penetrative), during the fertile (follicular) and non-fertile (luteal) phases of their menstrual cycle, with the order of cycle phase at the first testing session counter-balanced. Women tested first in the fertile phase showed significantly greater genital arousal to female-male penetrative versus oral sex in both testing sessions, whereas self-reports of sexual arousal were not affected by cycle phase or testing order. These results contribute to a growing body of research suggesting that fertility status at first exposure to sexual stimuli has a significant effect on subsequent sexual responses to sexual stimuli, and that this effect may differ for subjective versus genital sexual arousal. PMID- 24486568 TI - Emergence of GII.e as a major ORF 1 norovirus genotype and its associated ORF 2 GII.4 variant forms. AB - The noroviruses are a major cause of outbreaks of gastroenteritis. The norovirus genotype "GII.e", identified by ORF (Open Reading Frame) 1 nucleotide sequencing, appears to be an obligatory recombinant, in that no unique GII.e ORF 2 genotype has been identified. In 2012 GII.e norovirus became the predominant ORF 1 genotype in norovirus outbreaks in Victoria, Australia, and the current study documents changes in the ORF 1 region of GII.e norovirus since it first emerged in 2008, as well as in the ORF 2 genotypes associated with GII.e norovirus. GII.e norovirus underwent significant genetic change in ORF 1 between 2010 and 2012 and this genetic change corresponded to a significant increase in the prevalence of the virus. Nucleotide sequencing of the ORF 2 region of GII.e specimens showed that in 2008-2009, all the ORF 2 sequences corresponded to the GII.4 (2007) variant, in 2010 all the ORF 2 sequences corresponded to the GII.4 (2012-like) variant and in 2012 all the ORF 2 sequences corresponded to the GII.4 (2012) variant, the GII.4 (2012-like) variant, or the GII.4 (2009-like) variant. The evidence indicated that the development of the 2012 GII.e epidemic strains was due to evolutionary change rather than a novel recombination event. The results also support the notion that ORF 1 is critical in determining the virulence of a norovirus strain. PMID- 24486564 TI - Influence of mindfulness-based stress reduction (MBSR) on telomerase activity in women with breast cancer (BC). AB - Mindfulness-based stress reduction (MBSR) reduces symptoms of depression, anxiety, and fear of recurrence among breast cancer (BC) survivors. However, the effects of MBSR (BC) on telomere length (TL) and telomerase activity (TA), known markers of cellular aging, psychological stress, and disease risk, are not known. This randomized, wait-listed, controlled study, nested within a larger trial, investigated the effects of MBSR (BC) on TL and TA. BC patients (142) with Stages 0-III cancer who had completed adjuvant treatment with radiation and/or chemotherapy at least 2 weeks prior to enrollment and within 2 years of completion of treatment with lumpectomy and/or mastectomy were randomly assigned to either a 6-week MBSR for BC program or a usual care. Assessments of TA and TL were obtained along with psychological measurements at baseline, 6 weeks, and 12 weeks after completing the MBSR(BC) program. The mean age of 142 participants was 55.3 years; 72% were non-Hispanic White; 78% had Stage I or II cancer; and 36% received both chemotherapy and radiation. In analyses adjusted for baseline TA and psychological status, TA increased steadily over 12 weeks in the MBSR(BC) group (approximately 17%) compared to essentially no increase in the control group (approximately 3%, p < .01). In contrast, no between-group difference was observed for TL (p = .92). These results provide preliminary evidence that MBSR(BC) increases TA in peripheral blood mononuclear cells from BC patients and have implications for understanding how MBSR(BC) may extend cell longevity at the cellular level. PMID- 24486569 TI - PM060184, a new tubulin binding agent with potent antitumor activity including P glycoprotein over-expressing tumors. AB - PM060184 belongs to a new family of tubulin-binding agents originally isolated from the marine sponge Lithoplocamia lithistoides. This compound is currently produced by total synthesis and is under evaluation in clinical studies in patients with advanced cancer diseases. It was recently published that PM060184 presents the highest known affinities among tubulin-binding agents, and that it targets tubulin dimers at a new binding site. Here, we show that PM060184 has a potent antitumor activity in a panel of different tumor xenograft models. Moreover, PM060184 is able to overcome P-gp mediated resistance in vivo, an effect that could be related to its high binding affinity for tubulin. To gain insight into the mechanism responsible of the observed antitumor activity, we have characterized its molecular and cellular effects. We have observed that PM060184 is an inhibitor of tubulin polymerization that reduces microtubule dynamicity in cells by 59%. Interestingly, PM060184 suppresses microtubule shortening and growing at a similar extent. This action affects cells in interphase and mitosis. In the first case, the compound induces a disorganization and fragmentation of the microtubule network and the inhibition of cell migration. In the second case, it induces the appearance of multipolar mitosis and lagging chromosomes at the metaphase plate. These effects correlate with prometaphase arrest and induction of caspase-dependent apoptosis or appearance of cells in a multinucleated interphase-like state unrelated to classical apoptosis pathways. Taken together, these results indicate that PM060184 represents a new tubulin binding agent with promising potential as an anticancer agent. PMID- 24486570 TI - Plaques and tangles: birthmarks of the aging soul. Preface. PMID- 24486572 TI - Endothelin-1 induces connective tissue growth factor expression in human lung fibroblasts by ETAR-dependent JNK/AP-1 pathway. AB - Endothelin-1 (ET-1) acts as a key mediator of vasoconstriction and tissue repair. Overproduction of connective tissue growth factor (CTGF) underlies the development of lung fibrosis. ET-1 induces expression of matrix-associated genes in lung fibroblasts, however, little is known about the signaling pathway of CTGF expression caused by ET-1. In this study, we found that ET-1 caused concentration and time-dependently increases in CTGF expression in human embryonic lung fibroblast cell line (WI-38). ET-1-induced CTGF expression was inhibited by BQ123 (ETAR antagonist), but not BQ788 (ETBR antagonist). Moreover, ET-1-induced CTGF expression was significantly reduced by JNK inhibitor (SP600125), the dominant negative mutants of JNK1/2 (JNK1/2 DN), and AP-1 inhibitor (curcumin). ET-1 induced phosphorylations of JNK and c-Jun in time-dependent manners. AP-1 luciferase activity was concentration-dependently increased by ET-1, and this effect was attenuated by SP600125. We also found that ET-1-induced CTGF expression was most controlled by the AP-1 binding region of CTGF promoter. ET-1 indiced CTGF luciferase activity was predominately controlled by the sequence 747 to -408 bp upstream of the transcription start site on the human CTGF promoter. Furthermore, ET-1 caused the formation of AP-1-specific DNA-protein complex and the recruitment of c-Jun to the CTGF promoter. Moreover, we found that ET-1 induced alpha-smooth muscle actin (alpha-SMA) expression, which was inhibited by BQ123, SP600125, curcumin, and anti-CTGF antibody. These results suggest that ET-1 stimulates expressions of CTGF and alpha-SMA through ETAR/JNK/AP-1 signaling pathway, and CTGF is required for ET-1-induced alpha-SMA expression in human lung fibroblasts. PMID- 24486571 TI - Merging old and new perspectives on nicotinic acetylcholine receptors. AB - This review covers history underlying the discovery of the molecular mediators of nicotine's effects in the brain and the diversity of the nicotinic acetylcholine receptor (nAChR) subtypes. Models are presented for both their structure and their function as mediators of signal transduction, with special consideration of the differences between the two main subtypes: heteromeric receptors, which are specialized for rapid electrochemical signal transduction, and homomeric alpha7 receptors, which have come to be implicated in both ionotropic and metabotropic signaling. This review presents perspectives on the pharmacology and therapeutic targeting of nAChRs for the treatment of nicotine dependence or disease. PMID- 24486573 TI - Sustained and selective suppression of intestinal cholesterol synthesis by Ro 48 8071, an inhibitor of 2,3-oxidosqualene:lanosterol cyclase, in the BALB/c mouse. AB - The small intestine plays a fundamentally important role in regulating whole body cholesterol balance and plasma lipoprotein composition. This is articulated through the interplay of a constellation of genes that ultimately determines the net amount of chylomicron cholesterol delivered to the liver. Major advances in our insights into regulation of the cholesterol absorption pathway have been made using genetically manipulated mouse models and agents such as ezetimibe. One unresolved question is how a sustained pharmacological inhibition of intestinal cholesterol synthesis in vivo may affect cholesterol handling by the absorptive cells. Here we show that the lanosterol cyclase inhibitor, Ro 48-8071, when fed to BALB/c mice in a chow diet (20 mg/day/kg body weight), leads to a rapid and sustained inhibition (>50%) of cholesterol synthesis in the whole small intestine. Sterol synthesis was also reduced in the large intestine and stomach. In contrast, hepatic cholesterol synthesis, while markedly suppressed initially, rebounded to higher than baseline rates within 7 days. Whole body cholesterol synthesis, fractional cholesterol absorption, and fecal neutral and acidic sterol excretion were not consistently changed with Ro 48-8071 treatment. There were no discernible effects of this agent on intestinal histology as determined by H&E staining and the level of Ki67, an index of proliferation. The mRNA expression for multiple genes involved in intestinal cholesterol regulation including NPC1L1 was mostly unchanged although there was a marked rise in the mRNA level for the PXR target genes CYP3A11 and CES2A. PMID- 24486575 TI - HLA-C antibodies are associated with irreversible rejection in kidney transplantation: Shared molecular eplets characterization. AB - We report an interesting case concerning an irreversible antibody-mediated rejection (AMR), associated with anti-HLA-C DSA, which occurred after a second kidney transplantation despite having determined a low number of antibodies directed against HLA-C antigens (MFI<1000) in the previous transplantation (which was then considered to be an indicator of low risk of AMR). A 63-year-old woman was re-transplanted with pre-transplant (PrT) sensitization. On day 7 post transplantation, oligoanuria occurred and increased MFIs for the detected PrT antibodies and other antibodies (non-detected or detected with very low PrT MFI) were observed. SAB assay also showed antibodies against the second donor HLA-C mismatches and other HLA-C antigens. Nephrologists suspected AMR and the patient was therefore treated with methylprednisolone/plasmapheresis/IVIG/anti-CD20 without improvement, which led to transplantectomy. Histologic analysis confirmed acute AMR. Interestingly, it was possible to define exactly the potential immunizing epitopes whose recognition determines the specific antibody production. So, 1st donor DSAs (detected PrT with low MFI), 2nd donor DSAs (detected PTP), and non-DSA detected PTP have several shared eplets, being the 11AVR eplet the only one present on all alleles. Thus, the recognition of 11AVR eplet in the first transplant modeled the patient's antibody response. Therefore, we propose that donor HLA-C typing should always be performed for recipients with anti-HLA-C antibodies, and specific shared-eplets should be investigated in order to determine previous transplant mismatches. PMID- 24486574 TI - Role of Bcl-xL/Beclin-1 in interplay between apoptosis and autophagy in oxaliplatin and bortezomib-induced cell death. AB - Recent studies indicate that a complex relationship exists between autophagy and apoptosis. In this study we investigated a regulatory relationship between autophagy and apoptosis in colorectal cancer cells utilizing molecular and biochemical approaches. For this study, human colorectal carcinoma HCT116 and CX 1 cells were treated with two chemotherapeutic agents-oxaliplatin, which induces apoptosis, and bortezomib, which triggers both apoptosis and autophagy. A combinatorial treatment of oxaliplatin and bortezomib caused a synergistic induction of apoptosis which was mediated through an increase in caspase activation. The combinational treatment of oxaliplatin and bortezomib promoted the JNK-Bcl-xL-Bax pathway which modulated the synergistic effect through the mitochondria-dependent apoptotic pathway. JNK signaling led to Bcl-xL phosphorylation at serine 62, oligomerization of Bax, alteration of mitochondrial membrane potential, and subsequent cytochrome c release. Overexpression of dominant-negative mutant of Bcl-xL (S62A), but not dominant-positive mutant of Bcl-xL (S62D), suppressed cytochrome c release and synergistic death effect. Interestingly, Bcl-xL also affected autophagy through alteration of interaction with Beclin-1. Beclin-1 was dissociated from Bcl-xL and initiated autophagy during treatment with oxaliplatin and bortezomib. However, activated caspase 8 cleaved Beclin-1 and suppressed Beclin-1-associated autophagy and enhanced apoptosis. A combinatorial treatment of oxaliplatin and bortezomib-induced Beclin 1 cleavage was abolished in Beclin-1 double mutant (D133AA/D149A) knock-in HCT116 cells, restoring the autophagy-promoting function of Beclin-1 and suppressing the apoptosis induced by the combination therapy. In addition, the combinatorial treatment significantly inhibited colorectal cancer xenografts' tumor growth. An understanding of the molecular mechanisms of crosstalk between apoptosis and autophagy will support the application of combinatorial treatment to colorectal cancer. PMID- 24486576 TI - The role of TLR2, TLR4 and CD36 in macrophage activation and foam cell formation in response to oxLDL in humans. AB - Toll-like receptor (TLR)2, TLR4 and CD36 are central in inflammation and the development of atherosclerosis. Oxidized low-density lipoprotein (oxLDL) plays a critical role in this disease through its involvement in the formation of foam cells and the activation of leukocytes. The aim of this research was to analyze the role of TLR2, TLR4 and CD36 in foam cell differentiation and macrophage activation. METHODS: Human macrophages were incubated with monoclonal antibodies specific for TLR2, TLR4 and CD36 prior to stimulation with oxLDL. Subsequently, we analyzed foam cell formation, cytokine secretion, histocompatibility complex (MHC) class II molecules and CD86 expression and T cell proliferation. RESULTS: The stimulation of macrophages with oxLDL induced foam cell formation, cytokine secretion, HLA-DR and CD86 expression and T cell proliferation. The blockage of TLR2, TLR4 and CD36 reduced the secretion of IL-1beta, IL-6 and IL-8, the expression of HLA-DR and CD86, T cell proliferation and foam cell formation. However, the blockage of TLR2 did not affect the formation of foam cells. CONCLUSION: Our study demonstrates that TLR2, TLR4 and CD36 participate in the immune response to oxLDL by inducing an increase in pro-inflammatory cytokines, the expression HLA-DR and CD86 and the proliferation of T cells. However, TLR2 does not participate in the formation of foam cells, while TLR4 and CD36 play a relevant role in this process. These findings suggest that the activation of these receptors by oxLDL contributes to the pathogenesis of atherosclerosis. PMID- 24486577 TI - Association of ABCB1 gene polymorphisms and haplotypes with therapeutic efficacy of glucocorticoids in Chinese patients with immune thrombocytopenia. AB - Resistance to glucocorticoids (GCs) remains a tricky problem complicating the therapy of ITP. Recently, ATP binding cassette gene B1 gene (ABCB1) was reported to be correlated with susceptibility and therapeutic efficacy of autoimmune diseases through P-glycoprotein (Pgp). We investigated three single nucleotide polymorphisms (SNPs) of ABCB1 and their haplotypes by PCR-RFLP (restriction fragment length polymorphism) method in 471 ITP patients and 383 healthy controls, patients were further assigned into GCs-responsive and -non-responsive group according to the therapeutic effects of GCs. We observed a remarkable difference in genotypes of G2677T/A between GCs-responsive and non-responsive group, but not between patients and controls. A frequently expression of T/A allele within G2677T/A was recorded in GCs-responsive group. Furthermore, we found that some haplotypes (CGC, CTC/CAC, CTT/CAT, TGC, TGT, TTC/TAC and TTT/TAT, in the order of position 1236-2677-3435) were presented significantly differences between non-responsive and responsive group. No difference of C1236T and C3435T polymorphisms was observed between ITP and controls, and between the GCs responsive and -non-responsive group. Our findings suggest that ABCB1 polymorphisms, as well as haplotypes derived from C1235T, G2677T/A and C3435T, are associated with inter-individual differences of GCs treatment in ITP. PMID- 24486578 TI - Inter-relation of Th1, Th2, Th17 and Treg cytokines in oral cancer patients and their clinical significance. AB - BACKGROUND: Altered cytokine production can lead to immune dysfunction in cancer patients. Hence, we investigated the cytokine balance in oral squamous cell carcinoma (OSCC) patients and their significance in providing new therapeutic insights. METHODS: We quantified Th17 (IL17A), Treg (TGFbeta1), Th1 (IL2, IFNgamma) and Th2 (IL4, IL10) like cytokines in the sera of 78 cases and 39 controls by ELISA. The intracellular expression of these cytokines was analyzed in 10 subjects from each group by flow cytometry. RESULTS: Serum levels of IL17A, TGFbeta1, IL4 and IL10 were significantly higher while IL2 and IFNgamma were relatively lower in patients as compared to controls. TGFbeta1 (r=0.55), IL4 (r=0.75) and IL10 (r=0.80) significantly (P<0.0001) correlated with disease progression and their elevated levels showed increased odd ratios of approximately 18, 14 and 37, respectively. IL17A appeared as a risk factor (OR=2.21, 95% CI=0.89-5.42) although statistically insignificant. The levels neither correlated with disease progression nor with TGFbeta1, IL4 and IL10 but showed positive association with IL2 (r=0.51, P<0.0001) and IFNgamma (r=0.24). Flow cytometry data also showed similar trend. CONCLUSIONS: We reported a distinct TGFbeta1 and Th2 (IL4, IL10) polarization with a borderline elevation of IL17A while, a suppression of Th1 (IL2, IFNgamma) cytokines in OSCC patients. PMID- 24486579 TI - Polymorphisms assessment in the promoter region of IL12RB2 in Amazon leprosy patients. AB - Leprosy displays a wide clinical spectrum that is dependent of the type of immune response. We investigate here whether polymorphisms in the promoter region of the IL12RB2 gene are associated with susceptibility or resistance to clinical forms of leprosy. Nucleotide sequencing of the promoter region of IL12RB2 encompassing SNPs -1035 A/G, -1033 T/C, -1023 A/G, -650 del/G and -464 A/G was performed on DNA samples from 105 leprosy patients and 108 healthy controls. However, none of the SNPs were associated with susceptibility to the disease or any of its clinical forms. Similarly, haplotype analysis did not show any association. The haplotype -1035A/-1033T/-650G/-464A was prevalent, and homozygosity for this haplotype was associated to a lower distribution of CD4(+) T cells (p=0.041). Our data suggest that polymorphisms present in the promoter region of IL12RB2 may not be associated with susceptibility to leprosy or its clinical forms. PMID- 24486580 TI - Association of KCNQ1 and KLF14 polymorphisms and risk of type 2 diabetes mellitus: A global meta-analysis. AB - rs151290 in KCNQ1 and rs972283 in KLF14 have been evaluated in terms of risk of type 2 diabetes mellitus (T2DM), but the results are inconsistent. We performed an meta-analysis to assess the contributions of rs151290 in KCNQ1 and rs972283 in KLF14 to risk of T2DM. We searched the worldwide literature published from 2008 to 2013 in MEDLINE via PubMed, EMBASE, Cochrane CENTRAL and Chinese databases. Two reviewers extracted data independently using a standardized protocol, and any discrepancies were resolved by a third reviewer. Fixed- and random-effects meta analyses were performed to pool the odds ratios (ORs). Publication bias and heterogeneity were examined. A total of 11 articles were included in the meta analysis: 6 studies with 6696 cases and 7151 controls investigated rs151290 in KCNQ1, and 5 studies with 50,552 cases and 106,535 controls investigated rs972283 in KLF14. We obtained highly significant ORs for the risk allele C for rs151290 and the risk allele G for rs972283. The population attributable risk percentage for rs151290 and rs972283 was 6.83% and 4.18%, respectively. The risk allele C of rs151290 in KCNQ1 and risk allele G of rs972283 in KLF14 were both associated with increased risk of T2DM in a global population. PMID- 24486581 TI - Transcriptional regulation of abscisic acid signal core components during cucumber seed germination and under Cu2+, Zn2+, NaCl and simulated acid rain stresses. AB - Abscisic acid (ABA) is an important phytohormone that regulates lots of physiological and biochemical processes in plant life cycle, especially in seed germination and stress responses. For exploring the transcriptional regulation of ABA signal transduction during cucumber (Cucumis sativus L.) seed germination and under Cu(2+), Zn(2+), NaCl and simulated acid rain stresses, nine CsPYLs, three group A CsPP2Cs and two subclass III CsSnRK2s were identified from cucumber genome, which respectively showed high sequence similarities and highly conserved domains with homologous genes in Arabidopsis. Based on Real-time PCR analysis, most of the tested genes' expression decreased during cucumber seed germination, which was in accordance with the ABA level variation. In addition, according to the absolute expression, CsPYL1, CsPYL3, CsPP2C5, CsABI1, CsSnRK2.3 and CsSnRK2.4 were highly expressed, indicating that they may play more important roles in ABA signaling during cucumber seed germination. Moreover, most of these highly expressed genes, except CsPYL3, were up-regulated by ABA treatment. Meanwhile, most of the tested genes' expression dramatically changed at the initial water uptake phase, indicating that this period may be critical in the regulation of ABA on seed germination. Under Cu(2+), Zn(2+), NaCl and simulated acid rain stresses, cucumber seed germination percentage decreased and ABA content increased. Meanwhile, the expression of ABA signal transduction core components genes showed specific response to a particular stress and was not always consist with ABA variation. Generally, the expression of CsPYL1, CsPYL3, CsABI1, CsSnRK2.3 and CsSnRK2.4 was sensitive to 120 mM NaCl and 0.5 mM Cu(2+) treatments. PMID- 24486582 TI - Role of the ubiquitin-proteasome pathway and some peptidases during seed germination and copper stress in bean cotyledons. AB - The role of the ubiquitin (Ub)-proteasome pathway and some endo- and aminopeptidases (EPs and APs, respectively) was studied in cotyledons of germinating bean seeds (Phaseolus vulgaris L.). The Ub system appeared to be important both in the early (3 days) and late (9 days) phases of germination. In the presence of copper, an increase in protein carbonylation and a decrease in reduced -SH pool occurred, indicating protein damage. This was associated with an enhancement in accumulation of malondialdehyde, a major product of lipid peroxidation, and an increase in content of hydrogen peroxide (H2O2), showing oxidative stress generation. Moreover, copper induced inactivation of the Ub proteasome (EC 3.4.25) pathway and inhibition of leucine and proline aminopeptidase activities (EC 3.4.11.1 and EC 3.4.11.5, respectively), thus limiting their role in modulating essential metabolic processes, such as the removal of regulatory and oxidatively-damaged proteins. By contrast, total trypsin and chymotrypsin-like activities (EC 3.4.21.4 and EC 3.4.21.1, respectively) increased after copper exposure, in parallel with a decrease in their inhibitor capacities (i.e. trypsin inhibitor and chymotrypsin inhibitor activity), suggesting that these endoproteases are part of the protective mechanisms against copper stress. PMID- 24486583 TI - Effects of concentrations of sodium chloride on photosynthesis, antioxidative enzymes, growth and fiber yield of hybrid ramie. AB - Ramie (Boehmeria nivea L.) is one of the oldest and most important fiber crops in China due to the comfortable textile of its fine fiber. Increased ramie fiber demand brings ramie cultivation to salt-affected regions. The aim of this research was to determine morphological, physiological and biochemical responses of ramie by subjecting plants to varying concentrations of NaCl (0, 2, 4, 6 and 8 g NaCl/kg dry soil) at vigorous growth stage for 10 and 20 days. Results indicated that salinity stress substantially inhibited the growth of hybrid ramie plants and led to remarkable decline in fiber yield. However, when grown at 2 g NaCl/kg growth and fiber yield were similar to non-saline control. In addition, chlorophyll fluorescence and gas exchange parameters were correlated with growth and yield response. Salt treatments promoted a subsequent decrease in maximum quantum efficiency of PSII photochemistry (Fv/Fm), quantum efficiency of open PSII reaction centers (Fv'/Fm') and quantum yield of PSII (phiPSII) while non photochemical quenching (NPQ) changed conversely. Photochemical quenching (qP) and electron transport rate of PSII (ETR) increased at 2 and 4 g NaCl/kg then decreased at 6 and 8 g NaCl/kg. Substantial decline in the PSII activity at high salinity was associated with the loss of chlorophyll contents. Moreover, marked decrease in net photosynthetic rate (A), transpiration rate (E), stomatal conductance (gs) was also recorded. Nonetheless, intercellular CO2 (Ci) decreased at low salt stress, subsequently increased at high salt stress while water use efficiency (WUE) and instantaneous water use efficiency (WUEi) altered in opposite direction. Substantial decrease of photosynthesis at high salinity was due to non-stomatal factors. Furthermore, salinity stress led to decrease of proteins and accumulation of proline and malondialdehyde (MDA), as well as enhanced activities of superoxide dismutase (SOD, EC 1.15.1.1) and peroxidase (POD, EC 1.11.1.6), whereas, catalase (CAT, EC 1.11.1.7) enhanced at low salinity, decreased at high salinity. Nonetheless, these changes were closely related with the severity and duration of the salinity stress and their interaction. The results suggested a certain tolerance to salinity stress for hybrid ramie. This meets the essential condition for utilization in salinity prone environments. PMID- 24486584 TI - Your personalized protein structure: Andrei N. Lupas fused to GCN4 adaptors. AB - This work presents a protein structure that has been designed purely for aesthetic reasons, symbolizing decades of coiled-coil research and praising its most fundamental model system, the GCN4 leucine zipper. The GCN4 leucine zipper is a highly stable coiled coil which can be tuned to adopt different oligomeric states via mutation of its core residues. For these reasons it is used in structural studies as a stabilizing fusion adaptor. On the occasion of the 50th birthday of Andrei N. Lupas, we used it to create the first personalized protein structure: we fused the sequence ANDREI-N-LVPAS in heptad register to trimeric GCN4 adaptors and determined its structure by X-ray crystallography. The structure demonstrates the robustness and versatility of GCN4 as a fusion adaptor. We learn how proline can be accommodated in trimeric coiled coils, and put the structure into the context of the other GCN4-fusion structures known to date. PMID- 24486585 TI - Cross-talk between EphA2 and BRaf/CRaf is a key determinant of response to Dasatinib. AB - PURPOSE: EphA2 is an attractive therapeutic target because of its diverse roles in cancer growth and progression. Dasatinib is a multikinase inhibitor that targets EphA2 and other kinases. However, reliable predictive markers and a better understanding of the mechanisms of response to this agent are needed. EXPERIMENTAL DESIGN: The effects of dasatinib on human uterine cancer cell lines were examined using a series of in vitro experiments, including MTT, Western blot analysis, and plasmid transfection. In vivo, an orthotopic mouse model of uterine cancer was utilized to identify the biologic effects of dasatinib. Molecular markers for response prediction and the mechanisms relevant to response to dasatinib were identified by using reverse phase protein array (RPPA), immunoprecipitation, and double immunofluorescence staining. RESULTS: We show that high levels of CAV-1, EphA2 phosphorylation at S897, and the status of PTEN are key determinants of dasatinib response in uterine carcinoma. A set of markers essential for dasatinib response was also identified and includes CRaf, pCRaf(S338), pMAPK(T202/Y204) (mitogen-activated protein kinase [MAPK] pathway), pS6(S240/244), p70S6k(T389) (mTOR pathway), and pAKT(S473). A novel mechanism for response was discovered whereby high expression level of CAV-1 at the plasma membrane disrupts the BRaf/CRaf heterodimer and thus inhibits the activation of MAPK pathway during dasatinib treatment. CONCLUSIONS: Our in vitro and in vivo results provide a new understanding of EphA2 targeting by dasatinib and identify key predictors of therapeutic response. These findings have implications for ongoing dasatinib-based clinical trials. PMID- 24486586 TI - Preclinical activity of the oral proteasome inhibitor MLN9708 in Myeloma bone disease. AB - PURPOSE: MLN9708 (ixazomib citrate), which hydrolyzes to pharmacologically active MLN2238 (ixazomib), is a next-generation proteasome inhibitor with demonstrated preclinical and clinical antimyeloma activity, but yet with an unknown effect on myeloma bone disease. Here, we investigated its bone anabolic and antiresorptive effects in the myeloma setting and in comparison with bortezomib in preclinical models. EXPERIMENTAL DESIGN: The in vitro effect of MLN2238 was tested on osteoclasts and osteoclast precursors from healthy donors and patients with myeloma, and on osteoprogenitors derived from bone marrow mesenchymal stem cells also from both origins. We used an in vivo model of bone marrow-disseminated human myeloma to evaluate MLN2238 antimyeloma and bone activities. RESULTS: Clinically achievable concentrations of MLN2238 markedly inhibited in vitro osteoclastogenesis and osteoclast resorption; these effects involved blockade of RANKL (receptor activator of NF-kappaB ligand)-induced NF-kappaB activation, F actin ring disruption, and diminished expression of alphaVbeta3 integrin. A similar range of MLN2238 concentrations promoted in vitro osteoblastogenesis and osteoblast activity (even in osteoprogenitors from patients with myeloma), partly mediated by activation of TCF/beta-catenin signaling and upregulation of the IRE1 component of the unfolded protein response. In a mouse model of bone marrow disseminated human multiple myeloma, orally administered MLN2238 was equally effective as bortezomib to control tumor burden and also provided a marked benefit in associated bone disease (sustained by both bone anabolic and anticatabolic activities). CONCLUSION: Given favorable data on pharmacologic properties and emerging clinical safety profile of MLN9708, it is conceivable that this proteasome inhibitor may achieve bone beneficial effects in addition to its antimyeloma activity in patients with myeloma. PMID- 24486587 TI - Having pancreatic cancer with tumoral loss of ATM and normal TP53 protein expression is associated with a poorer prognosis. AB - PURPOSE: To determine how often loss of ataxia-telangiectasia-mutated (ATM) protein expression occurs in primary pancreatic ductal adenocarcinomas and to determine its prognostic significance. EXPERIMENTAL DESIGN: The expression of ATM and TP53 was determined by immunohistochemistry in 397 surgically resected pancreatic ductal adenocarcinomas (Hopkins; Johns Hopkins Medical Institutions, Baltimore, MD), a second set of 159 cases (Emory; Emory University Hospital, Atlanta, GA), and 21 cancers after neoadjuvant chemoradiotherapy. Expression was correlated with the clinicopathologic parameters, including survival. RESULTS: Tumoral ATM loss was observed in one cancer known to have biallelic inactivation of ATM and 50 of the first 396 (12.8%) cases, significantly more often in patients with a family history of pancreatic cancer (12/49; 24.5%) than in those without (38/347; 11.0%; P = 0.019). In the Hopkins series, ATM loss was associated with a significantly decreased overall survival in patients whose cancers had normal TP53 expression (P = 0.019) and was a significant independent predictor of decreased overall survival (P = 0.014). Seventeen (10.7%) of 159 Emory cases had tumoral ATM loss and tumoral ATM loss/normal TP53 was associated with poorer overall survival (P = 0.1). Multivariate analysis of the combined Hopkins/Emory cases found that tumoral ATM loss/normal TP53 was an independent predictor of decreased overall survival [HR = 2.61; confidence interval (CI), 1.27-5.37; P = 0.009]. Of 21 cancers examined after neoadjuvant chemoradiotherapy, one had tumoral loss of ATM; it had no histologic evidence of tumor response. CONCLUSIONS: Tumoral loss of ATM protein was detected more often in patients with a family history of pancreatic cancer than in those without. Patients whose pancreatic cancers had loss of ATM but normal TP53 had worse overall survival after pancreatic resection. PMID- 24486588 TI - Establishing a diagnostic road map for MUTYH-associated polyposis. AB - The analysis of MUTYH-associated polyposis cases of the EPIPOLIP cohort confirms the importance of including serrated polyps in the diagnostic work-up of patients with oligopolyposis, suggests a role for screening polyps for the somatic c.34G>T KRAS mutation, and allows the implementation of a genetic testing strategy based on population data. PMID- 24486589 TI - Functional identification of cancer-specific methylation of CDO1, HOXA9, and TAC1 for the diagnosis of lung cancer. AB - PURPOSE: Non-small cell lung cancer (NSCLC) is the leading cause of cancer mortality in the world. Novel diagnostic biomarkers may augment both existing NSCLC screening methods as well as molecular diagnostic tests of surgical specimens to more accurately stratify and stage candidates for adjuvant chemotherapy. Hypermethylation of CpG islands is a common and important alteration in the transition from normal tissue to cancer. EXPERIMENTAL DESIGN: Following previously validated methods for the discovery of cancer-specific hypermethylation changes, we treated eight NSCLC cell lines with the hypomethylating agent deoxyazacitidine or trichostatin A. We validated the findings using a large publicly available database and two independent cohorts of primary samples. RESULTS: We identified >300 candidate genes. Using The Cancer Genome Atlas (TCGA) and extensive filtering to refine our candidate genes for the greatest ability to distinguish tumor from normal, we define a three-gene panel, CDO1, HOXA9, and TAC1, which we subsequently validate in two independent cohorts of primary NSCLC samples. This three-gene panel is 100% specific, showing no methylation in 75 TCGA normal and seven primary normal samples and is 83% to 99% sensitive for NSCLC depending on the cohort. CONCLUSION: This degree of sensitivity and specificity may be of high value to diagnose the earliest stages of NSCLC. Addition of this three-gene panel to other previously validated methylation biomarkers holds great promise in both early diagnosis and molecular staging of NSCLC. PMID- 24486590 TI - Integrative analysis of 1q23.3 copy-number gain in metastatic urothelial carcinoma. AB - PURPOSE: Metastatic urothelial carcinoma of the bladder is associated with multiple somatic copy-number alterations (SCNAs). We evaluated SCNAs to identify predictors of poor survival in patients with metastatic urothelial carcinoma treated with platinum-based chemotherapy. EXPERIMENTAL DESIGN: We obtained overall survival (OS) and array DNA copy-number data from patients with metastatic urothelial carcinoma in two cohorts. Associations between recurrent SCNAs and OS were determined by a Cox proportional hazard model adjusting for performance status and visceral disease. mRNA expression was evaluated for potential candidate genes by NanoString nCounter to identify transcripts from the region that are associated with copy-number gain. In addition, expression data from an independent cohort were used to identify candidate genes. RESULTS: Multiple areas of recurrent significant gains and losses were identified. Gain of 1q23.3 was independently associated with a shortened OS in both cohorts [adjusted HR, 2.96; 95% confidence interval (CI), 1.35-6.48; P = 0.01 and adjusted HR, 5.03; 95% CI, 1.43-17.73; P < 0.001]. The F11R, PFDN2, PPOX, USP21, and DEDD genes, all located on 1q23.3, were closely associated with poor outcome. CONCLUSIONS: 1q23.3 copy-number gain displayed association with poor survival in two cohorts of metastatic urothelial carcinoma. The identification of the target of this copy-number gain is ongoing, and exploration of this finding in other disease states may be useful for the early identification of patients with poor risk urothelial carcinoma. Prospective validation of the survival association is necessary to demonstrate clinical relevance. PMID- 24486591 TI - Radiation-enhanced lung cancer progression in a transgenic mouse model of lung cancer is predictive of outcomes in human lung and breast cancer. AB - PURPOSE: Carcinogenesis is an adaptive process between nascent tumor cells and their microenvironment, including the modification of inflammatory responses from antitumorigenic to protumorigenic. Radiation exposure can stimulate inflammatory responses that inhibit or promote carcinogenesis. The purpose of this study is to determine the impact of radiation exposure on lung cancer progression in vivo and assess the relevance of this knowledge to human carcinogenesis. EXPERIMENTAL DESIGN: K-ras(LA1) mice were irradiated with various doses and dose regimens and then monitored until death. Microarray analyses were performed using Illumina BeadChips on whole lung tissue 70 days after irradiation with a fractionated or acute dose of radiation and compared with age-matched unirradiated controls. Unique group classifiers were derived by comparative genomic analysis of three experimental cohorts. Survival analyses were performed using principal component analysis and k-means clustering on three lung adenocarcinoma, three breast adenocarcinoma, and two lung squamous carcinoma annotated microarray datasets. RESULTS: Radiation exposure accelerates lung cancer progression in the K-ras(LA1) lung cancer mouse model with dose fractionation being more permissive for cancer progression. A nonrandom inflammatory signature associated with this progression was elicited from whole lung tissue containing only benign lesions and predicts human lung and breast cancer patient survival across multiple datasets. Immunohistochemical analyses suggest that tumor cells drive predictive signature. CONCLUSIONS: These results demonstrate that radiation exposure can cooperate with benign lesions in a transgenic model of cancer by affecting inflammatory pathways, and that clinically relevant similarities exist between human lung and breast carcinogenesis. PMID- 24486592 TI - Topical application of a mucoadhesive freeze-dried black raspberry gel induces clinical and histologic regression and reduces loss of heterozygosity events in premalignant oral intraepithelial lesions: results from a multicentered, placebo controlled clinical trial. AB - PURPOSE: Approximately 30% higher grade premalignant oral intraepithelial neoplasia (OIN) lesions will progress to oral cancer. Although surgery is the OIN treatment mainstay, many OIN lesions recur, which is highly problematic for both surgeons and patients. This clinical trial assessed the chemopreventive efficacy of a natural product-based bioadhesive gel on OIN lesions. EXPERIMENTAL DESIGN: This placebo-controlled multicenter study investigated the effects of topical application of bioadhesive gels that contained either 10% w/w freeze-dried black raspberries (BRB) or an identical formulation devoid of BRB placebo to biopsy confirmed OIN lesions (0.5 g * q.i.d., 12 weeks). Baseline evaluative parameters (size, histologic grade, LOH events) were comparable in the randomly assigned BRB (n = 22) and placebo (n = 18) gel cohorts. Evaluative parameters were: histologic grade, clinical size, and LOH. RESULTS: Topical application of the BRB gel to OIN lesions resulted in statistically significant reductions in lesional sizes, histologic grades, and LOH events. In contrast, placebo gel lesions demonstrated a significant increase in lesional size and no significant effects on histologic grade or LOH events. Collectively, these data strongly support BRB's chemopreventive impact. A cohort of very BRB-responsive patients, as demonstrated by high therapeutic efficacy, was identified. Corresponding protein profiling studies, which demonstrated higher pretreatment levels of BRB metabolic and keratinocyte differentiation enzymes in BRB-responsive lesions, reinforce the importance of local metabolism and differentiation competency. CONCLUSIONS: Results from this trial substantiate the LOH reductions identified in the pilot BRB gel study and extend therapeutic effects to significant improvements in histologic grade and lesional size. PMID- 24486593 TI - Downregulation of FOXO3a promotes tumor metastasis and is associated with metastasis-free survival of patients with clear cell renal cell carcinoma. AB - PURPOSE: To explore the mechanisms underlying clear-cell renal cell carcinoma (ccRCC) metastasis using transcriptional profiling and bioinformatics analysis of ccRCC samples, and to elucidate the role of FOXO3a in ccRCC metastasis. EXPERIMENTAL DESIGN: Gene expression profiling was performed using four primary metastatic and five primary nonmetastatic ccRCC samples. The mRNA and protein levels of FOXO3a in ccRCC samples were investigated by real-time reverse transcription PCR and immunohistochemistry, respectively. The association between metastasis-free survival of patients with ccRCC and FOXO3a mRNA levels was analyzed. Biologic functions of FOXO3a in renal cancer cell lines were investigated. The influence of FOXO3a on tumor metastasis was also studied in vivo orthotopic xenograft tumor model. Finally, the mechanism by which FOXO3a attenuation could increase invasion and migration of tumor cells was explored. RESULTS: Bioinformatics analysis of the profiling data identified FOXO3a as a key factor in ccRCC metastasis. FOXO3a expression was decreased in primary metastatic ccRCC samples. Patients with low FOXO3a mRNA levels had poor metastasis-free survival (P = 0.003). Knocking down FOXO3a induced tumor cell invasion and migration in the nonmetastatic ccRCC cells. Induced FOXO3a overexpression in SN12 PM6 cells could inhibit tumor metastasis in vivo. Downregulation of FOXO3a increased SNAIL1 expression, thereby activating the epithelial-mesenchymal transition (EMT) of RCC cell lines. CONCLUSIONS: The loss of FOXO3a induced EMT of tumor cells by upregulating SNAIL1, which promoted tumor cells metastasis in vitro and in vivo. Thus, FOXO3a could be considered as an independent prognostic factor in ccRCC metastasis and could be a marker of occult metastases. PMID- 24486594 TI - Hypoxia-driven gene expression is an independent prognostic factor in stage II and III colon cancer patients. AB - PURPOSE: Hypoxia is considered a major microenvironmental factor influencing cancer behavior. Our aim was to develop a hypoxia-based gene score that could identify high and low risk within stage II and III colon cancer patients. EXPERIMENTAL DESIGN: Differential gene expression of CaCo-2 colon cancer cells cultured in chronic hypoxia versus normoxia was tested for correlation with prognostic variables in published microarray datasets. These datasets were further used to downsize and optimize a gene score, which was subsequently determined in paraffin-embedded material of 126 patients with colon cancer treated in our center. RESULTS: In the CaCo-2 cells, 923 genes with a 2-fold change and Limma corrected P <= 0.0001 were found differentially expressed in hypoxia versus normoxia. We identified 21 genes with prognostic value and overlapping in three different training sets and (n = 224). With a fourth published dataset (n = 177), the six-gene Colon Cancer Hypoxia Score (CCHS) was developed. Patients with low CCHS showed a significant better disease-free survival at three years (77.3%) compared with high CCHS patients (46.4%; log rank, P = 0.006). This was independently confirmed in an external patient cohort of 90 stage II patients (86.9% vs. 52.2%; P = 0.001). CONCLUSIONS: Hypoxia-driven gene expression is associated with high recurrence rates in stage II and III colon cancer. A six-gene score was found to be of independent prognostic value in these patients. Our findings require further validation and incorporation in the current knowledge on molecular classification of colon cancer. PMID- 24486596 TI - Cross Talk between Cellular Redox Status, Metabolism, and p53 in Neural Stem Cell Biology. AB - In recent years, the importance of the cellular redox status for neural stem cell (NSC) homeostasis has become increasingly clear. Similarly, the transcription factor and tumor suppressor p53 has been implicated in the regulation of cell metabolism, in antioxidant response, and in stem cell quiescence and fate commitment. Here, we explore the known and putative functions of p53 in antioxidant response and metabolic control and examine how reactive oxygen species, p53, and related cellular signaling may regulate NSC homeostasis, quiescence, and differentiation. We also discuss the role that PI3K-Akt-mTOR signaling plays in NSC biology and oxidative signaling and how p53 contributes to the regulation of this signaling cascade. Finally, we invite reflection on the several unanswered questions of the role that p53 plays in NSC biology and metabolism, anticipating future directions. PMID- 24486595 TI - Combination of YM155, a survivin suppressant, with bendamustine and rituximab: a new combination therapy to treat relapsed/refractory diffuse large B-cell lymphoma. AB - PURPOSE: There remains an unmet therapeutic need for patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). The purpose of this study was to evaluate the therapeutic potential of sepantronium bromide (YM155), a survivin suppressant, in combination with either bendamustine or both bendamustine and rituximab using DLBCL models. EXPERIMENTAL DESIGN: Human DLBCL cell lines, DB, SU-DHL-8, and WSU-DLCL2, were treated with YM155 in combination with bendamustine. Cell viability, apoptosis induction, protein expression, and cell-cycle distribution were evaluated. Furthermore, antitumor activities of YM155, in combination with bendamustine or both bendamustine and rituximab, were evaluated in mice bearing human DLBCL xenografts. RESULTS: The combination of YM155 with bendamustine showed greater cell growth inhibition and sub-G1 population than either agent alone. YM155 inhibited bendamustine-induced activation of the ATM pathway and accumulation of survivin at G2-M phase, with greater DNA damage and apoptosis than either single agent alone. In a DLBCL DB murine xenograft model, YM155 enhanced the antitumor activity of bendamustine, resulting in complete tumor regression without affecting body weight. Furthermore, YM155 combined with bendamustine and rituximab, decreased FLT-PET signals in lymph nodes and prolonged overall survival of mice bearing disseminated SU-DHL-8, an activated B-cell-like (ABC)-DLBCL xenografts when compared with the combination of either rituximab and bendamustine or YM155 with rituximab. CONCLUSIONS: These results support a clinical trial of the combination of YM155 with bendamustine and rituximab in relapsed/refractory DLBCL. PMID- 24486597 TI - Microbial molecular markers and epidemiological surveillance in the era of high throughput sequencing: an update from the IMMEM-10 conference. PMID- 24486598 TI - Alstonia scholaris (L.) R. Br. and Alstonia macrophylla Wall. ex G. Don: A comparative review on traditional uses, phytochemistry and pharmacology. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Alstonia scholaris (L.) R. Br. and Alstonia macrophylla Wall. ex G. Don are two vital medicinal plant species (family: Apocynaceae). In India, the therapeutic use of Alstonia scholaris has been described in both codified and non-codified drug systems for the treatment of malaria, jaundice, gastrointestinal troubles, cancer and in many other ailments. Other species, Alstonia macrophylla has been used in conventional medicines in Thailand, Malaysia and Philippines as a general tonic, aphrodisiac, anticholeric, antidysentery, antipyretic, emmenagogue, and vulnerary agents. In India, Alstonia macrophylla is used as a substitute for Alstonia scholaris in various herbal pharmaceutical preparations. However, one certainly cannot evaluate the truthfulness of a practice (i.e. in scientific terms). In this article we discuss and summarize comparative data about traditional uses, phytochemistry, pharmacology and toxicity of Alstonia scholaris and Alstonia macrophylla. Moreover, in order to unfold future research opportunities, lacunae in the present knowledge are also highlighted. MATERIALS AND METHODS: Literature about Alstonia scholaris and Alstonia macrophylla was collected by using electronic and library search. Additionally, referred books on traditional medicine and ethnopharmacology were also utilized for receiving traditional records about both the plant species. RESULTS: Both Alstonia scholaris and Alstonia macrophylla are rich in different types of bioactive alkaloids. So far, broad spectrum of in vitro and in vivo biological and pharmacological activities have been reported to both the species. Amongst them, antimicrobial and anticancer activities were promising. CONCLUSIONS: The use of Alstonia macrophylla as a substitute for Alstonia scholaris is not at all justifiable as both the species are distinct from each other in their phytochemistry and pharmacology. Further detail chemical fingerprinting and metabolic studies of these two species are warranted to prevent their mutual adulteration most importantly in the context of commercial preparations. PMID- 24486599 TI - Pharmacological characterization of different fractions of Calotropis procera (Asclepiadaceae) in streptozotocin induced experimental model of diabetic neuropathy. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Calotropis procera (Ait.) R.Br. is one of an ancient traditional shrub, which has been used for the treatment of diabetes, pain and inflammation for thousands of years in India. The root extract of Calotropis procera has been widely used by the tribal's of district Udaipur, Rajasthan (India) for treatment of diabetes mellitus and its associated complications like diabetic neuropathy. The present study was performed to explore the protective effect of root, stem and leaf extracts of Calotropis procera in diabetes and diabetic neuropathy against tactile allodynia, mechanical hyperalgesia and thermal hyperalgesia in streptozotocin induced diabetic rats. MATERIALS AND METHODS: Diabetes and peripheral neuropathy were induced in Wistar rats by injection of streptozotocin (45 mg/kg/intraperitoneally). The roots, stem and leaves of Calotropis procera were sequentially extracted with petroleum ether, chloroform, ethyl acetate and methanol. All the extracts were assessed by oral administration at 100 and 250 mg/kg in streptozotocin diabetic rats. The following compounds were used as positive controls: insulin NPH (1 IU/kg/day), metformin (500 mg/kg/day), glibenclamide (2.5 mg/kg/day) and a combination of acarbose (20 mg/kg/day) with methylcobalamine (500 ug/kg/day). In contrast, the streptozotocin induced untreated diabetic rats termed as negative control. Thermal hyperalgesia, mechanical hyperalgesia and tactile allodynia were evaluated in all groups of streptozotocin diabetic rats to assess the extent of neuropathy by Eddy's hot plate, tail immersion, Randall-Selitto and Von Frey hair tests. The basal nociceptive thresholds were assessed in week 4 of post streptozotocin injection. All groups received their treatment on a regular basis from 28 to 42 days following a confirmation of diabetic neuropathy. The nociceptive thresholds were assessed in all groups in week 5 and 6. The histopathology of pancreas and biochemical estimations of plasma insulin and glycosylated haemoglobin (HbA1C%) levels were also performed in week 6 of post streptozotocin injection. RESULTS: The negative control rats developed diabetes and diabetic neuropathy after 6 week of streptozotocin administration distinguished by significant (p<0.01) hyperalgesia and tactile allodynia with enhanced HbA1C% level compared to normoglycemic rats. Chronic administration of root methanol, stem methanol and leaf ethyl-acetate extracts of Calotropis procera for 2 weeks at 100 and 250 mg/kg doses significantly (p<0.01) attenuated the diabetes induced mechanical hyperalgesia, thermal hyperalgesia, tactile allodynia and HbA1C% level in streptozotocin diabetic rats as compared to negative control rats. Further, the root methanol extract of Calotropis procera in 100mg/kg dose showed the regeneration capability of beta cells in the histology of pancreas with significant (p<0.01) improvement in plasma insulin level in streptozotocin diabetic rats compared to negative control rats. CONCLUSION: Root methanol extract of Calotropis procera (100mg/kg) has shown ameliorative effect in diabetic neuropathy which may be attributed by its multiple actions including potent hypoglycemic and antioxidant. PMID- 24486600 TI - The role of morphology in phoneme prediction: evidence from MEG. AB - There is substantial neural evidence for the role of morphology (word-internal structure) in visual word recognition. We extend this work to auditory word recognition, drawing on recent evidence that phoneme prediction is central to this process. In a magnetoencephalography (MEG) study, we crossed morphological complexity (bruis-er vs. bourbon) with the predictability of the word ending (bourbon vs. burble). High prediction error (surprisal) led to increased auditory cortex activity. This effect was enhanced for morphologically complex words. Additionally, we calculated for each timepoint the surprisal corresponding to the phoneme perceived at that timepoint, as well as the cohort entropy, which quantifies the competition among words compatible with the string prefix up to that timepoint. Higher surprisal increased neural activity at the end of the word, and higher entropy decreased neural activity shortly after word onset. These results reinforce the role of morphology and phoneme prediction in spoken word recognition. PMID- 24486601 TI - Impaired timing adjustments in response to time-varying auditory perturbation during connected speech production in persons who stutter. AB - Auditory feedback (AF), the speech signal received by a speaker's own auditory system, contributes to the online control of speech movements. Recent studies based on AF perturbation provided evidence for abnormalities in the integration of auditory error with ongoing articulation and phonation in persons who stutter (PWS), but stopped short of examining connected speech. This is a crucial limitation considering the importance of sequencing and timing in stuttering. In the current study, we imposed time-varying perturbations on AF while PWS and fluent participants uttered a multisyllabic sentence. Two distinct types of perturbations were used to separately probe the control of the spatial and temporal parameters of articulation. While PWS exhibited only subtle anomalies in the AF-based spatial control, their AF-based fine-tuning of articulatory timing was substantially weaker than normal, especially in early parts of the responses, indicating slowness in the auditory-motor integration for temporal control. PMID- 24486602 TI - High GMFG expression correlates with poor prognosis and promotes cell migration and invasion in epithelial ovarian cancer. AB - OBJECTIVE: The aim of this study was to characterize the clinical significance of GMFG, a novel ADF/cofilin superfamily protein, and investigate its role in cell migration and invasion in epithelial ovarian cancer (EOC). METHODS: The expression of GMFG in EOC tissues and ovarian cancer cell lines was evaluated by immunohistochemistry and immunoblotting respectively. The data were statistically analyzed for the associations of GMFG expression with clinicopathologic parameters and survival. In vitro cell migration and invasion assays were performed to determine the role of GMFG in cell migratory behaviors. The effect of GMFG on reorganization of actin cytoskeleton was investigated by immunostaining. RESULTS: GMFG was overexpressed in EOC. Up-regulated GMFG expression was closely correlated with advanced FIGO stage and chemoresistance of the disease. EOC patients with higher GMFG expression showed poorer progression free survival (PFS) and overall survival (OS). In vitro cellular assays revealed that GMFG promoted cell migration and invasion. GMFG expression altered actin cytoskeleton organization probably by interacting with the Arp2/3 complex. CONCLUSION: GMFG expression independently predicts poorer prognosis in patients with EOC. Ectopic overexpression of GMFG contributes to the malignant biological behavior of ovarian cancer cells. PMID- 24486603 TI - Nuclear Y-box-binding protein-1 is a poor prognostic marker and related to epidermal growth factor receptor in uterine cervical cancer. AB - OBJECTIVE: Y-box binding protein-1 (YB-1) is a member of the cold shock protein family and functions in transcription and translation. Many studies indicate that YB-1 is strongly expressed in tumor cells and is considered a marker of tumor aggressiveness and clinical prognosis. Overexpression of epidermal growth factor receptor (EGFR) has been associated with poor outcomes in cervical cancer. Clinical trials of EGFR family-base therapy are currently being initiated in cervical cancer. Nuclear YB-1 expression correlates with EGFR expression in various types of cancer. However, the clinical significance of nuclear YB-1 expression in different settings, the correlation with EGFR, and the prognostic implications of YB-1 expression in cervical cancer remain elusive. PATIENTS AND METHODS: Nuclear YB-1 expression was immunohistochemically analyzed in tissue specimens obtained from 204 patients with cervical cancer who underwent surgery. Associations of nuclear YB-1 expression with clinicopathological factors such as survival, EGFR expression, and human epidermal growth factor receptor 2 (HER2) expression were investigated. RESULTS: Nuclear YB-1 expression was found in 41 (20.2%) of 204 cases of cervical cancer and correlated with disease stage, tumor diameter, stromal invasion, and lymph-node metastasis. Nuclear YB-1 expression also correlated with EGFR expression (P=0.0114) as well as HER2 expression (P=0.0053). Kaplan-Meier survival analysis showed that nuclear YB-1 expression was significantly associated with poor progression-free survival (P=0.0033) and overall survival (P=0.0003), respectively. CONCLUSION: Nuclear YB-1 expression is a prognostic marker and correlates with EGFR expression in cervical cancer. PMID- 24486604 TI - A systematic review comparing cisplatin and carboplatin plus paclitaxel-based chemotherapy for recurrent or metastatic cervical cancer. AB - INTRODUCTION: The prognosis of advanced/recurrent cervical cancer patients is generally poor with 1-year survival ranging between 15 and 20%. Cisplatin (CDDP) based treatments are considered the most effective regimens; unfortunately toxicity is an issue in a population in which the treatment remains palliative in the finality. Carboplatin (CBDCA), with its more favorable non toxicity profile and the convenience of outpatient administration, may be a suitable alternative to CDDP in combination regimens. MATERIALS AND METHODS: We performed a systematic review of the literature comparing CDDP and CBDCA based chemotherapy for advanced cervical cancer (recurrent, persistent or metastatic disease). Only studies that met the following criteria were considered for the present review: 1) patients treated with CDDP/paclitaxel or CBDCA/paclitaxel combinations as first line chemotherapy for metastatic disease; 2) one or more of the following data available: overall response rate (RR), progression free survival (PFS) or time to progression (TTP), overall survival (OS); 3) single-arm retrospective or prospective study; and 4) at least 20 patients enrolled. RESULTS: 17 eligible studies comprehensive of 1181 patients were included in the final analysis. The objective RR was 48.5% for CBDCA and 49.3% for CDDP-based chemotherapy. Median PFS for CDDP and CBDCA-based treatments was 6.9months and 5months respectively (p=0.03); the corresponding figures for median OS were 12.87 and 10months respectively (p=0.17). DISCUSSION: Our study indicates that CBDCA may represent an attractive and valid alternative to the more toxic and equally effective CDDP in the treatment of advanced or recurrent cervical cancer. PMID- 24486605 TI - Comparison of clinical outcomes of adenocarcinoma and adenosquamous carcinoma in uterine cervical cancer patients receiving surgical resection followed by radiotherapy: a multicenter retrospective study (KROG 13-10). AB - OBJECTIVE: To evaluate the prognostic influence of adenocarcinoma (AC) and adenosquamous carcinoma (ASC) in patients with FIGO stage IB-IIA cervical cancer who received radical hysterectomy followed by adjuvant radiotherapy (RT) or concurrent chemoradiotherapy (CCRT). METHODS: We analyzed 1323 patients who satisfied the following criteria: histologically proven squamous cell carcinoma (SCC), AC, or ASC of the uterine cervix; FIGO stage IB-IIA disease; no history of neoadjuvant chemotherapy; and a history of radical hysterectomy with pelvic lymph node (PLN) dissection, followed by postoperative pelvic RT at a dose >= 45 Gy. The median age was 50 years. Median RT dose delivered to the whole pelvis was 50.4 Gy, and 219 (16.6%) patients received brachytherapy at a median dose of 24 Gy. Concurrent chemotherapy was delivered to 492 (37.2%) patients. RESULTS: Pathologic risk factors were not different according to pathologic subtype. The median follow-up duration was 75.7 months. Locoregional recurrence-free survival, relapse-free survival (RFS), and overall survival were significantly affected by histology, tumor size, PLN metastasis, parametrial invasion, lymphovascular invasion, and deep stromal invasion. The 5-year RFS rates were 83.7%, 66.5%, and 79.6% in patients with SCC, AC, and ASC histology, respectively (P<0.0001). By multivariate analysis, AC histology was the only significant prognostic factor affecting all survival outcomes. CONCLUSIONS: AC histology was associated with poor survival outcomes in patients with FIGO stage IB-IIA cervical cancer who received adjuvant RT or CCRT. Prognosis of ASC histology was closer to that of SCC histology than that of AC histology. PMID- 24486606 TI - Pleural mesothelium lubrication after phospholipase treatment. AB - Coefficient of kinetic friction (MU) of rabbit pleural mesothelium increased after short treatment of specimens with phospholipase C. This increase was removed by addition of a solution with hyaluronan or sialomucin, as previously shown in post-blotting Ringer or after short pronase treatment. After phospholipase MU decreased with increase in sliding velocity, but at highest velocity it was still greater than control; this difference was removed by addition of hyaluronan or sialomucin, as in post-blotting Ringer or after short pronase treatment. Hyaluronan placed on specimen before phospholipase treatment reduced increase in MU by protecting phospholipids from enzyme, as shown by others for alveolar and synovial phospholipids. Samples of parietal pleura stained with silver nitrate showed that mesothelial cells were not disrupted by short phospholipase treatment. Instead, they were disrupted if this treatment was preceded by a short pronase treatment; but even after this disruption addition of hyaluronan or sialomucin brought MU back to control. PMID- 24486607 TI - Low-level laser therapy inhibits bronchoconstriction, Th2 inflammation and airway remodeling in allergic asthma. AB - Low-level laser therapy (LLLT) controls bronchial hyperresponsiveness (BHR) associated with increased RhoA expression as well as pro-inflammatory mediators associated with NF-kB in acute lung inflammation. Herein, we explore if LLLT can reduce both BHR and Th2 cytokines in allergic asthma. Mice were studied for bronchial reactivity and lung inflammation after antigen challenge. BHR was measured through dose-response curves to acetylcholine. Some animals were pretreated with a RhoA inhibitor before the antigen. LLLT (660 nm, 30 mW and 5.4 J) was applied on the skin over the right upper bronchus and two irradiation protocols were used. Reduction of BHR post LLLT coincided with lower RhoA expression in bronchial muscle as well as reduction in eosinophils and eotaxin. LLLT also diminished ICAM expression and Th2 cytokines as well as signal transducer and activator of transduction 6 (STAT6) levels in lungs from challenged mice. Our results demonstrated that LLLT reduced BHR via RhoA and lessened allergic lung inflammation via STAT6. PMID- 24486608 TI - A reevaluation of the effect of transrespiratory pressure on the breathing pattern of intubated mice. AB - This study aimed to determine if the effect of transrespiratory pressure on respiration was due to alveolar pressure minus the body surface pressure or from the co-effects of two-sided pressure. After introducing air pressure into the trachea of intubated mice, the tidal volume (VT) showed no significant changes, but the respiratory frequency (f) and minute ventilation (VE) were significantly decreased. Positive body surface pressure significantly increased f and VE; however, VT was not significantly affected. Interestingly, f and VE at 2.5 cm H2O were higher than at 5 cm H2O. Simultaneous positive air pressure on both the alveoli and body surface demonstrated no significant effect on the VT but significantly decreased f and VE. This inhibitory effect consisted of the combined activities of the inhibitory effects of positive tracheal pressure and the activated effects of positive body surface pressure. Taken together, the effect of transrespiratory pressure on respiration was due to the co-effect of alveolar pressure and body surface pressure. PMID- 24486610 TI - A novel C-terminal homologue of Aha1 co-chaperone binds to heat shock protein 90 and stimulates its ATPase activity in Entamoeba histolytica. AB - Cytosolic heat shock protein 90 (Hsp90) has been shown to be essential for many infectious pathogens and is considered a potential target for drug development. In this study, we have carried out biochemical characterization of Hsp90 from a poorly studied protozoan parasite of clinical importance, Entamoeba histolytica. We have shown that Entamoeba Hsp90 can bind to both ATP and its pharmacological inhibitor, 17-AAG (17-allylamino-17-demethoxygeldanamycin), with Kd values of 365.2 and 10.77 MUM, respectively, and it has a weak ATPase activity with a catalytic efficiency of 4.12*10(-4) min(-1) MUM(-1). Using inhibitor 17-AAG, we have shown dependence of Entamoeba on Hsp90 for its growth and survival. Hsp90 function is regulated by various co-chaperones. Previous studies suggest a lack of several important co-chaperones in E. histolytica. In this study, we describe the presence of a novel homologue of co-chaperone Aha1 (activator of Hsp90 ATPase), EhAha1c, lacking a canonical Aha1 N-terminal domain. We also show that EhAha1c is capable of binding and stimulating ATPase activity of EhHsp90. In addition to highlighting the potential of Hsp90 inhibitors as drugs against amoebiasis, our study highlights the importance of E. histolytica in understanding the evolution of Hsp90 and its co-chaperone repertoire. PMID- 24486609 TI - Structure and function of steroid receptor RNA activator protein, the proposed partner of SRA noncoding RNA. AB - In a widely accepted model, the steroid receptor RNA activator protein (SRA protein; SRAP) modulates the transcriptional regulatory activity of SRA RNA by binding a specific stem-loop of SRA. We first confirmed that SRAP is present in the nucleus as well as the cytoplasm of MCF-7 breast cancer cells, where it is expressed at the level of about 10(5) molecules per cell. However, our SRAP-RNA binding experiments, both in vitro with recombinant protein and in cultured cells with plasmid-expressed protein and RNA, did not reveal a specific interaction between SRAP and SRA. We determined the crystal structure of the carboxy-terminal domain of human SRAP and found that it does not have the postulated RRM (RNA recognition motif). The structure is a five-helix bundle that is distinct from known RNA-binding motifs and instead is similar to the carboxy-terminal domain of the yeast spliceosome protein PRP18, which stabilizes specific protein-protein interactions within a multisubunit mRNA splicing complex. SRA binding experiments with this domain gave negative results. Transcriptional regulation by SRA/SRAP was examined with siRNA knockdown. Effects on both specific estrogen-responsive genes and genes identified by RNA-seq as candidates for regulation were examined in MCF-7 cells. Only a small effect (~20% change) on one gene resulting from depletion of SRA/SRAP could be confirmed. We conclude that the current model for SRAP function must be reevaluated; we suggest that SRAP may function in a different context to stabilize specific intermolecular interactions in the nucleus. PMID- 24486611 TI - The C-terminal domain of SRA1p has a fold more similar to PRP18 than to an RRM and does not directly bind to the SRA1 RNA STR7 region. AB - Steroid receptor activator RNA protein (SRA1p) is the translation product of the bi-functional long non-coding RNA steroid receptor activator RNA 1 (SRA1) that is part of the steroid receptor coactivator-1 acetyltransferase complex and is indicated to be an epigenetic regulatory component. Previously, the SRA1p protein was suggested to contain an RNA recognition motif (RRM) domain. We have determined the solution structure of the C-terminal domain of human SRA1p by NMR spectroscopy. Our structure along with sequence comparisons among SRA1p orthologs and against authentic RRM proteins indicates that it is not an RRM domain but rather an all-helical protein with a fold more similar to the PRP18 splicing factor. NMR spectroscopy on the full SRA1p protein suggests that this structure is relevant to the native full-length context. Furthermore, molecular modeling indicates that this fold is well conserved among vertebrates. Amino acid variations in this protein seen across sequenced human genomes, including those in tumor cells, indicate that mutations that disrupt the fold occur vary rarely and highlight that its function is well conserved. SRA1p had previously been suggested to bind to the SRA1 RNA, but NMR spectra of SRA1p in the presence of its 80-nt RNA target suggest otherwise and indicate that this protein must be part of a multi-protein complex in order to recognize its proposed RNA recognition element. PMID- 24486612 TI - Post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin can reduce ischemia reperfusion injury. AB - Despite successful revascularization, reperfusion after prolonged ischemia causes ischemia reperfusion (I/R) injury. Recruitment and activation of neutrophils is thought to be a key event causing I/R injury. We examined whether post-ischemic intra-arterial infusion of liposome-encapsulated hemoglobin (LEH), an artificial oxygen carrier without neutrophils, could reduce I/R injury in a rat transient middle cerebral artery occlusion (MCAO) model. Male Sprague-Dawley rats were subjected to 2-h MCAO and then were divided into three groups: (1) LEH group (n=7) infused with LEH (Hb concentration of 6g/dl, 10ml/kg/h) through the recanalized internal carotid artery for 2h, (2) vehicle group (n=8) infused with saline (10ml/kg/h) in the same manner as the LEH group, and (3) control group (n=9) subjected to recanalization only. After 24-h reperfusion, all rats were tested for neurological score and then sacrificed to examine infarct and edema volumes, myeloperoxidase (MPO) expression, matrix metalloproteinase-9 (MMP-9) expression and activity, and reactive oxygen species (ROS) production. Compared with the control group and the vehicle group, the LEH group showed a significantly better neurological score and significantly smaller infarct and edema volumes. MPO expression, MMP-9 expression and activity, and ROS production in the LEH group were also significantly lower than those in the control and vehicle groups. The results in the present study suggest that post-ischemic intra arterial infusion of LEH can reduce I/R injury through reducing the effect of MMP 9, most likely produced by neutrophils. This therapeutic strategy may be a promising candidate to prevent I/R injury after thrombolysis and/or thromboectomy. PMID- 24486613 TI - Source recognition by stimulus content in the MTL. AB - Source memory is considered to be the cornerstone of episodic memory that enables us to discriminate similar but different events. In the present fMRI study, we investigated whether neural correlates of source retrieval differed by stimulus content in the medial temporal lobe (MTL) when the item and context had been integrated as a perceptually unitized entity. Participants were presented with a list of items either in verbal or pictorial form overlaid on a colored square and instructed to integrate both the item and context into a single image. At test, participants judged the study status of test items and the color in which studied items were presented. Source recognition invariant of stimulus content elicited retrieval activity in both the left anterior hippocampus extending to the perirhinal cortex and the right posterior hippocampus. Word-selective source recognition was related to activity in the left perirhinal cortex, whereas picture-selective source recognition was identified in the left posterior hippocampus. Neural activity sensitive to novelty detection common to both words and pictures was found in the left anterior and right posterior hippocampus. Novelty detection selective to words was associated with the left perirhinal cortex, while activity sensitive to new pictures was identified in the bilateral hippocampus and adjacent MTL cortices, including the parahippocampal, entorhinal, and perirhinal cortices. These findings provide further support for the integral role of the hippocampus both in source recognition and in detection of new stimuli across stimulus content. Additionally, novelty effects in the MTL reveal the integral role of the MTL cortex as the interface for processing new information. Collectively, the present findings demonstrate the importance of the MTL for both previously experienced and novel events. PMID- 24486614 TI - Functionalized hollow siliceous spheres for VOCs removal with high efficiency and stability. AB - Functionalized hollow siliceous spheres (HSSs) have been prepared by surface modification with trimethylchlorosilane (TMCS) for the removal of volatile organic compounds (VOCs). The resultant HSSs-TMCS possesses a uniform and well dispersed hollow spherical structure, high surface area, large total pore volume, high VOCs adsorption capacity, and small water vapor adsorption capacity. The adsorption and desorption performance of HSSs-TMCS under static (n-hexane and 93# gasoline) and dynamic (n-hexane) conditions was investigated. Compared with commercial silica gel (SG) and activated carbon (AC), HSSs-TMCS show higher capacity of adsorbing n-hexane and 93# gasoline with good stability and low water vapor adsorption capacity under static adsorption conditions, higher dynamic adsorption capacity and stable breakthrough time under dynamic adsorption conditions. The high efficiency and stability of functionalized HSSs are associated with their unique hollow morphology and structure parameters. The designed HSSs-TMCS with high VOCs removal capacity and recyclability are promising candidates for the treatment of air pollution. PMID- 24486615 TI - Experimental and numerical study of premixed hydrogen/air flame propagating in a combustion chamber. AB - An experimental and numerical study of dynamics of premixed hydrogen/air flame in a closed explosion vessel is described. High-speed shlieren cinematography and pressure recording are used to elucidate the dynamics of the combustion process in the experiment. A dynamically thickened flame model associated with a detailed reaction mechanism is employed in the numerical simulation to examine the flame flow interaction and effect of wall friction on the flame dynamics. The shlieren photographs show that the flame develops into a distorted tulip shape after a well-pronounced classical tulip front has been formed. The experimental results reveal that the distorted tulip flame disappears with the primary tulip cusp and the distortions merging into each other, and then a classical tulip is repeated. The combustion dynamics is reasonably reproduced in the numerical simulations, including the variations in flame shape and position, pressure build-up and periodically oscillating behavior. It is found that both the tulip and distorted tulip flames can be created in the simulation with free-slip boundary condition at the walls of the vessel and behave in a manner quite close to that in the experiments. This means that the wall friction could be unimportant for the tulip and distorted tulip formation although the boundary layer formed along the sidewalls has an influence to a certain extent on the flame behavior near the sidewalls. The distorted tulip flame is also observed to be produced in the absence of vortex flow in the numerical simulations. The TF model with a detailed chemical scheme is reliable for investigating the dynamics of distorted tulip flame propagation and its underlying mechanism. PMID- 24486616 TI - A model to assess dust explosion occurrence probability. AB - Dust handling poses a potential explosion hazard in many industrial facilities. The consequences of a dust explosion are often severe and similar to a gas explosion; however, its occurrence is conditional to the presence of five elements: combustible dust, ignition source, oxidant, mixing and confinement. Dust explosion researchers have conducted experiments to study the characteristics of these elements and generate data on explosibility. These experiments are often costly but the generated data has a significant scope in estimating the probability of a dust explosion occurrence. This paper attempts to use existing information (experimental data) to develop a predictive model to assess the probability of a dust explosion occurrence in a given environment. The pro-posed model considers six key parameters of a dust explosion: dust particle diameter (PD), minimum ignition energy (MIE), minimum explosible concentration (MEC), minimum ignition temperature (MIT), limiting oxygen concentration (LOC) and explosion pressure (Pmax). A conditional probabilistic approach has been developed and embedded in the proposed model to generate a nomograph for assessing dust explosion occurrence. The generated nomograph provides a quick assessment technique to map the occurrence probability of a dust explosion for a given environment defined with the six parameters. PMID- 24486617 TI - Characteristics of selective fluoride adsorption by biocarbon-Mg/Al layered double hydroxides composites from protein solutions: kinetics and equilibrium isotherms study. AB - In the study, two novel applied biocarbon-Mg/Al layered double hydroxides composites (CPLDH and CPLDH-Ca) were successfully prepared and characterized by TEM, ICP-AES, XFS, EDS, FTIR, XRD, BET and pHpzc. The fluoride removal efficiency (RF) and protein recovery ratio (RP) of the adsorbents were studied in protein systems of lysozyme (LSZ) and bovine serum albumin (BSA). The results showed that the CPLDH-Ca presented remarkable performance for selective fluoride removal from protein solution. It reached the maximum RF of 92.1% and 94.8% at the CPLDH-Ca dose of 2.0g/L in LSZ and BSA system, respectively. The RP in both systems of LSZ and BSA were more than 90%. Additionally, the RP of CPLDH-Ca increased with the increase of ionic strengths, and it almost can be 100% with more than 93% RF. Fluoride adsorption by the CPLDH-Ca with different initial fluoride concentrations was found to obey the mixed surface reaction and diffusion controlled adsorption kinetic model, and the overall reaction rate is probably controlled by intra-particle diffusion, boundary layer diffusion and reaction process. The adsorption isotherms of fluoride in BSA system fit the Langmuir Freundlich model well. The BSA has synergistic effect on fluoride adsorption and the degree increased with the increase of the initial BSA concentration. PMID- 24486618 TI - Mitigation of 5-Fluorouracil induced renal toxicity by chrysin via targeting oxidative stress and apoptosis in wistar rats. AB - 5-Fluorouracil (5-FU) is a potent antineoplastic agent commonly used for the treatment of various malignancies. It has diverse adverse effects such as cardiotoxicity, nephrotoxicity and hepatotoxicity which restrict its wide and extensive clinical usage. It causes marked organ toxicity coupled with increased oxidative stress and apoptosis. Chrysin (CH), a natural flavonoid found in many plant extracts, propolis, blue passion flower. It has antioxidative and anti cancerous properties. The present study was designed to investigate the protective effects of CH against 5-FU induced renal toxicity in wistar rats using biochemical, histopathological and immunohistochemical approaches. Rats were subjected to prophylactic oral treatment of CH (50 and 100mg/kg b.wt.) for 21 days against renal toxicity induced by single intraperitoneal administration of 5 FU (150 mg/kg b.wt.). The possible mechanism of 5-FU induced renal toxicity is the induction of oxidative stress; activation of apoptotic pathway by upregulation of p53, bax, caspase-3 and down regulating Bcl-2. However prophylactic treatment of CH decreased serum toxicity markers, increased anti oxidant armory as well as regulated apoptosis in kidney. Histopathological changes further confirmed the biochemical and immunohistochemical results. Therefore, results of the present finding suggest that CH may be a useful modulator in mitigating 5-FU induced renal toxicity. PMID- 24486619 TI - Iodine-131 and thyroid function: Ostroumova et al. respond. PMID- 24486620 TI - The effects of physical environments in medical wards on medication communication processes affecting patient safety. AB - Physical environments of clinical settings play an important role in health communication processes. Effective medication management requires seamless communication among health professionals of different disciplines. This paper explores how physical environments affect communication processes for managing medications and patient safety in acute care hospital settings. Findings highlighted the impact of environmental interruptions on communication processes about medications. In response to frequent interruptions and limited space within working environments, nurses, doctors and pharmacists developed adaptive practices in the local clinical context. Communication difficulties were associated with the ward physical layout, the controlled drug key and the medication retrieving device. Health professionals should be provided with opportunities to discuss the effects of ward environments on medication communication processes and how this impacts medication safety. Hospital administrators and architects need to consider health professionals' views and experiences when designing hospital spaces. PMID- 24486621 TI - Ceramides and sphingomyelinases in senile plaques. AB - The senile plaque is a hallmark lesion of Alzheimer disease (AD). We compared, without a priori, the lipidome of the senile plaques and of the adjacent plaque free neuropil. The analysis by liquid chromatography coupled with electrospray ionization mass spectrometry revealed that laser microdissected senile plaques were enriched in saturated ceramides Cer(d18:1/18:0) and Cer(d18:1/20:0) by 33 and 78% respectively with respect to the surrounding neuropil. This accumulation of ceramides was not explained by their affinity for Abeta deposits: no interaction between ceramide-liposomes and Abeta fibrils was observed in vitro by surface plasmon resonance and fluorescent ceramide-liposomes showed no affinity for the senile plaques in AD brain tissue. Accumulation of ceramides could be, at least partially, the result of a local production by acid and neutral sphingomyelinases that we found to be present in the corona of the senile plaques. PMID- 24486622 TI - Selective disruption of acetylcholine synthesis in subsets of motor neurons: a new model of late-onset motor neuron disease. AB - Motor neuron diseases are characterized by the selective chronic dysfunction of a subset of motor neurons and the subsequent impairment of neuromuscular function. To reproduce in the mouse these hallmarks of diseases affecting motor neurons, we generated a mouse line in which ~40% of motor neurons in the spinal cord and the brainstem become unable to sustain neuromuscular transmission. These mice were obtained by conditional knockout of the gene encoding choline acetyltransferase (ChAT), the biosynthetic enzyme for acetylcholine. The mutant mice are viable and spontaneously display abnormal phenotypes that worsen with age including hunched back, reduced lifespan, weight loss, as well as striking deficits in muscle strength and motor function. This slowly progressive neuromuscular dysfunction is accompanied by muscle fiber histopathological features characteristic of neurogenic diseases. Unexpectedly, most changes appeared with a 6-month delay relative to the onset of reduction in ChAT levels, suggesting that compensatory mechanisms preserve muscular function for several months and then are overwhelmed. Deterioration of mouse phenotype after ChAT gene disruption is a specific aging process reminiscent of human pathological situations, particularly among survivors of paralytic poliomyelitis. These mutant mice may represent an invaluable tool to determine the sequence of events that follow the loss of function of a motor neuron subset as the disease progresses, and to evaluate therapeutic strategies. They also offer the opportunity to explore fundamental issues of motor neuron biology. PMID- 24486624 TI - Venous thromboembolism in patients with myeloma: incidence and risk factors in a "real-world" population. AB - Myeloma has a well-described association with venous thromboembolism (VTE). There are few dedicated studies investigating the incidence and risk factors. Many assessment scores have been suggested to estimate the risk of VTE in patients with cancer but these have been validated in solid organ tumors. The records of patients with myeloma attending a university hospital between January 2007 and December 2012 were reviewed to investigate the incidence of VTE and the associated risk factors. In all, 217 patients with a mean (standard deviation) age at diagnosis of 65 (12) years were included. Of 217 patients, 12% had an episode of VTE, 69% received at least 1 immunomodulatory agent, and 95% had low or intermediate risk of VTE according to the Khorana score. Venous thromboembolism was a frequent occurrence in this cohort. Patients had many risk factors for VTE but no one was predictive. As myeloma outcomes continue to improve, a dedicated prospective study is warranted to investigate the most appropriate thromboprophylaxis strategy. PMID- 24486623 TI - An approach for the delineation of a generic cut-off value for local respiratory tract irritation by irritating or corrosive substances as a pragmatic tool to fulfill REACH requirements. AB - Under the current European legislation for the Registration, Evaluation, Authorisation and restriction of Chemicals (REACHs) a Derived No Effect Level (DNEL) has to be delineated for acute and chronic inhalation effects. The majority of available experimental studies are performed by the oral route of exposure. Route to route extrapolation poses particular problems for irritating or corrosive substances but the necessity for additional animal studies with inhalation exposure needs to be balanced with the regulatory information requirements. Existing occupational exposure limits (OEL) as surrogate for cut off limits representing safe exposure under working conditions were grouped under certain criteria for substances that are legally classified in Europe as irritating or corrosive. As a result, it was shown that the OEL for irritating substances in this dataset is not lower than 10mg/m(3) and for corrosives not lower than 1mg/m(3). Under certain conditions these generic limits could be applied as a pragmatic, but still sufficiently reliable and protective upper cut off limit approach to avoid additional animal tests with irritating or corrosive chemicals. The respective systemic toxicity profiles and physical-chemical properties need to be considered. Specific exclusion criteria for the discussed concept apply. PMID- 24486625 TI - Exploring the biophysical aspects and binding mechanism of thionine with bovine hemoglobin by optical spectroscopic and molecular docking methods. AB - In the present investigation, we have elucidated the interaction between thionine (TH) and bovine hemoglobin (BHb) under physiological conditions by using absorption, emission, time resolved fluorescence, synchronous fluorescence, circular dichroism (CD) and three dimensional emission (3D) spectral studies. Molecular docking experiment was also carried out to establish the possible binding site of TH on BHb. The emission spectral studies revealed that, TH have the ability to bind with BHb and form a ground state complex via static quenching process. The calculated binding constant and the number of binding sites was found to be 3.65*10(4)dm(3)mol(-1) and 1.04, respectively. Forster Resonance Energy Transfer (FRET) theory was employed to calculate the distance (r) between donor (BHb) and acceptor (TH) as 3.64nm. Furthermore, the conformational changes of BHb induced by TH complexation showed some degree of structural unfolding. In addition, molecular docking study confirmed that the most probable binding site of TH was located within the active cavity constituted by alpha1 and alpha2 subunits of BHb. PMID- 24486626 TI - Assessment of aflatoxin M1 in maternal breast milk in Eastern Turkey. AB - Breastfeeding may be considered as a risk factor for aflatoxin M1 (AFM1) exposure in early infancy. Hence, AFM1 levels in maternal breast milk (MBM) and the correlation between moldy cheese consumption of lactating mothers and infant exposure to AFM1 were investigated in this study. MBM samples from 73 lactating women randomly selected in hospitals located in Eastern Turkey were analysed for the presence of AFM1 using competitive ELISA. Out of 73 lactating mothers, 44 of them had the habit of cheese consumption (at least once a week), while remaining 29 had no such habit. AFM1 was detected in MBM of 18 out of 73 samples (24.6%); 12 MBM of 44 lactating mothers with moldy cheese consumption habit (27.2%) and 6 MBM of 29 mothers with no such habit (20.6%) with the range of 1.3-6.0 ng/l. None of the samples exceeded the limit set by EU and Turkish legislations. Moldy cheese consumption habit of lactating mothers exhibited no significant correlation with the presence of AFM1 in their milk (p>0.05). The results indicated that the relative risk of infant AFM1 exposure via MBM of moldy cheese consuming mother was not higher than MBM of mothers with no such habit. PMID- 24486627 TI - Deletions in the highly polymorphic region (HPR) of infectious salmon anaemia virus HPR0 haemagglutinin-esterase enhance viral fusion and influence the interaction with the fusion protein. AB - Since the discovery of a non-virulent infectious salmon anaemia virus (ISAV) HPR0 variant, many studies have speculated on the functional role of deletions within the highly polymorphic region (HPR) of genomic segment 6, which codes for the haemagglutinin-esterase (HE) protein. To address this issue, mutant HE proteins with deletions in their HPR were generated from the Scottish HPR0 template (NWM10) and fusion-inducing activity was measured using lipid (octadecyl rhodamine B) and content mixing assays (firefly luciferase). Segment six HPR was found to have a strong influence on ISAV fusion, and deletions in this near membrane region predominantly increased the fusion-inducing ability of the resulting HE proteins. The position and length of the HPR deletions were not significant factors, suggesting that they may affect fusion non-specifically. In comparison, the amino acid composition of the associated fusion (F) protein was a more crucial criterion. Antibody co-patching and confocal fluorescence demonstrated that the HE and F proteins were highly co-localized, forming defined clusters on the cell surface post-transfection. The binding of erythrocyte ghosts on the attachment protein caused a reduction in the percentage of co localization, suggesting that ISAV fusion might be triggered through physical separation of the F and HE proteins. In this process, HPR deletion appeared to modulate and reduce the strength of interaction between the two glycoproteins, causing more F protein to be released and activated. This work provides a first insight into the mechanism of virulence acquisition through HPR deletion, with fusion enhancement acting as a major contributing factor. PMID- 24486628 TI - Flavivirus RNA methylation. AB - The 5' end of eukaryotic mRNA contains the type-1 (m7GpppNm) or type-2 (m7GpppNmNm) cap structure. Many viruses have evolved various mechanisms to develop their own capping enzymes (e.g. flavivirus and coronavirus) or to 'steal' caps from host mRNAs (e.g. influenza virus). Other viruses have developed 'cap mimicking' mechanisms by attaching a peptide to the 5' end of viral RNA (e.g. picornavirus and calicivirus) or by having a complex 5' RNA structure (internal ribosome entry site) for translation initiation (e.g. picornavirus, pestivirus and hepacivirus). Here we review the diverse viral RNA capping mechanisms. Using flavivirus as a model, we summarize how a single methyltransferase catalyses two distinct N-7 and 2'-O methylations of viral RNA cap in a sequential manner. For antiviral development, a structural feature unique to the flavivirus methyltransferase was successfully used to design selective inhibitors that block viral methyltransferase without affecting host methyltransferases. Functionally, capping is essential for prevention of triphosphate-triggered innate immune activation; N-7 methylation is critical for enhancement of viral translation; and 2'-O methylation is important for subversion of innate immune response during viral infection. Flaviviruses defective in 2'-O methyltransferase are replicative, but their viral RNAs lack 2'-O methylation and are recognized and eliminated by the host immune response. Such mutant viruses could be rationally designed as live attenuated vaccines. This concept has recently been proved with Japanese encephalitis virus and dengue virus. The findings obtained with flavivirus should be applicable to other RNA viruses. PMID- 24486629 TI - Whole-genome analysis of bovine rotavirus species C isolates obtained in Yamagata, Japan, 2003-2010. AB - An epidemic of diarrhoea in adult cows occurred at a total of 105 dairy farms in Yamagata Prefecture, Japan, between 2003 and 2010. Reverse transcription-PCR diagnostic tests revealed the presence of bovine rotavirus species C (RVCs) in samples from each of six farms (5.7 %). In this study, we determined the full length nucleotide sequences of 11 RNA segments from six bovine RVC strains and investigated genetic diversity among them, including two bovine RVC strains identified in a previous study. Comparisons of all segmental nucleotide and the deduced amino acid sequences among bovine RVCs indicated high identities across all genes except for the VP4 gene. Phylogenetic analysis of each gene revealed that the six bovine RVCs belonged to a bovine cluster distinct from human and porcine RVCs. Bovine RVC strains could be clearly divided into two lineages of the VP4 genes. The nucleotide sequence identity for VP4 genes between lineage I and II was 83.7-84.8 %. Moreover, bovine RVC strains belonging to lineage I exhibited one amino acid deletion and three amino acid insertions, which differed for those strains belonging to lineage II. Our data suggest that multiple bovine RVCs originated from a common ancestor, but had different genetic backgrounds, not only in Yamagata Prefecture but also in the rest of Japan. PMID- 24486630 TI - Passive protective effect of chicken egg yolk immunoglobulins against experimental Vibrio anguillarum infection in ayu (Plecoglossus altivelis). AB - Oral administration of chicken egg yolk immunoglobulins (IgY) has attracted much attention as a means for controlling infectious diseases caused by microorganisms. This study evaluated the protective effect of IgY against Vibrio anguillarum infection in ayu, Plecoglossus altivelis. IgY was isolated from egg yolks laid by hens initially immunized with formalin-inactivated V. anguillarum. Lower mortality of ayu was observed in groups treated with anti-V. anguillarum IgY (aVIgY), compared with those treated with saline or with nonspecific IgY (nspIgY). All fish in saline-treated groups died within seven days after bacterial inoculation. The bacterial load in blood, liver, and spleen was significantly lower in fish treated with aVIgY than in fish treated with nspIgY. aVIgY treatment significantly reduced tumor necrosis factor-alpha (PaTNF-alpha), interleukin-1beta (PaIL-1beta), transforming growth factor-beta (PaTGF-beta), and leukocyte cell-derived chemotaxin-2 (PaLECT2) transcript levels in the head kidney, spleen, and liver of ayu challenged by V. anguillarum, compared with nspIgY treatment. The phagocytic activity of macrophages for V. anguillarum in the presence of specific IgY was significantly higher than that seen for nonspecific IgY. These results suggest that passive immunization by oral intubation with pathogen-specific IgY may provide a valuable treatment for V. anguillarum infection in ayu. PMID- 24486631 TI - Characterization of the LECT2 gene and its associations with resistance to the big belly disease in Asian seabass. AB - Leukocyte cell-derived chemotaxin-2 (LECT2) is an important protein of the innate immune system for the defense against bacterial infection. We cloned and characterized the LECT2 gene from Asian seabass (Lates calcarifer). Its complete cDNA consisted of an open reading frame of 459 bp encoding a protein of 152 amino acids. The genomic DNA sequence of this gene consists of four exons and three introns. Quantitative real-time PCR revealed that the LECT2 gene was expressed predominantly in liver while its expression was moderate in spleen and heart, and weak in other tissues. The LECT2 transcript was up-regulated in the kidney, spleen and liver in response to a challenge with a pathogenic bacterium Vibrio harveyi. In addition, we identified three single nucleotide polymorphisms (SNPs) in the LECT2 gene, and found significant associations between these polymorphisms and resistance to the big belly disease. These results suggest that the LECT2 gene play an important role in resistance to bacterial pathogens in fish. The SNP markers in the gene associated with the resistance to bacterial pathogens may facilitate selecting Asian seabass resistant to bacterial diseases. PMID- 24486632 TI - Variations of serum and mucus lysozyme activity and total protein content in the male and female Caspian kutum (Rutilus frisii kutum, Kamensky 1901) during reproductive period. AB - Serum and mucus lysozyme were measured in male and female Caspian kutum (Rutilus frisii kutum) under seasonal temperature, gonadal growth and reproductive migration. Significant difference with almost similar trend in serum and mucus lysozyme of the female Caspian kutum in sampling time and ovarian growth was observed. However, while there was no significant difference in serum lysozyme of the male specimen in sampling time and testicular growth, significant variations was observed in mucus lysozyme. In addition, there was significant difference in mucus total protein both for male and female specimens. The effectiveness ratio of factors on lysozyme variations followed in descending order by seasonal temperature (main factor), reproductive activity and migration with negligible effect and the lysozyme level was not significantly different in male and female Caspian kutum. PMID- 24486633 TI - Variations of physiological and innate immunological responses in goldfish (Carassius auratus) subjected to recurrent acute stress. AB - This study was undertaken to investigate the influence of repeated acute stress on the physiological status and non-specific immune response of goldfish, Carassius auratus. The acute stress was a succession of a 3 min-chasing period followed by a 2 min-air exposure. The goldfish in triplicate tanks were subjected 3 times daily to this stress for one (S3) or three (S9) days. A separate group of unstressed fish was used as control for each sampling time. Blood samples were collected 12, 48 and 120 h after the last stress procedure. Variations of globulin levels, plasma anti-protease and bactericidal activities were not significant in the present study. The haematological parameters and plasma total protein and albumin strongly declined in S9 fish 12 h post-stress compared to control fish. However, plasma cortisol, glucose and lactate levels in both S3 and S9 transiently increased compared to the control fish. Similarly, plasma peroxidase activity transiently increased in both stressed groups 12 h after stress. An increase in plasma lysozyme and complement activities suggested a hormesis-like effect with one-day acute stress improving the immunological response of goldfish while an extension of the stress period to three days impaired physiology and immunity for up to 5 days. This study revealed that recurrent acute stress could immunosuppress goldfish as usually expected of chronic stress. PMID- 24486634 TI - Immunological effects of paraquat on common carp, Cyprinus carpio L. AB - Paraquat (PQ) is a nonselective worldwide used herbicide and it has been demonstrated to be highly toxic to animals and humans. However, relatively little is known about PQ effect on the immune system and histopathology of fish. In the present study, we aimed to determine the lysozyme activities, content of IgM, and complement C3 content in the liver, kidney, and spleen of common carp exposed to 1.596 or 3.192 mg/L of PQ for 7 d. The results showed that lysozyme activity in the liver, kidney, or spleen of common carp was increased at the earlier stages of PQ-exposure (from 1 to 3 d) while decreased at the end of treatment. Moreover, PQ-exposure caused irregular change of IgM content while decreased C3 content. These results suggest that PQ-exposure may disturb the innate immunity of common carp and could result in dysfunction of the specific immunity in common carp. In addition, PQ-exposure also caused remarkable histopathological damages in fish gill, fin, liver, spleen, kidney, and intestine, indicating that PQ has immunotoxicity on common carp. PMID- 24486635 TI - Teaching tobacco dependence treatment and counseling skills during medical school: rationale and design of the Medical Students helping patients Quit tobacco (MSQuit) group randomized controlled trial. AB - INTRODUCTION: Physician-delivered tobacco treatment using the 5As is clinically recommended, yet its use has been limited. Lack of adequate training and confidence to provide tobacco treatment is cited as leading reasons for limited 5A use. Tobacco dependence treatment training while in medical school is recommended, but is minimally provided. The MSQuit trial (Medical Students helping patients Quit tobacco) aims to determine if a multi-modal and theoretically-guided tobacco educational intervention will improve tobacco dependence treatment skills (i.e. 5As) among medical students. METHODS/DESIGN: 10 U.S. medical schools were pair-matched and randomized in a group-randomized controlled trial to evaluate whether a multi-modal educational (MME) intervention compared to traditional education (TE) will improve observed tobacco treatment skills. MME is primarily composed of TE approaches (i.e. didactics) plus a 1st year web-based course and preceptor-facilitated training during a 3rd year clerkship rotation. The primary outcome measure is an objective score on an Objective Structured Clinical Examination (OSCE) tobacco-counseling smoking case among 3rd year medical students from schools who implemented the MME or TE. DISCUSSION: MSQuit is the first randomized to evaluate whether a tobacco treatment educational intervention implemented during medical school will improve medical students' tobacco treatment skills. We hypothesize that the MME intervention will better prepare students in tobacco dependence treatment as measured by the OSCE. If a comprehensive tobacco treatment educational learning approach is effective, while also feasible and acceptable to implement, then medical schools may substantially influence skill development and use of the 5As among future physicians. PMID- 24486636 TI - Protocol and recruitment results from a randomized controlled trial comparing group phone-based versus newsletter interventions for weight loss maintenance among rural breast cancer survivors. AB - Obesity is a risk factor for breast cancer recurrence and death. Women who reside in rural areas have higher obesity prevalence and suffer from breast cancer treatment-related disparities compared to urban women. The objective of this 5 year randomized controlled trial is to compare methods for delivering extended care for weight loss maintenance among rural breast cancer survivors. Group phone based counseling via conference calls addresses access barriers, is more cost effective than individual phone counseling, and provides group support which may be ideal for rural breast cancer survivors who are more likely to have unmet support needs. Women (n=210) diagnosed with Stage 0 to III breast cancer in the past 10 years who are >= 3 months out from initial cancer treatments, have a BMI 27-45 kg/m(2), and have physician clearance were enrolled from multiple cancer centers. During Phase I (months 0 to 6), all women receive a behavioral weight loss intervention delivered through group phone sessions. Women who successfully lose 5% of weight enter Phase II (months 6 to 18) and are randomized to one of two extended care arms: continued group phone-based treatment or a mail-based newsletter. During Phase III, no contact is made (months 18 to 24). The primary outcome is weight loss maintenance from 6 to 18 months. Secondary outcomes include quality of life, serum biomarkers, and cost-effectiveness. This study will provide essential information on how to reach rural survivors in future efforts to establish weight loss support for breast cancer survivors as a standard of care. PMID- 24486637 TI - The Refractory Overactive Bladder: Sacral NEuromodulation vs. BoTulinum Toxin Assessment: ROSETTA trial. AB - We present the rationale for and design of a randomized, open-label, active control trial comparing the effectiveness of 200 units of onabotulinum toxin A (Botox A(r)) versus sacral neuromodulation (InterStim(r)) therapy for refractory urgency urinary incontinence (UUI). The Refractory Overactive Bladder: Sacral NEuromodulation vs. BoTulinum Toxin Assessment (ROSETTA) trial compares changes in urgency urinary incontinence episodes over 6 months, as well as other lower urinary tract symptoms, adverse events and cost effectiveness in women receiving these two therapies. Eligible participants had previously attempted treatment with at least 2 medications and behavioral therapy. We discuss the importance of evaluating two very different interventions, the challenges related to recruitment, ethical considerations for two treatments with significantly different costs, follow-up assessments and cost effectiveness. The ROSETTA trial will provide information to healthcare providers regarding the technical attributes of these interventions as well as the efficacy and safety of these two interventions on other lower urinary tract and pelvic floor symptoms. Enrollment began in March, 2012 with anticipated end to recruitment in mid 2014. PMID- 24486638 TI - Finding genomic function for genetic associations in nicotine addiction research: the ENCODE project's role in future pharmacogenomic analysis. AB - Tobacco-related behaviors and the underlying addiction to nicotine are complex tangles of genetic and environmental factors. Efforts to understand the genetic component of these traits have identified sites in the genome (single nucleotide polymorphisms, or SNPs) that might account for some part of the role of genetics in nicotine addiction. Encouragingly, some of these candidate SNPs remain significant in meta-analyses. However, genetic associations cannot be fully assessed, regardless of statistical significance, without an understanding of the functional consequences of the alleles present at these SNPs. The proper experimental test for allelic function can be very difficult to define, representing a roadblock in translating genetic results into treatment to prevent smoking and other nicotine-related behaviors. This roadblock can be navigated in part with a new web-based tool, the Encyclopedia of DNA Elements (ENCODE). ENCODE is a compilation of searchable data on several types of biochemical functions or "marks" across the genome. These data can be queried for the co-localization of a candidate SNP and a biochemical mark. The presence of a SNP within a marked region of DNA enables the generation of better-informed hypotheses to test possible functional roles of alleles at a candidate SNP. Two examples of such co localizations are presented. One example reveals ENCODE's ability to relate a candidate SNP's function with a gene very far from the physical location of the SNP. The second example reveals a new potential function of the SNP, rs4105144, that has been genetically associated with the number of cigarettes smoked per day. Details for accessing the ENCODE data for this SNP are provided to serve as a tutorial. By serving as a bridge between genetic associations and biochemical function, ENCODE has the power to propel progress in untangling the genetic aspects of nicotine addiction - a major public health concern. PMID- 24486640 TI - ALSPAC mercury study and fish consumers. PMID- 24486639 TI - GPU-based high-performance computing for radiation therapy. AB - Recent developments in radiotherapy therapy demand high computation powers to solve challenging problems in a timely fashion in a clinical environment. The graphics processing unit (GPU), as an emerging high-performance computing platform, has been introduced to radiotherapy. It is particularly attractive due to its high computational power, small size, and low cost for facility deployment and maintenance. Over the past few years, GPU-based high-performance computing in radiotherapy has experienced rapid developments. A tremendous amount of study has been conducted, in which large acceleration factors compared with the conventional CPU platform have been observed. In this paper, we will first give a brief introduction to the GPU hardware structure and programming model. We will then review the current applications of GPU in major imaging-related and therapy related problems encountered in radiotherapy. A comparison of GPU with other platforms will also be presented. PMID- 24486642 TI - Fabrication of highly interconnected porous silk fibroin scaffolds for potential use as vascular grafts. AB - Silk fibroin (SF) scaffolds have been designed and fabricated for multiple organ engineering owing to SF's remarkable mechanical property, excellent biocompatibility and biodegradability, as well as its low immunogenicity. In this study, an easy-to-adopt and mild approach based on a modified freeze-drying method was developed to fabricate a highly interconnected porous SF scaffold. The physical properties of the SF scaffold, including pore morphology, pore size, porosity and compressive modulus, could be adjusted by the amount of ethanol added, the freezing temperature and the concentration of SF. Fourier transform infrared spectroscopy illustrated that treatment of the lyophilized scaffolds with 90% methanol led to a structure transition of SF from silk I (random coil) to silk II (beta-sheet), which stabilized the SF scaffolds in water. We also incorporated heparin during fabrication to obtain a heparin-loaded scaffold which possessed excellent anticoagulant property. The heparin that was incorporated into the SF scaffolds could be released in a sustain manner for approximately 7days, inhibiting the proliferation of human smooth muscle cells within the scaffold in vitro while promoting neovascularization in vivo. We therefore propose that the SF porous scaffold fabricated here may be an attractive candidate for use as a potential vascular graft for implantation based on its high porosity, excellent blood compatibility and mild fabrication process. PMID- 24486643 TI - Manipulation of endothelial cells by KSHV: implications for angiogenesis and aberrant vascular differentiation. AB - Kaposi sarcoma (KS), a viral cancer associated to Kaposi sarcoma herpesvirus (KSHV) infection, is currently the most common tumor in men in sub-Saharan Africa. KS is an angiogenic tumor and characterized by the presence of aberrant vascular structures in the lesion. Although our understanding of how KSHV causes the aberrant differentiation of endothelial cells and the typical vascular abnormalities in KS tumors is far from complete, the experimental evidence reviewed here provides a comprehensive description of the role of KSHV in the pathogenesis of this unusual tumor. In contrast to other tumor viruses, whose interference with cellular processes relating to cell cycle, apoptosis and DNA damage may be at the heart of their oncogenic properties, KSHV may cause KS primarily by its ability to engage with the differentiation and function of endothelial cells. Although the intracellular pathways engaged by KSHV in the endothelial cells are being explored as drug targets, a better understanding of the impact of KSHV on endothelial cell differentiation and vasculogenesis is needed before the encouraging findings can form the basis for new targeted therapeutic approaches to KS. PMID- 24486644 TI - Tumor viruses and replicative immortality--avoiding the telomere hurdle. AB - Tumor viruses promote cell proliferation in order to gain access to an environment suitable for persistence and replication. The expression of viral products that promote growth transformation is often accompanied by the induction of multiple signs of telomere dysfunction, including telomere shortening, damage of telomeric DNA and chromosome instability. Long-term survival and progression to full malignancy require the bypassing of senescence programs that are triggered by the damaged telomeres. Here we review different strategies by which tumor viruses interfere with telomere homeostasis during cell transformation. This frequently involves the activation of telomerase, which assures both the integrity and functionality of telomeres. In addition, recent evidence suggests that oncogenic viruses may activate a recombination-based mechanism for telomere elongation known as Alternative Lengthening of Telomeres (ALT). This error-prone strategy promotes genomic instability and could play an important role in viral oncogenesis. PMID- 24486645 TI - Catabolic cancer-associated fibroblasts transfer energy and biomass to anabolic cancer cells, fueling tumor growth. AB - Fibroblasts are the most abundant "non-cancerous" cells in tumors. However, it remains largely unknown how these cancer-associated fibroblasts (CAFs) promote tumor growth and metastasis, driving chemotherapy resistance and poor clinical outcome. This review summarizes new findings on CAF signaling pathways and their emerging metabolic phenotypes that promote tumor growth. Although it is well established that altered cancer metabolism enhances tumor growth, little is known about the role of fibroblast metabolism in tumor growth. New studies reveal that metabolic coupling occurs between catabolic fibroblasts and anabolic cancer cells, in many types of human tumors, including breast, prostate, and head & neck cancers, as well as lymphomas. These catabolic phenotypes observed in CAFs are secondary to a ROS-induced metabolic stress response. Mechanistically, this occurs via HIF1-alpha and NFkappaB signaling, driving oxidative stress, autophagy, glycolysis and senescence in stromal fibroblasts. These catabolic CAFs then create a nutrient-rich microenvironment, to metabolically support tumor growth, via the local stromal generation of mitochondrial fuels (lactate, ketone bodies, fatty acids, glutamine, and other amino acids). New biomarkers of this catabolic CAF phenotype (such as caveolin-1 (Cav-1) and MCT4), which are reversible upon treatment with anti-oxidants, are strong predictors of poor clinical outcome in various types of human cancers. How cancer cells metabolically reprogram fibroblasts can also help us to understand the effects of cancer cells at an organismal level, explaining para-neoplastic phenomena, such as cancer cachexia. In conclusion, cancer should be viewed more as a systemic disease, that engages the host-organism in various forms of energy-transfer and metabolic co-operation, across a whole-body "ecosystem". PMID- 24486646 TI - Development of an immunoassay for the kidney-specific protein myo-inositol oxygenase, a potential biomarker of acute kidney injury. AB - BACKGROUND: Acute kidney injury (AKI) affects 45% of critically ill patients, resulting in increased morbidity and mortality. The diagnostic standard, plasma creatinine, is nonspecific and may not increase until days after injury. There is significant need for a renal-specific AKI biomarker detectable early enough that there would be a potential window for therapeutic intervention. In this study, we sought to identify a renal-specific biomarker of AKI. METHODS: We analyzed gene expression data from normal mouse tissues to identify kidney-specific genes, one of which was Miox. We generated monoclonal antibodies to recombinant myo-inositol oxygenase (MIOX) and developed an immunoassay to quantify MIOX in plasma. The immunoassay was tested in animals and retrospectively in patients with and without AKI. RESULTS: Kidney tissue specificity of MIOX was supported by Western blot. Immunohistochemistry localized MIOX to the proximal renal tubule. Serum MIOX, undetectable at baseline, increased 24 h following AKI in mice. Plasma MIOX was increased in critically ill patients with AKI [mean (SD) 12.4 (4.3) ng/mL, n = 42] compared with patients without AKI [0.5 (0.3) ng/mL, n = 17] and was highest in patients with oliguric AKI [20.2 (7.5) ng/mL, n = 23]. Plasma MIOX increased 54.3 (3.8) h before the increase in creatinine. CONCLUSIONS: MIOX is a renal-specific, proximal tubule protein that is increased in serum of animals and plasma of critically ill patients with AKI. MIOX preceded the increases in creatinine concentration by approximately 2 days in human patients. Large-scale studies are warranted to further investigate MIOX as an AKI biomarker. PMID- 24486647 TI - Using glycan microarrays to understand immunity. AB - Host immunity represents a complex array of factors that evolved to provide protection against potential pathogens. While many factors regulate host immunity, glycan binding proteins (GBPs) appear to play a fundamental role in orchestrating this process. In addition, GBPs also reside at the key interface between host and pathogen. While early studies sought to understand GBP glycan binding specificity, limitations in the availability of test glycans made it difficult to elucidate a detailed understanding of glycan recognition. Recent developments in glycan microarray technology revolutionized analysis of GBP glycan interactions with significant implications in understanding the role of GBPs in host immunity. In this review, we explore different glycan microarray formats with a focus on the impact of these arrays on understanding the binding specificity and function of GBPs involved in immunity. PMID- 24486648 TI - Hes1 upregulation contributes to the development of FIP1L1-PDGRA-positive leukemia in blast crisis. AB - We have previously shown that elevated expression of Hairy enhancer of split 1 (Hes1) contributes to blast crisis transition in Bcr-Abl-positive chronic myelogenous leukemia. Here we investigate whether Hes1 is involved in the development of other myeloid neoplasms. Notably, Hes1 expression was elevated in only a few cases of 65 samples with different types of myeloid neoplasms. Interestingly, elevated expression of Hes1 was found in two of five samples of Fip1-like1 platelet-derived growth factor receptor-alpha (FIP1L1-PDGFA)-positive myeloid neoplasms associated with eosinophilia. Whereas FIP1L1-PDGFRalpha alone induced acute T-cell leukemia or myeloproliferative neoplasms in mouse bone marrow transplantation models, mice transplanted with bone marrow cells expressing both Hes1 and FIP1L1-PDGFRalpha developed acute leukemia characterized by an expansion of myeloid blasts and leukemic cells without eosinophilic granules. FIP1L1-PDGFRalpha conferred cytokine-independent growth to Hes1 transduced common myeloid progenitors, interleukin-3-dependent cells. Imatinib inhibited the growth of common myeloid progenitors expressing Hes1 with FIP1L1 PDGFRalpha, but not with imatinib-resistant FIP1L1-PDGFRalpha mutants harboring T674I or D842V. In contrast, ponatinib efficiently eradicated leukemic cells expressing Hes1 and the imatinib-resistant FLP1L1-PDGFRAlpha mutant in vitro and in vivo. Thus, we have established mouse models of FIP1L1-PDGFRA-positive leukemia in myeloid blast crisis, which will help elucidate the pathogenesis of the disease and develop a new treatment for it. PMID- 24486649 TI - Blood-based biomarkers for traumatic brain injury: evaluation of research approaches, available methods and potential utility from the clinician and clinical laboratory perspectives. AB - Blood-based biomarkers for traumatic brain injury (TBI) have been investigated and proposed for decades, yet the current clinical assessment of TBI is largely based on clinical symptoms that can vary widely amongst patients, and have significant overlap with unrelated disease states. A careful review of current treatment guidelines for TBI further highlights the potential utility of a blood based TBI biomarker panel in augmenting clinical decision making. Numerous expert reviews on blood-based TBI biomarkers have been published but a close look at the methods used and the astonishing paucity of validation and quality control data has not been undertaken from the vantage point of the clinical laboratory. Further, the field of blood-based TBI biomarker research has failed to adequately examine sex and gender differences between men and women with respect to the clinical care settings, as well as differences in physiological outcomes of TBI biomarker studies. Discussions of tried-and-true laboratory techniques in addition to a few new ones already operating in the clinical laboratory are summarized with a consideration of their utility in TBI biomarker assessment. In the context of TBI biomarkers, the central concerns discussed in this review are the readiness of the clinical laboratory, the willingness of the research environment and the inherent ability of each to radically affect patient outcomes in TBI. PMID- 24486650 TI - B-type natriuretic peptide predicts an ischemic etiology of acute heart failure in patients with stage 4-5 chronic kidney disease. AB - OBJECTIVES: The non-invasive differentiation of ischemic and non-ischemic acute heart failure (AHF) not resulting from acute myocardial infarction is difficult and has therapeutic and prognostic implications. The aim of this study was to assess whether plasma B-type natriuretic peptide (BNP) can identify ischemic etiology in patients with stage 4-5 chronic kidney disease (CKD) presenting with AHF. DESIGN AND METHODS: We prospectively analyzed 61 patients. The diagnosis of ischemic AHF was confirmed by coronary angiography or stress myocardial perfusion imaging. Plasma levels of BNP were measured at admission (BNP1) and 48 h after admission (BNP2). RESULTS: The mean age of the study patients was 67 years. In these patients, 70.5% had diabetes and 47.5% had dialysis-dependent CKD; 28 of these patients (45.9%) had an ischemic etiology with significantly higher concentrations of BNP1 and BNP2 than did patients without ischemia. The area under the receiver operating characteristic curve was 0.755 (P=0.001) for BNP1 and 0.868 (P<0.001) for BNP2 to detect ischemic etiology of AHF. Plasma BNP1 >2907 ng/L (odds ratio [OR], 10.9; 95% confidence interval [CI] 2.5-48.4; P=0.002) and BNP2 >2322 ng/L (OR 93.1, 95% CI 7.0-1238.7; P=0.001) were independently associated with an ischemic etiology of AHF. CONCLUSIONS: Plasma BNP may represent a clinically useful non-invasive tool for identification of ischemic etiology of AHF in patients with stage 4-5 CKD. PMID- 24486651 TI - Utility of measuring serum or red blood cell folate in the era of folate fortification of flour. AB - Folic acid is an essential nutrient involved in one-carbon metabolism. Insufficient folate can result in megaloblastic anemia and an increased risk of neural tube defects. In response to the latter, some governments have mandated the fortification of flour with folate. This had resulted in a documented rise in the serum and red blood cell folate levels in the population. This has impacted the potential utility of folate measurements to detect folate deficiency in the clinical context. Folate measurements, whether done in serum or red blood cells, are subject to analytical variation, especially the latter, which also affects the utility of such measurements. Examining the literature reveals that in clinical situations, generally <1% of the subjects will have folate deficiency regardless of potentially pre-disposing factors (e.g. anemia, anti-folate agents, inflammatory bowel disease). Data from our center for both pediatric and adult populations is presented that supports this observation. Consequently, there exists very few indications for folate determinations (unexplained macrocytosis, inborn errors of metabolism) and it may be more efficient to simply treat suspected cases. PMID- 24486652 TI - Differential interferences of hemoglobin and hemolysis on insulin assay with the Abbott Architect-Ci8200 immunoassay. AB - OBJECTIVES: This paper evaluates the effect of hemoglobin (Hb) and hemolysis on insulin measurements with the Architect-Ci8200 analyzer. DESIGN AND METHODS: Insulin concentrations were measured using the Architect-Ci8200. Interference studies were performed by spiking serum pools of defined insulin concentrations with increasing concentrations of either free Hb or hemolysate. A change of more than 10% was taken as evidence of significant interference. RESULTS: A significant negative bias in insulin results was observed only in samples spiked with hemolysate but not with free Hb. The bias was proportional to the degree of hemolysis and to the time elapsed before insulin assay. This interference was decreased when samples were kept at +4 degrees C. CONCLUSIONS: For all insulin requests, hemolysis must be systematically checked before biological interpretation of insulin results. PMID- 24486653 TI - Higher-order structure and epidemic dynamics in clustered networks. AB - Clustering is typically measured by the ratio of triangles to all triples regardless of whether open or closed. Generating clustered networks, and how clustering affects dynamics on networks, is reasonably well understood for certain classes of networks (Volz et al., 2011; Karrer and Newman, 2010), e.g. networks composed of lines and non-overlapping triangles. In this paper we show that it is possible to generate networks which, despite having the same degree distribution and equal clustering, exhibit different higher-order structure, specifically, overlapping triangles and other order-four (a closed network motif composed of four nodes) structures. To distinguish and quantify these additional structural features, we develop a new network metric capable of measuring order four structure which, when used alongside traditional network metrics, allows us to more accurately describe a network's topology. Three network generation algorithms are considered: a modified configuration model and two rewiring algorithms. By generating homogeneous networks with equal clustering we study and quantify their structural differences, and using SIS (Susceptible-Infected Susceptible) and SIR (Susceptible-Infected-Recovered) dynamics we investigate computationally how differences in higher-order structure impact on epidemic threshold, final epidemic or prevalence levels and time evolution of epidemics. Our results suggest that characterising and measuring higher-order network structure is needed to advance our understanding of the impact of network topology on dynamics unfolding on the networks. PMID- 24486654 TI - Spreading speeds for stage structured plant populations in fragmented landscapes. AB - Landscape fragmentation has huge ecological and economic implications and affects the spatial dynamics of many plant species. Determining the speed of population spread in fragmented/heterogeneous landscapes is therefore of utmost importance to ecologists. Stage-structured integrodifference equations (IDEs) are deterministic models which accurately reflect the life cycles and dispersal patterns for numerous species. Existing approximations to wave-speeds consider only particular kernels, or landscapes in which the scale of variation is much smaller than the dispersal scale. We propose an analytical approximation to the wave-speeds of IDE solutions with periodic landscapes of alternating good and bad patches, where the dispersal scale is greater than the extent of each good patch and where the ratio of the demographic rates in the good and bad patches is given by a small parameter, denoted as epsilon. We formulate this approximation for the Gaussian and Laplace dispersal kernels and for stage structured and non-stage structured populations, and compare the results against numerical simulations. We find that the approximation is accurate for the landscapes considered, and that the type of dispersal kernel affects the relationship between landscape structure, as classified by landscape period and good patch size, and the spreading speed. This indicates that accurately fitting a kernel to data is important in determining the relationship between landscape structure and spreading speed. PMID- 24486655 TI - Development of temperamental effortful control mediates the relationship between maturation of the prefrontal cortex and psychopathology during adolescence: a 4 year longitudinal study. AB - This study investigated the relationship between the development of effortful control (EC), a temperamental measure of self-regulation, and concurrent development of three regions of the prefrontal cortex (anterior cingulate cortex, ACC; dorsolateral prefrontal cortex, dlPFC; ventrolateral prefrontal cortex, vlPFC) between early- and mid-adolescence. It also examined whether development of EC mediated the relationship between cortical maturation and emotional and behavioral symptoms. Ninety-two adolescents underwent baseline assessments when they were approximately 12 years old and follow-up assessments approximately 4 years later. At each assessment, participants had MRI scans and completed the Early Adolescent Temperament Questionnaire-Revised, as well as measures of depressive and anxious symptoms, and aggressive and risk taking behavior. Cortical thicknesses of the ACC, dlPFC and vlPFC, estimated using the FreeSurfer software, were found to decrease over time. EC also decreased over time in females. Greater thinning of the left ACC was associated with less reduction in EC. Furthermore, change in effortful control mediated the relationship between greater thinning of the left ACC and improvements in socioemotional functioning, including reductions in psychopathological symptoms. These findings highlight the dynamic association between EC and the maturation of the anterior cingulate cortex, and the importance of this relationship for socioemotional functioning during adolescence. PMID- 24486656 TI - MicroRNAs as potential biomarkers in diseases and toxicology. AB - MiRNAs (microRNAs) are single-stranded non-coding RNAs of approximately 21-23 nucleotides in length whose main function is to inhibit gene expression by interfering with mRNA processes. MicroRNAs suppress gene expression by affecting mRNA (messenger RNAs) stability, targeting the mRNA for degradation, or both. In this review, we have examined how microRNA expression could be altered following exposure to chemicals and how they could represent appropriate tissue and more interestingly circulating biomarkers. Among the key questions before using the microRNA for evaluation of risk toxicity, it remains still to clarify how they could be causally involved in the adverse effects and how stable their changes are. PMID- 24486657 TI - Functional coronary revascularization: an idea whose time has arrived. PMID- 24486658 TI - Takotsubo syndrome after permanent pacemaker implantation. PMID- 24486659 TI - Thin-strut drug-eluting stents are more favorable for severe calcified lesions after rotational atherectomy than thick-strut drug-eluting stents. AB - AIM: Percutaneous coronary intervention (PCI) for severe calcified lesions is still challenging, and there are few studies of drug-eluting stent (DES) implantation for severe calcified lesions, especially regarding long-term results and hemodialysis patients. The study purpose was to clarify the factors, including DES strut thickness, that affect the long-term outcome of severe calcified lesion treated with rotational atherectomy. METHODS: We analyzed 79 consecutive patients (138 stents) with DES implantation for severe calcified lesions that required rotational atherectomy before stent implantation. Rotational atherectomy was performed for the lesions that showed over 270 degrees severe calcification by intravascular ultrasound (IVUS) or where IVUS could not cross the lesion. We compared coronary risk factors, acute coronary syndrome and hemodialysis, the patients' history of coronary bypass graft and myocardial infarction, medication, and procedure characteristics, including the thickness of the DES used (thin- or thick-strut [>100 MUm] DES) between the patients with target vessel revascularization (TVR) versus those without TVR. RESULTS: During the follow-up, TVR was performed in 30 patients (38.5%). A multivariate analysis revealed that age and thin-strut DES were independently related to TVR (P=.01 for both). A Kaplan-Meier curve showed a lower TVR rate in the thin-strut DES patients compared to the thick-strut DES patients. CONCLUSIONS: For severe calcified lesions that needed rotational atherectomy, thin-strut DESs resulted in lower rates of TVR compared to thick-strut DESs. PMID- 24486660 TI - Timing of early angiography in non-ST elevation acute coronary syndrome. AB - OBJECTIVES: We aimed to determine the best time period for an early invasive intervention in non-ST elevation acute coronary syndrome (NSTEACS) patients. BACKGROUND: Studies assessing the timing of percutaneous coronary intervention (PCI) in patients with NSTEACS have failed to generate a consensus on when PCI should be performed in such patients. METHODS: Literature searches were conducted for randomized, controlled trials (RCTs) on NSTEACS from 1970 through September 2012. Patients were analyzed who were at moderate to high risk for NSTEACS and who underwent angiography within 96 hours. The major outcomes were the rate of death, recurrent myocardial infarction (re-MI), stroke, and major bleeding. RESULTS: Eight RCTs, which included 5761 patients, were eligible. There were no significant differences in the odds of death or stroke between time points. Conversely, patients undergoing angiography before 2 hours were associated with a higher rate of re-MI, compared with those undergoing angiography more than 2 hours later (odds ratio [OR], 2.15; 95% confidence interval [CI], 1.53-3.02; P<.001; I2 = 0%). Major bleeding events decreased only with angiography performed within 12 hours, compared to more than 12 hours (OR, 0.65; 95% CI, 0.44-0.96; P=.03; I2 = 0%). Angiography before 2 hours was not associated with a lower rate of major bleeding compared with angiography after 2 hours (OR, 0.61; 95% CI, 0.28 1.30; P=.20; I2 = 0%). CONCLUSIONS: Angiography within 12 hours reduces the risk of major bleeding. There is no need to push for angiography within 2 hours. PMID- 24486661 TI - The immediate and follow-up results of transcatheter occlusion of the ruptured sinus of Valsalva aneurysm with duct occluder. AB - BACKGROUND: Percutaneous transcatheter closure is an alternative strategy to traditional conventional surgical repair for ruptured sinus of Valsalva aneurysm (RSVA). The immediate and follow-up results of transcatheter occlusion in 13 patients were reported. METHODS: From February 2004 to June 2009, a total of 13 patients (9 males, 4 females), ages 18-38 years, were involved in the report. The diagnosis of RSVA was made based on a combination of several imaging modalities. None of the patients had other associated congenital heart disease, and all underwent local anesthesia. Transthoracic echocardiography was used during the procedure. All patients received aspirin (100 mg/day) and clopidogrel (75 mg/day) for a 6-month period after the procedure. Enalapril (5-20 mg/day) was administered to the patients with heart failure and/or cardiac dilatation. Chest radiography, electrocardiogram, and transthoracic echocardiography were undertaken at intervals of 1, 6, 12, 24, 36, 48, and 60 months during the follow up. RESULTS: The size of the duct occluder selected was up to 1-3 mm larger than the maximal diameter of the RSVA opening site. The devices were successfully deployed without any complications. On follow-up, no severe arrhythmia occurred; there was no device embolization, residual shunt, RVOT obstruction, new aortic regurgitation, or rupture site. Compared with the preoperative results, the cardiothoracic ratio and left ventricular were significantly decreased in the patients with cardiac dilatation (0.54 +/- 0.05 vs 0.50 +/- 0.04, P<.05 and 54.11 +/- 2.32 vs 50.11 +/- 2.47 mm, P<.01, respectively). CONCLUSIONS: Transcatheter closure is a safe and effective alternative in the treatment of RSVA. The mid term follow-up outcomes are good. PMID- 24486662 TI - Quantitative assessment of myocardial perfusion using time-density curve analysis after elective percutaneous coronary intervention. AB - The aim of this study was to assess myocardial blush (MB) using a novel software algorithm that quantifies time-density curves (TDC) after percutaneous coronary intervention (PCI). METHODS: Thirty-two patients referred for elective PCI were enrolled. TDC curves were generated and mean maximal myocardial contrast density (Dmax) was calculated from 5 regions of interest in the PCI territory. Dmax was normalized to contrast injected in the proximal coronary artery (DI). RESULTS: Mean DI significantly increased after PCI in all subjects. Dmax correlated directly with subjective grading of Thrombolysis in Myocardial Infarction (TIMI) myocardial blush (R=0.47; P<.01). In 7 subjects referred for PCI of a chronic total occlusion (CTO), mean DI remained increased after PCI. Mean DI was lower in CTO versus non-CTO subjects; however, fold-improvement was higher after PCI of CTO lesions. CONCLUSION: Quantifying MB using TDC analysis is feasible and correlates with subjective MB grading. The clinical utility of MB quantitation after PCI requires further study. PMID- 24486663 TI - Comparison of in vivo longitudinal strength and conformability following stent implantation in rabbit iliac artery. AB - OBJECTIVES: The aim of this study was to determine the in vivo longitudinal strength and conformability of various stent platforms following stent implantation in rabbit iliac arteries. BACKGROUND: Recently, longitudinal coronary stent deformation has been highlighted and bench tests have demonstrated differences in longitudinal strength among various stent platforms. However, this has not been investigated in an in vivo setting. This is of interest because there may be a trade-off between longitudinal strength and conformability. METHODS: We evaluated 4 types of commercially available stents: Multi-Link 8 (Abbott Vascular); Omega (Boston Scientific); Integrity (Medtronic); and Nobori (Terumo Corporation). To investigate the longitudinal strength, constant axial force was applied to the stent edge by a guiding catheter after deployment in a rabbit iliac artery. The amount of longitudinal stent deformation was calculated by measuring stent length. In order to evaluate conformability, stents were deployed crossing over the iliac bifurcation and the bifurcation angles were measured before and after stent implantation. If the change in the angle was small, the stent was considered to be more conformable. RESULTS: The Omega stent demonstrated significantly greater longitudinal compression compared with other stents (Omega, 17.4 +/- 9.3%; Multi-Link 8, 2.8 +/- 2.3%; Integrity, 2.8 +/- 1.4%; Nobori, 3.8 +/- 3.2%; P=.01), but Omega showed better conformability, as evidenced by the smallest percent change in the bifurcation angle (Omega, 12.7 +/ 0.8%; Multi-Link 8, 25.7 +/- 2.4%; Integrity, 28.3 +/- 1.1%; Nobori, 28.1 +/- 6.8%; P=.03). CONCLUSION: In this rabbit model, the Omega stent, which has the platform of the Element stent, showed less longitudinal strength but greater conformability compared with the other stent platforms. PMID- 24486664 TI - Coronary sinus anatomy: Ajmer Working Group Classification. AB - BACKGROUND: Coronary sinus (CS) anatomy is a major predictor of successful implantation of left ventricular (LV) lead and procedural outcome. We therefore made an attempt to look at the CS anatomy and possible feasibility to classify them into categories depending upon their size, branching pattern, location of posterolateral vein (PLV), and other parameters in order to guide the cardiologist for successful cannulation of the CS and LV lead implantation. METHODS: We analyzed the levophase angiograms of patients (n = 100) undergoing routine coronary angiography in the right anterior oblique view. We have made an attempt to classify these observations on the basis of predetermined parameters and a working classification was brought out for the ease of the operator and to predict the bottlenecks of the procedure. OBSERVATIONS: On the basis of predetermined parameters, venograms obtained from 100 patients were analyzed and findings were divided into three groups depending upon the ease of cannulation of posterolateral vein for LV lead placement. These 3 groups were further classified as type I, type II, and type III coronary sinuses. CONCLUSIONS: This observational study proposes a new anatomical working classification for CS for purposes of successful LV lead placement and optimal operative success. PMID- 24486665 TI - Removal of intracardiac fractured port-A catheter utilizing an existing forearm peripheral intravenous access site in the cath lab. AB - The intravenous port-A catheters are widely used for long-term central venous access in cancer patients. Spontaneous fracture and migration of implanted port catheters is a known complication and necessitates immediate removal. Percutaneous retrieval of intravascular foreign body has become a common practice and is commonly performed through central venous access, mostly using femoral, subclavian, or internal jugular veins. Although the percutaneous approach is relatively safe, it can lead to potential iatrogenic complications. We report the first case report of percutaneous removal of intravascular foreign body using forearm peripheral intravenous access. PMID- 24486666 TI - Detection by intracoronary near-infrared spectroscopy of lipid core plaque at culprit sites in survivors of cardiac arrest. AB - With an estimated 300,000 cases occurring per year in the United States alone, sudden cardiac death remains a major public health problem and in many cases is the first manifestation of coronary artery disease. Autopsy studies have established that the causative event in many cases of sudden death is rupture of an intracoronary lipid core plaque with subsequent thrombus formation. Until recently, identification of lipid core plaque in vivo has not been possible; however, a combined near-infrared spectroscopy (NIRS) and intravascular ultrasound (IVUS) catheter has become available that can detect lipid core plaque in patients undergoing coronary angiography. In this report, we present findings in 5 patients who experienced a documented sudden cardiac arrest, were successfully resuscitated, and then were studied with intracoronary NIRS-IVUS to assess the extent and location of lipid core plaque. Although the detection of lipid core plaque at the culprit site in victims of sudden death is not novel, the novelty of the present report is that NIRS permitted identification of the large lipid core plaque underlying sudden cardiac arrest in vivo, a finding in striking accord with prior autopsy observations implicating ruptured lipid core plaque in the pathogenesis of sudden cardiac death. PMID- 24486667 TI - Operator and institutional experience reduces room-to-balloon times for transradial primary percutaneous coronary intervention. AB - BACKGROUND: Transradial (TR) access for primary percutaneous coronary intervention (PCI) is becoming accepted as the preferred approach but has not gained widespread adoption due to technical challenges that may limit procedural success and delay time to revascularization, particularly among patients treated by inexperienced operators. We report our experience over the first 2 years of our TR primary PCI program and determined the impact of TR access on clinical and procedural outcomes. METHODS: Clinical characteristics and procedural outcomes were collected prospectively from 488 patients presenting with ST-segment elevation myocardial infarction and compared according to whether patients underwent primary PCI via the TR or transfemoral (TF) approach. RESULTS: Hospital mortality was very low in both groups (1.1% [TR] vs 2.6% [TF]; P=.23). Access site intended procedural success for primary PCI was equivalent (98.4% for TR vs 98.6% for TF; P=.85). Catheterization room-to-balloon (RTB) times were significantly lower among patients undergoing TR primary PCI as compared with those in the TF group (20:33 +/- 06:41 [TR] vs 25:11 +/- 08:22 [TF]; P<.001). TR patients treated by operators who had performed >50 TR PCIs had lower RTB times (20:03 +/- 06:12 vs 24:26 +/- 10:01; P<.06) and lower doses of radiation exposure (1812 +/- 1007 mGy vs 2827 +/- 954 mGy; P<.01) than patients treated by less experienced operators. Dual-purpose guide catheter usage was also associated with lower RTB times (18:38 +/- 5:42 vs 25:15 +/- 8:20; P<.001) and radiation exposure (1824 +/- 6205 mGy vs 2407 +/- 1389 mGy; P<.01). CONCLUSIONS: TR primary PCI may be performed rapidly and successfully despite only modest operator and institutional experience. PMID- 24486668 TI - Simultaneous transradial coronary angioplasty and contralateral coronary angiography with a single guide catheter for total coronary occlusions. AB - OBJECTIVE: In order to prevent double arterial access for contralateral angiography for percutaneous coronary intervention (PCI) of occluded coronary arteries, a new technique is under development, requiring only one puncture site and one guide catheter (1P1G). BACKGROUND: Percutaneous intervention for coronary artery occlusions frequently requires visualization of the segment distal to the occlusion via contralateral coronary angiography. This technique requires the use of two catheters and two entry sites. The use of two entry sites increases the risk for entry-site complications and is uncomfortable to the patient. METHODS: Careful rotation of a transradial multipurpose guide allows contralateral angiography while a guidewire is maintained in the occluded coronary artery. RESULTS: This report describes 3 patients with successful contralateral angiography with the same guide as used for PCI. CONCLUSION: Visualizing the contralateral artery with the same guide that is simultaneously used for angioplasty of the occluded coronary artery is feasible. PMID- 24486669 TI - First-in-man implantation of bioresorbable vascular scaffold in left internal mammary artery graft. AB - Bioresorbable vascular scaffold has many advantages over the metallic stent in the treatment of coronary stenotic lesions. It has added advantages in lesions that are close to the ostium of the culprit vessel, as in the left main coronary artery, right coronary artery, or left internal mammary artery, as in our case. As the hanging segments of the stent dissolve in 2 years, it reduces difficulty in engaging the vessel for future interventions if needed. To the best of our knowledge, this is the first case report of the Absorb bioresorbable vascular scaffold implanted in the left internal mammary artery from the left radial approach. PMID- 24486670 TI - Reevaluation of the indications for permanent pacemaker implantation after transcatheter aortic valve implantation. AB - AIMS: Conduction abnormalities (CA) requiring permanent pacemaker (PPM) are a well-known complication after transcatheter aortic valve implantation (TAVI). This study aimed to determine the incidence of TAVI-related PPM and reevaluate the indications for PPM after the periprocedural period. METHODS AND RESULTS: A total of 258 consecutive patients underwent TAVI with the Medtronic CoreValve (MCV), whereas 24 patients were excluded from the study. TAVI-related PPM was defined as PPM implantation <=30 days after the procedure and due to atrioventricular block (AVB). Third-degree AVB, second-degree type-II, or advanced second-degree AVB were considered as absolute indications for PPM. The incidence of TAVI-related PPM implantation was 27.4%. Forty-six patients (19.7%) had an absolute indication for PPM, but CA had resolved in 50% beyond the periprocedural period. Electrocardiographic analysis of the patients who did not have a TAVI-related PPM implantation showed that the PR and QRS intervals increased following TAVI, reaching a peak on days 4-6 and 7-9, respectively, before decreasing to near baseline levels. CONCLUSION: Although the incidence of periprocedural PPM implantation following TAVI was high, most CAs following TAVI tend to resolve after the periprocedural period. This suggests that delaying the decision for PPM implantation after TAVI may reduce the PPM rate. PMID- 24486671 TI - A useful trick for difficult transseptal access during cryoballoon ablation for atrial fibrillation. AB - A 76-year-old man with history of coronary artery bypass graft surgery was referred to our department for cryoballoon ablation of symptomatic drug-resistant paroxysmal atrial fibrillation. Thick septum can complicate such procedures; we describe a useful maneuver to circumvent this problem. PMID- 24486672 TI - Multiple coronary thrombi with cisplatin. AB - Testicular cancer is the most common malignancy in young men (15-29 years old). Combination therapy with bleomycin, etoposide, and cisplatin has been the standard first-line treatment for testicular metastatic disease. We present a case of multicoronary thrombi causing acute inferior myocardial infarction in a patient who recently received chemotherapy for testicular tumor. PMID- 24486673 TI - Sinus arrest following angioplasty and stenting for superior vena cava syndrome. AB - Superior vena cava (SVC) syndrome is a complication resulting from long-term residence of leads or in-dwelling catheters at the SVC to right atrial (RA) junction. SVC syndrome management is complicated by variable responses to anticoagulation therapies and technically challenging interventional procedures, such as balloon dilatation or stent placement at the SVC-RA junction to relieve blood-flow obstruction. Potential complications resulting from angioplasty/stenting for SVC syndrome are serious and include stent migration, major bleeding, and embolism. Bradyarrhythmias have not been reported. We describe a case of balloon angioplasty and stenting for SVC syndrome in a dialysis patient that resulted in sinus arrest. The complication developed within hours of angioplasty/stenting of her chronic, non-thrombotic SVC obstruction. We highlight the management approach to this patient and discuss potential mechanisms underlying the complication. PMID- 24486674 TI - Hematoma of the breast: a rare complication of transradial angiography and its treatment with handmade stent graft. AB - Mediastinal hematoma is a very rare complication of coronary angiography. The catheters or guidewires passing through the lumen may lead to bleeding and hematoma formation at adjacent sites along the tract of the vessels. We present a 72-year-old female patient with a right internal mammary artery perforation following transradial coronary angiography, which was managed with implantation of a handmade stent graft. PMID- 24486675 TI - Acceptability, efficacy and safety of two treatment protocols for dental fluorosis: a randomized clinical trial. AB - OBJECTIVES: This parallel randomized clinical trial evaluated the efficacy of two treatments for removing fluorosis stains. METHODS: Seventy individuals living in an area endemic for fluorosis, with at least four maxillary anterior teeth presenting fluorosis with a Thylstrup and Fejerskov index from 1 to 7, were randomized into two treatment groups (n=35): GI - enamel microabrasion or GII - microabrasion associated with at-home bleaching. Microabrasion was performed using 37% phosphoric acid and pumice and, at-home tooth bleaching was performed with 10% carbamide peroxide. Areas of enamel opacities were recorded by digital camera at baseline and 1-month (1M) after treatment. Two blinded examiners evaluated the reduction in the area (mm(2)) of opacity using software. Two visual analogue scales were used: one for recording tooth sensitivity and/or gingival irritation ranging from 1 (none) to 5 (severe) and the other to evaluate participant satisfaction with the treatment used ranging from 1 (no improvement) to 7 (exceptional improvement). RESULTS: 1M after treatment, both groups showed a significant reduction in the area of enamel opacity (p=0.0001) and there was no difference between groups (p=0.1). Most of the participants from both treatment groups reported no or mild tooth sensitivity and gingival irritation (p>0.05). Participants reported that they were happy with the improvement in dental appearance, however, individuals from GII reported that they were happier than those from GI (p=0.004). CONCLUSIONS: Both treatment protocols were effective in reducing fluoride stains, however, when home bleaching was associated to enamel microabrasion, patients reported a major satisfaction with dental appearance. PMID- 24486676 TI - Hospital-based surveillance of rotavirus gastroenteritis among children under 5 years of age in the Republic of Ivory Coast: a cross-sectional study. AB - OBJECTIVES: To estimate the proportion of rotavirus gastroenteritis (RVGE) among children aged less than 5 years who had been diagnosed with acute gastroenteritis (AGE) and admitted to hospitals and emergency rooms (ERs). The seasonal distribution of RVGE and most prevalent rotavirus (RV) strains was also assessed. DESIGN: A cross-sectional hospital-based surveillance study. SETTING: 5 reference paediatric hospitals across Abidjan. PARTICIPANTS: Children aged less than 5 years, who were hospitalised/visiting ERs for WHO-defined AGE, were enrolled. Written informed consent was obtained from parents/guardians before enrolment. Children who acquired nosocomial infection were excluded from the study. PRIMARY AND SECONDARY OUTCOME MEASURES: The proportion of RVGE among AGE hospitalisations and ER visits was expressed with 95% exact CI. Stool samples were collected from all enrolled children and were tested for the presence of RV using an enzyme immunoassay. RV-positive samples were serotyped using reverse transcriptase-PCR. RESULTS: Of 357 enrolled children (mean age 13.6+/-11.14 months), 332 were included in the final analyses; 56.3% (187/332) were hospitalised and 43.7% (145/332) were admitted to ERs. The proportion of RVGE hospitalisations and ER visits among all AGE cases was 30.1% (95% CI 23.6% to 37.3%) and 26.9% (95% CI 19.9% to 34.9%), respectively. Ninety-five children (28.6%) were RV positive; the highest number of RVGE cases was observed in children aged 6-11 months. The number of GE cases peaked in July and August 2008; the highest percentage of RV positive cases was observed in January 2008. G1P[8] wild-type and G8P[6] were the most commonly detected strains. CONCLUSIONS: RVGE causes substantial morbidity among children under 5 years of age and remains a health concern in the Republic of Ivory Coast, where implementation of prevention strategies such as vaccination might help to reduce disease burden. PMID- 24486678 TI - Journey to vaccination: a protocol for a multinational qualitative study. AB - INTRODUCTION: In the past two decades, childhood vaccination coverage has increased dramatically, averting an estimated 2-3 million deaths per year. Adult vaccination coverage, however, remains inconsistently recorded and substandard. Although structural barriers are known to limit coverage, social and psychological factors can also affect vaccine uptake. Previous qualitative studies have explored beliefs, attitudes and preferences associated with seasonal influenza (flu) vaccination uptake, yet little research has investigated how participants' context and experiences influence their vaccination decision-making process over time. This paper aims to provide a detailed account of a mixed methods approach designed to understand the wider constellation of social and psychological factors likely to influence adult vaccination decisions, as well as the context in which these decisions take place, in the USA, the UK, France, India, China and Brazil. METHODS AND ANALYSIS: We employ a combination of qualitative interviewing approaches to reach a comprehensive understanding of the factors influencing vaccination decisions, specifically seasonal flu and tetanus. To elicit these factors, we developed the journey to vaccination, a new qualitative approach anchored on the heuristics and biases tradition and the customer journey mapping approach. A purposive sampling strategy is used to select participants who represent a range of key sociodemographic characteristics. Thematic analysis will be used to analyse the data. Typical journeys to vaccination will be proposed. ETHICS AND DISSEMINATION: Vaccination uptake is significantly influenced by social and psychological factors, some of which are under-reported and poorly understood. This research will provide a deeper understanding of the barriers and drivers to adult vaccination. Our findings will be published in relevant peer-reviewed journals and presented at academic conferences. They will also be presented as practical recommendations at policy and industry meetings and healthcare professionals' forums. This research was approved by relevant local ethics committees. PMID- 24486677 TI - Access to rheumatologists among patients with newly diagnosed rheumatoid arthritis in a Canadian universal public healthcare system. AB - OBJECTIVES: Our objective was to estimate the percentage of patients with incident rheumatoid arthritis (RA) who were seen by a rheumatologist within 3, 6 and 12 months of suspected diagnosis by a family physician, and assess what factors may influence the time frame with which patients are seen. SETTING: Ontario, Canada. PARTICIPANTS: Over 2000-2009, we studied patients with incident RA who were initially diagnosed by a family physician. PRIMARY AND SECONDARY OUTCOME MEASURES: We assessed secular trends in rheumatology encounters and differences between patients who received versus did not receive rheumatology care. We performed hierarchical logistic regression analyses to determine whether receipt of rheumatology care was associated with patient, primary care physician and geographical factors. RESULTS: Among 19 760 patients with incident RA, 59%, 75% and 84% of patients were seen by a rheumatologist within 3, 6 and 12 months, respectively. The prevalence of initial consultations within 3 months did not increase over time; however, access within 6 and 12 months increased over time. Factors positively associated with timely consultations included higher regional rheumatology supply (adjusted OR (aOR) 1.35 (95% CI 1.13 to 1.60)) and higher patient socioeconomic status (aOR 1.18 (95% CI 1.07 to 1.30)). Conversely, factors inversely associated with timely consultations included remote patient residence (aOR 0.51 (95% CI 0.41 to 0.64)) and male family physicians (aOR 0.88 (95% CI 0.81 to 0.95)). CONCLUSIONS: Increasing access to rheumatologists within 6 and 12 months occurred over time; however, consultations within 3 months did not change over time. Measures of poor access (such as proximity to and density of rheumatologists) were negatively associated with timely consultations. Additional factors that contributed to disparities in access included patient socioeconomic status and physician sex. PMID- 24486679 TI - Infrequent and incomplete registration of test accuracy studies: analysis of recent study reports. AB - OBJECTIVES: To identify the proportion of articles reporting on test accuracy for which the corresponding study had been registered. DESIGN: Analysis of a consecutive sample of published study reports. PARTICIPANTS: PubMed was searched for publications in journals with an impact factor of 5 or higher in May and June 2012. Articles were included if they reported on original studies evaluating the accuracy of one or more diagnostic or prognostic tests or markers against a clinical reference standard in humans. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was registration of the reported test accuracy study. We additionally explored study characteristics associated with registration. RESULTS: We found 1941 references; 351 study reports fulfilled the inclusion criteria, of which 52 studies (15%) had been registered. Of these, 27 (52%) provided a registration number in the publication, and 12 (23%) provided a reference to the publication in the registry. Registration rates were similar for studies on diagnostic versus those on prognostic tests, and among studies on imaging tests versus those on laboratory techniques. Studies reporting some form of industry involvement were more often registered (33%) than studies reporting another source of funding (11%), and studies without a (reported) source of (external) funding (9%; p<0.001). Of the registered studies, 8 (15%) had been registered after completion, 14 were registered before initiation (27%) and 30 (58%) between initiation and completion. Only 16 (31%; 5% of the total sample) had registered the published primary outcome measures before completion. CONCLUSIONS: Few test accuracy studies published in higher impact journals are registered. Only 1 in 22 of such studies register their primary outcomes before study completion. Owing to the reasons for registering studies that investigate the cause-and-effect relationship between health-related interventions and health outcomes also apply to test accuracy studies, prospective study registration of these studies should be further promoted among investigators and journal editors. PMID- 24486680 TI - Comparison of perioperative outcomes and cost between robotic-assisted and conventional laparoscopy for transperitoneal infrarenal para-aortic lymphadenectomy (TIPAL). AB - STUDY OBJECTIVE: To compare perioperative outcomes and cost of robotic-assisted and laparoscopic transperitoneal infrarenal para-aortic lymphadenectomy (TIPAL) for treatment of gynecologic malignant conditions. DESIGN: Prospective non randomized study (Canadian Task Force classification II-2). SETTING: Tertiary center for women's health. PATIENTS: Sixty-two patients with gynecologic cancer operated on by the same surgical team. INTERVENTIONS: Thirty-two patients underwent TIPAL via robotic-assisted laparoscopy, and 30 via conventional laparoscopy. Comparison analyses of perioperative outcomes and estimated costs were performed. MEASUREMENTS AND MAIN RESULTS: There were no differences between robotic-assisted and laparoscopy insofar as age, body mass index, presurgical morbidity, operating time (92.5 minutes for robotics vs 96.6 minutes for laparoscopy), number of aortic nodes (12 vs. 12), hospitalization stay (2 vs. 2 days), or rate of complications (12.5% vs. 13.3%). Blood loss tended to be lower in the robotic group (75.0 vs. 92.5 mL; p = .08). Surgical cost was higher in the robotic group ($3.42 vs. $2.55; p < .001), although hospitalization cost was similar. CONCLUSION: Robotic-assisted and laparoscopy provide similar perioperative outcomes. However, the robotic-assisted approach is associated with higher surgical cost. PMID- 24486681 TI - Diverse immune functions of hemocyanins. AB - Substantial evidence gathered recently has revealed the multiple functionalities of hemocyanin. Contrary to previous claims that this ancient protein is involved solely in oxygen transport within the hemolymph of invertebrates, hemocyanin and hemocyanin-derived peptides have been linked to key aspects of innate immunity, in particular, antiviral and phenoloxidase-like activities. Both phenoloxidase and hemocyanin belong to the family of type-3 copper proteins and share a high degree of sequence homology. While the importance of phenoloxidase in immunity and development is well characterised, the contribution of hemocyanin to biological defence systems within invertebrates is not recognised widely. This review focusses on the conversion of hemocyanin into a phenoloxidase-like enzyme and the array of hemocyanin-derived immune responses documented to date. PMID- 24486682 TI - A metabolomic approach to determine the geographical origins of Anemarrhena asphodeloides by using UPLC-QTOF MS. AB - An ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-QTOF MS) method was developed for metabolite profiling of Anemarrhena asphodeloides Bunge from two different geographical origins. In this study, the metabolite profile data obtained using UPLC-QTOF MS was subjected to multivariate statistical analyses, such as the principal component analysis and the hierarchical clustering analysis, to compare metabolite patterns among A. asphodeloides samples. Furthermore, a metabolite selection method known as significance analysis of microarrays (SAM) was applied to further select metabolites and to identify key constituents to efficiently distinguish between geographical origins. The UPLC-QTOF MS analysis successfully classified 21 samples into two distinct groups according to their geographical origins. The validation method used to assess the analytical stability and accuracy of these data is also described. These results suggest that this proposed method is reliable, accurate, and effective for geographic classification of A. asphodeloides, thus guiding its proper use for therapeutic purposes. PMID- 24486683 TI - Metabolites identification of harmane in vitro/in vivo in rats by ultra performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry. AB - Harmane, a beta-carboline alkaloid with a wide spectrum of pharmacological activities, is naturally present in the human diet, in numerous foodstuffs and in hallucinogenic plants such as Peganum harmala, Banisteriopsis caapi and Tribulus terrestris. However, the precise metabolic fate of harmane remains unknown. In order to know whether harmane is extensively metabolized, a rapid and sensitive method using ultra-performance liquid chromatography combined with electrospray ionization quadrupole time-of-flight tandem mass spectrometry (UPLC/ESI-QTOF-MS) was used to analyze the metabolic profile of harmane in vitro and in vivo in rats. A total of 21 metabolites were identified from the rat liver microsomes and rat liver S9 (9), rat urine (11), feces (16), bile (16), and plasma (10) after a single oral administration of harmane using MetaboLynxTM and MassFragment TM software tools. It indicated that the biliary and faecal clearance were the major excretion routes for harmane as well as its metabolites. The specific CLogP values combined with different acidic and alkaline mobile phase were helpful and useful for distinguishing N-oxidation and monohydroxylation metabolites. The metabolic transformation pathways of harmane included monohydroxylation, dihydroxylation, N-oxidation, O-glucuronide conjugation, O-sulphate conjugation, and glutathione conjugation. In conclusion, this study showed an insight into the metabolism of harmane. PMID- 24486684 TI - Characterization of the key aroma compounds in beef extract using aroma extract dilution analysis. AB - Aroma extract dilution analysis (AEDA) of an ether extract prepared from beef extract (BE) and subsequent identification experiments led to the determination of seven aroma-active compounds in the flavor dilution (FD) factor range of 32 128. Omission experiments to select the most aroma-active compounds from the seven aroma compounds suggested that 2,3,5-trimethyl pyrazine, 1-octen-3-ol, 3 methylbutanoic acid, and 4-hydroxy-2,5-dimethyl-3(2H)-furanone were the main active compounds contributing to the aroma of BE. Aroma recombination, addition, and omission experiments of the four aroma compounds in taste-reconstituted BE showed that each compound had an individual aroma profile. A comparison of the overall aroma between this recombination mixture and BE showed a high similarity, suggesting that the key aroma compounds had been identified successfully. PMID- 24486685 TI - Effect of enriched housing on welfare, production performance and meat quality in finishing lambs: the use of feeder ramps. AB - This study analyses the effect of environmental enrichment on the welfare, productive traits and meat quality of lambs housed in feedlots. Sixty lambs were placed in enriched (EE) or conventional (CO) pens (3 pens for each treatment, 10 lambs/pen) where EE had a wooden platform with ramps that provided access to a concentrate hopper, cereal straw as bedding and forage, and one play ramp. The CO pen was barren, similar to commercial feedlots. The physiological adaptation response of EE lambs was more efficient than CO, since the latter mobilised more body reserves (i.e., increased NEFA, P<0.05), and had lower levels of immunity (i.e., increased N/L, P<0.05), which indicate chronic stress, probably associated with the barren environment. The EE lambs had a higher (P<0.05) average daily gain, with heavier carcasses and higher fattening scores, as well as lower pHult, higher L and b values, and lower values of texture (P<0.05). PMID- 24486686 TI - Added value of blue dye injection in sentinel node biopsy of breast cancer patients: do all patients need blue dye? AB - BACKGROUND: In the current study, we evaluated the incremental value of blue dye injection in sentinel node mapping of early breast cancer patients. We specially considered the experience of the surgeons and lymphoscintigraphy results in this regard. METHODS: 605 patients with early stage breast cancer were retrospectively evaluated in the study. Patients underwent sentinel node mapping using combined radiotracer and blue dye techniques. Lymphoscintiraphy was also performed for 590 patients. Blue dye, radioisotope, and overall success rates in identifying the sentinel lymph node were evaluated in different patient groups. The benefit of blue dye and radioisotope in identifying the sentinel lymph nodes was also evaluated. RESULTS: Marginal benefits of both blue dye and isotope for overall sentinel node detection as well as pathologically involved sentinel nodes were statistically higher in inexperienced surgeons and in patients with sentinel node visualization failure. In the patients with sentinel node visualization on lymphoscintigraphy, 6 sentinel nodes were detected by blue dye only. All these six nodes were harvested by inexperienced surgeons. On the other hand 8 sentinel nodes were detected by dye only in the patients with sentinel node non visualization. All these nodes were harvested by experienced surgeons. CONCLUSIONS: The use of blue dye should be reserved for inexperienced surgeons during their learning phase and for those patients in whom lymphoscintigraphy failed to show any uptake in the axilla. PMID- 24486688 TI - Impairments in deductive reasoning and working memory in Parkinson's disease. AB - This study was designed to investigate the nature and extent of executive impairments in medicated subjects with Parkinson's disease (PD) and matched control subjects. They performed two tasks involving strategic processing, deductive reasoning and memory updating. PD patients differed significantly from controls in solving two- and four-dimensional deductive reasoning problems, and they also showed impairment in memory updating. The findings are discussed in relation to previous studies which have shown deficits in strategic processing in PD. PMID- 24486687 TI - Efficacy of combination of 0.2% GTN and lignocaine ointments in wound healing and pain relief after Milligan Morgan hemorrhoidectomy--a comparison with lignocaine and 0.2% GTN ointments separately. AB - OBJECTIVE: To compare the analgesic efficacy and rate of wound healing of combination of 0.2% Glyceryl Trinitrate and 2% lignocaine ointments with 0.2% Glyceryl Trinitrate and 2% lignocaine ointment separately after Milligan Morgan hemorrhoidectomy. DESIGN: Randomized control trial. PLACE AND DURATION OF STUDY: Combined Military Hospital, Kharian, Malir and Bannu. November 2007 to August 2011. PATIENTS AND METHODS: Patients undergoing Milligan Morgan hemorrhoidectomy were randomized into 3 groups by using computer generated table. Group A received combination of 0.2% Glyceryl Trinitrate and 2% lignocaine ointment, Group B 2% lignocaine and Group C received 0.2% Glyceryl Trinitrate ointment. These ointments were given on twice daily basis. Pain scores were measured on a 100 mm Visual Analog Scale. Pain scores and quantity of oral analgesics used were compared daily until the 7th post-operative day. The time required for complete healing (in weeks) was also compared. RESULTS: Out of 210 patients, 192 (67 Group A, 64 Group B and 61 Group C) completed the study. Demographic data were comparable in all three groups. There were statistically significant reductions in pain scores and quantity of analgesics used from the first to the fourth post operative days in Group A. The time required for complete healing was also significantly reduced in the combination group. There were no significant side effects in any group. CONCLUSION: The combination of 0.2% GTN and 2% lignocaine showed better pain relief resulting in less use of oral analgesics and faster healing of the wound after Milligan Morgan hemorrhoidectomy. PMID- 24486689 TI - Asymmetric central processing of sensory stimuli in idiopathic focal dystonia. AB - Idiopathic torsion dystonia is characterized by persistent abnormalities of posture. We tested the hypothesis that abnormal sensorimotor processing is involved pathophysioiogically by looking for asymmetry of sensory processing in patients with asymmetric symptoms. Sixteen patients with torticollis (ten with head turning to the right and six to the left), seven with simple writer's cramp and 19 healthy control subjects were tested. The tasks involved matching one of five lengths of stick or weights presented to one hand with sticks and weights chosen by the other hand. All experiments were performed with the subject blindfolded. Patients with torticollis tended to underestimate weights presented to the hand away from which the head tended to turn. Control subjects showed no significant tendency to overestimate or underestimate lengths or weights with either hand, and dystonic patients showed no tendency to overestimate or underestimate lengths. Those with writer's cramp underestimated weights when the stimulus was presented to the affected hand. An asymmetry can thus be detected in muscles remote from the site of dystonia, indicating a generalized abnormality of sensorimotor processing. PMID- 24486690 TI - Syndrome-specific deficits of performance and effects of practice on arm movements with deafferentation due to posterior thalamic lesion. AB - Aiming and tapping movements were analysed repeatedly over a three-week period in a patient who was hemideafferented due to an ischaemic posterior thalamic lesion. Contrasting behaviour observed in six healthy subjects, nine hemiparetic patients and one patient with hemianopic stroke, allowed the determination of behavioural deficits related to deafferentation. Finger tapping was not impaired specifically and did not improve with practice in the deafferented patient. When aiming movements were investigated, accuracy of the first, largely preprogrammed, phase of movement and timing of the late homing-in phase were impaired specifically in the deafferented patient. Practice led to a step-like change in preprogramming amplitude of the ballistic movement component, a gradual improvement of temporal efficiency of the early movement phase and a more marked improvement of the homing-in phase. Qualitatively comparable but quantitatively less marked effects of practice were documented for hemiparetic patients. These results demonstrated that deafferentation affects preprogrammed aspects of movement and those influenced by current control and that motor learning is possible with central deafferentation, even for aspects of performance that are impaired specifically. It is postulated that motor learning was mediated by changes in strategy (motor programming) and improved efficiency of intact motor control processes (visuomotor control). PMID- 24486691 TI - Manic pseudo-delirium - two case reports. AB - We wish to report two cases which illustrate a subtype of bipolar affective disorder and suggest that it should be termed Manic Pseudo-Delirium (MP-D) as it incorporates features of both mania and delirium. This will facilitate consistent recognition and characterization since mania remains the primary diagnosis and delirium is not thought to co-exist with functional psychoses. Extensive investigations were done to exclude underlying medical causes for the delirium. Possible explanations for MP-D are put forward for their heuristic value in the hope that further research will improve understanding of the pathophysiology of both mania and delirium. PMID- 24486692 TI - Reversible aphasia in adolescence: A late-onset form of Landau Kleffner syndrome? Report of a single case. AB - An adolescent boy developed a long-lasting pattern of global aphasia, concomitant to focal (left temporal) EEG abnormalities; this was followed by complete recovery. Laboratory and neuroimaging studies were within normal limits. The possibility of a late-onset Landau Kleffner syndrome is discussed. PMID- 24486693 TI - Word-retrieval in two cases of progressive supranuclear palsy. AB - In this paper, we describe the detailed neuropsychological investigation of two cases of progressive supranuclear palsy (PSP) and demonstrate word-finding difficulties associated with pervasive problems in word-retrieval. The pattern of deficits resembles that seen in Parkinson's Disease (PD) but is more severe, even in very mild PSP, and appears less amenable to cue facilitation. Performance on a variety of word-production tasks is compared, and experimental controls for motor effects on performance are included. The role of stimulus cues in speeded word finding is addressed experimentally, as are central executive influences on task performance. This combines with functional brain-scan data from single photon emission computed tomography (SPECT) which shows reduced frontal perfusion in one of the two cases. PMID- 24486694 TI - Hemiballismus and normal pressure hydrocephalus as long-term sequelae following a hemispherectomy for intractable epilepsy in a man with a learning disability. AB - We report here a case of a 48-year-old gentleman with mild/moderate learning disability who developed late complications of hemispherectomy 28 years following the operation. The original operation was performed to treat intractable epilepsy (both generalized tonic/clonic and complex partial seizures) in an 8-year-old boy. After a 28 year seizure-free period, the patient developed cognitive decline, seizures, hemiballismus and a subacute confusional state, possibly related to normal pressure hydrocephalus. A ventriculo-peritoneal shunt operation, along with treatment with high doses of sulpiride, brought improvement in both mental state and hemiballismus. PMID- 24486697 TI - Once upon a mine: the legacy of uranium on the Navajo Nation. PMID- 24486698 TI - Nonalcoholic steatohepatitis as a novel player in metabolic syndrome-induced erectile dysfunction: an experimental study in the rabbit. AB - A pathogenic link between erectile dysfunction (ED) and metabolic syndrome (MetS) is now well established. Nonalcoholic steatohepatitis (NASH), the hepatic hallmark of MetS, is regarded as an active player in the pathogenesis of MetS associated cardiovascular disease (CVD). This study was aimed at evaluating the relationship between MetS-induced NASH and penile dysfunction. We used a non genomic, high fat diet (HFD)-induced, rabbit model of MetS, and treated HFD rabbits with testosterone (T), with the selective farnesoid X receptor (FXR) agonist obeticholic acid (OCA), or with the anti-TNFalpha mAb infliximab. Rabbits fed a regular diet were used as controls. Liver histomorphological and gene expression analysis demonstrated NASH in HFD rabbits. Several genes related to inflammation (including TNFalpha), activation of stellate cells, fibrosis, and lipid metabolism parameters were negatively associated to maximal acetylcholine (Ach)-induced relaxation in penis. When all these putative liver determinants of penile Ach responsiveness were tested as covariates in a multivariate model, only the association between hepatic TNFalpha expression and Ach response was confirmed. Accordingly, circulating levels of TNFalpha were increased 15-fold in HFD rabbits. T and OCA dosing in HFD rabbits both reduced TNFalpha liver expression and plasma levels, with a parallel increase of penile eNOS expression and responsiveness to Ach. Also neutralization of TNFalpha with infliximab treatment fully normalized HFD-induced hypo-responsiveness to Ach, as well as responsiveness to vardenafil, a phosphodiesterase type 5 inhibitor. Thus, MetS induced NASH in HFD rabbits plays an active role in the pathogenesis of ED, likely through TNFalpha, as indicated by treatments reducing liver and circulating TNFalpha levels (T or OCA), or neutralizing TNFalpha action (infliximab), which significantly improve penile responsiveness to Ach in HFD rabbits. PMID- 24486699 TI - ALSPAC mercury study and fish consumers: Golding et al. respond. PMID- 24486700 TI - Pentyl-4-yn-VPA, a histone deacetylase inhibitor, ameliorates deficits in social behavior and cognition in a rodent model of autism spectrum disorders. AB - In utero exposure of rodents to valproic acid (VPA) has been proposed to induce an adult phenotype with behavioural characteristics reminiscent of those observed in autism spectrum disorder (ASD). Our previous studies have demonstrated the social cognition deficits observed in this model, a major core symptom of ASD, to be ameliorated following chronic administration of histone deacetylase (HDAC) inhibitors. Using this model, we now demonstrate pentyl-4-yn-VPA, an analogue of valproate and HDAC inhibitor, to significantly ameliorate deficits in social cognition as measured using the social approach avoidance paradigm as an indicator of social reciprocity and spatial learning to interrogate dorsal stream cognitive processing. The effects obtained with pentyl-4-yn-VPA were found to be similar to those obtained with SAHA, a pan-specific HDAC inhibitor. Histones isolated from the cerebellar cortex and immunoblotted with antibodies recognising lysine-specific modification revealed SAHA and pentyl-4-yn-VPA to enhance the acetylation status of H4K8. Additionally, the action of pentyl-4-yn-VPA, could be differentiated from that of SAHA by its ability to decrease H3K9 acetylation and enhance H3K14 acetylation. The histone modifications mediated by pentyl-4-yn-VPA are suggested to act cooperatively through differential acetylation of the promoter and transcription regions of active genes. PMID- 24486701 TI - The cannabinoid agonist HU-210: pseudo-irreversible discriminative stimulus effects in rhesus monkeys. AB - Synthetic cannabinoid abuse and case reports of adverse effects have raised concerns about the pharmacologic mechanisms underlying in vivo effects. Here, a synthetic cannabinoid identified in abused products (HU-210) was compared to the effects of Delta(9)-THC and two other synthetic cannabinoid agonists used extensively in pre-clinical studies (CP 55,940 and WIN 55,212-2). One group of monkeys discriminated ?(9)-THC (0.1mg/kg i.v.); a separate group received chronic ?(9)-THC (1mg/kg/12h s.c.) and discriminated rimonabant (1mg/kg i.v.). CP 55,940, HU-210, ?(9)-THC, and WIN 55,212-2 produced ?(9)-THC lever responding. HU-210 had a long duration (i.e., 1-2 days), whereas that of the other cannabinoids was 5h or less. Rimonabant (1mg/kg) produced surmountable antagonism; single dose apparent affinity estimates determined in the presence of ?(9)-THC, CP 55,940, and WIN 55,212-2 did not differ from each other. In contrast, rimonabant (1mg/kg) produced a smaller rightward shift in the HU-210 dose-effect function. In ?(9) THC treated monkeys, the relative potency of CP 55,940, ?(9)-THC, and WIN 55,212 2 to attenuate the discriminative stimulus effects of rimonabant was the same as that evidenced in the ?(9)-THC discrimination, whereas HU-210 was unexpectedly more potent in attenuating the effects of rimonabant. In conclusion, the same receptor subtype mediates the discriminative stimulus effects of ?(9)-THC, CP 55,940 and WIN 55,212-2. The limited effectiveness of rimonabant to either prevent or reverse the effects of HU-210 appears to be due to very slow dissociation or pseudo-irreversible binding of HU-210 at cannabinoid receptors. PMID- 24486702 TI - SIRT1 activation by methylene blue, a repurposed drug, leads to AMPK-mediated inhibition of steatosis and steatohepatitis. AB - Sirtuins maintain energy balance. Particularly, sirtuin 1 (SIRT1) activation mimics calorie restriction and nutrient utilization. However, no medications are available for the up-regulation of SIRT1. Methylene blue (MB) had been in clinical trials for the treatment of neurological diseases. This study investigated the effect of MB on sirtuin expression in association with the treatment of steatosis and steatohepatitis, and explored the underlying basis. The effects of MB on mitochondrial function, molecular markers, pharmacokinetics, and histopathology were assessed using hepatocyte and/or mouse models. Immunoblotting, PCR and reporter assays were done for molecular experiments. After oral administration, MB was well distributed in the liver. MB treatment increased NAD(+)/NADH ratio in hepatocytes. Of the major forms, MB treatment up regulated SIRT1, and thereby decreased PGC-1alpha acetylation. Consistently, hepatic mitochondrial DNA contents and oxygen consumption rates were enhanced. MB treatment also notably activated AMPK, CPT-1 and PPARalpha: the AMPK activation relied on SIRT1. Activation of LXRalpha and the induction of SREBP-1c and its target genes by T0901317 were diminished by MB. In addition, MB treatment antagonized the ability of palmitate to acetylate PGC-1alpha, and increase SERBP 1c, FAS, and ACC levels. In mice fed on a high-fat diet for 8 weeks, MB treatment inhibited excessive hepatic fat accumulation and steatohepatitis. The ability of MB to activate SIRT1 promotes mitochondrial biogenesis and oxygen consumption and activates AMPK, contributing to anti-lipogenesis in the liver. Our results provide new information on the potential use of MB for the treatment of steatosis and steatohepatitis. PMID- 24486703 TI - PPARdelta activation inhibits homocysteine-induced p22(phox) expression in EA.hy926 cells through reactive oxygen species/p38MAPK pathway. AB - Increased expression of the p22(phox) subunit of the NADPH oxidase complex may possibly contribute to both the enzyme's increased activation and the occurrence of oxidative stress during hyperhomocysteinaemia. However, the activation of peroxisome proliferator-activated receptor (PPAR) delta has been shown to inhibit p22(phox) expression. The purpose of this study was to elucidate the signaling pathway by which PPARdelta activation regulated homocysteine-induced expression of p22(phox). EA.hy926 cells were stimulated with homocysteine (Hcy) in the presence or absence of the PPARdelta-specific agonist, GW0742, or of various signaling inhibitors, including the antioxidants N-acetylcysteine (NAC), NADPH oxidase inhibitor, diphenyleneiodonium (DPI), and the p38MAPK inhibitor, SB203580. Expression of p22(phox) mRNA and phospho-p38MAPK protein were measured by real-time PCR and western blot analysis, respectively, and reactive oxygen species were measured by fluorescence microscopy. Our data indicate that Hcy increased both the expression of p22(phox) in a concentration-dependent manner and also increased phosphoryation of p38 MAPK and reactive oxygen species production in a time-dependent manner. However, activation of the PPARdelta signaling pathway by the agonist GW0742 reversed all these changes induced by Hcy. Furthermore, SB203580 prevented the increase in p22(phox) expression, and NAC and DPI not only inhibited Hcy-induced phosphorylation of p38MAPK, but also prevented expression of p22(phox). These findings indicate that Hcy-induced expression of p22(phox) is regulated by the reactive oxygen species/p38MAPK pathway and that PPARdelta activation is capable of attenuating this pathway by eliminating Hcy-induced reactive oxygen species production. PMID- 24486704 TI - Antinociceptive effect of certain dimethoxy flavones in mice. AB - The aim of the present study was to evaluate the antinociceptive action of certain dimethoxy flavones (DMF, (7,2'-dimethoxy flavone, 7,3'-dimethoxy flavone, 7,4'-dimethoxy flavone and 7,8,-dimethoxy flavone) and the possible mechanisms involved. The antinociceptive effect of dimethoxy flavones was investigated in mice employing acetic acid-induced abdominal writhings, formalin-induced nociception and hot water tail immersion assay procedures. To identify the possible mechanisms involved in the antinociceptive action of these compounds, acetic acid-induced abdominal constriction assay alone was employed. Mice were pretreated with naloxone, yohimbine, ondansetron, haloperidol, bicuculline or glibenclamide before dimethoxy flavone treatment to identify the role of opioid, adrenergic, 5HT3-serotonergic, dopaminergic, gamma-amino butyric acid (GABA) receptor or potassium channels, respectively. The investigated dimethoxy flavones produced a significant reduction in the number of abdominal constrictions in acetic acid assay. A dose dependent decrease in paw-licking response time was evident in both the early and late phases of formalin induced nociception. A significant increase in reaction time was also evident after treatment with various dimethoxy flavones in hot water tail immersion assay. Pretreatment with naloxone, ondansetron or glibenclamide significantly attenuated the antinociceptive effect of all the four dimethoxy flavones. Yohimbine pretreatment attenuated the antinociceptive response of 7,3'-dimethoxy flavone, 7,4'-dimethoxy flavone and 7,8-dimethoxy flavone. Pretreatment with haloperidol potentiated the antinociceptive response of all the tested dimethoxy flavones. The antinociceptive effect of 7,2'-dimethoxy flavone and 7,3'-dimethoxy flavone was annulled by bicuculline pretreatment. The results of the present study reveal the antinociceptive effect of dimethoxy flavones involving multiple pathways. PMID- 24486705 TI - Effects of the selective adenosine A2A receptor antagonist, SCH 412348, on the parkinsonian phenotype of MitoPark mice. AB - Adenosine A2A receptors are predominantly localized on striatopallidal gamma aminobutyric acid (GABA) neurons, where they are colocalized with dopamine D2 receptors and are involved in the regulation of movement. Adenosine A2A receptor antagonists have been evaluated as a novel treatment for Parkinson's disease and have demonstrated efficacy in a broad spectrum of pharmacological and toxicological rodent and primate models. Fewer studies have been performed to evaluate the efficacy of adenosine A2A receptor antagonists in genetic models of hypodopaminergic states. SCH 412348 is a potent and selective adenosine A2A receptor antagonist that shows efficacy in rodent and primate models of movement disorders. Here we evaluated the effects of SCH 412348 in the MitoPark mouse, a genetic model that displays a progressive loss of dopamine neurons. The dopamine cell loss is associated with a profound akinetic phenotype that is sensitive to levodopa (l-dopa). SCH 412348 (0.3-10mg/kg administered orally) dose dependently increased locomotor activity in the mice. Moreover, SCH 412348 retained its efficacy in the mice as motor impairment progressed (12-22 weeks of age), demonstrating that the compound was efficacious in mild to severe Parkinson's disease-like impairment in the mice. Additionally, SCH 412348 fully restored lost functionality in a measure of hind limb bradykinesia and partially restored functionality in a rotarod test. These findings provide further evidence of the anti-Parkinsonian effects of selective adenosine A2A receptor antagonists and predict that they will retain their efficacy in both mild and severe forms of motor impairment. PMID- 24486706 TI - Effect of sauchinone, a lignan from Saururus chinensis, on bacterial phagocytosis by macrophages. AB - AMP-activated protein kinase (AMPK) plays an important role in inflammation in various cells and increases the phagocytic ability of macrophages. In this study, we found that sauchinone increased the phosphorylation of AMPK and acetyl-CoA carboxylase (ACC), a downstream target of AMPK, in mouse peritoneal macrophages. Sauchinone increased macrophage phagocytosis of fluorescent Escherichia coli, which was blocked by compound C, an AMPK inhibitor. Sauchinone also increased the phosphorylation of p38 mitogen activated protein kinase (MAPK) in cultured macrophages in a concentration-dependent fashion, which was not blocked by compound C. However, the increase of sauchinone-induced phagocytosis was prevented by SB203580. An inhibitor of the upstream kinase TGF-beta-activated kinase (TAK1), (5z)-7-oxozeaenol, abolished the phosphorylation of ACC and p38 MAPK. Systemic administration of sauchinone to mice led to increased phosphorylation of AMPK and p38 MAPK in the lung, and enhanced phagocytosis of fluorescent E. coli in bronchoalveolar lavage fluid as compared with control mice. These results suggest sauchinone to be a useful adjunctive treatment for bacterial infection. PMID- 24486707 TI - EETs alleviate ox-LDL-induced inflammation by inhibiting LOX-1 receptor expression in rat pulmonary arterial endothelial cells. AB - Oxidized low-density lipoprotein (Ox-LDL) is associated with atherosclerotic events through the modulation of arachidonic acid (AA) metabolism and activation of inflammatory signaling. Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) mitigate inflammation through nuclear factor kappaB (NF-kappaB). In this study, we explored the effects and mechanisms of exogenous EETs on the ox-LDL-induced inflammation of pulmonary artery endothelial cells (PAECs), which were cultured from rat pulmonary arteries. We determined that pre-treatment with 11,12-EET or 14,15-EET attenuated the ox-LDL-induced expression and release of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1) in a concentration-dependent manner. In addition, the ox-LDL-induced expression of CYP2J4 was upregulated by 11,12-EET and 14,15-EET (1MUM). Furthermore, the endothelial receptor of lectin like oxidized low-density lipoprotein (LOX-1) was downregulated in PAECs treated with EETs. The inflammatory responses evoked by ox-LDL (100MUg/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-kappaB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IkappaBalpha, and activation of NF-kappaB (p65), whereas 14,15-EET can significantly suppress the phosphorylation of p38 and Erk1/2. Our results indicate that EETs exert beneficial effects on ox-LDL-induced inflammation primarily through the inhibition of LOX-1 receptor upregulation, MAPK phosphorylation, and NF-kappaB activation and through the upregulation of CYP2J4 expression. This study helps focus the current understanding of the contribution of EETs to the regulation of the inflammation of pulmonary vascular endothelial cells. Furthermore, the therapeutic potential of targeting the EET pathway in pulmonary vascular disease will be highlighted. PMID- 24486708 TI - Pentadecapeptide BPC 157 and anaphylactoid reaction in rats and mice after intravenous dextran and white egg administration. AB - Anesthetized mice or rats received intravenously 6%, 10%, 20%, 40%, 60%, 80%, and 90% dextran and/or white egg (1ml/rat or 0.15ml/mouse) into their tails. Medication (/kg b.w., 5ml/kg) was given intraperitoneally (BPC 157 10ug, 1ug, 10ng, and 10pg/kg, chloropyramine 20mg/kg, and cimetidine 10mg/kg intraperitoneally, alone or in combination while controls received an equivolume of saline), immediately after challenge or, alternatively, at 5min after or 24 or 48h before challenge. The effect was assessed at 5, 10, 20 and 30min after dextran and/or white egg challenge. We commonly noted prominent edema involving the face, upper and lower lip, snout, paws and scrotum (presented with extreme cyanosis), poor respiration and the number of fatalities after dextran and/or white egg application. Contrary, BPC 157 regimens (10ug, 1ug, 10ng, and 10pg/kg) effectively, may both prevent anaphylactoid reactions that may arise from dextran and/or white egg application and furthermore, rescue already advanced reactions when given after the challenge. Chloropyramine and cimetidine given alone were only moderately effective. When given together with BPC 157, the observed effect correlates with the strong effect of BPC 157 given alone. PMID- 24486709 TI - Pertussis toxin modulates microglia and T cell profile to protect experimental autoimmune encephalomyelitis. AB - Pertussis toxin (PTx) has various effects in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). This study was designed to explore the protective effects of PTx of different doses and subunits. EAE model was induced with myelin oligodendrocyte glycoprotein (MOG35 55, 200 ug) plus complete Freund's adjuvant in 6-7 week-old female C57BL/6 mice. PTx reduced clinical deficits of EAE by 91.3%. This reduction in clinical deficits was achieved by attenuating demyelination by 75.5%. Furthermore, PTx reduced the lymphocyte infiltration, deactivated microglia activation and changed T cell profile by increasing T helper (type 1 and 2) and T regulatory cells. PMID- 24486710 TI - Serotonergic pharmacology in animal models: from behavioral disorders to dyskinesia. AB - Serotonin (5-HT) dysfunction has been involved in both movement and behavioral disorders. Serotonin pharmacology improves dyskinetic movements as well as depressive, anxious, aggressive and anorexic symptoms. Animal models have been useful to investigate more precisely to what extent 5-HT is involved and whether drugs targeting the 5-HT system can counteract the symptoms exhibited. We review existing rodent and non-human primate (NHP) animal models in which selective 5-HT or dual 5-HT-norepinephrine (NE) transporter inhibitors, as well as specific 5-HT receptors agonists and antagonists, monoamine oxidase A inhibitors (IMAO-A) and MDMA (Ecstasy) have been used. We review overlaps between the various drug classes involved. We confront behavioral paradigms and treatment regimen. Some but not all animal models and associated pharmacological treatments have been extensively studied in the litterature. In particular, the impact of selective serotonin reuptake inhibitors (SSRI) has been extensively investigated using a variety of pharmacological or genetic rodent models of depression, anxiety, aggressiveness. But the validity of these rodent models is questioned. On the contrary, few studies did address the potential impact of targeting the 5-HT system on NHP models of behavioral disorders, despite the fact that those models may match more closely to human pathologies. Further investigations with carefull behavioral analysis will improve our understanding of neural bases underlying the pathophysiology of movement and behavioral disorders. PMID- 24486711 TI - Involvement of GABAB receptors in biochemical alterations induced by anxiety related responses to nicotine in mice: genetic and pharmacological approaches. AB - Previous studies from our laboratory showed that anxiety-related responses induced by nicotine (NIC), measured by the elevated plus maze, were abolished by 2-OH-saclofen (GABAB receptor antagonist) (1 mg/kg; ip) or the lack of GABAB receptors (GABAB1 knockout mice). Based on these behavioral data, the aims of the present study were: 1) to evaluate the possible neurochemical changes (dopamine, DA, serotonin, 5-HT, 3,4-dihydroxyphenylacetic acid, DOPAC, 5-hydroxyindoleacetic acid, 5-HIAA and noradrenaline, NA) and the c-Fos expression induced by the anxiolytic (0.05 mg/kg) or anxiogenic (0.8 mg/kg) doses of NIC in the dorsal raphe (DRN) and lateral septal (LSN) nucleus; 2) to study the possible involvement of GABAB receptors on the neurochemical alterations and c-Fos expression induced by NIC (0.05 and 0.8 mg/kg), using both pharmacological (2-OH saclofen) and genetic (mice GABAB1 knockout) approaches. The results revealed that in wild-type mice, NIC (0.05 mg/kg) increased the concentration of 5-HT and 5-HIAA (p < 0.05) in the DRN, and NIC (0.8 mg/kg) increased the levels of 5-HT (p < 0.01) and NA (p < 0.05) in the LSN. Additionally, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors abolished these neurochemical changes induced by NIC (p < 0.01, p < 0.05, respectively). On the other hand, NIC 0.05 and 0.8 mg/kg increased (p < 0.01) the c-Fos expression in the DRN and LSN respectively, in wild-type mice. In addition, 2-OH-saclofen pretreatment (1 mg/kg, ip) or the lack of GABAB receptors prevented the c-Fos alterations induced by NIC (p < 0.01). In summary, both approaches show that GABAB receptors would participate in the modulation of anxiolytic- and anxiogenic-like responses induced by NIC, suggesting the potential therapeutic target of these receptors for the tobacco addiction treatment. PMID- 24486712 TI - Neuroepigenetics of memory formation and impairment: the role of microRNAs. AB - MicroRNAs (miRNAs) are a class of short non-coding RNAs that primarily regulate protein synthesis through reversible translational repression or mRNA degradation. MiRNAs can act by translational control of transcription factors or via direct action on the chromatin, and thereby contribute to the non-genetic control of gene-environment interactions. MiRNAs that regulate components of pathways required for learning and memory further modulate the influence of epigenetics on cognition in the normal and diseased brain. This review summarizes recent data exemplifying the known roles of miRNAs in memory formation in different model organisms, and describes how neuronal plasticity regulates miRNA biogenesis, activity and degradation. It also examines the relevance of miRNAs for memory impairment in human, using recent clinical observations related to neurodevelopmental and neurodegenerative diseases, and discusses the potential mechanisms by which these miRNAs may contribute to memory disorders. PMID- 24486713 TI - Paternal ethanol exposure and behavioral abnormities in offspring: associated alterations in imprinted gene methylation. AB - Research confirms that maternal ethanol (EtOH) exposure can induce physical and mental disorders in offspring, yet the effect of paternal ethanol exposure on offspring is unclear. Methylation alterations in imprinted genes may be related to the well-documented teratogenic effects of ethanol. Here, we report that ethanol (0, 1.1, 3.3 g/kg) was administered intragastrically to male mice and a behavioral study was performed on their F1 generation. Data show that F1 mice with fathers exposed to the highest dose of ethanol had delayed cognitive performance and increased anxiety and depression. A specific circling behavior was observed in the offspring of the paternally ethanol-exposed group. The degree of methylation and mRNA expression of H19, Peg3, Ndn and Snrpn were assessed in paternal sperm and in the cerebral cortices of each offspring. It did affect methylation in paternal sperm (H19 and Peg3) and in the offspring's cerebral cortices (CpG7 and CpG11 in Peg3 and Snrpn), but the level of mRNA expression has not changed. In the circling mice, the highest ethanol exposure increase in methylation (CpG 1, 2, 7 and 11) and decreases in mRNA of Peg3.Thus, chronic paternal ethanol exposure can affect the methylation of imprinted genes in sire sperm that may be passed on to offspring, giving rise to mental deficits. PMID- 24486714 TI - Optimisation and performance of NaClO-assisted maintenance cleaning for fouling control in membrane bioreactors. AB - Based on conventional chemical cleaning and physical backflush methods, a novel in situ chemical backflush method, i.e., chemically assisted maintenance cleaning with NaClO as the principal reagent, was developed for membrane fouling control in membrane bioreactors (MBRs). The results demonstrated that, compared with a control MBR with water backflush, the use of low NaClO loads had few adverse effects on nutrient removal; on the contrary, the exposure to NaClO enhanced the denitrification performance of the MBR as a result of the formation of sludge granules. Measurements of transmembrane pressure (TMP) showed that an NaClO backflush at 0.2 ppm could achieve effective membrane fouling control in MBRs. Ex situ backflush tests showed that an NaClO backflush enhanced the detachment of biopolymers from the fouled membranes compared with a water backflush. Comparative 16S rRNA sequencing showed differing bacterial community composition in the fouling layers of the two MBRs. Specifically, the NaClO backflush could suppress filament-caused membrane fouling (i.e., lowered the abundance of Thiothrix eikelboomii in the fouling layers). Both the water and NaClO backflush resulted in significant increases in the pure water permeability of the membranes as a result of the enlargement of membrane pores. The results of Fourier transform infrared spectrometry indicated that the frequent NaClO backflush did not change the functional groups of the active layer of the membranes significantly. This study could provide an alternative for the implementation of membrane cleaning in MBR plants. PMID- 24486715 TI - Synergy of photocatalysis and adsorption for simultaneous removal of Cr(VI) and Cr(III) with TiO2 and titanate nanotubes. AB - An one-step efficient simultaneous removal of Cr(VI) and Cr(III) was achieved with mixture of TiO2 and titanate nanotubes (TNTs). Unlike the conventional two step Cr removal with a first photocatalytic reduction of Cr(VI) and a subsequent adsorption of Cr(III), the proposed single process significantly reduced reaction time (over 50%). The synergy of photocatalysis and adsorption played an important role in enhancing Cr removal process. The synergetic mechanism was interpreted and indirectly confirmed with H2O2 variation during photocatalysis. The instant transfer of the reduced Cr from TiO2 surface to TNTs interlayer greatly promoted the release of photocatalytic sites of TiO2, which in turn considerably enhanced photocatalytic activity of TNTs by inhibiting electron-hole pairs recombination. The optimum condition for the whole process was at pH 5. Adsorption of Cr(III) was primarily in the interlayer of TNTs at pH <= 5. However, higher pH would lead to precipitation of Cr(OH)3 onto TNTs as observed by X-ray photoelectron spectroscopy (XPS). Addition of Ca(2+) could promoted photocatalysis owing to its ionic bridging function and form of =TiOH(+)-Cr(VI)-Ca(2+)-Cr(VI) linkages, while SO4(2-) only slightly inhibited photo-reduction of Cr(VI), indicating good synergy of photocatalysis and adsorption even at high ionic strength of electrolyte. Besides, the desorbed TNTs could be easily regenerated by remedying the damaged tubular structure and reused for Cr removal with excellent performance. The outstanding synergetic effects with essential explanation of the mechanism make this study not only fundamentally important but also potentially practical applicable. PMID- 24486716 TI - Sperm functional parameters and erythrocytes oxidant-antioxidant imbalance during municipal landfill leachate treatment withdrawal in rats. AB - Adequate information on how leachates affect hematological and reproductive functions is necessary to help in linking causality with predictable response. The present study investigated the effects of Olushosun municipal landfill leachate (OMLL) exposure and withdrawal on sperm characteristics and erythrocytes oxidant-antioxidant balance in rats. Adult male Wistar rats were exposed to 0%, 12.5% and 25% OMLL in drinking water for 28 days. One-half of the rats in each group were sacrificed on day 29 while the remaining one-half stayed an additional 28 days without treatment. OMLL exposure significantly decreased sperm functional parameters, disrupted antioxidant systems with concomitant elevation in hydrogen peroxide and malondialdehyde levels in erythrocytes and sperm. Following withdrawal of treatment, OMLL-mediated decrease in sperm count and daily sperm production were reversed to near control. However, erythrocytes and sperm oxidative damage, increased sperm abnormalities, decreased epididymis weight, sperm progressive motility and testicular sperm number persisted and were consistent with results obtained from rats sacrificed immediately after OMLL treatment. Collectively, OMLL-induced irreversible oxidative damage to erythrocytes and sperm in rats within the time course of investigation. These findings highlight potential adverse effects of OMLL on individuals unduly exposed to leachates contaminated substances. PMID- 24486717 TI - Proteome compression via protein domain compositions. AB - In this paper, we study domain compositions of proteins via compression of whole proteins in an organism for the sake of obtaining the entropy that the individual contains. We suppose that a protein is a multiset of domains. Since gene duplication and fusion have occurred through evolutionary processes, the same domains and the same compositions of domains appear in multiple proteins, which enables us to compress a proteome by using references to proteins for duplicated and fused proteins. Such a network with references to at most two proteins is modeled as a directed hypergraph. We propose a heuristic approach by combining the Edmonds algorithm and an integer linear programming, and apply our procedure to 14 proteomes of Dictyostelium discoideum, Escherichia coli, Saccharomyces cerevisiae, Schizosaccharomyces pombe, Caenorhabditis elegans, Drosophila melanogaster, Arabidopsis thaliana, Oryza sativa, Danio rerio, Xenopus laevis, Gallus gallus, Mus musculus, Pan troglodytes, and Homo sapiens. The compressed size using both of duplication and fusion was smaller than that using only duplication, which suggests the importance of fusion events in evolution of a proteome. PMID- 24486718 TI - Curcumin inhibits proliferation of breast cancer cells through Nrf2-mediated down regulation of Fen1 expression. AB - Curcumin can inhibit cell proliferation of breast cancer, but the mechanism for this inhibition remains unclear. Over-expression of Flap endonuclease 1 (Fen1), a DNA repair-specific nuclease, is involved in the development of breast cancer. Nrf2 is a master regulator of cellular antioxidant defense systems. Curcumin can induce the expression of Nrf2 in both non-breast cancer cells and breast cancer cells. However, whether curcumin-induced inhibition of breast cancer cell proliferation may involve Nrf2-mediated Fen1 expression is not yet understood. In this study, we demonstrated that curcumin inhibited Fen1-dependent proliferation of MCF-7 cells and significantly induced Nrf2 protein expression while inhibiting Fen1 protein expression. Curcumin could down-regulate Fen1 gene expression in a Nrf2-dependent manner. Further investigation revealed that curcumin could lead to Nrf2 translocation from the cytoplasm to the nucleus and decrease Fen1 promoter activity by decreasing the recruitment of Nrf2 to the Fen1 promoter. These data suggest that curcumin may inhibit the proliferation of breast cancer cells through Nrf2-mediated down-regulation of Fen1 expression, which may be a new mechanism of curcumin-induced tumor growth inhibition. PMID- 24486719 TI - Rapid dynamic radial MRI via reference image enforced histogram constrained reconstruction. AB - Exploiting spatio-temporal redundancies in sub-Nyquist sampled dynamic MRI for the suppression of undersampling artifacts was shown to be of great success. However, temporally averaged and blurred structures in image space composite data poses the risk of false information in the reconstruction. Within this work we assess the possibility of employing the composite image histogram as a measure of undersampling artifacts and as basis of their suppression. The proposed algorithm utilizes a histogram, computed from a composite image within a dynamically acquired interleaved radial MRI measurement as reference to compensate for the impact of undersampling in temporally resolved data without the incorporation of temporal averaging. In addition an image space regularization utilizing a single frame low-resolution reconstruction is implemented to enforce overall contrast fidelity. The performance of the approach was evaluated on a simulated radial dynamic MRI acquisition and on two functional in vivo radial cardiac acquisitions. Results demonstrate that the algorithm maintained contrast properties, details and temporal resolution in the images, while effectively suppressing undersampling artifacts. PMID- 24486720 TI - In vivo single-shot 13C spectroscopic imaging of hyperpolarized metabolites by spatiotemporal encoding. AB - Hyperpolarized metabolic imaging is a growing field that has provided a new tool for analyzing metabolism, particularly in cancer. Given the short life times of the hyperpolarized signal, fast and effective spectroscopic imaging methods compatible with dynamic metabolic characterizations are necessary. Several approaches have been customized for hyperpolarized (13)C MRI, including CSI with a center-out k-space encoding, EPSI, and spectrally selective pulses in combination with spiral EPI acquisitions. Recent studies have described the potential of single-shot alternatives based on spatiotemporal encoding (SPEN) principles, to derive chemical-shift images within a sub-second period. By contrast to EPSI, SPEN does not require oscillating acquisition gradients to deliver chemical-shift information: its signal encodes both spatial as well as chemical shift information, at no extra cost in experimental complexity. SPEN MRI sequences with slice-selection and arbitrary excitation pulses can also be devised, endowing SPEN with the potential to deliver single-shot multi-slice chemical shift images, with a temporal resolution required for hyperpolarized dynamic metabolic imaging. The present work demonstrates this with initial in vivo results obtained from SPEN-based imaging of pyruvate and its metabolic products, after injection of hyperpolarized [1-(13)C]pyruvate. Multi-slice chemical-shift images of healthy rats were obtained at 4.7T in the region of the kidney, and 4D (2D spatial, 1D spectral, 1D temporal) data sets were obtained at 7T from a murine lymphoma tumor model. PMID- 24486721 TI - Segmented negative strand RNA virus nucleoprotein structure. AB - Negative strand RNA virus (NSV) genomes are never free, but always found assembled with multiple copies of their nucleoprotein, as RNPs. A flurry of papers describing the X-ray crystal structures of several segmented NSV nucleoproteins have recently appeared. The most significant feature of these various structures is that the arms that are used to oligomerize the nucleoproteins on their genome RNAs are highly flexible, permitting these RNPs to assume virtually unlimited geometries. The structural flexibility of segmented NSV RNPs is undoubtedly important in all aspects of their biology, including genome replication and circularization, and the selection of one copy of each segment for packaging into virus particles. PMID- 24486722 TI - Fractionating theory of mind: a meta-analysis of functional brain imaging studies. AB - We meta-analyzed imaging studies on theory of mind and formed individual task groups based on stimuli and instructions. Overlap in brain activation between all task groups was found in the mPFC and in the bilateral posterior TPJ. This supports the idea of a core network for theory of mind that is activated whenever we are reasoning about mental states, irrespective of the task- and stimulus formats (Mar, 2011). In addition, we found a number of task-related activation differences surrounding this core-network. ROI based analyses show that areas in the TPJ, the mPFC, the precuneus, the temporal lobes and the inferior frontal gyri have distinct profiles of task-related activation. Functional accounts of these areas are reviewed and discussed with respect to our findings. PMID- 24486723 TI - Mycoepoxydiene induces apoptosis and inhibits TPA-induced invasion in human cholangiocarcinoma cells via blocking NF-kappaB pathway. AB - Human cholangiocarcinoma (CCA) is a chemoresistant bile duct carcinoma with a poor prognosis. Conventional chemotherapy and radiotherapy have not been reported to be effective in improving long-term survival. Mycoepoxydiene (MED), a polyketide isolated from the marine fungal strain Diaporthe sp. HLY-1 associated with mangroves, has been shown to be an agent capable of inducing apoptosis in MCF-7 and Hela cell lines. However, little is known about the effect of MED in CCA. Herein, we investigated the effect of MED on CCA cells proliferation and invasion. The results demonstrated that MED induced apoptosis in CCA cells such as SK-ChA-1 and Mz-ChA-1 through inhibiting the expression of anti-apoptotic proteins such as Bcl-XL and Bcl-2, two targets of NF-kappaB. In addition, MED significantly inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced CCA cells invasion in a dose-dependent manner by reducing the expression of matrix metalloelastase 9 (MMP-9). Moreover, MED inhibited TPA-induced NF-kappaB activation via blocking phosphorylation and degradation of IkappaBalpha and phosphorylation of IkappaB kinase (IKK). MED had no effect on the activation of extracellular signal-regulated kinase (ERK), c-jun N-terminal kinase (JNK) and p38, which are also involved in regulating the MMP-9 expression. Collectively, MED significantly suppressed proliferation and invasion of CCA cells such as SK ChA-1 and Mz-ChA-1, suggesting that MED is a potential lead compound for the development of novel drugs for therapy of CCA. PMID- 24486725 TI - Adolescents' view of health concept and its risk factors: a literature review. AB - BACKGROUND: Adolescence is the important period in human life. It is an essential prerequisite for playing social roles. OBJECTIVE: The current study conducted a review on the concept, dimensions, and influential factors on health and risk taking, instruments and measurements of high-risk behaviors, risk factors, and high-risk behavior protective factors through adolescent perspectives. METHODS: This literature review was conducted by electronic searching and library study on health and adolescents using Wiley Interscience, ScienceDirect, ProQuest, and Springer (1990-2012). The keywords for searching data collection sources included health, youth, young, adolescents, risk behaviors, risk taking, related factors, protective factors, risk factors, adolescent perspectives, quantitative study, qualitative study, measurement, and instrument. RESULTS: This literature review led to the arrangement of subjects in nine general categories titled definition of health concept and its dimensions, adolescents and health in adolescence, risk taking in adolescence and its measuring tools, gender differences in adolescence health and risk taking, adolescents' health and relationships, socioeconomic conditions and health, adolescents and psychiatric health, religion, and health, educational facilities and health, non-governmental organizations and their role in adolescents' health. What has been achieved from a review of these articles is that several personal, social, and family factors are associated with health and risk taking in adolescents. CONCLUSION: Generally, adolescents cared more about the psychosocial aspects of health than the physical dimensions. They also considered factors such as independence, communication, socioeconomic conditions, mental health, religion, and educational facilities synonymous with the concept of health. Therefore, in formulation and implementation of health promotion programs for adolescents, the concept of health and its various dimensions must be considered from adolescent perspectives. PMID- 24486724 TI - Inducible costimulator facilitates T-dependent B cell activation by augmenting IL 4 translation. AB - The inducible costimulator (ICOS) is highly expressed in follicular helper T (Tfh) cells, a subset of CD4 T cells that migrate into the B cell zone and facilitate germinal center reactions. Although ICOS is known to play a critical role in forming the Tfh cell population during immune responses, its contribution to the effector functions of Tfh cells remains unclear. Using activated mouse splenic CD4 T cells we demonstrate that ICOS assists TCR-mediated signal transduction by potentiating the PI3K-AKT-mTOR signaling cascade that leads to hyper-phosphorylation of p70S6K and 4E-BP1, events that are known to augment cap dependent mRNA translation. Consequently, ICOS costimulation promotes the formation of polysomes on IL-4 mRNA in a PI3K-dependent manner. Furthermore, we show that the supply of IL-4 becomes a limiting factor for T-dependent B cell activation during in vitro co-culture when the ICOS-PI3K signaling axis is disrupted in T cells. This ICOS costimulation-dependent translational control may ensure targeted delivery of IL-4 to cognate B cells during T-B collaborations in the germinal center. PMID- 24486726 TI - A conceptual framework for early adolescence: a platform for research. AB - Early adolescence (ages 10-14 years) is among the most neglected stages of development, yet there are few stages during the life course where changes are as dramatic. The present conceptual framework proposes four central goals to be achieved by early adolescence: engagement with learning, emotional and physical safety, positive sense of self/self-efficacy, acquisition of life/decision-making skills. The framework proposes an ecological model where the macro level factors (economic forces, historical events, national priorities, laws/policies/norms and values, national events, and political realities) all set the contexts that influence community, family, school and peer factors that all in turn influence the adolescent. Existing indicators for points of development are noted as are future areas of research priority. PMID- 24486727 TI - Quality of life measures and psychiatric symptoms in adolescents with systemic lupus erythematosus and familial Mediterranean fever. AB - PURPOSE: To describe the relation between global Quality of Life (QL) and psychiatric symptoms in adolescents with systemic lupus erythematosus (SLE) and familial Mediterranean fever (FMF), and to analyze the perceptions of parents and adolescents. METHODS: This study included 51 adolescents diagnosed with SLE (n=25) and FMF (n=26), and 51 healthy adolescents. The Health Related QL (HRQL) of SLE patients was rated by parents and adolescents using the Simple Measurement of Impact of Lupus Erythematosus in Youngsters(c) (SMILEY(c)). The global QL of FMF patients and healthy adolescents was rated by the response given to the first question of the SMILEY(c) by each parent and adolescent. All participants completed the Brief Symptom Inventory (BSI), which measures psychiatric symptoms. RESULTS: In total, 92.3% with FMF, 56% with SLE and 76.5% of healthy adolescents reported their global QL as good and very good using the first question of the SMILEY(c). The global QL perceptions of adolescents and their parents did not correlate (FMF, p=0.94; SLE, p=0.16). SLE patients had the highest rate of depression (54.2%), whereas hostility was detected among 54.9% of healthy adolescents. Significant relations were detected between BSI and SMILEY(c) scores. CONCLUSION: The global QL perceptions of adolescents with FMF were better than those of healthy adolescents, which may be explained by their perceived relief of anguish they suffer during their short-lived attacks. The global QL perceptions of adolescents with SLE were the worst, most probably due to the chronic course resulting in an awareness of limitations and intense treatment. Adolescents with SLE had similar psychopathological symptom scores when compared with FMF patients and healthy adolescents. This could be explained by developing resilience. Differences in the perception of adolescents versus their parents regarding global QL emphasized the importance of adolescent-specific interviews for chronic illnesses and multidisciplinary follow-up with adolescent medicine. PMID- 24486728 TI - Association of oral hygiene habits and food intake with the risk of dental caries among undergraduate university women in Saudi Arabia. AB - OBJECTIVE: The purpose of this study was to determine the risk of dental caries in relation to oral hygiene habits and food intake among women at university in Saudi Arabia. METHODS: A sample of 935 undergraduate university women was selected from the King Abdulaziz University in Jeddah, Saudi Arabia. A previously pretested questionnaire was used to collect the data. Odds ratios were calculated to estimate the risk of dental caries associated with oral hygiene and food intake. RESULTS: The findings revealed that women who cleaned their teeth three times or more per day mostly cleaned their teeth after intake of sweets and chocolates, and had no gingivitis were at less risk of dental caries than other women (p=0.029, p=0.000 and p=0.000, respectively). The intake of milk, fruit and vegetables on 4 days or more per week was found to protect against dental caries (odds ratios=0.34, 0.64 and 0.73, respectively), whereas the intake of chocolate and soft drinks for the same period was found to be a risk factor for dental caries (odds ratios=1.8 and 1.4, respectively). CONCLUSION: The results of this study are useful for public health intervention programs to combat dental caries in the Saudi community. PMID- 24486729 TI - The concepts of work, study, and leisure of parents and children. AB - The present work examines how a group of Italian parents and their adolescent children view work, study, and leisure in order to check for possible relations between the ideas of parents and their children's. A total of 160 adolescents and 160 parents were recruited. Semi-structured interviews that assessed the participants' concepts about work, study, and leisure were conducted. The analyses carried out demonstrate that there are connections between the parents' and adolescents' perceptions regarding work, study, and leisure. The results confirm the importance of considering both constructs and the parents' perspectives on them, and of involving parents in their children vocational guidance actions. PMID- 24486730 TI - Serotonergic 5-HT7 receptors and cognition. AB - The abundant distribution of serotonin (5-HT) in different areas of the central nervous system can explain the involvement of this neurotransmitter in the regulation of several functions, such as sleep, pain, feeding, and sexual and emotional behaviors. Moreover, the serotonergic system is also involved in other more complex roles, such as cognition, including learning and memory processes. Recent studies led to the discovery of various types and subtypes of receptors differentially associated to cognitive mechanisms. 5-HT7 is the most recently discovered receptor for 5-HT; therefore, it is also one of the least well characterized. Studies exist hypothesizing the role of 5-HT7 on the modulation of learning and memory processes and other cognitive functions. Moreover, much attention has been devoted to the possible role of 5-HT7 receptors in psychiatric disorders. Therefore, the aim of this review is to clarify the behavioral role of the recently discovered 5-HT7 type receptor and highlight its involvement in the cognitive functions, with particular attention to the modulation of learning and memory processes, thus providing a basis to obtain new therapeutic agents and strategies for the treatment of cognitive disorders. PMID- 24486731 TI - Neurochemical dysfunction in treated and nontreated schizophrenia - a retrospective analysis of in vivo imaging studies. AB - To evaluate the contribution of individual synaptic constituents, all available in vivo imaging studies on schizophrenic patients were subjected to a retrospective analysis. For the pool of drug-naive, drug-free, and acutely medicated patients, major findings were increases in neostriatal dopamine (DA) synthesis and release and decreases in neostriatal DA transporters and D1 receptors, neostriatal, thalamic, frontal, and parietal D2 receptors, mesencephalic/pontine and temporal 5-HT1A receptors, frontal and temporal HT2A and MU-amino butyric acid (GABA)A receptors. Based on the findings on drug-naive and drug-free patients, it may be hypothesized that schizophrenia initially is characterized by an impaired mechanism of D2 autoreceptor and heteroreceptor sensitization leading to sensitization instead of desensitization in response to increased levels of neostriatal DA. Neuroleptic medication blocks neostriatal D2 autoreceptor and heteroreceptors, reducing neostriatal DA and disinhibiting DA action mediated by D2 heteroreceptor binding sites. Ultimately, this may result in a restitution of GABA function, leading to a recovery of inhibitory input to the target regions of the descending corticothalamostriatal efferents. Furthermore, a blockade of inhibitory and excitatory neocortical 5-HT function may be inferred, which is likely to reduce (excitatory) DAergic input to the mesolimbic target regions of corticothalamostriatal projections. PMID- 24486732 TI - A randomised controlled trial of a consumer-focused e-health strategy for cardiovascular risk management in primary care: the Consumer Navigation of Electronic Cardiovascular Tools (CONNECT) study protocol. AB - INTRODUCTION: Fewer than half of all people at highest risk of a cardiovascular event are receiving and adhering to best practice recommendations to lower their risk. In this project, we examine the role of an e-health-assisted consumer focused strategy as a means of overcoming these gaps between evidence and practice. Consumer Navigation of Electronic Cardiovascular Tools (CONNECT) aims to test whether a consumer-focused e-health strategy provided to Aboriginal and Torres Strait Islander and non-indigenous adults, recruited through primary care, at moderate-to-high risk of a cardiovascular disease event will improve risk factor control when compared with usual care. METHODS AND ANALYSIS: Randomised controlled trial of 2000 participants with an average of 18 months of follow-up to evaluate the effectiveness of an integrated consumer-directed e-health portal on cardiovascular risk compared with usual care in patients with cardiovascular disease or who are at moderate-to-high cardiovascular disease risk. The trial will be augmented by formal economic and process evaluations to assess acceptability, equity and cost-effectiveness of the intervention. The intervention group will participate in a consumer-directed e-health strategy for cardiovascular risk management. The programme is electronically integrated with the primary care provider's software and will include interactive smart phone and Internet platforms. The primary outcome is a composite endpoint of the proportion of people meeting the Australian guideline-recommended blood pressure (BP) and cholesterol targets. Secondary outcomes include change in mean BP and fasting cholesterol levels, proportion meeting BP and cholesterol targets separately, self-efficacy, health literacy, self-reported point prevalence abstinence in smoking, body mass index and waist circumference, self-reported physical activity and self-reported medication adherence. ETHICS AND DISSEMINATION: Primary ethics approval was received from the University of Sydney Human Research Ethics Committee and the Aboriginal Health and Medical Research Council. Results will be disseminated via the usual scientific forums including peer-reviewed publications and presentations at international conferences CLINICAL TRIALS REGISTRATION NUMBER: ACTRN12613000715774. PMID- 24486733 TI - Radionuclides in fracking wastewater: managing a toxic blend. PMID- 24486734 TI - Inconclusive findings: now you see them, now you don't! PMID- 24486736 TI - A modern form of Rapunzel syndrome: trichobezoar composed of synthetic hair extensions. PMID- 24486735 TI - Durable resistance: a key to sustainable management of pathogens and pests. AB - This review briefly addresses what has been learned about resistance durability in recent years, as well as the questions that still remain. Molecular analyses of major gene interactions have potential to contribute to both breeding for resistance and improved understanding of virulence impacts on pathogen fitness. Though the molecular basis of quantitative resistance is less clear, substantial evidence has accumulated for the relative simplicity of inheritance. There is increasing evidence for specific interactions with quantitative resistance, though implications of this for durability are still unknown. Mechanisms by which resistance gene pyramids contribute to durability remain elusive, though ideas have been generated for identifying gene combinations that may be more durable. Though cultivar mixtures and related approaches have been used successfully, identifying the diseases and conditions that are most conducive to the use of diversity has been surprisingly difficult, and the selective influence of diversity on pathogen populations is complex. The importance of considering resistance durability in a landscape context has received increasing emphasis and is an important future area of research. Experimental systems are being developed to test resistance gene deployment strategies that previously could be addressed only with logic and observation. The value of molecular markers for identifying and pyramiding major genes is quite clear, but the successful use of quantitative trait loci (QTL) for marker-assisted selection of quantitative resistance will depend greatly on the degree to which the identified QTL are expressed in different genetic backgrounds. Transgenic approaches will likely provide opportunities for control of some recalcitrant pathogens, though issues of durability for transgenes are likely to be no different than other genes for resistance. The need for high quality phenotypic analysis and screening methodologies is a priority, and field-based studies are likely to remain of signal importance in the foreseeable future. PMID- 24486737 TI - One size fits one: pharmacogenetics in gastroenterology. AB - Individual variability in response and development of adverse effects to drugs is a major challenge in clinical practice. Pharmacogenomics refers to the aspect of personalized medicine where the patient's genetic information instructs the selection and dosage of therapy while also predicting its adverse effects profile. Sequencing of the entire human genome has given us the opportunity to study commonly used drugs as well as newer therapeutic agents in a new light, opening up opportunities for better drug efficacy and decreased adverse effects. This article highlights developments in pharmacogenomics, relates these to practice of gastroenterology, and outlines roadblocks in translation of this knowledge into clinical practice. PMID- 24486738 TI - Iron homeostasis in breast cancer. AB - Iron is an essential element and a critical component of molecules involved in energy production, cell cycle and intermediate metabolism. However, the same characteristic chemistry that makes it so biologically versatile may lead to iron associated toxicity as a consequence of increased oxidative stress. The fact that free iron accumulates with age and generates ROS led to the hypothesis that it could be involved in the etiogenesis of several chronic diseases. Iron has been consistently linked to carcinogenesis, either through persistent failure in the redox balance or due to its critical role in cellular proliferation. Several reports have given evidence that alterations in the import, export and storage of cellular iron may contribute to breast cancer development, behavior and recurrence. In this review, we summarize the basic mechanisms of systemic and cellular iron regulation and highlight the findings that link their deregulation with breast cancer. To conclude, progresses in iron chelation therapy in breast cancer, as a tool to fight chemotherapy resistance, are also reviewed. PMID- 24486740 TI - Activated pregnane X receptor inhibits cervical cancer cell proliferation and tumorigenicity by inducing G2/M cell-cycle arrest. AB - Pregnane X receptor (PXR) regulates cell proliferation and carcinogenesis in female reproductive tissue. We showed that PXR was expressed in cervical cells and tissue samples. PXR were lower or greatly diminished in cancer tissues compared to normal control. Functionally, activation of human PXR by rifampicin or ectopic expression of constitutively-activated human VP-PXR inhibited cervical cell proliferation. Constitutively-activated VP-PXR attenuated CaSki and HeLa xenograft tumor growth in nude mice compared with control. The cellular proliferation inhibition of PXR by causing G2/M cell-cycle arrest is involved up regulation of Cullin1-3, MAD2L1, and down-regulation of ANAPC2 and CDKN1A. Our data suggests that PXR signaling inhibits tumor cell proliferation in vitro and cervical carcinoma growth in vivo. PMID- 24486739 TI - Is cure of chronic myeloid leukemia in the third millennium a down to earth target (ed) or a castle in the air? AB - The therapeutic approach in chronic myeloid leukemia (CML) has undergone a revolutionary change during the last 2 decades with the introduction of the tyrosine kinase inhibitors. The use of these agents has changed overall survival as well as the quality of life of CML patients. Since the introduction of imatinib, newer agents have been developed and their role as first line treatment was examined. The use of genomics and proteomics as a means to tailor treatment of CML patients is underway. Meanwhile, clinical parameters as disease phase and response to treatment are used to guide a personalized approach. In this review, we will discuss the various aspects of personalized medicine in CML, including the use of the different scoring systems to guide treatment, disease phase as a means to choose the proper approach and the value of early response evaluation in decision-making. The approach towards patients resistant to tyrosine kinase inhibitors (TKIs), individual strategies for discontinuation of TKIs and "operational" cure in CML will also be discussed and finally the personalized treatment for CML patients in the near future based on present outcomes. PMID- 24486741 TI - Hydroxytyrosol, a natural molecule from olive oil, suppresses the growth of human hepatocellular carcinoma cells via inactivating AKT and nuclear factor-kappa B pathways. AB - The present study aimed to investigate the anti-cancer effects of hydroxytyrosol (HT) in human hepatocellular carcinoma (HCC) cells. Our results show that HT could inhibit proliferation, induce G2/M cell cycle arrest and apoptosis in human HCC cells. Mechanically, we found that HT could suppress the activation of AKT and nuclear factor-kappa B (NF-kappaB) pathways. HT also significantly inhibited the tumor growth, angiogenesis and the activation of AKT and NF-kappaB pathways in an orthotopic model of human HCC in vivo. These data suggest that HT may be a promising candidate agent for the treatment of HCC. PMID- 24486743 TI - Standards in neurological rehabilitation, June 1997. AB - The European Federation of Neurological Societies (EFNS) Scientific Panel on Neurorehabilitation established a Task Force on standards in neurological rehabilitation in June 1996. The remit for the Task Force was to: (1) produce a report on the state of neurological rehabilitation across Europe; and (2) recommend standards for the provision of neurological services for disabled people. The main conclusions of the Task Force were as follows:(1) A questionnaire circulated to each European member country has indicated a significant lack of adequate neurological rehabilitation facilities across Europe. Very few countries have any established network of neurological rehabilitation centres. Few countries have adequately trained neurological rehabilitation physicians, therapists or nurses. Such poor facilities should be seen in the context of the large numbers and increasing prevalence of people with neurological disabilities.(2) The Task Force has summarized the significant benefits that can follow from the establishment of a dedicated and cost effective neurological rehabilitation service including functional improvement, reduction of unnecessary complications, better coordination and use of limited resources, improved opportunities for education, training and research and a clear point of contact for the disabled person.(3) The Task Force recommends minimum standards for the prevention of neurological disability including access to health education, genetic counselling and emergency resources. The Task Force also encourages governments to invest in improved legislation for accident prevention.(4) The Task Force has outlined some minimum standards for the staffing of a neurological rehabilitation service including improved training both for neurologists and rehabilitation physicians. Such training could include a cross-national training programme both for physicians and other health care staff.(5) The Task Force supports a two-tier system of neurological services. We believe that disabled individuals should have access to a regional specialist service as well as a local community service. The regional specialist service would cater for people with more complicated and severe disabilities, including spinal injury and severe brain injury. The regional centres would provide specialist expertise for wheelchairs and special seating, orthotics, continence and urological services, aids and equipment including communication aids and environmental controls, prosthetics and driving assessment. The Task Force additionally endorses the development of local and community based rehabilitation teams with clear links to the regional centre.(6) The Task Force recognizes the limited amount of rehabilitation research and encourages individuals, universities and governments to invest more in rehabilitation research. Such investment should produce benefits for disabled people and their carers and in the long term benefits for the national economy.(7) The Task Force realizes that neurological rehabilitation is poorly developed both in Europe and the world as a whole. We firmly endorse international co-operation in this field and are happy to co-operate with any international organization in order to develop such links for clinical, educational or research initiatives.(8) The Task Force encourages individual countries to produce a document summarizing their own situation with regard to these standards and to produce a timetable for action to improve their situation. The EFNS Task Force would be pleased to assist in the publication of such deliberations or to act as a focus for international education and research or for sharing of examples of good practice. PMID- 24486742 TI - miRNA423-5p regulates cell proliferation and invasion by targeting trefoil factor 1 in gastric cancer cells. AB - TFF1 is a small, secreted protein in the TFF family that has a pivotal role as a motogenic factor in epithelial restitution and cell motility, and as a tumor suppressor gene in the stomach. In this study, we identified TFF1 as a novel target gene of miRNA-423-5p. miRNA-423-5p negatively regulated the expression of TFF1 by binding to its 3'UTR and participated in proliferation/invasion-related processes via a TFF1-dependent manner in gastric cancer cells. Our findings suggested that miR-423-5p may be a novel target for the future development of specific therapeutic interventions for gastric cancer. PMID- 24486744 TI - Representation activity of the right and left hemispheres of the brain. AB - Drawings by psychiatric patients were studied in various states (i) in depression; (ii) after neuroleptic injection; and (iii) during left hemisphere suppression induced by unilateral electroconvulsive seizure (UES). In these states, right hemisphere activation predominates. The results of the study demonstrate that, under the predominance of right hemisphere activation over the left hemisphere, there is a tendency to reproduce the image of the object and to represent it in near space. Drawings by psychiatric patients were also investigated in (i) the manic state; (ii) after injection of psychotropic drugs which improved the mood; and (iii) during right hemisphere suppression following right-sided UES. Under these conditions, left hemisphere activation predominates and the drawings loose the illusion of three-dimensional space. A tendency to reproduce the knowledge and the ideas of the object and to represent it in distant space was observed. Thus, both hemispheres may represent space and elaborate perceptive and conceptional models of the world in different ways. It is probable that different types of representation are based on global (right hemispheric) in comparison with focal (left-hemispheric) attention to space. PMID- 24486745 TI - High frequency non-invasive stimulation over the spine: Effects on mood and mechanical pain tolerance in normal subjects. AB - We investigated the effects of non-invasive high frequency (625Hz) stimulation over the spine on mechanical pain tolerance and subjective mood. Sixty healthy subjects were divided equally into three groups receiving either high intensity (250 V), low intensity (3-4 V) or sham electrical stimulation directly over the spinal cord for 30 minutes. Following high intensity stimulation, subjects felt significantly more elated, leisurely and less tense and, contrary to reports on patients with clinical pain, had lower mechanical pain tolerances. There were no correlations between changes in mood and changes in mechanical pain tolerances. These findings contrasted with the lack of any significant differences in mood or mechanical pain tolerances in a second study where 20 subjects received either high intensity or sham stimulation across the left shoulder joint. The results indicate that decreases in mechanical pain tolerance are independent of changes in mood following non-invasive high frequency, high intensity cutaneous stimulation but that both effects are dependent on that stimulation being applied over the spine. PMID- 24486746 TI - Basal ganglia disease and visuospatial cognition: Are there disease-specific impairments? AB - Visuospatial deficits in basal ganglia disease may be a non-specific function of the severity of dementia or they could reflect disease-specific impairments. To examine this question, Huntington (HD) patients, demented and non-demented Parkinson (PD) patients and healthy controls were examined with neuropsychological tests emphasising visuospatial abilities. Global intellectual function and general visuospatial cognition were less efficient in the two demented patient groups relative to both controls and non-demented PD patients and they did not differ significantly between non-demented Parkinsonians and controls nor between demented PD and HD patients. However, HD patients but not demented PD patients were impaired on a test of person-centred spatial judgement compared to non-demented subjects while demented PD patients scored significantly lower than HD patients on a test of field independence. Factor analysis yielded a factor reflecting general visuospatial processing capacity which discriminated between demented and non-demented PD patients but not between demented PD and HD patients. A unique factor associated with the manipulation of person-centred space discriminated between demented PD and HD patients. These results suggest general visuospatial processing is impaired as a non-specific function of dementia presence in HD and PD. Abnormalities in circumscribed aspects of visuospatial function, on the other hand, may differentiate between HD and PD, suggesting differential involvement of the basal ganglia in the respective illnesses. PMID- 24486747 TI - Visual problems in Parkinson's disease: A questionnaire survey. AB - A questionnaire was completed by 53 putative sufferers from Parkinson's disease and 31 putative age-matched normal controls. The aim of the questionnaire was to elicit reports of any changes in visual perception. The incidence of self reported Parkinsonian symptoms was very much higher in the patient group than in the controls. The patients reported significantly more problems with depth and motion perception than the controls. They also reported a significantly higher incidence of hallucinations, double vision and the need to turn the head to see objects in the periphery. However, the reported incidence of changes in brightness, colour, shape and size perception was not significantly different in the two groups. The results are discussed with reference to laboratory studies of Parkinsonian vision and to the likely neurological basis of some of the changes. PMID- 24486748 TI - Short-term and procedural memory for colours and inferior temporal cortex activity. AB - Two children (male, 10 years, and female, 13 years one month) with tumours of the inferior temporal (IT) cortex of the brain were studied post-surgically for their abilities to carry out a short-term memory test. This involved: differences in colour, number and shape of small plastic objects; differences in receptacles where these objects should be placed and in ways in which this placement should be done; a procedural task involving differences either in colour or in size of wooden rings employed in the task. Their performances in these tests, and those of patients with tumours of other encephalic areas, were compared with the performances of normal controls. The subjects with IT tumours spent a significantly greater amount of time than normal subjects of their age in carrying out the procedural task involving differences in colour. One of the IT subjects also spent a significantly greater amount of time in the procedural task involving size differences. Other differences in the performances of patients with encephalic tumours and the performances of normal controls were not significant. Results are discussed in relation to findings of colour and size perception and memory localized to the inferior temporal and middle temporal cortices. PMID- 24486749 TI - Differential effects of an alpha-2 agonist on wakefulness and paradoxical sleep in the rat: A polygraphic and biochemical approach. AB - The purpose of this experiment was to determine the sensitivity of wakefulness and paradoxical sleep to the alpha2-agonist, c1onidine. The drug inhibited both wakefulness and paradoxical sleep but the smallest dose necessary to inhibit wakefulness was 64 times larger than the smallest dose inhibiting paradoxical sleep. The effect on paradoxical sleep was inhibitory for all the clonidine doses but wakefulness was enhanced transiently after the four largest doses used. The time between injection and maximum wakefulness enhancement was highly correlated with the dose of c1onidine. The brain level measured after these four different doses at the moment of maximum wakefulness enhancement was the same, suggesting that this effect occurred only when a critical concentration of the drug was attained in the brain and not when the concentration was higher or lower. These data suggest that different alpha2-adrenoceptors are involved in these two states of vigilance or, alternatively, that their sensitivity is modulated physiologically. In addition, a sensitivity imbalance between different alpha2 adrenoceptors may exist in wakefulness but not in paradoxical sleep. PMID- 24486750 TI - Obsessive compulsive disorder in a woman with left basal ganglia infarct: A case report. AB - This report presents a syndrome resembling obsessive convulsive disorder (OCD) secondary to a stroke in the left basal ganglia. The patient's syndrome is virtually identical to those that have been described in bilateral damage of the basal ganglia. However, the stroke described in this case report is located unilaterally in the left basal ganglia. In addition, experience in treating a patient with OCD induced by structural damage of basal ganglia is presented. PMID- 24486752 TI - Posterior malleolus fracture. PMID- 24486753 TI - Application of biologics in the treatment of the rotator cuff, meniscus, cartilage, and osteoarthritis. AB - Advances in our knowledge of cell signaling and biology have led to the development of products that may guide the healing/regenerative process. Therapies are emerging that involve growth factors, blood-derived products, marrow-derived products, and stem cells. Animal studies suggest that genetic modification of stem cells will be necessary; studies of cartilage and meniscus regeneration indicate that immature cells are effective and that scaffolds are not always necessary. Current preclinical animal and clinical human data and regulatory requirements are important to understand in light of public interest in these products. PMID- 24486754 TI - Arthroscopic subscapularis repair. AB - As the largest and most powerful rotator cuff muscle, the subscapularis plays a critical role in proper shoulder function. The diagnosis of subscapularis tears is made based on history and physical examination and confirmed with imaging studies. Historically, subscapularis tears have been addressed in an open fashion. Recent literature has demonstrated successful all-arthroscopic repair of isolated subscapularis tears and anterosuperior rotator cuff tears. Successful arthroscopic treatment follows several critical steps: patient positioning, portal placement, obtaining adequate visualization and working space, identifying and mobilizing the subscapularis tendon, preparation of the tendon edge and lesser tuberosity, appropriate anchor placement, suture passage, and finally, secure knot-tying and fixation. Excellent functional and clinical outcomes following these steps have been demonstrated by various investigators. Additional research is needed, however, because direct comparison between all-arthroscopic and open subscapularis repair is limited, and neither technique has proved to be superior. PMID- 24486755 TI - Surgical management of metastatic long bone fractures: principles and techniques. AB - Management of metastatic long bone fractures requires identification of the lesion and the use of sound fracture fixation principles to relieve pain and restore function. The treating surgeon must understand the principles of pathologic fracture fixation before initiating treatment. Because these fractures occur in the context of a progressive systemic disease, management typically involves a multidisciplinary approach. When considering surgical stabilization of these fractures, the abnormal (or absent) healing environment associated with diseased bone and the overall condition of the patient must be taken into account. The goal of surgery is to obtain a rigid mechanical construct, which allows for early mobility and weight bearing. This can be achieved using internal fixation with polymethyl methacrylate cement or segmental resection and joint reconstruction. Prosthetic joint arthroplasty is a more reliable means of fracture management when insufficient bone is present for fixation. Prophylactic stabilization of impending pathologic fractures can reduce the morbidity associated with metastatic lesions. PMID- 24486756 TI - Management of chronic musculoskeletal pain. AB - Chronic musculoskeletal pain results from a complex interplay of mechanical, biochemical, psychological, and social factors. Effective management is markedly different from that of acute musculoskeletal pain. Understanding the physiology of pain transmission, modulation, and perception is crucial for effective management. Pharmacologic and nonpharmacologic therapies such as psychotherapy and biofeedback exercises can be used to manage chronic pain. Evidence-based treatment recommendations have been made for chronic pain conditions frequently encountered by orthopaedic surgeons, including low back, osteoarthritic, posttraumatic, and neuropathic pain. Extended-release tramadol; select tricyclic antidepressants, serotonin reuptake inhibitors, and anticonvulsants; and topical medications such as lidocaine, diclofenac, and capsaicin are among the most effective treatments. However, drug efficacy varies significantly by indication. Orthopaedic surgeons should be familiar with the widely available safe and effective nonnarcotic options for chronic musculoskeletal pain. PMID- 24486757 TI - Composite bone models in orthopaedic surgery research and education. AB - Composite bone models are increasingly used in orthopaedic biomechanics research and surgical education-applications that traditionally relied on cadavers. Cadaver bones are suboptimal for many reasons, including issues of cost, availability, preservation, and inconsistency between specimens. Further, cadaver samples disproportionately represent the elderly, whose bone quality may not be representative of the greater orthopaedic population. The current fourth generation composite bone models provide an accurate reproduction of the biomechanical properties of human bone when placed under bending, axial, and torsional loads. The combination of glass fiber and epoxy resin components into a single phase has enabled manufacturing by injection molding. The high level of anatomic fidelity of the cadaver-based molds and negligible shrinkage properties of the epoxy resin results in a process that allows for excellent definition of anatomic detail in the cortical wall and optimized consistency of features between models. Recent biomechanical studies of composites have validated their use as a suitable substitute for cadaver specimens. PMID- 24486758 TI - Fresh osteochondral allograft transplantation for the knee: current concepts. AB - Fresh osteochondral allograft (OCA) transplantation has been used to manage a wide spectrum of chondral and osteochondral knee disorders. Basic science and clinical studies support the safety and efficacy of the procedure. Transplantation of viable, mature hyaline cartilage into the affected area is an advantage of the procedure, which can be used to restore bone stock in complex or salvage scenarios. Indications for OCA transplantation in the knee include primary management of large chondral or osteochondral defects and salvage of previously failed cartilage repair. The procedure also can be used for complex biologic knee reconstruction in the setting of osteonecrosis, fracture malunion, or posttraumatic arthritis. Challenges associated with OCA transplantation include allograft storage and size matching, tissue availability, chondrocyte viability, the possibility of immunologic graft response, and a demanding surgical technique. Future research should focus on optimizing allograft viability and healing and refining current surgical indications and techniques. PMID- 24486759 TI - Antisense-mediated exon skipping: taking advantage of a trick from Mother Nature to treat rare genetic diseases. AB - Rare diseases can be caused by genetic mutations that disrupt normal pre-mRNA splicing. Antisense oligonucleotide treatment to the splicing thus has therapeutic potential for many rare diseases. In this review we will focus on the state of the art on exon skipping using antisense oligonucleotides as a potential therapy for rare genetic diseases, outlining how this versatile approach can be exploited to correct for different mutations. PMID- 24486760 TI - miR-125b/Ets1 axis regulates transdifferentiation and calcification of vascular smooth muscle cells in a high-phosphate environment. AB - OBJECTIVES: Vascular calcification is highly prevalent in patients with chronic kidney disease (CKD) and contributes to increased risk of cardiovascular disease and mortality. Accumulated evidences suggested that vascular smooth muscle cells (VSMCs) to osteoblast-like cells transdifferentiation (VOT) plays a crucial role in promoting vascular calcification. MicroRNAs (miRNAs) are a novel class of small RNAs that negatively regulate gene expression via repression of the target mRNAs. In the present work, we sought to determine the role of miRNAs in VSMCs phenotypic transition and calcification induced by beta-glycerophosphoric acid. APPROACH AND RESULTS: Primary cultured rat aortic VSMCs were treated with beta glycerophosphoric acid for different periods of time. In VSMCs, after beta glycerophosphoric acid treatment, the expressions of cbf beta1, osteocalcin and osteopontin were significantly increased and SM-22beta expression was decreased. ALP activity was induced by beta-glycerophosphoric acid in a time or dose dependent manner. Calcium deposition was detected in VSMCs incubated with calcification media; then, miR-125b expression was detected by real-time RT PCR. miR-125b expression was significantly decreased in VSMCs after incubated with beta-glycerophosphoric acid. Overexpression of miR-125b could inhibit beta glycerophosphoric acid-induced osteogenic markers expression and calcification of VSMCs whereas knockdown of miR-125b promoted the phenotypic transition of VSMCs and calcification. Moreover, miR-125b targeted Ets1 and regulated its protein expression in VSMCs. Downregulating Ets1 expression by its siRNA inhibited beta glycerophosphoric acid-induced the VSMCs phenotypic transition and calcification. CONCLUSION: Our study suggests that down-regulation of miR-125b after beta glycerophosphoric acid treatment facilitates VSMCs transdifferentiation and calcification through targeting Ets1. PMID- 24486761 TI - A unique HEAT repeat-containing protein SHOOT GRAVITROPISM6 is involved in vacuolar membrane dynamics in gravity-sensing cells of Arabidopsis inflorescence stem. AB - Plant vacuoles play critical roles in development, growth and stress responses. In mature cells, vacuolar membranes (VMs) display several types of structures, which are formed by invagination and folding of VMs into the lumenal side and can gradually move and change shape. Although such VM structures are observed in a broad range of tissue types and plant species, the molecular mechanism underlying their formation and maintenance remains unclear. Here, we report that a novel HEAT-repeat protein, SHOOT GRAVITROPISM6 (SGR6), of Arabidopsis is involved in the control of morphological changes and dynamics of VM structures in endodermal cells, which are the gravity-sensing cells in shoots. SGR6 is a membrane associated protein that is mainly localized to the VM in stem endodermal cells. The sgr6 mutant stem exhibits a reduced gravitropic response. Higher plants utilize amyloplast sedimentation as a means to sense gravity direction. Amyloplasts are surrounded by VMs in Arabidopsis endodermal cells, and the flexible and dynamic structure of VMs is important for amyloplast sedimentation. We demonstrated that such dynamic features of VMs are gradually lost in sgr6 endodermal cells during a 30 min observation period. Histological analysis revealed that amyloplast sedimentation was impaired in sgr6. Detailed live-cell imaging analyses revealed that the VM structures in sgr6 had severe defects in morphological changes and dynamics. Our results suggest that SGR6 is a novel protein involved in the formation and/or maintenance of invaginated VM structures in gravity-sensing cells. PMID- 24486762 TI - Multiple BiP genes of Arabidopsis thaliana are required for male gametogenesis and pollen competitiveness. AB - Immunoglobulin-binding protein (BiP) is a molecular chaperone of the heat shock protein 70 (Hsp70) family. BiP is localized in the endoplasmic reticulum (ER) and plays key roles in protein translocation, protein folding and quality control in the ER. The genomes of flowering plants contain multiple BiP genes. Arabidopsis thaliana has three BiP genes. BIP1 and BIP2 are ubiquitously expressed. BIP3 encodes a less well conserved BiP paralog, and it is expressed only under ER stress conditions in the majority of organs. Here, we report that all BiP genes are expressed and functional in pollen and pollen tubes. Although the bip1 bip2 double mutation does not affect pollen viability, the bip1 bip2 bip3 triple mutation is lethal in pollen. This result indicates that lethality of the bip1 bip2 double mutation is rescued by BiP3 expression. A decrease in the copy number of the ubiquitously expressed BiP genes correlates well with a decrease in pollen tube growth, which leads to reduced fitness of mutant pollen during fertilization. Because an increased protein secretion activity is expected to increase the protein folding demand in the ER, the multiple BiP genes probably cooperate with each other to ensure ER homeostasis in cells with active secretion such as rapidly growing pollen tubes. PMID- 24486763 TI - Differential expression patterns of non-symbiotic hemoglobins in sugar beet (Beta vulgaris ssp. vulgaris). AB - Biennial sugar beet (Beta vulgaris spp. vulgaris) is a Caryophyllidae that has adapted its growth cycle to the seasonal temperature and daylength variation of temperate regions. This is the first time a holistic study of the expression pattern of non-symbiotic hemoglobins (nsHbs) is being carried out in a member of this group and under two essential environmental conditions for flowering, namely vernalization and length of photoperiod. BvHb genes were identified by sequence homology searches against the latest draft of the sugar beet genome. Three nsHb genes (BvHb1.1, BvHb1.2 and BvHb2) and one truncated Hb gene (BvHb3) were found in the genome of sugar beet. Gene expression profiling of the nsHb genes was carried out by quantitative PCR in different organs and developmental stages, as well as during vernalization and under different photoperiods. BvHb1.1 and BvHb2 showed differential expression during vernalization as well as during long and short days. The high expression of BvHb2 indicates that it has an active role in the cell, maybe even taking over some BvHb1.2 functions, except during germination where BvHb1.2 together with BvHb1.1-both Class 1 nsHbs-are highly expressed. The unprecedented finding of a leader peptide at the N-terminus of BvHb1.1, for the first time in an nsHb from higher plants, together with its observed expression indicate that it may have a very specific role due to its suggested location in chloroplasts. Our findings open up new possibilities for research, breeding and engineering since Hbs could be more involved in plant development than previously was anticipated. PMID- 24486765 TI - The ESCRT-III-interacting deubiquitinating enzyme AMSH3 is essential for degradation of ubiquitinated membrane proteins in Arabidopsis thaliana. AB - Post-translational modification by ubiquitin plays a key role in the regulation of endocytic degradation in which ubiquitinated plasma membrane cargos are transported to the vacuole for degradation dependent on the ESCRT (endosomal sorting complex required for transport) machinery. Arabidopsis AMSH3 (ASSOCIATED MOLECULE WITH THE SH3 DOMAIN OF STAM 3) is a deubiquitinating enzyme that interacts with at least two subunits of the ESCRT-III machinery, VPS2.1 and VPS24.1. amsh3 null mutation causes seedling lethality, and amsh3 null mutants show defects in multiple intracellular trafficking pathways. In this study, we further analyzed the amsh3 mutant phenotype and showed that amsh3 accumulates membrane-associated ubiquitinated proteins, supporting the indication that AMSH3 functions in ubiquitin-mediated endocytic degradation. In accordance with this, an enzymatic inactive variant of AMSH3 inhibits the AvrPtoB-dependent endocytic degradation of CERK1 (CHITIN ELICITOR RECEPTOR KINASE 1). Furthermore, we showed that the interaction of AMSH3 with ESCRT-III is important for its function in planta. Together, our data indicate the importance of AMSH3 and the AMSH3-ESCRT III interaction for deubiquitination and degradation of ubiquitinated membrane substrates in plants. PMID- 24486764 TI - Suppression of NDA-type alternative mitochondrial NAD(P)H dehydrogenases in arabidopsis thaliana modifies growth and metabolism, but not high light stimulation of mitochondrial electron transport. AB - The plant respiratory chain contains several pathways which bypass the energy conserving electron transport complexes I, III and IV. These energy bypasses, including type II NAD(P)H dehydrogenases and the alternative oxidase (AOX), may have a role in redox stabilization and regulation, but current evidence is inconclusive. Using RNA interference, we generated Arabidopsis thaliana plants simultaneously suppressing the type II NAD(P)H dehydrogenase genes NDA1 and NDA2. Leaf mitochondria contained substantially reduced levels of both proteins. In sterile culture in the light, the transgenic lines displayed a slow growth phenotype, which was more severe when the complex I inhibitor rotenone was present. Slower growth was also observed in soil. In rosette leaves, a higher NAD(P)H/NAD(P)+ ratio and elevated levels of lactate relative to sugars and citric acid cycle metabolites were observed. However, photosynthetic performance was unaffected and microarray analyses indicated few transcriptional changes. A high light treatment increased AOX1a mRNA levels, in vivo AOX and cytochrome oxidase activities, and levels of citric acid cycle intermediates and hexoses in all genotypes. However, NDA-suppressing plants deviated from the wild type merely by having higher levels of several amino acids. These results suggest that NDA suppression restricts citric acid cycle reactions, inducing a shift towards increased levels of fermentation products, but do not support a direct association between photosynthesis and NDA proteins. PMID- 24486766 TI - A novel AP2-type transcription factor, SMALL ORGAN SIZE1, controls organ size downstream of an auxin signaling pathway. AB - The organ size of flowering plants is determined by two post-embryonic developmental events: cell proliferation and cell expansion. In this study, we identified a new rice loss-of-function mutant, small organ size1 (smos1), that decreases the final size of various organs due to decreased cell size and abnormal microtubule orientation. SMOS1 encodes an unusual APETALA2 (AP2)-type transcription factor with an imperfect AP2 domain, and its product belongs to the basal AINTEGUMENTA (ANT) lineage, including WRINKLED1 (WRI1) and ADAP. SMOS1 expression was induced by exogenous auxin treatment, and the auxin response element (AuxRE) of the SMOS1 promoter acts as a cis-motif through interaction with auxin response factor (ARF). Furthermore, a functional fluorophore-tagged SMOS1 was localized to the nucleus, supporting the role of SMOS1 as a transcriptional regulator for organ size control. Microarray analysis showed that the smos1 mutation represses expression of several genes involved in microtubule based movement and DNA replication. Among the down-regulated genes, we demonstrated by gel-shift and chromatin immunoprecipitation (ChIP) experiments that OsPHI-1, which is involved in cell expansion, is a target of SMOS1. SMOS1 homologs in early-diverged land plants partially rescued the smos1 phenotype of rice. We propose that SMOS1 acts as an auxin-dependent regulator for cell expansion during organ size control, and that its function is conserved among land plants. PMID- 24486767 TI - How social neuroscience can inform theories of social comparison. AB - Social comparison pervades our interactions with others, informing us of our standing and motivating improvement, but producing negative emotional and behavioral consequences that can harm relationships and lead to poor health outcomes. Social neuroscience research has begun to illuminate some mechanisms by which status divides lead to interpersonal consequences. This review integrates core findings on the neuroscience of social comparison processes, showing the effects of comparing the self to relevant others on dimensions of competence and warmth. The literature converges to suggest that relative status divides initiate social comparison processes, that upward and downward comparisons initiate pain- and pleasure-related neural responses, and that these responses can predict people's kindly or aggressive intentions toward one another. Across different types of comparisons, brain regions involved in mentalizing are also sometimes involved. Along with future work, the research reviewed here may inform efforts to mitigate negative outcomes of constant social comparisons. PMID- 24486768 TI - Cognitive and neural foundations of discrete sequence skill: a TMS study. AB - Executing discrete movement sequences typically involves a shift with practice from a relatively slow, stimulus-based mode to a fast mode in which performance is based on retrieving and executing entire motor chunks. The dual processor model explains the performance of (skilled) discrete key-press sequences in terms of an interplay between a cognitive processor and a motor system. In the present study, we tested and confirmed the core assumptions of this model at the behavioral level. In addition, we explored the involvement of the pre supplementary motor area (pre-SMA) in discrete sequence skill by applying inhibitory 20 min 1-Hz off-line repetitive transcranial magnetic stimulation (rTMS). Based on previous work, we predicted pre-SMA involvement in the selection/initiation of motor chunks, and this was confirmed by our results. The pre-SMA was further observed to be more involved in more complex than in simpler sequences, while no evidence was found for pre-SMA involvement in direct stimulus response translations or associative learning processes. In conclusion, support is provided for the dual processor model, and for pre-SMA involvement in the initiation of motor chunks. PMID- 24486769 TI - Modeling injury rates as a function of industrialized versus on-site construction techniques. AB - It is often predicted that the industrialization of building activities will lead to a reduction of accident rates in the construction sector, particularly as a result of switching activities from building sites to factories. However, to date no scientific research has provided objective quantitative results to back up this claim. The aim of this paper is to evaluate how industrialization affects the accident rate in different industrialized building systems in Spain. Our results revealed that the industrialized steel modular system presents the lowest accident rate, while the highest accident rate was recorded in the construction method with cast-in-place concrete. The lightweight construction system also presents a high accident rate. Accordingly, industrialized building systems cannot claim to be safer than traditional ones. The different types of "on-site work" seem to be the main variable which would explain the accident rates recorded in industrialized construction systems. PMID- 24486770 TI - Vertebral fractures in motor vehicle accidents - a medical and technical analysis of 33,015 injured front-seat occupants. AB - Spinal injuries pose a considerable risk to life and quality of life. In spite of improvements in active and passive safety of motor vehicles, car accidents are regarded as a major cause for vertebral fractures. The purpose of this study was to evaluate the current incidence of vertebral fractures among front-seat occupants in motor vehicle accidents, and to identify specific risk factors for sustaining vertebral fractures in motor vehicle accidents. Data from an accident research unit were accessed to collect collision details, preclinical data, and clinical data. We included all data on front-seat occupants. Hospital records were retrieved, and radiological images were evaluated. We analysed 33,015 front seat occupants involved in motor vehicle accidents over a 24-year period. We identified 126 subjects (0.38%) with cervical spine fractures, 78 (0.24%) with thoracic fractures, and 99 (0.30%) with lumbar fractures. The mean relative collision speeds were 48, 39, and 40 kph in subjects with cervical, thoracic, and lumbar spine fractures, respectively, while it was 17.3 kph in the whole cohort. Contrary to the overall cohort, these patients typically sustained multiple hits rather than simple front collisions. Occupants with vertebral fractures frequently showed numerous concomitant injuries; for example, additional vertebral fractures. The incidence of vertebral fractures corresponded with collision speed. Safety belts were highly effective in the prevention of vertebral fractures. Apart from high speed, complex injury mechanisms as multiple collisions or rollovers were associated with vertebral fractures. Additional preventive measures should focus on these collision mechanisms. PMID- 24486771 TI - Factors affecting the probability of bus drivers being at-fault in bus-involved accidents. AB - Previous research has provided little insight into factors that influence the probability of bus drivers being at-fault in bus-involved accidents. In this study, an analysis was conducted on accident data compiled by a bus company that include an assessment on whether the bus driver was deemed by the company to hold primary responsibility for accident occurrence. Using a mixed logit modelling approach, roadway/environmental, vehicle and driver related variables that were identified to be influential were road type, speed limit, traffic/lighting conditions, bus priority, bus age/length and driver's age/gender/experience/historic at-fault accident record. Results were indicative of possible confined road-space issues that bus drivers face along routes with roadside traffic friction and point to the provision of exclusive right of way for buses as a possible way to address this. Results also suggest benefits in assigning routes comprising mainly divided roads as well as newer and shorter buses to less experienced drivers. PMID- 24486772 TI - A novel missense mutation in CACNA1A evaluated by in silico protein modeling is associated with non-episodic spinocerebellar ataxia with slow progression. AB - Spinocerebellar ataxia type 6 (SCA6), episodic ataxia type 2 (EA2) and familial hemiplegic migraine type 1 (FHM1) are allelic disorders of the gene CACNA1A encoding the P/Q subunit of a voltage gated calcium channel. While SCA6 is related to repeat expansions affecting the C-terminal part of the protein, EA2 and FHM phenotypes are usually associated with nonsense and missense mutations leading to impaired channel properties. In three unrelated families with dominant cerebellar ataxia, symptoms cosegregated with CACNA1A missense mutations of evolutionary highly conserved amino acids (exchanges p.E668K, p.R583Q and p.D302N). To evaluate pathogenic effects, in silico, protein modeling analyses were performed which indicate structural alterations of the novel mutation p.E668K within the homologous domain 2 affecting CACNA1A protein function. The phenotype is characterised by a very slowly progressive ataxia, while ataxic episodes or migraine are uncommon. These findings enlarge the phenotypic spectrum of CACNA1A mutations. PMID- 24486773 TI - A novel heterozygous mutation of three consecutive nucleotides causing Apert syndrome in a Congolese family. AB - Apert syndrome (OMIM 101200) is a rare genetic condition characterized by craniosynostosis and syndactyly of hands and feet with clinical variability. Two single nucleotides mutations in the linker region between the immunoglobulin-like domains II and IIIa of the ectodomainin the Fibroblast Growth Factor Receptor 2 gene (FGFR2, OMIM 176943) are responsible of the vast majority of cases: c.755C > G; p.Ser252Trp (65%) and c.758C > G; p.Pro253Arg (34%. Three exceptional cases carry multiple substitutions of adjacent nucleotides in the linker region. Here we present a Congolese male patient and his mother, both affected with Apert syndrome of variable severity, carrying a previously undescribed heterozygous mutation of three consecutive nucleotides (c.756_758delGCCinsCTT) in the IgII IgIIIa linker region. This is the fourth live-born patient to carry a multiple nucleotide substitution in the linker region and is the second alternative amino acid substitutions of the Pro253. Remarkably, this novel mutation was detected in the first Central African patient ever to be tested molecularly for the Apert syndrome. To discriminate between a hitherto unreported mutation and an ethnic specific polymorphism, we tested 105 Congolese controls, and no variation was detected. PMID- 24486774 TI - SALL4 and NFATC2: two major actors of interstitial 20q13.2 duplication. AB - Interstitial duplication within the long arm of chromosome 20 is an uncommon chromosome structural abnormality. We report here the clinical and molecular characterization associated with pure 20q13.2 duplication in three unrelated patients. The most frequent clinical features were developmental delay, facial dysmorphism, cardiac malformation and skeletal anomalies. All DNA gains occurred de novo, ranging from 1.1 Mb to 11.5 Mb. Compared with previously reported conventional cytogenetic analyses, oligonucleotides array CGH allowed us to refine breakpoints and determine the genes of interest in the region. Involvement of SALL4 in cardiac malformations and NFATC2 gene disruption in both cardiac and skeletal anomalies are discussed. PMID- 24486775 TI - Genomic analysis of the interactions between social environment and social communication systems in honey bees (Apis mellifera). AB - Social context is often a primary regulator of social behavior, but genes that affect or are affected by social context have rarely been investigated. In social insects, caste specific pheromones are key modulators of social behavior, e.g., in honey bees the queen mandibular gland (MG) pheromone mediates reproductive dominance, its absence prompting ovary activation and queen pheromone production in workers. Here, we investigate the effect of social environment on genome-wide expression patterns in the MG, to determine how social context modulates expression of genes that, in turn alter social environment. We used microarrays to examine the MGs of virgin and mated queens, and queenright (QR) and queenless (QL) workers with or without activated ovaries. Approximately 2554 transcripts were significantly differentially expressed among these groups, with caste and social context being the main regulators of gene expression patterns, while physiological state (ovary activation) only minimally affecting gene expression. Thus, social context strongly regulates expression of genes, which, in turn, shape social environment. Among these, 25 genes that are putatively involved in caste selective production of the fatty-acid derived MG pheromone were differentially expressed in queens and workers. These genes whose functions correspond with enzymatic or transport processes emphasize the occurrence of disparate pheromone biosynthetic pathways for queens and workers, adding another dimension regarding the regulation of these important pheromones. Gene ontology analysis also revealed genes of different functional categories whose expression was impacted by caste or by the social environment, suggesting that the MG has broader functions than pheromone biosynthesis. PMID- 24486776 TI - Developmental neurotoxicity of ortho-phthalate diesters: review of human and experimental evidence. AB - Ortho-phthalate diesters, or phthalates, are widely used synthetic chemicals found primarily in consumer products and polyvinyl chloride plastics. Experimental evidence suggests that several phthalates possess antiandrogenic properties and may disrupt endocrine pathways resulting in abnormal reproductive outcomes. Low-level exposure to phthalates has been well documented in humans, with higher levels found in children and women of childbearing age. Recent epidemiologic studies postulate that prenatal exposure to measurable urine phthalate concentrations may be associated with altered genital and pubertal development in infants and children. This review addresses the emerging evidence that some phthalates may have an adverse impact on the developing brain. The supporting animal studies and proposed mechanisms underlying the deleterious properties of phthalates in relation to neurodevelopmental outcomes are also discussed. While the observed associations are based on limited studies with a broad range of endpoints, the implications of such outcomes are of concern from a public health standpoint and merit further investigation given the widespread nature of the exposure. PMID- 24486777 TI - Trans-oral brush biopsies and quantitative PCR for EBV DNA detection and screening of nasopharyngeal carcinoma. AB - OBJECTIVES: To evaluate a newly developed noninvasive ambulatory, quantitative polymerase chain reaction (Q-PCR) Epstein-Barr virus (EBV) DNA detection and screening system (NP ScreenTM) for nasopharyngeal carcinoma (NPC). STUDY DESIGN: Correlation of the nasopharyngeal epithelial EBV-DNA levels and clinical findings by nasopharyngoscopy and final pathologic diagnosis of NPC with biopsy. SETTING: Multicenter ENT/Oncology clinics in Hong Kong (Radiation Oncology Clinic at the Queen Elizabeth Hospital and Radiation Oncology Clinic and Head and Neck Clinic, Queen Mary Hospital, University of Hong Kong) and in Toronto, Canada (the Otolaryngology-Head and Neck Clinic at the Rouge Valley Health System and 2 large ENT practices in Toronto). METHODS: A single-use trans-oral brush was used for rapid, nontraumatic nasopharyngeal (NP) epithelial cells DNA harvest in 600 Chinese patients, combined with a preservation and shipping kit for remote, real time Q-PCR EBV DNA determinations. RESULTS: All 600 patients had NP brushings using NP Screen in an ambulatory environment, and no adverse events or complications were recorded. A final 578 patients were included with sufficient amount of DNA for completion of the Q-PCR assay. Of these 578 patients, 94 were confirmed positive for NPC histologically. The study yielded a sensitivity of 98.9%, specificity of 99.3%, positive predictive value (PPV) of 96.9%, and negative predictive value (NPP) of 99.7% for NP Screen in detecting NPC. Endoscopy had a sensitivity of 94%, specificity 97.1%, PPV 85%, and NPP 98.9%. CONCLUSIONS: The trans-oral brushing system fulfills the characteristics of a noninvasive, sensitive, specific detection method suitable for routine, large scale ambulatory NPC risk assessment for high-risk NPC populations. PMID- 24486778 TI - Patients with pediatric obstructive sleep apnea show altered T-cell populations with a dominant TH17 profile. AB - OBJECTIVE: To characterize the immunologic changes of the tonsil as they correlate with increasing apnea-hypopnea index (AHI) in children. STUDY DESIGN: Prospective immunologic analysis. SETTING: Tertiary care pediatric otolaryngology practice. SUBJECTS: Tonsils were collected from 24 children with obstructive sleep apnea, all of whom had undergone polysomnography at an accredited sleep center using scoring determined by the American Academy of Sleep Medicine 2007 scoring manual. Patients were excluded if they had been diagnosed with craniofacial abnormalities, neuromuscular disorders, or immunodeficiency. METHODS: Single-cell suspensions were isolated from tonsils of 13 individuals and stained with fluor-conjugated antibodies and analyzed using fluorescence activated cell sorting. Single-cell suspensions from tonsils of 11 additional individuals were incubated 21 hours and subjected to multiplexed enzyme-linked immunosorbent assay cytokine analysis. RESULTS: In patients with an AHI >5 events/h, there was a statistically significant increase in the fraction of CD4(+) CD45RO(+) T cells (P < .01), and the percentage of CD8(+) FoxP3(+) T cells (TcREG) showed a statistically significant decrease (P < .005). Cytokine analysis revealed high levels of interleukin (IL)-17A, IL-1b, IL-10, and IL-12p70 production. Cytokine profiles revealed a conspicuous absence of IL-4 and IL-2. CONCLUSIONS: Our results indicate the tonsils of patients with obstructive sleep apnea have an ongoing inflammatory response characterized by increased effector CD4 T cells and decreased FoxP3 CD8 T cells. The TH17 skewing suggests that local immune activation may be either autoimmune or due to an extracellular pathogen. PMID- 24486779 TI - Craniofacial pain secondary to occult head and neck tumors. AB - OBJECTIVES: To review the natural history of occult head and neck malignancy presenting with facial pain and evaluate the risk factors, diagnostic workup, and management of facial pain in the setting of occult malignancy. STUDY DESIGN: Retrospective chart review. SETTING: Tertiary care center. SUBJECTS AND METHODS: All patients presenting from 1980 to 2010 with facial pain and a delayed diagnosis of a head and neck cancer were reviewed. RESULTS: Thirty-eight patients were included. Onset of pain was rapid or sudden in 94.7%, intermittent in 84.2%, and sharp in 86.8%. Facial nerve weakness was present in 15.8%. Five patients had a history of locoregional skin cancer, and 14% had a history of malignancy. Average delay to diagnosis was 18.4 months. On average, the suspicious lesion was identified on the second scan (mean, 2.1; range, 1-4 scans). Diagnosis was suggested by magnetic resonance imaging in 54.8% and computed tomography in 38.7% of patients. The most common pathology was squamous cell carcinoma (39.5%), and the predominant location was the parotid gland (28.9%). Surgical resection (66%) was the most common intervention. In patients who received treatment and had clinical follow-up available for review, 97.0% (32/33) reported symptomatic improvement. CONCLUSIONS: In our series, sudden-onset, intermittent, sharp facial pain without resolution or improvement was associated with occult malignancy and should be considered in the differential diagnosis for facial pain. Based on the high incidence of early negative imaging, consideration should be given to repeat imaging when there is concern for malignancy. Therapeutic interventions often result in improvement of facial pain. PMID- 24486781 TI - Cooperation between medicine and sociology in head and neck oncology. AB - Twenty-first-century medicine is facing many challenges--knowledge and command of technical advances, research development, team management, knowledge transmission, and adaptation to economic constraints--without neglecting "human" aspects, via transformed carer-patient relationships, social change, and so on. The "modern" physicians know that simply treating disease is no longer enough. One of their essential missions lies in offering the individual patient overall care, which implies acknowledging the latter as an individual within a family, social, and professional environment. Indeed, medical practice requires pluridimensional knowledge of the patients' experience of their disease. Yet the contribution sociology can offer to health care remains largely unknown to many physicians, and medical training includes only limited instruction in the human sciences. On the basis of a few observations taken from sociological research, we would like to demonstrate how, in head and neck oncology, interdisciplinary collaboration between medicine and sociology can prove propitious to improving patient care and attention to their close relations. PMID- 24486780 TI - Quantitative video laryngoscopy to monitor recovery from recurrent laryngeal nerve injury in the rat. AB - Recovery from unilateral vocal-fold paralysis is lengthy, unpredictable, and often incomplete, highlighting the need for better treatments of the injured recurrent laryngeal nerve. To be able to monitor recovery of vocal-fold motion in studies with rats, we developed a procedure for quantitative video laryngoscopy. An asymmetry index was defined as a continuous and robust measure of unequal vocal-fold motion and calculated from spectral-density plots of vocal-fold displacements. In a cohort of 8 animals, unilateral vocal-fold paralysis was observed within seconds after clamping of the right recurrent laryngeal nerve and was accompanied by a markedly negative asymmetry index. Over the next month, the asymmetry index gradually returned to zero, concomitant with a visible recovery of vocal-fold motion. Our results suggest that quantitative video laryngoscopy is a sensitive and discriminating method for monitoring recovery from recurrent laryngeal nerve injury and set the stage for testing novel surgical and pharmacological treatments of unilateral vocal-fold paralysis. PMID- 24486782 TI - Z-plasty of the alar subunit to correct nasal vestibular stenosis. AB - Nasal vestibular stenosis can result in a challenging cosmetic deformity, for which a variety of techniques have been described, including scar excision and replacement with local flaps, composite or cartilage grafts, with or without stents. We describe the Z-plasty technique to widen the alar base and assess patient satisfaction from the surgery. A retrospective review of patients who underwent Z-plasty to the alar subunit for nasal vestibular stenosis over a 4 year period was conducted. Demographic data and patient satisfaction were evaluated using pre- and postoperative visual analog scores and Rhinoplasty Outcome Evaluation questionnaires. Eight patients underwent the procedure, and all confirmed significant improvement in their esthetic outcome. We describe our Z-plasty technique to the alar base and review patient satisfaction. PMID- 24486783 TI - Displacement of Residual Gore-Tex Thyroplasty Implant Presenting as a True Vocal Fold Mass. PMID- 24486784 TI - Comparison of early oncological results of diode laser surgery with radiotherapy for early glottic carcinoma. AB - OBJECTIVE: To evaluate the oncologic results of transoral endolaryngeal microscopic diode laser surgery (MDLS) and radiotherapy (RT) for T1 and T2 glottic carcinoma. STUDY DESIGN: Case series with planned chart review. SETTING: Ankara Oncology Education and Research Hospital. SUBJECTS AND METHODS: The study was conducted on a series of 140 cases of early glottic carcinoma (T1, T2) treated with MDLS or RT. The tumors were defined according to T stage and the involvement of the anterior commissure (AC). RESULTS: The 3-year locoregional control rate of MDLS and RT groups was 93.1% and 89.7%, respectively (P = .434). There was no difference in 3-year disease-free survival when comparing T1 and T2 tumors treated with MDLS and those treated with RT (P = .618 for T1, P = .084 for T2). There was no difference in disease-free survival when comparing AC- and AC+ tumors treated with MDLS and those treated with RT (P = .291 for AC- and P = .530 for AC+ tumors). CONCLUSIONS: Microscopic diode laser surgery in early glottic cancer seems to be an oncologically safe procedure that has similar oncological results with RT. In T2 glottic tumors and AC involvement, the results with either treatment are less satisfactory. PMID- 24486785 TI - Development of on-line spectroscopic determination approach of dispersive liquid liquid microextraction based on an effective device. AB - A novel, rapid, simple, and low-cost on-line determination approach of dispersive liquid-liquid microextraction (DLLME) with low-density solvents was developed with the support of a specially designed effective homemade device. The proposed method surmounted the drawbacks of conventional DLLME of the need of high-density solvents as extractants, and the requirement of centrifugation operation to obtain phase separation, and the difficulties to realize on-line determination. The amount of sample utilized can conveniently change according to practical needs by varying the volume of the extraction tube of the device to perform a more effective DLLME. A case study was carried out to assess this method utilizing the dye rhodamine B as the model analyte. The experiment parameters influencing the extraction were systematically investigated. Under optimum conditions, the linearity was obtained in the range of 0.015-1.000 MUg/mL with the correlation coefficient (r(2)) of 0.9980. The limit of detection and quantification were 6.1 and 20.4 MUg/L, respectively. Good repeatability was achieved with the relative standard deviations (RSD) for five replicate measurements of different concentration samples less than 4.06%, and the presented method was successfully employed to quantify rhodamine B in three real samples. PMID- 24486786 TI - Interactions of ruthenium complexes containing indoloquinoline moiety with human telomeric G-quadruplex DNA. AB - G-quadruplex structures are attractive targets for the development of anticancer drugs, as their formation in human telomere could impair telomerase activity, thus inducing apoptosis in cancer cells. Vast majority of G-quadruplex binding molecules have been designed and synthesized. Ruthenium complexes have also been reported to induction or stabilization of G-quadruplex structure of human telomeric sequence, whereas most of them generally promote the formation of antiparallel or hybrid-type G-quadruplex structure. Ruthenium complex that selectively promotes the formation of parallel G-quadruplex structure has rarely been reported. We reported here the interaction of two ruthenium complexes [Ru(bpy)2(mitatp)](2+)1 and [Ru(phen)2(mitatp)](2+)2 (bpy=2,2' bipyridine, phen=1,10-phenanthroline, mitatp=5-methoxy-isatino[1,2-b]-1,4,8,9 tetraazatriphenylene) containing indoloquinoline moiety with human telomeric G quadruplex DNA (Telo22). Complex 1 binds to Telo22 tightly via a stable pi-pi stacking interaction and efficiently stabilizes the G-quadruplex structure. Circular dichroism (CD) spectra titration results suggest that complex 1 could induce Telo22 to fold into antiparallel G-quadruplex conformation. Complex 2 exhibits moderate G-quadruplex binding and stabilizing ability, while CD titration data reveals that complex 2 could promote the formation of parallel G quadruplex structure. PMID- 24486787 TI - Molecular structure, Mulliken charge, frontier molecular orbital and first hyperpolarizability analysis on 2-nitroaniline and 4-methoxy-2-nitroaniline using density functional theory. AB - In the present study, we made an attempt to calculate the energy gap, molecular dipole moment and first hyperpolarizability of 2-nitroaniline (2NA) and 4-methoxy 2-nitroaniline (4M2N) with a basis set 6-31G (d, p) function has been employed at density functional theory (DFT) methods. Geometry optimizations was carried out with DFT-B3LYP/6-31G (d, p), the results have revealed that intramolecular hydrogen bonding present in both the molecular system. We analyzed the energy gap, molecular dipole moment and hyperpolarizability changes due to substitution effect of the methoxy group in 2NA molecule. It is confirmed that strong electron acceptor and donor groups in a material yield higher NLO response. PMID- 24486788 TI - Surface enhanced Raman scattering (SERS) of silver ions embedded nanocomposite glass. AB - Silver nanocomposites (Ag-NCs) glasses are formed by the ion exchange technique of dipping the host matrix in the molten metal salt bath. These ions exchanged glasses are then annealed at different temperatures in air for one hour. They exhibit striking linear and nonlinear optical properties with potential applications in the field of photonics materials. The optical absorption spectra of Ag ion exchanged and annealed glasses confirm the presence of the nano sized metal (Ag) cluster embedded inside the glass matrix. The size and morphology of the embedded silver nanoclusters are studied from their surface plasmon resonance (SPR) and surface enhanced Raman spectroscopy (SERS). Post Ag ion exchange made some structural changes in the soda lime glass which can be observed from Raman spectroscopy. It is observed that diffusion process lead to depolymerization of the glass network as it determined by analyzing the various peaks of SERS spectra. Significant enhancement in the Raman signal by these Ag-NCs, prove them as effective SERS substrates. PMID- 24486789 TI - Infants' ability to associate motion paths with object kinds. AB - The goal of the present research was to examine whether infants associate different paths of motion with animate beings and inanimate objects. An infant controlled habituation procedure was used to examine 10-20-month-old infants' ability to associate a non-linear motion path (jumping) with animals and a linear (rebounding) motion path with vehicles (Experiment 1) and furniture (Experiment 2). During the habituation phase, infants saw a dog jumping over a barrier and either a vehicle or a piece of furniture rebounding off the barrier. In the test phase, infants looked longer when another inanimate object jumped rather than rebounded, but showed no such differential looking in the case of another animate object. The ability to restrict the animate motion path of jumping to animate beings was present by 10 months of age. The present findings support the hypothesis that motion path is associated with the animate-inanimate distinction early in infancy. PMID- 24486790 TI - High level soluble expression, purification, and characterization of human ciliary neuronotrophic factor in Escherichia coli by single protein production system. AB - Ciliary neurotrophic factor (CNTF) is characterized as a neuropoietic cytokine for a broad spectrum of neurons, leading to its evaluation in humans suffering from neurodegenerative diseases. Due to its wide range of biological applications, high yield production of soluble biologically active recombinant human CNTF (rhCNTF) in heterologous expression system is demanded. Many attempts had been undertaken to product rhCNTF in Escherichia coli (E. coli), however, the expression level of rhCNTF was low and most of which formed insoluble inclusion bodies. In this study, we described a new and efficient method to express rhCNTF. The human CNTF gene was codon optimized and then expressed by the single protein production (SPP) expression system in E. coli. The results showed that rhCNTF was expressed as a soluble biologically active protein, and upon purification, the final yield was about 250 mg/L in shake flask with a specific neuroprotective activity in Abeta-induced SH-SY5Y cell injury model. Our study might open up a new strategy for large-scale production of functional rhCNTF for clinical applications as well as basic research. PMID- 24486791 TI - Tissue-specific aging: a tale of functional asymmetry. PMID- 24486792 TI - A smoking gun? Epigenetic markers of tobacco use history. PMID- 24486793 TI - Role of Ca2+ -dependent and Ca2+ -sensitive mechanisms in sphingosine 1-phosphate induced constriction of isolated porcine retinal arterioles in vitro. AB - Although sphingosine 1-phosphate (S1P), a bioactive lipid derived from activated platelets, has a variety of physiologic effects on vessels, no reports have described the effect of S1P on the retinal circulation. We examined the effect and underlying mechanism of the vasomotor action of S1P on porcine retinal arterioles. The porcine retinal arterioles were isolated, cannulated, and pressurized without flow for in vitro study. S1P-induced diameter changes were recorded using videomicroscopic techniques. S1P elicited concentration-dependent (1 nM-10 MUM) vasoconstriction of the retinal arterioles that was abolished by the S1P receptor 2 (S1PR2) antagonist JTE-013. S1P-induced vasoconstriction was abolished by the Rho kinase (ROCK) inhibitor H-1152 and was inhibited partly by the protein kinase C (PKC) inhibitor Go-6983. The inhibition of phospholipase C by U73122 and L-type voltage-operated calcium channels (L-VOCCs) by nifedipine inhibited S1P-induced vasoconstriction; a combination of both inhibitors abolished S1P-induced vasoconstriction. Furthermore, inhibition of myosin light chain kinase (MLCK) by ML-9 significantly blocked S1P-induced vasoconstriction; further coadministration of ML-9 with H-1152 or Go-6983 abolished S1P-induced vasoconstriction. The current data suggest that S1P elicits vasoconstriction of the retinal arterioles via S1PR2 in vascular smooth muscle cells and this vasoconstriction may be mediated by the Ca2+ -sensitive pathway via activation of PKC leading to activation of ROCK and the Ca2+ -dependent pathway via activation of L-VOCCs resulting in activation of MLCK. PMID- 24486795 TI - Patients' resuscitation preferences in context: lessons from POLST. PMID- 24486796 TI - Microbial Baeyer-Villiger oxidation of 5alpha-steroids using Beauveria bassiana. A stereochemical requirement for the 11alpha-hydroxylation and the lactonization pathway. AB - Beauveria bassiana KCH 1065, as was recently demonstrated, is unusual amongst fungal biocatalysts in that it converts C19 3-oxo-4-ene and 3beta-hydroxy-5-ene as well as 3beta-hydroxy-5alpha-saturated steroids to 11alpha-hydroxy ring-D lactones. The Baeyer-Villiger monooxygenase (BVMO) of this strain is distinguished from other enzymes catalyzing BVO of steroidal ketones by the fact that it oxidizes solely substrates with 11alpha-hydroxyl group. The current study using a series of 5alpha-saturated steroids (androsterone, 3alpha-androstanediol and androstanedione) has highlighted that a small change of the steroid structure can result in significant differences of the metabolic fate. It was found that the 3alpha-stereochemistry of hydroxyl group restricted "normal" binding orientation of the substrate within 11alpha-hydroxylase and, as a result, androsterone and 3alpha-androstanediol were converted into a mixture of 7beta-, 11alpha- and 7alpha-hydroxy derivatives. Hydroxylation of androstanedione occurred only at the 11alpha-position, indicating that the 3-oxo group limits the alternative binding orientation of the substrate within the hydroxylase. Only androstanedione and 3alpha-androstanediol were metabolized to hydroxylactones. The study uniquely demonstrated preference for oxidation of equatorial (11alpha-, 7beta-) hydroxyketones by BVMO from B. bassiana. The time course experiments suggested that the activity of 17beta-HSD is a factor determining the amount of produced ring-D lactones. The obtained 11alpha-hydroxylactones underwent further transformations (oxy-red reactions) at C-3. During conversion of androstanedione, a minor dehydrogenation pathway was observed with generation of 11alpha,17beta dihydroxy-5alpha-androst-1-en-3-one. The introduction of C1C2 double bond has been recorded in B. bassiana for the first time. PMID- 24486794 TI - Lipid-protein interactions in plasma membranes of fiber cells isolated from the human eye lens. AB - The protein content in human lens membranes is extremely high, increases with age, and is higher in the nucleus as compared with the cortex, which should strongly affect the organization and properties of the lipid bilayer portion of intact membranes. To assess these effects, the intact cortical and nuclear fiber cell plasma membranes isolated from human lenses from 41- to 60-year-old donors were studied using electron paramagnetic resonance spin-labeling methods. Results were compared with those obtained for lens lipid membranes prepared from total lipid extracts from human eyes of the same age group [Mainali, L., Raguz, M., O'Brien, W. J., and Subczynski, W. K. (2013) Biochim. Biophys. Acta]. Differences were considered to be mainly due to the effect of membrane proteins. The lipid bilayer portions of intact membranes were significantly less fluid than lipid bilayers of lens lipid membranes, prepared without proteins. The intact membranes were found to contain three distinct lipid environments termed the bulk lipid domain, boundary lipid domain, and trapped lipid domain. However, the cholesterol bilayer domain, which was detected in cortical and nuclear lens lipid membranes, was not detected in intact membranes. The relative amounts of bulk and trapped lipids were evaluated. The amount of lipids in domains uniquely formed due to the presence of membrane proteins was greater in nuclear membranes than in cortical membranes. Thus, it is evident that the rigidity of nuclear membranes is greater than that of cortical membranes. Also the permeability coefficients for oxygen measured in domains of nuclear membranes were significantly lower than appropriate coefficients measured in cortical membranes. Relationships between the organization of lipids into lipid domains in fiber cells plasma membranes and the organization of membrane proteins are discussed. PMID- 24486797 TI - The lysine-specific demethylase 1 is a novel substrate of protein kinase CK2. AB - Protein kinase CK2 is a pleiotropic serine/threonine kinase responsible for the generation of a substantial proportion of the human phosphoproteome. CK2 is generally found as a tetramer with two catalytic, alpha and alpha' and two non catalytic beta subunits. CK2alpha C-terminal tail phosphorylation is regulated during the mitotic events and the absence of these phosphosites in alpha' suggests an isoform specialization. We used a proteomic approach to identify proteins specifically phosphorylated by a CK2alpha phosphomimetic mutant, CK2alphaT344ET360ES362ES370E (CK2alpha4E), in human neuroblastoma SKNBE cellular extract. One of these proteins is lysine-specific demethylase 1 (LSD1 or KDM1A), an important player of the epigenetic machinery. LSD1 is a FAD-dependent amine oxidase and promotes demethylation of lysine 4 and lysine 9 of mono- and di methylated histone H3. We found that LSD1 is a new substrate and an interacting partner of protein kinase CK2. Three CK2 phosphosites, (Ser131, Ser137 and Ser166) in the N-terminal region of LSD1 have been identified. This domain is found in all chordates but not in more ancient organisms and it is not essential for LSD1 catalytic event while it could modulate the interaction with CK2 and with other partners in gene repressing and activating complexes. Our data support the view that the phosphorylation of the N-terminal domain by CK2 may represent a mechanism for regulating histone methylation, disclosing a new role for protein kinase CK2 in epigenetics. PMID- 24486798 TI - Structural features important for differences in protein partitioning in aqueous dextran-polyethylene glycol two-phase systems of different ionic compositions. AB - Partitioning of 15 proteins in dextran-70-polyethylene glycol (PEG)-8000 aqueous two-phase systems (ATPSs) in the presence of 0.01M sodium phosphate buffer, pH7.4 was studied. The effect of salt additives (NaCl, CsCl, Na2SO4, NaClO4 and NaSCN) at different concentrations on the protein partition behavior was examined. The salt effects on protein partitioning were analyzed by using the Collander solvent regression relationship between the protein partition coefficients in ATPSs with and without salt additives. The results obtained show that the presence and concentration of salt additives affect the protein partition behavior. Analysis of ATPSs in terms of the differences between the relative hydrophobicity and electrostatic properties of the phases does not explain the protein partition behavior. The differences between protein partitioning could not be explained by the protein size. The structural signatures for the proteins were constructed from partition coefficient values in four ATPSs with different salt additives, and the structural distances were calculated using cytochrome c as the reference structure. The structural distances for all the examined proteins (except lysozyme) were found to be interrelated. Analysis of about 50 different descriptors of the protein structures revealed that the partition behavior of proteins is determined by the peculiarities of their surfaces (e.g., the number of water-filled cavities and the averaged hydrophobicity of the surface residues) and by the intrinsic flexibility of the protein structure measured in terms of the B-factor (or temperature factor). PMID- 24486799 TI - Role of defibrillation threshold testing during implantable cardioverter defibrillator placement: data from the Israeli ICD Registry. AB - BACKGROUND: Defibrillation threshold (DFT) testing during placement of an implantable cardioverter-defibrillator (ICD) has been considered mandatory. Accumulating data suggest a more limited role for DFT. OBJECTIVE: The purpose of this study was to compare the outcome of ICD recipients who underwent DFT testing compared with those who did not. METHODS: In this prospective cohort analysis of patients who received an ICD between July 2010 and March 2013, we compared patients who underwent DFT testing and those who did not. Primary end-points were death and malignant ventricular arrhythmias. Secondary end-points included the composite end-points and inappropriate ICD discharges. RESULTS: Of the 3596 patients in the registry, 614 patients (17%) underwent DFT testing during ICD placement vs 2982 (83%) who did not. Variables associated with ICD testing were implantation for secondary prevention (relative risk [RR] 1.87), prior ventricular arrhythmias (RR 1.81), use of antiarrhythmic medication (RR 1.59), and sinus rhythm (RR 2.05). Factors predisposing against testing were cardiac resynchronization therapy defibrillator implantation (RR 0.56) and concomitant diuretic use (RR 0.71). ICD testing was not associated with 1-year mortality (5.3% vs 5.1%, P = .74), delivery of appropriate shocks (8.6% vs 5.6%, P = .16), combined outcomes of ventricular arrhythmias and death (12.9% vs 11.3%, P = .45), or inappropriate ICD discharges (3.9% vs 2.1%, P = .2) compared to no DFT testing. CONCLUSION: No significant differences in the incidence of mortality, malignant ventricular arrhythmias, or inappropriate ICD discharges were observed between patients who underwent DFT testing compared to those who did not. Our results may support avoiding DFT testing during ICD placement, but this requires confirmation by additional prospective studies. PMID- 24486800 TI - Interference within hands: retrieval-induced forgetting of left and right hand movements. AB - We examined retrieval-induced forgetting of motor sequences that were categorized by the effectors (left or right hand) involved in their execution. This left right categorization was independent from input locations or input devices. In addition, the acquired motor sequences were arbitrarily assigned to left and right. Participants learned twelve sequential joystick movements as responses to letter stimuli. Half of the sequences pertained to the left, half to the right hand. Subsequent retrieval-practice of half the items of one hand induced forgetting for the non-retrieved rest of the items of that hand in a final recall test. This finding demonstrates that the hands were used to organize the memory storage of motor sequences in a way that gave rise to later interference between commonly stored items, that is, linked to the same hand. PMID- 24486801 TI - Priming and implicit recognition depend on similar temporal changes in perceptual representations. AB - Previous studies have reported that longer stimulus presentation decreases the magnitude of priming. In the present study, we used meaningless kaleidoscope images, which were reported to minimize conceptual processing, to investigate the mechanism of the phenomenon. We assessed the impact of stimulus duration on perceptual priming (Experiment 1) and implicit recognition memory (Experiment 2). Both the magnitude of priming and the accuracy of implicit recognition were lower with the longer stimulus presentation (350 ms) compared with the shorter presentation (250 ms). This coincidence of temporal dynamics between priming and implicit recognition suggests similar underlying memory mechanisms. In both cases, the decrease of performance with longer presentation can be explained by either changes in perceptual processes or interference from explicit memory retrieval. PMID- 24486802 TI - Cue type affects preparatory influences on task inhibition. AB - The present study investigates the influence of preparation on inhibitory effects in cued task switching. In three experiments, we assessed n - 2 repetition costs as marker of inhibition of the just executed and now irrelevant task by comparing performance in task sequences such as ABA (i.e., n - 2 repetitions, with A, B and C standing for different tasks) to task sequences such as CBA (i.e., n - 2 switches). Specifically, we varied the cue-target interval (CTI) to examine cue based preparation effects. In addition, we manipulated cue type (i.e., abstract, verbal, and direct cues) across the three experiments. We obtained significant reductions of n - 2 repetition costs with prolonged CTI when using abstract cues (i.e., coloured frames) and task names (i.e., digit), but not when using the task specific stimulus-response mapping as cue for the upcoming task. These data suggest that cue-based preparation is not a uniform process but depends on the information provided by the cue. PMID- 24486803 TI - Making working memory work: the effects of extended practice on focus capacity and the processes of updating, forward access, and random access. AB - We investigated the effects of 10h of practice on variations of the N-Back task to investigate the processes underlying possible expansion of the focus of attention within working memory. Using subtractive logic, we showed that random access (i.e., Sternberg-like search) yielded a modest effect (a 50% increase in speed) whereas the processes of forward access (i.e., retrieval in order, as in a standard N-Back task) and updating (i.e., changing the contents of working memory) were executed about 5 times faster after extended practice. We additionally found that extended practice increased working memory capacity as measured by the size of the focus of attention for the forward-access task, but not for variations where probing was in random order. This suggests that working memory capacity may depend on the type of search process engaged, and that certain working-memory-related cognitive processes are more amenable to practice than others. PMID- 24486804 TI - Relationships between mind-wandering and attentional control abilities in young adults and adolescents. AB - Recent findings suggest that mind-wandering-the occurrence of thoughts that are both stimulus-independent and task-unrelated-corresponds to temporary failures in attentional control processes involved in maintaining constant task-focused attention. Studies supporting this proposal are, however, limited by a possible confound between mind-wandering episodes and other kinds of conscious experiences, such as external distractions (i.e., interoceptive sensations and exteroceptive perceptions). In the present study, we addressed this issue by examining, in adolescents and young adults, the relations between tasks measuring attentional control abilities and a measure of mind-wandering that is distinct from external distractions. We observed (1) that adolescents experienced more frequent external distractions, but not more mind-wandering, than young adults during the Sustained Attention to Response Task (SART) and (2) that, in young adults, the influence of external distractions on SART performance was fully accounted for by attentional control abilities, whereas mind-wandering was associated with decreases in SART performance above and beyond what was explained by attentional control abilities. These results show that mind-wandering cannot be entirely reduced to failures in the ability to maintain one's attention focused on task, and suggest that external distractions rather than mind wandering are due to attentional control failures. PMID- 24486805 TI - Adaptive processing of fractions--evidence from eye-tracking. AB - Recent evidence indicated that fraction pair type determined whether a particular fraction is processed holistically, componentially or in a hybrid manner. Going beyond previous studies, we investigated how participants adapt their processing of fractions not only to fraction type, but also to experimental context. To examine adaptation in fraction processing, we recorded participants' eye-fixation behaviour in a fraction magnitude comparison task. Participants' eye fixation behaviour indicated componential processing of fraction pairs with common components for which the decision-relevant components are easy to identify. Importantly, we observed that fraction processing was adapted to experimental context: Evidence for componential processing was stronger, when experimental context allowed valid expectations about which components are decision-relevant. Taken together, we conclude that fraction processing is adaptive beyond the comparison of different fraction types, because participants continuously adjust to the experimental context in which fractions are processed. PMID- 24486806 TI - Effects of stimulus duration and inter-letter spacing on letter-in-string identification. AB - Effects of stimulus duration and inter-letter spacing were studied in a letter-in string identification paradigm. Participants were shown strings of 5 random consonants (e.g., PGKDM) centered on fixation and were asked to identify the letter that had appeared at a post-cued location. Stimulus duration was manipulated in Experiment 1 (13 ms-91 ms), and inter-letter spacing manipulated in Experiment 2 (for a fixed stimulus duration of 26 ms). We contrasted performance to outer-letters (positions 1 and 5) with non-central inner letters (positions 2 and 4), the first-letter (position 1) with the final letter (position 5), and the central-letter (position 3) with the other inner letters (positions 2 and 4). The outer-letter advantage and the first-letter advantage were present throughout the entire range of exposure durations, whereas the central-letter advantage increased with longer exposures. On the other hand, increased spacing reduced both the outer-letter advantage and the first-letter advantage, whereas it led to a greater central-letter advantage. Changes in acuity and crowding as a function of stimulus exposure and inter-letter spacing, can account for this pattern of results. PMID- 24486807 TI - How do we code the letters of a word when we have to write it? Investigating double letter representation in French. AB - How do we code the letters of a word when we have to write it? We examined whether the orthographic representations that the writing system activates have a specific coding for letters when these are doubled in a word. French participants wrote words on a digitizer. The word pairs shared the initial letters and differed on the presence of a double letter (e.g., LISSER/LISTER). The results on latencies, letter and inter-letter interval durations revealed that L and I are slower to write when followed by a doublet (SS) than when not (ST). Doublet processing constitutes a supplementary cognitive load that delays word production. This suggests that word representations code letter identity and quantity separately. The data also revealed that the central processes that are involved in spelling representation cascade into the peripheral processes that regulate movement execution. PMID- 24486808 TI - How fast can you (possibly) do it, or how long will it (certainly) take? Communicating uncertain estimates of performance time. AB - Recent research on verbal probability statements has revealed that some expressions (e.g., possible) are especially appropriate for describing outcomes in the high end of a distribution, whereas other expressions (e.g., certain) are more appropriate for describing low-end values. However, some dimensions appear to be reversible, with higher achievements sometimes associated with high and sometimes with low values, depending on frame. We report three experiments where this "reframing effect" is studied in communications of estimated performance time, both from a speaker's and from a listener's perspective. We hypothesize that statements describing tasks as "taking time" suggest a duration frame, and find accordingly that statements about how many hours that possibly will be spent on a task, or the time a task possibly takes, lead to high time estimates. Statements focusing on the actor's role suggest, in contrast, a speed frame, thus statements about what the actor can possibly do lead to low time estimates. Estimates of the time a task certainly takes or when it is certainly done follow the opposite pattern. The results are in line with approaches that see production and comprehension of language as a dynamical and context-driven process. PMID- 24486809 TI - Facilitation of responses by task-irrelevant complex deviant stimuli. AB - Novel stimuli reliably attract attention, suggesting that novelty may disrupt performance when it is task-irrelevant. However, under certain circumstances novel stimuli can also elicit a general alerting response having beneficial effects on performance. In a series of experiments we investigated whether different aspects of novelty--stimulus novelty, contextual novelty, surprise, deviance, and relative complexity--lead to distraction or facilitation. We used a version of the visual oddball paradigm in which participants responded to an occasional auditory target. Participants responded faster to this auditory target when it occurred during the presentation of novel visual stimuli than of standard stimuli, especially at SOAs of 0 and 200 ms (Experiment 1). Facilitation was absent for both infrequent simple deviants and frequent complex images (Experiment 2). However, repeated complex deviant images did facilitate responses to the auditory target at the 200 ms SOA (Experiment 3). These findings suggest that task-irrelevant deviant visual stimuli can facilitate responses to an unrelated auditory target in a short 0-200 millisecond time-window after presentation. This only occurs when the deviant stimuli are complex relative to standard stimuli. We link our findings to the novelty P3, which is generated under the same circumstances, and to the adaptive gain theory of the locus coeruleus-norepinephrine system (Aston-Jones and Cohen, 2005), which may explain the timing of the effects. PMID- 24486810 TI - Does knowing speaker sex facilitate vowel recognition at short durations? AB - A man, woman or child saying the same vowel do so with very different voices. The auditory system solves the complex problem of extracting what the man, woman or child has said despite substantial differences in the acoustic properties of their voices. Much of the acoustic variation between the voices of men and woman is due to changes in the underlying anatomical mechanisms for producing speech. If the auditory system knew the sex of the speaker then it could potentially correct for speaker sex related acoustic variation thus facilitating vowel recognition. This study measured the minimum stimulus duration necessary to accurately discriminate whether a brief vowel segment was spoken by a man or woman, and the minimum stimulus duration necessary to accuately recognise what vowel was spoken. Results showed that reliable vowel recognition precedesreliable speaker sex discrimination, thus questioning the use of speaker sex information in compensating for speaker sex related acoustic variation in the voice. Furthermore, the pattern of performance across experiments where the fundamental frequency and formant frequency information of speaker's voices were systematically varied, was markedly different depending on whether the task was speaker-sex discrimination or vowel recognition. This argues for there being little relationship between perception of speaker sex (indexical information) and perception of what has been said (linguistic information) at short durations. PMID- 24486811 TI - Costs and benefits of tool-use on the perception of reachable space. AB - Previous studies have shown that using a tool modifies in a short time-scale both near-body space perception and arm-length representation in the body schema. However, to date no research has specifically investigated the effect of tool-use on an action-related perceptual task. We report here a study assessing the effect of tool-use on the perception of reachable space for perceptual estimates made in reference to either the tool or the hand. Using the tool on distal objects resulted in an extension of perceived reachable space with the tool and reduced the variability of reachability estimates. Tool use also extended perceived reachable space with the hand, but with a concomitant increase of the variability of reachability estimates. These findings suggest that tool incorporation into the represented arm following tool-use improves the anticipation of action possibilities with the tool, while hand representation becomes less accurate. PMID- 24486812 TI - Proteome-wide identification of predominant subcellular protein localizations in a bacterial model organism. AB - Proteomics data provide unique insights into biological systems, including the predominant subcellular localization (SCL) of proteins, which can reveal important clues about their functions. Here we analyzed data of a complete prokaryotic proteome expressed under two conditions mimicking interaction of the emerging pathogen Bartonella henselae with its mammalian host. Normalized spectral count data from cytoplasmic, total membrane, inner and outer membrane fractions allowed us to identify the predominant SCL for 82% of the identified proteins. The spectral count proportion of total membrane versus cytoplasmic fractions indicated the propensity of cytoplasmic proteins to co-fractionate with the inner membrane, and enabled us to distinguish cytoplasmic, peripheral inner membrane and bona fide inner membrane proteins. Principal component analysis and k-nearest neighbor classification training on selected marker proteins or predominantly localized proteins, allowed us to determine an extensive catalog of at least 74 expressed outer membrane proteins, and to extend the SCL assignment to 94% of the identified proteins, including 18% where in silico methods gave no prediction. Suitable experimental proteomics data combined with straightforward computational approaches can thus identify the predominant SCL on a proteome-wide scale. Finally, we present a conceptual approach to identify proteins potentially changing their SCL in a condition-dependent fashion. BIOLOGICAL SIGNIFICANCE: The work presented here describes the first prokaryotic proteome-wide subcellular localization (SCL) dataset for the emerging pathogen B. henselae (Bhen). The study indicates that suitable subcellular fractionation experiments combined with straight-forward computational analysis approaches assessing the proportion of spectral counts observed in different subcellular fractions are powerful for determining the predominant SCL of a large percentage of the experimentally observed proteins. This includes numerous cases where in silico prediction methods do not provide any prediction. Avoiding a treatment with harsh conditions, cytoplasmic proteins tend to co-fractionate with proteins of the inner membrane fraction, indicative of close functional interactions. The spectral count proportion (SCP) of total membrane versus cytoplasmic fractions allowed us to obtain a good indication about the relative proximity of individual protein complex members to the inner membrane. Using principal component analysis and k-nearest neighbor approaches, we were able to extend the percentage of proteins with a predominant experimental localization to over 90% of all expressed proteins and identified a set of at least 74 outer membrane (OM) proteins. In general, OM proteins represent a rich source of candidates for the development of urgently needed new therapeutics in combat of resurgence of infectious disease and multi-drug resistant bacteria. Finally, by comparing the data from two infection biology relevant conditions, we conceptually explore methods to identify and visualize potential candidates that may partially change their SCL in these different conditions. The data are made available to researchers as a SCL compendium for Bhen and as an assistance in further improving in silico SCL prediction algorithms. PMID- 24486813 TI - Expression and purification of mouse peptide ESP4 in Escherichia coli. AB - Pheromones are species-specific chemical signals that regulate a wide range of social and sexual behaviors in many animals. In mice, the male-specific peptide ESP1 (exocrine gland-secreting peptide 1) is secreted into tear fluids and enhances female sexual receptive behavior. ESP1 belongs to the ESP family, a multigene family with 38 genes in mice. ESP1 shares the highest homology with ESP4. ESP1 is expressed in the extraorbital lacrimal gland, whereas ESP4 is expressed in some exocrine glands. Thus, ESP4 is expected to have a function that has not been elucidated yet. Large amounts of the purified ESP4 protein are required for structural and biochemical studies. Here we present an expression and purification scheme for the recombinant ESP4 protein. The N-terminally histidine-tagged ESP4 fusion protein was expressed in Escherichia coli as inclusion bodies, which were solubilized and purified by nickel affinity chromatography. The histidine tag was cleaved with thrombin and removed by a second nickel affinity chromatography step. The ESP4 protein was isolated with high purity by reversed-phase chromatography. For NMR analyses, we prepared a stable isotope-labeled ESP4 protein. Three repeated freeze-drying steps after the reversed-phase chromatography were required, to remove a volatile contaminating compound and to obtain an NMR spectrum with a homogeneous line shape. AMS modification and far-UV CD spectroscopic analyses suggested that ESP4 has an intramolecular disulfide bridge and a helical structure, respectively. The present study provides a powerful tool for structural and biochemical studies of ESP4, leading toward the elucidation of the roles of the ESP family members. PMID- 24486814 TI - High-level production of active human TFPI-2 Kunitz domain in plant. AB - Plants are an attractive production system alternative to cell bioreactor not only because of its lower production costs, but also due to its lack of mammalian pathogens and contaminants, plant capacity to generate appropriate eukaryotic folding and in many cases correct post-translational modifications. In recent years, several recombinant proteins and antibodies have been introduced in the biopharmaceutical market, in particular in cancer therapeutics. Kunitz domain 1 (KD1), a domain of Human Tissue Factor Pathway Inhibitor-2 (TFPI-2), has an outstanding potential in cancer treatment because it is a potent inhibitor of extracellular serine proteinases involved in tumor progression and angiogenesis. We present here the expression and purification of active human KD1 in different Nicotiana species as hosts and its stability during the infection process using a construct derived from a Tobacco mosaic virus (TMV) vector. Our purification protocol allows to recover over 100mg of active human KD1 per batch of 1 kg of plant tissue at about 97% purity. The yields are reproducible, being N. benthamiana the best system where higher levels of KD1 are obtained. Recombinant KD1 was also used to produce a high-sensitivity polyclonal antibody able to detect not only KD1 but also full-length TFPI-2. Finally, we show that this platform is a valuable alternative for the large scale production of KD1. PMID- 24486816 TI - Young adults' childhood experiences of support when living with a parent with a mental illness. AB - There are several concerns in relation to children living with a parent suffering from a mental illness. In such circumstances, the health-care professionals need to involve the whole family, offering help to the parents on parenting as well as support for their children. These children are often helped by participating in meetings that provide them with contact with others with similar experiences. The aim of this study was to investigate young adults' childhood experiences of support groups when living with a mentally ill parent. Seven young women were chosen to participate in this study. A qualitative descriptive method was chosen. The main category emerged as 'the influence of life outside the home because of a parent's mental illness' from the two generic categories: 'a different world' and 'an emotion-filled life'. The participants' friends did not know that their parent was ill and they 'always had to...take responsibility for what happened at home'. These young adults appreciated the support group activities they participated in during their childhood, stating that the meetings had influenced their everyday life as young adults. Despite this, they associated their everyday life with feelings of being different. This study highlights the need for support groups for children whose parents suffer from mental illness. PMID- 24486815 TI - Children having magnetic resonance imaging: A preparatory storybook and audio/visual media are preferable to anesthesia or deep sedation. AB - As a magnetic resonance imaging (MRI) examination lasts about 45 minutes and as the technique is sensitive to motion, children are often given sedation or anesthesia. The aim of this study was to examine whether children aged three to nine years could undergo MRI while awake and achieve adequate image quality if age-adjusted routines were used. A two-group controlled experimental design was used. Thirty-six children were assigned to a control group and underwent MRI with the prevalent routines. Thirty-three children were assigned to an intervention group and underwent the MRI while awake. The age-adjusted routine included a booklet and a story book, a model of the MRI scanner with the MRI sound, and a DVD film during the examination. In the control group, 30 children underwent the examination under anesthesia and 6 underwent the examination while they were awake. All had acceptable examinations. In the intervention group, 33 children had their examination while awake and 30 of them had acceptable examinations. The parents' satisfaction with the care was assessed to be equal or higher in the intervention group and the costs were calculated to be lower. Thus, many children receiving age-appropriate preparation and distraction can undergo MRI examinations while awake. PMID- 24486817 TI - Parenting interventions for childhood chronic illness: a review and recommendations for intervention design and delivery. AB - Every day, thousands of children suffer the effects of chronic health conditions and families struggle with illness management and children's behavioural and emotional adjustment. Many parents experience difficulties with their caregiving role and lack confidence in their ability to manage their child's illness and ensure the child's well-being. While there is consistent evidence as to the extent and impact of childhood chronic illness, there is a paucity of evidence based parenting approaches to help children with chronic health conditions and their families. This paper provides a narrative review of the current literature to examine relationships between chronic childhood illness, emotional and behavioural disorders and parenting. Key guidelines and recommendations for the development of evidence-based parenting programs for parents of children affected by chronic health conditions are provided. PMID- 24486818 TI - An understanding of Japanese children's perceptions of fun, barriers, and facilitators of active free play. AB - Physical activity contributes to children's physical and mental well-being. Research suggests that active free play helps to maintain and increase physical activity in children and also contributes to social and emotional well-being. To date, these studies have focused on Western countries. Thus, this study was conducted to gain insights into the factors of perceptions of fun, barriers, and facilitators affecting active free play from the perspective of Japanese children using focus group interviews. In Japan, 12 focus groups were conducted with 60 children aged 9-11 years. Children's perceptions of fun in active free play were categorized into socializing, achievement, emotions, and freedom. Additionally, active boys' groups were interested in free play and adventure play; girls' groups were interested in free play with less physical movement and challenges; inactive boys' groups were interested in relaxing and competitive play with bodily contact. However, children mentioned that busy schedules, weather, and health-related factors acted as main barriers. Lastly, children noted facilitators include setting schedules, having access to equipment and playgrounds, and holding special events. The findings provide insights into active free play-related factors for active and inactive Japanese children and also clarify the differences between Japanese and Western children. Such findings will contribute to designing interventions to increase active free play. PMID- 24486819 TI - Suicide of a close family member through the eyes of a child: A narrative case study report. AB - A narrative case study approach was used to collect a storied account from Joseph about his recollections and experience of the completed suicide of a family member with whom he lived with at 13 years of age. Data are presented longitudinally to capture Joseph's perceptions and recollections of events leading up to, surrounding and following the suicide. Findings reveal that, as a child Joseph felt strong responsibility to keep his uncle safe and maintain his uncle's life; and perceived a lack of support for himself and his family throughout the events. Today as a young man, Joseph remains profoundly affected by this suicide and the events surrounding it, and experiences flashbacks and intrusive thoughts, though his distress remains largely invisible to others. It is important that the acute and longer term needs of children affected by suicidality and suicide are recognised. We argue that increased awareness on the part of health professionals about the ongoing grief and distress surrounding suicide survivorship can create opportunities for opportunistic assessment and review of child survivor welfare. PMID- 24486820 TI - Alois Alzheimer and Gaetano Perusini: should man divide what fate united? AB - Three points of interest lie in considering how Alzheimer, and more significantly Perusini, struggled to throw light on the cause of this devastating disease. There is a stimulating possibility that Perusini believed presenile forms of Alzheimer's disease described the same disease as senile forms. If so this would anticipate current opinion, and reveal Perusini to dissent from Kraepelin. In addition, Perusini may have understood the pathological relationship between neuritic plaques and vascular changes, once more foreseeing the modern view of Alzheimer's disease. Finally, Perusini and Alzheimer disagreed with Jung's view concerning the relationship between neuropathology and clinical psychiatry. This point highlights the major change occurring at that time from classical neurology to the psychoanalytic era. In his last work (1911) Alzheimer quoted his Italian disciple many times, even speaking of 'Perusini's cases' (Perusinischen Falle). This article is an attempt to change the eponym of Alzheimer's disease into the Alzheimer-Perusini disease. This is a brief history of a master and his disciple, whose scientific lives were, by events, divided. PMID- 24486821 TI - Neuropsychology and advances in memory function. AB - Recent developments in the functional and neural bases of several aspects of memory are described including long term cortical memory storage, the transition from immediate to permanent memory mediated by medial temporal structures, working memory, memory retrieval, and implicit memory. These are linked to current data on the nature of anterograde and retrograde amnesia in the degenerative diseases, and also to issues in the clinical diagnosis of memory impairments. Understanding the bases of memory can inform the diagnosis of memory impairments in degenerative diseases, and the patterns of impairment seen in the degenerative diseases can help contribute to knowledge of the mechanisms of normal memory. PMID- 24486822 TI - Premorbid personality characteristics in Alzheimer's disease: an exploratory case control study. AB - Linking data from a case-control study of Alzheimer's disease with data from a Minnesota Multiphasic Personality Inventory (MMPI) outpatient study, we identified 13 Alzheimer's disease cases and 16 controls for case-control comparison. The mean time between personality testing and onset of Alzheimer's disease (or corresponding age for controls) was 13 years in cases and 14 years in controls. Alzheimer's disease cases, but not the controls, had scores significantly greater than the normative reference on MMPI scales measuring Social Introversion (p = 0.05), and Pessimism (p = 0.01). When compared to controls, Alzheimer's disease cases had significantly greater scores on the Social Introversion scale (p = 0.03). Despite the small sample size and some design limitations of this exploratory study, our findings may suggest that subjects who score higher on these personality scales have a greater risk of Alzheimer's disease. PMID- 24486823 TI - SPECT findings in Alzheimer's disease and Parkinson's disease with dementia. AB - We examined, with single photon emission tomography (SPECT) and (99mTc)-HMPAO, 18 patients with idiopathic Parkinson's disease and no dementia (PD), 12 patients with PD and dementia, 24 patients with probable Alzheimer's disease (AD), and 14 controls. While the three patient groups showed significantly lower perfusion in frontal inferior and temporal inferior areas as compared to controls, both demented groups showed significantly more severe bilateral hypoperfusion in superior frontal, superior temporal and parietal areas as compared to non demented PD patients and controls. On the other hand, no significant differences in cerebral perfusion were found between patients with AD and patients with PD and dementia. In conclusion, our findings demonstrated specific but similar cerebral perfusion deficits in demented patients with either AD or PD. PMID- 24486824 TI - Follow-up of 53 Alzheimer patients with the MODA (Milan Overall Dementia Assessment). AB - Fifty-three patients affected by Alzheimer's disease entered a longitudinal survey aimed at studying which factors influence the rate of progression, assessed by means of the Milan Overall Dementia Assessment (MODA). The second examination was carried out, on average, after 16 months from the first assessment. Only age proved to influence the decline rate, which was faster in elders. PMID- 24486825 TI - Strategies and structures in verbal fluency tasks in patients with Alzheimer's disease. AB - Reduced word production in verbal fluency tasks is a sensitive indicator for brain damage. Patients with Alzheimer's disease (AD) are supposedly more affected in semantic than in letter fluency, which is probably resulting from partially destroyed structure of semantic knowledge, whereas in letter fluency tasks the patients can use phonemic cues for searching. In this study, 21 patients with probable AD according to NINCDS-ADRDA criteria were examined on a verbal fluency task with F, A, S as initial letters, and a supermarket task. Performances were compared with a control group. Patients with AD showed lower word rate in all tasks than the control group. The difference was most significant in the supermarket task. Both groups produced most of the words in the supermarket task, followed by S, A and F. They both showed a percentuallikely distribution pattern of items into different supermarket categories. The items of the supermarket task were mostly ranged in clusters (patients with AD 70%, control group 83%). Patients with AD, however, on average, used fewer categories which they also filled with fewer items. In the F, A, S test, patients with AD mainly produced nouns, whereas the control group named nearly twice as many adjectives and verbs. In patients with AD word generation was highly correlated with degree of dementia, free recall of a verbal memory task, and the Token test. Low word production and qualitatively changed output in patients with AD might relate to an inefficient searching strategy, attentional deficits and/or degraded semantic knowledge. PMID- 24486826 TI - Memory training for individuals with Alzheimer's disease improves name recall. AB - Alzheimer's disease is clinically characterized by a variety of progressive cognitive deficits, most notably an impaired ability to acquire new information, such as name recall. Eleven demented patients and 11 controls participated in a 4 week memory program that included training in name-face recall. Individuals were taught strategies for name-face rehearsal, and administered task specific and standardized tests to assess the intervention efficacy. During the memory training patients improved recall of names and faces (p < 0.05), while controls remained stable. Patients also improved on the weekly standardized measures, including the Kendrick Digit Copy and Geriatric Depression Scale (p < 0.05). Thus, the memory training can be beneficial for improving name recall and some aspects of behavior. This can provide a framework for development of programs to enhance cognitive function in patients with dementia and may tap biological mechanisms that promote neural plasticity to compensate for the degenerative condition. PMID- 24486827 TI - Attitudes toward predictive testing for Alzheimer's disease in a student population. AB - Attitudes toward predictive testing for Alzheimer's disease and knowledge about this disease were investigated in a group of medical and psychology students. Overall, knowledge was poor and their own chance of getting Alzheimer's disease was mostly perceived as small. About half the students thought the development of a predictive test for Alzheimer's disease important, while the other half held the opposite view. Considerable variability was also observed in the judgement of the (dis)advantages of such a test. Only a minority of the students would like to have had a predictive test themselves. Important arguments against a predictive test concerned the absence of a treatment for Alzheimer's disease and the emotional burden of a positive test result. Arguments in favour dealt with the ability to make plans for the future and to prepare oneself for the disease. The divergence in attitudes and opinions reflects the complexity of predictive testing for Alzheimer's disease. Stepwise regression revealed that knowledge about Alzheimer's disease and, to a lesser extent, risk perception are significant predictors of attitudes toward predictive testing. However, they only explain a small part of the variance in attitudes. Moreover, why attitudes are less positive when knowledge and perceived susceptibility increase is not clear. PMID- 24486828 TI - Targeting mast cells in inflammatory diseases. AB - Although mast cells have long been known to play a critical role in anaphylaxis and other allergic diseases, they also participate in some innate immune responses and may even have some protective functions. Data from the study of mast cell-deficient mice have facilitated our understanding of some of the molecular mechanisms driving mast cell functions during both innate and adaptive immune responses. This review presents an overview of the biology of mast cells and their potential involvement in various inflammatory diseases. We then discuss some of the current pharmacological approaches used to target mast cells and their products in several diseases associated with mast cell activation. PMID- 24486829 TI - Multiple neural mechanisms for coloring words in synesthesia. AB - Grapheme-color synesthesia is a phenomenon in which achromatic letters/digits automatically induce particular colors. When multiple letters are integrated into a word, some synesthetes perceive that all those letters are changed into the same color, reporting lexical color to that word. Previous psychological studies found several "rules" that determine those lexical colors. The colors to most words are determined by the first letters of the words, while some words in ordinal sequences have their specific colors. Recent studies further reported the third case where lexical colors might be influenced by semantic information of words. Although neural mechanisms determining those lexical colors remained unknown, here we identified three separate neural systems in the synesthete's brain underlying three rules for illusory coloring of words. In addition to the occipito-temporal and parietal regions previously found to be associated with the grapheme-color synesthesia, neural systems for lexical coloring extended to linguistic areas in the left inferior frontal and anterior temporal regions that were engaged in semantic analyses of words. Those results indicate an involvement of wider and higher neural networks than previously assumed in a production of synesthetic colors to visual stimuli and further showed a multiplicity of synesthetic mechanisms represented in the single brain. PMID- 24486830 TI - Varieties of perceptual instability and their neural correlates. AB - We report experiments designed to learn whether different kinds of perceptually unstable visual images engage different neural mechanisms. 21 subjects viewed two types of bi-stable images while we scanned the activity in their brains with functional magnetic resonance imaging (fMRI); in one (intra-categorical type) the two percepts remained within the same category (e.g. face-face) while in the other (cross-categorical type) they crossed categorical boundaries (e.g. face body). The results showed that cross- and intra-categorical reversals share a common reversal-related neural circuitry, which includes fronto-parietal cortex and primary visual cortex (area V1). Cross-categorical reversals alone engaged additional areas, notably anterior cingulate cortex and superior temporal gyrus, which have been posited to be involved in conflict resolution. PMID- 24486831 TI - The neural representation of faces and bodies in motion and at rest. AB - The neural organization of person processing relies on brain regions functionally selective for faces or bodies, with a subset of these regions preferring moving stimuli. Although the response properties of the individual areas are well established, less is known about the neural response to a whole person in a natural environment. Targeting an area of cortex that spans multiple functionally selective face and body regions, we examined the relationship among neural activity patterns elicited in response to faces, bodies, and people in static and moving displays. When both stimuli were static or moving, pattern classification analyses indicated highly discriminable responses to faces, bodies, and whole people. Neural discrimination transferred in both directions between representations created from moving or static stimuli. It transferred also to stimuli experienced across static and dynamic presentations (one static and the other dynamic). In both transfer cases, however, discrimination accuracy decreased relative to the case where the representations were both created and tested with static or moving forms. Next, we examined the relative contribution of activity pattern and response magnitude to discrimination by comparing classifiers that operated with magnitude-normalized scans with classifiers that retained pattern and magnitude information. When both stimuli were moving or static, response magnitude contributed to classification, but the spatially distributed activity pattern accounted for most of the discrimination. Across static and moving presentations, activity pattern accounted completely for the discriminability of neural responses to faces, bodies, and people, with no contribution from response magnitude. Combined, the results indicate redundant and flexible access to person-based shape codes from moving and static presentations. The transfer of shape information across presentation types that preferentially access dorsal and ventral visual processing streams indicates that a common shape code may ground functional divisions in the processing of face and body information. PMID- 24486832 TI - Fabrication of a new fluorescent polymeric nanoparticle containing naphthalimide and investigation on its interaction with bovine serum albumin. AB - A new fluorescent nanoparticle was synthesized by chemical crosslinking of polyacrylic acid using 4-aminoethanol-N-hydroxyethanyl-1,8-naphthalimide as the crosslinker. The particle possesses excellent characteristics, including low cytotoxicity, water solubility and good fluorescence properties. The interaction of the particle with bovine serum albumin was investigated by absorbance, fluorescence and circular dichroism spectroscopic methods. The interaction mechanisms, binding model and reciprocal effects on structure and fluorescence between nanoparticle and protein are discussed. The spectral data indicated that the nanoparticle could spontaneously form a reversible complex with bovine serum albumin in solution used mainly by hydrogen bonds and van der Waals forces. Fluorescence resonance energy transfer from tryptophan to naphthalimide in the complex was demonstrated and employed to determine their relative separation distance. During the interaction process, unfolding of polypeptide chains in the protein occurred but no adjustments of local polarities around the tryptophan and tyrosine residues were observed. In addition, it was found that the presence of protein induced a notable enhancement in nanoparticle fluorescence and a blue shift in the emission maximum. These results will be useful for further applications of the developed nanoparticle in biomedical areas. PMID- 24486833 TI - Antitumor activity of galactoxyloglucan-gold nanoparticles against murine ascites and solid carcinoma. AB - Galactoxyloglucan polysaccharide (PST001), isolated from the seed kernels of Tamarindus indica (Ti), was used both as reducing and capping agent for the preparation of gold nanoparticles (PST-Gold) of 20 nm size. The present study evaluated the anticancer effects of the PST-Gold nanoparticles both in vitro and in vivo. The cytotoxicity was evaluated in the murine cancer cell lines, Dalton's lymphoma ascites (DLA) and Ehrlich's ascites carcinoma (EAC). Galactoxyloglucan gold nanoparticles (PST-Gold) not only retained the anticancer effects of PST001, but also showed enhanced cytotoxicity via induction of apoptosis even at lower doses and lesser incubation times. In vivo antitumor activity was tested in DLA and EAC murine ascites and EAC solid-tumor syngeneic mouse models. PST-Gold nanoparticles reduced tumor burden and increased median survival and life span significantly in both tumor models compared to the controls. The PST-Gold nanoparticles were very effective as a chemopreventive agent, showing the best overall response when administered prior to tumor induction. In the case of solid tumors, intratumoral administration of the PST-Gold nanoparticles yielded significant results with regard to survival and increment in lifespan as compared to intraperitoneal mode of drug administration. Further studies in higher animal models and in patients at high-risk for recurrence are warranted to fully explore and develop the potential of PST-Gold nanoconjugates as a chemopreventive and therapeutic anti-cancer agent. PMID- 24486834 TI - Cellular uptake and anticancer effects of mucoadhesive curcumin-containing chitosan nanoparticles. AB - Curcumin, which is derived from turmeric has gained much attention in recent years for its anticancer activities against various cancers. However, due to its poor absorption, rapid metabolism and elimination, curcumin has a very low oral bioavailability. Therefore, we have formulated mucoadhesive nanoparticles to deliver curcumin to the colon, such that prolonged contact between the nanoparticles and the colon leads to a sustained level of curcumin in the colon, improving the anticancer effect of curcumin on colorectal cancer. The current work entails the ex vivo mucoadhesion study of the formulated nanoparticles and the in vitro effect of mucoadhesive interaction between the nanoparticles and colorectal cancer cells. The ex vivo study showed that curcumin-containing chitosan nanoparticles (CUR-CS-NP) have improved mucoadhesion compared to unloaded chitosan nanoparticles (CS-NP), suggesting that curcumin partly contributes to the mucoadhesion process. This may lead to an enhanced anticancer effect of curcumin when formulated in CUR-CS-NP. Our results show that CUR-CS-NP are taken up to a greater extent by colorectal cancer cells, compared to free curcumin. The prolonged contact offered by the mucoadhesion of CUR-CS-NP onto the cells resulted in a greater reduction in percentage cell viability as well as a lower IC50, indicating a potential improved treatment outcome. The formulation and free curcumin appeared to induce cell apoptosis in colorectal cancer cells, by arresting the cell cycle at G2/M phase. The superior anticancer effects exerted by CUR-CS-NP indicated that this could be a potential treatment for colorectal cancer. PMID- 24486835 TI - Nitrous oxide does not produce a clinically important sparing effect during closed-loop delivered propofol-remifentanil anaesthesia guided by the bispectral index: a randomized multicentre study. AB - BACKGROUND: Nitrous oxide (N2O) offers both hypnotic and analgesic characteristics. We therefore tested the hypothesis that N2O administration decreases the amount of propofol and remifentanil given by a closed-loop automated controller to maintain a similar bispectral index (BIS). METHODS: In a randomized multicentre double-blind study, patients undergoing elective surgery were randomly assigned to breathe 60% inspired N2O (N2O group) or 40% oxygen (AIR group). Anaesthesia depth was evaluated by the proportion of time where BIS was within the range of 40-60 (BIS40-60). The primary outcomes were propofol and remifentanil consumption, with reductions of 20% in either being considered clinically important. RESULTS: A total of 302 patients were randomized to the N2O group and 299 to the AIR group. At similar BIS40-60 [79 (67-86)% vs 76 (65-85)%], N2O slightly decreased propofol consumption [4.5 (3.7-5.5) vs 4.8 (4.0-5.9) mg kg(-1) h(-1), P=0.032], but not remifentanil consumption [0.17 (0.12-0.23) vs 0.18 (0.14-0.24) ug kg(-1) min(-1)]. For the subgroups of men, at similar BIS40 60 [80 (72-88)% vs 80 (70-87)%], propofol [4.2 (3.4-5.3) vs 4.4 (3.6-5.4) mg kg( 1) h(-1)] and remifentanil [0.19 (0.13-0.25) vs 0.18 (0.15-0.23) ug kg(-1) min( 1)] consumptions were similar in the N2O vs AIR group, respectively. For the subgroups of women, at similar BIS40-60 [76 (64-84)% vs 72 (62-82)%], propofol [4.7 (4.0-5.8) vs 5.3 (4.5-6.6) mg kg(-1) h(-1), P=0.004] and remifentanil [0.18 (0.13-0.25) vs 0.20 (0.15-0.27) ug kg(-1) min(-1), P=0.029] consumptions decreased with the co-administration of N2O. CONCLUSIONS: With automated drug administration titrated to comparable BIS, N2O only slightly reduced propofol consumption and did not reduce remifentanil consumption. There was a minor gender dependence, but not by a clinically important amount. Clinical trial registration This study was registered at ClinicalTrials.gov, number NCT00547209. PMID- 24486836 TI - Peri-partum reference ranges for ROTEM(R) thromboelastometry. AB - BACKGROUND: Post-partum haemorrhage (PPH) causes rapidly developing deficiencies in clotting factors and contributes to substantial maternal morbidity and mortality. Rotational thromboelastometry (ROTEM((r))) is increasingly used as a point of care coagulation monitoring device in patients with massive haemorrhage; however, there are limited data on reference ranges in the peri-partum period. These are required due to the haemostatic changes in pregnancy. METHODS: In a Dutch multi-centre trial, 161 subjects were included; blood samples were obtained during labour (T1) and within 1 h of delivery (T2). Reference ranges of ROTEM((r)) INTEM, EXTEM, FIBTEM, and APTEM were set and correlation with laboratory results was investigated using the guidelines of the International Federation of Clinical Chemistry. RESULTS: Reference ranges were obtained for clotting time (CT), clot formation time (CFT), alpha-angle, clot firmness at 10 and 20 min (A10, A20), maximum clot firmness (MCF), and maximum lysis (ML). These were comparable from centre to centre, and between T1 and T2. Reference ranges T1: EXTEM: CT 31-63 s, CFT 41-120 s, and MCF 42-78 mm. INTEM: CT 109-225 s, CFT 40-103, and MCF 63-78 mm. FIBTEM: CT 31-79 s and MCF 13-45 mm. APTEM: CT 33-62 s, CFT 42-118, and MCF 61-79 mm. CONCLUSIONS: Reference values for ROTEM((r)) parameters are reported. The previously published correlation between FIBTEM parameters and plasma fibrinogen levels by the Clauss method is confirmed. Further research is needed to define threshold values for haemostatic therapy in the course of PPH. Clinical trial registration NTR 2515 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=2515). PMID- 24486837 TI - Cyclin-dependent kinase 5 phosphorylates and induces the degradation of ataxin-2. AB - The expansion of a polyQ repeat within the ataxin-2 protein causes spinocerebellar ataxia type 2 (SCA2). However, neither the precise pathological mechanism nor the physiological functions of ataxin-2 are known. Ataxin-2 contains 47 (S/T)P sequences, which are targeted by proline-directed protein kinases such as the cyclin-dependent kinase 5 (Cdk5). We hypothesized that ataxin 2 is phosphorylated by Cdk5. In fact, phosphorylation of ataxin-2 by Cdk5-p25 was shown using two methods: in vitro(32)P labeling and electrophoretic mobility shift on Phos-tag SDS-PAGE. The fractionation of ataxin-2 into three portions, the N-terminal fragment (NF, amino acids 1-507), the middle fragment (MF, amino acids 508-905), and the C-terminal fragment (CF, amino acids 906-1313) showed that NF and MF were phosphorylated slightly and highly, respectively, by Cdk5-p25 when expressed in COS-7 cells. Cdk5-mediated phosphorylation induced the degradation of NF remarkably and MF moderately. Furthermore, toxic ataxin-2-41Q underwent proteasomal degradation after phosphorylation by Cdk5. These results suggest that Cdk5 controls the abundance of both normal and polyQ-expanded ataxin 2 protein in neurons, which implies that Cdk5 activity is a therapeutic approach for SCA2. PMID- 24486839 TI - Discriminative and affective touch in human experimental tactile allodynia. AB - Recently, several studies have suggested a role for unmyelinated (C-tactile, CT) low-threshold mechanoreceptive afferents in the allodynic condition. In this psychophysical study we explored the integrity of both Abeta and CT afferent processing following application of the heat capsaicin model of tactile allodynia on the left forearm in healthy subjects (n=40). We measured tactile direction discrimination (TDD) to target the integrity of Abeta processing (n=20). The TDD accuracy was significantly lower in the allodynic compared to a control zone. In addition, we measured the perceived pleasantness and pain of brush stroking at CT targeted (slow) and CT sub-optimal (fast) stroking velocities to investigate the integrity of CT processing (n=20). When comparing touch pleasantness in the allodynic and control zone, there was a significantly larger difference in ratings for CT targeted compared to CT suboptimal stimulation. The results suggest a disturbance in both Abeta-mediated discriminative and CT-mediated affective touch processing in human experimental tactile allodynia. Our findings support the canonical view that tactile allodynia is signaled by Abeta afferents but that CTs seem to contribute by the loss of a pain inhibiting role. PMID- 24486838 TI - Intrathecal carbenoxolone inhibits neuropathic pain and spinal wide-dynamic range neuronal activity in rats after an L5 spinal nerve injury. AB - Spinal glial gap junctions may play an important role in dorsal horn neuronal sensitization and neuropathic pain. In rats after an L5 spinal nerve ligation (SNL), we examined the effects of intrathecal injection of carbenoxolone (CBX), a gap junction decoupler, on neuropathic pain manifestations and on wide-dynamic range (WDR) neuronal activity in vivo. Intrathecal injection of CBX dose dependently (0.1-50 MUg, 10 MUl) inhibited mechanical hypersensitivity in rats at 2-3 weeks post-SNL. However, the same doses of glycyrrhizic acid (an analogue of CBX that does not affect gap junctions) and mefloquine hydrochloride (a selective neuronal gap junction decoupler) were ineffective. Intrathecal CBX (5MUg) also attenuated heat hypersensitivity in SNL rats. Further, rats did not develop tachyphylaxis to CBX-induced inhibition of mechanical hypersensitivity after repetitive drug treatments (25 MUg/day) during days 14-16 post-SNL. Electrophysiological study in SNL rats showed that spinal topical application of CBX (100 MUg, 50 MUl), which mimics intrathecal drug administration, attenuated WDR neuronal responses to mechanical stimuli and to repetitive intracutaneous electrical stimuli (0.5 Hz) that induce windup, a short-form of activity dependent neuronal sensitization. The current findings suggest that the inhibition of neuropathic pain manifestations by intrathecal injection of CBX in SNL rats may involve an inhibition of glial gap junctions and an attenuation of WDR neuronal activity in the dorsal horn. PMID- 24486840 TI - Dynamin protein in stroke and vascular dementia. AB - Damage to sub-cortical white matter is a key substrate of vascular dementia (VaD) leading to deficits in executive function and cognitive processing speed. Dynamin1 is a 100 kDa protein, accounting for 0.4% of the total brain protein, and has a central role in many intracellular processes such as synaptic vesicle trafficking and recycling. In this study, we examined the status of Dynamin1 in the white matter from frontal cortex area. In order to measure the levels of Dynamin1, we isolated cortical white matter from a total of 34 post-mortem brains derived from controls (N=11), mixed Alzheimer's disease (AD) and VaD (N=8), VaD (N=7), and stroke no dementia (SND, N=8) subjects. A commercial ELISA kit was then used to determine the level of Dynamin1. In comparison to controls, Dynamin1 was elevated in patients SND (+400%) and reduced in patients with mixed VaD ( 50%). Furthermore, levels of Dynamin1 were significantly associated with preserved cognition as indicated by the MMSE and CAMCOG and upregulation of vesicular glutamate transporter 1. This work indicates that Dynamin1 is associated with both preserved cognition and regenerative responses in older people with cerebrovascular disease and may represent a novel treatment target. PMID- 24486841 TI - Evidence for the exclusive expression of functional homomeric alpha7 nAChRs in hypothalamic histaminergic tuberomammillary neurons in rats. AB - Hypothalamic histaminergic tuberomammillary (TM) neurons in rats express high densities of nicotinic acetylcholine receptors (nAChRs) whose Ca(2+) permeability, kinetic and pharmacological properties are similar to those of heterologous homomeric alpha7 nAChRs. However, native alpha7 nAChR subunits can co-assemble with beta or alpha5 nAChR subunits to form functional heteromeric alpha7-containing alpha7beta or alpha7alpha5 nAChRs with kinetics and pharmacology similar to those of alpha7 homomers. Therefore, although TM nAChRs have been used as an ex vivo model of functional alpha7 homomers, the molecular makeup of TM nAChRs has not been determined and the expression of functional alpha7-containing heteromers in TM neurons has not been excluded. To determine the profile of TM nAChR subunit transcripts, we have conducted single-cell qRT PCR experiments using acutely dissociated TM neurons in rats. TM neurons were found to express transcripts of only principal alpha3, alpha6 and alpha7 nAChR subunits. Transcripts of other known mammalian neuronal subunits (alpha2, alpha4 5, alpha9-10, beta2-4) were not detected. In the absence of beta and alpha5 subunits, the expression of functional alpha7-containing heteromers in TM neurons is highly unlikely because principal alpha3, alpha6 and alpha7 nAChR subunits alone are not known to form functional heteromeric nAChRs. These results support the exclusive expression of native functional alpha7 homomers in rat TM neurons and introduce these neurons as a unique reliable source of native functional homomeric alpha7 nAChRs suitable for ex vivo and in vitro pharmacological assays in developing selective alpha7 nAChR agents. PMID- 24486842 TI - A novel method using intranasal delivery of EdU demonstrates that accessory olfactory ensheathing cells respond to injury by proliferation. AB - Olfactory ensheathing cells (OECs) play an important role in the continuous regeneration of the primary olfactory nervous system throughout life and for regeneration of olfactory neurons after injury. While it is known that several individual OEC subpopulations with distinct properties exist in different anatomical locations, it remains unclear how these different subpopulations respond to a major injury. We have examined the proliferation of OECs from one distinct location, the peripheral accessory olfactory nervous system, following large-scale injury (bulbectomy) in mice. We used crosses of two transgenic reporter mouse lines, S100beta-DsRed and OMP-ZsGreen, to visualise OECs, and main/accessory olfactory neurons, respectively. We surgically removed one olfactory bulb including the accessory olfactory bulb to induce degeneration, and found that accessory OECs in the nerve bundles that terminate in the accessory olfactory bulb responded by increased proliferation with a peak occurring 2 days after the injury. To label proliferating cells we used the thymidine analogue ethynyl deoxyuridine (EdU) using intranasal delivery instead of intraperitoneal injection. We compared and quantified the number of proliferating cells at different regions at one and four days after EdU labelling by the two different methods and found that intranasal delivery method was as effective as intraperitoneal injection. We demonstrated that accessory OECs actively respond to widespread degeneration of accessory olfactory axons by proliferating. These results have important implications for selecting the source of OECs for neural regeneration therapies and show that intranasal delivery of EdU is an efficient and reliable method for assessing proliferation of olfactory glia. PMID- 24486843 TI - Fish consumption caveat: advisories may not help with long-lived contaminants. PMID- 24486844 TI - [Sentinel lymph node status and axillary lymph node dissection in the surgical treatment of breast cancer]. AB - Axillary lymph node dissection has been traditionally perceived as a therapeutic and a staging procedure and unselectively removes all axillary lymph nodes. There still remains some controversy as concerns the survival benefit associated with axillary clearance. Sentinel lymph node biopsy removes the most likely sites of regional metastases, the lymph nodes directly connected with the primary tumour. It allows a more accurate staging and a selective indication for clearing the axilla, restricting this to patients who may benefit of it. Axillary dissection was performed in all patients during the learning phase of sentinel lymphadenectomy, but later only patients with metastasis to a sentinel node underwent this operation. Currently, even some patients with minimal sentinel node involvement, including some with macrometastasis may skip axillary clearance. This review summarizes the changes that have occurred in the surgical management of the axilla, the evidences and controversies behind these changes, along with current recommendations. PMID- 24486846 TI - [Is ceCT necessary beyond FDG-PET/CT for primary staging in Hodgkin lymphoma?]. AB - INTRODUCTION: Several study supported that 18F-Fluoro-deoxy-glucose (FDG) positron emission tomography/computer tomography with low dose CT (standard PET/CT) is more accurate than contrast-enhanced CT (ceCT) in the primary staging of Hodgkin disease. AIM: The authors compared the accuracy of these examinations with this indication in their practice, and analysed the added value of ceCT which was performed as a supplement to standard PET/CT. METHOD: Twenty-eight patients were categorized based on ceCT, single standard PET/CT and standard PET/CT with ceCT. RESULTS: Twenty-four patients were in the same disease-stage based on all methods. Disease was upstaged by standard PET/CT compared to ceCT in 4 patients. There was no change in stage when comparing standard PET/CT and standard PET/CT with ceCT. CONCLUSIONS: Standard PET/CT is more accurate than ceCT in the primary staging of Hodgkin disease. The authors established that it is not reasonable to supplement standard PET/CT with ceCT in this indication. PMID- 24486845 TI - [Management of bone metastases]. AB - The skeleton is the most common site to be affected by advanced breast, prostatic, lung, kidney, thyroid and other solid tumors (in addition to myeloma multiplex). Bone metastases cause significant morbidity with nearly always fatal outcome. Over 600 000 new patients diagnosed in the developed countries yearly. On average every 4-6 months patients suffer from series of severe skeletal complications such as pathologic fractures, spinal cord compression, hypercalcemic events, etc., besides the permanent pain. Local external beam radiotherapy, systemic radioisotope-, endocrine-, and chemotherapy, oral and i.v. bisphosphonates and recently s.c. denosumab are the mainstays of treatment, in addition to pain-killers and other usual "classical" interventions. The modern treatments singificantly reduce the probability of skeletal complications and improve the patients' quality of life and, sometimes, they extend the survival as well. The authors briefly summarize the available treatment options. PMID- 24486847 TI - [Prof. Dr. Gyula Szegedi, member of the Hungarian Academy of Sciences (1936 2013)]. PMID- 24486848 TI - [Caesarean sections of the Esterhazy regiments' surgeons]. PMID- 24486849 TI - [Uzsoki -- building the hospital of the future. Conversation with Dr. Andrea Ficzere]. PMID- 24486852 TI - Tuning dissimilarity explains short distance decline of spontaneous spike correlation in macaque V1. AB - Fast spike correlation is a signature of neural ensemble activity thought to underlie perception, cognition, and action. To relate spike correlation to tuning and other factors, we focused on spontaneous activity because it is the common 'baseline' across studies that test different stimuli, and because variations in correlation strength are much larger across cell pairs than across stimuli. Is the probability of spike correlation between two neurons a graded function of lateral cortical separation, independent of functional tuning (e.g. orientation preferences)? Although previous studies found a steep decline in fast spike correlation with horizontal cortical distance, we hypothesized that, at short distances, this decline is better explained by a decline in receptive field tuning similarity. Here we measured macaque V1 tuning via parametric stimuli and spike-triggered analysis, and we developed a generalized linear model (GLM) to examine how different combinations of factors predict spontaneous spike correlation. Spike correlation was predicted by multiple factors including color, spatiotemporal receptive field, spatial frequency, phase and orientation but not ocular dominance beyond layer 4. Including these factors in the model mostly eliminated the contribution of cortical distance to fast spike correlation (up to our recording limit of 1.4mm), in terms of both 'correlation probability' (the incidence of pairs that have significant fast spike correlation) and 'correlation strength' (each pair's likelihood of fast spike correlation). We suggest that, at short distances and non-input layers, V1 fast spike correlation is determined more by tuning similarity than by cortical distance or ocular dominance. PMID- 24486850 TI - Oleanolic acid and its synthetic derivatives for the prevention and therapy of cancer: preclinical and clinical evidence. AB - Oleanolic acid (OA, 3beta-hydroxyolean-12-en-28-oic acid) is a ubiquitous pentacyclic multifunctional triterpenoid, widely found in several dietary and medicinal plants. Natural and synthetic OA derivatives can modulate multiple signaling pathways including nuclear factor-kappaB, AKT, signal transducer and activator of transcription 3, mammalian target of rapamycin, caspases, intercellular adhesion molecule 1, vascular endothelial growth factor, and poly (ADP-ribose) polymerase in a variety of tumor cells. Importantly, synthetic derivative of OA, 2-cyano-3,12-dioxoolean-1,9-dien-28-oic acid (CDDO), and its C 28 methyl ester (CDDO-Me) and C28 imidazole (CDDO-Im) have demonstrated potent antiangiogenic and antitumor activities in rodent cancer models. These agents are presently under evaluation in phase I studies in cancer patients. This review summarizes the diverse molecular targets of OA and its derivatives and also provides clear evidence on their promising potential in preclinical and clinical situations. PMID- 24486851 TI - Prenatal cigarette smoke exposure causes hyperactivity and aggressive behavior: role of altered catecholamines and BDNF. AB - Smoking during pregnancy is associated with a variety of untoward effects on the offspring. However, recent epidemiological studies have brought into question whether the association between neurobehavioral deficits and maternal smoking is causal. We utilized an animal model of maternal smoking to determine the effects of prenatal cigarette smoke (CS) exposure on neurobehavioral development. Pregnant mice were exposed to either filtered air or mainstream CS from gestation day (GD) 4 to parturition for 4h/d and 5d/wk, with each exposure producing maternal plasma concentration of cotinine equivalent to smoking <1 pack of cigarettes per day (25ng/ml plasma cotinine level). Pups were weaned at postnatal day (PND) 21 and behavior was assessed at 4weeks of age and again at 4-6months of age. Male, but not female, offspring of CS-exposed dams demonstrated a significant increase in locomotor activity during adolescence and adulthood that was ameliorated by methylphenidate treatment. Additionally, male offspring exhibited increased aggression, as evidenced by decreased latency to attack and number of attacks in a resident-intruder task. These behavioral abnormalities were accompanied by a significant decrease in striatal and cortical dopamine and serotonin and a significant reduction in brain-derived neurotrophic factor (BDNF) mRNA and protein. Taken in concert, these data demonstrate that prenatal exposure to CS produces behavioral alterations in mice that are similar to those observed in epidemiological studies linking maternal smoking to neurodevelopmental disorders. Further, these data also suggest a role for monaminergic and BDNF alterations in these effects. PMID- 24486853 TI - Enhancing the effect of 5-aminolevulinic acid based photodynamic therapy in human meningioma cells. AB - BACKGROUND: The interest in photodynamic therapy (PDT) in cancer treatment has continuously increased since its' advent in the 1960s. In neurosurgery, 5 aminolevulinic acid based photodynamic therapy (5-ALA PDT) is used for malignant glioma in vitro and in vivo. Data about PDT in meningioma, which is the second most frequent primary brain tumor, is sparse. Preliminary work indicated that meningiomas are more resistant to PDT than gliomas. In the present study we evaluated whether the effect of 5-ALA PDT on malignant meningioma cells can be increased by ciprofloxacin and changes in incubation time, factors known to influence the effectiveness of PDT in other tumor entities. METHODS: An in vitro PDT model of a malignant human meningioma cell line (KT21-MG) was chosen as screening method. Cultured cells were incubated with varying 5-ALA concentrations for 4h and exposed to PDT (control group). Two experimental groups, one with 5 ALA and ciprofloxacin (group I) and one with 24-h ALA incubation time (group II), were studied, respectively. Cell viability was assessed by WST-1 assay. RESULTS: Ciprofloxacin and longer ALA incubation time significantly increased the lethal effect of 5-ALA PDT on meningioma cells. CONCLUSIONS: Efficacy of 5-ALA PDT could be increased by adjunction of ciprofloxacin in conventional clinical dosing and by prolongation of ALA incubation time. As ciprofloxacin is a common antibiotic with good tissue penetration, low toxicity and a favorable risk profile it represents a clinically interesting method for future PDT trials in meningiomas. PMID- 24486854 TI - Water movement and fate of nitrogen during drip dispersal of wastewater effluent into a semi-arid landscape. AB - Drip dispersal of partially treated wastewater was investigated as an approach for onsite water reclamation and beneficial reuse of water and nutrients in a semi-arid climate. At the Mines Park Test Site in Golden, Colorado, a drip dispersal system (DDS) was installed at 20- to 30-cm depth in an Ascalon sandy loam soil profile. Two zones with the same layout were established to enable study of two different hydraulic loading rates. Zones 1 and 2 each had one half of the landscape surface with native vegetation and the other with Kentucky bluegrass sod. After startup activities, domestic septic tank effluent was dispersed five times a day at footprint loading rates of 5 L/m(2)/d for Zone 1 and 10 L/m(2)/d for Zone 2. Over a two-year period, monitoring included the frequency and volume of effluent dispersed and its absorption by the landscape. After the first year of operation in October a (15)N tracer test was completed in the sodded portion of Zone 1 and samples of vegetation and soil materials were collected and analyzed for water content, pH, nitrogen, (15)N, and bacteria. Research revealed that both zones were capable of absorbing the effluent water applied at 5 or 10 L/m(2)/d. Effluent water dispersed from an emitter infiltrates at the emitter and along the drip tubing and water movement is influenced by hydrologic conditions. Based on precipitation and evapotranspiration at the Test Site, only a portion of the effluent water dispersed migrated downward in the soil (approx. 34% or 64% for Zone 1 or 2, respectively). Sampling within Zone 1 revealed water filled porosities were high throughout the soil profile (>85%) and water content was most elevated along the drip tubing (17-22% dry wt.), which is also where soil pH was most depressed (pH 4.5) due to nitrification reactions. NH4(+) and NO3(-) retention occurred near the dispersal location for several days and approximately 51% of the N applied was estimated to be removed by plant uptake and denitrification. Heterotrophic bacteria levels were elevated (up to 1 log) in the subsurface within the DDS but there was effective elimination of effluent fecal coliform and Escherichia coli bacteria. PMID- 24486855 TI - Drinking water quality and hospital admissions of elderly people for gastrointestinal illness in Eastern Massachusetts, 1998-2008. AB - We used a Poisson regression to compare daily hospital admissions of elderly people for acute gastrointestinal illness in Boston against daily variations in drinking water quality over an 11-year period, controlling for weather, seasonality and time trends. The Massachusetts Water Resources Authority (MWRA), which provides non-filtered water to 1.5 million people in the greater Boston area, changed its disinfection method from chlorination to ozonation during the study period so we were also able to evaluate changes in risk associated with the change in disinfection method. Other available water quality data from the MWRA included turbidity, fecal coliforms, UV-absorbance, and planktonic algae and cyanobacteriae concentrations. Daily weather, rainfall data and water temperature were also available. Low water temperature, increases in turbidity and, to a lesser extent, in fecal coliform and cyanobacteriae were associated with a higher risk of hospital admissions, while the shift from chlorination to ozonation has possibly reduced the health risk. The MWRA complied with US drinking water regulations throughout the study period. PMID- 24486856 TI - Three-dimensional architecture of macrofibrils in the human scalp hair cortex. AB - Human scalp hairs are comprised of a central cortex enveloped by plate-like cuticle cells. The elongate cortex cells of mature fibres are composed primarily of macrofibrils-bundles of hard-keratin intermediate filaments (IFs) chemically cross-linked within a globular protein matrix. In wool, three cell types (ortho-, meso- and paracortex) contain macrofibrils with distinctly different filament arrangements and matrix fractions, but in human hair macrofibril-cell type relationships are less clear. Here we show that hair macrofibrils all have a similar matrix fraction (~0.4) and are typically composed of a double-twist architecture in which a central IF is surrounded by concentric rings of tangentially-angled IFs. The defining parameter is the incremental angle increase (IF-increment) between IFs of successive rings. Unlike the wool orthocortex, hair double-twist macrofibrils have considerable inter-macrofibril variation in IF increment (0.05-0.35 degrees /nm), and macrofibril size and IF increment are negatively correlated. Correspondingly, angular difference between central and outer-most IFs is up to 40 degrees in small macrofibrils, but only 5-10 degrees in large macrofibrils. Single cells were observed containing mixtures of macrofibrils with different diameters. These new observations advance our understanding of the nano-level and cell-level organisation of human hair, with implications for interpretation of structure with respect the potential roles of cortex cell types in defining the mechanical properties of hair. PMID- 24486857 TI - In vivo biodistribution of platinum-based drugs encapsulated into multi-walled carbon nanotubes. AB - Carbon nanotubes (CNTs) are promising drug delivery systems due to their external functionalizable surface and their hollowed cavity that can encapsulate several bioactive molecules. In this study, the chemotherapeutic drug cisplatin or an inert platinum(IV) complex were entrapped inside functionalized-multi-walled-CNTs and intravenously injected into mice to investigate the influence of CNTs on the biodistribution of Pt-based molecules. The platinum levels in vital organs suggested that functionalized-CNTs did not affect cisplatin distribution, while they significantly enhanced the accumulation of Pt(IV) sample in some tissues (e.g. in the lungs, suggesting their potential application in lung cancer therapy) and reduced both kidney and liver accumulation (thus decreasing eventual nephrotoxicity, a typical side effect of cisplatin). Concurrently, CNTs did not induce any intrinsic abnormal immune response or inflammation, as confirmed by normal cytokine levels and histological evaluations. Therefore, functionalized nanotubes represent an efficient nano-carrier to improve accumulation of Pt species in targeted tissues/organs. From the clinical editor: In this preclinical study functionalized carbon nanotubes are reported to be safe and efficient for targeted delivery of platinum-containing compounds in rodents. Approaches like this may improve the treatment of specific cancers, since platinum based chemotherapies are commonly used, yet limited by toxicity and relatively poor target tissue concentration. PMID- 24486858 TI - Spectrum of short bowel syndrome in adults: intestinal insufficiency to intestinal failure. AB - Short bowel syndrome (SBS) refers to the malabsorptive state caused by physical or functional loss of portions of the small intestine, most commonly following extensive intestinal resection. Such resections hinder absorption of adequate amounts of macronutrients, micronutrients, electrolytes, and water, resulting in malnutrition, diarrhea, and dehydration. Clinical features of SBS vary along a continuum, depending on the extent and anatomy of intestine lost and the ability of the patient and the remaining intestine to compensate for the loss. The impact of SBS can be extensive, leading to diminished health-related quality of life because of its many physical and psychological effects on patients. SBS is associated with decreased survival; risk factors for SBS-related mortality include very short remnant small bowel, end-jejunal remnant anatomy, and arterial mesenteric infarction as primary cause. Although parenteral nutrition and/or intravenous fluid (PN/IV) is a life-saving measure for many patients with SBS, patients with the most severe malabsorption (ie, dependent on PN/IV) are at risk for severe, chronic complications and death. Patients' treatment needs vary depending on disease severity and resection type; thus, each patient should be individually managed. This review discusses the spectrum of disease in patients with SBS and presents common complications encountered by these patients to highlight the importance of individualized management and treatment. PMID- 24486859 TI - Impact of Postoperative Weight Loss on Survival After Resection for Pancreatic Cancer. AB - BACKGROUND: The aim of this study was to assess the effects of postoperative body weight loss on long-term survival after resection for pancreatic cancer. METHODS: A total of 93 patients with primary pancreatic cancer underwent pancreatic resection between April 2005 and December 2011. Patient characteristics, preoperative body mass index, and changes in postoperative body weight were evaluated retrospectively and correlated with long-term survival. RESULTS: There was no significant association between survival and preoperative body mass index. Body weight fell by 8.4% at 2 months after surgery and by 9.0% at 4 months after surgery. Severe postoperative body weight losses, both at 2 months (P = .033) and 4 months (P = .014) after surgery, were significantly associated with poor prognosis, especially among patients with stage IA-IIA pancreatic cancer (n = 43) (P = .005 at 2 months and P < .001 at 4 months). Additionally, severe body weight loss tended to be associated with shorter survival among patients with stage IIB III pancreatic cancer (n = 50), although the difference was not significant. Multivariate analysis revealed that postoperative body weight loss was an independent prognostic factor. CONCLUSIONS: The results of this study demonstrated that pancreatic cancer patients with severe postoperative body weight loss have poorer postoperative outcomes. PMID- 24486860 TI - Three-dimensional hollow intracranial aneurysm models and their potential role for teaching, simulation, and training. PMID- 24486861 TI - A sensitive and robust HPLC assay with fluorescence detection for the quantification of pomalidomide in human plasma for pharmacokinetic analyses. AB - Pomalidomide is a second generation IMiD (immunomodulatory agent) that has recently been granted approval by the Food and Drug Administration for treatment of relapsed multiple myeloma after prior treatment with two antimyeloma agents, including lenalidomide and bortezomib. A simple and robust HPLC assay with fluorescence detection for pomalidomide over the range of 1-500ng/mL has been developed for application to pharmacokinetic studies in ongoing clinical trials in various other malignancies. A liquid-liquid extraction from human plasma alone or pre-stabilized with 0.1% HCl was performed, using propyl paraben as the internal standard. From plasma either pre-stabilized with 0.1% HCl or not, the assay was shown to be selective, sensitive, accurate, precise, and have minimal matrix effects (<20%). Pomalidomide was stable in plasma through 4 freeze-thaw cycles (<12% change), in plasma at room temperature for up to 2h for samples not pre-stabilized with 0.1% HCl and up to 8h in samples pre-stabilized with 0.1% HCl, 24h post-preparation at 4 degrees C (<2% change), and showed excellent extraction recovery (~90%). This is the first reported description of the freeze/thaw and plasma stability of pomalidomide in plasma either pre-stabilized with 0.1% HCl or not. The information presented in this manuscript is important when performing pharmacokinetic analyses. The method was used to analyze clinical pharmacokinetics samples obtained after a 5mg oral dose of pomalidomide. This relatively simple HPLC-FL assay allows a broader range of laboratories to measure pomalidomide for application to clinical pharmacokinetics. PMID- 24486862 TI - Influence of electron beam irradiation on spectral, thermal, morphological and catalytic properties of Co(II) complex immobilized on chitosan's Schiff base. AB - This study was carried out to investigate the effect of electron beam irradiation on the spectral and catalytic properties of chitosan supported (ONClCl) tetra coordinated Co(II) complex, [Co(OIAC)Cl2]. The complex was subjected to electron beam irradiation of 100 Gy, 1 kGy and 10 kGy doses. Chain scission of chitosan was observed on irradiation at 100 Gy and 10 kGy and chain linking at 1 kGy as evidenced by viscosity and FT-IR spectroscopic studies. This observation was also confirmed by thermo gravimetric and differential thermogravimetric (TG-DTG) analysis. It revealed that the thermal stability of the complex was increased at 1 kGy irradiation and decreased at 100 Gy and 10 kGy. In addition, the effect of electron beam irradiation on the surface morphology of the complex was studied by scanning electron microscopy. Catalytic abilities of both non-irradiated complex and irradiated complexes were determined and compared in the cyclohexane oxidation using hydrogen peroxide oxidant. The catalytic activity was found to increase after irradiation at all doses. Though the complex irradiated at 10 kGy showed highest conversion efficiency, irradiation at 1 kGy is suggested as the best dose due to the extensive reusability and adequate catalytic ability of the complex. PMID- 24486863 TI - Lemon peels mediated synthesis of silver nanoparticles and its antidermatophytic activity. AB - There is an increasing commercial demand for nanoparticles due to their wide applicability in various areas. Metallic nanoparticles are traditionally synthesized by wet chemical techniques, where the chemicals used are quite often toxic and flammable. In this work, The extract of lemon peel was prepared and mixed with 1 mM AgNO3 solution .The bioreduction of Ag(+) ion in solution was monitored using UV-visible spectrometer, FESEM and EDAX analysis. Skin scales were collected from patients with suspected dermatophytosis and the dermatophytes were isolated and identified. The AgNPs produced from lemon peels showed good activity against the isolated dermatophytes. The present research work emphasizes the use of lemon peels for the effective synthesize of AgNPs and could be used against the dermatophytes which are found to develop drug resistant towards broad spectrum antibiotics. The biosynthesis of AgNPs using lemon peel extract is very simple and economic. The use of environmentally benign and renewable plant material offers enormous benefits of eco-friendliness. PMID- 24486864 TI - The structures of heterocyclic complexes ruled by hydrogen bonds and halogen interactions: interaction strength and IR modes. AB - In this work, the existence of multiple interactions in heterocyclic complexes of C2H4O?nHCCl3 and C2H4S?nHCCl3 with n=2 and 3 was unveiled at the B3LYP/6 311++G(d,p) level of theory. The forward analyses of the vibrational spectra revealed the appearing of red-shifts in the H-C bond. In agreement with this and through the optimized geometries of these systems, an increase in the H-C bond length was also observed. Besides O?H and S?H, other hydrogen bonds formed between chlorine?hydrogen and mainly the halogen interactions formed by chlorine?chlorine were identified. Thereby, the vibration spectra of the heterocyclic complexes were reanalyzed with the purpose to locate new red-shifts, although only those characterized in H-C have been detected up to then. In addition to the correlation between the frequencies shifted to downward values followed by increases in the bond lengths, the interpretation of the red-shifts was conducted by means of the Bent rule of the hybridization theory. The interaction strength was examined in several viewpoints, and one of them was the relationship between the H-bond energies and the intermolecular electronic density computed by means of the Quantum Theory of Atoms in Molecules (QTAIM). Moreover, the prediction of the interaction strength was also made through the combination between vibration modes (red-shifts) and variation of topological parameters, such as the electronic density and Laplacian of the proton donor bond (C-H). PMID- 24486865 TI - Vibrational spectroscopic [FT-IR, FT-Raman] investigation on (2,4,5 Trichlorophenoxy) Acetic acid using computational [HF and DFT] analysis. AB - In the present methodical study, FT-IR, FT-Raman and NMR spectra of the (2,4,5 Trichlorophenoxy) Acetic acid are recorded. The observed fundamental frequencies (IR and Raman) are assigned according to their distinctiveness region. The hybrid computational calculations are carried out by HF and DFT (B3LYP and B3PW91) methods with 6-31++G(d,p) and 6-311++G(d,p) basis sets and the corresponding results are tabulated. The impact of the presence of tri-chlorine atoms in phenyl structure of the compound is investigated. The vibrational sequence pattern of the molecule related to CH2COOH is analyzed. Moreover, (13)C NMR and (1)H NMR are calculated by using the gauge independent atomic orbital (GIAO) method with B3LYP methods and the 6-311++G(d,p) basis set and their spectra are simulated and the chemical shifts related to TMS are compared. A study on the electronic and optical properties; absorption wavelengths, excitation energy, dipole moment and frontier molecular orbital energies, are performed by HF and DFT methods. The Kubo gap of the present compound is calculated related to HOMO and LUMO energies which confirm the occurring of charge transformation between the base and ligand group. Besides frontier molecular orbitals (FMO), molecular electrostatic potential (MEP) was performed. NLO properties related to Polarizability and hyperpolarizability are also discussed. PMID- 24486866 TI - Accurate calculations on the 22 electronic states and 54 spin-orbit states of the O2 molecule: potential energy curves, spectroscopic parameters and spin-orbit coupling. AB - The potential energy curves (PECs) of 54 spin-orbit states generated from the 22 electronic states of O2 molecule are investigated for the first time for internuclear separations from about 0.1 to 1.0nm. Of the 22 electronic states, the X(3)Sigmag(-), A(')(3)Deltau, A(3)Sigmau(+), B(3)Sigmau(-), C(3)Pig, a(1)Deltag, b(1)Sigmag(+), c(1)Sigmau(-), d(1)Pig, f(1)Sigmau(+), 1(5)Pig, 1(3)Piu, 2(3)Sigmag(-), 1(5)Sigmau(-), 2(1)Sigmau(-) and 2(1)Deltag are found to be bound, whereas the 1(5)Sigmag(+), 2(5)Sigmag(+), 1(1)Piu, 1(5)Deltag, 1(5)Piu and 2(1)Piu are found to be repulsive ones. The B(3)Sigmau(-) and d(1)Pig states possess the double well. And the 1(3)Piu, C(3)Pig, A'(3)Deltau, 1(5)Deltag and 2(5)Sigmag(+) states are the inverted ones when the spin-orbit coupling is included. The PEC calculations are done by the complete active space self consistent field (CASSCF) method, which is followed by the internally contracted multireference configuration interaction (icMRCI) approach with the Davidson correction. Core-valence correlation and scalar relativistic corrections are taken into account. The convergence of present calculations is evaluated with respect to the basis set and level of theory. The vibrational properties are discussed for the 1(5)Pig, 1(3)Piu, d(1)Pig and 1(5)Sigmau(-) states and for the second well of the B(3)Sigmau(-) state. The spin-orbit coupling effect is accounted for by the state interaction method with the Breit-Pauli Hamiltonian. The PECs of all the electronic states and spin-orbit states are extrapolated to the complete basis set limit. The spectroscopic parameters are obtained, and compared with available experimental and other theoretical results. Analyses demonstrate that the spectroscopic parameters reported here can be expected to be reliably predicted ones. The conclusion is obtained that the effect of spin-orbit coupling on the spectroscopic parameters are small almost for all the electronic states involved in this paper except for the 1(5)Sigmau(-), 1(5)Pig and 1(3)Piu. PMID- 24486867 TI - New luminescent 2-methoxy-6-(4-methoxy-phenyl)-4-p-tolyl-nicotinonitrile: synthesis, crystal structure, DFT and photophysical studies. AB - In the current communication, we report the synthesis, spectroscopic, crystal structure, DFT and photophysical studies of a new nicotinonitrile derivative, viz. 2-methoxy-6-(4-methoxy-phenyl)-4-p-tolyl-nicotinonitrile (2) as a potential blue light emitting material. The compound 2 was synthesized in good yield via a simple route. The acquired spectral and elemental analysis data were in consistent with the chemical structure of 2. The single crystal study further confirms its three dimensional structure, molecular shape, and nature of short contacts. Its DFT calculations reveal that compound 2 possesses a non-planar structure and its theoretical IR spectral data are found to be in accordance with experimental values. In addition, its UV-visible and fluorescence spectral measurements prove that the compound exhibits good absorption and fluorescence properties. Also, it shows positive solvatochromic effect when the solvent polarity was varied from non-polar to polar. PMID- 24486868 TI - A highly sensitive and selective assay of doxycycline by dualwavelength overlapping resonance Rayleigh scattering. AB - A dual-wavelength overlapping resonance Rayleigh scattering (DWO-RRS) method was developed and validated for highly sensitive and selective assay of doxycycline residues in several meat samples. The response signals were dependent on the specific multi-site coordination between lanthanum(III) and doxycycline (DOTC). And La(III)-DOTC complex would further aggregate to form [La(III)-DOTC]n nanoparticles, resulting in the occurrence of two new scattering peaks. Notably, with the addition of DOTC, the increments of both of these two wavelengths were proportional to the concentration of DOTC over the ranges of 3.9-4.0*10(3) nmol L(-1) (1.7-1.8*10(3) MUg/kg). The detection limit of DWO-RRS was 1.1 nmol L(-1) (0.5 MUg/kg), which was lower than or comparable to most of the published methods. Additionally, the generating mechanisms of multi-response RRS signals were discussed and a semi-empirical principle was established for better design of multi-response RRS probes. PMID- 24486869 TI - Sensitized luminescence of Eu(III) complexes with Schiff-base and 1,10 phenanthroline: role of Schiff-base as a sensitizer. AB - The synthesis and characterization of two europium(III) complexes, [Eu(L)(H2O)]Cl and [Eu(L)(phen)(H2O)]Cl (L=N,N'-bis(salicylidene)-3,6-dioxa-1,8-diaminooctanato and phen=1,10-phenanthroline) are reported. Exciting the Eu(III) complexes with near-UV light resulted in sensitized red luminescence by a transfer of energy from the triplet excited states of L to the Eu(III) ion. Introducing phen to the complex increased the quantum yield of the L-sensitized luminescence of [Eu(L)(phen)(H2O)](+) by more than 18 times relative to [Eu(L)(H2O)](+). The optimized structures and the configurational interaction singles (CIS) of the [Eu(L)(phen)(H2O)](+) and [Eu(L)(H2O)](+) molecules were theoretically studied using ab initio Hartree-Fock (HF). The theoretical calculations showed that the first nearly degenerate 1A and 2A excited states, more specifically the pi->pi(*) transitions of the two phenolate terminals, contributed significantly to the energy transfer process. Although the phen excitation route was forbidden in [Eu(L)(phen)(H2O)](+), the coordination of phen enhanced the absorbing ability of L markedly and caused the energy transfer from the 1A and 2A states to the (5)D1 and (5)D0 states of Eu(III) to predominate over any radiative and nonradiative processes occurring between the excited states and the ground states of the L moiety. Consequently, the quantum yield of the sensitized luminescence was enhanced significantly in [Eu(L)(phen)(H2O)](+). PMID- 24486870 TI - Population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children with tuberculosis: in silico evaluation of currently recommended doses. AB - OBJECTIVES: To describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid in children and evaluate the adequacy of steady-state exposures. PATIENTS AND METHODS: We used previously published data for 76 South African children with tuberculosis to describe the population pharmacokinetics of rifampicin, pyrazinamide and isoniazid. Monte Carlo simulations were used to predict steady-state exposures in children following doses in fixed-dose combination tablets in accordance with the revised guidelines. Reference exposures were derived from an ethnically similar adult population with tuberculosis taking currently recommended doses. RESULTS: The final models included allometric scaling of clearance and volume of distribution using body weight. Maturation was included for clearance of isoniazid and clearance and absorption transit time of rifampicin. For a 2-year-old child weighing 12.5 kg, the estimated typical oral clearances of rifampicin and pyrazinamide were 8.15 and 1.08 L/h, respectively. Isoniazid typical oral clearance (adjusted for bioavailability) was predicted to be 4.44, 11.6 and 14.6 L/h for slow, intermediate and fast acetylators, respectively. Higher oral clearance values in intermediate and fast acetylators also resulted from 23% lower bioavailability compared with slow acetylators. CONCLUSIONS: Simulations based on our models suggest that with the new WHO dosing guidelines and utilizing available paediatric fixed-dose combinations, children will receive adequate rifampicin exposures when compared with adults, but with a larger degree of variability. However, pyrazinamide and isoniazid exposures in many children will be lower than in adults. Further studies are needed to confirm these findings in children administered the revised dosages and to optimize pragmatic approaches to dosing. PMID- 24486871 TI - Proteogenomic characterization of antimicrobial resistance in extensively drug resistant Acinetobacter baumannii DU202. AB - OBJECTIVES: To determine the genomic sequence of extensively drug-resistant Acinetobacter baumannii DU202 and to perform proteomic characterization of antibiotic resistance in this strain using genome data. METHODS: The genome sequence of A. baumannii DU202 was determined using the Hi-Seq 2000 system and comparative analysis was performed to determine the unique characteristics of A. baumannii DU202. Previous proteomic results from the cell wall membrane fraction by one-dimensional electrophoresis and liquid chromatography combined with mass spectrometry analysis (1DE-LC-MS/MS), using the A. baumannii ATCC 17978 genome as a reference, were reanalysed to elucidate the resistance mechanisms of A. baumannii DU202 using strain-specific genome data. Additional proteomic data from the cytosolic fraction were also analysed. RESULTS: The genome of A. baumannii DU202 consists of 3660 genes and is most closely related to the Korean A. baumannii 1656-2 strain. More than 144 resistance genes were annotated in the A. baumannii DU202 genome, of which 72 that encoded proteins associated with antibiotic resistance were identified in the proteomic analysis of A. baumannii DU202 cultured in tetracycline, imipenem and Luria-Bertani broth (control) medium. Strong induction of beta-lactamases, a multidrug resistance efflux pump and resistance-nodulation-cell division (RND) multidrug efflux proteins was found to be important in the antibiotic resistance responses of A. baumannii DU202. CONCLUSIONS: Combining genomic and proteomic methods provided comprehensive information about the unique antibiotic resistance responses of A. baumannii DU202. PMID- 24486872 TI - Prevalence and molecular characterization of azole resistance in Aspergillus spp. isolates from German cystic fibrosis patients. AB - OBJECTIVES: Aspergillus spp. are the most frequently isolated filamentous fungi in the sputum of patients with cystic fibrosis (CF). Resistance to the azoles, the mainstay of current antifungal therapy, has been increasingly observed worldwide, but few data are available on the resistance of Aspergillus spp. in German CF patients. This study investigated the epidemiology of Aspergillus spp. and the molecular origin of azole resistance in a large German CF centre. METHODS: In total, 2677 respiratory samples from 221 CF patients collected between April 2010 and April 2013 were analysed; of these, 573 yielded Aspergillus spp., which were screened for azole resistance. Isolates with reduced susceptibility to itraconazole and/or voriconazole were tested according to the EUCAST reference procedure. Sequencing of cyp51A, the target of azole antifungals, was performed in all resistant isolates. RESULTS: Six isolates obtained from four patients were highly resistant to itraconazole (all identified as Aspergillus fumigatus sensu stricto); five of them were pan-azole resistant. The TR34/L98H mutation was the most frequent mutation identified in azole resistant isolates (n = 4), followed by M220L and TR46/Y121F/T289A, a mutation previously reported from Belgium and the Netherlands only. Three of four patients harbouring azole-resistant A. fumigatus had not received any prior azole treatment. CONCLUSIONS: Resistance to azoles in Aspergillus spp. is still infrequent in German CF patients and is mainly caused by the TR34/L98H mutation. Worryingly, pan-azole-resistant TR46/Y121F/T289A has spread to Germany. Azole resistance has to be considered also in azole-naive CF patients and susceptibility testing of Aspergillus spp. isolates should be performed in all patients requiring treatment. PMID- 24486873 TI - Mechanical alloydnia induced by traumatic brain injury is independent of restraint stress. AB - BACKGROUND: This study identifies the relationship between a test for post traumatic headache and a marker for acute stress in rodent models of traumatic brain injury. NEW METHOD: C57BL/6 mice and Sprague Dawley rats were divided into Controlled Cortical Impact (CCI) injury, craniotomy (CR), and incision groups. Periorbital and paw allodynia were evaluated using the von Frey test prior to injury and up to four weeks post-operatively. Serum corticosterone was evaluated in groups with and without mild restraint. RESULTS: Periorbital and forepaw thresholds, but not hindpaw thresholds, were reduced in CCI and CR mice compared to incision (p<0.0001 and p<0.01). In contrast to mice, reduced periorbital and forepaw periorbital thresholds were found in CCI rats but not CR rats compared to incision (p<0.0001). Right periorbital thresholds were reduced compared to left thresholds for both rat and mouse at one week (p<0.01), but there were no side differences for forepaw thresholds. Hindpaw thresholds did not change from baseline values for any groups of mice or rats. In mice serum corticosterone levels were increased at one, two and four weeks post-CCI and CR, while the levels for rats were not different from incision (p<0.0001). Corticosterone levels were not different in mice subjected to restraint compared to no restraint. COMPARISON WITH EXISTING METHODS: This study presents novel data for allodynia in a rat model of TBI, and differences among mouse and rat species. CONCLUSIONS: Mechanical allodynia occurs independent of evoked restraint stress, while hypothalamic pituitary adrenal axis activity is dependent on head trauma and species. PMID- 24486874 TI - An iterative subspace denoising algorithm for removing electroencephalogram ocular artifacts. AB - BACKGROUND: Electroencephalogram (EEG) measurements are always contaminated by non-cerebral signals, which disturb EEG interpretability. Among the different artifacts, ocular artifacts are the most disturbing ones. In previous studies, limited improvement has been obtained using frequency-based methods. Spatial decomposition methods have shown to be more effective for removing ocular artifacts from EEG recordings. Nevertheless, these methods are not able to completely separate cerebral and ocular signals and commonly eliminate important features of the EEG. NEW METHOD: In a previous study we have shown the applicability of a deflation algorithm based on generalized eigenvalue decomposition for separating desired and undesired signal subspaces. In this work, we extend this idea for the automatic detection and removal of electrooculogram (EOG) artifacts from multichannel EEG recordings. The notion of effective number of identifiable dimensions, is also used to estimate the number of dominant dimensions of the ocular subspace, which enables the precise and fast convergence of the algorithm. RESULTS: The method is applied on real and synthetic data. It is shown that the method enables the separation of cerebral and ocular signals with minimal interference with cerebral signals. COMPARISON WITH EXISTING METHOD(S): The proposed approach is compared with two widely used denoising techniques based on independent component analysis (ICA). CONCLUSIONS: It is shown that the algorithm outperformed ICA-based approaches. Moreover, the method is computationally efficient and is implemented in real-time. Due to its semi-automatic structure and low computational cost, it has broad applications in real-time EEG monitoring systems and brain-computer interface experiments. PMID- 24486875 TI - Application of adaptive nonlinear Granger causality: disclosing network changes before and after absence seizure onset in a genetic rat model. AB - BACKGROUND: Advanced methods of signal analysis of the preictal and ictal activity dynamics characterizing absence epilepsy in humans with absences and in genetic animal models have revealed new and unknown electroencephalographic characteristics, that has led to new insights and theories. NEW METHOD: Taking into account that some network associations can be considered as nonlinear, an adaptive nonlinear Granger causality approach was developed and applied to analyze cortico-cortical, cortico-thalamic and intrathalamic network interactions from local field potentials (LFPs). The outcomes of adaptive nonlinear models, constructed based on the properties of electroencephalographic signal and on statistical criteria to optimize the number of coefficients in the models, were compared with the outcomes of linear Granger causality. RESULTS: The nonlinear adaptive method showed statistically significant preictal changes in Granger causality in almost all pairs of channels, as well as ictal changes in cortico cortical, cortico-thalamic and intrathalamic networks. Current results suggest rearrangement of interactions in the thalamo-cortical network accompanied the transition from preictal to ictal phase. COMPARISON WITH EXISTING METHOD(S): The linear method revealed no preictal and less ictal changes in causality. CONCLUSIONS: Achieved results suggest that this proposed adaptive nonlinear method is more sensitive than the linear one to dynamics of network properties. Since changes in coupling were found before the seizure-related increase of LFP signal amplitude and also based on some additional tests it seems likely that they were not spurious and could not result from signal to noise ratio change. PMID- 24486876 TI - The IBB forelimb scale as a tool to assess functional recovery after peripheral nerve injury in mice. AB - BACKGROUND: This study was conducted to test whether the IBB Forelimb Scale (Irvine et al., 2010) which was originally developed for rats with spinal cord injury, is also capable of measuring the functional performance of Swiss mice with lesions of the median and ulnar nerves inflicted via crushing with standardized strength. NEW METHOD: This test was performed at days 1, 3, 7, 10, 14 and 21 after surgery and each animal gives a score of 9, where 0 represented the worst functionality and 9 represented the habitual behavior. RESULTS: The control animals usually exhibited movements in the task that were scored as 9 during the experimental period. The lesion group began with a score of 2 on the 1st and 3rd post-operative days. On the 7th and 10th postoperative days, respectively, they scored 7, and on the 14th post-operative day, they achieved a score of 8. Only on the 21st post-operative day, did they exhibit habitual skillful behaviors. COMPARISON WITH EXISTING METHOD(S): IBB Forelimb Scale is effective for determining how the animals perform the movements in detail, which is not readily revealed by other methods. Furthermore, this test show similar recovery periods with grasping test, staircase test and seems to be more sensitive than paw print analysis for this type of lesion. CONCLUSIONS: Our data demonstrate that IBB scale was capable of measuring gradual improvements in motor forelimb functions in this model and may be a new and effective assessment tool for peripheral nerve injury. PMID- 24486877 TI - Implementation of a chronic unilateral intraparenchymal drug delivery system in a swine model. AB - BACKGROUND: Systemic delivery of pharmacologic agents has led to many significant advances in the treatment of neurologic and psychiatric conditions. However, this approach has several limitations, including difficulty penetrating the blood brain barrier and enzymatic degradation prior to reaching its intended target. Here, we describe the testing of a system allowing intraparenchymal (IPa) infusion of therapeutic agents directly to the appropriate anatomical targets, in a swine model. NEW METHOD: Five male pigs underwent 3.0T magnetic resonance (MR) guided placement of an IPa catheter into the dorso-medial putamen, using a combined system of the Leksell stereotactic arc, a Mayo-developed MRI-compatible pig head frame, and a custom-designed Fred Haer Company (FHC) delivery system. RESULTS: Our results show hemi-lateral coverage of the pig putamen is achievable from a single infusion point and that the volume of the bolus detected in each animal is uniform (1544+/-420mm(3)). COMPARISON WITH EXISTING METHOD: The IPa infusion system is designed to isolate the intracranial catheter from bodily induced forces while delivering drugs and molecules into the brain tissue by convection-enhanced delivery, with minimal-to-no catheter track backflow. CONCLUSION: This study presents an innovative IPa drug delivery system, which includes a sophisticated catheter and implantable pump designed to deliver drugs and various molecules in a precise and controlled manner with limited backflow. It also demonstrates the efficacy of the delivery system, which has the potential to radically impact the treatment of a wide range of neurologic conditions. Lastly, the swine model used here has certain advantages for translation into clinical applications. PMID- 24486878 TI - Fossil-calibrated phylogeny and historical biogeography of Southeast Asian water monitors (Varanus salvator Complex). AB - We utilize robust geographical genetic sampling, a multilocus dataset, a new synthesis of numerous fossil calibration points, a time-calibrated phylogeny, and the Dispersal-Extinction-Cladogenesis model to test the prediction that widespread Southeast Asian water monitor species initially diversified on the Asian mainland and subsequently invaded the island archipelagos of the Philippines, Sundaland, and Wallacea. Our results strongly contradict these expectations and instead infer an initial water monitor radiation of range restricted but highly divergent evolutionary lineages (now recognized as endemic species) in one archipelago around 3.6 mya, followed by an out-of-the-Philippines reinvasion of the mainland (2.2 mya), resulting in a few, widespread species that now inhabit most the islands of the Sunda Shelf and the Southeast Asian mainland as far north as Myanmar, as well as an out-of-the-Philippines invasion of Sulawesi (2.1 mya). Our analyses both confirm the importance of island archipelagos as drivers of diversification for mainland biodiversity and emphasize the global evolutionary significance and conservation priority of the Philippines for understanding processes of diversification in island archipelagos. PMID- 24486879 TI - Paramecium putrinum (Ciliophora, Protozoa): the first insight into the variation of two DNA fragments - molecular support for the existence of cryptic species. AB - Paramecium putrinum (Claparede & Lachmann 1858) is one of the smallest (80-140 MUm long) species of the genus Paramecium. Although it commonly occurs in freshwater reservoirs, no molecular studies of P. putrinum have been conducted to date. Herein we present an assessment of molecular variation in 27 strains collected from widely separated populations by using two selected DNA fragments (ITS1-5.8S-ITS2-5'LSU rDNA and COI mtDNA). Both the trees and haplotype networks reconstructed for both genome fragments show that the studied strains of P. putrinum form five main haplogroups. The mean distance between the studied strains is p-distance=0.007/0.068 (rDNA/COI) and exhibits similar variability as that between P. bursaria syngens. Based on these data, one could hypothesize that the clusters revealed in the present study may correspond to previously reported syngens and that there are at least five cryptic species within P. putrinum. PMID- 24486880 TI - Effects of the antidepressant venlafaxine on fish brain serotonin and predation behavior. AB - Antidepressants that enter receiving waters through final treated wastewater effluent have exhibited relatively low acute toxicity in traditional fish tests at currently measured concentrations. However, the psychotropic mode of action of these compounds warrants examination of the behavioral effects these chemicals may have on aquatic organisms. Previous research has demonstrated that exposure to the antidepressant fluoxetine causes decreased brain serotonin levels in fish and results in a decreased ability to capture prey. Another antidepressant, venlafaxine, has been found at low MUg/L concentrations in final treated wastewater effluent. The objective of this study was to quantify the effects of venlafaxine on fish predation behavior and determine if this effect was correlated with changes in brain neurotransmitter concentrations. The predator prey bioassay used hybrid striped bass (Morone saxatilis x Morone chrysops) as the predator and fathead minnows (Pimephales promelas) as prey. Bass were exposed to venlafaxine (0-500 MUg/L) for a period of 6 days and then allowed to recover for 6 days. During both exposure and recovery, bass were fed four minnows every third day. The time to capture the minnows was quantified and compared among treatments to determine if there was an effect on predation behavior. Brain tissue was analyzed for serotonin, norepinephrine, and dopamine, to determine the relationship between exposure concentration, brain monoamine levels, and predation behavior. Results indicated that venlafaxine exposures increased time to capture prey 1 and 2 by day 6 for the 250 and 500 MUg/L treatments. Time to capture prey 3 was increased for all venlafaxine treatments by day 6. Venlafaxine caused a statistically significant decrease in brain serotonin concentrations that initially decreased in a dose dependent manner before reaching a steady state by the end of exposures for all treatments. No significant, dose-dependent changes in dopamine or norepinephrine were seen. Brain serotonin alone did not adequately explain behavioral results. Serotonin response in other tissues as well as peripheral effects may have accounted for additional behavioral responses after brain serotonin reached a depressed steady state. PMID- 24486881 TI - First evidence for toxic defense based on the multixenobiotic resistance (MXR) mechanism in Daphnia magna. AB - The water flea Daphnia magna is widely used as test species in ecotoxicological bioassays. So far, there is no information available to which extent ATP binding cassette (ABC) transporter based multixenobiotic resistance (MXR) counteracts adverse chemical effects in this species. This, however, would be important for assessing to which extent the bio-active potential of a compound determined with this species depends on this cellular defense. We here present molecular, functional and toxicological studies that provide first evidence for ABC transporter-based MXR in D. magna. We cloned putatively MXR-related partial abcb1, abcc1/3, abcc4 and abcc5 coding sequences; respective transcripts were constitutively expressed in different D. magna life stages. MXR associated efflux activity was monitored in D. magna using the fluorescent substrate dyes rhodamine 123, rhodamine B and calcein-AM combined with inhibitors of human ABCB1 and/or ABCC transporter activities reversin 205, MK571 and cyclosporin A. With inhibitors present, efflux of dye substrates was reduced in D. magna in a concentration-dependent mode, as indicated by elevated accumulation of the dyes in D. magna tissues. In animals pre-exposed to mercury, pentachlorophenol or dacthal applied as inducers of ABC transporter expression, levels of some ABC transporter transcripts were increased in some cases showing that these genes can be chemically induced. Likewise, pre-exposure of animals to these chemicals decreased dye accumulation in tissue, indicating enhanced MXR transporter activity, likely associated with higher transporter protein levels. Toxicity assays with toxic transporter substrates mitoxantrone and chlorambucil that were applied singly and in combination with inhibitors were performed to study the tolerance role of Abcb1 and Abcc efflux transporters in D. magna. Joint toxicities of about half of the binary combinations of test compounds applied (substrate/inhibitor, substrate/substrate, inhibitor/inhibitor) were greater than joint effects predicted with mixture toxicity models, which can be explained by chemosensitization through MXR efflux transporter interference. Our data indicate the presence of an MXR efflux system in D. magna. It needs to be considered when assessing the bioactive potential of test compounds with this species. Further, chemosensitization may explain joint toxicities of compound mixtures to D. magna that are higher than expected. PMID- 24486882 TI - Fighting noise pollution: a public health strategy. PMID- 24486883 TI - Safety, tolerability, pharmacokinetics, and effects on human experimental pain of the selective ionotropic glutamate receptor 5 (iGluR5) antagonist LY545694 in healthy volunteers. AB - The objective of this study was to establish in healthy volunteers the maximally tolerated multiple dose (MTMD) of the ionotropic glutamate receptor 5 antagonist LY545694 (part A), and to investigate whether that dose had analgesic or antihyperalgesic effects in the brief thermal stimulation (BTS) pain model (Part B). Part A was a double-blind, placebo-controlled study in 3 groups of 10 healthy men. To simulate an extended-release formulation, study drug was administered orally over 6hours (12 equally divided aliquots at 30-minute intervals). Part B was a double-blind, placebo-controlled, double-dummy, 3-way crossover study in 27 healthy men. At each of the 3 study periods, subjects received either LY545694 (MTMD; as determined during part A) as a simulated, twice daily extended-release formulation for 4 doses over 3days, gabapentin (600mg 8hours apart; 6 doses over 3days; positive control), or matching placebo. The BTS model was induced twice with a 1-hour interval on each of the 2 study days, before drug administration and at the time of expected peak analgesia of LY545694. Plasma exposure for LY545694 was approximately linear over the 25- to 75-mg dose range. The MTMD of LY545694 was 25mg twice daily. Areas of secondary hyperalgesia were significantly smaller after administration of LY545694 and gabapentin compared with placebo (P<.0001 and P=.0004, respectively), but there was no difference between areas after administration of gabapentin and LY545694 (P=.400). Neither gabapentin nor LY545694 reduced the painfulness of skin heating during BTS model induction. The most common treatment-emergent adverse event was dizziness. The results of this study suggest that LY545694 should be explored further as a potential treatment for chronic pain involving neuronal sensitization. PMID- 24486884 TI - Does the epidermal nerve fibre density measured by skin biopsy in patients with peripheral neuropathies correlate with neuropathic pain? AB - The different neuropathic pain types (e.g., ongoing burning pain and allodynia) are frequent and disabling complaints in patients with peripheral neuropathies. Although the reference standard technique for diagnosing painful small-fibre neuropathies is nerve fibre density assessment by skin biopsy, the relationship between the epidermal nerve fibre (ENF) density and neuropathic pain is still unclear. In a clinical and skin biopsy study designed to investigate whether changes in ENF density are directly related to pain, we enrolled 139 consecutive patients with distal symmetric peripheral neuropathy. All patients underwent clinical examination. The Neuropathic Pain Symptom Inventory was used to distinguish the different neuropathic pain types. A skin biopsy was conducted, and ENFs were immunostained with the antiprotein gene product 9.5, and their linear density was quantified with bright-field microscopy. No difference was found in ENF density between patients with and without neuropathic pain, nor between patients with and without ongoing burning pain. Conversely, ENF density was higher in patients with provoked pains (including mechanical dynamic allodynia) than in those without. The variable association between ENF density and symptoms of neuropathic pain supports the idea that neuropathic pain symptoms arise through distinct underlying mechanisms. The lack of relationship between ongoing burning pain and ENF density suggests that this type of pain reflects factors other than loss of nociceptive afferents. The association between ENF density and provoked pain (including mechanical dynamic allodynia) suggests that this type of pain might be mediated by spared and sensitised nociceptive afferents. PMID- 24486885 TI - Transgenic mice expressing S129 phosphorylation mutations in alpha-synuclein. AB - Aggregated alpha-synuclein is a predominant constituent of Lewy bodies, the intracellular protein aggregates seen in Parkinson's disease. While most alpha synuclein in the nervous system is unphosphorylated, the majority of alpha synuclein in Lewy bodies is phosphorylated at serine 129 (S129). We developed transgenic mice expressing human SNCA with either a phosphomimic (S129D) or a non phosphorylatable (S129A) mutation, on a mouse Snca knockout background. Transgenic lines with each mutation expressing the human alpha-synuclein protein at levels ranging from 0.3 to 1.9 fold of endogenous mouse protein were chosen to avoid toxic overexpression effects. We previously demonstrated an altered distribution of presynaptic vesicles in Snca knockout mice, as well as enhanced interaction between presynaptic cytoskeletal proteins and alpha-synuclein when phosphorylated at S129 or carrying an S129D mutation. We therefore examined alpha synuclein's synaptic localization and the distribution of presynaptic vesicles in these mutants. In addition, we evaluated the transgenic lines for reduced colonic motility, an early marker of alpha-synuclein pathology, and alpha-synuclein aggregates. No abnormalities were detected in mice expressing either phosphorylation mutant protein as their only alpha-synuclein protein. These results suggest the S129A and S129D mutations have no obvious effect on alpha synuclein function. PMID- 24486886 TI - Involvement of protein isoprenylation in neuropathic pain induced by sciatic nerve injury in mice. AB - Isoprenylation is crucial step for activating many intracellular signaling. The present study examined whether inhibition of the protein isoprenylation could affect neuropathic pain in partial sciatic nerve-ligated mice. Intrathecal treatment with a geranylgeranyl transferase I inhibitor GGTI-2133, but not with a farnesyl transferase inhibitor FTI-277, dose-dependently blocked the thermal hyperalgesia in partial sciatic nerve-ligated mice. Intrathecal treatment with GGTI-2133 also attenuated the mechanical allodynia in partial sciatic nerve ligated mice. Phosphorylated MARCKS expression was increased in the ipsilateral side of the spinal cord dorsal horn in partial sciatic nerve-ligated mice, and this increase was attenuated by GGTI-2133 but not by FTI-277. These results suggest that protein isoprenylation by geranylgeranyl transferase I is involved in the neuropathic pain. PMID- 24486887 TI - AP4M1 is abnormally expressed in oxygen-glucose deprived hippocampal neurons. AB - AP4M1 mutations have been suggested to be associated with autosomal recessive cerebral palsy syndrome. But the pathogenic mechanism remains uncertain. The purpose of this study is to investigate whether and how AP4M1 expression is changed in injured neurons. Primary cultured hippocampal neurons were prepared for this experiment. They were subjected to oxygen-glucose deprivation (OGD) leading to apoptosis, mimicking brain ischemia. Neuron-specific enolase (NSE) was labeled immunofluorescently to confirm that the purity of neuron was higher than 90%. Real-time PCR and western blotting were performed to measure the gene expression. AP4M1 was labeled with MAP2 or Tau-1 to observe the distribution. We found that the AP4M1 protein levels immediately after the procedure were similar between the OGD group and the sham group. However, down-regulation was observed 12h after the reperfusion, and became more notable at 24h. The real-time PCR showed similar results, except that the down-regulation of mRNA was able to be detected immediately after the OGD. Immunofluorescent labeling revealed AP4M1 distributed in the dendrites of normal neurons, but it redistributed to the axons after the OGD procedure. In conclusion, AP4M1 is not only down-regulated at both the mRNA and protein levels, but also redistributed from dendrites to axons in oxygen-glucose deprived hippocampal neurons. PMID- 24486888 TI - The SORL1 polymorphism rs985421 may confer the risk for amnestic mild cognitive impairment and Alzheimer's disease in the Han Chinese population. AB - Although the pathogenetic mechanisms driving Alzheimer's disease (AD) are unclear, genetic variations may play an important role. Previous studies have identified that single nucleotide polymorphisms (SNPs) in the sortilin-related receptor, L (DLR class) A repeats containing (SORL1) gene are associated with AD or amnestic mild cognitive impairment (aMCI) patients. However, the association of SORL1 variants with AD or aMCI susceptibility in the Han Chinese population has not been adequately reported. Thus, we conducted a case-control study in 106 sporadic AD patients, 67 aMCI patients, and 179 healthy control Han Chinese subjects to determine whether SORL1 genetic variations alter the risk for AD or aMCI. Using the LDR-PCR method to genotype five polymorphisms in SORL1, we found significant associations (for AD: OR=1.968, 95% CI=1.273-3.042; for aMCI: OR=2.210, 95% CI=1.353-3.610) between the 'A' allele of the SORL1 SNP rs985421 and AD and aMCI, which may represent an ApoE E4-independent risk factor for SAD. These findings suggest that the SORL1 SNP rs985421 may alter the risk for sporadic AD and aMCI in the Han Chinese population. PMID- 24486889 TI - Early sexual experience alters voluntary alcohol intake in adulthood. AB - Steroid hormones signaling before and after birth sexually differentiates neuronal circuitry. Additionally, steroid hormones released during adolescence can also have long lasting effects on adult behavior and neuronal circuitry. As adolescence is a critical period for the organization of the nervous system by steroid hormones it may also be a sensitive period for the effects of social experience on adult phenotype. Our previous study indicated that early adolescent sexual activity altered mood and prefrontal cortical morphology but to a much smaller extent if the sexual experience happened in late adolescence. In humans, both substance abuse disorders and mood disorders greatly increase during adolescence. An association among both age of first sexual activity and age of puberty with both mood and substance disorders has been reported with alcohol being the most commonly abused drug in this population. The goal of this experiment was do determine whether sexual experience early in adolescent development would have enduring effects on adult affective and drug-seeking behavior. Compared to sexually inexperienced hamsters and those that experienced sex for the first time in adulthood, animals that mated at 40 days of age and were tested either 40 or 80 days later significantly increased depressive- but not anxiety-like behaviors and increased self-administration of saccharine sweetened ethanol. The results of this study suggest that an isolated, though highly relevant, social experience during adolescence can significantly alter depressive-like behavior and alcohol self-administration in adulthood. PMID- 24486890 TI - Expression and anatomical distribution of TrkB in the encephalon of the adult zebrafish (Danio rerio). AB - Neurotrophins are a family of growth factor primarily acting in the nervous system, throughout two categories of membrane receptors on the basis of their high (Trk receptors) or low (p75NTR) affinity. Both neurotrophins and Trk receptors are phylogenetically conserved and are expressed not only in the central and peripheral nervous system but also in non-nervous tissues of vertebrates and some invertebrates. The brain-derived neurotrophic factor (BDNF)/TrkB system plays an important role in the development, phenotypic maintenance and plasticity of specific neuronal populations. Considering that this system is poorly characterized in the central nervous system of teleosts, the expression and anatomical distribution of TrkB in the brain of the adult zebrafish using reverse transcriptase-polymerase chain reaction (RT-PCR), Western blot and immunohistochemistry were analysed. Both the riboprobe and the antibody used were designed to map within the catalytic domain of TrkB. RT-PCR detected specific TrkB mRNA in brain homogenates, while Western-blot identified one unique protein band with an estimated molecular weight of 145kDa, thus corresponding with the TrkB full-length isiform of the receptor. Immunohistochemistry showed specific TrkB immunoreactivity in restricted areas of the encephalon, i.e. the hypothalamus and a specific neuronal subpopulation of the reticular formation. The present results demonstrate, for the first time, that, as in mammals, the encephalon of adult zebrafish expresses TrkB in specific zones related to food intake, behaviour or motor activity. PMID- 24486891 TI - The N2 ERP component as an index of impaired cognitive control in smokers. AB - Impaired cognitive control has been proposed as a hallmark of nicotine dependence and is thought to arise, in part, from synaptic alterations in anterior cingulate cortex (ACC), a primary component of the dopamine reward pathway. The N2 component of the event-related potential (ERP) appears to index a cognitive control process in paradigms such as the visual go/no-go task. Moreover, as dipole-modeling has suggested that the neural generator of the N2 component can be localized to the ACC, this component may prove useful for investigating impairments of cognitive control in smokers. Given conflicting reports of whether the N2 is reduced in smokers (as compared to non-smoker controls), the current study further examined the suitability of this component as an index for impaired cognitive control in smokers. Smokers and non-smokers performed a visual go/no-go task while electroencephalogram (EEG) was recorded. As predicted, the no-go N2 of smokers was significantly smaller than that of non-smoker controls, while the no go P3 did not differ between groups. Importantly, behavioral performance (reaction time and accuracy) did not differ between smokers and nonsmokers, which might reflect the low levels of nicotine dependence (assessed by the Fagerstrom test) in our sample. The observed N2 modulation in the absence of behavioral impairments provides evidence for the utility of the N2 component as a sensitive measure of impaired cognitive control in smokers, even in those with low levels of nicotine dependence. PMID- 24486892 TI - Personality dimensions and deep repetitive transcranial magnetic stimulation (DTMS) for treatment-resistant depression: a pilot trial on five-factor prediction of antidepressant response. AB - BACKGROUND: Prognostication is poor in repetitive transcranial magnetic stimulation (rTMS) treatment for major depressive disorder (MDD). Personality traits, particularly extraversion and neuroticism, have attracted increasing attention for both trait- and state-dependent characteristics in predicting response to pharmacotherapy, psychotherapy, and more recently to therapeutic neuromodulation for MDD. The advent of deep rTMS (DTMS) allows stimulation of deeper cortical regions, and we aimed to prospectively characterize personality dimensions and antidepressant response to DTMS in treatment-resistant MDD. METHODS: A convenience sample of 15 patients with treatment-resistant MDD received four weeks of daily sessions of DTMS (20 Hz, 3000 pulses/session) of the left dorsolateral prefrontal cortex (DLFPC). At baseline and at the conclusion of treatment, patients completed the Big Five Inventory, a five-factor assessment of major personality dimensions. Clinical response was measured using the 21-item Hamilton Depression Rating Scale. RESULTS: Four weeks of DTMS treatment were not associated with changes in personality measures. Clinical remission was associated with higher baseline levels of agreeableness (score >= 29:100% sensitive and 72.7% specific) and conscientiousness (score >= 30:75% sensitive and 81.8% specific). Levels of agreeableness and extraversion were linearly associated with antidepressant response. Neuroticism was not associated with the antidepressant effects of DTMS in this cohort. CONCLUSIONS: Five-factor personality assessment may have prognostic value in DTMS for resistant MDD. Agreeableness, extraversion, and conscientiousness are associated with decreases in depressive symptoms during treatment with DTMS. PMID- 24486893 TI - Comparative analysis of vestibular receptor and baroreceptor inputs to the nucleus tractus solitarius following acute hypotension in conscious rats. AB - Blood pressure is maintained by the interaction between the arterial baroreflexes and the vestibulo-cardiovascular reflexes during postural changes. In this study, the influence of the vestibular receptors on the maintenance of blood pressure following acute hypotension was quantitatively compared with the role of baroreceptors in terms of c-Fos protein expression in the nucleus tractus solitarius (NTS). Expression of c-Fos protein in the NTS was measured in conscious rats that had undergone bilateral labyrinthectomy (BL) and/or sinoaortic denervation (SAD). Expression of c-Fos protein increased significantly in the NTS in the sham group after sodium nitroprusside (SNP) administration. However, the BL, SAD, and SAD+BL groups showed significant decreases in c-Fos protein expression compared to that of the sham group. The SAD group showed relatively more reduction in c-Fos protein expression than the BL group, and the SAD+BL group showed the least expression among the three experimental groups. The c-Fos protein expression in the NTS following acute hypotension was localized to the caudal portions of the nuclei in the BL and SAD groups. These results suggest that the role of vestibular receptors in maintaining blood pressure following acute hypotension is less potent than that of the baroreceptors but more potent than other afferent inputs in conscious rats. In addition, afferent signals for maintaining blood pressure originating from the vestibular receptors and the baroreceptors may converge in the caudal portion of the NTS. PMID- 24486895 TI - Editorial. PMID- 24486894 TI - Social status and living with a chronic illness: an exploration of assessment and meaning attributed to work and employment. AB - BACKGROUND: Traditional measures of social status are predicated on position in the labour market. There has been less attention directed to the meanings of social position for people with a long-term condition whose relationship to employment is precarious. Previous research has demonstrated that the MacArthur scale is capable of capturing contextualised aspects of social status, which makes it a useful tool for exploring changes in meaning. AIMS: The paper explores the meanings and experiences of social status of people living with a long-term condition with particular reference to employment status. METHODS: A sample of 300 participants was drawn from diabetes and chronic heart disease registers of General Practices in North West England. A cross-sectional survey with nested qualitative interviews was used in collecting and analysing the data. FINDINGS: Having financial independence and participating in valued activities are more important for people with chronic illness than power and status mediated through the labour market. Income and the lack and loss of employment were given a central role in respondents' narratives reflecting the absence of acceptable alternative routes through which social status for those with a long-term condition can realistically be rebuilt outside of participation in the labour market. CONCLUSION: Social participation, where people with chronic illness feel valued and of tangible utility to other people, might offer some opportunities for rebuilding social status outside the labour market. Chronic illness management interventions need to focus on improving people's engagement with such activities. PMID- 24486896 TI - Psychiatry and the necker cube. Neurological and psychological conceptions of psychiatric disorder. AB - Neurological and psychological conceptions of psychiatric disorder are in conflict at the present time. This conflict is considered in the context of the history of psychiatry and the philosophy of science. Its practical consequences are considered for the motor disorder of schizophrenia, the cognitive impairment in psychiatric illnesses, the use of the terms organic and functional and the association of neurological disorder with psychotic and neurotic disorders. The conflict is also examined in individual cases and the implications for treatment assessed. PMID- 24486897 TI - Persistent left unilateral apraxia and a disconnection theory. AB - A case of persistent left unilateral apraxia caused by a post-traumatic callosal lesion is reported. Based on an analysis of the nature of the motor disturbances it is concluded that the disconnection is neither for linguistic nor mnemonic information about praxis but motor control information which is activated through conscious intention. PMID- 24486898 TI - Some personality variables in functional neurological disorders. AB - Patients with spasmodic torticollis, writer's cramp and the Gilles de la Tourette Syndrome (GTS) were given rating scales to assess personality dimensions, especially hostility and obsessionality. The data have been compared with age and sex matched controls. Significant differences arose, especially for hostility for the GTS and writer's cramp patients, whereas those with spasmodic torticollis do not differ from controls. PMID- 24486899 TI - Kindling: a model for the development of tardive dyskinesia? AB - Tardive dyskinesia (TD) from long-term neuroleptic treatment may be irreversible; therefore prevention has become a major concern. A controversial issue with regard to the clinical use of neuroleptic drugs is the possible influence on the development of TD of drug holidays. The major characteristics of kindling, theories of TD and the role of multiplicity in the development of TD are described. Some clinical studies point to interruption of neuroleptic therapy being a risk factor for development of irreversible TD. Induction of dyskinesia in non-human primates has been demonstrated after repeated administration of haloperidol. Rodent studies have not been conclusive. Several experimental results link TD with kindling: both conditions involve repeated stimulations, both seem to involve increased receptor responsiveness and in both conditions does depression in GABA transmission in SNR (substantia nigra; pars reticulata) play an important role. It is concluded that the kindling hypothesis is relevant to the investigation of TD. PMID- 24486900 TI - Tardive dystonia: clinical spectrum and novel manifestations. AB - Tardive dystonia was identified in 25 patients: involvement of the face and neck was most common; truncal and limb dystonia were also observed. There were 3 cases of laryngospasm and 2 of spasmodic dysphonia. The latter has not been previously reported as a manifestation of tardive dystonia. In all cases, movements typical of classic tardive dyskinesia could be demonstrated. This group illustrates the variety of dystonic disorders that may occur in conjunction with tardive dyskinesia. PMID- 24486901 TI - Altered behavior associated with damage to the ventromedial hypothalamus: a distinctive syndrome. AB - An adult manifested a tetrad of neurobehavioral findings consisting of episodic rage, emotional lability, hyperphagia with obesity, and memory impairment with intellectual decline following surgical removal of a craniopharyngioma. Post mortem investigation of the topography of the lesion as well as review of previously reported cases suggest that this tetrad represents a specific neurobehavioral syndrome referable to damage to the ventromedial hypothalamus. PMID- 24486903 TI - Deep transcriptome sequencing of Pecten maximus hemocytes: a genomic resource for bivalve immunology. AB - Pecten maximus, the king scallop, is a bivalve species with important commercial value for both fisheries and aquaculture, traditionally consumed in several European countries. Major problems in larval rearing, however, still limit hatchery-based seed production. High mortalities during early larval stages, likely related to bacterial pathogens, represent the most relevant bottleneck. To address this issue, understanding host defense mechanisms against microbes is extremely important. In this study next-generation RNA-sequencing was carried on scallop hemocytes. To enrich for immune-related transcripts, cDNA libraries from hemocytes challenged in vivo with inactivated-Vibrio anguillarum and in vitro with pathogen-associated molecular patterns, as well as unchallenged controls, were sequenced yielding 216,444,674 sequence reads. De novo assembly of the scallop hemocyte transcriptome consisted of 73,732 contigs (31% annotated). A total of 934 contigs encoded proteins with a known immune function, grouped into several functional categories. Particular attention was reserved to Toll-like receptors (TLRs), a family of pattern recognition receptors (PRRs) involved in non-self recognition. Through mining the scallop hemocyte transcriptome, at least four TLRs could be identified. The organization of canonical TLR domains demonstrated that single cysteine cluster and multiple cysteine cluster TLRs co exist in this species. In addition, preliminary data concerning their mRNA level following bacterial challenge suggested that different members of this family could exhibit opposite responses to pathogenic stimuli. Finally, a global analysis of differential expression comparing gene-expression levels in in vitro and in vivo stimulated hemocytes against controls provided evidence on a large set of transcripts involved in the great scallop immune response. PMID- 24486904 TI - Development and efficacy of feed-based recombinant vaccine encoding the cell wall surface anchor family protein of Streptococcus agalactiae against streptococcosis in Oreochromis sp. AB - This study was carried out to determine the antibody responses and protective capacity of an inactivated recombinant vaccine expressing the cell wall surface anchor family protein of Streptococcus agalactiae following oral vaccination against streptococcosis in tilapia. Tilapia were vaccinated orally with 10(6) CFU/mL of the recombinant vaccine incorporated in feed (feed-based recombinant vaccine) (vaccinated group or Group 1), 10(6) CFU/mL of pET-32 Ek/LIC vector without cell wall surface anchor family protein (control group or Group 2), 10(6) CFU/mL of formalin-killed cells of S. agalactiae vaccine incorporated in feed was also prepared (feed-based vaccine) (vaccinated group or Group 3), and unvaccinated control group or Group 4 (fed with commercial pellets). During the course of study, serum, mucus and gut lavage fluid were collected to evaluate the antibody levels via enzyme-linked immunosorbent assay (ELISA). The results showed that tilapia immunized with the feed-based recombinant vaccine developed a strong and significantly (P < 0.05) higher IgM antibody response in serum, mucus and gut lavage fluid samples compared to groups 2, 3 and 4. Following heat intervenes and intraperitoneal challenge, the rate of survivors (RPS) was 70% for the vaccinated group, and 0% for the rest of the groups. Therefore, the study revealed that the feed-based recombinant vaccine significantly provides high protection against high dose challenge in heat stress environment and enhances the production of the mucosal and humoral immunity. PMID- 24486905 TI - The role of connexin40 in developing atrial conduction. AB - Connexin40 (Cx40) is the main connexin expressed in the murine atria and ventricular conduction system. We assess here the developmental role of Cx40 in atrial conduction of the mouse. Cx40 deficiency significantly prolonged activation times in embryonic day 10.5, 12.5 and 14.5 atria during spontaneous activation; the severity decreased with increasing age. In a majority of Cx40 deficient mice the impulse originated from an ectopic focus in the right atrial appendage; in such a case the activation time was even longer due to prolonged activation. Cx40 has thus an important physiological role in the developing atria. PMID- 24486906 TI - A plausible model for bimodal p53 switch in DNA damage response. AB - p53 is a tumor suppressor and the p53 dynamics displays stimulus dependent patterns. Recent evidence suggests a bimodal p53 switch in cell fate decision. However, no theoretical studies have been proposed to investigate bimodal p53 induction. Here we constructed a model and showed that MDM2-p53 mRNA binding might contribute to bimodal p53 switch through an intrinsic positive feedback loop. Lower damage favored pulsing while monotonic increasing was generated with higher damage. Bimodal p53 dynamics was largely influenced by cellular MDM2 and elevated p53/MDM2 ratios with increasing etoposide favor mono-ubiquitination. Our model replicated recent experiments and provided potential insights into dynamic mechanisms of bimodal switch. PMID- 24486907 TI - Induction of microRNA-138 by pro-inflammatory cytokines causes endothelial cell dysfunction. AB - Exposure to pro-inflammatory cytokines, such as Angiotensin II, endothelin-1 or TNF leads to endothelial dysfunction, characterized by the reduced production of nitric oxide via endothelial nitric oxide synthase (eNOS). We recently identified the Ca(2+) binding protein S100A1 as an essential factor required for eNOS activity. Here we report that pro-inflammatory cytokines down-regulate expression of S100A1 in primary human microvascular endothelial cells (HMVECs) via induction of microRNA-138 (miR-138), in a manner that depends on the stabilization of HIF1 alpha. We show that loss of S100A1 in ECs reduces stimulus-induced NO production, which can be prevented by inhibition of miR-138. Our study suggests that targeting miR-138 might be beneficial for the treatment of cardiovascular disease. PMID- 24486908 TI - Understanding the anti-kindling role and its mechanism of Resveratrol in Pentylenetetrazole induced-kindling in a rat model. AB - BACKGROUND: Resveratrol is a polyphone chemical found in a number of plant species, including peanuts and grapes, but with significant amounts in red wine. In normal plant physiology, Resveratrol is produced as a defensive response to injury or parasitic attacks. Resveratrol has diverse biological properties and actions with potential clinical applications, including anti-inflammatory, antioxidant, anti proliferative, and neuroprotective effects. AIM: The aim of the present study was to explore the effect and mechanism of Resveratrol in Pentylenetetrazole (PTZ) induced kindling in rats. MATERIALS AND METHODS: In a PTZ kindled Wistar rat model, different doses of Resveratrol (25mg/kg, 50mg/kg and 75 mg/kg) were administered orally 30 min before the PTZ injection. The PTZ injection was given on alternate day till the animal became fully kindled or till 10 weeks. The following parameters were compared between control and various experimental groups: the course of kindling, stages of seizures, histopathological scoring of hippocampus, antioxidant parameters, DNA fragmentation and caspase-3 expression in the hippocampus, and neuron-specific enolase in the blood. One way ANOVA followed by Bonferroni post hoc analysis and Fischer's Exact test were used for statistical analyses. THE RESULTS: In the present study, Resveratrol showed dose-dependent anti-seizure effect. Resveratrol (75 mg/kg) significantly increased the latency to myoclonic jerks, clinic seizures as well as generalized tonic-clinic seizures, improved the seizure score and decreased the number of myoclonic jerks. PTZ induced kindling caused a significant neuronal injury, oxidative stress and apoptosis which were reversed by pretreatment with Resveratrol in a dose-dependent manner. CONCLUSION: Our study suggests that Resveratrol has a potential antiepileptogenic effect on PTZ induced kindling in rats. The possible underlying mechanisms of Resveratrol as an antiepileptic agent may be due to its antioxidative property and neuroprotective effect. PMID- 24486909 TI - Controlled release of strontium ions from a bioactive Ti metal with a Ca-enriched surface layer. AB - A nanostructured sodium hydrogen titanate layer ~1MUm in thickness was initially produced on the surface of titanium metal (Ti) by soaking in NaOH solution. When the metal was subsequently soaked in a mixed solution of CaCl2 and SrCl2, its Na ions were replaced with Ca and Sr ions in an Sr/Ca ratio in the range 0.18-1.62. The metal was then heat-treated at 600 degrees C to form strontium-containing calcium titanate (SrCT) and rutile on its surface. The treated metal did not form apatite in a simulated body fluid (SBF) even after 7days. When the metal formed with SrCT was subsequently soaked in water at 80 degrees C, the treated metal formed bone-like apatite on its surface within 1day in SBF since the Ca ions were partially replaced with H3O(+) ions. However, it released only 0.06ppm of Sr ions even after 7days in phosphate-buffered saline. When the metal was soaked after the heat treatment in 1M SrCl2 solution instead of water, the treated metal released 0.92ppm of Sr ions within 7days while maintaining its apatite-forming ability. The Ti formed with this kind of bioactive SrCT layer on its surface is expected to be highly useful for orthopedic and dental implants, since it should be able to promote bone growth by releasing Sr ions and tightly bond to the bone through the apatite formed on its surface. PMID- 24486911 TI - Facile route to versatile nanoplatforms for drug delivery by one-pot self assembly. AB - There is still unmet demand for developing powerful approaches to produce polymeric nanoplatforms with versatile functions and broad applications, which are essential for the successful bench-to-bedside translation of polymeric nanotherapeutics developed in the laboratory. We have discovered a facile, convenient, cost-effective and easily scalable one-pot strategy to assemble various lipophilic therapeutics bearing carboxyl groups into nanomedicines, through which highly effective cargo loading and nanoparticle formation can be achieved simultaneously. Besides dramatically improving water solubility, the assembled nanopharmaceuticals showed significantly higher bioavailability and much better therapeutic activity. These one-pot assemblies may also serve as nanocontainers to effectively accommodate other highly hydrophobic drugs such as paclitaxel (PTX). PTX nanomedicines thus formulated display strikingly enhanced in vitro antitumor activity and can reverse the multidrug resistance of tumor cells to PTX therapy. The special surface chemistry offers these assembled entities the additional capability of efficiently packaging and efficaciously transfecting plasmid DNA, with a transfection efficiency markedly higher than that of commonly used positive controls. Consequently, this one-pot assembly approach provides a facile route to multifunctional nanoplatforms for simultaneous delivery of multiple therapeutics with improved therapeutic significance. PMID- 24486912 TI - Determination of orientation and adsorption-induced changes in the tertiary structure of proteins on material surfaces by chemical modification and peptide mapping. AB - The labeling of amino acid residues followed by peptide mapping via mass spectrometry (AAL/MS) is a promising technique to provide detailed information on the adsorption-induced changes in its solvent accessibility. However, the potential of this method for the study of adsorbed protein structure is largely undeveloped at this time. The objective of this research was therefore to extend these capabilities by developing and applying AAL/MS techniques for a range of amino acid types to identify the dominant configurations of an adsorbed protein on a material surface. In this study, the configuration of hen egg white lysozyme (HEWL) adsorbed on fused silica glass, high-density polyethylene (HDPE) and poly(methyl methacrylate) (PMMA) was mapped by combining the labeling profiles obtained from five amino acid labels, which were independently applied. In order to be able to combine the results from the different amino acid labeling processes, the intensity of the HEWL segment without the target amino acids was used as an internal control to normalize the intensity shifts to an equivalent level. The resulting quantitative differences in the normalized amino acid profiles were then used to provide insights into adsorbed orientation, protein protein interactions and adsorption-induced tertiary unfolding of HEWL, which were found to be distinctly different between the fused silica glass, HDPE and PMMA surfaces. The developed technique has the potential for broad application and for expansion to additional targeted amino acids to provide highly detailed information on the adsorbed state of any protein on any given surface. PMID- 24486910 TI - Immunogenicity in xenogeneic scaffold generation: antigen removal vs. decellularization. AB - Decades of research have been undertaken towards the goal of tissue engineering using xenogeneic scaffolds. The primary advantages associated with use of xenogeneic tissue-derived scaffolds for in vitro development of replacement tissues and organs stem from the inherent extracellular matrix (ECM) composition and architecture. Native ECM possesses appropriate mechanical properties for physiological function of the biomaterial and signals for cell binding, growth and differentiation. Additionally, xenogeneic tissue is readily available. However, translation of xenogeneic scaffold-derived engineered tissues or organs into clinical therapies requires xenoantigenicity of the material to be adequately addressed prior to implantation. Failure to achieve this goal will result in a graft-specific host immune rejection response, jeopardizing in vivo survival of the resultant scaffold, tissue or organ. This review explores (i) the appropriateness of scaffold acellularity as an outcome measure for assessing reduction of the immunological barriers to the use of xenogeneic scaffolds for tissue engineering applications and (ii) the need for tissue engineers to strive for antigen removal during xenogeneic scaffold generation. PMID- 24486913 TI - Synthesis and characterization of CREKA-conjugated iron oxide nanoparticles for hyperthermia applications. AB - One of the current challenges in the systemic delivery of nanoparticles in cancer therapy applications is the lack of effective tumor localization. Iron oxide nanoparticles (IONPs) coated with crosslinked dextran were functionalized with the tumor-homing peptide CREKA, which binds to fibrinogen complexes in the extracellular matrix of tumors. This allows for the homing of these nanoparticles to tumor tissue. The IONP core allows for particle heating upon exposure to an alternating magnetic field (AMF), while the dextran coating stabilizes the particles in suspension and decreases the cytotoxicity of the system. Magnetically mediated hyperthermia (MMH) allows for the heating of tumor tissue to increase the efficacy of traditional cancer treatments using IONPs. While MMH provides the opportunity for localized heating, this method is currently limited by the lack of particle penetration into tumor tissue, even after effective targeted delivery to the tumor site. The CREKA-conjugated nanoparticles presented were characterized for their size, stability, heating capabilities and biocompatibility. The particles had a hydrated diameter of 52nm, were stable in phosphate buffered saline solution and media with 10% v/v fetal bovine serum over at least 12h, and generated enough heat to raise solution temperatures well into the hyperthermia range (41-45 degrees C) when exposed to an AMF, owing to an average specific absorption rate of 83.5Wg(-1). Cytotoxicity studies demonstrated that the particles have low cytotoxicity over long exposure times at low concentrations. A fibrinogen clotting assay was used to determine the binding affinity of CREKA-conjugated particles, which was significantly greater than the binding affinity of dextran, only coated IONPs demonstrating the potential for this particle system to effectively home to a variety of tumor locations. Finally, it was shown that in vitro MMH increased the effects of cisplatin compared with cisplatin or MMH treatments alone. PMID- 24486914 TI - Understanding the usage of content in a mental health intervention for depression: an analysis of log data. AB - BACKGROUND: Web-based interventions for the early treatment of depressive symptoms can be considered effective in reducing mental complaints. However, there is a limited understanding of which elements in an intervention contribute to effectiveness. For efficiency and effectiveness of interventions, insight is needed into the use of content and persuasive features. OBJECTIVE: The aims of this study were (1) to illustrate how log data can be used to understand the uptake of the content of a Web-based intervention that is based on the acceptance and commitment therapy (ACT) and (2) to discover how log data can be of value for improving the incorporation of content in Web-based interventions. METHODS: Data from 206 participants (out of the 239) who started the first nine lessons of the Web-based intervention, Living to the Full, were used for a secondary analysis of a subset of the log data of the parent study about adherence to the intervention. The log files used in this study were per lesson: login, start mindfulness, download mindfulness, view success story, view feedback message, start multimedia, turn on text-message coach, turn off text-message coach, and view text message. Differences in usage between lessons were explored with repeated measures ANOVAs (analysis of variance). Differences between groups were explored with one-way ANOVAs. To explore the possible predictive value of the login per lesson quartiles on the outcome measures, four linear regressions were used with login quartiles as predictor and with the outcome measures (Center for Epidemiologic Studies-Depression [CES-D] and the Hospital Anxiety and Depression Scale-Anxiety [HADS-A] on post-intervention and follow-up) as dependent variables. RESULTS: A significant decrease in logins and in the use of content and persuasive features over time was observed. The usage of features varied significantly during the treatment process. The usage of persuasive features increased during the third part of the ACT (commitment to value-based living), which might indicate that at that stage motivational support was relevant. Higher logins over time (9 weeks) corresponded with a higher usage of features (in most cases significant); when predicting depressive symptoms at post-intervention, the linear regression yielded a significant model with login quartile as a significant predictor (explained variance is 2.7%). CONCLUSIONS: A better integration of content and persuasive features in the design of the intervention and a better intra-usability of features within the system are needed to identify which combination of features works best for whom. Pattern recognition can be used to tailor the intervention based on usage patterns from the earlier lessons and to support the uptake of content essential for therapy. An adaptable interface for a modular composition of therapy features supposes a dynamic approach for Web-based treatment; not a predefined path for all, but a flexible way to go through all features that have to be used. PMID- 24486915 TI - Primary endometrial stromal sarcoma: cause of pelvic pain and mass in a posthysterectomy patient. PMID- 24486916 TI - Psychometric properties of reaction time based experimental paradigms measuring anxiety-related information-processing biases in children. AB - Theoretical frameworks highlight the importance of threat-related information processing biases for understanding the emergence of anxiety in childhood. The psychometric properties of several tasks measuring these biases and their associations with anxiety were examined in an unselected sample of 9-year-old children (N=155). In each task, threat bias was assessed using bias scores reflecting task performance on threat versus non-threat conditions. Reliability was assessed using split-half and test-retest correlations of mean reaction times (RTs), accuracy and bias indices. Convergence between measures was also examined. Mean RTs showed substantial split-half and test-retest correlations. Bias score reliability coefficients were near zero and non-significant, suggesting poor reliability in children of this age. Additionally, associations between bias scores and anxiety were weak and inconsistent and performance between tasks showed little convergence. Bias scores from RT based paradigms in the current study lacked adequate psychometric properties for measuring individual differences in anxiety-related information-processing in children. PMID- 24486918 TI - Neuroma of medial dorsal cutaneous nerve of superficial peroneal nerve after ankle arthroscopy. AB - Superficial peroneal neuropathy is a known complication of foot and ankle arthroscopy. A 27-year-old man developed pain and paresthesia on the medial side of the dorsum of his left foot after ankle arthroscopy. An electrodiagnostic study revealed conduction abnormality in the medial branch of superficial peroneal nerve, in which neuroma-in-continuity was subsequently detected by ultrasonography. After neuroma excision and nerve graft, the subject's neuropathic pain was substantially improved. PMID- 24486919 TI - Ultrasound images of groin pain in the athlete: a pictorial essay. AB - Chronic groin pain in the athlete is a common condition, with, at times, protracted recovery that leads to prolonged disability. There are soft-tissue and bony contributors to pain, with the mechanism of injury usually an acute or chronic overload of the hip adductor tendons, abdominal aponeurosis, hip joint, or symphysis pubis. The complexity of the regional anatomy often necessitates imaging modalities for precise diagnosis and prompt management. Imaging options include magnetic resonance imaging, computed tomography, nuclear bone scan, radiography, and ultrasound. In this report, we present a series of images that represent the value of musculoskeletal ultrasound in the diagnosis and treatment of groin pain in the athlete. PMID- 24486917 TI - Assessing needs and assets for building a regional network infrastructure to reduce cancer related health disparities. AB - Significant cancer health disparities exist in the United States and Puerto Rico. While numerous initiatives have been implemented to reduce cancer disparities, regional coordination of these efforts between institutions is often limited. To address cancer health disparities nation-wide, a series of regional transdisciplinary networks through the Geographic Management Program (GMaP) and the Minority Biospecimen/Biobanking Geographic Management Program (BMaP) were established in six regions across the country. This paper describes the development of the Region 3 GMaP/BMaP network composed of over 100 investigators from nine institutions in five Southeastern states and Puerto Rico to develop a state-of-the-art network for cancer health disparities research and training. We describe a series of partnership activities that led to the formation of the infrastructure for this network, recount the participatory processes utilized to develop and implement a needs and assets assessment and implementation plan, and describe our approach to data collection. Completion, by all nine institutions, of the needs and assets assessment resulted in several beneficial outcomes for Region 3 GMaP/BMaP. This network entails ongoing commitment from the institutions and institutional leaders, continuous participatory and engagement activities, and effective coordination and communication centered on team science goals. PMID- 24486920 TI - Neuromuscular ultrasound application to the electrodiagnostic evaluation of quadrilateral space syndrome. AB - Quadrilateral space syndrome (QSS) is a rare neurovascular compression syndrome that results from the compression of the axillary nerve and posterior circumflex humeral artery in the quadrilateral space. Electromyography often is used to evaluate for the presence of neuropathic changes in the deltoid and teres minor in cases of suspected QSS. Needle examination of the teres minor may be challenging because of the muscle's small size and proximity to the infraspinatus. In cases in which patients are overweight or have significant teres minor atrophy, localization of the muscle through conventional methods may be extremely difficult. We present a case of an overweight man with posterior shoulder pain who was diagnosed with QSS via the use of a combination of ultrasound and electromyography. PMID- 24486922 TI - A simple and efficient method for detecting avian influenza virus in water samples. AB - Waterborne transmission plays an essential role in the transmission and spread of avian influenza viruses. The abundance of influenza viruses in environmental water is usually extremely low and viruses or viral genomes can hardly be detected by conventional reverse transcription (RT-) PCR without concentration. In the present study, an electropositive filter membrane was used to concentrate influenza viruses from water sample, in addition, a glass fiber filter has been used prior to positive charged membrane for the prefiltration. Unlike the traditional adsorption-elution method, Trizol-LS reagent was used to lyse the viruses attached directly to the electropositive filter membrane and the influenza virus genomic RNA was extracted, followed by RT-PCR analysis. The method established in this study could improve the efficiency of the conventional RT-PCR technique used to detect the M, NP, and HA genes of influenza virus in natural water samples. This method could also reduce the time taken for the traditional adsorption-elution concentration procedure. PMID- 24486921 TI - Adverse childhood experiences and disability in U.S. adults. AB - OBJECTIVE: To assess relationships between adverse childhood experiences and self reported disabilities in adult life. DESIGN: Cross-sectional, random-digit dialed, state-population-based survey (Behavioral Risk Factor Surveillance System). SETTING: Fourteen states and the District of Columbia. PARTICIPANTS: Noninstitutionalized adults ages >=18 years surveyed in 2009 and/or in 2010 (n = 81,184). METHODS: The Behavioral Risk Factor Surveillance System Adverse Childhood Experience (ACE) Module asks about abuse (physical, sexual, emotional), family dysfunction (exposures to domestic violence, living with mentally ill, substance abusing, or incarcerated family member(s), and/or parental separation and/or divorce) that occurred before age 18 years. The ACE score sums affirmed ACE categories (range, 0-8). We controlled for demographic characteristics (age, race, education, income, and marital status) and self-reported physical health conditions (stroke, myocardial infarction, diabetes, coronary heart disease, asthma). Five states asked participants about mental health conditions (anxiety, depression). A subset analysis of participants in these states evaluated the effect of adjusting for these conditions. MAIN OUTCOME MEASUREMENTS: The primary outcome was disability (self-reported activity limitation and/or assistive device use). RESULTS: More than half of participants (57%) reported at least 1 adverse childhood experience category, and 23.2% reported disability. The odds ratio (95% confidence interval) of disability increased in a graded fashion from odds ratio 1.3 (95% confidence interval, 1.2-1.4) among those who experienced 1 adverse experience to odds ratio 5.8 (95% confidence interval, 4.6-7.5) among those with 7-8 adverse experiences compared with those with no such experiences when adjusting for demographic factors. The relationship between adverse experiences and disability remained strong after adjusting for physical and mental health conditions. CONCLUSIONS: There is a strong graded relationship between childhood exposure to abuse and household dysfunction and self-reported disability in adulthood, even after adjusting for potentially mediating health conditions. Greater clinician, researcher, and policymaker awareness of the impact of childhood adversity on disability is crucial to help those affected by childhood adversity lead more functional lives. PMID- 24486923 TI - Development of a varicella-zoster virus neutralization assay using a glycoprotein K antibody enzyme-linked immunosorbent spot assay. AB - Plaque-reduction assays have been used to detect varicella-zoster virus (VZV) neutralizing antibodies in sera for many decades. The current study characterized the mouse monoclonal antibody (MAb) 18A10, specific for VZV envelope glycoprotein K (gK), and applied this antibody to a new type of neutralization assay in the VZV field. The procedure is called the neutralization enzyme-linked immunosorbent spot (N-ELISPOT) assay and evolved from the VZV immunoperoxidase focus assay. Optimization of the assay involved defining the optimum combination of virus plaque-forming units (PFU) and antibody dilution, which were found to be 0-100 PFU and 1:200, respectively. Furthermore, the N-ELISPOT assay produced results consistent with that obtained for the plaque-reduction neutralization assay. Considering that the plaque-reduction neutralization assay is time-consuming and labor-intensive, the VZV N-ELISPOT assay offers several advantages including reproducibility and applicability for high-throughput analysis of humoral immune responses to VZV. PMID- 24486924 TI - The use of the NDDI-E in Arabic to identify symptoms of depression of moderate or greater severity in people with epilepsy. AB - AIM: The aims of the current study were to translate and to validate the NDDI-E to the Arabic language to be used as a screening instrument to identify moderately severe symptoms of depression in people with epilepsy. METHODS: The English version of the NDDI-E was translated to Arabic and back translated to English by two independent translators. A total of 51 patients, aged 18-56years old, with a diagnosis of epilepsy, completed the Arabic versions of the Beck Depression Inventory (BDI-II) and the NDDI-E. Patients with BDI scores >20 were considered to be suffering from moderately severe depressive symptoms. Cutoff scores, sensitivity, specificity, and positive and negative predictive values of the NDDI-E to identify symptomatic patients on the BDI were calculated. RESULTS: A sensitivity of 93.33% and a specificity of 94.44% were found with NDDI-E total scores >15. The positive predictive value was 87.5%, and the negative predictive value was 97.14%. Spearman's rank correlation between the BDI and the NDDI-E was high (r=.78, p=0.000, N=51). Internal consistency was at 0.926 (Cronbach's alpha). CONCLUSION: The Arabic version of the NDDI-E appears to be a reliable and sensitive instrument in the identification of moderately severe or severe depressive symptoms in people with epilepsy, and it can be used with all Arabic speaking patients. PMID- 24486925 TI - Creating a dashboard to track progress toward IOM recommendations for the future of nursing. AB - This article explains the process used to identify and develop a set of data used to track national progress toward the recommendations of the Institute of Medicine Committee for the Future of Nursing. The data are presented in a dashboard format to visually summarize information and quickly measure progress. The approach selected by the research team is outlined, the criteria for selecting candidate metrics are detailed, the process for seeking external guidance is described, and the final dashboard measures are presented. Finally, the methods for data collection for each metric are explicated, to guide states and local regions in the collection of their own data. PMID- 24486926 TI - Right ventricular function and prognosis in stable heart failure patients. AB - BACKGROUND: Right ventricular ejection fraction (RVEF) is a mortality predictor in heart failure (HF) patients. There are controversial results regarding the influence of RVEF on other important prognostic variables. The purpose of this study was to investigate the effect of RVEF on exercise parameters obtained during cardiopulmonary exercise testing (CPET), creatinine and B-type natriuretic peptide (BNP) levels, and a composite outcome of death, heart transplantation, or ventricular assist device implantation in ambulatory HF patients. METHODS AND RESULTS: This retrospective cohort study included 246 ambulatory HF patients with CPET and RVEF evaluated with the use of first-pass radionuclide angiography. We analyzed the impact of RVEF on other prognostic factors with the use of multivariable linear regression. The mean age was 49 +/- 12 years. The mean peak VO2 was 16.4 +/- 5.7 mL kg(-1) min(-1), mean peak VE/VCO2 34.1 +/- 9.1, mean creatinine 1.17 +/- 0.40 mg/dL, and median BNP 158 pg/mL (interquartile range 374 pg/mL). The mean left ventricular ejection fraction was 35 +/- 12% and the mean RVEF 38 +/- 10%. For every 10% decrease in RVEF, peak VO2 decreased 0.97 mL kg( 1) min(-1) (P < .05), creatinine increased 0.12 mg/dL (P < .01), and log BNP increased 0.26 (P < .05). CONCLUSIONS: We found an independent association between RVEF and prognostic markers in HF patients. Worsening RV function may exert its negative effect on prognosis through increasing congestion (elevated BNP), affecting renal blood flow (increased creatinine) and limiting left ventricular preload, thereby reducing exercise tolerance. PMID- 24486927 TI - Hypoalbuminemia in acute heart failure patients: causes and its impact on hospital and long-term mortality. AB - BACKGROUND: The causes of hypoalbuminemia in patients with acute heart failure (HF) remain poorly defined, and the association between hypoalbuminemia and hospital and long-term mortality has been only partially evaluated. This study sought to analyze the causes of hypoalbuminemia in acute HF patients and determine its impact on hospital and long-term mortality. METHODS AND RESULTS: A total of 362 consecutive acute HF patients were assessed. The patients were divided into 2 groups according to the presence or absence of hypoalbuminemia (albumin <=3.4 g/dL), and the independent association of each variable with hypoalbuminemia and hospital mortality was assessed with the use of multiple logistic regression. The association between hypoalbuminemia and long-term mortality was assessed with the use of Cox multivariate analysis. In total, 108 patients (29.8%) were classified as having hypoalbuminemia. Older age, higher C reactive protein levels, and lower levels of total protein, prealbumin, transferrin, and lymphocytes were independently associated with hypoalbuminemia. Hospital mortality was 8% and was independently associated with hypoalbuminemia. A total of 333 patients were discharged. Hypoalbuminemia was an independent predictor of mortality. CONCLUSIONS: Hypoalbuminemia in acute HF patients was associated with higher hospital mortality and served as an independent predictor of long-term mortality. Malnutrition and inflammation were factors causing hypoalbuminemia in this clinical setting. PMID- 24486928 TI - Latent obstruction and left atrial size are predictors of clinical deterioration leading to septal reduction in hypertrophic cardiomyopathy. AB - BACKGROUND: Exercise echocardiography is a reliable tool to assess left ventricular (LV) dynamic obstruction in hypertrophic cardiomyopathy (HCM). The aim of this study was to determine the role of exercise echocardiography in the evaluation of latent obstruction and in predicting clinical deterioration in HCM patients. METHODS AND RESULTS: We considered 283 HCM patients studied with exercise echocardiography. The end point was clinical deterioration leading to septal reduction (myectomy or alcohol septal ablation). LV latent obstruction was present at enrollment in 67 patients (24%). During a mean follow-up of 42 +/- 31 months, 42 patients had clinical deterioration leading to septal reduction therapy: in 12/67 (22%) patients with a latent obstruction at enrollment, in 28/84 (33%) patients with obstruction at rest, and in 2/132 (1.5%) with obstruction neither at rest or during stress. Multivariate analysis identified the following variables as independently associated with the end point: LV gradient >30 mm Hg at rest (hazard ratio [HR] 2.56, 95% CI 1.27-5.14; P = .009), LV gradient >30 mm Hg during stress (HR 4.96, 95% CI 1.81-13.61; P = .002), and indexed left atrial volume (LAVi ) >40 mL/m(2) (HR 2.86, 95% CI 1.47-5.55; P = .002). In patients with a latent obstruction, the strongest independent predictor of outcome was LAVi >40 mL/m(2) (HR 3.75, 95% CI 1.12-12.51; P = .032). CONCLUSIONS: Assessment of LV gradient during stress with exercise echocardiography is an important tool for the evaluation of latent obstruction in HCM and may have a role in risk stratification of these patients. PMID- 24486929 TI - Utilization pattern of mineralocorticoid receptor antagonists in contemporary patients hospitalized with acute decompensated heart failure: a single-center experience. AB - BACKGROUND: Recent studies have broadened the potential use of mineralocorticoid receptor antagonist (MRA) in patients with systolic heart failure after cardiovascular hospitalization. Real-world data on safety and tolerability of MRA initiation during hospitalization for acute decompensated heart failure (ADHF) are lacking. We examined the patterns of utilization of MRAs in patients admitted for ADHF in contemporary clinical practice. METHODS AND RESULTS: We reviewed consecutive hospitalized patients admitted with a primary diagnosis of ADHF from March to June 2011. The treatment patterns of MRA use or discontinuation before, during, and after hospitalization were reviewed and analyzed retrospectively. In the study cohort of 500 patients, 106 patients (21%) were on MRAs before admission. During hospitalization, preadmission and newly started MRAs were discontinued in 64 out of 177 (36%), with worsening renal function being the most common identifiable reason. In a multivariate analysis, high admission creatinine was the only significant predictor of MRA discontinuation during hospitalization (P = .01). Of the 394 patients who did not receive MRA before admission, 81 were eligible for MRAs, but only 17 (21%) were initiated. After a median follow up of 57 days, 21 additional patients discontinued MRAs; of 72 eligible patients for MRA, 55 patients (76%) were still appropriately taking it. CONCLUSIONS: Despite recent data, MRAs are still underutilized in patients admitted with ADHF who are otherwise eligible for it. Elevated serum creatinine and worsening of renal function are the most common cause of in-hospital discontinuation, which highlights the importance of meticulous follow-up after MRA initiation. PMID- 24486930 TI - Standardization of morbidity assessment in breast cancer surgery using the Clavien Dindo Classification. AB - INTRODUCTION: There are no published data on standardized scoring systems for morbidity after breast cancer surgery. Aim of the study was to establish the Clavien Dindo Classification (CDC) as assessment tool and to identify risk factors for morbidity after breast surgery investigating new techniques including oncoplastic surgery and neoadjuvant chemotherapy. PATIENTS AND METHODS: Between 2008 and 2010, data were retrospectively evaluated from 485 women with breast cancer who underwent surgery at a university hospital. The CDC was used to assess the severity of postoperative complications. Multivariable analyses were adjusted by body-mass index, smoking, diabetes mellitus and tumour size. RESULTS: Overall complications (CDC 1-4) were reported in 28.7%. Second surgery related to major complications (CDC 3-4) was mandatory in 4.7%. Axillary dissection was an independent predictor for CDC 1-4 in all patients (P = 0.008, OR of 1.81, 95%CI 1.17-2.82). We found no independent predictor for CDC 3-4. Oncoplastic surgery increased the rate of wound infections (P = 0.010, OR: 2.94, 95%CI 1.30-6.67) and necroses (P < 0.001, OR: 8.38, 95%CI 3.28-21.4). Axillary dissection elevated wound infection (P = 0.040, OR: 2.07, 95%CI 1.03-4.14) and seroma rates (P < 0.001, OR: 2.46, 95%CI 1.51-4.01). Neoadjuvant chemotherapy had no impact on morbidity. CONCLUSION: The CDC is a valid assessment tool for future clinical trials and may be useful for hospital quality control. While axillary dissection and oncoplastic surgery raised morbidity, no single factor predicted for morbidity related second surgery. PMID- 24486931 TI - The implementation and effectiveness of an enhanced recovery programme after oesophago-gastrectomy: a prospective cohort study. AB - BACKGROUND: Oesophageal resection is notoriously complicated and produces a cohort of patients prone to postoperative complications. Maintaining quality care demands a systematic approach to patient management yet postoperative recovery after oesophagectomy is often needlessly inefficient, heterogeneous and governed by the idiosyncrasies of the operating surgeon. Enhanced recovery after surgery (ERAS) programmes are now well established in colorectal surgery and here we describe the implementation and effectiveness of an ERAS programme for the postoperative management of Ivor Lewis oesophago-gastrectomy (ILOG). METHODS: An ERAS programme was devised and implemented with the support of a dedicated in hospital task-force. Three consultant surgeons allocated consecutive patients to the programme (ERAS) and outcomes were compared to consecutive patients not on the ERAS programme (non-ERAS) and a pre-ERAS cohort (pre-ERAS). Principal outcome measures were total length of stay (TLOS), Accordion postoperative complication grade and 30-day readmission rate. RESULTS: 75 patients were enrolled on the ERAS programme, 41 continued as a non-ERAS cohort and 80 consecutive pre-ERAS patients were identified. A significant improvement in median TLOS was observed in the ERAS group (10 days r.7-58) compared to pre-ERAS (13 days r. 8-57) (p = <0.001) and non-ERAS patients (13 days r.8-42) (p = <0.001). No significant difference in Accordion scores for postoperative complications or 30-day readmission rates were observed. DISCUSSION: The introduction of an ERAS programme after ILOG can significantly reduce TLOS without jeopardising patient safety or clinical outcomes. The successful introduction of an ERAS programme requires full motivation and support from all team members including the patient. PMID- 24486932 TI - A novel practical scoring for early diagnosis of traumatic bowel injury without obvious solid organ injury in hemodynamically stable patients. AB - OBJECTIVES: To develop a scoring tool based on clinical and radiological findings for early diagnosis and intervention in hemodynamically stable patients with traumatic bowel and mesenteric injury (TBMI) without obvious solid organ injury (SOI). METHODS: A retrospective analysis was conducted for all traumatic abdominal injury patients in Qatar from 2008 to 2011. Data included demographics and clinical, radiological and operative findings. Multivariate logistic regression was performed to analyze the predictors for the need of therapeutic laparotomy. RESULTS: A total of 105 patients met the inclusion criteria with a mean age of 33 +/- 15. Motor Vehicle Crashes (58%) and fall (21%) were the major MOI. Using Receiver operating characteristic curve, Z-score of >9 was the cutoff point (AUC = 0.98) for high probability of the presence of TBMI requiring surgical intervention. Z-Score >9 was found to have sensitivity (96.7%), specificity (97.4%), PPV (93.5%) and NPV (98.7%). Multivariate regression analysis found Z-score (>9) to be an independent predictor for the need of exploratory laparotomy (OR7.0; 95% CI: 2.46-19.78, p = 0.001). CONCLUSION: This novel tool for early diagnosis of TBMI is found to be simple and helpful in selecting stable patients with free intra-abdominal fluid without SOI for exploratory Laparotomy. However, further prospective studies are warranted. PMID- 24486933 TI - Impact of obesity on surgical outcomes post-pancreaticoduodenectomy: a case control study. AB - BACKGROUND: Obesity is a growing worldwide epidemic. There is association between obesity and pancreatic cancer risk. However, the impact of obesity on the outcome of pancreatoduodenectomy (PD) is controversial. The aim of this study was to elucidate effect of obesity on surgical outcomes of PD. STUDY DESIGN: A case control study. PATIENT AND METHODS: We retrospectively studied all patients who underwent PD in our center between January 2000 and June 2012. Patients were divided into two groups; Group A (patients with BMI <25) and Group B (patients with BMI > 25). Preoperative demographic data, intraoperative data, and postoperative details were collected. RESULTS: Only 112/471 patients (25.9%) had BMI > 25. The median intraoperative blood loss was more in overweight patients (P = 0.06). The median surgical time in group B was significantly longer than that in group A (P = 0.003). The overall incidence of complications was higher in the overweight group (P = 0.001). The severity of complications was also higher in the overweight group (P = 0.0001). Postoperative pancreatic fistula (POPF) (P = 0.0001) and hospital mortality (P = 0.001) were significantly higher in overweight patients. Oral intake was significantly delayed in overweight patients in comparison to normal weight group (P = 0.02). Postoperative stay was significantly longer in overweight patients (P = 0.0001). CONCLUSION: PD is associated with an increased risk of postoperative morbidity in overweight patient. Overweight patients must not be precluded from undergoing PD. However, operative techniques and pharmacological prophylaxis to decrease POPF should be considered in overweight patients. PMID- 24486934 TI - Early predictors for tissue healing deficit and leakage in geriatric critically ill patients receiving emergent abdominal surgery: a case control study. AB - BACKGROUND: As our world ages and the elderly population grows. Surgery on the aged critically ill tend to result in additional morbidity and mortality. We sought to determine early predicting factors that were associated with postoperative leakage and tissue healing deficiency after emergent abdominal surgery in geriatric critically ill patients. MATERIAL AND METHOD: Retrospectively, geriatric critically ill patients received anticipated, single stage emergent abdominal surgery via emergency room were enrolled. Patients who received only one definitive surgery during their hospital course were labeled as group A, patients received anticipated one-stage surgery and eventually with postoperative leakage and tissue healing deficiency were labeled as group B. The demographics and parameters were obtained for comparison. RESULT: There were 45 patients in group A, and 34 patients in group B. The mean age is 77.4 +/- 6.1 years in Group A and 76.9 +/- 8.5 years in Group B, the mean APACHE score was 20.3 +/- 7.5 vs. 21.6 +/- 7.7. There were no significances in age, gender, comorbidities, and physiological scores. There were significances in the persistent post-operative use of vasopressors and hypoalbuminemia. The 30-day mortality rate was 0% in group A and 38.2% in group B. CONCLUSION: Persistent post operative vasopressor use and hypoalbuminemia are associated with higher rate of morbidity and mortality after emergent abdominal surgery in geriatric critically ill patients. Early recognition is essential for proper management. Further studies are required for a better understanding in identifying risk factors. PMID- 24486935 TI - Torrefaction of agriculture straws and its application on biomass pyrolysis poly generation. AB - This study investigated the properties of corn stalk and cotton stalk after torrefaction, and the effects of torrefaction on product properties obtained under the optimal condition of biomass pyrolysis polygeneration. The color of the torrefied biomass chars darkened, and the grindability was upgraded, with finer particles formed and grinding energy consumption reduced. The moisture and oxygen content significantly decreased whereas the carbon content increased considerably. It was found that torrefaction had different effects on the char, liquid oil and biogas from biomass pyrolysis polygeneration. Compared to raw straws, the output of chars from pyrolysis of torrefied straws increased and the quality of chars as a solid fuel had no significant change, while the output of liquid oil and biogas decreased. The liquid oil contained more concentrated phenols with less water content below 40wt.%, and the biogas contained more concentrated H2 and CH4 with higher LHV up to 15MJ/nm(3). PMID- 24486936 TI - Fresh water green microalga Scenedesmus abundans: A potential feedstock for high quality biodiesel production. AB - Present investigation studied the potential of fresh water green microalga Scenedesmus abundans as a feedstock for biodiesel production. To study the biomass and lipid yield, the culture was grown in BBM, Modified CHU-13 and BG-11 medium. Among the tested nitrogen concentration using Modified CHU-13 medium, the highest biomass and lipid yield of 1.113+/-0.05g/L and 489+/-23mg/L respectively was found in the culture medium with 0.32g/L of nitrogen (KNO3). Different lipid extraction as well as transesterification methods were also tested. Fatty acid profile of alga grown in large scale indigenous made photobioreactor has shown abundance of fatty acids with carbon chain length of C16 and C18. Various biodiesel properties such as cetane number, iodine value and saponification value were found to be in accordance with Brazilian National Petroleum Agency (ANP255) and European biodiesel standard EN14214 which makes S. abundans as a potential feedstock for biodiesel production. PMID- 24486937 TI - Inactivating effects of lignin-derived compounds released during lignocellulosic biomass pretreatment on the endo-glucanase catalyzed hydrolysis of carboxymethylcellulose: A study in continuous stirred ultrafiltration-membrane reactor. AB - This study focusses on the reversible/irreversible damage that selected phenolic compounds, released during steam-explosion pretreatment, mandatory for cellulose accessibility, causes on both stability and activity of a commercial cellulase (half-life=173h) during carboxymethyl-cellulose hydrolysis. Long-term experiments performed in continuous stirred UF-membrane bioreactors, operating at steady state regime, in controlled operational conditions, allowed evaluating the inactivation-constant in the phenol presence (kd1) and after its removal (kd2) from the reactor feed. p-Hydroxybenzoic acid (1 and 2g L(-1)) are the extreme limits in the inactivating effect with enzyme half-lives 99.02 and 14.15h, respectively. The inactivation reversibility was assessed for vanillic acid, p hydroxybenzoic acid, syringaldehyde, p-coumaric acid, being kd1>kd2. p Hydroxybenzaldehyde and protocatechuic acid irreversibly affected cellulase stability increasing its inactivation with kd2>kd1. p-Hydroxybenzaldehyde, 1g L( 1), syringaldehyde, and vanillin, at 2gL(-1), had similar kd1/kd2. PMID- 24486938 TI - Devolatilisation kinetics and pyrolytic analyses of Tectona grandis (teak). AB - Devolatilisation kinetics and pyrolytic analyses were carried out on Tectona grandis (teak) using iso-conversional methods (Flynn-Wall-Ozawa and Starink) and analytical Py-GC/MS technique respectively. Proximate and elemental analyses were also performed and they showed that the ash and C contents and the HHV were 0.7%, 49.6% and 19.8MJ/kg respectively. Biomass sample was subjected to multiple heating rates (5-35K/min) in thermogravimetric experiments and kinetic parameters were evaluated from the non-isothermal TGA curves. The activation energy (E) varied between 222 and 300kJ/mol as a function of degree of conversion. Similarly, the pre-exponential frequency factor (A) varied between 9.6*10(17) and 9.55*10(24)min(-1). Analytical Py-GC/MS showed the presence of CO2, acetic acid, furan+2-butanone, levoglucosan, trans-coniferyl alcohol and lignin derivatives. The proportion of phenolic compounds identified was more than one-third with isoeugenol, acetoguaiacone, and 4-vinylguaiacol showing dominance. PMID- 24486939 TI - Anaerobic digestion characteristics of pig manures depending on various growth stages and initial substrate concentrations in a scaled pig farm in Southern China. AB - The characteristics of anaerobic digestion of pig manure from different growth stages were investigated. According to growth stage, batch experiments were performed using gestating sow manure (GSM), swine nursery with post-weaned piglet manure (SNM), growing fattening manure (GFM) and mixed manure (MM) as substrates at four substrate concentrations (40, 50, 65 and 80gVS/L) under mesophilic conditions. The maximum methane yields of MM, SNM, GSM and GFM were 354.7, 328.7, 282.4 and 263.5mLCH4/gVSadded, respectively. Volatile fatty acids/total inorganic carbon (VFA/TIC) ratio increased from 0.10 to 0.89 when loading increased from 40 to 80gVS/L for GFM. The modified Gompertz model shows a better fit to the experimental results than the first order model with a lower difference between measured and predicted methane yields. The kinetic parameters indicated that the methane production curve on the basis of differences in biodegradability of the pig manure at different growth stages. PMID- 24486940 TI - High quality fuel gas from biomass pyrolysis with calcium oxide. AB - The removal of CO2 and tar in fuel gas produced by biomass thermal conversion has aroused more attention due to their adverse effects on the subsequent fuel gas application. High quality fuel gas production from sawdust pyrolysis with CaO was studied in this paper. The results of pyrolysis-gas chromatography/mass spectrometry (Py-GC/MS) experiments indicate that the mass ratio of CaO to sawdust (Ca/S) remarkably affects the behavior of sawdust pyrolysis. On the basis of Py-GC/MS results, one system of a moving bed pyrolyzer coupled with a fluid bed combustor has been developed to produce high quality fuel gas. The lower heating value (LHV) of the fuel gas was above 16MJ/Nm(3) and the content of tar was under 50mg/Nm(3), which is suitable for gas turbine application to generate electricity and heat. Therefore, this technology may be a promising route to achieve high quality fuel gas for biomass utilization. PMID- 24486941 TI - The Neurobehavioural Abnormalities in Parkinson's Disease and their Relationship to Psychomotor Retardation and Obsessional Compulsive Disorders. PMID- 24486942 TI - Patterns of neglect dissociation. AB - Extinction in the visual, tactile and auditory modality, and visual, tactile and motor neglect were investigated in 40 right brain-damaged (RBD) and 50 left brain damaged (LBD) patients. The presence of neglect was assessed with reference to the performance of 50 control patients. Visual neglect was only found in RBD patients and its severity could vary from one test to another. Tactile neglect was much rarer and it occurred with lesions in either hemisphere. Five cases of motor neglect were found in patients with right parietal damage. Both extinction and neglect could be present either confined to I modality or involving 2 or more. The assumption that extinction always represents an attenuated form of neglect was challenged by the finding of 1 patient with visual neglect but no visual extinction and of3 patients with extinction in all modalities and no sign of neglect. Exploration of contralateral space would appear to be a process monitored by mechanisms decentralized at the level of the single modality rather than by a supramodal supervisor. PMID- 24486943 TI - Alcoholism, Korsakoff's Syndrome and the Frontal Lobes. AB - A subset of the diffuse cerebral changes and psychometric deficits found in chronic alcoholics is similar to that seen in the frontal lobe syndrome. Certain features of alcoholic Korsakoff's syndrome (AKS) also point to cortical involvement, and this may have a basis in alcohol neurotoxicity.Twenty-five patients with AKS and 24 non-Korsakoff alcoholic controls were compared using an automated CT brain scan program. In addition to evidence of their diencephalic lesions (wide third ventricles), AKS patients revealed widespread cerebral damage with greater Sylvian and interhemispheric fissure (IHF) size than alcoholics. Korsakoffs were also inferior to alcoholics in performance on a category sorting test, in which non-perseverative error scores correlated significantly with IHF size.The principle of distinguishing between selective memory decline and global intellectual decline (GID) was applied to 38 patients with AKS. Indices were developed for each type of deficit and much variation found in their distributions. The degree of GID correlated significantly with IHF size, showing similar trends with other cortical measures.These results suggest a cortical substrate for the degree of GID and a frontal substrate for category sorting deficits; with a probable basis in alcohol neurotoxicity rather than thiamine deficiency, which is not known to impair cortical structure. A new model is proposed of the pathophysiology of alcoholic brain damage and AKS which includes recent work on neurotransmitter sources and thalamo-frontal connections. PMID- 24486944 TI - Clock-drawing in neurological disorders. AB - Clock-drawing is a widely used bedside test of constructional ability, but it has never been systematically studied or standardized. We examined 87 clocks drawn by neurologically impaired patients and age-matched controls, and propose a set of criteria for scoring clocks. Patients with probable Alzheimer's disease and other dementias have gross impairments in clock-drawing. These deficits include poor spatial arrangement of numbers, incorrect numerical sequence, insertion of stray lines, and addition of extra numbers. In Alzheimer's disease, the total score on the clock-drawing test correlates with the score on the Modified "Mini-Mental State" Examination. Non-demented patients with Parkinson's disease showed only defects in the spatial organization of the numbers, and non-demented patients with other diseases perform as well as controls. PMID- 24486945 TI - Affective disorders in epilepsies: a neuropsychiatric review. AB - Psychiatry and neurology are well-established as separate disciplines and they may view an issue of mutual concern, such as affective disorder in people with epilepsy, from such different premises that the important synthesis of behavioural neurology, or neuropsychiatry, will be made ineffective. Nosological problems stemming from the use of diagnostic manuals are discussed and revealed in case reports. Reports of affective disorder in persons with brain disorders are relatively rare, possibly as a consequence of nosological problems which stem from a maintenance of a tradition of "functional" disorder. New cases of bipolar disorder and organic mania are given with commentary on the preponderant lateralization of cerebral dysfunction to the right cerebral hemisphere in manic cases. PMID- 24486947 TI - Effect of memantine on L-DOPA-induced dyskinesia in the 6-OHDA-lesioned rat model of Parkinson's disease. AB - An increasing body of experimental evidence demonstrates that the glutamatergic system is involved in the genesis of l-3,4-dihydroxyphenylalanine (L-DOPA) induced dyskinesia (LID). Indeed, the N-methyl-d-aspartate (NMDA) receptor antagonist amantadine is the only anti-dyskinetic compound used in patients, albeit with limited efficacy and side effects. In this study, we investigated the anti-dyskinetic properties of memantine, a non-competitive NMDA receptor antagonist in clinical use for the treatment of dementia, in the 6-hydroxy dopamine (6-OHDA)-lesion rat model of Parkinson's disease. For comparison, parallel experiments were also performed with amantadine. First, we investigated the acute effect of different doses of memantine (5, 10, 15 and 20mg/kg), and amantadine (10, 20, 40, 60mg/kg) on established dyskinesia induced by L-DOPA (6mg/kg plus benserazide). Results showed that both memantine and amantadine produced a significant reduction of LID. Afterward, drug-naive and L-DOPA-primed 6-OHDA-lesioned rats were sub-chronically treated with daily injections of L-DOPA (6mg/kg plus benserazide) alone, or in combination with the effective doses of memantine, while amantadine was tested in already dyskinetic rats. Results showed that memantine significantly dampened dyskinesia in both drug-naive and L-DOPA primed rats, but only during the first few days of administration. In fact, the anti-dyskinetic effect of memantine was completely lost already at the fifth administration, indicating a rapid induction of tolerance. Interestingly, a 3 week washout period was not sufficient to restore the anti-dyskinetic effect of the drug. Similarly, amantadine was able to dampen already established dyskinesia only during the first day of administration. Moreover, memantine partially decreased the therapeutic effect of L-DOPA, as showed by the result of the stepping test. Finally, loss of the anti-dyskinetic effect of memantine was associated to increased synaptic GluN2A/GluN2B ratio at striatal synaptic membranes. Our results are in line with clinical observations suggesting that NMDA receptor blockade may only be transiently effective against LID in PD patients. PMID- 24486948 TI - Molecular typing of canine parvovirus strains circulating from 2008 to 2012 in an organized kennel in India reveals the possibility of vaccination failure. AB - Canine parvovirus-2 (CPV-2), which emerged in 1978, is considered as the major viral enteric pathogen of the canine population. With the emergence of new antigenic variants and incidences of vaccine failure, CPV has become one of the dreaded diseases of the canines worldwide. The present study was undertaken in an organized kennel from North India to ascertain the molecular basis of the CPV outbreaks in the vaccinated dogs. 415 samples were collected over a 5year period (2008-2012). The outbreak of the disease was more severe in 2012 with high incidence of mortality in pups with pronounced clinical symptoms. Molecular typing based on the VP2 gene was carried out with the 11 isolates from different years and compared with the CPV prototype and the vaccine strains. All the isolates in the study were either new CPV-2a (2012 isolates) or new CPV-2b (2008 and 2011 isolates). There were amino acid mutations at the Tyr324Ile and at the Thr440Ala position in five isolates from 2012 indicating new CPV mutants spreading in India. The CPV vaccines used in the present study failed to generate protective antibody titer against heterogeneous CPV antigenic types. The findings were confirmed when the affected pups were treated with hyper-immune heterogeneous purified immunoglobulin's against CPV in dogs of different antigenic types. PMID- 24486949 TI - Heme exporter FLVCR1a regulates heme synthesis and degradation and controls activity of cytochromes P450. AB - BACKGROUND & AIMS: The liver has one of the highest rates of heme synthesis of any organ. More than 50% of the heme synthesized in the liver is used for synthesis of P450 enzymes, which metabolize exogenous and endogenous compounds that include natural products, hormones, drugs, and carcinogens. Feline leukemia virus subgroup C cellular receptor 1a (FLVCR1a) is plasma membrane heme exporter that is ubiquitously expressed and controls intracellular heme content in hematopoietic lineages. We investigated the role of Flvcr1a in liver function in mice. METHODS: We created mice with conditional disruption of Mfsd7b, which encodes Flvcr1a, in hepatocytes (Flvcr1a(fl/fl);alb-cre mice). Mice were analyzed under basal conditions, after phenylhydrazine-induced hemolysis, and after induction of cytochromes P450 synthesis. Livers were collected and analyzed by histologic, quantitative real-time polymerase chain reaction, and immunoblot analyses. Hepatic P450 enzymatic activities were measured. RESULTS: Flvcr1a(fl/fl);alb-cre mice accumulated heme and iron in liver despite up regulation of heme oxygenase 1, ferroportin, and ferritins. Hepatic heme export activity of Flvcr1a was closely associated with heme biosynthesis, which is required to sustain cytochrome induction. Upon cytochromes P450 stimulation, Flvcr1a(fl/fl);alb-cre mice had reduced cytochrome activity, associated with accumulation of heme in hepatocytes. The expansion of the cytosolic heme pool in these mice was likely responsible for the early inhibition of heme synthesis and increased degradation of heme, which reduced expression and activity of cytochromes P450. CONCLUSIONS: In livers of mice, Flvcr1a maintains a free heme pool that regulates heme synthesis and degradation as well as cytochromes P450 expression and activity. These findings have important implications for drug metabolism. PMID- 24486950 TI - Hepatitis C virus attenuates interferon-induced major histocompatibility complex class I expression and decreases CD8+ T cell effector functions. AB - BACKGROUND & AIMS: Major histocompatibility complex (MHC) class I-restricted CD8(+) T cells are required for clearance of hepatitis C virus (HCV) infection. MHC class I expression is up-regulated by type I and II interferons (IFNs). However, little is known about the effects of HCV infection on IFN-induced expression of MHC class I. METHODS: We used the HCV cell culture system (HCVcc) with the genotype 2a Japanese fulminant hepatitis-1 strain to investigate IFN induced expression of MHC class I and its regulatory mechanisms. HCVcc-infected Huh-7.5 cells were analyzed by flow cytometry, metabolic labeling, immunoprecipitation, and immunoblotting analyses. Protein kinase R (PKR) was knocked down with lentiviruses that express small hairpin RNAs. The functional effects of MHC class I regulation by HCV were demonstrated in co-culture studies, using HCV-specific CD8(+) T cells. RESULTS: Although the baseline level of MHC class I was not affected by HCV infection, IFN-induced expression of MHC class I was notably attenuated in HCV-infected cells. This was associated with replicating HCV RNA, not with viral protein. HCV infection reduced IFN-induced synthesis of MHC class I protein and induced phosphorylation of PKR and eIF2alpha. IFN-induced MHC class I expression was restored by small hairpin RNA mediated knockdown of PKR in HCV-infected cells. Co-culture of HCV-specific CD8(+) T cells and HCV-infected cells that expressed HLA-A2 demonstrated that HCV infection reduced the effector functions of HCV-specific CD8(+) T cells; these functions were restored by small hairpin RNA-mediated knockdown of PKR. CONCLUSIONS: IFN-induced expression of MHC class I is attenuated in HCV-infected cells by activation of PKR, which reduces the effector functions of HCV-specific CD8(+) T cells. This appears to be an important mechanism by which HCV circumvents antiviral adaptive immune responses. PMID- 24486951 TI - Inhibition of HCV replication by cyclophilin antagonists is linked to replication fitness and occurs by inhibition of membranous web formation. AB - BACKGROUND & AIMS: Replication of hepatitis C virus (HCV) requires host cell factors, such as cyclophilin A (CypA). CypA binds to HCV's nonstructural protein (NS)5A to promote replication of viral RNA. CypA antagonists, such as cyclosporines, are potent inhibitors of HCV replication. NS2 modulates sensitivity of HCV to cyclosporines. We investigated why cyclosporines require NS2 to increase their inhibitory effect and how they block HCV replication. METHODS: We determined replication fitness and sensitivity of various HCV replicons, containing or lacking NS2, to cyclosporine and other direct-acting antiviral agents. We also analyzed the effects of cyclosporine on membranous web formation by electron microscopy. RESULTS: NS2-5B replicons of genotype 2a (JFH1), but not genotype 1b, had increased sensitivity to cyclosporine. This difference was lost with replication-attenuated NS3-5B JFH1 RNAs, showing that cyclosporine sensitivity is linked to reduced replication fitness of NS2 containing HCV RNAs. Fitness also determined sensitivity to a nucleoside analogue and an NS5A inhibitor, but not to telaprevir. Cyclosporine blocked de novo formation of the membranous web, but had little effect on established membranous replication factories. This block was prevented by cyclosporine resistance mutations in NS5A. CONCLUSIONS: Cleavage at the NS2/3 junction is a rate-limiting step in replication of particular HCV isolates and determines their sensitivity to CypA inhibitors. These drugs target de novo formation of the membranous web and RNA replication. PMID- 24486952 TI - Favipiravir (T-705) protects against peracute Rift Valley fever virus infection and reduces delayed-onset neurologic disease observed with ribavirin treatment. AB - Rift Valley fever is a zoonotic, arthropod-borne disease that affects livestock and humans. The etiologic agent, Rift Valley fever virus (RVFV; Bunyaviridae, Phlebovirus) is primarily transmitted through mosquito bites, but can also be transmitted by exposure to infectious aerosols. There are presently no licensed vaccines or therapeutics to prevent or treat severe RVFV infection in humans. We have previously reported on the activity of favipiravir (T-705) against the MP-12 vaccine strain of RVFV and other bunyaviruses in cell culture. In addition, efficacy has also been documented in mouse and hamster models of infection with the related Punta Toro virus. Here, hamsters challenged with the highly pathogenic ZH501 strain of RVFV were used to evaluate the activity of favipiravir against lethal infection. Subcutaneous RVFV challenge resulted in substantial serum and tissue viral loads and caused severe disease and mortality within 2-3 days of infection. Oral favipiravir (200 mg/kg/day) prevented mortality in 60% or greater of hamsters challenged with RVFV when administered within 1 or 6h post exposure and reduced RVFV titers in serum and tissues relative to the time of treatment initiation. In contrast, although ribavirin (75 mg/kg/day) was effective at protecting animals from the peracute RVFV disease, most ultimately succumbed from a delayed-onset neurologic disease associated with high RVFV burden observed in the brain in moribund animals. When combined, T-705 and ribavirin treatment started 24 h post-infection significantly improved survival outcome and reduced serum and tissue virus titers compared to monotherapy. Our findings demonstrate significant post-RVFV exposure efficacy with favipiravir against both peracute disease and delayed-onset neuroinvasion, and suggest added benefit when combined with ribavirin. PMID- 24486953 TI - Inhibition of BmNPV replication in silkworm cells using inducible and regulated artificial microRNA precursors targeting the essential viral gene lef-11. AB - Bombyx mori nucleopolyhedrovirus (BmNPV) is a major silkworm pathogen, causing substantial economic losses to the sericulture industry annually. We demonstrate a novel anti-BmNPV system expressing mature artificial microRNAs (amiRNAs) targeting the viral lef-11 gene. The mature amiRNAs inhibited the lef-11 gene in silkworm BmN-SWU1 cells. Antiviral assays demonstrated that mature amiRNAs silenced the gene and inhibited BmNPV proliferation efficiently. As constitutive overexpression of mature amiRNAs may induce acute cellular toxicity, we further developed a novel virus-induced amiRNA expression system. The amiRNA cassette is regulated by a baculovirus-induced fusion promoter. This baculovirus-induced RNA interference system is strictly regulated by virus infection, which functions in a negative feedback loop to activate the expression of mature amiRNAs against lef 11 and subsequently control inhibition of BmNPV replication. Our study advances the use of a regulatable amiRNA cassette as a safe and effective tool for research of basic insect biology and antiviral application. PMID- 24486954 TI - Small molecule inhibition of Epstein-Barr virus nuclear antigen-1 DNA binding activity interferes with replication and persistence of the viral genome. AB - The replication and persistence of extra chromosomal Epstein-Barr virus (EBV) episome in latently infected cells are primarily dependent on the binding of EBV encoded nuclear antigen 1 (EBNA1) to the cognate EBV oriP element. In continuation of the previous study, herein we characterized EBNA1 small molecule inhibitors (H20, H31) and their underlying inhibitory mechanisms. In silico docking analyses predicted that H20 fits into a pocket in the EBNA1 DNA binding domain (DBD). However, H20 did not significantly affect EBNA1 binding to its cognate sequence. A limited structure-relationship study of H20 identified a hydrophobic compound H31, as an EBNA1 inhibitor. An in vitro EBNA1 EMSA and in vivo EGFP-EBNA1 confocal microscopy analysis showed that H31 inhibited EBNA1 dependent oriP sequence-specific DNA binding activity, but not sequence nonspecific chromosomal association. Consistent with this, H31 repressed the EBNA1-dependent transcription, replication, and persistence of an EBV oriP plasmid. Furthermore, H31 induced progressive loss of EBV episome. In addition, H31 selectively retarded the growth of EBV-infected LCL or Burkitt's lymphoma cells. These data indicate that H31 inhibition of EBNA1-dependent DNA binding decreases transcription from and persistence of EBV episome in EBV-infected cells. These new compounds might be useful probes for dissecting EBNA1 functions in vitro and in vivo. PMID- 24486955 TI - Circulating interleukin-8 levels explain breast cancer osteolysis in mice and humans. AB - Skeletal metastases of breast cancer and subsequent osteolysis connote a dramatic change in the prognosis for the patient and significantly increase the morbidity associated with disease. The cytokine interleukin 8 (IL-8/CXCL8) is able to directly stimulate osteoclastogenesis and bone resorption in mouse models of breast cancer bone metastasis. In this study, we determined whether circulating levels of IL-8 were associated with increased bone resorption and breast cancer bone metastasis in patients and investigated IL-8 action in vitro and in vivo in mice. Using breast cancer patient plasma (36 patients), we identified significantly elevated IL-8 levels in bone metastasis patients compared with patients lacking bone metastasis (p<0.05), as well as a correlation between plasma IL-8 and increased bone resorption (p<0.05), as measured by NTx levels. In a total of 22 ER+ and 15 ER- primary invasive ductal carcinomas, all cases examined stained positive for IL-8 expression. In vitro, human MDA-MB-231 and MDA MET breast cancer cell lines secrete two distinct IL-8 isoforms, both of which were found to stimulate osteoclastogenesis. However, the more osteolytic MDA-MET derived full length IL-8(1-77) had significantly higher potency than the non osteolytic MDA-MB-231-derived IL-8(6-77), via the CXCR1 receptor. MDA-MET breast cancer cells were injected into the tibia of nude mice and 7days later treated daily with a neutralizing IL-8 monoclonal antibody. All tumor-injected mice receiving no antibody developed large osteolytic bone tumors, whereas 83% of the IL-8 antibody-treated mice had no evidence of tumor at the end of 28days and had significantly increased survival. The pro-osteoclastogenic activity of IL-8 in vivo was confirmed when transgenic mice expressing human IL-8 were examined and found to have a profound osteopenic phenotype, with elevated bone resorption and inherently low bone mass. Collectively, these data suggest that IL-8 plays an important role in breast cancer osteolysis and that anti-IL-8 therapy may be useful in the treatment of the skeletal related events associated with breast cancer. PMID- 24486956 TI - Mortality of combined serum phosphorus and parathyroid hormone concentrations and their changes over time in hemodialysis patients. AB - BACKGROUND: Mineral and bone disorder (MBD) is common and associated with mortality in patients with chronic kidney disease (CKD) Given that disarrays in serum phosphorus (P) and parathyroid hormone (PTH) levels and their changes over time are closely interrelated, modeling mortality-predictability of their combinations may help improve CKD patient management. METHODS: A historical cohort study was undertaken to evaluate the joint effect of serum P and PTH levels on mortality in 107,299 chronic hemodialysis (HD) patients. Changes in serum P and PTH levels over 6months, in particular discordant changes, were also modeled with mortality. RESULTS: HD patients were 64+/-15 (mean+/-SD)years old and included 45% women, 33% African-American, and 59% diabetic. Compared with serum P level >=7.0mg/dL and PTH level >=600pg/mL, adjusted hazard ratio (HR) tended to be lowest in patients with serum P level of 3.5-<5.5mg/dL combined with PTH level of 150-<300pg/mL (HR 0.64, 95% confidence interval 0.61-0.67). A change over time in serum P level towards the 3.5-<5.5mg/dL range from higher or lower ranges was associated with a decreased mortality, whereas only change in PTH level from <150pg/mL to 150-<300pg/mL range was associated with a lower risk of mortality. Upon discordant changes of PTH and P, i.e., decrease in one of the two measures while the other increased, no change in mortality risk was observed. CONCLUSION: In CKD-MBD management, patent survival is the greatest with controlling both serum P and PTH levels in balance. Tailoring an individualized treatment strategy in CKD-MBD may benefit patients. Further studies are needed. PMID- 24486958 TI - The neuroprotective effects of cordycepin inhibit glutamate-induced oxidative and ER stress-associated apoptosis in hippocampal HT22 cells. AB - Glutamate toxicity increases the formation of reactive oxygen species (ROS) and intracellular calcium levels, resulting in neuronal dysfunction, neurodegenerative disorders, and death. Cordycepin is a derivative of the nucleoside adenosine, and is believed to exert neuroprotective effects against glutamate-induced oxidative toxicity in HT22 neuronal cells. Excessive glutamate induces oxidative and endoplasmic reticulum (ER) stress, gradually increasing ER related pro-apoptotic transcription factor C/EBP homologous protein (CHOP) expression, and eventually up-regulating expression of the pro-apoptotic factor Bax. Cordycepin inhibits CHOP and Bax expressions, as well as p-ERK, p-JNK, and p p38, all of which are involved in oxidative or ER stress-induced apoptosis. In addition, the increased production of ROS from excessive glutamate leads to elevation of mitochondrial membrane potential (MMP), a hallmark of mitochondrial dysfunction. Cordycepin retains MMP and reduces the elevated levels of ROS and Ca(2+) induced by glutamate. Caspases are crucial mediators involved in mitochondrial apoptosis, and while glutamate disrupts mitochondrial function, it does not change expression levels of caspase 3 and caspase 9. Similarly, cordycepin has no effect on caspase 3 and caspase 9 expressions; however, it decreases the expression of ER stress-specific caspase 12, which plays a key role in the initiation of ER stress-induced apoptosis. Finally, we found that the anti apoptotic effects of cordycepin are partially dependent on activation of the adenosine A1 receptor, whereas an antagonist selectively attenuated the neuroprotective effects of cordycepin. Collectively, these results suggest that cordycepin could be a potential future therapeutic agent for neuronal disorders. PMID- 24486957 TI - Consequences of developmental exposure to concentrated ambient ultrafine particle air pollution combined with the adult paraquat and maneb model of the Parkinson's disease phenotype in male mice. AB - Current evidence suggests suceptibility of both the substantia nigra and striatum to exposure to components of air pollution. Further, air pollution has been associated with increased risk of PD diagnsosis in humans or PD-like pathology in animals. This study examined whether exposure of mice to concentrated ambient ultrafine particles (CAPS; <100nm diameter) during the first two weeks of life would alter susceptibility to induction of the Parkinson's disease phenyotype (PDP) in a pesticide-based paraquat and maneb (PQ+MB) model during adulthood utilizing i.p. injections of 10mg/kg PQ and 30mg/kg MB 2* per week for 6 weeks. Evidence of CAPS-induced enhancement of the PQ+MB PDP was limited primarily to delayed recovery of locomotor activity 24 post-injection of PQ+MB that could be related to alterations in striatal GABA inhibitory function. Absence of more extensive interactions might also reflect the finding that CAPS and PQ+MB appeared to differentially target the nigrostriatal dopamine and amino acid systems, with CAPS impacting striatum and PQ+MB impacting dopamine-glutamate function in midbrain; both CAPS and PQ+MB elevated glutamate levels in these specific regions, consistent with potential excitotoxicity. These findings demonstrate the ability of postnatal CAPS to produce locomotor dysfunction and dopaminergic and glutamateric changes, independent of PQ+MB, in brain regions involved in the PDP. PMID- 24486959 TI - Role of dopamine in the recruitment of immune cells to the nigro-striatal dopaminergic structures. AB - Research indicates that inflammation and microglial activation are involved in the initiation and progression of Parkinson's disease (PD). Neuroinflammation contributes to the infiltration of peripheral immune cells and blood-brain barrier (BBB) leakage, linking peripheral and central inflammatory events in the pathogenesis of PD. Dopamine (DA) likely plays a role in this process. In the present study, the dopaminergic toxin 6-hydroxydopamine (6-OHDA) was used to damage dopaminergic neurons. Injection of 6-OHDA within the nigrostriatal pathway produced loss of astrocytes, disruption of the BBB, microglia activation and a reduction in osteopontin (OPN) immunoreactivity. Depletion of DA content by alpha methylparatyrosine (alpha-MPT, a tyrosine hydroxylase inhibitor) reduced the infiltration of peripheral macrophages as well as the 6-OHDA-induced increase in microglial cells. DA could therefore be relevant in sustaining inflammation and lymphocyte recruitment induced by 6-OHDA, supporting DA implication in the degeneration of dopaminergic neurons induced by inflammatory processes. PMID- 24486960 TI - Neuroprotective role of hydroalcoholic extract of Vitis vinifera against aluminium-induced oxidative stress in rat brain. AB - The present study was designed to examine the protective potential of hydroalcoholic extract of Vitis vinifera in ameliorating the alterations induced by aluminium (Al) on behavioural and neurochemical indices. Al was given orally (100mg/kg b.wt./day) whereas V. vinifera extract was administered through diet (400mg/kg, p.o.) to rats for a total duration of 45 days. Passive avoidance and open field tests revealed significant alterations in the short-term memory and cognitive behaviour in rats treated with Al. Further, locomotor as well as muscular activities were also found to be significantly affected. Co administration of V. vinifera extract with Al caused significant improvement in the short-term memory, cognition, anxiety, locomotion and muscular activity. Al exposure led to a significant decrease in the acetylcholinesterase activity in the brain, increase in serum glucose, TG, TC, ALP and ALT. Anti-oxidant parameters-reduced glutathione, catalase and glutathione reductase levels were also found to be significantly decreased but the levels of lipid peroxidation was significantly increased in brain following Al treatment. V. vinifera extract supplementation to Al treated animals caused a significant improvement in the activity of enzyme acetylcholinesterase which was altered by Al. Serum glucose, TG, TC, ALP and ALT were brought back to normal levels. Further, V. vinifera extract when given along with Al was also able to regulate the levels of Anti oxidant parameters in brain and the values were found close to the normal controls. Histopathological studies revealed neurodegeneration and vacuolated cytoplasm after Al treatment. Therefore, the study strengthens the hypothesis that V. vinifera extract can be used as a neuroprotectant during Al induced neurotoxicity. PMID- 24486961 TI - Minocycline alleviates behavioral deficits and inhibits microglial activation induced by intrahippocampal administration of Granulocyte-Macrophage Colony Stimulating Factor in adult rats. AB - Some evidence has shown an increased number of activated microglial cells in patients with schizophrenia. It is hypothesized that activated microglia may contribute to the pathogenesis of schizophrenia. We injected saline or Granulocyte-Macrophage Colony-Stimulating Factor (GM-CSF) into the ventral hippocampus in adult Sprague-Dawley rats via micro-pump; at the same time, the rats were intragastrically administrated with saline or minocycline once a day for 14 consecutive days. Then, behavioral tests were examined and microglia were assessed using immunohistochemistry method. GM-CSF-injected group showed significant behavioral deficits (hyperlocomotion, social interaction deficits, prepulse inhibition (PPI) deficits). There was a dramatic increase of the number of activated microglial cells in the hippocampus and other brain regions such as cerebral cortex and thalamus compared with those in saline-injected group in immunohistochemistry. Minocycline was able to ameliorate deficits of social interaction and PPI but not hyperlocomotion. Minocycline was also able to inhibit the microglial activation. In conclusion, intrahippocampal administration of GM CSF in adult rats may serve as a potential schizophrenia animal model, which may be related with the microglia hypothesis of schizophrenia. PMID- 24486962 TI - Distribution of vasopressin, oxytocin and vasoactive intestinal polypeptide in the hypothalamus and extrahypothalamic regions of tree shrews. AB - Vasopressin (VP), oxytocin (OXT) and vasoactive intestinal polypeptide (VIP) in the brain modulate physiological and behavioral processes in many vertebrates. Day-active tree shrews, the closest relatives of primates, live singly or in pairs in territories that they defend vigorously against intruding conspecifics. However, anatomy concerning peptidergic neuron distribution in the tree shrew brain is less clear. Here, we examined the distribution of VP, OXT and VIP immunoreactivity in the hypothalamus and extrahypothalamic regions of tree shrews (Tupaia belangeri chinensis) using the immunohistochemical techniques. Most of VP and OXT immunoreactive (-ir) neurons were found in the paraventricular nucleus (PVN) and supraoptic nucleus (SON) of the hypothalamus. In addition, VP-ir or OXT ir neurons were scattered in the preoptic area, anterior hypothalamic areas, dorsomedial hypothalamic nucleus, stria terminalis, bed nucleus of the stria terminalis and medial amygdala. Interestingly, a high density of VP-ir fibers within the ventral lateral septum was observed in males but not in females. Both VP-ir and VIP-ir neurons were found in different subdivisions of the suprachiasmatic nucleus (SCN) with partial overlap. VIP-ir cells and fibers were also scattered in the cerebral cortex, anterior olfactory nucleus, amygdala and dentate gyrus of the hippocampus. These findings provide a comprehensive description of VIP and a detailed mapping of VP and OXT in the hypothalamus and extrahypothalamic regions of tree shrews, which is an anatomical basis for the participation of these neuropeptides in the regulation of circadian behavior and social behavior. PMID- 24486964 TI - Epigenetic control and the circadian clock: linking metabolism to neuronal responses. AB - Experimental and epidemiological evidence reveal the profound influence that industrialized modern society has imposed on human social habits and physiology during the past 50 years. This drastic change in life-style is thought to be one of the main causes of modern diseases including obesity, type 2 diabetes, mental illness such as depression, sleep disorders, and certain types of cancer. These disorders have been associated to disruption of the circadian clock, an intrinsic time-keeper molecular system present in virtually all cells and tissues. The circadian clock is a key element in homeostatic regulation by controlling a large array of genes implicated in cellular metabolism. Importantly, intimate links between epigenetic regulation and the circadian clock exist and are likely to prominently contribute to the plasticity of the response to the environment. In this review, we summarize some experimental and epidemiological evidence showing how environmental factors such as stress, drugs of abuse and changes in circadian habits, interact through different brain areas to modulate the endogenous clock. Furthermore we point out the pivotal role of the deacetylase silent mating-type information regulation 2 homolog 1 (SIRT1) as a molecular effector of the environment in shaping the circadian epigenetic landscape. PMID- 24486963 TI - Nuclear architecture as an epigenetic regulator of neural development and function. AB - The nervous system of higher organisms is characterized by an enormous diversity of cell types that function in concert to carry out a myriad of neuronal functions. Differences in connectivity, and subsequent physiology of the connected neurons, are a result of differences in transcriptional programs. The extraordinary complexity of the nervous system requires an equally complex regulatory system. It is well established that transcription factor combinations and the organization of cis-regulatory sequences control commitment to differentiation programs and preserve a nuclear plasticity required for neuronal functions. However, an additional level of regulation is provided by epigenetic controls. Among various epigenetic processes, nuclear organization and the control of genome architecture emerge as an efficient and powerful form of gene regulation that meets the unique needs of the post-mitotic neuron. Here, we present an outline of how nuclear architecture affects transcription and provide examples from the recent literature where these principles are used by the nervous system. PMID- 24486965 TI - Amygdala kindling disrupts trace and delay fear conditioning with parallel changes in Fos protein expression throughout the limbic brain. AB - Amygdala kindling is well known to increase unconditioned fear and anxiety. However, relatively little is known about whether this form of kindling causes functional changes within the neural circuitry that mediates fear learning and the retrieval of fear memories. To address this issue, we examined the effect of short- (i.e., 30 stimulations) and long-term (i.e., 99 stimulations) amygdala kindling in rats on trace and delay fear conditioning, which are aversive learning tasks that rely predominantly on the hippocampus and amygdala, respectively. After memory retrieval, we analyzed the pattern of neural activity with Fos, the protein product of the immediate early gene c-fos. We found that kindling had no effect on acquisition of the trace fear conditioning task but it did selectively impair retrieval of this fear memory. In contrast, kindling disrupted both acquisition and retrieval of fear memory in the delay fear conditioning task. We also found that kindling-induced impairments in memory retrieval were accompanied by decreased Fos expression in several subregions of the hippocampus, parahippocampus, and amygdala. Interestingly, decreased freezing in the trace conditioning task was significantly correlated with dampened Fos expression in hippocampal and parahippocampal regions whereas decreased freezing in the delay conditioning task was significantly correlated with dampened Fos expression in hippocampal, parahippocampal, and amygdaloid circuits. Overall, these results suggest that amygdala kindling promotes functional changes in brain regions involved in specific types of fear learning and memory. PMID- 24486966 TI - RanBP9 overexpression reduces dendritic arbor and spine density. AB - RanBP9 is a multi-domain scaffolding protein known to integrate extracellular signaling with intracellular targets. We previously demonstrated that RanBP9 enhances Abeta generation and amyloid plaque burden which results in loss of specific pre- and postsynaptic proteins in vivo in a transgenic mouse model. Additionally, we showed that the levels of spinophilin, a marker of dendritic spines were inversely proportional to the RanBP9 protein levels within the synaptosomes isolated from AD brains. In the present study, we found reduced dendritic intersections within the layer 6 pyramidal neurons of the cortex as well as the hippocampus of RanBP9 transgenic mice compared to age-matched wild type (WT) controls at 12 months of age but not at 6months. Similarly, the dendritic spine numbers were reduced in the cortex at only 12 months of age by 30% (p<0.01), but not at 6months. In the hippocampus also the spine densities were reduced at 12 months of age (38%, p<0.01) in the RanBP9 transgenic mice. Interestingly, the levels of phosphorylated form of cofilin, an actin binding protein that plays crucial role in the regulation of spine numbers were significantly decreased in the cortical synaptosomes at only 12months of age by 26% (p<0.01). In the hippocampal synaptosomes, the decrease in cofilin levels were 36% (p<0.01) at 12 months of age. Thus dendritic arbor and spine density were directly correlated to the levels of phosphorylated form of cofilin in the RanBP9 transgenic mice. Similarly, cortical synaptosomes showed a 20% (p<0.01) reduction in the levels of spinophilin in the RanBP9 transgenic mice. These results provided the physical basis for the loss of synaptic proteins by RanBP9 and most importantly it also explains the impaired spatial learning and memory skills previously observed in the RanBP9 transgenic mice. PMID- 24486967 TI - Retrieval-induced forgetting under psychosocial stress: no reduction by delayed stress and beta-adrenergic blockade. AB - Retrieval-induced forgetting (RIF) is the phenomenon that 'retrieval-practice', the repeated retrieval of a subset of initially learned material, can impair the recall of episodically related memories. Previous studies showed that RIF is eliminated when retrieval-practice is carried out under psycho-social stress, anxiety, or in negative mood. However, pharmacological manipulation by hydrocortisone did not eliminate the effect. This study investigated the effect of beta-adrenergic blockade on stress-induced modulations of RIF, addressing possible interactive effects of the glucocorticoid and sympatho-adrenomedullary systems. Participants learned categorized word lists and then received either 60 mg propranolol or a placebo. After 90 min they were exposed to the TSST. A third group did not receive any medication and performed a non-stressful control task with the same timing as the other two groups. Finally, all participants underwent retrieval-practice and final recall. Both TSST groups exhibited a stress-induced increase in cortisol-levels, and the placebo group also exhibited large increases in markers of sympathetic nervous system activity and more psychological distress at the time of retrieval-practice. Although, overall recall was poorer under stress, an overall RIF effect emerged irrespective of group and showed no clear modulation by stress with or without beta-adrenergic blockade. In previous demonstrations of RIF elimination by negative emotion, state induction and retrieval-practice followed very briefly after initial learning. Given that both the previous study of hydrocortisone effects on RIF and the present study used longer delays between learning and retrieval-practice, the possibility that stress effects on retrieval-practice eliminate RIF only relatively briefly after learning is discussed. PMID- 24486968 TI - Transport of persistent organic pollutants across the human placenta. AB - Prenatal life is the most sensitive stage of human development to environmental pollutants. Early exposure to persistent organic pollutants (POPs) may increase the risk of adverse health effects during childhood. The mechanisms of transference of POPs during pregnancy are still not well understood. The present study is aimed to investigate the transfer of POPs between mother and fetus. The concentrations of 14 organochlorine pesticides, 7 polychlorinated biphenyls (PCBs) and 14 polybromodiphenyl ether (PBDEs) congeners have been measured in 308 maternal serum samples, their respective umbilical cords and 50 placental tissues from a mother-infant cohort representative of Spanish general population. In general, the adjusted lipid-basis concentrations were higher in maternal serum than in cord serum and placenta. The concentrations of most pollutants between maternal serum and cord serum and between maternal serum and placenta were significantly correlated. These distributions were consistent with a predominant maternal source that transfers the pollutants into the placenta and the fetus. However, this distribution did not correspond to passive diffusion of these compounds between these tissues according to lipid content. The compounds more readily metabolized were higher in newborns, which suggest that differences in metabolic capabilities may be responsible of the observed variations in POP distributions between mother and newborns. Prenatal exposure to 4,4'-DDT and some PBDEs such as BDE 99 and BDE 209 is much higher than it could be anticipated from the composition of maternal serum. POP exposure assessment studies of newborns may overlook the effects of some of these pollutants if they only consider maternal determinations. PMID- 24486969 TI - Isotopic fractionation of tritium in biological systems. AB - Isotopic fractionation of tritium is a highly relevant issue in radiation protection and requires certain radioecological considerations. Sound evaluation of this factor is indeed necessary to determine whether environmental compartments are enriched/depleted in tritium or if tritium is, on the contrary, isotopically well-distributed in a given system. The ubiquity of tritium and the standard analytical methods used to assay it may induce biases in both the measurement and the signification that is accorded to the so-called fractionation: based on an exhaustive review of the literature, we show how, sometimes large deviations may appear. It is shown that when comparing the non exchangeable fraction of organically bound tritium (neOBT) to another fraction of tritium (e.g. tritiated water) the preparation of samples and the measurement of neOBT reported frequently led to underestimation of the ratio of tritium to hydrogen (T/H) in the non-exchangeable compartment by a factor of 5% to 50%. In the present study, corrections are proposed for most of the biological matrices studied so far. Nevertheless, the values of isotopic fractionation reported in the literature remain difficult to compare with each other, especially since the physical quantities and units often vary between authors. Some improvements are proposed to better define what should encompass the concepts of exchangeable and non-exchangeable fractions. PMID- 24486970 TI - Prenatal exposure to perfluoroalkyl acids and allergic diseases in early childhood. AB - Perfluoroalkyl acids (PFAAs) are persistent organic pollutants that are detected in humans worldwide. Laboratory animal studies have shown that PFAAs are associated with immunotoxic effects. However, epidemiological studies investigating the role of PFAAs, in particular PFAAs with longer chains than perfluorooctanoic acid, are scarce. We investigated associations between prenatal exposure to PFAAs, including long-chain compounds, and infant allergic diseases at 12 and 24months in a large study population. The participants included mothers and their infants who enrolled in the Hokkaido Study on Environment and Children's Health 2003-2009. Eleven PFAAs were measured in maternal plasma taken at 28-32weeks of gestation using ultra-performance liquid chromatography coupled to triple quadrupole tandem mass spectrometry. Characteristics of participants and information on infant allergic diseases were obtained from self-administered questionnaires and medical records. At 24months, the adjusted odds ratio (OR) (first vs. fourth quartiles) for eczema in association with higher maternal perfluorotridecanoic acid (PFTrDA) levels was 0.62 (95% confidence interval (CI) 0.45, 0.86). After stratification by gender, the adjusted ORs in female infants from mothers with higher maternal perfluoroundecanoic acid (PFUnDA) and PFTrDA levels were also statistically significant (PFUnDA: OR=0.50; 95% CI, 0.30, 0.81; PFTrDA: OR=0.39; 95% CI, 0.23, 0.64). Our findings suggest that lower prenatal exposure to PFTrDA may decrease the risk of developing eczema in early childhood, only in female infants. PMID- 24486971 TI - Polycyclic aromatic compounds (PAHs and oxygenated PAHs) and trace metals in fish species from Ghana (West Africa): bioaccumulation and health risk assessment. AB - We report the concentrations of 28 PAHs, 15 oxygenated PAHs (OPAHs) and 11 trace metals/metalloids (As, Cd, Co, Cr, Cu, Fe, Mn, Ni, Pb, Se, and Zn) in muscle and gut+gill tissues of demersal fishes (Drapane africana, Cynoglossus senegalensis and Pomadasys peroteti) from three locations along the coast of the Gulf of Guinea (Ghana). The concentrations of ?28PAHs in muscle tissues averaged 192ngg( 1) dw (range: 71-481ngg(-1) dw) and were not statistically different between locations. The concentrations of ?28 PAHs were higher in guts+gills than in muscles. The PAH composition pattern was dominated by low molecular weight compounds (naphthalene, alkyl-naphthalenes and phenanthrene). All fish tissues had benzo[a]pyrene concentrations lower than the EU limit for food safety. Excess cancer risk from consumption of some fish was higher than the guideline value of 1*10(-6). The concentrations of ?15 OPAHs in fish muscles averaged 422ngg(-1) dw (range: 28-1715ngg(-1)dw). The ?15 OPAHs/?16 US-EPA PAHs concentration ratio was >1 in 68% of the fish muscles and 100% of guts+gills. The log-transformed concentrations of PAHs and OPAHs in muscles, guts+gills were significantly (p<0.05) correlated with their octanol-water partitioning coefficients, strongly suggesting that equilibrium partitioning from water/sediment into fish tissue was the main mechanism of bioaccumulation. The trace metal concentrations in the fish tissues were in the medium range when compared to fish from other parts of the world. The concentrations of some trace metals (Cd, Cu, Fe, Mn, Zn) were higher in guts+gills than in muscle tissues. The target hazard quotients for metals were<1 and did not indicate a danger to the local population. We conclude that the health risk arising from the consumption of the studied fish (due to their PAHs and trace metals content) is minimal. PMID- 24486973 TI - Person centered medicine: an evolving landscape. PMID- 24486972 TI - Levels and trends of PBDEs and HBCDs in the global environment: status at the end of 2012. AB - In this paper, we have compiled and reviewed the most recent literature, published in print or online from January 2010 to December 2012, relating to the human exposure, environmental distribution, behaviour, fate and concentration time trends of polybrominated diphenyl ether (PBDE) and hexabromocyclododecane (HBCD) flame retardants, in order to establish their current trends and priorities for future study. More data are now becoming available for remote areas not previously studied, Indian Ocean islands, for example. Decreasing time trends for penta-mix PBDE congeners were seen for soils in northern Europe, sewage sludge in Sweden and the USA, carp from a US river, trout from three of the Great Lakes and in Arctic and UK marine mammals and many birds, but increasing time trends continue in polar bears and some birds at high trophic levels in northern Europe. This may be partially a result of the time delay inherent in long-range atmospheric transport processes. In general, concentrations of BDE209 (the major component of the deca-mix PBDE product) are continuing to increase. Of major concern is the possible/likely debromination of the large reservoir of BDE209 in soils and sediments worldwide, to yield lower brominated congeners which are both more mobile and more toxic, and we have compiled the most recent evidence for the occurrence of this degradation process. Numerous studies reported here reinforce the importance of this future concern. Time trends for HBCDs are mixed, with both increases and decreases evident in different matrices and locations and, notably, with increasing occurrence in birds of prey. Temporal trends for both PBDEs and HBCD in Asia are unclear currently. A knowledge gap has been noted in relation to metabolism and/or debromination of BDE209 and HBCD in birds. Further monitoring of human exposure and environmental contamination in areas of e-waste recycling, particularly in Asia and Africa, is warranted. More data on temporal trends of BDE and HBCD concentrations in a variety of matrices and locations are needed before the current status of these compounds can be fully assessed, and the impact of regulation and changing usage patterns among different flame retardants determined. PMID- 24486974 TI - [Economic crisis and mental health: effects on the prevalence of common mental disorders]. AB - Economic crises have been found to bring adverse repercussions on physical and mental health internationally through various pathways. Research corroborates a link between financial distress and common mental disorders. In this context, the University Mental Health Research Institute conducted epidemiological nationwide surveys in an endeavour to gauge the impact of the ongoing financial crisis on the mental health of the Greek population. The purpose of the present analysis pertains to investigating changes in the prevalence of common mental disorders in the population as a whole as well as in various population sub-groups between years 2009 and 2011. In addition, the association of financial strain with common mental disorders was also explored. For investigating the particular research objectives, two cross-sectional surveys following the same methodology were conducted. A random and representative sample of 2192 respondents in 2009 and 2256 respondents in 2011 took part in telephone interviews. Generalized anxiety disorder and major depression were assessed with the germane modules of Structured Clinical Interview, while financial difficulties with the Index of Personal Economic Distress (IPED), an original scale developed for the purposes of the particular surveys. All measures displayed good psychometric properties. Between the two years, a noteworthy, albeit non-significant, increase in one prevalence of major depression was documented. On the other hand, the prevalence of generalized anxiety disorder remained largely unchanged. Statistically significant differences in the prevalence of both disorders were reported for particular population subgroups, with married persons and employed people emerging as the most afflicted individuals. Regarding financial distress, it was found to bear a statistically significant association with major depression but not with generalized anxiety disorder. For mitigating the mental health effects of the crisis on the general population, study findings underline the necessity of implementing targeted interventions, tailored to the needs and difficulties of each population sub-group. PMID- 24486975 TI - [Epidemiological characteristics of minors' exposure to experiences of violence in Greece: the BECAN study]. AB - In this study preliminary results are presented by the Hellenic part (n=10,451, children's response rate: 71.87%) of the BECAN study. This study, funded by EU's FP7 (ID: 223478), was an international epidemiological field research in a representative randomly selected sample of school children ageing 11, 13 and 16 years old in 9 Balkan countries, conducted via self completed questionnaires ICAST-C and ICAST-P by the children and their parents. In virtue of the research's design, anonymity of responders could be preserved via a unique code resulting in pairs of child-parent questionnaires. ICAST tools inquiring exposure to various forms of violence are structured in sub-scales. In Greek part's results, incidence and prevalence were respectfully found to be 47.38% and 76.37% for physical violence, 70.02% and 83.16% for psychological violence, 9.54% and 15.84% for sexual violence, 4.45% and 7.60% for the part of the later including some short of physical contact and 26.41% and 37.20% for self-reported subjective feelings of neglect. In contrast with the rather disappointing findings regarding exposure of Greek children to violence, most of the participant subjects reported also at least one recollection of positive, non violence parental behaviors in percentages reaching 96.21% and 98.18% for the last year or during childhood respectfully. Further analysis of results documented that statistically significant differences regarding increased figures of females' prevalence rates for exposure to physical and sexual violence (p-value <5%) and both their prevalence and incidence rates regarding subjective feelings of neglect (p-value <1%). On the contrary, males' rates were found to be more increased towards females' ones at a level of statistically significance (p-value <1%) regarding exposure to sexual violence both overall and the part of it including physical contact. Moreover, females reported more often than boys experiences of positive parental practices (p-value <5%). Relatively minor diversities were found in regards to venue of residence with some mild differences (p-value <5%) of increased incidence rates of exposure to physical violence and decreased prevalence rates of exposure to physiological and overall sexual violence of children living in rural areas. A constant statistically significant differentiation was established regarding school grade of responders with a gradual increase of exposure rates to psychological and sexual violence and feelings of neglect for both incidence and prevalence; the most outstanding of these increase trends were found between 1st school-grade of Gymnasium and 1st school-grade of Lyceum (roughly corresponding to age period between 13 and 16 years old children) which is by and large attributable more to male subjects and the constant increase of feelings of been neglected as children move towards adulthood which is caused mainly in virtue of female responders. In overall, findings of this research are differentiated from results reported from other countries in terms of almost equation of male to female ratio of exposure to physical and sexual violence (in contrast with male's and females' rates respectful regularly reported predominance), while regarding incidence rates of males' sexual victimization the sex ratio was found to be reverse than the anticipated according to international scientific literature. PMID- 24486976 TI - [Neurological soft signs in schizophrenia: correlations with age, sex, educational status and psychopathology]. AB - Though the pathobiology of schizophrenia can be examined in multiple levels, the organic notion of brain disease suggests that neurological features will be present. One straightforward, inexpensive method of investigating brain dysfunction in schizophrenia is thought the bedside assessment of neurological abnormalities with a standard neurological examination. Neurological abnormalities are traditionally classified as "hard signs" (impairments in basic motor, sensory, and reflex behaviors, which do not appear to be affected in schizophrenia) and "soft signs", which refer to more complex phenomena such as abnormalities in motor control, integrative sensory function, sensorimotor integration, and cerebral laterality. Additionally, neurological soft signs (NSS) are minor motor and sensory abnormalities that are considered to be normal in the course of early development but abnormal when elicited in later life or persist beyond childhood. Soft signs also, have no definitive localizing significance but are indicative of subtle brain dysfunction. Most authors believe that they are a reflection not only of deficient integration between the sensory and motor systems, but also of dysfunctional neuronal circuits linking subcortical brain structures such as the basal ganglia, the brain stem, and the limbic system. Throughout the last four decades, studies have consistently shown that NSS are more frequently present in patients with schizophrenia than in normal subjects and non-psychotic psychiatric patients. However, the functional relevance of NSS remains unclear and their specificity has often been challenged, even though there is indication for a relative specificity with regard to diagnosis, or symptomatology. Many studies have considered soft signs as categorical variables thus hampering the evaluation of fluctuation with symptomatology and/or treatment, whereas other studies included insufficient number of assessed signs, or lacked a comprehensive assessment of extrapyramidal symptomatology. Factors such as sex, age or family history of schizophrenia, are said to influence the performance of neurological examination, whereas relative few studies have provided longitudinal follow-up data on neurological soft signs in a sufficient number of patients, in order to address a possible deterioration of neurological functions. Finally, one additional difficulty when analyzing the NSS literature lies in the diversity of symptoms that are evaluated in the studies and/or non standardized procedures or scoring. We will review some basic issues concerning recurrent difficulties in the measurement and definition of soft signs, as well as controversies on the significance of these signs with respect to clinical subtyping of schizophrenia, and social and demographic variables. PMID- 24486977 TI - [Ultra-short questionnaires for the detection of depression and anxiety]. AB - Depression and anxiety disorders are the two most common mental health problems seen in the primary care and the general hospital settings. They are both associated with poorer patient functioning, worse quality of life, more frequent utilization of health services, and higher health care costs. However, detection rates of depression and anxiety by non-mental health specialists remain very low, while most of the proposed screening tools are rather not practical and therefore they have not been widely used in practice. Over the last two decades, ultra short tools including one to three questions have been developed and suggested as case-finding methods and their sensitivity and specificity have been investigated. We reviewed all the ultra-short screening tools for depression and anxiety and the existing evidence on their accuracy in detecting major depression and anxiety disorders. Two simple screening questions for depression, about depressed mood and loss of interest or pleasure in doing things, have been repeatedly applied in primary care settings and found to have satisfactory sensitivity but low specificity. The addition of a third question inquiring if help is needed to the two screening questions for depression improves the specificity, however on the cost of reducing the sensitivity of the method. Screening for depression using only one of these questions alone was found to be less accurate strategy than the two or three question tests. The Patient Health Questionnaire-2 (PHQ-2) includes the same two depression-questions with rating scale answer choices and it was found to be more accurate than the two question test with dichotomous (yes or no) answers. Ultra-short screening strategies for depression in older people were found to have acceptable levels of accuracy, while in patients with cancer the two question tests had higher sensitivity and specificity than in other patient groups. According to the existing data, the Generalized Anxiety Disorder-2 (GAD-2) questionnaire, which includes two questions on "feeling nervous, anxious or on edge" and "not being able to stop or control worrying" appears to have acceptable accuracy in identifying clinically significant anxiety. We concluded that there is sufficient evidence on the suitability of the ultra-short screening instruments for depression and anxiety especially the PHQ-2, the GAD-2 and their combination, the PHQ-4- for use in epidemiological studies. In primary and secondary care settings, the ultra-short tools can be used only as an initial screening method but diagnosis made by specially-trained clinicians or mental health specialists is warranted for patients who initially screen positive. PMID- 24486978 TI - Lexical access and evoked traveling alpha waves. AB - Retrieval from semantic memory is usually considered within a time window around 300-600ms. Here we suggest that lexical access already occurs at around 100ms. This interpretation is based on the finding that semantically rich and frequent words exhibit a significantly shorter topographical latency difference between the site with the shortest P1 latency (leading site) and that with the longest P1 latency (trailing site). This latency difference can be described in terms of an evoked traveling alpha wave as was already shown in earlier studies. PMID- 24486979 TI - The inferior colliculus is involved in deviant sound detection as revealed by BOLD fMRI. AB - Rapid detection of deviant sounds is a crucial property of the auditory system because it increases the saliency of biologically important, unexpected sounds. The oddball paradigm in which a deviant sound is randomly interspersed among a train of standard sounds has been traditionally used to study this property in mammals. Currently, most human studies have only revealed the involvement of cortical regions in this property. Recently, several animal electrophysiological studies have reported that neurons in the inferior colliculus (IC) exhibit reduced responses to a standard sound but restore their responses at the occurrence of a deviant sound (i.e., stimulus-specific adaptation or SSA), suggesting that the IC may also be involved in deviance detection. However, by adopting an invasive method, these animal studies examined only a limited number of neurons. Although SSA appears to be more prominent in the external cortical nuclei of the IC for frequency deviant, a thorough investigation of this property throughout the IC using other deviants and efficient imaging techniques may provide more comprehensive information on this important phenomenon. In this study, blood-oxygen-level-dependent (BOLD) fMRI with a large field of view was applied to investigate the role of the IC in deviance detection. Two sound tokens that had identical frequency spectrum but temporally inverted profiles were used as the deviant and standard. A control experiment showed that these two sounds evoked the same responses in the IC when they were separately presented. Two oddball experiments showed that the deviant induced higher responses than the standard (by 0.41+/-0.09% and 0.41+/-0.10%, respectively). The most activated voxels were in the medial side of the IC in both oddball experiments. The results clearly demonstrated that the IC is involved in deviance detection. BOLD fMRI detection of increased activities in the medial side of the IC to the deviant revealed the highly adaptive nature of a substantial population of neurons in this region, probably those that belong to the rostral or dorsal cortex of the IC. These findings highlighted the complexity of auditory information processing in the IC and may guide future studies of the functional organizations of this subcortical structure. PMID- 24486980 TI - Evaluation of activity-dependent functional pH and T1rho response in the visual cortex. AB - Recent experiments suggest that T1 relaxation in the rotating frame (T1rho) detects localized metabolic changes in the human visual cortex induced by a flashing checkerboard task. Possible sources of the T1rho signal include pH, glucose, and glutamate concentrations as well as changes in cerebral blood volume. In this study we explored the relationship of the T1rho signal changes related to cerebral blood volume changes by employing inferior saturation pulses. Our hypothesis was that there would be a contribution of cerebral blood volume to the functional T1rho signal, but a majority of the signal would correspond to metabolic changes. In addition, the relationship between T1rho and pH was explored by manipulating the frequency of the flashing checkerboard and imaging with T1rho, BOLD, and (31)P spectroscopy. We hypothesized that T1rho and pH changes would be sensitive to the stimulation frequency. To test this hypothesis, we used a full-field visual flashing checkerboard and varied the frequency between 1, 4, and 7Hz. Supporting our hypotheses, we found that approximately 73% of the measured signal change corresponds to metabolism in vivo and that increasing stimulation frequency increased responses measured by all three imaging modalities. The activation area detected by T1rho overlapped to a large degree with that detected by BOLD, although the T1rho response area was significantly smaller. (31)P spectroscopy detected a greater acidosis with the higher stimulation frequencies. These observations suggest that, similar to the BOLD response, the magnitude of the T1rho and pH response depends on stimulation frequency and is thus likely to be activity-dependent. PMID- 24486982 TI - Structural elucidation of the capsular polysaccharide from Streptococcus pneumoniae serotype 47A by NMR spectroscopy. AB - The structure of the serotype 47A (Danish nomenclature system) capsular polysaccharide from Streptococcus pneumoniae was elucidated by NMR spectroscopy. The following structure of the repeating heptasaccharide was deduced: [structure: see text]. The serotype 47A capsular polysaccharide is one of 91 structurally and serologically distinct capsular polysaccharides that have been recognized in S. pneumoniae, a significant human pathogenic bacterium and model system in medical microbiology. Structure and NMR spectra are compared to previously solved capsular polysaccharide structures of other serotypes. PMID- 24486983 TI - PFCs and early menopause: association raises questions about causality. PMID- 24486981 TI - Contributions of episodic retrieval and mentalizing to autobiographical thought: evidence from functional neuroimaging, resting-state connectivity, and fMRI meta analyses. AB - A growing number of studies suggest the brain's "default network" becomes engaged when individuals recall their personal past or simulate their future. Recent reports of heterogeneity within the network raise the possibility that these autobiographical processes comprised of multiple component processes, each supported by distinct functional-anatomic subsystems. We previously hypothesized that a medial temporal subsystem contributes to autobiographical memory and future thought by enabling individuals to retrieve prior information and bind this information into a mental scene. Conversely, a dorsal medial subsystem was proposed to support social-reflective aspects of autobiographical thought, allowing individuals to reflect on the mental states of one's self and others (i.e. "mentalizing"). To test these hypotheses, we first examined activity in the default network subsystems as participants performed two commonly employed tasks of episodic retrieval and mentalizing. In a subset of participants, relationships among task-evoked regions were examined at rest, in the absence of an overt task. Finally, large-scale fMRI meta-analyses were conducted to identify brain regions that most strongly predicted the presence of episodic retrieval and mentalizing, and these results were compared to meta-analyses of autobiographical tasks. Across studies, laboratory-based episodic retrieval tasks were preferentially linked to the medial temporal subsystem, while mentalizing tasks were preferentially linked to the dorsal medial subsystem. In turn, autobiographical tasks engaged aspects of both subsystems. These results suggest the default network is a heterogeneous brain system whose subsystems support distinct component processes of autobiographical thought. PMID- 24486984 TI - Isoangustone A induces apoptosis in SW480 human colorectal adenocarcinoma cells by disrupting mitochondrial functions. AB - Licorice and its components have been reported to posses various anti-tumor activities, but its active ingredients and underlying mechanisms are not well understood yet. In the present study, a group of representative licorice-derived compounds that could be detected in rat plasma or urine were screened for anti tumor activity. Among these compounds, isoangustone A (IAA) was found to promptly inhibit the viability of SW480 human colorectal adenocarcinoma cells in a time- and concentration-dependent manner. Further analyses indicate that IAA activated caspase-dependent pro-apoptotic signaling and induced significant apoptosis, while had little effect on cell cycle. IAA strongly inhibited Akt phosphorylation within 5 min; however, overexpression of constitutively activated Akt could not rescue IAA-mediated inhibition, indicating that inhibition of Akt was not involved in IAA-induced apoptosis. Further examinations show that IAA induced dissipation of mitochondria membrane potential and release of cytochrome C within 1h, accompanied by swelling of mitochondrial matrix and disrupting of mitochondrial outer membrane, and followed by decreasing of cellular ATP. The above results suggest that IAA induced apoptosis in colorectal cancer cells principally by inducing mitochondrial outer membrane permeabilization, and deserves further investigations as a novel anti-colorectal cancer agent. PMID- 24486985 TI - Global proteomic analysis of Chelidonium majus and Corydalis cava (Papaveraceae) extracts revealed similar defense-related protein compositions. AB - Chelidonium majus and Corydalis cava are phylogenetically closely related (Papaveraceae family). The medicinal and pharmaceutical interest in these plants is based on their synthesis of pharmaceutically important compounds, such as alkaloids, flavonoids, phenolic acids and proteins. C. majus shoot and C. cava tuber extracts have been used in traditional folk medicine to treat many diseases, such as fungal, bacterial and viral infections, liver disorders, fever, post-traumatic, colic, abdominal and menstrual pains and even cancer. This study attempts to perform a global comparative proteomic analysis of pharmacologically important extracts from these two closely related unsequenced plant species to gain insights into the protein basis of these plant organs and to compare their common and specific proteomic compositions. We used a shotgun proteomic approach combined with label-free protein quantitation according to the exponentially modified protein abundance index (emPAI). In total, a mean number of 228 protein identification results were recorded in C. cava tuber extracts and about 1240 in C. majus shoot extracts. Comparative analysis revealed a similar stress and defense-related protein composition of pharmacologically active plant species and showed the presence of different pathogenesis-related and low molecular inducible antimicrobial peptides. These findings could form the basis for further elucidation of the mechanism of the strong pharmacological activities of these medicinal plant extracts. PMID- 24486986 TI - Characterization and cytological effects of a novel glycated gelatine substrate. AB - Hyperglycemia in diabetes results in the glycation of long-lived proteins. Protein glycation leads to the formation of advanced glycation end products (AGEs), which are implicated in delayed wound healing and other diabetes associated pathologies, one of which is periodontal disease. Research into the mechanisms by which glycated long-lived proteins such as collagen exert their effects can allow for the understanding of diabetic pathologies and the development of appropriate treatments. However, the high cost of purified protein can be a limitation for many laboratories around the world. The objective of this study was to develop a low-cost in vitro model of glycated gelatine as an alternative to the glycated collagen model. We investigated the glycation of gelatine type A, a denatured form of collagen, which is low-cost and abundantly available. In this study, gelatine was incubated for 7 days with ribose or methylglyoxal (MG). Cross-linking, autofluorescence and UV-Vis spectrophotometry assays were performed and indicated a dose-dependent linear increase in cross linking and autofluorescence of gelatine by ribose and MG. MG produced more cross linking compared to ribose at the same concentrations. The UV-Vis spectra of the glycated gelatines confirmed the presence of AGE fluorophores. Because diabetes is a risk factor for periodontal disease, the effect of the glycated substrates on the basic behaviour of human periodontal ligament (HPDL) cells was evaluated. Glycation dose dependently reduced HPDL attachment and cell spreading, indicating that the novel glycated gelatine substrate affects cell behaviour. These results show that gelatine glycated with ribose or MG can be used as low-cost in vitro models to study the effects of protein glycation on cell behaviour in diabetes and ageing. PMID- 24486988 TI - Clinicians', policy makers' and patients' views of pediatric cross-border care between Malta and the UK. AB - OBJECTIVE: The Malta-UK cross-border health care collaboration gives Maltese patients access to highly specialized care that is not available locally. Our aim was to identify the issues that arise in cross-border specialized care for rare childhood diseases. METHODS: We conducted 31 semi-structured face-to-face interviews with policy makers, consultant pediatricians from Mater Dei Hospital in Malta, the Royal Marsden Hospital and Great Ormond Street Hospital in England and the parents of a random sample of children referred for treatment abroad in 2011. We conducted qualitative thematic analysis of the data. RESULTS: Respondents viewed the collaboration as successful in providing timely access to high quality specialist care. Four factors facilitated implementation: long established personal relationships; communication and data sharing; shared care approach; and well established support systems. The key challenges are logistical, financial, communication and cultural and psychological. CONCLUSION: Cross-border care pathways can successfully support access to high quality specialized care that is acceptable to health professionals and patients. PMID- 24486987 TI - Postnatal diagnosis of 9q interstitial imbalances involving PTCH1, resulting from a familial intrachromosomal insertion. AB - Insertions are rare chromosomal rearrangements resulting from a three breaks mechanism. The risk of chromosomal imbalance in the offspring is estimated to be 15-50%. We have identified a familial history of direct, paracentric intrachromosomal 9q insertion, balanced in healthy members. For intrachromosomal insertions, unbalanced products in the offspring are always recombinants and in our case, reciprocal deletion and duplication of the inserted segment (9q22.31 9q31.1) were observed. These imbalances involved several genes, including PTCH1. PTCH1 haploinsufficiency causes Gorlin syndrome, an autosomal dominant disorder usually linked to the gene mutation but sometimes due to a 9q deletion. Clinical findings are different in 9q deletions and duplications including PTCH1, notably concerning the predisposition to benign and malignant tumors reported in the Gorlin syndrome. Furthermore, some features may be reciprocal. This history of intrachromosomal insertion highlights the importance of morphological cytogenetic analyses to provide an accurate genetic counseling. PMID- 24486989 TI - The secret of the mermaid's purse: phylogenetic affinities within the Rajidae and the evolution of a novel reproductive strategy in skates. AB - The systematics of the skates in the family Rajidae have been contentious for over 250years, with most studies inferring relationships among geographically clustered species, and non-overlapping taxa and data sets. Rajid skates are oviparous, and lay egg capsules with a single embryo. However, two species exhibit a derived form of egg laying, with multiple embryos per egg capsule. We provide a molecular assessment of the phylogenetic relationships of skates in the family Rajidae based on three mitochondrial genes. The resulting topology supports monophyly the family. However the genusRajais polyphyletic, and several species assemblages need to be revised. We propose a new assemblage, the Rostrajini, which organizesrajid species into three well-supported tribal lineages for the first time. Further, these data provide an independent assessment of monophyly for the two species exhibiting multiple embryos per egg capsule, supporting their status as the unique genusBeringraja. In addition, we find that among the different size classes of egg capsules, ranging from 1 to 8 embryos per capsule in this genus, there is variation in frequency and survivorship. InBeringraja binoculata, the strategy of having two embryos per egg capsule occurs most frequently and with the highest fitness. PMID- 24486990 TI - Phylogeography of the ancient catfish family Diplomystidae: biogeographic, systematic, and conservation implications. AB - The catfish family Diplomystidae is one of the earliest branching lineages within the diverse order Siluriformes and shows a deep phylogenetic split from all other extant and extinct major catfish groups. Despite its relevance in the evolution of siluriforms, phylogenetic relationships within the Diplomystidae are poorly understood, and prior to this study, no phylogenetic hypotheses using molecular data had been published. By conducting a phylogeographic study across the entire distribution of the family, that encompasses river systems from Central-South Chile and Argentina, we provide the first molecular phylogenetic hypothesis among all known species of Diplomystidae, and in addition, investigate how their evolutionary history relates to major historical events that took place in southern South America. Our phylogenetic analyses show four main lineages and nine sub-lineages strongly structured geographically. All Pacific basin populations, with one exception (those found in the Baker basin) clustered within three of the four main lineages (clades I-III), while all populations from Atlantic basins and those from the Baker basin clustered in a single main clade (clade IV). There was a tendency for genetic diversity to decrease from north to south for Pacific basins consistent with an increasing north-south ice coverage during the last glacial maximum. However, we did not find a statistically significant correlation between genetic diversity and latitude. Analysis of molecular variance (AMOVA) showed that river basins and the barrier created by the Andes Mountains explained a high percentage of the genetic variation. Interestingly, most of the genetic variation among drainages was explained among Pacific basins. Molecular phylogenetic analyses agree only partially with current systematics. The geographical distribution of main lineages did not match species distribution and suggests a new taxonomic hypothesis with support for four species of Diplomystes, three species distributed allopatrically from the Rapel to the Valdivia basin, and only one species distributed in Baker and Atlantic basins. High genetic differentiation among river basins suggests that conservation efforts should focus on protecting populations in each basin in order to preserve the genetic diversity of one of the oldest groups of catfishes on the earth today. PMID- 24486991 TI - Phylogeography and demographic history of two widespread Indo-Pacific mudskippers (Gobiidae: Periophthalmus). AB - This study provides a first description of the phylogeographic patterns and evolutionary history of two species of the mudskipper genus Periophthalmus. These amphibious gobies are distributed throughout the whole Indo-Pacific region and Atlantic coast of Africa, in peritidal habitats of soft-bottom coastal ecosystems. Three sequence datasets of two widely distributed species, Periophthalmus argentilineatus and P. kalolo, were obtained by amplifying and sequencing two mtDNA markers (D-loop and 16S rDNA) and the nDNA rag1 region. The three datasets were then used to perform phylogeographic, demographic and population genetic analyses. Our results indicate that tectonic events and past climatic oscillations strongly contributed to shape present genetic differentiation, phylogeographic and demographic patterns. We found support for the monophyly of P. kalolo, and only shallow genetic differentiation between East African and Indo-Malayan populations of this species. However, our collections of the morphospecies P. argentilineatus include three molecularly distinct lineages, one of them more closely related to P. kalolo. The presence of Miocenic timings for the most recent common ancestors of some of these morphologically similar clades, suggests the presence of strong stabilising selection in mudskippers' habitats. At population level, demographic analyses and palaeoecological records of mangrove ecosystems suggest that Pleistocene bottlenecks and expansion plus secondary contact events of the studied species were associated with recurrent sea transgressions during interglacials, and sea regressions or stable regimes during glacials, respectively. PMID- 24486992 TI - Body Image Disorders: Comparison between Unilateral Hemisphere Damage and Schizophrenia. AB - The records of a consecutive series of 100 schizophrenics were examined for any mention of body image disorders. These were present in 45 patients, the most common varieties being anomalous bodily experiences. The pattern of these was then compared with the sorts of body image disorders which occur in patients with left hemisphere lesions and in those with right hemisphere lesions. Schizophrenic body image disorders resembled those seen with right-sided lesions much more than they did those occurring following left-sided damage. This result is discussed in relationship to theories of hemisphere imbalance in schizophrenia. PMID- 24486993 TI - Rett Syndrome: some Behavioural Aspects and an Overview. AB - A brief review of the Rett syndrome is presented. The main clinical features are onset of mental deterioration, in girls only, between the ages of6 and 18 months, all of whom later develop peculiar stereotyped repetitive movements resembling hand washing. The cause is unknown; the condition occurs more often than phenylketonuria and laboratory tests are normal. Random sequences of hyper ventilation-apnoea-normal breathing appear in a considerable number of girls and are accompanied by certain EEG features. The nature of the repetitive manual and respiratory phenomena is discussed. We suggest that these behavioural peculiarities may be a form of communication, possibly pleasurable and to some extent interchangeable. PMID- 24486994 TI - Conversion "v" profiles in torticollis. AB - The assumption that spasmodic torticollis represents a conversion reaction was examined by evaluating profiles of 61 patients on the hypochondriasis, depression, and hysteria scales of the Minnesota Multiphasic Personality Inventory. Thirty-six per cent of the sample had normal profiles. A conversion "V" profile with scores above 70 was found in a minority (9%) of the patients. The profile of the majority of the group was characterized by the presence of mild depression. It was concluded that a personality profile suggestive of conversion reaction is not typical of patients with spasmodic torticollis. PMID- 24486995 TI - The psychopathology of Basal Ganglia calcification. AB - Basal ganglia calcification (BGC) was found in 36 of 4122 patients undergoing computed tomography as part of a clinical investigation of their psychiatric illness. The prevalence of BGC increased with age in both men and women. No psychiatric diagnosis was specifically associated with BGC although calcification of the putamen and the caudate was only found in patients with functional disorders. No abnormalities of calcium or phosphate metabolism were found. The results do not support the hypothesis that BGC is an aetiological factor in schizophrenia-like psychoses. PMID- 24486996 TI - Language, culture and the neurobiology of pain: a theoretical exploration. AB - Language and culture, as conceptualized in traditional anthropology, may have an important influence on pain and brain-behavior relations. The paradigm case for the influence of language and culture on perception and cognition is stipulated in the Sapir-Whorf hypothesis which has been applied to phenomena "external" to the individual. In this paper, the paradigm is applied to information the person retrieves from "inside" his body; namely, "noxious" stimuli which get registered in consciousness as pain. PMID- 24486998 TI - Cumulative index, volumes 1 and 2. PMID- 24486999 TI - Introduced species: domestic mammals are more significant transmitters of parasites to native mammals than are feral mammals. AB - The study of parasitism related to biological invasion has focused on attributes and impacts of parasites as invaders and the impact of introduced hosts on endemic parasitism. Thus, there is currently no study of the attributes of hosts which influence the invasiveness of parasites. We aimed to determine whether the degree of domestication of introduced mammalian species - feral introduced mammals, livestock or pets, hereafter 'D' - is important in the spillover of introduced parasites. The literature on introduced parasites of mammals in Chile was reviewed. We designed an index for estimating the relevance of the introduced host species to parasite spillover and determined whether the D of introduced mammals predicted this index. A total of 223 introduced parasite species were found. Our results indicate that domestic mammals have a higher number of introduced parasites and spillover parasites, and the index indicates that these mammals, particularly pets, are more relevant introducers than introduced feral mammals. Further analyses indicated that the higher impact is due to higher parasite richness, a longer time since introduction and wider dispersal, as well as how these mammals are maintained. The greater relevance of domestic mammals is important given that they are basically the same species distributed worldwide and can become the main transmitters of parasites to native mammals elsewhere. This finding also underlines the feasibility of management in order to reduce the transmission of parasites to native fauna through anti-parasitic treatment of domestic mammals, animal-ownership education and the prevention of importing new parasite species. PMID- 24487000 TI - Schistosoma japonicum soluble egg antigens induce apoptosis and inhibit activation of hepatic stellate cells: a possible molecular mechanism. AB - Hepatic stellate cells play a key role in the development of hepatic fibrosis. Activated hepatic stellate cells can be reversed to a quiescent-like state or apoptosis can be induced to reverse fibrosis. Some studies have recently shown that Schistosoma mansoni eggs could suppress the activation of hepatic stellate cells and that soluble egg antigens from schistosome eggs could promote immunocyte apoptosis. Hence, in this study, we attempt to assess the direct effects of Schistosoma japonicum soluble egg antigens on hepatic stellate cell apoptosis, and to explore the mechanism by which the apoptosis of activated hepatic stellate cells can be induced by soluble egg antigens, as well as the mechanism by which hepatic stellate cell activation is inhibited by soluble egg antigens. Here, it was shown that S. japonicum-infected mouse livers had increased apoptosis phenomena and a variability of peroxisome proliferator activated receptor gamma expression. Soluble egg antigens induce morphological changes in the hepatic stellate cell LX-2 cell line, inhibit cell proliferation and induce cell-cycle arrest at the G1 phase. Soluble egg antigens also induce apoptosis in hepatic stellate cells through the TNF-related apoptosis-inducing ligand/death receptor 5 and caspase-dependent pathways. Additionally, soluble egg antigens could inhibit the activation of hepatic stellate cells through peroxisome proliferator-activated receptor gamma and the transforming growth factor beta signalling pathways. Therefore, our study provides new insights into the anti-fibrotic effects of S. japonicum soluble egg antigens on hepatic stellate cell apoptosis and the underlying mechanism by which the liver fibrosis could be attenuated by soluble egg antigens. PMID- 24487002 TI - A rare case of histopathological bladder necrosis associated with Actinobaculum schaalii: the incremental value of an accurate microbiological diagnosis using 16S rDNA sequencing. AB - We describe here a rare case of bladder wall necrosis associated with Actinobaculum schaalii in a 72-year-old patient with non-muscle-invasive bladder cancer (NMIBC). A. schaalii microbiological diagnosis requires high index of suspicion and accurate identification methods such as 16S rDNA sequencing or MALDI-TOF Mass spectrometry. PMID- 24487003 TI - Reply: To PMID 22516620. PMID- 24487001 TI - Analysis of the transcriptome of adult Dictyocaulus filaria and comparison with Dictyocaulus viviparus, with a focus on molecules involved in host-parasite interactions. AB - Parasitic nematodes cause diseases of major economic importance in animals. Key representatives are species of Dictyocaulus (=lungworms), which cause bronchitis (=dictyocaulosis, commonly known as "husk") and have a major adverse impact on the health of livestock. In spite of their economic importance, very little is known about the immunomolecular biology of these parasites. Here, we conducted a comprehensive investigation of the adult transcriptome of Dictyocaulus filaria of small ruminants and compared it with that of Dictyocaulus viviparus of bovids. We then identified a subset of highly transcribed molecules inferred to be linked to host-parasite interactions, including cathepsin B peptidases, fatty-acid and/or retinol-binding proteins, beta-galactoside-binding galectins, secreted protein 6 precursors, macrophage migration inhibitory factors, glutathione peroxidases, a transthyretin-like protein and a type 2-like cystatin. We then studied homologues of D. filaria type 2-like cystatin encoded in D. viviparus and 24 other nematodes representing seven distinct taxonomic orders, with a particular focus on their proposed role in immunomodulation and/or metabolism. Taken together, the present study provides new insights into nematode-host interactions. The findings lay the foundation for future experimental studies and could have implications for designing new interventions against lungworms and other parasitic nematodes. The future characterisation of the genomes of Dictyocaulus spp. should underpin these endeavours. PMID- 24487004 TI - Pelvic pain and mode of delivery. AB - OBJECTIVE: We sought to determine the long-term effect of mode of delivery on the prevalence and severity of pelvic pain. STUDY DESIGN: Six to eleven years after a first delivery, pelvic pain (dysmenorrhea, dyspareunia, and pelvic pain not related to menses or intercourse) was measured using the Oxfordshire Women's Health Study Questionnaire. Obstetrical exposures were assessed by review of the hospital delivery record. The prevalence of moderate to severe pelvic pain was compared between the 577 women who delivered via cesarean for all births and the 538 who delivered at least 1 child vaginally. Other obstetrical exposures were also studied. RESULTS: Prevalence of pelvic pain was similar between women who delivered vaginally and by cesarean. Among women who delivered vaginally, those who experienced at least 1 forceps delivery and women who delivered at least 1 baby >=4 kg vaginally reported a higher rate of dyspareunia. Perineal trauma was not associated with dyspareunia. CONCLUSION: Forceps delivery and a vaginal delivery of a baby >=4 kg are associated with dyspareunia 6-11 years after vaginal birth. Vaginal birth is not associated with a higher rate of pelvic pain when compared to cesarean delivery. PMID- 24487005 TI - Sling surgery for stress urinary incontinence in women: a systematic review and metaanalysis. AB - OBJECTIVE: Understanding the long-term comparative effectiveness of competing surgical repairs is essential as failures after primary interventions for stress urinary incontinence (SUI) may result in a third of women requiring repeat surgery. STUDY DESIGN: We conducted a systematic review including English language randomized controlled trials from 1990 through April 2013 with a minimum 12 months of follow-up comparing a sling procedure for SUI to another sling or Burch urethropexy. When at least 3 randomized controlled trials compared the same surgeries for the same outcome, we performed random effects model metaanalyses to estimate pooled odds ratios (ORs). RESULTS: For midurethral slings (MUS) vs Burch, metaanalysis of objective cure showed no significant difference (OR, 1.18; 95% confidence interval [CI], 0.73-1.89). Therefore, we suggest either intervention; the decision should balance potential adverse events (AEs) and concomitant surgeries. For women considering pubovaginal sling vs Burch, the evidence favored slings for both subjective and objective cure. We recommend pubovaginal sling to maximize cure outcomes. For pubovaginal slings vs MUS, metaanalysis of subjective cure favored MUS (OR, 0.40; 95% CI, 0.18-0.85). Therefore, we recommend MUS. For obturator slings vs retropubic MUS, metaanalyses for both objective (OR, 1.16; 95% CI, 0.93-1.45) and subjective cure (OR, 1.17; 95% CI, 0.91-1.51) favored retropubic slings but were not significant. Metaanalysis of satisfaction outcomes favored obturator slings but was not significant (OR, 0.77; 95% CI, 0.52-1.13). AEs were variable between slings; metaanalysis showed overactive bladder symptoms were more common following retropubic slings (OR, 1.413; 95% CI, 1.01-1.98, P = .046). We recommend either retropubic or obturator slings for cure outcomes; the decision should balance AEs. For minislings vs full-length MUS, metaanalyses of objective (OR, 4.16; 95% CI, 2.15-8.05) and subjective (OR, 2.65; 95% CI, 1.36-5.17) cure both significantly favored full-length slings. Therefore, we recommend a full-length MUS. CONCLUSION: Surgical procedures for SUI differ for success rates and complications, and both should be incorporated into surgical decision-making. Low to high-quality evidence permitted mostly level-1 recommendations when guidelines were possible. PMID- 24487007 TI - What is the role of primary methotrexate treatment in scar ectopic pregnancy? PMID- 24487006 TI - Elevated day 3 follicle-stimulating hormone in younger women: is gonadotropin stimulation/intrauterine insemination a good option? AB - OBJECTIVE: The objective of the study was to determine the fecundity of young women (<35 years) with an elevated day 3 follicle stimulating hormone (FSH) undergoing gonadotropin-stimulation/intrauterine insemination. STUDY DESIGN: This was a retrospective study. The study was conducted at an academic fertility center. A total of 1396 gonadotropin stimulation/intrauterine insemination cycles from 563 women were stratified by day 3 FSH levels (<10 vs >=10 U/L) and outcomes were compared. Gonadotropin dose, treatment duration, peak estradiol (E2), number of preovulatory follicles (total, large, and medium size), E2/follicle, endometrial thickness, spontaneous abortion, clinical and multiple pregnancy rates were measured. The statistics included a Student t test, a chi(2), regression, and a discrete survival analysis. RESULTS: An elevated day 3 FSH was found in 10.2% of the women, despite favorable age (31.9 +/- 2.5 years). Women with a day 3 FSH of 10 U/L or greater when compared with women with a normal day 3 level required significantly more medication (1058.9 +/- 1106.0 vs 632.7 +/- 477.5 IU, P < .0001) were triggered a day earlier (10.6 +/- 2.4 vs 11.5 +/- 2.9 days, P = .0006) and had E2 levels (on the day of and the day prior to human chorionic gonadotropin administration) that were significantly higher (529.5 +/- 244.3 vs 450.0 +/- 244.2 and 359.6 +/- 141.7 vs 306.8 +/- 160.9 pg/mL, respectively, P < .05). Clinical pregnancy rates were comparable among the groups (14.6 vs 14%, respectively, P > .05). Spontaneous abortion and multiple pregnancy rates were higher among women with an FSH of 10U/L or greater but not significantly so (27.8% vs 12.0%, 22.2% vs 13.8% for FSH of >=10 vs FSH < or >10 U/L, P > .05). CONCLUSION: Women younger than 35 years with an elevated day 3 FSH, when treated aggressively with gonadotropins have pregnancy rates comparable with those of women with a normal baseline FSH. To achieve this outcome, they need higher doses of medication to stimulate the production of a larger preovulatory follicular cohort. PMID- 24487008 TI - The cost-effectiveness of a trial of labor accrues with multiple subsequent vaginal deliveries. AB - OBJECTIVE: The purpose of this study was to estimate costs and outcomes of subsequent trials of labor after cesarean delivery (TOLAC) compared with elective repeat cesarean deliveries (ERCD). STUDY DESIGN: To compare TOLAC and ERCD, maternal and neonatal decision analytic models were built for each hypothetic subsequent delivery. We assumed that only women without previa would undergo TOLAC for their second delivery, that women with successful TOLAC would desire future TOLAC, and that women who chose ERCD would undergo subsequent ERCD. Main outcome measures were maternal and neonatal mortality and morbidity rates, direct costs, and quality-adjusted life years. Values were derived from the literature. One-way and Monte-Carlo sensitivity analyses were performed. RESULTS: TOLAC was less costly and more effective for most models. A progression of decreasing incremental cost and increasing incremental effectiveness of TOLAC was found for maternal outcomes with increasing numbers of subsequent deliveries. This progression was also displayed among neonatal outcomes and was most prominent when neonatal and maternal outcomes were combined, with an incremental cost and effectiveness of -$4700.00 and .073, respectively, for the sixth delivery. Net benefit analysis showed an increase in the benefit of TOLAC with successive deliveries for all outcomes. The maternal model of the second delivery was sensitive to cost of delivery and emergent cesarean delivery. Successive maternal models became more robust, with the models of the third-sixth deliveries sensitive only to cost of delivery. Neonatal models were not sensitive to any variables. CONCLUSION: Although nearly equally effective relative to ERCD for the second delivery, TOLAC becomes less costly and more effective with subsequent deliveries. PMID- 24487009 TI - Novel behavioral tasks to explore cerebellar temporal processing in milliseconds in rats. AB - Temporal processing in milliseconds has been reported to rely on the cerebellum; however, no detailed neuronal mechanisms have been published yet. This is because there are too few studies on the relationship between temporal processing in milliseconds and cerebellar neuronal spikes that organize behavioral timing. To demonstrate this relationship, it is necessary to record the spike activity while the animal is performing a behavioral task that requires specific temporal processing in milliseconds. In this study, we describe two novel timing tasks. These behavioral tasks comprise the following schedules: fixed ratio (FR) and differential reinforcement of low rate (DRL). This paper describes the behavioral differences between the absolute timing of individual intervals (duration based timing) and the relative timing of rhythmic sequences (beat-based timing) in these novel tasks. PMID- 24487010 TI - Acute nicotine delays extinction of contextual fear in mice. AB - Smoking is linked to post-traumatic stress disorder (PTSD) which suggests smoking is either a risk factor or an attempt at self-medication. The ability to reduce or extinguish fear-related memories may be altered in patients with PTSD and it is possible that nicotine modulates this. Although there are numerous studies examining the effects of nicotine on acquisition of fear learning, the effects of nicotine on extinction of contextual fear are not well understood. In the present study, we examined the effects of acute nicotine (0.18 mg/kg) on extinction of contextual fear in C57BL/6J mice. Animals were first trained in a background contextual fear conditioning paradigm using a white noise as a conditioned stimulus (CS), which co-terminated with a 2 s 0.57 mA unconditioned foot-shock stimulus (US). Animals were then administered either nicotine or saline and exposed to either the training context or a novel context in order to measure freezing to the context during extinction. Our results demonstrate that nicotine administration during extinction delays extinction of contextual freezing while nicotine did not affect cued freezing or freezing to the novel context. PMID- 24487012 TI - Developmental changes in performance monitoring: how electrophysiological data can enhance our understanding of error and feedback processing in childhood and adolescence. AB - Performance monitoring includes learning from errors and feedback and depends on the functioning of the mediofrontal cortex, especially the anterior cingulate cortex (ACC) and the mesencephalic dopamine system. Error and feedback monitoring develop during childhood until early adulthood and are important in a lot of learning situations. The aims of this article are twofold: First, to review the present literature on the development of performance monitoring, and second, to highlight how electrophysiological data can contribute to the understanding of error and feedback processing in childhood and adolescence. PMID- 24487011 TI - Time-dependent effects of prazosin on the development of methamphetamine conditioned hyperactivity and context-specific sensitization in mice. AB - The present experiments examined the effects of prazosin, a selective alpha1 adrenergic receptor antagonist, on the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Mice received an injection of vehicle (distilled water) or prazosin (0.5, 1.0 or 2.0 mg/kg) 30 min prior to a second injection of vehicle (saline) or methamphetamine (1.0 mg/kg) during the conditioning sessions (Experiment 1). Following the conditioning sessions, mice were tested for conditioned hyperactivity and then tested for context-specific sensitization. In subsequent experiments, mice received an injection of vehicle (distilled water) or prazosin (2.0 mg/kg) immediately (Experiment 2) or 24 h (Experiment 3) after the conditioning sessions and then tested for conditioned hyperactivity and context-specific sensitization. Prazosin dose-dependently blocked the development of methamphetamine conditioned hyperactivity and context specific sensitization when administered prior to the methamphetamine during the conditioning phase; however nonspecific motor impairments also were observed (Experiment 1). Immediate (Experiment 2), but not the 24-h delay (Experiment 3), post-session administration of prazosin attenuated the development of methamphetamine conditioned hyperactivity and context-specific sensitization. Nonspecific motor impairments were not observed in these latter experiments. Collectively, these results suggest that the alpha1-adrenergic receptor mediates the development of methamphetamine-conditioned hyperactivity and context-specific sensitization, perhaps by altering memory consolidation and/or reconsolidation processes. PMID- 24487014 TI - Goal preference shapes confrontations of sexism. AB - Although most women assume they would confront sexism, assertive responses are rare. We test whether women's preference for respect or liking during interpersonal interactions explains this surprising tendency. Women report preferring respect relative to liking after being asked sexist, compared with inappropriate, questions during a virtual job interview (Study 1, n = 149). Women's responses to sexism increase in assertiveness along with their preference for being respected, and a respect-preference mediates the relation between the type of questions and response assertiveness (Studies 1 and 2). In Study 2 (n = 105), women's responses to sexist questions are more assertive when the sense of belonging is enhanced with a belonging manipulation. Moreover, preference for respect mediates the effect of the type of questions on response assertiveness, but only when belonging needs are met. Thus the likelihood of confrontation depends on the goal to be respected outweighing the goal to be liked. PMID- 24487013 TI - Nicotine administration in adolescence reprograms the subsequent response to nicotine treatment and withdrawal in adulthood: sex-selective effects on cerebrocortical serotonergic function. AB - Nicotine exposure in adolescence produces lasting changes in subsequent behavioral responses to addictive agents. We gave nicotine to adolescent rats (postnatal days PN30-47), simulating plasma levels in smokers, and then examined the subsequent effects of nicotine given again in adulthood (PN90-107), focusing on cerebrocortical serotonin levels and utilization (turnover) as an index of presynaptic activity of circuits involved in emotional state. Our evaluations encompassed responses during the period of adult nicotine treatment (PN105) and withdrawal (PN110, PN120, PN130), as well as long-term changes (PN180). In males, prior exposure to nicotine in adolescence greatly augmented the increase in serotonin turnover evoked by nicotine given in adulthood, an interaction that was further exacerbated during withdrawal. The effect was sufficiently large that it led to significant depletion of serotonin stores, an effect that was not seen with nicotine given alone in either adolescence or adulthood. In females, adolescent nicotine exposure blunted or delayed the spike in serotonin turnover evoked by withdrawal from adult nicotine treatment, a totally different effect from the interaction seen in males. Combined with earlier work showing persistent dysregulation of serotonin receptor expression and receptor coupling, the present results indicate that adolescent nicotine exposure reprograms future responses of 5HT systems to nicotine, changes that may contribute to life-long vulnerability to relapse and re-addiction. PMID- 24487015 TI - Sciatic nerve injury: a simple and subtle model for investigating many aspects of nervous system damage and recovery. AB - Sciatic nerve injury has been used for over a century to investigate the process of nerve damage, to assess the absolute and relative capacity of the central and peripheral nervous systems to recover after axotomy, and to understand the development of chronic pain in many pathologies. Here we provide a historical review of the contributions of this experimental model to our current understanding of fundamental questions in the neurosciences, and an assessment of its continuing capacity to address these and future problems. We describe the different degrees of nerve injury - neurapraxia, axonotmesis, neurotmesis - together with the consequences of selective damage to the different functional and anatomic components of this nerve. The varied techniques used to model different degrees of nerve injury and their relationship to the development of neuropathic pain states are considered. We also provide a detailed anatomical description of the sciatic nerve from the spinal cord to the peripheral branches in the leg. A standardized protocol for carrying out sciatic nerve axotomy is proposed, with guides to assist in the accurate and reliable dissection of the peripheral and central branches of the nerve. Functional, histological, and biochemical criteria for the validation of the injury are described. Thus, this paper provides a review of the principal features of sciatic nerve injury, presents detailed neuroanatomical descriptions of the rat's inferior limb and spine, compares different modes of injury, offers material for training purposes, and summarizes the immediate and longterm consequences of damage to the sciatic nerve. PMID- 24487016 TI - Realistic thermodynamic and statistical-mechanical measures for neural synchronization. AB - Synchronized brain rhythms, associated with diverse cognitive functions, have been observed in electrical recordings of brain activity. Neural synchronization may be well described by using the population-averaged global potential VG in computational neuroscience. The time-averaged fluctuation of VG plays the role of a "thermodynamic" order parameter O used for describing the synchrony-asynchrony transition in neural systems. Population spike synchronization may be well visualized in the raster plot of neural spikes. The degree of neural synchronization seen in the raster plot is well measured in terms of a "statistical-mechanical" spike-based measure Ms introduced by considering the occupation and the pacing patterns of spikes. The global potential VG is also used to give a reference global cycle for the calculation of Ms. Hence, VG becomes an important collective quantity because it is associated with calculation of both O and Ms. However, it is practically difficult to directly get VG in real experiments. To overcome this difficulty, instead of VG, we employ the instantaneous population spike rate (IPSR) which can be obtained in experiments, and develop realistic thermodynamic and statistical-mechanical measures, based on IPSR, to make practical characterization of the neural synchronization in both computational and experimental neuroscience. Particularly, more accurate characterization of weak sparse spike synchronization can be achieved in terms of realistic statistical-mechanical IPSR-based measure, in comparison with the conventional measure based on VG. PMID- 24487017 TI - The efficiency of fMRI region of interest analysis methods for detecting group differences. AB - BACKGROUND: Using a standard space brain template is an efficient way of determining region-of-interest (ROI) boundaries for functional magnetic resonance imaging (fMRI) data analyses. However, ROIs based on landmarks on subject specific (i.e., native space) brain surfaces are anatomically accurate and probably best reflect the regional blood oxygen level dependent (BOLD) response for the individual. Unfortunately, accurate native space ROIs are often time intensive to delineate even when using automated methods. NEW METHOD: We compared analyses of group differences when using standard versus native space ROIs using both volume and surface-based analyses. Collegiate and military-veteran participants completed a button press task and a digit-symbol verification task during fMRI acquisition. Data were analyzed within ROIs representing left and right motor and prefrontal cortices, in native and standard space. Volume and surface-based analysis results were also compared using both functional (i.e., percent signal change) and structural (i.e., voxel or node count) approaches. RESULTS AND COMPARISON WITH EXISTING METHOD(S): Results suggest that transformation into standard space can affect the outcome of structural and functional analyses (inflating/minimizing differences, based on cortical geography), and these transformations can affect conclusions regarding group differences with volumetric data. CONCLUSIONS: Caution is advised when applying standard space ROIs to volumetric fMRI data. However, volumetric analyses show group differences and are appropriate in circumstances when time is limited. Surface-based analyses using functional ROIs generated the greatest group differences and were less susceptible to differences between native and standard space. We conclude that surface-based analyses are preferable with adequate time and computing resources. PMID- 24487018 TI - Isolating specific cell and tissue compartments from 3D images for quantitative regional distribution analysis using novel computer algorithms. AB - BACKGROUND: Isolating specific cellular and tissue compartments from 3D image stacks for quantitative distribution analysis is crucial for understanding cellular and tissue physiology under normal and pathological conditions. Current approaches are limited because they are designed to map the distributions of synapses onto the dendrites of stained neurons and/or require specific proprietary software packages for their implementation. NEW METHOD: To overcome these obstacles, we developed algorithms to Grow and Shrink Volumes of Interest (GSVI) to isolate specific cellular and tissue compartments from 3D image stacks for quantitative analysis and incorporated these algorithms into a user-friendly computer program that is open source and downloadable at no cost. RESULTS: The GSVI algorithm was used to isolate perivascular regions in the cortex of live animals and cell membrane regions of stained spinal motoneurons in histological sections. We tracked the real-time, intravital biodistribution of injected fluorophores with sub-cellular resolution from the vascular lumen to the perivascular and parenchymal space following a vascular microlesion, and mapped the precise distributions of membrane-associated KCC2 and gephyrin immunolabeling in dendritic and somatic regions of spinal motoneurons. COMPARISON WITH EXISTING METHODS: Compared to existing approaches, the GSVI approach is specifically designed for isolating perivascular regions and membrane-associated regions for quantitative analysis, is user-friendly, and free. CONCLUSIONS: The GSVI algorithm is useful to quantify regional differences of stained biomarkers (e.g., cell membrane-associated channels) in relation to cell functions, and the effects of therapeutic strategies on the redistributions of biomolecules, drugs, and cells in diseased or injured tissues. PMID- 24487019 TI - The effective control of a bleeding injury using a medical adhesive containing batroxobin. AB - Many types of hemostatic agents have been studied for the effective control of bleeding. In this study, a powdery medical adhesive composed of aldehyded dextran and epsilon-poly (L-lysine) was used with the recombinant batroxobin. Batroxobin is a venomous component from the snake Bothrops atrox moojeni and catalyzes fibrinogen conversion to form soluble fibrin clots. This research aims to examine the performance of the batroxobin-containing adhesive for hemostasis, and evaluate its potential as a novel hemostatic adhesive. The fibrinogen conversion ability of batroxobin was evaluated by a fibrinogen clotting assay and a whole blood clotting assay. Both experiments demonstrated the effectiveness of the batroxobin-containing adhesive for blood clot formation. Animal experiments were also conducted. After a pricking wound was made in an ICR (imprinting control region) mouse liver, the adhesive and various concentrations of batroxobin were applied. The total amount of blood loss was reduced with increasing concentrations of batroxobin. For excessive bleeding conditions, the femoral artery wound model of SD (Sprague-Dawley) rats was adopted. With higher concentrations of batroxobin, hemostasis was more rapidly achieved. Histological analysis of the liver model also supports the hemostatic effects through fibrin clot formation. In conclusion, batroxobin and medical adhesive effectively facilitate blood coagulation, and could be developed for clinical use. PMID- 24487020 TI - Four structural subclasses of the antivirulence drug target disulfide oxidoreductase DsbA provide a platform for design of subclass-specific inhibitors. AB - By catalyzing oxidative protein folding, the bacterial disulfide bond protein A (DsbA) plays an essential role in the assembly of many virulence factors. Predictably, DsbA disruption affects multiple downstream effector molecules, resulting in pleiotropic effects on the virulence of important human pathogens. These findings mark DsbA as a master regulator of virulence, and identify the enzyme as a target for a new class of antivirulence agents that disarm pathogenic bacteria rather than killing them. The purpose of this article is to discuss and expand upon recent findings on DsbA and to provide additional novel insights into the druggability of this important disulfide oxidoreductase by comparing the structures and properties of 13 well-characterized DsbA enzymes. Our structural analysis involved comparison of the overall fold, the surface properties, the conformations of three loops contributing to the binding surface and the sequence identity of residues contributing to these loops. Two distinct structural classes were identified, classes I and II, which are differentiated by their central beta sheet arrangements and which roughly separate the DsbAs produced by Gram-negative from Gram-positive organisms. The classes can be further subdivided into a total of four subclasses on the basis of surface features. Class Ia is equivalent to the Enterobacteriaceae class that has been defined previously. Bioinformatic analyses support the classification of DsbAs into 3 of the 4 subclasses, but did not pick up the 4th subclass which is only apparent from analysis of DsbA electrostatic surface properties. In the context of inhibitor development, the discrete structural subclasses provide a platform for developing DsbA inhibitory scaffolds with a subclass-wide spectrum of activity. We expect that more DsbA classes are likely to be identified, as enzymes from other pathogens are explored, and we highlight the issues associated with structure-based inhibitor development targeting this pivotal mediator of bacterial virulence. This article is part of a Special Issue entitled: Thiol-Based Redox Processes. PMID- 24487021 TI - Gastric bypass improves beta-cell function and increases beta-cell mass in a porcine model. AB - The most frequently used and effective treatment for morbid obesity is Roux-en-Y gastric bypass surgery (RYGB), which results in rapid remission of type 2 diabetes in most cases. To what extent this is accounted for by weight loss or other factors remains elusive. To gain insight into these mechanisms, we investigated the effects of RYGB on beta-cell function and beta-cell mass in the pig, a species highly reminiscent of the human. RYGB was performed using linear staplers during open surgery. Sham-operated pigs were used as controls. Both groups were fed a low-calorie diet for 3 weeks after surgery. Intravenous glucose tolerance tests were performed 2 weeks after surgery. Body weight in RYGB pigs and sham-operated, pair-fed control pigs developed similarly. RYGB pigs displayed improved glycemic control, which was attributed to increases in beta-cell mass, islet number, and number of extraislet beta-cells. Pancreatic expression of insulin and glucagon was elevated, and cells expressing the glucagon-like peptide 1 receptor were more abundant in RYGB pigs. Our data from a pig model of RYGB emphasize the key role of improved beta-cell function and beta-cell mass to explain the improved glucose tolerance after RYGB as food intake and body weight remained identical. PMID- 24487022 TI - Preserved energy balance in mice lacking FoxO1 in neurons of Nkx2.1 lineage reveals functional heterogeneity of FoxO1 signaling within the hypothalamus. AB - Transcription factor forkhead box O1 (FoxO1) regulates energy expenditure (EE), food intake, and hepatic glucose production. These activities have been mapped to specific hypothalamic neuronal populations using cell type-specific knockout experiments in mice. To parse out the integrated output of FoxO1-dependent transcription from different neuronal populations and multiple hypothalamic regions, we used transgenic mice expressing Cre recombinase from the Nkx2.1 promoter to ablate loxP-flanked Foxo1 alleles from a majority of hypothalamic neurons (Foxo1KO(Nkx2.1) mice). This strategy resulted in the expected inhibition of FoxO1 expression, but only produced a transient reduction of body weight as well as a decreased body length. The transient decrease of body weight in male mice was accompanied by decreased fat mass. Male Foxo1KO(Nkx2.1) mice show food intake similar to that in wild-type controls, and, although female knockout mice eat less, they do so in proportion to a reduced body size. EE is unaffected in Foxo1KO(Nkx2.1) mice, although small increases in body temperature are present. Unlike other neuron-specific Foxo1 knockout mice, Foxo1KO(Nkx2.1) mice are not protected from diet-induced obesity. These studies indicate that, unlike the metabolic effects of highly restricted neuronal subsets (proopiomelanocortin, neuropeptide Y/agouti-related peptide, and steroidogenic factor 1), those of neurons derived from the Nkx2.1 lineage either occur in a FoxO1-independent fashion or are compensated for through developmental plasticity. PMID- 24487023 TI - Effects of AMPK activation on insulin sensitivity and metabolism in leptin deficient ob/ob mice. AB - AMP-activated protein kinase (AMPK) is a heterotrimeric complex, composed of a catalytic subunit (alpha) and two regulatory subunits (beta and gamma), which act as a metabolic sensor to regulate glucose and lipid metabolism. A mutation in the gamma3 subunit (AMPKgamma3(R225Q)) increases basal AMPK phosphorylation, while concomitantly reducing sensitivity to AMP. AMPKgamma3(R225Q) (gamma3(R225Q)) transgenic mice are protected against dietary-induced triglyceride accumulation and insulin resistance. We determined whether skeletal muscle-specific expression of AMPKgamma3(R225Q) prevents metabolic abnormalities in leptin-deficient ob/ob (ob/ob-gamma3(R225Q)) mice. Glycogen content was increased, triglyceride content was decreased, and diacylglycerol and ceramide content were unaltered in gastrocnemius muscle from ob/ob-gamma3(R225Q) mice, whereas glucose tolerance was unaltered. Insulin-stimulated glucose uptake in extensor digitorum longus muscle during the euglycemic-hyperinsulinemic clamp was increased in lean gamma3(R225Q) mice, but not in ob/ob-gamma3(R225Q) mice. Acetyl-CoA carboxylase phosphorylation was increased in gastrocnemius muscle from gamma3(R225Q) mutant mice independent of adiposity. Glycogen and triglyceride content were decreased after leptin treatment (5 days) in ob/ob mice, but not in ob/ob-gamma3(R225Q) mice. In conclusion, metabolic improvements arising from muscle-specific expression of AMPKgamma3(R225Q) are insufficient to ameliorate insulin resistance and obesity in leptin-deficient mice. Central defects due to leptin deficiency may override any metabolic benefit conferred by peripheral overexpression of the AMPKgamma3(R225Q) mutation. PMID- 24487024 TI - Grg3/TLE3 and Grg1/TLE1 induce monohormonal pancreatic beta-cells while repressing alpha-cell functions. AB - In the pancreas, alpha- and beta-cells possess a degree of plasticity. In vitro differentiation of pluripotent cells yields mostly alpha- and polyhormonal beta like cells, indicating a gap in understanding of how functional monohormonal beta cells are formed and of the endogenous repressive mechanisms used to maintain beta-cell identity. We show that the corepressor Grg3 is expressed in almost all beta-cells throughout embryogenesis to adulthood. However, Grg3 is expressed in fewer nascent alpha-cells and is progressively lost from alpha-cells as endocrine cells mature into adulthood. We show that mouse Grg3(+/-) beta-cells have increased alpha-specific gene expression, and Grg3(+/-) pancreata have more alpha cells and more polyhormonal cells, indicating that Grg3 is required for the physiologic maintenance of monohormonal beta-cell identity. Ectopic expression of Grg3 in alpha-cells represses glucagon and Arx, and the addition of Pdx1 induces Glut2 expression and glucose-responsive insulin secretion. Furthermore, we found that Grg1 is the predominant Groucho expressed in human beta-cells but acts functionally similarly to Grg3. Overall, we find that Grg3 and Grg1 establish a monohormonal beta-cell identity, and Groucho family members may be useful tools or markers for making functional beta-cells. PMID- 24487025 TI - Vagal hyperactivity due to ventromedial hypothalamic lesions increases adiponectin production and release. AB - In obese humans and animals, adiponectin production and release in adipose tissue are downregulated by feedback inhibition, resulting in decreased serum adiponectin. We investigated adiponectin production and release in ventromedial hypothalamic (VMH)-lesioned animals. VMH-lesioned mice showed significant increases in food intake and body weight gain, with hyperinsulinemia and hyperleptinemia at 1 and 4 weeks after VMH-lesioning. Serum adiponectin was elevated in VMH-lesioned mice at 1 and 4 weeks, despite adipocyte hypertrophy in subcutaneous and visceral adipose tissues and increased body fat. Adiponectin production and mRNA were also increased in both adipose tissues in VMH-lesioned mice at 1 week. These results were replicated in VMH-lesioned rats at 1 week. Daily atropine administration for 5 days or subdiaphragmatic vagotomy completely reversed the body weight gain and eliminated the increased adiponectin production and release in these rats, with reversal to a normal serum adiponectin level. Parasympathetic nerve activation by carbachol infusion for 5 days in rats increased serum adiponectin, with increased adiponectin production in visceral and subcutaneous adipose tissues without changes of body weight. These results demonstrate that activation of the parasympathetic nerve by VMH lesions stimulates production of adiponectin in visceral and subcutaneous adipose tissues and adiponectin release, resulting in elevated serum adiponectin. PMID- 24487026 TI - Reduced incorporation of fatty acids into triacylglycerol in myotubes from obese individuals with type 2 diabetes. AB - Altered skeletal muscle lipid metabolism is a hallmark feature of type 2 diabetes (T2D). We investigated muscle lipid turnover in T2D versus BMI-matched control subjects (controls) and examined whether putative in vivo differences would be preserved in the myotubes. Male obese T2D individuals (n = 6) and BMI-matched controls (n = 6) underwent a hyperinsulinemic-euglycemic clamp, VO2max test, dual energy X-ray absorptiometry scan, underwater weighing, and muscle biopsy of the vastus lateralis. (14)C-palmitate and (14)C-oleate oxidation rates and incorporation into lipids were measured in muscle tissue as well as in primary myotubes. Palmitate oxidation (controls: 0.99 +/- 0.17 nmol/mg protein; T2D: 0.53 +/- 0.07 nmol/mg protein; P = 0.03) and incorporation of fatty acids (FAs) into triacylglycerol (TAG) (controls: 0.45 +/- 0.13 nmol/mg protein; T2D: 0.11 +/- 0.02 nmol/mg protein; P = 0.047) were significantly reduced in muscle homogenates of T2D. These reductions were not retained for palmitate oxidation in primary myotubes (P = 0.38); however, incorporation of FAs into TAG was lower in T2D (P = 0.03 for oleate and P = 0.11 for palmitate), with a strong correlation of TAG incorporation between muscle tissue and primary myotubes (r = 0.848, P = 0.008). The data indicate that the ability to incorporate FAs into TAG is an intrinsic feature of human muscle cells that is reduced in individuals with T2D. PMID- 24487027 TI - Tissue-specific inactivation of type 2 deiodinase reveals multilevel control of fatty acid oxidation by thyroid hormone in the mouse. AB - Type 2 deiodinase (D2) converts the prohormone thyroxine (T4) to the metabolically active molecule 3,5,3'-triiodothyronine (T3), but its global inactivation unexpectedly lowers the respiratory exchange rate (respiratory quotient [RQ]) and decreases food intake. Here we used FloxD2 mice to generate systemically euthyroid fat-specific (FAT), astrocyte-specific (ASTRO), or skeletal-muscle-specific (SKM) D2 knockout (D2KO) mice that were monitored continuously. The ASTRO-D2KO mice also exhibited lower diurnal RQ and greater contribution of fatty acid oxidation to energy expenditure, but no differences in food intake were observed. In contrast, the FAT-D2KO mouse exhibited sustained (24 h) increase in RQ values, increased food intake, tolerance to glucose, and sensitivity to insulin, all supporting greater contribution of carbohydrate oxidation to energy expenditure. Furthermore, FAT-D2KO animals that were kept on a high-fat diet for 8 weeks gained more body weight and fat, indicating impaired brown adipose tissue (BAT) thermogenesis and/or inability to oxidize the fat excess. Acclimatization of FAT-D2KO mice at thermoneutrality dissipated both features of this phenotype. Muscle D2 does not seem to play a significant metabolic role given that SKM-D2KO animals exhibited no phenotype. The present findings are unique in that they were obtained in systemically euthyroid animals, revealing that brain D2 plays a dominant albeit indirect role in fatty acid oxidation via its sympathetic control of BAT activity. D2-generated T3 in BAT accelerates fatty acid oxidation and protects against diet-induced obesity. PMID- 24487028 TI - Hydrogen sulfide improves wound healing via restoration of endothelial progenitor cell functions and activation of angiopoietin-1 in type 2 diabetes. AB - Impaired angiogenesis and its induced refractory wound lesions are common complications of diabetes. Hydrogen sulfide (H2S) has been reported to have proangiogenic effects. We hypothesize that H2S improves diabetic wound healing by restoring endothelial progenitor cell (EPC) function in type 2 diabetes. db/db Mice were treated with sodium hydrosulfide (NaHS), 4-hydro-xythiobenzamide group (HTB), or saline for 18 days. db/+ Mice were treated with dl-propargylglycine (PAG) or saline for 18 days. Plasma H2S levels were significantly decreased in db/db mice and restored in the NaHS and HTB mice compared with the diabetic control group. Wound-closure rates were significantly faster in the NaHS and HTB groups than in the db/db group, in which the PAG group had slower wound-closure rates. Wound skin capillary densities were enhanced in the NaHS and HTB groups. EPC functions were significantly preserved in the NaHS and HTB groups but were decreased in the PAG group. Meanwhile, EPC functions of the db/+ mice were significantly reduced after in vitro PAG treatment or cystathionine-gamma-lyase (CSE) silencing; EPC functions of db/db mice were significantly improved after in vitro NaHS treatment. The expressions of Ang-1 in wound skin tissue and in EPCs were upregulated in the NaHS and HTB groups compared with db/db controls, but were downregulated by in vivo PAG and in vitro siCSE treatment compared with normal controls. Diabetic EPC tube formation capacity was significantly inhibited by Ang-1 small interfering RNA before NaHS treatment compared with db/db EPCs treated with NaHS only. Taken together, these results show that H2S improves wound healing by restoration of EPC functions and activation of Ang-1 in type 2 diabetic mice. PMID- 24487029 TI - shRNA kinome screen identifies TBK1 as a therapeutic target for HER2+ breast cancer. AB - HER2(+) breast cancer is currently treated with chemotherapy plus anti-HER2 inhibitors. Many patients do not respond or relapse with aggressive metastatic disease. Therefore, there is an urgent need for new therapeutics that can target HER2(+) breast cancer and potentiate the effect of anti-HER2 inhibitors, in particular those that can target tumor-initiating cells (TIC). Here, we show that MMTV-Her2/Neu mammary tumor cells cultured as nonadherent spheres or as adherent monolayer cells select for stabilizing mutations in p53 that "immortalize" the cultures and that, after serial passages, sphere conditions maintain TICs, whereas monolayer cells gradually lose these tumorigenic cells. Using tumorsphere formation as surrogate for TICs, we screened p53-mutant Her2/Neu(+) tumorsphere versus monolayer cells with a lentivirus short hairpin RNA kinome library. We identified kinases such as the mitogen-activated protein kinase and the TGFbetaR protein family, previously implicated in HER2(+) breast cancer, as well as autophagy factor ATG1/ULK1 and the noncanonical IkappaB kinase (IKK), TANK binding kinase 1 (TBK1), which have not been previously linked to HER2(+) breast cancer. Knockdown of TBK1 or pharmacologic inhibition of TBK1 and the related protein, IKKepsilon, suppressed growth of both mouse and human HER2(+) breast cancer cells. TBK1/IKKepsilon inhibition promoted cellular senescence by suppressing p65-NF-kappaB and inducing p16(Ink4a). In addition, TBK1/IKKepsilon inhibition cooperated with lapatinib, a HER2/EGFR1-targeted drug, to accelerate apoptosis and kill HER2(+) breast cancer cells both in culture and in xenografts. Our results suggest that patients with HER2(+) breast cancer may benefit from anti-TBK1/IKKepsilon plus anti-HER2 combination therapies and establish conditions that can be used to screen for additional TIC-specific inhibitors of HER2(+) breast cancer. PMID- 24487030 TI - On several factors that control rates of discounting. AB - Discounting occurs when the subjective value of an outcome decreases because its delivery is either delayed or uncertain. Discounting has been widely studied because of its ubiquitous nature. Research from our laboratory has demonstrated that rates of discounting are systematically altered by several different factors. This paper outlines how the type of data-collection method (i.e., multiple choice vs. fill in the blank), how one frames the outcome being discounted (i.e., won vs. owed), and the type of outcome (i.e., money vs. medical treatment) by magnitude of the outcome (i.e., small vs. large) by type of discounting (i.e., delay vs. probability) interaction can potentially control observed rates of discounting. Such findings should not only be of interest to individuals who study the quantitative analyses of discounting, but also to researchers and theoreticians trying to understand and generalize findings from studies on discounting. PMID- 24487031 TI - NMDA and AMPA receptors in the anterior cingulate cortex mediates visceral pain in visceral hypersensitivity rats. AB - Several studies have shown that N-methyl-D-aspartate (NMDA)-receptor activation in anterior cingulate cortex (ACC) neurons plays critical roles in modulating visceral pain responses in visceral hypersensitivity (VH) rats. However, there are few reports about the expressions of NMDA and alpha-amino-3-hydroxy-5-methyl 4-isox-azolepropionic-acid (AMPA) receptor subtypes in ACC of VH model rats at different time points. The current study was undertaken to investigate NR2A, NR2B and GluR2 expressions in ACC of VH rats that were induced by administration with 5% mustard oil. Our results indicated that NR2B, but not NR2A, was highly expressed in VH model group on day 15, 22, and 36 compared with normal group (p < 0.05). GluR2 expression was also higher in VH model group on day 15, 22, and 36 than that of normal group (p < 0.05). These findings suggested increased expression of NR2B and GluR2 might be key mechanisms for long-term synaptic plastic changes in VH rats. PMID- 24487032 TI - PLGA-nanoparticle mediated delivery of anti-OX40 monoclonal antibody enhances anti-tumor cytotoxic T cell responses. AB - OX40 (CD134) is a tumor necrosis factor (TNF) receptor expressed mainly on activated T cells and transmits a potent costimulatory signal once engaged. Agonistic anti-OX40 monoclonal antibody (mAb) enhances tumor immune response leading to therapeutic effects in mouse tumor models. However, when tested in phase I clinical trials it did not show objective clinical activity in cancer patients. In this study, we examined the feasibility of nanoparticle (NP) mediated delivery of anti-OX40 mAb to efficiently induce cytotoxic T lymphocyte (CTL) responses. The biodegradable poly(DL-lactide-co-glycolide) nanoparticle (PLGA-NP) carrying anti-OX40 mAb, anti-OX40-PLGA-NP, was prepared by double emulsion method and showed an average diameter of 86 nm with a loading efficiency of 25%. We found that anti-OX40-PLGA-NP induced CTL proliferation and tumor antigen-specific cytotoxicity as well as cytokine production more strongly than free anti-OX40 mAb. These results suggest that PLGA-based nanoparticle formulation may provide efficient delivery system of anti-OX40 mAb for cancer immunotherapy. PMID- 24487033 TI - Intratumoral regulatory T cells are associated with suppression of colorectal carcinoma metastasis after resection through overcoming IL-17 producing T cells. AB - With opposite immune activities, regulatory T cells (Tregs) and IL-17 producing T cells were accumulated in various malignant tumors and played critical roles in pathophysiologic course of these diseases. In this study, we investigated the mix effect of the intratumoral Tregs and IL-17 producing T cells on metastasis of colorectal carcinoma (CRC) after resection. The frequency of intratumoral Tregs and IL-17A+ T cells, and the levels of FoxP3 and IL-17 mRNA were analyzed. The ratio of Tregs/IL-17A+T cells and the ratio of FoxP3 mRNA/IL-17 mRNA were calculated. The activities of matrix metalloproteases (MMPs) in tumor tissues were analyzed. Meanwhile, Tregs from patient's blood was co-cultured with human CRC cells in the presence of IL-17. MMPs protein and mRNA levels were determined after 48 or 24h incubation. We found that Tregs and IL-17A+T cells were accumulated in CRC. The ratio of Tregs/IL-17A+T cells was decreased in CRC tissues. More intratumoral Tregs and less IL-17A+T cells were associated with suppressed MMPs activities and decreased metastases score. In addition, vitro studies demonstrated that Tregs suppressed MMPs expression in the presence of IL 17. Our findings suggested the possibility that intratumoral Tregs protected against metastasis of CRC after resection through overcoming IL-17 producing T cells. PMID- 24487034 TI - HLA-G1 increases the radiosensitivity of human tumoral cells. AB - Different molecules regulate the response of tumoral tissues to ionizing radiation. The objective of this work was to determine if HLA-G1 expression modulates the radiosensitivity of human tumoral cell lines. To this end, human melanoma M8 and human erythroleukemia K562 cell lines, with their correspondent HLA-G1 negative and positive variants, were gamma irradiated and the survival frequency was determined by clonogenic assay. The survival fraction of HLA-G1 expressing cells was around 60% of HLA-G1 negative cells. The generation of acidic vesicular organelles was higher in HLA-G1 positive cells. Apoptosis levels showed statistically significant differences only in K562 cells, whereas the variation in G2/M cycle progression was only significant in M8 cells. In addition, irradiation diminished cell-surface HLA-G1 and increased soluble HLA-G1 levels. Soluble HLA-G1 has no influence on cell survival in any cell line. In summary, we could demonstrate that HLA-G1 confers higher radiosensitivity to HLA G1 expressing cells. PMID- 24487035 TI - Amelioration of autoimmune arthritis by naringin through modulation of T regulatory cells and Th1/Th2 cytokines. AB - Naringin, a well-known flavanone glycoside found in grapefruit and other citrus fruits, was determined to be an effective anti-inflammatory compound. We investigated the effect of naringin on the key mediators of arthritic inflammation, namely T cell subsets, CD4(+)GITR(+) expressing cells, CD4(+)CD25(+)Foxp3(+) (Treg), Th1/Th2 cytokines and inflammatory mediators. We treated Balb/c mice (p.o.) with naringin (20, 40 and 80 mg/kg) for 14 days. Compared with the vehicle-treated and arthritic-control mice, the naringin treatment demonstrated a considerable decrease in the level of T cells, CD4(+)GITR(+), Th1 cytokine and inflammatory mediator expressions. In contrast, naringin treatment resulted in significantly up-regulated Treg and Th2 cytokine levels. Therefore, the naringin-induced inhibition of the T cells, various pro inflammatory cytokines and inflammatory mediators that facilitate cellular infiltration into the joints might have contributed to its anti-arthritic activity. Our data suggest that naringin diminished the AIA in mice and it could be a potential alternative/adjunct treatment for RA. PMID- 24487036 TI - Quantitative proteomics of Sesuvium portulacastrum leaves revealed that ion transportation by V-ATPase and sugar accumulation in chloroplast played crucial roles in halophyte salt tolerance. AB - Physiological and proteomic responses of Sesuvium portulacastrum leaves under salinity were investigated. Different from glycophytes, this halophyte had optimal growth at 200-300mM NaCl and accumulated more starch grains in chloroplasts under high salinity. Increased contents of soluble sugars, proline, and Na(+) were observed upon salinity. X-ray microanalysis revealed that Na(+) was mainly compartmentalized into cell vacuole. Quantitative proteomics produced 96 salt responsive proteins, and the majority was chloroplast-located proteins. Gene ontology analysis revealed that proteins involved in ion binding, proton transport, photosynthesis and ATP synthesis were overrepresented. The expressions of a Na(+)/H(+) antiporter and several ATP synthase subunits were activated upon high salinity. ATP hydrolysis assay demonstrated that V-ATPase activity at tonoplast was dramatically increased upon NaCl whereas vacuolar H(+) pyrophosphatase and plasma membrane P-ATPase activities were not increased, which indicated that sodium compartmentalization was mainly performed by enhancing V ATPase activity rather than P-ATPase and H(+)-pyrophosphatase. Accumulation of soluble sugars as well as sodium compartmentalization maintained the osmotic balance between vacuole and cytoplasm, which finally established ionic homeostasis in saline cells in true halophytes. BIOLOGICAL SIGNIFICANCE: Physiological and proteomic analyses of S. portulacastrum leaves under different salinities were investigated. This true halophyte accumulated more soluble sugars, starch, proline and Na(+) under high salinity. Differential proteomics produced 96 salt responsive proteins and the majority was involved in ion binding, proton transport, photosynthesis, and ATP synthesis. A Na(+)/H(+) antiporter and several ATP synthase subunits were induced upon high salinity. ATP hydrolysis assay demonstrated that V-ATPase activity at tonoplast was dramatically increased whereas vacuolar H(+)-pyrophosphatase and plasma membrane ATPase activities were stable upon NaCl. These findings demonstrated that the increased Na(+) was compartmentalized into vacuole by enhancing V-ATPase activity rather than H(+)-ATPase. PMID- 24487037 TI - Proteomic identification of immunodominant membrane-related antigens in Campylobacter jejuni associated with sheep abortion. AB - Campylobacter jejuni clone SA is the predominant agent inducing sheep abortion and a zoonotic agent causing gastroenteritis in humans in the United States. In an attempt to identify antigens of clone SA that may be useful for vaccine development, immunoproteomic analyses were conducted to characterize the membrane proteome of C. jejuni clone SA. 2-DE of C. jejuni membrane-related proteins was followed by immunoblotting analyses using convalescent sera that were derived from ewes naturally infected by C. jejuni clone SA. Totally 140 immunoreactive spots were identified, 50 of which were shared by all tested convalescent sheep sera. Conserved and immunodominant spots were identified by mass spectrometry. Among the 26 identified immunogenic proteins, there were 8 cytoplasmic proteins, 2 cytoplasmic membrane proteins, 11 periplasmic proteins, 3 outer membrane proteins, and 2 extracellular proteins. Notably, many of the immunodominant antigens were periplasmic proteins including HtrA, ZnuA, CjaA, LivK, CgpA, and others, some of which were previously shown to induce protective immunity. Interestingly, 11 immunoreactive proteins including 9 periplasmic proteins are known N-linked glycosylated proteins. These findings reveal immunogens that may potentially elicit protective immune responses and provide a foundation for developing vaccines against C. jejuni induced sheep abortion. BIOLOGICAL SIGNIFICANCE: Campylobacter jejuni clone SA is the predominant agent inducing sheep abortion and incurs a significant economic loss to sheep producers. This emergent strain is also a zoonotic agent, causing gastroenteritis in humans. However, the immunogens of C. jejuni induced abortion are largely unknown. Considering the significance of C. jejuni clone SA in causing sheep abortion and foodborne illnesses, protective vaccines are needed to control its transmission and spread. Additionally, immunological markers are required for detection and identification of this highly pathogenic clone. To address these needs, we applied an immunoproteomic approach to identify the membrane-associated antigens of this highly virulent C. jejuni clone associated with sheep abortions in the U.S. The findings reveal immunogens that may potentially elicit protective immune responses and provide a foundation for developing vaccines against C. jejuni induced sheep abortion. PMID- 24487038 TI - Proteomic and biochemical analyses of short-tailed pit viper (Gloydius brevicaudus) venom: age-related variation and composition-activity correlation. AB - We conducted an in-depth analysis of the proteomic and biochemical profiles of the venom of neonate and adult short-tailed pit vipers (Gloydius brevicaudus). Identified proteins were assigned to a few main toxin families. Disintegrin, phospholipase A2 (PLA2), serine proteinase, cysteine-rich secretory protein, C type lectin-like protein, l-amino acid oxidase and snake venom metalloproteinase (SVMP) were detected in both venoms, while 5'-nucleotidase was detected only in the adult venom. SVMP was the predominant protein family in both venoms (neonate: 65.7%; adult: 64.4%), followed by PLA2 (neonate: 13.4%; adult: 25.0%). Antivenomic analysis revealed that commercial G. brevicaudus antivenom almost neutralized the chromatographic peaks with medium and high molecular masses in both venoms, but did not completely recognize peaks with low molecular mass. Toxicological and enzymatic activities show remarkable age-related variation in G. brevicaudus venom, probably resulting from variation in venom composition. Our data demonstrate age-related variation across venomics, antivenomics and biochemical profiles of G. brevicaudus venom, and have implications for the management of G. brevicaudus bites, including improving antivenom preparation by combining both venoms. BIOLOGICAL SIGNIFICANCE: This study investigates the composition and biochemical activity of neonate and adult Gloydius brevicaudus venoms. We found remarkable age-related variation in venom biological activity, likely the result of variation in venom composition. Antivenomics analysis was used to explore difference in neonate and adult G. brevicaudus venoms. Our findings have implications for the diagnosis and clinical management of G. brevicaudus bites, and the design of venom mixtures that will increase the efficacy of commercial antivenom. This article is part of a Special Issue entitled: Proteomics of non-model organisms. PMID- 24487039 TI - Determination of 26 veterinary antibiotics residues in water matrices by lyophilization in combination with LC-MS/MS. AB - A sensitive, simple and reliable multi-residue method was developed for the determination of 26 widely used veterinary antibiotics including 6 macrolides, 2 pleuromutilins, 4 tetracyclines, 2 lincosamides, 6 fluoroquinolones and 6 sulfonamides in different water matrices using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Water samples were lyophilized to dryness. Target compounds were separated on Zorbax SB-Aq column (150mm*2.1mm i.d., 3.5MUm) and determined by LC-MS/MS operating in positive electrospray ionization mode. Spiked at concentration levels of 0.02, 0.4 and 4MUgL(-1), recoveries of all target compounds were over 70% except sulfaquinoxaline (59.0% at 0.02MUgL(-1)) with relative standard deviations below 20%. Limits of detection (LOD) and limits of quantification (LOQ) of 26 drugs ranged from 0.1 to 6.5ngL(-1) and from 0.3 to 19ngL(-1), respectively. The developed method was successfully applied to the analysis of 26 antibiotics residues in fish pond water, groundwater, biogas digester water, and lagoon wastewater samples collected from local pig farms. PMID- 24487040 TI - Application of solidified floating organic drop microextraction method for biomonitoring of chlorpyrifos and its oxon metabolite in urine samples. AB - A simple, efficient and green analytical procedure for monitoring sub ppb amounts of chlorpyrifos (CP) and chlorpyrifos-oxon (CPO) in urine samples was reported. The methodology is based on the solidified floating organic drop microextraction of the analytes with a free microdrop of 2-dodecanol. The parameters those can affect the microextraction efficiency, such as solvent type, extraction solvent volume, extraction time and temperature, salt effect, pH and stirring rate on extraction were optimized. The analytes were extracted from the urine samples by using 10MUL of 2-dodecanol for 40min at 70 degrees C and then, the extracts were injected to GC-MS column by applying 100kPa injection pressure. The regression coefficients relating to linearity were at least 0.99. The accuracy of the developed method was tested upon recovery studies for CP and CPO calculated as 100+/-7% and 110+/-9% (at 0.1ngmL(-1) level), respectively. LOD value for CP was found 4.8ngL(-1) and for CPO it was found 3.8ngL(-1). This method can easily be adopted by clinical laboratories for the contribution to policies aiming to reduce exposure of pesticides. PMID- 24487041 TI - Identification of metabolites of deoxyschizandrin in rats by UPLC-Q-TOF-MS/MS based on multiple mass defect filter data acquisition and multiple data processing techniques. AB - Deoxyschizandrin is an active lignin ingredient originating from Schisandra chinensis (Turcz.) Baill or Schisandrae Sphenantherae Fructus. In the present study, a novel and efficient strategy was developed for the in vivo screening and identification of deoxyschizandrin metabolites using ultra high performance liquid chromatography combined with triple TOF mass spectrometry (UPLC TOF/MS/MS). This strategy was characterized by the following: a novel and unique multiple mass defect filter (MMDF) combined with an on-line data acquisition method that is dependent on dynamic background subtraction (DBS) was developed to trace all of the probable metabolites of deoxyschizandrin. The MMDF and DBS methods could trigger an IDA scan for the low-level metabolites that are masked by background noise and endogenous components. A combination of data processing methods including extracted ion chromatography (XIC), mass defect filtering (MDF), product ion filtering (PIF) and neutral loss filtering (NLF) were employed to identify the metabolites of deoxyschizandrin. Next, the structures of the metabolites were elucidated based on an accurate mass measurement, the fragmentation patterns of the parent drug and relevant drug bio-transformation knowledge. Finally, an important parameter ClogP was used to estimate the retention time of isomers. Based on the proposed strategy, 51 metabolites (including 49 phase I and 2 phase II metabolites) were identified in rats after the oral administration of deoxyschizandrin. Among these metabolites, 41 metabolites were characterized in the rat urine, and 28 metabolites were identified in the rat bile. The results indicated that oxidization was the main metabolic pathway and that the methoxy group and the biphenyl cyclooctene were the metabolic sites. Conjugation with sulfate and cysteine groups produced two phase-II metabolites. This study firstly reported the description of deoxyschizandrin metabolism in vivo. This study provided a practical strategy for rapidly screening and identifying metabolites, and this methodology can be widely applied for the structural characterization of the metabolites of other compounds. PMID- 24487042 TI - Gastrointestinal Stromal Tumors With De Novo Anaplastic Dedifferentiation: Considerations on a Little-Known Neoplastic Metamorphosis. PMID- 24487043 TI - Fibrin glue improves osteochondral scaffold fixation: study on the human cadaveric knee exposed to continuous passive motion. AB - OBJECTIVE: To evaluate stability and integrity of bi-layer and three-layer collagen-hydroxyapatite (C-HA) osteochondral scaffolds in a human cadaveric knee exposed to continuous passive motion (CPM) with and without loading and the role of added fibrin glue to improve the press-fit fixation of C-HA scaffolds. DESIGN: Osteochondral lesions (2.0 * 1.5 cm) were chiseled out on both condyles and trochlea in eight human cadaveric knees. A total of 24 bi-layer (5 mm, four in each condyle) or three-layer C-HA scaffolds (8 mm, eight in the trochlea, four in each condyle) were first press-fit implanted and underwent testing with CPM, 90 cycles, 0 degrees -90 degrees . The second set of 24 scaffolds was implanted in cleaned lesions with the addition of fibrin glue. Two knees with fibrin glue fixation were additionally exposed to 15 kg loading, with 30 cycles of CPM, 0 degrees -30 degrees . Then, the knees were reopened and the scaffolds were evaluated using semi-quantitative Drobnic and modified Bekkers scores. RESULTS: All but two scaffolds remained in the lesions site throughout CPM. Two implants failed: both were bi-layer osteochondral scaffolds, press-fit implanted at the lateral femoral condyle (LFC). A statistically significant difference was obtained between press-fit and fibrin glue implants with both Drobnic (2.9 +/- 0.7 vs 4.3 +/- 0.1, P < 0.0005) and Bekkers (3.3 +/- 1.0 vs 5.0 +/- 0.1, P < 0.0005) scores. Additional knee loading did not affect fibrin glue scaffold fixation or integrity. CONCLUSION: This cadaveric study showed fibrin glue notably improved bi-layer or three-layer C-HA scaffold press-fit fixation regardless of lesion location. It is therefore recommended that fibrin glue be used during surgery to improve early post-operative C-HA scaffold stability and integrity. PMID- 24487045 TI - Allogeneic transplantation as therapy for acute myelogenous leukemia in the elderly. PMID- 24487044 TI - Pharmacologic regimens for knee osteoarthritis prevention: can they be cost effective? AB - OBJECTIVE: We sought to determine the target populations and drug efficacy, toxicity, cost, and initiation age thresholds under which a pharmacologic regimen for knee osteoarthritis (OA) prevention could be cost-effective. DESIGN: We used the Osteoarthritis Policy (OAPol) Model, a validated state-transition simulation model of knee OA, to evaluate the cost-effectiveness of using disease-modifying OA drugs (DMOADs) as prophylaxis for the disease. We assessed four cohorts at varying risk for developing OA: (1) no risk factors, (2) obese, (3) history of knee injury, and (4) high-risk (obese with history of knee injury). The base case DMOAD was initiated at age 50 with 40% efficacy in the first year, 5% failure per subsequent year, 0.22% major toxicity, and annual cost of $1,000. Outcomes included costs, quality-adjusted life expectancy (QALE), and incremental cost effectiveness ratios (ICERs). Key parameters were varied in sensitivity analyses. RESULTS: For the high-risk cohort, base case prophylaxis increased quality adjusted life-years (QALYs) by 0.04 and lifetime costs by $4,600, and produced an ICER of $118,000 per QALY gained. ICERs >$150,000/QALY were observed when comparing the base case DMOAD to the standard of care in the knee injury only cohort; for the obese only and no risk factors cohorts, the base case DMOAD was less cost-effective than the standard of care. Regimens priced at $3,000 per year and higher demonstrated ICERs above cost-effectiveness thresholds consistent with current US standards. CONCLUSIONS: The cost-effectiveness of DMOADs for OA prevention for persons at high risk for incident OA may be comparable to other accepted preventive therapies. PMID- 24487046 TI - Half-fluence versus half-dose photodynamic therapy in chronic central serous chorioretinopathy. AB - PURPOSE: To compare the efficacy and safety of half-fluence vs half-dose photodynamic therapy (PDT) in chronic central serous chorioretinopathy (CSC). DESIGN: Multicenter retrospective comparison study. METHODS: Retrospective review of 56 patients affected by chronic CSC, including 28 patients (31 eyes) who received half-fluence PDT and 28 patients (29 eyes) who received half-dose PDT. Best-corrected visual acuity (BCVA), central foveal thickness (CFT), and resolution of subretinal fluid on optical coherence tomography at 1 and 12 months were assessed. RESULTS: The mean logMAR BCVA improved significantly (P < .001), both in the half-fluence group (from 0.187 [+/- 0.187] to 0.083 [+/- 0.164]) and in the half-dose group (from 0.126 [+/- 0.091] to 0.068 [+/- 0.091]), at 12 months, without significant difference between the 2 groups. At 1 month a complete resolution of subretinal fluid was observed in 19 half-fluence-treated eyes (61.3%) and in 25 half-dose-treated eyes (86.2%) (P = .04). At 12 months, a complete resolution of subretinal fluid was achieved in 26 half-fluence-treated eyes (83.9%) and 29 half-dose-treated eyes (100%) (P = .0529). Nine eyes (29%) in the half-fluence group and 5 eyes (17.2%) in the half-dose group had at least 1 recurrence of subretinal fluid during the follow-up. Overall there were 15 and 5 recurrences in the half-fluence PDT and half-dose PDT groups, respectively (P = .07). In no eye of either groups was atrophy of the retinal pigment epithelium observed in the area of treatment. CONCLUSION: Half-dose PDT induced a more rapid reabsorption of the fluid, a more lasting effect, and equal safety with respect to half-fluence PDT. PMID- 24487048 TI - Pediatric microbial keratitis in Taiwan: clinical and microbiological profiles, 1998-2002 versus 2008-2012. AB - PURPOSE: To identify the change in clinical and microbiological profiles of pediatric microbial keratitis in Taiwan between 1998-2002 and 2008-2012. DESIGN: Retrospective, observational study. METHOD: setting: Chang Gung Memorial Hospital, a referral center in Taiwan. patient population: We retrospectively reviewed the medical records of 68 eyes of 67 children aged 16 years or younger who were diagnosed with microbial keratitis and treated at our hospital between July 2008 and December 2012. main outcomes and measures: Predisposing factors, isolated organisms, antibiotic susceptibility, and clinical outcomes. The findings were compared with the results of our previous study conducted between July 1998 and December 2002. RESULTS: As in 1998-2002, the leading risk factor for microbial keratitis during 2008-2012 was contact lens use, and the infection rate significantly increased from 40.7% to 52.9% (P = .024), which was mainly attributable to the recent increase in the rate of orthokeratology-related keratitis from 9.9% to 19.1% (P = .011). Pseudomonas aeruginosa remained the most commonly isolated organism (30.6%), but the number of isolated coagulase-negative Staphylococcus cases increased significantly in the 2008-2012 cases (P = .04). Antibiotic susceptibility of organisms did not change significantly between the 2 study periods. By using multiple linear stepwise regression analysis, we found that gram-negative bacterial infection played a crucial role in poor visual outcome. CONCLUSIONS: Contact lens-related microbial keratitis increased in Taiwanese children over time, especially because of the use of overnight orthokeratology. Clinicians must understand the infection background and pay further attention to contact lens use in pediatric patients. PMID- 24487047 TI - Correlation of retinal nerve fiber layer thickness and visual fields in glaucoma: a broken stick model. AB - PURPOSE: To determine the retinal nerve fiber layer (RNFL) thickness at which visual field (VF) damage becomes detectable and associated with structural loss. DESIGN: Retrospective cross-sectional study. METHODS: Eighty-seven healthy and 108 glaucoma subjects (1 eye per subject) were recruited from an academic institution. All patients had VF examinations (Swedish Interactive Threshold Algorithm 24-2 test of the Humphrey Visual Field Analyzer 750i) and spectral domain optical coherence tomography RNFL scans. Comparison of RNFL thickness values with VF threshold values showed a plateau of VF threshold values at high RNFL thickness values and then a sharp decrease at lower RNFL thickness values. A broken stick statistical analysis was used to estimate the tipping point at which RNFL thickness values are associated with VF defects. The slope for the association between structure and function was computed for data above and below the tipping point. RESULTS: The mean RNFL thickness value that was associated with initial VF loss was 89 MUm. The superior RNFL thickness value that was associated with initial corresponding inferior VF loss was 100 MUm. The inferior RNFL thickness value that was associated with initial corresponding superior VF loss was 73 MUm. The differences between all the slopes above and below the aforementioned tipping points were statistically significant (P < .001). CONCLUSIONS: In open-angle glaucoma, substantial RNFL thinning or structural loss appears to be necessary before functional visual field defects become detectable. PMID- 24487049 TI - Epiretinal membranes in uveitic macular edema: effect on vision and response to therapy. AB - PURPOSE: To evaluate the effects of epiretinal membranes on the response of uveitic macular edema to therapy and on visual acuity outcomes. DESIGN: Retrospective case series. METHODS: One hundred four eyes of 77 patients with uveitic macular edema were identified at a tertiary care center. Epiretinal membranes were diagnosed when identified by 2 investigators' grading of spectral domain optical coherence tomography and scored for the presence or absence of surface wrinkling. Outcomes included best-corrected visual acuity, central subfield thickness, and rates of macular edema improvement (>20% reduction in central subfield thickness) and resolution (reduction of central subfield thickness to <315 MUm) at 3 and 6 months follow-up. RESULTS: Seventy-two eyes of 59 patients had an epiretinal membrane on presentation. Eyes without epiretinal membranes and with epiretinal membranes without surface wrinkling were not significantly different at presentation or at 3 and 6 months follow-up. Conversely, eyes with an epiretinal membrane with retinal surface wrinkling had a greater proportion of eyes with 20/200 or worse visual acuity at presentation, and had worse mean acuities at 3 months (20/94 vs 20/35 for eyes without an epiretinal membrane, P = .002) and at 6 months follow-up (20/110 vs 20/36 for eyes without an epiretinal membrane, P = .02). At 6 months of follow-up the mean central subfield thicknesses were: eyes without an epiretinal membrane, 338 +/- 23 MUm; and eyes with an epiretinal membrane and surface wrinkling, 405 +/- 22 MUm (P = .05). CONCLUSIONS: In eyes with epiretinal membranes and retinal surface wrinkling, uveitic macular edema had a poorer visual acuity response to medical therapy and thicker maculae at 6 months. PMID- 24487050 TI - Subfoveal choroidal thickness as a potential predictor of visual outcome and treatment response after intravitreal ranibizumab injections for typical exudative age-related macular degeneration. AB - PURPOSE: To investigate the prognostic implication of subfoveal choroidal thickness on treatment outcome after intravitreal ranibizumab injections for typical exudative age-related macular degeneration (AMD). DESIGN: Retrospective study. METHODS: A total of 40 eyes of 37 patients who completed 6-month follow-up were analyzed. Patients' data were retrieved from medical records including best corrected visual acuity (BCVA). Subfoveal choroidal thickness at baseline, 3 months, and 6 months was measured by enhanced depth imaging optical coherence tomography and adjusted for age and sex before statistical analysis. Treatment response was after 3 monthly intravitreal ranibizumab injections. Responders (responder group) were defined as a 100 MUm or more decrease or complete resolution of subretinal fluid, whereas nonresponders (nonresponder group) were defined as changes less than 100 MUm or more than 100 MUm increase of subretinal fluid by optical coherence tomography. RESULTS: Mean age at diagnosis was 72.1 +/ 8.1 years, and 22 eyes (55.0%) were responders. The responder group had thicker subfoveal choroid (257.2 +/- 108.3 MUm) and smaller lesions (1.3 +/- 0.8 MUm) at baseline than the nonresponder group (167.1 +/- 62.4 MUm, P = .003; and 2.0 +/- 1.0 MUm, P = .008). The responder group showed significantly better BCVA and thicker subfoveal choroid than the nonresponder group at 3 months (P = .002 and P = .023) and 6 months (P = .004 and P = .031). Stepwise and binary regression analysis demonstrated that subfoveal choroidal thickness was significantly correlated with visual outcome (B = -0.002, P = .003) and treatment response (B = 8.136, P = .018). CONCLUSION: Subfoveal choroidal thickness may be a predictive factor for visual outcome and treatment response in typical exudative AMD after intravitreal ranibizumab injections. PMID- 24487051 TI - Whole eye axial biometry during accommodation using ultra-long scan depth optical coherence tomography. AB - PURPOSE: To investigate changes of whole eye axial biometry during accommodation using ultra-long scan depth optical coherence tomography (UL-OCT). DESIGN: Prospective, observational case series. METHODS: Twenty-one adult subjects were enrolled. Using UL-OCT, the left eye of each subject was imaged with relaxed diopters (0 D) and accommodative stimuli (+6 D). Full eye biometry included central corneal thickness (CCT), anterior chamber depth (ACD), lens thickness, vitreous length, and axial length (AL). RESULTS: During accommodation (+6 D), the axial biometry of the whole eye changed significantly. Compared to the rest state, ACD at the accommodative state decreased significantly from 3.128 +/- 0.305 mm to 2.961 +/- 0.298 mm (paired t test, P < .001). The lens thickness increased significantly from 3.723 +/- 0.237 mm to 3.963 +/- 0.234 mm (P < .001). The vitreous length decreased significantly from 17.129 +/- 0.864 mm to 17.057 +/ 0.848 mm (P < .001). AL was 24.519 +/- 0.917 mm at the rest state and increased to 24.545 +/- 0.915 mm with +6 D accommodation stimulus. The elongated AL of 26.1 +/- 13.4 MUm between the rest and accommodative states was significant (P < .001). CONCLUSIONS: During accommodation, whole eye axial biometry changed, including a decrease in ACD and vitreous length and an increase in lens thickness and AL. UL-OCT provides an alternative method that is suitable for full eye biometry during accommodation. PMID- 24487052 TI - Variable phenotype in 17q12 microdeletions: clinical and molecular characterization of a new case. AB - Microdeletions of 17q12 including the hepatocyte nuclear factor 1 beta (HNF1B) gene, as well as point mutations of this gene, are associated with the Renal Cysts and Diabetes syndrome (RCAD, OMIM 137920) and genitourinary alterations. Also, microdeletions encompassing HNF1B were identified as a cause of Mayer Rokitansky-Kuster-Hauser Syndrome (MRKH, OMIM 277000) in females and, recently, were associated with intellectual disability, autistic features, cerebral anomaly and facial dysmorphisms. In this report, we describe a boy with a deletion in 17q12 region detected by SNP array, encompassing the HNF1B gene, that showed dysmorphic features, intellectual disability (ID), serious speech delay and autistic features. In addition, obesity was observed. In order to study the parental origin of the rearrangement, we analyzed selected SNPs in the deleted area in the patient and his parents, showing Mendelian incompatibilities suggesting a de novo deletion on the chromosome of maternal origin. Our case confirms the incomplete penetrance and variable expressivity of this deletion, its complex clinical variability, and strengthens the evidence that ID and stereotyped behaviors may be part of the phenotypic spectrum characterizing the affected patients. Also, it is useful to further delineate the phenotypes associated to the deletion being the first case in which obesity has been documented. We present a genotype-phenotype correlation discussing the possible role of some genes, encompassed by the deletion, in the etiology of the observed phenotypes. PMID- 24487053 TI - Mitogenomic perspectives into sciaenid fishes' phylogeny and evolution origin in the New World. AB - Sciaenid fishes are widely distributed throughout the coastal waters and estuaries of the world. A total of 23 genera of this family are endemic to the Old World. However, evolutionary relationships among Old World sciaenid fishes and their origin have remained unresolved despite their diversity and importance. Besides, hypotheses that explain the origin and biogeographical distribution of sciaenid fishes are controversial. In this study, the complete mitochondrial genome sequences of seven representative sciaenid species were determined and a well-resolved tree was recovered. This new timescale demonstrated that the sciaenid originated during the late Jurassic to early Cretaceous Period. The estimated origin time of sciaenid fish is 208 Mya, and the origin of Old World sciaenid is estimated at 126 Mya. Reconstruction of ancestral distributions indicated a plesiomorphic distribution and center of origin in the New World, with at least one lineage subsequently dispersed to the Old World. Moreover, we conclude that the common ancestors of Old World sciaenid fishes were derived from species of New World. PMID- 24487054 TI - Novel transcriptome data analysis implicates circulating microRNAs in epigenetic inheritance in mammals. AB - Experimental evidence supports a role of mobile small non-coding RNAs in mediating soma to germline hereditary information transfer in epigenetic inheritance in plants and worms. Similar evidence in mammals has not been reported so far. In this bioinformatic analysis, differentially expressed microRNAs (miRNAs) or mRNAs reported previously in genome level expression profiling studies related to or relevant in epigenetic inheritance in mammals were examined for circulating miRNA association. The reported sets of differentially expressed miRNAs or miRNAs that are known to target the reported sets of differentially expressed genes, in that order, showed enrichment of circulating miRNAs across environmental factors, tissues, life cycle stages, generations, genders and species. Circulating miRNAs commonly representing the expression profiles enriched various epigenetic processes. These results provide bioinformatic evidence for a role of circulating miRNAs in epigenetic inheritance in mammals. PMID- 24487055 TI - MicroRNA-27 promotes the differentiation of odontoblastic cell by targeting APC and activating Wnt/beta-catenin signaling. AB - MicroRNAs (miRNAs) play an essential role in regulating cell differentiation either by inhibiting mRNA translation or by inducing its degradation. However, the role of miRNAs in odontoblastic cell differentaion is largely unknown. In the present study, we demonstrate that the expression of miR-27 was significantly increased during MDPC-23 odontoblastic cell differentiation. Furthermore, the up regulation of miR-27 promotes the differentiation of MDPC-23 odontoblastic cells and accelerates mineralization without cell proliferation. In addition, our results of target gene prediction revealed that the mRNA of adenomatous polyposis coli (APC) associated with Wnt/beta-catenin signaling pathway has miR-27 binding site in the its 3' UTR and is suppressed by miR-27. Subsequentially, the down regulated APC by miR-27 triggered the activation of Wnt/beta-catenin signaling through accumulation of beta-catenin in the nucleus. Our data suggest that miR-27 promotes MDPC-23 odontoblastic cell differentiation by targeting APC and activating Wnt/beta-catenin signaling. Therefore, miR-27 might be considered a critical candidate as an odontoblastic differentiation molecular target for the development of miRNA based therapeutic agents in the dental medicine. PMID- 24487056 TI - Characterisation of the genetic effects of the ADFP gene and its association with production traits in dairy goats. AB - Adipose differentiation-related protein (ADFP) is important for regulation of lipid metabolism and insulin secretion in beta-cells. In this study, we investigated polymorphisms within the caprine ADFP gene and determined its relationship with production traits. As there was no sequence information available for the caprine ADFP gene, we generated DNA sequence data and examined the genomic organisation. The caprine ADFP gene is organised into 7 exons and 6 introns that span approximately 8.7 kbp and is transcribed into mRNA containing 1,353 bp of sequence coding for a protein of 450 amino acids. The protein sequences showed substantial similarity (71-99%) to orthologues from cattle, human and mouse. We identified polymorphisms in the sequences using DNA sequencing, PCR-RFLP and forced PCR-RFLP methods. Seven single nucleotide polymorphisms (SNPs) were identified using samples from 4 different goat populations consisting of 1408 healthy and unrelated individuals. Six haplotypes involving the 7 SNPs from the caprine ADFP gene were identified and their effects on production traits were analysed. Haplotype 6 had the highest haplotype frequency and was highly significantly associated with chest circumference and milk yield in the analysed populations. The results of this study suggest that the ADFP gene is a strong candidate gene affecting production traits and may be used for marker-assisted selection and management in Chinese dairy goat breeding programmes. PMID- 24487057 TI - Long-range crystalline order in spicules from the calcareous sponge Paraleucilla magna (Porifera, Calcarea). AB - We investigated the ultrastructure and crystallographic orientation of spicules from the calcareous sponge Paraleucilla magna (subclass Calcaronea) by transmission and scanning electron microscopy using two different methods of sample preparation: ultramicrotomy and focused ion beam (FIB). It was found that the unpaired actine from the spicules was oriented in the [211] zone axis. The plane that contains the unpaired actine and divides symmetrically the paired actines is the (-120). This plane is a mirror plane of the hexagonal lattice system. All the spicule types analyzed presented the same crystallographic orientation. Electron nanodiffraction maps from 4MUm*4MUm regions prepared by FIB showed disorientation of <2 degrees between diffraction patterns obtained from neighbor regions, indicating the presence of a unique, highly aligned calcite crystalline phase. Among the eight FIB sections obtained, four presented high pore density. In one section perpendicular to the actine axis pores were observed only in the center of the spicule aligned in a circular pattern and surrounded by a faint circular contour with a larger radius. The presence of amorphous carbon representative of organic molecules detected by electron energy loss spectroscopy was correlated neither with porosity nor with specific lattice planes. PMID- 24487058 TI - Optimization of solid phase extraction clean up and validation of quantitative determination of carbazochrome sodium sulfonate in human plasma by liquid chromatography-electrospray ionization tandem mass spectrometry. AB - A mixed-mode anion exchange solid phase extraction (SPE) method for extraction and clean up of carbazochrome sodium sulfonate (CSS) and (1S)-(+)-10 camphorsulfonic acid (IS) was optimized for quantification by high-performance liquid chromatography/negative electrospray ionization mass spectrometry. The analytes were extracted from 1mL of human plasma via SPE on Oasis((r)) WAX cartridge. Chromatographic separation was achieved on a Zorbax SB-Aq (4.6*250mm, 5MUm) column under an isocratic condition. Detection was performed using electrospray ionization in negative ion multiple reaction monitoring (MRM) mode. The deprotonated precursor to product ion transitions monitored for CSS and IS was at m/z 299.0->256.0 and m/z 230.9->79.8, respectively. The method was fully validated for its selectivity, sensitivity, precision, accuracy, recovery, matrix effect and stability. Linear range was 0.189-37.8ng/mL with a high square regression coefficient (r=0.9995). The intra-and inter-day precision (RSD, %) ranged from 0.95% to 4.17%, and the intra-and inter-day accuracy was between 95.03% and 105.9%. This method was successfully applied to a bioequivalence study of 90mg CSS formulation in 18 healthy Chinese male subjects under fasting condition. PMID- 24487059 TI - Persistent inflammation in HIV infection: established concepts, new perspectives. AB - Immune activation is now considered a main driving force for the progressive immune failure in HIV infection. During the early phases of infection, a rapid depletion of gastrointestinal CD4+ T cells occurs that is followed by a deterioration of the gut epithelium and by the subsequent translocation of microbial products into the blood. Activation of innate immunity results in massive production of proinflammatory cytokines, which can trigger activation induced cell death phenomena among T lymphocytes. Moreover, persistent antigenic stimulation and inflammatory status causes immune exhaustion. The chronic immune activation also damages lymphoid tissue architecture, so contributing to the impairment of immune reconstitution. Recently, new mechanisms were identified, so opening new perspective on the innate immune sensing in HIV-1 infection. Cell death is followed by the release of molecules containing "damage-associated molecular patterns", that trigger a potent innate immune response through the engagement of Toll-like receptors. Then, also different types of HIV-related nucleic acids can act as potent stimulators of innate immunity. All these events contribute to the loss of T cell homeostatic regulation and to the failure of adaptive immunity. PMID- 24487060 TI - Successful unrelated cord blood transplantation for adult acquired aplastic anemia using reduced intensity conditioning without ATG. PMID- 24487061 TI - Arraying the post-translational glycoproteome (PTG). AB - Glycosylation is chemically the most complex post-translational modification of proteins and therefore understanding the structural and biological implications of post-translational glycosylation is a major challenge. The need for rapid and reliable investigations of protein-glycan interaction events and the substantial efforts required to synthesize glycans and glycopeptides with a variety of structures has called for the development of miniaturized analytical techniques. In the last decade, glycan and glycopeptide microarrays have enabled high throughput analysis of diverse protein-glycan interactions. Evaluations of enzyme activities and substrate specificities, characterization of glycan binding proteins, mapping of antibody epitopes, detection of autoantibodies and serodiagnosis are typically conducted on microarrays. The most significant developments in synthesis, immobilization and applications of glycopeptide microarrays are covered in this review. PMID- 24487063 TI - The anti-fibrotic effects of CCN1/CYR61 in primary portal myofibroblasts are mediated through induction of reactive oxygen species resulting in cellular senescence, apoptosis and attenuated TGF-beta signaling. AB - Cysteine-rich protein 61 (CCN1/CYR61) is a CCN (CYR61, CTGF (connective tissue growth factor), and NOV (Nephroblastoma overexpressed gene)) family matricellular protein comprising six secreted CCN proteins in mammals. CCN1/CYR61 expression is associated with inflammation and injury repair. Recent studies show that CCN1/CYR61 limits fibrosis in models of cutaneous wound healing by inducing cellular senescence in myofibroblasts of the granulation tissue which thereby transforms into an extracellular matrix-degrading phenotype. We here investigate CCN1/CYR61 expression in primary profibrogenic liver cells (i.e., hepatic stellate cells and periportal myofibroblasts) and found an increase of CCN1/CYR61 expression during early activation of hepatic stellate cells that declines in fully transdifferentiated myofibroblasts. By contrast, CCN1/CYR61 levels found in primary parenchymal liver cells (i.e., hepatocytes) were relatively low compared to the levels exhibited in hepatic stellate cells and portal myofibroblasts. In models of ongoing liver fibrogenesis, elevated levels of CCN1/CYR61 were particularly noticed during early periods of insult, while expression declined during prolonged phases of fibrogenesis. We generated an adenovirus type 5 encoding CCN1/CYR61 (i.e., Ad5-CMV-CCN1/CYR61) and overexpressed CCN1/CYR61 in primary portal myofibroblasts. Interestingly, overexpressed CCN1/CYR61 significantly inhibited production of collagen type I at both mRNA and protein levels as evidenced by quantitative real-time polymerase chain reaction, Western blot and immunocytochemistry. CCN1/CYR61 further induces production of reactive oxygen species (ROS) leading to dose-dependent cellular senescence and apoptosis. Additionally, we demonstrate that CCN1/CYR61 attenuates TGF-beta signaling by scavenging TGF-beta thereby mitigating in vivo liver fibrogenesis in a bile duct ligation model. CONCLUSION: In line with dermal fibrosis and scar formation, CCN1/CYR61 is involved in liver injury repair and tissue remodeling. CCN1/CYR61 gene transfer into extracellular matrix-producing liver cells is therefore potentially beneficial in liver fibrotic therapy. PMID- 24487062 TI - Chemistry of natural glycan microarrays. AB - Glycan microarrays have become indispensable tools for studying protein-glycan interactions. Along with chemo-enzymatic synthesis, glycans isolated from natural sources have played important roles in array development and will continue to be a major source of glycans. N-glycans and O-glycans from glycoproteins, and glycans from glycosphingolipids (GSLs) can be released from corresponding glycoconjugates with relatively mature methods, although isolation of large numbers and quantities of glycans is still very challenging. Glycosylphosphatidylinositol (GPI) anchors and glycosaminoglycans (GAGs) are less represented on current glycan microarrays. Glycan microarray development has been greatly facilitated by bifunctional fluorescent linkers, which can be applied in a 'Shotgun Glycomics' approach to incorporate isolated natural glycans. Glycan presentation on microarrays may affect glycan binding by GBPs, often through multivalent recognition by the GBP. PMID- 24487064 TI - A non-canonical function of eukaryotic elongation factor 1A1: regulation of interleukin-6 expression. AB - Interleukin-6 is one of the most prominent triggers of inflammatory processes. We have shown recently that heteroarylketones (HAKs) interfere with stimulated interleukin-6 expression in astrocytes by suppression of STAT3 phosphorylation at serine 727. Surprisingly, this effect is not based on the inhibition of STAT3 relevant kinases. Therefore, we here used the structurally modified HAK compound biotin-HAK-3 in a reverse chemical approach to identify the relevant molecular target in UV-mediated cross-linking experiments. Employing streptavidin-specific 2D-immunoblotting followed by mass spectrometry we identified nine proteins putatively interacting with biotin-HAK-3. After co-immunoprecipitation, co immunofluorescence, surface plasmon resonance analyses and RNAi-mediated knock down, the eukaryotic elongation factor 1A1 (eEF1A1) was verified as the relevant target of HAK bioactivity. eEF1A1 forms complexes with STAT3 and PKCdelta, which are crucial for STAT3(S727) phosphorylation and for NF-kappaB/STAT3-enhanced interleukin-6 expression. Furthermore, the intracellular HAK accumulation is strongly dependent on eEF1A1 expression. Taken together, the results reveal a novel molecular mechanism for a non-canonical role of eEF1A1 in signal transduction via direct modulation of kinase-dependent phosphorylation events. PMID- 24487065 TI - Bovine seminal ribonuclease triggers Beclin1-mediated autophagic cell death in pancreatic cancer cells. AB - Among the large number of variants belonging to the pancreatic-type secretory ribonuclease (RNase) superfamily, bovine pancreatic ribonuclease (RNase A) is the proto-type and bovine seminal RNase (BS-RNase) represents the unique natively dimeric member. In the present manuscript, we evaluate the anti-tumoral property of these RNases in pancreatic adenocarcinoma cell lines and in nontumorigenic cells as normal control. We demonstrate that BS-RNase stimulates a strong anti proliferative and pro-apoptotic effect in cancer cells, while RNase A is largely ineffective. Notably, we reveal for the first time that BS-RNase triggers Beclin1 mediated autophagic cancer cell death, providing evidences that high proliferation rate of cancer cells may render them more susceptible to autophagy by BS-RNase treatment. Notably, to improve the autophagic response of cancer cells to BS-RNase we used two different strategies: the more basic (as compared to WT enzyme) G38K mutant of BS-RNase, known to interact more strongly than wt with the acidic membrane of cancer cells, or BS-RNase oligomerization (tetramerization or formation of larger oligomers). Both mutant BS-RNase and BS RNase oligomers potentiated autophagic cell death as compared to WT native dimer of BS-RNase, while the various RNase A oligomers remained completely ineffective. Altogether, our results shed more light on the mechanisms lying at the basis of BS-RNase antiproliferative effect in cancer cells, and support its potential use to develop new anti-cancer strategies. PMID- 24487066 TI - P2X7 receptors mediate resistance to toxin-induced cell lysis. AB - In the majority of cells, the integrity of the plasmalemma is recurrently compromised by mechanical or chemical stress. Serum complement or bacterial pore forming toxins can perforate the plasma membrane provoking uncontrolled Ca(2+) influx, loss of cytoplasmic constituents and cell lysis. Plasmalemmal blebbing has previously been shown to protect cells against bacterial pore-forming toxins. The activation of the P2X7 receptor (P2X7R), an ATP-gated trimeric membrane cation channel, triggers Ca(2+) influx and induces blebbing. We have investigated the role of the P2X7R as a regulator of plasmalemmal protection after toxin induced membrane perforation caused by bacterial streptolysin O (SLO). Our results show that the expression and activation of the P2X7R furnishes cells with an increased chance of surviving attacks by SLO. This protective effect can be demonstrated not only in human embryonic kidney 293 (HEK) cells transfected with the P2X7R, but also in human mast cells (HMC-1), which express the receptor endogenously. In addition, this effect is abolished by treatment with blebbistatin or A-438079, a selective P2X7R antagonist. Thus blebbing, which is elicited by the ATP-mediated, paracrine activation of the P2X7R, is part of a cellular non-immune defense mechanism. It pre-empts plasmalemmal damage and promotes cellular survival. This mechanism is of considerable importance for cells of the immune system which carry the P2X7R and which are specifically exposed to toxin attacks. PMID- 24487067 TI - Map2k4delta - identification and functional characterization of a novel Map2k4 splice variant. AB - Mitogen-activated protein kinase kinase 4 (Map2k4) is a dual specificity serin/threonine protein kinase that is unique among all MAP2Ks in activating two different subfamilies of mitogen-activated protein kinases, the c-Jun N-terminal kinases (JNKs) and p38 kinases. Map2k4 is essential during embryogenesis and involved in a variety of physiological and pathological processes. However, studies on its role in cancer development revealed partially conflicting data. In the present study, we report the identification of a novel splice variant of Map2k4, Map2k4delta, with an additional exon in front of the substrate binding D domain. Map2k4delta is expressed together with Map2k4 in various tissues from rat, mouse and human. In PC12 cells, both splice variants control cell cycle progression and basal apoptosis by using different signaling pathways. If expression and activation of Map2k4 and Map2k4delta are at a certain, cell type specific equilibrium, an appropriate cell growth is ensured. Overexpression of one kinase disrupts the intricate balance and either results in a highly proliferative or pro-apoptotic phenotype, partially reflecting the discrepancies in the literature on Map2k4 and its role in tumor development. Our findings contribute to the understanding of previous studies and point out that Map2k4 has not always a definite function, but rather triggers a cellular reaction in concert with other modulators. PMID- 24487069 TI - Introduction: toward a historical/anthropological approach in neuropsychology. PMID- 24487068 TI - To divide or not to divide: a key role of Rim15 in calorie-restricted yeast cultures. AB - The PAS kinase Rim15 is proposed to integrate signals from different nutrient sensing pathways and to control transcriptional reprogramming of Saccharomyces cerevisiae upon nutrient depletion. Despite this proposed role, previous transcriptome analyses of rim15 mutants solely focused on growing cultures. In the present work, retentostat cultivation enabled analysis of the role of Rim15 under severely calorie-restricted, virtually non-growing conditions. Under these conditions, deletion of RIM15 affected transcription of over 10-fold more genes than in growing cultures. Transcriptional responses, metabolic rates and cellular morphology indicated a key role of Rim15 in controlled cell-cycle arrest upon nutrient depletion. Moreover, deletion of rim15 reduced heat-shock tolerance in non-growing, but not in growing cultures. The failure of rim15 cells to adapt to calorie restriction by entering a robust post-mitotic state resembles cancer cell physiology and shows that retentostat cultivation of yeast strains can provide relevant models for healthy post-mitotic and transformed human cells. PMID- 24487070 TI - Prefrontal abilities. AB - The neuroanatomical region that has most prominently altered with the advancing cognitive competency of the human is the prefrontal cortex, particularly the rostral extreme. While the prefrontal cortex does not appear to contain the neural networks that carry out cognitive activities, the management of these high level manipulations, so uniquely characteristic of the human, appears dependent upon the prefrontal cortex. PMID- 24487071 TI - Historical evolution of spatial abilities. AB - Historical evolution and cross-cultural differences in spatial abilities are analyzed. Spatial abilities have been found to be significantly associated with the complexity of geographical conditions and survival demands. Although impaired spatial cognition is found in cases of, exclusively or predominantly, right hemisphere pathology, it is proposed that this asymmetry may depend on the degree of training in spatial abilities. It is further proposed that spatial cognition might have evolved in a parallel way with cultural evolution and environmental demands. Contemporary city humans might be using spatial abilities in some new, conceptual tasks that did not exist in prehistoric times: mathematics, reading, writing, mechanics, music, etc. Cross-cultural analysis of spatial abilities in different human groups, normalization of neuropsychological testing instruments, and clinical observations of spatial ability disturbances in people with different cultural backgrounds and various spatial requirements, are required to construct a neuropsychological theory of brain organization of spatial cognition. PMID- 24487072 TI - On the origins of calculation abilities. AB - A historical review of calculation abilities is presented. Counting, starting with finger sequencing, has been observed in different ancient and contemporary cultures, whereas number representation and arithmetic abilities are found only during the last 5000-6000 years. The rationale for selecting a base of ten in most numerical systems and the clinical association between acalculia and finger agnosia are analyzed. Finger agnosia (as a restricted form of autotopagnosia), right-left discrimination disturbances, semantic aphasia, and acalculia are proposed to comprise a single neuropsychological syndrome associated with left angular gyrus damage. A classification of calculation disturbances resulting from brain damage is presented. It is emphasized that using historical/anthropological analysis, it becomes evident that acalculia, finger agnosia, and disorders in right-left discrimination (as in general, in the use of spatial concepts) must constitute a single clinical syndrome, resulting from the disruption of some common brain activity and the impairment of common cognitive mechanisms. PMID- 24487073 TI - People recognition: a historical/anthropological perspective. AB - Using current neurological and neuropsychological literature, and the analysis of different cultural and historical conditions, people recognition is analyzed. Different "subsystems" or "modules" could be involved in individuals' recognition: living versus non-living, own species versus other species, familiar versus non-familiar, males versus females, and individual identification versus emotional identification. Not only visual, but also auditory and even olfactory information may be involved in people recognition. Visual information involved in people recognition is proposed to include not only the perception of faces, but also the perception of whole body and gait, clothes, emotional expressions, and individual marks. PMID- 24487074 TI - Neuropsychology of illiteracy. AB - It is proposed that analysis of illiteracy can not only discern the influence of schooling background on neuropsychological test performance, but also contributes to obtaining a better understanding about the cerebral organization of cognitive activity. Brain organization of cognition, and cognitive sequelae of brain pathology in illiterates are reviewed. It is concluded that: (1) cognitive abilities, as measured by standard neuropsychological tests, are significantly influenced by schooling background; and (2) educational and cultural variables may affect the degree (albeit, not the direction) of hemispheric dominance for language, and other cognitive abilities. A more bilateral representation of cognitive abilities in illiterates is hypothesized. PMID- 24487075 TI - The impact of competition on quality and prices in the English care homes market. AB - This study assesses the impact of competition on quality and price in the English care/nursing homes market. Considering the key institutional features, we use a theoretical model to assess the conditions under which further competition could increase or reduce quality. A dataset comprising the population of 10,000 care homes was used. We constructed distance/travel-time weighted competition measures. Instrumental variable estimations, used to account for the endogeneity of competition, showed quality and price were reduced by greater competition. Further analyses suggested that the negative quality effect worked through the effect on price - higher competition reduces revenue which pushes down quality. PMID- 24487076 TI - Mating clusters in the mosquito parasitic nematode, Strelkovimermis spiculatus. AB - Mating aggregations in the mosquito parasitic nematode, Strelkovimermis spiculatus, were investigated in the laboratory. Female postparasites, through their attraction of males and, remarkably, other females, drive the formation of mating clusters. Clusters may grow in size by merging with other individual or clusters. Female molting to the adult stage and reproductive success are enhanced in larger clusters. Male mating behavior is initiated when the female begins to molt to the adult stage by shedding dual juvenile cuticles posteriorly. Males coil their tail around the adult cuticle, migrating progressively along the female in intimate synchrony with the molting cuticle until the vulva is exposed and mating can occur. The first arriving male is assured of access to a virgin female, as his intermediate location between the vulva and subsequently arriving males blocks these competitors. Males deposit an adhesive gelatinous copulatory plug into and over the vulva before departing the female. Fecundity was greater in larger mating clusters, but this was a function of a greater rate of molting which is a prerequisite for mating. Males compete for virgin females by emerging and molting to the adult stage earlier than females. Mating aggregations have previously only been examined in snakes, but these studies have tended to be observational as snakes offer a challenging system for study. The relatively easy to culture and manipulate mermithid system may offer a model for experimental studies of male-male competition, protandry, copulatory plugs and female choice in mating clusters. PMID- 24487077 TI - Reinforcement of denture base PMMA with ZrO(2) nanotubes. AB - In the research described, ZrO2 nanotubes were prepared by anodization. The morphologies, crystal structure, etc. were characterised by scanning electron microscope (SEM), transmission electron microscope (TEM), X-ray diffractometer (XRD), and Fourier transform infrared spectroscopy (FTIR). ZrO2 nanotubes were pre-stirred with the denture base PMMA powder by a mechanical blender and mixed with MMA liquid to fabricate reinforced composites. The composites were tested by an electromechanical universal testing machine to study the influences of contents and surface-treatment effect on the reinforcement. The ZrO2 nanoparticles were also investigated for comparative purposes. Results indicated that ZrO2 nanotubes had a better reinforcement effect than ZrO2 nanoparticles, and surface-treatment would lower the reinforcement effect of the ZrO2 nanotubes which itself was significantly different from that of the ZrO2 nanoparticles. The flexural strength of the composite was maximised when 2.0wt% untreated ZrO2 nanotubes were added. PMID- 24487078 TI - A new technique to improve the mechanical and biological performance of ultra high molecular weight polyethylene using a nylon coating. AB - A new patent pending technique is proposed in this study to improve the mechanical and biological performance of ultra high molecular weight polyethylene (UHMWPE), i.e., to uniformly coat nylon onto the UHMWPE fiber (Firouzi et al., 2012). Mechanical tests were performed on neat and new nylon coated UHMWPE fibers to examine the tensile strength and creep resistance of the samples at different temperatures. Cytotoxicity and osteolysis induced by wear debris of the materials were investigated using (MTT) assay, and RT-PCR for tumor necrosis factor alpha (TNFalpha) and interleukin 6 (IL-6) osteolysis markers. Mechanical test results showed substantial improvement in maximum creep time, maximum breaking force, and toughness values of Nylon 6,6 and Nylon 6,12 coated UHMWPE fibers between average 15% and 60% at 25, 50, and 70 degrees C. Furthermore, cytotoxicity studies have demonstrated significant improvement in cell viability using the nylon coated UHMWPE over the neat one (72.4% vs 54.8%) for 48h and (80.7 vs 5%) for 72h (P<0.01). Osteolysis test results have shown that the expression levels of TNFalpha and IL-6 markers induced by the neat UHMWPE fiber were significantly higher than those induced by the Nylon 6,6 coated UHMWPE (2.5 fold increase for TNFalpha at 48h, and three fold increase for IL-6 at 72h (P<0.01)). This study suggests that UHMWPE coated with nylon could be used as a novel material in clinical applications with lower cytotoxicity, less wear debris-induced osteolysis, and superior mechanical properties compared to neat UHMWPE. PMID- 24487080 TI - Pharmacokinetics of Anti-epileptic Drugs and their Clinical Significance. AB - The serum concentration achieved and maintained following the administration of a fixed drug dosage is a direct consequence of the interactions of a wide variety of interrelated processes, including drug absorption, distribution, metabolism, and excretion, and the physiological status of the patient. These interrelationships are reviewed with specific reference to the major anti epileptic drugs, phenobarbitone, phenytoin, sodium valproate, and carbamazepine, as well as a new first-line antiepileptic, oxcarbazepine.Both older drugs, such as phenobarbitone and phenytoin, and newer drugs, such as carbamazepine (CBZ) and sodium valproate, have been studied extensively over the past years giving valuable information for drug treatment. An important feature of oxcarbazepine (OXC) , which was developed through minimal changes in the structure of CBZ in order to improve on the tolerability of CBZ without sacrificing efficacy, is that its metabolites do not include the 11-epoxide which has been implicated in the side-effects of CBZ. In man, OXC is metabolized to a monohydroxy derivative which has independent anti-epileptic properties. OXC seems to lack several disadavantageous pharmacokinetic properties common to other major anti-epileptic drugs. OXC does not influence its own metabolism after repeated administration, in contrast to the auto-induction displayed by CBZ. The metabolism of OXC is not influenced by anti-epileptic co-medication and does not influence the kinetics of other anti-epileptic drugs - or if it does, then to a lesser extent than CBZ. PMID- 24487079 TI - Rapid touch-stimulated movement in the androgynophore of Passiflora flowers (subgen. Decaloba; Sect. Xerogona): an adaptation to enhance cross-pollination? AB - Plant touch-sensitive organs have been described since Darwin's observations and are related to a quick response to environment stimuli. Sensitive flower organs have been associated to an increase in the chances of cross pollination but there are few studies regarding this topic. Here we describe for the first time the kinetic of the androgynophore movement of 4 Passiflora species (P. sanguinolenta, P. citrina, P. capsularis, and P. rubra). For that, we collected flowers and recorded the movement after mechano-stimulating the androgynophore. From the recordings, we described the movement regarding its response and sensibility to mechanical stimulus and calculated the duration, speed, and the angle formed by the androgynophore before and after the movement. From our data we were able to propose a link to the pollination habit of these species. The movement of the androgynophore in these Passiflora is a noteworthy floral feature that might lead us to another astonishing example of a mechanism that evolved among angiosperms to assure sexual reproduction. PMID- 24487081 TI - Trends in Anti-epileptic Drug Development. AB - Several avenues are being explored in the development of new anti-epileptic drugs (AEDs).For a number of years efforts have been directed towards compounds which may augment neuronal inhibition, and these efforts have resulted in the development of several valuable drugs. More recently, increased attention has been focused on the role which excitatory transmitters may play in epileptogenesis, and various substances which decrease excitation are currently being investigated at the preclinical level. Since considerable potential still resides in several of the drugs already on the market, resources have been spent on trying to modify/improve the chemical formula of some of these substances, and a number of new drugs has emerged as a result of this approach.The major accomplishments reviewed here in the development of new anti-epileptic drugs suggest that even more successful advances may be achieved in the near future. PMID- 24487082 TI - Metabolic characteristics of oxcarbazepine ((r)trileptal) and their beneficial implications for enzyme induction and drug interactions. AB - Hepatic oxygenases of the cytochrome P-450 family play a major role in the clearance of various anti-epileptic drugs. These enzymes are susceptible both to induction and to inhibition. Phenytoin, carbamazepine (CBZ), primidone, and phenobarbitone, for instance, are potent enzyme inducers. Other drugs, such as chloramphenicol, propoxyphene, verapamil, and viloxazine, inhibit cytochrome P 450. Pharmacokinetic behaviour is thus often altered, especially in combined medication, so that the dosage has to be re-adjusted if an optimum therapeutic outcome is to be ensured.Oxcarbazepine (OXC) is a keto analogue of CBZ. In the human liver the keto group is readily reduced, and the resulting monohydroxy metabolite is cleared by glucuronidation. The two enzymes mediating these reactions, i.e. aldo-keto reductase and UDP-glucuronyltransferase, do not depend on cytochrome P-450. The monohydroxy metabolite is the major active substance in plasma. Its elimination is not enhanced by OXC. Moreover, OXC seems to have little effect on cytochrome P-450. Aldo-keto reductases and glucuronyltransferases are in general less sensitive to induction and inhibition than are P-450 dependent enzymes. On the whole, OXC possesses very little potential for metabolic drug interactions, and thus differs favourably from other anti-epileptic drugs. PMID- 24487083 TI - Oxcarbazepine in monotherapy. AB - Altogether 235 patients with newly diagnosed epilepsy were randomly allocated to treatment with either oxcarbazepine (OXC) or carbamazepine (CBZ) in a double blind multicentre trial. After a titration phase of 4-8 weeks the optimum individual dose of trial medication was determined and treatment with this dose was continued for another 48 weeks.The results of the study indicate that there is no significant difference in seizure frequency between OXC and CBZ; no correlation was found between the therapeutic effect and EEG in either treatment group. OXC caused significantly (p = 0.04) fewer "severe" side-effects than CBZ. Global evaluation of tolerability showed a trend towards better tolerability of OXC. There way no correlation between either efficacy or tolerability and serum trough levels of the investigational drugs. Clinically relevant abnormal laboratory test findings were observed in two patients, both on CBZ.In conclusion, OXC is a major anti-epileptic drug, which is as effective as CBZ in the treatment of partial seizures and generalized convulsions. With fewer side effects than CBZ, it represents a valuable alternative particularly in patients who develop side-effects which prevent optimum seizure control. PMID- 24487085 TI - Discussion. PMID- 24487084 TI - Oxcabazepine ((r)Trileptal) in Anti-epileptic Polytherapy. AB - The anti-epileptic activity of oxcarbazepine (OXC) was compared with that of carbamazepine (CBZ) and the primary active metabolite of OXC, a monohydroxy derivative (MHD). Altogether 255 patients receiving either OXC or MHD (192 and 63 patients respectively) were included in the analysis of efficacy. Out of these 255 patients a total of 40 were children. The duration of treatment varied between 8 and 24weeks. The daily dose of OXC or MHD varied between 600 and 5400 mg (in children 600-2400 mg). Out of five studies two were double-blind controlled studies (including a total of 105 patients) whereas the remaining three were open studies.The results of these studies indicate that, in adults with epilepsy, there is no statistically significant difference in overall seizure frequency between CBZ and OXC. In one double-blind study the number of generalized tonic-clonic seizures was significantly less frequent during treatment with OXC than with CBZ. No statistically significant difference with regard to side-effects was observed between OXC and CBZ.The results in children with epilepsy show a statistically significant difference in seizure frequency in favour of OXC, in comparison with CBZ.Overall, the polytherapy studies in adults and children support the effectiveness and safety of oxcarbazepine. PMID- 24487086 TI - Preface. PMID- 24487087 TI - Effects of an interatrial shunt on rest and exercise hemodynamics: results of a computer simulation in heart failure. AB - BACKGROUND: A treatment based on an interatrial shunt device has been proposed for counteracting elevated pulmonary capillary wedge pressure (PCWP) in patients with heart failure and mildly reduced or preserved ejection fraction (HFpEF). We tested the theoretical hemodynamic effects of this approach with the use of a previously validated cardiovascular simulation. METHODS AND RESULTS: Rest and exercise hemodynamics data from 2 previous independent studies of patients with HFpEF were simulated. The theoretical effects of a shunt between the right and left atria (diameter up to 12 mm) were determined. The interatrial shunt lowered PCWP by ~3 mm Hg under simulated resting conditions (from 10 to 7 mm Hg) and by ~11 mm Hg under simulated peak exercise conditions (from 28 to 17 mm Hg). Left ventricular cardiac output decreased ~0.5 L/min at rest and ~1.3 L/min at peak exercise, with corresponding increases in right ventricular cardiac output. However, because of the reductions in PCWP, right atrial and pulmonary artery pressures did not increase. A majority of these effects were achieved with a shunt diameter of 8-9 mm. The direction of flow though the shunt was left to right in all of the conditions tested. CONCLUSIONS: The interatrial shunt reduced left-sided cardiac output with a marked reduction in PCWP. This approach may reduce the propensity for heart failure exacerbations and allow patients to exercise longer, thus attaining higher heart rates and cardiac outputs with the shunt compared with no shunt. These results support clinical investigation of this approach and point out key factors necessary to evaluate its safety and hemodynamic effectiveness. PMID- 24487088 TI - Poly (glycerol sebacate) elastomer supports osteogenic phenotype for bone engineering applications. AB - For bone engineering, the optimal scaffolding material and composition has yet to be elucidated. In this study, we investigated poly (glycerol sebacate) (PGS), an elastomer known primarily for its soft tissue regeneration ability, as a suitable substrate to support osteo-precursor cell attachment and function. We synthesized PGS in the form of sheets where MC3T3-E1 cells were seeded in three different densities of 25,000, 50,000 and 100,000 cells mm(-3) and we investigated the cells/scaffold constructs for their cellular proliferation, matrix deposition, maturation, mineralization and their mechanical compression strength at 24 h and two and four weeks. MC3T3-E1 cells proliferated, synthesized a collagenous matrix and expressed osteogenic markers Runx2, bone sialoprotein and osteocalcin according to their initial seeding density on PGS. We conclude that PGS can support the osteoblastic phenotype in vitro and is a promising osteoconductive substrate for bone regeneration research and for future clinical translation. PMID- 24487089 TI - Conserved transcription factor binding sites suggest an activator basal promoter and a distal inhibitor in the galanin gene promoter in mouse ES cells. AB - Galanin and its receptors have been shown to be expressed in undifferentiated mouse embryonic stem (ES) cells through transcriptome and proteomic analyses. Although transcriptional regulation of galanin has been extensively studied, the regulatory proteins that mediate galanin expression in mouse ES cells have not yet been determined. Through sequence alignments, we have found a high degree of similarity between mouse and human galanin upstream sequences at -146 bp/+69 bp (proximal region) and -2,408 bp/-2,186 bp (distal region). These regions could be recognized by ES cell nuclear proteins, and EMSA analysis suggests a specific functionality. Analysis of the proximal region (PR) using EMSA and ChIP assays showed that the CREB protein interacts with the galanin promoter both in vitro and in vivo. Additional EMSA analysis revealed that an SP1 consensus site mediated protein-DNA complex formation. Reporter assays showed that CREB is an activator of galanin expression and works cooperatively with SP1. Furthermore, analysis of the distal region (DR) using EMSA assays demonstrated that both HOX-F and PAX 4/6 consensus sites mediated protein-DNA complex formation, and both sites inhibited luciferase activity in reporter assays. These data together suggest that CRE and SP1 act as activators at the basal promoter, while HOX-F and PAX 4/6 act as silencers of transcription. The interplay of these transcription factors (TF) may drive regulated galanin expression in mouse ES cells. PMID- 24487090 TI - Characterization of a cDNA from Beta maritima that confers nickel tolerance in yeast. AB - Nickel is an essential micronutrient due to its involvement in many enzymatic reactions as a cofactor. However, excess of this element is toxic to biological systems. Here, we constructed a cDNA library from Beta maritima and screened it in the yeast system to identify genes that confer resistance to toxic levels of nickel. A cDNA clone (NIC6), which encodes for a putative membrane protein with unknown function, was found to help yeast cells to tolerate toxic levels of nickel. A GFP fused form of Nic6 protein was localized to multivesicular structures in tobacco epidermal cells. Thus, our results suggest a possible role of Nic6 in nickel and intracellular ion homeostasis. PMID- 24487091 TI - Tissue expression pattern and polymorphism of G0S2 gene in porcine. AB - Adipose triglyceride lipase (ATGL), catalyzing the initial step of hydrolysis of triacylglycerol (TAG) in adipocytes, has been known to be inhibited by G0/G1 switch protein 2 (G0S2). In this study, we determined tissue expression pattern and polymorphism of G0S2 gene in porcine. The results showed that the G0S2 transcript levels were very high in the liver and, to a lesser degree, in adipose tissues of greater omentum and suet fat; and low G0S2 transcript levels were observed in other tissues. A comparative study on the transcript levels between ATGL and G0S2 genes showed that ATGL transcript levels were high in all six adipose tissues, but negligible in the liver. Higher transcript levels were obtained for sows in adipose tissues of the inner layer of subcutaneous fat and suet fat, but higher expression values were found for boars in the liver, spleen, and stomach. 19 single nucleotide polymorphisms (SNPs), including 4 nonsynonymous SNPs (g.-307A>T, g.-394C>G, g.-565G>A, and g.-566T>C), were found in porcine G0S2 genomic DNA. Association analyses showed that the g.-565G>A and g.-742T>A SNPs were associated with back fat thickness (BFT). In conclusion, G0S2 mRNAs are abundantly expressed in porcine liver and adipose tissues of greater omentum and suet fat, and sex affects porcine G0S2 tissue transcript levels; meanwhile, the genetic diversity of porcine G0S2 gene is abundant and 2 SNPs are a genetic factor affecting BFT. PMID- 24487092 TI - A case-control study between interleukin-10 gene variants and periodontal disease in dogs. AB - Periodontal disease (PD) refers to a group of inflammatory diseases that affect the periodontium, the organ which surrounds and supports the teeth. PD is a highly prevalent disease with a multifactorial etiology and, in humans the individual susceptibility is known to be strongly determined by genetic factors. Several candidate genes have been studied, namely genes related with molecules involved in the inflammatory response. Interleukin-10 (IL-10) is a cytokine with important anti-inflammatory and immunomodulatory roles, and several studies indicate an association between IL10 polymorphisms and PD. In dogs, an important animal model in periodontology, PD is also a highly prevalent naturally occurring disease, and only now are emerging the first studies evaluating the genetic predisposition. In this case-control study, a population of 90 dogs (40 dogs with PD and 50 healthy dogs) was used to study the IL10 gene, and seven new genetic variations in this gene were identified. No statistically significant differences were detected in genotype and allele frequencies of these variations between the PD cases and control groups. Nevertheless, one of the variations (IL10/2_g.285G>A) leads to an amino acid change (glycine to arginine) in the putative signal peptide, being predicted a potential influence on IL-10 protein functionality. Further investigations are important to clarify the biological importance of these new findings. The knowledge of these genetic determinants can help to understand properly the complex causal pathways of PD, with important clinical implications. PMID- 24487093 TI - Migraine and hemorrhagic stroke: association or causation? PMID- 24487094 TI - The safety of the semisitting position in craniocervical 3-dimensional image guided fusion surgery. PMID- 24487095 TI - A comprehensive surface proteome analysis of myeloid leukemia cell lines for therapeutic antibody development. AB - A detailed characterization of the cell surface proteome facilitates the identification of target antigens, which can be used for the development of antibody-based therapeutics for the treatment of hematological malignancies. We have performed cell surface biotinylation of five human myeloid leukemia cell lines and normal human granulocytes, which was used for mass spectrometric analysis and allowed the identification and label-free, relative quantification of 320 membrane proteins. Several proteins exhibited a pronounced difference in expression between leukemia cell lines and granulocytes. We focused our attention on CD166/ALCAM, as this protein was strongly up-regulated on all AML cell lines and AML blasts of some patients. A human monoclonal antibody specific to CD166 (named H8) was generated using phage display technology. H8 specifically recognized AML cells in FACS analysis while demonstrating tumor targeting properties in vivo. After in vitro screening of five potent cytotoxic agents, a duocarmycin derivative was used for the preparation of an antibody-drug conjugate, which was able to kill AML cells in vitro with an IC50 of 8nM. The presented atlas of surface proteins in myeloid leukemia provides an experimental basis for the choice of target antigens, which may be used for the development of anti-AML therapeutic antibodies. BIOLOGICAL SIGNIFICANCE: The ability to discriminate between malignant and healthy, essential cells represents an important requirement for the development of armed antibodies for the therapy of hematological malignancies. Our proteomic study is, to our knowledge, the first large scale comparison of the accessible cell surface proteome of leukemia cells and normal blood cells, facilitating the choice of a suitable target for the treatment of acute myeloid leukemia (AML). An antibody drug conjugate was generated recognizing the CD166 antigen which was found to be strongly up regulated in all AML cell lines and AML blasts of some patients. This antibody drug conjugate SIP(H8)-Duo might be further characterized in therapy experiments and might lead to a new targeted treatment option for AML. PMID- 24487096 TI - Occupational exposure to pesticides and consequences on male semen and fertility: a review. AB - Exposure to pesticides affects many body organs including reproductive system. Disorder of the reproductive system leads to infertility and therefore has been in the center of attention within the recent decades. Pesticides are one of the compounds that might reduce the semen quality in the exposed workers according to current knowledge. Although many underlying mechanisms have been proposed, the mechanisms of action are not clarified yet. The object of the present review was to criticize all the results of studies which evaluated the pesticide effects on male reproductive system. Results indicate that semen changes are multifactorial in the workers exposed to pesticides as there are numerous factors affecting sperm quality in occupational exposures. Majority of pesticides including organophosphoruses affect the male reproductive system by mechanisms such as reduction of sperm density and motility, inhibition of spermatogenesis, reduction of testis weights, reduction of sperm counts, motility, viability and density, and inducing sperm DNA damage, and increasing abnormal sperm morphology. Reduced weight of testes, epididymis, seminal vesicle, and ventral prostate, seminiferous tubule degeneration, change in plasma levels of testosterone, follicle stimulating hormone (FSH), and luteinizing hormone (LH), decreased level and activity of the antioxidant enzymes in testes, and inhibited testicular steroidogenesis are other possible mechanisms. Moreover, DDT and its metabolites have estrogenic effects on males. Although effect of pesticides on sperm quality is undeniable, well-designed long-term studies are needed to elucidate all the possible affecting variables such as socioeconomic, cultural, nutritional, occupational, physical, and clinical characteristics alongside pesticides. PMID- 24487097 TI - The estrogenic effects of apigenin, phloretin and myricetin based on uterotrophic assay in immature Wistar albino rats. AB - Chemicals that occur in vegetal food and known as phytoestrogens, because of their structures similarity to estrogen, have benefits on chronic diseases. Despite this, when they are taken at high amounts, they can cause harmful effects on endocrine system of human and animals. In this study, it has been intended to determine the estrogenic potencies of phytoestrogens apigenin, phloretin and myricetin whose affinities for estrogen receptors in vitro. The female rats divided into 17 groups, each containing six rats. There was a negative control group and there were positive control dose groups which contains ethinyl estradiol, ethinyl estradiol+tamoxifen and genistein. The other dose groups which were tested for estrogenic activity contains apigenin, myricetin and phloretin All chemicals have been given to Wistar immature female rats with oral gavage for 3 consecutive days. By using uterotrophic analysis, uterus wet and blotted weights, vaginal opening, uterus length of female rats has been recorded at the end of the experiment. For detect of cell response, luminal epithelium height, gland number and lactoferrin intensity in luminal epithelium of uterus were evaluated. Biochemical analysises in blood were performed. Relative uterus weights of rats in 100 mg/kg/day dose group of myricetin were statistically increased according to vehicle control and positive control groups. In dose groups of apigenin and phloretin it was found that there were cell responses in uterus. All treatment groups had a significant difference in the high intensity of lactoferrin and uterine gland count compared to oil control group. There was no difference between phloretin and apigenin treatment groups in uterine weight statictically. Uterine heights were increased in positive control groups and 100 mg/kg/day dose group of myricetin. Epithelial cell heights were increased in treatment groups except apigenin and phloretin dose groups. There was no difference between all treatment groups in vaginal opening values according to positive control. PMID- 24487098 TI - Screening for hepatitis C virus infection in a high prevalence country by an antigen/antibody combination assay versus a rapid test. AB - In low-income-countries, screening for hepatitis C virus (HCV) infection is often based on rapid tests (RT). Their lower sensitivity compared to enzyme immunoassay (EIA) suggests that newer HCV Antigen/Antibody (Ag/Ab) combination assays might have a role in such countries. To test this idea, 1998 blood donors were tested at the University Teaching Hospital blood bank in Yaounde, Cameroon simultaneously with a RT (HCV rapid test, Human Diagnostics, Berlin, Germany) according to standard practice (S1) and with an Ag/Ab assay (Monolisa HCV Ag/Ab Ultra, Biorad, France) (S2). All discordant, borderline and reactive samples were submitted to confirmatory testing by immunoblot and/or HCV-RNA. Of the 86 (4.3%) samples positive with one or both strategies, 29 were confirmed negative, 37 positive and 20 were false positive or resolved infection. There was a significant difference in test sensitivity (p=0.01) between S1 (70.3%) and S2 (91.9%) but not in test specificity (99.4% and 98.6%, respectively). The benefit of the Ag/Ab assay in the detection of recent HCV seronegative infections could not be evaluated since no Antigen-only donations were identified. However, better Ag/Ab test sensitivity compared to RT supports the implementation of these newer immunoassays for HCV screening in the African blood bank setting. PMID- 24487099 TI - Evaluation of fully automated assays for the detection of Rubella IgM and IgG antibodies by the Elecsys((r)) immunoassay system. AB - Screening for acute rubella infection in pregnancy is an important element of antenatal care. This study compared the sensitivity, specificity and reproducibility of two new, fully automated Elecsys((r)) Rubella IgM and IgG immunoassays designed for the Elecsys 2010, Modular Analytics E170, COBAS e-411 and COBAS e-601 and e602 analytical platforms, with current assays using serum from patients with primary rubella infections, vaccinated patients, patients with potentially cross-reacting infections and on routine samples in clinical laboratories in France, Germany and Italy. Both assays showed good within-run and within-laboratory precision. A sensitivity of 79.8-96.0% was demonstrated for Elecsys IgM in primary, early acute infection, consistent with existing assays. In samples obtained from routine antenatal screening, the Elecsys Rubella IgM assay revealed high specificity (98.7-99.0%). A significantly (p<0.0001) lower reactivity was demonstrated in samples from previously infected patients where acute rubella infection was excluded, and the incidence of false positives in patients with potentially cross-reacting infections was lower with Elecsys Rubella IgM compared with other. The Elecsys Rubella IgG assay exhibited a relative sensitivity of 99.9-100.0% and specificity of 97.4-100.0% in samples from routine antenatal screening. The Elecsys Rubella IgM and IgG assays allow convenient, rapid and reliable determination of anti-rubella antibodies. Sensitivity, specificity and reproducibility were comparable with existing assay systems. Assay results were available in approximately half the time required for currently employed methods and the assays are compatible with widely used analytical platforms. PMID- 24487100 TI - Evaluation of an automated SPF10-LiPA25 assay for detection and typing of human papillomavirus in archival samples. AB - An automated blotter was evaluated for detection of the HPV SPF10-LiPA25 RHA for HPV genotyping with 63 FFPE tissue and 45 WHO proficiency panel samples. The results showed that 10-20% more types were detected and bands were of significantly stronger intensity (p<0.0001) compared to manual processing. Therefore it was concluded that automated detection of HPV genotypes using the HPV SPF10-LiPA25 is more sensitive for low copy number and mixed-type HPV samples. PMID- 24487101 TI - A homogeneous immunosensor for AFB1 detection based on FRET between different sized quantum dots. AB - Mycotoxins are fatal threats in food safety due to their strong carcinogenesis and toxicity, thus requiring highly sensitive detections. Herein, different-sized quantum dots (QDs) were used to construct a Forster resonance energy transfer (FRET) based immunosensor for sensitive detection of aflatoxin B1 (AFB1) in rice grains. To avoid irregular aggregation between two kinds of QDs, monovalent monoclonal antibody (mAb)-labeled red QDs (~0.84 anti-AFB1 mAbs per QD) and multivalent hapten-labeled green QDs (~6.8 AFB1 per QD) were designed as acceptor and donor, respectively. The anti-AFB1 mAbs and AFB1 interactions promoted one or more acceptors bound with a multivalent AFB1-labeled donor, resulting in energy transfer from the green QDs to the red QDs. Various parameters that influence the immunoassay including reactant ratio of donor to acceptor, buffer pH value, buffer ionic strength and immunoreaction time were systematically investigated and optimized. With optimal conditions, the obtained energy transfer efficiency is proportional to the logarithm of AFB1 concentration in a range over 0.19-16 pM (0.06-5 ng/mL), while offering a limit of detection of 0.13 pM (0.04 ng/mL) in rice extracts. The recovery rates of the intra-assay for spiked samples at AFB1 concentrations of 0.1, 1.0, and 5.0 ng/mL were 83.27% +/- 3.27%, 97.36% +/- 4.55% and 83.04% +/- 4.94%, respectively, and those for the inter-assay were 81.28% +/- 6.11%, 95.97% +/- 7.07%, and 82.78% +/- 5.99%, respectively. Statistical analysis using t-test had no significant difference between the proposed FRET-based immunoassay and the commercial enzyme-linked immunosorbent assay kit. PMID- 24487103 TI - The effect of acidic pH on the inhibitory efficacy of peptides against the interaction ICAM-1/LFA-1 studied by surface plasmon resonance (SPR). AB - Synthetic peptides have been developed for therapeutic applications for decades. The therapeutic efficacy often depends not only on the stabilization of the peptides but also on their binding specificity and affinity to the target molecules to interfere with designated molecular interaction. In this study, the binding affinity of human intercellular adhesion molecule 1 (ICAM-1) chimera and leukocyte function-associated antigen-1 (LFA-1) derived peptides was measured by surface plasmon resonance (SPR) detection, and the results were compared with that of the interaction (of ICAM-1) with the LFA-1 whole protein. To mimic diverse pathological situations in vivo where a low pH has been reported, we studied pH regulated binding affinity of ICAM-1/LFA-1 at pH 7.4, 6.5, and 4.0 without and with magnesium ion. We have found that the binding affinity of LFA-1 whole protein and ICAM-1 increases significantly as the environmental pH decreases, regardless of the absence or the presence of magnesium ion. The affinity of different (LFA-1) derived peptides also depends on the pH, although in all cases the peptides retain its ability to inhibit ICAM-1/LFA-1 interaction. The biomedical relevance of these data has been confirmed using a cell aggregation assay, suggesting that LFA-1 derived peptides show great potential for peptide drug development with a wide functional window of pH range for potential applications in LFA-1 related tumor therapy and autoimmune disease treatment. PMID- 24487102 TI - Real-time monitoring of cell mechanical changes induced by endothelial cell activation and their subsequent binding with leukemic cell lines. AB - Endothelial cell (EC) activation and their subsequent binding with different cells have various mechanical consequences that, if monitored real time, can serve as a functional biomarker of many pathophysiological response mechanisms. This work presents an innovative and facile strategy to conduct such monitoring using quartz crystal microbalance (QCM), thereby relating the shifts in its frequency and motional resistance to morphological changes upon cell-cell and cell-substrate interactions. By activating ECs with TNF-alpha and then characterizing their binding with HL-60 and KG-1 leukemia cells, we are able to induce the mechanical changes in ECs especially in the region of cell-substrate contact which resulted in dynamically coupled mass and viscoelastic changes representing the extent of both activation and binding. The activated ECs suffered a decrease of cellular contact area, leading to positive frequency shift and decreased motional resistance. The binding of leukemia cells onto pre activated ECs exerted a mechanical force to regain the cell surface contact which resulted in the obvious QCM responses opposite to that of activation, and proportional to the number of cells added, in spite of the fact that these added cells are extremely outside the extinction boundary of the shear wave generated by QCM. Different cell lines demonstrate different attachment behavior, which was detected by the QCM. Despite these variations are quite subtle, yet the sensitivity of the technique for dynamic changes at the interface makes them detectable. Moreover, the reproducibility of the generated data determined at each step by deviation measurements (<10%) in response plot was very high despite the high possible heterogeneity in cell populations. The results are explained on the basis of simple theoretical and physical models, although, the development of a more quantitative and precise model is underway in our laboratory. PMID- 24487104 TI - Multiplex electrochemical origami immunodevice based on cuboid silver-paper electrode and metal ions tagged nanoporous silver-chitosan. AB - A 3D microfluidic electrochemical origami immunodevice (denoted as u-ECOI in this work) for sensitive detection of tumor markers was designed. High sensitivity was achieved by using novel cuboid silver modified paper working electrode (CS-PWE) as sensor platform and different metal ions-coated nanoporous silver-chitosan (NSC) as labels. The CS-PWE was fabricated through a seed-mediated growth approach and served as a promising platform for antibodies attachment. The metal ions could be detected directly through square wave voltammetry without metal preconcentration, and each biorecognition event produced a distinct voltammetric peak, whose position and size reflected the identity and amount of the corresponding antigen. The large number of metal ions loading on the NSC greatly amplified the detection signals, and the good biocompatibility of CS-PWE retained good stability for the sandwich-type immunoassay. Using cancer antigen 125 (CA125) and carcinoma antigen 199 (CA199) as model analytes, the simultaneous multiplex immunoassay showed linear ranges of over 4 orders of magnitude with the detection limits down to 0.02 and 0.04 mU mL(-1), respectively. Moreover, this strategy accurately detected the concentrations of CA125 and CA199 in human serum samples. The detection limits of CA125 and CA199 were 0.08 and 0.10 mU mL(-1), respectively. This facile biosensing u-ECOI exhibited high sensitivity and specificity with excellent stability, reproducibility, and accuracy, indicating its wide range of potential applications in point-of-care testing. PMID- 24487105 TI - Simultaneous electrochemical detection of multiple tumor markers using metal ions tagged immunocolloidal gold. AB - In this work, a sandwich-format electrochemical immunosensor has been fabricated in the aim of simultaneous detection of carcinoembryonic antigen (CEA) and alpha fetoprotein (AFP) using metal ions tagged immunocolloidal gold nanocomposites as signal tags. The capture anti-CEA and anti-AFP were immobilized onto the chitosan Au nanoparticles (CHIT-AuNPs) membrane modified glassy carbon electrode through glutaraldehyde (GA). The metal ion labels could be detected directly through differential pulse voltammetry (DPV) without metal pre-concentration, and the distinct voltammetric peaks had a close relationship with each sandwich-type immunoreaction. Under the optimized conditions, the multiplexed immunoassay exhibited good sensitivity and selectivity for the simultaneous determination of CEA and AFP with linear ranges of 0.01-50 ng mL(-1). The detection limits for CEA and AFP are 4.6 pg mL(-1) and 3.1 pg mL(-1), respectively. The method was successfully applied for the determination of AFP and CEA levels in clinical serum samples, and the results were in good agreement with standard enzyme linked immunosorbent assay (ELISA). This approach gives a promising simple and sensitive immunoassay strategy for clinical applications. PMID- 24487107 TI - Memory functioning in obsessive-compulsive disorder. AB - A number of studies have reported neuropsychological deficits in obsessive compulsive disorder (OCD). These have mainly implicated frontal or temporal dysfunction. In this study, we compared the performances of OCD patients and normal subjects using a factorial interpretation of the Wechsler Memory Scale. Our results do not demonstrate significant memory impairment in OCD patients but point to the possibility of frontal lobe dysfunction as a factor in the pathophysiology of OCD. PMID- 24487108 TI - Prevalence of psychosomatic and other medical illnesses in anorexic and bulimic patients. AB - The occurrence of psychosomatic disorders (PSD) in patients with anorexia nervosa and bulimia nervosa has rarely been investigated. We examined the prevalence of four psychosomatic disorders [peptic ulcer (PU), bronchial asthma (BA), neurodermatitis (ND), and rheumatoid arthritis (RA)] in patients consecutively admitted to an eating disorders (ED) program. Responses to a validated questionnaire and clinical file information were obtained from 152 patients, 60% of whom were bulimic and 40% were anorexic. The average age of the patients was 27.5 years and all but two patients were female. There was a higher life-time prevalence of the psychosomatic disorders among anorexics compared with bulimic patients, except for RA. PU and BA were reported by 10% of anorexics compared with 7.6% and 8.7%, respectively, by bulimic patients. RA was rare in both anorexic (1.6%) and bulimic patients (5.4%). The young age of the patients under study was to be considered limiting the life-time prevalence. The study contains epidemiological data on the prevalence of other medical illnesses in ED patients as well as the prevalence of PSD and eating disorders in their families. PMID- 24487106 TI - Affective touch modulates the rubber hand illusion. AB - INTRODUCTION: Humans experience touch as pleasant when this occurs with a certain velocity (1-10cm/s). Affective, pleasant touch is thought to be mediated by a distinct neural pathway consisting of un-myelinated tactile afferents (C tactile fibers) that respond to stroking with a low velocity on the hairy skin. As pleasant touch provides additional information on bodily signals we hypothesized that, compared to regular touch, pleasant touch would have a stronger effect on body ownership as measured through induction of the rubber hand illusion (RHI). METHODS: Two experiments involving the RHI were conducted. In the first experiment, the effects of stroking velocity (3cm/s and 30cm/s) and stroking material (soft/rough) on the RHI were tested. In the second experiment, the effect of an additional stroking velocity (0.3cm/s) and side of stimulation (hairy and glabrous) was examined. RESULTS: The first experiment showed that low velocity stroking in combination with a soft material was not only regarded as most pleasant but also resulted in an enhanced RHI on proprioceptive drift and temperature measurements. In the second experiment, we confirmed that stroking with a velocity of 3cm/s resulted in a larger RHI in terms of proprioceptive drift. In addition, compared to regular touch, pleasant touch of the hairy skin resulted in a larger proprioceptive drift, while similar stroking on the glabrous side of the skin did not induce a stronger effect of RHI on proprioceptive drift. CONCLUSION: Our data suggest that pleasant touch modulates the body representation which is consistently reflected in a larger proprioceptive drift. Our data also suggest that C tactile fibers are likely to be involved in the modulation of body ownership. PMID- 24487109 TI - Implicit memory in multiple sclerosis. AB - A number of neuropsychological studies have revealed that memory problems are relatively common in patients with multiple sclerosis (MS). It may be useful to compare MS with conditions such as Huntington's disease (HD), which have been referred to as subcortical dementia. A characteristic of these conditions may be an impairment in implicit (unconscious) memory, but not in explicit (conscious) memory. The present study examined the functioning of explicit and implicit memory in MS. Results showed that implicit memory was not significantly impaired in the MS subjects, and that they were impaired on recall but not recognition. A correlation was found between implicit memory performance and disability status in MS patients. Findings also suggest the possibility of long-term priming of implicit memory in the control subjects. The implications of these results are discussed. PMID- 24487110 TI - Completion phenomenon in transcortical sensory aphasia. AB - We investigated completion phenomenon for proverbs in cases demonstrating transcortical sensory aphasia due to a variety of diseases. Lack of this completion was exclusively observed in patients with focal atrophy. These patients showed a selective and consistent impairment in word comprehension without phonemic cue effects in naming. The completion phenomenon was present in patients demonstrating transcortical sensory aphasia due to other cerebral diseases. In these patients, comprehension deficits were not selective for words, or words not comprehended were inconsistent and some phonemic cue effects were observed. In a previous study, we reported that completion phenomena for multiplication tables, serial numbers and names of days were frequently noted in patients with focal atrophy. Together with the present findings, these results suggest that lack of proverb completion may be attributed to a selective, systematic and complete loss of the meaning representations for language units such as words and proverbs. In addition, pathological processes of focal atrophy with temporal predominance might selectively affect the semantic memory for language as a unit. PMID- 24487111 TI - Unilateral neglect: the fate of the extinguished visual stimuli. AB - Recent neuropsychological literature has provided evidence for the phenomenon of perception without awareness, also referred to as covert (or implicit) knowledge or tacit awareness. Yet little is known to date about the fate of extinguished stimuli in patients with unilateral spatial neglect. Six right brain-damaged patients with USN and one control subject were presented with single lateralized visual stimuli and with pairs of same or different visual stimuli (one right, one left). A same/different judgement and a multiple choice recognition task were performed on overtly unidentified left-sided stimuli, to unveil possible phenomena of covert knowledge. Some evidence of covert knowledge was observed, and its relation to stimulus characteristics and task demands is discussed. PMID- 24487112 TI - Anxiety and depression in Parkinson's disease. AB - We examined a consecutive series of 40 patients with Parkinson's disease (PD) for the presence of anxiety. We found that 40 % met DSM-III criteria for generalized anxiety disorders, and half of them also met criteria for either major depression or minor depression. While depression was associated with long duration of illness and more severe cognitive and physical impairments, anxiety was not associated with greater impairment. We conclude that anxiety, with or without depression, constitutes a frequent psychiatric problem among patients with PD. PMID- 24487113 TI - Left imaginal neglect in heminattention: experimental study with the O'clock Test. AB - Both sensory and imaginal defects have been reported in unilateral neglect, but their assessment based on the description of famous squares can be difficult in a clinical setting. The O'clock Test is an alternative tool for revealing imaginal defects. Our aim was to demonstrate imaginal neglect in patients with left heminattention. Ten patients were studied and a mild unilateral defect in imaginal processes was found with an increase in the defect when the patients were fatigued. PMID- 24487114 TI - Progressive dysphasic dementia with bucco-facial apraxia: a case report. AB - A patient with progressive dementia, prominent non-fluent aphasia and signs of frontal lobe involvement, was evaluated by neuropsychological testing, magnetic resonance imaging (MRI) and high resolution single photon emission tomography (SPET). The presence of severe bucco-facial apraxia, associated with spared imitation of limb movements, correlated well with a marked reduction of cerebral perfusion in the left fronto-temporal cortex. This case emphasizes the usefulness of SPET as a valuable alternative to PET for the diagnosis of conditions, such as progressive neuropsychological syndromes, where a coupled reduction of metabolism and blood flow can be expected. PMID- 24487115 TI - Dementia reversible by plasmapheresis in multiple myeloma. AB - Although hyperviscosity syndrome may lead to cerebral hypoxia and produce some degree of dementia, this condition is rarely recognized. We report a patient in whom moderate dementia was the only manifestation of a hyperviscosity syndrome due to an IgG-kappa myeloma. Dementia dramatically improved following plasmapheresis. PMID- 24487116 TI - The possible contribution of the amygdala to memory. AB - The processing of episodic memories is believed to depend on the proper functioning of so-called bottleneck structures through which information apparently must pass in order to be stored long term. These regions are seen in the basal forebrain, the medial diencephalon, and the medial temporal lobe. We here report a case with circumscribed bilateral temporal lobe damage, principally involving the amygdaloid area. Neuropsychological investigation demonstrated preserved intelligence, intact general memory and several other undisturbed cognitive functions, but a specific, affect-related, memory disorder. We conclude from these findings that the role of the amygdala is to process mnemonic events in a way that a specific emotional significance can be found and reactivated. Therefore it is suggested that the amygdala is likely to be a bottleneck structure for affect-related long-term memory functions. PMID- 24487118 TI - S-nitrosylation of TRIM72 at cysteine 144 is critical for protection against oxidation-induced protein degradation and cell death. AB - Oxidative stress and membrane damage following myocardial ischemia/reperfusion injury are important contributors to cardiomyocyte death and the loss of myocardial function. Our previous study identified cysteine 144 (C144) of tripartite motif-containing protein 72 (TRIM72) as a potential site for S nitrosylation (SNO). TRIM72 is a cardioprotective membrane repair protein that can be both activated and targeted for degradation by different oxidative modifications. Consistent with the potential regulation of TRIM72 by various oxidative modifications, we found that SNO levels increased at C144 of TRIM72 with ischemic preconditioning. Therefore, to investigate the role of C144 in the regulation of TRIM72 function, we mutated C144 of TRIM72 to a serine residue (TRIM72(C144S)), and expressed either TRIM72(WT) or TRIM72(C144S) in HEK-293 cells, which lack endogenous TRIM72, in order to examine the effect of this mutation on the functional stability of TRIM72 and on cell survival. We hypothesized that SNO of TRIM72 stabilizes the protein, thus allowing for membrane repair and enhanced cell survival. Upon treatment with hydrogen peroxide (H2O2), we found that TRIM72(WT) levels were decreased, but not TRIM72(C144S) and this correlated with increased H2O2-induced cell death in TRIM72(WT) cells. Additionally, we found that treatment with the cardioprotective S-nitrosylating agent S-nitrosoglutathione (GSNO), was able to preserve TRIM72(WT) protein levels and enhance TRIM72(WT)-mediated cell survival, but had no effect on TRIM72(C144S) levels. Consistent with our hypothesis, GSNO was also found to increase SNO levels and inhibit H2O2-induced irreversible oxidation for TRIM72(WT) without affecting TRIM72(C144S). In further support of our hypothesis, GSNO blocked the ischemia/reperfusion-induced decrease in TRIM72 levels and reduced infarct size in a Langendorff-perfused heart model. The results of these studies have important implications for cardioprotection and suggest that SNO of TRIM72 at C144 prevents the oxidation-induced degradation of TRIM72 following oxidative insult, therefore enhancing cardiomyocyte survival. PMID- 24487119 TI - Examining Antisocial Behavioral Antecedents of Juvenile Sexual Offenders and Juvenile Non-Sexual Offenders. AB - In prospective longitudinal studies of juvenile offenders, the presence of multiple developmental pathways of antisocial behaviors has consistently been identified. An "antisocial" type of juvenile sex offender (JSO) has also been identified; however, whether antisocial JSOs follow different antisocial pathways has not been examined. In the current study, differences in antisocial pathways within JSOs and between JSOs and juvenile non-sex offenders (JNSOs) were examined. Data on Canadian male incarcerated adolescent offenders were used to identify whether behavioral antecedents differed within JSOs and between JSOs (n = 51) and JNSOs (n = 94). Using latent class analysis (LCA), three behavioral groups were identified. For both JSOs and JNSOs, there was a Low Antisocial, Overt, and Covert group. Overall, there were important within-group differences in the behavioral patterns of JSOs, but these differences resembled differences in the behavioral patterns of their JNSO counterpart. Risk factors including offense history, abuse history, and family history were more strongly associated with the Overt and Covert groups compared with the Low Antisocial group. Implications for JSO assessment practices were discussed. PMID- 24487120 TI - 6beta-Hydroxycortisol is an endogenous probe for evaluation of drug-drug interactions involving a multispecific renal organic anion transporter, OAT3/SLC22A8, in healthy subjects. AB - 6beta-Hydroxycortisol (6beta-OHF) is a substrate of the organic anion transporter 3 (OAT3) and the multidrug and toxin extrusion proteins MATE1 and MATE-2K in the corresponding cDNA-transfected cells. This study aimed to examine the contribution of OAT3 and MATEs to the urinary excretion of 6beta-OHF in humans using the appropriate in vivo inhibitors, probenecid and pyrimethamine, for OAT3 and MATEs, respectively. Oat3(-/-) mice showed significantly reduced renal clearance of 6beta-OHF (CL(renal, 6beta-OHF)) compared with wild-type mice (18.1 +/- 1.5 versus 7.60 +/- 1.8 ml/min/kg). 6beta-OHF uptake by human kidney slices was inhibited significantly by probenecid to 20-45% of the control values and partly by 1-methyl-4-phenylpyridinium. 6beta-OHF plasma concentration and the amount of 6beta-OHF excreted into the urine (X(6beta-OHF)) were measured in healthy subjects enrolled in drug-drug interaction studies of benzylpenicillin alone or with probenecid (study 1), adefovir alone or with probenecid (study 2), and metformin alone or with pyrimethamine (study 3). Probenecid treatment caused a 57 and 76% increase in the area under the plasma concentration-time curve for 6beta-OHF (AUC(6beta-OHF)) in studies 1 and 2, respectively, but did not affect X(6beta-OHF). Consequently, CL(renal, 6beta-OHF) (milliliters per minute) decreased significantly from 231 +/- 11 to 135 +/- 9 and from 225 +/- 26 to 141 +/- 12 after probenecid administration in studies 1 and 2, respectively. By contrast, neither AUC(6beta-OHF) nor CL(renal, 6beta-OHF) was significantly altered by pyrimethamine administration. Taken together, these data suggest that OAT3 plays a significant role in the urinary excretion of 6beta-OHF, and that 6beta-OHF can be used to investigate the perpetrators of the pharmacokinetic drug interactions involving OAT3 in humans. PMID- 24487121 TI - A pulse artifact removal method considering artifact variations in the simultaneous recording of EEG and fMRI. AB - A simultaneous recording of electroencephalogram (EEG) and functional magnetic resonance imaging (fMRI) can provide high spatiotemporal information of brain activity. However, a proper analysis of the EEG signals is often hindered by various artifacts. In particular, pulse artifact (PA) induced from the heartbeat of a subject interferes with reliable measurements of the EEG signal. A new PA removal method that takes into account the delay variation between the heartbeat and PA and the window size variation in PA is presented in order to improve the detection and suppression of PA in EEG signals. A PA is classified into either a normal PA or a deformed PA. Only normal PAs are averaged to generate a PA template that is used to remove PAs from the measured EEG signals. The performance of the proposed method was evaluated by simulated data and real EEG measurements from epilepsy patients. The results are compared with those from conventional methods. PMID- 24487123 TI - Comparison of in vitro and in vivo bioactivity: cuttlefish-bone-derived hydroxyapatite and synthetic hydroxyapatite granules as a bone graft substitute. AB - Bone reconstruction in clinical settings often requires bone substitutes. Hydroxyapatite (HAp) is a widely used bone substitute due to its osteoconductive properties and bone bonding ability. The aim of this study was to evaluate HAp granules derived from cuttlefish bone (CB-HAp) as a substitute biomaterial for bone grafts. In this study, HAp granules were prepared from raw CB by using a hydrothermal reaction. The formation of HAp from CB was confirmed by scanning electron microscopy and x-ray diffraction analysis. The bioactivity of the CB-HAp granules was evaluated both in vitro and in vivo. Our results show that CB-HAp is non-toxic and that CB-HAp granules supported improved cell adhesion, proliferation and differentiation compared to stoichiometric synthetic HAp granules. Furthermore, in vivo bone defect healing experiments show that the formation of bone with CB-HAp is higher than that with pure HAp. These results show that CB-HAp granules have excellent potential for use as a bone graft material. PMID- 24487122 TI - A critical role of autophagy in antileukemia/lymphoma effects of APO866, an inhibitor of NAD biosynthesis. AB - APO866, an inhibitor of NAD biosynthesis, exhibits potent antitumor properties in various malignancies. Recently, it has been shown that APO866 induces apoptosis and autophagy in human hematological cancer cells, but the role of autophagy in APO866-induced cell death remains unclear. Here, we report studies on the molecular mechanisms underlying APO866-induced cell death with emphasis on autophagy. Treatment of leukemia and lymphoma cells with APO866 induced both autophagy, as evidenced by an increase in autophagosome formation and in SQSTM1/p62 degradation, but also increased caspase activation as revealed by CASP3/caspase 3 cleavage. As an underlying mechanism, APO866-mediated autophagy was found to deplete CAT/catalase, a reactive oxygen species (ROS) scavenger, thus promoting ROS production and cell death. Inhibition of autophagy by ATG5 or ATG7 silencing prevented CAT degradation, ROS production, caspase activation, and APO866-induced cell death. Finally, supplementation with exogenous CAT also abolished APO866 cytotoxic activity. Altogether, our results indicated that autophagy is essential for APO866 cytotoxic activity on cells from hematological malignancies and also indicate an autophagy-dependent CAT degradation, a novel mechanism for APO866-mediated cell killing. Autophagy-modulating approaches could be a new way to enhance the antitumor activity of APO866 and related agents. PMID- 24487124 TI - Potential role of HSP90 in mediating the interactions between estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) signaling pathways. AB - The estrogen receptor (ER) and aryl hydrocarbon receptor (AhR) are ligand activated transcription factors involved in estrogen or xenobiotic exposure, whereas the 90-kDa heat shock protein (HSP90), which is a ubiquitously expressed molecular chaperone, is involved in the signal transduction process. Although the interactions between these pathways have been under investigation, the mechanisms are unclear and the potential role of HSP90 in these interactions has not been reported. The results of goldfish primary hepatocytes showed that exposure to PCB77 and 17beta-estradiol (E2) alone induced significant protein expression of cytochrome P450 1A (CYP1A) and vitellogenin (VTG), respectively. On the other hand, the combined exposure to PCB77 and E2 led to the reduction of CYP1A and VTG compared to the single treatments. Although the AhRs and ERs were naturally induced during the co-treatment, the total amount of HSP90 binding to the receptors was not changed. Furthermore, while the HSP90 chaperon activity was blocked by the specific inhibitor (geldanamycin), reciprocal inhibition between AhR and ER pathways was not observed. These findings indicate a potential role of HSP90 where competition between AhR and ER for binding to HSP90 can occur and cause reciprocal inhibition. PMID- 24487125 TI - Use of fluoroquinolones and third-generation cephalosporins in the emergency department: an 11-year survey. AB - Fluoroquinolones and third-generation cephalosporins are particularly prone to select bacterial resistance to antibiotics. We aimed to assess the temporal trends of antibiotic use in the emergency department adults unit of an academic hospital between 2002 and 2012. Antibiotic use was converted in defined daily doses (DDD). The total antibiotic consumption tended to decrease, from 53.1+/-8.5 to 48.6+/-11.9 DDD/1000 patient visits (estimate decrease per year, -0.9+/-0.5 DDD/1000 visits, P=0.07). Use of third-generation cephalosporins increased significantly, from 9.7% of total antibiotic use to 22.6% (estimate per year, 1.2+/-0.2%, P<0.0001), whereas use of fluoroquinolones decreased from 19.5 to 12.3% (estimate per year, -0.7+/-0.2%, P<0.003). Given their ability to select bacterial resistance, especially extended-spectrum beta-lactamases, particular attention should be paid to increasing use of third-generation cephalosporins in the emergency department. PMID- 24487127 TI - Exertional rhabdomyolysis of the elbow flexor muscles from weight lifting. AB - Ultrasound imaging of rhabdomyolysis previously has been reported in the literature, but differing descriptions of its appearance exist. In this report, we describe a relatively rare case of exertional rhabdomyolysis of the anterior arm muscles. This injury may appear sonographically different than more severe cases of rhabdomyolysis. Our patient was a young, active individual participating in a weight-lifting exercise as part of a physiology laboratory experiment. Ultrasound was helpful to assist in the diagnosis and rule out other conditions. He was treated conservatively and eventually made a complete recovery. PMID- 24487126 TI - Co-registration of multi-modality imaging allows for comprehensive analysis of tumor-induced bone disease. AB - Bone metastases are a clinically significant problem that arises in approximately 70% of metastatic breast cancer patients. Once established in the bone, tumor cells induce changes in the bone microenvironment that lead to bone destruction, pain, and significant morbidity. While much is known about the later stages of bone disease, less is known about the earlier stages or the changes in protein expression in the tumor micro-environment. Due to promising results of combining magnetic resonance imaging (MRI) and Matrix-Assisted Laser Desorption/Ionization Imaging Mass Spectrometry (MALDI IMS) ion images in the brain, we developed methods for applying these modalities to models of tumor-induced bone disease in order to better understand the changes in protein expression that occur within the tumor-bone microenvironment. Specifically, we integrated 3-dimensional-volume reconstructions of spatially resolved MALDI IMS with high-resolution anatomical and diffusion weighted MRI data and histology in an intratibial model of breast tumor-induced bone disease. This approach enables us to analyze proteomic profiles from MALDI IMS data with corresponding in vivo imaging and ex vivo histology data. To the best of our knowledge, this is the first time that these three modalities have been rigorously registered in the bone. The MALDI mass-to charge ratio peaks indicate differential expression of calcyclin, ubiquitin, and other proteins within the tumor cells, while peaks corresponding to hemoglobin A and calgranulin A provided molecular information that aided in the identification of areas rich in red and white blood cells, respectively. This multi-modality approach will allow us to comprehensively understand the bone-tumor microenvironment and thus may allow us to better develop and test approaches for inhibiting bone metastases. PMID- 24487128 TI - Plantar pressures and ground reaction forces during walking of individuals with unilateral transfemoral amputation. AB - OBJECTIVE: To describe and compare the plantar pressures, temporal foot roll over, and ground reaction forces (GRFs) between both limbs of subjects with unilateral transfemoral amputation and with those of able-bodied participants during walking. We also verify the relevance of a force plate and a pressure plate to discriminate changes in gait parameters of subjects with limb loss. DESIGN: Cross-sectional study. SETTING: Biomechanics laboratory. SUBJECTS: A total of 14 subjects with unilateral transfemoral amputation and 21 able-bodied participants. METHODS: We used a force plate and a pressure plate to assess biomechanical gait parameters while the participants were walking at their self selected gait speed. MAIN OUTCOME MEASUREMENTS: We measured plantar pressure peaks in 6 foot regions and the instant of their occurrence (temporal foot roll over); and GRF peaks and impulses of anterior-posterior (braking and propulsive phases), medial-lateral, and vertical (load acceptance and thrust phases) components. RESULTS: The thrust, braking, and propulsive peaks, and the braking and propulsive impulses, were statistically significantly lower in the amputated limb than in the sound limb (P < .05) and in able-bodied participants (P < .05). In the amputated limb, we observed higher pressure peaks in the lateral rearfoot and medial and lateral midfoot, and lower values in the forefoot regions compared to those in the other groups (P < .05). The temporal foot roll-over showed statistically significant differences among the groups (P < .05). CONCLUSIONS: The plantar pressures, temporal foot roll-over, and GRFs in subjects with unilateral transfemoral amputation showed an asymmetric gait pattern, and different values were observed in both of their lower limbs as compared with those of able-bodied subjects during walking. The force plate and pressure plate were able to determine differences between participants in gait pattern, suggesting that both plantar pressure and GRF analyses are useful tools for gait assessment in individuals with unilateral transfemoral amputation. Because of the convenience of pressure plates, their use in the clinical context for prosthetic management appears relevant to guide the rehabilitation of subjects with lower limb amputation. PMID- 24487130 TI - Periodontal ligament versus bone marrow mesenchymal stem cells in combination with Bio-Oss scaffolds for ectopic and in situ bone formation: A comparative study in the rat. AB - The aim of this study was to compare the osteogenic effects of periodontal ligament stem cells (PDLSCs) versus bone marrow mesenchymal stem cells (BMMSCs) in combination with Bio-Oss scaffolds on subcutaneous and critical-size defects in the immunodeficient rat calvarium. PDLSCs and BMMSCs were obtained from the same canine donor. Twenty-four rats were randomly assigned to one of four experimental groups (n = 6 each): group A (no-graft negative control), group B (Bio-Oss positive control), group C (BMMSC/Bio-Oss test group), and group D (PDLSC/Bio-Oss test group). Eight weeks post-transplantation, ectopic and in situ bone regeneration was evaluated by micro-computed tomography (u-CT), histology, histomorphometry, and immunohistochemistry. The stem cell/Bio-Oss constructs were significantly superior to the controls in terms of their ability to promote osteogenesis (p < 0.01), while the PDLSC/Bio-Oss construct tended to be superior to the BMMSC/Bio-Oss construct. Thus, engineered stem cell/Bio-Oss complexes can successfully reconstruct critical-size defects in rats, and PDLSCs and BMMSCs are both suitable as seed cells. PMID- 24487129 TI - Differential localization and high expression of SURVIVIN splice variants in human embryonic stem cells but not in differentiated cells implicate a role for SURVIVIN in pluripotency. AB - The BIRC5 gene encodes the oncofetal protein SURVIVIN, as well as four additional splice variants (DeltaEx3, 2B, 3B and 2alpha). SURVIVIN, an inhibitor of apoptosis, is also a chromosomal passenger protein (CPP). Previous results have demonstrated that SURVIVIN is expressed at high levels in embryonic stem cells and inhibition of SURVIVIN function results in apoptosis, however these studies have not investigated the other four splice variants. In this study, we demonstrate that all variants are expressed at significantly higher levels in human embryonic stem (hES) cells than in differentiated cells. We examined the subcellular localization of the three most highly expressed variants. SURVIVIN displayed canonical CPP localization in mitotic cells and cytoplasmic localization in interphase cells. In contrast, SURVIVIN-DeltaEx3 and SURVIVIN-2B did not localize as a CPP; SURVIVIN-DeltaEx3 was found constitutively in the nucleus while SURVIVIN-2B was distributed along the chromosomes during mitosis and also to the mitotic spindle poles. We used inducible shRNA against SURVIVIN to inhibit expression in a titratable fashion. Using this system, we reduced the mRNA levels of these three variants to approx. 40%, resulting in a concomitant reduction of OCT4 and NANOG mRNA, suggesting a role for the SURVIVIN variants in pluripotency. PMID- 24487131 TI - Carboxyl functionalised MWCNT/polymethyl methacrylate bone cement for orthopaedic applications. AB - The incorporation of carboxyl functionalised multi-walled carbon nanotube (MWCNT COOH) into a leading proprietary grade orthopaedic bone cement (Simplex PTM) at 0.1 wt% has been investigated. Resultant static and fatigue mechanical properties, in addition to thermal and polymerisation properties, have been determined. Significant improvements (p <= 0.001) in bending strength (42%), bending modulus (55%) and fracture toughness (22%) were demonstrated. Fatigue properties were improved (p <= 0.001), with mean number of cycles to failure and fatigue performance index being increased by 64% and 52%, respectively. Thermal necrosis index values at >=44C and >=55C were significantly reduced (p <= 0.001) (28% and 27%) versus the control. Furthermore, the onset of polymerisation increased by 58% (p < 0.001), as did the duration of the polymerisation reaction (52%). Peak energy during polymerisation increased by 672% (p < 0.001). Peak area of polymerisation increased by 116% (p < 0.001) indicating that the incorporation of MWCNT-COOH reduced the rate of polymerisation significantly. A non-significant reduction (8%) in percentage monomer conversion was also recorded. Raman spectroscopy clearly showed that the addition of MWCNT-COOH increased the ratio between normalised intensities of the G-Band and D-Band (IG/ID ), and also increased the theoretical compressive strain (-1.72%) exerted on the MWCNT-COOH by the Simplex PTM cement matrix. Therefore, demonstrating a level of chemical interactivity between the MWCNT-COOH and the Simplex PTM bone cement exists and consequently a more effective mechanism for successful transfer of mechanical load. The extent of homogenous dispersion of the MWCNT-COOH throughout the bone cement was determined using Raman mapping. PMID- 24487132 TI - Editorial farewell. PMID- 24487133 TI - Anatomic and physiological bases of social blushing: speculations from neurology and psychology. AB - Although a common and occasionally troubling reaction, social blushing has received little systematic attention from either medical or behavioral researchers. This article reviews what is known of the physiological and psychological processes that mediate social blushing, and speculates regarding the role of central mechanisms in the phenomenon. Blushing is characterized by the unusual combination of cutaneous vasodilatation of the face, neck, and ears, accompanied by activation of the sympathetic nervous system. Psychologically, blushing appears to occur when people receive undesired social attention from others and may be analogous to the appeasement displays observed in non-human primates. Although poorly understood, the central mechanisms that mediate blushing obviously involve both involuntary autonomic effector systems and higher areas that involve self-reflective thought. Questions for future research are suggested. PMID- 24487134 TI - Cortical activation during a cognitive challenge in patients with chronic temporal lobe epilepsy-a dynamic SPECT study. AB - In a pilot group of six patients suffering from chronic temporal lobe epilepsy, single photon emission computerized tomography (SPECT) has been used to image the changes in relative cerebral blood flow between rest (static scan) and conditions of cognitive activation (activated scan). The cognitive challenge used during activation comprised a test of word memory, and the performance was expressed as a word memory score (WMS) for each individual. An activation index (AI) was calculated from the mean normalized density counts in specific regions of interest (ROIs), and values obtained were analysed for correlation with the WMS. The mean AI was increased significantly in the right lateral temporal cortex, the right and left inferior frontal regions, the left temporal pole, and the right medial temporal cortex. A positive correlation with the WMS was found in the medial temporal cortices, and this relationship was significant for the right medial temporal ROI. PMID- 24487135 TI - Space deficits in Parkinson's disease patients: quantitative or qualitative differences from normal controls? AB - Twenty-seven patients with idiopathic Parkinson's disease (PD) and the same number of normal controls (NCs) were studied on a test battery including five conceptual categories of spatial ability. The two groups of subjects were matched for age, sex, years of education, socioeconomic status and non-verbal (Raven Standard Progressive Matrices) intelligence. A multivariate analysis of variance (MANOVA) showed that the PD patients performed less efficiently on almost all the tasks. A logistic regression analysis (LRA) classified 81.48% of the subjects into the PD group and 92.59% into NC group, indicating that left-right and back front Euclidean orientation, three dimensional mental rotation and visuospatial immediate recognition memory of mirror image patterns discriminate well between the two groups. Application of a structural model (confirmatory factor analysis) demonstrated that both PD patients and the NC group stemmed from a homogeneous population, suggesting that the differences found between the two groups are of a quantitative rather than of a qualitative nature. PMID- 24487136 TI - Sensitivity and specificity of the Mini-Mental State Exam in the diagnosis of dementia. AB - The Mini-Mental State Exam (MMSE) is a brief cognitive test that assesses several cognitive domains, such as orientation, attention, concentration, memory, language, and constructional abilities. While the MMSE was found to be valid and reliable in the diagnosis of moderate dementia, its sensitivity and specificity for the diagnosis of mild dementia has been rarely examined. We assessed the specificity and sensitivity of the MMSE in a consecutive series of 44 patients with mild dementia, and a group of age-comparable normal controls. While the specificity of the MMSE for the diagnosis of mild dementia was very high (100%), the sensitivity was only 55% [20 of the 44 patients with mild dementia had an MMSE score in the normal range (>=26 points)]. On the other hand, the assessment with both the Buschke Selective Reminding and the Boston Naming tests discriminated mild Alzheimer's disease patients with normal MMSE scores from controls with a sensitivity and specificity of 64%. In conclusion, the assessment with verbal memory and naming tasks provided a significantly more sensitive measure of early dementia than the MMSE. PMID- 24487137 TI - Confabulations related to tacit awareness in visual neglect. AB - The case of a man with left-sided visuospatial neglect is reported. His performance on a test for neglect, the "burning house test", is analysed and compared with that of other patients referred to in the literature. We suggest that the confabulations neglect patients may produce when confronted with this test reflect the degree of preconscious awareness for left-sided features. PMID- 24487138 TI - Seizures induced by music. AB - Musicogenic epilepsy is a rare disorder. Much remains to be learned about the electroclinical features. This report describes a patient who has been followed at our institution for 17 years, and was investigated with long-term telemetered simultaneous video-EEG recordings. She began to have seizures at the age of 10 years. She experienced complex partial seizures, often preceded by elementary auditory hallucination and complex auditory illusion. The seizures occurred in relation to singing, listening to music or thinking about music. She also had occasional generalized tonic clonic seizures during sleep. There was no significant antecedent history. The family history was negative for epilepsy. The physical examination was unremarkable. CT and MRI scans of the brain were normal. During long-term simultaneous video-EEG recordings, clinical and electrographic seizure activities were recorded in association with singing and listening to music. Mathematical calculation, copying or viewing geometric patterns and playing the game of chess failed to evoke seizures. PMID- 24487139 TI - Paradoxical akathisia caused by clonazepam, clorazepate and lorazepam in patients with traumatic encephalopathy and seizure disorders: a subtype of benzodiazepine induced disinhibition? AB - Akathisia is frequently reported to be caused by neuroleptic drugs and sometimes by certain other agents such as fluoxetine. Benzodiazepines are a common treatment. The principal mechanism of akathisia is thought to be neurochemical, probably dopaminergic with serotonin also playing an important role. It is not usually thought to be related to benzodiazepine-caused disinhibition. Four episodes of atypical or paradoxical benzodiazepine-induced akathisia in three patients are reported and analyzed. All four episodes of akathisia were atypical because they were caused by clonazepam, clorazepate, or lorazepam. In one patient neither thiothixene nor lorazepam caused akathisia, but clonazepam and clorazepate did. In another patient both lorazepam and fluoxetine caused akathisia. It is also noted that all three patients had a history of traumatic brain injury and seizure disorder. The data support the hypothesis that atypical benzodiazepine-induced akathisia exists. Its mechanism may be different from neuroleptic-induced akathisia, but may still involve serotonergic systems or the forced normalization phenomenon. The similarity of these cases to reports of benzodiazepine-induced disinhibition raises the possibility that in some patients they may be the same entity. PMID- 24487140 TI - Voice recognition impairment in a blind Capgras patient. AB - We report a case of a blind woman, M.N., who experienced the Capgras delusion. She thought that her pet cat had been replaced by a replica which was "ill intentioned" towards her. M.N.'s case shows that the basis of the Capgras delusion cannot lie exclusively in damage to the visual system. However, testing of M.N.'s auditory recognition abilities revealed a deficit in the recognition of familiar voices. This impairment is consistent with the view that the Capgras delusion may arise in connection with damage to recognition mechanisms, and parallels findings of face processing impairments in sighted Capgras patients. PMID- 24487141 TI - Neurobehavioural changes in a patient with bilateral lesions of the globus pallidus. AB - This study has characterized the long-term neurobehavioural changes in a woman who, following the intake of an unidentified substance, sustained subtotal bilateral lesions of the globus pallidus and small lesions at selective sites adjacent to it. Associated with these lesions was a significantly reduced blood flow in multiple frontal cortical regions, most prominently in area 10, the anterior cingulate and the supplementary motor cortex. Her cognitive deficits were generally consistent with those found in patients with frontal lobe dysfunction but some deficits, i.e. in visual memory and learning, were more compatible with temporal lobe dysfunction. Incapacitating personality or obsessive compulsive changes as reported by others with similar lesions were absent and she could live independently. The cognitive changes are consistent with the view that the globus pallidus has important functions in mediating how internal representations of stimulus input are converted into various forms of action, for example, in planning solutions to problems and in working memory. PMID- 24487142 TI - Progressive decline of semantic memory with preservation of number processing and calculation. AB - A 75-year-old man with seven years of formal education displayed a syndrome of progressive and severe lexical impairments to word comprehension and production (semantic dementia). While he lost the ability to recognize written arithmetical signs, he could still retrieve the arithmetical facts for addition and subtraction of all number combinations of 1 to 9 and 11 to 19, though his mastery of multiplication tables (2 to 9) was unreliable. Calculation procedures were intact. Over the course of 18 months the components of the calculation system dissolved selectively: arithmetical procedures and number reading were spared, despite increasing damage to the arithmetic fact store. He retained the ability to read the time on analogue clocks. Selective preservation of components of the calculation system in the context of severe language deficits and dementia, supports the independent status of numerical abilities. The dissociation between intact arithmetical procedures and impaired table fact retrieval was paralleled by a dissociation between preserved procedures of phonology and syntax of language and impaired retrieval of content words, suggesting that the core deficit was a degradation of the central semantic store of learned knowledge of both words and arithmetic table facts. PMID- 24487143 TI - Schizophrenia and atypical motor features in a case of progressive supranuclear palsy (the Steele-Richardson-Olszewski syndrome). AB - Mental manifestations are characteristic of the syndrome described by Steele, Richardson, and Olszewski as progressive supranuclear palsy (SRO). Discussions emphasize cognitive aspects, namely the "subcortical dementia" for which the disease is prototypical, but personality change has been mentioned beginning with the earliest accounts. Psychosis has been virtually absent from neuropsychiatric descriptions, perhaps curiously so in view of the association between subcortical disease and delusions. We report here a case of autopsy-proven SRO in which a schizophrenia-like psychosis was a central feature. PMID- 24487145 TI - Disconnection Syndrome and Verbal, Spatial and Tactile Amnesia following a Tumor of the Splenium of the Corpus Callosum. AB - A patient with a severe amnesic syndrome following a glioma of the splenium of the corpus callosum is reported. The long-term memory deficit involved anterograde as well as retrograde events dating back to 40 years and causing topographical disorientation. Short-term memory test performance was in the normal range, with the exception of tactile memory which was severely impaired.The patient also showed disconnection symptoms, due to severing of occipito-parietal and parieto-temporal connections, while parieto-parietal connections were undamaged. PMID- 24487146 TI - Varieties of Pathological Self-mutilation. AB - Pathological self-mutilation appears as a non-specific symptom as well as a specific syndrome. Since psychotic persons may commit horrifying acts, such as enucleation of an eye or amputation of a body part, identification of high risk patients is crucial. Stereotypical self-mutilation, such as head banging and biting off of fingertips, is associated with mental retardation and with the syndromes of Lesch-Nyhan, deLange, and Tourette. This type of self-mutilation is the focus of biological research or endorphins and on dopamine receptors. Skin cutting and burning, the most common type of self-mutilation, is often associated with personality disorders, post-traumatic stress disorder, and multiple personality disorder. When cutting and burning become established as responses to disturbing psychological symptoms on environmental events, a specific Axis I impulse disorder known as Repetitive Self Mutilation may be diagnosed. Patients with this newly identified syndrome may alternate their direct acts of self mutilation with eating disorders and episodic alcoholism. PMID- 24487147 TI - Cerebellar structures and the programming of movement sequences. AB - Two patients with unilateral damage to the medial and lateral cerebellum were examined to determine whether local structures in the cerebellum are used to execute programmed movement sequences. Both patients performed a sequential tapping task which required the execution of either a single keystroke or of a sequence of three keystrokes. Movements executed with the contralateral hand showed increases in response onset times as the movement sequence increased from one to three response elements (sequence length effect). Furthermore, noninitial response elements were executed considerably faster than sequence initial responses (position effect). Movements executed with the ipsilateral hand showed a different pattern of results. Damage to medial cerebellar structure had no qualifying effect but damage to the lateral cerebellar structure eliminated effects of sequence length and of response position. The results suggest that the lateral cerebellum is implicated in the execution of programmed manual movement sequences. PMID- 24487148 TI - Tics. AB - Tics are an incontinent form of non-verbal communication associated with obsessional and aggressive urges and anxiety. The motor phenomena seen in socially acceptable forms of emotional release are compared and contrasted with tics. It is proposed that brain dysfunction in Gilles de la Tourette syndrome involves frontal limbic and basal ganglia loops. PMID- 24487149 TI - The categorical organization of semantic and lexical knowledge in the brain. AB - In recent years several papers have shown that different verbal and non-verbal semantic categories can be selectively disrupted by brain damage and that consistent anatomical localizations correspond to each category-specific semantic disorder.This paper aims to suggest that the brain regions typically damaged in a given type of category-specific semantic disorder might be critically involved in processing the kind of information which mainly contributes to organizing that semantic category and to distinguishing among its members.This general hypothesis is discussed taking into account: (a) comprehension and production of object names (nouns) and of action names (verbs) in agrammatic and in anomic aphasic patients; (b) verbal and non-verbal identification of body parts; (c) verbal and non-verbal identification of living beings and of man made artefacts. PMID- 24487150 TI - Body concept, disability, and depression in patients with spasmodic torticollis. AB - Eighty-five patients with idiopathic spasmodic torticollis were compared with an equally chronic group of 49 cervical spondylosis sufferers in terms of body concept, depression, and disability. The torticollis patients were significantly more depressed and disabled and had a more negative body concept. Depression had different determinants in the two groups. Extent of disfigurement was a major predictor of depression in torticollis. Neuroticism accounted for the greatest proportion of the variance of depression in cervical spondylosis. PMID- 24487151 TI - Comparison of the long-term results of Roux-en-Y gastric bypass and sleeve gastrectomy for morbid obesity: a systematic review and meta-analysis of randomized and nonrandomized trials. AB - PURPOSE: Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are 2 of the most widely used bariatric procedures today, in this meta-analysis, both techniques were compared for evaluating the efficacy and safety of the treatment of morbid obesity. MATERIALS AND METHODS: Systematic literature search of Cochrane Controlled Trials Register Databases, Medline, Embase, ISI databases, and Chinese Biomedical Literature Database was performed. Statistical analyses were carried out using RevMan software. RESULTS: Thirty-two recent studies including 6526 patients in total were included in this meta-analysis. Compared with SG, RYGB had significantly better effect in resolving type 2 diabetes mellitus, hypertension, hypercholesterolemia, gastroesophageal reflux disease, and arthritis. However, RYGB had higher incidence of complications and reoperation, and longer operation time than SG. CONCLUSIONS: RYGB was more effective than SG in the resolution of obesity-related comorbidities, SG was a safer procedure with a reduced rate of complications and reoperation. PMID- 24487152 TI - Single-port laparoscopic appendectomy versus conventional laparoscopic appendectomy: evidence from randomized controlled trials and nonrandomized comparative studies. AB - BACKGROUND: Single-port laparoscopic appendectomy (SPLA) has gained widespread acceptance and is increasingly performed. The evidence assessing the safety and efficacy of SPLA compared with conventional laparoscopic appendectomy (CLA) is growing; however, very few randomized trials exist and individual studies often have small patient numbers with varying results. We integrated the available data to enhance the current literature by comparing these techniques. METHODS: A systematic review of the literature was performed to identify studies comparing SPLA and CLA. Operative parameters, postoperative outcomes, and postoperative complications were evaluated. Meta-analysis was performed using Review Manage Version 5.0 software. RESULTS: Fifteen studies matched the selection criteria, including 1560 patients (46.1% SPLA, 53.9% CLA). SPLA was associated with longer operative time compared with CLA procedure (P=0.001). There were no significant statistical differences between the SPLA and CLA groups in terms of postoperative outcomes including postoperative visual analog scale pain scores (P=0.12), time to return to diet (P=0.45), time to flatus (P=0.89), leukocyte count (P=0.86) and C-reactive protein level (P=0.70) evaluation after operation, cosmetic satisfaction level (P=0.95), and length of hospital stay (P=0.16). The overall complication rates were not significantly different between the 2 groups (P=0.44). There was no evidence to suggest heterogeneity of trial results. CONCLUSIONS: SPLA shows no benefit over CLA, including even parameters such as postoperative pain and cosmetic results, and, therefore, there is no indication to use this approach over standard laparoscopic appendectomy. SPLA does take longer to perform. Further studies are needed to confirm that the procedure is more costly. PMID- 24487153 TI - Laparoscopic approach for Wilms tumor. AB - INTRODUCTION: Traditionally, radical nephrectomy for Wilms tumor has been performed through an open approach. Advances in minimally invasive surgery have led to the application of these techniques to malignant lesions, including Wilms tumor. We aim to present our experience with laparoscopic nephrectomy (LN) for Wilms tumor. PATIENTS AND METHODS: Four patients with Wilms tumor were treated preoperatively with chemotherapy and afterwards underwent an LN and lymph node sampling. Four ports were placed and the tumors were removed without morcellation in an endoscopic bag through an incision by extending the umbilical or the suprapubic port site. RESULTS: The average age at the time of surgery was 3 years and 7 months (range, 23 mo to 6 y). There were no intraoperative complications and the blood loss was minimal in all cases. The mean operative time was 125 minutes (range, 90 to 160 min). Among our patients, we had 2 stage IV and 2 stage I cases. The mean time of hospitalization was 3 days (range, 2 to 4 d). There were no long-term complications at the mean follow-up of 3 years and 6 months. CONCLUSIONS: LN for Wilms tumor may be considered as an option in selected patients. Minimally invasive surgery allows the surgeon to follow all the oncologic principles required for surgical treatment of this neoplasm and provides the advantages of these techniques for cancer patients. Preoperative chemotherapy is essential to decrease tumor size and facilitate the dissection avoiding tumor rupture. PMID- 24487154 TI - Bibliometric analysis of scientific contributions in minimally invasive general surgery. AB - Publication of scientific articles in peer-reviewed medical journals is considered as a measure of research productivity. The aim of the present study was to quantify the research contributions of different countries in minimally invasive surgery and to critically discuss the results under the prism of recent socioeconomic developments. The electronical archives of 4 major surgical journals (Annals of Surgery, British Journal of Surgery, Journal of the American College of Surgeons, and Surgical Endoscopy) were searched between 2009 and 2012. Publications on minimally invasive general surgery were assessed according to the country. A total of 6595 records were identified; 2160 articles were related to minimally invasive surgery. The volume of publication activity was evenly distributed in North America (34%) and Europe (39%). The United States (31%), the United Kingdom (7.6%), and Japan (6.7%) were the most productive countries. When adjusted for country population, the Netherlands (7.7/10), Denmark (4.4/10), and Switzerland (4.1/10) occupied the highest ranks. Although the United States dominates in terms of absolute number of publications, several smaller countries were more prolific, when the number of inhabitants was taken into account. The recent financial crisis is expected to undermine international collaborative conditions in the field of minimally invasive surgery. The need for a stepped-up international scientific collaboration is hereto highlighted. PMID- 24487155 TI - How to improve the efficacy of endoscopic ultrasound-guided celiac plexus neurolysis in pain management in patients with pancreatic cancer: analysis in a single center. AB - Visceral pain secondary to pancreatic cancer is often difficult to control and poses a challenge to the physician. We retrospectively analyzed the efficacy and safety of endoscopic ultrasound-guided celiac plexus neurolysis (EUS-CPN) in patients with unresectable pancreatic cancer. Forty-one patients with severe pain despite treatment with opioids underwent EUS-CPN with absolute alcohol. Patients scored their pain on a scale of 0 to 10 and were interviewed after the procedure. Of the 41 patients, 33, 37, and 25 patients reported improvement in their pain within 3 days, at 1 week, and at 3 months, respectively, following the procedure. Of all the patients, 19 patients reported substantial improvement and 4 patients showed complete disappearance of pain. Complication appeared in 2 patients with transient hypotension. In our study, EUS-CPN is a safe and effective form of treatment for intractable pain secondary to advanced pancreatic cancer. PMID- 24487156 TI - The effects of transoral incisionless fundoplication on chronic GERD patients: 12 month prospective multicenter experience. AB - PURPOSE: This study aimed to assess the impact of transoral incisionless fundoplication (TIF) on patients with chronic gastroesophageal reflux disease (GERD) at 12-month follow-up. METHODS: Clinical outcomes of 100 consecutive patients with chronic GERD who underwent TIF between January 2010 and February 2011 were analyzed. RESULTS: There were no major complications reported. Esophageal acid exposure was normalized in 14/27 (52%) of patients who underwent 12-month pH testing. Seventy-four percent of all patients were off proton pump inhibitors versus 92% on daily proton pump inhibitors before TIF, P<0.001. Daily bothersome heartburn and regurgitation symptoms were eliminated in 66/85 (78%) and 48/58 (83%) of patients. Median reflux symptom index score was reduced from 20 (0 to 41) to 5 (0 to 44), P<0.001. Two patients reported de novo dysphagia and 1 patient reported bloating (scores 0 to 3). Six patients underwent revision; 5 laparoscopic Nissen fundoplication and 1 TIF. CONCLUSIONS: TIF provided a safe and effective therapeutic option for carefully selected patients with chronic GERD. PMID- 24487157 TI - Laparoscopic splenectomy 15 years after. AB - OBJECTIVE: The authors aim to analyze the impact of spleen size on the operative time, the splenic weight, the surgical technique, and the immediate clinical outcome in a series of 116 laparoscopic splenectomies (LS) performed in our department in the last 15 years. This study was also aimed to evaluate the efficacy of hand-assisted LS for splenomegaly. MATERIALS AND METHODS: From July 1995 to January 2010, 116 LS were performed. In all the procedures, the 3- or 4 trocar lateral approach was used. The mean indication for surgery was hematologic diseases. RESULTS: Of the 116 patients (69 females, mean age 41.7), the average weight of the spleens removed was about 450 g. The mean operative time was 100 minutes. Five patients underwent conversion. The mean duration of postoperative hospitalization was 4 days. No long-term complications were reported. Postoperative complications were reported in 3.5% of the cases. CONCLUSIONS: The laparoscopic approach is safe and effective, with a shorter hospital stay and improved morbidity and mortality. LS may be considered as an acceptable indication even in cases of massive splenomegaly, and hand-assisted LS could be considered as a viable alternative to open surgery in patients with massive spleens. PMID- 24487158 TI - Soft-light overhead illumination systems improve laparoscopic task performance. AB - PURPOSE: The aim of this study was to evaluate the impact of attached shadow cues for laparoscopic task performance. METHODS: We developed a soft-light overhead illumination system (SOIS) that produced attached shadows on objects. We compared results using the SOIS with those using a conventional illumination system with regard to laparoscopic experience and laparoscope-to-target distances (LTDs). Forty-two medical students and 23 surgeons participated in the study. A peg transfer task (LTD, 120 mm) for students and surgeons, and a suture removal task (LTD, 30 mm) for students were performed. Illumination systems were randomly assigned to each task. Endpoints were: total number of peg transfers; percentage of peg-dropping errors; and total execution time for suture removal. After the task, participants filled out a questionnaire on their preference for a particular illumination system. RESULTS: Total number of peg transfers was greater with the SOIS for both students and surgeons. Percentage of peg-dropping errors for surgeons was lower with the SOIS. Total execution time for suture removal was shorter with the SOIS. Forty-five participants (69% in total) evaluated the SOIS for easier task performance. CONCLUSIONS: The present results confirm that the SOIS improves laparoscopic task performance, regardless of previous laparoscopic experience or LTD. PMID- 24487159 TI - Early rise in C-reactive protein is a marker for infective complications in laparoscopic colorectal surgery. AB - INTRODUCTION: Infective complications are the most significant cause of morbidity associated with elective colorectal surgery. It can sometimes be difficult to differentiate complications from the normal postoperative course. C-reactive protein (CRP) is an acute phase reactant which has been reported to be predictive of postoperative infective complications. METHODS: Between July 2010 and June 2012, 169 patients underwent elective laparoscopic colorectal surgery. Daily postoperative CRP was measured until discharge and infective complications were observed. RESULTS: A total of 169 patients underwent laparoscopic colorectal surgery. Twenty-one (12.4%) had infective complications, 6 (3.6%) had anastomotic leaks. There was a significant difference in CRP levels between those with infective complications and those without infective complications on postoperative days 3 and 5 (day 3 postop, P=0.0001; day 5 postop, P=0.0001). Of those with infective complications, there was a significant difference between CRP levels when comparing preoperative levels with those on day 3 and day 5 (preoperative vs. day 3, P=0.0001; preoperative vs. day 5, P=0.0003). A raised CRP is a predictor of infective complication from day 3 (odds ratio 1.012, P<0.001) where as white cell count is not an accurate predictor. A CRP cutoff of 148 on day 3 provided the highest sensitivity and specificity of predicting infective complications, 86% and 77%, respectively. CONCLUSIONS: CRP is effective as an early predictor of infective complications after laparoscopic colorectal surgery and may be a useful adjunct in conjunction with an enhanced recovery program in reducing morbidity. A CRP of >148 mg/mL on postoperative day 3 or a persistently elevated CRP should heighten clinical suspicion of an infective complication. PMID- 24487160 TI - Comparison of outcomes after laparoscopic versus posterior retroperitoneoscopic adrenalectomy: a pilot study. AB - BACKGROUND: Posterior retroperitoneoscopic adrenalectomy (PRA) was popularized by Walz and colleagues as an alternative approach to minimally invasive adrenalectomy, offering less postoperative pain and faster return to normal activity compared with laparoscopic transperitoneal adrenalectomy (LA). The authors have recently changed from LA to PRA in suitable patients and audited their outcomes. METHODS: Data were prospectively collected for 10 patients who underwent PRA, and a chart review and telephone interviews were conducted with 13 consecutive patients who underwent LA by the same surgeon. Patient demographics, tumor characteristics, analgesia use, operative and anesthetic time, length of stay, and complications were recorded. RESULTS: Data were collected for 13 LAs and 10 PRAs. Patients' baseline characteristics, including age, BMI, and tumor size, were similar between the 2 groups. There were no conversions to open surgery, transfusions, or deaths. Operative time was similar between the 2 groups. PRA patients required less, inpatient postoperative opioid analgesia compared with LA patients (median 1.25 vs. 23 mg of intravenous morphine equivalent, P=0.003), and had a shorter length of stay (median 1 vs. 2 d, P<0.001). The median total days on opioids were lower for PRA patients compared with LA patients (0.5 vs. 9 d, P<0.001). CONCLUSION: Our initial results supports previously published findings that PRA is a safe procedure, with a relatively short learning curve, resulting in reduced postoperative analgesia use, and reduced length of hospital stay when compared with the laparoscopic transperitoneal approach. PMID- 24487161 TI - Central neck dissection using a bilateral axillo-breast approach for robotic thyroidectomy: comparison with conventional open procedure after propensity score matching. AB - BACKGROUND: Despite advancements in surgical robot technology, the da Vinci assisted central neck dissection (CND) in thyroid cancer remains challenging. The aim of this study is to evaluate the feasibility of robotic thyroidectomy and CND. METHODS: Between March 2011 and July 2012, 515 consecutive patients who had undergone thyroidectomy and CND for papillary thyroid carcinoma were retrospectively reviewed. A thyroid surgeon performed either an open thyroidectomy and CND (n=392) or a robotic thyroidectomy and CND (n=123) using the bilateral axillo-breast approach (BABA). Propensity score matching using 10 clinicopathologic factors was used to generate 2 matched cohorts, each composed of 123 patients. RESULTS: Mean age, body mass index, and tumor size were lower in those who underwent BABA compared with an open procedure before propensity matching. Evaluation of stimulated thyroglobulin levels did not show significant differences between the 2 groups. After cohort matching, significant differences in age, body mass index, and tumor size between the 2 groups were no longer present. The matched cohort showed that the number of retrieved lymph nodes was lower in the BABA (8.74+/-5.13) than in the open thyroidectomy (10.71+/-6.68) (P=0.006). CONCLUSIONS: BABA robotic thyroidectomy revealed that a less-extensive CND was obtained when compared with an open procedure. BABA may be suitable for thyroid cancer without lymphadenopathy in central neck compartment. Conversely, BABA should not be recommended to a patient with thyroid cancer when multiple lymph node metastases in the lower central neck compartment are suspected. PMID- 24487162 TI - Meta-analysis of complications of colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction. AB - BACKGROUND: Left-sided malignant colonic obstruction is one of the most difficult clinical problems, whereas both emergency operations and colonic stenting may have their own advantages and disadvantages. The purpose of this study was to evaluate the complications of colonic stenting versus emergency surgery for acute left-sided malignant colonic obstruction. MATERIALS AND METHODS: Medline, Embase, and the Cochrane Library were searched. Only prospective randomized controlled trials that compared the 2 methods were included. Evaluation indexes in our study involved hospital death rates and complications. RESULTS: No significant difference in either hospital death rates or the overall complications between the 2 groups was found. Heterogeneity analysis found that there was no significant heterogeneity. Removing individual studies from the data editor did not substantially change the RR or the level of heterogeneity of significance for our 2 outcome measures. Testing for publication bias showed that hospital death rates and the overall complications had no serious publication bias. CONCLUSIONS: Colonic stenting was no better than emergency surgery, and should be only used as an alternative to emergency surgery carefully. PMID- 24487163 TI - The risk of arteriovenous fistula formation after en bloc stapling of the renal hilum during transperitoneal laparoscopic nephrectomies. AB - Our aim was to evaluate the risk of arteriovenous fistula (AVF) formation after en bloc stapling of the renal hilum during transperitoneal laparoscopic nephrectomies (LNs). A retrospective review of 35 laparoscopic simple or radical nephrectomies or LNs was carried out. Patients were clinically followed up for renal hilar AVF formation, which could lead to new onset diastolic hypertension, abdominal murmur, and congestive heart failure. In addition, abdominal computed tomography and arteriography were carried out to diagnose renal hilar AVF formation during 6 to 20 months' follow-up. No statistically significant differences were measured between the systolic and the diastolic blood pressures between the preoperative and the postoperative periods (P>0.005). Abdominal murmur and new-onset congestive heart failure were not detected in any of the patients on physical examination. Our results suggest that en bloc stapling of the renal hilum during LN procedures is safe and effective. PMID- 24487164 TI - Feasibility and outcomes of surgical therapy in very elderly patients with colorectal cancer. AB - PURPOSE: Short-term and midterm outcomes of surgery remain unclear in very elderly patients (>=85 y) with colorectal cancer. This study was designed to clarify the safety and therapeutic usefulness of surgery for colorectal cancer in this subgroup of patients. We compared postoperative short-term and midterm outcomes between laparoscopic surgery and open surgery to evaluate the feasibility of laparoscopic surgery in very elderly patients. MATERIALS AND METHODS: The study group comprised 80 patients [38 men (48%) and 42 women (52%)] aged 85 years or older who had colorectal cancer and were treated in our department from 1987 to 2010. The mean age was 87.3+/-2.3 years, and the median follow-up was 45 months (range, 4 to 252 mo). Sixty-nine patients (86%) were 85 to 89 years old, and 11 (14%) were aged 90 years or older. The American Society of Anesthesiologists' (ASA) risk class was I in 2 patients (2%), II in 44 (55%), and III in 34 (43%). Open surgery was performed in 46 patients (58%), and laparoscopic surgery was performed in 34 patients (42%). RESULTS: The ASA risk class was II or III in 78 patients (98%). Postoperative complications occurred in 21 patients (26%), including ileus in 8 patients (10%), wound infection in 7 (9%), and anastomotic leakage in 3 (4%). As compared with open surgery, laparoscopic surgery had significantly lower intraoperative blood loss (P<0.0001) and a significantly shorter postoperative hospital stay (P=0.0001) but required a significantly longer operation time (P=0.0017). Clinicopathologically, laparoscopic surgery was associated with a significantly smaller tumor size (P=0.0371), significantly fewer dissected lymph nodes (P=0.0181), and significantly fewer patients with stage II or III disease (P=0.0090). Postoperative complications occurred in 14 patients (30%) in the open surgery group and 6 (18%) in the laparoscopic surgery group, but this difference was not significant. As for midterm outcomes, the disease-free survival rate and the overall survival rate were, respectively, 90.9% and 100% in stage I disease, 89.7% and 100% in stage II disease, and 68.4% and 75.9% in stage III disease. CONCLUSIONS: Colorectal surgery was safe, therapeutically useful, and had good short-term and midterm outcomes in very elderly patients with colorectal cancer. As compared with open surgery, laparoscopic surgery was associated with lower intraoperative blood loss and a shorter postoperative hospital stay. These results suggest that laparoscopic surgery is suitable for very elderly patients with colorectal cancer because it is less invasive than open surgery. PMID- 24487165 TI - Technique and outcomes of laparoscopic-combined linear stapler and hand-sutured side-to-side esophagojejunostomy with Roux-en-Y reconstruction as a treatment modality in patients undergoing proximal gastrectomy for benign and malignant disease of the gastroesophageal junction. AB - BACKGROUND: Circular stapler and hand-sutured esophagojejunostomy has been the most popular technique utilized in patients undergoing proximal gastrectomy through Roux-en-Y reconstruction for disease processes of the gastroesophageal junction. In recent years, with the advent of laparoscopic bariatric surgical techniques and refined linear stapler cutters, surgeons have developed the linear stapler side-to-side technique as a valid option. The aim of this study is to describe our technique and review the outcomes using the Roux-en-Y reconstruction with linear staplers after laparoscopic proximal gastrectomy for malignant and benign disease. METHODS: After Internal Review Board approval and with adherence to the Health Insurance Portability and Accountability Act guidelines, a retrospective review of a prospectively collected database was conducted. A total of 14 patients underwent proximal laparoscopic gastric resection at our institution during a 3-year period from January 2008 to January 2011. Sex, body mass index, prior surgeries, complications of the prior surgery, intraoperative complications, pathologic findings, postoperative complications, hospital stay, and outpatient follow-up were measured in the preoperative and postoperative period. RESULTS: Our patient population consisted of 9 women and 5 men, with a mean age and body mass index of 45.42 years and 35.64 kg/m, respectively. Indications for proximal gastrectomy was in 4 patients a leak at the angle of His secondary to sleeve gastrectomy for morbid obesity, 1 patient was a stricture after a vertical banded gastroplasty, 1 patient a revision of a eroded gastric band, 1 patient a revision of a eroded mesh secondary to a hiatal hernia repair, 1 patient a conversion of a failed Nissen, 3 patients had a total gastrectomy due to a stage 2 gastric cancer, and 1 patient a gastrointestinal stromal tumor. There were no intraoperative complications. All the procedures were completed laparoscopically. The mean operative time was 137.16 minutes. The mean hospital stay was 7.6 days. One patient had a postoperative stricture at the esophagojejunal anastomosis that required multiple dilatations. All patients with gastric cancer are free of tumor recurrence. CONCLUSION: The use of a laparoscopic proximal gastrectomy with Roux-en-Y reconstruction through combined side-to-side linear stapler and hand-sewn esophagojejunal anastomosis seems to be a feasible and safe approach. PMID- 24487166 TI - Safety of Veress needle insertion in laparoscopic bariatric surgery. AB - BACKGROUND: Creating the pneumoperitoneum is the first surgical procedure in laparoscopic abdominal surgery. Morbid obesity is a risk factor for iatrogenic injuries because of the considerable thickness of the abdominal wall. The aim of this study was to assess the feasibility and the incidence of complications when using Veress needles (VN) in obese patients undergoing bariatric surgery. METHODS: Between March 2004 and December 2010, a retrospective analysis was performed on 139 obese patients (mean body mass index=45.94 kg/m). Blind VN insertion followed by optical trocar insertion was the most widely used technique. RESULTS: Of the 139 patients, VN was successfully used in 138 cases (99.28%), and in 1 patient the procedure failed and an open laparoscopy was performed (0.72%). During the study period, there were 63 gastric bypasses, 18 sleeve gastrectomies, 50 gastric bandings, and 8 reoperations. The VN was inserted in the left upper quadrant in 46 cases and in the midline above the umbilicus in 93 cases. A colonic perforation after VN insertion at the left upper quadrant occurred. The overall rate of complications was 0.72%. There were no access-related complications when VN was inserted above the umbilicus; complication rate was 2.17% at upper left quadrant VN placement. No cases of subcutaneous emphysema or extraperitoneal insufflation were observed. CONCLUSIONS: In our experience, the success rate was 98.28% and the overall rate of complications was 0.72%. The VN technique can be considered feasible and safe even when used in obese population. PMID- 24487167 TI - Needle-knife fistulotomy with percutaneous transhepatic cholangioscopy for managing complete bilioenteric anastomosis occlusion. AB - Untreated benign biliary stricture can lead to serious complications including recurrent cholangitis, biliary cirrhosis, hepatic failure, and death. Benign stricture of a postoperative anastomosis site is also a problematic issue after biliary surgery. Percutaneous transhepatic cholangioscopy (PTCS) with balloon dilatation is a recently introduced noninvasive therapeutic option for biliary stricture. Guidewire insertion through the stricture site is essential for the success of PTCS treatment. Recently, we treated a difficult case with complete bilioenteric anastomosis stricture that failed to allow passage of the guidewire for balloon dilation. The stricture was treated with artificial bilioenteric fistula using a needle-knife papillotome during the PTCS. PMID- 24487168 TI - Usefulness of moistening seprafilm before use in laparoscopic surgery. AB - PURPOSE: Seprafilm is an ideal synthetic adhesion barrier, but its insertion into the abdomen in laparoscopic surgery is difficult because of its stiff and brittle nature. We tested the usefulness of a novel technique of moistening Seprafilm before use to increase its flexibility before insertion through a trocar during laparoscopic surgery. METHODS: Laparoscopic pelvic surgeries that were followed by insertion of Seprafilm were evaluated in 67 women. A piece of Seprafilm (1/6 or 1/4 the size of a full sheet) was placed on gauze moistened with saline solution to soften it. The prepared piece was then rolled, inserted with forceps through a 12-mm trocar port, and placed at the intended site. RESULTS: A total of 245 pieces of Seprafilm sheets were pretreated and inserted using a 12-mm trocar port with a success rate of 100% and placed correctly with a success rate of 80.0% (196 of the 245 pieces). The mean total time required for placement of all pieces per surgery was 601+/-248 seconds. CONCLUSIONS: This is a simple and effective technique that enables the film to be applied securely without breaking and without the need for special equipment. PMID- 24487169 TI - Laparoscopic frey procedure for chronic pancreatitis. AB - BACKGROUND: Chronic pancreatitis can be relentless, resulting in debilitating pain and endocrine and exocrine insufficiency. Medical interventions are used initially but when these fail, surgical therapy is often indicated. Surgical options include resection, drainage, and hybrid procedures. Hybrid procedures, such as the Frey procedure are associated with improved outcomes in select patients. These advantages are even greater when the Frey is performed laparoscopically. METHODS: A patient with chronic pancreatitis was referred to our clinic. Preoperative imaging revealed a dilated main pancreatic duct with multiple large pancreatic duct stones. She subsequently underwent a laparoscopic Frey procedure. RESULTS: The patient did very well with no pancreatic leak, wound infection, or delayed gastric emptying. She was discharged home on postoperative day 6, symptom free with no narcotic requirement. CONCLUSIONS: For patients in whom the laparoscopic Frey procedure is possible, it can be used to treat chronic pancreatitis with the benefits of a minimally invasive approach. PMID- 24487170 TI - Predictors of conversion in laparoscopic-assisted colectomy for colorectal cancer and clinical outcomes. AB - This study investigated risk factors and impact of open conversion on outcomes of 207 consecutive patients who had laparoscopic resection of colorectal cancer at our institution. Conversion occurred in 15.9% of patients, mostly because of invasion to adjacent structures (30.3%), bulky tumor (21.2%), and adhesions (18.2%). Converted patients had significant larger tumor size, advanced stage, increased operative blood loss, time to walk independently, prolonged hospital stay, number of massive hemorrhage, ileus, anastomotic hemorrhage, abdominal hemorrhage, peritonitis/septic shock, and wound infection than completed laparoscopy patients. Factors associated with conversion were obesity [relative risk (RR)=6.92; 95% confidence interval (CI), 1.7-28.09], date of operation (RR=0.37; 95% CI, 0.15-0.95), advanced tumor stage (RR=7.67; 95% CI; 1.19-49.2), size (RR=1.97; 95% CI, 1.42-2.72), and rectum location (RR=2.73; 95% CI, 1.09 6.84). Converted patients had worse cumulative disease-free (P<0.001) and overall survival (P<0.001) than laparoscopic completed patients. PMID- 24487171 TI - Late reoperation for retained gallstone after laparoscopic cholecystectomy. AB - Complications due to retained gallstones after a laparoscopic cholecystectomy occur in 1.7 per 1000 cases. Significant delay to definitive diagnosis and treatment is common due to late presentation and nonspecific symptoms. Despite the low frequency, complications due to retained gallstones may be serious, including abscess and fistula formation. In the present case, we discuss the removal of abdominal wall and peritoneal stones 8 months after the original laparoscopic cholecystectomy. The case illustrates that complications may arise months to years after the original procedure and requires a high degree of clinical suspicion for expeditious diagnosis. Ultrasound is a sensitive and specific test to identify retained stones. Laparoscopic retrieval is recommended upon identification of intraperitoneal stones within this timeline. PMID- 24487172 TI - Pediatric robotic pyeloplasty in patients weighing less than 10 kg initial experience. AB - AIM: To report the feasibility and safety of a robotic-assisted laparoscopic pyeloplasty (RALP) in patients weighing <10 kg. MATERIALS AND METHODS: Three patients weighing between 5 and 8 kg who were affected by severe congenital ureteropelvic junction obstruction, including a child with solitary kidney, were subjected to RALP. Three trocars were placed; sutures and pyeloplasty remodeling were performed with interrupted stitches. A double J stent was inserted through a 2-mm transparietal angiocatheter to protect the pyelic suture. RESULTS: The procedures were all completed within 90 minutes, the "docking" time requiring 20 minutes. The patients were discharged on postoperative day 2, without any complications. CONCLUSIONS: Comprehensive assessment of pyelic suture in a very narrow field with 2 operative instruments is feasible and safe. Robotic pyeloplasty provides all the advantages of mini-invasive surgery with the added advantage of higher magnification and excellent surgical navigation in very small spaces and on fragile infant tissues. PMID- 24487173 TI - Treatment of esophageal stricture due to lichen planus with intralesional corticosteroid injection. AB - Herein we presented a male patient with esophageal stricture due to lichen planus successfully treated with repeated injections of intralesional triamcinolone and review the current literature on esophageal lichen planus with special emphasis on its treatment. PMID- 24487174 TI - Single-incision laparoscopic surgery for stage IV colon cancer. AB - AIM: : The safety and efficacy of single-incision laparoscopic resections for patients with stage IV colorectal cancer have not been examined explicitly. This article describes our experience with single-incision laparoscopic procedures for patients with stage IV colorectal cancer. METHODS: Seventy-seven patients who underwent single-incision laparoscopic colectomy between August 2010 and January 2012 were investigated retrospectively. Eleven patients were in clinical stage IV (ST4 group) and were compared with 66 patients in clinical stages 0 to III (control group). RESULTS: There were no differences in the intraoperative and the postoperative complications, the 30-day mortality rate, the number of the lymph nodes harvested, and the duration of postoperative hospital stay between the 2 groups. CONCLUSIONS: Our initial experiences suggested that single-incision laparoscopic colectomy is feasible for stage IV colon cancer patients. This is a good start comparing the outcomes of single-incision colectomy in stage IV patients with open and traditional laparoscopic colectomy. PMID- 24487175 TI - Segmental omental infarction: a rare cause of acute abdominal pain in children. AB - Segmental omental infarction (SOI) is an unusual and rare cause of abdominal pain in children and is often mistaken for acute appendicitis preoperatively. SOI once diagnosed preoperatively should be treated conservatively. Surgical intervention, however, may be necessary in order to establish definitive diagnosis and treatment. We present 2 children with SOI diagnosed as acute appendicitis preoperatively. Laparoscopy established the diagnosis and treatment. Laparoscopy should be the procedure of choice in children presenting with right-sided abdominal pain that is not well established preoperatively. This is especially so in obese children. Laparoscopy not only establishes the diagnosis of SOI but laparoscopic omentectomy results in resolution of symptoms and faster recovery. PMID- 24487176 TI - Hernioscopy: a simple application of single-port endoscopic surgery in acute inguinal hernias. AB - Strangulated hernia remains one of the most common emergencies encountered in general surgery. During induction of general or spinal anesthesia, the potential self-reduction of a gangrenous bowel can occur in approximately 1% of cases. In these cases, bowel viability can no longer be directly assessed unless a more extensive operation (laparoscopy or laparotomy) is performed. A simple alternative to unnecessary laparotomy or to a standard laparoscopy is a hernia sac laparoscopy (hernioscopy). Here, we presented 4 patients with a diagnosis of small-bowel obstruction secondary to incarcerated inguinal hernias, in which the incarcerated hernia content was evaluated by hernioscopy. Only 1 case presented persistent signs of bowel ischemia after hernia reduction and required a small bowel segmental resection. All hernias were repaired using prosthetic tension free technique. Hernia sac laparoscopy (hernioscopy), the introduction of the laparoscope through an open inguinal hernia sac, can be useful to evaluate the viability of the incarcerated hernia content, to avoid unnecessary laparotomy. PMID- 24487177 TI - Letter to the editor: "Deconstructing the dogma of sympathetic restraint and its role in the cardiovascular response to exercise". PMID- 24487178 TI - Reply to "Letter to the editor: 'Deconstructing the dogma of sympathetic restraint and its role in the cardiovascular response to exercise'". PMID- 24487179 TI - Chain elongation in anaerobic reactor microbiomes to recover resources from waste. AB - Different microbial pathways can elongate the carbon chains of molecules in open cultures of microbial populations (i.e. reactor microbiomes) under anaerobic conditions. Here, we discuss three such pathways: 1. homoacetogenesis to combine two carbon dioxide molecules into acetate; 2. succinate formation to elongate glycerol with one carbon from carbon dioxide; and 3. reverse beta oxidation to elongate short-chain carboxylates with two carbons into medium-chain carboxylates, leading to more energy-dense and insoluble products (e.g. easier to separate from solution). The ability to use reactor microbiomes to treat complex substrates can simultaneously address two pressing issues: 1. providing proper waste management; and 2. producing renewable chemicals and fuels. PMID- 24487180 TI - Molecular docking, spectroscopic studies and quantum calculations on nootropic drug. AB - A systematic vibrational spectroscopic assignment and analysis of piracetam [(2 oxo-1-pyrrolidineacetamide)] have been carried out using FT-IR and FT-Raman spectral data. The vibrational analysis was aided by an electronic structure calculation based on the hybrid density functional method B3LYP using a 6 311G++(d,p) basis set. Molecular equilibrium geometries, electronic energies, IR and Raman intensities, and harmonic vibrational frequencies have been computed. The assignments are based on the experimental IR and Raman spectra, and a complete assignment of the observed spectra has been proposed. The UV-visible spectrum of the compound was recorded and the electronic properties, such as HOMO and LUMO energies and the maximum absorption wavelengths lambdamax were determined by the time-dependent DFT (TD-DFT) method. The geometrical parameters, vibrational frequencies and absorption wavelengths were compared with the experimental data. The complete vibrational assignments are performed on the basis of the potential energy distributions (PED) of the vibrational modes in terms of natural internal coordinates. The simulated FT-IR, FT-Raman, and UV spectra of the title compound have been constructed. Molecular docking studies have been carried out in the active site of piracetam by using Argus Lab. In addition, the potential energy surface, HOMO and LUMO energies, first-order hyperpolarizability and the molecular electrostatic potential have been computed. PMID- 24487181 TI - Folding and unfolding pathways of the human telomeric G-quadruplex. AB - Sequence analogs of human telomeric DNA such as d[AGGG(TTAGGG)3] (Tel22) fold into monomeric quadruplex structures in the presence of a suitable cation. To investigate the pathway for unimolecular quadruplex formation, we monitored the kinetics of K(+)-induced folding of Tel22 by circular dichroism (CD), intrinsic 2 aminopurine fluorescence, and fluorescence resonance energy transfer (FRET). The results are consistent with a four-step pathway U <-> I1 <-> I2 <-> I3 <-> F where U and F represent unfolded and folded conformational ensembles and I1, I2, and I3 are intermediates. Previous kinetic studies have shown that I1 is formed in a rapid pre-equilibrium and may consist of an ensemble of "prefolded" hairpin structures brought about by cation-induced electrostatic collapse of the DNA. The current study shows that I1 converts to I2 with a relaxation time tau1=0.1s at 25 degrees C in 25 mM KCl. The CD spectrum of I2 is characteristic of an antiparallel quadruplex that could form as a result of intramolecular fold-over of the I1 hairpins. I3 is relatively slowly formed (tau2~3700s) and has CD and FRET properties consistent with those expected of a triplex structure as previously observed in equilibrium melting studies. I3 converts to F with tau3~750s. Identical pathways with different kinetic constants involving a rapidly formed antiparallel intermediate were observed with oligonucleotides forming mixed parallel/antiparallel hybrid-1 and hybrid-2 topologies {e.g. d[TTGGG(TTAGGG)3A] and d[TAGGG(TTAGGG)3TT]}. Aspects of the kinetics of unfolding were also monitored by the spectroscopic methods listed above and by time resolved fluorescence lifetime measurements using a complementary strand trap assay. These experiments reveal a slow, rate-limiting step along the unfolding pathway. PMID- 24487182 TI - Real-time fluorescence loop-mediated isothermal amplification for the diagnosis of hemorrhagic enteritis virus. AB - Suspected cases of hemorrhagic enteritis associated with hemorrhagic enteritis virus (HEV) are becoming more frequent among yellow chickens in the Guangdong Province of China. In this study, we have developed a one-step, ecumenical, real time fluorescence loop-mediated isothermal amplification (RealAmp) assay for the rapid diagnosis of HEV. The RealAmp assay was performed at 63 degrees C and reduced the assay time to 15min, using a simple and portable device, the ESE Quant Tube Scanner. The detection limit of DNA was 1fg/MUl, and the detection was specific only to HEV. We also used nested PCR to evaluate the application of the RealAmp assay. The coincidence rate of the two methods was 100%. Our data indicated that the RealAmp assay provides a sensitive, specific, and user friendly diagnostic tool for the identification and quantification of HEV for field diagnosis and in laboratory research. PMID- 24487183 TI - Serological diagnosis with recombinant N antigen for hantavirus infection. AB - Hantaviruses are causative agents of two rodent-borne zoonoses, hemorrhagic fever with renal syndrome (HFRS) and nephropathia epidemica (NE) in the Old World and hantavirus pulmonary syndrome (HPS) in the New World. Serological examinations to detect hantavirus antibodies have been most widely used for surveillance among humans and rodent reservoirs. Here, we will review antigenic structure of nucleocapsid (N) protein of hantaviruses and application of recombinant N protein as diagnostic antigen for screening and serotyping. PMID- 24487184 TI - In vitro growth characteristics and volatile sulfur compound production of Solobacterium moorei. AB - Solobacterium moorei has recently been implicated as a causative agent of halitosis. In vitro experiments to evaluate the role of S. moorei in halitosis have, however, been complicated by a paucity of information on the ideal conditions for culturing this organism. This work aimed to optimize a liquid culture medium for S. moorei, and to determine the growth-curve of the organism. Further, the ability of S. moorei to generate volatile sulfur compounds was investigated and compared quantitatively to other oral anaerobes by an optimized head-space gas chromatography method. Serum-supplementation of standard liquid growth media gave greater growth of S. moorei than non-supplemented broths, with the best medium found to be serum-supplemented tryptone soya broth. S. moorei was able to metabolize cysteine directly to hydrogen sulfide, but was unable to produce methanethiol from methionine. S. moorei produced 2-3 times more hydrogen sulfide (normalized for colony forming units) than Porphyromonas gingivalis and Veillonella dispar, but considerably less than Fusobacterium nucleatum. The study has identified reliable growth conditions for culture of S. moorei, which were employed to show that S. moorei has the requisite biochemistry consistent with a potential role in halitosis. PMID- 24487185 TI - The immune contexture of primary and metastatic human tumours. AB - A tumour grows in a complex microenvironment composed of stromal cells, lymphoid and myeloid cells, vascular and lymphatic vessels, and the resultant cytokine and chemokine milieu. In most primary tumours, a strong Th1/cytotoxic T cells infiltration correlates with a longer survival. This beneficial effect can be hampered by the presence of M2 polarized macrophages and high VEGF production. Recent studies revealed that the pattern of the tumour microenvironment remains a major prognostic factor even in the metastatic lesions, while been reproducible between the primary and metastatic tumour. Nevertheless the prognostic impact of the Th1/cytotoxic T cell infiltrate could be different according to the origin of the primary tumour. This model highlights a novel tumour cell-dependent immune contexture that predicts patient's clinical outcome and has implications in the use of immunotherapies. PMID- 24487187 TI - Synthesis, antifungal activities and molecular docking studies of novel 2-(2,4 difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates. AB - A series of 2-(2,4-difluorophenyl)-2-hydroxy-3-(1H-1,2,4-triazol-1-yl)propyl dithiocarbamates as new analogs of fluconazole were synthesized and their antifungal activities were evaluated. Among these compounds, 2a-f and 3a-q exhibited higher activities than fluconazole against nearly all fungi tested except Aspergillus fumigatus. Noticeably, the in vitro biological activities of 2b, 3a, 3c, 3h-k, and 3o-q against Candida species were much better than those of fluconazole and ketoconazole. Also, 2a-d, 3a-d, 3e-f, 3h-k, 3p and 3q showed higher activities against A. fumi than fluconazole. Computational docking experiments indicated that the inhibition of CYP51 involved a coordination bond with iron of the heme group, the hydrophilic H-bonding region, the hydrophobic region, and the narrow hydrophobic cleft. PMID- 24487186 TI - The promoter of the Arabidopsis PIN6 auxin transporter enabled strong expression in the vasculature of roots, leaves, floral stems and reproductive organs. AB - Cellular auxin homeostasis controls many aspects of plant growth, organogenesis and development. The existence of intracellular auxin transport mediated by endoplasmic reticulum (ER)-localized PIN5, PIN6 and PIN8 proteins is a relatively recent discovery shaping a new era in understanding auxin-mediated growth processes. Here we summarize the importance of PIN6 in mediating intracellular auxin transport during root formation, leaf vein patterning and nectary production. While, it was previously shown that PIN6 was strongly expressed in rosette leaf cell types important in vein formation, here we demonstrate by use a PIN6 promoter-reporter fusion, that PIN6 is also preferentially expressed in the vasculature of the primary root, cotyledons, cauline leaves, floral stem, sepals and the main transmitting tract of the reproductive silique. The strong, vein- specific reporter gene expression patterns enabled by the PIN6 promoter emphasizes that transcriptional control is likely to be a major regulator of PIN6 protein levels, during vasculature formation, and supports the need for ER localized PIN proteins in selecting specialized cells for vascular function in land plants. PMID- 24487188 TI - Synthesis of novel ring-A fused hybrids of oleanolic acid with capabilities to arrest cell cycle and induce apoptosis in breast cancer cells. AB - Six novel oleanolic acid ring-A fused hybrids (5-10) have been synthesized by employing a four step protocol with the introduction of benzylidene functionality at C-2 as the key step. Their structures were established by high resolution NMR and Mass spectral data. The synthesized compounds have been screened against seven human cancer cell lines including ME-180 & HeLa (cervix), MCF-7, MDA-MB-453 & MDA-MB-231 (breast), PC-3 (prostate) and HT-29 (colon) using MTT assay. Most significantly, compound 10 showed potent activity against the three breast cancer cell lines. The IC50 value (10.60 MUM) of compound 10 against MCF-7 found to be much lower than that of the standards and parent compound. Flow cytometric analysis reveals that compound 10 arrests cell cycle in S phase and induces apoptosis in MCF cells. PMID- 24487190 TI - Pharmaceutical salts and cocrystals involving amino acids: a brief structural overview of the state-of-art. AB - Salification of new drug substances in order to improve physico-chemical or solid state properties (e.g. dissolution rate or solubility, appropriate workup process, storage for further industrial and marketing development) is a well accepted procedure. Amino acids, like aspartic acid, lysine or arginine take a great part in this process and are implicated in several different formulations of therapeutic agent families, including antibiotics (amoxicillin from beta lactam class or cephalexin from cephalosporin class), NSAIDs (ketoprofen, ibuprofen and naproxen from profen family, acetylsalicylic acid) or antiarrhythmic agents (e.g. ajmaline). Even if more than a half of known pharmaceutical molecules possess a salifiable moiety, what can be done for new potential drug entity that cannot be improved by transformation into a salt? In this context, after a brief review of pharmaceutical salts on the market and the implication of amino acids in these formulations, we focus on the advantage of using amino acids even when the target compound is not salifiable by exploiting their zwitterionic potentialities for cocrystal edification. We summarize here a series of new examples coming from literature to support the advantages of broadening the application of amino acids in formulation for new drug substances improvement research for non-salifiable molecules. PMID- 24487189 TI - Synthesis and evaluation of the antimicrobial activities of 3-((5-phenyl-1,3,4 oxadiazol-2-yl)methyl)-2-thioxothiazolidin-4-one derivatives. AB - Two novel series of 3-((5-phenyl-1,3,4-oxadiazol-2-yl)methyl)-2-thioxothiazolidin 4-one derivatives were designed and synthesized, and their anti-bacterial activities evaluated. These compounds showed broad-spectrum inhibitory activities against both Gram-positive and Gram-negative bacteria with minimum inhibitory concentration (MIC) values in the range of 1-64 MUg/mL. The activity of compound 6c was the more potent with MIC values of 1 MUg/mL against the MRSA (3167 and 3506) strains than those of gatifloxacin, oxacillin, and norfloxacin. Compared to the previously reported rhodanine derivatives, 2-thioxothiazolidin-4-one derivatives exhibited an inhibition against Gram-negative strains due to the introduction of a 1,3,4-oxadiazole moiety, among which compounds 3 showed moderate activities against the Gram-negative bacteria (Escherichiacoli 1924) with MIC values of 16 MUg/mL. PMID- 24487191 TI - Synthesis and evaluation of new coumarin derivatives as potential atypical antipsychotics. AB - In this paper, we report the synthesis of novel, potential antipsychotic coumarin derivatives combining potent dopamine D2, D3 and serotonin 5-HT(1A), 5-HT(2A) receptors properties. We describe the structure activity relationship that leads us to the promising derivative: 7-(4-(4-(6-fluorobenzo[d]isoxazol-3-yl)piperidin 1-yl)butoxy)-6-methyl-2,3-dihydrocyclopenta[c]chromen-4(1H)-one 27. The unique pharmacological features of compound 27 are a high affinity for dopamine D2, D3 and serotonin 5-HT(1A), 5-HT(2A) receptors, together with a low affinity for H1 receptor (to reduce the risk of obesity under chronic treatment). In animal models, compound 27 inhibited apomorphine-induced climbing and MK-801-induced hyperactivity without observable catalepsy at the highest dose tested. In particular, compound 27 was more potent than clozapine. PMID- 24487192 TI - Structural optimization of indole based compounds for highly promising anti cancer activities: structure activity relationship studies and identification of lead molecules. AB - Based on the anti-cancer data of previous compounds, 27 more compounds were synthesized and subjected to anti-cancer screening. Compounds were tested over 60 human tumor cell lines of different types of cancer. As per the data available, some compounds exhibited appreciable anti-cancer properties over certain cell lines with their GI50 in nM range. With the help of UV-vis spectral studies, enzyme immunoassay and molecular modeling studies, dihydrofolate reductase was found to be the probable cellular target of the compounds under present investigation. PMID- 24487193 TI - Probing the selective antitumor activity of 22-oxo-26-selenocyanocholestane derivatives. AB - Diverse steroidal compounds have shown antiproliferative activity on certain tumor cell lines; however, their complete role on cancer cells has not been extensively established since the research is quite recent. Hence, deeper study in this field is required. Due to the importance of selenium in animal and human health; herein, we report the synthesis, characterization, and biological evaluation of two novel 22-oxo-26-selenocyanocholestanic steroids on cervicouterine cancer cells and non-tumor cells. The title compounds were straightforward prepared from diosgenin and hecogenin in excellent overall yields. We determined their effect on cell proliferation on HeLa, CaSki, and ViBo cell cultures. Their cytotoxic effect on tumor cells, as well as on peripheral blood lymphocytes was also evaluated. The increase in the expression of active caspase-3 along with the fragmentation of DNA confirm that the new 22-oxo-26 selenocyanocholestane frameworks potentiate apoptosis in tumor cells. The antiproliferative activity on tumor cells affects to some extent the proliferative potential of peripheral blood lymphocytes, so an immunosuppressive effect has also been established. The novel 22-oxo-26-selenocyanocholestane compounds show selective antitumor activity and therefore are promising lead candidates for further in vivo evaluation. PMID- 24487194 TI - 1-Phenyl-1H- and 2-phenyl-2H-1,2,3-triazol derivatives: design, synthesis and inhibitory effect on alpha-glycosidases. AB - Due to aging and increasingly overweight in human population, the incidence of non-insulin dependent diabetes mellitus (NIDDM or Type 2 DM) is increasing considerably. Therefore, searching for new alpha-glycosidase inhibitors (GIs) capable of slowing down carbohydrate assimilation by humans is an important strategy towards control of NIDDM. In this report, we disclose the search for new easily accessible synthetic triazoles as anti-diabetic compounds. Two series of non-glycosid triazoles were synthesized (series A and B) and screened against baker's yeast alpha-glucosidase (MAL12) and porcine pancreatic alpha-amylase activity (PPA). Of the 60 compounds tested at 500 MUM, were considered hits (>=60% inhibition) six triazoles against MAL12 and three against PPA, with the inhibition reaching up to 99.4% on MAL12 and 88.6% on PPA. The IC50 values were calculated for both enzymes and ranged from 54 to 482 MUM for MAL12 and 145 to 282 MUM for PPA. These results demonstrated the potential activity of simple and non-glycosidic triazoles as an important novel class of GIs for the development of drugs to treat Type 2 DM. PMID- 24487195 TI - Experimental shielding evaluation of the radiation protection provided by the structurally significant components of residential structures. AB - The human health and environmental effects following a postulated accidental release of radioactive material to the environment have been a public and regulatory concern since the early development of nuclear technology. These postulated releases have been researched extensively to better understand the potential risks for accident mitigation and emergency planning purposes. The objective of this investigation is to provide an updated technical basis for contemporary building shielding factors for the US housing stock. Building shielding factors quantify the protection from ionising radiation provided by a certain building type. Much of the current data used to determine the quality of shielding around nuclear facilities and urban environments is based on simplistic point-kernel calculations for 1950s era suburbia and is no longer applicable to the densely populated urban environments realised today. To analyse a building's radiation shielding properties, the ideal approach would be to subject a variety of building types to various radioactive sources and measure the radiation levels in and around the building. While this is not entirely practicable, this research analyses the shielding effectiveness of ten structurally significant US housing stock models (walls and roofs) important for shielding against ionising radiation. The experimental data are used to benchmark computational models to calculate the shielding effectiveness of various building configurations under investigation from two types of realistic environmental source terms. Various combinations of these ten shielding models can be used to develop full-scale computational housing-unit models for building shielding factor calculations representing 69.6 million housing units (61.3%) in the United States. Results produced in this investigation provide a comparison between theory and experiment behind building shielding factor methodology. PMID- 24487196 TI - Joseph-Marie Dubreuil (1790-1852): the innovative surgeon who first discovered the indicative murmur that could indicate the aneurysm of the descending aorta. PMID- 24487197 TI - A positive approach to negative results. PMID- 24487198 TI - A statistical editor for epidemiology. PMID- 24487199 TI - Commentary: Class action lawsuits: can they advance epidemiologic research? PMID- 24487200 TI - Association among socioeconomic status, health behaviors, and all-cause mortality in the United States. AB - BACKGROUND: Health behaviors may contribute to socioeconomic inequalities in mortality, although the extent of such contribution remains unclear. We assessed the extent to which smoking, alcohol consumption, and physical inactivity have mediated the association between socioeconomic status (SES) and all-cause mortality in a representative sample of US adults. METHODS: Initiated in 1992, the Health and Retirement Study is a longitudinal, biennial survey of a national sample of US adults born between 1931 and 1941. Our analyses are based on a sample of 8037 participants enrolled in 1992 and followed for all-cause mortality from 1998 through 2008. We used exploratory and confirmatory factor analysis to derive a measure of adult SES based on respondents' education, occupation, labor force status, household income, and household wealth. Potential mediators (smoking, alcohol consumption, and physical inactivity) were assessed biennially. We used inverse probability-weighted mediation models to account for time-varying covariates. RESULTS: During the 10-year mortality follow-up, 859 (10%) participants died. After accounting for age, sex, and baseline confounders, being in the most-disadvantaged quartile of SES compared with the least disadvantaged was associated with a mortality risk ratio of 2.84 (95% confidence interval = 2.25-3.60). Together, smoking, alcohol consumption, and physical inactivity explained 68% (35-104%) of this association, leaving a risk ratio of 1.59 (1.03 2.45) for low SES. CONCLUSIONS: The distribution of health-damaging behaviors may explain a substantial proportion of excess mortality associated with low SES in the United States, suggesting the importance of social inequalities in unhealthy behaviors. PMID- 24487201 TI - Commentary: Socioeconomic status, health behavior, and mortality: old question plus modern methods equals new insights? PMID- 24487202 TI - Income differences in life expectancy: the changing contribution of harmful consumption of alcohol and smoking. AB - BACKGROUND: Social differences in mortality have increased in high-income countries, but the causes of these changes remain unclear. We quantify the contribution of alcohol and smoking to trends in income differences in life expectancy from 1988 through 2007 in Finland. METHODS: An 11% sample from the population registration data of Finns 25 years and older was linked with an 80% oversample of death records. Alcohol-attributable mortality was based on underlying and contributory causes of death on individual death certificates and smoking-attributable mortality on an indirect method that used lung cancer mortality as an indicator for the impact of smoking on mortality. RESULTS: Alcohol- and smoking-attributable deaths reduced life expectancy by about 4.5 years among men. Alcohol-attributable mortality increased and smoking attributable mortality decreased over the period 1988-2007, leaving the joint contribution stable. Among women, the contribution of these risk factors to life expectancy over the same period increased from 0.7 to 1.2 years. In 2003-2007, life expectancy differentials between the lowest and highest income quintile were 11.4 years (men) and 6.3 years (women). In the absence of alcohol and smoking, these differences would have been 60% less for men and 36% less for women. Life expectancy differentials increased rapidly over the study period; without alcohol and smoking, the increase would have been 69% less among men and 85% less among women. CONCLUSIONS: Alcohol and smoking have a major influence on income differences in mortality and, with the exception of smoking among men, their contribution is increasing. Without alcohol and smoking, there would have been little change in life expectancy differentials. PMID- 24487203 TI - Commentary: When people behave badly. PMID- 24487204 TI - Optimal CD4 count for initiating HIV treatment: impact of CD4 observation frequency and grace periods, and performance of dynamic marginal structural models. AB - BACKGROUND: In HIV infection, dynamic marginal structural models have estimated the optimal CD4 for treatment initiation to minimize AIDS/death. The impact of CD4 observation frequency and grace periods (permitted delay to initiation) on the optimal regimen has not been investigated nor has the performance of dynamic marginal structural models in moderately sized data sets-two issues that are relevant to many applications. METHODS: To determine optimal regimens, we simulated 31,000,000 HIV-infected persons randomized at CD4 500-550 cells/mm to regimens "initiate treatment within a grace period following observed CD4 first 0.5% lower AIDS-free survival compared with the true optimal regimen. CONCLUSIONS: The optimal regimen is strongly influenced by CD4 frequency and less by grace period length. Dynamic marginal structural models lack precision at moderate sample sizes. PMID- 24487205 TI - In utero exposure to compounds with dioxin-like activity and birth outcomes. AB - BACKGROUND: Maternal exposure to dioxins and dioxin-like compounds may affect fetal growth and development. We evaluated the association between in utero dioxin-like activity and birth outcomes in a prospective European mother-child study. METHODS: We measured dioxin-like activity in maternal and cord blood plasma samples collected at delivery using the Dioxin-Responsive Chemically Activated LUciferase eXpression (DR CALUX) bioassay in 967 mother-child pairs, in Denmark, Greece, Norway, Spain, and England. Multiple linear regression models were used to investigate the associations with birth weight, gestational age, and head circumference. RESULTS: Plasma dioxin-like activity was higher in maternal sample than in cord samples. Birth weight was lower with medium (-58 g [95% confidence interval (CI) = -176 to 62]) and high (-82 g [-216 to 53]) tertiles of exposure (cord blood) compared with the lowest tertile. Gestational age was shorter by approximately half a week in the highest compared with the lowest ( 0.4 weeks [95% CI = -0.8 to -0.1]). This association was stronger in boys than in girls, although the statistical evidence for interaction was weak (P = 0.22). Analysis based on CALUX-toxic equivalents expressed per milliliter of plasma showed similar trends. We found no association between dioxin-like activity in maternal plasma and birth outcomes. CONCLUSIONS: Results from this international general population study suggest an association between low-level prenatal dioxin like activity and shorter gestational age, particularly in boys, with weaker associations for birth weight. PMID- 24487206 TI - Commentary: Does air pollution confound studies of temperature? PMID- 24487208 TI - Commentary: On NRI, IDI, and "good-looking" statistics with nothing underneath. PMID- 24487207 TI - Estimating the effect of cumulative occupational asbestos exposure on time to lung cancer mortality: using structural nested failure-time models to account for healthy-worker survivor bias. AB - BACKGROUND: Previous estimates of the effect of occupational asbestos on lung cancer mortality have been obtained by using methods that are subject to the healthy-worker survivor bias. G-estimation of a structural nested model provides consistent exposure effect estimates under this bias. METHODS: We estimated the effect of cumulative asbestos exposure on lung cancer mortality in a cohort comprising 2564 textile factory workers who were followed from January 1940 to December 2001. RESULTS: At entry, median age was 23 years, with 42% of the cohort being women and 20% nonwhite. During the follow-up period, 15% of person-years were classified as occurring while employed and 13% as occupationally exposed to asbestos. For a 100 fiber-year/ml increase in cumulative asbestos, a Weibull model adjusting for sex, race, birth year, baseline exposure, and age at study entry yielded a survival time ratio of 0.88 (95% confidence interval = 0.83 to 0.93). Further adjustment for work status yielded no practical change. The corresponding survival time ratio obtained using g-estimation of a structural nested model was 0.57 (0.33 to 0.96). CONCLUSIONS: Accounting for the healthy worker survivor bias resulted in a 35% stronger effect estimate. However, this estimate was considerably less precise. When healthy-worker survivor bias is suspected, methods that account for it should be used. PMID- 24487209 TI - Studies with many covariates and few outcomes: selecting covariates and implementing propensity-score-based confounding adjustments. AB - BACKGROUND: Propensity scores are useful for confounding adjustment in the commonly observed setting of many potential confounders, frequent exposure, and rare events. However, with few exposed outcomes to inform covariate selection and many candidate confounders, optimal approaches to construct and implement propensity-score-based confounding adjustment remain unclear. METHODS: In a cohort study on the effect of anticonvulsant drugs on cardiovascular risk among adult patients from the HealthCore Integrated Research Database, we compared the performance for confounding control of various covariate-selection strategies for propensity-score estimation (expert knowledge only, expert knowledge informed by empirical covariate selection via high-dimensional propensity-score, and high dimensional propensity-score empirical specification only) and propensity-score based adjustment methods (propensity-score-matching and propensity-score-decile stratification). This article focuses on the first 90 days of follow-up because any treatment effect identified in this temporal window almost certainty originates from residual confounding rather than pharmacologic action. RESULTS: We identified 166,031 new users and 564 ischemic cardiovascular events. Among those, 12,580 patients initiated anticonvulsants that strongly induce cytochrome P450 enzymes and experienced 68 events. The unadjusted hazard ratio was 1.72 (95% confidence interval = 1.34-2.22). Adjustment for investigator-identified covariates led to 41% to 59% reductions in the hazard ratio; adjustment for both investigator-identified and high-dimensional propensity-score empirically identified covariates led to larger reductions (54% to 72%). A selection strategy based on high-dimensional propensity-score empirical specification alone produced less-attenuated and more-volatile hazard ratio estimates. This volatility seemed to be slightly attenuated in a trimmed propensity-score-stratified analysis. CONCLUSIONS: The high-dimensional propensity-score algorithm complements expert knowledge for confounding adjustment, but in settings with few exposed outcomes, its performance without investigator-specified covariates is less clear and may be associated with an increased likelihood of bias. In our example, investigator specification of variables combined with high-dimensional propensity-score empirical selection and the use of trimmed propensity-score-stratified analysis seem to improve effect estimation. Plotting the relation of effect estimates to the increasing number of empirical covariates is a useful diagnostic. PMID- 24487211 TI - Identification of natural direct effects when a confounder of the mediator is directly affected by exposure. AB - Natural direct and indirect effects formalize traditional notions of mediation analysis into a rigorous causal framework and have recently received considerable attention in epidemiology and in social sciences. Sufficient conditions for the identification of natural direct effects were formulated by Judea Pearl under a nonparametric structural equations model, which assumes certain independencies between potential outcomes. A common situation in epidemiology is that a confounder of the mediator-outcome relationship is itself affected by the exposure, in which case natural direct effects fail to be nonparametrically identified without additional assumptions, even under Pearl's nonparametric structural equations model. In this article, we show that when a single binary confounder of the mediator is affected by the exposure, the natural direct effect is nonparametrically identified under the model, assuming monotonicity about the effect of the exposure on the confounder. A similar result is shown to hold for a vector of binary confounders of the mediator under a certain independence assumption about the confounders. Finally, we show that natural direct effects are more generally identified if there is no additive mean interaction between the mediator and the confounders of the mediator affected by exposure. When correct, this latter assumption is particularly appealing because it does not require monotonicity of effects of the exposure. In addition, it places no restriction on the nature of the confounders of the mediator, which can be continuous or polytomous. PMID- 24487210 TI - Commentary: Balancing automated procedures for confounding control with background knowledge. PMID- 24487212 TI - Constructing inverse probability weights for continuous exposures: a comparison of methods. AB - Inverse probability-weighted marginal structural models with binary exposures are common in epidemiology. Constructing inverse probability weights for a continuous exposure can be complicated by the presence of outliers, and the need to identify a parametric form for the exposure and account for nonconstant exposure variance. We explored the performance of various methods to construct inverse probability weights for continuous exposures using Monte Carlo simulation. We generated two continuous exposures and binary outcomes using data sampled from a large empirical cohort. The first exposure followed a normal distribution with homoscedastic variance. The second exposure followed a contaminated Poisson distribution, with heteroscedastic variance equal to the conditional mean. We assessed six methods to construct inverse probability weights using: a normal distribution, a normal distribution with heteroscedastic variance, a truncated normal distribution with heteroscedastic variance, a gamma distribution, a t distribution (1, 3, and 5 degrees of freedom), and a quantile binning approach (based on 10, 15, and 20 exposure categories). We estimated the marginal odds ratio for a single-unit increase in each simulated exposure in a regression model weighted by the inverse probability weights constructed using each approach, and then computed the bias and mean squared error for each method. For the homoscedastic exposure, the standard normal, gamma, and quantile binning approaches performed best. For the heteroscedastic exposure, the quantile binning, gamma, and heteroscedastic normal approaches performed best. Our results suggest that the quantile binning approach is a simple and versatile way to construct inverse probability weights for continuous exposures. PMID- 24487213 TI - Effect decomposition in the presence of an exposure-induced mediator-outcome confounder. AB - Methods from causal mediation analysis have generalized the traditional approach to direct and indirect effects in the epidemiologic and social science literature by allowing for interaction and nonlinearities. However, the methods from the causal inference literature have themselves been subject to a major limitation, in that the so-called natural direct and indirect effects that are used are not identified from data whenever there is a mediator-outcome confounder that is also affected by the exposure. In this article, we describe three alternative approaches to effect decomposition that give quantities that can be interpreted as direct and indirect effects and that can be identified from data even in the presence of an exposure-induced mediator-outcome confounder. We describe a simple weighting-based estimation method for each of these three approaches, illustrated with data from perinatal epidemiology. The methods described here can shed insight into pathways and questions of mediation even when an exposure-induced mediator-outcome confounder is present. PMID- 24487214 TI - Impact factors: do potential authors care? PMID- 24487215 TI - Impact factors: do potential authors care? PMID- 24487216 TI - Alternative definitions of "proportion eliminated". PMID- 24487217 TI - On the "proportion eliminated" for risk differences versus excess relative risks. PMID- 24487218 TI - Kawasaki disease and pertussis epidemics. PMID- 24487219 TI - A no-cost geocoding strategy using R. PMID- 24487220 TI - The impact of temperature variability on years of life lost. PMID- 24487221 TI - Supplementary infant feeding and growth. PMID- 24487222 TI - Reuse of controls in nested case-control studies. PMID- 24487223 TI - Recruiting by registered versus standard mail. PMID- 24487224 TI - Fruits, vegetables, and hypertensive disease mortality. PMID- 24487225 TI - Fluorescence Lifetime-Based Competitive Binding Assays for Measuring the Binding Potency of Protease Inhibitors In Vitro. AB - Fluorescence lifetime (FLT)-based assays have developed to become highly attractive tools in drug discovery. All recently published examples of FLT-based assays essentially describe their use for monitoring enzyme-mediated peptide modifications, such as proteolytic cleavage or phosphorylation/dephosphorylation. Here we report the development of competitive binding assays as novel, inhibitor centric assays, principally employing the FLT of the acridone dye Puretime 14 (PT14) as the readout parameter. Exemplified with two case studies on human serine proteases, the details of the rationale for both the design and synthesis of probes (i.e., active site-directed low-molecular-weight inhibitors conjugated to PT14) are provided. Data obtained from testing inhibitors with the novel assay format match those obtained with alternative formats such as FLT-based protease activity and time-resolved fluorescence resonance energy transfer-based competitive binding assays. PMID- 24487227 TI - Editorial. PMID- 24487226 TI - Working memory, worry, and algebraic ability. AB - Math anxiety (MA)-working memory (WM) relationships have typically been examined in the context of arithmetic problem solving, and little research has examined the relationship in other math domains (e.g., algebra). Moreover, researchers have tended to examine MA/worry separate from math problem solving activities and have used general WM tasks rather than domain-relevant WM measures. Furthermore, it seems to have been assumed that MA affects all areas of math. It is possible, however, that MA is restricted to particular math domains. To examine these issues, the current research assessed claims about the impact on algebraic problem solving of differences in WM and algebraic worry. A sample of 80 14-year old female students completed algebraic worry, algebraic WM, algebraic problem solving, nonverbal IQ, and general math ability tasks. Latent profile analysis of worry and WM measures identified four performance profiles (subgroups) that differed in worry level and WM capacity. Consistent with expectations, subgroup membership was associated with algebraic problem solving performance: high WM/low worry>moderate WM/low worry=moderate WM/high worry>low WM/high worry. Findings are discussed in terms of the conceptual relationship between emotion and cognition in mathematics and implications for the MA-WM-performance relationship. PMID- 24487228 TI - Abstracts of the international symposium on dementia in Parkinson's disease. PMID- 24487230 TI - In vitro assessment of antiretroviral drugs demonstrates potential for ototoxicity. AB - Several studies have reported an increased incidence of auditory dysfunction among HIV/AIDS patients. We used auditory HEI-OC1 cells in cell viability, flow cytometry and caspases 3/7-activation studies to investigate the potential ototoxicity of fourteen HIV antiretroviral agents: Abacavir, AZT, Delavirdine, Didenosine, Efavirenz, Emtricitabine, Indinavir, Lamivudine, Nefinavir, Nevirapine, Tenofovir, Ritonavir, Stavudine and Zalcitabine, as well as combinations of these agents as used in the common anti-HIV cocktails AtriplaTM, CombivirTM, EpzicomTM, TrizivirTM, and TruvadaTM. Our results suggested that most of the single assayed anti-HIV drugs are toxic for HEI-OC1 auditory cells. The cocktails, on the other hand, decreased auditory cells' viability with high significance, with the following severity gradient: Epzicom ~ Trizivir >> Atripla ~ Combivir > Truvada. Interestingly, our results suggest that Trizivir- and Epzicom-induced cell death would be mediated by a caspase-independent mechanism. l-Carnitine, a natural micronutrient known to protect HEI-OC1 cells against some ototoxic drugs as well as to decrease neuropathies associated with anti-HIV treatments, increased viability of cells treated with Lamivudine and Tenofovir as well as with the cocktail Atripla, but had only minor effects on cells treated with other drugs and drug combinations. Altogether, these results suggest that some frequently used anti-HIV agents could have deleterious effects on patients' hearing, and provide arguments in favor of additional studies aimed at elucidating the potential ototoxicity of current as well as future anti-HIV drugs. PMID- 24487231 TI - NMDA spikes enhance action potential generation during sensory input. AB - Recent evidence in vitro suggests that the tuft dendrites of pyramidal neurons are capable of evoking local NMDA receptor-dependent electrogenesis, so-called NMDA spikes. However, it has so far proved difficult to demonstrate their existence in vivo. Moreover, it is not clear whether NMDA spikes are relevant to the output of pyramidal neurons. We found that local NMDA spikes occurred in tuft dendrites of layer 2/3 pyramidal neurons both spontaneously and following sensory input, and had a large influence on the number of output action potentials. Using two-photon activation of an intracellular caged NMDA receptor antagonist (tc MK801), we found that isolated NMDA spikes typically occurred in multiple branches simultaneously and that sensory stimulation substantially increased their probability. Our results demonstrate that NMDA receptors have a vital role in coupling the tuft region of the layer 2/3 pyramidal neuron to the cell body, enhancing the effectiveness of layer 1 input. PMID- 24487232 TI - Bump attractor dynamics in prefrontal cortex explains behavioral precision in spatial working memory. AB - Prefrontal persistent activity during the delay of spatial working memory tasks is thought to maintain spatial location in memory. A 'bump attractor' computational model can account for this physiology and its relationship to behavior. However, direct experimental evidence linking parameters of prefrontal firing to the memory report in individual trials is lacking, and, to date, no demonstration exists that bump attractor dynamics underlies spatial working memory. We analyzed monkey data and found model-derived predictive relationships between the variability of prefrontal activity in the delay and the fine details of recalled spatial location, as evident in trial-to-trial imprecise oculomotor responses. Our results support a diffusing bump representation for spatial working memory instantiated in persistent prefrontal activity. These findings reinforce persistent activity as a basis for spatial working memory, provide evidence for a continuous prefrontal representation of memorized space and offer experimental support for bump attractor dynamics mediating cognitive tasks in the cortex. PMID- 24487233 TI - Cortical activity in the null space: permitting preparation without movement. AB - Neural circuits must perform computations and then selectively output the results to other circuits. Yet synapses do not change radically at millisecond timescales. A key question then is: how is communication between neural circuits controlled? In motor control, brain areas directly involved in driving movement are active well before movement begins. Muscle activity is some readout of neural activity, yet it remains largely unchanged during preparation. Here we find that during preparation, while the monkey holds still, changes in motor cortical activity cancel out at the level of these population readouts. Motor cortex can thereby prepare the movement without prematurely causing it. Further, we found evidence that this mechanism also operates in dorsal premotor cortex, largely accounting for how preparatory activity is attenuated in primary motor cortex. Selective use of 'output-null' vs. 'output-potent' patterns of activity may thus help control communication to the muscles and between these brain areas. PMID- 24487234 TI - Deficient neuron-microglia signaling results in impaired functional brain connectivity and social behavior. AB - Microglia are phagocytic cells that infiltrate the brain during development and have a role in the elimination of synapses during brain maturation. Changes in microglial morphology and gene expression have been associated with neurodevelopmental disorders. However, it remains unknown whether these changes are a primary cause or a secondary consequence of neuronal deficits. Here we tested whether a primary deficit in microglia was sufficient to induce some autism-related behavioral and functional connectivity deficits. Mice lacking the chemokine receptor Cx3cr1 exhibit a transient reduction of microglia during the early postnatal period and a consequent deficit in synaptic pruning. We show that deficient synaptic pruning is associated with weak synaptic transmission, decreased functional brain connectivity, deficits in social interaction and increased repetitive-behavior phenotypes that have been previously associated with autism and other neurodevelopmental and neuropsychiatric disorders. These findings open the possibility that disruptions in microglia-mediated synaptic pruning could contribute to neurodevelopmental and neuropsychiatric disorders. PMID- 24487235 TI - Imagined gait modulates neuronal network dynamics in the human pedunculopontine nucleus. AB - The pedunculopontine nucleus (PPN) is a part of the mesencephalic locomotor region and is thought to be important for the initiation and maintenance of gait. Lesions of the PPN induce gait deficits, and the PPN has therefore emerged as a target for deep brain stimulation for the control of gait and postural disability. However, the role of the PPN in gait control is not understood. Using extracellular single-unit recordings in awake patients, we found that neurons in the PPN discharged as synchronous functional networks whose activity was phase locked to alpha oscillations. Neurons in the PPN responded to limb movement and imagined gait by dynamically changing network activity and decreasing alpha phase locking. Our results indicate that different synchronous networks are activated during initial motor planning and actual motion, and suggest that changes in gait initiation in Parkinson's disease may result from disrupted network activity in the PPN. PMID- 24487236 TI - Optimization, pharmacophore modeling and 3D-QSAR studies of sipholanes as breast cancer migration and proliferation inhibitors. AB - Sipholenol A, a triterpene isolated from the Red Sea sponge Callyspongia siphonella, was previously shown to reverse multidrug resistance in P glycoprotein-overexpressing cancer cells. Moreover, sipholanes showed promising in vitro inhibitory effects against the invasion and migration of the metastatic human breast cancer cell line MDA-MB-231. The breast tumor kinase (Brk), a mediator of cancer cell phenotypes important for proliferation, survival, and migration, was proposed as a potential target. This study reports additional semisynthetic optimization of sipholenol A esters to improve the breast cancer antimigratory and antiproliferative activities as well as Brk phosphorylation inhibition. Fifteen new sipholenol A analogs (25-39) were semisynthesized. Sipholenol A 4beta-4',5'-dichlorobenzoate ester (29) was the most potent, with an IC50 value of 1.3 MUM in the migration assay. The level of Brk phosphorylation inhibition of 29 was assessed using the Z'-LYTETM kinase assay and Western blot analysis. Active analogs showed no toxicity on the non-tumorigenic epithelial breast cell line MCF10A at doses equal to their IC50 values or higher in migration and proliferation assays, suggesting their selectivity towards malignant cells. Pharmacophore modeling and 3D-QSAR studies were conducted to identify important pharmacophoric features and correlate 3D-chemical structure with activity. These studies provided the evidence for future design of novel antimigratory compounds based on a simplified sipholane structure possessing rings A and B (perhydrobenzoxepine) connected to substituted aromatic esters, with the elimination of rings C and D ([5,3,0]bicyclodecane system). This will enable the future synthesis of the new active entities feasibly and cost effectively. These results demonstrate the potential of marine natural products for the discovery of novel scaffolds for the control and management of metastatic breast cancer. PMID- 24487237 TI - Convulsive pseudoseizures: a review of current concepts. AB - Convulsive pseudoseizures thought to represent psychiatric disease can usually be detected early if they are considered in the epileptologist's differential diagnosis. No single diagnostic criterion for this behavioural disorder is known to be pathognomonic. Epilepsy and all physiological explanations have to be thoroughly ruled out and positive evidence of relevant psychopathology has to be gathered.The presence of pseudo seizures often heralds severe psychopathology, most frequently major affective disorder and major personality disorder, and occasionally, factitious disorder. Pseudoseizures can coexist with epileptic seizures and are often triggered by anticonvulsant toxicity.Diagnostic problems are more likely to be encountered in patients with frontal or parietal epilepsies, and in patients whose severe psychopathology is refractory to psychiatric intervention. PMID- 24487238 TI - Hyperlalia: a right cerebral hemisphere syndrome. AB - We describe a new right hemispheric behavioural syndrome for which we propose the name "hyperlalia". In a typical case an apparently unconcerned and expressionless patient is easily prompted to remarkable volubility with a content which is loose and incoherent. The voice is low and monotonous. All the lesions confirmed by computed tomography of the brain overlapped in the perisylvian area in the territory of the right middle cerebral artery.Loss of a subtle balance between the left hemispheric speech area and the corresponding area in the right hemisphere caused by acute damage of the right perisylvian area may have resulted in disinhibition of the speech function. Similarities and dissimilarities with the known pathology of talkativeness are also discussed. PMID- 24487239 TI - Face processing impairments and delusional misidentification. AB - We report detailed investigations of the face processing abilities of four patients who had shown symptoms involving delusional misidentification. One (GC) was diagnosed as a Fregoli case, and the other three (SL, GS, and JS) by symptoms of intermetamorphosis. The face processing tasks examined their ability to recognize emotional facial expressions, identify familiar faces, match photographs of unfamiliar faces, and remember photographs of faces of unfamiliar people. The Fregoli patient (GC) was impaired at identifying familiar faces, and severely impaired at matching photographs of unfamiliar people wearing different disguises to undisguised views. Two of the intermetamorphosis patients (SL and GS) also showed impaired face processing abilities, but the third US) performed all tests at a normal level. These findings constrain conceptions of the relation between delusional misidentification, face processing impairment, and brain injury. PMID- 24487240 TI - The neurology of proverbs. AB - Although proverb tests are commonly used in the mental status examination surprisingly little is known about either normal comprehension or the interpretation of proverbial expressions. Current proverbs tests have conceptual and linguistic shortcomings, and few studies have been done to investigate the specific effects of neurological and psychiatric disorders on the interpretation of proverbs. Although frontal lobes have traditionally been impugned in patients who are "concrete", recent studies targeting deficient comprehension of non literal language (e.g. proverbs, idioms, speech formulas, and indirect requests) point to an important role of the right hemisphere (RH). Research describing responses of psychiatrically and neurologically classified groups to tests of proverb and idiom usage is needed to clarify details of aberrant processing of nonliteral meanings. Meanwhile, the proverb test, drawing on diverse cognitive skills, is a nonspecific but sensitive probe of mental status. PMID- 24487241 TI - Cortical lewy body dementia. AB - In cortical Lewy body dementia the distribution of Lewy bodies in the nervous system follows that of Parkinson's disease, except for their greater profusion in the cerebral cortex. The cortical tangles and plaques of Alzheimer pathology are often present, the likely explanation being that Alzheimer pathology provokes dementia in many patients. Pure cortical Lewy body dementia without Alzheimer pathology is uncommon. The age of onset reflects that of Parkinson's disease, and clinical features, though not diagnostic, include aphasias, apraxias, agnosias, paranoid delusions and visual hallucinations. Parkinsonism may present before or after the dementia, and survival duration is approximately half that seen in Parkinson's disease without dementia. PMID- 24487242 TI - Characterizing nano-scale electrocatalysis during partial oxidation of methane. AB - Electrochemical analysis allows in situ characterization of solid oxide electrochemical cells (SOCs) under operating conditions. However, the SOCs that have been analyzed in this way have ill-defined or uncommon microstructures in terms of porosity and tortuosity. Therefore, the nano-scale characterization of SOCs with respect to three-phase boundaries has been hindered. We introduce novel in situ electrochemical analysis for SOCs that uses combined solid electrolyte potentiometry (SEP) and impedance measurements. This method is employed to investigate the oscillatory behavior of a porous Ni-yttria-stabilized zirconia (YSZ) anode during the partial oxidation of methane under ambient pressure at 800 degrees C. The cyclic oxidation and reduction of nickel induces the oscillatory behavior in the impedance and electrode potential. The in situ characterization of the nickel surface suggests that the oxidation of the nickel occurs predominantly at the two-phase boundaries, whereas the nickel at the three-phase boundaries remains in the metallic state during the cyclic redox reaction. PMID- 24487243 TI - Early inductive events in ectodermal appendage morphogenesis. AB - The embryonic surface ectoderm gives rise to the epidermis and ectodermal appendages including hair follicles, teeth, scales, feathers, and mammary, sweat, and salivary glands. Their early development proceeds largely the same through the induction, placode, and bud stages prior to diversification of epithelial morphogenesis which ultimately produces the wide array of mature organs. In this review we summarize the current knowledge on the molecular and cellular processes driving the shared stages of skin appendage development revealed by analysis of mouse mutants. We focus on three mammalian organs: hair follicle, tooth, and mammary gland. We reevaluate the information gained from classic epithelial mesenchymal tissue recombination experiments in light of current molecular knowledge. We place special emphasis on the signaling pathways that mediate tissue interactions, and attempt to link the signaling outputs to changes in cellular behavior that ultimately shape the developing organ. PMID- 24487244 TI - Brain-heart interactions in health and disease. PMID- 24487245 TI - No pain, no gain: somatosensation from skeletal muscle. PMID- 24487246 TI - Promising neuroprotective effects of the angiotensin-(1-7)-angiotensin-converting enzyme 2-Mas axis in stroke. PMID- 24487247 TI - Muscle-specific functional sympatholysis in humans. PMID- 24487248 TI - Sex differences in the perception of breathlessness: insights from measurements of neural respiratory drive. PMID- 24487249 TI - Analysis of fetal heart rate variability in frequency domain: methodical considerations. PMID- 24487250 TI - Quantifying the power spectrum of fetal heart rate variability. PMID- 24487252 TI - Intrapartum magnesium sulfate and the potential for cardiopulmonary drug-drug interactions. AB - BACKGROUND: This study sought to determine the frequency of possible cardiopulmonary drug-drug interactions among pregnant women who received intrapartum magnesium sulfate (MgSO4). METHODS: Pregnant women admitted to an Intermountain Healthcare facility between January 2009 and October 2011 were studied, if they received 1 or more doses of MgSO4. Concomitant medications were electronically queried from an electronic health records system. Adverse events were identified using administrative discharge codes. The frequency of cardiopulmonary drug-drug interactions was compared among women who did, and did not, receive aminoglycoside antibiotics, antacids/laxatives, calcium channel blockers, corticosteroids, diuretics, neuromuscular blocking agents, and vitamin D analogs, all of which were contraindicated for patients receiving MgSO4. RESULTS: Overall, 683 women received intrapartum MgSO4 during the study period. A total of 219 MgSO4 potentially interacting drugs were identified among 155 (23%) unique patients. The most commonly identified potentially interacting agents included calcium channel blockers (26%), diuretics (25%), and antacids/laxatives (19%). Longer hospital stays were significantly associated with increasing numbers of MgSO4 interacting drugs (P < 0.001). Three of 53 (6%) women who received furosemide experienced a cardiac arrest, compared with 0 of 618 (0%) women who did not receive furosemide (Fisher exact test, P < 0.001). CONCLUSIONS: Intrapartum administration of drugs that interact with MgSO4 is common and associated with prolonged hospital stays and potentially cardiopulmonary drug drug interactions. Caution is warranted when prescribing MgSO4 in combination with known interacting medications. PMID- 24487253 TI - Pharmacokinetics of treosulfan in pediatric patients undergoing hematopoietic stem cell transplantation. AB - BACKGROUND: High-dose treosulfan is used in conditioning regimens before hematopoietic stem cell transplantation in children. Pharmacokinetic data to optimize treosulfan dosing are scarce in this patient population. The aims of this study were the development and validation of an analytical method for treosulfan in human serum and the development of a pharmacokinetic model for treosulfan in pediatric patients. Furthermore, we aimed to develop a limited sampling strategy to estimate treosulfan systemic exposure with a minimum of inconvenience and risk for the patient. METHODS: A reversed phase high performance liquid chromatography method using ultraviolet detection to determine treosulfan in human serum samples was developed and validated according to food and drug administration guidelines. Serum pharmacokinetics after the first treosulfan administration was investigated in 20 children using nonlinear mixed effect modeling, and a limited sampling strategy was developed and validated. RESULTS: The assay was validated in a 10-500 mg/L concentration range with a lower limit of quantification of 10 mg/L. Accuracies were within the 90%-110% limit. The coefficients of variation of the within-day imprecision and between days imprecision were less than 5%. Pharmacokinetics was adequately described with a 1-compartment model. The population estimates for clearance (CL) and volume of distribution were 6.85 L/h and 13.2 L for a typical patient of 20 kg, respectively. Treosulfan exposure could be adequately quantified with 2 samples, at 4 and 7 hours after the start of a 3-hour treosulfan infusion, with a mean deviation of 3% of individual CL and area under the curve based on limited sampling in comparison with the full data set in a total cohort. CONCLUSIONS: In this study, a bioanalytical method, PK model, and limited sampling model were developed and validated. Furthermore, PK parameters of 20 pediatric patients were analyzed, demonstrating an interpatient variability in area under the curve of 14.5%. This study demonstrates the essential developments in the optimization of treosulfan therapy based on PK data. PMID- 24487254 TI - Novel electrochemical sensing platform based on magnetic field-induced self assembly of Fe3O4@Polyaniline nanoparticles for clinical detection of creatinine. AB - A novel electrochemical sensing platform based on magnetic field-induced self assembly of Fe3O4@Polyaniline nanoparticles (Fe3O4@PANI NPs) has been for the first time fabricated for the sensitive detection of creatinine in biological fluids. The template molecule, creatinine, was self-assembled on the surface of Fe3O4@PANI NPs together with the functional monomer aniline by the formation of N H hydrogen bonds. After pre-assembled, through the magnetic-induction of the magnetic glassy carbon electrode (MGCE), the ordered structure of molecularly imprinted polymers (MIPs) were established by the electropolymerization and assembled on the surface of MGCE with the help of magnetic fields by a simple one step approach. The structural controllability of the MIPs film established by magnetic field-induced self-assembly was further studied. The stable and hydrophilic Fe3O4@PANI can not only provide available functionalized sites with which the template molecule creatinine can form hydrogen bond by the abundant amino groups in PANI matrix, but also afford a promoting pathway for electron transfer. The as-prepared molecularly imprinted electrochemical sensor (MIES) shows good stability and reproducibility for the determination of creatinine with the detection limit reached 0.35 nmol L(-1) (S/N=3). In addition, the highly sensitive and selective MIES has been successfully used for the clinical determination of creatinine in human plasma and urine samples. The average recoveries were 90.8-104.9% with RSD lower than 2.7%. PMID- 24487255 TI - Sensitive SERS glucose sensing in biological media using alkyne functionalized boronic acid on planar substrates. AB - In this work, we propose a novel glucose binding mechanism on a highly sensitive SERS substrate, in order to overcome challenges in specific glucose detection in bio-fluids. We make use of phenylboronic acid as a receptor for saccharide capture onto the substrate and the ability of the captured glucose molecule to undergo secondary binding with an alkyne-functionalized boronic acid to form a glucose-alkyne-boronic acid complex. The formation of this complex shows high selectivity for glucose, over other saccharides. In addition, the alkyne group of the alkyne-functionalized boronic acid exhibits a distinct Raman peak at 1996 cm( 1) in a biological silent region (1800-2800 cm(-1)) where most endogenous molecules, including glucose, show no Raman scattering, thus offering a high sensitivity over other SERS glucose sensing. The substrate offers long-term stability, as well as high SERS enhancement to the glucose-alkyne boronic acid complex on substrate. In addition, the reversibility of SERS signals at various incubation stages also shows reusability capabilities, whereas positive results in clinical urine samples demonstrate clinical feasibility. All these strongly suggest that this newly developed SERS-based assay offers great potential in glucose sensing. PMID- 24487256 TI - Annual variation of (7)Be soil inventory in a semiarid region of central Argentina. AB - Reliable information on environmental radionuclides atmospheric entrance, and their distribution along the soil profile, is a necessary condition for using these soil and sediment tracers to investigate key environmental processes. To address this need, (7)Be content in rainwater and the wet deposition in a semiarid region at San Luis Province, Argentina, were studied. Following these researches, in the same region, we have assessed the (7)Be content along a soil profile, during 2.5 years from September 2009 to January 2012. As expected, the specific activity values in soil samples in the wet period (November-April) were higher than in the dry period (May-October). During the investigated period (2009 - beginning 2012) and for all sampled points, the maximum value of the (7)Be specific activity (Bq kg(-1)) was measured at the surface level. A typical decreasing exponential function of (7)Be areal activity (Bq m(-2)) with soil mass depth (kg m(-2)) was found and the key distribution parameters were determined for each month. The minimum value of areal activity was 51 Bq m(-2) in August, and the maximum was 438 Bq m(-2) in February. The relaxation mass depth ranges from 2.9 kg m(-2) in March to 1.3 kg m(-2) in August. (7)Be wet deposition can explain in a very significant proportion the (7)Be inventory in soil. During the period of winds in the region (September and October), the (7)Be content in soil was greater than the expected contribution from wet deposition, situation that is compatible with a higher relative contribution of dry deposition at this period of the year. PMID- 24487257 TI - Dick Tracy, APRN. PMID- 24487258 TI - Intravenous magnesium sulfate reduces rates of mechanical ventilation in pediatric asthma. AB - In this column, we examine an original research article by S. Torres et al. (2012) on the subject of magnesium sulfate use in pediatric patients with acute asthma. These researchers found that patients treated with 25 mg/kg of intravenous magnesium sulfate in addition to the conventional treatment options for acute asthma were less likely to require mechanical ventilation than patients in the control group. We review and critique this article and use a case study to illustrate the clinical implications of this research. We also examine some of the research and guidelines pertaining to the use of magnesium sulfate in acute asthma. PMID- 24487259 TI - Assessment of acute hand injuries: part I. AB - More than 140,000 hand injuries occur yearly, and an estimated 5 days of loss of work per patient occurs (Bureau of Labor Statistics, 2012). Advanced practice registered nurses (APRNs) are responsible for managing many of these injuries in primary and emergency care settings. Hand injuries are responsible for approximately 10% of all emergency department visits annually (P. Shayne, S.H. Plantz, & F. Talavera, 2012). This article reviews approaches to the assessment of the patient with a hand injury and establishes a process for basic identification of the hand structures and function. Approaches to history taking and specific evaluations for the hand will be discussed and examples of the assessments will be provided. Diagnostic approaches to support physical findings will be discussed, and methods of radiologic assessment will support the audience in making appropriate diagnosis in relation to hand injuries. This is Part I of a three-part series that will validate the approaches to hand assessment for adults and children and identify specific injuries and their management for the APRN. PMID- 24487260 TI - Being prepared: emergency treatment following a nerve agent release. AB - Nerve agents are extremely toxic and are some of the most lethal substances on earth. This group of chemicals consists of sarin, cyclosarin, soman, tabun, VX, and VR. It is currently unknown how many countries possess these chemicals and in what quantities. These agents work through altering the transmission and breakdown of acetylcholine by binding to, and inactivating, acetylcholinesterase. This results in an uncontrolled and overwhelming stimulation of both muscarinic and nicotinic receptors. Receptor activation at these sites can lead to a wide variety of clinical symptoms, with death frequently resulting from pulmonary edema. Antidotal therapy in this setting largely consists of atropine, pralidoxime, and benzodiazepines, all of which must be administered emergently to limit the progression of symptoms and prevent the enzyme inactivation from becoming permanent. This article reviews the mechanism of action of the nerve agents and their effects on the human body, the currently available therapies to mitigate their impact, and important therapeutic considerations for health care practitioners in the emergency department. PMID- 24487262 TI - Pyogenic flexor tenosynovitis: assessment and management in the emergency department setting. AB - Emergency departments are frequently confronted with had infections. Significant morbidity can result from hand infections when they are not appropriately diagnosed or treated. Clinical recognition, proper initial evaluation, and treatment are key to prevent functional deficit or devastated morbidity when confronted with hand infections. Pyogenic flexor tenosynovitis is an orthopedic emergency where health care outcomes depend on timely management, prompt recognition, and appropriate treatment. A case report is presented of a patient with worsening pain of a digit after a penetrating injury. The diagnosis was made on the basis of clinical findings and plain radiography. PMID- 24487263 TI - Handoff communication from the emergency department to primary care. AB - Handoff communication deficiencies between the emergency department (ED) and primary care have been recognized as the result of delays and/or omissions in follow-up care for patients. This quality improvement project addresses the gaps in follow-up care for patients with low-risk chest pain by implementing an electronic Emergency Provider Written Plan of Discharge (eEPWPD) template to notify primary care providers (PCPs) that follow-up care is needed for their patients. This retrospective study evaluated effectiveness of the template in providing additional diagnostic and follow-up care. Results indicated that following the implementation of the eEPWPD template, follow-up for this population increased significantly. This study provides evidence that standardizing handoff communication from the ED to PCP can improve the quality of patient care by ensuring timely diagnostic and follow-up care. PMID- 24487264 TI - An innovative fever management education program for parents, caregivers, and emergency nurses. AB - Parents frequently present to the emergency department (ED) concerned about their child's fever. Fever management education programs have been found to improve parents' knowledge of managing fever, although no education program was identified that specifically considered parents with lower functional health literacy. This article describes the development of an easily understood children's fever management education program for parents with varying levels of health literacy. A review of existing literature and guidelines was conducted. Pictorial images and written material constrained to fifth-grade level of readability were used. Academics and ED experts confirmed the content of this evidence-based program. The education program, a combination of Digital Video Disc (DVD) and a brochure in relation to child fever management, is currently being trailed at an ED in Sydney and is appropriate for EDs or primary care settings. Tailoring education programs with plain and simple language is potentially beneficial to all parents (or caregivers) presenting to the ED with children experiencing fever. This program will provide nurses with a simple and clear fever management brochure or DVD to give to parents or caregivers with varying levels of health literacy. We envisage that this program will be continuously televised within local EDs and available for parents or caregivers to view online. PMID- 24487265 TI - Requesting wrist radiographs in emergency department triage: developing a training program and diagnostic algorithm. AB - Crowding is extremely problematic in Canada, as the emergency department (ED) utilization is considerably higher than in any other country. Consequently, an increase has been noted in waiting times for patients who present with injuries of lesser acuity such as wrist injuries. Wrist fractures are the most common broken bone in patients younger than 65 years. Many nurses employed within EDs are requesting wrist radiographs for patients who present with wrist complaints as a norm within their working practice. Significant potential advantages can ensue if EDs adopt a triage nurse-requested radiographic protocol; patients can benefit from a significant time-saving of 36% in ED length of stay (M. Lindley Jones & B. J Finlayson, 2000)- when nurses initiated radiographs in triage. In addition, the literature suggests that increased rates of patient and staff satisfaction may be achieved, without compromising quality of radiographic request or quality of service (W. Parris,S. McCarthy, A. M. Kelly, & S. Richardson, 1997). Studies have shown that nurses are capable of requesting appropriate radiographs on the basis of a preset protocol. As there are no standardized set of rules for assessing patients, presenting with suspected wrist fractures, a training program as well as a diagnostic algorithm was developed to prepare emergency nurses to appropriately request wrist radiographs. The triage nurse-specific training program includes the following topics: wrist anatomy and physiology, commonly occurring wrist injuries, mechanisms of injury, physical assessment techniques, and types of radiographic images required. The triage nurse algorithm includes the clinical decision-making process. Providing triage nurses with up-to-date evidence-based educational material not only allowed triage nurses to independently assess and request wrist radiographs for patients with potential wrist fractures but also strengthening the link between competent nursing care and better patient outcomes. A review of the literature also found that such initiatives increase patient and staff satisfaction as well as promoting efficient use of right staff at the right time. PMID- 24487266 TI - Implementing diagnostic reasoning to differentiate Todd's paralysis from acute ischemic stroke. AB - Emergency department clinicians with limited resources are relied upon to deliver safe and timely patient care. Clinicians rely on cognitive biases such as anchoring, availability, and premature closure based on experience and quick mental algorithms to streamline medical data and arrive at a diagnosis. Although this is a time-saving and efficient method in the management of uncomplicated illnesses, it can result in a wrong diagnosis when managing patients with complicated presentations such as a stroke or a stroke mimic. Two conditions that present similarly, making it difficult to differentiate between them, are Todd's paralysis (a stroke mimic seen in selected patients with epilepsy) and acute ischemic stroke. However, by clinical reasoning, clinicians can formulate an accurate diagnosis while avoiding diagnostic biases. Incorporating clinical reasoning into the diagnostic process consists of gathering pertinent data, performing a diagnostic time-out, and arriving at a diagnosis reflective of data findings. PMID- 24487267 TI - Teaching management of the unexpected birth: application of multimodal techniques. AB - The ability to safely manage birth in the emergency department is a competency for emergency nurse practitioner practice. However, it is difficult to ensure that students receive enough practice with this low-frequency event. To meet this need, we created a learning environment combining readings, skills videos, lecture, practice with models, simulation, and debriefing to assist students in providing safe care to women giving birth in the emergency department. This program, which includes a high-fidelity, low-technology simulation, has been successfully implemented with excellent results. The realistic nature of the simulations, use of recently graduated nurse-midwives as the simulated patients, and group interactions during the births were keys to this successful simulation experience. When paired with appropriate preparation, simulation of an unexpected birth in the emergency department promotes confidence and safe practice among advanced practice nursing students. PMID- 24487268 TI - Children at risk of maltreatment: identification and intervention in the emergency department. AB - Child maltreatment is a leading cause of pediatric morbidity and mortality, described as one of the greatest threats facing the health, welfare, and social well-being of children in the United States (U.S. Department of Health and Human Services, 2012). Despite mandatory reporting laws, the poignant reality is that this public health problem is significantly underrecognized and underreported by heath care providers. The purpose of this project was to implement a series of strategies in a pediatric emergency department to identify children who are at risk of maltreatment and initiate interventions to ensure their safety and protection before a devastating outcome occurs. The results of this project support the implementation of nursing education, a screening program for risk of child maltreatment, and collaboration with interdisciplinary stakeholders to achieve best practice in emergency medicine. PMID- 24487272 TI - Norovirus triggered microbiota-driven mucosal inflammation in interleukin 10 deficient mice. AB - BACKGROUND: Infection may trigger clinically overt mucosal inflammation in patients with predisposition for inflammatory bowel disease. However, the impact of particular enteropathogenic microorganisms is ill-defined. In this study, the influence of murine norovirus (MNV) infection on clinical, histopathological, and immunological features of mucosal inflammation in the IL10-deficient (Il10) mouse model of inflammatory bowel disease was examined. METHODS: C57BL/6J and C3H/HeJBir wild-type and Il10 mice kept under special pathogen-free conditions and devoid of clinical and histopathological signs of mucosal inflammation were monitored after MNV infection for structural and functional intestinal barrier changes by in situ MNV reverse transcription PCR, transgene reporter gene technology, histology, flux measurements, quantitative real-time PCR, immunohistology, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. In addition, the influence of the enteric microbiota was analyzed in MNV-infected germfree Il10 mice. RESULTS: Although MNV-infected wild-type mice remained asymptomatic, mucosal inflammation was noted in previously healthy Il10 mice 2 to 4 weeks after infection. MNV-induced changes in Il10 mice included increased paracellular permeability indicated by increased mucosal mannitol flux, reduced gene expression of tight junction molecules, and an enhanced rate of epithelial apoptosis. MNV-induced reduction of tight junction protein expression and inflammatory lesions were absent in germfree Il10 mice, whereas epithelial apoptosis was still observed. CONCLUSIONS: Despite its subclinical course in wild type animals, MNV causes epithelial barrier disruption in Il10 animals representing a potent colitogenic stimulus that largely depends on the presence of the enteric microbiota. MNV might thus trigger overt clinical disease in individuals with a nonsymptomatic predisposition for inflammatory bowel disease by impairment of the intestinal mucosa. PMID- 24487273 TI - Discrepancies in health information found on web sites discussing cures for inflammatory bowel disease, an "incurable" disease. AB - BACKGROUND: Inflammatory bowel disease, which can take the form of ulcerative colitis or Crohn's disease, is said by most doctors to be incurable, although surgery is sometimes considered a cure for ulcerative colitis but not Crohn's disease. Because of the unpredictable nature of the disease, however, and the devastating symptoms it can have, many people are driven to search for cures online, despite what their doctors may recommend. METHODS: This qualitative content analysis looked at the top search results in Google and Bing for inflammatory bowel disease cures. We examined 63 search results returned using a variety of search terms. Search results included articles, entire Web sites, YouTube videos, health forums, and an e-book. RESULTS: The Web sites generally fell into 2 categories: those that said no cure exists and those that advocated for specific cures. The following themes were pulled from the data: an inconsistent definition of a cure; an anti-Western medicine bias; medical disclaimers that are ignored by Web sites that feature them; a lack of clarity in cure regimens; and inter-article contradictions. CONCLUSIONS: Many people with inflammatory bowel disease do not like hearing that the disease has no cure or they do not believe their doctor when told this. Medical professional Web sites often say very little about what a cure looks like or how it is defined medically. Well-meaning patients have filled this void with their own definitions of a cure. Physicians need to be aware of what information patients can find online because many patients are unwilling to share this information. PMID- 24487271 TI - Clinical, serologic, and genetic factors associated with pyoderma gangrenosum and erythema nodosum in inflammatory bowel disease patients. AB - BACKGROUND: Pyoderma gangrenosum (PG) and erythema nodosum (EN) are the most common cutaneous manifestations of inflammatory bowel disease (IBD) but little is known regarding their etiopathogenesis. METHODS: We performed a case-control study comparing characteristics between IBD patients with a documented episode of PG (PG+) and/or EN (EN+) with those without PG (PG-) and EN (EN-). Data on clinical features were obtained by chart review. IBD-related serology was determined using enzyme-linked immunosorbent assay and genome-wide data generated using Illumina technology. Standard statistical tests for association were used. RESULTS: We identified a total of 92 cases of PG and 103 cases of EN with genetic and clinical characteristics, of which 64 PG and 55 EN cases were available for serological analyses. Fewer male subjects were identified in the PG(+) (odds ratio 0.6, P = 0.009) and EN(+) groups (odds ratio 0.31, P = 0 < 0.0001). Colonic disease, previous IBD-related surgery, and noncutaneous extra-intestinal manifestations were more common among both PG(+) and EN(+) patients compared with controls. PG(+) was associated with anti-nuclear cytoplasmic antibody seropositivity (P = 0.03) and higher anti-nuclear cytoplasmic antibody level (P = 0.02) in Crohn's disease. Genetic associations with PG included known IBD loci (IL8RA [P = 0.00003] and PRDM1 [0.03]) as well as with USP15 (4.8 * 10) and TIMP3 (5.6 *10). Genetic associations with EN included known IBD susceptibility genes (PTGER4 [P = 8.8 * 10], ITGAL [0.03]) as well as SOCS5 (9.64 * 10), CD207 (3.14 * 10), ITGB3 (7.56 * 10), and rs6828740 (4q26) (P < 5.0 * 10). Multivariable models using clinical, serologic, and genetic parameters predicted PG (area under the curve = 0.8) and EN (area under the curve = 0.97). CONCLUSION: Cutaneous manifestations in IBD are associated with distinctive genetic characteristics and with the similar clinical characteristics, including the development of other extra-intestinal manifestations suggesting shared and distinct etiologies. PMID- 24487274 TI - Radioactive impact of the Fukushima nuclear accident on Shenyang in the northeast of China. AB - Environmental monitoring was carried out in Shenyang in the northeast of China after the Fukushima Daiichi nuclear accident which was caused by the earthquake and tsunami on 11 March 2011. The fission product radionuclide (131)I was detected as present in the atmosphere on the 20th day after the nuclear accident, while the radionuclides (134)Cs and (137)Cs were found in the atmosphere on the 27th day after the accident. The radionuclides (131)I, (134)Cs and (137)Cs continued to be present in the atmosphere for 25, 4 and 6 days, respectively, with maximum concentrations of 4.60 +/- 0.2, 0.29 +/- 0.06 and 0.42 +/- 0.08 mBq m(-3). The contents of fission radionuclides in vegetables, drinking water and milk from Shenyang were below the detection limits. The atmosphere was slightly contaminated in Shenyang due to the Fukushima nuclear accident, but no contamination was detected in vegetables, milk and drinking water. PMID- 24487275 TI - Lis1 regulates asymmetric division in hematopoietic stem cells and in leukemia. AB - Cell fate can be controlled through asymmetric division and segregation of protein determinants, but the regulation of this process in the hematopoietic system is poorly understood. Here we show that the dynein-binding protein Lis1 is critically required for hematopoietic stem cell function and leukemogenesis. Conditional deletion of Lis1 (also known as Pafah1b1) in the hematopoietic system led to a severe bloodless phenotype, depletion of the stem cell pool and embryonic lethality. Further, real-time imaging revealed that loss of Lis1 caused defects in spindle positioning and inheritance of cell fate determinants, triggering accelerated differentiation. Finally, deletion of Lis1 blocked the propagation of myeloid leukemia and led to a marked improvement in survival, suggesting that Lis1 is also required for oncogenic growth. These data identify a key role for Lis1 in hematopoietic stem cells and mark its directed control of asymmetric division as a critical regulator of normal and malignant hematopoietic development. PMID- 24487276 TI - A general framework for estimating the relative pathogenicity of human genetic variants. AB - Current methods for annotating and interpreting human genetic variation tend to exploit a single information type (for example, conservation) and/or are restricted in scope (for example, to missense changes). Here we describe Combined Annotation-Dependent Depletion (CADD), a method for objectively integrating many diverse annotations into a single measure (C score) for each variant. We implement CADD as a support vector machine trained to differentiate 14.7 million high-frequency human-derived alleles from 14.7 million simulated variants. We precompute C scores for all 8.6 billion possible human single-nucleotide variants and enable scoring of short insertions-deletions. C scores correlate with allelic diversity, annotations of functionality, pathogenicity, disease severity, experimentally measured regulatory effects and complex trait associations, and they highly rank known pathogenic variants within individual genomes. The ability of CADD to prioritize functional, deleterious and pathogenic variants across many functional categories, effect sizes and genetic architectures is unmatched by any current single-annotation method. PMID- 24487277 TI - Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing. AB - Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73-75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development. PMID- 24487279 TI - Dewetting properties of metallic liquid film on nanopillared graphene. AB - In this work, we report simulation evidence that the graphene surface decorated by carbon nanotube pillars shows strong dewettability, which can give it great advantages in dewetting and detaching metallic nanodroplets on the surfaces. Molecular dynamics (MD) simulations show that the ultrathin liquid film first contracts then detaches from the graphene on a time scale of several nanoseconds, as a result of the inertial effect. The detaching velocity is in the order of 10 m/s for the droplet with radii smaller than 50 nm. Moreover, the contracting and detaching behaviors of the liquid film can be effectively controlled by tuning the geometric parameters of the liquid film or pillar. In addition, the temperature effects on the dewetting and detaching of the metallic liquid film are also discussed. Our results show that one can exploit and effectively control the dewetting properties of metallic nanodroplets by decorating the surfaces with nanotube pillars. PMID- 24487278 TI - Whole-genome sequence of a flatfish provides insights into ZW sex chromosome evolution and adaptation to a benthic lifestyle. AB - Genetic sex determination by W and Z chromosomes has developed independently in different groups of organisms. To better understand the evolution of sex chromosomes and the plasticity of sex-determination mechanisms, we sequenced the whole genomes of a male (ZZ) and a female (ZW) half-smooth tongue sole (Cynoglossus semilaevis). In addition to insights into adaptation to a benthic lifestyle, we find that the sex chromosomes of these fish are derived from the same ancestral vertebrate protochromosome as the avian W and Z chromosomes. Notably, the same gene on the Z chromosome, dmrt1, which is the male-determining gene in birds, showed convergent evolution of features that are compatible with a similar function in tongue sole. Comparison of the relatively young tongue sole sex chromosomes with those of mammals and birds identified events that occurred during the early phase of sex-chromosome evolution. Pertinent to the current debate about heterogametic sex-chromosome decay, we find that massive gene loss occurred in the wake of sex-chromosome 'birth'. PMID- 24487280 TI - Solid-phase extraction and purification of membrane proteins using a UV-modified PMMA microfluidic bioaffinity MUSPE device. AB - We present a novel microfluidic solid-phase extraction (MUSPE) device for the affinity enrichment of biotinylated membrane proteins from whole cell lysates. The device offers features that address challenges currently associated with the extraction and purification of membrane proteins from whole cell lysates, including the ability to release the enriched membrane protein fraction from the extraction surface so that they are available for downstream processing. The extraction bed was fabricated in PMMA using hot embossing and was comprised of 3600 micropillars. Activation of the PMMA micropillars by UV/O3 treatment permitted generation of surface-confined carboxylic acid groups and the covalent attachment of NeutrAvidin onto the MUSPE device surfaces, which was used to affinity select biotinylated MCF-7 membrane proteins directly from whole cell lysates. The inclusion of a disulfide linker within the biotin moiety permitted release of the isolated membrane proteins via DTT incubation. Very low levels (~20 fmol) of membrane proteins could be isolated and recovered with ~89% efficiency with a bed capacity of 1.7 pmol. Western blotting indicated no traces of cytosolic proteins in the membrane protein fraction as compared to significant contamination using a commercial detergent-based method. We highlight future avenues for enhanced extraction efficiency and increased dynamic range of the MUSPE device using computational simulations of different micropillar geometries to guide future device designs. PMID- 24487281 TI - Sideritis scardica Griseb., an endemic species of Balkan peninsula: traditional uses, cultivation, chemical composition, biological activity. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Sideritis scardica Griseb. is an endemic species in the Balkan Peninsula. It is used in traditional medicine as a loosening agent in bronchitis and bronchial asthma; against the common cold and lung emphysema; in the treatment of inflammation, gastrointestinal disorders and coughs; and as an active constituent of dietary supplements for the prevention of anemia. This review aims to provide a comprehensive overview of the traditional use, phytochemistry, biological activity, cultivation, and extraction of Sideritis scardica and to highlight the gaps in our knowledge which deserves further research. MATERIALS AND METHODS: The present review is based on information collected from scientific journals, books, and electronic search. These sources include Scopus, Pubmed, Web of Science, and Google scholar as well as local books on ethnopharmacology and botany of this plant. RESULTS: The reported data on phytochemical studies, biological activity, cultivation, extraction, and traditional uses have been reviewed. Variability in essential oil composition of wild growing and cultivated taxa depending on ecological conditions was discussed. Flavonoids, phenylethanoids, diterpenoids, aliphatic compounds, etc. identified so far have been summarized. A comparative study on the effectiveness of different methods, solvents, and parameters of extraction has also been discussed. A broad range of activities of plant extracts and fractions as antimicrobial, anti-inflammatory, cytotoxic, antioxidant, gastroprotective, antiglioma, and triple monoamine reuptake inhibition as well as cultivation of the species as an approach for conservation of the natural habitats and provision of herb with high and permanent quality has also been presented. CONCLUSIONS: Sideritis scardica has become very popular and widely advertised herb in Europe. Although some of ethnobotanical uses have been proved through in vitro experiments, further studies of the individual compounds or chemical class of compounds responsible for the pharmacological effects and the mechanisms of action are necessary. In addition, the toxicity and the side effects from the use of Sideritis scardica as well as clinical trails need attention. The variability in the chemical composition of this medicinal plant depending on the origin requires development of a protocol for its standardization. For the practice it is important to improve cultivation conditions in order to increase the accumulation of biologically active compounds and to obtain herb with permanent and good quality. PMID- 24487283 TI - Intra-articular fractures of the distal radius: bridging external fixation in slight flexion and ulnar deviation along articular surface instead of radial shaft. AB - Forty-one patients with intra-articular fracture of the distal radius (AO Type C) were treated with a double joint-bridging external fixator placed radial side of the fracture site and the wrist placed in slight flexion and ulnar deviation equal to the palmar tilt and radial inclination of the uninjured wrist. The patients were evaluated according to the system of Gartland and Werley an average of 43 months (range, 34 to 53 mo) after surgery. There were 14 excellent, 18 good, 7 fair, and 2 poor results. The average flexion was 94% of the normal side, extension 91%, pronation 95%, and supination 84%. The average radial inclination was 22 +/- 10 degrees, palmar tilt 8 +/- 14 degrees, and maximum articular step or gap was 2 mm. Bridging external fixation with slight wrist flexion and ulnar deviation equal to preinjured palmar tilt and radial inclination provides acceptable clinical and radiologic results. PMID- 24487282 TI - Treating acute Essex-Lopresti injury with the TightRope device: a case study. AB - Essex-Lopresti injury consists of a fracture or dislocation of the radial head, rupture of the interosseous membrane (IOM), which is the main pathology, and a dislocated distal radio-ulnar joint. There are several reports in the literature, including cadaveric studies, which suggest an operative solution for this complicated injury. The torn IOM is not treated during the traditional operative repair. In the following paper, we suggest a treatment for the IOM by unloading it with the TightRope device. This device temporarily takes the tension off the torn IOM and assists in reduction and maintenance of the longitudinal ratios between the radius and the ulna, while allowing its healing. Recently, we have treated one patient with this system. The application of the TightRope technique in this acute injury and the follow-up are described in this case report. PMID- 24487284 TI - Beyond the technique. PMID- 24487285 TI - Dorsoradial ligament imbrication for thumb carpometacarpal joint instability. AB - Dorsoradial ligament imbrication is a direct and effective alternative to ligament reconstruction or metacarpal osteotomy in patients with symptomatic thumb carpometacarpal (CMC) joint instability. This procedure is performed by imbricating either the trapezial or the metacarpal attachment of the dorsoradial ligament with the use of a suture anchor. The procedure is indicated in the setting of chronic hyperlaxity or instability of the thumb CMC joint. Significant arthritic changes in the thumb CMC joint are a contraindication for this procedure. We present our technique along with an anatomic dissection to demonstrate the ligament and surgical procedure on an anatomic specimen. We also present results from 3 patients who underwent this technique with images and clinical results for 3 patients with long-term follow-up. LEVEL OF EVIDENCE: Level IV-Therapeutic. PMID- 24487287 TI - Is disturbed transfer of learning in callosal agenesis due to a disconnection syndrome? AB - Disturbed intermanual transfer of tactile learning in callosal agenesis has been interpreted as a sign of disconnection syndrome. We observed this sign in one of four acallosal patients with a conventional form-board task, and tried to elucidate the nature of the deficit. The form-board performance of the patient with disturbed transfer of learning totally depended on motor skill, while the other acallosals and normal controls executed the task based on spatial and somesthetic information. All acallosals and normals, however, failed to show transfer of learning with another tactile task which needed motor skill but not spatial-somesthetic information. These findings suggest that the task-performing strategies in form-board learning change the state of interhemispheric transfer. Unimanual learning effect is transferred if spatial-somesthetic information is acquired in the process of learning, but is not transferred if motor skill is the exclusive content of learning. We conclude that disturbed "transfer" of learning in some acallosals is not a true disconnection sign. It should be attributed to a lack of appropriate strategy, as a result of ineffective problem solving in tactile tasks. PMID- 24487286 TI - The P2Y13 receptor regulates phosphate metabolism and FGF-23 secretion with effects on skeletal development. AB - Purinergic signaling mediates many cellular processes, including embryonic development and regulation of endocrine signaling. The ADP P2Y13 receptor is known to regulate bone and stem cells activities, although relatively little is known about its role in bone development. In this study we demonstrate, using contemporary techniques, that deletion of the P2Y13 receptor results in an age dependent skeletal phenotype that is governed by changes in phosphate metabolism and hormone levels. Neonatal and postnatal (2 wk) P2Y13 receptor-knockout (KO) mice were indistinguishable from their wild-type (WT) littermate controls. A clear bone phenotype was observed in young (4-wk-old) KO mice compared WT controls, with 14% more trabecular bone, 35% more osteoblasts, 73% fewer osteoclasts, and a 17% thicker growth plate. Mature (>10 wk of age) KO mice showed the opposite bone phenotype, with 14% less trabecular bone, 22% fewer osteoblasts, and 10% thinner growth plate. This age-dependent phenotype correlated with serum fibroblast growth factor-23 (FGF-23) and phosphorus levels that were 65 and 16% higher, respectively, in young KO mice but remained unchanged in mature mice. These findings provide novel insights for the role of the P2Y13 receptor in skeletal development via coordination with hormonal regulators of phosphate homeostasis. PMID- 24487288 TI - Factorial structure of cognitive activity using a neuropsychological test battery. AB - A general neuropsychological test battery was assembled and individually given to a 98-subject sample, aged 11-12 years old. The battery included some basic and common tests routinely used in the evaluation of language, memory, spatial abilities, concept formation, and praxic abilities. Twenty-five different scores were calculated. A factor analysis with varimax rotation disclosed nine different factors, accounting for about 70% of the variance. Factor I was measured by a Sequential Verbal Memory test and Verbal Fluency subtests ("verbal factor"). Factor II was measured by the Wechsler Memory Scale Visual Memory subtests (immediate and delayed reproduction), and the Rey-Osterrieth Complex Figure (copy and immediate reproduction) ("non-verbal memory and constructional factor"). Factor III was measured by the WMS Logical Memory subtests (immediate and delayed; "verbal memory factor"). Factor IV was associated with fine movements (tapping subtests, right and left hand; "fine movements factor"). Factor V was specially measured by the Information subtest of the WMS and the Boston Naming Test ("verbal knowledge"). Factor VI represented a "praxic ability factor" (ideomotor praxis tests). Delayed Associative Learning subtest measured Factor VII; and Digits measured Factor VIII. Factor IX was a "mental control factor" (Mental Control subtest of the Wechsler Memory Scale). The implications of these results to theories relating to the structure of cognitive activity are discussed. PMID- 24487289 TI - Do young schizophrenics with recent onset of illness show evidence of hypofrontality? AB - Young schizophrenic patients (n=43), manic controls (n=32), both groups diagnosed according to the Research Diagnostic Criteria and on remission from acute illness, and 53 normal subjects were given a battery of neuropsychologic tests selected to assess different functional areas in the brain. Compared with normal controls, patient groups showed evidence of impaired functioning of many cortical areas but with the schizophrenics having the worst performance. In addition, schizophrenic patients performed poorly in tests designed to assess frontotemporal cortical functioning. This pattern of deficits differentiated schizophrenics from both manic and normal subjects. The results suggest that widespread cognitive deficits are a feature of both schizophrenia and mania but that frontal lobe dysfunction may be more specific to the former. It would also appear that these impairments are not artefacts of age, chronicity or of institutionalization, and are present even in schizophrenic patients who may have an illness with putative better outcome than those studied in previous reports. PMID- 24487290 TI - Can tactile neglect occur at an intra-limb level? Vibrotactile reaction times in patients with right hemisphere damage. AB - Visual reaction time (RT) studies on patients with right hemisphere (RH) damage have demonstrated that the attentional imbalance to stimuli occupying left and right positions exists even within the "intact" ipsilesional hemifield. The purpose of the present study was to test whether such patients might also exhibit relative left-sided impairments in the tactile modality, where stimuli and responses involve the index and middle fingers of the non-hemiplegic ipsilesional hand. Eight patients with RH damage, and eight matched normal controls, were tested using a vibrotactile choice RT paradigm, with the responding hand held in prone or supine posture, and located either at the body midline, or in left or right hemispace. Patients showed significantly slower RTs with the left than the right finger in both hand postures, a difference which remained constant as a function of the hemispatial location of the responding hand. In the prone posture, patients' left finger RTs were slower than those of controls, who showed no difference between left and right finger RTs, while their right finger RTs were faster than those of controls. In the supine posture, both patients and controls exhibited slower left than right finger RTs, though in controls the left finger disadvantage was attributed to biomechanical rather than attentional factors. Patients also made more errors with left than right finger stimuli, both as failures of detection and as incorrect responses, while controls made fewer errors overall and showed no differences between fingers. These data demonstrate a bias in the distribution of attention to tactile stimuli at an intra-limb level, and suggest that the attentional imbalance created by RH damage may be supramodal. PMID- 24487291 TI - A selective agraphia of Kana. AB - We report a patient who developed selective Kana (phonogram) agraphia following an infarct in the left middle frontal gyrus known as Exner's area. He had well preserved ability for comprehension, reading, and writing Kanji (ideogram). Kana errors consisted of substitution with another letter while the number of target words was well preserved. It is suggested that a dominant middle frontal gyrus lesion can result in agraphia. PMID- 24487292 TI - Progressive perceptual-motor impairment without generalized dementia: a type of cortical degenerative syndrome. AB - A patient developed slowly progressive clumsiness of both upper extremities with associated impainnent of daily activities without loss of muscle strength or abnormal muscle tone. Her sensory function was normal in the primary modalities but was impaired in the discriminative tasks. A single photon emission computed tomography using 123I-iodoamphetamine showed the areas with reduced uptake in the postcentral cortices. Based on the analysis of her motor impairment, we conclude that clumsiness of hands results from higher sensory disturbance. PMID- 24487293 TI - Anterograde and retrograde amnesia following bitemporal infarction. AB - A patient suffered very severe anterograde and retrograde amnesia following infarction of both medial temporal lobes (hippocampus and adjacent cortex) and the left inferior temporo-occipital area. The temporal stem and the amygdala were intact; these structures do not appear to be critical for new learning in humans. Extension of the left-sided infarct into the inferior temporo-occipital lobe, an area critically involved in visual processing, appears to be responsible for our patient's loss of remote memories. PMID- 24487294 TI - An unusual psychiatric emergency: herpes simplex encephalitis. AB - A case of fatal herpes simplex virus (HSV) encephalitis, presenting as a psychiatric emergency, is reported. The possibility of HSV encephalitis presenting mainly or solely with psychiatric symptoms is highlighted. HSV can cause a severe form of encephalitis which may present with mainly psychiatric symptoms in some cases. Early treatment with anti-viral agents can reduce mortality and morbidity, but accurate early diagnosis may be very difficult. HSV encephalopathy may mimic psychiatric illness and has been likened to syphilis as the great imitator. The case presented here should serve to raise awareness of the psychiatric features and the need to consider this diagnosis in patients with atypical behavioural disturbance. PMID- 24487295 TI - Asymmetrical blood flow in the temporal lobe in the Charles Bonnet syndrome: serial neuroimaging study. AB - Clinical features and results of neuroimagings of an 86 year old woman with the Charles Bonnet syndrome are reported. She had become completely blind bilaterally due to cataracts and glaucoma. Shortly after an operation for cataracts, she developed visual hallucinations which lasted for 22 years. She had no deterioration of intelligence. Computed tomography (CT) and magnetic resonance imaging (MRI) showed moderate generalized atrophy, particularly of the temporal lobes. A serial single photon emission computed tomography (SPECT) study during visual hallucinations demonstrated hyperperfusion in the left temporal region and the basal ganglia and hypoperfusion in the right temporal region. These findings suggest that asymmetrical blood flow, particularly in the temporal regions, may be correlated with visual hallucination in the Charles Bonnet syndrome. PMID- 24487296 TI - Psychopathology of time in brain disease and schizophrenia. AB - The literature on disturbance of time-sense in brain disease and schizophrenia is reviewed and the subjective experience of altered time-sense reported by 45 out of 350 personally interviewed schizophrenics is analyzed. A review of the literature on the effect of brain damage revealed that some phenomena (deja vu, reduplication of time, altered tempo to events) were linked with right hemisphere dysfunction, one phenomenon (incorrect sequencing of events) was linked with left anterior brain damage, and others (disrupted "biological clock", disturbed serise of rate of flow of current or past events) could arise from subcortical as well as focal cortical damage. The sparse literature on disturbed time-sense in schizophrenia suggested that there was a shared psychopathology in this respect with right hemisphere dysfunction. The phenomena encountered in the 45 schizophrenics are described and classified. PMID- 24487297 TI - Motor Habits in Visuo-manual Tracking: Manifestation of an Unconscious Short-term Motor Memory? AB - Normal subjects were tested in short, repetitive trials of a tracking task, with an identical shape of target movement being used throughout one session. Analysis of the net error curves (pursuit minus target movement) revealed that subjects regularly exhibit a remoteness effect: neighbouring trials were more similar than distant ones. The effect is demonstrated to be stronger in the absence of visual cues, and was found to be absent in a patient with complete loss of proprioception when he was performing without visual feedback as well.The results are discussed in terms of a short term memory store contributing to unconscious movement habits in tracking. This may represent part of the motor learning process working together with conscious visuo-motor control mechanisms. Its function is probably related to the acquisition of automatic movements. PMID- 24487298 TI - A Longitudinal Follow-up Study of Depression, Disability, and Body Concept in Torticollis. AB - Changes in depression, disability, body concept, and severity of head deviation were examined in a sample of 67 patients with idiopathic torticollis, who were reassessed 2 years after taking part in an initial study (before the use of botulinum toxin injections). Over the follow-up period, torticollis was unchanged in 41.8%, had improved in 26.9% and deteriorated in 31.3% of cases. The overall levels of depression, disability, and body concept across the two occasions did not change. Changes in the clinical severity of torticollis over the follow-up period had a significant effect on psychological adjustment. Those whose torticollis improved were less depressed and disabled and a had a more positive body concept compared to the patients whose torticollis had worsened. Measures of illness severity had stronger associations with measures of psychological adjustment at follow-up than at the time of initial study. Longer duration of torticollis was associated with larger increases in depression and disability during the 2 years of follow-up. The results suggest that the experience of depression, disability, and negative body concept in a proportion of torticollis sufferers is a reaction to the neurological illness. A minority of the patients who remain chronically depressed are primary candidates for therapeutic intervention aiming at improving their adjustment to the illness. PMID- 24487299 TI - Biological and quantitative issues in neuropsychiatry. AB - During the recent resurgence of interest in neuropsychiatry, rapid technological advances have outpaced developments in the underlying theoretical framework. Neurophilosophy has tended to overlook clinical problems. This paper aims to redress the balance by examining a number of conceptual issues. Two groups of problems are considered: those related to brain functioning and psychiatric symptoms, and those related to the measurement of symptoms and their statistical analysis. It is emphasized that psychiatric symptoms appear to reflect the modular organization of the brain; and the particular psychiatric symptomatology associated with individual neurological diseases may be more distinct than is generally assumed, both cross-sectionally and over time. PMID- 24487302 TI - Cumulative index: volumes 1, 2 and 3. PMID- 24487300 TI - Type a behaviours and heart disease: epidemiological and experimental foundations. AB - This paper critically examines three strands of evidence that concern the relationship between type A behaviours and coronary heart disease; prospective epidemiological studies of healthy populations, studies of those at high risk for coronary heart disease, and angiographic studies of atherosclerosis. The first of these would seem to provide the strongest test. Methodological and conceptual issues mean that the results of studies using the other methods should be interpreted with care. It is concluded that there is relatively strong evidence of an association between Type A behaviour as measured by Structured Interview and coronary heart disease. Hostility and anger appear to be the most powerful determinants of CHD. However, it is likely that they interact with other type A behaviours and related environmental factors in determining risk. PMID- 24487303 TI - Characterization of the endocrine, digestive and morphological adjustments of the intestine in response to food deprivation and torpor in cunner, Tautogolabrus adspersus. AB - The cunner, Tautogolabrus adspersus, is a marine teleost endemic to the cold waters of the Northwest Atlantic Ocean. The cunner is non-migratory and is known for its remarkable ability to endure the freezing winter months with little to no food by entering a torpid/dormant state. To evaluate the physiological strategies employed by the cunner's intestinal tract to withstand food deprivation, fish were sampled for their gut after a four-week period of acute food deprivation during their summer (active/feeding) state, as well as after 4months of overwinter fasting. Digestive capacity was evaluated by measuring digestive enzyme activity and related mRNA transcript expression for trypsin, alkaline phosphatase, alanine aminopeptidase and lipase. In order to assess how gut hormones affect/are affected by acute fasting and torpor, we examined the intestinal mRNA expression of several putative appetite regulators, i.e. CCK, apelin, orexin and mTOR. Short-term summer fasting induced a reduction in the activity, but not the transcript expression, of all digestive enzymes examined as well as a reduction in gut apelin mRNA. Torpor induced a reduction in the activity of all enzymes with the exception of alanine aminopeptidase, and a decrease in mRNA levels of alanine aminopeptidase, orexin, CCK and mTOR. Our results suggest that both acute fasting and long-term fasting induce a reduction in the intestinal function of cunner, as evidenced by an overall decrease in the activities of digestive enzymes and mRNA expression of several factors involved in feeding and digestion. PMID- 24487304 TI - Investigation of microbial community structure in constructed mangrove microcosms receiving wastewater-borne polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenyl ethers (PBDEs). AB - The study aims to examine relationships between microbial community structure and mixed pollutants of polycyclic aromatic hydrocarbons (PAHs) and polybrominated diphenyl ethers (PBDEs) in constructed wetland microcosms, planted with Excoecaria agallocha or Kandelia obovata, two common mangrove plant species, and under two tidal regimes, everyday tidal (Te) and no tidal flooding (Tn). Results showed both microbial community structure and the retained amounts of pollutants were significantly determined by tidal regime, while the effect of plant species was small. Higher amounts of PAHs but lower amounts of PBDEs were always retained in sediments under Te than Tn regimes. Accordingly, temporal and vertical distributions of microbial community structure differed greatly between the two tidal regimes. Redundancy analysis further revealed significant correlation between a subgroup of the mixed PAHs and PBDEs with variation in microbial community structure. The findings will help to propose specific strategies to improve the bioremediation efficiency of constructed wetland. PMID- 24487306 TI - No evidence of apoptotic cells in pemphigus acantholysis. PMID- 24487305 TI - IL-9 regulates allergen-specific Th1 responses in allergic contact dermatitis. AB - The cytokine IL-9, derived primarily from T-helper 9 (Th9) lymphocytes, promotes expansion of the Th2 subset and is implicated in the mechanisms of allergic asthma. We hypothesize that IL-9 also has a role in human allergic contact dermatitis (ACD). To investigate this hypothesis, skin biopsy specimens of positive patch-test sites from non-atopic patients were assayed using quantitative PCR and immunohistochemistry. The cytokines IFN-gamma, IL-4, IL-17A, IL-9, and PU.1, a Th9 associated transcription factor, were elevated when compared with paired normal skin. Immunohistochemistry on ACD skin biopsies identified PU.1+ CD3+ and PU.1+ CD4+ cells, consistent with Th9 lymphocytes, in the inflammatory infiltrate. Peripheral blood mononuclear cells from nickel allergic patients, but not nonallergic controls, show significant IL-9 production in response to nickel. Blocking studies with mAbs to HLA-DR (but not HLA-A, -B, C) or chloroquine significantly reduced this nickel-specific IL-9 production. In addition, blockade of IL-9 or IL-4 enhanced allergen-specific IFN-gamma production. A contact hypersensitivity model using IL-9(-/-) mice shows enhanced Th1 lymphocyte immune responses, when compared with wild-type mice, consistent with our human in vitro data. This study demonstrates that IL-9, through its direct effects on Th1 and ability to promote IL-4 secretion, has a regulatory role for Th1 lymphocytes in ACD. PMID- 24487307 TI - Bisphenol A exposure and cardiac electrical conduction in excised rat hearts. AB - BACKGROUND: Bisphenol A (BPA) is used to produce polycarbonate plastics and epoxy resins that are widely used in everyday products, such as food and beverage containers, toys, and medical devices. Human biomonitoring studies have suggested that a large proportion of the population may be exposed to BPA. Recent epidemiological studies have reported correlations between increased urinary BPA concentrations and cardiovascular disease, yet the direct effects of BPA on the heart are unknown. OBJECTIVES: The goal of our study was to measure the effect of BPA (0.1-100 MUM) on cardiac impulse propagation ex vivo using excised whole hearts from adult female rats. METHODS: We measured atrial and ventricular activation times during sinus and paced rhythms using epicardial electrodes and optical mapping of transmembrane potential in excised rat hearts exposed to BPA via perfusate media. Atrioventricular activation intervals and epicardial conduction velocities were computed using recorded activation times. RESULTS: Cardiac BPA exposure resulted in prolonged PR segment and decreased epicardial conduction velocity (0.1-100 MUM BPA), prolonged action potential duration (1-100 MUM BPA), and delayed atrioventricular conduction (10-100 MUM BPA). These effects were observed after acute exposure (<= 15 min), underscoring the potential detrimental effects of continuous BPA exposure. The highest BPA concentration used (100 MUM) resulted in prolonged QRS intervals and dropped ventricular beats, and eventually resulted in complete heart block. CONCLUSIONS: Our results show that acute BPA exposure slowed electrical conduction in excised hearts from female rats. These findings emphasize the importance of examining BPA's effect on heart electrophysiology and determining whether chronic in vivo exposure can cause or exacerbate conduction abnormalities in patients with preexisting heart conditions and in other high-risk populations. PMID- 24487318 TI - The burden of infection in severely injured trauma patients and the relationship with admission shock severity. AB - BACKGROUND: Infection following severe injury is common and has a major impact on patient outcomes. The relationship between patient, injury, and physiologic characteristics with subsequent infections is not clearly defined. The objective of this study was to characterize the drivers and burden of all-cause infection in critical care trauma patients. METHODS: A prospective cohort study of severely injured adult patients admitted to critical care was conducted. Data were collected prospectively on patient and injury characteristics, baseline physiology, coagulation profiles, and blood product use. Patients were followed up daily for infectious episodes and other adverse outcomes while in the hospital. RESULTS: Three hundred patients (Injury Severity Score [ISS] >15) were recruited. In 48 hours or less, 29 patients (10%) died, leaving a cohort of 271. One hundred forty-one patients (52%) developed at least one infection. Three hundred four infections were diagnosed overall. Infection and noninfection groups were matched for age, sex, mechanism, and ISS. Infection rates were greater with any degree of admission shock and threefold higher in the most severely shocked cohort (p < 0.01). In multivariate analysis, base deficit (odds ratio [OR], 1.78, 95% confidence interval [CI], 1.48-1.94; p < 0.001) and lactate (OR, 1.36; 95% CI, 1.10-1.69; p = 0.05) were independently associated with the development of infection. Outcomes were significantly worse for the patients with infection. In multivariate logistic regression, infection was the only factor independently associated with multiple-organ failure (p < 0.001; OR, 15.4; 95% CI, 8.2-28.9; r = 0.402), ventilator-free days (p < 0.001; beta, -4.48; 95% CI, -6.7 to -2.1; r = 0.245), critical care length of stay (p < 0.001; beta, 13.2; 95% CI, 10.0-16.4; r = 0.466), and hospital length of stay (p < 0.001; beta, 31.1; 95% CI, 24.0-38.2; r = 0.492). CONCLUSION: Infectious complications are a burden for severely injured patients and occur early in the critical care stay. Severity of admission shock was predictive of infection and represents an opportunity for interventions to improve infectious outcomes. The incidence of infection may also have utility as an end point for clinical trials in trauma hemorrhage given the relationship with patient-experienced outcomes. LEVEL OF EVIDENCE: Prognostic/epidemiologic study, level II. PMID- 24487319 TI - Multicontrast photoacoustic in vivo imaging using near-infrared fluorescent proteins. AB - Non-invasive imaging of biological processes in vivo is invaluable in advancing biology. Photoacoustic tomography is a scalable imaging technique that provides higher resolution at greater depths in tissue than achievable by purely optical methods. Here we report the application of two spectrally distinct near-infrared fluorescent proteins, iRFP670 and iRFP720, engineered from bacterial phytochromes, as photoacoustic contrast agents. iRFPs provide tissue-specific contrast without the need for delivery of any additional substances. Compared to conventional GFP-like red-shifted fluorescent proteins, iRFP670 and iRFP720 demonstrate stronger photoacoustic signals at longer wavelengths, and can be spectrally resolved from each other and hemoglobin. We simultaneously visualized two differently labeled tumors, one with iRFP670 and the other with iRFP720, as well as blood vessels. We acquired images of a mouse as 2D sections of a whole animal, and as localized 3D volumetric images with high contrast and sub millimeter resolution at depths up to 8 mm. Our results suggest iRFPs are genetically-encoded probes of choice for simultaneous photoacoustic imaging of several tissues or processes in vivo. PMID- 24487320 TI - Leukocyte extravasation and vascular permeability are each controlled in vivo by different tyrosine residues of VE-cadherin. AB - Tyrosine phosphorylation of the adhesion molecule VE-cadherin is assumed to affect endothelial junction integrity. However, it remains unclear whether tyrosine residues of VE-cadherin are required for the induction of vascular permeability and the regulation of leukocyte extravasation in vivo. We found here that knock-in mice expressing a Y685F mutant of VE-cadherin had impaired induction of vascular permeability, but those expressing a Y731F mutant did not. In contrast, mice expressing the Y731F VE-cadherin mutant showed decreased neutrophil-extravasation in cremaster tissue, but those expressing the Y685F mutant did not. Whereas inflammatory mediators induced the phosphorylation of Tyr685 in vivo, Tyr731 showed high baseline phosphorylation. Leukocytes triggered dephosphorylation of Tyr731 via the tyrosine phosphatase SHP-2, which allowed the adaptin AP-2 to bind and initiate endocytosis of VE-cadherin. Thus, Tyr685 and Tyr731 of VE-cadherin distinctly and selectively regulate the induction of vascular permeability or leukocyte extravasation. PMID- 24487323 TI - Measuring dysgraphia: a graded-difficulty spelling test. AB - In this paper we describe the construction of a graded-difficulty spelling test for adults consisting of two alternative forms each containing 30 words (GDST, Forms A and B). The spelling test, together with background tests of verbal and non-verbal skills, was administered to 100 control patients with orthopaedic injuries. The two forms of the spelling test were highly correlated (0.92). Spelling was highly correlated with reading (0.75, 0.77) and moderately correlated with vocabulary (0.57) and naming (0.39, 0.40). There was no correlation between spelling skills and non-verbal reasoning. The test was validated in a group of 26 patients with left hemisphere and 20 patients with right hemisphere lesions. Spelling was shown to be lateralized to the left hemisphere and there appeared to be a shift in scores of the left hemisphere group towards the lower quartile, with 65% of the left hemisphere group falling within this band. The most severe spelling impairments were invariably associated with other language disorders but a number of dissociations were documented at spelling levels falling between the 5th and 25th percentile band. Two patients with left hemisphere lesions (8%) were identified as having selective dysgraphias. The lack of overlap between the anatomical sites of the two patients with specific lexical dysgraphia argues against a single site for this type of dysgraphia and argues for further refinement of this classification of spelling disorder. PMID- 24487321 TI - The transcription factor DREAM represses the deubiquitinase A20 and mediates inflammation. AB - Here we found that the transcription repressor DREAM bound to the promoter of the gene encoding A20 to repress expression of this deubiquitinase that suppresses inflammatory NF-kappaB signaling. DREAM-deficient mice displayed persistent and unchecked A20 expression in response to endotoxin. DREAM functioned by transcriptionally repressing A20 through binding to downstream regulatory elements (DREs). In contrast, binding of the transcription factor USF1 to the DRE associated E-box domain in the gene encoding A20 activated its expression in response to inflammatory stimuli. Our studies define the critical opposing functions of DREAM and USF1 in inhibiting and inducing A20 expression, respectively, and thereby the strength of NF-kappaB signaling. Targeting of DREAM to induce USF1-mediated A20 expression is therefore a potential anti-inflammatory strategy for the treatment of diseases associated with unconstrained NF-kappaB activity, such as acute lung injury. PMID- 24487322 TI - Intrinsic CD4+ T cell sensitivity and response to a pathogen are set and sustained by avidity for thymic and peripheral complexes of self peptide and MHC. AB - Interactions of T cell antigen receptors (TCRs) with complexes of self peptide and major histocompatibility complex (MHC) are crucial to T cell development, but their role in peripheral T cell responses remains unclear. Specific and nonspecific stimulation of LLO56 and LLO118 T cells, which transgenically express a TCR specific for the same Listeria monocytogenes epitope, elicited distinct interleukin 2 (IL-2) and phosphorylated kinase Erk responses, the strength of which was set in the thymus and maintained in the periphery in proportion to the avidity of the binding of the TCR to the self peptide-MHC complex. Deprivation of self peptide-MHC substantially compromised the population expansion of LLO56 T cells in response to L. monocytogenes in vivo. Despite their very different self reactivity, LLO56 T cells and LLO118 T cells bound cognate peptide-MHC with an identical affinity, which challenges associations made between these parameters. Our findings highlight a crucial role for selecting ligands encountered during thymic 'education' in determining the intrinsic functionality of CD4+ T cells. PMID- 24487324 TI - Psychiatric sequelae of organophosphorous poisoning: a case study and review of the literature. AB - This is the case of a young farm worker presenting with episodes of acute organic psychosis superimposed on a state of chronic anergy and hypersomnia. It is suggested that he developed an encephalopathic illness presenting with an organic bipolar affective disorder as a result of organophosphate exposure. In proposing this aetiology, an hypothesis is developed which links clinical observations and investigative results with research findings in relation to organophosphorus compounds and neuropharmacology. PMID- 24487325 TI - Crossed non-dominant hemisphere syndrome in a right-hander. AB - A right-handed patient with a large left temporo-parietal infarction manifested various non-dominant hemisphere signs. He had two left-handed children. On neurobehavioural examinations, he did not show aphasia or ideomotor apraxia, but did show hemispatial neglect, spatial agraphia, constructional apraxia, auditory and tactile extinction, anosodiaphoria and affective changes, all of which are usually observed after right hemispheric damage. We conclude that he has a reversed cerebral laterality of cognitive functions and showed crossed non dominant hemisphere syndrome. PMID- 24487326 TI - Structural correlates of neurological signs in Huntington's disease: a quantitative approach. AB - Huntington's disease (HD) is a genetically transmitted disorder associated with atrophy of the basal ganglia. Studies of the neuroanatomical correlates of HD have focused primarily on the anterior areas of the basal ganglia and on establishing an association between structural changes resulting from the presence and course of the illness. The objective of the present study was to assess the value of measurements of the third ventrical and lentiform regions. Computed tomographic (CT) brain scan measures of the basal ganglia of patients in the "early" and "late" stages of the disease were correlated with scores on a quantified neurological examination (QNE) and compared with scans of age-matched control groups. Basal ganglia atrophy was assessed by two conventional "anterior" measures: the maximal distance between the frontal horns of the lateral ventricles (FH) and the minimum distance between the caudate nuclei (CC), and two measures of more "posterior" regions: the width of the third ventricle (3V), and a measure of the lentiform regions (LENTI). In the group of patients with HD, CT scan measures were strongly correlated with disease duration. Further, in the "late" group, all CT measures were significantly correlated with QNE scores, with the two "posterior" measures being equally, if not more strongly correlated with QNE scores than the conventional "anterior" measures. Separate correlations of the CT indices of atrophy and QNE scores in the "early" and "late" HD groups revealed relationships between basal ganglia atrophy and motor abnormality consistent with earlier reports. PMID- 24487327 TI - Reduplication of visual stimuli. AB - Investigation of P.T., a man who experienced reduplicative delusions, revealed significant impairments on tests of recognition memory for faces and understanding of emotional facial expressions. On formal tests of his recognition abilities, P.T. showed reduplication to familiar faces, buildings, and written names, but not to familiar voices. Reduplication may therefore have been a genuinely visual problem in P.T.'s case, since it was not found to auditory stimuli. This is consistent with hypotheses which propose that the basis of reduplication can lie in part in malfunction of the visual system. PMID- 24487328 TI - Abnormalities of early "memory-scanning" event-related potentials in patients with temporal lobe epilepsy. AB - We have recorded auditory event-related potentials (ERPs) evoked by the "memory scanning" (digit-probe identification/matching) paradigm that was originally described by Sternberg (1966), in 17 patients with complex partial seizures (temporal lobe epilepsy) and in 17 matched healthy control subjects. The patients, who had all complained spontaneously of memory difficulties, had significantly reduced scores on psychological tests of memory with relatively intact digit span and cognition. Their performance of the memory-scanning task was characterized by a higher error rate, longer reaction times and an increased slope of the reaction time/set size relationship. The associated ERPs in both patients and controls showed there were significant effects of memory load on several major components, but only a reduced amplitude of the N170 and a prolonged latency of the N290 waves distinguished the patients. In addition, the N170 wave in the patients decreased further as memory load increased. The prolonged N290 latency in the patients appeared to reflect the slowed processing time. This study has shown that ERPs generated by a short-term memory task are abnormal in patients with temporal lobe epilepsy who have neuropsychologically documented cognitive and memory deficits. Some of the significant waveform alterations occur earlier than those reported in previous ERP studies and provide electrophysiological support for the hypothesis that abnormalities of the early stages of short-term memory processing may contribute to the memory difficulties experienced by patients with temporal lobe epilepsy. PMID- 24487329 TI - Psychiatric symptoms in patients with focal cortical degeneration. AB - The psychiatric phenomenology exhibited by a mixed group of patients with focal cortical degeneration (FCD) is described. The diagnosis of FCD was made in the presence of a slowly progressive focal neuropsychological deficit without evidence of infarct or neoplasm. Localized or asymmetric atrophy was present on neuroimaging (CT or MRI) and positron emission tomography demonstrated focal hypometabolism or in those assessed later in the disease an area of maximal hypometabolism which correlated with the neuropsychological deficit. FCD patients exhibited prominent obsessive-compulsive behaviour. Obsessive-compulsive features were often repetitive, stereotyped and bizarre and occurred in association with frontal and left temporal atrophy and hypometabolism and were absent in those with predominant posterior cortical pathology. PMID- 24487330 TI - Is there a place for ipsilesional eye patching in neglect rehabilitation? AB - Neglect behavior of experimental animals with unilateral posterior cortical lesions improves with the placement of a second lesion in the contralesional superior colliculus or in the intercollicular commissure. Given that the retinotectal fibers are mainly crossed, it has been speculated that ipsilesional eye patching, by depriving the contralesional superior colliculus of its main facilitatory visual input, might achieve similar results, and thus be used as a remediation maneuver in patients with neglect. From six patients with severe persistent neglect, only one showed an unequivocal beneficial effect from ipsilesional eye patching. We discuss the factors which possibly underlie success and failure with this procedure, and the place for it in neglect rehabilitation. PMID- 24487331 TI - Unexpected reading dissociation in a Brazilian "nisei" with crossed aphasia. AB - There is an increased interest in reading impairments in the Japanese language, due to its particular writing system which includes two different scripts, Kanji (logograms) and Kana (phonograms). Reading dissociations between Kanji and Kana have been described, showing that each system is processed differently by the cerebral hemispheres. We describe the case of a 68 year old Brazilian "nisei" (i.e. born from Japanese parents) who had knowledge of both Japanese and Portuguese. He presented an ischemic stroke affecting the right hemisphere and subsequently developed a Broca's aphasia and an unexpected reading dissociation, with an impairment in Kana reading comprehension and a good performance in Kanji and in Portuguese. These findings suggest that the patient's right and left hemispheres have assumed opposite roles not only for oral but also for written language decodification. PMID- 24487332 TI - Neurogenic stuttering and lateralized motor deficits induced by tranylcypromine. AB - A case of neurogenic stuttering induced by the monoamine oxidase inhibitor tranylcypromine is described. The association of neurogenic stuttering with acquired lateralized motor deficits in the patient described is discussed with reference to current theories regarding the pathogenesis of neurogenic stuttering. PMID- 24487333 TI - Pathways and patterns of cell loss in verified Alzheimer's disease: a factor and cluster analysis of clinico-pathological subgroups. AB - Thirty-seven patients with neuropathologically verified Alzheimer's disease (AD) have been studied prospectively. A principal components analysis of neuron numbers in cortical and subcortical areas revealed two variables: Variable I with high loadings for the hippocampo-parahippocampo-parietal neuron counts and Variable II with high loadings for coeruleo-frontal cell numbers. Both may reflect functional neuroanatomical connections which may act as pathways of neurodegeneration in AD. A cluster analysis based on these neuron numbers yielded three groups of patients: Cluster A with low hippocampo-parahippocampo-parietal cell counts, Cluster B with well-preserved neuron numbers, and Cluster C with low coeruleo-frontal neuron numbers. Differences in clinical features between these patient groups indicated the potential clinical relevance of these clusters. PMID- 24487334 TI - Suicide in patients with motor neuron disease. AB - The aim of the present study was to assess, through an epidemiological study, whether suicide risk is increased in patients with motor neuron disease (MND). The study involved 116 patients with MND. In the study period 92 patients died, 47 males and 45 females. No patients committed suicide. The number of expected suicides was 0.27 for males and 0.12 for females, a total of 0.38. The difference between observed and expected suicides was not statistically significant for males and females. PMID- 24487335 TI - Multiple cerebral infarction associated with neuroleptic-induced lupus anticoagulant. AB - A 39 year old schizophrenic woman with a 20 year history of neuroleptic treatment suffered bilateral cerebral infarcts and coagulation studies revealed a lupus anticoagulant (LA). She highlights the poorly recognized risk of thrombosis in patients on neuroleptics who develop LA. In this case the LA may have been induced by long-term therapy with haloperidol, a novel and potentially important association. PMID- 24487336 TI - Contact with a nurse practitioner: a short-term evaluation study in Parkinson's disease and dystonia. AB - Forty patients with Parkinson's disease and 24 patients with dystonia took part in a study aiming to assess the value of access to and contact with a nurse practitioner over a 6 month period. Patients in each group were randomly allocated to "intervention" or "control" groups, which were matched on important variables. All patients completed a set of questionnaires relating to psychosocial function at two time points separated by 6 months. In the intervening period, those allocated to the "intervention" group received two home visits and five telephone calls from the nurse practitioner. This contact was not provided to the "control" group. The nurse practitioner had a major impact on the provision of information and the facilitation of referral to other health-care agencies. The results of an independent assessment indicated that the patients in the "intervention" programme had found access to and contact with a nurse practitioner of great value. In contrast, the results of the questionnaire assessment did not reveal any statistically significant change in psychosocial functioning from the first to the second assessment for either the "intervention" or "control" groups. The lack of change in the questionnaire measures is discussed in terms of possible sampling bias and the duration of intervention and follow-up. Recommendations are made for future studies, and for the possible provision of clinical services. PMID- 24487337 TI - Creutzfeldt-Jakob disease with mixed transcortical aphasia: insights into echolalia. AB - Aphasia is a common manifestation of Creutzfeldt-Jakob disease (CJD), and investigation of the linguistic disorders of CJD patients may provide insights into the neurobiological mechanisms of language and aphasia. We report an autopsy confirmed case of CJD in which the presenting symptom was change in language abilities. The patient ultimately evidenced mixed transcortical aphasia (MTA) with echolalia. Disruption of frontal-subcortical circuits with environmental dependency accounts for the symptoms in MTA, including intact repetition and echolalia. Observation in this patient and a review of the literature suggest that frontal-subcortical circuit dysfunction may contribute to the syndrome of echolalia. This hypothesis offers an alternative explanation to "isolation" of the speech area as the cause of MTA. PMID- 24487338 TI - Long-term follow-up of patients suffering from obsessive-compulsive disorder treated as in-patients. AB - Few patients with obsessive-compulsive disorder (OCD) require in-patient treatment. There is sparse information on outcome of OCD patients treated as in patients. This paper is a descriptive account of the current functioning of 54 OCD patients treated in hospital, on average 10 years prior to the study. Follow up reveals that outcome for the majority of patients is poor with 29 (59%) of the sample showing at least mild symptomatology or some difficulty in several areas of functioning. PMID- 24487339 TI - An MRI, SPECT and neuropsychological study of a patient presenting with Capgras syndrome. AB - A 25 year old male patient presented with the "delusion of doubles" (Capgras syndrome). The patient underwent detailed neuropsychological, single photon emission computed tomography (SPECT) and magnetic resonance imaging (MRI) investigations. The neuropsychological results indicated that he was of average premorbid intelligence, which was consistent with current estimates, and had a degree of everyday memory dysfunction which was below norms derived from healthy controls, but was average relative to schizophrenic norms. He demonstrated average or above average recognition memory for patterns, spaces or words, but exhibited a marked and disproportionate impairment in face recognition, performing at the 5th percentile. In addition he demonstrated markedly impaired performance on various tests of executive function. MRI scanning revealed no focal abnormality; slight ventricular dilatation was noted. SPECT scanning, however, revealed marked right/left asymmetries of tracer uptake, restricted to occipital and calcarine cortices. These asymmetries were well outside those derived from a cohort of healthy controls. These results are discussed in relation to current neuropsychological models of Capgras syndrome. PMID- 24487341 TI - Emerging principles of population coding: in search for the neural code. AB - Population coding theory aims to provide quantitative tests for hypotheses concerning the neural code. Over the last two decades theory has focused on analyzing the ways in which various parameters that characterize neuronal responses to external stimuli affect the information content of these responses. This article reviews and provides an intuitive explanation for the major effects of noise correlations and neuronal heterogeneity, and discusses their implications for our ability to investigate the neural code. It is argued that to test neural code hypotheses further, additional constraints are required, including relating trial-to-trial variation in neuronal population responses to behavioral decisions and specifying how information is decoded by downstream networks. PMID- 24487342 TI - Photophoretic separation of single-walled carbon nanotubes: a novel approach to selective chiral sorting. AB - For over two decades single-walled carbon nanotubes (SWCNTs) have been used in a broad range of electronic and optical applications, however the selective chiral sorting of SWCNTs with guaranteed optoelectronics characteristics is imperative to the industrial realization of such applications. In this paper we provide the results of modeling an optical sorting method that utilizes the inherent opto electronic properties of the SWCNTs, thus guaranteeing the properties of the extracted populations. Utilizing the resonant transfer of photonic momentum, we simulate chiral sorting of two chiral populations in an aqueous environment based on the frequency dependent optical absorption properties of the nanotubes. We show that photonic sorting is not only feasible, but may be up to faster than density gradient centrifugation techniques. Our simulations investigate the effects of laser power, temperature and orientation. We find that 96% purity can be achieved in less than 12 minutes by operating at 9 * 10(7) W m(-2) (20 mW in a 20 MUm chamber) at elevated temperatures. PMID- 24487343 TI - Can mindfulness and acceptance be learnt by self-help?: a systematic review and meta-analysis of mindfulness and acceptance-based self-help interventions. AB - There is growing evidence that mindfulness and acceptance-based interventions have positive consequences for psychological and physical health. The most well established of these interventions typically involve relatively large resource commitments, in terms of both the provider and participant. A number of recent studies have begun to explore whether the benefits of such interventions can be generalised to less intensive methods. Methods include pure and guided self-help utilising resources such as books and workbooks, computer programmes and applications and audio-visual materials. This paper presents a systematic review and meta-analysis of studies that have evaluated the effectiveness and acceptability of low-intensity interventions including mindfulness and acceptance based components. Fifteen RCTs (7 ACT-based, 4 mindfulness-based and 4 multi component interventions including elements of mindfulness and/or acceptance) were identified and reviewed. Interventions that included mindfulness and/or acceptance-based components produced significant benefits in comparison to control conditions on measures of mindfulness/acceptance, depression and anxiety with small to medium effect sizes. Engagement with the self-help interventions varied but on average two-thirds of participants completed post-intervention measures. Emerging research into low-intensity mindfulness and acceptance-based interventions is hopeful. Recommendations for research and practice are presented. PMID- 24487344 TI - Psychological treatment of generalized anxiety disorder: a meta-analysis. AB - Recent years have seen a near-doubling of the number of studies examining the effects of psychotherapies for generalized anxiety disorder (GAD) in adults. The present article integrates this new evidence with the older literature through a quantitative meta-analysis. A total of 41 studies (with 2132 patients meeting diagnostic criteria for GAD) were identified through systematic searches in bibliographical databases, and were included in the meta-analysis. Most studies examined the effects of cognitive behavior therapy (CBT). The majority of studies used waiting lists as control condition. The pooled effect of the 38 comparisons (from 28 studies) of psychotherapy versus a control group was large (g=0.84; 95% CI: 0.71-0.97) with low to moderate heterogeneity. The effects based on self report measures were somewhat lower than those based on clinician-rated instruments. The effects on depression were also large (g=0.71; 95% CI: 0.59 0.82). There were some indications for publication bias. The number of studies comparing CBT with other psychotherapies (e.g., applied relaxation) or pharmacotherapy was too small to draw conclusions about comparative effectiveness or the long-term effects. There were some indications that CBT was also effective at follow-up and that CBT was more effective than applied relaxation in the longer term. PMID- 24487345 TI - Immune parameters identify Italian centenarians with a longer five-year survival independent of their health and functional status. AB - Centenarians are rare and exceptional individuals characterized by a peculiar phenotype. They are the best example of healthy aging in humans as most of them have escaped or substantially delayed the onset of major age-related diseases. Within this scenario, the purpose of the present work was to understand if immune status is associated with survival and health status in centenarians. To this aim, 116 centenarians were concomitantly characterized for their immunological, health and functional status, and followed-up for five-year survival. On the basis of previous knowledge we focused on a core of fundamental and basic immune parameters (number of leukocytes, monocytes, total lymphocytes, CD3(+) T lymphocytes, CD4(+) helper T lymphocytes, CD8(+) cytotoxic T lymphocytes, CD19(+) B lymphocytes and plasma levels of IgM), and the most important findings can be summarized as follows: i. a hierarchical cluster analysis was able to define Cluster1 (88 centenarians) and Cluster2 (28 centenarians) characterized by low and high values of all these immune parameters, respectively; ii. centenarians of Cluster2 showed a statistically longer five-year survival and more favorable values of other important immune (naive, activated/memory and effector/memory T cells) and metabolic (glycemia, insulin and HOMA-IR) parameters, in accord with previous observations that centenarians have a peculiar immune profile, a preserved insulin pathway and a lower incidence of type 2 diabetes; and iii. unexpectedly, parameters related to frailty, as well as functional and cognitive status, did not show any significant correlation with the immune clustering, despite being capable per se of predicting survival. In conclusion, high values of basic immunological parameters and important T cell subsets correlate with five-year survival in centenarians, independent of other phenotypic characteristics. This unexpected biological scenario is compatible with the general hypothesis that in centenarians a progressive disconnection and loss of biological coherence among the different functions of the body occur, where survival/mortality result from the failure of any of these domains which apparently follow an independent age-related trajectory. PMID- 24487346 TI - Changes of synovial fluid protein concentrations in supra-patellar bursitis patients after the injection of different molecular weights of hyaluronic acid. AB - Knee pain is commonly seen in orthopedic and rehabilitation outpatient clinical settings, and in the aging population. Bursitis of the knee joint, especially when the volume of the synovial fluid is large enough, can compress and distend the nearby soft tissues, causing pain in the knee joint. Out of all the bursae surrounding the knee joint, supra-patellar bursitis is most often associated with knee pain. Treatment strategies in managing supra-patellar bursitis include the aspiration of joint synovial fluid and then followed by steroid injection into the bursa. When supra-patellar bursitis is caused by degenerative disorders, the concept of viscosupplementation treatment may be effective by injecting hyaluronic acid into the bursa. However, the rheology or the changes in the concentrations of proteins (biomarkers) that are related to the development of bursitis in the synovial fluid is virtually unexplored. Therefore, this study aimed to identify the concentration changes in the synovial fluid total protein amount and individual proteins associated with supra-patellar bursitis using the Bradford protein assay and western immunoglobulin methods. A total of 20 patients were divided into two groups with 10 patients in each group. One group received the high molecular weight hyaluronic acid product of Synvisc Hylan G-F 20 and the other group received the low molecular weight hyaluronic acid product of Hya Joint Synovial Fluid Supplement once per week injection into the bursa for a total of 3 weeks. Significant decreases in the synovial fluid total protein concentrations were observed after the second dosage of high molecular weight hyaluronic acid injections. Apolipoprotein A-I, interleukin 1 beta, alpha 1 antitrypsin, and matrix metalloproteinase 1 proteins revealed a trend of decreasing western immunoblotting band densities after hyaluronic acid injections. The decreases in apolipoprotein A-I and interleukin 1 beta protein band densities were significant in the high molecular weight hyaluronic acid injection group. Transthyretin, complement 5, and matrilin 3 proteins revealed a trend of increasing western immunoblotting band densities after hyaluronic acid injections. Transthyretin revealed significant increases in protein band densities in both the high and low molecular weight hyaluronic acid injection groups. This study may provide the rationale for targeting several biomarkers associated with lipid transport, inflammation, and anti-aging as possible disease modifying therapies for the treatment of supra-patellar bursitis and even degenerative joint disorders. PMID- 24487347 TI - Optimization of the performance of segmented scintillators for radiotherapy imaging through novel binning techniques. AB - Thick, segmented crystalline scintillators have shown increasing promise as replacement x-ray converters for the phosphor screens currently used in active matrix flat-panel imagers (AMFPIs) in radiotherapy, by virtue of providing over an order of magnitude improvement in the detective quantum efficiency (DQE). However, element-to-element misalignment in current segmented scintillator prototypes creates a challenge for optimal registration with underlying AMFPI arrays, resulting in degradation of spatial resolution. To overcome this challenge, a methodology involving the use of a relatively high resolution AMFPI array in combination with novel binning techniques is presented. The array, which has a pixel pitch of 0.127 mm, was coupled to prototype segmented scintillators based on BGO, LYSO and CsI:Tl materials, each having a nominal element-to-element pitch of 1.016 mm and thickness of ~ 1 cm. The AMFPI systems incorporating these prototypes were characterized at a radiotherapy energy of 6 MV in terms of modulation transfer function, noise power spectrum, DQE, and reconstructed images of a resolution phantom acquired using a cone-beam CT geometry. For each prototype, the application of 8 * 8 pixel binning to achieve a sampling pitch of 1.016 mm was optimized through use of an alignment metric which minimized misregistration and thereby improved spatial resolution. In addition, the application of alternative binning techniques that exclude the collection of signal near septal walls resulted in further significant improvement in spatial resolution for the BGO and LYSO prototypes, though not for the CsI:Tl prototype due to the large amount of optical cross-talk resulting from significant light spread between scintillator elements in that device. The efficacy of these techniques for improving spatial resolution appears to be enhanced for scintillator materials that exhibit mechanical hardness, high density and high refractive index, such as BGO. Moreover, materials that exhibit these properties as well as offer significantly higher light output than BGO, such as CdWO4, should provide the additional benefit of preserving DQE performance. PMID- 24487348 TI - Alcohol intoxication alters cognitive skills mediated by frontal and temporal brain regions. AB - Alcohol intoxication affects frontal and temporal brain areas and may functionally impair cognitive processes mediated by these regions. This study examined this hypothesis by testing the effects of alcohol on sustained attention, impulsivity, and verbal memory. Sober and placebo control groups were used to distinguish pharmacological from expectancy effects of alcohol. One hundred nine university students were assigned to an alcohol (low, medium, or high dose), placebo or sober group. Moderate and high doses of alcohol impaired all cognitive measures. A gender effect was revealed in that alcohol impaired sustained attention in males, but not females. Both sustained attention and verbal memory exhibited a U-shaped pattern, in that the medium-dose alcohol group showed the greatest impairment. This study adds to knowledge about the effects of alcohol intoxication on frontally- and temporally-mediated cognitive function. These findings have specific relevance for heavy-drinking undergraduate populations, particularly in light of the fact that repeated alcohol administration produces persistent changes in brain neurocircuitry. PMID- 24487349 TI - The disorder named koro. AB - The koro syndrome is a triad of deep-seated fear of penile shrinkage, its disappearance into the abdomen and consequent death. The disorder, which is considered culture related, is endemic in South-East Asia and China, where it occurs in both epidemic and sporadic form. In the western hemisphere single cases are occasionally encountered. The association with psychiatric pathology in sporadic cases of koro has been well described, but lately attention has been drawn to systemic or neurologic involvement in these patients. The clinical, historical and cultural features of koro, as well as therapeutic strategies, are discussed. PMID- 24487350 TI - Ideomotor Apraxia in Left Thalamic Hemorrhage: Discrepancy between Clinical Course and SPECT. AB - We present a patient who developed severe ideomotor apraxia (IA) and subcortical aphasia after a hemorrhage involving the posterior part of the left thalamus and the posterior limb of the internal capsule. The cerebral blood flow (CBF) of the left hemisphere as measured by 99Tc-HM-PAO SPECT was initially diminished as compared to the right hemisphere. The apraxia and aphasia eventually resolved. Despite this clinical improvement CBF of the left hemisphere worsened. Our findings do not support the view that apraxia and aphasia following lesion of deep subcortical structures is due to cortical derangement induced by disruption of unspecific activating thalamo-cortical pathways. The results call for caution in the functional interpretation of perfusion deficits detected by SPECT. PMID- 24487351 TI - Symptomatic schizophrenia with moya moya disease. AB - A young man with Moya Moya disease diagnosed in childhood following two episodes of transient hemiplegia, presented 12 years later with a schizophrenia-like psychosis.A causal link is suggested on the basis of the main site of the cerebral lesion. PMID- 24487352 TI - Convulsive tic disorder georges gilles de la tourette, guinon and grasset on the phenomenology and psychopathology of gilles de la tourette syndrome. AB - Gilles de la Tourette gained eponymous fame when he described nine cases of multiple tics, coprolalia and echolalia, and later he, Guinon and Grasset were the first to document the psychopathology of the Gilles de la Tourette syndrome. In particular, they noted the association between obsessional thoughts and behaviours and the tic disorder. In this paper we present the first English translations of their works referring to the psychopathology, comparing and contrasting their ideas to current concepts. PMID- 24487353 TI - Emotionalism following brain damage. AB - Emotionalism is an heightened tendency to cry, or more rarely, laugh. It is commonly associated with brain damage and is often distressing to both patients and carers. Emotionalism is easily confused with depression, and when severe it can interfere with treatment. The aetiology is poorly understood but its response to drugs with different modes of action suggests that there is more than one underlying mechanism. When the components of emotionalism are studied separately a wide range is observed and they combine in a more complex and varied way than commonly held stereotyped views suggest. Most patients with emotionalism are helped by simple education and reassurance. Some severe cases respond dramatically to tricyclic antidepressants, levodopa or fluoxetine. PMID- 24487354 TI - Career advancement opportunities and the ACVP/STP Coalition. AB - A new service to facilitate career advancement opportunities has been implemented by the American College of Veterinary Pathologists (ACVP)/Society of Toxicologic Pathology (STP) Coalition for Veterinary Pathology Fellows. This service will allow rapid communication of these opportunities between veterinary pathologists in academia, industry, and government, and will be useful to trainees as well as established pathologists. PMID- 24487355 TI - Injection-site malignant fibrous histiocytomas in a pegvisomant carcinogenicity study in SD rats. AB - In a 2-year rat carcinogenicity study, pegvisomant injected subcutaneously on a daily basis at doses of 0, 2, 8, or 20 mg/kg/day produced malignant fibrous histiocytomas (MFHs) at the injection sites of 3 male rats (5%) given 8 mg/kg/day and 5 males (8%) given 20 mg/kg/day. MFH was characterized by unencapsulated dermal and subcutaneous sheets of fusiform and spindle-shaped cells sometimes with areas of round and/or irregular, pleomorphic cells and variable numbers of large multinucleated giant cells. Some regions of MFH had a fibroblastic appearance with streaming cells forming storiform patterns, while other areas consisted primarily of round to plump irregular cells with more giant cells. Pegvisomant did not increase the incidence of MFH in female rats and did not produce any other neoplastic responses in rats. In the dermis and subcutis at the injection sites of many males and females, pegvisomant produced dose-related increased incidences and severity of histiocytic infiltrates consisting of vacuolated macrophages with variable mature or immature fibrous tissue. Neoplasms at injection sites did not result in marketing restrictions or a label warning for human cancer risk, highlighting that injection-site neoplasms in rats have low relevance for human risk assessment. PMID- 24487356 TI - Extending the statistical analysis and graphical presentation of toxicity test results using standardized effect sizes. AB - The results of repeat-dose toxicity tests are usually presented as tables of means and standard deviations (SDs), with an indication of statistical significance for each biomarker. Interpretation is based mainly on the pattern of statistical significance rather than the magnitude of any response. Multiple statistical testing of many biomarkers leads to false-positive results and, with the exception of growth data, few graphical methods for showing the results are available. By converting means and SDs to standardized effect sizes, a range of graphical techniques including dot plots, line plots, box plots, and quantile quantile plots become available to show the patterns of response. A bootstrap statistical test involving all biomarkers is proposed to compare the magnitudes of the response between treated groups. These methods are proposed as an extension rather than an alternative to current statistical analyses. They can be applied to published work retrospectively, as all that is required is tables of means and SDs. The methods are illustrated using published articles, where the results range from strong positive to completely negative responses to the test substances. PMID- 24487359 TI - Kidney international web focus on transplantation. PMID- 24487361 TI - HIF meets NF-kappaB signaling. AB - An inflammatory stimulus prior to an ischemic insult can be protective in acute kidney injury (AKI) as well as other acute organ injury models, an effect called cross-tolerance. He et al. investigated mechanisms of cross-tolerance whereby pretreatment with lipopolysaccharide (LPS) protects from a subsequent ischemic insult of the kidney. The protection was mediated by LPS-induced nuclear factor kappaB and hypoxia-inducible factor-2alpha (HIF-2alpha) signaling. These results link two central cellular pathways and give new insight into HIF-mediated renoprotection in AKI models. PMID- 24487362 TI - Myofibroblasts: the ideal target to prevent arteriovenous fistula failure? AB - The arteriovenous fistula (AVF) failure is a major cause of morbidity in the hemodialysis population. Most AVFs fail due to neointimal hyperplasia (NIH). In this issue, Yang et al. delineated a mechanism responsible for transforming the fistula adventitia into a fertile soil for neointimal precursors. These authors pondered the role of hypoxia-regulated hypoxia-inducible factor-1 (HIF-1alpha), vascular endothelial growth factor A (VEGF-A), and matrix metalloproteinases (MMPs) in the activation of those adventitial myofibroblasts that may significantly contribute to the formation of the fistula neointima. PMID- 24487363 TI - The importance of quantifying genetic heterogeneity in ADPKD. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common hereditary renal disease. New data from Paul et al. suggest that mutations in the PKD1 and PKD2 genes may account for all cases of ADPKD. Further improvements in mutation detection methodologies are needed to determine the true relative frequency of PKD1 versus PKD2 as well as to establish the value of mutation type and location to predict disease severity in this disorder. PMID- 24487364 TI - Soluble fms-like tyrosine kinase-1 and atherosclerosis in chronic kidney disease. AB - Vascular endothelial growth factor (VEGF) and its cousins, such as placental growth factor, have moved into the daily clinical arena. One-step-removed regulators, such as the VEGF splice variant soluble fms-like tyrosine kinase-1 (sFlt-1), now clinically emerge. sFlt-1 keeps our corneas 'clean.' However, sFlt 1 could also cause disease, such as preeclampsia. The report by Matsui et al. on ApoE and sFlt-1 gene-deleted mice could foster important subsequent research. We are limited only by our imaginations. PMID- 24487365 TI - Modulating kidney transplant interstitial fibrosis and tubular atrophy: is the RAAS an important target? AB - In follow-up to a recently published randomized controlled clinical trial, Issa et al. provide evidence that systemic activity and physiological responsiveness of the renin aldosterone angiotensin system (RAAS) are well within normal limits in most kidney recipients during the first 5 years post-transplant. Implications of the results include the need to better understand intra-renal RAAS activity in transplanted kidneys and to identify patients in which the graft-protective effects of RAAS blockade are most relevant. PMID- 24487366 TI - Lipoprotein glomerulopathy may provide a key to unlock the puzzles of renal lipidosis. AB - Lipoprotein glomerulopathy is an inherited renal disease characterized by unique lipoprotein thrombi in the glomerulus and is associated with the APOE mutation. Hu and colleagues investigated the genetic and clinical features of a large group of patients with lipoprotein glomerulopathy who carried APOE Kyoto, a major APOE variant. Their findings suggest its descent through a founder effect. Fibrate therapy in this group showed favorable results in the patient and renal survival rates. PMID- 24487367 TI - Can we prevent donor-specific antibodies from developing after ABO-incompatible kidney transplantation? AB - The burden of chronic kidney disease is increasing worldwide and its costs are skyrocketing, particularly for those with end-stage kidney disease (ESKD). Thus, kidney transplantation needs to be available to as many as ESKD patients as possible. In countries where a donor swap or a donor-chain program is not feasible, ABO-incompatible (ABO-i) and/or HLA incompatible (HLAi) programs have been developed. In the setting of ABOi kidney transplantation, pretransplant desensitization is mandatory; this is based on the removal of isoagglutinins by plasmapheresis or immunoadsorption, and often using splenectomy (SPx) or, more recently, rituximab (RTx) infusion instead. Because RTx and SPx interfere with B cell function, one wonders whether these desensitization protocols alter the occurrence of post-transplant donor-specific alloantibodies. PMID- 24487368 TI - Could the pattern of water consumption alter its potential medicinal effects? PMID- 24487369 TI - Survival with daily hemodialysis. PMID- 24487370 TI - Bile cast nephropathy. PMID- 24487371 TI - The author replies:. PMID- 24487372 TI - Response to Heyman et al. and Bredewold et al. PMID- 24487373 TI - Graft pyelonephritis causing graft failure from de novo AA amyloid. PMID- 24487374 TI - Renal infarction in a child with Henoch-Schonlein purpura. PMID- 24487375 TI - The case | peculiar fibrous nodules in a renal transplant biopsy. PMID- 24487376 TI - Oligodontia and curly hair occur with ectodysplasin-a mutations. AB - Oligodontia is the developmental absence of more than 5 permanent teeth except for the third molar. Familial oligodontia can occur as an isolated form or as part of a genetic syndrome. Mutations in the MSX1, PAX9, AXIN2, EDA, and WNT10A genes have been identified in familial non-syndromic oligodontia. Ectodermal dysplasia is a group of syndromes involving abnormalities of the ectodermal structures and is comprised of more than 150 different forms. Mutations in the ectodysplasin-A (EDA) gene have been associated with X-linked hypohidrotic ectodermal dysplasia, and partial disruption of the EDA signaling pathway has been shown to cause an isolated form of oligodontia. We identified 2 X-linked oligodontia families and performed mutational analysis of the EDA gene. The mutational analysis revealed 2 novel EDA mutations: c.866G>T, p.Arg289Leu and c.1135T>G, p.Phe379Val (reference sequence NM_001399.4). These mutations were perfectly segregated with oligodontia and curly hair within each family and were not found in the 150 control X-chromosomes with the same ethnic background and in the exome variant server. This study broadens the mutational spectrum of the EDA gene and the understanding of X-linked oligodontia with curly hair. PMID- 24487377 TI - Dental caries and enamelin haplotype. AB - In the literature, the enamelin gene ENAM has been repeatedly designated as a possible candidate for caries susceptibility. Here, we checked whether ENAM variants could increase caries susceptibility. To this aim, we sequenced coding exons and exon-intron boundaries of ENAM in 250 children with a severe caries phenotype and in 149 caries-free patients from 9 French hospital groups. In total, 23 single-nucleotide polymorphisms (SNPs) were found, but none appeared to be responsible for a direct change of ENAM function. Six SNPs had a high minor allele frequency (MAF) and 6 others were identified for the first time. Statistical and evolutionary analyses showed that none of these SNPs was associated with caries susceptibility or caries protection when studied separately and challenged with environmental factors. However, haplotype interaction analysis showed that the presence, in a same variant, of 2 exonic SNPs (rs7671281 and rs3796704; MAF 0.12 and 0.10, respectively), both changing an amino acid in the protein region encoded by exon 10 (p.I648T and p.R763Q, respectively), increased caries susceptibility 2.66-fold independent of the environmental risk factors. These findings support ENAM as a gene candidate for caries susceptibility in the studied population. PMID- 24487378 TI - Candida and other fungal species: forgotten players of healthy oral microbiota. AB - In the last half-decade or so, interest in the bacterial part of the human microbiome and its role in maintaining health have received considerable attention. Since 2009, over 300 publications have appeared describing the oral bacterial microbiome. Strikingly, fungi in the oral cavity have been studied exclusively in relation to pathologies. However, little to nothing is known about a role of fungi in establishing and maintaining a healthy oral ecology. In a healthy ecology, balance is maintained by the combined positive and negative influences between and among its members. Interactions between fungi and bacteria occur primarily at a physical and chemical level. Physical interactions are represented by (co-)adhesion and repulsion (exclusion), while chemical interactions include metabolic dependencies, quorum-sensing, and the production of antimicrobial agents. Information obtained from oral model systems and also from studies on the role of fungi in gastro-intestinal ecology indicates that fungi influence bacterial behavior through these different interactions. This review describes our current knowledge of the interactions between fungi and bacteria and aims to illustrate that further research is required to establish the role of fungi in maintaining a healthy oral cavity. PMID- 24487379 TI - Multifocal motor neuropathy: lost in conduction block? PMID- 24487381 TI - Fcgamma receptor IIIA genotype is associated with rituximab response in antimyelin-associated glycoprotein neuropathy. AB - BACKGROUND: Treatment with anti-B cell antibody rituximab may ameliorate the disease course in a subgroup of patients with polyneuropathy associated with IgM monoclonal gammopathy. Polymorphisms of leukocyte IgG receptors (FcgammaR) that influence efficiency of antibody-dependent cell-mediated cytotoxicity determine rituximab efficacy in patients with lymphoma and autoimmune disease. OBJECTIVE: To investigate the association of FcgammaRIIA and FcgammaRIIIA polymorphisms with the response to rituximab treatment in a cohort of patients with polyneuropathy associated with IgM monoclonal gammopathy (PNP-IgM) with and without antimyelin associated glycoprotein antibodies. METHODS: We determined FcgammaRIIA-R/H131 and FcgammaRIIIA-V/F158 genotypes in 27 patients with PNP-IgM using allele-specific PCR and Sanger sequencing. RESULTS: The FcgammaRIIIA-V/V158 genotype was associated with functional improvement (p=0.02) after 1 year. CONCLUSIONS: FcgammaRIIIA polymorphisms are potential biomarkers for response to rituximab treatment in polyneuropathy associated with IgM monoclonal gammopathy. PMID- 24487382 TI - To clap or not to clap? Applause sign in apathetic and disinhibited/stereotypical behavioural variants of FTD. PMID- 24487380 TI - Tricks in dystonia: ordering the complexity. AB - Sensory tricks are various manoeuvres that can ameliorate dystonia. Common characteristics are well known, but their variety is wide, sensory stimulation is not necessarily the critical feature, and their physiology is unknown. To enumerate the various forms of sensory tricks and describe their nature, research findings and theories that may elucidate their neurophysiologic mechanism, we reviewed the literature pertaining to sensory tricks, including variants like motor tricks, imaginary tricks, forcible tricks and reverse sensory tricks. On the basis of this information, we propose a new classification of sensory tricks to include its variants. We highlight neurophysiologic evidence suggesting that sensory tricks work by decreasing abnormal facilitation. We tie this with established dystonia pathogenesis and postulate that sensory tricks decrease abnormally increased facilitation to inhibition ratios in the dystonic brain. It appears worthwhile for patients to search for possible sensory tricks. PMID- 24487383 TI - Engraved hexagons on an Ice Age ivory: a neurological perspective on an anthropological debate. PMID- 24487384 TI - Vacancy diffusion and coalescence in graphene directed by defect strain fields. AB - The formation of extended defects in graphene from the coalescence of individual mobile vacancies can significantly alter its mechanical, electrical and chemical properties. We present the results of ab initio simulations which demonstrate that the strain created by multi-vacancy complexes in graphene determine their overall growth morphology when formed from the coalescence of individual mobile lattice vacancies. Using density functional theory, we map out the potential energy surface for the motion of mono-vacancies in the vicinity of multi-vacancy defects. The inhomogeneous bond strain created by the multi-vacancy complexes strongly biases the activation energy barriers for single vacancy motion over a wide area. Kinetic Monte Carlo simulations based on rates from ab initio derived activation energies are performed to investigate the dynamical evolution of single vacancies in these strain fields. The resultant coalescence processes reveal that the dominant morphology of multi-vacancy complexes will consist of vacancy lines running in the two primary crystallographic directions, and that more thermodynamically stable structures, such as holes, are kinetically inaccessible from mono-vacancy aggregation alone. PMID- 24487385 TI - Dose-dependent incidence of hepatic tumors in adult mice following perinatal exposure to bisphenol A. AB - BACKGROUND: Bisphenol A (BPA) is a high production volume chemical with hormone like properties that has been implicated as a potential carcinogen. Early-life exposure has been linked to increased risk for precancerous lesions in mammary and prostate glands and the uterus, but no prior study has shown a significant association between BPA exposure and cancer development. OBJECTIVE: We explored the effects of BPA exposure during gestation and lactation on adult incidence of hepatic tumors in mice. METHODS: Isogenic mice were perinatally exposed to BPA through maternal diets containing one of four environmentally relevant doses of BPA (0, 50 ng, 50 MUg, or 50 mg per kilogram of diet), and we followed approximately one male and one female per litter until they were 10 months of age. Animals were tested for known risk factors for hepatocellular carcinoma, including bacterial and viral infections. RESULTS: We found dose-dependent incidence of hepatic tumors in 10-month-old BPA-exposed mice. Of the offspring examined, 23% presented with hepatic tumors or preneoplastic lesions. We observed a statistically significant dose-response relationship, with an odds ratio for neoplastic and preneoplastic lesions of 7.23 (95% CI: 3.23, 16.17) for mice exposed to 50 mg BPA/kg diet compared with unexposed controls. Observed early disease onset, absence of bacterial or viral infection, and lack of characteristic sexual dimorphism in tumor incidence support a nonclassical etiology. CONCLUSIONS: To our knowledge, this is the first report of a statistically significant association between BPA exposure and frank tumors in any organ. Our results link early-life exposure to BPA with the development of hepatic tumors in rodents, and have potential implications for human health and disease. PMID- 24487386 TI - IL-1beta induction of MUC5AC gene expression is mediated by CREB and NF-kappaB and repressed by dexamethasone. AB - Chronic airway diseases are characterized by inflammation and mucus overproduction. The MUC5AC mucin gene is upregulated by the proinflammatory cytokine interleukin-1 beta (IL-1beta) via activation of cAMP response element binding protein (CREB) in the NCI-H292 cancer cell line and nuclear factor-kappaB (NF-kappaB) in the HBE1 transformed cell line, with each transcription factor binding to a cognate cis site in the proximal or distal region, respectively, of the MUC5AC promoter. We utilized primary differentiated human bronchial epithelial (HBE) and A549 lung adenocarcinoma cells to further investigate the contributions of CREB and NF-kappaB subunits to the IL-1beta-induced upregulation of MUC5AC. Data show that ligand binding of IL-1beta to the IL-1beta receptor is required to increase MUC5AC mRNA abundance. Chromatin immunoprecipitation analyses show direct binding of CREB to the previously identified cAMP response element site and binding of p65 and p50 subunits to a novel NF-kappaB site in a mucin-regulatory domain in the proximal promoter and to a previously identified NF-kappaB site in the distal promoter. P50 binds to both NF-kappaB sites at 1 h following IL-1beta exposure, but is replaced at 2 h by p65 in A549 cells and by a p50/p65 heterodimer in HBE cells. Thus IL-1beta activates multiple domains in the MUC5AC promoter but exhibits some cell-specific responses, highlighting the complexity of MUC5AC transcriptional regulation. Data show that dexamethasone, a glucocorticoid that transcriptionally represses MUC5AC gene expression under constitutive conditions, also represses IL-1beta-mediated upregulation of MUC5AC gene expression. A further understanding of mechanisms mediating MUC5AC regulation should lead to a honing of therapeutic approaches for the treatment of mucus overproduction in inflammatory lung diseases. PMID- 24487388 TI - Protection against LPS-induced acute lung injury by a mechanism-based inhibitor of NADPH oxidase (type 2). AB - The phospholipase A2 activity of peroxiredoxin 6 is inhibited by the transition state analog, 1-hexadecyl-3-(trifluoroethyl)-sn-glycero-2-phosphomethanol (MJ33). This activity is required for the activation of NADPH oxidase, type 2. The present study evaluated the effect of MJ33 on manifestations of acute lung injury. Mice were injected intratracheally (IT) with LPS from Escherichia coli 0111:B4 (LPS, 1 or 5 mg/kg), either concurrently with LPS or 2 h later, and evaluated for lung injury 24 h later. MJ33 inhibited reactive oxygen species (ROS) generation by lungs when measured at 24 h after LPS. LPS at either a low or high dose significantly increased lung infiltration with inflammatory cells, secretion of proinflammatory cytokines (IL-6, TNF-alpha, and the chemokine macrophage inflammatory protein-2), expression of lung vascular cell adhesion molecule, lung permeability (protein in bronchoalveolar lavage fluid, leakage of FITC-dextran, lung wet-to-dry weight ratio), tissue lipid peroxidation (thiobarbituric acid reactive substances, 8-isoprostanes), tissue protein oxidation (protein carbonyls), and activation of NF-kappaB. MJ33, given either concurrently or 2 h subsequent to LPS, significantly reduced all of these measured parameters. Previous studies of toxicity showed a high margin of safety for MJ33 in the intact mouse. Thus we have identified MJ33 as a potent, nontoxic, and specific mechanism-based inhibitor of NADPH oxidase type 2-mediated ROS generation that protects mice against lung injury associated with inflammation. PMID- 24487387 TI - MKK3 regulates mitochondrial biogenesis and mitophagy in sepsis-induced lung injury. AB - Sepsis is a systemic inflammatory response to infection and a major cause of death worldwide. Because specific therapies to treat sepsis are limited, and underlying pathogenesis is unclear, current medical care remains purely supportive. Therefore targeted therapies to treat sepsis need to be developed. Although an important mediator of sepsis is thought to be mitochondrial dysfunction, the underlying molecular mechanism is unclear. Modulation of mitochondrial processes may be an effective therapeutic strategy in sepsis. Here, we investigated the role of the kinase MKK3 in regulation of mitochondrial function in sepsis. Using clinically relevant animal models, we examined mitochondrial function in primary mouse lung endothelial cells exposed to LPS. MKK3 deficiency reduces lethality of sepsis in mice and by lowering levels of lung and mitochondrial injury as well as reactive oxygen species. Furthermore, MKK3 deficiency appeared to simultaneously increase mitochondrial biogenesis and mitophagy through the actions of Sirt1, Pink1, and Parkin. This led to a more robust mitochondrial network, which we propose provides protection against sepsis. We also detected higher MKK3 activation in isolated peripheral blood mononuclear cells from septic patients compared with nonseptic controls. Our findings demonstrate a critical role for mitochondria in the pathogenesis of sepsis that involves a previously unrecognized function of MKK3 in mitochondrial quality control. This mitochondrial pathway may help reveal new diagnostic markers and therapeutic targets against sepsis. PMID- 24487389 TI - Microfluidic shear stress-regulated surfactant secretion in alveolar epithelial type II cells in vitro. AB - We investigated the role of flow-induced shear stress on the mechanisms regulating surfactant secretion in type II alveolar epithelial cells (ATII) using microfluidic models. Following flow stimulation spanning a range of wall shear stress (WSS) magnitudes, monolayers of ATII (MLE-12 and A549) cells were examined for surfactant secretion by evaluating essential steps of the process, including relative changes in the number of fusion events of lamellar bodies (LBs) with the plasma membrane (PM) and intracellular redistribution of LBs. F-actin cytoskeleton and calcium levels were analyzed in A549 cells subjected to WSS spanning 4-20 dyn/cm(2). Results reveal an enhancement in LB fusion events with the PM in MLE-12 cells upon flow stimulation, whereas A549 cells exhibit no foreseeable changes in the monitored number of fusion events for WSS levels ranging up to a threshold of ~8 dyn/cm(2); above this threshold, we witness instead a decrease in LB fusion events in A549 cells. However, patterns of LB redistribution suggest that WSS can potentially serve as a stimulus for A549 cells to trigger the intracellular transport of LBs toward the cell periphery. This observation is accompanied by a fragmentation of F-actin, indicating that disorganization of the F-actin cytoskeleton might act as a limiting factor for LB fusion events. Moreover, we note a rise in cytosolic calcium ([Ca(2+)]c) levels following stimulation of A549 cells with WSS magnitudes ranging near or above the experimental threshold. Overall, WSS stimulation can influence key components of molecular machinery for regulated surfactant secretion in ATII cells in vitro. PMID- 24487390 TI - Pseudomonas aeruginosa flagellar motility activates the phagocyte PI3K/Akt pathway to induce phagocytic engulfment. AB - Phagocytosis of the bacterial pathogen Pseudomonas aeruginosa is the primary means by which the host controls bacterially induced pneumonia during lung infection. Previous studies have identified flagellar swimming motility as a key pathogen-associated molecular pattern (PAMP) recognized by phagocytes to initiate engulfment. Correspondingly, loss of flagellar motility is observed during chronic pulmonary infection with P. aeruginosa, and this likely reflects a selection for bacteria resistant to phagocytic clearance. However, the mechanism underlying the preferential phagocytic response to motile bacteria is unknown. Here we have identified a cellular signaling pathway in alveolar macrophages and other phagocytes that is specifically activated by flagellar motility. Genetic and biochemical methods were employed to identify that phagocyte PI3K/Akt activation is required for bacterial uptake and, importantly, it is specifically activated in response to P. aeruginosa flagellar motility. Based on these observations, the second important finding that emerged from these studies is that titration of the bacterial flagellar motility results in a proportional activation state of Akt. Therefore, the Akt pathway is responsive to, and corresponds with, the degree of bacterial flagellar motility, is independent of the actin polymerization that facilitates phagocytosis, and determines the phagocytic fate of P. aeruginosa. These findings elucidate the mechanism behind motility-dependent phagocytosis of extracellular bacteria and support a model whereby phagocytic clearance exerts a selective pressure on P. aeruginosa populations in vivo, which contributes to changes in pathogenesis during infections. PMID- 24487391 TI - Sox2 modulates Lef-1 expression during airway submucosal gland development. AB - Tracheobronchial submucosal glands (SMGs) are derived from one or more multipotent glandular stem cells that coalesce to form a placode in surface airway epithelium (SAE). Wnt/beta-catenin-dependent induction of lymphoid enhancer factor (Lef-1) gene expression during placode formation is an early event required for SMG morphogenesis. We discovered that Sox2 expression is repressed as Lef-1 is induced within airway SMG placodes. Deletion of Lef-1 did not activate Sox2 expression in SMG placodes, demonstrating that Lef-1 activation does not directly inhibit Sox2 expression. Repression of Sox2 protein in SMG placodes occurred posttranscriptionally, since the activity of its endogenous promoter remained unchanged in SMG placodes. Thus we hypothesized that Sox2 transcriptionally represses Lef-1 expression in the SAE and that suppression of Sox2 in SMG placodes activates Wnt/beta-catenin-dependent induction of Lef-1 during SMG morphogenesis. Consistent with this hypothesis, transcriptional reporter assays, ChIP analyses, and DNA-protein binding studies revealed a functional Sox2 DNA binding site in the Lef-1 promoter that is required for suppressing beta-catenin-dependent transcription. In polarized primary airway epithelium, Wnt induction enhanced Lef-1 expression while also inhibiting Sox2 expression. Conditional deletion of Sox2 also enhanced Lef-1 expression in polarized primary airway epithelium, but this induction was significantly augmented by Wnt stimulation. Our findings provide the first evidence that Sox2 acts as a repressor to directly modulate Wnt-responsive transcription of the Lef 1 gene promoter. These studies support a model whereby Wnt signals and Sox2 dynamically regulate the expression of Lef-1 in airway epithelia and potentially also during SMG development. PMID- 24487392 TI - Reprogramming of COPD lung fibroblasts through formation of induced pluripotent stem cells. AB - Reprogramming somatic cells to induced pluripotent stem cells (iPSCs) eliminates many epigenetic modifications that characterize differentiated cells. In this study, we tested whether functional differences between chronic obstructive pulmonary disease (COPD) and non-COPD fibroblasts could be reduced utilizing this approach. Primary fibroblasts from non-COPD and COPD patients were reprogrammed to iPSCs. Reprogrammed iPSCs were positive for oct3/4, nanog, and sox2, formed embryoid bodies in vitro, and induced teratomas in nonobese diabetic/severe combined immunodeficient mice. Reprogrammed iPSCs were then differentiated into fibroblasts (non-COPD-i and COPD-i) and were assessed either functionally by chemotaxis and gel contraction or for gene expression by microarrays and compared with their corresponding primary fibroblasts. Primary COPD fibroblasts contracted three-dimensional collagen gels and migrated toward fibronectin less robustly than non-COPD fibroblasts. In contrast, redifferentiated fibroblasts from iPSCs derived from the non-COPD and COPD fibroblasts were similar in response in both functional assays. Microarray analysis identified 1,881 genes that were differentially expressed between primary COPD and non-COPD fibroblasts, with 605 genes differing by more than twofold. After redifferentiation, 112 genes were differentially expressed between COPD-i and non-COPD-i with only three genes by more than twofold. Similar findings were observed with microRNA (miRNA) expression: 56 miRNAs were differentially expressed between non-COPD and COPD primary cells; after redifferentiation, only 3 miRNAs were differentially expressed between non-COPD-i and COPD-i fibroblasts. Interestingly, of the 605 genes that were differentially expressed between COPD and non-COPD fibroblasts, 293 genes were changed toward control after redifferentiation. In conclusion, functional and epigenetic alterations of COPD fibroblasts can be reprogrammed through formation of iPSCs. PMID- 24487394 TI - Mouse Flk-1+Sca-1- mesenchymal stem cells: functional plasticity in vitro and immunoregulation in vivo. AB - OBJECTIVES: Mesenchymal stem cells (MSCs) represent a powerful tool in regenerative medicine because of their differentiation and migration capacities. Moreover, the immunomodulatory ability of MSCs may be used to develop therapies for the treatment of autoimmune diseases. METHODS: In this study, we isolated Flk 1Sca-1 MSCs from bone marrow (bMSCs). Next, we studied their biological characteristics and immunologic functions. We also investigated their effects on graft-versus-host disease (GVHD) associated with allogeneic bone marrow transplantation in mice. RESULTS: Flk-1Sca-1 bMSCs were able to differentiate into fat and cartilage cells, indicating that the isolated cells had stem cell properties. They could also suppress alloantigen-induced T cell proliferation in vitro in a dose-dependent manner. Infusion of bMSCs into allogeneic bone marrow transplanted mice alleviated the lethal GVHD that occurred in control recipient mice. There was significantly lower mortality among the recipients of the Flk 1Sca-1 bMSCs that also ameliorated the clinical symptoms and GVHD histopathology. Beneficial effects on GVHD by Flk-1Sca-1 bMSCs were also observed when MSCs were engineered to express anti-inflammatory cytokines IL-4 and IL-10 and decrease expression of proinflammatory cytokines IFN-gamma, TNF-alpha, and IL-2. CONCLUSION: Flk-1Sca-1 bMSCs have stem cell properties and can efficiently ameliorate the GVHD associated with allogeneic bone marrow transplantation in mice. PMID- 24487395 TI - Increased soluble CD154 (CD40 ligand) levels in xenograft recipients correlate with the development of de novo anti-pig IgG antibodies. AB - BACKGROUND: De novo anti-pig antibodies are associated with acute humoral xenograft rejection. We explored the relative efficacy of CD40/CD154-pathway blockade versus CD28/B7-pathway blockade in the prevention of de novo anti-pig IgG antibodies in xenograft recipients. METHODS: After alpha1,3 galactosyltransferase gene-knockout pig artery patch xenotransplantation, recipient baboons received no immunosuppression (IS; n=3), or anti-CD154mAb-based (n=5) or CTLA4-Ig-based (n=5) IS. CD4 T-cell and CD20 B-cell numbers in blood were determined. Serum anti-pig IgG antibodies and serum soluble (s)CD154 levels were measured. In lymph nodes, germinal center formation was examined and numbers of proliferating cells were evaluated by Ki-67 staining. RESULTS: After transplantation, with no IS, CD4 T-cell and CD20 B-cell numbers were increased, but were reduced by IS.In lymph nodes, with no IS, there was enhanced germinal center formation, which was significantly reduced by anti-CD154mAb-based (P<0.01) or CTLA4-Ig-based (P<0.01) IS. With no IS, there was strong expression of Ki-67 positive cells in lymph nodes, indicating extensive cellular proliferation. Ki-67 positive cells were significantly reduced by anti-CD154mAb-based (P<0.05) but not by CTLA4-Ig-based IS. High mean levels of sCD154 were detected with no IS (3324 pg/mL), in comparison to naive control baboons (214 pg/mL). With anti-CD154mAb based IS, sCD154 was reduced to less than 1 pg/mL and with CTLA4-Ig-based IS to 65 pg/mL. There was significant positive correlation between sCD154 and anti-pig IgG levels (P<0.01). CONCLUSIONS: In xenograft recipients, anti-CD154mAb may reduce class-switching of anti-pig antibodies by binding both T-cell surface CD154 and circulating sCD154, thus preventing subsequent stimulation of B cells and activation of lymphoid follicles in secondary lymphoid tissues. PMID- 24487393 TI - Aging causes a slowing in ciliary beat frequency, mediated by PKCepsilon. AB - The elderly are at much higher risk for developing pneumonia than younger individuals. Pneumonia is a leading cause of death and is the third most common reason for hospitalization in the elderly. One reason that elderly people may be more susceptible to pneumonia is a breakdown in the lung's first line of defense, mucociliary clearance. Cilia beat in a coordinated manner to propel out invading microorganisms and particles. Ciliary beat frequency (CBF) is known to slow with aging, however, little is known about the mechanism(s) involved. We compared the CBF in BALB/c and C57BL/6 mice aged 2, 12, and 24 mo and found that CBF diminishes with age. Cilia in the mice at age 12 and 24 mo retained their ability to be stimulated by the beta2 agonist procaterol. To help determine the mechanism of ciliary slowing, we measured protein kinase C alpha and epsilon (PKCalpha and PKCepsilon) activity. There were no activity differences in PKCalpha between the mice aged 2, 12, or 24 mo. However, we demonstrated a significantly higher PKCepsilon activity in the mice at 12 and 24 mo than the in the mice 2 mo of age. The increase in activity is likely due to a nearly threefold increase in PKCepsilon protein in the lung during aging. To strengthen the connection between activation of PKCepsilon and ciliary slowing, we treated tracheas of mice at 2 mo with the PKCepsilon agonist 8-[2-(2-pentylcyclopropylmethyl)-cyclopropyl] octanoic acid (DCP-LA). We noted a similar decrease in baseline CBF, and the cilia remained sensitive to stimulation with beta2 agonists. The mechanisms for the slowing of baseline CBF have not been previously determined. In this mouse model of aging we were able to show that decreases in CBF are related to an increase in PKCepsilon activity. PMID- 24487396 TI - Impact of IgM and IgG3 anti-HLA alloantibodies in primary renal allograft recipients. AB - BACKGROUND: With standard IgG donor-specific anti-HLA antibody (DSA) testing, it is unclear which immunoglobulin-G (IgG) DSA positive patients will fail. We looked further into the immune response by studying immunoglobulin-M (IgM) and IgG subclass 3 (IgG3) DSA to determine if these identify the IgG DSA patients at highest risk for allograft loss. METHODS: In 189 consecutively transplanted primary renal allograft recipients, sera were collected sequentially pre- and posttransplant. Of the 189, 179 patients had sera available to retrospectively test for anti-HLA IgG, IgM, and IgG3 antibodies via LABScreen single-antigen bead assay and were included in the study. All patients had a negative crossmatch. Per patient, all DSA (IgM, IgG3, and IgG) refers to the same serologic specificity. RESULTS: Overall, 100 (56%) patients developed an alloimmune response (IgM or IgG DSA positive, or both). Ninety-five patients developed IgM DSA and 47 patients developed IgG DSA. IgM DSA was detected in 42 of 47 patients with IgG DSA. IgM DSA alone did not increase the allograft loss risk, whereas IgG DSA did (P=0.002). Once IgG DSA appeared, IgM DSA persisted in 33 patients and an isotype switch to IgG3 positive DSA occurred in 25 patients. Patients with IgM persistent IgG3 positive DSA (n=19) were more likely to have allograft failure than those without (P=0.02). CONCLUSION: This study shows the evolution of the humoral immune response from IgM to IgG DSA posttransplant. We found that development of IgM persistent IgG3 positive DSA identifies the most dangerous IgG DSA subpopulation. PMID- 24487397 TI - Effects of simultaneously applied short-term transcutaneous electrical nerve stimulation and tactile stimulation on memory and affective behaviour of patients with probable Alzheimer's disease. AB - In previous studies beneficial effects of peripheral electrical or tactile nerve stimulation were observed on memory and affective behaviour in patients with probable Alzheimer's disease. In the present study, it was investigated whether electrical and tactile stimulation applied simultaneously to Alzheimer patients would exceed the effects which were observed following treatment by each type of stimulation separately. Our data reveal that the simultaneous application of the two types of stimulation had a beneficial effect on non-verbal and verbal long term recognition memory. In addition, patients who were treated participated more in activities of daily living, and were more interested in social contacts. In spite of these positive results, comparisons with those of previous studies suggest that a combination of electrical and tactile stimulation does not yield more effects than application of each type of stimulation separately. PMID- 24487398 TI - Mini-Mental Parkinson: first validation study of a new bedside test constructed for Parkinson's disease. AB - We have developed a brief screening test aimed at identifying cognitive disorders in Parkinson's disease. The Mini-Mental Parkinson derives from the Mini-Mental State Examination of Folstein. It includes seven ordered subsections, with a total score of 32. A pilot study was conducted in 50 community-dwelling parkinsonian patients, in order to establish its metrological qualities. Comparisons were made with a neuropsychological battery including several tests widely used in the assessment of specific cognitive disorders in Parkinson's disease. The correlations between the Mini-Mental Parkinson and each component of this battery were substantial, especially for the performance subtests of the WAIS-R (r = 0.62 to 0.72), the Stroop test (r = 0.65) the 15-objects test (r = 0.64), the word fluency (r = 0.63) and the Odd Man Out test (r = 0.61). The validity of each subtest of the Mini-Mental Parkinson was adequate except for one, based on a word choice, which requires a modification in French before definitive use. The test-retest reliability was high (r = 0.84). There was a significant difference in the mean scores in cases with confusional event (22.4), even without current signs of dementia, compared with patients with no such history (27.2). In conclusion, this brief test is suitable for assessment of parkinsonian patients. PMID- 24487399 TI - Differential classification of dementia. AB - In the absence of biological markers, dementia classification remains complex both in terms of characterization as well as early detection of the presence or absence of dementing symptoms, particularly in diseases with possible secondary dementia. An empirical, statistical approach using neuropsychological measures was therefore developed to distinguish demented from non-demented patients and to identify differential patterns of cognitive dysfunction in neurodegenerative disease. Age-scaled neurobehavioral test results (Wechsler Adult Intelligence Scale-Revised and Wechsler Memory Scale) from Alzheimer's (AD) and Huntington's (HD) patients, matched for intellectual disability, as well as normal controls were used to derive a classification formula. Stepwise discriminant analysis accurately (99% correct) distinguished controls from demented patients, and separated the two patient groups (79% correct). Variables discriminating between HD and AD patient groups consisted of complex psychomotor tasks, visuospatial function, attention and memory. The reliability of the classification formula was demonstrated with a new, independent sample of AD and HD patients which yielded virtually identical results (classification accuracy for dementia: 96%; AD versus HD: 78%). To validate the formula, the discriminant function was applied to Parkinson's (PD) patients, 38% of whom were classified as demented. The validity of the classification was demonstrated by significant PD subgroup differences on measures of dementia not included in the discriminant function. Moreover, a majority of demented PD patients (65%) were classified as having an HD-like pattern of cognitive deficits, in line with previous reports of the subcortical nature of PD dementia. This approach may thus be useful in classifying presence or absence of dementia and in discriminating between dementia subtypes in cases of secondary or coincidental dementia. PMID- 24487400 TI - Computed tomographic density changes in schizophrenic and manic Nigerian subjects. AB - There is paucity of computed tomography (CT) studies from developing countries, where schizophrenia is said to have more favourable outcome and present predominantly with positive symptoms. We highlight the densitometric analysis of frontal and parietal areas, assessed by tracing of regions of interest on the slice that passes through the foramen of Monro and the pineal gland. The relationships of the density values with clinical and CT measures were investigated. Fifty schizophrenics, 14 manic and 41 normal subjects were compared. The schizophrenics were assessed with Andreasen's scale for negative symptoms, and outcome was based on the social and clinical condition in the past year. There were no significant differences in mean ages and brain slice area across the groups. In analysis of variance, schizophrenics and manics had significantly higher frontal density than normals. Schizophrenics had significantly higher parietal density than manics and normals (p < 0.001). Parietal density was significantly higher than frontal density, for schizophrenics and normals (p < 0.001). For the patients, density values were not significantly correlated with linear CT measures of atrophy (e.g. ventricle: brain area ratio) and duration of illness. Density values were not significantly associated with outcome, presence of negative symptoms, and visual ratings of cortical sulci and central atrophy. Our findings indicate that schizophrenia in developing countries is also associated with non-specific brain abnormalities. PMID- 24487401 TI - Umbilical cord blood lead levels and neonatal behaviour. AB - Negative correlations have been found between cord blood lead levels and scores on the Brazelton Neonatal Behaviour Assessment in 30 otherwise healthy newborns. Items in the Habituation, Orientation and Regulation of state clusters, particularly those items related to self-regulatory, self-quieting and auditory habituation, showed lower scores (worse performance) in those newborns with higher cord blood lead levels. These disturbances are potentially important since this type of behavior may interfere with the normal process of adaptation to their environment, leading to a less than optimal bonding between newborns and their carers. PMID- 24487402 TI - Psychiatric symptomatology in early-onset Binswanger's disease: two case reports. AB - We describe two cases of Binswanger's disease of pre-senile onset which presented with affective and psychotic symptoms well before the appearance of cognitive deterioration and neurological signs, initially evading an accurate diagnosis. Psychiatrists should be aware of white matter disease and its role in the pathogenesis of psychiatric illness. Particular attention should be given to a history of hypertension as a risk factor in the early identification of these cases. PMID- 24487403 TI - Neurobehavioral aspects of the delayed encephalopathy of carbon monoxide intoxication: case report and review. AB - We report the neurobehavioral aspects of the delayed encephalopathy of carbon monoxide (CO) intoxication in a 29 year old woman and review the literature. Four weeks after CO poisoning, the patient developed a frontal lobe syndrome, visuoperceptual impairment, and diffuse white matter lesions with an otherwise normal neurological examination. In contrast, patients with the classical syndrome also have a parkinsonian state or an akinetic-mute state. The delayed encephalopathy of CO poisoning usually results from demyelination of subcortical white matter, necrosis of the globus pallidus, or both. The clinical aspects, risk factors, neurobiological features, and therapy and prognosis are discussed. PMID- 24487405 TI - Advancing recovery science: reliability and validity properties of the Recovery Assessment Scale. AB - OBJECTIVE: The promotion of recovery is the driving philosophy underlying national, state, and local mental health systems. Although numerous recovery oriented measures have been developed in response, the scientific assessment of recovery measures has lagged behind. The purpose of this literature review was to review the psychometric properties of the Recovery Assessment Scale (RAS), which is arguably the most commonly used measure of recovery in the published literature. Such information is critical for advancing recovery science. METHODS: A thorough literature search using the search term "Recovery Assessment Scale" was conducted in August 2012, yielding a total of 222 articles published from around the world. A total of 77 articles that included psychometric data on the RAS were used in this review. RESULTS: Means and standard deviations across studies were fairly consistent. Overall, the studies indicate very good results for internal consistency, test-retest reliability, and interrater reliability. A number of studies also reported consistent factor structures for the measure. The RAS was found to have positive associations with other related constructs and negative associations with constructs such as symptoms. Finally, the RAS appears to be sensitive to change over time. CONCLUSIONS: The review found significant evidence to support the use of the RAS in recovery science as a means to measure recovery and to include it in mental health research. PMID- 24487406 TI - Mosaic analysis and tumor induction in zebrafish by microsatellite instability mediated stochastic gene expression. AB - Mosaic analysis, in which two or more populations of cells with differing genotypes are studied in a single animal, is a powerful approach to study developmental mechanisms and gene function in vivo. Over recent years, several genetic methods have been developed to achieve mosaicism in zebrafish, but despite their advances, limitations remain and different approaches and further refinements are warranted. Here, we describe an alternative approach for creating somatic mosaicism in zebrafish that relies on the instability of microsatellite sequences during replication. We placed the coding sequences of various marker proteins downstream of a microsatellite and out-of-frame; in vivo frameshifting into the proper reading frame results in expression of the protein in random individual cells that are surrounded by wild-type cells. We optimized this approach for the binary Gal4-UAS expression system by generating a driver line and effector lines that stochastically express Gal4-VP16 or UAS:H2A-EGFP and self maintaining UAS:H2A-EGFP-Kaloop, respectively. To demonstrate the utility of this system, we stochastically expressed a constitutively active form of the human oncogene H-RAS and show the occurrence of hyperpigmentation and sporadic tumors within 5 days. Our data demonstrate that inducing somatic mosaicism through microsatellite instability can be a valuable approach for mosaic analysis and tumor induction in Danio rerio. PMID- 24487407 TI - Cellular characterization of ultrasound-stimulated microbubble radiation enhancement in a prostate cancer xenograft model. AB - Tumor radiation resistance poses a major obstacle in achieving an optimal outcome in radiation therapy. In the current study, we characterize a novel therapeutic approach that combines ultrasound-driven microbubbles with radiation to increase treatment responses in a prostate cancer xenograft model in mice. Tumor response to ultrasound-driven microbubbles and radiation was assessed 24 hours after treatment, which consisted of radiation treatments alone (2 Gy or 8 Gy) or ultrasound-stimulated microbubbles only, or a combination of radiation and ultrasound-stimulated microbubbles. Immunohistochemical analysis using in situ end labeling (ISEL) and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) revealed increased cell death within tumors exposed to combined treatments compared with untreated tumors or tumors exposed to radiation alone. Several biomarkers were investigated to evaluate cell proliferation (Ki67), blood leakage (factor VIII), angiogenesis (cluster of differentiation molecule CD31), ceramide-formation, angiogenesis signaling [vascular endothelial growth factor (VEGF)], oxygen limitation (prolyl hydroxylase PHD2) and DNA damage/repair (gammaH2AX). Results demonstrated reduced vascularity due to vascular disruption by ultrasound-stimulated microbubbles, increased ceramide production and increased DNA damage of tumor cells, despite decreased tumor oxygenation with significantly less proliferating cells in the combined treatments. This combined approach could be a feasible option as a novel enhancing approach in radiation therapy. PMID- 24487408 TI - Synaptic abnormalities in a Drosophila model of Alzheimer's disease. AB - Alzheimer's disease (AD) is an age-related neurodegenerative disease characterized by memory loss and decreased synaptic function. Advances in transgenic animal models of AD have facilitated our understanding of this disorder, and have aided in the development, speed and efficiency of testing potential therapeutics. Recently, we have described the characterization of a novel model of AD in the fruit fly, Drosophila melanogaster, where we expressed the human AD-associated proteins APP and BACE in the central nervous system of the fly. Here we describe synaptic defects in the larval neuromuscular junction (NMJ) in this model. Our results indicate that expression of human APP and BACE at the larval NMJ leads to defective larval locomotion behavior, decreased presynaptic connections, altered mitochondrial localization in presynaptic motor neurons and decreased postsynaptic protein levels. Treating larvae expressing APP and BACE with the gamma-secretase inhibitor L-685,458 suppresses the behavioral defects as well as the pre- and postsynaptic defects. We suggest that this model will be useful to assess and model the synaptic dysfunction normally associated with AD, and will also serve as a powerful in vivo tool for rapid testing of potential therapeutics for AD. PMID- 24487409 TI - Loss of lysosomal membrane protein NCU-G1 in mice results in spontaneous liver fibrosis with accumulation of lipofuscin and iron in Kupffer cells. AB - Human kidney predominant protein, NCU-G1, is a highly conserved protein with an unknown biological function. Initially described as a nuclear protein, it was later shown to be a bona fide lysosomal integral membrane protein. To gain insight into the physiological function of NCU-G1, mice with no detectable expression of this gene were created using a gene-trap strategy, and Ncu g1(gt/gt) mice were successfully characterized. Lysosomal disorders are mainly caused by lack of or malfunctioning of proteins in the endosomal-lysosomal pathway. The clinical symptoms vary, but often include liver dysfunction. Persistent liver damage activates fibrogenesis and, if unremedied, eventually leads to liver fibrosis/cirrhosis and death. We demonstrate that the disruption of Ncu-g1 results in spontaneous liver fibrosis in mice as the predominant phenotype. Evidence for an increased rate of hepatic cell death, oxidative stress and active fibrogenesis were detected in Ncu-g1(gt/gt) liver. In addition to collagen deposition, microscopic examination of liver sections revealed accumulation of autofluorescent lipofuscin and iron in Ncu-g1(gt/gt) Kupffer cells. Because only a few transgenic mouse models have been identified with chronic liver injury and spontaneous liver fibrosis development, we propose that the Ncu-g1(gt/gt) mouse could be a valuable new tool in the development of novel treatments for the attenuation of fibrosis due to chronic liver damage. PMID- 24487411 TI - Multistep soft chemistry method for valence reduction in transition metal oxides with triangular (CdI2-type) layers. AB - Transition metal (M) oxides with MO2 triangular layers demonstrate a variety of physical properties depending on the metal oxidation states. In the known compounds, metal oxidation states are limited to either 3+ or mixed-valent 3+/4+. A multistep soft chemistry synthetic route for novel phases with M(2+/3+)O2 triangular layers is reported. PMID- 24487410 TI - Subcutaneous preconditioning increases invasion and metastatic dissemination in mouse colorectal cancer models. AB - Mouse colorectal cancer (CRC) models generated by orthotopic microinjection of human CRC cell lines reproduce the pattern of lymphatic, haematological and transcoelomic spread but generate low metastatic efficiency. Our aim was to develop a new strategy that could increase the metastatic efficiency of these models. We used subcutaneous implantation of the human CRC cell lines HCT116 or SW48 prior to their orthotopic microinjection in the cecum of nude mice (SC+ORT). This subcutaneous preconditioning significantly enhanced metastatic dissemination. In the HCT116 model it increased the number and size of metastatic foci in lymph nodes, lung, liver and peritoneum, whereas, in the SW48 model, it induced a shift from non-metastatic to metastatic. In both models the number of apoptotic bodies in the primary tumour in the SC+ORT group was significantly reduced compared with that in the direct orthotopic injection (ORT) group. Moreover, in HCT116 tumours the number of keratin-positive tumour buddings and single epithelial cells increased at the invasion front in SC+ORT mice. In the SW48 tumour model, we observed a trend towards a higher number of tumour buds and single cells in the SC+ORT group but this did not reach statistical significance. At a molecular level, the enhanced metastatic efficiency observed in the HCT116 SC+ORT model was associated with an increase in AKT activation, VEGF-A overexpression and downregulation of beta1 integrin in primary tumour tissue, whereas, in SW48 SC+ORT mice, the level of expression of these proteins remained unchanged. In summary, subcutaneous preconditioning increased the metastatic dissemination of both orthotopic CRC models by increasing tumour cell survival and invasion at the tumour invasion front. This approach could be useful to simultaneously study the mechanisms of metastases and to evaluate anti-metastatic drugs against CRC. PMID- 24487412 TI - Final report of phase II study of sorafenib, cytarabine and idarubicin for initial therapy in younger patients with acute myeloid leukemia. PMID- 24487415 TI - Dynamics of Li4Ti5O12/sulfone-based electrolyte interfaces in lithium-ion batteries. AB - Binary mixtures of cyclic (TMS) or acyclic sulfones (MIS, EIS and EMS) with EMC or DMC have been used in electrolytes containing LiPF6 (1 M) in both Li4Ti5O12/Li half-cells and Li4+xTi5O12/Li4Ti5O12 symmetric cells and compared with standard EC/EMC or EC/DMC mixtures. In half-cells, sulfone-based electrolytes cannot be satisfactorily cycled owing to the formation of a resistive layer at the lithium interface, which is not stable and generates species (RSO2(-) and RSO3(-)) able to migrate toward the titanate electrode interface. Potentiostatic and galvanostatic tests of Li4Ti5O12/Li half-cells show that charge transfer resistance increases drastically when sulfones are used in the electrolyte composition. Moreover, cyclability and coulombic efficiency are low. Conversely, when symmetric Li4+xTi5O12/Li4Ti5O12 cells are used, it is demonstrated that MIS (methyl isopropyl sulfone) and TMS-(tetra methyl sulfone) based electrolytes exhibit reasonable electrochemical performances as compared to the EC/DMC or EC/EMC standard mixtures. Surface analysis by XPS of both the Li4+xTi5O12 (partially oxidized) and Li7Ti5O12 (reduced) electrodes taken from symmetric cells reveals that sulfones do not participate in the formation of surface layers. Alkylcarbonates (EMC or DMC), used as co-solvents in sulfone-based binary electrolytes, ensure the formation of surface layers at the titanate interfaces. Therefore, EMC reduction at the two Li4+xTi5O12/electrolyte interfaces in symmetric cells leads to the formation of carbonates, ethers and mineral compounds such as ROCO2Li and Li2CO3. Finally, huge amounts of LiF are detected at the titanate electrode surface, resulting in an increase in the resistivity of symmetric cells and capacity losses. PMID- 24487413 TI - Comprehensive analysis of genetic alterations and their prognostic impacts in adult acute myeloid leukemia patients. AB - To clarify the cooperative roles of recurrently identified mutations and to establish a more precise risk classification system in acute myeloid leukemia (AML), we comprehensively analyzed mutations in 51 genes, as well as cytogenetics and 11 chimeric transcripts, in 197 adult patients with de novo AML who were registered in the Japan Adult Leukemia Study Group AML201 study. We identified a total of 505 mutations in 44 genes, while only five genes, FLT3, NPM1, CEBPA, DNMT3A and KIT, were mutated in more than 10% of the patients. Although several cooperative and exclusive mutation patterns were observed, the accumulated mutation number was higher in cytogenetically normal AML and lower in AML with RUNX1-RUNX1T1 and CBFB-MYH11, indicating a strong potential of these translocations for the initiation of AML. Furthermore, we evaluated the prognostic impacts of each sole mutation and the combinations of mutations and/or cytogenetics, and demonstrated that AML patients could be clearly stratified into five risk groups for overall survival by including the mutation status of DNMT3A, MLL-PTD and TP53 genes in the risk classification system of the European LeukemiaNet. These results indicate that the prognosis of AML could be stratified by the major mutation status in combination with cytogenetics. PMID- 24487414 TI - Inhibitor of Apoptosis (IAP) proteins in hematological malignancies: molecular mechanisms and therapeutic opportunities. AB - Inhibitor of Apoptosis (IAP) proteins exert essential functions during tumorigenesis as well as treatment resistance by simultaneously blocking cell death pathways and promoting cell survival. As IAP proteins are typically aberrantly expressed in human cancers including hematological malignancies, they represent in principle promising targets for therapeutic interventions. There are currently exciting opportunities to rationally exploit the therapeutic targeting of IAP proteins for the treatment of leukemia and lymphoma. Further insights into the signaling pathways that are under the control of IAP proteins and into the specific IAP protein-dependent vulnerabilities of hematological neoplasms are expected to pave the avenue to novel treatment strategies. PMID- 24487416 TI - Prevalence of polypharmacy in a Scottish primary care population. AB - PURPOSE: Polypharmacy-the use of multiple medications by a single patient-is an important issue associated with various adverse clinical outcomes and rising costs. It is also a topic rarely addressed by clinical guidelines. We used routine Scottish health records to address the lack of data on the prevalence of polypharmacy in the broader, adult primary care population, particularly in relation to long-term conditions. METHODS: We conducted a cross-sectional analysis of adult electronic primary healthcare records and used linear regression models to examine the association between the number of medicines prescribed regularly and both multimorbidity and specific clinical conditions, adjusting for age, gender and socioeconomic deprivation. RESULTS: Overall, 16.9 % of the adults assessed were receiving four to nine medications, and 4.6 % were receiving ten or more medications, increasing with age (28.6 and 7.4 %, respectively, in those aged 60-69 years; 51.8 and 18.6 %, respectively, in those aged >= 80 years), but relatively unaffected by gender or deprivation. Of those patients with two clinical conditions, 20.8 % were receiving four to nine medications, and 1.1 % were receiving ten or more medications; in those patients with six or more comorbidities, these values were 47.7 and 41.7 %, respectively. The number of medications varied considerably between clinical conditions, with cardiovascular conditions associated with the greatest number of additional medications. The accumulation of additional medicines was less with concordant conditions. CONCLUSIONS: Polypharmacy is common in UK primary care. The main factor associated with this is multimorbidity, although considerable variation exists between different conditions. The impact of clinical conditions on the number of medicines is generally less in the presence of co-existing concordant conditions. PMID- 24487417 TI - The Benefit of Chemotherapy in Esophageal Cancer Patients With Residual Disease After Trimodality Therapy. AB - INTRODUCTION: The objective of this retrospective study was to determine the potential benefits of chemotherapy in esophageal cancer patients treated with chemoradiation followed by surgery. MATERIALS AND METHODS: At our institution, 145 patients completed trimodality therapy from 1993 to 2009. Neoadjuvant treatment predominantly consisted of 5-fluorouracil and cisplatin with a concurrent median radiation dose of 50.4 Gy. Sixty-two patients received chemotherapy postoperatively. The majority (49/62) received 3 cycles of docetaxel. RESULTS: Within the entire cohort, a 5-year overall survival (OS) benefit was found in those who received postoperative chemotherapy, OS 37.1% versus 18.0% (P=0.024). The response after neoadjuvant chemoradiation was as follows: 33.8% had a pathologic complete response and 62.8% with residual disease. A 5-year OS and cause-specific survival (CSS) advantage were associated with postoperative chemotherapy among those with macroscopic residual disease after neoadjuvant therapy: OS 38.7% versus 13.9% (P=0.016), CSS 42.8% versus 18.8% (P=0.048). This benefit was not seen in those with a pathologic complete response or those with microscopic residual. A stepwise multivariate Cox regression model evaluating the partial response group revealed that postoperative chemotherapy and M stage were independent predictors of overall and CSS. CONCLUSIONS: This analysis revealed that patients with gross residual disease after trimodality therapy for esophageal cancer who received postoperative chemotherapy had an improved overall and CSS. These data suggest that patients with residual disease after trimodality therapy and a reasonable performance status may benefit from postoperative chemotherapy. Prospective trials are needed to confirm these results to define the role of postoperative treatment after trimodality therapy. PMID- 24487418 TI - Chemotherapy, Irradiation, and Surgery for Function-preserving Curative Therapy of Primary Extremity Soft Tissue Sarcomas: Initial Treatment With I-MAP and Inhalation GM-CSF During Preoperative Irradiation and Postoperatively. AB - PURPOSE: To determine if aerosol granulocyte macrophage-colony-stimulating factor (GM-CSF) decreases the 2-year pulmonary metastasis rate for soft tissue sarcoma. PATIENTS AND METHODS: Patients with high-grade soft tissue sarcomas were treated with 2 cycles of ifosfamide, mitomycin, doxorubicin, and cisplatin plus GM-CSF subcutaneous followed by 45 Gy irradiation with concurrent 2 cycles of mitomycin, doxorubicin, and cisplatin followed by surgery +/- intraoperative radiation or brachytherapy. Aerosol GM-CSF (250 mcg twice a day) was administered for 1 week every other week 3* during neoadjuvant therapy and beginning 4 weeks postoperatively every other week 5*. RESULTS: A total of 39 patients were enrolled between November 2001 and April 2006. The median age was 51 years (range, 19 to 65 y). The median lesion size was 9 cm (range, 2.3 to 26.7 cm). Seventy-six percent experienced grade 3-4 hematologic toxicity. Twenty-four of the first 35 evaluable patients (69%; 95% CI, 41%-84%) were free of pulmonary metastasis at 2 years. A total of 82% (95% CI, 70%-95%) of patients were still alive after 3 years, with a median follow-up of 5.5 years (range, 3.4 to 7.6 y). A total of 58% (95% CI, 44%-76%) of patients remained progression free after 3 years. CONCLUSIONS: The addition of aerosol GM-CSF to combined chemotherapy, irradiation, and surgery for soft tissue sarcomas did not achieve the study endpoint to decrease the 2-year pulmonary metastasis rate. PMID- 24487419 TI - Effect of Surgical Intervention on Survival of Patients With Clinical N2 Non Small Cell Lung Cancer: A Veterans' Affairs Central Cancer Registry (VACCR) Database Analysis. AB - BACKGROUND: Optimal management of locally advanced non-small cell lung cancer (NSCLC) lacks consensus. A retrospective analysis of patient data entered in the Veterans Affairs Central Cancer Registry was conducted to evaluate these issues. PATIENTS AND METHODS: Data of patients with cT1-4, cN2, and cM0 NSCLC diagnosed in the VA Health System between 1995 and 2003 were evaluated. Age, sex, race, smoking history, TNM stage, treatment, and overall survival were abstracted. Survival was compared using multivariate Cox proportional hazards regression analysis. RESULTS: Of the 7328 patients analyzed, 7218 (98.5%) were male, 6061 (82.7%) were white, and 321 (4.4%) were never smokers. The treatment received included: none, 23.8%; chemotherapy alone, 14.3%; radiation alone, 23%; and chemoradiation (sequential or concurrent), 31.4%. Only 7.5% of patients had a surgical resection, with or without multimodality therapy. The median survival (months) of these patient groups were: surgery, 19.3; chemoradiation, 13; chemotherapy alone, 9.2; radiation alone, 7.3; and no treatment, 4 (P<0.0001). African Americans had a significantly decreased risk of mortality compared with whites (hazard ratio 0.92; 95% confidence interval, 0.87-0.98). CONCLUSIONS: Inclusion of surgical resection as a treatment modality was associated with a better overall survival. Also, African Americans appeared to do better than whites. These hypothesis-generating findings should be useful in the ongoing pursuit of better treatment strategies for locally advanced NSCLC. PMID- 24487420 TI - Low-Dose-Rate Brachytherapy Boosting Concurrent Chemoradiation as a Definitive Treatment Modality for Cervical Cancer: Long-term Clinical Results of Outcomes and Associated Toxicity. AB - PURPOSE: To review and report the long-term treatment-induced adverse events (AEs) and outcomes of concomitant chemoradiotherapy boosted by low-dose-rate (LDR) conventional brachytherapy (BT) planning in patients with locoregionally advanced cervical cancer. PATIENTS AND METHODS: After obtaining institutional review board approval, we reviewed the records of patients with stage IB1 to IVA, intact cervical cancer who were treated at our institution between 1983 and 2009. Eligible patients underwent definitive radiotherapy with external-beam radiation concomitant with cisplatin-based chemotherapy and boosted by LDR BT. Patient, tumor, and treatment characteristics; treatment-induced AEs, namely, gastrointestinal and genitourinary toxicities, as well as treatment outcomes; locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were reviewed and reported. RESULTS: The study included 129 eligible cervical cancer patients; the median age was 46 years (mean, 47 +/- 11 y; range, 28 to 81 y), consisting of stages I, II, III, and IV (29.5%, 48.1%, 17.8%, and 4.6%, respectively). The median follow-up was 37 months (mean, 58 +/- 59 mo; range, 3 to 275 mo). The 3-year OS, PFS, LRC, and DC were 75.9%, 71.6%, 84.7%, and 80.2%, respectively. The 5-year OS, PFS, LRC, and DC were 70.7%, 68.7%, 84.7%, and 78.3%, respectively. The 10-year OS, PFS, LRC, and DC were 68.7%, 62.3%, 82.5%, and 73.2%, respectively. Gastrointestinal and genitourinary grade 3 and 4 acute AEs were reported in 3.9% and 0%, and chronic grade 3 and 4 AEs were reported in 20.9% and 12.4% of all patients, respectively. CONCLUSIONS: Definitive chemoradiotherapy followed by conventional LDR BT boost is effective, feasible, and tolerable treatment modality for cervical cancer. A comparison with MRI image-guided BT shows comparable treatment outcomes with superior OS in favor of LDR BT but inferior LC with a relatively worse toxicity profile. PMID- 24487421 TI - Limitations of the Cancer of the Prostate Risk Assessment (CAPRA) Prognostic Tool for Prediction of Metastases and Prostate Cancer-specific Mortality in Patients Treated With External Beam Radiation Therapy. AB - OBJECTIVES: To assess the performance of the Cancer of the Prostate Risk Assessment (CAPRA) prognostic tool for freedom-from-metastases (FFM) and cause specific survival (CSS) in patients with localized prostate cancer treated with definitive external beam radiotherapy (EBRT), and to determine whether the performance of CAPRA is influenced by androgen deprivation therapy (ADT) use or the presence of Gleason pattern 5 (GP-5). MATERIALS AND METHODS: A total of 612 patients from a prospective database of 718 patients treated with dose-escalated EBRT from 1998 to 2008 who met CAPRA scoring criteria were included in the study. Performance of CAPRA and association of CAPRA score, GP-5 and short-term or long term ADT use (STAD or LTAD, respectively) with FFM and CSS were evaluated using Cox models. The impact of ADT use on accuracy of the CAPRA-based CaPSURE model for CSS was assessed. The discriminatory ability of the CAPRA model and modified models incorporating GP-5 and ADT use were compared using the C-index. RESULTS: Increasing CAPRA score correlated with worse FFM and CSS, and was prognostic for FFM and CSS for the overall cohort. CAPRA showed poorer discrimination for FFM and CSS in patients treated with EBRT+LTAD than those who received EBRT alone or EBRT+STAD. The addition of GP-5 and ADT use to CAPRA score increased the predictive accuracy of the CAPRA model for both FFM (C-index 0.809 vs. 0.779, P<0.001) and CSS (C-index 0.864 vs. 0.796, P=0.003). CONCLUSIONS: The CAPRA score should be modified to incorporate GP-5 and ADT use for risk adjustment and risk prediction in prostate cancer patients who receive EBRT. PMID- 24487423 TI - Frontal cognitive function and memory in Parkinson's disease: toward a distinction between prospective and declarative memory impairments? AB - Memory dysfunction is a frequent concomitant of Parkinson's disease (PD). Historically, two classes of hypotheses, focusing on different cognitive mechanisms, have been advanced to explain this memory impairment: one postulating retrieval deficits (common to several neurodegenerative disorders involving the basal ganglia), and the other postulating frontally mediated executive deficits as fundamental to memory impairment. After outlining empirical support for the retrieval deficit hypothesis, research on the more recent "frontal executive deficit hypothesis" is reviewed, and major challenges to this hypothesis are identified. It is concluded that the frontal executive deficit hypothesis cannot adequately account for all memory impairments in PD, and that a more parsimonious theoretical account might invoke a distinction between prospective and declarative memory impairments. It is suggested that there may be three subgroups of PD patients: one demonstrating prospective memory dysfunction only, one with declarative memory dysfunction only, and one with both prospective and declarative memory dysfunction. Consequently, PD might provide a useful model within which to investigate the relationship between prospective and declarative memory. PMID- 24487422 TI - Morning melatonin serum values do not correlate with disease activity in rheumatoid arthritis: a cross-sectional study. AB - Rheumatoid arthritis (RA), the most prevalent autoimmune arthritis worldwide, usually presents with a circannual manner and, meanwhile, follows a circadian rhythm for symptoms like morning stiffness. Therefore, association between RA and some hormones such as melatonin (MLT) and vitamin D, whose serum values are related to body circadian rhythms or seasonal variations, has become more noticeable recently. Since some studies proposed that RA patients show altered MLT circadian rhythms, especially in concordance with symptoms, in this research, we present the correlation between MLT serum values and RA disease activity score (DAS28ESR). The current cross-sectional study was carried out on 80 volunteers (60 patients and 20 healthy controls). Fifty percent of the participants in each group were sampled in cold, and the same percentage were sampled in warm seasons at 8 a.m. Disease activity was estimated utilizing DAS28ESR. Patients with possible known confounders of MLT secretion were excluded. A commercial MLT ELISA kit was employed to measure MLT. Statistical analysis was conducted by SPSS-11 software. This study outlined higher serum values of MLT in RA patients compared with controls (P = 0.006, z = -2.73). However, MLT did not correlate with DAS in patients (P = 0.45, r = -0.09). GLM analysis demonstrated that DAS28ESR, age, disease duration, medications, gender, and season of sampling had no influence on serum MLT. However, newly diagnosed RA patients presented higher MLT values than established ones (P = 0.03, t = -2.2). A cutoff point value of 23 pg/mL (63.3 % sensitivity and 90 % specificity) for MLT was computed between patients and controls. This study denoted that morning MLT serum values are higher in RA patients than in healthy volunteers. However, MLT and RA disease activity or other disease characteristics do not correlate. MLT serum values were higher in newly diagnosed RA patients than established ones. PMID- 24487424 TI - Gilles de la Tourette syndrome: clinical features of 75 cases from Argentina. AB - A series of 75 cases of Gilles de la Tourette syndrome (GTS) from Argentina, whose ages ranged from 6 to 55 with a mean of 20.02, were evaluated to compare findings with those reported for other countries. Mean age at onset was 7.44 years and mean overall duration of symptoms was 12.58 years; 6.7% of cases were mild, 49% moderate and 44.3% severe. Most frequent presenting motor tics were excessive blinking in 41 followed by head jerking in 16 and eye winking in six, while phonic tics included coprolalia in 28.0%, echolalia in 17.5% and palilalia in 10.8%. Abnormal perinatal events were reported in 40.5%, while positive family history for tics was present in 26.66%. Obsessive-compulsive behaviour was evident in 66% and attention deficit disorder in 16% of cases. Self-injurious behaviour comprised onychophagia in 28 patients, lip-biting in seven and self slapping in eight cases. Almost half of our patients were initially interpreted as having a psychogenic disorder indicating that GTS in Argentina is most likely underdiagnosed. It may be concluded that the overall pattern of GTS is not dissimilar to that described for European, Asian and American populations, thus highlighting the previously recognized cross-cultural uniformity. PMID- 24487425 TI - Verbal short-term memory and motor speech processes in Broca's aphasia. AB - The present study investigated the relationship between verbal short-term memory and motor speech processes in healthy control subjects and five patients suffering from Broca's aphasia. Control subjects showed a phonological similarity effect, a word length effect and an articulatory suppression effect, supporting the hypothesis of a phonological store and an articulatory loop component of short-term memory. A similar effect of phonological similarity was observed in the aphasic patients, while the effects of word length and articulatory suppression were reduced. In control subjects, measures of short-term memory were correlated to measures of motor speech rate only if speech rate was assessed in more complex conditions (such as sentence rather than syllable repetition). There was also evidence of an association of speech impairment and short-term memory deficits in the aphasic patients. PMID- 24487426 TI - Memory and cerebral blood flow in cases of transient global amnesia during and after the attack. AB - We administered various memory tests and neuroimaging examinations to four pure cases who met Hodges' clinical criteria for transient global amnesia (TGA), during and after the attack. The purpose of the present study was to determine whether procedural learning is acquired during TGA and whether priming effects are preserved during TGA, and to investigate the anatomical basis of various memory subcomponents through these cases. Episodic memory was severely disturbed only during TGA, consistent with previous studies. Procedural learning during TGA examined by a drawing skill test and a reading skill test developed by us, and the Tower of Toronto, was preserved during TGA, consistent with one earlier report dealing with procedural memory during TGA. Priming effects during TGA have never been assessed. A word completion priming task with Kanji letters developed by us demonstrated that priming effects were preserved during TGA. Neuroradiologically, single photon emission computed tomograph hippocampal images clearly revealed a hypoperfusion confined to the medial portion of the bilateral temporal lobe only during the attack. These findings indicate that the medial portion of the temporal lobe is important for episodic memory as described in previous reports, but did not play an important role in procedural memory and priming effects. PMID- 24487427 TI - Unilateral temporal lobe damage and the partial Kluver-Bucy syndrome. AB - The characteristic behavioural constellation of Kluver-Bucy syndrome is believed to be diagnostic of bilateral temporal lobe damage, even in the partial syndrome. The case described is that of a 54 year old woman with gross atrophy of her right temporal lobe following neurosurgery who developed hyperphagia (with driven food seeking behaviour), placidity and hyposexuality. Her case thereby meets criteria for the partial syndrome but without evidence of bilateral damage. The discussion covers the various presentations of hyperphagia, the significance of the symptom cluster of Kluver-Bucy syndrome and the management difficulties presented by hyperphagia. PMID- 24487428 TI - Migraine with prolonged aura: correlation of clinical and EEG features. AB - Migraine with prolonged aura has rarely been examined with regard to the sequence of the neurological symptoms and the associated EEG changes. This report describes five patients who underwent clinical assessment and EEG recordings during attacks of migraine with prolonged aura. CT scan of the brain was obtained in four of them. Follow-up EEG was also obtained. The aura symptoms either preceded the headache or were coincident with it. The aura symptoms evolved in a manner consistent with posterior-to-anterior dysfunction of the cerebral cortex. The EEG abnormalities were non-epileptiform and consisted of focal delta slow waves or theta slow waves. The EEG abnormalities showed good correlation with the patients' aura symptoms and resolved when the patients became symptom free. The posterior-to-anterior sequence of the aura symptoms is in accord with the findings during cerebral blood flow studies in patients having migraine with aura. Also the symptoms and EEG changes in our patients indicate dysfunction of the cerebral cortex, consistent with the notion that spreading cortical depression may be the underlying pathophysiological event in migraine with aura. PMID- 24487429 TI - Facial expressions and Parkinson's disease. AB - Patients with Parkinson's disease (PD) and matched control subjects were photographed posing a range of facial expressions. The same subjects were later asked to identify the posed expressions of the other subjects. They were also asked to rate the quality of expressions posed by the control subjects after being told what each expression was. Expressions posed by healthy control subjects were more readily identifiable than expressions posed by Parkinson's patients, but the two groups did not differ in their ability to recognize facial expressions or in the goodness ratings they gave, and their error patterns were closely similar. There was no significant difference between the groups on other tests of face processing or on ratings of emotionality except for greater reported anxiety in the Parkinson's patients. We conclude that although patients with PD have reduced facial expressiveness, there is no apparent diminution in their comprehension of facial expressions or their day-to-day experience of emotion. PMID- 24487430 TI - A crossed Kana agraphia. AB - We report a right-handed man who developed selective Kana (phonogram) agraphia following an infarct in the non-dominant right cerebral hemisphere. His ability for comprehension, reading and writing of Kanji (ideogram) was unaffected. Kana errors consisted of substitution with another letter and the number of target words was well preserved. The lesion responsible for his Kana agraphia included the right Wernicke's area (the posterior one-third or one-half of the superior temporal gyrus) on MRI, but he did not have aphasia. Based on these findings, we conclude that the language function in some dextral people may be partially lateralized to the right cerebral hemisphere. PMID- 24487435 TI - Magnetic attraction of gaze: further evidence of hemispheric imbalance in schizophrenia? AB - A case is reported of a young man with a clinical diagnosis of schizophrenia and unusual oculo-motor abnormalities. The relationship between oculo-motor dysfunction and hemispheric balance in schizophrenia is discussed. PMID- 24487433 TI - Noninvasive imaging of Staphylococcus aureus infections with a nuclease-activated probe. AB - Technologies that enable the rapid detection and localization of bacterial infections in living animals could address an unmet need for infectious disease diagnostics. We describe a molecular imaging approach for the specific, noninvasive detection of S. aureus based on the activity of the S. aureus secreted nuclease, micrococcal nuclease (MN). Several short synthetic oligonucleotides, rendered resistant to mammalian serum nucleases by various chemical modifications and flanked with a fluorophore and quencher, were activated upon degradation by purified MN and in S. aureus culture supernatants. A probe consisting of a pair of deoxythymidines flanked by several 2'-O-methyl modified nucleotides was activated in culture supernatants of S. aureus but not in culture supernatants of several other pathogenic bacteria. Systemic administration of this probe to mice bearing S. aureus muscle infections resulted in probe activation at the infection sites in an MN-dependent manner. This new bacterial imaging approach has potential clinical applicability for infections with S. aureus and several other medically important pathogens. PMID- 24487436 TI - Palinopsia: a review of the literature. AB - The literature on palinopsia (visual perseveration) is reviewed, utilizing case reports of 46 patients who demonstrated this symptom. The most common etiologies for this symptom are space-occupying lesions, cerebral infarct, and seizure activity. The vast majority are due to central nervous system pathology occurring in the posterior (occipital or parieto-occipital) region, often in the right hemisphere. Proposed mechanisms for palinopsia are also discussed. PMID- 24487437 TI - Transient Crossed Aphasia: a Case Study with SPECT. AB - A 45-year-old right-handed man developed "crossed" anomie aphasia, neglect and inaccurate reaching of his left arm in both hemispaces due to a right parietal haemorrhage. Aphasia cleared in a few days. SPECT failed to demonstrate crossed left hemispheric diaschisis. This report emphasizes the importance of evaluating patients in the acute stage and of coupling "static" and "functional" imaging methods when studying brain-behavior relationships. PMID- 24487434 TI - Fas ligand-mediated immune surveillance by T cells is essential for the control of spontaneous B cell lymphomas. AB - Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance. PMID- 24487438 TI - Delusional misidentification incident in a right hemisphere stroke patient. AB - We report a delusional misidentification incident lasting some hours in which a man who had suffered a right hemisphere stroke, HW, mistook a student for his daughter. Investigation of HW's face processing abilities showed unimpaired ability to recognize familiar faces and match facial expressions, but severe impairments of unfamiliar face matching both on the Benton test and a task requiring the matching of disguised and undisguised faces. The incident shows some similarity to the Fregoli delusion, which has also been noted following brain injury affecting the right cerebral hemisphere. PMID- 24487439 TI - Specificity of cognitive impairment in neurological disease: a methodological critique of Parkinson's disease. AB - Multiple cognitive deficits have been recognized in many neurological disorders but the specificity of the findings and the relationship to the underlying neuropathology remain obscure. Definitions of dementia have been proposed based on symptom profiles of the cognitive disorder and qualitative differences have been claimed between dementias of different aetiology. Some conditions have been claimed to show patterns of cognitive deficit that are distinguished from dementia and related to specific neuropathology or psychological processes, e.g. frontal lobe deficits in Parkinson's disease. Sometimes, a relationship has been established between certain cognitive deficits and particular neurochemical deficits which has led to the notion of specific drug treatment, e.g. cholinergic deficits and memory failure in Alzheimer's disease. However, these conclusions are often potentially flawed by methodological inadequacies. This critique presents some methodological issues relevant to the study of brain-behaviour and drug-behaviour relationships in syndromes of multiple cognitive deficit, using Parkinson's disease as the model. The following recommendations are made: rigid diagnostic criteria; representative patient groups; avoidance of arbitrary quantitative criteria to limit definitions of dementia; matching of groups for overall level of cognitive impairment in the search for qualitative cognitive differences related to neuropathology or effects of particular drugs; the use of suitable controls in patient groups, neuropsychological tests and treatment regimes; the use of specific quantitative tests of cognition, affect and motor disability; and longitudinal, compared with cross-sectional, study design. PMID- 24487440 TI - Lack of selective vulnerability to anticholinergic induced cognitive impairment in early Parkinson's disease. AB - Thirteen patients with idiopathic Parkinson's disease of recent onset (mean age 63.2 years) and a group of 10 young healthy volunteers (mean age 26.1 years) underwent a series of neuropsychological tests for assessment of memory, learning ability and mental processing speed before and during treatment with trihexyphenidyl. Retesting after anticholinergic exposure (mean of 2 weeks for patients and 1 week for controls) revealed in young healthy controls the same pattern and magnitude of decline in memory function as in Parkinson patients. Non demented subjects with Parkinson's disease of recent onset thus do riot seem to be selectively vulnerable to cognitive side-effects of anticholinergic treatment. PMID- 24487441 TI - Neurobehavioural correlates of abnormal repetitive behaviour. AB - Conditions in which echolalia and echopraxia occur are reviewed, followed by an attempt to elicit possible mechanisms of these phenomena. A brief description of stereotypical and perseverative behaviour and obsessional phenomena is given. It is suggested that abnormal repetitive behaviour may occur partly as a result of central dopaminergic dysfunction. PMID- 24487442 TI - Processing of words and faces by patients with left and right temporal lobe epilepsy. AB - Tests of word and face processing were given to patients with complex partial epilepsy focussed on the left or right temporal lobe, and to non-epileptic control subjects. The left TLE group showed the greatest impairment on object naming and on reading tests, but the right TLE group also showed a lesser impairment relative to the normal control subjects on both tests. The right TLE group was selectively impaired on distinguishing famous from non-famous faces while the left TLE group was impaired at naming famous faces they had successfully recognized as familiar. There was no significant difference between the three groups on recognition memory for words. The implications of the results for theories of the role of the temporal lobes in word and face processing, and the possible neural mechanisms responsible for the deficits in TLE patients, are discussed. PMID- 24487443 TI - Instability of the growth-limiting proteins of the Avena coleoptile and their pool size in relation to auxin. AB - The stability and pool size of the growth-limiting proteins (GLP) of the Avena coleoptile have been studied by measuring the time required for cycloheximide to inhibit the growth of auxin-treated segments. Inhibition of growth follows inhibition of protein synthesis by 20-25 min regardless of the growth rate. This indicates that the growth inhibition is due to inherent instability of the GLP rather than to exhaustion of the pool through growth. A study of the amount and rate of auxin-induced growth which occurs when cycloheximide is added just before or after the auxin indicates that the rate of elongation is determined by the size of the GLP pool, and that the pool of GLP is low in the absence of auxin, but rapidly expands and reaches a maximum 20-25 min after addition of auxin. Three ways in which auxin might expand the pool of GLP are discussed. PMID- 24487444 TI - Plating of isolated tobacco mesophyll protoplasts on agar medium. AB - A technique was developed to derive cell and plant clones from isolated mesophyll protoplasts of tobacco. The protoplasts, plated on a fully defined agar medium, divided and grew actively forming visible colonies after one month of culture. Efficiency of colony formation depended on cell density and light condition during incubation. Under standard conditions, 60% of plated protoplasts formed colonies. Upon transfer onto suitable media, these colonies differentiated shoots and roots, and eventually regenerated whole plants. Advantages of mesophyll protoplasts as the source of clones as well as implication of the plating technique for genetical studies are discussed. PMID- 24487445 TI - Non-uniformities in the metabolism of excised leaves and leaf discs. AB - In intact tobacco and Chinese-cabbage (Brassica pekinensis) leaves an "ageing" process begins as soon as the leaves are excised. The terminal few millimetres of the petiole increasingly preempt materials such as phosphate and uracil taken up by the leaf. Actinomycin D treatment blocks this process and leads to increased uptake of such materials into the lamina.Immediately after excision there is a radial "geographical" gradient, in the ability of excised leaf discs to accumulate phosphate and uracil from solution. Tissue near the cut edge accumulates much more of these materials than that near the centre, and total nucleic acids isolated from the outer zone have a higher specific activity.Over the first day after excision there is a marked increase in this ability of the outer tissue of discs to accumulate labelled precursors but the changes taking place with time are complex and variable. Specific activity of total nucleic acids increases somewhat less than the increased uptake of labelled precursor. Actinomycin D becomes very unevenly distributed in leaf discs floated on solutions of the drug. These various effects are of sufficient magnitude to affect the interpretation of studies using excised leaf tissues. PMID- 24487446 TI - N-1-napthylphthalamic-acid-binding activity of a plasma membrane-rich fraction from maize coleoptiles. AB - Plasma membrane-rich fractions were prepared from maize coleoptiles by low-shear homogenization and differential and sucrose-gradient centrifugation. Plasma membrane fragments were identified using a specific cytochemical stain based on phosphotungstic acid prepared in chromic acid. In a comparison of 10 different cell fractions of varying plasma membrane content, the N-1-napthylphthalamic-acid (NPA)-binding activity of the fractions was directly proportional to the content of plasma membrane. The NPA binding appears to be strong K M between 10(-8) and 10(-7) M) but non-covalent. NPA is known to inhibit auxin transport efficiently and quickly. Thus, the results are consistent with the localization of auxin transport sites at the plasma membrane of plant cells. PMID- 24487447 TI - [The effect of rifampicin on the RNA- and protein synthesis as well as on the morphogenesis and on the chlorophyll content of nucleate and anucleate cells of Acetabularia]. AB - Rifampicin (10MUg/ml) strongly inhibits the incorporation of [5-(3)H]-uridine into the chloroplast RNA of anucleate cells of the green alga Acetabularia mediterranea, whereas incorporation into nuclear RNA is hardly affected.Furthermore, at a concentration range of 1-10[Symbol: see text]g/ml rifampicin has only a small effect on stalk- and cap formation in nucleate posterior parts of the stalk. As has already been shown, the morphogenesis of such cell segments depends on the synthesis of new RNA in the nucleus. Similarly rifampicin only slightly inhibits the synthesis of the enzyme UDPG pyrophosphorylase, which is coded by nuclear DNA.These slight inhibitions are interpreted as secondary effects arising from a blockage of plastid RNA synthesis, since both nucleate and anucleate cells respond in a similar manner and to the same degree.In contrast the increase in the chlorophyll content in nucleate and anucleate cells is severely impaired by the antibiotic. These findings indicate that the nucleus and the plastids contain different DNA dependent RNA-polymerases. PMID- 24487448 TI - Possible involvement of a glycerophosphate compound in auxin induced growth. AB - An unknown compound previously extracted from sterile pea stem sections, has been identified as a glycerol and phosphate containing compound with a molecular weight of 5000. The auxin, IAA, has been shown to stimulate the incorporation of (32)P orthophosphate into the compound in five minutes i.e., before the onset of stimulated growth rates.Possible mechanisms underlying auxin induced growth are discussed in the light of the above findings. PMID- 24487449 TI - [Variation of peroxidase and phenoloxidase activities during the growth of Coleus blumei Benth. var. Automne]. AB - The specific peroxidase (1.11.1.7) and phenoloxidase (1.10.3.1) activities are quantitatively measured during the life of Coleus, from germination until flowering. In most organs investigated, the peroxidase activity increases rapidly with growth while the phenoloxidase activity remains low. The latter activity is higher in root apices than in more differentiated regions of roots. From the results obtained it may be concluded that the phenoloxidase activity accompanies cellular proliferation. It is suggested that the peroxidase activity plays an indirect role in root initiation through its role in cellular differentiation. PMID- 24487450 TI - Studies on the movement of indole auxins in willow (Salix viminalis L.). AB - Auxin activity was detected in honeydew obtained from the aphid Tuberolachnus salignus (Gmelin) feeding on willow (Salix viminalis). Active uptake of (14)C indolyl-3-acetic acid (IAA) into the sieve tubes was demonstrated by irrigating the cambial surface of willow bark with (14)C-IAA solution and assaying aphid stylet exudate. When, however, (14)C-IAA was applied to the peridermal tissues of the bark or to a mature leaf most of the radioactivity (collected in honeydew or stylet exudate) co-chromatographed with indolyl-3-acetyl-aspartic acid (IAAsp). The presence of IAAsp in honeydew was not affected by extraction procedure or by aphid metabolism. Honeydew obtained from willow treated with (14)C-tryptophan contained only (14)C-tryptophan. When (14)C-IAA was applied in agar to the cut end of willow segments the radioactivity was found to move in a basipetally polar manner. The direction of movement of radioactivity in the sieve tubes, however, was found to be influenced by the proximity of the roots. Nevertheless, there was evidence that endogenous auxin in the sieve tubes does move in a predominantly basipetal direction. PMID- 24487451 TI - Soil physical properties influence "black truffle" fructification in plantations. AB - Although the important effects of pH and carbonate content of soils on "black truffle" (Tuber melanosporum) production are well known, we poorly understand the influence of soil physical properties. This study focuses on physical soil characteristics that drive successful production of black truffles in plantations. Seventy-eight Quercus ilex ssp. ballota plantations older than 10 years were studied in the province of Teruel (eastern Spain). Soil samples were analyzed for various edaphic characteristics and to locate T. melanosporum ectomycorrhizae. The influence of cultivation practices, climatic features, and soil properties on sporocarp production was assessed using multivariate analyses. Low contents of fine earth and silt and high levels of bulk density, clay content, and water-holding capacity appear to promote fructification. Watering is also highly positive for truffle fructification. We develop and discuss a logistic model to predict the probability of truffle fructification in field sites under consideration for truffle plantation establishment. The balance between water availability and aeration plays a crucial role in achieving success in black truffle plantations. PMID- 24487452 TI - Using social network analysis to evaluate health-related adaptation decision making in Cambodia. AB - Climate change adaptation in the health sector requires decisions across sectors, levels of government, and organisations. The networks that link these different institutions, and the relationships among people within these networks, are therefore critical influences on the nature of adaptive responses to climate change in the health sector. This study uses social network research to identify key organisational players engaged in developing health-related adaptation activities in Cambodia. It finds that strong partnerships are reported as developing across sectors and different types of organisations in relation to the health risks from climate change. Government ministries are influential organisations, whereas donors, development banks and non-government organisations do not appear to be as influential in the development of adaptation policy in the health sector. Finally, the study highlights the importance of informal partnerships (or 'shadow networks') in the context of climate change adaptation policy and activities. The health governance 'map' in relation to health and climate change adaptation that is developed in this paper is a novel way of identifying organisations that are perceived as key agents in the decision-making process, and it holds substantial benefits for both understanding and intervening in a broad range of climate change-related policy problems where collaboration is paramount for successful outcomes. PMID- 24487453 TI - Risk factors associated with the choice to drink bottled water and tap water in rural Saskatchewan. AB - A cross-sectional study investigated risk factors associated with choices to drink bottled water and tap water in rural Saskatchewan. Of 7,500 anonymous postal questionnaires mailed out, 2,065 responses were analyzed using generalized linear mixed models. Those who reported a water advisory (p < 0.001) or living in the area for L10 years (p = 0.01) were more likely to choose bottled water. Those who reported tap water was not safe to drink were more likely to choose bottled water, an effect greater for those who had no aesthetic complaints (p <= 0.001), while those with aesthetic complaints were more likely to choose bottled water if they believed the water was safe (p < 0.001). Respondents who treated their water and did not use a community supply were more likely to choose bottled water (p < 0.001), while those who did not treat their water were more likely to choose bottled water regardless of whether a community supply was used (p < 0.001). A similar pattern of risk factors was associated with a decreased likelihood of consuming tap water daily; however, the use of a community water supply was not significant. Understanding the factors involved in drinking water choices could inform public health education efforts regarding water management in rural areas. PMID- 24487454 TI - Associations of serum retinol, alpha-tocopherol, and gamma-tocopherol with biomarkers among healthy Japanese men. AB - Retinol, alpha-tocopherol, and gamma-tocopherol are fat-soluble vitamins acting as antioxidants via the prevention of lipid oxidation. Little is known about circulatory levels in healthy individuals. The present cross-sectional study aimed at elucidating the relationship between these antioxidants and clinical biomarkers in 206 male (median age 41 years, range 23-67) employees from companies located in the Okayama Prefecture, Japan. Subjects younger than 40 years (n = 94) showed a positive association of the frequency of alcohol consumption with the circulating retinol (beta = 0.344, p = 0.001) and gamma tocopherol levels (beta = 0.219, p = 0.041), and an inverse association of fast insulin with serum retinol (beta = -0.301, p = 0.009). In participants older than 40 years (n = 112) we found that an inverse association of HOMA-R with serum retinol (beta = -0.262, p = 0.021), alpha-tocopherol (beta = -0.236, p = 0.035), and gamma-tocopherol levels (beta = -0.224, p = 0.052); and cigarette smoking was inversely associated with the levels of serum alpha-tocopherol (beta = -0.286, p = 0.008) and gamma-tocopherol (beta = -0.229, p = 0.040). We further found negative relationships between serum ferritin and the retinol (beta = -0.211, p = 0.032) and alpha-tocopherol levels (beta = -0.223, p = 0.022) in men over 40 years of age. The present study suggests that the circulatory levels of antioxidant vitamins may modulate the action of insulin and that higher levels of iron might decrease the levels of antioxidant vitamins in the blood. PMID- 24487456 TI - Analysis of ecological quality of the environment and influencing factors in China during 2005-2010. AB - Since the twentieth century, China has been facing various kinds of environmental problems. It is necessary to evaluate and analyze the ecological status of the environment over China, which is of great importance for environmental protection measures. In this article, an Eco-environmental Quality Index (EQI) model is established using national remote sensing land-use data, NDVI data from MODIS and other statistical data. The model is used to evaluate the ecological status over China during 2005, 2008 and 2010, and spatial and temporal variations in EQI are analyzed during the period 2005-2010. We also discuss important factors affecting ecological quality, with special emphasis on meteorological conditions (including rainfall and sunshine duration) and anthropogenic factors (including normalized population and gross domestic product densities). The results show that, EQIs in northwestern China are generally lower than those in the southeast of the country, presenting a ladder-like distribution. There is significant correlation between EQI, rainfall and sunshine duration. Population density and GDP also have some relation to EQI. On the whole, the environmental quality results showed little variation during 2005-2010, with national average EQIs of 54.86, 55.07 and 54.43 in 2005, 2008 and 2010, respectively. During 2005-2010, differences in EQI were observed at the local level, but those at the provincial level were small. PMID- 24487455 TI - A seventeen-year epidemiological surveillance study of Borrelia burgdorferi infections in two provinces of northern Spain. AB - This paper reports a 17-year seroepidemiological surveillance study of Borrelia burgdorferi infection, performed with the aim of improving our knowledge of the epidemiology of this pathogen. Serum samples (1,179) from patients (623, stratified with respect to age, sex, season, area of residence and occupation) bitten by ticks in two regions of northern Spain were IFA-tested for B. burgdorferi antibodies. Positive results were confirmed by western blotting. Antibodies specific for B. burgdorferi were found in 13.3% of the patients; 7.8% were IgM positive, 9.6% were IgG positive, and 4.33% were both IgM and IgG positive. Five species of ticks were identified in the seropositive patients: Dermacentor marginatus (41.17% of such patients) Dermacentor reticulatus (11.76%), Rhiphicephalus sanguineus (17.64%), Rhiphicephalus turanicus (5.88%) and Ixodes ricinus (23.52%). B. burgdorferi DNA was sought by PCR in ticks when available. One tick, a D. reticulatus male, was found carrying the pathogen. The seroprevalence found was similar to the previously demonstrated in similar studies in Spain and other European countries. PMID- 24487457 TI - Association between health-related quality of life and being an immigrant among adolescents, and the role of socioeconomic and health-related difficulties. AB - To develop satisfactorily, adolescents require good health-related quality of life (QOL, including physical health, psychological health, social relationships and living environment). However, for poorly understood reasons, it is often lacking, especially among immigrants with lower family and socioeconomic resources. This study assessed health-related QOL of European and non-European immigrant adolescents and the contributions of socioeconomic difficulties, unhealthy behaviors, and violence. It included 1,559 middle-school adolescents from north-eastern France (mean age 13.5, SD 1.3; 1,451 French adolescents, 54 European immigrants and 54 non-European immigrants), who completed a self administered questionnaire including sex, age, socioeconomic characteristics (family structure, parents' education, occupation, and income), unhealthy behaviors (uses of tobacco/alcohol/cannabis/hard drugs, obesity, and involvement in violence), having sustained violence, sexual abuse, and the four QOL domains measured with the World Health Organization's WHOQOL-BREF (poor: score < 25PthP percentile). Data were analyzed using logistic regression models. Poor physical health, psychological health, social relationships, and living environment affected more European immigrants (26% to 35%) and non-European immigrants (43% to 54%) than French adolescents (21% to 26%). European immigrants had a higher risk of poor physical health and living environment (gender-age-adjusted odds ratio 2.00 and 1.88, respectively) while non-European immigrants had a higher risk for all poor physical health, psychological health, social relationships, and living environment (3.41, 2.07, 3.25, and 3.79, respectively). Between 20% and 58% of these risks were explained by socioeconomic difficulties, parts of which overlapped with unhealthy behaviors and violence. The associations between the two sets of covariates greatly differed among French adolescents and immigrants. Poor QOL was more common among European and non-European immigrants due to socioeconomic difficulties and associated unhealthy behaviors and violence. The different risk patterns observed between French adolescents and immigrants may help prevention. PMID- 24487458 TI - Prophylactic effectiveness of budesonide inhalation in reducing postoperative throat complaints. AB - Postoperative sore throat (POST) is one of the main postoperative complaints. This study was to evaluate the efficacy of budesonide inhalation suspension (BIS) in reducing the incidence and severity of POST. One hundred and twenty patients scheduled for thyroid surgery with general anesthesia were enrolled and randomized into three groups. Group A received 200 mcg BIS 10 min prior to the tracheal intubation and received the same treatment 6 and 24 h after extubation. Group B received 200 mcg BIS 6 and 24 h after extubation. Control group received the same scheduled treatment as Group A, but the BIS was replaced with 2 ml normal saline. The patients were evaluated for sore throat and hoarseness 1, 24 and 48 h after extubation. The status of laryngopharynx was also recorded. There was no statistically significant difference in the incidence of sore throat among three groups. However, hoarseness occurred significantly less frequently in Group A (P < 0.05). One hour after extubation, Group A exhibited significantly less severe sore throat and hoarseness compared to the other two groups (P < 0.05), which disappeared 24 h later. The mucositis scores of laryngopharynx at 1, 24 and 48 h post-extubation were significantly lower in Group A (P < 0.05). BIS can reduce the incidence and severity of the POST prophylactically. PMID- 24487459 TI - Bacteriological evaluation of tonsillar microbial flora according to age and tonsillar size in recurrent tonsillitis. AB - Although numerous studies based on the bacteriology of the tonsil have been carried out, none of them analyzed the variation of tonsillar flora with respect to both age and tonsillar size. The purpose of this study was to isolate the facultative and obligate anaerobes both from the surface and the core of tonsils in recurrent tonsillitis as well as to analyze the variation of isolated bacterial strains according to age and tonsillar size. A prospective study was performed on 111 patients who underwent tonsillectomy. We analyzed the differences between the bacterial pathogens in recurrent tonsillitis and semi growth estimates with regard to age and tonsillar grade. Among 111 cases, 604 bacterial strains of 21 different from the tonsil superficial and core were isolated. The most common facultative anaerobic species isolated from the surface and core were Coagulase-negative staphylococci, Alpha-hemolytic streptococci and Diphtheroid bacilli in all subgroups except patients below 8 years old. The most commonly obligate anaerobic species isolated from the core were Propionibacterium acnes, Prevotella melaninogenica and Peptostreptococcus anaerobius. We found no significant difference in the cultured bacteria with respect to age and tonsillar size. The study subgroups did not differ in the occurrence of semiquantitative growth estimates of 3-4+. Our study demonstrates that there is polymicrobial aerobic and anaerobic flora in tonsils with regardless of patient's age and tonsillar size. This polymicrobial spectrum of bacteria may contribute to recurrence and to the failure of conservative treatment of these cases and therefore leads to surgical therapy. PMID- 24487460 TI - Automatic release of silicon nanowire arrays with a high integrity for flexible electronic devices. AB - Automatic release and vertical transferring of silicon/silicon oxide nanowire arrays with a high integrity are demonstrated by an Ag-assisted ammonia etching method. By adding a water steaming step between Ag-assisted HF/H2O2 and ammonia etching to form a SiOx protective layer sheathing Si nanowires, we can tune the composition of the nanowires from SiOx (0 <= x <= 2) to Si nanowires. Ag plays a key role to the neat and uniform release of Si/SiOx nanowire arrays from Si wafer in the ammonia etching process. The vertical Si nanowire array device, with both sides having high-quality Ohmic contact, can be transferred to arbitrary substrates, especially on a flexible substrate. The method developed here offers a facile method to realize flexible Si nanowire array functional devices. PMID- 24487461 TI - Investigation of the clinical potential of scattering foil free electron beams. AB - Electron beam therapy has been an important radiation therapy modality for many decades. Studies have been conducted recently for more efficient and advanced delivery of electron beam radiation therapy. X-ray contamination is a common problem that exists with all of the advanced electron beam therapy techniques such as Bolus Electron conformal therapy, segmented electron conformal therapy, and modulated electron arc therapy. X-ray contamination could add some limitations to the advancement and clinical utility of those electron modalities. It was previously shown in the literature that the scattering foil is one of the major accelerator parts contributing to the generation of bremsstrahlung photons. Thus, in this work we investigate the dosimetric characteristics of scattering foil free (SFF) electron beams and the feasibility of using those beams for breast cancer boosts. The SFF electron beams were modeled and simulated using the Monte Carlo method. CT scans of six previously treated breast patients were used for the treatment plan generation utilizing our in-house Monte Carlo-based treatment planning system. Electron boost plans with conventional beams and the SFF beams were generated, respectively, for all patients. A significant reduction of the photon component was observed with the removal of the primary scattering foil for beam energies higher than 12 MeV. Flatness was greatly affected but the difference in flatness between conventional and SFF beams was much reduced for small cone sizes, which were often used clinically for breast boosts. It was found that the SFF electron beams could deliver high-quality dose distributions as conventional electron beams for boost treatments of the breast with an added advantage of a further reduced dose to the lung and the heart. PMID- 24487462 TI - Endometrial hyperplasia and carcinoma with superimposed secretory changes: a double whammy. PMID- 24487463 TI - Hyperplasia and carcinoma in secretory endometrium: a diagnostic challenge. AB - The diagnosis of endometrial hyperplasia or carcinoma in a background of secretory endometrium can be difficult. We attempt to establish the diagnostic criteria to be used in such cases. We examined 80 cases of endometrial hyperplasia, carcinoma, and other conditions with glandular crowding arising in secretory endometrium, analyzed their morphologic features, assessed the volume percentage stroma in each case and performed Ki67 immunostaining on 27 cases. Thirteen cases each of secretory and gestational endometrium served as controls. The mean age of the patients was 45 yr. The non-neoplastic diseases included simple hyperplasia without atypia (56%), endometrial polyps (12.5%), and chronic endometritis with glandular crowding (3%). The proportion of cases with complex hyperplasia without atypia was 10%. Neoplastic diseases included atypical complex hyperplasia (12.5%) and endometrioid carcinoma (6%). The secretory changes were usually less advanced in the hyperplastic glands than in the background endometrium. The morphologic features that best distinguished hyperplasia or carcinoma from secretory endometrium included glandular crowding that stood out from the background; architectural disorder (the long axes of the glands pointing in different directions or parallel to the endometrial surface); dilated, irregularly shaped glands, including budding or branching glands and staghorn shaped glands; stroma of a polyp; cribriform or confluent glands in cases of carcinoma; nuclear atypia in cases of atypical hyperplasia and carcinoma; and crowded nonsecretory glands. The volume percentage stroma of neoplastic lesions was less than that of non-neoplastic ones (34% vs. 61%, P=0.000001) and that of secretory endometrium (34% vs. 68%, P=0.000038). Non-neoplastic lesions did not have significantly more crowded glands than secretory endometrium (61% vs. 68%, P=0.11). Gestational endometrium had more crowded glands than non-neoplastic lesions (39% vs. 61%, P=0.000004), an approximately equal volume percentage stroma with complex hyperplasia without atypia (39% vs. 43%, P=0.51), and less crowded glands than neoplastic lesions (39% vs. 34%, P=0.03). The Ki67 index of the neoplastic lesions was higher than that of the controls, including secretory and gestational endometria (positive nuclei per 100 epithelial cells, 44.8 vs. 4.6, P=0.0004), of the non-neoplastic lesions (44.8 vs. 5.4, P=0.002) and of complex hyperplasia without atypia (44.8 vs. 9.3, P=0.007). Hyperplasia and carcinoma in secretory endometrium can be diagnosed on the basis of increased glandular crowding, architectural irregularity, nuclear atypia, and increased Ki67 index. PMID- 24487464 TI - Ki-67 index as an ancillary tool in the differential diagnosis of proliferative endometrial lesions with secretory change. AB - "Secretory change" can accompany a variety of proliferative endometrial lesions, ranging from hyperplasia to carcinoma. It is characterized by subnuclear or supranuclear vacuolization, mimicking early secretory endometrium (SEM). As an additional diagnostic challenge, mitotic activity and cytologic atypia are often low in hyperplastic lesions with secretory change. As mitotic activity in lesions with secretory change is decreased, the mitotic index may not be useful to distinguish SEM with glandular crowding from hyperplasia with secretory change. We therefore hypothesized that Ki-67 immunohistochemistry, an alternative marker of proliferative activity, might be useful in this setting. Forty-four endometrial lesions with secretory change and 30 controls were stained for Ki-67. Three "hot spot" areas per case were photographed and 200 to 300 cells were manually counted to obtain the ratio of Ki-67-positive cells versus total cells. A second pathologist performed an independent review of the same preselected fields and estimates without preselection. There was an incremental increase in the Ki-67 index from 2.6% in SEM to 17% in nonatypical hyperplasia, 36% in atypical hyperplasia, and 60% in endometrial carcinoma. The Ki-67 index for SEM was significantly (P<0.01) lower than hyperplastic lesions and carcinoma with secretory change. Similar, statistically significant results were obtained by independent estimates of Ki-67 immunopositivity. In the setting of secretory morphology, the Ki-67 index was highly sensitive and specific (>90%) for the differential diagnosis of SEM with crowding versus nonatypical hyperplasia, atypical hyperplasia, and endometrial carcinoma. In summary, the Ki-67-labeling index is a useful technique to distinguish SEM with crowding, an exaggerated physiological condition, from cancer precursors. PMID- 24487465 TI - Architectural versus nuclear atypia-defined FIGO grade 2 endometrial endometrioid adenocarcinoma (EEC): a clinicopathologic comparison of 154 cases with clinical follow-up. AB - International Federation of Gynecology and Obstetrics (FIGO) Grade 2 endometrial endometrioid adenocarcinoma carries a 88% 5-yr survival rate. They are defined by >5% but <50% solid epithelial component. A small subset may display <5% solid growth, but marked nuclear atypia and are designated Grade 2. We compared tumor characteristics, staging, and clinical outcome of patients with architectural versus atypia-defined Grade 2 endometrial endometrioid adenocarcinoma. A total of 154 Grade 2 endometrial endometrioid adenocarcinoma cases were reviewed to confirm grade; percent solid growth, and presence of atypia. Only marked atypia (significant nuclear pleomorphism identifiable at 10* or enlarged nuclei, 1.5 to 2* normal, with irregular nuclear contours, dispersed chromatin, and prominent nucleoli) increased the FIGO Grade 1 level. Depth of invasion, tumor stage, lymph node status, and clinical outcomes were then compared. A total of 154 cases were evaluated. Twenty-three were eliminated (6 Grade 3, 17 Grade 1). Of the 131 FIGO II cases, 19 (15%) were based on the presence of severe atypia and 112 (85%) met the architecturally defined criteria. Atypia-defined versus architecturally defined Grade 2 endometrial endometrioid adenocarcinoma's show no significant difference in stage and prognosis. An increase in grade based on presence of nuclear atypia stratifies patients at increased risk as 89% of these patients have myoinvasion at the time of hysterectomy which is in distinct contrast to our previous study (International Journal of Gynecologic Pathology. 2012 July; 31(4): 337-43), where 70% of Grade I cases were noninvasive. No significant correlation between percentage of solid component and risk of recurrence was identified in this study. PMID- 24487466 TI - Lymphovascular space invasion in microcystic elongated and fragmented (MELF) pattern well-differentiated endometrioid adenocarcinoma is associated with a higher rate of lymph node metastasis. AB - The microcystic elongated and fragmented (MELF) pattern of myoinvasion is a feature of some well-differentiated endometrial endometrioid adenocarcinomas that has been associated with poor prognosis. The myoinvasion in MELF-pattern tumors can be subtle and lead to underestimation of the depth of myometrial invasion resulting in tumor understaging; the presence of lymphvascular space invasion (LVSI) and lymph node metastasis in MELF-pattern tumors can also be subtle and lead to tumor understaging. To investigate the association of MELF-pattern invasion and lymph node metastasis, we reviewed a series of well-differentiated endometrioid adenocarcinomas and correlated the presence of MELF-pattern myoinvasion and LVSI with lymph node metastasis. Cases of T1 stage well differentiated endometrioid adenocarcinomas with LVSI and a concurrent lymph node dissection were identified from departmental files. Hematoxylin and eosin-stained slides from the hysterectomy specimen and lymph nodes were reviewed for the presence of MELF-pattern myoinvasion, LVSI, and nodal metastasis. MELF-pattern myoinvasion was identified at least focally in 36% of cases. The pattern of LVSI differed between cases with MELF-pattern invasion and conventional-type invasion, as did the pattern of nodal metastasis. A statistically significantly higher rate of lymph node metastasis was present in cases with MELF-pattern invasion than in cases with conventional invasion, and the rate stratified with the proportion of MELF-pattern adenocarcinomas. MELF-pattern cases carry an increased rate of lymph node metastasis even within the subset of endometrioid tumors with LVSI, which has implications in routine clinical practice as it signals the importance of recognizing MELF-pattern myoinvasion. PMID- 24487467 TI - Methylene blue: how to visualize the endometrium in uterine morcellation material. AB - The aim of the study was to evaluate whether the preoperative intrauterine injection of methylene blue could help in visualizing the endometrium of uterine morcellation specimens. A total of 48 laparoscopic subtotal hysterectomies using the uterine morcellation technique were used for the study. In 19 of these cases, a preoperative intrauterine administration of methylene blue had been performed (study group). The total number of slides for each group, without and with methylene blue, was counted. Moreover, the number of slides comprising endometrial tissue was evaluated. The number of sections included in the control group to adequately assess the endometrium ranged from 6 to 95 (mean 27.24+/ 4.01), whereas the respective number for the study group ranged from 4 to 10 (mean 7.21+/-0.44). The efficacy of recognizing adequate endometrial tissue (defined by the percentage of slides with adequate endometrial tissue over the overall slides requested to evaluate complete uterine histology) was significantly higher in the study group compared with that in the control group (67.05%+/-2.36% vs. 17.46%+/-2.66%, respectively; P<10(-3)). The preoperative intrauterine methylene blue administration when programming a uterine morcellation is an easy, cheap, harmless, and quick procedure that has many advantages. It reduces the time of gross handling and the number of tissue blocks submitted for examination without harming the morphologic appearance of the endometrial tissue. Moreover, it helps pathologists in identifying areas with endometrial pathology that would have probably escaped from attention in conventionally handled material. PMID- 24487468 TI - Pelvic intravascular leiomyomatosis associated with benign pulmonary metastasizing leiomyoma: clinicopathologic, clonality, and copy number variance analysis. AB - Benign metastasizing leiomyoma and intravascular leiomyomatosis are both rare smooth-muscle proliferations that of special interest due to their quasi malignant behaviors. To elucidate the pathogenesis of these lesions, we checked the surgical samples from a 43-year-old female presenting multiple pulmonary and tricuspid valve lesions after a history of hysterectomy. Histopathological studies confirmed pelvic intravascular leiomyomatosis in the hysterectomy sections and the pulmonary nodules were proved to be benign metastasizing leiomyoma with strong positivity of estrogen as well as progesterone receptors. Clonality and copy number variance analysis, which were performed on pulmonary and uterine tumors, showed an identical X-chromosome inactivation pattern and a balanced karyotype respectively. Sequential occurrence of benign metastasizing leiomyoma and intravascular leiomyomatosis in same patient implied they were histogenetically related and our molecular genetic proofs further suggested that benign metastasizing leiomyoma is a unicentric, benign metastasizing process arising from initial intravascular leiomyomatosis. PMID- 24487469 TI - Primary uterine mullerian mucinous borderline tumor (MMBT) associated with adenomyosis: a case report. AB - Mullerian mucinous borderline tumors (MMBTs) usually arise from the ovary. The present report is the first case of primary uterine MMBTs associated with adenomyosis. A 51-year-old woman was referred to our hospital for a complex cystic and solid 4*3 cm right adnexal mass. She had a history of a left ovarian endometriotic cyst and had undergone a left oophorectomy 2 yr prior. A laparotomy was performed, and the tumor was found to be originating in the posterior wall of the uterus. She underwent a total abdominal hysterectomy, right salpingo oophorectomy, and left salpingectomy. Microscopically, the solid portion of the tumor contained papillary proliferations of glands, which were covered by a mucinous epithelium with mild to moderate nuclear atypia, accompanied by stromal infiltration of inflammatory cells. Islands of adenomyosis were also observed around the cyst. These pathologic findings were similar to the features of ovarian MMBT. We diagnosed this tumor as a uterine MMBT, probably arising from adenomyosis. PMID- 24487470 TI - A uterine tumor resembling ovarian sex cord tumor associated with tamoxifen treatment: a case report and literature review. AB - Uterine tumors resembling ovarian sex cord tumors are rare neoplasms of unknown etiology that are classified as distinct from endometrial stromal tumors on the basis of their morphologic, molecular, and behavioral characteristics. These neoplasms have a variable immunophenotype, sometimes coexpressing epithelial, myoid, and sex cord markers. To date, only 2 cases of uterine tumors resembling ovarian sex cord tumors associated with tamoxifen use have been reported. Here, we report the case of a 49-year-old woman who had been using tamoxifen for 5 years to treat breast cancer. The tumor was initially diagnosed by hysteroscopy biopsy on the basis of morphologic and immunohistochemical features. Hysterectomy revealed a polypoid mass measuring 20 mm. After an 18-month follow-up, the patient remains disease free. Here, we review the clinical, pathologic, and immunohistochemical features of uterine tumors resembling ovarian sex cord tumors and endometrial stromal tumors with a sex cord component associated with tamoxifen treatment. PMID- 24487471 TI - Recurrent intestinal mucinous borderline tumors of the ovary: a report of 5 cases causing problems in diagnosis, including distinction from mucinous carcinoma. AB - Intestinal mucinous borderline tumors (IMBTs) of the ovary are generally associated with a highly favorable outcome and rarely recur. We describe 5 cases of IMBT initially treated by cystectomy or by salpingo-oophorectomy that was likely incomplete, with subsequent recurrences. Three cases were received in consultation, and in each of these, the clinical and intraoperative findings were worrisome for mucinous carcinoma, and diagnostic difficulty was encountered by the referring pathologist. The patient age ranged from 28 to 69 (median 53) yrs. All tumors were clinically Stage I at presentation; in at least 3 cases, extensive adhesiolysis was required during their removal. A pathologic diagnosis of IMBT was made in 4 cases; the remaining tumor was inadequately sampled (3 blocks from a 7.5-cm tumor showed predominantly benign to focally borderline mucinous epithelium). A total of 8 recurrences, all as IMBT, developed at mean follow-up of 26 (range, 6-102) mo; 6 of these occurred within <=2 yr. In 4 cases, removal of recurrent tumor required an extensive operation because of bowel and/or vaginal involvement. Residual ovarian stroma was identified in all recurrences. There was no evidence of invasive mucinous carcinoma, pseudomyxoma peritonei, or a primary tumor elsewhere (including appendix) in any of the cases. Our findings indicate that patients with IMBTs who undergo cystectomy or oophorectomy requiring adhesiolysis are at increased risk of recurrence, which may occur early, be multiple, and potentially require extensive resection if sites such as bowel or vagina are involved. Recurrences of IMBT that develop in this setting likely represent regrowth of incompletely resected IMBT, or arise within residual ovarian tissue. This is the first detailed clinicopathologic study of such cases. PMID- 24487472 TI - Expression profile of mucins in ovarian mucinous tumors: distinguishing primary ovarian from metastatic tumors. AB - Ovarian mucinous tumors (OMTs) of the intestinal type share morphologic features with primary tumors of other sites, and it can often be difficult to distinguish primary ovarian from metastatic mucinous tumors. MUC1, MUC2, MUC5AC, and MUC6 expressions were studied by immunohistochemistry in 36 OMTs of intestinal type (17 malignant, 19 borderline), 18 pancreatic, 12 biliary, 15 esophageal, 9 gastric, and 7 colorectal/appendiceal adenocarcinomas. All samples were from primary sites, except for colorectal tumors which were from ovarian metastases. Borderline and malignant OMTs show similar mucin immunoprofile, being strongly and uniformly positive for MUC5AC (97.2% of cases), whereas only focally positive for MUC1 (19.4%), MUC2 (38.9%), and MUC6 (22.2%). The positive frequencies of pancreatic adenocarcinomas for MUC1, MUC2, MUC5AC, and MUC6, respectively, were 100%, 16.7%, 94.4%, and 61.1%; for biliary (cholangiocarcinomas) were 91.7%, 0%, 16.7%, and 8.3%; for esophageal carcinomas were 73.3%, 33.3%, 53.3%, and 26.7%; for gastric carcinomas were 44.4%, 44.4%, 44.4%, and 0% and for lower gastrointestinal tract cancers were 28.6%, 85.7%, 42.9%, and 0%. Our study shows that OMTs are usually MUC5AC+/MUC1-, which is different from pancreatic, biliary, esophageal, gastric, and colorectal/appendiceal carcinomas. We recommend that these mucin stains be added to the panel of immunostains to differentiate metastatic tumors to the ovary from primary OMTs. PMID- 24487473 TI - Primary ovarian mucinous adenocarcinoma of intestinal type: a clinicopathologic study of 46 cases. AB - This study was aimed to evaluate the clinicopathologic details of primary ovarian mucinous adenocarcinoma and their prognostic significance. The clinicopathologic characteristics of 46 cases of mucinous adenocarcinoma were reviewed. The diagnosis of mucinous adenocarcinoma required the presence of stromal invasion of either the expansile (confluent glandular) pattern or the infiltrative pattern in an area size >10 mm(2). The cases were stratified using different grading methods and different cutoff limits of stromal invasion. Regarding the invasive pattern, 20 cases had the infiltrative pattern only, 8 had both infiltrative and expansile patterns, 7 had the expansile pattern only, and 11 had the expansile pattern with infiltrative microinvasion (area <=10 mm(2)). The patients with tumors containing the expansile pattern had a younger mean age compared with those with the infiltrative pattern only (42.3 vs. 53.7 yr; P=0.004). On follow-up, 12 patients had tumor recurrence, 9 of whom died of disease. Tumor recurrence was associated with stage >=II (P<0.001) and infiltrative area >10 mm(2) (P=0.015). Decreased progression-free survival and cancer-specific survival was strongly associated with tumor stage >=II (P<0.001 for each survival) and infiltrative area >50 mm(2) (P=0.003 and 0.010, respectively). Among 27 stage IA patients, the infiltrative extent (area >50 mm or dimension >20 mm) was the only variable that was significantly associated with recurrence and decreased survival. Tumor grading was not significantly associated with the recurrence risk or the survival. The extent of infiltrative invasion in ovarian mucinous adenocarcinoma may provide additional prognostic value to the tumor stage and the pattern of stromal invasion. PMID- 24487474 TI - Immunophenotype and K-RAS mutation in mucinous ovarian adenocarcinoma with mural nodule of high-grade sarcoma: case report. AB - Ovarian mucinous tumors with mural nodules are rare. The mural nodules are microscopically divergent neoplasms of varying sizes that may be benign (eg, sarcoma-like and carcinosarcoma-like), or malignant (eg, anaplastic carcinoma and sarcoma). The K-RAS gene mutation in ovarian mucinous neoplasms with mural nodules has not been previously reported. This is a case report of a 25-year-old female diagnosed with ovarian invasive mucinous adenocarcinoma with mural nodule of high-grade sarcoma. The mucinous tumor component demonstrated a K-RAS codon 12/13 mutation (p.G12V, c.35 G>T), whereas the sarcomatous component demonstrated a K-RAS codon 12/13 mutation (p.G12D, c.35 G>A). Although both tumor components revealed a mutation in codon 12 of K-RAS, they were of different nucleotide substitutions, indicating that these 2 tumor components were of different clonal origins. However, the fact that the 2 mutations identified in the tumor components are the most common mutations reported in mucinous tumors of the ovary, raises the possibility that sarcomatous mural nodules simply represent a form of dedifferentiation in mucinous tumors. PMID- 24487475 TI - Myoepithelioma of the ovary: first reported case. AB - A wide variety of neoplasms of varying histogenesis occur within the ovary. We report the first case of a primary ovarian myoepithelioma, a diagnosis made on the basis of the morphologic features coupled with immunoreactivity with epithelial and myoid markers. The tumor had a lobulated appearance with variable architectural patterns including anastomosing cords, trabeculae, and nests of epithelioid to spindled tumor cells within a hyalinised and focally myxoid stroma. Fluorescence in situ hybridization for EWS gene rearrangement and reverse transcriptase polymerase chain reaction for EWSR1-POU5F1 and EWSR1-PBX1, molecular abnormalities which are found in some extrasalivary myoepitheliomas, were negative. In reporting this unique neoplasm, we discuss the wide differential diagnosis generated by the case. PMID- 24487477 TI - Spindle cell carcinoma of the vulva: a series of 4 cases and review of the literature. AB - Spindle cell or sarcomatoid squamous cell carcinoma is an uncommon variant of squamous cell carcinoma of the vulva (SCCV) with only 12 well-documented cases reported to date. Morphologically tumors may be biphasic or monophasic, and uncommonly include heterologous elements. Only 1 reported vulval tumor has previously been investigated for human papillomavirus DNA content. We describe 4 women with spindle cell (sarcomatoid) SCCV, 3 of which occurred de novo and 1 followed radiotherapy for previous SCCV. The tumors in all 4 women arose in a background of lichen sclerosus, and 3 were associated with vulval intraepithelial neoplasia differentiated (simplex) type. All tumors were negative for human papillomavirus DNA on polymerase chain reaction analysis. One case is the second reported with malignant heterologous elements described in the vulva. These tumors seem to be more aggressive than conventional SCCV. PMID- 24487476 TI - Cervical cancer screening in Ghana, west Africa: prevalence of abnormal cytology and challenges for expanding screening. AB - Aims were to assess the prevalence of Papanicolaou (Pap) abnormalities found with cervical cancer screening in Agogo and Nkawie, communities in the Ashanti region of Ghana, and compare the correlation between Pap readings performed at the Komfo Anokye Teaching Hospital in Kumasi, Ghana, and at the Mayo Clinic cytology laboratory in Rochester, MN. Demographic data was collected and Pap tests were performed on women recruited for screening in the communities of Agogo (n=119) and Nkawie (n=255). The Pap tests were assessed by pathology laboratory staff at Komfo Anokye Teaching Hospital and Mayo Clinic. There was a significant difference in prevalence of abnormal cytology between the sites with a rate of 12.6% in Agogo and 3.5% in Nkawie (P=0.016). Demographic differences were noted in education level (P<0.001), occupation (P<0.001), religion (P=0.002), and marital status (P<0.001). The Cohen correlation coefficient between the two pathology departments interpreting samples was 0.185, which indicates a significant degree of discordance (P<0.001). Currently Ghana does not have a national cervical cancer screening program. Identifying higher risk communities and patients as a priority for screening may be useful with limited resources. Accurate identification of Pap abnormalities is necessary to implement an effective screening program. PMID- 24487479 TI - Conformational modulation of peptide secondary structures using beta aminobenzenesulfonic acid. AB - This communication describes the influence of beta-aminobenzenesulfonic acid ((S)Ant) on the conformational preferences of hetero foldamers. The designed (Aib (S)Ant-Aib)n and (Aib-(S)Ant-Pro)n oligomers display a well-defined folded conformation featuring intramolecular mixed hydrogen bonding (7/11) and intra residual (6/5) H-bonding interactions, respectively. PMID- 24487480 TI - Decreased serum fetuin-A levels and active inflammatory bowel disease. AB - BACKGROUND: Fetuin-A is a mediator of inflammatory response that might also be involved in the pathogenesis of inflammatory bowel disease (IBD). This study aims to assess whether serum fetuin-A levels are associated with the disease activity in patients with Crohn's disease (CD) and ulcerative colitis (UC). METHODS: A total of 139 patients with CD, 114 patients with UC, and 46 controls were enrolled in this study. The serum fetuin-A levels of the participants were measured using commercially available sandwich enzyme-linked immunosorbent assay. RESULTS: The patients with IBD had significantly lower serum fetuin-A levels compared with the healthy controls. The active patients with CD and patients with UC both had significantly decreased serum fetuin-A levels compared with the inactive patients with CD and patients with UC. Multivariable logistic regression analysis revealed that decreased serum fetuin-A levels were independently associated with the disease activity of CD and UC. Serum fetuin-A levels were negatively associated with C-reactive protein concentrations and white blood cell count in patients with CD but not in patients with UC. CONCLUSIONS: Decreased serum fetuin-A levels were independently associated with disease activity in patients with CD and UC. The utilization of fetuin-A concentration measurements as markers of disease activity in patients with IBD warrants further investigations. PMID- 24487482 TI - La-doped Al2O3 supported Au nanoparticles: highly active and selective catalysts for PROX under PEMFC operation conditions. AB - La-doped gamma-Al2O3 supported Au catalysts show high activity and selectivity for the PROX reaction under PEMFC operation conditions. The superior performance is attributed to the formation of LaAlO3, which suppresses H2 oxidation and strengthens CO adsorption on Au sites, thereby improving competitive oxidation of CO at elevated temperature. PMID- 24487481 TI - A multisite study of the prevalence of serious mental illness, PTSD, and substance use disorders of women in jail. AB - OBJECTIVES: This multisite study aimed to answer the following research questions about women in urban and rural jails. First, what is the current and lifetime prevalence of serious mental illness (major depressive disorder, bipolar disorder, and psychotic spectrum disorders) of women in jail? Second, what level of impairment is associated with their serious mental illness? Third, what is the proportion of incarcerated women with serious mental illness who also have posttraumatic stress disorder (PTSD), a substance use disorder, or both? METHODS: Participants were 491 women randomly sampled in jails in Colorado, Idaho, South Carolina, and the metropolitan area of Washington, D.C. Structured interviews assessed lifetime and 12-month prevalence of disorders and level of impairment. RESULTS: Forty-three percent of participants met lifetime criteria for a serious mental illness, and 32% met 12-month criteria; among the latter, 45% endorsed severe functional impairment. Fifty-three percent met criteria for ever having PTSD. Almost one in three (29%) met criteria for a serious mental illness and PTSD, 38% for a serious mental illness and a co-occurring substance use disorder, and about one in four (26%) for all three in their lifetime. CONCLUSIONS: The prevalence of serious mental illness and its co-occurrence with substance use disorders and PTSD in this multisite sample suggest the critical need for comprehensive assessment of mental health at the point of women's entry into the criminal justice system and the necessity for more programs that offer alternatives to incarceration and that can address the complexity of female offenders' treatment needs. PMID- 24487483 TI - Excitation wavelength dependence of the charge separation pathways in tetraporphyrin-naphthalene diimide pentads. AB - The excited-state dynamics of two multichromophoric arrays composed of a naphthalene diimide centre and four zinc or free-base porphyrins substituted on the naphthalene core via aniline bridges has been investigated using a combination of stationary and ultrafast spectroscopy. These pentads act as efficient antennae as they absorb over the whole visible region, with a band around 700 nm, associated with a transition to the S1 state delocalised over the whole arrays, and bands at higher energy due to transitions centred on the porphyrins. In non-polar solvents, population of these porphyrin states is followed by sub-picosecond internal conversion to the S1 state. The existence of a charge-separated state located above the S1 state could enhance this process. The decay of the S1 state is dominated by non-radiative deactivation on the 100 ps timescale, most probably favoured by the small S1-S0 energy gap and the very high density of vibrational states of these very large chromophores. In polar solvents, the charge-separated state lies just below the S1 state. It can be populated within a few picoseconds by a thermally activated hole transfer from the S1 state as well as via sub-picosecond non-equilibrium electron transfer from vibrationally hot porphyrin excited states. Because of the small energy gap between the charge-separated state and the ground state, charge recombination is almost barrierless and occurs within a few picoseconds. Despite their very different driving forces, charge separation and recombination occur on similar timescales. This is explained by the electronic coupling that differs considerably for both processes. PMID- 24487484 TI - Safety, effectiveness, and pharmacokinetics of adalimumab in children with polyarticular juvenile idiopathic arthritis aged 2 to 4 years. AB - The objective of this study was to assess the safety of adalimumab in patients aged 2 to <4 years old or >=4 years old weighing <15 kg with moderately to severely active polyarticular juvenile idiopathic arthritis (JIA). Clinical effectiveness and pharmacokinetics (PK) of adalimumab were also evaluated. This was an international, multicenter, open-label, phase 3b study in 32 patients with active JIA that were treated with adalimumab 24 mg/m(2) (maximum = 20 mg/dose) every other week up to 120 weeks, with or without concomitant methotrexate. Adverse events (AEs) were summarized for completed visits. Efficacy endpoints included American College of Rheumatology pediatric (PedACR) 30/50/70/90 responses and JIA core components. Adalimumab serum trough concentrations were measured in a subset of patients. Among the patients, 88 % were female. Baseline mean age, weight, and JIA duration were 3 years, 13 kg, and 12 months, respectively; 39 % had elevated C-reactive protein. AE incidence rates included any AEs (29/32, 91 %), serious AEs (5/32, 16 %), infectious AEs (25/32, 78 %), and serious infections (3/32, 9 %). No deaths, malignancies, or opportunistic infections were reported. Growth was not adversely impacted. At week 96, 92 % of patients achieved PedACR30, and 77 % achieved PedACR70. Improvements in JIA core components were observed. Mean steady-state serum adalimumab trough concentrations were 7-8 MUg/mL at weeks 12 and 24. Adalimumab was well tolerated in JIA patients aged 2 to <4 years old or >=4 years old weighing <15 kg. The efficacy and PK of adalimumab were comparable to those seen in older JIA patients. PMID- 24487485 TI - The effectiveness and cost of corticosteroid injection and physiotherapy in the treatment of frozen shoulder-a single-centre service evaluation. AB - Frozen shoulder is a common condition resulting in pain, stiffness and functional impairment. Symptoms can persist for months or even years if left untreated. Various treatments are available, but a standard care package does not exist and the most cost-effective treatment has not been established. The objective of this study was to conduct a service evaluation of current practice to establish the effectiveness of corticosteroid injection and physiotherapy intervention and the costs associated. A review of all patients with a diagnosis of frozen shoulder who had received a corticosteroid injection and physiotherapy was undertaken for a 12-month period at a single NHS hospital in the UK. Patient-reported outcome measures were analysed and the costs for treatment calculated. Out of the 55 patients, 43 were happy to be discharged following treatment. Ten were referred for a surgical opinion and two were lost to follow-up. The median pain rating significantly reduced from 8 (interquartile range (IQR) 7, 9) to 2 (IQR 0, 3.75) (p < 0.001). Of the patients, 62 % reported a greater than 60 % improvement. On average, patients attended for an initial consultation and four follow-up sessions at a total cost to the NHS of L135. Based on this small service evaluation study, corticosteroid injection administered by an experienced physiotherapist with follow-up physiotherapy appears to be an effective treatment for frozen shoulder. PMID- 24487486 TI - Risk factors for severe bacterial infections in patients with systemic autoimmune diseases receiving rituximab. AB - The risk of serious bacterial infectious events (SIEs) after an RTX course used in severe and refractory cases of systemic autoimmune diseases (SAID) is well known. Risk factors for SIEs merit investigation. For this case-control study, data were collected in a single centre of internal medicine and included all patients who received rituximab (RTX) for SAID between 2005 and 2011 (rheumatoid arthritis was excluded). Sixty-nine patients with SAID received a total of 87 RTX courses. Thirteen SIEs were reported in 12 patients leading to death in 5 patients. Patients with a history of SIE were significantly older (63.6+/-18.8 vs 48.8+/-16.7; p=0.0091), suffered most frequently of diabetes mellitus (33.3% vs 5.3%, p=0.015), had a lower CD19 count (1.0+/-1.2/mm3 vs 3.9+/-7.2/mm3) and had most frequently a prednisone dose>15 mg/day (91.7% vs 47.7%) at the start of the first RTX course. The SIE rate was 18.7 per 100 patient-years. At the initiation of the RTX course, risk factors for SIEs were lower IgG levels (OR=0.87, 95%CI=0.77-0.99, p=0.03), lower CD19 count (OR=0.85, 95%CI=0.73-1.00) and creatinine clearance<=45 ml/min (OR=7.78, 95%CI=1.36-44.38, p=0.002). Conversely history of pneumococcal vaccination significantly decreased the risk of SIEs (OR=0.11, 95%CI=0.03-0.41, p=0.0009). Concomitant treatment with prednisone at a dose>15 mg/day significantly increased the SIE risk (OR=8.07, 95%CI=1.94-33.59, p=0.0004). SIEs are frequent in SAID treated with RTX, particularly in patients receiving high-dose corticosteroids, in patients with renal insufficiency and in patients with low IgG levels or a low CD19 count. PMID- 24487487 TI - The relationship between radiological severity and functional status in patients with knee osteoarthritis. AB - In this study, we aimed to explore the relationship between radiological findings and functional status in patients with knee osteoarthritis (OA). In this study, 117 female patients diagnosed with knee osteoarthritis according to the ACR criteria were included. Antero-posterior knee radiographs of the patients were graded according to Kellgren-Lawrence, and functional capacity was evaluated with WOMAC and Lequesne indexes. Quadriceps and hamstring muscle strengths were also concentrically measured using an isokinetic dynamometer, five repetitions at 90 degrees /s and 20 repetitions at 180 degrees /s. In this study, a significant relationship was determined between the age, weight, praying period, and pain period of the patients with the radiological findings. No significant relationship was determined between the functional capacity of knee and muscle strength and the radiological findings. However, left hamstring functioning capacity was found as lower in the group with the radiological findings. The radiological findings in knee OA are not associated with decrease in knee muscle strength and functional capacity. Clinical symptoms such as pain, decrease in range of motion, etc. in knee OA may be responsible for decrease in knee muscle strength and functional capacity. PMID- 24487488 TI - Commonalities and discrepancies in the relationships between behavioural outcome and the results of neuroimaging in brain-damaged patients. AB - Variables which are of influence in establishing clear predictions of neuropsychological alterations from neuroradiological data (and vice versa) are documented and discussed. It is concluded that personality factors and the kind and locus of brain lesions are the most crucial determinants. The locus of the brain damage may have cumulative effects either when it is situated in a strategic place (usually within the white matter, affecting interneuronal communication) or when various types of lesions appear superimposed (combination of focal and diffuse lesions). Consequently, the consideration of the patient's personality background and of as many neuropsychological facts as possible may considerably increase the validity of outcome predictions. When static or dynamic neuroimaging fails to show abnormalities in spite of obvious psychological alterations, an intensive neuropsychological documentation may even replace neuroradiology. PMID- 24487489 TI - Autobiographical memory for emotional events in amnesia. AB - This study investigated autobiographical memory for emotionally flavoured experiences in amnesia. Ten amnesic patients and 10 matched control subjects completed the Autobiographical Memory Interview and three semi-structured interviews which assessed memory for personal events associated with pain, happiness and fear. Despite retrograde amnesia for autobiographical facts and incidents, amnesics remembered a similar number of emotionally significant personal experiences as control subjects. Their recollections generally lacked elaboration and detail, but pain-related memories appeared to be more mildly impaired than memories associated with happiness and fear. The findings are discussed in relation to recent views on the relationship between affect and memory. PMID- 24487490 TI - Event related potentials and serial list picture memory in Parkinson's patients. AB - Two experiments examined short-term memory for order information in six patients diagnosed with Parkinson's disease (PD) and six control subjects while event related potentials (ERPs) were recorded. The subjects were tested for recognition of abstract spatial designs and words after a 5 s retention interval. The PD patients failed to respond in 29% of all trials, but the overall accuracy was similar to that in the control group when these trials were excluded. The corresponding ERP results show serial position variations both after presentation of the probe items, and after presentation of the memory set items. The amplitudes were generally lower at all positions for the PD patients at the parietal midline electrode, and the amplitudes were similar for both groups at the frontal electrode. Also, the ERP latencies were significantly slower for the PD patients than for the control group at all conditions. Indirectly the data are consistent with an interpretation of cognitive deficit in PD stressing attention resources. PMID- 24487491 TI - Spasmodic torticollis - a multicentre study on behavioural aspects II: signs, symptoms and course. AB - This paper deals with signs, symptoms and course in spasmodic torticollis (ST). Two hundred and fifty-six patients were included in the study, 59.3% women, 40.7% men. The mean age was 49.1 years. Rotating torticollis out-numbered latero- and antero-retrocollis. A family history of ST occurred in 3.1% of the total sample. First degree relatives were affected in 2.3%. Thirty-four per cent of the patients had additional dystonic symptoms. Most frequently these affected the upper extremities (13%), and less often the legs. Of the patients 19.1% had experienced a period of complete remission. The correlations between the severity of the signs and the neurological symptoms are surprisingly weak. PMID- 24487492 TI - Spasmodic torticollis - a multicentre study on behavioural aspects III: psychosocial changes and coping. AB - Psychosocial changes in spasmodic torticollis (ST) affect predominantly social life, professional life and psychological well-being. Concerning social life, 84.6% of the patients felt that they attracted considerable public attention due to their neurological illness and 65% had reduced participation in social events. A substantial number of patients had retired from professional activities; others felt severely impaired in their working capacity. The psychosocial sequelae in ST, however, seemed to depend less on the neurological signs per se than on the physical symptoms and on coping. Depressive coping in particular emerged as a predictor of psychosocial distress. PMID- 24487493 TI - Spasmodic torticollis - a multicentre study on behavioural aspects IV: psychopathology. AB - The GSI (General Symptom Index) of the Symptom Checklist 90 R (SCL 90 R) (as a global indicator of the severity of psychiatric symptoms) of 27% of the spasmodic torticollis (ST) sample fell outside the 95% range of the normal control group (two standard deviations). Patients with a higher GSI were younger, more functionally disabled and subject to higher psychosocial stress due to the illness. The highest scores were reached on the subscales of somatization, interpersonal sensitivity and depression. On the depression scale, 23% of the patients' scores were abnormal. This scale correlated significantly with the neurological signs, particularly the TSUI-index and laterocollis. A statistically significant correlation also existed between psychiatric morbidity and a family history of mental disorder. More than 50% of the patients reported that stressful life events had triggered their illness. In order of frequency, a death came first, followed by marital strife, changes in employment and family arguments. The data suggest that psychopathology in ST should generally be considered as a result of a variety of interacting factors, biological, psychological and social. PMID- 24487495 TI - Voltage tuning of thermal spin current in ferromagnetic tunnel contacts to semiconductors. AB - Spin currents are paramount to manipulate the magnetization of ferromagnetic elements in spin-based memory, logic and microwave devices, and to induce spin polarization in non-magnetic materials. A unique approach to create spin currents employs thermal gradients and heat flow. Here we demonstrate that a thermal spin current can be tuned conveniently by a voltage. In magnetic tunnel contacts to semiconductors (silicon and germanium), it is shown that a modest voltage (~200 mV) changes the thermal spin current induced by Seebeck spin tunnelling by a factor of five, because it modifies the relevant tunnelling states and thereby the spin-dependent thermoelectric parameters. The magnitude and direction of the spin current is also modulated by combining electrical and thermal spin currents with equal or opposite sign. The results demonstrate that spin-dependent thermoelectric properties away from the Fermi energy are accessible, and open the way towards tailoring thermal spin currents and torques by voltage, rather than material design. PMID- 24487497 TI - Speech and the right hemisphere. AB - Two facts are well recognized: the location of the speech centre with respect to handedness and early brain damage, and the involvement of the right hemisphere in certain cognitive functions including verbal humour, metaphor interpretation, spatial reasoning and abstract concepts. The importance of the right hemisphere in speech is suggested by pathological studies, blood flow parameters and analysis of learning strategies. An insult to the right hemisphere following left hemisphere damage can affect residual language abilities and may activate non propositional inner speech. The prosody of speech comprehension even more so than of speech production-identifying the voice, its affective components, gestural interpretation and monitoring one's own speech-may be an essentially right hemisphere task. Errors of a visuospatial type may occur in the learning process. Ease of learning by actors and when learning foreign languages is achieved by marrying speech with gesture and intonation, thereby adopting a right hemisphere strategy. PMID- 24487496 TI - Cognitive function in multiple sclerosis: a subcortical pattern of neuropsychological impairment? AB - In order to evaluate cognitive impairment in multiple sclerosis (MS) neuropsychological tests were administered to 25 patients with clinically definite disease. Four (16%) showed diffuse cognitive impairment, whereas the others, compared with controls showed a specific deficit on tests known to be sensitive to frontal lobe damage. These results are interpreted in the light of current hypotheses relating to subcortical contributions in cognition. PMID- 24487498 TI - Visuoconstructional impairment in dementia syndromes. AB - Dementia of the Alzheimer type (DAT) affects most neuropsychological domains including language, memory, and visuo-spatial skills. The latter are usually assessed by poorly quantifiable copying tasks. We assessed constructional abilities using the Developmental Test of Visuomotor Integration (VMI) comprised of a series of model drawings of increasing complexity. Twenty-six patients meeting NINCDS-ADRDA criteria for DAT, 21 normal aged subjects with normal mental status examinations, and 14 patients with vascular dementia were tested. In DAT, we found significant correlations between visuoconstructive ability and memory registration, delayed recall, and language functions such as confrontation naming and word-list generation. Less marked, but significant correlations were found in the vascular dementia group between visuoconstructive ability and memory registration and word-list generation. A few normal elderly subjects were unable to copy the most challenging figures. The study demonstrates that: (1) VMI is a convenient method for quantifying constructional deficits in DAT and other dementing illnesses; (2) constructional deficits are highly correlated with dementia severity and memory and language deficits in DAT; (3) neuropsychological deficits are less highly inter-correlated in vascular dementia than in DAT; and (4) abnormal constructional skills are present in some normal elderly. PMID- 24487499 TI - "Alice in wonderland" syndrome: a manifestation of infectious mononucleosis in children. AB - The association between "Alice in Wonderland" Syndrome (AWS) and infectious mononucleosis (IM) has been previously described in three patients.We describe two additional cases in children, where in one case, the visual symptoms of AWS appeared during the course of active IM and in the second, 2 weeks following a clinically mild, but serologically proven attack. PMID- 24487500 TI - Alien Hand Sign and Other Cognitive Deficits following Ruptured Aneurysm of the Anterior Communicating Artery. AB - We describe a right-handed patient who suffered a ruptured aneurysm of the anterior communicating artery (ACoA) which was clipped successfully. Computerized tomography indicated a low density area in the genu of the corpus callosum and the infero-lateral aspect of the left frontal lobe. On recovery the patient's most notable deficit was the "alien hand sign" whereby the left hand would frequently interfere with the actions of the right hand. Problems in response initiation were also evident. There was significant memory loss and performance was impaired on some tests of frontal lobe function. Discussion centres on the functional locus of the alien hand sign but other aspects of the patient's deficits are also considered. PMID- 24487501 TI - Body language in Parkinson's disease. PMID- 24487503 TI - Letters to the editor. PMID- 24487502 TI - Impulse regulation in anorexia nervosa and bulimia nervosa: some formulations. AB - Empirical observations imply that impulsivity is specifically associated with poor prognosis in eating disorders. The present paper cites studies suggesting that this factor is predominantly associated with the bulimic pattern of eating disturbance, while "restriction" may be associated rather with hypercontrol of behaviour. Further evidence is cited suggesting that the relationship between hyper- and hypocontrol is actually very intimate, both on a behavioural and biochemical level. Rather than bulimics being generally impulsive and "restrictors" generally hypercontrolled, future studies may reveal impulse regulation difficulties of both kinds in both groups. Single-minded preoccupation with dieting may be an ill-equipped individual's effort to simplify life in periods of change and environmental challenge that demand capacity for flexible impulse regulation. PMID- 24487505 TI - Validation of the Comprehensive ICF Core Set for obstructive pulmonary diseases from the patient's perspective. AB - This study aimed to validate the Comprehensive International Classification of Functioning, Disability and Health (ICF) Core Set for obstructive pulmonary diseases (OPDs) from the perspective of patients with chronic obstructive pulmonary disease. A cross-sectional qualitative study was carried out with outpatients with chronic obstructive pulmonary disease using focus groups with an ICF-based approach. Qualitative data were analysed using the meaning condensation procedure by two researchers with expertise in the ICF. Thirty-two participants (37.5% women; 63.8 +/- 11.3 years old) were included in six focus groups. A total of 61 (86%) ICF categories of the Comprehensive ICF Core Set for OPD were confirmed. Thirty-nine additional second-level categories not included in the Core Set were identified: 15 from the body functions component, four from the body structures, nine from the activities and participation and 11 from the environmental factors. The majority of the categories included in the Comprehensive ICF Core Set for OPD were confirmed from the patients' perspective. However, additional categories, not included in the Core Set, were also reported. The categories included in the Core Set were not confirmed and the additional categories need to be investigated further to develop an instrument tailored to patients' needs. This will promote patient-centred assessments and rehabilitation interventions. PMID- 24487507 TI - Structural characterization and in-vivo reliability evaluation of silicon microneedles. AB - This work presents an analysis of the failure mechanisms, structural properties and reliability of wet-etched silicon microneedles, which have wide-ranging applications in transdermal delivery, sensing and diagnostics. For the first time, in-vivo skin insertion forces are measured and the structural properties of individual silicon microneedles are assessed using both compression and shear tests. Compressive failure of this particular microneedle design does not occur because of buckling, but instead is predominantly due to progressive fracture along the relatively weak {111} crystal plane. Compressive and shear failure strengths are experimentally determined to be (2.9 +/- 0.3) GPa and (9.2 +/- 0.2) MPa, respectively. It is also shown that basic mechanical tests that are commonly used in the field of microneedle development may significantly underestimate safety factors for this type of needle due to the unrepresentative nature of the interaction of a rigid surface with the needle tips. Therefore, a new figure-of merit for the reliability of such microneedles is proposed, which is based on the ratio of material failure strength to peak stress during skin insertion. The distribution of forces over the sharp, conical needle tip during skin penetration leads to a very large safety margin of over 700, and a correspondingly high degree of reliability when applied to in-vivo human tissue. PMID- 24487506 TI - Beneficial effects of melatonin combined with exercise on endogenous neural stem/progenitor cells proliferation after spinal cord injury. AB - Endogenous neural stem/progenitor cells (eNSPCs) proliferate and differentiate into neurons and glial cells after spinal cord injury (SCI). We have previously shown that melatonin (MT) plus exercise (Ex) had a synergistic effect on functional recovery after SCI. Thus, we hypothesized that combined therapy including melatonin and exercise might exert a beneficial effect on eNSPCs after SCI. Melatonin was administered twice a day and exercise was performed on a treadmill for 15 min, six days per week for 3 weeks after SCI. Immunohistochemistry and RT-PCR analysis were used to determine cell population for late response, in conjunction with histological examination and motor function test. There was marked improvement in hindlimb function in SCI+MT+Ex group at day 14 and 21 after injury, as documented by the reduced size of the spinal lesion and a higher density of dendritic spines and axons; such functional improvements were associated with increased numbers of BrdU-positive cells. Furthermore, MAP2 was increased in the injured thoracic segment, while GFAP was increased in the cervical segment, along with elevated numbers of BrdU-positive nestin-expressing eNSPCs in the SCI+MT+Ex group. The dendritic spine density was augmented markedly in SCI+MT and SCI+MT+Ex groups.These results suggest a synergistic effect of SCI+MT+Ex might create a microenvironment to facilitate proliferation of eNSPCs to effectively replace injured cells and to improve regeneration in SCI. PMID- 24487508 TI - Evaluation of in vivo detection properties of 22Na, 65Zn, 86Rb, 109Cd and 137Cs in plant tissues using real-time radioisotope imaging system. AB - In plant research, radioisotope imaging provides useful information about physiological activities in various tissues and elemental transport between plant organs. To expand the usage of imaging techniques, a new system was developed to visualize beta particles, x-rays and gamma-rays emitted from plant bodies. This real-time radioisotope imaging system (RRIS) visualizes radioactivity after conversion into light with a CsI(Tl) scintillator plate. Herein, the RRIS detection properties of the gamma-ray emitters (22)Na, (65)Zn, (86)Rb, (109)Cd and (137)Cs were evaluated in comparison with those of radioluminography (RLG) using an imaging plate. The lower quantitative detection limit (Bq mm(-2)) during a 15 min period ranged from 0.1 to 4, depending on the nuclide, similar to that of RLG. When the quantitative ability to detect radiation from various Arabidopsis tissues was analyzed, the quantitative capability in silique and the thick internode tended to be low. In an EGS5 simulation, beta particles were the greatest contributors to RRIS imaging of (22)Na, (86)Rb and (137)Cs, and low energy x-rays contributed significantly to (65)Zn and (109)Cd detection. Thus, both self-absorption and air space between the sample and scintillator surface could impair quantitative RRIS imaging. Despite these issues, RRIS is suggested for quantitative time-course measurements of radionuclide motion within plants. PMID- 24487509 TI - The Geschwind-Behan-Galaburda model (GBGM) of cerebral lateralization: a critique and prospective. AB - In the wake of, and as a complement to, a recently published major meta-analytic review of empirical support of the Geschwind-Behan-Galaburda model (GBGM) of cerebral lateralization (CL) the present brief essay attempts to present a critical assessment of the theoretical approach underlying the GBGM. The GBGM is criticized for having been misguided in its representation of the cerebral basis of handedness, and of the links between testosterone and immune function. Some guidelines are presented for the development of a general theory of CL, emphasizing animal research, greater interdisciplinary communication, a hierarchical model-building approach, and the relevance of neuropharmacology and psychiatry. PMID- 24487510 TI - Mirror-reversal of a face is perceived as expressing emotions more intensely. AB - This study examined hemispatial bias in a free-viewing condition of the judgement of facial expressions of emotions. Right-handed male subjects were asked to judge the intensity, in terms of expressiveness, of facial emotion in normal and mirror reversed orientations. Expressions in mirror-reversed orientation were perceived as more intense than in normal orientation. PMID- 24487511 TI - Family history of handedness and language problems in Mexican reading-disabled children. AB - A sample of 120 Spanish-speaking children, 60 with reading disabilities and 60 normal readers was studied. Individual and family history of handedness, language problems, and reading disabilities were analyzed in each case. The results suggest that reading disabilities are more common among boys, that associated language problems are frequent and that handedness is not a significant factor. Insofar as family history is concerned, there were more affected families and relatives in the reading disabled group than in the control group. Finally an association was established between the variables of handedness and language problems. PMID- 24487512 TI - Procedural memory: computer learning in control subjects and in Parkinson's disease patients. AB - We used perceptual motor tasks involving the learning of mouse control by looking at a Macintosh computer screen. We studied 90 control subjects aged between sixteen and seventy-five years. There was a significant time difference between the scales of age but improvement was the same for all subjects. We also studied 24 patients with Parkinson's disease (PD). We observed an influence of age and also of educational levels. The PD patients had difficulties of learning in all tests but they did not show differences in time when compared to the control group in the first learning session (Student's t-test). They learned two or four and a half times less well than the control group. In the first test, they had some difficulty in initiating the procedure and learned eight times less well than the control group. Performances seemed to be heterogeneous: patients with only tremor (seven) and patients without treatment (five) performed better than others but learned less. Success in procedural tasks for the PD group seemed to depend on the capacity to initiate the response and not on the development of an accurate strategy. Many questions still remain unanswered, and we have to study different kinds of implicit memory tasks to differentiate performance in control and basal ganglia groups. PMID- 24487513 TI - Neuropsychological investigation of anterior and posterior cortical function in early-stage probable Alzheimer's disease. AB - In vivo neuroimaging studies have generally indicated a greater involvement of posterior cortical areas in early-stage dementia of the Alzheimer type (DAT) relative to frontal involvement. By contrast, some recent neuropsychological studies have shown that DAT patients perform poorly in frontal lobe tasks even in the early stages of the disease, although there is disagreement as to whether this necessarily implicates frontal pathology. The main aim of this study was to examine the hypothesis prompted by both neuroimaging studies and the traditional clinical conception of the disease, that, compared with the functioning of posterior association cortex, executive functions (thought to depend on frontal lobe integrity) are relatively spared in the early stages of DAT. A group of patients with a diagnosis of early-stage, probable DAT (n = 17) was compared with age- and IQ-matched controls (n = 17) across a range of neuropsychological tasks presumed to exercise frontal or temporoparietal functions. A profile of strengths and weaknesses was observed across 'anterior' and 'posterior' cognitive tests, including dissociations among some tests of temporoparietal function, in particular visual object perception (impaired) and spatial analysis skills (intact). Thus there was little support for the notion that the disease progresses cortically in a posterior-to-anterior direction. Possible reasons for the discrepancy between neurophysiological and neuropsychological observations are discussed, including the possibility that neuropsychological tests do not provide a valid indication of regional brain function when used in the context of DAT. Caution is urged in the clinical application of 'frontal lobe tests' for the differential diagnosis of DAT. PMID- 24487514 TI - Somatosensory evoked potentials and dopaminergic responsiveness to apomorphine and levodopa in parkinsonian patients. AB - Short-latency somatosensory evoked potentials (SSEPs) were recorded from 10 parkinsonian patients in 'off' and 'on' states induced by apomorphine and levodopa. The effects of apomorphine and long-term levodopa treatment on the frontal N30 component were assessed and compared with healthy controls. Nine of 10 patients tested with apomorphine showed a significant improvement (p<0.01) in N30 frontal component amplitude whereas in six of eight patients similarly assessed with levodopa we obtained a comparable improvement in SSEPs (p<0.01). Parietal SSEPs remained unchanged. This normalization of frontal SSEPs was concomitant with the clinical response and in some patients preceded the motor response. No changes were obtained in control subjects. The improvement in N30 potential occurred regardless of disease duration or the presence of motor fluctuations. SSEPs may represent an objective approach for assessing the dopaminergic response and the fluctuations of motor disability in parkinsonian patients. PMID- 24487515 TI - Crossed aphasia. I: A case-study with purely deep lesion. AB - In this paper, we describe the case of a right-handed man, MR, who after right thalamic haemorrhage presented subtranscortical aphasia. Of the disturbances generally associated with standard left hemisphere functions, the patient presented acalculia but not apraxia. Among the functions attributed to the standard right hemisphere, MR showed impairment in affective language and presented unilateral neglect and a strong position preference. PMID- 24487516 TI - Crossed aphasia. II: Why are deep lesions overrepresented with respect to standard aphasia? AB - In this paper we have reviewed the cases of vascular crossed aphasia reported in the literature, in order to check whether deep lesions are really overrepresented in crossed aphasia with respect to standard aphasia. The comparison with a large sample of standard left-hemisphere-damaged aphasics revealed a significantly higher incidence of purely deep lesions in crossed aphasics than in standard aphasics. The overrepresentation of deep lesions in crossed aphasia appears to be contingent on the co-occurrence of aphasia and Unilateral Neglect after right hemisphere lesion. This suggests an interaction between language and attentional mechanisms in the case of reversed language lateralisation: the overcrowding of these functions in the right hemisphere could make language more vulnerable after right deep lesions. PMID- 24487517 TI - PET study in a patient with spinocerebellar degeneration before and after long term administration of thyrotropin releasing hormone. AB - We studied the chronic effect of thyrotropin releasing hormone (TRH) in a patient with spinocerebellar degeneration by measuring cerebral metabolic rate for glucose (CMRG1c) using 2-[18F]fluoro-2-deoxy-D-glucose (18FDG) and positron emission tomography (PET). A 56-year-old female, who had suffered from progressive ataxia for 2 years, was treated by intravenous administration of 2 mg TRH for 3 weeks, and CMRG1c of the brain was measured before and after treatment. CMRG1c was markedly decreased in the cerebellum and there was no significant difference before and after the treatment, i.e. mean CMRG1c values were 4.92 and 4.90 mg/100 g/min, and the ratios of the cerebellum versus the frontal cortex were 0.50 and 0.51, respectively. The degree of disequilibrium of her body examined with stabilography became better by the 19th day and further improved by the 26th day after the start of TRH treatment. Based on the present study we conclude that long-term administration of TRH did not improve CMRG1c in the cerebellum, but evidently improved the sway of gravity center by stabilography. We speculate that the chronic effect of TRH was not necessarily due to an improvement of cerebellar function, because TRH receptors are widely distributed throughout the central nervous system. PMID- 24487518 TI - Compulsive painting: a variant of hypergraphia? PMID- 24487523 TI - Manipulating frequency-bin entangled states in cold atoms. AB - Optical manipulation of entanglement harnessing the frequency degree of freedom is important for encoding of quantum information. We here devise a phase-resonant excitation mechanism of an atomic interface where full control of a narrowband single-photon two-mode frequency entangled state can be efficiently achieved. We illustrate the working physical mechanism for an interface made of cold (87)Rb atoms where entanglement is well preserved from degradation over a typical 100 MUm length scale of the interface and with fractional delays of the order of unity. The scheme provides a basis for efficient multi-frequency and multi-photon entanglement, which is not easily accessible to polarization and spatial encoding. PMID- 24487525 TI - Detection and prevalence of verotoxin-producing Escherichia coli O157 and non O157 serotypes in a Canadian watershed. AB - Verotoxin-producing Escherichia coli (VTEC) strains are the cause of food-borne and waterborne illnesses around the world. Traditionally, surveillance of the human population as well as the environment has focused on the detection of E. coli O157:H7. Recently, increasing recognition of non-O157 VTEC strains as human pathogens and the German O104:H4 food-borne outbreak have illustrated the importance of considering the broader group of VTEC organisms from a public health perspective. This study presents the results of a comparison of three methods for the detection of VTEC in surface water, highlighting the efficacy of a direct VT immunoblotting method without broth enrichment for detection and isolation of O157 and non-O157 VTEC strains. The direct immunoblot method eliminates the need for an enrichment step or the use of immunomagnetic separation. This method was developed after 4 years of detecting low frequencies (1%) of E. coli O157:H7 in surface water in a Canadian watershed, situated within one of the FoodNet Canada integrated surveillance sites. By the direct immunoblot method, VTEC prevalence estimates ranged from 11 to 35% for this watershed, and E. coli O157:H7 prevalence increased to 4% (due to improved method sensitivity). This direct testing method provides an efficient means to enhance our understanding of the prevalence and types of VTEC in the environment. This study employed a rapid evidence assessment (REA) approach to frame the watershed findings with watershed E. coli O157:H7 prevalences reported in the literature since 1990 and the knowledge gap with respect to VTEC detection in surface waters. PMID- 24487526 TI - Characterization of a planctomycetal organelle: a novel bacterial microcompartment for the aerobic degradation of plant saccharides. AB - Bacterial microcompartments (BMCs) are organelles that encapsulate functionally linked enzymes within a proteinaceous shell. The prototypical example is the carboxysome, which functions in carbon fixation in cyanobacteria and some chemoautotrophs. It is increasingly apparent that diverse heterotrophic bacteria contain BMCs that are involved in catabolic reactions, and many of the BMCs are predicted to have novel functions. However, most of these putative organelles have not been experimentally characterized. In this study, we sought to discover the function of a conserved BMC gene cluster encoded in the majority of the sequenced planctomycete genomes. This BMC is especially notable for its relatively simple genetic composition, its remote phylogenetic position relative to characterized BMCs, and its apparent exclusivity to the enigmatic Verrucomicrobia and Planctomycetes. Members of the phylum Planctomycetes are known for their morphological dissimilarity to the rest of the bacterial domain: internal membranes, reproduction by budding, and lack of peptidoglycan. As a result, they are ripe for many discoveries, but currently the tools for genetic studies are very limited. We expanded the genetic toolbox for the planctomycetes and generated directed gene knockouts of BMC-related genes in Planctomyces limnophilus. A metabolic activity screen revealed that BMC gene products are involved in the degradation of a number of plant and algal cell wall sugars. Among these sugars, we confirmed that BMCs are formed and required for growth on l-fucose and l-rhamnose. Our results shed light on the functional diversity of BMCs as well as their ecological role in the planctomycetes, which are commonly associated with algae. PMID- 24487527 TI - RNA-stable-isotope probing shows utilization of carbon from inulin by specific bacterial populations in the rat large bowel. AB - Knowledge of the trophisms that underpin bowel microbiota composition is required in order to understand its complex phylogeny and function. Stable-isotope ((13)C) labeled inulin was added to the diet of rats on a single occasion in order to detect utilization of inulin-derived substrates by particular members of the cecal microbiota. Cecal digesta from Fibruline-inulin-fed rats was collected prior to (0 h) and at 6, 12, 18 and 24 h following provision of the [(13)C]inulin diet. RNA was extracted from these cecal specimens and fractionated in isopycnic buoyant density gradients in order to detect (13)C-labeled nucleic acid originating in bacterial cells that had metabolized the labeled dietary constituent. RNA extracted from specimens collected after provision of the labeled diet was more dense than 0-h RNA. Sequencing of 16S rRNA genes amplified from cDNA obtained from these fractions showed that Bacteroides uniformis, Blautia glucerasea, Clostridium indolis, and Bifidobacterium animalis were the main users of the (13)C-labeled substrate. Culture-based studies of strains of these bacterial species enabled trophisms associated with inulin and its hydrolysis products to be identified. B. uniformis utilized Fibruline-inulin for growth, whereas the other species used fructo-oligosaccharide and monosaccharides. Thus, RNA-stable-isotope probing (RNA-SIP) provided new information about the use of carbon from inulin in microbiota metabolism. PMID- 24487528 TI - Prokaryotic communities in pit mud from different-aged cellars used for the production of Chinese strong-flavored liquor. AB - Chinese strong-flavored liquor (CSFL) accounts for more than 70% of all Chinese liquor production. Microbes in pit mud play key roles in the fermentation cellar for the CSFL production. However, microbial diversity, community structure, and cellar-age-related changes in pit mud are poorly understood. Here, we investigated the prokaryotic community structure and diversity in pit-mud samples with different cellar ages (1, 10, 25, and 50 years) using the pyrosequencing technique. Results indicated that prokaryotic diversity increased with cellar age until the age reached 25 years and that prokaryotic community structure changed significantly between three cellar ages (1, 10, and 25 years). Significant correlations between prokaryotic communities and environmental variables (pH, NH4(+), lactic acid, butyric acid, and caproic acid) were observed. Overall, our study results suggested that the long-term brewing operation shapes unique prokaryotic community structure and diversity as well as pit-mud chemistry. We have proposed a three-phase model to characterize the changes of pit-mud prokaryotic communities. (i) Phase I is an initial domestication period. Pit mud is characterized by abundant Lactobacillus and high lactic acid and low pH levels. (ii) Phase II is a transition period. While Lactobacillus abundance decreases dramatically, that of Bacteroidetes and methanogens increases. (iii) Phase III is a relative mature period. The prokaryotic community shows the highest diversity and capability to produce more caproic acid as a precursor for synthesis of ethyl caproate, the main flavor component in CSFL. This research provides scientific evidence to support the practical experience that old fermentation cellars produce high-quality liquor. PMID- 24487529 TI - Comparative analysis and limitations of ethidium monoazide and propidium monoazide treatments for the differentiation of viable and nonviable campylobacter cells. AB - The lack of differentiation between viable and nonviable bacterial cells limits the implementation of PCR-based methods for routine diagnostic approaches. Recently, the combination of a quantitative real-time PCR (qPCR) and ethidium monoazide (EMA) or propidium monoazide (PMA) pretreatment has been described to circumvent this disadvantage. In regard to the suitability of this approach for Campylobacter spp., conflicting results have been reported. Thus, we compared the suitabilities of EMA and PMA in various concentrations for a Campylobacter viability qPCR method. The presence of either intercalating dye, EMA or PMA, leads to concentration-dependent shifts toward higher threshold cycle (CT) values, especially after EMA treatment. However, regression analysis resulted in high correlation coefficient (R(2)) values of 0.99 (EMA) and 0.98 (PMA) between Campylobacter counts determined by qPCR and culture-based enumeration. EMA (10 MUg/ml) and PMA (51.10 MUg/ml) removed DNA selectively from nonviable cells in mixed samples at viable/nonviable ratios of up to 1:1,000. The optimized EMA protocol was successfully applied to 16 Campylobacter jejuni and Campylobacter coli field isolates from poultry and indicated the applicability for field isolates as well. EMA-qPCR and culture-based enumeration of Campylobacter spiked chicken leg quarters resulted in comparable bacterial cell counts. The correlation coefficient between the two analytical methods was 0.95. Nevertheless, larger amounts of nonviable cells (>10(4)) resulted in an incomplete qPCR signal reduction, representing a serious methodological limitation, but double staining with EMA considerably improved the signal inhibition. Hence, the proposed Campylobacter viability EMA-qPCR provides a promising rapid method for diagnostic applications, but further research is needed to circumvent the limitation. PMID- 24487524 TI - The atrial fibrillation ablation pilot study: a European Survey on Methodology and results of catheter ablation for atrial fibrillation conducted by the European Heart Rhythm Association. AB - AIMS: The Atrial Fibrillation Ablation Pilot Study is a prospective registry designed to describe the clinical epidemiology of patients undergoing an atrial fibrillation (AFib) ablation, and the diagnostic/therapeutic processes applied across Europe. The aims of the 1-year follow-up were to analyse how centres assess in routine clinical practice the success of the procedure and to evaluate the success rate and long-term safety/complications. METHODS AND RESULTS: Seventy two centres in 10 European countries were asked to enrol 20 consecutive patients undergoing a first AFib ablation procedure. A web-based case report form captured information on pre-procedural, procedural, and 1-year follow-up data. Between October 2010 and May 2011, 1410 patients were included and 1391 underwent an AFib ablation (98.7%). A total of 1300 patients (93.5%) completed a follow-up control 367 +/- 42 days after the procedure. Arrhythmia documentation was done by an electrocardiogram in 76%, Holter-monitoring in 52%, transtelephonic monitoring in 8%, and/or implanted systems in 4.5%. Over 50% became asymptomatic. Twenty-one per cent were re-admitted due to post-ablation arrhythmias. Success without antiarrhythmic drugs was achieved in 40.7% of patients (43.7% in paroxysmal AF; 30.2% in persistent AF; 36.7% in long-lasting persistent AF). A second ablation was required in 18% of the cases and 43.4% were under antiarrhythmic treatment. Thirty-three patients (2.5%) suffered an adverse event, 272 (21%) experienced a left atrial tachycardia, and 4 patients died (1 haemorrhagic stroke, 1 ventricular fibrillation in a patient with ischaemic heart disease, 1 cancer, and 1 of unknown cause). CONCLUSION: The AFib Ablation Pilot Study provided crucial information on the epidemiology, management, and outcomes of catheter ablation of AFib in a real-world setting. The methods used to assess the success of the procedure appeared at least suboptimal. Even in this context, the 12-month success rate appears to be somewhat lower to the one reported clinical trials. PMID- 24487530 TI - Identification of bacteriophages for biocontrol of the kiwifruit canker phytopathogen Pseudomonas syringae pv. actinidiae. AB - Pseudomonas syringae pv. actinidiae is a reemerging pathogen which causes bacterial canker of kiwifruit (Actinidia sp.). Since 2008, a global outbreak of P. syringae pv. actinidiae has occurred, and in 2010 this pathogen was detected in New Zealand. The economic impact and the development of resistance in P. syringae pv. actinidiae and other pathovars against antibiotics and copper sprays have led to a search for alternative management strategies. We isolated 275 phages, 258 of which were active against P. syringae pv. actinidiae. Extensive host range testing on P. syringae pv. actinidiae, other pseudomonads, and bacteria isolated from kiwifruit orchards showed that most phages have a narrow host range. Twenty-four were analyzed by electron microscopy, pulse-field gel electrophoresis, and restriction digestion. Their suitability for biocontrol was tested by assessing stability and the absence of lysogeny and transduction. A detailed host range was performed, phage-resistant bacteria were isolated, and resistance to other phages was examined. The phages belonged to the Caudovirales and were analyzed based on morphology and genome size, which showed them to be representatives of Myoviridae, Podoviridae, and Siphoviridae. Twenty-one Myoviridae members have similar morphologies and genome sizes yet differ in restriction patterns, host range, and resistance, indicating a closely related group. Nine of these Myoviridae members were sequenced, and each was unique. The most closely related sequenced phages were a group infecting Pseudomonas aeruginosa and characterized by phages JG004 and PAK_P1. In summary, this study reports the isolation and characterization of P. syringae pv. actinidiae phages and provides a framework for the intelligent formulation of phage biocontrol agents against kiwifruit bacterial canker. PMID- 24487531 TI - H(2)O(2) production in species of the Lactobacillus acidophilus group: a central role for a novel NADH-dependent flavin reductase. AB - Hydrogen peroxide production is a well-known trait of many bacterial species associated with the human body. In the presence of oxygen, the probiotic lactic acid bacterium Lactobacillus johnsonii NCC 533 excretes up to 1 mM H(2)O(2), inducing growth stagnation and cell death. Disruption of genes commonly assumed to be involved in H(2)O(2) production (e.g., pyruvate oxidase, NADH oxidase, and lactate oxidase) did not affect this. Here we describe the purification of a novel NADH-dependent flavin reductase encoded by two highly similar genes (LJ_0548 and LJ_0549) that are conserved in lactobacilli belonging to the Lactobacillus acidophilus group. The genes are predicted to encode two 20-kDa proteins containing flavin mononucleotide (FMN) reductase conserved domains. Reductase activity requires FMN, flavin adenine dinucleotide (FAD), or riboflavin and is specific for NADH and not NADPH. The Km for FMN is 30 +/- 8 MUM, in accordance with its proposed in vivo role in H(2)O(2) production. Deletion of the encoding genes in L. johnsonii led to a 40-fold reduction of hydrogen peroxide formation. H(2)O(2) production in this mutant could only be restored by in trans complementation of both genes. Our work identifies a novel, conserved NADH dependent flavin reductase that is prominently involved in H(2)O(2) production in L. johnsonii. PMID- 24487532 TI - The cockroach origin of the termite gut microbiota: patterns in bacterial community structure reflect major evolutionary events. AB - Termites digest wood and other lignocellulosic substrates with the help of their intestinal microbiota. While the functions of the symbionts in the digestive process are slowly emerging, the origin of the bacteria colonizing the hindgut bioreactor is entirely unknown. Recently, our group discovered numerous representatives of bacterial lineages specific to termite guts in a closely related omnivorous cockroach, but it remains unclear whether they derive from the microbiota of a common ancestor or were independently selected by the gut environment. Here, we studied the bacterial gut microbiota in 34 species of termites and cockroaches using pyrotag analysis of the 16S rRNA genes. Although the community structures differed greatly between the major host groups, with dramatic changes in the relative abundances of particular bacterial taxa, we found that the majority of sequence reads belonged to bacterial lineages that were shared among most host species. When mapped onto the host tree, the changes in community structure coincided with major events in termite evolution, such as acquisition and loss of cellulolytic protists and the ensuing dietary diversification. UniFrac analysis of the core microbiota of termites and cockroaches and construction of phylogenetic tree of individual genus level lineages revealed a general host signal, whereas the branching order often did not match the detailed phylogeny of the host. It remains unclear whether the lineages in question have been associated with the ancestral cockroach since the early Cretaceous (cospeciation) or are diet-specific lineages that were independently acquired from the environment (host selection). PMID- 24487533 TI - Metabolic responses of Lactobacillus plantarum strains during fermentation and storage of vegetable and fruit juices. AB - Strains of Lactobacillus plantarum were grown and stored in cherry (ChJ), pineapple (PJ), carrot (CJ), and tomato (TJ) juices to mimic the chemical composition of the respective matrices. Wheat flour hydrolysate (WFH), whey milk (W), and MRS broth were also used as representatives of other ecosystems. The growth rates and cell densities of L. plantarum strains during fermentation (24 h at 30 degrees C) and storage (21 days at 4 degrees C) differed only in part, being mainly influenced by the matrix. ChJ and PJ were the most stressful juices for growth and survival. Overall, the growth in juices was negatively correlated with the initial concentration of malic acid and carbohydrates. The consumption of malic acid was noticeable for all juices, but mainly during fermentation and storage of ChJ. Decreases of branched-chain amino acids (BCAA)-with the concomitant increase of their respective branched alcohols-and His and increases of Glu and gamma-aminobutyric acid (GABA) were the main traits of the catabolism of free amino acids (FAA), which were mainly evident under less acidic conditions (CJ and TJ). The increase of Tyr was found only during storage of ChJ. Some aldehydes (e.g., 3-methyl-butanal) were reduced to the corresponding alcohols (e.g., 3-methyl-1-butanol). After both fermentation and storage, acetic acid increased in all fermented juices, which implied the activation of the acetate kinase route. Diacetyl was the ketone found at the highest level, and butyric acid increased in almost all fermented juices. Data were processed through multidimensional statistical analyses. Except for CJ, the juices (mainly ChJ) seemed to induce specific metabolic traits, which differed in part among the strains. This study provided more in-depth knowledge on the metabolic mechanisms of growth and maintenance of L. plantarum in vegetable and fruit habitats, which also provided helpful information to select the most suitable starters for fermentation of targeted matrices. PMID- 24487534 TI - Inactivation of human norovirus in contaminated oysters and clams by high hydrostatic pressure. AB - Human norovirus (NoV) is the most frequent causative agent of food-borne disease associated with shellfish consumption. In this study, the effect of high hydrostatic pressure (HHP) on inactivation of NoV was determined. Genogroup I.1 (GI.1) or genogroup II.4 (GII.4) NoV was inoculated into oyster homogenates and treated at 300 to 600 MPa at 25, 6, and 1 degrees C for 5 min. After HHP, samples were treated with RNase and viral particles were extracted with porcine gastric mucin (PGM)-conjugated magnetic beads (PGM-MBs). Viral RNA was then quantified by real-time reverse transcription (RT)-PCR. Since PGM contains histo-blood group like antigens, which can act as receptors for NoV, deficiency for binding to PGM is an indication of loss of infectivity of NoV. After binding to PGM-MBs, RT-PCR detectable NoV RNA in oysters was reduced by 0.4 to >4 log10 by HHP at 300 to 600 MPa. The GI.1 NoV was more resistant to HHP than the GII.4 NoV (P < 0.05). HHP at lower temperatures significantly enhanced the inactivation of NoV in oysters (P < 0.05). Pressure treatment was also conducted for clam homogenates. Treatment at 450 MPa at 1 degrees C achieved a >4 log10 reduction of GI.1 NoV in both oyster and clam homogenates. It is therefore concluded that HHP could be applied as a potential intervention for inactivating NoV in raw shellfish. The method of pretreatment of samples with RNase, extraction of viral particles using PGM-MB binding, and quantification of viral RNA using RT-PCR can be explored as a practical means of distinguishing between infectious and noninfectious NoV. PMID- 24487535 TI - A comparative quantitative proteomic study identifies new proteins relevant for sulfur oxidation in the purple sulfur bacterium Allochromatium vinosum. AB - In the present study, we compared the proteome response of Allochromatium vinosum when growing photoautotrophically in the presence of sulfide, thiosulfate, and elemental sulfur with the proteome response when the organism was growing photoheterotrophically on malate. Applying tandem mass tag analysis as well as two-dimensional (2D) PAGE, we detected 1,955 of the 3,302 predicted proteins by identification of at least two peptides (59.2%) and quantified 1,848 of the identified proteins. Altered relative protein amounts (>=1.5-fold) were observed for 385 proteins, corresponding to 20.8% of the quantified A. vinosum proteome. A significant number of the proteins exhibiting strongly enhanced relative protein levels in the presence of reduced sulfur compounds are well documented essential players during oxidative sulfur metabolism, e.g., the dissimilatory sulfite reductase DsrAB. Changes in protein levels generally matched those observed for the respective relative mRNA levels in a previous study and allowed identification of new genes/proteins participating in oxidative sulfur metabolism. One gene cluster (hyd; Alvin_2036-Alvin_2040) and one hypothetical protein (Alvin_2107) exhibiting strong responses on both the transcriptome and proteome levels were chosen for gene inactivation and phenotypic analyses of the respective mutant strains, which verified the importance of the so-called Isp hydrogenase supercomplex for efficient oxidation of sulfide and a crucial role of Alvin_2107 for the oxidation of sulfur stored in sulfur globules to sulfite. In addition, we analyzed the sulfur globule proteome and identified a new sulfur globule protein (SgpD; Alvin_2515). PMID- 24487536 TI - Acidic pH strongly enhances in vitro biofilm formation by a subset of hypervirulent ST-17 Streptococcus agalactiae strains. AB - Streptococcus agalactiae, also known as group B Streptococcus (GBS), is a primary colonizer of the anogenital mucosa of up to 40% of healthy women and an important cause of invasive neonatal infections worldwide. Among the 10 known capsular serotypes, GBS type III accounts for 30 to 76% of the cases of neonatal meningitis. In recent years, the ability of GBS to form biofilm attracted attention for its possible role in fitness and virulence. Here, a new in vitro biofilm formation protocol was developed to guarantee more stringent conditions, to better discriminate between strong-, low-, and non-biofilm-forming strains, and to facilitate interpretation of data. This protocol was used to screen the biofilm-forming abilities of 366 GBS clinical isolates from pregnant women and from neonatal infections of different serotypes in relation to medium composition and pH. The results identified a subset of isolates of serotypes III and V that formed strong biofilms under acidic conditions. Importantly, the best biofilm formers belonged to serotype III hypervirulent clone ST-17. Moreover, the abilities of proteinase K to strongly inhibit biofilm formation and to disaggregate mature biofilms suggested that proteins play an essential role in promoting GBS biofilm initiation and contribute to biofilm structural stability. PMID- 24487537 TI - Antiviral properties of silver nanoparticles on a magnetic hybrid colloid. AB - Silver nanoparticles (AgNPs) are considered to be a potentially useful tool for controlling various pathogens. However, there are concerns about the release of AgNPs into environmental media, as they may generate adverse human health and ecological effects. In this study, we developed and evaluated a novel micrometer sized magnetic hybrid colloid (MHC) decorated with variously sized AgNPs (AgNP MHCs). After being applied for disinfection, these particles can be easily recovered from environmental media using their magnetic properties and remain effective for inactivating viral pathogens. We evaluated the efficacy of AgNP MHCs for inactivating bacteriophage PhiX174, murine norovirus (MNV), and adenovirus serotype 2 (AdV2). These target viruses were exposed to AgNP-MHCs for 1, 3, and 6 h at 25 degrees C and then analyzed by plaque assay and real-time TaqMan PCR. The AgNP-MHCs were exposed to a wide range of pH levels and to tap and surface water to assess their antiviral effects under different environmental conditions. Among the three types of AgNP-MHCs tested, Ag30-MHCs displayed the highest efficacy for inactivating the viruses. The PhiX174 and MNV were reduced by more than 2 log10 after exposure to 4.6 * 10(9) Ag30-MHCs/ml for 1 h. These results indicated that the AgNP-MHCs could be used to inactivate viral pathogens with minimum chance of potential release into environment. PMID- 24487538 TI - Surface expression of omega-transaminase in Escherichia coli. AB - Chiral amines are important for the chemical and pharmaceutical industries, and there is rapidly growing interest to use transaminases for their synthesis. Since the cost of the enzyme is an important factor for process economy, the use of whole-cell biocatalysts is attractive, since expensive purification and immobilization steps can be avoided. Display of the protein on the cell surface provides a possible way to reduce the mass transfer limitations of such biocatalysts. However, transaminases need to dimerize in order to become active, and furthermore, they require the cofactor pyridoxal phosphate; consequently, successful transaminase surface expression has not been reported thus far. In this work, we produced an Arthrobacter citreus omega-transaminase in Escherichia coli using a surface display vector based on the autotransporter adhesin involved in diffuse adherence (AIDA-I), which has previously been used for display of dimeric proteins. The correct localization of the transaminase in the E. coli outer membrane and its orientation toward the cell exterior were verified. Furthermore, transaminase activity was detected exclusively in the outer membrane protein fraction, showing that successful dimerization had occurred. The transaminase was found to be present in both full-length and proteolytically degraded forms. The removal of this proteolysis is considered to be the main obstacle to achieving sufficient whole-cell transaminase activity. PMID- 24487539 TI - Microgravity alters the physiological characteristics of Escherichia coli O157:H7 ATCC 35150, ATCC 43889, and ATCC 43895 under different nutrient conditions. AB - The aim of this study is to provide understanding of microgravity effects on important food-borne bacteria, Escherichia coli O157:H7 ATCC 35150, ATCC 43889, and ATCC 43895, cultured in nutrient-rich or minimal medium. Physiological characteristics, such as growth (measured by optical density and plating), cell morphology, and pH, were monitored under low-shear modeled microgravity (LSMMG; space conditions) and normal gravity (NG; Earth conditions). In nutrient-rich medium, all strains except ATCC 35150 showed significantly higher optical density after 6 h of culture under LSMMG conditions than under NG conditions (P < 0.05). LSMMG-cultured cells were approximately 1.8 times larger than NG-cultured cells at 24 h; therefore, it was assumed that the increase in optical density was due to the size of individual cells rather than an increase in the cell population. The higher pH of the NG cultures relative to that of the LSMMG cultures suggests that nitrogen metabolism was slower in the latter. After 24 h of culturing in minimal media, LSMMG-cultured cells had an optical density 1.3 times higher than that of NG-cultured cells; thus, the higher optical density in the LSMMG cultures may be due to an increase in both cell size and number. Since bacteria actively grew under LSMMG conditions in minimal medium despite the lower pH, it is of some concern that LSMMG-cultured E. coli O157:H7 may be able to adapt well to acidic environments. These changes may be caused by changes in nutrient metabolism under LSMMG conditions, although this needs to be demonstrated in future studies. PMID- 24487540 TI - Distribution of indigenous bacterial pathogens and potential pathogens associated with roof-harvested rainwater. AB - The harvesting of rainwater is gaining acceptance among many governmental authorities in countries such as Australia, Germany, and South Africa, among others. However, conflicting reports on the microbial quality of harvested rainwater have been published. To monitor the presence of potential pathogenic bacteria during high-rainfall periods, rainwater from 29 rainwater tanks was sampled on four occasions (during June and August 2012) in a sustainable housing project in Kleinmond, South Africa. This resulted in the collection of 116 harvested rainwater samples in total throughout the sampling period. The identities of the dominant, indigenous, presumptive pathogenic isolates obtained from the rainwater samples throughout the sampling period were confirmed through universal 16S rRNA PCR, and the results revealed that Pseudomonas (19% of samples) was the dominant genus isolated, followed by Aeromonas (16%), Klebsiella (11%), and Enterobacter (9%). PCR assays employing genus-specific primers also confirmed the presence of Aeromonas spp. (16%), Klebsiella spp. (47%), Legionella spp. (73%), Pseudomonas spp. (13%), Salmonella spp. (6%), Shigella spp. (27%), and Yersinia spp. (28%) in the harvested rainwater samples. In addition, on one sampling occasion, Giardia spp. were detected in 25% of the eight tank water samples analyzed. This study highlights the diverse array of pathogenic bacteria that persist in harvested rainwater during high-rainfall periods. The consumption of untreated harvested rainwater could thus pose a potential significant health threat to consumers, especially children and immunocompromised individuals, and it is recommended that harvested rainwater be treated for safe usage as an alternative water source. PMID- 24487541 TI - Genetic manipulations of the hyperthermophilic piezophilic archaeon Thermococcus barophilus. AB - In this study, we developed a gene disruption system for Thermococcus barophilus using simvastatin for positive selection and 5-fluoroorotic acid (5-FOA) for negative selection or counterselection to obtain markerless deletion mutants using single- and double-crossover events. Disruption plasmids carrying flanking regions of each targeted gene were constructed and introduced by transformation into wild-type T. barophilus MP cells. Initially, a pyrF deletion mutant was obtained as a starting point for the construction of further markerless mutants. A deletion of the hisB gene was also constructed in the UBOCC-3256 (DeltapyrF) background, generating a strain (UBOCC-3260) that was auxotrophic for histidine. A functional pyrF or hisB allele from T. barophilus was inserted into the chromosome of UBOCC-3256 (DeltapyrF) or UBOCC-3260 (DeltapyrF DeltahisB), allowing homologous complementation of these mutants. The piezophilic genetic tools developed in this study provide a way to construct strains with multiple genetic backgrounds that will allow further genetic studies for hyperthermophilic piezophilic archaea. PMID- 24487542 TI - In-feed use of heavy metal micronutrients in U.S. swine production systems and its role in persistence of multidrug-resistant salmonellae. AB - The study aimed to characterize the role of heavy metal micronutrients in swine feed in emergence of heavy-metal-tolerant and multidrug-resistant Salmonella organisms. We conducted a longitudinal study in 36 swine barns over a 2-year period. The feed and fecal levels of Cu(2+) and Zn(2+) were measured. Salmonella was isolated at early and late finishing. MICs of copper sulfate and zinc chloride were measured using agar dilution. Antimicrobial susceptibility was tested using the Kirby-Bauer method, and 283 isolates were serotyped. We amplified pcoA and czcD genes that encode Cu(2+) and Zn(2+) tolerance, respectively. Of the 283 isolates, 113 (48%) showed Cu(2+) tolerance at 24 mM and 164 (58%) showed Zn(2+) tolerance at 8 mM. In multivariate analysis, serotype and source of isolates were significantly associated with Cu(2+) tolerance (P < 0.001). Fecal isolates were more likely to be Cu(2+) tolerant than those of feed origin (odds ratio [OR], 27.0; 95% confidence interval [CI], 2.8 to 250; P = 0.0042) or environmental origin (OR, 5.8), implying the significance of gastrointestinal selective pressure. Salmonella enterica serotypes Typhimurium and Heidelberg, highly significant for public health, had higher odds of having >20 mM MICs of Cu(2+) than did "other" serotypes. More than 60% of Salmonella isolates with resistance type (R-type) AmStTeKm (32 of 53) carried pcoA; only 5% with R-type AmClStSuTe carried this gene. czcD gene carriage was significantly associated with a higher Zn(2+) MIC (P < 0.05). The odds of having a high Zn(2+) MIC (>=8 mM) were 14.66 times higher in isolates with R-type AmClStSuTe than in those with R-type AmStTeKm (P < 0.05). The findings demonstrate strong association between heavy metal tolerance and antimicrobial resistance, particularly among Salmonella serotypes important in public health. PMID- 24487543 TI - PerR-regulated manganese ion uptake contributes to oxidative stress defense in an oral streptococcus. AB - Metal homeostasis plays a critical role in antioxidative stress. Streptococcus oligofermentans, an oral commensal facultative anaerobe lacking catalase activity, produces and tolerates abundant H2O2, whereas Dpr (an Fe(2+)-chelating protein)-dependent H2O2 protection does not confer such high tolerance. Here, we report that inactivation of perR, a peroxide-responsive repressor that regulates zinc and iron homeostasis in Gram-positive bacteria, increased the survival of H2O2-pulsed S. oligofermentans 32-fold and elevated cellular manganese 4.5-fold. perR complementation recovered the wild-type phenotype. When grown in 0.1 to 0.25 mM MnCl2, S. oligofermentans increased survival after H2O2 stress 2.5- to 23 fold, and even greater survival was found for the perR mutant, indicating that PerR is involved in Mn(2+)-mediated H2O2 resistance in S. oligofermentans. Mutation of mntA could not be obtained in brain heart infusion (BHI) broth (containing ~0.4 MUM Mn(2+)) unless it was supplemented with >=2.5 MUM MnCl2 and caused 82 to 95% reduction of the cellular Mn(2+) level, while mntABC overexpression increased cellular Mn(2+) 2.1- to 4.5-fold. Thus, MntABC was identified as a high-affinity Mn(2+) transporter in S. oligofermentans. mntA mutation reduced the survival of H2O2-pulsed S. oligofermentans 5.7-fold, while mntABC overexpression enhanced H2O2-challenged survival 12-fold, indicating that MntABC-mediated Mn(2+) uptake is pivotal to antioxidative stress in S. oligofermentans. perR mutation or H2O2 pulsing upregulated mntABC, while H2O2 induced upregulation diminished in the perR mutant. This suggests that perR represses mntABC expression but H2O2 can release the suppression. In conclusion, this work demonstrates that PerR regulates manganese homeostasis in S. oligofermentans, which is critical to H2O2 stress defenses and may be distributed across all oral streptococci lacking catalase. PMID- 24487545 TI - Vibrio trends in the ecology of the Venice lagoon. AB - Vibrio is a very diverse genus that is responsible for different human and animal diseases. The accurate identification of Vibrio at the species level is important to assess the risks related to public health and diseases caused by aquatic organisms. The ecology of Vibrio spp., together with their genetic background, represents an important key for species discrimination and evolution. Thus, analyses of population structure and ecology association are necessary for reliable characterization of bacteria and to investigate whether bacterial species are going through adaptation processes. In this study, a population of Vibrionaceae was isolated from shellfish of the Venice lagoon and analyzed in depth to study its structure and distribution in the environment. A multilocus sequence analysis (MLSA) was developed on the basis of four housekeeping genes. Both molecular and biochemical approaches were used for species characterization, and the results were compared to assess the consistency of the two methods. In addition, strain ecology and the association between genetic information and environment were investigated through statistical models. The phylogenetic and population analyses achieved good species clustering, while biochemical identification was demonstrated to be imprecise. In addition, this study provided a fine-scale overview of the distribution of Vibrio spp. in the Venice lagoon, and the results highlighted a preferential association of the species toward specific ecological variables. These findings support the use of MLSA for taxonomic studies and demonstrate the need to consider environmental information to obtain broader and more accurate bacterial characterization. PMID- 24487546 TI - Social inequalities in early antidepressant discontinuation. AB - OBJECTIVE: This study aimed to test for social disparities in early discontinuation of antidepressant treatment and to explore associations with type of drug and composition of prescriber's clientele. METHODS: The cohort was 14,518 Marseille residents (ages 18-64 years) covered by the National Health Insurance Fund who had a new episode of antidepressant treatment (specifically, no prescription claim in the six months before the index claim) prescribed by a private general practitioner in 2008 or 2009. Factors associated with early discontinuation (prescription filled or refilled fewer than four times in the six months after the index claim) were analyzed with multilevel models that were adjusted for patient morbidity and number of consultations with private general practitioners and psychiatrists. Sensitivity analyses were conducted with different definitions of new treatment and early discontinuation. RESULTS: Low income, type of antidepressant (tricyclics versus selective serotonin reuptake inhibitors), and prescribers' clientele composition (specifically, a high proportion of socioeconomically disadvantaged patients) were independently associated with an increased risk of early antidepressant discontinuation. A significant interaction was found between low income and gender. Low-income patients were more likely than other patients to receive tricyclic antidepressants. CONCLUSIONS: These results add further evidence of inequalities in care for major depression and suggest that women are at greater disadvantage than men. Educational programs for general practitioners should focus on the risks of antidepressant discontinuation among disadvantaged patients. Enhancing therapeutic education of low-income patients may improve their treatment adherence. PMID- 24487544 TI - Polysaccharides and proteins added to flowing drinking water at microgram-per liter levels promote the formation of biofilms predominated by bacteroidetes and proteobacteria. AB - Biopolymers are important substrates for heterotrophic bacteria in (ultra)oligotrophic freshwater environments, but information about their utilization at microgram-per-liter levels by attached freshwater bacteria is lacking. This study aimed at characterizing biopolymer utilization in drinking water-related biofilms by exposing such biofilms to added carbohydrates or proteins at 10 MUg C liter(-1) in flowing tap water for up to 3 months. Individually added amylopectin was not utilized by the biofilms, whereas laminarin, gelatin, and caseinate were. Amylopectin was utilized during steady state biofilm growth with simultaneously added maltose but not with simultaneously added acetate. Biofilm formation rates (BFR) at 10 MUg C liter(-1) per substrate were ranked as follows, from lowest to highest: blank or amylopectin (<=6 pg ATP cm(-2) day(-1)), gelatin or caseinate, laminarin, maltose, acetate alone or acetate plus amylopectin, and maltose plus amylopectin (980 pg ATP cm(-2) day(-1)). Terminal restriction fragment length polymorphism (T RFLP) and 16S rRNA gene sequence analyses revealed that the predominant maltose utilizing bacteria also dominated subsequent amylopectin utilization, indicating catabolic repression and (extracellular) enzyme induction. The accelerated BFR with amylopectin in the presence of maltose probably resulted from efficient amylopectin binding to and hydrolysis by inductive enzymes attached to the bacterial cells. Cytophagia, Flavobacteriia, Gammaproteobacteria, and Sphingobacteriia grew during polysaccharide addition, and Alpha-, Beta-, and Gammaproteobacteria, Cytophagia, Flavobacteriia, and Sphingobacteriia grew during protein addition. The succession of bacterial populations in the biofilms coincided with the decrease in the specific growth rate during biofilm formation. Biopolymers can clearly promote biofilm formation at microgram-per-liter levels in drinking water distribution systems and, depending on their concentrations, might impair the biological stability of distributed drinking water. PMID- 24487547 TI - Cell kinetics, development of stomata and some effects of colchicine in barley. AB - The developmental sequence of the formation of stomatal complexes in the leaf epidermis of barley was studied. Cell-kinetic parameters were obtained from two genotypes - "Early Bonus" and eceriferum-g, a mutant with an abnormal stomatal pattern. The distribution of mitotic frequencies as a function of position in the stomatal rows was analyzed at each stage of development leading to mature stomata. Regression curves obtained for each stage showed that the distributions were stage-specific. Thus, the mitotic frequencies presented similar values throughout the portion of the file where the first asymmetrical divisions take place, had a parabolic distribution for the stage of subsidiary formation, and showed a linear shape, with a negative slope, for the stage of guard-mother-cell divisions. The mutant genotype differed from the normal by having a faster rate of ordinary guard-mother-cell divisions as a function of position in the row. The higher level of subsidiary cell formation in the mutant was interpreted as a consequence of a displacement of the used markers, suggesting a precocious initiation of subsidiary-cell formation in eceriferum-g. Time estimations of the length of the cell cycles were obtained by cell-population studies after a pulse with colchicine. Eceriferum-g appeared to have slower cell cycles. The leaves treated with colchicine showed a shift in the elongation axis of the cells. Autoradiography after treatment with (3)H-thymidine showed ineorporation of the label in the portions of the row proximal to all three peaks of divisions indicating that all mitoses were preceded by the usual period of DNA synthesis. Labelling of lateral cells at a mature stage suggested DNA synthesis leading to endoploidy. PMID- 24487548 TI - The effects of abscisic acid, kinetin and 5-fluorouracil on ribonucleic acid and protein synthesis in senescing radish leaf disks. AB - The effects of abscisic acid and kinetin on RNA synthesis in senescing radish leaf disks were investigated using the improved resolution afforded by polyacrylamide gel electrophoresis. Kinetin stimulated and abscisic acid inhibited incorporation of radioactivity into cytoplasmic ribosomal RNA and soluble RNA. Chloroplast ribosomal RNA synthesis appeared to be confined to the period of leaf expansion and was not detected in fully mature leaves. The effects of kinetin in retarding and of abscisic acid in accelerating leaf senescence were not altered by the inhibition of cytoplasmic ribosomal RNA synthesis with 5 fluorouracil. Following inhibition of cytoplasmic ribosomal RNA synthesis with 5 fluorouracil, kinetin stimulated and abscisic acid inhibited incorporation of radioactivity into polydisperse RNA. These results are discussed in relation to the possible mode of action of kinetin and abscisic acid in senescing leaf tissue. PMID- 24487549 TI - Further investigations into hormone-directed transport in stems. AB - The effect of IAA and three synthetic auxins on the upward movement of (32)P orthophosphate and (14)C-sucrose has been investigated in decapitated stems of Phaseolus vulgaris L., Pisum sativum L., Coleus blumci L. and Helianthus annuus L. IAA greatly enhanced the accumulation of (32)P-orthophosphate in Phaseolus vulgaris and Pisum sativum, whereas in C. blumei and H. annuus it did not. 2,4-D like IAA, caused an increase in (14)C-sucrose and (32)P-orthophosphate accumulation in Phaseolus vulgaris but, unlike IAA, caused no increase in Pisum sativum. The downward transport of (14)C-IAA, (14)C-NAA, (14)C-2,4-D and (14)C 2,4,5-T from the decapitated apex was also studied. Results are discussed in terms of current theories of hormone-directed transport. PMID- 24487550 TI - Development of spherical organelles from the endoplasmic reticulum in the nucellus of some Euphorbia species. AB - The development of characteristic cytoplasmic inclusions from endoplasmic reticulum (ER) cisternae in nucellar cells of some species of Euphorbia has been studied by electron microscopy. The formation of these organelles is preceded by the appearance of rough ER cisternae filled with an electron-dense material and forming complicated networks. Vesicular structures are formed which grow rapidly to give electron-dense, spherical dilations. On the outer surface of their limiting membrane numerous ribosomes and often polysomes are present. This membrane can be seen to remain continuous with the membranes of one or more cisternae of the rough ER up to when the dilations have a maximum diameter of 2.5 3 MU. At this time, continuity between the ER cisternae and the spherical dilations ceases. After this the new cell organelles remain unchanged in size, shape, and electron-density until the cell is disintegrated by the growing embryo sac. The fate of the contents of these organelles is discussed. PMID- 24487551 TI - Gibberellins and the photosensitivity of isolated embryos from non-stratified apple seeds. AB - The phytochrome system is responsible for the photosensitivity of dormant, isolated apple embryos in culture. Maximum photosensitivity occurs on the second day of culture and it is unaffected by gibberellins (GAs) in concentrations below 10(-4)M. Higher concentrations of GA decrease the photosensitivity.The endogenous quantities of GA4 and GA7 were determined in embryos grown at white light, in darkness and in darkness following an exposure to red light. The GA7 level remained unaffected by the light conditions, whereas the amount of GA4 was three times higher in light or red-light-treated cultures than in the dark grown ones.Similar experiments were done using AMO-1618, an inhibitor of GA biosynthesis, which is also a strong inhibitor of apple seed germination. In this case the level of both GA4 and GA7 was light-independent. These experiments suggest that the phytochrome system participates in the regulation of GAs biosynthesis by mediating one of the last steps of GA4 formation. PMID- 24487552 TI - [The incorporation of (32)PO 4 (---) into organic compounds in sieve tube sap]. AB - 1. Phloem exudates collected from the secondary phloem of Tilia platyphyllos, from the flower stalks of Yucca flaccida and from stems of Salix triandra (obtained by the aphid method) were incubated with (32)PO4 (---). The radioactivity was incorporated into a series of organic compounds very similar to those synthesized after the whole phloem is incubated with (32)PO4 (---). This synthetic ability of the exudate was completely destroyed by heating; therefore it is very probably due to enzymes. 2. ATP is one of the very first compounds labeled after incubation of the sieve tube sap with (32)PO4 (---). It already shows radioactivity after 10 sec. 3. The phloem exudate of Yucca flaccida does not lose the synthetic ability even after several hours of secretion. This indicates that the enzymes and the substrates for the phosphorylations are secreted continuously into the lumen of the sieve tubes. 4. The formation of the organic phosphorus compounds in the sieve tube sap is in accordance with the results of the enzyme analyses in this material (Kennecke et al., 1971). PMID- 24487553 TI - [Investigation of the light dependence of the uptake of rubidium, zinc, cobalt, lead and cerium by Chlorella by a flow method]. AB - A flow method for the measurement of the uptake of labelled substances by plant cells has been developed. Accumulation in the medium of substances released by the plants is thereby avoided, and a more precise determination of the rate of uptake-also of transients-than through the usual, static methods is possible. The time function of the stimulation of the uptake of Rb by Chlorella fusca by light at 30 degrees has been analyzed, and the component believed to represent active transport separated from other components that have shorter time constants; at 3 degrees the active component is much reduced.In the cases of the heavy metal ions Zn, Co, Pb and Ce, even after presaturation with the ions in the dark for the suppression of the short-term uptake the light-independent long-term uptake is far stronger than with Rb. Moreover, for Zn and Co the uptake is greatly stimulated by light at 30 degrees , but little if at all at 5 degrees . No stimulation was found under any conditions with Ce. With Pb, the light effect was hardly reproducible, and in any case extremely small. The energy-dependent transport of Zn and Co is probably active. PMID- 24487554 TI - The effect of light quality on the induction of apogamy in prothalli of Pteridium aquilinum. AB - Pteridium gametophytes cultured on a medium containing 4% sucrose under various qualities of light exhibit different developmental responses. Under far-red illumination (690-730 nm) apogamy is produced without enhanced gametophytic growth, thus allowing a distinct separation of the specific induction of apogamy from a general enhancement of gametophytic growth. PMID- 24487555 TI - Molecular weights of Cucurbita sieve tube proteins. AB - By means of SDS-polyacrylamide-gel electrophoresis, molecular weights of 15000, 28000, 59000, 116000 and 220000 were determined for the main sieve tube proteins from Cucurbita maxima. PMID- 24487556 TI - Finding balance between minimally invasive surgery and laryngotracheal resection in the management of adult laryngotracheal stenosis. AB - Management of adult laryngotracheal stenosis is complex and several treatment options are known. The present study focuses on finding the right balance between minimally invasive surgery and laryngotracheal resection by reviewing a single institution's experiences. Retrospective analysis was performed of all adult and adolescent patients with laryngotracheal stenosis who underwent treatment in a tertiary referral center, between 1990 and 2012. Age, gender, etiology, treatment, recurrence, pre- and post-operative peak flow (PF), and pre- and post treatment subjective complain scores (SCS) were registered. 87 patients with 267 interventions were analyzed. There were 238 dilatation tracheoscopies, 22 open surgeries and various other endoscopic procedures registered. Idiopathic stenoses required the most dilatation tracheoscopies, while post-tracheotomy stenoses required the least. Patients in the post-intubation and post-tracheotomy groups were significantly more often treated with open surgery compared to those in the granulomatosis with polyangiitis (GPA) and idiopathic groups. The gain in PF flow after dilatation tracheoscopy was significantly higher in the idiopathic group compared to the other groups. The median SCS of dyspnoea decreased in the whole population, while other SCS did not change remarkably. Repeated endoscopic procedures are recommended in patients with severe systemic disease which do not allow open surgery or when other comorbidities contraindicate open surgery. Open surgery very often offers the definitive solution in the treatment of laryngotracheal stenosis and cannot be avoided when the laryngeal or the tracheal framework is damaged. Patients' personal preferences have to be considered in the pre-operative assessment process. PMID- 24487557 TI - Surgical correction of scoliosis in Rett syndrome: cord monitoring and complications. AB - AIM: Rett syndrome is a progressive neurodevelopmental disorder that predominantly affects females and is associated with a high incidence of scoliosis and epilepsy. There is scant published work about intraoperative spinal cord monitoring in these patients and little more regarding the rate of perioperative complications. We investigated our institutions' experience with both. METHODS: We retrospectively reviewed the records of 11 patients with Rett syndrome who underwent surgical correction of scoliosis at our institution between 2004 and 2010. RESULTS: Eleven patients underwent successful correction of their scoliosis at an average age of 12. Eight of the patients suffered one or more significant complications. The average curve was corrected from 71 degrees to 27 degrees . Successful spinal cord monitoring was achieved in eight of the nine patients where it was attempted. No patient suffered any neurological complications. Average inpatient stay was 18.2 days. CONCLUSION: Scoliosis surgery in patients with Rett syndrome carries a very high rate of complications and an average hospital stay approaching 3 weeks. Both caregivers and surgeons should be aware of this when planning any intervention. These patients frequently have useful lower limb function and spinal cord monitoring is a valid tool to aid in its preservation. We would suggest aggressive optimisation of these patients prior to surgery, with an emphasis on nutrition. PMID- 24487559 TI - Reviewer's comment concerning "Calcified giant thoracic disc herniations- considerations and treatment strategies" (DOI 10.1007/s00586-014-3210-5 by N.A. Quraishi et al.). PMID- 24487560 TI - Harnessing the immune system to potentiate oncolytics. PMID- 24487558 TI - Surgical site infection in spinal surgery: a comparative study between 2-octyl cyanoacrylate and staples for wound closure. AB - BACKGROUND: Surgical site infection (SSI) after spinal surgery is a devastating complication. Various methods of skin closure are used in spinal surgery, but the optimal skin-closure method remains unclear. A recent report recommended against the use of metal staples for skin closure in orthopedic surgery. 2-Octyl cyanoacrylate (Dermabond; Ethicon, NJ, USA) has been widely applied for wound closure in various surgeries. In this cohort study, we assessed the rate of SSI in spinal surgery using metal staples and 2-octyl-cyanoacrylate for wound closure. METHODS: This study enrolled 609 consecutive patients undergoing spinal surgery in our hospital. From April 2007 to March 2010 surgical wounds were closed with metal staples (group 1, n = 294). From April 2010 to February 2012 skin closure was performed using 2-octyl-cyanoacrylate (group 2, n = 315). We assessed the rate of SSI using these two different methods of wound closure. Prospective study of the time and cost evaluation of wound closure was performed between two groups. RESULTS: Patients in the 2-octyl-cyanoacrylate group had more risk factors for SSI than those in the metal-staple group. Nonetheless, eight patients in the metal-staple group compared with none in the 2-octyl cyanoacrylate group acquired SSIs (p < 0.01). The closure of the wound in length of 10 cm with 2-octyl-cyanoacrylate could save 28 s and $13.5. CONCLUSIONS: This study reveals that in spinal surgery, wound closure using 2-octyl-cyanoacrylate was associated with a lower rate of SSI than wound closure with staples. Moreover, the use of 2-octyl-cyanoacrylate has a more time saving effect and cost effectiveness than the use of staples in wound closure of 10 cm in length. PMID- 24487563 TI - False-positive HIV PCR test following ex vivo lentiviral gene transfer treatment of X-linked severe combined immunodeficiency vector. PMID- 24487564 TI - There must be a way out of here: identifying a safe and efficient combination of promoter, transgene, and vector backbone for gene therapy of neurological disease. PMID- 24487565 TI - Development of preclinical models for immunogene therapy of brain cancer: it's not monkey business! PMID- 24487566 TI - One microRNA controls both angiogenesis and TLR-mediated innate immunity to nucleic acids. PMID- 24487567 TI - Crataegus pinnatifida: chemical constituents, pharmacology, and potential applications. AB - Crataegus pinnatifida (Hawthorn) is widely distributed in China and has a long history of use as a traditional medicine. The fruit of C. pinnatifida has been used for the treatment of cardiodynia, hernia, dyspepsia, postpartum blood stasis, and hemafecia and thus increasing interest in this plant has emerged in recent years. Between 1966 and 2013, numerous articles have been published on the chemical constituents, pharmacology or pharmacologic effects and toxicology of C. pinnatifida. To review the pharmacologic advances and to discuss the potential perspective for future investigation, we have summarized the main literature findings of these publications. So far, over 150 compounds including flavonoids, triterpenoids, steroids, monoterpenoids, sesquiterpenoids, lignans, hydroxycinnamic acids, organic acids and nitrogen-containing compounds have been isolated and identified from C. pinnatifida. It has been found that these constituents and extracts of C. pinnatifida have broad pharmacological effects with low toxicity on, for example, the cardiovascular, digestive, and endocrine systems, and pathogenic microorganisms, supporting the view that C. pinnatifida has favorable therapeutic effects. Thus, although C. pinnatifida has already been widely used as pharmacological therapy, due to its various active compounds, further research is warranted to develop new drugs. PMID- 24487570 TI - Recent developments in the application of nanomaterials to understanding molecular level processes in cobalt catalysed Fischer-Tropsch synthesis. AB - This perspective offers an overview of using nanomaterials for understanding cobalt catalysed Fischer-Tropsch chemistry. Nanomaterials now afford unprecedented control of size, shape and structure at the nanometre scale. This makes them invaluable tools for studying heterogeneous catalysis. The Fischer Tropsch reaction, especially using cobalt based catalysts, is a linchpin in many processes for utilising other feedstocks (via gasification) that have been envisaged as short/medium term replacements for crude oil. The underlying chemistry has therefore garnered considerable renewed interest. The current state of the art in mechanistic understanding is summarised and the application of nanomaterials to developing this further is explored. Several specific questions, to which nanomaterials have already contributed answers, are addressed: how do nanomaterials contribute to our understanding of cobalt particle size effects, reducibility, and the effect of support porosity and how do precious metal promoters operate in cobalt catalysed Fischer-Tropsch chemistry? Future possible uses for nanomaterials in studying this field are also identified. PMID- 24487568 TI - Synthesis and evaluation of poly(Sodium 2-Acrylamido-2-Methylpropane Sulfonate-co Styrene)/magnetite nanoparticle composites as corrosion inhibitors for steel. AB - Self-stabilized magnetic polymeric composite nanoparticles of coated poly-(sodium 2-acrylamido-2-methylpropane sulfonate-co-styrene)/magnetite (PAMPS-Na-co St/Fe3O4) were prepared by emulsifier-free miniemulsion polymerization using styrene (St) as a monomer, 2-acrylamido-2-methylpropane sulfonic acid sodium salt (AMPS-Na) as an ionic comonomer, N,N-methylenebisacrylamide (MBA) as crosslinker, hexadecane (HD) as a hydrophobic solvent, and 2,2-azodiisobutyronitrile (AIBN) as an initiator in the presence of hydrophobic oleic acid coated magnetite particles. Hydrophobic oleic acid coated magnetite particles with an average size of about 7-10 nm were prepared with the new modified water-based magnetite ferrofluid, synthesized by a chemical modified coprecipitation method. The morphology and the particle size distributions of the crosslinked PAMPS-Na-co St/Fe3O4 composite were observed and analyzed by transmission electron microscopy (TEM). The average Fe3O4 content of PAMPS-Na-co-St/Fe3O4 was determined by thermogravimetric analysis (TGA). The inhibitory action of PAMPS-Na-co-St/Fe3O4 towards steel corrosion in 1 M HCl solutions has been investigated by polarization and electrochemical impedance spectroscopy (EIS) methods. Polarization measurements indicate that PAMPS-Na-co-St/Fe3O4 acts as a mixed type inhibitor and the inhibition efficiency increases with inhibitor concentration. The results of potentiodynamic polarization and EIS measurements clearly showed that the inhibition mechanism involves blocking of the steel surface by inhibitor molecules via adsorption. PMID- 24487571 TI - Pharmacologic inhibition of L-tyrosine degradation ameliorates cerebral dopamine deficiency in murine phenylketonuria (PKU). AB - Monoamine neurotransmitter deficiency has been implicated in the etiology of neuropsychiatric symptoms associated with chronic hyperphenylalaninemia in phenylketonuria (PKU). Two proposed explanations for neurotransmitter deficiency in PKU include first, that chronically elevated blood L-phenylalanine (Phe) inhibits the transport of L-tyrosine (Tyr) and L-tryptophan (Trp), the substrates for dopamine and serotonin synthesis respectively, into brain. In the second hypothesis, elevated Phe competitively inhibits brain tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) activities, the rate limiting steps in dopamine and serotonin synthesis. Dietary supplementation with large neutral amino acids (LNAA) including Tyr and Trp has been recommended for individuals with chronically elevated blood Phe in an attempt to restore amino acid and monoamine homeostasis in brain. As a potential alternative treatment approach, we demonstrate that pharmacologic inhibition of Tyr degradation through oral administration of nitisinone (NTBC) yielded sustained increases in blood and brain Tyr, decreased blood and brain Phe, and consequently increased dopamine synthesis in a murine model of PKU. Our results suggest that Phe-mediated inhibition of TH activity is the likely mechanism of impaired dopamine synthesis in PKU. Pharmacologic inhibition of Tyr degradation may be a promising adjunct therapy for CNS monoamine neurotransmitter deficiency in hyperphenylalaninemic individuals with PKU. PMID- 24487572 TI - Chronic pain in patients with the hypermobility type of Ehlers-Danlos syndrome: evidence for generalized hyperalgesia. AB - Chronic widespread pain is highly present in patients with the Ehlers-Danlos syndrome hypermobility type (EDS-HT), but up to now, evidence for generalized hyperalgesia is lacking. The aim of this study is to investigate whether pressure pain thresholds (PPTs) at both symptomatic and asymptomatic body areas differ in EDS-HT patients compared to healthy subjects. Twenty-three women with EDS-HT and 23 gender- and age-matched healthy controls participated. All subjects marked on Margolis Pain Diagram where they felt pain lasting longer than 24 h in the past 4 weeks. Then, they completed several questionnaires assessing pain cognitions, fatigue, disability, and general health status, in order to take the possible influence of these factors on PPTs into account. Patients also completed a form concerning the type of pain they experienced. Thereupon, a blinded researcher assessed PPTs at 14 body locations on the trunk and extremities. PPTs were compared for the two complete groups. In addition, PPTs of patients and controls who did not report pain in a respective zone were compared. PPTs of the patients were significantly lower compared to those of the control group, also when pain free samples per zone were compared. The mean (SD) PPT was 2.9 (1.62) kg/cm(2) in the EDS-HT patients and 5.2 (1.88) kg/cm(2) in the controls (P < 0.001). No confounding factors responsible for the observed differences could be revealed. In half of the patient group, a predominantly neuropathic pain component was likely present. This study provides evidence for the existence of hyperalgesia even in asymptomatic areas (generalized secondary hyperalgesia). The generalized hyperalgesia may represent the involvement of a sensitized central nervous system, which inquires an adapted pain management for this patient group. PMID- 24487573 TI - Simulation of dosimetric consequences of 4D-CT-based motion margin estimation for proton radiotherapy using patient tumor motion data. AB - For the radiation treatment of lung cancer patients, four-dimensional computed tomography (4D-CT) is a common practice used clinically to image tumor motion and subsequently determine the internal target volume (ITV) from the maximum intensity projection (MIP) images. ITV, which is derived from short pre-treatment 4D-CT scan (<6 s per couch position), may not adequately cover the extent of tumor motion during the treatment, particularly for patients that exhibit a large respiratory variability. Inaccurate tumor localization may result in under-dosage of the tumor or over-dosage of the surrounding tissues. The purpose of this study is therefore to assess the degree of tumor under-dosage in case of regular and irregular breathing for proton radiotherapy using ITV-based treatment planning. We place a spherical lesion into a modified XCAT phantom that is also capable of producing 4D images based on irregular breathing, and move the tumor according to real tumor motion data, which is acquired over multiple days by tracking gold fiducial markers implanted into the lung tumors of patients. We derive ITVs by taking the union of all tumor positions during 6 s of tumor motion in the phantom using the first day patient tumor tracking data. This is equivalent to ITVs generated clinically from cine-mode 4D-CT MIP images. The treatment plans created for different ITVs are then implemented on dynamic phantoms with tumor motion governed by real tumor tracking data from consecutive days. By comparing gross tumor volume dose distribution on days of 'treatment' with the ITV dose distribution, we evaluate the deviation of the actually delivered dose from the predicted dose. Our results have shown that the proton treatment planning on ITV derived from pre-treatment cine-mode 4D-CT can result in under-dosage (dose covering 95% of volume) of the tumor by up to 25.7% over 3 min of treatment for the patient with irregular respiratory motion. Tumor under-dosage is less significant for the patient with relatively regular breathing. We have demonstrated that proton therapy using the pre-treatment 4D-CT based ITV method can lead to significant under-dosage of the tumor, highlighting the need for daily customization to generate a target volume that represents tumor positions during the treatment more accurately. PMID- 24487574 TI - Shaker IR T449 mutants separate C- from U-type inactivation. AB - Previous studies demonstrated that slow inactivation of the Shaker potassium channel can be made ~100-fold faster or slower by point mutations at a site in the outer pore (T449). However, the discovery that two forms of slow inactivation coexist in Shaker raises the question of which inactivation process is affected by mutation. Equivalent mutations in K(V)2.1, a channel exhibiting only U-type inactivation, have minimal effects on inactivation, suggesting that mutation of Shaker T449 acts on C-type inactivation alone, a widely held yet untested hypothesis. This study reexamines mutations at Shaker T449, confirming that T449A speeds inactivation and T449Y/V slow it. T449Y and T449V exhibit U-type inactivation that is enhanced by high extracellular potassium, in contrast to C type inactivation in T449A which is inhibited by high potassium. Automated parameter estimation for a 12-state Markov model suggests that U-type inactivation occurs mainly from closed states upon weak depolarization, but primarily from the open state at positive voltages. The model also suggests that WT channels, which in this study exhibit mostly C-type inactivation, recover from inactivation through closed-inactivated states, producing voltage-dependent recovery. This suggests that both C-type and U-type inactivation involve both open-inactivated and closed-inactivated states. PMID- 24487576 TI - Long Term Neuropsychological Follow-up in Patients With Herpes Simplex Encephalitis and Predominantly Left-sided Lesions. AB - Five patients with predominantly dominant cerebral hemisphere lesions due to herpes simplex encephalitis are described. Verbal amnesia was the main deficit but amnesic aphasia sometimes associated with impairment of remote memory also occurred. Semantic and episodic memory deficits were also explored in one case and the role of the right cerebral hemisphere in facilitating recovery of learning is discussed. PMID- 24487575 TI - Novel one-pot fabrication of lab-on-a-bubble@Ag substrate without coupling-agent for surface enhanced Raman scattering. AB - Through in-situ reduction of silver nitrate without using any coupling-agent, a substrate for surface-enhanced Raman scattering (SERS) was prepared by coating silver on hollow buoyant silica microspheres as a lab on a bubble (LoB). The silver coated LoBs (LoBs@Ag) floated on surface of a solution could provide a very convenient platform for the detection of target molecules in the solution. The LoBs@Ag substrate not only immobilized well-distributed Ag nanoparticles on the surface LoBs, but excluded the interference of coupling agents. This yielded high-resolution SERS spectra with excellent reproducibility. The adsorption of crystal violet (CV) on the LoBs@Ag substrate was investigated by means of SERS combined with density functional theory (DFT) calculations. The LoBs@Ag substrate exhibited a remarkable Raman enhancement effect for CV with an enhancement factor of 6.9 * 10(8) and wide adaptability from dye, pesticide to bio-molecules. On the basis of this substrate, a simple and sensitive SERS method was proposed for the determination of trace organic pollutants or bio-molecules. PMID- 24487577 TI - Long-term Perseveration in Alzheimer's Disease: A Case Report. AB - The most common clinical sign of Alzheimer's disease (AD) is progressive memory loss. Presented here is a case of AD who, despite ultimate profound dementia with severe amnesia, showed retention of a perseverative response she developed during 26 encounters, over 4.5 years, with the Brown-Peterson distractor test. From Test 9 onwards, she responded from the first distractor-filled trial with one consonant trigram, appearing in none of the seven test forms given her. At Test 26, she could not repeat heard trigrams yet faithfully responded with her perseverative trigram. The trigram, ostensibly declarative information, apparently became part and parcel of the task's procedure. Although perseveration is a form of impairment probably resulting from Alzheimer pathology involving frontal and parietal cortex, it may also reflect a form of preserved memory, albeit distorted, supported by posterior cortical regions spared in AD. PMID- 24487578 TI - Autobiographical memory in normal ageing and dementia. AB - Autobiographical memories in young and elderly normal subjects are drawn mostly from the recent past but elderly subjects relate a second peak of memories from early adulthood. Memory for remote past public events is relatively preserved in dementia, possibly reflecting integrity of semantic relative to episodic memory. We examined recall of specific, consistent autobiographical episodes in Alzheimer's disease (AD) in response to cue words. Patients and control subjects drew most memories from the recent 20 years: episode age related to anterograde memory function but not subject age or dementia. Subjects also related a secondary peak of memories from early adulthood; episode age related to subject age and severity of dementia. The results suggest that preferential recall of memories from early adulthood is based on the salience of retrieval cues, altered by age and dementia, superimposed on a temporal gradient of semantic memory. Further, AD shows behavioural similarity to normal ageing. PMID- 24487579 TI - Posterior fossa tumours presenting to psychiatrists. AB - Posterior fossa tumours may in their early stages give rise to dizziness, nausea and subjective unsteadiness. Such symptoms are commonly accompanied by psychological distress and are not always easy to diagnose. In the presence of a past psychiatric history, they may be wrongly interpreted as exacerbations of neurotic disorder. Two examples of this are given. Because of the commonness of vestibular symptoms and the rapid growth of these tumours, a normal scan early in the history may be misleading. PMID- 24487580 TI - Matching Top-Bottom Parts of Facial Expressions by Brain-damaged Patients. AB - Patients with focal brain-damage, right/left hemisphere-damage (RHD/LHD) and anterior/posterior region-damage (ARD/PRD), and normal controls (NC) were asked to match photographs of top-bottom facial parts expressing different emotions, positive (happy, surprise), negative-aroused (fear, anger), negative-nonaroused (sad, disgust). The LHD patients performed significantly worse than the RHD patients, and the ARD patients were significantly worse than the PRD patients, in the perceptual-matching task with affective stimuli. NC subjects performed significantly better than any of the brain damaged sub-groups. PMID- 24487581 TI - Transient stuttering in catatonic bipolar patients. AB - Two cases of transient stuttering occurring in association with catatonia and bipolar disorder are described. Affective decompensation has been associated with lateralized cerebral dysfunction, and it is hypothesized that in some bipolar catatonic patients a concomitant disorder of the lateralization of language function may lead to a variety of clinical presentations including aphasia, mutism, and stuttering. PMID- 24487582 TI - Minimal, encapsulated proteomic-sample processing applied to copy-number estimation in eukaryotic cells. AB - Mass spectrometry (MS)-based proteomics typically employs multistep sample preparation workflows that are subject to sample contamination and loss. We report an in-StageTip method for performing sample processing, from cell lysis through elution of purified peptides, in a single, enclosed volume. This robust and scalable method largely eliminates contamination or loss. Peptides can be eluted in several fractions or in one step for single-run proteome analysis. In one day, we obtained the largest proteome coverage to date for budding and fission yeast, and found that protein copy numbers in these cells were highly correlated (R(2) = 0.78). Applying the in-StageTip method to quadruplicate measurements of a human cell line, we obtained copy-number estimates for 9,667 human proteins and observed excellent quantitative reproducibility between replicates (R(2) = 0.97). The in-StageTip method is straightforward and generally applicable in biological or clinical applications. PMID- 24487584 TI - Functional annotation of noncoding sequence variants. AB - Identifying functionally relevant variants against the background of ubiquitous genetic variation is a major challenge in human genetics. For variants in protein coding regions, our understanding of the genetic code and splicing allows us to identify likely candidates, but interpreting variants outside genic regions is more difficult. Here we present genome-wide annotation of variants (GWAVA), a tool that supports prioritization of noncoding variants by integrating various genomic and epigenomic annotations. PMID- 24487583 TI - Multiplexed 3D cellular super-resolution imaging with DNA-PAINT and Exchange PAINT. AB - Super-resolution fluorescence microscopy is a powerful tool for biological research, but obtaining multiplexed images for a large number of distinct target species remains challenging. Here we use the transient binding of short fluorescently labeled oligonucleotides (DNA-PAINT, a variation of point accumulation for imaging in nanoscale topography) for simple and easy-to implement multiplexed super-resolution imaging that achieves sub-10-nm spatial resolution in vitro on synthetic DNA structures. We also report a multiplexing approach (Exchange-PAINT) that allows sequential imaging of multiple targets using only a single dye and a single laser source. We experimentally demonstrate ten-color super-resolution imaging in vitro on synthetic DNA structures as well as four-color two-dimensional (2D) imaging and three-color 3D imaging of proteins in fixed cells. PMID- 24487585 TI - Angiotensin-converting enzyme overexpression in myelomonocytes prevents Alzheimer's-like cognitive decline. AB - Cognitive decline in patients with Alzheimer's disease (AD) is associated with elevated brain levels of amyloid beta protein (Abeta), particularly neurotoxic Abeta(1-42). Angiotensin-converting enzyme (ACE) can degrade Abeta(1-42), and ACE overexpression in myelomonocytic cells enhances their immune function. To examine the effect of targeted ACE overexpression on AD, we crossed ACE(10/10) mice, which overexpress ACE in myelomonocytes using the c-fms promoter, with the transgenic APP(SWE)/PS1(DeltaE9) mouse model of AD (AD+). Evaluation of brain tissue from these AD+ACE(10/10) mice at 7 and 13 months revealed that levels of both soluble and insoluble brain Abeta(1-42) were reduced compared with those in AD+ mice. Furthermore, both plaque burden and astrogliosis were drastically reduced. Administration of the ACE inhibitor ramipril increased Abeta levels in AD+ACE(10/10) mice compared with the levels induced by the ACE-independent vasodilator hydralazine. Overall, AD+ACE(10/10) mice had less brain-infiltrating cells, consistent with reduced AD-associated pathology, though ACE-overexpressing macrophages were abundant around and engulfing Abeta plaques. At 11 and 12 months of age, the AD+ACE(10/WT) and AD+ACE(10/10) mice were virtually equivalent to non AD mice in cognitive ability, as assessed by maze-based behavioral tests. Our data demonstrate that an enhanced immune response, coupled with increased myelomonocytic expression of catalytically active ACE, prevents cognitive decline in a murine model of AD. PMID- 24487586 TI - Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis. AB - Mutations of the tumor suppressor TP53 are present in many forms of human cancer and are associated with increased tumor cell invasion and metastasis. Several mechanisms have been identified for promoting dissemination of cancer cells with TP53 mutations, including increased targeting of integrins to the plasma membrane. Here, we demonstrate a role for the filopodia-inducing motor protein Myosin-X (Myo10) in mutant p53-driven cancer invasion. Analysis of gene expression profiles from 2 breast cancer data sets revealed that MYO10 was highly expressed in aggressive cancer subtypes. Myo10 was required for breast cancer cell invasion and dissemination in multiple cancer cell lines and murine models of cancer metastasis. Evaluation of a Myo10 mutant without the integrin-binding domain revealed that the ability of Myo10 to transport beta1 integrins to the filopodia tip is required for invasion. Introduction of mutant p53 promoted Myo10 expression in cancer cells and pancreatic ductal adenocarcinoma in mice, whereas suppression of endogenous mutant p53 attenuated Myo10 levels and cell invasion. In clinical breast carcinomas, Myo10 was predominantly expressed at the invasive edges and correlated with the presence of TP53 mutations and poor prognosis. These data indicate that Myo10 upregulation in mutant p53-driven cancers is necessary for invasion and that plasma-membrane protrusions, such as filopodia, may serve as specialized metastatic engines. PMID- 24487587 TI - Hyaluronan digestion controls DC migration from the skin. AB - The breakdown and release of hyaluronan (HA) from the extracellular matrix has been hypothesized to act as an endogenous signal of injury. To test this hypothesis, we generated mice that conditionally overexpressed human hyaluronidase 1 (HYAL1). Mice expressing HYAL1 in skin either during early development or by inducible transient expression exhibited extensive HA degradation, yet displayed no evidence of spontaneous inflammation. Further, HYAL1 expression activated migration and promoted loss of DCs from the skin. We subsequently determined that induction of HYAL1 expression prior to topical antigen application resulted in a lack of an antigenic response due to the depletion of DCs from the skin. In contrast, induction of HYAL1 expression concurrent with antigen exposure accelerated allergic sensitization. Administration of HA tetrasaccharides, before or simultaneously with antigen application, recapitulated phenotypes observed in HYAL1-expressing animals, suggesting that the generation of small HA fragments, rather than the loss of large HA molecules, promotes DC migration and subsequent modification of allergic responses. Furthermore, mice lacking TLR4 did not exhibit HA-associated phenotypes, indicating that TLR4 mediates these responses. This study provides direct evidence that HA breakdown controls the capacity of the skin to present antigen. These events may influence DC function in injury or disease and have potential to be exploited therapeutically for modification of allergic responses. PMID- 24487589 TI - Chemical chaperone ameliorates pathological protein aggregation in plectin deficient muscle. AB - The ubiquitously expressed multifunctional cytolinker protein plectin is essential for muscle fiber integrity and myofiber cytoarchitecture. Patients suffering from plectinopathy-associated epidermolysis bullosa simplex with muscular dystrophy (EBS-MD) and mice lacking plectin in skeletal muscle display pathological desmin-positive protein aggregation and misalignment of Z-disks, which are hallmarks of myofibrillar myopathies (MFMs). Here, we developed immortalized murine myoblast cell lines to examine the pathogenesis of plectinopathies at the molecular and single cell level. Plectin-deficient myotubes, derived from myoblasts, were fully functional and mirrored the pathological features of EBS-MD myofibers, including the presence of desmin positive protein aggregates and a concurrent disarrangement of the myofibrillar apparatus. Using this cell model, we demonstrated that plectin deficiency leads to increased intermediate filament network and sarcomere dynamics, marked upregulation of HSPs, and reduced myotube resilience following mechanical stretch. Currently, no specific therapy or treatment is available to improve plectin-related or other forms of MFMs; therefore, we assessed the therapeutic potential of chemical chaperones to relieve plectinopathies. Treatment with 4 phenylbutyrate resulted in remarkable amelioration of the pathological phenotypes in plectin-deficient myotubes as well as in plectin-deficient mice. Together, these data demonstrate the biological relevance of the MFM cell model and suggest that this model has potential use for the development of therapeutic approaches for EBS-MD. PMID- 24487588 TI - HSC commitment-associated epigenetic signature is prognostic in acute myeloid leukemia. AB - Acute myeloid leukemia (AML) is characterized by disruption of HSC and progenitor cell differentiation. Frequently, AML is associated with mutations in genes encoding epigenetic modifiers. We hypothesized that analysis of alterations in DNA methylation patterns during healthy HSC commitment and differentiation would yield epigenetic signatures that could be used to identify stage-specific prognostic subgroups of AML. We performed a nano HpaII-tiny-fragment-enrichment by-ligation-mediated-PCR (nanoHELP) assay to compare genome-wide cytosine methylation profiles between highly purified human long-term HSC, short-term HSC, common myeloid progenitors, and megakaryocyte-erythrocyte progenitors. We observed that the most striking epigenetic changes occurred during the commitment of short-term HSC to common myeloid progenitors and these alterations were predominantly characterized by loss of methylation. We developed a metric of the HSC commitment-associated methylation pattern that proved to be highly prognostic of overall survival in 3 independent large AML patient cohorts, regardless of patient treatment and epigenetic mutations. Application of the epigenetic signature metric for AML prognosis was superior to evaluation of commitment-based gene expression signatures. Together, our data define a stem cell commitment associated methylome that is independently prognostic of poorer overall survival in AML. PMID- 24487590 TI - TSHZ1-dependent gene regulation is essential for olfactory bulb development and olfaction. AB - The olfactory bulb (OB) receives odor information from the olfactory epithelium and relays this to the olfactory cortex. Using a mouse model, we found that development and maturation of OB interneurons depends on the zinc finger homeodomain factor teashirt zinc finger family member 1 (TSHZ1). In mice lacking TSHZ1, neuroblasts exhibited a normal tangential migration to the OB; however, upon arrival to the OB, the neuroblasts were distributed aberrantly within the radial dimension, and many immature neuroblasts failed to exit the rostral migratory stream. Conditional deletion of Tshz1 in mice resulted in OB hypoplasia and severe olfactory deficits. We therefore investigated olfaction in human subjects from families with congenital aural atresia that were heterozygous for TSHZ1 loss-of-function mutations. These individuals displayed hyposmia, which is characterized by impaired odor discrimination and reduced olfactory sensitivity. Microarray analysis, in situ hybridization, and ChIP revealed that TSHZ1 bound to and regulated expression of the gene encoding prokineticin receptor 2 (PROKR2), a G protein-coupled receptor essential for OB development. Mutations in PROKR2 lead to Kallmann syndrome, characterized by anosmia and hypogonadotrophic hypogonadism. Our data indicate that TSHZ1 is a key regulator of mammalian OB development and function and controls the expression of molecules involved in human Kallmann syndrome. PMID- 24487591 TI - Relative acidic compartment volume as a lysosomal storage disorder-associated biomarker. AB - Lysosomal storage disorders (LSDs) occur at a frequency of 1 in every 5,000 live births and are a common cause of pediatric neurodegenerative disease. The relatively small number of patients with LSDs and lack of validated biomarkers are substantial challenges for clinical trial design. Here, we evaluated the use of a commercially available fluorescent probe, Lysotracker, that can be used to measure the relative acidic compartment volume of circulating B cells as a potentially universal biomarker for LSDs. We validated this metric in a mouse model of the LSD Niemann-Pick type C1 disease (NPC1) and in a prospective 5-year international study of NPC patients. Pediatric NPC subjects had elevated acidic compartment volume that correlated with age-adjusted clinical severity and was reduced in response to therapy with miglustat, a European Medicines Agency approved drug that has been shown to reduce NPC1-associated neuropathology. Measurement of relative acidic compartment volume was also useful for monitoring therapeutic responses of an NPC2 patient after bone marrow transplantation. Furthermore, this metric identified a potential adverse event in NPC1 patients receiving i.v. cyclodextrin therapy. Our data indicate that relative acidic compartment volume may be a useful biomarker to aid diagnosis, clinical monitoring, and evaluation of therapeutic responses in patients with lysosomal disorders. PMID- 24487593 TI - Immunostaining for polycomb group protein EZH2 and senescent marker p16INK4a may be useful to differentiate cholangiolocellular carcinoma from ductular reaction and bile duct adenoma. AB - Intrahepatic cholangiocarcinoma arising in chronic advanced liver disease sometimes contains a component of cholangiolocellular carcinoma. Bile duct adenoma, a benign tumor/tumorous lesion and ductular reaction, is also composed of bile ductular cells, and the differential diagnosis is sometimes difficult. We have previously reported that cholangiolocellular carcinoma showed overexpression of a polycomb group protein EZH2, which participates in bypass/escape from cellular senescence during carcinogenesis. In contrast, the ductular reaction showed high expression of senescence-associated p16(INK4a). In this study, we examined whether immunostaining for EZH2 and p16(INK4a) is useful for differential diagnosis among cholangiolocellular carcinoma, bile duct adenoma, and ductular reactions. Subjects included 33 patients with intrahepatic cholangiocarcinoma and combined hepatocellular-cholangiocarcinoma with components of cholangiolocellular carcinoma and 16 patients with bile duct adenoma. The expressions of EZH2 and p16(INK4a) were examined immunohistochemically. The expression of EZH2 was seen in all cases of cholangiolocellular carcinomas, but it was not observed in bile duct adenomas and ductular reactions, which were seen around carcinomas in 80% of cases. The extensive expression of p16(INK4a) was seen only in 4 cases of cholangiolocellular carcinomas (12%). In contrast, the expression of p16(INK4a) was seen in 13 cases (81%) of bile duct adenomas and in all cases of ductular reactions. The borderline between the component of cholangiolocellular carcinoma and the surrounding ductular reaction was clearly highlighted by the reverse expression pattern of EZH2 and p16(INK4a) in 69% of cases. In conclusion, immunostaining for EZH2 and p16(INK4a) may be useful for differential diagnosis among cholangiolocellular carcinomas, bile duct adenomas, and ductular reactions. PMID- 24487594 TI - A profession in transition. PMID- 24487592 TI - Long-lived intestinal tuft cells serve as colon cancer-initiating cells. AB - Doublecortin-like kinase 1 protein (DCLK1) is a gastrointestinal tuft cell marker that has been proposed to identify quiescent and tumor growth-sustaining stem cells. DCLK1+ tuft cells are increased in inflammation-induced carcinogenesis; however, the role of these cells within the gastrointestinal epithelium and their potential as cancer-initiating cells are poorly understood. Here, using a BAC CreERT-dependent genetic lineage-tracing strategy, we determined that a subpopulation of DCLK1+ cells is extremely long lived and possesses rare stem cell abilities. Moreover, genetic ablation of Dclk1 revealed that DCLK1+ tuft cells contribute to recovery following intestinal and colonic injury. Surprisingly, conditional knockdown of the Wnt regulator APC in DCLK1+ cells was not sufficient to drive colonic carcinogenesis under normal conditions; however, dextran sodium sulfate-induced (DSS-induced) colitis promoted the development of poorly differentiated colonic adenocarcinoma in mice lacking APC in DCLK1+ cells. Importantly, colonic tumor formation occurred even when colitis onset was delayed for up to 3 months after induced APC loss in DCLK1+ cells. Thus, our data define an intestinal DCLK1+ tuft cell population that is long lived, quiescent, and important for intestinal homeostasis and regeneration. Long-lived DCLK1+ cells maintain quiescence even following oncogenic mutation, but are activated by tissue injury and can serve to initiate colon cancer. PMID- 24487595 TI - Dentistry is changing: leaders needed. PMID- 24487596 TI - Boomers and rehabs. PMID- 24487597 TI - Crown placement. PMID- 24487598 TI - More about crowns. PMID- 24487599 TI - Restoration overload? PMID- 24487600 TI - Author's response. PMID- 24487601 TI - Questioning chiropractics. PMID- 24487602 TI - More about chiropractics. PMID- 24487603 TI - Response from the JADA Editor and the Associate Editor, Research. PMID- 24487604 TI - Designing a safety checklist for dental implant placement: a Delphi study. AB - BACKGROUND: Complications during and after dental implant placement can be a hindrance to successful treatment. Checklists are emerging as useful tools in error reduction in various fields. The authors selected a Delphi panel to explore the appropriate clinical practices involved in implant placement, with the objective of formulating a safety checklist that would aid in reducing errors. METHODS: The authors administered a Delphi method survey to an expert panel of 24 board-certified periodontists to determine if consensus existed regarding the critical steps involved in implant placement. They defined consensus as 90 percent agreement among participants. Using the Delphi data, the authors designed a safety checklist for implant placement. RESULTS: The panelists generated 20 consensus statements regarding essential steps in implant placement. The authors divided the statements into preoperative, intraoperative and postoperative phases. To determine the rationale for consensus decisions, the authors conducted a thematic qualitative analysis of responses to all open-ended questionnaire items, asking panel members how or why a particular procedure was performed. CONCLUSION: The panelists reached a consensus regarding the steps they considered critical in implant placement. Further research is needed to assess the acceptance and effectiveness of this type of checklist in a clinical setting. Practical Implications. The authors developed a checklist that may be useful in reducing errors in placement of dental implants. If effective, this checklist ultimately will aid in minimizing risk and increasing implant success rates, especially for inexperienced practitioners, dental students, surgical residents and dental implant trainees (that is, dentists undergoing training to place implants through continuing education courses). PMID- 24487605 TI - Parents' understanding of and accuracy in using measuring devices to administer liquid oral pain medication. AB - BACKGROUND: Dentists recommend over-the-counter medications for postoperative pain in children, and parents often make dosing errors when administering these medications. The authors compared the dosing accuracy when parents used various measuring devices and aimed to identify risk factors associated with dosing errors. METHODS: The authors recruited parent-child pairs visiting the Pediatric Clinic at the College of Dentistry at The University of Tennessee Health Science Center, Memphis, and three private dental offices. The parents completed a survey and a liquid measuring exercise. The authors instructed parents to measure 5 milliliters of liquid by using a medicine cup with clear markings, a medicine cup with printed markings, a cylindrical measuring spoon and an oral syringe. For the medicine cup with printed markings, the authors placed the parents randomly into one of two groups: those receiving text-only instructions or those receiving text pictogram instructions. The authors weighed each device before and after the measuring exercise and compared the difference in weight with a reference weight of 5 mL. RESULTS: A total of 120 parent-child pairs participated. The results of a McNemar test revealed a significant difference in parents' ability to measure accurate doses with the various devices. The results of a Pearson chi(2) test showed no statistically significant difference between the control and study groups for dosing accuracy. The chi(2) analysis results showed no significant differences in risk factors that could be associated with dosing errors. CONCLUSIONS: Medicine cups were the devices parents reported using most frequently. Medicine cups had a higher occurrence of dosing errors when compared with the other devices. No sociodemographic factors were associated with dosing errors. Practical Implications. Dentists can improve pain management in pediatric patients by educating parents about accurate measuring devices, weight-based dosing and correct interpretation of medication dosing charts. PMID- 24487606 TI - Community factors predicting dental care utilization among older adults. AB - BACKGROUND: Few investigators have studied the influence of community factors on dental care utilization among older adults. The authors' objective in this study was to investigate the effect of community factors on dental care utilization after adjustment for individual factors. METHODS: Using data from a cross sectional survey of Ohio residents, the authors assessed dental care utilization in a sample of 2,166 adults 65 years or older. They linked individual-level dental care utilization, predisposing factors (age, sex, race or ethnicity, marital status, education), enabling factors (poverty, dental insurance) and need related factors (physical and mental health problems) with county-level data (socioeconomic environment and health resource environment) from the 2010 Area Health Resource Files (from the U.S. Department of Health and Human Services) and the American Community Survey (from the 2006-2010 U.S. census). By using multilevel logistic regression models, the authors evaluated the association between dental care utilization and community factors after adjustment for individual factors. RESULTS: The results indicated that individual factors such as being female, married and nonpoor and having a higher educational level and private dental insurance were associated with higher odds of having utilized dental care. Furthermore, older adults living in a county with a higher dentist to-population ratio were more likely to use dental services even after the authors adjusted the results for the individual-level factors (odds ratio = 1.10; P = .03). CONCLUSIONS: County-level dentist-to-population ratio has independent effects on older adults' dental care utilization even after adjustment for individual-level characteristics. Practical Implications. A comprehensive policy plan is required to intervene at both the individual and community levels to improve dental care utilization among older adults. By understanding the factors influencing dental care utilization among older adults, U.S. dentists will be better positioned to meet the dental needs of this population. PMID- 24487607 TI - Strategies for communicating with older dental patients. AB - BACKGROUND: Communication between dentists and patients 65 years or older is a critical aspect of providing optimum care, particularly given the increasing number of older adults and the communication barriers they often encounter. METHODS: The authors conducted a targeted literature review of the broad health communication literature and published health literacy guidelines to examine the barriers to effective communication that are specific to the older adult population, as well as strategies for overcoming these barriers. RESULTS: Findings from health communication and health literacy research provide insight into techniques to improve communication with older patients, such as preparing an agenda for the appointment, exhibiting warm nonverbal behavior, listening attentively, asking open-ended questions, using simple language, presenting key points one at a time and providing patients with written instructions. CONCLUSIONS: Physical, psychological and literacy issues pertaining to both patients and providers present barriers to effective communication. Practitioners can surmount these barriers by enacting communication strategies tailored to older adults. Practical Implications. Dentists can overcome barriers to communication and improve the quality of patient care by considering the communication barriers specific to older adults and enacting strategies to overcome these barriers. PMID- 24487608 TI - Diagnostic capability of questionnaires and clinical examinations to assess sleep disordered breathing in children: a systematic review and meta-analysis. AB - BACKGROUND: The reference standard for the diagnosis of pediatric sleep-disorder breathing (SDB) is a full polysomnography (PSG) (an overnight sleep study). There are many obstacles to children being able to undergo a full PSG; therefore, the authors evaluated the diagnostic value of alternative diagnostic methods (clinical history and physical examination) for pediatric SDB. TYPES OF STUDIES REVIEWED: The authors selected articles in which the investigators' primary objective was to evaluate the diagnostic capability of physical evaluations and questionnaires compared with the current reference standard (that is, a full PSG) to diagnose SDB in children younger than 18 years. The authors searched several electronic databases without limitations. RESULTS: Using a two-step selection process, the authors identified 24 articles and used them to conduct a qualitative analysis. They conducted a meta-analysis on 11 of these articles. Among these articles, only one involved a test that had diagnostic accuracy good enough to warrant its use as a screening method for pediatric SDB, but its diagnostic accuracy was not sufficient to be considered a true diagnostic tool (that is, a replacement for full PSG) for pediatric SDB. Practical Implications. The involvement of dentists in the screening process for pediatric SDB can contribute significantly to children's health. The identified questionnaire could be considered an acceptable screening test to determine which children to refer to a sleep medicine specialist. PMID- 24487609 TI - Limited evidence shows a possible causal relationship between secondhand smoke and caries in children. PMID- 24487610 TI - Fluoride toothpaste efficacy and safety in children younger than 6 years: a systematic review. AB - BACKGROUND: The authors conducted a systematic review to assess the efficacy and safety of fluoride toothpaste use in children younger than 6 years. METHODS: The authors defined research questions to formulate a search strategy. They screened studies, extracted data and assessed risk of bias systematically. They conducted meta-analyses to determine the effects of brushing with fluoride toothpaste. RESULTS: Use of fluoride toothpaste brushing had a statistically significant effect on mean decayed, missing and filled primary tooth surfaces and decayed, missing and filled primary teeth for populations at high risk of developing caries (standard mean difference [95 percent confidence interval {CI}], -0.25 [ 0.36 to -0.14] and -0.19 [-0.32 to -0.06], respectively). The effects of using different fluoride concentration toothpastes on caries varied. Study findings showed either a decrease in the odds of having fluorosis (odds ratio [OR] [95 percent CI] = 0.66 [0.48-0.90]) when the use of fluoride toothpaste was initiated after 24 months or no statistically significant difference (OR [95 percent CI] = 0.92 [0.71-1.18]). Beginning use after 12 or 14 months of age decreased the risk of fluorosis (OR = 0.70 [0.57-0.88]). CONCLUSIONS: Limited scientific evidence demonstrates that for children younger than 6 years, fluoride toothpaste use is effective in caries control. Ingesting pea-sized amounts or more can lead to mild fluorosis. Practical Implications. To minimize the risk of fluorosis in children while maximizing the caries-prevention benefit for all age groups, the appropriate amount of fluoride toothpaste should be used by all children regardless of age. Dentists should counsel caregivers by using oral description, visual aids and actual demonstration to help ensure that the appropriate amount of toothpaste is used. PMID- 24487611 TI - Fluoride toothpaste use for young children. PMID- 24487612 TI - Is the rush to all-ceramic crowns justified? PMID- 24487613 TI - Setting fees in the new dental economy. PMID- 24487614 TI - Providing emergency care for an abused minor who is not a patient. PMID- 24487615 TI - Further evidence for the association between a polymorphism in the promoter region of SLC6A3/DAT1 and ADHD: findings from a sample of adults. AB - The dopamine transporter (SLC6A3/DAT1) plays a key role in the regulation of dopaminergic neurotransmission and is the major site of action for methylphenidate, a first-line medication for attention deficit hyperactivity disorder (ADHD). Most genetic association studies with ADHD have investigated a 40-bp variable number of tandem repeats (VNTR) polymorphism in the 3' untranslated region (UTR) of the DAT1, but these investigations have reported heterogeneous findings. The few studies focused on the 5' region have reported promising results. Despite rs2652511 not being included, nor having any proxy SNP available in GWAS, the few candidate gene studies that analyzed it suggested an association with ADHD and schizophrenia. Here, we analyzed the -839 C/T (rs2652511) promoter variant and the 3'-UTR and intron 8 (Int8) VNTR polymorphisms in 522 adults with ADHD and 628 blood donor controls. The diagnostic procedures followed the DSM-IV criteria. A significant association was detected (P = 0.002) between the rs2652511 C-allele with ADHD. In addition, the 6 repeat allele of Int8 VNTR was associated with higher inattention scores (P = 0.034). The haplotype analysis including DAT1 3'-UTR and Int8 VNTR polymorphisms did not reveal associations with ADHD susceptibility or severity dimensions. These findings extend to adult samples previous findings from children samples on the role of the rs2652511 polymorphism in the promoter region of DAT1 as a risk factor for ADHD susceptibility. PMID- 24487616 TI - The effects of exercise on oxidative stress (TBARS) and BDNF in severely depressed inpatients. AB - Exercise can be an effective treatment for depression. Although the efficacy of exercise is well established, little is known concerning the biological changes associated with the antidepressant effects of exercise. A randomized, controlled trial was conducted to evaluate the effects of adding exercise to the usual treatment on the thiobarbituric acid-reactive substances (TBARS) and brain derived neurotrophic factor (BDNF) serum levels of severely depressed inpatients. Twenty-six participants were randomized to an exercise group (n=15, exercise+treatment as usual) or a control group (n=11, treatment as usual). The participants in the exercise group completed a targeted dose of 16.5 kcal/kg/week of aerobic exercise, three times per week, throughout their hospitalizations. The control group did not exercise during their hospitalizations. The mean hospitalization length was of 21.63 (4.5)*23.82 (5.7) days for exercise and control groups, respectively. The exercise group performed a median of nine sessions. After adjusting for previous tobacco use, a significant group*time interaction was found for TBARS serum levels (p=0.02). A post hoc Bonferroni test revealed differences between the exercise and control groups at discharge. A significant time effect (p<0.001) but no group*time interaction was found (p=0.13) for BDNF serum levels. Adding exercise to the usual treatment of severely depressed inpatients decreases the TBARS serum levels of severely depressed inpatients after 3 weeks. Adding exercise had no additional effects on BDNF serum levels. PMID- 24487617 TI - Skilled reaching relies on a V2a propriospinal internal copy circuit. AB - The precision of skilled forelimb movement has long been presumed to rely on rapid feedback corrections triggered by internally directed copies of outgoing motor commands, but the functional relevance of inferred internal copy circuits has remained unclear. One class of spinal interneurons implicated in the control of mammalian forelimb movement, cervical propriospinal neurons (PNs), has the potential to convey an internal copy of premotor signals through dual innervation of forelimb-innervating motor neurons and precerebellar neurons of the lateral reticular nucleus. Here we examine whether the PN internal copy pathway functions in the control of goal-directed reaching. In mice, PNs include a genetically accessible subpopulation of cervical V2a interneurons, and their targeted ablation perturbs reaching while leaving intact other elements of forelimb movement. Moreover, optogenetic activation of the PN internal copy branch recruits a rapid cerebellar feedback loop that modulates forelimb motor neuron activity and severely disrupts reaching kinematics. Our findings implicate V2a PNs as the focus of an internal copy pathway assigned to the rapid updating of motor output during reaching behaviour. PMID- 24487618 TI - Mosaic two-lengthscale quasicrystals. AB - Over the past decade, quasicrystalline order has been observed in many soft matter systems: in dendritic micelles, in star and tetrablock terpolymer melts and in diblock copolymer and surfactant micelles. The formation of quasicrystals from such a broad range of 'soft' macromolecular micelles suggests that they assemble by a generic mechanism rather than being dependent on the specific chemistry of each system. Indeed, micellar softness has been postulated and shown to lead to quasicrystalline order. Here we theoretically explore this link by studying two-dimensional hard disks decorated with step-like square-shoulder repulsion that mimics, for example, the soft alkyl shell around the aromatic core in dendritic micelles. We find a family of quasicrystals with 10-, 12-, 18- and 24-fold bond orientational order which originate from mosaics of equilateral and isosceles triangles formed by particles arranged core-to-core and shoulder-to shoulder. The pair interaction responsible for these phases highlights the role of local packing geometry in generating quasicrystallinity in soft matter, complementing the principles that lead to quasicrystal formation in hard tetrahedra. Based on simple interparticle potentials, quasicrystalline mosaics may well find use in diverse applications ranging from improved image reproduction to advanced photonic materials. PMID- 24487619 TI - Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. AB - The recognition events that mediate adaptive cellular immunity and regulate antibody responses depend on intercellular contacts between T cells and antigen presenting cells (APCs). T-cell signalling is initiated at these contacts when surface-expressed T-cell receptors (TCRs) recognize peptide fragments (antigens) of pathogens bound to major histocompatibility complex molecules (pMHC) on APCs. This, along with engagement of adhesion receptors, leads to the formation of a specialized junction between T cells and APCs, known as the immunological synapse, which mediates efficient delivery of effector molecules and intercellular signals across the synaptic cleft. T-cell recognition of pMHC and the adhesion ligand intercellular adhesion molecule-1 (ICAM-1) on supported planar bilayers recapitulates the domain organization of the immunological synapse, which is characterized by central accumulation of TCRs, adjacent to a secretory domain, both surrounded by an adhesive ring. Although accumulation of TCRs at the immunological synapse centre correlates with T-cell function, this domain is itself largely devoid of TCR signalling activity, and is characterized by an unexplained immobilization of TCR-pMHC complexes relative to the highly dynamic immunological synapse periphery. Here we show that centrally accumulated TCRs are located on the surface of extracellular microvesicles that bud at the immunological synapse centre. Tumour susceptibility gene 101 (TSG101) sorts TCRs for inclusion in microvesicles, whereas vacuolar protein sorting 4 (VPS4) mediates scission of microvesicles from the T-cell plasma membrane. The human immunodeficiency virus polyprotein Gag co-opts this process for budding of virus like particles. B cells bearing cognate pMHC receive TCRs from T cells and initiate intracellular signals in response to isolated synaptic microvesicles. We conclude that the immunological synapse orchestrates TCR sorting and release in extracellular microvesicles. These microvesicles deliver transcellular signals across antigen-dependent synapses by engaging cognate pMHC on APCs. PMID- 24487622 TI - Development of a wireless sensor network for individual monitoring of panels in a photovoltaic plant. AB - With photovoltaic (PV) systems proliferating in the last few years due to the high prices of fossil fuels and pollution issues, among others, it is extremely important to monitor the efficiency of these plants and optimize the energy production process. This will also result in improvements related to the maintenance and security of the installation. In order to do so, the main parameters in the plant must be continuously monitored so that the appropriate actions can be carried out. This monitoring should not only be carried out at a global level, but also at panel-level, so that a better understanding of what is actually happening in the PV plant can be obtained. This paper presents a system based on a wireless sensor network (WSN) that includes all the components required for such monitoring as well as a power supply obtaining the energy required by the sensors from the photovoltaic panels. The system proposed succeeds in identifying all the nodes in the network and provides real-time monitoring while tracking efficiency, features, failures and weaknesses from a single cell up to the whole infrastructure. Thus, the decision-making process is simplified, which contributes to reducing failures, wastes and, consequently, costs. PMID- 24487620 TI - An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. AB - Hunger is a hard-wired motivational state essential for survival. Agouti-related peptide (AgRP)-expressing neurons in the arcuate nucleus (ARC) at the base of the hypothalamus are crucial to the control of hunger. They are activated by caloric deficiency and, when naturally or artificially stimulated, they potently induce intense hunger and subsequent food intake. Consistent with their obligatory role in regulating appetite, genetic ablation or chemogenetic inhibition of AgRP neurons decreases feeding. Excitatory input to AgRP neurons is important in caloric-deficiency-induced activation, and is notable for its remarkable degree of caloric-state-dependent synaptic plasticity. Despite the important role of excitatory input, its source(s) has been unknown. Here, through the use of Cre recombinase-enabled, cell-specific neuron mapping techniques in mice, we have discovered strong excitatory drive that, unexpectedly, emanates from the hypothalamic paraventricular nucleus, specifically from subsets of neurons expressing thyrotropin-releasing hormone (TRH) and pituitary adenylate cyclase activating polypeptide (PACAP, also known as ADCYAP1). Chemogenetic stimulation of these afferent neurons in sated mice markedly activates AgRP neurons and induces intense feeding. Conversely, acute inhibition in mice with caloric deficiency-induced hunger decreases feeding. Discovery of these afferent neurons capable of triggering hunger advances understanding of how this intense motivational state is regulated. PMID- 24487621 TI - Brainstem nucleus MdV mediates skilled forelimb motor tasks. AB - Translating the behavioural output of the nervous system into movement involves interaction between brain and spinal cord. The brainstem provides an essential bridge between the two structures, but circuit-level organization and function of this intermediary system remain poorly understood. Here we use intersectional virus tracing and genetic strategies in mice to reveal a selective synaptic connectivity matrix between brainstem substructures and functionally distinct spinal motor neurons that regulate limb movement. The brainstem nucleus medullary reticular formation ventral part (MdV) stands out as specifically targeting subpopulations of forelimb-innervating motor neurons. Its glutamatergic premotor neurons receive synaptic input from key upper motor centres and are recruited during motor tasks. Selective neuronal ablation or silencing experiments reveal that MdV is critically important specifically for skilled motor behaviour, including accelerating rotarod and single-food-pellet reaching tasks. Our results indicate that distinct premotor brainstem nuclei access spinal subcircuits to mediate task-specific aspects of motor programs. PMID- 24487623 TI - A mobility enabled inpatient monitoring system using a ZigBee medical sensor network. AB - This paper presents a ZigBee In-Patient Monitoring system embedded with a new ZigBee mobility management solution. The system enables ZigBee device mobility in a fixed ZigBee network. The usage, the architecture and the mobility framework are discussed in details in the paper. The evaluation shows that the new algorithm offers a good efficiency, resulting in a low management cost. In addition, the system can save lives by providing a panic button and can be used as a location tracking service. A case study focused on the Princes of Wales Hospital in Hong Kong is presented and findings are given. This investigation reveals that the developed mobile solutions offer promising value-added services for many potential ZigBee applications. PMID- 24487624 TI - A high temperature capacitive pressure sensor based on alumina ceramic for in situ measurement at 600 degrees C. AB - In response to the growing demand for in situ measurement of pressure in high temperature environments, a high temperature capacitive pressure sensor is presented in this paper. A high-temperature ceramic material-alumina is used for the fabrication of the sensor, and the prototype sensor consists of an inductance, a variable capacitance, and a sealed cavity integrated in the alumina ceramic substrate using a thick-film integrated technology. The experimental results show that the proposed sensor has stability at 850 degrees C for more than 20 min. The characterization in high-temperature and pressure environments successfully demonstrated sensing capabilities for pressure from 1 to 5 bar up to 600 degrees C, limited by the sensor test setup. At 600 degrees C, the sensor achieves a linear characteristic response, and the repeatability error, hysteresis error and zero-point drift of the sensor are 8.3%, 5.05% and 1%, respectively. PMID- 24487625 TI - Cortical Thickness Changes Associated with Photoparoxysmal Response. AB - Photoparoxysmal response (PPR) is an EEG trait of spike and spike-wave discharges in response to photic stimulation that is closely linked to idiopathic generalized epilepsy (IGE). In our previous studies we showed that PPR is associated with functional alterations in the occipital and frontal cortices. The aim of the present study was to determine structural changes associated with PPR. For this purpose we analysed the cortical thickness as derived from T1 MRI images in PPR-positive-subjects (n = 12; 15.5 +/- 8.6 years; 4 males), PPR-positive-IGE patients (n = 12; 14.9 +/- 2.7 years; 4 males) and compared these groups with a group of PPR-negative-healthy-controls (HC, n = 17; 15.3 +/- 3.6 years; 6 males). Our results revealed an increase of cortical thickness in the occipital, frontal and parietal cortices bilaterally in PPR-positive-subjects in comparison to HC. Moreover PPR-positive-subjects presented a significant decrease of cortical thickness in the temporal cortex in the same group contrast. IGE patients exhibited lower cortical thickness in the temporal lobe bilaterally and in the right paracentral region in comparison to PPR-positive-subjects. Our study demonstrates structural changes in the occipital lobe, frontoparietal regions and temporal lobe, which also show functional changes associated with PPR. Patients with epilepsy present changes in the temporal lobe and supplementary motor area. PMID- 24487626 TI - Quantification of continuous in vivo flexion-extension kinematics and intervertebral strains. AB - PURPOSE: Healthy subjects performed lumbar flexion and were assessed by video fluoroscopy to measure the in vivo kinematics of the lower lumbar motion segments. METHODS: Fifteen healthy subjects (8 male, 7 female, 28 +/- 10 years) performed lumbar flexion and extension back to neutral while their vertebrae were imaged. The sagittal plane vertebral margins of L3-S1 were identified. Lumbar angle, segmental margin strains, axial displacements, anterior-posterior (A-P) translations, and segmental rotations over the course of flexion were measured. RESULTS: L4-L5 had the largest posterior margin Green strain (65%). Each segment displayed more axial displacement than A-P translation. Peak vertebral angulation occurred at approximately 75% of peak flexion during the extension phase. CONCLUSION: L4-L5 exhibited the largest anterior and posterior margin strains (29 and 65%, respectively). Strains in the disc during in vivo lumbar flexion are due to both angular rotation and linear translation. PMID- 24487627 TI - Effects of silver nanoparticle on soil-nitrification processes. AB - The release of silver (Ag) nanoparticles (NPs) from the use of consumer products to the environment has raised concern about the risk to ecosystems because of its unpredictable toxicological impact to microorganisms in terrestrial environment. In this study, the impact of Ag chemical speciation (Ag(+) and Ag-NPs [50-nm uncoated and 15-nm polyvinylpyrrolidone (PVP)-coated Ag-NPs]) to soil nitrification kinetics was investigated using a batch soil-slurry nitrification method along with sorption isotherm and dissolution experiments. The results of nitrification potential (i.e., kinetic rate) suggest that Ag(+)/Ag-NPs, which strongly sorb in soils, suppressed the nitrification processes. Among each chemical species, the degree of suppression increased with increasing [Ag]total. Although ionic Ag (Ag(+)) species is known to exhibit greater antimicrobial effects than the solid state Ag species, such as Ag-NPs, in most studies, PVP coated 15-nm Ag-NPs, however, more effectively suppressed the soil nitrification process than did Ag(+) under the same dose. Although several physicochemical based toxicity mechanisms of dispersed Ag-NPs were discussed in pure culture and aquatic systems, it is not clearly understood how PVP-coated Ag-NPs could exhibit greater toxicity to nitrifying bacteria than Ag(+) in soils. In assessing the impact of Ag-NPs to microbial mediated processes (e.g., N cycles) in the terrestrial environment, it might be critical to understand the interactions and reactivity of Ag-NPs at the soil-water interface. PMID- 24487628 TI - First-ever optic neuritis: distinguishing subsequent neuromyelitis optica from multiple sclerosis. AB - To identify factors distinguishing subsequent neuromyelitis optica (NMO) from multiple sclerosis (MS) after first-ever optic neuritis (ON), we compared ophthalmic findings and MRI features of 24 NMO and 55 MS patients who initially presented with ON. The female-to-male ratio was higher, and bilateral ON was more common in NMO patients than in MS patients (p = 0.044 and p = 0.020, respectively). The visual acuity (VA) score was higher in NMO patients (p = 0.034), and a greater proportion of NMO patients had a VA score >= 5 (p = 0.003). The frequency of patients without pattern-reversal and flash visual evoked potentials was higher in the NMO group (p = 0.015). Brain MRI abnormalities were more common in the MS group (p = 0.001). The optic chiasm was affected in 25 % of NMO patients and was unaffected in MS patients, although it did not reach statistical significance (p = 0.096). There were no differences with respect to the severity of swelling and enhancement of the optic nerve. In conclusion, severe optic nerve damage at the first ON attack was associated with subsequent development of NMO, whereas presence of brain MRI abnormalities was associated with developing MS. PMID- 24487630 TI - The structure of the salt gland of Aegiceras corniculatum. AB - The salt glands of Aegiceras corniculatum have been examined by light- and electron-microscope techniques. A gland consists of a large number of abutting secretory cells and a single, large basal cell. The secretory cells and basal cell are joined by well defined plasmodesmata. The glandular cuticle shows differences between the top and sides of the gland, which may indicate a variation in the nature or quality of wax deposited. These variations may be significant in the secretion process, in view of the lack of evidence for the presence of pores. In ultrastructure, the secretory cells are generally similar to others that have been described, though there is no evidence of any particular association of vacuoles within these cells. PMID- 24487629 TI - Sequence-specific inhibition of microRNA via CRISPR/CRISPRi system. AB - Here, we report a convenient and efficient miRNA inhibition strategy employing the CRISPR system. Using specifically designed gRNAs, miRNA gene has been cut at a single site by Cas9, resulting in knockdown of the miRNA in murine cells. Using a modified CRISPR interference system (CRISPRi), inactive Cas9 can reversibly prevent the expression of both monocistronic miRNAs and polycistronic miRNA clusters. Furthermore, CRISPR/CRISPRi is also capable of suppressing genes in porcine cells. PMID- 24487631 TI - Isoelectric patterns of peroxidase isoenzymes from tobacco tissue cultures. AB - Peroxidases from tobacco tissue cultures have been separated by thin-layer isoelectric focusing into 12-14 isoenzymes, which have been divided into three groups according to differences in isoelectric points. The isoelectric patterns of callus tissues with and without buds have been compared with those of leaves and stems developed in vitro. Qualitatively, there was a basic similarity of the isoelectric patterns, the same isoenzymes being present in all samples. Distinct quantitative differences in the content and substrate specificity were noted for some of the isoenzymes. PMID- 24487632 TI - Release of carboxylating enzymes from maize and sugar cane leaf tissue during progressive grinding. AB - The release of chlorophyll, chloroplasts, o-diphenols, o-diphenol oxidase activity and carboxylating enzyme activity during the grinding of maize and sugar cane leaf tissue has been correlated with the breakage of different types of cell. Enzymes of the photosynthetic carbon reduction cycle were released in the grinding stage during which the bulk of the mesophyll tissue was disrupted and grana-containing chloroplasts released. Since the largest amount of phenol oxidase activity and of phenols was also released at this stage it is likely that the enzymes were partly inhibited by phenol oxidation products and, therefore, underestimated. PEP carboxylase is released earlier in the grinding process. It is concluded that the photosynthetic carbon reduction cycle enzymes studied are located in mesophyll cell chloroplasts and that the PEP carboxylase resides outside the chloroplasts, either in the cytoplasm of mesophyll cells or in colourless tissue. These results are discussed in relation to current theories regarding the assimilation and shuttling of carbon dioxide in leaves of tropical grasses. PMID- 24487633 TI - The localized incorporation of (3)H-L-fucose into cell-wall polysaccharides of the cap and epidermis of corn roots : Autoradiographic and biosynthetic studies. AB - When (3)H-L-fucose is provided to corn roots, a large proportion of the radioactivity is recovered in the polysaccharides extracted from the cell wall. Hydrolysis of this material yields (3)H-L-fucose as the sole radioactive product. Two metabolites, identified tentatively as L-fucose-1-phosphate and a nucleoside diphosphate derivative of L-fucose have been isolated from the ethanol soluble fractions of the roots and are possibly precursors of the polysaccharide. Autoradiographs of tissue sections indicate that the synthesis of polysaccharides containing L-fucose is confined largely to the root-cap and epidermis. The outer epidermal wall and root-cap slime are particularly radioactive and, therefore, likely to be relatively rich in fucose. By contrast the cell walls from more deeply lying tissues incorporate negligible amounts of the sugar. PMID- 24487634 TI - Dark starvation and chloroplast function : I. The decrease of enzyme activities correlated with NADP reduction and their regeneration by light. AB - Mature spinach plants were held in the dark for several days. The photochemical activities and the activity of some enzymes related to NADP reduction were follwed in the chloroplasts isolated from leaves after dark starvation. Photosystem-II, measured by reduction of DPIP, remained stable during 6 days of darkening. The decrease of NADP reduction which appeared after 2 days of starvation was found to be due to protein autolysis rather than inactivation of the photosystems. The stability of photosystem-I was demonstrated by reactivation of NADP reduction after addition of purified ferredoxin and ferredoxin-NADP reductase. After 4 days of starvation the restoration of the NADP reduction required in addition another, low-molecular-weight factor. From the isolation procedure and from its properties this factor is assumed to be identical with FRS. However, even in the presence of FRS only half of the total activity is restored after 7 days. The activity of the NADP-reducing system is restored in vivo when plants kept for 7 days in the dark are again illuminated. PMID- 24487635 TI - On the acceptor specificity of glycollate oxidase of Nicotiana tabacum. AB - The effect of compounds on the activity of ammonium sulphate preparations of glycollate oxidase from Nicotiana tabacum cv. John Williams' Broadleaf and the aurea mutant Su/su is reported. Coupling to DCPIP as terminal oxidant under anaerobic conditions gave greater rates of glycollate oxidation than when measured as O2 uptake in the presence of cyanide. The enzyme also linked to DCPIP in the presence of O2, showing that it is a facultative aerobic dehydrogenase. Catalytic amounts of PMS stimulated enzyme-dependent oxygen uptake and DCPIP reduction under aerobic and anaerobic conditions. This further suggests that an intermediate carrier, or alternate acceptor, depending on concentration, exists before O2 in vivo. Naturally occurring quinoid compounds may fulfill such a role, as evidenced by the enhancement of aerobic DCPIP reduction upon addition of catalytic amounts of caffeic and chlorogenic acid. The observation that PMS, caffeic and chlorogenic acid, biopterin, 6-hydroxy-2-amino-4-hydroxypteridine and a quinone extract of N. tabacum quenched the inhibitory effect of blue light on tobacco glycollate oxidase, is in accordance with the possible function of such compounds in glycollate oxidation. PMID- 24487636 TI - Investigations on the growth and metabolism of cultured explants of Daucus carota : IV. Effects of iron, molybdenum and the components of growth promoting systems and their interactions. AB - The induction and maintenance of growth in small, standard explants of carrot root exposed to a trace-element-free basal nutrient medium (B (**)) have been investigated. The organic growth factors that induce the growth are complex as represented by a trace-element-limited coconut-milk preparation (CM(**)) or the component parts of distinct growth promoting systems mediated by inositol or by 3 indoleacetic acid (IAA). In System I inositol interacts with growth factors from Aesculus, of which a known example is an IAA-rhamnoseglucose compound; in System II IAA interacts with adenyl compounds, of which zeatin is a known example. But the organic growth-promoting substances also interact with trace elements; therefore, the effects of the component parts of the growth promoting systems, separately and in combination, have been investigated with respect to their interactions with Mo, with Fe and also with these trace elements in combination. The growth so induced has been measured in terms of the fresh weight of the explants, the number and average size of their cells, as well as their total content of protein and nucleic acids. The metabolic responses of the cultured explants to the combined effects of growth factors and of trace elements are also described in terms of the principal soluble nitrogenous compounds. Each basis is informative, and suitable graphical devices are adopted so that the interactions of the multivariate factors that affect the behavior of the cultured tissue may be seen with respect to the various parameters selected. The study shows the range of complexity to be understood before the exogenous factors that determine cell growth and metabolism are both known and controllable; it also shows the limitations when attention is directed, simplistically, to one parameter or to the controlling influence of any single factor, or class, of growth factors. PMID- 24487637 TI - Induction of amylase in mustard seedlings by phytochrome. AB - In the cotyledons of mustard seedlings (Sinapis alba L.) amylase activity can be induced by phytochrome. In the dark amylase activity remains low. Gibberellic acid (GA3) does not stimulate an increase of amylase activity in this system. Inhibitors of RNA and protein synthesis strongly inhibit the increase of amylase activity mediated by phytochrome. In gel electrophoresis amylase from mustard seedlings reveals 3 bands. The electrophoretic pattern is the same for extracts from dark-grown and from irradiated seedlings. When mustard amylases were incubated with starch the pattern of products was similar to that produced by commercially available barley beta-amylase and not similar to that produced by Bacillus subtilis alpha-amylase. PMID- 24487638 TI - Waste not, want not. AB - As of the writing of this Editorial, the current JCI Editorial Board has evaluated approximately 7,000 manuscripts over the past 22 months for their suitability for publication in our journal. While many of you have received a negative decision on your manuscript, I suspect few are aware of the changes we have made to our review process to limit reviewers' requests for what is in our view unnecessary and excessive experimentation. PMID- 24487639 TI - A conversation with Don Ganem. PMID- 24487641 TI - From ST segments to endothelial pathophysiology: hypercholesterolemia and endothelial superoxide production. AB - As a young medical resident, I encountered a patient suffering from spontaneous coronary vasospasm and was puzzled by these dramatic alterations in vasomotion. This encounter piqued my interest in understanding the drivers of vascular reactivity. In a paper published in the JCI, my colleagues and I revealed a role for superoxide production in the vascular dysfunction associated with hypercholesterolemia. Subsequent work by our group and others has unveiled complex associations between ROS generation and vascular disease. PMID- 24487643 TI - Equol induces apoptosis in human hepatocellular carcinoma SMMC-7721 cells through the intrinsic pathway and the endoplasmic reticulum stress pathway. AB - Equol, a microbial metabolite of the isoflavone daidzein, is currently receiving much attention because of its strong antiproliferative effect on hormone-related human breast cancer cells; however, in our previous study, we observed that racemic equol [(+/-)-equol] shows the highest antiproliferative effect on human hepatocellular carcinoma SMMC-7721 cells compared with other cells, including human breast cancer MCF-7 and MDA-MB-231 cell lines. In the present study, we use the SMMC-7721 cancer cell line to investigate the mechanisms of (+/-)-equol induced, R-(+)-equol-induced, and S-(-)-equol-induced apoptosis. Our purpose was to provide some guidelines to introduce equol into a clinical situation. R-(+) equol and S-(-)-equol were prepared from (+/-)-equol by chiral stationary phase high performance liquid chromatography. The antiproliferative effect of equol on SMMC-7721 cells was investigated by crystal violet staining. Equol-induced apoptosis was detected by acridine orange/ethidium bromide staining and by flow cytometry. Western blotting was performed to study the molecular mechanisms of equol-induced apoptosis. The results showed that (+/-)-equol, R-(+)-equol, and S (-)-equol inhibited the proliferation of SMMC-7721 cells in a concentration dependent manner. Exposure of SMMC-7721 cells to equol caused significant cell cycle arrest in the S-phase. In addition, equol was shown to induce endoplasmic reticulum stress-mediated apoptosis by activating caspase-12 and caspase-8, and by upregulating Chop and Bip. Mitochondrion-mediated apoptosis was caused by upregulation of Bax and downregulation of Bcl-2, followed by activation of caspase-9, caspase-3, and cleaved poly (ADP-ribose) polymerase, respectively. This is the first report that shows that R-(+)-equol, S-(-)-equol, and (+/-) equol can induce apoptosis of human hepatocellular carcinoma SMMC-7721 cells through the intrinsic pathway and the endoplasmic reticulum stress pathway. PMID- 24487640 TI - Bone marrow mesenchymal stem cells and TGF-beta signaling in bone remodeling. AB - During bone resorption, abundant factors previously buried in the bone matrix are released into the bone marrow microenvironment, which results in recruitment and differentiation of bone marrow mesenchymal stem cells (MSCs) for subsequent bone formation, temporally and spatially coupling bone remodeling. Parathyroid hormone (PTH) orchestrates the signaling of many pathways that direct MSC fate. The spatiotemporal release and activation of matrix TGF-beta during osteoclast bone resorption recruits MSCs to bone-resorptive sites. Dysregulation of TGF-beta alters MSC fate, uncoupling bone remodeling and causing skeletal disorders. Modulation of TGF-beta or PTH signaling may reestablish coupled bone remodeling and be a potential therapy. PMID- 24487644 TI - Electroconvulsive therapy performed 6 days after repair of an intracranial aneurysm using a liquid embolic system. AB - There exists a small, but growing body of literature that describes electroconvulsive therapy (ECT) performed on patients with intracranial aneurysms. These reports include patients with unrepaired aneurysms and others in which aneurysms have been repaired by clipping or coil embolization methods. To date, these cases have described favorable results and minimal complications. We describe the case of a 34-year-old woman, who received ECT 6 days after balloon assisted embolization, with Onyx HD-500, of a 7-mm aneurysm of the ophthalmic segment of her left internal carotid artery. The patient experienced a significant reduction in depressive symptoms and tolerated a series of 8 treatments with no aneurysm-related complications. To our knowledge, this represents the earliest administration of ECT after repair of an intracranial aneurysm reported in the literature. Also, this is the only report in the literature of ECT performed after an intracranial aneurysm was repaired using the Onyx Liquid Embolic System. PMID- 24487645 TI - Are reports of cognitive testing among older electroconvulsive therapy recipients clinically valid? AB - OBJECTIVES: Electroconvulsive therapy (ECT) administration rises in frequency with age, with older depressed adults often showing clinical features predictive of good response. Recent reviews suggest that older people experience few if any long-term cognitive adverse effects after contemporary ECT, despite their increased vulnerability to these. However, the broader clinical validity of research findings is not assured as most studies of ECT-related cognitive effects do not discuss cognitive test nonparticipants. This study examines whether cognitive test participants and nonparticipants are comparable. METHODS: We recently completed a study of cognition in depressed patients 65 years and older treated with ECT. Only 35% of eligible patients completed neuropsychological testing at 2 time points, the remainder either refusing or unable to consent. To examine whether exclusion of most eligible patients from cognitive testing might have affected the clinical applicability of findings, we compared demographic and clinical characteristics of patients who participated with those who did not based on a subset of patients from our original study. RESULTS: The 2 patient groups differed in several respects. Most notably, nonparticipants were significantly more likely to be involuntary patients; to refuse food and fluids; and to require treatment with a bitemporal or mixed electrode placement. CONCLUSIONS: Our findings suggest cognitive test nonparticipants to be more severely psychiatrically unwell than test participants. As their exclusion might bias results and confound understanding of this important ECT-related topic, special mention of participation rates and comparison of participants and nonparticipants is recommended to establish the clinical relevance of future study findings. PMID- 24487646 TI - Symptoms and observations: differences in time course during electroconvulsive therapy in geriatric depressed patients. AB - Electroconvulsive therapy is used for the management of severe and refractory depression across the age spectrum. Treatment is guided by clinical response. However, there may be differences between the time course of improvement in clinical observations and patients' self-report of improvements. We report 4 cases of depression in late life that illustrate this issue. We discuss the potential significance of such differences and the need for research. PMID- 24487647 TI - Electroconvulsive therapy practice in Ukraine. AB - BACKGROUND: Patterns of electroconvulsive therapy (ECT) use have recently been extensively surveyed in Central-Eastern Europe. However, data from post-USSR countries are limited. OBJECTIVE: This study aimed to survey ECT practice in Ukraine. METHODS: All psychiatric services in Ukraine were identified and contacted to obtain information on the use of ECT in 2011 using a 22-item questionnaire. RESULTS: Of the 146 psychiatric inpatient facilities, only 5 confirmed that they performed ECT in 2011. Three other services also performed ECT but refused to provide further information. In the only private psychiatric institute where ECT was offered, 14.28% of inpatients received this treatment in 2011, whereas the corresponding figure in the 6 public psychiatric facilities was a mere 0.4%. Three centers used unmodified ECT, and only 2 centers had equipment that monitored electroencephalogram. In 7 services, in line with international recommendations, affective disorders were the first indications for ECT in Ukraine, whereas uncommon indications such as anorexia or Parkinsonism were also reported. CONCLUSIONS: This was the first survey of ECT practice conducted in Ukraine. The provision of ECT in only 8 centers is clearly insufficient for a large country such as Ukraine, which is reflected in the low rate of inpatients treated with ECT. The very limited availability of this effective treatment modality should be addressed by the Ukrainian health authorities. PMID- 24487648 TI - Driving charge separation for hybrid solar cells: photo-induced hole transfer in conjugated copolymer and semiconductor nanoparticle assemblies. AB - This work reports on the use of an internal electrostatic field to facilitate charge separation at inorganic-organic interfaces, analogous to those in hybrid solar cells. Systematic charge transfer studies show that the donor-acceptor charge transfer rate is highly sensitive to the direction of the internal electric field. PMID- 24487649 TI - A novel T-DNA integration in rice involving two interchromosomal translocations. AB - A male sterile transgenic rice plant TC-19 harboured a novel T-DNA integration in chromosome 8 with two interchromosomal translocations of 6.55 kb chromosome 3 and 29.8 kb chromosome 9 segments. We report a complex Agrobacterium T-DNA integration in rice (Oryza sativa) associated with two interchromosomal translocations. The T-DNA-tagged rice mutant TC-19, which harboured a single copy of the T-DNA, displayed male sterile phenotype in the homozygous condition. Analysis of the junctions between the T-DNA ends and the rice genome by genome walking showed that the right border is flanked by a chromosome 3 sequence and the left border is flanked by a chromosome 9 sequence. Upon further walking on chromosome 3, a chromosome 3/chromosome 8 fusion was detected. Genome walking from the opposite end of the chromosome 8 break point revealed a chromosome 8/chromosome 9 fusion. Our findings revealed that the T-DNA, together with a 6.55 kb region of chromosome 3 and a 29.8-kb region of chromosome 9, was translocated to chromosome 8. Southern blot analysis of the homozygous TC-19 mutant revealed that the native sequences of chromosome 3 and 9 were restored but the disruption of chromosome 8 in the first intron of the gene Os08g0152500 was not restored. The integration of the complex T-DNA in chromosome 8 caused male sterility. PMID- 24487651 TI - Performance of FBK high-density SiPM technology coupled to Ce:LYSO and Ce:GAGG for TOF-PET. AB - This paper presents the performance, in terms of energy and timing resolution, of high-density silicon photomultipliers (SiPMs) produced at Fondazione Bruno Kessler for time-of-flight positron emission tomography application. The new SiPM technology allows us to produce devices with a small cell size maintaining a high fill factor (FF). The sensors considered in this paper are composed by 30 * 30 MUm(2) cells with a FF exceeding 70% to cover a total area of 4 * 4 mm(2). The SiPM performance was evaluated using two types of scintillators (Ce:LYSO and Ce:GaGG) both with a short height (5 mm) in order to minimize the time jitter caused by light propagation in the crystal. With Ce:LYSO, an energy resolution of 9.0% FWHM at 511 keV and a coincidence resolving time (CRT) of 125 ps FWHM were obtained at -20 degrees C. With Ce:GaGG, an energy resolution of 6.4% FWHM and a CRT of 260 ps FWHM were achieved at the same temperature. The novel SiPM technology, combining a high PDE with a low correlated noise (i.e., crosstalk and afterpulse), allows us to improve the state-of-the-art of energy and timing resolution with both the tested crystals. PMID- 24487650 TI - Universal control and error correction in multi-qubit spin registers in diamond. AB - Quantum registers of nuclear spins coupled to electron spins of individual solid state defects are a promising platform for quantum information processing. Pioneering experiments selected defects with favourably located nuclear spins with particularly strong hyperfine couplings. To progress towards large-scale applications, larger and deterministically available nuclear registers are highly desirable. Here, we realize universal control over multi-qubit spin registers by harnessing abundant weakly coupled nuclear spins. We use the electron spin of a nitrogen-vacancy centre in diamond to selectively initialize, control and read out carbon-13 spins in the surrounding spin bath and construct high-fidelity single- and two-qubit gates. We exploit these new capabilities to implement a three-qubit quantum-error-correction protocol and demonstrate the robustness of the encoded state against applied errors. These results transform weakly coupled nuclear spins from a source of decoherence into a reliable resource, paving the way towards extended quantum networks and surface-code quantum computing based on multi-qubit nodes. PMID- 24487653 TI - A novel poly(2,6-dimethyl-1,4-phenylene oxide) with trifunctional ammonium moieties for alkaline anion exchange membranes. AB - 2,4,6-Tri(dimethylaminomethyl)-phenol was synthesized as a trifunctional moiety and incorporated onto poly(2,6-dimethyl-1,4-phenylene oxide) (PPO) to obtain a novel quaternary ammonium functionalized PPO (PPO-TQA). Membranes of the polymer were fabricated and exhibited high conductivity, a low swelling ratio and water uptake. PMID- 24487652 TI - A simple 5-point scoring system, NaURSE (Na+, urea, respiratory rate and shock index in the elderly), predicts in-hospital mortality in oldest old. AB - BACKGROUND: the mortality is high in acutely ill oldest old patients. Understanding the prognostic factors which influence mortality will help clinicians make appropriate management decisions. METHODS: we analysed prospective mortality audit data (November 2008 to January 2009) to identify variables associated with in-patient mortality in oldest old. We selected those with P < 0.10 from univariate analysis and determined at which cut-point they served as the strongest predictor of mortality. Using these cut-off points, we constructed multivariate logistic regression models. A 5-point score was derived from cut-off points which were significantly associated with mortality tested in a smaller independent re-audit sample conducted in October 2011. RESULTS: a total of 405 patients (mean 93.5 +/- 2.7 years) were included in the study. The mean length of stay was 18.5 +/- 42.4 days and 13.8% died as in-patients. Variables (cut-off values) found to be significantly associated with in-patient mortality were admission sodium (>145 mmol/l), urea (>=14 mmol/l), respiratory rate (>20/min) and shock index (>1.0): creating a 5-point score (NaURSE: NaURS in the Elderly). The crude mortality rates were 9.5, 19.9, 34.4, 66.7, and 100% for scores 0, 1, 2, 3 and 4, respectively. Using the cut-off point of >=2, the NaURSE score has a specificity of 87% (83.1-90.3) and sensitivity of 39% (28.5-50.0), with an AUC value of 0.69 (0.63-0.76). An external independent validation study (n = 121) showed similar results. CONCLUSIONS: the NaURSE score may be particularly useful in identifying oldest old who are likely to die in that admission to guide appropriate care. PMID- 24487654 TI - Obsessive-compulsive symptoms in neurologic disease: a review. AB - Obsessive-compulsive disorder (OCD) is an increasingly recognized disorder with a prevalence of 2-3% (Robins et al., 1984). Once thought to be psychodynamic in origin, OCD is now generally recognized as having a neurobiological cause. Although the exact pathophysiology of OCD in its pure form remains unknown, there are numerous reports of obsessive-compulsive symptoms arising in the setting of known neurological disease. In this paper, we review the reported cases of obsessive-compulsive symptoms associated with neurologic diseases and outline the known facts about the underlying neurobiology of OCD. Finally, we synthesize these findings into a proposed theory of the pathophysiology of OCD, in both its pure form and when it accompanies other neurological illness. PMID- 24487655 TI - Ideational and ideomotor apraxia: a qualitative analysis. AB - This paper reviews research into both ideational and ideomotor apraxia focusing on the qualitative aspects of limb apraxia. The criteria based on a distinction between different type of movements which have been used to distinguish between ideational (IA) and ideomotor apraxia (IMA) are reviewed together with an evaluation of the most frequent methods of testing and their effects on patients responses. Finally a list of the types of response reported in the literature is presented and their relationship with IA and IMA is proposed. PMID- 24487656 TI - Lithium intoxication presenting as a mixed misidentification syndrome. AB - A case is reported of lithium intoxication presenting with a mixed misidentification syndrome including features of Capgras syndrome. CT scanning showed cerebral atrophy, greater on the right, consistent with earlier evidence, suggesting that misidentification syndromes are more common with right hemisphere lesions. PMID- 24487657 TI - Recognition memory in psychotic patients. AB - Preliminary data are reported from experiments in which Warrington's (1984) Recognition Memory Tests were given to patients with misidentification delusions including the Capgras type and to psychotic patients. The results showed a profound impairment on face recognition for most groups, especially those with the Capgras delusion. It was rare to find a patent whose score on the word test was anything but normal. PMID- 24487658 TI - Do some cases of anorexia nervosa reflect underlying autistic-like conditions? AB - In a sample of 51 teenagers with anorexia nervosa (AN)-which included 24 cases constituting the total population of AN cases born in 1970-several had shown social, communicative and behaviour patterns suggestive of autistic-like conditions as children, long before the onset of AN. One of the three boys in the AN group had Asperger syndrome. Three of the 48 girls had histories suggesting high functioning autism and continued to show many features typical of autism. Two further girls had Tourette syndrome and obsessive-compulsive traits in combination with social interaction problems. Eighteen other girls met criteria for obsessive-compulsive personality disorder (OCPD) and most of these also had had moderate-severe childhood social interaction problems. In a sex- and age matched comparison group from the same schools, two girls had OCPD, but none had autistic-like conditions or Tourette syndrome. The results are discussed in the context of a recently suggested link between Asperger syndrome, Tourette syndrome and obsessive-compulsive problems, and it is suggested that AN in a subgroup of cases might represent a disorder belonging in the same class as autism and autistic-like conditions. PMID- 24487659 TI - Thought and language. AB - From aphasics' self records, common experience, changes in signification of sentences according to a verbal or non-verbal context, animals and non speaking children performances, it seems possible to get some evidence that thought is distinct from language even though there is a permanent interaction between both in normal adult human beings. Some considerations on formalisation of language suggests that the more formalised it is, the less information it contains. If it is true, it is not reasonable to hope that a formalised language like that used by computers may be a model for thought. Finally, the lack of status of thought, as far as it is a subjective experience and the impossibility of giving it a definition as far as it exceeds language, make it clear that in spite of progress in scientific psychology, thought, per se, is not an object for science. PMID- 24487660 TI - Gilles de la Tourette syndrome-a case report from Guyana in South America. AB - A case of the Gilles de la Tourette syndrome from Guyana in South America is presented. The patient had a positive family history as well as coprolalia, echolalia, and attention deficit disorder with hyperactivity. The family history and cross-cultural similarity emphasise the biological factors in the aetiology of the syndrome. PMID- 24487661 TI - Interhemispheric transfer in Down's syndrome. AB - Callosal agenesics and callosotomized epileptics manifest markedly increasing simple visual reaction time (SVRT) from conditions of ipsilateral to contralateral stimulus-response relation (SRR). In the contralateral SRR, a response is presumed possible because of presence of other commissures (anterior, intercollicular). The SRR effect is prolonged presumably because the remaining commissures are less efficient than the corpus callosum in relaying necessary visual or motor information. Consequently, the SRR effect is believed to correspond to callosal relay time (CRT) in the normal subject. However, both callosal agenesics and callosotomy patients manifest general slowing of SVRT in addition to a prolonged SRR effect. These patients have massive extra-callosal damage which could plausibly cause both the SVRT and the CUD prolongation. If such were the case, the CRT inference would be in jeopardy. A test of the CRT inference is therefore required where patients with massive diffuse extra callosal brain damage and normal callosi would show marked general SVRT prolongation and a normal SRR effect. Four trisomy-21 (T21) males were compared to age and sex-matched normal controls. General SVRT was highly significantly prolonged in T21, but the CUD was nearly identical in both groups. PMID- 24487662 TI - A socio behavioural perspective for understanding and managing behaviour problems in children with epilepsy. AB - In this paper, reasons for the occurrence of interictal behaviour disturbance in children with epilepsy, and the management of such problems, are considered. The search for a direct relationship between epilepsy related variables and behaviour disorders is far from conclusive. While such a relationship may exist with respect to ictal behaviour problems, this line of investigation is of limited value in respect of its implications for the management of interictal problems. In the latter case it is proposed that organic factors may be considered to be a risk factor. In addition, the negative psychosocial sequelae of a diagnosis of epilepsy can result in conditions which are likely to foster the development of inappropriate behaviours. Learning theory would further suggest that environmental contingencies have a role to play in the shaping and maintenance of such behaviours. This broader framework for conceptualising the development and maintenance of interictal behaviour disorders has clear management implications. Clinical examples of the successful application of this approach to the management of persistent behavioural problems in two young people with epilepsy are presented. PMID- 24487663 TI - Basal ganglia mineralization in Alzheimer's disease: a comparative study of clinical, neuroradiological and neuropathological findings. AB - Fifty patients from a longitudinal study on 178 cases of Alzheimer's disease were examined at postmortem. The clinical features, CT-scans and neuropathological findings of five patients, with verified Alzheimer's disease, who had bilateral basal ganglia mineralization (BGM; 2 male, 3 female; age 78-91 years) were compared with the data of five age- and sex-matched Alzheimer patients without BGM and of five control subjects. Persecutory and other delusions (4 patients), persistent depression (2), parkinsonism (4), myoclonus (1) and epileptic seizures (1) were observed more frequently in the patients with BGM than was expected. The BGM-group had significantly lower counts of large neurons in the pallidum internum than the demented patients without BGM or the control group. We did not find other differences between the dementia groups regarding the CT-scans, or plaque, tangle and neuron counts in neocortex and brainstem. We suggest that the combined effects of Alzheimer pathology and BGM might lead to an increased manifestation of psychotic and motor disturbances. PMID- 24487665 TI - PEEK rod systems for the spine. AB - Traditional materials for the spine such as titanium and stainless steel have produced satisfying long-term fusion rates, mainly due to their strength and stiffness. However, although fixation with titanium rods leads to high fusion rates, increased stiffness of titanium constructs may also contribute to stress shielding and adjacent segment degeneration. Dynamic and flexible materials such as the Dynesys system allow better stress distribution to all of the spinal columns, but increase the rate of complications including screw loosening, infection, back and leg pain, and endplate vertebral fracture. Semi-rigid instrumentation systems using rods made from synthetic polymers such as the polyetheretherketone (PEEK) have been recently introduced as an alternative biomaterial for the spine. PEEK is a fully biocompatible and inert semi crystalline thermoplastic polymer with minimal toxicity; it has a modulus of elasticity between that of cortical and cancellous bone, and significantly lower than titanium. However, there are very few clinical studies with small sample size and short-term follow-up using PEEK rod-pedicle screw spinal instrumentation systems. Additionally, their results are conflicting. To enhance the literature, this review discusses the effect of this medical for the spine and summarizes the results of the most important related series. PMID- 24487666 TI - Effects of aerobic exercise on cognitive performance and individual psychopathology in depressive and schizophrenia patients. AB - Cognitive deficits are core symptoms in patients with schizophrenia (SZ) and major depressive disorder (MDD), but specific and approved treatments for cognitive deterioration are scarce. Experimental and clinical evidence suggests that aerobic exercise may help to reduce psychopathological symptoms and support cognitive performance, but this has not yet been systematically investigated. In the current study, we examined the effects of aerobic training on cognitive performance and symptom severity in psychiatric inpatients. To our knowledge, to date, no studies have been published that directly compare the effects of exercise across disease groups in order to acquire a better understanding of disease-specific versus general or overlapping effects of physical training intervention. Two disease groups (n=22 MDD patients, n=29 SZ patients) that were matched for age, gender, duration of disease and years of education received cognitive training combined either with aerobic physical exercise or with mental relaxation training. The interventions included 12 sessions (3 times a week) over a time period of 4 weeks, lasting each for 75 min (30 min of cognitive training+45 min of cardio training/mental relaxation training). Cognitive parameters and psychopathology scores of all participants were tested in pre- and post-testing sessions and were then compared with a waiting control group. In the total group of patients, the results indicate an increase in cognitive performance in the domains visual learning, working memory and speed of processing, a decrease in state anxiety and an increase in subjective quality of life between pre- and post-testing. The effects in SZ patients compared with MDD patients were stronger for cognitive performance, whereas there were stronger effects in MDD patients compared with SZ patients in individual psychopathology values. MDD patients showed a significant reduction in depressive symptoms and state anxiety values after the intervention period. SZ patients reduced their negative symptoms severity from pre- to post-testing. In sum, the effects for the combined training were superior to the other forms of treatment. Physical exercise may help to reduce psychopathological symptoms and improve cognitive skills. The intervention routines employed in this study promise to add the current psychopathological and medical treatment options and could aid the transition to a multidisciplinary approach. However, a limitation of the current study is the short time interval for interventions (6 weeks including pre- and post-testing). PMID- 24487668 TI - Upstream, downstream: currents of health. PMID- 24487667 TI - Disparities in the use and quality of alcohol treatment services and some proposed solutions to narrow the gap. AB - OBJECTIVES: This study assessed racial-ethnic disparities in access to high quality treatment for at-risk drinking and alcohol abuse in the United States and simulated strategies to narrow the gap. METHODS: Longitudinal data collected in 2001-2002 and 2004-2005 from the National Epidemiologic Survey on Alcohol and Related Conditions were analyzed to examine racial-ethnic disparities in receipt of alcohol interventions that were provided in primary care and specialty treatment settings and that met published clinical guidelines. The sample consisted of 9,116 respondents who met criteria for at-risk drinking or alcohol abuse in 2001-2002. Simulation analyses projected how disparities in treatment services utilization might change if clinical guidelines promoted access to care in more varied health and human service settings. RESULTS: Compared with whites, members of racial-ethnic minority groups had less than two-thirds the odds of receiving an alcohol intervention over the roughly four-year study period (odds ratio [OR]=.62, p<.05). This disparity increased after adjustment for socioeconomic confounders and frequency of heavy drinking (adjusted OR=.47, p=.003). The most pronounced disparities were between whites and U.S.-born and foreign-born Hispanics. Simulation analyses suggested that these disparities could be partially mitigated by extending care into nonmedical service venues. CONCLUSIONS: Current efforts to extend evidence-based alcohol interventions into medical settings address an important need but are likely to increase racial ethnic disparities in access to high-quality treatment. Partial solutions may be found in expanding the range and quality of alcohol-related services provided in alternative delivery sites, including faith-based and social service institutions. PMID- 24487669 TI - Well child care: a comprehensive strategy for Cuban children and adolescents. AB - The notable rise in survival rates of Cuban children has presented new challenges in the search for continued improvement of their welfare and quality of life. These advances can be achieved only to the extent that preventive care and health promotion are also improved. This article describes the design of a strategy for comprehensive care of children and adolescents based on better quality of well child visits, defining visit components, age-specific activities for each visit, and guidelines for followup based on visit findings. Complementary to the strategy, indicators and standards are identified for systematic evaluation of visit quality, enabling collection of objective and specific information about individual visits and assessment of trends over time, which in turn facilitates further improvements in this strategy over the long term. PMID- 24487670 TI - Cuba's human breast milk banks. PMID- 24487671 TI - Anemia in children under five years old in Eastern Cuba, 2005-2011. AB - INTRODUCTION: Anemia is the main nutritional problem in Cuban preschool children, prompting several interventions to prevent and control it. An enhanced national strategy was established in 2008, and particular attention paid to the eastern provinces, the region with greatest challenges in social determinants of health. OBJECTIVE: Determine anemia prevalence in children aged 6-59 months in Cuba's five eastern provinces in three separate years within a decade, as well as association of anemia with epidemiological and nutritional factors, to assess impact of Cuba's Comprehensive Plan for Prevention and Control of Iron-Deficiency Anemia in Cuba. METHODS: Cross-sectional studies of children aged 6-59 months (completed) were conducted in 2005, 2008 and 2011. Hemoglobin levels were measured to diagnose anemia (hemoglobin <110 g/L) and data were collected on independent variables such as age, sex, area of residence (urban or rural), daycare center enrollment, birth weight, breastfeeding history, and maternal anemia during pregnancy. Frequency distributions were created and comparisons tested with the chi square, and odds ratios calculated with 95% confidence intervals. RESULTS: Anemia prevalence in the region fell from 31.8% in 2005 to 26% in 2011; most of cases were mild (hemoglobin: 100-109 g/L). Prevalence was higher in children aged 6-23 months than in those aged 24-59 months throughout. No significant differences were found in anemia prevalence between boys and girls. Prevalence was higher in rural than in urban areas in 2005 (p = 0.026) and 2011 (p = 0.012). Daycare enrollment emerged as a protective factor in all three years. Low birth weight was associated with anemia only in 2011 (OR 1.74, CI 1.04 2.92). Prevalence of exclusive breastfeeding for six months increased over the study period; lack of breastfeeding was found to be associated with anemia in 2005 (OR 1.57, CI 1.05-2.34). Maternal anemia at onset of and during pregnancy was a significant risk factor in 2005 (OR 1.98, CI 1.27-3.10) and 2011 (OR 1.43, CI 1.05-1.94). CONCLUSIONS: Although anemia prevalence steadily decreased over the study period, it continues to be a public health problem in Cuba and anemia prevention and control measures should be maintained and strengthened: interventions for women of childbearing age, fostering exclusive breastfeeding of infants through their sixth month, and encouraging compliance with recommendations on complementary feeding per Cuba's nutritional guidelines for children aged <2 years. Further evaluation is needed to identify the causes of anemia in the population of preschool children. PMID- 24487672 TI - Frailty, dependency and mortality predictors in a cohort of Cuban older adults, 2003-2011. AB - INTRODUCTION: Population aging translates into more people with chronic non communicable diseases, disability, frailty and dependency. The study of frailty- a clinical syndrome associated with an increased risk of falls, disability, hospitalization, institutionalization and death--is important to improve clinical practice and population health indicators. OBJECTIVES: In a cohort of older adults in Havana and Matanzas provinces, Cuba, estimate prevalence of frailty and its risk factors; determine incidence of dependency; estimate mortality risk and identify mortality predictors. METHODS: A prospective longitudinal study was conducted door to door, from June 2003 through July 2011, in a cohort of 2813 adults aged >=65 years living in selected municipalities of Havana and Matanzas provinces; mean followup time was 4.1 years. Independent variables included demographics, behavioral risk factors and socioeconomic indicators, chronic non communicable diseases (hypertension, stroke, dementia, depression, diabetes, anemia), number of comorbidities, and APOE epsilon4 genotype. Dependent variables were frailty, dependency and mortality. Criteria for frailty were slow walking speed, exhaustion, weight loss, low physical activity and cognitive decline. Prevalence and frailty risk were estimated by Poisson regression, while dependency and mortality risks and their predictors were determined using Cox regression. RESULTS: Frailty syndrome prevalence was 21.6% (CI 17.9%-23.8%) at baseline; it was positively associated with advanced age, anemia and presence of comorbidities (stroke, dementia, depression, three or more physically debilitating diseases). Male sex, higher educational level, married or partnered status, and more household amenities were inversely associated with frailty prevalence. In followup, dependency incidence was 33.1 per 1000 person-years (CI 29.1-37.6) and mortality was 55.1 per 1000 person-years. Advanced age, male sex, lower occupational status during productive years, dependency, frailty, dementia, depression, cerebrovascular disease and diabetes were all associated with higher risk of death. CONCLUSIONS: Given the challenge for developing countries presented by demographic and epidemiologic transition; the high prevalence in older adults of frailty syndrome, dependency and chronic non-communicable diseases; and the association of all these with higher mortality, attention should be targeted to older adults as a risk group. This should include greater social protection, age-appropriate health services, and modification and control of cardiovascular risk factors. PMID- 24487673 TI - P-wave dispersion: a possible warning sign of hypertension in children. AB - INTRODUCTION: Hypertension and obesity in adults have been linked to increased EKG P-wave dispersion; the association has been shown in relation to hypertension, left ventricular hypertrophy and atrial enlargement. Though studies in children have linked P-wave dispersion to left ventricular hypertrophy, scant pediatric literature relates P-wave dispersion to hypertension and obesity. OBJECTIVE: Assess the association of P-wave dispersion with blood pressure and nutritional status in a pediatric population. METHODS: This cross-sectional study is part of the PROCDEC II project for pediatric hypertension diagnosis and control in Santa Clara, Cuba. Twelve-lead EKG and four blood pressure readings were conducted on a sample of 656 children aged 8-11 years. Blood pressure <90th percentile for age, sex and height was considered normal; 90th-95th percentile, prehypertension; and >95th percentile, hypertension. The main study variables were P-wave dispersion and systolic, diastolic and mean arterial pressure (MAP). Secondary variables were sex, height, weight, and body mass index. Comparisons of means, analysis of variance and linear correlations were done. RESULTS: Mean P wave dispersion differed significantly (p <=0.05) among normotensive (30.10 ms), prehypertensive (32.99 ms) and hypertensive children (39.14 ms), as did mean MAP (p <0.05). P-wave dispersion and MAP were significantly correlated in prehypertensive and hypertensive children. Most overweight and obese children with high P-wave dispersion were prehypertensive or hypertensive. CONCLUSIONS: Associations observed between P-wave dispersion and MAP in normotensive, prehypertensive and hypertensive children suggest potential for early detection of EKG patterns showing vulnerability. Given the relationship between increased P wave dispersion and hypertension already described in adults, use of P-wave dispersion could be a simple, economical and noninvasive method of predicting risk of hypertensive cardiomyopathy in prehypertensive and hypertensive children; this in turn could guide timely, effective treatment and secondary prevention. Similar studies on a larger sample are needed to corroborate these results. PMID- 24487674 TI - Platelet serotonin concentration and clinical status in alcohol withdrawal syndrome, preliminary results. AB - INTRODUCTION: Alcohol withdrawal syndrome is an important problem for management of alcoholism. It is known that alcohol alters the function of neurotransmitters such as serotonin, but our review found no studies associating serotonin concentration changes with patient clinical status during detoxification. The authors hypothesized that total platelet serotonin concentration should significantly increase during alcohol detoxification. OBJECTIVE: Assess possible association between total (endogenous and captured) platelet serotonin concentration and clinical status of patients with alcohol withdrawal syndrome, at beginning and end of detoxification with clomethiazole. METHODS: Thirty-one alcohol-dependent patients, diagnosed with alcohol withdrawal syndrome according to DSM-IV and classified in three clinical groups (18-20, 21-22 and 23-26 points) per the Clinical Institute Withdrawal Assessment for Alcohol Scale, were included in a prospective case series from May 2009 through May 2011 at the Hermanos Ameijeiras Clinical-Surgical Teaching Hospital in Cuba. Patients were predominantly male (87%), ranging in age from 22 to 57 years; 40% were white, 40% mestizo and 20% black. All had been hospitalized for detoxification in the hospital's psychiatry service. Blood samples taken were mixed with 1% EDTA and centrifuged for isolating platelets. Serotonin concentrations (endogenous and captured) were measured within 2 hours of blood collection and mean values at treatment days 1 and 12 compared by t test (p <0.05). RESULTS: Total serotonin concentration mean values (ug of serotonin per mg of total platelet protein) were statistically different between days 1 and 12 of treatment (1.329+/-0.916 ug/mg vs. 2.573+/-1.224 ug/mg; p <0.001). There was a direct association between total serotonin concentration and patient clinical classification both initially and at day 12. At day 1, the 29 patients in the group with 18-20 points had mean serotonin of 1.358+/-0.0.94 ug/mg; one patient with 21 points had serotonin of 1.25 ug/mg; and one patient with 24 points had serotonin of 0.740 ug/mg. At day 12, 26 patients had 0-1 points, with mean serotonin 2.688+/-1.244 ug/mg; and 5 patients had 2-8 points, with mean serotonin 1.244+/-0.596 ug/mg. No patient had >8 points at day 12. CONCLUSIONS: Serotonin is a potential biomarker for initial clinical classification and outcome monitoring and could be useful to psychiatrists working with patients in this area of medical practice and research. Further studies including more patients and variables are necessary to support these preliminary results. PMID- 24487675 TI - Implementation of chronic disease risk factor surveillance in 12 Cuban municipalities. AB - Chronic non-communicable diseases have been called the pandemic of the 21st century and constitute a high-priority public health challenge; hence growing interest in chronic disease risk factor surveillance. Cuba is implementing decentralized risk factor surveillance in each of its municipalities as part of a strategy to address non-communicable diseases. Decentralized surveillance with this level of detail and explicitly designed to inform municipal and provincial decisionmaking is unprecedented in Cuba. We describe the methodology for planning and implementing measurement of major risk factors in 12 municipalities in 10 provinces, as part of Cuba's National Surveillance System. The results have facilitated timely use of information and evidence-based decisionmaking at the local level. PMID- 24487676 TI - Exercise: the first prescription for Cubans of all ages. AB - Regular physical exercise improves quality of life and benefits the body's organs and systems: it tones and strengthens muscles; improves joint function; contributes to healthier heart and lungs; increases resistance to fatigue, and thus capacity for both physical and mental exertion; helps combat anxiety, depression and stress; improves sleep patterns; and is an important factor in maintaining healthy weight. It also provides a simple way of sharing with family and friends, even an opportunity for improving intergenerational communication and relations. PMID- 24487677 TI - Intramuscular capillary-type hemangioma: radiologic-pathologic correlation. AB - BACKGROUND: Infantile hemangiomas demonstrate a pattern of proliferative growth in infancy followed by a slow phase of involution. In contrast a rare type of vascular tumor, intramuscular capillary-type hemangioma, usually presents beyond the period of infancy with nonspecific symptoms and no evidence of involution. OBJECTIVE: The purpose of this study was to characterize the clinical, imaging, histopathological characteristics and management of intramuscular capillary-type hemangioma. MATERIALS AND METHODS: We performed a retrospective review of a 20 year period to identify children diagnosed with intramuscular capillary-type hemangioma. Patient demographics, imaging and histopathological findings were recorded. RESULTS: We included 18 children (10 boys, 8 girls) with histologically proven intramuscular capillary-type hemangioma - and adequate imaging. The mean age at presentation was 8.1 years (range 1 day to 19 years). Twelve lesions involved muscles of the extremities, 4 were located in the trunk and 2 were in the head and neck. MRI had been performed in all children and demonstrated a soft tissue mass with flow voids, consistent with fast flow. The lesion was well circumscribed in 16 children and intralesional fat was seen in 14. Doppler US demonstrated a heterogeneous lesion, predominantly isoechoic to surrounding muscle, with enlarged arterial feeders. Enlarged feeding arteries, inhomogeneous blush and lack of arteriovenous shunting were noted on angiography (n = 5). The most common histopathological findings were lobules of capillaries with plump endothelium and at least some adipose tissue. The lesions were excised in six children. Two children were lost to follow-up. In the remaining 10, follow-up MRI studies ranging from 3 months to 10 years showed that the lesion enlarged in proportion to the child (n = 7), demonstrated slow growth (n = 2) or remained stable (n = 1). There was no change in imaging characteristics on follow-up. CONCLUSION: Intramuscular capillary-type hemangioma is a rare benign vascular tumor of skeletal muscle. The most typical imaging features show a heterogeneous intramuscular mass with fast flow, and intralesional fat. Although the lesion is relatively stable in appearance over time, imaging does not obviate the need for a biopsy to rule out sarcoma. The diagnosis can usually be established by typical findings on histopathology. PMID- 24487678 TI - Distribution of growth regulators and sugars by the tangential and radial transport systems of stem segments of Willow. AB - The tangential transport of labelled growth regulators and sugars, through the bark of isolated stem segments of Willow (Salix viminalis L.), has been studied. It has been shown that these compounds have distinct patterns of distribution, particularly in the case of plant growth regulators. IAA moves preferentially into the lower half of a horizontal stem, kinetin into the upper half when these substances are applied via a bark abrasion made on the side of the stem. Distribution patterns of sugars were more variable, in some instances upward movement occurred, in others downward. The distinctness of the distribution patterns was accentuated by pretreatment of the stem segments in a horizontal position for 7 days prior to experimentation. Radial movement of labelled IAA and kinetin, centrifugally from the centre of the xylem to the bark, showed no difference in distribution between the upper and lower portions of the stem. PMID- 24487679 TI - Genetic control of multiple esterases from needles and macrogametophytes ofPicea abies. AB - The patterns of multiple esterases from needles and macrogametophytes ofPicea abies were examined by polyacrylamide-gel disc-electrophoresis. There are three patterns: (1) two slow-migrating bands, (2) three fast-migrating bands, and (3) a combination of (1) and (2). Re-electrophoresis of the individual bands and genetic analysis demonstrated the existence of two distinct isozymes controlled by two alleles at one locus. In a native population the esterase patterns were in a Hardy-Weinberg equilibrium. In the offspring of crosses between clonal grafts which represent individual trees with different esterase patterns, the patterns segregated in Mendelian ratios. In the haploid macrogametophytes of individual trees they also segregated as expected, i.e. in a 1:1 ratio. This latter fact allows a genetic analysis of individual trees without crossing experiments by investigation of the isozyme patterns only. PMID- 24487680 TI - Formation of bound gibberellins inPharbitis nil. AB - Developing seeds ofPharbitis nil accumulate free as well as bound gibberellins until a maximum level is reached at approximately 25 days after anthesis. Seeds from CCC-treated parent plants have a strongly reduced level of free as well as bound gibberellins. When different spray reagents were used it was found that trichloroacetic acid in particular was suitable to locate non-hydrolysed bound GA fractions on thin-layer plates. Chromatography showed two major bound GA fractions, determined with spray reagents as well as by means of hydrolysis.(3)H GA1 applied to youngPharbitis plants was converted to two water-soluble compounds present in the aqueous phase. The rate of conversion was significantly enhanced when(3)H-GA1 and(14)C-glucose were applied to the same plants. Chromatography indicated that one of the conversion products of(3)H-GA1 became at least partly associated with the applied(14)C-glucose (or its products). This suggestion was also supported by the fact that mild acid hydrolysis of the aqueous fraction resulted in the reappearance of(3)H-GA1 and a conversion product of(3)H-GA1, including a(14)C-radioactivity peak cochromatographing with(14)C-glucose. However, the conversion products obtained with(3)H-GA1 applied to plants appeared to be chromatographycally different from any of the bound-GA fraction established by means of hydrolysis or spray reagents in developing seeds. PMID- 24487681 TI - The demonstrationin vivo of more than one form ofP fr. AB - Phototransformation studies of pumpkin phytochromein vivo indicate two populations, a slow and a fast one. The ratio between the two populations can be altered by different light-dark-pretreatments. The destruction kinetics ofP fr also show a deviation from a first order curve which indicates the existence of two populations ofP fr with respect to decay. No significantP fr ->P r dark reversion could be detected. Two models are discussed, which could explain the shape of the destruction kinetics observed and the different ratios of the two populations obtained from phototransformation measurements. PMID- 24487682 TI - [Changes in enzyme activities during the growth of cell suspension cultures ofGlycine max: Phenylalanine ammonia-lyase and p-coumarate: CoA ligase]. AB - 1. A typical growth curve including a lag phase, phases of cell division and cell expansion and a stationary phase could be demonstrated for batch propagated cells ofGlycine max. in synthetic liquid medium. 2. Shortly before the stationary phase was reached, dramatic changes in the activities of two enzymes of "secondary plant metabolism", phenylalanine ammonia-lyase and p-coumarate: CoA ligase, were observed. In contrast, the activity of acetate:CoA ligase remained constant during this period of time, indicating that primary cell metabolism was unaffected. 3. Activities of both enzymes, phenylalanine ammonia-lyase and p coumarate: CoA ligase, could be enhanced by light. Using disc gel electrophoresis it was not possible to detect isoenzymes of phenylalanine ammonia-lyase in extracts either from cells grown in the dark or from those treated with light. PMID- 24487683 TI - [Influence of ferredoxin on ferredoxin-NADP reductase]. AB - Transhydrogenase and diaphorase activity of ferredoxin-NADP reductase are enhanced by plant ferredoxins. This stimulation is specific; ferredoxin cannot be replaced by sulfhydryl compounds such as cysteine or dithiothreitol, the apoprotein of ferredoxin or Fe(2+), Fe(3+) ions.The effect is particularly obvious with the reductase from the heterokont algaBumilleriopsis filiformis Vischer.Reductase and ferredoxin form a complex in the molar ratio of 1:1, which is sensitive to high ionic strength. Under these conditions the complex is destroyed thus eliminating the enhancement by ferredoxin of both transhydrogenase and diaphorase activities. It is concluded that the effect is due to complex formation.Higher concentrations of NAD (>3 mM) and of NADPH (>0.01 mM) inhibit transhydrogenase activity without any effect on its enhancement by ferredoxin. A specific binding site on the reductase for ferredoxin is assumed for which NAD is a poor competitor. Only in the absence of ferredoxin does NAD seem to activate the reductase by occupying both the ferredoxin site and that of the pyridine nucleotides. Reaction kinetics (as a function of NAD concentration) therefore switch from a sigmoid shape when no ferredoxin is added to the normal hyperbolic shape in its presence. Kinetic studies further suggest a "ping pong" type reaction mechanism for the transhydrogenase and diaphorase reaction. A possible change of the underlying mechanism in the presence of ferredoxin is discussed. PMID- 24487684 TI - [Phenylalanine ammonia-lyase (PAL, EC 4.3.1.5) of the mustard seedling (Sinapis alba L.), an electrophoretically homogeneous enzyme]. AB - Improved techniques in localization of phenylalanine ammonia-lyase (PAL) on polyacrylamide disk electrophoresis columns indicate that the enzyme synthesized under the control of phytochrome is electrophoretically indistinguishable from the enzyme present in dark grown mustard seedlings. Furthermore, no heterogeneity of PAL with respect to molecular size has been detected. However, the formation of high molecular weight aggregates with PAL activity in tris buffer of low concentration has been demonstrated. The data lead to the conclusion that phytochrome does not induce the synthesis of a novel PAL enzyme differing in its structural properties from the PAL in dark grown seedlings. The observations of other investigators on separable forms of PAL are critically discussed. PMID- 24487685 TI - Specificity and reversibility of the rapid stomatal response to abscisic acid. AB - Closure of stomata caused by low (10(-7)M) concentrations of abscisic acid (ABA) is specific for cis-trans ABA, and is initiated within 5 minutes. Upon withdrawal of the hormone supply, reopening starts within 5 minutes. Gas analysis of leaves treated with ABA or DCMU allows one to distinguish effects on the stomatal apparatus from inhibition of photosynthesis and to conclude that ABA acts on stomata directly. PMID- 24487686 TI - The association of chloroplast peripheral reticulum with low photorespiration rates in a photorespiring plant species. AB - A peripheral reticulum occurs in mesophyll chloroplasts of the pentose cycle plantDactylis glomerata L. (orchardgrass). This structural feature was previously thought to occur primarily in the chloroplasts of tropical grasses and other species utilizing the C4-dicarboxylic-acid photosynthesis pathway. Since the peripheral reticulum is seen in a selection ofD. glomerata which has a low rate of photorespiration, but not in a selection which has a high rate of photorespiration (Carlsonet al., 1971), photorespiratory rates may be dependent in part on the presence or absence of a chloroplast peripheral reticulum. PMID- 24487687 TI - Polar transport and accumulation of indole-3-acetic acid during root regeneration byPinus lambertiana embryos. PMID- 24487688 TI - Diallyl trisulfide inhibits estrogen receptor-alpha activity in human breast cancer cells. AB - Organosulfur compounds from garlic effectively inhibit growth of transplanted as well as spontaneous cancers in preclinical animal models without any adverse side effects. However, the mechanisms underlying anticancer effect of this class of compounds are not fully understood. This study reports, for the first time, that garlic organosulfide diallyl trisulfide (DATS) inhibits estrogen receptor-alpha (ER-alpha) activity in human breast cancer cells. Exposure of MCF-7 and T47D cells to DATS resulted in downregulation of ER-alpha protein, which peaked between 12- and 24-h post-treatment. DATS was relatively more effective in suppressing ER-alpha protein expression compared with its mono and disulfide analogs. The 17beta-estradiol (E2)-induced expression of pS2 and cyclin D1, ER alpha target gene products, was also decreased in the presence of DATS. Downregulation of ER-alpha protein expression resulting from DATS treatment was accompanied by a decrease in nuclear levels of ER-alpha protein, ER-alpha mRNA suppression, and inhibition of ERE2e1b-luciferase reporter activity. DATS mediated inhibition of cell viability and apoptosis induction were not affected in the presence of E2. In agreement with these results, ectopic expression of ER alpha in MDA-MB-231 cell line failed to confer any protection against cell proliferation inhibition or apoptosis induction resulting from DATS exposure. DATS treatment caused a decrease in protein levels of peptidyl-prolyl cis-trans isomerase (Pin1), and overexpression of Pin1 partially attenuated ER-alpha downregulation by DATS. DATS-induced apoptosis was modestly but significantly augmented by overexpression of Pin1. In conclusion, this study identifies ER alpha as a novel target of DATS in mammary cancer cells. PMID- 24487689 TI - Estrogen receptor (ER) alpha mutations in breast cancer: hidden in plain sight. AB - The idea that somatic ERalpha mutations could play an important role in the evolution of hormone-dependent breast cancers was proposed some years ago (Fuqua J Mammary Gland Biol Neoplasia 6(4):407-417, 2001; Dasgupta et al. Annu Rev Med 65:279-292, 2013), but has remained controversial until recently. A significant amount of new data has confirmed these initial observations and shown their significance, along with much additional work relevant to the treatment of breast cancer. Thus, it is the purpose of this review to summarize the research to date on the existence and clinical consequences of ERalpha mutations in primary and metastatic breast cancer. PMID- 24487690 TI - Effect of multiplicity, laterality, and age at onset of breast cancer on familial risk of breast cancer: a nationwide prospective cohort study. AB - The objective of this nationwide prospective cohort study is to find out the risk of breast cancer (BC) in relatives of patients with multiple BCs by laterality and age at diagnosis of first BC. Having family history of single (HR 1.8; 95 % CI 1.8-1.9) or multiple (HR 2.7; 95 % CI 2.6-2.9) BC was associated with higher risk of BC. Those with an FDR with contralateral BC at any age had the highest risk of familial cancer except at age <40 in which those whose young FDR was affected by multiple ipsilateral BC had the highest risk (HR 9.7; 95 % CI 6.0 15.6). The familial risk of BC in these families decreased as the subject's and FDRs' age at diagnosis of first BC increased. The HR was still significantly increased (2.2) for old individuals (>60) having a FDR with contralateral BC at an advanced age (>=80). Despite the common belief that later onset breast cancer is more associated with sporadic breast cancer, our data suggest that breast cancer at any age in the family is associated with some increase in the familial risk, though that risk decreases as the age of onset increases. Contralateral and multiple ipsilateral breast cancers might be associated with distinct shared familial risk factors. Our results have implication for genetic counseling and urge gene identification studies. PMID- 24487692 TI - Bacteriophages use an expanded genetic code on evolutionary paths to higher fitness. AB - Bioengineering advances have made it possible to fundamentally alter the genetic codes of organisms. However, the evolutionary consequences of expanding an organism's genetic code with a noncanonical amino acid are poorly understood. Here we show that bacteriophages evolved on a host that incorporates 3 iodotyrosine at the amber stop codon acquire neutral and beneficial mutations to this new amino acid in their proteins, demonstrating that an expanded genetic code increases evolvability. PMID- 24487691 TI - Bone mineral density and circulating biomarkers in the BIG 1-98 trial comparing adjuvant letrozole, tamoxifen and their sequences. AB - The purpose of the study is to determine the effects of the BIG 1-98 treatments on bone mineral density. BIG 1-98 compared 5-year adjuvant hormone therapy in postmenopausal women allocated to four groups: tamoxifen (T); letrozole (L); 2 years T, 3-years L (TL); and 2-years L, 3-years T (LT). Bone mineral density T score was measured prospectively annually by dual energy X-ray absorption in 424 patients enrolled in a sub-study after 3 (n = 150), 4 (n = 200), and 5 years (n = 74) from randomization, and 1 year after treatment cessation. Prevalence of osteoporosis and the association of C-telopeptide, osteocalcin, and bone alkaline phosphatase with T-scores were assessed. At 3 years, T had the highest and TL the lowest T-score. All arms except for LT showed a decline up to 5 years, with TL exhibiting the greatest. At 5 years, there were significant differences on lumbar T-score only between T and TL, whereas for femur T-score, differences were significant for T versus L or TL, and L versus LT. The 5-year prevalence of spine and femur osteoporosis was the highest on TL (14.5 %, 7.1 %) then L (4.3 %, 5.1 %), LT (4.2 %, 1.4 %) and T (4 %, 0). C-telopeptide and osteocalcin were significantly associated with T-scores. While adjuvant L increases bone mineral density loss compared with T, the sequence LT has an acceptable bone safety profile. C-telopeptide and osteocalcin are useful markers of bone density that may be used to monitor bone health during treatment. The sequence LT may be a valid treatment option in patients with low and intermediate risk of recurrence. PMID- 24487693 TI - An orthogonal DNA replication system in yeast. AB - An extranuclear replication system, consisting of an orthogonal DNA plasmid-DNA polymerase pair, was developed in Saccharomyces cerevisiae. Engineered error prone DNA polymerases showed complete mutational targeting in vivo: per-base mutation rates on the plasmid were increased substantially and remained stable with no increase in genomic rates. Orthogonal replication serves as a platform for in vivo continuous evolution and as a system whose replicative properties can be manipulated independently of the host's. PMID- 24487694 TI - Negative selection and stringency modulation in phage-assisted continuous evolution. AB - Phage-assisted continuous evolution (PACE) uses a modified filamentous bacteriophage life cycle to substantially accelerate laboratory evolution experiments. In this work, we expand the scope and capabilities of the PACE method with two key advances that enable the evolution of biomolecules with radically altered or highly specific new activities. First, we implemented small molecule-controlled modulation of selection stringency that enables otherwise inaccessible activities to be evolved directly from inactive starting libraries through a period of evolutionary drift. Second, we developed a general negative selection that enables continuous counterselection against undesired activities. We integrated these developments to continuously evolve mutant T7 RNA polymerase enzymes with ~10,000-fold altered, rather than merely broadened, substrate specificities during a single three-day PACE experiment. The evolved enzymes exhibit specificity for their target substrate that exceeds that of wild-type RNA polymerases for their cognate substrates while maintaining wild type-like levels of activity. PMID- 24487695 TI - Patients' perceptions of bedside handoff: the need for a culture of always. AB - Current literature on patients' perceptions of bedside handoff describes studies using qualitative, anecdotal, and/or indirect measurement. This study identifies patients' perceptions of the bedside handoff through direct and quantitative measurement. The statistically significant findings from a survey of 103 medical surgical adult patients demonstrate that registered nurse bedside handoff has a positive effect on patient perceptions of safety, understanding, and satisfaction. Bedside end-of-shift handoff is most effective when it is performed consistently. PMID- 24487697 TI - Oxygen evolution reaction electrocatalyzed on a Fenton-treated gold surface. AB - Hydroxyl radicals arising from the Fenton reagent remove metastable surface gold atoms (low coordinated high-energy surface atoms) on the Au surface, thus precluding the formation of stable oxides. The resultant smooth surface, upon hydroxyl-radical activation, electrocatalyzes oxygen evolution reaction in 0.1 M NaOH at overpotentials lowered by 190 mV @ 10 mA cm(-2). PMID- 24487696 TI - Feasibility, acceptability, and effectiveness of an electronic sensor bed/chair alarm in reducing falls in patients with cognitive impairment in a subacute ward. AB - Falls from bed are common in subacute hospital settings, particularly for patients with cognitive impairment. This repeated measures, single cohort study in 1 subacute ward evaluated effectiveness of an electronic sensor alarm in reducing falls in patients (n = 34) with cognitive impairment. Nursing staff feedback (focus group, survey) was used to determine electronic sensor alarm feasibility. The electronic alarm system was found to be a feasible, effective, and acceptable fall prevention strategy for patients with cognitive impairment. PMID- 24487698 TI - Detecting hepatic steatosis using ultrasound-induced thermal strain imaging: an ex vivo animal study. AB - Hepatic steatosis or fatty liver disease occurs when lipids accumulate within the liver and can lead to steatohepatitis, cirrhosis, liver cancer and eventual liver failure requiring liver transplant. Conventional brightness mode (B-mode) ultrasound (US) is the most common noninvasive diagnostic imaging modality used to diagnose hepatic steatosis in clinics. However, it is mostly subjective or requires a reference organ such as the kidney or spleen with which to compare. This comparison can be problematic when the reference organ is diseased or absent. The current work presents an alternative approach to noninvasively detecting liver fat content using US-induced thermal strain imaging (US-TSI). This technique is based on the difference in the change in the speed of sound as a function of temperature between water- and lipid-based tissues. US-TSI was conducted using two system configurations including a mid-frequency scanner with a single linear array transducer (5-14 MHz) for both imaging and heating and a high-frequency (13-24 MHz) small animal imaging system combined with a separate custom-designed US heating transducer array. Fatty livers (n = 10) with high fat content (45.6 +/- 11.7%) from an obese mouse model and control livers (n = 10) with low fat content (4.8 +/- 2.9%) from wild-type mice were embedded in gelatin. Then, US imaging was performed before and after US induced heating. Heating time periods of ~ 3 s and ~ 9.2 s were used for the mid-frequency imaging and high frequency imaging systems, respectively, to induce temperature changes of approximately 1.5 degrees C. The apparent echo shifts that were induced as a result of sound speed change were estimated using 2D phase-sensitive speckle tracking. Following US-TSI, histology was performed to stain lipids and measure percentage fat in the mouse livers. Thermal strain measurements in fatty livers ( 0.065 +/- 0.079%) were significantly (p < 0.05) higher than those measured in control livers (-0.124 +/- 0.037%). Using histology as a gold standard to classify mouse livers, US-TSI had a sensitivity and specificity of 70% and 90%, respectively. The area under the receiver operating characteristic curve was 0.775. This ex vivo study demonstrates the feasibility of using US-TSI to detect fatty livers and warrants further investigation of US-TSI as a diagnostic tool for hepatic steatosis. PMID- 24487699 TI - Further evidence about the crucial role of CSF biomarkers in diagnosis of posterior cortical atrophy. AB - Cerebrospinal fluid (CSF) biomarkers (protein tau, phosphorylated tau and amyloid Beta 1-42) are recognized as a supportive feature in diagnosis of Alzheimer's disease (AD) and their role in identifying atypical variants of AD is currently under investigation. We dosed these proteins in nine patients clinically and instrumentally affected by posterior cortical atrophy (PCA), a rare disorder characterized by a progressive neurodegenerative process that involves primarily the posterior brain regions. We compared the obtained values with a large group of AD patients (N = 117), recruited in our neurological department. Our data revealed no differences in the CSF profile between PCA and AD, showing abnormal values of protein tau, phosphorylated tau and amyloid Beta 1-42 in both groups of patients. This study underlines the diagnostic importance of CSF biomarkers in PCA patients, supporting the hypothesis that PCA is an atypical variant of AD with an onset before the age of 65. PMID- 24487702 TI - A photo- and electrochemical investigation of BODIPY-cobaloxime complexes for hydrogen production, coupled with quantum chemical calculations. AB - Two BODIPY-cobaloxime complexes; [{Co(dmgH)2Cl}{3-[bis-(4-ethyl-3,5-dimethyl-1H pyrrol-2-yl)-methyl]-pyridine-borondiflouride}] (1a) and [{Co(dmgH)2Cl}{4-[bis-(4 ethyl-3,5-dimethyl-1H-pyrrol-2-yl)-methyl]-pyridine-borondiflouride}] (2a) (BODIPY = boron dipyrromethene), (dmgH = dimethylglyoxime) have been synthesised and studied as model catalytic systems for the generation of hydrogen gas in aqueous media. Under photochemical conditions, neither complex catalysed the reduction of water to hydrogen. However, both complexes showed considerable activity under electrochemical conditions. Turn-over-numbers for hydrogen production of 1.65 * 10(4) and 1.08 * 10(4) were obtained for 1a and 2a respectively following potentiostatic electrolysis at -1.2 V vs. Ag/AgCl after 1 hour. Quantum chemical calculations were performed to provide an explanation for the lack of photochemical activity. PMID- 24487701 TI - Repetitive transcranial magnetic stimulation in restless legs syndrome: preliminary results. AB - Our aim was to compare the effect of high-frequency repetitive transcranial magnetic stimulation (rTMS) over supplementary motor area with that of sham stimulation in restless legs syndrome (RLS). In this prospective study, patients were randomly assigned to either real stimulation group (11 patients), or sham stimulation group (8 patients) in a double-blinded fashion. Five patients, who were initially in the sham stimulation group, received real stimulation 1 month after the sham stimulation. One session of intervention was performed once every 3 days and total of ten sessions were done in each group. The International RLS Rating Scale (IRLS-RS) was assessed at baseline and after 5th and 10th sessions in both groups and also in five patients in whom both sham and real stimulation were performed. A statistically significant difference was seen in the IRLS scores between real (n = 11) and sham stimulation (n = 8) after 5th and 10th sessions. The real stimulation significantly improved the IRLS-RS scores although they were unaffected by the sham stimulation. In five patients, in whom both sham and real stimulation were performed, a statistically significant improvement was seen in the IRLS-RS scores with the real stimulation and a statistically significant difference was seen in the IRLS scores between real and sham stimulation after 10th session. In conclusion, this method is safe and non invasive, and the results of this pilot study may support that rTMS has the potential to be used in the treatment of RLS, which should be verified in larger series. PMID- 24487703 TI - Enzyme-inducing anticonvulsants increase plasma clearance of dexmedetomidine: a pharmacokinetic and pharmacodynamic study. AB - BACKGROUND: Dexmedetomidine is useful during mapping of epileptic foci as it facilitates electrocorticography unlike most other anesthetic agents. Patients with seizure disorders taking enzyme-inducing anticonvulsants appear to be resistant to its sedative effects. The objective of the study was to compare the pharmacokinetic and pharmacodynamic profile of dexmedetomidine in healthy volunteers with volunteers with seizure disorders receiving enzyme-inducing anticonvulsant medications. METHODS: Dexmedetomidine was administered using a step-wise, computer-controlled infusion to healthy volunteers (n = 8) and volunteers with seizure disorders (n = 8) taking phenytoin or carbamazapine. Sedation and dexmedetomidine plasma levels were assessed at baseline, during the infusion steps, and after discontinuation of the infusion. Sedation was assessed by using the Observer's Assessment of Alertness/Sedation Scale, Ramsay Sedation Scale, and Visual Analog Scale and processed electroencephalography (entropy) monitoring. Pharmacokinetic analysis was performed on both groups, and differences between groups were determined using the standard two-stage approach. RESULTS: A two-compartment model was fit to dexmedetomidine concentration-time data. Dexmedetomidine plasma clearance was 43% higher in the seizure group compared with the control group (42.7 vs. 29.9 l/h; P = 0.007). In contrast, distributional clearance and the volume of distribution of the central and peripheral compartments were similar between the groups. No difference in sedation was detected between the two groups during a controlled range of target plasma concentrations. CONCLUSION: This study demonstrates that subjects with seizure disorders taking enzyme-inducing anticonvulsant medications have an increased plasma clearance of dexmedetomidine as compared with healthy control subjects. PMID- 24487704 TI - Fatal pancreatic injury due to trauma after successful cardiopulmonary resuscitation with automatic mechanical chest compression. PMID- 24487705 TI - Leading departmental change to advance perioperative quality. PMID- 24487706 TI - The risk versus benefit of LUCAS: is it worth it? PMID- 24487707 TI - Irrelevant, incidental and core features in the retrograde amnesia associated with Korsakoff's psychosis: a review. AB - A brief review of the literature on retrograde amnesia in Korsakoff's syndrome is presented. Various explanations of the phenomenon are discussed including the notions that it results from the effects of "state-dependency", that it occurs as a result of a progressive learning problem and that it arises through a failure in contextual processing. None of these hypotheses can satisfactorily account for the length and temporal gradient of alcoholic amnesics retrograde amnesia. Although some evidence points towards the hypothesis that anterograde and retrograde amnesia might result from separate and independent impairments, this view is presently unproven and leaves open what causes the form and duration of Korsakoffs retrograde amnesia. PMID- 24487708 TI - Partnership and depression in Parkinson's disease. AB - In this study, the influence of partnership on depression and coping with Parkinson's disease has been investigated. Twenty-three single female patients, 46 married patients (23 female, 23 male) with unimpaired partnership and 42 patients (21 female, 21 male) whose partnership had worsened since the onset of disease, were compared with regard to depression and self reported extent of psychosocial distress. Single female patients tended to have higher depression scores than patients in a stable partnership, especially in items concerning personal worthlessness and senselessness of life. Patients differed in the extent of distress concerning social behavior, psychological problems/anxiety and efficiency. Within the group of single female patients two subgroups emerged: (1) patients with low extent of distress in all aspects; (2) patients who were highly distressed by psychological problems and physical disability but weakly distressed from social interaction. Male and female patients living in a stable partnership reported only a generally low to moderate extent of distress. More than half of the male and female patients who reported an impairment of their relationship also had scores of moderate to severe depression. These patients also had the highest extent of distress in each of the aspects assessed. The results are discussed with regard to possible interactive effects of the disease, quality of the partnership and availability of coping strategies. PMID- 24487709 TI - Hallucinations and parkinsonian motor fluctuations. AB - Thirty patients with Parkinson's disease experiencing hallucinations during long term treatment were compared with 20 parkinsonian patients without hallucinations. No differences were found in the duration of disease, L-dopa treatment or disease severity between the two groups. The hallucinators however, were significantly older and more cognitively impaired. Visual hallucinations occurring only during "off periods of immobility" were relatively common and improved concurrently with parkinsonian disabilities after L-dopa. Although visual hallucinations were commonest auditory hallucinations occurred in one third of the hallucinators. PMID- 24487710 TI - Dementia of frontal lobe type and amyotrophy. AB - Dementia of frontal lobe type may precede motor signs in a number of adult patients with amyotrophy. Neuropathological studies have shown neuron loss, spongiosis and gliosis mainly in layers II and III of the frontal and temporal lobes, together with myelin pallor of the subcortical white matter. Golgi studies revealed loss of dendritic spines on the apical dendrite of layer III pyramidal neurons, decreased numbers of dendrites, amputation and tortuosities of dendrites, and distal and proximal dendritic swellings and enlargements. Calbindin D-28K immunocytochemistry revealed a marked decrease in the number of cortical immunoreactive neurons and loss of immunoreactivity in dendrites of the remaining cells. These features indicate that pyramidal and non-pyramidal neurons in layers II and III are severely damaged, and suggest that cortical processing is seriously impaired in patients with frontal lobe type dementia. PMID- 24487711 TI - A 54-point verbal-performance IQ discrepancy on the WISC-R: cognitive functioning of a child from an alternative school. AB - Marked WISC-R verbal-performance discrepancy commonly leads to the assumption that such children have brain pathology or cognitive disorders. Children without brain dysfunction may also exhibit wide discrepancy, but a discrepancy score of 30 is assumed to occur in only 2% of the population. The actual investigation presents an 11-year-old child showing a 54-point discrepancy between the two scales of the WISC-R. Results of wide ranging testing and other considerations strongly suggested that this child didn't manifest any kind of brain dysfunction. It was concluded that the particular academic environment of the child, an alternative school, exerted a very strong influence on her results on the WISC-R. This conclusion is furthermore supported by the results of a follow-up evaluation, done 1 year after the child has been transferred to a traditional school, which revealed a WISC-R verbal-performance discrepancy of only 12 points. PMID- 24487712 TI - Aborting seizures by painful stimulation. AB - It has been well established that serious consequences may result from allowing seizures to continue. The opportunities for early interruption of seizures by medication is often restricted to medical personnel, leaving non-trained bystanders unable to intervene. We were able to interrupt seizures (including status epilepticus) by application of painful dorsiflexion. The mode of action that enables pain to elevate the seizure threshold remains to be elucidated, although the phenomenon is consistent with earlier laboratory studies in experimental epilepsy. The technique may be recommended as an effective and easily learned procedure that may have wide applicability. PMID- 24487713 TI - Cognitive retardation in a patient with preservation of psychomotor speed. AB - We describe a patient (R.S.) who after a bout of probable TB exhibited an unusual pattern of response retardation, although given time he was able to score at a satisfactory level. He was strikingly slow to initiate speaking and to carry out higher level cognitive tasks, at a time when he could complete a variety of psychomotor activities at normal speed. He showed many similarities with patients previously described as having subcortical dementia. The selective preservation of psychomotor responding in the context of his gross bradyphrenia, however, was unexpected. PMID- 24487714 TI - Transformation of Broca's aphasia into conduction aphasia: a case report. AB - We describe a patient with a cerebral infarction localized mainly in the left posterior frontal and anterior parietal subcortices who experienced a Broca's aphasia which evolved into a conduction aphasia. Such a rare recovery pattern of aphasia appeared to result from amelioration of the damage to the left precentral gyrus. PMID- 24487715 TI - A case with probable herpes simplex encephalitis characterized by specific emotional and behavioral disorders and Gogi (word-meaning) aphasia-like syndrome with neologism and neologistic kanji processing. AB - A right-handed male patient with probable herpes simplex encephalitis is presented because of the rarity of the clinicial picture. Brain X-ray CT scans showed lesions located in the bilateral fronto-temporal regions primarily involving the left lower temporal lobe. The clinical picture following the acute phase of the disease was characterized by specific emotional and behavioral disorders, i.e. oral tendency, hyperactivity, thoughtless talkativeness, random speech and exhilaration, which were partly compatible with the Kluver-Bucy syndrome. Furthermore, this case was characterized by Gogi (word-meaning) aphasia like transcortical sensory aphasia and neologism produced saliently when naming objects and peculiar neologistic kanji processing in writing to dictation and oral reading. Both the neologism and neologistic kanji processing varied in quantity in parallel with the specific emotional and behavioral disorders. The relationships of these clinical features to lesional sites demonstrated by X-ray CT are discussed. PMID- 24487716 TI - Relapsing depression in paramedian thalamic infarctions. AB - Depression has recently been associated with lesions in the CNS, particularly with large infarctions in the cerebral hemispheres. We report a patient in whom two episodes of acute depression were related to relapsing paramedian thalamic infarctions, which were accompanied by additional transient mild neuropsychological deficits, hypersomnia and a discrete sensory disturbance of the left face. Thalamic infarctions have been shown to mimic a variety of higher functional deficits, such as aphasias, apraxias and attentional disorders, traditionally associated with hemispheric strokes. We conjecture that the paramedian thalamic infarctions observed in our patient have in a similar manner been responsible for the transient depression. PMID- 24487718 TI - Reducing the risk of flexor pollicis longus tendon rupture after volar plate fixation for distal radius fractures: validation of the tendon irritation test. AB - BACKGROUND: We have proposed that a positive tendon irritation test is suggestive of flexor pollicis longus (FPL) tendon damage that can lead to tendon rupture after volar plate fixation for distal radius fractures. We investigated cases of postsurgical hardware removal and validated the tendon irritation test as a way to elicit a sign of FPL tendon irritation. PATIENTS AND METHODS: We performed hardware removal from 30 wrists in 28 consecutive patients after volar plate fixation. Subjects included 9 men and 19 women with an average age of 58.8 years. The duration of internal fixation averaged 14.5 months. We investigated the efficacy of the tendon irritation test to elicit a sign of tendon irritation before hardware removal, and we intraoperatively evaluated the presence of FPL tendon injuries. RESULTS: Twenty-four of 30 wrists exhibited a sign of tendon irritation. There was no statistical correlation between a sign of tendon irritation and patient age or the duration of internal fixation. We diagnosed 10 wrists with tenosynovitis and 8 frayed tendons. The sensitivity of the tendon irritation test to identify a sign of tendon irritation that was associated with FPL tendon injuries was 80.0%, and its specificity to correctly identify non injured FPL tendons was 40.0%. The duration of internal fixation associated with tendon fraying was significantly longer than it was in cases of non-injured tendons and tenosynovitis. CONCLUSION: Our results suggest that subsequent examinations should be performed when the tendon irritation test is positive for signs of tendon irritation that may require plate removal. PMID- 24487717 TI - Hospital variation in survival after in-hospital cardiac arrest. AB - BACKGROUND: In-hospital cardiac arrest (IHCA) is common and often fatal. However, the extent to which hospitals vary in survival outcomes and the degree to which this variation is explained by patient and hospital factors is unknown. METHODS AND RESULTS: Within Get with the Guidelines-Resuscitation, we identified 135 896 index IHCA events at 468 hospitals. Using hierarchical models, we adjusted for demographics comorbidities and arrest characteristics (eg, initial rhythm, etiology, arrest location) to generate risk-adjusted rates of in-hospital survival. To quantify the extent of hospital-level variation in risk-adjusted rates, we calculated the median odds ratio (OR). Among study hospitals, there was significant variation in unadjusted survival rates. The median unadjusted rate for the bottom decile was 8.3% (range: 0% to 10.7%) and for the top decile was 31.4% (28.6% to 51.7%). After adjusting for 36 predictors of in-hospital survival, there remained substantial variation in rates of in-hospital survival across sites: bottom decile (median rate, 12.4% [0% to 15.6%]) versus top decile (median rate, 22.7% [21.0% to 36.2%]). The median OR for risk-adjusted survival was 1.42 (95% CI: 1.37 to 1.46), which suggests a substantial 42% difference in the odds of survival for patients with similar case-mix at similar hospitals. Further, significant variation persisted within hospital subgroups (eg, bed size, academic). CONCLUSION: Significant variability in IHCA survival exists across hospitals, and this variation persists despite adjustment for measured patient factors and within hospital subgroups. These findings suggest that other hospital factors may account for the observed site-level variations in IHCA survival. PMID- 24487720 TI - Uncovering hidden nodes in complex networks in the presence of noise. AB - Ascertaining the existence of hidden objects in a complex system, objects that cannot be observed from the external world, not only is curiosity-driven but also has significant practical applications. Generally, uncovering a hidden node in a complex network requires successful identification of its neighboring nodes, but a challenge is to differentiate its effects from those of noise. We develop a completely data-driven, compressive-sensing based method to address this issue by utilizing complex weighted networks with continuous-time oscillatory or discrete time evolutionary-game dynamics. For any node, compressive sensing enables accurate reconstruction of the dynamical equations and coupling functions, provided that time series from this node and all its neighbors are available. For a neighboring node of the hidden node, this condition cannot be met, resulting in abnormally large prediction errors that, counterintuitively, can be used to infer the existence of the hidden node. Based on the principle of differential signal, we demonstrate that, when strong noise is present, insofar as at least two neighboring nodes of the hidden node are subject to weak background noise only, unequivocal identification of the hidden node can be achieved. PMID- 24487721 TI - Epigenetic modification and inheritance in sexual reversal of fish. AB - Environmental sex determination (ESD) occurs in divergent, phylogenetically unrelated taxa, and in some species, co-occurs with genetic sex determination (GSD) mechanisms. Although epigenetic regulation in response to environmental effects has long been proposed to be associated with ESD, a systemic analysis on epigenetic regulation of ESD is still lacking. Using half-smooth tongue sole (Cynoglossus semilaevis) as a model-a marine fish that has both ZW chromosomal GSD and temperature-dependent ESD-we investigated the role of DNA methylation in transition from GSD to ESD. Comparative analysis of the gonadal DNA methylomes of pseudomale, female, and normal male fish revealed that genes in the sex determination pathways are the major targets of substantial methylation modification during sexual reversal. Methylation modification in pseudomales is globally inherited in their ZW offspring, which can naturally develop into pseudomales without temperature incubation. Transcriptome analysis revealed that dosage compensation occurs in a restricted, methylated cytosine enriched Z chromosomal region in pseudomale testes, achieving equal expression level in normal male testes. In contrast, female-specific W chromosomal genes are suppressed in pseudomales by methylation regulation. We conclude that epigenetic regulation plays multiple crucial roles in sexual reversal of tongue sole fish. We also offer the first clues on the mechanisms behind gene dosage balancing in an organism that undergoes sexual reversal. Finally, we suggest a causal link between the bias sex chromosome assortment in the offspring of a pseudomale family and the transgenerational epigenetic inheritance of sexual reversal in tongue sole fish. PMID- 24487723 TI - Autopsy in undergraduate medical education--what do students really learn? AB - Forensic medicine can provide access to autopsies for students in undergraduate medical education. Previous qualitative studies reported that attending autopsies promotes learning and is helpful in organising information in the context of self directed learning, covering cognitive, emotional and societal issues. In the present study, learning outcome regarding specific pathophysiological learning objectives of students who attended an autopsy elective (intervention group, n = 32) was estimated in comparison to peer students who signed up for the course but were not selected (control group A, n = 47) and students who had not signed up (control group B, n = 186). Learning outcome (expressed as a percent knowledge gain) was measured by means of comparative self-assessments (CSA). Furthermore, group interviews were conducted to evaluate the attending students' perceptions and experiences of the course. In the intervention group, the percent knowledge gain for learning objectives reflecting pathophysiological mechanisms was about twice as high than that in the control groups, while all three groups showed comparable knowledge gain for learning objectives covered by mandatory courses that were held during the study period. Results of mandatory post-course assessments showed no statistically significant differences between the intervention and control groups. Therefore, the knowledge gain regarding learning objectives not covered by mandatory courses that was observed in the intervention group reflected the additional benefit of attending the autopsy course. Group interviews with the participants revealed gain of integrated knowledge and understanding of pathophysiological relations as important issues, while negative effects were reported infrequently. Our findings suggest that attendance of a series of autopsies fosters learning and understanding of important issues in medical education and should therefore be part of undergraduate medical curricula wherever possible. PMID- 24487722 TI - D-K6L 9 peptide combination with IL-12 inhibits the recurrence of tumors in mice. AB - D-K6L9 peptide is bound by phosphatidylserine and induces necrosis in cancer cells. In our therapeutic experience, this peptide, when administered directly into B16-F10 murine melanoma tumors, inhibited their growth. Cessation of therapy results, however, in tumor relapse. We aimed at developing a combined therapy involving D-K6L9 and additional factors that would yield complete elimination of tumor cells in experimental animals. To this purpose, we employed glycyrrhizin, an inhibitor of HMGB1 protein, BP1 peptide and interleukin (IL)-12. Glycyrrhizin or BP1, when combined with D-K6L9, inhibits growth of primary tumors only during the period of their administration. A long-term tumor growth inhibitory effect was obtained only in combining D-K6L9 with IL-12. At 2 months following therapy cessation, 60 % of animals were alive. Prolonged survival was noted in mice bearing B16-F10 tumors as well as in mice bearing C26 colon carcinoma tumors. PMID- 24487724 TI - One-way transparency of four-coloured spin-wave excitations in multiferroic materials. AB - The coupling between spins and electric dipoles governs magnetoelectric phenomena in multiferroics. The dynamical magnetoelectric effect, which is an inherent attribute of the spin excitations in multiferroics, drastically changes the optical properties of these compounds compared with conventional materials where light-matter interaction is expressed only by the dielectric permittivity or magnetic permeability. Here we show via polarized terahertz spectroscopy studies on multiferroic Ca2CoSi2O7, Sr2CoSi2O7 and Ba2CoGe2O7 that such magnetoeletric spin excitations exhibit quadrochroism, that is, they have different colours for all the four combinations of the two propagation directions (forward or backward) and the two orthogonal polarizations of a light beam. We demonstrate that one-way transparency can be realized for spin-wave excitations with sufficiently strong optical magnetoelectric effect. Furthermore, the transparent and absorbing directions of light propagation can be reversed by external magnetic fields. This magnetically controlled optical-diode function of magnetoelectric multiferroics may open a new horizon in photonics. PMID- 24487725 TI - Cigarette smoking and endometrial carcinoma risk: the role of effect modification and tumor heterogeneity. AB - PURPOSE: The inverse relationship between cigarette smoking and endometrial carcinoma risk is well established. We examined effect modification of this relationship and associations with tumor characteristics in the National Institutes of Health-AARP Diet and Health Study. METHODS: We examined the association between cigarette smoking and endometrial carcinoma risk among 110,304 women. During 1,029,041 person years of follow-up, we identified 1,476 incident endometrial carcinoma cases. Multivariable Cox proportional hazards regression models were used to estimate relative risks (RRs) and 95 % confidence intervals (CIs) for the association between smoking status, years since smoking cessation, and endometrial carcinoma risk overall and within strata of endometrial carcinoma risk factors. Effect modification was assessed using likelihood ratio test statistics. Smoking associations by histologic subtype/grade and stage at diagnosis were also evaluated. RESULTS: Reduced endometrial carcinoma risk was evident among former (RR 0.89, 95 % CI 0.80, 1.00) and current (RR 0.65, 95 % CI 0.55, 0.78) smokers compared with never smokers. Smoking cessation 1-4 years prior to baseline was significantly associated with endometrial carcinoma risk (RR 0.65, 95 % CI 0.48, 0.89), while cessation >= 10 years before baseline was not. The association between smoking and endometrial carcinoma risk was not significantly modified by any endometrial carcinoma risk factor, nor did we observe major differences in risk associations by tumor characteristics. CONCLUSION: The cigarette smoking-endometrial carcinoma risk relationship was consistent within strata of important endometrial carcinoma risk factors and by clinically relevant tumor characteristics. PMID- 24487726 TI - Bilateral oophorectomy and risk of cancer in African American women. AB - PURPOSE: African American women are more likely to undergo hysterectomy, with or without bilateral oophorectomy, at younger ages than white women. It is well established that women who have a bilateral oophorectomy at younger ages are at reduced risk of breast cancer, and there is some evidence of an increased risk of colorectal and lung cancer. METHODS: Using data from 44,514 women in the Black Women's Health Study, we prospectively investigated the relation of hysterectomy and oophorectomy to incidence of breast, colorectal, and lung cancer and to mortality from cancer. Hazard ratios (HRs) and 95 % confidence intervals (CIs) were estimated using Cox proportional hazards regression with control for confounding factors. RESULTS: During 16 years of follow-up, hysterectomy alone, relative to no hysterectomy, was not associated with risk of breast, lung, or colorectal cancer. Bilateral oophorectomy, relative to hysterectomy with ovarian conservation, was inversely associated with risk of estrogen receptor-positive (ER+) breast cancer (HR 0.62; 95 % CI 0.45-0.85) but not with ER-negative breast cancer; age at surgery and menopausal hormone use did not modify the associations. HRs for the association of bilateral oophorectomy with incidence of colorectal and lung cancer were nonsignificantly increased for women who had surgery before age 40 years and had used menopausal hormones for less than 2 years (HR 1.65; 95 % CI 0.73-3.73 for colorectal cancer and HR 1.71; 95 % CI 0.68 4.31 for lung cancer). Bilateral oophorectomy was not associated with cancer mortality. CONCLUSIONS: Bilateral oophorectomy was associated with reduced risk of ER+ breast cancer regardless of age at surgery and use of menopausal hormones. There were nonsignificant increases in risk of colorectal and lung cancer for women with oophorectomy at younger ages and short duration of menopausal hormone use. PMID- 24487727 TI - Generality and specificity in cognitive control: conflict adaptation within and across selective-attention tasks but not across selective-attention and Simon tasks. AB - To explain how cognitive control is modulated contextually, Botvinick, Braver, Barch, Carter, and Cohen (Psychol Rev 108:624-652, 2001) proposed that detecting information-processing conflict attenuates the disruptive influence of information-processing conflicts encountered subsequently, by which time appropriate cognitive-control mechanisms already will have been engaged. This conflict-adaptation hypothesis has motivated extensive programs of research while also attracting vigorous methodological critiques that highlight alternative accounts of trial n * trial n - 1 sequential effects in cognitive-control tasks. Addressing those alternatives through precluding analyzing stimulus repetitions without creating any sort of confounds among any stimulus or trial characteristics, the present research observed significant conflict-adaptation effects within and across several selective-attention tasks. Moreover, across task conflict-adaptation effects were largest when spanning tasks (i.e., a newly developed Stroop-trajectory task and a flanker task, which both require resolving conflict among stimulus elements) that presumably depend on the same mechanism of cognitive control (selective attention) than when spanning tasks that do not (i.e., the Stroop-trajectory task and a Simon task, the latter-but not former-of which requires resolving conflict between stimulus and response elements). These findings contribute to advancing beyond examining whether or not conflict adaptation exists to clarifying the conditions under which it is and is not observed. PMID- 24487728 TI - Time pressure affects the efficiency of perceptual processing in decisions under conflict. AB - The negative correlation between speed and accuracy in perceptual decision making is often explained as a tradeoff, where lowered decision boundaries under time pressure result in faster but more error-prone responses. Corresponding implementations in sequential sampling models confirmed the success of this account, which has led to the prevalent assumption that a second component of decision making, the efficiency of perceptual processing, is largely independent from temporal demands. To test the generality of this claim, we examined time pressure effects on decisions under conflict. Data from a flanker task were fit with a sequential sampling model that incorporates two successive phases of response selection, driven by the output of an early and late stage of stimulus selection, respectively. The fits revealed the canonical decrease of response boundaries with increasing time pressure. In addition, time pressure reduced the duration of non-decisional processes and impaired the early stage of stimulus selection, together with the subsequent first phase of response selection. The results show that the relation between speed and accuracy not only relies on the strategic adjustment of response boundaries but involves variations of processing efficiency. The findings support recent evidence of drift rate modulations in response to time pressure in simple perceptual decisions and confirm their validity in the context of more complex tasks. PMID- 24487729 TI - Candida albicans arteritis transmitted by preservation fluid after liver transplantation. AB - BACKGROUND: Fungal infections remain among the main causes of mortality in the chronically immunosuppressed liver transplant (LT) patient. Bacterial and fungal contamination of preservation fluid (PF), in which grafts are stored, represents a potential source of infection for recipients. CASE REPORT: A 54-year-old patient underwent LT for chronic alcoholic cirrhosis. Mycological culture of the liver PF was positive for Candida albicans. The patient received antimycotic prophylaxis for 4 weeks in absence of clinical and serological signs of infection. He was urgently readmitted 4 months later with hemobilia caused by an arterial pseudoaneurysm that was fistulized in the biliary anastomosis. After an unsuccessful embolization, arterial resection and reconstruction and a biliodigestive anastomosis were performed, with an uneventful postoperative course. Pathology found a mycotic arteritis of the graft artery. Mycotic culture of the arterial segment confirmed the presence of the same Candida albicans genotype previously isolated in the PF. CONCLUSIONS: Mycotic arteritis is one of the possible complications of yeast contamination of PF. Surgeons and physicians involved in the care of LT patients should be aware of this potentially lethal complication and adopt all the available means for early detection. PMID- 24487730 TI - 2D square arrays of protein nanocages through channel-directed electrostatic interactions with poly(alpha, l-lysine). AB - Reconstructed ferritin nanocages with expanded 4-fold channels can self-assemble into 2D square arrays through channel-directed electrostatic interactions with poly(alpha, l-lysine) at pH 7.0. Structurally, protein cages are aligned along their common 4-fold symmetry axis, imposing a fixed disposition of neighboring ferritins. PMID- 24487732 TI - Direct comparison of the effect of desflurane and sevoflurane on intraoperative motor-evoked potentials monitoring. AB - BACKGROUND: During spinal surgery, intraoperative monitoring of motor-evoked potentials (MEPs) is a useful means of assessing the intraoperative integrity of corticospinal pathways. However, MEPs are known to be particularly sensitive to the suppressive effects of inhalational halogenated anesthetic agents. OBJECTIVE: To investigate the effects of increasing end-tidal concentrations of desflurane and sevoflurane anesthesia in a background of propofol and remifentanil with multipulse cortical stimulation on intraoperative monitoring of MEPs. METHODS: In this randomized crossover trial, 14 consecutive patients (7 in each arm) undergoing major spine surgery, under a background anesthetic of propofol (75 to 125 mcg/kg/min) and remifentanil (0.1 to 0.2 mcg/kg/min), were randomly assigned to receive the sequence of inhalational agents studied: either DES-SEVO (desflurane followed by sevoflurane); or SEVO-DES (sevoflurane followed by desflurane). Multiples (0.3, 0.5, and 0.7) of minimum alveolar concentration (MAC) of desflurane and sevoflurane were administered. After a washout period of 15 minutes using high fresh oxygen/air flows, each of the patients then received the other gas as the second agent. Cortical stimulation was achieved with a train of 5 equivalent square pulses, each 0.05 ms in duration, delivered at 2 ms intervals. MEP recordings were made in the upper limb (UL) from first dorsal interosseus and lower limb (LL) from tibialis anterior with subdermal needle electrodes. RESULTS: At 0.3 MAC desflurane, there was no statistical significant difference in transcranial-evoked MEP amplitudes from the baseline in both UL and LL stimulation. However, this was not the case for sevoflurane for which even a low concentration at 0.3 MAC significantly depressed MEP amplitudes of LL (but not UL) from baseline value. Desflurane at 0.5 and 0.7 MAC depresses LL MEP to 58.4% and 59.9% of baseline, respectively (P<0.05), whereas sevoflurane at 0.3, 0.5, and 0.7 MAC depresses LL MEP to 66.2%, 41.3%, and 25.3% of baseline, respectively (P<0.05). There was no difference in latency of the responses at any MAC. CONCLUSIONS: Inhalational anesthetic agents (sevoflurane >desflurane) suppress MEP amplitudes in a dose-dependent manner. The use of 0.3 MAC of desflurane (but not sevoflurane) provided good MEP recordings acceptable for clinical interpretation for both upper and LLs. The LL appears to be more sensitive to anesthetic-induced depression compared with the UL. All patients studied had normal neurological examination hence, these results may not be applicable to those with preexisting deficits. PMID- 24487733 TI - The brain relaxation and cerebral metabolism in stroke volume variation-directed fluid therapy during supratentorial tumors resection: crystalloid solution versus colloid solution. AB - BACKGROUND: Compared with goal-directed crystalloid therapy, goal-directed colloid therapy during high-risk surgery may improve postoperative outcome. Whether intraoperative fluid therapy based on goal-directed protocol with different types of fluid has distinctive effects on brain relaxation and cerebral metabolism during craniotomy remains unclear. METHODS: Forty patients with supratentorial brain tumors undergoing craniotomy were randomly assigned to either a Ringer's Lactate-based goal-directed group (LR group, n=20) or a 6% hydroxyethyl starch-based goal-directed group (HES group, n=20). The goal was achieved by maintaining a target stroke volume variation (SVV<13%) by volume loading with LR or HES throughout the procedure. The primary outcome is brain relaxation scales, an indirect evaluation of ICP; secondary endpoints include cerebral metabolism variables (jugular venous oxygen saturation [SjvO(2)], arterial-jugular venous differences in oxygen [CajvO(2)], glucose [A-JvGD], lactate [A-JvLD], and cerebral extraction ratio for oxygen [CERO(2)]) and fluid volumes. RESULTS: There is no significant difference between the LR and HES groups on brain relaxation scales (P=0.845), or measures of cerebral oxygenation and metabolism. Intragroup comparisons showed that CERO(2) increased by 14.3% (P=0.009, LR group) and 13.2% (P=0.032, HES group), respectively, and SjvO(2) was decreased by 8.8% (P=0.016, LR group) and 8.1% (P=0.026, HES group), respectively, after tumor removal, compared with baseline. During surgery, the LR group (3070+/-1138 mL) received more fluid than the HES group (2041+/-758 mL, P=0.002). CONCLUSIONS: In patients undergoing supratentorial tumor resection, goal-directed HES therapy was not superior to goal-directed LR therapy for brain relaxation or cerebral metabolism, although less fluid was needed to maintain the target SVV in the HES-based group than in the LR-based group. PMID- 24487734 TI - Magnetic nanoparticle clusters as actuators of ssDNA release. AB - One of the major areas of research in nanomedicine is the design of drug delivery systems with remotely controllable release of the drug. Despite the enormous progress in the field, this aspect still poses a challenge, especially in terms of selectivity and possible harmful interactions with biological components other than the target. We report an innovative approach for the controlled release of DNA, based on clusters of core-shell magnetic nanoparticles. The primary nanoparticles are functionalized with a single-stranded oligonucleotide, whose pairing with a half-complementary strand in solution induces clusterization. The application of a low frequency (6 KHz) alternating magnetic field induces DNA melting with the release of the single strand that induces clusterization. The possibility of steering and localizing the magnetic nanoparticles, and magnetically actuating the DNA release discloses new perspectives in the field of nucleic-acid based therapy. PMID- 24487735 TI - Posttreatment with propofol attenuates lipopolysaccharide-induced up-regulation of inflammatory molecules in primary microglia. AB - BACKGROUND: Activation of microglia is involved in a broad range of neuroinflammatory diseases. Suppression of microglial activation may, therefore, contribute to alleviate the progression of neuroinflammatory diseases. It has been reported that propofol has a potent anti-inflammatory property. In the present study, we investigated the effects of posttreatment with propofol on the production of inflammatory molecules in lipopolysaccharide (LPS)-stimulated microglia. MATERIALS AND METHODS: Microglia were exposed to various concentrations (25, 50, 100, 250 MUM) of propofol for 1 h after LPS stimulation for 24 h. The levels of proinflammatory mediators inducible nitric oxide synthase (iNOS)/nitric oxide (NO), cyclooxygenase-2 (COX-2)/prostaglandin E2 (PGE2), tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) were measured. RESULTS: Propofol at a concentration of 25 MUM did not affect the production of proinflammatory mediators, which was enhanced by LPS. At the concentrations of 50, 100, and 250 MUM, propofol significantly inhibited LPS-mediated production of NO, PGE2, TNF-alpha, and IL-1beta and the expression of iNOSmRNA, COX-2mRNA, TNF alpha mRNA, and IL-1beta mRNA. CONCLUSIONS: These results suggest that propofol, at clinically relevant concentrations, can reduce inflammatory responses in LPS induced inflammation in activated microglia and might be an intravenous anesthetic of choice when patients with neuroinflammatory diseases require sedation and/or general anesthesia. PMID- 24487738 TI - Single-photon emission computerized tomography (SPECT) in neuropsychiatry: a review. AB - Cranial single-photon emission computerized tomography (SPECT or SPET) can now give regional cerebral blood flow images with a resolution approaching that of positron emission tomography (PET). In this paper, the use of high resolution SPECT neuroimaging in neuropsychiatric disorders, including Alzheimer's disease, multi-infarct dementia, Pick's disease, progressive supranuclear palsy, Korsakoff's psychosis, Creutzfeld-Jakob disease, Parkinson's disease, Huntington's disease, schizophrenia, mood disorders, obsessive-compulsive disorder, HIV infection and AIDS is reviewed. Finally, further potential research and clinical uses, based on ligand studies, are outlined. PMID- 24487736 TI - p-Synephrine suppresses lipopolysaccharide-induced acute lung injury by inhibition of the NF-kappaB signaling pathway. AB - OBJECTIVE: We investigated whether p-synephrine exerts potent anti-inflammatory effects against acute lung injury (ALI) induced by lipopolysaccharide (LPS) in vivo, and we further investigated the inhibitory mechanism of p-synephrine in LPS induced ALI. METHODS: Lipopolysaccharide (0.5 mg/kg) was instilled intranasally in phosphate-buffered saline to induce acute lung injury, and 6, 24, and 48 h after LPS was given, bronchoalveolar lavage fluid was obtained to measure pro inflammatory mediator. We also evaluated the effects of p-synephrine on LPS induced the severity of pulmonary injury. The phosphorylation of nuclear factor kappaB (NF-kappaB) p65 protein was analyzed by Western blotting. RESULTS: Our data showed that p-synephrine significantly reduced the amount of inflammatory cells, the lung wet-to-dry weight (W/D) ratio, reactive oxygen species, myeloperoxidase activity and enhanced superoxide dismutase (SOD) in mice with LPS induced ALI. Tumor necrosis factor alpha and interleukin (IL)-6 concentrations decreased significantly while the concentration of IL-10 was significantly increased after p-synephrine pretreatment. In addition, p-synephrine suppressed not only the phosphorylation of NF-kappaB but also the degradation of its inhibitor (IkappaBalpha). CONCLUSIONS: These results suggested that the inhibition of NF-kappaB activation and the regulation of SOD are involved in the mechanism of p-synephrine's protection against ALI. PMID- 24487739 TI - Sleep disturbances and epileptiform activity in a subpopulation of children with attention deficit hyperactivity disorder (ADHD): a literature review generating an hypothesis with implications for drug therapy. AB - The use of electroencephalography and sleep studies in attention deficit hyperactivity disorder (ADHD), and the associated behavioral disorders is reviewed. Based on the available literature, we propose a hypothesis indicating four subtypes of ADHD. The usefulness of EEGs and sleep laboratory indices in detecting a subgroup of patients with submaximal responses to methylphenidate is also discussed. PMID- 24487737 TI - Relationship between glycine transporter 1 inhibition as measured with positron emission tomography and changes in cognitive performances in nonhuman primates. AB - Several lines of evidence suggest that schizophrenia is associated with deficits in glutamatergic transmission at the N-methyl-d-aspartate (NMDA) receptors. Glycine is a NMDA receptor co-agonist, and extracellular levels of glycine are regulated in the forebrain by the glycine type-1 transporters (GlyT-1). GlyT-1 inhibitors elevate extracellular glycine and thus potentiate NMDA transmission. This mechanism represents a promising new avenue for the treatment of schizophrenia. Here, the recently introduced positron emission tomography radiotracer [11C]GSK931145 was used to quantify the relationship between occupancy of GlyT-1 by a GlyT-1 inhibitor, Org 25935, and its impact on spatial working memory performances in rhesus monkeys. The effect of Org 25935 on working memory was assessed both in control conditions and during a state of relative NMDA hypofunction induced by ketamine administration, at a dose selected for each animal to reduce task performance by about 50%. Under control conditions, Org 25935 had no effect on working memory at GlyT-1 occupancies lower than 75% and significantly impaired working memory at occupancies higher than 75%. Under ketamine conditions, Org 25935 reversed the deficit in working memory induced by ketamine and did so optimally in the 40-70% GlyT-1 occupancy range. The results confirm the efficacy of this mechanism to correct working memory deficits associated with NMDA hypofunction. These data also suggest the existence of an inverted-U dose-response curve in the potential therapeutic effect of this class of compounds. PMID- 24487740 TI - Empirical research on deja vu experiences: a review. AB - A deja vu experience is a dissociative phenomenon, which can be characterized as a subjectively inappropriate impression of familiarity of the present with an undefined past. This paper reviews empirical studies on deja vu experiences and summarizes the most salient findings. Overall, the findings appear to be inconsistent and inconclusive. The authors conclude that the available empirical research is of limited significance due to various methodological and conceptual issues. In order to evaluate the clinical psychiatric relevance of deja vu experiences, further research which also addresses its qualitative features is warranted. PMID- 24487741 TI - Possession states: approaches to clinical evaluation and classification. AB - The fields of anthropology and sociology have produced a large quantity of literature on possession states, physicians however rarely report on such phenomena. As a result clinical description of possession states has suffered, even though these states may be more common and less deviant than supposed. Both ICD-10 and DSM-IV may include specific criteria for possession disorders. The authors briefly review Western notions about possession and kindred states and present guidelines for evaluation and classification. PMID- 24487742 TI - Hemifacial display of emotion in the resting state. AB - The human face at rest displays distinguishable asymmetries with some lateralization of emotion or expression. The asymmetrical nature of the resting face was examined by preparing hemifacial composites, left-left, right-right, along with normal facial orientation. The left side and right side composites were constructed by using the lateral half of one side of the face and its mirror reversal. The left side facial composites were found to be more emotional than the right side or normal facial orientations of neutral expressions. PMID- 24487743 TI - A prospective psychological study of patients with undiagnosed episodes of disturbed consciousness. AB - We have carried out a prospective psychological and clinical study of neurological out-patients with episodes of disturbed consciousness that were mostly unexplained after clinical assessments and prolonged follow up. When compared with matched healthy subjects, both the undiagnosed patients and a control group with chronic epilepsy, had evidence of abnormal personality and psychological disturbance. However, in the undiagnosed patients there were significant differences between two subgroups defined by the results of clinical follow up. Patients whose symptoms resolved spontaneously were psychologically indistinguishable from healthy control subjects, whereas patients whose unexplained symptoms continued, with or without empirical treatment trials, had highly abnormal personality profiles. Although the basic psychological tests we used cannot reliably separate individual patients with epilepsy from those with non-epilepsy, they do have some predictive value with respect to the prognosis of unexplained symptoms. Further detailed prospective studies may help to establish the relationship between psychological disorder and unexplained symptoms and perhaps reduce the need for repeated, expensive investigations. PMID- 24487744 TI - A patient with difficulty of object recognition: semantic amnesia for manipulable objects. AB - We studied a patient who had recognition difficulty for manipulable objects. MRI showed a lesion in the left occipito-parietotemporal area. Differential diagnosis of agnosia, aphasia and apraxia is discussed. We believe this "object meaning amnesia" constitutes a distinct subtype of semantic amnesia. PMID- 24487745 TI - Absence of neurobehavioral disturbance in a focal lesion of the left paracentral lobule. AB - The case of a right-handed woman with an infarcation confined to the left paracentral lobule and sparing the supplementary motor area (SMA) is reported. She presented with a right leg monoplegia and displayed no mutism. The absence of any associated neurobehavioral disturbances (mutism, forced grasping, reduced spontaneous arm activity or aphasia raises the possibility that the left SMA has discrete neurobehavioral functions. PMID- 24487746 TI - Association between intentional injury and long-term survival after trauma. AB - OBJECTIVE: To determine the risk-adjusted mortality of intentionally injured patients within 7 to 9 years postinjury, compared with unintentionally injured patients. BACKGROUND: Violent injury contributes significantly to trauma mortality in the United States. Homicide is the second leading killer of American youth, aged 15 to 24 years. Long-term survival among intentionally injured patients has not been well studied. It is also unknown whether intentionally injured patients have worse long-term survival compared with unintentionally or accidentally injured patients with equivalent injuries. METHODS: Adult trauma patients admitted for 24 hours or more and discharged alive from the Johns Hopkins Hospital from January 1, 1998, to December 31, 2000, were included. The primary outcome was mortality within 7 to 9 years postinjury. Long-term patient survival was determined using the National Death Index. The association between injury intentionality and mortality was investigated using a Cox proportional hazard regression model, adjusted for confounders such as injury severity and patient race, socioeconomic status, and comorbid conditions. Overall differences in survival between those with intentional versus unintentional injury were also determined by comparing adjusted Kaplan-Meier survival curves. RESULTS: A total of 2062 patients met inclusion criteria. Of these, 56.4% were intentionally injured and 43.6% were unintentionally injured. Compared with unintentionally injured patients, intentionally injured patients were younger and more often male and from a zip code with low median household income. Approximately 15% of all patients had died within 7 to 9 years of follow-up. Older age and presence of comorbidities were associated with this outcome; however, intentional injury was not found to be significantly associated with long-term mortality rates. There was also no significant difference in survival curves between groups; intentionally injured patients were much more likely to die of a subsequent injury, whereas those with unintentional injury commonly died of noninjury causes. CONCLUSIONS: There was no significant difference in mortality between intentionally injured and unintentionally injured patients within 7 to 9 years postinjury. These results confirm the long-term effectiveness of lifesaving trauma care for those with intentional injury. However, given that patients with intentional injuries were more likely to suffer a subsequent violent death, interventions focused on breaking the cycle of violence are needed. PMID- 24487747 TI - Laparoscopic wedge fundectomy for collis gastroplasty creation in patients with a foreshortened esophagus. AB - OBJECTIVE: To assess the outcome of a laparoscopic wedge-fundectomy Collis gastroplasty for a short esophagus during fundoplication and hiatal hernia repair. BACKGROUND: The Collis gastroplasty provides a surgical solution for a foreshortened esophagus but has been associated with postoperative dysphagia and esophagitis. METHODS: We identified 150 patients who underwent a Collis gastroplasty from 1998 to 2012, and of these, 85 patients underwent laparoscopic procedures using the wedge-fundectomy technique. RESULTS: The median age of the 85 patients (42 men/43 women) was 66 years (range, 37-84 years). A Nissen fundoplication was added to the Collis gastroplasty in 56 patients (66%) and a Toupet fundoplication in 29 patients. No patient had a staple line leak or abscess, and the median hospital stay was 3.5 days (interquartile range, 3-4.5 days). At a median follow-up of 12 months, 93% of patients were free of heartburn. Dysphagia was significantly less common after surgery (preoperative: 58% vs postoperative: 16%; P < 0.0001). New-onset dysphagia developed in only 2 patients. An upper endoscopy was performed in 54 patients at a median of 6 months after surgery, and erosions above the fundoplication were seen in 6 patients (11%). A small (1-2 cm) recurrent hernia was seen in 2 patients (2.4%). CONCLUSIONS: The laparoscopic wedge-fundectomy Collis gastroplasty can be performed safely and is associated with a low prevalence of new-onset dysphagia and esophagitis. The addition of a Collis gastroplasty to an antireflux operation is an effective strategy in patients with short esophagus, and its more liberal use is encouraged. PMID- 24487748 TI - Reply to Letter: "Identifying Important Predictors for Anastomotic Leak After Colon and Rectal Resection: Prospective Study on 616 Patients". PMID- 24487750 TI - Tar Heel footprints in health care: Thomas J. Bacon, DrPH. PMID- 24487751 TI - The epidemiology of traumatic brain injuries treated in emergency departments in North Carolina, 2010-2011. AB - BACKGROUND: Traumatic brain injuries (TBIs) are a leading cause of injury morbidity and mortality in the United States. An estimated 1.7 million TBIs occur each year, and TBIs may lead to severe lifelong disability and death; even mild to-moderate TBIs may have long-term consequences. North Carolina's population wide data on TBIs are limited, so it is important to analyze the available data regarding TBI-related emergency department (ED) visits. METHODS: Statewide data on TBI-related ED visits were obtained from the North Carolina Disease Event Tracking and Epidemiologic Collection Tool (NC DETECT), an electronic public health surveillance system. Counts and rates were produced by sex, age, county of residence, disposition, mode of transport, and mechanism of injury. RESULTS: In 2010-2011, there were 140,234 TBI-related ED visits in North Carolina, which yields a rate of 7.3 ED visits per 1,000 person-years. The rate was higher for men (7.9 visits per 1,000 person-years) than for women (6.8 visits per 1,000 person-years). Rates were highest in individuals aged 0-4 years (13.1 visits per 1,000 person-years), 15-19 years (10.6 visits per 1,000 person-years), 75-79 years (11.3 visits per 1,000 person-years), 80-84 years (17.9 visits per 1,000 person-years), and 85 years or older (30.6 visits per 1,000 person-years). TBI related ED visits were principally the result of falls (39.0%), being struck by a person or object (17.6%), or motor vehicle traffic-related crashes (14.1%). LIMITATIONS: This study utilizes data collected primarily for administrative purposes, such as hospital billing. CONCLUSION: TBIs are a common cause of ED visits in North Carolina. These descriptive statistics demonstrate needs for statewide ED surveillance to monitor the incidence of TBIs and for the development of prevention strategies. PMID- 24487752 TI - A cross-sectional study of medical students' knowledge of patient safety and quality improvement. AB - BACKGROUND: The Association of American Medical Colleges and the World Health Organization have endorsed formal patient safety and quality improvement (QI) education for medical students. We surveyed medical students to assess their current level of patient safety and QI knowledge and to identify factors associated with increased knowledge. METHODS: A literature review, focus groups with medical students, and local expert interviews were used to develop an electronic survey, which was distributed to all medical students at a single medical school in the spring of 2012. RESULTS: Fifty-seven percent of the medical school student body (N = 790) participated in the survey. A greater proportion of students reported previous exposure to patient safety education than to QI education (79% vs 47%). Students scored an average of 56% and 58% on the patient safety and QI knowledge tests, respectively. Having or pursuing an advanced degree (P = .02) and previous exposure to patient safety education (P = .02) were associated with higher knowledge scores. After adjusting for confounding variables, only previous exposure to QI education (P = .02) was associated with higher QI knowledge scores. LIMITATIONS: There is a risk of measurement bias due to the use of an unvalidated instrument. Students who have greater knowledge of patient safety or QI might recall exposure at a greater frequency, inflating the association between exposure and knowledge. Also, this is a cross-sectional study, so we cannot draw conclusions about causality. CONCLUSION: Medical students' knowledge of patient safety and QI is low. Previous formal or informal education about these topics is associated with increased knowledge. PMID- 24487753 TI - Training tomorrow's health professionals. PMID- 24487754 TI - Innovations in the education of health professionals. AB - Dramatic and unprecedented changes in health care have altered the health care landscape and have significant implications for health professions education. This issue of the NCMJ explores these changes and highlights innovative models across the health professions that are designed to prepare graduates to practice in the emerging health care system and to deliver high-quality care in a cost effective manner. These new educational programs--which include training for future doctors, nurses, dentists, pharmacists, and various allied health professionals--aim to prepare providers to meet the needs of North Carolina communities, and they use new educational models to give graduates the competencies they need to practice in health care teams and to contribute in other ways to improved health outcomes for the people of the state. PMID- 24487755 TI - The pediatrics primary care residency program at the University of North Carolina. AB - The Pediatrics Primary Care Residency Program at the University of North Carolina School of Medicine will graduate its first class in 2014. Funded by the Health Resources and Services Administration through the Patient Protection and Affordable Care Act, this innovative program has a unique curriculum that offers several benefits, but sustainability of the program remains a challenge. PMID- 24487756 TI - Innovation in rural family medicine training: the Mountain Area Health Education Center's rural-track residency program. PMID- 24487757 TI - Population health initiatives for primary care at Duke University School of Medicine. AB - To help shape the future of health care in North Carolina, Duke University School of Medicine has implemented several new initiatives aimed at providing primary care providers with the knowledge, skills, and attitudes required to improve population health and health care. PMID- 24487758 TI - Shaping oral health care in North Carolina with East Carolina University's community service learning centers. AB - East Carolina University School of Dental Medicine is responding to the changes in today's health care system by implementing an innovative model of community based dental education that prepares tomorrow's dentists to meet North Carolina's future oral health challenges while also providing much-needed care in many underserved areas. PMID- 24487759 TI - The RIBN initiative: a new effort to increase the number of baccalaureate nurses in North Carolina. AB - To meet the increasing demand for a more educated nursing workforce, the Regionally Increasing Baccalaureate Nurses (RIBN) initiative provides an economically feasible educational pathway between community colleges and universities so that more North Carolina nursing students can achieve a baccalaureate degree at the beginning of their career. PMID- 24487760 TI - A community college's perspective on the RIBN initiative. PMID- 24487761 TI - New initiatives in allied health in North Carolina. AB - In addition to providing a well-prepared and diverse workforce of allied health professionals, North Carolina universities are helping to improve access to care and outreach to underserved communities. This commentary will discuss workforce preparation initiatives and innovations that help all North Carolinians access timely and high-quality services. PMID- 24487762 TI - A renaissance in pharmacy education at the University of North Carolina at Chapel Hill. AB - The UNC Eshelman School of Pharmacy is transforming its doctor of pharmacy program to emphasize active engagement of students in the classroom, foster scientific inquiry and innovation, and immerse students in patient care early in their education. The admissions process is also being reengineered. PMID- 24487763 TI - Training physician assistants for rural Appalachia: an academic partnership for interprofessional collaboration. AB - Wake Forest School of Medicine and the College of Health Sciences at Appalachian State University are partnering to train physician assistants to practice as primary care providers in medically underserved parts of Western North Carolina. The partnership will also develop interprofessional education and team-based training activities for health professions students. PMID- 24487764 TI - The third-year longitudinal integrated clerkship at the Asheville campus of the University of North Carolina School of Medicine. AB - Consumers, health delivery planners, and public officials are calling for patient centered, primary care-based, cost-effective health care. The Asheville campus of the University of North Carolina School of Medicine has responded to this need by developing a longitudinal integrated clerkship that trains third-year medical students to provide such care. PMID- 24487765 TI - New frontiers in medical education: simulation technology at Campbell University School of Osteopathic Medicine. AB - Campbell University School of Osteopathic Medicine is using a variety of medical simulation systems in the training of its medical students. The simulators allow students to learn and practice skills in a controlled environment, and they enable faculty to challenge students with a broader range of conditions than might ordinarily be encountered during medical training. PMID- 24487766 TI - Retention initiatives in the North Carolina Community College System. AB - Over the past 15 years, the North Carolina Community College System has provided education and instruction to 258,713 allied health professionals, 183,059 nurse aides, 27,125 associate-degree nurses, and 9,926 practical nurses. Innovations that can increase program retention will have a positive impact on the state's future health care workforce. PMID- 24487767 TI - Meeting North Carolina's health care needs through interprofessional education and practice. AB - To meet the future health care needs of North Carolinians, health professions students must learn how to work together as part of an interdisciplinary team. This commentary describes how interprofessional education and team-based care can decrease the number of adverse events, improve health care delivery, and support consistent outcomes. PMID- 24487768 TI - Winston-Salem State University and Duke University's Bridge to the Doctorate Program. AB - To address the underrepresentation of ethnic minorities in research-focused nursing doctoral programs, Winston-Salem State University (WSSU) Division of Nursing has partnered with Duke University School of Nursing to establish a Bridge to the Doctorate program. This program provides a research honors track for graduate nursing students from underrepresented minority groups who are enrolled at WSSU, with the aim of preparing them to seamlessly transition into a PhD program at Duke University. PMID- 24487769 TI - A postprofessional distance-education program in neurodiagnostics and sleep science. AB - Sleep medicine is a quickly growing field of allied health and preventive medicine. The University of North Carolina has proven innovative and timely in offering a neurodiagnostics and sleep science bachelor's degree program for the sleep medicine profession. PMID- 24487770 TI - Running the numbers: the maldistribution of health care providers in rural and underserved areas in North Carolina. PMID- 24487771 TI - Spotlight on the safety net: creation of a family medicine residency track in care of the underserved: a collaboration between the University of North Carolina Department of Family Medicine and Piedmont Health Services. PMID- 24487772 TI - Philanthropy profile: the mentor's role in training health professionals: the Family Medicine Interest and Scholars Program. PMID- 24487773 TI - Computerized characterization of lung nodule subtlety using thoracic CT images. AB - The goal of this work is to design computerized image analysis techniques for automatically characterizing lung nodule subtlety in CT images. Automated subtlety estimation methods may help in computer-aided detection (CAD) assessment by quantifying dataset difficulty and facilitating comparisons among different CAD algorithms. A dataset containing 813 nodules from 499 patients was obtained from the Lung Image Database Consortium. Each nodule was evaluated by four radiologists regarding nodule subtlety using a 5-point rating scale (1: most subtle). We developed a 3D technique for segmenting lung nodules using a prespecified initial ROI. Texture and morphological features were automatically extracted from the segmented nodules and their margins. The dataset was partitioned into trainers and testers using a 1:1 ratio. An artificial neural network (ANN) was trained with average reader subtlety scores as the reference. Effective features for characterizing nodule subtlety were selected based on the training set using the ANN and a stepwise feature selection method. The performance of the classifier was evaluated using prediction probability (PK) as an agreement measure, which is considered a generalization of the area under the receiver operating characteristic curve when the reference standard is multi level. Using an ANN classifier trained with a set of 2 features (selected from a total of 30 features), including compactness and average gray value, the test concordance between computer scores and the average reader scores was 0.789 +/- 0.014. Our results show that the proposed method had strong agreement with the average of subtlety scores provided by radiologists. PMID- 24487774 TI - The role of diffusion-weighted MR imaging for differentiating benign from malignant bile duct strictures. AB - OBJECTIVES: To assess the added value of diffusion-weighted imaging (DWI) to conventional magnetic resonance imaging (MRI) for differentiating benign from malignant bile duct strictures. METHODS: Twenty-seven patients with a benign stricture and 42 patients with a malignant stricture who had undergone gadoxetic acid-enhanced MRI with DWI were enrolled. Qualitative (signal intensity, dynamic enhancement pattern) and quantitative (wall thickness and length) analyses were performed. Two observers independently reviewed a set of conventional MRI and a combined set of conventional MRI and DWI, and receiver operating characteristic (ROC) curve analysis was assessed. RESULTS: Benign strictures showed isointensity (18.5-70.4 %) and a similar enhancement pattern (22.2 %) to that of normal bile duct more frequently than malignant strictures (0-40.5 % and 0 %) on conventional MRI (P < 0.05). Malignant strictures (90.5-92.9 %) showed hypervascularity on arterial and portal venous phase images more frequently than benign strictures (37.0-70.4 %) (P < 0.01) On DWI, all malignant strictures showed hyperintensity compared with benign cases (70.4 %) (P < 0.001). Malignant strictures were significantly thicker and longer than benign strictures (P < 0.001). The diagnostic performance of both observers improved significantly after additional review of DWI. CONCLUSIONS: Adding DWI to conventional MRI is more helpful for differentiating benign from malignant bile duct strictures than conventional MRI alone. KEY POINTS: * Accurate diagnosis and exclusion of benign strictures of bile duct are important. * Diffusion-weighted MRI helps to distinguish benign from malignant bile duct strictures. * DWI plus conventional MRI provides superior diagnostic accuracy to conventional MRI alone. PMID- 24487775 TI - Effect of body mass and clothing on decomposition of pig carcasses. AB - Carcass mass and carcass clothing are factors of potential high forensic importance. In casework, corpses differ in mass and kind or extent of clothing; hence, a question arises whether methods for post-mortem interval estimation should take these differences into account. Unfortunately, effects of carcass mass and clothing on specific processes in decomposition and related entomological phenomena are unclear. In this article, simultaneous effects of these factors are analysed. The experiment followed a complete factorial block design with four levels of carcass mass (small carcasses 5-15 kg, medium carcasses 15.1-30 kg, medium/large carcasses 35-50 kg, large carcasses 55-70 kg) and two levels of carcass clothing (clothed and unclothed). Pig carcasses (N = 24) were grouped into three blocks, which were separated in time. Generally, carcass mass revealed significant and frequently large effects in almost all analyses, whereas carcass clothing had only minor influence on some phenomena related to the advanced decay. Carcass mass differently affected particular gross processes in decomposition. Putrefaction was more efficient in larger carcasses, which manifested itself through earlier onset and longer duration of bloating. On the other hand, active decay was less efficient in these carcasses, with relatively low average rate, resulting in slower mass loss and later onset of advanced decay. The average rate of active decay showed a significant, logarithmic increase with an increase in carcass mass, but only in these carcasses on which active decay was driven solely by larval blowflies. If a blowfly-driven active decay was followed by active decay driven by larval Necrodes littoralis (Coleoptera: Silphidae), which was regularly found in medium/large and large carcasses, the average rate showed only a slight and insignificant increase with an increase in carcass mass. These results indicate that lower efficiency of active decay in larger carcasses is a consequence of a multi-guild and competition-related pattern of this process. Pattern of mass loss in large and medium/large carcasses was not sigmoidal, but rather exponential. The overall rate of decomposition was strongly, but not linearly, related to carcass mass. In a range of low mass decomposition rate increased with an increase in mass, then at about 30 kg, there was a distinct decrease in rate, and again at about 50 kg, the rate slightly increased. Until about 100 accumulated degree-days larger carcasses gained higher total body scores than smaller carcasses. Afterwards, the pattern was reversed; moreover, differences between classes of carcasses enlarged with the progress of decomposition. In conclusion, current results demonstrate that cadaver mass is a factor of key importance for decomposition, and as such, it should be taken into account by decomposition related methods for post-mortem interval estimation. PMID- 24487776 TI - Investigation of the surgical complications during thoracic endovascular aortic repair: experiences with 148 consecutive cases treated at a single institution in Japan. AB - PURPOSE: To investigate the risk factors associated with thoracic endovascular aortic repair at The Sakakibara Heart Institute of Okayama in Japan. METHODS: A total of 148 consecutive patients who underwent thoracic endovascular aortic repair between November 2009 and October 2012 were investigated. RESULTS: The patients' mean age at the time of the operation was 72.8 +/- 11.7 years. The initial success rate of the procedure was 92.6 %. The 30-day mortality rate was 3.4 %, and the multivariable risk factors for mortality were urgent/emergency surgery and a sternotomy approach. The incidence of permanent stroke was 3.4 %. The multivariable risk factors for stroke included an age over 70 years and cases requiring the debranching procedure. The rate of paraplegia/paraparesis was 5.4 %. The mean follow-up was 14.8 +/- 9.2 months, and the follow-up rate was 97.3 %. The overall mortality rate was 12.8 %. The survival rates after thoracic endovascular repair were 88.3 % in the first year, 87.0 % in the second year and 69.6 % in the third year. The freedom from aorta-related death rate was 97.1 % at 3 years. Primary technical success was a strong negative predictor of aorta related death. CONCLUSIONS: The use of a debranching technique and sternotomy approach in patients with extensive atherosclerotic changes of the aortic arch were risk factors for major complications of TEVAR. Such patients may benefit from open surgery rather than TEVAR. PMID- 24487777 TI - Iridium oxide nanotube electrodes for sensitive and prolonged intracellular measurement of action potentials. AB - Intracellular recording of action potentials is important to understand electrically-excitable cells. Recently, vertical nanoelectrodes have been developed to achieve highly sensitive, minimally invasive and large-scale intracellular recording. It has been demonstrated that the vertical geometry is crucial for the enhanced signal detection. Here we develop nanoelectrodes of a new geometry, namely nanotubes of iridium oxide. When cardiomyocytes are cultured upon those nanotubes, the cell membrane not only wraps around the vertical tubes but also protrudes deep into the hollow centre. We show that this nanotube geometry enhances cell-electrode coupling and results in larger signals than solid nanoelectrodes. The nanotube electrodes also afford much longer intracellular access and are minimally invasive, making it possible to achieve stable recording up to an hour in a single session and more than 8 days of consecutive daily recording. This study suggests that the nanoelectrode performance can be significantly improved by optimizing the electrode geometry. PMID- 24487779 TI - Lanthanum-containing hydroxyapatite coating on ultrafine-grained titanium by micro-arc oxidation: a promising strategy to enhance overall performance of titanium. AB - Titanium is widely used in biomedical materials, particularly in dental implants, because of its excellent biocompatibility and mechanical characteristics. However, titanium implant failures still remain in some cases, varying with implantation sites and patients. Improving its overall performance is a major focus of dental implant research. Equal-channel angular pressing (ECAP) can result in ultrafine-grained titanium with superior mechanical properties and better biocompatibility, which significantly benefits dental implants, and without any harmful alloying elements. Lanthanum (La) can inhibit the acidogenicity of dental plaque and La-containing hydroxyapatite (La-HA) possesses a series of attractive properties, in contrast to La-free HA. Micro-arc oxidation (MAO) is a promising technology that can produce porous and firmly adherent hydroxyapatite (HA) coatings on titanium substrates. Therefore, we hypothesize that porous La-containing hydroxyapatite coatings with different La content (0.89%, 1.3% and 1.79%) can be prepared on ultrafine-grained (~200-400 nm) titanium by ECAP and MAO in electrolytic solution containing 0.2 mol/L calcium acetate, 0.02 mol/L beta-glycerol phosphate disodium salt pentahydrate (beta-GP), and lanthanum nitrate with different concentrations to further improve the overall performance of titanium, which are expected to have great potential in medical applications as a dental implant. PMID- 24487778 TI - The many faces of tobacco use among women. AB - Smoking is still considered to be mainly a male problem. However, it is estimated that there are approximately 250 million women worldwide who smoke cigarettes and millions more women who use smokeless tobacco products. This article addresses the many facets of tobacco use among women. The aim of the paper is to increase recognition among clinicians and researchers of the specific characteristics of female tobacco use. Together with providing epidemiological data on the distribution of tobacco use among women and data from population-based analyses on sociocultural factors that influence it, the article presents tobacco use during pregnancy as a particularly important public health problem. Further, the article points out sex-related differences (ie, physiological, psychological, or behavioral) between male and female tobacco use. A special focus is on the important role of ovarian hormones. Adverse effects of tobacco use to women and their children as well as tobacco-related morbidities and comorbidities are presented, and women's greater susceptibility to tobacco constituents as compared to men is stressed. Awareness of these differences can contribute to improvement of the effectiveness of smoking cessation programs addressed both to the specific female population and to an individual smoking woman. PMID- 24487780 TI - Evaluation of exhaled nitric oxide in acute paraquat poisoning: a pilot study. AB - BACKGROUND: Fractional exhaled nitric oxide (FENO) is nitric oxide (NO) in the lower airway measured by oral exhalation. FENO can be a useful non-invasive marker for asthma. Paraquat-mediated lung injury can be reflective of an ROS induced lung injury. We aimed to verify if FENO is a clinical parameter of ROS formation and responsiveness to medical therapies in acute paraquat intoxication. MATERIAL AND METHODS: We recruited 12 patients admitted with acute paraquat poisoning. A portable and noninvasive device called NIOX MINOTM (Aerocrine AB, Solna, Sweden) was used to measure FENO. Measurements were made at the time of hospital admission and at 24, 48, 72, 96, and 120 h after paraquat ingestion. RESULTS: Six out of the total 12 recruited patients had general conditions (e.g. oral pain) that made it difficult for them to exhale with adequate force. Mean plasma paraquat level was 1.4 +/- 2.5 g/mL. We found no direct correlation between the paraquat levels (both ingestion amount and plasma concentration) and FENO (initial, maximal, and minimal values). All the measured FENO values were no greater than 20 ppb for the 2 patients who died. FENO did not vary more than 20% from the baseline. Compared to the above findings, FENO measurements were found to be greater than 20 ppb for the patients who survived. FENO tends to reach its peak value at between 50 h and 80 h. CONCLUSIONS: FENO did not predict mortality, and there was no increase of FENO in patients with severe paraquat intoxication. PMID- 24487781 TI - Evaluation of the Trail Making Test and interval timing as measures of cognition in healthy adults: comparisons by age, education, and gender. AB - BACKGROUND: Human cognitive functioning can be assessed using different methods of testing. Age, level of education, and gender may influence the results of cognitive tests. MATERIAL AND METHODS: The well-known Trail Making Test (TMT), which is often used to measure the frontal lobe function, and the experimental test of Interval Timing (IT) were compared. The methods used in IT included reproduction of auditory and visual stimuli, with the subsequent production of the time intervals of 1-, 2-, 5-, and 7-seconds durations with no pattern. Subjects included 64 healthy adult volunteers aged 18-63 (33 women, 31 men). Comparisons were made based on age, education, and gender. RESULTS: TMT was performed quickly and was influenced by age, education, and gender. All reproduced visual and produced intervals were shortened and the reproduction of auditory stimuli was more complex. Age, education, and gender have more pronounced impact on the cognitive test than on the interval timing test. The reproduction of the short auditory stimuli was more accurate in comparison to other modalities used in the IT test. CONCLUSIONS: The interval timing, when compared to the TMT, offers an interesting possibility of testing. Further studies are necessary to confirm the initial observation. PMID- 24487782 TI - Molecular functions and cellular roles of the ChlR1 (DDX11) helicase defective in the rare cohesinopathy Warsaw breakage syndrome. AB - In 2010, a new recessive cohesinopathy disorder, designated Warsaw breakage syndrome (WABS), was described. The individual with WABS displayed microcephaly, pre- and postnatal growth retardation, and abnormal skin pigmentation. Cytogenetic analysis revealed mitomycin C (MMC)-induced chromosomal breakage; however, an additional sister chromatid cohesion defect was also observed. WABS is genetically linked to bi-allelic mutations in the ChlR1/DDX11 gene which encodes a protein of the conserved family of Iron-Sulfur (Fe-S) cluster DNA helicases. Mutations in the budding yeast ortholog of ChlR1, known as Chl1, were known to cause sister chromatid cohesion defects, indicating a conserved function of the gene. In 2012, three affected siblings were identified with similar symptoms to the original WABS case, and found to have a homozygous mutation in the conserved Fe-S domain of ChlR1, confirming the genetic linkage. Significantly, the clinically relevant mutations perturbed ChlR1 DNA unwinding activity. In addition to its genetic importance in human disease, ChlR1 is implicated in papillomavirus genome maintenance and cancer. Although its precise functions in genome homeostasis are still not well understood, ongoing molecular studies of ChlR1 suggest the helicase plays a critically important role in cellular replication and/or DNA repair. PMID- 24487783 TI - Prognostic biomarkers in thyroid cancer. AB - Thyroid carcinomas represent a challenging problem from the prognostic standpoint. Despite an overall good prognosis of the most frequent endocrine malignancy, 10-15 % of papillary thyroid carcinomas (PTCs) turn refractory to radioactive iodine therapy. The increased incidence of thyroid cancer has led to the search for solid prognostic biomarkers that predict the behaviour of these tumours. Clinical and histopathological prognostic factors remain the only safe elements to be used for diagnosis and prognosis of patients with thyroid tumours. Despite the huge amount of genetic information of thyroid tumours, very few new markers revealed diagnostic or prognostic value per se. BRAF mutation can have some value if associated to other clinico-pathological parameters, or in the particular setting of iodine refractory tumours. Others can prove interesting in the future as predictive biomarkers of therapeutic response, but more studies are needed to confirm these potential biomarkers. PMID- 24487784 TI - Testicular cancer: biology and biomarkers. AB - The term "human germ cell tumors" (GCTs) refers to a heterogeneous group of neoplasms, all with a defined histological appearance. They have specific epidemiological characteristics, clinical behavior, and pathogenesis. Histologically, GCTs contain various tissue elements, which are homologs of normal embryogenesis. We have proposed a subclassification of GCTs in five subtypes, three of which preferentially occur in the testis. These include teratomas and yolk sac tumors of neonates and infants (type I), seminomas and nonseminomas of (predominantly) adolescents and adults (type II), and spermatocytic seminomas of the elderly (type III). Both spontaneous and induced animal models have been reported, of which the relevance for human GCTs is still to be clarified. Multidisciplinary studies have recently shed new light on the (earliest steps in the) pathogenesis of GCTs, mainly in regard of malignant type II GCTs (germ cell cancer (GCC)). This review discusses novel understanding of the pathogenesis of (mainly) GCC, focusing on identification of informative diagnostic markers suitable for application in a clinical setting. These include OCT3/4, SOX9/FOXL2, SOX17/SOX2, as well as embryonic microRNAs. These markers have been identified through studies on normal embryogenesis, specifically related to the gonads, including the germ cell lineage. Their strengths and limitations are discussed as well as the expected future approach to identify the group of individuals at highest risk for development of a GCC. The latter would allow screening of defined populations, early diagnosis, optimal follow-up, and potentially early treatment, preventing long-term side effects of systemic treatment. PMID- 24487786 TI - Methodological requirements for valid tissue-based biomarker studies that can be used in clinical practice. AB - Paralleling the growth of ever more cost efficient methods to sequence the whole genome in minute fragments of tissue has been the identification of increasingly numerous molecular abnormalities in cancers--mutations, amplifications, insertions and deletions of genes, and patterns of differential gene expression, i.e., overexpression of growth factors and underexpression of tumor suppressor genes. These abnormalities can be translated into assays to be used in clinical decision making. In general terms, the result of such an assay is subject to a large number of variables regarding the characteristics of the available sample, particularities of the used assay, and the interpretation of the results. This review discusses the effects of these variables on assays of tissue-based biomarkers, classified by macromolecule--DNA, RNA (including micro RNA, messenger RNA, long noncoding RNA, protein, and phosphoprotein). Since the majority of clinically applicable biomarkers are immunohistochemically detectable proteins this review focuses on protein biomarkers. However, the principles outlined are mostly applicable to any other analyte. A variety of preanalytical variables impacts on the results obtained, including analyte stability (which is different for different analytes, i.e., DNA, RNA, or protein), period of warm and of cold ischemia, fixation time, tissue processing, sample storage time, and storage conditions. In addition, assay variables play an important role, including reagent specificity (notably but not uniquely an issue concerning antibodies used in immunohistochemistry), technical components of the assay, quantitation, and assay interpretation. Finally, appropriateness of an assay for clinical application is an important issue. Reference is made to publicly available guidelines to improve on biomarker development in general and requirements for clinical use in particular. Strategic goals are formulated in order to improve on the quality of biomarker reporting, including issues of analyte quality, experimental detail, assay efficiency and precision, and assay appropriateness. PMID- 24487785 TI - Tissue prognostic biomarkers in primary cutaneous melanoma. AB - Cutaneous melanoma (CM) causes the greatest number of skin cancer-related deaths worldwide. Predicting CM prognosis is important to determine the need for further investigation, counseling of patients, to guide appropriate management (particularly the need for postoperative adjuvant therapy), and for assignment of risk status in groups of patients entering clinical trials. Since recurrence rate is largely independent from stages defined by morphological and morphometric criteria, there is a strong need for identification of additional robust prognostic factors to support decision-making processes. Most data on prognostic biomarkers in melanoma have been evaluated in tumor tissue samples by conventional morphology and immunohistochemistry (IHC) as well as DNA and RNA analyses. In the present review, we critically summarize main high-quality studies investigating IHC-based protein biomarkers of melanoma outcome according to Reporting Recommendations for Tumor Marker Prognostic Studies (REMARK)-derived criteria. Pathways have been classified and conveyed in the "biologic road" previously described by Hanahan and Weinberg. Data derived from genomic and transcriptomic technologies have been critically reviewed to better understand if any of investigated proteins or gene signatures should be incorporated into clinical practice or still remain a field of melanoma research. Despite a wide body of research, no molecular prognostic biomarker has yet been translated into clinical practice. Conventional tissue biomarkers, such as Breslow thickness, ulceration, mitotic rate and lymph node positivity, remain the backbone prognostic indicators in melanoma. PMID- 24487787 TI - Prognostic biomarkers in colorectal cancer: where do we stand? AB - Colorectal cancer remains a major cause of cancer-related death worldwide. One way to reduce its staggering mortality rate and socio-economic burden is to predict outcome based on the aggressiveness of the tumor biology in order to treat patients accordingly to their risk profile. As such, it comes as no surprise that prognostic biomarker discovery is a hot topic in colorectal cancer research. The last two decades have literally produced tons of new data and an avalanche of potential clinically applicable biomarkers. This review explores and summarizes data concerning the prognostic strength and clinical utility of current and future tissue biomarkers in the diagnosis and treatment of colorectal cancer. PMID- 24487788 TI - Biomarkers for gastric cancer: prognostic, predictive or targets of therapy? AB - Gastric cancer is an aggressive disease often diagnosed at an advanced stage. Despite improvements in surgical and adjuvant treatment approaches, gastric cancer remains a global public health problem with a 5-year overall survival of less than 25 %. This is a heterogeneous disease, both in terms of biology and genetics, and many prognostic biomarkers have been pointed out in the literature; nevertheless, their application remains debatable. In this review, we opted to give relevance to those biomarkers that have been the subject of studies with significant statistical power, which have been replicated and have been/are in targeted therapy clinical trials and, which as a consequence, have their prognostic and/or predictive value established. Some gastric cancer biomarkers that may help in defining the course of treatment are also discussed. Accepted practical guidelines, wet-lab protocols for the detection of these biomarkers, as well as ongoing and completed clinical trials have been compiled. In summary, clinical approaches based on the combination of correct staging with targeted and conventional systemic therapies may improve gastric cancer patients' outcome, but are only in their infancy. Some major challenges in identifying reliable prognostic/predictive biomarkers are individual genetic variation and tumour heterogeneity that often influence response to therapy and drug resistance. Prognostic and predictive biomarkers may nevertheless be extremely valuable to correctly stratify gastric cancer patients for treatment and, ultimately, improve survival. PMID- 24487789 TI - Molecular tests as prognostic factors in breast cancer. AB - In early breast cancer, prognostic tests are used to guide decisions on adjuvant systemic hormonal therapy, chemotherapy and targeted therapy treatment. This has led to large research efforts to identify novel prognostic markers in breast cancer. At present, the tissue factors used to guide treatment of breast cancer patients are tumor size, lymph node status, histologic grade, ER status, PR status, and HER2 status; in addition, multigene-expression-based prognostic tests are rapidly emerging. While identification of prognostic gene expression profiles has been successful, it has not been possible yet to identify robust clinically useful predictors of response to systemic treatment. As a result of rapid advances in technology and bioinformatics, it has become possible to analyze large series of breast carcinomas using high-throughput genetic techniques, including whole genome sequence analysis and gene expression profiling. These genomic studies will lead to the development of additional prognostic and predictive tissue-based tests. The most important aspects of the currently used tissue-based prognostic and predictive tests and the research in this area are reviewed. PMID- 24487790 TI - Prognostic prostate tissue biomarkers of potential clinical use. AB - In prostate biopsies and in prostatectomy specimens, the Gleason score remains the strongest prognosticator of prostate cancer progression, in addition to serum PSA level and DRE findings, in spite of numerous potential biomarkers discovered during the last few decades. Inter- and intratumoural heterogeneity may have limited the employment of tissue biomarkers on prostate biopsies. Nevertheless, the monoclonality of morphologically heterogeneous (Gleason score 7) tumour foci would suggest that genetic biomarkers, arising early in prostate carcinogenesis, may overcome issues related to intratumoural heterogeneity. In spite of the above limitations, a few biomarkers including the proliferation marker Ki-67 and genetic markers such as c-MYC and PTEN have consistently shown their independent prognostic impact both for biochemical recurrence and for clinical outcome parameters such as metastatic disease or prostate-specific mortality. The routine application of biomarkers requiring immunostaining (e.g. Ki-67) has particularly been hindered by the lack of standardized protocols for processing and scoring, while the application of fluorescence in situ hybridization (FISH) technology is considered more labour intensive but better standardized. Future steps to enhance the uptake of prostate tissue biomarkers should be focused on prospective studies, particularly on prostate biopsy specimens, using protocols that are highly standardized for the processing and scoring of the biomarkers. A few recently developed RNA-based test signatures may provide an alternative to FISH or immunohistochemistry-based tests. PMID- 24487792 TI - Gene expression profiling in patients with carcinoma of unknown primary site: from translational research to standard of care. AB - Carcinoma of unknown primary site (CUP) is diagnosed in approximately 3 % of patients with advanced cancer, and most patients have traditionally been treated with empiric chemotherapy. As treatments improve and become more specific for individual solid tumor types, therapy with a single empiric combination chemotherapy regimen becomes increasingly inadequate. Gene expression profiling (GEP) is a new diagnostic method that allows prediction of the site of tumor origin based on gene expression patterns retained from the normal tissues of origin. In blinded studies in tumors of known origin, GEP assays correctly identified the site of origin in 85 % of cases and compares favorably with immunohistochemical (IHC) staining. In patients with CUP, GEP is able to predict a site of origin in >95 % of patients versus 35-55 % for IHC staining. Although confirmation of the accuracy of these predictions is difficult, the diagnoses made by IHC staining and GEP are identical in 77 % of cases when IHC staining predicts a single primary site. GEP diagnoses appear to be most useful when IHC staining is inconclusive. Site-specific treatment of CUP patients based on GEP and/or IHC predictions appears to improve overall outcomes; patients predicted to have treatment-sensitive tumor types derived the most benefit. GEP adds to the diagnostic evaluation of patients with CUP and should be included when IHC staining is unable to predict a single site of origin. Site-specific treatment, based on tissue of origin diagnosis, should replace empiric chemotherapy in patients with CUP. PMID- 24487791 TI - The histopathological approach to inflammatory bowel disease: a practice guide. AB - Inflammatory bowel diseases (IBDs) are lifelong disorders predominantly present in developed countries. In their pathogenesis, an interaction between genetic and environmental factors is involved. This practice guide, prepared on behalf of the European Society of Pathology and the European Crohn's and Colitis Organisation, intends to provide a thorough basis for the histological evaluation of resection specimens and biopsy samples from patients with ulcerative colitis or Crohn's disease. Histopathologically, these diseases are characterised by the extent and the distribution of mucosal architectural abnormality, the cellularity of the lamina propria and the cell types present, but these features frequently overlap. If a definitive diagnosis is not possible, the term indeterminate colitis is used for resection specimens and the term inflammatory bowel disease unclassified for biopsies. Activity of disease is reflected by neutrophil granulocyte infiltration and epithelial damage. The evolution of the histological features that are useful for diagnosis is time- and disease-activity dependent: early disease and long standing disease show different microscopic aspects. Likewise, the histopathology of childhood-onset IBD is distinctly different from adult-onset IBD. In the differential diagnosis of severe colitis refractory to immunosuppressive therapy, reactivation of latent cytomegalovirus (CMV) infection should be considered and CMV should be tested for in all patients. Finally, patients with longstanding IBD have an increased risk for the development of adenocarcinoma. Dysplasia is the universally used marker of an increased cancer risk, but inter-observer agreement is poor for the categories low-grade dysplasia and indefinite for dysplasia. A diagnosis of dysplasia should not be made by a single pathologist but needs to be confirmed by a pathologist with expertise in gastrointestinal pathology. PMID- 24487793 TI - Biomarkers in renal cancer. AB - Treatment options for primary and metastatic renal cancer are increasing. Accurate data from the pathological examination of renal cancer specimens aid clinicians in stratifying patients for surveillance and adjuvant therapies. This review focuses on biomarkers in diagnosis, prognosis and prediction of the biologic behavior of renal tumors which should be recorded in pathology reports and which are under investigation. Special emphasis is given to the use of immunohistochemical markers in differential diagnosis of various renal tumor subtypes. The relevance of cytogenetic and molecular findings is also discussed. The review includes the 2012 International Society for Urological Pathology Consensus conference recommendations. PMID- 24487794 TI - Single nucleotide polymorphisms in nucleotide excision repair genes, cancer treatment, and head and neck cancer survival. AB - PURPOSE: Head and neck cancers (HNC) are commonly treated with radiation and platinum-based chemotherapy, which produce bulky DNA adducts to eradicate cancerous cells. Because nucleotide excision repair (NER) enzymes remove adducts, variants in NER genes may be associated with survival among HNC cases both independently and jointly with treatment. METHODS: Cox proportional hazards models were used to estimate race-stratified (White, African American) hazard ratios (HRs) and 95 % confidence intervals for overall (OS) and disease-specific (DS) survival based on treatment (combinations of surgery, radiation, and chemotherapy) and 84 single nucleotide polymorphisms (SNPs) in 15 NER genes among 1,227 HNC cases from the Carolina Head and Neck Cancer Epidemiology Study. RESULTS: None of the NER variants evaluated were associated with survival at a Bonferroni-corrected alpha of 0.0006. However, rs3136038 [OS HR = 0.79 (0.65, 0.97), DS HR = 0.69 (0.51, 0.93)] and rs3136130 [OS HR = 0.78 (0.64, 0.96), DS HR = 0.68 (0.50, 0.92)] of ERCC4 and rs50871 [OS HR = 0.80 (0.64, 1.00), DS HR = 0.67 (0.48, 0.92)] of ERCC2 among Whites, and rs2607755 [OS HR = 0.62 (0.45, 0.86), DS HR = 0.51 (0.30, 0.86)] of XPC among African Americans were suggestively associated with survival at an uncorrected alpha of 0.05. Three SNP treatment joint effects showed possible departures from additivity among Whites. CONCLUSIONS: Our study, a large and extensive evaluation of SNPs in NER genes and HNC survival, identified mostly null associations, though a few variants were suggestively associated with survival and potentially interacted additively with treatment. PMID- 24487795 TI - Expression and cellular distribution of the interleukin 2 signaling system in cortical lesions from patients with focal cortical dysplasia. AB - Focal cortical dysplasia (FCD) is a well-known cause of medically intractable epilepsy. To understand the potential role of the inflammatory cytokine interleukin 2 (IL-2) in the pathogenesis of FCD, we investigated the expression patterns of IL-2 and its receptors (IL-2Rs) in FCD and control samples that included epileptic neocortex from mesial temporal lobe epilepsy patients and nonepileptic normal cortex (CTX). Greater mRNA and protein levels of IL-2 and IL 2Rs were observed in FCD versus CTX samples. Moreover, the expression of IL-2 and IL-2Rs was significantly higher in FCD II than FCD I. In situ hybridization and immunohistochemistry results indicated that IL-2 and IL-2Rs were strongly expressed in hypertrophic neurons and neuronal microcolumns in FCD I and highly expressed in malformed cells in FCD II. In addition, the protein levels of Janus kinase 1, Janus kinase 3, phosphorylated signal transducer and activator of transcription 5, which are important downstream factors in the IL-2 signaling pathway, were increased in FCD lesions. Soluble IL-2R was decreased in FCD compared with that in CTX samples. These results suggest that upregulation of IL 2 and IL-2Rs combined with activation of IL-2-dependent signaling pathways may contribute to the pathogenesis of FCD. PMID- 24487797 TI - Alzheimer disease and cellular mechanisms of memory storage. AB - Most ongoing efforts to combat Alzheimer disease (AD) are focused on treating its clinical symptoms, but the neuropathologic changes underlying AD appear decades earlier and become essentially irreversible by the time the disease reaches its clinical stages. This necessitates treating AD at preclinical stages, which requires a better understanding of the primary mechanisms leading to AD pathology. Here I argue that such an understanding calls for addressing perhaps the most puzzling question in AD-why the underlying pathology selectively impairs neurons that are involved in memory formation and storage. Memory formation is associated with epigenetic chromatin modifications and may, therefore, be accompanied by the synthesis of proteins unique to neurons involved in memory. These proteins could be recognized by the immune system as "nonself" antigens. This does not happen in the healthy brain because of its isolation from the immune system by the blood-brain barrier (BBB). All risk factors for AD impair the BBB, which may allow the immune system to attack memory-involved neurons and make them vulnerable to AD-associated pathology. This hypothesis is testable and, if confirmed, could redirect therapeutic efforts toward maintaining BBB integrity people belonging to AD risk groups rather than treating them when it is too late. PMID- 24487796 TI - Clinicopathological outcomes of prospectively followed normal elderly brain bank volunteers. AB - Existing reports on the frequencies of neurodegenerative diseases are typically based on clinical diagnoses. We sought to determine these frequencies in a prospectively assessed, community-based autopsy series. Included subjects had normal cognitive and movement disorder assessments at study entry. Of the 119 cases meeting these criteria, 52% were women; the median age of study entry was 83.5 years (range, 67-99 years), and the median duration from the first visit until death was 4.3 years (range, 0-10 years). At autopsy, clinicopathological diagnoses were made in 30 cases (25%). These diagnoses included 20 with Alzheimer disease (AD) (17%), 7 with vascular dementia (6%), 4 with progressive supranuclear palsy (3%), 3 with Parkinson disease and 1 each with dementia with Lewy bodies, corticobasal degeneration, or multiple system atrophy (0.8% each). Of the 87 subjects still clinically normal at death (73%), 33 had extensive AD pathology (preclinical AD) (38%), 17 had incidental Lewy bodies (20%), and 4 had incidental pathology consistent with progressive supranuclear palsy (5%). The diagnoses were not mutually exclusive. Although limited by a relatively small sample size, the neuropathological outcome of these initially normal elderly subjects represents a rough estimate of the incidence of these neurodegenerative conditions over a defined time period. PMID- 24487798 TI - Donepezil enhances Purkinje cell survival and alleviates motor dysfunction by inhibiting cholesterol synthesis in a murine model of Niemann Pick disease type C. AB - Neurodegenerative processes are often accompanied by disruption of cholinergic systems; therefore, acetylcholinesterase (AChE) inhibitors (AChEIs) may have therapeutic potential in some neurological conditions. We evaluated the effects of administration of donepezil, a widely used AChEI, in the cerebellum in a murine model of Niemann-Pick disease type C (NPC). The NPC mice developed Purkinje cell loss at the age of 8 weeks; 4-week-old NPC mice given donepezil led to improvement of Purkinje cell survival that was associated with improvement of motor dysfunction in the mice. Because abnormal accumulation of cholesterol caused by impaired lipid homeostasis is the principal pathogenetic mechanism underlying NPC, we investigated the effects of donepezil on cholesterol metabolism in the NPC mice. Donepezil treatment reduced cholesterol accumulation in adult neural stem cells in vitro, and it downregulated the expression of the cholesterol synthesis factors' sterol regulatory element-binding proteins and 3 hydroxy-3-methylglutaryl-CoA reductase in the cerebellum, implying that AChE activity might be associated with cholesterol homeostasis. Taken together, our findings suggest the role of a cholinergic pathway as a novel regulator of NPC progression and the potential application of AChEIs for the treatment of human NPC. PMID- 24487799 TI - Arx is required for specification of the zona incerta and reticular nucleus of the thalamus. AB - Mutations in the aristaless-related homeobox (ARX) gene result in a spectrum of structural and functional nervous system disorders including lissencephaly, movement disorders, intellectual disabilities, and epilepsy. Some patients also have symptoms indicating hypothalamic dysfunction, but little is known about the role of ARX in diencephalic development. To begin evaluating diencephalic defects, we examined the expression of a panel of known genes and gene products that label specific diencephalic nuclei in 2 different Arx mutant mouse lines at E18.5. Male mice engineered to have a polyalanine expansion mutation (Arx) revealed no expression differences in any diencephalic nucleus when compared with wild-type littermates. In contrast, mice null for Arx (Arx) lost expression of specific markers of the thalamic reticular nucleus and zona incerta (ZI) while retaining expression in other thalamic nuclei and in the hypothalamus. Tyrosine hydroxylase, a marker of the dopaminergic A13 subnucleus of ZI, was among those lost, suggesting a requirement for Arx in normal thalamic reticular nucleus and ZI development and, specifically, for A13 dopaminergic fate. Because the ZI and A13 regions make connections to several hypothalamic nuclei, such misspecification may contribute to the "hypothalamic dysfunction" observed in some patients. PMID- 24487800 TI - Neuropathologic characterization of INF2-related Charcot-Marie-Tooth disease: evidence for a Schwann cell actinopathy. AB - The association of Charcot-Marie-Tooth (CMT) disease with renal dysfunction is uncommon but has long been recognized in several families. Recently, mutations in the INF2 gene, which encodes inverted formin-2, were identified in patients with focal segmental glomerulosclerosis and a dominant intermediate form of CMT (CMTDIE, OMIM #614455). We describe the pathologic lesions of nerve biopsies from 6 patients with INF2-related CMTDIE. There were 4 females and 2 males; ages were from 12 to 47 years; durations between neuropathy onset and biopsy were from 2 to 37 years. Clinical phenotypes were similar to those seen in other forms of CMT disease, but there was always an associated proteinuria (and later renal failure). Motor median nerve conduction velocities were in the range of intermediate CMT disease. Pathologic lesions suggested chronic demyelination and remyelination associated with progressive axonal loss. By electron microscopy, we observed unusual whorl-like proliferations of flattened Schwann cell cytoplasm and anomalies of unmyelinating Schwann cell cytoplasm with supernumerary elongated extensions similar to those described in CMT4C. We also observed abnormal accumulation of beta-actin in the cytoplasm of Schwann cells. Our results suggest that these lesions reflect a global disorder of the actin cytoskeleton in Schwann cells and that CMTDIE is the first peripheral nerve disorder associated with a Schwann cell actinopathy. PMID- 24487801 TI - CLIPPERS with chronic small vessel damage: more overlap with small vessel vasculitis? PMID- 24487802 TI - Re: Disconnection of the ascending arousal system in traumatic coma. J Neuropathol Exp Neurol 2013;72: 505-523. PMID- 24487803 TI - Autobiography series: a hitchhiker's road to neuropathology. PMID- 24487804 TI - Use of introspection in scientific psychological research. AB - The use of introspection is unavoidable even in psychological research on animals. Difficulties may arise from the absence of reliable introspective data; it is suggested that this could be the case for the so-called "reward system". In other circumstances confusion comes from using introspection without being aware of it: speaking and thinking have for many years been considered as the same operation, but the reason for this belief is not clearly documented and it may be suspected of being only introspection. Amongst other evidence, a careful and conscious use of introspection demonstrated by auto-analyses of former aphasic patients strongly suggests that language and thought are quite distinct entities. PMID- 24487805 TI - The role of the caudate in nonmotor behaviors in Huntington's disease. AB - Neuropsychologic data suggest an important role for the caudate nucleus (CN) in behavioral impairments in Huntington's disease (HD). These include abnormalities in executive function, egocentric visuospatial representations, communication, and retrieval of declarative memories, changes in personality, and psychiatric disturbances. Animal paradigms of CN lesions support a role for the CN in some of these behaviors. Current theories of basal ganglia function add explanatory value to the role of the CN in these behaviors. A disconnection of the caudate from limbic structures, including the amygdala may account for many nonmotor behaviors observed in HD. PMID- 24487806 TI - A case of epilepsy and psychosis in the seventeenth century. AB - A seventeenth-century painter left an account of his seizures, trances and visions; in 1923 Freud commented on this "demonological neurosis" without discussing the seizures. Attention is drawn to the concurrence of epilepsy and psychosis in this early autobiographical source. PMID- 24487807 TI - Imitation in autism. A preliminary research note. AB - Previous studies have claimed that children with autism are poor imitators and a lack of imitative capacity has been included by some investigators as one early sign of autism. Presented here are results from a pilot study focusing on observed imitation after presenting 15 tasks to five children with autism (mental age 25-51 months). Imitation tasks involving simple object manipulation, vocal responses, facial and manual gestures, and object substitution were presented to each child. The performance of the children with autism is compared with (1) three normal 4-year-old children (for all 15 tasks), and (2) observations from 28 healthy 1-year-olds (for 10 of the tasks used). The findings indicate that the autistic group displayed the highest level of imitation on object manipulation and vocal tasks while object substitution, facial, and motor imitation acts seemed to be difficult for children with autism. However, the small number of children included as well as the individual variation observed among the autistic subjects precludes any definite conclusions from these pilot observations. It is hypothesized that imitation in children with autism has to be studied separately for different domains and probably also for different subgroups within the autistic population. PMID- 24487808 TI - The clinical features of 67 patients with clinically definite Steele-Richardson Olszewski syndrome. AB - The clinical features of 67 patients with probable Steele-Richardson-Olszewski syndrome have been analysed. Bradykinesia was present in 92.5% of cases at the time of initial assessment and the two commonest presenting complaints were walking difficulties and stiffness. Only 11 patients had a supranuclear gaze palsy when first seen. Forty-nine patients developed cognitive impairment in the course of their illness based on neuropsychological testing. In addition to the classical clinical findings occasional other findings included focal dystonia, tonic inhibition of levator palpebrae and blepharospasm, respiratory disturbances and impaired hearing. Only nine cases responded at all to levodopa therapy. PMID- 24487809 TI - Factors affecting the clinical measurement of visuo-spatial neglect. AB - The present study examined a battery of tests to evaluate unilateral spatial neglect; the tests included different tasks involving several modalities of spatial exploration mapping perceptual, motor, attentional and personal or extrapersonal space dimensions. The subjects, 121 right-brain-damaged patients with unilateral neglect, were studied in seven laboratories in four European countries. Relationships among the various tests were examined by correlations, a cluster analysis and by an analysis of individual cases. Different sensitivity was found among various tests for detecting neglect performances. Both the cluster analysis and the single case analysis clearly showed a segregation between personal and extrapersonal neglect. Analysis of the large cluster, including a variety of tests of extra personal neglect, together with the study of single cases, suggests the possibility of differentiating the various manifestations of spatial neglect which can be interpreted on the basis of the descriptions of other individual cases previously reported in the literature. Finally, the present study indicated the relative stability of neglect following the acute phase and its independence from age. PMID- 24487810 TI - Two forms of palilalia: a clinicoanatomical study. AB - The clinical and neuroradiological findings of three patients with marked palilalia due to different neurological disorders are reported. These cases and others in the literature suggest the possibility of different variations. "Spasmodic, heterophonic palilalia" is typically observed in Parkinson's syndrome and pseudobulbar palsy: the content of palilalia is characteristically changed by interruption. "Atonic, homophonic, autoecholalic palilalia" is mainly seen in Pick's disease, and is not affected by external interruption. PMID- 24487811 TI - Crossed aphasia in a dextral without "minor" hemisphere signs. AB - A case of severe aphasia after right hemisphere stroke, confirmed by CT, in an unambiguously dextral patient is reported. The patient showed no limb apraxia, and performed well on a test of "closure" (Mooney faces). Extensive testing revealed no signs of visuo-spatial neglect. We conclude that "pure" crossed aphasia can occur in the absence of symptoms normally associated with right hemisphere lesions. PMID- 24487815 TI - Other factors ought to be kept in mind when analyzing plasma asymmetric dimethylarginine levels. PMID- 24487816 TI - Response to "Other factors ought to be kept in mind when analyzing plasma asymmetric dimethylarginine levels". PMID- 24487817 TI - Viral Infection: Sugar-coated poliovirus. PMID- 24487819 TI - Symbiotic digestion of lignocellulose in termite guts. AB - Their ability to degrade lignocellulose gives termites an important place in the carbon cycle. This ability relies on their partnership with a diverse community of bacterial, archaeal and eukaryotic gut symbionts, which break down the plant fibre and ferment the products to acetate and variable amounts of methane, with hydrogen as a central intermediate. In addition, termites rely on the biosynthetic capacities of their gut microbiota as a nutritional resource. The mineralization of humus components in the guts of soil-feeding species also contributes to nitrogen cycling in tropical soils. Lastly, the high efficiency of their minute intestinal bioreactors makes termites promising models for the industrial conversion of lignocellulose into microbial products and the production of biofuels. PMID- 24487824 TI - Monitor backscatter factors for the Varian 21EX and TrueBeam linear accelerators: measurements and Monte Carlo modelling. AB - Linac backscattered radiation (BSR) into the monitor chamber affects the chamber's signal and has to be accounted for in radiotherapy dose calculations. In Monte Carlo (MC) calculations, the BSR can be modelled explicitly and accounted for in absolute dose. However, explicit modelling of the BSR becomes impossible if treatment head geometry is not available. In this study, monitor backscatter factors (MBSFs), defined as the ratio of the charge collected in the monitor chamber for a reference field to that of a given field, have been evaluated experimentally and incorporated into MC modelling of linacs with either known or unknown treatment head geometry. A telescopic technique similar to that by Kubo (1989 Med. Phys. 16 295-98) was used. However, instead of lead slits, a 1.8 mm diameter collimator and a small (2 mm diameter) detector positioned at extended source to detector distance were used. This setup provided a field of view to the source of less than 3.1 mm and allowed for MBSF measurements of open fields from 1 * 1 to 40 * 40 cm(2). For the fields with both X and Y dimensions exceeding 15 cm, a diode detector was used. A pinpoint ionization chamber was used for smaller fields. MBSFs were also explicitly modelled in MC calculations using BEAMnrc and DOSXYZnrc codes for 6 and 18 MV beams of a Varian 21EX linac. A method for deriving the D(ch)(forward) values that are used in MC absolute dose calculations was demonstrated. These values were derived from measured MBSFs for two 21EX and four TrueBeam energies. MBSFs were measured for 6 and 18 MV beams from Varian 21EX, and for 6 MV, 10 MV-FFF, 10 MV, and 15 MV beams from Varian TrueBeam linacs. For the open field sizes modelled in this study for the 21EX, the measured MBSFs agreed with MC calculated values within combined statistical (0.4%) and experimental (0.2%) uncertainties. Variation of MBSFs across field sizes was about a factor of two smaller for the TrueBeam compared to 21EX Varian linacs. Measured MBSFs and the derived [Formula: see text] factors allow for the incorporation of the BSR effect into accurate radiotherapy dose calculations without explicit backscatter modelling. PMID- 24487820 TI - The path of anti-tuberculosis drugs: from blood to lesions to mycobacterial cells. AB - For the successful treatment of pulmonary tuberculosis, drugs need to penetrate complex lung lesions and permeate the mycobacterial cell wall in order to reach their intracellular targets. However, most currently used anti-tuberculosis drugs were introduced into clinical use without considering the pharmacokinetic and pharmacodynamic properties that influence drug distribution, and this has contributed to the long duration and limited success of current therapies. In this Progress article, I describe new methods to quantify and image drug distribution in infected lung tissue and in mycobacterial cells, and I explore how this technology could be used to design optimized multidrug regimens. PMID- 24487825 TI - Paroxysmal exercise-induced dystonia due to GLUT1 mutation can be responsive to levodopa: a case report. PMID- 24487826 TI - Deep brain stimulation in Parkinson's disease: meta-analysis of randomized controlled trials. AB - Until recent years there has been no evidence from randomized controlled trials (RCTs) on the efficacy of deep brain stimulation (DBS) for Parkinson's disease (PD). This review and meta-analysis of RCTs describes the efficacy of DBS in improving motor signs, functionality and quality of life of PD patients. Several electronic databases were consulted up to April 2013. RCTs that compared DBS plus medication versus medication (alone or plus sham DBS) in PD patients were included. Outcome measures were motor function, waking time on good functioning without troublesome dyskinesias, levodopa-equivalent dose reduction, medication induced complications, activities of daily living, health-related quality of life, and neurocognitive and psychiatric effects. Six RCTs (n = 1,184) that compared DBS plus medication versus medication alone were included. The results show that DBS significantly improves patients' symptoms, functionality and quality of life. Effects sizes are intense for the reduction of motor signs and improvement of functionality in the off-medication phase, in addition to the reduction of the required medication dose and its associated complications. Moderate effects were observed in the case of motor signs and time in good functionality in the on-medication phase, in addition to the quality of life. Although the number of RCTs obtained is small, the total sample size is relatively large, confirming the efficacy of DBS in the control of motor signs and improvement of patients' functionality and quality of life. More controlled research is required on the neurocognitive and psychiatric effects of DBS. PMID- 24487828 TI - Aberration compensation for objective phase curvature in phase holographic microscopy: comment. AB - In a recent Letter by Seo et al. [Opt. Lett.37, 4976 (2012)], the numerical correction of the quadratic phase distortion introduced by the microscope objective in digital holographic microscopy (DHM) has been presented. In this comment, we would like to draw to the attention of the authors and the readers in general that this approach could not be the optimal solution for maintaining the accuracy of the quantitative phase via DHM. We recall that the use of telecentric imaging systems in DHM simplifies the numerical processing of the phase images and produces more accurate measurements. PMID- 24487829 TI - Simplified calibration procedure for Mueller polarimeter in transmission configuration. AB - We address calibration of Mueller polarimeters in transmission configuration and in the presence of noise. By comparing the maximum likelihood (ML) method and the extended eigenvalue calibration method, it is found that the ML method yields higher precision in the presence of noise. Moreover, we show that by employing the ML method together with simple constraints on the calibration matrices, it is possible to perform the calibration without using a retarder, and with only polarizers. This result is of great interest for the calibration of multispectral polarimeters. PMID- 24487827 TI - Selective retinal ganglion cell loss in familial dysautonomia. AB - To define the retinal phenotype of subjects with familial dysautonomia (FD). A cross-sectional study was carried out in 90 subjects divided in three groups of 30 each (FD subjects, asymptomatic carriers and controls). The study was developed at the Dysautonomia Center, New York University Medical Center. All subjects underwent spectral domain optical coherence tomography (OCT) and full neuro-ophthalmic examinations. In a subset of affected subjects, visual evoked potentials and microperimetry were also obtained. We compared the retinal nerve fiber layer (RNFL) thickness from OCT between the three groups. OCT showed loss of the RNFL in all FD subjects predominantly in the maculopapillary region (63 % temporally, p < 0.0001; and 21 % nasally, p < 0.005). RNFL loss was greatest in older FD subjects and was associated with decreased visual acuity and color vision, central visual field defects, temporal optic nerve pallor, and delayed visual evoked potentials. Asymptomatic carriers of the FD gene mutation all had thinner RNFL (12 % globally, p < 0.005). OCT and clinical neuro-ophthalmological findings suggest that maculopapillary ganglion cells are primarily affected in FD subjects, leading to a specific optic nerve damage that closely resembles mitochondrial optic neuropathies. This raises the possibility that reduced IKAP levels may affect mitochondrial proteins and their function in the nervous system, particularly in the retina. PMID- 24487830 TI - Pure ultraviolet emission from ZnO nanowire-based p-n heterostructures. AB - Well-aligned ZnO nanowires have been prepared on sapphire substrate, and structural and optical characterizations indicate that the nanowires are of single crystalline and have relatively high luminescent quality. By employing the ZnO nanowires as an active layer, p-Zn0.68Mg0.32O:N/n-ZnO nanowire heterostructure light-emitting devices (LEDs) have been fabricated. The LEDs show pure ultraviolet emission when a forward bias is applied, while the deep-level emission frequently observed in ZnO p-n junctions is almost totally invisible. The devices can work continuously for over 27 h under the injection of a current density of 500 mA/cm2, indicating their good stability. PMID- 24487831 TI - Efficient inverted quantum-dot light-emitting devices with TiO2/ZnO bilayer as the electron contact layer. AB - We have demonstrated an efficient inverted CdSe/CdS/ZnS core/shell quantum-dot light-emitting device (QD-LED) using a solution-processed sol-gel TiO2 and ZnO nanoparticle composite layer as an electron-injection layer with controllable morphology and investigated the electroluminescence mechanism. The introduction of the ZnO layer can lead to the formation of spin-coated uniform QD films and fabrication of high-luminance QD-LEDs. The TiO2 layer improves the balance of charge injection due to its lower electron mobility relative to the ZnO layer. These results offer a practicable platform for the realization of a trade-off between the luminance and efficiency in the inverted QD-LEDs with TiO2/ZnO composites as the electron contact layer. PMID- 24487832 TI - Spatially Fourier-encoded photoacoustic microscopy using a digital micromirror device. AB - We have developed spatially Fourier-encoded photoacoustic (PA) microscopy using a digital micromirror device. The spatial intensity distribution of laser pulses is Fourier-encoded, and a series of such encoded PA measurements allows one to decode the spatial distribution of optical absorption. The throughput and Fellgett advantages were demonstrated by imaging a chromium target. By using 63 spatial elements, the signal-to-noise ratio in the recovered PA signal was enhanced by ~4*. The system was used to image two biological targets, a monolayer of red blood cells and melanoma cells. PMID- 24487833 TI - Fabrication of microelectrodes based on precursor doped with metal seeds by femtosecond laser direct writing. AB - Silver (Ag) seeds for assisting femtosecond laser direct writing (FsLDW) were employed in the fabrication of microelectrodes (MEs). Pattern-controllable and size-tunable MEs can be easily constructed by introducing Ag seeds to the ion precursor solution in the process of laser-induced photoreduction of the Ag ions. The fabrication process is stable under sufficient material supply, and the applied laser power is reduced to one-tenth of that without Ag seeds. Finally, as a representative application, an organic field effect transistor (OFET) was fabricated, based on this laser-fabricated Ag ME. The OFET exhibited good photoelectric properties, and achieved an on-off ratio of 200. PMID- 24487834 TI - Pulse shaping in mode-locked fiber lasers by in-cavity spectral filter. AB - We numerically show the possibility of pulse shaping in a passively mode-locked fiber laser by inclusion of a spectral filter into the laser cavity. Depending on the amplitude transfer function of the filter, we are able to achieve various regimes of advanced temporal waveform generation, including ones featuring bright and dark parabolic-, flat-top-, triangular- and saw-tooth-profiled pulses. The results demonstrate the strong potential of an in-cavity spectral pulse shaper for controlling the dynamics of mode-locked fiber lasers. PMID- 24487835 TI - Continuous wave, frequency-tunable terahertz laser radiation generated via stimulated polariton scattering. AB - We report the generation of CW THz radiation, generated via stimulated polariton scattering in MgO:LiNbO3. The system is capable of producing frequency tunable radiation across the range 1.5-2.3 THz and requires only 2.3 W incident diode pump power to reach threshold. Maximum THz output power of 2.3 MUW has been detected for just 5.9 W incident diode pump power, at a frequency of 1.8 THz. PMID- 24487836 TI - One-dimensional ultracold medium of extreme optical depth. AB - We report on the preparation of a one-dimensional ultracold medium in a hollow core photonic crystal fiber, reaching an effective optical depth of 1000(150). We achieved this extreme optical depth by transferring atoms from a magneto-optical trap into a far-detuned optical dipole trap inside the hollow-core fiber, yielding up to 2.5(3)*10(5) atoms inside the core with a loading efficiency of 2.5(6)%. The preparation of an ultracold medium of such huge optical depth paves the way toward new applications in quantum optics and nonlinear optics. PMID- 24487837 TI - Calibration-free B-scan images produced by master/slave optical coherence tomography. AB - We report on a novel method to produce B-scan images in spectral domain optical coherence tomography (SD-OCT). The method proceeds in two steps. In the first step, using a mirror in the sample arm of the interferometer, channelled spectra are acquired for different values of the optical path difference (OPD) and stored as masks. In the second step, the mirror is replaced with an object and the captured channelled spectrum is correlated with each mask, providing the interference strength from the OPD value used to collect the respective mask. Such a procedure does not require data organized in equal frequency slots, and therefore there is no need for resampling as practiced in the conventional fast Fourier transform (FFT)-based SD-OCT technology. We show that the sensitivity drop-off versus OPD and the quality of B-scan images of the novel method are similar to those obtained in the conventional FFT-based SD-OCT, using spectral data linearly organized in frequency. PMID- 24487838 TI - Highly sensitive optical thermometry based on upconversion emissions in Tm3+/Yb3+ codoped LiNbO3 single crystal. AB - Under 980 nm excitation, upconversion emissions originating from 3F(2,3)->3H(6) and 3H(4)->3H(6) transitions of Tm3+ ion in LiNbO3 single crystal were studied as a function of temperature in the range of 323-773 K. The 3F(2,3) and 3H(4) levels of Tm3+ ion are confirmed to be thermally coupled levels. By using fluorescence intensity ratio technique, the sensitivity of optical temperature sensor achieved in our work is higher than other reported temperature sensors. Additionally, this optical temperature sensor is well suited to high operating temperature. Tm3+/Yb3+ codoped LiNbO3 is a promising candidate for fabricating excellent optical temperature sensors. PMID- 24487839 TI - Effective thermal resistance of a photonic crystal microcavity. AB - We present a simple method to accurately measure the effective thermal resistance of a photonic crystal microcavity. The cavity is embedded between two Schottky contacts forming a metal-semiconductor-metal device. The photocarriers circulating in the device provide a local temperature rise that can be dominated by Joule effect under certain conditions. We show that the effective thermal resistance (R(th)) can be experimentally deduced from the spectral shift of the cavity resonance wavelength measured at different applied bias. We deduce a value of R(th)1.6*10(4) KW(-1) for a microcavity on silicon-on-insulator, which is in good agreement with 3D thermal modeling by finite elements. PMID- 24487840 TI - Nonlinear coupled-mode theory for periodic plasmonic waveguides and metamaterials with loss and gain. AB - We derive general coupled-mode equations describing the nonlinear interaction of electromagnetic modes in periodic media with loss and gain. Our approach is rigorously based on the Lorentz reciprocity theorem, and it can be applied to a broad range of metal-dielectric photonic structures, including plasmonic waveguides and metamaterials. We verify that our general results agree with the previous analysis of particular cases, and predict novel effects on self- and cross-phase modulation in multilayer nonlinear fishnet metamaterials. PMID- 24487841 TI - 1617 nm emission control of an Er:YAG laser by a corrugated single-layer resonant grating mirror. AB - A resonant grating mirror (RGM) that combines a single layer planar waveguide and a subwavelength grating is used to simultaneously control the beam quality, the spectral bandwidth, and the polarization state of an Er:YAG laser. This simple device is compared to classical methods using several intracavity components: an etalon for wavelength selection, a thin film polarizer for polarization selection, and an aperture for spatial filtering. It is demonstrated that the RGM provides the same polarization purity, an enhanced spectral filtering, and a significant improvement of the beam quality. In CW operation, the Er:YAG laser with a RGM emits an output power of 1.4 W at 1617 nm with a M2 of 1.4. PMID- 24487842 TI - Resonantly pumped Tm-doped fiber laser with >90% slope efficiency. AB - We have demonstrated what we believe is the highest slope efficiency reported for a Tm-doped fiber laser operating in the 2-micron spectral region. Using a 1908 nm Tm-doped fiber laser as an in-band pump source, we generated 1.43 W of output power at 2005 nm with 81.25% optical efficiency and 90.2% slope efficiency, with respect to launched pump power. This resonant-pumping approach allowed us to examine the bleaching effects in Tm-doped fiber under resonant pumping. We also analytically show that this pumping method can scale to high power levels while maintaining high efficiency. PMID- 24487843 TI - Enhanced optical limiting in polystyrene-ZnO nanotop composite films. AB - In this work we investigate the optical limiting property of polystyrene-zinc oxide (ZnO) nanotop composite films, using an open aperture Z-scan technique. The nanocomposites are prepared for different loading concentrations of ZnO and are fabricated using spin and dip coating techniques. On exposing the films to a pulsed nanosecond laser at 532 nm, the nonlinear absorption (NLA) coefficient is found to be greater for spin-coated films compared to dip-coated films. The measured NLA coefficient is found to be enhanced with an increase in loading concentration of ZnO in the monomer for both spin- and dip-coated films. PMID- 24487844 TI - Dynamic control of spatial wavelength dispersion in holographic femtosecond laser processing. AB - Dynamic control of spatial wavelength dispersion is effective due to a potentially large spectral bandwidth of femtosecond pulses, in particular, when using sub-100-fs pulses. We demonstrate spatial wavelength dispersion control, which drastically reduces focal spot distortion in the reconstruction of a hologram, using a pair of spatial light modulators. The improved diffraction spots had nearly diffraction-limited spot sizes, agreeing well with theoretical predictions. The dynamic control of dispersion is also demonstrated in order to restrain unnecessary processing given by the zeroth-order pulse. PMID- 24487845 TI - Reduction and control of stimulated Brillouin scattering in polymer-coated chalcogenide optical microwires. AB - We investigate the onset of nonlinear effects in hybrid polymer-chalcogenide optical microwires and show that they provide an enhanced Kerr nonlinearity while simultaneously mitigating stimulated Brillouin scattering as compared to both chalcogenide and silica optical fibers. It is shown in particular that the polymer cladding surrounding the microwire significantly broadens the Brillouin linewidth and increases the threshold, thus enabling Kerr nonlinear applications. We also study the influence of the wire diameter on the Brillouin dynamics and demonstrate that the Brillouin frequency shift can be finely tuned over a wide radio-frequency range. PMID- 24487846 TI - Guided-mode resonant coherent light absorbers. AB - We present a new class of coherent perfect absorbers based on guided-mode resonance in thin semiconductor films. Using particle-swarm optimization methods, we design a thin-film amorphous silicon grating that maximizes coherent modulation of the absorbance. The optimized device exhibits a maximum scattering power of ~94% and a power absorption limit approaching 100% at the 1550-nm wavelength. PMID- 24487847 TI - Exciton photoluminescence in resonant quasi-periodic Thue-Morse quantum wells. AB - This Letter investigates exciton photoluminescence (PL) in resonant quasi periodic Thue-Morse quantum wells (QWs). The results show that the PL properties of quasi-periodic Thue-Morse QWs are quite different from those of resonant Fibonacci QWs. The maximum and minimum PL intensities occur under the anti-Bragg and Bragg conditions, respectively. The maxima of the PL intensity gradually decline when the filling factor increases from 0.25 to 0.5. Accordingly, the squared electric field at the QWs decreases as the Thue-Morse QW deviates from the anti-Bragg condition. PMID- 24487848 TI - Mid-infrared fiber lasers at and beyond 3.5 MUm using dual-wavelength pumping. AB - We report the first, to the best of our knowledge, erbium-doped zirconium fluoride-based glass fiber laser operating well beyond 3 MUm with significant power. This fiber laser achieved 260 mW in CW at room temperature. The use of two different wavelength pump sources allows us to take advantage of the long-lived excited states that would normally cause a bottleneck, and this enables maximum incident optical-to-optical efficiency of 16% with respect to the total incident pump power. Both output power and efficiency are an order of magnitude improvement over similar lasers demonstrated previously. The fiber laser operating at 3.604 MUm also exhibited the longest wavelength of operation obtained to date for a room temperature, nonsupercontinuum fiber laser. PMID- 24487849 TI - Reduced efficiency droop in blue InGaN light-emitting diodes by thin AlGaN barriers. AB - The phenomenon of efficiency droop in blue InGaN light-emitting diodes (LEDs) is studied numerically. Simulation results indicate that the severe Auger recombination is one critical mechanism corresponding to the degraded efficiency under high current injection. To solve this issue, LED structure with thin AlGaN barriers and without the use of an AlGaN EBL is proposed. The purpose of the strain-compensation AlGaN barriers is to mitigate the strain accumulation in a multiquantum well (MQW) active region in this thin-barrier structure. With the proposed LED structure, the hole injection and transportation of the MQW active region are largely improved. The carriers can thus distribute/disperse much more uniformly in QWs, and the Auger recombination is suppressed accordingly. The internal quantum efficiency and the efficiency droop are therefore efficiently improved. PMID- 24487850 TI - Interplay between absorption and radiative decay rates of surface plasmon polaritons for field enhancement in periodic arrays. AB - We studied the effects of absorption and radiative decay rates of surface plasmon polaritons on the field enhancement in periodic metallic arrays by temporal coupled mode theory and finite-difference time-domain simulation. When two rates are equal, the field enhancement is the strongest and the peak height of the orthogonal reflectivity reaches 0.25. To demonstrate this fact, we fabricated two series of two-dimensional Au and Ag nanohole arrays with different geometries and measured their corresponding reflectivity and decay rates. The experimental results agree well with the analytical and numerical results. PMID- 24487851 TI - Smoothed spectra for enhanced dispersion-free pulse duration reduction of passively Q-switched microchip lasers. AB - We present an enhanced technique for dispersion-free pulse shortening, which exploits the interplay of different third-order nonlinear effects in a waveguide structure. When exceeding a certain value of the pulse energy coupled into the waveguide, the typical oscillations of self-phase modulation (SPM)-broadened spectra vanish during pulse propagation. Such smoothed spectra ensure a high pulse quality of the spectrally filtered and, therefore, temporally shortened pulses independently of the filtering position. A reduction of the pulse duration from 138 to 24 ps has been achieved while preserving a high temporal quality. To the best of our knowledge, the nonlinear smoothing of SPM-broadened spectra is used in the context of dispersion-free pulse duration reduction for the first time. PMID- 24487852 TI - Vortex confinement and bending with nonlocal solitons. AB - We investigate the routing of vortex beams in nonlocal media by means of coaxial, co-propagating spatial optical solitons. By introducing a refractive index perturbation in the form of a localized defect or a dielectric interface, the soliton waveguide can be curved and, therefore, can deviate the collinear vortex, effectively routing it, while preventing its destabilization and breakup. PMID- 24487853 TI - Enhanced interferometric detection in two-dimensional spectroscopy with a Sagnac interferometer. AB - An intrinsically phase-stable Sagnac interferometer is introduced for optimized interferometric detection in partially collinear two-dimensional (2D) spectroscopy. With a pump-pulse pair from an actively stabilized Mach-Zehnder interferometer, the Sagnac scheme is demonstrated in broadband, short-wave IR (1 2 MUm), 2D electronic spectroscopy of IR-26 dye. PMID- 24487854 TI - Spoof surface plasmon waveguide forces. AB - Spoof surface plasmons (SP) are SP-like waves that propagate along metal surfaces with deeply sub-wavelength corrugations and whose dispersive properties are determined primarily by the corrugation dimensions. Two parallel corrugated surfaces separated by a sub-wavelength dielectric gap create a "spoof" analog of the plasmonic metal-insulator-metal waveguides, dubbed a "spoof-insulator-spoof" (SIS) waveguide. Here we study the optical forces generated by the propagating "bonding" and "anti-bonding" waveguide modes of the SIS geometry and the role that surface structuring plays in determining the modal properties. By changing the dimensions of the grooves, strong attractive and repulsive optical forces between the surfaces can be generated at nearly any frequency. PMID- 24487855 TI - Resolving directional ambiguity in dynamic light scattering-based transverse motion velocimetry in optical coherence tomography. AB - Dynamic light scattering-based optical coherence tomography approaches have been successfully implemented to measure total transverse (xy) flow speed, but are unable to resolve directionality. We propose a method to extract directional velocity in the transverse plane by introducing a variable scan bias to our system. Our velocity estimation, which yields the directional velocity component along the scan axis, is also independent of any point-spread function calibration. By combining our approach with Doppler velocimetry, we show three component velocimetry that is appropriately dependent on latitudinal and longitudinal angle. PMID- 24487856 TI - Toward an all-optically stabilized frequency comb based on a mode-locked fiber laser. AB - We present an erbium-doped mode-locked fiber laser comprising two all-optical control mechanisms acting on the carrier envelope offset (CEO)-frequency as well as the repetition frequency. The laser's repetition frequency is stabilized via optically pumping a distinct ytterbium-doped fiber module. By proving that additionally controlling the pump power of the erbium-doped gain fiber acts sufficiently complementary on the laser's CEO-frequency compared with repetition frequency stabilization, we demonstrate the feasibility of this concept for an all-optically controlled frequency comb in an all-fiber setup. PMID- 24487857 TI - Collimated blue and infrared beams generated by two-photon excitation in Rb vapor. AB - Utilizing two-photon excitation in hot Rb vapor we demonstrate the generation of collimated optical fields at 420 and 1324 nm. Input laser beams at 780 and 776 nm enter a heated Rb vapor cell collinear and circularly polarized, driving Rb atoms to the 5D(5/2) state. Under phase-matching conditions coherence among the 5S(1/2) >5P(3/2)->5D(5/2)->6P(3/2) transitions produces a blue (420 nm) beam by four-wave mixing. We also observe a forward and backward propagating IR (1324 nm) beam, due to cascading decays through the 6S(1/2)->5(1/2) states. Power saturation of the generated beams is investigated by scaling the input powers to greater than 200 mW, resulting in a coherent blue beam of 9.1 mW power, almost an order of magnitude larger than previously achieved. We measure the dependences of both beams in relation to the Rb density, the frequency detuning between Rb ground state hyperfine levels, and the input laser intensities. PMID- 24487858 TI - Extreme ultraviolet tomography using a compact laser-plasma source for 3D reconstruction of low density objects. AB - A tomographic method for three-dimensional reconstruction of low density objects is presented and discussed. The experiment was performed in the extreme ultraviolet (EUV) spectral region using a desktop system for enhanced optical contrast and employing a compact laser-plasma EUV source, based on a double stream gas puff target. The system allows for volume reconstruction of transient gaseous objects, in this case gas jets, providing additional information for further characterization and optimization. Experimental details and reconstruction results are shown. PMID- 24487859 TI - Atomic cooling via AC Stark shift. AB - We theoretically investigate atomic cooling using a spatially varying AC Stark shift to compensate for the changing Doppler shift of an unchirped cooling beam. An integrated approach using waveguide-based atom photonics is ideal to achieve the required spatial tailoring of the AC Stark beam intensity. We present two examples of the design procedure to cool sodium atoms in hollow-core antiresonant reflecting optical waveguides over tens of centimeters resulting in final velocities comparable to a Zeeman slower. The methods presented here are applicable to other experimental arrangements and atomic species. PMID- 24487860 TI - Point-by-point inscription of phase-shifted fiber Bragg gratings with electro optic amplitude modulated femtosecond laser pulses. AB - Femtosecond laser pulses were used for the direct point-by-point inscription of phase-shifted fiber Bragg gratings (FBGs) in a single fabrication step without postprocessing. An electro-optic amplitude modulator is used in the setup to generate a defined delay between two identical laser pulse trains for the grating inscription. The grating structure with a central phase shift is formed by focusing the modulated laser pulses into the core of a fiber, while the fiber is translated with a constant velocity. The induced phase shift leads to a narrow transmission band with a bandwidth considerably below 10 pm within the stop band of the FBG. The inscribed FBGs show a birefringence of 3.9*10(-5) whereas their temperature and strain sensitivities are 10.4 pm/K and 1.4 pm/MUstrain, respectively. The fabrication process is fast and offers a high grade of flexibility for the control of all grating parameters. PMID- 24487861 TI - Acoustic frequency combs for carrier-envelope phase stabilization. AB - A method for improved performance of feed-forward carrier-envelope phase stabilization in amplified laser sources is presented and experimentally demonstrated. The phase stabilization scheme is applicable for a broad range of repetition rates spanning from subhertz to 100 kHz. The method relies on driving an acousto-optic frequency shifter by few-cycle transients. The phase of these transients suitably controls the grating phase of the generated index grating inside the shifter material. This approach removes beam pointing as well as amplitude noise issues observed in continuously driven feed-forward schemes. The synthesis of these gratings can be understood as the acoustic equivalent of mode locking or acoustic frequency combs. PMID- 24487862 TI - Energy-efficient low-Fresnel-number Bessel beams and their application in optical coherence tomography. AB - Bessel beams feature a very large depth-of-focus (DOF) compared to conventional focusing schemes, but their central lobe carries only a small fraction of the total beam power, leading to a strongly reduced peak irradiance. This is problematic for power-limited applications, such as optical coherence tomography (OCT) or optical coherence microscopy, as it can result in a prohibitive reduction of the signal-to-noise ratio (SNR). Using scalar diffraction theory, we show that the trade-off between DOF and peak irradiance of Bessel beams depends solely on the Fresnel number N. We demonstrate the existence of a low-Fresnel number regime, N<10, in which axicons with Gaussian illumination can generate energy-efficient Bessel beams with a small number of sidelobes. In the context of OCT, this translates into DOF enhancements of up to 13* for a SNR penalty below 20 dB, which is confirmed by our experiments. We expect that these findings will enable improved performance of optical systems with extended DOF. PMID- 24487863 TI - Timing optimization utilizing order statistics and multichannel digital silicon photomultipliers. AB - We present an optimization technique utilizing order statistics with a multichannel digital silicon photomultiplier (MD-SiPM) for timing measurements. Accurate timing measurements are required by 3D rangefinding and time-of-flight positron emission tomography, to name a few applications. We have demonstrated the ability of the MD-SiPM to detect multiple photons, and we verified the advantage of detecting multiple photons assuming incoming photons follow a Gaussian distribution. We have also shown the advantage of utilizing multiple timestamps for estimating time-of-arrivals more accurately. This estimation technique can be widely available in various applications, which have a certain probability density function of incoming photons, such as a scintillator or a laser source. PMID- 24487864 TI - Confocal supercritical angle microscopy for cell membrane imaging. AB - We demonstrate subwavelength sectioning on biological samples with a conventional confocal microscope. This optical sectioning is achieved by the phenomenon of supercritical angle fluorescence, wherein only a fluorophore next to the interface of a refractive index discontinuity can emit propagating components of radiation into the so-called forbidden angles. The simplicity of this technique allows it to be integrated with a high numerical aperture confocal scanning microscope by only a simple modification on the detection channel. Confocal supercritical angular fluorescence microscopy would be a powerful tool to achieve high-resolution surface imaging, especially for membrane imaging in biological samples. PMID- 24487865 TI - Determination of refractive index, size, and concentration of nonabsorbing colloidal nanoparticles from measurements of the complex effective refractive index. AB - We describe a method for obtaining the refractive index (RI), size, and concentration of nonabsorbing nanoparticles in suspension from relatively simple optical measurements. The method requires measuring the complex effective RI of two dilute suspensions of the particles in liquids of different refractive indices. We describe the theoretical basis of the proposed method and provide experimental results validating the procedure. PMID- 24487866 TI - Phosphor-converted LEDs with low circadian action for outdoor lighting. AB - Dichromatic phosphor-converted (pc) light-emitting diodes (LEDs) with low circadian action are proposed for low-luminance photobiologically safe outdoor illumination. The LEDs feature the partial conversion of blue radiation in an orange phosphor with the resulting correlated color temperature in the "firelight" range of 1700-2500 K. The circadian action factor, which is the ratio of the biological efficacy of radiation due to the excitation of intrinsically photosensitive retinal ganglion cells to the mesopic luminous efficacy of radiation, is considerably lower than that of commercial white pc LEDs. The equivalent general color-rendering index estimated with regard to the reduced color-discrimination ability of human vision at low luminances has appropriate values in between those of common white pc LEDs and high-pressure sodium lamp. PMID- 24487867 TI - Composition-dependent electron transport in CdS(x)Se(1-x) nanobelts: a THz spectroscopy study. AB - We present a study on the composition-dependent electron transport in ternary CdS(x)Se(1-x) nanobelts at equilibrium and nonequilibrium conditions via THz spectroscopy. The measured spectra are analyzed using a Drude-Smith model combined with a harmonic oscillator. The physical origin of parameters in the Drude-Smith model is studied in detail. Under equilibrium conditions, the surface depletion region is the dominant factor to free-carrier backscattering. However, under nonequilibrium conditions, the influence of the surface depletion region is masked by the high bulk concentration and the free carriers are mainly localized by composition disorder. The contributions from different mechanisms to the carrier mobility are also explored. In equilibrium, alloy scattering is the most vital scattering mechanism for nanobelts with x=0.25->0.9 since composition disorder is significant in this range. On the other hand, the effect of electron phonon interaction increases under photoexcitation. PMID- 24487868 TI - Direct determination of the resonance properties of metallic conical nanoantennas. AB - We present a simple method that is able to predict the resonant frequencies of a metallic conical nanoantenna. The calculation is based on an integral relation that takes into account the dependence of the effective refractive index of the plasmonic mode on the cone radius. Numerical simulations retrieving the near field properties of nanocones with different lengths are also performed for comparison. The fine agreement between the two approaches demonstrates the validity of our method. PMID- 24487869 TI - Reflection and transmission of electromagnetic waves at a temporal boundary. AB - We consider propagation of an electromagnetic (EM) wave through a dynamic optical medium whose refractive index varies with time. Specifically, we focus on the reflection and transmission of EM waves from a temporal boundary and clarify the two different physical processes that contribute to them. One process is related to impedance mismatch, while the other results from temporal scaling related to a sudden change in the speed of light at the temporal boundary. Our results show that temporal scaling of the electric field must be considered for light propagation in dynamic media. Numerical solutions of Maxwell's equations are in full agreement with our theory. PMID- 24487870 TI - Anomalous effective strain-optic constants of nonparaxial optical fiber modes. AB - We demonstrate that the experimental strain-optic coefficients for strong guided modes are not consistent with the accepted photoelastic theory. It is shown that for modes with significant nonparaxial components, such as modes guided by strong refractive index differences or in waveguides with dimensions that are much larger than the wavelengths used, the photoelastic theory should be modified to include the effect of the longitudinal components of the electromagnetic fields of the modes. Moreover, we highlight that the strain-optics coefficients depend on the state of polarization of the mode and provide a formula to calculate the necessary corrections. PMID- 24487871 TI - Nanoscale high-intensity light focusing with pure dielectric nonspherical scatterer. AB - Light scattering from nonspherically symmetric pure dielectric structures is examined. From the finite element full-wave analysis, it is found that teardrop shaped scatterers can focus visible light to a ~10 nm spot with an intensity enhancement ~10(5) when the incident light is radially polarized. PMID- 24487872 TI - 0.35 MUm CMOS avalanche photodiode with high responsivity and responsivity bandwidth product. AB - A highly sensitive avalanche photodiode (APD) in 0.35 MUm CMOS technology is presented. Due to a thick intrinsic absorption layer, a high responsivity at a low bias voltage, where the avalanche gain is 1, is combined with an excellent avalanche gain at high voltages to achieve a maximum overall responsivity of the APD of more than 10 kA/W. This responsivity exceeds that of other submicrometer CMOS APDs by a factor of more than 700. As a figure of merit the responsivity bandwidth product is defined, and the achieved value of 23.46 A/W.GHz is 2.4 times higher than the values found in the literature. PMID- 24487873 TI - Spectral long-range interaction of temporal incoherent solitons. AB - We study the interaction of temporal incoherent solitons sustained by a highly noninstantaneous (Raman-like) nonlinear response. The incoherent solitons exhibit a nonmutual interaction, which can be either attractive or repulsive depending on their relative initial distance. The analysis reveals that incoherent solitons exhibit a long-range interaction in frequency space, which is in contrast with the expected spectral short-range interaction described by the usual approach based on the Raman-like spectral gain curve. Both phenomena of anomalous interaction and spectral long-range behavior of incoherent solitons are described in detail by a long-range Vlasov equation. PMID- 24487874 TI - Differential laser absorption spectroscopy of uranium in an atmospheric pressure laser-induced plasma. AB - A two-beam differential laser absorption technique is used to measure 238U absorption spectra with high signal-to-noise ratios in an atmospheric pressure laser-induced plasma. High-resolution absorption spectra are presented for the 238U 861 nm transition in the presence of dry air at pressures up to 760 Torr. A spectral linewidth (FWHM) of 2.23+/-0.13 GHz was found for the 238U line in dry air at 760 Torr. Absorption spectrum measurements using a low 238U concentration NIST glass standard were used to demonstrate sensitivity of the approach. PMID- 24487875 TI - Phase recovery by using optical fiber dispersion. AB - We propose a simple and fast procedure to retrieve the phase profile of arbitrary light pulses. It combines a first experimental stage, followed by a one-step numerical stage. To this end, it is necessary to perform a Fresnel transform, which is obtained just by propagating the light pulses through an optical fiber. We experimentally test this proposal recovering the phase profile in the light pulses provided by a passively mode-locked laser. The proposal is then compared with a temporal variation of the Gerchberg-Saxton recursive algorithm, which is specially modified for this purpose. PMID- 24487876 TI - Edge states in disordered photonic graphene. AB - The impact of uncorrelated composite and structural disorder on the edge states of photonic graphene (a honeycomb waveguide lattice) is investigated numerically and experimentally. We find that in the case of structural (off-diagonal) disorder, the chiral symmetry preserves the confinement of the zero-energy edge state in contrast to composite disorder. PMID- 24487877 TI - Rapid fabrication of a large-area close-packed quasi-periodic microlens array on BK7 glass. AB - Large-area close-packed microlens arrays (MLAs) are highly desirable for structured light and integrated optical applications. However, efficient realization of ultralarge area MLAs with a high fill factor is still technically challenging, especially on glass material. In this Letter we propose a high efficiency MLA fabrication method using single-pulsed femtosecond laser wet etch and close-packed quasi-periodic concave MLAs consisting of three million units fabricated on silica glass within an hour. The fabricated MLAs are demonstrated to have extreme optical smoothness (~8.5 nm) by an atomic force microscope. It has also been demonstrated that the profile of the quasi-periodic concave structures could be easily tuned by changing the laser scanning speed or the pulse energy. Additionally, the optical performances of the MLA diffusers were investigated by using sharp focusing, high-resolution imaging, and flat-top illumination. PMID- 24487878 TI - Analysis of contrast and motion signals generated by human blood constituents in capillary flow. AB - The flow of individual corpuscles through retinal capillaries may now be observed noninvasively by using adaptive optics (AO). To explore their imaging properties, we imaged retinal capillary flow in two healthy subjects at 593 nm with a flood based AO ophthalmoscope, at a variety of retinal locations and levels of defocus. The image intensity of red cells and plasma depends upon capillary depth relative to focus: red cells appear brighter than background, and plasma darker, for capillaries posterior to focus. The reverse is true for capillaries anterior to focus. Contrast reversals were obtained over 0.05 D (~14 MUm), which are well within the typical undulations in depth of retinal capillaries. We relate these observations to phase-contrast defocusing microscopy. This defocusing effect confounds flow measurements, which rely on correlation of image intensity between successive locations along the same capillary, a requirement made further difficult by high physiological variability in flow. Peak correlation was maintained >0.25 over a distance of 22+/-15 MUm (roughly the spacing between red cells) and over a duration of 154+/-49 ms (roughly eight times the temporal period between red cells). We provide a 2D correlogram approach that significantly improves robustness in the face of optical and physiological variability, compared to the traditional spatiotemporal plot, without requiring additional data. PMID- 24487879 TI - High-power thulium fiber laser Q switched with single-layer graphene. AB - We report high-power 2 MUm Tm3+ fiber lasers passively Q switched by double-piece single-layer graphene transferred onto a glass plate. Through manipulating intracavity laser beam size and increasing pump ratios, an average power of 5.2 W is directly achieved from the laser oscillator with an optical-to-optical slope efficiency of 26%. The laser pulse energy can be as high as ~18 MUJ, comparable to that from actively Q-switched fiber lasers. The narrowest pulse width is 320 ns, and the pulse repetition rate can be tuned from tens of kilohertz to 280 kHz by changing the pump power. To the best of our knowledge, this is the highest average power and pulse energy, as well as the narrowest pulse width, from graphene-based Q-switched 2 MUm fiber lasers. PMID- 24487880 TI - Third-harmonic generation in cuprous oxide: efficiency determination. AB - The efficiency of third-harmonic generation in cuprous oxide was measured. Intensities followed a noncubic power law that indicates nonperturbative behavior. Polarization anisotropy of the harmonic generation was demonstrated and related to the third-order susceptibility. The results will influence the understanding of harmonic generation in centrosymmetric materials and are potentially relevant to device design and the interpretation of exciton behavior. PMID- 24487881 TI - Megahertz all-optical swept-source optical coherence tomography based on broadband amplified optical time-stretch. AB - We demonstrate all-optical ultrahigh-speed swept-source optical coherence tomography (OCT) based on amplified optical time-stretch (AOT). Such an inertia free wavelength-swept mechanism, via group velocity dispersion, enables us to realize OCT with an A-scan rate well above MHz. More importantly, the key significance of AOT-OCT is its simultaneous broadband Raman amplification during the time-stretch process-greatly enhancing the detection sensitivity compared with prior attempts to apply optical time-stretch to OCT. Here, we report on an AOT-OCT system which is operated at an A-scan rate of 7.14 MHz, a superior roll off performance (>2 mm/dB), a record-high sensitivity of time-stretch-based OCT (>80 dB) with a broadband gain bandwidth of 80 nm, which results in an axial resolution of ~15 MUm. Our AOT-OCT system is thus able to, for the first time to the best of our knowledge, perform time-stretch-based OCT of biological tissue in vivo. It represents a major step forward in utilizing AOT as an alternative for achieving practical MHz OCT, without any long-term mechanical stability concerns as in typical swept-source OCT or bypassing the speed limitation of the image sensor employed in spectral-domain OCT. PMID- 24487882 TI - Three-dimensional measurements of a millimeter wave orbital angular momentum vortex. AB - Initial three-dimensional phase and intensity measurements of a 100 GHz l=+/-1 orbital angular momentum (OAM) vortex are presented. The vortex was generated by illuminating a polypropylene spiral phase plate. Measurements were taken with a three-dimensional field scanner operating in the W-band (75-100 GHz). Early analysis shows splitting of the OAM phase dislocation at the vortex center, resulting in a complex inner vortex intensity pattern. PMID- 24487883 TI - Creation of vectorial bottle-hollow beam using radially or azimuthally polarized light. AB - We propose a single-beam generation scheme to obtain a bottle-hollow (BH) beam using a binary phase mask and a focusing lens. The resulting BH beam is shown to possess an open bottle-shaped null intensity region, which has two hollow tube shaped null intensity regions located on two opposite sides of this bottle. It is found that this scheme works identically under incident illumination with radial or azimuthal polarization. Another advantage of this scheme is that the same binary mask can be employed as a focusing lens with different choices of numerical aperture (NA). Furthermore, we observe that the length of the BH beam is inversely proportional to NA2 while the diameters of both the bottle and hollow regions are inversely proportional to NA; thereby leading to an adjustable BH beam. This BH beam may find attractive applications in noninvasive manipulation of microscopic particles over large distances. PMID- 24487884 TI - Influence of the characteristics of a light source and target on the Monge-Ampere equation method in freeform optics design. AB - It was previously demonstrated in [Opt. Lett.38, 229 (2013)] that the problem of freeform surface illumination design can be converted into a nonlinear boundary problem for the elliptic Monge-Ampere equation based on the ideal source assumption. But how the Monge-Ampere equation method is affected by the characteristics of the light source and target was not discussed there. This Letter systematically analyzes the influence of discontinuity, nonconvexity, and connectivity of light source and target on the Monge-Ampere equation method and presents some intrinsic features of this design method. These features are applied in practical examples in freeform optics design. PMID- 24487885 TI - One-dimensional rainbow thermometry system by using slit apertures. AB - A new rainbow thermometry system by using slit apertures and a laser light sheet, called a one-dimensional rainbow thermometry (ORT) system, has been developed as an extension of global rainbow thermometry (GRT). This system is capable of one dimensional or line measurements of the size and refractive index of droplets in the spray space, while the conventional GRT system is normally considered a typical "single-point" or "small volume" measurement method. The performance of this new system was tested and verified with both water and ethanol spray. The results show the feasibility and potential of ORT in simultaneous and one dimensional measurement of the size and refractive index of liquid droplets, especially in the research field of spray evaporation and combustion. PMID- 24487886 TI - Tunable WDM sampling pulse streams using a spatial phase modulator in a biased pulse shaper. AB - We generate transform-limited WDM optical sampling pulse bursts by filtering ultrashort pulses from a mode-locked laser. A phase spatial light modulator (SLM) is used in a biased pulse shaper to circumvent the need to modulate with 2pi phase wraps, which are known to limit the phase response. The arrangement compresses and retimes user-selectable bandwidths from the optical short pulse source with precise control of pulse bandwidth, pulse stream rates, and duty cycle. PMID- 24487887 TI - Single-image-based solution for optics temperature-dependent nonuniformity correction in an uncooled long-wave infrared camera. AB - In this Letter, we propose an efficient and accurate solution to remove temperature-dependent nonuniformity effects introduced by the imaging optics. This single-image-based approach computes optics-related fixed pattern noise (FPN) by fitting the derivatives of correction model to the gradient components, locally computed on an infrared image. A modified bilateral filtering algorithm is applied to local pixel output variations, so that the refined gradients are most likely caused by the nonuniformity associated with optics. The estimated bias field is subtracted from the raw infrared imagery to compensate the intensity variations caused by optics. The proposed method is fundamentally different from the existing nonuniformity correction (NUC) techniques developed for focal plane arrays (FPAs) and provides an essential image processing functionality to achieve completely shutterless NUC for uncooled long-wave infrared (LWIR) imaging systems. PMID- 24487888 TI - Particle trapping and structuring on the surface of LiNbO3:Fe optical waveguides using photovoltaic fields. AB - We report on the successful trapping and patterning of micro- and nanometric particles on the surface of LiNbO3 optical waveguides via photovoltaic tweezers. A waveguide configuration is used for the first time combined with this recently proposed technique. The electric field pattern is generated by light propagating in the waveguide, allowing us to separate the light channel with the region in which particles are deposited. Results on micro- and nanoparticle trapping, by two different deposition methods on two types of planar waveguides (by soft proton exchanged and by swift heavy ion irradiation), and using single-beam and two-beam interferometric configuration, are presented and discussed. PMID- 24487890 TI - Light field moment imaging: comment. AB - We comment on the recent Letter [Opt. Lett.38, 2666 (2013)10.1364/OL.38.002666], in which the authors presented an imaging technique called light field moment imaging. We wish to show that this method can be associated with transport of intensity equation at the geometric optics limit. PMID- 24487891 TI - Angular distribution of random laser emission. AB - We present an experimental analysis of the angular distribution of the emission of a random laser (RL) operating in the diffusive regime (~1% volume fraction of scatterers). The RL ensemble was made of silica particles suspended in a 1:1 methanol:water matrix with Rhodamine 6G dye as the active medium. We found that, for specific pumping-energy-dependent scattering strength, the RL spectrum reached stable features that were angularly preserved. From the analysis, we propose that this defines a novel parametric condition that may well be the equivalent of the RL critical volume, as proposed by Letokhov. PMID- 24487892 TI - Use of ferroelectric liquid crystal panels to control state and degree of polarization in light beams. AB - We propose a new technique that is able to generate a light beam with a controlled state of polarization (SoP) and a customized degree of polarization (DoP). The technique relies on the fact that effective depolarization can be achieved by temporally averaging a time-dependent SoP. Our proposed setup is based on a ferroelectric liquid crystal panel of retardance lambda/2, with a fast polarization switching capability (33 Hz). A mathematical basis describing the experiment is given. In addition, simulation data is discussed, showing the possibility of generating any SoP with full control of the DoP. Finally, to prove the potential of the invention proposed, experimental results are provided as well, reaching an experimental minimum DoP of 0.14. PMID- 24487893 TI - Optimization of spatial filter with volume Bragg gratings in photo-thermo refractive glass. AB - We present a method for optimizing spatial filter performance by inserting volume Bragg gratings (VBGs) in front of the traditional spatial filters. The experimental results show that the cutoff frequency is modified with the insertion of VBGs. We also demonstrate the optimization of filtering performance in both the spatial and frequency domains, with detailed comparison of near-field modulation, contrast ratio, and power spectral density of output laser beams. PMID- 24487894 TI - Modal instability-suppressing, single-frequency photonic crystal fiber amplifier with 811 W output power. AB - An acoustic- and gain-tailored Yb-doped polarization-maintaining photonic crystal fiber is used to demonstrate 811 W single-frequency output power with near diffraction-limited beam quality. The fiber core is composed of 7 individually doped segments arranged to create three distinct transverse acoustic regions; including one region that is Yb-free. The utility of the Yb-free region is to reduce coupling between the LP01 and LP11 modes to mitigate the modal instability. The application of thermal gradients is utilized in conjunction with the transverse acoustic tailoring to suppress stimulated Brillouin scattering. To the best of our knowledge, the 811 W output represents the highest power ever reported from a near diffraction-limited single-frequency fiber laser. PMID- 24487895 TI - 3-lambda characterization of phase response for optical receivers. AB - We propose a novel digital signal processing (DSP) algorithm for photodiode characterization probed by three wavelengths. The DSP algorithm has low computational complexity. The required number of measurements increases logarithmically with the number of spectral points. For the first time to our knowledge, the phase response of photodiode is characterized up to 20 GHz. PMID- 24487896 TI - Influence of longitudinal mode beating on laser-induced damage in fused silica. AB - In our study, the laser-induced damage densities on a fused silica surface produced by multiple longitudinal mode (MLM) pulses are found to be higher than those produced by single longitudinal mode pulses at 1064 nm. This behavior is explained by the enhancement of the three-photon absorption due to the intensity spikes related to longitudinal mode beating. At 355 nm, the absorption is linear and an opposite behavior occurs. It can be explained with the help of a process involving thermomechanics coupled with the fine time structure of MLM pulses, leading to the possible annealing of part of the absorbent defects. PMID- 24487898 TI - Origin of the Abraham spin angular momentum of surface modes. AB - By considering the transverse spin angular momentum (SAM) that results from the rotation of the electric-field component of a surface mode as a longitudinal SAM of an elliptically polarized light propagating through a homogeneous medium, an alternate route to deriving the formula of the Abraham SAM carried by the surface mode can be achieved. The findings prove in an explicit manner that it is the Abraham SAM that is directly related to the rotation of the electric field. PMID- 24487897 TI - Simple correction factor for laser speckle imaging of flow dynamics. AB - One of the major constraints facing laser speckle imaging for blood-flow measurement is reliable measurement of the correlation time (tau(C)) of the back scattered light and, hence, the blood's speed in blood vessels. In this Letter, we present a new model expression for integrated speckle contrast, which accounts not only for temporal integration but spatial integration, too, due to the finite size of the pixel of the CCD camera; as a result, we find that a correction factor should be introduced to the measured speckle contrast to properly determine tau(C); otherwise, the measured blood's speed is overestimated. Experimental results support our theoretical model. PMID- 24487899 TI - View synthesis with a partitioned-aperture microscope. AB - We present a simple and fast algorithm for view synthesis based on the acquisition of four high-resolution oblique images with a conventional widefield microscope. The images are acquired simultaneously using a partitioned aperture add-on. The technique provides physically valid views of thin samples that are transmitting or fluorescent, as demonstrated with biopsied tissue or green fluorescent protein-labeled brain slices. The goal of this technique is to facilitate image interpretation by conferring impressions of depth that are otherwise absent in standard microscope images. PMID- 24487900 TI - Fast-tuning, low-noise, compact Brillouin/erbium fiber laser. AB - We demonstrate a fast-tuning Brillouin/erbium fiber laser (BEFL) using 4 m erbium doped fiber (EDF) as both the Brillouin and erbium gain media. The BEFL frequency is fast tuned via modulating a piezoelectric transducer on which the EDF is coiled. Over 60 MHz frequency-tuning range is obtained at less than 5 V voltage amplitude and the tuning rates can achieve 48 kHz. This fast-tuning BEFL presents a low phase noise of -124 dB/Hz(1/2) at 1 kHz (normalized to 1 m interferometer optical path difference) with 32 kHz modulating frequency. It presents potential applications in fiber sensors and optical communications. PMID- 24487901 TI - Nonlinear lightwave circuits in chalcogenide glasses fabricated by ultrafast laser. AB - This Letter reports a nonlinear directional waveguide coupler written by ultrafast laser in gallium lanthanum sulfide chalcogenide glass. The nonlinear waveguide device is tested with laser pulses input in two orthogonal polarizations, and all optical switching at 1040 nm between the two coupled waveguides is observed at a peak fluence of 16 GW/cm2. The spectra and autocorrelation measurement from the waveguide outputs show dominant nonlinear effects and negligible dispersion for light propagation in both channels. PMID- 24487902 TI - Dihedron dielectric loaded surface plasmon athermal polarization converter. AB - We investigate numerically a novel plasmonic polarization converter relying on the excitation of a so-called dihedron dielectric loaded plasmon polariton. The dihedron dielectric loaded waveguide consists of a dielectric ridge implemented at the inner corner of a metal-coated dielectric step. For a dielectric ridge with a square cross section, the plasmon polariton modes supported by each side of the metallized step hybridize to create supermodes with crossed polarizations. We show that the two supermodes can be operated in a dual-mode interferometer configuration to perform an efficient (24 dB) TE-TM/TM-TE polarization conversion over typical distances below 30 MUm at telecommunications wavelengths. In addition, on the basis of the thermo-optical properties of our device, we find that the dihedron plasmonic polarization converter is temperature insensitive. PMID- 24487903 TI - Tunable nanophotonic delay lines using linearly chirped contradirectional couplers with uniform Bragg gratings. AB - We demonstrate an integrated tunable optical delay line in grating-assisted contradirectional couplers using a CMOS-compatible photonic technology. The input signal is delayed through dispersive Bragg gratings and distributedly coupled to the drop port of the coupler without backreflections. This add-drop design enables monolithic integration of grating-based delay lines without using optical circulators. The gratings are formed by slab perturbations in rib waveguides, with the index chirping realized by linearly tapering the rib widths. Both the pitch and size of the gratings are constant through the entire coupler, for a higher tolerance to fabrication errors. Continuous tuning of the optical group delay of up to 96 ps has been obtained, with a low insertion loss of less than 2 dB and a negative chromatic dispersion of -11 ps/nm that allows for bit rates of up to almost 100 Gb/s at the maximal delay. The device has a small footprint of 0.015 mm2, and can be used for on-chip optical buffering, dispersion compensation, and pulse compression. PMID- 24487904 TI - Doughnut laser beam as an incoherent superposition of two petal beams. AB - Laguerre-Gaussian beams with a nonzero azimuthal index are known to carry orbital angular momentum (OAM), and are routinely created external to laser cavities. The few reports of obtaining such beams from laser cavities suffer from inconclusive evidence of the real electromagnetic field. In this Letter we revisit this question and show that an observed doughnut beam from a laser cavity may not be a pure Laguerre-Gaussian azimuthal mode but can be an incoherent sum of petal modes, which do not carry OAM. We point out the requirements for future analysis of such fields from laser resonators. PMID- 24487905 TI - Dammann-grating-based passive phase locking by an all-optical feedback loop. AB - A Dammann grating is used as a spatial filter for a passive coherent beam combination (CBC) of three Yb-doped fiber amplifiers with an all-optical feedback loop. Using this diffractive-optics-based spatial filtering technique, we demonstrate CBC with 20 W output power, and the visibility of the far-field interference pattern is up to 88.7%. Measurements suggest that this approach is robust with respect to laboratory environment perturbations, and it can scale to high powers and large arrays. PMID- 24487906 TI - Measurement and tuning of the chromatic dispersion of a silicon photonic wire around the half band gap spectral region. AB - We demonstrate the measurement and tuning of second-to-fourth order dispersion of a silicon wire waveguide in a spectral region of low nonlinear losses. Using white light interferometry we extract the chromatic dispersion of our waveguide from 1950 to 2300 nm. Moreover we demonstrate tuning of the zero dispersion wavelength over more than 100 nm, pushing it to longer wavelength by partially underetching the waveguide. PMID- 24487907 TI - Investigation of 90 degrees submicrometer radius bends of metal-insulator silicon-insulator-metal waveguides. AB - We theoretically and experimentally investigate 90 degrees submicrometer radius bends (SRB) of metal-insulator-silicon-insulator-metal (MISIM) waveguides that are plasmonic waveguides fabricated with standard CMOS technology. We focus on the bends of MISIM waveguides with a wide (e.g., 160-220 nm) silicon line. This study shows that the bend efficiently turns the direction of the MISIM waveguide by 90 degrees if its radius is about 0.7 MUm. Moreover, we discuss the fact that the bend may be superior to a SRB of a silicon photonic waveguide when it is used to implement a ring resonator with a high quality factor and small volume. PMID- 24487908 TI - Long-distance channeling of cold atoms exiting a 2D magneto-optical trap by a Laguerre-Gaussian laser beam. AB - Using a blue-detuned laser, shaped into a nearly Laguerre-Gaussian (LG) donut mode, we channel atoms exiting a two-dimensional magneto-optical trap (2D-MOT) over a 30 cm distance. Compared to a freely propagating beam, the atomic flux (~10(10) at/s) is conserved whereas the divergence is reduced from 40 to 3 mrad. So, 30 cm far the 2D-MOT exit, the atomic beam has a 1 mm diameter and the atomic density is increased by a factor of ~200. The LG-channeled-2D-MOT has been studied versus the order of the LG mode (from 2 to 10) and versus the laser-atom frequency detuning (from 2 to 120 GHz). PMID- 24487909 TI - Simultaneous operations at 1125 nm, 1161 nm, and 1567 nm from a single KTiOPO4 crystal pumped by a passively Q-switched Nd:GGG laser. AB - A multiwavelength operation generated from an intracavity optical parametric oscillator (OPO) pumped by a passively Q-switched Nd:GGG laser with a Cr(4+):YAG saturable absorber is demonstrated. KTiOPO4 simultaneously worked as nonlinear OPO and Raman crystal. Maximum output powers of 302 mW at 1566.8 nm and 115 mW at 1124.9/1160.7 nm were obtained at a diode power of 10.5 W, corresponding to the optical-to-optical conversion efficiencies of 2.88% and 1.1%, respectively. The measured shortest pulse duration at 1566.8 nm was 1.61 ns, while the obtained minimum pulse duration at 1124.9/1160.7 nm was 2.88 ns. PMID- 24487910 TI - Chemical routes to modify, uplift, and detach a silicene layer from a metal substrate. AB - Experimental studies have shown that honeycomb silicene layers can grow on various metal substrates. Here we demonstrate using first-principles calculations that hydrogenation and calcium intercalation can be employed to break bonds between a silicene overlayer and a silver surface. The end result of the former process is the creation of a silicane mono-layer, a wide band-gap semiconductor. In this way, the Si overlayer can eventually be etched away, in agreement with pertinent experiments. Ca intercalation, on the other hand, lifts the silicene sheet up without destroying its sp(2) honeycomb bonding. Both approaches augment thus the functionalities of silicene overlayers by creating two-dimensional materials with distinct properties. PMID- 24487911 TI - (1-3)-beta-D-glucan in association with lactate dehydrogenase as biomarkers of Pneumocystis pneumonia (PcP) in HIV-infected patients. AB - Pneumocystis pneumonia (PcP) is a major HIV-related illness caused by Pneumocystis jirovecii. Definitive diagnosis of PcP requires microscopic detection of P. jirovecii in pulmonary specimens. The objective of this study was to evaluate the usefulness of two serum markers in the diagnosis of PcP. Serum levels of (1-3)-beta-d-glucan (BG) and lactate dehydrogenase (LDH) were investigated in 100 HIV-positive adult patients and 50 healthy blood donors. PcP cases were confirmed using indirect immunofluorescence with monoclonal anti Pneumocystis antibodies and nested-PCR to amplify the large subunit mitochondrial rRNA gene of P. jirovecii in pulmonary specimens. BG and LDH levels in serum were measured using quantitative microplate-based assays. BG and LDH positive sera were statistically associated with PcP cases (P <= 0.001). Sensitivity, specificity, positive/negative predictive values (PPV/NPV), and positive/negative likelihood ratios (PLR/NLR) were 91.3 %, 61.3 %, 85.1 %, 79.2 %, 2.359, and 0.142, respectively, for the BG kit assay, and 91.3 %, 35.5 %, 75.9 %, 64.7 %, 1.415 and 0.245, respectively, for the LDH test. Serologic markers levels combined with the clinical diagnostic criteria for PcP were evaluated for their usefulness in diagnosis of PcP. The most promising cutoff levels for diagnosis of PcP were determined to be 400 pg/ml of BG and 350 U/l of LDH, which combined with clinical data presented 92.8 % sensitivity, 83.9 % specificity, 92.8 % PPV, 83.9 % NPV, 5.764 PLR and 0.086 NLR (P < 0.001). This study confirmed that BG is a reliable indicator for detecting P. jirovecii infection. The combination between BG/LDH levels and clinical data is a promising alternative approach for PcP diagnosis. PMID- 24487912 TI - Male Enchenopa treehoppers (Hemiptera: Membracidae) vary mate-searching behavior but not signaling behavior in response to spider silk. AB - Finding and attracting mates can impose costs on males in terms of increased encounters with, and attraction of, predators. To decrease the likelihood of predation, males may modify mate-acquisition efforts in two main ways: they may reduce mate-searching efforts or they may reduce mate-attraction efforts. The specific behavior that males change in the presence of predator cues should depend upon the nature of risk imposed by the type of predator present in the environment. For example, sit-and-wait predators impose greater costs to males moving in search of mates. Here, we test whether cues of the presence of a sit and-wait predator lead to a reduction in mate-searching but not mate-acquisition behavior. We used a member of the Enchenopa binotata complex of treehoppers-a clade of vibrationally communicating insects in which males fly in search of mates and produce mate-attraction signals when they land on plant stems. We tested for changes in mate-searching and signaling behaviors when silk from a web building spider was present or absent. We found that males delayed flight when spider silk was present but only if they were actively searching for mates. These results suggest that males have been selected to reduce predation risk by adjusting how they move about their environment according to the cues of sit-and wait predators. PMID- 24487914 TI - The transient receptor potential vanilloid-1 is localized at excitatory synapses in the mouse dentate gyrus. AB - The transient receptor potential vanilloid type 1 (TRPV1) is a non-selective cation channel that plays an important role in pain perception and modulates neurotransmitter release and synaptic plasticity in the brain. TRPV1 function must lay on its anatomical distribution in the peripheral and central nervous system regions involved in the physiological roles of the channel. However, the anatomical localization of TRPV1 is well established in the periphery, but in the brain it is a matter of debate. While some studies support the presence of TRPV1 in several brain regions, recent evidences suggest a restricted distribution of the channel in the central nervous system. To investigate to what extent central TRPV1 function stands on a precise brain distribution of the channel, we examined the mouse hippocampal dentate molecular layer (ML) where TRPV1 mediates long-term synaptic plasticity. Using pre-embedding immunocytochemistry for high resolution electron microscopy, we show that TRPV1 immunoparticles are highly concentrated in postsynaptic dendritic spines to asymmetric perforant path synapses in the outer 2/3 of the ML. However, TRPV1 is poorly expressed at the excitatory hilar mossy cell synapses in the inner 1/3 of this layer. Importantly, the TRPV1 pattern distribution disappeared in the ML of TRPV1-knockout mice. Taken together, these findings support the notion of the presence of TRPV1 in a brain region where the channel has been shown to have a functional role, such as the perforant path synapses in the hippocampal dentate ML. PMID- 24487915 TI - Characterization of localized osteosarcoma of the extremity in children, adolescents, and young adults from a single institution in South Texas. AB - BACKGROUND: Osteosarcoma is the most common bone malignancy in children, adolescents, and young adults. Most study cohorts have 10% to 15% Hispanic patients that encompass many different Hispanic backgrounds. This study characterizes the effect of mainly Mexican American ethnicity on the outcome of children, adolescents, and young adults with osteosarcoma. METHODS: A retrospective analysis of demographics, tumor characteristics, response to treatment, and survival outcome of all localized osteosarcoma of the extremity patients below 30 years of age was performed. A Kaplan-Meier estimates with log rank tests and Cox proportional hazard regression models were used. RESULTS: Fifty patients (median age, 15; range, 2 to 28 y) with localized high-grade osteosarcoma of the extremity were diagnosed between January 2000 and December 2010. The cohort was 70% Mexican Americans. With a median follow-up of 39 months (range, 5 to 142 mo), patients had a 5-year overall survival and event-free survival of 65% and 48%, respectively. We observed a significantly decreased 5 year event-free survival in patients diagnosed before age 12 relative to patients diagnosed between ages 12 and 29 (11% vs. 57%, P<0.001). We also found that tumor necrosis was not predictive of outcome in our patients. CONCLUSIONS: The preadolescent patients of predominately Mexican American ethnicity had an increased rate of relapse when compared with previous studies. Tumor necrosis is not directly predictive of outcome in this population. PMID- 24487916 TI - Patient involvement in informed consent for pediatric phase I cancer research. AB - OBJECTIVE: To examine children's and adolescents' involvement in the informed consent conference for phase I cancer trials and test associations with patient age, ease of understanding, and pressure to participate. PROCEDURE: Participants included 61 patients aged 7 through 21 years who were offered participation in a phase I trial. Consent conferences were audiotaped, transcribed, and coded for communication between patients and physicians and between patients and parents. RESULTS: On the basis of word counts, the mean proportion of the consent conference in which the physician was talking to the patient was 36%; the vast majority (73%) of this communication consisted of giving information. Physician patient communication increased with age, but overall levels of patient-to physician communication were low (3%). After controlling for patient age, greater physician-to-patient communication was associated with greater ease of understanding. CONCLUSIONS: The focus on providing information in the context of informed consent may come at the expense of other communication exchanges that are important to patients, especially in the context of end-of-life decisions. Children and adolescents may benefit from the assent process when physicians direct more of their communication to them. Future research should identify the reasons for low patient communication during the consent conference and strategies to enhance their participation in decision making about phase I trial enrollment. PMID- 24487917 TI - Childhood cancer in Africa: an overview of resources. AB - BACKGROUND: Information about pediatric oncology in most of Africa is not widely available. The aim of this study was to provide an overview of childhood cancer and resources for patient care in a cross-section of African hospitals. METHODS: Between 2011 and 2013, 49 health professionals involved in the care of children with cancer, from 38 hospitals in 29 African countries, were asked to respond to a questionnaire about the types and number of childhood cancers seen in their facilities; types and numbers of health care professionals; diagnostic, therapeutic, and palliative capabilities; survival statistics and compliance with treatment; support from parent groups; opportunities for ongoing medical training; and perceived challenges to care delivery. RESULTS: New diagnoses annually ranged from 10 to 350, with nephroblastoma, leukemia, retinoblastoma, and Burkitt lymphoma being the most common in most centers. Care was provided often by nonpediatric oncologists. Radiotherapy was available in 21/38 hospitals, palliation in 27/38, and tumor registries in 21/38 centers. CONCLUSIONS: Capabilities for care of children with cancer varied widely. Recommendations for improving care are discussed. PMID- 24487918 TI - Thalidomide influences atherogenesis in aortas of ApoE(-/-)/LDLR (-/-) double knockout mice: a nano-CT study. AB - Plaque progression in atherosclerosis is closely connected to angiogenesis due to vasa vasorum (VV) growth. Objective of this study was to determine the unknown long-term effect of thalidomide on adventitial VV neovascularization and plaque progression using nano-focussed computed tomography (nano-CT). Proliferation and migration assays in human coronary artery endothelial cells (HCAEC) measured number of viable cells after incubation with thalidomide. Male ApoE(-/-)/LDLR(-/ ) (AL) mice (n = 5) received a thalidomide containing western diet (WD) over 29 weeks. Another five male AL mice (WD without thalidomide) served as control group. Descending aortas were scanned with nano-CT at (1.5 MUm)(3) isotropic voxel size. Number and area of adventitial VV as well as plaque cross sectional area were measured. Results were complemented by histology. Thalidomide inhibited proliferation and migration of HCAEC dose-dependently. VV neovascularization decreased in number per cross section (7.66 +/- 0.301 vs. 8.62 +/- 0.164, p < 0.001) and in cross sectional area (0.0183 +/- 0.0011 vs. 0.0238 +/- 0.0008 mm(2), p < 0.001). Cross sectional area of plaque decreased significantly when treated with thalidomide (0.57 +/- 0.0187 vs. 0.803 +/- 0.0148 mm(2), p < 0.001). Nano-CT imaging revealed a reduced plaque growth and VV neovascularization after long-term application of thalidomide. Therefore, nano-CT can be considered as a new method to detect therapeutic effects in experimental models of atherosclerosis. PMID- 24487919 TI - Unintentional boluses during drug infusions: pump up the volume! PMID- 24487920 TI - Long livestock farming history and human landscape shaping revealed by lake sediment DNA. AB - The reconstruction of human-driven, Earth-shaping dynamics is important for understanding past human/environment interactions and for helping human societies that currently face global changes. However, it is often challenging to distinguish the effects of the climate from human activities on environmental changes. Here we evaluate an approach based on DNA metabarcoding used on lake sediments to provide the first high-resolution reconstruction of plant cover and livestock farming history since the Neolithic Period. By comparing these data with a previous reconstruction of erosive event frequency, we show that the most intense erosion period was caused by deforestation and overgrazing by sheep and cowherds during the Late Iron Age and Roman Period. Tracking plants and domestic mammals using lake sediment DNA (lake sedDNA) is a new, promising method for tracing past human practices, and it provides a new outlook of the effects of anthropogenic factors on landscape-scale changes. PMID- 24487922 TI - Pt nanoparticles entrapped in titanate nanotubes (TNT) for phenol hydrogenation: the confinement effect of TNT. AB - A Pt@TNT catalyst with Pt nanoparticles entrapped in titanate nanotubes (TNT) was prepared by hydrophobic modification of the exterior surface of the TNT and impregnation with hexachloroplatinic acid (H2PtCl6) aqueous solution. The catalyst's enhanced activity towards the hydrogenation of phenol (as high as ~3200 gphenol h(-1) gPt(-1) of qTOF) can be ascribed to the confinement effect. PMID- 24487921 TI - The Collaborative Cross as a resource for modeling human disease: CC011/Unc, a new mouse model for spontaneous colitis. AB - Inflammatory bowel disease (IBD) is an immune-mediated condition driven by improper responses to intestinal microflora in the context of environmental and genetic background. GWAS in humans have identified many loci associated with IBD, but animal models are valuable for dissecting the underlying molecular mechanisms, characterizing environmental and genetic contributions and developing treatments. Mouse models rely on interventions such as chemical treatment or introduction of an infectious agent to induce disease. Here, we describe a new model for IBD in which the disease develops spontaneously in 20-week-old mice in the absence of known murine pathogens. The model is part of the Collaborative Cross and came to our attention due to a high incidence of rectal prolapse in an incompletely inbred line. Necropsies revealed a profound proliferative colitis with variable degrees of ulceration and vasculitis, splenomegaly and enlarged mesenteric lymph nodes with no discernible anomalies of other organ systems. Phenotypic characterization of the CC011/Unc mice with homozygosity ranging from 94.1 to 99.8% suggested that the trait was fixed and acted recessively in crosses to the colitis-resistant C57BL/6J inbred strain. Using a QTL approach, we identified four loci, Ccc1, Ccc2, Ccc3 and Ccc4 on chromosomes 12, 14, 1 and 8 that collectively explain 27.7% of the phenotypic variation. Surprisingly, we also found that minute levels of residual heterozygosity in CC011/Unc have significant impact on the phenotype. This work demonstrates the utility of the CC as a source of models of human disease that arises through new combinations of alleles at susceptibility loci. PMID- 24487924 TI - Letter to the editor. PMID- 24487923 TI - Monitoring the immune competence of cancer patients to predict outcome. AB - A new era of cancer immunotherapy has brought not only successful cancer vaccines but also immunomodulators, such as those that target checkpoint blockade in order to induce endogenous host immune responses. However, the immune system of cancer patients can be compromised through multiple means, including immune suppression by the tumor and by prior therapies such as chemotherapy and radiation. Therefore, a comprehensive means of assessing patient immunocompetence would seem helpful for determining whether patients are ready to benefit from immunotherapy, and perhaps even which immunotherapy might be most appropriate for them. Unfortunately, there are no standardized tests for immune competence, nor is there agreement on what to measure and what will be predictive of outcome. In this review, we will discuss the technologies and assays that might be most useful for this purpose. We argue for a comprehensive approach that should maximize the chances of developing predictive biomarkers for eventual clinical use. PMID- 24487925 TI - The psychomotor disorders: disorders of the supervisory mental processes. AB - Clinical evidence suggests that three major patterns of disturbance of the supervisory mental processes that regulate self-generated mental activity can occur, either alone or together, in a variety of neurological and psychiatric conditions. Psychomotor poverty involves a diminished ability to initiate activity. Psychomotor disorganization reflects impaired ability to select between activities. Reality distortion, which is manifest as delusions and hallucinations, appears to reflect an abnormality of internal monitoring of mental activity. Each of these three syndromes is associated with a specific pattern of disordered function in multimodal association cortex and related subcortical nuclei. The evidence suggests that the neurotransmitter dopamine plays a major role in modulating the supervisory mental processes, though serotonin and noradrenaline are also implicated. While a particular neurotransmitter might have conflicting influences on different syndromes, the differential involvement of different anatomic sites and different neuroreceptor types offers the possibility of successful treatment even when different syndromes co-exist. PMID- 24487926 TI - Event-related potentials in Parkinson's disease: a review. AB - This article reviews the findings of event-related potentials (ERP) in Parkinson's disease (PD) published during the last 10 years. Basic principles and methods of ERP are briefly presented with particular regard to the auditory "odd ball" paradigm almost uniquely employed for the ERP assessment in PD to date. The results of respective studies are overviewed and discussed with respect to three main axes:(1) The slowing down of cognitive processing in PD is reflected by the delays of N2 and P3 components of ERP which are more important in demented than in non-demented patients. The Nl component is delayed in demented patients with PD as well as in other dementias of presumed subcortical origin.(2) Various neuropsychological deficits observed in PD correlate with the delays of ERP evoking the implication of common subcortico-cortical cerebral mechanisms.(3) The variations of ERP under dopaminergic manipulation suggest conflicting effects of levodopa treatment on cognition, at least in certain categories of PD patients. These findings are discussed in the light of current knowledge on neurotransmitter brain systems and some hypothetic explanations are proposed.Finally, an attempt is made to outline further perspectives of clinical and research utilization of ERP in Parkinson's disease. PMID- 24487927 TI - Covert face recognition without prosopagnosia. AB - An experiment is reported where subjects were presented with familiar or unfamiliar faces for supraliminal durations or for durations individually assessed as being below the threshold for recognition. Their electrodermal responses to each stimulus were measured and the results showed higher peak amplitude skin conductance responses for familiar than for unfamiliar faces, regardless of whether they had been displayed supraliminally or subliminally. A parallel is drawn between elevated skin conductance responses to subliminal stimuli and findings of covert recognition of familiar faces in prosopagnosic patients, some of whom show increased electrodermal activity (EDA) to previously familiar faces. The supraliminal presentation data also served to replicate similar work by Tranel et al (1985). The results are considered alongside other data indicating the relation between non-conscious, "automatic" aspects of normal visual information processing and abilities which can be found to be preserved without awareness after brain injury. PMID- 24487928 TI - Transdermal physostigmine-absence of effect on topographic brain mapping. AB - Nine patients with primary degenerative dementia (PDD) participated in an open trial of transdermal physostigmine (TPh). In order to evaluate the neurophysiologic effects of TPh, EEG data were recorded and compared at baseline and following 2 months of continuous treatment. There was no significant effect of TPh on EEG spectra in patients with PDD. PMID- 24487929 TI - A selective impairment in the phonological output lexicon. AB - It has been proposed that words are stored in a functional structure which consists of a semantic system and modality-specific input and output lexicons. We report a patient with disturbed word finding for given letters, but not for specific categories. The patient had difficulty in phonological similarity judgements of pictures, but performed normally on semantic similarity judgements. We conclude that this patient's impairments stemmed from a disturbance restricted to the subsystem for active judgement and selection of representations in the phonological output lexicon. PMID- 24487930 TI - Aggressive behaviour in Huntington's disease: a cross-sectional study in a nursing home population. AB - We describe a cross-sectional study of aggressive behaviour in a sample of patients suffering from Huntington's disease in a residential nursing home. Data were obtained using the RAGE, a behaviourally oriented rating scale for measuring aggressive behaviour in cognitively impaired patients. Nursing staff rated 27 patients after a 3 day observation period. A third of the sample were rated to be at least mildly aggressive; the frequencies of some specific types of aggressive behaviour were high. In contrast, the frequency of injuries sustained and the use of restraints and medication for aggressive behaviour were low. Aggressive behaviour was found to be significantly related to the degree of functional impairment. These data are compared with those reported in a study using the RAGE to assess aggressive behaviour in a sample of elderly patients with dementia. PMID- 24487931 TI - Dyspraxia and agnosia in schizophrenia. AB - A battery of tests for dyspraxia and agnosia was administered to 51 chronic schizophrenic patients to test the hypothesis that these cortical neurological signs are associated with psychomotor poverty syndrome (poverty of speech, flat affect, decreased spontaneous movement), disorganization syndrome (various disorders of the form of thought, inappropriate affect), abnormal involuntary movements, cognitive impairment, and duration of illness. The findings supported all elements of the hypothesis, and in particular, demonstrated a strong correlation of cortical signs with psychomotor poverty and with cognitive impairment. PMID- 24487932 TI - Behavioral disorders in association with posterior callosal and frontal cerebral infarction. AB - Behavioral disorders were a prominent clinical feature after the surgical treatment of an anterior communicating artery aneurysm rupture in a 44-year-old man. Callosal apraxia was associated with an alien hand. The latter remained 1 year after surgery while diagonistic apraxia disappeared after 3 months. Other callosal signs included left agraphia, tactile anomia and auditory suppression. MRI revealed posterior callosal infarction and a right frontal infarct. The association of diagonistic apraxia and alien hand is rarely reported. PMID- 24487933 TI - A case of corticobasal degeneration studied with positron emission tomography. AB - We measured cerebral blood flow, oxygen metabolism, glucose utilization, and dopamine metabolism in the brain of a patient with corticobasal degeneration using positron emission tomography (PET). The clinical picture is distinctive, comprising features referable to both cortical and basal ganglionic dysfunction. Brain imagings of glucose and dopamine metabolism can demonstrate greater abnormalities in the cerebral cortex and in the striatum contralateral to the more affected side than those of blood flow and oxygen metabolism. This unique combination study measuring both cerebral glucose utilization and dopamine metabolism in the nigrostriatal system can provide efficient information about the dysfunctions which are correlated with individual clinical symptoms, and this study is essential to diagnosis of corticobasal degeneration. PMID- 24487935 TI - Single-site umbilical laparoscopic pyloromyotomy in neonates less than 21-day old. AB - PURPOSE: Single-site umbilical laparoscopic pyloromyotomy for hypertrophic pyloric stenosis in neonates <3-week old has rarely been reported in the literature. This article reports our initial experience with this procedure. METHODS: Overall, 13 cases of hypertrophic pyloric stenosis occurred in neonates <3-week old from January 2010 to April 2013 in our hospital. All neonates were treated by a single-site laparoscopic procedure. A 5-mm trocar and endoscope were introduced through an incision in the center of the umbilicus, and two 3-mm working instruments were inserted directly into the abdomen via separate lateral fascial stab incisions in the umbilical fold, and a single-site umbilical laparoscopic pyloromyotomy was then performed. RESULTS: The procedure was performed in 13 infants (12 male) with mean age of 17.3 days. The average length of the operation was 26 min. The mean postoperative hospital stay was 4.5 days. All patients were discharged home on full feeds. Follow-up examinations were scheduled 2 to 6 weeks after discharge, and no postoperative complications were noted in any of the patients. CONCLUSION: These cases had shorter and thinner pylori than their older counterparts. However, the laparoscopic procedure was safe and feasible, with good postoperative results and excellent cosmesis. Surgeons should have a firm foundation of advanced minimal access surgical skills prior to attempting the procedure. PMID- 24487936 TI - Novel phage display-derived H5N1-specific scFvs with potential use in rapid avian flu diagnosis. AB - The highly pathogenic avian influenza A (HPAI) viruses of the H5N1 subtype infect poultry and have also been spreading to humans. Although new antiviral drugs and vaccinations can be effective, rapid detection would be more efficient to control the outbreak of infections. In this study, a phage-display library was applied to select antibody fragments for HPAI strain A/Hubei/1/2010. As a result, three clones were selected and sequenced. A hemagglutinin inhibition assay of the three scFvs revealed that none exhibited hemagglutination inhibition activity towards the H5N1 virus, yet they showed a higher binding affinity for several HPAI H5N1 strains compared with other influenza viruses. An ELISA confirmed that the HA protein was the target of the scFvs, and the results of a protein structure simulation showed that all the selected scFvs bound to the HA2 subunit of the HA protein. In conclusion, the three selected scFVs could be useful for developing a specific detection tool for the surveillance of HPAI epidemic strains. PMID- 24487937 TI - 1-aminocyclopropane-1-carboxylate deaminase from Pseudomonas fluorescens promoting the growth of Chinese cabbage and its polyclonal antibody. AB - Bacterial 1-aminocyclopropane-1-carboxlyate (ACC) deaminase (AcdS) is an enzyme that cleaves ACC, a precursor of the plant hormone ethylene, into alpha ketobutyrate and ammonia. The acdS gene was cloned from Pseudomonas fluorescens, which was capable of improving the seedling of Chinese cabbage under salinity condition. The recombinant AcdS (rAcdS) exhibited optimal activity at pH 8.5 and 30 degrees C. Strong activity was sustained at up to 100 mM NaCl. The polyclonal anti-P. fluorescens AcdS antibody was produced in a rabbit that had been immunized with the purified rAcdS. This antibody successfully recognized the homologous antigens derived from the total proteins of isolated plant growth promoting microorganisms. A statistically significant correlation was observed between the intensity of hybridization signal and AcdS activity measured by a biochemical method, suggesting its application as a useful indicator for active deaminases. PMID- 24487938 TI - Occurrence and molecular characterization of noroviruses in Korean surface water between 2007 and 2010. AB - The occurrence of human norovirus (NoV) genogroup I (GI) and genogroup II (GII) strains was investigated in Korea. Between 2007 and 2010, 265 samples were collected from 89 Korean water source locations. NoV GI was detected in 4.5% and NoV GII in 1.5%. Samples collected in winter had the highest occurrence; 9.4% for NoV GI and 6.3% for NoV GII. NoV GI detection was highest in groundwater, with the next highest in river water and the lowest in lake water (5.9%, 5.4%, and 1.6%, respectively), and NoV GII was found only in river water. When three representative Korean basin systems (Han (H)-, Geum/Seom (G/S)-, and Nakdong (N) river basins) were compared, both NoV genogroups were high in the G/S-, but absent in the H- river basin. The most prevalent genotypes within the GI and GII groups were GI.5 and GII.4, respectively. The NoVs found in surface water were identical to those found in patients and those found in groundwater. The NoVs appeared to be transmitted from the patient to the surface water, and then to the groundwater, suggesting a fecal-oral route of transmission. This is the first nationwide surveillance of NoV in major Korean water sources. PMID- 24487939 TI - Association between the atrial natriuretic peptide rs5065 gene polymorphism and the presence and severity of coronary artery disease in an Iranian population. AB - OBJECTIVE: The atrial natriuretic peptide (ANP) gene expression and some of its related single-nucleotide polymorphisms have been well established as a characterized biomarker of cardiovascular diseases. In the present study, we aimed to evaluate the potential association between one of the introduced ANP gene polymorphisms of 2238 T/C (rs5065) with coronary artery disease (CAD) in an Iranian population. BASIC METHODS: A total of 573 patients with CAD according to angiography reports and 293 controls without any evidence of CAD were enrolled. Allelic discrimination of the single-nucleotide polymorphism rs5065 in both groups was performed using a High Resolution Melt technique in real-time PCR analysis. MAIN RESULTS: With respect to the prevalence of different genotypes of rs5065 polymorphism, the frequency of the T allele in the CAD group was significantly lower in CAD than that in the non-CAD group (59.7 vs. 65.1%, P=0.032). A significant inverse association was also found between the frequency of T allele and severity of CAD assessed by the Gensini score; the average of this score in T-allele carriers was 38.6+/-41.6 and that in C-allele carriers was 57.7+/-46.3 (P<=0.0001). Using multivariable linear regression modeling with the presence of baseline variables, the presence of the rs5065 ANP T allele could predict decreased severity of CAD assessed by the Gensini score in our population. PRINCIPAL CONCLUSION: The presence of the rs5065 ANP polymorphism is potentially associated with a reduced risk of CAD as well as with reduced severity of CAD independent of the general risk factors of CAD. PMID- 24487941 TI - Hybrid coronary revascularization for multivessel coronary artery disease. AB - Hybrid coronary revascularization intends to combine the durability and survival advantage of the left internal mammary artery to left anterior descending coronary artery graft by a minimally invasive surgical procedure and the interventional therapy for non-left anterior descending coronary artery vessels to achieve complete revascularization. It provides a feasible and attractive alternative to conventional coronary artery bypass grafting and percutaneous coronary intervention to target multivessel coronary artery disease, and advances the individualized, patient-oriented treatment for heart disease. In initial experiences, this new approach has yielded favorable early or midterm results in selected patients with multivessel coronary artery disease. However, available data related to these outcomes following hybrid revascularization are limited to retrospective studies with relatively small sample sizes. In this review, we aim to provide an overview of hybrid revascularization, and discuss appropriate patient selection, procedure techniques, and the main literature pertaining to the hybrid revascularization. PMID- 24487940 TI - The association of serum parathyroid hormone and severity of coronary artery diseases. AB - INTRODUCTION: The serum level of parathyroid hormone (PTH) has been shown to be a predictor of cardiovascular mortality. Data on the association between PTH level and degree of atherosclerosis severity are lacking. The objective of this study was to determine the relationship of serum PTH level and number of stenotic coronary arteries. PATIENTS AND METHODS: The present article is a descriptive cross-sectional study on 476 patients who had undergone coronary angiography according to documented indications and had coronary lesion more than 50% in at least one main vessel during 2010-2012. The outcome was evaluated by comparison between PTH levels and the number of stenotic coronary arteries. RESULTS: Demographic data of the patients, severity, and number of stenotic vessels were evaluated. Of the 476 patients included, 183 (38.4%) had PTH more than 40 pg/ml. There was a significant association between PTH level and severity and number of coronary lesion: 80% of three-vessel disease patients had PTH more than 40 pg/ml but only 7% of single-vessel disease patients had PTH more than 40 pg/ml (P<0.001). The mean levels of PTH serum in single-vessel, two-vessel, and three vessel disease were 24.8, 35.8, and 49.8 pg/ml, respectively (P<0.001). Individuals with the higher PTH level had longer history of hypertension and lower left ventricular ejection fraction (P<0.01 and P<0.002, respectively). CONCLUSION: In this relatively small prospective study, serum PTH level is associated with the number of stenotic coronary arteries. There is a correlation between high PTH level with hypertension and low ejection fraction. A prospective study that evaluates the additional value added (by ROC analysis) by PTH to already known cardiac risk factors is recommended. PMID- 24487942 TI - Degradation of organic pollutants in/on snow and ice by singlet molecular oxygen (1O2*) and an organic triplet excited state. AB - Singlet molecular oxygen (1O2*) can be a significant sink for a variety of electron-rich pollutants in surface waters and atmospheric drops. We recently found that 1O2* concentrations are enhanced by up to a factor of 10(4) on illuminated ice compared to in the equivalent liquid solution, suggesting that 1O2* could be an important oxidant for pollutants in snow. To examine this, here we study the degradation of three model organic pollutants: furfuryl alcohol (to represent furans), tryptophan (for aromatic amino acids), and bisphenol A (for phenols). Each compound was studied in illuminated aqueous solution and ice containing Rose Bengal (RB, a sensitizer for 1O2*) and sodium chloride (to adjust the concentration of total solutes). The RB-mediated loss of each organic compound is enhanced on illuminated ice compared to in solution, by factors of 6400 for furfuryl alcohol, 8300 for tryptophan, and 50 for bisphenol A for ice containing 0.065 mM total solutes. Rates of loss of furfuryl alcohol and tryptophan decrease at a higher total solute concentration, in qualitative agreement with predictions from freezing-point depression. In contrast, the loss of bisphenol A on ice is independent of total solute concentration. Relative to liquid tests, the enhanced loss of tryptophan on ice during control experiments made with deoxygenated solutions and solutions in D2O show that the triplet excited state of Rose Bengal may also contribute to loss of pollutants on ice. PMID- 24487943 TI - "It Is Not Wit, It Is Truth:" Transcending the Narrative Bounds of Professional and Personal Identity in Life and in Art. AB - Taking inspiration from the film Wit (2001), adapted from Margaret Edson's (1999) Pulitzer Prize-winning play, this article explores the particularities of witnessing a cinematic cancer narrative juxtaposed with the author's own cancer narrative. The analysis reveals the tenuous line between death and dying, illness and wellness, life and living and the resulting identities shaped in the process of understanding both from a personal and professional lens. By framing these representations of illness experience within the narrative constructions of drama, time, metaphor and morality, the personal stories of intellectual knowledge converging with intimate and embodied knowing are revealed. PMID- 24487945 TI - Identification of Yr59 conferring high-temperature adult-plant resistance to stripe rust in wheat germplasm PI 178759. AB - KEY MESSAGE: This manuscript reports a new gene for non-race-specific resistance to stripe rust and molecular markers for incorporating it into wheat cultivars for control of the disease with durable resistance. Stripe rust, caused by Puccinia striiformis f. sp. tritici, is one of the most destructive wheat diseases worldwide. The spring wheat germplasm 'PI 178759' originating from Iraq showed effective resistance to stripe rust in field evaluations over 8 years in Washington state, USA. To map the resistance gene(s), PI 178759 was crossed with 'Avocet Susceptible', and the parents and 176 F2:3 lines were phenotyped in the fields under natural infection and in a greenhouse with selected races of P. striiformis f. sp. tritici. PI 178759 was identified to have high-temperature adult-plant (HTAP) resistance. Resistance gene analog polymorphism and simple sequence repeat techniques were used to identify molecular markers linked to the resistance gene and a chromosome region was mapped using a quantitative trait locus approach. One major gene was mapped to the long arm of chromosome 7B. Flanked by Xwgp5175 and Xbarc32 in a 2.1 cM region, the gene explained 31.8 and 54.7 % of the phenotypic variation in rAUDPC and IT, respectively. Based on genetic distances among markers and allelism tests, the HTAP resistance gene in PI 178759 is different from the previously reported Yr39, Yr52, YrZH84, and YrC591, also located on chromosome 7BL, and is therefore designated as Yr59. The gene and its flanking markers should be useful for developing wheat cultivars with durable resistance. PMID- 24487946 TI - Comparison of hardness of three temporary filling materials cured by two light curing devices. AB - AIM: Polymerization ability of light-curing devices can affect the light-cured material hardness. The purpose of the present study was to evaluate and compare the hardness of three temporary filling materials that had been light-cured by either a light emitting diode (LED) or a halogen light-curing unit. METHODS: The temporary filling materials, First Fill, Voco Clip and Bioplic, were placed in wells in a Teflon plate. The 24 specimens of each material were divided into two groups (N.=12/group) for photo-activation by either of the two light-curing units. The LED or halogen device was applied for 40s to the top surface of each specimen. A Knoop hardness test was performed on the top and bottom surface of each specimen, with five measurements per specimen. RESULTS: The highest hardness values for both the LED and halogen treated groups were observed for First Fill and the lowest values were for Voco Clip in top and bottom surfaces. The hardness obtained for the three materials with the halogen unit were significantly higher than the values obtained with the LED unit in both surfaces (P<0.05). CONCLUSION: First Fill light-cured temporary material exhibited the highest hardness values on the top and bottom surfaces than Voco Clip and Bioplic temporary materials. The hardness of light-cured temporary filling materials can be affected by the type of light-curing unit. PMID- 24487947 TI - Piezolelectric surgery in dentistry: a review. AB - In the last ten years was observed a significant increase of publications about piezoelectric bone surgery. The purpose of this review was to define the state of art and to realize a comparison between piezoelectric devices and manual or rotating traditional techniques, analyzing advantages and disadvantages from a clinical and histological point of view for various dental procedures. The literature review has been carried out using medical databases on line: MEDLINE and COCHRANE LIBRARY. The authors selected 37 publications about dental field and consistent with inclusion criteria established. From the clinical point of view, the analysis of selected publications concerning procedures such as maxillary sinus lift, alveolar ridge expansion, samples of autologous bone, etc, showed surgical trauma reduction, especially towards to soft and nervous tissues, surgical mini-invasiveness, cut precision and selectivity and speed of learning guaranteed by piezoelectric devices compared to traditional ones. Histologically, however, the study of biology and postintervention bone tissue healing showed a lower loss of bone with piezoelectric instruments than with conventional devices, as well as a better healing quality by reducing patient's postsurgery morbidity. The use of piezoelectric devices seems thus to simplify different sinus lift surgical procedures and to allow greater predictability, although some studies reveal that there are not substantial differences in comparison of long-term results between conventional and piezoelectric instruments and also criticize their increase in operation time. PMID- 24487948 TI - Adjuvant aqueous ozone in the treatment of bisphosphonate induced necrosis of the jaws: report of two cases and long-term follow-up. AB - Bisphosphonate induced necrosis of the jaws (BONJ) does not have a unique protocol of treatment and many therapeutic approaches have been arising in oral medicine with debatable results. A male and a female attended the University Oral Surgery Clinic presenting oral bone lesions induced by intravenous and oral bisphosphonates respectively as complications of dental extraction. Treatment included daily mouthwashes and weekly intra oral irrigations with 4 mg/L of aqueous-ozone, antibiotic therapy and sequential superficial debridment for sequestrectomies. Long-standing follow-ups showed complete mucosa covering of exposed bone area and resolution of purulent secretion. Antibacterial and antifungal properties of aqueous ozone may have played important roles in the treatment. The outcome measured intra oral examination and panoramic radiographs of the affected bone. The application of aqueous ozone daily mouthwashes and weekly professional irrigation were safe; free from adverse effects, easily of handling and worked as an important adjuvant therapeutic strategy for the treatment of BONJ. PMID- 24487949 TI - Treatment of craniofacial fibrous dysplasia: a case report. AB - The concept of "fibro-osseous lesions" of bone has evolved over the last several years and now includes two mayor entities: the fibrous dysplasia (FD) and the cement-ossifying fibroma (COF). Fibrous dysplasia is considered to be a developmental, tumor-like (hamartomatous), fibro-osseous disease of unknown etiology. There is a maxillary predominance when craniofacial FD occurs in the jaws and the maxillary sinus is commonly involved. Differentiation of OF from FD is important because of differences in treatment and behaviour. This article report a case of 60-year-old female with a history of painless unilateral palatal swelling. PMID- 24487950 TI - The impact of high-normal blood pressure on left ventricular mechanics: a three dimensional and speckle tracking echocardiography study. AB - To assess the presence of subclinical left ventricular myocardial dysfunction in subjects with high-normal blood pressure (BP) and untreated arterial hypertension, using three-dimensional (3D) echocardiography strain analysis. This cross-sectional study included 49 subjects with optimal BP, 50 subjects with high normal BP, and 50 newly diagnosed untreated hypertensive patients matched by gender and age. All the subjects underwent 24 h blood pressure monitoring and complete two-dimensional and 3D echocardiography examination. The enrolled subjects were grouped according to 24 h systolic BP values, dividing the subjects with optimal BP from those with high-normal BP and the hypertensive patients (cut off values were 120 and 130 mmHg, respectively). 3D global longitudinal strain was significantly lower in the high-normal BP group and the hypertensive patients, in comparison with the optimal BP group (-20.5 +/- 3.3 vs. -18.7 +/- 2.8 vs. -17.6 +/- 2.7%, p < 0.001). Similar results were obtained for 3D global circumferential strain (-18.6 +/- 3 vs. -17.1 +/- 2.9 vs. -16 +/- 2.5 %, p < 0.001), as well for 3D global radial strain (49.4 +/- 9.5 vs. 44.7 +/- 8.1 vs. 43.5 +/- 7.8%, p = 0.002), and global area strain (-31.2 +/- 4.8 vs. -28.7 +/- 4.2 vs. -27.1 +/- 4.5%, p < 0.001). LV twist was increased in the hypertensive patients in comparison with the high-normal and the optimal BP groups (10.1 degrees +/- 2.4 degrees vs. 10.8 degrees +/- 2.6 degrees vs. 13.8 degrees +/ 3.1 degrees , p < 0.01), whereas untwisting rate significantly and gradually decreased from the optimal BP group, across the high-normal BP group, to the hypertensive patients (-135 +/- 35 vs. -118 +/- 31 vs. -102 +/- 27 degrees /s, p < 0.001). 3D echocardiography revealed that the subjects with high-normal BP suffered subclinical impairment of LV mechanics similar as the hypertensive patients. PMID- 24487951 TI - The impact of revision of one or more rods on refracture rate and implant survival following rod fracture in instrumentation without fusion constructs in the management of early-onset scoliosis. AB - Growing rods are used in the treatment of early-onset scoliosis. It is uncertain how many rods should be replaced following rod fracture. This is a 13-year retrospective study of 33 single-rod fractures. After treatment, there were 15 refractures (45%), 80% in the same rod. In 11 with single-rod revision, seven refractured with a mean time of 16 months. When both rods were revised (n=18), six refractured (P=0.14) after a mean of 18 months (P=0.43). Our unit policy is revision of the broken rod alone following initial single-rod fracture and revision of all rods for subsequent fractures. PMID- 24487952 TI - Tear-drop fracture of the axis in a child with an 8-year follow-up: a case report. AB - We reported a 12-year-old boy with neck pain and dysphagia 6 days after his neck being tied by another boy's arms from the back. The boy was found to have a tear drop fracture of the axis in both radiograph and MRI, which was a rare case in children. He was placed in a cervical traction with Glisson belt and received transfusion for 2 weeks until his neck pain and dysphagia were released. Thereafter, an operation of anterior fusion and fixation was chosen to ensure further stability of the cervical spine and replacement of the fracture fragment. An 8-year follow-up examination showed a satisfactory range of motion of the cervical spine, fusion at C2-3 intervertebral space, and normal signal of C3-4 intervertebral disk. We conclude that tear-drop fractures of the axis in children may be caused by extension injury without a high-energy trauma, and operation of anterior fusion and fixation can be the treatment of choice. PMID- 24487954 TI - Coefficient estimates for initial Taylor-Maclaurin coefficients for a subclass of analytic and bi-univalent functions defined by Al-Oboudi differential operator. AB - We introduce and investigate an interesting subclass NP(lambda,delta)(Sigma) (n, beta; h) of analytic and bi-univalent functions in the open unit disk U. For functions belonging to the class NP(lambda,delta)(Sigma) (n, beta; h), we obtain estimates on the first two Taylor-Maclaurin coefficients |a2| and |a3|. PMID- 24487953 TI - Cholecystokinin protects rats against sepsis induced by Staphylococcus aureus. AB - Staphylococcus aureus is a Gram-positive bacteria described as an important causative agent of sepsis. The contact between host leukocytes and bacteria activates the innate immune response. Nitric oxide, tumor necrosis factor (TNF) alpha and interleukin (IL)-1beta play a key role in increasing microbicidal activity and controlling cell influx into infectious focus. Contrarily, IL-10 acts as an anti-inflammatory cytokine and bacterial killing suppressor. Immunoregulatory properties have also been attributed to hormones, including cholecystokinin (CCK). CCK protects cardiovascular function and inhibits the inflammatory response induced by lipopolysaccharide, product derived from Gram negative bacteria. Nevertheless, the role of CCK during Gram-positive infection remains a literature gap. Our aims were to investigate whether CCK protects rats against bacterial dissemination during sepsis induced by S. aureus. We determined whether CCK modulates local and systemic inflammatory response, as well as the cell migration into the infectious focus and the bactericidal capacity of leukocytes. Our results revealed that proglumide (nonselective CCK receptor antagonist) pretreated rats showed higher bacterial counts in blood and peritoneal lavage fluid (PLF) and reduced TNF-alpha and IL-10 levels in PLF. Moreover, the dissemination of S. aureus may be related to the failure of neutrophil and macrophage migration into the peritoneal cavity. Also, CCK improved the phagocytic and bactericidal ability of these inflammatory cells. Noteworthy is that the adoptive transfer of CCK-treated neutrophils and macrophages in septic rats improved immune defense, reducing bacterial number in blood and PLF. All together, our study clearly demonstrates an important protective role of CCK against sepsis induced by S. aureus. PMID- 24487955 TI - Comparison of two different laser wavelengths' dental bleaching results by photo Fenton reaction: in vitro study. AB - The purpose of this study was to perform a preliminary in vitro test on the possible use of two different laser wavelengths, 405 and 532 nm, to improve the dental bleaching results. To perform the test, the degradation of a dye, rhodamine B, under the effects of hydrogen peroxide was used. One hundred and twenty vials were divided into four groups of 30 samples each and, while three of them were irradiated with different wavelengths, 365 nm (reference), 405 nm and 532 nm, the fourth was the non-irradiated control group. Each of the four groups was further divided into three subgroups of 10 cuvettes (n = 10) each. The three subgroups included a group with a rhodamine (RH) solution, a rhodamine and hydrogen peroxide (RH + HP) solution and a rhodamine plus hydrogen peroxide and ferrous gluconate (RH + FR) solution. When hydrogen peroxide was present, only UVA irradiation was able to produce significant results, whereas when the photo Fenton reaction occurred, all the three wavelengths were able to produce a significant degradation of rhodamine B, with better results for longer wavelengths in comparison with short wavelengths. Within the limitations of this in vitro study, the light of the two laser devices, even remaining less effective than UV activation, showed its ability to improve the performance of bleaching agents based on Fenton photocatalysis, whereas when used in combination with hydrogen peroxide only, the 405-nm laser displayed a small effect and the 532-nm laser produced no effects. PMID- 24487956 TI - Variables affecting clinical response to treatment of facial port-wine stains by flash lamp-pumped pulsed dye laser: the importance of looking beyond the skin. AB - The response of port-wine stains (PWS) to conventional laser treatment in adults is difficult to predict. To assess the influence of local or systemic hemodynamic variables on the clearance of PWS by using flash lamp-pumped pulsed (FLPP) dye laser. All consecutive patients ages 18 years or older undergoing laser treatment for a facial PWS were eligible. Laser sessions were scheduled every 8 weeks. All patients were evaluated based on a standard scale with four evaluation categories, from no or minimal improvement to total or almost total clearance. Clearance was achieved by 50.1 % (95 % confidence interval 35.6-64.7) of patients after a maximum of 15 treatment sessions. In multivariate analysis, increased age, a newly described Type III capillaroscopic pattern, and presence of lesions in dermatome V2 were all associated with a reduced clinical response to treatment. In a model restricted to demographic pattern and patient characteristics, arterial hypertension was also associated with a lower clinical response. A strong association was found between arterial hypertension and the Type III capillaroscopic pattern. Age, arterial hypertension, capillaroscopic pattern, and body location should be considered when planning laser treatment of PWS. PMID- 24487957 TI - High-intensity versus low-level laser therapy in the treatment of patients with knee osteoarthritis: a randomized controlled trial. AB - The aim of this randomized controlled study was to compare the effects of low level laser therapy (LLLT) and high-intensity laser therapy (HILT) on pain relief and functional improvement in patients with knee osteoarthritis (KOA). A total of 53 male patients participated in this study, with a mean (SD) age of 54.6 (8.49) years. Patients were randomly assigned into three groups and treated with HILT and exercise (HILT + EX), LLLT and exercise (LLLT + EX), and placebo laser plus exercise (PL + EX) in groups 1, 2, and 3, respectively. The outcomes measured were pain level measured by visual analog scale (VAS) and knee function measured by Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Statistical analyses were performed to compare the differences between baseline and posttreatment measurements. The level of statistical significance was set as P < 0.05. The result showed that HILT and LLLT combined with exercise were effective treatment modalities in decreasing the VAS and WOMAC scores after 6 weeks of treatment. HILT combined with exercises was more effective than LLLT combined with exercises, and both treatment modalities were better than exercises alone in the treatment of patients with KOA. PMID- 24487958 TI - Structural mechanism of voltage-dependent gating in an isolated voltage-sensing domain. AB - The transduction of transmembrane electric fields into protein motion has an essential role in the generation and propagation of cellular signals. Voltage sensing domains (VSDs) carry out these functions through reorientations of positive charges in the S4 helix. Here, we determined crystal structures of the Ciona intestinalis VSD (Ci-VSD) in putatively active and resting conformations. S4 undergoes an ~5-A displacement along its main axis, accompanied by an ~60 degrees rotation. This movement is stabilized by an exchange in countercharge partners in helices S1 and S3 that generates an estimated net charge transfer of ~1 eo. Gating charges move relative to a ''hydrophobic gasket' that electrically divides intra- and extracellular compartments. EPR spectroscopy confirms the limited nature of S4 movement in a membrane environment. These results provide an explicit mechanism for voltage sensing and set the basis for electromechanical coupling in voltage-dependent enzymes and ion channels. PMID- 24487959 TI - Sustained active site rigidity during synthesis by human DNA polymerase MU. AB - DNA polymerase MU (Pol MU) is the only template-dependent human DNA polymerase capable of repairing double-strand DNA breaks (DSBs) with unpaired 3' ends in nonhomologous end joining (NHEJ). To probe this function, we structurally characterized Pol MU's catalytic cycle for single-nucleotide incorporation. These structures indicate that, unlike other template-dependent DNA polymerases, Pol MU shows no large-scale conformational changes in protein subdomains, amino acid side chains or DNA upon dNTP binding or catalysis. Instead, the only major conformational change is seen earlier in the catalytic cycle, when the flexible loop 1 region repositions upon DNA binding. Pol MU variants with changes in loop 1 have altered catalytic properties and are partially defective in NHEJ. The results indicate that specific loop 1 residues contribute to Pol MU's unique ability to catalyze template-dependent NHEJ of DSBs with unpaired 3' ends. PMID- 24487960 TI - Influence of post-exercise hypoxic exposure on hepcidin response in athletes. AB - PURPOSE: To assess the influence of a simulated altitude exposure (~2,900 m above sea level) for a 3 h recovery period following intense interval running on post exercise inflammation, serum iron, ferritin, erythropoietin, and hepcidin response. METHODS: In a cross-over design, ten well-trained male endurance athletes completed two 8 * 3 min interval running sessions at 85 % of their maximal aerobic velocity on a motorized treadmill, before being randomly assigned to either a hypoxic (HYP: F IO2 ~0.1513) or a normoxic (NORM: F IO2 0.2093) 3 h recovery period. Venous blood was collected pre- and immediately post-exercise, and after 3 and 24 h of recovery. Blood was analyzed for interleukin-6, serum iron, ferritin, erythropoietin, and hepcidin. RESULTS: Interleukin-6 was significantly elevated (p < 0.01) immediately post-exercise compared to baseline (NORM: 1.08 +/- 0.061 to 3.12 +/- 1.80) (HYP: 1.32 +/- 0.86 to 2.99 +/- 2.02), but was not different between conditions. Hepcidin levels were significantly elevated (p < 0.01) at 3 h post-exercise for both conditions when compared to baseline (NORM: 3.25 +/- 1.23 to 7.40 +/- 4.00) (HYP: 3.24 +/- 1.94 to 5.42 +/- 3.20), but were significantly lower (p < 0.05) in the HYP trial compared to NORM. No significant differences existed between HYP and NORM for erythropoietin, serum iron, or ferritin. CONCLUSION: Simulated altitude exposure (~2,900 m) for 3 h following intense interval running attenuates the peak hepcidin levels recorded at 3 h post-exercise. Consequently, a hypoxic recovery after exercise may be useful for athletes with compromised iron status to potentially increase acute dietary iron absorption. PMID- 24487961 TI - Immunologic response to the survivin-derived multi-epitope vaccine EMD640744 in patients with advanced solid tumors. AB - PURPOSE: Survivin is a member of the inhibitor-of-apoptosis family. Essential for tumor cell survival and overexpressed in most cancers, survivin is a promising target for anti-cancer immunotherapy. Immunogenicity has been demonstrated in multiple cancers. Nonetheless, few clinical trials have demonstrated survivin vaccine-induced immune responses. EXPERIMENTAL DESIGN: This phase I trial was conducted to test whether vaccine EMD640744, a cocktail of five HLA class I binding survivin peptides in Montanide((r)) ISA 51 VG, promotes anti-survivin T cell responses in patients with solid cancers. The primary objective was to compare immunologic efficacy of EMD640744 at doses of 30, 100, and 300 MUg. Secondary objectives included safety, tolerability, and clinical efficacy. RESULTS: In total, 49 patients who received >=2 EMD640744 injections with available baseline- and >=1 post-vaccination samples [immunologic-diagnostic (ID) intention-to-treat] were analyzed by ELISpot- and peptide/MHC-multimer staining, revealing vaccine-activated peptide-specific T-cell responses in 31 patients (63 %). This cohort included the per study protocol relevant ID population for the primary objective, i.e., T-cell responses by ELISpot in 17 weeks following first vaccination, as well as subjects who discontinued the study before week 17 but showed responses to the treatment. No dose-dependent effects were observed. In the majority of patients (61 %), anti-survivin responses were detected only after vaccination, providing evidence for de novo induction. Best overall tumor response was stable disease (28 %). EMD640744 was well tolerated; local injection site reactions constituted the most frequent adverse event. CONCLUSIONS: Vaccination with EMD640744 elicited T-cell responses against survivin peptides in the majority of patients, demonstrating the immunologic efficacy of EMD640744. PMID- 24487963 TI - A theoretical study on the injection, transport, absorption and phosphorescence properties of heteroleptic iridium(III) complexes with different ancillary ligands. AB - We have reported a theoretical analysis of a series of heteroleptic iridium(III) complexes (mpmi)2Ir(fppi) [mpmi = 1-(4-tolyl)-3-methyl-imidazole, fppi = 4-fluoro 2-(pyrrol-2-yl)-pyridine] (1a), (mpmi)2Ir(dfpi) [dfpi = 4-fluoro-2-(3-fluoro pyrrol-2-yl)-pyridine] (1b), (mpmi)2Ir(tfpi) [tfpi = 2-(pyrrol-2-yl)-4 trifluoromethyl-pyridine] (1c), (mpmi)2Ir(priq) [priq = 1-(pyrrol-2 yl)isoquinoline] (2a), (mpmi)2Ir(isql) [isql = 1-(indol-2-yl)-isoquinoline] (2b), and (mpmi)2Ir(biql) [biql = 1-(benzoimidazol-2-yl)-isoquinoline] (2c) by using the density functional theory (DFT) method to investigate their electronic structures, photophysical properties, and the phosphorescent efficiency mechanism. The results reveal that the nature of the ancillary ligands can affect the electron density distributions and energies of frontier molecular orbitals, resulting in changes of charge transfer performances and emission color. It is found that the studied complex 1c with the -CF3 substituent at the pyridine moiety results in the lower HOMO-LUMO energy gap and LUMO energy level, which will lead to a rich electron injection ability compared with that of 1a. For each complex studied (except 2b), the hole-transporting performance is better than the electron-transporting performance. In addition, for complexes 2a and 2b, the differences between reorganization energies for hole transport (lambda(ih)) and reorganization energies for electron transport (lambda(ie)) are relatively smaller, indicating that the hole and electron transfer balance could be achieved more easily in the emitting layer. It is believed that the largest metal to ligand charge transfer (MLCT) character, the higher MU(S1) and E(T1) values, as well as the smallest DeltaE(S1-T1) value could result in higher phosphorescent quantum efficiency for 1b than those of other complexes. PMID- 24487962 TI - USP11 regulates PML stability to control Notch-induced malignancy in brain tumours. AB - The promyelocytic leukaemia (PML) protein controls multiple tumour suppressive functions and is downregulated in diverse types of human cancers through incompletely characterized post-translational mechanisms. Here we identify USP11 as a PML regulator by RNAi screening. USP11 deubiquitinates and stabilizes PML, thereby counteracting the functions of PML ubiquitin ligases RNF4 and the KLHL20 Cul3 (Cullin 3)-Roc1 complex. We find that USP11 is transcriptionally repressed through a Notch/Hey1-dependent mechanism, leading to PML destabilization. In human glioma, Hey1 upregulation correlates with USP11 and PML downregulation and with high-grade malignancy. The Notch/Hey1-induced downregulation of USP11 and PML not only confers multiple malignant characteristics of aggressive glioma, including proliferation, invasiveness and tumour growth in an orthotopic mouse model, but also potentiates self-renewal, tumour-forming capacity and therapeutic resistance of patient-derived glioma-initiating cells. Our study uncovers a PML degradation mechanism through Notch/Hey1-induced repression of the PML deubiquitinase USP11 and suggests an important role for this pathway in brain tumour pathogenesis. PMID- 24487964 TI - TNF-alpha induces CXCL1 chemokine expression and release in human vascular endothelial cells in vitro via two distinct signaling pathways. AB - AIM: Chemokines usually direct the movement of circulating leukocytes to sites of inflammation or injury. CXCL1/GRO-alpha has been shown to be upregulated in atherosclerotic lesions and various cancers. The aim of this study was to investigate the mechanisms underlying the TNF-alpha-induced release of CXCL1 from human vascular endothelial cells in vitro. METHODS: Human umbilical vein endothelial cells (HUVECs) were treated with different proinflam-matory mediators and growth factors. CXCL1 expression and secretion were determined using RT-PCR and ELISA, respectively. TNF-alpha-induced cell signaling was assayed with Western blotting. Cell viability/growth was determined using MTT assay. Monocyte migration was measured with transwell migration assay. RESULTS: Among the 17 mediators and growth factors tested, TNF-alpha, LPS and thrombin induced marked increase in CXCL1 release from HUVEC cells. TNF-alpha (2, 5 ng/mL) induced CXCL1 release and mRNA expression in the cells in concentration- and time-dependent manners. TNF-alpha (5 ng/mL) caused activation of JNK, p38 MAPK, PI3K and Akt, whereas pretreatment with JNK inhibitor (SP600125), p38 MAPK inhibitor (SB202190) or PI-3K inhibitor (LY294002) significantly suppressed TNF-alpha-induced CXCL1 release from the cells. But only SP600125 significantly reduced TNF-alpha-induced CXCL1 mRNA expression in the cells. Moreover, dexamethasone (up to 500 nmol/L) failed to affect TNF-alpha-induced CXCL1 release from the cells. In functional studies, recombinant CXCL1 enhanced HUVEC proliferation, and both recombinant CXCL1 and TNF-alpha-induced CXCL1 from HUVECs attracted human monocyte migration. CONCLUSION: TNF-alpha stimulates CXCL1 release from human ECs through JNK mediated CXCL1 mRNA expression and p38 MAPK- and PI-3K-mediated CXCL1 secretory processes. PMID- 24487965 TI - Association of the polymorphisms of MMP-9 and TIMP-3 genes with thoracic aortic dissection in Chinese Han population. AB - AIM: Thoracic aortic dissection (TAD) is the most common life-threatening disorder, and a shifted balance of matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs) is involved in TAD pathogenesis. The aim of this study was to evaluate the association of 4 single-nucleotide polymorphisms (SNPs) in MMP-9 and TIMP-3 genes with TAD risk in Chinese Han population. METHODS: A total of 206 Chinese patients with TAD and 180 controls were included in this study. Four SNPs (rs3918249, rs2274756, rs9609643 and rs8136803) were genotyped using high-throughput MALDI-TOF mass spectrometry. Allele and genotype association analyses were conducted using PLINK. RESULTS: All the 4 SNPs resulted in Hardy-Weinberg equilibrium in patients and controls. The G allele frequency for the MMP-9 SNP rs2274756 was significantly higher in female TAD patients than in female controls (P=0.0099). Moreover, after adjusting for traditional cardiovascular risk factors (sex, age, hypertension, dyslipidemia, diabetes and smoking habit), the rs2274756 polymorphism (odds ratio: 0.30; 95% confidence interval: 0.11 to 0.79, P=0.015) resulted in an independent susceptibility factor for TAD in females. No associations were found between the other SNPs and TAD. CONCLUSION: The results provide strong evidence for an association between MMP-9 SNP rs2274756 and female TAD risk in Chinese Han population. PMID- 24487966 TI - Multi-algorithm and multi-model based drug target prediction and web server. AB - AIM: To develop a reliable computational approach for predicting potential drug targets based merely on protein sequence. METHODS: With drug target and non target datasets prepared and 3 classification algorithms (Support Vector Machine, Neural Network and Decision Tree), a multi-algorithm and multi-model based strategy was employed for constructing models to predict potential drug targets. RESULTS: Twenty one prediction models for each of the 3 algorithms were successfully developed. Our evaluation results showed that ~30% of human proteins were potential drug targets, and ~40% of putative targets for the drugs undergoing phase II clinical trials were probably non-targets. A public web server named D3TPredictor (http://www.d3pharma.com/d3tpredictor) was constructed to provide easy access. CONCLUSION: Reliable and robust drug target prediction based on protein sequences is achieved using the multi-algorithm and multi-model strategy. PMID- 24487967 TI - Correlation between serum CEA levels and EGFR mutations in Chinese nonsmokers with lung adenocarcinoma. AB - AIM: To evaluate the relationship between epidermal growth factor receptor (EGFR) mutations and serum carcinoembryonic antigen (CEA) levels in Chinese nonsmokers with pulmonary adenocarcinoma. METHODS: We sequenced exons 18-21 of the EGFR gene in 98 cases. The patients were divided into two groups based on their pre treatment serum CEA levels (below or above 5 ng/mL) for analyzing the correlations with EGFR mutations. RESULTS: Sixty-seven cases harbored EGFR mutations. The rates of EGFR mutations and exon 19 mutations in the high-CEA group (78.2% and 49.1%, respectively) were significantly higher those in the low CEA group (55.8% and 20.9%, respectively). Serum CEA levels were found to be the only independent predictor of EGFR mutation (OR 2.837; 95% CI: 1.178-6.829) and exon 19 mutation (OR 3.618; 95% CI: 1.319-9.918). Furthermore, a higher serum CEA level was associated with a higher EGFR mutation rate and a higher exon 19 mutation rate: patients with serum CEA levels <5 ng/mL, >=5 and <20 ng/mL, >=20 ng/mL showed the EGFR mutation rate of 55.8%, 74.1%, 82.1%, respectively, and the exon 19 mutation rate of 20.9%, 40.7%, 57.1%, respectively. Patients with EGFR mutations displayed a significantly higher incidence of abnormal serum CEA levels (>5 ng/mL) than patients without EGFR mutations (64.2% vs 38.7%). CONCLUSION: Elevated serum CEA levels predict the presence of EGFR gene mutations in Chinese nonsmokers with pulmonary adenocarcinoma. PMID- 24487968 TI - Curcumin derivative C817 inhibits proliferation of imatinib-resistant chronic myeloid leukemia cells with wild-type or mutant Bcr-Abl in vitro. AB - AIM: To find new kinase inhibitors that overcome the imatinib resistance in treatment of chronic myeloid leukemia (CML), we synthesized C817, a novel derivative of curcumin, and tested its activities against wild-type (WT) and imatinib-resistant mutant Abl kinases, as well as in imatinib-sensitive and resistant CML cells in vitro. METHODS: 32D cells harboring WT or mutant Abl kinases (nucleotide binding P-loop mutants Q252H, Y253F, and imatinib contact residue mutant T315I), as well as K562/G01 cells (with whole Bcr-Abl gene amplication) were tested. Kinase activity was measured using Kinase-Glo Luminescent Kinase Assay Platform in recombinant WT and mutant (Q252H, Y253F, and T315I) Abl kinases. Cell proliferation and apoptosis were examined using MTT assay and flow cytometry, respectively. The phosphorylation levels of Bcr-Abl initiated signaling proteins were analyzed using Western blotting. Colony forming units (CFU) growth and long term culture-initiating cells (LTC-ICs) were used to test the effects of C817 on human leukemia progenitor/stem cells. RESULTS: C817 potently inhibited both WT and mutant (Q252H, Y253F, and T315I) Abl kinase activities in a non-ATP competitive manner with the values of IC50 at low nanomole levels. In consistent with above results, C817 suppressed the growth of both imatinib-sensitive and resistant CML cells, including wild-type K562, K562/G01, 32D-T315I, 32D-Q252H, and 32D-Y253F cells with the values of IC50 at low micromole levels. C817 (0.5 or 1 MUmol/L) dose-dependently inhibited the phosphorylation of Bcr-Abl and downstream proteins STAT-5 and CrkL in imatinib resistant K562/G01 cells. Furthermore, C817 significantly suppressed CFU growth and LTC-ICs, implicating that C817 could eradiate human leukemia progenitor/stem cells. CONCLUSION: C817 is a promising compound for treatment of CML patients with Bcr-Abl kinase domain mutations that confer imatinib resistance. PMID- 24487970 TI - Genomic analysis of a girl with incontinentia pigmenti but without NEMO mutation. PMID- 24487971 TI - Phenotypic features of diploid/triploid mosaicism in an adult. PMID- 24487969 TI - Isothiafludine, a novel non-nucleoside compound, inhibits hepatitis B virus replication through blocking pregenomic RNA encapsidation. AB - AIM: To investigate the action of isothiafludine (NZ-4), a derivative of bis heterocycle tandem pairs from the natural product leucamide A, on the replication cycle of hepatitis B virus (HBV) in vitro and in vivo. METHODS: HBV replication cycle was monitored in HepG2.2.15 cells using qPCR, qRT-PCR, and Southern and Northern blotting. HBV protein expression and capsid assembly were detected using Western blotting and native agarose gel electrophoresis analysis. The interaction of pregenomic RNA (pgRNA) and the core protein was investigated by RNA immunoprecipitation. To evaluate the anti-HBV effect of NZ-4 in vivo, DHBV infected ducks were orally administered NZ-4 (25, 50 or 100 mg.kg-1.d-1) for 15 d. RESULTS: NZ-4 suppressed intracellular HBV replication in HepG2.2.15 cells with an IC50 value of 1.33 MUmol/L, whereas the compound inhibited the cell viability with an IC50 value of 50.4 MUmol/L. Furthermore, NZ-4 was active against the replication of various drug-resistant HBV mutants, including 3TC/ETV dual-resistant and ADV-resistant HBV mutants. NZ-4 (5, 10, 20 MUmol/L) concentration-dependently reduced the encapsidated HBV pgRNA, resulting in the assembly of replication-deficient capsids in HepG2.2.15 cells. Oral administration of NZ-4 dose-dependently inhibited DHBV DNA replication in the DHBV-infected ducks. CONCLUSION: NZ-4 inhibits HBV replication by interfering with the interaction between pgRNA and HBcAg in the capsid assembly process, thus increasing the replication-deficient HBV capsids. Such mechanism of action might provide a new therapeutic strategy to combat HBV infection. PMID- 24487973 TI - Assessing trichloromethane formation and control in algal-stimulated waters amended with nitrogen and phosphorus. AB - Nitrogen (N) and phosphorus (P) enrichments can stimulate algal growth in drinking water sources, which can cause increased production of disinfection byproduct (DBP) precursors. However, the effect of systematic N and P enrichments on DBP formation and control has not been adequately studied. In this work, we enriched samples from a drinking water source - sampled on April 5, May 30, and August 19, 2013 - with N and P to stimulate algal growth at N : P ratios covering almost five orders of magnitude (0.2-4429). To simulate DBP-precursor removal processes at drinking water treatment plants (DWTPs), the samples were treated with ClO2 followed by alum coagulation prior to free chlorine addition to assess the DBP formation potential (FP). Trichloromethane (TCM) was the predominant DBP formed and the TCMFP was the highest at intermediate N : P molar ratios (~10 to 50), which corresponded with the peak in algal biomass, as measured by chlorophyll-a (Chl-a). Algal biomass was P-limited throughout the study period, and co-limited by N for the August 19 sampling set. The differences in TCMFP between the raw and treated waters decreased with increasing P amendment, indicating that ClO2 and alum coagulation became less effective for TCM precursor removal as algal biomass increased. This study highlights the impact of nutrient enrichments on TCM formation and control and has implications for nutrient management strategies related to source water protection and for DWTPs that use source waters increasingly enriched with N and P. PMID- 24487974 TI - Outcomes following removal of instrumentation after posterior spinal fusion. AB - BACKGROUND: Although there is good evidence to support the removal of instrumentation for infection following posterior spine fusion, there are few studies that report outcomes following removal for late operative site pain. The purpose of this study was 3-fold: (1) to determine whether removal of instrumentation following posterior spinal fusion resolves preoperative pain, (2) to determine whether indolent infection not detected before removal of instrumentation is related to late operative site pain, and (3) to determine whether curve progression differs when spinal hardware is removed for infection versus late operative site pain. METHODS: A retrospective study of consecutive patients aged 10 to 21 years, who underwent removal of instrumentation after posterior spinal fusion over a 10-year-period was conducted. Patient demographics, preoperative and postoperative imaging results, laboratory studies, and operative findings were reviewed. All patients had a minimum 2-year follow up. Statistical analysis was performed using 2-sample t test, bivariate analysis, and multivariate logistic regression models. RESULTS: Seventy-five patients were included. Indications for removal of spinal instrumentation were pain (57%), infection (28%), hardware failure (8%), and prominent hardware (7%). The mean time from index procedure to hardware removal was 2.8 years. The average loss of curve correction following complete hardware removal was 23.1 degrees. Patients who underwent removal of hardware because of infection had bigger changes in their curves than those without infection (mean, 33.8 degrees vs. 18.8 degrees). Of the 43 patients with pain, only 40% reported relief of their symptoms following removal of hardware. Sixteen of the 43 patients were found to have indolent infection confirmed by positive intraoperative culture results. CONCLUSIONS: Patients should be cautioned that hardware removal after posterior spinal fusion may not provide complete pain relief. Furthermore, there is risk for curve progression following removal of instrumentation, particularly in the setting of infection. Back pain may be an indicator of infection, and intraoperative cultures should be taken at the time of implant removal. LEVEL OF EVIDENCE: Level IV; retrospective case series. PMID- 24487975 TI - Plantar pressures following anterior tibialis tendon transfers in children with clubfoot. AB - BACKGROUND: Relapses following nonoperative treatment for clubfoot occur in 29% to 37% of feet after initial correction. One common gait abnormality is supination and inversion of the foot caused by an imbalance of the anterior tibialis tendon muscle. The purpose of this study was to determine if plantar pressures are normalized following an anterior tibialis tendon transfer (ATTT). METHODS: Thirty children (37 clubfeet) who underwent an ATTT, were seen for plantar pressure testing preoperatively and postoperatively. Each foot was subdivided into 7 regions: medial/lateral hindfoot and midfoot, and the forefoot (first, second, and third to fifth metatarsal heads). Variables included: contact time as a percentage of stance time (CT%), contact area as a percentage of the total foot (CA%), peak pressure (PP), hindfoot-forefoot angle (H-F), location of initial contact, and deviation of the center-of-pressure line (COP). Paired t tests were used for group comparisons, whereas multiple comparisons were assessed with ANOVA (alpha set to 0.05 with Bonferroni correction). RESULTS: Significant changes were seen in preoperative to postoperative comparison. PP, CT%, and CA% had significant increases in the medial hindfoot, midfoot, and first metatarsal regions, whereas the involvement of the lateral midfoot and forefoot were reduced. Compared with controls, postoperative results following ATTT continue to show increased PP, CA%, and CT% in the lateral midfoot, increased CA% and CT% in the lateral forefoot, whereas CA% was decreased in the first metatarsal region. Compared with controls, the COP line continues to move laterally and the H-F angle continues to show forefoot adductus following ATTT. No differences were found between patients treated with an isolated ATTT and those treated with concomitant procedures. CONCLUSIONS: The changes seen in plantar pressures following ATTT would suggest that the foot is better aligned for a more even distribution of pressure throughout the foot, but is not fully normalized. LEVEL OF EVIDENCE: Therapeutic level II. PMID- 24487976 TI - CNS Schwann cells display oligodendrocyte precursor-like potassium channel activation and antigenic expression in vitro. AB - Central nervous system (CNS) injury triggers production of myelinating Schwann cells from endogenous oligodendrocyte precursors (OLPs). These CNS Schwann cells may be attractive candidates for novel therapeutic strategies aiming to promote endogenous CNS repair. However, CNS Schwann cells have been so far mainly characterized in situ regarding morphology and marker expression, and it has remained enigmatic whether they display functional properties distinct from peripheral nervous system (PNS) Schwann cells. Potassium channels (K+) have been implicated in progenitor and glial cell proliferation after injury and may, therefore, represent a suitable pharmacological target. In the present study, we focused on the function and expression of voltage-gated K+ channels Kv(1-12) and accessory beta-subunits in purified adult canine CNS and PNS Schwann cell cultures using electrophysiology and microarray analysis and characterized their antigenic phenotype. We show here that K+ channels differed significantly in both cell types. While CNS Schwann cells displayed prominent K D-mediated K+ currents, PNS Schwann cells elicited K(D-) and K(A-type) K+ currents. Inhibition of K+ currents by TEA and Ba2+ was more effective in CNS Schwann cells. These functional differences were not paralleled by differential mRNA expression of Kv(1-12) and accessory beta-subunits. However, O4/A2B5 and GFAP expressions were significantly higher and lower, respectively, in CNS than in PNS Schwann cells. Taken together, this is the first evidence that CNS Schwann cells display specific properties not shared by their peripheral counterpart. Both Kv currents and increased O4/A2B5 expression were reminiscent of OLPs suggesting that CNS Schwann cells retain OLP features during maturation. PMID- 24487977 TI - Genetic mapping of a putative Thinopyrum intermedium-derived stripe rust resistance gene on wheat chromosome 1B. AB - KEY MESSAGE: Stripe rust resistance transferred from Thinopyrum intermedium into common wheat was controlled by a single dominant gene, which mapped to chromosome 1B near Yr26 and was designated YrL693. Stripe rust caused by Puccinia striiformis f. sp. tritici (Pst) is a highly destructive disease of wheat (Triticum aestivum). Stripe rust resistance was transferred from Thinopyrum intermedium to common wheat, and the resulting introgression line (L693) exhibited all-stage resistance to the widely virulent and predominant Chinese pathotypes CYR32 and CYR33 and to the new virulent pathotype V26. There was no cytological evidence that L693 had alien chromosomal segments from Th. intermedium. Genetic analysis of stripe rust resistance was performed by crossing L693 with the susceptible line L661. F(1), F(2), and F(2:3) populations from reciprocal crosses showed that resistance was controlled by a single dominant gene. A total 479 F(2:3) lines and 781 pairs of genomic simple sequence repeat (SSR) primers were employed to determine the chromosomal location of the resistance gene. The gene was linked to six publicly available and three recently developed wheat genomic SSR markers. The linked markers were localized to wheat chromosome 1B using Chinese Spring nulli-tetrasomic lines, and the resistance gene was localized to chromosome 1B based on SSR and wheat genomic information. A high-density genetic map was also produced. The pedigree, molecular marker data, and resistance response indicated that the stripe rust resistance gene in L693 is a novel gene, which was temporarily designated YrL693. The SSR markers that co segregate with this gene (Xbarc187-1B, Xbarc187-1B-1, Xgwm18-1B, and Xgwm11-1B) have potential application in marker-assisted breeding of wheat, and YrL693 will be useful for broadening the genetic basis of stripe rust resistance in wheat. PMID- 24487978 TI - Cyane-carvone, a synthetic derivative of carvone, inhibits inflammatory response by reducing cytokine production and oxidative stress and shows antinociceptive effect in mice. AB - Cyane-carvone (CC) was studied to elucidate its anti-inflammatory, antinociceptive, and antioxidant effects in Mus musculus. Anti-inflammatory (bradykinin, histamine, prostaglandin E2, serotonin, and carrageenan) and antinociceptive (acetic acid and formalin) models were utilized. Myeloperoxidase activity, interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), and glutathione (GSH) levels were evaluated. Analysis of variance followed by Student Newman-Keuls' test was done. Results were compared with control groups (significantly when p < 0.05). In bradykinin, histamine, prostaglandin E2, and serotonin tests, 75 mg/kg CC decreased significantly paw edema (t = 30, 60, 90, and/or 120 min). In carrageenan test, 50 and 75 mg/kg CC (t = 3 h and t = 4 h) and 25 mg/kg CC (t = 4 h) decreased significantly paw edema. CC (75 mg/kg) inhibited significantly mieloperoxidase activity and decreased IL-1beta and TNF alpha, and all doses increased GSH levels. CC (75 mg/kg) decreased significantly the number of contortions of animals and time of licking (phase 2). CC showed anti-inflammatory, antinociceptive, and antioxidant effects in mice. PMID- 24487979 TI - IL-25 promotes Th2 immunity responses in airway inflammation of asthmatic mice via activation of dendritic cells. AB - Allergic asthma occurs as a consequence of inappropriate immunologic inflammation to allergens and characterized by Th2 adaptive immune response. Recent studies indicated that interleukin (IL)-25, a member of the IL-17 cytokine family, had been implicated in inducing Th2 cell-dependent inflammation in airway epithelium and IL-25-deficient mice exhibit impaired Th2 immunity responses; however, how these cytokines influence innate immune responses remains poorly understood. In this study, we used ovalbumin (OVA) sensitization and challenge to induce the murine asthmatic model and confirmed by histological analysis of lung tissues and serum levels of total and OVA-specific immunoglobulin (Ig)-E. The expression of IL-25 was detected by quantitative real-time PCR and immunohistochemistry, respectively, and the dendritic cells (DCs) activation was detected by levels of CD80 and CD86 in bronchoalveolar lavage fluid (BALF) by flow cytometry. The mice sensitized and challenged with OVA showed high expression of IL-25 in both mRNA and protein levels in lungs. We detected the expression of CD80 and CD86 in BALF was also increased. A tight correlation between IL-25 mRNA and other Th2 cells producing cytokines such as IL-4, IL-5, and IL-13 in BALF was identified. Furthermore, when the asthmatic mice were treated with inhaled corticosteroids, the inflammatory cells infiltration and the inflammatory cytokines secretion were significantly decreased. In this study, we show that IL-25 promoted the accumulation of co-stimulatory molecules of CD80 and CD86 on DCs and then induced the differentiation of prime naive CD4(+) T cells to become proinflammatory Th2 cells and promoted Th2 cytokine responses in OVA-induced airway inflammation. The ability of IL-25 to promote the activation and differentiation of DCs population was identified as a link between the IL-17 cytokine family and the innate immune response and suggested a previously unrecognized innate immune pathway that promotes Th2 cytokine responses in asthmatic airway inflammation. Inhaled corticosteroids might be capable of inhibiting the promotion of IL-25 and present a promising strategy for the treatment of asthma. PMID- 24487980 TI - Polymorphisms in the RAC1 gene are associated with hypertension risk factors in a Chilean pediatric population. AB - BACKGROUND: The GTPase Rac1 has been implicated in hypertension as a modulator of mineralocorticoid receptor activity. Our aim is to investigate the frequency of polymorphisms rs10951982 (intron 1, G>A) and rs836478 (intron 3, T>C) in the RAC1 gene and perform association studies with clinical and biochemical parameters in a Chilean pediatric cohort. METHODS: Two hundred two normotensive (NT) subjects (aged 4-16 years) were divided into 2 groups: NT subjects with hypertensive parents (NH; n = 103) and NT subjects with NT parents (NN; n = 99). We measured markers of inflammation (high-sensitivity C-reactive protein, interleukin 6 (IL 6), interleukin 8, and tumor necrosis factor alpha), endothelial damage (Plasminogen activator inhibitor-1 metalloproteinase-9, and metalloproteinase-2), and oxidative stress (malondialdehyde). Data were expressed as median and interquartile range (IQR). RESULTS: We found differences in polymorphism rs836478 (intron 3, C>T) in both genotypic (chi(2) = 15.2, 2 df; P = 0.0005) and allelic (X(2)=5.5, 1 df; P = 0.01) frequencies in NH vs. NN subjects. NH subjects with a TT genotype showed increase MMP9 expression (median = 2.3, IQR - 1.6-3.2; vs. median = 1.6, IQR = 1.6-2.3 AU; P = 0.01) and lower IL-6 expression (median = 8.8, IQR = 7.0-11.8; vs. median = 12.1, IQR = 8.2-14.7 pg/ml; P = 0.02) compared with subjects with TC/CC genotype. No difference in the allelic frequency distribution was seen in the polymorphism rs10951982 (NH vs. NN: chi(2)=0.2, 1 df; P = 0.6). For this SNP, NN subjects with GA/AA genotype showed decreased diastolic BP indexes compared with subjects with native GG genotype (median = 1.08, IQR = 1.0-1.2; vs. median = 0.99, IQR = 0.94-1.1; P = 0.02). CONCLUSIONS: We report the frequency of polymorphisms rs836478 and rs10951982 of the RAC1 gene in a Spanish-Amerindian cohort. The polymorphism rs836478 was associated with an increased expression in markers of inflammation and endothelial damage (MMP9 and IL-6) in pediatric subjects with a hypertensive genetic background. PMID- 24487981 TI - Sleep duration and its association with ambulatory blood pressure in a school based, diverse sample of adolescents. AB - BACKGROUND: Evidence is accumulating that sleep duration is related to blood pressure (BP) and hypertensive status, but the strength of the association varies by age, and findings are inconsistent for adolescents. This cross-sectional study tested the hypothesis that sleep duration, both during the night and during naps, would be negatively associated with ambulatory systolic BP (SBP) and diastolic BP (DBP) measured over 24 hours in adolescents. METHODS: In this ethnically diverse (37% non-Hispanic black, 31% Hispanic, 29% non-Hispanic white, 3% other), school based sample of 366 adolescents aged 11-16 years, ambulatory BP was measured every 30 minutes for 24 hours on a school day; actigraphy was used to measure sleep duration. Covariables included demographic factors, anthropometric indices, physical activity, and position and location at the time of each BP measurement. Mixed models were used to test day and night sleep duration as predictors of 24 hour SBP and DBP, controlling for covariables. RESULTS: The mean sleep duration was 6.83 (SD = 1.36) hours at night, and 7.23 (SD = 1.67) hours over 24 hours. Controlling for duration of sleep during the day and covariables, each additional hour of nighttime sleep was associated with lower SBP (-0.57; P < 0.0001); controlling for nighttime sleep duration and covariables, each additional hour of daytime sleep was associated with lower SBP (-0.73; P < 0.001) and lower DBP ( 0.50; P < 0.001). CONCLUSIONS: Longer sleep duration was significantly associated with lower ambulatory SBP and DBP in adolescents. The findings have potential implications for cardiovascular health in this age group. PMID- 24487982 TI - Leptin in association with common variants of MC3R mediates hypertension. AB - BACKGROUND: Recent research illustrates the role of central melanocortin signaling and leptin in the regulation of arterial blood pressure in animal models. Unraveling the genetic basis of interactions between melanocortin and leptin in humans will provide new insight into the regulation of arterial pressure. METHOD: Our study population consisted of 332 Kuwaiti natives. Polymorphisms from exons of leptin, MC3R, and MC4R genes were identified by Sanger sequencing. MC3R expression and leptin levels were determined. Linear regression models, adjusted for age, gender, antihypertensive medication, and body mass index, were used to perform statistical association tests. RESULTS: We observed a significant association between the MC3R missense variant (rs3827103 [Val81 Ile]) and systolic blood pressure (SBP; P = 0.01, beta = 4.9). The N terminus variant (rs3746619 [Thr6->Lys]) is in linkage disequilibrium (r2 = 0.65) with the rs3827103 variant. The AA haplotype of rs3746619-rs3827103 is significantly associated with SBP (P = 0.005, beta=5.03). Minor allele frequencies of these two variants in the Kuwaiti population are twice those seen in European population. In individuals who harbor these variants, we found that the plasma leptin levels were positively correlated with SBP and that the expression of MC3R was downregulated. Leptin levels correlated with obesity traits irrespective of the genotypes at the variant positions. CONCLUSION: An increase in leptin levels is known to increase sympathetic nerve activity that, in turn, increases blood pressure. Thus, it is possible that the observed MC3R variants in association with leptin levels are involved in regulation of blood pressure in humans. PMID- 24487983 TI - Genetic predisposition of RSV infection-related respiratory morbidity in preterm infants. AB - The aim of this study was to assess whether prematurely born infants have a genetic predisposition to respiratory syncytial virus (RSV) infection-related respiratory morbidity. One hundred and forty-six infants born at less than 36 weeks of gestation were prospectively followed. Nasopharygeal aspirates were obtained on every occasion the infants had a lower respiratory tract infection (LRTI) regardless of need for admission. DNA was tested for 11 single-nucleotide polymorphisms (SNPs). Chronic respiratory morbidity was assessed using respiratory health-related questionnaires, parent-completed diary cards at a corrected age of 1 year and review of hospital notes. Lung function was measured at a post menstrual age (PMA) of 36 weeks and corrected age of 1 year. A SNP in ADAM33 was associated with an increased risk of developing RSV LRTIs, but not with significant differences in 36-week PMA lung function results. SNPs in several genes were associated with increased chronic respiratory morbidity (interleukin 10 (IL10), nitric oxide synthase 2A (NOS2A), surfactant protein C (SFTPC), matrix metalloproteinase 16 (MMP16) and vitamin D receptor (VDR)) and reduced lung function at 1 year (MMP16, NOS2A, SFTPC and VDR) in infants who had had RSV LRTIs. CONCLUSIONS: Our results suggest that prematurely born infants may have a genetic predisposition to RSV LRTIs and subsequent respiratory morbidity which is independent of premorbid lung function. PMID- 24487984 TI - Atomoxetine resulting in Takotsubo syndrome: is the locally-released norepinephrine from the autonomic sympathetic cardiac nerves or the blood-borne catecholamines the cause? PMID- 24487985 TI - Construction and application of an intelligent air quality monitoring system for healthcare environment. AB - Indoor air quality monitoring in healthcare environment has become a critical part of hospital management and policy. Manual air sampling and analysis are cost inhibitive and do not provide real-time air quality data and response measures. In this month-long study over 14 sampling locations in a public hospital in Taiwan, we observed a positive correlation between CO(2) concentration and population, total bacteria, and particulate matter concentrations, thus monitoring CO(2) concentration as a general indicator for air quality could be a viable option. Consequently, an intelligent environmental monitoring system consisting of a CO(2)/temperature/humidity sensor, a digital plug, and a ZigBee Router and Coordinator was developed and tested. The system also included a backend server that received and analyzed data, as well as activating ventilation and air purifiers when CO(2) concentration exceeded a pre-set value. Alert messages can also be delivered to offsite users through mobile devices. PMID- 24487986 TI - [Validity of instrument development research in korean nursing research]. AB - PURPOSE: This integrative review study was done to analyze methods used for validation studies in Korean nursing research. METHODS: In this study, the literature on instrument development in nursing research from Research Information Sharing Service (RISS) and major nursing journal databases in Korea were examined. The MeSH search terms included 'nursing', 'instrument', 'instrument development', 'validation' and 189 articles were included in the review. RESULTS: The most frequently reported validity type was content validity, followed by construct validity, and criterion validity. One third reported a single type of validity, and 15% of the studies demonstrated three kinds of validity at the same time. In about 40% of the studies, both content and construct validity were examined. CONCLUSION: The results of the study indicate that it is necessary to provide a wider variety of evidence to establish whether instruments are valid enough to use in nursing research. PMID- 24487987 TI - [Mothers' parenting experience of premature infants: Q methodological approach]. AB - PURPOSE: This study was done to identify the parenting experience of mothers of premature infants in order to provide basic data for educational solutions and desirable directions. METHODS: Q-methodology was used as it provides a method of analyzing the subjectivity of each item. The participants were 33 mothers of premature infants who sorted 34 selected Q-statements which were then classified into the shape of a normal distribution using a 9-point scale. Subjectivity on parenting experience among the mothers was analyzed using the pc-QUANAL program. RESULTS: Four types of parenting experience were identified. Type I was named 'struggling', type II, 'self blame', type III, 'information collecting', and type IV, 'self-introspection'. CONCLUSION: The results of this study indicate that different approaches to educational programs are needed for mothers of premature infants based on the four types of parenting experience. PMID- 24487988 TI - [Construction of the addiction prevention core competency model for preventing addictive behavior in adolescents]. AB - PURPOSE: This study was done to provide fundamental data for the development of competency reinforcement programs to prevent addictive behavior in adolescents through the construction and examination of an addiction prevention core competency model. METHODS: In this study core competencies for preventing addictive behavior in adolescents through competency modeling were identified, and the addiction prevention core competency model was developed. It was validated methodologically. RESULTS: Competencies for preventing addictive behavior in adolescents as defined by the addiction prevention core competency model are as follows: positive self-worth, self-control skill, time management skill, reality perception skill, risk coping skill, and positive communication with parents and with peers or social group. After construction, concurrent cross validation of the addiction prevention core competency model showed that this model was appropriate. CONCLUSION: The study results indicate that the addiction prevention core competency model for the prevention of addictive behavior in adolescents through competency modeling can be used as a foundation for an integral approach to enhance adolescent is used as an adjective and prevent addictive behavior. This approach can be a school-centered, cost-efficient strategy which not only reduces addictive behavior in adolescents, but also improves the quality of their resources. PMID- 24487989 TI - [Effects of aroma massage on pruritus, skin pH, skin hydration and sleep in elders in long-term care hospitals]. AB - PURPOSE: The purpose of this study was to examine the effects of aroma massage on pruritus, skin pH, skin hydration and sleep in elders in long-term care hospitals. METHODS: The participants were elders over 65 years old admitted to long-term care. They were assigned to the experimental group (26) or control group (28). Data were collected from May to August, 2012. Visual Analogue Scale and Verran and Snyder-Halpern Sleep scale were used to identify levels of pruritus and sleep. A skin-pH meter and moisture checker were used to measure skin pH and skin hydration. Aroma massage was performed three times a week for 4 weeks for elders in the experimental group. The data were analyzed using the SPSS Win 17.0 program. RESULTS: There were significant differences in pruritus, skin pH and skin hydration between the two groups. However there was no significant difference in sleep. CONCLUSION: The results indicate that aroma massage is effective in reducing pruritus, skin pH and increasing skin hydration in elders. Therefore, this intervention can be utilized in clinical practice as an effective nursing intervention to reduce pruritus in elders in long-term care hospitals. PMID- 24487990 TI - [A quality assessment of meta-analyses of nursing in South Korea]. AB - PURPOSE: The purpose of the study was to assess the quality of meta-analyses on nursing published in South Korea. METHODS: Relevant meta-analyses were identified through searches of the National Assembly Library, KISS (Korean Studies Information Service System), and the DBpia and RISS4U databases from 1990 to May 2013. Quality assessments were conducted using AMSTAR, a validated tool for assessing the quality of systematic reviews. RESULTS: Forty-two meta-analyses were included in this study. Twenty-nine published between 1990 and 2010, and 13, between 2011 and May 2013. Two high quality studies and 11 moderate quality studies were published in the latter period. The mean score for the reviews was 5.61 (range 3-10); 11 studies were rated as low quality, 29 as moderate quality, and two as high quality. CONCLUSION: Although an improvement in the quality of meta-analyses conducted by nursing researchers in South Korea was observed across the study period, the study results indicate a need to use of more rigorous research methods when conducting systematic reviews or meta-analyses. PMID- 24487991 TI - [Systematic review and meta-analyses of diagnostic accuracy of infrared thermometer when identifying fever in children]. AB - PURPOSE: Infrared thermometers are increasingly used as a convenient, non invasive assessment method for febrile children. However, the diagnostic accuracy of the infrared thermometer for children has been questioned, particularly in relation to sensitivity and specificity. The aim of this study was to evaluate diagnostic accuracy of infrared thermometers in febrile children. METHODS: Articles published between 1966 and 2012 from periodicals indexed in the Ovid Medline, Embase, CINAHL, Cochrane, KoreaMed, NDSL, KERIS and other databases were selected, using the following keywords: 'infrared thermometer'. The QUADAS-II was applied to assess the internal validity of the diagnostic studies. Selected studies were analyzed using meta-analysis with MetaDisc 1.4. RESULTS: Nineteen diagnostic studies with high methodological quality, involving 4,304 children, were included. The results of meta-analysis showed that the pooled sensitivity, specificity and AUC (Area Under the Curve) of infrared tympanic thermometers in children over 1 year were 0.80 (95% CI 0.78, 0.81), 0.94 (95% CI 0.93, 0.95) and 0.95 respectively. However the diagnostic accuracy of infrared tympanic thermometers in children with hyperthermia was low. CONCLUSION: The diagnostic accuracy of infrared tympanic thermometer was similar to axillary and rectal thermometers indicating a need for further research to substantiate these findings in children with hyperthermia. PMID- 24487992 TI - [Factors associated with physical activity among Chinese immigrant women]. AB - PURPOSE: This study was done to assess the level of physical activity among Chinese immigrant women and to determine the relationships of physical activity with individual characteristics and behavior-specific cognition. METHODS: A cross sectional descriptive study was conducted with 161 Chinese immigrant women living in Busan. A health promotion model of physical activity adapted from Pender's Health Promotion Model was used. Self-administered questionnaires were used to collect data during the period from September 25 to November 20, 2012. Using SPSS 18.0 program, descriptive statistics, t-test, analysis of variance, correlation analysis, and multiple regression analysis were done. RESULTS: The average level of physical activity of the Chinese immigrant women was 1,050.06 +/- 686.47 MET min/week and the minimum activity among types of physical activity was most dominant (59.6%). As a result of multiple regression analysis, it was confirmed that self-efficacy and acculturation were statistically significant variables in the model (p<.001), with an explanatory power of 23.7%. CONCLUSION: The results indicate that the development and application of intervention strategies to increase acculturation and self-efficacy for immigrant women will aid in increasing the physical activity in Chinese immigrant women. PMID- 24487993 TI - [Analysis of factors affecting unmet healthcare needs of married immigrant women]. AB - PURPOSE: The purpose of this study was to identify the factors affecting the unmet healthcare needs of married immigrant women. METHODS: This study was a secondary data analysis using data from the 2009 National Survey of Multicultural Families. Data collected from 58,735 married immigrant women who had spouses were analyzed using descriptive statistics, Chi-square test, and logistic regression. RESULTS: Overall, 9.9% of married immigrant women have unmet healthcare needs. The significant predictors related to unmet healthcare needs were young age, high level of education, employed, country of origin, long period of residence, low income, uninsured, urban area, low level of subjective health status, and illness experience over past two weeks. In particular, four variables (long period of residence, low income, subjective health status, and illness experience over past two weeks) significantly predicted unmet healthcare needs for women from all countries of origin. CONCLUSION: The results of the study indicate that common predictors related to unmet healthcare needs of married immigrant women are a long period of residence, low income, subjective health status, and illness experience over past two weeks. Therefore intervention strategies to decrease unmet healthcare needs should focus on these significant predictors. PMID- 24487994 TI - [Experience in acceptance of hospice by patients with terminal cancer: a phenomenological research]. AB - PURPOSE: The purpose of this study was to further understanding of the experience in acceptance of hospice by patients with terminal cancer and to explore the structure of this experience. METHODS: A phenomenological methodology was used for the study. Participants were nine patients who were admitted to the hospice unit of a university hospital. In-depth interviews were done for data collection and the data were analyzed using Colaizzi's method. RESULTS: Four categories, eight theme clusters and 18 themes were identified for the experience in acceptance of hospice by patients with terminal cancer. The three categories were 'Hope for a comfortable death', 'Overcoming barrier of prejudice about hospice', 'Incessant craving for life', 'The last consideration for self and family'. CONCLUSION: While accepting the hospice care, participants experienced inner conflict between giving up medical treatments that prolong life and choosing a comfortable death, and also experienced an incessant craving for life. By accepting hospice care, they showed a human dignity that entails careful concerns for both self and family members. PMID- 24487995 TI - [Structural equation modeling on case management outcomes and factors influencing outcomes in the community-dwelling vulnerable elders]. AB - PURPOSE: This study was done to test a structural equation modeling of case management outcomes in order to identify parameters affecting case management outcomes for the community-dwelling vulnerable elders. METHODS: Data were collected from 309 nurses (case managers) and community-dwelling vulnerable elders (clients) from public health centers. For data analysis, descriptive statistics, Pearson correlation analysis, factor analysis, and covariance structure analysis were performed using SPSS Version 18.0 for Windows and Amos 16.0. RESULTS: The hypothetical model had an acceptable fit: GFI=.97, CFI=.95, RMSEA=.02, SRMR=.05. The factor "case managers' singularity" had the greatest impact on case management outcomes in this model. In addition, the factor "case management practice" influenced case management outcomes; however, client characteristics did not. Case managers' singularity affected case management outcomes directly and indirectly, with case management practice mediating the latter effect. CONCLUSION: These results suggest that the causal relationship between case management outcomes and factors influencing these outcomes should be clarified through longitudinal research including a variety of client characteristics. In addition, in future studies, analysis of the effects of programs to improve manpower quality and examine the relationships among case management outcomes should be done. PMID- 24487996 TI - [Changes in quality of life and related factors in thyroid cancer patients with radioactive iodine remnant ablation]. AB - PURPOSE: To investigate changes in Quality of life (QOL) and related factors in patients with thyroid cancer undergoing Radioactive Iodine remnant ablation (RAI). METHODS: Data were collected longitudinally 3 times for 6 months (2 weeks post-surgery, post RAI, 3 months post RAI) in a hospital located in Seoul. Questionnaires were used to measure levels of physical symptoms, anxiety, depression, and QOL. Ninety-eight patients with thyroid cancer who had RAI were included in the analysis. Data were analyzed using SPSS (18.0). RESULTS: Findings for the three data collection times respectfully were: mean scores for physical symptoms, 0.53, 1.21 and 0.62, patients with depression, 47%, 36.7% and 37.7%, patients with anxiety, 18.4%, 19.4% and 20.4%, mean scores for QOL, 7.06, 7.01 and 7.28. QOL score was highest 3 months post RAI (p=.031). In the stepwise multiple regression analysis, depression and fatigue were predicting factors for low QOL at all data collection times. Dysponia was a predicting factor for low QOL post RAI and 3 months post RAI. CONCLUSION: To increase QOL, it is necessary to provide information in advance regarding physical & psychological symptoms and to develop nursing intervention programs to decrease depression and fatigue. PMID- 24487997 TI - [Structural relationship of burnout and related variables among family caregivers of cancer patients]. AB - PURPOSE: The purpose of this study was to construct a structural equational model to explain and predict burnout in family caregivers of patients with cancer. The study was based on the Stress-Appraisal-Coping Model of Lazarus and Folkman (1984) and Family Stress Theory (Hill, 1958). METHODS: Data were collected from July 10 to September 30, 2012 through direct interviews and a self-report questionnaire survey. Participants in this study were 206 family caregivers providing care for patients with cancer in In-patient or Out-patient departments of three different general hospitals located in Busan. Measured variables were exogenous variables (social support and perceived health status) and endogenous variables (perceived stress, hope and burnout). RESULTS: Goodness of fit in the hypothetical model was chi2=174.07, TLI=.95, CFI=.97, RMSEA=.08. Perceived health status, perceived stress, and hope showed statistically significant direct effects on burnout of family caregivers. Social support affected burnout of family caregivers indirectly. These variables explained 68.5% of total variance in burnout. CONCLUSION: The results from this study suggest that perceived stress, perceived health status, and hope should be considered as major influential factors when developing nursing interventions to control burnout of family caregivers (of patients with cancer). PMID- 24488000 TI - Real-Time Retinal Vessel Mapping and Localization for Intraocular Surgery. AB - Computer-aided intraocular surgery requires precise, real-time knowledge of the vasculature during retinal procedures such as laser photocoagulation or vessel cannulation. Because vitreoretinal surgeons manipulate retinal structures on the back of the eye through ports in the sclera, voluntary and involuntary tool motion rotates the eye in the socket and causes movement to the microscope view of the retina. The dynamic nature of the surgical workspace during intraocular surgery makes mapping, tracking, and localizing vasculature in real time a challenge. We present an approach that both maps and localizes retinal vessels by temporally fusing and registering individual-frame vessel detections. On video of porcine and human retina, we demonstrate real-time performance, rapid convergence, and robustness to variable illumination and tool occlusion. PMID- 24487999 TI - Profiling of phospho-AKT, phospho-mTOR, phospho-MAPK and EGFR in non-small cell lung cancer. AB - Activation of numerous pathways has been documented in non-small cell lung cancer (NSCLC). Epidermal growth factor receptor (EGFR) has emerged as a common therapeutic target. The mitogen-activated protein kinase (MAPK) and AKT signaling pathways are downstream of EGFR and deregulated via genetic and epigenetic mechanisms in many human cancers. We evaluated selected markers in the EGFR pathway with reference to outcome. Tissues from 220 cases of NSCLC patients presented in a tissue microarray were assayed with immunohistochemistry for phosphorylated AKT, phosphorylated MAPK, phosphorylated mTOR, and EGFR and then quantified by automated image analysis. Individually, the biomarkers did not predict. Combined as ratios, p-mTOR/p-AKT, and p-MAPK/EGFR function as prognostic markers of survival (p=0.008 and p=0.029, respectively), however, no significance was found after adjustment (p=0.221, p=0.103). The sum of these ratios demonstrates a stronger correlation with survival (p<0.001) and remained statistically significant after adjustment (p=0.026). The algebraic combination of biomarkers offer the capacity to understand factors that predict outcome better than current approaches of evaluating biomarkers individually or in pairs. Our results show the sum of p-mTOR/p-AKT and p-MAPK/EGFR is a potential predictive marker of survival in NSCLC patients. PMID- 24488001 TI - Protective effects of aliskiren on atrial ionic remodeling in a canine model of rapid atrial pacing. AB - PURPOSE: Aliskiren inhibits the activation of the renin-angiotensin system. Here, we investigated the effects of aliskiren on chronic atrial iron remodeling in the experimental canine model of rapid atrial pacing. METHODS: Twenty-eight dogs were assigned to sham (S), control paced (C), paced + aliskiren (10 mg Kg(-1) d(-1), A1), and paced + aliskiren (20 mg Kg(-1) d(-1), A2) groups. Rapid atrial pacing at 500 bpm was maintained for 2 weeks, while group S was not paced. Levels of serum angiotensin-converting enzyme and angiotensin II after pacing were determined by ELISA. Whole-cell patch-clamp technique, western blot, and RT-PCR were applied to assess atrial ionic remodeling. RESULTS: The density of I CaL and I Na currents (pA/pF) was significantly lower in group C compared with group S (I CaL: -4.09 +/- 1.46 vs. -6.12 +/- 0.58,P < 0.05; I Na: 30.48 +/- 6.08 vs. 46.31 +/- 4.73, P < 0.05). However, the high dose of aliskiren elevated the density of I CaL and I Na currents compared with group C (I CaL: -6.23 +/- 1.35 vs. -4.09 +/ 1.46, P < 0.05; I Na: 58.62 +/- 16.17 vs. 30.48 +/- 6.08, P < 0.01). The relative mRNA and protein expression levels of Cav1.2 and Nav1.5alpha were downregulated in group C respectively (Cav1.2: 0.46 +/- 0.08; Nav1.5alpha: 0.52 +/- 0.08, P < 0.01; Cav1.2: 0.31 +/- 0.03; Nav1.5alpha: 0.41 +/- 0.04, P < 0.01;), but were upregulated by aliskiren. CONCLUSIONS: Aliskiren has protective effects on atrial tachycardia-induced atrial ionic remodeling. PMID- 24488002 TI - Revealing lithium-silicide phase transformations in nano-structured silicon-based lithium ion batteries via in situ NMR spectroscopy. AB - Nano-structured silicon anodes are attractive alternatives to graphitic carbons in rechargeable Li-ion batteries, owing to their extremely high capacities. Despite their advantages, numerous issues remain to be addressed, the most basic being to understand the complex kinetics and thermodynamics that control the reactions and structural rearrangements. Elucidating this necessitates real-time in situ metrologies, which are highly challenging, if the whole electrode structure is studied at an atomistic level for multiple cycles under realistic cycling conditions. Here we report that Si nanowires grown on a conducting carbon fibre support provide a robust model battery system that can be studied by (7)Li in situ NMR spectroscopy. The method allows the (de)alloying reactions of the amorphous silicides to be followed in the 2nd cycle and beyond. In combination with density-functional theory calculations, the results provide insight into the amorphous and amorphous-to-crystalline lithium-silicide transformations, particularly those at low voltages, which are highly relevant to practical cycling strategies. PMID- 24488003 TI - Herbal medications and plastic surgery: a hidden danger. AB - Herbal medicine is a multibillion-pound industry, and surveys suggest that ~10% of the UK population uses herbal supplements concurrently with prescription medications. Patients and health care practitioners are often unaware of the adverse side effects of herbal medicines. In addition, because many of these herbal supplements are available over the counter, many patients do not disclose these when listing medications to health care providers. A 39-year-old nurse underwent an abdominoplasty with rectus sheath plication after weight loss surgery. Postoperatively, she experienced persistent drain output, and after discharge, a seroma developed requiring repeated drainage in the clinic. After scar revision 10 months later, the woman bled postoperatively, requiring suturing. Again, a seroma developed, requiring repeated drainage. It was discovered that the patient had been taking a herbal menopause supplement containing ingredients known to have anticoagulant effects. Complementary medicine is rarely taught in UK medical schools and generally not practiced in UK hospitals. Many supplements are known to have anticoagulant, cardiovascular, and sedative effects. Worryingly, questions about herbal medicines are not routinely asked in clinics, and patients do not often volunteer such information. With the number and awareness of complementary medications increasing, their usage among the population is likely to increase. The authors recommend specific questioning about the use of complementary medications and consideration of ceasing such medications before surgery. Level of Evidence V This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24488004 TI - Ligating perforators in abdominoplasty reduces the risk of seroma. AB - BACKGROUND: Seroma formation, a common complication of abdominoplasty, can cause patient discomfort and inconvenience. This study aimed to compare seroma rates after ligation and diathermy of large abdominal perforating vessels during abdominoplasty. METHODS: Consecutive patients undergoing abdominoplasty with epigastric undermining between 2004 and 2011 were studied. Body mass index (BMI), age at operation, smoking history, preoperative weight loss, operative details, perioperative fluid infiltration, concomitant abdominal liposuction, ligation of perforators by clips, suture or diathermy, use of quilting sutures, weight of tissue removed, postoperative drainage, inpatient stay, and seroma rates were recorded. Statistical analysis was undertaken using the unpaired t test, Fisher's exact test, the Mann-Whitney U test, and Kendall's tau-b test. RESULTS: The study included 90 patients. The incidence of seroma was significantly lower among the patients who had perforators ligated (4/60, 6.7%) than among those who had diathermy (10/30, 33%) (p=0.002, Fisher's exact test). Seroma formation was significantly associated with a higher BMI, (27.45 vs. 25.16 kg/m2; p=0.025, t test) but not with preoperative weight loss. Postoperative fluid drainage did not differ significantly between ligated and diathermied perforators (p=0.716 Mann Whitney U test). CONCLUSIONS: Use of ligation by clip or suture rather than by diathermy to ablate large abdominal perforators significantly reduced the incidence of seroma among abdominoplasty patients. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 . PMID- 24488005 TI - Editor's invited commentary: Whitening effects of adipose-derived stem cells: an in vivo study. PMID- 24488006 TI - Heart failure in congenital heart disease: the role of genes and hemodynamics. AB - Heart failure can be a consequence of insufficient palliation of structural malformations in patients with congenital heart disease (CHD) or genetic perturbations resulting in cardiomyopathies. Although CHD is traditionally considered a pediatric clinical problem, there is a rapidly increasing population of patients surviving into adulthood with CHD and a corresponding increase in the rate of hospital admissions for adult CHD patients with heart failure. Therefore, there is recognition of the clinical importance in translating conventional heart failure pharmacotherapies to patients with CHD, improving management of heart failure in the context of structural consequences of CHD, and understanding the underlying genetic abnormalities which impact myocardial performance. Heart failure in CHD typically involves complex interactions between primary structural defects, the consequences of interventions (i.e., residual lesions), and the heart's response to enhanced myocardial mechanical stress which depends on many other genetic factors (i.e., gene modifiers). In this review, we will examine how altered genes and hemodynamic loading contribute to heart failure seen in congenital heart patients. Understanding mechanisms of myocardial response and remodeling within the congenital population can provide insight into physiological principles and improve our understanding of heart failure. PMID- 24488007 TI - Pressure-overload-induced right heart failure. AB - Although pulmonary arterial hypertension originates in the lung and is caused by progressive remodeling of the small pulmonary arterioles, patients die from the consequences of pressure-overload-induced right heart failure. Prognosis is poor, and currently there are no selective treatments targeting the failing right ventricle. Therefore, it is of utmost importance to obtain more insights into the mechanisms of right ventricular adaptation and the transition toward right heart failure. In this review, we propose that the same adaptive mechanisms, which initially preserve right ventricular systolic function and maintain cardiac output, eventually initiate the transition toward right heart failure. PMID- 24488008 TI - Myofilament dysfunction as an emerging mechanism of volume overload heart failure. AB - Two main hemodynamic overload mechanisms [i.e., volume and pressure overload (VO and PO, respectively] result in heart failure (HF), and these two mechanisms have divergent pathologic alterations and different pathophysiological mechanisms. Extensive evidence from animal models and human studies of PO demonstrate a clear association with alterations in Ca(2+) homeostasis. By contrast, emerging evidence from animal models and patients with regurgitant valve disease and dilated cardiomyopathy point toward a more prominent role of myofilament dysfunction. With respect to VO HF, key features of excitation-contraction coupling defects, myofilament dysfunction, and extracellular matrix composition will be discussed. PMID- 24488009 TI - Maladaptive modifications in myofilament proteins and triggers in the progression to heart failure and sudden death. AB - In this review, we address the following question: Are modifications at the level of sarcomeric proteins in acquired heart failure early inducers of altered cardiac dynamics and signaling leading to remodeling and progression to decompensation? There is no doubt that most inherited cardiomyopathies are caused by mutations in proteins of the sarcomere. We think this linkage indicates that early changes at the level of the sarcomeres in acquired cardiac disorders may be significant in triggering the progression to failure. We consider evidence that there are rate-limiting mechanisms downstream of the trigger event of Ca(2+) binding to troponin C, which control cardiac dynamics. We discuss new perspectives on how modifications in these mechanisms may be of relevance to redox signaling in diastolic heart failure, to angiotensin II signaling via beta arrestin, and to remodeling related to altered structural rigidity of tropomyosin. We think that these new perspectives provide a rationale for future studies directed at a more thorough understanding of the question driving our review. PMID- 24488010 TI - Delaying mitotic exit downregulates FLIP expression and strongly sensitizes tumor cells to TRAIL. AB - Many of the current antitumor therapeutic strategies are based on the perturbation of the cell cycle, especially during mitosis. Antimitotic drugs trigger mitotic checkpoint activation, mitotic arrest and eventually cell death. However, mitotic slippage represents a major mechanism of resistance to these treatments. In an attempt to circumvent the process of slippage, targeting mitotic exit has been proposed as a better strategy to kill tumor cells. In this study, we show that treatments that induce mitotic checkpoint activation and mitotic arrest downregulate FLICE-like inhibitory protein (FLIP) levels and sensitize several tumor cell lines to TRAIL (tumor necrosis factor-related apoptosis-inducing ligand)-induced apoptosis. Interestingly, we also demonstrate that in absence of mitotic checkpoint activation, mitotic arrest induced either by Cdc20 knockdown or overexpression of nondegradable cyclin B is sufficient to induce both FLIP downregulation and sensitivity to TRAIL. In summary, our data suggest that a combination of antimitotic drugs targeting cyclin B degradation and TRAIL might prevent mitotic slippage and allow tumor cells to reach the threshold for apoptosis induction, thereby facilitating tumor suppression. PMID- 24488011 TI - E-Cadherin and EpCAM expression by NSCLC tumour cells associate with normal fibroblast activation through a pathway initiated by integrin alphavbeta6 and maintained through TGFbeta signalling. AB - Fibroblasts in the tumour stroma (cancer-associated fibroblasts) influence tumour progression and response to therapeutics; little is known about the mechanisms through which the tumour cell co-opts a normal fibroblast. To study the activation of fibroblasts by tumour cells, a panel of non-small cell lung cancer (NSCLC) cell lines and normal human dermal fibroblasts were co-cultured. A subset of the NSCLC cells induced an activated cancer-associated fibroblast-like fibroblast phenotype defined by induction of fibroblast alpha-smooth muscle actin expression. Tumour cells that activated fibroblasts were associated with E Cadherin and EpCAM expression and expression of integrin alphavbeta6. Co-culture of activating tumour cells with fibroblasts resulted in induction of transcripts associated with tumour cell invasion and growth, TGFbeta1 and TGFBR1, SERPINE-1, BMP6, SPHK1 and MMP9. Fibroblast activation was inhibited by an alphavbeta6/8 integrin blocking antibody (264RAD) and a small molecule inhibitor of the TGF beta type I receptor activin-like kinase (ALK5) (SB431542), demonstrating that transactivation of the TGFbeta pathway initiates fibroblast activation. Both integrin and ALK5 antagonists inhibited initiation. Only ALK5 was effective when added after 3 days of co-culture. This suggests that although activation is alphavbeta6-dependent, once fibroblasts are activated alternative TGFbeta pathway regulators maintain an activation loop. In co-culture activating cells had reduced sensitivity to selumetinib, AZD8931 and afatinib compared with mono culture. In contrast, non-activating cells were insensitive to selumetinib and AZD8931 in both mono-culture and co-culture. In conclusion NSCLC cell lines, positive for E-Cadherin, EpCAM and alphavbeta6 expression, activate normal fibroblasts through avbeta6/TGFbeta signalling in vitro, and influence both gene expression and response to therapeutic agents. PMID- 24488012 TI - Next-generation sequencing reveals novel rare fusion events with functional implication in prostate cancer. AB - Gene fusions, mainly between TMPRSS2 and ERG, are frequent early genomic rearrangements in prostate cancer (PCa). In order to discover novel genomic fusion events, we applied whole-genome paired-end sequencing to identify structural alterations present in a primary PCa patient (G089) and in a PCa cell line (PC346C). Overall, we identified over 3800 genomic rearrangements in each of the two samples as compared with the reference genome. Correcting these structural variations for polymorphisms using whole-genome sequences of 46 normal samples, the numbers of cancer-related rearrangements were 674 and 387 for G089 and PC346C, respectively. From these, 192 in G089 and 106 in PC346C affected gene structures. Exclusion of small intronic deletions left 33 intergenic breaks in G089 and 14 in PC346C. Out of these, 12 and 9 reassembled genes with the same orientation, capable of generating a feasible fusion transcript. Using PCR we validated all the reliable predicted gene fusions. Two gene fusions were in frame: MPP5-FAM71D in PC346C and ARHGEF3-C8ORF38 in G089. Downregulation of FAM71D and MPP5-FAM71D transcripts in PC346C cells decreased proliferation; however, no effect was observed in the RWPE-1-immortalized normal prostate epithelial cells. Together, our data showed that gene rearrangements frequently occur in PCa genomes but result in a limited number of fusion transcripts. Most of these fusion transcripts do not encode in-frame fusion proteins. The unique in frame MPP5-FAM71D fusion product is important for proliferation of PC346C cells. PMID- 24488014 TI - Flavonoids from persimmon (Diospyros kaki) leaves (FPL) attenuate H2O2-induced apoptosis in MC3T3-E1 cells via the NF-kappaB pathway. AB - The leaves of persimmon (Diospyros kaki L.) have long been used in Chinese medicine for the treatment of paralysis, frostbite, burns, and to stop bleeding. Flavonoids of persimmon leaves (FPL) are known for their antioxidant activity in murine osteoblast MC3T3-E1 cells, but their mechanisms in osteoblast cells injured by oxidative stress are unknown. In this study, the effects of FPL on oxidative damage were investigated by addressing their potential therapeutic or toxic effects on H2O2-stimulated MC3T3-E1 cells. MC3T3-E1 cells were pretreated with FPL (1.25, 2.5 and 5 MUg mL(-1)) for 24 h and were then exposed to 250 MUM H2O2 for an additional 6 h. FPL pre-incubated with MC3T3-E1 cells did not present any cytotoxicity, instead they increased cell viability and DeltaPsim in a dose dependent manner when challenged with H2O2. Treatment with this pro-incubated FPL also significantly suppressed the production of MDA and NO and the activity of iNOS. The mRNA expression of iNOS, COX-2, Bax, Bcl-2, and caspase-3 and the protein expression of NF-kappaB/p65 showed that FPL significantly inhibited apoptosis in H2O2-stimulated MC3T3-E1 cells. These results suggest that the molecular mechanism of FPL in anti-apoptosis was associated with the suppression of the translocation of NF-kappaB/p65 into the nucleus. The protective effect of FPL could provide a promising approach for the treatment of osteoporosis. PMID- 24488013 TI - EphA2 promotes infiltrative invasion of glioma stem cells in vivo through cross talk with Akt and regulates stem cell properties. AB - Diffuse infiltrative invasion is a major cause for the dismal prognosis of glioblastoma multiforme (GBM), but the underlying mechanisms remain incompletely understood. Using human glioma stem cells (GSCs) that recapitulate the invasive propensity of primary GBM, we find that EphA2 critically regulates GBM invasion in vivo. EphA2 was expressed in all seven GSC lines examined, and overexpression of EphA2 enhanced intracranial invasion. The effects required Akt-mediated phosphorylation of EphA2 on serine 897. In vitro the Akt-EphA2 signaling axis is maintained in the absence of ephrin-A ligands and is disrupted upon ligand stimulation. To test whether ephrin-As in tumor microenvironment can regulate GSC invasion, the newly established Efna1;Efna3;Efna4 triple knockout mice (TKO) were used in an ex vivo brain slice invasion assay. We observed significantly increased GSC invasion through the brain slices of TKO mice relative to wild-type (WT) littermates. Mechanistically EphA2 knockdown suppressed stem cell properties of GSCs, causing diminished self-renewal, reduced stem marker expression and decreased tumorigenicity. In a subset of GSCs, the reduced stem cell properties were associated with lower Sox2 expression. Overexpression of EphA2 promoted stem cell properties in a kinase-independent manner and increased Sox2 expression. Disruption of Akt-EphA2 cross-talk attenuated stem cell marker expression and neurosphere formation while having minimal effects on tumorigenesis. Taken together, the results show that EphA2 endows invasiveness of GSCs in vivo in cooperation with Akt and regulates glioma stem cell properties. PMID- 24488015 TI - New molecular staging with G-factor supplements TNM classification in gastric cancer: a multicenter collaborative research by the Japan Society for Gastroenterological Carcinogenesis G-Project committee. AB - BACKGROUND: The G-Project committee was erected by the Japan Society for Gastroenterological Carcinogenesis with an aim of establishing a new classification scheme based on molecular biological characteristics that would supplement the conventional TNM classification to better predict outcome. METHODS: In a literature search involving 822 articles on gastric cancer, eight molecules including p53, vascular endothelial growth factor (VEGF)-A, VEGF-C, matrix metalloproteinase-7 (MMP-7), human epidermal growth factor receptor 2, Regenerating islet-derived family, member 4, olfactomedin-4 and Claudin-18 were selected as candidates to be included in the new molecular classification scheme named G-factor. A total of 210 cases of gastric cancer who underwent curative R0 resection were registered from four independent facilities. Immunohistochemical staining for the aforementioned molecules was performed for the surgically resected specimens of the 210 cases to investigate the correlation between clinicopathological factors and expression of each molecule. RESULTS: No significant correlation was observed between the immunostaining expression of any of the eight factors and postoperative recurrence. However, the expressions of p53 and MMP-7 were significantly correlated with overall survival (OS). When 210 gastric cancer patients were divided into three groups based on the expression of p53 and MMP-7 (G0 group: negative for both p53 and MMP-7, n = 69, G1 group: positive for either p53 or MMP-7, n = 97, G2 group: positive for both of the molecules, n = 44), G2 group demonstrated significantly higher recurrence rate (59%) compared to 38% in G0 (p = 0.047). The multivariate regression analysis revealed that G2 group was independently associated with a shorter disease-free survival (DFS) (hazard ratio 1.904, 95% CI 1.098-3.303; p = 0.022), although the association with OS was not significant. Stage II patients among the G2 group had significantly inferior prognosis both in terms of OS and DFS when compared with those among the G0/G1 group, with survival curves similar to those of Stage III cases. CONCLUSIONS: G-factor based on the expression of p53 and MMP-7 was found to be a promising factor to predict outcome of Stage II/III gastric cancer, and possibly to help select the treatment for Stage II cancer, thus supplementing the conventional TNM system. PMID- 24488016 TI - Trends in the management of gastric cancer over a 32-year period: a French population-based study. AB - BACKGROUND: Gastric cancer is still generating interest because of its poor prognosis. The aim of this study was to investigate time trends in diagnostic assessment, patterns of care, and survival of gastric cancers. METHODS: We considered 5,010 gastric cancers diagnosed between 1976 and 2007 in a well defined French population. Logistic regressions were used to identify factors associated with R0 resection and operative mortality. A multivariate relative survival analysis was performed. RESULTS: Diagnostic modalities have changed. Since 1988, endoscopy is performed when gastric cancer is suspected (95.5%). However, there has been no strong variation in stage over time: the proportion of stage I cancers increased from 5.5% to 13.4% between the periods 1976-1979 and 2004-2007 (p < 0.001) whereas that of advanced cases remained stable, 64.8% and 65.0%, respectively. R0 resections rose from 36.7% (1976-1979) to 46.7% between 1980 and 1999, and decreased to 32.7% thereafter. Age, tumor location, and period were associated with R0 resection. Neoadjuvant and adjuvant chemotherapy were rarely used before 2000, then reached 15.0% and 19.1%, respectively, during the later period. Operative mortality after R0 resection decreased from 18.3% during the 1976-1979 period to 4.3% during the 2004-2007 period (p < 0.001). Prognosis slightly improved during the three first periods, from 13.0% to 22.6%, then leveled off, not exceeding 26.0% thereafter. Stage, age, histology, and time period significantly influenced survival. CONCLUSION: Changes in diagnostic modalities were associated with minor changes in stage and prognosis for gastric cancer. Earlier diagnosis and new therapeutic strategies are the best way to improve the prognosis. PMID- 24488017 TI - Selective phonotaxis of female crickets under natural outdoor conditions. AB - Acoustic mate choice in insects has been extensively studied under laboratory conditions, using different behavioural paradigms. Ideally, however, mate choice designs should reflect natural conditions, including the physical properties of the transmission channel for the signal. Since little is known about the discrimination ability of females between male song variants under natural conditions, we performed phonotaxis experiments with female field crickets (Gryllus bimaculatus) outdoors, using two-choice decisions based on differences in carrier frequency, sound pressure level, and chirp rate. For all three song parameters, minimum differences necessary for a significant preference between two song models were considerably larger outdoors compared to laboratory conditions. A minimum amplitude difference of 5 dB was required for a significant choice in the field, compared to only 1-2 dB reported for lab-based experiments. Due to the tuned receiver system, differences in carrier frequency equal differences in perceived loudness, and the results on choice for differences in carrier frequency corroborate those in amplitude. Similarly, chirp rate differences of 50 chirps/min were required outdoors compared to only 20 chirps/min in the lab. For predictions about patterns of sexual selection, future studies need to consider the different outcomes of mate choice decisions in lab and field trials. PMID- 24488018 TI - TypingSuite: integrated software for presenting stimuli, and collecting and analyzing typing data. AB - Research into typing patterns has broad applications in both psycholinguistics and biometrics (i.e., improving security of computer access via each user's unique typing patterns). We present a new software package, TypingSuite, which can be used for presenting visual and auditory stimuli, collecting typing data, and summarizing and analyzing the data. TypingSuite is a Java-based software package that is platform-independent and open-source. To validate TypingSuite as a beneficial tool for researchers who are interested in keystroke dynamics, two studies were conducted. First, a behavioural experiment based on single word typing was conducted that replicated two well-known findings in typing research, namely the lexicality and frequency effects. The results confirmed that words are typed faster than pseudowords and that high frequency words are typed faster than low frequency words. Second, in regard to biometrics, it was also shown that typing data from the same user are more similar than data from different users. Because TypingSuite allows its users to easily implement an experiment and to collect and analyze data within a single software package, it holds promise for being a valuable educational and research tool in language-related sciences such as psycholinguistics and natural language processing. PMID- 24488019 TI - The effect of orthographic neighborhood in the reading span task. AB - This study aimed at examining whether and to what extent orthographic neighborhood of words influences performance in a working memory span task. Twenty-five participants performed a reading span task in which final words to be memorized had either no higher frequency orthographic neighbor or at least one. In both neighborhood conditions, each participant completed three series of two, three, four, or five sentences. Results indicated an interaction between orthographic neighborhood and list length. In particular, an inhibitory effect of orthographic neighborhood on recall appeared in list length 5. A view is presented suggesting that words with higher frequency neighbors require more resources to be memorized than words with no such neighbors. The implications of the results are discussed with regard to memory processes and current models of visual word recognition. PMID- 24488020 TI - The National Toxicology Program Web-based nonneoplastic lesion atlas: a global toxicology and pathology resource. AB - Toxicologists and pathologists worldwide will benefit from a new, website-based, and completely searchable Nonneoplastic Lesion Atlas just released by the U.S. National Toxicology Program (NTP). The atlas is a much-needed resource with thousands of high-quality, zoomable images and diagnostic guidelines for each rodent lesion. Liver, gallbladder, nervous system, bone marrow, lower urinary tract and skin lesion images, and diagnostic strategies are available now. More organ and biological systems will be added with a total of 22 chapters planned for the completed project. The atlas will be used by the NTP and its many pathology partners to standardize lesion diagnosis, terminology, and the way lesions are recorded. The goal is to improve our understanding of nonneoplastic lesions and the consistency and accuracy of their diagnosis between pathologists and laboratories. The atlas is also a useful training tool for pathology residents and can be used to bolster any organization's own lesion databases. Researchers have free access to this online resource at www.ntp.niehs.nih.gov/nonneoplastic. PMID- 24488022 TI - Non-invasive quantification of the beta cell mass by SPECT with 111In-labelled exendin. AB - AIMS/HYPOTHESIS: A reliable method for in vivo quantification of pancreatic beta cell mass (BCM) could lead to further insight into the pathophysiology of diabetes. The glucagon-like peptide 1 receptor, abundantly expressed on beta cells, may be a suitable target for imaging. We investigated the potential of radiotracer imaging with the GLP-1 analogue exendin labelled with indium-111 for determination of BCM in vivo in a rodent model of beta cell loss and in patients with type 1 diabetes and healthy individuals. METHODS: The targeting of (111)In labelled exendin was examined in a rat model of alloxan-induced beta cell loss. Rats were injected with 15 MBq (111)In-labelled exendin and single photon emission computed tomography (SPECT) acquisition was performed 1 h post injection, followed by dissection, biodistribution and ex vivo autoradiography studies of pancreatic sections. BCM was determined by morphometric analysis after staining with an anti-insulin antibody. For clinical evaluation SPECT was acquired 4, 24 and 48 h after injection of 150 MBq (111)In-labelled exendin in five patients with type 1 diabetes and five healthy individuals. The tracer uptake was determined by quantitative analysis of the SPECT images. RESULTS: In rats, (111)In-labelled exendin specifically targets the beta cells and pancreatic uptake is highly correlated with BCM. In humans, the pancreas was visible in SPECT images and the pancreatic uptake showed high interindividual variation with a substantially lower uptake in patients with type 1 diabetes. CONCLUSIONS/INTERPRETATION: These studies indicate that (111)In-labelled exendin may be suitable for non-invasive quantification of BCM. TRIAL REGISTRATION: ClinicalTrials.gov NCT01825148, EudraCT: 2012-000619-10. PMID- 24488023 TI - Pharmacological application of carbon monoxide ameliorates islet-directed autoimmunity in mice via anti-inflammatory and anti-apoptotic effects. AB - AIMS/HYPOTHESIS: Recent studies have identified carbon monoxide (CO) as a potential therapeutic molecule for the treatment of autoimmune diseases owing to its anti-inflammatory and anti-apoptotic properties. We explored the efficacy and the mechanisms of action of the CO-releasing molecule (CORM)-A1 in preclinical models of type 1 diabetes. METHODS: The impact of CORM-A1 on diabetes development was evaluated in models of spontaneous diabetes in NOD mice and in diabetes induced in C57BL/6 mice by multiple low-dose streptozotocin (MLDS). Ex vivo analysis was performed to determine the impact of CORM-A1 both on T helper (Th) cell and macrophage differentiation and on their production of soluble mediators in peripheral tissues and in infiltrates of pancreatic islets. The potential effect of CORM-A1 on cytokine-induced apoptosis in pancreatic islets or beta cells was evaluated in vitro. RESULTS: CORM-A1 conferred protection from diabetes in MLDS-induced mice and reduced diabetes incidence in NOD mice as confirmed by preserved insulin secretion and improved histological signs of the disease. In MLDS-challenged mice, CORM-A1 attenuated Th1, Th17, and M1 macrophage response and facilitated Th2 cell differentiation. In addition, CORM-A1 treatment in NOD mice upregulated the regulatory arm of the immune response (M2 macrophages and FoxP3(+) regulatory T cells). Importantly, CORM-A1 interfered with in vitro cytokine-induced beta cell apoptosis through the reduction of cytochrome c and caspase 3 levels. CONCLUSIONS/INTERPRETATION: The ability of CORM-A1 to protect mice from developing type 1 diabetes provides a valuable proof of concept for the potential exploitation of controlled CO delivery in clinical settings for the treatment of autoimmune diabetes. PMID- 24488025 TI - The Year in Cardiology 2013: a series of Annual Review articles. PMID- 24488024 TI - Inhibition of macrophage fatty acid beta-oxidation exacerbates palmitate-induced inflammatory and endoplasmic reticulum stress responses. AB - AIMS/HYPOTHESIS: Saturated fatty acids (SFAs) such as palmitate activate inflammatory pathways and elicit an endoplasmic reticulum (ER) stress response in macrophages, thereby contributing to the development of insulin resistance linked to the metabolic syndrome. This study addressed the question of whether or not mitochondrial fatty acid beta-oxidation (FAO) affects macrophage responses to SFA. METHODS: We modulated the activity of carnitine palmitoyl transferase 1A (CPT1A) in macrophage-differentiated THP-1 monocytic cells using genetic or pharmacological approaches, treated the cells with palmitate and analysed the proinflammatory and ER stress signatures. RESULTS: To inhibit FAO, we created THP 1 cells with a stable knockdown (KD) of CPT1A and differentiated them to macrophages. Consequently, in CPT1A-silenced cells FAO was reduced. CPT1A KD in THP-1 macrophages increased proinflammatory signalling, cytokine expression and ER stress responses after palmitate treatment. In addition, in human primary macrophages CPT1A KD elevated palmitate-induced inflammatory gene expression. Pharmacological inhibition of FAO with etomoxir recapitulated the CPT1A KD phenotype. Conversely, overexpression of a malonyl-CoA-insensitive CPT1A M593S mutant reduced inflammatory and ER stress responses to palmitate in THP-1 macrophages. Macrophages with a CPT1A KD accumulated diacylglycerols and triacylglycerols after palmitate treatment, while ceramide accumulation remained unaltered. Moreover, lipidomic analysis of ER phospholipids revealed increased palmitate incorporation into phosphatidylethanolamine and phosphatidylserine classes associated with the CPT1A KD. CONCLUSIONS/INTERPRETATION: Our data indicate that FAO attenuates inflammatory and ER stress responses in SFA-exposed macrophages, suggesting an anti-inflammatory impact of drugs that activate FAO. PMID- 24488027 TI - Genetic diversity and phylogenetic analysis of glycoprotein gp85 of avian leukosis virus subgroup J wild-bird isolates from Northeast China. AB - Avian leukosis virus subgroup J (ALV-J), first isolated in 1989, preferentially infects meat-type birds. Chinese layer flocks have experienced outbreaks of this virus since 2008. To analyze the status of ALV-J infection in wild birds in China, 585 wild birds collected from three provinces of Northeast China from 2010 to 2012 were tested, and six ALV-J strains were isolated for the first time. Furthermore, the gp85 genes of the six strains were amplified, cloned, and sequenced. The results indicated that two different ALV-J strains coexisted in Chinese wild birds from 2010 to 2012. These results not only expand the epidemiological data available for ALV-J and provide necessary information for the further understanding of the evolution of ALV-J, but they also highlight the potential role of wild-bird migration in the spread of ALV-J. PMID- 24488028 TI - Development of a neural circuit in the superior colliculus: analysis of the propagation of neuronal excitation from intermediate to superficial layers. AB - The superior colliculus is important for orientation behaviors, in which visuomotor transformation is performed by the pathway from the superficial layer (SGS) to the intermediate layers (SGI). The opposite pathway (from the SGI to the SGS) also exists, raising the possibility of a feedback circuit, although it could be either negative (inhibitory) or positive (excitatory). In this study, we focused on the development of the feedback circuit. We used optical imaging methods that can measure neuronal population responses directly, as the orientation behaviors are determined by large population activities of superior colliculus neurons. We examined the postnatal development of the propagation pattern of neuronal excitation from the SGI to the SGS using a GABAA receptor antagonist. The optical response propagated within the SGI, but not to the SGS in infant mice that have not opened their eyes. In contrast, in young mice after eye opening, the optical response propagated initially in the SGI and then to the SGS. The GABAA receptor antagonist increased the optical response in the SGS in young mice, as well as that in the SGI in infant mice. Together, these results suggest that axons of SGI neurons terminate to the SGS during development after eye opening. PMID- 24488029 TI - Prism adaptation improves postural imbalance in neglect patients. AB - Several studies have found a negative relation between neglect and postural imbalance. The aim of the current study was to investigate the influence of a single session of prism adaptation on balance [i.e. mediolateral and anteroposterior center of pressure (CoP)] and postural sway (i.e. mean variance of displacement in horizontal and vertical planes) in neglect patients. CoP and postural sway were measured in a single session while sitting unaided on a Wii Balance Board. With respect to mediolateral as well as anteroposterior CoP, there was an improvement in postural imbalance after prism adaptation when measurements were performed with the eyes open, but not with the eyes closed. With respect to postural sway, only horizontal sway was significantly reduced after prism adaptation, but no changes were found for vertical sway. Prism adaptation may produce the recalibration of disturbed representation of space as well as higher level representations of extrapersonal and internal body space (i.e. internal body midline). Given the important role of postural control in daily life functioning in stroke patients, this study might open possibilities for a successful rehabilitation procedure to alleviate deficits in postural imbalance. PMID- 24488030 TI - Expression of TRPV1 in the C57BL/6 mice brain hippocampus and cortex during development. AB - Transient receptor potential vanilloid 1 (TRPV1) channel has been found to be expressed in a variety of tissues over the last few years, including the central nervous system (CNS). However, the distribution of TRPV1 in the CNS remains a controversial question. Here, we reveal that the expression of TRPV1 can be detected in the C57BL/6 mouse hippocampus and cortex using real-time PCR and western blot. Beyond that, mRNA and protein expression levels of TRPV1 show dynamic changes during brain development. Compared with the earliest timepoint examined at 2 weeks, the expression levels of mRNA progressively increased at 4 and 8 weeks, peaking at the later timepoint, then declined at 16 weeks but remained elevated. However, compared with 2-week-old mice, the expression levels of the other three groups (4-, 8-, and 16-week-old mice) increased overall. These results indicate that TRPV1 channel expression is detectable in the CNS and it varies during postnatal development. PMID- 24488031 TI - Sex differences in preattentive perception of emotional voices and acoustic attributes. AB - Sex stereotypes consider women to be superior in terms of voice sensitivity. However, whether such sex differences are driven by voice perception per se or by low-level acoustic attributes remains unclear. Using a passive auditory oddball paradigm, we studied the emotionally spoken meaningless syllables 'dada' (neutral, happy, fearful) along with corresponding nonvocal sounds in female and male adults. Mismatch negativity (MMN) and P3a were identified in the waveforms obtained by subtraction of the responses to standard stimuli from the deviant stimuli. Results showed that MMN in response to fearful syllables was stronger in women, whereas MMN elicited by nonvocal sounds was comparable between sexes. This sex effect was specifically found in MMN, but not in P3a. These findings suggest that sex differences in voice sensitivity are selectively driven by voice perception. The sex effect in preattentive processing of emotional voices may further implicate possible etiological pathways for mental disorders characterized by disturbance in emotional processes as well as disparities in the prevalence between sexes. PMID- 24488032 TI - Androgens and opiates: testosterone interaction with morphine self-administration in male rats. AB - Abuse of anabolic androgenic steroids (AAS) and opioids intersects in athletics. Evidence from humans and animals suggests that AAS may act in the brain through opioidergic mechanisms, and may potentiate effects of opioids. To determine whether AAS enhance motivation for opioid intake, in this study, male rats were treated chronically for 6 weeks with high levels of testosterone (7.5 mg/kg) or vehicle subcutaneously, and they were tested for morphine self-administration under fixed-ratio (FR) and progressive-ratio (PR) schedules. Initially, rats received chronic morphine infusion (16.8-50 mg/kg/day) over 7 days. Subsequently, rats were tested for morphine self-administration (3.2 mg/kg) 6 h/day for 3 days under an FR1 schedule, and for 7 days under a PR 9-4 schedule. Under the FR1 schedule, controls self-administered more morphine (95.9+/-8.5 mg/kg) than testosterone-treated rats (63.2+/-7.2 mg/kg; P<0.05). Under the PR schedule, there was no effect of testosterone on morphine intake or operant responding (26.7+/-5.7 responses vs. 30.9+/-5.9 responses for vehicle; NS). To determine whether testosterone enhances morphine sedation, additional rats were treated with testosterone or vehicle and evaluated for locomotor behavior and rearing activity over 30 min in response to saline or 10 mg/kg morphine. Morphine inhibited locomotor activity and rearing; testosterone selectively reduced rearing behavior, but did not alter locomotor behavior. These results suggest that testosterone does not increase motivation for morphine. PMID- 24488033 TI - Inhibition of prothrombin kringle-2-induced inflammation by minocycline protects dopaminergic neurons in the substantia nigra in vivo. AB - Prothrombin kringle-2 (pKr-2), a domain of prothrombin, can cause the degeneration of mesencephalic dopaminergic neurons through microglial activation. However, the chemical products that inhibit pKr-2-induced inflammatory activities in the brain are still not well known. The present study investigated whether minocycline, a semisynthetic tetracycline derivative, could inhibit pKr-2-induced microglial activation and prevent the loss of nigral dopaminergic (DA) neurons in vivo. To address this question, rats were administered a unilateral injection of pKr-2 in the substantia nigra in the presence or absence of minocycline. Our results show that pKr-2 induces the production of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta), and inducible nitric oxide synthase from the activated microglia. In parallel, 7 days after pKr-2 injection, tyrosine hydroxylase immunocytochemical analysis and western blot analysis showed a significant loss of nigral DA neurons. This neurotoxicity was antagonized by minocycline and the observed neuroprotective effects were associated with the ability of minocycline to suppress the expression of tumor necrosis factor-alpha, interleukin-1beta, and nitric oxide synthase. These results suggest that minocycline may be promising as a potential therapeutic agent for the prevention of DA neuronal degeneration associated with pKr-2-induced microglial activation. PMID- 24488034 TI - Strong Schottky barrier reduction at Au-catalyst/GaAs-nanowire interfaces by electric dipole formation and Fermi-level unpinning. AB - Nanoscale contacts between metals and semiconductors are critical for further downscaling of electronic and optoelectronic devices. However, realizing nanocontacts poses significant challenges since conventional approaches to achieve ohmic contacts through Schottky barrier suppression are often inadequate. Here we report the realization and characterization of low n-type Schottky barriers (~0.35 eV) formed at epitaxial contacts between Au-In alloy catalytic particles and GaAs-nanowires. In comparison to previous studies, our detailed characterization, employing selective electrical contacts defined by high precision electron beam lithography, reveals the barrier to occur directly and solely at the abrupt interface between the catalyst and nanowire. We attribute this lowest-to-date-reported Schottky barrier to a reduced density of pinning states (~10(17) m(-2)) and the formation of an electric dipole layer at the epitaxial contacts. The insight into the physical mechanisms behind the observed low-energy Schottky barrier may guide future efforts to engineer abrupt nanoscale electrical contacts with tailored electrical properties. PMID- 24488036 TI - Rational design of sulfoxide-phosphine ligands for Pd-catalyzed enantioselective allylic alkylation reactions. AB - A new type of chiral sulfoxide-phosphine ligands have been developed by a rational combination of two privileged scaffolds for Pd-catalyzed asymmetric allylic alkylation reactions. Under optimized conditions, generally high yields (up to 97%) and excellent enantioselectivities (up to >99% ee) were obtained. PMID- 24488035 TI - Association between NQO1 C609T polymorphism and acute lymphoblastic leukemia risk: evidence from an updated meta-analysis based on 17 case-control studies. AB - PURPOSE: Quinone oxidoreductase (NQO1) C609T polymorphisms have been implicated in acute lymphoblastic leukemia (ALL) risk, but previously published studies were inconsistent and recent meta-analyses were not adequate. The aim of this study was to determine more precise estimations for the relationship between the NQO1 C609T polymorphism and the risk of ALL. METHODS: Electronic searches for all publications were conducted on association between this variant and ALL in several databases updated in May 2013. The quality of studies was evaluated using the Newcastle-Ottawa Scale. Crude odds ratios (ORs) with 95 % confidence intervals (CIs) were used to assess the strength of the association. Seventeen studies were identified, including 2,264 ALL patients and 3,798 controls. RESULTS: Overall, significantly elevated ALL risk was associated with NQO1 C609T variant genotypes when all of the studies were pooled into the meta-analysis (TT vs. CC: OR 1.46, 95 % CI 1.18-1.79; dominant model: OR 1.45, 95 % CI 1.19-1.77). In the subgroup analysis by ethnicity, significantly increased risks were found for non-Asians (T/T vs. C/C: OR 1.74, 95 % CI 1.29-2.36; dominant model: T/T + C/T vs. C/C: OR 1.7, 95 % CI 1.27-2.29). When stratified by adult or children studies, statistically significantly elevated risks were found among adult studies (codominant model: C/T vs. C/C: OR 1.38, 95 % CI 1.02-1.87; dominant model: T/T + C/T vs. C/C: OR 1.52, 95 % CI 1.18-1.97) and children studies (recessive model: T/T vs. C/T + C/C: OR 1.34, 95 % CI 1.05-1.7). CONCLUSIONS: Our results indicate that the C609T polymorphism of the NQO1 gene is an important genetic risk factor in ALL. PMID- 24488037 TI - Comparison of Positive End-Expiratory Pressure of 8 versus 5 cm H2O on Outcome After Cardiac Operations. AB - PURPOSE: Postoperative positive end-expiratory pressure (PEEP) selection in patients who are mechanically ventilated after cardiac operations often seems random. The aim of this investigation was to compare the 2 most common postoperative initial PEEP settings at our institution, 8 and 5 cm H2O, on postoperative initial tracheal intubation time (primary outcome); cardiovascular intensive care unit (CVICU); hospital length of stay (LOS); occurrence of pneumonia; and hospital mortality (secondary outcomes). MATERIALS AND METHODS: The electronic medical records of patients who were mechanically ventilated after isolated coronary artery bypass grafting (CABG) or combined CABG and valve operations were reviewed. Propensity score matching was used to compare patients with an initial postoperative PEEP setting of 8 cm H2O (n = 4722 [25.9%]) with those who had PEEP of 5 cm H2O (n = 13 535 [74.1%]) on the primary and secondary outcomes listed earlier. RESULTS: There was no difference in initial postoperative intubation time between the PEEP of 8 cm H2O and the PEEP of 5 cm H2O patient groups (mean 11.9 vs 12.0 hours [median 8.2 vs 8.8 hours], P = .89). The groups did not differ on the occurrence of pneumonia (0.43% vs 0.60%, P = .25) nor on hospital mortality (0.47% vs 0.43%, P = .76). Aspiration pneumonia occurrence approached a significant difference (0.06% vs 0.21%, P value = .052), as did CVICU LOS (mean: 47.9 vs 49.8 hours [median: 28.5 vs 28.4 hours], P = .057), but were not statistically different. There was a slight but likely clinically unimportant difference in hospital LOS (7.7 vs 7.4 days, PEEP = 8 vs 5, P < .001). CONCLUSION: Patients being mechanically ventilated after cardiac operations with an initial postoperative PEEP setting of 8 versus 5 cm H2O differed significantly only on hospital LOS but the difference was likely clinically unimportant. Thus, use of 8 cm H2O PEEP in these patients without a clinical indication, although likely not harmful, does not seem beneficial. PMID- 24488038 TI - Environmental awareness and public support for protecting and restoring Puget sound. AB - In an effort to garner consensus around environmental programs, practitioners have attempted to increase awareness about environmental threats and demonstrate the need for action. Nonetheless, how beliefs about the scope and severity of different types of environmental concerns shape support for management interventions are less clear. Using data from a telephone survey of residents of the Puget Sound region of Washington, we investigate how perceptions of the severity of different coastal environmental problems, along with other social factors, affect attitudes about policy options. We find that self-assessed environmental understanding and views about the seriousness of pollution, habitat loss, and salmon declines are only weakly related. Among survey respondents, women, young people, and those who believe pollution threatens Puget Sound are more likely to support policy measures such as increased enforcement and spending on restoration. Conversely, self-identified Republicans and individuals who view current regulations as ineffective tend to oppose governmental actions aimed at protecting and restoring Puget Sound. Support for one policy measure-tax credits for environmentally-friendly business practices-is not significantly affected by political party affiliation. These findings demonstrate that environmental awareness can influence public support for environmental policy tools. However, the nature of particular management interventions and other social forces can have important mitigating effects and need to be considered by practitioners attempting to develop environment-related social indicators and generate consensus around the need for action to address environmental problems. PMID- 24488039 TI - Relation between edaphic factors and vegetation development on copper mine wastes: a case study from Bor (Serbia, SE Europe). AB - The relationship between edaphic characteristics and vegetation growing on mine wastes in the Bor region (East Serbia, SE Europe) was studied using multivariate statistical analysis. The influence of edaphic factors on the composition of plant life-forms was also investigated, since it could reflect strategies for the avoidance of or tolerance to disturbances of ecosystems. The goal was to provide potential models for the restoration and management of this and similar mine waste areas. The results of this study imply that soil textures, nitrogen contents, reclamation technology and the presence of hydrothermally altered andesite as the type of bedrock significantly influenced plant colonization and vegetation composition of the Bor mine wastes. These edaphic factors explained 30.3 % of the total variation in the vegetation data set. It was also revealed that the pattern of plant life-forms found on the considered site groups corresponded to the soil texture. Based on their relative abundance on the investigated sites and relationships with soil properties it is concluded that therophytes and geophytes are unsuccessful primary colonizers of the Bor mine wastes. Hemicryptophytes of psammophytic character were the most successful primary colonizers and therefore potential candidates for anthropogenically assisted natural recovery. This study suggested that an assessment of edaphic factors should be widely used in the characterization of mine wastes prior to reclamation. Estimation of their role in the development of existing mine vegetation should predate reclamation procedures. Thus, approaches based on adequate plant life-forms should have a more prominent role in future mine reclamation schemes. PMID- 24488040 TI - Multiple determinants of anuran richness and occurrence in an agricultural region in South-eastern Brazil. AB - In agricultural landscapes, studies that identify factors driving species richness and occupancy are important because they can guide farmers to use conservation practices that minimize species loss. In this context, anurans are threatened by habitat loss because they depend on the characteristics of both local water bodies and adjacent landscapes. We used a model selection approach to evaluate the influence of local and landscape variables in determining anuran species richness and occurrence in 40 freshwater bodies in a heavily deforested region of semideciduous Atlantic Forest in southeastern Brazil. Our aim was to develop recommendations for conservation of anuran communities in rural areas. Pond hydroperiod and area were the most important variables for explaining anuran species richness and occupancy, with greatest species richness being found in water bodies with intermediate hydroperiod and area. Other important variables that reflected individual species occupancies were the number of vegetation types and pond isolation. In addition, recent studies evidenced that water bodies near forest fragments have higher anuran abundance or diversity. In conclusion, we suggest the maintenance of semi-permanent ponds, isolated from large rivers or reservoirs and near forest fragments, as an effective strategy to conserve anuran fauna in agricultural landscapes of southeastern Brazil. Brazilian government requires the maintenance of forests as legal reserve in each farm, and farmers need to maintain ponds as drinking water for cattle or crop irrigation. For this reason, the guidelines suggested in the present study can be easily adopted, without additional costs to rural productivity. PMID- 24488041 TI - Treatment of myopic choroidal neovascularization with posterior sub-Tenon's bevacizumab injection (Avastin (r)). AB - The aim of this study was to report the successful treatment of choroidal neovascularization (CNV) in pathologic myopia (PM) with a posterior sub-Tenon bevacizumab (PSTB; Avastin((r))) injection. The study was a prospective case series including nine eyes of eight patients with PM and CNV. All nine eyes were injected with PSTB (12.5 mg/0.5 ml). Treatment effectiveness was evaluated with optical coherence tomography (OCT). If intraretinal edema or subretinal fluid were detected, injections were repeated after 2 weeks. The main outcome measures were logMAR best-corrected visual acuity (BCVA) and central foveal thickness. The mean follow-up time was 77.56 weeks. BCVA improved by a mean of -0.38 logMAR (>3 lines). The average reduction in absolute central foveal thickness was 25.67 MUm. OCT revealed marked CNV volume reduction and fluid-free status in seven eyes. The fluid-free status remained for >= 1 year in these eyes. Fluorescein angiography revealed CNV resolution in three eyes. Corneal stromal penetration of subconjunctival bevacizumab has been demonstrated in animal studies. PSTB may be an equally effective, yet less invasive alternative for the treatment of myopic CNV. PMID- 24488042 TI - Different visible colors and green fluorescence were obtained from the mutated purple chromoprotein isolated from sea anemone. AB - Green fluorescent protein (GFP)-like proteins have been studied with the aim of developing fluorescent proteins. Since the property of color variation is understudied, we isolated a novel GFP-like chromoprotein from the carpet anemone Stichodactyla haddoni, termed shCP. Its maximum absorption wavelength peak (lambda(max)) is located at 574 nm, resulting in a purple color. The shCP protein consists of 227 amino acids (aa), sharing 96 % identity with the GFP-like chromoprotein of Heteractis crispa. We mutated aa residues to examine any alteration in color. When E63, the first aa of the chromophore, was replaced by serine (E63S), the lambda(max) of the mutated protein shCP-E63S was shifted to 560 nm and exhibited a pink color. When Q39, T194, and I196, which reside in the surrounding 5 A of the chromophore's microenvironment, were mutated, we found that (1) the lambda(max) of the mutated protein shCP-Q39S was shifted to 518 nm and exhibited a red color, (2) shCP-T194I exhibited a purple-blue color, and (3) an additional mutation at I196H of the mutated protein shCP-E63L exhibited green fluorescence. In contrast, when the aa located neither at the chromophore nor within its microenvironment were mutated, the resultant proteins shCP-L122H, E138G, -S137D, -T95I, -D129N, -T194V, -E138Q, -G75E, -I183V, and -I70V never altered their purple color, suggesting that mutations at the shCP chromophore and the surrounding 5 A microenvironment mostly control changes in color expression or cause fluorescence to develop. Additionally, we found that the cDNAs of shCP and its mutated varieties are faithfully and stably expressed both in Escherichia coli and zebrafish embryos. PMID- 24488045 TI - Use of the extended Strengths and Difficulties Questionnaire (SDQ) to predict psychiatric caseness in Hong Kong. AB - The extended Strengths and Difficulties Questionnaire (SDQ) provides information on problem behaviours and impairment measures. Western studies found impairment measures to be as good as symptom scores in predicting clinical caseness. The high levels of comorbidities among child psychiatric disorders also meant that disorders not specifically captured by the questionnaire could be identified. This study examines its applicability among Chinese school children in Hong Kong. Results found that impairment measures were more predictive of clinical status than were symptom scores. Children with low symptom but high impairment ratings had profiles that were intermediate between the low symptom low impairment and high symptom low impairment groups. The extended SDQ is useful in identifying children who might otherwise be missed if symptom scores alone were used in screening. The acceptance of child psychiatric care in Hong Kong is a multi-step process that depends on how symptoms are perceived. PMID- 24488047 TI - Treatment of poor graft function after allogeneic hematopoietic cell transplantation with a booster of CD34-selected cells infused without conditioning. PMID- 24488046 TI - Mesenchymal stem cells support hepatocyte function in engineered liver grafts. AB - Recent studies suggest that organ decellularization is a promising approach to facilitate the clinical application of regenerative therapy by providing a platform for organ engineering. This unique strategy uses native matrices to act as a reservoir for the functional cells which may show therapeutic potential when implanted into the body. Appropriate cell sources for artificial livers have been debated for some time. The desired cell type in artificial livers is primary hepatocytes, but in addition, other supportive cells may facilitate this stem cell technology. In this context, the use of mesenchymal stem cells (MSC) is an option meeting the criteria for therapeutic organ engineering. Ideally, supportive cells are required to (1) reduce the hepatic cell mass needed in an engineered liver by enhancing hepatocyte function, (2) modulate hepatic regeneration in a paracrine fashion or by direct contact, and (3) enhance the preservability of parenchymal cells during storage. Here, we describe enhanced hepatic function achieved using a strategy of sequential infusion of cells and illustrate the advantages of co-cultivating bone marrow-derived MSCs with primary hepatocytes in the engineered whole-liver scaffold. These co-recellularized liver scaffolds colonized by MSCs and hepatocytes were transplanted into live animals. After blood flow was established, we show that expression of adhesion molecules and proangiogenic factors was upregulated in the graft. PMID- 24488048 TI - Azacitidine salvage therapy for relapse of myeloid malignancies following allogeneic hematopoietic SCT. AB - Patients with hematopoietic malignancies relapsing after allogeneic hematopoietic SCT (allo-HSCT) have a poor prognosis. We retrospectively analyzed the patients who received azacitidine in our center in the course of treatment of their post transplant relapse. We identified 31 patients. Relapse occurred at a median of 3.7 (1.7-37.6) months following allo-HSCT. Patients received a median number of three cycles (1-12) of azacitidine (7 days, 75 mg/m(2) daily). Thirty-nine percent of patients had either a monosomal karyotype or a complex karyotype. Eleven patients (35%) received at least one DLI. Eleven patients responded to azacitidine, with four patients achieving a CR (13%). Median time to best response was 92 (35-247) days, with a median duration of 209 (64-751) days. One year estimated survival rate was 14%. In conclusion, azacitidine may reinduce durable remissions in very few patients with AML or myelodysplastic syndrome. The toxicity related to azacitidine was high, although it may be difficult to distinguish between treatment-related side effects, namely due to cytopenia and toxicity due to the relapse or disease progression itself. Early administration of azacitidine after transplant followed by DLI should be considered as a pre emptive therapy for potential relapse in patients with minimal residual disease or high-risk myeloid malignancies. PMID- 24488049 TI - High burden of BK virus-associated hemorrhagic cystitis in patients undergoing allogeneic hematopoietic stem cell transplantation. AB - BK virus (BKV) reactivation has been increasingly associated with the occurrence of late-onset hemorrhagic cystitis (HC) after allogeneic hematopoietic SCT (allo HSCT) resulting in morbidity and sometimes mortality. We investigated the incidence, risk factors and outcome of BKV-HC in 323 consecutive adult patients undergoing allo-HSCT over a 5-year period. BK viremia values for HC staging were evaluated, as well as the medico-economic impact of the complication. Forty-three patients developed BKV-HC. In univariate analysis, young age (P=0.028), unrelated donor (P=0.0178), stem cell source (P=0.0001), HLA mismatching (P=0.0022) and BU in conditioning regimen (P=0.01) were associated with a higher risk of developing BKV-HC. In multivariate analysis, patients receiving cord blood units (CBUs) (P=0.0005) and peripheral blood stem cells (P=0.011) represented high-risk subgroups for developing BKV-HC. BK viremia was directly correlated to HC severity (P=0.011) with a 3 to 6-log peak being likely associated with grades 3 or 4 HC. No correlation was found between BKV-HC and acute graft versus host disease or mortality rate. Patients with BKV-HC required a significantly longer duration of hospitalization (P<0.0001), more RBC (P=0.0003) and platelet transfusions (P<0.0001). Over the 5-year study period, the financial cost of the complication was evaluated at ?[euro]2 376 076 ($3 088 899). Strategies to prevent the occurrence of late-onset BKV-HC after allo-HSCT are urgently needed, especially in CBU and peripheral blood stem cell recipients. BK viremia correlates with the severity of the disease. Prospective studies are required to test prophylactic approaches. PMID- 24488051 TI - Indications and alternatives to hysterectomy. AB - Hysterectomy remains one the most common procedures performed in North America. Because of a better understanding of a wide array of disease states and with emerging, more focused minimally invasive treatment options, a relative decline has been documented in the last several years. Although hysterectomy will ultimately eliminate all potential sources of abnormal uterine bleeding, various pharmacologic and surgical alternatives exist that may provide comparable benefit to the majority of women, especially if older than 40 years. Women experiencing chronic pelvic pain; however, should be counseled against hysterectomy until a more clear etiology has been identified. PMID- 24488050 TI - The intersection of flow cytometry with microfluidics and microfabrication. AB - A modern flow cytometer can analyze and sort particles on a one by one basis at rates of 50,000 particles per second. Flow cytometers can also measure as many as 17 channels of fluorescence, several angles of scattered light, and other non optical parameters such as particle impedance. More specialized flow cytometers can provide even greater analysis power, such as single molecule detection, imaging, and full spectral collection, at reduced rates. These capabilities have made flow cytometers an invaluable tool for numerous applications including cellular immunophenotyping, CD4+ T-cell counting, multiplex microsphere analysis, high-throughput screening, and rare cell analysis and sorting. Many bio analytical techniques have been influenced by the advent of microfluidics as a component in analytical tools and flow cytometry is no exception. Here we detail the functions and uses of a modern flow cytometer, review the recent and historical contributions of microfluidics and microfabricated devices to field of flow cytometry, examine current application areas, and suggest opportunities for the synergistic application of microfabrication approaches to modern flow cytometry. PMID- 24488052 TI - Prevention and management of hysterectomy complications. AB - Hysterectomy is the most common gynecologic surgical procedure performed in the United States. Although most hysterectomies proceed without incident, complications with serious consequences may occur. This chapter reviews the incidence, predisposing factors, intraoperative risk, diagnosis, and management and prevention of complications of hysterectomy. These include hemorrhage, infection, thromboembolism, injury to viscera, and neuropathy. The prepared surgeon is familiar with anatomy, surgical risk factors, current recommendations for prophylaxis and prevention, as well as modern management of complications of hysterectomy. PMID- 24488053 TI - Hysterectomy controversies: ovarian and cervical preservation. AB - The decision to retain or remove the ovaries and cervix at the time of hysterectomy is complex and controversial. We present a summary of the current literature on the risks and benefits of elective oophorectomy and subtotal hysterectomy to inform surgical decision making. There are no randomized trials of oophorectomy compared with hysterectomy and ovarian preservation. Observational studies have conflicting evidence on long-term health outcomes following oophorectomy. In contrast, there are high-quality randomized trials of subtotal versus total hysterectomy; there is a decrease in some short-term surgical complications for women who undergo subtotal hysterectomy, but no differences in long-term outcomes. PMID- 24488054 TI - Hysterectomy for the treatment of gynecologic malignancy. AB - The current literature shows that minimally invasive hysterectomy for cancer is relatively safe and provides benefits in terms of blood loss and length of stay with less or equal complication rates over laparotomy. These benefits may even be greater in the morbidly obese and those with other comorbidities. Available techniques include laparotomy, laparoscopy, single-site laparoscopy, robotics, and single-site robotics. Collection of comprehensive and reliable data on complications and outcomes will prove to be the key in defining the role of new techniques in the treatment of women with gynecologic malignancies. PMID- 24488055 TI - Second trimester ultrasound markers of fetal aneuploidy. AB - Although it is widely accepted that the best time to screen for chromosomal abnormalities is the first trimester, ultrasound evaluation of the fetus in the second trimester has also been shown to be useful for this purpose. A multitude of markers of varying strength has been developed over the past 30 years. In addition, the optimal time to diagnose fetal anomalies with confidence is also the mid second trimester. Therefore, performance of obstetrical ultrasound at this point in gestation continues to be an important component of prenatal care. PMID- 24488056 TI - Maternal serum analyte screening for fetal aneuploidy. AB - In the first and second trimesters, chemicals produced by the fetoplacental unit are measured to assess risks of fetal abnormalities. Consistent associations between levels of these proteins in such pregnancies enable these biomarkers to be used to calculate risk for Down syndrome and other chromosomal abnormalities in individual pregnancies. Special consideration may be required when assessing risk in multiple pregnancies and pregnancies achieved with infertility therapy. PMID- 24488057 TI - The role of fetal echocardiography in the assessment of fetal aneuploidy. AB - Advances in both imaging technology and understanding of fetal cardiac disease have contributed to a dramatic increase in the sensitivity and specificity of fetal echocardiography over the last few decades. Fetal echocardiography now plays an important role in the prenatal evaluation of fetuses with known or suspected aneuploidy. In this article, specific situations in which fetal echocardiography has a part in noninvasive aneuploidy screening algorithms are discussed. PMID- 24488061 TI - Proton pump inhibitors for reflux therapy in infants: effectiveness determined by impedance pH monitoring. AB - PURPOSE: To evaluate the influence of proton pump inhibitors (PPI) in predominantly milk-fed infants with symptoms of GERD by 24-h pH-multichannel intraluminal impedance (24-h pH-MII). METHODS: Ten infants (8 males and 2 females) with a mean gestational age of 39 weeks (28-40) were included. 24-h pH MII was performed before prescription and during intake of PPI. Total acid exposure time, bolus exposure time (acidic/non-acidic/total) and the number of refluxes (acidic/non-acidic/total) were determined. Clinical symptoms were recorded and used to calculate the Reflux Symptom Index (RSI) and the Symptom Severity Index (SSI). RESULTS: There was a significant decrease in the number of acidic refluxes, total acid exposure and acidic bolus exposure time. However, this went along with a significant increase in non-acidic bolus exposure time. The total number of refluxes and the total bolus exposure time remained unchanged. Under PPI, a decrease of SSI and RSI for pain-related symptoms could be observed. For respiratory symptoms and vomiting however no significant changes could be demonstrated. CONCLUSIONS: Under PPI, an improvement of pain-related symptoms could be shown. The decrease of acid exposure went along with an increase of non-acidic refluxes resulting in almost constant total reflux numbers. This finding is interpreted as main reason for some persisting symptoms despite adequate PPI dosage. Concluding from our data PPI therapy should only be indicated in case of pain, but has no effect in case of vomiting or recurrent respiratory symptoms. PMID- 24488063 TI - Binaphthol-derived phosphoric acids as efficient chiral organocatalysts for the enantiomer-selective polymerization of rac-lactide. AB - A high enantiomer-selectivity for the polymerization of rac-lactide was achieved using chiral binaphthol-derived monophosphoric acids as organocatalysts. During the polymerization, d-lactide (DLA) preferentially polymerized via kinetic resolution with the maximum selectivity factor (kD/kL) of 28.3. The selective polymerization of DLA was derived from a dual activation, i.e., monomer activation and chain-end activation. PMID- 24488062 TI - Effect of surgical subspecialty training on patent ductus arteriosus ligation outcomes. AB - PURPOSE: Surgical outcomes data for patent ductus arteriosus (PDA) ligation come primarily from single institution case series. The purpose of this study was to evaluate national PDA ligation trends, and to compare outcomes between pediatric general (GEN) and pediatric cardiothoracic (CT) surgeons. METHODS: The Pediatric Health Information System database was queried to identify neonates who underwent PDA ligation from 2006 through 2009. Outcomes evaluated included surgical morbidity, in-hospital mortality, length of stay, and total charges. Outcomes were compared between pediatric general and pediatric cardiothoracic surgeons. RESULTS: The records of 1,482 neonates who underwent PDA ligation were identified and analyzed. Overall mean gestational age was 26 +/- 3 weeks and birth weight was 888 +/- 428 g. The majority of patients among both surgeons had birth weights of <=1,000 g (77.2%) and were born at <=27-week gestation (81.5%). Most of the PDA ligations were performed by pediatric CT surgeons (n = 1,196, 80.7%). The mortality rate did not differ by surgeon subspecialty training (GEN = 5.2%, CT 7.9%, p = 0.16). Neonates in the cardiothoracic surgeon cohort showed lower length of stay (p < 0.001-0.05) and total hospital charges (p < 0.05) among patients with birth weight <=1,200 g. Proxy measures of surgical morbidity gastrostomy, fundoplication, and tracheostomy-showed no significant differences between the two surgical subspecialists overall or across birth weight subgroups (p > 0.05). CONCLUSION: These data provide a contemporary snapshot of PDA ligation outcomes at American children's hospitals. Pediatric general surgeons achieve comparable outcomes performing PDA ligation compared to pediatric cardiothoracic surgeons. PMID- 24488064 TI - Oral supplementation of standardized extract of Withania somnifera protects against diabetes-induced testicular oxidative impairments in prepubertal rats. AB - Male reproductive dysfunctions and infertility are the common consequences of overt diabetes. Available evidence support oxidative stress to be the underlying mechanism for the manifestation of testicular complications during diabetes. In the present study, we assessed the attenuating effects of Withania somnifera root extract (WS) on diabetes-induced testicular oxidative disturbances in prepubertal rats. Four-week-old prepubertal rats were assigned into nondiabetic control, streptozotocin (STZ)-treated and STZ+WS supplemented (500 mg/kg b.w./d, oral, 15 days) groups. Experimental diabetes was induced by a single intraperitoneal injection of STZ (90 mg/kg b.w). Terminally, all animals were killed, and markers of oxidative stress were determined in the testis cytosol and mitochondrial fraction. Severe hyperglycemia and regression in testis size were apparent in diabetic rats. A decline in antioxidant defenses with subsequent elevation in the generation of reactive oxygen species and lipid peroxidation was discernible in testis cytosol and mitochondria of diabetic prepubertal rats, which was significantly reversed by WS. However, there was partial restoration of glucose-6 phosphate dehydrogenase, lactate dehydrogenase, and 3-beta hydroxysteroid dehydrogenase activities in testis of diabetic prepubertal rats administered with WS. Taken together, data accrued suggest the potential of WS to improve diabetes induced testicular dysfunctions in prepubertal rats. PMID- 24488065 TI - The lymphoscintigraphic manifestation of (99m)Tc-dextran lymphatic imaging in primary intestinal lymphangiectasia. AB - PURPOSE: The aim of this study was to analyze the imaging characteristics of (99m)Tc-dextran ((99m)Tc-DX) lymphatic imaging in the diagnosis of primary intestinal lymphangiectasia (PIL). MATERIALS AND METHODS: Forty-one PIL patients were diagnosed as having PIL with the diagnosis being subsequently confirmed by laparotomy, endoscopy, biopsy, or capsule colonoscopy. Nineteen patients were male and 22 were female. A whole-body (99m)Tc-DX scan was performed at 10 min, 1 h, 3 h, and 6 h intervals after injection. The 10 min and 1 h postinjection intervals were considered the early phase, the 3 h postinjection interval was considered the middle phase, and the 6 h postinjection interval was considered the delayed phase. RESULTS: The imaging characteristics of (99m)Tc-DX lymphatic imaging in PIL were of five different types: (i) presence of dynamic radioactivity in the intestine, associated with radioactivity moving from the small intestine to the ascending and transverse colon; (ii) presence of delayed dynamic radioactivity in the intestine, no radioactivity or little radioactivity distributing in the intestine in the early phase, or significant radioactivity distributing in the intestine in the delayed phase; (iii) radioactivity distributing in the intestine and abdominal cavity; (iv) radioactivity distributing only in the abdominal cavity with no radioactivity in the intestines; and (v) no radioactivity distributing in the intestine and abdominal activity. CONCLUSION: (99m)Tc-DX lymphatic imaging in PIL showed different imaging characteristics. Caution should be exercised in the diagnosis of PIL using lymphoscintigraphy. Lymphoscintigraphy is a safe and accurate examination method and is a significant diagnostic tool in the diagnosis of PIL. PMID- 24488066 TI - CrossTalk proposal: The late sodium current is an important player in the development of diastolic heart failure (heart failure with a preserved ejection fraction). PMID- 24488067 TI - CrossTalk opposing view: the late sodium current is not an important player in the development of diastolic heart failure (heart failure with a preserved ejection fraction). PMID- 24488068 TI - Rebuttal from Marc Pourrier, Sarah Williams, Donald McAfee, Luiz Belardinelli and David Fedida. PMID- 24488069 TI - Rebuttal from Zoltan Papp, Attila Borbely and Walter J. Paulus. PMID- 24488070 TI - Strategies in diabetic nephropathy: apelin is making its way. PMID- 24488071 TI - The challenge of protecting the perinatal brain against hypoxic ischaemic injury hasten slowly. PMID- 24488072 TI - Supplementing exercise: translational considerations for nutraceutical and lifestyle interventions. PMID- 24488073 TI - Recent advances in understanding mechanisms regulating breathing during exercise. PMID- 24488074 TI - Resveratrol as a supplement to exercise training: friend or foe? PMID- 24488075 TI - Reply fromLasse Gliemann, Jesper Olesen, Rasmus Sjorup Bienso, Stefan Peter Mortensen, Michael Nyberg, Jens Bangsbo, Henriette Pilegaard and Ylva Hellsten. PMID- 24488076 TI - Ultrastructural evidence for completion of the entire miracidial maturation in intrauterine eggs of the digenean Brandesia turgida (Brandes, 1888) (Plagiorchiida: Pleurogenidae). AB - Results of this TEM study provide ultrastructural evidence that miracidial morphogenesis is fully completed within the intrauterine eggs situated in the most posterior uterine regions of the pleurogenid trematode Brandesia turgida (Brandes, 1888). The ultrastructural characteristic of different larval organelles and cell types of these eggshell-enclosed, but fully formed, cilated miracidia is described. The body wall of the pyriform mature miracidium of B. turgida is composed of ciliated epidermis and underlying peripheral body musculature. Two miracidial flame cells of the protonephridial excretory system are localized in the central region of the ciliated larvae. Three types of miracidial glands were observed: a single apical gland, two lateral glands, and several small vesiculated glands; each gland type contains characteristic, but different types of secretory granules. The anterior end of each miracidium consists of an apical papilla on which are situated the exits of the three main larval glands: an exit of a single apical gland as well as the individual exits of two lateral glands. The exits of vesiculated glands, containing characteristic spherical membrane-bound and highly electron-dense granules, evidently different from the two other types of secretory granules of apical and lateral glands, were not identified. Germinative cells, grouped together in a sac-like germinative follicle, are situated in the medioposterior part of the larva, the germatophore. The germinative cells contain numerous electron-dense heterochromatin islands arranged in the form of a network or chain-like pattern and distributed mainly in the karyoplasm adjacent to the nuclear membrane. The thin layer of granular cytoplasm is rich in free ribosomes and contains a few small mitochondria. Both nuclear and cytoplasmic features if these cells indicate their great developmental potential for further growth and multiplication in postembryonic stages of the life cycle. In the mature eggs, the areas of focal cytoplasmic degradation were frequently observed and may be involved in the autolysis of some embryonic structures. Obtained results are compared with available literature data on the functional ultrastructure of the miracidia of other digeneans. PMID- 24488077 TI - Proliferation and resistance difference of a liver-parasitized myxosporean in two different gynogenetic clones of gibel carp. AB - Some myxosporeans have been demonstrated to be harmful to worldwide aquaculture. However, the proliferation information has remained unclear in the fish hosts. In this study, we utilized the mix-culturing equality to reveal significant difference in disease assistance between two different clones of gibel carp, in which clone D had been cultured for nearly 40 years, whereas clone A(+) was a newly created clone. According to morphological and genetic analysis of isolated spores, the diseasing pathogen was identified as Myxobolus wulii of the genus Myxobolus in Myxosporea. Subsequently, a polyclonal antibody specific to soluble proteins of the purified spores was generated. Using the antibody, we performed immunofluorescence observation of the liver lump sections sampled from the heavily diseased clone D individuals, and found that the liver lumps were completely composed of numerous honeycomb-like cysts, full of maturing and mature myxosporean spores, and almost all of liver tissues were destroyed. Comparative co-localization detection revealed a significantly inducing expression of apo-14 protein around the infected myxosporean sporoplasms and plasmodia, and the inducing level was much stronger in clone A(+) than in clone D. Furthermore, a primarily screening of 15 different major histocompatibility complex class Ialpha variants also excavated major variants that respectively belong to clones D and A(+). Therefore, these data provide significant information for differences in myxosporean proliferation and disease resistance in fish clone hosts with different genetic background. Further studies on myxosporean development and the mechanism for disease resistance will be very important for preventing and controlling the parasitic myxosporean disease. PMID- 24488078 TI - Ovicidal, larvicidal and adulticidal properties of Asparagus racemosus (Willd.) (Family: Asparagaceae) root extracts against filariasis (Culex quinquefasciatus), dengue (Aedes aegypti) and malaria (Anopheles stephensi) vector mosquitoes (Diptera: Culicidae). AB - Several diseases are associated to the mosquito-human interaction. Mosquitoes are the carriers of severe and well-known illnesses such as malaria, arboviral encephalitis, dengue fever, chikungunya fever, West Nile virus and yellow fever. These diseases produce significant morbidity and mortality in humans and livestock around the world. The present investigation was undertaken to study the ovicidal, larvicidal and adulticidal activities of crude hexane, ethyl acetate, benzene, chloroform and methanol extracts of root of Asparagus racemosus were assayed for their toxicity against three important vector mosquitoes, viz., Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi (Diptera: Culicidae). The mean percent hatchability of the eggs was observed after 48 h post-treatment. The percent hatchability was inversely proportional to the concentration of extract and directly proportional to the eggs. All the five solvent extracts showed moderate ovicidal activity; however, the methanol extract showed the highest ovicidal activity. The methanol extract of Asparagus racemosus against Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi exerted 100% mortality (zero hatchability) at 375, 300 and 225 ppm, respectively. Control eggs showed 99 100% hatchability. The larval mortality was observed after 24 h of exposure. All extracts showed moderate larvicidal effects; however, the highest larval mortality was found in methanol extract of root of Asparagus racemosus against the larvae of Culex quinquefasciatus, Aedes aegypti and Anopheles stephensi with the LC50 and LC90 values were 115.13, 97.71 and 90.97 ppm and 210.96, 179.92, and 168.82 ppm, respectively. The adult mortality was observed after 24 h recovery period. The plant crude extracts showed dose-dependent mortality. At higher concentrations, the adult showed restless movement for some times with abnormal wagging and then died. Among the extracts tested, the highest adulticidal activity was observed in methanol extract against Anopheles stephensi followed by Aedes aegypti and Culex quinquefasciatus with the LD50 and LD90 values were 120.44, 135.60, and 157.71 ppm and 214.65, 248.35, and 290.95 ppm, respectively. No mortality was recorded in the control. The finding of the present investigation revealed that the root extract of Asparagus racemosus possess remarkable ovicidal, larvicidal and adulticidal activity against medically important vector mosquitoes and this is the low cost and ideal eco-friendly approach for the control of mosquitoes. This is the first report on the mosquito ovicidal, larvicidal and adulticidal activities of the reported Asparagus racemosus root. PMID- 24488079 TI - Seasonal fluctuation and histopathology of Henneguya ghaffari (Myxozoa: Myxosporea) infection in the gills of the Nile perch, Lates niloticus, in the River Nile: a new locality record. AB - Henneguya ghaffari Ali (Dis Aquat Org 38:225-230, 1999), which was originally described in Lake Wadi El-Rayan in the western desert of Egypt, has been discovered in the gills of the Nile perch, Lates niloticus, sourced from the River Nile at Beni-Suef governorate. The species identification was based on the spore morphometry. Of 180 Nile perch, 68 were found to be naturally infected with H. ghaffari (37.7%). A significant seasonal fluctuation in the prevalence was discerned, with the maximum rate occurring in the winter (68.8%) and the minimum rate in the summer (8.8%). The plasmodia of the parasite were evident as white rods, occupying almost a third of the gill filament and with mean dimensions of 0.7 * 0.2 mm. Histological investigations revealed that the present plasmodia were potentially compatible with the intrafilamental type. Infection with H. ghaffari initiated epithelial hyperplasia and curling and atrophy of the respiratory lamellae, which underpin its deleterious effect on the host by decreasing the functional respiratory surface of the gills. The present study concluded that infection with H. ghaffari originated in the River Nile before moving to the new ecosystem of Lake Wadi El-Rayan through drainage water. PMID- 24488080 TI - Effect of supplemental vitamin D and calcium on serum sclerostin levels. AB - OBJECTIVE: Serum sclerostin levels have been reported to be inversely associated with serum 25OHD levels, but the effect of vitamin D and calcium supplementation on serum sclerostin levels is unknown. This study was carried out to determine whether vitamin D and calcium supplementation altered serum sclerostin levels in healthy older adults. DESIGN: We measured serum sclerostin levels at baseline and after 2 years in 279 men and women who participated in a placebo-controlled vitamin D (700 IU/day) and calcium (500 mg/day) intervention trial carried out in men and women aged >=65 years. METHOD: Serum sclerostin levels were measured using the MesoScale Discovery chemiluminescence assay. RESULTS: In the men, sclerostin levels increased over 2 years by 4.11+/-1.81 ng/l (13.1%) in the vitamin D plus calcium-supplemented group and decreased by 3.16+/-1.78 ng/l (10.9%) in the placebo group (P=0.005 for difference in change). Adjustments for the season of measurement, baseline physical activity levels, baseline serum sclerostin levels, and total body bone mineral content did not substantially alter the changes. In the women, there was no significant group difference in change in serum sclerostin levels either before or after the above-mentioned adjustments. In both the sexes, vitamin D and calcium supplementation significantly increased serum ionized calcium levels and decreased parathyroid hormone levels. CONCLUSION: Men and women appear to have different serum sclerostin responses to vitamin D and calcium supplementation. The reason for this difference remains to be determined. PMID- 24488081 TI - Gene co-expression network analysis reveals common system-level properties of prognostic genes across cancer types. AB - Prognostic genes are key molecules informative for cancer prognosis and treatment. Previous studies have focused on the properties of individual prognostic genes, but have lacked a global view of their system-level properties. Here we examined their properties in gene co-expression networks for four cancer types using data from 'The Cancer Genome Atlas'. We found that prognostic mRNA genes tend not to be hub genes (genes with an extremely high connectivity), and this pattern is unique to the corresponding cancer-type-specific network. In contrast, the prognostic genes are enriched in modules (a group of highly interconnected genes), especially in module genes conserved across different cancer co-expression networks. The target genes of prognostic miRNA genes show similar patterns. We identified the modules enriched in various prognostic genes, some of which show cross-tumour conservation. Given the cancer types surveyed, our study presents a view of emergent properties of prognostic genes. PMID- 24488083 TI - On January 13 of this year, The New York Times carried the obituary of Ian Barbour. Introduction. PMID- 24488082 TI - Associations between DSM-IV mental disorders and diabetes mellitus: a role for impulse control disorders and depression. AB - AIMS/HYPOTHESIS: No studies have evaluated whether the frequently observed associations between depression and diabetes could reflect the presence of comorbid psychiatric conditions and their associations with diabetes. We therefore examined the associations between a wide range of pre-existing Diagnostic Statistical Manual, 4th edition (DSM-IV) mental disorders with self reported diagnosis of diabetes. METHODS: We performed a series of cross-sectional face-to-face household surveys of community-dwelling adults (n = 52,095) in 19 countries. The World Health Organization Composite International Diagnostic Interview retrospectively assessed lifetime prevalence and age at onset of 16 DSM IV mental disorders. Diabetes was indicated by self-report of physician's diagnosis together with its timing. We analysed the associations between all mental disorders and diabetes, without and with comorbidity adjustment. RESULTS: We identified 2,580 cases of adult-onset diabetes mellitus (21 years +). Although all 16 DSM-IV disorders were associated with diabetes diagnosis in bivariate models, only depression (OR 1.3; 95% CI 1.1, 1.5), intermittent explosive disorder (OR 1.6; 95% CI 1.1, 2.1), binge eating disorder (OR 2.6; 95% CI 1.7, 4.0) and bulimia nervosa (OR 2.1; 95% CI 1.3, 3.4) remained after comorbidity adjustment. CONCLUSIONS/INTERPRETATION: Depression and impulse control disorders (eating disorders in particular) were significantly associated with diabetes diagnosis after comorbidity adjustment. These findings support the focus on depression as having a role in diabetes onset, but suggest that this focus may be extended towards impulse control disorders. Acknowledging the comorbidity of mental disorders is important in determining the associations between mental disorders and subsequent diabetes. PMID- 24488084 TI - The right tree for the job? perceptions of species suitability for the provision of ecosystem services. AB - Stakeholders in plantation forestry are increasingly aware of the importance of the ecosystem services and non-market values associated with forests. In New Zealand, there is significant interest in establishing species other than Pinus radiata D. Don (the dominant plantation species) in the belief that alternative species are better suited to deliver these services. Significant risk is associated with this position as there is little objective data to support these views. To identify which species were likely to be planted to deliver ecosystem services, a survey was distributed to examine stakeholder perceptions. Stakeholders were asked which of 15 tree attributes contributed to the provision of five ecosystem services (amenity value, bioenergy production, carbon capture, the diversity of native habitat, and erosion control/water quality) and to identify which of 22 candidate tree species possessed those attributes. These data were combined to identify the species perceived most suitable for the delivery of each ecosystem service. Sequoia sempervirens (D.Don) Endl. closely matched the stakeholder derived ideotypes associated with all five ecosystem services. Comparisons to data from growth, physiological and ecological studies demonstrated that many of the opinions held by stakeholders were inaccurate, leading to erroneous assumptions regarding the suitability of most candidate species. Stakeholder perceptions substantially influence tree species selection, and plantations established on the basis of inaccurate opinions are unlikely to deliver the desired outcomes. Attitudinal surveys associated with engagement campaigns are essential to improve stakeholder knowledge, advancing the development of fit-for-purpose forest management that provides the required ecosystem services. PMID- 24488085 TI - Participatory forest management in Ethiopia: learning from pilot projects. AB - Different arrangements of decentralized forest management have been promoted as alternatives to centralized and top down approaches to halt tropical deforestation and forest degradation. Ethiopia is one of the countries piloting one of these approaches. To inform future programs and projects it is essential to learn from existing pilots and experiences. This paper analyses five of the pilot participatory forest management (PFM) programs undertaken in Ethiopia. The study is based on the Forest User Group (FUG) members' analyses of the programs using selected outcome variables: forest income, change in forest conditions, forest ownership feelings and effectiveness of FUGs as forest managing institutions. These variables were assessed at three points in time-before the introduction of PFM, during the project implementation and after the projects ended. Data were collected using group discussions, key informant interviews and transect walks through the PFM forests. The results show that in all of the five cases the state of the forest is perceived to have improved with the introduction of PFM, and in four of the cases the improvement was maintained after projects ended. Regulated access to the forests following introduction of PFM was not perceived to have affected forest income negatively. There are, however, serious concerns about the institutional effectiveness of the FUGs after projects ended, and this may affect the success of the PFM approach in the longer term. PMID- 24488086 TI - How to preserve coastal wetlands, threatened by climate change-driven rises in sea level. AB - A habitat transition model, based on the correlation between individual habitats and micro-elevation intervals, showed substantial changes in the future spatial distributions of coastal habitats. The research was performed within two protected areas in Slovenia: Secovlje Salina Nature Park and Skocjan Inlet Nature Reserve. Shifts between habitats will occur, but a general decline of 42 % for all Natura 2000 habitats is projected by 2060, according to local or global (IPCC AR4) sea level rise predictions. Three different countermeasures for the long term conservation of targeted habitat types were proposed. The most "natural" is displacement of coastal habitats using buffer zones (1) were available. Another solution is construction of artificial islets, made of locally dredged material (2); a feasible solution in both protected areas. Twenty-two islets and a dried salt pan zone at the desired elevations suitable for those habitats that have been projected to decease in area would offer an additional 10 ha in the Secovlje Salina. Twenty-one islets and two peninsulas at two different micro-altitudes would ensure the survival of 13 ha of three different habitats. In the area of Secovlje Salina, abandoned salt pans could be terrestrialized by using permanent, artificial sea barriers, in a manner close to poldering (3). By using this countermeasure, another 32 ha of targeted habitat could be preserved. It can be concluded that, for each coastal area, where wetland habitats will shrink, strategic plans involving any of the three solutions should be prepared well in advance. The specific examples provided might facilitate adaptive management of coastal wetlands in general. PMID- 24488087 TI - Effects of preoperative hypoxia on white matter injury associated with cardiopulmonary bypass in a rodent hypoxic and brain slice model. AB - BACKGROUND: White matter (WM) injury is common after cardiopulmonary bypass or deep hypothermic circulatory arrest in neonates who have cerebral immaturity secondary to in utero hypoxia. The mechanism remains unknown. We investigated effects of preoperative hypoxia on deep hypothermic circulatory arrest-induced WM injury using a combined experimental paradigm in rodents. METHODS: Mice were exposed to hypoxia (prehypoxia). Oxygen-glucose deprivation was performed under three temperatures to simulate brain conditions of deep hypothermic circulatory arrest including ischemia-reperfusion/reoxygenation under hypothermia. RESULTS: WM injury in prenormoxia was identified after 35 degrees C-oxygen-glucose deprivation. In prehypoxia, injury was displayed in all groups. Among oligodendrocyte stages, the preoligodendrocyte was the most susceptible, while the oligodendrocyte progenitor was resistant to insult. When effects of prehypoxia were assessed, injury of mature oligodendrocytes and oligodendrocyte progenitors in prehypoxia significantly increased as compared with prenormoxia, indicating that mature oligodendrocytes and progenitors that had developed under hypoxia had greater vulnerability. Conversely, damage of oligodendrocyte progenitors in prehypoxia were not identified after 15 degrees C-oxygen-glucose deprivation, suggesting that susceptible oligodendrocytes exposed to hypoxia are protected by deep hypothermia. CONCLUSION: Developmental alterations due to hypoxia result in an increased WM susceptibility to injury. Promoting WM regeneration by oligodendrocyte progenitors after earlier surgery using deep hypothermia is the most promising approach for successful WM development in congenital heart disease patients. PMID- 24488088 TI - High-dose intravenous immunoglobulin exerts neuroprotective effect in the rat model of neonatal asphyxia. AB - BACKGROUND: Neonatal asphyxia is one of the leading causes of death in newborn and permanent neurological disabilities in surviving children. The underlying hypoxic-ischemic (HI) injury triggers an inflammatory response leading to neuronal damage. Here, we tested the hypothesis that high-dose intravenous immunoglobulin (IVIG) could exert immunomodulatory effect in rat pups subjected to HI injury. METHODS: HI injury was induced in 7-d-old pups by ligating the common carotid artery followed by exposure to 8% oxygen for 2 h. Brain infarction was evaluated by imaging stained coronal brain sections. Neurological deficits were assessed in weeks 1 through 4 after HI. Western blotting and immunohistochemistry were used to assess complement fragment deposition in the brain tissue. RESULTS: Treatment with IVIG at 2 g/kg significantly and in a dose responsive manner reduced brain infarction size as well as mortality and neurological deficits caused by HI. Anatomical and functional improvements in IVIG-treated pups correlated with decreased deposition of C3b complement fragments in the injured brain hemisphere. CONCLUSION: IVIG significantly improved the outcome of HI injury in rat pups and could potentially be used for the treatment of human neonatal asphyxia to target proinflammatory complement fragments. PMID- 24488089 TI - Nebulized PPARgamma agonists: a novel approach to augment neonatal lung maturation and injury repair in rats. AB - BACKGROUND: By stimulating lipofibroblast maturation, parenterally administered peroxisome proliferator-activated receptor gamma (PPARgamma) agonists promote lung homeostasis and injury repair in the neonatal lung. In this study, we determined whether PPARgamma agonists could be delivered effectively via nebulization to neonates, and whether this approach would also protect against hyperoxia-induced lung injury. METHODS: One-day old Sprague-Dawley rat pups were administered PPARgamma agonists rosiglitazone (RGZ, 3 mg/kg), pioglitazone (PGZ, 3 mg/kg), or the diluent, via nebulization every 24 h; animals were exposed to 21% or 95% O2 for up to 72 h. Twenty-four and 72 h following initial nebulization, the pups were sacrificed for lung tissue and blood collection to determine markers of lung maturation, injury repair, and RGZ and PGZ plasma levels. RESULTS: Nebulized RGZ and PGZ enhanced lung maturation in both males and females, as evidenced by the increased expression of markers of alveolar epithelial and mesenchymal maturation. This approach also protected against hyperoxia-induced lung injury, since hyperoxia-induced changes in bronchoalveolar lavage cell and protein contents and lung injury markers were all blocked by nebulized PGZ. CONCLUSION: Nebulized PPARgamma agonist administration promotes lung maturation and prevents neonatal hyperoxia-induced lung injury in both males and females. PMID- 24488090 TI - Role of per-rectal portal scintigraphy in long-term follow-up of congenital portosystemic shunt. AB - BACKGROUND: Congenital portosystemic shunt (CPSS) has the potential to cause hepatic encephalopathy and thus needs long-term follow-up, but an effective follow-up method has not yet been established. We aimed to evaluate the importance of per-rectal portal scintigraphy (PRPS) for long-term follow-up of CPSS. METHODS: We retrospectively examined shunt severity time course in patients (median: 9.6 y, range: 5.2-16.6 y) with intrahepatic (n = 3) or extrahepatic (n = 3) CPSS by using blood tests, ultrasonography or computed tomography, and PRPS. Per-rectal portal shunt index (cutoff: 10%) was calculated by PRPS. RESULTS: PRPS demonstrated that the initial shunt index was reduced in all intrahepatic cases (from 39.7 +/- 9.8% (mean +/- SD) to 14.6 +/- 4.7%) and all extrahepatic cases (from 46.2 +/- 10.9 to 27.5 +/- 12.6%) during the follow-up period. However, ultrasonography and computed tomography disclosed different shunt diameter time courses between intrahepatic and extrahepatic CPSSs. Initial shunt diameter (5.8 +/- 3.5 mm) reduced to 2.0 +/- 0.3 mm in intrahepatic cases, but the initial diameter (6.3 +/- 0.7 mm) increased to 10.6 +/- 1.0 mm in extrahepatic cases. All patients had elevated serum total bile acid or ammonia levels at initial screening, but these blood parameters were insufficient to assess shunt severity because the values fluctuate. CONCLUSION: PRPS can track changes in the shunt severity of CPSS and is more reliable than ultrasonography and computed tomography in patients with extrahepatic CPSS. PMID- 24488091 TI - A comparative study of sutureless scleral tunnel trabeculectomy versus conventional trabeculectomy in the management of primary open-angle glaucoma. AB - The aim of this study was to compare the outcome and complications of sutureless trabeculectomy with conventional trabeculectomy. A total of 52 eyes were randomly assigned to two groups. One group received standard conventional trabeculectomy and the other group received sutureless trabeculectomy. The patients were evaluated at 1, 3, 6 and 12 months after surgery. Patient data such as sex, age, intraocular pressure (IOP), logMAR visual acuity, antiglaucoma medications, and intraoperative and postoperative complications were collected and statistically analyzed. The mean age of the conventional and sutureless groups was 48.5 +/- 15.4 and 57.3 +/- 13.9 years, respectively. All patients achieved IOP levels <21 mmHg with a mean IOP of 13.4 +/- 5.3 mmHg in the conventional group and 12.8 +/- 2.6 mmHg in the sutureless group at 6 months and 11.00 +/- 1.3 and 12.4 +/- 3.2 mmHg at 12 months post surgery, respectively. These results showed a significant decrease compared to preoperative measures but did not show a significant difference between the two groups (p = 0.659). The number of antigalucoma medications used postoperatively showed a significant decline from preoperative status of 0.7 +/- 0.58 in the conventional group and 0.4 +/- 0.4 in the sutureless trabeculectomy group after 6 months and 0.68 +/- 0.8 and 0.78 +/- 0.9 after 12 months, respectively; however, there was no significant difference between the two groups (p = 0.112). No intraoperative complications were encountered in any of the groups. One patient in the sutureless trabeculectomy group developed mild hyphema which was managed medically. In the conventional group, two patients had failed trabeculectomy which was successfully revised, two patients showed hypotony 2 days after surgery which was managed medically and normal pressure was achieved within 5 days. Sutureless trabeculectomy appears to be a safe and easy method with results comparable to conventional trabeculectomy. PMID- 24488092 TI - The role of violence exposure and negative affect in understanding child and adolescent aggression. AB - Aggressive behaviors in youth tend to be relatively stable across the lifespan and are associated with maladaptive functioning later in life. Researchers have recently identified that both violence exposure and negative affective experiences are related to the development of aggressive behaviors. Children exposed to violence also often experience negative affect (NA) in the form of anxiety and depression. Bringing these findings together, the current study used a clinical sample of youth (N = 199; ages 7-17 years) referred to a psychiatric residential treatment facility to examine the specific contributions of NA and exposure to violence on the development of aggressive behaviors in youth. Using structural equation modeling, both NA and recent exposure to violence significantly predicted aggressive behaviors. More importantly, negative affect partially mediated the relationship between exposure to violence and aggression. Implications of these findings from a clinical perspective and future directions for research on aggression are discussed. PMID- 24488094 TI - Mexican origin youths' trajectories of perceived peer discrimination from middle childhood to adolescence: variation by neighborhood ethnic concentration. AB - Developmentally salient research on perceived peer discrimination among minority youths is limited. Little is known about trajectories of perceived peer discrimination across the developmental period ranging from middle childhood to adolescence. Ethically concentrated neighborhoods are hypothesized to protect minority youths from discrimination, but strong empirical tests are lacking. The first aim of the current study was to estimate trajectories of perceived peer discrimination from middle childhood to adolescence, as youths transitioned from elementary to middle and to high school. The second aim was to examine the relationship between neighborhood ethnic concentration and perceived peer discrimination over time. Using a diverse sample of 749 Mexican origin youths (48.9% female), a series of growth models revealed that youths born in Mexico, relative to those born in the U.S., perceived higher discrimination in the 5th grade and decreases across time. Youths who had higher averages on neighborhood ethnic concentration (across the developmental period) experienced decreases in perceived peer discrimination over time; those that had lower average neighborhood ethnic concentration levels showed evidence of increasing trajectories. Further, when individuals experienced increases in their own neighborhood ethnic concentration levels (relative to their own cross-time averages), they reported lower levels of perceived peer discrimination. Neighborhood ethnic concentration findings were not explained by the concurrent changes youths were experiencing in school ethnic concentrations. The results support a culturally-informed developmental view of perceived peer discrimination that recognizes variability in co-ethnic neighborhood contexts. The results advance a view of ethnic enclaves as protective from mainstream threats. PMID- 24488093 TI - Future prospects for tissue engineered lung transplantation: decellularization and recellularization-based whole lung regeneration. AB - The shortage of donor lungs for transplantation causes a significant number of patient deaths. The availability of laboratory engineered, functional organs would be a major advance in meeting the demand for organs for transplantation. The accumulation of information on biological scaffolds and an increased understanding of stem/progenitor cell behavior has led to the idea of generating transplantable organs by decellularizing an organ and recellularizing using appropriate cells. Recellularized solid organs can perform organ-specific functions for short periods of time, which indicates the potential for the clinical use of engineered solid organs in the future. The present review provides an overview of progress and recent knowledge about decellularization and recellularization-based approaches for generating tissue engineered lungs. Methods to improve decellularization, maturation of recellularized lung, candidate species for transplantation and future prospects of lung bioengineering are also discussed. PMID- 24488095 TI - Smac mimetic promotes glioblastoma cancer stem-like cell differentiation by activating NF-kappaB. AB - Recently, a broader role of inhibitor of apoptosis (IAP) proteins besides their antiapoptotic functions has been described. Therefore, we investigated the effect of non-toxic concentrations of the small-molecule Smac mimetic BV6, which antagonizes IAP proteins, on differentiation of cancer stem-like cells (CSLCs) derived from primary glioblastoma (GBM) specimens. Here, we identify a novel function of BV6 in regulating differentiation of GBM CSLCs by activating NF kappaB. BV6 at non-lethal doses stimulates morphological changes associated with the differentiation of GBM CSLCs. BV6 increases transcriptional activity, mRNA and protein levels of the astrocytic marker GFAP without altering expression of the neuronal marker beta-III-tubulin, indicating that BV6 induces astrocytic differentiation of GBM CSLCs. Molecular studies reveal that BV6 triggers processing of the NF-kappaB subunit p100 to p52, nuclear translocation of p52 and p50 and increased NF-kappaB DNA-binding. Intriguingly, inhibition of NF-kappaB by overexpression of dominant-negative IkappaBalpha super-repressor (IkappaBalpha SR) blocks the BV6-stimulated increase in GFAP and differentiation. Interestingly, this BV6-stimulated differentiation is associated with reduced expression of stemness markers such as CD133, Nanog and Sox2 in GBM CSLCs. In contrast, BV6 does not alter cell morphology, differentiation and expression of stemness markers in non-malignant neural stem cells. Importantly, BV6 treatment reduces clonogenicity of GBM CSLCs in vitro and in vivo, suppresses their tumorigenicity in orthotopic and subcutaneous mouse models and significantly increases the survival of mice. By identifying a novel role of BV6 in promoting differentiation of GBM CSLCs, these findings provide new insights into Smac mimetic-regulated non-apoptotic functions with important implications for targeting GBM CSLCs. PMID- 24488097 TI - Antitumor effect of miR-197 targeting in p53 wild-type lung cancer. AB - Lung cancer is the leading cause of tumor-related death. The lack of effective treatments urges the development of new therapeutic approaches able to selectively kill cancer cells. The connection between aberrant microRNA (miRNA - miR) expression and tumor progression suggests a new strategy to fight cancer by interfering with miRNA function. In this regard, LNAs (locked nucleic acids) have proven to be very promising candidates for miRNA neutralization. Here, we employed an LNA-based anti-miR library in a functional screening to identify putative oncogenic miRNAs in non-small-cell lung cancer (NSCLC). By screening NIH H460 and A549 cells, miR-197 was identified as a new functional oncomiR, whose downregulation induces p53-dependent lung cancer cell apoptosis and impairs the capacity to establish tumor xenografts in immunodeficient mice. We further identified the two BH3-only proteins NOXA and BMF as new miR-197 targets responsible for induction of apoptosis in p53 wild-type cells, delineating miR 197 as a key survival factor in NSCLC. Thus, we propose the inhibition of miR-197 as a novel therapeutic approach against lung cancer. PMID- 24488096 TI - The granzyme B-Serpinb9 axis controls the fate of lymphocytes after lysosomal stress. AB - Cytotoxic lymphocytes (CLs) contain lysosome-related organelles (LROs) that perform the normal degradative functions of the lysosome, in addition to storage and release of powerful cytotoxins employed to kill virally infected or abnormal cells. Among these cytotoxins is granzyme B (GrB), a protease that has also been implicated in activation (restimulation)-induced cell death of natural killer (NK) and T cells, but the underlying mechanism and its regulation are unclear. Here we show that restimulation of previously activated human or mouse lymphocytes induces lysosomal membrane permeabilisation (LMP), followed by GrB release from LROs into the CL cytosol. The model lysosomal stressors sphingosine and Leu-Leu-methyl-ester, and CLs from gene-targeted mice were used to show that LMP releases GrB in both a time- and concentration-dependent manner, and that the liberated GrB is responsible for cell death. The endogenous GrB inhibitor Serpinb9 (Sb9) protects CLs against LMP-induced death but is decreasingly effective as the extent of LMP increases. We also used these model stressors to show that GrB is the major effector of LMP-mediated death in T cells, but that in NK cells additional effectors are released, making GrB redundant. We found that limited LMP and GrB release occurs constitutively in proliferating lymphocytes and in NK cells engaged with targets in vitro. In Ectromelia virus-infected lymph nodes, working NK cells lacking Sb9 are more susceptible to GrB-mediated death. Taken together, these data show that a basal level of LMP occurs in proliferating and activated lymphocytes, and is increased on restimulation. LMP releases GrB from LROs into the lymphocyte cytoplasm and its ensuing interaction with Sb9 dictates whether or not the cell survives. The GrB-Sb9 nexus may therefore represent an additional mechanism of limiting lymphocyte lifespan and populations. PMID- 24488098 TI - MDM2 restrains estrogen-mediated AKT activation by promoting TBK1-dependent HPIP degradation. AB - Restoration of p53 tumor suppressor function through inhibition of its interaction and/or enzymatic activity of its E3 ligase, MDM2, is a promising therapeutic approach to treat cancer. However, because the MDM2 targetome extends beyond p53, MDM2 inhibition may also cause unwanted activation of oncogenic pathways. Accordingly, we identified the microtubule-associated HPIP, a positive regulator of oncogenic AKT signaling, as a novel MDM2 substrate. MDM2-dependent HPIP degradation occurs in breast cancer cells on its phosphorylation by the estrogen-activated kinase TBK1. Importantly, decreasing Mdm2 gene dosage in mouse mammary epithelial cells potentiates estrogen-dependent AKT activation owing to HPIP stabilization. In addition, we identified HPIP as a novel p53 transcriptional target, and pharmacological inhibition of MDM2 causes p53 dependent increase in HPIP transcription and also prevents HPIP degradation by turning off TBK1 activity. Our data indicate that p53 reactivation through MDM2 inhibition may result in ectopic AKT oncogenic activity by maintaining HPIP protein levels. PMID- 24488100 TI - The structure and arrangement of nuclear pores in plant cells. AB - A study of the structure and arrangement of nuclear pores has been made in a number of species. In Selaginella kraussiana, the species investigated most extensively, the pores were arranged in a manner consistent with the view that each pore was located at the centre of an hexagonal structure lying on the nuclear surface. The significance of this arrangement and some evidence relating to the structure of the pores is discussed. In other species examined, no evidence of a regular arrangement of the pores was observed. PMID- 24488099 TI - High sphingomyelin levels induce lysosomal damage and autophagy dysfunction in Niemann Pick disease type A. AB - Niemann Pick disease type A (NPA), which is caused by loss of function mutations in the acid sphingomyelinase (ASM) gene, is a lysosomal storage disorder leading to neurodegeneration. Yet, lysosomal dysfunction and its consequences in the disease are poorly characterized. Here we show that undegraded molecules build up in neurons of acid sphingomyelinase knockout mice and in fibroblasts from NPA patients in which autophagolysosomes accumulate. The latter is not due to alterations in autophagy initiation or autophagosome-lysosome fusion but because of inefficient autophago-lysosomal clearance. This, in turn, can be explained by lysosomal membrane permeabilization leading to cytosolic release of Cathepsin B. High sphingomyelin (SM) levels account for these effects as they can be induced in control cells on addition of the lipid and reverted on SM-lowering strategies in ASM-deficient cells. These results unveil a relevant role for SM in autophagy modulation and characterize autophagy anomalies in NPA, opening new perspectives for therapeutic interventions. PMID- 24488101 TI - [Nitrate-dependent noncyclic photophosphorylation in Ankistrodesmus braunii in the absence of CO2 and O 2]. AB - Manometric measurements show that oxygen evolution proceeds in synchronised cells of Ankistrodesmus braunii even in an atmosphere of pure nitrogen. In this case the slow oxygen evolution is dependent on the presence of nitrate (Table 1). Light saturation is found at a low light intensity at pH 5.6, at a higher light intensity at pH 8.0 (Fig. 1). The light saturation curves are in good agreement with those of (32)P-labelling in Ankistrodesmus under the same conditions (Fig. 2).DCMU inhibition in N2 of both O2-evolution and (32)P-labelling begins only at a DCMU concentration of 5*10(-7)M or more. Complete inhibition of O2-evolution is reached only at 10(-5)M (Fig.3). In (32)P-labelling a variable percentage is still left uninhibited at 10(-5) M DCMU (Fig. 4, Table 2), which is at least partly due to cyclic photophsphorylation. Nitrate starvation for several hours causes a considerable decrease in O2-evolution and also in the sensitivity to those high concentrations of DCMU (Fig. 5), but it leads to a sensitivity to antimycin A not observed under normal conditions (Table 3). The effects of nitrate starvation thus become comparable to those of far-red light, under which noncyclic electron transport is slow or completely prevented.The inhibition by DCMU of electron transport in photosystem II is also estimated by measuring the increase in fluorescence at 684 nm in air containing additional CO2. This fluorescence is saturated only at 10(-5)M DCMU and shows that a certain percentage of photosystem II remains uninhibited at 5*10(-7)M (Fig. 6), a concentration found to be almost ineffective in inhibiting O2-evolution and (32)P labelling in an N2-atmosphere.The results indicate that in synchronised cells of Ankistrodesmus noncyclic electron flow and noncyclic photophosphorylation can proceed in an atmosphere of pure nitrogen if nitrate is available as the electron acceptor. In this case noncyclic photophosphorylation, inspite of its low rates, still dominates over cyclic photphosphorylation. At low pH, when nitrate reduction is slow, cyclic photophosphorylation accounts for a greater part of the total phosphorylation than at high pH. Thus in the absence of CO2 and O2 cyclic photophosphorylation can be regarded as the main process of ATP formation only after nitrate starvation, in far-red light or in the presence of high concentrations of DCMU.Inhibition by DCMU, though very efficient under conditions of high photosynthetic activity, becomes rate-limiting only if the electron transport is so far reduced by DCMU that the remaining rate is of the same order as the low rate of the control or less. Therefore high concentrations of DCMU are required for the inhibition of low rates of noncyclic photophosphorylation. PMID- 24488102 TI - [Cucurbitacins as stathmokinetic agents]. AB - A synergism of colchicine and different cucurbitacins has been shown, to be a cause in the formation of ball-metaphases in Bryonia species. The bitter principles cucurbitacin L and I, dihydrocucurbitacin B, and tetrahydrocucurbitacin I, which were examined more closely with respect to their karyological effects, were shown to give rise to C-metaphases in Hordeum and Vicia at concentrations of about 0.016 per cent. On the one hand the number of mitotic stages is reduced, and on the other hand there is an increase of metaphase stages. Higher concentrations lead to pycnotic degenerations of nuclei and are toxic. When colchicine is applied together with cucurbitacins, ball metaphases result. This could be demonstrated in plants lacking colchicine and cucurbitacins (Hordeum) when both substances were applied at the same time. Ball metaphases also appear in plants containing cucurbitacins (Bryonia alba, B. dioica, Citrullus colocythis, Iberis amara) when they are treated with colchicine. PMID- 24488103 TI - [Experiments and hypothesis concerning the primary action of auxin in elongation growth]. AB - 1. Sections of auxin-starved hypocotyls of Helianthus annuus do not show any significant growth rate in water of buffers of pH?>-6. However, in buffers with pH-values of approximately 4, elongation growth is observed; its rate is similar to the rate of auxin-stimulated growth (after 6 h incubation). ?3- This phenomenon of acid-induced growth occurs also under anaerobic conditions in contrast to auxin-induced growth (Hager 1962). 2. Intact cell wall aggregates of Helianthus hypocotyls were obtained by complete plasmolysis of hypocotyls in 50% glycerol; cell wall associated enzymes were still active after this treatment, at least in part. While cell walls in solutions of pH?>-6 show only a small plastic extension during the first minute in response to a 50 g stretching force, a constant rate of elongation over longer periods of time (measured up to 1 h) is observed in weakly acid buffers. The highest rate of elongation is observed at about pH 4. This acid-induced plastic extension is completely inhibited by Cu(2+) ions (5mM); the elongation of cell walls is apparently the consequence of an enzyme-catalysed increase in plasticity having a pH optimum of about 4. The pH optimum of acid-induced cell wall extension observed during stretching of plasmolysed hypocotyls coincides with the pH optimum of acid-induced growth of intact hypocotyl sections (around pH 4). 3. Under anaerobic conditions the growth rate of intact coleoptiles stays unchanged (at a low value) if the sections are incubated in a buffer of pH 5.0. Higher proton concentrations, however, stimulate growth immediately, whereas low proton concentrations are inhibitory (Fig. 7 and 8). The strongest initial growth response is elicited by buffers or acids of pH 3.9 (Fig. 9). Acid-induced growth of coleoptiles with a similar pH optimum is also found under anaerobic conditions. The growth of coleoptile cylinders can be switched on or off by repeatedly changing to acid or basic medium, respectively (under conditions of anaerobiosis) (Fig. 10). IAA-induced growth (aerobic conditions, pH>=5) can also be inhibited immediately by basic buffers or NaOH solutions, and resumes after the pH value is lowered (Fig. 11). This pH dependency may be taken as an indication that auxin affects the same reaction which is stimulated by high proton concentrations and which may be the last step in the process of cell elongation. CCCP, known to make membranes permeable for protons, rapidly inhibits the auxin-induced elongation growth (pH 6,5) when applied at a concentration which does not influence respiration; removal of CCCP shows that the growth inhibition by CCCp is partly reversible (Fig. 12). In contrast, acid-induced elongation growth (pH 4) shows inhibition by CCCP not before 10 min after application.-These findings suggest that auxin induces a proton accumulation in a cell wall compartment and, as a consequence, enzymatic cell wall softening. Such an accumulation could be brought about by an auxin activated, membrane-bound, anisotropic ATPase or ion pump. The notion that ATPases or pumps may be located in the outer layers of the cell membrane is supported by the observation that addition of ATP to coleoptile cylinders under anaerobic conditions results in an immediate stimulation of elongation (Fig. 14). This effect is further enhanced by Mg(2+)-and K(+)-ions (Figs. 15 and 16). Mg(2+) can be partly replaced by Ca(2+). The stimulatory effect of ATP is increased considerably if the coleoptiles are treated with IAA under aerobic conditions prior to ATP addition (Figs. 15 b and 14). ITP, GTP, UTP, and CTP induce elongation growth under anaerobiosis similarly to ATP. In the presence of ITP or GTP the increase in growth rate is maintained over a longer period of time than in the presence of the other nucleoside triphosphates (Fig. 17). IAA, which causes no elongation growth under anaerobiosis (Fig. 13) is also unable to further stimulate the elongation growth induced by ATP, UTP, or CTP under anaerobiosis (Fig. 18); however, if IAA is added after growth has been stimulated by GTP or ITP, a temporary inhibition and, 10 min later, a strong stimulation is noticed (Fig. 19). If the sequence of addition is reversed, -that is, if IAA (without growth effect) and, after 20 min, GTP or ITP are added to the coleoptiles-, the same initial inhibition and subsequent increase of the growth rate is found (Fig. 20). Thus, IAA can stimulate growth of coleoptiles even under anaerobic conditions if GTP or ITP is present at the same time. 4. The results support the following hypothesis (Fig. 21): auxin acts cooperatively with GTP (ITP) as an effector of a membrane-bound, anisotropic ATPase or proton pump. This pump, activated by auxin, utilizes respiration energy (ATP or other nucleoside triphosphates) to raise the proton concentration in a compartment at the cell wall. This event leads to an increase in the activity of enzymes softening cell walls and thus triggers cell elongation. The transport or secretion of protons into the cell wall compartment should be compensated by a flow of cations into the interior of the cytoplasm or by a flow of anions to the cell periphery, thus causing secondary auxin effects. PMID- 24488104 TI - Responses of stomata to changes in humidity. AB - Large areas of the lower epidermis of full-grown leaves of Polypodium vulgare (and Valerianella locusta) are normally separated from the mesophyll by an extensive subepidermal airspace. Epidermal stripes were prepared for experiments to simulate these conditions in order to investigate stomatal reactions. They were placed with their inner surface in contact with an airspace of uniformly high humidity. The outer surface was treated with air of varying degrees of humidity. The stomatal reactions were observed by microscope and the opening of the guard cells determined photographically.Treatment of the outer side of the epidermis with dry air led to a rapid closing of the stomata, whilst moist air caused opening. This induction of opening and closing movements could be repeated up to 15 times with the same stoma by changing the degree of humidity. Neighbouring groups of stomata showed different apertures according to their individual humidity conditions. The degree of aperture of the stomata depended on the water potential of the ambient air and also on the humidity conditions in the subepidermal airspace.The cause of this stomatal behaviour could lie in the "peristomatal transpiration". In this way, the guard cells are able to function as "humidity sensors" which "measure" the difference in water potential inside and outside the leaf. Their aperture thus is controlled by their individual transpiration conditions. This controlling mechanism could be very important for the water economy of plants. They would appear to be able to reduce their transpiration through an increase in diffusion resistance of the stomata during decreasing humidity in the ambient air, without changing the water status of the whole leaf. PMID- 24488105 TI - The lack of carbon dioxide evolution in maize leaves in the light. AB - Significant carbon dioxide evolution in the light could not be betected in maize leaves held in single-leaf chambers. The leaves that were used remained attached to the plant and were kept at 30 degrees C and with 200 w m(-2) of light incident on the leaf surface. Several experimental techniques were combined in an attempt to detect CO2 evolution from cells within the leaf; these techniques included that of passing air through, rather than over, the leaf, using different levels of O2 and obtaining CO2 response curves. PMID- 24488106 TI - Downregulation of p300 gene expression in airway mesenchyme of nitrofen-induced hypoplastic lungs. AB - PURPOSE: Congenital diaphragmatic hernia (CDH) is a relatively common developmental abnormality causing life-threatening respiratory distress at birth. The nitrofen model has been widely used to investigate the pathogenesis of hypoplastic lungs associated with CDH. Embryos lacking p300 and CBP genes are significantly smaller in lung formation. We hypothesized that pulmonary gene expression of p300 and CBP is downregulated during late gestation in the nitrofen induced CDH model. METHODS: Time-pregnant rats were treated with either nitrofen or vehicle on gestational day 9 (D9). Fetal lungs were harvested on D18 and D21 (n = 8 at each time point). Pulmonary gene expression of p300 and CBP was analyzed by quantitative real-time PCR. Immunohistochemistry was performed to investigate expression and localization of pulmonary p300 and CBP proteins. RESULTS: Relative mRNA expression levels of p300 were significantly decreased in nitrofen-induced hypoplastic lungs on D18 compared to controls (3.00 +/- 0.20 vs. 3.76 +/- 0.14; p = 0.0039), while CBP levels were not altered. p300 immunoreactivity was markedly diminished in surrounding mesenchymal compartments and nuclei of proximal and distal airway cells, while CBP expression was not altered. CONCLUSION: Downregulation of p300 gene expression during the early canalicular stage may disrupt epithelial-mesenchymal signaling interactions, contributing to the development of hypoplastic lungs in the nitrofen-induced CDH model. PMID- 24488107 TI - The antitrichomonal efficacy of garlic and metronidazole against Trichomonas gallinae infecting domestic pigeons. AB - Trichomonas gallinae is the causative agent of canker in pigeon. This work was carried out to investigate in the vitro and in vivo efficacy of aqueous water extract of garlic (AGE) on the growth of T. gallinae infecting pigeons compared to those of metronidazole (MTZ). MTZ and AGE were added, at different concentrations, to glucose-serum broth medium containing 1 * 10(4) trophozoites/ml. In the in vivo experiment, 48 squabs were grouped into four groups. The first group (gr. I) was not infected and not treated. Each squab of the other group was infected with 1 * 10(4) trophozoites. The second group (gr. II) was infected and not treated. On day 0, the third group (gr. III) was treated with MTZ (50 mg/kg BW) and the fourth group (gr. IV) was treated with AGE (200 mg/kg BW) for seven successive days in drinking water. In vitro study revealed that the MLC, 24, 48, and 72 h post treatment were 50, 25, and 12.5 MUg/ml, respectively, for MTZ and 75, 50, and 50 mg/ml, respectively, for AGE. Garlic (200 mg/kg BW) had the highest antitrichomonal effect and shortened course of treatment of pigeons from 7 days in gr. III to 5 days. Squabs in gr. II suffered from macrocytic hypochromic anemia, whereas squabs in grs. III and IV showed normal blood pictures. Serum total protein, albumin, and globulin were increased, whereas AST, ALT, and the total cholesterol were decreased in grs. III and IV when compared to those of gr. II. Pigeons protected with AGE showed increased body weight and reduced mortality percentage than the other groups. Our results indicated that garlic may be a promising phytotherapeutic agent for protection against trichomoniasis in pigeons. PMID- 24488108 TI - Structural and molecular characterization of Kudoa quraishii n. sp. from the trunk muscle of the Indian mackerel Rastrelliger kanagurta (Perciforme, Scombridae) in Saudi Arabia coasts. AB - A new Myxozoa, Kudoa quraishii n. sp., is reported in the striated muscle of the Indian mackerel Rastrelliger kanagurta from the Red Sea and the Arabian Gulf in Saudi Arabia. Mean prevalence of infection is about 20% and varies between localities. The parasite develops whitish and oval or rounded pseudocysts of 0.2 3 mm in the striated muscles of the body. Pseudocysts are filled with mature spores. Myxospores are quadrate in shape in apical view with rounded edges and ovoid in side view. Each spore is formed by four equal shell valves and four symmetrical polar capsules. Polar capsules are pyriform in apical view and drop like in side view. Myxospore measurements in micrometers are 6.14 (5.9-6.34) in width, 5.48 (5.3-5.71) in thickness, and 4.27 (4.1-4.42) in length. Polar capsule measurements in apical view in micrometers are 2.08 (1.88-2.28) and 1.31 (1.10 1.52) length by width. Molecular analysis based on SSU rDNA gene shows closest association with K. amamiensis and K. kenti with respectively 98 and 97.2% of similarities. PMID- 24488109 TI - Microtubule array formation during root hair infection thread initiation and elongation in the Mesorhizobium-Lotus symbiosis. AB - Nuclear migration during infection thread (IT) development in root hairs is essential for legume-Rhizobium symbiosis. However, little is known about the relationships between IT formation, nuclear migration, and microtubule dynamics. To this aim, we used transgenic Lotus japonicus expressing a fusion of the green fluorescent protein and tubulin-alpha6 from Arabidopsis thaliana to visualize in vivo dynamics of cortical microtubules (CMT) and endoplasmic microtubules (EMTs) in root hairs in the presence or absence of Mesorhizobium loti inoculation. We also examined the effect of microtubule-depolymerizing herbicide, cremart, on IT initiation and growth, since cremart is known to inhibit nuclear migration. In live imaging studies of M. loti-treated L. japonicus root hairs, EMTs were found in deformed, curled, and infected root hairs. The continuous reorganization of the EMT array linked to the nucleus appeared to be essential for the reorientation, curling, and IT initiation and the growth of zone II root hairs which are susceptible to rhizobial infection. During IT initiation, the EMTs appeared to be linked to the root hair surface surrounding the M. loti microcolonies. During IT growth, EMTs dissociated from the curled root hair tip, remained linked to the nucleus, and appeared to surround the IT tip. Lack or disorganized EMT arrays that were no longer linked to the nucleus were observed only in infection-aborted root hairs. Cremart affected IT formation and nodulation in a concentration-dependent manner, suggesting that the microtubule (MT) organization and successive nuclear migration are essential for successful nodulation in L. japonicus by M. loti. PMID- 24488110 TI - Enhanced photovoltaic performance of Cu-based metal-organic frameworks sensitized solar cell by addition of carbon nanotubes. AB - In the present work, TiO2 nanoparticle and multi-walled carbon nanotubes composite powder is prepared hydrothermally. After doctor blading the paste from composite powder, the resulted composite film is sensitized with Cu-based metal organic frameworks using a layer-by-layer deposition technique and the film is characterized using FE-SEM, EDX, XRD, UV/Visible spectrophotometry and photoluminescence spectroscopy. The influence of the carbon nanotubes in photovoltaic performance is studied by constructing a Gratzel cell with I3(-)/I( ) redox couple containing electrolyte. The results demonstrate that the introduction of carbon nanotubes accelerates the electron transfer, and thereby enhances the photovoltaic performance of the cell with a nearly 60% increment in power conversion efficiency. PMID- 24488112 TI - Factors affecting carisoprodol metabolism in pain patients using urinary excretion data. AB - Carisoprodol is a skeletal muscle relaxant prescribed to treat pain. Carisoprodol is metabolized to meprobamate, an active metabolite with anxiolytic effects, by the genetically polymorphic CYP2C19 enzyme. Concomitant use of CYP2C19 substrates or inhibitors may alter carisoprodol metabolism, with therapeutic and/or toxic implications for effectively treating patients with pain. This was a retrospective analysis of urinary excretion data collected from patients with pain from March 2008 to May 2011. Carisoprodol and meprobamate urine concentrations were measured by liquid chromatography-tandem mass spectrometry, and the metabolic ratio (MR) of meprobamate to carisoprodol concentrations was determined in 14,965 subjects. The MR geometric mean and 95% confidence interval (95% CI) of the young group (105, 95% CI = 99.1-113) were ~47.4% higher than the middle-aged group (71.9, 95% CI = 70-73.8) and nearly two times higher than the elderly group (54.4, 95% CI = 51.3-57.6). Females had a 20.7% higher MR compared with males. No significant change in the MR was observed with overall CYP2C19 inhibitor or substrate use. However, evaluation of individual inhibitors showed co-administration with esomeprazole or fluoxetine was associated with a 31.8 and 24.6% reduction in MR, respectively, compared with controls (P < 0.05). Omeprazole did not significantly affect the MR. Patient-specific factors such as age, sex and co-medications may be important considerations for effective carisoprodol therapy. PMID- 24488111 TI - Inorganic phosphate blocks binding of pre-miRNA to Dicer-2 via its PAZ domain. AB - In Drosophila, Dicer-1 produces microRNAs (miRNAs) from pre-miRNAs, whereas Dicer 2 generates small interfering RNAs from long double-stranded RNA (dsRNA), a process that requires ATP hydrolysis. We previously showed that inorganic phosphate inhibits Dicer-2 cleavage of pre-miRNAs, but not long dsRNAs. Here, we report that phosphate-dependent substrate discrimination by Dicer-2 reflects dsRNA substrate length. Efficient processing by Dicer-2 of short dsRNA requires a 5' terminal phosphate and a two-nucleotide, 3' overhang, but does not require ATP. Phosphate inhibits cleavage of such short substrates. In contrast, cleavage of longer dsRNA requires ATP but no specific end structure: phosphate does not inhibit cleavage of these substrates. Mutation of a pair of conserved arginine residues in the Dicer-2 PAZ domain blocked cleavage of short, but not long, dsRNA. We propose that inorganic phosphate occupies a PAZ domain pocket required to bind the 5' terminal phosphate of short substrates, blocking their use and restricting pre-miRNA processing in flies to Dicer-1. Our study helps explain how a small molecule can alter the substrate specificity of a nucleic acid processing enzyme. PMID- 24488113 TI - Evaluation of abalone beta-glucuronidase substitution in current urine hydrolysis procedures. AB - This study examined the potential of abalone beta-glucuronidase as a viable and cost effective alternative to current hydrolysis procedures using acid, Helix pomatia beta-glucuronidase and Escherichia coli beta-glucuronidase. Abalone beta glucuronidase successfully hydrolyzed oxazepam-glucuronide and lorazepam glucuronide within 5% of the spiked control concentration. Benzodiazepines present in authentic urine specimens were within 20% of the concentrations obtained with the current hydrolysis procedure using H. pomatia beta glucuronidase. JWH 018 N-(5-hydroxypentyl) beta-d-glucuronide was hydrolyzed within 10% of the control concentration. Authentic urine specimens showed improved glucuronide cleavage using abalone beta-glucuronidase with up to an 85% increase of drug concentration, compared with the results obtained using E. coli beta-glucuronidase. The JWH 018 and JWH 073 carboxylic acid metabolites also showed increased drug concentrations of up to 24%. Abalone beta-glucuronidase was able to completely hydrolyze a morphine-3-glucuronide control, but only 82% of total morphine was hydrolyzed in authentic urine specimens compared with acid hydrolysis results. Hydrolysis of codeine and hydromorphone varied between specimens, suggesting that abalone beta-glucuronidase may not be as efficient in hydrolyzing the glucuronide linkages in opioid compounds compared with acid hydrolysis. Abalone beta-glucuronidase demonstrates effectiveness as a low cost option for enzyme hydrolysis of benzodiazepines and synthetic cannabinoids. PMID- 24488114 TI - Violence Against College Women: A Review to Identify Limitations in Defining the Problem and Inform Future Research. AB - Over the past 25 years, our understanding about violence against college women has greatly expanded, but it has been concentrated in particular areas. As a result, despite this increased attention, significant gaps in our knowledge still exist. One is a failure to take stock in how "violence" is defined and assess whether its current use adequately covers the variety of risks to which college women are exposed. We identify limitations in how the current literature operationalizes violence against college women and illustrate how addressing these limitations can inform and advance the field by identifying new patterns and correlates. We also propose a research agenda to explicitly examine the definition and scope of "violence" as considered in the study of college women. PMID- 24488115 TI - Structural origins of Johari-Goldstein relaxation in a metallic glass. AB - Johari-Goldstein or beta relaxation, persisting down to glassy state from a supercooled liquid, is a universal phenomenon of glassy dynamics. Nevertheless, the underlying micromechanisms leading to the relaxation are still in debate despite great efforts devoted to this problem for decades. Here we report experimental evidence on the structural origins of Johari-Goldstein relaxation in an ultra-quenched metallic glass. The measured activation energy of the relaxation (~26 times of the product of gas constant and glass transition temperature) is consistent with the dynamic characteristics of Johari-Goldstein relaxation. Synchrotron X-ray investigations demonstrate that the relaxation originates from short-range collective rearrangements of large solvent atoms, which can be realized by local cooperative bonding switch. Our observations provide experimental insights into the atomic mechanisms of Johari-Goldstein relaxation and will be helpful in understanding the low-temperature dynamics and properties of metallic glasses. PMID- 24488116 TI - A second-generation ligand for the enantioselective rhodium-catalyzed addition of arylboronic acids to alkenylazaarenes. AB - A 2,4,6-trialkylanilide-containing chiral diene has been identified as a superior ligand for the enantioselective rhodium-catalyzed arylation of alkenylazaarenes with arylboronic acids. PMID- 24488117 TI - The problem of transition from pediatric to adult healthcare in patients with steroid-sensitive nephrotic syndrome (SSNS): a survey of the experts. AB - BACKGROUND: The importance of the transition from pediatric to adult healthcare has recently been recognized. In patients with steroid-sensitive nephrotic syndrome (SSNS), the shift in steroid dose during the transition period is a big problem. Thus, change in treatment methods during this transition need to be clarified. METHODS: Questionnaires were sent to all councilors of the Japanese Society for Pediatric Nephrology who managed SSNS in children. The questionnaires asked about steroid dose, informed consent, and transition programs. Councilors in 50 of 57 (87.7 %) institutes responded within 2 weeks. RESULTS: About one third of pediatric nephrologists (PNs) did not transfer patients to adult units, and half of PNs followed patients after they reached adulthood (i.e., age >20 years). The dose of steroids after puberty varied between doctors, but 74 % of PNs provided short-term daily therapy. 72 % of PNs informed the patients of the shift in steroid dose, but 26 % of PNs did not. About two-thirds of PNs did not consult with adult nephrologists before the transition from pediatric to adult care. No institute had a transition program for SSNS and 2 institutes had transition coordinators. CONCLUSION: Transition programs are needed in Japan. But the difference in the steroid regimen between pediatric and adult patients with SSNS is a barrier to transition. This difference needs to be discussed. PMID- 24488118 TI - Empathy and empathy induced prosocial behavior in 6- and 7-year-olds with autism spectrum disorder. AB - The present study aimed to assess empathy and prosocial behavior in 6-7 year old children with autism spectrum disorders (ASDs). Results showed, first, lower levels of parent- and teacher-rated cognitive empathy, and similar levels of affective empathy in children with ASD compared to typically developing (TD) children. Second, emotion recognition for basic emotions, one aspect of cognitive empathy, in a story task was adequate in ASD children, but ASD children with severe impairments in social responsiveness had difficulties in recognizing fear. Third, prosocial behavior in response to signals of distress of a peer in a computer task was similar in ASD as in TD children. In conclusion, early elementary school children with ASD show specific impairments in cognitive empathy. PMID- 24488119 TI - Brief report: effects of solution-focused brief therapy group-work on promoting post-traumatic growth of mothers who have a child with ASD. AB - The study evaluated the impact of solution-focused brief therapy (SFBT) group work on the post-traumatic growth (PTG) of mothers who have a child with ASD. A quasi-experimental design was used in which 43 mothers participated. 18 mothers in 2 SFBT groups (n = 9 in each group) received a 6-session SFBT group therapy while 25 mothers in a control group received no treatment. The Post-traumatic Growth Inventory was used to measure the PTG levels of the participants at baseline, post-treatment and 6-month follow-up assessments. Mothers who attended SFBT group-work reported higher PTG scores both at post-treatment (t = 4.065, p = .001) and 6-month follow-up (t = 2.980, p = .006) assessments. Further investigations to prove whether SFBT in groups can increase the positivity of clients would promote the use of SFBT. PMID- 24488120 TI - Young friendship in HFASD and typical development: friend versus non-friend comparisons. AB - This study conducted comparative assessment of friendship in preschoolers with high-functioning autism spectrum disorder (HFASD, n = 29) versus preschoolers with typical development (n = 30), focusing on interactions with friends versus acquaintances. Groups were matched on SES, verbal/nonverbal MA, IQ, and CA. Multidimensional assessments included: mothers' and teachers' reports about friends' and friendship characteristics and observed individual and dyadic behaviors throughout interactions with friends versus non-friends during construction, drawing, and free-play situations. Findings revealed group differences in peer interaction favoring the typical development group, thus supporting the neuropsychological profile of HFASD. However, both groups' interactions with friends surpassed interactions with acquaintances on several key socio-communicative and intersubjective capabilities, thus suggesting that friendship may contribute to enhancement and practice of social interaction in HFASD. PMID- 24488122 TI - Associations Between Dysfunctional Personality Traits and Intimate Partner Violence in Perpetrators and Victims. AB - In the current study, the role of borderline and antisocial personality traits and psychological and physical forms of intimate partner violence were examined. Using self- and partner-reports, 30 perpetrators (28 males) and 30 victims (29 females) of partner violence, including 23 (former) couples, were interviewed. Results showed that perpetrators (i.e., males) were higher on antisocial personality traits than victims (i.e., females), but the two groups did not differ on borderline traits and self-reported violence. Moreover, borderline traits were associated with partner violence in general, whereas antisocial personality traits were associated with physical, but not psychological, partner violence. Analyses on (former) couples suggest that there is little congruence between perpetrators' and victims' reports of partner violence. In conclusion, the findings of the current study not only emphasized the complex nature of intimate partner violence but also showed that dysfunctional personality traits and gender play a significant role in both the display and reporting of partner violence. PMID- 24488121 TI - A proteomic survey of widespread protein aggregation in yeast. AB - Many normally cytosolic yeast proteins form insoluble intracellular bodies in response to nutrient depletion, suggesting the potential for widespread protein aggregation in stressed cells. Nearly 200 such bodies have been found in yeast by screening libraries of fluorescently tagged proteins. In order to more broadly characterize the formation of these bodies in response to stress, we employed a proteome-wide shotgun mass spectrometry assay in order to measure shifts in the intracellular solubilities of endogenous proteins following heat stress. As quantified by mass spectrometry, heat stress tended to shift the same proteins into insoluble form as did nutrient depletion; many of these proteins were also known to form foci in response to arsenic stress. Affinity purification of several foci-forming proteins showed enrichment for co-purifying chaperones, including Hsp90 chaperones. Tests of induction conditions and co-localization of metabolic enzymes participating in the same metabolic pathways suggested those foci did not correspond to multi-enzyme organizing centers. Thus, in yeast, the formation of stress bodies appears common across diverse, normally diffuse cytoplasmic proteins and is induced by multiple types of cell stress, including thermal, chemical, and nutrient stress. PMID- 24488123 TI - The Non-Medical Use of Prescription Drugs and Lifetime Experiences of Sexual Victimization Among College Men. AB - The non-medical use of prescription drugs (NMUPD) has been linked with many negative outcomes in previous studies. Recent literature has begun to examine the role of NMUPD among sexual victimization survivors. The present study examined the associations between NMUPD, recreational drug use, and experiences of sexual victimization among college men. Undergraduate men (n = 253) elected to take an online survey examining drug use and lifetime sexual victimization experiences. A total of 17% of the sample reported instances of being sexually victimized in their lifetime across four domains (being coerced, threatened, physically forced, or taken advantage of while incapacitated). Results indicate that, across all domains of sexual victimization, non-medical sedative use was robustly associated with sexual victimization in a multivariate model controlling for recreational drug use and demographics. No other non-medically used drug class (anxiolytics, pain medications, and stimulants) was associated with experiences of sexual victimization in the multivariate model. Results expand past literature by illustrating specific drug classes used by survivors of sexual victimization. Implications for interventions for male sexual victimization survivors are discussed. PMID- 24488124 TI - Thyroid nodules >= 4 cm: can ultrasound and cytology reliably exclude cancer? Reply. PMID- 24488126 TI - Identity styles, positive youth development, and civic engagement in adolescence. AB - Identity formation is a core developmental task of adolescence. Adolescents can rely on different social-cognitive styles to seek, process, and encode self relevant information: information-oriented, normative, and diffuse-avoidant identity styles. The reliance on different styles might impact adolescents' adjustment and their active involvement in the society. The purpose of this study was to examine whether adolescents with different identity styles report differences in positive youth development (analyzed with the Five Cs-Competence, Confidence, Character, Connection, and Caring-model) and in various forms of civic engagement (i.e., involvement in school self-government activities, volunteering activities, youth political organizations, and youth non-political organizations). The participants were 1,633 (54.1 % female) 14-19 year old adolescents (M age = 16.56, SD age = 1.22). The findings indicated that adolescents with different identity styles differed significantly on all the Five Cs and on two (i.e., involvement in volunteering activities and in youth non political organizations) forms of civic engagement. Briefly, adolescents with an information-oriented style reported high levels of both the Five Cs and civic engagement; participants with a normative style reported moderate to high scores on the Five Cs but low rates of civic engagement; diffuse-avoidant respondents scored low both on the Five Cs and on civic engagement. These findings suggest that the information-oriented style, contrary to the diffuse-avoidant one, has beneficial effects for both the individual and the community, while the normative style has quite beneficial effects for the individual but not for his/her community. Concluding, adolescents with different identity styles display meaningful differences in positive youth development and in rates of civic engagement. PMID- 24488127 TI - Alkali burn to the eye: protection using TNF-alpha inhibition. AB - PURPOSE: The aim of this study was to evaluate early retinal damage after induction of ocular surface alkali burns and the protective effects of tumor necrosis factor alpha (TNF-alpha) blockade. METHODS: Alkali injury was induced in mouse corneas by using 1 N NaOH. Retinal damage was assessed using a terminal deoxynucleotidyl transferase 2'-deoxyuridine 5-triphosphate nick end labeling (TUNEL) assay, 15 minutes to 14 days postburn. Immune cell infiltration was assessed by CD45 immunolocalization. Retinal cytokines were quantified using the enzyme-linked immunosorbent assay for interleukin (IL)1beta, IL2, IL6, TNF-alpha, CCL5, and macrophage inflammatory protein-1alpha. Protection against retinal damage was attempted with a single dose of either anti-TNF-alpha antibody (infliximab, 6.25 mg/kg) or control immunoglobulin G (IgG), administered intraperitoneally 15 minutes after the burn was inflicted. Corneal injury was evaluated by using TUNEL and CD45 immunolocalization and by quantifying corneal neovascularization. RESULTS: There was significant damage to the retina within 24 hours of the corneal burn being inflicted. TUNEL+ labeling was present in 80% of the retinal ganglion cells, including a few CD45+ cells. There was a 10-fold increase in the retinal inflammatory cytokines in the study groups compared with that in controls. A single intraperitoneal dose of anti-TNF-alpha antibody, administered 15 minutes after the burn, markedly reduced retinal TUNEL+, CD45+ labeling, and inflammatory cytokine expression, compared with that in the controls. Additionally, TNF-alpha blockade caused a marked reduction in corneal neovascularization, and in cornea TUNEL and CD45 labeling, 5 days after the burn. CONCLUSIONS: This study shows that alkali corneal burns can induce significant retinal damage within 24 hours. A single dose of anti-TNF-alpha antibody, administered 15 minutes after inflicting the burn, provides significant retinal and corneal protection. This could lead to the discovery of novel therapies for patients with alkali injuries. PMID- 24488128 TI - Short-term influence of aspirating speculum use on dry eye after cataract surgery: a prospective study. AB - PURPOSE: The aim of this study was to investigate the short-term influence of the use of an aspirating speculum on dry eye after performing cataract surgery. METHODS: This study was conducted using a prospective, consecutive, comparative, interventional case series of 58 eyes of 58 patients who underwent clear corneal cataract surgery; 29 eyes were treated using an aspirating speculum, and 29 eyes were treated without using a nonaspirating speculum. The main outcome measures were sequential changes of dry eye parameters including conjunctival staining, tear film break-up time (tBUT), conjunctivochalasis grades, and ocular surface disease index (OSDI). RESULTS: In the nonaspirating speculum group, tBUT and conjunctivochalasis grades were aggravated on day 1 postoperatively (P < 0.001), but conjunctival staining and OSDI did not show any significant change during the follow-up. In the aspirating speculum group, significant aggravation was observed by conjunctival staining on day 1 postoperatively (P = 0.001), tBUT and conjunctivochalasis grades were evaluated on day 1 and day 7 postoperatively (P < 0.001), and the OSDI was evaluated on day 7 postoperatively (P = 0.011). CONCLUSIONS: The use of an aspirating speculum aggravated dry eye parameters during the early postoperative period. Although these parameters returned to their preoperative values at 1 month postoperatively, the use of an aspirating speculum has the potential to aggravate dry eyes after cataract surgery is performed. PMID- 24488129 TI - Distribution of non-gal antigens in pig cornea: relevance to corneal xenotransplantation. AB - PURPOSE: The aim of this study was to investigate the distribution of antigens other than galactose-alpha-1,3-galactose (Gal) (non-Gal) recognized by human and rhesus monkey serum antibodies in the alpha-1,3-galactosyltransferase gene knockout (GTKO) pig cornea. METHODS: The distribution of non-Gal, specifically N glycolylneuraminic acid (NeuGc), in the corneas from wild-type (WT) and GTKO pigs was identified. Corneal sections from WT and GTKO pigs were incubated with human or rhesus monkey serum to determine immunoglobulin (Ig)M and IgG binding to corneal tissue by means of fluorescent microscopy. RESULTS: Strong expression of NeuGc was found in all layers of both WT and GTKO pig corneas. In both humans and monkeys, antibody binding (IgG > IgM) to GTKO was found to be weaker than that to entire WT pig corneas, but in both, most antibody binding, especially IgG, was to the epithelium. There was weak diffuse antibody binding, especially of IgG, to the corneal stroma, suggesting binding to antigens expressed on collagen. There was no or minimal binding of IgM/IgG to the corneal endothelium. CONCLUSIONS: Although the cornea is avascular, antibodies in primate serum can bind to pig antigens, especially on epithelial cells and stromal collagen. Although the binding to entire GTKO corneas was weaker than that to WT corneas, deletion of the expression of NeuGc and expression of human complement-regulatory proteins in the pig cornea will be important if prolonged clinical corneal xenograft survival is to be achieved. PMID- 24488130 TI - New graft inserter for descemet stripping automated endothelial keratoplasty. AB - PURPOSE: The aim of this study was to introduce a newly developed graft inserter for Descemet stripping automated endothelial keratoplasty, which can be readily used with 1 hand, and to examine endothelial cell loss (ECL) after graft insertion using this new inserter in an ex vivo rabbit model. METHODS: Rabbit corneal grafts (~150 MUm) were prepared by using a femtosecond laser. The grafts were inserted into an artificial anterior chamber by the pull-through technique using a Busin glide or the push-out technique using our new inserter. ECL was evaluated by means of trypan blue and alizarin red S staining. Grafts that were not injected served as a control group. RESULTS: The mean percentages of ECL area in the control, Busin glide, and new inserter groups were 18.7 +/- 1.79%, 25.4 +/ 2.32%, and 24.7 +/- 1.56%, respectively. The mean percentages of the ECL area in both the Busin glide group and new inserter groups were significantly greater than that in the control group (P = 0.001). There was no statistically significant difference between the Busin glide group and the new inserter group. CONCLUSIONS: Our new inserter may provide a favorable option for donor tissue insertion in Descemet stripping automated endothelial keratoplasty procedures. PMID- 24488131 TI - Evidence of donor corneal endothelial cell migration from immune reactions occurring after descemet membrane endothelial keratoplasty. AB - PURPOSE: The migratory capacity of donor corneal endothelial cells after Descemet membrane endothelial keratoplasty (DMEK) is not fully understood. We report 2 patients who developed immune reactions after DMEK with endothelial precipitates detectable not only on the grafts but also on host corneal areas stripped off the host Descemet membrane during surgery and initially not covered by the donor Descemet membrane and endothelium ("naked stroma"), strongly suggesting that migration of donor-derived endothelial cells had occurred. METHODS: Observational case series of 2 patients. RESULTS: A 71-year-old man (case 1) and an 84-year-old man (case 2) with Fuchs endothelial dystrophy underwent successful DMEK surgery. Postoperatively, the peripheral corneal stroma showed a denuded area that was not covered by the DMEK graft or by the patients' residual Descemet membrane (because of large descemetorhexis and slight graft decentration). After 18 (case 1) and 6 (case 2) months, a diffuse endothelial immune reaction with precipitates on the graft and, surprisingly, also on peripheral corneal areas that were initially denuded of the host Descemet membrane and not covered by the donor Descemet membrane was observed. The outermost corneal parts covered by the patients' own residual Descemet membrane showed no precipitates. Under treatment with topical corticosteroids, the precipitates rapidly disappeared. Visual acuity, central corneal thickness, and endothelial cell counts were not significantly affected. CONCLUSIONS: The immune reaction episodes in our patients with endothelial precipitates detectable on adjacent host areas initially stripped off and not covered by donor Descemet membrane provide direct in vivo evidence of donor corneal endothelial cell migration after DMEK, filling areas of "naked stroma." PMID- 24488132 TI - Descemet membrane endothelial keratoplasty combined with epithelial debridement and mitomycin-C application for fuchs dystrophy with preoperative subepithelial fibrosis or anterior basement membrane dystrophy. AB - PURPOSE: The aim of this study was to evaluate the anterior corneal surface regularity and light scattering before and after Descemet membrane endothelial keratoplasty (DMEK) with epithelial debridement and application of mitomycin C in Fuchs dystrophy-affected eyes with preoperative subepithelial fibrosis or anterior basement membrane dystrophy. METHODS: In this case-control study, a chart review identified 37 eyes with Fuchs dystrophy and anterior corneal changes evident on preoperative slit lamp examination and that underwent DMEK combined with epithelial removal plus mitomycin-C application. These cases were compared with 83 contemporaneous DMEK procedures performed in eyes with Fuchs dystrophy without clinically evident anterior surface problems (controls). The outcome measures were corrected distance visual acuity (CDVA), corneal surface regularity assessed by topography, anterior corneal light scattering by densitometry, endothelial cell loss, and complications. RESULTS: Cases and controls had comparable demographics. Preoperatively, the cases had significantly poorer corneal surface regularity and transparency than did controls (P < 0.0001). Six months postoperatively, the cases achieved comparable CDVA, corneal surface regularity, and transparency as did controls (all P > 0.05), and 77% had a CDVA >= 20/25, excluding 2 eyes with preexisting retinal problems. The median 6-month endothelial cell loss was 25% and did not differ significantly between cases and controls (P = 0.31). In 1 case, there was delayed epithelial healing. CONCLUSIONS: Even patients with endothelial dysfunction with anterior stromal changes can realize a significant improvement in corneal surface topography and transparency by undergoing combined epithelial removal with DMEK, and this can preclude the need for a subsequent procedure to address residual corneal surface problems or the need for a penetrating keratoplasty. PMID- 24488134 TI - The uptake of simple phenols by barley roots. AB - Kinetic studies of the uptake of hydroquinone-beta-D-glucoside (arbutin) by excised roots of barley demonstrated that this compound is actively transported. Similar studies on the uptake of hydroquinone indicated that the latter compound enters the root tissues by diffusion. A concentration gradient favouring diffusion is maintained for at least three hours by the conversion of the aglucone to its correspondings glucoside. Hydroquinone, at a concentration of 5 mM, reduced uptake of (86)rubidium ion by approximately 30%. PMID- 24488133 TI - A30P alpha-Synuclein interferes with the stable integration of adult-born neurons into the olfactory network. AB - Impaired olfaction is an early symptom in Parkinson disease (PD), although the exact cause is as yet unknown. Here, we investigated the link between PD-related mutant alpha-Synuclein (alpha-SYN) pathology and olfactory deficit, by examining the integration of adult-born neurons in the olfactory bulb (OB) of A30P alpha SYN overexpressing mice. To this end, we chose to label one well-known vulnerable subpopulation of adult-born cells, the dopaminergic neurons. Using in vivo two photon imaging, we followed the dynamic process of neuronal turnover in transgenic A30P alpha-SYN and wild-type mice over a period of 2.5 months. Our results reveal no difference in the number of cells that reach, and possibly integrate into, the glomerular layer in the OB. However, in mutant transgenic mice these new neurons have a significantly shortened survival, resulting in an overall reduction in the addition of neurons to the glomerular layer over time. We therefore propose unstable integration and impaired homeostasis of functional new neurons as a likely contributor to odour discrimination deficits in mutant alpha-SYN mice. PMID- 24488135 TI - [Aging of the photosynthetic apparatus : III. Variations and characteristics of o diphenoloxidase activity (Polyphenoloxidase) during aging in vitro of isolated spinach chloroplasts]. AB - The variations and characteristics of o-diphenoloxidase activity (O-diphenol-O2 oxidoreductase EC 1.10.3.1) were examined in aging, isolated spinach chloroplasts to determine whether this activity, measured in the presence of 4-methylcatechol as substrate, could be responsible for the inhibition of O2 evolution during aging of these organelles in dark and light.The rate of the Hill reaction (oxygen evolution and the corresponding photoreduction of ferricyanide) during aging in the dark was inhibited at pH 8.0 and stimulated at pH 6.5. This difference did not depend on the nature of the buffer used (Tris-HCl or phosphate). Furthermore, the pH optimum for the ferricyanide-Hill reaction was shifted to lower values (from pH 8.0 to 6.5) on aging of chloroplasts. This phenomenon is probably due to uncoupling during aging. In the light, the Hill reaction was markedly inhibited. However, the ratio MUmoles O2 evolved/MUmoles ferricyanide reduced diminished slowly in darkness and rapidly when the chloroplasts were aged in the light.Aging of chloroplasts in darkness was accompanied by a slow decrease in the latent period which precedes the initiation of the oxidation, followed by an increase in O-diphenoloxidase activity. Light-aged chloroplasts showed an initial stimulation and then a smaller increase in enzyme activity compared with that of the dark aged chloroplasts. This latter phenomenon was probably due to secondary reactions caused by photo-inactivation. Under light conditions, the latent period decreased rapidly and disappeared after one hour.This latent period varied considerably with the season and was reduced or obliterated by treatments with light, fatty acids, Triton-X, hypotonic medium and increasing concentrations of substrate: that is by treatments which generally enhance chloroplast swelling. Thus it appears that the latent period is not a characteristic of O-diphenoloxidase but depends on the integrity of chloroplast structure.The enzyme activity was characterized by a stoichiometry of about 1 MUmoles O2 consumed per 1.2 MUmoles substrate oxidized, indicating that oxidation was probably proceeding further than conversion of O-diphenol to O-diquinone. The latter compound could be used as a Hill oxidant and it permitted measurement of O2 evolution in the same reaction mixture in the presence of light. Under these experimental conditions, O2 evolution (a DCMU sensitive reaction) was first stimulated in dark-aged chloroplasts and rapidly inhibited in light-aged chloroplasts.At appropriate concentrations, KCN, a potent inhibitor of oxidases, enhanced O2 evolution, suggesting that O-diphenoloxidase activity interferes with O2 evolution. This possibility is discussed in view of our previous findings on chloroplast aging in vitro. PMID- 24488136 TI - Phosphopyruvate carboxylase activity and carbon dioxide fixation via C4 acids over the division cycle in synchronized Euglena cultures. AB - Phosphoryruvate carboxylase activity was determined in division synchronized Euglena gracilis strain Z cultures. The profile of enzyme activity was essentially that of a "peak enzyme"; activity increased over the light phase of the cycle, doubling by early dark phase followed by a substantial decline in activity near the end of the dark phase. Dark carbon dioxide fixation did not parallel changes in phosphoryruvate carboxylase activity. The rate of carbon dioxide fixation increased fourfold over the light phase but decreased in the dark phase until it was only double the rate at the beginning of the light phase.Although the specific activity of phosphopyruvate carboxylase was greater than that of ribulose 1-5 diphosphate carboxylase in Euglena cell extracts at all stages over the division cycle C4 acids were not an early product of carbon dioxide fixation in the light, neither did they ever account for more than a small proportion of the total (14)C present in the soluble fraction of the cells. Phosphopyruvate carboxylase was shown by the non-aqueous localization technique to be present in the cytoplasm in Euglena, and it is concluded that the main function of this enzyme in algal cells is to provide an anaplerotic sequence to the tricarboxylic acid cycle. PMID- 24488137 TI - Reserve carbohydrate metabolism in germinating seeds of trigonella foenum-graecum L. (Leguminosae). AB - Seeds of Trigonella foenum-graecum are examined light microscopically and by chemical analysis at different stages of germination.In the earliest stages of germination the raffinose family oligosaccharides are metabolised both in the endosperm and in the cotyledons of the seed but there is no change in the appearance, amount or composition of the main carbohydrate reserve, a galactomannan localised in the endosperm. About 18 hours after the emergence of the radicle the endosperm galactomannan begins to be mobilised. In a period of 24 hours the polysaccharide is completely degraded and the breakdown products, mainly galactose and mannose, are absorbed by the cotyledons in which sucrose increases and starch is formed.Mobilisation of the galactomannan is accompanied by the formation in the endosperm of a dissolution zone the form of which implies that the aleurone layer is involved in the degradation process. PMID- 24488138 TI - An analysis of the response in phloem exudation on application of massage to Ricinus. AB - A study, made on the phloem exudation profiles from Ricinus plants given varying degrees of pre-treatment by massage, has revealed that the profiles are governed by sealing systems of considerable complexity. One of the most interesting profiles observed involves an initial rapid escape of sap from a single cut which ceases after several minutes, then recommences and builds up prior to a second slow decline; this has been called the "rebleed" phenomenon. At least two mechanisms must be postulated to explain this profile satisfactorily.Massage pre treatment seems to enhance potential exudation quite locally; even half an internode may be treated with little influence on adjacent tissue. The induced build up in potential exudation gradually increased over several days and after suspension of massage declined at a comparable rate. Massage during exudation can be used to stop flow but exudation may recommence after a period, resembling the "rebleed" exudation profile. PMID- 24488139 TI - [Microbodies and diaminobenzidine reaction in the acetate flagellates Polytomella caeca and Chlorogonium elongatum]. AB - In two forms of acetate flagellates, the colourless Volvocale Polytomella caeca and the green Volvocale Chlorogonium elongatum, cell organelles can be demonstrated which are ultrastructurally similar to microbodies of higher organisms. The organelles do not have a close association with the endoplasmic reticulum and are located in the peripheral cytoplasm between the elongated mitochondria. In Polytomella they exhibit more or less spherical profiles in section and have a maximum diameter of approximately 0.2-0.25 MU. In Chlorogonium the organelles occasionally have an elongated shape and are larger than in Polytomella. Employing the electron microscopic cytochemical reagent diaminobenzidine (DAB)/H2O2 to localize the microbodial marker enzyme catalase in these organelles, it was found that no accumulation of the electron-opaque product occurs in the microbodies either at alkaline or neutral pH or at room temperature or 37 degrees C. Only the cristae of mitochondria are stained with the DAB reaction caused by cytochrome oxidase and possibly by a cytochrome peroxidase.Organelles of Polytomella caeca containing catalase or cytochrome oxidase can be separated by rate centrifugation of a crude particulate fraction on a sucrose gradient (Gerhardt, 1971). The particles isolated from the peak of catalase activity show the same fine structural characteristics as the microbodies in situ do. But again, there is no detectable staining of these organelles by the DAB/H2O2 reaction.The identity of the microbody-like particles in Polytomella caeca and Chlorogonium elongatum with microbodies in general is deduced despite the negative results in cytochemical localization of catalase in these organelles. PMID- 24488140 TI - [Demonstration of a threshold regulation by phytochrome in the photomodulation of longitudinal growth of the hypocotyl of mustard seedlings (Sinapis alba L.)]. AB - The inhibition of hypocotyl lengthening in intact mustard seedlings is controlled by two photosensitive systems which can be experimentally separated. 1. Kinetics of the growth response in the dark after red and far-red irradiation (Figs. 1, 2) demonstrate the operation of Pfr in the ground state via a threshold mechanism similar to the regulation of lipoxygenase synthesis in the mustard cotyledons (c. f. ref. [27]). This threshold mechanism determines the duration of the growth inhibition (Deltat) following irradiation (Fig. 1, 2). Deltat is dependent on the relative Pfr concentration at the beginning of the dark period and on the half life of Pfr destruction, but it is independent of the quantum flux density of far red light (Fig. 4). The effect of 5 min red light on Deltat can be fully reversed by 5 min far-red light (Fig. 3). The data reveal a quantitative relationship between the relative Pfr concentration and the photomorphogenetic response, Deltat (Fig. 6). This relationship may explain in principle the logarithmic correlation between the percentage of phytochrome converted to Pfr by an initial irradiation and the subsequent response which has also been reported in the literature. 2. In continuous far-red light the velocity constant of the steady state growth is controlled by a "high intensity reaction" which shows the usual logarithmic dependence on quantum flux density (Fig. 4, 5), but no phytochrome destruction is apparent (Fig. 2). According to Hartmann (ref.[11-13]) this "high intensity reaction" can also be attributed to Pfr, which in this case acts through some excited state, P fr (*) . It is concluded that the two photoreactive systems involve separate populations of phytochrome, which inhibit cell lengthening by independent control mechanisms. PMID- 24488141 TI - Standardization of the nomenclature based on contemporary mesocolic anatomy is paramount prior to performing a complete mesocolic excision. PMID- 24488142 TI - Copper-catalyzed ortho-C-H amination of protected anilines with secondary amines. AB - A practical Cu-catalyzed picolinamide-directed o-amination of anilines showing excellent mono-substitution selectivity and high functional group tolerance has been developed. PMID- 24488143 TI - Exposure-response relationship of T-DM1: insight into dose optimization for patients with HER2-positive metastatic breast cancer. AB - Exposure-response (E-R) analyses for ado-trastuzumab emtansine (T-DM1, Kadcyla) were performed using data from a randomized, active control (lapatinib plus capecitabine) trial in patients with human epidermal growth factor 2-positive metastatic breast cancer. Kaplan-Meier survival analyses stratified by T-DM1 trough concentration on day 21 of cycle 1 (Cmin,C1D21) were performed for overall survival (OS) and progression-free survival (PFS). E-R analyses indicated that after adjusting for baseline risk factors, higher T-DM1 exposure is associated with improved efficacy. T-DM1-treated patients with Cmin,C1D21 lower than the median value had values of OS and PFS comparable to those of the active control arm. The percentage of patients who received T-DM1 dose adjustments was similar across the exposure range and was lower than that of the active control arm. Our findings suggest that there may be an opportunity to optimize Kadcyla dose in the patient subgroup with low T-DM1 exposure for improved efficacy with acceptable tolerability. PMID- 24488145 TI - Atypical manifestation of IgG4-related disease mimicking musculoskeletal infection. PMID- 24488144 TI - Drug resistance of a viral population and its individual intrahost variants during the first 48 hours of therapy. AB - Using hepatitis C virus (HCV) and interferon (IFN) resistance as a proof of concept, we have devised a new method for calculating the effect of a drug on a viral population, as well as the resistance of the population's individual intrahost variants. By means of next-generation sequencing, HCV variants were obtained from sera collected at nine time points from 16 patients during the first 48 h after injection of IFN-alpha. IFN-resistance coefficients were calculated for individual variants using changes in their relative frequencies, and for the entire intrahost viral population using changes in viral titer. Population-wide resistance and presence of IFN-resistant variants were highly associated with pegylated IFN-alpha2a/ribavirin treatment outcome at week 12 (P = 3.78 * 10(-5) and 0.0114, respectively). This new method allows an accurate measurement of resistance based solely on changes in viral titer or the relative frequency of intrahost viral variants during a short observation time. PMID- 24488146 TI - Synthetic polymers enable non-vitreous cellular cryopreservation by reducing ice crystal growth during thawing. AB - The cryopreservation of cells, tissue and organs is fundamental to modern biotechnology, transplantation medicine and chemical biology. The current state of-the-art method of cryopreservation is the addition of large amounts of organic solvents such as glycerol or dimethyl sulfoxide, to promote vitrification and prevent ice formation. Here we employ a synthetic, biomimetic, polymer, which is capable of slowing the growth of ice crystals in a manner similar to antifreeze (glyco)proteins to enhance the cryopreservation of sheep and human red blood cells. We find that only 0.1 wt% of the polymer is required to attain significant cell recovery post freezing, compared with over 20 wt% required for solvent-based strategies. These results demonstrate that synthetic antifreeze (glyco)protein mimics could have a crucial role in modern regenerative medicine to improve the storage and distribution of biological material for transplantation. PMID- 24488148 TI - Effect of preoperative consumption of high carbohydrate drink (Pre-Op) on postoperative metabolic stress reaction in patients undergoing radical prostatectomy. AB - AIM: To investigate the effects of oral carbohydrate solution consumed until 2 h before the surgery in the patients that would undergo open radical retropubic prostatectomy on postoperative metabolic stress, patient anxiety, and comfort. METHOD: A total of 50 adult patients, who were in ASA I-II group and would undergo open radical retropubic prostatectomy, were included in the study. While Group 1 = CH (n = 25) received oral glucose solution, Group 2 = FAM (n = 25) was famished starting from 24:00 h. Blood glucose, insulin, and procalcitonin levels of the patients were recorded, and the patients completed state-trait anxiety inventory (STAI) test, which reflects the anxiety level of the patients, both before surgery and on the postoperative 24th hour. In order to evaluate patient comfort, senses of hunger, thirst, nausea, and cold were assessed in the morning prior to the surgery. RESULTS: No difference was observed between the two groups in terms of demographic data and insulin resistance levels (p > 0.05). Comparing with the preoperative levels, insulin resistance showed statistically significant elevation in both groups (p < 0.05). Procalcitonin levels were similarly increased in both groups in the postoperative period (p < 0.05). Preoperative and postoperative STAI state scores were similar in both groups (p > 0.05). With regard to preoperative patient comfort, sense of hunger was present in lesser number of subjects and at lower level in Group 1 (p < 0.05). CONCLUSION: Preoperative consumption of high carbohydrate drink (Pre-op) decreases insulin resistance and enhances patient comfort leading to lesser sense of hunger and thirst in the preoperative period in open radical retropubic prostatectomies. PMID- 24488147 TI - The reciprocal interactions between astrocytes and prostate cancer cells represent an early event associated with brain metastasis. AB - Tumor establishment, growth, and survival are supported by interactions with microenvironment components. Here, we investigated whether the interactions between prostate cancer cells and cortical astrocytes are associated to a potential role for astrocytes in tumor establishment. We demonstrate that astrocytes interact in vitro with prostatic cancers cells derived from different metastatic sites. Astrocytes and their secreted extracellular matrix, stimulate DU145 cell (a brain-derived prostate tumor cell line) proliferation while inhibiting cell death and modulating the expression of several genes related to prostate cancer progression, suggesting the activation of EMT process in these cells. In contrast, DU145 cells and their conditioned medium inhibited cell proliferation and induced cell death of astrocytes. On the other hand, the astrocytes were unable to significantly induce an increment of LNCaP cell (a lymph node-derived prostate tumor cell line) proliferative activity. In addition, LNCaP cells were also unable to induce cell death of astrocytes. Thus, we believe that DU145 cells, but not LNCaP cells, present an even more aggressive behavior when interacting with astrocytes. These results provide an important contribution to the elucidation of the cellular mechanisms involved in the brain microenvironment colonization. PMID- 24488149 TI - A retrospective study of laparoscopic unilateral adrenalectomy for primary hyperaldosteronism caused by unilateral adrenal hyperplasia. AB - OBJECTIVE: To evaluated the long-term outcomes of laparoscopic unilateral adrenalectomy for primary aldosteronism (PA) caused by unilateral adrenal hyperplasia (UAH). METHODS: One hundred and sixty-four patients who underwent laparoscopic unilateral adrenalectomy for UAH from January 2004 to December 2011 were entered in this retrospective analysis. Patients demographics, perioperative parameters, and follow-up results were recorded and analyzed statistically. RESULTS: All 164 cases suffered hypertension with biochemical evidence of hyperaldosteronism prior to operation. Hypokalemia was observed in 52/164 (37.14%) patients. UAH was proved by multi-slice computed tomography (MSCT). All operations were completed successfully without any conversions or complications. Postoperative pathology confirmed that 164 cases were cortical nodular hyperplasia, of which 4 cases coexist with medullary hyperplasia and 7 with micro adenoma. At the median follow-up of 48 months, hypertension was cured in 88 (53.7%) patients, improved in 71 (43.3%) patients, and refractory in 5 (3.05%) patients. Hypokalemia and hyperaldosteronism were cured in all patients except re elevation of blood pressure and plasma aldosterone in two patients 1 month after adrenalectomy. CONCLUSIONS: As an underestimated subtype of PA, UAH is accepted gradually. Laparoscopic unilateral adrenalectomy is nowadays the preferred approach to treat patients with PA caused by UAH. When adrenal venous sampling is not allowed, high-resolution MSCT is a reliable test for lateralization of aldosterone hypersecretion in carefully selected patients and 97% had either cure or improvement in blood pressure control. PMID- 24488150 TI - Comparative analysis of alternative splicing, alternative polyadenylation and the expression of the two KIN genes from cytoplasmic male sterility cabbage (Brassica oleracea L. var. capitata L.). AB - The KIN genes are crucial members of the cold-regulated gene family. They play exclusive roles during the developmental processes of many organs and respond to various abiotic stresses in plants. However, little is known about the regulation of KIN gene expression in cytoplasmic male sterility (CMS) cabbages (Brassica oleracea L. var. capitata L.). We carried out a genome-wide analysis to identify the KIN genes in the CMS cabbage. Two non-redundant KIN genes, named BoKIN1 (Bol021262) and BoKIN2 (Bol030498), were identified. Reverse transcriptase PCR detected alternative splicing (AS) products of BoKIN1 (four AS products) and BoKIN2 (three AS products). In addition, alternative polyadenylation (APA) was observed for BoKIN1 and BoKIN2 in the CMS cabbage, resulting in variable 3'UTRs in their transcripts. Furthermore, the transcription levels of BoKIN1-0 and BoKIN2-0, the introns of which were spliced completely, were analyzed in various organs and young leaves treated by abiotic stresses. Our data indicated that BoKIN1-0 is highly expressed in various organs, whereas BoKIN2-0 is expressed exclusively in the stamen. Our study also suggested that BoKIN1-0 was upregulated significantly in young leaves of plants exposed to abscisic acid treatment, and cold and heat stress. BoKIN1 and BoKIN2 had differential AS and APA patterns in pre-mRNA processing, and showed differences in their expression patterns and transcript levels. BoKIN1 participates widely in organ development and responds to diverse abiotic stresses, whereas BoKIN2 plays a main role in stamen development in the CMS cabbage. PMID- 24488151 TI - Mental and substance use disorders from early adolescence to young adulthood among indigenous young people: final diagnostic results from an 8-year panel study. AB - OBJECTIVE: Our objective was to investigate change in prevalence rates for mental and substance abuse disorders between early adolescence and young adulthood in a cohort of indigenous adolescents who participated in an 8-year panel study. METHOD: The data are from a lagged, sequential study of 671 indigenous adolescents (Wave 1) from a single culture in the Northern Midwest USA and Canada. At Wave 1 (mean age 11.3 years, Wave 4 (mean age 14.3 years), Wave 6 (mean age 16.2 years), and at Wave 8 (mean age 18.3 years) the tribally enrolled adolescents completed a computer-assisted personal interview that included DISC-R assessment for 11 diagnoses. Our yearly retention rates by diagnostic wave were: Wave 2, 94.7 %; Wave 4, 87.7 %; Wave 6, 88.0 %; Wave 8, 78.5 %. RESULTS: The findings show a dramatic increase in lifetime prevalence rates for substance use disorders. By young adulthood, over half had met criteria of substance abuse or dependence disorder. Also at young adulthood, 58.2 % had met lifetime criteria of a single substance use or mental disorder and 37.2 % for two or more substance use or mental disorders. The results are compared to other indigenous diagnostic studies and to the general population. CONCLUSIONS: A mental health crisis exists within the indigenous populations that participated in this study. Innovations within current mental health service systems are needed to address the unmet demand of adolescents and families. PMID- 24488152 TI - Prevalence and comorbidity of psychiatric disorders among 6-year-old children: 2004 Pelotas Birth Cohort. AB - PURPOSE: Most studies published on the prevalence of psychiatric disorders in children were conducted in high-income countries despite the fact that nearly 90 % of the world's population aged under 18 live in low- and middle-income countries. The study aimed to assess the prevalence of psychiatric disorders among children of 6 years of age, to examine the distribution of psychiatric disorders by gender and socioeconomic status and to evaluate the occurrence of psychiatric comorbidities. METHODS: The 2004 Pelotas Birth Cohort originally comprised 4,231 live births from Pelotas, southern Brazil. A total of 3,585 (84.7 % of 4,231 births) children aged 6 years were assessed using the Development and Well-Being Assessment (DAWBA). RESULTS: Nearly 13 % of the children presented a psychiatric diagnosis according to DSM-IV, being more prevalent among males than females (14.7 and 11.7 %, respectively, p = 0.009). Anxiety disorders were the most prevalent of all disorders (8.8 %) and specific phobias (5.4 %) and separation anxiety disorder (3.2 %) were the most common subtypes. Attention deficit hyperactivity disorder (2.6 %), oppositional defiant disorder/conduct disorder (2.6 %), and depression (1.3 %) were also diagnosed. More than one psychiatric disorder was presented by 17 % of children. Socioeconomically disadvantaged children had a higher prevalence of psychiatric disorders. CONCLUSION: Our findings underline the early onset of psychiatric disorders among children and the frequent occurrence of psychiatric comorbidity. Early prevention is needed in the field of mental health in Brazil and should start during infancy. PMID- 24488154 TI - Transretroperitoneal CT-guided embolization of growing internal iliac artery aneurysm after repair of abdominal aortic aneurysm: a transretroperitoneal approach with intramuscular lidocaine injection technique. AB - This study was designed to evaluate the efficacy and safety of CT-guided embolization of internal iliac artery aneurysm (IIAA) after repair of abdominal aortic aneurysm by transretroperitoneal approach using the lidocaine injection technique to iliacus muscle, making window for safe needle path for three patients for whom CT-guided embolization of IIAA was performed by transretroperitoneal approach with intramuscular lidocaine injection technique. Transretroperitoneal access to the IIAA was successful in all three patients. In all three patients, the IIAA was first embolized using microcoils. The aneurysmal sac was then embolized with glue and coils without complication. With a mean follow-up of 7 months, the volume of the IIAAs remained stable without residual endoleaks. Transretroperitoneal CT-guided embolization of IIAA using intramuscular lidocaine injection technique is effective, safe, and results in good outcome. PMID- 24488153 TI - Depressive symptoms among adolescents and older adults in Mexico City. AB - PURPOSE: Determine the structure of depressive symptoms among adolescents and older adults through the person-centered approach of latent class analysis (LCA). METHODS: The study is based on data from two independent samples collected in Mexico City (2,444 adolescents and 2,223 older adults) which included the revised version of the CES-D. The presence or absence of depressed mood (dysphoria), diminished pleasure (anhedonia), drastic change in weight, sleep problems, thinking and concentration difficulties, excessive or inappropriate guilt, fatigue, psychomotor agitation/retardation, and suicide ideation were used in LCA to determine the structure of depressive symptoms for adolescents and older adults. RESULTS: Adolescents reported higher excessive or inappropriate guilt compared to older adults, while older adults had higher proportions of anhedonia, sleep problems, fatigue, and psychomotor agitation/retardation. Similar proportions were found in other symptoms. The LCA analysis showed the best fit with four latent classes (LC): LC 1, "symptoms suggestive of major depressive episode (MDE)" with prevalence of 5.9 % (n = 144) and 10.3 % (n = 230) among adolescents and older adults, respectively; LC 2, "probable MDE symptoms" 18.2 % (n = 446) and 23.0 % (n = 512); LC 3, "possible MDE" 27.7 % (n = 676) and 21.8 % (n = 485); LC 4, "without significant depressive symptoms" 48.2 % (n = 1,178) and 44.8 % (n = 996). The differences in item thresholds between the two groups (adolescents vs. older adults) were statistically significant (Wald test = 255.684, df = 1, p < 0.001). CONCLUSIONS: This study documented important similarities and differences in the structure of depressive symptoms between adolescents and older adults that merit acknowledgment, further study, and consideration of their potential clinical and public health implications. PMID- 24488155 TI - Investigation of retinal nerve fiber layer thickness in patients with neurofibromatosis-1. AB - PURPOSE: To compare the optical coherence tomography (OCT) findings of neurofibromatosis-1 (NF-1) patients with/without optic pathway glioma (OPG) with those of healthy controls. METHODS: Ten patients with NF-1, 17 patients with NF-1 associated OPGs, and 17 control subjects were included in the study. Retinal nerve fiber layer (RNFL) and macular thickness findings measured with Stratus OCT were compared between the groups. RESULTS: The average RNFL thickness was significantly lower in the OPG group (76.72 +/- 22.16 MUm) than in the controls (108.89 +/- 9.92 MUm) and NF-1 patients without OPGs (111.17 +/- 12.13 MUm) (p < 0.001). The macular volume was also found to be lower in NF-1 patients with OPG (6.41 +/- 0.66 mm(3)) than in the healthy controls (7.19 +/- 0.36 mm(3); p = 0.001) and NF-1 patients without OPGs (7.25 +/- 0.26 mm(3); p = 0.005). Following this analysis the OPG group was further subdivided into two categories: OPG patients with normal visual acuity (VA) and OPG patients with decreased VA. The statistical analysis was repeated for these four subgroups, revealing that while the decrement in the average RNFL thickness was significant for both OPG groups that in the macular volume was only significant for OPG patients with decreased VA. CONCLUSION: The results of our study suggest that RNFL thinning can be a helpful marker for the detection of OPGs in NF-1 patients. Larger studies with longitudinal data are required to confirm the role of OCT in the diagnosis and follow-up of these patients. PMID- 24488156 TI - Tracking the sensory environment: an ERP study of probability and context updating in ASD. AB - We recorded visual event-related brain potentials from 32 adult male participants (16 high-functioning participants diagnosed with autism spectrum disorder (ASD) and 16 control participants, ranging in age from 18 to 53 years) during a three stimulus oddball paradigm. Target and non-target stimulus probability was varied across three probability conditions, whereas the probability of a third non target stimulus was held constant in all conditions. P3 amplitude to target stimuli was more sensitive to probability in ASD than in typically developing participants, whereas P3 amplitude to non-target stimuli was less responsive to probability in ASD participants. This suggests that neural responses to changes in event probability are attention-dependant in high-functioning ASD. The implications of these findings for higher-level behaviors such as prediction and planning are discussed. PMID- 24488157 TI - A parent-mediated intervention that targets responsive parental behaviors increases attachment behaviors in children with ASD: results from a randomized clinical trial. AB - The current study is a randomized clinical trial evaluating the efficacy of Focused Playtime Intervention (FPI) in a sample of 70 children with Autism Spectrum Disorder. This parent-mediated intervention has previously been shown to significantly increase responsive parental communication (Siller et al. in J Autism Dev Disord 43:540-555, 2013a). The current analyses focus on children's attachment related outcomes. Results revealed that children who were randomly assigned to FPI showed bigger increases in attachment-related behaviors, compared to children assigned to the control condition. Significant treatment effects of FPI were found for both an observational measure of attachment-related behaviors elicited during a brief separation-reunion episode and a questionnaire measure evaluating parental perceptions of child attachment. The theoretical and clinical implications of these findings are discussed. PMID- 24488158 TI - Overweight and obesity: prevalence and correlates in a large clinical sample of children with autism spectrum disorder. AB - Autism Spectrum Disorders (ASDs) and childhood obesity (OBY) are rising public health concerns. This study aimed to evaluate the prevalence of overweight (OWT) and OBY in a sample of 376 Oregon children with ASD, and to assess correlates of OWT and OBY in this sample. We used descriptive statistics, bivariate, and focused multivariate analyses to determine whether socio-demographic characteristics, ASD symptoms, ASD cognitive and adaptive functioning, behavioral problems, and treatments for ASD were associated with OWT and OBY in ASD. Overall 18.1% of children met criteria for OWT and 17.0% met criteria for OBY. OBY was associated with sleep difficulties, melatonin use, and affective problems. Interventions that consider unique needs of children with ASD may hold promise for improving weight status among children with ASD. PMID- 24488159 TI - All that wheezes is not asthma: cognitive bias in pediatric emergency medical decision making. AB - OBJECTIVE: The objectives of this study were to highlight the intimate role that cognitive biases play in clinical decision making in the pediatric emergency department and to recommend strategies to limit their negative impact on patient care outcomes. METHODS: This was a descriptive study of 3 cases of presumed asthma exacerbation evolving into alternate diagnoses. RESULTS: The role cognitive biases played in either delay to diagnosis or missed diagnosis contributing to patient morbidity are illustrated in each case. CONCLUSIONS: Common cognitive biases play a role in the unique milieu of the pediatric emergency department. A case series of presumed patients with asthma illustrates how mental shortcuts (heuristics) taken in times of high decision density and uncertainty may lead to diagnostic errors and patient harm. Suggestions to address and prevent cognitive biases are presented. PMID- 24488160 TI - Posttraumatic superior ophthalmic vein thrombosis in a 2 years old. AB - Superior ophthalmic vein thrombosis (SOVT) usually results from inflammatory, infectious, or malignant causes. This case describes a 2-year-old boy with severe prolapsing chemosis and proptosis due to thrombosis of the right superior ophthalmic vein resulting from midfacial and right orbital fractures 1 week after the initial trauma. Magnetic resonance imaging and internal carotid artery angiogram are essential in the diagnosis of SOVT. The literature on issues surrounding this case was reviewed with emphasis on the diagnostic evaluation, differential diagnoses, and management of posttraumatic SOVT. PMID- 24488161 TI - An unexpected clinical course in a 29-day-old infant with ethanol exposure. AB - Ethanol exposure can affect all pediatric age groups but occurs most commonly in ambulatory children and adolescents. Infants are less likely to ingest ethanol because they have limited ability to explore their environments. However, ethanol exposures in infants can occur. We report the case of a 29-day-old (3.5 kg) baby girl who presented with a blood alcohol level of 301 mg/dL after ingesting formula that had been prepared with gin. To our knowledge, she is the youngest reported child with such an elevated ethanol level in the medical literature. Despite her markedly elevated blood alcohol level, she had an unexpectedly mild clinical course, exhibiting subtle neurologic symptoms but no hypothermia, hypoglycemia, or cardiorespiratory impairment. This case demonstrates that the ethanol-exposed infant may lack typical or clear symptoms of acute intoxication. Therefore, the clinician must have a low threshold for pursuing blood alcohol testing in infants and young children with altered mental status. A prompt diagnosis of ethanol exposure is important for ensuring the health and safety of the child. PMID- 24488162 TI - Traumatic asphyxia. AB - Traumatic asphyxia is a rare condition in children that usually occurs after severe compression to the chest or abdomen. We report 3 cases in patients 18, 20, and 36 months of age who presented signs and symptoms of traumatic asphyxia after car accidents. Two clinical features were consistent in all 3 patients: multiple petechiae on the face and bulbar conjunctival hemorrhage; 2 patients had facial cyanosis, and 1 had facial edema.In children, the number of clinical manifestations that should be evident to diagnose traumatic asphyxia has not been ascertained. However, in any history of trauma with compression of the chest or abdomen and signs of increased intravenous craniocervical pressure, traumatic asphyxia should be suspected. PMID- 24488163 TI - Acute posterior fossa epidural hematoma in a newborn infant with Menkes disease. AB - Epidural hematoma (EDH) in newborn infants is rare compared with other types of intracranial hemorrhages. Furthermore, posterior fossa EDH is extremely rare. We present a case of posterior fossa EDH in an infant with Menkes disease with accessory bones in the occiput. A male infant with a condition diagnosed with Menkes disease by prenatal testing was born at 39 weeks via vacuum extraction. The patient presented with a mild tremor at 2 days after delivery. A brain computed tomography (CT) scan showed an acute EDH in the posterior fossa, extending into the occipitoparietal area. Three-dimensional CT and bone window CT scan revealed several accessory bones, diastasis of 1 accessory suture, a communicated fracture, and a linear fracture in the occipital bone. Furthermore, a bone fragment from a communicated fracture displaced toward the inside. The patient was treated conservatively for EDH because of his good general condition. The hematoma gradually resolved, and his tremor did not recur. We suggest the following mechanism of posterior fossa EDH development in our patient: (1) external force was applied to the occiput inside the birth canal during delivery, resulting in diastasis; (2) a communicated fracture occurred, and a bone fragment displaced toward the inside (linear fracture was caused indirectly by the force); (3) a transverse sinus was injured by the fragment; and (4) EDH developed in both the posterior fossa and supratentorial region. Copper deficiency can also cause fragility of connective tissues, vessels, and bones. PMID- 24488164 TI - Infant botulism and indications for administration of botulism immune globulin. AB - Infant botulism is caused by the ingestion of Clostridium botulinum spores and leads to a life-threatening descending motor weakness and flaccid paralysis in infant children. This disease presents with symptoms such as constipation, weakness, and hypotonia and can lead to respiratory failure. Botulism immune globulin (BIG) was created to treat this deadly disease and functions by neutralizing all systemically circulating botulism toxins. It is indicated in children with clinically diagnosed infant botulism, before diagnostic confirmation, and has been shown to lead to a significant reduction in intensive care unit and hospital stay for these patients. This review article discusses the epidemiology, clinical presentation, history of BIG, and indications for administration of BIG. PMID- 24488166 TI - Emergency point-of-care ultrasound diagnosis of hematocolpometra and imperforate hymen in the pediatric emergency department. AB - A 12-year-old girl presented to the pediatric emergency department with a history of difficulty voiding and was found to have a firm, tender suprapubic mass on examination. Transabdominal emergency point-of-care ultrasound was used at the bedside to diagnose hematocolpometra due to an imperforate hymen. The diagnosis was confirmed by a comprehensive abdominal ultrasound and magnetic resonance imaging in the radiology suite. The patient was discharged on oral contraceptive medication and scheduled for an outpatient surgical hymenectomy following consultation with the gynecology service. PMID- 24488167 TI - Pediatric emergency medicine: legal briefs. PMID- 24488168 TI - ECGs in the ED. PMID- 24488169 TI - Accidental intra-arterial injection of propofol. PMID- 24488170 TI - Urine drug screens in pediatric psychiatric patients. PMID- 24488171 TI - Don't get in a flap!: a case report of progression through the spectrum of an acute aortic syndrome. AB - PURPOSE: To present a single case that clearly demonstrates the progression through the whole spectrum of an acute aortic syndrome, from a solitary penetrating aortic ulcer (PAU) through to multiple PAUs with intra-mural haematoma (IMH) progression. The index images show that despite the clinical presentation of an acute type B aortic dissection, a classical dissection flap is never demonstrated in this patient and thus highlights the need for early input from vascular surgery for all potential acute aortic syndromes. CASE REPORT: We present the case of a 71-year-old lady who attended the emergency department with hypertension and inter-scapular chest pain. Upon investigation with computed tomography aortography (CTA), she was found to have a solitary PAU only with minimal IMH. She did not demonstrate any classical radiological signs of acute type B aortic dissection. She was admitted under a medical team and her chest pain abated with no treatment. The treating medical team adjusted her anti hypertensive medication and discharged her home with an urgent vascular surgical outpatient appointment for further follow-up and surveillance. We acknowledge that a preferred approach would have been, at least admission and close blood pressure monitoring, with a repeat CTA the next day. Two days later, she represented with further chest pain and on repeat CTA was found to have multiple PAUs and progression of the small IMH. She was then admitted under vascular surgery and subsequently transferred to the parent tertiary referral vascular surgical unit. Despite aggressive anti-hypertensive management, she had persistent intractable chest pain and was treated with a single thoracic stent graft. Completion angiography demonstrated total resolution of the PAUs. CONCLUSION: This case along with index images demonstrates the whole spectrum of the acute aortic syndrome from a solitary PAU to multiple PAUs with IMH extension. Despite an eventual clinical picture of an acute type B aortic dissection, there was a notable absence of a classical dissection flap on any imaging. We recommend that all aortic pathologies should be at least discussed with and preferably managed by vascular surgeons. The absence of a classical dissection flap on imaging is not a contra-indication to emergent treatment with thoracic stent grafting and in select patients is actually the only therapy that will treat this pathology. PMID- 24488172 TI - Global gene expression distribution in non-cancerous complex diseases. AB - For gene expression in non-cancerous complex diseases, we systemically evaluated the sensitivities of biological discoveries to violation of the common normalization assumption. Our results indicated that gene expression may be widely up-regulated in digestive system and musculoskeletal diseases. However, global signal intensities showed little difference in other four disease types. PMID- 24488173 TI - TNFalpha-induced apoptosis in human myeloid cell lines HL-60 and K562 is dependent of intracellular ROS generation. AB - The present study determines the role of reactive oxygen species (ROS) production and calcium signaling evoked by the tumor necrosis factor-alpha (TNFalpha) on apoptosis in the human leukemia HL-60 and K562 cell lines. The results show that treatment of both cell lines cells with 10 ng/mL TNFalpha resulted in a rise in the percentage of apoptotic cells after 6 h of treatment. It was also observed that the administration of 10 ng/mL TNFalpha increased intracellular ROS production, as well as a time-dependent increase in caspase-8, -3, and -9 activities. The present results also show that the pretreatment with well-known antioxidants such as trolox and N-acetyl cysteine partially reduced the caspase activation caused by the administration of TNFalpha. The findings suggest that TNFalpha-induced apoptosis is dependent on alterations in intracellular ROS generation in human leukemia HL-60 and K562 cells. PMID- 24488174 TI - The Ras GTPase-activating-like protein IQGAP1 is downregulated in human diabetic nephropathy and associated with ERK1/2 pathway activation. AB - Podocyte injury may contribute to the pathogenesis of diabetic nephropathy (DN), but the underlying mechanism of hyperglycemia induced podocyte damage is not fully understood. The Ras GTPase-activating-like protein IQGAP1 is associated to the slit diaphragm proteins and the actin cytoskeleton in podocyte. Here, we studied IQGAP1 expression alterations in human DN biopsies and extracellular signal-regulated kinase (ERK)-dependent pathways of IQGAP1 expression in podocyte under high glucose (HG) media. In vivo, analysis of renal biopsies from patients with DN revealed a significant reduction in IQGAP1 expression compared to controls. In vitro, IQGAP1 mRNA and protein expression were observed to decline under HG media at 48 h. But phosphorylation of ERK1/2 was activated under HG media at 24 h and 48 h. However, HG-induced downregulation of IQGAP1 protein was attenuated by specific ERK1/2 activation inhibitor PD98059. Taken together, these results highlight the importance of IQGAP1 in DN, and suggest that IQGAP1 expression in podocyte under HG media is modulated by the ERK1/2 pathway, which may lead to the future development of therapies targeting IQGAP1 dysfunction in podocytes in DN. PMID- 24488175 TI - Association of multiple biomarkers and classical risk factors with early carotid atherosclerosis: results from the Gutenberg Health Study. AB - BACKGROUND: In the Gutenberg Health Study, a random sample of the population was scanned with vascular ultrasound for early atherosclerosis. A continuous classical risk marker model (waist circumference, HbA1c, LDL/HDL ratio, pack years and pulse pressure) was compared to a model of modern biomarkers (C reactive protein, troponin I, N-terminal pro B-type natriuretic peptide, copeptin, mid-regional pro-adrenomedullin, and asymmetric dimethylarginine) with regard to the ability of ruling out abnormal intima-media thickness (IMT), respectively, carotid plaques. METHODS: Data of the first consecutive 5,000 participants (aged 35-74 years; 2,540 men, 2,460 women) were analyzed. IMT was measured at both common carotid arteries using an edge detection system. Plaques were defined as protrusion of >=1.5 mm in common, internal and external carotid artery. RESULTS: For classical risk factors, in comparison to a model of six modern biomarkers, regarding the variable (a) IMT>0.85 mm negative and positive predictive value (NPV and PPV) were 0.98 and 0.16 for both the classical risk factor model and the biomarker model. The second variable (b) presence of plaque could be ruled out with an NPV of 0.84 and identified with a PPV of 0.61 for classical risk factors, and 0.84 and 0.58 for biomarkers, respectively. Values were calculated using logistic regression analysis. CONCLUSION: Classical risk factors allow ruling out pathologic IMT and presence of carotid plaques in a population of primary prevention in a reliable way. Modern biomarkers performed almost equally well but did not provide further information. PMID- 24488176 TI - Temperature alters Plasmodium blocking by Wolbachia. AB - Very recently, the Asian malaria vector (Anopheles stephensi) was stably transinfected with the wAlbB strain of Wolbachia, inducing refractoriness to the human malaria parasite Plasmodium falciparum. However, conditions in the field can differ substantially from those in the laboratory. We use the rodent malaria P. yoelii, and somatically transinfected An. stephensi as a model system to investigate whether the transmission blocking potential of wAlbB is likely to be robust across different thermal environments. wAlbB reduced malaria parasite prevalence and oocyst intensity at 28 degrees C. At 24 degrees C there was no effect on prevalence but a marked increase in oocyst intensity. At 20 degrees C, wAlbB had no effect on prevalence or intensity. Additionally, we identified a novel effect of wAlbB that resulted in reduced sporozoite development across temperatures, counterbalancing the oocyst enhancement at 24 degrees C. Our results demonstrate complex effects of temperature on the Wolbachia-malaria interaction, and suggest the impacts of transinfection might vary across diverse environments. PMID- 24488177 TI - Accuracy of radiographs in assessment of displacement in lateral humeral condyle fractures. AB - PURPOSE: Determining the magnitude of displacement in pediatric lateral humeral condyle fractures can be difficult. The purpose of this study was to (1) assess the effect of forearm rotation on true fracture displacement using a cadaver model and to (2) determine the accuracy of radiographic measurements of the fracture gap. METHODS: A non-displaced fracture was created in three human cadaveric arms. The specimens were mounted on a custom apparatus allowing forearm rotation with the humerus fixed. First, the effect of pure rotation on fracture displacement was simulated by rotating the forearm from supination to pronation about the central axis of the forearm, to isolate the effects of muscle pull. Then, the clinical condition of obtaining a lateral oblique radiograph was simulated by rotating the forearm about the medial aspect of the forearm. Fracture displacements were measured using a motion-capture system (true displacement) and clinical radiographs (apparent-displacement). RESULTS: During pure rotation of the forearm, there were no significant differences in fracture displacement between supination and pronation, with changes in displacement of <1.0 mm. During rotation about the medial aspect of the forearm, there was a significant difference in true displacements between supination and pronation at the posterior edge (p < 0.05). CONCLUSION: Overall, true fracture displacement measurements were larger than apparent radiographic displacement measurements, with differences from 1.6 to 6.0 mm, suggesting that the current clinical methods may not be sensitive enough to detect a displacement of 2.0 mm, especially when positioning the upper extremity for an internal oblique lateral radiograph. PMID- 24488178 TI - Attenuated Listeria monocytogenes as a cancer vaccine vector for the delivery of CD24, a biomarker for hepatic cancer stem cells. AB - Attenuated Listeria monocytogenes (LM) is a promising candidate vector for the delivery of cancer vaccines. After phagocytosis by antigen-presenting cells, this bacterium stimulates the major histocompatibility complex (MHC)-I and MHC-II pathways and induces the proliferation of antigen-specific T lymphocytes. A new strategy involving genetic modification of the replication-deficient LM strain DeltadalDeltadat (Lmdd) to express and secrete human CD24 protein has been developed. CD24 is a hepatic cancer stem cell biomarker that is closely associated with apoptosis, metastasis and recurrence of hepatocellular carcinoma (HCC). After intravenous administration in mice, Lmdd-CD24 was distributed primarily in the spleen and liver and did not cause severe organ injury. Lmdd CD24 effectively increased the number of interferon (IFN)-gamma-producing CD8(+) T cells and IFN-gamma secretion. Lmdd-CD24 also enhanced the number of IL-4- and IL-10-producing T helper 2 cells. The efficacy of the Lmdd-CD24 vaccine was further investigated against Hepa1-6-CD24 tumors, which were inguinally inoculated into mice. Lmdd-CD24 significantly reduced the tumor size in mice and increased their survival. Notably, a reduction of T regulatory cell (Treg) numbers and an enhancement of specific CD8(+) T-cell activity were observed in the tumor-infiltrating lymphocytes (TILs). These results suggest a potential application of the Lmdd-CD24 vaccine against HCC. PMID- 24488180 TI - Characterization of mitochondrial haplogroups in a large population-based sample from the United States. AB - Mitochondrial DNA (mtDNA) haplogroups are valuable for investigations in forensic science, molecular anthropology, and human genetics. In this study, we developed a custom panel of 61 mtDNA markers for high-throughput classification of European, African, and Native American/Asian mitochondrial haplogroup lineages. Using these mtDNA markers, we constructed a mitochondrial haplogroup classification tree and classified 18,832 participants from the National Health and Nutrition Examination Surveys (NHANES). To our knowledge, this is the largest study to date characterizing mitochondrial haplogroups in a population-based sample from the United States, and the first study characterizing mitochondrial haplogroup distributions in self-identified Mexican Americans separately from Hispanic Americans of other descent. We observed clear differences in the distribution of maternal genetic ancestry consistent with proposed admixture models for these subpopulations, underscoring the genetic heterogeneity of the United States Hispanic population. The mitochondrial haplogroup distributions in the other self-identified racial/ethnic groups within NHANES were largely comparable to previous studies. Mitochondrial haplogroup classification was highly concordant with self-identified race/ethnicity (SIRE) in non-Hispanic whites (94.8 %), but was considerably lower in admixed populations including non Hispanic blacks (88.3 %), Mexican Americans (81.8 %), and other Hispanics (61.6 %), suggesting SIRE does not accurately reflect maternal genetic ancestry, particularly in populations with greater proportions of admixture. Thus, it is important to consider inconsistencies between SIRE and genetic ancestry when performing genetic association studies. The mitochondrial haplogroup data that we have generated, coupled with the epidemiologic variables in NHANES, is a valuable resource for future studies investigating the contribution of mtDNA variation to human health and disease. PMID- 24488179 TI - The long non-coding RNA Paupar regulates the expression of both local and distal genes. AB - Although some long noncoding RNAs (lncRNAs) have been shown to regulate gene expression in cis, it remains unclear whether lncRNAs can directly regulate transcription in trans by interacting with chromatin genome-wide independently of their sites of synthesis. Here, we describe the genomically local and more distal functions of Paupar, a vertebrate-conserved and central nervous system-expressed lncRNA transcribed from a locus upstream of the gene encoding the PAX6 transcription factor. Knockdown of Paupar disrupts the normal cell cycle profile of neuroblastoma cells and induces neural differentiation. Paupar acts in a transcript-dependent manner both locally, to regulate Pax6, as well as distally by binding and regulating genes on multiple chromosomes, in part through physical association with PAX6 protein. Paupar binding sites are enriched near promoters and can function as transcriptional regulatory elements whose activity is modulated by Paupar transcript levels. Our findings demonstrate that a lncRNA can function in trans at transcriptional regulatory elements distinct from its site of synthesis to control large-scale transcriptional programmes. PMID- 24488181 TI - Universal prevention of schizophrenia and surrogate endpoints at population level. AB - Despite significant progresses in our knowledge of the risk factors for schizophrenia, we still are several steps short of implementing effective prevention strategies. Universal prevention strategies have several theoretical advantages but their implementation has been limited to date by their costs and lack of methods to assess their efficiency. To overcome this limitation, we suggest, based on research from therapeutic trials at individual level, the use of surrogate endpoints (SEs) at population level. We further suggest that subclinical measures of psychosis at population level are good SEs candidates for assessing universal measures for schizophrenia prevention. PMID- 24488182 TI - High-performance supercapacitor electrodes based on hierarchical Ti@MnO(2) nanowire arrays. AB - Ti nanowire arrays (NAs) prepared by a facile and template-free hydrothermal method were used as three-dimensional (3D) current collectors for the electrodeposition of MnO2. The resulting Ti@MnO2 NAs exhibit remarkable electrochemical behavior with high specific capacitance, good rate performance and desired cycling stability. PMID- 24488183 TI - Ethnicity reporting practices for empirical research in three autism-related journals. AB - This review examines ethnicity reporting in three autism-related journals (Autism, Focus on Autism and Other Developmental Disabilities, and Journal of Autism and Developmental Disorders) over a 6-year period. A comprehensive multistep search of articles is used to identify ethnicity as a demographic variable in these three journals. Articles that identified research participants' ethnicity were further analyzed to determine the impact of ethnicity as a demographic variable on findings of each study. The results indicate that ethnicity has not been adequately reported in these three autism related journals even though previous recommendations have been made to improve inadequacies of descriptive information of research participants in autism research (Kistner and Robbins in J Autism Dev Disord 16:77-82, 1986). Implications for the field of autism spectrum disorders are discussed in addition to further recommendations for future research. PMID- 24488184 TI - How does direct to consumer advertising affect the stigma of mental illness? AB - Stigma interferes with life goals of people with mental illness. Direct-to consumer advertising (DTCA) may impact stigmatizing attitudes. The purpose of this study is to examine the effects of psychiatric medication DTCA on the stigmatizing and affirming attitudes of the general population versus individuals self-identified with mental illness. Participants (n = 272) were randomly assigned to watch a DTCA about Cymbalta, an antidepressant, embedded in two other advertisements for non-pharmaceutical products. Participants completed measures of stigmatizing and affirming attitudes before and after viewing this DTCA. Results indicate that the Cymbalta DTCA worsened the attitudes of the general public. These participants were less likely to offer help, endorse recovery, and agree with self-determination attitudes towards people with mental illness following viewing the DTCA. The self-identified group reported less blame, less dangerousness, less social avoidance, more pity, and greater willingness to help after viewing the DTCA. Moreover, there was significant improvement in their endorsement of recovery. Results suggest that DTCAs about psychiatric medication may increase the public's stigma towards people with mental illness but reduce stigma among individuals who identify as having a mental illness. Findings are somewhat limited by selection biases and self-report. Implications for further development of DTCAs are considered. PMID- 24488185 TI - The relationship between behavioural problems in preschool children and parental distress after a paediatric burn event. AB - This study examines mother- and father-rated emotional and behaviour problems in and worries about 0- to 5-year-old children at 3 and 12 months after a burn event and the relation with parental distress. Mothers (n = 150) and fathers (n = 125) representing 155 children participated in this study. Child emotional and behaviour problems and parental worries about the child were assessed with the Child Behavior Checklist at both time points. Parents' level of acute subjective distress was assessed within the first month after the burn event with the Impact of Event Scale. Mothers and fathers held comparable views of their child's emotional and behaviour problems, which were generally within the normal limits. Parents' own acute stress reactions were significantly related to parent-rated child behaviour problems at 3 and 12 months postburn. A substantial part of mothers' and fathers' worries about the child concerned physical and emotional aspects of the burn trauma, and potential future social problems. Parents with high acute stress scores more often reported burn-related concerns about their child at 3 and 12 months postburn. Health-care professionals should be informed that parents' distress in the subacute phase of their child's burn event may be related to subsequent worries about their child and to (parent-observed) child emotional and behaviour problems. The authors recommend a family perspective, with particular attention for the interplay between parents' distress and parent reported child behaviour problems and worries, in each phase of paediatric burn care. PMID- 24488188 TI - The circle. PMID- 24488186 TI - Experience of a high-risk aortic valve clinic in Ireland. AB - BACKGROUND: The advent of transcatheter aortic valve implantation (TAVI) has broadened the management options for severe aortic stenosis. The indications for TAVI are narrow. Selecting those that will benefit most from this intervention warrants careful consideration and input from cardiologists, anaesthetists and cardiac surgeons familiar with TAVI and surgical aortic valve replacement (SAVR). AIMS: The aims of this paper were to assess the feasibility of establishing a high-risk aortic clinic in Ireland, and report stratification of the referred group into those suitable for SAVR, TAVI and conservative management. METHODS: Patient data was prospectively collected by a dedicated clinical nurse specialist. ANOVA was used to assess variance in means between groups. Analyses were performed using IBM SPSS v20 (Armonk, NY: IBM Corp.). RESULTS: A total of 105 patients were assessed. Eighty-five patients were deemed suitable for TAVI, 9 (10.5 %) died awaiting the procedure and a further 6 (7 %) declined intervention. Eleven (10.5 %) underwent conventional SAVR, 1 (0.9 %) a balloon valvuloplasty, 4 (3.8 %) entered surveillance and 4 (3.8 %) were declined treatment. CONCLUSIONS: Establishment of a high-risk aortic clinic is feasible in the Irish context. The advent of TAVI has reduced the proportion of patients denied intervention to a minority. Despite being considered high risk, a number of patients were suitable candidates for SAVR. Measuring frailty continues to provide a challenge; a TAVI specific frailty assessment tool would be advantageous to patient stratification. PMID- 24488189 TI - An exploration of how perceptions of the risk of avian influenza in poultry relate to urbanization in Vietnam. AB - This research examined how perceptions of outbreaks of highly pathogenic avian influenza (HPAI) subtype H5N1 in poultry are related to urbanization. Via in depth interviews with village leaders, household farmers, and large farm operators in modern, transitional, and traditional communes in the north of Vietnam, we explored behaviors, attitudes, cultural values, and traditions that might amplify or attenuate HPAI outbreaks. We also explored conceptualizations of urbanization and its impacts on animal husbandry and disease outbreaks. Qualitative theme analyses identified the key impacts, factors related to HPAI outbreaks, and disease prevention and management strategies. The analyses also highlighted how urbanization improves some aspects of life (e.g., food security, family wealth and health, more employment opportunities, and improved infrastructure), but simultaneously poses significant challenges for poultry farming and disease management. Awareness of qualitative aspects of HPAI risk perceptions and behaviors and how they vary with urbanization processes may help to improve the prevention and management of emerging infectious diseases. PMID- 24488191 TI - Abscisic acid inhibition of root nodule initiation in Pisum sativum. AB - The effect of exogenous abscisic acid (ABA) on root nodule formation in Pisum sativum cv. Alaska was examined. ABA supplied to the roots at 1.9*10(-6)M reduced the number of nodules/plant 61% without affecting root or shoot growth. The first noticeable inhibition of nodulation occurred at 3.8*10(-7)M ABA. ABA at a concentration of 1.9*10(-6)M inhibited neither root hair formation nor infection of root hairs by Rhizobium leguminosarum. Similar numbers of infection threads penetrated the cortex in both control and treated plants. ABA concentrations of 3.8*10(-6)M had no effect on the doubling time or maximum density of R. leguminosarum in pure cultures. Normal nodule formation involves a polyploid cortical proliferation. This response to rhizobial infection can be imitated by culturing 1-mm pea-root segments on a medium containing 4.7*10(-6)M kinetin. Under these conditions a highly significant reduction in the number of polyploid mitoses after 72 h is produced by 3.8*10(-8)M ABA. A maximum inhibition of 68% was found with 3.8*10(-6)M ABA. A similar range of ABA concentrations also inhibited the cytokinin-induced cell division in soybean callus. It is concluded that ABA reduces the number of root nodules/plant by inhibiting the cortical cell divisions required for root nodule formation. PMID- 24488190 TI - Using risk assessment as part of a systems approach to the control and prevention of HPAIV H5N1. AB - Since its emergence in China in 1996, highly pathogenic avian influenza virus subtype H5N1 has spread across Asia, Africa, and Europe. Countries had to promptly implement control and prevention measures. Numerous research and capacity building initiatives were conducted in the affected regions to improve the capacity of national animal health services to support the development of risk-based mitigation strategies. This paper reviews and discusses risk assessments initiated in several South-East Asian and African countries under one of these projects. Despite important data gaps, the risk assessment results improved the ability of policy makers to design appropriate risk management policies. Disease risk was strongly influenced by various human behavioral factors. The ongoing circulation of HPAIV H5N1 in several Asian countries and in Egypt, despite major disease control efforts, supports the need for an interdisciplinary approach to development of tailored risk management policies, in accordance with the EcoHealth paradigm and the broad concept of risk governance. In particular, active stakeholders engagement and integration of economic and social studies into the policy making process are needed to optimize compliance and sustainable behavioral changes, thereby increasing the effectiveness of mitigation strategies. PMID- 24488192 TI - Fine structure of the host-fungus interface in orchid mycorrhiza. AB - Electron microscopy of protocorms of Dactylorhiza purpurella infected with a symbiotic Rhizoctonia sp. showed that the intracellular hyphae examined did not penetrate the plasmalemma of the host cell. Walls of hyphae within cells bore many hemispherical protuberances over which the host plasmalemma was closely pressed. we estimate that these protuberances would increase the area of contact between hyphae and host plasmalemma by about 15%. They were not found on hyphae growing on agar. Except for these protuberances, and some vesicles or tubules which invaginated the fungus plasmalemma, no other structures were seen which could be suggested to be adaptations to transport across the living fungus-host interface. PMID- 24488193 TI - Phloem transport of (14)C-labelled assimilates in Ricinus. AB - Exudate can be obtained from incisions made in the bark of the stem of actively growing Ricinus plants. (14)C-labelled assimilates from a fed leaf are rapidly detected in the exudate. This movement was both acropetal and basipetal from the fed leaf, at rates of over 100 cm h(-1). Estimated rates within intact plants were 80-84 cm h(-1).In contrast with xylem sap obtained from the same plant, the exudate obtained had an alkaline pH (8.2), a high dry matter content (10-12.5%), high sugar content (8-10%) which was predominantly sucrose; high potassium content (60-80 mM) and low calcium content (0.5-1.0 mM).It is concluded, on the basis of the present evidence, that the exudate is a true sample of the sieve tube sap undergoing translocation. PMID- 24488194 TI - Proteins of the sieve-tube exudate of Cucurbita maxima. AB - Sieve-tube exudate which appears on cut surfaces of stems of Cucurbita maxima as distinct droplets has been depicted in electron micrographs of longitudinal sections of the phloem. The exudate, which was produced from mature sieve tubes only, contained filaments of P-protein, but no mitochondria or vesicles of endoplasmic reticulum. The water-soluble part of the exudate contained at least 12 proteins, as shown by disc-electrophoresis. Enzymic activity was found for peroxidases, acid phosphatases, and aldolases. Color tests and assays for other enzymes, including ATPase, fructokinase, several dehydrogenases, and UDP-glucose: D-fructose-2-glucosyl transferase, gave negative results. With repeated cutting of a stem, the protein content of the exudate increased, while the amount of exudate decreased. PMID- 24488195 TI - [Allosteric regulation of the activity of glutamate dehydrogenase from pea seedlings by the substrate alpha-ketoglutarate]. AB - Several investigations on the properties of glutamate dehydrogenase from plant sources indicate that the enzymatic activity (reductive amination) follows a Michaelis-Menten-type kinetic when velocity is plotted versus rising concentrations of the substrate alpha-ketoglutarate. In the course of our investigations on the effect of SO2 on pea plant enzymes we found that SO 4 (2-) , added as (NH4)2SO4 to the assay system, causes this type of activity response because of its ability to function as an activator. When (NH4)2SO4 is replaced by NH4Cl in the in vitro system however, activity response is sigmoidal. Addition of competitive inhibitor to the latter system again gives rise to a sigmoidal kinetic with reduced initial velocities. Identical kinetic behaviour is observed when either 120 fold enriched enzyme from shoots or highly purified glutamate dehydrogenase from pea roots is used, a fact which justifies the assumption that the enzyme from pea plants belongs to the MIC-type of regulatory proteins (modulator independent cooperativity). The activity response caused by other effectors, especially purine nucleotides, is discussed with regard to the above findings. PMID- 24488196 TI - The kinetics of hydrogen photoproduction by adapted Scenedesmus. AB - In our earlier work we have shown that hydrogen photoproduction by photosystem I of Scenedesmus does not require O2 evolution or cyclic photophosphorylation but must be due to non-cyclic electron flow from organic substrate(s) through photosystem I to hydrogenase, where molecular H2 is released. The kinetics of this reaction are rather complex, in that H2 photoproduction by Scenedesmus evidently occurs in two phases: a rapid initial phase which depends upon the dehydrogenation of a "pool" of H donors, and a later and slower second phase which is limited by the flow of electrons from fermentation. When adapted cells were incubated in the dark with an inhibitor (Cl-CCP or salicylaldoxime), the pool utilized by photosystem I gradually disappeared. However, the pool gave a rapid rate of hydrogen photoproduction when the adapted cells were illuminated immediately after adding the inhibitor. The rate at which the pool was utilized depended upon the light intensity and was not light-saturated at the highest intensity tested (3.4*10(3) MUW cm(-2)).With light of at least medium intensity (1.67*10(3) MUW cm(-2)), the pool was rapidly exhausted and the reaction became dependent upon the "leak" of electrons from fermentation. The size of the "leak" was found to depend upon the level of reduced organic compounds in the cell, since this process was depressed by starving the cells and was much enhanced by adding glucose or by growing the cells heterotrophically. A quantitative relationship was found between the amount of glucose added and the resulting stimulation of H2 photoproduction, in that one MUmole of glucose gave about 0.5 MUmole of H2 gas. PMID- 24488197 TI - Photoinduced division synchrony in permanently bleached Euglena gracilis. AB - Ultraviolet light-induced, bleached Euglena clones exhibit synchronous steps of cell division in response to daily cycles of light and dark. The cyclic division activity, in the bleached cells, will persist in constant lighting conditions with a period, independent of temperature, of about 24 h. This persisting rhythm of cell division supports the hypothesis that this phase of the cell cycle may be coupled to the fluctuations of the endogenous circadian clock of the cell.Newly isolated bleached clones are sensitive to light in their growth rates and metabolic characteristics, showing light induced difference in substrate stimulated respiration, and production of the polyglucan, paramylon. After repeated subculturing of a bleached clone the photosensitivity of the metabolic characteristics and of the growth rate are diminished along with the ability to photo-entrain division synchrony. Division control and the induction of cell synchrony in this organism apparently involve both the temporal influence of the endogenous cell clock and one or more other photosensitive reactions in the metabolism of the cell.A unique culture mixing technique utilizing the bleached Euglena, failed to support the hypothesis of the involvement of intercellular communication in the maintenance of cell synchrony in constant lighting conditions. PMID- 24488198 TI - The biosynthesis of canavanine from (14)CO 2 and its asymmetric labeling in isolated pericarp, tissue of Canavalia ensiformis. AB - Pericarp disks from the fruit of the jackbean (Canavalia ensiformis) when exposed to (14)CO2 for 2 days carried out photosynthesis and the canavanine extracted from the tissue was labeled with the radioisotope. When beef liver arginase was allowed to react with this canavanine the products were homoserine, canaline, urea and an unknown compound. The activity ratio of C4:C1 compounds was close to 2:1. No label could be detected in the canavanine from leaves exposed in the same way to (14)CO2 and it was concluded that normally canavanine synthesis occurs in the pericarp chlorenchyma. PMID- 24488199 TI - Sieve-plate pores in leaf veins of Hordeum vulgare. AB - The sieve-plate pores of sieve elements in leaf veins of Hordeum vulgare, fixed in glutaraldehyde with postfixation in osmium tetroxide, were lined by the plasmalemma and variable amounts of callose. All pores were filled with endoplasmic reticulum, which was continuous from cell to cell. Mature sieve elements lacked P-protein. PMID- 24488200 TI - In vitro loss of nucleic acids from cells of aseptically cultured excised pea roots. AB - Analysis of pea root tips taken from attached seedling roots and excised roots cultured in vitro has revealed major differences in cell constituents. The cells of cultured roots have only 40% and 13% of the protein and amino acid content of attached root cells. The nucleic acid content of cultured root cells was shown to be only 20% and 27% of the RNA and DNA respectively found in attached roots. It is suggested that there is excess nucleic acid in whole plant tissues above that required for transfer of genetic information necessary for normal growth and differentiation of root cells. PMID- 24488201 TI - The occurrence of shoot teratomata in tissue cultures of Taraxacum officinale. AB - Tissue cultures of Taraxacum officinale have been isolated showing either normal organogenesis, callus growth only, or teratological shoots. The latter are apparently stable and the teratomata range from tumerous outgrowths, to flattened thalloid forms and short shoots with strap shaped leaves. The proximal regions of such shoots are tumerous and no distinction between apex, leaf and bud primordia is possible. PMID- 24488202 TI - Evaluation of the nasopalatine canal and variations with cone-beam computed tomography. AB - PURPOSE: Although nasopalatine canal (NPC) is one of the most important anatomical structures in premaxillary region, few documents are available with regard to anatomic variations, size, and morphology of NPC in the literature. In recent years, the need for radiological identification of anatomical structures has grown with increased dental implant applications in anterior maxillary region with higher esthetic expectations. This study aimed at investigating the NPC's shape and anatomical variations by cone-beam computed tomography (CBCT) in the Turkish society, in a particular region. METHODS: A total of 500 individual CBCT images were investigated in terms of morphological, dimensional, and anatomical features of NPC. In addition, the width of incisive foramen (IF) and foramina of Stenson were evaluated. RESULTS: There was no statistically significant difference (p = 0.234) between women and men in terms of NPC shape. Morphological assessment of NPC revealed that 38.78 % of NPCs were hourglass-like in shape, 27.35 % of canals were funnel-shaped, 9.18 % of canals were conical shaped, and 8.25 % of canals were cylindrical shaped. The mean IF width and NPC length was found as 5.06 and 12.59 mm, respectively. And the mean canal length was found significantly longer in men than women (p < 0.001). CONCLUSION: It has been shown that NPC has a lot of anatomical variations with regard to its dimensions as well as its morphological appearance. Therefore, identification of the anatomical structure of this region with two- and three-dimensional imaging techniques maybe thought to be important in facilitating surgical management and preventing possible complications. PMID- 24488203 TI - Delocalization and dielectric screening of charge transfer states in organic photovoltaic cells. AB - Charge transfer (CT) states at a donor-acceptor heterojunction have a key role in the charge photogeneration process of organic solar cells, however, the mechanism by which these states dissociate efficiently into free carriers remains unclear. Here we explore the nature of these states in small molecule-fullerene bulk heterojunction photovoltaics with varying fullerene fraction and find that the CT energy scales with dielectric constant at high fullerene loading but that there is a threshold C60 crystallite size of ~4 nm below which the spatial extent of these states is reduced. Electroabsorption measurements indicate an increase in CT polarizability when C60 crystallite size exceeds this threshold, and that this change is correlated with increased charge separation yield supported by CT photoluminescence transients. These results support a model of charge separation via delocalized CT states independent of excess heterojunction offset driving energy and indicate that local fullerene crystallinity is critical to the charge separation process. PMID- 24488204 TI - A comparison of spectral quality in magnetic resonance spectroscopy data acquired with and without a novel EPI-navigated PRESS sequence in school-aged children with fetal alcohol spectrum disorders. AB - Single voxel spectroscopy (SVS) can generate useful information regarding metabolite concentrations provided that the MR signal can be averaged over several minutes during which the subject remains stationary. This requirement can be particularly challenging for children who cannot otherwise be scanned without sedation. To address this problem we developed an EPI volume navigated (vNav) SVS PRESS sequence, which applies real-time head pose (location and orientation), frequency, and first-order B0 shim adjustments. A water-independent preprocessing algorithm removes residual frequency and phase shifts resulting from within-TR movements. We compare results and performance of the standard and vNav PRESS sequences in a sample of 9- to 10-year-olds from a South African cohort of children with fetal alcohol spectrum disorders (FASD) and healthy controls. Magnetic resonance spectroscopy (MRS) data in the deep cerebellar nuclei were initially acquired with the standard PRESS sequence. The children were re-scanned 1 year later with the vNav PRESS sequence. Good quality data were acquired in 73% using the vNav PRESS sequence, compared to only 50% for the standard PRESS sequence. Additionally, tighter linewidths and smaller variances in the measured concentrations were observed. These findings confirm previous reports demonstrating the efficacy of our innovative vNav sequence with healthy volunteers and young children with HIV and expand its application to a school aged population with FASD-disorders often associated with attention problems and hyperactivity. This study provides the most direct evidence to date regarding degree to which these new methods can improve data quality in research studies employing MRS. PMID- 24488205 TI - Glutathione metabolism enzymes in brain and liver of hyperphenylalaninemic rats and the effect of lipoic acid treatment. AB - Phenylketonuria (PKU) is a disorder caused by a deficiency in phenylalanine hydroxylase activity, which converts phenylalanine (Phe) to tyrosine, leading to hyperphenylalaninemia (HPA) with accumulation of Phe in tissues of patients. The neuropathophysiology mechanism of disease remains unknown. However, recently the involvement of oxidative stress with decreased glutathione levels in PKU has been reported. Intracellular glutathione (GSH) levels may be maintained by the antioxidant action of lipoic acid (LA). The aim of this study was to evaluate the activity of the enzymes involved in the metabolism and function of GSH, such as glutathione peroxidase (GSH-Px), glucose-6-phosphate dehydrogenase (G6PD), glutathione reductase (GR), glutamate-cysteine ligase (GCL), glutathione-S transferase (GST) and GSH content in brain and liver of young rats subjected to a chemically induced model of HPA and the effect of LA for a week. In brain, the administration of Phe reduced the activity of the GSH-Px, GR and G6PD and LA prevented these effects totally or partially. GCL activity was increased by HPA and was not affect by LA antioxidant treatment. GST activity did not differ between groups. GSH content was increased by LA and decreased by HPA treatment in brain samples. Considering the liver, all parameters analyzed were increased in studied HPA animals and LA was able to hinder some effects except for the GCL, GST enzymes and GSH content. These results suggested that HPA model alter the metabolism of GSH in rat brain and liver, which may have an important role in the maintenance of GSH function in PKU although liver is not a directly affected organ in this disease. So, an antioxidant therapy with LA may be useful in the treatment of oxidative stress in HPA. PMID- 24488206 TI - Cu-catalyzed amidation of halogenated imidazoles. AB - An efficient methodology involving the Cu-catalyzed amidation of halogenated imidazoles has been successfully developed. The amidated product of 5-bromo-1 alkylimidazole was further applied to the synthesis of a new chiral imidazole nucleophilic catalyst for the kinetic resolution of secondary alcohols. PMID- 24488208 TI - Effects of chronic fluoride exposure on object recognition memory and mRNA expression of SNARE complex in hippocampus of male mice. AB - This study aimed to investigate the effects of long-term fluoride exposure on object recognition memory and mRNA expression of soluble N ethylmaleimidesensitive fusion protein attachment protein receptors (SNARE) complex (synaptosome-associated protein of 25 kDa (SNAP-25), vesicle-associated membrane protein 2 (VAMP-2), and syntaxin 1A) in the hippocampus of male mice. Sixty sexually matured male Kunming mice were randomly divided into four groups: control group (given distilled water), low F group (25 mg/L NaF, corresponding to 11 mg/L F(-)), medium F group (50 mg/L NaF, corresponding to 22 mg/L F(-)), and high F group (100 mg/L NaF, corresponding to 45 mg/L F(-)). After 180 days, the spontaneous locomotor behavior and object recognition memory were detected by open field test and novel object recognition (NOR) test. Results showed that compared with the control group, frequency in each zone, total distance, and line crosses were significantly increased in low F and medium F groups, suggesting fluoride enhanced excitement of mice, while there were no marked changes in high F group. Twenty-four hours after training, a deficit of long-term memory (LTM) occurred only in high F group (P < 0.05), but there was no significant change of short-term memory (STM) 1.5 h later. The mRNA expression levels of SNAP-25, VAMP 2, and syntaxin 1A were detected by real-time quantitative RT-PCR, which revealed that the mRNA expression of VAMP-2 was significantly increased in medium F and high F groups (P < 0.01). Taken together, these results indicated that long-term fluoride administration can enhance the excitement of male mice, impair recognition memory, and upregulate VAMP-2 mRNA expression, which are involved in the adverse effects of fluoride on the object recognition memory of nervous system. PMID- 24488209 TI - Marginal zinc deficiency negatively affects recovery from muscle injury in mice. AB - The aim of the present study was to elucidate whether the recovery from muscle injury is impaired in marginal zinc deficiency. C57BL/6 male mice were fed a marginally zinc-deficient diet (MZD: 8 mg Zn/kg diet), a zinc-adequate diet (ZA: zinc 35 mg Zn/kg diet), and a zinc-high diet (ZH: 190 mg Zn/kg diet) for 4 weeks. Muscle injury was induced in the gastrocnemius muscles using cardiotoxin. The gastrocnemius muscles of these mice were harvested at 3, 5, 7, 10, 14, and 20 days after injury. We evaluated the regeneration of the skeletal muscle with hematoxylin and eosin staining and developmental myosin heavy-chain (dMHC: implicated in regeneration) immunostaining. The rate of dMHC-positive cells was significantly low in MZD mice compared with ZA mice at 3 days after cardiotoxin injection. The peak dMHC expression was found at 3 days after injection in ZA mice, 5 days in ZH mice, and 7 days in MZD mice. These results suggest that recovery from muscle injury might be partly impaired and delayed in MZD mice. Therefore, we strongly suggest the appropriate zinc intake to prevent the impairment of skeletal muscle regeneration. PMID- 24488210 TI - The alteration of zinc transporter gene expression is associated with inflammatory markers in obese women. AB - Obesity, a chronic inflammatory state, is associated with altered zinc metabolism. ZnT and Zip transporters are involved in the regulation of zinc metabolism. This study examined the relationships among obesity, zinc transporter gene expression, and inflammatory markers in young Korean women. The messenger RNA (mRNA) levels of leukocyte zinc transporters between obese (BMI = 28.3 +/- 0.5 kg/m(2), n = 35) and nonobese (BMI = 20.7 +/- 0.2 kg/m(2), n = 20) women aged 18-28 years were examined using quantitative real-time polymerase chain reaction. Inflammatory markers, such as C-reactive protein (CRP), tumor necrosis factor alpha (TNF-alpha), and interleukin (IL)-6, were measured in serum by enzyme immunoassay. ZnT1 and Zip1 were the most abundantly expressed zinc transporters in leukocytes. The mRNA levels of many zinc transporters (ZnT4, ZnT5, ZnT9, Zip1, Zip4, and Zip6) were significantly lower in obese women, and expression of these genes was inversely correlated with BMI and body fat percentage. In addition, inflammatory markers (CRP and TNF-alpha) were significantly higher in obese women. The mRNA levels of ZnT4, Zip1, and Zip6 were inversely correlated with CRP (P < 0.05), and mRNA levels of ZnT4 and ZnT5 were inversely correlated with TNF alpha (P < 0.05). In standardized simple regression models, levels of TNF-alpha and CRP were negatively associated with mRNA levels of zinc transporters such as ZnT4, ZnT5, Zip1, and Zip6 (P < 0.05). These results suggest that the expression of zinc transporters may be altered in obese individuals. Changes in zinc transporters may also be related to the inflammatory state associated with obesity. PMID- 24488211 TI - Outcome of carotid angioplasty with a novel open-cell carotid stent system. AB - BACKGROUND: The choice of carotid stent systems depends primarily on the anatomy of the carotid artery, the lesion morphology, and the patient's risk factors. Design improvements in devices, in terms of crossing profile and the ability to precisely position the stent, may greatly contribute to the procedural success without compromising acute clinical outcomes. METHODS AND RESULTS: The primary objective of this clinical registry was to evaluate the early safety and efficacy of a novel open-cell carotid stent system in an "all comer" population suitable for carotid artery stenting. The primary end point was the composite of ipsilateral stroke and "all-cause mortality" within 30 days after the procedure. Secondary end points entailed the rates of myocardial infarction and other clinical complications within the first 30 days following the procedure and up to the 6-month follow-up. Unsuccessful placement and/or withdrawal of the delivery system, as well as device-related complications involving the carotid artery and the rate of nonlesion-related embolisms, were evaluated relative to other currently available carotid stents. The 30-day composite death/stroke rate was 2.8% (3 of 106) while the overall stent system performance was similar to commonly used carotid stent systems. CONCLUSIONS: The utilized open-cell carotid stent system had favorable lesion crossing and positioning characteristics without compromising the 30-day composite death/stroke rate. PMID- 24488212 TI - Exploring the nature of collisionless shocks under laboratory conditions. AB - Collisionless shocks are pervasive in astrophysics and they are critical to understand cosmic ray acceleration. Laboratory experiments with intense lasers are now opening the way to explore and characterise the underlying microphysics, which determine the acceleration process of collisionless shocks. We determine the shock character - electrostatic or electromagnetic - based on the stability of electrostatic shocks to transverse electromagnetic fluctuations as a function of the electron temperature and flow velocity of the plasma components, and we compare the analytical model with particle-in-cell simulations. By making the connection with the laser parameters driving the plasma flows, we demonstrate that shocks with different and distinct underlying microphysics can be explored in the laboratory with state-of-the-art laser systems. PMID- 24488213 TI - Human-resource subsidies alter the dietary preferences of a mammalian top predator. AB - Resource subsidies to opportunistic predators may alter natural predator-prey relationships and, in turn, have implications for how these predators affect co occurring prey. To explore this idea, we compared the prey available to and eaten by a top canid predator, the Australian dingo (Canis lupus dingo), in areas with and without human-provided food. Overall, small mammals formed the majority of dingo prey, followed by reptiles and then invertebrates. Where human-provided food resources were available, dingoes ate them; 17% of their diet comprised kitchen waste from a refuse facility. There was evidence of dietary preference for small mammals in areas where human-provided food was available. In more distant areas, by contrast, reptiles were the primary prey. The level of seasonal switching between small mammals and reptiles was also more pronounced in areas away from human-provided food. This reaffirmed concepts of prey switching but within a short, seasonal time frame. It also confirmed that the diet of dingoes is altered where human-provided food is available. We suggest that the availability of anthropogenic food to this species and other apex predators therefore has the potential to alter trophic cascades. PMID- 24488214 TI - Nutritional biomarkers and subsequent cognitive decline among community-dwelling older Japanese: a prospective study. AB - BACKGROUND: Micronutrients are associated with dementia and cognitive decline among older adults. However, nutritional biomarkers of such decline have not been identified. We attempted to identify nutritional biomarkers that were independent risk markers of cognitive decline in a population of older Japanese. METHODS: Among 873 cognitively intact adults aged 70 years or older at baseline, 682 (mean age [standard deviation], 75.5 [4.4] years; women 59.7%) were followed for a period of up to 4 years, and nutritional biomarkers in a blood panel were assessed, namely, red blood cell count, hematocrit, mean corpuscular volume, hemoglobin, total cholesterol, high-density lipoprotein cholesterol, hemoglobin A1c, creatinine, albumin, blood glucose, gamma-glutamyl transpeptidase, triglyceride, and white blood cell count. Cognition was assessed by the Mini Mental State Examination, and cognitive decline was defined as a decrease of at least three points on the Mini-Mental State Examination. RESULTS: During an average follow-up of 2.7 years, 115 adults (16.9%) developed cognitive decline. After controlling for important confounders, the odds ratios for cognitive decline in the lowest and middle tertiles of red blood cell count were 2.62 (95% confidence interval: 1.44-4.74) and 2.18 (1.20-3.96), respectively, as compared with the highest tertile. The corresponding odds ratios were 1.81 (1.05-3.22) and 1.03 (0.58-1.83), respectively, for high-density lipoprotein cholesterol and 2.06 (1.14-3.77) and 1.02 (0.54-1.94) for albumin. CONCLUSIONS: Low red blood cell count, high-density lipoprotein cholesterol, and albumin were independent risk markers for subsequent cognitive decline in a general population of older adults and may be useful in early clinical screening. PMID- 24488215 TI - Simple and inexpensive perturbative correction schemes for antisymmetric products of nonorthogonal geminals. AB - A new multireference perturbation approach has been developed for the recently proposed AP1roG scheme, a computationally facile parametrization of an antisymmetric product of nonorthogonal geminals. This perturbation theory of second-order closely follows the biorthogonal treatment from multiconfiguration perturbation theory as introduced by Surjan et al., but makes use of the additional feature of AP1roG that the expansion coefficients within the space of closed-shell determinants are essentially correct already, which further increases the predictive power of the method. Building upon the ability of AP1roG to model static correlation, the perturbation correction accounts for dynamical electron correlation, leading to absolute energies close to full configuration interaction results. Potential surfaces for multiple bond dissociation in H2O and N2 are predicted with high accuracy up to bond breaking. The computational cost of the method is the same as that of conventional single-reference MP2. PMID- 24488216 TI - Impact of molecular subtype on locoregional recurrence in mastectomy patients with T1-T2 breast cancer and 1-3 positive lymph nodes. AB - BACKGROUND: Postmastectomy radiation (PMRT) in T1-T2 tumors with 1-3 positive axillary lymph nodes (ALNs) is controversial. Impact of molecular subtype (MST) on locoregional recurrence (LRR) and PMRT benefit is uncertain. We examined the association between MST and LRR, recurrence-free survival (RFS), and overall survival (OS), in T1-T2 tumors with 1-3 positive ALNs. METHODS: From an institutional database, we identified mastectomy patients with 1-3 positive ALNs between 1995 and 2006. Patients who received neoadjuvant chemotherapy, had T3-T4 tumors, or >=4 positive ALNs were excluded. MST was defined as: hormone receptor (HR)+/HER2-(luminal A/B), HR+/HER2+(luminal HER2), HR-/HER2+(HER2), and HR-/HER2 (basal). Kaplan-Meier method and Cox regression analysis were used to examine association between MST and LRR, RFS, and OS. RESULTS: This study included 884 patients (700 no PMRT, 141 PMRT): 72.8 % luminal A/B, 7.8 % luminal HER2, 6.8 % HER2, and 12.6 % basal. Median follow-up was 6.3 years; 39 LRRs occurred. Luminal A/B subtype had the smallest tumors (p = 0.03), lowest intraductal component (p = 0.01), histologic grade (p < 0.0001), lymphovascular invasion (LVI) (p = 0.008), and multifocality/multicentricity (p = 0.02). On univariate analyses, there was no association between MST and LRR. MST was associated with RFS and OS; the basal and HER2 subtype had the lowest RFS (p = 0.0002) and OS (p < 0.0001). On multivariate analysis, only age <=50 years (p = 0.003) and presence of LVI (p = 0.0003) were predictive of LRR; MST was not (p = 0.38). CONCLUSION: In patients with T1-T2 breast cancer and 1-3 positive lymph nodes who did not receive PMRT, MST was not an independent predictor of LRR and may not be useful in selecting PMRT candidates in that group. PMID- 24488217 TI - Recurrent menstrual toxic shock syndrome with and without tampons in an adolescent. PMID- 24488219 TI - Microwave flash annealing for stability of chemically doped single-walled carbon nanotube films on plastic substrates. AB - Microwave flash annealing dramatically enhances the environmental stability of AuCl3-doped single-walled carbon nanotube (SWCNT) films on plastic substrates using fast microwave nanoheating to produce a large temperature difference between the films and the substrates. Within one second, the microwave nanoheating rapidly caused thermal decomposition of AuCl3 dopants as well as simultaneous embedding of SWCNTs in the substrate, without deforming it. The hygroscopic Cl atoms were partially desorbed from the SWCNTs by rapid thermal decomposition, and the embedded substrate surface acted as a passivation layer, which synergistically contributed to the stability of the doped and annealed SWCNTs. PMID- 24488218 TI - Erratum to: Catalyser-21TM, a mineral water derived from leaf soil, inhibits tumor cell invasion and angiogenesis. PMID- 24488227 TI - Fungal endophyte increases the allelopathic effects of an invasive forb. AB - Endophytic plant symbionts can have powerful effects on the way their hosts interact with pathogens, competitors, and consumers. The presence of endophytes in plants can alter food webs, community composition and ecosystem processes, suggesting that endophyte-plant symbioses may represent unique forms of extended phenotypes. We tested the impact of the fungal endophyte Alternaria alternata (phylotype CID 120) on the allelopathic effect of the invasive forb Centaurea stoebe when in competition with the North American native bunchgrass Koeleria macrantha in a greenhouse competition experiment. The allelopathic effect of C. stoebe on K. macrantha when infected with the fungal endophyte was more than twice that of endophyte-free C. stoebe. However, this allelopathic effect was a small part of the very large competitive effect of C. stoebe on K. macrantha in all treatments, likely because of the priority effects in our experimental design. To our knowledge, these results are the first experimental evidence for a symbiotic relationship between plants and fungal endophytes affecting allelopathic interactions between competing plants, and thus provide insight into the mechanisms by which fungal endophytes may increase the competitive ability of their hosts. PMID- 24488223 TI - Limited therapeutic benefits of intra-articular cortisone injection for patients with femoro-acetabular impingement and labral tear. AB - PURPOSE: Intra-articular (IA) hip cortisone injection is commonly performed as a therapeutic modality in patients with femoral acetabular impingement (FAI). To our knowledge, there is no published data evaluating the clinical benefit of these injections. The purpose of this study was to assess the efficacy of therapeutic IA cortisone injection in these patients. METHODS: At our institution, patients with FAI and labral tear prospectively recorded their numerical rating scale (NRS) pain scores pre-injection, during post-injection anaesthetic phase, and at 14 days post-injection. From this cohort, all patients treated with guided IA cortisone injection, no radiographic evidence of arthritis (Tonnis grade 0 or 1) and pain relief during the anaesthetic phase of the IA injection were included. An absolute change of two points on the NRS score was considered the minimal amount of clinically significant pain relief. Pain scores were compared between the different types of steroid injected. RESULTS: Fifty four patients (35 females, 19 males) with a mean age of 32 +/- 12 years were included. Average median pre-injection NRS score was 7.0 (range 2.5-10.0), post injection anaesthetic phase was 1.0 (range 0.0-5.0), and 14 day post-injection was 5.0 (range 0.0-10.0). As a group, NRS scores significantly diminished from post-injection anaesthetic phase to 14 days post-injection (p < 0.001). At 14 days post-injection, only 20 patients (37 %) and at 6 weeks, only 3 patients (6 %) reported a clinically significant decrease in pain. Average duration of pain relief was 9.8 days. There was no difference in pain reduction between steroid preparations. CONCLUSION: In patients with symptomatic FAI and labral tear, intra articular cortisone injection has limited clinical benefit as a therapeutic modality. However, anaesthetic-only IA injections for patients who may be candidates for hip arthroscopy can be a useful diagnostic tool. PMID- 24488225 TI - Independent growth of diffuse large B cell lymphoma and angioimmunoblastic T cell lymphoma originating from composite lymphoma. PMID- 24488226 TI - Application of the optimized CO-rebreathing method for determination of hemoglobin mass in patients with polycythemia vera. AB - Determination of red cell volume (RCV) might contribute to establishing the diagnosis of polycythemia vera (PV). A novel simplified method to detect RCV through CO rebreathing is nowadays applied in healthy young individuals but was not tested in a clinical or PV setting. The aim of the present study is to evaluate whether this spirometric approach is applicable in older subjects and contributes to PV diagnosis in a proof-of-concept approach. At first, RCV was determined by the optimized CO-rebreathing method in healthy subjects >50 years of age (n = 81, age 66 +/- 9 years). Failure rate and age distribution of subjects who failed with CO rebreathing were analyzed. Then, RCV was measured in male PV patients (n = 7) and compared to healthy male controls (n = 35). RCV values in relation to several anthropometric references (body weight, body surface area (BSA), lean body mass (LBM)) were calculated to determine the sensitivity and specificity of established RCV thresholds when using optimized CO rebreathing. In healthy subjects, test failure rate was 9.9 %, but failure was not associated with age. Sensitivity and specificity (sens/spec) to detect PV was 100 %/83 % using the criteria of the PV study group. Using criteria based on BSA, sens/spec was 14 %/100 %. An arbitrary threshold of 50 ml/kg LBM yielded sens/spec of 100 %/97 %. In conclusion, this proof-of-concept indicates that optimized CO rebreathing is applicable in older subjects and allows determining RCV for the diagnosis of PV. Normalized values for RCV measures obtained from CO rebreathing are needed to grant sufficient sensitivity and/or specificity. PMID- 24488229 TI - Short-term memory for order but not for item information is impaired in developmental dyslexia. AB - Recent findings suggest that people with dyslexia experience difficulties with the learning of serial order information during the transition from short- to long-term memory (Szmalec et al. Journal of Experimental Psychology: Learning, Memory, & Cognition 37(5): 1270-1279, 2011). At the same time, models of short term memory increasingly incorporate a distinction of order and item processing (Majerus et al. Cognition 107: 395-419, 2008). The current study is aimed to investigate whether serial order processing deficiencies in dyslexia can be traced back to a selective impairment of short-term memory for serial order and whether this impairment also affects processing beyond the verbal domain. A sample of 26 adults with dyslexia and a group of age and IQ-matched controls participated in a 2 * 2 * 2 experiment in which we assessed short-term recognition performance for order and item information, using both verbal and nonverbal material. Our findings indicate that, irrespective of the type of material, participants with dyslexia recalled the individual items with the same accuracy as the matched control group, whereas the ability to recognize the serial order in which those items were presented appeared to be affected in the dyslexia group. We conclude that dyslexia is characterized by a selective impairment of short-term memory for serial order, but not for item information, and discuss the integration of these findings into current theoretical views on dyslexia and its associated dysfunctions. PMID- 24488222 TI - Bone substitutes and implantation depths for subchondral bone repair in osteochondral defects of porcine knee joints. AB - PURPOSE: The purpose of this study was to identify the optimal material and implantation method for subchondral bone repair. METHODS: Four osteochondral defects in a femoral groove were created in both knees of 12 pigs, and the total number of defects was 96. Eight defects were left empty (empty group). Beta tricalcium phosphate (beta-TCP) bone substitutes with 75 and 67 % porosity were implanted in 30 and 29 defects, respectively (beta-TCP75 and beta-TCP67 groups). Hydroxyapatite (HA) bone substitutes with 75 % porosity were filled in 29 defects (HA group). Bone substitutes were implanted at 0, 2, or 4 mm below the subchondral bone plate (SBP). The reparative tissue was assessed using microfocus computed tomography and histology 3 months after implantation. RESULTS: Regardless of the kind of bone substitutes, the defects were filled almost completely after implanting them at the level of the SBP, while the defects remained after implanting them at 2 or 4 mm below the SBP. Reparative tissue of the beta-TCP75 group was similar to the normal cancellous bone, while that of the beta-TCP67 or HA group was not. CONCLUSIONS: Subchondral bone defects were filled almost completely only when bone substitutes were implanted at the level of the SBP. The reparative tissue after implanting the beta-TCP bone substitutes with 75 % porosity was the most similar to the normal cancellous bone. Therefore, implanting the beta-TCP bone substitutes with 75 % porosity at the level of the SBP could be recommended as a treatment method for subchondral bone repair in osteochondral defects. LEVEL OF EVIDENCE: I. PMID- 24488228 TI - Sustainable, heat-resistant and flame-retardant cellulose-based composite separator for high-performance lithium ion battery. AB - A sustainable, heat-resistant and flame-retardant cellulose-based composite nonwoven has been successfully fabricated and explored its potential application for promising separator of high-performance lithium ion battery. It was demonstrated that this flame-retardant cellulose-based composite separator possessed good flame retardancy, superior heat tolerance and proper mechanical strength. As compared to the commercialized polypropylene (PP) separator, such composite separator presented improved electrolyte uptake, better interface stability and enhanced ionic conductivity. In addition, the lithium cobalt oxide (LiCoO2)/graphite cell using this composite separator exhibited better rate capability and cycling retention than that for PP separator owing to its facile ion transport and excellent interfacial compatibility. Furthermore, the lithium iron phosphate (LiFePO4)/lithium cell with such composite separator delivered stable cycling performance and thermal dimensional stability even at an elevated temperature of 120 degrees C. All these fascinating characteristics would boost the application of this composite separator for high-performance lithium ion battery. PMID- 24488234 TI - Multiprocess dynamic modeling of tumor evolution with bayesian tumor-specific predictions. AB - We propose a sequential probabilistic mixture model for individualized tumor growth forecasting. In contrast to conventional deterministic methods for estimation and prediction of tumor evolution, we utilize all available tumor specific observations up to the present time to approximate the unknown multi scale process of tumor growth over time, in a stochastic context. The suggested mixture model uses prior information obtained from the general population and becomes more individualized as more observations from the tumor are sequentially taken into account. Inference can be carried out using the full, possibly multimodal, posterior, and predictive distributions instead of point estimates. In our simulation study we illustrate the superiority of the suggested multi process dynamic linear model compared to the single process alternative. The validation of our approach was performed with experimental data from mice. The methodology suggested in the present study may provide a starting point for personalized adaptive treatment strategies. PMID- 24488221 TI - Midterm outcomes of arthroscopic remplissage for the management of recurrent anterior shoulder instability. AB - PURPOSE: The purpose of the study was to present midterm results concerning the management of recurrent anterior shoulder instability with the remplissage technique in addition to the classic Bankart repair, in patients with engaging Hill-Sachs lesions. METHODS: During a time period of 4 years (January 2007 December 2010), 48 patients with an average age of 28.9 +/- 7.8 years were operated on in our department. They all had a positive apprehension sign pre operatively and satisfied the inclusion criteria of this study. Seventy-nine per cent of these patients were involved in sport activities of different levels. The mean follow-up period was 37.2 +/- 9.9 months. RESULTS: Three patients (6.3 %) had suffered a new dislocation: one of them after a low-energy trauma and the two other after a high-energy trauma. The rest of the patients (93.7 %) were satisfied with the surgical result and returned to their previous everyday activities while 70.8 % continued to participate in sporting activities without restrictions. The ASES score increased from 67.7 +/- 21.5 points pre-operatively to 90.8 +/- 21.7 points post-operatively (p < 0.01), the modified Rowe score from 38 +/- 17.3 to 93.8 +/- 14.5 (p < 0.001) and the Oxford Instability score from 27.6 +/- 11.1 to 45.1 +/- 8.3 (p < 0.001). No significant restriction in shoulder range of motion was documented. CONCLUSIONS: The outcome of the enhancement of the classic Bankart repair with tenodesis of the infraspinatus and posterior capsular plication is very good as far as the management of recurrent anterior shoulder instability is concerned, without significantly influencing the range of motion of the shoulder. LEVEL OF EVIDENCE: Therapeutic study-case series with no comparison group, Level IV. PMID- 24488238 TI - Phase evolution of magnetron sputtered nanostructured ATO on grid during lithiation-delithiation processes as model electrodes for Li-ion battery. AB - Sb-doped SnO2 (ATO) nanostructured thin films were deposited on holey carbon grids by magnetron sputtering at room temperature. Li/electrolyte/ATO cells were assembled by using the deposited ATO grids as test electrodes. The phase component of the ATO electrodes deposited on grids before and after induction at different charge-discharge stages was characterized by using a transmission electron microscope. The results of the investigation show that the nanostructured ATO thin films undergo a reversible lithiation-delithiation process: the decomposition of SnO2 and the occurrence of metallic Sn followed by the formation of an Li-Sn alloy during the discharge process, and then the reversible de-alloying reaction of the Li-Sn alloy and Sn reaction with Li2O, and even partial formation of SnO2 during charge process. The work also shows that the method deposited the active materials directly on the holey carbon grids is a simple and effective way for the investigation of the phase evolution of the electrodes in electrochemical cells. PMID- 24488237 TI - Directional emission from a single plasmonic scatterer. AB - Directing light emission is key for many applications in photonics and biology. Optical antennas made from nanostructured plasmonic metals are suitable candidates for this purpose but designing antennas with good directional characteristics can be challenging, especially when they consist of multiple elements. Here we show that strongly directional emission can also be obtained from a simple individual gold nanodisk, utilizing the far-field interference of resonant electric and magnetic modes. Using angle-resolved cathodoluminescence spectroscopy, we find that the spectral and angular response strongly depends on excitation position. For excitation at the nanodisk edge, interference between in plane and out-of-plane dipole components leads to strong beaming of light. For large nanodisks, higher-order multipole components contribute significantly to the scattered field, leading to enhanced directionality. Using a combination of full-wave simulations and analytical point scattering theory we are able to decompose the calculated and measured scattered fields into dipolar and quadrupolar contributions. PMID- 24488233 TI - Architectural trends in the human normal and bicuspid aortic valve leaflet and its relevance to valve disease. AB - The bicuspid aortic valve (AV) is the most common cardiac congenital anomaly and has been found to be a significant risk factor for developing calcific AV disease. However, the mechanisms of disease development remain unclear. In this study we quantified the structure of human normal and bicuspid leaflets in the early disease stage. From these individual leaflet maps average fiber structure maps were generated using a novel spline based technique. Interestingly, we found statistically different and consistent regional structures between the normal and bicuspid valves. The regularity in the observed microstructure was a surprising finding, especially for the pathological BAV leaflets and is an essential cornerstone of any predictive mathematical models of valve disease. In contrast, we determined that isolated valve interstitial cells from BAV leaflets show the same in vitro calcification pathways as those from the normal AV leaflets. This result suggests the VICs are not intrinsically different when isolated, and that external features, such as abnormal microstructure and altered flow may be the primary contributors in the accelerated calcification experienced by BAV patients. PMID- 24488231 TI - Characterization of Toll-like receptors 1-10 in spotted hyenas. AB - Previous research has shown that spotted hyenas (Crocuta crocuta) regularly survive exposure to deadly pathogens such as rabies, canine distemper virus, and anthrax, suggesting that they have robust immune defenses. Toll-like receptors (TLRs) recognize conserved molecular patterns and initiate a wide range of innate and adaptive immune responses. TLR genes are evolutionarily conserved, and assessing TLR expression in various tissues can provide insight into overall immunological organization and function. Studies of the hyena immune system have been minimal thus far due to the logistical and ethical challenges of sampling and preserving the immunological tissues of this and other long-lived, wild species. Tissue samples were opportunistically collected from captive hyenas humanely euthanized for a separate study. We developed primers to amplify partial sequences for TLRs 1-10, sequenced the amplicons, compared sequence identity to those in other mammals, and quantified TLR expression in lymph nodes, spleens, lungs, and pancreases. Results show that hyena TLR DNA and protein sequences are similar to TLRs in other mammals, and that TLRs 1-10 were expressed in all tissues tested. This information will be useful in the development of new assays to understand the interactions among the hyena immune system, pathogens, and the microbial communities that inhabit hyenas. PMID- 24488230 TI - Cerebral effects of ammonia in liver disease: current hypotheses. AB - Hyperammonemia is necessary for development of the cerebral complications to liver disease including hepatic encephalopathy and cerebral edema but the mechanisms are unclear. Ammonia is taken up by the brain in proportion to its arterial concentration. The flux into the brain is most likely by both diffusion of NH3 and mediated transport of NH4 (+) . Astrocytic detoxification of ammonia involves formation of glutamine at concentrations high enough to produce cellular edema, but compensatory mechanisms reduce this effect. Glutamine can be taken up by astrocytic mitochondria and initiate the mitochondrial permeability transition but the clinical relevance is uncertain. Elevated astrocytic glutamine interferes with neurotransmission. Thus, animal studies show enhanced glutamatergic neurotransmission via the NMDA receptor which may be related to the acute cerebral complications to liver failure, while impairment of the NMDA activated glutamate-NO-cGMP pathway could relate to the behavioural changes seen in hepatic encephalopathy. Elevated glutamine also increases GABA-ergic tone, an effect which is aggravated by mitochondrial production of neurosteroids; this may relate to decreased neurotransmission and precipitation of encephalopathy by GABA targeting drugs. Hyperammonemia may compromise cerebral energy metabolism as elevated cerebral lactate is generally reported. Hypoxia is unlikely since cerebral oxygen:glucose utilisation and lactate:pyruvate ratio are both normal in clinical studies. Ammonia inhibits alpha-ketoglutaratedehydrogenase in isolated mitochondria, but the clinical relevance is dubious due to the observed normal cerebral oxygen:glucose utilization. Recent studies suggest that ammonia stimulates glycolysis in excess of TCA cycle activity, a hypothesis that may warrant further testing, in being in accordance with the limited clinical observations. PMID- 24488235 TI - Evaluating the diagnoses of gastric antral lesions using magnifying endoscopy with narrow-band imaging in a Chinese population. AB - AIM: To evaluate the accuracy of diagnosing gastric antral lesions in routine clinical practice using magnifying endoscopy with narrow-band imaging (M-NBI) as a real-time diagnosing technique. METHODS: Consecutive patients undergoing upper endoscopy were selected for the study. In each patient, the mucosa of the gastric antrum was observed by M-NBI, and the gastric microstructure was categorized into five types (A-E). Based on these patterns, histological types were predicted in a real-time manner. The accuracy of these predictions was evaluated based on histological findings. Inter-observer agreement was also assessed. RESULTS: A total of 207 sites in 90 patients were examined by M-NBI. Compared with type A gastric microstructure, types B and C gastric microstructure showed a significantly higher degree of inflammation (P < 0.001). The sensitivity, specificity and accuracy of types B + C microstructure as a predictor of gastric inflammation were 85.4, 81.7 and 83.1 %, respectively. Similarly, the sensitivity, specificity and accuracy of type D microstructure as a predictor of gastric intestinal metaplasia were 71.8, 95.2 and 90.8 %, respectively, and those of type E microstructure as a predictor of early gastric cancer were 80.0, 98.9 and 97.6 %, respectively. The sensitivity and specificity of type B alone, type C alone and types B + C combined for the detection of Helicobacter pylori infection were 52.2 and 87.0 %, 22.8 and 92.2 %, 75.0 and 79.1 %, respectively. The kappa value for the inter-observer agreement was 0.715 (95 % confidence interval 0.655 0.895). CONCLUSIONS: In conclusion, M-NBI can significantly improve the accuracy of the prediction of histopathology of gastric antral lesions in vivo, implying the possibility of using M-NBI as an effective diagnosis technique. PMID- 24488224 TI - Post-operative Oxford knee score can be used to indicate whether patient expectations have been achieved after primary total knee arthroplasty. AB - PURPOSE: The aim of this study was to identify threshold values in the post operative Oxford knee score (OKS) and change in the score for achievement of specific patient expectations and satisfaction, and whether failure to meet specific patient expectations influenced the rate of satisfaction after total knee arthroplasty (TKA). METHODS: Prospectively complied data for 322 primary TKA were used. Patient demographics, and pre- and post-operative (1 year) OKS, and expectation fulfilment were collected. Patient satisfaction was also assessed 1 year post-operatively. RESULTS: Patient pre-operative expectations varied in prevalence and differed according to gender, age, and severity of knee symptoms according the OKS. Fulfilment of patient expectations was variable and was dependent upon the specific expectation; the majority of patients achieved their expectation of pain relief and improved ability to walk (>70%), however, few fulfilled their expectation to kneel or squat (<25%). The threshold according to the post-operative OKS at which these expectations were achieved varied by more than ten points, ranging from >=31 for pain relief to >=42 for kneeling. Failure to fulfil patient expectations, for 15 of the 17 assessed, significantly increased the risk of dissatisfaction at 1 year (p < 0.05). CONCLUSION: The post operative OKS can be used to predict the point at which the greatest proportion of patient expectations is achieved. Some expectations, however, are rarely fulfilled after a TKA and patients should be made aware of this pre-operatively which may improve their satisfaction post-operatively. LEVEL OF EVIDENCE: Retrospective comparative study, Level III. PMID- 24488236 TI - The surgical epicondylar axis is a consistent reference of the distal femur in the coronal and axial planes. AB - PURPOSE: Various rotational landmarks including the surgical epicondylar axis (SEA) are used for preoperative planning and intra-operative reference of total knee arthroplasty (TKA) in the axial plane. The aim of the study was to elucidate the relationships between the SEA and other femoral anatomical landmarks, including the mechanical axis, distal and posterior knee joints, the trochlear groove, and the anterior femoral condyle, in both the coronal and axial planes. METHODS: Angular and linear measurements were taken of sixty femora using Orthomap3D, which has a tool to analyse computed tomography image data that makes it possible to measure three-dimensional distances and angles precisely. The inter- and intra-observer reliabilities of these measurements were evaluated. Comparisons were made according to height, weight, body mass index, and gender. RESULTS: The angle between the mechanical axis and the SEA was 90.2 degrees (95% CI 90.0 degrees -90.4 degrees ). There was a significant correlation for each linear measurement between the SEA and the distal/posterior knee joint line and for each linear measurement between the SEA and the anterior medial/lateral femoral condyle. A significant difference was observed between genders in the linear measurements. Significant correlations were found between height and weight and linear parameters. CONCLUSION: Knowledge of the relationships between the SEA and other femoral anatomical landmarks is useful in preoperative planning, intra-operative landmark, and postoperative assessment of TKA. The SEA is a consistent parameter of femoral alignment in the coronal plane and a stable reference for femoral rotation in the axial plane. LEVEL OF EVIDENCE: III. PMID- 24488239 TI - Sexual maturation among youth with ADHD and the impact of stimulant medication. AB - OBJECTIVE: Evaluate the differences in achieving puberty between ADHD and non ADHD participants and the effects of medication on that process among ADHD participants. PROCEDURE: A subset of participants with ADHD from the Multimodal Treatment study of ADHD (n = 342) were compared with respect to Tanner staging to participants from a comparison group without ADHD (n = 159) at the 36-month follow-up assessment. Further comparisons were made for Tanner stages and Auxology of the participants in the ADHD group who were always (n = 61), never (n = 56), newly (n = 74) and inconsistently (n = 116) treated with stimulants. RESULTS: No statistically significant differences in Tanner stages of sexual development were found between the ADHD and non-ADHD groups at the age of assessment (between 10 and 14 years of age) or among the ADHD medication subgroups, although a trend was observed for stimulant-associated delayed pubertal initiation using auxological analysis. CONCLUSION: Children with or without ADHD did not differ in Tanner stages at the 3-year follow-up assessment, and exposure to stimulant medication does not appear to affect sexual development within this age range. PMID- 24488232 TI - Cellular regulation of extension and retraction of pseudopod-like blebs produced by nanosecond pulsed electric field (nsPEF). AB - Recently we described a new phenomenon of anodotropic pseudopod-like blebbing in U937 cells exposed to nanosecond pulsed electric field (nsPEF). In Ca(2+)-free buffer such exposure initiates formation of pseudopod-like blebs (PLBs), protrusive cylindrical cell extensions that are distinct from apoptotic and necrotic blebs. PLBs nucleate predominantly on anode-facing cell pole and extend toward anode during nsPEF exposure. Bleb extension depends on actin polymerization and availability of actin monomers. Inhibition of intracellular Ca(2+), cell contractility, and RhoA produced no effect on PLB initiation. Meanwhile, inhibition of WASP by wiskostatin causes dose-dependent suppression of PLB growth. Soon after the end of nsPEF exposure PLBs lose directionality of growth and then retract. Microtubule toxins nocodazole and paclitaxel did not show immediate effect on PLBs; however, nocodazole increased mobility of intracellular components during PLB extension and retraction. Retraction of PLBs is produced by myosin activation and the corresponding increase in PLB cortex contractility. Inhibition of myosin by blebbistatin reduces retraction while inhibition of RhoA-ROCK pathway by Y-27632 completely prevents retraction. Contraction of PLBs can produce cell translocation resembling active cell movement. Overall, the formation, properties, and life cycle of PLBs share common features with protrusions associated with ameboid cell migration. PLB life cycle may be controlled through activation of WASP by its upstream effectors such as Cdc42 and PIP2, and main ROCK activator-RhoA. Parallels between pseudopod-like blebbing and motility blebbing may provide new insights into their underlying mechanisms. PMID- 24488240 TI - Characterization of the protein from gas-vacuole membranes of the blue-green alga, Microcystis aeruginosa. AB - The purified protein which constitutes the membranes of the gas vacuoles of the the blue-green alga, Microcystis aeruginosa, was partially characterized. Gel electrophoresis and end-group analysis indicate that the protein is a single species. Strongly protic solvents such as formic acid are the only reagents causing appreciable solubilization of the membrane protein. Infrared spectroscopy shows that the membrane protein has both alpha-helix or random-coil conformation, and beta-conformation. PMID- 24488244 TI - [Growth rate of the axillary buds and variation of the type of correlation between the cotyledon and its axillary bud in Bidens pilosus L]. AB - Application of various growth substances to seedlings of Bidens with an inhibitory cotyledon causes a cotyledonary correlative stimulation. At the same time, if we measure the influence of these substances on the growth rate of the buds during the experiment, we see that the cotyledonary correlative stimulation is always associated with a decrease of this growth rate. If the control had an indifferent or stimulating cotyledon, the application of the same various substances either causes an increase of this cotyledonary correlative stimulation or brings about a cotyledonary correlative inhibition. In the first case a decrease of the growth rate is always noted, while the cotyledonary correlative inhibition is associated with an increase in the growth rate. PMID- 24488245 TI - A detailed analysis of phytochrome decay and dark reversion in mustard cotyledons. AB - During the first 10 min after a saturating dose of red light, 72 h dark-grown mustard cotyledons show no phytochrome decay. Within the same time interval there exists a transient form of P fr (=P fr (T) ) which is no longer photoconvertible at 0 degrees C, but is at 25 degrees C. This P fr (T) converts in the dark to P fr and P r . These "dark reversions" take about 10 min. After a lag phase of 10 min the P fr decay can be described by a single, first order kinetic curve. The time courses of these reactions are functions of the time of etiolation. PMID- 24488241 TI - Studies in seed dormancy : V. The content of endogenous gibberellins in seeds of Corylus avellana L. AB - The endogenous gibberellins of hazel seeds have been studied by a thin layer chromatography/pea epicotyl bioassay (TLC/bioassay) procedure and also by gas liquid chromatography (GLC) of the gibberellin methyl esters and the trimethylsilyl ethers of the methyl esters. Consistent results were obtained from the two techniques and provisional identifications of some of the gibberellins were obtained by GLC. The gibberellin which was present in the newly harvested seeds, which do not show embryo dormancy, had largely disappeared after the development of embryo dormancy. During 28 days chilling at 5 degrees there was a small increase in endogenous gibberellin but on transfer to 20 degrees there was a considerable rise in endogenous gibberellins, variously estimated as 64-fold (GLC) or 79-fold (TLC/bioassay), this rise preceding the detection of measurable growth of the embryonic axis. The GLC procedure gave provisional identifications of GA1, GA4 and/or GA7, GA5 and/or GA20, GA6 and/or GA17, and GA8. The gibberellin concentration in the embryonic axis was several hundred-fold greater than that in the cotyledons. PMID- 24488243 TI - Light-stimulation of alanine aminotransferase activity in dark-grown leaves of Lolium temulentum L. as related to chlorophyll formation. AB - The activity of alanine aminotransferase (=glutamate-pyruvate transaminase, GPT) in dark-grown first leaves of Lolium temulentum L. was increased, after an initial lag-phase of 4-6 hr, by more than 130% during the first 24 hr of light exposure. In comparison, aspartate aminotransferase (=glutamateoxalacetate transaminase, GOT) activity rose by only 18%. Red light treatments of up to 60 min duration produced subsequent increases in GPT activity but the effects were too small to indicate a phytochrome-mediated response. The amounts of enzyme formed were equivalent to those obtained with similar incident intensities of white light. Retuern to darkness after light exposure resulted in an arrestation of the light-stimulated GPT increase. Pre-treatment with cycloheximide caused either stimulatory or inhibitory effects depending upon the concentration applied but, in general, chlorophyll formation and GPT activity responded in a similar manner, whilst GOT showed virtually no response. Chloramphenicol at 6x10(-3) M depressed chlorophyll and Fraction 1 protein synthesis but stimulated GPT activity.The data are discussed in relation to the possible roles of GPT in the leaf. It is suggested that the enzyme, as determined, may be a complex of forms and that at least part of the activity may be involved in the early stages of chlorophyll biosynthesis. PMID- 24488247 TI - [Investigations upon the binding of plant growth substances to several components of the chromatin in vitro : II. experiments with differently reconstituted nucleoproteins]. AB - Several growth substances (IAA, alpha-NAA) are able to reduce thermal stability of artificially reconstituted nucleoproteins without splitting off measurable amounts of protein from DNA. This effect is not shown by substances structurally related to auxins (beta-NAA, tryptophan), but other growth substances (GA, KI) also reduce thermal stability of several reconstituated nucleoproteins.The effect of growth substances on the Tm of nucleoproteins strongly depends upon the concentration of the growth substances. The effective concentrations of IAA are lowered by increasing acidity of the protein component in the nucleoprotein. IAA and GA diminish the binding capacity of histones and residual nucleoproteins to DNA at different concentrations.Nucleoproteins containing histones and residual nuclear proteins (DNA/resid. prot. 1:0,5: 0,5) exhibited different thermal stability depending on whether part of the histones or residual nuclear proteins were first bound to DNA. Furthermore, these nucleoproteins showed different thermal stability after treatment with growth substances. PMID- 24488249 TI - Uptake of 3-O-methyl-(14)C-D-glucose by a unicellular blue-green alga. AB - The uptake of 3-O-methyl-(14)C-D-glucose, a non-metabolizable sugar, by autotrophically grown Synechococcus cedrorum was studied at low sugar concentrations in the incubation medium (0.71-11.36 MUM), in the light and in the dark. Optimum sugar accumulation against a concentration gradient occurred within dark-treated "starved" cells that were incubated in the light. This phenomenon was greatly inhibited by metabolic inhibitors; it was much less when sugar uptake was observed in the dark. Control cells incubated in the light accumulated 3-O methyl-(14)C-D-glucose against a concentration gradient only at lower sugar concentrations (0.71-2.84 MUM) and to a lesser extent than the dark-treated cells. Sugar uptake against a concentration gradient by the control cells was completely inhibited in the dark. The results indicate that the morphologically simple unicellular blue-green alga, S. cedrorum, is under certain conditions capable of obtaining a sugar from its medium by an active transport process. PMID- 24488242 TI - Studies in seed dormancy : VI. The effects of growth retardants on the gibberellin content and germination of chilled seeds of Corylus avellana L. AB - The germination at 20 degrees , of hazel seeds which had been chilled, was significantly inhibited by 10(-4) M solutions of ABA and of five substances which are considered to be inhibitors of gibberellin synthesis, namely CCC, AMO 1618, Phosphon D, B-995 and C-011. When the endogenous gibberellins were extracted from chilled seeds which had been held at 20 degrees for 7 days in the presence of 10(-4) M solutions of three of the most effective inhibitors of germination (Phosphon D, B-995 and C-011) it was found that gibberellin accumulation had been substantially inhibited. It is postulated that the inhibition of gibberellin synthesis inhibits the germination of previously chilled hazel seeds. PMID- 24488250 TI - Effect of chilling and gibberellic acid on growth potential of excised embryos of Ruellia humilis. AB - Dormancy in intact seeds of Ruellia humilis is broken by chilling or by treatment with gibberellic acid (GA3). Embryos are nondormant and will grow when the seed coat is removed completely. Embryos from chilled or GA3-treated seeds have more growth potential than embryos from nontreated seeds. Dormancy is ascribed to the mechanical restriction of the embryo by the seed coat. Chilling and treatment with GA3 break dormancy by increasing the expansive force of the embryo; thus, chilled or GA3-treated embryos exert enough expansive force to break through the seed coat, whereas nontreated embryos do not. PMID- 24488248 TI - "Bristly" cristae in algal mitochondria. AB - In forming zoospores of Oedogonium, mitochondria were found to contain numerous, evenly-spaced bristle-like structures projecting from the surface of cristae. PMID- 24488246 TI - [Isolation and properties of mitochondria from leaves of Spinacia oleracea and Beta vulgaris]. AB - From mature green leaves of Spinacia oleracea and Beta vulgaris a fraction has been obtained which is enriched in mitochondria. Washed leaves were crushed in a meat-mill in an isotonic or slightly hypertonic medium containing sucrose, EDTA, MgSO4, bovine serum albumin, mercaptoethanol, KH2PO4, and HEPES as a buffer substance. After squeezing through nylon the suspension was centrifuged first at 1500xg, and following removal of the sediment a second time at 25000xg. After resuspension in a washing medium, the pellet was centrifuged in a swing-out rotor for 30 min at 35000xg on a density gradient generated from a silica sol ("Ludox HS 40"). A temperature of 2 degrees C was maintained during the whole procedure.Whereas the usual isolation techniques are unsatisfactory for the preparation of intact leaf cell mitochondria, the above procedure enabled us to obtain a fraction from the gradient which had the following properties. The respiration rate was 29.5 MUatoms O/mg protein-N/h with alpha-ketoglutarate as a substrate. Phosphorylation rates as calculated from the phosphate measurements and P/O ratios were low. This has been interpreted as a consequence of ATPase activity in the fraction. In polarographic studies ADP/O ratios of 1.32-2.15 with succinate as a substrate were measured. Respiratory control was also observed. This indicates the presence of tightly coupled mitochondria in the fraction.The fine structure of the mitochondria was shown to be intact as far as electron microscopical evidence can be used as a criterion. The procedure appears to be suitable for isolating active mitochondria and intact chloroplasts from green leaves. It may permit the study of interrelationships between these organelles. PMID- 24488252 TI - The impact of certified diabetes educators on diabetes performance and variation among primary care sites within an integrated health system. AB - OBJECTIVES: Primary care networks within integrated health systems can experience significant variation in diabetes care. We studied an established, 20-site network to determine the impact of a quality improvement intervention to add certified diabetes educators (CDEs). We sought to measure whether sites with CDEs had higher quality and whether care improved over time more in sites with CDEs, beyond the existing differences among sites. METHODS: Diabetes quality outcomes were (1) HbA1c <=8%, (2) low-density lipoprotein (LDL) <=100 mg/dL, (3) microalbumin checked, (4) blood pressure (BP) <=130/80 mm Hg (tight control), and (5) BP <=140/90 mm Hg (lenient control). Baseline differences brought us to divide sites into 3 site types by predominant payer and teaching status (commercial/nonteaching, mixed [mostly government-sponsored]/teaching and mixed/nonteaching). We measured the association between CDEs and each outcome using a 2-level mixed effects logistic regression with site type as a random effect. RESULTS: Our analysis included 13 001 patients with visits and labs pre- and post-CDE implementation. Sites with CDEs improved significantly in 2 of 5 outcomes compared with sites without CDEs. Improvements occurred in microalbumin checks (odds ratio = 2.21, P < .001) and BP <140/90 mm Hg (odds ratio = 1.46, P = .03). There was no improvement in the other measures of diabetes quality. Of note, commercial/nonteaching and mixed/teaching sites also improved significantly in these 2 outcomes compared with mixed/nonteaching sites during that time period. CONCLUSIONS: We found that CDEs are associated with significant improvements in some diabetes outcomes. However, heterogeneity among primary care sites in an integrated network persists and all types of sites might not benefit equally from a quality improvement intervention like CDEs. PMID- 24488251 TI - Dormancy-release of celery seed by a growth retardant, N-dimethylaminosuccinamic acid (alar). AB - Alar (N-dimethylaminosuccinamic acid) was more effective than the cytokinin benzyladenine (BA) in breaking dormancy of light-sensitive celery seed treated with a mixture of gibberellins A4 and A7 (GA4/7). PMID- 24488254 TI - Temperature driven assembly of like-charged nanoparticles at non-planar liquid liquid or gel-air interfaces. AB - Gold nanoparticles (NPs) functionalized with 2-fluoro-4-mercaptophenol (FMP) ligands form densely packed NP films at liquid-liquid interfaces, including surfaces of liquid droplets. The process is driven by a gradual lowering of temperature that changes the solution's pH, altering both the energy of interfacial adsorption for NPs traveling from solution to the interface as well as the balance between electrostatic and vdW interactions between these particles. Remarkably, the system shows hysteresis in the sense that the films remain stable when the temperature is increased back to the initial value. The same phenomena apply to gel-air interfaces, enabling patterning of these wet materials with durable NP films. PMID- 24488253 TI - Do the Guidelines for Adolescent Preventive Services (GAPS) facilitate mental health diagnosis? AB - OBJECTIVE: To determine if the Guidelines for Adolescent Preventive Services (GAPS) increases detection or shortens time to diagnosis of mental health (MH) disorders, particularly adolescent depression. METHODS: Starting in May 1999, GAPS questionnaires were routinely administered at adolescent annual visits at 1 primary care clinic in a rural health network. Using an administrative database, we enumerated all MH diagnostic codes for outpatient visits of adolescents aged 13 to 15 years. Population based rates were derived using school enrollment data. Using time series, the rates of MH diagnoses were compared pre- and post-GAPS. Using survival analysis, the time to any MH diagnosis subsequent to index annual visits was also compared pre- and post-GAPS. Because the GAPS questionnaire includes questions for depressed mood, anhedonia, and suicidality, ICD-9-CM codes for depression and mood disorder were also analyzed separately. RESULTS: Time series analysis included 8112 adolescents. The rate of MH diagnosis did not change pre- and post-GAPS (P = .13). Time to any MH diagnosis was similar pre GAPS (9.0 months) and post-GAPS (7.0 months, log rank P = .30). Time to any first diagnosis of depression or mood disorder was similar post-GAPS (12.2 months) versus pre-GAPS (11.0 months, log rank P = .34). CONCLUSIONS: Use of the GAPS was not associated with change in the rate of or time to MH diagnosis. Our results challenge the prevalent expectation that requiring mental health screening will reduce unmet need for MH treatment. Validated MH screening tools, primary care provider training, and access to MH services may also be needed but further study is required. PMID- 24488255 TI - The Vicious Cycle of Parental Caregiving and Financial Well-being: A Longitudinal Study of Women. AB - OBJECTIVES: This study examines the relationship between caring for older parents and the financial well-being of caregivers by investigating whether a reciprocal association, or vicious cycle, exists between female caregiver's lower household incomes and caring for elderly parents. METHOD: Data for women aged 51 or older with at least 1 living parent or parent-in-law were drawn from the Health and Retirement Survey 2006, 2008, and 2010 (N = 2,093). A cross-lagged panel design was applied with structural equation modeling. RESULTS: We found support for the reciprocal relationship between parental caregiving and lower household income. Female caregivers were more likely than noncaregivers to be in lower household income at later observation points. Also, women with lower household income were more likely than women with higher household income to assume caregiving at later observation points. DISCUSSION: This study suggests that there exists a vicious cycle of parental care and lower household income among women. A key concern for policy is female caregivers' financial status when care of older parents is assumed and care burden when women's financial status declines. PMID- 24488256 TI - Type VI secretion and bacteriophage tail tubes share a common assembly pathway. AB - The Type VI secretion system (T6SS) is a widespread macromolecular structure that delivers protein effectors to both eukaryotic and prokaryotic recipient cells. The current model describes the T6SS as an inverted phage tail composed of a sheath-like structure wrapped around a tube assembled by stacked Hcp hexamers. Although recent progress has been made to understand T6SS sheath assembly and dynamics, there is no evidence that Hcp forms tubes in vivo. Here we show that Hcp interacts with TssB, a component of the T6SS sheath. Using a cysteine substitution approach, we demonstrate that Hcp hexamers assemble tubes in an ordered manner with a head-to-tail stacking that are used as a scaffold for polymerization of the TssB/C sheath-like structure. Finally, we show that VgrG but not TssB/C controls the proper assembly of the Hcp tubular structure. These results highlight the conservation in the assembly mechanisms between the T6SS and the bacteriophage tail tube/sheath. PMID- 24488257 TI - The G8 screening tool detects relevant geriatric impairments and predicts survival in elderly patients with a haematological malignancy. AB - The G8 screening tool was developed to separate fit older cancer patients who were able to receive standard treatment from those that should undergo a geriatric assessment to guide tailoring of therapy. We set out to determine the discriminative power and prognostic value of the G8 in older patients with a haematological malignancy. Between September 2009 and May 2013, a multi dimensional geriatric assessment was performed in consecutive patients aged >=67 years diagnosed with blood cancer at the Innsbruck University Hospital. The assessment included (instrumental) activities of daily living, cognition, mood, nutritional status, mobility, polypharmacy and social support. In parallel, the G8 was also administered (cut-off <= 14). Using a cut-off of >=2 impaired domains, 70 % of the 108 included patients were considered as having an impaired geriatric assessment while 61 % had an impaired G8. The G8 lacked discriminative power for impairments on full geriatric assessment: sensitivity 69, specificity 79, positive predictive value 89 and negative predictive value 50 %. However, G8 was an independent predictor of mortality within the first year after inclusion (hazard ratio 3.93; 95 % confidence interval 1.67-9.22, p < 0.001). Remarkably, patients with impaired G8 fared poorly, irrespective of treatment choices (p < 0.001). This is the first report on the clinical and prognostic relevance of G8 in elderly patients with haematological malignancies. Although the G8 lacked discriminative power for outcome of multi-dimensional geriatric assessment, this score appears to be a powerful prognosticator and could potentially represent a useful tool in treatment decisions. This novel finding certainly deserves further exploration. PMID- 24488260 TI - Chemical modification with functionalized ionic liquids: a novel method to improve the enzymatic properties of Candida rugosa lipase. AB - Chemical modification of lysine residues in Candida rugosa lipase (CRL) was carried out using five different functional ionic liquids, and about 15.4-25.0 % of the primary amino groups of lysine were modified. Enzymatic properties of the native and modified CRLs were investigated in olive oil hydrolysis reaction. Improved thermal stability, catalytic activity in organic solvents, and adaptability to temperature and pH changes were achieved compared with the native enzyme. CRL modified by [choline][H2PO4] showed the best results, bearing a maximum improvement of 16.7 % in terms of relative activity, 5.2-fold increase in thermostability (after incubation at 45 degrees C for 5 h), and 2.3-fold increase in activity in strong polar organic solvent (80 % dimethyl sulfoxide) compared with the native enzyme. The results of ultraviolet, circular dichroism and fluorescence spectroscopy suggested that the change of the secondary and tertiary structures of CRL caused by the chemical modification resulted in the enhancement of enzymatic performance. The modification of CRL with functional ionic liquids was proved to be a novel and efficient method for improving the enzymatic properties of CRL. PMID- 24488259 TI - Immobilized anaerobic fermentation for bio-fuel production by Clostridium co culture. AB - Clostridium thermocellum/Clostridium thermolacticum co-culture fermentation has been shown to be a promising way of producing ethanol from several carbohydrates. In this research, immobilization techniques using sodium alginate and alkali pretreatment were successfully applied on this co-culture to improve the bio ethanol fermentation performance during consolidated bio-processing (CBP). The ethanol yield obtained increased by over 60 % (as a percentage of the theoretical maximum) as compared to free cell fermentation. For cellobiose under optimized conditions, the ethanol yields were approaching about 85 % of the theoretical efficiency. To examine the feasibility of this immobilization co-culture on lignocellulosic biomass conversion, untreated and pretreated aspen biomasses were also used for fermentation experiments. The immobilized co-culture shows clear benefits in bio-ethanol production in the CBP process using pretreated aspen. With a 3-h, 9 % NaOH pretreatment, the aspen powder fermentation yields approached 78 % of the maximum theoretical efficiency, which is almost twice the yield of the untreated aspen fermentation. PMID- 24488262 TI - Berberine regulates the expression of E-prostanoid receptors in diabetic rats with nephropathy. AB - Diabetic nephropathy (DN) is a major cause of morbidity and mortality in diabetic patients. Effective therapies to prevent the development of this disease and to improve advanced kidney injury are required. Berberine (BBR) has preventive effects on diabetes and its complications. This study is to investigate the effects of BBR on the expression of E-prostanoid receptors (EPs) in rats with high-fat diet and streptozotocin (STZ)-induced DN and underlying molecular mechanisms of BBR on DN rats. DN model was induced in male Sprague-Dawley rats with high-fat diet and low dose of STZ injection. BBR (50, 100, 200 mg/kg/d) were orally administered to rats after STZ injection and conducted for 8 weeks. The levels of interleukin-6 (IL-6) and prostaglandin E2 (PGE2) in renal cortex were measured by enzyme-linked immunosorbent assay. Expression of EPs receptors (EP1 EP4) were determined by western blotting. Remarkable renal damage, hyperglycemia and hyperlipidemia were observed in DN rats. BBR could restore renal functional parameters, suppress alterations in histological and ultrastructural changes in the kidney tissues, improve glucose and lipid metabolism disorders, and increase cAMP levels compared with those of DN model group (Wang et al. in Mol Biol Rep 40:2405-2418, 2013). The level of IL-6 and PGE2 were significantly increased in DN model group compared with normal group, BBR could apparently reduced the level of IL-6 and PGE2. Furthermore, the expression of EP1 and EP3 were both increased and EP4 was lessened in the DN model group compared with normal group, BBR could down-regulate total protein expression of EP1 and EP3 of renal cortex in DN rats and up-regulate the expression of EP4, and there is no significant difference on the expression of EP2 among all groups. These studies demonstrate, for the first time, that BBR exerts renoprotection in high-fat diet and STZ-induced DN rats by modulating the proteins expression of EPs in EP-G protein-cAMP signaling pathway. PMID- 24488263 TI - Great expectations: autism spectrum disorder and induced pluripotent stem cell technologies. AB - New applications of iPSC technology to research on complex idiopathic conditions raise several important ethical and social considerations for potential research participants and their families. In this short review, we examine these issues through the lens of emerging research on autism spectrum disorder (ASD). We begin by describing the current state of iPSC technology in research on ASD. Then we discuss how the social history of and current controversies in autism research combined with the emergence of autism-specific iPSC biobanks indicate an urgent need for researchers to clearly communicate the limitations and possibilities of iPSC research to ensure research participants have the ability to provide fully informed, voluntary consent. We conclude by offering recommendations to bolster informed consent for research involving iPSC biobanks, both in the specific context of ASD and more broadly. PMID- 24488261 TI - Differential expression of the melanocortin-4 receptor in male and female C57BL/6J mice. AB - The melanocortin 4 receptor is a member of melanocortin receptors of G-protein coupled receptors. By binding to melanocortin receptor agonists or antagonists, MC4R participates in the regulating of food intake, weight, energy homeostasis and sexual behavior. By activating the protein kinase A and leptin-melanocortin signalling pathways, MC4R mediates the amplification of signals from the hypothalamo-pituitary-adrenal and hypothalamo-pituitary-thyroid axes. This process permits peripheral information about the status of energy metabolism to be transmitted to the central nervous system. The hypothalamic nuclei then integrate these signals to evoke the appropriate reaction. We found that different sexes exhibited distinct metabolic regulation abilities, likely due to differences in these signalling pathways. MC4R plays a key role in coordinating the afferent messages from the peripheral and regulatory signals by controlling food intake and energy expenditure. To probe the disparities in metabolism and weight regulation between the sexes, we analyzed the expression of MC4R in different tissues from male and female mice by qRT-PCR and immunofluorescence. The results show that the expression of MC4R in brain and kidney is higher in female mice than in male mice, but in the livers, the result is opposition. Additionally, in both sexes, the expression of MC4R is higher in the brain than in the kidneys, and its expression in the liver is lowest, in males, the expression of MC4R in the testis is higher than that in the kidneys. These data show that the expression of MC4R exist different between sexes mice. PMID- 24488270 TI - In situ relationships between spatial-temporal variations in potential ecological risk indexes for metals and the short-term effects on periphyton in a macrophyte dominated lake: a comparison of structural and functional metrics. AB - Heavy metals may adversely affect the structure and function of the periphyton community in lake ecosystems. We carried out samplings of three habitats at eight sites located in the Lake Baiyangdian that is strongly influenced by wastewater discharge (Sites 1 and 2), aquaculture and densely populated villages (Sites 3, 6, and 8), and the least disturbed (Sites 4, 5, and 7). Cu, Ni, Pb, Zn, Hg, Cd, and Cr were determined in these samples, and the periphyton community was simultaneously studied. The contamination factor (C f (i) ) was estimated for every metal as the ratio between pre-industrial records from sediments (C n (i) ) and present concentration values (C (i) ), and the individual potential risk (E r (i) ) was calculated by multiply the toxic response factor (Tr (i) ) and C f (i) for a given substance were based on Hakanson's methodology. The RI was obtained for each sampling site by summing the values of E r (i) first and the average was calculated across the sampling sites. The results showed that the RI for all three habitats was lower than 94, and they are in decreasing order: wastewater discharge, aquaculture and densely populated villages, and the least anthropogenic impacted. When the three sampling seasons were compared, August appeared to show the highest risk, followed by April and November. The RI values showed negative correlations (r = -0.444 to -0.851, p < 0.05) with the structural and functional metrics. The best correlation was detected between chlorophyll c/chlorophyll a (Chl c/a) ratio and E r (i) Hg (r = -0.851, p < 0.01). Our results suggest the periphyton community can be used in bio-monitoring. PMID- 24488258 TI - Environmental remediation in the treatment of allergy and asthma: latest updates. AB - In the modern era, the prevalence of asthma and allergies are increasing. It has been speculated that environmental exposures are contributing to this rise. Several studies demonstrate that common indoor allergen exposures exacerbate asthma. Minimizing exposure to allergens and remediating the environment play a critical role in the treatment of asthma and allergies. The most effective environmental control measures are tailored multifaceted interventions which include education, thorough cleaning, using high-efficiency particulate air (HEPA) filters, integrated pest management, and maintenance of these practices. PMID- 24488271 TI - Presentation of orf (ecthyma contagiosum) after sheep slaughtering for religious feasts. AB - We report two cases of orf (ecthyma contagiosum) acquired during religious practices. In the first patient, a 34-year-old Muslim man from Tunisia, orf occurred on the left hand after the patient had handled lamb meat during the "Feast of Sacrifice." In the second patient, a 57-year-old Jewish man, orf was acquired after the "kosherization" of lamb meat and occurred on a finger of the left hand. As approximately 350,000 Muslims reside in the metropolitan area of Milan (Italy), it is possible that in the next future cases of orf acquired after religious practices will occur more often. PMID- 24488272 TI - Combined effects of urinary phytoestrogens metabolites and polymorphisms in metabolic enzyme gene on idiopathic male infertility. AB - Phytoestrogens are plant-derived compounds that may interact with estrogen receptors and mimic estrogenic effects. It remains unclear whether the individual variability in metabolizing phytoestrogens contributes to phytoestrogens-induced beneficial or detrimental effects. Our aim was to determine whether there is any interaction between metabolic rates (MR) of phytoestrogens and genetic polymorphisms in related xenobiotic metabolizing enzyme genes. MR was used to assess phytoestrogen exposure and individual metabolic ability. The amount of phytoestrogens in urine was measured by ultra-high performance liquid chromatography-tandem mass spectrometry in 600 idiopathic infertile male patients and 401 controls. Polymorphisms were genotyped using the SNPstream platform combined with the Taqman method. Prototypes and metabolites of secoisolariciresinol (SEC) have inverse effects on male reproduction. It was found that low MR of SEC increased the risk of male infertility (OR 2.49, 95 % CI 1.78, 3.48, P trend = 8.00 * 10(-8)). Novel interactions were also observed between the MR of SEC and rs1042389 in CYP2B6, rs1048943 in CYP1A1, and rs1799931 in NAT2 on male infertility (P inter = 1.06 * 10(-4), 1.14 * 10(-3), 3.55 * 10( 3), respectively). By analyzing the relationships between urinary phytoestrogen concentrations, their metabolites and male infertility, we found that individual variability in metabolizing SEC contributed to the interpersonal differences in SEC's effects on male reproduction. PMID- 24488274 TI - Roseovarius albus sp. nov., a new Alphaproteobacterium isolated from the Mediterranean Sea. AB - Strain 4SM10(T), an aerobic marine, Gram-negative, heterotrophic and non pigmented bacterium isolated from seawater from Vinaroz in Castellon, Spain, was characterized using a polyphasic approach. Analysis of the 16S rRNA gene sequence placed the strain within the Roseobacter clade in the family Rhodobacteraceae. Phylogenetic analyses also showed that strain 4SM10(T) forms a stable clade with species of the genus Roseovarius, being related to Roseovarius nubinhibens ISM(T) and Roseovarius aestuarii SMK-122(T) at 97.5 and 97.4 % 16S rRNA sequence similarity, respectively. Average Nucleotide Identity (ANI) values, determined as a measure of overall genomic resemblance, confirmed that strain 4SM10(T) does not belong to the same species as R. aestuarii CECT 7745(T) and Roseovarius nubinhibens CECT 7750(T) displaying ANI values well below the 95 % boundary for genomic species. Strain 4SM10(T) requires Na(+) plus a divalent cation (either Mg(2+) or Ca(2+)) to grow, reduces nitrate to nitrite and uses a large number of amino acids and organic acids (but no carbohydrates) as sole carbon sources. Enzymatic activities displayed in API ZYM tests are alkaline phosphatase, leucine arylamidase and acid phosphatase. The major cellular fatty acids were identified as C18:1 omega7c and/or C18:1 omega6c (67.1 %). The DNA G+C content was determined to be 54.27 mol%. Based on the genotypic and phenotypic data obtained, the name Roseovarius albus sp. nov. is proposed for this novel taxon, with the type strain 4SM10(T) (=CECT 7450(T) = KCTC 22653(T)). PMID- 24488275 TI - A survey of the knowledge of cardiopulmonary rescucitation and the impact of training on nurses at the University of Benin teaching hospital, Nigeria. AB - BACKGROUND: Early Cardiopulmonary resuscitation maintains cardiac output and tissue oxygenation following cardiac arrest and it prevents brain death. Nurses are usually the first set of hospital staff to arrive at the scene of a cardiopulmonary arrest occurring in the ward or intensive care unit and a good knowledge of cardiopulmonary resuscitation is usually essential for patient's survival. OBJECTIVES: The objective of this study was to assess the knowledge of cardiopulmonary resuscitation and the impact of training on clinical nurses. METHODS: A cross-sectional study was conducted in a period of twelve consecutive weeks for clinical nurses during their academic session. Self-completed questionnaire were administered to 366 nursing staff. A pre-test was conducted before the lecture and this was followed by a film show, practical demonstration and practice on teaching aids with skill guide. A post- test was then conducted afterwards. The results were analyzed using Graphpad Instat 3. RESULTS: Three hundred and sixty six nurses participated in the study. Twenty one (5.7%) participants were males and three hundred and forty five (94.3%) were females. The age range was between 24 and 60 years. The mean post- test score (9.27) was higher than the mean pre-test score (7.81) and the difference was statistically significant with p<0.0001. CONCLUSION: This study demonstrates that constant training improves the knowledge of CPR , which will result in the reduction of mortality in patients who suffer cardiac arrest. PMID- 24488273 TI - Identification of a proton-chloride antiporter (EriC) by Himar1 transposon mutagenesis in Lactobacillus reuteri and its role in histamine production. AB - The gut microbiome may modulate intestinal immunity by luminal conversion of dietary amino acids to biologically active signals. The model probiotic organism Lactobacillus reuteri ATCC PTA 6475 is indigenous to the human microbiome, and converts the amino acid L-histidine to the biogenic amine, histamine. Histamine suppresses tumor necrosis factor (TNF) production by human myeloid cells and is a product of L-histidine decarboxylation, which is a proton-facilitated reaction. A transposon mutagenesis strategy was developed based on a single-plasmid nisin inducible Himar1 transposase/transposon delivery system for L. reuteri. A highly conserved proton-chloride antiporter gene (eriC), a gene widely present in the gut microbiome was discovered by Himar1 transposon (Tn)-mutagenesis presented in this study. Genetic inactivation of eriC by transposon insertion and genetic recombineering resulted in reduced ability of L. reuteri to inhibit TNF production by activated human myeloid cells, diminished histamine production by the bacteria and downregulated expression of histidine decarboxylase cluster genes compared to those of WT 6475. EriC belongs to a large family of ion transporters that includes chloride channels and proton-chloride antiporters and may facilitate the availability of protons for the decarboxylation reaction, resulting in histamine production by L. reuteri. This report leverages the tools of bacterial genetics for probiotic gene discovery. The findings highlight the widely conserved nature of ion transporters in bacteria and how ion transporters are coupled with amino acid decarboxylation and contribute to microbiome-mediated immunomodulation. PMID- 24488276 TI - Cardiovascular risk factors in adult staff of Federal Medical Centre, Umuahia: a comparison with other Nigerian studies. AB - Changing lifestyle, driven by socio-economic trends, is changing the cardiovascular risk and disease profile in developing countries. We studied the cardiovascular risk factors of Federal Medical Centre, Umuahia hospital staff between 40 and 60 years. 297 members of hospital staff were consecutively recruited in October 2010. Data obtained include blood pressure, height and weight, body mass index (BMI), fasting blood sugar, serum cholesterol (total and differential) and serum triglyceride. The data were analysed using the SPSS package (version 10). The following prevalence levels were found: hypertension 37.5%, obesity 40.8%, diabetes mellitus 5.7%, hypercholesterolemia 18.1% and metabolic syndrome 24.7%. LDL, low HDL and elevated TG were elevated in 26.8%, 41.9% and 9.7% respectively. Only 2% had very low risk for cardiovascular disease. PMID- 24488220 TI - Radiographic prevalence of CAM-type femoroacetabular impingement after open reduction and internal fixation of femoral neck fractures. AB - PURPOSE: The purpose of this study was to estimate the radiographic prevalence of CAM-type femoroacetabular impingement (FAI) in elderly patients (>= 50 years) who have undergone internal fixation for femoral neck fracture. METHODS: A total of 187 frog-leg lateral radiographs of elderly patients who underwent internal fixation for a femoral neck fracture were reviewed by two independent reviewers. The alpha angle, beta angle, and femoral head-neck offset ratio were calculated. The presence of two abnormal radiographic parameters was deemed to be diagnostic of radiographic CAM-type impingement. RESULTS: Radiographic CAM-type FAI was identified in 157 out of 187 (84 %) patients who underwent internal fixation for fractures of the femoral neck. Moderate-to-good inter-observer reliability was achieved in the measurement of radiographic parameters. With reference to fracture subtypes and prevalence of radiographic features of CAM-type morphology, 97 (72 %) out of 134 patients were positive for CAM in Garden subtypes I and II, whereas 49 (85.9 %) out of 57 patients had radiographic CAM in Garden III and IV subtypes. CONCLUSION: There was a high prevalence of CAM-type FAI in patients that underwent surgical fixation of femoral neck fractures. This is significantly higher than the reported prevalence in non-fracture patient populations. The high prevalence of CAM morphology could be related to several factors, including age, fracture morphology, quality of reduction, type of fixation, and fracture healing. PMID- 24488277 TI - Evaluation and treatment of failed amalgam restorations at Ibadan, Nigeria. AB - OBJECTIVE: Failure of tooth restoration is a major clinical problem of interest to patients, dentists and employers of labour. This study was designed to find out the average life span of amalgam as well as causes and management of failed amalgam restorations at the dental center, University College Hospital, Ibadan. The distribution of new caries in patients with this condition was also investigated. MATERIALS AND METHODS: This was an interventional study conducted among consenting patients who presented with failed amalgam restoration in our conservative clinic over a three-year period. Oral examination was conducted to detect primary caries and causes of failure of the restoration. Bitewing radiograph was taken where necessary. The following data were recorded: socio demographic variables of the patients and their complaints; life span of the failed restorations and the treatment given. Summary statistics was generated. RESULTS: One hundred and forty three patients (54 males, 89 females) presented with 198 defective restorations. Sixty five (45.5%) of these had 118 new carious lesions which were majority occlusal cavities (66.9%). Fractured restoration was the commonest cause of failure. Management was variable, but replacement with amalgam was the commonest treatment. The average life span of restoration was 8.3 years. CONCLUSION: The average life span of amalgam restoration was 8.3 years and the major cause of failure was amalgam fracture. Replacement with amalgam was the commonest treatment. PMID- 24488278 TI - Carcinoid tumours in a tertiary hospital in northern Nigeria: morphological pattern and review of the literature. AB - BACKGROUND: Carcinoid tumours are uncommon neuroendocrine neoplasms that may be found anywhere in the body but are most commonly seen in the gastro-intestinal and respiratory tracts and usually follow an indolent course. However, some tumours particularly the larger ones may metastasize to liver or regional lymph nodes. This study described the histological types of carcinoid tumors seen in a tertiary institution in Northern Nigeria. METHODS: This is a retrospective study in which surgical biopsy specimens seen over a 10-year period were reviewed with respect to age, sex, site and histological type. RESULTS: Five cases consisting of 1 endoscopic, 1 wedge, 3 hemicolectomy specimens were studied. There was a slight female preponderance with a female to male ratio of 1.5:1. The peak age of occurrence was the 6th decade of life (mean age was 36.4 years). Two cases were located in the large colon and a case each in the stomach, lymph node, and tongue. Three cases show trabecular pattern, while 2 cases were mixed pattern, in all the cases there are neither mitosis nor necrosis. These features are in keeping with typical carcinoids. Two out of the five cases were metastases to the lymph node and the tongue. CONCLUSION: Carcinoid tumours are rare, slow-growing NETs that display a relatively indolent disease course. Carcinoid tumours are uncommon in our environment and the cases seen are of good prognostic type. PMID- 24488279 TI - Knowledge, attitude and practice of hepatitis B vaccination among health workers at the Lagos State accident and emergency centre, Toll-Gate, Alausa, Lagos State. AB - BACKGROUND: Hepatitis B virus infection is a priority job related disease that has both serious public and private health implications. Hepatitis B vaccine is the first anticancer vaccine that has outstanding record of safety and effectiveness and 95% effective in preventing children and adults from developing chronic infection. STUDY DESIGN/METHODOLOGY: The study design was a cross sectional descriptive study. All the 88 health workers at the Lagos state accident and emergency centre who gave their consent to participate in the study were enrolled. Pre-tested, structured, self-administered questionnaire was used for data collection. RESULTS: Majority (70.2%) had good knowledge of hepatitis B infection and vaccination and the mean knowledge score (%) was 61.2 +/- 20.7. Majority (90.4%) knew that hepatitis B virus can be acquired through a needle stick injury. Majority (67.9%) were aware of the existence of an effective vaccine against hepatitis B infection; however, only 45.1% knew correctly that a post hepatitis B vaccination test is necessary to confirm protection. Majority (86.9%) knew that a complete dose of hepatitis B vaccine is 95% effective; however, only 49.4% knew for how long the vaccine protects. Only 36.9% knew correctly that hepatitis B virus is 100 times more infectious than HIV. Attitude towards hepatitis B vaccination was good among all of the respondents and the mean attitude score (%) was 92.9 +/- 14.3. Majority (84.5%) had poor practice of hepatitis B vaccination and the mean practice score (%) was 24.2 +/- 25.0. Among those who did not receive the vaccine, majority (67.6%) gave non-availability of the vaccine as reason for this. CONCLUSION: The respondents had good knowledge and good attitude but poor practice of hepatitis B vaccination. There is therefore need to provide health workers with adequate information on blood-borne viruses in order to reinforce the knowledge and attitude which will eventually translate into a good practice of hepatitis B vaccination. A clear and concise immunization policies and effective monitoring should be put in place to ensure compliance at all government health facilities. PMID- 24488280 TI - Male urinary incontinence and dementia in Zaria, Nigeria. AB - BACKGROUND: Ageing population in all parts of the world has make dementia in the elderly an important public health issue. Behavioural and Psychological symptom of dementia like urinary incontinence seldom attract the attention of clinicians providing care for the elderly. OBJECTIVE: To determine the prevalence of dementia among elderly male patients presenting with urinary incontinence to a urology clinic. SUBJECTS AND METHOD: We recruited consecutive elderly patients and their caregivers presenting to the urology clinic of Ahmadu Bello University Teaching Hospital for the treatment of urinary incontinence. The patients were assessed using Socio-demographic data collecting sheet, Consortium to Establish Registry for Alzheimer's Disease (CERAD), Stick Design Test and physical examination. While the caregivers were interviewed using the Blessed Dementia Scale. A consensus diagnosis was made for each of the patients based on criteria for dementia in both Diagnostic and Statistical Manual 4th edition (DSM-IV) and International Classification for Diseases 10 edition( ICD-10). All test of statistics were carried out at 5%level of probability. RESULTS: A total of 121 patients participated in the study. The mean age of the patients was 70.58 +/- 5.47 years (95% CI=69.10-71.55). A total of 11 patients (9.10%, 95% CI=3.98 14.22) have dementia based on the consensus diagnosis. Dementia among this cohort is significantly associated with advancing age and enuresis. CONCLUSION: Dementia is common among elderly patients with urinary incontinence in Africa but remains large undetected and unrecognised. PMID- 24488281 TI - Periodontitis & sub-fertility; opinions and practices of Nigerian specialists. AB - BACKGROUND: Increasing evidence in the emerging field of periodontal medicine continues to stimulate research to verify the association between chronic periodontitis and general health. The link between chronic periodontitis and sub fertility has not been well-investigated except for a handful of reports spanned over several decades. METHODS: As a prelude to a series of observational and interventional studies, 119 specialists and doctors participated in an online survey to ascertain their practices and opinions about this link. Our main exposure variables were dental history taking, periodontal/dental referrals and knowledge of possible link between chronic periodontitis and sub-fertility. RESULTS/FINDINGS: Our findings showed that dental history taking and periodontal/dental referrals were not part of sub-fertility management protocols of Nigerian specialists and doctors. These findings proved true irrespective of basic and postgraduate experience. Specialty was the only explanatory variable that accounted for statistical significance with the main exposure variables but the figures of members of different specialties were too low for any meaningful comparisons. CONCLUSIONS: The findings confirmed our suspicion of an almost complete lack of knowledge of this unlikely yet plausible association which deserves further research. PMID- 24488282 TI - Postpartum practices among the Igbos in Nnewi Southeast, Nigeria. AB - BACKGROUND: Women all over the world engage in some forms of postpartum practices aimed at keeping mother and child healthy. Although some of the practices are beneficial, some are of no value while some are out rightly harmful. The objective of this study was to determine the prevailing postpartum practices engaged in by Igbo women of South Eastern Nigeria. The above knowledge could be used to reinforce the beneficial ones while discouraging the harmful ones. METHODS: This is a questionnaire survey of mothers attending infant welfare clinic of our hospital augmented by in-depth interviews of patients, nurses and nurse midwives. RESULTS: Three hundred and thirty (330) mothers were studied. The peak age group was 26 to 30 years (30%), 93% were currently married while trading was the most common occupation. Most of the mothers, 270 (81.8%) regularly drink hot water, 282(85.5%) bathed with hot water while another 270(81.8%) consistently took hot food. Three-quarter of the women or 250(75.8%) took very peppery food, 218(66.1%) tied cloth across the abdomen, 210(63.6%) applied hot compresses to the abdomen while 230(69.7%) regularly did sitz bath with hot water. One hundred and forty six (44.2%) resumed sexual intercourse within 12 weeks of delivery while menstruation returned within 12 weeks in 68(20.6%) of the mothers. Fifty four mothers(16.4%) test breast milk with ants to detect spoilt milk while 64(19.4%), 100(30.3%) and 176(53.3%) took hot water, palm wine and tea respectively to improve the flow of breast milk. Ninety four (28.5%) regularly apply mascara to their babies eyes to 'clear' the eyes. CONCLUSION: Although some of the postpartum practices engaged in by Igbo women were neither useful nor harmful, some were out rightly dangerous and should be discouraged. The findings would be incorporated in antenatal health talks. PMID- 24488283 TI - Helicobacter pylori indyspeptic Nigerians. AB - BACKGROUND: Dyspepsia is a common gastrointestinal disorder, and is the most common indication for upper gastrointestinal endoscopy. Helicobacter pylori is a significant aetiological factor in acid peptic diseases and gastric cancer. Detection of this organism during upper gastrointestinal endoscopy has become standard clinical practice. Data is scanty from North-Eastern Nigeria on the subject. OBJECTIVES: To determine the prevalence of Helicobacter pylori among dyspeptic patients, and alsoto find out the association of H. pylori and degree of activity in chronic gastritis. METHODS: This is a hospital-based cross sectional study which was carried out at the Endoscopy unit of Federal Medical Centre, Yola and Histopathology unit, University of Maiduguri Teaching Hospital, Maiduguri from November, 2006 to May, 2010. Patients with dyspepsia who underwent upper gastrointestinal endoscopy as part of their work-up, also had endoscopic biopsies taken from the antral portions of their stomach. The biopsy specimens were fixed in 10% formalin and transported from Yola to Maiduguri by courier for processing. RESULTS: Three hundred and forty-nine patients comprising 152(43.6%) males and 197(56.4%) females with dyspepsia had upper gastrointestinal endoscopy. Their age ranged between 14 and 103 years with a median of 44.1 years. A prevalence rate of 56.7% for Helicobacter pylori was found.Helicobacter pylori associated with severe activity accounted for 80.3%; moderate activity- 57.5%; mild activity - 20% and normal gastric mucosa- 9.1%. CONCLUSION: There is a high prevalence of Helicobacter pylori among patients with dyspepsia, and a strong association between H. pylori and chronic gastritis with severe activity. PMID- 24488284 TI - Screening programme for retinopathy of prematurity in Ilorin, Nigeria: a pilot study. AB - BACKGROUND: The Neonatal Intensive Care Unit (NICU) of our hospital has a 30% survival rate among babies born premature weighing <1,000g. This hospital serves about 10 million people; there was no retinopathy of prematurity (ROP) screening program in place in Nigeria. MATERIALS AND METHODS: Babies born premature were recruited based on preset criteria: <= 35 weeks Gestation Age and birth weight <= 1.9 kg. The first retina examination was done at 3-4 weeks post-delivery and were documented on a proforma and analyzed with SPSS 15 Statistical Package. RESULTS: 58 eyes of 29 babies were examined. The birth weight range was 950-1900g, 17(58.6%) babies were <= 1500g, and 12 (41.4%) 1500-1900g. The Gestation age range was 27-35 weeks with a mean of 30. Avascularity in retina zones 2&3 was found in 52(89.6%) eyes mostly among babies <32 weeks gestation age and <1500g. Risk factors associated with retinal avascularity are highlighted. The challenges were with co-ordination of follow-up visits and accessibility to treatment such as laser and newer treatment methods. CONCLUSION: A cost effect screening criteria for ROP in Nigeria is suggested to include birth weight <= 1500g and gestational age <= 32 weeks. Dedicated staff & resources for treatment and imaging are needed for a successful program. An opportunity exists to study the effect of genetics on the development and severity of ROP among native African babies. PMID- 24488285 TI - Skin tumors at the Lagos University Teaching Hospital, Nigeria. AB - INTRODUCTION: Skin tumours can be malignant or benign. Skin cancer is the most common malignancy among Caucasians and noted to be rare in Africans and negroid skin. In view of the rarity of skin cancers in Africans, there is delayed diagnosis; and consequent advanced presentation and poor prognosis. OBJECTIVE: This is to document the frequency of skin tumours (benign and malignant) from a 7 year review (January 2001 to December 2007) of histology reports of all skin samples seen at the pathology department of the Lagos University Teaching Hospital. METHODS AND MATERIALS: Reports of all skin samples seen at the pathology department between January 2001 and December 2008 were reviewed. The frequencies of various skin tumours (both benign and malignant) were determined and the result displayed using frequency tables. RESULTS: Skin tumours represented 19.8% of all reports made on skin during the study period. One hundred and twenty one (68.7%) were benign tumours while 55 (31.2%) were malignant tumours. There is a female preponderance for both malignant and benign tumours. The male to female ratio was 1:1.28 for benign tumours and 1:1.39 for malignant tumors. Squamous cell carcinoma (SCC) was the commonest malignant tumor, followed by malignant melanoma, Kaposi's sarcoma and dermatofibrosarcoma protuberans. Cutaneous papilloma was the commonest benign tumour. CONCLUSION: A wide range of skin tumours, benign and malignant were documented; hence there is need for more vigilance in order to diagnose them early. PMID- 24488286 TI - The role of dentists as a stop-gap in the initial management of patients with delusional halitosis. AB - OBJECTIVE: This article proposes a 'stop-gap protocol'for the initial management of delusional halitosis, which dental practitioners can apply where a multidisciplinary team of dentists and mental health experts (psychiatrist and psychologist) cannot be assembled. METHODS: A 4-year prospective study of delusional halitosis patients managed with a 3-step 'Stop-gap protocol' is presented in this paper, to demonstrate our experience in applying the 'Stop-gap protocol'. RESULTS: Twenty three (23) patients diagnosed with delusional halitosis were managed with the 'Stop-gap protocol' within the study period. There were 13 (56.5%) males and 10 (43.5%) females, giving a male to female ratio of 1.3:1.Most of the patients were in the 3rd decade of life (n=10, 43.5%), the mean duration of the bad breath complaint was 5 years, with unknown trigger factor (n=19, 82.6%) in most of the patients and a mean psychological score of 7 +/- 1.8. No clinical oral malodour was observed in all of these patients. A normal oral flora was observed in 13 (56.5%) of the cases and a low level of volatile sulphur compound (VSC) was found in 12 (52.2%) of the patients, with a mean VSC level of 22.3 +/- 2 ppb. Twenty (87.0%) of the patients presented for follow up /counselling and the mean duration of follow up was 13 weeks. Three (13.0%) patients responded to referral to the joint clinic with mental health experts. CONCLUSION: Although we do not claim that the 'Stop-gap protocol' is comprehensive, it is hoped that this paper will serve as a useful guide for dentists practising in health facilities without mental health specialists and also to encourage the formation of multi-disciplinary teams in centres where they are present. PMID- 24488287 TI - Retrospective study of childhood burkitts lymphoma in north eastern Nigeria. AB - BACKGROUND: Burkitt's lymphoma (BL) is one of the leading childhood cancers in tropical Africa. Despite this, after extensive literature search most literature reviews on BL found were old. Therefore, it is useful to learn the trend in the epidemiology of BL in north eastern Nigeria especially now that changing ecology of the disease are being published. OBJECTIVE: To determine the prevalence of BL, and the pattern of distribution of the tumour in relation to gender, sites and socio-demographic background of children. METHODS: A retrospective study of cases of BL over a 20 year period in the Paediatric Department of University of Maiduguri Teaching Hospital (UMTH) was conducted. A structured questionnaire was used to document socio-demographic characteristics and clinical features for all cases. Data were analyzed using SPSS software version 16 Illinois, Chicago USA and a computer program for epidemiologist (PEPI version 3.01). Student t test was used to test for significance of means. Kendall's rank correlation coefficient (tau b) hand Jonckheere-Terpstra test of relationship of socio-demographic variables and presenting symptoms of BL were determined. Likely ratio Chi-square (c2) by William's criterion was used to investigate association between yearly prevalence and trends in time and also between anatomical sites and staging of BL. RESULTS: During the period, 49 cases, 32 (65.3%) males and 17 (34.7%) females, were identified out of the 29,636 total paediatric admissions during the period under review. The prevalence of BL was 0.17%. , The 6-10-year age bracket were mostly affected by BL 31 (63.3%) and males had the disease more than females (p = 0.021). The majority of children affected by BL were the Fulani ethnic group 15 (30.6%), those from Borno state 18 (36.7%) and rural dwellers 20 (40.8%). Most patients presented with stage C disease 27 (42.9%), and the most common primary site was the maxilla 11 (40.7). There was no significant change in yearly prevalence of Burkitts lymphoma (P = 0.983). The association between anatomical sites and staging of BL was significant (p = 0.003). CONCLUSIONS: Males were more prone to BL than females and most cases of BL presented late to the hospital. There is no significant change in the yearly occurrence of BL. Socio-demographic and clinical features did not contribute significantly to the epidemiology of BL. PMID- 24488288 TI - Thoracic endometriosis syndrome. AB - BACKGROUND: Thoracic endometriosis syndrome is a rare constellation of different pathological entities arising from intrathoracic endometriosis. Reports from centers in Africa are scanty. Varying theories have been proposed but none satisfactorily explains the varying clinical manifestations. OBJECTIVE: To describe the demographics, pathological spectrum, and outcome of treatment of patients seen at a single centre in West Africa with intrathoracic endometriosis. METHODS: Twelve women who were seen at Ghana's National Cardiotharacic Centre with intrathoracic endometriosis from 2004-2012 were retrospectively reviewed. RESULTS: The age range was from 24 - 39 years with a mean of 32 +/- 5 years. Pelvic endometriosis was confirmed in 8 (66.7%) of the patients, 2 (16.7%) had ectopic endometrial tissue at the umbilicus and one (16.7%) had ectopic endometrial tissue at the mons pubis. Seven (58.3%) of the patients had undergone prior uterine surgery before the clinical onset of thoracic endometriosis. The right hemithorax was involved in all 12 (100%) patients studied. Pneumothorax was present in six (50%) women, hemothorax in five (41.7%) and hemopneumothorax in one (8.3%). Three of the four patients who benefited from video assisted thoracoscopy had abrasive pleurodesis followed by hormonal therapy. The rest of the patients had chemical pleurodesis with or without hormonal therapy. CONCLUSION: Thoracic endometriosis may be more prevalent in West Africa than previously believed. Outcome of treatment is satisfactory using a multidisciplinary approach. PMID- 24488289 TI - Post-operative surgical-site infection from skin bleaching: a case report. AB - BACKGROUND: Prolonged application of steroid containing cream can pose a serious challenge to users. Apart from making the skin lighter it creates a spectrum of diseases in those that use them as the adrenal glands are suppressed and are unable to secrete more steroids when required. OBJECTIVE: The objective is to report on a patient who presented with severe sepsis after a long period of application of steroids to the skin. METHODS: A patient who has applied steroids to the skin over a prolonged period was followed up during treatment to ascertain the complications that the patient sustained during the period of treatment. CONCLUSION: The patient was found to have developed a pelvic induration without abscess. She also had a large anterior abdominal wall abscess superficial to the external oblique muscle extending towards the left flank. PMID- 24488290 TI - The growth physics and water relations of red-light-induced germination in lettuce seeds : I. Embryos germinating in osmoticum. AB - Redlight is known to increase the growth potential in the embryo of photodormant lettuce seed, enabling it to overcome the resistance offered by the seed coats (particularly the endosperm) or by an osmotically active medium. Determinations of the water potential of lettuce embryos germinating in osmoticum. carried out with a modified gravimetric technique which eliminates errors intro, duced by solute penetration into cellular osmotic space, showed that the water potential of red-light-treated embryos was lower than that of dark-treated ones, the difference being equivalent to the potential of a 0.30 molal mannitol solution. The force necessary for the radicle to penetrate the seed coats, measured directly, was found to be equivalent to the osmotic potential of 0.16 to 0.38 molal mannitol. Thus red light, acting through phytochrome, induces in photodormant lettuce embryos a decrease in water potential which is equal to that which is required for germination. A mechanism for this phytochrome-induced decrease in water potential is discussed. PMID- 24488291 TI - The growth physics and water relations of red-light-induced germination in lettuce seeds : II. Embryos germinating in water. AB - A study of photodormant lettuce embryos germinating in water showed that red light induces an increased rate of water uptake. Determinations of the water potential, carried out by a modified gravimetric technique which eliminates errors introduced by solute penetration into cellular osmotic space, showed that the water potential of embryos germinating in water after dark and red light treatment was equivalent and equal to the osmotic potential of a 0.0 to 0.1 molal mannitol solution. Osmotic potentials of the embryos were determined using two new methods. One of the methods utilizes penetration of deuterated water; the other, penetration of a labeled osmoticum into the tissue. For both light- and dark-treated embryos in water, the osmotic potential was equivalent to that of a 0.34 to 0.41 molal mannitol solution. Lettuce embryos thus require that turgor pressure reach a threshold considerably above zero before growth can occur. PMID- 24488292 TI - A simple kinetic model for leaf photosynthesis and respiration. AB - A simple kinetic model for leaf photosynthesis and respiration is described. The model takes into account the different natures of the physical and chemical processes involved in photosynthesis, and examines the response of net photosynthesis to changes in the incident light flux density, ambient carbon dioxide concentration and leaf temperature.It is shown that a quantitative description of the response to light flux density may be obtained. The model qualitatively describes the response of net photosynthesis to changing ambient carbon dioxide concentration and temperature. PMID- 24488293 TI - [Correlation of characteristics of C4-photosynthesis within different orders of angiosperms]. AB - A study of leaf anatomy, chloroplast ultrastructure, labelling pattern after short-time (14)CO2 fixation, and CO2 compensation point indicates that Chamaesyce buxifolia (Engelm. ex Hitche.) Small (Geraniales), Pectis leptocephala (Cass.) Urb. (Campanulales), and Imperata arundinacea Cyr. (Graminales) have typical features of plants exhibiting the C4-dicarboxylic acid pathway of photosynthesis. Thus it is established that the correlation of these C4 properties, well known in various orders of Monocotyledons (Graminales, Cyperales) and in the dicotyledonous order of the Centrospermae, is also characteristic of some species in other systematically widely separated orders within the Dicotyledons. PMID- 24488294 TI - Abscisic acid in immature apical tissue of sugar cane and in leaves of plants subjected to drought. AB - Abscisic acid was extracted from immature leaf and stem tissue of sugar cane. Mature leaves of well watered plants contained trace quantities of this hormone but plants subjected to drought accumulated relatively large amounts in their mature leaves. Extracts from wilting leaves contained a substance similar to or identical with (+)-phaseic acid. PMID- 24488295 TI - The synthesis and distribution of ribonucleic acid in developing archegonia of Pteridium aquilinum. AB - SUMMAY: Feeding gametophytes of Pteridium aquilinum with tritiated uridine, followed by autoradiography, revealed two waves of incorporation of the nucleoside into nuclei during oognesis. The first, affecting the nucleus of the primary cell of the archegonium, is interpreted as indicating the activation of the genes initiating oogenesis. The second, seen in the nucleus of the maturing egg, is believed to be concerned with the differentiation of the egg itself.The results of the autoradiography, corroborated by enzyme digestion and fluorescence microscopy, also demonstrated a high concentration of ribonucleic acid towards the periphery of the mature egg, some possibly located in nucleolus-like bodies found only in this region of the cytoplasm. It is suggested that part of this cytoplasmic ribonucleic acid may represent genetic information remaining untranslated until after fertilization.No evidence was found of any asymmetry in the distribution of the ribonucleic acid in mature eggs which might account for the polarity of developing zygotes. PMID- 24488296 TI - Cytokinin-induced chlorophyll formation in cucumber cotyledons. AB - Cotyledons of cucumber plants grown in the dark for 7 days were treated with various concentrations of cytokinins for 14 h and then moved into light. After 3 h the treated cotyledons had up to 450% more chlorophyll than the water controls. This suggests that cytokinins have an important role in the formation of chlorophyll. The increase in chlorophyll level was proportional to cytokinin concentration and was apparent at concentrations as low as 0.001 mg/l. Sensitivity to cytokinins depended on the age of the cotyledons and the time of exposure to light. Gibberellic acid, indoleacetic acid, adenine and sucrose did not cause a similar increase in chlorophyll levels. This effect of cytokinins on chlorophyll formation is valuable as a simple, rapid bioassay for cytokinins. PMID- 24488297 TI - Gibberellin-induced dormancy in bulbils of Dioscorea. AB - The sprouting of bulbils of some plants in genus Dioscorea was inhibited by gibberellin (GA) treatment and was promoted by treatment with growth retardants. The results suggest that endogenous GAs in some manner induce and maintain the dormant state in these bulbils. PMID- 24488298 TI - DFT study on the atomic-scale nucleation path of graphene growth on the Cu(111) surface. AB - The nucleation path of graphene growth on the Cu(111) surface is investigated by importing carbon atoms step-by-step using density functional theory (DFT) calculations. An overall path of graphene nucleation has been proposed based on configuration and energy analysis. At the very first stage, linear chains will be formed and dominate the copper surface. Then, Y-type (furcate) carbon species will be shaped when new carbon atoms are absorbed aside the linear chains. Finally, ring-containing carbon species and graphene islands will be formed stepwise, with energetic preference. We find that the Y-type and ring-containing carbon species are not likely formed directly at the initial stage of graphene nucleation, but should be formed starting from linear chains. The nucleation limiting step is the formation of the Y-type species, which must pass an energy barrier of about 0.25 eV. These underlying observations are instructive to stimulate future experimental efforts on graphene synthesis. PMID- 24488299 TI - Energetic carbon-based hybrids: green and facile synthesis from soy milk and extraordinary electrocatalytic activity towards ORR. AB - Novel Co-N-C hybrids were successfully fabricated via one-step pyrolysed soy milk with the aid of cobalt(II) nitrate in a synthetic process. Because of the formation of the Co-N-C structures, the resulting product showed excellent electrocatalytic activity for the ORR in alkaline electrolytes, potentially making Co-N-C a nonprecious metal cathode catalyst for ORR. The technique can also be scaled up easily and this research provides a great opportunity for industry to produce an eco-friendly carbon nanomaterial for fuel cells and other electrochemical energy devices. PMID- 24488304 TI - Recommended childhood and adolescent immunization schedule--United States, 2014. PMID- 24488306 TI - Shaping suvorexant: application of experimental and theoretical methods for driving synthetic designs. AB - Dual Orexin Receptor Antagonists (DORA) bind to both the Orexin 1 and 2 receptors. High resolution crystal structures of the Orexin 1 and 2 receptors, both class A GPCRs, were not available at the time of this study, and thus, ligand-based analyses were invoked and successfully applied to the design of DORAs. Computational analysis, ligand based superposition, unbound small-molecule X-ray crystal structures and NMR analysis were utilized to understand the conformational preferences of key DORAs and excellent agreement between these orthogonal approaches was seen in the majority of compounds examined. The predominantly face-to-face (F2F) interaction observed between the distal aromatic rings was the core 3D shape motif in our design principle and was used in the development of compounds. A notable exception, however, was seen between computation and experiment for suvorexant where the molecule exhibits an extended conformation in the unbound small-molecule X-ray structure. Even taking into account solvation effects explicitly in our calculations, we nevertheless find support that the F2F conformation is the bioactive conformation. Using a dominant states approximation for the partition function, we made a comprehensive assessment of the free energies required to adopt both an extended and a F2F conformation of a number of DORAs. Interestingly, we find that only a F2F conformation is consistent with the activities reported. PMID- 24488307 TI - Extensive all-atom Monte Carlo sampling and QM/MM corrections in the SAMPL4 hydration free energy challenge. AB - We present our predictions for the SAMPL4 hydration free energy challenge. Extensive all-atom Monte Carlo simulations were employed to sample the compounds in explicit solvent. While the focus of our study was to demonstrate well converged and reproducible free energies, we attempted to address the deficiencies in the general Amber force field force field with a simple QM/MM correction. We show that by using multiple independent simulations, including different starting configurations, and enhanced sampling with parallel tempering, we can obtain well converged hydration free energies. Additional analysis using dihedral angle distributions, torsion-root mean square deviation plots and thermodynamic cycles support this assertion. We obtain a mean absolute deviation of 1.7 kcal mol(-1) and a Kendall's tau of 0.65 compared with experiment. PMID- 24488308 TI - Chemokine-mediated redirection of T cells constitutes a critical mechanism of glucocorticoid therapy in autoimmune CNS responses. AB - Glucocorticoids (GCs) are the standard therapy for treating multiple sclerosis (MS) patients suffering from an acute relapse. One of the main mechanisms of GC action is held to be the induction of T cell apoptosis leading to reduced lymphocyte infiltration into the CNS, yet our analysis of experimental autoimmune encephalomyelitis (EAE) in three different strains of genetically manipulated mice has revealed that the induction of T cell apoptosis is not essential for the therapeutic efficacy of GCs. Instead, we identified the redirection of T cell migration in response to chemokines as a new therapeutic principle of GC action. GCs inhibited the migration of T cells towards CCL19 while they enhanced their responsiveness towards CXCL12. Importantly, blocking CXCR4 signaling in vivo by applying Plerixafor((r)) strongly impaired the capacity of GCs to interfere with EAE, as revealed by an aggravated disease course, more pronounced CNS infiltration and a more dispersed distribution of the infiltrating T cells throughout the parenchyma. Our observation that T cells lacking the GC receptor were refractory to CXCL12 further underscores the importance of this pathway for the treatment of EAE by GCs. Importantly, methylprednisolone pulse therapy strongly increased the capacity of peripheral blood T cells from MS patients of different subtypes to migrate towards CXCL12. This indicates that modulation of T cell migration is an important mechanistic principle responsible for the efficacy of high-dose GC therapy not only of EAE but also of MS. PMID- 24488309 TI - TMEM106B: a strong FTLD disease modifier. PMID- 24488310 TI - RNase E affects the expression of the acyl-homoserine lactone synthase gene sinI in Sinorhizobium meliloti. AB - Quorum sensing of Sinorhizobium meliloti relies on N-acyl-homoserine lactones (AHLs) as autoinducers. AHL production increases at high population density, and this depends on the AHL synthase SinI and two transcriptional regulators, SinR and ExpR. Our study demonstrates that ectopic expression of the gene rne, coding for RNase E, an endoribonuclease that is probably essential for growth, prevents the accumulation of AHLs at detectable levels. The ectopic rne expression led to a higher level of rne mRNA and a lower level of sinI mRNA independently of the presence of ExpR, the AHL receptor, and AHLs. In line with this, IPTG (isopropyl beta-D-thiogalactopyranoside)-induced overexpression of rne resulted in a shorter half-life of sinI mRNA and a strong reduction of AHL accumulation. Moreover, using translational sinI-egfp fusions, we found that sinI expression is specifically decreased upon induced overexpression of rne, independently of the presence of the global posttranscriptional regulator Hfq. The 28-nucleotide 5' untranslated region (UTR) of sinI mRNA was sufficient for this effect. Random amplification of 5' cDNA ends (5'-RACE) analyses revealed a potential RNase E cleavage site at position +24 between the Shine-Dalgarno site and the translation start site. We postulate therefore that RNase E-dependent degradation of sinI mRNA from the 5' end is one of the steps mediating a high turnover of sinI mRNA, which allows the Sin quorum-sensing system to respond rapidly to changes in transcriptional control of AHL production. PMID- 24488311 TI - The Salmonella Spi1 virulence regulatory protein HilD directly activates transcription of the flagellar master operon flhDC. AB - Infection of intestinal epithelial cells is dependent on the Salmonella enterica serovar Typhimurium pathogenicity island 1 (Spi1)-encoded type III injectisome system and flagellar motility. Thus, the expression of virulence and flagellar genes is subject to tight regulatory control mechanisms in order to ensure the correct spatiotemporal production of the respective gene products. In this work, we reveal a new level of cross-regulation between the Spi1 and flagellar regulatory systems. Transposon mutagenesis identified a class of mutants that prevented flhDC autorepression by overexpressing HilD. HilD, HilC, RtsA, and HilA comprise a positive regulatory circuit for the expression of the Spi1 genes. Here, we report a novel transcriptional cross talk between the Spi1 and flagellar regulons where HilD transcriptionally activates flhDC gene expression by binding to nucleotides -68 to -24 upstream from the P5 transcriptional start site. We additionally show that, in contrast to the results of a previous report, HilA does not affect flagellar gene expression. Finally, we discuss a model of the cross-regulation network between Spi1 and the flagellar system and propose a regulatory mechanism via the Spi1 master regulator HilD that would prime flagellar genes for rapid reactivation during host infection. PMID- 24488312 TI - Comparative functional genomics of Lactobacillus spp. reveals possible mechanisms for specialization of vaginal lactobacilli to their environment. AB - Lactobacilli are found in a wide variety of habitats. Four species, Lactobacillus crispatus, L. gasseri, L. iners, and L. jensenii, are common and abundant in the human vagina and absent from other habitats. These may be adapted to the vagina and possess characteristics enabling them to thrive in that environment. Furthermore, stable codominance of multiple Lactobacillus species in a single community is infrequently observed. Thus, it is possible that individual vaginal Lactobacillus species possess unique characteristics that confer to them host specific competitive advantages. We performed comparative functional genomic analyses of representatives of 25 species of Lactobacillus, searching for habitat specific traits in the genomes of the vaginal lactobacilli. We found that the genomes of the vaginal species were significantly smaller and had significantly lower GC content than those of the nonvaginal species. No protein families were found to be specific to the vaginal species analyzed, but some were either over- or underrepresented relative to nonvaginal species. We also found that within the vaginal species, each genome coded for species-specific protein families. Our results suggest that even though the vaginal species show no general signatures of adaptation to the vaginal environment, each species has specific and perhaps unique ways of interacting with its environment, be it the host or other microbes in the community. These findings will serve as a foundation for further exploring the role of lactobacilli in the ecological dynamics of vaginal microbial communities and their ultimate impact on host health. PMID- 24488313 TI - Germination of spores of Bacillus species: what we know and do not know. AB - Spores of Bacillus species can remain in their dormant and resistant states for years, but exposure to agents such as specific nutrients can cause spores' return to life within minutes in the process of germination. This process requires a number of spore-specific proteins, most of which are in or associated with the inner spore membrane (IM). These proteins include the (i) germinant receptors (GRs) that respond to nutrient germinants, (ii) GerD protein, which is essential for GR-dependent germination, (iii) SpoVA proteins that form a channel in spores' IM through which the spore core's huge depot of dipicolinic acid is released during germination, and (iv) cortex-lytic enzymes (CLEs) that degrade the large peptidoglycan cortex layer, allowing the spore core to take up much water and swell, thus completing spore germination. While much has been learned about nutrient germination, major questions remain unanswered, including the following. (i) How do nutrient germinants penetrate through spores' outer layers to access GRs in the IM? (ii) What happens during the highly variable and often long lag period between the exposure of spores to nutrient germinants and the commitment of spores to germinate? (iii) What do GRs and GerD do, and how do these proteins interact? (iv) What is the structure of the SpoVA channel in spores' IM, and how is this channel gated? (v) What is the precise state of the spore IM, which has a number of novel properties even though its lipid composition is very similar to that of growing cells? (vi) How is CLE activity regulated such that these enzymes act only when germination has been initiated? (vii) And finally, how does the germination of spores of clostridia compare with that of spores of bacilli? PMID- 24488314 TI - The acetylation motif in AMP-forming Acyl coenzyme A synthetases contains residues critical for acetylation and recognition by the protein acetyltransferase pat of Rhodopseudomonas palustris. AB - The AMP-forming acyl coenzyme A (acyl-CoA) synthetases are a large class of enzymes found in both anabolic and catabolic pathways that activate fatty acids to acyl-CoA molecules. The protein acetyltransferase (Pat) from Rhodopseudomonas palustris (RpPat) inactivates AMP-forming acyl-CoA synthetases by acetylating the epsilon-amino group of a conserved, catalytic lysine residue. In all of the previously described RpPat substrates, this lysine residue is located within a PX4GK motif that has been proposed to be a recognition motif for RpPat. Here, we report five new substrates for RpPat, all of which are also AMP-forming acyl-CoA synthetases. This finding supports the idea that Pat enzymes may have evolved to control the activity of this family of enzymes. Notably, RpPat did not acetylate the wild-type long-chain acyl-CoA synthetase B (RpLcsB; formerly Rpa2714) enzyme of this bacterium. However, a single amino acid change two residues upstream of the acetylation site was sufficient to convert RpLcsB into an RpPat substrate. The results of mutational and functional analyses of RpLcsB and RpPimA variants led us to propose PK/RTXS/T/V/NGKX2K/R as a substrate recognition motif. The underlined positions within this motif are particularly important for acetylation by RpPat. The first residue, threonine, is located 4 amino acids upstream of the acetylation site. The second residue can be S/T/V/N and is located two positions upstream of the acetylation site. Analysis of published crystal structures suggests that the side chains of these two residues are very close to the acetylated lysine residue, indicating that they may directly interact with RpPat. PMID- 24488315 TI - Roles of cyclic Di-GMP and the Gac system in transcriptional control of the genes coding for the Pseudomonas putida adhesins LapA and LapF. AB - LapA and LapF are large extracellular proteins that play a relevant role in biofilm formation by Pseudomonas putida. Current evidence favors a sequential model in which LapA is first required for the initial adhesion of individual bacteria to a surface, while LapF participates in later stages of biofilm development. In agreement with this model, lapF transcription was previously shown to take place at late times of growth and to respond to the stationary phase sigma factor RpoS. We have now analyzed the transcription pattern of lapA and other regulatory elements that influence expression of both genes. The lapA promoter shows a transient peak of activation early during growth, with a second increase in stationary phase that is independent of RpoS. The same pattern is observed in biofilms although expression is not uniform in the population. Both lapA and lapF are under the control of the two-component regulatory system GacS/GacA, and their transcription also responds to the intracellular levels of the second messenger cyclic diguanylate (c-di-GMP), although in surprisingly reverse ways. Whereas expression from the lapA promoter increases with high levels of c-di-GMP, the opposite is true for lapF. The transcriptional regulator FleQ is required for the modulation of lapA expression by c-di-GMP but has a minor influence on lapF. This work represents a further step in our understanding of the regulatory interactions controlling biofilm formation in P. putida. PMID- 24488317 TI - Functional analysis of the accessory protein TapA in Bacillus subtilis amyloid fiber assembly. AB - Bacillus subtilis biofilm formation relies on the assembly of a fibrous scaffold formed by the protein TasA. TasA polymerizes into highly stable fibers with biochemical and morphological features of functional amyloids. Previously, we showed that assembly of TasA fibers requires the auxiliary protein TapA. In this study, we investigated the roles of TapA sequences from the C-terminal and N terminal ends and TapA cysteine residues in its ability to promote the assembly of TasA amyloid-like fibers. We found that the cysteine residues are not essential for the formation of TasA fibers, as their replacement by alanine residues resulted in only minor defects in biofilm formation. Mutating sequences in the C-terminal half had no effect on biofilm formation. However, we identified a sequence of 8 amino acids in the N terminus that is key for TasA fiber formation. Strains expressing TapA lacking these 8 residues were completely defective in biofilm formation. In addition, this TapA mutant protein exhibited a dominant negative effect on TasA fiber formation. Even in the presence of wild type TapA, the mutant protein inhibited fiber assembly in vitro and delayed biofilm formation in vivo. We propose that this 8-residue sequence is crucial for the formation of amyloid-like fibers on the cell surface, perhaps by mediating the interaction between TapA or TapA and TasA molecules. PMID- 24488316 TI - Natural competence and the evolution of DNA uptake specificity. AB - Many bacteria are naturally competent, able to actively transport environmental DNA fragments across their cell envelope and into their cytoplasm. Because incoming DNA fragments can recombine with and replace homologous segments of the chromosome, competence provides cells with a potent mechanism of horizontal gene transfer as well as access to the nutrients in extracellular DNA. This review starts with an introductory overview of competence and continues with a detailed consideration of the DNA uptake specificity of competent proteobacteria in the Pasteurellaceae and Neisseriaceae. Species in these distantly related families exhibit strong preferences for genomic DNA from close relatives, a self specificity arising from the combined effects of biases in the uptake machinery and genomic overrepresentation of the sequences this machinery prefers. Other competent species tested lack obvious uptake bias or uptake sequences, suggesting that strong convergent evolutionary forces have acted on these two families. Recent results show that uptake sequences have multiple "dialects," with clades within each family preferring distinct sequence variants and having corresponding variants enriched in their genomes. Although the genomic consensus uptake sequences are 12 and 29 to 34 bp, uptake assays have found that only central cores of 3 to 4 bp, conserved across dialects, are crucial for uptake. The other bases, which differ between dialects, make weaker individual contributions but have important cooperative interactions. Together, these results make predictions about the mechanism of DNA uptake across the outer membrane, supporting a model for the evolutionary accumulation and stability of uptake sequences and suggesting that uptake biases may be more widespread than currently thought. PMID- 24488318 TI - Structural and functional in silico analysis of LRRK2 missense substitutions. AB - The LRRK2 gene (Leucine-Rich Repeat Kinase 2, PARK8) is mutated in a significant number of cases of autosomal dominant Parkinson's disease (PD) and in some sporadic cases of late-onset PD. LRRK2 is a large, complex protein that comprises several interaction domains: armadillo, ankyrin, leucine-rich repeats and WD40 domains; two catalytic domains: ROC-GTPase and serine/threonine kinase; and a COR domain (unknown function). Pathogenic mutations are scattered all over the domains of LRRK2, although the prevalence of mutations in some domains is higher (ROC-GTPase, COR and kinase). In this work, we model the structure of each domain to predict and explore the effects of described missense mutations and polymorphisms. The results allow us to postulate the possible effects of pathogenic mutations in the function of the protein, and hypothesize the importance of some polymorphisms that have not been linked directly to PD, but act as risk factors for the disease. In our analysis, we also study the effects of PD-related mutations in the kinase domain structure and in the phosphorylation of the activation loop to determine effects on kinase activity. PMID- 24488319 TI - Agrobacterium-mediated genetic transformation and regeneration of transgenic plants using leaf midribs as explants in ramie [Boehmeria nivea (L.) Gaud]. AB - In this study, leaf midribs, the elite explants, were used for the first time to develop an efficient regeneration and transformation protocol for ramie [Boehmeria nivea (L.) Gaud.] via Agrobacterium-mediated genetic transformation. Sensitivity of leaf midribs regeneration to kanamycin was evaluated, which showed that 40 mg l(-1) was the optimal concentration needed to create the necessary selection pressure. Factors affecting the ramie transformation efficiency were evaluated, including leaf age, Agrobacterium concentration, length of infection time for the Agrobacterium solution, acetosyringone concentration in the co cultivation medium, and the co-cultivation period. The midrib explants from 40 day-old in vitro shoots, an Agrobacterium concentration at OD600 of 0.6, 10-min immersion in the bacteria solution, an acetosyringone concentration of 50 mg l( 1) in the co-cultivation medium and a 3-day co-cultivation period produced the highest efficiencies of regeneration and transformation. In this study, the average transformation rate was 23.25%. Polymerase chain reactions using GUS and NPTII gene-specific primers, Southern blot and histochemical GUS staining analyses further confirmed that the transgene was integrated into the ramie genome and expressed in the transgenic ramie. The establishment of this system of Agrobacterium-mediated genetic transformation and regeneration of transgenic plants will be used not only to introduce genes of interest into the ramie genome for the purpose of trait improvement, but also as a common means of testing gene function by enhancing or inhibiting the expression of target genes. PMID- 24488320 TI - Association analysis, genetic diversity and structure analysis of tobacco based on AFLP markers. AB - Knowledge in the area of genetic diversity could aid in providing useful information in the selection of material for breeding such as hybridization programs and quantitative trait loci mapping. To this end, 50 Nicotiana tabacum genotypes were genotyped with 21 primer combination of amplified fragment length polymorphism (AFLP). A total of 480 unambiguous DNA fragments and 373 polymorphic bands were produced with an average of 17.76 per primer combination. Also, the results revealed high polymorphic rate varing from 52.63 to 92.59%, demonstrating that AFLP technique utilized in this research can be a powerful and valuable tool in the breeding program of N. tabacum. Cluster analysis based on complete linkage method using Jaccard's genetic distance, grouped the 50 tobacco genotypes into eight clusters including three relatively big clusters, one cluster including Golden gift, Burly 7022 and Burly Kreuzung, one cluster consisting of two individuals (Pereg234, R9) and three single-member clusters (Pennbel69, Coker176 and Budisher Burley E), Recent genotypes showed high genetic distance from other genotypes belonging to cluster I and II. Association analysis between seven important traits and AFLP markers were performed using four statistical models. The results revealed the model containing both the factors, population structure (Q) and general similarity in genetic background arising from shared kinship (K), reduces false positive associations between markers and phenotype. According to the results nine markers were determined that could be considered to be the most interesting candidates for further studies. PMID- 24488321 TI - Association of Xmn1 -158 gammaG variant with severity and HbF levels in beta thalassemia major and sickle cell anaemia. AB - Haemoglobinopathies including beta-thalassemia and sickle cell anaemia (SCA) are considered to be classical monogenic diseases. There is considerable clinical variability between patients inheriting identical beta-globin mutations. The reasons for this variability are not well understood. Previous studies have suggested that a variety of genetic determents influence different clinical phenotypes. The genetic variants that modulate HbF levels have a very strong impact on ameliorating the clinical phenotype. In the present study 6,500 blood samples from suspected cases were analysed using HPLC, ARMS-PCR, RDB techniques. Patients with beta-thalassemia and SCA were classified into mild, moderate, severe according to the severity score based on Hb levels, age of onset, age at which patients received their first blood transfusion, the degree of growth retardation and splenectomy. Patients with beta-thalassemia and SCA were analysed for Xmn1 polymorphism and association between this polymorphism and severity of beta-thalassemia and SCA was evaluated. We found a significant difference in genotypic and allelic frequencies of Xmn1 polymorphism between mild and moderate and mild and severe cases. There was a significant difference in high and low percentage of HbF in CC, CT and TT bearing individuals. The TT bearing individuals were found to have a high percentage of HbF in beta-thalassemia as well as SCA. This study confirms that increased gammaG-globin expression associated with Xmn1 polymorphism ameliorates the clinical severity in beta thalassemia as well as SCA in the study population. PMID- 24488322 TI - Figitumumab in patients with refractory metastatic colorectal cancer previously treated with standard therapies: a nonrandomized, open-label, phase II trial. AB - PURPOSE: Figitumumab (CP-751,871) is a human IgG2 monoclonal antibody that binds and down-regulates insulin-like growth factor receptor-1 (IGF-1R) and inhibits activation of this receptor by IGF-1 and IGF-2. This nonrandomized, open-label, single-arm, phase II trial evaluated the antitumor activity and safety of figitumumab in patients with metastatic colorectal cancer that was refractory to >=2 systemic therapies. METHODS: Cohorts A and B received intravenous figitumumab 20 and 30 mg/kg in 3-week cycles, respectively. Both received loading doses (20 or 30 mg/kg) on days 1 and 2 of cycle 1. The primary endpoint was 6-month survival (null hypothesis for each cohort, H0: p6 mo surv = 0.45). Secondary endpoints included progression-free survival (PFS), overall survival (OS), objective response, safety, and pharmacokinetics. RESULTS: A total of 168 patients (Cohort A, n = 85; Cohort B, n = 83) received figitumumab. Estimated 6 month survival was 49.4 % (95 % CI 38.8-60.0) in Cohort A and 44.1 % (95 % CI 33.4-54.9) in Cohort B. Median OS was 5.8 and 5.6 months, respectively; median PFS was 1.4 months in both cohorts. No objective partial or complete responses occurred. The respective rates of treatment discontinuation due to treatment related adverse events (AEs) were 5 and 7 %. The most common grade 3/4 nonhematologic AEs in both cohorts were hyperglycemia and asthenia. No grade 4 hematologic laboratory abnormalities occurred. Most deaths were reported as due to progressive disease; none were due to figitumumab. CONCLUSION: Six-month survival data do not support further study of figitumumab 20 or 30 mg/kg in this patient population. PMID- 24488323 TI - Phase I dose-escalation and pharmacokinetic study (TED 11576) of cabazitaxel in Japanese patients with castration-resistant prostate cancer. AB - PURPOSE: The purpose of the study is to analyze the pharmacokinetic (PK) profile of cabazitaxel and evaluate its safety and tolerability as a 1-h IV infusion every 3 weeks in Japanese patients with castration-resistant prostate cancer (CRPC). METHODS: Seventeen patients were treated with cabazitaxel at doses of 20 and 25 mg/m(2) for PK analyses. Dose escalation was performed only in the absence of dose-limiting toxicity (DLT). The maximum tolerated dose (MTD) was the highest dose at which less than 33 % of the patients developed DLT. RESULTS: Cabazitaxel exhibited a triphasic elimination profile with a long terminal half-life of 116 +/- 29.0 or 113 +/- 28.0 h after IV infusion of 20 or 25 mg/m(2) cabazitaxel, respectively. The major differences in the PK parameters of cabazitaxel and docetaxel were cabazitaxel's fairly high clearance rate, representing approximately half the hepatic flow, and its large volume of distribution at steady-state conditions. No DLT was observed during Cycle 1. Mild-to-moderate hematological adverse events (AEs), including neutropenia, and other AEs typically associated with taxanes were observed; all AEs were manageable. Cabazitaxel at 25 mg/m(2) every 3 weeks was selected as the MTD in Japanese patients. CONCLUSIONS: The PK parameters of cabazitaxel in Japanese CRPC patients were comparable with those previously determined in Caucasian subjects. The safety and tolerability of cabazitaxel were also comparable in both ethnic populations. PMID- 24488324 TI - Clinical pharmacokinetics of Icotinib, an anti-cancer drug: evaluation of dose proportionality, food effect, and tolerability in healthy subjects. AB - PURPOSE: Icotinib, an oral epidermal growth factor receptor tyrosine kinase inhibitor, has proved effectiveness in xenografted nude mice. Purpose of the present studies was to investigate tolerability and pharmacokinetics of Icotinib in healthy subjects for the first time, including dose proportionality, food effect, and tolerability. METHODS: Two studies were conducted in total of 22 healthy subjects: a randomized, two-Latin-square crossover, dose proportional study (n = 12) and a randomized two-way crossover food-effect study (n = 10). RESULTS: Plasma concentration of Icotinib reached peak at a median Tmax of 0.75 3.5 h after single dose and then declined with a mean t1/2beta of 6.02-7.83 h. Over the dose range of 100-600 mg, AUC values were proportional to dose and Cmax showed a slight saturation when dose increases. Only 0.2 % of the dose was excreted through kidney in unchanged Icotinib. After dosing 400 mg of Icotinib with high-fat and high-calorie meal, mean Cmax and AUC were significantly increased by 59 and 79 %, respectively. Three subjects experienced four adverse events (rash, increase in AST and ALT, and external injury). Rash and increased levels of AST and ALT were considered as drug-related. No serious adverse events were reported. CONCLUSION: The current work demonstrated that Icotinib was well tolerated in healthy male subjects (n = 22) over the dose range of 100-600 mg with or without food. Icotinib exposure, expressed in AUC, was proportionally increased with dose over the above dose range. Food intake significantly increased the absorption and exposure of Icotinib in healthy subjects. PMID- 24488325 TI - Does the rate of competing isomerisation during alkene metathesis depend on pre catalyst initiation rate? AB - Experimental studies of the ring-closing metathesis reaction of 1,8-nonadiene and the ROMP reaction of cycloheptene show that the rate of isomerisation is not correlated to the initiation rate of the pre-catalyst, and that the absence of phosphine leads to a greatly increased rate of isomerisation. A range of pre catalysts and solvents were probed and it is proposed that the isomerisation is mediated by a ruthenium hydride complex; our results are consistent with the rate determining formation of such a species, which might be trapped in situ by tricyclohexylphosphane. PMID- 24488326 TI - Spatio-temporal variations of carbon dioxide and its gross emission regulated by artificial operation in a typical hydropower reservoir in China. AB - Supersaturation and excess emission of greenhouse gases in freshwater reservoirs have received a great deal of attention in recent years. Although impoundment of reservoirs has been shown to contribute to the net emission of greenhouse gases, reservoir age, geographical distribution, submerged soil type and artificial regulation also have a great impact on their emissions. To examine how large scale reservoir operation impact the water column CO2 and its air-water interface flux, a field study was conducted in 2010 to evaluate potential ecological processes that regulate the partial pressure of CO2 (pCO2) in the water column in the Pengxi River backwater area (PBA), a typical tributary in the Three Gorges Reservoir, China. Measurements of total alkalinity (TA), pH and water temperature were applied to compute the pCO2. And this approach was also validated by calculation of pCO2 from the dissolved inorganic carbon data of samples. Partial least squares (PLS) regression was used to determine how the dynamics of the water pCO2 were related to the available variables. The estimated pCO2 in our sample ranged from 26 to 4,087 MUatm in the surface water. During low water operation from July to early September, there was an obvious pCO2 stratification, and pCO2 in the surface was almost unsaturated. This phenomenon was also observed in the spring bloom during discharge period. Conversely, there was no significant pCO2 stratification and the entire water column was supersaturated during high water operation from November to the following February. Significant correlation was observed between the magnitude of pCO2, DO and chlorophyll a, suggesting that phytoplankton dynamics regulate pCO2 in the PBA. The average areal rate of CO2 emissions from the Pengxi River ranged from 18.06 to 48.09 mmol m(-2) day(-1), with an estimated gross CO2 emission from the water surface of 14-37 t day(-1) in this area in 2010. Photosynthesis and respiration rates by phytoplankton might be the dominant processes that regulated pCO2 in the water column. We conclude that pCO2 values in the surface water of Pengxi River could be regarded as potential sources of CO2 to the atmosphere were smaller or similar to those that have been reported for many other reservoirs to date. PMID- 24488327 TI - Determination of trace amounts of zirconium in real samples after microwave digestion and ternary complex dispersive liquid-liquid microextraction. AB - In this study, a ternary Zr(IV) system with 2-(5-bromo-2-pyridylazo)-5 diethylaminophenol (5-Br-PADAP) and fluoride was chosen on the basis of dispersive liquid-liquid microextraction method. Zirconium was extracted into the fine droplets of dichlorobenzene as extracting solvent. These drops dispersed as a cloud in the aqueous sample with the help of ultrasonic waves, and the procedure was done. Finally, atomic absorption spectrometry was applied for the determination of zirconium. The effects of different factors that influence complex formation and extraction, such as pH, amounts of complexing agents, type and volume of the extracting solvent, as well as sonication and centrifuging time, were optimized. Under optimum conditions, the calibration curve was linear in the range of 150.0-800.0 ng mL(-1) with a limit of detection of 44.0 ng mL( 1). Relative standard deviation was calculated to be 4.1 % (n = 7, c = 400.0 ng mL(-1)). The enrichment factor was 80. The proposed method was successfully used to determine the zirconium in several water, wastewater, and soil samples. PMID- 24488328 TI - A framework for adaptive monitoring of the cumulative effects of human footprint on biodiversity. AB - Effective ecological monitoring is imperative in a human-dominated world, as our ability to manage functioning ecosystems will depend on understanding biodiversity responses to anthropogenic impacts. Yet, most monitoring efforts have either been narrowly focused on particular sites, species and stressors - thus inadequately considering the cumulative effects of multiple, interacting impacts at scales of management relevance - or too unfocused to provide specific guidance. We propose a cumulative effects monitoring framework that integrates multi-scaled surveillance of trends in biodiversity and land cover with targeted evaluation of hypothesized drivers of change. The framework is grounded in a flexible conceptual model and uses monitoring to generate and test empirical models that relate the status of diverse taxonomic groups to the nature and extent of human "footprint" and other landscape attributes. An adaptive cycle of standardized sampling, model development, and model evaluation provides a means to learn about the system and guide management. Additional benefits of the framework include standardized data on status and trend for a wide variety of biodiversity elements, spatially explicit models for regional planning and scenario evaluation, and identification of knowledge gaps for complementary research. We describe efforts to implement the framework in Alberta, Canada, through the Alberta Biodiversity Monitoring Institute, and identify key challenges to be addressed. PMID- 24488331 TI - Particle exposures and infections. AB - Particle exposures increase the risk for human infections. Particles can deposit in the nose, pharynx, larynx, trachea, bronchi, and distal lung and, accordingly, the respiratory tract is the system most frequently infected after such exposure; however, meningitis also occurs. Cigarette smoking, burning of biomass, dust storms, mining, agricultural work, environmental tobacco smoke (ETS), wood stoves, traffic-related emissions, gas stoves, and ambient air pollution are all particle-related exposures associated with an increased risk for respiratory infections. In addition, cigarette smoking, burning of biomass, dust storms, mining, and ETS can result in an elevated risk for tuberculosis, atypical mycobacterial infections, and meningitis. One of the mechanisms for particle related infections includes an accumulation of iron by surface functional groups of particulate matter (PM). Since elevations in metal availability are common to every particle exposure, all PM potentially contributes to these infections. Therefore, exposures to wood stove emissions, diesel exhaust, and air pollution particles are predicted to increase the incidence and prevalence of tuberculosis, atypical mycobacterial infections, and meningitis, albeit these elevations are likely to be small and detectable only in large population studies. Since iron accumulation correlates with the presence of surface functional groups and dependent metal coordination by the PM, the risk for infection continues as long as the particle is retained. Subsequently, it is expected that the cessation of exposure will diminish, but not totally reverse, the elevated risk for infection. PMID- 24488329 TI - Evaluation and treatment of critical asthma syndrome in children. AB - The heterogeneity of asthma is illustrated by the significantly different features of pediatric asthma compared to adult asthma. One phenotype of severe asthma in pediatrics includes atopy, lack of reduction in lung function, and absence of gender bias as the main characteristics. Included in the NIH NAEPP EPR 3 are recommendations for the treatment and management of severe pediatric asthma and critical asthma syndrome, such as continuous nebulization treatments, intubation and mechanical ventilation, heliox, and magnesium sulfate. In addition, epinephrine, intravenous immunoglobulin, intravenous montelukast, extracorporeal membrane oxygenation, and many biological modulators currently under investigation are additional current and/or future treatment modalities for the severe pediatric asthmatic. But, perhaps the most important strategy for managing the severe asthmatic is preventative treatment, which can significantly decrease impairment and risk, particularly for severe acute exacerbations requiring emergency care and/or hospitalization. In order for preventative therapy to be successful, several challenges must be met, including selecting the correct therapy for each patient and then ensuring compliance or adherence to a treatment plan. The heterogeneity of asthma renders the former difficult in that not all patients will respond equally to the same treatment; the latter is only helpful if the correct treatment is employed. Strategies to ensure compliance include education of caregivers and patients and their families. As newer medications are introduced, options for individualized or customized medicine increase, and this may pave the way for significant decreases in morbidity and mortality in severe pediatric asthma. PMID- 24488332 TI - Case of Shigella flexneri infection with treatment failure due to azithromycin resistance in an HIV-positive patient. PMID- 24488333 TI - Amplified detection of femtomolar DNA based on a one-to-few recognition reaction between DNA-Au conjugate and target DNA. AB - A sensitive electrochemical DNA biosensor based on the amplification of Au nanoparticles (AuNPs) has been developed. The AuNPs were modified with two types of signaling reporter DNAs, i.e. a methylene blue probe (MB-probe 2-SH) and T10 with a methylene blue signaling molecule (MB-T10-SH), forming DNA-AuNP conjugates. The MB-probe 2-SH is complementary to the target DNA, while MB-T10-SH is not. The presence of MB-T10-SH reduces the cross-reaction between target DNA and MB-probe 2-SH on the AuNPs, resulting in increased sensitivity of the biosensor. In our assay, the DNA sensor is fabricated by immobilizing a capture probe on the surface of the Au electrode, which then hybridizes with the corresponding target DNA, and further hybridizes with a DNA-Au conjugate. The signal of MB is measured by differential pulse voltammetry, while the DNA-Au conjugate enables the detection of target DNA in the linear range of 10(-13) to 10(-8) M with the detection limit as low as 50 fM. PMID- 24488334 TI - TPX2 overexpression in medullary thyroid carcinoma mediates TT cell proliferation. AB - TPX2 (targeting protein for xenopus kinesin-like protein 2), a microtubule associated protein, plays an important role in the formation of the mitotic spindle. Abnormal expression of TPX2 in various types of malignant tumors has been reported, but less is known for medullary thyroid cancer (MTC). We investigated the expression of TPX2 in human MTC tissues and its potential use as a therapeutic target. Immunohistochemical analysis of TPX2 expression was performed for 32 cases of MTC and 8 cases of normal thyroid. TPX2 expression was found to be significantly higher in MTC compared to normal thyroid tissues (P < 0.05), and to be associated with tumor size, lymph node metastasis, and advanced disease stage. The cellular effects of TPX2 knockdown, including cell proliferation, apoptosis, cell cycle diffusions, and mitotic gene expression were investigated using small interfering RNA (siRNA). TPX2-siRNA caused G1 and G2 phase cell cycle arrest, inhibited cell proliferation, and induced apoptosis. TPX2-siRNA also downregulated Aurora-A and cyclinB1 protein expression in MTC cells and enhanced the expression of p53 protein (P < 0.05). These results suggest that TPX2 may be of potential use as a new marker for MTC prognosis and therapy. PMID- 24488335 TI - Evaluation of significance of lymphocyte subpopulations and non-specific serologic markers in B-cell non-Hodgkin's lymphoma patients. AB - The use of rituximab brought attention to the hosts' immune system and to the microenvironment in non-Hodgkin's lymphoma cases. Our aim was to identify prognostic factors that can be measured easily to indicate the current state of the patient's immune status and possible reaction against malignant cells. In the retrospective analysis (2000-2008), 66 patients diagnosed with B-cell non Hodgkin's lymphomas were enrolled (40 women, 26 men; mean age: 51 years). White blood cells, lymphocytes, CD3 +; CD4 +; CD8 + T-cells, immunoglobulin types A; G; M, anti-cardiolipin antibody isotypes A; G; M; and levels of beta-2-microglobulin were measured before the initiation of the first cycle of chemotherapy, during and after 4-weeks treatment. As for CD 3+ T-lymphocytes, the absolute CD 3+ T lymphocyte numbers were higher before (0.78 * 10(9)/L) versus during (0.27 * 10(9)/L) treatment, and increased percentages were detected in pre- (66.57 %) and post-treatment (75.32 %). Absolute numbers of CD 8+ T-lymphocyte levels showed reduction before (0.26 * 10(9)/L) versus during (0.10 * 10(9)/L) therapy, but were elevated after (0.28 * 10(9)/L) treatment, while increased percentage before (21.99 %) versus after (29.85 %), and during (24.56 %) versus after (29.85 %) therapy were seen. Average white blood cell numbers were increased before (9.71 * 10(9)/L) versus during (12.07 * 10(9)/L) treatment, while decreased numbers could be observed, after (5.47 * 10(9)/L) treatment. IgA levels were decreased before (2.51 g/L) versus after (1.63 g/L) therapy. IgG levels were higher before (12.25 g/L) vs. after (8.64 g/L) treatment. IgM levels were decreased before (1.76 g/L) and after (0.83 g/L) as well as before (1.76 g/L) versus during (0.73 g/L) treatment. Anti-cardiolipin antibody type A level were decreased before (2.76 U/ml) versus after (2.49 U/ml) treatment. Decreased level of beta-2-microglobulin could be observed before (2.91 mg/L) versus post (2.28 mg/L) chemotherapy. Findings may provide better insight into the effects of immuno-chemotherapy on the hosts' immune system. PMID- 24488336 TI - Absence of fks1p in lager brewing yeast results in aberrant cell wall composition and improved beer flavor stability. AB - The flavor stability during storage is very important to the freshness and shelf life of beer. However, beer fermented with a yeast strain which is prone to autolyze will significantly affect the flavor of product. In this study, the gene encoding beta-1,3-glucan synthetase catalytic subunit (fks1) of the lager yeast was destroyed via self-clone strategy. beta-1,3-glucan is the principle cell wall component, so fks1 disruption caused a decrease in beta-1,3-glucan level and increase in chitin level in cell wall, resulting in the increased cell wall thickness. Comparing with wild-type strain, the mutant strain had 39.9 and 63.41 % less leakage of octanoic acid and decanoic acid which would significantly affect the flavor of beer during storage. Moreover, the results of European Brewery Convention tube fermentation test showed that the genetic manipulation to the industrial brewing yeast helped with the anti-staling ability, rather than affecting the fermentation ability. The thiobarbituric acid value reduced by 65.59 %, and the resistant staling value increased by 26.56 %. Moreover, the anti staling index of the beer fermented with mutant strain increased by 2.64-fold than that from wild-type strain respectively. China has the most production and consumption of beer around the world, so the quality of beer has a significant impact on Chinese beer industry. The result of this study could help with the improvement of the quality of beer in China as well as around the world. PMID- 24488337 TI - School nurses' experiences with motivational interviewing for preventing childhood obesity. AB - Motivational interviewing is a counseling method used to bring about behavior change; its application by school nurses for preventing obesity in children is still new. This study, based on in-depth interviews with 12 school nurses, shows how school nurses adapted motivational interviewing and integrated it into their daily practice along with other methods they knew from the past. Three dilemmas for school nurses were revealed: when the child was severely overweight and the parents did not perceive this as a problem, when the child and the parents were at different stages of motivation to change, and when applying an individualized approach such as motivational interviewing for preventing a complex societal problem, in this instance obesity. The study raises an important issue to consider, with implications for school nursing and obesity prevention: motivational interviewing as either a counseling method or a prevention strategy. PMID- 24488338 TI - Engaging African American and Latino adolescent males through school-based health centers. AB - African American and Latino males are less likely to seek mental health services and obtain adequate care than their White counterparts. They are more likely to receive mental health services in school-based health centers (SBHCs) than in other community-based setting. The purpose of this article was to understand the issues and reasons these adolescents sought mental health services at SBHCs and what their perceptions of the services were. A content analysis of 22 individual interviews was conducted using Krippendorff's method. Five themes emerged from the analysis of the data: the burdens and hurdles of my life, the door is always open, sanctuary within chaos, they get to us, and achieve my best potential. Each of the themes was explored in detail with rich quotations from the adolescents. The findings illuminated the daily struggles these adolescents faced and the impact mental health services in SBHCs had on their daily lives. PMID- 24488339 TI - The isolation of barley-aleurone protoplasts. AB - A procedure is described for the isolation of large numbers of viable aleurone protoplasts. After treatment with "Onozuka" cellulase protoplasts were obtained which were surrounded by a thin, "Onozuka"-resistant wall. These cells were termed "spheroplasts". Treatment of spheroplasts with "Glusulase" digested away the residual wall, yielding naked protoplasts. Measurements of respiration using a Clarke-type oxygen electrode indicated that aleurone cells isolated by this procedure were viable. PMID- 24488340 TI - [Influence of the cell metabolism on the pigment composition in ageing cultures of Euglena gracilis]. AB - The qualitative and quantitative composition of the carotenoids of young cells of Euglena gracilis strain 1224-5/9 corresponded to that of the "Z"-strain.The frequently observed yellow-reddish discolouration of ageing cells was found to be caused by a heavy breakdown of the chlorophylls and not by an increased synthesis of the carotenoids.Furthermore there could be observed a remarkable decrease in the concentration of diadinoxanthin together with an increase in the amount of zeaxanthin in the course of the stationary growth phase. This phenomenon was attributed to a direct deepoxidation of diadinoxanthin on the basis of experiments with (14)C-diadinoxanthin showing a transformation of the pigment into zeaxanthin and some other Euglena carotenoids, e.g. neoxanthin and beta carotene.Because of their interconvertibility diadinoxanthin and neoxanthin are regarded as auxiliary pigments for the photosynthetic O2-evolution.The transformation of diadinoxanthin into zeaxanthin in the ageing cells coincides in time with the switch from an aerobic to an anerobic cell metabolism. The latter is characterized by a decrease in the O2-incorporation together with a simultaneous increase in the NADH-concentration and by a heavy excretion of glycolytic end products such as pyruvate and lactate after cell respiration has stopped completely. The transformation of diadinoxanthin into zeaxanthin is therefore attributed to a reduction of diadinoxanthin by the cytoplasmic NADH.As the same pigment transformation could be observed in cells kept in darkness and under conditions of artificially stopped respiration, it is likely that this transformation takes place independently of photosynthetic processes.The origin of the commutation of the cell metabolism and the cessation of respiration is still unknown. As the respiration of ageing cells can be revived in the darkness it is certainly linked to photosynthesis under light conditions. PMID- 24488341 TI - [An action spectrum of photoinduced coremia-zonation of two mutants of Penicillium claviforme bainier]. AB - An action spectrum of light induced coremia-zonation was obtained for the fungus Penicillium claviforme mut. olivicolor Abe et Ura. Zonation is induced only by light of wavelengths shorter than 510 nm. The action spectrum has maxima at 370 nm and at 450-460 nm and a definite shoulder at 470-480 nm. Penicillium claviforme mut. album is somewhat less sensitive to light but possesses the same spectral sensitivity.Measurable amounts of carotenoids are not found in the mycelium. The presence of diphenylamine in the nutrition medium has no effect on the fungal sensitivity to light. It is therefore assumed that the photoreceptor pigment involved is a flavoprotein. PMID- 24488342 TI - Sucrose suppression of chlorophyll synthesis in carrot tissue cultures: The role of invertase. AB - Free space invertase activities were determined in carrot callus strains CRT1 and CRT2 grown under conditions in which sucrose suppression of chlorophyll synthesis occurred in CRT1 but not CRT2. CRT2 possessed a high free space acid invertase activity (pH optimum 5.0 Km for sucrose 3.1*10(-3)M) while CRT1 lacked this enzyme. [U-(14)C] sucrose introduced into the free space of calluses was rapidly inverted by CRT2, but not by CRT1.Despite their different invertase levels, CRT1 and CRT2 showed similar sucrose uptake rates and took up [U-(14)C-glucosyl] sucrose and [5-T-glucosyl] sucrose from external bathing media essentially without prior inversion.It is concluded that acid invertase in callus tissue relieves the suppression of chlorophyll synthesis caused by sucrose in the free space. The invertase may in some circumstances hydrolyse sucrose before uptake, but is not an essential part of the sucrose uptake mechanism in carrot tissue cultures. PMID- 24488343 TI - Unidirectional movement of tracers along the stolon of Saxifraga sarmentosa. AB - When radioactive tracer is applied locally to the stolon of Saxifraga its long distance movement after 18 hours is found to be strongly polarised; there is in addition a short-distance movement which is unpolarised. With caesium, the long distance movement is predominantly in the phloem; with strontium in the xylem. These interpretations, a priori probable, were confirmed by artifically reversing, separately, the xylem and the phloem currents. With long pieces of excised stolon only the unpolarised short-distance movement is observed. These results constitute evidence against simultaneous bidirectional translocation in the same sieve tube, and are consistent with either the Munch or the electro osmotic theory. PMID- 24488344 TI - Effects of abscisic acid on potassium uptake and starch content of stomatal guard cells. AB - Abscisic acid (ABA) at a concentration of 100 MUm reduced the mean stomatal aperture on isolated epidermis of Commelina communis from 9.5 to 3.1 MUm. This closure resulted from a fall in osmotic pressure of the guard cells from 14.1 to 9.8 bars; the osmotic pressure of the subsidiary cells did not change significantly. Histochemical tests showed that the potassium concentration in guard cells was reduced by ABA-treatment, while the starch content of the chloroplasts increased. ABA was found to exert a significant effect on Rb(86) uptake into leaf discs, but this was relatively small in magnitude. It is concluded that ABA has a greater effect on ion uptake into guard cells than into the leaf tissues as a whole.Recent hypotheses of the stomatal mechanism are discussed in relation to these new observations, and the rejection by some writers of any major role for starch hydrolysis is challenged. Evidence from several sources suggests that starch disappearance occurs simultaneously with K(+) entry into guard cells. Breakdown of starch may lead to formation of organic anions, with which K(+) uptake may be associated. In this case starch breakdown would contribute as much to the increased osmotic pressure as does K(+) uptake. PMID- 24488345 TI - [Evidence of a neurohormone in moss callus and its regulation by the phytochrome]. AB - The presence of a neurohormone in moss callus could be demonstrated by means of pharmacological experiments on the heart of the frog (Rana temporaria L.) and by chromatography.The hearts react in the same manner as they do to application of acetylcholine and the substance resembles acetylcholine in its Rf-value. Therefore it is suggested that this hormone is identical with acetylcholine. The concentration of the hormone in the callus cells is mediated by the phytochrome. Moss callus cultivated under red and far-red illumination contain less substance than moss callus grown in red light. PMID- 24488346 TI - Effects of temperature on accumulation of starch or lipid in chloroplasts of grapevine. AB - The amount of starch accumulated in chloroplasts of grapevine leaves fell, with increasing temperature, from 23% of dry weight at 18/13 degrees C (day/night) to 1% at 35/30 degrees C, whereas total lipids in the leaf rose from 6 to 16% of dry weight. Preparations viewed by electron microscopy had large starch granules in the chloroplasts at 18/13 degrees C, and large lipid droplets at 35/30 degrees C. At 35/30 degrees C chlorophyll content of chloroplasts was high and grana prominent, suggesting that the results were due to selective effects of temperature on metabolic pathways. PMID- 24488347 TI - Pyridine nucleotide transhydrogenase from Chlorella. AB - A pyridine nucleotide transhydrogenase which could facilitate the transfer of hydrogen between chloroplastic and non-chloroplastic pools of pyridine nucleotides, was found to be present in Chlorella pyrenoidosa. PMID- 24488348 TI - Changes in the capacity for protein-synthesis in embryonic axes of hazel fruits during the breaking of dormancy by GA3. AB - Embryonic axes of hazel seeds sown on GA3 (non-dormant) show a higher rate of protein synthesis than those of seeds sown on water (dormant). Associated with this increased protein synthesis are changes in tRNA and aminoacyl-tRNA synthetases. These changes appear to be consequences of changes at the transcriptional level which have previously been described. PMID- 24488349 TI - The presence of microbodies in three strains of Chlorella. AB - Electron microscopic investigations show that cells of three strains of Chlorella contain microbodies. The organelles have a dense granular matrix and are surrounded by a single membrane. PMID- 24488350 TI - Phytochrome-mediated bud development in Pisum sativum. AB - Light-grown dwarf peas were disbudded except for a single lateral bud, then transferred to darkness at 24 degrees C. During the dark period the seedlings were irradiated daily for 5 or 7 min with R or FR. The buds exposed to R developed into shoots faster than those irradiated with FR. The R effect was FR reversible, and the FR effect was R reversible. The Pfr form of phytochrome thus promoted shoot growth including cell division, DNA and RNA synthesis. PMID- 24488351 TI - Evaluation of the safety and efficacy of esophagojejunostomy after totally laparoscopic total gastrectomy using a trans-orally inserted anvil: a single center comparative study. AB - BACKGROUND: Although laparoscopic surgery is frequently performed for the treatment of gastric cancer, laparoscopic total gastrectomy is not widely performed because of its technical difficulty. Since December 2007 we have performed esophagojejunostomy after totally laparoscopic total gastrectomy (TLTG) in more than 110 cases in our institution by using a circular stapler with a trans-orally inserted anvil. We performed a single-center comparative study to evaluate the safety and efficacy of esophagojejunostomy using a trans-orally inserted anvil in patients who underwent TLTG for the treatment of gastric cancer. METHODS: In the present study, we examined 329 patients with gastric cancer who underwent esophagojejunostomy using a circular stapler after total gastrectomy. Data on the clinicopathological features, operative time, amount of intraoperative blood loss, and incidence of anastomosis-related complications among the surgical groups were obtained by reviewing the medical records, which were then analyzed. RESULTS: Approximately 67% of the patients were men, and the average patient age was 64.0 years (range 26-93 years). In addition, 166 (50.5%) and 163 (49.5%) patients underwent open and laparoscopic surgery, respectively. Leakage following esophagojejunostomy was noted in 7 (4.2%) of 166 patients who underwent total gastrectomy with open laparotomy, and 0 of 46 patients who underwent laparoscopic-assisted total gastrectomy (LATG). However, only 2 (1.7%) of 117 patients who underwent TLTG using a trans-orally inserted anvil exhibited leakage following esophagojejunostomy. Anastomotic stenosis of the esophagojejunostomy was observed in 5 (3.0%) of 166 patients who underwent total gastrectomy with open laparotomy, 2 (4.3%) of 46 patients who underwent LATG, and 2 (1.7%) of 117 patients who underwent TLTG using a trans-orally inserted anvil. CONCLUSIONS: We believe that esophagojejunostomy using a trans-orally inserted anvil after TLTG for gastric cancer is a safe and useful surgical procedure. PMID- 24488352 TI - Stereoscopic augmented reality for laparoscopic surgery. AB - BACKGROUND: Conventional laparoscopes provide a flat representation of the three dimensional (3D) operating field and are incapable of visualizing internal structures located beneath visible organ surfaces. Computed tomography (CT) and magnetic resonance (MR) images are difficult to fuse in real time with laparoscopic views due to the deformable nature of soft-tissue organs. Utilizing emerging camera technology, we have developed a real-time stereoscopic augmented reality (AR) system for laparoscopic surgery by merging live laparoscopic ultrasound (LUS) with stereoscopic video. The system creates two new visual cues: (1) perception of true depth with improved understanding of 3D spatial relationships among anatomical structures, and (2) visualization of critical internal structures along with a more comprehensive visualization of the operating field. METHODS: The stereoscopic AR system has been designed for near term clinical translation with seamless integration into the existing surgical workflow. It is composed of a stereoscopic vision system, a LUS system, and an optical tracker. Specialized software processes streams of imaging data from the tracked devices and registers those in real time. The resulting two ultrasound augmented video streams (one for the left and one for the right eye) give a live stereoscopic AR view of the operating field. The team conducted a series of stereoscopic AR interrogations of the liver, gallbladder, biliary tree, and kidneys in two swine. RESULTS: The preclinical studies demonstrated the feasibility of the stereoscopic AR system during in vivo procedures. Major internal structures could be easily identified. The system exhibited unobservable latency with acceptable image-to-video registration accuracy. CONCLUSIONS: We presented the first in vivo use of a complete system with stereoscopic AR visualization capability. This new capability introduces new visual cues and enhances visualization of the surgical anatomy. The system shows promise to improve the precision and expand the capacity of minimally invasive laparoscopic surgeries. PMID- 24488353 TI - What should be the correct indications for laparoscopic inguinal hernia repair? PMID- 24488354 TI - Therapy and follow-up for ampullary adenomas: one size clearly does not fit all, although we ought to keep trying in clinical practice. PMID- 24488356 TI - Clinicopathologic factors and outcomes of histologic discrepancy between differentiated and undifferentiated types after endoscopic resection of early gastric cancer. AB - BACKGROUND: Histologic discrepancies among specimens obtained by forceps biopsy and endoscopic resection (ER) between the differentiated and undifferentiated types often occur in early gastric cancer (EGC). This study aimed to evaluate the predictive clinicopathologic characteristics and clinical implications of histologic discrepancies in EGC. METHODS: From August 2005 to March 2012, 596 lesions from 579 patients underwent ER for EGC. The lesions studied were diagnosed as the differentiated histologic type from forceps biopsy specimens. The lesions were grouped according to the occurrence of histologic discrepancy between the differentiated and undifferentiated types in specimens obtained by ER as concordant (n = 570) or discordant (n = 26). The main outcome measures were en bloc resection, complete resection, and curative resection rates. RESULTS: The histologic discrepancy rate was 4.4% among the studied lesions. Larger size, lesion location in the mid third of the stomach, easy friability, exudates, and submucosal invasion shown on endoscopic ultrasound were significantly related to histologic discrepancy in the univariate analysis. In the multivariate analysis, lesion location in the mid third of the stomach [odds ratio (OR) 5.34, 95% confidence interval (CI) 1.59-19.13] and easy friability (OR 29.26, 95% CI 2.30 to >999.9) were significant factors associated with histologic discrepancy. The complete resection and curative resection rates were significantly lower and the additional operation rates after ER were significantly higher in the discordant group. CONCLUSIONS: The EGCs with histologic discrepancy between the differentiated and undifferentiated types changed the therapeutic outcomes of ER. Easily friable lesions located in the mid third of the stomach carry a significant risk for histologic discrepancy in undifferentiated histology when ER of EGCs is performed. PMID- 24488355 TI - Does obesity increase early postoperative complications after laparoscopic colorectal surgery? Results from a single center. AB - BACKGROUND: Laparoscopic colorectal surgery (LCRS) has several advantages over open surgery, but LCRS has been associated with a higher rate of postoperative complications (POCs) among obese patients [body mass index (BMI), >=30 kg/m(2)]. The prevalence of obesity in Chile is increasing, up to 25.1% in 2010, suggesting that a higher percentage of patients undergoing LCRS will be obese. This study compared POC rates between obese and nonobese patients undergoing LCRS. METHODS: This study included case and control patients in a prospectively maintained LCRS database who underwent LCRS between July 2007 and June 2012 at Clinica Las Condes, Santiago, Chile. Obese and nonobese (BMI <30 kg/m(2)) patients were paired by gender, age, American Society of Anesthesiologists class, preoperative diagnosis, and type of surgery. Intraoperative complications and POCs were documented up to 30 days. The severity of each POC was classified by Clavien Dindo score. RESULTS: In this study, 449 patients who underwent LCRS during the study period were identified. The study paired 53 obese patients (mean BMI 33.1 kg/m(2)) with 53 nonobese patients (mean BMI 25.9 kg/m(2)). The median age was 55 years in the obese group and 57 years in the nonobese group, and 60% of the patients in both groups were men. The findings showed POCs in 13 obese (24.5%) and 15 nonobese (28.3%) patients (p = 0.66). Stratified by severity of POCs, the two groups were similar (p = 0.62). The two groups did not differ in terms of the median time to the first feeding (1 day each) or the hospital length of stay (4 days each). Similar percentages of patients in the two groups required reoperation (p = 0.4), intensive care unit (ICU) admission (p = 0.77), and readmission to the hospital (p = 0.65) because of POCs. CONCLUSION: The frequency of POCs after LCRS was no higher among the obese patients than among the nonobese patients. PMID- 24488357 TI - Integration of open and laparoscopic approaches for rectal cancer resection: oncologic and short-term outcomes. AB - BACKGROUND: Laparoscopy is increasingly used for rectal cancer surgery. Laparoscopic surgery is not attempted for some suitable patients because of concerns for conversion or technical difficulty. This study aimed to evaluate oncologic and short-term outcomes for patients undergoing curative resection for rectal cancer via laparoscopic and open approaches. METHODS: A prospective database was reviewed to identify rectal cancer resections from 2005 to 2011. Patients who had primary rectal cancer within 15 cm of the anal verge were included in the study. Those with recurrent or metastatic disease were excluded. Patients were assigned to laparoscopic or open approaches preoperatively based on clinical criteria and imaging. All patients underwent a standard total mesorectal excision and followed a standardized enhanced recovery pathway. The oncologic and clinical outcomes were evaluated by approach. RESULTS: The analysis included 81 patients. The preoperative assignments consisted of 62 laparoscopic (77%) and 19 open (23%) procedures. Nine laparoscopic procedures (14.5%) were converted to open procedures. After a median follow-up period of 25 months, all oncologic outcomes were comparable. Three patients (two laparoscopic, one open) had a positive circumferential margin (<=1 mm). The laparoscopic and open groups were similar in terms of their 3-year disease-free periods (93.6 vs. 88.2%; P = 0.450) and overall survival periods (93.5 vs. 90.9%; P = 0.766). The local recurrence rate was 2.5%. CONCLUSIONS: Laparoscopic resection for rectal cancer can be attempted for most patients. Conversion to open procedure does not compromise clinical or oncologic outcomes. In practice, combining laparoscopic and open surgery optimizes resource use and results in at least equivalent outcomes. PMID- 24488358 TI - Routine colonoscopy is not required in uncomplicated diverticulitis: a systematic review. AB - BACKGROUND: It is generally accepted that patients following an episode of diverticulitis should have additional colonoscopy screening to rule out a colorectal malignancy. We aimed to investigate the rate of CRC found by colonoscopy after an attack of uncomplicated diverticulitis. METHODS: MEDLINE, Embase, and Cochrane databases were searched systematically for clinical trials or observational studies on colonic evaluation by colonoscopy after the initial diagnosis of acute uncomplicated diverticulitis, followed by hand-searching of reference lists. RESULTS: Nine studies met the inclusion criteria and included a total number of 2,490 patients with uncomplicated diverticulitis. Subsequent colonoscopy after an episode of uncomplicated diverticulitis was performed in 1,468 patients (59%). Seventeen patients were diagnosed with CRC, having a prevalence of 1.16% (95% confidence interval 0.72-1.9% for CRC). Hyperplastic polyps were seen in 156 patients (10.6%), low-grade adenoma in 90 patients (6.1%), and advanced adenoma was reported in 32 patients (2.2%). CONCLUSION: Unless colonoscopy is regarded for screening in individuals aged 50 years and older, routine colonoscopy in the absence of other clinical signs of CRC is not required. PMID- 24488360 TI - Fate of large donor site defects in osteochondral transfer procedures in the knee joint with and without TruFit plugs. AB - INTRODUCTION: Because of the potential donor site morbidity, cartilage lesions of more than 3 cm(2) in size are considered to be critical regarding autologous osteochondral transplantation (OCT). In this study, the potential donor site morbidity for large defects should be reduced by means of OBI TruFit Plugs. MATERIALS AND METHODS: An autologous OCT was carried out on 37 patients and the cylinders were received from the dorsal medial femoral condyle. The donor site defects of 21 patients (average defect size 5.5 cm(2)) were filled with artificial TruFit cylinders (study group); the donor site defects (average defect size 4.6 cm(2)) were left untreated for 16 patients. RESULTS: In the study group, the Tegner, Western Ontario and McMaster Universities (WOMAC), knee society score, and visual analogue scale pain scores improved from preoperatively 3.2 (+/ 0.8), 60.9 (+/-41.6), 133.6 (+/-27.1), and 4.8 (+/-2.3) points, respectively, to 3.9 (+/-0.6), 35.5 (+/-27.1), 177.8 (+/-16.6), and 3.3 (+/-2.9) points, respectively, at the time of the second follow-up; the control group's preoperative score values came to 2.8 (+/-0.9), 73.3 (+/-50.2), 123.8 (+/-41.5), and 5.3 (+/-2.7) points, respectively, and changed to 3.6 (+/-0.8), 41.4 (+/ 28.8), 179.3 (+/-17.5), and 3.1 (+/-2.0) points, respectively, at the time of the second follow-up. The smaller the initial chondral defect was in the study group, the better the WOMAC score values became (p < 0.05). The modified Henderson score at the study group's donor sites improved from 19.2 (+/-3.3) to 13.7 (+/-2.1) points (p < 0.001); the control group's score values for the donor sites were 18.3 (+/-3.4) and 15.4 (+/-4.4) points (p = 0.0015). CONCLUSIONS: OCT is an effective therapy even for large chondral defects >3 cm(2). By filling the defects with TruFit implants, no clinical improvements could be found since the donor site morbidity was already low anyway. However, the regeneration of defects filled with TruFit implants took more than 2 years. PMID- 24488359 TI - The intraoperative use of ultrasound facilitates significantly the arthroscopic debridement of calcific rotator cuff tendinitis. AB - INTRODUCTION: During arthroscopy, the localization of calcific deposit in patients suffering from calcifying tendinitis can be demanding and time consuming, frequently using ionizing radiation. Intraoperative ultrasound has been recently promoted, facilitating deposit localization and reducing radiation dose. MATERIAL AND METHODS: In this prospective, randomized, controlled and clinical observer-blinded pilot trial, 20 patients with calcific tendinitis were operated. In group I, the deposit was localized conventionally. In group II, the deposit was localized using intraoperative ultrasound. The needle punctures to detect the deposit and operation times were noted. Patients were postoperatively evaluated after 2 and 6 weeks and 9 months. RESULTS: In group II, the needle punctures to detect the deposit were significantly lower than in group I (p < 0.0001). Operation time to localize the deposit was also significantly less in group II (p < 0.033). In both groups, patients improved significantly with increased shoulder function (p < 0.0001) and decreased pain (p < 0.0001) 2 weeks and 9 months (p < 0.001) after surgery. The difference between the groups was not significant. Excellent radiological findings were obtained in both groups after 9 months. CONCLUSIONS: Intraoperative US significantly facilitates the detection of calcific deposits during arthroscopic debridement by speeding up surgery and reducing the number of needle punctures. Hence, we have changed our method of detecting calcific deposits intraoperatively from fluoroscopy to ultrasound. PMID- 24488361 TI - Highly selective and controllable synthesis of arylhydroxylamines by the reduction of nitroarenes with an electron-withdrawing group using a new nitroreductase BaNTR1. AB - A new bacterial nitroreductase has been identified and used as a biocatalyst for the controllable reduction of a variety of nitroarenes with an electron withdrawing group to the corresponding N-arylhydroxylamines under mild reaction conditions with excellent selectivity (>99%). This method therefore represents a green and efficient method for the synthesis of arylhydroxylamines. PMID- 24488363 TI - Application of geographically weighted regression model to analysis of spatiotemporal varying relationships between groundwater quantity and land use changes (case study: Khanmirza Plain, Iran). AB - Understanding the spatiotemporal relationships between land use/cover changes (LUCC) and groundwater resources is necessary for effective and efficient land use management. In this paper, geographically weighted regression (GWR) and ordinary least squares (OLS) models have been expanded to analyze varying spatial relationships between groundwater quantity changes and LUCC for three periods: 1987-2000, 2000-2010, and 1987-2010 in the Khanmirza Plain of southwestern Iran. For this purpose, TM images were used to generate LUCC (rainfed, irrigated, meadow, and bare lands). Groundwater quantity variables, including groundwater level changes (GLC) and groundwater withdrawal differences (GWD), were gathered from piezometric and agricultural wells data. The analysis of spatial autocorrelation (Moran's I and local indicators of spatial association ) demonstrated that GWR has a better ability to model spatially varying data with very minimal clustering of residuals. The results R (2) and corrected Akaike's Information Criterion parameters revealed that the GWR has the lowest similarity in space and time in neighboring situations and it has the high ability to explain more variance in the LUCC as a function of the groundwater quantity changes. All results of the distribution of local R (2) values from GWR confirm our assertion that there is a spatiotemporal relationship between types of land use and each of groundwater quantity variables within the region. According to the t test results from GWR, there are significant differences between the GLC and GWD and the land use types in different places of region in each of the three time series. The GWR results can help decision-makers to make appropriate decisions for future planning. PMID- 24488362 TI - Marine polyphenol phlorotannins promote non-rapid eye movement sleep in mice via the benzodiazepine site of the GABAA receptor. AB - RATIONALE: In psychopharmacology, researchers have been interested in the hypnotic effects of terrestrial plant polyphenols and their synthetic derivatives. Phlorotannins, a marine plant polyphenol, could have potential as a source of novel hypnotic drugs. OBJECTIVES: The effects of phlorotannins and major phlorotannin constituent eckstolonol on sleep-wake profiles in mice were evaluated in comparison with diazepam, and their hypnotic mechanism was also investigated. METHODS: The effects of phlorotannin preparation (PRT) and eckstolonol orally given on sleep-wake profiles were measured by recording electroencephalograms (EEG) and electromyograms in C57BL/6N mice. Flumazenil, a GABAA-benzodiazepine (BZD) receptor antagonist, was injected 15 min before PRT and eckstolonol to reveal its hypnotic mechanism. RESULTS: PRT administration (>250 mg/kg) produced a significant decrease in sleep latency and an increase in the amount of non-rapid eye movement sleep (NREMS). Eckstolonol significantly decreased sleep latency (>12.5 mg/kg) and increased the amount of NREMS (50 mg/kg). PRT and eckstolonol had no effect on EEG power density of NREMS. The hypnotic effects of PRT or eckstolonol were completely abolished by pretreatment with flumazenil. CONCLUSIONS: We demonstrated that phlorotannins promote NREMS by modulating the BZD site of the GABAA receptor. These results suggest that phlorotannins can be potentially used as an herbal medicine for insomnia and as a promising structure for developing novel sedative-hypnotics. PMID- 24488364 TI - Validation of spectrophotometric method for Se(IV) determination: analytical applications. AB - As selenium is an important part of the antioxidant enzymes and also because there are several studies suggesting a possible link between cancer and selenium deficiency, this paper presents a spectrophotometric method for the assay of Se(IV), using N,N-diethyl-p-phenylenediamine monohydrochloride as reagent. The proposed method is based on the reaction between the selenium and potassium iodide in low acidic medium, when iodine is released. This last product will further oxidise the new reagent. The final obtained product is strongly coloured in red and has an absorption maximum at 552 nm and molar extinction coefficient (epsilon) of 6.1 * 10(4) L mol(-1) cm(-1). The optimum working conditions were established, and the developed method was validated, being characterised by a good linearity (in the range of 0.5-3.0 MUg/mL), a limit of detection (0.0573 MUg/mL) and a limit of quantification (0.1737 MUg/mL). At the same time, the repeatability, the precision of the method and the accuracy were established. The proposed and validated method was applied with good results for the determination of Se(IV) in spring and bottled water from Iasi and also in pharmaceutical and cosmetic products. PMID- 24488365 TI - Source identification study of heavy metal contamination in the industrial hub of Unnao, India. AB - India's Unnao region is home to many leather-treatment facilities and related industries. Industrial and agricultural waste leads to heavy metal contamination that infiltrates groundwater and leads to human health hazards. This work measured the amount of heavy metal in groundwater at specific sites near the industrial facilities in Unnao and identified potential sources of contamination as anthropogenic or lithogenic. Groundwater samples were taken from 10 bore well sites chosen for depth and proximity to industry. Data obtained from sample sites was interpreted using a multivariate statistical analytical approach, i.e., principal component analysis, clustering analysis, and correlation analysis. The results of the multivariate analysis showed that cadmium, copper, manganese, nickel, lead, and zinc were correlated with anthropogenic sources, while iron and chromium were associated with lithogenic sources. These findings provide information on the possible sources of heavy metal contamination and could be a model for assessing and monitoring heavy metal pollution in groundwater in other locales. This study analyzed a selection of heavy metals chosen on the basis of industries located in the study area, which might not provide a complete range of information about the sources and availability of all heavy metals. Therefore, an extended investigation on heavy metal fractions will be developed in further studies. PMID- 24488367 TI - Haloplanus litoreus sp. nov. and Haloplanus ruber sp. nov., from a marine solar saltern and an aquaculture farm, respectively. AB - Two halophilic archaea, strains GX21(T) and R35(T), were isolated from a marine solar saltern and an aquaculture farm in China, respectively. Cells of the two strains were observed to be pleomorphic, flat, to contain gas vesicles, stain Gram-negative and produce red-pigmented colonies. Strain GX21(T) was found to be able to grow at 25-50 degrees C (optimum 37 degrees C), at 2.6-4.8 M NaCl (optimum 3.4 M NaCl), at 0.05-1.0 M MgCl2 (optimum 0.1 M MgCl2) and at pH 6.0-8.5 (optimum pH 6.5) while strain R35(T) was found to be able to grow at 25-45 degrees C (optimum 37 degrees C), at 2.1-4.8 M NaCl (optimum 3.1 M NaCl), at 0 0.7 M MgCl2 (optimum 0.03 M MgCl2) and at pH 5.5-9.5 (optimum pH 6.5-7.0). The cells of both isolates were observed to lyse in distilled water. The minimum NaCl concentrations that prevented cell lysis were determined to be 15 % (w/v) for strain GX21(T) and 12 % (w/v) for strain R35(T). The major polar lipids of the two strains were identified as phosphatidylglycerol, phosphatidylglycerol phosphate methyl ester, phosphatidylglycerol sulfate, one major glycolipid and a minor lipid chromatographically identical to sulfated mannosyl glucosyl diether and mannosyl glucosyl diether, respectively. 16S rRNA gene sequence analysis revealed that strains GX21(T) and R35(T) show 97.1 % sequence similarity to each other and are closely related to Haloplanus aerogenes TBN37(T) (96.8 and 95.8 %), Haloplanus vescus RO5-8(T) (96.7 and 96.1 %), Haloplanus salinus YGH66(T) (96.4 and 95.8 %) and Haloplanus natans JCM 14081(T) (96.3 and 95.4 %). The rpoB' gene similarity between strains GX21(T) and R35(T) is 90.5 % and show 88.5-90.8 % similarity to the Haloplanus species with validly published names. The DNA G+C content of strain GX21(T) and R35(T) were determined to be 65.8 and 66.0 mol%, respectively. The DNA-DNA hybridization values between strain GX21(T) and strain R35(T), and the two strains with the Haloplanus species with validly published names, showed less than 50 % DNA-DNA relatedness. It was concluded that strain GX21(T) (=CGMCC 1.10456(T) = JCM 17092(T)) and strain R35(T) (=CGMCC 1.10594 (T) = JCM 17271(T)) represent two new species of Haloplanus, for which the names Haloplanus litoreus sp. nov. and Haloplanus ruber sp. nov. are proposed. PMID- 24488368 TI - Electronic structure of positive and negative polarons in functionalized dithienylthiazolo[5,4-d]thiazoles: a combined EPR and DFT study. AB - 2,5-Dithienylthiazolo[5,4-d]thiazole (DTTzTz) derivatives have high potential for solution-processed organic field-effect transistors and solar cells, both as electron acceptors and donors. Here, the electronic structure of positive and negative radicals (polarons) of two functionalized DTTzTz materials is studied using multi-frequency and multi-resonance electron paramagnetic resonance (EPR) in combination with density functional theory (DFT). It is shown that the negative and positive DTTzTz polarons can be distinguished on the basis of their characteristic EPR parameters. The chemically induced polarons are compared to light-generated states observed in a blend of one of the DTTzTz derivatives with a donor polymer. The study gives in-depth information about the spread of the electron or hole in the DTTzTz molecules. PMID- 24488370 TI - A DFT study of the unimolecular decomposition of 1,2,4-butanetriol trinitrate. AB - To improve understanding of the unimolecular decomposition mechanism of 1,2,4 butanetriol trinitrate (BTTN) in the gas phase, density functional theory calculations were performed to determine various decomposition pathways at the B3LYP/6-311G** level. Two main mechanisms for the unimolecular decomposition of BTTN were found. In the first, homolysis of one of the O-NO2 bonds occurs to form *NO2 and CH2ONO2CHONO2CH2CH2O*, which subsequently decomposes to form CH3CHO + *CHO + 3NO2 + HCHO. In the second, successive HONO elimination reactions yield three HONO and OHCCH2CHONO2CH2ONO2 fragments, which subsequently decompose to form CH3CHO + 2CO + 3HONO. We also found that the first pathway has a slightly lower activation energy than the second. The results show that the pathway involving O-NO2 cleavage is slightly more energetically favorable than that involving HONO elimination. PMID- 24488369 TI - Innovative uses of electronic health records and social media for public health surveillance. AB - Electronic health records (EHRs) and social media have the potential to enrich public health surveillance of diabetes. Clinical and patient-facing data sources for diabetes surveillance are needed given its profound public health impact, opportunity for primary and secondary prevention, persistent disparities, and requirement for self-management. Initiatives to employ data from EHRs and social media for diabetes surveillance are in their infancy. With their transformative potential come practical limitations and ethical considerations. We explore applications of EHR and social media for diabetes surveillance, limitations to approaches, and steps for moving forward in this partnership between patients, health systems, and public health. PMID- 24488371 TI - A cluster of lung injury cases associated with home humidifier use: an epidemiological investigation. AB - BACKGROUND: In April 2011 a tertiary hospital in Seoul, Korea reported several cases of severe respiratory distress of unknown origin in young adults. METHODS: To find the route of transmission, causative agent and patient risk factors of the outbreak, an investigation of the epidemic was initiated. Clinicopathological conferences led to the suspicion that the cases related to an inhalation injury. An age- and sex-matched case-control study was therefore performed to examine the inhalation exposure of the patients to various agents. RESULTS: Of the 28 confirmed cases, 18 agreed to participate. A total of 121 age- and sex-matched controls with pulmonary, allergic or obstetric disease were selected. All patients and controls completed questionnaires with questions about exposure to various inhalants. The crude ORs for patient exposure to indoor mould, humidifier use, humidifier detergent use and insecticide use were 4.4 (95% CI 1.5 to 13.1), 13.7 (95% CI 1.8 to 106.3), 47.3 (95% CI 6.1 to 369.7) and 3.9 (95% CI 1.3 to 11.7), respectively. However, when considered concurrently, indoor mould and insecticide use lost statistical significance. Moreover, humidifier use was ruled out as the cause because of a lack of biological plausibility and the weak strength of the association. This suggested that humidifier disinfectant was the cause of the outbreak. This information led the Korean government to order the removal of humidifier detergents from the market. In the years following the ban, no additional cases were detected. CONCLUSIONS: Epidemiological evidence strongly suggests that the lung injury outbreak was caused by humidifier detergent use at home. PMID- 24488372 TI - A deadly web. PMID- 24488373 TI - Vitamin D and lung function. PMID- 24488375 TI - Hierarchical foam of exposed ultrathin nickel nanosheets supported on chainlike Ni-nanowires and the derivative chalcogenide for enhanced pseudocapacitance. AB - Foamlike nickel hierarchical structures of ultrathin nanosheets supported on thin wires composed of nanoparticles are prepared by a facile one-pot synthesis via controlled nucleation and growth process. By further sulfidation, the sulfide derivative of loose porous fibrous structure shows a high electrochemical capacity for potential pseudocapacitor applications. PMID- 24488374 TI - Combination antiretroviral therapy (cART) component ritonavir significantly alters docetaxel exposure. AB - PURPOSE: Non-AIDS-defining cancers (NADCs) now exceed rates of AIDS-defining cancers in HIV-positive patients. Treatment of NADCs may be complicated by drug drug interactions between antiretrovirals and chemotherapy. Docetaxel is a widely used anticancer agent that is primarily metabolized by CYP3A4 enzymes and used to treat NADCs. A preclinical in vivo assessment was performed to gain a better understanding of CYP3-mediated drug-drug interactions between antiretrovirals and docetaxel, as well as to assess any alterations in gene expression with these combinations. METHODS: Docetaxel (20 mg/kg i.v.) was administered to male FVB mice in the presence and absence of dexamethasone (10 mg/kg p.o. *4d), efavirenz (25 mg/kg p.o. *4d), ketoconazole (50 mg/kg p.o.), or ritonavir (12.5 mg/kg p.o.). At various time points, plasma and liver tissue were harvested. Docetaxel concentrations were determined by LC/MS/MS. Pharmacokinetic parameters were calculated. Liver tissue RNA was used to evaluate alterations in Cyp3a11 and Abcb1a gene expression. RESULTS: Docetaxel exposure was altered by CYP3A4 inhibitors but not by inducers. The CYP3A4 inducers efavirenz and dexamethasone did not have a significant effect on docetaxel exposure (AUC). However, the CYP3A4 inhibitors ritonavir and ketoconazole resulted in a 6.9- and 3.1-fold increase in AUC, respectively. Alterations in gene expression did not account for the altered docetaxel exposure. CONCLUSIONS: Docetaxel exposure was significantly altered by CYP3A4 inhibitors. Until a definitive clinical trial is performed, docetaxel should be used with caution in patients on a ritonavir-containing antiretroviral regimen or an alternative antineoplastic therapy or antiretroviral regimen should be considered. PMID- 24488376 TI - Dose regimen of para-aminosalicylic acid gastro-resistant formulation (PAS-GR) in multidrug-resistant tuberculosis. AB - BACKGROUND AND OBJECTIVES: Resurgence of multidrug-resistant tuberculosis (MDR TB) has raised a renewed interest in para-aminosalicylic acid (PAS) and other efficacious drugs. A gastro-resistant granule formulation (PAS-GR) was designed to be better tolerated than earlier forms of PAS, with fewer adverse effects from reduced production of meta-aminophenol. PAS release from PAS-GR granules is slower than with earlier formulations. Pharmacokinetic data are, however, limited and only a few studies have assisted in defining the best PAS-GR dose regimen. Interest in refining the latter continues and recent data contributed in better defining the optimal PAS-GR dose regimen in adults and children. The present paper draws on these recent studies, synthesizes pharmacokinetic results from different population groups, and draws comparisons with in vitro data and the results of earlier pharmacokinetic studies in order to discuss the most appropriate dosing regimen for PAS-GR. METHODS: A comparative in vitro dissolution study was carried out with a 1 g acid PAS equivalent of various formulations of PAS and PAS-GR and in vitro-in vivo correlations. Retrospective comparisons between recent and earlier clinical studies were also gathered to clarify the dose regimen of PAS-GR in adults and children. RESULTS: Exposure after a 4 g twice- or three times daily dose regimen in adult MDR-TB patients confirmed that both dose regimens can be used. The twice-daily dose regimen does not, however, confer any safety margin over the potentiality of "too" high plasma concentrations after a three times daily dose regimen and may lead to under dosage when a dose is missed, as compliance often decreases over time. CONCLUSIONS: Based on available data and practical considerations, a 4 g three times daily dose regimen of PAS-GR should be the preferred dose in hospital settings, where it remains the best regimen to cover the around-the-clock suppression of mycobacteria based on the minimal inhibitory concentration for PAS. In MDR-TB adults and in hospital settings, there is no safety advantage in administering a regimen of 4 g twice daily. As compliance is critical to the effectiveness of the treatment, a 4 g three times daily dose regimen may be more forgiving if the patient misses a dose. PMID- 24488377 TI - Mortality in a pediatric secondary-care hospital in post-conflict Liberia in 2009. AB - OBJECTIVE: To describe and analyze the causes of death in a pediatric secondary care hospital (run by Medecins sans Frontieres), in Monrovia, Liberia, 6 years post-civil war, to determine the quality of care and mortality in a setting with limited resources. METHODS: Data were retrospectively collected from March 2009 to October 2009. Patient charts and laboratory records were reviewed to verify cause of death. Additionally, charts of patients aged over 1 month with an infectious cause of death were analyzed for decompensated septic shock, or fluid refractory septic shock. RESULTS: Of 8,254 admitted pediatric patients, 531 died, with a mortality rate of 6.4%. Ninety percent of deaths occurred in children <5 years old. Most deaths occurred within 24 hours of admission. The main cause of death (76%) was infectious disease. Seventy-eight (23.6%) patients >1 month old with infectious disease met the criteria for septic shock, and 28 (8.6%) for decompensated or fluid-refractory septic shock. CONCLUSION: Since the end of Liberia's devastating civil war, Island Hospital has improved care and mortality outcomes, despite operating with limited resources. Based on the available data, mortality in Island Hospital appears to be lower than that of other Liberian and African institutions and similar to other hospitals run by Medecins sans Frontieres across Africa. This can be explained by the financial and logistic support of Medecins sans Frontieres. The highest mortality burden is related to infectious diseases and neonatal conditions. The mortality of sepsis varied among different infections. This suggests that further mortality reduction can be obtained by tackling sepsis management and improving neonatal care. PMID- 24488378 TI - Therapeutic touch: influence on vital signs of newborns. AB - OBJECTIVE: To compare vital signs before and after the therapeutic touch observed in hospitalized newborns in neonatal intensive care unit. METHODS: This was a quasi-experimental study performed at a neonatal intensive care unit of a municipal hospital, in the city of Sao Paulo (SP), Brazil. The sample included 40 newborns submitted to the therapeutic touch after a painful procedure. We evaluated the vital signs, such as heart and respiratory rates, temperature and pain intensity, before and after the therapeutic touch. RESULTS: The majority of newborns were male (n=28; 70%), pre-term (n=19; 52%) and born from vaginal delivery (n=27; 67%). Respiratory distress was the main reason for hospital admission (n=16; 40%). There was a drop in all vital signs after therapeutic touch, particularly in pain score, which had a considerable reduction in the mean values, from 3.37 (SD=1.31) to 0 (SD=0.0). All differences found were statistically significant by the Wilcoxon test (p<0.05). CONCLUSION: The results showed that therapeutic touch promotes relaxation of the baby, favoring reduction in vital signs and, consequently in the basal metabolism rate. PMID- 24488379 TI - Assessment of posture and joint movements of the upper limbs of patients after mastectomy and lymphadenectomy. AB - OBJECTIVE: To evaluate alterations in posture and range of motion of the upper limbs in women after mastectomy and lymphadenectomy, submitted to radiotherapy as adjuvant treatment. METHODS: Two groups were evaluated: 16 post-mastectomy women with lymphedema of the upper limb and 14 post-mastectomy women without lymphedema. Patients were submitted to analysis made by software, one for posture and the other to measure ranges of movement of the shoulder, elbow, and wrists. The results obtained were compared between the right and left sides, and operated and non-operated sides, and then were submitted to statistical tests. RESULTS: Both groups presented with anteriorization of the trunk. The women with lymphedema had head rotation to the right, protrusion of the left shoulder, and trunk inclination angle smaller on the operated side, besides bilateral elevation of the scapula when compared to the group with no lymphedema. Changes in range of motion were also smaller on the operated side in terms of flexion, abduction, and external rotation of the shoulder for all women, and for those with lymphedema, elbow extension and wrist flexion had a smaller range of motion. CONCLUSION: Women submitted to mastectomy presented with asymmetries and modifications in posture, and lymphedema seemed to worsen this condition. Additionally, they had deficits in range of motion in the shoulders on the operated side. Women with lymphedema also showed deficits in the elbows and wrist. PMID- 24488380 TI - Paullinia cupana for control of hot flashes in breast cancer patients: a pilot study. AB - OBJECTIVE: To evaluated whether Paullinia cupana decrease number and severity of hot flashes in breast cancer survivors. METHODS: This was a prospective phase II pilot study. We studied female breast cancer survivors who had completed the cancer treatment 3 months previously and who were experiencing at least 14 hot flashes per week. At least 9 of the 15 patients were required to have a decrease of at least 50% in hot flash severity score in keeping with the Simon Design. Patients received 50mg of dry extract of Paullinia cupana orally twice a day for 6 weeks. We assessed both frequency and severity of hot flashes. RESULTS: A total of 18 patients started the Paullinia cupana treatment, and 15 completed the study. Three patients left the study immediately after starting the treatment because of personal difficulties in participation or noncompliance. Of the 15 patients who completed the study 10 had a decrease of more than 50% in hot flash severity scores. During the 6 weeks of treatment, statistically significant decreases were seen in both numbers of hot flashes (p=0.0009) and severity scores (p<0.0001). Paullinia cupana was well tolerated, and there were no instances of discontinuation because of toxicity. CONCLUSIONS: Paullinia cupana appears promising for controlling hot flashes. More extensive studies seem warranted. PMID- 24488381 TI - Intraoperative radiotherapy as a protocol for the treatment of initial breast cancer. AB - OBJECTIVE: To report on preliminary outcomes of single-dose intraoperative radiotherapy for early-stage breast cancer based on local recurrence rates and complications. METHODS: Fifty postmenopausal women with <2.5cm breast tumors and clinically normal axillary lymph nodes were submitted to quadrantectomy, sentinel lymph node biopsy and intraoperative radiotherapy and studied. Mean follow-up time was 52.1 months. RESULTS: Mean patient age was 65.5 years; mean tumor diameter was 1.41cm 82% of nodules were hormonal receptor positive and HER-2 negative. All patients received a 21 Gy radiation dose for a mean time of 8.97 minutes. Distant metastases were not observed. Local recurrence was documented in three cases, with identical histological diagnosis as the primary tumors. Thirty five (70%) patients had local fibrosis, with gradual improvement and complete resolution over 18 months. Postoperative infection and seroma formation were not observed. CONCLUSION: Partial radiotherapy is a potentially feasible and promising technique. Careful patient selection is recommended before a longer follow-up period has elapsed to confirm intraoperative radiotherapy safety and efficacy. PMID- 24488382 TI - Neoadjuvant chemotherapy and pathologic response: a retrospective cohort. AB - OBJECTIVE: To evaluate the complete pathologic response attained by patients diagnosed with locally advanced breast cancer submitted to neoadjuvant chemotherapy based on the doxorubicin/cyclophosphamide regimen followed by paclitaxel. METHODS: A retrospective cohort of patients with locally advanced breast cancer, admitted to the Hospital de Cancer de Barretos between 2006 and 2008 submitted to the doxorubicin/cyclophosphamide protocol followed by paclitaxel (4 cycles of doxorubicin 60mg/m2 and cyclophosphamide 600mg/m2 every 21 days; 4 cycles of paclitaxel 175mg/m2 every 21 days). The following variables were assessed: age, menopause, performance status, initial clinical staging, anthropometric data, chemotherapy (dose - duration), toxicity profile, post treatment staging, surgery, pathologic complete response rate, disease-free survival, and pathological characteristics (type and histological degree, hormonal profile and lymph node involvement). Statistical analysis was performed using a 5% level of significance. RESULTS: Of the 434 patients evaluated, 136 were excluded due to error in staging or because they had received another type of chemotherapy. Median age was 50 years, all with performance status 0-1. Median initial clinical size of tumor was 65mm and the median final clinical size of the tumor was 22mm. Fifty-one (17.1%) patients experienced a pathologic complete response. Those with a negative hormonal profile or who were triple-negative (negative Her-2 and hormonal profile) experienced a favorable impact on the pathologic complete response. CONCLUSION: Neoadjuvant chemotherapy with doxorubicin/cyclophosphamide followed by paclitaxel provided a pathologic complete response in the population studied in accordance with that observed in the literature. Triple-negative patients had a greater chance of attaining this response. PMID- 24488383 TI - How important is the number of pelvic lymph node retrieved to locorregional staging of cervix cancer? AB - OBJECTIVE: To explore how important is the number of pelvic lymph nodes dissected for the nodal staging in FIGO IA2-IB2 cervical cancer, submitted to radical surgical treatment. METHODS: A cross-sectional study was carried out on patients who underwent Piver class II radical hysterectomy and pelvic lymphadenectomy, in two centers in the state of Pernambuco, from January, 2001 to December, 2008. The analysis of the area under the ROC curve was adopted as a summary-measure of discriminatory power of the number of nodes dissected in predicting the pelvic nodal status. Additionally, we also confirm our findings using logistic regression and the Fisher's exact test. RESULTS: The postoperative pathological study included 662 pelvic lymph nodes dissected (median per-patient=9, q25=6 - q75=13) from 69 patients. The ROC curve analysis revealed AUC=0.642, for the discriminatory value of the number of nodes dissected in predicting the pelvic nodal status. Similar findings were found after categorization using 10 and 15 lymph nodes as cut-offs (AUC=0.605 and 0.526, respectively). Logistic regression revealed odds ratio of 0.912 (95%CI=0.805-1.032; p=0.125) for the predictive value of the number of nodes dissected, and a number of nodes >=10 or >=15 lymph nodes was not significantly associated with the nodal status by the Fischer's exact test (p=0.224 and p=0.699, respectively). CONCLUSION: The number of pelvic lymph nodes dissected did not correlate with pelvic lymph node metastatic involvement. This study suggests that dissection of a greater number of lymph nodes does not increase locoregional nodal staging in cervical cancer. PMID- 24488384 TI - Immunoexpression of the COX-2, p53, and caspase-3 proteins in colorectal adenoma and non-neoplastic mucosa. AB - OBJECTIVE: To analyze the immunoexpression of the COX-2, p53, and caspase-3 proteins in colorectal adenomas and non-neoplastic mucosa. METHODS: 72 individuals were subjected to colonoscopy, which provided 50 samples of adenomas and 45 samples of non-neoplastic colorectal mucosa. The tissue samples were obtained via the tissue microarray technique and subjected to immunohistochemical analysis using primary anti-p53, anti-COX-2, and anti-caspase-3 antibodies. The positivity and intensity of the immunoreaction were classified. The analyzed variables were as follows: site of the adenomas in the colon, degree of dysplasia, size, and score of positivity and intensity of immunoexpression of the p-53, caspase-3, and COX-2 proteins. RESULTS: The immunoexpression of mutated protein p53 was positive in 30 (60%) adenoma samples and negative in 20 (40%) adenoma samples. The immunoexpression of mutated protein p53 was negative in 39 (86.6%) samples and positive in 6 (13.3%) samples of the non-neoplastic colorectal mucosa (p<0.0001). Significant differences were seen between both the largest size (p=0.006) and the highest degree of dysplasia (p<0.0001) of the adenomas and the intensity of immunoexpression of mutated protein p53. The positivity and intensity of immunoexpression of COX-2 (p=0.14) and caspase-3 (p=0.23) showed no significant differences between the adenomas and the non neoplastic colorectal mucosa. CONCLUSION: Mutated protein p53 was hyperexpressed in the adenomas compared with the non-neoplastic mucosa. Greater size and greater degree of dysplasia in the adenomas were associated with higher expression of mutated protein p53. The immunoexpression of COX-2 and caspase-3 in the adenomas did not exhibit a correlation with the anatomical-pathological features of the tumors and did not differ from the corresponding expression levels in the non neoplastic mucosa. PMID- 24488385 TI - Drug interaction in the emergency service. AB - OBJECTIVE: To identify the occurrence of potential drug interactions in prescriptions for adult patients admitted to the Emergency Department of Hospital Sao Paulo. METHODS: A cross-sectional and descriptive study. Its sample consisted of 200 medical prescriptions. The analysis of drug interactions was performed using the Drugs.com database, where they are classified according to severity of interaction as severe, moderate, mild and without interaction. RESULTS: The number of drugs in prescriptions ranged from 2 to 19, and the average per prescription was 4.97 drugs. A total of 526 potential drug interactions were identified in 159 prescriptions (79.5%); in that, 109 were severe, 354 moderate, 63 mild interactions, and 41 showed no interaction. CONCLUSION: This study demonstrated potential drug interactions in 79.5% of prescriptions examined in the Emergency Department. Drug interactions can occur at any time when using medications and, during this working process, the nursing staff is involved in several steps. Therefore, training the nursing staff for the rational use of drugs can increase safety of care delivered to patients. PMID- 24488386 TI - Adequacy of oxygenation parameters in elderly patients undergoing mechanical ventilation. AB - OBJECTIVE: To compare ideal PaO2 with PaO2 found, ideal PaO2/FiO2 of room air with the one found, and ideal FiO2 with FiO2 found in mechanically ventilated elderly patients. METHODS: Cross-sectional study that evaluated elderly mechanically ventilated patients for at least 72 hours and who underwent three subsequent blood gas analyses. RESULTS: The sample consisted of 48 elderly with mean age of 74.77+/-9.36 years. There was a significant difference between the ideal PaO2 and the one found (p<0.001), between FiO2 corrected and the offered one, and also between ideal PaO2/FiO2 of room air and the PaO2/FiO2 found (p<0,001). CONCLUSION: A significant increase was seen in PaO2 and FiO2 and in alterations of gas exchange by PaO2/FiO2 index than those found in normal parameters. PMID- 24488387 TI - Serum soluble-Fas is a predictor of red blood cell transfusion in critically ill patients. AB - OBJECTIVE: To investigate the relation between the need for red blood cell transfusion and serum levels of soluble-Fas, erythropoietin and inflammatory cytokines in critically ill patients with and without acute kidney injury. METHODS: We studied critically ill patients with acute kidney injury (n=30) and without acute kidney injury (n=13), end-stage renal disease patients on hemodialysis (n=25) and healthy subjects (n=21). Serum levels of soluble-Fas, erythropoietin, interleukin 6, interleukin 10, iron status, hemoglobin and hematocrit concentration were analyzed in all groups. The association between these variables in critically ill patients was investigated. RESULTS: Critically ill patients (acute kidney injury and non-acute kidney injury patients) had higher serum levels of erythropoietin than the other groups. Hemoglobin concentration was lower in the acute kidney injury patients than in other groups. Serum soluble-Fas levels were higher in acute kidney injury and end-stage renal disease patients. Critically ill patients requiring red blood cell transfusions had higher serum levels of soluble-Fas (5,906+/-2,047 and 1,920+/-1,060; p<0.001), interleukin 6 (518+/-537 and 255+502; p=0.02) and interleukin 10 (35.8+/-30.7 and 18.5+/-10.9; p=0.02), better iron status and higher mortality rates in the first 28 days in intensive care unit. Serum soluble-Fas levels were independently associated with the number of red blood cell units transfused (p=0.02). Serum soluble-Fas behaved as an independent predictor of the need for red blood cell transfusion in critically ill patients (p=0.01). CONCLUSIONS: Serum soluble-Fas level is an independent predictor of the need for red blood cell transfusion in critically ill patients with or without acute kidney injury. Further studies are warranted to reconfirm this finding. PMID- 24488388 TI - Medical awareness concerning primary immunodeficiency diseases in the city of Sao Paulo, Brazil. AB - OBJECTIVE: To evaluate medical knowledge of primary immunodeficiency in the city of Sao Paulo (SP). METHODS: A 14-item questionnaire about primary immunodeficiency was applied to physicians who worked at general hospitals. One of the questions presented 25 clinical situations that could be associated or not with primary immunodeficiency, and the percentage of appropriate answers generated a knowledge indicator. RESULTS: Seven hundred and forty-six participated in the study, among them 215 pediatricians (28.8%), 244 surgeons (32.7%), and 287 clinicians (38.5%). About 70% of the physicians responded that they had learned about primary immunodeficiency in graduate school or in residency training. Treatment of patients that use antibiotics frequently was reported by 75% dos physicians, but only 34.1% had already investigated a patient and 77.8% said they did not know the ten warning signs for primary immunodeficiency. The knowledge indicator obtained showed a mean of 45.72% (+/ 17.87). Only 26.6% if the pediatricians and 6.6% of clinicians and surgeons showed a knowledge indicator of at least 67% (equivalent to an appropriate answer in two thirds of the clinical situations). CONCLUSION: There is a deficit in medical knowledge of primary immunodeficiency in the city of Sao Paulo, even among pediatricians, despite having greater contact with the theme over the last few years. The improvement of information on primary immunodeficiency in the medical community is an important step towards the diagnosis and treatment process of these diseases. PMID- 24488389 TI - Excess weight in employees of food and nutrition units at a university in Sao Paulo State. AB - OBJECTIVE: To describe the prevalence and identify the factors associated with excess weight in restaurant employees at a public university in the city of Sao Paulo. METHODS: A socioeconomic and nutritional census was conducted with 174 individuals to obtain data on body mass, height, and socioeconomic status, using a structured questionnaire. The body mass index was determined, and the cut-off points recommended by the World Health Organization were used. Student's t test, Fisher's exact test, and the chi2 test were used to verify the differences between the means and prevalences. Poisson regression analyses with robust variance were performed, and the outcomes were excess weight or no excess weight. RESULTS: Most of the employees (57.5%) were women; 59.8% were non-white, 45.4% lived with a partner, 26.4% were smokers, and 50.6% were sedentary. There was a predominance of individuals with excess weight (60.9%), and most of them (64.0%) were women, non-white (66.3%), lived alone (58.8%), and were non-smokers (63.3%); furthermore, 62.8% of the subjects engaged in physical activities. There was a significant difference (p=0.03) regarding body mass index and gender, demonstrating more excess weight among the women. Excess weight was dependent on the age group and was more likely to occur in individuals over 50 years of age (adjusted prevalence ratio: 1.72; 95% confidence interval: 1.02 - 2.98). CONCLUSION: There was a high prevalence of excess weight in these professionals, indicating the necessity for interventions to control this important risk factor for chronic non-communicable diseases. PMID- 24488390 TI - Retention rates of infliximab and tocilizumab during a 3-year period in a Brazilian hospital. AB - OBJECTIVE: To compare the efficacy and the period of use of tocilizumab and infliximab during treatment of rheumatoid arthritis patients. METHODS: The period of use of two biologics with different mechanisms of action were compared in treatment of rheumatoid arthritis patients. RES ULTS: Both medications showed efficacy, but the period of use with no loss of efficacy was longer in patients receiving tocilizumab when compared to infliximab. CONCLUSION: Tocilizumab maintains a period of use significantly longer as compared with infliximab in patients with rheumatoid arthritis treated at a single organization. PMID- 24488391 TI - Comparison between subjective and objective methods to assess functional capacity during clinical treatment in patients with intermittent claudication. AB - OBJECTIVE: To analyze if there is any relation between functional capacity assessed by subjective and objective methods regarding the current state and after clinical treatment in patients with intermittent claudication. METHODS: A total of 500 patients with intermittent claudication were enrolled. All patients underwent clinical examination and a functional evaluation by subjective (clinical visit) and objective method (treadmill test). Additionally, 50 patients were selected to evaluate the effect of clinical treatment by subjective and objective methods in relation to functional capacity. RESULTS: Out of 500 patients, only 60 (12.0%) had similar results in both methods. The remaining, that is 440 patients (88.0%) had subject values in disagreement with stress test findings. Regarding the clinical effect of the treatment on the functional outcomes, results were similar in both methods (chi2=1.7; p=0.427). CONCLUSION: Although the subjective method overestimates the functional capacity when compared to the objective method, no significant differences were observed between both methods when analyzing the effect of clinical treatment. Thus, the subjective method provides similar information as compared with objective method, in monitoring the clinical treatment of patients with intermittent claudication. PMID- 24488392 TI - High correlation between microbubble contrast-enhanced ultrasound, magnetic resonance and histopathology in the evaluation of hepatocellular carcinoma. AB - OBJECTIVES: To evaluate the efficacy of microbubble contrast ultrasound in diagnosis of hepatocellular carcinoma and to compare its results with those of magnetic resonance and histopathology. METHODS: A total of 29 patients suffering from chronic liver diseases and awaiting liver transplants at Hospital Israelita Albert Einstein were subject to magnetic resonance, microbubble contrast ultrasound, and excision liver biopsies. RESULTS: Excellent agreement between magnetic resonance and microbubble contrast ultrasound was observed in this study. There was moderate agreement between both imaging methods and histopathology results. CONCLUSION: Microbubble contrast ultrasound was as accurate as magnetic resonance to evaluate hepatocellular carcinoma. These results were confirmed by comparing both methods to histopathological diagnosis. PMID- 24488393 TI - Academic profile, beliefs, and self-efficacy in research of clinical nurses: implications for the Nursing Research Program in a Magnet JourneyTM hospital. AB - OBJECTIVE: To describe the academic profile, research experience, beliefs, and self-efficacy in research of clinical nurses in a Magnet JourneyTM hospital. METHODS: Quantitative descriptive designed to assess research experience of clinical nurses. The survey was divided into demographics characteristics; scientific/academic profile (Nursing degree; membership in academic research groups, involvement in papers, teaching activities, scientific conferences, and posters presented); beliefs related to nursing research (about skills, benefits to career, reputation of institution, patient care; job satisfaction level); and Research Self-Efficacy (conducting literature review; evaluating quality of studies; using theory; understanding evidence; and scientific writing: putting ideas on paper easily; recognize and adapt the text to the reader; write to the standards required by science; write with objectivity, logical sequence, coherence, simplicity, clarity, and precision; insert the references in the text correctly; write the references appropriately; use correct spelling and grammar; write texts in English). RESULTS: Most clinical nurses had low research experience, yet had positive beliefs in and perception of well-developed research skills. CONCLUSION: Our findings should contribute to the preparation of research programs aimed at facilitating the engagement of clinical nurses in the development of scientific projects. PMID- 24488394 TI - Expenses related to hospital admissions for the elderly in Brazil: perspectives of a decade. AB - OBJECTIVE: To describe the profile of morbidities and expenses related to hospitalization of the elderly compared to the adult population (20 to 59 years). METHODS: A descriptive, cross-sectional investigation of hospitalizations of the elderly (60 years or older) in Brazil during the period from 2002 to 2011, with data from DATASUS and based on ICD-10. RESULTS: Although the highest number of hospitalizations were in the adult age range, the expenses were greater with the elderly, and in this case especially with mental and behavioral disorders, musculoskeletal and connective tissue diseases, followed by circulatory diseases and external causes. CONCLUSION: The results suggest the adoption of more comprehensive policies and increased investment in health promotion, disease prevention, and appropriate and suitable treatment for the most prevalent diseases in the elderly, particularly in primary care. PMID- 24488395 TI - Meningitis due to Haemophilus influenzae type f. AB - With the decline in the rate of infections caused by Haemophilus influenzae serotype b since the widespread vaccination, non-b serotypes should be considered as potential pathogenic agents in children with invasive disease younger than 5 years old. We report the case of an immunocompetent 1-year-old boy with Haemophilus influenzae type f meningitis. The agent was identified in cerebrospinal fluid and blood cultures. Serotyping was performed by tests using polyclonal sera and confirmed by polymerase chain reaction. All Haemophilus influenzae isolates associated with invasive disease should be serotyped and notified as a way to evaluate the changes and trends in serotype distribution of this disease. PMID- 24488396 TI - Minimally invasive treatment of hepatic adenoma in special cases. AB - Hepatocellular adenoma is a rare benign tumor that was increasingly diagnosed in the 1980s and 1990s. This increase has been attributed to the widespread use of oral hormonal contraceptives and the broader availability and advances of radiological tests. We report two cases of patients with large hepatic adenomas who were subjected to minimally invasive treatment using arterial embolization. One case underwent elective embolization due to the presence of multiple adenomas and recent bleeding in one of the nodules. The second case was a victim of blunt abdominal trauma with rupture of a hepatic adenoma and clinical signs of hemodynamic shock secondary to intra-abdominal hemorrhage, which required urgent treatment. The development of minimally invasive locoregional treatments, such as arterial embolization, introduced novel approaches for the treatment of individuals with hepatic adenoma. The mortality rate of emergency resection of ruptured hepatic adenomas varies from 5 to 10%, but this rate decreases to 1% when resection is elective. Arterial embolization of hepatic adenomas in the presence of bleeding is a subject of debate. This observation suggests a role for transarterial embolization in the treatment of ruptured and non-ruptured adenomas, which might reduce the indication for surgery in selected cases and decrease morbidity and mortality. Magnetic resonance imaging showed a reduction of the embolized lesions and significant avascular component 30 days after treatment in the two cases in this report. No novel lesions were observed, and a reduction in the embolized lesions was demonstrated upon radiological assessment at a 12-month follow-up examination. PMID- 24488397 TI - Iron overload in a teenager with xerocytosis: the importance of nuclear magnetic resonance imaging. AB - To report a case of iron overload secondary to xerocytosis, a rare disease in a teenager, diagnosed, by T2* magnetic resonance imaging. We report the case of a symptomatic patient with xerocytosis, a ferritin level of 350ng/mL and a significant cardiac iron overload. She was diagnosed by T2* magnetic resonance imaging and received chelation therapy Ektacytometric analysis confirmed the diagnosis of hereditary xerocytosis. Subsequent T2* magnetic resonance imaging demonstrated complete resolution of the iron overload in various organs, as a new echocardiography revealed a complete resolution of previous cardiac alterations. The patient remains in chelation therapy. Xerocytosis is a rare autosomal dominant genetic disorder characterized by dehydrated stomatocytosis. The patient may present with intense fatigue and iron overload. We suggest the regular use of T2* magnetic resonance imaging for the diagnosis and control of the response to iron chelation in xerocytosis, and we believe it can be used also in other hemolytic anemia requiring transfusions. PMID- 24488398 TI - Opsoclonus-myoclonus-ataxia syndrome in an AIDS patient. AB - We report the case of a 38-year-old woman with AIDS who developed opsoclonus myoclonus-ataxia syndrome during a period different from other cases reported in literature. Opsoclonus-myoclonus-ataxia syndrome had already been reported as the initial neurological presentation of AIDS, as well as at the time of HIV seroconversion and immune reconstitution syndrome. Our case is unique since the patient had an elevated CD4 count and negative viral load in the period when the opsoclonus-myoclonus-ataxia syndrome occurred. PMID- 24488399 TI - Swallowing sounds in speech therapy practice: a critical analysis of the literature. AB - This study aimed to investigate international scientific papers published on the subject of cervical auscultation and its use in speech therapy. The study involved a qualitative review of the literature spanning the last 10 years. Articles were selected from the PubMed database using the following keywords: cervical auscultation, swallowing and swallowing disorders. Research was included that was conducted on adult humans (over 18 years of age) and was written in English. Each citation retrieved from the database was analyzed independently by each of the study researchers to ascertain its relevance for inclusion in the study. The methodology involved formulating the research question, locating and selecting studies and critically evaluating the articles according to the precepts of the Cochrane Handbook. As a result, 35 studies were identified; 13 articles were analyzed because they allowed access to the full text and were related directly to the subject. We found that the studies were performed with groups of healthy subjects and subjects with different types of base pathology. Some studies compared the patterns found in the different groups. Some of the research sought to study the pattern of swallowing sounds with different factors evaluator experience, the specificity and sensitivity of the method and how to improve the technique of cervical auscultation through the use of instruments other than the stethoscope. The conclusion of this critical analysis is that cervical auscultation is an important tool to be used in conjunction with other assessment methods in the routine clinical evaluation of swallowing. PMID- 24488400 TI - Apoptosis deregulation in myeloproliferative neoplasms. AB - Philadelphia-chromosome negative chronic myeloproliferative neoplasms are clonal hematologic diseases characterized by hematopoietic progenitor independence from or hypersensitivity to cytokines. The cellular and molecular mechanisms involved in the pathophysiology of myeloproliferative neoplasms have not yet been fully clarified. Pathophysiologic findings relevant for myeloproliferative neoplasms are associated with genetic alterations, such as, somatic mutation in the gene that codifies JAK-2 (JAK V617F). Deregulation of the process of programmed cellular death, called apoptosis, seems to participate in the pathogenesis of these disorders. It is known that expression deregulation of pro- and anti apoptotic genes promotes cell resistance to apoptosis, culminating with the accumulation of myeloid cells and establishing neoplasms. This review will focus on the alterations in apoptosis regulation in myeloproliferative neoplasms, and the importance of a better understanding of this mechanism for the development of new therapies for these diseases. PMID- 24488401 TI - Disseminated fusariosis with endophthalmitis in a patient with hematologic malignancy. PMID- 24488402 TI - Vaccination against human papillomavirus. AB - Human papillomavirus infection is common and causes different manifestations. This infection is a public health concern because it has been associated with genital tract malignant diseases among men and women. Currently two vaccines are available to prevent the human papillomavirus infection and its associated diseases. PMID- 24488403 TI - Health information system. PMID- 24488404 TI - Mefloquine and psychotomimetics share neurotransmitter receptor and transporter interactions in vitro. AB - RATIONALE: Mefloquine is used for the prevention and treatment of chloroquine resistant malaria, but its use is associated with nightmares, hallucinations, and exacerbation of symptoms of post-traumatic stress disorder. We hypothesized that potential mechanisms of action for the adverse psychotropic effects of mefloquine resemble those of other known psychotomimetics. OBJECTIVES: Using in vitro radioligand binding and functional assays, we examined the interaction of (+)- and (-)-mefloquine enantiomers, the non-psychotomimetic anti-malarial agent, chloroquine, and several hallucinogens and psychostimulants with recombinant human neurotransmitter receptors and transporters. RESULTS: Hallucinogens and mefloquine bound stereoselectively and with relatively high affinity (K i = 0.71 341 nM) to serotonin (5-HT) 2A but not 5-HT1A or 5-HT2C receptors. Mefloquine but not chloroquine was a partial 5-HT2A agonist and a full 5-HT2C agonist, stimulating inositol phosphate accumulation, with similar potency and efficacy as the hallucinogen dimethyltryptamine (DMT). 5-HT receptor antagonists blocked mefloquine's effects. Mefloquine had low or no affinity for dopamine D1, D2, D3, and D4.4 receptors, or dopamine and norepinephrine transporters. However, mefloquine was a very low potency antagonist at the D3 receptor and mefloquine but not chloroquine or hallucinogens blocked [(3)H]5-HT uptake by the 5-HT transporter. CONCLUSIONS: Mefloquine, but not chloroquine, shares an in vitro receptor interaction profile with some hallucinogens and this neurochemistry may be relevant to the adverse neuropsychiatric effects associated with mefloquine use by a small percentage of patients. Additionally, evaluating interactions with this panel of receptors and transporters may be useful for characterizing effects of other psychotropic drugs and for avoiding psychotomimetic effects for new pharmacotherapies, including antimalarial quinolines. PMID- 24488405 TI - Antidepressant activity of the adenosine A2A receptor antagonist, istradefylline (KW-6002) on learned helplessness in rats. AB - RATIONALE: Istradefylline, an adenosine A2A receptor antagonist, improves motor function in animal models of Parkinson's disease (PD) and in patients with PD. In addition, some A2A antagonists exert antidepressant-like activity in rodent models of depression, such as the forced swim and the tail suspension tests. OBJECTIVE: We have investigated the effect of istradefylline on depression-like behaviors using the rat learned helplessness (LH) model. RESULTS: Acute, as well as chronic, oral administration of istradefylline significantly improved the inescapable shock (IES)-induced escape deficit with a degree of efficacy comparable to chronic treatment with the tricyclic antidepressant desipramine and the selective serotonin (5-HT) reuptake inhibitor, fluoxetine. Both the A1/A2A receptor nonspecific antagonist theophylline and the moderately selective antagonist CGS15943, but not the A1 selective antagonist DPCPX, ameliorated the IES-induced escape deficit. The enhancement of escape response by istradefylline was reversed by a local injection of the A2A specific agonist CGS21680 either into the nucleus accumbens, the caudate-putamen, or the paraventricular nucleus of the hypothalamus, but not by the A1 specific agonist R-PIA into the nucleus accumbens. Moreover, neither the 5-HT2A/2C receptor antagonist methysergide or the adrenergic alpha 2 antagonist yohimbine, nor the beta-adrenergic antagonist propranolol, affected the improvement of escape response induced by istradefylline. CONCLUSIONS: Istradefylline exerts antidepressant-like effects via modulation of A2A receptor activity which is independent of monoaminergic transmission in the brain. Istradefylline may represent a novel treatment option for depression in PD as well as for the motor symptoms. PMID- 24488406 TI - On-the-road driving performance and driving-related skills in older untreated insomnia patients and chronic users of hypnotics. AB - RATIONALE: Many older adults report sleep problems and use of hypnotics. Several studies have shown that hypnotics can have acute adverse effects on driving the next morning. It is unclear however whether driving of chronic hypnotic users is impaired. Therapeutic effects on insomnia and development of tolerance may reduce the residual effects on driving. OBJECTIVES: The present study aimed to compare actual driving performance and driving-related skills of chronic hypnotic users to good sleepers. To determine whether insomnia itself affects driving performance, driving and driving-related skills were compared between insomnia patients who do not or infrequently use hypnotics and good sleepers. METHODS: Twenty-two frequent users of hypnotics (using hypnotics >= 4 nights per week for more than 3 months), 20 infrequent users (using hypnotics <= 3 nights per week), and 21 healthy, age-matched controls participated in this study. On the night before testing, all subjects were hospitalized for an 8-h sleep recorded by polysomnography. Frequent hypnotic users used their regular medication at bedtime (2330 hours), while infrequent users and controls received no medication. Cognitive performance (word learning, digit span, tracking, divided attention, vigilance, and inhibitory control) was assessed 8.5 h and driving performance between 10 and 11 h after bedtime and dosing. RESULTS: Polysomnographic recordings did not significantly differ between the groups, but the insomnia patients, treated or untreated, still reported subjective sleep complaints. Results show no differences in driving performance and driving-related skills between both groups of insomnia patients and controls. CONCLUSIONS: Driving performance in chronic users of hypnotics and untreated insomnia patients is not impaired. For chronic users, this may be due to prescription of relatively safe drugs and low doses. For untreated insomniacs, this corroborates previous findings showing an absence of neuropsychological deficits in this group of patients. PMID- 24488408 TI - Pointing the wrong way? A subtle finding on cervical plain films. PMID- 24488409 TI - I can't believe it's not retrobulbar.... PMID- 24488407 TI - alpha2-Adrenoceptors are targets for antipsychotic drugs. AB - RATIONALE: Almost all antipsychotic drugs (APDs), irrespective of whether they belong to the first-generation (e.g. haloperidol) or second-generation (e.g. clozapine), are dopamine D2 receptor antagonists. Second-generation APDs, which differ from first-generation APDs in possessing a lower propensity to induce extrapyramidal side effects, target a variety of monoamine receptors such as serotonin (5-hydroxytryptamine) receptors (e.g. 5-HT1A, 5-HT2A, 5-HT2C, 5-HT6, 5 HT7) and alpha1- and alpha2-adrenoceptors in addition to their antagonist effects at D2 receptors. OBJECTIVE: This short review is focussed on the potential role of alpha2-adrenoceptors in the antipsychotic therapy. RESULTS: Schizophrenia is characterised by three categories of symptoms: positive symptoms, negative symptoms and cognitive deficits. alpha2-Adrenoceptors are classified into three distinct subtypes in mammals, alpha2A, alpha2B and alpha2C. Whereas the alpha2B adrenoceptor seems to play only a minor role in the brain, activation of postsynaptic alpha2A-adrenoceptors in the prefrontal cortex improves cognitive functions. Preclinical models such as D-amphetamine-induced locomotion, the conditioned avoidance response and the pharmacological N-methyl-D-aspartate receptor hypofunction model have shown that alpha2C-adrenoceptor blockade or the combination of D2 receptor antagonists with idazoxan (alpha2A/2C-adrenoceptor antagonist) could be useful in schizophrenia. A potential benefit of a treatment combination of first-generation APDs with the alpha2A/2C-adrenoceptor antagonists idazoxan or mirtazapine was also demonstrated in patients with schizophrenia. CONCLUSIONS: It is concluded that alpha2-adrenoceptors may be promising targets in the antipsychotic therapy. PMID- 24488410 TI - Identification of a gonad-expression differential gene insulin-like growth factor 1 receptor (Igf1r) in the swamp eel (Monopterus albus). AB - In vertebrate species, the biopotential embryonic gonad differentiation is affected by many key genes and key steroidogenic enzymes. Insulin-like growth factor-1 receptor (Igf1r) has been considered as an important sex-differentiation gene in mammals and could mediate the biological action of Igf1, an important regulator of key steroidogenic enzymes. However, Igf1r gene is still unknown in the swamp eel, an economically important fish. In our study, we identified Igf1r gene in the swamp eel, which was a 2,148-bp open-reading frame encoding a protein of 716 amino acids. The alignment and the phylogenetic tree showed that Igf1r of the swamp eel had a conservative sequence with other vertebrates, especial fishes. Western blotting of Igf1r showed that Igf1r expressed much more in ovotestis and testis than in ovary, indicating an important role of Igf1r during gonad differentiation. We analyzed ubiquitination of Igf1r by co immunoprecipitation and found the amount of ubiquitinated Igf1r was increased from ovary, ovotestis to testis, which was reversely to the trend of Hsp10 expression during gonadal transformation. It was possible that Hsp10 could suppress Igf1r ubiquitination during gonadal development of the swamp eel. PMID- 24488411 TI - Patients with systemic sclerosis present increased DNA damage differentially associated with DNA repair gene polymorphisms. AB - OBJECTIVE: Patients with systemic sclerosis (SSc) exhibit increased toxicity when exposed to genotoxic agents. In our study, we evaluated DNA damage and polymorphic sites in 2 DNA repair genes (XRCC1 Arg399Gln and XRCC4 Ile401Thr) in patients with SSc. METHODS: A total of 177 patients were studied for DNA repair gene polymorphisms. Fifty-six of them were also evaluated for DNA damage in peripheral blood cells using the comet assay. RESULTS: Compared to controls, the patients as a whole or stratified into major clinical variants (limited or diffuse skin involvement), irrespective of the underlying treatment schedule, exhibited increased DNA damage. XRCC1 (rs: 25487) and XRCC4 (rs: 28360135) allele and genotype frequencies observed in patients with SSc were not significantly different from those observed in controls; however, the XRCC1 Arg399Gln allele was associated with increased DNA damage only in healthy controls and the XRCC4 Ile401Thr allele was associated with increased DNA damage in both patients and controls. Further, the XRCC1 Arg399Gln allele was associated with the presence of antinuclear antibody and anticentromere antibody. No association was observed between these DNA repair gene polymorphic sites and clinical features of patients with SSc. CONCLUSION: These results corroborate the presence of genomic instability in SSc peripheral blood cells, as evaluated by increased DNA damage, and show that polymorphic sites of the XRCC1 and XRCC4 DNA repair genes may differentially influence DNA damage and the development of autoantibodies. PMID- 24488413 TI - Independent relationship of osteoprotegerin concentrations with endothelial activation and carotid atherosclerosis in patients with severe rheumatoid arthritis. AB - OBJECTIVE: Osteoprotegerin (OPG) may contribute to the link between systemic inflammation and increased cardiovascular risk. We investigated the relationship of OPG concentrations with endothelial activation and carotid atherosclerosis in rheumatoid arthritis (RA). METHODS: OPG concentrations and those of endothelial activation molecules were measured by using ELISA in 34 patients who were treated with infliximab (IFX), both immediately before and after an IFX infusion. Carotid intima-media thickness (CIMT) and plaque were determined by ultrasound in 27 of the study participants. RESULTS: Median (interquartile range) OPG concentrations decreased from 4.8 pmol/l (2.8-6.5) to 4.4 pmol/l (2.9-6.1; p = 0.04) upon IFX infusion. Baseline OPG concentrations were inversely associated with those of total and low-density lipoprotein (LDL) cholesterol (partial R = -0.50, p = 0.004, and R = -0.48, p = 0.007, respectively). Prior to IFX administration, OPG concentrations were associated with those of intercellular adhesion molecule (ICAM)-1 (partial R = 0.34, p = 0.05), CIMT (partial R = 0.51 to 0.52, p < 0.009), and plaque (OR = 1.52, 95% CI 1.01-2.29 to OR = 1.61, 95% CI 1.03-2.51; p < 0.04), independent of conventional risk factors and C-reactive protein concentrations or disease activity. Except for the OPG concentrations-plaque association (p = 0.09), these relationships remained significant subsequent to IFX administration (p < 0.05). Reductions in OPG levels related to those in vascular cell adhesion molecule (VCAM)-1 concentrations (partial R = 0.35, p = 0.04) and had borderline significance (p = 0.09) with those in ICAM-1 (partial R = 0.29) concentrations. CONCLUSION: OPG concentrations are independently associated with endothelial activation and carotid atherosclerosis in RA. Reductions in OPG concentrations upon IFX administration are associated with decreased endothelial activation. OPG may be involved in increased cardiovascular disease risk and may improve its stratification in patients with RA. PMID- 24488414 TI - Is the MAdrid Sonographic Enthesitis Index useful for differentiating psoriatic arthritis from psoriasis alone and healthy controls? AB - OBJECTIVE: To assess the usefulness of the MAdrid Sonographic Enthesitis Index (MASEI) in classifying patients as having psoriatic arthritis (PsA) and comparing entheseal abnormalities between patients with PsA, psoriasis alone (PsC), and healthy controls (HC). METHODS: Patients with PsC were assessed to exclude inflammatory arthritis. The MASEI scoring system was used to quantify the extent of ultrasonographic (US) entheseal abnormalities. The total MASEI score was categorized into items that reflected inflammatory abnormalities (MASEI inflammatory) and chronic damage (MASEI-damage). Nonparametric tests were used to compare MASEI scores across the groups. A cutoff point of MASEI >= 20 was used to calculate the sensitivity and specificity of the MASEI to classify patients as having PsA. RESULTS: Patients with PsA (n = 50), PsC (n = 66), and HC (n = 60) were assessed. Total MASEI scores were higher in patients with PsA than in those with PsC, and both those groups were higher than HC (p < 0.0001). MASEI inflammatory showed a similar trend (p < 0.0001). MASEI-damage was higher in patients with PsA compared to both patients with PsC and HC (p < 0.0001); however, no difference was observed between patients with PsC and HC. No significant difference in MASEI scores was found across the 3 groups in patients with a body mass index > 30. The sensitivity of the MASEI score to correctly classify patients as having PsA was 30% and the specificity was 95% when compared to HC and 89% when compared to PsC. CONCLUSION: The severity of US entheseal abnormalities is highest in patients with PsA followed by PsC and is lowest in healthy controls. MASEI can specifically classify patients as having PsA. PMID- 24488415 TI - Ultrasound of synovitis in rheumatoid arthritis: advantages of the dorsal over the palmar approach to finger joints. AB - OBJECTIVE: To compare the dorsal and palmar ultrasound (US) examination of finger joints in early rheumatoid arthritis (RA) with regard to the concurrence of greyscale (GSUS) and power Doppler (PDUS) positivity, and to correlate both approaches with clinical variables. METHODS: Patients with newly diagnosed RA were assessed by clinical examination and US. GSUS and PDUS of metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints were performed using the dorsal and palmar approach. Findings of synovitis in GSUS and PDUS were graded semiquantitatively from 0 to 3. Clinical and sonographic reevaluation was performed after 6 months. RESULTS: With 44.6% versus 32.2% positive findings, palmar GSUS identified significantly more joints with synovitis than did dorsal GSUS. With 22.1% versus 8.9%, PDUS abnormalities were detected significantly more often from the dorsal side. With 71.2% versus 21.8% for the MCP and 57.5% versus 17.4% for the PIP joints, significantly more GSUS and PDUS double-positive joints were found with the dorsal as opposed to the palmar approach. These differences remained significant at Month 6. Both palmar and dorsal GSUS and PDUS correlated with comparable strength with clinical variables such as the Disease Activity Score 28, Clinical Disease Activity Index, and Simple Disease Activity Index. CONCLUSION: Although the dorsal approach detected fewer GSUS findings than the palmar approach, PDUS signals were significantly more frequently detected by dorsal US. In addition, the prevalence of double-positive joints with concurrent GSUS and PDUS findings was significantly higher with the dorsal approach. These data argue in favor of the dorsal US approach to finger joints in RA. PMID- 24488416 TI - Blood monocyte heterogeneity and markers of endothelial activation in ankylosing spondylitis. AB - OBJECTIVE: Ankylosing spondylitis (AS) is associated with excessive cardiovascular (CV) morbidity. Interactions between activated endothelium and monocytes precede atherosclerotic plaques. Our aim was to quantify blood monocyte subsets in relation to endothelial activation and inflammatory activity in subjects with AS who were free of clinical atherosclerotic CV disease. METHODS: Markers of inflammation and endothelial activation were measured in 47 patients with AS receiving no disease-modifying antirheumatic drugs, and 22 healthy controls. Exclusion criteria included atherosclerotic CV disease and traditional risk factors. Flow cytometry was used to identify monocyte subsets: classical CD14(++)CD16(-), intermediate CD14(++)CD16(+), and nonclassical CD14(+)CD16(++) monocytes and to evaluate their expression of CD11b and CD11c. RESULTS: Traditional risk factors were comparable among the groups, except for lower high density lipoprotein cholesterol in AS (p = 0.007). Relative to controls, in subjects with AS counts of classical monocytes were higher (84.3 +/- 5.4 vs 78.9 +/- 5.3% of blood monocytes, p < 0.001) and nonclassical monocytes lower (2.9 +/- 2.2 vs 5.5 +/- 2.3%, p < 0.001). In AS we observed increased soluble intercellular adhesion molecule-1 [251 (224-293) vs 202 (187-230) ng/ml, p = 0.002], an endothelial ligand for monocytic beta2-integrin CD11b/CD18. CD11b expression on all 3 monocyte subsets was elevated in 21 AS subjects with a Bath Ankylosing Spondylitis Disease Activity Index score >= 4 versus the remaining patients (p = 0.005-0.03). C-reactive protein, interleukin 6 (IL-6), and pentraxin-3 were increased in AS, in contrast to tumor necrosis factor-alpha and IL-18. IL-6 correlated with classical monocytes numbers in AS (r = 0.56, p < 0.0001) but not in the controls (r = 0.10, p = 0.65). CONCLUSION: Our findings suggest a contribution of immune dysregulation to enhanced monocyte-endothelial interactions in AS, especially in patients with active disease, which possibly can accelerate atherogenesis on a longterm basis. PMID- 24488417 TI - Patient perceptions of osteoporosis treatment thresholds. AB - OBJECTIVE: Many older patients express concerns about medication risks, and have higher risk thresholds than physicians for cardiovascular preventive medications. We hypothesized that patients have relatively high risk thresholds for fracture preventive medications. METHODS: Women >= 60 years old were recruited from 3 primary care internal medicine clinics in Wisconsin. Participants were provided information regarding fracture risks and treatment risks and benefits, followed by a series of vignettes depicting a 70-year-old woman at baseline fracture risks between 5-50%. Fracture risks were shown graphically and treatment side effects were provided for each vignette, and participants were asked to respond regarding whether they would accept treatment. The association of vignette treatment acceptance with participant beliefs regarding medication risks was examined in analyses adjusted for perceived risk of medications, patient numeracy, and prior respondent experience with osteoporosis. RESULTS: The mean age of women in the cohort was 69.4 years (SD 7.29). Ninety-one percent were non-Hispanic whites, 34% reported a history of fracture, and 20.3% a history of osteoporosis. Subjects varied substantially in their responses to vignettes, but only 51% reported they would accept prescription osteoporosis treatment at the threshold currently recommended by national physician treatment guidelines, and fewer would accept treatment at lower risks. Belief that medications are generally not worth their risks was associated with lower acceptance of treatment at all levels of fracture risk. CONCLUSION: There is substantial variability in preferences for postmenopausal osteoporosis treatment. Presentation of individualized fracture risks as recommended by current guidelines has potential to allow better targeting to higher-risk patients, but further work is needed regarding how to present this information and counsel patients. PMID- 24488412 TI - Reconciling healthcare professional and patient perspectives in the development of disease activity and response criteria in connective tissue disease-related interstitial lung diseases. AB - Interstitial lung diseases (ILD), including those related to connective tissue disease (CTD), and idiopathic pulmonary fibrosis (IPF) carry high morbidity and mortality. Great efforts are under way to develop and investigate meaningful treatments in the context of clinical trials. However, efforts have been challenged by a lack of validated outcome measures and by inconsistent use of measures in clinical trials. Lack of consensus has fragmented effective use of strategies in CTD-ILD and IPF, with a history of resultant difficulties in obtaining agency approval of treatment interventions. Until recently, the patient perspective to determine domains and outcome measures in CTD-ILD and IPF had never been applied. Efforts described here demonstrate unequivocally the value and influence of patient involvement on core set development. Regarding CTD-ILD, this is the first OMERACT working group to directly address a manifestation/comorbidity of a rheumatic disease (ILD) as well as a disease not considered rheumatic (IPF). The OMERACT 11 proceedings of the CTD-ILD Working Group describe the forward and lateral process to include both the medical and patient perspectives in the urgently needed identification of a core set of preliminary domains and outcome measures in CTD-ILD and IPF. PMID- 24488420 TI - Development of a disease activity and responder index for psoriatic arthritis- report of the Psoriatic Arthritis Module at OMERACT 11. AB - This module reflected work within the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) to develop and validate composite disease activity measures in psoriatic arthritis (PsA). At the Outcome Measures in Rheumatology (OMERACT) 8 Meeting, a core set of domains to be assessed in randomized controlled trials (RCT) and longitudinal observational studies of PsA was agreed upon. At OMERACT 10, 5 proposed composite responder definitions for PsA were reviewed and discussed, including new data from the GRACE (GRAppa Composite Exercise) study. At OMERACT 11, ongoing retrospective analyses of RCT data using the 3 proposed measures (Composite Psoriatic Disease Activity Index, Psoriatic Arthritis Disease Activity Score, and Arithmetic Mean of the Desirability Function) were discussed in detail. There was agreement that developing composite outcome measures for use in RCT and longitudinal observational studies in PsA was important. Concerns were expressed regarding development of a single measure that encompassed diverse domains, such as joint counts, quality of life (QOL), and disability measures. It was emphasized that the use of any composite measure should include the ability to differentiate between activity in individual domains, such as enthesitis or psoriasis, such that the effect of each could be assessed independently. It was also agreed that patients would be systematically involved in further development and refinement of composite measures. Future plans include qualitative work with patients to explore their experience of disease activity and statistical modeling to explore how each of the proposed measures will perform in different disease subgroups. PMID- 24488419 TI - National trends in pediatric systemic lupus erythematosus hospitalization in the United States: 2000-2009. AB - OBJECTIVE: In the setting of recent healthcare advances and emphasis on reduced spending, we aimed to characterize US trends in inpatient healthcare use and mortality for pediatric systemic lupus erythematosus (SLE). METHODS: We performed a retrospective, serial, cross-sectional analysis of the national Kids' Inpatient Database (for 2000, 2003, 2006, and 2009). We identified patients with SLE aged 2 to 21 years using an International Classification of Diseases, 9th revision (ICD 9) code of 710.0 listed as a discharge diagnosis. Using sampling weights, we estimated trends in hospitalization, inpatient mortality, procedure rates, and length of stay (LOS). We analyzed patient and hospital-specific risk factors for mortality and LOS, and compared those outcomes to those without SLE. RESULTS: We identified 26,903 estimated pediatric SLE hospitalizations. The hospitalization rate of 8.6 (95% CI 7.6-9.6) per 100,000 population and mean LOS of 5.9 days (95% CI 5.6-6.2) were stable over time. We found a significant downward trend in mortality, decreasing from 1% to 0.6% (p = 0.04), which paralleled a less pronounced trend for those without SLE. The rate of dialysis, blood transfusions, and vascular catheterization procedures increased. Patients with SLE nephritis and non-white race were at risk for increased healthcare use and death. CONCLUSION: Pediatric SLE hospitalization rate and LOS remained stable, but inpatient mortality decreased as the rate of common therapeutic procedures increased. More research is needed to understand the drivers of these relationships. PMID- 24488421 TI - Limitations in the classification of childhood-onset rheumatoid arthritis. AB - OBJECTIVE: Rheumatoid factor-positive polyarthritis (RF+ poly) is the juvenile idiopathic arthritis (JIA) category that resembles adult seropositive rheumatoid arthritis (RA). We studied children with RF+ and/or anticyclic citrullinated peptide antibody (anti-CCP)+ JIA to determine what proportion of those children meet International League of Associations for Rheumatology (ILAR) criteria for RF+ poly JIA and to assess for significant differences between children who meet RF+ poly criteria and those who are classified in other categories. METHODS: Charts of children with JIA who were RF+ and/or anti-CCP+ were reviewed. Children with RF+ poly JIA were compared to children in other categories. Statistical analysis was performed using chi-square, Fisher's exact test, and the Student's t test. RESULTS: Of 56 children with RF+ and/or anti-CCP+ JIA, 34 (61%) met ILAR criteria for RF+ poly JIA. Twelve children had RF-/anti-CCP+ JIA with low anti CCP titers. When these 12 children were excluded, there were few significant differences between children who met criteria for RF+ poly and those who were classified in other categories. The American College of Rheumatology/European League Against Rheumatism criteria for RA identified more RF+ children than did the ILAR RF+ poly classification (100% vs 77%). CONCLUSION: A number of children with RF+ arthritis were excluded from the RF+ poly JIA classification, though many demographic features and disease measures were similar to those of children who met criteria for RF+ poly JIA. We propose prioritization of RF/anti-CCP positivity over specific exclusions, along with inclusion of anti-CCP, in future revisions of the JIA classification criteria, to improve the sensitivity of diagnosing childhood-onset RA. PMID- 24488422 TI - Polymyalgia Rheumatica (PMR) Special Interest Group at OMERACT 11: outcomes of importance for patients with PMR. AB - We worked toward developing a core outcome set for clinical research studies in polymyalgia rheumatica (PMR) by conducting (1) patient consultations using modified nominal group technique; (2) a systematic literature review of outcome measures in PMR; (3) a pilot observational study of patients presenting with untreated PMR, and further discussion with patient research partners; and (4) a qualitative focus group study of patients with PMR on the meaning of stiffness, using thematic analysis. (1) Consultations included 104 patients at 4 centers. Symptoms of PMR included pain, stiffness, fatigue, and sleep disturbance. Function, anxiety, and depression were also often mentioned. Participants expressed concerns about diagnostic delay, adverse effects of glucocorticoids, and fear of relapse. (2) In the systematic review, outcome measures previously used for PMR include pain visual analog scores (VAS), morning stiffness, blood markers, function, and quality of life; standardized effect sizes posttreatment were large. (3) Findings from the observational study indicated that asking about symptom severity at 7 AM, or "on waking," appeared more relevant to disease activity than asking about symptom severity "now" (which depended on the time of assessment). (4) Preliminary results were presented from the focus group qualitative study, encompassing broad themes of stiffness, pain, and the effect of PMR on patients' lives. It was concluded that further validation work is required before a core outcome set in PMR can be recommended. Nevertheless, the large standardized effect sizes suggest that pain VAS is likely to be satisfactory as a primary outcome measure for assessing response to initial therapy of PMR. Dissection of between-patient heterogeneity in the subsequent treatment course may require attention to comorbidity as a potential confounding factor. PMID- 24488424 TI - Erosions and fatty lesions of sacroiliac joints in patients with axial spondyloarthritis: evaluation of different MRI techniques and two scoring methods. AB - OBJECTIVE: Assessment of structural damage of sacroiliac joints (SIJ) in patients with axial spondyloarthritides (axSpA) has been discussed as a useful outcome measure in clinical trials. The aim of our study was to evaluate different magnetic resonance imaging (MRI) scoring methods and pulse sequences with a focus on fatty lesions and bony erosions. METHODS: Seventy-five patients with the diagnosis of axSpA underwent MRI at 3 timepoints as part of the ESTHER trial, which compared 2 groups of patients treated with etanercept or sulfasalazine. Two MRI sequences [unenhanced T1-weighted (T1w) turbo spin-echo (TSE) and unenhanced T1w opposed-phase gradient-echo sequences (opGRE)] and 2 different scoring systems (simple and comprehensive Berlin method) were used for the evaluation of fatty lesions and erosions of the SIJ. Differences between techniques and methods were evaluated by intraclass correlation coefficients (ICC) and standardized response means (SRM). RESULTS: Applying the simple Berlin method, mean fatty lesion scores for etanercept-treated patients were 4.59 and 5.19 at baseline and Week 48, respectively, while the comprehensive Berlin method revealed mean fatty lesion scores of 6.59 and 7.64, respectively. Corresponding SRM were 0.59 and 0.86 for simple and comprehensive methods, respectively, while ICC dropped from 0.76-0.77 to 0.59-0.62. Scoring of erosions on T1w opGRE images resulted in a higher interreader agreement (ICC of 0.65) compared to T1w TSE sequences (ICC of 0.18). CONCLUSION: Better characterization of fatty lesion changes within 1 year was achieved by the comprehensive Berlin scoring method; however, more reader variation has to be taken into account. The delineation of erosions is markedly improved when using T1w opGRE pulse sequences. PMID- 24488423 TI - Influence of psychological stress on headache in patients with systemic lupus erythematosus. AB - OBJECTIVE: To compare the prevalence and disability of headache in patients with systemic lupus erythematosus (SLE) with the general population and to assess the role of chronic psychological stress (CPS) in headache development. METHODS: One hundred seventy patients with SLE and 102 control subjects matched for age, sex, and level of education were included in this multicenter, cross-sectional study. CPS, headache-related disability, and chronic analgesic intake (CAI) were evaluated in all participants. RESULTS: No statistical differences in the prevalence of headache between both groups were observed but headache disability was significantly higher in patients with SLE. In addition, a higher average score in the Cohen Perceived Stress Scale (CPSS) and a higher prevalence of patients with CAI were observed in patients with SLE. In multivariate analysis, CPSS score was positively (OR 1.09; 95% CI: 1.03-1.14; p = 0.001) and CAI negatively (OR 0.43; 95% CI: 0.19-0.99; p = 0.049) associated with headache in patients with SLE. CONCLUSION: Despite the prevalence of headache in patients with SLE and the general population being similar, headache-related disability may be higher in patients with SLE. Moreover, CPS might play a role in the pathogenesis of SLE headache, whereas CAI might have a protective effect against it. PMID- 24488425 TI - Dynamics of the O((3)P) + C2H2 reaction from crossed molecular beam experiments with soft electron ionization detection. AB - The reaction between ground state oxygen atoms, O((3)P), and the acetylene molecule, C2H2, has been investigated in crossed molecular beam experiments with mass-spectrometric detection and time-of-flight analysis at three different collision energies, Ec = 34.4, 41.1 and 54.6 kJ mol(-1). From product angular and velocity distribution measurements of the HCCO and CH2 products in the laboratory frame, product angular and translational energy distributions in the center-of mass frame were determined. Measurements on the CH2 product were made possible by employing for product detection the recently implemented soft electron-ionization (EI) technique with low-energy, tunable electrons, which has permitted suppressing interference coming from the dissociative ionization of reactants, products and background gases. It has been found that the title reaction leads only to two competing channels: H + HCCO (ketenyl) and CO + CH2 (triplet methylene). The branching ratio of cross sections between the two competing channels has been determined to be sigma(HCCO)/[sigma(HCCO) + sigma(CH2)] = 0.79 +/- 0.05, independent of collision energy within the experimental uncertainty. This value is in line with that obtained in the most recent and accurate kinetics determination at room temperature as well as with that predicted from recent theoretical calculations based on statistical rate theory and weak-collision master equation analysis and on dynamics surface-hopping quasiclassical trajectory calculations on-the-fly on coupled triplet/singlet ab initio potential energy surfaces. The firm assessment of the branching ratio as a function of translational energy for this important reaction, besides its fundamental significance, is of considerable relevance for the implementation of theoretical models of hydrocarbon combustion. PMID- 24488418 TI - Outcome measures used in clinical trials for Behcet syndrome: a systematic review. AB - Behcet syndrome (BS) is a multisystem vasculitis that is most active during young adulthood, causing serious disability and significant impairment in quality of life. Differences in the disease course, severity, and organ involvement between patients, depending on the age at presentation and sex, makes it impossible to determine a single management strategy. The diversity and variability in the outcome measures used in clinical trials in BS makes it difficult to compare the results or inform physicians about the best management strategy for individual patients. There is a large unmet need to determine or develop validated outcome measures for use in clinical trials in BS that are acceptable to researchers and regulatory agencies. We conducted a systematic review to describe the outcomes and outcome measures that have been used in clinical trials in BS. This review revealed the diversity and variability in the outcomes and outcome measures and the lack of standard definitions for most outcomes and rarity of validated outcome tools for disease assessment in BS. This systematic literature review will identify domains and candidate instruments for use in a Delphi exercise, the next step in the development of a core set of outcome measures that are properly validated and widely accepted by the collaboration of researchers from many different regions of the world and from different specialties, including rheumatology, ophthalmology, dermatology, gastroenterology, and neurology. PMID- 24488426 TI - The structure and composition of aleurone grains in the barley aleurone layer. AB - Cytochemical methods have been used in conjunction with light and electron microscopy to determine the nature of the inclusions in aleurone grains of barley aleurone layers. Two kinds of inclusions were found: (1) Globoids within globoid cavities which were not enclosed by a membrane: the globoids stained red with toluidin blue due to the presence of phytin, and with lipid stains; (2) Protein carbohydrate bodies which stained green with toluidin blue. The characteristics of globoids and protein-carbohydrate bodies as seen in the electron microscope are described in detail using both glutaraldehyde- and permanganatefixed tissues. The protein-carbohydrate body was identified by silver-hexaminestaining; this was not caused by carbohydrate but by some component which stained green in toluidin blue and which also occurred in cell walls in a thin band adjacent to the cytoplasm. The characteristics of both bodies are discussed in relation to apparent confusion in their identities in previous electron-microscope studies. PMID- 24488427 TI - Cytological studies on the inhibition by 5-fluorouracil of ribosome synthesis and growth in jerusalem artichoke tuber slices. AB - Rapid auxin-induced cell expansion in artichoke tuber slices is obtained by aerating the slices in water ("aging") prior to auxin treatment. 5-fluorouracil (5-FU), an inhibitor of ribosomal RNA synthesis in plant cells, markedly inhibits auxin-induced growth only if present in the pre-growth aging period. Autoradiographic studies show that 5-FU given in the aging and/or growth periods reduces the incorporation of RNA precursors into the cytoplasm. Pulse-chase experiments suggest that the reduced cytoplasmic incorporation is in large part due to decreased stability of ribosomal rNA, as nucleolar and chromatin label are only slightly depressed at the end of the pulse. Though the nucleoli continue to incorporate RNA precursors following 5-FU treatment, they lack a distinct granular zone, and appear as homogeneous fibrillar structures under the electron microscope. 5-FU has a parallel inhibitory effect on growth and protein synthesis as shown by (3)H-leucine studies during the growth period. Electron-microscope studies show that treatment with 5-FU causes decreased numbers of ribosomes and rough endoplasmic reticulum. The results suggest that the ribosomes and rough endoplasmic reticulum formed during aging are important in obtaining subsequent rapid auxin-induced expansion. The new ribosomes serve in part to replace pre existing ribosomes present at the time of excision, which from electron microscopic evidence from 5-FU treated tissue, appear to slowly disappear. PMID- 24488428 TI - Structural modification of gibberellins by in-vitro hydroxylating systems. AB - The behaviour of gibberellins A4, A5 and A7 (GA4, GA5 and GA7) has been studied in various in vitro hydroxylating systems. Incubation of GA4 and GA7 in peroxidase/dihydroxyfumarate or tyrosinase/ascorbate formulations resulted in the production of additional biologically-active zones on thin-layer chromatograms of the reaction mixtures. The product from GA7/peroxidase incubations was conclusively identified as GA7 norketone by gas/liquid chromatography-mass spectrometry and nuclear magnetic resonance spectrometry. A similar reaction is inferred for GA4 in the same system and for both GA4 and GA7 with tyrosinase/ascorbate. By analogy, the product derived from GA5 in the non enzymatic ascorbate/ferrous iron system may be GA5 norketone. The reaction kinetics and the biological activity of the products are discussed. PMID- 24488429 TI - [Energy-dependent uptake of thallium by Chlorella]. AB - The uptake of labelled thallous ion into the interior of Chlorella fusca is enhanced by light. This is ascribed to active transport by way of the K (and Rb) pump. The Michaelis constants differ between the higher and the lower concentration ranges, but they are similar for Rb and Tl.The additional, rapid, light-independent adsorption of Tl, mainly by the cell wall, is stronger than that of the alkali ions, but weaker than that of divalent cations. The adsorbed Tl is subject to elution by complexing agents (probably mainly glycolic acid) secreted by the cells, especially in the light.In spite of the similarity of the Michaelis constants, the inhibition of the light-dependent uptake of labelled Rb by unlabelled Tl is far stronger than the inhibition of Tl uptake by Rb. The efficiency of Tl may be due to double action: namely, competition with Rb for the carrier and negative influence on a transport ATPase. PMID- 24488430 TI - [Light dependent carotenoid synthesis : VII. Cycloheximide or anaerobic conditions as reversible blocks of the sequence of light-induced reactions]. AB - Anaerobic conditions completely block the synthesis of carotenoids in Fusarium aquaeduciuum or Neurospora crassa. Even after sufficient illumination of the mycelia in the presence of air, the subsequent production of carotenoids in the dark is suppressed entirely when the fungi are transferred to an oxygen-free atmosphere. In turn, restoring aerobic conditions sets off the pigment synthesis in the dark without renewed photoinduction at any time within 48 hours, although the yields of carotenoids decrease. Thus the "photo-induced state" appears to be fairly stable. In order to locate this state the sequence of light-induced reactions was specifically blocked before and after the synthesis of carotenogenic enzymes.Cycloheximide is a potent inhibitor of protein synthesis in fungi. When applied prior to illumination to either of the two molds it suppresses the photo-induced carotenoid formation, apparently by blocking the production of carotenogenic enzymes. This inhibition can be overcome by removing cycloheximide (e.g. by rinsing the mycelium with buffer) at any time (up to 30 h) during the dark period following illumination; however, gradually declining quantities of pigment are produced. These results provide evidence for the formation of a remarkably lasting "induction product" which can clearly be distinguished from the "photooxidative product" and from the carotenogenic enzymes.Under anaerobic conditions Fusarium is capable of producing plentiful amounts of carotenogenic enzymes, while Neurospora crassa forms only small quantities. In order to test the stability of these enzymes in vivo the following experimental setting was employed: in the presence of air the fungi were illuminated and subsequently kept in the dark for a period as long as the absolute lag phase of the pigment synthesis. Then cycloheximide was added to block any further protein synthesis, and at the same time the mycelia were transferred to a nitrogen atmosphere. Returning the fungi to aerobic conditions after various incubation periods resulted in a successively reduced pigment production. It thus appears that the activity of the photo-induced carotenogenic enzymes diminishes only slowly in vivo. These enzymes somehow seem to be stabilized as long as carotenogenesis is blocked. PMID- 24488431 TI - On the phytochrome phototransformation kinetics in mustard seedlings. AB - The in vivo phototransformation kinetics of mustard hook and cotyledon phytochrome exhibit a deviation from a single first order curve, quite similar to that for pumpkin hooks as reported in a previous paper (Boisard, Marme and Schafer, 1971). The P fr->Prkinetics can be characterized by the ratios E fr,lambda (I) . P fr (I) /E fr,lambda (II) . P fr,lambda (II) and [Formula: see text] where P fr (I) and P fr (II) are two populations of phytochrome molecules which convert to P rwith a first order half-life of [Formula: see text] and [Formula: see text]. These ratios depend on the length of time of etiolation. The ratio E fr,lambda (I) . P fr (I) /E fr,lambda (II) . P fr,lambda (II) is independent of the amount of total P frpresent at the beginning of the P fr >Prphototransformation after a non-saturating dose of red light. The half-lives of the two populations, however, depend on the concentration of total P frinitially present. P fr->Prphototransformation kinetics with different light intensities show that reciprocity holds. PMID- 24488432 TI - Maintenance of gibberellin biosynthesis in excised sunflower apical buds by exogenous sucrose or mevalonate. AB - Diffusible-gibberellin yields in agar from green sunflower apical buds fell within 40 hr of excision of the buds when they were incubated on 1.5% agar. Incubation on agar containing either 2.0% sucrose or 0.1% mevalonate allowed continued gibberellin production by the buds for at least 72 hr. Mevalonate was more effective than sucrose as a stimulant of gibberellin synthesis. Gibberellins obtained from the buds did not appear to be products of wounded tissues at the cut stem surface, but represented normal gibberellin biosynthesis by bud tissues. PMID- 24488433 TI - Phytochrome-mediated flavone glycoside synthesis in cell suspension cultures of Petroselinum hortense after preirradiation with ultraviolet light. AB - Ultraviolet light was demonstrated to stimulate flavone glycoside synthesis in Petroselinum cell suspension cultures. The data presented suggest the involvement of phytochrome in this response: Flavone glycoside formation resulting from 1 h of ultraviolet irradiation was increased by subsequent continuous far-red light irradiation. However, the ultraviolet effect was reduced by a subsequent irradiation with 10 min of far-red. This far-red effect was fully reversed by a sub-sequent irradiation with 10 min of red. Red and far-red irradiations were ineffective without ultraviolet preirradiation. It is concluded that in this system ultraviolet irradiation is required in order to change the cells in such a way as to allow a physiological effectiveness of the phytochrome system. PMID- 24488434 TI - The structure and composition of Aleurone grains in the Barley Aleurone layer. PMID- 24488436 TI - The coexistence of second and third malignancies in adult-onset cancer patients. PMID- 24488435 TI - New insights on non-B non-C hepatocellular carcinoma in mid Delta Region, Egypt. AB - PURPOSE: The rate of hepatocellular carcinoma (HCC) is increasing worldwide, including in Egypt. Hepatitis B (HBV) and C (HCV) viruses are major risks. Non-B non-C HCC was reported in some countries. We investigated non-B non-C HCC independent risk factors and associated profiles in viral hepatitis endemic region. METHODS: In a consecutive series, 281 patients were diagnosed with HCC and received for management, at Tanta University Hospitals, within the past 3 years. Demographic variables and environmental exposures were recorded by direct application of a modified questionnaire. Sera were tested for HCV (antibodies by ELISA and RNA by RT-PCR) and HBV (HBs Ag by ELISA and HBV DNA). Antinuclear antibody, serum copper, and iron were assessed in non-viral HCC. Liver biopsy was performed for HCC diagnosis and grading and liver tissue in all patients by histopathological and immunohistochemical methods to assess HBV and/or HCV etiology. RESULTS: Non-B non-C HCC patients were 13.87% of the total and were associated with multiple risks, predominantly pesticides (100%, p < 0.001) and super phosphate and ammonium sulfate fertilizers (94.87%, p < 0.001) with significant exposure in industry, farming, and residence. Their tumors were mainly solitary, smaller sizes, and of lower alpha-fetoprotein titers. The study showed insignificant increase in prevalence of non-B non-C HCC and had special characters. Multivariate analysis showed significance of pesticides and smoking as independent risks for non-B non-C HCC. CONCLUSIONS: Pesticides and smoking heavy exposure can be considered as primary risks for non-B non-C HCC. Phosphate and ammonium sulfate fertilizers were associations. The study will increase awareness for better prevention and management. PMID- 24488437 TI - Electronic and optical properties of dye-sensitized TiO2 interfaces. AB - Dye-sensitized solar cells (DSCs) represent a promising approach to the direct conversion of sunlight to electrical energy at low cost and high efficiency. DSCs are based on a film of anatase TiO2 nanoparticles covered by adsorbed molecular dyes and immersed in a liquid redox electrolyte. Upon photoexcitation of the chemisorbed dye, electrons are injected into the TiO2 conduction band and can travel across the nanostructured film to reach the counter-electrode, while the oxidized dye is regenerated by the redox electrolyte. In this review we present a summary of recent computational studies of the electronic and optical properties of dye-sensitized TiO2 interfaces, with the aim of providing the basic understanding of the operation principles of DSCs and establishing the conceptual basis for their design and optimization.We start with a discussion of isolated dyes in solution, focusing on the dye's atomic structure, ground and excited state oxidation potentials, and optical absorption spectra. We examine both Ru(II)-polypyridyl complexes and organic "push-pull" dyes with a D-pi-A structure, where the donor group (D) is an electron-rich unit, linked through a conjugated linker (pi) to the electron-acceptor group (A). We show that a properly calibrated computational approach based on Density Functional Theory (DFT) combined with Time Dependent DFT (TD-DFT) can provide a good description of both the absorption spectra and ground and excited state oxidation potential values of the Ru(II) complexes. On the other hand, organic push-pull dyes are not well described by the standard DFT/TD-DFT approach. For these dyes, an excellent description of the electronic structure in gas phase can be obtained by the many body perturbation theory GW method, which has, however, a much higher computational cost.We next consider interacting dye/semiconductor systems. Key properties are the dye adsorption structure onto the semiconductor, the nature and localization of the dye@semiconductor excited states, and the alignment of ground and excited state energy levels at the dye/semiconductor heterointerface. These properties, along with an estimate of the electronic coupling, constitute the fundamental parameters that determine the electron injection and dye regeneration processes. For metallorganic dyes, standard DFT/TDDFT methods are again found to reproduce accurately most of the relevant electronic and optical properties. For highly conjugated organic dyes, characterized by a high degree of charge transfer excited states, instead, the problems associated to the charge transfer nature of their excited states extend to their interaction with TiO2 and translate into an erroneous description of the relative energetics of dye/semiconductor excited states. A full description of push-pull organic dyes/semiconductor excited states, which is essential for modeling the key process of electron injection in DSCs, still represents a challenge which should be addressed by next generation DFT or post-DFT methods. PMID- 24488438 TI - Composite scaffolds of nano calcium deficient hydroxyapatite/multi-(amino acid) copolymer for bone tissue regeneration. AB - In this study, nano calcium deficient hydroxyapatite (n-DA)/multi-(amino acid) copolymer composite scaffolds were prepared by injection molding foaming method using calcium sulphate dihydrate as a foaming agent. The composite scaffolds showed well interconnected macropores with the pore size of ranging from 100 to 600 MUm, porosity of 81 % and compressive strength of 12 MPa, and the compressive strength obviously affected by the porosity. The composite scaffolds could be slowly degraded in phosphate buffered solution (PBS), which lost its initial weight of 61 w % after immersion into PBS for 12 weeks, and the porosity significantly affected the degradability of the scaffolds. Moreover, it was found that the composite scaffolds could promote the MG-63 cells growth and proliferation, and enhance its alkaline phosphatase activity. The implantation of the scaffolds into the femoral bone of rabbits confirmed that the composite scaffolds were biocompatibitive, degradable, and osteoconductive in vivo. PMID- 24488439 TI - Role of vesicular nucleotide transporter VNUT (SLC17A9) in release of ATP from AR42J cells and mouse pancreatic acinar cells. AB - ATP is released from cells in response to various stimuli. Our previous studies on pancreas indicated that pancreatic acini could be major stores of secreted ATP. In the present study, our aim was to establish the role of the vesicular nucleotide transporter (VNUT), SLC17A9, in storage and release of ATP. Freshly prepared acini from mice and AR42J rat acinar cells were used in this study. We illustrate that in AR42J cells, quinacrine (an ATP store marker) and Bodipy ATP (a fluorescent ATP analog) co-localized with VNUT-mCherry to vesicles/granules. Furthermore, in acini and AR42J cells, a marker of the zymogen granule membranes, Rab3D, and VNUT co-localized. Dexamethasone treatment of AR42J cells promoted formation of acinar structures, paralleled by increased amylase and VNUT expression, and increased ATP release in response to cholinergic stimulation. Mechanical stimulus (pressure) and cell swelling also induced ATP release, but this was not influenced by dexamethasone, most likely indicating different non zymogen-related release mechanism. In conclusion, we propose that VNUT-dependent ATP release pathway is associated with agonist-induced secretion process and downstream purinergic signalling in pancreatic ducts. PMID- 24488440 TI - Structural basis for selective cross-reactivity in a bactericidal antibody against inner core lipooligosaccharide from Neisseria meningitidis. AB - The structure of a antigen-binding fragment (Fab) from the bactericidal monoclonal antibody LPT3-1 specific to lipooligosaccharide (LOS) inner cores from Neisseria meningitidis has been solved in complex with an eight-sugar inner core fragment NmL3 galE lpt3 KOH to 2.69 A resolution. The epitope is centered about an inner core N-acetylglucosamine residue unique to N. meningitidis and does not include the lipid A moiety, which is disordered in the structure, but is positioned to allow the binding of free and membrane-anchored full-length LOS. All the amino acid residues that contact antigen are of germline origin but, remarkably, two consecutive somatic mutations of serine to glycine in the heavy chain at residues 52 and 52a are positioned to deprive the antibody of advantageous interactions and so weaken binding. However, these mutations are key to allowing selective cross-reactivity with the HepII-3-PEtn inner core variant expressed by 70% of strains. Neisseria meningitidis is a leading cause of disease in the developed world and is especially dangerous to children, who lack the necessary protective antibodies. The structure of Fab LPT3-1 in complex with LOS provides insight into the antibody's selective ability to recognize multiple clinically relevant variations of the LOS inner core from N. meningitidis. PMID- 24488441 TI - Driving CAR-based T-cell therapy to success. AB - T cells that have been genetically modified, activated, and propagated ex vivo can be infused to control tumor progression in patients who are refractory to conventional treatments. Early-phase clinical trials demonstrate that the tumor associated antigen (TAA) CD19 can be therapeutically engaged through the enforced expression of a chimeric antigen receptor (CAR) on clinical-grade T cells. Advances in vector design, the architecture of the CAR molecule especially as associated with T-cell co-stimulatory pathways, and understanding of the tumor microenvironment, play significant roles in the successful treatment of medically fragile patients. However, some recipients of CAR(+) T cells demonstrate incomplete responses. Understanding the potential for treatment failure provides a pathway to improve the potency of adoptive transfer of CAR(+) T cells. High throughput single-cell analyses to understand the complexity of the inoculum coupled with animal models may provide insight into the therapeutic potential of genetically modified T cells. This review focuses on recent advances regarding the human application of CD19-specific CAR(+) T cells and explores how their success for hematologic cancers can provide a framework for investigational treatment of solid tumor malignancies. PMID- 24488442 TI - Effect of clot aging and cholesterol content on ultrasound-assisted thrombolysis. AB - Exposure to 2-MHz transcranial diagnostic ultrasound enhances the thrombolytic activity of intravenously administered tissue plasminogen activator (IV-tPA) in acute ischemic stroke (sonothrombolysis). However, rates of arterial recanalization vary widely, depending upon the clot burden, its location, and stroke subtype. We evaluated the influence of age and cholesterol level of the blood clots on sonothrombolysis in an in vitro model. To "age" the clots, serum was replaced by fresh blood periodically. We increased the cholesterol content of the clots by adding cholesterin to the blood. The clots were lysed by tPA and/or transcranial Doppler ultrasound sonication for 1 h. The extent of thrombolysis induced by various treatment protocols (controls, sonication, tPA, and sonothrombolysis) was evaluated with relative changes in the clot weights and in the clot structure by scanning electron microscopy (SEM) at end of the experiment. Sonothrombolysis induced significantly higher weight reduction in fresh clots (37.3 % in 2-h old clots versus 24.8 % in 10-h ones, p < 0.005) as well as the clots with higher cholesterol levels (41.7 versus 30.6 % in normal cholesterol clots, p < 0.005). SEM demonstrated patterns of clot dissolution among various treatment modalities. Sonothrombolysis induced better clot lysis in fresh thrombi with high cholesterol levels. PMID- 24488443 TI - Ontogenetic variation in the mandibular ramus of great apes and humans. AB - Considerable variation exists in mandibular ramus form among primates, particularly great apes and humans. Recent analyses of adult ramal morphology have suggested that features on the ramus, especially the coronoid process and sigmoid notch, can be treated as phylogenetic characters that can be used to reconstruct relationships among great ape and fossil hominin taxa. Others have contended that ramal morphology is more influenced by function than phylogeny. In addition, it remains unclear how ontogeny of the ramus contributes to adult variation in great apes and humans. Specifically, it is unclear whether differences among adults appear early and are maintained throughout ontogeny, or if these differences appear, or are enhanced, during later development. To address these questions, the present study examined a broad ontogenetic sample of great apes and humans using two-dimensional geometric morphometric analysis. Variation within and among species was summarized using principal component and thin plate spline analyses, and Procrustes distances and discriminant function analyses were used to statistically compare species and age classes. Results suggest that morphological differences among species in ramal morphology appear early in ontogeny and persist into adulthood. Morphological differences among adults are particularly pronounced in the height and angulation of the coronoid process, the depth and anteroposterior length of the sigmoid notch, and the inclination of the ramus. In all taxa, the ascending ramus of the youngest specimens is more posteriorly inclined in relation to the occlusal plane, shifting to become more upright in adults. These results suggest that, although there are likely functional influences over the form of the coronoid process and ramus, the morphology of this region can be profitably used to differentiate among great apes, modern humans, and fossil hominid taxa. PMID- 24488444 TI - Non-deep-seated primary CNS lymphoma: therapeutic responses and a molecular signature. AB - The survival of patients with primary CNS lymphoma (PCNSL) has been improved by high-dose methotrexate (HD-MTX). Since the combination therapy of HD-MTX and whole-brain radiotherapy (WBRT) carries a significant risk for delayed neurotoxicity, it is important to know the therapeutic potential and prognostic factors for HD-MTX without WBRT. We retrospectively reviewed 46 consecutive patients with PCNSL treated with a HD-MTX (3.5 g/m(2)) and deferred WBRT. Patients who achieved complete response or partial response after three courses of HD-MTX were cautiously followed-up without additional treatment. Patients who had either stable disease, progressive disease, or disease relapse were offered salvage therapy. The median progression-free survival period was 10 months and the median overall survival period was 52 months, with a 5-year survival rate of 39 %. Nineteen patients (49 % of the evaluable patients) achieved a complete response at the initial response assessment. Involvement of deep structures of the brain (corpus callosum, basal ganglia and brainstem) was significantly associated with the worse progression-free survivals (p = 0.0058) and overall survivals (p = 0.0177). Gene expression profiling analysis by microarray was compared in eight patients between PCNSLs located in the deep structures of the brain and non-deep-seated tumors. The result showed that up-regulation of signal transduction-related genes and down-regulation of catalytic activity-related genes in the non-deep-seated PCNSL compared with the deep-seated tumors. The present study shows that PCNSL located in non-deep structures of the brain responds better to HD-MTX alone than those involved deep-structures. PMID- 24488445 TI - Intensive chemotherapy followed by reduced-dose radiotherapy for biopsy-proven CNS germinoma with elevated beta-human chorionic gonadotropin. AB - In this study, 10 patients with biopsy-proven germinoma with a beta-human chorionic gonadotropin (beta-HCG) level >50 mIU/ml received intensive chemotherapy followed by reduced-dose radiotherapy (RT) to reduce late effects from RT. CSF beta-HCG levels were >200 mIU/ml in five patients. After endoscopic or stereotactic biopsy, four cycles of induction chemotherapy were administered prior to RT. A CEB regimen (carboplatin + etoposide + bleomycin) and a CyEB regimen (cyclophosphamide + etoposide + bleomycin) were alternated. No residual tumor remained after induction chemotherapy in six patients, only cystic lesions were present at the primary tumor site in three, and a small solid residual tumor was observed in the remaining patient; however, all these patients had normal beta-HCG levels. If complete response was achieved before initiation of RT, 19.5 Gy craniospinal RT (CSRT) + 10.8 Gy local RT was administered to the tumor bed. If residual lesion was suspected, the dose of RT was selected according to the presence/absence of tumor dissemination at diagnosis (19.5 Gy CSRT + 19.8 Gy local RT for localized tumors and 24.0 Gy CSRT + 16.2 Gy local RT for disseminated tumors). Eight patients, including four patients with a beta-HCG level >200 mIU/ml, received 19.5 Gy CSRT. All patients remain disease free at a median follow-up of 58 (range 35-94) months from diagnosis. Our data suggest that pathologically pure germinoma with a significantly elevated beta-HCG level might be cured with reduced-dose RT if intensive chemotherapy is provided. PMID- 24488446 TI - Fractionated stereotactic radiosurgery for patients with brain metastases. AB - Stereotactic radiosurgery (SRS) delivered in 2-5 fractions (multi-fraction SRS) has been employed in patients with brain metastases as an alternative to single fraction SRS with the aim to reduce late radiation-induced toxicity while maintaining high local control rate. In the present study we have evaluated the efficacy and toxicity of multi-fraction SRS in patients with 1-3 brain metastases. Between March 2006 and October 2012, 135 patients (63 men and 72 women) with 171 brain metastases have been treated with multi-fraction SRS (3 * 9 Gy or 3 * 12 Gy). At a median follow-up of 11.4 months, 16 lesions recurred locally. The 1- and 2-year local control rates were 88 and 72 %, respectively. The 1- and 2-year survival rates were 57 and 25 %, and respective distant failure rates were 52 and 73 %. Seventy-eight percent of patients succumbed to their extracranial disease and 22 % died of progressive intracranial disease. Multivariate analysis showed that melanoma histology was predictive of local failure (p = 0.02; HR 6.1, 95 % CI 1.5-24). Specifically, the 1-year local control rates were 68 % for melanoma, 92 % for breast carcinoma, and 88 % for NSCLC, respectively. Stable extracranial disease (p = 0.004) and Karnofsky performance status (p = 0.01) were predictive of longer survival. Radiologic changes suggestive of radionecrosis occurred in 12 (7 %) out of 171 lesions, with an actuarial risk of 9 % at 1 year and 17 % at 2 years, respectively. In conclusion, multi-fraction SRS appears to be an effective and safe treatment modality for brain metastases. It may represent an alternative to single-dose SRS for patients with large lesions or lesions located near critical structures. PMID- 24488447 TI - Comparison of minor bleeding complications using dabigatran or enoxaparin after cemented total hip arthroplasty. AB - BACKGROUND: Orally administered chemical thromboprophylactic agents for total hip replacement (THR) have become popular in recent years. Certain clinical trials suggest that the efficacy and the risk of major bleeding after administration of direct thrombin inhibitor dabigatran etexilate are equivalent to the clinical trial comparator, subcutaneous low-molecular-weight heparin enoxaparin. Our aim was to compare and evaluate the incidence of minor haemorrhagic and soft-tissue adverse effects of enoxaparin and dabigatran. MATERIALS AND METHODS: 122 patients who were treated by elective cemented primary THR were enrolled in our quasi randomised study. Two groups were formed according to which perioperative thromboprophylactic agent was used: 61 patients in enoxaparin group versus 61 patients in dabigatran group. Thigh volume changes, calculated perioperative blood loss, area of haematoma, wound bleeding, duration of wound discharge and intensity of serous wound discharge on postoperative day 3 and day 7 were recorded. RESULTS: The duration and intensity of serous wound discharge differed significantly between the two groups. Duration of wound discharge after drain removal was 2.2 (+/-2.7) days in the dabigatran group and 1.2 (+/-1.9) days in the enoxaparin group (p < 0.05). Significant increase in serous discharge was found in the dabigatran group (p < 0.05) on third and seventh postoperative days compared to the enoxaparin group. CONCLUSION: Both thromboprophylactic agents were found to have appropriate antithrombotic effects after THR. However, dabigatran was associated with an increased incidence of prolonged serous wound discharge, which might cause longer hospitalization and might instigate the use of prolonged antibiotic prophylaxis. PMID- 24488448 TI - Intramedullary control of distal femoral resection results in precise coronal alignment in TKA. AB - INTRODUCTION: There is still a relevant rate of outliers in coronal alignment >3 degrees when the conventional technique is used, potentially accompanied by a poorer long-term clinical outcome and a reduced longevity of the implant. Intraoperative implementation of preoperative planning and above all checking of the bone resections carried out are decisive for reinstating a straight leg axis. Intramedullary control of femoral resection has not been described to date. The objective of this study was to present a new technique for the intramedullary control of femoral resection and the results obtained using this method. METHODS: All patients who underwent primary total knee arthroplasty with the new intramedullary control of femoral resection were included in this retrospective study. The frequency of the need for correction of the saw cuts was documented. The radiological assessment included pre- and postoperative whole-leg standing radiographs. In the process, the whole-leg axis, AMA, entry point, LDFA and MPTA were evaluated preoperatively. On the postoperative radiographs, the whole-leg axis and the alignment of the femoral and tibial components were evaluated. RESULTS: One hundred and sixty-two total knee arthroplasties (TKAs) were included in the study. The average age was 68.7 years. The preoperative malalignment was on the average 8.2 degrees +/- 4.7 degrees (23.8 degrees varus to 17.3 degrees valgus). The postoperative whole-leg axis was on the average 1.3 degrees +/- 1.1 degrees (5.5 degrees varus to 4.3 degrees valgus). The femoral component showed a deviation from the mechanical axis of 0.1 degrees +/- 1.2 degrees (4.3 degrees varus to 3.7 degrees valgus) and the tibial component a deviation from the mechanical tibial axis of 0.3 degrees +/- 1.2 degrees (4.2 degrees varus to 2.5 degrees valgus). CONCLUSIONS: The new technique of intramedullary control of distal femoral resection, together with preoperative planning, leads to a precise alignment of the femoral component in the coronal plane. Thus, for the first time, a simple and effective tool for checking distal femoral resection is available for standardized use. PMID- 24488449 TI - The dark side of hydrogen bonds in the design of optical materials: a charge density perspective. AB - A combined investigation of the structural, electronic, and optical properties of three crystalline nonaaqualanthanoid(III) triflates, [Ln(H2 O)9 (CF3 SO3 )3 ], has provided unambiguous experimental evidence for charge redistribution in the first coordination sphere of a lanthanide ion as a result of hydrogen bonds with outer-sphere anions. As well as resulting in charge transfer from the noncoordinated anions to the coordinated water molecules, these hydrogen bonds give rise to a new excited state, an hydrogen-bond-induced charge-transfer state, which is observed experimentally for the first time. This state was shown to be responsible for the previously unknown negative aspect of hydrogen bonds with a lanthanide-bound water molecule: rather than increasing the luminescence efficiency of the complex, they can lead to additional quenching that is unfavorable for the task-specific design of optical materials. PMID- 24488450 TI - Rio de Janeiro welcomed and cared of the Brazilian nursing. PMID- 24488451 TI - [Characterization of nursing professionals who care for people with vascular ulcers in outpatient facilities]. AB - The purpose of the study was to describe the demographic and professional competence characteristics of the nursing workers who treat people with vascular ulcers in the dressing rooms of the municipal healthcare network. This cross sectional, descriptive and quantitative study was performed in a large city in Midwestern Brazil, from September of 2010 to February of 2011. Data collection was performed using a questionnaire, and the data were subjected to descriptive analysis and qui square test (p<0,05). The participants were 218 workers, 58.3% of which had never been involved in update activities related to wound evaluation and treatment, 40.7% reported having little experience in this field, 61% were nursing technicians and nurses' aides. Approximately 10% of the nurses worked exclusively in the dressing rooms, and the others helped in when called. The collected data indicate weaknesses in the nursing care delivered to people with vascular ulcers. PMID- 24488452 TI - [Performance of nurses in prescribing hormonal contraceptives in the primary health care network]. AB - The aim of this study was to evaluate the performance of nurses in the prescription of hormonal reversible contraceptives in Primary Care. A descriptive and transversal study was conducted, with 64 nurses at healthcare units as subjects, in the period of September-November 2010 in the county of Rio Branco Acre. Data were collected through structured interviews using a questionnaire. The results showed that 96.9% of nurses are prescribing hormonal contraceptives and that the majority (90.6%) is aware of the government laws about nursing prescription. We also observed that the contraceptive was chosen based on client's decision and anamnesis (36% and 34% respectively), and that 90% of the nurses always give orientation about advantages and disadvantages of each contraceptive method. Thus, for choosing a contraceptive method based on given information and free will, the methods must be available and dispensed by trained professionals, after correct and complete orientation. PMID- 24488453 TI - [Practices of nursing staff in the process of preterm baby hospital discharge]. AB - The objective of this study was to identify the strategies used by the nursing team in the neonatal unity care of a school-hospital during the preparation of the family for the premature baby discharge. It is a descriptive study with qualitative approach. The data was collected between March and June 2011, by means of observation and semi-structured interviews. From the discourse analysis two categories appeared: Orientations and professional strategies in preparing the family for the premature baby hospital discharge and Difficulties and potentialities in the neonatal attention space. The main strategy mentioned was the family early insertion in the caring process and the stressed difficulty was the parents' absence during the child's hospital staying. The potentialities and limitations pointed out in this study revealed that the assistance process is dynamic, asking for constant correction and adequacies to effectively and wholly care for the premature baby and its family. PMID- 24488454 TI - [Complementary health practices and challenges of its applicability in hospital: nurses' point of view]. AB - This is a qualitative, descriptive and exploratory research, aiming to describe the set of ideas and knowledge that guide the use of complementary and integrative health practices (CIHP) by nurses, and analyze the challenges facing the applicability of these therapies by nurses in the hospital setting. The subjects were nurses in public hospital institutions of Rio de Janeiro. Data collection was done through semi-structured interviews and a technique of creativity and sensibility called Almanac. The results showed that the hegemony of the biomedical model in the formation and performance of health professionals hinders implementation of CIHP in hospital. However, as this model does not account for the complexity of the human being emerges the possibility of sharing with CIHP in care aiming, therefore, at comprehensiveness of the human being. PMID- 24488455 TI - [Care management for tuberculosis: from education to the nurse practice]. AB - The study aimed to analyze the relation between the training of the nurse and the actions directed to the management of the care to the tuberculosis. With qualitative nature, it was performed in one of the cities of the metropolitan region of Joao Pessoa-PB. The subjects were ten nurses of the Health Family Strategy. The data collection was performed in February 2010 using a semi structured interview script. To examine the empiric material it was used the technique of content analyzes. In the testimonies of the nurses there was predominance of the thematic TB in the hospital space; they approach either the superficiality and the distance of the care to TB related to the relation between the theory and the practice, and the absence of direct care to the patient of TB during training; according to them, the organization of the services points to a mechanicist and task based practice. One concluded that there is necessity of training institutions to come close to the health services, in a dialogic relation, to organize better the learning spaces. PMID- 24488456 TI - [Multi-causality in nursing work accidents with biological material]. AB - In order to analyze the multiple causes of occupational accidents with biological exposure among nursing staff was carried out a descriptive and exploratory research in a medium-sized hospital in the State of Parana, in the period between January 2008 and January 2009. The population was 26 nursing staff of the medical clinic. Data collection was performed by semi-structured interviews with five of the eight injured in the period and its contents were analyzed by Causes and Effects Diagram. The categories of causes material, organizational, institutional and worker's behavior, showed the inappropriate disposal of sharps, work overload, no use of bio-security standards and poor supervision and training of workers, as factors for the occurrence of these accidents. The adoption of the tool of Causes and Effects Diagram provided an analysis of accidents in its multiple causes, showing the interaction between them. PMID- 24488457 TI - [Health status of nursing workers in functional retraining and readaptation]. AB - Cross-sectional descriptive study aimed to assess the health status of nursing staff retrained due to illness of a public university hospital in northern Parana, Brazil. Data of 34 workers were collected through the application of the Medical Outcomes Studies 36 items - Short Form (MOS SF-36). The results showed that physical problems were the reason for retraining in 91.2 % of cases. Of the eight domains assessed by the MOS SF -36, the worst scores referred to bodily pain, vitality and general health and the best scores were attributed to aspects of the mental health component. Workers retrained due to physical reason had lower scores in all domains except emotional performance in relation to those with mental problem. The evaluation of the perceived health of these workers showed that retraining due to illness is a strategy developed to enhance the functional capacity of workers, despite their limitations. PMID- 24488458 TI - [The family revealing itself as a being of rights during hospitalization of the child]. AB - This is a descriptive study with a qualitative approach, carried out during the second half of 2011, in a Pediatric Unit in a city in the extreme South of Brazil. The study aimed to understand the situations in which families reveal themselves as beings of rights during the hospitalization of the child. Fifteen family caregivers participated, divided into three sample groups. Data collection was conducted through semi-structured interviews, and the data were analyzed using open, axial and selective analysis. The study had the Grounded Theory as methodological framework. It was found that the family revealed itself as a being of rights, when recognized as such, is called and fights for their rights; suggests improvements for the care and maintains its autonomy, even if it has to submit to the decisions of the team in the child favor. It was concluded that is essential to allow them to be families in the hospital, enabling the exercise of their rights and citizenship. PMID- 24488459 TI - [Life after childhood cancer: experiences of the survivors]. AB - Late effects of cancer treatment in children, adolescents and young adults may be physical, social, and emotional, with effects on their quality of life. Through an ethnographic study, we sought to identify the impact on survivors' quality of life caused by late effects of treatment of childhood cancer. Twenty-one survivors participated in the study with aged between 10 and 29 years. Data were collected through interviews, observation, and clinical data from the medical charts. The data were analyzed around two themes: the experience of living with the late effects and life satisfaction. The experience revealed by children, adolescents and young adults, survivors of cancer, showed that they feel the impact of late effects in their lives. The intensity of these effects varied according to age groups, socio-cultural context, support health service and their families. PMID- 24488461 TI - [Care integrality in HIV testing: the look of women]. AB - The positive detection during partum labor makes women weak and generates specific care demands. The aim of this research was to analyze professional care to women with positive result from fast HIV test based on the point of view of women who knew the positive result during partum labor or postpartum. This is an exploratory study with a qualitative approach. Data were collected through semi structured interviews and analyzed using the discourse analysis technique. It was observed that the relations of care for women with positive rapid HIV test are far away from integrality, since they remain distant and superficial, being guided by the biomedical model. The mainstreaming of integrality in health care requires consideration by the professional, public health system managers, as well as training of those professionals. PMID- 24488460 TI - [Rituals of care performed by families in preparing for the experience of planned home birth]. AB - This ethnographic study aimed to understand the rituals of care performed by families, while preparing for the experience of planned home birth. 25 families participated in the period September 2010 to April 2011. The techniques of data collection were participant observation and interview. Through the processes of apprehension, synthesis, theorization and re-contexture, two categories emerged: The house to be born in and Preparing baby's arrival. Homebirth is an experience built within the pregnant couple. The house is considered the sacred place to experience childbirth, aggregating existential values to the physiological act of giving birth. Understanding these rituals contributes to offer a nursing care of quality in order to respect the cultural aspects involved in this assistance. PMID- 24488462 TI - [Marks on oneself: experiencing the pain of (self) preconception]. AB - Qualitative research whose objective was to understand the social representations of the body by women with alterations caused by leprosy, for nursing care can meet more broadly to your needs. The theoretical framework was the social representations. Forty-three women participated, all of them from a reference unit specialized in sanitary dermatology. Interviews were conducted, which contents were processed by the software ALCESTE, generating a class whose words were associated with preconception anchored in the negative perception of leprosy. The explanatory framework of social representations showed a strong brand of the social memory of leprosy, whose symbolic construction sustains itself on fear of the disease. It was concluded on the need to invest in the deconstruction of archaic beliefs about leprosy so that to have new ways of acting towards the disease. PMID- 24488463 TI - [Prevalence and sociodemographic factors associated with frailty in elderly women]. AB - Cross-sectional study that aimed to estimating the prevalence of frailty in older women living in the city of Joao Pessoa, Paraiba, Brazil; and to identify possible associations between frailty and socio-demographic variables. The sample included 166 elderly women were interviewed in their home between April and June 2011. For data was collected using a structure instrument to questions on socio demographic variables and the Edmonton Frail Scale. The descriptive data analysis, performed by SPSS 15.0, showed that most elderly women 60.8% showed some degree of fragility. Among them, 21.7% were apparently vulnerable, 23.5% mild frailty, 7.8% moderate and 7.8% severe frailty. It was found an association of the phenomena with age, education and income, conditions under which nurses must act in order to prevent the event. PMID- 24488464 TI - [Functional capacity of elderly patients attended in SUS primary healthcare units]. AB - This study aimed to analyze the functional capacity of elderly registered in Basic Health Units of Guarapuava-PR, Brazil. The subjects were 359 elderly, interviewed from January to April 2010, using Section I and IV of the questionnaire Brazil Old Age Schedule. The results showed that 89.9% had some degree of dependency, of which 70.8% light and 19.2% moderate or severe dependence. Women have a higher degree of mild (70.5%) and moderate and severe dependence (62.3%). Factors associated with the degree of dependence among the elderly living in Guarapuava were age, schooling, living arrangements, employment, place of residence, marital status and family income. It is concluded that most of the elderly in the community is affected by limitations and live with some kind of dependence to perform basic activities of daily living. PMID- 24488465 TI - [Functional ability of elderly with chronic diseases living in Long-Stay Institutions]. AB - The study aimed to describe the functional performance and the presence of chronic diseases in 164 elderly residents in long-stay institutions in Recife-PE, Brazil .A socio-demographic questionnaire, the Functional Independence Measurement, Lawton's scale and the Mini-Mental test were applied. Analysis of variance was used to assess differences in performance. The elders were predominantly single, women, and with low educational level. Among the reasons for admission stood out: abandonment, fragile health and living in the streets. It was found a high percentage of chronic diseases; 70% of elders were dependent for activities of daily living; and all were dependent for instrumental activities. Dementia was the disease that most affected functionality, followed by the osteoarticulares diseases and mental disorder. It was highlighted, among the impaired activities, the use of stairs and the sphincter control, with eating as the best performance. It was found that the institutionalized elderly showed functional impairment and social vulnerability. PMID- 24488466 TI - [Social control of the Single Health System: what think the municipal health counselors]. AB - This study uses a qualitative approach based on semi-structured interview for analyzing the social control perspective of health counselors, considering that there are still challenges for the consolidation of community participation. It was identified that some counselors do not recognize the social participation as a Single Health System directive. Despite the recognition of the councils as deliberative spaces, there are difficulties such as the centralization of decisions in the management, an over evaluation of technical knowledge and lack of health conferences. There are limitations on the exercise of effective advisory role because of the influence of the municipal administration, difficulties of communication with the bases of representation and access to information. It is concluded that it is necessary to search for the strengthening of social control to highlight the continuing health education for empowerment of counselors inside the councils established by the Health Pact. PMID- 24488467 TI - [Health promotion and community participation in organized local groups]. AB - The study aimed at knowing the articulation of groups locally organized with the team of professionals of Family Health Strategy for promoting socio-environmental health. It was used the recorded semi-structured interview technique with 70 participants of 13 groups investigated, analyzed according to qualitative approach of content. The category consumer participation revealed the professional and collective mobilization for participative management in health. The interest in participating in groups locally organized indicates the individual propositions which increase collectively and can be noticed in the service of psychological basic human and socio-environmental necessities. PMID- 24488468 TI - [Learning trends in the production of knowledge in nursing education in the state of Sao Paulo]. AB - This is a qualitative, descriptive, exploratory and analytical research, with documentary basis. The objective was to characterize and analyze teaching trends found in scientific articles related to the topic Education in Nursing, captured from the publication of the researchers of Research Groups in Nursing Education of the State of Sao Paulo from 2004 to 2010. We identified the following teaching trends: Traditional, Renewed, Tecnicist, Liberating and Critical Social-Contents. We analyzed 131 studies, of which 46.56% are graded in trends centrally marked by political and social concerns. He noticed a movement in search of intense transformation of Nursing Education within Research Groups. A large concentration of studies grounded in liberating tendencies or the ambition to adopt such postures, reveals a positive factor of Research Groups in Nursing Education. PMID- 24488469 TI - [The action control scale for diagnosing performance in nursing students]. AB - Quantitative research aimed to verify the relevance of Action Control Theory for the identification of risk for poor performance in the planning of preventive care for pressure ulcers. The action - state orientation deals with individual differences and the ability to regulate emotions, cognitions and attitudes to complete the intentional actions. The instruments used were the Student Assessment Instrument and HAKEMP 90, derived from this theory, in 46 undergraduate nursing students. The analysis showed high sensitivity (0.84) for the diagnosis of risk for poor performance and high specificity (0.90) for detecting the absence of risk in the care planning. The results suggest the HAKEMP 90 as a diagnostic tool for identifying essential elements of nursing education as active learning, regulation of cognitive processes and relevance of basic nursing care in hospital. PMID- 24488470 TI - [Internet use in primary data collection in nursing research]. AB - This is an experience report on the use of an instrument to collect data from primary sources available on the Internet. Considering the advances in technology that are changing the formation and the professional scenarios, the use of informatics in nursing research encourages the development of methodologies and information search. This study described since the construction of the instrument to collect data and revealed the possibility of facilities like approach much interviewed and offered a similar instrument used by professionals. The main difficulty was the low rate of response. It was considered a positive experience and even the low return of responses did not compromise the results of the qualitative study. It is expected that, in the near future, professionals use computational tools and make them instruments of performance in the routine of health services. PMID- 24488471 TI - [Letter from Rio de Janeiro to Brazilian nursing]. PMID- 24488473 TI - Stomatal movement and potassium transport in epidermal strips of Zea mays: The effect of CO2. AB - The correlation between stomatal action and potassium movement in the epidermis of Zea mays was examined in isolated epidermal strips floated on distilled water. Stomatal opening in the isolated epidermis is reversible in response to alternate periods of light or darkness, and is always correlated with a shift in the potassium content of the guard cells. K accumulates in guard cells during stomatal opening, and moves from the guard cells into the subsidiary cells during rapid stomatal closure. When epidermal strips are illuminated in normal air, as against CO2-free air, the stomata do not open and there is a virtually complete depletion of K from the stomatal apparatus. In darkness CO2-containing air inhibits stomatal opening and K accumulation in guard cells, but does not lead to a depletion of K from the stomata as observed in the light. PMID- 24488474 TI - Stomatal movement in Zea mays: Shuttle of potassium and chloride between guard cells and subsidiary cells. AB - When stomates of Zea mays open K and Cl migrate from the subsidiary cells into the guard cells; when the stomates close both elements return to the subsidiary cells. Subsidiary cells function as reservoirs for K and Cl. Import of K and Cl into the guard cells and loss of both elements from the guard cells become observable 1 or 2 min after light is turned on or off, both when histochemical methods and the electron-probe microanalyzer are used for detection. Each stomatal complex of maize contains on the average 10+/-3*10(-13) gram equivalents (eq) of K and 4+/-1*10(-13) eq of Cl. Guard cells accumulate K in the light and CO2-free air at an average rate of 10*10(-15) eq K per minute, and Cl at approximately half that rate. PMID- 24488475 TI - Increase in ribonuclease activity following mechanical damage to leaf and tuber tissues of Solanum tuberosum L. AB - Major increases occurred in the capacity of damaged potato leaf and tuber tissues to hydrolyse ribonucleic acid whilst relatively minor increases were found in the activity of acid phosphomonoesterase and acid phosphodiesterase. Partial purification of homogenates by gel filtration on Sephadex G-100 revealed that much of the increased capacity to degrade ribonucleic acid following damage was due to increased ribonuclease activity. Although appreciable differences in the elution patterns of tuber homogenates subjected to gel filtration were observed before and after the breaking of dormancy the increased ribonuclease activity following damage was a constant feature. Actinomycin D had a relatively small effect on preventing these increases in phosphate-ester hydrolase activities whilst the effect of cycloheximide was very pronounced. Isopycnic equilibrium centrifugation experiments, using deuterium oxide as a density label, provided no evidence that the increased enzyme activity following damage was due to synthesis of new enzyme. PMID- 24488476 TI - Purification of a ribonuclease from potato tubers and its use as an antigen in the immunochemical assay of this protein following tuber damage. AB - A method for the purification of a ribonuclease from potato tubers is described. The preparation was free from deoxyribonuclease and phosphodiesterase activities and possessed only slight phosphomonoesterase activity. Specific antibodies against the ribonuclease preparation were raised in rabbits. Two precipitin arcs were observed on Ouchterlony plates and three by the use of immunoelectrophoresis suggesting that the preparation contained three antigens. Development of one of the arcs on the diffusion plates could be prevented by prior absorption of the RNase preparation with an antiserum specific for phosphomonoesterase from potato tubers. Two of the arcs developing upon immunoelectrophoresis, one of which had low electrophoretic mobility and the other which migrated to the anode, corresponded in position to that of ribonuclease fractionated by agar gel electrophoresis. The remaining arc corresponded to the position of that arising when the RNase antigen was cross-reacted with specific antibodies against phosphomonoesterase from potato tubers. It was concluded that the anti-acid RNase antiserum may be useful for the immunochemical assay of RNase protein when used in conjunction with an anti-phosphomonoesterase antiserum and it was used for this purpose with homogenates derived from damaged and undamaged tuber tissue cv. Majestic. The observations suggested that RNase protein did not parallel the increase in ribonuclease activity following tissue damage and it was concluded that the enhanced RNase activity following mechanical damage may be due to activation of the pre-formed enzyme. PMID- 24488477 TI - The effect of 2,4-dichlorophenoxyacetic acid and (2-chloroethyl) trimethylammonium chloride on chlorophyll synthesis in barley leaves. AB - 2.4-dichlorophenoxyacetic acid (2.4-D) and (2-chloroethyl)-trimethylammonium chloride (CCC) inhibit chlorophyll synthesis and protochlorophyllide 652 regeneration in 6-8 day old barley leaves whilst having little effect on the rates of protochlorophyll 632 synthesis from exogenous delta-aminelevulinic acid (ALA) and ALA-dehydratase activity. Longer pretreatments with 2.4-D and CCC show it is only after 50 to 60 hr that the rates of P632 production from exogenous ALA and ALA-dehydratase activity are affected. Similar response times were obtained for chloramphenicol (CAP). The results indicate that 2.4-D and CCC may act by directly inhibiting specific plastid-protein synthesis similar to CAP. Hence it seems that it is only those proteins (enzymes) having a rapid turnover that are affected first i.e. the enzymes necessary for ALA synthesis in the plastid. PMID- 24488478 TI - [The rate of photosynthesis of different stalk regions of Acetabularia mediterranea]. AB - The rate of photosynthesis ((14)C-incorporation) of cell parts isolated from the stalk of the alga Acetabularia mediterranea is highest in parts derived from the tip region and lowest in parts from the basal region of the stalk (Table 1).Similar results are obtained when whole cells are used for photosynthesis and divided afterwards into tip region, basal region and middle region (Fig. 1, Table 2).There is a gradient of photosynthetic capacity within the stalk which shows a pattern similar to that demonstrated for the morphogenetic capacity of the different stalk regions. PMID- 24488480 TI - Erratum. PMID- 24488479 TI - Ethylene-light relationship in the growth of the rice coleoptile. AB - Ethylene stimulated growth of rice coleoptiles in the dark and after an irradiation with red light. The red-light inhibition of rice-coleoptile growth was more pronounced when only endogenously evolved C2H4 was involved than it was under C2H4-free (C2H4 removed) or C2H4-saturated (20 ppm C2H4 added) conditions. PMID- 24488481 TI - A fast NMR method for resonance assignments: application to metabolomics. AB - We present a new method for rapid NMR data acquisition and assignments applicable to unlabeled ((12)C) or (13)C-labeled biomolecules/organic molecules in general and metabolomics in particular. The method involves the acquisition of three two dimensional (2D) NMR spectra simultaneously using a dual receiver system. The three spectra, namely: (1) G-matrix Fourier transform (GFT) (3,2)D [(13)C, (1)H] HSQC-TOCSY, (2) 2D (1)H-(1)H TOCSY and (3) 2D (13)C-(1)H HETCOR are acquired in a single experiment and provide mutually complementary information to completely assign individual metabolites in a mixture. The GFT (3,2)D [(13)C, (1)H] HSQC TOCSY provides 3D correlations in a reduced dimensionality manner facilitating high resolution and unambiguous assignments. The experiments were applied for complete (1)H and (13)C assignments of a mixture of 21 unlabeled metabolites corresponding to a medium used in assisted reproductive technology. Taken together, the experiments provide time gain of order of magnitudes compared to the conventional data acquisition methods and can be combined with other fast NMR techniques such as non-uniform sampling and covariance spectroscopy. This provides new avenues for using multiple receivers and projection NMR techniques for high-throughput approaches in metabolomics. PMID- 24488484 TI - In vitro characterization of uptake mechanism of L-[methyl-(3)H]-methionine in hepatocellular carcinoma. AB - PURPOSE: Methionine (Met) could be a useful imaging biomarker for the diagnosis of hepatocellular carcinoma (HCC), as demonstrated by PET imaging with L-[methyl (11)C]-Met. In HCC cells, protein synthesis mainly contributes to radiopharmaceutical uptake. In contrast, lipid synthesis via the phosphatidylethanolamine (PE) methylation pathway is the major metabolic route of L-[methyl-(11)C]-Met in normal hepatocytes, which contributes to the background contrast observed in PET images. However, the mechanisms of amino acid transport and the roles of the two key enzymes, methionine adenosyltransferase (MAT) and phosphatidylethanolamine N-methyltransferase (PEMT), are not yet completely understood. The aim of this study was to investigate the roles of the amino acid transporters and these two key enzymes in the uptake of L-[methyl-(11)C]-Met in HCC cells. PROCEDURES: A well-differentiated woodchuck HCC cell line, WCH17, was used for the study. The amino acid transporter of WCH17 cells was assayed to investigate the Met transport process in HCC. WCH17 cells were treated with 5 mM S-adenosylmethionine (SAM) for 8, 16, 24, and 48 h to downregulate MAT2A gene expression. Control or SAM-treated WCH17 cells were pulsed with L-[methyl-(3)H] Met for 5 min and chased with cold media to mimic the rapid blood clearance of radiolabeled Met (pulse-chase experiment). In parallel, WCH17 cells were transfected with a mouse liver PEMT2 expression vector, and the pulse-chase experiment was performed to investigate the uptake of the radiolabeled Met in HCC cells. The water-soluble, protein, and lipid phases from the total uptake were subsequently extracted and measured, respectively. RESULTS: Met was transported into HCC cells via a facilitative transport process, which was characterized as system L and ASC-like, Na(+) dependent, and low affinity with partial energy dependence. The total uptake of L-[methyl-(3)H]-Met was decreased in HCC cells with SAM treatment. This reduction pattern followed that of MAT2A expression (the duration of SAM treatment). The incorporated (3)H was mostly distributed in the protein phase and, to a lesser degree, in the lipid phase via PE methylation pathway in HCC cells with SAM treatment. The downregulated MAT2A expression led to the decreased uptake in protein and water-soluble phases. In addition, an increased uptake in the lipid phase was observed in WCH17 cells transfected with PEMT2 expression vector. CONCLUSIONS: The amino acid transport processes may be responsible for the rapid accumulation of radiolabeled Met after the intravenous injection of tracers for the imaging of HCC. Upregulated MAT2A expression and impaired PEMT2 activities in HCC are associated with the specific metabolic pattern of L-[methyl-(11)C]-Met detected by PET. PMID- 24488483 TI - Nephron number and its determinants in early life: a primer. AB - Although there is wide variation, humans possess on average 900,000 nephrons per kidney. So far as is known, nephrons cannot regenerate; therefore, an individual's nephron endowment has profound implications in determining his or her long-term risk of developing chronic kidney disease. Most of the variability in human nephron number is determined early in life. Nephrogenesis is a complex and carefully orchestrated process that occurs during a narrow time window until 36 weeks gestation in humans, and disruption of any part of this sequence may lead to reduced nephron number. In utero, genetic abnormalities, toxic insults, and nutritional deficiencies can each alter final nephron number. Infants born prematurely must continue nephrogenesis in an ex utero environment where there may be multiple threats to successful nephrogenesis. Once the nephron endowment is determined, postnatal factors (such as acute kidney injury or chronic illnesses) can only decrease nephron number. Current techniques for estimating nephron number require an invasive procedure or complete destruction of the tissue, making noninvasive means for counting nephron surgently needed. A better understanding of nephron number and its determinants, particularly during growth and maturation, could allow the development of therapies to support, prolong, or resume nephrogenesis. PMID- 24488485 TI - Late hypertension in patients with repaired aortic coarctation. AB - Coarctation of the aorta represents more than a simple obstructive lesion, as there is often evidence of hypertension and vascular dysfunction despite successful surgery at an early age. There are ample data showing that a large proportion of patients develop arterial hypertension, and this appears to increase with age. Our understanding of the pathogenesis of late hypertension is incomplete, and there is limited information on which drugs are most appropriate. Increased arterial rigidity is now well described in this patient group, although it is not known how this should influence therapy. The increase in afterload associated with this increased rigidity has been found to have an impact on the left ventricle at an early stage, and the interaction between the vascular dysfunction and the ventricle is an area of interest and active research. This article reviews some recent studies and highlights areas where research questions remain. PMID- 24488486 TI - Status in calculating electronic excited states in transition metal oxides from first principles. AB - Characterization of excitations in transition metal oxides is a crucial step in the development of these materials for photonic and optoelectronic applications. However, many transition metal oxides are considered to be strongly correlated materials, and their complex electronic structure is challenging to model with many established quantum mechanical techniques. We review state-of-the-art first principles methods to calculate charged and neutral excited states in extended materials, and discuss their application to transition metal oxides. We briefly discuss developments in density functional theory (DFT) to calculate fundamental band gaps, and introduce time-dependent DFT, which can model neutral excitations. Charged excitations can be described within the framework of many-body perturbation theory based on Green's functions techniques, which predominantly employs the GW approximation to the self-energy to facilitate a feasible solution to the quasiparticle equations. We review the various implementations of the GW approximation and evaluate each approach in its calculation of fundamental band gaps of many transition metal oxides. We also briefly review the related Bethe Salpeter equation (BSE), which introduces an electron-hole interaction between GW derived quasiparticles to describe accurately neutral excitations. Embedded correlated wavefunction theory is another framework used to model localized neutral or charged excitations in extended materials. Here, the electronic structure of a small cluster is modeled within correlated wavefunction theory, while its coupling to its environment is represented by an embedding potential. We review a number of techniques to represent this background potential, including electrostatic representations and electron density-based methods, and evaluate their application to transition metal oxides. PMID- 24488487 TI - Post-transcriptional regulation of ITGB6 protein levels in damaged skeletal muscle. AB - We have identified integrin beta 6 (Itgb6) as a transcript highly enriched in skeletal muscle. This finding is unexpected because Itgb6 is typically associated with epithelial expression domains in normal tissue. Further we find that ITGB6 protein expression in muscle is post-transcriptionally regulated. Uninjured muscle expresses Itgb6 RNA but no ITGB6 protein is detectable. Muscle injury induces ITGB6 protein accumulation rapidly post-injury in myofibers adjacent to the site of injury. As regeneration of the injured muscle tissue progresses ITGB6 protein is found in newly formed fibers up to at least 15 days post-injury. PMID- 24488488 TI - Resveratrol does not increase body fat loss induced by energy restriction. AB - Resveratrol (RSV) is known to have an antiobesogenic effect because it mimics energy restriction. However, hardly any evidence exists concerning the combined effects of RSV and energy restriction on body fat reduction. So, the aim of the present study was to determine whether RSV increases body fat reduction induced by energy restriction. Male Wistar rats were fed a high-fat, high-sucrose diet for 6 weeks to obtain a diet-induced obesity model. Then they were submitted to a mild energy restriction (25%) without or with RSV supplementation (30 mg/kg body weight/day) for 2 weeks. Final body weight, subcutaneous and intra-abdominal white adipose tissues weights, Adipose Index, and serum triacylglycerol, cholesterol, glucose, and insulin were assessed. Lipoprotein lipase (LPL), fatty acid synthase (FAS), and acetyl coenzyme A carboxylase (ACC) activities, as well as their genetic expressions, were measured in white adipose tissue. Final body weight, white adipose tissue weights, Adipose Index, and serum triacylglycerol, cholesterol, and insulin were reduced in both groups, but no differences were found among them. FAS, ACC, and LPL activities and expressions were also similar in both groups. These results suggest a lack of any adjuvant effect of RSV on energy restriction for obesity treatment purposes. PMID- 24488489 TI - Is there an optimal dose for dietary linoleic acid? Lessons from essential fatty acid deficiency supplementation and adipocyte functions in rats. AB - Differential effects of n-3 and n-6 polyunsaturated fatty acids (PUFAs) have been demonstrated on adipose tissue physiology. Facing to the widely recognized beneficial effects of n-3 PUFAs, the n-6 PUFA effects remain controversial. Thus, we further analyzed the linoleic acid (LA) influence on adipocyte functions. To this aim, we treated by LA supplementation at three distinct doses (1, 2.5, or 5% of energy intake) rats with essential fatty acids deficiency (EFAD). PUFA composition was determined in blood and white adipose tissue (WAT), while lipolytic and lipogenic activities were measured in isolated adipocytes. EFAD rats exhibited reduced WAT mass and increased EFAD biomarkers. WAT mass was completely recovered after supplementation, irrespective of LA dose. However, neither body mass nor EFAD biomarkers returned to control with 1% LA, while LA abundance doubled in adipocytes from rats supplemented with 5% LA. Regarding lipolysis, 2.5% LA normalized the EFAD-induced alterations. A trend to decrease the maximal stimulation of lipolysis was observed with 1 and 5% LA. Regarding lipogenesis, the lower and higher LA doses increased basal activity and hampered insulin to further stimulate glucose incorporation into lipids whereas 2.5% LA normalized the basal or insulin-stimulated levels. Our results show that dietary linoleate at 2.5% restored anatomical, biochemical, and functional disturbances induced by EFAD. At higher dose, LA tended to reduce triacylglycerol breakdown, to increase triacylglycerol assembly, and to provoke insulin resistance. Therefore, LA influence on adipocyte functions does not appear to follow a typical dose-response relationship, adding further complexity to the definition of its dietary requirement. PMID- 24488490 TI - Effect of lifestyle intervention on the reproductive endocrine profile in women with polycystic ovarian syndrome: a systematic review and meta-analysis. AB - Polycystic ovarian syndrome (PCOS) affects 18-22% of women at reproductive age. We conducted a systematic review and meta-analysis evaluating the expected benefits of lifestyle (exercise plus diet) interventions on the reproductive endocrine profile in women with PCOS. Potential studies were identified by systematically searching PubMed, CINAHL and the Cochrane Controlled Trials Registry (1966-April 30, 2013) systematically using key concepts of PCOS. Significant improvements were seen in women receiving lifestyle intervention vs usual care in follicle-stimulating hormone (FSH) levels, mean difference (MD) 0.39 IU/l (95% CI 0.09 to 0.70, P=0.01), sex hormone-binding globulin (SHBG) levels, MD 2.37 nmol/l (95% CI 1.27 to 3.47, P<0.0001), total testosterone levels, MD -0.13 nmol/l (95% CI -0.22 to -0.03, P=0.008), androstenedione levels, MD -0.09 ng/dl (95% CI -0.15 to -0.03, P=0.005), free androgen index (FAI) levels, MD -1.64 (95% CI -2.94 to -0.35, P=0.01) and Ferriman-Gallwey (FG) score, MD -1.01 (95% CI -1.54 to -0.48, P=0.0002). Significant improvements were also observed in women who received exercise-alone intervention vs usual care in FSH levels, MD 0.42 IU/l (95% CI 0.11 to 0.73, P=0.009), SHBG levels, MD 3.42 nmol/l (95% CI 0.11 to 6.73, P=0.04), total testosterone levels, MD -0.16 nmol/l (95% CI -0.29 to -0.04, P=0.01), androstenedione levels, MD -0.09 ng/dl (95% CI -0.16 to 0.03, P=0.004) and FG score, MD -1.13 (95% CI -1.88 to -0.38, P=0.003). Our analyses suggest that lifestyle (diet and exercise) intervention improves levels of FSH, SHBG, total testosterone, androstenedione and FAI, and FG score in women with PCOS. PMID- 24488491 TI - Plasma signature of neurological disease in the monogenetic disorder Niemann-Pick Type C. AB - Early diagnosis of neurological disorders would greatly improve their management and treatment. A major hurdle is that inflammatory products of cerebral disease are not easily detected in blood. Inflammation in multiple organs and heterogeneity in disease present additional challenges in distinguishing the extent to which a blood-based marker reflects disease in brain or other afflicted organs. Murine models of the monogenetic disorder Niemann-Pick Type C present aggressive forms of cerebral and liver inflammatory disease. Microarray analyses previously revealed age-dependent changes in innate immunity transcripts in the mouse brain. We have now validated four putative secretory inflammatory markers that are also elevated in mouse liver. We include limited, first time analysis of human Niemann-Pick Type C liver and cerebellum. Furthermore, we utilized 2 hydroxypropyl-beta-cyclodextrin (HPbetaCD, an emerging therapeutic) administered intraperitoneally in mice, which abrogates inflammatory pathology in the liver but has limited effect on the brain. By analyzing the corresponding effects on inflammatory plasma proteins, we identified cathepsin S as a lead indicator of liver disease. In contrast, lysozyme was a marker of both brain and liver disease. 2-Hydroxypropyl-beta-cyclodextrin had no effect on transcripts of neuron specific 24-hydroxylase, and its product 24(S)-hydroxycholesterol was not a useful indicator in mouse plasma. Our data suggest that dual analysis of levels of the inflammatory markers lysozyme and cathepsin S may enable detection of multiple distinct states of neurodegeneration in plasma. PMID- 24488492 TI - The methyltransferase WBSCR22/Merm1 enhances glucocorticoid receptor function and is regulated in lung inflammation and cancer. AB - Glucocorticoids (GC) regulate cell fate and immune function. We identified the metastasis-promoting methyltransferase, metastasis-related methyltransferase 1 (WBSCR22/Merm1) as a novel glucocorticoid receptor (GR) regulator relevant to human disease. Merm1 binds the GR co-activator GRIP1 but not GR. Loss of Merm1 impaired both GR transactivation and transrepression by reducing GR recruitment to its binding sites. This was accompanied by loss of GR-dependent H3K4Me3 at a well characterized promoter. Inflammation promotes GC resistance, in part through the actions of TNFalpha and IFNgamma. These cytokines suppressed Merm1 protein expression by driving ubiquitination of two conserved lysine residues. Restoration of Merm1 expression rescued GR transactivation. Cytokine suppression of Merm1 and of GR function was also seen in human lung explants. In addition, striking loss of Merm1 protein was observed in both inflammatory and neoplastic human lung pathologies. In conclusion, Merm1 is a novel regulator of chromatin structure affecting GR recruitment and function, contributing to loss of GC sensitivity in inflammation, with suppressed expression in pulmonary disease. PMID- 24488493 TI - Structure of the chicken CD3epsilondelta/gamma heterodimer and its assembly with the alphabetaT cell receptor. AB - In mammals, the alphabetaT cell receptor (TCR) signaling complex is composed of a TCRalphabeta heterodimer that is noncovalently coupled to three dimeric signaling molecules, CD3epsilondelta, CD3epsilongamma, and CD3zetazeta. The nature of the TCR signaling complex and subunit arrangement in different species remains unclear however. Here we present a structural and biochemical analysis of the more primitive ancestral form of the TCR signaling complex found in chickens. In contrast to mammals, chickens do not express separate CD3delta and CD3gamma chains but instead encode a single hybrid chain, termed CD3delta/gamma, that is capable of pairing with CD3epsilon. The NMR structure of the chicken CD3epsilondelta/gamma heterodimer revealed a unique dimer interface that results in a heterodimer with considerable deviation from the distinct side-by-side architecture found in human and murine CD3epsilondelta and CD3epsilongamma. The chicken CD3epsilondelta/gamma heterodimer also contains a unique molecular surface, with the vast majority of surface-exposed, nonconserved residues being clustered to a single face of the heterodimer. Using an in vitro biochemical assay, we demonstrate that CD3epsilondelta/gamma can assemble with both chicken TCRalpha and TCRbeta via conserved polar transmembrane sites. Moreover, analogous to the human TCR signaling complex, the presence of two copies of CD3epsilondelta/gamma is required for zetazeta assembly. These data provide insight into the evolution of this critical receptor signaling apparatus. PMID- 24488494 TI - Transcriptional factors smad1 and smad9 act redundantly to mediate zebrafish ventral specification downstream of smad5. AB - Bone morphogenetic proteins (BMPs) are multifunctional growth factors that play crucial roles during embryonic development and cell fate determination. Nuclear transduction of BMP signals requires the receptor type Smad proteins, Smad1, Smad5, and Smad9. However, how these Smad proteins cooperate in vivo to regulate various developmental processes is largely unknown. In zebrafish, it was widely believed that the maternally expressed smad5 is essential for dorso-ventral (DV) patterning, and the zygotically transcribed smad1 is not required for normal DV axis establishment. In the present study, we have identified zygotically expressed smad9, which cooperates with smad1 downstream of smad5, to mediate zebrafish early DV patterning in a functional redundant manner. Although knockdown of smad1 or smad9 alone does not lead to visible dorsalization, double knockdown strongly dorsalizes zebrafish embryos, which cannot be efficiently rescued by smad5 overexpression, whereas the dorsalization induced by smad5 knockdown can be fully rescued by overexpression of smad1 or smad9. We have further revealed that the transcription initiations of smad1 and smad9 are repressed by each other, that they are direct transcriptional targets of Smad5, and that smad9, like smad1, is required for myelopoiesis. In conclusion, our study uncovers that smad1 and smad9 act redundantly to each other downstream of smad5 to mediate ventral specification and to regulate embryonic myelopoiesis. PMID- 24488496 TI - The Drosophila small GTPase Rac2 is required for normal feeding and mating behaviour. AB - All multicellular organisms require the ability to regulate bodily processes in order to maintain a stable condition, which necessitates fluctuations in internal metabolics, as well as modifications of outward behaviour. Understanding the genetics behind this modulation is important as a general model for the metabolic modification of behaviour. This study demonstrates that the activity of the small GTPase Rac2 is required in Drosophila for the proper regulation of lipid storage and feeding behaviour, as well as aggression and mating behaviours. Rac2 mutant males and females are susceptible to starvation and contain considerably less lipids than controls. Furthermore, Rac2 mutants also have disrupted feeding behaviour, eating fewer but larger meals than controls. Intriguingly, Rac2 mutant males rarely initiate aggressive behaviour and display significantly increased levels of courtship behaviour towards other males and mated females. From these results we conclude that Rac2 has a central role in regulating the Drosophila homeostatic system. PMID- 24488497 TI - Perforation of bowel lymphoma: beware of atypical presentations. AB - INTRODUCTION: Intestinal lymphomas can present as surgical complications such as perforation. There is little data regarding the risk factors, clinical features, management, and prognosis of bowel perforation in patients with intestinal lymphoma. The aims of this study were to analyze the risk factors for this complication and to describe the clinical picture. PATIENTS AND METHODS: All patients undergoing surgery for lymphoma-related perforation between 2002 and 2012 in the University Hospital of Dijon were retrospectively analyzed. The clinical, histological, and imaging features were recorded. RESULTS: Six patients underwent emergent laparotomy for this cause: in three patients, the perforation revealed the underlying disease, and in the other three patients, it occurred during chemotherapy treatment for known lymphoma. The clinical picture was a typical acute peritonitis in the first group, but was nonspecific and insidious in the chemotherapy-induced group. In all cases, aggressive lymphomas were present, and three patients had coexisting infection with the human immunodeficiency virus. CONCLUSION: Lymphoma-related perforation presents as an acute peritonitis in previously untreated patients in which it reveals the disease. However, it may be induced by chemotherapy and present with nonspecific insidious symptoms. The prognosis is also different according to these characteristics. The particularities of this disease warrant its knowledge to ensure an optimal management. PMID- 24488495 TI - RelB-induced expression of Cot, an MAP3K family member, rescues RANKL-induced osteoclastogenesis in alymphoplasia mice by promoting NF-kappaB2 processing by IKKalpha. AB - The alternative nuclear factor-kappaB (NF-kappaB) pathway, mainly the RelB-p52 heterodimer, plays important roles in bone metabolism through an unknown mechanism. We have previously reported that alymphoplasia (aly/aly) mice, which lack active NF-kappaB-inducing kinase (NIK), show mild osteopetrosis due to the inhibition of osteoclastogenesis. p100 retains RelB in the cytoplasm and inhibits RANKL-induced osteoclastogenesis in aly/aly cells. Furthermore, the overexpression of RelB in aly/aly cells rescues RANKL-induced osteoclastogenesis by inducing p100 processing. In contrast, the overexpression of p65 in aly/aly cells has no effect. However, the overexpression of RelB fails to rescue RANKL induced osteoclastogenesis in the presence of p100DeltaGRR, which cannot be processed to p52, suggesting that p100 processing is a key step in RelB-rescued, RANKL-induced osteoclastogenesis in aly/aly cells. In this study, Cot (cancer Osaka thyroid), an MAP3K, was up-regulated by RelB overexpression. Analysis of the Cot promoter demonstrated that p65 and RelB bound to the distal NF-kappaB binding site and that RelB but not p65 bound to the proximal NF-kappaB-binding site in the Cot promoter. The knocking down of Cot expression significantly reduced the RANKL-induced osteoclastogenesis induced by RelB overexpression. The phosphorylation of IKKalpha at threonine 23 and its kinase activity were indispensable for the processing of p100 and osteoclastogenesis by RelB-induced Cot. Finally, constitutively activated Akt enhanced osteoclastogenesis by RelB induced Cot, and a dominant-negative form of Akt significantly inhibited it. Taken together, these results indicate that the overexpression of RelB restores RANKL-induced osteoclastogenesis by activation of Akt/Cot/IKKalpha-induced p100 processing. PMID- 24488498 TI - The preventive effects of low-dose enteric-coated aspirin tablets on the development of colorectal tumours in Asian patients: a randomised trial. AB - OBJECTIVE: To evaluate the influence of low-dose, enteric-coated aspirin tablets (100 mg/day for 2 years) on colorectal tumour recurrence in Asian patients with single/multiple colorectal tumours excised by endoscopy. DESIGN: A double blinded, randomised, placebo-controlled multicentre clinical trial was conducted. PARTICIPANTS: 311 subjects with single/multiple colorectal adenomas and adenocarcinomas excised by endoscopy were enrolled in the study (152 patients in the aspirin group and 159 patients in the placebo group). Enrolment began at the hospitals (n=19) in 2007 and was completed in 2009. RESULTS: The subjects treated with aspirin displayed reduced colorectal tumourigenesis and primary endpoints with an adjusted OR of 0.60 (95% CI 0.36 to 0.98) compared with the subjects in the placebo group. Subgroup analysis revealed that subjects who were non-smokers, defined as those who had smoked in the past or who had never smoked, had a marked reduction in the number of recurrent tumours in the aspirin-treated group. The adjusted OR for aspirin treatment in non-smokers was 0.37 (CI 0.21 to 0.68, p<0.05). Interestingly, the use of aspirin in smokers resulted in an increased risk, with an OR of 3.44. In addition, no severe adverse effects were observed in either group. CONCLUSIONS: Low-dose, enteric-coated aspirin tablets reduced colorectal tumour recurrence in an Asian population. The results are consistent with those obtained from other randomised controlled trials in Western countries. THE CLINICAL TRIAL REGISTRY WEBSITE AND THE CLINICAL TRIAL NUMBER: http://www.umin.ac.jp (number UMIN000000697). PMID- 24488499 TI - Cell lineage distribution atlas of the human stomach reveals heterogeneous gland populations in the gastric antrum. AB - OBJECTIVE: The glands of the stomach body and antral mucosa contain a complex compendium of cell lineages. In lower mammals, the distribution of oxyntic glands and antral glands define the anatomical regions within the stomach. We examined in detail the distribution of the full range of cell lineages within the human stomach. DESIGN: We determined the distribution of gastric gland cell lineages with specific immunocytochemical markers in entire stomach specimens from three non-obese organ donors. RESULTS: The anatomical body and antrum of the human stomach were defined by the presence of ghrelin and gastrin cells, respectively. Concentrations of somatostatin cells were observed in the proximal stomach. Parietal cells were seen in all glands of the body of the stomach as well as in over 50% of antral glands. MIST1 expressing chief cells were predominantly observed in the body although individual glands of the antrum also showed MIST1 expressing chief cells. While classically described antral glands were observed with gastrin cells and deep antral mucous cells without any parietal cells, we also observed a substantial population of mixed type glands containing both parietal cells and G cells throughout the antrum. CONCLUSIONS: Enteroendocrine cells show distinct patterns of localisation in the human stomach. The existence of antral glands with mixed cell lineages indicates that human antral glands may be functionally chimeric with glands assembled from multiple distinct stem cell populations. PMID- 24488500 TI - Neuropsychology of environmental navigation in humans: review and meta-analysis of FMRI studies in healthy participants. AB - In the past 20 years, many studies in the cognitive neurosciences have analyzed human ability to navigate in recently learned and familiar environments by investigating the cognitive processes involved in successful navigation. In this study, we reviewed the main experimental paradigms and made a cognitive-oriented meta-analysis of fMRI studies of human navigation to underline the importance of the experimental designs and cognitive tasks used to assess navigational skills. We performed a general activation likelihood estimation (ALE) meta-analysis of 66 fMRI experiments to identify the neural substrates underpinning general aspects of human navigation. Four individual ALE analyses were performed to identify the neural substrates of different experimental paradigms (i.e., familiar vs. recently learned environments) and different navigational strategies (allocentric vs. egocentric). Results of the general ALE analysis highlighted a wide network of areas with clusters in the occipital, parietal, frontal and temporal lobes, especially in the parahippocampal cortex. Familiar environments seem to be processed by an extended temporal-frontal network, whereas recently learned environments require activation in the parahippocampal cortex and the parietal and occipital lobes. Allocentric strategy is subtended by the same areas as egocentric strategy, but the latter elicits greater activation in the right precuneus, middle occipital lobe and angular gyrus. Our results suggest that different neural correlates are involved in recalling a well-learned or recently acquired environment and that different networks of areas subtend egocentric and allocentric strategies. PMID- 24488502 TI - Impact of treatment beliefs and social network encouragement on initiation of care by VA service users with PTSD. AB - OBJECTIVES: Despite the U.S. Department of Veterans Affairs' (VA) expansion of mental health services to treat VA service users with posttraumatic stress disorder (PTSD), many with PTSD do not engage in treatment. Numerous studies suggest that beliefs about treatment and social network factors, such as encouragement to seek treatment by others, affect engagement; however, prospective studies examining these factors are largely absent in this population. This study sought to understand social and attitudinal factors influencing treatment initiation, which may help to inform outreach interventions for VA service users with PTSD. METHODS: A prospective, national cohort study of mental health care use among veterans recently diagnosed as having PTSD (N=7,645) was undertaken. Data from self-administered surveys and administrative databases were analyzed to assess contributions of treatment-related beliefs and social network encouragement to subsequent mental health care use, after facility, demographic, need, and access factors were controlled. RESULTS: After the analysis controlled for treatment need and accessibility, the odds of initiating mental health care were greater for veterans who believed that they needed help for PTSD or other emotional problems and those who were encouraged to seek help by friends and family. Beliefs about the effectiveness of PTSD treatments were associated with the type of treatment received. Negative illness identity was not a barrier to treatment initiation. CONCLUSIONS: VA service users' social networks, veterans' perceptions of their need for mental health care, and their beliefs about PTSD treatment effectiveness may be fruitful targets for future treatment engagement interventions. PMID- 24488501 TI - Identification of genes required for soil survival in Burkholderia thailandensis by transposon-directed insertion site sequencing. AB - Transposon-directed insertion site sequencing was used to identify genes required by Burkholderia thailandensis to survive in plant/soil microcosms. A total of 1,153 genetic loci fulfilled the criteria as being likely to encode survival characteristics. Of these, 203 (17.6 %) were associated with uptake and transport systems; 463 loci (40.1 %) coded for enzymatic properties, 99 of these (21.4 %) had reduction/oxidation functions; 117 (10.1 %) were gene regulation or sensory loci; 61 (5.3 %) encoded structural proteins found in the cell envelope or with enzymatic activities related to it, distinct from these, 46 (4.0 %) were involved in chemotaxis and flagellum, or pilus synthesis; 39 (3.4 %) were transposase enzymes or were bacteriophage-derived; and 30 (2.6 %) were involved in the production of antibiotics or siderophores. Two hundred and twenty genes (19.1 %) encoded hypothetical proteins or those of unknown function. Given the importance of motility and pilus formation in microcosm persistence the nature of the colonization of the rhizosphere was examined by confocal microscopy. Wild type B. thailandensis expressing red fluorescent protein was inoculated into microcosms. Even though the roots had been washed, the bacteria were still present but they were motile with no attachment having taken place, perhaps being retained in a biofilm. PMID- 24488503 TI - Growth factor-heparan sulfate "switches" regulating stages of branching morphogenesis. AB - The development of branched epithelial organs, such as the kidney, mammary gland, lung, pancreas, and salivary gland, is dependent upon the involvement and interaction of multiple regulatory/modulatory molecules, including soluble growth factors, extracellular matrix components, and their receptors. How the function of these molecules is coordinated to bring about the morphogenetic events that regulate iterative tip-stalk generation (ITSG) during organ development remains to be fully elucidated. A common link to many growth factor-dependent morphogenetic pathways is the involvement of variably sulfated heparan sulfates (HS), the glycosaminoglycan backbone of heparan sulfate proteoglycans (HSPG) on extracellular surfaces. Genetic deletions of HS biosynthetic enzymes (e.g., C5 epimerase, Hs2st), as well as considerable in vitro data, indicate that variably sulfated HS are essential for kidney development, particularly in Wolffian duct budding and early ureteric bud (UB) branching. A role for selective HS modifications by enzymes (e.g., Ext, Ndst, Hs2st) in stages of branching morphogenesis is also strongly supported for mammary gland ductal branching, which is dependent upon a set of growth factors similar to those involved in UB branching. Taken together, these studies provide support for the notion that the specific spatio-temporal HS binding of growth factors during the development of branched epithelial organs (such as the kidney, mammary gland, lung and salivary gland) regulates these complex processes by potentially acting as "morphogenetic switches" during the various stages of budding, branching, and other developmental events central to epithelial organogenesis. It may be that two or more growth factor-selective HS interactions constitute a functionally equivalent morphogenetic switch; this may help to explain the paucity of severe branching phenotypes with individual growth factor knockouts. PMID- 24488504 TI - Predictors of remission and relapse in idiopathic nephrotic syndrome: a prospective cohort study. AB - BACKGROUND: Although most children with idiopathic nephrotic syndrome will respond to corticosteroid therapy, 80-90 % suffer one or more relapses. METHODS: Using Cox proportional hazard models, we analyzed predictors of remission and relapse in 1-year follow-up data on children aged below 15 years with new-onset nephrotic syndrome. RESULTS: Of 129 children, 107 achieved remission with corticosteroid therapy and 86 subsequently relapsed. Boys achieved remission more often than girls (adjusted hazard ratio [AHR] 1.52, 95 % confidence interval (CI) 1.02-2.3). Boys relapsed significantly more frequently than girls (AHR 1.77, 95 % CI 1.11-2.83) and were more likely to have frequently relapsing disease (AHR 3.3, 95 % CI 1.18-9.23). The risk of first relapse increased with the number of days to first remission (AHR 1.02, 95 % CI 1.01-1.04). The risk for a frequently relapsing course increased with a shorter time from remission to first relapse (AHR 0.92, 95 % CI 0.87-0.97). CONCLUSIONS: In idiopathic nephrotic syndrome, boys are more likely to respond initially, more likely to relapse, and to be classified as having frequently relapsing nephrotic syndrome. A decrease in time from remission to first relapse predicts for a frequently relapsing course. PMID- 24488505 TI - Heart rate and blood pressure variability in children with chronic kidney disease: a report from the CKiD study. AB - BACKGROUND: Autonomic nervous system dysfunction and sympathetic nervous system over-activity play important roles in the development of hypertension associated with chronic kidney disease (CKD). In adults, increased blood pressure variability (BPV) appears to be directly related to sympathetic over-activity with increased risk of end-organ damage and cardiovascular events. Decreased heart rate variability (HRV) has been observed in adults with CKD, and is an independent predictor of mortality. METHODS: The purpose of this study was to evaluate BPV and HRV in pediatric patients enrolled in the Chronic Kidney Disease in Children Study. Ambulatory blood pressure monitoring data were available for analysis of 215 person-visits from 144 children that were not receiving antihypertensive medications. RESULTS: BPV and HRV were determined by standard deviation and coefficient of variation for heart rate and systolic and diastolic blood pressure for each patient averaged for wake/sleep periods during 24-h monitoring. Uniformly lower values were displayed during sleep versus wake periods: BPV was 20 % lower during sleep (p < 0.001) and HRV was 30 % lower during sleep (p < 0.001). A significant increase in systolic BPV was observed in hypertensive children compared to children with normal blood pressure (6.9 %, p = 0.009). Increased diastolic BPV was detected among hypertensive children during sleep period compared to children with normal blood pressure (11.5 %, p = 0.008). There was a significant decrease in HRV in hypertensive compared to normotensive children (-8.2 %, p = 0.006). CONCLUSIONS: These findings are similar to those in adult patients and may underscore childhood origin and natural progression of adverse cardiovascular outcomes in adults with CKD. PMID- 24488506 TI - Anterior ischemic optic neuropathy in pediatric peritoneal dialysis: risk factors and therapy. AB - BACKGROUND: Sudden blindness caused by anterior ischemic optic neuropathy (AION) is a rare complication for patients undergoing peritoneal dialysis (PD). Prognosis is generally poor, with AION commonly resulting in permanent visual loss. METHODS: We first describe four case reports of children with AION during PD treatment. We then review ten additional AION cases reported in the literature and compare these 14 affected patients with a control cohort of 59 non-affected patients in the Vienna PD registry. RESULTS: Significant risk factors for AION were identified as median age (4 vs. 27 months; p < 0.001), autosomal recessive polycystic kidney disease (28.6 vs. 3.4%; p = 0.01), anephric status (53.8 vs. 6.8%; p < 0.001) and low to normal blood pressure evidenced by the number of patients having to be treated with antihypertensive medications (14.3 vs. 62.7%; p = 0.01). Severe hypovolemia was reported in 50% of all cases. Outcome was visual loss with optic atrophy in nine patients; five patients had a good visual outcome. The major difference in treatment was a rapid bolus of saline within 12 h after the initial symptoms. CONCLUSIONS: Young age, autosomal recessive polycystic kidney disease, anephric status and hypotension are substantial risk factors for AION. Early hospitalization with vascular refilling within a few hours following onset of blindness leads to improved visual outcome. PMID- 24488507 TI - Effect of alarm therapy on conditioning of central reflex control in nocturnal enuresis: pilot study on changes in prepulse inhibition (PPI). AB - BACKGROUND: Alarm therapy is a long-established first-line therapy for nocturnal enuresis (NE). Desamino-arginine vasopressin (dDAVP) as alternative first-line therapy was shown to increase the prepulse inhibition (PPI) of startle reflexes, thus supporting the hypothesis of a maturational delay of reflex inhibition in NE. Effects of alarm therapy on PPI have not yet been investigated. METHODS: The PPI of startle reflexes was measured in 20 children with NE (13 boys, 7 girls, median age 8.5 years, range 5-13) before and after at least 6 weeks of alarm treatment and compared with repeated PPI measurements in 11 healthy controls (7 boys, 4 girls, median age 8 years, range 6-13). RESULTS: In the NE patients, PPI increased from a median baseline of 20-46% under alarm therapy (p = 0.005), with a reduction from a median of 7 to 2 wet nights per week (p = 0.002). The controls showed no difference in PPI (52% median at first, 40% at second measurement, p = 0.966). CONCLUSIONS: The increase of PPI trough alarm therapy was comparable with that under dDAVP, suggesting an analogous method of action and explaining the alternative or synergistic effect of both therapies. In addition, it further substantiates the hypothesis of a maturational delay of reflex control in NE. PMID- 24488508 TI - Analysis of the abdominal musculo-aponeurotic anatomy in rectus diastasis: comparison of CT scanning and preoperative clinical assessment with direct measurement intraoperatively. AB - PURPOSE: To evaluate and compare the consistency of agreement of two methods for measuring abdominal rectus diastasis (ARD), preoperative computed tomography (CT) scanning and preoperative clinical assessment were compared with direct measurement intraoperatively. METHODS: Fifty-five consecutive patients were retrieved from an ongoing prospective randomised trial comparing two operative techniques for the repair of ARD. All patients underwent a preoperative clinical assessment and CT scan, and the results were compared with intraoperative measurement of the ARD width. Agreement between methods was described with Bland Altman plots (BA plots) and calculated using Lin's Concordance Correlation Coefficient (CCC). RESULTS: The median width of the diastasis was 4.0 cm in the upper midline and 3.0 cm in the lower midline for the intraoperative measurement. BA plots showed that measurements on CT and intraoperatively are not in agreement in the lower midline, whereas the agreement was stronger between the clinical and the intraoperative method. The CCC was higher for clinical vs. intraoperative measurement (0.479) than for CT vs. intraoperative measurement (-0.002) in the lower midline, although the agreement was over all low. CT scanning underestimated the width of the ARD when compared to 87 % of preoperative clinical assessments, and 83 % of intraoperative measurements. Preoperative clinical assessment overestimated ARD in 35 % when compared with intraoperative measurements. CONCLUSION: Clinical assessment prior to surgery provides more accurate information than CT scanning in the assessment of ARD width. CT scanning underestimates ARD width when compared with intraoperative measurement. PMID- 24488509 TI - Carrell et al. respond to "Observational research and the EHR". PMID- 24488510 TI - HealthViEWS: mortality study of female US Vietnam era veterans, 1965-2010. AB - We conducted a retrospective study among 4,734 women who served in the US military in Vietnam (Vietnam cohort), 2,062 women who served in countries near Vietnam (near-Vietnam cohort), and 5,313 nondeployed US military women (US cohort) to evaluate the associations of mortality outcomes with Vietnam War service. Veterans were identified from military records and followed for 40 years through December 31, 2010. Information on underlying causes of death was obtained from death certificates and the National Death Index. Based on 2,743 deaths, all 3 veteran cohorts had lower mortality risk from all causes combined and from several major causes, such as diabetes mellitus, heart disease, chronic obstructive pulmonary disease, and nervous system disease relative to comparable US women. However, excess deaths from motor vehicle accidents were observed in the Vietnam cohort (standardized mortality ratio = 3.67, 95% confidence interval (CI): 2.30, 5.56) and in the US cohort (standardized mortality ratio = 1.91, 95% CI: 1.02, 3.27). More than two-thirds of women in the study were military nurses. Nurses in the Vietnam cohort had a 2-fold higher risk of pancreatic cancer death (adjusted relative risk = 2.07, 95% CI: 1.00, 4.25) and an almost 5-fold higher risk of brain cancer death compared with nurses in the US cohort (adjusted relative risk = 4.61, 95% CI: 1.27, 16.83). Findings of all-cause and motor vehicle accident deaths among female Vietnam veterans were consistent with patterns of postwar mortality risk among other war veterans. PMID- 24488512 TI - Invited commentary: Observational research in the age of the electronic health record. AB - Historically, clinical epidemiologic research has been constrained by the costs and time associated with manually identifying cases and abstracting clinical data. In this issue, Carrell et al. (Am J Epidemiol. 2014;179(6);749-758) report on their impressive success using natural language processing techniques to correctly identify cases of cancer recurrence among women with previous breast cancer. They report a 10-fold decrease in the need for chart abstraction, though with an 8% loss in case detection. This commentary outlines some recent history associated with the development of "high-throughput clinical phenotyping" of electronic health records and speculates on the impact such computational capabilities may have for observational research and patient consent. PMID- 24488511 TI - Using natural language processing to improve efficiency of manual chart abstraction in research: the case of breast cancer recurrence. AB - The increasing availability of electronic health records (EHRs) creates opportunities for automated extraction of information from clinical text. We hypothesized that natural language processing (NLP) could substantially reduce the burden of manual abstraction in studies examining outcomes, like cancer recurrence, that are documented in unstructured clinical text, such as progress notes, radiology reports, and pathology reports. We developed an NLP-based system using open-source software to process electronic clinical notes from 1995 to 2012 for women with early-stage incident breast cancers to identify whether and when recurrences were diagnosed. We developed and evaluated the system using clinical notes from 1,472 patients receiving EHR-documented care in an integrated health care system in the Pacific Northwest. A separate study provided the patient-level reference standard for recurrence status and date. The NLP-based system correctly identified 92% of recurrences and estimated diagnosis dates within 30 days for 88% of these. Specificity was 96%. The NLP-based system overlooked 5 of 65 recurrences, 4 because electronic documents were unavailable. The NLP-based system identified 5 other recurrences incorrectly classified as nonrecurrent in the reference standard. If used in similar cohorts, NLP could reduce by 90% the number of EHR charts abstracted to identify confirmed breast cancer recurrence cases at a rate comparable to traditional abstraction. PMID- 24488513 TI - Figure of the year. PMID- 24488514 TI - Invited commentary: Some advantages of the relative excess risk due to interaction (RERI)--towards better estimators of additive interaction. AB - In the accompanying commentary, Rose and van der Laan (Am J Epidemiol. 2014;179(6):663-669) criticize the relative excess risk due to interaction (RERI) measure, the use of additive interaction, and the weighting approach we developed to assess RERI with case-control data. In this commentary, we note some of the advantages of using additive measures of interaction, such as RERI, in making decisions about targeting interventions toward certain subgroups and in assessing mechanistic interaction. We discuss the relationship between Rose and van der Laan's estimator for case-control data and the one we had previously proposed. We also develop a new doubly robust estimator for determining the RERI with case control data when the prevalence or incidence of the outcome is known. PMID- 24488515 TI - A double robust approach to causal effects in case-control studies. AB - In a recent issue of the Journal, VanderWeele and Vansteelandt (Am J Epidemiol. 2011;174(10):1197-1203) discussed an inverse probability weighting method for case-control studies that could be used to estimate an additive interaction effect, referred to as the "relative excess risk due to interaction." In this article, we reinforce the well-known disadvantages of inverse probability weighting and comment on the desirability of the described parameter. Further, we review an existing double robust estimator not considered by VanderWeele and Vansteelandt, the case-control-weighted targeted maximum likelihood estimator, which has improved properties in comparison with a previously described inverse probability-weighted estimator. This targeted maximum likelihood estimator can be used to target various parameters of interest, and its implementation has been described previously for the risk difference, relative risk, and odds ratio. PMID- 24488516 TI - Rose and van der Laan respond to "Some advantages of the relative excess risk due to interaction". PMID- 24488517 TI - Study on the dynamics of grass microgametophytes from urban vegetation. AB - Urban sprawl and increasing economical pressure on agricultural production raises new unprecedented environmental questions. The presented study proved that higher level of fertilization of the urban vegetation significantly increases the concentration of male microgametophytes in the air during the flowering season. The levels of fertilization had no significant effect on the pollen grain size, nor on the profile and content of the phenolic compounds, however, the content of tryptophan (protein with a key role in allergies) was significantly influenced. The metabolism of tryptophan and its role in human imunilogy is not yet completely understood, however, it is recommended to avoid unnecessary fertilization in urbanized areas. PMID- 24488518 TI - Chemically coupled microwave and ultrasonic pre-hydrolysis of pulp and paper mill waste-activated sludge: effect on sludge solubilisation and anaerobic digestion. AB - The effects of alkali-enhanced microwave (MW; 50-175 degrees C) and ultrasonic (US) (0.75 W/mL, 15-60 min) pretreatments, on solubilisation and subsequent anaerobic digestion efficiency of pulp and paper mill waste-activated sludge, were investigated. Improvements in total chemical oxygen demand and volatile suspended solids (VSS) solubilisation were limited to 33 and 39 % in MW pretreatment only (175 degrees C). It reached 78 and 66 % in combined MW-alkali pretreatment (pH 12 + 175 degrees C), respectively. Similarly, chemical oxygen demand and VSS solubilisation were 58 and 37 % in US pretreatment alone (60 min) and it improved by 66 and 49 % after US-alkali pretreatment (pH 12 + 60 min), respectively. The biogas yield for US 60 min-alkali (pH 12)-pretreated sludge was significantly improved by 47 and 20 % over the control and US 60 reactors, respectively. The biogas generation for MW (150 degrees C)-alkali (pH 12) pretreated sludge was only 6.3 % higher than control; however, it was 8.3 % lower than the MW (150 degrees C) reactor, which was due to the inhibition of anaerobic activity under harsh thermal-alkali treatment condition. PMID- 24488519 TI - Suitability of oil bioremediation in an Artic soil using surplus heating from an incineration facility. AB - A 168-day period field study, carried out in Sisimiut, Greenland, assessed the potential to enhance soil remediation with the surplus heating from an incineration facility. This approach searches a feasible ex situ remediation process that could be extended throughout the year with low costs. Individual and synergistic effects of biostimulation were also tested, in parallel. An interim evaluation at the end of the first 42 days showed that biostimulation and active heating, as separate treatments, enhanced petroleum hydrocarbon (PHC) removal compared to natural attenuation. The coupling of both technologies was even more effective, corroborating the benefits of both techniques in a remediation strategy. However, between day 42 and day 168, there was an opposite remediation trend with all treatments suggesting a stabilization except for natural attenuation, where PHC values continued to decrease. This enforces the "self purification" capacity of the system, even at low temperatures. Coupling biostimulation with active heating was the best approach for PHC removal, namely for a short period of time (42 days). The proposed remediation scheme can be considered a reliable option for faster PHC removal with low maintenance and using "waste heating" from an incineration facility. PMID- 24488520 TI - Source apportionment and location by selective wind sampling and Positive Matrix Factorization. AB - In order to determine the pollution sources in a suburban area and identify the main direction of their origin, PM2.5 was collected with samplers coupled with a wind select sensor and then subjected to Positive Matrix Factorization (PMF) analysis. In each sample, soluble ions, organic carbon, elemental carbon, levoglucosan, metals, and Polycyclic Aromatic Hydrocarbons (PAHs) were determined. PMF results identified six main sources affecting the area: natural gas home appliances, motor vehicles, regional transport, biomass combustion, manufacturing activities, and secondary aerosol. The connection of factor temporal trends with other parameters (i.e., temperature, PM2.5 concentration, and photochemical processes) confirms factor attributions. PMF analysis indicated that the main source of PM2.5 in the area is secondary aerosol. This should be mainly due to regional contributions, owing to both the secondary nature of the source itself and the higher concentration registered in inland air masses. The motor vehicle emission source contribution is also important. This source likely has a prevalent local origin. The most toxic determined components, i.e., PAHs, Cd, Pb, and Ni, are mainly due to vehicular traffic. Even if this is not the main source in the study area, it is the one of greatest concern. The application of PMF analysis to PM2.5 collected with this new sampling technique made it possible to obtain more detailed results on the sources affecting the area compared to a classical PMF analysis. PMID- 24488521 TI - Photodegradation of hexabromocyclododecane (HBCD) by Fe(III) complexes/H2O 2 under simulated sunlight. AB - Hexabromocyclododecane (HBCD) is a globally produced brominated flame retardant used primarily as an additive flame retardant in polystyrene and textile products. Photodegradation of HBCD in the presence of Fe(III)-carboxylate complexes/H2O2 was investigated under simulated sunlight. The degradation of HBCD decreased with increasing pH in the Fe(III)-oxalate solutions. In contrast, the optimum pH was 5.0 for the Fe(III)-citrate-catalyzed photodegradation within the range of 3.0 to 7.0. For both Fe(III)-oxalate and Fe(III)-citrate complexes, the increase of carboxylate concentrations facilitated the photodegradation. The photochemical removal of HBCD was related to the photoreactivity and speciation distribution of Fe(III) complexes. The addition of H2O2 markedly accelerated the degradation of HBCD in the presence of Fe(III)-citrate complexes. The quenching experiments showed that .OH was responsible for the photodegradation of HBCD in the Fe(III)-carboxylate complexes/H2O2 solutions. The results suggest that Fe(III) complexes/H2O2 catalysis is a potential method for the removal of HBCD in the aqueous solutions. PMID- 24488522 TI - Composition and effects of inhalable size fractions of atmospheric aerosols in the polluted atmosphere: part I. PAHs, PCBs and OCPs and the matrix chemical composition. AB - Atmospheric particulate matter (PM) abundance, mass size distribution (MSD) and chemical composition are parameters relevant for human health effects. The MSD and phase state of semivolatile organic pollutants were determined at various polluted sites in addition to the PM composition and MSD. The distribution pattern of pollutants varied from side to side in correspondence to main particle sources and PM composition. Levels of particle-associated polycyclic aromatic hydrocarbons (PAHs) were 1-30 ng m(-3) (corresponding to 15-35 % of the total, i.e., gas and particulate phase concentrations), of polychlorinated biphenyls (PCBs) were 2-11 pg m(-3) (4-26 % of the total) and of DDT compounds were 2-12 pg m(-3) (4-23 % of the total). The PM associated amounts of other organochlorine pesticides were too low for quantification. The organics were preferentially found associated with particles <0.45 MUm of aerodynamic equivalent diameter. The mass fractions associated with sub-micrometer particles (PM0.95) were 73-90 %, 34 71 % and 36-81 % for PAHs, PCBs and DDT compounds, respectively. The finest particles fraction had the highest aerosol surface concentration (6.3-29.7)*10( 6) cm(-1) (44-70 % of the surface concentration of all size fractions). The data set was used to test gas-particle partitioning models for semivolatile organics for the first time in terms of the organics' MSD and size-dependent PM composition. The results of this study prove that at the various sites particles with diverse size, matrix composition, amount of contaminants and toxicological effects occur. Legislative regulation based on gravimetric determination of PM mass can clearly be insufficient for assessment. PMID- 24488523 TI - The combined effects of urea application and simulated acid rain on soil acidification and microbial community structure. AB - Our aim was to test the effects of simulated acid rain (SAR) at different pHs, when applied to fertilized and unfertilized soils, on the leaching of soil cations (K, Ca, Mg, Na) and Al. Their effects on soil pH, exchangeable H(+) and Al(3+) and microbial community structure were also determined. A Paleudalfs soil was incubated for 30 days, with and without an initial application of urea (200 mg N kg(-1)soil) as nitrogen (N) fertilizer. The soil was held in columns and leached with SAR at three pH levels. Six treatments were tested: SAR of pH 2.5, 4.0 and 5.6 leaching on unfertilized soil (T1, T2 and T3), and on soils fertilized with urea (T4, T5 and T6). Increasing acid inputs proportionally increased cation leaching in both unfertilized and fertilized soils. Urea application increased the initial Ca and Mg leaching, but had no effect on the total concentrations of Ca, Mg and K leached. There was no significant difference for the amount of Na leached between the different treatments. The SAR pH and urea application had significant effects on soil pH, exchangeable H(+) and Al(3+). Urea application, SAR treated with various pH, and the interactions between them all had significant impacts on total phospholipid fatty acids (PLFAs). The highest concentration of total PLFAs occurred in fertilized soils with SAR pH5.6 and the lowest in soils leached with the lowest SAR pH. Soils pretreated with urea then leached with SARs of pH 4.0 and 5.6 had larger total PLFA concentrations than soil without urea. Bacterial, fungal, actinomycete, Gram negative and Gram-positive bacterial PLFAs had generally similar trends to total PLFAs. PMID- 24488524 TI - Differential expression of the brassinosteroid receptor-encoding BRI1 gene in Arabidopsis. AB - Brassinosteroid (BR)-regulated growth and development in Arabidopsis depends on BRASSINOSTEROID INSENSITIVE 1 (BRI1), the BR receptor that is responsible for initiating the events of BR signalling. We analysed the temporal and spatial regulation of BRI1 expression using stable transgenic lines that carried BRI1 promoter:reporter fusions. In both seedlings and mature plants the tissues undergoing elongation or differentiation showed elevated BRI1 gene activity, and it could be demonstrated that in the hypocotyl this was accompanied by accumulation of the BRI1 transcript and its receptor protein product. In seedlings the BRI1 promoter was also found to be under diurnal regulation, determined primarily by light repression and a superimposed circadian control. To determine the functional importance of transcriptional regulation we complemented the severely BR insensitive bri1-101 mutant with a BRI1-luciferase fusion construct that was driven by promoters with contrasting specificities. Whereas the BRI1 promoter-driven transgene fully restored the wild phenotype, expression from the photosynthesis-associated CAB3 and the vasculature-specific SUC2 and ATHB8 promoters resulted in plants with varying morphogenic defects. Our results reveal complex differential regulation of BRI1 expression, and suggest that by influencing the distribution and abundance of the receptor this regulation can enhance or attenuate BR signalling. PMID- 24488525 TI - A comparison of the herbicide tolerances of rare and common plants in an agricultural landscape. AB - Declining plant biodiversity in agroecosystems has often been attributed to escalating use of chemical herbicides, but other changes in farming systems, including the clearing of seminatural habitat fragments, confound the influence of herbicides. The present study introduces a new approach to evaluate the impacts of herbicide pollution on plant communities at landscape or regional scales. If herbicides are in fact a key factor shaping agricultural plant diversity, one would expect to see the signal of past herbicide impacts in the current plant community composition of an intensively farmed region, with common, successful species more tolerant to widely used herbicides than rare or declining species. Data from an extensive field survey of plant diversity in Lancaster County, Pennsylvania, USA, were compared with herbicide bioassay experiments in a greenhouse to test the hypothesis that common species possess higher herbicide tolerances than rare species. Five congeneric pairs of rare and common species were treated with 3 commonly used herbicide modes of action in bioassay experiments, and few significant differences were found in the tolerances of rare species relative to common species. These preliminary results suggest that other factors beyond herbicide exposure may be more important in shaping the distribution and abundance of plant species diversity across an agricultural landscape. PMID- 24488526 TI - Interventions for preventing delirium in older people in institutional long-term care. AB - BACKGROUND: Delirium is a common and distressing complication of a range of stressor events including infection, new medications and environment change that is often experienced by older people with frailty and dementia. Older people living in institutional long-term care (LTC)are at high risk of delirium, which increases the risk of admission to hospital, development of or worsening of dementia, and mortality.Delirium is also associated with substantial healthcare costs. Although it is possible to prevent delirium in the hospital setting by providing multicomponent delirium prevention interventions it is currently unclear whether interventions to prevent delirium in LTCare effective. OBJECTIVES: To assess the effectiveness of interventions for preventing delirium in older people in long term care. SEARCH METHODS: We searched ALOIS (www.medicine.ox.ac.uk/alois) - the Cochrane Dementia and Cognitive Improvement Group's Specialised Register- on 23 April 2013. The search was as sensitive as possible to identify all studies on ALOIS relating to delirium. We ran additional separate searches in major healthcare databases, trial registers, the Cochrane Central Register of Controlled Trials (CENTRAL) and grey literature sources, to ensure that the search was as comprehensive as possible. SELECTION CRITERIA: We included randomised controlled trials (RCTs) and cluster-randomised controlled trials (cluster-RCTs) of single- and multi componentn on-pharmacological and pharmacological interventions for preventing delirium in older people (aged 65 years and over) in permanent LTC residence. DATA COLLECTION AND ANALYSIS: Two independent review authors examined the titles and abstracts of citations identified by the search for eligibility and extracted data, with any disagreements settled by consensus. Primary outcomes were prevalence, incidence and severity of delirium. Secondary outcomes included new diagnosis of dementia, activities of daily living, quality of life and adverse outcomes. We used risk ratios (RRs)as measures of treatment effect for dichotomous outcomes and hazard ratios (HR) for time to event data.Main results We included two trials that recruited 3636 participants.Both were complex single-component non pharmacological delirium prevention interventions. Risk of bias for many items was unclear due to inadequate reporting. Notably, there was no evidence of blinding of trial participants or assessors in either trial. One small cluster RCT (n = 98) of a hydration-based intervention reported no reduction in delirium incidence in the intervention group compared to control (RR 0.85, 95% confidence interval (CI) 0.18 to 4.00, analysis not adjusted for clustering, very low quality evidence). Results were imprecise and there were serious limitations evident in trial design.One large cluster-RCT (n = 3538) of a computerised system to identify medications that may contribute to delirium risk and trigger a pharmacist-led medication review reported a large reduction in delirium incidence (12-month HR 0.42, CI 0.34 to 0.51, moderat equality evidence) but no clear evidence of reduction in hospital admissions (HR 0.89, CI 0.72 to 1.10, moderate quality evidence), in mortality (HR 0.88, CI 0.66 to 1.17, moderate quality evidence) or in falls risk (HR 1.03, CI 0.92 to 1.15, moderate quality evidence).Authors' conclusions Our review identified very limited evidence on interventions for preventing deliriumin older people in LTC. Introduction of a software based intervention to identify medications that could contribute to delirium risk so that a pharmacist-led medication review and monitoring plan can be initiated may reduce incidence of delirium for older people in institutional LTC. This is based on one large RCT in the United States and may not be practical in other countries which do not have comparable information technology services available in care homes. Our review identified only one ongoing pilot trial of a multicomponent delirium prevention intervention and no trials of pharmacological agents. Future trials of computerised medication management systems and multicomponent non-pharmacological and pharmacological delirium prevention interventions for older people in LTC are needed to help inform the provision of evidence based care for this vulnerable group. PMID- 24488527 TI - Warfarin overdose: a 25-year experience. AB - Warfarin, a vitamin K antagonist, is widely used for the prophylaxis and treatment of thromboembolic disease. While guidelines exist for management of a supratherapeutic international normalized ratio following therapeutic warfarin use, these guidelines are not designed for management of the acute warfarin overdose. There is a paucity of literature describing the latter. The primary objective of this manuscript is to characterize the coagulopathy and describe the bleeding events that occur after a warfarin overdose. A secondary goal is to describe the amount of vitamin K administered to patients presenting with warfarin overdoses. A retrospective chart review of patients admitted with an acute warfarin overdose at two tertiary care medical centers in the USA was conducted. Clinical characteristics were abstracted, and bleeding categories (major, minor, trivial) were defined a priori. Twenty-three patients were admitted during the time period; males accounted for 15/23 (62.5 %) subjects. The median (interquartile range (IQR)) age was 43 (32-48.5) years. Seventeen subjects received vitamin K, with a median (IQR) dose of 15 (10-50) mg. The maximal total amount of vitamin K administered to a single patient during the index hospitalization was 110 mg. Three bleeding events occurred; one classified as major, and two as minor. All patients made a full recovery. In this case series of acute warfarin overdose, nearly all patients developed a coagulopathy, and nearly three-quarters of patients received vitamin K. Bleeding events occurred in a minority of patients. PMID- 24488528 TI - Grafting perylenes to ZnO nanoparticles. AB - A new prototype of dendritic perylenes suitable for the chemical functionalization of inorganic nanoparticles was synthesized and characterized. The bay-functionalized perylene core of these molecular architectures was coupled to a catechol moiety, which serves as an anchor group for the functionalization of metal oxides, in particular ZnO. To increase the solubility of both the perylene and the targeted hybrid nanostructures, a Newkome-type dendron bearing nine positive charges was introduced. This charge was also employed to stabilize the nanoparticles and further protect them from Ostwald ripening through Coulombic repulsion. ZnO quantum dots with an average diameter of 5 nm were synthesized and functionalized with the perylene derivative. Successful functionalization was clearly demonstrated by dynamic light scattering, zeta potential measurements, thermogravimetric analysis/MS, and UV/Vis and fluorescence spectroscopy. The generated particle dispersions were stable against agglomeration for more than eight weeks. PMID- 24488529 TI - Reply: spontaneous spinal accessory nerve palsy: the diagnostic usefulness of ultrasound. PMID- 24488530 TI - Exploring the human tear fluid: discovery of new biomarkers in multiple sclerosis. AB - PURPOSE: Multiple sclerosis is the first cause of progressive neurological disability among young adults living in Western countries. Its diagnosis is mostly based on clinical evaluation, neuroimaging, and in some cases cerebrospinal fluid (CSF) analysis, but no definitive diagnostic test exists. We proposed here that the exploration of tears from multiple sclerosis patients could lead to the discovery of new biomarkers. EXPERIMENTAL DESIGN: Thirty multiple sclerosis patients (20% men) recruited to the Geneva University Hospitals were included in our study (mean age +/- SD [years]: 42.4 +/- 15.9). Twenty-five control patients (32% men) were also enrolled (mean age +/- SD [years]: 42.7+/-15.1). Tears, CSF or blood was collected for each patient. Three independent quantitative (tandem mass tag) experiments were carried out between tears from multiple sclerosis and control patients. Protein verification was performed by Western blot on tears and CSF and by ELISA on serum samples. RESULTS: Combined proteomics analyses provided 185 identified tear proteins. Among the differential proteins, alpha-1 antichymotrypsin was the only one to be significantly increased in the three experiments with similar ratios (ratios 1.6 to 2.5, p < 0.05). Its tear, CSF and serum elevation were further confirmed by Western blot and ELISA, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: This study supports the concept that modifications of the tear proteome can reflect biological abnormalities associated with multiple sclerosis and perhaps other inflammatory conditions affecting the CNS. In addition, alpha-1 antichymotrypsin elevation in tear fluid emerges as a promising biomarker for the diagnosis of multiple sclerosis. PMID- 24488531 TI - Quercetin and omega 3 ameliorate oxidative stress induced by aluminium chloride in the brain. AB - Exposure to high levels of aluminum (Al) leads to neurodegeneration, which may be mediated through over-generation of free radicals. So, in the present study, we investigated the ability of both quercetin and omega 3 to ameliorate adverse effects of Al on brain antioxidants by monitoring the main brain antioxidant enzymes on molecular and cellular levels. The obtained results indicated that Al induced oxidative stress through induction of free radical production and inhibition of activity and expression of the antioxidant enzymes catalase (CAT), glutathione reductase (GR), and glutathione peroxidase (GPx); and at the same time induced superoxide dismutase (SOD) activity and gene expression. Both quercetin (QE) and omega 3 have the ability to overcome Al-induced oxidative stress, manifested by the significant reduction in free radical concentration and induction of the activity and gene expression of the brain antioxidant enzymes. PMID- 24488532 TI - Misperception of peer weight norms and its association with overweight and underweight status among adolescents. AB - Previous research has revealed pervasive misperceptions of peer norms for a variety of behaviors among adolescents such as alcohol use, smoking, and bullying and that these misperceptions are predictors of personal behavior. Similarly, misperception of peer weight norms may be a pervasive and important risk factor for adolescent weight status. Thus, the comparative association of actual and perceived peer weight norms is examined in relation to personal weight status. Secondary school students in 40 middle and high schools (n = 40,328) were surveyed about their perceptions of the peer weight norm for same gender and grade within their school. Perceived norms were compared to aggregate self reports of weight for these same groups. Overestimation of peer weight norms by more than 5 % occurred among 26 % of males and 20 % of females (by 22 and 16 lb on average, respectively). Underestimation occurred among 38 % of males as well as females (by 16 and 13 lb on average, respectively). Personal overweight status based on body mass index (BMI) was much more prevalent among respondents who overestimated peer weight norms as was personal underweight status among respondents who underestimated norms. Perception of the peer norm was the strongest predictor of personal BMI among all personal and school variables examined for both male and female students. Thus, reducing misperceived weight norms should be given more attention as a potential avenue for preventing obesity and eating disorders. PMID- 24488534 TI - Validation of Dermaphot((r)) for the assessment of steroid-induced skin atrophy. PMID- 24488533 TI - Assessing the quality of a non-randomized pragmatic trial for primary prevention of falls among older adults. AB - Current approaches to falls prevention mostly rely on secondary and tertiary prevention and target individuals at high risk of falls. An alternative is primary prevention, in which all seniors are screened, referred as appropriate, and educated regarding falls risk. Little information is available on research designs that allow investigation of this approach in the setting of aging services delivery, where randomization may not be possible. Healthy Steps for Older Adults, a statewide program of the Pennsylvania (PA) Department of Aging, involves a combination of education about falls and screening for balance problems, with referral to personal physicians and home safety assessments. We developed a non-randomized statewide trial, Falls Free PA, to assess its effectiveness in reducing falls incidence over 12 months. We recruited 814 seniors who completed the program (503 first-time participants, 311 people repeating the program) and 1,020 who did not participate in the program, from the same sites. We assessed the quality of this non-randomized design by examining recruitment, follow-up across study groups, and comparability at baseline. Of older adults approached in senior centers, 90.5 % (n = 2,219) signed informed consent, and 1,834 (82.4 %) completed baseline assessments and were eligible for follow-up. Attrition in the three groups over 12 months was low and non differential (<10 % for withdrawal and <2 % for other loss to follow-up). Median follow-up, which involved standardized monthly assessment of falls, was 10 months in all study groups. At baseline, the groups did not differ in measures of health or falls risk factors. Comparable status at baseline, recruitment from common sites, and similar experience with retention suggest that the non-randomized design will be effective for assessment of this approach to primary prevention of falls. PMID- 24488535 TI - Pediatric palliative care and pediatric medical ethics: opportunities and challenges. AB - The fields of pediatric palliative care (PPC) and pediatric medical ethics (PME) overlap substantially, owing to a variety of historical, cultural, and social factors. This entwined relationship provides opportunities for leveraging the strong communication skills of both sets of providers, as well as the potential for resource sharing and research collaboration. At the same time, the personal and professional relationships between PPC and PME present challenges, including potential conflict with colleagues, perceived or actual bias toward a palliative care perspective in resolving ethical problems, potential delay or underuse of PME services, and a potential undervaluing of the medical expertise required for PPC consultation. We recommend that these challenges be managed by: (1) clearly defining and communicating clinical roles of PPC and PME staff, (2) developing questions that may prompt PPC and PME teams to request consultation from the other service, (3) developing explicit recusal criteria for PPC providers who also provide PME consultation, (4) ensuring that PPC and PME services remain organizationally distinct, and (5) developing well-defined and broad scopes of practice. Overall, the rich relationship between PPC and PME offers substantial opportunities to better serve patients and families facing difficult decisions. PMID- 24488537 TI - Communicating about prognosis: ethical responsibilities of pediatricians and parents. AB - Clinicians are sometimes reluctant to discuss prognosis with parents of children with life-threatening illness, usually because they worry about the emotional impact of this information. However, parents often want this prognostic information because it underpins informed decision-making, especially near the end of life. In addition, despite understandable clinician concerns about its emotional impact, prognostic disclosure can actually support hope and peace of mind among parents struggling to live with a child's illness. Children, too, may need to understand what is ahead to manage uncertainty and make plans for the ways their remaining life will be lived. In this article, we describe the ethical issues involved in disclosure of prognostic information to parents and children with life-threatening illness and offer practical guidance for these conversations. PMID- 24488536 TI - Relational autonomy: moving beyond the limits of isolated individualism. AB - Although clinicians may value respecting a patient's or surrogate's autonomy in decision-making, it is not always clear how to proceed in clinical practice. The confusion results, in part, from which conception of autonomy is used to guide ethical practice. Reliance on an individualistic conception such as the "in control agent" model prioritizes self-sufficiency in decision-making and highlights a decision-maker's capacity to have reason transcend one's emotional experience. An alternative model of autonomy, relational autonomy, highlights the social context within which all individuals exist and acknowledges the emotional and embodied aspects of decision-makers. These 2 conceptions of autonomy lead to different interpretations of several aspects of ethical decision-making. The in control agent model believes patients or surrogates should avoid both the influence of others and emotional persuasion in decision-making. As a result, providers have a limited role to play and are expected to provide medical expertise but not interfere with the individual's decision-making process. In contrast, a relational autonomy approach acknowledges the central role of others in decision-making, including clinicians, who have a responsibility to engage patients' and surrogates' emotional experiences and offer clear guidance when patients are confronting serious illness. In the pediatric setting, in which decision-making is complicated by having a surrogate decision-maker in addition to a patient, these conceptions of autonomy also may influence expectations about the role that adolescents can play in decision-making. PMID- 24488538 TI - Judging the quality of mercy: drawing a line between palliation and euthanasia. AB - Clinicians frequently worry that medications used to treat pain and suffering at the end of life might also hasten death. Intentionally hastening death, or euthanasia, is neither legal nor ethically appropriate in children. In this article, we explore some of the historical and legal background regarding appropriate end-of-life care and outline what distinguishes it from euthanasia. Good principles include clarity of goals and assessments, titration of medications to effect, and open communication. When used appropriately, medications to treat symptoms should rarely hasten death significantly. Medications and interventions that are not justifiable are also discussed, as are the implications of palliative sedation and withholding fluids or nutrition. It is imperative that clinicians know how to justify and use such medications to adequately treat suffering at the end of life within a relevant clinical and legal framework. PMID- 24488539 TI - Unilateral pediatric "do not attempt resuscitation" orders: the pros, the cons, and a proposed approach. AB - A unilateral do not attempt resuscitation (DNAR) order is written by a physician without permission or assent from the patient or the patient's surrogate decision maker. Potential justifications for the use of DNAR orders in pediatrics include the belief that attempted resuscitation offers no benefit to the patient or that the burdens would far outweigh the potential benefits. Another consideration is the patient's right to mercy, not to be made to undergo potentially painful interventions very unlikely to benefit the patient, and the physician's parallel obligation not to perform such interventions. Unilateral DNAR orders might be motivated in part by the moral distress caregivers sometimes experience when feeling forced by parents to participate in interventions that they believe are useless or cruel. Furthermore, some physicians believe that making these decisions without parental approval could spare parents needless additional emotional pain or a sense of guilt from making such a decision, particularly when imminent death is unavoidable. There are, however, several risks inherent in unilateral DNAR orders, such as overestimating one's ability to prognosticate or giving undue weight to the physician's values over those of parents, particularly with regard to predicted disability and quality of life. The law on the question of unilateral DNAR varies among states, and readers are encouraged to learn the law where they practice. Arguments in favor of, and opposed to, the use of unilateral DNAR orders are presented. In some settings, particularly when death is imminent regardless of whether resuscitation is attempted, unilateral DNAR orders should be viewed as an ethically permissible approach. PMID- 24488540 TI - Tracheostomies and assisted ventilation in children with profound disabilities: navigating family and professional values. AB - Parental requests for gastrostomies, tracheostomies, or assisted ventilation in children with profound disabilities raise ethical concerns about children's interests, parental decision-making, and health care costs. The underlying concern for many relates to the perceived value of these children. Clinicians should make efforts to appreciate the family's perspective regarding children with profound disabilities who require respiratory and nutritional medical support. Finding opportunities to learn about the family members' lives outside of the health care setting may facilitate a deeper understanding of what it means to live with a child who has profound disabilities. In conversations with families, referring to interventions as futile and conditions as lethal will obscure the value-based nature of these decisions. Respiratory and nutritional interventions are not clearly against the interests of most children. Even for children with a limited life span, life-sustaining interventions may be important for the child and family. Health care costs are a serious societal issue; however, the costs associated with profound disabilities are not the most significant contributor. Societal decisions not to provide life-sustaining health care to children with profound disabilities would require a public process. Clinicians may have personal views regarding decisions for their own family or for their vision for society. However, clinicians have professional obligations to families who have different values. It is important to present balanced information and support parental decision-making so parents may decide to forgo or use life-sustaining interventions according to their values and goals. PMID- 24488541 TI - The duty of the physician to care for the family in pediatric palliative care: context, communication, and caring. AB - Pediatric palliative care physicians have an ethical duty to care for the families of children with life-threatening conditions through their illness and bereavement. This duty is predicated on 2 important factors: (1) best interest of the child and (2) nonabandonment. Children exist in the context of a family and therefore excellent care for the child must include attention to the needs of the family, including siblings. The principle of nonabandonment is an important one in pediatric palliative care, as many families report being well cared for during their child's treatment, but feel as if the physicians and team members suddenly disappear after the death of the child. Family-centered care requires frequent, kind, and accurate communication with parents that leads to shared decision making during treatment, care of parents and siblings during end-of-life, and assistance to the family in bereavement after death. Despite the challenges to this comprehensive care, physicians can support and be supported by their transdisciplinary palliative care team members in providing compassionate, ethical, and holistic care to the entire family when a child is ill. PMID- 24488542 TI - Efficiency of plant induced volatiles in attracting Encarsia formosa and Serangium japonicum, two dominant natural enemies of whitefly Bemisia tabaci in China. AB - BACKGROUND: Whitefly Bemisia tabaci is a globally distributed and most destructive pest to agriculture. Owing to increasing chemical resistance, a long lasting strategy to manage this pest must involve biological control. Herbivore induced plant volatiles (HIPVs) usually play a profoundly important role in the foraging behaviour of natural enemies. Here, the effects of HIPVs from Chinese broccoli on the foraging behaviour of two dominant natural enemy species of B. tabaci in China, Encarsia formosa and Serangium japonicum, were investigated using a four-arm olfactometer, and exogenous jasmonic acid (JA) was used to induce plant volatiles to mimic the damage of the herbivore pest. RESULTS: The parasitoid E. formosa was found to be more attracted by the volatiles from JA induced broccoli than those from control plants. The residence times of E. formosa in the final-choice areas closed to volatiles from shoot JA (SJA)- and root JA (RJA)-induced plants were 119.8 +/- 35.2 s and 99.8 +/- 34.7 s respectively in the dual-choice experiments, and 123.8 +/- 32.0 s and 102.3 +/- 28.7 s respectively in the three-choice experiment. All are significantly longer than those spent in the final-choice area closed to volatiles from control plants (CON). JA-induced volatiles were also only a little more attractive to the predator S. japonicum. However, there was no significant difference between each of the two natural enemies in residence time spent in the final-choice areas closed to SJA, RJA or CON volatiles in both the dual- and three-choice experiments. Furthermore, the number of times that the parasitoid or predator entered the SJA, RJA and CON final-choice areas was not significantly different in any of the experiments. CONCLUSION: The present results indicate that RJA- and SJA-induced plant volatiles have higher efficiencies in attracting the natural enemies of whitefly B. tabaci. The attractive efficiencies varied according to the plant volatiles that JA induced, and also depended on the natural enemy species. The parasitoid E. formosa seems to be more sensitive to and attracted by the induced volatiles than the predator S. japonicum. PMID- 24488543 TI - Monitoring style of coping with cancer related threats: a review of the literature. AB - Building on the Cognitive-Social Health Information-Processing model, this paper provides a theoretically guided review of monitoring (i.e., attend to and amplify) cancer-related threats. Specifically, the goals of the review are to examine whether individuals high on monitoring are characterized by specific cognitive, affective, and behavioral responses to cancer-related health threats than individuals low on monitoring and the implications of these cognitive affective responses for patient-centered outcomes, including patient-physician communication, decision-making and the development of interventions to promote adherence and adjustment. A total of 74 reports were found, based on 63 studies, 13 of which were intervention studies. The results suggest that although individuals high on monitoring are more knowledgeable about health threats, they are less satisfied with the information provided. Further, they tend to be characterized by greater perceived risk, more negative beliefs, and greater value of health-related information and experience more negative affective outcomes. Finally, individuals high on monitoring tend to be more demanding of the health providers in terms of desire for more information and emotional support, are more assertive during decision-making discussions, and subsequently experience more decisional regret. Psychoeducational interventions improve outcomes when the level and type of information provided is consistent with the individual's monitoring style and the demands of the specific health threat. Implications for patient-centered outcomes, in terms of tailoring of interventions, patient provider communication, and decision-making, are discussed. PMID- 24488544 TI - Next-generation sequencing for inherited breast cancer risk: counseling through the complexity. AB - Next-generation sequencing technology affords an unprecedented opportunity to analyze multiple breast cancer susceptibility genes simultaneously. With the incarnation of gene panels that combine testing for moderate- and high-penetrance genes, this technology has given birth to a paradigm shift in clinical genetic test offerings. A transformation in genetic counseling for cancer susceptibility will necessarily follow, with a shift from the traditional approach of single gene testing to considerations of testing by multi-gene panels. At the same time, however, the opportunity to identify rare lesions underlying hereditary susceptibility has introduced new challenges. Available cancer risk estimates for genes included in panel tests may not be supported by evidence, and there is increased risk of identifying variants of uncertain significance (VUS). Management of individuals with rare pathogenic mutations may be unclear. We provide a summary of available evidence for breast cancer risks conferred by pathogenic mutations in genes commonly included in breast cancer susceptibility panels, as well as a review of limitations and counseling points. PMID- 24488545 TI - Surgery for rectal cancer-what is on the horizon? AB - The management of rectal cancer has improved considerably in recent decades. Surgery remains the cornerstone of the treatment. However, the role of preoperative imaging has made it possible to optimize the treatment plan in rectal patients. Neoadjuvant treatment may be indicated in efforts to sterilize possible tumor deposits outside the surgical field, or may be used to downsize and downstage the tumor itself. The optimal sequence of treatment modalities can be determined by a multidisciplinary team, who not only use pretreatment imaging, but also review pathologic results after surgery. The pathologist plays a pivotal role in providing feedback about the success of surgery, i.e., the distance between the tumor and the circumferential resection margin, the quality of surgery, and the effect of neoadjuvant treatment. Registry and auditing of all treatment variables can further improve outcomes. In this century, rectal cancer treatment has become a team effort. PMID- 24488546 TI - Nonsurgical treatment for localized hepatocellular carcinoma. AB - The most common non-surgical approaches for the treatment of localized hepatocellular carcinoma remain hepatic artery-delivered particles laden with chemotherapy (TACE), or radioactive microparticles (TARE). External beam radiotherapy has been an effective option in many parts of the world for selected HCC patients, but now has an expanded role with stereotactic and proton beam technologies. This review focuses on existing evidence and current guidance for utilizing these modalities for localized, but unresectable, non-transplantable HCC patients.x. PMID- 24488547 TI - The contemporary role of minimally invasive esophagectomy in esophageal cancer. AB - Open surgical resection via transhiatal or transthoracic, including McKeown, access is the most viable option for curing esophageal cancer; however, the extensive nature of open surgery in both the chest and abdomen results in significant rates of morbidity and mortality. A natural response was the introduction of minimally invasive esophagectomy (MIE) and, later, endoscopic resection. In the hands of experienced surgeons, MIE can achieve equivalent or better perioperative mortality, morbidity, and oncologic outcomes as compared to open surgery. This review starts with an overview of open esophagectomy before delving into the evolving body of evidence on MIE outcomes and practices. PMID- 24488549 TI - Outcomes measurement in patients with head and neck cancer. AB - Outcomes research is defined as clinical and population-based research that investigates the results of healthcare practices or interventions through the filter of the benefit to the patient and other stakeholders. Outcomes research is an increasingly important field or research, because of the pressing need for evidence-based information that can be used to make better informed health and healthcare decisions, and define desired health care practices in the current era of healthcare reform. This article will review the head and neck cancer (HNCA) outcomes literature published in the past year, with a focus on studies evaluating treatment and survival, short-term and long-term complications, and quality of life (QOL). PMID- 24488548 TI - Counseling the patient with potentially HPV-related newly diagnosed head and neck cancer. AB - The recent emergence of a clinically distinct subset of head and neck cancers (HNC) caused by infection with the human papillomavirus (HPV) necessitates critical reevaluation of the existing counseling paradigm for patients with newly diagnosed HNC. Herein we propose a structural framework for patient counseling in which HPV testing is incorporated and the impact of HPV-status is discussed in the context of multiple medical and psychosocial domains. We strive to maintain a balance between making recommendations based on the best available scientific evidence and acknowledgment of uncertainty for both patients and providers. We anticipate that both the standard-of-care diagnostic workup and treatment, and counseling guidelines for these patients will change rapidly in the years ahead, as data from ongoing and planned prospective clinical trials become available. PMID- 24488550 TI - Conversion from long-term AB-5000 to EVAHEART using a combined left thoracotomy and sternotomy approach. AB - Because of the extreme donor shortage in Japan, waiting times for heart transplantation exceed 2 years. Since 1980s in Japan, device availability has also been an issue, with only a few paracorporeal ventricular assist devices (VADs) available as a bridge to transplantation or recovery. However, two implantable VADs became commercially available in 2011. Given these constraints in our healthcare system, we report a relatively rare case of bridge-to-bridge use of an implanted EVAHEART after having used a paracorporeal AB-5000 support for an extended period of time. We successfully employed a combined left thoracotomy and median sternotomy approach as a conversion technique. PMID- 24488551 TI - Internal loop photo-biodegradation reactor used for accelerated quinoline degradation and mineralization. AB - Biofilm biodegradation was coupled with ultra-violet photolysis using the internal loop photobiodegradation reactor for degradation of quinoline. Three protocols-photolysis alone (P), biodegradation alone (B), and intimately coupled photolysis and biodegradation (P&B)-were used for degradation of quinoline in batch and continuous-flow experiments. For a 1,000 mg/L initial quinoline concentration, the volumetric removal rate for quinoline was 38 % higher with P&B than with B in batch experiments, and the P&B kinetics were the sum of kinetics from the P and B experiments. Continuous-flow experiments with an influent quinoline concentration of 1,000 mg/L also gave significantly greater quinoline removal in P&B, and the quinoline-removal kinetics for P&B were approximately equal to the sum of the removal kinetics for P and B. P&B similarly increased the rate and extent of quinoline mineralization, for which the kinetics for P&B were nearly equal to the sum of kinetics for P and B. These findings support that the rate-limiting step for mineralization was transformation of quinoline, which was accelerated by the simultaneous action of photolysis and biodegradation. PMID- 24488552 TI - Surface-sediment and hermit-crab contamination by butyltins in southeastern Atlantic estuaries after ban of TBT-based antifouling paints. AB - Butyltin (BT) contamination was evaluated in hermit crabs from 25 estuaries and in sediments from 13 of these estuaries along about 2,000 km of the Brazilian coast. BT contamination in hermit crabs ranged from 2.22 to 1,746 ng Sn g(-1) of DBT and 1.32 to 318 ng Sn g(-1) of TBT. In sediment samples, the concentration also varied widely, from 25 to 1,304 ng Sn g(-1) of MBT, from 7 to 158 ng Sn g( 1) of DBT, and from 8 to 565 ng Sn g(-1) of TBT. BTs are still being found in surface sediments and biota of the estuaries after the international and Brazilian bans, showing heterogeneous distribution among and within estuaries. Although hermit crabs were previously tested as an indicator of recent BT contamination, the results indicate the presence of contamination, probably from resuspension of BTs from deeper water of the estuary. PMID- 24488554 TI - Crop protection: new strategies for sustainable development. PMID- 24488553 TI - Persistence, variance and toxic levels of organochlorine pesticides in fluvial sediments and the role of black carbon in their retention. AB - The present study assesses the persistence and variation of organochlorine pesticides (OCPs) and their regulation by total organic carbon (TOC) and black carbon (BC) in freshwater sediment. Sediment samples from the Yamuna River, a major tributary of the Ganges (one of the most populated and intensively used rivers in Asia), had high levels of Sigma20OCPs (21.41 to 139.95 ng g(-1)). beta Hexachlorocyclohexane (beta-HCH) was the most predominant component. SigmaHCH and Sigmadichloro-diphenyl-trichloroethane (DDT) constituted ~86% of Sigma20OCPs. Isomer ratios indicated fresh usage of lindane, DDT and technical-grade HCH. Toxicological comparison with freshwater sediment quality guidelines showed gamma HCH and DDT at high levels of concern. beta-HCH, alpha-HCH, endrin, heptachlor epoxide, dichloro-diphenyl-dichloroethane (DDD), dichloro-diphenyl dichloroethylene and chlordane were above some of the guideline levels. TOC and BC had mean concentrations of 1.37 +/- 0.51% and 0.46 +/- 0.23 mg g(-1), respectively. BC constituted 1.25 to 10.56% of TOC. We observed low to moderate correlations of BC with isomers of HCH, p,p'-DDT and methoxychlor while of TOC with Sigma20OCPs, gamma-HCH, endosulfan sulfate and methoxychlor. Principal component analysis enabled correlating and clustering of various OCPs, BC and TOC. OCP distribution was related with pH, electrical conductivity, soil moisture and finer fractions of sediment. OCPs with similarity in properties that determine their interactions with carbonaceous components of sediment clustered together. A number of factors may, thus, be involved in the regulation of interactive forces between BC and OCPs. BC in this study may be more important than TOC in the retention of some OCPs into fluvial sediments, thereby reducing their bioavailability. The finding is probably the first of its kind to report and emphasises the role of BC in the persistence of OCPs in fluvial sediments. PMID- 24488555 TI - Oxidative stress status, antioxidant metabolism and polypeptide patterns in Juncus maritimus shoots exhibiting differential mercury burdens in Ria de Aveiro coastal lagoon (Portugal). AB - This study assessed the oxidative stress status, antioxidant metabolism and polypeptide patterns in salt marsh macrophyte Juncus maritimus shoots exhibiting differential mercury burdens in Ria de Aveiro coastal lagoon at reference and the sites with highest, moderate and the lowest mercury contamination. In order to achieve these goals, shoot-mercury burden and the responses of representative oxidative stress indices, and the components of both non-glutathione- and glutathione-based H2O2-metabolizing systems were analyzed and cross-talked with shoot-polypeptide patterns. Compared to the reference site, significant elevations in J. maritimus shoot mercury and the oxidative stress indices such as H2O2, lipid peroxidation, electrolyte leakage and reactive carbonyls were maximum at the site with highest followed by moderate and the lowest mercury contamination. Significantly elevated activity of non-glutathione-based H2O2 metabolizing enzymes such as ascorbate peroxidase and catalase accompanied the studied damage-endpoint responses, whereas the activity of glutathione-based H2O2 scavenging enzymes glutathione peroxidase and glutathione sulfo-transferase was inhibited. Concomitantly, significantly enhanced glutathione reductase activity and the contents of both reduced and oxidized glutathione were perceptible in high mercury-exhibiting shoots. It is inferred that high mercury-accrued elevations in oxidative stress indices were obvious, where non-glutathione-based H2O2-decomposing enzyme system was dominant over the glutathione-based H2O2 scavenging enzyme system. In particular, the glutathione-based H2O2-scavenging system failed to coordinate with elevated glutathione reductase which in turn resulted into increased pool of oxidized glutathione and the ratio of oxidized glutathione-to-reduced glutathione. The substantiation of the studied oxidative stress indices and antioxidant metabolism with approximately 53-kDa polypeptide warrants further studies. PMID- 24488556 TI - Low Cd concentration-activated morphogenic defence responses are inhibited by high Cd concentration-induced toxic superoxide generation in barley root tip. AB - Exposure of roots to low Cd concentration induced morphogenic responses including the inhibition of root growth and the radial swelling of root tip. High Cd concentrations within a few minutes caused a robust induction of superoxide generation leading to the cell death and root growth arrest. This toxic superoxide generation blocked the development of low Cd concentration-activated morphogenic responses. While the morphogenic responses of roots to low Cd concentration are induced very rapidly and probably due to the interaction of Cd with the apoplast of root tissue, high Cd concentration-induced superoxide production required the entry of Cd into the symplast. Auxin signaling is involved in the activation of Cd-induced morphogenic defence responses but not in the Cd-induced toxic superoxide generation. These results suggest that oxidative stress is not a primary cause for the Cd-induced morphogenic responses such as growth reduction and radial cell expansion in barley root tips. PMID- 24488557 TI - A qualitative assessment of the social cultural factors that influence cervical cancer screening behaviors and the health communication preferences of women in Kumasi, Ghana. AB - Cervical cancer is the leading cause of cancer death among women in Ghana. Despite the availability of cervical cancer screening in healthcare facilities throughout the country, less than 4 % of Ghanaian women seek preventive cervical cancer screenings regularly. There is a lack of culturally relevant cervical cancer education material available in Ghana. The aims of this study were to assess the social cultural factors that influence cervical cancer screening behaviors and the health communication preferences of Ghanaian women. A focus group guide based on the constructs of the PEN-3 model was used to conduct six focus groups that were stratified by educational attainment. Thirty-four women participated in the study. The qualitative data revealed that most participants were not aware of cervical cancer or cervical cancer screening. However, many of the participants were willing to seek screening if they knew more about it. The most common sources of health information were television, radio, friends, and family. And the participants preferred inspirational cervical-cancer-screening messages that would be delivered by a doctor and a cancer survivor. PMID- 24488558 TI - Evaluating teaching techniques in the Hmong breast and cervical cancer health awareness project. AB - Cancer health disparities are a reality for Hmong women who are often diagnosed at a later stage and have low literacy and experienced care that are not culturally appropriate. Lack of attention to cultural appropriateness and literacy levels of cancer screening materials may contribute to disproportionately low levels of cancer screening among Hmong women. The purposes of this study were to evaluate the Hmong Health Awareness Project (HHAP), a program designed to create awareness and acceptance of breast and cervical cancer screening, and to examine participants' perceptions of the utility of the content of the workshops. Hmong researchers partnered with three Midwestern Hmong community centers to implement six workshops. Three teaching techniques: pictographs, videos, and hands-on activities were utilized to teach Hmong participants about cancer screening. Participants included 150 Hmong (male participants = 30 and female participants = 120). Teach-back method was used to assess the participants' understanding of cancer screening throughout the workshops. Qualitative data were collected in focus groups to assess the feasibility of teaching methods and participants' perceptions of the utility of the content of the workshops. Directed content analysis was used to analyze participants' responses. The three teaching techniques were helpful in increasing the Hmong people's understanding about breast and cervical cancer screening. Nearly, all participants perceived an increased in their understanding, greater acceptance of cancer screening, and increased willingness to be screened. Men expressed support for screening after the workshops. Findings can guide future interventions to improve health communications and screening and reduce diagnostic disparities among Hmong and immigrant populations. PMID- 24488559 TI - Microvesicles and exosomes for intracardiac communication. AB - The heart is an organ with a complex mixture of well-organized interactions of different cell types that facilitate proper myocardial contractility, sufficient perfusion, balanced myocardial extracellular stiffness, and controlled functioning of the immune system. Several cell types, including cardiomyocytes, endothelial cells, smooth muscle cells, fibroblasts, immune cells, and cardiac derived stem cells, need a well-controlled communication system to use the complex orchestra of signalling molecules. The intercellular communication includes direct cell-cell contact, cell-matrix interaction, long-range signals, and electrical and extracellular chemical molecules. In addition to the extracellular molecules that cells can use to influence their environment, more and more attention is focused on the release of extracellular membrane vesicles by cells. These vesicles were always thought to be cell debris derivatives, but it appeared that these vesicles are used for horizontal transfer of information between cells, containing proteins, peptides, several classes of RNA molecules, and sometimes DNA. The main populations of released vesicles are classified on their (intra)cellular origin and include apoptotic bodies, microvesicles, and exosomes. Here, we provide an overview on the role of vesicles in cardiac communication and their use as potential therapeutics and biomarkers. PMID- 24488561 TI - The International Prognostic Scoring System does not accurately discriminate different risk categories in patients with post-essential thrombocythemia and post-polycythemia vera myelofibrosis. PMID- 24488560 TI - A phase II multicenter rabbit anti-thymocyte globulin trial in patients with myelodysplastic syndromes identifying a novel model for response prediction. AB - Immune dysregulation is a mechanism contributing to ineffective hematopoiesis in a subset of myelodysplastic syndrome patients. We report the first US multicenter non-randomized, phase II trial examining the efficacy of rabbit(r)-anti-thymocyte globulin using 2.5 mg/kg/day administered daily for 4 doses. The primary end point was hematologic response; secondary end points included duration of response, time to response, time to progression, and tolerance. Nine (33%;95% confidence interval=17%-54%) of the 27 patients treated experienced durable hematologic improvement in an intent-to-treat analysis with a median time to response and median response duration of 75 and 245 days, respectively. While younger age is the most significant factor favoring equine(e)-anti-thymocyte globulin response, treatment outcome on this study was independent of age (P=0.499). A shorter duration between diagnosis and treatment showed a positive trend (P=0.18), but International Prognostic Scoring System score (P=0.150), karyotype (P=0.319), and age-adjusted bone marrow cellularity (P=0.369) were not associated with response classification. Since activated T-lymphocytes are the primary cellular target of anti-thymocyte globulin, a T-cell expression profiling was conducted in a cohort of 38 patients consisting of rabbit and equine antithymocyte globulin-treated patients. A model containing disease duration, CD8 terminal memory T cells and T-cell proliferation-associated-antigen expression predicted response with the greatest accuracy using a leave-one-out cross validation approach. This profile categorized patients independent of other covariates, including treatment type and age using a leave-one-out-cross validation approach (75.7%). Therefore, rabbit-anti-thymocyte globulin has hematologic remitting activity in myelodysplastic syndrome and a T-cell activation profile has potential utility classifying those who are more likely to respond (NCT00466843 clinicaltrials.gov). PMID- 24488562 TI - Use of the quality management system "JACIE" and outcome after hematopoietic stem cell transplantation. AB - Competent authorities, healthcare payers and hospitals devote increasing resources to quality management systems but scientific analyses searching for an impact of these systems on clinical outcome remain scarce. Earlier data indicated a stepwise improvement in outcome after allogeneic hematopoietic stem cell transplantation with each phase of the accreditation process for the quality management system "JACIE". We therefore tested the hypothesis that working towards and achieving "JACIE" accreditation would accelerate improvement in outcome over calendar time. Overall mortality of the entire cohort of 107,904 patients who had a transplant (41,623 allogeneic, 39%; 66,281 autologous, 61%) between 1999 and 2006 decreased over the 14-year observation period by a factor of 0.63 per 10 years (hazard ratio: 0.63; 0.58-0.69). Considering "JACIE" accredited centers as those with programs having achieved accreditation by November 2012, at the latest, this improvement was significantly faster in "JACIE"-accredited centers than in non-accredited centers (approximately 5.3% per year for 49,459 patients versus approximately 3.5% per year for 58,445 patients, respectively; hazard ratio: 0.83; 0.71-0.97). As a result, relapse-free survival (hazard ratio 0.85; 0.75-0.95) and overall survival (hazard ratio 0.86; 0.76 0.98) were significantly higher at 72 months for those patients transplanted in the 162 "JACIE"-accredited centers. No significant effects were observed after autologous transplants (hazard ratio 1.06; 0.99-1.13). Hence, working towards implementation of a quality management system triggers a dynamic process associated with a steeper reduction in mortality over the years and a significantly improved survival after allogeneic stem cell transplantation. Our data support the use of a quality management system for complex medical procedures. PMID- 24488563 TI - Leukemia-induced phenotypic and functional defects in natural killer cells predict failure to achieve remission in acute myeloid leukemia. AB - The majority of patients with acute myeloid leukemia will relapse, and older patients often fail to achieve remission with induction chemotherapy. We explored the possibility that leukemic suppression of innate immunity might contribute to treatment failure. Natural killer cell phenotype and function was measured in 32 consecutive acute myeloid leukemia patients at presentation, including 12 achieving complete remission. Compared to 15 healthy age-matched controls, natural killer cells from acute myeloid leukemia patients were abnormal at presentation, with downregulation of the activating receptor NKp46 (P=0.007) and upregulation of the inhibitory receptor NKG2A (P=0.04). Natural killer cells from acute myeloid leukemia patients had impaired effector function against autologous blasts and K562 targets, with significantly reduced CD107a degranulation, TNF alpha and IFN-gamma production. Failure to achieve remission was associated with NKG2A overexpression and reduced TNF-alpha production. These phenotypic and functional abnormalities were partially restored in the 12 patients achieving remission. In vitro co-incubation of acute myeloid leukemia blasts with natural killer cells from healthy donors induced significant impairment in natural killer cell TNF-alpha and IFN-gamma production (P=0.02 and P=0.01, respectively) against K562 targets and a trend to reduced CD107a degranulation (P=0.07). Under transwell conditions, the inhibitory effect of AML blasts on NK cytotoxicity and effector function was still present, and this inhibitory effect was primarily mediated by IL-10. These results suggest that acute myeloid leukemia blasts induce long-lasting changes in natural killer cells, impairing their effector function and reducing the competence of the innate immune system, favoring leukemia survival. PMID- 24488564 TI - Molecular and cytogenetic characterization of expanded B-cell clones from multiclonal versus monoclonal B-cell chronic lymphoproliferative disorders. AB - Chronic antigen-stimulation has been recurrently involved in the earlier stages of monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The expansion of two or more B-cell clones has frequently been reported in individuals with these conditions; potentially, such coexisting clones have a greater probability of interaction with common immunological determinants. Here, we analyzed the B-cell receptor repertoire and molecular profile, as well as the phenotypic, cytogenetic and hematologic features, of 228 chronic lymphocytic leukemia-like and non-chronic lymphocytic leukemia-like clones comparing multiclonal (n=85 clones from 41 cases) versus monoclonal (n=143 clones) monoclonal B-cell lymphocytosis, chronic lymphocytic leukemia and other B-cell chronic lymphoproliferative disorders. The B-cell receptor of B-cell clones from multiclonal cases showed a slightly higher degree of HCDR3 homology than B-cell clones from mono clonal cases, in association with unique hematologic (e.g. lower B-lymphocyte counts) and cytogenetic (e.g. lower frequency of cytogenetically altered clones) features usually related to earlier stages of the disease. Moreover, a subgroup of coexisting B-cell clones from individual multiclonal cases which were found to be phylogenetically related showed unique molecular and cytogenetic features: they more frequently shared IGHV3 gene usage, shorter HCDR3 sequences with a greater proportion of IGHV mutations and del(13q14.3), than other unrelated B-cell clones. These results would support the antigen-driven nature of such multiclonal B-cell expansions, with potential involvement of multiple antigens/epitopes. PMID- 24488565 TI - Baseline characteristics and disease burden in patients in the International Paroxysmal Nocturnal Hemoglobinuria Registry. AB - Paroxysmal nocturnal hemoglobinuria is a rare, acquired disease associated with hemolytic anemia, bone marrow failure, thrombosis, and, frequently, poor quality of life. The International PNH Registry is a worldwide, observational, non interventional study collecting safety, effectiveness, and quality-of-life data from patients with a confirmed paroxysmal nocturnal hemoglobinuria diagnosis or detectable paroxysmal nocturnal hemoglobinuria clone, irrespective of treatment. In addition to evaluating the long-term safety and effectiveness of eculizumab in a global population, the registry aims to improve diagnosis, optimize patient management and outcomes, and enhance the understanding of the natural history of paroxysmal nocturnal hemoglobinuria. Here we report the characteristics of the first 1610 patients enrolled. Median disease duration was 4.6 years. Median granulocyte paroxysmal nocturnal hemoglobinuria clone size was 68.1% (range 0.01 100%). Overall, 16% of patients had a history of thrombotic events and 14% a history of impaired renal function. Therapies included anticoagulation (31%), immunosuppression (19%), and eculizumab (25%). Frequently reported symptoms included fatigue (80%), dyspnea (64%), hemoglobinuria (62%), abdominal pain (44%), and chest pain (33%). Patients suffered from poor quality of life; 23% of patients had been hospitalized due to paroxysmal nocturnal hemoglobinuria-related complications and 17% stated that paroxysmal nocturnal hemoglobinuria was the reason they were not working or were working less. This international registry will provide an ongoing, valuable resource to further the clinical understanding of paroxysmal nocturnal hemoglobinuria. PMID- 24488566 TI - Global warming will reshuffle the areas of high prevalence and richness of three genera of avian blood parasites. AB - The importance of parasitism for host populations depends on local parasite richness and prevalence: usually host individuals face higher infection risk in areas where parasites are most diverse, and host dispersal to or from these areas may have fitness consequences. Knowing how parasites are and will be distributed in space and time (in a context of global change) is thus crucial from both an ecological and a biological conservation perspective. Nevertheless, most research articles focus just on elaborating models of parasite distribution instead of parasite diversity. We produced distribution models of the areas where haemosporidian parasites are currently highly diverse (both at community and at within-host levels) and prevalent among Iberian populations of a model passerine host: the blackcap Sylvia atricapilla; and how these areas are expected to vary according to three scenarios of climate change. On the basis of these models, we analysed whether variation among populations in parasite richness or prevalence are expected to remain the same or change in the future, thereby reshuffling the geographic mosaic of host-parasite interactions as we observe it today. Our models predict a rearrangement of areas of high prevalence and richness of parasites in the future, with Haemoproteus and Leucocytozoon parasites (today the most diverse genera in blackcaps) losing areas of high diversity and Plasmodium parasites (the most virulent ones) gaining them. Likewise, the prevalence of multiple infections and parasite infracommunity richness would be reduced. Importantly, differences among populations in the prevalence and richness of parasites are expected to decrease in the future, creating a more homogeneous parasitic landscape. This predicts an altered geographic mosaic of host-parasite relationships, which will modify the interaction arena in which parasite virulence evolves. PMID- 24488567 TI - Best lung function equations for the very elderly selected by survival analysis. AB - We evaluated which equations best predicted the lung function of a cohort of nonagenarians based on which best accounted for subsequent survival. In 1998, we measured lung function, grip strength and dementia score (Mini Mental State Examination (MMSE)) in a population-based sample of 2262 Danes born in 1905. Mortality was registered to 2011 when only five (0.2%) subjects were alive. In half the cohort, we recorded forced expiratory volume in 1 s (FEV1). Complete data were available in 592 subjects with results expressed as standardised residuals (SR) using various prediction equations. Cox proportional hazard regression found lower FEV1SR was a predictor of mortality having controlled for MMSE, grip strength and sex. The US National Health and Nutrition Examination Survey (NHANES) III (1999) equations gave a better spread of median survival by FEV1SR quartile: 3.94, 3.65, 3.51 and 2.61 years with a hazard ratio for death of 1, 1.16, 1.32 and 1.60 respectively, compared with equations derived with the inclusion of elderly subjects. We conclude that extrapolating from NHANES III equations to predict lung function in nonagenarians gave better survival predictions from spirometry than when employing equations derived using very elderly subjects with possible selection bias. These findings can help inform how future lung function equations for the elderly are derived. PMID- 24488568 TI - Rituximab in the treatment of refractory pulmonary sarcoidosis. PMID- 24488570 TI - Is continuous positive airway pressure necessarily an everyday therapy in patients with obstructive sleep apnoea? AB - There are limited data on the evolution of obstructive sleep apnoea (OSA) during continuous positive airway pressure (CPAP) therapy and whether this treatment is required every night. 125 OSA patients with an original oxygen desaturation index (ODI) >10 events per hour, established on CPAP, were asked to withdraw CPAP for four nights and performed ambulatory nocturnal pulse oximetry on the fourth night of CPAP withdrawal. An ODI >10 events per hour during pulse oximetry was considered to indicate persistent OSA. Patients not experiencing recurrence of OSA underwent repeat ambulatory pulse oximetry after a further 2-week period off CPAP. In 71% of the patients, OSA recurred after four nights of CPAP withdrawal (group 1); thus, OSA did not recur in 29% (group 2). 55% of group 2 had an ODI >10 events per hour after 2 weeks off CPAP; thus, 45% remained without a recurrence. In multivariate analysis, higher original ODI, longer duration of CPAP therapy, current smoking status and larger neck circumference were independently associated with a higher ODI after four nights of CPAP withdrawal (all p<0.05). Following CPAP withdrawal, a third of CPAP-treated patients do not experience significant recurrence of oxygen desaturations after 4 days and ~10% do not after 2 weeks. Thus, a significant proportion of patients may be able to stop CPAP for short periods. PMID- 24488569 TI - Association of ambient air pollution with the prevalence and incidence of COPD. AB - The role of air pollution in chronic obstructive pulmonary disease (COPD) remains uncertain. The aim was to assess the impact of chronic exposure to air pollution on COPD in four cohorts using the standardised ESCAPE exposure estimates. Annual average particulate matter (PM), nitrogen oxides (NOx) and road traffic exposure were assigned to home addresses using land-use regression models. COPD was defined by NHANES reference equation (forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC) less than the lower limit of normal) and the Global Initiative for Chronic Obstructive Lung Disease criterion (FEV1/FVC <0.70) and categorised by severity in non-asthmatics. We included 6550 subjects with assigned NOx and 3692 with PM measures. COPD was not associated with NO2 or PM10 in any individual cohort. In meta-analyses only NO2, NOx, PM10 and the traffic indicators were positively, although not significantly, associated with COPD. The only statistically significant associations were seen in females (COPD prevalence using GOLD: OR 1.57, 95% CI 1.11-2.23; and incidence: OR 1.79, 95% CI 1.21-2.68). None of the principal results were statistically significant, the weak positive associations of exposure with COPD and the significant subgroup findings need to be evaluated in further well standardised cohorts followed up for longer time, and with time-matched exposure assignments. PMID- 24488571 TI - Prevalence of night-time dyspnoea in COPD and its implications for prognosis. AB - The information on night-time symptoms in chronic obstructive pulmonary disease (COPD) is sparse. We investigated the prevalence of night-time dyspnoea in 6616 individuals with COPD recruited from the general population in the Copenhagen area, Denmark, and described characteristics and prognosis of subjects with this symptom. The prevalence of night-time dyspnoea was 4.3%: 2.1% in Global Initiative for Chronic Obstructive Lung Disease (GOLD) group A, 12.9% in GOLD B, 2.6% in GOLD C and 16.3% in GOLD D. Compared with individuals without night-time dyspnoea, those with night time dyspnoea had lower forced expiratory volume in 1 s, higher daytime dyspnoea scores (modified Medical Research Council scale) and more wheezing, more often had chronic mucus hypersecretion, ischaemic heart disease and atrial fibrillation, and more often reported stress, nervousness and tiredness. After adjustment for age and sex, the presence of night-time dyspnoea was associated with future COPD exacerbations (hazard ratio (HR) 2.3, 95% CI 1.7 3.0), hospital admissions due to COPD (HR 3.2, 95% CI 2.3-4.4) and mortality (HR 1.7, 95% CI 1.2-2.3). Prevalence of night-time dyspnoea in COPD increases with disease severity according to both spirometric and clinical GOLD classification, and is associated with presence of daytime respiratory symptoms and cardiac comorbidities. Night-time dyspnoea is a significant predictor of poor prognosis in individuals with COPD. PMID- 24488572 TI - Kinship care for the safety, permanency, and well-being of children removed from the home for maltreatment. AB - BACKGROUND: Every year a large number of children around the world are removed from their homes because they are maltreated. Child welfare agencies are responsible for placing these children in out-of-home settings that will facilitate their safety, permanency, and well-being.However, children in out-of home placements typically display more educational, behavioural, and psychological problems than do their peers, although it is unclear whether this results from the placement itself, the maltreatment that precipitated it, or inadequacies in the child welfare system. OBJECTIVES: To evaluate the effect of kinship care placement compared to foster care placement on the safety, permanency, and well-being of children removed from the home for maltreatment. SEARCH METHODS: We searched the following databases for this updated review on 14 March 2011: the Cochrane Central Register of Controlled Trials(CENTRAL),MEDLINE, PsycINFO, CINAHL, Sociological Abstracts, Social Science Citation Index, ERIC, Conference Proceedings Citation Index-Social Science and Humanities, ASSIA, and Dissertation Express. We handsearched relevant social work journals and reference lists of published literature reviews, and contacted authors. SELECTION CRITERIA: Controlled experimental and quasi-experimental studies, in which children removed from the home for maltreatment and subsequently placed in kinship foster care were compared with children placed in non-kinship foster care for child welfare outcomes in the domains of well-being, permanency, or safety. DATA COLLECTION AND ANALYSIS: Two review authors independently read the titles and abstracts identified in the searches, and selected appropriate studies. Two review authors assessed the eligibility of each study for the evidence base and then evaluated the methodological quality of the included studies.Lastly, we extracted outcome data and entered them into Review Manager 5 software (RevMan) for meta-analysis with the results presented in written and graphical forms. MAIN RESULTS: One hundred-and-two quasi-experimental studies,with 666,615 children are included in this review.The 'Risk of bias' analysis indicates that the evidence base contains studies with unclear risk for selection bias, performance bias, detection bias, reporting bias, and attritionbias, with the highest risk associated with selection bias and the lowest associated with reporting bias. The outcome data suggest that children in kinship foster care experience fewer behavioural problems (standardised mean difference effect size -0.33, 95% confidence interval (CI) -0.49 to -0.17), fewer mental health disorders (odds ratio (OR) 0.51, 95% CI 0.42 to 0.62), better well-being (OR 0.50,95% CI 0.38 to 0.64), and less placement disruption (OR 0.52, 95% CI 0.40 to 0.69) than do children in non kinship foster care. For permanency, there was no difference on re unification rates, although children in non-kinship foster care were more likely to be adopted(OR 2.52, 95% CI 1.42 to 4.49), while children in kinship foster care were more likely to be in guardianship (OR 0.26, 95% CI 0.17 to 0.40). Lastly, children in non-kinship foster care were more likely to utilise mental health services (OR 1.79, 95% CI 1.35 to 2.37). AUTHORS' CONCLUSIONS: This review supports the practice of treating kinship care as a viable out-of-home placement option for children removed from the home for maltreatment. However, this conclusion is tempered by the pronounced methodological and design weaknesses of the included studies. PMID- 24488574 TI - Time-dependent decrease of clusterin as a potential cerebrospinal fluid biomarker for drug-resistant epilepsy. AB - Our previous study on proteomic analysis has shown that clusterin (CLU) is significantly decreased in the cerebrospinal fluid (CSF) of patients with epilepsy. Therefore, the present study aimed to confirm CLU concentration reduction in the CSF of patients with drug-resistant epilepsy and drug-responsive epilepsy. Fifty-two patients with epilepsy (23 drug resistance and 29 drug effectivity) and 20 control individuals were recruited. The concentrations of CSF and serum CLU were detected. Moreover, alteration of CLU was detected in the rat hippocampus over time after pilocarpine-induced status epilepticus (SE). Our results showed that human CSF-CLU levels were decreased in patients with both drug-resistant epilepsy and drug-responsive epilepsy compared to controls, and concentration of CSF-CLU was obviously lower in drug-resistant epilepsy than in drug-responsive epilepsy. In the pilocarpine-induced seizure rats, expression of neuronal CLU was gradually decreased in a time-dependent manner from acute phase to chronic phase after the onset of SE. In conclusion, CLU level is decreased in the CSF of human epilepsy and the similar alteration is confirmed in a rat model with epilepsy. Therefore, CLU might contribute to the development of epilepsy and be a potential CSF biomarker for resistant epilepsy. PMID- 24488573 TI - Depressive symptoms, health-related quality of life, and cardiac event-free survival in patients with heart failure: a mediation analysis. AB - PURPOSE: Health-related quality of life (HRQOL) and depressive symptoms both are associated with an adverse prognosis in heart failure (HF), although their associations with outcomes have been examined only in isolation. Therefore, it is unknown how HRQOL and depressive symptoms might interact in their associations with outcomes. The present study was conducted to determine whether the association between HRQOL and cardiac event-free survival is mediated by depressive symptoms in HF patients given that depressive symptoms are associated strongly with HRQOL. METHODS: A total of 209 HF patients (61 +/- 11 years, 24 % female, 49 % NYHA III/IV) participated. The Minnesota Living with HF Questionnaire and the Patient Health Questionnaire-9 were used to measure HRQOL and depressive symptoms, respectively. Patients were followed for a median of 357 days to determine cardiac event-free survival. RESULTS: In Cox regression analysis, HRQOL [hazard ratio (HR) 1.013; 95 % confidence interval (CI) 1.001 1.026] and depressive symptoms (HR 1.075; 95 % CI 1.025-1.127) predicted cardiac event-free survival separately, controlling for demographic and clinical variables. HRQOL independently explained 38.7 % of the variance in depressive symptoms (p < 0.05; standardized beta = 0.695) in a multiple regression. When HRQOL and depressive symptoms were entered in the model simultaneously, only depressive symptoms independently predicted cardiac event-free survival (HR 1.068; 95 % CI 1.001-1.139), demonstrating a mediation effect of depressive symptoms. CONCLUSIONS: Depressive symptoms mediated the relationship between HRQOL and cardiac event-free survival. Interventions targeting HRQOL to enhance patient outcomes must also address patient depressive symptoms to be fully efficacious. PMID- 24488575 TI - Davunetide (NAP) protects the retina against early diabetic injury by reducing apoptotic death. AB - Davunetide (NAP) is an eight amino acid peptide that has been shown to provide potent neuroprotection. In the present study, we investigated the neuroprotective effect of NAP in diabetic retinopathy using an in vivo streptozotocin (STZ) induced diabetic model. A single intraocular injection of NAP (100 MUg/mL) or vehicle was administered 1 week after STZ injection. Three weeks after diabetes induction, we assessed the retinal expression and distribution of apoptosis markers, cleaved caspase-3, and Bcl2, by Western blot and immunofluorescent analysis. Furthermore, we evaluated the activation of mitogen-activated protein kinase/extracellular signal-regulated protein kinase (MAPK/ERK) and/or phosphatidylinositol-3 kinase/Akt pathways by measuring the protein levels of p ERK and p-AKT with or without NAP treatment. Results demonstrated that NAP treatment reduced apoptotic event in diabetic retina, and it restored cleaved caspase-3 expression levels in the retina of STZ-injected rats as well as the decreased Bcl2. NAP treatment improved cellular survival through the activation of the MAPK/ERK pathway. Taken together, these findings suggested that NAP might be useful to treat retinal degenerative diseases. PMID- 24488576 TI - Methods for identifying the cost-effective case definition cut-off for sequential monitoring tests: an extension of Phelps and Mushlin. AB - The arrival of personalized medicine in the clinic means that treatment decisions will increasingly rely on test results. The challenge of limited healthcare resources means that the dissemination of these technologies will be dependent on their value in relation to their cost, i.e., their cost effectiveness. Phelps and Mushlin have described how to optimize tests to meet a cost-effectiveness target. However, when tests are applied repeatedly the case mix of the patients tested changes with each administration, and this impacts upon the value of each subsequent test administration. In this article, we present a modification of Phelps and Mushlin's framework for diagnostic tests; to identify the cost effective cut-off for monitoring tests. Using the Ca125 test monitoring for relapse in ovarian cancer, we show how the repeated use of the initial cut-off can lead to a substantially increased false-negative rate compared with the monitoring cut-off-over 4% higher than in this example-with the associated harms for individual and population health. PMID- 24488577 TI - Spontaneous spinal accessory nerve palsy: the diagnostic usefulness of ultrasound. PMID- 24488578 TI - The effect of soil properties on the toxicity of silver to the soil nitrification process. AB - Silver (Ag) is being increasingly used in a range of consumer products, predominantly as an antimicrobial agent, leading to a higher likelihood of its release into the environment. The present study investigated the toxicity of Ag to the nitrification process in European and Australian soils in both leached and unleached conditions. Overall, leaching of soils was found to have a minimal effect on the final toxicity data, with an average leaching factor of approximately 1. Across the soils, the toxicity was found to vary by several orders of magnitude, with concentrations of Ag causing a 50% reduction in nitrification relative to the controls (EC50) ranging from 0.43 mg Ag/kg to >640 mg Ag/kg. Interestingly, the dose-response relationships in most of the soils showed significant stimulation in nitrification at low Ag concentrations (i.e., hormesis), which in some cases produced responses up to double that observed in the controls. Soil pH and organic carbon were the properties found to have the greatest influence on the variations in toxicity thresholds across the soils, and significant relationships were developed that accounted for approximately 90% of the variability in the data. The toxicity relationships developed from the present study will assist in future assessment of potential Ag risks and enable the site-specific prediction of Ag toxicity. PMID- 24488579 TI - Security and efficiency of a closed-system, turbulent-flow circuit for hyperthermic intraperitoneal chemotherapy after cytoreductive ovarian surgery: perioperative outputs. AB - OBJECTIVE: To present physiologic intraoperative data and immediate postoperative outcomes of patients diagnosed with epithelial ovarian cancer submitted to cytoreductive surgery and hyperthermic peritoneal intraoperative chemotherapy (HIPEC) with a closed-circuit, turbulent-flow system. MATERIALS AND METHODS: A closed-circuit system with CO2 turbulent flow was used for paclitaxel HIPEC during 60 min for patients diagnosed with stage II or higher and recurrent epithelial ovarian cancer. Perioperative hemodynamic and metabolic statuses were followed, as well as physiologic recovery during the first 12 postoperative hours. A non-parametric statistical analysis was performed. RESULTS: At the end of the hyperthermia phase, temperature was 37.7 +/- 0.6 degrees C, heart rate 88 +/- 19 bpm, cardiac index 2.8 +/- 0.5 L min(-1) m(-2), stroke volume variation 14.6 +/- 3.6 % and extravascular lung water 8.7 +/- 1.9 mL kg(-1). No hyperdynamic status was recorded. The length of stay in the ICU was 21/2 days, and 12.7 +/- 7 days in hospital. Average postoperative intubation time was 11.7 +/- 17.4 h. At the ICU admission time, glucose, lactic acid and hemoglobin were the only values out of range, but close to normal. SOFA median was 3 at admission and 0 the following day. CONCLUSION: A turbulent-flow, closed-circuit use for hyperthermic peritoneal intraoperative chemotherapy resulted in no hyperdynamic response or coagulopathy, had good tolerance and promoted early physiologic recovery. PMID- 24488580 TI - Characterizing the need for re-laparotomy during puerperium after cesarean section. AB - OBJECTIVE: As inconsistency exists concerning the rate and risk factors for re laparotomy after cesarean section (CS), we aimed to determine the incidence, risk factors and indications for re-laparotomy after CS. METHODS: This is a retrospective study. Women underwent re-laparotomy following CS were compared to a control group in a 1:3 ratio. Demographic, obstetrical and surgical data were analyzed. CS complications were defined as intra-operative abnormal hemorrhage, summoning surgical personnel, inverted T incision, uterine and/or hypogastric arteries ligation or cesarean hysterectomy. RESULTS: Overall, 35,779 women delivered during the study, of them 7,926 by CS (22.1 %) and 62 patients (0.7 %) underwent re-laparotomy. Re-laparotomies occur during the first 24 h, first week and beyond it, following CS in 64.5, 22.6 and 12.9 %, respectively. Previous abdominal/pelvic surgery (14.5 vs. 8.1 %, p < 0.01), emergent surgery (24.2 vs. 13.4 %, p = 0.04), intra-operative complications (26.8 vs. 0.5 %, p < 0.001), post-operative complication (40.7 vs. 0.5 %, p < 0.001) and adhesions (65.5 vs. 33.3 %, p < 0.001) were significantly increased in the study group. Indications for re-laparotomy varied according to the interval elapsed to the re-laparotomy with post-partum hemorrhage (27.4 %) being the leading indication in the early period. CONCLUSION: Risk factors for re-laparotomy following CS can be recognized and are mainly associated with previous abdominal and/or pelvic surgeries and intra-operative adhesions. PMID- 24488581 TI - Ovarian stripping versus cystectomy: recurrence of endometriosis and pregnancy rate. AB - PURPOSE: To compare two different surgical techniques, stripping or cystectomy, in patients treated with the same post-operative medical therapy in terms of recurrence of endometrioma, recurrence of pain and spontaneous pregnancy rate within 2 years from surgery. METHODS: The inclusion criteria of this study were: (1) 25-40 years old; (2) ovarian endometrioma more than 3 cm of diameter detected by transvaginal ultrasonography (3) regular menstrual cycle (4) post-operative treatment with GnRH analogs, (5) tubal patency assessed by laparoscopic chromopertubation (6) normal human semen characteristics. Exclusion criteria were uterine myoma, previous medical treatment for endometriosis, presence of adenomyosis, previous surgery of ovarian endometrioma, multiple cysts, bilateral involvement, co-existence of deep endometriosis. Patients were assigned to two study groups: group A (N = 45) patients undergoing stripping technique and group B (N = 64) patients undergoing cystectomy technique for ovarian endometrioma. RESULTS: In group B the percentage of ultrasonographic recurrence (15.4 %, N = 15) is much lower than in group A (55.6 %, N = 25). (p value 0.001). In group B the percentage of symptomatic recurrence (21.8 %, N = 14) is much lower than in group A (53.3 %, N = 24) (p value 0.001). Spontaneous pregnancy rate in group A patients was of 4.4 % (N = 2) and in group B 22.3 % (N = 21), (p value 0.0072). However, the percentage of specimen with adjacent healthy ovarian tissue was lower in group A (26.6 %) than in group B (50 %) (p value 0.01). CONCLUSIONS: Among the different treatment options for surgical treatment of ovarian endometrioma, in our experience cystectomy appears to be the most appropriate treatment, both in terms of recurrence and pregnancy rate. PMID- 24488582 TI - Comparison of the efficacy of micronized progesterone and lynestrenol in treatment of simple endometrial hyperplasia without atypia. AB - PURPOSE: To evaluate the treatment of simple endometrial hyperplasia without atypia with different gestagens. METHODS: Sixty premenopausal women with histologically documented endometrial hyperplasia without atypia were included in this prospective controlled study. Patients were randomized into two groups: Group I included 30 patients who received lynestrenol (LYN) in a dose of 15 mg/d, while Group II included 30 patients who received micronized progesterone (MP) 200 mg/d for 12 days per cycle for 3 months. Patients were reevaluated with endometrial curettage after treatment. MP and LYN regimens were compared to regression, resolution or persistence rates and metabolic parameters. RESULTS: After 3 months of treatment in both groups, none of the cases progressed. In LYN group, the rate of resolution was observed to be higher compared to MP group (p = 0.045). LYN was found more effective inducing resolution in patients more than 45 years compared to MP (p = 0.036). When we compare both groups after 3 months of treatment, there was no statistically significant difference in BMI, total cholesterol, HDL, LDL and fibrinogen level between two groups. The rate of patients without any side effects was found to be similar in both groups (p = 0.5). CONCLUSION: LYN which is a synthetic progestin ensures better endometrial control compared to MP in simple hyperplasia without atypia in the patients of premenopausal age especially in ages more than 45 years. PMID- 24488583 TI - Copeptin is associated with the severity of endometriosis. AB - PURPOSE: Endometriosis is defined as the presence of endometrial glands and stroma in ectopic locations and may be associated with local and systemic inflammatory processes. Copeptin is elevated in acute and chronic inflammation conditions. The aim of the present study was to determine whether serum copeptin levels were altered in women with endometriosis and played a role in the pathophysiology of the disease. METHODS: A total of 86 women were recruited for this case-control study. 50 patients with surgically proven endometriosis were included, while 36 patients without endometriosis comprised the control group. Patients were classified as having minimal, mild, moderate and severe disease in accordance with American Society of Reproductive Medicine revised classification. Two subgroups were formed by combining patients with minimal and mild disease and with moderate and severe disease (Stage 1-2, stage 3-4; respectively). Levels of copeptin, tumor markers (CA-125, CA-19-9, CA-15-3) and C-reactive protein in serum were measured. RESULTS: Serum copeptin, CA-125, CA-15-3 and CA-19-9 levels were higher in the endometriosis group (p: 0.002; 0.001; 0.017; 0.015; respectively). Copeptin and CA-19-9 levels were significantly higher in stage 3-4 group as compared to stage 1-2 group (p: 0.004; 0.036 respectively). Serum copeptin levels were positively correlated with stage of the disease and size of endometriomas. ROC analysis revealed that CA-125 had the highest AUC for predicting endometriosis (0.938; 95 % confidence interval 0.882-0.993; p: 0.001). CONCLUSIONS: Serum copeptin levels were significantly higher in patients with endometriosis as compared to healthy controls. Moreover, severity of the disease was correlated with serum copeptin levels. PMID- 24488585 TI - Capping methodology in cyclodextrin chemistry: use of a symmetrical diketone reagent for regiospecific installation of unsymmetrical imine-enamine and imidazole caps. AB - Methylated alpha- and beta-cyclodextrin skeletons were both equipped with an unsymmetrical N-(2-N-alkylaminoacenaphthenyl)alkylimine rigid handle. The capping reaction, which consists of condensing a diaminocyclodextrin with highly symmetrical acenaphthenequinone, was found to be regiospecific when starting from cyclodextrin-diamines without any symmetry element. All modified cyclooligosaccharides have intra-annular nitrogen donor atoms. They undergo further cyclization on oxidation, whether chemically with 2,3-dichloro-5,6 dicyano-1,4-benzoquinone or electrochemically, to give highly strained cyclodextrins capped with an unsymmetrical 1,2-disubstituted 1H-imidazole unit. PMID- 24488584 TI - Steroid cell tumor of the ovary in a pregnant woman whose androgenic symptoms were masked by pregnancy. AB - INTRODUCTION: Ovarian steroid cell tumors are very rare sex cord-stromal tumors, and most of them are unilateral and almost one-third of the cases are malignant. CASE REPORT: Here, we present a pregnant woman, who diagnosed with steroid cell tumor of the ovary and underwent surgical staging. DISCUSSION: We will discuss the clinical presentation of the case, management options and follow-up strategies. PMID- 24488586 TI - The effects of aging on the expression of Wnt pathway genes in mouse tissues. AB - The Wnt signaling pathway is involved in the regulation of tissue patterning and organ development during embryogenesis and continues to contribute to the maintenance of tissue homeostasis in adulthood. Recently, Wnt signaling has also been implicated in the establishment and progression of replicative cellular senescence. Given the known roles of tissue homeostasis and cellular senescence in aging, we sought to determine whether Wnt signaling changes with age. We examined the expression of 84 Wnt pathway-related genes in the liver, lung, skeletal muscle, and brain tissue from young and old mice. Expression changes were compared with those seen in cellular senescence, and transcription factors that might mediate these changes were predicted bioinformatically. In aggregate, our data are indicative of a general decrease in Wnt signaling with age, especially in the lung and brain. Furthermore, the set of genes that are differentially expressed with age is distinct from the genes differentially expressed in cellular senescence. The transcription factors predicted to regulate these changes, Nf-kappaB, Myb, Nkx2-1, Nr5a2, and Ep300, are known to regulate inflammation, differentiation, lipid metabolism, and chromatin remodeling, all of which have previously been implicated in aging. Although our study does not address whether altered Wnt signaling is a cause or an effect of aging, the presence of a relationship between the two provides a starting point for further investigation. PMID- 24488587 TI - Assessing the challenges of Fourier transform infrared spectroscopic analysis of blood serum. AB - There are many approaches to measuring the infrared spectrum of a blood serum sample. Naturally, each approach will have both advantages and disadvantages. We report on the progress of the application of infrared spectroscopy in the field of blood serum analysis towards clinical application, with a focus on prostate cancer. In order to perform a high-powered study with clinical relevance, choosing the most suitable approach must undergo careful consideration. We review the possibilities of using different sample preparation methods and speculate upon the potential pitfalls of both transmission and attenuated total reflectance (ATR) techniques. PMID- 24488588 TI - Vitamin D deficiency and its role in muscle-bone interactions in the elderly. AB - In this commentary, we focus on common 'downstream' links of vitamin D between muscle and bone health. Both direct and indirect effects of 1,25 dihydroxyvitamin D (1,25(OH)D) link the mutual age-related decline in muscle function and bone density, independent of physical activity. Changes in calcium absorption associated with vitamin D deficiency affect both muscle and bone mass. The age related decline in vitamin D receptor expression and 1,25(OH)D activity impact on proinflammatory cytokines such as tumor necrosis factor -alpha and interleukin-6 in skeletal muscle and vitamin D deficiency appears to enhance both bone marrow adipogenesis and intramuscular adipose tissue impacting as reduced functionality in both skeletal tissues. Controversial findings on the role of 1,25(OH)D on skeletal muscle may relate to differences in vitamin D receptor expression throughout different stages of muscle cell differentiation. Prolonged vitamin D insufficiency in the elderly is associated with reductions in both bone mineral density and type 2 muscle fibers with the outcomes of skeletal fragility in combination with reduced muscle power, leading to increased risk of falls and fracture. PMID- 24488589 TI - Does knowledge influence pap test screening among young African-American women? AB - Pap test screening among African-American women has substantially increased. However, African-American women continue to bear the burden of cervical cancer as compared to White women. The objective of this study was to assess the influence of Pap test knowledge on cervical screening history among young African-American women. Between January and April 2009, 320 women from historically black colleges and universities located in the southeastern United States who met study inclusion criteria completed an anonymous self-report questionnaire to assess their awareness, knowledge, and behaviors related to human papillomavirus and cervical cancer prevention and control. Seventy-six percent of women reported ever having a Pap test, 54 % reported having a Pap test less than 1 year ago, and 25 % reported ever having an abnormal Pap test result. The overall mean score on the six-point Pap test knowledge scale was 4.46 +/- 1.02. Women who reported having an abnormal Pap test (4.96 +/- 0.82) had significantly higher Pap test knowledge compared to those never having an abnormal result (4.49 +/- 1.04), p < 0.01. No other differences were found. Efforts to improve Pap test knowledge among all women, including those with no prior abnormal Pap test history, are critical to cervical cancer prevention and control over the life course. Such efforts should include creating information that is relevant to the population and enables informed decision making about cervical health. PMID- 24488590 TI - Physician behaviors to promote informed decisions for prostate cancer screening: a National Research Network study. AB - Clinical guidelines for prostate cancer screening (PCS) advise physicians to discuss the potential harms and benefits of screening. However, there is a lack of training programs for informed decision-making (IDM), and it is unknown which IDM behaviors physicians have the most difficulty performing. Identifying difficult behaviors can help tailor training programs. In the context of developing a physician-IDM program for PCS, we aimed to describe physicians' use of nine key IDM behaviors for the PCS discussion and to examine the relation between the behaviors and physician characteristics. A cross-sectional sample of The American Academy of Family Physicians National Research Network completed surveys about their behavior regarding PCS (N = 246; response rate = 58%). The surveys included nine physician key IDM behaviors for PCS and a single-item question describing their general practice style for PCS. The most common IDM behavior was to invite men to ask questions. The two least common reported behaviors concerned patients uncertain about screening (i.e., arrange follow-up and provide additional information for undecided men). Physicians reported difficulty with these two behaviors regardless whether they reported to discuss or not to discuss PCS with patients. Reported use of key IDM behaviors was associated with a general practice style for PCS and being affiliated with a residency-training program. Physician training programs for IDM should include physician skills to address the needs of patients uncertain about screening. Future research should determine if actual behavior is associated with self reported behavior for the PCS discussion. PMID- 24488591 TI - Exploring attitudes of Canadian radiation oncologists, radiation therapists, physicists, and oncology nurses regarding interprofessional teaching and learning. AB - The purposes of this exploratory study were to investigate the attitudes of radiation oncology professionals regarding interprofessional (IP) teaching and interprofessional education (IPE), to identify the challenges faced by radiation oncologists who teach within an IP context, and to discover new strategies to aid professionals teaching IP students. A questionnaire was developed through the review of existing literature on IPE using Medline. The proposed group of questions was selected by educators from different professions actively involved in IPE. The final revised questionnaire consisted of three main domains assessing the understanding of IP concepts, attitudes toward IP teaching and learning environments, and attitudes toward health-care teams. An open-ended comment section was included. The questionnaire was administered to health-care professionals (physicists, radiation oncologists, and radiation therapists) nationally through SurveyMonkey(r) (electronic survey). A total of 220 respondents provided demographic information. Half of these respondents indicated that they previously received education relating to IPE. A high level of agreement was received for nearly all the questions. There were no significant statistical differences among the three different professional respondent groups for any question. Overall, most of the respondents demonstrated a good knowledge and understanding of IP concepts and advocated IP training and collaboration. PMID- 24488592 TI - Expression and functional characterisation of a soluble form of Tomato yellow leaf curl virus coat protein. AB - BACKGROUND: Tomato yellow leaf curl virus (TYLCV), a member of the genus Begomovirus within the family Geminiviridae, is an important pathogen of tomato in many tropical, subtropical and temperate regions. TYLCV is exclusively transmitted by the whitefly Bemisia tabaci in a circulative manner. The viral coat protein (CP) has been assumed to play important roles in the entry of TYLCV into the insect midgut cells. RESULTS: Testing the hypothesis that CP plays an important role in TYLCV acquisition by B. tabaci, a soluble form of the CP was expressed and purified. The purified recombinant CP made it possible to examine the function of TYLCV CP without other viral proteins. In an in vivo binding assay, specific binding of TYLCV CP to B. tabaci midguts was detected when purified CP was fed to B. tabaci. In addition, real-time polymerase chain reaction analysis of virus titre revealed that B. tabaci fed with purified CP had reduced the level of virus in their midgut compared with those fed with bovine serum albumin or maltose-binding protein. These results suggest that binding of TYLCV CP to the B. tabaci midgut specifically inhibits virus acquisition. CONCLUSIONS: The findings that TYLCV CP binds to B. tabaci midguts and decreases virus acquisition provide direct evidence that CP mediates the attachment of TYLCV to receptors on the epithelial cells of the B. tabaci midgut. PMID- 24488593 TI - Cervical cancer screening by high risk HPV testing in routine practice: results at one year recall of high risk HPV-positive and cytology-negative women. AB - OBJECTIVE: Cervical cancer screening by human papillomavirus (HPV) testing requires the use of additional triage and follow-up analyses. We evaluated women's compliance with and the performance of this strategy in a routine setting. SETTING: Five cervical service screening programmes in North-East Italy. METHODS: Eligible women aged 25-64 invited for a new screening episode underwent HPV testing for high risk types (hrHPV by Hybrid Capture 2) and cytology triage. Women with positive HPV and cytology results were referred for colposcopy; women with positive HPV but negative cytology results were referred to 1-year repeat hrHPV testing. RESULTS: Of 46,694 women screened by HPV testing up to December 2011, 3,211 (6.9%) tested hrHPV positive; 45% of these had a positive triage cytology. Those with negative cytology were invited for 1-yr repeat testing. Compliance with invitation was 61.6% at baseline and 85.3% at 1-yr repeat. Rate of persistent hrHPV positivity was 58% (830/1,435). Colposcopy performed in women with a positive hrHPV test at 1-yr repeat accounted for 36% of all colposcopies performed within the screening programmes. Cumulatively, a histological high grade lesion was detected in 276 women (5.90/00 detection rate), 234 at baseline (85%), and 42 (15%) at 1-yr repeat. CONCLUSIONS: Compliance with hrHPV-based screening programmes was high both at baseline and at 1-yr repeat. Compared with the randomized trials, a higher proportion of triage cytology was read as positive, and only a small number of high-grade lesions were detected among the group of hrHPV positive cytology negative women who repeated testing 1-yr after baseline. PMID- 24488594 TI - Condom use in prevention of Human Papillomavirus infections and cervical neoplasia: systematic review of longitudinal studies. AB - OBJECTIVES: Based on cross-sectional studies, the data on protection from Human Papillomavirus (HPV) infections related to using male condoms appear inconsistent. Longitudinal studies are more informative for this purpose. We undertook a systematic review of longitudinal studies on the effectiveness of male condoms in preventing HPV infection and cervical neoplasia. METHODS: We searched PubMed using MeSH terms for articles published until May 2013. Articles were included if they studied a change in non-immunocompromized women's cervical HPV infection or cervical lesion status along with the frequency of condom use. RESULTS: In total, 384 abstracts were retrieved. Eight studies reported in 10 articles met the inclusion criteria for the final review. Four studies showed a statistically significantly protective effect of consistent condom use on HPV infection and on regression of cervical neoplasia. In the remaining four studies, a protective effect was also observed for these outcomes, although it was not statistically significant. CONCLUSIONS: Consistent condom use appears to offer a relatively good protection from HPV infections and associated cervical neoplasia. Advice to use condoms might be used as an additional instrument to prevent unnecessary colposcopies and neoplasia treatments in cervical screening, and to reduce the risk of cervical cancer. PMID- 24488595 TI - A novel transchromosomic system: stable maintenance of an engineered Mb-sized human genomic fragment translocated to a mouse chromosome terminal region. AB - Transchromosomic (Tc) technology using human chromosome fragments (hCFs), or human artificial chromosomes (HACs), has been used for generating mice containing Mb-sized segments of the human genome. The most significant problem with freely segregating chromosomes with human centromeres has been mosaicism, possibly due to the instability of hCFs or HACs in mice. We report a system for the stable maintenance of Mb-sized human chromosomal fragments following translocation to mouse chromosome 10 (mChr.10). The approach utilizes microcell-mediated chromosome transfer and a combination of site-specific loxP insertion, telomere directed chromosome truncation, and precise reciprocal translocation for the generation of Tc mice. Human chromosome 21 (hChr.21) was modified with a loxP site and truncated in homologous recombination-proficient chicken DT40 cells. Following transfer to mouse embryonic stem cells harboring a loxP site at the distal region of mChr.10, a ~4 Mb segment of hChr.21 was translocated to the distal region of mChr.10 by transient expression of Cre recombinase. The residual hChr.21/mChr.10ter fragment was reduced by antibiotic negative selection. Tc mice harboring the translocated ~4 Mb fragment were generated by chimera formation and germ line transmission. The hChr.21-derived Mb fragment was maintained stably in tissues in vivo and expression profiles of genes on hChr.21 were consistent with those seen in humans. Thus, Tc technology that enables translocation of human chromosomal regions onto host mouse chromosomes will be useful for studying in vivo functions of the human genome, and generating humanized model mice. PMID- 24488596 TI - Study of polycation-capped Mn:ZnSe quantum dots as a novel fluorescent probe for living cells. AB - Transition metal manganese ion (Mn(2+)) doped zinc selenide quantum dots (Mn:ZnSe D-Dots) have been considered as a new material for fluorescent probes in biological labeling. However, this application is limited by the low membrane permeability of D-Dots. In this work, Mn:ZnSe D-Dots were capped with the polycation Sofast to label living cells. For the first time, the efficiency of cellular uptake in living cells is significantly enhanced. Various molar ratios of Sofast to D-Dots were explored and compared to obtain the optimal reaction conditions between Sofast and D-Dots for preparing Sofast/D-Dots nano-compound. A comparison on the fluorescence labeling ability of living cells were made between Sofast/D-Dots and pure D-Dots. Results from laser scanning confocal microscope show that Sofast/D-Dots complexes enter the cells more efficiently than pure D Dots, even with a lower concentration and shorter incubation time. The cytotoxicities of D-Dots and Sofast/D-Dots were also studied. It was found that Sofast/D-Dots have a much lower cytotoxicity than cadmium-containing quantum dots (i.e. CdTe and CdTe/ZnS). Our results suggest that the non-heavy-metal-containing Sofast/D-Dots complexes have a great potential in the application of biological labeling, especially of long-time bioimaging in living cells. PMID- 24488597 TI - DSM-5: new opportunities and challenges for teaching and training. AB - The development of the DSM-5 over the past decade included a systematic review of the major scientific and methodological advances made in the last two decades. The organizational chapter structure for the DSM has been reorganized to facilitate both clinical practice and teaching to improve assessment skills and at the same time, appreciate how to incorporate new knowledge not ready to be specified as diagnostic criteria. More specifically, we anticipate that we will have a structure that contains "receptors" for new biological, neurocognitive, and environmental risk factors as they emerge to guide future research and clinical practice. The emphasis in the manual on the medical psychiatric interface is of particular relevance for residency education. In addition to the didactic and practical import of the content of DSM-5, increased attention is being given to the new communication technology that makes it possible for the emergence of electronic versions and various types of "apps." PMID- 24488598 TI - Stiripentol for focal refractory epilepsy. AB - BACKGROUND: Nearly 30%of people with epilepsy do not have their seizures controlled with current treatments. Stiripentol is a new antiepileptic drug(AED) developed in France and recently approved by the European Medicines Agency (EMA) for the treatment of Dravet syndrome as an adjunctive therapy with valproate and clobazam, with a promising effect. OBJECTIVES: To evaluate the efficacy and tolerability of stiripentol as add-on treatment for patients with focal refractory epilepsy taking any AEDs. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (19 August 2013), Cochrane Central Register of Controlled Trials(CENTRAL Issue 7, The Cochrane Library July 2013), MEDLINE (Ovid) (1946 to 19 August 2013) and EMBASE (31 May 2012).(The last search in EMBASE was made on 31th May 2012. Since then we no longer have access to that database.) We also contacted Biocodex (the manufacturer of stiripentol) and epilepsy experts to identify published, unpublished and ongoing trials. SELECTION CRITERIA: Randomised controlled add-on trials of stiripentol in patients with focal refractory epilepsy. DATA COLLECTION AND ANALYSIS: Review authors independently selected trials for inclusion and extracted data. The outcomes investigated included 50% or greater reduction in seizure frequency, seizure freedom, adverse effects, treatment withdrawal and changes in quality of life. MAIN RESULTS: Using our selection criteria, one study was included (32 children with focal epilepsy). This study adopted a 'responder enriched' design.There was no clear evidence of a reduction in seizure reduction 50% seizure reduction) (RR 1.51, 95% CI 0.81 to 2.82) or in seizure freedom (RR 1.18, 95% CI 0.31 to 4.43) with add on stiripentol compared with placebo. Add-on stiripentol led to a greater risk of adverse effects considered as a whole (RR 2.65, 95% CI 1.08 to 6.47) compared with placebo. When considered as specific adverse events, the confidence intervals are very wide and include the possibility of substantial increases and small reductions in the risk of neurological (RR 2.65, 95% CI 0.88 to 8.01) or gastrointestinal adverse effects (RR 11.56, 95% CI 0.71 to 189.36). There was no clear reduction in the risk of study withdrawal (RR 0.66, 95% CI 0.30 to 1.47), which was high in both groups (35.0% in add-on placebo and 53.3% in stiripentol group). The external validity of the study was limited because only responders to stiripentol (that is patients experiencing at least a 50% decrease in seizure frequency compared with baseline) were included in the randomised add on placebo-controlled double-blind phase. Furthermore, a carry over and a withdrawal effect probably affected the outcome related to seizure frequency. Although restricted by the very limited information derived by the only one included study, adverse effects considered as a whole seemed to occur significantly more often with add-on stiripentol compared with add-on placebo. AUTHORS' CONCLUSIONS: No conclusions can be drawn to support the use of stiripentol as add-on treatment for focal refractory epilepsy. Further large, randomised,well-conducted trials are needed. PMID- 24488599 TI - Diagnostic overview of blood-based dysferlin protein assay for dysferlinopathies. AB - INTRODUCTION: Dysferlin deficiency causes dysferlinopathies. Among peripheral blood mononuclear cells (PBMCs), the dysferlin protein is expressed specifically in CD14(+) monocytes. METHODS: We quantified dysferlin protein levels in PBMC lysates of 77 individuals suspected clinically of having a dysferlinopathy to screen for true positives. Subsequent molecular confirmation was done by Sanger sequencing and comparative genomic hybridization arrays to establish diagnosis. RESULTS: Of the 44 individuals who had significantly reduced dysferlin levels (<=10%), 41 underwent molecular testing. We identified at least 1 mutation in 85% (35 of 41), and 2 mutations, establishing a dysferlinopathy diagnosis, in 61% (25 of 41) of these individuals. Among those with dysferlin protein levels of >10% (33 of 77), only 1 individual (of 14 who underwent molecular testing) had a detectable mutation. CONCLUSIONS: Our results suggest that dysferlin protein levels of <=10% in PBMCs, are highly indicative of primary dysferlinopathies. However, this assay may not distinguish carriers from those with secondary dysferlin reduction. PMID- 24488600 TI - Reversible binding of solvent to naked PbII centers in unusual homoleptic alkynyl based Pt2Pb2 clusters. AB - We report a series of luminescent sandwich-type clusters [Pt2 Pb2 (C=CR)8] (R=Tol, 1; C6 H4 OMe-3, 2; C6 H4 OMe-4, 3) with a dynamic Pt2 Pb2 metallic core, which is key to their intriguing stimuli-responsive photophysical properties. The solvent-free solids 1-3 display an orange emission ascribed to charge transfer from Pt-alkynyl fragments to a delocalized orbital with mixed Pt2 Pb2 /C=CR nature, with a predominant lead contribution and Pb???Pb bonding character ((3) MLCCT/(3) IL). They exhibit mechanical, color, and luminescence changes that are reversible and perceivable with the naked eye, which are attributed to small inter- and intramolecular structural modifications induced by gentle grinding. Interestingly, 1 and 2 also exhibit remarkable and fast reversible vapochromic responses to donor solvent vapors (acetone, THFMe-2: yellow; NCMe: green, vs. dry solids: orange). The structures of 1(acetone)2 ?2(Me2 CO), 2(acetone)3 , and 2(THFMe-2)2 allow the vapochromic responses to be ascribed to the fast creation/disruption of solvate clusters [Pt2 Pb2 (C=CR)8 Sx] (x>=2), with concomitant electronic and geometrical modifications within the Pt2 Pb2 core, which are easily accessible through a slight change in the stereochemical activity of the lone pair. The binding of one (or two) solvent molecules to Pb(2+) increases the Pb???Pb separation in the metallic core, causing a destabilization of the target orbital and larger energy gaps of the transitions. All the solvates exhibit remarkable rigidochromism upon a decrease in temperature, which is also associated with the gradual increase in the transannular Pb???Pb separation, as revealed by X-ray crystallography of 1(acetone)2 at different temperatures. Investigation of the crystal lattice of 1?CH2 Cl2 and 3?2 CH2 Cl2 further suggests that the lack of vapor stimuli response of complex 3 could be attributed to the presence of competitive additional secondary intermolecular Pb???O(OMe) contacts, which give rise to a more compact network built up from extended chains of clusters. PMID- 24488601 TI - Neuroprotective effects of 3,6'-disinapoyl sucrose through increased BDNF levels and CREB phosphorylation via the CaMKII and ERK1/2 pathway. AB - 3,6'-Disinapoyl sucrose (DISS) is an oligosaccharide ester natural product originating from the root of wild Polygala tenuifolia. Our previous reports suggested that DISS can have neuroprotective effects and antidepressive activity in rats, at least in part, by increased expression of cyclic AMP response element (CRE)-binding protein (CREB) and its downstream target protein, brain-derived neurotrophic factor (BDNF). The aim of the present study was to explore the mechanism of DISS-modulated BDNF and CREB expression. In this study, we confirmed its neuroprotective effect by showing that DISS, at concentrations above 30 MUM, could promote the neuron cell viability and protected the glutamate and H2O2 induced toxicity in the human neuroblastoma (SH-SY5Y) cell line. DISS treatment also increased acute (from 15 to 30 min) BDNF expression and CREB phosphorylation in a dose-dependent manner. Pharmacological inhibition of mitogen-activated protein kinase 1 (ERK1/2), CaMKII, and Trk (with U0126, KN93, or K252a, respectively) partially attenuated the stimulatory effect of DISS on phospho-CREB and BDNF expression; however, it was not inhibited by pharmacological inhibition of PKA or PI3K (with H89 and LY294002, respectively). The results are consistent with the effects of DISS on CRE-directed gene transcription, as U0126 and KN-93 treatment also blocked the DISS-induced expression of the CRE-luciferase reporter gene. The results from the present study suggest that DISS-mediated regulation of BDNF gene expression is associated with CREB-mediated transcription of BDNF and upstream activation of ERK1/2 and CaMKII. Finally, DISS may exert neuroprotective and antidepressant effects through these signaling pathways in neuronal cells. PMID- 24488602 TI - Conditioned media of choroid plexus epithelial cells induces Nrf2-activated phase II antioxidant response proteins and suppresses oxidative stress-induced apoptosis in PC12 cells. AB - Based on the critical role of the choroid plexus (CP) in detoxification processes in the central nervous system (CNS), herein we investigated the effect of choroid plexus epithelial cells conditioned media (CPECs-CM) under oxidative conditions. CPECs were isolated from rat brains, cultured, and the conditioned media were collected. Then pheochromocytoma neuron-like cells (PC12) were treated simultaneously with CPECs-CM and H2O2 as the oxidative stressor. Next, the effect of CPECs-CM on neurite outgrowth and cell differentiation in the presence of H2O2 was determined. Our results showed that CPECs-CM improved the expansion of neurites and differentiation in PC12 cells under oxidative stress conditions. Changes in apoptotic factors, nuclear factor erythroid 2-related factor 2 (Nrf2) and gamma-glutamylcysteine synthetase as the highlighted pathway in the antioxidant defense system were determined by western blot. Also, the activity of antioxidant enzymes and lipid peroxidation level were determined. CPECs-CM treated PC12 cells could survive after exposure to H2O2 by reduction of caspase-3 cleavage and Bax level and elevation of anti-apoptotic factor Bcl2. Our data also revealed that Nrf2 activation, and consequently its downstream protein levels, increased in the presence of CPECs-CM. Based on our data, we can conclude that CPECs-CM protects PC12 cells against oxidative stress and apoptosis. It seems that CPECs secrete antioxidative agents and neurotrophic factors that have a role in the health of the CNS. PMID- 24488603 TI - Opioid receptor gene expression in human neuroblastoma SH-SY5Y cells following tapentadol exposure. AB - Recent studies showed that combination of mu opioid receptor (MOP) agonism and monoamine reuptake inhibition may improve the therapeutic effect of opioids by reducing requirement for MOP activation. Tapentadol, showing such a combined mechanism of action, exhibits delayed analgesic tolerance development compared to pure MOP agonists. Here we investigated how opioid receptors are regulated following different schedules (two ranges of concentrations for 24 and 48 h) of tapentadol exposure in vitro in SH-SY5Y cells. MOP and nociceptin/orphaninFQ (NOP) receptor gene expressions were quantified using qReal-Time PCR. Moreover, studies were performed in U2 cells to assess tapentadol effect on MOP internalization compared with morphine and DAMGO. Ten and 100 nM tapentadol for 48 h induced a significant increase of MOP gene expression; cells exposed to 100 MUM tapentadol for 24 and 48 h showed a significant increase of MOP mRNA levels. NOP gene expression showed a significant decrease following tapentadol at all low concentrations used after 24 h and at high concentrations (45 and 60 MUM) after 24 h and (60 MUM) after 48 h. Differently from DAMGO, tapentadol or morphine showed no effects on MOP internalization. This study suggests that tapentadol affects MOP and NOP gene expression and MOP internalization showing a pattern distinct from classical MOP agonists. Whether these differences can explain the improved therapeutic profile of tapentadol remains to be investigated. PMID- 24488605 TI - Erratum to: The Contribution of Cdc2 in Rotenone-Induced G2/M Arrest and Caspase 3-Dependent Apoptosis. PMID- 24488606 TI - Direct synthesis of 1,4-diols from alkenes by iron-catalyzed aerobic hydration and C-H hydroxylation. AB - Various 1,4-diols are easily accessible from alkenes through iron-catalyzed aerobic hydration. The reaction system consists of a user-friendly iron phthalocyanine complex, sodium borohydride, and molecular oxygen. Furthermore, the effect of additional ligands on the iron complex was examined for a model reaction. The second hydroxy group is installed by direct C(sp(3))-H oxygenation, which is based on a [1,5] hydrogen shift process of a transient alkoxy radical that is formed by formal hydration of the olefin. PMID- 24488604 TI - Trans-caryophyllene suppresses hypoxia-induced neuroinflammatory responses by inhibiting NF-kappaB activation in microglia. AB - Microglia cells have been reported to mediate hypoxia-induced inflammation through the production of proinflammatory cytokines, including interleukin-1 beta (IL-1beta), tumor necrosis factor alpha (TNF-alpha), and IL-6. Given the fact that the activation of the type 2 cannabinoid receptor (CB2R) provides antioxidative and anti-inflammatory results, it is suspected that its selective agonist, trans-caryophyllene (TC), may have protective effects against hypoxia induced neuroinflammatory responses. In this study, TC was found to significantly inhibit hypoxia-induced cytotoxicity as well as the release of proinflammatory cytokines, including IL-1beta, TNF-alpha, and IL-6, through activation of BV2 microglia following hypoxic exposure (1 % O2, 24 h). Furthermore, TC significantly inhibited hypoxia-induced generation of reactive oxygen species (ROS) in mitochondria as well as the activation of nuclear factor kappa B (NF kappaB) in microglia. Importantly, TC's effects on inhibiting the activation of NF-kappaB and the secretion of inflammatory cytokines can be abolished by muting the CB2R using small RNA interference. These observations indicate that TC suppresses the hypoxia-induced neuroinflammatory response through inhibition of NF-kappaB activation in microglia. Therefore, TC may be beneficial in preventing hypoxia-induced neuroinflammation. PMID- 24488607 TI - Intersex (testicular oocytes) in largemouth bass (Micropterus salmoides) on the Delmarva Peninsula, USA. AB - The authors describe the prevalence and severity of intersex in the form of testicular oocytes in largemouth bass (Micropterus salmoides) collected over a 5 yr period from a variety of surface waters on the Delmarva Peninsula, USA, a region dominated by poultry production and agricultural land use. During a survey from 2005 to 2007 of approximately 200 male specimens representing 6 fish and 2 frog species collected from numerous small-order streams on Delmarva, intersex was observed in only largemouth bass (system-wide prevalence 17%). During 2008 and 2009, testicular oocytes were encountered in male largemouth bass from 6 lakes and 1 large river system, with prevalence ranging from 33% to 88% (weighted arithmetic mean, 57%). The prevalence of testicular oocytes in largemouth bass from Delmarva lakes was comparable to the highest levels reported in a national US Geological Survey reconnaissance of this species, which also occurred in regions of the Atlantic coastal plain with intensive row-crop and animal agriculture. To the authors' knowledge, the present study represents the first report in the peer-reviewed scientific literature of testicular oocytes in fish on the Delmarva Peninsula. PMID- 24488608 TI - Aspirin versus vitamin K antagonist treatment guided by transoesophageal echocardiography in patients with atrial fibrillation: a pilot study. AB - OBJECTIVE: Current stroke risk schemes need improvement of predictive value in patients with atrial fibrillation. Transoesophageal echocardiography (TEE) may facilitate stroke risk assessment in such patients and guide antithrombotic treatment. METHODS: We randomised 238 patients with non-valvular atrial fibrillation and a moderate stroke risk to aspirin or adjusted vitamin K antagonist therapy after TEE had ruled out thrombogenic features in the atria and aorta. The primary outcome was a composite of stroke, major bleeding, peripheral embolism and all-cause mortality. RESULTS: Mean CHA2DS2-VASc score was 2.1+/-1.1. The incidences of the composite primary outcome at a mean follow-up of 1.6 years were 3.2% (2.02% per year) in the aspirin group compared to 6.1% (3.84% per year) in the vitamin K antagonists group with an absolute advantage of 2.9 percentage points. Aspirin was non-inferior to vitamin K antagonists (p<0.0001) because the upper limit of the 90% CI did not exceed the 7% absolute difference in event rate between the two treatment arms. CONCLUSIONS: This hypothesis-generating pilot trial has found that TEE may be used for refinement of stroke risk in paroxysmal atrial fibrillation patients. A larger trial is needed to confirm these data. (ClinicalTrials.gov number NTC00224757). PMID- 24488609 TI - Release kinetics of early ischaemic biomarkers in a clinical model of acute myocardial infarction. AB - OBJECTIVE: To determine the release kinetics of different biomarkers with potential as novel early ischaemic biomarkers in patients with acute coronary syndrome (ACS); it is difficult to establish the detailed release kinetics in patients with acute myocardial infarction (AMI). METHODS: We analysed the release kinetics of soluble fms-like tyrosine kinase (sFlt-1), ischaemia modified albumin (IMA), and heart-type fatty acid binding protein (hFABP) in patients with hypertrophic obstructive cardiomyopathy who were undergoing transcoronary ablation of septal hypertrophy (TASH), a procedure mimicking AMI. Consecutive patients (n=21) undergoing TASH were included. Blood samples were collected before TASH and 15, 30, 45, 60, 75, 90, and 105 min and 2, 4, 8, and 24 h after TASH. sFlt-1 and hFABP were quantified in serum, and IMA was quantified in plasma using immunoassays. RESULTS: sFLT-1 and hFABP increased significantly 15 min after induction of AMI vs baseline as follows: sFlt-1, 3657.5 ng/L (IQR 2302.3 4475.0) vs 76.0 ng/L (IQR 71.2-88.8) (p<0.001); hFABP, 9.0 ng/mL (IQR 7.0-15.4) vs 4.6 ng/mL (IQR 3.4-7.1) (p<0.001). sFlt-1 demonstrated a continuous decrease after the 15th min. hFABP showed a continuous increase until the 8th hour with a decline afterwards. The IMA concentrations increased significantly 30 min after induction of AMI vs baseline, with values of 26.0 U/mL (IQR 21.8-38.6) vs 15.6 U/mL (IQR 10.1-24.7) (p=0.02), and then decreased after 75 min. CONCLUSIONS: sFlt 1 and hFABP increased very early after induction of myocardial ischaemia, showing different release kinetics. The additional information provided by these findings is helpful for developing their potential combined use with cardiac troponins in patients with suspected AMI. PMID- 24488610 TI - The effect of cyclosporin-A on peri-operative myocardial injury in adult patients undergoing coronary artery bypass graft surgery: a randomised controlled clinical trial. AB - OBJECTIVE: Cyclosporin-A (CsA) has been reported to reduce myocardial infarct size in both the experimental and clinical settings. This protective effect is dependent on its ability to prevent the opening of the mitochondrial permeability transition pore, a critical determinant of cell death in the setting of acute ischaemia-reperfusion injury. Whether CsA can reduce the extent of peri-operative myocardial injury (PMI) in patients undergoing coronary artery bypass graft (CABG) surgery is unknown, and is investigated in this randomised controlled clinical trial. METHODS: 78 adult patients undergoing elective CABG surgery were randomised to receive either an intravenous bolus of CsA (2.5 mg/kg) or placebo administered after induction of anaesthesia and prior to sternotomy. PMI was assessed by measuring serum cardiac enzymes, troponin T (cTnT) and CK-MB at 0, 6, 12, 24, 48 and 72 h after surgery. RESULTS: There was no significant difference in mean peak cTnT levels between control (n=43) and CsA treatment (n=40) patients (0.56+/-0.06 ng/mL with control vs 0.35+/-0.05 ng/mL with CsA; p=0.07). However, in higher-risk patients with longer cardiopulmonary bypass times, there was a significant reduction in PMI with CsA therapy (p=0.049), with a reduced postoperative cTnT rise by 0.03 ng/mL for every 10 min, when compared with control. CONCLUSIONS: In patients with longer cardiopulmonary bypass times, a single intravenous bolus of CsA administered prior to CABG surgery reduced the extent of PMI. PMID- 24488611 TI - Hybrid approach in hypoplastic left heart syndrome. PMID- 24488612 TI - A tunable fluorescent timer method for imaging spatial-temporal protein dynamics using light-driven photoconvertible protein. AB - Cellular function is largely determined by protein behaviors occurring in both space and time. While regular fluorescent proteins can only report spatial locations of the target inside cells, fluorescent timers have emerged as an invaluable tool for revealing coupled spatial-temporal protein dynamics. Existing fluorescent timers are all based on chemical maturation. Herein we propose a light-driven timer concept that could report relative protein ages at specific sub-cellular locations, by weakly but chronically illuminating photoconvertible fluorescent proteins inside cells. This new method exploits light, instead of oxygen, as the driving force. Therefore its timing speed is optically tunable by adjusting the photoconverting laser intensity. We characterized this light-driven timer method both in vitro and in vivo and applied it to image spatiotemporal distributions of several proteins with different lifetimes. This novel timer method thus offers a flexible "ruler" for studying temporal hierarchy of spatially ordered processes with exquisite spatial-temporal resolution. PMID- 24488614 TI - Detoxification enzymes of Bemisia tabaci B and Q: biochemical characteristics and gene expression profiles. AB - BACKGROUND: The sweetpotato whitefly, Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae), is one of the most invasive and destructive pests of field crops worldwide. The sibling species B and Q are the two most damaging members of the B. tabaci species complex. That Q is more resistant than B to many insecticides has been well documented. Over the last decade, Q has gradually displaced B and has become the dominant form of B. tabaci in field agricultural systems in most parts of China. To help understand the differences in insecticide resistance, the activities and gene expression profiles of detoxification enzymes in B. tabaci B and Q were investigated. RESULTS: The activity of P450 towards 7-ethoxycoumarin was significantly higher (1.46-fold higher) in Q than in B. The expression of 43 of 65 P450 genes was higher (>1-fold) in Q than in B, and expression for eight P450 genes was more than 50-fold greater in Q than in B. The increased expression of selected P450 genes in Q relative to B was confirmed with two other B strains and two other Q strains. On the other hand, carboxylesterase (CarE) activity was significantly lower (0.71-fold lower) in Q than in B; the Km value of CarE was significantly lower in B than in Q, but the opposite was true for the Vmax value of CarE. Glutathione S-transferase activity and values of Km and Vmax did not differ between B and Q. CONCLUSION: Enhanced metabolic detoxification of insecticides by P450s may be an important reason why B. tabaci Q is more resistant than B. tabaci B to insecticides. PMID- 24488613 TI - An Exploratory Factor Analysis of the Knowledge of Evidence-Based Services Questionnaire. AB - Recent developments for disseminating and implementing evidence-based practices (EBPs) have emphasized the importance of increasing therapists' knowledge of such techniques. However, systematic efforts to measure knowledge in therapists serving youth have mostly relied on poorly researched study-specific measures. This study investigated the structure of EBP knowledge in a large sample of youth community therapists (N = 240) via a therapist report instrument emphasizing therapeutic commonalities across various types of treatment approaches. Findings supported a three-factor structure of knowledge with scores on factors varying by therapists' primary practice setting and education level. The relationships between therapist knowledge of and attitudes towards EBPs are also discussed. PMID- 24488615 TI - Changes in motor unit properties in SOD1 (G93A) rats. AB - INTRODUCTION: In amyotrophic lateral sclerosis (ALS), progressive death of motor neurons results in denervation and reinnervation of muscles. It is not clear how ALS affects the properties of motor units (MUs). METHODS: Properties of single MUs in the medial gastrocnemius (MG) muscle of rats bearing the human mutated superoxide dismutase gene type 1 (SOD1) were determined at 3 stages: asymptomatic (ALS I); early symptomatic (ALS II); and terminal (ALS III). RESULTS: In ALS II, higher proportions of FF (fast fatigable) and S (slow) MUs were observed, whereas in ALS III higher percentages of S and lower percentages of FF MUs were noted compared with controls. S motor neurons reinnervated fast muscle fibers, and those MUs gained some properties of fast MUs, including lower fatigue resistance, greater force generation, and higher action potential amplitudes. CONCLUSION: Changes in MU properties of SOD1 rats have progressive and multidirectional character and speed depending on the MU type. PMID- 24488616 TI - Pharmacological interventions for hypertension in children. AB - BACKGROUND: Hypertension is a major risk factor for stroke, coronary artery disease and kidney damage in adults. There is a paucity of data on the long-term sequelae of persistent hypertension in children, but it is known that children with hypertension have evidence of end organ damage and are at risk of hypertension into adulthood. The prevalence of hypertension in children is rising, most likely due to a concurrent rise in obesity rates. In children with hypertension, non-pharmacological measures are often recommended as first-line therapy, but a significant proportion of children will eventually require pharmacological treatment to reduce blood pressure, especially those with evidence of end organ damage at presentation or during follow-up. A systematic review of the effects of antihypertensive agents in children has not previously been conducted. OBJECTIVES: To determine the dose-related effects of different classes of antihypertensive medications, as monotherapy compared to placebo; as combination therapy compared to placebo or a single medication; or in comparisons of various doses within the same class, on systolic or diastolic blood pressure (or both) in children with hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Group Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2013, Issue 9), Ovid MEDLINE (1946 to October 2013), Ovid EMBASE (1974 to October 2013) and bibliographic citations. SELECTION CRITERIA: The selection criteria were deliberately broad due to there being few clinical trials in children. We included randomised controlled trials (RCTs) of at least two weeks duration comparing antihypertensive agents either as monotherapy or combination therapy with either placebo or another medication, or comparing different doses of the same medication, in children with hypertension. Hypertension was defined as an average (over a minimum of three readings) systolic or diastolic blood pressure (or both) on the 95(th) percentile or above for age, height and gender. DATA COLLECTION AND ANALYSIS: Two authors independently selected relevant studies, extracted data and assessed risk of bias. We summarised data, where possible, using a random-effects model. Formal assessment of heterogeneity was not possible because of insufficient data. MAIN RESULTS: A total of 21 trials evaluated antihypertensive medications of various drug classes in 3454 hypertensive children with periods of follow-up ranging from three to 24 weeks. There were five RCTs comparing an antihypertensive drug directly with placebo, 12 dose-finding trials, two trials comparing calcium channel blockers with angiotensin receptor blockers, one trial comparing a centrally acting alpha blocker with a diuretic and one trial comparing an angiotensin-converting enzyme inhibitor with an angiotensin receptor blocker. No randomised trial was identified that evaluated the effectiveness of antihypertensive medications on target end organ damage. The trials were of variable quality and most were funded by pharmaceutical companies.Among the angiotensin receptor blockers, candesartan (one trial, n = 240), when compared to placebo, reduced systolic blood pressure by 6.50 mmHg (95% confidence interval (CI) -9.44 to -3.56) and diastolic blood pressure by 5.50 mmHg (95% CI -9.62 to 1.38) (low-quality evidence). High dose telmisartan (one trial, n = 76), when compared to placebo, reduced systolic blood pressure by -8.50 (95% CI -13.79 to 3.21) but not diastolic blood pressure (-4.80, 95% CI -9.50 to 0.10) (low-quality evidence). Beta blocker (metoprolol, one trial, n = 140), when compared with placebo , significantly reduced systolic blood pressure by 4.20 mmHg (95% CI 8.12 to -0.28) but not diastolic blood pressure (-3.20 mmHg 95% CI -7.12 to 0.72) (low-quality evidence). Beta blocker/diuretic combination (Bisoprolol/hydrochlorothiazide, one trial, n = 94)when compared with placebo , did not result in a significant reduction in systolic blood pressure (-4.0 mmHg, 95% CI -8.99 to -0.19) but did have an effect on diastolic blood pressure (-4.50 mmHg, 95% CI -8.26 to -0.74) (low-quality evidence). Calcium channel blocker (extended-release felodipine,one trial, n = 133) was not effective in reducing systolic blood pressure (-0.62 mmHg, 95% CI -2.97 to 1.73) or diastolic blood pressure (-1.86 mmHg, 95% CI -5.23 to 1.51) when compared with placebo. Further, there was no consistent dose response observed among any of the drug classes. The adverse events associated with the antihypertensive agents were mostly minor and included headaches, dizziness and upper respiratory infections. AUTHORS' CONCLUSIONS: Overall, there are sparse data informing the use of antihypertensive agents in children, with outcomes reported limited to blood pressure and not end organ damage. The most data are available for candesartan, for which there is low quality evidence of a modest lowering effect on blood pressure. We did not find evidence of a consistent dose response relationship for escalating doses of angiotensin receptor blockers, calcium channel blockers or angiotensin-converting enzyme inhibitors. All agents appear safe, at least in the short term. PMID- 24488617 TI - The difference in miR-21 expression levels between invasive and non-invasive breast cancers emphasizes its role in breast cancer invasion. AB - MicroRNA-21 (miR-21) overexpression is characteristic for various types of tumors, but it is still unknown whether its expression levels differ between invasive and non-invasive breast carcinomas. The main goal of the study was to determine the difference in miR-21 expression among normal tissue, non-invasive, invasive with non-invasive component, and pure invasive breast cancer samples, to explain its potential role and significance in breast cancer invasiveness. The second goal was to propose miR-21 as molecular marker of breast cancer invasiveness and potential target for future anti-miR therapies for the prevention of invasion and metastasis. In order to reveal the role of miR-21 in breast cancer invasiveness, we measured miR-21 expression levels in 44 breast cancer and four normal samples by stem-loop real-time RT-PCR using TaqMan technology. Relative expression levels of miR-21 were significantly higher in invasive than in other groups (P=0.002) and significantly higher in invasive compared with invasive with non-invasive component group in histological (P=0.043) and nuclear grade 2 (P=0.036), estrogen-receptor-positive (ER+) (P=0.006), progesterone-receptor-positive (PR+) (P=0.008), ER+PR+ (P=0.007), and proliferation index (Ki-67)<=20% (P=0.036) tumors. Our findings suggest that miR 21 could be independent molecular marker of breast cancer invasiveness and potential target for future anti-miR therapies for the prevention of invasion and metastasis. PMID- 24488618 TI - Association between EZH2 polymorphisms and colorectal cancer risk in Han Chinese population. AB - The aim of this study is to investigate the associations between EZH2 gene polymorphisms and colorectal cancer (CRC) risk. We undertook a case-control study to analyze three EZH2 polymorphisms (148505302C>T, 2110+6A>C and 626-394T>C) in an Han Chinese population, by extraction of genomic DNA from the peripheral blood of 512 patients with CRC and 546 control participants, and performed EZH2 genotyping using DNA sequencing. The obtained results indicated that overall, no statistically significant association was observed in 2,110+6A>C. Nevertheless, 148505302C>T genotype demonstrated a protective effect in CRCs (P=0.014; odds ratio (OR) 0.777, CI 95%:0.647-0.933). Furthermore, 148505302 T allele CRC was more significantly common in patients with tumor size of <4 cm than C allele CRC and in cases of good differentiation and lower advanced pathological stage. However, 626-394T>C genotype was at increased risk of CRCs (P<0.001; odds ratio (OR) 1.457, CI 95%:1.160-1.829). Moreover, 626-394C/C genotype CRCs were more significantly common in patients with tumor size of >4 cm than T allele CRC and in cases of poor differentiation and lower advanced pathological stage. In conclusion, polymorphism in 626-394T>C was observed to be associated with susceptibility of CRC. However, 148505302C>T polymorphism indicated to play a protective role in susceptibility to CRC. Nevertheless, further investigation with a larger sample size is needed to support our results. PMID- 24488619 TI - The role of Wnt signaling and sclerostin in the pathogenesis of glucocorticoid induced osteoporosis. AB - Bone formation is suppressed in glucocorticoid-induced osteoporosis. One of the mechanisms by which glucocorticoids depress bone formation is through their effects on the Wnt/beta-catenin signaling pathway, a critical regulator of osteoblastogenesis. Thus, Wnt signaling induces the differentiation of osteoblast precursors toward mature osteoblasts and prevents osteoblast and osteocyte apoptosis. Glucocorticoids increase the expression of Wnt signaling antagonists (sclerostin and Dkk-1) in experimental studies in rodents and cell cultures. However, the scarce data of their effects in humans are somewhat contradictory, probably due to the dose and duration of treatment as well as the characteristics of the patients. A progressive decrease in Dkk-1 serum levels and an increase in circulating sclerostin levels at long-term follow-up have recently been reported in patients treated with high doses of glucocorticoids. This review describes the most recent data on the effects of glucocorticoids on the Wnt signaling pathway, especially on their antagonists, sclerostin and Dkk-1. PMID- 24488620 TI - Personalized genomic results: analysis of informational needs. AB - Use of genomic information in healthcare is increasing; however data on the needs of consumers of genomic information is limited. The Coriell Personalized Medicine Collaborative (CPMC) is a longitudinal study investigating the utility of personalized medicine. Participants receive results reflecting risk of common complex conditions and drug-gene pairs deemed actionable by an external review board. To explore the needs of individuals receiving genomic information we reviewed all genetic counseling sessions with CPMC participants. A retrospective qualitative review of notes from 157 genetic counseling inquiries was conducted. Notes were coded for salient themes. Five primary themes; "understanding risk", "basic genetics", "complex disease genetics", "what do I do now?" and "other" were identified. Further review revealed that participants had difficulty with basic genetic concepts, confused relative and absolute risks, and attributed too high a risk burden to individual single nucleotide polymorphisms (SNPs). Despite these hurdles, counseled participants recognized that behavior changes could potentially mitigate risk and there were few comments alluding to an overly deterministic or fatalistic interpretation of results. Participants appeared to recognize the multifactorial nature of the diseases for which results were provided; however education to understand the complexities of genomic risk information was often needed. PMID- 24488621 TI - Prevalence of cutaneous pathological conditions and factors associated with the presence of skin wounds in working equids in tropical regions of Veracruz, Mexico. AB - A wide spectrum of welfare issues is encountered on working equids. The objectives of this study were: (i) to determine the prevalence of cutaneous lesions in working equids in tropical regions of the North-Central of Veracruz State, Mexico, (ii) to identify the most prevalent cutaneous pathological conditions in this population of working equids, and (iii) to identify risk factors associated to the presence of work-related skin wounds. A number of 467 working equids presented for treatment at Donkey Sanctuary Mobile Clinic Program National Autonomous University of Mexico from seven different villages in the North-Central region of Veracruz State were evaluated. Animals with signs of cutaneous pathology underwent a physical examination and samples were obtained of exudates, hair, and tissue for cytology examination, fungal cultures, and dermo histopathology examination. The overall prevalence of cutaneous pathological conditions in working equids was 20.6 %. The prevalence per species was 22.6 % for horses, 18.2 % for donkeys, and 14.3 % for mules. The most common cause of skin lesions was trauma (abrasions, lacerations, and abscesses) followed in frequency by parasitic dermatitis and sarcoids. No strong associations among species were observed (P > 0.20). Multivariate analysis showed that there was greater association between BCS and age with the presence of skin wounds (P < 0.05). Equids who's BCS was rated as "moderate" as well as adult animals showed significantly more skin wounds compared with the young and the elderly (P < 0.05). These findings can help to develop a better management practices to improve the welfare of equids in tropical regions of Veracruz, Mexico. PMID- 24488622 TI - Transcription profiling of 12 asian gypsy moth (Lymantria dispar) cytochrome P450 genes in response to insecticides. AB - As the main group of detoxification enzymes, cytochrome P450 monoxygenases (P450s) catalyse an extremely diverse range of reactions that play an important role in the detoxification of foreign compounds. Transcription profiling of 12 Lymantria dispar P450 genes from the CYP6 subfamily believed to be involved in insecticide metabolism was performed in this study. Life-stage transcription profiling of CYP6 genes revealed significant variations between eggs, larvae, pupae, and adult males and females. Exposure of larvae to sublethal doses of deltamethrin, omethoate, and carbaryl enhanced the transcription of most of the CYP6 P450 genes, with induction peaking between 24 and 72 h after exposure. Transcription profiles were dependent on the levels of insecticide exposure and the various developmental stages. PMID- 24488623 TI - A coordination compound of Ge(0) stabilized by a diiminopyridine ligand. AB - Reduction of the cationic Ge(II) complex [dimpyrGeCl][GeCl3] (dimpyr=2,6 (ArN=CMe)2NC5H3, Ar=2,6-iPr2C6H3) with potassium graphite in benzene affords an air sensitive, dark green compound of Ge(0), [dimpyrGe], which is stabilized by a bis(imino)pyridine platform. This compound is the first example of a complex of a zero-valent Group 14 element that does not contain a carbene or carbenoid ligand. This species has a singlet ground state. DFT studies revealed partial delocalization of one of the Ge lone pairs over the pi*(C=N) orbitals of the imines. This delocalization results in a partial multiple-bond character between the Ge atom and imine nitrogen atoms, a fact supported by the X-ray crystallography and IR spectroscopy data. PMID- 24488624 TI - Synthesis of 2,5-diaryl-substituted thiophenes as helical mimetics: towards the modulation of islet amyloid polypeptide (IAPP) amyloid fibril formation and cytotoxicity. AB - A range of 2,5-diarylated thiophenes were synthesised as small molecule mimetics of the alpha-helix to modulate the amyloidogenesis and cytotoxic effect of islet amyloid polypeptide (IAPP). 3-Substituted thiophene-2-carboxylic acids were used as key intermediates and functionalised by palladium decarboxylative cross coupling and direct C-H activation successively with overall yields ranging from 23 to 95 %. The effect of the ligands on IAPP amyloid fibril formation was evaluated with the thioflavin T (ThT) fluorescence-based assay. Furthermore, the capacity of these compounds to inhibit the cytotoxic effect of IAPP was assessed using beta-pancreatic cells. PMID- 24488625 TI - The effects of p53 Arg72Pro polymorphism on glioma susceptibility: a meta analysis. AB - The potentially functional polymorphism Arg72Pro in p53 gene has been implicated in glioma risk, but published studies have mixed findings. The aim of current investigation was to identify whether p53 Arg72Pro polymorphism was significantly associated with the risk of glioma. By searching the databases of PubMed, EMBASE, and Web of Science, our meta-analysis included ten eligible studies consisting of 2,645 glioma cases and 3,920 control subjects. The association between p53 Arg72Pro polymorphism and glioma risk was assessed by summarizing the odds ratios (ORs) with the corresponding 95% confidence intervals (CIs). We found that there was no overall risk of glioma in relation to any genetic model of p53 Arg72Pro polymorphism. Similar results were implicated in the analyses which are subgrouped by ethnicity and source of controls. This nonsignificant association remained stable when analyses were restrained to the studies consistent with HWE. In conclusion, our meta-analysis, based on the combined data from published papers before May 2013, reveals no evidence for significant association between p53 Arg72Pro polymorphism and glioma risk. PMID- 24488626 TI - Positive association between MTHFR C677T polymorphism and oral cancer risk: a meta-analysis. AB - Methylenetetrahydrofolate reductase (MTHFR) is a central enzyme involved in regulating the metabolic function of folate, which plays a pivotal role in DNA synthesis, repair, and methylation. The role of MTHFR C677T polymorphism in oral cancer risk has been reported with conflicting evidence. We conducted this study to appropriately estimate the effect size. We searched eligible studies in medicine-specific databases (PubMed, EMBASE, and Web of Knowledge) using (polymorphism) OR (polymorphisms) AND (methylenetetrahydrofolate reductase) OR (MTHFR) AND (oral cancer). A total of seven studies were summarized. This meta analysis of the combined data showed a marginal association of MTHFR C677T polymorphism with oral cancer risk [odds ratio (OR) = 0.86, 95% confidence interval (CI) = 0.73-1.00 for CT vs. CC]. We also found decreased oral cancer risk in Asian population and hospital-based studies. Moreover, heavy drinkers were found to have a significantly higher risk of developing such cancer as compared to the non-heavy drinkers. These results suggest that MTHFR C677T polymorphism may play a role in oral cancer carcinogenesis in Asian population and heavy drinkers. PMID- 24488627 TI - Association of p53 codon 72 polymorphism with prostate cancer: an update meta analysis. AB - Many studies have been conducted to explore the association between p53 codon 72 polymorphism and prostate cancer (PCa). However, the results remain inconsistent. Therefore, we performed a large meta-analysis of relevant studies to determine a more precise estimation of this relationship. Systematic searches of the electronic databases PubMed, EMBASE, Cochrane Library, and China National Knowledge Infrastructure (CNKI) up to October 2013 were performed. Fixed or random-effects meta-analytical models were used to calculate the summary odds ratio (OR) and corresponding 95% confidence intervals (CIs). Meta-regression, Galbraith plots, subgroup analysis, and sensitivity analysis were also performed. The study included 17 case-control studies involving 2,371 PCa cases and 2,854 controls. Our results showed that the p53 codon 72 polymorphism was not associated with PCa risk in all genetic models in the overall populations. When limiting the meta-analysis to the studies conforming to Hardy-Weinberg equilibrium, the pooled analyses showed a significant association between p53 codon 72 polymorphism and PCa in a Caucasian population in co-dominant model Pro/Pro vs. Arg/Arg (OR = 1.57, 95% CI = 1.08-2.28, P = 0.017) and recessive model Pro/Pro vs. (Arg/Pro + Arg/Arg) (OR = 1.60, 95% CI = 1.12-2.27, P = 0.009). In subgroup analysis stratified by PCa stages and Gleason grades, a slight but significant association was found when advanced PCa was compared with localized PCa only in recessive model Pro/Pro vs. (Arg/Pro + Arg/Arg) (OR = 1.51, 95% CI = 1.02-2.23, P = 0.039). This meta-analysis suggested that the Pro/Pro genotype of p53 codon 72 polymorphism was associated with increased prostate cancer risk, especially among Caucasians. PMID- 24488629 TI - Dynamics of biotypes B and Q of the whitefly Bemisia tabaci and its impact on insecticide resistance. AB - BACKGROUND: The whitefly Bemisia tabaci (Gennadius) (Hemiptera: Aleyrodidae) is a key pest in many agricultural crops, including vegetables, ornamentals and field crops. B. tabaci is known for its genetic diversity, which is expressed in a complex of biotypes or, as recently suggested, a complex of distinct cryptic species. The biotypes are largely differentiated on the basis of biochemical or molecular polymorphism and differ in characteristics such as host plant range, attraction by natural enemies, secondary symbionts and expression of insecticide resistance. An extensive survey of B. tabaci biotypes and their impact on insecticide resistance was conducted from 2003 to 2012 in cotton fields and other crops from several locations in Israel. RESULTS: Two biotypes of B. tabaci, B and Q, were identified, and some differences in the biotype dynamics were recorded from different areas. In northern Israel from 2003 to 2007, a higher proportion of the B biotype was consistently found in early season. However, by the end of the season a definite rise of the Q biotype was sampled, ranging from 60 to 100%, along with high resistance to the insect growth regulator (IGR) pyriproxyfen and to a lesser extent to the neonicotinoid insecticides. In fields located in the central part of Israel, the Q biotype was predominant throughout the seasons, with high resistance to pyriproxyfen. Since 2009, a significant shift in the biotype ratios has been observed: the B biotype has come to predominate over the Q biotype ranging up to 90% or more in most fields. At the same time, resistance to the IGR pyriproxyfen was reduced considerably. CONCLUSION: The possible reasons for the change in the dynamics of B. tabaci biotypes, and its implications for resistance management, are discussed. Strong B. tabaci resistance to pyriproxyfen in Israel has been associated with the Q rather than with the B biotype. The B biotype is more competitive than the Q biotype under untreated conditions. Reduction in the acreage of cotton fields during recent years, along with a decrease in insecticide use, especially pyriproxyfen, has resulted in the expansion of the B biotype. PMID- 24488628 TI - Comparative suitability of CFDA-SE and rhodamine 6G for in vivo assessment of leukocyte-endothelium interactions. AB - Intravital fluorescence microscopy (IVM) is a predestined tool for investigating the fate of leukocytes during the process of leukocyte recruitment. In the present study, the commonly used dye for this purpose, rhodamine 6G, and carboxyfluorescein diacetate succinimidyl ester (CFDA-SE) were compared for leukocytes labelling with respect to suitability for IVM studies. Their potential in labelling different leukocytes subpopulations as well as their fluorescence intensities were assessed by flow cytometry revealing distinct differences between both dyes. These differences had a profound impact on their application for in vivo imaging of leukocyte-endothelium interactions. In summary, CFDA-SE revealed superior in labelling leukocytes for in vivo microscopy with respect to image quality. In addition, we could show the efficiency of CFDA-SE also under disease condition in an animal model of sepsis. PMID- 24488630 TI - Classical and state-of-the-art skin rejuvenation. PMID- 24488631 TI - Nonprescription topical treatments for skin rejuvenation. AB - Topical skin care regimens are a mainstay treatment for aging skin. All patients seeking skin rejuvenation can benefit from this low-risk intervention. This article reviews available nonprescription topical treatments for rejuvenation including moisturizers, antioxidants, retinols, and sunscreen. PMID- 24488632 TI - Topicals in skin rejuvenation: prescription topicals. AB - With the recent proliferation of over the counter cosmeceuticals, prescription topical skin treatments have the cache of being evidence-based and not being available outside the setting of a patient-physician interaction. In the setting of facial rejuvenation, patient demand for prescription topical skin treatments falls into three main roles: (1) stimulation of collagen production; (2) improvement of dyspigmentation; and (3) amelioration of adult acne. PMID- 24488633 TI - Treatment of unwanted pigment. AB - Disorders of skin pigmentation pose significant challenges to both patients and physicians, as they have the unfortunate duality of being both common and difficult to treat conditions. This article reviews the etiology, pathophysiology, clinical presentation, and treatment options for melasma and postinflammatory hyperpigmentation. A thorough understanding of the disease process itself, expected agent efficacy, risks, and benefits of various treatments is crucial while treating these complex conditions. PMID- 24488634 TI - Chemical peels. AB - Chemical peels are a method of resurfacing with a long-standing history of safety in the treatment of various skin conditions. This article reviews the classification of different chemical agents based on their depth of injury. The level of injury facilitates cell turnover, epidermal thickening, skin lightening, and new collagen formation. Preprocedural, periprocedural, and postprocedural skin care are briefly discussed. To select the appropriate chemical peel, the provider should evaluate the patient's expectations, medical history, skin type, and possible complications to determine the best chemical peel to achieve the desired results. Patients with Fitzpatrick skin types IV to VI have increased risk of dyspigmentation, hypertrophic, and keloid scarring. These individuals respond well to superficial and medium-depth chemical peels. Advances in the use of combination peels allow greater options for skin rejuvenation with less risk of complications. PMID- 24488635 TI - Dermabrasion. AB - For many patients, sun damage, trauma, prior cutaneous carcinomas, and aging have created a less than optimal skin appearance. There are currently multiple forms of ablative therapy to correct such concerns. Dermabrasion is a form of resurfacing that mechanically alters the skin at the level of the dermis, to promote collagen remodeling and re-epithelialization. Facial skin has a rich vascular and adnexal network, allowing the rapid healing of controlled damage because blood, macronutrients, and oxygen are readily available. Sebaceous glands and hair follicles are important in the regeneration process of the dermis. Dermabrasion can be taken down layer by layer to remove the proper level of skin, so that the desired effect is obtained. By completely removing the epidermis and penetrating into the reticular and papillary dermis, controlled damage is obtained and remodeling of the skin's structural proteins, into a more organized manner, occurs during the healing process. This abrasion technique leads to clinically significant improvements in skin structure, quality, and appearance. PMID- 24488636 TI - Histologic effects of resurfacing lasers. AB - By utilizing resurfacing lasers, physicians can significantly improve the appearance of sun-damaged skin, scars, and more. The carbon dioxide and erbium:yttrium-aluminum-garnet lasers were the first ablative resurfacing lasers to offer impressive results although these earlier treatments were associated with significant downtime. Later, nonablative resurfacing lasers such as the neodymium:yttrium-aluminum-garnet laser proved effective, after a series of treatments with less downtime, but with more modest results. The theory of fractional photothermolysis has revolutionized resurfacing laser technology by increasing the safety profile of the devices while delivering clinical efficacy. A review of the histologic and molecular consequences of the resurfacing laser tissue interaction allows for a better understanding of the devices and their clinical effects. PMID- 24488637 TI - Nonablative fractional resurfacing. AB - Since its introduction in 2004 by Manstein et al, fractional resurfacing has revolutionized the manner in which we treat photoaging. Fractional resurfacing delivers microscopic beams of light to the skin resulting in coagulation or vaporization of fragments of the epidermis and dermis. The wavelengths of these devices may vary, yielding different clinical results. This article will discuss the various uses of fractional ablative and nonablative devices available today. PMID- 24488638 TI - Ablative skin resurfacing. AB - Ablative laser resurfacing has evolved as a safe and effective treatment for skin rejuvenation. Although traditional lasers were associated with significant thermal damage and lengthy recovery, advances in laser technology have improved safety profiles and reduced social downtime. CO2 lasers remain the gold standard of treatment, and fractional ablative devices capable of achieving remarkable clinical improvement with fewer side effects and shorter recovery times have made it a more practical option for patients. Although ablative resurfacing has become safer, careful patient selection and choice of suitable laser parameters are essential to minimize complications and optimize outcomes. This article describes the current modalities used in ablative laser skin resurfacing and examines their efficacy, indications, and possible side effects. PMID- 24488639 TI - Skin tightening technologies. AB - Radiofrequency (RF) and intense focused ultrasound (IFUS) are increasingly used to address skin laxity of the face and neck. Both nonablative RF and ultrasound create a heat-induced tissue response that leads to collagen remodeling and other ultrastructural changes. Although these treatments are not meant to replace surgical procedures, patient satisfaction in the majority of studies has been consistently high. This article discusses the various RF and IFUS technologies currently in use and reviews pertinent clinical studies evaluating their efficacy and safety. PMID- 24488640 TI - Neurotoxins and fillers for skin rejuvenation. AB - The ephemeral effects of neurotoxins and fillers are well described for facial remodeling and rejuvenation. Less is known about their long-term effects on skin rejuvenation and neocollagenesis. This article aims to review current available science and literature to support the use of these cosmetic procedures as lasting antiaging treatments. PMID- 24488641 TI - Future directions in facial rejuvenation. AB - Future directions in the advancement and refinement of facial rejuvenation techniques represent a response to patient demand for higher aesthetic impact with less procedural downtime and with minimal scarring as evidence of previous surgery. With surgical procedures, the trend of innovation in response to demand has been toward more minimally invasive approaches that have the predictability and durability of results of more traditional approaches. With nonsurgical procedures, there have been new developments in achieving more significant aesthetic improvements with less downtime and less invasively. PMID- 24488642 TI - The rabbit costal cartilage reconstructive surgical model. AB - Rib grafts in facial plastic surgery are becoming more frequently used. Small animal models, although not ideal may be used to emulate costal cartilage-based procedures. A surgical characterization of this tissue will assist future research in the selection of appropriate costal segments, based on quantitative and qualitative properties. The objective of this study is to assess the surgical anatomy of the rabbit costal margin and evaluate costal cartilage for use in either in vivo or ex vivo studies and to examine reconstructive procedures. Detailed thoracic dissections of 21 New Zealand white rabbits were performed post mortem. Costal cartilage of true, false, and floating ribs were harvested. The length, thickness, and width at proximal, medial, and distal locations of the cartilage, with perichondrium intact were measured. Further qualitative observation and digital images of curvature, flexibility, and segmental cross sectional shape were recorded. The main outcome measure(s) is to characterize, describe, and assess the consistency of dimensions, location, and shape of costal cartilage. In this study, 12 to 13 ribs encase the thoracic cavity. Cartilage from true ribs has an average length, width, and depth of 23.75 +/- 0.662, 3.02 +/- 0.025, and 2.18 +/- 0.018 mm, respectively. The cartilage from false ribs has an average length, width, and depth of 41.97 +/- 1.48, 2.00 +/- 0.07, 1.19 +/- 0.03 mm, and that of floating ribs are 7.66 +/- 0.29, 1.98 +/- 0.04, and 0.96 +/- 0.03 mm. Rib 8 is found to be the longest costal cartilage (49.10 +/- 0.64 mm), with the widest and thickest at ribs 1 (3.91 +/- 0.08 mm) and 6 (2.41 +/- 0.11 mm), respectively. Cross-sectional segments reveal the distal cartilage to maintain an hourglass shape that broadens to become circular and eventually ovoid at the costochondral junction. The New Zealand white rabbit is a practical source of costal cartilage that is of sufficient size and reproducibility to use in surgical research where the long-term effects of operations, therapies, devices, and pharmacologic on cartilage can be studied in vivo. PMID- 24488643 TI - Hyaluronan-induced cosmetic reconstruction of the nostril. AB - Tissue loss of the nostrils presents a considerable surgical challenge due to the greatly reduced availability of local tissue within such a peculiar anatomical region. The traditional reconstructive methods, such as direct suture, secondary healing, skin grafts, and local skin flaps, have shown poor provision of desirable cosmetic outcomes in this area. The authors propose an innovative and alternative method of cosmetic reconstruction of small skin defects of the nostril based on a hyaluronan-induced skin regeneration. Such a procedure allowed the healing of relatively large areas of skin loss with the formation of a truly regenerated tissue whose clinical features closely resemble those of the local normal skin. Nevertheless, the proposed procedure is lengthy and time-consuming and requires high levels of cooperation from patients. In our practice, the hyaluronan-induced skin regeneration is now considered the first choice for cosmetic reconstruction of small defects of the nostril in needy patients. PMID- 24488644 TI - Does phosphodiesterase inhibition lessen facial flap necrosis in tobacco cigarette users? AB - Tobacco cigarette smoking remains a serious risk factor for necrosis of local facial skin flaps. To date, no pharmacological therapies exist for cigarette smoke-induced impairment of skin flap tissue survival. Accumulating evidence suggest that phosphodiesterase-5 (PDE-5) inhibitor therapy may counteract the negative effects of cigarette smoke on flap survival. Here, we evaluate skin flap survival in a series of consecutive tobacco cigarette users treated with the PDE 5 inhibitor, sildenafil, who underwent local flap facial reconstruction. We included 11 patients (5 females; median age: 64) with a significant smoking history. Seventeen facial flaps were performed for 14 defects. All patients received sildenafil in the postoperative setting. One complication of necrosis of the flap distal margin was encountered. Follow-up was available for all patients. Our results demonstrate that facial reconstruction in tobacco cigarette smokers can be performed with improved success and that sildenafil therapy may mitigate the deleterious effects of smoking on flap survival. PMID- 24488646 TI - Primary health care: hope and challenges for public health in Maldives. AB - The government of Maldives considers that the enjoyment of the highest attainable level of health is a basic right of every citizen. Thus it lays emphasis on the accessibility and affordability of health care services. In order to achieve these objectives, it is very important to expand curative services as well as preventive services in the country. The major hurdles faced by the country are result of the inherent structural problem faced by the county which leads to sever diseconomies of scale in the provision of healthcare services. Community and individual involvement and self-reliance are very important to achieve Health for All by the Year 200 AD. Community participation is one of the domains of community capacity building in a small island country. It is one of the mechanisms to empower people to take part in community development. In this paper, the nature, the dimensions of community participation, and its role and scope in implementation of different components of primary health care have been described. The health services in public and curative care have been briefed. Some of the achievements in health sector have also been briefly presented. PMID- 24488645 TI - Post-seizure alpha-tocopherol treatment decreases neuroinflammation and neuronal degeneration induced by status epilepticus in rat hippocampus. AB - Vitamin E (as alpha-tocopherol, alpha-T) was shown to have beneficial effects in epilepsy, mainly ascribed to its antioxidant properties. Besides radical-induced neurotoxicity, neuroinflammation is also involved in the pathophysiology of epilepsy, since neuroglial activation and cytokine production exacerbate seizure induced neurotoxicity and contribute to epileptogenesis. We previously showed that alpha-T oral supplementation before inducing status epilepticus, markedly reduces astrocytic and microglial activation, neuronal cell death and oxidative stress in the hippocampus, as observed 4 days after seizure. In order to evaluate the possibility that such a neuroprotective and anti-inflammatory effect may also provide a strategy for an acute intervention in epilepsy, in this study, seizures were induced by single intaperitoneal injection of kainic acid and, starting from 3 h after status epilepticus, rats were treated with an intraperitoneal bolus of alpha-T (250 mg/kg b.w.; once a day) for 4 days, that was the time after which morphological and biochemical analyses were performed on hippocampus. Post seizure alpha-T administration significantly reduced astrocytosis and microglia activation, and decreased neuron degeneration and spine loss; these effects were associated with the presence of a lowered lipid peroxidation in hippocampus. These results confirm and further emphasize the anti-inflammatory and neuroprotective role of alpha-T in kainic acid-induced epilepsy. Moreover, the findings show that post-seizure treatment with alpha-T provides an effective secondary prevention against post-seizure inflammation-induced brain damages and possibly against their epileptogenic effects. PMID- 24488647 TI - The effect of neighborhood and individual characteristics on pediatric critical illness. AB - The relationship between neighborhood/individual characteristics and pediatric intensive care unit (PICU) outcomes is largely unexplored. We hypothesized that individual-level racial/ethnic minority status and neighborhood-level low socioeconomic status and minority concentration would adversely affect children's severity of illness on admission to the PICU. Retrospective analyses (1/1/2007 5/23/2011) of clinical, geographic, and demographic data were conducted at an academic, tertiary children's hospital PICU. Clinical data included age, diagnosis, insurance, race/ethnicity, Pediatric Index of Mortality 2 score on presentation to the PICU (PIM2), and mortality. Residential addresses were geocoded and linked with 2010 US Census tract data using geographic information systems geocoding techniques. Repeated measures models to predict PIM2 and mortality were constructed using three successive models with theorized covariates including the patient's race/ethnicity, the predominant neighborhood racial/ethnic group, interactions between patient race/ethnicity and neighborhood race/ethnicity, neighborhood socioeconomic status, and insurance type. Of the 5,390 children, 57.8% were Latino and 70.1% possessed government insurance. Latino children (beta = 0.31; p < 0.01), especially Latino children living in a Latino ethnic enclave (beta = 1.13; p < 0.05), had higher PIM2 scores compared with non-Latinos. Children with government insurance (beta = 0.29; p < 0.01) had higher PIM2 scores compared to children with other payment types and median neighborhood income was inversely associated with PIM2 scores (beta = -0.04 per $10,000/year of income; p < 0.05). Lower median neighborhood income, Latino ethnicity, Latino children living in a predominantly Latino neighborhood, and children possessing government insurance were associated with a higher severity of illness on PICU admission. The reasons why these factors affect critical illness severity require further exploration. PMID- 24488648 TI - An analysis of sodium, total fat and saturated fat contents of packaged food products advertised in Bronx-based supermarket circulars. AB - Americans' consumption of sodium, fat, and saturated fat exceed federally recommended limits for these nutrients and has been identified as a preventable leading cause of hypertension and cardiovascular disease. More than 40% of the Bronx population comprises African-Americans, who have increased risk and earlier onset of hypertension and are also genetically predisposed to salt-sensitive hypertension. This study analyzed nutrition information for packaged foods advertised in Bronx-based supermarket circulars. Federally recommended limits for sodium, saturated fat and total fat contents were used to identify foods that were high in these nutrients. The proportion of these products with respect to the total number of packaged foods was calculated. More than a third (35%) and almost a quarter (24%) of the 898 advertised packaged foods were high in saturated fat and sodium respectively. Such foods predominantly included processed meat and fish products, fast foods, meals, entrees and side dishes. Dairy and egg products were the greatest contributors of high saturated fat. Pork and beef products, fast foods, meals, entrees and side dishes had the highest median values for sodium, total fat and saturated fat content. The high proportion of packaged foods that are high in sodium and/or saturated fat promoted through supermarket circulars highlights the need for nutrition education among consumers as well as collaborative public health measures by the food industry, community and government agencies to reduce the amounts of sodium and saturated fat in these products and limit the promotion of foods that are high in these nutrients. PMID- 24488649 TI - Effects of a school-based sexuality education program on peer educators: the Teen PEP model. AB - This study evaluated the impact of the Teen Prevention Education Program (Teen PEP), a peer-led sexuality education program designed to prevent unintended pregnancy and sexually transmitted infections (STIs) including HIV among high school students. The study design was a quasi-experimental, nonrandomized design conducted from May 2007 to May 2008. The sample consisted of 96 intervention (i.e. Teen PEP peer educators) and 61 comparison students from five high schools in New Jersey. Baseline and 12-month follow-up surveys were conducted. Summary statistics were generated and multiple regression analyses were conducted. In the primary intent-to-treat analyses, and secondary non-intent-to-treat analyses, Teen PEP peer educators (versus comparison students) reported significantly greater opportunities to practice sexual risk reduction skills and higher intentions to talk with friends, parents, and sex partners about sex and birth control, set boundaries with sex partners, and ask a partner to be tested for STIs including HIV. In addition in the secondary analysis, Teen PEP peer educators (as compared with the comparison students) had significantly higher scores on knowledge of sexual health issues and ability to refuse risky sexual situations. School-based sexuality education programs offering comprehensive training to peer educators may improve sexual risk behavior knowledge, attitudes and behaviors among high school students. PMID- 24488650 TI - Using process data to understand outcomes in sexual health promotion: an example from a review of school-based programmes to prevent sexually transmitted infections. AB - This article discusses how process indicators can complement outcomes as part of a comprehensive explanatory evaluation framework, using the example of skills based behavioural interventions to prevent sexually transmitted infections and promote sexual health among young people in schools. A systematic review was conducted, yielding 12 eligible outcome evaluations, 9 of which included a process evaluation. There were few statistically significant effects in terms of changes in sexual behaviour outcomes, but statistically significant effects were more common for knowledge and self-efficacy. Synthesis of the findings of the process evaluations identified a range of factors that might explain outcomes, and these were organized into two overarching categories: the implementation of interventions, and student engagement and intervention acceptability. Factors which supported implementation and engagement and acceptability included good quality teacher training, involvement and motivation of key school stakeholders and relevance and appeal to young people. Factors which had a negative impact included teachers' failure to comprehend the theoretical basis for behaviour change, school logistical problems and omission of topics that young people considered important. It is recommended that process indicators such as these be assessed in future evaluations of school-based sexual health behavioural interventions, as part of a logic model. PMID- 24488651 TI - Prevalence and correlates of HIV and sexually transmitted infections among female sex workers and their non-commercial male partners in two Mexico-USA border cities. AB - Female sex workers (FSWs) acquire HIV and other sexually transmitted infections (STIs) through unprotected sex with commercial and non-commercial (intimate) male partners. Little research has focused on FSWs' intimate relationships, within which condom use is rare. We sought to determine the prevalence and correlates of HIV/STIs within FSWs' intimate relationships in Northern Mexico. From 2010 to 2011, we conducted a cross-sectional survey of FSWs and their non-commercial male partners in Tijuana and Ciudad Juarez, Mexico. Eligible FSWs and their verified male partners were aged >=18 years; FSWs reported lifetime use of heroin, cocaine, crack, or methamphetamine and recently exchanged sex (past month). Participants completed baseline questionnaires and testing for HIV, chlamydia, gonorrhea, and syphilis. We determined the prevalence and correlates of individuals' HIV/STI positivity using bivariate probit regression. Among 212 couples (n = 424), prevalence of HIV was 2.6 % (n = 11). Forty-two (9.9 %) tested positive for any HIV/STIs, which was more prevalent among women than men (12.7 % vs. 7.1 %, p < 0.05). FSWs with regular sex work clients were less likely to test positive for HIV/STIs than those without regular clients. Similarly, male partners of FSWs who had regular clients were 9 % less likely to have HIV/STIs. Higher sexual decision-making power was protective against HIV/STIs for women. Men who recently used methamphetamine or reported perpetrating any conflict within steady relationships were more likely to test positive for HIV/STIs. Within FSWs' intimate relationships in two Mexican-US border cities, nearly one in ten partners tested positive for HIV/STIs. Couple-based prevention interventions should recognize how intimate relationship factors and social contexts influence HIV/STI vulnerability. PMID- 24488652 TI - Spatial variation in environmental noise and air pollution in New York City. AB - Exposure to environmental noise from traffic is common in urban areas and has been linked to increased risks of adverse health effects including cardiovascular disease. Because traffic sources also produce air pollutants that increase the risk of cardiovascular morbidity, associations between traffic exposures and health outcomes may involve confounding and/or synergisms between air pollution and noise. While prior studies have characterized intraurban spatial variation in air pollution in New York City (NYC), limited data exists on the levels and spatial variation in noise levels. We measured 1-week equivalent continuous sound pressure levels (Leq) at 56 sites during the fall of 2012 across NYC locations with varying traffic intensity and building density that are routinely monitored for combustion-related air pollutants. We evaluated correlations among several noise metrics used to characterize noise exposures, including Leq during different time periods (night, day, weekday, weekend), Ldn (day-night noise), and measures of intermittent noise defined as the ratio of peak levels to median and background levels. We also examined correlations between sound pressure levels and co-located simultaneous measures of nitric oxide (NO), nitrogen dioxide (NO2), fine particulate matter (PM2.5), and black carbon (BC) as well as estimates of traffic and building density around the monitoring sites. Noise levels varied widely across the 56 monitoring sites; 1-week Leq varied by 21.6 dBA (range 59.1-80.7 dBA) with the highest levels observed during the weekday, daytime hours. Indices of average noise were well correlated with each other (r > 0.83), while indices of intermittent noise were not well correlated with average noise levels (r < 0.41). One-week Leq correlated well with NO, NO2, and EC levels (r = 0.61 to 0.68) and less so with PM2.5 levels (r = 0.45). We observed associations between 1-week noise levels and traffic intensity within 100 m of the monitoring sites (r = 0.58). The high levels of noise observed in NYC often exceed recommended guidelines for outdoor and personal exposures, suggesting unhealthy levels in many locations. Associations between noise, traffic, and combustion air pollutants suggest the possibility for confounding and/or synergism in intraurban epidemiological studies of traffic-related health effects. The different spatial pattern of intermittent noise compared to average noise level may suggest different sources. PMID- 24488653 TI - Neuromodulation for intractable headaches. AB - Intractable chronic headaches are a major challenge for both patients and healthcare professionals. Over the last two decades, implantable electrical neuromodulators, previously established to manage other forms of chronic pain, have been used increasingly for intractable primary and secondary headache disorders. We review the current approaches to the management of refractory headaches using neuromodulation. Indications, operative considerations and complications are discussed based on our experience and a review of the literature. The field of neuromodulation has been rapidly advancing, with many new targets being discovered and novel devices being developed for treating craniofacial pain. We discuss some of these targets, detailing the latest advances in the area of neuromodulation for intractable headaches. PMID- 24488654 TI - Immediate-release versus controlled-release carbamazepine in the treatment of epilepsy. AB - BACKGROUND: Epilepsy is defined as the tendency to spontaneous, excessive neuronal discharge manifesting as seizures. It is a common disorder with an incidence of 50 per 100,000 per year and a prevalence of 0.5% to 1% (Hauser 1993) in the developed world.Carbamazepine (CBZ) is a widely used antiepileptic drug that is associated with a number of troublesome adverse events including dizziness, double vision and unsteadiness. These often occur during peaks in plasma concentration. The occurrence of such adverse events may limit the daily dose that can be tolerated and reduce the chances of seizure control for patients requiring higher doses (Vojvodic 2002). A controlled-release formulation of carbamazepine delivers the same dose over a longer period of time when compared to a standard formulation, thereby reducing post-dose peaks and potentially reducing adverse events associated with peak plasma levels. OBJECTIVES: To determine the efficacy of immediate-release CBZ (IR CBZ) versus controlled release CBZ (CR CBZ) in patients diagnosed with epilepsy. The following hypotheses were tested.(1) For newly diagnosed patients commencing CBZ, how do immediate-release and controlled-release formulations compare for efficacy and tolerability?(2) For patients on established treatment with immediate-release CBZ but experiencing unacceptable adverse events, what is the effect on seizure control and tolerability of a switch to a controlled-release formulation versus remaining on the immediate-release formulation? SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (5 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) (Issue 8, 2013) in The Cochrane Library and MEDLINE (1946 to 5 September 2013). SELECTION CRITERIA: Randomised controlled trials comparing IR CBZ to CR CBZ in patients commencing monotherapy and patients presently treated with IR CBZ but experiencing unacceptable adverse events.Primary outcome measures include seizure frequency, incidence of adverse events, proportion with treatment failure and quality of life measures. DATA COLLECTION AND ANALYSIS: The methodological quality of each study was assessed with respect to study design, type of control, method and the concealment of allocation, blinding and completeness of follow up, and the presence of blinding for assessment of non-fatal outcomes. We did not make use of an overall quality score.Two review authors (GP, MS) independently extracted the data and recorded relevant information on a standardised data extraction form. Results were assessed for inclusion.The heterogeneity of the included trials resulted in only a narrative, descriptive analysis being possible for both the categorical and time-to-event data. MAIN RESULTS: Ten trials fulfilled the criteria for inclusion in this review. One trial included patients with newly diagnosed epilepsy and nine included patients on treatment with IR CBZ.Eight trials reported heterogeneous measures of seizure frequency with conflicting results. A statistically significant difference was observed in only one trial, with patients prescribed CR CBZ experiencing fewer seizures than patients prescribed IR CBZ.Nine trials reported measures of adverse events. There was a trend in favour of CR CBZ with four trials reporting a statistically significant reduction in adverse events compared to IR CBZ. A further two trials reported fewer adverse events with CR CBZ but the reduction was not statistically significant. One trial found no difference, with a further trial reporting increased adverse events in the CR CBZ group although not statistically significant. AUTHORS' CONCLUSIONS: At present, data from trials do not confirm or refute an advantage for CR CBZ over IR CBZ for seizure frequency or adverse events in patients with newly diagnosed epilepsy.For trials involving epilepsy patients already prescribed IR CBZ, no conclusions can be drawn concerning the superiority of CR CBZ with respect to seizure frequency.There is a trend for CR CBZ to be associated with fewer adverse events when compared to IR CBZ. A change to CR CBZ may therefore be a worthwhile strategy in patients with acceptable seizure control on IR CBZ but experiencing unacceptable adverse events. The included trials were of small size, poor methodological quality and possessed a high risk of bias, limiting the validity of this conclusion.Randomised controlled trials comparing CR CBZ to IR CBZ and using clinically relevant outcomes are required to inform the choice of CBZ preparation for patients with newly diagnosed epilepsy. PMID- 24488656 TI - Metabolite ratios in 1H MR spectroscopic imaging of the prostate. AB - In (1)H MR spectroscopic imaging ((1)H-MRSI) of the prostate the spatial distribution of the signal levels of the metabolites choline, creatine, polyamines, and citrate are assessed. The ratio of choline (plus spermine as the main polyamine) plus creatine over citrate [(Cho+(Spm+)Cr)/Cit] is derived from these metabolites and is used as a marker for the presence of prostate cancer. In this review, the factors that are of importance for the metabolite ratio are discussed. This is relevant, because the appearance of the metabolites in the spectrum depends not only on the underlying anatomy, metabolism, and physiology of the tissue, but also on acquisition parameters. These parameters influence especially the spectral shapes of citrate and spermine resonances, and consequently, the (Cho+(Spm+)Cr)/Cit ratio. Both qualitative and quantitative approaches can be used for the evaluation of (1)H-MRSI spectra of the prostate. For the quantitative approach, the (Cho+(Spm+)Cr)/Cit ratio can be determined by integration or by a fit based on model signals. Using the latter, the influence of the acquisition parameters on citrate can be taken into account. The strong overlap between the choline, creatine, and spermine resonances complicates fitting of the individual metabolites. This overlap and (unknown, possibly tissue related) variations in T1, T2, and J-modulation hamper the application of corrections needed for a "normalized" (Cho+(Spm+)Cr)/Cit ratio that would enable comparison of spectra measured with different prostate MR spectroscopy protocols. Quantitative (Cho+(Spm+)Cr)/Cit thresholds for the evaluation of prostate cancer are therefore commonly established per institution or per protocol. However, if the same acquisition and postprocessing protocol were used, the ratio and the thresholds would be institution-independent, promoting the clinical usability of prostate (1)H-MRSI. PMID- 24488655 TI - Late adult-onset of X-linked myopathy with excessive autophagy. AB - INTRODUCTION: X-linked myopathy with excessive autophagy (XMEA) is characterized by autophagic vacuoles with sarcolemmal features. Mutations in VMA21 result in insufficient lysosome acidification, causing progressive proximal weakness with onset before age 20 years and loss of ambulation by middle age. METHODS: We describe a patient with onset of slowly progressive proximal weakness of the lower limbs after age 50, who maintains ambulation with the assistance of a cane at age 71. RESULTS: Muscle biopsy at age 66 showed complex muscle fiber splitting, internalized capillaries, and vacuolar changes characteristic of autophagic vacuolar myopathy. Vacuoles stained positive for sarcolemmal proteins, LAMP2, and complement C5b-9. Ultrastructural evaluation further revealed basal lamina reduplication and extensive autophagosome extrusion. Sanger sequencing identified a known pathologic splice site mutation in VMA21 (c.164-7T>G). CONCLUSIONS: This case expands the clinical phenotype of XMEA and suggests VMA21 sequencing be considered in evaluating men with LAMP2-positive autophagic vacuolar myopathy. PMID- 24488657 TI - Acute phase endovascular intervention on a pseudoaneurysm formed due to rupture of an anterior communicating artery aneurysm. AB - A 79-year-old woman presented with a subarachnoid hemorrhage. Angiography revealed pseudoaneurysm formation due to rupture of a true saccular anterior communicating artery aneurysm. Coil embolization, limited to the true aneurysm, was performed successfully with a favorable clinical outcome. This procedure can be considered as an alternative treatment option for similar aneurysms in cases where surgical clipping is contraindicated. PMID- 24488658 TI - Histopathological insight of complex odontoma associated with a dentigerous cyst. AB - Odontomas and dentigerous cysts are common findings for practicing dental professionals. However, simultaneous occurrence of pathologies like odontoma and dentigerous cyst are uncommon and their diagnosis based on the radiographic appearance alone is a challenge to overcome. They together are a potential for complications like attaining large size, root resorption, destruction of the jaw bones and sometimes neoplastic changes like ameloblastoma. This paper presents a case of complex odontoma associated with dentigerous cyst in relation to a retained deciduous tooth in the maxillary anterior region and confirming its diagnosis histopathologically. PMID- 24488659 TI - Clown nose: a case of disfiguring nodular squamous cell carcinoma of the face. AB - 'Clown nose' (CN) is the common medical term referring to a reddish-brown bulge involving the tip of the nose, reminding of a clown's fake red nose. Reports about these tumours are scarce. Most reports refer to metastatic skin manifestation of systemic malignancies: this condition has been rarely described as a primary skin neoplasm. We report a case of a 31-year-old patient with a giant cutaneous squamous cell carcinoma of the nose which evolved into a CN. After ruling out genetic or immune risk factors, the patient was treated with surgical excision of the lesion and local reconstruction with good aesthetic outcome and no recurrence over a 2-year follow-up. PMID- 24488660 TI - Solid pseudopapillary tumour (Frantz's tumour) of the pancreas in childhood. AB - An 11-year-old girl presented with acute pancreatitis and mass in the head of the pancreas. MRI revealed a heterogeneous right-upper quadrant retroperitoneal mass measuring 6.8*6.1*5.5 cm arising from the pancreatic head. Endoscopic ultrasound with fine-needle aspirate revealed a solid pseudopapillary tumour (SPT) of the pancreas. The patient underwent a pylorus-preserving Whipple procedure. Pathology confirmed SPT. First described by Frantz, SPT represents less than 3% of all exocrine tumours. It is especially rare in children and shows different clinical features compared with adults. In our patient, tumour cells were arranged at the periphery of fibrovascular cores, but they did not show definite gland formation, keratinisation or cytoplasmic pigment accumulation. A periodic acid-Schiff stain without diastase did not show appreciable glycogen within the tumour cells, classic for Frantz's tumour. The literature, diagnosis, management and pathogenesis on this rare entity in children are reviewed and discussed. PMID- 24488661 TI - Serositis and desquamation of fingers and toes. PMID- 24488662 TI - The effect of bumetanide treatment on the sensory behaviours of a young girl with Asperger syndrome. AB - Sensory behaviours were not considered as core features of autism spectrum disorders until recently. However, they constitute an important part of the observed symptoms that result in social maladjustment and are currently quite difficult to treat. One promising strategy for the treatment of these behaviours is the use of bumetanide, which was previously shown to reduce the severity of autism spectrum disorders. In this study, we proposed to evaluate sensory behaviours using Dunn's Sensory Profile after 18 months of bumetanide treatment in a 10-year-old girl with Asperger syndrome. Reported improvements covered a large range of sensory behaviours, including auditory, vestibular, tactile, multisensory and oral sensory processing. Although our results were limited to a single case report, we believe that our clinical observations warrant clinical trials to test the long-term efficacy of bumetanide to manage the sensory behaviours of people with autism spectrum disorders. PMID- 24488664 TI - Stomach infarction in an ex-premature infant. AB - Gastric pneumatosis and thickened gastric wall are rare radiological findings that may be indicative of severe gastrointestinal tract ischaemia or necrosis; we report a case with a brief discussion of the literature. The premature neonate conveyed an interesting series of rare X-ray findings which were secondary to extensive gastric, duodenal and proximal jejunal infarction. She was managed palliatively and died. PMID- 24488663 TI - Leucoerythroblastosis and thrombocytopenia as clues to metastatic malignancy. AB - The association of metastatic breast cancer presenting as thrombocytopenia and anaemia is demonstrated in the following case of a 79-year-old woman. Her main symptoms were abdominal pain, altered bowel habit and weight loss. Without a clear causative pathology, she underwent a CT scan which demonstrated multiple sclerotic bone lesions. With a raised CA15-3 and strong oestrogen receptor positivity on immunohistochemistry on a trephine bone marrow biopsy, a diagnosis of metastatic lobular breast cancer was made. Interestingly, only a small breast mass was noted on mammography. The patient was managed conservatively and initiated on supportive therapy. This case report summarises the varying presentation of bone marrow suppression secondary to metastatic infiltration, especially in the absence of classical symptoms associated with primary solid tumour. Accurate bone marrow analysis is also vital in establishing the final diagnosis. PMID- 24488665 TI - Salter-Harris II forearm fracture reduction and fixation using a buttress plate. AB - Distal radius fractures are common injuries in children. Those that affect the growth plate (physis) need to be managed carefully as inadequate management may lead to long-term deformity and a reduction in function. However, different management strategies all have drawbacks and controversy exists over how best to manage these cases. This is the case of a 13-year-old girl who presented with a Salter Harris II fracture, which was managed using a novel approach of utilising a T plate in a buttress mode to stabilise the fracture after anatomical reduction. This provided effective fracture fixation and should allow good bone healing without causing any iatrogenic growth plate damage and without fixing a plate across the physis, which may need removal in the future. PMID- 24488666 TI - Fibrin sheath following pleurodesis. PMID- 24488667 TI - Type I keratoprosthesis for visual rehabilitation of patients with xeroderma pigmentosum. AB - A 6-year-old girl, a case of xeroderma pigmentosum (XP), presented with a visual acuity (VA) of 20/20 and 20/400 in the right and left eye, respectively. For a diagnosis of vascularised corneal scar, penetrating keratoplasty was performed in the left eye twice and ultimately graft failed following multiple episodes of rejection. Type I keratoprosthesis was performed in the left eye. She continues to maintain VA of 20/40 in the left eye for more than a year. Similarly, a 24 year-old man, a case of XP, presented with VA of finger counting at 1 metre in both eyes. Ocular examination showed bilateral vascularised corneal scar and conjunctivalisation. Type I keratoprosthesis was performed as primary procedure in the left eye. He maintains a VA of 20/30 for more than a year. Type I keratoprosthesis could be a primary procedure for visual rehabilitation in patients with XP with severe ocular surface disease. PMID- 24488668 TI - Polyamidoamine dendrimer liposome-mediated survivin antisense oligonucleotide inhibits hepatic cancer cell proliferation by inducing apoptosis. AB - Polyamidoamine dendrimer (PAMAM) is a new nanometer material, which can transfer the target genes to cells with high efficiency and lower toxicity. This study aims to evaluate antitumor effects of survivin antisense oligonucleotide (survivin-asODN) (carried by polyamidoamine dendrimer liposome) on hepatic cancer in nude mice. Hepatic cancer model was established by injecting SMMC-7721 cells subcutaneously into flanks of nude mice. Polyamidoamine dendrimer and liposome were mixed with survivin-asODN, respectively. The shape and size of complex were observed by transmission electron microscope, and zeta potential was measured by an analytical tool. Encapsulation efficiency and DNA loading level were determined by an ultraviolet spectrophotometer in centrifuging method. Expression of survivin in transplant tumor was measured by Western blotting. No significant difference appeared for diameter and envelopment ratio between PAMAM liposome survivin-asODN and PAMAM-survivin-asODN (P > 0.05). Both zeta potential and transfection efficiency in PAMAM liposome-survivin-asODN were higher than that in PAMAM-survivin-asODN complex (P < 0.05). Expression of survivin protein and weight of tumors in transplanted tumors in PAMAM liposome-survivin-asODN group was less than that in PAMAM-survivin-asODN group (P < 0.05). Cell apoptosis rate in PAMAM liposome-survivin-asODN group was higher than that of PAMAM-survivin asODN group (P < 0.05). In conclusion, polyamidoamine dendrimer liposome can deliver survivin-asODN into hepatic transplanted tumor cells effectively. Ployamidoamine dendrimer liposome-mediated survivin-asODN can inhibit hepatic cell proliferation by inducing apoptosis. PMID- 24488669 TI - Differential expression of Pim-3, c-Myc, and p-p27 proteins in adenocarcinomas of the gastric cardia and distal stomach. AB - Gastric cardia adenocarcinoma (GCA) is distinct from adenocarcinoma of the distal stomach because of its different etiological factors, tumor characteristics, and biological behavior. However, its pathogenesis is not fully understood. The purpose of this study is to characterize the role of Pim-3, c-Myc, and p-p27 in the tumorigenesis and progression of different sites of gastric adenocarcinoma by determining its pathogenetic significance. The expression of Pim-3, c-Myc, and p p27 proteins was evaluated by immunohistochemistry in 140 resection specimens of gastric adenocarcinomas (78 GCAs , 62 DGAs and 20 normal gastric tissues). The level of expression of Pim-3, c-Myc, and p-p27 and the co-expression of all three markers (Pim-3+/c-Myc+/p-p27+) in GCA were significantly lower than that in DGA tumors (P < 0.05). Detailed analysis of the immunoreactivity patterns showed that in DGA, Pim-3 immunoreactivity was associated significantly with poor tumor differentiation, advanced tumor stage, and presence of lymph node metastasis. In addition, c-Myc overexpression correlated with tumor stage and lymph node metastasis, and positive p-p27 expression correlated with poor differentiation and tumor stage. The phenotype of Pim-3(+)/c-Myc(+)/p-p27(+) co-expression was closely correlated with tumor stage and lymph node metastasis (P < 0.05). In contrast, GCA only demonstrated a close correlation of Pim-3 overexpression with poor tumor differentiation and tumor stage (P < 0.05). Our results demonstrate the presence of different expression patterns of Pim-3, c-Myc, p-p27, and Pim 3(+)/c-Myc(+)/p-p27(+) and their clinicopathologic significance in GCA and DGA tumors. Our results add support to the notion that distinct molecular mechanisms may be involved in the development and progression of adenocarcinomas from the gastric cardia and distal portion of stomach. PMID- 24488670 TI - Biocompatibility and hemocompatibility of polyvinyl alcohol hydrogel used for vascular grafting--In vitro and in vivo studies. AB - Polyvinyl alcohol hydrogel (PVA) is a synthetic polymer with an increasing application in the biomedical field that can potentially be used for vascular grafting. However, the tissue and blood-material interactions of such gels and membranes are unknown in detail. The objectives of this study were to: (a) assess the biocompatibility and (b) hemocompatibility of PVA-based membranes in order to get some insight into its potential use as a vascular graft. PVA was evaluated isolated or in copolymerization with dextran (DX), a biopolymer with known effects in blood coagulation homeostasis. The effects of the mesenchymal stem cells (MSCs) isolated from the umbilical cord Wharton's jelly in the improvement of PVA biocompatibility and in the vascular regeneration were also assessed. The biocompatibility of PVA was evaluated by the implantation of membranes in subcutaneous tissue using an animal model (sheep). Histological samples were assessed and the biological response parameters such as polymorphonuclear neutrophilic leucocytes and macrophage scoring evaluated in the implant/tissue interface by International Standards Office (ISO) Standard 10993-6 (annex E). According to the scoring system based on those parameters, a total value was obtained for each animal and for each experimental group. The in vitro hemocompatibility studies included the classic hemolysis assay and both human and sheep bloods were used. Relatively to biocompatibility results, PVA was slightly irritant to the surrounding tissues; PVA-DX or PVA plus MSCs groups presented the lowest score according to ISO Standard 10993-6. Also, PVA was considered a nonhemolytic biomaterial, presenting the lowest values for hemolysis when associated to DX. PMID- 24488671 TI - Prevalence of gastrointestinal disease and its associated risk factors in Sikkim and Darjeeling Districts. AB - The gastrointestinal disease accounts for a large number of deaths in several parts of the world. Gastrointestinal infection has been an emerging problem in Sikkim and Darjeeling District and also in other parts of our country. To study the prevalence and to explore the risk factors associated with gastrointestinal diseases in Sikkim and Darjeeling District. The present study is the population based descriptive type cross sectional study. The study design was based on random selection among 100 individuals from different areas of Sikkim and Darjeeling district of West Bengal. Questionnaire based anonymous feedback system was followed to collect the data. The data were analyzed using statistical tool and the relative risk was calculated. Total 65 (65%) cases of gastrointestinal disease were found in 100 individuals out of which 24 were males and 41 were females. Cases of diarrhea, gastroenteritis, dysentery, food poisoning, amoebiosis and enterocolitis was 34, 18, 3, 3, 1 and 0% respectively. The statistical analysis reveals that a gastrointestinal disease is more prevalent in females as compared to males and in the age group between 15 and 25 years. The various associated risk factors for gastrointestinal disease which was observed during the study were frequency of diet, diet type, consumption of spicy food, fermented food, smoking, consumption of alcohol, consumption of fruits available in market and an inappropriate sanitary condition. PMID- 24488672 TI - Erratum to: JCCS: a comprehensive journal for publishing all aspects of cell communication and signaling. PMID- 24488673 TI - Catalytic asymmetric formal [3+3] cycloaddition of an azomethine ylide with 3 indolylmethanol: enantioselective construction of a six-membered piperidine framework. AB - A catalytic asymmetric formal [3+3] cycloaddition of 3-indolylmethanol and an in situ-generated azomethine ylide has been established to construct a chiral six membered piperidine framework with two stereogenic centers. This approach not only represents the first enantioselective cycloaddition of isatin-derived 3 indolylmethanol, but also has realized an unusual enantioselective formal [3+3] cycloaddition of azomethine ylide rather than its common [3+2] cycloadditions. Besides, this protocol combines the merits of a multicomponent reaction and organocatalysis, which efficiently assembles a variety of isatin-derived 3 indolylmethanols, aldehydes, and amino esters into structurally diverse spiro[indoline-3,4'-pyridoindoles] with one all-carbon quaternary stereogenic center in high yields and excellent enantioselectivities (up to 93 % yield, >99 % enantiomeric excess (ee)). Although the diastereoselectivity of the reaction is generally moderate, most of the diastereomers can be separated by using column chromatography followed by preparative TLC. PMID- 24488674 TI - Electrocatalytically switchable CO2 capture: first principle computational exploration of carbon nanotubes with pyridinic nitrogen. AB - The front cover artwork for issue 12/2013 is provided by the group of Prof. Zhonghua Zhu, in collaboration with Prof. Sean C. Smith of Oak Ridge National Laboratory, and Prof. Aijun Du from Queensland University of Technology. The image shows how carbon nanotubes and/or graphene with doped pyridinic nitrogen could be applied for controllable, highly selective, and reversible CO2 capture. The Full Paper itself is available at 10.1002/cssc.201300624. PMID- 24488677 TI - Electrocatalytically switchable CO2 capture: first principle computational exploration of carbon nanotubes with pyridinic nitrogen. AB - Carbon nanotubes with specific nitrogen doping are proposed for controllable, highly selective, and reversible CO2 capture. Using density functional theory incorporating long-range dispersion corrections, we investigated the adsorption behavior of CO2 on (7,7) single-walled carbon nanotubes (CNTs) with several nitrogen doping configurations and varying charge states. Pyridinic-nitrogen incorporation in CNTs is found to induce an increasing CO2 adsorption strength with electron injecting, leading to a highly selective CO2 adsorption in comparison with N2 . This functionality could induce intrinsically reversible CO2 adsorption as capture/release can be controlled by switching the charge carrying state of the system on/off. This phenomenon is verified for a number of different models and theoretical methods, with clear ramifications for the possibility of implementation with a broader class of graphene-based materials. A scheme for the implementation of this remarkable reversible electrocatalytic CO2 -capture phenomenon is considered. PMID- 24488678 TI - Benzochalcogenodiazole-based donor-acceptor-acceptor molecular donors for organic solar cells. AB - Four new molecules with a donor-acceptor-acceptor (D-A-A) configuration, in which 2,1,3-benzoxadiazole or 2,1,3-benzoselenodiazole were adopted as the central bridging acceptor, were synthesized as electron donors for small-molecule organic solar cells. In conjunction with two previously reported 2,1,3-benzothiadiazole based compounds, the influences of the benzochalcogenodiazole acceptor unit and the ditolylarylamine donor moiety on the molecular structure, electrochemical behavior, and optical properties of the materials were investigated systematically to obtain a clear structure-property relationship. Vacuum deposited hybrid planar mixed-heterojunction devices fabricated with the new donors and C70 as the acceptor showed power conversion efficiencies in the range of 2.9-4.3 % under 1 sun (100 mW cm(-2) ) AM 1.5 G simulated solar illumination. The current density-voltage characteristics of solar cells at various light intensities were measured, which revealed a high bimolecular recombination. PMID- 24488679 TI - Dye-sensitized solar cells with vertically aligned TiO2 nanowire arrays grown on carbon fibers. AB - One-dimensional semiconductor TiO2 nanowires (TNWs) have received widespread attention from solar cell and related optoelectronics scientists. The controllable synthesis of ordered TNW arrays on arbitrary substrates would benefit both fundamental research and practical applications. Herein, vertically aligned TNW arrays in situ grown on carbon fiber (CF) substrates through a facile, controllable, and seed-assisted thermal process is presented. Also, hierarchical TiO2 -nanoparticle/TNW arrays were prepared that favor both the dye loading and depressed charge recombination of the CF/TNW photoanode. An impressive conversion efficiency of 2.48 % (under air mass 1.5 global illumination) and an apparent efficiency of 4.18 % (with a diffuse board) due to the 3D light harvesting of the wire solar cell were achieved. Moreover, efficient and inexpensive wire solar cells made from all-CF electrodes and completely flexible CF-based wire solar cells were demonstrated, taking into account actual application requirements. This work may provide an intriguing avenue for the pursuit of lightweight, cost-effective, and high-performance flexible/wearable solar cells. PMID- 24488681 TI - Synthesis of ethers by GaBr3 -catalyzed reduction of carboxylic acid esters and lactones by siloxanes. AB - Ethers were synthesized by reduction of the respective esters catalyzed by gallium bromide (GaBr3 ) and using siloxanes, preferentially 1,1,3,3 tetramethyldisiloxane, as reductant. Methyl oleate, triglycerides, that is, tributyrine and glyceryl triundec-10-enoate as well as gamma- and delta-lactones were converted into the respective ethers in high to moderate yields. gamma Lactones were reduced with high selectivity in the presence of a methyl ester functionality. The reduction has been carried out at room temperature or moderately elevated temperature of up to 60 degrees C using stoichiometric amounts of the reductant and 0.005-0.01 equiv of GaBr3 as catalyst per ester functionality without any solvent added. After a reaction time of 1-4 h the conversion of the substrate was 100 %. The product was separated from polymeric siloxanes formed as coupled product by simple distillation. PMID- 24488680 TI - Capacity decay mechanism of microporous separator-based all-vanadium redox flow batteries and its recovery. AB - The results of the investigation of the capacity decay mechanism of vanadium redox flow batteries with microporous separators as membranes are reported. The investigation focuses on the relationship between the electrochemical performance and electrolyte compositions at both the positive and negative half-cells. Although the concentration of total vanadium ions remains nearly constant at both sides over cycling, the net transfer of solution from one side to the other and thus the asymmetrical valance of vanadium ions caused by the subsequent disproportionate self-discharge reactions at both sides lead to capacity fading. Through in situ monitoring of the hydraulic pressure of the electrolyte during cycling at both sides, the convection was found to arise from differential hydraulic pressures at both sides of the separators and plays a dominant role in capacity decay. A capacity-stabilizing method is developed and was successfully demonstrated through the regulation of gas pressures in both electrolyte tanks. PMID- 24488682 TI - alpha-MsO/TsO/Cl ketones as oxidized alkyne equivalents: redox-neutral rhodium(III)-catalyzed C-H activation for the synthesis of N-heterocycles. AB - alpha-Halo and pseudohalo ketones are used for the first time as C(sp(3))-based electrophiles in transition-metal-catalyzed C-H activation and as oxidized alkyne equivalents in Rh(III)-catalyzed redox-neutral annulations to generate diverse N heterocycles. This transformation is efficient and scalable. Due to the mild reaction conditions, a variety of functional groups could be tolerated. PMID- 24488683 TI - Conformation and EPR characterization of rigid, 310 -helical peptides with TOAC spin labels: Models for short distances. AB - For 3D-structure determination in biophysical systems EPR is rapidly gaining ground. Proteins labeled specifically with two nitroxide spin labels can be prepared, and several EPR methods are available for distance determination, which makes it possible to determine distance constraints. However, such methods require frozen solutions, potentially causing non-physiological states of the sample. Here, we target spin- spin interaction in liquid solution at room temperature using rigid model compounds. A series of 310 -helical peptides, based on alpha-aminoisobutyric acid (Aib), is synthesized with pairs of spin labels separated by three, four, and five amino acids. To avoid flexibility, the noncoded nitroxyl-containing alpha-amino acid TOAC that is rigidly connected with the peptide backbone, is used. The EPR spectra of the peptides show a decreasing amount of coupling between the two spin labels within this series. We suggest through-bond interaction as the dominating mechanism for exchange interaction (J) and find a stronger J-coupling than in the corresponding Ala-based TOAC-peptides investigated previously (Hanson, et al., J Am Chem Soc 1996, 118, 7618-7625). We speculate that stronger coupling in Aib- vs Ala- peptides is due to intrinsically stronger through-bond interaction in the Aib-based peptides. PMID- 24488684 TI - Off-resonance suppression for multispectral MR imaging near metallic implants. AB - PURPOSE: Metal artifact reduction in MRI within clinically feasible scan-times without through-plane aliasing. THEORY AND METHODS: Existing metal artifact reduction techniques include view angle tilting (VAT), which resolves in-plane distortions, and multispectral imaging (MSI) techniques, such as slice encoding for metal artifact correction (SEMAC) and multi-acquisition with variable resonances image combination (MAVRIC), that further reduce image distortions, but significantly increase scan-time. Scan-time depends on anatomy size and anticipated total spectral content of the signal. Signals outside the anticipated spatial region may cause through-plane back-folding. Off-resonance suppression (ORS), using different gradient amplitudes for excitation and refocusing, is proposed to provide well-defined spatial-spectral selectivity in MSI to allow scan-time reduction and flexibility of scan-orientation. Comparisons of MSI techniques with and without ORS were made in phantom and volunteer experiments. RESULTS: Off-resonance suppressed SEMAC (ORS-SEMAC) and outer-region suppressed MAVRIC (ORS-MAVRIC) required limited through-plane phase encoding steps compared with original MSI. Whereas SEMAC (scan time: 5'46") and MAVRIC (4'12") suffered from through-plane aliasing, ORS-SEMAC and ORS-MAVRIC allowed alias-free imaging in the same scan-times. CONCLUSION: ORS can be used in MSI to limit the selected spatial-spectral region and contribute to metal artifact reduction in clinically feasible scan-times while avoiding slice aliasing. PMID- 24488685 TI - Case study interpretation: Report from the ICCS Annual Meeting, Fort Lauderdale, 2013. Introduction. PMID- 24488686 TI - A comprehensive evaluation of bladder cancer epidemiology and outcomes in Australia. AB - OBJECTIVE: To review bladder cancer statistics and management in Australia and identify gaps for future work here. METHODS: Evidence was reviewed from GLOBOCAN 2008v2.0, Pubmed, and conference presentations. We also use data from reports from Cancer Council Australia, State Cancer Councils, and Australian Institute of Health and Welfare. RESULTS: The incidence and mortality rates of bladder cancer in Australia closely parallel those of other developed countries. Bladder cancer was the 8th most common cause of cancer in men, and the 17th most common cause of cancer in women. Bladder cancer was the 13th most common cause of cancer death in men, and the 17th most common cause of cancer death in women. We briefly review the evidence regarding causality, including nutritional, occupational, and environmental factors. We compare Australian incidence and mortality rates internationally, by state/territory, by socioeconomic strata, and by geographical regions. Importantly, we review evidence on the quality of bladder cancer management in Australia. CONCLUSIONS: The geographical, regional, and socioeconomic differences in Australian bladder cancer statistics may be associated with different patterns of diagnosis and treatment. IMPLICATIONS: The quality of bladder cancer surveillance and cystectomies in Australia requires improvement to conform to global standards and to improve decreasing survival rates. PMID- 24488688 TI - Matrix metalloproteinase-7 and matrix metalloproteinase-25 in oral tongue squamous cell carcinoma. AB - BACKGROUND: Predicting the clinical course of early-stage oral tongue squamous cell carcinoma (SCC) is challenging. As matrix metalloproteinases (MMPs) are enzymes associated with invasion, metastasis, and poor survival in many cancers, we examined MMP-7 and MMP-25 in oral tongue SCC. METHODS: We used tissue microarray (TMA) technique and immunohistochemistry to study the expression of MMP-7 and MMP-25 in 73 patients with stage I to II oral tongue SCC and compared their immunoexpressions with clinical data. RESULTS: Immunohistochemistry revealed MMP-7 and MMP-25 expression in 90% (n = 63 of 70) and 90% (n = 64 of 71) of the tumors, respectively. MMP-7 protein expression was associated with presence of occult cervical metastases (odds ratio [OR], 3.67; p = .013), increased invasion depth (OR, 4.60; p = .005), and higher tumor grade (OR, 3.30; p = .007). MMP-7 expression was predictive for poor outcome (p = .021). Immunostaining of MMP-25 did not correlate with any clinical parameters. CONCLUSION: We conclude that MMP-7, but not MMP-25, expression may have prognostic significance in early-stage oral tongue SCC. PMID- 24488687 TI - Preoperative findings, pathological stage PSA recurrence in men with prostate cancer incidentally detected at radical cystectomy: our experience in 242 cases. AB - PURPOSE: Preoperative findings, pathological stage PSA recurrence in patients with prostate cancer incidentally detected (iPCa) at radical cystectomy (RCP) were prospectively evaluated. METHODS: From July 2000 to July 2013, 242 men 71 years old (median) underwent RCP; preoperatively, all patients underwent digital rectal examination (DRE), total and free/total PSA. The bladder was totally examined; moreover, the prostate gland was step-sectioned at 4-mm intervals. The incidence of iPCa that fulfilled criteria for clinically significant iPCa was recorded: tumor volume >=0.5 mL, Gleason grade >=4, extracapsular extension, seminal vesicle invasion, lymph node metastasis or positive surgical margins. In the presence of iPCa, the patients underwent PSA evaluation during the follow-up and recurrence was defined as two subsequent rises >0.2 ng/mL. RESULTS: Among the 50 (20.6%) out of 242 patients submitted to RCP, an iPCa was found and 18 (36%) of them met criteria for insignificant iPCa; moreover, 30% of the patients had apex involvement. Median total PSA and PSA F/T values were not significantly different in the presence versus the absence of iPCa (2.6 vs 2.7 ng/mL and 26 vs 27%; p > 0.05) and between significant versus insignificant iPCa (p > 0.05). None of the patients during the follow-up (median 58 months; range 6-102 months) had PSA recurrence. CONCLUSIONS: PSA and PSA F/T values are provided for poor accuracy in distinguishing preoperatively significant from insignificant iPCa; however, the life expectancy of the patients is dramatically influenced by bladder cancer pTN (in our series, none developed PSA failure). In younger men in whom a prostate-sparing cystectomy could be proposed, an accurate preoperative evaluation should be mandatory to rule out significant iPCa at the risk of apex involvement (in our series equal to 30% of the cases). PMID- 24488689 TI - Genetic heterogeneity of amyotrophic lateral sclerosis: implications for clinical practice and research. AB - Genetic insights into the pathophysiology of amyotrophic lateral sclerosis (ALS) are untangling the clinical heterogeneity that may contribute to poor clinical trial outcomes and thus to a lack of effective treatments. Mutations in a large number of genes, including SOD1, C9ORF72, TARDBP, FUS, VAPB, VCP, UBQLN2, ALS2, SETX, OPTN, ANG, and SPG11, are thought to cause ALS, whereas others, including ATAXN2, GRN, HFE, NEFH, UNC13A, and VEGF, appear to be disease-modifying genes. Epigenetic influences may also play important roles. An improved understanding of ALS genetics should lead to better trial designs, insights into common molecular pathways, and better characterization of preclinical models. New genetic sequencing techniques, which use high-throughput methods to assess variants across the genome or exome, may facilitate rational patient stratification for clinical trials and permit more individualized prognostic information and treatment decisions in clinical care. Muscle Nerve 49: 786-803, 2014. PMID- 24488691 TI - Diffuse granulomatous lung disease: combined pathological-HRCT approach. AB - Granulomatous lung diseases include a large number of conditions among granulomas are the pathological hallmark. Some of these conditions are frequently encountered in clinical practice. Differentiating infectious from noninfectious forms is a priority for the different specialists approaching these diseases, given the different implications for management and treatment. However, differential diagnosis is not always straightforward and the diagnosis of granulomatous disease, considering separately the clinical, radiological and pathological aspects, is at times incomplete or uncertain and requires multidisciplinary assessment. In this paper, we propose a combined HRCT pathological approach to assess both the topographical and morphological features of the lesions. Based on topography, we can distinguish between granulomatous lesions distributed along the lymphatic vessels, with random distribution or centred on the airways. The prototype of the disease with lymphatic granulomas is sarcoidosis. In contrast, diseases exhibiting a random distribution of granulomas are those with haematogenous spread, the most typical of which is miliary tuberculosis (TB). Many diseases have distribution along the airways including hypersensitivity pneumonia and granulomatous bronchiolitis (including infections with bronchial spread, especially mycobacteriosis). The anatomical approach is completed by the assessment of the morphological aspects of the lesions and associated signs, reflecting both the possible mechanisms of spread and the different types of pathological and/or reparative tissue related to the disease. PMID- 24488692 TI - Characteristics of immigrant and non-immigrant patients in a dual-diagnosis psychiatric ward and treatment implications. AB - Two studies were conducted among patients in a male dual diagnosis (severe mental illness [SMI] with substance use) ward. The research examined the following questions: (1) Do immigrant and non-immigrant dual diagnosis patients exhibit similar or different socio-demographic, clinical and criminological characteristics? (2) What are the implications for treatment of immigrant (and non-immigrant) patients? Study one analyzed computerized hospital records of 413 male patients; Study two examined patient files of a subgroup of 141 (70 immigrant) male patients. Alongside similarities, non-immigrant patients reported higher numbers of repeat and involuntary hospitalizations and more drug use while immigrants showed longer hospitalizations, more suicide attempts, more violent suicide attempts, more violent offenses and more alcohol use. Among non immigrants significant relationships were found between severity of SMI and crime/violence while among immigrants a significant relationship was found between suicidality and crime/violence. Implications for treatment include need for awareness of suicide risk among immigrant dual-diagnosis patients and an understanding of the differential relationship with crime/violence for the two populations. PMID- 24488693 TI - Social and Proximate Determinants of the Frequency of Condom Use Among African, Caribbean, and Other Black People in a Canadian City: Results from the BLACCH Study. AB - African, Caribbean, and other Black (ACB) people are a priority group for HIV prevention in Canada, but little is known about condom use in this population. This exploratory community-based research project addresses this gap in knowledge. 125 sexually active ACB people completed a questionnaire covering condom use and social determinants of health. The data were analyzed using ordinal logistic regression and mediation analyses. 20.5 % of sexually active ACB adults used condoms consistently. Male gender, wealth, unstable immigration classes, and unsecure employment statuses were independently associated with more frequent condom use. Proximate determinants mediating these relationships included: not having a cohabiting regular partner, not disliking condoms, and having a history of unwanted sex. The proximate determinants mediated 85.7-97.6 % of the effects of the social determinants. These results link social context and proximate factors with condom use. They can be used to design evidence-informed interventions for ACB people. PMID- 24488695 TI - Long-term Effects of Mitiglinide in Japanese Diabetics Inadequately Controlled with DPP-4 Inhibitor or Biguanide Monotherapy. AB - INTRODUCTION: The goal of treatment in diabetes is to control hyperglycemia to near-normal glucose levels, which is important to prevent the progression of microvascular and macrovascular complications. Mitiglinide is a rapid- and short acting insulinotropic sulfonylurea receptor ligand that is known to improve postprandial hyperglycemia in patients with type 2 diabetes. The aim of this study was to investigate the long-term efficacy and safety of mitiglinide in Japanese type 2 diabetic patients inadequately controlled by dipeptidyl peptidase 4 (DPP-4) inhibitor or biguanide monotherapy. METHODS: In patients with type 2 diabetes mellitus (T2DM) receiving a stable monotherapy regimen with a DPP-4 inhibitor or biguanide added to dietary therapy, an additional 10 mg mitiglinide was administered for 52 weeks. The efficacy end points were postprandial plasma glucose (PPG) (30 min, 1 h, 2 h), postprandial insulin (30 min, 1 h, 2 h), insulinogenic index, 1,5-anhydroglucitol (1,5-AG), glycated hemoglobin (HbA1c), and fasting plasma glucose. The safety end points included the incidence and types of adverse events and adverse drug reactions. RESULTS: A total of 136 patients with T2DM were eligible for enrollment in this study and received mitiglinide. The average HbA1c before the start of mitiglinide administration (baseline) was 7.47% in the DPP-4 inhibitor combined treatment group (DPP-4 inhibitor CTG) and 7.50% in the biguanide combined treatment group (biguanide CTG), and the 2 h PPG was 248.1 and 243.3 mg/dL, respectively. Following the addition of mitiglinide to the treatment regimen for 52 weeks, the early postprandial decrease in insulin secretion improved and PPG improved in both the DPP-4 inhibitor CTG and biguanide CTG. At final evaluation, the HbA1c <7.0% achievement rate was 57.4% in the DPP-4 inhibitor CTG and 29.2% in the biguanide CTG. The incidence of hypoglycemia in the DPP-4 inhibitor CTG and biguanide CTG was 3.0% (2/67 patients) and 2.9% (2/69 patients), respectively. The hypoglycemic symptoms were mild in all cases. CONCLUSION: Combination therapy with mitiglinide and DPP-4 inhibitors or biguanides improved glycemic control over the long term without increasing risks to safety due to events such as hypoglycemia, and this is a clinically promising therapeutic strategy in T2DM. PMID- 24488694 TI - Retinal regeneration is facilitated by the presence of surviving neurons. AB - Teleost fish regenerate their retinas after damage, in contrast to mammals. In zebrafish subjected to an extensive ouabain-induced lesion that destroys all neurons and spares Muller glia, functional recovery and restoration of normal optic nerve head (ONH) diameter take place at 100 days postinjury. Subsequently, regenerated retinas overproduce cells in the retinal ganglion cell (RGC) layer, and the ONH becomes enlarged. Here, we test the hypothesis that a selective injury, which spares photoreceptors and Muller glia, results in faster functional recovery and fewer long-term histological abnormalities. Following this selective retinal damage, recovery of visual function required 60 days, consistent with this hypothesis. In contrast to extensively damaged retinas, selectively damaged retinas showed fewer histological errors and did not overproduce neurons. Extensively damaged retinas had RGC axons that were delayed in pathfinding to the ONH, and showed misrouted axons within the ONH, suggesting that delayed functional recovery following an extensive lesion is related to defects in RGC axons exiting the eye and/or reaching their central targets. The atoh7, fgf8a, Sonic hedgehog (shha), and netrin-1 genes were differentially expressed, and the distribution of hedgehog protein was disrupted after extensive damage as compared with selective damage. Confirming a role for Shh signaling in supporting rapid regeneration, shha(t4) +/- zebrafish showed delayed functional recovery after selective damage. We suggest that surviving retinal neurons provide structural/molecular information to regenerating neurons, and that this patterning mechanism regulates factors such as Shh. These factors in turn control neuronal number, retinal lamination, and RGC axon pathfinding during retinal regeneration. PMID- 24488696 TI - Frame-guided assembly of vesicles with programmed geometry and dimensions. AB - In molecular self-assembly molecules form organized structures or patterns. The control of the self-assembly process is an important and challenging topic. Inspired by the cytoskeletal-membrane protein lipid bilayer system that determines the shape of eukaryotic cells, we developed a frame-guided assembly process as a general strategy to prepare heterovesicles with programmed geometry and dimensions. This method offers greater control over self-assembly which may benefit the understanding of the formation mechanism as well as the functions of the cell membrane. PMID- 24488697 TI - The matricellular protein CCN5 regulates podosome function via interaction with integrin alphavbeta 3. AB - CCN proteins play crucial roles in cell motility, matrix turnover, and proliferation. In particular, CCN5 plays a role in cell motility and proliferation in several cell types; however, no functional binding proteins for CCN5 have been identified. In this study we report that CCN5 binds to the cell surface receptor integrin alphavbeta3 in vascular smooth muscle cells. Furthermore, this interaction takes place in podosomes, organelles known to degrade matrix and mediate motility. We show that CCN5 regulates the ability of podosomes to degrade matrix, but does not affect podosome formation. The level of CCN5 present in a podosome negatively correlates with its ability to degrade matrix. Conversely, knockdown of CCN5 greatly enhances the matrix-degrading ability of podosomes. These findings suggest that the antimotility effects of CCN5 may be mediated through the direct interaction of CCN5 and integrin alphavbeta3 in podosomes and the concomitant suppression of matrix degradation that is required for cell migration. PMID- 24488698 TI - Organocatalytic one-pot synthesis of highly substituted pyridazines from Morita Baylis-Hillman carbonates and diazo compounds. AB - A biologically inspired organocatalytic one-pot synthesis of highly functionalized pyridazines, which are ubiquitous structural units in a number of biologically active compounds, has been developed by starting from readily available diazo compounds and Morita-Baylis-Hillman (MBH) carbonates. Under mild reaction conditions, this synthetic route tolerated significant substrate variation to deliver a broad range of substituted products, including CF3 substituted pyridazines derivatives. Moreover, the introduction of trifluoromethyl groups into the ring of pyridazine could be completed conveniently from 2,2,2-trifluorodiazoethane. PMID- 24488699 TI - Hydrothermal treatment and iodine binding provide insights into the organization of glucan chains within the semi-crystalline lamellae of corn starch granules. AB - The importance of glucan chains that pass through both the amorphous and crystalline lamellae (tie chains) in the organization of corn starch granules was studied using heat-moisture treatment (HMT), annealing (ANN), and iodine binding. Molecular structural analysis showed that hylon starches (HV, HVII, and HVIII) contained higher proportion of intermediate glucan chains (HVIII > HVII > HV) than normal corn (CN) starch. Wide angle X-ray scattering revealed that on HMT, the extent of polymorphic transition in hylon starches decreased with increasing proportion of intermediate and long chains. Iodine treated hylon starches exhibited increased order in the V-type polymorphism as evidenced by the intense peak at 20 degrees 2theta and the strong reflection intensity at 7.5 degrees 2theta and the extent of the change depended on the type of hylon starch. DSC results showed that the gelatinization enthalpy of CN and waxy corn starch (CW) remained unchanged after ANN. However, hylon starches showed a significant increase in enthalpy with more distinct endotherms after ANN. It can be concluded that tie chains influence the organization of crystalline lamellae in amylose extender mutant starches. PMID- 24488700 TI - Neither cytochrome P450 family genes nor neuroendocrine factors could independently predict the SSRIs treatment in the Chinese Han population. AB - OBJECTIVE: This study was intended to explore the relationship between the genetic polymorphisms of the 8 single nucleotide polymorphisms (SNPs) at CYP genes, neuroendocrine factors and the response to selective serotonin reuptake inhibitors (SSRIs) in Chinese Han depressive patients. METHOD: This was a 6-week randomized controlled trial consisting of 290 Chinese Han depressive patients treated with SSRIs. 8 SNPs of CYP450 genes and 7 neuroendocrine factors were detected. Allele and genotype frequencies were compared between responders and non-responders. The relationships between neuroendocrine factors and treatment response were also analyzed. RESULTS: No significant differences were found in clinical features between 2 groups at the baseline. No statistical correlation was found between either the genotype or allele frequencies of SNPs in CYP1A2, CYP2C19, or CYP2D6 gene and the -efficacy of SSRIs. There were strong linkage disequilibria between rs4986894, rs1853205, and rs12767583 of CYP2C19 genes, and rs2472299, rs2472300 of CYP1A2 genes. No associations were found between the above haplotypes and the antidepressant response. No neuroendocrine factor was a significant predictor for a response to SSRI antidepressants independently. The combination of neuroendocrine factors, however, predicted the response by 76.1%. CONCLUSION: There were no significant associations between the 6 SNPs of CYP gene polymorphisms and SSRI response. Neither cytochrome P450 family genes nor neuroendocrine factors independently predict the patients' response to the antidepressants separately. A combination of neuroendocrine factors, however, does have the potential to predict the response. PMID- 24488701 TI - Ripple artifact reduction using slice overlap in slice encoding for metal artifact correction. AB - PURPOSE: Multispectral imaging (MSI) significantly reduces metal artifacts. Yet, especially in techniques that use gradient selection, such as slice encoding for metal artifact correction (SEMAC), a residual ripple artifact may be prominent. Here, an analysis is presented of the ripple artifact and of slice overlap as an approach to reduce the artifact. METHODS: The ripple artifact was analyzed theoretically to clarify its cause. Slice overlap, conceptually similar to spectral bin overlap in multi-acquisition with variable resonances image combination (MAVRIC), was achieved by reducing the selection gradient and, thus, increasing the slice profile width. Time domain simulations and phantom experiments were performed to validate the analyses and proposed solution. RESULTS: Discontinuities between slices are aggravated by signal displacement in the frequency encoding direction in areas with deviating B0. Specifically, it was demonstrated that ripple artifacts appear only where B0 varies both in-plane and through-plane. Simulations and phantom studies of metal implants confirmed the efficacy of slice overlap to reduce the artifact. CONCLUSION: The ripple artifact is an important limitation of gradient selection based MSI techniques, and can be understood using the presented simulations. At a scan-time penalty, slice overlap effectively addressed the artifact, thereby improving image quality near metal implants. PMID- 24488703 TI - The Wnt cries many: Wnt regulation of neurogenesis through tissue patterning, proliferation, and asymmetric cell division. AB - During early development Wnt signaling has a key role in patterning the prospective nervous system by regulation of cell fate specification, cell polarity, and cell migration. Wnt also coordinates the formation of neural circuits on multiple levels such as transcription, cell cycle, and asymmetric cell division. Here we review the latest findings addressing the role of canonical Wnt/beta-catenin signaling during developmental and adult neurogenesis; exploring the connection of in vivo data to the recently described Wnt-driven asymmetric stem cell division in vitro. Understanding how Wnt orchestrates these processes in a spatiotemporal manner during corticogenesis will be of crucial importance for the development of new strategies to regenerate neuronal circuits. PMID- 24488704 TI - Case study interpretation--Fort Lauderdale: Case 1. PMID- 24488702 TI - An update on medication management of behavioral disorders in autism. AB - Autism spectrum disorder is often comorbid with behavioral disturbances such as irritability, aggression and hyperactivity. Throughout the mid 2000s, several large-scale controlled clinical trials were published leading to the approval of two medications (aripiprazole and risperidone) for treatment of irritability in this condition. This review serves as an update regarding new research findings regarding psychopharmacology for children and adolescents with ASD. In summary, the past five years have yielded no further approved medications with ASD as a primary indication. Important new research results include 1) long-term safety and efficacy data (52 week) regarding treatment with aripiprazole for irritability, 2) consensus regarding potential harm from SSRIs for treatment of repetitive behaviors in children/ adolescents with ASD, 3) a randomized controlled trial showing modest benefits from atomoxetine on hyperactivity, 4) many novel agents currently under investigation. PMID- 24488705 TI - Clinical impact of "true whole-body" (18)F-FDG PET/CT: lesion frequency and added benefit in distal lower extremities. AB - OBJECTIVES: The purpose of this study was to evaluate the lesion frequency and incremental added benefit with "true whole-body" (18)F-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) of distal lower extremities. We compared this field of view with the typical whole-body view, from head to upper thighs, in numerous patients with known or suspected malignancy. METHODS: True whole-body (18)F-FDG PET/CT, from the top of the head to the bottom of the feet, was performed on 4574 consecutively registered patients with known or suspected malignancy. Using a variable sampling method, the PET images of head and torso were acquired for 90 s per bed position, and the images of lower extremities were acquired for 30 s per position, thus requiring between 22 and 24 min of emission scanning per patient. A log was maintained to record cases of abnormal findings in distal lower extremities outside the typical whole-body field of view. Suspected malignant lesions in distal lower extremities were verified by correlation with pathological findings and clinical follow-up. RESULTS: Abnormal findings in distal lower extremities were found in 647 (14.1 %; 95 % CI 13.1-15.2 %) of 4574 examinations. Increased FDG uptake was found in 559 examinations (12.2 %; 95 % CI 11.3-13.2 %). Lesions appeared malignant or equivocal in 67 examinations (1.5 %; 95 % CI 1.1-1.8 %) on the PET images. In 42 (0.9 %; 95 % CI 0.6-1.2 %) of 4574 examinations, these lesions were pathologically or clinically proven to be malignant. Detection of these malignancies resulted in changing clinical management in 21 (50 %) of 42 examinations. Definitive benign lesions were found in 492 examinations (10.7 %; 95 % CI 9.9-11.7 %) on the PET images. Abnormal findings were noted in 90 examinations (2.0 %; 95 % CI 1.6-2.4 %) consisting of 88 benign and 2 malignancies on the CT images alone. CONCLUSION: True whole-body (18)F-FDG PET/CT was not of high yield and appears to offer little additional benefit, as to detection of additional metastases and involvement, but it may affect clinical management in patients with known or suspected malignancy. PMID- 24488706 TI - Asymmetric total synthesis of onoseriolide, bolivianine, and isobolivianine. AB - In this article, we describe our efforts on the total synthesis of bolivianine (1) and isobolivianine (2), involving the synthesis of onoseriolide (3). The first generation synthesis of bolivianine was completed in 21 steps by following a chiral resolution strategy. Based on the potential biogenetic relationship between bolivianine (1), onoseriolide (3), and beta-(E)-ocimene (8), the second generation synthesis of bolivianine was biomimetically achieved from commercially available (+)-verbenone in 14 steps. The improved total synthesis features an unprecedented palladium-catalyzed intramolecular cyclopropanation through an allylic metal carbene, for the construction of the ABC tricyclic system, and a Diels-Alder/intramolecular hetero-Diels-Alder (DA/IMHDA) cascade for installation of the EFG tricyclic skeleton with the correct stereochemistry. Transformation from bolivianine to isobolivianine was facilitated in the presence of acid. The biosynthetic mechanism and the excellent regio- and endo selectivities in the cascade are well supported by theoretical chemistry based on the DFT calculations. PMID- 24488708 TI - Inflamed benign tumors of the parotid gland: diagnostic pitfalls from a potentially misleading entity. AB - BACKGROUND: The purpose of this study was to evaluate our experience in the diagnostic approach to inflamed benign tumors of the parotid gland at a single tertiary center. METHODS: A retrospective evaluation was carried out for all patients with signs of inflammation in the parotid gland on the ground of a benign parotid tumor, as confirmed by permanent histology. RESULTS: Sixteen patients were detected for our study. Histopathologic examination confirmed cystadenolymphoma in 11 cases (with metaplastic changes in 2 cases), 2 pleomorphic adenomas, 2 monomorphic adenomas, and 1 oncocytic cystadenoma. Diverse clinical signs (inflammation signs, facial palsy), ultrasound and MRI findings (poorly defined lesion margins), and the presence of squamous metaplastic changes on cytology often raised the suspicion of parotid malignancy or abscess. CONCLUSION: In most cases, a high suspicion index combined with close monitoring of the patient may allow prompt and successful diagnosis and therapy. PMID- 24488707 TI - Neuroimaging the epileptogenic process. AB - Epilepsy is one of the most common chronic neurological conditions worldwide. Anti-epileptic drugs (AEDs) can suppress seizures, but do not affect the underlying epileptic state, and many epilepsy patients are unable to attain seizure control with AEDs. To cure or prevent epilepsy, disease-modifying interventions that inhibit or reverse the disease process of epileptogenesis must be developed. A major limitation in the development and implementation of such an intervention is the current poor understanding, and the lack of reliable biomarkers, of the epileptogenic process. Neuroimaging represents a non-invasive medical and research tool with the ability to identify early pathophysiological changes involved in epileptogenesis, monitor disease progression, and assess the effectiveness of possible therapies. Here we will provide an overview of studies conducted in animal models and in patients with epilepsy that have utilized various neuroimaging modalities to investigate epileptogenesis. PMID- 24488709 TI - In vitro response to functionalized self-assembled peptide scaffolds for three dimensional cell culture. AB - Nanomaterials are rich in potential, particularly for the formation of scaffolds that mimic the landscape of the host environment of the cell. This niche arises from the spatial organization of a series of biochemical and biomechanical signals. Self-assembling peptides have emerged as an important tool in the development of functional (bio-)nanomaterials; these simple, easily synthesized subunits form structures which present the properties of these larger, more complex systems. Scaffolds based upon these nanofibrous matrices are promising materials for regenerative medicine as part of a new methodology in scaffold design where a "bottom-up" approach is used in order to simulate the native cellular milieu. Importantly, SAPs hold the potential to be bioactive through the presentation of biochemical and biomechanical signals in a context similar to the natural extracellular matrix, making them ideal targets for providing structural and chemical support in a cellular context. Here, we discuss a new methodology for the presentation of biologically relevant epitopes through their effective presentation on the surface of the nanofibers. Here, we demonstrate that these signals have a direct effect on the viability of cells within a three-dimensional matrix as compared with an unfunctionalized, yet mechanically and morphologically similar system. PMID- 24488710 TI - Fourier transform EPR spectroscopy of trityl radicals for multifunctional assessment of chemical microenvironment. AB - Pulse techniques in electron paramagnetic resonance (EPR) allow for a reduction in measurement times and increase in sensitivity but require the synthesis of paramagnetic probes with long relaxation times. Here it is shown that the recently synthesized phosphonated trityl radical possesses long relaxation times that are sensitive to probe the microenvironment, such as oxygenation and acidity of an aqueous solution. In principle, application of Fourier transform EPR (FT EPR) spectroscopy makes it possible to acquire the entire EPR spectrum of the trityl probe and assess these microenvironmental parameters within a few microseconds. The performed analysis of the FT-EPR spectra takes into consideration oxygen-, proton-, buffer-, and concentration-induced contributions to the spectral shape, therefore enabling quantitative and discriminative assessment of pH, pO2, and concentrations of the probe and inorganic phosphate. PMID- 24488715 TI - Retinal stem/progenitor cells in the ciliary marginal zone complete retinal regeneration: a study of retinal regeneration in a novel animal model. AB - Our research group has extensively studied retinal regeneration in adult Xenopus laevis. However, X. laevis does not represent a suitable model for multigenerational genetics and genomic approaches. Instead, Xenopus tropicalis is considered as the ideal model for these studies, although little is known about retinal regeneration in X. tropicalis. In the present study, we showed that a complete retina regenerates at approximately 30 days after whole retinal removal. The regenerating retina was derived from the stem/progenitor cells in the ciliary marginal zone (CMZ), indicating a novel mode of vertebrate retinal regeneration, which has not been previously reported. In a previous study, we showed that in X. laevis, retinal regeneration occurs primarily through the transdifferentiation of retinal pigmented epithelial (RPE) cells. RPE cells migrate to the retinal vascular membrane and reform a new epithelium, which then differentiates into the retina. In X. tropicalis, RPE cells also migrated to the vascular membrane, but transdifferentiation was not evident. Using two tissue culture models of RPE tissues, it was shown that in X. laevis RPE culture neuronal differentiation and reconstruction of the retinal three-dimensional (3-D) structure were clearly observed, while in X. tropicalis RPE culture neither betaIII tubulin-positive cells nor 3-D retinal structure were seen. These results indicate that the two Xenopus species are excellent models to clarify the cellular and molecular mechanisms of retinal regeneration, as these animals have contrasting modes of regeneration; one mode primarily involves RPE cells and the other mode involves stem/progenitor cells in the CMZ. PMID- 24488716 TI - Fast quantification of S-adenosyl-L-methionine in dietary health products utilizing reversed-phase high-performance liquid chromatography: teaching an old method new tricks. AB - S-adenosyl-L-methionine is a ubiquitous methyl donor in living bodies. It is known to participate in several physiological processes including homocysteine metabolism and glutathione synthesis regulation, and cellular antioxidant mechanism. S-adenosyl-L-methionine containing dietary supplements has been prescribed recently for the treatment of depression, arthritis, and liver diseases with encouraging results. The development of an efficient analytical protocol for S-adenosyl-L-methionine containing dietary supplements is crucial for maintaining product quality and consumer health. In this study, the S adenosyl-L-methionine content of several yeast products and commercial healthy food product samples was quantitatively analyzed utilizing HPLC. The chromatographic separation was achieved on a reversed-phase column and 2 % acetonitrile with a 98 % ammonium-acetate mobile phase under pH 4.5, with a flow rate of 1.0 mL/min. The wavelength used for detection with the UV detector was 254 nm. The total analysis time was short and the target compound showed a well defined peak. The correlation coefficient of the regression curve showed good linearity and sensitivity with r = 0.999. All experiments were replicated five times and the relative standard deviations as well as the relative error values were all less than 3 %. Moreover, the achieved precision and accuracy values were high with 97.4-100.9 % recovery. Qualitative determination of S-adenosyl-L methionine in the tested products was achieved using NMR and LC-MS techniques. The developed protocol is robust, fast, and suitable for the quality control analysis of yeast and commercial S-adenosyl-L-methionine products. PMID- 24488717 TI - Sphaeralcic acid and tomentin, anti-inflammatory compounds produced in cell suspension cultures of Sphaeralcea angustifolia. AB - Sphaeralcea angustifolia, an endangered plant species in Mexico, is employed to treat inflammatory processes and as a wound healing remedy. Scopoletin (1) was reported as one of the main bioactive compounds in this plant. Here, we isolated and identified compounds with anti-inflammatory properties from the suspension cultured cells of S. angustifolia. The CH2Cl2 : CH3OH extract of the cells exhibited anti-inflammatory properties in acute inflammation models. Two compounds were isolated, 5-hydroxy-6,7-dimethoxycoumarin, named tomentin (2), and 2-(1,8-dihydroxy-4-isopropyl-6-methyl-7-methoxy)-naphthoic acid, denominated as sphaeralcic acid (3). Their structures were determined by spectroscopic and spectrometric analyses. The anti-inflammatory effects of both compounds were also evaluated. At a dose of 45 mg/kg, compound 2 inhibited the formation of lambda carrageenan footpad edema at 58 %, and compound 3 at 66 %. Local application of compound 2 (225 mM per ear) or 3 (174 mM per ear) inhibited the phorbol ester induced auricular edema formation by 57 % or 86 %, respectively. The effect of compound 3 was dose-dependent and the ED50 was 93 mM. PMID- 24488718 TI - Inhibition of bacterial quorum sensing and biofilm formation by extracts of neotropical rainforest plants. AB - Bacterial biofilms are responsible for many persistent infections by many clinically relevant pathogens such as Staphylococcus aureus and Pseudomonas aeruginosa. Biofilms are much more resistant to conventional antibiotics than their planktonic counterparts. Quorum sensing, an intercellular communication system, controls pathogenesis and biofilm formation in most bacterial species. Quorum sensing provides an important pharmacological target since its inhibition does not provide a selective pressure for resistance. In this study, we investigated the quorum sensing and biofilm inhibitory activities of 126 plant extracts from 71 species collected from neotropical rainforests in Costa Rica. Quorum sensing and biofilm interference were assessed using a modified disc diffusion bioassay with Chromobacterium violaceum ATCC 12,472 and a spectrophotometric bioassay with Pseudomonas aeruginosa PA14, respectively. Species with significant anti-quorum sensing and/or anti-biofilm activities belonged to the Meliaceae, Melastomataceae, Lepidobotryaceae, Sapindaceae, and Simaroubaceae families. IC50 values ranged from 45 to 266 ug/mL. Extracts of these active species could lead to future development of botanical treatments for biofilm-associated infections. PMID- 24488719 TI - Acaricidal activities against house dust mites of spearmint oil and its constituents. AB - The aim of this study was to evaluate the acaricidal activities of spearmint oil and carvone derivatives against house dust mites using contact and fumigant toxicity bioassays to replace benzyl benzoate as a synthetic acaricide. Based on the LD50 values, the contact toxicity bioassay revealed that dihydrocarvone (0.95 and 0.88 ug/cm2) was 7.7 and 6.8 times more toxic than benzyl benzoate (7.33 and 6.01 ug/cm2) against Dermatophagoides farinae and Dermatophagoides pteronyssinus, respectively, followed by carvone (3.78 and 3.23 ug/cm2), spearmint oil (5.16 and 4.64 ug/cm2), carveol (6.00 and 5.80 ug/cm2), and dihydrocarveol (8.23 and 7.10 ug/cm2). Results of the fumigant toxicity bioassay showed that dihydrocarvone (2.73 and 2.16 ug/cm2) was approximately 4.0 and 4.8 times more effective than benzyl benzoate (11.00 and 10.27 ug/cm2), followed by carvone (6.63 and 5.78 ug/cm2), carveol (7.58 and 7.24 ug/cm2), spearmint oil (9.55 and 8.10 ug/cm2), and dihydrocarveol (9.79 and 8.14 ug/cm2). Taken together, spearmint oil and carvone derivatives are a likely viable alternative to synthetic acaricides for managing house dust mites. PMID- 24488720 TI - Ferulic acid enhances the chemical and biological properties of astragali radix: a stimulator for danggui buxue tang, an ancient Chinese herbal decoction. AB - Danggui buxue tang, an ancient formula composed of astragali radix and Angelicae sinensis radix, has been used for treating menopausal irregularity in women for more than 800 years in China. In danggui buxue tang, the complete functions of astragali radix require the assistance of Angelicae sinensis radix, and both herbs have to work harmoniously in order to achieve the maximal therapeutic purposes. In order to analyze the relationship of the two herbs, the role of ferulic acid, a major chemical within Angelicae sinensis radix, in chemical and biological properties of astragali radix was determined. Using ferulic acid in the extraction of astragali radix, the amounts of astragaloside IV, calycosin, and formononetin were increased in the final extract; however, the astragali radix polysaccharide showed a minor increase. The chemical-enriched astragali radix extract showed robust induction in osteogenic and estrogenic activities in cultured osteosarcoma MG-63 and breast MCF-7 cells. However, ferulic acid itself did not show such biological responses. The current results strongly suggest that Angelicae sinensis radix-derived ferulic acid is a positive regulator for danggui buxue tang, which enhanced the solubilities of active ingredients derived from astragali radix, and which therefore increased the biological efficacies of danggui buxue tang. PMID- 24488722 TI - On the spot ethical decision-making in CBRN (chemical, biological, radiological or nuclear event) response: approaches to on the spot ethical decision-making for first responders to large-scale chemical incidents. AB - First responders to chemical, biological, radiological, or nuclear (CBRN) events face decisions having significant human consequences. Some operational decisions are supported by standard operating procedures, yet these may not suffice for ethical decisions. Responders will be forced to weigh their options, factoring-in contextual peculiarities; they will require guidance on how they can approach novel (indeed unique) ethical problems: they need strategies for "on the spot" ethical decision making. The primary aim of this paper is to examine how first responders should approach on the spot ethical decision-making amid the stress and uncertainty of a CBRN event. Drawing on the long-term professional CBRN experience of one of the authors, this paper sets out a series of practical ethical dilemmas potentially arising in the context of a large-scale chemical incident. We propose a broadly consequentialist approach to on the spot ethical decision-making, but one which incorporates ethical values and rights as "side constraints". PMID- 24488721 TI - Tideglusib reduces progression of brain atrophy in progressive supranuclear palsy in a randomized trial. AB - It is believed that glycogen synthase kinase-3 hyperphosphorylates tau protein in progressive supranuclear palsy (PSP). The Tau Restoration on PSP (TAUROS) trial assessed the glycogen synthase kinase-3 inhibitor tideglusib as potential treatment. For the magnetic resonance imaging (MRI) substudy reported here, we assessed the progression of brain atrophy. TAUROS was a multinational, phase 2, double-blind, placebo-controlled trial in patients with mild-to-moderate PSP who were treated with oral tideglusib (600 mg or 800 mg daily) or with placebo for 1 year. A subset of patients underwent baseline and 52-week MRI. Automated, observer-independent, atlas-based, and mask-based volumetry was done on high resolution, T1-weighted, three-dimensional data. For primary outcomes, progression of atrophy was compared both globally (brain, cerebrum) and regionally (third ventricle, midbrain, pons) between the active and placebo groups (Bonferroni correction). For secondary outcomes, 15 additional brain structures were explored (Benjamini & Yekutieli correction). In total, MRIs from 37 patient were studied (placebo group, N = 9; tideglusib 600 mg group, N = 19; tideglusib 800 mg group, N = 9). The groups compared well in their demographic characteristics. Clinical results showed no effect of tideglusib over placebo. Progression of atrophy was significantly lower in the active group than in the placebo group for the brain (mean +/- standard error of the mean: -1.3% +/- 1.4% vs. -3.1% +/- 2.3%, respectively), cerebrum (-1.3% +/- 1.5% vs. -3.2% +/- 2.1%, respectively), parietal lobe (-1.6% +/- 1.9% vs. -4.1% +/- 3.0%, respectively), and occipital lobe (-0.3% +/- 1.8% vs. -2.7% +/- 3.2%, respectively). A trend toward reduced atrophy also was observed in the frontal lobe, hippocampus, caudate nucleus, midbrain, and brainstem. In patients with PSP, tideglusib reduced the progression of atrophy in the whole brain, particularly in the parietal and occipital lobes. PMID- 24488723 TI - Penetrating the omerta of predatory publishing: the romanian connection. AB - Not so long ago, a well institutionalized predatory journal exposed itself by publishing a hoax article that blew the whistle for its devastating influence on the academic affairs of a small country. This paper puts that experiment in context, gives all the important details and analyzes the results. The experiment was inspired by well-known cases of scientific activism and is in line with recent efforts against predatory publishers. The paper presents the evidence in detail and uses it to analyze the publishing practices of the offending journal, using established criteria for assessing predatory publications. That journal somehow acquired an impact factor and charged money to publish thousands of "scientific" papers without any peer review. Since the impact factor is the major official evaluation criteria for scientists in Serbia, these papers disturbed the whole academic evaluation process. Credentials acquired by those publications form a strong obstacle to institutionalized reasoned efforts against such practices. This case warns the whole community of the long lasting damage when journals with low publishing ethics are taken seriously. PMID- 24488724 TI - The Swedish Research Council's definition of 'scientific misconduct': a critique. AB - There is no consensus over the proper definition of 'scientific misconduct.' There are differences in opinion not only between countries but also between research institutions in the same country. This is unfortunate. Without a widely accepted definition it is difficult for scientists to adjust to new research milieux. This might hamper scientific innovation and make cooperation difficult. Furthermore, due to the potentially damaging consequences it is important to combat misconduct. But how frequent is it and what measures are efficient? Without an appropriate definition there are no interesting answers to these questions. In order to achieve a high degree of consensus and to foster research integrity, the international dialogue over the proper definition of 'scientific misconduct' must be on going. Yet, the scientific community should not end up with the definition suggested by the Swedish Research Council. The definition the council advocates does not satisfy the ordinary language condition. That is, the definition is not consistent with how 'scientific misconduct' is used by scientists. I will show that this is due to the fact that it refers to false results. I generalise this and argue that no adequate definition of 'scientific misconduct' makes such a reference. PMID- 24488725 TI - Case study interpretation--Fort Lauderdale: Case 2. PMID- 24488726 TI - Effect of synergists on organic pigment particle charging in apolar media. AB - The current work investigates the apolar charging behavior of organic pigment particles and the role that synergists play in regard to particle charging. Organic pigments are often used in apolar paints, inks, and most recently electrostatic lithography. For electrolithography to work, the particles must be both stable and possess the correct polarity and magnitude of charge. It is therefore important to better understand the charging behavior and potential charging mechanisms of these particles that have received little or no attention in the literature. Unfortunately, these already complex systems are further complicated by the fact that the stability of organic pigments is often improved through the use of synergists. Synergists are designed to enhance the adsorption of steric stabilizers to the particles. However, their effect on particle charging has not been previously published. In this study, the particle zeta potential is determined for apolar dispersions of magenta and cyan particles in heptane (with and without synergist present). The particles are dispersed with three different surfactants commonly used in apolar charging studies: Span 80, Aerosol-OT, and OLOA 11000. Acid-base interactions appear to play an important role, particularly for cyan. However, due to the complexity of these systems, any general rule must be applied with caution as the particle, surfactant, and synergist chemistry all determine the nature of the particle charge. PMID- 24488728 TI - What makes a great resident? The programme director perspective. AB - A career in orthopedic surgery in the United Kingdom is highly competitive. Great residents are trainees who understand that ultimately, they are responsible for their own training. They need to work with their Training Program Director to plan their career, to develop as surgeons, to reflect on their performance and any feedback they receive, be flexible, and plan ahead. There is competition but it is fair for everyone and the great resident will excel within this environment and will be successful in the long term. PMID- 24488727 TI - Highly enantioselective extraction of underivatized amino acids by the uryl pendant hydroxyphenyl-binol ketone. AB - The hydroxyphenyl chiral ketone, (S)-3, reacts with D-amino acids bearing hydrophobic side chains exclusively over the L-amino acids in a two-phase liquid liquid extraction, and thus acts as a highly stereoselective extractant. Calculations for the energy-minimized structures for the imine diastereomers and the comparison of the selectivities with other phenyl ketones, (S)-4 and (S)-5, demonstrate that the hydrogen bond between the carboxylate group and the phenolic hydroxyl group contributes to the remarkable enantioselectivities. The multiple hydrogen bonds present in the imine of (S)-3 reinforce the rigidity, and results in the difference between the stabilities of the imine diastereomers. The imine could be hydrolyzed in methanolic HCl solution, and the extraction of the evaporated residues revived the organic layer of (S)-3, which could enter into a new extractive cycle and leaves the D-amino acid with enantiomeric excess (ee) values of over 97 % in the aqueous layer. PMID- 24488732 TI - Biosynthesis of the insecticidal xenocyloins in Xenorhabdus bovienii. AB - The biosynthesis gene cluster for the production of xenocyloins was identified in the entomopathogenic bacterium Xenorhabdus bovienii SS-2004, and their biosynthesis was elucidated by heterologous expression and in vitro characterization of the enzymes. XclA is an S-selective ThDP-dependent acyloin like condensation enzyme, and XclB and XclC are examples of the still-rare acylating ketosynthases that catalyze the acylation of the XclA-derived initial xenocyloins with acetyl-, propionyl-, or malonyl-CoA, thereby resulting in the formation of further xenocyloin derivatives. All xenocyloins were produced mainly by the more virulent primary variant of X. bovienii and showed activity against insect hemocytes thus contributing to the overall virulence of X. bovienii against insects. PMID- 24488729 TI - Improved chemical synthesis of hydrophobic Abeta peptides using addition of C terminal lysines later removed by carboxypeptidase B. AB - Many amyloidogenic peptides are highly hydrophobic, introducing significant challenges to obtaining high quality peptides by chemical synthesis. For example, while good yield and purity can be obtained in the solid-phase synthesis of the Alzheimer's plaque peptide Abeta40, addition of a C-terminal Ile-Ala sequence to generate the more toxic Abeta42 molecule creates a much more difficult synthesis resulting in low yields and purities. We describe here a new method that significantly improves the Fmoc solid-phase synthesis of Abeta peptides. In our method, Lys residues are linked to the desired peptide's C-terminus through standard peptide bonds during the synthesis. These Lys residues are then removed post-purification using immobilized carboxypeptidase B (CPB). With this method we obtained both Abeta42 and Abeta46 of superior quality that, for Abeta42, rivals that obtained by recombinant expression. Intriguingly, the method appears to provide independent beneficial effects on both the total synthetic yield and on purification yield and final purity. Reversible Lys addition with CPB removal should be a generally useful method for making hydrophobic peptides that is applicable to any sequence not ending in Arg or Lys. As expected from the additional hydrophobicity of Abeta46, which is extended from the sequence Abeta42 by a C-terminal Thr-Val-Ile-Val sequence, this peptide makes typical amyloid at rates significantly faster than for Abeta42 or Abeta40. The enhanced amyloidogenicity of Abeta46 suggests that, even though it is present in relatively low amounts in the human brain, it could play a significant role in helping to initiate Abeta amyloid formation. PMID- 24488733 TI - Pediatric clinical practice guidelines for acute procedural pain: a systematic review. AB - BACKGROUND: Procedural pain assessment and management have been extensively studied through multiple research studies over the past decade. Results of this research have been included in numerous pediatric pain practice guidelines. OBJECTIVE: To systematically review the quality of existing practice guidelines for acute procedural pain in children and provide recommendations for their use. METHODS: A systematic search was conducted on Medline, Embase, CINAHL, PsycINFO, and Scopus from 2000 to July 2013. A gray literature search was also conducted through the Translating Research Into Practice database, Guidelines International Network database, and National Guideline Clearinghouse. Four reviewers rated relevant guidelines using the Appraisal of Guidelines for Research and Evaluation (AGREE) II Instrument. Screening of guidelines, assessment of methodological quality, and data abstraction were conducted by 2 pairs of raters. Disagreements in overall assessments were resolved through consensus. RESULTS: Eighteen guidelines from 4930 retrieved abstracts were included in this study. Based on the AGREE II domains, the guidelines generally scored high in the scope and purpose and clarity of presentation areas. Information on the rigor of guideline development, applicability, and editorial independence were specified infrequently. Four of the 18 guidelines provided tools to help clinicians apply the recommendations in practice settings; 5 were recommended for use in clinical settings, and the remaining 13 were recommended for use with modification. CONCLUSIONS: Despite the increasing availability of clinical practice guidelines for procedural pain in children, the majority are of average quality. More transparency and comprehensive reporting are needed for the guideline development process. PMID- 24488734 TI - Asymptomatic viral gastrointestinal infection: the missing link? AB - We present the case of an 8-month-old boy who presented with apparent life threatening events later characterized as seizures in clusters. A total of 14 apneic episodes were observed within 24 hours before loading the patient with phenobarbital at which point the seizures stopped. There was no obvious explanation for his seizures. EEG revealed midline interictal discharges; MRI head was normal; and all other investigations were normal. The patient's stool was sent for virology with the clinical suspicion of benign infantile seizures associated with mild gastroenteritis (BISMG) despite lack of gastrointestinal symptoms. A small round virus was found. His clinical course followed the same progression as typical BISMG. This begs the question whether it is possible for virus in the stool to cause an asymptomatic gastrointestinal infection with its only clinical manifestation as seizures. We conclude that it may be possible for BISMG to present without gastrointestinal symptoms. As well, BISMG may be an unrecognized cause of apparent life-threatening events and should be considered in the differential diagnosis. PMID- 24488735 TI - Sexual orientation and anabolic-androgenic steroids in U.S. adolescent boys. AB - OBJECTIVES: We compared the lifetime prevalence of anabolic-androgenic steroid (AAS) misuse among sexual minority versus heterosexual U.S. adolescent boys, and secondarily, sought to explore possible intermediate variables that may explain prevalence differences. METHODS: Participants were 17,250 adolescent boys taken from a pooled data set of the 14 jurisdictions from the 2005 and 2007 Youth Risk Behavior Surveys that assessed sexual orientation. Data were analyzed for overall prevalence of AAS misuse and possible intermediary risk factors. RESULTS: Sexual minority adolescent boys were at an increased odds of 5.8 (95% confidence interval 4.1-8.2) to report a lifetime prevalence of AAS (21% vs. 4%) compared with their heterosexual counterparts, P < .001. Exploratory analyses suggested that increased depressive symptoms/suicidality, victimization, and substance use contributed to this disparity. CONCLUSIONS: This is the first known study to test and find substantial health disparities in the prevalence of AAS misuse as a function of sexual orientation. Prevention and intervention efforts are needed for sexual minority adolescent boys. PMID- 24488736 TI - Parental underestimates of child weight: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: Parental perceptions of their children's weight play an important role in obesity prevention and treatment. The objective of this study was to determine the proportion of parents worldwide who underestimate their children's weight and moderators of such misperceptions. METHODS: Original studies published to January 2013 were chosen through literature searches in PUBMED, PSYCHINFO, and CINAHL databases. References of retrieved articles were also searched for relevant studies. Studies were published in English and assessed parental perceptions of children's weight and then compared perceptions to recognized standards for defining overweight based on anthropometric measures. Data were extracted on study-level constructs, child- and parent-characteristics, procedural characteristics, and parental underestimates separately for normal weight and overweight/obese samples. Pooled effect sizes were calculated using random-effects models and adjusted for publication bias. Moderators were explored using mixed-effect models. RESULTS: A total of 69 articles (representing 78 samples; n = 15,791) were included in the overweight/obese meta-analysis. Adjusted effect sizes revealed that 50.7% (95% confidence interval 31.1%-70.2%) of parents underestimate their overweight/obese children's weight. Significant moderators of this effect included child's age and BMI. A total of 52 articles (representing 59 samples; n = 64,895) were included in the normal-weight meta analysis. Pooled effect sizes indicated that 14.3% (95% confidence interval 11.7% 17.4%) of parents underestimate their children's normal-weight status. Significant moderators of this effect included child gender, parent weight, and the method (visual versus nonvisual) in which perception was assessed. CONCLUSIONS: Half of parents underestimated their children's overweight/obese status and a significant minority underestimated children's normal weight. Pediatricians are well positioned to make efforts to remedy parental underestimates and promote adoption of healthy habits. PMID- 24488737 TI - Sporadic fatal insomnia in an adolescent. AB - The occurrence of sporadic prion disease among adolescents is extremely rare. A prion disease was confirmed in an adolescent with disease onset at 13 years of age. Genetic, neuropathologic, and biochemical analyses of the patient's autopsy brain tissue were consistent with sporadic fatal insomnia, a type of sporadic prion disease. There was no evidence of an environmental source of infection, and this patient represents the youngest documented case of sporadic prion disease. Although rare, a prion disease diagnosis should not be discounted in adolescents exhibiting neurologic signs. Brain tissue testing is necessary for disease confirmation and is particularly beneficial in cases with an unusual clinical presentation. PMID- 24488740 TI - Pediatric oncology drug shortages: a multifaceted problem. PMID- 24488739 TI - Reducing unnecessary antibiotics prescribed to children: what next? PMID- 24488738 TI - Dietary sodium, adiposity, and inflammation in healthy adolescents. AB - OBJECTIVES: To determine the relationships of sodium intake with adiposity and inflammation in healthy adolescents. METHODS: A cross-sectional study involved 766 healthy white and African American adolescents aged 14 to 18 years. Dietary sodium intake was estimated by 7-day 24-hour dietary recall. Percent body fat was measured by dual-energy x-ray absorptiometry. Subcutaneous abdominal adipose tissue and visceral adipose tissue were assessed using magnetic resonance imaging. Fasting blood samples were measured for leptin, adiponectin, C-reactive protein, tumor necrosis factor-alpha, and intercellular adhesion molecule-1. RESULTS: The average sodium intake was 3280 mg/day. Ninety-seven percent of our adolescents exceeded the American Heart Association recommendation for sodium intake. Multiple linear regressions revealed that dietary sodium intake was independently associated with body weight (beta = 0.23), BMI (beta = 0.23), waist circumference (beta = 0.23), percent body fat (beta = 0.17), fat mass (beta = 0.23), subcutaneous abdominal adipose tissue (beta = 0.25), leptin (beta = 0.20), and tumor necrosis factor-alpha (beta = 0.61; all Ps < .05). No relation was found between dietary sodium intake and visceral adipose tissue, skinfold thickness, adiponectin, C-reactive protein, or intercellular adhesion molecule-1. All the significant associations persisted after correction for multiple testing (all false discovery rates < 0.05). CONCLUSIONS: The mean sodium consumption of our adolescents is as high as that of adults and more than twice the daily intake recommended by the American Heart Association. High sodium intake is positively associated with adiposity and inflammation independent of total energy intake and sugar-sweetened soft drink consumption. PMID- 24488741 TI - Chemotherapy drug shortages in pediatric oncology: a consensus statement. AB - Shortages of essential drugs, including critical chemotherapy drugs, have become commonplace. Drug shortages cost significant time and financial resources, lead to adverse patient outcomes, delay clinical trials, and pose significant ethical challenges. Pediatric oncology is particularly susceptible to drug shortages, presenting an opportunity to examine these ethical issues and provide recommendations for preventing and alleviating shortages. We convened the Working Group on Chemotherapy Drug Shortages in Pediatric Oncology (WG) and developed consensus on the core ethical values and practical actions necessary for a coordinated response to the problem of shortages by institutions, agencies, and other stakeholders. The interdisciplinary and multiinstitutional WG included practicing pediatric hematologist-oncologists, nurses, hospital pharmacists, bioethicists, experts in emergency management and public policy, legal scholars, patient/family advocates, and leaders of relevant professional societies and organizations. The WG endorsed 2 core ethical values: maximizing the potential benefits of effective drugs and ensuring equitable access. From these, we developed 6 recommendations: (1) supporting national polices to prevent shortages, (2) optimizing use of drug supplies, (3) giving equal priority to evidence-based uses of drugs whether they occur within or outside clinical trials, (4) developing an improved clearinghouse for sharing drug shortage information, (5) exploring the sharing of drug supplies among institutions, and (6) developing proactive stakeholder engagement strategies to facilitate prevention and management of shortages. Each recommendation includes an ethical rationale, action items, and barriers that must be overcome. Implemented together, they provide a blueprint for effective and ethical management of drug shortages in pediatric oncology and beyond. PMID- 24488742 TI - Symmetrical and asymmetrical growth restriction in preterm-born children. AB - OBJECTIVE: To determine how symmetric (proportionate; SGR) and asymmetric (disproportionate; AGR) growth restriction influence growth and development in preterms from birth to 4 years. METHODS: This community-based cohort study of 810 children comprised 86 SGR, 61 AGR, and 663 non-growth restricted (NGR) preterms, born in 2002 and 2003. Symmetrical growth restriction was defined as a birth weight below the 16th percentile (-1 SD) compared with full-terms and a head circumference (HC) z score not exceeding the infant's birth weight z score by >1 SD. Asymmetric growth restriction was defined as a HC z score exceeding that for by >1 SD as a proxy of brain sparing. Developmental delay was assessed by the Ages and Stages Questionnaire at 4 years. RESULTS: Longitudinal gains in weight and height were similar for SGR and AGR children and less compared with NGR children. At age 4, z scores for weight were -1.1 for SGR and -0.7 for AGR children vs -0.3 for NGR children. z scores for height were -0.8 and -0.5 vs. 0.2. HC gain were 2 cm more in SGR, but at 1 year, they were -0.2 vs. 0.2 (AGR) and 0.1 (NGR). Developmental delay increased with odds ratios of 2.5 (95% confidence interval 1.1-6.0) for SGR and 2.1 (95% confidence interval 0.7-5.9) for AGR. CONCLUSIONS: Weight and height gains were similar for AGR and SGR children but poorer compared with NGR children. SGR children caught up on HC. Developmental delay was more likely in growth-restricted preterms independent of HC at birth. PMID- 24488743 TI - Indiscriminate behaviors in previously institutionalized young children. AB - OBJECTIVE: This study included 54-month-old children with a history of institutional care. Our goal was to: (1) examine differences in indiscriminate social behaviors in children with a history of institutional care compared with home-reared children; (2) test whether foster care reduces indiscriminate social behaviors in a randomized controlled trial; and (3) examine early predictors of indiscriminate behaviors. METHODS: Participants were 58 children with a history of institutional care and 31 never-institutionalized control (NIG) subjects enrolled in a randomized controlled trial of foster care for institutional care, assessed from toddlerhood to 54 months. Indiscriminate social behaviors were measured naturalistically by using the Stranger at the Door procedure. RESULTS: In the Stranger at the Door procedure, children with a history of institutional care left with a stranger at higher rates than NIG subjects (33% vs. 3.5%; P < .001). Children in the care as usual group left more than NIG subjects (41.9% vs. 3.6%; P <= .001). The differences between the foster care group (24.1%) and the care as usual group and between foster care group and NIG were not significant. In a logistic regression, early disorganized attachment behaviors, baseline developmental quotient, and caregiving quality after randomization contributed to variance at 54 months. In the same analysis using only children with a history of institutional care, only disorganized attachment contributed significantly to 54 month indiscriminate social behaviors (Exp[B] = 1.6 [95% confidence interval: 1.1 2.5]). CONCLUSIONS: Observed socially indiscriminate behaviors at 54 months were associated with prolonged exposure to institutional care. Young children raised in conditions of deprivation who fail to develop organized attachments as toddlers are at increased risk for subsequent indiscriminate behaviors. PMID- 24488744 TI - Recent trends in outpatient antibiotic use in children. AB - OBJECTIVE: The goal of this study was to determine changes in antibiotic dispensing rates among children in 3 health plans located in New England [A], the Mountain West [B], and the Midwest [C] regions of the United States. METHODS: Pharmacy and outpatient claims from September 2000 to August 2010 were used to calculate rates of antibiotic dispensing per person-year for children aged 3 months to 18 years. Differences in rates by year, diagnosis, and health plan were tested by using Poisson regression. The data were analyzed to determine whether there was a change in the rate of decline over time. RESULTS: Antibiotic use in the 3- to <24-month age group varied at baseline according to health plan (A: 2.27, B: 1.40, C: 2.23 antibiotics per person-year; P < .001). The downward trend in antibiotic dispensing slowed, stabilized, or reversed during this 10-year period. In the 3- to <24-month age group, we observed 5.0%, 9.3%, and 7.2% annual declines early in the decade in the 3 plans, respectively. These dropped to 2.4%, 2.1%, and 0.5% annual declines by the end of the decade. Third-generation cephalosporin use for otitis media increased 1.6-, 15-, and 5.5-fold in plans A, B, and C in young children. Similar attenuation of decline in antibiotic use and increases in use of broad-spectrum agents were seen in other age groups. CONCLUSIONS: Antibiotic dispensing for children may have reached a new plateau. Along with identifying best practices in low-prescribing areas, decreasing broad spectrum use for particular conditions should be a continuing focus of intervention efforts. PMID- 24488745 TI - Role of financial and social hardships in asthma racial disparities. AB - BACKGROUND AND OBJECTIVES: Health care reform offers a new opportunity to address child health disparities. This study sought to characterize racial differences in pediatric asthma readmissions with a focus on the potential explanatory role of hardships that might be addressed in future patient care models. METHODS: We enrolled 774 children, aged 1 to 16 years, admitted for asthma or bronchodilator responsive wheezing in a population-based prospective observational cohort. The outcome was time to readmission. Child race, socioeconomic status (measured by lower income and caregiver educational attainment), and hardship (caregivers looking for work, having no one to borrow money from, not owning a car or home, and being single/never married) were recorded. Analyses used Cox proportional hazards. RESULTS: The cohort was 57% African American, 33% white, and 10% multiracial/other; 19% were readmitted within 12 months. After adjustment for asthma severity classification, African Americans were twice as likely to be readmitted as whites (hazard ratio: 1.98; 95% confidence interval: 1.42 to 2.77). Compared with whites, African American caregivers were significantly more likely to report lower income and educational attainment, difficulty finding work, having no one to borrow money from, not owning a car or home, and being single/never married (all P <= .01). Hardships explained 41% of the observed racial disparity in readmission; jointly, socioeconomic status and hardship explained 49%. CONCLUSIONS: African American children were twice as likely to be readmitted as white children; hardships explained >40% of this disparity. Additional factors (eg, pollution, tobacco exposure, housing quality) may explain residual disparities. Targeted interventions could help achieve greater child health equity. PMID- 24488746 TI - Risk and prevalence of developmental delay in young children with congenital heart disease. AB - BACKGROUND AND OBJECTIVE: Children with congenital heart disease (CHD) are at risk for developmental delay (DD). Changes in cognitive, language, and motor skills in early childhood have not been described. We report the results of a structured approach using longitudinal testing to identify problems and ensure early intervention in accordance with published guidelines. METHODS: Bayley Scales of Infant Development, Third Edition, were used to assess cognitive, language, and motor skills in 99 children with CHD. Subjects were evaluated 3 to 6 times in the first 3 years of life. DD was defined as scores >1 SD below the population mean. RESULTS: Cardiac anatomy was single ventricle (1V) in 34 subjects and 2 ventricles (2V) in 65. Medical comorbidities were present in 21% and genetic syndromes in 19%. Most subjects (75%) had DD in >=1 area at >=1 assessments. Subjects with 1V anatomy had equivalent outcomes to those with 2V. Cognitive and language scores declined in subjects with genetic syndromes but were stable and within the average range for subjects with 1V and 2V. Motor scores improved for subjects with 1V and 2V but remained low for those with genetic syndromes. In addition to age, need for supplemental tube feeding, longer cardiopulmonary bypass time, and shorter time since last hospitalization were significant predictors of developmental outcomes. CONCLUSIONS: DDs in young children with CHD are both common and dynamic. Providers should encourage longitudinal surveillance for children with CHD because exposure to risk and prevalence of DD change over time. PMID- 24488748 TI - Firearms, children, and health care professionals. PMID- 24488747 TI - Risk perceptions and subsequent sexual behaviors after HPV vaccination in adolescents. AB - OBJECTIVES: Concerns have been raised that human papillomavirus (HPV) vaccination could lead to altered risk perceptions and an increase in risky sexual behaviors among adolescents. The aim of this study was to assess whether adolescent risk perceptions after the first vaccine dose predicted subsequent sexual behaviors. METHODS: Young women 13 to 21 years of age (N = 339) completed questionnaires immediately after HPV vaccination, and 2 and 6 months later, assessing demographic characteristics, knowledge/attitudes about HPV vaccination, risk perceptions, and sexual behaviors. Risk perceptions were measured by using 2 5 item scales assessing: (1) perceived risk of sexually transmitted infections (STI) other than HPV, and (2) perceived need for safer sexual behaviors after HPV vaccination. We assessed associations between risk perceptions at baseline and sexual behaviors over the next 6 months by using logistic regression, stratifying participants by sexual experience at baseline and age (13-15 vs. 16-21 years). RESULTS: Among all sexually inexperienced participants (42.5%), baseline risk perceptions were not associated with subsequent sexual initiation; in age stratified analyses, girls 16 to 21 years of age who reported lower perceived risk for other STI (an inappropriate perception) were less likely to initiate sex (odds ratio [OR] 0.13, 95% confidence interval [CI] 0.03-0.69). Among all sexually experienced participants (57.5%) and in age-stratified analyses, baseline risk perceptions were not associated with subsequent number of sexual partners or condom use. CONCLUSIONS: Risk perceptions after HPV vaccination were not associated with riskier sexual behaviors over the subsequent 6 months in this study sample. PMID- 24488749 TI - Incidence and impact of CMV infection in very low birth weight infants. AB - BACKGROUND AND OBJECTIVES: Congenital cytomegalovirus (CMV) is the leading cause of nongenetic deafness in children in the United States and can cause neurodevelopmental impairment in term infants. Limited data exist regarding congenital CMV infections in preterm infants. We aimed to determine the incidence and association with outcomes of congenital CMV in very low birth weight (VLBW) preterm infants. METHODS: VLBW infants born in 1993 to 2008 and admitted to the University of Alabama in Birmingham Regional Neonatal ICU were screened on admission for congenital CMV. CMV status and clinical outcomes were identified by using internal patient databases and hospital-based medical records. The primary outcome was death. Secondary outcomes included evidence of neurologic injury in the form of abnormal cranial ultrasound findings, sensorineural hearing loss, or abnormal motor development. Multivariate analysis was performed. RESULTS: Eighteen of 4594 VLBW infants had congenital CMV (0.39%; 95% confidence interval, 0.25%-0.62%). An additional 16 infants (0.35%; 95% confidence interval, 0.21% 0.57%) were identified who acquired CMV postnatally. Congenital CMV was not associated with death. Compared with controls, congenitally infected VLBW infants were more likely to have hearing loss at initial screening (67% vs. 9%, P < .0001) and confirmed at follow-up (83% vs. 2.1%, P < .0001). Congenital CMV was also associated with abnormal neuroimaging (72% vs. 25%, P < .0001) and adverse developmental motor outcomes (43% vs. 9%, P = .02). Acquired CMV was not associated with any adverse outcomes. CONCLUSIONS: Congenital CMV in VLBW infants is associated with high rates of neurologic injury and hearing loss but not death. PMID- 24488750 TI - Minimally invasive surgical techniques in adult degenerative spinal deformity: a systematic review. AB - BACKGROUND: Minimally invasive surgery (MIS) approaches have the potential to reduce procedure-related morbidity when compared with traditional approaches. However, the magnitude of radiographic correction and degree of clinical improvement with MIS techniques for adult spinal deformity remain undefined. QUESTION/PURPOSES: In this systematic review, we sought to determine whether MIS approaches to adult spinal deformity correction (1) improve pain and function; (2) reliably correct deformity and result in fusion; and (3) are safe with respect to surgical and medical complications. METHODS: A systematic review of PubMed and Medline databases was performed for published articles from 1950 to August 2013. A total of 1053 papers were identified. Thirteen papers were selected based on prespecified criteria, including a total of 262 patients. Studies with limited short-term followup (mean, 12.1 months; range, 1.5-39 months) were included to capture early complications. All of the papers included in the review constituted Level IV evidence. Patient age ranged from 20 to 86 years with a mean of 65.8 years. Inclusion and exclusion criteria were variable, but all required at minimum a diagnosis of adult degenerative scoliosis. RESULTS: Four studies demonstrated improvement in leg/back visual analog scale, three demonstrated improvement in the Oswestry Disability Index, one demonstrated improvement in treatment intensity scale, and one improvement in SF-36. Reported fusion rates ranged from 71.4% to 100% 1 year postoperatively, but only two of 13 papers relied consistently on CT scan to assess fusion, and, interestingly, only four of 10 studies reporting radiographic results on deformity correction found the procedures effective in correcting deformity. There were 115 complications reported among the 258 patients (46%), including 37 neurological complications (14%). CONCLUSIONS: The literature on these techniques is scanty; only two of the 13 studies that met inclusion criteria were considered high quality; CT scans were not generally used to evaluate fusion, deformity correction was inconsistent, and complication rates were high. Future directions for analysis must include comparative trials, longer-term followup, and consistent use of CT scans to assess for fusion to determine the role of MIS techniques for adult spinal deformity. PMID- 24488751 TI - CORR Insights((r)): external rotation immobilization for primary shoulder dislocation: a randomized controlled trial. PMID- 24488752 TI - Arthrodesis should be strongly considered after failed two-stage reimplantation TKA. AB - BACKGROUND: A two-stage reimplantation procedure is a well-accepted procedure for management of first-time infected total knee arthroplasty (TKA). However, there is a lack of consensus on the treatment of subsequent reinfections. QUESTIONS/PURPOSES: The purpose of this study was to perform a decision analysis to determine the treatment method likely to yield the highest quality of life for a patient after a failed two-stage reimplantation. METHODS: We performed a systematic review to estimate the expected success rates of a two-stage reimplantation procedure, chronic suppression, arthrodesis, and amputation for treatment of infected TKA. To determine utility values of the various possible health states that could arise after two-stage revision, we used previously published values and methods to determine the utility and disutility tolls for each treatment option and performed a decision tree analysis using the TreeAgePro 2012 software suite (Williamstown, MA, USA). These values were subsequently varied to perform sensitivity analyses, determining thresholds at which different treatment options prevailed. RESULTS: Overall, the composite success rate for two stage reimplantation was 79.1% (range, 33.3%-100%). The utility (successful outcome) and disutility toll (cost for treatment) for two-stage reimplantation were determined to be 0.473 and 0.20, respectively; the toll for undergoing chronic suppression was set at 0.05; the utility for arthrodesis was 0.740 and for amputation 0.423. We set the utilities for subsequent two-stage revision and other surgical procedures by subtracting the disutility toll from the utility each time another procedure was performed. The two-way sensitivity analysis varied the utility status after an additional two-stage reimplantation (0.47 0.99) and chance of a successful two-stage reimplantation (45%-95%). The model was then extended to a three-way sensitivity analysis twice: once by setting the variable arthrodesis utility at a value of 0.47 and once more by setting utility of two-stage reimplantation at 0.05 over the same range of values on both axes. Knee arthrodesis emerged as the treatment most likely to yield the highest expected utility (quality of life) after initially failing a two-stage revision. For a repeat two-stage revision to be favored, the utility of that second two stage revision had to substantially exceed the published utility of primary TKA of 0.84 and the probability of achieving infection control had to exceed 90%. CONCLUSIONS: Based on best available evidence, knee arthrodesis should be strongly considered as the treatment of choice for patients who have persistent infected TKA after a failed two-stage reimplantation procedure. We recognize that particular circumstances such as severe bone loss can preclude or limit the applicability of fusion as an option and that individual clinical circumstances must always dictate the best treatment, but where arthrodesis is practical, our model supports it as the best approach. PMID- 24488753 TI - Radical additions to aromatic residues in peptides facilitate unexpected side chain and backbone losses. AB - Accurate identification of fragments in tandem mass spectrometry experiments is aided by knowledge of relevant fragmentation mechanisms. Herein, novel radical addition reactions that direct unexpected side-chain dissociations at tryptophan and tyrosine residues are reported. Various mechanisms that can account for the observed dissociation channels are investigated by experiment and theory. The propensity for radical addition at a particular site is found to be primarily under kinetic control, which is largely dictated by molecular structure. In certain peptides, intramolecular radical addition reactions are favored, which leads to the observation of numerous unexpected fragments. In one pathway, radical addition leads to migration of an aromatic side chain to another residue. Alternatively, radical addition followed by hydrogen atom loss leads to cyclization of the peptide and increased observation of internal sequence fragments. Radical addition reactions should be considered when assigning fragmentation spectra obtained from activation of hydrogen deficient peptides. PMID- 24488755 TI - The canine jaw-ear connection: The malleomandibular and tympanomandibular ligaments. AB - In the human, two ligaments derived from the first embryonic pharyngeal (branchial) arch that unite the mandible and temporomandibular joint (TMJ) with the middle ear have been identified as the discomalleolar ligament (DML) and sphenomandibular ligament (SML), also known as the malleomandibular ligament (MML), anterior ligament of the malleus (AML), and tympanomandibular ligament (TML). Neither of these structures has been previously described in the dog. The homologue of the human sphenomandibular ligament (SML) exists in the dog and is represented as a fibrous remnant of Meckel's cartilage. In the newborn puppy, the ligament is a true malleomandibular ligament (MML), extending from the medial mandible to the rostral process of the malleus with no intermittent attachments. In the adult dog, the ligament is entrapped within a bony passageway, likely due to the development and ossification of the tympanic bulla, making it difficult to grossly view the complete course of the ligament. The majority of the ligamentous fibers attach near the tympanic bulla in the adult dog, thus this portion of the ligament has been named the tympanomandibular ligament (TML). Those fibers of the ligament not attaching near the tympanic bulla appear to continue through a canal, located between the tympanic annulus and the surrounding tympanic bone, to become continuous with a connective tissue sheet within the cavity of the middle ear that has attachments to the malleus and incus. Tension on the adult canine TML did not result in movement of the malleus. PMID- 24488754 TI - Insights into the binding sites of organometallic ruthenium anticancer compounds on peptides using ultra-high resolution mass spectrometry. AB - The binding sites of two ruthenium(II) organometallic complexes of the form [(eta(6)-arene)Ru(N,N)Cl](+), where arene/N,N = biphenyl (bip)/bipyridine (bipy) for complex AH076, and biphenyl (bip)/o-phenylenediamine (o-pda) for complex AH078, on the peptides angiotensin and bombesin have been investigated using Fourier transform ion cyclotron resonance (FTICR) mass spectrometry. Fragmentation was performed using collisionally activated dissociation (CAD), with, in some cases, additional data being provided by electron capture dissociation (ECD). The primary binding sites were identified as methionine and histidine, with further coordination to phenylalanine, potentially through a pi stacking interaction, which has been observed here for the first time. This initial peptide study was expanded to investigate protein binding through reaction with insulin, on which the binding sites proposed are histidine, glutamic acid, and tyrosine. Further reaction of the ruthenium complexes with the oxidized B chain of insulin, in which two cysteine residues are oxidized to cysteine sulfonic acid (Cys-SO3H), and glutathione, which had been oxidized with hydrogen peroxide to convert the cysteine to cysteine sulfonic acid, provided further support for histidine and glutamic acid binding, respectively. PMID- 24488756 TI - Simultaneous determination of erlotinib and metabolites in human urine using capillary electrophoresis. AB - The purpose of this study was to develop a simple and sensitive CE-UV method to quantify erlotinib and metabolites in urine. Following liquid-liquid extraction, erlotinib, and metabolites were separated with a BGE whose composition was phosphate buffer (pH 2.5, 65 mM) with 0.5% Tween 20. The applied voltage was 22 kV, capillary temperature 25 degrees C and the sample injection was performed in the hydrodynamic mode. All the analyses were carried out in a fused silica capillary with an internal diameter of 75 MUm and a total length of 37 cm. The detection of target compounds was performed at 240 nm. The calibration was linear in the range 0.15-20 mg/L for erlotinib and metabolites. Inter-and intraday imprecision were less than 4%. This simple, sensitive, accurate, and cost effective method can be used in routine clinical practice to monitor erlotinib concentrations in urine from nonsmall cell lung cancer patients. PMID- 24488757 TI - Expression of stress-induced phosphoprotein1 (STIP1) is associated with tumor progression and poor prognosis in epithelial ovarian cancer. AB - Stress-induced phosphoprotein1 (STIP1) is a candidate biomarker in epithelial ovarian cancer (EOC). In this study, we investigated in detail the expression of STIP1, as well as its functions, in EOC. STIP1 expression was assessed by immunohistochemistry (IHC) and the results were compared with clinicopathologic factors, including survival data. The effects of STIP1 gene silencing via small interfering RNA (siRNA) were examined in EOC cells and a xenograft model. The expression of STIP1 protein in EOC was significantly higher than in the other study groups (P < 0.001), and this increase of expression was significantly associated with tumor stage (P = 0.005), tumor grade (P = 0.029), and lymph node metastasis (P = 0.020). In multivariate analysis, overall survival in EOC was significantly shorter in cases with high STIP1 expression (HR = 2.78 [1.01-7.63], P = 0.047). STIP1 silencing in EOC cells resulted in inhibition of cell proliferation and invasion. In addition, in vivo experiments using STIP1 siRNA clearly showed a strong inhibition of tumor growth and a modulation of expression of prosurvival and apoptotic genes, further suggesting that STIP1 silencing can prevent cell proliferation and invasion. In conclusion, increased STIP1 expression is associated with poor survival outcome in EOC, and STIP1 may represent a useful therapeutic target in EOC patients. PMID- 24488758 TI - Effects of the intragastric balloon MedSil on weight loss, fat tissue, lipid metabolism, and hormones involved in energy balance. AB - BACKGROUND: The prevalence of obesity continues to increase worldwide. Because obesity is associated with a number health-related problems as well as a shortened life span, treating obesity is an important clinical concern. Although various treatments are currently available, many are not efficacious in the long term. Therefore, additional medical treatment options for morbidly obese individuals must be explored. In this study, we examined the effects of the intragastric balloon MedSil on anthropometric measures and hormones associated with lipid and energy metabolism. METHODS: Twenty-two obese patients underwent insertion of the intragastric balloon MedSil following a clinical exam, body composition scan, and collection of blood samples. Six months following implantation of the balloon, additional anthropometric and serological measures were taken. RESULTS: Six months following insertion of the MedSil balloon, we observed significant decreases in body weight, body mass index, and fat mass. Compared with baseline levels, ghrelin serum levels were increased significantly, while leptin, FGF21, and glycated hemoglobin levels significantly decreased, 6 months after balloon insertion. CONCLUSIONS: The MedSil intragastric balloon is a safe and effective treatment for morbid obesity, with positive effects on anthropometric measures and lipid metabolism. PMID- 24488759 TI - Techniques to evaluate glenoid bone loss. AB - Assessing glenoid morphology as well as quantifying bone loss is critical when treating patients with recurrent anterior glenohumeral instability because this greatly affects surgeons surgical planning. Although many surgeons agree that 3 dimensionally reconstructed computed tomography (3DCT) images with humeral head digitally subtracted has been considered to be a gold standard when assessing glenoid morphology, there are some surgeons who are making an attempt to replace computed tomography with magnetic resonance imaging to reduce cost for imaging studies and avoid possible radiation exposure, and demonstrated that MRI was equally valuable as 3DCT to quantify glenoid bone loss. However, the role of preoperative imaging study is not only quantifying glenoid bone loss but to assess the glenoid shape and morphology to facilitate surgeons stabilizing the shoulder. In this view, 3DCT is the most recommended preoperative imaging study for bony tissue which provides critical and substantial information of the glenoid. PMID- 24488760 TI - Neuropathology of prodromal Lewy body disease. AB - BACKGROUND: Current evidence suggests that there is a prodromal stage in Parkinson disease characterized by a variety of nonmotor symptoms. METHODS AND RESULTS: A 69-year-old man presented to our sleep center with isolated rapid eye movement sleep behavior disorder. During a 10-year follow-up period, longitudinal clinical and laboratory assessments indicated the development of hyposmia, depression, mild cognitive impairment, and constipation. Parkinsonism was absent, but dopamine transporter imaging showed subclinical substantia nigra damage. Postmortem examination demonstrated neuronal loss and Lewy body pathology in the peripheral autonomic nervous system (eg, cardiac and myenteric plexus), olfactory bulb, medulla, pons, substantia nigra pars compacta (estimated cell loss, 20% 30%), nucleus basalis of Meynert, and amygdala, sparing the neocortex. CONCLUSIONS: Our observations indicate that nonmotor symptoms plus widespread peripheral and central nervous system pathological changes occur before parkinsonism and dementia onset in diseases associated with Lewy pathology. The current diagnostic criteria for Parkinson's disease miss these patients, who present only with nonmotor symptoms. PMID- 24488761 TI - Case study interpretation--Fort Lauderdale: Case 4. PMID- 24488762 TI - Because statistics don't tell the whole story: a call for comprehensive care for children with cancer. PMID- 24488763 TI - [Adalimumab for the treatment of ulcerative colitis--a consensus report by the working group inflammatory bowel diseases of the Austrian Society of Gastroenterology and Hepatology]. AB - TNF alpha antibodies have clearly improved the outcome of moderately to severely active ulcerative colitis. Adalimumab is the first fully human, monoclonal TNF alpha antibody, which is administered subcutaneously. Since April 2012 adalimumab is approved for the treatment of moderately to severely active ulcerative colitis in patients who have not responded despite a full and adequate course of therapy with a corticosteroid and an immunosuppressant or who are intolerant to or have medical contraindications for such therapies. Adalimumab can induce and maintain clinical remission and mucosal healing compared to placebo in moderately to severely active ulcerative colitis, can reduce the rate of ulcerative colitis related hospitalisations and improve health-related quality of life. The response can be observed after two weeks of treatment. The safety profile of adalimumab is comparable to those of other TNF alpha inhibitors. Studies on the treatment of ulcerative colitis with adalimumab did not reveal new safety aspects. The present consensus report by the Working Group Inflammatory Bowel Diseases of the Austrian Society of Gastroenterology and Hepatology presents the existing evidence of adalimumab for the treatment of ulcerative colitis and is aimed to assist as code of its practice. PMID- 24488764 TI - Inorganic double-helix nanotoroid of simple lithium-phosphorus species. AB - A theoretical study of Li90 P90 , which possesses a circular double-helix structure that resembles the Watson-Crick DNA structure, is reported. This is a new bonding motif in inorganic chemistry. The calculations show that the molecule might become synthesized and that it could be a model for other inorganic species which possess a double-helix structure. PMID- 24488765 TI - Saturated excitation microscopy with optimized excitation modulation. AB - Saturated excitation (SAX) microscopy utilizes the nonlinear relation between fluorescence emission and excitation under saturated excitation to improve the spatial resolution of confocal microscopy. In this study, we theoretically and experimentally investigate the saturation of fluorescence excitation under modulated excitation to optimize the excitation conditions for SAX microscopy. Calculation of the relationships between fluorescence and excitation intensity with different modulation frequencies reveals that the lifetime of the triplet state of the fluorescent probe strongly affects the strength of the demodulated fluorescence signals. We also find that photobleaching shows little dependence on the modulation frequency. These investigations allow us to determine the optimum excitation conditions, that is, the conditions providing sufficient fluorescence saturation without strong photobleaching. For a sample stained with ATTO Rho6G phalloidin, we estimate the optimal excitation conditions, which are produced with 50 kHz excitation modulation and a 50 MUsec pixel dwell time, and successfully perform three-dimensional imaging with sub-diffraction resolution. PMID- 24488766 TI - Review of the CE-MS platform as a powerful alternative to conventional couplings in bio-omics and target-based applications. AB - Many recent papers and reviews have confirmed the powerful coupling between CE and MS due to efficient and selective separation in combination with selective detection allowing detailed characterization of many biomolecules. It is known that CE-MS is an increasingly used and sought after technique for analysis in different fields such as environmental science, food analysis, biotechnology, pharmaceutical analysis, biomedical science, forensic science, toxicology, and genetic analysis. CE-MS is particularly used in bio-omic applications (proteomic, metabolomic, and also genomic applications) for the determination of biomarkers, disease diagnosis, and therapeutic treatment monitoring. Biomarker qualification, clinical proteomics, and its implementation in routine clinical analysis have certain limitations associated with reproducibility and analytical robustness. However, CE-MS has been successfully used in numerous clinical applications in recent years when compared with other platforms. The main advantage lies in the availability of large comparable datasets that were all obtained by using the same procedure for sample preparation, analysis, and subsequent data evaluation. The scope of this review is to discuss the performance of CE-MS as a platform for bio-omics analysis and target-based applications focusing on quadrupole (Q), IT, and TOF analyzers, and the types of bioapplications that apply to the particular analyzers. Papers and reviews that were published in 2012 and 2013 with relevant CE-MS applications are considered in this review. PMID- 24488768 TI - Gne depletion during zebrafish development impairs skeletal muscle structure and function. AB - GNE Myopathy is a rare recessively inherited neuromuscular disorder caused by mutations in the GNE gene, which codes for the key enzyme in the metabolic pathway of sialic acid synthesis. The process by which GNE mutations lead to myopathy is not well understood. By in situ hybridization and gne promoter-driven fluorescent transgenic fish generation, we have characterized the spatiotemporal expression pattern of the zebrafish gne gene and have shown that it is highly conserved compared with the human ortholog. We also show the deposition of maternal gne mRNA and maternal GNE protein at the earliest embryonic stage, emphasizing the critical role of gne in embryonic development. Injection of morpholino (MO)-modified antisense oligonucleotides specifically designed to knockdown gne, into one-cell embryos lead to a variety of phenotypic severity. Characterization of the gne knockdown morphants showed a significantly reduced locomotor activity as well as distorted muscle integrity, including a reduction in the number of muscle myofibers, even in mild or intermediate phenotype morphants. These findings were further confirmed by electron microscopy studies, where large gaps between sarcolemmas were visualized, although normal sarcomeric structures were maintained. These results demonstrate a critical novel role for gne in embryonic development and particularly in myofiber development, muscle integrity and activity. PMID- 24488767 TI - Fat mass and obesity-associated (FTO) protein interacts with CaMKII and modulates the activity of CREB signaling pathway. AB - Polymorphisms in the fat mass and obesity-associated (FTO) gene have been associated with obesity in humans. FTO is a nuclear protein and its physiological function remains largely unknown, but alterations in its expression in mice influence energy expenditure, food intake and, ultimately, body weight. To understand the molecular functions of FTO, we performed a yeast two-hybrid screen to identify the protein(s) that could directly interact with human FTO protein. Using multiple assays, we demonstrate that FTO interacts with three isoforms of calcium/calmodulin-dependent protein kinase II: alpha, beta and gamma, which are protein kinases that phosphorylate a broad range of substrates. This interaction is functional; overexpression of FTO delays the dephosphorylation of cAMP response element-binding protein (CREB) in human neuroblastoma (SK-N-SH) cells, which in turn leads to a dramatic increase in the expression of the CREB targets neuropeptide receptor 1 (NPY1R) and brain-derived neurotrophic factor (BDNF), which already are known to regulate food intake and energy homeostasis. Thus, our results suggest that FTO could modulate obesity by regulating the activity of the CREB signaling pathway. PMID- 24488769 TI - A distinct set of long non-coding RNAs in childhood MLL-rearranged acute lymphoblastic leukemia: biology and epigenetic target. AB - Long non-coding RNAs (lncRNAs) have been recently found to be pervasively transcribed in human genome and link to diverse human diseases. However, the expression patterns and regulatory roles of lncRNAs in hematopoietic malignancies have not been reported. Here, we carried out a genome-wide lncRNA expression study in MLL-rearranged acute lymphoblastic leukemia (MLL-r ALL) and established lncRNA/messenger RNA coexpression networks to gain insight into the biological roles of these dysregulated lncRNAs. We detected a number of lncRNAs that were differentially expressed in MLL-r ALL samples compared with MLL-r wild-type and identified unique lncRNA expression patterns between MLL-r subtypes with different translocations as well as between infant MLL-r ALL with other MLL-r ALL patients, suggesting that they might be served as novel biomarkers for the disease. Importantly, several lncRNAs that correspond with membrane protein genes, including a lysosome-associated membrane protein, were identified. No such link between the membrane proteins and MLL-r leukemia has been reported previously. Impressively, the functional analysis showed that several lncRNAs corresponded to the expression of MLL-fusion protein target genes, including HOXA9, MEIS1, etc., while some other associated with histone-related functions or membrane proteins. Further experiments characterize the effect of some lncRNAs on MLL-r leukemia apoptosis and proliferation as the function of the coexpressed HOXA gene cluster. Finally, a set of lncRNAs epigenetically regulated by H3K79 methylation were also discovered. These findings may provide novel insights into the mechanisms of lncRNAs involved in the initiation of MLL-r leukemia. This is the first study linking lncRNAs to leukemogenesis. PMID- 24488771 TI - Early and progressive circadian abnormalities in Huntington's disease sheep are unmasked by social environment. AB - Insidious changes in behaviour herald the onset of progressive neurodegenerative disorders such as Huntington's disease (HD), sometimes years before overt symptoms are seen. Sleep and circadian disturbances are particularly disruptive symptoms in patients with neurological disorders, but they are difficult to measure in humans. Here we studied circadian behaviour in transgenic HD sheep expressing the full-length human huntingtin protein with an expanded CAG repeat mutation in the juvenile range. Young HD sheep with no other symptoms exhibited circadian behavioural abnormalities that worsened with age. The most obvious change was a disturbed evening behaviour reminiscent of 'sundowning' that is seen in some patients with dementia. There were no structural abnormalities seen with magnetic resonance imaging, even in 5-year-old HD sheep. Interestingly, detection of the circadian abnormalities depended upon their social grouping. Abnormalities emerged in sheep kept in an 'HD-only' flock, whereas the behaviour of HD sheep kept mixed with normal sheep was relatively normal. Sleep-wake abnormalities in HD patients are also likely to be hidden, and may precede overt symptoms by many years. Sleep disruption has deleterious effects, even in normal people. The knock on effects of sleep-wake disturbance may exacerbate, or even cause symptoms such as irritability and depression that are common in early stage HD patients. HD sheep will be useful models for probing the mechanisms underlying circadian behavioural disorder in HD. PMID- 24488770 TI - IFT27, encoding a small GTPase component of IFT particles, is mutated in a consanguineous family with Bardet-Biedl syndrome. AB - Bardet-Biedl syndrome (BBS) is an autosomal recessive ciliopathy with multisystem involvement. So far, 18 BBS genes have been identified and the majority of them are essential for the function of BBSome, a protein complex involved in transporting membrane proteins into and from cilia. Yet defects in the identified genes cannot account for all the BBS cases. The genetic heterogeneity of this disease poses significant challenge to the identification of additional BBS genes. In this study, we coupled human genetics with functional validation in zebrafish and identified IFT27 as a novel BBS gene (BBS19). This is the first time an intraflagellar transport (IFT) gene is implicated in the pathogenesis of BBS, highlighting the genetic complexity of this disease. PMID- 24488772 TI - Plasma thyroid hormones and corticosterone levels in blood of chicken embryos and post hatch chickens exposed during incubation to 1800 MHz electromagnetic field. AB - INTRODUCTION: This study attempted to determine the effect of a 1800 MHz electromagnetic field (EMF) (only carrier frequency) on thyroxine (T4), triiodothyronine (T3) and corticosterone (CORT) concentrations in the blood plasma of chick embryos, and to investigate the effect of electromagnetic field (EMF) exposure during embryogenesis on the level of these hormones in birds that are ready for slaughter. MATERIAL AND METHODS: Throughout the incubation period, embryos from the experimental group were exposed to a 1800 MHz EMF with power density of 0.1 W/m(2), 10 times during 24 h for 4 min. Blood samples were collected to determine T4, T3 and CORT concentrations on the 12th (E12) and 18th (E18) day of incubation, from newly hatched chicks (D1) and from birds ready for slaughter (D42). RESULTS: The experiment showed that T4 and T3 concentrations decreased markedly and CORT levels increased in the embryos and in the newly hatched chicks exposed to EMF during embryogenesis. However, no changes were found in the level of the analyzed hormones in the birds ready for slaughter. Differences in T4 and T3 plasma concentrations between the EMF-exposed group and the embryos incubated without additional EMF were the highest in the newly hatched chicks, which may be indicative of the cumulative effect of electromagnetic field on the hypothalamo-pituitary-thyroid axis (HPT). DISCUSSION: The obtained results suggest that additional 1800 MHz radio frequency electromagnetic field inhibits function of HPT axis, however, it stimulates hypothalamo-pituitary-adrenal axis by inducing adrenal steroidogenic cells to synthesize corticosterone. Further investigations are needed to elucidate the mechanisms by which radio EMFs affect HPT and HPA axis function in the chicken embryos. PMID- 24488773 TI - Airborne contact dermatitis and asthma in a nail art operator. AB - Nail art (creation and decoration of artificial nails) is a growing fashion trend. Proportionally to its popularity, the number of allergic reactions to the materials used has recently increased. We report the case of a nail art operator who developed occupational allergy to acrylates, manifested with the unusual simultaneous presence of asthma and dermatitis. Cutaneous lesions only affected areas not covered by individual protection devices or clothes, even if such areas were not in direct contact with acrylates, suggesting airborne allergic contact dermatitis. While respiratory problems were solved with the correct use of a mask at the workplace, facial dermatitis proved impossible to avoid or control and, for this reason, the patient had to change her work. PMID- 24488774 TI - The significance of the sense of coherence for various coping resources in stress situations used by police officers in on-the-beat service. AB - BACKGROUND: Police officers meet many stressors as part of their occupation. The psychological resource "sense of coherence" (SOC) protects against ill-health, but its impact on coping resources for stress situations has not been studied in the population of police officers. Different approaches to investigate the significance of SOC for different outcomes have been identified in literature, leading to some difficulties in the interpretation and generalization of results. The aim was therefore to explore SOC and the coping resources, and to examine the significance of SOC for various coping resources for stress using different models in a sample of Swedish police officers providing on-the-beat service. MATERIALS AND METHODS: One hundred and one police officers (age: mean = 33 years, SD = 8; 29 females) were included, and the Orientation to Life Questionnaire (SOC 29) and the Coping Resources Inventory (CRI) were used. The dependent variable in each regression analysis was one of the coping resources: cognitive, social, emotional, spiritual/philosophical, physical, and a global resource. Global SOC 29 and/or its components (comprehensibility, manageability, and meaningfulness) were investigated as independent variables. RESULTS: All CRI and SOC-29 scores except for that of spiritual/philosophical resources were higher than those of reference groups. Manageability was the most important component of SOC for various coping resources in stress situations used by police officers. CONCLUSION: A deeper study of manageability will give useful information, because this component of SOC is particularly significant in the variation in resources used by police officers to cope with stress. Salutogenesis, the origin of well being, should be more in focus of future research on workplaces with a high level of occupational stress. PMID- 24488775 TI - Which health professionals are most at risk for cardiovascular disease? Or do not be a manager. AB - OBJECTIVES: Health care workers constitute a high-risk occupational category owing to the character of their work that includes high-risk environment, shift work and mental as well as physical stress. In occupational medicine, caring for their health condition should be a priority and include measures aimed at preventing cardiovascular diseases. The study aimed at determining the prevalence of cardiovascular disease (CVD) risk factors in employees of a large hospital and assessing their effect on the incidence of cardiovascular events. MATERIALS AND METHODS: The group comprised 3124 employees with a mean age of 36.1 years (SD = 11.4), out of whom 562 were males (mean age of 37.1 years, range: 18-72; SD = 12.26) and 2562 were females (mean age of 35.9 years, range: 18-68; SD = 11.24). At their initial examination, the employees filled in a questionnaire on basic CVD risk factors (according to valid recommendations). This was supplemented with objective data to determine the risk of CVD using valid charts. From this group, a subset of persons at a high or intermediate risk was selected, comprising 247 individuals with a mean age of 54.1 years (SD = 5.73). After 5-9 years (mean 7.24+/-1.38 years), they either underwent another examination or their health status was ascertained by phone or in a computer database. The end point was the incidence of cardiovascular events (sudden death, acute myocardial infarction, unstable angina pectoris, percutaneous coronary intervention, cardiac failure, stroke or transient ischemic attack). RESULTS: The end point was noted in a total of 15 males (6.07%) and 6 females (2.42%), being statistically significantly present in managers (males p < 0.00007, females p < 0.00001), male physicians/surgeons (p < 0.025), tertiary-educated males (p < 0.0095), female smokers (p < 0.015), male ex-smokers (p < 0.007), overweight or obese males (p < 0.02) and those with the waist-to-hip ratio above 1.0 (p < 0.005). CONCLUSIONS: Cardiovascular events are most likely to occur in obese male physicians/surgeons holding managerial positions and in female managers. PMID- 24488776 TI - Recent developments in experimental animal models of Henipavirus infection. AB - Hendra (HeV) and Nipah (NiV) viruses (genus Henipavirus (HNV; family Paramyxoviridae) are emerging zoonotic agents that can cause severe respiratory distress and acute encephalitis in humans. Given the lack of effective therapeutics and vaccines for human use, these viruses are considered as public health concerns. Several experimental animal models of HNV infection have been developed in recent years. Here, we review the current status of four of the most promising experimental animal models (mice, hamsters, ferrets, and African green monkeys) and their suitability for modeling the clinical disease, transmission, pathogenesis, prevention, and treatment for HNV infection in humans. PMID- 24488777 TI - A new alkaliphilic cold-active esterase from the psychrophilic marine bacterium Rhodococcus sp.: functional and structural studies and biotechnological potential. AB - The special features of cold-adapted lipolytic biocatalysts have made their use possible in several industrial applications. In fact, cold-active enzymes are known to be able to catalyze reactions at low temperatures, avoiding side reactions taking place at higher temperatures and preserving the integrity of products. A lipolytic gene was isolated from the Arctic marine bacterium Rhodococcus sp. AW25M09 and expressed in Escherichia coli as inclusion bodies. The recombinant enzyme (hereafter called RhLip) showed interesting cold-active esterase activity. The refolded purified enzyme displayed optimal activity at 30 degrees C and was cold-active with retention of 50% activity at 10 degrees C. It is worth noting that the optimal pH was 11, and the low relative activity below pH 10 revealed that RhLip was an alkaliphilic esterase. The enzyme was active toward short-chain p-nitrophenyl esters (C2-C6), displaying optimal activity with the butyrate (C4) ester. In addition, the enzyme revealed a good organic solvent and salt tolerance. These features make this an interesting enzyme for exploitation in some industrial applications. PMID- 24488778 TI - Mineral supplementation increases erythrose reductase activity in erythritol biosynthesis from glycerol by Yarrowia lipolytica. AB - The aim of this study was to examine the impact of divalent copper, iron, manganese, and zinc ions on the production of erythritol from glycerol by Yarrowia lipolytica and their effect on the activity of erythrose reductase. No inhibitory effect of the examined minerals on yeast growth was observed in the study. Supplementation with MnSO4 . 7H2O (25 mg l(-1)) increased erythritol production by Y. lipolytica by 14.5%. In the bioreactor culture with manganese ion addition, 47.1 g l(-1) of erythritol was produced from 100.0 g l(-1) of glycerol, which corresponded to volumetric productivity of 0.87 g l(-1) h(-1). The addition of Mn(2+) enhanced the intracellular activity of erythrose reductase up to 24.9 U g(-1) of dry weight of biomass (DW), hence, about 1.3 times more than in the control. PMID- 24488779 TI - Childhood and adolescent cancer statistics, 2014. AB - In this article, the American Cancer Society provides estimates of the number of new cancer cases and deaths for children and adolescents in the United States and summarizes the most recent and comprehensive data on cancer incidence, mortality, and survival from the National Cancer Institute, the Centers for Disease Control and Prevention, and the North American Association of Central Cancer Registries (which are reported in detail for the first time here and include high-quality data from 45 states and the District of Columbia, covering 90% of the US population). In 2014, an estimated 15,780 new cases of cancer will be diagnosed and 1960 deaths from cancer will occur among children and adolescents aged birth to 19 years. The annual incidence rate of cancer in children and adolescents is 186.6 per 1 million children aged birth to 19 years. Approximately 1 in 285 children will be diagnosed with cancer before age 20 years, and approximately 1 in 530 young adults between the ages of 20 and 39 years is a childhood cancer survivor. It is therefore likely that most pediatric and primary care practices will be involved in the diagnosis, treatment, and follow-up of young patients and survivors. In addition to cancer statistics, this article will provide an overview of risk factors, symptoms, treatment, and long-term and late effects for common pediatric cancers. PMID- 24488780 TI - Eight-color immunophenotyping of T-, B-, and NK-cell subpopulations for characterization of chronic immunodeficiencies. AB - BACKGROUND: The heterogeneity of primary and secondary immunodeficiencies demands for the development of a comprehensive flow cytometric screening system, based on reference values that support a standardized immunophenotypic characterization of most lymphocyte subpopulations. METHODS: Peripheral blood samples from healthy adult volunteers (n = 25) were collected and split into eight panel fractions (100 ul each). Subsequently, premixed eight-color antibody cocktails were incubated per specific panel of whole blood to detect and differentiate cell subsets of: (i) a general lymphocyte overviews, (ii) B-cell subpopulations, (iii) CD4+ subpopulations, (iv) CD8+ subpopulations, (v) regulatory T-cells, (vi) recent thymic emigrants (RTE), (vii) NK-cell subpopulations, and (viii) NK-cell activation markers. All samples were lysed, washed, and measured by flow cytometry. FACS DIVA software was used for data analysis and calculation of quadrant statistics (mean values, standard error of mean, and percentile ranges). RESULTS: Whole blood staining of lymphocytes provided the analysis of: (i) CD3+, 4+, 8+, 19+, 16/56+, and activated CD4/8 cells; (ii) immature, naive, nonswitched/switched, memory, (activated) CD21(low) , transitional B-cells, plasmablasts/plasmacells; (iii and iv) naive, central memory, effector, effector memory, TH1/TH2/TH17-like, and CCR5+CD8-cells; (v) CD25+, regulatory T-cells (naive/memory, HLA-DR+); (vi) alpha/beta- and gamma/delta-T-cells, RTE in CD4/CD8 cells; (vii) immature/mature CD56(bright) , CD94/NKG2D+ NK-cells; and (viii) Nkp30, 44, 46, and CD57+NK-cells. Clinical examples and quadrant statistics are provided. CONCLUSION: The present study represents a practical approach to standardize the immunophenotyping of most T-, B-, and NK-cell subpopulations. That allows differentiating whether abnormalities or developmental shifts observed in lymphocyte subpopulations originates either from primary or secondary immunological disturbance. PMID- 24488781 TI - Structural and sequence features of two residue turns in beta-hairpins. AB - Beta-turns in beta-hairpins have been implicated as important sites in protein folding. In particular, two residue beta-turns, the most abundant connecting elements in beta-hairpins, have been a major target for engineering protein stability and folding. In this study, we attempted to investigate and update the structural and sequence properties of two residue turns in beta-hairpins with a large data set. For this, 3977 beta-turns were extracted from 2394 nonhomologous protein chains and analyzed. First, the distribution, dihedral angles and twists of two residue turn types were determined, and compared with previous data. The trend of turn type occurrence and most structural features of the turn types were similar to previous results, but for the first time Type II turns in beta hairpins were identified. Second, sequence motifs for the turn types were devised based on amino acid positional potentials of two-residue turns, and their distributions were examined. From this study, we could identify code-like sequence motifs for the two residue beta-turn types. Finally, structural and sequence properties of beta-strands in the beta-hairpins were analyzed, which revealed that the beta-strands showed no specific sequence and structural patterns for turn types. The analytical results in this study are expected to be a reference in the engineering or design of beta-hairpin turn structures and sequences. PMID- 24488782 TI - A combination of fludarabine, half-dose cyclophosphamide, and anti-thymocyte globulin is an effective conditioning regimen before allogeneic stem cell transplantation for aplastic anemia. AB - Conditioning regimens consisting of reduced-dose cyclophosphamide (CY) and fludarabine (FDR) have been investigated for use in allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with aplastic anemia to reduce the toxicities associated with CY. However, the ideal dose of CY has not been identified. In addition, little information is available regarding donor cell chimerism after allo-HSCT with these regimens. Therefore, we retrospectively analyzed 13 patients who underwent allo-HSCT with half-dose CY (100 mg/kg in total), FDR, and anti-thymocyte globulin at total doses of 2.5-10 mg/kg at our center. All the patients except one, who died due to encephalopathy on day 20, achieved neutrophil engraftment a median of 18.5 days after HSCT with complete donor-type chimerism. Two patients who received a graft from an HLA-matched donor subsequently developed mixed chimerism (MC) associated with transfusion-dependent cytopenia. One became transfusion-independent after donor lymphocyte infusion, but continues to exhibit MC. The other regained complete donor-type chimerism after the cessation of cyclosporine, but remains transfusion-dependent. These findings suggest that a conditioning regimen with half-dose CY and FDR is effective for achieving neutrophil engraftment and complete donor-type chimerism. However, subsequent MC may be observed, especially after HLA-matched HSCT. PMID- 24488783 TI - Descriptive profile of beta-thalassemia mutations in West Bengal population: a hospital-based study. AB - The present study was based in a hospital at which 660 individuals have been screened for thalassemia in the past 4 years. The main purposes of the study were to identify different types of beta mutations prevailing among these patients, and to establish a genotype-phenotypic correlation. Complete blood count, high performance liquid chromatography, and amplification refractory mutation system based polymerase chain reaction were performed on peripheral blood samples to detect beta mutations. Of the 660 subjects studied, 380 (57.6 %) were male and 280 (42.4 %) were female. These included 258 (39.09 %) normal individuals, 176 (26.67 %) beta-thalassemia carriers, 44 (6.67 %) beta-thalassemia major, 6 (0.91 %) cases of sickle beta-thalassemia, 6 (0.91 %) carriers of sickle cell anemia, 102 (15.45 %) Hb Ebeta-thalassemia, 42 (6.36 %) HbE carriers, 16 (2.42 %) HbE homozygous, and 10 (1.52 %) carriers of other mutations. Genotypic study of beta mutations revealed the prevalence of IVS1-5 mutation among the studied beta carriers to be 46.6 %, and codon 26 (G>A) mutation to be 31.54 %. Other prevailing mutations among the screened individuals include codon 30 (7.53 %), codon 15 (5.01 %), codon 41/42 (3.58 %), and codon 8/9 (1.07 %). Genotype phenotype correlation revealed that the phenotype of the above-mentioned mutations is associated with mild, moderate, and severe forms of thalassemia. PMID- 24488784 TI - Acute myeloid leukemia of mixed megakaryocytic and erythroid origin following chemotherapy for T-cell lymphoblastic lymphoma. PMID- 24488785 TI - The role of PML in hematopoietic and leukemic stem cell maintenance. AB - The tumor suppressor promyelocytic leukemia (PML) was first identified as a component of PML-RARalpha fusion protein, one of the initiating cytogenetic abnormalities in acute promyelocytic leukemia. PML is now known to have diverse functions regulating the DNA-damage response, apoptosis, senescence, and angiogenesis. Recent investigations have identified PML as a regulator of metabolic pathways in stem cell compartments, including the hematopoietic system, and have provided researchers with new strategies for controlling stem cell maintenance and differentiation. Studies of PML in leukemia-initiating cells demonstrate that PML is also an essential component of their maintenance, which has drawn tremendous attention to PML from scientists in various stem cell fields. Here, we review research into PML and its associated pathways, including recent studies of PML as it relates to stem cell biology, as well as our finding that PML regulates fatty acid oxidation, which is essential to the maintenance of normal hematopoietic stem cells. We also discuss the therapeutic potential of controlling PML-associated pathways. In particular, we describe promising evidence for the use of arsenic trioxide in the treatment of chronic myeloid leukemia. PMID- 24488787 TI - Metastatic signature in lung cancer is associated with sensitivity to anti integrin alpha(V) monoclonal antibody intetumumab. AB - Intetumumab is a fully human monoclonal antibody that inhibits alphav integrins. It has been shown in in vitro assays to effectively inhibit cell viability, metastasis, and adhesion of human cancer cells and endothelial cells. However, the response to Intetumumab varies in different tumor cell lines. To understand the growth inhibition mechanism of Intetumumab and to identify a molecular signature that can predict sensitivity, we focused on lung cancer cell lines and performed a series of proliferation assays. We then assessed the global gene expression profiles, DNA copy number variations, and microRNA profiles from a total of 23 lung cancer lines. The results revealed that lung cancer sensitivity to Intetumumab is associated with several chromosomal alterations, particularly genetic loss at chromosome arm 19p, which resulted in gene expression changes. We identified a genetic signature that can be used to predict Intetumumab sensitivity for lung cancer cell lines. Independently, microRNA analysis revealed a panel of signature microRNAs that includes several markers of epithelial to mesenchymal transition and tumor metastasis such as miR-200 family and miR-205. Both the genetic and microRNA signatures provide insights into the potential mechanism of Intetumumab activity and serve as the first step to develop a patient stratification strategy for Intetumumab therapy in lung cancer. PMID- 24488788 TI - Cleavage of the C=N bond in carbodiimides via release of high ring strain: a new strategy for the selective synthesis of 2-aminoaryl alkynyl imines. AB - A novel pattern of the cleavage and reorganization of C=N bond in the multicomponent reaction (MCR) of terminal alkynes or haloalkynes, carbodiimides, and benzynes is achieved for the first time to construct efficiently 2-aminoaryl alkynyl imines. The selective formation and ring-opening of the azetine intermediate with the high ring strain is essential for this reaction. Further transformation of 2-aminoaryl alkynyl imines via the Cu-catalyzed cycloisomerization is explored to provide steroselectively the bi-, tri-, and tetracyclic fused pyrrolines. PMID- 24488786 TI - Gene transfer into hematopoietic stem cells as treatment for primary immunodeficiency diseases. AB - Gene transfer into the hematopoietic stem cell has shown curative potential for a variety of hematological disorders. Primary immunodeficiency diseases have led to the way in this field of gene therapy as an example and a model. Clinical results from the past 15 years have shown that significant improvement and even cure can be achieved for diseases such as X-linked severe combined immunodeficiency, adenosine deaminase deficiency, chronic granulomatous disease and Wiskott-Aldrich syndrome. Unfortunately, with the initial clear clinical benefits, the first serious complications of gene therapy have also occurred. In a significant number of patients treated using vectors based on murine gamma-retroviruses and carrying powerful viral enhancer elements, insertional oncogenesis events have resulted in acute leukemias that, in some cases, have had fatal outcomes. These serious adverse events have sparked a revision of the assessment of risks and benefits of integrating gene transfer for hematological diseases and prompted the development and application of new generations of viral vectors with recognized superior safety characteristics. This review summarizes the clinical experience of gene therapy for primary immunodeficiencies and discusses the likely avenues of progress in the future development of this expanding field of clinical investigations. PMID- 24488789 TI - Proteomic strategies for the discovery of novel diagnostic and therapeutic targets for infectious diseases. AB - Viruses have developed numerous and elegant strategies to manipulate the host cell machinery to establish a productive infectious cycle. The interaction of viral proteins with host proteins plays an important role in infection and pathogenesis, often bypassing traditional host defenses such as the interferon response and apoptosis. Host-viral protein interactions can be studied using a variety of proteomic approaches ranging from genetic and biochemical to large scale high-throughput technologies. Protein interactions between host and viral proteins are greatly influenced by host signal transduction pathways. In this review, we will focus on comparing proteomic information obtained through differing technologies and how their integration can be used to determine the functional aspect of the host response to infection. We will briefly review and evaluate techniques employed to elucidate viral-host interactions with a primary focus on Protein Microarrays (PMA) and Mass Spectrometry (MS) as potential tools in the discovery of novel therapeutic targets. As many potential molecular markers and targets are proteins, proteomic profiling is expected to yield both clearer and more direct answers to functional and pharmacologic questions. PMID- 24488790 TI - Total serum calcium level may have adverse effects on serum cholesterol and triglycerides among female university faculty and staffs. AB - Our previous studies showed that serum calcium level may have influence in the blood pressure to older male subjects, but the relationship between serum calcium level and blood lipids is unclear. The aim of this study was to evaluate the relationship between total serum calcium level and blood lipids. In our study, total serum calcium level and blood lipids were measured among 1,075 subjects, with age range of 30-60 years, who were recruited for the routine health screening in 2006. The results showed that serum calcium level was positively correlated with triglyceride and total cholesterol weight, but not HDL cholesterol and LDL-cholesterol in female subjects (P < 0.05). No correlation was found between total serum calcium level and blood lipids in male subjects (P > 0.05). These findings suggest that a higher total serum calcium level may have a adverse effects on serum cholesterol and triglycerides among female subjects. PMID- 24488791 TI - Organohelium compounds: structures, stabilities and chemical bonding analyses. AB - This paper deals with the possibility of forming short and relatively strong carbon-helium bonds in small typical organic molecules through substitution of one or several H atoms by He(+). A structural and energetics study (based on high level calculations) of this unusual bonding, as well as a topological characterization of the resulting cations, is undertaken. Stable species generally requires substitution of about half of the hydrogen atoms for formation. Under these conditions, the number of such species appears to be potentially unlimited. "True" C-He bonds exhibit equilibrium distances ranging from 1.327 (C2H2He2(2+)) to 1.129 A (He2CO(2+)). The energies of neutral He releasing range from approximately 5 kcal mol(-1) [He2CO(2+), (Z)-C2H2He2(2+)] to 25 kcal mol(-1) (C2HHe3(3+)), but remain most frequently around 10 kcal mol(-1). However, most of He(+)-substituted hydrocarbons are metastable with respect to C C cleavage, except derivatives of ethene. Atoms in molecules (AIM) and electron localization function (ELF) topological descriptors classify the C-He bond as a weak charge-shift interaction [S. Shaik, D. Danovich, B. Silvi, D. L. Lauvergnat, P. C. Hiberty, Chem. Eur. J. 2005, 11, 6358-6371] in agreement with a recent publication by Rzepa [S. H. Rzepa, Nat. Chem. 2010, 2, 390-393]. He2CO(2+) is the only investigated compound that presents a C-He bonding ELF basin, which indicates a non-negligible covalent contribution to the bond. Other modifications in the electronic structure, such as the breaking of the triple bond in ethyne derivatives or the loss of aromaticity in C6H3He3(3+), are also nicely revealed by the ELF topology. PMID- 24488792 TI - Going for distance and going for speed: effort and optical variables shape information for distance perception from observation to response. AB - Visually guided distance perception reflects a relationship of geometrical optical variables with the effort required when traversing the distance. We probed how the representations encoding optical variables might define this relationship. Participants visually judged distances on sloped surfaces and reproduced these distances over flat terrain by walking while blindfolded. We examined the responses for the effects of optical variables (i.e., angular declinations from eye height) and tested whether four measures of trial-by-trial effort moderated the use of the represented optical variables. We predicted that observation time and response speed relative to the observed distance would accentuate the effects of encoded optical variables, and that response time and response speed relative to the traversed distance would reduce the effects of those variables. The results confirmed all of the effects except those of observation time. Given the benefits of longer study for strengthening a memory trace, the failure of observation time to predict the use of optical variables raises questions about the representational encoding of visual traces for distance perception. Relationships among optical variables and other effort measures implicate the interaction of processes across multiple time scales, as in cascade dynamics. Cascade dynamics may provide new directions for accounts of visually guided distance perception. PMID- 24488793 TI - Preoperative cryotherapy use in anterior cruciate ligament reconstruction. AB - Unrelieved postoperative pain may impair rehabilitation, compromise functional outcomes, and lead to patient dissatisfaction. Preemptive multimodal analgesic techniques may improve outcomes after surgery. We hypothesized that patients using preoperative cryotherapy plus a standardized postoperative treatment plan will have lower pain scores and require less pain medication compared with patients receiving a standardized postoperative treatment plan alone after arthroscopically assisted anterior cruciate ligament reconstruction (ACLR). A total of 53 consecutive patients undergoing arthroscopically assisted ACLR performed by one of seven surgeons were randomly assigned to one of two groups. Group 1 received no preoperative cryotherapy and group 2 received 30 to 90 minutes of preoperative cryotherapy to the operative leg using a commercial noncompressive cryotherapy unit. Visual analog scale pain scores and narcotic use were recorded for the first 4 days postoperatively. Total hours of cold therapy and continuous passive motion (CPM) use and highest degree of flexion achieved were recorded as well. Group 1 consisted of 26 patients (15 allograft Achilles tendon and 11 autograft bone patellar tendon bone [BPTB]), and group 2 consisted of 27 patients (16 allograft Achilles tendon and 11 autograft BPTB). Group 2 patients reported less pain (average 1.3 units, p < 0.02) and used less narcotic use (average 1.7 tablets, p < 0.02) for the first 36 hours compared with group 1. No statistically significant differences were identified between the two groups with regard to demographics, hours of postoperative cryotherapy, hours of CPM use, or maximum knee flexion achieved. Complications did not occur in either group. This is the first report we are aware of showing the postoperative effects of preoperative cryotherapy. Our results support the safety and efficacy of preoperative cryotherapy in a multimodal pain regimen for patients undergoing ACL reconstruction. PMID- 24488794 TI - Sequential double fluorescent detections of total proteins and phosphoproteins in SDS-PAGE. AB - A fluorescent staining technique, using selective chelation with fluorophore and metal ion to the phosphate groups of phosphoproteins in SDS-PAGE is described. As a fluorescent dye and a metal ion, Fura 2 pentapotassium salt and Al(3+) were employed, respectively. The staining method, Fura 2 stain, has sensitivities of 16-32 ng of alpha-casein and beta-casein, 62 ng of ovalbumin, phosvitin, and kappa-casein using an ultraviolet transilluminator. Furthermore, Fura 2 stain is able to carry out continuative double detection of total proteins and phosphoproteins on the same gel within 3.5 h. Consequently, selective phosphoprotein and total protein detections could be obtained without other poststaining. Considering the low cost, simplicity, and speed, Fura 2 staining may provide great practicalities in routine phosphoproteomics research. PMID- 24488795 TI - Cation-pi, amino-pi, pi-pi, and H-bond interactions stabilize antigen-antibody interfaces. AB - The identification of immunogenic regions on the surface of antigens, which are able to stimulate an immune response, is a major challenge for the design of new vaccines. Computational immunology aims at predicting such regions--in particular B-cell epitopes--but is far from being reliably applicable on a large scale. To gain understanding into the factors that contribute to the antigen-antibody affinity and specificity, we perform a detailed analysis of the amino acid composition and secondary structure of antigen and antibody surfaces, and of the interactions that stabilize the complexes, in comparison with the composition and interactions observed in other heterodimeric protein interfaces. We make a distinction between linear and conformational B-cell epitopes, according to whether they consist of successive residues along the polypeptide chain or not. The antigen-antibody interfaces were shown to differ from other protein-protein interfaces by their smaller size, their secondary structure with less helices and more loops, and the interactions that stabilize them: more H-bond, cation-pi, amino-pi, and pi-pi interactions, and less hydrophobic packing; linear and conformational epitopes can clearly be distinguished. Often, chains of successive interactions, called cation/amino-pi and pi-pi chains, are formed. The amino acid composition differs significantly between the interfaces: antigen-antibody interfaces are less aliphatic and more charged, polar and aromatic than other heterodimeric protein interfaces. Moreover, paratopes and epitopes-albeit to a lesser extent-have amino acid compositions that are distinct from general protein surfaces. This specificity holds promise for improving B-cell epitope prediction. PMID- 24488796 TI - Retention behavior of a homologous series and positional isomers of aliphatic amino acids in hydrophilic interaction chromatography. AB - The retention behavior of several series of free alpha- and omega-amino acids and positional isomers of amino pentanoic acid in the hydrophilic interaction chromatography mode (HILIC) was studied. The study was carried out on three stationary phases followed by post-column derivatization with fluorescence detection in order to describe the retention mechanism of the tested amino acids. The effect of chromatographic conditions including acetonitrile content in the mobile phase, mobile phase pH (ranging from 3.5 to 6.5) and concentration of buffer in the mobile phase was investigated. The effect of the number of carbon atoms (nC) in aliphatic chains of the individual homologue of alpha- and omega amino acids and the logarithm of the partition coefficient (logD) on retention was also a part of the presented study. A good correlation (r > 0.98) between the logk and logD values of amino acids or nC, respectively, was observed. The described linear relationships were subsequently applied to predict the retention behavior of individual members of the homologous series of amino acids and to optimize the mobile phase composition in HILIC. The obtained results confirmed that the retention mechanism of alpha-amino acids, omega-amino acids and positional isomers of amino acids was based on the logD values and the number of carbon atoms in the aliphatic chains of amino acids. The elution order of omega amino acids and positional isomers of amino pentanoic acid was strongly dependent on the mobile phase pH in the investigated range whereas the retention factors of all alpha-amino acids remained essentially unchanged on all tested stationary phases. PMID- 24488797 TI - High mobility group box 1 (HMGB1) protein in human uterine fluid and its relevance in implantation. AB - STUDY QUESTION: Does a differential abundance of high mobility group box 1 (HMGB1) protein in uterine fluid (UF) have a functional significance? SUMMARY ANSWER: In rats, an excess of HMGB1 in UF during the receptive phase is detrimental to pregnancy. WHAT IS KNOWN ALREADY: The identification of constituents of the human uterine secretome has been a subject of renewed interest, due to the advent of high throughput proteomic technologies. Proteomic based investigations of human UF have revealed the presence of several proteins such as mucins, host defense proteins S100, heat shock protein 27 and haptoglobin, etc. The present study reports on the presence of HMGB1, a nuclear protein, in human UF. Activated macrophages/monocytes, natural killer cells, mature dendritic cells, pituicytes and erythroleukemic cells are also known to secrete HMGB1. Existing data suggest that extracellular HMGB1 plays a role in inflammation. STUDY DESIGN, SIZE, DURATION: The human part of this study was cross-sectional in design. UF and endometrial tissues were collected from regularly cycling women in the early secretory (i.e. pre-receptive phase, Day 2 post-ovulation, n = 7) or secretory phase (i.e. receptive phase, Day 6 post ovulation, n = 7) of their menstrual cycles. Samples were also collected from cycling rats in the proestrous (n = 8) or metestrous (n = 8) phase of their estrous cycles. Uteri were also collected from HMGB1-treated pregnant (n = 7) and untreated pseudo-pregnant (n = 7) rats and from pregnant rats at Day 3-5 post coitum (p.c.) (n = 18, 3 each for six-time points). PARTICIPANTS/MATERIALS, SETTING, METHODS: In each group of human samples, four samples were used for isobaric tag for relative and absolute quantification (iTRAQ) analysis and three samples were used for immunoblotting experiments to determine the abundance of HMGB1 in pre-receptive and receptive phase UF samples. HMGB1 levels in rat UF and endometrial tissue samples were estimated by ELISA and immunohistochemical studies, respectively. The expression of inflammation-associated molecules, such as nuclear factor kappa B (NFkappaB), receptor for advanced glycation end products (RAGEs), tumor necrosis factor alpha (TNF-alpha) and interleukin-6 (IL 6), was analyzed by immunohistochemistry in HMGB1-treated and pseudo-pregnant rats. MAIN RESULTS AND THE ROLE OF CHANCE: HMGB1 was identified as one of the differentially abundant proteins in the list generated by 8-plex iTRAQ analysis of receptive and pre-receptive phase UF samples. In both humans and rats, secreted and cellular levels of HMGB1 showed a similar pattern, i.e. significantly (P < 0.05) lower abundance in the receptive phase compared with that in the pre-receptive phase. A significant (P < 0.05) decline was also observed in the endometrial expression of HMGB1 on the day of implantation in pregnant rats. Exogenous administration of recombinant HMGB1, on Day 3 p.c., led to pregnancy failure, whereas administration of recombinant leukemia inhibitory factor or saline had no effect on pregnant rats. Further investigations revealed morphological changes in the endometrium, an increase in the expression of luminal epithelial NFkappaB and significantly (P < 0.05) higher expression levels of endometrial RAGE, TNF-alpha and IL-6 in HMGB1-treated rats, compared with untreated pseudo-pregnant rats. LIMITATIONS, REASONS FOR CAUTION: The mechanisms, contributing to a decline in the cellular and extracellular levels of HMGB1 during the receptive phase, remain to be ascertained. WIDER IMPLICATIONS OF THE FINDINGS: An excess of HMGB1 in the UF may be associated with infertility in women. PMID- 24488798 TI - Phase I study of cladribine, cytarabine, granulocyte colony stimulating factor (CLAG regimen) and midostaurin and all-trans retinoic acid in relapsed/refractory AML. AB - We conducted a phase I study using midostaurin (25 or 50 mg orally twice daily), all-trans retinoic acid (ATRA) and CLAG chemotherapy to target multiple pathways in relapsed/refractory AML. 10 patients received the combination and no dose limiting toxicities were observed. Two patients (22 %) achieved complete remission and 1 patient (11 %) achieved complete remission with incomplete count recovery. Pharmacokinetic data showed that the 25 mg dosing of midostaurin achieved therapeutic levels with no significant interaction between midostaurin and ATRA. With evidence of activity of ATRA in NPM1-mutated AML and midostaurin in FLT3-ITD AML, this combination warrants further investigation. PMID- 24488799 TI - Does short-term potassium fertilization improve recovery from drought stress in laurel? AB - Xylem hydraulic conductance varies in response to changes in sap solute content, and in particular of potassium (K(+)) ion concentration. This phenomenon, known as the 'ionic effect', is enhanced in embolized stems, where it can compensate for cavitation-induced loss of hydraulic conductance. Previous studies have shown that in well-watered laurel plants (Laurus nobilis L.), potassium concentration of the xylem sap and plant hydraulic conductance increased 24 h after fertilization with KCl. The aim of this work was to test whether water-stressed laurel plants, grown under low potassium availability, could recover earlier from stress when irrigated with a KCl solution instead of potassium-free water. Two year-old potted laurel seedlings were subjected to water stress by suspending irrigation until leaf conductance to water vapour (g(L)) dropped to ~30% of its initial value and leaf water potential (psi(L)) reached the turgor loss point (psi(TLP)). Plants were then irrigated either with water or with 25 mM KCl and monitored for water status, gas exchange and plant hydraulics recovery at 3, 6 and 24 h after irrigation. No significant differences were found between the two experimental groups in terms of psi(L), g(L), plant transpiration, plant hydraulic conductance or leaf-specific shoot hydraulic conductivity. Analysis of xylem sap potassium concentration showed that there were no significant differences between treatments, and potassium levels were similar to those of potassium-starved but well-watered plants. In conclusion, potassium uptake from the soil solution and/or potassium release to the xylem appeared to be impaired in water-stressed plants, at least up to 24 h after relief from water stress, so that fertilization after the onset of stress did not result in any short-term advantage for recovery from drought. PMID- 24488800 TI - Coping with drought-induced xylem cavitation: coordination of embolism repair and ionic effects in three Mediterranean evergreens. AB - Embolism repair and ionic effects on xylem hydraulic conductance have been documented in different tree species. However, the diurnal and seasonal patterns of both phenomena and their actual role in plants' responses to drought-induced xylem cavitation have not been thoroughly investigated. This study provides experimental evidence of the ability of three Mediterranean species to maintain hydraulic function under drought stress by coordinating the refilling of xylem conduits and ion-mediated enhancement of stem hydraulic conductance (K stem). Vessel grouping indices and starch content in vessel-associated parenchyma cells were quantified to verify eventual correlations with ionic effects and refilling, respectively. Experiments were performed on stems of Ceratonia siliqua L., Olea europaea L. and Laurus nobilis L. Seasonal, ion-mediated changes in K stem (DeltaK stem) and diurnal and/or seasonal embolism repair were recorded for all three species, although with different temporal patterns. Field measurements of leaf specific stem hydraulic conductivity showed that it remained quite constant during the year, despite changes in the levels of embolism. Starch content in vessel-associated parenchyma cells changed on diurnal and seasonal scales in L. nobilis and O. europaea but not in C. siliqua. Values of DeltaK stem were significantly correlated with vessel multiple fraction values (the ratio of grouped vessels to total number of vessels). Our data suggest that the regulation of xylem water transport in Mediterranean plants relies on a close integration between xylem refilling and ionic effects. These functional traits apparently play important roles in plants' responses to drought-induced xylem cavitation. PMID- 24488801 TI - Plant nitrogen status and co-occurrence of organic and inorganic nitrogen sources influence root uptake by Scots pine seedlings. AB - Insights into how the simultaneous presence of organic and inorganic nitrogen (N) forms influences root absorption will help elucidate the relative importance of these N forms for plant nutrition in the field as well as for nursery cultivation of seedlings. Uptake of the individual N forms arginine, ammonium (NH4(+)) and nitrate (NO3(-)) was studied in Scots pine (Pinus sylvestris (L.)) seedlings supplied as single N sources and additionally in mixtures of NO3(-) and NH4(+) or NO3(-) and arginine. Scots pine seedlings displayed a strong preference for NH4(+)-N and arginine-N as compared with NO3(-)-N. Thus, NO3(-) uptake was generally low and decreased in the presence of NH4(+) in the high-concentration range (500 uM N), but not in the presence of arginine. Moreover, uptake of NO3(-) and NH4(+) was lower in seedlings displaying a high internal N status as a result of high N pre-treatment, while arginine uptake was high in seedlings with a high internal N status when previously exposed to organic N. These findings may have practical implications for commercial cultivation of conifers. PMID- 24488802 TI - Two-lung ventilation in the prone position: is it the standard anesthetic management for thoracoscopic esophagectomy? PMID- 24488804 TI - Palladium-catalyzed direct thiolation of aryl C-H bonds with disulfides. AB - A catalytic variant of the direct thiolation of arenes, bearing directing groups, with disulfides or thiols has been developed under palladium and copper co catalysis. Both sulfenyl moieties of the disulfide could be incorporated into the thiolated products, therefore, the reactions reached completion with only half an equivalent of disulfide, with respect to the starting arene. Experimental evidence suggested that the reaction proceeds through a Pd(II)/Pd(IV) mechanism. PMID- 24488803 TI - Clear cell sarcoma of the kidney demonstrates an embryonic signature indicative of a primitive nephrogenic origin. AB - Clear cell sarcoma of the kidney (CCSK) is a tumor affecting children with a median age of 3 years at diagnosis. The cell of origin of CCSK is unknown and data on the molecular changes giving rise to CCSK is scarce. This has hindered the identification of positive diagnostic markers and development of molecularly targeted treatment protocols for CCSK. We have characterized a panel of CCSK to gain information regarding its molecular profile and possible origin. High resolution genomic analysis with single nucleotide polymorphism array of 37 tumors did not reveal any clues to the mechanisms behind tumor development as remarkably few genetic imbalances were found. Gene expression analysis revealed a highly characteristic gene signature, enriched for pathways involved in embryonic development, including kidney formation. The presence of markers for two different developmental lineages in the embryonic kidney was therefore investigated in the tumor cells. FOXD1 which identifies cells giving rise to stromal elements, and CITED1, a marker for cells primed for nephrogenic epithelial differentiation, were both highly expressed in CCSK. In addition, the early embryonic marker OSR1 was expressed at higher levels in CCSK than in Wilms tumor, normal fetal kidney or adult kidney. As this marker discriminates the intermediate mesoderm from other mesodermal structures, our study could suggest that CCSK arises from a mesodermal cell type that retains the capacity to initiate differentiation towards both nephrons and stroma, but remains locked in a primitive state. PMID- 24488805 TI - Biodegradable thermogelling polymers: working towards clinical applications. AB - As society ages, aging medical problems such as organ damage or failure among senior citizens increases, raising the demand for organ repair technologies. Synthetic materials have been developed and applied in various parts of human body to meet the biomedical needs. Hydrogels, in particular, have found extensive applications as wound healing, drug delivery and controlled release, and scaffold materials in the human body. The development of the next generation of soft hydrogel biomaterials focuses on facile synthetic methods, efficacy of treatment, and tunable multi-functionalities for applications. Supramolecular 3D entities are highly attractive materials for biomedical application. They are assembled by modules via various non-covalent bonds (hydrogen bonds, p-p stacking and/or van der Waals interactions). Biodegradable thermogels are a class of such supramolecular assembled materials. Their use as soft biomaterials and their related applications are described in this Review. PMID- 24488806 TI - Attentional capture by evaluative stimuli: gain- and loss-connoting colors boost the additional-singleton effect. AB - In a valence induction task, one color acquired positive valence by indicating the chance to win money (in the case of fast and correct responses), and a different color acquired negative valence by indicating the danger to lose money (in the case of slow or incorrect responses). In the additional-singleton trials of a visual search task, the task-irrelevant singleton color was either the positive one, the negative one, or one of two neutral colors. We found an additional-singleton effect (i.e., longer RTs with a singleton color than in the no-singleton control condition). This effect was significantly increased for the two valent colors (with no differences between them) relative to the two neutral colors (with no differences between them, either). This result favors the hypothesis that the general relevance of stimuli elicits attentional capture, rather than the negativity bias hypothesis. PMID- 24488807 TI - Mesodermal mesenchymal cells give rise to myofibroblasts, but not epithelial cells, in mouse liver injury. AB - Hepatic stellate cells (HSCs) and portal fibroblasts (PFs) are believed to be the major source of myofibroblasts that participate in fibrogenesis by way of synthesis of proinflammatory cytokines and extracellular matrices. Previous lineage tracing studies using MesP1(Cre) and Rosa26lacZ(flox) mice demonstrated that MesP1+ mesoderm gives rise to mesothelial cells (MCs), which differentiate into HSCs and PFs during liver development. In contrast, several in vivo and in vitro studies reported that HSCs can differentiate into other cell types, including hepatocytes, cholangiocytes, and progenitor cell types known as oval cells, thereby acting as stem cells in the liver. To test whether HSCs give rise to epithelial cells in adult liver, we determined the hepatic lineages of HSCs and PFs using MesP1(Cre) and Rosa26mTmG(flox) mice. Genetic cell lineage tracing revealed that the MesP1+ mesoderm gives rise to MCs, HSCs, and PFs, but not to hepatocytes or cholangiocytes, in the adult liver. Upon carbon tetrachloride injection or bile duct ligation surgery-mediated liver injury, mesodermal mesenchymal cells, including HSCs and PFs, differentiate into myofibroblasts but not into hepatocytes or cholangiocytes. Furthermore, differentiation of the mesodermal mesenchymal cells into oval cells was not observed. These results indicate that HSCs are not sufficiently multipotent to produce hepatocytes, cholangiocytes, or oval cells by way of mesenchymal-epithelial transition in vivo. CONCLUSION: Cell lineage tracing demonstrated that mesodermal mesenchymal cells including HSCs are the major source of myofibroblasts but do not differentiate into epithelial cell types such as hepatocytes, cholangiocytes, and oval cells. PMID- 24488808 TI - Profiling of rutin-mediated alleviation of cadmium-induced oxidative stress in Zygophyllum fabago. AB - Zygophyllum fabago grows in arid, saline soil, or disturbed sites, such as former industrial or mining areas. This species is able to grow in coarse mineral substrates contaminated with heavy metals. To investigate the effects of the flavonoid rutin (Rtn) on certain heavy metal stress responses such as antioxidant defense systems and water status, seedlings were subjected to 100 and 200 MUM CdCl2 treatment without or with 0.25 and 1 mM Rtn for 7 and 14 d (days). Cd stress decreased growth (RGR), water content (RWC), leaf osmotic potential (Psi(Pi)), and chlorophyll fluorescence, all of which could be partly alleviated by addition of Rtn. Activities of superoxide dismutase, peroxidase (POX), ascorbate peroxidase, and glutathione reductase increased within the first 7 d after exposure to Cd. However, failure of antioxidant defense in the scavenging of reactive oxygen species (ROS) was evidenced by an abnormal rise in superoxide anion radical ( O2(*-)) and hydrogen peroxide contents and a decline in hydroxyl radical (OH(*)) scavenging activity, resulting in enhancement of lipid peroxidation (TBARS) as a marker of Cd-induced oxidative stress. However, exogenously applied Rtn considerably improved the stress tolerance of plants via a reduction in Cd accumulation, modulation of POX activity, increase of proline (Pro) content, decrease in TBARS and ROS content and consequent lowering of oxidative damage of membrane. Overall, 0.25 and 1 mM Rtn could protect Z. fabago from the harmful effects of 100 MUM Cd-induced oxidative stress throughout the experiment. PMID- 24488809 TI - Effects of dietary selenium deficiency or excess on gene expression of selenoprotein N in chicken muscle tissues. AB - Previous studies have determined the effects of dietary selenium (Se) supplementation on selenoprotein N (SelN, SEPN1), selenophosphate synthetase-1 (SPS1), and selenocysteine-synthase (SecS) mRNA abundance in chicken skeletal and cardiac muscles. To investigate collective responses of these genes to dietary Se concentrations ranging from deficiency to moderately high level in muscle tissues of chicken, 1-day-old chickens were exposed to a diet of deficient Se and supplemented with Se (0.15 mg Se/kg and 1.50 mg Se/kg) as sodium selenite in the feed for 35 days. Muscle tissues (flight, breast, leg, and cardiac muscles) were collected and examined for Se content and mRNA levels of SelN on days 1, 15, 25, and 35 days, respectively. Moreover, SPS1 and SecS mRNA levels were analyzed. The results showed that the expression of SelN gene in cardiac muscle responded to dietary Se concentrations. SelN gene was downregulated in the Se deficiency group (L group), and upregulated in the Se excess group (H group) compared with the moderate Se group (M group) (P < 0.05) in cardiac muscle. Se deficiency mainly unregulated SelN mRNA level in skeletal muscles compared with M group. Excess dietary Se mainly resulted in the upregulation of SelN mRNA level in skeletal muscles compared with the M group. SecS mRNA levels responded to dietary Se concentrations showed a similar change compared with SelN in cardiac muscle. SPS1 mRNA levels responded to dietary Se concentrations showed a downregulation in L group and upregulation in H group. However, SelN mRNA levels displayed a different expression pattern in different skeletal and cardiac muscles. Moreover, Se also regulated the levels of SPS1 and SecS mRNAs. In summary, Se regulated the expression of SelN gene and affected the mRNA levels of SecS and SPS1. The level of Se in the feed may regulate SelN biosynthesis by affecting the levels of SPS1 and SecS mRNA. PMID- 24488810 TI - CD34+ stromal cells/fibroblasts/fibrocytes/telocytes as a tissue reserve and a principal source of mesenchymal cells. Location, morphology, function and role in pathology. AB - We review the morphofunctional characteristics of CD34+ stromal fibroblastic/fibrocytic cells (CD34+ SFCs) and report our observations. We consider the following aspects of CD34+ SFCs: A) The confusing terms applied to this cell type, often combining the prefix CD34 with numerous names, including fibroblasts, fibrocytes, dendrocytes, keratocytes, telocytes and stromal, dendritic, adventitial, supraadventitial, perivascular, paravascular and delimiting cells; B) Changes in their immunophenotype, e.g., loss of CD34 expression and gain of other markers, such as those defining mesenchymal and derivate cells (myofibroblasts, osteoblasts, chondroblasts, adipocytes); C) Morphology (elongated or triangular cell body and thin, moniliform, bipolar or multipolar cytoplasmic processes), immunohistochemistry (co-expression of and changes in molecular expression) and structure (characteristics of nucleus and cytoplasmic organelles, and points of contact and junctions in quiescent and activated stages by light and electron microscopy); D) Location and distribution in the vessels (adventitia or external layer), in the tissues (connective, adipose, blood, muscle and nervous) and in the organs and systems (skin, oral cavity and oropharynx, respiratory, digestive, urinary, male, female, endocrine and lymphoid systems, serosal and synovial membranes, heart, eye and meninges); E) Origin from the mesoderm and cranial neural crest in the embryo, and from stem cells (themselves or other cells) and/or peripheral blood pluripotent stem cells (circulating progenitor cells) in post-natal life; F) Functions, such as synthesis of different molecules, progenitor of mesenchymal cells, immunomodulation, parenchymal regulation (growth, maturation and differentiation of adjacent cells), induction of angiogenesis, scaffolding support of other cells and phagocytic properties. Since CD34+ SFCs are the main reservoir of tissue mesenchymal cells (great mesenchymal potential, probably higher than that proposed for pericytes and other stromal cells), we dedicate a broad section to explain their in vivo behaviour during proliferation and differentiation in different physiologic and pathologic conditions, in addition to their characteristics in the human tissues of origin (adult stem cell niches); G) Involvement in pathological processes, e.g., repair (regeneration and repair through granulation tissue), fibrosis, tumour stroma formation and possible CD34+ SFC-derived tumours (e.g., solitary fibrous tumour, dermatofibrosarcoma protuberans, giant cell fibroblastoma, nuchal-type fibroma, mammary and extramammary myofibroblastoma, spindle and pleomorphic cell lipoma, and elastofibroma) and H) Clinical and therapeutic implications. PMID- 24488811 TI - Genotyping of Staphylococcus aureus strains isolated from healthy persistent carriers. AB - The paper presents results on the relatedness of Staphylococcus aureus strains colonizing the upper respiratory tract isolated from healthy persistent carriers. Genotyping was carried out using two methods--multiple-locus variable-number tandem-repeat fingerprinting (MLVF) and pulsed-field gel electrophoresis (PFGE). By comparison of the results obtained by both methods, good correlations between MLVF and PFGE genotyping of strains isolated from the asymptomatic carriers were observed. Further studies are needed to evaluate methods useful for genotyping of S. aureus strains circulating in the community. PMID- 24488812 TI - Physicochemical and adsorption properties of hypercross-linked polystyrene with ultimate cross-linking density. AB - The paper describes unexpected properties of hypercross-linked polystyrenes with ultimate cross-linking degrees of 300, 400, and 500%, where three, four, or five methylene links, respectively, could bind each polystyrene phenyl ring to its spacious neighbors. The polymers exhibit a strong electron spin resonance signal, unusual spectra in IR, UV, and visible ranges, and they are not typical dielectrics. The nonfunctionalized hypercross-linked polymers absorb significant amounts of inorganic acids, salts, and bases due to interactions of protons or other cations with electron-donating fragments of the aromatic network with the high extent of mutual connectivity and also due to dispersion interactions of anions with the polymer matrix. PMID- 24488813 TI - The sirtuin class of histone deacetylases: regulation and roles in lipid metabolism. AB - After the completion of the human genome sequence and that from many other organisms, last decade has witnessed a spectacular gain of knowledge on gene functions. These studies provided new insights on the roles of genes in physiology and disease. Nonetheless, the availability of genetically modified models and of "omics" technologies such as next generation sequencing unveiled clear evidences on epigenetic regulation of many cellular functions. At this regard, sirtuins, belonging to class III histone deacetylase family, have emerged as regulators of metabolism as well as other cellular processes and seem ideally suited as targets of future therapeutical interventions. This review deals on general aspects of the biology of sirtuins and focuses on their relevance in lipid metabolism in different tissues, pointing to their exploitation as potential pharmacological targets of compounds that could be used as new therapeutic alternatives in several disorders ranging from type 2 diabetes and obesity to age-related cardiovascular and neurodegenerative diseases. PMID- 24488814 TI - Weighting strategies in the meta-analysis of single-case studies. AB - Establishing the evidence base of interventions taking place in areas such as psychology and special education is one of the research aims of single-case designs, in conjunction with the aim of improving the well-being of participants in the studies. The scientific criteria for solid evidence focus on the internal and external validity of the studies, and for both types of validity, replicating studies and integrating the results of these replications (i.e., meta-analyzing) is crucial. In the present study, we deal with one of the aspects of meta analysis-namely, the weighting strategy used when computing an average effect size across studies. Several weighting strategies suggested for single-case designs are discussed and compared in the context of both simulated and real-life data. The results indicated that there are no major differences between the strategies, and thus, we consider that it is important to choose weights with a sound statistical and methodological basis, while scientific parsimony is another relevant criterion. More empirical research and conceptual discussion are warranted regarding the optimal weighting strategy in single-case designs, alongside investigation of the optimal effect size measure in these types of designs. PMID- 24488815 TI - A behavioral database for masked form priming. AB - Reading involves a process of matching an orthographic input with stored representations in lexical memory. The masked priming paradigm has become a standard tool for investigating this process. Use of existing results from this paradigm can be limited by the precision of the data and the need for cross experiment comparisons that lack normal experimental controls. Here, we present a single, large, high-precision, multicondition experiment to address these problems. Over 1,000 participants from 14 sites responded to 840 trials involving 28 different types of orthographically related primes (e.g., castfe-CASTLE) in a lexical decision task, as well as completing measures of spelling and vocabulary. The data were indeed highly sensitive to differences between conditions: After correction for multiple comparisons, prime type condition differences of 2.90 ms and above reached significance at the 5% level. This article presents the method of data collection and preliminary findings from these data, which included replications of the most widely agreed-upon differences between prime types, further evidence for systematic individual differences in susceptibility to priming, and new evidence regarding lexical properties associated with a target word's susceptibility to priming. These analyses will form a basis for the use of these data in quantitative model fitting and evaluation and for future exploration of these data that will inform and motivate new experiments. PMID- 24488816 TI - Recent trends in published occupational cancer epidemiology research: results from a comprehensive review of the literature. AB - OBJECTIVE: To assess trends in occupational cancer epidemiology research through a literature review of occupational health and epidemiology journals. METHODS: Fifteen journals were reviewed from 1991 to 2009, and characteristics of articles that assessed the risk of cancer associated with an occupation, industry, or occupational exposure, were incorporated into a database. RESULTS: The number of occupational cancer epidemiology articles published annually declined in recent years (2003 onwards) in the journals reviewed. The number of articles presenting dose-response analyses increased over the review period, from 29% in the first 4 years of review to 49% in the last 4 years. CONCLUSION: There has been a decrease in the number of occupational cancer epidemiology articles published annually during the review period. The results of these articles help determine the carcinogenicity of workplace exposures and permissible exposure limits, both of which may be hindered with a decline in research. PMID- 24488817 TI - Shift work and cancer screening: do females who work alternative shifts undergo recommended cancer screening? AB - BACKGROUND: Alternative shift work is classified as a probable human carcinogen. Certain cancer screening tests reduce cancer mortality. METHODS: The 2010 National Health Interview Survey was used to examine associations between adherence to breast, cervical, and colon cancer screening recommendations and alternative shift work among female workers. RESULTS: Workers on alternative shifts, compared to workers on daytime shifts, were more likely to be non adherent to screening recommendations for breast (34% vs. 23%) and colorectal (55% vs. 48%) cancer (P < 0.05). Workers on alternative shifts in two industries ("Manufacturing" and "Accommodation/Food Services") and three occupations ("Food Preparation/Serving," "Personal Care Services," and "Production") were more likely to be non-adherent to screening recommendations for at least two cancers (P < 0.05). CONCLUSIONS: The Affordable Care Act eliminates out-of-pocket screening expenses for these three cancers. Greater efforts are needed to promote this benefit, particularly among workers with demonstrated non-adherence. Am. J. Ind. Med. 57:265-275, 2014. Published 2013. This article is a U.S. Government work and is in the public domain in the USA. PMID- 24488818 TI - Incidental detection of late subsequent intracranial neoplasms with magnetic resonance imaging among adult survivors of childhood cancer. AB - PURPOSE: Survivors of childhood cancer are at an increased risk of developing subsequent neoplasms. In long-term survivors of childhood malignancies treated with and without cranial radiation therapy (CRT), undergoing unenhanced magnetic resonance imaging (MRI) of the brain, we estimated detection of intracranial neoplasms. METHODS: To investigate neurocognitive outcomes, 219 survivors of childhood cancer underwent unenhanced screening MRI of the brain. Of the survivors, 164 had been treated for acute lymphoblastic leukemia (ALL) (125 received CRT) and 55 for Hodgkin lymphoma (HL) (none received CRT). MRI examinations were reviewed and systematically coded by a single neuroradiologist. Demographic and treatment characteristics were compared for survivors with and without subsequent neoplasms. RESULTS: Nineteen of the 219 survivors (8.7 %) had a total of 31 subsequent intracranial neoplasms identified by neuroimaging at a median time of 25 years (range 12-46 years) from diagnosis. All neoplasms occurred after CRT, except for a single vestibular schwannoma within the cervical radiation field in a HL survivor. The prevalence of subsequent neoplasms after CRT exposure was 14.4 % (18 of 125). By noncontrast MRI, intracranial neoplasms were most suggestive of meningiomas. Most patients presented with no specific, localizing neurological complaints. In addition to the schwannoma, six tumors were resected based on results of MRI screening, all of which were meningiomas on histologic review. CONCLUSION: Unenhanced brain MRI of long-term survivors of childhood cancer detected a substantial number of intracranial neoplasms. Screening for early detection of intracranial neoplasms among aging survivors of childhood cancer who received CRT should be evaluated. IMPLICATIONS FOR CANCER SURVIVORS: The high prevalence of incidentally detected subsequent intracranial neoplasms after CRT in long-term survivors of childhood cancer and the minimal symptoms reported by those with intracranial tumors in our study indicate that brain MRI screening of long-term survivors who received CRT may be warranted. Prospective studies of such screening are needed. PMID- 24488819 TI - A critical survey of average distances between catalytic carboxyl groups in glycoside hydrolases. AB - Published X-ray crystallographic structures for glycoside hydrolases (GHs) from 39 different families are surveyed according to some rigorous selection criteria, and the distances separating 208 pairs of catalytic carboxyl groups (20 alpha retaining, 87 beta-retaining, 38 alpha-inverting, and 63 beta-inverting) are analyzed. First, the average of all four inter-carboxyl O...O distances for each pair is determined; second, the mean of all the pair-averages within each GH family is determined; third, means are determined for groups of GH families. No significant differences are found for free structures compared with those complexed with a ligand in the active site of the enzyme, nor for alpha-GHs as compared with beta-GHs. The mean and standard deviation (1sigma) of the unimodal distribution of average O...O distances for all families of inverting GHs is 8 +/ 2A, with a very wide range from 5A (GH82) to nearly 13A (GH46). The distribution of average O...O distances for all families of retaining GHs appears to be bimodal: the means and standard deviations of the two groups are 4.8 +/- 0.3A and 6.4 +/- 0.6A. These average values are more representative, and more likely to be meaningful, than the often-quoted literature values, which are based on a very small sample of structures. The newly-updated average values proposed here may alter perceptions about what separations between catalytic residues are "normal" or "abnormal" for GHs. PMID- 24488821 TI - Analgesic efficacy and safety of thoracic paravertebral and epidural analgesia for thoracic surgery: a systematic review and meta-analysis. AB - Though once considered the gold standard, epidural anaesthesia has complications that may be significant and include hypotension, urinary retention, partial or patchy block and, in rare cases, devastating neurological injuries also. Paravertebral block (PVB) is an alternative technique for unilateral surgical procedures like thoracotomy, which may offer similar analgesic effectiveness and a more favourable side-effect profile than epidural analgesia. This systematic review and meta-analysis of published randomized clinical trials aims to compare thoracic paravertebral with thoracic epidural analgesia (TEA) in thoracotomy for lung surgery. Five hundred and forty-one patients from 12 clinical trials have been included in this systematic review and meta-analysis. We found that visual analogue scale (VAS) scores at rest and during activity/coughing at 4-8, 24 and 48 h postoperatively were similar in both the PVB and TEA groups. Considering studies not included in the previous meta-analysis, a VAS score on activity at 48 h is significantly better in the PVB group (mean difference 0.40 cm; 95% confidence interval [95% CI] 0.77, 0.02; Mantel-Haenszel (M-H) fixed). Hypotension (odds ratio 0.13; 95% CI 0.06, 0.31; M-H fixed) and urinary retention are more common in the epidural analgesia group. So, we conclude that thoracic PVB may be as effective as thoracic epidural analgesia for post-thoracotomy pain relief and is also associated with fewer complications. PMID- 24488820 TI - Effect of neck muscle strength and anticipatory cervical muscle activation on the kinematic response of the head to impulsive loads. AB - BACKGROUND: Greater neck strength and activating the neck muscles to brace for impact are both thought to reduce an athlete's risk of concussion during a collision by attenuating the head's kinematic response after impact. However, the literature reporting the neck's role in controlling postimpact head kinematics is mixed. Furthermore, these relationships have not been examined in the coronal or transverse planes or in pediatric athletes. HYPOTHESES: In each anatomic plane, peak linear velocity (DeltaV) and peak angular velocity (Deltaomega) of the head are inversely related to maximal isometric cervical muscle strength in the opposing direction (H1). Under impulsive loading, DeltaV and Deltaomega will be decreased during anticipatory cervical muscle activation compared with the baseline state (H2). STUDY DESIGN: Descriptive laboratory study. METHODS: Maximum isometric neck strength was measured in each anatomic plane in 46 male and female contact sport athletes aged 8 to 30 years. A loading apparatus applied impulsive test forces to athletes' heads in flexion, extension, lateral flexion, and axial rotation during baseline and anticipatory cervical muscle activation conditions. Multivariate linear mixed models were used to determine the effects of neck strength and cervical muscle activation on head DeltaV and Deltaomega. RESULTS: Greater isometric neck strength and anticipatory activation were independently associated with decreased head DeltaV and Deltaomega after impulsive loading across all planes of motion (all P < .001). Inverse relationships between neck strength and head DeltaV and Deltaomega presented moderately strong effect sizes (r = 0.417 to r = 0.657), varying by direction of motion and cervical muscle activation. CONCLUSION: In male and female athletes across the age spectrum, greater neck strength and anticipatory cervical muscle activation ("bracing for impact") can reduce the magnitude of the head's kinematic response. Future studies should determine whether neck strength contributes to the observed sex and age group differences in concussion incidence. CLINICAL RELEVANCE: Neck strength and impact anticipation are 2 potentially modifiable risk factors for concussion. Interventions aimed at increasing athletes' neck strength and reducing unanticipated impacts may decrease the risk of concussion associated with sport participation. PMID- 24488822 TI - Poly(trimethylene carbonate) and biphasic calcium phosphate composites for orbital floor reconstruction: a feasibility study in sheep. AB - In the treatment of orbital floor fractures, bone is ideally regenerated. The materials currently used for orbital floor reconstruction do not lead to the regeneration of bone. Our objective was to render polymeric materials based on poly(trimethylene carbonate) (PTMC) osteoinductive, and to evaluate their suitability for use in orbital floor reconstruction. For this purpose, osteoinductive biphasic calcium phosphate (BCP) particles were introduced into a polymeric PTMC matrix. Composite sheets containing 50 wt% BCP particles were prepared. Also laminates with poly(D,L-lactide) (PDLLA) were prepared by compression moulding PDLLA films onto the composite sheets. After sterilisation by gamma irradiation, the sheets were used to reconstruct surgically-created orbital floor defects in sheep. The bone inducing potential of the different implants was assessed upon intramuscular implantation. The performance of the implants in orbital floor reconstruction was assessed by cone beam computed tomography (CBCT). Histological evaluation revealed that in the orbital and intramuscular implantations of BCP containing specimens, bone formation could be seen after 3 and 9 months. Analysis of the CBCT scans showed that the composite PTMC sheets and the laminated composite sheets performed well in orbital floor reconstruction. It is concluded that PTMC/BCP composites and PTMC/BCP composites laminated with PDLLA have osteoinductive properties and seem suitable for use in orbital floor reconstruction. PMID- 24488823 TI - Spatial control of bone formation using a porous polymer scaffold co-delivering anabolic rhBMP-2 and anti-resorptive agents. AB - Current clinical delivery of recombinant human bone morphogenetic proteins (rhBMPs) utilises freeze-dried collagen. Despite effective new bone generation, rhBMP via collagen can be limited by significant complications due to inflammation and uncontrolled bone formation. This study aimed to produce an alternative rhBMP local delivery system to permit more controllable and superior rhBMP-induced bone formation. Cylindrical porous poly(lactic-co-glycolic acid) (PLGA) scaffolds were manufactured by thermally-induced phase separation. Scaffolds were encapsulated with anabolic rhBMP-2 (20 ug) +/- anti-resorptive agents: zoledronic acid (5 ug ZA), ZA pre-adsorbed onto hydroxyapatite microparticles, (5 ug ZA/2% HA) or IkappaB kinase (IKK) inhibitor (10 ug PS 1145). Scaffolds were inserted in a 6-mm critical-sized femoral defect in Wistar rats, and compared against rhBMP-2 via collagen. The regenerate region was examined at 6 weeks by 3D microCT and descriptive histology. MicroCT and histology revealed rhBMP-induced bone was more restricted in the PLGA scaffolds than collagen scaffolds (-92.3% TV, p < 0.01). The regenerate formed by PLGA + rhBMP-2/ZA/HA showed comparable bone volume to rhBMP-2 via collagen, and bone mineral density was +9.1% higher (p < 0.01). Local adjunct ZA/HA or PS-1145 significantly enhanced PLGA + rhBMP-induced bone formation by +78.2% and +52.0%, respectively (p <= 0.01). Mechanistically, MG-63 human osteoblast-like cells showed cellular invasion and proliferation within PLGA scaffolds. In conclusion, PLGA scaffolds enabled superior spatial control of rhBMP-induced bone formation over clinically-used collagen. The PLGA scaffold has the potential to avoid uncontrollable bone formation-related safety issues and to customise bone shape by scaffold design. Moreover, local treatment with anti-resorptive agents incorporated within the scaffold further augmented rhBMP-induced bone formation. PMID- 24488824 TI - Stable mixed-valent radicals from platinum(II) complexes of a bis(dioxolene) ligand. AB - Three diplatinum(II) complexes [{PtL}2(MU-thea)] (H4thea = 2,3,6,7-tetrahydroxy 9,10-dimethyl-9,10-dihydro-9,10-ethanoanthracene) have been prepared, with diphosphine or bipyridyl "L" co-ligands. One-electron oxidation of these complexes gave radical cations containing a mixed-valent [thea.](3-) ligand with discrete catecholate and semiquinonate centers separated by quaternary methylene spacers. The electronic character of these radicals is near the Robin-Day class II/III border determined by UV/Vis/NIR and EPR spectroscopies. Crystal-structure determinations and a DFT calculation imply that oxidation of the thea(4-) ligand may lead to an increased through-space interaction between the dioxolene pi systems. PMID- 24488825 TI - Cytokines in serum in relation to future non-Hodgkin lymphoma risk: evidence for associations by histologic subtype. AB - Specific associations for lymphoma in the general population suggest that chronic immune dysfunction/dysregulation may be associated with the development of B-cell non-Hodgkin lymphoma (NHL). Furthermore, polymorphisms in several cytokine genes have been associated with increased lymphoma risk, most consistently with genes for TNF and IL10. To evaluate the hypothesis that prediagnostic circulating cytokine levels would be associated with increased B-cell lymphoma risk, we conducted a nested case-control study within the Women's Health Initiative Observational Study cohort involving 491 B-cell NHL cases and 491 controls. Levels of eleven cytokines, including IL1beta, IL2, IL4, IL5, IL6, IL10, IL12, IL13, TNF, IFNgamma and GM-CSF, were measured using a Luminex suspension bead based multiplexed array in prediagnostic serum samples collected a median of 6 years prior to the lymphoma diagnosis. We observed a modestly increased risk of all B-cell NHL in women with increased levels of the cytokines TNF and IL10 (OR1.22, CI 1.07-1.38 and OR 1.09, CI 1.04-1.15, respectively, per doubling in the serum cytokine concentration) and this association showed some variation according to histologic subtype. The increased risk was strongest for those neoplasms diagnosed in close proximity to the blood draw for some histologic subtypes but not others, suggesting a component of reverse causation. Further study will be required to better understand how genetic polymorphisms in TNF and IL10 genes may interact with circulating cytokine levels and states of chronic immune dysfunction/stimulation to contribute to the risk of B-cell NHL. PMID- 24488827 TI - Analysis of estrogens and estrogen mimics in edible matrices--a review. AB - This review provides a brief survey of the biological effects of selected endocrine-disrupting compounds that are formed after internal exposure of organisms. Further, the present analytical methods available for the determination of these compounds in foodstuffs are critically evaluated. The attention is primarily devoted to the methods for sample pretreatment, which are the main source of errors and are usually the most time-consuming step of the whole analysis. This review is focused on selected natural and synthetic estrogens, estrogen conjugates, and chemical additives used in the plastic industry that can act as estrogen mimics. PMID- 24488828 TI - Health-related quality of life worsens disproportionately to objective signs of psoriasis after withdrawal of adalimumab therapy. AB - INTRODUCTION: Health-related quality of life (HRQoL) is an important part of the clinical assessment and management of psoriasis. Few studies have investigated the effects of withdrawing treatment on the relationship between HRQoL and objective clinical manifestations of psoriasis. This post hoc subanalysis of a clinical trial (REVEAL) examined the relationship of HRQoL [assessed with the Dermatology Life Quality Index (DLQI)] and objective disease activity [assessed with the Psoriasis Area and Severity Index (PASI)] among patients before and after they underwent protocol-mandated discontinuation of psoriasis therapy. METHODS: Adult patients with moderate-to-severe plaque psoriasis who received adalimumab from baseline and had 75% or greater improvement in the PASI score at weeks 16 and 33 were re-randomized to adalimumab 40 mg or placebo every other week from weeks 33 to 52. DLQI and PASI scores were compared at baseline (week 0), early in treatment (week 4), directly before randomized withdrawal (week 33), and up to 19 weeks after treatment discontinuation (week 52; last observations carried forward). Correlations between DLQI total score and PASI score at week 4 and week 52 were modeled by linear regression. RESULTS: In the patients (N = 240) who underwent protocol-mandated discontinuation of psoriasis treatment after achieving PASI 75 response, mean PASI scores at week 52 were lower (i.e., better) compared with week 4, yet mean DLQI scores were higher (i.e., worse). An approximately twofold disproportionately greater degree of worsening of DLQI score compared with the degree of worsening of PASI was observed while patients underwent discontinuation of therapy (week 52) compared with early in treatment (week 4). There was a significant interaction (P < 0.0001) between the PASI-DLQI correlation and study period (week 4 or 52). CONCLUSION: Discontinuing therapy in patients who initially responded to treatment, as seen in this analysis with adalimumab, disproportionately worsened patient-reported HRQoL relative to the worsening of PASI. PMID- 24488826 TI - Hepatic cytochrome P450 ubiquitination: conformational phosphodegrons for E2/E3 recognition? AB - Hepatic endoplasmic reticulum (ER) integral cytochromes P450 (P450s) are monooxygenases engaged in the biotransformation and elimination of endo- as well as xenobiotics. Of the human liver P450s, CYP3A4 is the major and most dominant catalyst responsible for the biotransformation of over 50% of clinically prescribed drugs. CYP2E1 metabolizes smaller molecular weight compounds (EtOH), carcinogens, environmental toxins, and endobiotics, and is justly implicated in various toxigenic/pathogenic mechanisms of human disease. Both P450s are notorious for their potential to generate pathogenic reactive oxygen species (ROS) during futile oxidative cycling and/or oxidative uncoupling. Such ROS not only oxidatively damage the P450 catalytic cage, but on their escape into the cytosol, also the P450 outer surface and any surrounding cell organelles. Given their ER-monotopic topology coupled with this high potential to acquire oxidative lesions in their cytosolic (C) domain, not surprisingly these P450 proteins exhibit shorter lifespans and are excellent prototype substrates of ER-associated degradation ("ERAD-C") pathway. Indeed, we have shown that both CYP3A4 and CYP2E1 incur ERAD-C, during which they are first phosphorylated by protein kinases A and C, which greatly enhance/accelerate their ubiquitination by UBC7/gp78 and UbcH5a/CHIP/Hsp70/Hsp40 E2/E3 ubiquitin ligase complexes. Such P450 phosphorylation occurs on Ser/Thr residues within linear sequences as well as spatially clustered acidic (Asp/Glu) residues. We propose that such S/T phosphorylation within these clusters creates negatively charged patches or conformational phosphodegrons for interaction with positively charged E2/E3 domains. Such P450 S/T phosphorylation we posit serves as a molecular switch to turn on its ubiquitination and ERAD-C. PMID- 24488829 TI - Muscle disease. AB - On the basis of strong research evidence, Duchenne muscular dystrophy (DMD), the most common severe childhood form of muscular dystrophy, is an X-linked recessive disorder caused by out-of-frame mutations of the dystrophin gene. Thus, it is classified asa dystrophinopathy. The disease onset is before age 5 years. Patients with DMD present with progressive symmetrical limb-girdle muscle weakness and become wheelchair dependent after age 12 years. (2)(3). On the basis of some research evidence,cardiomyopathy and congestive heart failure are usually seen in the late teens in patients with DMD. Progressive scoliosis and respiratory in sufficiency often develop once wheelchair dependency occurs. Respiratory failure and cardiomyopathy are common causes of death, and few survive beyond the third decade of life. (2)(3)(4)(5)(6)(7). On the basis of some research evidence, prednisone at 0.75 mg/kg daily (maximum dose, 40 mg/d) or deflazacort at 0.9 mg/kg daily (maximum dose, 39 mg/d), a derivative of prednisolone (not available in the United States), as a single morning dose is recommended for DMD patients older than 5 years, which may prolong independent walking from a few months to 2 years. (2)(3)(16)(17). Based on some research evidence, treatment with angiotensin-converting enzyme inhibitors, b-blockers, and diuretics has been reported to be beneficial in DMD patients with cardiac abnormalities. (2)(3)(5)(18). Based on expert opinion, children with muscle weakness and increased serum creatine kinase levels may be associated with either genetic or acquired muscle disorders (Tables 1 and 3). (14)(15) PMID- 24488830 TI - The clinician's guide to autism. AB - On the basis of the most recent epidemiologic research, Autism Spectrum Disorder (ASD) affects approximately 1% to 2% of all children. (1)(2) On the basis of some research evidence and consensus, the Modified Checklist for Autism in Toddlers isa helpful tool to screen for autism in children between ages 16 and 30 months. (11) The Diagnostic Statistical Manual of Mental Disorders, Fourth Edition, changes to a 2-symptom category from a 3-symptom category in the Diagnostic Statistical Manual of Mental Disorders, Fifth Edition(DSM-5): deficits in social communication and social interaction are combined with repetitive and restrictive behaviors, and more criteria are required per category. The DSM-5 subsumes all the previous diagnoses of autism (classic autism, Asperger syndrome, and pervasive developmental disorder not otherwise specified) into just ASDs. On the basis of moderate to strong evidence, the use of applied behavioral analysis and intensive behavioral programs has a beneficial effect on language and the core deficits of children with autism. (16) Currently, minimal or no evidence is available to endorse most complementary and alternative medicine therapies used by parents, such as dietary changes (gluten free), vitamins, chelation, and hyperbaric oxygen. (16) On the basis of consensus and some studies, pediatric clinicians should improve their capacity to provide children with ASD a medical home that is accessible and provides family-centered, continuous, comprehensive and coordinated, compassionate, and culturally sensitive care. (20) PMID- 24488831 TI - Congenital muscular torticollis and positional plagiocephaly. AB - On the basis of observational studies, child health practitioners in primary care settings should consider the diagnosis of congenital muscular torticollis (CMT)in infants with risk factors from birth history for intrauterine malpositioning or constraint (C). On the basis of observational studies, CMT is often associated with other conditions, including positional plagiocephaly and gross motor delays from weakened truncal muscles and/or lack of head control in early infancy (C). On the basis of observational studies, child health practitioners should counsel parents that infants should be on their stomachs frequently whenever they are awake and under direct adult supervision to develop their prone motor skills (C). On the basis of consensus, early identification of CMT(with or without positional plagiocephaly) and prompt referral to a physical therapist experienced in the treatment of CMT should be considered to avoid more costly or invasive treatments, such as cranial orthoses or surgery (D). PMID- 24488832 TI - Index of suspicion. PMID- 24488833 TI - Mastoiditis. PMID- 24488834 TI - Visual diagnosis: 12-year-old girl with constipation and rectal bleeding. AB - Rectal duplication cysts are rare, thought to be due to defects in embryologic development, and often associated with other structural abnormalities. Clues to the existence of a rectal cyst are mainly due to bowel compression and presence of ectopic gastric mucosa within the cyst, leading to rectal bleeding. The diagnosis of a rectal duplication cyst requires a high index of suspicion. Confirming the diagnosis can be difficult based on the location of the cyst. Efforts to confirm the diagnosis include digital rectal examination, computed tomography, magnetic resonance imaging, ultrasonography, and Meckel scan. Surgical resection is the treatment of choice, especially because of the cyst's potential for malignant transformation. Because of the cyst's proximal location to the nerves innervating the anal canal and sphincters, surgical resection can lead to fecal incontinence. PMID- 24488835 TI - Factors associated with recovery from anorexia nervosa: a population-based study. AB - BACKGROUND: To examine factors associated with the outcome of anorexia nervosa among women from the general population. METHOD: Women (N = 2,881) from the 1975 1979 birth cohorts of Finnish twins were screened for lifetime DSM-IV anorexia nervosa (N = 55 cases) using questionnaires and the SCID interview. Potential factors associated with the likelihood of recovery were addressed in the same assessment. Recovery was defined as restoration of weight, menstruation, and the absence of bingeing and purging for at least one year prior to assessment. Using two-tailed t tests and Pearson's chi-square tests, we contrasted recovered (N = 39) and unrecovered (N = 16) women. We then used logistic regression adjusted for duration of illness and Cox proportional hazard models to account for the variable lengths of illness on prognostic factors. RESULTS: Unrecovered women were more likely to suffer from depressive symptoms prior to eating disorder onset (18.8% vs. 2.6%, p = 0.04), remain unemployed (18.8% vs. 2.6%, p = 0.04), report dissatisfaction with their current partner/spouse (p = 0.02), and report high perfectionism (p = 0.05) than were recovered women. When duration of illness was accounted for in the analyses, premorbid depression was the sole factor significantly associated with decreased likelihood of recovery (hazard ratio 0.17, 95% confidence interval: 0.03-0.89). DISCUSSION: Predicting the course of anorexia remains fraught with difficulty, but premorbid depressive symptoms are associated with poor outcome of anorexia nervosa in the general population. PMID- 24488836 TI - Typical and atypical anorexia nervosa in a Japanese sample. AB - OBJECTIVE: We examined the existence of nonfat-phobic anorexia nervosa (NFP-AN) and fat-phobic AN, with no evidence of distortions related to body shape and weight (AN-NED), in a Japanese sample and studied eating disorder pathology and psychopathology in NFP-AN and AN-NED. METHOD: The study participants were 200 (52.2%) women with typical AN, 86 (22.5%) women with NFP-AN, and 97 (25.3%) women with AN-NED. Diagnosis of the three types of AN was made by structured clinical interviews. The Eating Attitudes Test (EAT) and the Eating Disorder Inventory (EDI) were administered to all the participants. RESULTS: There were significant differences among the three groups in terms of duration of illness, maximum and minimum BMIs and AN subtypes. There was no transition from the NFP-AN and AN-NED groups to the typical AN group during the 2- to 7-year follow-up period. There were significant differences among the three groups in scores of the EAT, the EDI total, and all the subscales of the EDI. DISCUSSION: Besides typical AN, there were two types of atypical AN in terms of fat phobia and body image disturbance in this Japanese sample. The findings of the current study suggest that there may be significant differences among the three groups in terms of eating disorder pathology and psychopathology. PMID- 24488837 TI - Examining implicit attitudes toward emaciation and thinness in anorexia nervosa. AB - OBJECTIVE: To determine if females with anorexia nervosa (AN) associate emaciation with beauty by examining implicit attitudes toward emaciated bodies relative to thin bodies. METHOD: Thirty women with AN and 29 healthy control women were primed by viewing images of either emaciated or thin women. Participants then completed a lexical decision task (LDT), wherein they distinguished words from nonwords as quickly and accurately as possible. Response times were measured. Real words consisted of beautiful, ugly, neutral, and positive words. Body mass index (BMI) was measured and several clinical interviews were completed, including the Eating Disorders Examination Questionnaire 4 (EDEQ-4). RESULTS: There was a significant effect of group in the emaciated condition; participants with AN responded faster to both beautiful and ugly words than control women did. Eating disorder symptom severity (as measured by the EDEQ-4 subscales) predicted the strength of the association between emaciation and beauty. DISCUSSION: At an implicit, automatic level, women with AN in this study had stronger associations between emaciation and both beauty and ugliness than control women did, suggesting that women with AN may have atypical beliefs about beauty. Thin ideal internalization is an important factor in the development and maintenance of eating disorders; the type of thin ideal being internalized may be important to consider, particularly given the extent to which pro-eating disorder websites promote idealization of emaciation. The associations found by using the LDT highlight the utility of implicit measures, particularly when conducting assessments involving sensitive or atypical beliefs. PMID- 24488839 TI - Diamine oxidase activity levels in anorexia nervosa. AB - OBJECTIVE: Anorexia nervosa (AN) patients often experience gastrointestinal complications caused by their malnutrition. We hypothesized that intestinal integrity is disturbed in AN. Therefore, the objective of the present study was to investigate serum diamine oxidase (DAO) activity, which is considered to be a clinical indicator of the integrity of the intestinal mucosa, in AN patients. METHOD: Thirty-six AN female patients including 21 AN restricting type (AN-R) and 15 AN binge-eating/purging type (AN-BP) were compared with twenty healthy women on serum DAO activity using immunoassay. RESULTS: DAO levels in AN-R patients were significantly lower than in AN-BP patients and healthy controls. DISCUSSION: DAO levels were decreased in AN-R patients. This finding suggests the presence of intestinal structural disturbance as one of the physical complications of malnutrition in AN-R patients. PMID- 24488838 TI - Confronting fear using exposure and response prevention for anorexia nervosa: A randomized controlled pilot study. AB - OBJECTIVE: Anorexia nervosa (AN) is a severe illness with high rates of relapse. Exposure and Response Prevention for AN (AN-EXRP) is a new approach that specifically addresses maladaptive eating behavior by targeting eating-related fear and anxiety. The aim of this study was to evaluate AN-EXRP as an adjunctive strategy to improve eating behavior during weight restoration, at a pivotal moment when treatment goals shift toward relapse prevention. METHOD: A randomized controlled trial was conducted to compare AN-EXRP with a comparison condition, Cognitive Remediation Therapy (CRT). Hospitalized patients with AN (n = 32) who had achieved weight restoration to a BMI > 18.5 kg/m(2) received 12 sessions of either AN-EXRP or CRT. Outcome was assessed by change in caloric intake in an objective assessment of eating behavior. RESULTS: The average test meal caloric intake of participants who received AN-EXRP increased from 352 +/- 263 kcal at baseline to 401 +/- 215 kcal post-treatment, while that of participants who received CRT decreased from 501 +/- 232 kcal at baseline to 424 +/- 221 kcal post treatment [t(28) = 2.5, p = .02]. Improvement in intake was significantly associated with improvement in eating-related anxiety (Spearman's rho = 0.40, p = .03). DISCUSSION: These data demonstrate that AN-EXRP, compared to a credible comparison intervention, is associated with better caloric intake in a laboratory meal over time in AN. Additional studies are required to determine whether incorporation of these techniques into a longer treatment program leads to enduring and clinically significant change. PMID- 24488840 TI - Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain. AB - Insomnia, depression, and anxiety disorder are common problems for people with neuropathic pain. In this study, mild noxious heat stimuli increased the duration and number of spontaneous pain-like behaviors in sciatic nerve-ligated mice. We used functional magnetic resonance imaging to visualize the increased blood oxygenation level-dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve ligated mice. In addition, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Furthermore, glutamate induced the translocation of GAT-3 to astrocyte cell membranes using primary cultured glial cells from the mouse cortex. Moreover, the GABA level at the synaptic cleft in the ACC of nerve ligated mice was significantly decreased exposure to mild noxious stimuli. Finally, we investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool channel rhodopsin-2 (ChR2), we demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, these results suggest that neuropathic pain-like stimuli activated astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, these findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice. PMID- 24488841 TI - Editorial. PMID- 24488842 TI - Kingella kingae septic arthritis in children: recognising an elusive pathogen. AB - PURPOSE: Kingella kingae is an increasingly identified cause of musculoskeletal infections in young children. We report our experience with a recently developed polymerase chain reaction (PCR) method and review the clinical course of children diagnosed with K. kingae septic arthritis in a tertiary referral paediatric hospital. METHODS: All positive cases of K. kingae identified by PCR analysis of synovial fluid from August 2010 until July 2013 were included. A chart review was undertaken to determine history, presentation and management. RESULTS: 27 Children (14 male, 13 female) had PCR positive synovial fluid samples for K. kingae with median age of 19 months (range 4 months to 5 years 3 months). The sites of infection were knee (17 cases), hip (2 cases), ankle (5 cases), shoulder (2 cases) and elbow. The median temperature on presentation was 37.1 degrees C, median peripheral white blood cell count 12.4 (9.9-13.8) * 10(9)/L, erythrocyte sedimentation rate 55 (48-60) mm/h and C-reactive protein 24 (8-47) mg/L. The median synovial fluid white cell count was 21.8 (16.7-45.0) * 10(9)/L. Routine cultures identified K. kingae in only two synovial fluid samples. Two samples were additionally positive for Staphylococcus aureus. CONCLUSIONS: Kingella kingae is a significant cause of septic arthritis in young children. The authors recommend maintaining a high index of suspicion in young children presenting with joint inflammation, especially if indices of infection are mild. It appears likely that children historically treated with antibiotics for "culture negative" septic arthritis were infected with K. kingae. PCR techniques for detection of K. kingae should be encouraged. PMID- 24488843 TI - LCP 140 degrees Pediatric Hip Plate for fixation of proximal femoral valgisation osteotomy. AB - PURPOSE: Femoral osteotomy is one of the most widely performed reconstructive operations in pediatric orthopedic surgery. Many implants for fixation have been used, but so far there is no literature about the application and outcome of the LCP 140 degrees Pediatric Hip Plate for proximal femoral valgisation in children. METHODS: Data of patients with a valgisation of the proximal femur using the LCP 140 degrees Pediatric Hip Plate between February 2011 and July 2012 were retrospectively collected and analyzed. RESULTS: We included 10 patients (11 hips) with a mean follow-up of 15.3 +/- 6.3 months (range 5.6-23 months). The mean age was 9.6 +/- 1.2 years (range 7.3-11.8 years) with a mean hospital stay of 5.2 +/- 1.7 days (range 3-9 days). Callus formation was observed in all cases at 6 weeks postoperative control and consolidation was shown after a mean time of 14.1 +/- 2.3 weeks (range 12.1-19.1 weeks). There was no delayed union or any case of non-union in our series. The stability of the operative reduction including the corrected neck-shaft angle (mean 19 degrees +/- 7.9 degrees ; range 10.5 degrees -38.5 degrees ) was maintained during the follow-up period. No cases of recurrence (varisation) or complications requiring further treatment or revision were observed. CONCLUSIONS: In our series, the 140 degrees LCP Pediatric Hip Plate was shown to be safe and applicable in the clinical setting with good results. We therefore consider this device to be valuable for the correction of pathologic varus conditions of the proximal femur in children. PMID- 24488844 TI - Stair falls: caregiver's "missed step" as a source of childhood fractures. AB - BACKGROUND: The purpose of this study was to describe fractures sustained by children and to analyze the associated costs when a caretaker falls down stairs while holding a child. MATERIALS AND METHODS: Between 2004 and 2012, 16 children who sustained a fracture after a fall down stairs while being carried by a caregiver were identified. Parents/caregivers were interviewed to see how the fall occurred, and a cost analysis was performed. RESULTS: The average age of the patients was 14.5 months (7-51 months). The lower extremity was involved in 15 of 16 fractures, with 8 involving the femur. The majority were buckle fractures, but all diaphyseal femur fractures were spiral. Three patients required a reduction in the operating room. All fractures healed with cast immobilization. Five patients underwent skeletal surveys, as the treating physicians were concerned about potential child abuse. The average cost of treatment was $6785 (range $948 45,876). Detailed histories from the caregivers showed that they "missed a step" due to the child being carried in front of the caregiver, obscuring their vision. CONCLUSIONS: A fall in a caregiver's arms while going down stairs can result in multiple orthopedic injuries. The costs of treating these injuries are not insignificant, and the suspicion of child abuse can be both costly and unnecessary in the case of a true accident. While descending the stairs with a child in their arms, the caregiver should hold the child to the side so as not to obscure their vision of the step with one arm, ideally holding the handrail with the other. LEVEL OF EVIDENCE: IV case series. PMID- 24488845 TI - An operative approach to address severe genu valgum deformity in the Ellis-van Creveld syndrome. AB - BACKGROUND: The genu valgum deformity seen in the Ellis-van Creveld syndrome is one of the most severe angular deformities seen in any orthopaedic condition. It is likely a combination of a primary genetic-based dysplasia of the lateral portion of the tibial plateau combined with severe soft-tissue contractures that tether the tibia into valgus deformations. Progressive weight-bearing induces changes, accumulating with growth, acting on the initially distorted and valgus angulated proximal tibia, worsening the deformity with skeletal maturation. The purpose of this study is to present a relatively large case series of a very rare condition that describes a surgical technique to correct the severe valgus deformity in the Ellis-van Creveld syndrome by combining extensive soft-tissue release with bony realignment. METHODS: A retrospective review examined 23 limbs in 13 patients with Ellis-van Creveld syndrome that were surgically corrected by two different surgeons from 1982 to 2011. Seven additional patients were identified, but excluded due to insufficient chart or radiographic data. A successful correction was defined as 10 degrees or less of genu valgum at the time of surgical correction. Although not an outcomes study, maintenance of 20 degrees or less of genu valgum was considered desirable. Average age at surgery was 14.7 years (range 7-25 years). Clinical follow-up is still ongoing, but averages 5.0 years (range 2 months to 18 years). Charts and radiographs were reviewed for complications, radiographic alignment, and surgical technique. The surgical procedure was customized to each patient's deformity, consisting of the following steps: 1. Complete proximal to distal surgical decompression of the peroneal nerve 2. Radical release and mobilization of the severe quadriceps contracture and iliotibial band contracture 3. Distal lateral hamstring lengthening/tenotomy and lateral collateral ligament release 4. Proximal and distal realignment of the subluxed/dislocated patella, medial and lateral retinacular release, vastus medialis advancement, patellar chondroplasty, medial patellofemoral ligament plication, and distal patellar realignment by Roux Goldthwait technique or patellar tendon transfer with tibial tubercle relocation 5. Proximal tibial varus osteotomy with partial fibulectomy and anterior compartment release 6. Occasionally, distal femoral osteotomy RESULTS: In all cases, the combination of radical soft-tissue release, patellar realignment and bony osteotomy resulted in 10 degrees or less of genu valgum at the time of surgical correction. Complications of surgery included three patients (five limbs) with knee stiffness that was successfully manipulated, one peroneal nerve palsy, one wound slough and hematoma requiring a skin graft, and one pseudoarthrosis requiring removal of hardware and repeat fixation. At last follow up, radiographic correction of no more than 20 degrees of genu valgum was maintained in all but four patients (four limbs). Two patients (three limbs) had or currently require revision surgery due to recurrence of the deformity. CONCLUSION: The operative approach presented in this study has resulted in correction of the severe genu valgum deformity in Ellis-van Creveld syndrome to 10 degrees or less of genu valgum at the time of surgery. Although not an outcomes study, a correction of no more than 20 degrees genu valgum has been maintained in many of the cases included in the study. Further clinical follow-up is still warranted. LEVEL OF EVIDENCE: IV. PMID- 24488846 TI - A protocol for the management of pediatric type I open fractures. AB - BACKGROUND: The management of pediatric type I open fractures remains controversial. There has been no consistent protocol established in the literature for the non-operative management of these injuries. METHODS: A protocol was developed at our institution for the non-operative management of pediatric type I open forearm fractures. Each patient was given a dose of intravenous antibiotics at the time of the initial evaluation in the emergency department. The wound was then irrigated and a closed reduction performed in the emergency department. The patient was admitted for three doses of intravenous antibiotics (over approximately a 24-h period) and then discharged home without oral antibiotics. RESULTS: In total, 45 consecutive patients were managed with this protocol at our hospital between 2004 and 2008. The average age was 10 (range 4-17) years. The average number of doses of intravenous antibiotics was 4.06 per patient. Thirty patients (67 %) received cefazolin (Ancef(r)) as the treating medication and 15 patients received clindamycin (33 %). There were no infections in any of the 45 patients. CONCLUSION: In this study we outline a consistent management protocol for type I open pediatric forearm fractures that has not previously been documented in the literature. Our results corroborate the those reported in the literature that pediatric type I open fractures may be managed safely in a non-operative manner. There were no infections in our prospective series of 45 consecutive type I open pediatric forearm fractures using our protocol. Using a protocol of only four doses of intravenous antibiotics (one in the emergency department and three additional doses during a 24-h hospital admission) is a safe and efficient method for managing routine pediatric type I open fractures non-operatively. PMID- 24488848 TI - The epidemiology of transient synovitis in Liverpool, UK. AB - BACKGROUND: The epidemiology of transient synovitis is poorly understood, and the aetiology is unknown, although a suggestion of a viral association predominates. PURPOSE: This population-based study investigated the epidemiology in order to formulate aetiological theories of pathogenesis. PATIENT AND METHODS: Cases in Merseyside were identified between 2004 and 2009. Incidence rates were determined and analysed by age, sex, season and region of residence. Socioeconomic deprivation scores were generated using the Index of Multiple Deprivation, allocated by postcode. Poisson confidence intervals were calculated and Poisson regression was used to check for trends. RESULTS: Two hundred and fifty-nine cases were identified over 5.5 years. The annual incidence was 25.1 (95 % CI 22.1 28.5) per 100,000 0-14 year-olds. Male to female ratio was 3.2:1 (p < 0.001). Mean age at presentation was 5.4 years (95 % CI 5.0-5.8), which demonstrated a near-normal distribution. No relationship was identified between seasonality and incidence (p = 0.64). A correlation was identified with socioeconomic deprivation in Merseyside: incidence rate ratio 1.16 (95 % CI 1.06-1.26, p < 0.001), although further analysis within the subregion of Liverpool did not confirm this finding (p = 0.35). CONCLUSIONS: The normal distribution for age at disease presentation suggests a specific disease entity. The absence of seasonality casts some doubt on the popular theory of a viral aetiology. The absence of a consistent socioeconomic gradient in both Merseyside and Liverpool challenges a previous suggestion of an association with Perthes' disease. This paper provides ecological evidence that may challenge existing aetiological theories, though transient synovitis remains an enigma. PMID- 24488847 TI - Long-term results of a nationwide general ultrasound screening system for developmental disorders of the hip: the Austrian hip screening program. AB - BACKGROUND: Diagnosis and early treatment of developmental dysplasia of the hip (DDH) continue to be issues of discussion. In 1992, a nationwide general ultrasound screening program using Graf technique was introduced to detect DDH in Austria. We investigated the effects of this program on the rates of operative and conservative interventions and the influence of the program on the number of hospital admissions for the treatment of DDH. METHODS: All cases of DDH documented in Austrian hospitals from 1992 to 2008 were included in this retrospective study. The database of the Austrian Ministry of Health was used to extract documented diagnoses and treatments. RESULTS: Since the introduction of the screening program, the number of patients who require pelvic surgery to treat DDH has decreased by 46 % and the number of open reductions is as low as 0.16 per 1,000 live births. Hospital admissions for the treatment of DDH decreased from 9.5 to 3.6 per 1,000 live births. All noted results gained statistical significance. CONCLUSION: Compared with routine clinically based screening programs, our results confirm low numbers of open reductions and pelvic surgeries. We, therefore, advocate a standardized nationwide general ultrasound screening program to reduce the rates of operative interventions and hospital admissions associated with the treatment of DDH. LEVEL OF EVIDENCE: Level III, diagnostic. PMID- 24488849 TI - Lumbo-sacral motion conserved after isthmic reconstruction: long-term results. AB - PURPOSE: The purpose of this study was to analyze the clinical and radiological results of repair of the interarticularis pars defect by a modified Buck's repair technique in patients with symptomatic spondylolysis with grade 1 spondylolisthesis. These patients with painful spondylolisthesis are the most eligible for direct repair of the defect rather than lumbo-sacral fusion in an attempt to save motion segments. METHODS: Forty-six patients with symptomatic spondylolysis with grade 1 spondylolisthesis and normal L4-L5 and L5-S1 disks, following the failure of conservative treatment, underwent surgery between 1988 and 2010. All interventions involved direct pars repair by a modified Buck's repair technique with internal fixation of the defect using screws and cancellous bone grafting. The Oswestry Disability Index (ODI) was used to evaluate the functional outcome. Healing of the pars defect was assessed by plain radiographs and computed tomography (CT) scanning. Motion of the L4-L5 and L5-S1 segments was measured with dynamic radiographs in flexion and extension. RESULTS: Thirty-five patients were evaluated. The mean follow-up period was 10 years. Functional outcome was excellent in 22 patients (ODI <= 10) and good for 8 patients (10 < ODI <= 20); five patients continued to have pain (ODI >20). Isthmus bone union occurred in 32 of 35 patients (91.4 %). L4-L5 motion was conserved with a mean angle of 11.8 degrees (0-22); the mean lumbo-sacral angle was 9.9 degrees (0 21). CONCLUSION: Direct repair of spondylolisthesis was described to avoid fusion in young patients with slight slipping and painful symptoms. A modified Buck's repair technique allows the conservation of L4-L5 motion with a rate of consolidation comparable to other series. The anatomy and stability of the spine were normalized by restoring the continuity of the loose posterior elements using this modified Buck's technique. PMID- 24488850 TI - Measuring flares in rheumatoid arthritis. (Why) do we need validated criteria? PMID- 24488851 TI - Belimumab in systemic lupus erythematosus -- what can be learned from longterm observational studies? PMID- 24488852 TI - Pannus tissue mimicking enchondroma. PMID- 24488853 TI - Immunoglobulin G subclass profile of anticitrullinated peptide antibodies specific for Epstein Barr virus-derived and histone-derived citrullinated peptides. PMID- 24488854 TI - Human bartonella infective endocarditis is associated with high frequency of antiproteinase 3 antibodies. PMID- 24488855 TI - Chondrogenic differentiation of human bone marrow-derived mesenchymal stem cells in a simulated osteochondral environment is hydrogel dependent. AB - Hydrogels pose interesting features for cartilage regeneration strategies, such as the option for injectability and in situ gelation resulting in optimal filling of defects. We aimed to study different hydrogels for their capability to support chondrogenesis of human bone marrow-derived mesenchymal stem cells (hBMSCs). hBMSCs were encapsulated in alginate, alginate with hyaluronic acid (alginate/HA), fibrin or thermoresponsive HA grafted with poly(N-isopropyl acrylamide) side-chains (HA-pNIPAM). Glycosaminoglycan production and cartilage related gene expression were significantly higher in hBMSC-alginate and hBMSC fibrin constructs than in the other constructs. Supplementation of alginate with HA was not beneficial. hBMSC-alginate, hBMSC-fibrin and hBMSC-HA-pNIPAM constructs were placed in simulated defects in osteochondral biopsies and cultured in vitro for 28 d. Biopsies containing hBMSC-alginate and hBMSC-fibrin were implanted subcutaneously in nude mice for 12 weeks. hBMSC-alginate constructs had significantly higher cartilage-related gene expression after 28 d of culture as well as significantly more safranin-O positive repair tissue after 12 weeks in vivo than hBMSC-fibrin constructs. Although initial experiments with hBMSC-hydrogel constructs suggested comparable results of hBMSC-alginate, hBMSC fibrin and hBMSC-HA-pNIPAM constructs, culture in the osteochondral biopsy model in vitro as well as in vivo revealed differences, suggests that chondrogenesis of hBMSCs in an osteochondral environment is hydrogel-dependent. PMID- 24488857 TI - Axial vessel widening in arborescent monocots. AB - Dicotyledons have evolved a strategy to compensate for the increase in hydraulic resistance to water transport with height growth by widening xylem conduits downwards. In monocots, the accumulation of hydraulic resistance with height should be similar, but the absence of secondary growth represents a strong limitation for the maintenance of xylem hydraulic efficiency during ontogeny. The hydraulic architecture of monocots has been studied but it is unclear how monocots arrange their axial vascular structure during ontogeny to compensate for increases in height. We measured the vessel lumina and estimated the hydraulic diameter (Dh) at different heights along the stem of two arborescent monocots, Bactris gasipaes (Kunth) and Guadua angustifolia (Kunth). For the former, we also estimated the variation in Dh along the leaf rachis. Hydraulic diameter increased basally from the stem apex to the base with a scaling exponent (b) in the range of those reported for dicot trees (b = 0.22 in B. gasipaes; b = 0.31 and 0.23 in G. angustifolia). In B. gasipaes, vessels decrease in Dh from the stem's centre towards the periphery, an opposite pattern compared with dicot trees. Along the leaf rachis, a pattern of increasing Dh basally was also found (b = 0.13). The hydraulic design of the monocots studied revealed an axial pattern of xylem conduits similar to those evolved by dicots to compensate and minimize the negative effect of root-to-leaf length on hydrodynamic resistance to water flow. PMID- 24488856 TI - Physiological strategies of co-occurring oaks in a water- and nutrient-limited ecosystem. AB - Oak species are well suited to water-limited conditions by either avoiding water stress through deep rooting or tolerating water stress through tight stomatal control. In co-occurring species where resources are limited, species may either partition resources in space and/or time or exhibit differing efficiencies in the use of limited resources. Therefore, this study seeks to determine whether two co occurring oak species (Quercus prinus L. and Quercus velutina Lam.) differ in physiological parameters including photosynthesis, stomatal conductance, water use (WUE) and nitrogen-use efficiency (NUE), as well as to characterize transpiration and average canopy stomatal responses to climatic variables in a sandy, well-drained and nutrient-limited ecosystem. The study was conducted in the New Jersey Pinelands and we measured sap flux over a 3-year period, as well as leaf gas exchange, leaf nitrogen and carbon isotope concentrations. Both oak species showed relatively steep increases in leaf-specific transpiration at low vapor pressure deficit (VPD) values before maximum transpiration rates were achieved, which were sustained over a broad range in VPD. This suggests tight stomatal control over transpiration in both species, although Q. velutina showed significantly higher leaf-level and canopy-level stomatal conductance than Q. prinus. Average daytime stomatal conductance was positively correlated with soil moisture and both oak species maintained at least 75% of their maximum canopy stomatal conductance at soil moistures in the upper soil layer (0-0.3 m) as low as 0.03 m(3) m(3)(-3). Quercus velutina had significantly higher photosynthetic rates, maximum Rubisco-limited and electron-transport-limited carboxylation rates, dark respiration rates and nitrogen concentration per unit leaf area than Q. prinus. However, both species exhibited similar WUEs and NUEs. Therefore, Q. prinus has a more conservative resource-use strategy, while Q. velutina may need to exploit niches that are locally higher in nutrients and water. Likewise, both species appear to tap deep, stable water sources, highlighting the importance of rooting depth in modeling transpiration and stomatal conductance in many oak ecosystems. PMID- 24488858 TI - Is the use of cuttings a good proxy to explore phenological responses of temperate forests in warming and photoperiod experiments? AB - For obvious practical reasons, tree phenological data obtained in warming and photoperiod experiments are generally conducted on juvenile trees (saplings and seedlings) or on watered or rooted cuttings collected from adult trees. As juvenile trees differ from adult trees in their phenological response to environmental conditions, they represent inappropriate plant material to experimentally assess the phenological responses of forests to seasonality. Cuttings are physiologically closer to adult trees, but cutting itself and the disruption of hormonal signals may create artefacts. This study aimed to investigate the potential deviation between phenological responses of cuttings vs donor trees. We hypothesized that, once dormant, buds may respond autonomously to environmental influences such as chilling, photoperiod and warming, and, thus, cuttings may exhibit similar phenological responses to mature trees. We compared bud development of seedlings, saplings and mature trees of three deciduous tree species with bud development of cuttings that were excised from both saplings and adults and positioned in situ in the vicinity of adult trees within a mature mixed forest in the foothills of the Swiss Jura Mountains. No significant difference was detected in the timing of bud burst between cuttings and donor trees for the three studied tree species when the vertical thermal profile was accounted for. However, a significant difference in the timing of flushing was found between seedlings, saplings and adults, with earlier flushing during the juvenile stage. At least for the three studied species, this study clearly demonstrates that cuttings are better surrogates than juvenile trees to assess potential phenological responses of temperate forests to climate change in warming and photoperiod experiments. PMID- 24488859 TI - Minimally invasive therapy for fetal sacrococcygeal teratoma: case series and systematic review of the literature. AB - OBJECTIVE: Large solid sacrococcygeal teratomas (SCT) can cause high-output cardiac failure and fetal or neonatal death. The aim of this study was to describe the outcomes of minimally invasive antenatal procedures for the treatment of fetal SCT. METHODS: A case review was performed of five fetuses with a large SCT treated antenatally using minimally invasive techniques, and a systematic literature review on fetal therapy for solid SCTs was carried out. RESULTS: Five women were referred between 17 + 5 and 26 + 4 weeks' gestation for a large fetal SCT with evidence of fetal cardiac failure. Vascular flow to the tumors was interrupted by fetoscopic laser ablation (n = 1), radiofrequency ablation (RFA; n = 2) or interstitial laser ablation +/- vascular coiling (n = 2). There were two intrauterine fetal deaths. The other three cases resulted in preterm labor within 10 days of surgery. One neonate died. Two survived without procedure-related complications but had long-term morbidity related to prematurity. The systematic literature review revealed 16 SCTs treated minimally invasively for (early) hydrops. Including our cases, six of 20 hydropic fetuses survived after minimally invasive therapy (30%). Survival after RFA or interstitial laser ablation was 45% (5/11). Of 12 fetuses treated for SCT without obvious hydrops and for which perinatal survival data were available, eight (67%) survived. Mean gestational age at delivery after minimally invasive therapy was 29.7 +/- 4.0 weeks. Survival after open fetal surgery in hydropic fetuses was 6/11 (55%), with a mean gestational age at delivery of 29.8 +/- 2.9 weeks. CONCLUSIONS: Fetal therapy can potentially improve perinatal outcomes for hydropic fetuses with a solid SCT, but is often complicated by intrauterine death and preterm birth. PMID- 24488860 TI - Giant remnant of fetal circulation leading to cyanosis: pseudo-cor triatriatum dexter. AB - Remnants of the right valve of the sinus venosus, which fail to regress may present as an obstructing membrane within the right atrium as a very rare congenital anomaly. When associated with an atrial septal defect, primary cyanosis may occur due to a large right-to-left shunt. We report on a 1-week old girl with a pseudo-cor triatriatum dexter and immediate cyanosis after an uncomplicated birth. She was successfully treated with surgical excision of the obstructing membrane. PMID- 24488861 TI - Expanding the mutational spectrum of CRLF1 in Crisponi/CISS1 syndrome. AB - Crisponi syndrome (CS) and cold-induced sweating syndrome type 1 (CISS1) share clinical characteristics, such as dysmorphic features, muscle contractions, scoliosis, and cold-induced sweating, with CS patients showing a severe clinical course in infancy involving hyperthermia associated with death in most cases in the first years of life. To date, 24 distinct CRLF1 mutations have been found either in homozygosity or in compound heterozygosity in CS/CISS1 patients, with the highest prevalence in Sardinia, Turkey, and Spain. By reporting 11 novel CRLF1 mutations, here we expand the mutational spectrum of CRLF1 in the CS/CISS1 syndrome to a total of 35 variants and present an overview of the different molecular and clinical features of all of them. To catalog all the 35 mutations, we created a CRLF1 mutations database, based on the Leiden Open (source) Variation Database (LOVD) system (https://grenada.lumc.nl/LOVD2/mendelian_genes/variants). Overall, the available functional and clinical data support the fact that both syndromes actually represent manifestations of the same autosomal-recessive disorder caused by mutations in the CRLF1 gene. Therefore, we propose to rename the two overlapping entities with the broader term of Crisponi/CISS1 syndrome. PMID- 24488862 TI - Six1: a critical transcription factor in tumorigenesis. AB - In the past two decades, many studies have shown that sine oculis homeobox 1 (Six1) is a powerful regulator of organogenesis and disease, with important roles in tumorigenesis; therefore, it is important to review the biology of Six1 gene comprehensively. This review describes the function of Six1 in normal organ development, summarizes its role in several diseases, including cancer. The review will extend our understanding about the functional roles of Six1 and suggests opportunities to target Six1 for diagnostic, prognostic, and therapeutic purposes. PMID- 24488863 TI - The role of long noncoding RNAs in the epigenetic control of gene expression. AB - Recent advances in the methodologies employed to deeply analyse the complexity of transcriptomes have unveiled the existence of a new class of transcripts, long noncoding RNAs (lncRNAs). A significant amount of effort has been dedicated to the study of lncRNAs, and a large body of evidence now exists indicating their relevant role in different regulatory steps of gene expression. Given the role of epigenetics in disease development and progression, this Minireview focuses on lncRNAs involved in epigenetic control and provides an overview of the mechanisms used to guide epigenetic-modifying complexes to adjacent (cis-acting) or independent (trans-acting) genomic loci. Furthermore, it describes the activities of these transcripts in controlling the formation and spreading of heterochromatin domains. Just as other RNA molecules have found therapeutic application, though much remains to be elucidated about the structure and function of these lncRNAs, they too could hold potential as biomarkers, targets, and therapeutic agents. PMID- 24488864 TI - A linearization approach for the model-based analysis of combined aggregate and individual patient data. AB - The application of model-based meta-analysis in drug development has gained prominence recently, particularly for characterizing dose-response relationships and quantifying treatment effect sizes of competitor drugs. The models are typically nonlinear in nature and involve covariates to explain the heterogeneity in summary-level literature (or aggregate data (AD)). Inferring individual patient-level relationships from these nonlinear meta-analysis models leads to aggregation bias. Individual patient-level data (IPD) are indeed required to characterize patient-level relationships but too often this information is limited. Since combined analyses of AD and IPD allow advantage of the information they share to be taken, the models developed for AD must be derived from IPD models; in the case of linear models, the solution is a closed form, while for nonlinear models, closed form solutions do not exist. Here, we propose a linearization method based on a second order Taylor series approximation for fitting models to AD alone or combined AD and IPD. The application of this method is illustrated by an analysis of a continuous landmark endpoint, i.e., change from baseline in HbA1c at week 12, from 18 clinical trials evaluating the effects of DPP-4 inhibitors on hyperglycemia in diabetic patients. The performance of this method is demonstrated by a simulation study where the effects of varying the degree of nonlinearity and of heterogeneity in covariates (as assessed by the ratio of between-trial to within-trial variability) were studied. A dose-response relationship using an Emax model with linear and nonlinear effects of covariates on the emax parameter was used to simulate data. The simulation results showed that when an IPD model is simply used for modeling AD, the bias in the emax parameter estimate increased noticeably with an increasing degree of nonlinearity in the model, with respect to covariates. When using an appropriately derived AD model, the linearization method adequately corrected for bias. It was also noted that the bias in the model parameter estimates decreased as the ratio of between trial to within-trial variability in covariate distribution increased. Taken together, the proposed linearization approach allows addressing the issue of aggregation bias in the particular case of nonlinear models of aggregate data. PMID- 24488865 TI - The anatomy of nuchal translucency at 10-14 weeks gestation in fetuses with trisomy 21: An incredible medical mystery. AB - Nuchal translucency (NT) is a hypo-echoic region of subcutaneous fluid accumulation in the posterior neck at the level of the cervical spine between the skin and soft tissues found at 10-14 weeks gestation. This ultrasound finding is important because increased NT measurements place the fetus at increased risk for chromosomal and structural abnormalities. It is a fascinating phenomenon that displays the intersection of anatomy, development, and imaging. In addition, with the ever increasing use of ultrasound in anatomy, NT is a readily demonstrable example of how important ultrasound has become to the practice of medicine. Articles on NT were obtained from OVID database and reviewed for their contribution to an understanding of the anatomical basis of NT. Whereas it is well established that the ultrasound finding of increased NT is a sensitive marker for Trisomy 21 at 10-14 weeks gestation, why this phenomena occurs has yet to be explained. The basis of nuchal edema is most likely multifactorial, a combination of delayed or disturbed lymphangiogenesis, cardiac and vascular abnormalities, and abnormal extracellular matrix components. Further research on the development of the fetal head and neck related to lymphatic development and fluid regulation during 8-14 weeks gestation will enable a greater understanding of how and why increased NT occurs compared to what is currently known. This could lead to early intervention to manage some of the repercussions of Trisomy 21 and other abnormalities related to NT. PMID- 24488866 TI - What is the value of graduate education? An economic analysis of Army Medical Department Graduate Programs. AB - Current and forward-looking resource constraints within the federal health system and general health market are generating questions of fiscal or economic viability of a number of programs including graduate education. This article establishes a framework for assessing economic value among graduate health related programs within the Army Medical Department. The findings of this analysis indicated that the programs evaluated in the study generate positive economic value based on a market-based valuation of extrinsic benefits compared to extrinsic costs for conducting graduate education within each of the programs. Suggestions for future research and policy application are also discussed. PMID- 24488867 TI - Incorporation of learning styles into the graduate program in nutrition curriculum. PMID- 24488868 TI - An active learning approach to Bloom's Taxonomy. AB - As educators strive toward improving student learning outcomes, many find it difficult to instill their students with a deep understanding of the material the instructors share. One challenge lies in how to provide the material with a meaningful and engaging method that maximizes student understanding and synthesis. By following a simple strategy involving Active Learning across the 3 primary domains of Bloom's Taxonomy (cognitive, affective, and psychomotor), instructors can dramatically improve the quality of the lesson and help students retain and understand the information. By applying our strategy, instructors can engage their students at a deeper level and may even find themselves enjoying the process more. PMID- 24488869 TI - Impact of an innovative clinical internship model in the US Army-Baylor Doctoral Program in physical therapy. AB - STUDY DESIGN: Retrospective case-control. BACKGROUND AND PURPOSE: Physical therapy education has been characterized by positive reform including the transition to doctoral level education and the emergence of evidence-based practice as a standard part of the curricula. However, clinical education remains largely unaffected by these advancements and continues as a highly fragmented and ill-equipped model marked by an inefficient 1:1 student to faculty ratio. Current clinical educational models provide highly variable and suboptimal learning experiences for many students, which contribute to disjointed and noncollaborative learning. The purpose of this study is to examine the implications of a one-year collaborative internship model in the US Army-Baylor University Doctoral Program in Physical Therapy in which interns train in groups rather than 1:1 on productivity and efficiency of care. CASE DESCRIPTION: The Army-Baylor program culminates in a 12-month clinical internship conducted at 4 locations within south central Texas (3 military academic medical centers and one multisite outpatient privately-owned physical therapy practice). Each site can accommodate up to 8 (range=4 to 8) students who complete a standardized internship curricula across the full continuum of learning experiences. In this retrospective case-control design, productivity and staffing metrics were extracted for the 3 military sites using the Department of Defense M2 database during the period from 2006-2010. A separate analysis was conducted for each site with descriptive statistics used to assess clinic productivity and efficiency. OUTCOMES: Data from all 3 sites indicate the presence of interns resulted in little variability in clinic productivity and efficiency. Decreased productivity and/or efficiency would bring into question the long term viability and sustainability of the collaborative internship model. Additionally, this model maximized the opportunity for highly engaged mentorship, individual attention, and quality instruction. COMMENT: The findings suggest clinics can accommodate multiple interns and provide high quality education in a collaborative model without a decline in productivity or efficiency. In addition to the standardized curricula across sites, this model facilitates a highly collaborative and peer learning environment in which the intern class supports, challenges, and holds one another accountable to a more standardized and higher level of practice. Each site contributes 1-2 clinical faculty who no longer engage their own patient schedule but rather are able to serve in a full time clinical mentorship role with the interns. In return, the clinical site receives 3-4 full time equivalents of productivity delivered by closely supervised interns who are afforded sufficient time to conduct their examinations and treatments in collaboration with the clinical faculty. Finally, the collaborative internship model supports the mission of each internship site, providing them a critical mass of labor via economies of scale in exchange for an enriched investment into their clinical education. PMID- 24488870 TI - The Army Social Work Internship Program: training today's uniformed social worker. AB - Uniformed social workers are involved in ensuring the well-being of Soldiers and their families during peace and war. The Army Medical Department Center and School is charged with the educational development of uniformed social workers. This article focuses on a relatively new approach to preparing social work officers for their dual role of providing garrison and operational behavioral health services to Soldiers and families. In the 4 years since implementation, this 2-year training program has become the model for the professional development of new uniformed social work graduates. PMID- 24488871 TI - US Army Veterinary Corps first year graduate Veterinary Education Program. PMID- 24488872 TI - Achieving army nursing evidence-based practice competencies through a civilian military nurse partnership. AB - Despite the Institute of Medicine's goal of 90% of all practice being evidence based by 2020, educational and practice institutions are not on target to achieve this goal. Evidence-based practice is one of 5 core elements of the Army Nurse Corps' patient care delivery system and a key focus of the Hawaii State Center for Nursing. In order to increase evidence-based practice (EBP), a civilian military partnership was formed to include healthcare organizations in the state, optimize resources, and share strategies for successful practice changes statewide. The partnership has been successful in meeting each of these goals using national EBP competencies and Bloom's taxonomy as a guide. The article presents a discussion regarding the history, processes, and outcomes of this partnership. PMID- 24488873 TI - Infusing evidence-based instructional strategies to prepare today's military practical nurses for tomorrow's practice. AB - Is there one best method to provide instruction to today's nursing students? The evidence found in the current literature clearly states the answer is no. The student of today is technology oriented. But for them, it's not about technology, it's about the learning that technology provides. With this understanding, this article provides a review of the efforts by the staff of the US Army Practical Nurse Course (68WM6) to infuse evidence-based instructional strategies into curriculum. Five strategies that were integrated into the curriculum are presented: computer assisted learning, gaming software, classroom response system, human patient simulators, and video recordings. All of the initiatives discussed in this article were implemented into the program of instruction over a 6-year period in an attempt to incorporate the use of appropriate technology in the learning process. The results are a testimony to the necessity of using a combination of strategies for teaching today's nursing students. In doing so, the organization not only improved the learning process, but found significant financial savings. PMID- 24488874 TI - The effects of using a human patient simulator compared to a CD-ROM in teaching critical thinking and performance. AB - BACKGROUND: Military healthcare personnel, including nurse anesthetists, must have the knowledge and skills to care for the extensive, severe injuries incurred on the battlefield. No studies have compared the 2 teaching strategies of using the human patient simulator (HPS) and a CD-ROM in caring for combat injuries relative to critical thinking and performance using nurse anesthesia participants. METHODS: A prospective, pretest-posttest experimental, mixed design (within and between) was used to determine if there were statistically significant differences in HPS and CD-ROM educational strategies relative to caring for patients who have trauma. Two instruments were used: critical thinking, which consisted of multiple-choice questions; and a combat performance instrument that measured ability to care for patients. RESULTS: A repeated analysis of variance and a least significant difference post-hoc test were used to analyze the data. The HPS group performed better than the CD-ROM and control groups relative to performance (P=.000) but not on critical thinking (P=.239). There was no difference between the CD-ROM and control group (P=.171) on the combat performance instrument. CONCLUSION: In this study, the HPS method of instruction was a more effective method of teaching than the CD-ROM approach. PMID- 24488875 TI - Raising the educational standard for army nursing faculty. PMID- 24488876 TI - Legal education for army medical department leaders and soldiers. PMID- 24488877 TI - Innovating to integrate the intangibles into the learning Air Force. AB - United States federal law and other regulations require the US military services to provide professional military education to their forces. Meeting that requirement will become increasingly difficult with the absence of a federal government budget, significant cuts to defense spending, and expected future cuts to both defense spending and manpower. Additionally, the operations tempo remains high despite the withdrawal of troops from Iraq and the planned withdrawal from Afghanistan. The resulting time and budget constraints will likely make it more difficult for the services to provide every member with the opportunity to compete for positions in coveted in-residence professional military education programs. Thus, the Air Force is considering a new lifetime learning approach to professional military education. As the Air Force seeks to develop its new paradigm, we must understand what benefits of the current system should be retained and what drawbacks should be allayed. Unfortunately, there is little research in this area. We content analyze data collected from Air Force officers attending in-residence professional military education, synthesize our findings with education and technology literature, and suggest innovative technologies that can maximize the intangible benefits and minimize the drawbacks of professional military education. The blended approach we present can create a richer, more meaningful learning experience for the service member, while simultaneously lowering the cost per member and providing greater opportunity to attend in-residence professional military education. PMID- 24488878 TI - To change or not to change a multiple choice answer. AB - It is a common belief that changing answers on multiple-choice examinations is detrimental, and such action usually results in changing from right to wrong. Over the past 60 years, studies have shown that changing answers on multiple choice examinations is generally beneficial. The misconception regarding answer changing behavior may be perpetuated by faculty despite evidence to the contrary. As a part of the US Army Graduate Program in Anesthesia Nursing process improvement program, the investigators examined answer changing behaviors of nursing anesthesia students. The results of this evaluation supported conclusions from previous studies in that the odds of students changing from wrong to right was 72% and from right to wrong was 20%. Students should be informed about the benefits of changing answers on multiple-choice examinations. PMID- 24488879 TI - Changes in fetal Doppler indices as a marker of failure to reach growth potential at term. AB - OBJECTIVE: To evaluate whether changes in the middle cerebral artery (MCA), umbilical artery (UA) and cerebroplacental ratio (CPR) Doppler indices at term might be used to identify those appropriate-for-gestational-age (AGA) fetuses that are failing to reach their growth potential (FRGP). METHODS: This was a retrospective cohort study of data obtained in a single tertiary referral center over a 10-year period from 2002 to 2012. The UA pulsatility index (PI), MCA-PI and CPR were recorded between 37+0 and 41+6 weeks within 14 days before delivery. The Doppler parameters were converted into multiples of the median (MoM), adjusting for gestational age, and their correlation with birth-weight (BW) centiles was evaluated by means of regression analysis. Doppler indices were also grouped according to BW quartiles and compared using Kruskal-Wallis and Dunn's post-hoc tests. RESULTS: The study included 11576 term fetuses, with 8645 (74.7%) classified as AGA. Within the AGA group, fetuses with lower BW had significantly higher UA-PI, lower MCA-PI and lower CPR MoM values. Large-for-gestational-age (LGA) fetuses were considered as the group least likely to be growth-restricted. The CPR MoM < 5(th) centile (0.6765 MoM) in these fetuses was used as a threshold for diagnosing FRGP. Using this definition, in the AGA pregnancies the percentage of fetuses with FRGP was 1% in the 75-90(th) BW centile group, 1.7% in the 50 75(th) centile group, 2.9% in the 25-50(th) centile group and 6.7% in the 10 25(th) centile group. CONCLUSION: AGA pregnancies may present with fetal cerebral and placental blood flow redistribution indicative of fetal hypoxemia. Fetal Doppler assessment may be of value in detecting AGA pregnancies that are subject to placental insufficiency, fetal hypoxemia and FRGP. Future studies are needed to evaluate the appropriate threshold for the diagnosis of FRGP and the diagnostic performance of this new approach for the management of growth disorders. PMID- 24488880 TI - How the TP53 family proteins TP63 and TP73 contribute to tumorigenesis: regulators and effectors. AB - In mammals, the p53 family comprises two additional members, p63 and p73 (hereafter referred to as TP53, TP63, and TP73, respectively). The usage of two alternative promoters produces protein variants either with (transactivating [TA] isoforms) or without (DeltaN isoforms) the N-terminal transactivation domain (TAD). In general, the TA proteins exert TP53-like tumor-suppressive activities through their ability to activate a common set of target genes. The DeltaN proteins can act as dominant-negative inhibitors of the transcriptionally active family members. Additionally, they possess intrinsic-specific biological activities due to the presence of alternative TADs, and as a result of engaging a different set of regulators. This review summarizes the current understanding of upstream regulators and downstream effectors of the TP53 family proteins, with particular emphasis on those that are relevant for their role in tumorigenesis. Furthermore, we highlight the existence of networks and cross-talks among the TP53 family members, their modulators, as well as the transcriptional targets. PMID- 24488881 TI - A score-type test for heterogeneity in zero-inflated models in a stratified population. AB - We propose a score-type statistic to evaluate heterogeneity in zero-inflated models for count data in a stratified population, where heterogeneity is defined as instances in which the zero counts are generated from two sources. Evaluating heterogeneity in this class of models has attracted considerable attention in the literature, but existing testing procedures have primarily relied on the constancy assumption under the alternative hypothesis. In this paper, we extend the literature by describing a score-type test to evaluate homogeneity against general alternatives that do not neglect the stratification information under the alternative hypothesis. The limiting null distribution of the proposed test statistic is a mixture of chi-squared distributions that can be well approximated by a simple parametric bootstrap procedure. Our numerical simulation studies show that the proposed test can greatly improve efficiency over tests of heterogeneity that ignore the stratification information. An empirical application to dental caries data in early childhood further shows the importance and practical utility of the methodology in using the stratification profile to detect heterogeneity in the population. PMID- 24488882 TI - High-grade cervical abnormalities and cervical cancer in women following a negative Pap smear with and without an endocervical component: a cohort study with 10 years of follow-up. AB - The proportion of Pap smears containing an endocervical component (ECC) has been declining in Australia. Given that ECC negative (ECC-) smears may be associated with reduced sensitivity, we undertook a retrospective cohort study to estimate rates of histologically confirmed high-grade cervical abnormality (HGA) and cancer in women with negative Pap smears with and without an ECC. Women 18-69 years with at least two Pap smears between 1 January 2001 and 31 December 2010 with the first smear in that period (index smear) showing no abnormality were eligible. Follow-up ended at date of the first abnormal smear, date of histological diagnosis, date of hysterectomy, date of death, or 31 December 2010, whichever came first. ECC status was treated as a time varying exposure. Follow up was split at each smear after the index smear. Poisson regression was used to estimate adjusted incidence rates and incidence rate ratios (IRR) by ECC status. The incidence rate of histologically confirmed HGA was significantly lower following ECC- smears than after ECC+ smears (adjusted IRR: 0.69, 95%Confidence Interval (CI) 0.62-0.77), particularly at older ages (interaction between ECC status and age, p = 0.001). In contrast, the overall rate of invasive cancer was not significantly different after ECC- than after ECC+ smears (IRR: 1.27, 95%CI 0.90-1.77). In conclusion, women had a lower rate of confirmed HGA and no significant increase in the rate of invasive cervical cancer following ECC- smears. This study does not support differential (accelerated) follow-up in women with a negative smear without an endocervical component. PMID- 24488883 TI - Ultrahigh hydrogen evolution performance of under-water "superaerophobic" MoS2 nanostructured electrodes. AB - The adhesion of as-formed gas bubbles on the electrode surface usually impedes mass-transfer kinetics and subsequently decreases electrolysis efficiency. Here it is demonstrated that nanostructured MoS2 films on conductive substrates show a faster hydrogen evolution reaction (HER), current increase, and a more-stable working state than their flat counterpart by significantly alleviating the adhesion of as-formed gas bubbles on the electrode. This study clearly reveals the importance of a nano-porous structure for HER, which should be general and beneficial for constructing other gas-evolution electrodes. PMID- 24488885 TI - Slowing the revolving door of hospitalization for acute heart failure. PMID- 24488886 TI - Pain assessment scales in nonverbal critically ill adult patients: ventilator related issues. PMID- 24488887 TI - Adaptation of the AACN Synergy Model for Patient Care to critical care transport. AB - Today's health care delivery system relies heavily on interhospital transfer of patients who require higher levels of care. Although numerous tools and algorithms have been used for the prehospital determination of mode of transport, no tool for the transfer of patients between hospitals has been widely accepted. Typically, the interfacility transport decision is left to the discretion of the referring provider, who may or may not be aware of the level of care provided or the means of transport available. A need exists to determine the appropriate level of care required to meet the needs of patients during transport. The American Association of Critical-Care Nurses (AACN) Synergy Model for Patient Care is a patient-centered model that focuses on optimizing patient care by matching the characteristics of the patient with the competencies of the nurse. This model shows significant promise in providing the theoretical backing to guide the decision on the level of care necessary to complete interfacility transfers safely and effectively. This article describes a new tool inspired by the AACN Synergy Model for Patient Care to determine the appropriate level of care required for interfacility transport. PMID- 24488888 TI - Sedation and its association with posttraumatic stress disorder after intensive care. AB - Overuse of sedation in patients treated with mechanical ventilation can increase duration of ventilation, duration of delirium, and time to discharge. Although current principles of care include implementation of sedation protocols and/or daily interruptions in sedation to improve patients' outcomes, these strategies remain underused. Historically, a barrier to use of protocols has been a perception that being awake and aware while intubated is intrinsically distressing and could cause psychological harm. Evidence of a link between lighter sedation and decreased signs and symptoms of posttraumatic stress disorder has partially dispelled these fears and even prompted the adoption of no sedation (eg, analgosedation) strategies. Published studies on posttraumatic stress disorder and sedation are limited by small sample size, heterogeneous sedation practices, and inadequate follow-up. Despite limitations, current data suggest contemporary sedation practices to keep patients calm and comfortable but awake, as appropriate, are not associated with increased rates or severity of posttraumatic stress disorder. PMID- 24488889 TI - The importance of tracheostomy progression in the intensive care unit. AB - A plan to progress a tracheostomy toward decannulation should be initiated unless the tracheostomy has been placed for irreversible conditions. In most cases, tracheostomy progression can begin once a patient is free from ventilator dependence. Progression often begins with cuff deflation, which frequently results in the patient's ability to phonate. A systematic approach to tracheostomy progression involves assessing (1) hemodynamic stability, (2) whether the patient has been free from ventilator support for at least 24 hours, (3) swallowing, cough strength, and aspiration risk, (4) management of secretions, and (5) toleration of cuff deflation, followed by (6) changing to a cuffless tube, (7) capping trials, (8) functional decannulation trials, (9) measuring cough strength, and (10) decannulation. Critical care nurses can facilitate the process and avoid unnecessary delays and complications. PMID- 24488890 TI - Addition of acute care nurse practitioners to medical and surgical rapid response teams: a pilot project. AB - Background Vanderbilt University Hospital's original rapid response team included a critical care charge nurse and a respiratory therapist. A frequently identified barrier to care was the time delay between arrival of the rapid response team and arrival of the primary health care team. Objective To assess the impact of adding an acute care nurse practitioner to the rapid response team. Methods Acute care nurse practitioners were added to surgical and medical rapid response teams in January 2011 to diagnose and order treatments on rapid response calls. Results In 2011, the new teams responded to 898 calls, averaging 31.8 minutes per call. The most frequent diagnoses were respiratory distress (18%), postoperative pain (13%), hypotension (12%), and tachyarrhythmia (10%). The teams facilitated 360 transfers to intensive care and provided 3056 diagnostic and therapeutic interventions. Communication with the primary team was documented on 97% of the calls. Opportunities for process improvement were identified on 18% of the calls. After implementation, charge nurses were surveyed, with 96% expressing high satisfaction associated with enhanced service and quality. Conclusions Teams led by nurse practitioners provide diagnostic expertise and treatment, facilitation of transfers, team communication, and education. PMID- 24488891 TI - Incorporating best practices into undergraduate critical care nursing education. AB - Incorporation of best clinical practices into the baccalaureate critical care nursing curriculum is important. At The College at Brockport, best clinical practices are introduced early in the semester and are reinforced throughout the semester in both class and clinical settings. Among the best clinical practices included are those recommended by the American Association of Critical-Care Nurses, The Centers for Medicare and Medicaid Services, the Institute for Healthcare Improvement, The Joint Commission, Quality and Safety Education for Nurses, the Surviving Sepsis Campaign, and the Institute for Safe Medication Practices. The culminating assignment of the semester requires students to focus on patient safety. Students describe the use of the National Patient Safety Goals and other best practices in the critical care setting. The role of the nurse leader and exploration of near-miss and work-around events also are described. Nursing students need to provide safe competent nursing care by incorporating best practices into their clinical practice now and in the future when they become registered professional nurses. PMID- 24488892 TI - "To know": a great reason for certification. PMID- 24488893 TI - Decreasing rates of central catheter infections. PMID- 24488897 TI - Assessing pain in the critically ill adult. PMID- 24488894 TI - The pause. PMID- 24488898 TI - I am a critical care nurse. PMID- 24488899 TI - Critical evaluation of adsorption-desorption hysteresis of heavy metal ions from carbon nanotubes: influence of wall number and surface functionalization. AB - Single-, double-, and multi-walled carbon nanotubes (SWCNTs, DWCNTs, and MWCNTs), and two oxidized MWCNTs with different oxygen contents (2.51 wt % and 3.5 wt %) were used to study the effect of the wall number and surface functionalization of CNTs on their adsorption capacity and adsorption-desorption hysteresis for heavy metal ions (Ni(II), Cd(II), and Pb(II)). Metal ions adsorbed on CNTs could be desorbed by lowering the solution pH. Adsoprtion of heavy metal ions was not completely reversible when the supernatant was replaced with metal ion-free electrolyte solution. With increasing wall number and amount of surface functional groups, CNTs had more surface defects and exhibited higher adsorption capacity and higher adsorption-desorption hysteresis index (HI) values. The coverage of heavy metal ions on the surface of CNTs, solution pH, and temperature affect the metal ion adsorption-desorption hysteresis. A possible shift in the adsorption mechanism from mainly irreversible to largely reversible processes may take place, as the amount of metal ions adsorbed on CNTs increases. Heavy metal ions may be irreversibly adsorbed on defect sites. PMID- 24488900 TI - Pharmacokinetics study of ferulic acid in rats after oral administration of gamma oryzanol under combined use of Tween 80 by LC/MS/MS. AB - AIM: gamma-oryzanol (OZ) is a rich source of commercially-important bioactive phytochemicals, most of them of interest in nutrition, pharmacy and cosmetics. However, the poor solubility of OZ limited the use. In the paper, ultraviolet visible (UV-Vis) analysis was conducted to analysis the solubilization of OZ under combined use of Tween 80 in vitro. In addition, to further confirm the solubilizing effect of Tween 80, a pharmacokinetic study of ferulic acid (FA) in rats after oral administration of OZ 100 mg/kg under combined use of Tween 80 though LCMS/MS was carried out. MATERIALS AND METHODS AND RESULTS: Solubility enhancement as high as 100-fold is achieved using 1% Tween 80 in vitro. Following oral administration of OZ-Tween 80 100 mg/kg, the values of Tmax, Cmax, AUC0 infinity, T1/2Ka and MRT0-infinity were 46.667 +/- 39.328, 129.498 +/- 27.025, 63738.28 +/- 599, 14.274 +/- 7.309 and 859.592 +/- 108.780 respectively. The values of T1/2Ka, AUC0-infinity, MRT0-t, and Tmax showed up to increase 16%, 58%, 44% and 47% while Cmax and CL/F decreased 22% and 12%, respectively. The decreased Cmax value indicated that Tween 80 can hardly enhance the absorption of FA in rats. However, T1/2Ka and Tmax values showed that the absorption of FA was extended, which resulted the increased values of AUC0-infinity and MRT0-infinity. CONCLUSIONS: Our results reveal that Tween 80 improves solubility of OZ in vitro and could enhance the bioavailability of OZ by extending its absorption and elimination. PMID- 24488901 TI - Non-alcoholic fatty liver disease (NAFLD) and MTHFR 1298A > C gene polymorphism. AB - INTRODUCTION: Non-Alcoholic Fatty Liver Disease (NAFLD) is related to unhealthy habits, mainly to unfavorable dietary profiles. MTHFR gene encodes MethyleneTetraHydroFolate Reductase, a regulatory enzyme whose polymorphisms are associated with hyperhomocysteinemia. Among polymorphisms, C677T, a thermolabile form, but not A1298C, thermostable, was associated with fatty liver and insulin resistance. AIM: to investigate if NAFLD, in subjects referred for nutritional assessment and counselling, has any difference of prevalence and severity when associated with isolated MTHFR A1298C polymorphism and hyperhomocysteinemia. PATIENTS AND METHODS: 94 subjects, age 55.65 +/- 15.43 years, BMI 27.88 +/- 5.17 kg/m2, 26 with MTHFR Wild type genotype (1298AA) and 68 with MTHFRA1298C single polymorphism were studied: of them, 35 were homozygous (MTHFR1298CC), 33 were heterozygous (MHTFR 1298AC). Insulin resistance was assessed by HOMA-IR, NAFLD by UltraSound Brigh-Liver-Score (BLS). RESULTS: MTHFR subgroups (wild and A1298C single polymorphism) were not different for age, gender, dietary profile and BMI. In NAFLD, MTHFR 1298AC (heterozygous) vs. homozygous wild genotype (MTHFR 1298AA) patients had more severe NAFLD (BLS: 1.12 +/- 1.14 vs. 0.54 +/- 0.76, p < 0.029), greater insulin resistance (HOMA 3.20+/-2.35 vs. 2.12 +/- 1.12; p < 0.036), higher AST and gammaGT. CONCLUSIONS: MTHFR1298AC gene heterozygous polymorphisms can be weakly predictive for NAFLD severity. This mutation occurs frequently in populations with low prevalence of overall mortality and of atherosclerosis associated disease: it could have maintained and maintain its persistence by an heterozygosis advantage mechanism, within significant adherence to healthy nutritional profiles. Interactions of nutrition, genetics and health are a part of the aging process throughout the life span and a greater consideration to the genetic characteristics of populations and individuals is warranted. PMID- 24488902 TI - Efficacy of Tiopronin in treatment of severe non-alcoholic fatty liver disease. AB - BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a clinicopathologic syndrome of which the main feature is diffuse macrovesicular hepatic steatosis caused by deposition of excessive free fatty acid and triglyceride in liver parenchyma. AIM: To observe the efficacy of Tiopronin in treatment of severe nonalcoholic fatty liver disease (NAFLD). PATIENTS AND METHODS: 30 patients with severe NAFLD were treated with Tiopronin for 3 months. 30 healthy people were selected as control. The body mass index (BMI) and plasma levels of endotoxin (ET), leptin, IL-6 and IL-8 were measured before and after treatment. RESULTS: The serum levels of ET, leptin, IL-6 and IL-8 in severe NAFLD group were significantly higher than those in control group (p < 0.05). After treatment with Tiopronin, these indexes were significantly lower than before (p < 0.05). CONCLUSIONS: The intestinal endotoxemia (IETM) occurs in patients with severe NAFLD. Leptin, IL-6 and IL-8 play important roles in pathogenesis of NAFLD. Tiopronin can reduce the levels of ET, leptin, IL-6 and IL-8 for treatment of NAFLD. PMID- 24488903 TI - Azathioprine treatment in inflammatory bowel disease patients: type and time of onset of side effects. AB - BACKGROUND: Azathioprine (AZA) and 6-mercaptopurine (6-MP), purine analogues, are the immunosuppressant drugs most frequently used for inducing and maintaining remission in inflammatory bowel disease (IBD). The occurrence of adverse effects is a major drawback in the use of these drugs, and short- and long-term toxicity represent a major limitation to their use. AIM: The present study investigated the prevalence, type and time of onset of AZA-related adverse events, in a cohort of IBD patients in a single referral Centre. PATIENTS AND METHODS: The records of consecutive IBD outpatients, referred to our Institution between 1987-2009, were retrospectively evaluated. RESULTS: We reviewed 2014 patients, in whom AZA was prescribed in 302 of them, 139 (46%) with ulcerative colitis (UC) and 163 (54%) with Crohn's disease (CD). Side-effects were complained by 98 (32.4%) out of 302 patients, 50 UC and 48 CD, (36% UC vs 29.4% CD, p = 0.26). In 20 (20.4%) patients, 11 UC and 9 CD, side-effects recovered after dosage reduction whilst in 78 (79.6%), 39 UC and 39 CD, the treatment was discontinued (dose-dependent side effects in 42 patients and dose-independent in 36). Overall, side-effects were observed after a mean period of 14.5 +/- 7.8 months (range 0.5-123) of AZA treatment. The majority (76%) of the dose-dependent adverse events were reported between 12-18 months after the beginning of treatment. CONCLUSIONS: The prevalence of side effects leading to withdrawal of AZA treatment, in our series of Italian patients, was higher respect to data reported in the literature (25.8%). PMID- 24488904 TI - Antimicrobial effects of Caulerpa sertularioides extract on foodborne diarrhea caused bacteria. AB - AIM: Caulerpa (C.) sertularioides has many therapeutic uses in the practice of traditional medicine in Malaysia. Crude methanolic, diethyl ether extract, ethyl acetate extract and butanolic extract from C. sertularioides were subjected to antimicrobial screening including the three Gram-positive and three Gram-negative diarrhea-caused bacteria. MATERIALS AND METHODS: The antimicrobial activities were studied by using disc diffusion method and broth dilution method. The effect of the extract on the growth profile of the bacteria was examined via time-kill assay. In addition to the bactericidal effects study, microscopic observations using Scanning electron microscopy (SEM) was done to determine the major alterations in the microstructure of Bacillus (B.) subtilis. RESULTS: Ethyl acetate extract demonstrated antibacterial activity towards all the tested bacteria and produced inhibition zone ranging from <= 9 mm - >= 15 mm. However, all the tested bacteria were resistant to the butanolic extract treatment. B. subtilis growth curve in the presence of the crude methanol extract at MIC showed bacteriostatic. The main abnormalities found from these microscopic observations were morphology alteration of the bacteria cells after exposure to the methanol extract. CONCLUSIONS: Data from this study revealed that C. sertularioides may be potential antimicrobial agents against foodborne Gram-positive and Gram-negative bacteria particularly cause diarrhea, and also food spoilage microorganisms. PMID- 24488905 TI - Interaction relationships of osteoarthritis and rheumatoid arthritis related genes. AB - BACKGROUND: Osteoarthritis (OA), also referred to as degenerative joint disease or wear-and-tear arthritis, is caused by the breakdown of joint cartilage. Rheumatoid arthritis (RA) is a chronic, inflammatory type of arthritis. RA is also classified as a kind of autoimmune disease. AIM: To find the important genes in RA and OA. MATERIALS AND METHODS: Comprehensively compared 3 datasets of RA with 2 datasets of OA, 98 genes were sifted. We explored protein-protein associations processed for the 98 genes by mining famous gene/protein interaction/association database. RESULTS: We found most of those genes appear to play a key role in the anti-inflammatory and immunosuppressive effects. CONCLUSIONS: Our research would play a useful role in the diagnosis and treatment of OA and RA. PMID- 24488906 TI - Application of peripheral blood Mycobacterium tuberculosis PCR for diagnosis of tuberculosis patients. AB - BACKGROUND: Mycobacterium tuberculosis (MTB) infection is a global health problem. Failure to accurately identify cases of active MTB has serious effects on both patients and the community. Acid-fast bacilli (AFB) smear has poor sensitivity and culture methods have a delay ranging from 1 to 8 weeks for diagnosis. Nucleic acid amplification assays may be suitable candidates for this purpose. PATIENTS AND METHODS: In a prospective study, we evaluated Mycobacterium tuberculosis DNA in peripheral blood samples with PCR technique in 190 patients with pulmonary and extra pulmonary tuberculosis whom were admitted to Tehran Imam Khomeini hospitals during 2006-2010. Three ml citrated blood samples were obtained from cases. DNA extraction was performed by QIAGEN commercial kit and PCR performed with IS1081 Primer. RESULTS: Fifty six cases had extra-pulmonary tuberculosis and 134 were pulmonary. Overall sensitivity and specificity of the PCR assay was 41.1% and 95.5%, respectively. CONCLUSIONS: MTB-PCR assay on PBMC using IS1081 primer has a low sensitivity and now can not use as a single or alternative diagnostic test for tuberculosis. However, with regard to its high specificity can use for help diagnosing of TB in cases have no enough sputum (or other specimens) to examination for acid-fast bacilli (AFB) smear and culture. PMID- 24488907 TI - Hydroxyurea-induced interstitial pneumonitis: case report and review of the literature. AB - Hydroxyurea is a cytotoxic agent widely used in the treatment of myeloproliferative disorders. It is considered a-well-tolerated antineoplastic drug, with a dose-related bone marrow suppression as main adverse effect. This report describes a patient with essential thrombocythemia who developed an interstitial pneumonitis and respiratory failure within 4 years from beginning therapy with hydroxyurea (HU). After discontinuing of HU. both clinical and radiological resolution of pneumonitis occurred. In conclusion, HU-induced pulmonary toxicity is a potentially life-threatening side effect. PMID- 24488908 TI - The protective effects of bioactive (RS)-glucoraphanin on the permeability of the mice blood-brain barrier following experimental autoimmune encephalomyelitis. AB - OBJECTIVES: Alterations in blood-brain barrier (BBB) permeability are due to the disruption of the Tight Junctions (TJs), large multiprotein complexes important for the maintenance of structural integrity and for permeability of the barrier. In this experimental study we evaluated the neuroprotective role of (RS) glucoraphanin, a glucosinolate present in Brassicaceae, notably in Tuscan black kale, and bioactivated with myrosinase enzyme (bioactive RS-GRA) (10 mg/kg/d intraperitoneally), to prevent the dysfunction of BBB, in an experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis (MS). MATERIALS AND METHODS: EAE was induced by immunization with myelin oligodendroglial glycoprotein peptide (MOG)35-55 in mice. By western blot analysis of brain tissues, we evaluated expression and distribution of the TJ-associated proteins, claudin-1, -3, -5 and ZO-1. Additionally, in order to gain a better insight into the mechanisms of action of bioactive RS-GRA, we investigated Foxp3, ERK1/2 and caspase 3 expression associated both to inflammatory response as well as to apoptotic pathway. RESULTS: Our results demonstrated that treatment with bioactive RS-GRA counteracts the alteration of all these parameters and preserves TJ integrity through an antinflammatory and antiapoptotic activity during MS. CONCLUSIONS: Bioactive RS-GRA, could be a therapeutic perspective helpful in preventing dysfunction of the BBB. PMID- 24488909 TI - FoxM1 regulates Sirt1 expression in glioma cells. AB - BACKGROUND AND OBJECTIVES: Glioma accounts for most of primary malignant brain tumors and usually results in poor survival. However, the key signaling networks regulating glioma cell proliferation remain poorly defined. The forkhead box M1 (FoxM1) is a key transcription factor regulating multiple aspects of cell biology. Prior studies have shown that FoxM1 is overexpressed in glioma and plays a critical role in cancer development and progression. MATERIALS AND METHODS: Western blot and Real-time PCR assays were used to determine the regulation roles of FoxM1 on Sirt1 (Sirtuin1) expression. Small interfering RNAs (siRNAs) were used to silence the expression of FoxM1. Luciferase assays were used to measure binding of FoxM1 to the promoter region of Sirt1. Direct binding of FoxM1 to promoter of Sirt1 was assessed by chromatin immunoprecipitation (CHIP) assays. RESULTS: We found that FoxM1 positively regulated mRNA expression of Sirt1. FoxM1 overexpression promoted while its knockdown inhibited Sirt1 expression. Besides, we identified a minimal FoxM1 binding site on the promoter region of Sirt1. CONCLUSIONS: Our results for the first time add a new FoxM1-Sirt1 connection that mediates cell proliferation in glioma. PMID- 24488910 TI - Partial least squares based gene expression analysis in estrogen receptor positive and negative breast tumors. AB - BACKGROUND: Breast cancer is categorized into two broad groups: estrogen receptor positive (ER+) and ER negative (ER-) groups. Previous study proposed that under trastuzumab-based neoadjuvant chemotherapy, tumor initiating cell (TIC) featured ER- tumors response better than ER+ tumors. Exploration of the molecular difference of these two groups may help developing new therapeutic strategies, especially for ER- patients. MATERIALS AND METHODS: With gene expression profile from the Gene Expression Omnibus (GEO) database, we performed partial least squares (PLS) based analysis, which is more sensitive than common variance/regression analysis. RESULTS: We acquired 512 differentially expressed genes. Four pathways were found to be enriched with differentially expressed genes, involving immune system, metabolism and genetic information processing process. Network analysis identified five hub genes with degrees higher than 10, including APP, ESR1, SMAD3, HDAC2, and PRKAA1. CONCLUSIONS: Our findings provide new understanding for the molecular difference between TIC featured ER- and ER+ breast tumors with the hope offer supports for therapeutic studies. PMID- 24488911 TI - Gene expression analysis of lung cancer. AB - OBJECTIVE: We aim to explore the expression difference between lung cancer cells and normal lung cells, and to investigate the mechanism of lung cancer development. Besides, we predicted the potential target site of transcriptional factors and microRNAs for differentially expressed genes (DEGs), which may help to regulate expression of DEGs. Small molecules were also identified to cure lung cancer. MATERIALS AND METHODS: Gene expression profiles we used were downloaded from Gene Expression Omnibus (GEO) using accession number of GSE2378. Firstly, we identified differential genes between lung cancer cells and normal lung cells by using R package limma. Then, we detected the processes and pathways that changed in lung cancer cells by Gene Ontology (GO) and KEGG pathway enrichment analysis. Potential target sites of transcriptional factors and microRNAs were also detected based on gene annotation data in MSigDB. Finally, small molecule drugs were screened via querying Connectivity Map database. RESULTS: We obtained 2961 differentially expressed genes between lung cancer cells and normal lung cells. Besides changes in cell cycle, metabolic processes and proteasome were also dramatically disordered. Some DEGs shared target sites of the transcription factor such as E2F, ETS and CEBPB. Target sites of hsa-miR-196a and hsa-miR-200c were also significantly enriched by DEGs. Iloprost simulated the state of normal cells, while MS-275 might be potential pathogenic substances. CONCLUSIONS: We investigate the lung cancer from Gene Ontology, pathway, transcription factors and microRNAs based on gene expression profiles. All these results may facilitate lung cancer treatment with a new breakthrough. PMID- 24488912 TI - Pulmonary hypertension and beta blockers: where do we stand? Where are we going? AB - Pulmonary hypertension (PH) is a chronic, progressive debilitating disease and associated with poor prognosis despite the novel numerous treatment options. Beta blockers constitute a cornerstone in left heart failure treatment; however, we still don't know the role of beta-blockers on PH and they are considered relatively contraindicated in patients with PH because of the possible negative effect on these patients' hemodynamics and exercise capacity. On the other hand, animal models of PH and non-randomized clinical trials have shown that beta blockers may improve right ventricular function and prevent remodeling in the heart muscle. As it is well-known, right heart function is the main prognostic determinants of the PH. The purpose of this chapter is to present the use of beta blockers for the treatment of PH, the purported mechanisms of action, previously conducted animal studies and clinical trials. PMID- 24488913 TI - Increased sympathetic activation in patients with vasovagal syncope is associated with higher mean platelet volume levels. AB - OBJECTIVES: Vasovagal syncope (VVS) is supposed to be modulated by increased sympathetic tone following an orthostatic maneuver. Increased sympathetic activity may have an important role in mean platelet volume (MPV), either by peripheral activation or by effects on thrombocytopoiesis. We aimed to show the effects of increased sympathetic activity on platelet size in patients with VVS in the present study. PATIENTS AND METHODS: Thirty-seven patients with VVS were compared with age- and sex-matched 33 patients without VVS. All patients have undergone 24 hour holter monitoring for heart rate variability (HRV) and time domain HRV analysis. Blood samples for MPV measurements were taken before 24 hour holter monitoring. RESULTS: Group 1 was consisted of 37 patients with VVS and group 2 was consisted of 33 patients without VVS. We observed that SDNN, SDNN index, SDSD, RMSDD, PNN50 count were significantly lower and MPV was found significantly higher in patients with VVS (p < 0.05 for all). Pearson's correlation analysis showed that MPV was moderately negatively correlated with SDNN (r = -0.421), SDSD (r = -0.396), NN50 count (r = -0.395) and RMSDD (r = 0.393). Multivariate regression analysis showed that SDNN was the only independent variable, which had a significant effect on increased MPV level (beta = -0.295 , p = 0.016). CONCLUSIONS: We found that MPV was closely associated with increased sympathetic activity in patients with VVS. Our analysis supports the hypothesis that alterations in autonomic status might play a role in the development of platelet size. PMID- 24488914 TI - Atorvastatin suppresses Toll-like receptor 4 expression and NF-kappaB activation in rabbit atherosclerotic plaques. AB - BACKGROUND: Toll-like receptor 4 (TLR4) plays an essential role in the pathogenesis and progression of atherosclerosis, which overexpresses in atherosclerotic lesions and mediates the production of inflammatory factors. The aim of this study was to investigate the effects of atorvastatin on TLR4 protein and mRNA expression and its downstream factor NF-kappaB activation in rabbit atherosclerotic plaques. MATERIALS AND METHODS: Rabbits continuously fed with high-fat diet for 24 weeks were randomly divided into two groups, the drug treated group orally administrated with atorvastatin (2 mg/kg/day) three weeks after high-fat diet feeding and the model group with no treatment. The expression of TLR4 protein and mRNA, the level of activated NF-kappaB (p65) were respectively detected by western blotting, quantitative RT-PCR, and ELISA. RESULTS: The results showed that atorvastatin treatment reduced the expression of TLR4 protein and mRNA by 24.1% (p < 0.05) and 46.9% (p < 0.01), respectively, and also inhibited NF-kappaB activation by 76.0% (p < 0.001) in the atherosclerotic plaques. CONCLUSIONS: Thus, it was suggested that atorvastatin could exert an anti-atherosclerotic activity besides inhibiting cholesterol biosynthesis. PMID- 24488915 TI - TSG-6 mediates the effect of tendon derived stem cells for rotator cuff healing. AB - BACKGROUND: Bone marrow stem cells (MSCs) were able to reduce fibrovascular tissues formation via TNF alpha-stimulated gene/protein 6 (6TSG-6) in various animal models. At the same time, tendon-derived stem cells (TDSCs) were able to promote rotator cuff healing; however, the mechanism is still unknown. AIM: To investigate the role of TSG-6 in the treatment of rotator cuff healing with TDSCs. MATERIALS AND METHODS: 45 rats underwent unilateral detachment and repair of the supraspinatus tendon. 15 animals received TDSCs in a fibrin glue carrier(Group A), 15 received TSG-6 silenced TDSCs (Group B), and 15 received fibrin glue for control (Group C). Animals were sacrificed at 4 weeks and evaluated for the biomechanical testing. Statistical analysis was performed with an independent t test with significance set at p = 0.05. RESULTS: The ultimate stress was greater in the TDSCs group (4.91 +/- 1.41 N/mm(2)) as compared with the Control group (2.99 +/- 1.04 N/mm(2)) (p < 0.05). However, when silent the expression of TSG-6, the TSG-6 silenced group (3.36 +/- 0.96 N/mm(2)) showed no benefit over the control group (p = 0.32). CONCLUSIONS: TSG-6 mediates the function of TDSCs to improve the structure and the attachment strength of the healing tendon-bone interface. PMID- 24488916 TI - Meniscal tears left in situ during anatomic single bundle anterior cruciate ligament reconstruction. AB - OBJECTIVES: Anterior cruciate ligament (ACL) injuries are a common finding in sports medicine. Our scope is to investigate whether stable, incomplete medial meniscus tears could be left untreated during single bundle anatomic anterior cruciate ligament reconstruction. PATIENTS AND METHODS: A prospective observational study on 597 knees from a single surgeon cohort, using the same reconstruction technique, found 23 medial and 48 lateral meniscus tears which could be left untreated. RESULTS: None of the cases required reintervention during the first postoperative year. In fact, 21.7% of the medial meniscus group and 14.6% of the lateral group had potential residual symptoms that were not confirmed and gradually disappeared within one year. A comparison of Cincinnati Knee, IKDC scores and limb symmetry index values (calculated using the triple hop for distance into the two groups) found no differences for the last two variables (both p = 0.065) and was marginal for the first score (p < 0.05). The between groups comparisons, performed in the KT-1000, also yielded no difference (p = 0.11). CONCLUSIONS: We than concluded that incomplete meniscal tears, left in situ at the time of anterior cruciate ligament reconstruction, could have favorable outcomes as long as decisions are carefully weighed with regard to the length of the lesion. Also, at least in this perspective, anatomic single bundle has proved a sufficient stabilizer for anterior translation of the tibia. PMID- 24488917 TI - High resolution 3-T MR imaging in the evaluation of the trigeminal nerve course. AB - BACKGROUND: The evaluation of the trigeminal course and his anatomical relationships with surrounding structures, is important for the assessment of the injury that may occur in tumors and several orofacial trauma and for avoiding the damage during surgeries. AIM: The aim of this retrospective study was to assess the use of 3-T MRI in the evaluation of the course of the four segments of the trigeminal nerve: cisternal and Meckels's cave, cavernous sinus, skull base and mandibular extracranial segments. PATIENTS AND METHODS: 78 patients were studied, for a total of 156 trigeminal nerves examined. T2-weighted 3D Fast imaging employing steady-state acquisition and T1-weighted Fast spoiled gradient recalled echo sequences were used. Two radiologists (reader A and B), independently, evaluated the course of the four segments of the trigeminal nerve according to a qualitative scale. The Intraclass correlation coefficient (ICC) and Pearson correlation coefficient were used to assess the intraobserver and interobserver variability in the nerve course evaluation. RESULTS: Reader A evaluated 47 trigeminal nerves excellent, 94 good, 12 fair and 3 poor. Reader B rated 43 trigeminal nerves excellent, 92 good, 16 fair and 5 poor. The intraobserver variability was ICC = 0.937 in reader A and ICC = 0.894 in reader B. The interobserver variability was 0.734 (p <= 0.01). CONCLUSIONS: High resolution 3-T MRI imaging allows an accurate study of the trigeminal nerve and especially of its mandibular branch. The knowledge of the course and of the anatomic relationships of these nerve bundles with surrounding structures, as well as of the anatomical variants, allow oral and maxillofacial surgical plannings thus reducing the risk of nerve damage. PMID- 24488918 TI - Diagnosis and treatment of a rare case of adenomatoid odontogenic tumor in a young patient affected by attenuated familial adenomatosis polyposis (aFAP): case report and 5 year follow-up. AB - BACKGROUND: The adenomatoid odontogenic tumor (AOT) is a quite rare odontogenic tumor, with an incidence rate of approximately 12 cases/year worldwide. Attenuated familial adenomatous polyposis (aFAP) is a syndrome characterized by a significant risk to develop colon cancer. The aim of the paper is to describe a case never reported before in the literature: an AOT developed in a patient with aFAP; moreover, we want to show how it appears 5 years after surgery and after the regeneration of the eroded bone tissue, using the Platelet-Rich Fibrin (PRF) as filling material. CASE PRESENTATION: We report the case of a female 18 years old patient, affected by aFAP; she comes to us with a swelling on the right hemi face. We performed several radiological exams, and they showed a neoformation approximately 2 cm in diameter: this neoformation packed the upper right canine, therefore, we hypothesized a dentigerous cyst. We decided to proceed to open biopsy and enucleation of the lesion. An intra-operative endodontic treatment on the adjacent partially resorbed teeth was also performed. Finally, we performed a reconstruction of eroded bone tissue, by use of Platelet-Rich Fibrin as filling material. The samples fixed and embedded in paraffin have led to the diagnosis of AOT. After 5 years from the surgery, we did not find any clear sign of relapse, in addition, the use of PRF has favored an optimal osteogenesis at the surgical site. CONCLUSIONS: Undoubtedly, a correct diagnosis of AOT allows to have a more performing clinical and surgical approach. Furthermore, this case could document a new manifestation of aFAP in extra-intestinal site. The onset of an AOT is quite rare in the general population, and this rarity could represent a critical point for its diagnosis; AOT onset in a patient with aFAP is a finding that could represent a new element of diagnosis and, therefore, the starting point to perform a more effective therapy. PMID- 24488919 TI - Myo-inositol, D-chiro-inositol, folic acid and manganese in second trimester of pregnancy: a preliminary investigation. AB - DESIGN AND PURPOSE: The supplemental administration of myo-inositol, D-chiro inositol, folic acid and manganese (MDFM) was tested in a prospective, randomized, double-blind, placebo controlled clinical trial, pilot study, to test the hypothesis that its supplemental administration in the second trimester of pregnancy would improve glucose and glycemic parameters and blood pressure. SUBJECTS AND METHODS: Non-obese uniparous healthy pregnant women between 13th and 24th week of pregnancy were divided into two groups: group I, control group with placebo, and the group II, women in treatment with myo-inositol, D-chiro inositol, folic acid and manganese. The main outcome measures were the comparative analysis of the parameters analyzed at time 0, after 30 days and 60 days; secondary outcome measure was the overall analysis of investigated parameters. RESULTS: 24 women were allocated to receive MDFM and 24 the placebo. The two groups did not significantly differ for demographic, lipidic and glycemic parameter and blood pressure. After 30 days, significantly lower cholesterol (p = 0.0001), significantly lower LDL (p = 0.0013), lower TG (p < 0.0001) and lower glycemia (p = 0.0021) were observed all favoring group II. No significant difference was observed for HDL, diastolic and systolic blood pressure. After 60 days, significant difference was observed for cholesterol (p = 0.0001), LDL (p = 0.0001), HDL (p = 0.0001), TG (p = 0.0001), glycemia (p = 0.0064), all favoring the group treated with MDFM. No significant differences were observed for systolic (p = 0.12) and diastolic blood pressure (p = 0.42). When examining for overall differences between the two groups, a significant difference was observed for examined parameters at time 0 and at time 60; cholesterol (p = 0.0001), LDL (p = 0.0001), HDL (p = 0.047), TG (p = 0.0001) and glycemia (p = 0.019) were reduced in the MDFM group. A significant reduction was also observed in group II for systolic blood pressure after 60 days of intervention (p = 0.0092), but not for diastolic blood pressure (p = 0.29). CONCLUSIONS: MDFM administration after 30 days in pregnancy improved glycemic and lipidic parameters, with significant gain after 60 days, without affecting diastolic blood pressure levels. PMID- 24488920 TI - Expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in the endometrium of patients with repeated implantation failure after in vitro fertilization. AB - AIM: To compare the immunohistochemical expression of extracellular matrix metalloproteinase inducer (EMMPRIN) in repeated implantation failure (RIF) patients with normal fertile controls. PATIENTS AND METHODS: The study group consisted of primary infertile patients with RIF and normal fertile controls between January 2011 and February 2013. Endometrial samples received at the luteal phase were exposed to immunohistochemical staining for EMMPRIN antibodies. EMMPRIN expression of endometrial glandular epithelial cells, stromal cells and vascular endothelial cells were evaluated. The main outcome measure was defined as immunohistochemical score with regard to the severity and extent of staining. RESULTS: The study group consisted of 26 primary infertile patients, whereas the control group consisted of 40 normal fertile controls. The fertile group was found to have stronger expression of EMMPRIN than the study group when endometrial glandular epithelial cells, stromal cells and vascular endothelial cells were evaluated with regards to the severity of staining (p < 0.001), the extent of staining (p < 0.001) and total staining score (p < 0.001). CONCLUSIONS: This is the first study showing low expression of EMMPRIN in the endometrial cells of the patients with RIF compared with fertile healthy controls. We suggest that reduced EMMPRIN expression in the human endometrium may lead to poor endometrial receptivity. PMID- 24488922 TI - Tramadol intoxication and shoulder pain. PMID- 24488921 TI - Borderline ovarian tumors, fertility-sparing surgery and pregnancy outcome. AB - BACKGROUND: Borderline ovarian tumors (BOTs) represent a type of epithelial tumors having a biologic intermediate behavior between clearly malignant and straight benign tumors. Most of BOTs interest women during fertile age, for which it is necessary to consider a fertility sparing surgery. AIM: To evaluate the clinical aspects and pregnancy rate of women affected by borderline ovarian tumors who have undergone fertility sparing surgery. PATIENTS AND METHODS: A study of 22 patients affected by BOTs who have been treated with a fertility sparing surgery was conducted between January 2005 and October 2011 at Sant'Andrea Hospital, "Sapienza" University of Rome. The patients' characteristics analyzed were: age, histological type, tumor size, adnexal surgery, pre-operative serum CA-125, diagnostic circumstances, number of patients who became pregnant and number of overall pregnancies. RESULTS: Among the 22 patients treated with a fertility sparing surgery, only sixteen wanted to get pregnant. Eleven patents out of 16 accomplished it. The pregnancy rate was 68.7%. CONCLUSIONS: Fertility sparing surgery can be considered a safe procedure for young women affected by borderline ovarian tumors. PMID- 24488923 TI - A decade of crystallization drops: crystallization of the cbb3 cytochrome c oxidase from Pseudomonas stutzeri. AB - The cbb3 cytochrome c oxidases are distant members of the superfamily of heme copper oxidases. These terminal oxidases couple O2 reduction with proton transport across the plasma membrane and, as a part of the respiratory chain, contribute to the generation of an electrochemical proton gradient. Compared with other structurally characterized members of the heme copper oxidases, the recently determined cbb3 oxidase structure at 3.2 A resolution revealed significant differences in the electron supply system, the proton conducting pathways and the coupling of O2 reduction to proton translocation. In this paper, we present a detailed report on the key steps for structure determination. Improvement of the protein quality was achieved by optimization of the number of lipids attached to the protein as well as the separation of two cbb3 oxidase isoenzymes. The exchange of n-dodecyl-beta-D-maltoside for a precisely defined mixture of two alpha-maltosides and decanoylsucrose as well as the choice of the crystallization method had a most profound impact on crystal quality. This report highlights problems frequently encountered in membrane protein crystallization and offers meaningful approaches to improve crystal quality. PMID- 24488926 TI - Nucleophile-dependent regio- and stereoselective ring opening of 1 azoniabicyclo[3.1.0]hexane tosylate. AB - 1-[(1R)-(1-Phenylethyl)]-1-azoniabicyclo[3.1.0]hexane tosylate was generated as a stable bicyclic aziridinium salt from the corresponding 2-(3 hydroxypropyl)aziridine upon reaction with p-toluenesulfonyl anhydride. This bicyclic aziridinium ion was then treated with various nucleophiles including halides, azide, acetate, and cyanide in CH3CN to afford either piperidines or pyrrolidines through regio- and stereoselective ring opening, mediated by the characteristics of the applied nucleophile. On the basis of DFT calculations, ring-opening reactions under thermodynamic control yield piperidines, whereas reactions under kinetic control can yield both piperidines and pyrrolidines depending on the activation energies for both pathways. PMID- 24488928 TI - Organic nanohybrids for fast and sustainable energy storage. AB - A nanohybridization strategy is presented for the fabrication of high performance lithium ion batteries based on redox-active organic molecules. The rearrangement of electroactive aromatic molecules from bulk crystalline particles into molecular layers is achieved by non-covalent nanohybridization of active molecules with conductive scaffolds. As a result, nano-hybrid organic electrodes in the form of a flexible self-standing paper-free of binder/additive and current collector-are synthesized, which exhibit high energy and power densities combined with excellent cyclic stability. PMID- 24488927 TI - A note on the kappa statistic for clustered dichotomous data. AB - The kappa statistic is widely used to assess the agreement between two raters. Motivated by a simulation-based cluster bootstrap method to calculate the variance of the kappa statistic for clustered physician-patients dichotomous data, we investigate its special correlation structure and develop a new simple and efficient data generation algorithm. For the clustered physician-patients dichotomous data, based on the delta method and its special covariance structure, we propose a semi-parametric variance estimator for the kappa statistic. An extensive Monte Carlo simulation study is performed to evaluate the performance of the new proposal and five existing methods with respect to the empirical coverage probability, root-mean-square error, and average width of the 95% confidence interval for the kappa statistic. The variance estimator ignoring the dependence within a cluster is generally inappropriate, and the variance estimators from the new proposal, bootstrap-based methods, and the sampling-based delta method perform reasonably well for at least a moderately large number of clusters (e.g., the number of clusters K ?50). The new proposal and sampling based delta method provide convenient tools for efficient computations and non simulation-based alternatives to the existing bootstrap-based methods. Moreover, the new proposal has acceptable performance even when the number of clusters is as small as K = 25. To illustrate the practical application of all the methods, one psychiatric research data and two simulated clustered physician-patients dichotomous data are analyzed. PMID- 24488924 TI - Human miR-1228 as a stable endogenous control for the quantification of circulating microRNAs in cancer patients. AB - Circulating microRNAs are promising biomarkers for non-invasive testing and dynamic monitoring in cancer patients. However, no consensus exists regarding the normalization of circulating microRNAs in the quantification, making the results incomparable. We investigated global circulating microRNA profiles to identify a stable endogenous control for quantifying circulating microRNAs using three cohorts (n = 544), including 168 control individuals (healthy subjects and those with chronic hepatitis B and cirrhosis) and 376 cancer patients (hepatocellular, colorectal, lung, esophageal, gastric, renal, prostate, and breast cancer patients). GeNorm, NormFinder, and coefficient of variability (CV) were used to select the most stable endogenous control, whereas Ingenuity Pathway Analysis (IPA) was adopted to explore its signaling pathways. Seven candidates (miR-1225 3p, miR-1228, miR-30d, miR-939, miR-940, miR-188-5p, and miR-134) from microarray analysis and four commonly used controls (miR-16, miR-223, let-7a, and RNU6B) from literature were subjected to real-time quantitative reverse transcription polymerase chain reaction validation using independent cohorts. MiR-1228 (CV = 5.4%) with minimum M value and S value presented as the most stable endogenous control across eight cancer types and three controls. IPA showed miR-1228 to be involved extensively in metabolism-related signal pathways and organ morphology, implying that miR-1228 functions as a housekeeping gene. Functional network analysis found that "hematological system development" was on the list of the top networks that associate with miR-1228, implying that miR-1228 plays an important role in the hematological system. The results explained the steady expression of miR-1228 in the blood. In conclusion, miR-1228 is a promising stable endogenous control for quantifying circulating microRNAs in cancer patients. PMID- 24488925 TI - The Mdm network and its regulation of p53 activities: a rheostat of cancer risk. AB - The potent transcriptional activity of p53 (Trp53, TP53) must be kept in check for normal cell growth and survival. Tumors, which drastically deviate from these parameters, have evolved multiple mechanisms to inactivate TP53, the most prevalent of which is the emergence of TP53 missense mutations, some of which have gain-of-function activities. Another important mechanism by which tumors bypass TP53 functions is via increased levels of two TP53 inhibitors, MDM2, and MDM4. Studies in humans and in mice reveal the complexity of TP53 regulation and the exquisite sensitivity of this pathway to small changes in regulation. Here, we summarize the factors that impinge on TP53 activity and thus cell death/arrest or tumor development. PMID- 24488929 TI - Modulation of Eg5 activity contributes to mitotic spindle checkpoint activation and Tat-mediated apoptosis in CD4-positive T-lymphocytes. AB - Tat, the transactivation factor of human immunodeficiency virus type 1 (HIV-1), represents one of the major players mediating the loss of CD4-positive T lymphocytes in HIV-1-infected patients, primarily due to the ability of Tat to trigger apoptosis. However, the molecular events underlying this process remain elusive. In this study, we provide evidence that Tat interacts with Eg5, a microtubule-associated motor protein, and allosterically modulates the ATPase activity of Eg5 by affecting ADP release from the enzyme's active centre. This action of Tat impairs the formation of the mitotic spindle and activates the spindle checkpoint, thereby blocking cell cycle progression at mitosis and leading to apoptosis. Further studies reveal that lysine 85 in the carboxyl terminus of Tat is critical for its interaction with Eg5 and hence its effects on Eg5 activity, mitotic progression, and apoptosis. These findings identify Tat as a viral regulator of Eg5 and provide novel insights into the mechanisms of action of Tat in mediating the reduction of CD4-positive T-lymphocytes. PMID- 24488930 TI - Pre-maturation with cAMP modulators in conjunction with EGF-like peptides during in vitro maturation enhances mouse oocyte developmental competence. AB - Recent studies have independently shown that cyclic adenosine 3'5'-monophosphate (cAMP) modulation prior to in vitro maturation (IVM) and epidermal growth factor (EGF)-like peptide supplementation during IVM improve subsequent oocyte developmental outcomes. This study investigated the effects of an IVM system that incorporates these two concepts. Cumulus-oocyte complexes (COCs) were collected from pre-pubertal mice either 46 hr post-equine chorionic gonadotropin (eCG) (IVM) or post-eCG + post-human chorionic gonadotropin (hCG) stimulation (in vivo maturation; IVV). IVM COCs were treated with the cAMP modulators forskolin and IBMX for 1, 2, or 4 hr (pre-IVM phase) prior to IVM. COCs then underwent IVM with the EGF-like peptides amphiregulin or epiregulin, or with the common IVM stimulants follicle-stimulating hormone (FSH) or EGF. A pre-IVM phase increased the size of the subsequent blastocysts' inner-cell-mass compared to standard IVM, regardless of IVM treatment (P < 0.05). Unlike FSH or EGF, amphiregulin or epiregulin significantly increased blastocyst quality (trophectoderm and total cell numbers) and/or yield (P < 0.01) compared to standard IVM, and were the only treatments that produced blastocysts comparable to IVV-derived blastocysts. Forskolin acutely up-regulated EGF-like peptide mRNA expression after a 2-hr pre IVM phase (P < 0.001), although EGF receptor and ERK1/2 activities were not significantly different than control. IVV-like levels of EGF-like peptide mRNA expression during IVM were maintained only by supplementing with EGF-like peptides and EGF, since expression levels induced by FSH were significantly lower in vitro than during IVV. However, EGF receptor and ERK1/2 phosphorylation levels were not significantly different across treatment groups. In conclusion, a pre IVM phase in conjunction with IVM in the presence of EGF-like peptides endows high oocyte developmental competence, as evidenced by increased embryo yield and/or quality relative to FSH and EGF. PMID- 24488931 TI - Thermotunica guangxiensis gen. nov., sp. nov., isolated from mushroom residue compost. AB - A novel thermophilic actinomycete, designated AG2-7T, was isolated from mushroom residue compost in Guangxi University, Nanning, China. The strain grew optimally at 45-60 degrees C, at pH 7.0 and with 0-3.0% (w/v) NaCl. Vegetative mycelia were branched and whitish to pale yellow without fragmentation. Aerial mycelium was abundant, whitish and differentiated into long chains of spores, with a membranous structure or tunica partially covering the surface of aerial hyphae. The non-motile spores were oval in shape with a ridged surface. Strain AG-27T contained meso-diaminopimelic acid as the diagnostic diamino acid, and the whole cell sugars were galactose and ribose. Major fatty acids were iso-C16:0 (27.51%), iso-C17:0 (10.47%) and anteiso-C17:0 (12.01%). MK-9(H4) was the predominant menaquinone. The polar phospholipids were diphosphatidylglycerol, ninhydrin positive glycophospholipid, phosphatidylinositol, phosphatidylinositol mannoside, phosphatidylethanolamine, phosphatidylmethylethanolamine, an unknown phospholipid and unknown glucosamine-containing phospholipids. The G+C content of the genomic DNA was 63.6 mol%. 16S rRNA gene sequence analysis showed that the organism belonged to the family Pseudonocardiaceae, suborder Pseudonocardineae and showed more than 5% divergence from other members of the family. Based on the phenotypic and phylogenetic data, strain AG2-7T represents a novel species of a new genus in the family Pseudonocardiaceae, for which the name Thermotunica guangxiensis gen. nov., sp. nov. is proposed. The type strain of the type species is AG2-7T (=ATCC BAA-2499T=CGMCC 4.7099T). PMID- 24488932 TI - Bacillus solimangrovi sp. nov., isolated from mangrove soil. AB - Two novel bacterial strains, GH2-4T and GH2-5, were isolated from mangrove soil near the seashore of Weno island in Chuuk state, Micronesia, and were characterized by a polyphasic approach. The two strains were strictly aerobic, Gram-staining-positive, motile, endospore-forming rods that were catalase- and oxidase-positive. Colonies were circular, convex, stringy and transparent yellowish (GH2-4T) or opaque whitish (GH2-5). The 16S rRNA gene sequences of the two isolates were identical. The most closely related strains in terms of 16S rRNA gene sequence similarity were Bacillus kochii WCC 4582T, B. horneckiae DSM 23495T, B. azotoformans LMG 9581T, B. cohnii DSM 6307T and B. halmapalus DSM 8723T (95.6, 95.4, 95.4, 95.2 and 95.2% similarity, respectively). The partial groEL sequence of strain GH2-4T was identical to that of strain GH2-5 and showed <85% similarity to those of the most closely related strains. The isolates grew at pH 5-12 (optimal growth at pH 9), at 10-40 degrees C (optimum 30-35 degrees C) and at 0-9% (w/v) NaCl (optimum 1-3% NaCl). The cell-wall peptidoglycan of strains GH2-4T and GH2-5 contained meso-diaminopimelic acid and cell-wall hydrolysates contained ribose as a major sugar. The DNA G+C content was 36 mol%, and DNA-DNA relatedness between the isolates and five related reference strains was 20-24%. Strain GH2-4T exhibited 81% DNA-DNA relatedness with strain GH2-5. The major cellular fatty acids of both strains were iso-C15:0, iso-C16:0, iso C14:0 and anteiso-C15:0 and the predominant menaquinone was MK-7. On the basis of the evidence from this polyphasic study, strains GH2-4T and GH2-5 (=KCTC 33143=JCM 18995=DSM 27084) represent a novel species of the genus Bacillus, for which the name Bacillus solimangrovi sp. nov. is proposed; the type strain is GH2 4T (=KCTC 33142T=JCM 18994T=DSM 27083T). PMID- 24488933 TI - Enhancement of host-guest interactions using rationally designed macrocyclic boronic esters with a naphthalene core. AB - Efficient inclusion of electron-deficient aromatic guest molecules in an organic solvent utilizing pi-stacking interactions was achieved by using two kinds of macrocyclic boronic esters, 1,4-naph-[2+2] and 1,5-naph-[2+2], which were easily prepared by self-assembly of 1,4-naphthalenediboronic acid (3) or 1,5 naphthalenediboronic acid (4) and racemic tetrol 1 with an indacene framework in a protic solvent. The X-ray crystallographic analyses revealed that the tilt angles of the two naphthalene rings are different: that of 1,4-naph-[2+2] is about 15 degrees and that of 1,5-naph-[2+2] is about 0 degrees . Owing to the parallel alignment of two aromatic rings, 1,5-naph-[2+2] has a much higher binding ability than 1,4-naph-[2+2]. This knowledge could be useful for the design of the new host molecules in organic solvents. PMID- 24488934 TI - Teardrop poikilocytes in metastatic carcinoma of the breast. PMID- 24488936 TI - Labyrinth-induced faceted electrochemical growth. AB - A path-length bias of nucleated electrochemical growth in a 3D periodic nano-maze is found to cause facet formation of an intrinsically isotropic material in a porous self-assembled gyroid network. This is the first report of faceted electrochemical growth that is not based on the crystallographic order of the constituent building blocks, but rather reflects the symmetry of the template in which the material is synthesized. PMID- 24488935 TI - DrRad51 is required for chiasmata formation in meiosis in planarian Dugesia ryukyuensis. AB - Rad51, a conserved eukaryotic protein, mediates the homologous-recombination repair of DNA double-strand breaks that occur during both mitosis and meiosis. During prophase I of meiosis, homologous recombination enhances the linkage between homologous chromosomes to increase the accuracy of segregation at anaphase I. In polyploidy situations, however, difficulties with homologous chromosome segregation often disrupt meiosis. Yet, triploid individuals of the planarian Dugesia ryukyuensis are able to produce functional gametes through a specialized form of meiosis. To shed light on the molecular mechanisms that promote successful meiosis in triploid D. ryukyuensis, we investigated rad51 gene function. We isolated three genes of the Rad51 family, the Rad51 homolog Dr-rad51 and the Rad51 paralogs Dr-rad51B and Dr-rad51C. Dr-rad51 was expressed in germ line and presumably in somatic stem cells, but was not necessary for the regeneration of somatic tissue. RNA-interference (RNAi) depletion of Dr-rad51 during sexualization did not affect chromosome behavior in zygotene oocytes, but did result in the loss of chiasmata at the diplotene stage. Thus, homologous recombination does not appear to be necessary for synapsis, but is needed for crossover and proper segregation in D. ryukyuensis. PMID- 24488938 TI - Nanowire shish-kebab structures and molecular orientation control of all conjugated diblock copolymers. AB - Herein we propose a facile strategy to prepare nanowires and nanowire "shish kebab" (NWSK) structures by controlling the crystallization behavior of all conjugated rod-rod diblock copolymers poly[(p-phenylene)-block-(3 hexylthiophene)]s (PPP-b-P3HT (BmTn)) with varying main chain lengths. Depending on the block length and ratio (i.e., PPP/P3HT, abbreviated as B/T), nanowires with low B/T ratios (copolymers with long P3HT blocks; B8T32 and B14T34) and NWSKs with high B/T ratios (copolymers with long PPP blocks; B29T9 and B39T18) were formed for PPP-b-P3HT all-conjugated diblock copolymers. The formation of nanowires is governed by a strong interchain pi-pi stacking similar to the P3HT homopolymer, with an edge-on orientation of the P3HT moiety, whereas NWSKs are formed as a result of the particular face-on molecular orientation of PPP moiety. As the length of the P3HT moiety was increased (the block ratio of PPP/P3HT reduced), the NWSKs were transformed into nanowires gradually because of the decreasing density of "kebabs". For diblock copolymers with high PPP/P3HT ratios, the transition of the molecular orientation from face-on to edge-on was obtained by thermal annealing. PMID- 24488939 TI - Position statement: National Gaucher Foundation Medical Advisory Board, January 7, 2014. PMID- 24488940 TI - Protein expression pattern of PAWP in bull spermatozoa is associated with sperm quality and fertility following artificial insemination. AB - Post-acrosomal WW-domain binding protein (PAWP) is a signaling molecule located in the post-acrosomal sheath (PAS) of mammalian spermatozoa. We hypothesized that the proper integration of PAWP in the sperm PAS is reflective of bull-sperm quality and fertility. Cryopreserved semen samples from 298 sires of acceptable, but varied, fertility used in artificial insemination services were analyzed using immunofluorescence microscopy and flow cytometry for PAWP protein. In normal spermatozoa, PAWP fluorescence formed a regular band around the proximal PAS. Anomalies of PAWP labeling in defective spermatozoa were reflected in flow cytometry by varied intensities of PAWP-induced fluorescence. Distinct sperm phenotypes were also identified, including morphologically normal and some defective spermatozoa with moderate levels of PAWP; grossly defective spermatozoa with low/no PAWP; and defective spermatozoa with high PAWP. Analysis by ImageStream flow cytometry confirmed the prevalence of abnormal sperm phenotypes in the spermatozoa with abnormal PAWP content. Live/dead staining and video recording showed that some abnormal spermatozoa are viable and capable of progressive motility. Conventional flow-cytometric measurements of PAWP correlated significantly with semen quality and fertility parameters that reflect the sires' artificial insemination fertility, including secondary sperm morphology, conception rate, non-return rate, and residual value. A multiplex, flow-cytometric test detecting PAWP, aggresomes (ubiquitinated protein aggregates), and acrosomal integrity (peanut-agglutinin-lectin labeling) had a predictive value for conception rate, as demonstrated by step-wise regression analysis. We conclude that PAWP correlates with semen/fertility parameters used in the cattle artificial insemination industry, making PAWP a potential biomarker of bull fertility. PMID- 24488941 TI - Brain Growth Gains and Losses in Extremely Preterm Infants at Term. AB - Premature exposure to the extrauterine environment negatively affects the brains' developmental trajectory. Our aim was to determine whether extremely preterm (EPT) infants, with no evidence of focal brain lesions, show morphological brain differences when compared with term-born infants. Additionally, we investigated associations between perinatal factors and neuroanatomical alterations. Conventional magnetic resonance imaging was acquired at term-equivalent age (TEA) from 47 EPT infants born before 27 weeks of gestation, and 15 healthy, term-born controls. Automatic segmentation and voxel-based morphometry-Diffeomorphic Anatomical Registration through Exponentiated Lie algebra (DARTEL) were used. Compared with controls, EPT infants displayed global reductions in cortical and subcortical gray matter, brainstem, and an increased cerebrospinal fluid volume. Regionally, they showed decreased volumes of all brain tissues, in particular cortical gray matter. Increased volumes of cortical gray and white matter were observed in regions involved in visual processing. Increasing prematurity, intraventricular hemorrhage grade I-II, and patent ductus arteriosus ligation were associated with decreased volumes and had a particular effect on the cerebellum. Concluding, EPT infants without focal brain lesions had an altered brain growth at TEA that particularly affected the gray matter, and varied when it came to the presence of perinatal risk factors. Brain growth gains in EPT infants may be related to a longer extrauterine experience. PMID- 24488942 TI - Resistant Against De-depression: LTD-Like Plasticity in the Human Motor Cortex Induced by Spaced cTBS. AB - The long-term depression (LTD)-like changes in human primary motor cortex (M1) excitability induced by continuous theta burst stimulation (cTBS) are subject to reversal (i.e., de-depression) following behavioral engagement of M1, limiting its therapeutic potential under behaviorally relevant conditions. Experiments in animals suggest that the repeated, spaced application of stimulation trains may consolidate synaptic plasticity, making it resistant to reversal by physiological activity. Although there is evidence that repeated cTBS prolongs LTD-like M1 neuroplasticity in humans, whether these effects are resistant to de-depression has not been tested. We investigated whether the neuroplastic effects of paired cTBS trains were resistant to de-depression by a sustained, submaximal voluntary contraction of the hand muscles. In the absence of cTBS, voluntary contraction had no effect on motor evoked potentials (MEPs) recorded from the right first dorsal interosseous muscle. While the LTD-like MEP depression induced by a single cTBS was abolished by subsequent voluntary contraction, paired cTBS induced MEP depression that was resistant to reversal. This MEP depression was also resistant to reversal when an experimental de-depression protocol was used instead of a voluntary contraction. Our findings suggest that repeated cTBS applications consolidate LTD-like M1 neuroplasticity, which may have important implications for the clinical application of cTBS. PMID- 24488943 TI - Alpha Oscillatory Dynamics Index Temporal Expectation Benefits in Working Memory. AB - Enhanced alpha power compared with a baseline can reflect states of increased cognitive load, for example, when listening to speech in noise. Can knowledge about "when" to listen (temporal expectations) potentially counteract cognitive load and concomitantly reduce alpha? The current magnetoencephalography (MEG) experiment induced cognitive load using an auditory delayed-matching-to-sample task with 2 syllables S1 and S2 presented in speech-shaped noise. Temporal expectation about the occurrence of S1 was manipulated in 3 different cue conditions: "Neutral" (uninformative about foreperiod), "early-cued" (short foreperiod), and "late-cued" (long foreperiod). Alpha power throughout the trial was highest when the cue was uninformative about the onset time of S1 (neutral) and lowest for the late-cued condition. This alpha-reducing effect of late compared with neutral cues was most evident during memory retention in noise and originated primarily in the right insula. Moreover, individual alpha effects during retention accounted best for observed individual performance differences between late-cued and neutral conditions, indicating a tradeoff between allocation of neural resources and the benefits drawn from temporal cues. Overall, the results indicate that temporal expectations can facilitate the encoding of speech in noise, and concomitantly reduce neural markers of cognitive load. PMID- 24488944 TI - Low band-gap conjugated polymers with strong interchain aggregation and very high hole mobility towards highly efficient thick-film polymer solar cells. AB - Absorption spectra of polymer FBT-Th4 (1,4) (M n = 46.4 Kg/mol, E g = 1.62 eV, and HOMO = -5.36 eV) indicate strong interchain aggregation ability. High hole mobilities up to 1.92 cm(2) (V s)(-1) are demonstrated in OFETs fabricated under mild conditions. Inverted solar cells with active layer thicknesses ranging from 100 to 440 nm display PCEs exceeding 6.5%, with the highest efficiency of 7.64% achieved with a 230 nm thick active layer. PMID- 24488945 TI - Ascorbic acid synergistically potentiates phloxine b-induced photocytotoxicity in human acute promyelocytic leukemia cells. AB - Ascorbic acid (AsA) is known as an antioxidant but concomitantly possesses a pro oxidant property. Because the impact of AsA on photodynamic therapy response is unclear, we investigated the effect of AsA on photocytotoxicity induced by phloxine B in human acute promyelocytic leukemia HL-60 cells. AsA synergistically enhanced phloxine B-induced photocytotoxic effects, including inhibition of cell proliferation, DNA ladder formation, and caspase-3 activation, whereas AsA itself showed no photocytotoxicity. AsA also enhanced the consumption of the reduced glutathione level compared with the cells treated with phloxine B alone under the light condition. Combination of AsA with phloxine B under the light condition enhanced the phosphorylation of c-Jun N-terminal kinase and p38 mitogen-activated protein kinase (MAPK). These effects were completely cancelled by catalase. These results suggest that AsA synergistically enhances phloxine B-induced photocytotoxicity, possibly through the extracellular oxidative stress-dependent MAPK pathway activation. PMID- 24488946 TI - Synthesis of new diphosphine ligands and their application in Pd-catalyzed alkoxycarbonylation reactions. AB - Carbocyclic and N-heterocyclic analogues of the industrially applied ligand bis(di-tert-butylphosphinomethyl)benzene (1) have been synthesized in moderate to very good yields. The new ligands are based on benzene, tetralin, lutidine, pyrazine, quinoxaline, and maleimide backbones. Electronic and steric variations of the phosphorous donor sites were performed. As a benchmark reaction, the palladium-catalyzed methoxycarbonylation of 1-octene has been tested. Ester yields up to 64% and high linear selectivities up to 92% were achieved. PMID- 24488951 TI - Copper-catalyzed cascade cyclization reaction of 2-haloaryltriazenes and sodium azide: selective synthesis of 2H-benzotriazoles in water. AB - A new approach to the synthesis of 2H-benzotriazoles is described. This strategy is based on the copper-catalyzed C-N coupling of 2-haloaryltriazenes or 2-haloazo compounds with sodium azide and the intramolecular addition of nitrene to N=N bonds. This approach allows the synthesis of various N-amino- and N-aryl-2H benzotriazoles in water, in good to excellent yields. The procedure is simple and the starting materials and catalyst are easily available, offering a practical and convenient synthetic route to 2-substituted benzotriazoles. PMID- 24488952 TI - Vertically oriented silica mesochannels as the template for electrodeposition of polyaniline nanostructures and their electrocatalytic and electroanalytical applications. AB - A mesoporous silica film (MSF) with vertically oriented mesochannels on a conductive substrate serves as a hard-template for electrodeposition of polyaniline (PANI). The PANI nanostructures thus prepared are orderly confined in silica mesochannels, eventually producing a robust hybrid film. The film displays a good electrocatalytic activity toward oxidation of ascorbic acid, and can be used for potentiometric pH sensing with a Nernstian response. PMID- 24488947 TI - Enhanced water and cryoprotectant permeability of porcine oocytes after artificial expression of human and zebrafish aquaporin-3 channels. AB - One of the major obstacles for the vitrification of mature porcine oocytes with ethylene glycol is their low permeability to this cryoprotectant, which results in osmotic stress-induced cell damage and low survival. Pig blastocysts, on the other hand, show enhanced water and cryoprotectant permeability, which has been related to the transcriptional activation of aquaporin-3 (AQP3) channels at this stage of development. In this study, we asked if expression of cRNAs encoding two aquaglyceroporins, human AQP3 (hAQP3) or the zebrafish Aqp3b-T85A mutant, in porcine oocytes can increase their permeability. Microinjection of germinal vesicle-stage oocytes with enhanced green fluorescent protein (EGFP) or AQP3 cRNAs resulted in the expression of the corresponding proteins in ~26% of the metaphase-II stage oocytes at 40-44 hr of in vitro culture; co-injection of EGFP cRNA appeared to be a suitable marker for oocyte selection since all EGFP positive oocytes also expressed the corresponding aquaporin. Using this method, we found that mature oocytes co-expressing EGFP and hAQP3 or EGFP and Aqp3b-T85A showed approximately a twofold increase of the hydraulic conductivity (Lp ) with respect non-injected or EGFP alone-injected oocytes in a 0.43 M sucrose or 1.3 M ethylene glycol solution, whereas the ethylene glycol permeability (PEG ) of EGFP + hAQP3 and EGFP + Aqp3b-T85A oocytes was 6.7- and 12-fold higher, respectively, than control oocytes. These data demonstrate that the artificial expression of aquaglyceroporins in porcine metaphase-II oocytes improves their permeability, and that the zebrafish Aqp3b-T85A mutant is more efficient than the human channel at increasing the oocyte permeability to ethylene glycol. PMID- 24488953 TI - CuI/Pd0 cooperative dual catalysis: tunable stereoselective construction of tetra substituted alkenes. AB - This paper describes a tunable and stereoselective dual catalytic system that uses copper and palladium reagents. This cooperative silylcupration and palladium catalyzed allylation readily affords trisubstituted alkenylsilanes. Fine-tuning the reaction conditions allows selective access to one stereoisomer over the other. This new methodology tolerates different substituents on both coupling partners with high levels of stereoselectivity. The one-pot reaction involving a Cu(I)/Pd(0) cooperative dual catalyst directly addresses the need to develop more time-efficient and less-wasteful synthetic pathways. PMID- 24488954 TI - Alkylation of terminal alkynes with transient sigma-alkylpalladium(II) complexes: a carboalkynylation route to alkyl-substituted alkynes. AB - A mild and general alkylation of terminal alkynes with transient sigma alkylpalladium(II) complexes for assembling alkyl-substituted alkynes is described. This method represents a new way to the use of transient sigma alkylpalladium(II) complexes in organic synthesis through 1,2-carboalkynylation of alkenes. PMID- 24488955 TI - Regeneration of a conjugated sp2 graphene system through selective defunctionalization of epoxides by using a proven synthetic chemistry mechanism. AB - Graphene is a promising material capable of driving technological advancement. It is, however, a challenge to obtain pristine graphene in large quantities given the limitation of current synthetic methods. Among the numerous methods available, the chemical approach provides an optimistic outlook and has garnered much interest within the graphene community as a potential alternative. One of the most crucial steps of the chemical approach is the chemical reduction of graphene oxide as this dictates the final quality of the graphene sheets. In recent years, much of the focus has shifted to the usage of established reducing agents or oxygen removal reagents, frequently applied in organic chemistry, onto a graphene oxide platform. Herein, the selective removal of epoxide groups and subsequent regeneration of disrupted conjugated sp(2) system is highlighted, based on the synergistic effect of indium and indium(I) chloride. The morphological, structural, and electrical properties of the resulting graphene were fully characterized with X-ray photoelectron, Fourier transform IR, solid state (13)C NMR, and Raman spectroscopy; thermogravimetric analysis; scanning electron microscopy; and conductivity measurements. The as-prepared graphene showed a tenfold increase in conductivity against conventional graphene treated with hydrazine reducing agent and demonstrated a high dispersion stability in ethanol. Moreover, the selective defunctionalization of the epoxide groups provides opportunities for potential tailoring of graphene properties for prospective applications. PMID- 24488956 TI - Clickable periodic mesoporous organosilicas: synthesis, click reactions, and adsorption of antibiotics. AB - Pharmaceutical antibiotics are not easily removed from water by conventional water-treatment technologies and have been recognized as new emerging pollutants. Herein, we report the synthesis of clickable azido periodic mesoporous organosilicas (PMOs) and their use as adsorbents for the adsorption of antibiotics. Ethane-bridged PMOs, functionalized with azido groups at different densities, were synthesized by the co-condensation of 1,2 bis(trimethoxysilyl)ethane (BTME) and 3-azidopropyltrimethoxysilane (AzPTMS), in the presence of nonionic-surfactant triblock-copolymer P123, in an acidic medium. Four different alkynes were conjugated to azide-terminated PMOs by means of an efficient click reaction. The clicked PMOs showed improved adsorption capacity (241 MUg g(-1)) for antibiotics (ciprofloxacin hydrochloride) compared with azido functionalized PMOs because of the enhanced pi-pi stacking interactions. These results indicate that click reactions can introduce multifunctional groups onto PMOs, thus demonstrating the great potential of PMOs for environmental applications. PMID- 24488957 TI - Representations of Invariant Musical Categories Are Decodable by Pattern Analysis of Locally Distributed BOLD Responses in Superior Temporal and Intraparietal Sulci. AB - In categorical perception (CP), continuous physical signals are mapped to discrete perceptual bins: mental categories not found in the physical world. CP has been demonstrated across multiple sensory modalities and, in audition, for certain over-learned speech and musical sounds. The neural basis of auditory CP, however, remains ambiguous, including its robustness in nonspeech processes and the relative roles of left/right hemispheres; primary/nonprimary cortices; and ventral/dorsal perceptual processing streams. Here, highly trained musicians listened to 2-tone musical intervals, which they perceive categorically while undergoing functional magnetic resonance imaging. Multivariate pattern analyses were performed after grouping sounds by interval quality (determined by frequency ratio between tones) or pitch height (perceived noncategorically, frequency ratios remain constant). Distributed activity patterns in spheres of voxels were used to determine sound sample identities. For intervals, significant decoding accuracy was observed in the right superior temporal and left intraparietal sulci, with smaller peaks observed homologously in contralateral hemispheres. For pitch height, no significant decoding accuracy was observed, consistent with the non-CP of this dimension. These results suggest that similar mechanisms are operative for nonspeech categories as for speech; espouse roles for 2 segregated processing streams; and support hierarchical processing models for CP. PMID- 24488958 TI - Effects of nicotine on proliferation and survival in human umbilical cord mesenchymal stem cells. AB - Cigarette smoking is known to have negative effects on tissue repair and healing. The aim of this study is to investigate the effects of nicotine in human umbilical cord mesenchymal stem cells (MSCs). After nicotine treatment, MSCs became pyknotic, vacuoles appeared in the cytoplasm and nucleus, and the nuclear boundary became fuzzy as observed using atomic force microscopy. Cell proliferation was inhibited in a dose-dependent manner (P < 0.05 for all concentrations). The proportion of apoptotic MSCs was significantly increased in a dose-dependent manner. The mitochondrial membrane potential was significantly decreased (P < 0.05). Nicotine-treated MSCs had a significantly higher G0/G1 ratio (P < 0.05). Peptide mass fingerprinting identified 27 proteins that were differentially expressed between MSCs with and without nicotine treatment. These nicotine exerted toxic effects on MSCs are likely related, at least in part, to the altered expression of multiple proteins that are essential to the health and proliferation of these cells. PMID- 24488959 TI - Switchable dielectric phase transition induced by a twisting transformation in diglycine methanesulfonate. AB - A new glycine-based reversible phase transition compound diglycine methanesulfonate (1) has been successfully synthesized. Differential scanning calorimetry (DSC) measurements of 1 showed a pair of broad peaks around 134 K (T(c)=phase transition temperature) with a slight thermal hysteresis during the heating/cooling cycle, thereby indicating that this compound undergoes a reversible second-order phase transition. Dielectric measurements further confirmed the phase transition and revealed a switchable response to the ambient temperature change for the dielectric constants of 1, namely, the dielectric constants have a distinctive step-like anomaly switching between a high dielectric state in the room temperature phase (RTP) and a low state in the low temperature phase (LTP). Variable-temperature single-crystal X-ray diffraction analyses show that 1 undergoes an atypical transition from the space group P21/m in the RTP to P21/c in the LTP. The origin of the switchable dielectric phase transition is ascribed to the movement of the moieties in 1 from the equilibrium position, and this stems from the twisting of the molecules in the compound. We believe that these findings will be useful in exploring switchable dielectric phase transition materials. PMID- 24488960 TI - Insights into the maize pan-genome and pan-transcriptome. AB - Genomes at the species level are dynamic, with genes present in every individual (core) and genes in a subset of individuals (dispensable) that collectively constitute the pan-genome. Using transcriptome sequencing of seedling RNA from 503 maize (Zea mays) inbred lines to characterize the maize pan-genome, we identified 8681 representative transcript assemblies (RTAs) with 16.4% expressed in all lines and 82.7% expressed in subsets of the lines. Interestingly, with linkage disequilibrium mapping, 76.7% of the RTAs with at least one single nucleotide polymorphism (SNP) could be mapped to a single genetic position, distributed primarily throughout the nonpericentromeric portion of the genome. Stepwise iterative clustering of RTAs suggests, within the context of the genotypes used in this study, that the maize genome is restricted and further sampling of seedling RNA within this germplasm base will result in minimal discovery. Genome-wide association studies based on SNPs and transcript abundance in the pan-genome revealed loci associated with the timing of the juvenile-to adult vegetative and vegetative-to-reproductive developmental transitions, two traits important for fitness and adaptation. This study revealed the dynamic nature of the maize pan-genome and demonstrated that a substantial portion of variation may lie outside the single reference genome for a species. PMID- 24488961 TI - The rice TAL effector-dependent resistance protein XA10 triggers cell death and calcium depletion in the endoplasmic reticulum. AB - The recognition between disease resistance (R) genes in plants and their cognate avirulence (Avr) genes in pathogens can produce a hypersensitive response of localized programmed cell death. However, our knowledge of the early signaling events of the R gene-mediated hypersensitive response in plants remains limited. Here, we report the cloning and characterization of Xa10, a transcription activator-like (TAL) effector-dependent R gene for resistance to bacterial blight in rice (Oryza sativa). Xa10 contains a binding element for the TAL effector AvrXa10 (EBEAvrXa10) in its promoter, and AvrXa10 specifically induces Xa10 expression. Expression of Xa10 induces programmed cell death in rice, Nicotiana benthamiana, and mammalian HeLa cells. The Xa10 gene product XA10 localizes as hexamers in the endoplasmic reticulum (ER) and is associated with ER Ca(2+) depletion in plant and HeLa cells. XA10 variants that abolish programmed cell death and ER Ca(2+) depletion in N. benthamiana and HeLa cells also abolish disease resistance in rice. We propose that XA10 is an inducible, intrinsic terminator protein that triggers programmed cell death by a conserved mechanism involving disruption of the ER and cellular Ca(2+) homeostasis. PMID- 24488962 TI - GLUTELIN PRECURSOR ACCUMULATION3 encodes a regulator of post-Golgi vesicular traffic essential for vacuolar protein sorting in rice endosperm. AB - In seed plants, a major pathway for sorting of storage proteins to the protein storage vacuole (PSV) depends on the Golgi-derived dense vesicles (DVs). However, the molecular mechanisms regulating the directional trafficking of DVs to PSVs remain largely elusive. Here, we report the functional characterization of the rice (Oryza sativa) glutelin precursor accumulation3 (gpa3) mutant, which exhibits a floury endosperm phenotype and accumulates excess proglutelins in dry seeds. Cytological and immunocytochemistry studies revealed that in the gpa3 mutant, numerous proglutelin-containing DVs are misrouted to the plasma membrane and, via membrane fusion, release their contents into the apoplast to form a new structure named the paramural body. Positional cloning of GPA3 revealed that it encodes a plant-specific kelch-repeat protein that is localized to the trans Golgi networks, DVs, and PSVs in the developing endosperm. In vitro and in vivo experiments verified that GPA3 directly interacts with the rice Rab5a-guanine exchange factor VPS9a and forms a regulatory complex with Rab5a via VPS9a. Furthermore, our genetic data support the notion that GPA3 acts synergistically with Rab5a and VPS9a to regulate DV-mediated post-Golgi traffic in rice. Our findings provide insights into the molecular mechanisms regulating the plant specific PSV pathway and expand our knowledge of vesicular trafficking in eukaryotes. PMID- 24488964 TI - Extensive translational regulation of gene expression in an allopolyploid (Glycine dolichocarpa). AB - All flowering plants have experienced repeated rounds of polyploidy (whole-genome duplication), which has in turn driven the evolution of novel phenotypes and ecological tolerances and been a major driver of speciation. The effects of polyploidy on gene expression have been studied extensively at the level of transcription and, to a much lesser extent, at the level of the steady state proteome, but not at the level of translation. We used polysome profiling by RNA Seq to quantify translational regulation of gene expression in a recently formed (~100,000 years ago) allotetraploid (Glycine dolichocarpa) closely related to the cultivated soybean (Glycine max). We show that there is a high level of concordance between the allopolyploid transcriptome and translatome overall but that at least one-quarter of the transcriptome is translationally regulated. We further show that translational regulation preferentially targets genes involved in transcription, translation, and photosynthesis, causes regional and possibly whole-chromosome shifts in expression bias between duplicated genes (homoeologs), and reduces transcriptional differences between the polyploid and its diploid progenitors, possibly attenuating misregulation resulting from genome merger and/or doubling. Finally, translational regulation correlates positively with long-term retention of homoeologs from a paleopolyploidy event, suggesting that it plays a significant role in polyploid evolution. PMID- 24488963 TI - In vivo mapping of arabidopsis scaffold/matrix attachment regions reveals link to nucleosome-disfavoring poly(dA:dT) tracts. AB - Scaffold or matrix attachment regions (S/MARs) are found in all eukaryotes. The pattern of distribution and genomic context of S/MARs is thought to be important for processes such as chromatin organization and modulation of gene expression. Despite the importance of such processes, much is unknown about the large-scale distribution and sequence content of S/MARs in vivo. Here, we report the use of tiling microarrays to map 1358 S/MARs on Arabidopsis thaliana chromosome 4 (chr4). S/MARs occur throughout chr4, spaced much more closely than in the large plant and animal genomes that have been studied to date. Arabidopsis S/MARs can be divided into five clusters based on their association with other genomic features, suggesting a diversity of functions. While some Arabidopsis S/MARs may define structural domains, most occur near the transcription start sites of genes. Genes associated with these S/MARs have an increased probability of expression, which is particularly pronounced in the case of transcription factor genes. Analysis of sequence motifs and 6-mer enrichment patterns show that S/MARs are preferentially enriched in poly(dA:dT) tracts, sequences that resist nucleosome formation, and the majority of S/MARs contain at least one nucleosome depleted region. This global view of S/MARs provides a framework to begin evaluating genome-scale models for S/MAR function. PMID- 24488965 TI - Characterizing olfactory perceptual similarity using carbon chain discrimination in Fischer 344 rats. AB - Performance on olfactory tests can be influenced by a number of stimulus characteristics including chemical structure, concentration, perceptual similarity, and previous experience with the test odorants. Few of these parameters have been extensively characterized in the Fischer 344 rat strain. To investigate how odor quality affects perception in this rat strain, we measured how graded perceptual similarity, created by varying carbon chain length across a series of homologous alcohol pairs, influenced odor discrimination using a liquid motivated go/no-go task. We employed an automated, liquid-dilution olfactometer to train Fischer 344 rats (N = 8) on a 2-odor discrimination task. Six odorants (1-propanol, 1-butanol, 1-pentanol, 1-hexanol, 1-heptanol, and 1-octanol) were arranged to produce 15 novel odorant pairs differing between 1 and 5 carbon atoms; testing sessions included presentation of only 1 pseudorandomly assigned pair daily (200 trials). Results show that although rats can learn to discriminate between any 2 odorant pairs, performance declines systematically as the pairs become more structurally similar and, therefore, more perceptually confusing. As such, the easier discrimination pairs produced reliable ceiling effects across all rats, whereas performance for the difficult discrimination pairs was consistently worse, even after repeated testing. These data emphasize the importance of considering odorant stimulus dimensions in experimental designs employing olfactory stimuli. Moreover, establishing baseline olfactory performance in Fischer 344 rats may be particularly useful for predicting age related cognitive decline in this model. PMID- 24488966 TI - The coordination of C4 photosynthesis and the CO2-concentrating mechanism in maize and Miscanthus x giganteus in response to transient changes in light quality. AB - Unequal absorption of photons between photosystems I and II, and between bundle sheath and mesophyll cells, are likely to affect the efficiency of the CO2 concentrating mechanism in C4 plants. Under steady-state conditions, it is expected that the biochemical distribution of energy (ATP and NADPH) and photosynthetic metabolite concentrations will adjust to maintain the efficiency of C4 photosynthesis through the coordination of the C3 (Calvin-Benson-Bassham) and C4 (CO2 pump) cycles. However, under transient conditions, changes in light quality will likely alter the coordination of the C3 and C4 cycles, influencing rates of CO2 assimilation and decreasing the efficiency of the CO2-concentrating mechanism. To test these hypotheses, we measured leaf gas exchange, leaf discrimination, chlorophyll fluorescence, electrochromatic shift, photosynthetic metabolite pools, and chloroplast movement in maize (Zea mays) and Miscanthus * giganteus following transitional changes in light quality. In both species, the rate of net CO2 assimilation responded quickly to changes in light treatments, with lower rates of net CO2 assimilation under blue light compared with red, green, and blue light, red light, and green light. Under steady state, the efficiency of CO2-concentrating mechanisms was similar; however, transient changes affected the coordination of C3 and C4 cycles in M. giganteus but to a lesser extent in maize. The species differences in the ability to coordinate the activities of C3 and C4 cycles appear to be related to differences in the response of cyclic electron flux around photosystem I and potentially chloroplast rearrangement in response to changes in light quality. PMID- 24488967 TI - Multiple RNA binding protein complexes interact with the rice prolamine RNA cis localization zipcode sequences. AB - RNAs for the storage proteins, glutelins and prolamines, contain zipcode sequences, which target them to specific subdomains of the cortical endoplasmic reticulum in developing rice (Oryza sativa) seeds. Fifteen RNA binding proteins (RBPs) specifically bind to the prolamine zipcode sequences and are likely to play an important role in the transport and localization of this storage protein RNA. To understand the underlying basis for the binding of multiple protein species to the prolamine zipcode sequences, the relationship of five of these RBPs, RBP-A, RBP-I, RBP-J, RBP-K, and RBP-Q, were studied. These five RBPs, which belong to the heterogeneous nuclear ribonucleoprotein class, bind specifically to the 5' coding regions as well as to the 3' untranslated region zipcode RNAs but not to a control RNA sequence. Coimmunoprecipitation-immunoblot analyses in the presence or absence of ribonuclease showed that these five RBPs are assembled into three multiprotein complexes to form at least two zipcode RNA-protein assemblies. One cytoplasmic-localized zipcode assembly contained two multiprotein complexes sharing a common core consisting of RBP-J and RBP-K and either RBP-A (A J-K) or RBP-I (I-J-K). A second zipcode assembly of possibly nuclear origin consists of a multiprotein complex containing RBP-Q and modified forms of the other protein complexes. These results suggest that prolamine RNA transport is initiated in the nucleus to form a zipcode-protein assembly, which is remodeled in the cytoplasm to target the RNA to its proper location on the cortical endoplasmic reticulum. PMID- 24488968 TI - Differential methylation during maize leaf growth targets developmentally regulated genes. AB - DNA methylation is an important and widespread epigenetic modification in plant genomes, mediated by DNA methyltransferases (DMTs). DNA methylation is known to play a role in genome protection, regulation of gene expression, and splicing and was previously associated with major developmental reprogramming in plants, such as vernalization and transition to flowering. Here, we show that DNA methylation also controls the growth processes of cell division and cell expansion within a growing organ. The maize (Zea mays) leaf offers a great tool to study growth processes, as the cells progressively move through the spatial gradient encompassing the division zone, transition zone, elongation zone, and mature zone. Opposite to de novo DMTs, the maintenance DMTs were transcriptionally regulated throughout the growth zone of the maize leaf, concomitant with differential CCGG methylation levels in the four zones. Surprisingly, the majority of differentially methylated sequences mapped on or close to gene bodies and not to repeat-rich loci. Moreover, especially the 5' and 3' regions of genes, which show overall low methylation levels, underwent differential methylation in a developmental context. Genes involved in processes such as chromatin remodeling, cell cycle progression, and growth regulation, were differentially methylated. The presence of differential methylation located upstream of the gene anticorrelated with transcript expression, while gene body differential methylation was unrelated to the expression level. These data indicate that DNA methylation is correlated with the decision to exit mitotic cell division and to enter cell expansion, which adds a new epigenetic level to the regulation of growth processes. PMID- 24488969 TI - Separating active and passive influences on stomatal control of transpiration. AB - Motivated by studies suggesting that the stomata of ferns and lycophytes do not conform to the standard active abscisic acid (ABA) -mediated stomatal control model, we examined stomatal behavior in a conifer species (Metasequoia glyptostroboides) that is phylogenetically midway between the fern and angiosperm clades. Similar to ferns, daytime stomatal closure in response to moderate water stress seemed to be a passive hydraulic process in M. glyptostroboides immediately alleviated by rehydrating excised shoots. Only after prolonged exposure to more extreme water stress did active ABA-mediated stomatal closure become important, because foliar ABA production was triggered after leaf turgor loss. The influence of foliar ABA on stomatal conductance and stomatal aperture was highly predictable and additive with the passive hydraulic influence. M. glyptostroboides thus occupies a stomatal behavior type intermediate between the passively controlled ferns and the characteristic ABA-dependent stomatal closure described in angiosperm herbs. These results highlight the importance of considering phylogeny as a major determinant of stomatal behavior. PMID- 24488970 TI - Neonatal screening. PMID- 24488972 TI - Modeling and data choices sway conclusions about climate-conflict links. PMID- 24488971 TI - Population genomics of the honey bee reveals strong signatures of positive selection on worker traits. AB - Most theories used to explain the evolution of eusociality rest upon two key assumptions: mutations affecting the phenotype of sterile workers evolve by positive selection if the resulting traits benefit fertile kin, and that worker traits provide the primary mechanism allowing social insects to adapt to their environment. Despite the common view that positive selection drives phenotypic evolution of workers, we know very little about the prevalence of positive selection acting on the genomes of eusocial insects. We mapped the footprints of positive selection in Apis mellifera through analysis of 40 individual genomes, allowing us to identify thousands of genes and regulatory sequences with signatures of adaptive evolution over multiple timescales. We found Apoidea- and Apis-specific genes to be enriched for signatures of positive selection, indicating that novel genes play a disproportionately large role in adaptive evolution of eusocial insects. Worker-biased proteins have higher signatures of adaptive evolution relative to queen-biased proteins, supporting the view that worker traits are key to adaptation. We also found genes regulating worker division of labor to be enriched for signs of positive selection. Finally, genes associated with worker behavior based on analysis of brain gene expression were highly enriched for adaptive protein and cis-regulatory evolution. Our study highlights the significant contribution of worker phenotypes to adaptive evolution in social insects, and provides a wealth of knowledge on the loci that influence fitness in honey bees. PMID- 24488973 TI - Distinguishing constitutional and acquired nonclonal aneuploidy. PMID- 24488974 TI - Effect of physician orders for life-sustaining treatment documents on antimicrobial use and antimicrobial-resistant organism infections in nursing home residents. PMID- 24488976 TI - Editorial commentary: Host and viral factors in emergent influenza virus infections. PMID- 24488975 TI - Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1. AB - BACKGROUND: Influenza A(H7N9) viruses isolated from humans show features suggesting partial adaptation to mammals. To provide insights into the pathogenesis of H7N9 virus infection, we compared risk factors, clinical presentation, and progression of patients hospitalized with H7N9, H5N1, and 2009 pandemic H1N1 (pH1N1) virus infections. METHODS: We compared individual-level data from patients hospitalized with infection by H7N9 (n = 123), H5N1 (n = 119; 43 China, 76 Vietnam), and pH1N1 (n = 3486) viruses. We assessed risk factors for hospitalization after adjustment for age- and sex-specific prevalence of risk factors in the general Chinese population. RESULTS: The median age of patients with H7N9 virus infection was older than other patient groups (63 years; P < .001) and a higher proportion was male (71%; P < .02). After adjustment for age and sex, chronic heart disease was associated with an increased risk of hospitalization with H7N9 (relative risk, 9.68; 95% confidence interval, 5.24 17.9). H7N9 patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase to those seen in H5N1 patients, which were all significantly different from pH1N1 patients (P < .005). H7N9 patients had a longer duration of hospitalization than either H5N1 or pH1N1 patients (P < .001), and the median time from onset to death was 18 days for H7N9 (P = .002) vs 11 days for H5N1 and 15 days for pH1N1 (P = .154). CONCLUSIONS: The identification of known risk factors for severe seasonal influenza and the more protracted clinical course compared with that of H5N1 suggests that host factors are an important contributor to H7N9 severity. PMID- 24488977 TI - Enhanced stabilization of a stable single domain antibody for SEB toxin by random mutagenesis and stringent selection. AB - Single domain antibodies, recombinant variable heavy domains derived from the unique heavy-chain only antibodies found in camelids and sharks, are exceptionally rugged due to their ability to refold following heat or chemical denaturation. In addition, a number of single domain antibodies have been found to possess high melting points which provide an even greater degree of stability; one of these, llama-derived A3, is a binder of Staphylococcal enterotoxin B and has a Tm of 83.5 degrees C. In this work, we utilized random mutagenesis and stringent selection in an effort to obtain variants of A3 with even higher melting points. This effort resulted in the selection of a double mutant, A3-T28I S72I, which has a melting point of 90.0 degrees C and near wild-type affinity for the target antigen. We further characterized the mutations individually to determine that while both contributed to the thermal stabilization, the T28I mutation accounted for ~ 4.1 degrees C of the 6.5 degrees C increase. This work demonstrates that by the addition of relatively subtle changes it is possible to further improve the melting temperature of single domain antibodies that are already remarkably stable. PMID- 24488978 TI - Electrophysiologic profile and results of invasive risk stratification in asymptomatic children and adolescents with the Wolff-Parkinson-White electrocardiographic pattern. AB - BACKGROUND: Data on the results and clinical effect of an invasive risk stratification strategy in asymptomatic young patients with the Wolff-Parkinson White electrocardiographic pattern are scarce. METHODS AND RESULTS: Eighty-five consecutive patients aged<18 years with a Wolff-Parkinson-White pattern and persistent preexcitation at maximum exercise undergoing invasive risk stratification were retrospectively studied. Adverse accessory pathway (AP) properties were defined according to currently consented criteria as any of the following: shortest preexcited RR interval during atrial fibrillation/rapid atrial pacing<=250 ms (or antegrade effective refractory period<=250 ms if shortest preexcited RR interval was not available) or inducible atrioventricular re-entrant tachycardia. Age at evaluation was median 14.9 years. Eighty-two patients had a structurally normal heart and 3 had hypertrophic cardiomyopathy. A single manifest AP was present in 80, 1 manifest and 1 concealed AP in 4, and 2 manifest APs in 1 patient. Adverse AP properties were present in 32 of 85 patients (37.6%) at baseline and in additional 16 of 44 (36.4%) after isoproterenol. Ablation was performed in 41 of these 48 patients. Ablation was deferred in the remaining 7 for pathway proximity to the atrioventricular node. In addition, 18 of the low-risk patients were ablated based on patient/parental decision. CONCLUSIONS: Adverse AP properties at baseline were exhibited by 37.6% of the evaluated patients with an asymptomatic Wolff-Parkinson-White preexcitation persisting at peak exercise. Isoproterenol challenge yielded additional 36.4% of those tested at higher risk. Ablation was performed in a total of 69.4% of patients subjected to invasive risk stratification. PMID- 24488980 TI - The relationship between anaemia and malaria: apparently simple, yet controversial. AB - Among many other factors, malaria plays a major causative role of anaemia globally. The mechanisms leading to anaemia in the course of malaria are extremely diverse, involving immunological factors that act differently according to age and malaria epidemiology. The malaria-attributable fraction of anaemia may then differ in different settings. While tremendous efforts are being made to control malaria, the availability of a simple and reliable biomarker of impact is of the upmost importance. Promising data are accumulating that Hb levels could be used as a proxy of malaria even in hypo-endemic areas, even if many grey areas still deserve research efforts. PMID- 24488979 TI - Prevalence and risk factors of soil-transmitted helminth infection in Nepal. AB - BACKGROUND: The purpose of this study is to evaluate the prevalence and intensity and examine the risk factors of soil transmitted helminth (STH; i.e., roundworm [Ascaris lumbricoides], hookworms [Ancylostoma duodenale and Necator americanus], and whipworm [Trichuris trichiura]) infections in Nepal. METHODS: Five hundred and ninety-four adults (256 men and 338 women) were selected via convenience sampling from five communities in Nepal. The Kato-Katz method was used to assess the prevalence and intensity of STH infection in this population. RESULTS: Prevalence of STH infection ranged from 3.3% in Birendranagar in Chitwan, 3.5% in Kuleshor in Kathmandu, 11.7% in Kanyam in Ilam, 17.0% in Dhikurpokhari in Kaski and 51.4% in Khokana in Lalitpur District [corrected]. Multivariable regression analysis revealed that not using soap for hand-washing was significantly associated with the prevalence and infection intensity of roundworm, hookworms and whipworm. Similarly, not wearing sandals or shoes outside was significantly associated with the prevalence and infection intensity of roundworm and hookworms, but not with infection intensity of whipworm. Literacy, being underweight or overweight, anemia and occupation were not associated with prevalence and intensity of roundworm and hookworms infection, but there was an association between occupation and the prevalence of whipworm infection. CONCLUSION: STH infection was associated with individual hygiene behavior, but not with nutritional status or socio-demographic characteristics. Health policy focusing on changing individual hygiene behaviors might be useful in addressing STH infection in Nepal. PMID- 24488981 TI - Quantitative Doppler-echocardiographic imaging and clinical outcomes with left ventricular systolic dysfunction: independent effect of pulmonary hypertension. AB - BACKGROUND: Doppler-echocardiography provides quantitative imaging of systolic and diastolic left ventricular (LV) function, functional mitral regurgitation (FMR), and pulmonary hypertension (PH) in patients with LV systolic dysfunction. Whether PH is linked to survival independently of LV features and FMR in symptomatic and asymptomatic patients is unknown. METHODS AND RESULTS: Patients with LV ejection fraction <=40% and quantitative Doppler-echocardiography assessment of FMR and PH were studied. Patients were frequency matched for those with Doppler-echocardiography estimated pulmonary systolic pressure >=45 mm Hg (n=692) and those without PH (n=692; pulmonary systolic pressure, <45 mm Hg) for age, sex, LV ejection fraction, and quantified FMR severity and analyzed for long term survival after diagnosis. During follow-up (median, 8.9 years), 885 deaths (63.5%) occurred, with PH being associated with higher 5-year mortality: 51+/-2% versus 37+/-2%, P<0.001. In multivariate analysis, PH demonstrated increased mortality risk independent of age, sex, severity of diastolic and systolic LV dysfunction, FMR, comorbidities, and symptom (hazard ratio, 1.34; 95% confidence limit, 1.17-1.53; P<0.001). Subgroup analysis, stratified by symptoms, degree of FMR, and severity of LV dysfunction, demonstrated that PH was associated with excess mortality in all subgroups. CONCLUSIONS: In this large cohort of patients with LV systolic dysfunction, in whom FMR and LV characteristics were quantified and matched between those with and without PH, the presence of PH was an independent factor for excess mortality and not a surrogate for the severity of LV systolic dysfunction or FMR. In asymptomatic or symptomatic patients with or without FMR, PH is a critical marker for poor outcomes. PMID- 24488982 TI - Metabolic activity of the spleen and bone marrow in patients with acute myocardial infarction evaluated by 18f-fluorodeoxyglucose positron emission tomograpic imaging. AB - BACKGROUND: Atherosclerosis is considered to be an inflammatory disease associated with the activation of hematopoietic and immune-related organs such as the bone marrow (BM) and spleen. We evaluated the metabolic activity of those organs and of the carotid artery with (18)F-fluorodeoxyglucose positron emission tomography in patients with coronary artery disease, including acute myocardial infarction. METHODS AND RESULTS: Whole-body combined (18)F-fluorodeoxyglucose positron emission tomography/computed tomography was performed in 32 patients with acute myocardial infarction, 33 patients with chronic stable angina, and 25 control subjects. The mean standard uptake value was calculated in the regions of interest in the spleen and the BM of lumbar vertebrae. The target-to-background ratio of the standard uptake values of the carotid artery and jugular vein was also calculated. In patients with acute myocardial infarction, the standard uptake values of the BM (1.67+/-0.16) and spleen (2.57+/-0.39), as well as the target-to-background ratio of the carotid artery (2.13+/-0.42), were significantly higher than the corresponding values of patients with angina (1.22+/-0.62; 2.03+/-0.35; 1.36+/-0.37; all P<0.001) and controls (0.80+/-0.44; 1.54+/-0.26; 1.22+/-0.22; all P<0.001), independent of traditional cardiovascular risk factors and high-sensitivity C-reactive protein. In all groups combined, the target-to-background ratio of the carotid artery was significantly associated with the standard uptake values of the BM (r=0.535; P<0.001), spleen (r=0.663; P<0.001), and high-sensitivity C-reactive protein (r=0.465; P<0.001). CONCLUSIONS: The metabolic activity of the BM and spleen, as well as of the carotid artery, was highest in patients with acute myocardial infarction, intermediate in patients with angina, and lowest in control subjects. The activation of the BM and spleen was significantly associated with inflammatory activity of the carotid artery. PMID- 24488985 TI - Asthma control in the workplace. PMID- 24488983 TI - Hospital variation in intravenous inotrope use for patients hospitalized with heart failure: insights from Get With The Guidelines. AB - BACKGROUND: Prior claims analyses suggest that the use of intravenous inotropic therapy for patients hospitalized with heart failure varies substantially by hospital. Whether differences in the clinical characteristics of the patients explain observed differences in the use of inotropic therapy is not known. METHODS AND RESULTS: We sought to characterize institutional variation in inotrope use among patients hospitalized with heart failure before and after accounting for clinical factors of patients. Hierarchical generalized linear regression models estimated risk-standardized hospital-level rates of inotrope use within 209 hospitals participating in Get With The Guidelines-Heart Failure (GWTG-HF) registry between 2005 and 2011. The association between risk standardized rates of inotrope use and clinical outcomes was determined. Overall, an inotropic agent was administered in 7691 of 126 564 (6.1%) heart failure hospitalizations: dobutamine 43%, dopamine 24%, milrinone 17%, or a combination 16%. Patterns of inotrope use were stable during the 7-year study period. Use of inotropes varied significantly between hospitals even after accounting for patient and hospital characteristics (median risk-standardized hospital rate, 5.9%; interquartile range, 3.7%-8.6%; range, 1.3%-32.9%). After adjusting for case-mix and hospital structural differences, model intraclass correlation indicated that 21% of the observed variation in inotrope use was potentially attributable to random hospital effects (ie, institutional preferences). Hospitals with higher risk-standardized inotrope use had modestly longer risk standardized length of stay (P=0.005) but had no difference in risk-standardized inpatient mortality (P=0.12). CONCLUSIONS: Use of intravenous inotropic agents during hospitalization for heart failure varies significantly among US hospitals even after accounting for patient and hospital factors. PMID- 24488984 TI - Innate response activator B cells aggravate atherosclerosis by stimulating T helper-1 adaptive immunity. AB - BACKGROUND: Atherosclerotic lesions grow via the accumulation of leukocytes and oxidized lipoproteins in the vessel wall. Leukocytes can attenuate or augment atherosclerosis through the release of cytokines, chemokines, and other mediators. Deciphering how leukocytes develop, oppose, and complement each other's function and shape the course of disease can illuminate our understanding of atherosclerosis. Innate response activator (IRA) B cells are a recently described population of granulocyte macrophage colony-stimulating factor secreting cells of hitherto unknown function in atherosclerosis. METHODS AND RESULTS: Here, we show that IRA B cells arise during atherosclerosis in mice and humans. In response to a high-cholesterol diet, IRA B cell numbers increase preferentially in secondary lymphoid organs via Myd88-dependent signaling. Mixed chimeric mice lacking B cell-derived granulocyte macrophage colony-stimulating factor develop smaller lesions with fewer macrophages and effector T cells. Mechanistically, IRA B cells promote the expansion of classic dendritic cells, which then generate interferon gamma-producing T helper-1 cells. This IRA B cell dependent T helper-1 skewing manifests in an IgG1-to-IgG2c isotype switch in the immunoglobulin response against oxidized lipoproteins. CONCLUSIONS: Granulocyte macrophage colony-stimulating factor-producing IRA B cells alter adaptive immune processes and shift the leukocyte response toward a T helper-1-associated milieu that aggravates atherosclerosis. PMID- 24488986 TI - Towards the next stage of novel biomarker discussion in COPD: Tekizai-Tekisho. PMID- 24488987 TI - Translational research in pulmonary hypertension: challenge and opportunity. PMID- 24488988 TI - Standing on shoulders. PMID- 24488989 TI - Pneumococcal serotypes and respiratory failure: soil or seed? PMID- 24488990 TI - Ambulatory management of primary spontaneous pneumothorax: the good is (not always) the enemy of the better (evidence). PMID- 24488991 TI - Relapses of sarcoidosis: what are they and can we predict who will get them? PMID- 24488992 TI - Lung function, genetics and ethnicity. PMID- 24488993 TI - Asymmetric dimethylarginine and asthma. PMID- 24488994 TI - Early-life wheeze: "the Child is father of the Man". PMID- 24488995 TI - Early-life wheeze: "the Child is father of the Man". PMID- 24488996 TI - Can overweight/obesity and smoking have combined effects on bronchial hyperresponsiveness? PMID- 24488997 TI - Can overweight/obesity and smoking have combined effects on bronchial hyperresponsiveness? PMID- 24488998 TI - Lung clearance index: should we really go back to nitrogen washout? PMID- 24488999 TI - Lung clearance index: should we really go back to nitrogen washout? PMID- 24489003 TI - HIV-1 Tat- and Vpr-responsive microRNAs of neuronal cells. PMID- 24489004 TI - In tribute: Helen Hislop and our time of progress. PMID- 24489005 TI - Quality of life. PMID- 24489006 TI - Femoral suspension devices for anterior cruciate ligament reconstruction: letter to the editor. PMID- 24489007 TI - Femoral suspension devices for anterior cruciate ligament reconstruction: response. PMID- 24489008 TI - Mesenchymal stem cell injection for osteochondral lesions of the talus: letter to the editor. PMID- 24489009 TI - Mesenchymal stem cell injection for osteochondral lesions of the talus: response. PMID- 24489010 TI - GPT2: a glucose 6-phosphate/phosphate translocator with a novel role in the regulation of sugar signalling during seedling development. AB - BACKGROUND AND AIMS: GPT2, a glucose 6-phosphate/phosphate translocator, plays an important role in environmental sensing in mature leaves of Arabidopsis thaliana. Its expression has also been detected in arabidopsis seeds and seedlings. In order to examine the role of this protein early in development, germination and seedling growth were studied. METHODS: Germination, greening and establishment of seedlings were monitored in both wild-type Arabidopsis thaliana and in a gpt2 T DNA insertion knockout line. Seeds were sown on agar plates in the presence or absence of glucose and abscisic acid. Relative expression of GPT2 in seedlings was measured using quantitative PCR. KEY RESULTS: Plants lacking GPT2 expression were delayed (25-40 %) in seedling establishment, specifically in the process of cotyledon greening (rather than germination). This phenotype could not be rescued by glucose in the growth medium, with greening being hypersensitive to glucose. Germination itself was, however, hyposensitive to glucose in the gpt2 mutant. CONCLUSIONS: The expression of GPT2 modulates seedling development and plays a crucial role in determining the response of seedlings to exogenous sugars during their establishment. This allows us to conclude that endogenous sugar signals function in controlling germination and the transition from heterotrophic to autotrophic growth, and that the partitioning of glucose 6-phosphate, or related metabolites, between the cytosol and the plastid modulates these developmental responses. PMID- 24489011 TI - Maintenance of strong morphological differentiation despite ongoing natural hybridization between sympatric species of Lomatia (Proteaceae). AB - BACKGROUND AND AIMS: When species cohesion is maintained despite ongoing natural hybridization, many questions are raised about the evolutionary processes operating in the species complex. This study examined the extensive natural hybridization between the Australian native shrubs Lomatia myricoides and L. silaifolia (Proteaceae). These species exhibit striking differences in morphology and ecological preferences, exceeding those found in most studies of hybridization to date. METHODS: Nuclear microsatellite markers (nSSRs), genotyping methods and morphometric analyses were used to uncover patterns of hybridization and the role of gene flow in morphological differentiation between sympatric species. KEY RESULTS: The complexity of hybridization patterns differed markedly between sites, however, signals of introgression were present at all sites. One site provided evidence of a large hybrid swarm and the likely presence of multiple hybrid generations and backcrosses, another site a handful of early generational hybrids and a third site only traces of admixture from a past hybridization event. The presence of cryptic hybrids and a pattern of morphological bimodality amongst hybrids often disguised the extent of underlying genetic admixture. CONCLUSIONS: Distinct parental habitats and phenotypes are expected to form barriers that contribute to the rapid reversion of hybrid populations to their parental character state, due to limited opportunities for hybrid/intermediate advantage. Furthermore, strong genomic filters may facilitate continued gene flow between species without the danger of assimilation. Stochastic fire events facilitate temporal phenological isolation between species and may partly explain the bi-directional and site-specific patterns of hybridization observed. Furthermore, the findings suggest that F1 hybrids are rare, and backcrosses may occur rapidly following these initial hybridization events. PMID- 24489012 TI - Osteoarthritis in Europe: impact on health status, work productivity and use of pharmacotherapies in five European countries. AB - OBJECTIVES: The aims of this study were to examine the impact of peripheral joint OA across five large European countries and how people with OA use pharmacotherapies. METHODS: People with self-reported peripheral joint OA were selected from the 2011 five European countries (5EU) National Health and Wellness Survey (NHWS), which included 57 512 respondents from France, Germany, Italy, Spain and the UK. Information was recorded on symptoms, health status, health care utilization, work productivity and medication usage. All variables were analysed descriptively for the total population and individual countries. RESULTS: A total of 3750 respondents met the inclusion criteria: 1635 (43.6%) UK, 961 (25.6%) France, 570 (15.2%) Germany, 316 (8.4%) Spain and 268 (7.1%) Italy. The majority were ages 55-74 years and most were overweight or obese. Health status [12-item Short Form version 2 (SF12v2)] was similar across all countries, with a mean (s.d.) of 40.53 (10.99); 21.5% self-reported experiencing depression. Most had visited a health care provider in the previous 6 months (n = 3537; 94.3%). One third were employed: 7% reported absenteeism and 24% presenteeism. The use of prescription medication for OA was reported by 46.9% of patients, over the-counter (OTC) medication by 26.5%, and both by 9.4%. Medication use increased with pain severity. NSAIDs were the most commonly used medication. Opioid use varied from 1.8% in Italy to 54.5% in France. Fifty per cent reported full adherence (4-point Morisky Medication Adherence Scale), but only 30% reported satisfaction with their OA medication. Most used medication for half the days of the month. CONCLUSION: Despite some wide variations in pharmacotherapy for OA treatment, the impact of OA on health status and work productivity is substantial and looks largely similar across major European countries. PMID- 24489013 TI - Art and rheumatology: the artist and the rheumatologist's perspective. AB - The reflection of medicine in the universal arts has motivated several rheumatologists to discover features of rheumatic diseases depicted by the artist's eyes long before they were defined as specific pathologic entities. The result has been the identification of several pieces of art dating from the Middle Ages, the Renaissance, the Baroque and Post-Impressionist periods that depict clear features of several rheumatic diseases such as RA, OA, camptodactyly and temporal arteritis, among others. On the other hand, great artists such as Pierre-Auguste Renoir, Antoni Gaudi, Raoul Dufy, Paul Klee, Frida Kahlo and Niki de Saint Phalle are good examples of how rheumatic diseases such as RA, scleroderma and chronic pain can influence the artist's perspective, the technique used and the content of their work. Art can serve as a powerful resource to understand the natural course of diseases. By learning through the artist's eyes the way illnesses behave and evolve in time, rheumatologists can trace the history of several conditions. PMID- 24489014 TI - A double-blind, randomized, placebo-controlled crossover trial of the alpha2C adrenoceptor antagonist ORM-12741 for prevention of cold-induced vasospasm in patients with systemic sclerosis. AB - OBJECTIVES: Our primary purpose was to evaluate the efficacy of the high-potency alpha2C-adrenoceptor antagonist ORM-12741 in the attenuation of a cold-induced reduction in finger blood flow and temperature in patients with RP secondary to SSc. Secondary objectives were to assess safety and tolerability. METHODS: This was a phase IIa, randomized, double-blind, crossover, single-dose, placebo controlled, single-centre study. Patients attended five times: initial screening, treatment visits 1-3 (each at least 1 week apart) and 1-2 weeks after the last treatment. At each treatment visit, each subject received a single oral dose of 30 mg or 100 mg of ORM-12741 or placebo. Thirty minutes later the subject underwent a cold challenge. Blood flow to the fingers was assessed by three methods [temperature by probe, laser Doppler imaging (LDI) and infrared thermography] performed before, during and after the cold challenge. RESULTS: Twelve patients (10 female, mean age 58 years) were included. The area under the rewarming curve (LDI) of the right index finger (arbitrary flux units * time) was lower for both 30 mg (P = 0.043) and 100 mg (P = 0.025) of ORM-12741 compared with placebo, indicating delayed reperfusion. The time to 70% temperature recovery (middle finger probe) was longer with active than placebo treatment: mean (s.d.) values for placebo, 30 mg of ORM-12741 and 100 mg of ORM-12741 were 21.4 min (12.4), 25.7 min (12.2) and 26.9 min (13.9), respectively. Overall ORM 12741 was well tolerated. CONCLUSION: ORM-12741 did not expedite recovery from a cold challenge in the fingers of patients with SSc. TRIAL REGISTRATION: https://www.clinicaltrialsregister.eu/; no. 2010-024005-13. PMID- 24489015 TI - Markers for work disability in anti-neutrophil cytoplasmic antibody-associated vasculitis. AB - OBJECTIVES: ANCA-associated vasculitis (AAV) commonly affects those of working age. Since survival rates have been transformed by immunotherapeutics, the measurement of other outcomes has become increasingly relevant. Work disability is an important outcome for both patient and society that has yet to be fully evaluated in AAV. We aimed to assess employment status in AAV patients and identify putative predictors of their work disability. METHODS: A cross-sectional study was undertaken. AAV cases were recruited according to consecutive clinic attendance. Subjects completed a questionnaire that determined employment status and other psychosocial measures. Clinical factors were concurrently recorded by the attending physician. From the data of those subjects of working age, a multivariable model was developed using forward stepwise logistic regression to identify the independent associations of work disability, defined by those subjects reporting unemployment secondary to ill-health. Results are expressed as odds ratios (ORs) and 95% CIs. RESULTS: Of the 410 participants (84.4% response rate), 149 (36.7%) were employed, 197 (48.6%) retired and 54 (13.3%) unemployed secondary to ill health. Of those of working age, 26.0% were considered work disabled. Fatigue (OR 7.1, 95% CI 1.5, 33.1), depression (OR 4.4, 95% CI 1.8, 10.8), severe disease damage [Vasculitis Damage Index (VDI) > 4 (OR 3.9, 95% CI 1.01, 14.7)] and being overweight (OR 3.4, 95% CI 1.3, 8.9) were independently associated with their unemployment. CONCLUSION: A quarter of working-age AAV subjects reported unemployment as a result of ill health and are characterized by high levels of fatigue, depression, disease damage and being overweight. These potentially modifiable factors may inform future multidisciplinary interventions aimed at alleviating work disability. PMID- 24489016 TI - Association of rheumatoid arthritis susceptibility gene with lipid profiles in patients with rheumatoid arthritis. AB - OBJECTIVE: RA patients have an increased risk of cardiovascular (CV) disease, although the mechanisms are unclear. As RA and CV disease may be associated through lipid profiles, we examined whether single nucleotide polymorphisms (SNPs) associated with RA susceptibility were associated with low-density lipoprotein (LDL), high-density lipoprotein (HDL) and triglyceride (TG) levels in RA subjects. METHODS: Patients (n = 763) enrolled in the Veterans Affairs RA registry who were not on hydroxymethylglutaryl-CoA reductase inhibitor were genotyped for human leukocyte antigen shared epitope (HLA-DRB1-SE) and SNPs in the following genes: CTLA-4 (cytotoxic T-lymphocyte antigen 4), IL-10, PTPN22 (protein tyrosine phosphatase, non-receptor type 22), REL (c-Rel), STAT4 (signal transducer and activator of transcription protein), TNF- and TRAF1 (TNF receptor associated factor 1). Other covariates included patient characteristics (age, gender, race, smoking status, education, BMI, modified CharlsonDeyo comorbidity index), CV characteristics (hypertension, diabetes, alcohol abuse), pharmacologic exposures (MTX, anti-TNF, glucocorticoids) and RA severity/activity markers (RA disease duration, mean DAS, CRP, RF positivity, anti-CCP positivity). Multivariate linear regression was performed to determine the factors associated with LDL, HDL and TG levels. RESULTS: The REL SNP rs9309331 homozygous minor allele was associated with higher LDL levels. Caucasian race and increasing BMI were associated with lower HDL. Factors associated with higher TG were diabetes, Caucasian race and higher BMI. CONCLUSION: The REL SNP rs9309331 was associated with LDL levels in our study. This association is a possible explanation of the increased risk of RA patients for CV disease and requires further inquiry. PMID- 24489017 TI - TNFAIP3 gene polymorphisms associated with differential susceptibility to rheumatoid arthritis and systemic lupus erythematosus in the Korean population. AB - OBJECTIVE: We investigated the relationship between polymorphisms in the TNF-a induced protein 3 (TNFAIP3) gene and genetic susceptibility to SLE and RA in the Korean population. METHODS: The present case control study included 422 patients with RA, 133 patients with SLE and 422 healthy controls. Genotyping for TNFAIP3 gene polymorphisms rs5029941 (C>T), rs2230926 (T>G), rs5029930 (C>A), rs5029937 (G>T) and rs5029939 (G>C) in TNFAIP3 gene polymorphisms was performed. The status of RA-related autoantibodies, including RF and anti-CCP, in RA and the presence of arthritis and nephritis in SLE were assessed. RESULTS: Significantly different frequencies of minor alleles in two TNFAIP3 polymorphisms were found in patients with SLE compared with healthy controls [odds ratio (OR) 2.13, 95% CI 1.25, 3.65, P= 0.02 for rs5029937; OR 2.17, 95% CI 1.27, 3.72, P= 0.01 for rs5029939). Moreover, patients with SLE showed different frequencies of haplotypes compared with healthy controls (P<0.001). However, no association was found between RA susceptibility and TNFAIP3 polymorphisms (P= 0.28). Interactions between RA related autoantibody status and TNFAIP3 polymorphisms were not associated with RA susceptibility. Interestingly, arthritis in patients with SLE was marginally associated with TNFAIP3 polymorphisms (P= 0.04). CONCLUSION: The results suggest that TNFAIP3 gene polymorphisms are associated with differential susceptibility to SLE and RA in the Korean population. The relationship between TNFAIP3 gene polymorphisms and RA susceptibility may be dependent on ethnic background. PMID- 24489018 TI - Development of portable long counter with two different moderator materials. AB - A portable, light-weight long counter (LC) with small dimensions was developed. This LC consists of a (3)He thermal neutron counter, a cylindrical moderator and outer shields. It was designed to have an almost flat response in a neutron energy range of 0.4 eV to 5 MeV. The portable LC has a radius of 11 cm and a length of 39 cm. Its weight was successfully reduced to 15 kg. Polystyrene was employed instead of polyethylene for the front part of the moderator in order to increase the sensitivity to low-energy neutrons. The response function calculated using the MCNP code was consistent with the results of experiments using monoenergetic neutron calibration fields. PMID- 24489019 TI - BcMF8, a putative arabinogalactan protein-encoding gene, contributes to pollen wall development, aperture formation and pollen tube growth in Brassica campestris. AB - BACKGROUND AND AIMS: The arabinogalactan protein (AGP) gene family is involved in plant reproduction. However, little is known about the function of individual AGP genes in pollen development and pollen tube growth. In this study, Brassica campestris male fertility 8 (BcMF8), a putative AGP-encoding gene previously found to be pollen specific in Chinese cabbage (B. campestris ssp. chinensis), was investigated. METHODS: Real-time reverse transcription-PCR and in situ hybridization were used to analyse the expression pattern of BcMF8 in pistils. Prokaryotic expression and western blots were used to ensure that BcMF8 could encode a protein. Antisense RNA technology was applied to silence gene expression, and morphological and cytological approaches (e.g. scanning electron microscopy and transmission electron microscopy) were used to reveal abnormal phenotypes caused by gene silencing. KEY RESULTS: The BcMF8 gene encoded a putative AGP protein that was located in the cell wall, and was expressed in pollen grains and pollen tubes. The functional interruption of BcMF8 by antisense RNA technology resulted in slipper-shaped and bilaterally sunken pollen with abnormal intine development and aperture formation. The inhibition of BcMF8 led to a decrease in the percentage of in vitro pollen germination. In pollen that did germinate, the pollen tubes were unstable, abnormally shaped and burst more frequently relative to controls, which corresponded to an in vivo arrest of pollen germination at the stigma surface and retarded pollen tube growth in the stylar transmitting tissues. CONCLUSIONS: The phenotypic defects of antisense BcMF8 RNA lines (bcmf8) suggest a crucial function of BcMF8 in modulating the physical nature of the pollen wall and in helping in maintaining the integrity of the pollen tube wall matrix. PMID- 24489020 TI - Modelling the structural response of cotton plants to mepiquat chloride and population density. AB - BACKGROUND AND AIMS: Cotton (Gossypium hirsutum) has indeterminate growth. The growth regulator mepiquat chloride (MC) is used worldwide to restrict vegetative growth and promote boll formation and yield. The effects of MC are modulated by complex interactions with growing conditions (nutrients, weather) and plant population density, and as a result the effects on plant form are not fully understood and are difficult to predict. The use of MC is thus hard to optimize. METHODS: To explore crop responses to plant density and MC, a functional structural plant model (FSPM) for cotton (named CottonXL) was designed. The model was calibrated using 1 year's field data, and validated by using two additional years of detailed experimental data on the effects of MC and plant density in stands of pure cotton and in intercrops of cotton with wheat. CottonXL simulates development of leaf and fruits (square, flower and boll), plant height and branching. Crop development is driven by thermal time, population density, MC application, and topping of the main stem and branches. KEY RESULTS: Validation of the model showed good correspondence between simulated and observed values for leaf area index with an overall root-mean-square error of 0.50 m(2) m(-2), and with an overall prediction error of less than 10% for number of bolls, plant height, number of fruit branches and number of phytomers. Canopy structure became more compact with the decrease of leaf area index and internode length due to the application of MC. Moreover, MC did not have a substantial effect on boll density but increased lint yield at higher densities. CONCLUSIONS: The model satisfactorily represents the effects of agronomic measures on cotton plant structure. It can be used to identify optimal agronomic management of cotton to achieve optimal plant structure for maximum yield under varying environmental conditions. PMID- 24489024 TI - The rationale for and implementation of learner-centered education: experiences at the Ostrow School of Dentistry of the University of Southern California. AB - This report describes the design, implementation, and function of integrated, learner-centered education at the Ostrow School of Dentistry of the University of Southern California. The 190 required courses of the previous curriculum have been condensed to forty-four courses. Four courses, presented for each of eleven trimesters of the four-year D.D.S. program, are entitled Human Structure, Human Function, Human Behavior, and Human Clinical Dentistry. An integrated biomedical sciences curriculum is supported by small-group, facilitator-based, problem-based learning (PBL) and an electronic PBL case library. Modules, rotations, and preclinical and clinical sessions make up remaining instructional units of the curriculum. Selected assessment outcomes measuring student knowledge, behavior, and skill development are discussed. As an external measure, first-attempt pass rates on the National Board Dental Examination (NBDE) Part I show a range of 87 96 percent over a ten-year period (for Classes 2005-14). First-attempt pass rates on the NBDE Part II for Classes 2005-12 ranged from 74 percent to 93 percent. Perceived barriers and opportunities for better performance on the NBDE Part II are addressed. Additionally, an exit survey, administered over the past four years, indicates a high level of student satisfaction with "depth and breadth" of their education (82-93 percent) and that graduates feel well prepared to enter the practice of dentistry (94-97 percent). PMID- 24489025 TI - The University of Saskatchewan's Aboriginal Equity Access Program in dentistry. AB - Persons of Aboriginal ancestry are underrepresented in the dental profession in North America. In Canada, the University of Saskatchewan College of Dentistry began a proactive program to recruit, retain, and graduate more Aboriginal students in 1996. This program, entitled the Aboriginal Equity Access Program, has seen the inclusion of twenty-two Aboriginal students in the predoctoral program. This article describes the program and reports on the success of the students enrolled via this route. The primary conclusion is that selection of Aboriginal dental students with lower entry scores--who would not have gained entry if the program did not exist--has not impaired their ability to successfully complete the dental undergraduate program and pass the National Dental Examining Board licensure examination. PMID- 24489026 TI - A survey of infection control teaching in U.S. dental schools. AB - This study was conducted to determine the content of infection control (IC) curricula, the extent of IC monitoring and compliance, and the number of bloodborne pathogen (BBP) exposures/year in U.S. dental schools. A questionnaire was emailed to persons responsible for predoctoral IC programs. The response rate was 60 percent. Most schools did not have an independent course and used classroom lectures and clinic demonstrations to teach IC. Schools with an IC committee were more likely to use online learning (p<0.05), utilize multiple teaching methods (p<0.05), issue written warnings for IC violations (p<0.0001), and use multiple disciplinary actions (p<0.005) than schools without an IC committee. Schools with an IC coordinator were less likely to issue grade reductions for IC violations than schools with no IC coordinator (p<0.05). Thirty eight percent reported >= 16 BBP exposures/year, and 18 percent reported <5. There was significant correlation between BBP exposure incidents and large class size (p<0.005). Respondents were satisfied with their IC curriculum and perceived that dental students had a high level of IC compliance and satisfaction, along with staff IC promotion and compliance. The findings suggest that schools without an IC committee should consider its benefits. Further investigation of schools with high numbers of BBP exposures is recommended. PMID- 24489027 TI - Implementation of a laboratory quality assurance program: the Louisville experience. AB - Remakes, or the refabrication of dental prostheses, can occur as a result of inherent inaccuracies in both clinical and laboratory procedures. Because dental schools manage large numbers of predoctoral dental students with limited familiarity and expertise as related to clinical prosthodontic techniques, it is likely these schools will experience an elevated incidence of laboratory remakes and their ramifications. The University of Louisville School of Dentistry, not unlike other dental schools, has experienced remakes associated with both fixed and removable prosthodontic procedures. Limitations in faculty standardization and variable enforcement of established preclinical protocols have been identified as variables associated with the high percentage of remakes documented. The purpose of this study was to introduce the implementation of a new multidepartmental quality assurance program designed to increase consistency and quality in both information provided to commercial dental laboratories and the prostheses returned. The program has shown to be advantageous in terms of cost-effectiveness and treatment outcomes. A statistically significant decrease in remake percentages has been recorded from inception of this program in December 2010 until December 2012. Furthermore, this program has resulted in more consistent communication between the dental school and commercial dental laboratories, among faculty members, and between faculty and students. PMID- 24489028 TI - Clinical audit teaching in record-keeping for dental undergraduates at International Medical University, Kuala Lumpur, Malaysia. AB - This study investigated the impact of clinical audit training on record-keeping behavior of dental students and students' perceptions of the clinical audit training. The training was delivered to Year 4 and Year 5 undergraduates at the School of Dentistry, International Medical University, Kuala Lumpur, Malaysia. It included a practical audit exercise on patient records. The results were presented by the undergraduates, and guidelines were framed from the recommendations proposed. Following this, an audit of Year 4 and Year 5 students' patient records before and after the audit training was carried out. A total of 100 records were audited against a predetermined set of criteria by two examiners. An email survey of the students was also conducted to explore their views of the audit training. Results showed statistically significant improvements in record-keeping following audit training. Responses to the email survey were analyzed qualitatively. Respondents reported that the audit training helped them to identify deficiencies in their record-keeping practice, increased their knowledge in record-keeping, and improved their record-keeping skills. Improvements in clinical audit teaching were also proposed. PMID- 24489029 TI - Extracurricular factors influence perceived stress in a large cohort of Colombian dental students. AB - The aim of this study was to investigate the association of extracurricular factors including socioeconomic status and career choice with perceived stress in dental school in a large cohort of Colombian dental students. Participants in the study were 5,700 students enrolled in seventeen Colombian dental schools. The study employed a Spanish adaptation of the Dental Environment Stressors (DES30 Sp) questionnaire and recorded an array of demographic, socioeconomic, career choice, and dental studies-related information. Data analyses relied on descriptive, bivariate, and multivariate methods based on multi-level mixed effects linear regression and post hoc estimation of predictive margins. "Fear of failing a course or year" emerged as the highest ranked item. Male students consistently reported less perceived stress than females, and stress scores were higher among seniors. Independent of gender, age, and study year, having dentistry as one's first career choice, relying on financial support, and belonging to higher socioeconomic strata were associated with lower stress levels. Academic environment interventions aimed to improve students' educational well-being will need to account for the individual heterogeneity among them. These data from a robust cohort of predoctoral dental students underscore the importance of considering students' educational experiences in a broader social and economic context. PMID- 24489030 TI - A systematic review of stress in dental students. AB - The aim of this study was to systematically review the available literature on the levels, causes, and impact of stress among dental students. The investigators searched eight electronic databases: Medline, Medline in process, Psychinfo, ERIC, Embase, Cochrane Library, Web of Science, and SCOPUS. Two independent reviewers conducted the selection, data extraction, and quality appraisal for included studies. The investigators then coded both quantitative and qualitative studies using similar codes and pooled results from studies that used the Dental Environment Stress questionnaire to demonstrate dental students' stress levels. The search initially identified 4,720 studies, of which 124 studies were included in the final qualitative synthesis and twenty-one were included in the meta analysis. Evidence from this research showed that dental students experience considerable amounts of stress during their training. This stress is mainly due to the demanding nature of the training. In addition, studies suggest adverse effects of elevated stress on students' health and well-being. Most of the available literature is based on cross-sectional studies; thus, future longitudinal studies are needed to follow students throughout their curriculum. In addition, further research needs to explore and test stress management interventions. PMID- 24489032 TI - Using tablet technology and instructional videos to enhance preclinical dental laboratory learning. AB - The purpose of this pilot study was to examine if tablet technology with accompanying instructional videos enhanced the teaching and learning outcomes in a preclinical dental laboratory setting. Two procedures deemed most challenging in Operative Dentistry II were chosen for the development of instructional videos. A random sample of thirty students was chosen to participate in the pilot. Comparison of faculty evaluations of the procedures between the experimental (tablet) and control (no tablet) groups resulted in no significant differences; however, there was a trend toward fewer failures in the experimental group. Examination of the ability to accurately self-assess was compared by exploring correlations between faculty and student evaluations. While correlations were stronger in the experimental group, the control group had significant correlations for all three procedures, while the experimental group had significant correlations on only two of the procedures. Students strongly perceived that the tablets and videos helped them perform better and more accurately self-assess their work products. Students did not support requiring that they purchase/obtain a specific brand of technology. As a result of this pilot study, further development of ideal and non-ideal videos are in progress, and the school will be implementing a "Bring Your Own Device" policy with incoming students. PMID- 24489031 TI - Effect of a rotation training system on the mental health status of postgraduate dental trainees at Kyushu University Hospital, Fukuoka, Japan. AB - In Japan, the increasing frequency of mental health problems in postgraduate dental trainees has recently become apparent. To our knowledge, there has been no previous research to investigate the influence of the type of training program on the mental health of dental residents during one year of postgraduate clinical training. Therefore, the purpose of this study was to compare changes in the mental health of two groups of dental trainees at Kyushu University Hospital, Fukuoka, Japan: those who undertook a rotation training program and those who trained solely in one department (the control group). Study subjects in both groups completed the Profile of Mood States (POMS) and the General Health Questionnaire (GHQ) at five intervals throughout the postgraduate training year. Analysis of the questionnaire responses were performed by Student's t-test, analysis of variance, Bonferroni's test, and the chi-square test. Statistical tests showed differences in the mean scores of POMS-30 subscales and GHQ-28. The mood of anger was the factor that seemed to best describe the trainees' response to stress. The study results led to the conclusion that dental trainees' mental health is influenced by the type of training program and that dental trainees in rotation training programs may need more mental health support. PMID- 24489033 TI - Dental Symphony. PMID- 24489039 TI - Two-component histidine phosphotransfer protein Ypd1 is not essential for viability in Candida albicans. AB - Prokaryotes and lower eukaryotes, such as yeasts, utilize two-component signal transduction pathways to adapt cells to environmental stress and to regulate the expression of genes associated with virulence. One of the central proteins in this type of signaling mechanism is the phosphohistidine intermediate protein Ypd1. Ypd1 is reported to be essential for viability in the model yeast Saccharomyces cerevisiae. We present data here showing that this is not the case for Candida albicans. Disruption of YPD1 causes cells to flocculate and filament constitutively under conditions that favor growth in yeast form. To determine the function of Ypd1 in the Hog1 mitogen-activated protein kinase (MAPK) pathway, we measured phosphorylation of Hog1 MAPK in ypd1Delta/Delta and wild-type strains of C. albicans. Constitutive phosphorylation of Hog1 was observed in the ypd1Delta/Delta strain compared to the wild-type strain. Furthermore, fluorescence microscopy revealed that green fluorescent protein (GFP)-tagged Ypd1 is localized to both the nucleus and the cytoplasm. The subcellular segregation of GFP-tagged Ypd1 hints at an important role(s) of Ypd1 in regulation of Ssk1 (cytosolic) and Skn7 (nuclear) response regulator proteins via phosphorylation in C. albicans. Overall, our findings have profound implications for a mechanistic understanding of two-component signaling pathways in C. albicans, and perhaps in other pathogenic fungi. PMID- 24489040 TI - Ste18p is a positive control element in the mating process of Candida albicans. AB - Heterotrimeric G proteins are an important class of eukaryotic signaling molecules that have been identified as central elements in the pheromone response pathways of many fungi. In the fungal pathogen Candida albicans, the STE18 gene (ORF19.6551.1) encodes a potential gamma subunit of a heterotrimeric G protein; this protein contains the C-terminal CAAX box characteristic of gamma subunits and has sequence similarity to gamma subunits implicated in the mating pathways of a variety of fungi. Disruption of this gene was shown to cause sterility of MTLa mating cells and to block pheromone-induced gene expression and shmoo formation; deletion of just the CAAX box residues is sufficient to inactivate Ste18 function in the mating process. Intriguingly, ectopic expression behind the strong ACT1 promoter of either the Galpha or the Gbeta subunit of the heterotrimeric G protein is able to suppress the mating defect caused by deletion of the Ggamma subunit and restore both pheromone-induced gene expression and morphology changes. PMID- 24489041 TI - Small-GTPase-associated signaling by the guanine nucleotide exchange factors CpDock180 and CpCdc24, the GTPase effector CpSte20, and the scaffold protein CpBem1 in Claviceps purpurea. AB - Monomeric GTPases of the Rho subfamily are important mediators of polar growth and NADPH (Nox) signaling in a variety of organisms. These pathways influence the ability of Claviceps purpurea to infect host plants. GTPase regulators contribute to the nucleotide loading cycle that is essential for proper functionality of the GTPases. Scaffold proteins gather GTPase complexes to facilitate proper function. The guanine nucleotide exchange factors (GEFs) CpCdc24 and CpDock180 activate GTPase signaling by triggering nucleotide exchange of the GTPases. Here we show that CpCdc24 harbors nucleotide exchange activity for both Rac and Cdc42 homologues. The GEFs partly share the cellular distribution of the GTPases and interact with the putative upstream GTPase CpRas1. Interaction studies show the formation of higher-order protein complexes, mediated by the scaffold protein CpBem1. Besides the GTPases and GEFs, these complexes also contain the GTPase effectors CpSte20 and CpCla4, as well as the regulatory protein CpNoxR. Functional characterizations suggest a role of CpCdc24 mainly in polarity, whereas CpDock180 is involved in stress tolerance mechanisms. These findings indicate the dynamic formation of small GTPase complexes and improve the model for GTPase-associated signaling in C. purpurea. PMID- 24489044 TI - Disease-related distress, self-care and clinical outcomes among low-income patients with diabetes. AB - BACKGROUND: The purpose of this study is to determine the prevalence of diabetes distress and its relationship with health behaviours and clinical outcomes in low income patients. METHODS: Secondary analyses were conducted using baseline data from a clinical trial evaluating a diabetes self-management intervention. Interviews were conducted with 666 participants receiving care at nine safety net clinics in Missouri. Distress was measured using the Diabetes Distress Scale, and outcomes included medication adherence, physical activity, nutrition and clinical biomarkers (haemoglobin A1C (HbA1C), blood pressure, low-density lipoprotein (LDL) cholesterol). RESULTS: In a sample of 666 participants, 14.1% and 27.3% of patients were identified as highly and moderately distressed, respectively, with higher rates among younger, female and lower income patients. When compared with moderately and no distress groups, highly distressed patients were less adherent to medications (20.7% vs 29.9% vs 39.4%, p<0.001) and had higher HbA1C values (9.3% (SD=2.0) vs 8.2% (SD=1.8) vs 7.8% (SD=1.7), p<0.001), diastolic blood pressure (81.8 (SD=9.4) vs 80.2 (9.7) vs 78.9 (SD=8.8), p=0.02) and LDL cholesterol (104.6 (SD=42.4) vs 97.2 (34.3) vs 95.5 (37.9)) In multivariable analyses, high and moderate distress were associated with lower medication adherence (OR=0.44; 0.27 to 0.23, p=0.001) and (OR=0.58; 0.42 to 0.79; p=0.001), respectively, and higher HbA1C in only the highly distressed group (B=1.3; 0.81 to 1.85; p<0.001) compared with the no distress group. CONCLUSIONS: Diabetes distress is prevalent and linked to poorer adherence to health behaviours and glycemic control in a sample of patients receiving care from low-income clinics. PMID- 24489045 TI - Scotland seeks views on banning wild animals in travelling circuses. PMID- 24489043 TI - Well London Phase-1: results among adults of a cluster-randomised trial of a community engagement approach to improving health behaviours and mental well being in deprived inner-city neighbourhoods. AB - BACKGROUND: We report the main results, among adults, of a cluster-randomised trial of Well London, a community-engagement programme promoting healthy eating, physical activity and mental well-being in deprived neighbourhoods. The hypothesis was that benefits would be neighbourhood-wide, and not restricted to intervention participants. The trial was part of a multicomponent process/outcome evaluation which included non-experimental components (self-reported behaviour change amongst participants, case studies and evaluations of individual projects) which suggested health, well-being and social benefits to participants. METHODS: Twenty matched pairs of neighbourhoods in London were randomised to intervention/control condition. Primary outcomes (five portions fruit/vegetables/day; 5*30 m of moderate intensity physical activity/week, abnormal General Health Questionnaire (GHQ)-12 score and Warwick-Edinburgh Mental Well-being Scale (WEMWBS) score) were measured by postintervention questionnaire survey, among 3986 adults in a random sample of households across neighbourhoods. RESULTS: There was no evidence of impact on primary outcomes: healthy eating (relative risk [RR] 1.04, 95% CI 0.93 to 1.17); physical activity (RR:1.01, 95% CI 0.88 to 1.16); abnormal GHQ12 (RR:1.15, 95% CI 0.84 to 1.61); WEMWBS (mean difference [MD]: -1.52, 95% CI -3.93 to 0.88). There was evidence of impact on some secondary outcomes: reducing unhealthy eating-score (MD: -0.14, 95% CI -0.02 to 0.27) and increased perception that people in the neighbourhood pulled together (RR: 1.92, 95% CI 1.12 to 3.29). CONCLUSIONS: The trial findings do not provide evidence supporting the conclusion of non-experimental components of the evaluation that intervention improved health behaviours, well-being and social outcomes. Low participation rates and population churn likely compromised any impact of the intervention. Imprecise estimation of outcomes and sampling bias may also have influenced findings. There is a need for greater investment in refining such programmes before implementation; new methods to understand, longitudinally different pathways residents take through such interventions and their outcomes, and new theories of change that apply to each pathway. PMID- 24489046 TI - Support for improving production efficiencies in Wales. PMID- 24489048 TI - Westpoint veterinary group acquired by investment company. PMID- 24489049 TI - Badger culling: potential licence applicants encouraged to begin preparations now. PMID- 24489050 TI - Surrey appoints contractor to build its new veterinary school. PMID- 24489051 TI - Pet health information website gets a revamp. PMID- 24489052 TI - Industry vets honour long-serving colleague. PMID- 24489053 TI - Students debate whether class matters in equine welfare. PMID- 24489054 TI - Veterinary medicines: product update. PMID- 24489055 TI - Fog fever-type pneumonia in housed beef cattle. PMID- 24489056 TI - Too many cats: how owner beliefs contribute to overpopulation. PMID- 24489057 TI - Suspected idiopathic cutaneous and renal glomerular vasculopathy in dogs. PMID- 24489058 TI - Developing one health. PMID- 24489060 TI - Identification of indicators of cattle and sheep welfare in abattoirs. PMID- 24489059 TI - Developing one health. PMID- 24489061 TI - Snake antivenom trial. PMID- 24489062 TI - Monitoring diseases in garden wildlife. PMID- 24489071 TI - Transporters involved in source to sink partitioning of amino acids and ureides: opportunities for crop improvement. AB - In most plant species, amino acids are the predominant chemical forms in which nitrogen is transported. However, in nodulated tropical or subtropical legumes, ureides are the main nitrogen transport compounds. This review describes the partitioning of amino acids and ureides within the plant, and follows their movement from the location of synthesis (source) to the sites of usage (sink). Xylem and phloem connect source and sink organs and serve as routes for long distance transport of the organic nitrogen. Loading and unloading of these transport pathways might require movement of amino acids and ureides across cell membranes, a task that is mediated by membrane proteins (i.e. transporters) functioning as export or import systems. The current knowledge on amino acid and ureide transporters involved in long-distance transport of nitrogen is provided and their importance for source and sink physiology discussed. The review concludes by exploring possibilities for genetic manipulation of organic nitrogen transporter activities to confer increases in crop productivity. PMID- 24489072 TI - Does change in device detected frequency of non-sustained or diverted episodes serve as a marker for inappropriate shock therapy? Analyses from the INTRINSIC RV and ALTITUDE-REDUCES Trials. AB - AIMS: Implantable cardioverter-defibrillators (ICDs) treat ventricular tachycardia or fibrillation but may also deliver unnecessary shocks. We sought to determine if the frequency of ICD-detected non-sustained or diverted (NSD) episodes increases before appropriate or inappropriate ICD shocks. METHODS AND RESULTS: We evaluated NSD episodes in the INTRINSIC RV Trial and their relationship to ICD shocks (appropriate and inappropriate). Time from NSD to shock was analysed. Results were validated by utilizing 1495 adjudicated ICD and cardiac resynchronization therapy-defibrillator shocks following NSD episodes collected through the LATITUDE remote monitoring system as part of the ALTITUDE REDUCES Study. In INTRINSIC RV, 185 participants received 373 shocks; 148 had at least 1 NSD episode. Non-sustained or diverted frequency increased 24 h before the first shock for those receiving an inappropriate (P < 0.01) but not an appropriate shock (P = 0.17). Patients with NSD episodes within 24 h of a shock were significantly more likely to receive inappropriate therapy [odds ratio (OR) = 3.12, P < 0.01]. At the receiver operator curve determined optimal cutoff, an NSD episode within 14 min before shock strongly predicted inappropriate therapy (sensitivity 48%, specificity 91%; OR = 8.8, and P < 0.001). The 14 min cut-off evaluated on an independent dataset of 1495 shock episodes preceded by an NSD in the ALTITUDE-REDUCES Study confirmed these results (sensitivity = 47%, specificity = 85%, OR = 5.0, and P < 0.001). CONCLUSION: Device-detected NSD episodes increase before inappropriate but not appropriate shocks. Novel alerts or automated algorithms based on NSD episodes may reduce inappropriate shocks. PMID- 24489073 TI - Treatment with novel oral anticoagulants in a real-world cohort of patients undergoing cardiac rhythm device implantations. AB - AIMS: The safety and efficacy of novel oral anticoagulants in patients with atrial fibrillation undergoing pacemaker or implantable cardioverter defibrillator interventions have not been clearly defined. Therefore, we compared the incidence of bleeding and thrombo-embolic complications following cardiac rhythm device (CRD) implantations under dabigatran vs. rivaroxaban in a real world cohort. METHODS AND RESULTS: We analysed 176 consecutive procedures performed in 93 patients treated peri-interventionally with dabigatran and 83 patients with rivaroxaban, respectively. Post-operative bleeding complications and thrombo-embolic events occurring within 30 days were compared. There were no significant differences in baseline characteristics between patients in the dabigatran and the rivaroxaban group. Most of the patients in both the groups received dual chamber or cardiac resynchronization devices (71 vs. 78%) as opposed to single-chamber systems (29 vs. 22%). In the dabigatran group, two (2%) bleeding complications (two pocket haematomas) were observed in comparison with four (5%, three pocket haematomas and one pericardial effusion) in the rivaroxaban group (P = 0.330). Three complications in the rivaroxaban group necessitated surgical intervention as opposed to none in the dabigatran group (P = 0.064). One case of a transient ischaemic attack occurred in the dabigatran group (P = 0.343). CONCLUSION: Bleeding and thrombo-embolic complications in patients treated with dabigatran or rivaroxban are rare. Further and larger studies are warranted to define the optimal anticoagulation management in patients with a need for oral anticoagulation and CRD interventions. PMID- 24489074 TI - Asymptomatic episodes of device-registered atrial tachyarrhythmia are not associated with worse cardiac resynchronization therapy response. AB - AIMS: To assess the influence of device-registered episodes of atrial tachyarrhythmia (AT) on the response to cardiac resynchronization therapy (CRT). METHODS AND RESULTS: Consecutive CRT patients without history of atrial fibrillation (AF; n = 118) were followed prospectively. AT was defined as a device-registered episode of atrial rate >190 b.p.m. for >=30 s. Episodes of electrocardiographically documented AF, accompanied by symptoms, or need for cardioversion, were classified as clinical AF. During mean follow-up of 26 +/- 9 months, 39 patients (33%) had >=1 episode of asymptomatic device-registered AT. Twenty-one patients (18%) developed clinical AF of whom seven had previously experienced episodes of asymptomatic device-registered AT. Patients with asymptomatic AT or AF had a higher body mass index, but otherwise similar baseline characteristics, compared with the subjects without AT. Reverse remodelling after CRT was similar among the groups. While clinical AF was significantly associated with the composite endpoint of all-cause mortality or unplanned hospital admission (hazard ratio = 2.43, 95% confidence interval: 1.40 4.24), this correlation was not observed in patients with asymptomatic device registered AT (P value = 0.540). CONCLUSION: Episodes of asymptomatic device registered AT are frequent in CRT patients, but are not associated with impaired reverse remodelling. In contrast to clinical AF, such episodes are not associated with worse clinical outcome. PMID- 24489075 TI - Evaluation of the current prognostic role of heart diseases in the history of patients with syncope. AB - AIMS: Pivotal studies showed that the 1-year mortality was consistently higher in cardiogenic than in non-cardiogenic syncope 10 years later, further studies questioned these evidences, showing that the risk of death was only predicted by underlying heart disease and not from the syncope itself. Accordingly, nearly all the prognostic scales now include cardiovascular variables, but their definition is often neither unique nor precise and it might lead to an excessive hospitalization. METHODS AND RESULTS: This is a prospective cohort study aimed to compare the prognosis of syncopal patients with vs. without heart diseases, considered both in a broad (all cardiovascular diseases) and limited sense (only high-risk diseases, that is coronary heart diseases, heart failure, severe aortic stenosis, cardiomyopathies, and primarily arrhythmic diseases). We studied 200 patients consecutively admitted to the emergency department of the University Hospital of Parma. At 1 month and 1 year after discharge, we compared the incidence of syncopal recurrences with trauma, major procedures, cardiovascular events, and death for any reason in patients with vs. without heart diseases, considered both in a broad and limited sense. The presence of heart diseases in a broad sense was not associated with the endpoints, both at short and long term. Conversely, high-risk heart diseases were strongly associated with the presence of serious outcomes at short time. CONCLUSION: We recommend that emergency department physicians adopt a strict definition of heart diseases considered at risk to promptly identify all patients at risk for serious events, while avoiding an excessive hospitalization. PMID- 24489076 TI - Paternity and gregariousness in the sex-changing sessile marine gastropod Crepidula convexa: comparison with other protandrous Crepidula species. AB - In sex-changing animals with internal fertilization, gregarious behavior may increase mating opportunities and the frequency of multiple paternity, thus increasing maternal reproductive success. Crepidula convexa is a direct developing protandrous gastropod characterized by only modest gregarious behavior compared with previously studied members of the genus: females are frequently found isolated. Using 6 microsatellite markers, we analyzed paternity profiles in 10 broods (25 embryos per mother). The number of assigned fathers varied among families from 1 to 4 fathers per brood. Interestingly, polyandry was not detected in solitary females but only in females grouped with conspecific individuals. Overall, we found an average of 1.8 fathers per brood, but this increased to 2.6 fathers per brood when considering only the nonisolated females. Among 18 unambiguously identified fathers, only 5 were collected in our samples, suggesting substantial male mobility. Comparison with previous paternity analyses in Crepidula fornicata and Crepidula coquimbensis revealed that polyandry appears as a common trait of these sex-changing gastropods despite their different grouping behaviors and life histories. As expected, the level of polyandry was nevertheless lower in the modestly gregarious C. convexa. PMID- 24489077 TI - Genome-wide dissection of hybrid sterility in Drosophila confirms a polygenic threshold architecture. AB - To date, different studies about the genetic basis of hybrid male sterility (HMS), a postzygotic reproductive barrier thoroughly investigated using Drosophila species, have demonstrated that no single major gene can produce hybrid sterility without the cooperation of several genetic factors. Early work using hybrids between Drosophila koepferae (Dk) and Drosophila buzzatii (Db) was consistent with the idea that HMS requires the cooperation of several genetic factors, supporting a polygenic threshold (PT) model. Here we present a genome wide mapping strategy to test the PT model, analyzing serially backcrossed fertile and sterile males in which the Dk genome was introgressed into the Db background. We identified 32 Dk-specific markers significantly associated with hybrid sterility. Our results demonstrate 1) a strong correlation between the number of segregated sterility markers and males' degree of sterility, 2) the exchangeability among markers, 3) their tendency to cluster into low-recombining chromosomal regions, and 4) the requirement for a minimum number (threshold) of markers to elicit sterility. Although our findings do not contradict a role for occasional major hybrid-sterility genes, they conform more to the view that HMS primarily evolves by the cumulative action of many interacting genes of minor effect in a complex PT architecture. PMID- 24489078 TI - Directions for future patient-centered and comparative effectiveness research for people with serious mental illness in a learning mental health care system. PMID- 24489083 TI - Serum-free light-chain assay: clinical utility and limitations. AB - In the last decade, the introduction of the serum-free light-chain (sFLC) assay has been an important advance in the diagnosis and management of plasma cell dyscrasias, particularly monoclonal light-chain diseases. The immunoassay was developed to detect free light chains in serum by using anti-FLC antibodies which specifically recognised epitopes on light chains that were 'hidden' in intact immunoglobulins. Since its introduction in 2001, there have been several publications in the English language literature discussing the clinical utility as well as analytical limitations of the sFLC assay. These studies have highlighted both positive and negative aspects of the assay particularly with regard to its sensitivity and specificity and the technical challenges that can affect its performance. The contribution and significance of the sFLC assay in the management of light-chain myeloma, primary amyloid light-chain (AL) amyloidosis and non-secretory myeloma are well recognised and will be addressed in this review. The aim of this article is to also review the published literature with a view to providing a clear understanding of its utility and limitations in the diagnosis, prognosis and monitoring of plasma dyscrasias including intact immunoglobulin multiple myeloma (MM) and monoclonal gammopathy of unknown significance (MGUS). The increasing interest in using this assay in other haematological conditions will also be briefly discussed. PMID- 24489084 TI - Sexuality education in Malaysia: perceived issues and barriers by professionals. AB - This research explored the perspectives of Malaysian professionals on the issues and barriers affecting the implementation of sexuality education in Malaysia. This qualitative study involved in-depth interviews with 15 key professionals working in the field of sexuality and reproductive health in Malaysia. Thematic analysis was selected to analyze data. Barriers to sexuality education were perceived from 5 aspects: feasibility, acceptability, accountability, strategies, and community unawareness. Respondents believed that implementing national sexuality education is a time-consuming project. They regarded Malaysian multicultural society as a barrier to national sexuality education, and they believed that school-based sexuality education is not easily accomplished in Malaysia; also abstinence-only policy restricts the access of young people to accurate information. Lack of community involvement was perceived as a key concern to sexuality education. Campaigning to promote awareness of families, teachers, community leaders, and policy makers are recommended to help establishing national sexuality education in Malaysia. PMID- 24489086 TI - IRF4 in dendritic cells inhibits IL-12 production and controls Th1 immune responses against Leishmania major. AB - IRF4 is a transcription factor from the IRF factor family that plays pivotal roles in the differentiation and function of T and B lymphocytes. Although IRF4 is also expressed in dendritic cells (DCs) and macrophages, its roles in these cells in vivo are not clearly understood. In this study, conditional knockout mice that lack IRF4 in DCs or macrophages were generated and infected with Leishmania major. Mice lacking DC expression of IRF4 showed reduced footpad swelling compared with C57BL/6 mice, whereas those lacking IRF4 in macrophages did not. Mice with IRF4-deficient DCs also showed reduced parasite burden, and their CD4(+) T cells produced higher levels of IFN-gamma in response to L. major Ag. In the draining lymph nodes, the proportion of activated CD4(+) T cells in these mice was similar to that in the control, but the proportion of IFN-gamma producing cells was increased, suggesting a Th1 bias in the immune response. Moreover, the numbers of migrating Langerhans cells and other migratory DCs in the draining lymph nodes were reduced both before and postinfection in mice with IRF4 defects in DCs, but higher levels of IL-12 were observed in IRF4-deficient DCs. These results imply that IRF4 expression in DCs inhibits their ability to produce IL-12 while promoting their migratory behavior, thus regulating CD4(+) T cell responses against local infection with L. major. PMID- 24489087 TI - PPAR-gamma/IL-10 axis inhibits MyD88 expression and ameliorates murine polymicrobial sepsis. AB - Polymicrobial sepsis induces organ failure and is accompanied by overwhelming inflammatory response and impairment of microbial killing. Peroxisome proliferator-activated receptor (PPAR)-gamma is a nuclear receptor with pleiotropic effects on lipid metabolism, inflammation, and cell proliferation. The insulin-sensitizing drugs thiazolidinediones (TZDs) are specific PPAR-gamma agonists. TZDs exert anti-inflammatory actions in different disease models, including polymicrobial sepsis. The TZD pioglitazone, which has been approved by the U.S. Food and Drug Administration, improves sepsis outcome; however, the molecular programs that mediate its effect have not been determined. In a murine model of sepsis, we now show that pioglitazone treatment improves microbial clearance and enhances neutrophil recruitment to the site of infection. We also observed reduced proinflammatory cytokine production and high IL-10 levels in pioglitazone-treated mice. These effects were associated with a decrease in STAT 1-dependent expression of MyD88 in vivo and in vitro. IL-10R blockage abolished PPAR-gamma-mediated inhibition of MyD88 expression. These data demonstrate that the primary mechanism by which pioglitazone protects against polymicrobial sepsis is through the impairment of MyD88 responses. This appears to represent a novel regulatory program. In this regard, pioglitazone provides advantages as a therapeutic tool, because it improves different aspects of host defense during sepsis, ultimately enhancing survival. PMID- 24489088 TI - CD4+ T cells contain early extrapulmonary tuberculosis (TB) dissemination and rapid TB progression and sustain multieffector functions of CD8+ T and CD3- lymphocytes: mechanisms of CD4+ T cell immunity. AB - The possibility that CD4(+) T cells can act as "innate-like" cells to contain very early Mycobacterium tuberculosis dissemination and function as master helpers to sustain multiple effector functions of CD8(+) T cells and CD3(-) lymphocytes during development of adaptive immunity against primary tuberculosis (TB) has not been demonstrated. We showed that pulmonary M. tuberculosis infection of CD4-depleted macaques surprisingly led to very early extrapulmonary M. tuberculosis dissemination, whereas CD4 deficiency clearly resulted in rapid TB progression. CD4 depletion during M. tuberculosis infection revealed the ability of CD8(+) T cells to compensate and rapidly differentiate to Th17 like/Th1-like and cytotoxic-like effectors, but these effector functions were subsequently unsustainable due to CD4 deficiency. Whereas CD3(-) non-T lymphocytes in the presence of CD4(+) T cells developed predominant Th22-like and NK-like (perforin production) responses to M. tuberculosis infection, CD4 depletion abrogated these Th22-/NK-like effector functions and favored IL-17 production by CD3(-) lymphocytes. CD4-depleted macaques exhibited no or few pulmonary T effector cells constitutively producing IFN-gamma, TNF-alpha, IL-17, IL-22, and perforin at the endpoint of more severe TB, but they presented pulmonary IL-4(+) T effectors. TB granulomas in CD4-depleted macaques contained fewer IL-22(+) and perforin(+) cells despite the presence of IL-17(+) and IL-4(+) cells. These results implicate a previously unknown innate-like ability of CD4(+) T cells to contain extrapulmonary M. tuberculosis dissemination at very early stage. Data also suggest that CD4(+) T cells are required to sustain multiple effector functions of CD8(+) T cells and CD3(-) lymphocytes and to prevent rapid TB progression during M. tuberculosis infection of nonhuman primates. PMID- 24489089 TI - A direct and nonredundant role for thymic stromal lymphopoietin on antiviral CD8 T cell responses in the respiratory mucosa. AB - Mucosally produced thymic stromal lymphopoietin (TSLP) regulates Th2 responses by signaling to dendritic cells and CD4 T cells. Activated CD8 T cells express the TSLP receptor (TSLPR), yet a direct role for TSLP in CD8 T cell immunity in the mucosa has not been described. Because TSLP shares signaling components with IL 7, a cytokine important for the development and survival of memory CD8 T cells in systemic infection models, we hypothesized that TSLP spatially and nonredundantly supports the development of these cells in the respiratory tract. In this study, we demonstrate that influenza infection induces the early expression of TSLP by lung epithelial cells with multiple consequences. The global loss of TSLP responsiveness in TSLPR(-/-) mice enhanced morbidity and delayed viral clearance. Using a competitive adoptive transfer system, we demonstrate that selective loss of TSLPR signaling on antiviral CD8 T cells decreases their accumulation specifically in the respiratory tract as early as day 8 after infection, primarily due to a proliferation deficiency. Importantly, the subsequent persistence of memory cells derived from this pool was also qualitatively and quantitatively affected. In this regard, the local support of antiviral CD8 T cells by TSLP is well suited to the mucosa, where responses must be tempered to prevent excessive inflammation. Taken together, these data suggest that TSLP uniquely participates in local immunity in the respiratory tract and modulation of TSLP levels may promote long-term CD8 T cell immunity in the mucosa when other prosurvival signals are limiting. PMID- 24489090 TI - IDO2 is a critical mediator of autoantibody production and inflammatory pathogenesis in a mouse model of autoimmune arthritis. AB - Rheumatoid arthritis and other autoimmune disorders are associated with altered activity of the immunomodulatory enzyme IDO. However, the precise contributions of IDO function to autoimmunity remain unclear. In this article, we examine the effect of two different IDO enzymes, IDO1 and IDO2, on the development of autoimmune arthritis in the KRN preclinical model of rheumatoid arthritis. We find that IDO2, not IDO1, is critical for arthritis development, providing direct evidence of separate in vivo functions for IDO1 and IDO2. Mice null for Ido2 display decreased joint inflammation relative to wild-type mice owing to a reduction in pathogenic autoantibodies and Ab-secreting cells. Notably, IDO2 appears to specifically mediate autoreactive responses, but not normal B cell responses, as total serum Ig levels are not altered and IDO2 knockout mice are able to mount productive Ab responses to model Ags in vitro and in vivo. Reciprocal adoptive transfer studies confirm that autoantibody production and arthritis are modulated by IDO2 expression in a cell type extrinsic to the T cell. Taken together, our results, provide important insights into IDO2 function by defining its pathogenic contributions to autoantibody-mediated autoimmunity. PMID- 24489091 TI - Antigen-dependent integration of opposing proximal TCR-signaling cascades determines the functional fate of T lymphocytes. AB - T cell anergy is a key tolerance mechanism to mitigate unwanted T cell activation against self by rendering lymphocytes functionally inactive following Ag encounter. Ag plays an important role in anergy induction where high supraoptimal doses lead to the unresponsive phenotype. How T cells "measure" Ag dose and how this determines functional output to a given antigenic dose remain unclear. Using multiparametric phospho-flow and mass cytometry, we measured the intracellular phosphorylation-dependent signaling events at a single-cell resolution and studied the phosphorylation levels of key proximal human TCR activation- and inhibition-signaling molecules. We show that the intracellular balance and signal integration between these opposing signaling cascades serve as the molecular switch gauging Ag dose. An Ag density of 100 peptide-MHC complexes/cell was found to be the transition point between dominant activation and inhibition cascades, whereas higher Ag doses induced an anergic functional state. Finally, the neutralization of key inhibitory molecules reversed T cell unresponsiveness and enabled maximal T cell functions, even in the presence of very high Ag doses. This mechanism permits T cells to make integrated "measurements" of Ag dose that determine subsequent functional outcomes. PMID- 24489093 TI - Inhibition of the membrane attack complex of the complement system reduces secondary neuroaxonal loss and promotes neurologic recovery after traumatic brain injury in mice. AB - Traumatic brain injury (TBI) is the leading cause of disability and death in young adults. The secondary neuroinflammation and neuronal damage that follows the primary mechanical injury is an important cause of disability in affected people. The membrane attack complex (MAC) of the complement system is detected in the traumatized brain early after TBI; however, its role in the pathology and neurologic outcome of TBI has not yet been investigated. We generated a C6 antisense oligonucleotide that blocks MAC formation by inhibiting C6, and we compared its therapeutic effect to that of Ornithodoros moubata complement inhibitor (OmCI), a known inhibitor of C5 activation that blocks generation of the anaphylatoxin C5a and C5b, an essential component of MAC. Severe closed head injury in mice induced abundant MAC deposition in the brain. Treatment with C6 antisense reduced C6 synthesis (85%) and serum levels (90%), and inhibited MAC deposition in the injured brain (91-96%). Treatment also reduced accumulation of microglia/macrophages (50-88%), neuronal apoptosis, axonal loss and weight loss (54-93%), and enhanced neurologic performance (84-92%) compared with placebo treated controls after injury. These data provide the first evidence, to our knowledge, that inhibition of MAC formation in otherwise complement-sufficient animals reduces neuropathology and promotes neurologic recovery after TBI. Given the importance of maintaining a functional complement opsonization system to fight infections, a critical complication in TBI patients, inhibition of the MAC should be considered to reduce posttraumatic neurologic damage. This work identifies a novel therapeutic target for TBI and will guide the development of new therapy for patients. PMID- 24489092 TI - Type I IFN induces binding of STAT1 to Bcl6: divergent roles of STAT family transcription factors in the T follicular helper cell genetic program. AB - CD4(+) T follicular helper cells (TFH) are critical for the formation and function of B cell responses to infection or immunization, but also play an important role in autoimmunity. The factors that contribute to the differentiation of this helper cell subset are incompletely understood, although several cytokines including IL-6, IL-21, and IL-12 can promote TFH cell formation. Yet, none of these factors, nor their downstream cognate STATs, have emerged as nonredundant, essential drivers of TFH cells. This suggests a model in which multiple factors can contribute to the phenotypic characteristics of TFH cells. Because type I IFNs are often generated in immune responses, we set out to investigate whether these factors are relevant to TFH cell differentiation. Type I IFNs promote Th1 responses, thus one possibility was these factors antagonized TFH-expressed genes. However, we show that type I IFNs (IFN-alpha/beta) induced B cell lymphoma 6 (Bcl6) expression, the master regulator transcription factor for TFH cells, and CXCR5 and programmed cell death-1 (encoded by Pdcd1), key surface molecules expressed by TFH cells. In contrast, type I IFNs failed to induce IL 21, the signature cytokine for TFH cells. The induction of Bcl6 was regulated directly by STAT1, which bound to the Bcl6, Cxcr5, and Pdcd1 loci. These data suggest that type I IFNs (IFN-alpha/beta) and STAT1 can contribute to some features of TFH cells but are inadequate in inducing complete programming of this subset. PMID- 24489094 TI - Halofuginone-induced amino acid starvation regulates Stat3-dependent Th17 effector function and reduces established autoimmune inflammation. AB - The IL-23 pathway is genetically linked to autoimmune disease in humans and is required for pathogenic Th17 cell function in mice. However, because IL-23R expressing mature Th17 cells are rare and poorly defined in mice at steady-state, little is known about IL-23 signaling. In this study, we show that the endogenous CCR6(+) memory T cell compartment present in peripheral lymphoid organs of unmanipulated mice expresses Il23r ex vivo, displays marked proinflammatory responses to IL-23 stimulation in vitro, and is capable of transferring experimental autoimmune encephalomyelitis. The prolyl-tRNA synthetase inhibitor halofuginone blocks IL-23-induced Stat3 phosphorylation and IL-23-dependent proinflammatory cytokine expression in endogenous CCR6(+) Th17 cells via activation of the amino acid starvation response (AAR) pathway. In vivo, halofuginone shows therapeutic efficacy in experimental autoimmune encephalomyelitis, reducing both established disease progression and local Th17 cell effector function within the CNS. Mechanistically, AAR activation impairs Stat3 responses downstream of multiple cytokine receptors via selective, posttranscriptional suppression of Stat3 protein levels. Thus, our study reveals latent pathogenic functions of endogenous Th17 cells that are regulated by both IL-23 and AAR pathways and identifies a novel regulatory pathway targeting Stat3 that may underlie selective immune regulation by the AAR. PMID- 24489095 TI - Inflammatory cytokines break down intrinsic immunological tolerance of human primary keratinocytes to cytosolic DNA. AB - Keratinocytes are involved in protecting the body from infections and environmental challenges, but also in inflammatory conditions like psoriasis. DNA has emerged as a potent stimulator of innate immune responses, but there is largely no information of how keratinocytes respond to cytosolic DNA. In this study, we report that human keratinocytes are tolerant to cytoplasmic DNA. However, if treated with inflammatory cytokines, keratinocytes gained the capacity to respond to DNA through a mechanism antagonized by the antimicrobial peptide LL37, proposed to be involved in activation and regulation of skin inflammation. The DNA sensor IFN-inducible protein 16 (IFI16) colocalized with DNA and the signaling molecule stimulator of IFN genes (STING) in the cytoplasm only in cytokine-stimulated cells, correlating with recruitment of the essential kinase TANK-binding kinase 1. Moreover, IFI16 was essential for DNA-driven innate immune responses in keratinocytes. Finally, IFI16 was upregulated in psoriasis skin lesions and localized to the cytoplasm in a subpopulation of cells. Collectively, this work suggests that inflammatory environments in the skin can lead to breakdown of tolerance for DNA in keratinocytes, which could contribute to the development of inflammatory diseases. PMID- 24489096 TI - A heterobivalent ligand inhibits mast cell degranulation via selective inhibition of allergen-IgE interactions in vivo. AB - Current treatments for allergies include epinephrine and antihistamines, which treat the symptoms after an allergic response has taken place; steroids, which result in local and systemic immune suppression; and IgE-depleting therapies, which can be used only for a narrow range of clinical IgE titers. The limitations of current treatments motivated the design of a heterobivalent inhibitor (HBI) of IgE-mediated allergic responses that selectively inhibits allergen-IgE interactions, thereby preventing IgE clustering and mast cell degranulation. The HBI was designed to simultaneously target the allergen binding site and the adjacent conserved nucleotide binding site (NBS) found on the Fab of IgE Abs. The bivalent targeting was accomplished by linking a hapten to an NBS ligand with an ethylene glycol linker. The hapten moiety of HBI enables selective targeting of a specific IgE, whereas the NBS ligand enhances avidity for the IgE. Simultaneous bivalent binding to both sites provided HBI with 120-fold enhancement in avidity for the target IgE compared with the monovalent hapten. The increased avidity for IgE made HBI a potent inhibitor of mast cell degranulation in the rat basophilic leukemia mast cell model, in the passive cutaneous anaphylaxis mouse model of allergy, and in mice sensitized to the model allergen. In addition, HBI did not have any observable systemic toxic effects even at elevated doses. Taken together, these results establish the HBI design as a broadly applicable platform with therapeutic potential for the targeted and selective inhibition of IgE mediated allergic responses, including food, environmental, and drug allergies. PMID- 24489097 TI - Human gammadelta thymocytes are functionally immature and differentiate into cytotoxic type 1 effector T cells upon IL-2/IL-15 signaling. AB - Cytotoxicity and IFN-gamma production by human gammadelta T cells underlie their potent antitumor functions. However, it remains unclear where and how human gammadelta T cells acquire these key effector properties. Given the recent disclosure of a major contribution of the thymus to murine gammadelta T cell functional differentiation, in this study we have analyzed a series of human pediatric thymuses. We found that ex vivo-isolated gammadelta thymocytes produced negligible IFN-gamma and lacked cytolytic activity against leukemia cells. However, these properties were selectively acquired upon stimulation with IL-2 or IL-15, but not IL-4 or IL-7. Unexpectedly, TCR activation was dispensable for these stages of functional differentiation. The effects of IL-2/IL-15 depended on MAPK/ERK signaling and induced de novo expression of the transcription factors T bet and eomesodermin, as well as the cytolytic enzyme perforin, required for the cytotoxic type 1 program. These findings have implications for the manipulation of gammadelta T cells in cancer immunotherapy. PMID- 24489098 TI - Glycoengineering of therapeutic antibodies enhances monocyte/macrophage-mediated phagocytosis and cytotoxicity. AB - Therapeutic Abs possess several clinically relevant mechanisms of action including perturbation of tumor cell signaling, activation of complement dependent cytotoxicity, Ab-dependent cellular cytotoxicity (ADCC), Ab-dependent cellular phagocytosis (ADCP), and induction of adaptive immunity. In view of the important role of phagocytic lineage cells in the mechanism of action of therapeutic Abs, we analyzed FcgammaR receptor-dependent effector functions of monocytes and macrophages triggered by glycoengineered (GE) Abs (having enhanced FcgammaRIIIa [CD16a] binding affinity) versus their wild-type (WT) counterparts under different experimental conditions. We first defined the precise FcgammaR repertoire on classical and nonclassical intermediate monocytes--M1 and M2c macrophage populations. We further show that WT and GE Abs display comparable binding and induce similar effector functions (ADCC and ADCP) in the absence of nonspecific, endogenous IgGs. However, in the presence of these IgGs (i.e., in a situation that more closely mimics physiologic conditions), GE Abs display significantly superior binding and promote stronger monocyte and macrophage activity. These data show that in addition to enhancing CD16a-dependent NK cell cytotoxicity, glycoengineering also enhances monocyte and macrophage phagocytic and cytotoxic activities through enhanced binding to CD16a under conditions that more closely resemble the physiologic setting. PMID- 24489099 TI - Thiopalmitoylation of altered peptide ligands enhances their protective effects in an animal model of multiple sclerosis. AB - Previously, we have shown that conjugation of a palmitic chain via a thioester bond to a cysteine residue in weakly or nonencephalitogenic or neuritogenic peptides markedly enhances their ability to induce autoimmune disease in an MHC class II-restricted manner. From those studies, however, it was not clear whether thiopalmitoylation of the peptides was merely enhancing their disease-inducing potential or whether the lipid was itself playing a pathogenic role. To investigate this further, we have now tested the effects of thiopalmitoylation on MHC class II-restricted altered peptide ligands (APLs), which are normally protective in experimental autoimmune encephalomyelitis, the animal model of multiple sclerosis. We hypothesized that if thiopalmitoylation of a peptide merely enhances its innate potential, then thiopalmitoylated APLs (S-palmAPLs) should show enhanced protective effects. Alternatively, if thiopalmitoylation itself can make a peptide pathogenic, then S-palmAPLs should have decreased therapeutic potential. We synthesized APLs and corresponding S-palmAPLs and showed that the S-palmAPLs were much more effective than the nonconjugated APL at inhibiting the development of experimental autoimmune encephalomyelitis. This was due to several features of the S-palmAPL:S-palmAPL-primed cells show an enhanced ability to proliferate and produce the anti-inflammatory cytokine, IL-10, in vitro. Furthermore, the bioavailability of S-palmAPL was greatly enhanced, compared with the nonpalmitoylated APL, and S-palm APL was taken up more rapidly into dendritic cells and channeled into the MHC class II processing pathway. These results show that thiopalmitoylation of MHC class II-restricted peptides is a simple way to enhance their effects in vivo and could have wide therapeutic application. PMID- 24489100 TI - GM-CSF-responsive monocyte-derived dendritic cells are pivotal in Th17 pathogenesis. AB - Although multiple dendritic cell (DC) subsets have the potential to induce Th17 differentiation in vitro, the key DC that is critical in Th17 induction and Th17 mediated disease remains moot. In this study, we revealed that CCR2(+) monocyte derived DCs (moDCs), but not conventional DCs, were critical for in vivo Th17 induction and autoimmune inflammation. Functional comparison in vitro indicated that moDCs are the most potent type of Th17-inducing DCs compared with conventional DCs and plasmacytoid DCs. Furthermore, we demonstrated that the importance of GM-CSF in Th17 induction and Th17-mediated disease is its endowment of moDCs to induce Th17 differentiation in vivo, although it has little effect on moDC numbers. Our findings identify the in vivo cellular targets that can be selectively manipulated to ameliorate Th17-mediated inflammatory diseases, as well as the mechanism of GM-CSF antagonism in such diseases. PMID- 24489102 TI - Involvement of Notch in activation and effector functions of gammadelta T cells. AB - Notch signaling plays a pivotal role in cell fate decision and lineage commitment of lymphocytes. Although the role of Notch in CD4(+) and CD8(+) alphabeta T cells is well documented, there are no reports on how Notch signaling regulates effector functions of gammadelta T cells. gammadelta T cells are a minor fraction in the peripheral blood but are known to play a major role in defense against pathogens and tumors. In this study, we show that Notch receptors (mRNA and protein) are expressed in peripheral gammadelta T cells. Inhibition of Notch signaling by gamma-secretase inhibitor inhibited the proliferation and IFN-gamma secretion of gammadelta T cells in response to stimulation with phosphoantigens and anti-CD3 mAb. In the presence of gamma-secretase inhibitor, the antitumor cytolytic ability of gammadelta T cells was inhibited with a decreased CD107a expression. Knockdown of Notch1 and Notch2 genes in gammadelta T cells using small interfering RNA inhibited their antitumor cytotoxic potential. Our study describes for the first time, to our knowledge, the role of Notch as an additional signal contributing to Ag-specific effector functions of gammadelta T cells. PMID- 24489101 TI - Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1beta in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway. AB - The accumulation of improperly folded proteins within the endoplasmic reticulum (ER) generates perturbations known as ER stress that engage the unfolded protein response. ER stress is involved in many inflammatory pathologies that are also associated with the production of the proinflammatory cytokine IL-1beta. In this study, we demonstrate that macrophages undergoing ER stress are able to drive the production and processing of pro-IL-1beta in response to LPS stimulation in vitro. Interestingly, the classical NLRP3 inflammasome is dispensable, because maturation of pro-IL-1beta occurs normally in the absence of the adaptor protein ASC. In contrast, processing of pro-IL-1beta is fully dependent on caspase-8. Intriguingly, we found that neither the unfolded protein response transcription factors XBP1 and CHOP nor the TLR4 adaptor molecule MyD88 is necessary for caspase-8 activation. Instead, both caspase activation and IL-1beta production require the alternative TLR4 adaptor TRIF. This pathway may contribute to IL-1 driven tissue pathology in certain disease settings. PMID- 24489104 TI - IFN-gamma-producing and IL-17-producing gammadelta T cells differentiate at distinct developmental stages in murine fetal thymus. AB - gammadelta T cells develop at the double-negative (DN) 2 and DN3 stages and acquire functions to produce IL-17 and IFN-gamma in fetal thymus. However, the relationship between differentiation stages and their functions was unclear. In this study, we found that, although IFN-gamma-producing and IL-17-producing gammadelta T cells developed from DN2 cells, only IFN-gamma-producing gammadelta T cells developed from DN3 cells, indicating the direct generation of IL-17 producing gammadelta T cells from the DN2 stage, not through the DN3 stage. Single-cell analysis revealed that DN2 cells contained heterogeneous gammadelta T cell precursors with or without an ability to develop IL-17 producers. Inactivation of B cell leukemia/lymphoma 11b, a zinc finger transcription factor responsible for transition from early to late stages of DN2 cells, completely abrogated the development of IL-17-producing gammadelta T cells, although a unique subset of IFN-gamma-producing gammadelta T cells expressing a high level of promyelocytic leukemia zinc finger was able to develop. Thus, our results reveal that gammadelta T cells are functionally differentiated to IFN-gamma and IL-17 producers at different developmental stages in fetal thymus. PMID- 24489103 TI - 8-oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors. AB - Among the insidious DNA base lesions, 8-oxo-7,8-dihydroguanine (8-oxoG) is one of the most abundant, a lesion that arises through the attack by reactive oxygen species on guanine, especially when located in cis-regulatory elements. 8-oxoG is repaired by the 8-oxoguanine glycosylase 1 (OGG1)-initiated DNA base excision repair pathway. In this study, we investigated whether 8-oxoG repair by OGG1 in promoter regions is compatible with a prompt gene expression and a host innate immune response. For this purpose, we used a mouse model of airway inflammation, supplemented with cell cultures, chromatin immunoprecipitation, small interfering RNA knockdown, real-time PCR, and comet and reporter transcription assays. Our data show that exposure of cells to TNF-alpha altered cellular redox, increased the 8-oxoG level in DNA, recruited OGG1 to promoter sequences, and transiently inhibited base excision repair of 8-oxoG. Promoter-associated OGG1 then enhanced NF-kappaB/RelA binding to cis-elements and facilitated recruitment of specificity protein 1, transcription initiation factor II-D, and p-RNA polymerase II, resulting in the rapid expression of chemokines/cytokines and inflammatory cell accumulation in mouse airways. Small interfering RNA depletion of OGG1 or prevention of guanine oxidation significantly decreased TNF-alpha-induced inflammatory responses. Taken together, these results show that nonproductive binding of OGG1 to 8-oxoG in promoter sequences could be an epigenetic mechanism to modulate gene expression for a prompt innate immune response. PMID- 24489105 TI - Dynamics of chemokine, cytokine, and growth factor serum levels in BRAF-mutant melanoma patients during BRAF inhibitor treatment. AB - The purpose of this study is to profile the changes in the serum levels of a range of chemokines, cytokines, and growth and angiogenic factors in MAPK inhibitor-treated metastatic melanoma patients and to correlate these changes with clinical outcome and changes in melanoma tissue biopsies taken from the same patients. Forty-two chemokine, cytokine, angiogenic, and growth factors were measured in the sera of 20 BRAF inhibitor-treated and four combination BRAF and MEK inhibitor-treated metastatic melanoma patients using a multiplex chemokine assay. The changes were correlated with Ki-67 and CD8(+) tumor-infiltrating lymphocytes in the tumor biopsies taken at the same time points, as well as clinical outcome, including response rate, progression-free survival, and overall survival. Serum levels of IFN-gamma, CCL4, and TNF-alpha were significantly increased, whereas CXCL8 significantly decreased from pretreatment (PRE) to early during treatment (EDT) serum samples. The decrease in serum CXCL8 levels from PRE to EDT significantly correlated with decreases in markers of melanoma proliferation (Ki-67) and increases in cytotoxic tumor-infiltrating T cells in corresponding tumor biopsies. In addition, a greater fold reduction in CXCL8 serum levels from PRE to EDT serum samples was associated with decreased overall survival. These results suggest that BRAF inhibition causes decreased CXCL8 secretion from melanoma cells and induce an immune response against the tumor associated with increased IFN-gamma, CCL4, and TNF-alpha. Further studies are needed to determine if CXCL8 is predictive of response and to confirm the functions of these chemokine and cytokine in BRAF-mutant melanoma under BRAF inhibition. PMID- 24489106 TI - The meaning of synthetic gametes for gay and lesbian people and bioethics too. AB - Some commentators indirectly challenge the ethics of using synthetic gametes as a way for same-sex couples to have children with shared genetics. These commentators typically impose a moral burden of proof on same-sex couples they do not impose on opposite-sex couples in terms of their eligibility to have children. Other commentators directly raise objections to parenthood by same-sex couples on the grounds that it compromises the rights and/or welfare of children. Ironically, the prospect of synthetic gametes neutralises certain of these objections, insofar as they would ensure that children have parents whom they can know as their genetic parents, which outcome is not always possible when same-sex couples involve third parties as the source of gametes or embryos. Not all commentators in bioethics throw the use of synthetic gametes into doubt as far as same-sex couples are concerned, but even these commentators put parenting by gay men and lesbians at the conclusion of an argument rather than presupposing parental legitimacy from the outset. Synthetic gametes do raise questions of ethics in regard to parenthood for gay men and lesbians, but these are largely questions of access and equity, not questions of parental fitness and/or child welfare. PMID- 24489107 TI - The genotoxin colibactin exacerbates lymphopenia and decreases survival rate in mice infected with septicemic Escherichia coli. AB - Sepsis is a life-threatening infection. Escherichia coli is the first known cause of bacteremia leading to sepsis. Lymphopenia was shown to predict bacteremia better than conventional markers of infection. The pks genomic island, which is harbored by extraintestinal pathogenic E. coli (ExPEC) and encodes the genotoxin colibactin, is epidemiologically associated with bacteremia. To investigate a possible relationship between colibactin and lymphopenia, we examined the effects of transient infection of lymphocytes with bacteria that were and those that were not producing the genotoxin. A mouse model of sepsis was used to compare the virulence of a clinical ExPEC isolate with its isogenic mutant impaired for the production of colibactin. We observed that colibactin induced double-strand breaks in the DNA of infected lymphocytes, leading to cell cycle arrest and to cell death by apoptosis. E. coli producing colibactin induced a more profound lymphopenia in septicemic mice, compared with the isogenic mutant unable to produce colibactin. In a sepsis model in which the mice were treated by rehydration and antibiotics, the production of colibactin by the bacteria was associated with a significantly lower survival rate. In conclusion, we demonstrate that production of colibactin by E. coli exacerbates lymphopenia associated with septicemia and could impair the chances to survive sepsis. PMID- 24489108 TI - Autonomy, best interests and the public interest: treatment, non-treatment and the values of medical law. AB - When constructing its responses to cases concerning the treatment and non treatment of patients, both competent and incompetent, English medical law primarily uses two analytic tools: the autonomy and the welfare (or best interests) of the patient. I argue, however, that the construction going on behind the facade involves the use of more-and more precise-tools. In such cases, the law effectively asks three questions. The first, autonomy, question asks: is the proposed course desired by the patient? The second, best interests, question asks: if the patient is not autonomous, then (what) is the proposed course in the patient's best interests? And the third, public interest, question asks: whether or not the patient is autonomous, is the proposed course in the public interest? In its responses to each question, law then offers three different answers, which reveal a plurality of ethical commitments. Thus, the wishes of the (autonomous) patient might reflect her current, her best, or her ideal desires. The best interests of the (non-autonomous) patient, meanwhile, are variously articulated in terms of (again) her desires, or the promotion or preservation of a particular mental state, or the attainment of certain objective goods. Finally, and most often obscured from view, there are public interest concerns-with the interests of the patient, some other (or others), or even the community at large. In identifying these different questions and answers, I hope to provide an explanatory typology. Whether law's plurality of answers-and values-is appropriate, however, remains open to question. PMID- 24489109 TI - Prevalence of faecal carriage of NDM-1-producing bacteria among patients with diarrhoea in Bangladesh. PMID- 24489110 TI - Lorenzo's oil inhibits ELOVL1 and lowers the level of sphingomyelin with a saturated very long-chain fatty acid. AB - X-linked adrenoleukodystrophy (X-ALD) is a peroxisomal disorder caused by impaired degradation of very long-chain fatty acids (VLCFAs) due to mutations in the ABCD1 gene responsible for VLCFA transport into peroxisomes. Lorenzo's oil, a 4:1 mixture of glyceryl trioleate and glyceryl trierucate, has been used to reduce the saturated VLCFA level in the plasma of X-ALD patients; however, the mechanism by which this occurs remains elusive. We report the biochemical characterization of Lorenzo's oil activity toward elongation of very long-chain fatty acid (ELOVL) 1, the primary enzyme responsible for the synthesis of saturated and monounsaturated VLCFAs. Oleic and erucic acids inhibited ELOVL1, and, moreover, their 4:1 mixture (the FA composition of Lorenzo's oil) exhibited the most potent inhibitory activity. The kinetics analysis revealed that this was a mixed (not a competitive) inhibition. At the cellular level, treatment with the 4:1 mixture reduced the level of SM with a saturated VLCFA accompanied by an increased level of SM with a monounsaturated VLCFA, probably due to the incorporation of erucic acid into the FA elongation cycle. These results suggest that inhibition of ELOVL1 may be an underlying mechanism by which Lorenzo's oil exerts its action. PMID- 24489111 TI - Elovl2 ablation demonstrates that systemic DHA is endogenously produced and is essential for lipid homeostasis in mice. AB - The potential role of endogenously synthesized PUFAs is a highly overlooked area. Elongation of very long-chain fatty acids (ELOVLs) in mammals is catalyzed by the ELOVL enzymes to which the PUFA elongase ELOVL2 belongs. To determine its in vivo function, we have investigated how ablation of ELOVL2, which is highly expressed in liver, affects hepatic lipid composition and function in mice. The Elovl2(-/-) mice displayed substantially decreased levels of 22:6(n-3), DHA, and 22:5(n-6), docosapentaenoic acid (DPA) n-6, and an accumulation of 22:5(n-3) and 22:4(n-6) in both liver and serum, showing that ELOVL2 primarily controls the elongation process of PUFAs with 22 carbons to produce 24-carbon precursors for DHA and DPAn 6 formation in vivo. The impaired PUFA levels positively influenced hepatic levels of the key lipogenic transcriptional regulator sterol-regulatory element binding protein 1c (SREBP-1c), as well as its downstream target genes. Surprisingly, the Elovl2(-/-) mice were resistant to hepatic steatosis and diet induced weight gain, implying that hepatic DHA synthesis via ELOVL2, in addition to controlling de novo lipogenesis, also regulates lipid storage and fat mass expansion in an SREBP-1c-independent fashion. The changes in fatty acid metabolism were reversed by dietary supplementation with DHA. PMID- 24489113 TI - Statistical distribution of single atoms and clusters of supported Au catalyst analyzed by global high-resolution HAADF-STEM observation with morphological image-processing operation. AB - We have developed a quantitative particle size analytical method at the single atomic level employing electron microscopy and image processing for the investigation of supported metal catalysts. In the present study, a supported gold (Au) catalyst containing sub-nano clusters and individual atoms was globally observed by high-resolution high-angle annular dark-field scanning transmission electron microscopy (HAADF-STEM) using spherical aberration (Cs)-corrected TEM. To fully extract structural information of the Au clusters and individual atoms from the HAADF-STEM images, a morphological image-processing operation was applied. The resulting mean particle size was in good agreement with particle sizes estimated from average information provided by X-ray absorption fine structure analysis. It is demonstrated that the present HAADF-STEM image analysis gives a quantitative particle size distribution measurement of supported Au clusters and individual atoms. PMID- 24489114 TI - The relation between recombination rate and patterns of molecular evolution and variation in Drosophila melanogaster. AB - Genetic recombination associated with sexual reproduction increases the efficiency of natural selection by reducing the strength of Hill-Robertson interference. Such interference can be caused either by selective sweeps of positively selected alleles or by background selection (BGS) against deleterious mutations. Its consequences can be studied by comparing patterns of molecular evolution and variation in genomic regions with different rates of crossing over. We carried out a comprehensive study of the benefits of recombination in Drosophila melanogaster, both by contrasting five independent genomic regions that lack crossing over with the rest of the genome and by comparing regions with different rates of crossing over, using data on DNA sequence polymorphisms from an African population that is geographically close to the putatively ancestral population for the species, and on sequence divergence from a related species. We observed reductions in sequence diversity in noncrossover (NC) regions that are inconsistent with the effects of hard selective sweeps in the absence of recombination. Overall, the observed patterns suggest that the recombination rate experienced by a gene is positively related to an increase in the efficiency of both positive and purifying selection. The results are consistent with a BGS model with interference among selected sites in NC regions, and joint effects of BGS, selective sweeps, and a past population expansion on variability in regions of the genome that experience crossing over. In such crossover regions, the X chromosome exhibits a higher rate of adaptive protein sequence evolution than the autosomes, implying a Faster-X effect. PMID- 24489112 TI - Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis. AB - In contrast to other fat-soluble vitamins, dietary vitamin K is rapidly lost to the body resulting in comparatively low tissue stores. Deficiency is kept at bay by the ubiquity of vitamin K in the diet, synthesis by gut microflora in some species, and relatively low vitamin K cofactor requirements for gamma-glutamyl carboxylation. However, as shown by fatal neonatal bleeding in mice that lack vitamin K epoxide reductase (VKOR), the low requirements are dependent on the ability of animals to regenerate vitamin K from its epoxide metabolite via the vitamin K cycle. The identification of the genes encoding VKOR and its paralog VKOR-like 1 (VKORL1) has accelerated understanding of the enzymology of this salvage pathway. In parallel, a novel human enzyme that participates in the cellular conversion of phylloquinone to menaquinone (MK)-4 was identified as UbiA prenyltransferase-containing domain 1 (UBIAD1). Recent studies suggest that side chain cleavage of oral phylloquinone occurs in the intestine, and that menadione is a circulating precursor of tissue MK-4. The mechanisms and functions of vitamin K recycling and MK-4 synthesis have dominated advances made in vitamin K biochemistry over the last five years and, after a brief overview of general metabolism, are the main focuses of this review. PMID- 24489115 TI - The transcriptomic and proteomic effects of ectopic overexpression of miR-30d in human endometrial epithelial cells. AB - miR-30d is known to be up-regulated during the acquisition of receptivity in the endometrium. In order to determine the transcriptomic and proteomic changes which occur after transient overexpression of miR-30d in primary endometrial epithelial cells, in vitro cultured human endometrial epithelial cells (hEECs) were studied experimentally. Two different miRNAs (scramble versus mimic; n = 15) were transiently transfected into primary hEECs from four different patients and were evaluated for mRNA and protein expression using Agilent's gene expression microarray and iTRAQ analysis techniques, respectively. A set of differentially expressed mRNAs were validated by qPCR and several differentially expressed proteins were validated by western blot. Finally, methylation differential immunoprecipitation (MeDIP) was used to validate the epigenetic changes in the H19 gene. The results showed that transient transfection with miR-30d miRNA induced the differential mRNA-expression of 176 genes (75 up-regulated and 101 down-regulated). Several of them have been associated with reproductive and endocrine system disorders, tissue development, and are implicated in epithelial cell proliferation. Also, the down-regulation of some genes such as H19 and N methyltransferase (NNMT) may suggest that epigenetic alterations are induced. Furthermore, upstream effects of genes regulated by the estrogen receptor alpha 1 (ESR1) transcription factor have been predicted. Proteomic analysis identified 2290 proteins, of which 108 were differentially expressed (47 up-regulated and 61 down-regulated). Among these differentially expressed proteins DNA methyl transferase (DNMT)1 was found to be up-regulated; this protein participates in the maintenance of DNA methylation, supporting an epigenetic role for miR-30d. Finally MeDIP showed an increase in methylation in the H19 DMR region. In conclusion transient in vitro overexpression of the receptivity-up-regulated miRNA miR-30d in hEECs seems to activate genes which are associated with hormonal response and the epigenetic status of these cells. PMID- 24489116 TI - Acetylation dynamics and stoichiometry in Saccharomyces cerevisiae. AB - Lysine acetylation is a frequently occurring posttranslational modification; however, little is known about the origin and regulation of most sites. Here we used quantitative mass spectrometry to analyze acetylation dynamics and stoichiometry in Saccharomyces cerevisiae. We found that acetylation accumulated in growth-arrested cells in a manner that depended on acetyl-CoA generation in distinct subcellular compartments. Mitochondrial acetylation levels correlated with acetyl-CoA concentration in vivo and acetyl-CoA acetylated lysine residues nonenzymatically in vitro. We developed a method to estimate acetylation stoichiometry and found that the vast majority of mitochondrial and cytoplasmic acetylation had a very low stoichiometry. However, mitochondrial acetylation occurred at a significantly higher basal level than cytoplasmic acetylation, consistent with the distinct acetylation dynamics and higher acetyl-CoA concentration in mitochondria. High stoichiometry acetylation occurred mostly on histones, proteins present in histone acetyltransferase and deacetylase complexes, and on transcription factors. These data show that a majority of acetylation occurs at very low levels in exponentially growing yeast and is uniformly affected by exposure to acetyl-CoA. PMID- 24489117 TI - Periodic mRNA synthesis and degradation co-operate during cell cycle gene expression. AB - During the cell cycle, the levels of hundreds of mRNAs change in a periodic manner, but how this is achieved by alterations in the rates of mRNA synthesis and degradation has not been studied systematically. Here, we used metabolic RNA labeling and comparative dynamic transcriptome analysis (cDTA) to derive mRNA synthesis and degradation rates every 5 min during three cell cycle periods of the yeast Saccharomyces cerevisiae. A novel statistical model identified 479 genes that show periodic changes in mRNA synthesis and generally also periodic changes in their mRNA degradation rates. Peaks of mRNA degradation generally follow peaks of mRNA synthesis, resulting in sharp and high peaks of mRNA levels at defined times during the cell cycle. Whereas the timing of mRNA synthesis is set by upstream DNA motifs and their associated transcription factors (TFs), the synthesis rate of a periodically expressed gene is apparently set by its core promoter. PMID- 24489118 TI - Data-driven modeling reconciles kinetics of ERK phosphorylation, localization, and activity states. AB - The extracellular signal-regulated kinase (ERK) signaling pathway controls cell proliferation and differentiation in metazoans. Two hallmarks of its dynamics are adaptation of ERK phosphorylation, which has been linked to negative feedback, and nucleocytoplasmic shuttling, which allows active ERK to phosphorylate protein substrates in the nucleus and cytosol. To integrate these complex features, we acquired quantitative biochemical and live-cell microscopy data to reconcile phosphorylation, localization, and activity states of ERK. While maximal growth factor stimulation elicits transient ERK phosphorylation and nuclear translocation responses, ERK activities available to phosphorylate substrates in the cytosol and nuclei show relatively little or no adaptation. Free ERK activity in the nucleus temporally lags the peak in nuclear translocation, indicating a slow process. Additional experiments, guided by kinetic modeling, show that this process is consistent with ERK's modification of and release from nuclear substrate anchors. Thus, adaptation of whole-cell ERK phosphorylation is a by product of transient protection from phosphatases. Consistent with this interpretation, predictions concerning the dose-dependence of the pathway response and its interruption by inhibition of MEK were experimentally confirmed. PMID- 24489119 TI - Structure of human RNA N6-methyladenine demethylase ALKBH5 provides insights into its mechanisms of nucleic acid recognition and demethylation. AB - ALKBH5 is a 2-oxoglutarate (2OG) and ferrous iron-dependent nucleic acid oxygenase (NAOX) that catalyzes the demethylation of N(6)-methyladenine in RNA. ALKBH5 is upregulated under hypoxia and plays a role in spermatogenesis. We describe a crystal structure of human ALKBH5 (residues 66-292) to 2.0 A resolution. ALKBH566-292 has a double-stranded beta-helix core fold as observed in other 2OG and iron-dependent oxygenase family members. The active site metal is octahedrally coordinated by an HXD...H motif (comprising residues His204, Asp206 and His266) and three water molecules. ALKBH5 shares a nucleotide recognition lid and conserved active site residues with other NAOXs. A large loop (betaIV-V) in ALKBH5 occupies a similar region as the L1 loop of the fat mass and obesity-associated protein that is proposed to confer single-stranded RNA selectivity. Unexpectedly, a small molecule inhibitor, IOX3, was observed covalently attached to the side chain of Cys200 located outside of the active site. Modelling substrate into the active site based on other NAOX-nucleic acid complexes reveals conserved residues important for recognition and demethylation mechanisms. The structural insights will aid in the development of inhibitors selective for NAOXs, for use as functional probes and for therapeutic benefit. PMID- 24489120 TI - Modulation of ATR-mediated DNA damage checkpoint response by cryptochrome 1. AB - Mammalian cryptochromes (Crys) are essential circadian clock factors implicated in diverse clock-independent physiological functions, including DNA damage responses. Here we show that Cry1 modulates the ATR-mediated DNA damage checkpoint (DDC) response by interacting with Timeless (Tim) in a time-of-day dependent manner. The DDC capacity in response to UV irradiation showed a circadian rhythm. Interestingly, clock-deficient Cry1 and Cry2 double knockout (Cry(DKO)) cells retained substantial DDC capacity compared with clock-proficient wild-type cells, although the Cry1-modulated oscillation of the DDC capacity was abolished in Cry(DKO) cells. We found temporal interaction of Cry1 and Tim in the nucleus. When Cry1 was expressed in the nucleus, it was critical for circadian ATR activity. We regenerated rhythmic DDC responses by ectopically expressing Cry1 in Cry(DKO) cells. In addition, we also investigated the DDC capacity in the liver of mice that were intraperitoneally injected with cisplatin at different circadian times (CT). When mice were injected at CT20, about 2-fold higher expression of phosphorylated minichromosome maintenance protein 2 (p-MCM2) was detected compared with mice injected at CT08, which consequently affected the removal rate of cisplatin-DNA adducts from genomic DNA. Taken together, our data demonstrate the intimate interaction between the circadian clock and the DDC system during genotoxic stress in clock-ticking cells. PMID- 24489121 TI - Antibiotic stress-induced modulation of the endoribonucleolytic activity of RNase III and RNase G confers resistance to aminoglycoside antibiotics in Escherichia coli. AB - Here, we report a resistance mechanism that is induced through the modulation of 16S ribosomal RNA (rRNA) processing on the exposure of Escherichia coli cells to aminoglycoside antibiotics. We observed decreased expression levels of RNase G associated with increased RNase III activity on rng mRNA in a subgroup of E. coli isolates that transiently acquired resistance to low levels of kanamycin or streptomycin. Analyses of 16S rRNA from the aminoglycoside-resistant E. coli cells, in addition to mutagenesis studies, demonstrated that the accumulation of 16S rRNA precursors containing 3-8 extra nucleotides at the 5' terminus, which results from incomplete processing by RNase G, is responsible for the observed aminoglycoside resistance. Chemical protection, mass spectrometry analysis and cell-free translation assays revealed that the ribosomes from rng-deleted E. coli have decreased binding capacity for, and diminished sensitivity to, streptomycin and neomycin, compared with wild-type cells. It was observed that the deletion of rng had similar effects in Salmonella enterica serovar Typhimurium strain SL1344. Our findings suggest that modulation of the endoribonucleolytic activity of RNase III and RNase G constitutes a previously uncharacterized regulatory pathway for adaptive resistance in E. coli and related gram-negative bacteria to aminoglycoside antibiotics. PMID- 24489123 TI - Curli synthesis and biofilm formation in enteric bacteria are controlled by a dynamic small RNA module made up of a pseudoknot assisted by an RNA chaperone. AB - RydC pseudoknot aided by Hfq is a dynamic regulatory module. We report that RydC reduces expression of curli-specific gene D transcription factor required for adhesion and biofilm production in enterobacteria. During curli formation, csgD messenger RNA (mRNA) synthesis increases when endogenous levels of RydC are lacking. In Escherichia coli and Salmonella enterica, stimulation of RydC expression also reduces biofilm formation by impairing curli synthesis. Inducing RydC early on in growth lowers CsgA, -B and -D protein and mRNA levels. RydC's 5' domain interacts with csgD mRNA translation initiation signals to prevent initiation. Translation inhibition occurs by an antisense mechanism, blocking the translation initiation signals through pairing, and that mechanism is facilitated by Hfq. Although Hfq represses csgD mRNA translation without a small RNA (sRNA), it forms a ternary complex with RydC and facilitates pseudoknot unfolding to interact with the csgD mRNA translation initiation signals. RydC action implies Hfq-assisted unfolding and mRNA rearrangements, but once the pseudoknot is disrupted, Hfq is unnecessary for regulation. RydC is the sixth sRNA that negatively controls CsgD synthesis. Hfq induces structural changes in the mRNA domains targeted by these six sRNAs. What we describe is an ingenious process whereby pseudoknot opening is orchestrated by a chaperone to allow RNA control of gene expression. PMID- 24489124 TI - Hybrid surgery for dural arteriovenous fistula in the neurosurgical hybrid operating suite. AB - Treatment of a dural arteriovenous fistula (AVF), which is difficult to access by either the surgical or endovascular approach, is challenging. A hybrid technique, combining a microsurgical approach and endovascular embolization, can provide less invasive management of dural AVFs in a modern neurosurgical hybrid operating suite. We present a case of intracerebral hemorrhage in the left cerebellum secondary to dural AVF, Cognard type IV with numerous tiny feeders from the ascending pharyngeal artery branches. No adequate arterial or venous route for endovascular embolization was found by neuroangiography. The hybrid technique, combining keyhole pterional craniotomy and embolization with n-butyl cyanoacrylate glue injection via direct cannulation of the periclival venous plexus, succeeded in obliterating the dural AVF. Intraoperative angiography showed successful embolization of the dural AVF without any complication. This report illustrates the usefulness of the neurosurgical hybrid operating suite for the treatment of difficult dural AVFs. PMID- 24489122 TI - Coordinated repressive chromatin-remodeling of Oct4 and Nanog genes in RA-induced differentiation of embryonic stem cells involves RIP140. AB - Maintaining pluripotency and indefinite self-renewal of embryonic stem cells requires a tight control of the expression of several key stemness factors, particularly Nanog and Oct4 transcription factors. The mammalian SWItch/Sucrose NonFermentable (SWI/SNF) complex contains Brg1 or Brm as its core subunit, along with Brg1-associated factors. Our previous studies have addressed chromatin remodeling of the Oct4 gene locus in retinoic acid (RA)-treated embryonal carcinoma cell line P19, which involves receptor-interacting protein 140 (RIP140) for heterochromatinization on the proximal promoter region of this gene locus. However, the mechanism of RIP140 action in RA-triggered repressive chromatin remodeling is unclear. The current study examines RA repression of the Nanog gene and compares the results with RA repression of the Oct4 gene on the chromatin level. The results show a loose nucleosome array on the Nanog gene promoter in undifferentiated embryonic stem cells. On RA treatment, the Nanog gene locus remodels specifically in the CR1 region of its proximal promoter, with the insertion of a nucleosome and compaction of this region. Further, RA induces coordinated chromatin-remodeling of both Nanog and Oct4 gene loci, which requires RA receptor-alpha, RIP140 and Brm. Finally, in these RA-triggered repressive chromatin-remodeling processes, lysine acetylation of RIP140 is critical for its recruiting Brm. PMID- 24489125 TI - Practical techniques for reducing radiation exposure during cerebral angiography procedures. AB - PURPOSE: DSA remains the gold standard imaging method for the evaluation of many cerebrovascular disorders, in particular cerebral aneurysms and vascular malformations. The purpose of this study was to demonstrate the effect of modifying DSA frame rate, fluoroscopic and roadmap pulse rates, and flat panel detector (FPD) position on the radiation dose delivered during routine views for a cerebral angiogram in a phantom model. MATERIALS AND METHODS: Adult skull and abdomen/pelvis anthropomorphic phantoms were used to compare the radiation dose metrics Ka,r (in mGy), PKA (in MUGym(2)), and fluoroscopy time (in minutes) after modification of fluoroscopic pulses per second (p/s), DSA frames per second (f/s), and FPD position and collimation in three components of a cerebral angiogram: (1) femoral artery access, (2) roadmap guidance, and (3) biplane cerebral DSA. RESULTS: For femoral artery access, DSA protocols resulted in significantly higher doses than those utilizing fluoroscopy alone (p=0.007). Roadmaps using 3 p/s or 4 p/s delivered significantly less dose than higher pulse rates (p=0.008). The ranges of delivered doses for biplane cerebral DSA were 347.3-1188.5 mGy and 3914.54-9518.78 MUGym(2). The lowest radiation doses were generated by the variable frame rate DSA protocols. CONCLUSIONS: Replacing femoral arterial access evaluations by DSA with fluoroscopy, utilizing lower pulse rates during fluoroscopy and roadmap guidance, and choosing variable frame rates for DSA are simple techniques that may be considered by operators in their clinical practices to lower radiation dose during cerebral angiography procedures. PMID- 24489126 TI - Acute seizures in the acute ischemic stroke setting: a step forward in their description. PMID- 24489127 TI - Big strokes for little folks. PMID- 24489128 TI - Volumes of intact gray matter outside the stroke predict gait performance. PMID- 24489130 TI - Intracranial artery stenosis and progression from mild cognitive impairment to Alzheimer disease. AB - OBJECTIVE: To assess the impact of intracranial arterial stenosis on the progression from mild cognitive impairment (MCI) to Alzheimer disease (AD). METHODS: A total of 423 participants with MCI were included and evaluated with clinical and neuropsychological examinations annually for 4 years. The incidence of dementia due to AD was investigated. CT angiography was used to measure the stenosis of major intracranial arteries in the studied population. A mixed effects regression model was used to analyze the association between intracranial arterial stenosis and the progression of MCI, which was assessed with the Mini Mental State Examination and the Activities of Daily Living scale. Cox proportional hazards models were used to identify the association between intracranial arterial stenosis and dementia progression. RESULTS: At the end of the follow-up, 116 participants had progressed to dementia due to AD, while 223 remained in the MCI stage. Participants with moderate or severe intracranial arterial stenosis had a faster decline in cognition and function relative to participants without such stenosis. The presence of moderate or severe intracranial arterial stenosis significantly increased the risk of dementia progression, even after controlling for age, sex, education, vascular risk factors, and silent MRI lesions. CONCLUSIONS: Intracranial arterial stenosis increased the risk of developing AD dementia after MCI. PMID- 24489129 TI - Mood, anxiety, and incomplete seizure control affect quality of life after epilepsy surgery. AB - OBJECTIVE: We examined the complex relationship between depression, anxiety, and seizure control and quality of life (QOL) outcomes after epilepsy surgery. METHODS: Seven epilepsy centers enrolled 373 patients and completed a comprehensive diagnostic workup and psychiatric and follow-up QOL evaluation. Subjects were evaluated before surgery and then at 3, 6, 12, 24, 48, and 60 months after surgery. Standardized assessments included the Quality of Life in Epilepsy Inventory-89, Beck Depression Inventory (BDI), and Beck Anxiety Inventory (BAI). A mixed-model repeated-measures analysis was used to analyze associations of depression, anxiety, seizure outcome, and seizure history with overall QOL score and QOL subscores (cognitive distress, physical health, mental health, epilepsy-targeted) prospectively. RESULTS: The groups with excellent and good seizure control showed a significant positive effect on the overall QOL compared to the groups with fair and poor seizure control. The BDI and BAI scores were both highly and negatively associated with overall QOL; increases in BDI and BAI scores were associated with decreased overall QOL score. CONCLUSIONS: Depression and anxiety are strongly and independently associated with worse QOL after epilepsy surgery. Interestingly, even partial seizure control, controlling for depression and anxiety levels, improved QOL. Management of mood and anxiety is a critical component to postsurgical care. PMID- 24489131 TI - Factors affecting cognitive outcome in early pediatric stroke. AB - OBJECTIVE: We examined cognitive performance in children after stroke to study the influence of age at stroke, seizures, lesion characteristics, neurologic impairment (NI), and functional outcome on cognitive outcome. METHODS: This was a prospectively designed study conducted in 99 children who sustained an arterial ischemic stroke (AIS) between the age of 1 month and 16 years. All children underwent cognitive and neurologic follow-up examination sessions 2 years after the insult. Cognitive development was assessed with age-appropriate instruments. RESULTS: Although mean cognitive performance was in the lower normative range, we found poorer results in subtests measuring visuoconstructive skills, short-term memory, and processing speed. Risk factors for negative cognitive outcome were young age at stroke, seizures, combined lesion location (cortical and subcortical), as well as marked NI. CONCLUSIONS: We recommend that all children with a history of AIS undergo regularly scheduled neuropsychological assessment to ensure implementation of appropriate interventions and environmental adjustments as early as possible. PMID- 24489133 TI - Influence of seizures on stroke outcomes: a large multicenter study. AB - OBJECTIVE: We compared clinical characteristics of seizures at ischemic stroke presentation (SSP) to seizures during hospitalization post ischemic stroke (SDH), and their impacts on stroke outcome, using the Registry of the Canadian Stroke Network (RCSN) database. METHODS: This cohort study included consecutive patients from the RCSN who had an acute ischemic stroke between July 2003 and March 2008. Outcome measures included morbidity, mortality, length of hospital stay, and discharge disposition. Clinical variables for either SSP or SDH were investigated and the stroke outcome was stratified by stroke severity. RESULTS: The study included 10,261 patients with ischemic strokes: 157 patients (1.53%) had SSP and 208 patients (2.03%) had SDH. Compared to stroke patients without seizures, patients with SSP and SDH were younger, had more severe strokes (p < 0.001), a higher admission rate to the intensive care unit (p < 0.001), higher morbidity, and higher mortality (p < 0.05). SSP was associated with female sex and less limb weakness, while SDH was associated with pneumonia and the presence of hemineglect. Importantly, patients with less severe strokes had higher morbidity and mortality (p < 0.005) if SDH occurred. Variables predicting overall mortality were SDH, older age, higher Charlson-Deyo index, more severe strokes, and nonalert status on arrival (all p < 0.001). CONCLUSIONS: SSP and SDH have different characteristics. SDH indicates a poorer prognosis in patients. Increased awareness of SSP and efforts to prevent SDH may be important in improving outcomes following clinical stroke care. PMID- 24489132 TI - Infarct hemisphere and noninfarcted brain volumes affect locomotor performance following stroke. AB - OBJECTIVE: Brain damage within the right middle cerebral artery (MCA) territory is particularly disruptive to mediolateral postural stabilization. The objective of this cross-sectional study was to test the hypothesis that chronic right MCA infarcts (as compared to left) are associated with slower and more bilaterally asymmetrical gait. We further hypothesized that in those with chronic right MCA infarct, locomotor performance is more dependent on gray matter (GM) volumes within noninfarcted regions of the brain that are involved in motor control yet lie outside of the MCA territory. METHODS: Gait speed was assessed in 19 subjects with right MCA infarct, 20 with left MCA infarct, and 108 controls. Bilateral plantar pressure and temporal symmetry ratios were calculated in a subset of the cohort. GM volumes within 5 regions outside of the MCA territory (superior parietal lobe, precuneus, caudate, putamen, and cerebellum) were quantified from anatomic MRIs. RESULTS: Right and left infarct groups had similar poststroke duration (7.6 +/- 6.0 years), infarct size, and functional independence. The right infarct group demonstrated slower gait speed and greater asymmetry compared to the left infarct group and controls (p < 0.05). In the right infarct group only, those with larger GM volumes within the cerebellum (r(2) = 0.32, p = 0.02) and caudate (r(2) = 0.56, p < 0.001) exhibited faster gait speed. CONCLUSION: Individuals with chronic lesions within the right MCA territory, as compared to the left MCA territory, exhibit slower, more asymmetrical gait. For these individuals, larger GM volumes within regions outside of the infarcted vascular territory may help preserve locomotor control. PMID- 24489135 TI - Abstracts from the European Workshop for Rheumatology Research, 20-22 February 2014, Lisbon, Portugal. PMID- 24489134 TI - Cortical thickness mediates the effect of beta-amyloid on episodic memory. AB - OBJECTIVE: To investigate the associations among beta-amyloid (Abeta), cortical thickness, and episodic memory in a cohort of cognitively normal to mildly impaired individuals at increased risk of vascular disease. METHODS: In 67 subjects specifically recruited to span a continuum of cognitive function and vascular risk, we measured brain Abeta deposition using [(11)C] Pittsburgh compound B-PET imaging and cortical thickness using MRI. Episodic memory was tested using a standardized composite score of verbal memory, and vascular risk was quantified using the Framingham Coronary Risk Profile index. RESULTS: Increased Abeta was associated with cortical thinning, notably in frontoparietal regions. This relationship was strongest in persons with high Abeta deposition. Increased Abeta was also associated with lower episodic memory performance. Cortical thickness was found to mediate the relationship between Abeta and memory performance. While age had a marginal effect on these associations, the relationship between Abeta and cortical thickness was eliminated after controlling for vascular risk except when examined in only Pittsburgh compound B positive subjects, in whom Abeta remained associated with thinner cortex in precuneus and occipital lobe. In addition, only the precuneus was found to mediate the relationship between Abeta and memory after controlling for vascular risk. CONCLUSION: These results suggest strong links among Abeta, cortical thickness, and memory. They highlight that, in individuals without dementia, vascular risk also contributes to cortical thickness and influences the relationships among Abeta, cortical thickness, and memory. PMID- 24489362 TI - Use of databases for clinical research. AB - Databases are electronic filing systems that have been set up to capture patient data in a variety of clinical and administrative settings. While randomised controlled trials are the gold standard for the evaluation of healthcare interventions, electronic databases are valuable research options for studies of aetiology and prognosis, or where trials are too expensive/not logistically feasible. However, databases exist in many different settings and formats (often developed for administrative or financial reimbursement purposes rather than clinical research), and researchers need to put careful thought into identifying and acquiring relevant data sets. Accuracy of records and validation of diagnoses are key issues when planning a database study. High-quality databases can readily capture outcome data (as part of routine clinical care) without the costs and burden of additional trial-related follow-up, and there are promising hybrid models which combine the benefits of randomisation with the efficiency of outcome ascertainment using existing databases. PMID- 24489363 TI - Frey's syndrome: differential diagnosis of food allergy. PMID- 24489364 TI - Getting evidence into practice--implementation science for paediatricians. PMID- 24489365 TI - bwtool: a tool for bigWig files. AB - BigWig files are a compressed, indexed, binary format for genome-wide signal data for calculations (e.g. GC percent) or experiments (e.g. ChIP-seq/RNA-seq read depth). bwtool is a tool designed to read bigWig files rapidly and efficiently, providing functionality for extracting data and summarizing it in several ways, globally or at specific regions. Additionally, the tool enables the conversion of the positions of signal data from one genome assembly to another, also known as 'lifting'. We believe bwtool can be useful for the analyst frequently working with bigWig data, which is becoming a standard format to represent functional signals along genomes. The article includes supplementary examples of running the software. AVAILABILITY AND IMPLEMENTATION: The C source code is freely available under the GNU public license v3 at http://cromatina.crg.eu/bwtool. PMID- 24489366 TI - Mobyle SNAP Workbench: a web-based analysis portal for population genetics and evolutionary genomics. AB - SUMMARY: Previously we developed the stand-alone SNAP Workbench toolkit that integrated a wide array of bioinformatics tools for phylogenetic and population genetic analyses. We have now developed a web-based portal front-end, using the Mobyle portal framework, which executes all of the programs available in the stand-alone SNAP Workbench toolkit on a high-performance Linux cluster. Additionally, we have expanded the selection of programs to over 189 tools, including population genetic, genome assembly and analysis tools, as well as metagenomic and large-scale phylogenetic analyses. The Mobyle SNAP Workbench web portal allows end users to (i) execute and manage otherwise complex command-line programs, (ii) launch multiple exploratory analyses of parameter-rich and computationally intensive methods and (iii) track the sequence of steps and parameters that were used to perform a specific analysis. Analysis pipelines or workflows for population genetic, metagenomic and genome assembly provide automation of data conversion, analysis and graphical visualization for biological inference. AVAILABILITY: The Mobyle SNAP Workbench portal is freely available online at http://snap.hpc.ncsu.edu/. The XMLs can be downloaded at http://carbonelab.org/system/files/snap_xmls.tgz. Each XML provides links to help files, online documentation and sample data. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24489367 TI - Bayesian joint analysis of heterogeneous genomics data. AB - SUMMARY: A non-parametric Bayesian factor model is proposed for joint analysis of multi-platform genomics data. The approach is based on factorizing the latent space (feature space) into a shared component and a data-specific component with the dimensionality of these components (spaces) inferred via a beta-Bernoulli process. The proposed approach is demonstrated by jointly analyzing gene expression/copy number variations and gene expression/methylation data for ovarian cancer patients, showing that the proposed model can potentially uncover key drivers related to cancer. AVAILABILITY AND IMPLEMENTATION: The source code for this model is written in MATLAB and has been made publicly available at https://sites.google.com/site/jointgenomics/. CONTACT: catherine.ll.zheng@gmail.com SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online. PMID- 24489368 TI - Event trigger identification for biomedical events extraction using domain knowledge. AB - MOTIVATION: In molecular biology, molecular events describe observable alterations of biomolecules, such as binding of proteins or RNA production. These events might be responsible for drug reactions or development of certain diseases. As such, biomedical event extraction, the process of automatically detecting description of molecular interactions in research articles, attracted substantial research interest recently. Event trigger identification, detecting the words describing the event types, is a crucial and prerequisite step in the pipeline process of biomedical event extraction. Taking the event types as classes, event trigger identification can be viewed as a classification task. For each word in a sentence, a trained classifier predicts whether the word corresponds to an event type and which event type based on the context features. Therefore, a well-designed feature set with a good level of discrimination and generalization is crucial for the performance of event trigger identification. RESULTS: In this article, we propose a novel framework for event trigger identification. In particular, we learn biomedical domain knowledge from a large text corpus built from Medline and embed it into word features using neural language modeling. The embedded features are then combined with the syntactic and semantic context features using the multiple kernel learning method. The combined feature set is used for training the event trigger classifier. Experimental results on the golden standard corpus show that >2.5% improvement on F-score is achieved by the proposed framework when compared with the state-of-the-art approach, demonstrating the effectiveness of the proposed framework. PMID- 24489369 TI - Comparing DNA integration site clusters with scan statistics. AB - MOTIVATION: Gene therapy with retroviral vectors can induce adverse effects when those vectors integrate in sensitive genomic regions. Retroviral vectors are preferred that target sensitive regions less frequently, motivating the search for localized clusters of integration sites and comparison of the clusters formed by integration of different vectors. Scan statistics allow the discovery of spatial differences in clustering and calculation of false discovery rates providing statistical methods for comparing retroviral vectors. RESULTS: A scan statistic for comparing two vectors using multiple window widths is proposed with software to detect clustering differentials and compute false discovery rates. Application to several sets of experimentally determined HIV integration sites demonstrates the software. Simulated datasets of various sizes and signal strengths are used to determine the power to discover clusters and evaluate a convenient lower bound. This provides a toolkit for planning evaluations of new gene therapy vectors. AVAILABILITY AND IMPLEMENTATION: The geneRxCluster R package containing a simple tutorial and usage hints is available from http://www.bioconductor.org. PMID- 24489370 TI - Integrative gene set analysis of multi-platform data with sample heterogeneity. AB - MOTIVATION: Gene set analysis is a popular method for large-scale genomic studies. Because genes that have common biological features are analyzed jointly, gene set analysis often achieves better power and generates more biologically informative results. With the advancement of technologies, genomic studies with multi-platform data have become increasingly common. Several strategies have been proposed that integrate genomic data from multiple platforms to perform gene set analysis. To evaluate the performances of existing integrative gene set methods under various scenarios, we conduct a comparative simulation analysis based on The Cancer Genome Atlas breast cancer dataset. RESULTS: We find that existing methods for gene set analysis are less effective when sample heterogeneity exists. To address this issue, we develop three methods for multi-platform genomic data with heterogeneity: two non-parametric methods, multi-platform Mann Whitney statistics and multi-platform outlier robust T-statistics, and a parametric method, multi-platform likelihood ratio statistics. Using simulations, we show that the proposed multi-platform Mann-Whitney statistics method has higher power for heterogeneous samples and comparable performance for homogeneous samples when compared with the existing methods. Our real data applications to two datasets of The Cancer Genome Atlas also suggest that the proposed methods are able to identify novel pathways that are missed by other strategies. AVAILABILITY AND IMPLEMENTATION: http://www4.stat.ncsu.edu/~jytzeng/Software/Multiplatform_gene_set_analysis/ PMID- 24489371 TI - StochHMM: a flexible hidden Markov model tool and C++ library. AB - Hidden Markov models (HMMs) are probabilistic models that are well-suited to solve many different classification problems in computation biology. StochHMM provides a command-line program and C++ library that can implement a traditional HMM from a simple text file. StochHMM provides researchers the flexibility to create higher-order emissions, integrate additional data sources and/or user defined functions into multiple points within the HMM framework. Additional features include user-defined alphabets, ability to handle ambiguous characters in an emission-dependent manner, user-defined weighting of state paths and ability to tie transition probabilities to sequence. AVAILABILITY AND IMPLEMENTATION: StochHMM is implemented in C++ and is available under the MIT License. Software, source code, documentation and examples can be found at http://github.com/KorfLab/StochHMM. PMID- 24489372 TI - Adaption of the global test idea to proteomics data with missing values. AB - MOTIVATION: Global test procedures are frequently used in gene expression analysis to study the relationship between a functional subset of RNA transcripts and an experimental group factor. However, these procedures have been rarely used for the analysis of high-throughput data from other sources, such as proteome expression data. The main difficulties in transferring global test procedures from genomics to proteomics data are the more complicated way of obtaining functional annotations and the handling of missing values in some types of proteomics data. RESULTS: We propose a simple mixed linear model in combination with a permutation procedure and missing values imputation to conduct global tests in proteomics experiments. This new approach is motivated by protein expression data obtained by means of 2-D gel electrophoresis within a mouse experiment of our current research. A simulation study yielded that power and testing level of the mixed model alone can be affected by missing values in the dataset. Imputation of missing values was able to correct for a bias in some simulation settings. Our new approach provides the possibility to rank Gene Ontology (GO) terms associated with protein sets. It is also helpful in the case in which a specific protein is represented by multiple spots on a 2-D gel by considering these spots also as a protein set. Analysis of our data points at correlations between the deficiency of the protein 'calreticulin' and protein sets related to biological processes in the heart muscle. AVAILABILITY AND IMPLEMENTATION: Our proposed approach is included in the R-package 'RepeatedHighDim', which already contains a global test procedure for gene expression data. The package can be retrieved from http://cran.r-project.org/. CONTACT: klaus.jung@ams.med.uni-goettingen.de. PMID- 24489373 TI - CoNtRol: an open source framework for the analysis of chemical reaction networks. AB - We introduce CoNtRol, a web-based framework for analysis of chemical reaction networks (CRNs). It is designed to be both extensible and simple to use, complementing existing CRN-related tools. CoNtRol currently implements a number of necessary and/or sufficient structural tests for multiple equilibria, stable periodic orbits, convergence to equilibria and persistence, with the potential for incorporation of further tests. AVAILABILITY AND IMPLEMENTATION: Reference implementation: reaction-networks.net/control/. Source code and binaries, released under the GPLv3: reaction-networks.net/control/download/. Documentation: reaction-networks.net/wiki/CoNtRol. PMID- 24489374 TI - Secondary iris-claw anterior chamber lens implantation in patients with aphakia without capsular support. AB - BACKGROUND/AIMS: To evaluate the efficacy, predictability, safety and complications of secondary iris-claw intraocular lens (IOL) implantation in aphakic eyes without capsular support. METHODS: Retrospective, non-comparative, interventional case series of 128 aphakic eyes, which consecutively underwent secondary iris-claw Artisan IOL (Ophtec BV) implantation, were included. Manifest refraction, uncorrected visual acuity, best-spectacle corrected visual acuity, biomicroscopy, tonometry, funduscopy and central endothelial cell count (cECC) were evaluated before surgery, and at yearly intervals up to 5 years. Minimum follow-up time was 1 year. RESULTS: One hundred twenty-eight eyes were treated. Mean age was 54.55 years (range, 1-98 years). Mean follow-up was 41.8 months (SD 23.63). Mean preoperative logarithm of the minimum angle of resolution BSCVA and spherical equivalent (SE) were 0.67 ((SD) 0.53) and 9.63 D (SD 5.50), respectively. One year postoperatively, mean logarithm of the minimum angle of resolution best-spectacle corrected visual acuity improved to 0.52 (SD 0.46) (p<0.05), and remained stable up to 5 years. One year postoperatively, mean SE was -0.52 (SD 2.21) (p<0.05). Mean SE progressively decreased during the 1st year, and remained stable thereafter (p<0.05). Mean preoperative cECC was 2237.47 (SD 793.33) cells/mm(2). cECC showed a slight, though statistically significant, decrease over the years (p=0.05). Main complications were: 2 pupillary block; 3 transient increase in intraocular pressure; 1 IOL replacement; 2 penetrating keratoplasty and 4 cystoid macular oedema. CONCLUSIONS: Iris-claw IOL implantation in aphakic eyes is an effective, predictable and safe procedure in the first 5 years of follow-up. However, a longer follow-up is required to demonstrate its long-term safety. PMID- 24489375 TI - Corneal biomechanical properties of patients with acromegaly. AB - PURPOSE: Growth hormone (GH) and insulin-like growth factor-1 (IGF-1) excess in acromegaly have various effects on many organs. The ophthalmologic effects of GH and IGF-1 excess have not yet been investigated in detail. The aim of the current study is to compare the corneal biomechanical properties of patients with acromegaly and those of healthy subjects. METHODS: 45 patients with acromegaly (F/M=27/18) and 42 age-matched and gender-matched healthy individuals (F/M=24/18) were enrolled in this cross-sectional study. Central corneal thickness (CCT), corneal resistance factor (CRF), corneal hysteresis (CH), corneal compensated intraocular pressure (IOPcc) and Goldmann correlated IOPG were measured in patients with acromegaly and in healthy individuals using the Ocular Response Analyser (ORA). GH and IGF1 values were also determined in the study group. RESULTS: The mean CH and CRF values were higher in acromegalic patients (12.1+/ 2.2 and 12.3+/-2.4, respectively) than in healthy subjects (11.0+/-1.6 and 10.8+/ 1.5, respectively; for CH, p=0.014; for CRF, p=0.001). Mean IOPG measurement was higher in the acromegaly group than in the control group (p=0.017). There was no statistically significant difference in measured CCT (p=0.117) and IOPcc (p=0.594) values between acromegalic patients and healthy subjects. CONCLUSIONS: These findings indicate that acromegaly has target organ effects on the eye. Consequently, it can change corneal biomechanical properties such as corneal hysteresis and the CRF. Corneal biomechanical properties are known to affect the accuracy of IOP measurements. These findings should be taken into account when measuring IOP values in acromegaly patients, as IOP readings may be overestimated. PMID- 24489376 TI - Authors' response. PMID- 24489377 TI - A novel RPGR mutation masquerading as Stargardt disease. PMID- 24489378 TI - The utility of routine tuberculosis screening in county hospital patients with uveitis. AB - BACKGROUND/AIM: To evaluate the utility of tuberculosis (TB) screening in diagnosing ocular TB in uveitis patients in a government-funded hospital. METHODS: The charts of 142 consecutive patients seen during August 2011-July 2012 at the Los Angeles County Hospital uveitis clinic were reviewed for manifestation/laterality of uveitis, purified protein derivative (PPD) test results, interferon gamma release assay, chest x-ray, birthplace, treatment history and diagnosis. 'Presumed TB-uveitis' was diagnosed when patients had positive TB screening and favourable response to anti-TB therapy, and definite ocular TB when Mycobacterium tuberculosis' presence was demonstrated. Post-test probabilities were determined. RESULTS: TB screening was positive in 21.1%. Six patients were diagnosed with TB-related uveitis: one definite, four presumed and one systemic TB with uveitis. With regard to PPD positivity, being foreign-born was the only statistically significant factor with OR of 2.26 (95% CI 1.01 to 5.13; p<0.01) if born in Mexico and 4.90 (95% CI 1.74 to 13.83; p<0.01) if born in other foreign countries. The post-test probabilities of a positive PPD in a uveitis patient showed a 17.2% (overall) or 30.3% (foreign-born patients) chance of ocular TB. CONCLUSIONS: PPD skin test plays an important role in the diagnosis of TB-associated uveitis in high-risk groups, such as immigrants from TB endemic regions. PMID- 24489379 TI - Mechanics of turning and jumping and skier speed are associated with injury risk in men's World Cup alpine skiing: a comparison between the competition disciplines. AB - BACKGROUND/AIM: In alpine ski racing, there is limited information about skiers' mechanical characteristics and their relation to injury risk, in particular for World Cup (WC) competitions. Hence, current findings from epidemiological and qualitative research cannot be linked to skiers' mechanics. This study was undertaken to investigate whether recently reported differences in numbers of injuries per 1000 runs for competition disciplines can be explained by differences in the skiers' mechanics. METHODS: During seven giant slalom, four super-G and five downhill WC competitions, mechanical characteristics of a forerunner were captured using differential global navigation satellite technology and a precise terrain surface model. Finally, the discipline-specific skiers' mechanics were compared with the respective number of injuries per hour skiing. RESULTS: While the number of injuries per hour skiing was approximately equal for all disciplines, kinetic energy, impulse, run time, turn radius and turn speed were significantly different and increased from giant slalom to super G and downhill. Turn ground reaction forces were largest for giant slalom, followed by super-G and downhill. The number of jumps was doubled from super-G to downhill. CONCLUSIONS: Associating the number of injuries per hour in WC skiing with skiers' mechanical characteristics, injuries in super-G and downhill seem to be related to increased speed and jumps, while injuries in giant slalom may be related to high loads in turning. The reported differences in the number of injuries per 1000 runs might be explained by a bias in total exposure time per run and thus potentially by emerged fatigue. PMID- 24489380 TI - No one knows who is accountable for England's midwife shortage, MPs say. PMID- 24489381 TI - Psoriasis: are clinicians too busy to assess disease severity? PMID- 24489382 TI - Pioneers and Followers: Migrant Selectivity and the Development of U.S. Migration Streams in Latin America. AB - We present a method for dividing the historical development of community migration streams into an initial period and a subsequent takeoff stage with the purpose of systemically differentiating pioneer migrants from follower migrants. The analysis is organized around five basic research questions. First, can we empirically identify a juncture in the historical development of community-based migration that marks the transition from an initial stage of low levels of migration and gradual growth into a takeoff stage in which the prevalence of migration grows at a more accelerated rate? Second, does this juncture point exist at roughly similar migration prevalence levels across communities? Third, are first-time migrants in the initial stage (pioneers) different from first-time migrants in the takeoff stage (followers)? Fourth, what is the nature of this migrant selectivity? Finally, does the nature and degree of pioneer selectivity vary across country migration streams? PMID- 24489383 TI - EXPLAINING THE DISTINCTIVENESS OF MEXICAN-IMMIGRANT WELFARE BEHAVIORS: THE IMPORTANCE OF EMPLOYMENT-RELATED CULTURAL REPERTOIRES. AB - Social scientists generally seek to explain welfare-related behaviors in terms of economic choice, social structural, or culture of poverty theories. Because such explanations incompletely account for nativity differences in public assistance receipt among those of Mexican origin, this paper draws upon the sociology of migration and culture literatures to develop alternative materialist-based cultural repertoire hypotheses to explain the welfare behaviors of Mexican immigrants. We argue that immigrants from Mexico arrive and work in the United States under circumstances fostering employment-based cultural repertoires that, compared with natives and other immigrant groups, encourage less welfare participation (in part because such repertoires lead to faster welfare exits) and more post-welfare employment, especially in states with relatively more generous welfare-policies. Using individual-level data predating Welfare Reform from multiple panels of the Survey of Income and Program Participation (SIPP), merged with state-level information on welfare-benefit levels, we assess these ideas by examining immigrant-group differences in welfare receipt, retention, and transition to employment across locales with varying levels of welfare benefits. Overall, the results are consistent with the notion that cultural repertoires incline Mexican immigrants to utilize welfare not primarily to avoid work, cope with disadvantage, or perpetuate a culture of dependency, but rather mostly to minimize employment discontinuities. This result carries important theoretical and policy implications. PMID- 24489384 TI - Boy will be boys: sex differences in wild infant chimpanzee social interactions. AB - Sex differences in the behaviour of human children are a hotly debated and often controversial topic. However, several recent studies have documented a biological basis to key aspects of child social behaviour. To further explore the evolutionary basis of such differences, we investigated sex differences in sociability in wild chimpanzee, Pan troglodytes schweinfurthii, infants at Gombe National Park, Tanzania. We used a long-term data set on mother-infant behaviour to analyse the diversity of infant chimpanzee social partners from age 30 to 36 months. Male infants (N = 12) interacted with significantly more individuals than female infants did (N = 8), even when maternal sociability was controlled for. Furthermore, male infants interacted with significantly more adult males than female infants did. Our data indicate that the well-documented sex differences in adult chimpanzee social tendencies begin to appear quite early in development. Furthermore, these data suggest that the behavioural sex differences of human children are fundamentally rooted in our biological and evolutionary heritage. PMID- 24489385 TI - Ethical question on Canadian regulatory veterinary jurisdictional limitations for PED--a comment. PMID- 24489386 TI - Bacterial contamination on surgical drapes--a comment. PMID- 24489388 TI - Can we trust peer-reviewed science? PMID- 24489389 TI - An ethicist's commentary on backyard chickens. PMID- 24489390 TI - Mindfulness-based stress reduction. PMID- 24489391 TI - Laryngeal obstruction caused by lymphoma in an adult dairy cow. AB - A Holstein cow was presented for inspiratory dyspnea. Endoscopic evaluation revealed swollen arytenoids and a presumptive diagnosis of bilateral arytenoidal chondritis was made. A partial arytenoidectomy was performed, the right arytenoid was submitted for histopathology, and a diagnosis of laryngeal lymphoma was made. Due to the poor prognosis, the cow was euthanized. PMID- 24489392 TI - Bilateral diffuse cystic renal dysplasia in a 9-day-old Thoroughbred filly. AB - A 9-day-old Thoroughbred filly was presented for diarrhea and lethargy. Diagnostic test results were compatible with severe renal dysfunction. Diffuse cystic lesions of both kidneys were identified on ultrasonographic examination. Postmortem examination confirmed the presence of multiple renal cysts. Congenital nephropathy compatible with bilateral diffuse cystic renal dysplasia was diagnosed. PMID- 24489393 TI - Transient Fanconi syndrome in Quarter horses. AB - Two Quarter horses with weight loss had glucosuria, euglycemia, and a mild metabolic acidosis suggesting a proximal renal tubular defect. Further testing revealed transient generalized aminoaciduria, lactic aciduria, and glucosuria, indicating Fanconi syndrome. Both horses recovered with supportive therapy. This is the first report of acquired Fanconi syndrome in horses. PMID- 24489394 TI - Jejunal perforation due to porcupine quill ingestion in a horse. AB - An 8-month-old Andalusian filly was treated for jejunal perforations due to ingestion of a porcupine quill. During exploratory laparotomy, 2 separate stapled side-to-side jejunojejunal resection and anastomoses were performed. Post operative complications after 2 years follow-up included mild incisional herniation following incisional infection and chronic intermittent colic. PMID- 24489395 TI - Evaluation of neostigmine antagonism at different levels of vecuronium-induced neuromuscular blockade in isoflurane anesthetized dogs. AB - Residual neuromuscular block (NMB) during recovery from general anesthesia may be minimized by antagonizing NMB with neostigmine. We examined neostigmine for restoring neuromuscular function when administered at 2 levels of vecuronium induced NMB in dogs. Eight healthy adult dogs received vecuronium 0.1 mg/kg body weight (BW), IV, during isoflurane anesthesia. Recovery from vecuronium occurred spontaneously (control group; C), or was enhanced with neostigmine, 0.04 mg/kg BW, IV, administered when 2 (N2) or 4 (N4) responses to train-of-four (TOF) stimulation were first observed. Duration of NMB was significantly shorter for N2 and N4 than for C. The period of complete NMB was equal for all groups; differences were observed during the recovery phase of NMB. Time of neostigmine enhanced recovery was significantly shorter for N4 than N2, but overall duration of NMB was not reduced. Recovery from NMB was faster with neostigmine. There is no clinical advantage in delaying neostigmine administration once 2 responses to TOF are present. PMID- 24489397 TI - Clinical and magnetic resonance imaging (MRI) findings in 26 dogs with canine osseous-associated cervical spondylomyelopathy. AB - The potential link between degenerative changes seen on magnetic resonance imaging (MRI) in osseous-associated cervical spondylomyelopathy (OA-CSM) and clinical signs has not been explored. Our goal was to retrospectively evaluate MRI findings, while investigating potential correlations between these changes, signalment, and clinical signs. Twenty-six dogs diagnosed with OA-CSM were included in the study. Clinical signs were converted into a Modified Frankel Score (MFS) and MRI findings were assessed and graded. Giant breeds had multiple compressed sites and presented at a younger age than large breeds, suggesting a different underlying pathophysiology. Spinal cord compression, most commonly bilateral, was present in 36.8% of intervertebral spaces. Synovial fluid loss and articular process sclerosis were the most common degenerative changes. Most dogs showed identical MFS scores, and no significant correlations were found between MFS and MRI changes. More detailed functional scales should be used to investigate this in the future. PMID- 24489396 TI - Comparison of serum amyloid A and C-reactive protein as diagnostic markers of systemic inflammation in dogs. AB - The diagnostic performance of canine serum amyloid A (SAA) was compared with that of C-reactive protein (CRP) in the detection of systemic inflammation in dogs. Sera from 500 dogs were retrospectively included in the study. C-reactive protein and SAA were measured using validated automated assays. The overlap performance, clinical decision limits, overall diagnostic performance, correlations, and agreement in the clinical classification between these 2 diagnostic markers were compared. Significantly higher concentrations of both proteins were detected in dogs with systemic inflammation (SAA range: 48.75 to > 2700 mg/L; CRP range: 0.4 to 907.4 mg/L) compared to dogs without systemic inflammation (SAA range: 1.06 to 56.4 mg/L; CRP range: 0.07 to 24.7 mg/L). Both proteins were shown to be sensitive and specific markers of systemic inflammation in dogs. Significant correlations and excellent diagnostic agreement were observed between the 2 markers. However, SAA showed a wider range of concentrations and a significantly superior overall diagnostic performance compared with CRP. PMID- 24489398 TI - The efficacy and adverse event profile of dexamethasone, melphalan, actinomycin D, and cytosine arabinoside (DMAC) chemotherapy in relapsed canine lymphoma. AB - In this retrospective study, a chemotherapy protocol using dexamethasone, melphalan, actinomycin D, and cytosine arabinoside (DMAC) was evaluated for efficacy and adverse event profile as a first line rescue protocol in 86 client owned dogs previously treated with a CHOP-based protocol. Forty-three dogs (43%) achieved remission (16% complete remission, 27% partial remission), and 57% were non-responders. The median overall progression-free survival (PFS) was 24 days. Adverse events included thrombocytopenia in 41% of dogs, neutropenia in 17% of dogs, and gastrointestinal toxicity in 13% of dogs. Overall, 16% (13/79) dogs experienced grade III to IV thrombocytopenia, 8% (6/74) dogs grade III to IV neutropenia and 1% (1/79) dogs grade III to IV gastrointestinal toxicity. The efficacy of the DMAC protocol is similar to that of other rescue protocols in dogs with relapsed lymphoma but is associated with shorter PFS. The main toxicity is thrombocytopenia, which may limit treatment. PMID- 24489400 TI - Ensuring quality communication when irreconcilable differences occur within the practice setting. PMID- 24489401 TI - International service and public health learning objectives for medical students. AB - OBJECTIVE: We aimed to improve the education of medical students involved in a longitudinal perinatal health improvement project in Gowa, Malawi. DESIGN: We conducted qualitative interviews with students who participated in the project, reviewed their quantitative reports, and assessed the application of methodologies consonant with the learning objectives of a novel community health improvement course within their experience. SETTING: The Gowa Health Promotions Project, designed to improve perinatal care for women and their families within the Gowa Health Clinic, used community participatory research strategies. METHOD: Medical students partnered with clinic workers and the local residents, evaluated, and revised an existing perinatal educational program. Qualitative and quantitative health and program data were collected, and program revisions were implemented. The value of the student experiences as a public health educational tool was evaluated by the authors. RESULTS: Project sustainability was enhanced by a fellowship and planning for sequential students. The community health course structure and goals enhanced learning in the project. Engagement of investigators as early as possible in an international public health enhancement project improves student learning and ongoing commitment. CONCLUSION: Service learning objectives aimed at providing valuable medical learning to student learners immersed in other cultures are consistent with evidence-based learning objectives in the field of public health. Proactively structuring this experience to explicate these goals can enhance student learning. This dual strategy may improve the sustainability of international health programs by educating medical students while leading them into careers where these skills will be leveraged. PMID- 24489399 TI - Suspected disseminated histiocytic sarcoma in a 3-year-old Perro de Presa Canario dog. AB - A 3-year-old intact male Perro de Presa Canario dog was presented with acutely inflamed and edematous right hind limb, scrotum, prepuce, and an enlarged left carpus. Two weeks later the dog returned with weight loss, draining tracts in the right hind limb, dermal nodules, a palpable abdominal mass, and uveitis in the left eye. The dog succumbed to his illness 2 days later and a widely disseminated round cell tumor compatible with histiocytic sarcoma was diagnosed following postmortem examination. PMID- 24489402 TI - Bodily Pain, Combat, and the Politics of Memoirs: Between the American Civil War and the War in Vietnam. AB - This article analyses the languages of wartime pain as seen in British and American memoirs from the American Civil War to the present. How did the rhetoric of wounding in these war memoirs change over time? One of the central shifts lies in the way that wounded men presented themselves as stoic in spite of severe wounding. From 1939, and in an even more dramatic fashion by the war in Vietnam, physical suffering remained a test of manliness, but the tone was defiant and aggressive rather than stoic or resigned. The article also looks at the role of individual publishers and the introduction of psychological dimensions of wounding in latter memoirs. PMID- 24489403 TI - Visual Attention and Applications in Multimedia Technologies. AB - Making technological advances in the field of human-machine interactions requires that the capabilities and limitations of the human perceptual system are taken into account. The focus of this report is an important mechanism of perception, visual selective attention, which is becoming more and more important for multimedia applications. We introduce the concept of visual attention and describe its underlying mechanisms. In particular, we introduce the concepts of overt and covert visual attention, and of bottom-up and top-down processing. Challenges related to modeling visual attention and their validation using ad hoc ground truth are also discussed. Examples of the usage of visual attention models in image and video processing are presented. We emphasize multimedia delivery, retargeting and quality assessment of image and video, medical imaging, and the field of stereoscopic 3D images applications. PMID- 24489404 TI - Waterborne cues from crabs induce thicker skeletons, smaller gonads and size specific changes in growth rate in sea urchins. AB - Indirect predator-induced effects on growth, morphology and reproduction have been extensively studied in marine invertebrates but usually without consideration of size-specific effects and not at all in post-metamorphic echinoids. Urchins are an unusually good system, in which, to study size effects because individuals of various ages within one species span four orders of magnitude in weight while retaining a nearly isometric morphology. We tracked growth of urchins, Strongylocentrotus droebachiensis (0.013-161.385 g), in the presence or absence of waterborne cues from predatory Jonah crabs, Cancer borealis. We ran experiments at ambient temperatures, once for 4 weeks during summer and again, with a second set of urchins, for 22 weeks over winter. We used a scaled, cube-root transformation of weight for measuring size more precisely and for equalizing variance across sizes. Growth rate of the smallest urchins (summer: <17 mm diameter; winter: <7 mm diameter) decreased by 40-42% in response to crab cues. In contrast, growth rate of larger urchins was unaffected in the summer and increased in response to crab scent by 7% in the winter. At the end of the 22-week experiment, additional gonadal and skeletal variables were measured. Cue-exposed urchins developed heavier, thicker skeletons and smaller gonads, but no differences in spine length or jaw size. The differences depended on urchin size, suggesting that there are size-specific shifts in gonadal and somatic investment in urchins. PMID- 24489405 TI - Seafloor ecosystem functioning: the importance of organic matter priming. AB - Organic matter (OM) remineralization may be considered a key function of the benthic compartment of marine ecosystems and in this study we investigated if the input of labile organic carbon alters mineralization of indigenous sediment OM (OM priming). Using 13C-enriched diatoms as labile tracer carbon, we examined shallow-water sediments (surface and subsurface layers) containing organic carbon of different reactivity under oxic versus anoxic conditions. The background OM decomposition rates of the sediment used ranged from 0.08 to 0.44 MUmol C mlws-1 day-1. Algal OM additions induced enhanced levels of background remineralization (priming) up to 31% and these measured excess fluxes were similar to mineralization of the added highly degradable tracer algal carbon. This suggests that OM priming may be important in marine sediments. PMID- 24489406 TI - Green abalone, Haliotis fulgens infected with the agent of withering syndrome do not express disease signs under a temperature regime permissive for red abalone, Haliotis rufescens. AB - All California abalone species have been shown to be susceptible to infection with the bacterial agent of abalone withering syndrome (WS), although expression of signs of the disease may vary between species and with environmental conditions. We examined thermal modulation of WS expression in green abalone Haliotis fulgens at temperatures mimicking El Nino (18.0 degrees C) and La Nina (14.2 degrees C) events in southern California. In contrast to results obtained from previous experiments with red abalone, H. rufescens, the higher temperature did not result in higher infection intensities of the causative agent of the disease nor increase in clinical signs of disease. These results demonstrate clear differences in thermal regulation of disease expression between abalone species, and provide further data suggesting that green abalone should be a target species of recovery efforts in southern California, where WS is endemic. PMID- 24489407 TI - Carbon conversion and metabolic rate in two marine sponges. AB - The carbon metabolism of two marine sponges, Haliclona oculata and Dysidea avara, has been studied using a 13C isotope pulse-chase approach. The sponges were fed 13C-labeled diatoms (Skeletonema costatum) for 8 h and they took up between 75 and 85%. At different times, sponges were sampled for total 13C enrichment, and fatty acid (FA) composition and 13C enrichment. Algal biomarkers present in the sponges were highly labeled after feeding but their labeling levels decreased until none was left 10 days after enrichment. The sponge-specific FAs incorporated 13C label already during the first day and the amount of 13C label inside these FAs kept increasing until 3 weeks after labeling. The algal-derived carbon captured by the sponges during the 8-h feeding period was thus partly respired and partly metabolized during the weeks following. Apparently, sponges are able to capture enough food during short periods to sustain longer-term metabolism. The change of carbon metabolic rate of fatty acid synthesis due to mechanical damage of sponge tissue was studied by feeding sponges with 13C isotope-labeled diatom (Pheaodactylum tricornutum) either after or before damaging and tracing back the 13C content in the damaged and healthy tissue. The filtration and respiration in both sponges responded quickly to damage. The rate of respiration in H. oculata reduced immediately after damage, but returned to its initial level after 6 h. The 13C data revealed that H. oculata has a higher metabolic rate in the tips where growth occurs compared to the rest of the tissue and that the metabolic rate is increased after damage of the tissue. For D. avara, no differences were found between damaged and non-damaged tissue. However, the filtration rate decreased directly after damage. PMID- 24489408 TI - Reconstructed 3D models of digestive organs of developing Atlantic cod (Gadus morhua) larvae. AB - Six 3D models of the digestive system during ontogeny were reconstructed from histological sections of Atlantic cod larvae. The 3D models clearly visualize the following features: folding of the gut rotation; subdivision of digestive tract into foregut, midgut, and hindgut by sphincters; development of stomach and pyloric caeca from 39 dph; location of entrances of bile and pancreatic ducts in the medial plane of the anterior midgut; ontogeny of pancreas from a compact organ to an elongated and branched (but not diffuse) organ along the posterior midgut; one dominant islet of Langerhans until 39 dph and several smaller satellite islets also visible from 53 dph; the relatively large volume of the anterior midgut that probably increases residence time of ingested food mixing with secretions from pancreas and bile. Calculated volumes of each digestive organ demonstrate allometric changes during ontogeny. Interactive 3D models are available as QuickTime format downloadable files. PMID- 24489409 TI - Bioluminescence in the high Arctic during the polar night. AB - This study examines the composition and activity of the planktonic community during the polar night in the high Arctic Kongsfjord, Svalbard. Our results are the first published evidence of bioluminescence among zooplankton during the Arctic polar night. The observations were collected by a bathyphotometer detecting bioluminescence, integrated into an autonomous underwater vehicle, to determine the concentration and intensity of bioluminescent flashes as a function of time of day and depth. To further understand community dynamics and composition, plankton nets were used to collect organisms passing through the bathyphotometer along with traditional vertical net tows. Additionally, using a moored bathyphotometer closed to the sampling site, the bioluminescence potential itself was shown not to have a diurnal or circadian rhythm. Rather, our results provide evidence for a diel vertical migration of bioluminescent zooplankton that does not correspond to any externally detectable changes in illumination. PMID- 24489410 TI - Surfacing behavior and gas release of the physostome sprat (Sprattus sprattus) in ice-free and ice-covered waters. AB - Upward-facing echosounders that provided continuous, long-term measurements were applied to address the surfacing behavior and gas release of the physostome sprat (Sprattus sprattus) throughout an entire winter in a 150-m-deep Norwegian fjord. During ice-free conditions, the sprat surfaced and released gas bubbles at night with an estimated surfacing rate of 3.5 times per fish day-1. The vertical swimming speeds during surfacing were considerably higher (~10 times) than during diel vertical migrations, especially when returning from the surface, and particularly when the fjord was not ice covered. The sprat released gas a few hours after surfacing, suggesting that the sprat gulped atmospheric air during its excursions to the surface. While the surface activity increased after the fjord became ice covered, the records of gas release decreased sharply. The under ice fish then displayed a behavior interpreted as "searching for the surface" by repeatedly ascending toward the ice, apparently with limited success of filling the swim bladder. This interpretation was supported by lower acoustic target strength in ice-covered waters. The frequent surfacing behavior demonstrated in this study indicates that gulping of atmospheric air is an important element in the life of sprat. While at least part of the population endured overwintering in the ice-covered habitat, ice covering may constrain those physostome fishes that lack a gas-generating gland in ways that remain to be established. PMID- 24489413 TI - The Political Socialization of Adolescent Children of Immigrants. AB - OBJECTIVES: This study aims to evaluate the adolescent political socialization processes that predict political participation in young adulthood, and whether these processes are different for children of immigrants compared to white 3rd plus generation adolescents. We focus on socialization agents based in the family, community and school. METHODS: We use a nationally representative longitudinal survey of adolescents to evaluate the predictors of three measures of political participation: Voter registration, voting, and political party identification, and whether the process leading to political participation varies by immigrant status and race/ethnic group. RESULTS: We find that the parental education level of adolescents is not as predictive for many minority children of immigrants compared to white children of native-born parents for registration. Additionally, the academic rigor of the courses taken in high school has a greater positive estimated effect on the likelihood of registration and party identification for Latino children of immigrants compared to white 3rd-plus generation young adults. CONCLUSIONS: The process of general integration into U.S. society for adolescent children of immigrants may lead to differing pathways to political participation in young adulthood, with certain aspects of their schooling experience having particular importance in developing political participation behaviors. PMID- 24489414 TI - Studies on the Biosynthesis of Chetomin: Enantiospecific Synthesis of a Putative, Late-Stage Biosynthetic Intermediate. AB - The enantiospecific synthesis of desthiochetomin, a putative biosynthetic intermediate of the epidithiodioxopiperazine natural product chetomin, is described. A diastereoselective N-alkylation was employed to form the key C3-N1' bond of the heterodimeric indoline core, followed by peptide coupling and dioxopiperazine cyclization with the requisite N-methyl amino acids. A related sarcosine-derived dioxopiperazine was prepared in the same manner. The first proposed biosynthesis of chetomin is also detailed in the text. PMID- 24489415 TI - Predictors of growth or attrition of the first language in Latino children with specific language impairment. AB - We investigated the factors that may help understand the differential rates of language development in the home language (i.e., Spanish) of Latino preschoolers with specific language impairment (SLI). Children were randomly assigned to either bilingual or English-only small group interventions and followed from preschool to kindergarten. Predictors of Spanish growth included the language of intervention, the child's level of language development or severity, the child's socio-emotional skills, and the child's level of English use. Spanish performance outcomes were assessed over time using a series of longitudinal models with baseline and post-treatment measures nested within child. Children demonstrated growth on Spanish outcomes over time. The language of instruction and the child's level of vocabulary and socio-emotional development at baseline were significant predictors of differences in rates of growth in the home language. Clinicians may need to take into consideration these factors when making clinical recommendations. PMID- 24489416 TI - Neural efficiency as a function of task demands. AB - The neural efficiency hypothesis describes the phenomenon that brighter individuals show lower brain activation than less bright individuals when working on the same cognitive tasks. The present study investigated whether the brain activation-intelligence relationship still applies when more versus less intelligent individuals perform tasks with a comparable person-specific task difficulty. In an fMRI-study, 58 persons with lower (n = 28) or respectively higher (n = 30) intelligence worked on simple and difficult inductive reasoning tasks having the same person-specific task difficulty. Consequently, less bright individuals received sample-based easy and medium tasks, whereas bright subjects received sample-based medium and difficult tasks. This design also allowed a comparison of lower versus higher intelligent individuals when working on the same tasks (i.e. sample-based medium task difficulty). In line with expectations, differences in task performance and in brain activation were only found for the subset of tasks with the same sample-based task difficulty, but not when comparing tasks with the same person-specific task difficulty. These results suggest that neural efficiency reflects an (ability-dependent) adaption of brain activation to the respective task demands. PMID- 24489418 TI - Rejoinder to comments on Evaluation of Viable Dynamic Treatment Regimes in a Sequentially Randomized Trial of Advanced Prostate Cancer. PMID- 24489417 TI - Genetic influence on family socioeconomic status and children's intelligence. AB - Environmental measures used widely in the behavioral sciences show nearly as much genetic influence as behavioral measures, a critical finding for interpreting associations between environmental factors and children's development. This research depends on the twin method that compares monozygotic and dizygotic twins, but key aspects of children's environment such as socioeconomic status (SES) cannot be investigated in twin studies because they are the same for children growing up together in a family. Here, using a new technique applied to DNA from 3000 unrelated children, we show significant genetic influence on family SES, and on its association with children's IQ at ages 7 and 12. In addition to demonstrating the ability to investigate genetic influence on between-family environmental measures, our results emphasize the need to consider genetics in research and policy on family SES and its association with children's IQ. PMID- 24489419 TI - Nonparametric estimation for censored mixture data with application to the Cooperative Huntington's Observational Research Trial. AB - This work presents methods for estimating genotype-specific distributions from genetic epidemiology studies where the event times are subject to right censoring, the genotypes are not directly observed, and the data arise from a mixture of scientifically meaningful subpopulations. Examples of such studies include kin-cohort studies and quantitative trait locus (QTL) studies. Current methods for analyzing censored mixture data include two types of nonparametric maximum likelihood estimators (NPMLEs) which do not make parametric assumptions on the genotype-specific density functions. Although both NPMLEs are commonly used, we show that one is inefficient and the other inconsistent. To overcome these deficiencies, we propose three classes of consistent nonparametric estimators which do not assume parametric density models and are easy to implement. They are based on the inverse probability weighting (IPW), augmented IPW (AIPW), and nonparametric imputation (IMP). The AIPW achieves the efficiency bound without additional modeling assumptions. Extensive simulation experiments demonstrate satisfactory performance of these estimators even when the data are heavily censored. We apply these estimators to the Cooperative Huntington's Observational Research Trial (COHORT), and provide age-specific estimates of the effect of mutation in the Huntington gene on mortality using a sample of family members. The close approximation of the estimated non-carrier survival rates to that of the U.S. population indicates small ascertainment bias in the COHORT family sample. Our analyses underscore an elevated risk of death in Huntington gene mutation carriers compared to non-carriers for a wide age range, and suggest that the mutation equally affects survival rates in both genders. The estimated survival rates are useful in genetic counseling for providing guidelines on interpreting the risk of death associated with a positive genetic testing, and in facilitating future subjects at risk to make informed decisions on whether to undergo genetic mutation testings. PMID- 24489421 TI - Simultaneous Phase and Scatter Correction for NMR Datasets. AB - Nuclear magnetic resonance (NMR) spectroscopy has proven invaluable in the diverse field of chemometrics due to its ability to deliver information-rich spectral datasets of complex mixtures for analysis by techniques such as principal component analysis (PCA). However, NMR datasets present a unique challenge during preprocessing due to differences in phase offsets between individual spectra, thus complicating the correction of random dilution factors that may also occur. We show that simultaneously correcting phase and dilution errors in NMR datasets representative of metabolomics data yields improved cluster quality in PCA scores space, even with significant initial phase errors in the data. PMID- 24489420 TI - The architecture of speech production and the role of the phoneme in speech processing. AB - Speech production has been studied within a number of traditions including linguistics, psycholinguistics, motor control, neuropsychology, and neuroscience. These traditions have had limited interaction, ostensibly because they target different levels of speech production or different dimensions such as representation, processing, or implementation. However, closer examination of reveals a substantial convergence of ideas across the traditions and recent proposals have suggested that an integrated approach may help move the field forward. The present article reviews one such attempt at integration, the state feedback control model and its descendent, the hierarchical state feedback control model. Also considered is how phoneme-level representations might fit in the context of the model. PMID- 24489422 TI - Pregnancy Risk Among Older Youth Transitioning Out Of Foster Care. AB - Youth served in the foster care system have higher rates of pregnancy than general population youth; yet we have little information about risk and protective factors to target in order to prevent early pregnancy in this population. We assessed early pregnancy risk and protective factors known for general population adolescents for their relevance to youth in the foster care system. Using data from a longitudinal study of 325 older youth from the foster care system, we examined bivariate and multivariate relationships between these factors and pregnancy between age 17 and 19 using logistic regression. Models examined risk for early parenting separately by gender. The pregnancy rate increased by 300% between ages 17 and 19. At 19, 55% of females had been pregnant, while 23% of males had fathered a child. Although this study assessed multiple known factors, few were significant for this high risk group. Females who were not sexually active at age 17 were less likely to become pregnant, but those who reported using birth control were as likely to become pregnant as those who did not. Also, females with a history of arrest were more likely to have a pregnancy between 17 and 19. Males who left the foster care system before their 19th birthday were more likely to make someone pregnant. Youth from the foster care system are at exceptional risk of early pregnancy, no matter their maltreatment history, religiosity, school connectedness, or academic achievement, particularly in the years between 17 and 19. This high risk group needs pregnancy prevention interventions and access to effective birth control. PMID- 24489423 TI - Hand over Heart Primes Moral Judgments and Behavior. AB - Morality is a prominent guide of both action and perception. We argue that non emotional gestures can prime the abstract concept of honesty. Four studies demonstrated that the emblematic gesture associated with honesty (putting a hand on one's heart) increased the level of honesty perceived by others, and increased the honesty shown in one's own behavior. Target persons performing this gesture were described in terms associated with honesty, and appeared more trustworthy to others than when the same targets were photographed with a control gesture. Persons performing the hand-over-heart gesture provided more honest assessments of others' attractiveness, and refrained from cheating, as compared to persons performing neutral gestures. These findings suggest that bodily experience associated with abstract concepts can influence both one's perceptions of others, and one's own complex actions. Further, our findings suggest that this influence is not mediated by changes in affective states. PMID- 24489424 TI - Work and Health of Parents of Adult Children with Serious Mental Illness. AB - This study examined the effects of work schedule flexibility and the spillover of work stress to family life on the health of parents of adult children with serious mental illness (SMI). We compared 100 parents of adult children with SMI to 500 parents with nondisabled adult children using data from the Wisconsin Longitudinal Study. The detrimental impact on health of a lack of work flexibility and of higher levels of negative work-to-family spillover were more pronounced among parents of adult children with SMI than parents with non disabled adult children. The results have significant implications for developing interventions to help midlife families of persons with SMI cope with work-related stress and for policies that provide for greater work schedule flexibility. PMID- 24489425 TI - Psycholinguistics of Aphasia Pharmacotherapy: Asking the Right Questions. AB - BACKGROUND: Among the obstacles to demonstrating efficacy of pharmacological intervention for aphasia is quantifying patients' responses to treatment in a statistically valid and reliable manner. In many of the review papers on this topic (e.g., Berthier et al., 2011; de Boissezon, Peran, de Boysson, & Demonet, 2007; Small & Llano, 2009), detailed discussions of various methodological problems are highlighted, with some suggestions on how these shortcomings should be addressed. Given this deep understanding of caveats associated with the experimental design of aphasia pharmacotherapy studies (e.g., Berthier et al., 2011), investigations continue to produce inconsistent results. AIM: In this review paper we suggest that inclusion of theory-driven linguistic measures in aphasia pharmacotherapy studies would add an important step toward elucidating precise patterns of improvement in language performance resulting from pharmacotherapeutic intervention. MAIN CONTRIBUTION: We provide a brief review of the clinical approaches currently used in pharmacotherapy studies of aphasia, which often lack psycholinguistic grounding. We then present ways in which psycholinguistic models can complement this approach, offering a rationale for task selection, and as a result, lead to a better understanding of treatment effects. We then follow with an example of how such an integrative approach can be implemented in studies targeting stress reduction in people with aphasia, via beta-blocking agents, as a means to augment language performance, using the psycholinguistic framework of "linguistic anxiety" outlined in Cahana-Amitay et al, 2011 as our guideline. CONCLUSION: We conclude that the incorporation of psycholinguistic models into aphasia pharmacotherapy studies can increase the resolution with which we can identify functional changes. PMID- 24489426 TI - The top 10 challenges in extreme-scale visual analytics. AB - A team of scientists and researchers discusses the top 10 challenges in extreme scale visual analytics (VA). The discussion covers applying VA technologies to both scientific and nonscientific data, evaluating the problems and challenges from both technical and social perspectives. PMID- 24489427 TI - The Utility of Platelet and Coagulation Testing of Antithrombotics: Fusing Science with Patient Care. AB - [Table: see text] There is an increasing need for the standardization of platelet function and coagulation testing for the assessment of antithrombotic therapies. Investigators continue to strive to identify ideal laboratory testing and monitoring procedures for acquired and inherited platelet function defects as well as for evaluating patient status when treated with existing or emerging antithrombotics. These therapies are used primarily in the treatment of ischemic complications. In patients receiving antithrombotic therapy, the balance between hemostasis and thrombosis is a challenge as there is an ongoing risk for bleeding when patients are receiving antiplatelet agents or anticoagulants to lessen their risk for secondary thrombotic events. There are several diverse tests for monitoring anticoagulant therapy; however, as new agents are developed, more specific tests will be required to directly assess these agents in relationship to overall coagulation status. Research in the platelet biology field is ongoing to provide point-of-care methodologies for the assessment of platelet reactivity in terms of both bleeding and thrombosis risk. Currently there are no instruments that reliably assess the risk of bleeding. The challenges that routinely faced are the complexity of physiology, the need for standardization of platelet testing methodology, and the necessity for appropriate interpretation of the test results. PMID- 24489428 TI - Isocyanide and Phosphine Oxide Coordination in Binuclear Chromium Pacman Complexes. AB - The new binuclear chromium Pacman complex [Cr2(L)] of the Schiff base pyrrole macrocycle H4L has been synthesized and structurally characterized. Addition of isocyanide, C=NR (R = xylyl, tBu), or triphenylphosphine oxide donors to [Cr2(L)] gives contrasting chemistry with the formation of the new coordination compounds [Cr2(MU-CNR)(L)], in which the isocyanides bridge the two Cr(II) centers, and [Cr2(OPPh3)2(L)], a Cr(II) phosphine oxide adduct with the ligands exogenous to the cleft. PMID- 24489429 TI - Oxidative Reactivity and Cytotoxic Properties of a Platinum(II) Complex Prepared by Outer-Sphere Amide Bond Coupling. AB - Benzyl amine was coupled to the dangling carboxylic acid groups of the platinum(II) complex [Pt(edda)Cl2], where edda = ethylenediamine-N,N'-diacetic acid, to give the diamidetethered complex [Pt(L)Cl2] (1), where L = ethylenediamine-N,N'-bis(N-benzylacetamide). Complex 1 was oxidized with both PhICl2 and Br2. Oxidation with PhICl2 cleanly afforded the tetrachloride complex, [Pt(L)Cl4] (2), whereas oxidation with Br2 gave rise to several mixed halide complexes of the general formula, [Pt(L)ClxBr4-x], where x = 1, 2, or 3. Complexes 1 and 2 were fully characterized by 1H, 13C, and 195Pt NMR spectroscopy, as well as by ESI-MS. These compounds exist as a mixture of diastereomers that arise from the chirality of the two coordinated nitrogen atoms. Crystal structures of 1, 2, and [Pt(L)ClxBry] (3) are reported. Although refined as the tetrabromide complex [Pt(L)Br4], the crystal structure of 3 is a mixture of species with site-occupancy disorder of chloride and bromide ligands. DFT calculations indicate that the two sets of diastereomers of 1 and 2 are effectively thermoneutral, a conclusion that is also supported by the observation of both members of each pair by NMR spectroscopy. The cytotoxicity of 1 and 2 was measured by the MTT assay in HeLa cells and compared to that of cisplatin. Both exhibit IC50 values close to 50 MUM and are therefore substantially less toxic than cisplatin, for which the IC50 is 1 MUM. PMID- 24489430 TI - Clinical use of ultrasensitive cardiac troponin I assay in intermediate- and high risk surgery patients. AB - BACKGROUND: Cardiac troponin levels have been reported to add value in the detection of cardiovascular complications in noncardiac surgery. A sensitive cardiac troponin I (cTnI) assay could provide more accurate prognostic information. METHODS: This study prospectively enrolled 142 patients with at least one Revised Cardiac Risk Index risk factor who underwent noncardiac surgery. cTnI levels were measured postoperatively. Short-term cardiac outcome predictors were evaluated. RESULTS: cTnI elevation was observed in 47 patients, among whom 14 were diagnosed as having myocardial infarction (MI). After 30 days, 16 patients had major adverse cardiac events (MACE). Excluding patients with a final diagnosis of MI, predictors of cTnI elevation included dialysis, history of heart failure, transoperative major bleeding, and elevated levels of pre- and postoperative N-terminal pro-B-type natriuretic peptide (NT-proBNP). Maximal cTnI values showed the highest sensitivity (94%), specificity (75%), and overall accuracy (AUC 0.89; 95% CI 0.80-0.98) for postoperative MACE. Postoperative cTnI peak level (OR 9.4; 95% CI 2.3-39.2) and a preoperative NT-proBNP level >=917 pg/mL (OR 3.47; 95% CI 1.05-11.6) were independent risk factors for MACE. CONCLUSIONS: cTnI was shown to be an independent prognostic factor for cardiac outcomes and should be considered as a component of perioperative risk assessment. PMID- 24489431 TI - The Causal Effects of Father Absence. AB - The literature on father absence is frequently criticized for its use of cross sectional data and methods that fail to take account of possible omitted variable bias and reverse causality. We review studies that have responded to this critique by employing a variety of innovative research designs to identify the causal effect of father absence, including studies using lagged dependent variable models, growth curve models, individual fixed effects models, sibling fixed effects models, natural experiments, and propensity score matching models. Our assessment is that studies using more rigorous designs continue to find negative effects of father absence on offspring well-being, although the magnitude of these effects is smaller than what is found using traditional cross sectional designs. The evidence is strongest and most consistent for outcomes such as high school graduation, children's social-emotional adjustment, and adult mental health. PMID- 24489432 TI - A Tool for Music Preference Assessment in Critically Ill Patients Receiving Mechanical Ventilatory Support. AB - Music is an ideal intervention to reduce anxiety and promote relaxation in critically ill patients. This article reviews the research studies on music listening interventions to manage distressful symptoms in this population, and describes the development and implementation of the Music Assessment Tool (MAT) to assist professionals in ascertaining patients' music preferences in the challenging, dynamic clinical environment of the intensive care unit (ICU). The MAT is easy to use with these patients who experience profound communication challenges due to fatigue and inability to speak because of endotracheal tube placement. The music therapist and ICU nursing staff are encouraged to work collaboratively to implement music in a personalized manner to ensure the greatest benefit for mechanically ventilated patients. PMID- 24489433 TI - Evaluation of Candidate Reference Genes for Real-Time Quantitative PCR of Plant Samples Using Purified cDNA as Template. AB - Quantitative real-time polymerase chain reaction (qRT-PCR) is a precise method to measure changes in gene transcript level. Accurate quantification requires careful RNA quality assessment, determination of primer efficiency, and selection of an appropriate reference gene. While many experimental procedures for these purposes have been described for mammalian samples, the direct application of these methods to plant samples often introduces unexpected experimental errors due to the complex and variable nature of the ribosomal RNA species present in typical plant extracts. In this paper, we report a simple procedure for the purification and quantification of complementary DNA (cDNA) after reverse transcriptase reactions by microcapillary electrophoresis. The use of purified cDNA allows template concentrations to be more accurately standardized for SYBR Green PCR reactions and increases amplification efficiencies so that these closely resemble those determined by the standard curve method. These advantages facilitate a more precise evaluation of the transcript levels of candidate reference genes under various experimental conditions without bias from differences in reverse transcriptase efficiency, template loading, or the presence of PCR inhibitors following reverse transcription. Using samples from Arabidopsis thaliana and Picea abies (Norway spruce), we demonstrate the value of this approach for selecting reference genes. PMID- 24489434 TI - Venous Outflow Reconstruction in Adult Living Donor Liver Transplant: Outcome of a Policy for Right Lobe Grafts without the Middle Hepatic Vein. AB - Introduction. The difficulty and challenge of recovering a right lobe graft without MHV drainage is reconstructing the outflow tract of the hepatic veins. With the inclusion or the reconstruction of the MHV, early graft function is satisfactory. The inclusion of the MHV or not in the donor's right lobectomy should be based on sound criteria to provide adequate functional liver mass for recipient, while keeping risk to donor to the minimum. Objective. Reviewing the results of a policy for right lobe grafts transplant without MHV and analyzing methods of venous reconstruction related to outcome. Materials and Methods. We have two groups Group A (with more than one HV anast.) (n = 16) and Group B (single HV anast.) (n = 24). Both groups were compared regarding indications for reconstruction, complications, and operative details and outcomes, besides describing different modalities used for venous reconstruction. Results. Significant increase in operative details time in Group A. When comparison came to complications and outcomes in terms of laboratory findings and overall hospital stay, there were no significant differences. Three-month and one-year survival were better in Group A. Conclusion. Adult LDLT is safely achieved with better outcome to recipients and donors by recovering the right lobe without MHV, provided that significant MHV tributaries (segments V, VIII more than 5 mm) are reconstructed, and any accessory considerable inferior right hepatic veins (IRHVs) or superficial RHVs are anastomosed. PMID- 24489435 TI - Ca-Doping of BiFeO3: The Role of Strain in Determining Coupling between Ferroelectric Displacements, Magnetic Moments, Octahedral Tilting, and Oxygen Vacancy Ordering. AB - Elastic and anelastic properties of a member of the BiFeO3-CaFeO2.5 perovskite solid solution (BCFO), which is known to have multiple instabilities, have been investigated by resonant ultrasound spectroscopy. This phase, with 64% Bi and 36% Ca on the A site, is antiferromagnetic (TN ~650 K) and has an ordered arrangement of oxygen vacancies with tetragonal lattice geometry. The inverse mechanical quality factor, Q-1, has a maximum near 100 K, correlating closely with a peak in dielectric loss, reported previously, consistent with a loss mechanism that involves the movement of oxygen vacancies accompanied by local lattice distortion. At higher temperature, there is a further acoustic loss peak that is correlated with complex impedance anomalies. There is no clear relationship to the magnetic transition, and the observations are interpreted as relating to ionic conductivity. A small stiffening, scaling with the square of the magnetic order parameter below TN, indicates that the main coupling with strain is biquadratic, confirming that conventional coupling of magnetic order with symmetry-breaking shear strains is weak in BCFO. Data from the literature for BCFO indicates that local strain fields are likely to be responsible for suppressing the spin cycloid present in BiFeO3. PMID- 24489436 TI - Thermoresponsive composite hydrogels with aligned macroporous structure by ice templated assembly. AB - Natural tissues, such as bone, tendon, and muscle, have well defined hierarchical structures, which are crucial for their biological and mechanical functions. However, mimicking these structural features still remains a great challenge. In this study, we use ice-templated assembly and UV-initiated cryo-polymerization to fabricate a novel kind of composite hydrogel which have both aligned macroporous structure at micrometer scale and a nacre-like layered structure at nanoscale. Such hydrogels are macroporous, thermoresponsive, and exhibit excellent mechanical performance (tough and high stretchable), attractive properties that are of significant impact on the wide applications of composite hydrogels, especially as tissue-engineering scaffolds. The fabrication method in this study including freeze-casting and cryo-polymerization can also be applied to other materials, which makes it promising for designing and developing smart and multifunctional composite hydrogels with hierar chical structures. PMID- 24489437 TI - Area Selective Growth of Titanium Diselenide Thin Films into Micropatterned Substrates by Low-Pressure Chemical Vapor Deposition. AB - The neutral, distorted octahedral complex [TiCl4(Se n Bu2)2] (1), prepared from the reaction of TiCl4 with the neutral Se n Bu2 in a 1:2 ratio and characterized by IR and multinuclear (1H, 13C{1H}, 77Se{1H}) NMR spectroscopy and microanalysis, serves as an efficient single-source precursor for low-pressure chemical vapor deposition (LPCVD) of titanium diselenide, TiSe2, films onto SiO2 and TiN substrates. X-ray diffraction patterns on the deposited films are consistent with single-phase, hexagonal 1T-TiSe2 (P3m1), with evidence of some preferred orientation of the crystallites in thicker films. The composition and structural morphology was confirmed by scanning electron microscopy (SEM), energy dispersive X-ray, and Raman spectroscopy. SEM imaging shows hexagonal plate crystallites growing perpendicular to the substrate, but these tend to align parallel to the surface when the quantity of reagent is reduced. The resistivity of the crystalline TiSe2 films is 3.36 +/- 0.05 * 10-3 Omega.cm with a carrier density of 1 * 1022 cm-3. Very highly selective film growth from the reagent was observed onto photolithographically patterned substrates, with film growth strongly preferred onto the conducting TiN surfaces of SiO2/TiN patterned substrates. TiSe2 is selectively deposited within the smallest 2 MUm diameter TiN holes of the patterned TiN/SiO2 substrates. The variation in crystallite size with different diameter holes is determined by microfocus X-ray diffraction and SEM, revealing that the dimensions increase with the hole size, but that the thickness of the crystals stops increasing above ~20 MUm hole size, whereas their lengths/widths continue to increase. PMID- 24489439 TI - Pain, sympathy and the medical encounter between the mid eighteenth and the mid twentieth centuries. AB - Witnessing people in pain inevitably elicits anxiety in physicians and other caregivers. Physicians are often required to inflict certain types of discomforts in order to alleviate other, more destructive, pains. Accusations that physicians lacked sympathy can be heard throughout the centuries. This article explores the diverse medical responses to such claims between the eighteenth and twentieth centuries. It interrogates changing definitions of clinical sympathy. The concept of sympathy was continually being reworked for each generation of medical professional. Crucially, in this reworking, philosophers (such as Adam Smith) and physicians came into dialogue. Cultures of sympathy were understood in both physiological and metaphorical terms, and were tied to changing notions of professionalization. PMID- 24489438 TI - Formation and Structure of Calcium Carbonate Thin Films and Nanofibers Precipitated in the Presence of Poly(Allylamine Hydrochloride) and Magnesium Ions. AB - That the cationic polyelectrolyte poly(allylamine hydrochloride) (PAH) exerts a significant influence on CaCO3 precipitation challenges the idea that only anionic additives have this effect. Here, we show that in common with anionic polyelectrolytes such as poly(aspartic acid), PAH supports the growth of calcite thin films and abundant nanofibers. While investigating the formation of these structures, we also perform the first detailed structural analysis of the nanofibers by transmission electron microscopy (TEM) and selected area electron diffraction. The nanofibers are shown to be principally single crystal, with isolated domains of polycrystallinity, and the single crystal structure is even preserved in regions where the nanofibers dramatically change direction. The formation mechanism of the fibers, which are often hundreds of micrometers long, has been the subject of intense speculation. Our results suggest that they form by aggregation of amorphous particles, which are incorporated into the fibers uniquely at their tips, before crystallizing. Extrusion of polymer during crystallization may inhibit particle addition at the fiber walls and result in local variations in the fiber nanostructure. Finally, we investigate the influence of Mg2+ on CaCO3 precipitation in the presence of PAH, which gives thinner and smoother films, together with fibers with more polycrystalline, granular structures. PMID- 24489440 TI - Uniform spacing interrogation of a Fourier domain mode-locked fiber Bragg grating sensor system using a polarization-maintaining fiber Sagnac interferometer. AB - A novel linearized interrogation method is presented for a Fourier domain mode locked (FDML) fiber Bragg grating (FBG) sensor system. In a high speed regime over several tens of kHz modulations, a sinusoidal wave is available to scan the center wavelength of an FDML wavelength-swept laser, instead of a conventional triangular wave. However, sinusoidal wave modulation suffers from an exaggerated non-uniform wavelength-spacing response in demodulating the time-encoded parameter to the absolute wavelength. In this work, the calibration signal from a polarization-maintaining fiber Sagnac interferometer shares the FDML wavelength swept laser for FBG sensors to convert the time-encoded FBG signal to the wavelength-encoded uniform-spacing signal. PMID- 24489441 TI - Exploring the Latent Structures of Psychological Constructs in Social Development Using the Dimensional-Categorical Spectrum. AB - This paper provides an introduction to a recently developed conceptual framework the dimensional-categorical spectrum-for utilizing general factor mixture models to explore the latent structures of psychological constructs. This framework offers advantages over traditional latent variable models that usually employ either continuous latent factors or categorical latent class variables to characterize the latent structure and require an a priori assumption about the underlying nature of the construct as either purely dimension or purely categorical. The modeling process is discussed in detail and then illustrated with data on the delinquency items of Achenbach's child behavior checklist from a sample of children in the National Adolescent and Child Treatment Study. PMID- 24489442 TI - How Mood and Task Complexity Affect Children's Recognition of Others' Emotions. AB - Previous studies examined how mood affects children's accuracy in matching emotional expressions and labels (label-based tasks). This study was the first to assess how induced mood (positive, neutral, or negative) influenced 5- to 8-year olds' accuracy and reaction time using both context-based tasks, which required inferring a character's emotion from a vignette, and label-based tasks. Both tasks required choosing one of four facial expressions to respond. Children responded more accurately to label-based questions relative to context-based questions at 5 to 7 years of age, but showed no differences at 8 years of age, and when the emotional expression being identified was happiness, sadness, or surprise, but not disgust. For the context-based questions, children were more accurate at inferring sad and disgusted emotions compared to happy and surprised emotions. Induced positive mood facilitated 5-year-olds' processing (decreased reaction time) in both tasks compared to induced negative and neutral moods. Results demonstrate how task type and children's mood influence children's emotion processing at different ages. PMID- 24489443 TI - Inhibitory effect of natural anti-inflammatory compounds on cytokines released by chronic venous disease patient-derived endothelial cells. AB - Large vein endothelium plays important roles in clinical diseases such as chronic venous disease (CVD) and thrombosis; thus to characterize CVD vein endothelial cells (VEC) has a strategic role in identifying specific therapeutic targets. On these bases we evaluated the effect of the natural anti-inflammatory compounds alpha-Lipoic acid and Ginkgoselect phytosome on cytokines/chemokines released by CVD patient-derived VEC. For this purpose, we characterized the levels of a panel of cytokines/chemokines (n = 31) in CVD patients' plasma compared to healthy controls and their release by VEC purified from the same patients, in unstimulated and TNF-alpha stimulated conditions. Among the cytokines/chemokines released by VEC, which recapitulated the systemic profile (IL-8, TNF-alpha, GM CSF, INF- alpha2, G-CSF, MIP-1beta, VEGF, EGF, Eotaxin, MCP-1, CXCL10, PDGF, and RANTES), we identified those targeted by ex vivo treatment with alpha-Lipoic acid and/or Ginkgoselect phytosome (GM-CSF, G-CSF, CXCL10, PDGF, and RANTES). Finally, by investigating the intracellular pathways involved in promoting the VEC release of cytokines/chemokines, which are targeted by natural anti-inflammatory compounds, we documented that alphaLipoic acid significantly counteracted TNF alpha-induced NF-kappaB and p38/MAPK activation while the effects of Ginkgo biloba appeared to be predominantly mediated by Akt. Our data provide new insights into the molecular mechanisms of CVD pathogenesis, highlighting new potential therapeutic targets. PMID- 24489444 TI - Usefulness of adalimumab in the treatment of refractory uveitis associated with juvenile idiopathic arthritis. AB - PURPOSE: To assess the efficacy and safety of adalimumab in patients with juvenile idiopathic arthritis (JIA) and associated refractory uveitis. DESIGN: Multicenter, prospective case series. METHODS: Thirty-nine patients (mean [SD] age of 11.5 [7.9] years) with JIA-associated uveitis who were either not responsive to standard immunosuppressive therapy or intolerant to it were enrolled. Patients aged 13-17 years were treated with 40 mg of adalimumab every other week for 6 months and those aged 4-12 years received 24 mg/m(2) body surface. RESULTS: Inflammation of the anterior chamber (2.02 [1.16] versus 0.42 [0.62]) and of the posterior segment (2.38 [2.97] versus 0.35 [0.71] decreased significantly between baseline and the final visit (P < 0.001). The mean (SD) macular thickness at baseline was 304.54 (125.03) MU and at the end of follow-up was 230.87 (31.12) MU (P < 0.014). Baseline immunosuppression load was 8.10 (3.99) as compared with 5.08 (3.76) at the final visit (P < 0.001). The mean dose of corticosteroids also decreased from 0.25 (0.43) to 0 (0.02) mg (P < 0.001). No significant side effects requiring discontinuation of therapy were observed. CONCLUSION: Adalimumab seems to be an effective and safe treatment for JIA associated refractory uveitis and may reduce steroid requirement. PMID- 24489445 TI - CD38 ligation in peripheral blood mononuclear cells of myeloma patients induces release of protumorigenic IL-6 and impaired secretion of IFNgamma cytokines and proliferation. AB - CD38, a surface receptor that controls signals in immunocompetent cells, is densely expressed by cells of multiple myeloma (MM). The immune system of MM patients appears as functionally impaired, with qualitative and quantitative defects in T cell immune responses. This work answers the issue whether CD38 plays a role in the impairment of T lymphocyte response. To this aim, we analyzed the signals implemented by monoclonal antibodies (mAb) ligation in peripheral blood mononuclear cells (PBMC) obtained from MM patients and compared to benign monoclonal gammopathy of undetermined significance (MGUS). PBMC from MM both failed to proliferate and secrete IFNgamma induced by CD38 ligation while it retained the ability to respond to TCR/CD3. The impaired CD38-dependent proliferative response likely reflects an arrest in the progression of cell cycle, as indicated by the reduced expression of PCNA. CD38 signaling showed an enhanced ability to induce IL-6 secretion. PBMC from MM patients displays a deregulated response possibly due to defects of CD38 activation pathways and CD38 may be functionally involved in the progression of this pathology via the secretion of high levels of IL-6 that protects neoplastic cells from apoptosis. PMID- 24489446 TI - Complement C3c as a biomarker in heart failure. AB - INTRODUCTION: Experimental data indicates an important role of the innate immune system in cardiac remodeling and heart failure (HF). Complement is a central effector pathway of the innate immune system. Animals lacking parts of the complement system are protected from adverse remodeling. Based on these data, we hypothesized that peripheral complement levels could be a good marker for adverse remodeling and prognosis in patients with HF. METHODS AND RESULTS: Since complement activation converges on the complement factor C3, we measured serum C3c, a stable C3-conversion product, in 197 patients with stable systolic HF. Subgroups with normal and elevated C3c levels were compared. C3c levels were elevated in 17% of the cohort. Patients with elevated C3c levels exhibited a trend to better survival, slightly higher LVEF, and lower NTpro-BNP values in comparison to patients with normal C3c values. No differences were found regarding NYHA functional class. Significantly more patients with elevated C3c had preexisting diabetes. The prevalence of CAD, arterial hypertension, and atrial fibrillation was not increased in patients with elevated C3c. CONCLUSION: Elevated C3c levels are associated with less adverse remodeling and improved survival in patients with stable systolic heart failure. PMID- 24489449 TI - A general semiparametric Z-estimation approach for case-cohort studies. AB - Case-cohort design, an outcome-dependent sampling design for censored survival data, is increasingly used in biomedical research. The development of asymptotic theory for a case-cohort design in the current literature primarily relies on counting process stochastic integrals. Such an approach, however, is rather limited and lacks theoretical justification for outcome-dependent weighted methods due to non-predictability. Instead of stochastic integrals, we derive asymptotic properties for case-cohort studies based on a general Z-estimation theory for semi-parametric models with bundled parameters using empirical process theory. Both the Cox model and the additive hazards model with time-dependent covariates are considered. PMID- 24489447 TI - Dietary intake of carotenoids and their antioxidant and anti-inflammatory effects in cardiovascular care. AB - Cardiovascular disease related to atherosclerosis represents nowadays the largest cause of morbidity and mortality in developed countries. Due to inflammatory nature of atherosclerosis, several studies had been conducted in order to search for substances with anti-inflammatory activity on arterial walls, able to exert beneficial roles on health. Researches investigated the role of dietary carotenoids supplementation on cardiovascular disease, due to their free radicals scavenger properties and their skills in improving low-density lipoprotein cholesterol resistance to oxidation. Nevertheless, literature data are conflicting: although some studies found a positive relationship between carotenoids supplementation and cardiovascular risk reduction, others did not find any positive effects or even prooxidant actions. This paper aimed at defining the role of carotenoids supplementation on cardiovascular risk profile by reviewing literature data, paying attention to those carotenoids more present in our diet (beta-carotene, alpha-carotene, beta-cryptoxanthin, lycopene, lutein, zeaxanthin, and astaxanthin). PMID- 24489448 TI - CD14 mediates binding of high doses of LPS but is dispensable for TNF-alpha production. AB - Activation of macrophages with lipopolysaccharide (LPS) involves a sequential engagement of serum LPS-binding protein (LBP), plasma membrane CD14, and TLR4/MD 2 signaling complex. We analyzed participation of CD14 in TNF-alpha production stimulated with 1-1000 ng/mL of smooth or rough LPS (sLPS or rLPS) and in sLPS binding to RAW264 and J744 cells. CD14 was indispensable for TNF-alpha generation induced by a low concentration, 1 ng/mL, of sLPS and rLPS. At higher doses of both LPS forms (100-1000 ng/mL), TNF-alpha release required CD14 to much lower extent. Among the two forms of LPS, rLPS-induced TNF-alpha production was less CD14-dependent and could proceed in the absence of serum as an LBP source. On the other hand, the involvement of CD14 was crucial for the binding of 1000 ng/mL of sLPS judging from an inhibitory effect of the anti-CD14 antibody. The binding of sLPS was also strongly inhibited by dextran sulfate, a competitive ligand of scavenger receptors (SR). In the presence of dextran sulfate, sLPS-induced production of TNF-alpha was upregulated about 1.6-fold. The data indicate that CD14 together with SR participates in the binding of high doses of sLPS. However, CD14 contribution to TNF alpha production induced by high concentrations of sLPS and rLPS can be limited. PMID- 24489450 TI - Multiple Change-Point Detection via a Screening and Ranking Algorithm. AB - Let Y1, ..., Yn be a sequence whose underlying mean is a step function with an unknown number of the steps and unknown change points. The detection of the change points, namely the positions where the mean changes, is an important problem in such fields as engineering, economics, climatology and bioscience. This problem has attracted a lot of attention in statistics, and a variety of solutions have been proposed and implemented. However, there is scant literature on the theoretical properties of those algorithms. Here, we investigate a recently developed algorithm called the Screening and Ranking Algorithm (SaRa). We characterize the theoretical properties of SaRa and show its superiority over other commonly used algorithms. In particular, we develop a false discovery rate approach to the multiple change-point problem and show a strong sure coverage property for the SaRa. PMID- 24489451 TI - CORRECTED SCORE WITH SIZABLE COVARIATE MEASUREMENT ERROR: PATHOLOGY AND REMEDY. AB - Corrected score (Nakamura, 1990; Stefanski, 1989) is an important consistent functional modeling method for covariate measurement error in nonlinear regression. Although its pathological behaviors are known to exacerbate with increasing error contamination, neither their nature nor severity is well understood. In this article, we conduct a detailed investigation with the log linear model for count data in the presence of sizable measurement error. Our study reveals that multiple roots, estimate-finding failure, and skewness in distribution are common and they may persist even when the sample size is practically large. Furthermore, these pathological behaviors are attributed to a surprising fact that desirable trend of the corrected score always goes astray as the parameter space approaches extremes. A novel remedy is proposed to constrain the derivatives with additional estimating functions. The resulting trend constrained corrected score may also substantially improve the estimation efficiency. These findings and estimation strategy shed light on the developments for other nonlinear models as well, including logistic and Cox regression models, and for nonparametric correction. PMID- 24489453 TI - Heat shock proteins in extracellular signaling. PMID- 24489452 TI - Inhibitory activities of omega-3 Fatty acids and traditional african remedies on keloid fibroblasts. AB - Keloids develop when scar tissue responds to skin trauma with proliferative fibrous growths that extend beyond the boundaries of the original wound and progress for several months or years. Keloids most frequently occur in individuals of indigenous sub-Saharan African origin. The etiology for keloids is still unknown and treatment can be problematic as patients respond differently to various treatment modalities. Keloids have a high rate of recurrence following surgical excision. Some West African patients claim to have had successful outcomes with traditional African remedies-boa constrictor oil (BCO) and shea butter-leading the authors to investigate their effects on cultured fibroblasts. The effects of emulsions of BCO, fish oil, isolated omega-3 fatty acids, and shea butter were tested in comparison to triamcinolone regarding inhibition of cell growth in keloid and control fibroblast cultures. In a series of controlled studies, it was observed that fish oil and BCO were more effective than triamcinolone, and that cis-5, 8, 11, 14, 17-eicosapentaenoic acid was more effective than -linolenic acid. While cell counts in control cultures continuously decreased over a period of 5 days, cell counts in keloid cultures consistently declined between day 1 and day 3, and then increased between day 3 and day 5 for all tested reagents except for fish oil. These results suggest that oils rich in omega-3 fatty acids may be effective in reducing actively proliferating keloid fibroblasts. Additional studies are warranted to investigate whether oils rich in omega-3 fatty acids offer effective and affordable treatment for some keloid patients, especially in the developing world. PMID- 24489454 TI - Canadian Children and Youth in Care: The Cost of Fetal Alcohol Spectrum Disorder. AB - BACKGROUND: A high prevalence of prenatal alcohol exposure has been reported among children in care and thus, the risk of fetal alcohol spectrum disorder (FASD) in this population is high. OBJECTIVE: The purpose of the current study was to estimate the number of children (0-18 years) in care with FASD and to determine the associated cost by age group, gender, and province/territory in Canada in 2011. METHODS: The prevalence of children in care by province/territory was obtained from the Canadian Child Welfare Research Portal, and the number of children in care with FASD for each province/territory was estimated from available epidemiological studies. In order to calculate the total cost per province/territory, the cost per individual per day, by age group, was applied to the respective number of children in care with FASD. RESULTS: The estimated number of children in care with FASD ranged from 2,225 to 7,620, with an annual cost of care ranging from $57.9 to $198.3 million Canadian dollars (CND). The highest overall cost ($29.5 to $101.1 million CND) was for 11-15 year-olds. CONCLUSION: The study findings can be used to demonstrate the substantial economic burden that FASD places on the child welfare system. Attention towards the needs of this population and prevention efforts to reduce FASD incidence in Canada, and other countries are urgently needed. PMID- 24489455 TI - Synthesis and structure evaluation of new complex butylarylpiperazin-1-yl derivatives. AB - A series of arylpiperazine derivatives of 1,16-diphenyl-19-azahexacyclo [14.5.1.02,15.03,8.09,14.017,21]docosa-2,3,5,7,8,9,11,13,14-nonaene-18,20,22 trione and 4,10-diphenyl-1H,2H,3H,5H-indeno[1,2-f]isoindole-1,3,5-trione was synthesized. The pharmacological profile of compound 4 at the 5-HT1A receptor was measured by binding assay. The title compounds were tested in cell-based assay against the human immunodeficiency virus type-1. The X-ray crystallographic studies of derivatives 2, 6, 7, 11, 19, and 20 were presented. PMID- 24489456 TI - Synthesis and pharmacological evaluation of pyrazolopyrimidopyrimidine derivatives: anti-inflammatory agents with gastroprotective effect in rats. AB - We report the synthesis of new anti-inflammatory 1,7 dihydropyrazolo[3',4':4,5]pyrimido[1,6-a]pyrimidine 5 from aminocyanopyrazole. All compounds were characterized by physical, chemical and spectral studies. Preliminary pharmacological evaluation of the resulting products showed that compounds 5a, b, f (50-100 mg/kg, i.p) are active anti-inflammatory agents in carrageenan-induced rat paw oedema assay, and their effects are comparable to that of acetylsalicylic-lysine (300 mg/kg, i.p.), used as a reference drug. The nature of substituent (Y, R3) had a pronounced effect on the anti-inflammatory activity. Studies of structure-activity relationships have led to selection of compound ethyl-3,5-dimethyl-7-imino-N1-phenyl-1,7 dihydropyrazolo[3',4':4,5]pyrimido[1,6-a]pyrimidine-6-carboxylate, 5f which exhibited the most potent anti-inflammatory activity. In addition, the compounds 5a, b, f showed a significant gastroprotective effect against HCl/EtOH-induced gastric ulcer. PMID- 24489457 TI - Statistical Power to Detect the Correct Number of Classes in Latent Profile Analysis. AB - Little research has examined factors influencing statistical power to detect the correct number of latent classes using latent profile analysis (LPA). This simulation study examined power related to inter-class distance between latent classes given true number of classes, sample size, and number of indicators. Seven model selection methods were evaluated. None had adequate power to select the correct number of classes with a small (Cohen's d = .2) or medium (d = .5) degree of separation. With a very large degree of separation (d = 1.5), the Lo Mendell-Rubin test (LMR), adjusted LMR, bootstrap likelihood-ratio test, BIC, and sample-size adjusted BIC were good at selecting the correct number of classes. However, with a large degree of separation (d = .8), power depended on number of indicators and sample size. The AIC and entropy poorly selected the correct number of classes, regardless of degree of separation, number of indicators, or sample size. PMID- 24489458 TI - STUDIES ON A SIMPLE AND EFFICIENT METHOD FOR LARGE-SCALE PREPARATION OF GENKWANIN FROM DAPHNE GENKWA SIEB. ET ZUCC. USING NORMAL-PHASE FLASH CHROMATOGRAPHY. AB - Genkwanin, a flavonoid which has anti-oxidant and anti-tumor activities, was isolated and purified from flowers of Daphne genkwa Sieb. et Zucc. in a large scale by normal-phase flash chromatography (NPFC). Dried flower buds were extracted with methanol at room temperature and concentrated. The residues were suspended in water and first extracted with petroleum ether, and then chloroform. Genkwanin was concentrated in the chloroform and insoluble fractions. Under the target-guidance of thin layer chromatography (TLC) as well as solubility, a solvent system composed of cyclohexane-acetone (22:3, v/v) was selected. At a flow rate of 30 mL/min,the insoluble and chloroform fractions were separated to yield 1.5 g and 1.35 g of genkwanin with high purities of 98.3% and 98.6% by HPLC analysis, respectively. The chemical structure of the compound was identified by ESI-MS and NMR. Results of the present study indicated that NPFC was a large preparative-scale, speedy and simple process separation technology and it was feasible to find the appropriate proportion of solvent system by transformation from TLC condition. PMID- 24489459 TI - Modeling the Etiology of Individual Differences in Early Reading Development: Evidence for Strong Genetic Influences. AB - We explored the etiology of individual differences in reading development from post-kindergarten to post-4th grade by analyzing data from 487 twin pairs tested in Colorado. Data from three reading measures and one spelling measure were fit to biometric latent growth curve models, allowing us to extend previous behavioral genetic studies of the etiology of early reading development at specific time points. We found primarily genetic influences on individual differences at post-1st grade for all measures. Genetic influences on variance in growth rates were also found, with evidence of small, nonsignificant, shared environmental influences for two measures. We discuss our results, including their implications for educational policy. PMID- 24489460 TI - Significant roadblocks exist in developing sputum sample libraries for clinical validation of novel in vitro diagnostics. AB - With the continuing rise of multiresistant pathogens, reliable, cost-effective, and novel diagnostics are urgently required by clinicians and clinical trialists to diagnose conditions such as respiratory tract infections to enable rational antimicrobial choice and enhance clinical outcomes. However, during product development, validation of these in vitro diagnostic devices, a key regulatory hurdle, requires sputum samples in large numbers. The Rapid Point-of-Care test Platform for Infectious Diseases (RAPP-ID) consortium is tasked with producing point of care test (POCT) platforms for rapid diagnosis of lower respiratory tract infections, including tuberculosis and blood stream infections. Validation of diagnostic platforms would ideally use well-characterized samples in a sputum library taken from a range of clinical settings to allow for a wide panel of pathogens to be assessed. These samples would be stored in specific stable conditions (monitored temperature, specific medium) until required for validation. Therefore we reviewed the current literature for details of storage conditions of sputum samples and for previous validation studies of other diagnostic tests using this methodology. However, we conclude that little data exists, and thus the acquisition and successful storage of good quality clinical samples are major roadblocks in the validation of novel POCT platforms, and that while not without limitations, spiked sputum samples appear the best solution until sputum library laboratory techniques allowing careful preservation of pathogens are improved. PMID- 24489461 TI - The use of potentially inappropriate medications and changes in quality of life among older nursing home residents. AB - BACKGROUND: Nursing home residents are mainly older people with multiple diseases and taking multiple medications. The quality use of medication and its association with health related quality of life (HRQoL) have not been reported in Malaysia. This study aims to investigate the association between the use of potentially inappropriate medications (PIMs) and the changes observed in the HRQoL among older nursing home residents. METHODS: A prospective follow up study was conducted at four nongovernmental organization nursing homes in Penang, Malaysia. Older residents (>=65 years old) taking at least one prescribed medication were included. Residents with PIMs were identified by using Screening Tool of Older Person's potentially inappropriate Prescriptions (STOPP) criteria. HRQoL was assessed using EuroQol-5 dimension (EQ-5D) and EuroQol-visual analog scale (EQ-VAS) at baseline and after a 3-month follow up. The association of PIMs with HRQoL was analyzed using Mann-Whitney U test. RESULTS: The median age of the 211 participants was 77 years (interquartile range 72-82 years) and the median number of prescription medicines was four (interquartile range three to six). The prevalence of PIMs was 23.7% and 18.6% at baseline and 3 months later, respectively. The most commonly prescribed PIMs in decreasing order were first generation antihistamine, prescriptions of duplicate drug class, glibenclamide with type 2 diabetes mellitus, and anticholinergic to treat extrapyramidal side effects of neuroleptic medications. At baseline, there was no significant difference among residents with or without PIMs in each bracket of EQ-5D, EQ-5D index, or EQ-VAS scores. Comparison of the differences in the mean score index of EQ-5D between baseline and after 3 months also showed no statistically significant differences. CONCLUSION: PIMs were found to be relatively common among older nursing home residents. However, no significant changes were observed in HRQoL among these residents. Further studies with a bigger sample size and longer follow up period are required to establish this association. PMID- 24489462 TI - The utility of rebound tonometer in late elderly subjects. AB - BACKGROUND: To compare intraocular pressure (IOP) readings using the Icare rebound tonometer (RBT) versus the Goldmann applanation tonometer (GAT) in late elderly (aged 75 years or older) subjects with or without glaucoma, and to evaluate the influence of central corneal thickness (CCT) on IOP readings. METHODS: The IOP measurements were obtained using the RBT and GAT, and CCT was measured using a specular-type microscope. Bland-Altman analysis was used to assess the clinical agreement between the two instruments. The influence of CCT adjusted for age on IOP readings was analyzed by multiple linear regression analysis. RESULTS: This study included 58 eyes of 29 normal subjects and 54 eyes of 28 glaucoma patients. The mean age was 80.7+/-4.3 years (normal subjects) and 83.1+/-5.1 years (glaucoma patients). The mean IOP readings were 13.6+/-3.5 mmHg and 13.2+/-2.8 mmHg (using the RBT and GAT, respectively) for normal subjects, and 13.6+/-3.3 mmHg and 13.5+/-2.9 mmHg for glaucoma patients. The 95% confidence interval of the differences between the two instruments was -3.3 to 4.0 mmHg for normal subjects and -2.9 to 1.6 mmHg for glaucoma patients. The IOP readings by two instruments were significantly correlated with CCT in eyes with glaucoma (for the RBT, beta=0.036 and P=0.002, and for the GAT, beta=0.021 and P=0.033) but not in normal eyes. CONCLUSION: IOP readings measured using the RBT and GAT showed within the allowable range in the late elderly subjects with or without glaucoma. Eyes with glaucoma were correlated closely with CCT using each instrument. PMID- 24489463 TI - Additional measures do not improve the diagnostic accuracy of the Hospital Admission Risk Profile for detecting downstream quality of life in community dwelling older people presenting to a hospital emergency department. AB - INTRODUCTION: The Hospital Admission Risk Profile (HARP) instrument is commonly used to assess risk of functional decline when older people are admitted to hospital. HARP has moderate diagnostic accuracy (65%) for downstream decreased scores in activities of daily living. This paper reports the diagnostic accuracy of HARP for downstream quality of life. It also tests whether adding other measures to HARP improves its diagnostic accuracy. METHODS: One hundred and forty eight independent community dwelling individuals aged 65 years or older were recruited in the emergency department of one large Australian hospital with a medical problem for which they were discharged without a hospital ward admission. Data, including age, sex, primary language, highest level of education, postcode, living status, requiring care for daily activities, using a gait aid, receiving formal community supports, instrumental activities of daily living in the last week, hospitalization and falls in the last 12 months, and mental state were collected at recruitment. HARP scores were derived from a formula that summed scores assigned to age, activities of daily living, and mental state categories. Physical and mental component scores of a quality of life measure were captured by telephone interview at 1 and 3 months after recruitment. RESULTS: HARP scores are moderately accurate at predicting downstream decline in physical quality of life, but did not predict downstream decline in mental quality of life. The addition of other variables to HARP did not improve its diagnostic accuracy for either measure of quality of life. CONCLUSION: HARP is a poor predictor of quality of life. PMID- 24489464 TI - Efficacy of indacaterol on quality of life and pulmonary function in patients with COPD and inhaler device preferences. AB - BACKGROUND: Indacaterol is a novel, once-daily, inhaled, long-acting b2-agonist for patients with chronic obstructive pulmonary disease (COPD). The study objective was to evaluate the efficacy of indacaterol on quality of life and pulmonary function in patients with COPD in a real-world setting, and also to evaluate its inhaler device (Breezhaler(r)), which is important for both adherence and management. METHODS: Twenty-eight outpatients with COPD were treated with indacaterol (150 MUg once daily for 8 weeks), and the effects on pulmonary function were evaluated using a questionnaire survey with the modified Medical Research Council (mMRC) dyspnea scale and COPD assessment test (CAT) before and after treatment. Similar investigations were also performed separately among different baseline medications. Moreover, original questionnaire surveys for indacaterol and its device were performed. RESULTS: Overall, mMRC dyspnea scale and CAT scores significantly improved (1.96+/-1.04 to 1.57+/-1.07 and 17.39+/-8.23 to 12.82+/-8.42, respectively; P<0.05). Significant improvements in forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1) were also observed on pulmonary function tests (2.91+/-0.66 L to 3.07+/-0.65 L and 1.46+/-0.60 L to 1.58+/-0.59 L, respectively; P<0.05). Replacement therapy from salmeterol to indacaterol significantly improved mMRC and FVC values, but did not significantly improve CAT scores or other pulmonary functions. Add-on therapy with indacaterol significantly improved mMRC score, CAT score, FVC, and FEV1, regardless of whether tiotropium was used as a baseline treatment. All subjects in a questionnaire survey found the inhaler device easy to use. There were no serious adverse events leading to treatment discontinuation. CONCLUSION: Indacaterol is thought to be effective and well tolerated as a bronchodilator for the management of COPD. Treatment with indacaterol in addition to a long-acting muscarinic antagonist was also useful. PMID- 24489465 TI - Barriers to and enablers of physical activity in patients with COPD following a hospital admission: a qualitative study. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by a persistent blockage of airflow, prompting episodes of shortness of breath, commonly leading to hospitalization. Hospitalization may lead to a decline in physical activity following discharge. Physical activity has been shown to improve symptoms of COPD and reduce readmissions, and to decrease morbidity and mortality. This study aims to explore, from the perspectives of people with COPD, the barriers to and enablers of participation in physical activity following hospitalization for COPD. METHODS: This study had a qualitative descriptive design and included semistructured interviews with 28 adult COPD patients who had been admitted to hospital with a primary diagnosis of exacerbation of COPD. RESULTS: A plethora of barriers to but fewer enablers of participation in physical activity and pulmonary rehabilitation were identified for this cohort of people. The main barriers identified were health-related (comorbidities, COPD symptoms, and physical injury or illness) environment-related (weather, transport, and finance), and self-related. The main enabling factors reported were access to health professionals and equipment, social support, routine and extracurricular activities, personal goals and motivation, and the effect of physical activity and "feeling better". CONCLUSION: This research provides a snapshot of the barriers to and enablers of physical activity and pulmonary rehabilitation in people with COPD. It is evident that there are significant barriers which hinder the ability of people with COPD to undertake and continue participation in physical activity and pulmonary rehabilitation. While there are some enablers that may counter these barriers, it is clear that health professionals dealing with people suffering from COPD need to actively recognize and address barriers to physical activity and pulmonary rehabilitation. Hospital admission may create an opportunity for implementation of interventions promoting physical activity (such as referral to pulmonary rehabilitation), which may assist in reducing hospital readmission, as well as decreasing morbidity and mortality. PMID- 24489466 TI - Regadenoson use in patients with chronic obstructive pulmonary disease: the state of current knowledge. AB - Stress testing is challenging in patients with chronic obstructive pulmonary disease (COPD). Functional capacity is generally decreased in this patient population, limiting patients' ability to achieve physiologic stress through exercise. Additionally, due to emphysematous changes, COPD patients tend to have poor acoustic windows that impair the quality and therefore diagnostic accuracy of stress echocardiography techniques. Pharmacologic stress myocardial perfusion imaging (MPI) testing is also problematic, particularly due to the concern for adenosine-induced bronchoconstriction with conventional vasodilator stress agents. Regadenoson, a selective A2A adenosine receptor agonist, has gained popularity due to its ease of administration and improved patient experience in the general population. The literature describing the experience with regadenoson in COPD patients, though limited, is rapidly growing and reassuring. This review summarizes the pharmacology and clinical application of this novel stress agent and presents the available data on the safety and tolerability of its use in COPD patients. PMID- 24489468 TI - Injectable thermosensitive hydrogel composite with surface-functionalized calcium phosphate as raw materials. AB - In this study, L-lactide was used to modify the tricalcium phosphate (beta-TCP) and tetracalcium phosphate (TTCP) surface which can form functionalized poly(l lactic acid) (PLLA)-grafted beta-TCP (g-beta-TCP) and PLLA-grafted TTCP (g-TTCP) particles. The g-beta-TCP and g-TTCP obtained were incorporated into a PEG-PCL PEG (PECE) matrix to prepare injectable thermosensitive hydrogel composites. The morphology of the hydrogel composites showed that the g-beta-TCP and g-TTCP particles dispersed homogeneously into the polymer matrix, and each hydrogel composite had a three-dimensional network structure. Rheologic analysis showed that the composite had good thermosensitivity. Changes in calcium concentration and pH in simulated body fluid solutions confirmed the feasibility of surface functionalized calcium phosphate for controlled release of calcium. All the results indicate that g-beta-TCP/PECE and g-TTCP/PECE hydrogels might be a promising protocol for tissue engineering. PMID- 24489467 TI - Overview of the role of nanotechnological innovations in the detection and treatment of solid tumors. AB - Nanotechnology, although still in its infantile stages, has the potential to revolutionize the diagnosis, treatment, and monitoring of disease progression and success of therapy for numerous diseases and conditions, not least of which is cancer. As it is a leading cause of mortality worldwide, early cancer detection, as well as safe and efficacious therapeutic intervention, will be indispensable in improving the prognosis related to cancers and overall survival rate, as well as health-related quality of life of patients diagnosed with cancer. The development of a relatively new field of nanomedicine, which combines various domains and technologies including nanotechnology, medicine, biology, pharmacology, mathematics, physics, and chemistry, has yielded different approaches to addressing these challenges. Of particular relevance in cancer, nanosystems have shown appreciable success in the realm of diagnosis and treatment. Characteristics attributable to these systems on account of the nanoscale size range allow for individualization of therapy, passive targeting, the attachment of targeting moieties for more specific targeting, minimally invasive procedures, and real-time imaging and monitoring of in vivo processes. Furthermore, incorporation into nanosystems may have the potential to reintroduce into clinical practice drugs that are no longer used because of various shortfalls, as well as aid in the registration of new, potent drugs with suboptimal pharmacokinetic profiles. Research into the development of nanosystems for cancer diagnosis and therapy is thus a rapidly emerging and viable field of study. PMID- 24489469 TI - Anacardic acid enhances the anticancer activity of liposomal mitoxantrone towards melanoma cell lines - in vitro studies. AB - THIS PAPER DESCRIBES A NOVEL FORMULATION OF ANTINEOPLASTIC DRUG: mitoxantrone loaded into liposomal carriers enriched with encapsulated anacardic acid in the liposomal bilayer using a vitamin C gradient. Anacardic acid is a potent epigenetic agent with anticancer activity. This is the first liposomal formulation to combine an actively encapsulated drug and anacardic acid. The liposomes were characterized in terms of basic parameters, such as size, zeta potential, optimal drug-to-lipid ratio, loading time and temperature, and stability at 4 degrees C and in human plasma in vitro. The formulation was found to be stable, and the loading process was rapid and efficient (drug-to-lipid ratio of up to 0.3 with over 90% efficiency in 5 minutes). The cytotoxicity of these formulations was assessed using the human melanoma cell lines A375 and Hs294T and the normal human dermal fibroblast line. The results showed that anacardic acid and to a smaller extent vitamin C significantly increased the cytotoxicity of the drug towards melanoma compared to ammonium sulfate liposomes. On the other hand, vitamin C and anacardic acid both protected normal cells from damage caused by the drug. The formulation combining anacardic acid, vitamin C, and mitoxantrone showed promising results in terms of cytotoxicity and cytoprotection. Therefore, it has potential for anticancer treatment. PMID- 24489470 TI - Evaluation of psoralen ethosomes for topical delivery in rats by using in vivo microdialysis. AB - This study aimed to improve skin permeation and deposition of psoralen by using ethosomes and to investigate real-time drug release in the deep skin in rats. We used a uniform design method to evaluate the effects of different ethosome formulations on entrapment efficiency and drug skin deposition. Using in vitro and in vivo methods, we investigated skin penetration and release from psoralen loaded ethosomes in comparison with an ethanol tincture. In in vitro studies, the use of ethosomes was associated with a 6.56-fold greater skin deposition of psoralen than that achieved with the use of the tincture. In vivo skin microdialysis showed that the peak concentration and area under the curve of psoralen from ethosomes were approximately 3.37 and 2.34 times higher, respectively, than those of psoralen from the tincture. Moreover, it revealed that the percutaneous permeability of ethosomes was greater when applied to the abdomen than when applied to the chest or scapulas. Enhanced permeation and skin deposition of psoralen delivered by ethosomes may help reduce toxicity and improve the efficacy of long-term psoralen treatment. PMID- 24489472 TI - Transitioning from physician to nurse practitioner. AB - Foreign-educated physicians (FEPs), also known as "international medical graduates", represent a rich source of potential primary-care providers. Despite their high level of medical knowledge and skills as well as ethnic and cultural diversity suited to meet the demands of patients, FEPs face many barriers in their attempt to continue to practice medicine in the USA. The program of study at Florida International University's Nicole Wertheim College of Nursing and Health Sciences provides FEPs the opportunity to have an impact on health care and continue to practice medicine in the USA by becoming nurse practitioners. PMID- 24489471 TI - Pediatric neurofibromatosis 1 and parental stress: a multicenter study. AB - BACKGROUND: Neurofibromatosis 1 (NF1) is a complex and multifaceted neurocutaneous syndrome with many and varied comorbidities. The literature about the prevalence and degree of maternal stress and the impact of NF1 in the parent child interaction is still scant. The aim of this study was to evaluate the prevalence of maternal stress in a large pediatric sample of individuals affected by NF1. METHODS: Thirty-seven children (19 boys, 18 girls) of mean age 7.86+/ 2.94 (range 5-11) years affected by typical NF1 and a control group comprising 405 typically developing children (207 boys, 198 girls; mean age 8.54+/-2.47 years) were included in this study. To assess parental stress, the mothers of all individuals (NF1 and comparisons) filled out the Parenting Stress Index-Short Form test. RESULTS: The two study groups were comparable for age (P=0.116), gender (P=0.886), and body mass index adjusted for age (P=0.305). Mothers of children affected by NF1 reported higher mean Parenting Stress Index-Short Form scores on the Parental Distress domain (P<0.001), Difficult Child domain (P<0.001), and Total Stress domain than the mothers of typically developing children (controls) (P<0.001). No significant differences between the two groups were found for the Parent-Child Dysfunctional Interaction domain (P=0.566) or Defensive Responding domain scores (P=0.160). CONCLUSION: NF1 is considered a multisystemic and complex disease, with many still unrecognized features in pediatric patients and in their families. In this light, our findings about the higher levels of maternal stress highlight the importance of considering the environmental aspects of NF1 management in developmental age. PMID- 24489474 TI - Treatment of elderly patients with advanced lipedema: a combination of laser assisted liposuction, medial thigh lift, and lower partial abdominoplasty. AB - BACKGROUND: Lipedema is a rare female disorder with a characteristic distribution of adipose tissue hypertrophy on the extremities, with pain and bruising. In advanced stages, reduction of adipose tissue is the only available effective treatment. In elderly patients with advanced lipedema, correction of increased skin laxity has to be considered for an optimal outcome. METHODS: We report on a tailored combined approach to improve advanced lipedema in elderly females with multiple comorbidities. Microcannular laser-assisted liposuction of the upper legs and knees is performed under tumescent anesthesia. Medial thigh lift and partial lower abdominoplasty with minimal undermining are used to correct skin laxity and prevent intertrigo. Postsurgical care with nonelastic flat knitted compression garments and manual lymph drainage are used. RESULTS: We report on three women aged 55-77 years with advanced lipedema of the legs and multiple comorbidities. Using this step-by-step approach, a short operation time and early mobilization were possible. Minor adverse effects were temporary methemoglobinemia after tumescent anesthesia and postsurgical pain. No severe adverse effects were seen. Patient satisfaction was high. CONCLUSION: A tailored approach may be useful in advanced lipedema and is applicable even in elderly patients with multiple comorbidities. PMID- 24489473 TI - Physical functioning after occupational rehabilitation and returning to work among employees with chronic musculoskeletal pain and comorbid depressive symptoms. AB - BACKGROUND: The aim of this investigation was to assess whether measures of physical functioning after multidisciplinary rehabilitation are associated with return to work among individuals with chronic musculoskeletal pain conditions and comorbid depressive symptoms. METHODS: Included were 92 employees with chronic musculoskeletal disorders who had participated in a 57- week multidisciplinary rehabilitation program. Their ages ranged from 25-59 years. The Hospital Anxiety and Depression Scale was used to assess depressive symptoms. Different aspects of physical functioning (muscle strength, mobility, endurance capacity, and balance) were measured with single-item visual analog scales, and physical fitness was measured with the validated COOP/WONCA charts. Being on "active work strategies," such as receiving rehabilitation benefit/vocational rehabilitation or being reported partly or completely fit, was defined as "on their way into/in work". Cross-sectional associations were measured using logistic regression models, estimating odds ratio with 95% confidence intervals. RESULTS: There were no differences between the "on their way into/in work" group (n=70) and the "on their way out/out of work" group (n=22) regarding age, sex, or levels of anxiety or pain. Surprisingly, regression analyses showed that those with higher levels of physical functioning had significantly lower odds of returning to work. CONCLUSION: The findings of an inverse relationship between self-reported physical function and returning to work in this sample illustrate that the return to-work process among employees with chronic musculoskeletal pain and comorbid depressive symptoms is multifactorial and influenced by factors other than physical functioning at the individual level. Further research, especially longitudinal studies, is needed to assess the occupational trajectories among employees with chronic musculoskeletal pain and comorbid depressive symptoms after participation in a multidisciplinary rehabilitation program. PMID- 24489475 TI - Pain-related mood influences pain perception differently in fibromyalgia and multiple sclerosis. AB - In patients, the perception of pain intensity may be influenced by the subjective representation of their disease. Although both multiple sclerosis (MS) and fibromyalgia (FM) possibly include chronic pain, they seem to elicit different disease representations because of the difference in their respective etiology, the former presenting evidence of underlying lesions as opposed to the latter. Thus, we investigated whether patients with FM differed from patients with MS with respect to their perception of "own" pain as well as others' pain. In addition, the psychological concomitant factors associated with chronic pain were considered. Chronic pain patients with FM (n=13) or with MS (n=13) participated in this study. To assess specific pain-related features, they were contrasted with 12 other patients with MS but without chronic pain and 31 controls. A questionnaire describing imaginary painful situations showed that FM patients rated situations applied to themselves as less painful than did the controls. Additionally, pain intensity attributed to facial expressions was estimated as more intense in FM compared with the other groups of participants. There is good evidence that the mood and catastrophizing reactions expressed in FM differentially modulated the perception of pain according to whether it was their own pain or other's pain. PMID- 24489478 TI - Chemotherapy-induced enterocutaneous fistula after perineal hernia repair using a biological mesh: a case report. AB - This is the first reported case of an enterocutaneous fistula as a late complication to reconstruction of the pelvic floor with a PermacolTM mesh after a perineal hernia. A 70-year-old man had a reconstruction of the pelvic floor with a biological mesh because of a perineal hernia after laparoscopic abdominoperineal resection. Nine months after the perineal hernia operation, the patient had multiple metastases in both lungs and liver. The patient underwent chemotherapy, including bevacizumab, irinotecan, calcium folinate, and fluorouracil. Six weeks into chemotherapy, the patient developed signs of sepsis and complained of pain from the right buttock. Ultrasound examination revealed an abscess, which was drained, guided by ultrasound. A computed tomography scan showed a subcutaneous abscess cavity located in the right buttock with communication to the small bowel. Operative findings confirmed a perineal fistula from the distal ileum to perineum. A resection of the small bowel with primary anastomosis was performed. The postoperative course was complicated by fluid and electrolyte disturbances, but the patient was stabilized and finally discharged to a hospice for terminal care after 28 days of hospital stay. It seems that hernia repairs with biological meshes have lower erosion and infection rates compared with synthetic meshes, and so far, evidence suggests that biological grafts are safe and effective in the treatment of pelvic floor reconstruction. There have been no reports of enteric fistulas after pelvic reconstruction with biological meshes. However, the development of intestinal fistulas after chemotherapy with bevacizumab has been described in the literature. Our case report supports this association between bevacizumab and fistula formation among rectal cancer patients, as symptoms of a fistula started only 6 weeks into bevacizumab treatment but approximately 12 months after the perineal hernia operation, even after pelvic reconstruction using a biological mesh and without local recurrence. PMID- 24489477 TI - A life course perspective on polycystic ovary syndrome. AB - Polycystic ovary syndrome (PCOS) is a major public health problem in the US. Worldwide, the public is largely unaware of the condition and health care providers do not seem to fully understand it. Research on PCOS has primarily focused on its etiology and clinical characteristics and less on the psychosocial aspects of human development associated with PCOS. This paper posits that a life course perspective provides a framework for further understanding the psychosocial experiences of women with PCOS and the contexts in which they live. The paper discusses how life course principles of human development, constraints on agency, interdependence of lives, time and place, and timing of events and experiences are relevant to the management of PCOS and prevention of its complications. PMID- 24489479 TI - The control of seed oil polyunsaturate content in the polyploid crop species Brassica napus. AB - Many important plant species have polyploidy in their recent ancestry, complicating inferences about the genetic basis of trait variation. Although the principal locus controlling the proportion of polyunsaturated fatty acids (PUFAs) in seeds of Arabidopsis thaliana is known (fatty acid desaturase 2; FAD2), commercial cultivars of a related crop, oilseed rape (Brassica napus), with very low PUFA content have yet to be developed. We showed that a cultivar of oilseed rape with lower than usual PUFA content has non-functional alleles at three of the four orthologous FAD2 loci. To explore the genetic basis further, we developed an ethyl methanesulphonate mutagenised population, JBnaCAB_E, and used it to identify lines that also carried mutations in the remaining functional copy. This confirmed the hypothesised basis of variation, resulting in an allelic series of mutant lines showing a spectrum of PUFA contents of seed oil. Several lines had PUFA content of ~6 % and oleic acid content of ~84 %, achieving a long standing industry objective: very high oleic, very low PUFA rapeseed without the use of genetic modification technology. The population contains a high rate of mutations and represents an important resource for research in B. napus. PMID- 24489480 TI - Razumikhin-Type Stability Criteria for Differential Equations with Delayed Impulses. AB - This paper studies stability problems of general impulsive differential equations where time delays occur in both differential and difference equations. Based on the method of Lyapunov functions, Razumikhin technique and mathematical induction, several stability criteria are obtained for differential equations with delayed impulses. Our results show that some systems with delayed impulses may be exponentially stabilized by impulses even if the system matrices are unstable. Some less restrictive sufficient conditions are also given to keep the good stability property of systems subject to certain type of impulsive perturbations. Examples with numerical simulations are discussed to illustrate the theorems. Our results may be applied to complex problems where impulses depend on both current and past states. PMID- 24489481 TI - Neuronal adhesion and synapse organization in recovery after brain injury. AB - Few specific therapeutic targets exist to manage brain injury, despite the prevalence of stroke or traumatic brain injury. With traumatic brain injury, characteristic neuronal changes include axonal swelling and degeneration, and the loss of synapses, the sites of communication between neurons. This is followed by axonal sprouting and alterations in synaptic markers in recovery. The resulting changes in neuronal connectivity are likely to contribute to the effects of traumatic brain injury on cognitive functions and the underlying mechanisms may represent points of therapeutic intervention. In agreement, animal studies implicate adhesion and signaling molecules that organize synapses as molecular players in neuronal recovery. In this article, the authors focus on the role of cell surface interactions in the recovery after brain injury in humans and animals. The authors review cellular and synaptic alterations that occur with injury and how changes in cell adhesion, protein expression and modification may be involved in recovery. The changes in neuronal surface interactions as potential targets and their possible value for the development of therapeutics are also discussed. PMID- 24489482 TI - Diffusion tensor imaging and related techniques in tuberous sclerosis complex: review and future directions. AB - In this article, the authors aim to introduce the nonradiologist to diffusion tensor imaging (DTI) and its applications to both clinical and research aspects of tuberous sclerosis complex. Tuberous sclerosis complex is a genetic neurocutaneous syndrome with variable and unpredictable neurological comorbidity that includes refractory epilepsy, intellectual disability, behavioral abnormalities and autism spectrum disorder. DTI is a method for modeling water diffusion in tissue and can noninvasively characterize microstructural properties of the brain. In tuberous sclerosis complex, DTI measures reflect well-known pathological changes. Clinically, DTI can assist with detecting the epileptogenic tuber. For research, DTI has a putative role in identifying potential disease biomarkers, as DTI abnormalities of the white matter are associated with neurocognitive morbidity including autism. If indeed DTI changes parallel phenotypical changes related to the investigational treatment of epilepsy, cognition and behavior with mTOR inhibitors, it will facilitate future clinical trials. PMID- 24489484 TI - CMOS Imaging of Pin-Printed Xerogel-Based Luminescent Sensor Microarrays. AB - We present the design and implementation of a luminescence-based miniaturized multisensor system using pin-printed xerogel materials which act as host media for chemical recognition elements. We developed a CMOS imager integrated circuit (IC) to image the luminescence response of the xerogel-based sensor array. The imager IC uses a 26 * 20 (520 elements) array of active pixel sensors and each active pixel includes a high-gain phototransistor to convert the detected optical signals into electrical currents. The imager includes a correlated double sampling circuit and pixel address/digital control circuit; the image data is read-out as coded serial signal. The sensor system uses a light-emitting diode (LED) to excite the target analyte responsive luminophores doped within discrete xerogel-based sensor elements. As a prototype, we developed a 4 * 4 (16 elements) array of oxygen (O2) sensors. Each group of 4 sensor elements in the array (arranged in a row) is designed to provide a different and specific sensitivity to the target gaseous O2 concentration. This property of multiple sensitivities is achieved by using a strategic mix of two oxygen sensitive luminophores ([Ru(dpp)3]2+ and ([Ru(bpy)3]2+) in each pin-printed xerogel sensor element. The CMOS imager consumes an average power of 8 mW operating at 1 kHz sampling frequency driven at 5 V. The developed prototype system demonstrates a low cost and miniaturized luminescence multisensor system. PMID- 24489483 TI - Molecular contributions to neurovascular unit dysfunctions after brain injuries: lessons for target-specific drug development. AB - The revised 'expanded' neurovascular unit (eNVU) is a physiological and functional unit encompassing endothelial cells, pericytes, smooth muscle cells, astrocytes and neurons. Ischemic stroke and traumatic brain injury are acute brain injuries directly affecting the eNVU with secondary damage, such as blood brain barrier (BBB) disruption, edema formation and hypoperfusion. BBB dysfunctions are observed at an early postinjury time point, and are associated with eNVU activation of proteases, such as tissue plasminogen activator and matrix metalloproteinases. BBB opening is accompanied by edema formation using astrocytic AQP4 as a key protein regulating water movement. Finally, nitric oxide dysfunction plays a dual role in association with BBB injury and dysregulation of cerebral blood flow. These mechanisms are discussed including all targets of eNVU encompassing endothelium, glial cells and neurons, as well as larger blood vessels with smooth muscle. In fact, the feeding blood vessels should also be considered to treat stroke and traumatic brain injury. This review underlines the importance of the eNVU in drug development aimed at improving clinical outcome after stroke and traumatic brain injury. PMID- 24489485 TI - An Interpersonal Model of Addiction Relapse. AB - In this article, we review the literature on interpersonal stress and rejection sensitivity and examine how these factors increase the risk of relapse in individuals with alcohol or drug dependence. We begin by considering the constructs of social pain and social threat, examining their evolutionary origins and their neuroanatomical, neuropsychological and neurophysiological dimensions. Together, these perspectives provide insight into the role of interpersonal stress as a powerful and oftentimes destructive factor that affects individuals in recovery from substance dependence. We then review the empirical evidence showing that intrapersonal traits and interpersonal environments interact to increase an addict's risk of relapse. We conclude by proposing that substance dependent individuals with high trait rejection sensitivity and a critical interpersonal environment are particularly vulnerable to relapse to substance use. PMID- 24489486 TI - Locally Contractive Dynamics in Generalized Integrate-and-Fire Neurons. AB - Integrate-and-fire models of biological neurons combine differential equations with discrete spike events. In the simplest case, the reset of the neuronal voltage to its resting value is the only spike event. The response of such a model to constant input injection is limited to tonic spiking. We here study a generalized model in which two simple spike-induced currents are added. We show that this neuron exhibits not only tonic spiking at various frequencies but also the commonly observed neuronal bursting. Using analytical and numerical approaches, we show that this model can be reduced to a one-dimensional map of the adaptation variable and that this map is locally contractive over a broad set of parameter values. We derive a sufficient analytical condition on the parameters for the map to be globally contractive, in which case all orbits tend to a tonic spiking state determined by the fixed point of the return map. We then show that bursting is caused by a discontinuity in the return map, in which case the map is piecewise contractive. We perform a detailed analysis of a class of piecewise contractive maps that we call bursting maps and show that they robustly generate stable bursting behavior. To the best of our knowledge, this work is the first to point out the intimate connection between bursting dynamics and piecewise contractive maps. Finally, we discuss bifurcations in this return map, which cause transitions between spiking patterns. PMID- 24489487 TI - Predicting the impact of multiwalled carbon nanotubes on the cement hydration products and durability of cementitious matrix using artificial neural network modeling technique. AB - In this study the feasibility of using the artificial neural networks modeling in predicting the effect of MWCNT on amount of cement hydration products and improving the quality of cement hydration products microstructures of cement paste was investigated. To determine the amount of cement hydration products thermogravimetric analysis was used. Two critical parameters of TGA test are PHP(loss) and CH(loss). In order to model the TGA test results, the ANN modeling was performed on these parameters separately. In this study, 60% of data are used for model calibration and the remaining 40% are used for model verification. Based on the highest efficiency coefficient and the lowest root mean square error, the best ANN model was chosen. The results of TGA test implied that the cement hydration is enhanced in the presence of the optimum percentage (0.3 wt%) of MWCNT. Moreover, since the efficiency coefficient of the modeling results of CH and PHP loss in both the calibration and verification stages was more than 0.96, it was concluded that the ANN could be used as an accurate tool for modeling the TGA results. Another finding of this study was that the ANN prediction in higher ages was more precise. PMID- 24489488 TI - A technical, economic, and environmental performance of grid-connected hybrid (photovoltaic-wind) power system in Algeria. AB - This paper studies the technical, economic, and environmental analysis of wind and photovoltaic power systems connected to a conventional grid. The main interest in such systems is on-site consumption of the produced energy, system hybridization, pooling of resources, and contribution to the environment protection. To ensure a better management of system energy, models have been used for determining the power that the constituting subsystems can deliver under specific weather conditions. Simulation is performed using MATLAB-SIMULINK. While, the economic and environmental study is performed using HOMER software. From an economic point of view, this allows to compare the financial constraints on each part of the system for the case of Adrar site which is located to the northern part of the south of Algeria. It also permits to optimally size and select the system presenting the best features on the basis of two parameters, that is, cost and effectiveness. From an environmental point of view, this study allows highlighting the role of renewable energy in reducing gas emissions related to greenhouse effects. In addition, through a set of sensitivity analysis, it is found that the wind speed has more effects on the environmental and economic performances of grid-connected hybrid (photovoltaic-wind) power systems. PMID- 24489489 TI - A hybrid genetic-simulated annealing algorithm for the location-inventory-routing problem considering returns under e-supply chain environment. AB - Facility location, inventory control, and vehicle routes scheduling are critical and highly related problems in the design of logistics system for e-business. Meanwhile, the return ratio in Internet sales was significantly higher than in the traditional business. Many of returned merchandise have no quality defects, which can reenter sales channels just after a simple repackaging process. Focusing on the existing problem in e-commerce logistics system, we formulate a location-inventory-routing problem model with no quality defects returns. To solve this NP-hard problem, an effective hybrid genetic simulated annealing algorithm (HGSAA) is proposed. Results of numerical examples show that HGSAA outperforms GA on computing time, optimal solution, and computing stability. The proposed model is very useful to help managers make the right decisions under e supply chain environment. PMID- 24489490 TI - A novel photocatalyst with ferromagnetic core used for the treatment of olive oil mill effluents from two-phase production process. AB - Photocatalytic degradation of olive oil mill wastewater from two-phase continuous centrifugation process was studied. A novel photocatalyst with ferromagnetic properties was characterized and investigated. The degradation capacity of the photocatalytic process of olive oil washing wastewater (OMW) and mixture of olives and olive oil (1 v/v) washing wastewaters (MOMW) was demonstrated. At lab scale, the %COD removal and residence time (tau) for MOMW and OMW were 58.4% (tau = 2 h) and 21.4% (tau = 3 h), respectively. On the other hand, at pilot scale, 23.4% COD(removal), 19.2% total phenols(removal), and 28.1% total suspended solids(removal) were registered at the end of the UV/TiO2 process for OMW, whereas 58.3% COD(removal), 27.5% total phenols(removal), and 25.0% total suspended solids(removal) for MOMW. Also, before the UV/TiO2 reaction, a pH-T flocculation operation as pretreatment was realized. The overall efficiency of the treatment process for MOMW was up to 91% of COD(removal), in contrast with 33.2% of COD(removal) for OMW. PMID- 24489491 TI - An improved hierarchical genetic algorithm for sheet cutting scheduling with process constraints. AB - For the first time, an improved hierarchical genetic algorithm for sheet cutting problem which involves n cutting patterns for m non-identical parallel machines with process constraints has been proposed in the integrated cutting stock model. The objective of the cutting scheduling problem is minimizing the weighted completed time. A mathematical model for this problem is presented, an improved hierarchical genetic algorithm (ant colony--hierarchical genetic algorithm) is developed for better solution, and a hierarchical coding method is used based on the characteristics of the problem. Furthermore, to speed up convergence rates and resolve local convergence issues, a kind of adaptive crossover probability and mutation probability is used in this algorithm. The computational result and comparison prove that the presented approach is quite effective for the considered problem. PMID- 24489492 TI - Dynamics of soil water evaporation during soil drying: laboratory experiment and numerical analysis. AB - Laboratory and numerical experiments were conducted to investigate the evolution of soil water evaporation during a continuous drying event. Simulated soil water contents and temperatures by the calibrated model well reproduced measured values at different depths. Results show that the evaporative drying process could be divided into three stages, beginning with a relatively high evaporation rate during stage 1, followed by a lower rate during transient stage and stage 2, and finally maintaining a very low and constant rate during stage 3. The condensation zone was located immediately below the evaporation zone in the profile. Both peaks of evaporation and condensation rate increased rapidly during stage 1 and transition stage, decreased during stage 2, and maintained constant during stage 3. The width of evaporation zone kept a continuous increase during stages 1 and 2 and maintained a nearly constant value of 0.68 cm during stage 3. When the evaporation zone totally moved into the subsurface, a dry surface layer (DSL) formed above the evaporation zone at the end of stage 2. The width of DSL also presented a continuous increase during stage 2 and kept a constant value of 0.71 cm during stage 3. PMID- 24489494 TI - TMA vessel segmentation based on color and morphological features: application to angiogenesis research. AB - Given that angiogenesis and lymphangiogenesis are strongly related to prognosis in neoplastic and other pathologies and that many methods exist that provide different results, we aim to construct a morphometric tool allowing us to measure different aspects of the shape and size of vascular vessels in a complete and accurate way. The developed tool presented is based on vessel closing which is an essential property to properly characterize the size and the shape of vascular and lymphatic vessels. The method is fast and accurate improving existing tools for angiogenesis analysis. The tool also improves the accuracy of vascular density measurements, since the set of endothelial cells forming a vessel is considered as a single object. PMID- 24489495 TI - Low-complexity saliency detection algorithm for fast perceptual video coding. AB - A low-complexity saliency detection algorithm for perceptual video coding is proposed; low-level encoding information is adopted as the characteristics of visual perception analysis. Firstly, this algorithm employs motion vector (MV) to extract temporal saliency region through fast MV noise filtering and translational MV checking procedure. Secondly, spatial saliency region is detected based on optimal prediction mode distributions in I-frame and P-frame. Then, it combines the spatiotemporal saliency detection results to define the video region of interest (VROI). The simulation results validate that the proposed algorithm can avoid a large amount of computation work in the visual perception characteristics analysis processing compared with other existing algorithms; it also has better performance in saliency detection for videos and can realize fast saliency detection. It can be used as a part of the video standard codec at medium-to-low bit-rates or combined with other algorithms in fast video coding. PMID- 24489496 TI - Online bridge crack monitoring with smart film. AB - Smart film crack monitoring method, which can be used for detecting initiation, length, width, shape, location, and propagation of cracks on real bridges, is proposed. Firstly, the fabrication of the smart film is developed. Then the feasibility of the method is analyzed and verified by the mechanical sensing character of the smart film under the two conditions of normal strain and crack initiation. Meanwhile, the coupling interference between parallel enameled wires of the smart film is discussed, and then low-frequency detecting signal and the custom communication protocol are used to decrease interference. On this basis, crack monitoring system with smart film is designed, where the collected crack data is sent to the remote monitoring center and the cracks are simulated and recurred. Finally, the monitoring system is applied to six bridges, and the effects are discussed. PMID- 24489498 TI - Decision tree approach for soil liquefaction assessment. AB - In the current study, the performances of some decision tree (DT) techniques are evaluated for postearthquake soil liquefaction assessment. A database containing 620 records of seismic parameters and soil properties is used in this study. Three decision tree techniques are used here in two different ways, considering statistical and engineering points of view, to develop decision rules. The DT results are compared to the logistic regression (LR) model. The results of this study indicate that the DTs not only successfully predict liquefaction but they can also outperform the LR model. The best DT models are interpreted and evaluated based on an engineering point of view. PMID- 24489497 TI - Flaxseed prevents leukocyte and platelet adhesion to endothelial cells in experimental atherosclerosis by reducing sVCAM-1 and vWF. AB - We studied the possible effect of flaxseed to prevent leukocytes and platelets adhesion to endothelial cells and to reduce soluble adhesion molecules (sVCAM-1) and endothelial integrity markers (vWF) in ovariectomized rats fed a high-fat diet. Forty-two female Wistar rats were either sham-operated or ovariectomized and randomly assigned for 36 weeks to three different diets: (1) low-fat diet (8% energy as fat); (2) high-fat diet (40% energy as fat, lard based, lard group); (3) high-fat diet enriched with ground flaxseed 15 g/100 g of food (40% energy as fat, lard + flaxseed group). The ovariectomized rats fed with lard + flaxseeds had significantly lower serum concentrations of sVCAM and vWF, reduced platelet adhesiveness, and lower extent of platelet and leukocyte adherence to endothelium in the histological evaluation of the aorta as compared to Ovx + lard group. In our study, high dose of ground flaxseed incorporated to lard-based diet prevented the progression of atherosclerotic lesions in estrogen deficiency rats by decreasing platelet and endothelium reactivity. Assessment of platelet adhesion, serum soluble adhesion molecule sVCAM, and endothelium integrity molecule vWF could be useful to detect the risk for atherosclerotic lesions in estrogen deficiency states and to estimate the effect of flaxseed supplementation. PMID- 24489499 TI - Generalized bifuzzy Lie subalgebras. AB - We introduce the concept of (gamma, delta)-bifuzzy Lie subalgebra, where gamma, delta are any two of {?, q, ??q, ??q} with gamma ? ??q, by using belongs to relation (?) and quasi-coincidence with relation (q) between bifuzzy points and bifuzzy sets and discuss some of its properties. Then we introduce bifuzzy soft Lie subalgebras and investigate some of their properties. PMID- 24489500 TI - Optimal transport on weighted networks for different node delivery capability schemes. AB - Many real networks can be best described by weighted networks with a diversity of interactions between nodes measured by the weights of the edges. It is of great importance to improve the overall capacity of these real-world networks. In this paper, the traffic capacity of weighted network is investigated based on three different node delivery capability schemes: the delivery capacity of each node is constant in the first scheme while in the second and third schemes it is proportional to its node degree and node strength. It is shown by simulations that the network transfer capacity depends strongly on the tunable parameter. And different tunable parameter is suitable for different node delivery capability. PMID- 24489501 TI - Nucleotide sequencing and identification of some wild mushrooms. AB - The rDNA-ITS (Ribosomal DNA Internal Transcribed Spacers) fragment of the genomic DNA of 8 wild edible mushrooms (collected from Eastern Chota Nagpur Plateau of West Bengal, India) was amplified using ITS1 (Internal Transcribed Spacers 1) and ITS2 primers and subjected to nucleotide sequence determination for identification of mushrooms as mentioned. The sequences were aligned using ClustalW software program. The aligned sequences revealed identity (homology percentage from GenBank data base) of Amanita hemibapha [CN (Chota Nagpur) 1, % identity 99 (JX844716.1)], Amanita sp. [CN 2, % identity 98 (JX844763.1)], Astraeus hygrometricus [CN 3, % identity 87 (FJ536664.1)], Termitomyces sp. [CN 4, % identity 90 (JF746992.1)], Termitomyces sp. [CN 5, % identity 99 (GU001667.1)], T. microcarpus [CN 6, % identity 82 (EF421077.1)], Termitomyces sp. [CN 7, % identity 76 (JF746993.1)], and Volvariella volvacea [CN 8, % identity 100 (JN086680.1)]. Although out of 8 mushrooms 4 could be identified up to species level, the nucleotide sequences of the rest may be relevant to further characterization. A phylogenetic tree is constructed using Neighbor-Joining method showing interrelationship between/among the mushrooms. The determined nucleotide sequences of the mushrooms may provide additional information enriching GenBank database aiding to molecular taxonomy and facilitating its domestication and characterization for human benefits. PMID- 24489502 TI - Comparison of multiobjective evolutionary algorithms for operations scheduling under machine availability constraints. AB - Many of the problems that arise in production systems can be handled with multiobjective techniques. One of those problems is that of scheduling operations subject to constraints on the availability of machines and buffer capacity. In this paper we analyze different Evolutionary multiobjective Algorithms (MOEAs) for this kind of problems. We consider an experimental framework in which we schedule production operations for four real world Job-Shop contexts using three algorithms, NSGAII, SPEA2, and IBEA. Using two performance indexes, Hypervolume and R2, we found that SPEA2 and IBEA are the most efficient for the tasks at hand. On the other hand IBEA seems to be a better choice of tool since it yields more solutions in the approximate Pareto frontier. PMID- 24489504 TI - Role of relative humidity in processing and storage of seeds and assessment of variability in storage behaviour in Brassica spp. and Eruca sativa. AB - The role of relative humidity (RH) while processing and storing seeds of Brassica spp. and Eruca sativa was investigated by creating different levels of relative humidity, namely, 75%, 50%, 32%, and 11% using different saturated salt solutions and 1% RH using concentrated sulphuric acid. The variability in seed storage behaviour of different species of Brassica was also evaluated. The samples were stored at 40 +/- 2 degrees C in sealed containers and various physiological parameters were assessed at different intervals up to three months. The seed viability and seedling vigour parameters were considerably reduced in all accessions at high relative humidity irrespective of the species. Storage at intermediate relative humidities caused minimal decline in viability. All the accessions performed better at relative humidity level of 32% maintaining seed moisture content of 3%. On analyzing the variability in storage behaviour, B. rapa and B. juncea were better performers than B. napus and Eruca sativa. PMID- 24489505 TI - Isolation, characterization, and molecular modeling of a rheumatoid factor from a Hepatitis C virus infected patient with Sjogren's syndrome. AB - We have previously isolated several IgG rheumatoid factors (RFs) from patients with both rheumatoid arthritis and idiopathic thrombocytopenia purpura using phage display system. To study IgG RFs in patients with other autoimmune diseases, phage display antibody libraries from a hepatitis C virus infected patient with Sjogren's syndrome were constructed. After panning, a specific clone RFL11 was isolated for characterization in advance. The binding activity and specificity of RFL11 to IgG Fc fragment were comparable to those of RFs previously isolated. The analysis with existed RF-Fc complex structures indicated the homology model of RFL11 is similar to IgM RF61 complex with high binding affinity of about 6 * 10-8 M. This effect resulted from longer complementarity determining region (CDR) combining key somatic mutations. In the RFL11-Fc interfaces, the CDR-H3 loop forms a finger-like structure extending into the bottom of Fc pocket and resulting in strong ion and cation-pi interactions. Moreover, a process of antigen-driven maturation was proven by somatically mutated VH residues on H2 and H3 CDR loops in the interfaces. Taken together, these results suggested that high affinity IgG RFs can be generated in patients with Sjogren's syndrome and may play an important role in the pathogenesis of this autoimmune disease. PMID- 24489506 TI - Amelioration of behavioural, biochemical, and neurophysiological deficits by combination of monosodium glutamate with resveratrol/alpha-lipoic acid/coenzyme Q10 in rat model of cisplatin-induced peripheral neuropathy. AB - Cisplatin or cis-diamminedichloroplatinum (II) (CDDP) is a cytotoxic chemotherapeutic agent with dose-dependent peripheral neuropathy as a foremost side effect characterised by ataxia, pain, and sensory impairment. Cumulative drug therapy of CDDP is known to produce severe oxidative damage. It mainly targets and accumulates in dorsal root ganglia that in turn cause damage resulting in secondary nerve fibre axonopathy. In the present study, we investigated the neuroprotective effect of the combination of monosodium glutamate (MSG) with three individual antioxidants, that is, resveratrol, alpha lipoic acid (ALA), and coenzyme Q10 (CoQ10), in cisplatin (2 mg/kg i.p. twice weekly) induced peripheral neuropathy in rats. After 8 weeks of treatment the degree of neuroprotection was determined by measuring behavioral and electrophysiological properties and sciatic nerve lipid peroxidation, as well as glutathione and catalase levels. The results suggested that pretreatment with the combination of MSG (500 mg/kg/day po) with resveratrol (10 mg/kg/day i.p.) or ALA (20 mg/kg/day i.p.) or CoQ10 (10 mg/kg weekly thrice i.p.) exhibited neuroprotective effect. The maximum neuroprotection of MSG was observed in the combination with resveratrol. PMID- 24489507 TI - Pancreaticobiliary maljunction is associated with common bile duct carcinoma: a meta-analysis. AB - OBJECTIVE: Pancreaticobiliary maljunction (PBM) has been reported to be associated with an increased risk of gallbladder carcinoma. However, the relationship between PBM and common bile duct carcinoma (CBDC) remains unclear. We aimed to conduct a meta-analysis to determine the available evidence on the association between PBM and CBDC. METHODS: The pooled odds ratio (OR) and standard mean differences (SMD) with 95% confidence interval (95% CI) were used to estimate the effects. RESULTS: A total of eight case-control studies and two cohort studies were identified. The incidence of PBM was higher in CBDC patients than in controls (OR = 1.45; 95% CI, 1.19-1.76). Compared with patients without PBM, CBDC patients with PBM were younger at the diagnosis age (SMD = -0.46; 95% CI, -0.64 to -0.28). A difference in the incidence of associated CDC was found between CBDC patients with or without PBM (OR = 2.14; 95% CI, 1.60-2.87). CONCLUSIONS: Compared with benign biliary tract diseases, the incidence of PBM was higher in CBDC patients, especially in relatively young patients. We also found that the incidence of CDC was higher in CBDC patients with PBM. These findings showed positive association between PBM and CBDC, which may help in identifying high-risk individuals. PMID- 24489508 TI - Stability analysis of distributed order fractional chen system. AB - We first investigate sufficient and necessary conditions of stability of nonlinear distributed order fractional system and then we generalize the integer order Chen system into the distributed order fractional domain. Based on the asymptotic stability theory of nonlinear distributed order fractional systems, the stability of distributed order fractional Chen system is discussed. In addition, we have found that chaos exists in the double fractional order Chen system. Numerical solutions are used to verify the analytical results. PMID- 24489510 TI - Reversible rings with involutions and some minimalities. AB - In continuation of the recent developments on extended reversibilities on rings, we initiate here a study on reversible rings with involutions, or, in short, * reversible rings. These rings are symmetric, reversible, reflexive, and semicommutative. In this note we will study some properties and examples of * reversible rings. It is proved here that the polynomial rings of *-reversible rings may not be *-reversible. A criterion for rings which cannot adhere to any involution is developed and it is observed that a minimal noninvolutary ring is of order 4 and that a minimal noncommutative *-reversible ring is of order 16. PMID- 24489511 TI - Failure behavior and constitutive model of weakly consolidated soft rock. AB - Mining areas in western China are mainly located in soft rock strata with poor bearing capacity. In order to make the deformation failure mechanism and strength behavior of weakly consolidated soft mudstone and coal rock hosted in Ili No. 4 mine of Xinjiang area clear, some uniaxial and triaxial compression tests were carried out according to the samples of rocks gathered in the studied area, respectively. Meanwhile, a damage constitutive model which considered the initial damage was established by introducing a damage variable and a correction coefficient. A linearization process method was introduced according to the characteristics of the fitting curve and experimental data. The results showed that samples under different moisture contents and confining pressures presented completely different failure mechanism. The given model could accurately describe the elastic and plastic yield characteristics as well as the strain softening behavior of collected samples at postpeak stage. Moreover, the model could precisely reflect the relationship between the elastic modulus and confining pressure at prepeak stage. PMID- 24489509 TI - Treatment of pseudomonas and Staphylococcus bronchopulmonary infection in patients with cystic fibrosis. AB - The optimal antibiotic regimen is unclear in management of pulmonary infections due to pseudomonas and staphylococcus in cystic fibrosis (CF). We systematically searched all the published literature that has considered the evidence for antimicrobial therapies in CF till June 2013. The key findings were as follows: inhaled antipseudomonal antibiotic improves lung function, and probably the safest/most effective therapy; antistaphylococcal antibiotic prophylaxis increases the risk of acquiring P. aeruginosa; azithromycin significantly improves respiratory function after 6 months of treatment; a 28-day treatment with aztreonam or tobramycin significantly improves respiratory symptoms and pulmonary function; aztreonam lysine might be superior to tobramycin inhaled solution in chronic P. aeruginosa infection; oral ciprofloxacin does not produce additional benefit in those with chronic persistent pseudomonas infection but may have a role in early or first infection. As it is difficult to establish a firm recommendation based on the available evidence, the following factors must be considered for the choice of treatment for each patient: antibiotic related (e.g., safety and efficacy and ease of administration/delivery) and patient related (e.g., age, clinical status, prior use of antibiotics, coinfection by other organisms, and associated comorbidities ones). PMID- 24489512 TI - Pueraria tuberosa DC extract improves androgenesis and sexual behavior via FSH LH cascade. AB - The aim of this study was to investigate the effects of ethanolic extract of Pueraria tuberosa (PT) on sexual behaviour and androgenic activity. Male albino rats were divided into four groups of six animals each: control group 1 (2% acacia solution), PT-treated group 2 (50 mg/Kg), PT-treated group 3 (100 mg/Kg), and PT-treated group 4 (150 mg/Kg). Sexual behavior of male rats in the presence of a female rat was recorded. The treated groups were evaluated for sexual parameters. The extract was characterized using LC-MS. The effect of treatment on anabolic and weight of secondary sexual organs was determined. The histological changes in section of testis and epididymis after treatment were observed. Sperm count in epididymis and fructose content in seminal vesicles were also measured. Levels of hormones like FSH, LH, and T were determined. A dose-dependent increase in sexual behaviors was evidenced in the animals of extract treated groups. Increase in testis weight was recorded in PT. At the highest dose PT also affects the hormones level. The four compounds namely puerarin, daidzein, biochanin-A and formononetin were identified in ethanolic extract using LC-MS. It concluded that PT extract possesses androgenic effect and it significantly increased the sexual behaviour and hormones level. PMID- 24489513 TI - A noninvasive neuroprosthesis augments hand grasp force in individuals with cervical spinal cord injury: the functional and therapeutic effects. AB - OBJECTIVES: The primary purpose of this study was to evaluate myoelectrically controlled functional electrical stimulation (MeCFES) for enhancing the tenodesis grip in people with tetraplegia. The second aim was to estimate the potential number of candidates for the MeCFES device. The application of MeCFES provides the user with direct control of the grasp force as opposed to triggered FES systems. METHODS: Screening 253 medical records of C5 to C7 spinal cord injury resulted in 27 participants who trained activities of daily living for 12 * 2 hours, using the MeCFES. Hand function was evaluated by the Action Research Arm Test (ARAT). Primary outcome was the ARAT change score with/without the device, before/after the intervention period. Secondary outcome was the number of positive or clinically relevant change scores with respect to the cohort. RESULTS: The MeCFES improved hand test score in 63% of the subjects at first application. Training resulted in a significant therapeutic effect, which resulted in an overall increase of hand function in 89% of the participants and 30% experienced a clinically relevant change (6 points or more). CONCLUSIONS: Clinical relevance was found both as an assistive aid and as a therapeutic tool in rehabilitation. The therapeutic effect deserves further investigation in clinical studies. PMID- 24489515 TI - Numerical simulation and comparison of conventional and sloped solar chimney power plants: the case for Lanzhou. AB - The solar chimney power plant (SCPP) generates updraft wind through the green house effect. In this paper, the performances of two SCPP styles, that is, the conventional solar chimney power plant (CSCPP) and the sloped solar chimney power plant (SSCPP), are compared through a numerical simulation. A simplified Computational Fluid Dynamics (CFD) model is built to predict the performances of the SCPP. The model is validated through a comparison with the reported results from the Manzanares prototype. The annual performances of the CSCPP and the SSCPP are compared by taking Lanzhou as a case study. Numerical results indicate that the SSCPP holds a higher efficiency and generates smoother power than those of the CSCPP, and the effective pressure in the SSCPP is relevant to both the chimney and the collector heights. PMID- 24489514 TI - Isolation of Escherichia coli 0157:H7 strain from fecal samples of zoo animal. AB - The isolation and characterization of Escherichia coli O157:H7 strains from 22 out of 174 fecal samples from petting zoo animals representing twenty-two different species (camel, lion, goats, zebra, bear, baboon monkey, Siberian monkey, deer, elk, llama, pony, horses, fox, kangaroo, wolf, porcupine, chickens, tiger, ostrich, hyena, dogs, and wildcats) were investigated. One petting Al Zawraa zoological society of Baghdad was investigated for E. coli O157:H7 over a 16-month period that spanned two summer and two autumn seasons. Variation in the occurrence of E. coli O157:H7-positive petting zoo animals was observed, with animals being culture positive only in the summer months but not in the spring, autumn, or winter. E. coli O157:H7 isolates were distinguished by agglutination with E. coli O157:H7 latex reagent (Oxoid), identified among the isolates, which showed that multiple E. coli strains were isolated from one petting zoo animal, in which a single animal simultaneously shed multiple E. coli strains; E. coli O157:H7 was isolated only by selective enrichment culture of 2 g of petting zoo animal feces. In contrast, strains other than O157:H7 were cultured from feces of petting zoo animals without enrichment. PMID- 24489516 TI - The Economic Burden of HIV/AIDS and myocardial infarction treatment in Brazil. AB - OBJECTIVE: To analyze the expenses of HIV/AIDS and acute myocardial infarction (AMI) treatment in Brazil. METHODS: A search in the Brazilian epidemiological database (DATASUS) on AMI and AIDS hospitalizations and their costs was done from January 1998 to December 2011. The number of HIV/AIDS cases and antiretroviral treatment (ART) costs was obtained from public Brazilian databases. RESULTS: In 5 years, HIV/AIDS cases increased 38.5%, mainly in patients aged 25-49. There were 180,640 patients in ART in 2007 at a cost of R$ 3,920 per patient/year. The hospitalizations due to AIDS were stable over the last 13 years; however, the hospitalizations due to AMI have increased 78%. In 2007, the expenses with hospitalizations for HIV/AIDS and AMI (25-49 years) were approximately 0.12 and 1.52% of the Ministry of Health budget allocated to reimburse inpatient costs. The expenses on ART totaled 1.5% of the total budget (all age groups). CONCLUSION: The prevalence of HIV/AIDS is still increasing in Brazil. There are scientific evidences suggesting an increased incidence of AIM in this population. Considering the high costs for the treatment of both diseases, an economic analysis is important to alert health managers to strengthen the preventive measures to guarantee the financial sustainability of such treatment. PMID- 24489517 TI - NHCs catalyzed hydrophosphonylation of alpha-ketoesters and alpha-trifluoromethyl ketones. AB - N-Heterocyclic carbenes catalyzed hydrophosphonylation reaction of alpha ketoesters and alpha-trifluoromethyl ketones was developed. Under the catalysis of 10 mol% IPr, alpha-ketoesters or alpha-trifluoromethyl ketones reacted with dialkyl phosphites to provide quaternary alpha-hydroxyphosphonates in good to excellent yield. PMID- 24489518 TI - Finite difference methods for option pricing under Levy processes: Wiener-Hopf factorization approach. AB - In the paper, we consider the problem of pricing options in wide classes of Levy processes. We propose a general approach to the numerical methods based on a finite difference approximation for the generalized Black-Scholes equation. The goal of the paper is to incorporate the Wiener-Hopf factorization into finite difference methods for pricing options in Levy models with jumps. The method is applicable for pricing barrier and American options. The pricing problem is reduced to the sequence of linear algebraic systems with a dense Toeplitz matrix; then the Wiener-Hopf factorization method is applied. We give an important probabilistic interpretation based on the infinitely divisible distributions theory to the Laurent operators in the correspondent factorization identity. Notice that our algorithm has the same complexity as the ones which use the explicit-implicit scheme, with a tridiagonal matrix. However, our method is more accurate. We support the advantage of the new method in terms of accuracy and convergence by using numerical experiments. PMID- 24489519 TI - Discrete-Time Survival Factor Mixture Analysis for Low-Frequency Recurrent Event Histories. AB - In this article, the latent class analysis framework for modeling single event discrete-time survival data is extended to low-frequency recurrent event histories. A partial gap time model, parameterized as a restricted factor mixture model, is presented and illustrated using juvenile offending data. This model accommodates event-specific baseline hazard probabilities and covariate effects; event recurrences within a single time period; and accounts for within- and between-subject correlations of event times. This approach expands the family of latent variable survival models in a way that allows researchers to explicitly address questions about unobserved heterogeneity in the timing of events across the lifespan. PMID- 24489520 TI - Detecting Anomalous Insiders in Collaborative Information Systems. AB - Collaborative information systems (CISs) are deployed within a diverse array of environments that manage sensitive information. Current security mechanisms detect insider threats, but they are ill-suited to monitor systems in which users function in dynamic teams. In this paper, we introduce the community anomaly detection system (CADS), an unsupervised learning framework to detect insider threats based on the access logs of collaborative environments. The framework is based on the observation that typical CIS users tend to form community structures based on the subjects accessed (e.g., patients' records viewed by healthcare providers). CADS consists of two components: 1) relational pattern extraction, which derives community structures and 2) anomaly prediction, which leverages a statistical model to determine when users have sufficiently deviated from communities. We further extend CADS into MetaCADS to account for the semantics of subjects (e.g., patients' diagnoses). To empirically evaluate the framework, we perform an assessment with three months of access logs from a real electronic health record (EHR) system in a large medical center. The results illustrate our models exhibit significant performance gains over state-of-the-art competitors. When the number of illicit users is low, MetaCADS is the best model, but as the number grows, commonly accessed semantics lead to hiding in a crowd, such that CADS is more prudent. PMID- 24489521 TI - Depression Diagnoses and Fundamental Frequency-Based Acoustic Cues in Maternal Infant-Directed Speech. AB - F0-based acoustic measures were extracted from a brief, sentence-final target word spoken during structured play interactions between mothers and their 3- to 14-month-old infants, and were analyzed based on demographic variables and DSM-IV Axis-I clinical diagnoses and their common modifiers. F0 range (DeltaF0) was negatively correlated with infant age and number of children. DeltaF0 was significantly smaller in clinically depressed mothers and mothers diagnosed with depression in partial remission, relative to non-depressed mothers, mothers diagnosed with depression in full remission, and those diagnosed with depressive disorder not otherwise specified. DeltaF0 was significantly lower in mothers experiencing their first major depressive episode relative to mothers with recurrent depression. Deficits in DeltaF0 were specific to diagnosed clinical depression, and were not well predicted by elevated self-report scores only, or by diagnosed anxiety disorders. Mothers with higher DeltaF0 had infants with reportedly larger productive vocabularies, but depression was unrelated to vocabulary development. Implications for cognitive-linguistic development are discussed. PMID- 24489523 TI - Assessing Restrictiveness: A Closer Look at the Foster Care Placements and Perceptions of Youth With and Without Disabilities Aging Out of Care. AB - The aim of the study was to examine the experience of restrictiveness among transition-aged youth with disabilities in foster care. Utilizing a sample of 207 youth, placement types were explored for differences in disability status, race and sex. Further, youth perceptions of restriction around communication, movement around one's home, and access to the community were examined for youth receiving special education services (SPED), youth receiving developmental disability services (DD), and youth without disabilities. Youth with disabilities were more likely to be placed in more restrictive placement types and had significantly higher levels of perceived restriction around communication, movement, and community when compared to youth without disabilities. Additionally, males with disabilities experienced higher levels of restrictiveness, particularly those who received DD services, while White youth with disabilities also experienced greater community restrictiveness. PMID- 24489522 TI - Forcefield_PTM: Ab Initio Charge and AMBER Forcefield Parameters for Frequently Occurring Post-Translational Modifications. AB - In this work, we introduce Forcefield_PTM, a set of AMBER forcefield parameters consistent with ff03 for 32 common post-translational modifications. Partial charges were calculated through ab initio calculations and a two-stage RESP fitting procedure in an ether-like implicit solvent environment. The charges were found to be generally consistent with others previously reported for phosphorylated amino acids, and trimethyllysine, using different parameterization methods. Pairs of modified and their corresponding unmodified structures were curated from the PDB for both single and multiple modifications. Background structural similarity was assessed in the context of secondary and tertiary structures from the global dataset. Next, the charges derived for Forcefield_PTM were tested on a macroscopic scale using unrestrained all-atom Langevin molecular dynamics simulations in AMBER for 34 (17 pairs of modified/unmodified) systems in implicit solvent. Assessment was performed in the context of secondary structure preservation, stability in energies, and correlations between the modified and unmodified structure trajectories on the aggregate. As an illustration of their utility, the parameters were used to compare the structural stability of the phosphorylated and dephosphorylated forms of OdhI. Microscopic comparisons between quantum and AMBER single point energies along key chi torsions on several PTMs were performed and corrections to improve their agreement in terms of mean squared errors and squared correlation coefficients were parameterized. This forcefield for post-translational modifications in condensed-phase simulations can be applied to a number of biologically relevant and timely applications including protein structure prediction, protein and peptide design, docking, and to study the effect of PTMs on folding and dynamics. We make the derived parameters and an associated interactive webtool capable of performing post translational modifications on proteins using Forcefield_PTM available at http://selene.princeton.edu/FFPTM. PMID- 24489524 TI - THE FORGOTTEN POPULATION? YOUTH, FOOD IN SECURITY, AND RISING PRICES: IMPLICATIONS FOR THE GLOBAL FOOD CRISIS. AB - The global food crisis has led to increased interest in food insecurity and its causes and consequences. Much of the focus however has been on mothers and young children, with little attention paid to the possible impacts on the large population of youth in developing countries. The objectives of this paper are to (1) draw attention to the food insecurity experience of a forgotten population, youth; (2) test whether the prevalence of food insecurity among Ethiopian adolescents is increasing with the rising cost of foods; and (3) to identify some individual, household, temporal, and spatial predictors of vulnerability. Data are drawn from a baseline survey in 2006 and a follow-up survey round conducted in 2007 of an ongoing population-based longitudinal study of approximately 2,100 youth living in southwestern Ethiopia. Results show high levels of food insecurity among youth, a marked increase in the experience of food insecurity among youth, and a bias in vulnerability toward youth in the poorest households and in rural households. During the intersurvey period boys were also more likely than girls to become food insecure. This latter finding effectively eliminates the gender bias in food insecurity observed in the baseline survey. Youth who became food insecure between survey rounds were also more likely to report worse health in 2007 than in 2006. Collectively our results suggest that youth are not being adequately buffered from food insecurity, and that generalizations about the current food crisis may be too broad and, thus, misrepresent vulnerable groups. Future research should focus on how to best protect vulnerable youth from the experience of food insecurity and its consequences. PMID- 24489525 TI - Industrialization Stresses, Alcohol Abuse & Substance Dependence: Differential Gender Effects in a Kenyan Rural Farming Community. AB - Developing countries' industrialization and urbanization attempts have been linked to psychological distress and alcohol abuse. We used Hobfoll's COR theory to examine the relationship between gender, perceived resource loss (an indicator of industrialization stress), and alcohol abuse and dependence in a sample of Kenyan rural village men and women (N = 186). Regression analyses indicated that both gender and COR loss predicted alcohol abuse and dependence. Additionally, results suggested that gender moderated the relationship between COR loss and alcohol dependence; such that higher COR loss scores predicted higher alcohol dependence for men, but COR loss scores did not predict alcohol dependence for women. Thus, we suggest that gender differences in substance abuse may be due less to actual differences in resource loss, but rather to gender differences in the response to resource loss. Limitations and opportunities for future research are discussed. PMID- 24489526 TI - Bayesian analysis of zero inflated spatiotemporal HIV/TB child mortality data through the INLA and SPDE approaches: Applied to data observed between 1992 and 2010 in rural North East South Africa. AB - Longitudinal mortality data with few deaths usually have problems of zero inflation. This paper presents and applies two Bayesian models which cater for zero-inflation, spatial and temporal random effects. To reduce the computational burden experienced when a large number of geo-locations are treated as a Gaussian field (GF) we transformed the field to a Gaussian Markov Random Fields (GMRF) by triangulation. We then modelled the spatial random effects using the Stochastic Partial Differential Equations (SPDEs). Inference was done using a computationally efficient alternative to Markov chain Monte Carlo (MCMC) called Integrated Nested Laplace Approximation (INLA) suited for GMRF. The models were applied to data from 71,057 children aged 0 to under 10 years from rural north east South Africa living in 15,703 households over the years 1992-2010. We found protective effects on HIV/TB mortality due to greater birth weight, older age and more antenatal clinic visits during pregnancy (adjusted RR (95% CI)): 0.73(0.53;0.99), 0.18(0.14;0.22) and 0.96(0.94;0.97) respectively. Therefore childhood HIV/TB mortality could be reduced if mothers are better catered for during pregnancy as this can reduce mother-to-child transmissions and contribute to improved birth weights. The INLA and SPDE approaches are computationally good alternatives in modelling large multilevel spatiotemporal GMRF data structures. PMID- 24489527 TI - Age-Related Changes in the Mechanical Properties of Human Fibroblasts and Its Prospective Reversal After Anti-Wrinkle Tripeptide Treatment. AB - One of an essential characteristic of human skin are time dependent mechanical properties. Here, we demonstrate that stiffness of human dermal fibroblast correlates with age and it can be restored after anti-wrinkle tripeptide treatment. The stiffness of human fibroblasts isolated from donors of 30-, 40- and 60 years old were examined. Additionally the effect of anti- wrinkle tripeptide of latter cells was investigated. The atomic force microscopy measurements were performed on untreated fibroblast as well as on treated with the peptide. The Young's modulus for two indentation depths 200 and 600 nm of each cell type was determined. The Young's modulus increases with age of the cells. The highest values of Young's modulus were obtained for fibroblasts collected from 60 years old donors, for indentation depth of ~200 nm. For larger indentation depth of 600 nm there are no significant differences in stiffness between cells. Fibroblasts treated with the anti-wrinkle tripeptide exhibit lower Young's modulus. The cells derived from 40- and 60-years old donors restored stiffness characteristic to the level of 30 years old subjects. The results show correlation between stiffness and age of the human fibroblast as well as impact of anti-wrinkle tripeptide on the mechanical properties of skin cells. PMID- 24489528 TI - Precursor-to-product ratios reflect biochemical phenotype in congenital adrenal hyperplasia. AB - Precursor-to-product ratios in steroid hormone metabolism may accurately reflect enzymatic activity and production of metabolites relative to their disappearance. The purpose of this study was to explore the use of direct precursor-to-product steroid ratios to discriminate between infants with congenital adrenal hyperplasia (CAH) due to 21- alpha -hydroxylase deficiency and infants with no disorder, thus characterizing the biochemical phenotype in CAH. Deidentified dried blood spot samples from confirmed CAH cases identified by newborn screen (CAH-positive, N = 8) and from cases with no disorder (CAH-negative, N = 10) were obtained from the California State Newborn Screening Program. Samples (~6.25 mm circular spots) underwent methanol and water extraction (9:1 ratio). Deuterated steroids served as isotope internal standards. 17-alpha-hydroxyprogesterone (17 OHP), 11-deoxycortisol (S), androstenedione (A4) and cortisol (F) concentrations were determined by liquid chromatography-tandem mass spectrometry (LC-MS/MS), and the 17-OHP/S, 17-OHP/A4, and S/F ratios were calculated. The mean 17-OHP and A4 concentrations in samples from CAH cases were significantly increased when compared to cases with no disorder (p = 0.003 for both). 17-OHP/S and 17-OHP/A4 ratios were also significantly elevated in CAH cases (p = 0.007 and p < 0.001, respectively). In contrast, S and F concentrations and the S/F ratio were similar between the two groups. In CAH, the elevated 17-OHP/S ratio is a biomarker of diminished 21-alpha-hydroxylase activity, and the elevated 17-OHP/A4 ratio is a biomarker of adrenal androgen excess via increased 17,20-lyase activity. The similar S/F ratio indicates that the rate of production via 11-beta-hydroxylase and disappearance of F is maintained in CAH. PMID- 24489529 TI - New modes of data partitioning based on PARS peak alignment for improved multivariate biomarker/biopattern detection in 1H-NMR spectroscopic metabolic profiling of urine. AB - This paper addresses the possibility of mathematically partition and process urine 1H-NMR spectra to enhance the efficiency of the subsequent multivariate data analysis in the context of metabolic profiling of a toxicity study. We show that by processing the NMR data with the peak alignment using reduced set mapping (PARS) algorithm and the use of sparse representation of the data results in the information contained in the original NMR data being preserved with retained resolution but free of the problem of peak shifts. We can now describe a method for differential expression analysis of NMR spectra by using prior knowledge, i.e., the onset of dosing, a partitioning not possible to achieve using raw or bucketed data. In addition we also outline a scheme for soft removal of "biological noise" from the aligned data: exhaustive bio-noise subtraction (EBS). The result is a straightforward protocol for detection of peaks that appear as a consequence of the drug response. In other words, it is possible to elucidate peak origin, either from endogenous substances or from the administered drug/biomarkers. The partition of data originating from the normally regulating metabolome can, furthermore, be analyzed free of the superimposed biological noise. The proposed protocol results in enhanced interpretability of the processed data, i.e., a more refined metabolic trace, simplification of detection of consistent biomarkers, and a simplified search for metabolic end products of the administered drug. PMID- 24489530 TI - PNU-91325 increases fatty acid synthesis from glucose and mitochondrial long chain fatty acid degradation: a comparative tracer-based metabolomics study with rosiglitazone and pioglitazone in HepG2 cells. AB - The mitochondrial membrane protein termed "mitoNEET," is a putative secondary target for insulin-sensitizing thiazolidinedione (TZD) compounds but its role in regulating metabolic flux is not known. PNU-91325 is a thiazolidinedione derivative which exhibits high binding affinity to mitoNEET and lowers cholesterol, fatty acid and blood glucose levels in animal models. In this study we report the stable isotope-based dynamic metabolic profiles (SIDMAP) of rosiglitazone, pioglitazone and PNU-91325 in a dose-matching, dose-escalating study. One and 10 MUM concentrations 1 and 10 MUM drug concentrations were introduced into HepG2 cells in the presence of either [1,2-13C2]-D-glucose or [U 13C18]stearate, GC/MS used to determine positional tracer incorporation (mass isotopomer analysis) into multiple metabolites produced by the Krebs and pentose cycles, de novo fatty acid synthesis, long chain fatty acid oxidation, chain shortening and elongation. Rosiglitazone and pioglitazone (10 MUM) increased pentose synthesis from [U-13C18]stearate by 127% and 185%, respectively, while PNU-91325 rather increased glutamate synthesis in the Krebs cycle by 113% as compared to control vehicle treated cells. PNU-91325 also increased stearate chain shortening into palmitate by 59%. Glucose tracer-derived de novo palmitate and stearate synthesis were increased by 1 and 10 MUM rosiglitazone by 41% and 83%, respectively, and by 63% and 75% by PNU-91325. Stearate uptake was also increased by 10 MUM PNU-91325 by 15.8%. We conclude that the entry of acetyl Co-A derived from long-chain fatty acid beta-oxidation into the mitochondria is facilitated by the mitoNEET ligand PNU-91325, which increases glucose-derived long chain fatty acid synthesis and breakdown via beta-oxidation and anaplerosis in the mitochondria. PMID- 24489531 TI - Assessing the performance of statistical validation tools for megavariate metabolomics data. AB - Statistical model validation tools such as cross-validation, jack-knifing model parameters and permutation tests are meant to obtain an objective assessment of the performance and stability of a statistical model. However, little is known about the performance of these tools for megavariate data sets, having, for instance, a number of variables larger than 10 times the number of subjects. The performance is assessed for megavariate metabolomics data, but the conclusions also carry over to proteomics, transcriptomics and many other research areas. Partial least squares discriminant analyses models were built for several LC-MS lipidomic training data sets of various numbers of lean and obese subjects. The training data sets were compared on their modelling performance and their predictability using a 10-fold cross-validation, a permutation test, and test data sets. A wide range of cross-validation error rates was found (from 7.5% to 16.3% for the largest trainings set and from 0% to 60% for the smallest training set) and the error rate increased when the number of subjects decreased. The test error rates varied from 5% to 50%. The smaller the number of subjects compared to the number of variables, the less the outcome of validation tools such as cross validation, jack-knifing model parameters and permutation tests can be trusted. The result depends crucially on the specific sample of subjects that is used for modelling. The validation tools cannot be used as warning mechanism for problems due to sample size or to representativity of the sampling. PMID- 24489533 TI - Blind deconvolution for ultrasound sequences using a noninverse greedy algorithm. AB - The blind deconvolution of ultrasound sequences in medical ultrasound technique is still a major problem despite the efforts made. This paper presents a blind noninverse deconvolution algorithm to eliminate the blurring effect, using the envelope of the acquired radio-frequency sequences and a priori Laplacian distribution for deconvolved signal. The algorithm is executed in two steps. Firstly, the point spread function is automatically estimated from the measured data. Secondly, the data are reconstructed in a nonblind way using proposed algorithm. The algorithm is a nonlinear blind deconvolution which works as a greedy algorithm. The results on simulated signals and real images are compared with different state of the art methods deconvolution. Our method shows good results for scatters detection, speckle noise suppression, and execution time. PMID- 24489532 TI - Ab initio prediction of metabolic networks using Fourier transform mass spectrometry data. AB - Fourier transform mass spectrometry has recently been introduced into the field of metabolomics as a technique that enables the mass separation of complex mixtures at very high resolution and with ultra high mass accuracy. Here we show that this enhanced mass accuracy can be exploited to predict large metabolic networks ab initio, based only on the observed metabolites without recourse to predictions based on the literature. The resulting networks are highly information-rich and clearly non-random. They can be used to infer the chemical identity of metabolites and to obtain a global picture of the structure of cellular metabolic networks. This represents the first reconstruction of metabolic networks based on unbiased metabolomic data and offers a breakthrough in the systems-wide analysis of cellular metabolism. PMID- 24489534 TI - PPARgamma Agonist Rosiglitazone Suppresses Renal mPGES-1/PGE2 Pathway in db/db Mice. AB - Evidence had shown the detrimental effect of prostaglandin (PG) E2 in diabetic nephropathy (DN) of STZ-induced type-1 diabetes but its role in the development of DN of type-2 diabetes remains uncertain. The present study was undertaken to investigate the regulation of PGE2 synthetic pathway and the interaction between peroxisome proliferator-activated receptor (PPAR) gamma and PGE2 synthesis in the kidneys of db/db mice. Strikingly, urinary PGE2 was remarkably elevated in db/db mice paralleled with the increased protein expressions of COX-2 and mPGES-1. In contrast, the protein expressions of COX-1, mPGES-2, cPGES, and 15 hydroxyprostaglandin dehydrogenase (15-PGDH) were not altered. Following 1-week rosiglitazone (Rosi) therapy, urinary PGE2, but not other prostanoids, was reduced by 57% in parallel with significant reduction of mPGES-1 protein and EP4 mRNA expressions. By immunohistochemistry, mPGES-1 was significantly induced in the glomeruli of db/db mice, which was almost entirely abolished by Rosi. In line with the reduction of glomerular mPGES-1, the glomerular injury score showed a tendency of improvement after 1 week of Rosi therapy. Collectively, the present study demonstrated an inhibitory effect of PPAR gamma activation on renal mPGES 1/PGE2/EP4 pathway in type-2 diabetes and suggested that mPGES-1 may potentially serve as a therapeutic target for treating type-2 diabetes-associated DN. PMID- 24489535 TI - Unsupervised approach data analysis based on fuzzy possibilistic clustering: application to medical image MRI. AB - The analysis and processing of large data are a challenge for researchers. Several approaches have been used to model these complex data, and they are based on some mathematical theories: fuzzy, probabilistic, possibilistic, and evidence theories. In this work, we propose a new unsupervised classification approach that combines the fuzzy and possibilistic theories; our purpose is to overcome the problems of uncertain data in complex systems. We used the membership function of fuzzy c-means (FCM) to initialize the parameters of possibilistic c means (PCM), in order to solve the problem of coinciding clusters that are generated by PCM and also overcome the weakness of FCM to noise. To validate our approach, we used several validity indexes and we compared them with other conventional classification algorithms: fuzzy c-means, possibilistic c-means, and possibilistic fuzzy c-means. The experiments were realized on different synthetics data sets and real brain MR images. PMID- 24489536 TI - Effect of Narrow Band Ultraviolet B Therapy versus Methotrexate on Serum Levels of Interleukin-17 and Interleukin-23 in Egyptian Patients with Severe Psoriasis. AB - Background. There is raised interest in the involvement of interleukin-(IL-)23/T helper 17 cells (Th17) axis in the pathogenesis of psoriasis. Objectives. To compare the effect of narrow band ultraviolet B (NB-UVB) and methotrexate (MTX) therapy on serum levels of IL-17 and IL-23 in psoriatic patients. Methods. Thirty patients with severe plaque psoriasis were included: 15 patients received NB-UVB three times weekly (group I) and 15 patients received MTX 0.3 mg/kg per week (group II), both for 8 weeks. Before and after treatment, serum levels of IL-17 and IL-23 were investigated by ELISA technique and psoriasis area and severity index (PASI) was calculated. Results. After treatment, all patients showed a reduction in their PASI score, IL-17 and IL-23 serum levels with a nonsignificant difference between both therapeutic modalities (P value >0.05). A positive correlation was detected between the percent of reduction of IL-17, IL-23 and the percent of reduction of PASI score for patients receiving both treatments. No correlation was found between the percent of reduction of IL-17, IL-23 and duration of disease or age of all patients in this study. Conclusion. Interleukin 17 and IL-23 serum level may serve as a potential biomarker for predicting the prognosis and therapeutic response of NB-UVB or MTX in treating psoriasis. PMID- 24489537 TI - Polydeoxyribonucleotide Dermal Infiltration in Male Genital Lichen Sclerosus: Adjuvant Effects during Topical Therapy. AB - Background. Lichen sclerosus (LS) is an autoimmune inflammatory skin disease that leads to tissue sclerosis. Actually, the first-line treatment consists of local steroid as clobetasol propionate (CP). Polydeoxyribonucleotide (PDRN) has demonstrated anti-inflammatory effects through the reduction of cytokine production and growth stimulation of fibroblast. Objective. To evaluate the efficacy of intradermal administration of PDRN in male patients suffering from genital lichen sclerosus in addition to topical 0.05% CP, as compared to administering 0.05% CP without PDRN injection. Patients/Methods. A group of male patients (n = 28; aged 25 to 65) suffering from LS were observed during topical therapy or subdermal in addition to topical therapy. Disease activity at baseline was evaluated on Investigator's Global Assessment (IGA) and the Dermatology Life Quality Index (DLQI). We used polydeoxyribonucleotide in a commercial preparation for human use and a topical CP emulsion. Results. After therapy, in all group A patients there has been a regression of most of clinical pathological signs, while there has been a moderate improvement in all group B patients. Conclusions. On site intradermal administration of PDRN, associated with CP 0.05% cream, seemed to be associated with a clinical improvement of lichen sclerosus better than CP used in single therapy. PMID- 24489538 TI - (99m) T c-DTPA Study to Validate an Experimental Model of Ureteral Obstruction in Rabbits: Preliminary Results. AB - Objective. To create a ureteral obstruction experimental model that can be proved through (99m)Tc-DTPA renal scintigraphy and histopathological studies, without causing total renal function loss. Materials and Methods. Ten New Zealand white rabbits were submitted to a surgical experiment to create a model of unilateral obstruction to urinary flow. Surgery procedure provided unilateral ureteral obstruction (left kidney) to urinary flow and posteriorly was evaluated by (99m)Tc-DTPA renal scintigraphy and histopathological study. (99m)Tc-DTPA renal study was performed to detect and quantify signs of obstruction and to evaluate renal function. Statistical analysis was performed through the Student t-test with a significance level of P<0.05. Results. Nine of the ten rabbits presented left renal unit obstruction and one nonobstructive on the (99m)Tc-DTPA and histopathological studies. All the right renal units, which were not submitted to surgical procedure, were nonobstructed by the studies. There was a general agreement between scintigraphy and histopathological results in both groups. Conclusion. The experimental model promoted the creation of ureteral obstruction in rabbits, confirmed by nuclear medicine scintigraphy and histopathology, and could be used in further studies to better understand urinary obstruction. PMID- 24489539 TI - Effects of a behavioral program on exercise adherence and exercise self-efficacy in community-dwelling older persons. AB - Background. This study determines the effects of a behavioral program on exercise adherence (step counts) and level of exercise self-efficacy (ESE) in community dwelling older persons. Methods. Sixty-three participants (age = 63.8 +/- 4.5 years) were enrolled in this controlled quasi-experimental study. They were divided into 3 groups: (1) EBG performed a 6-week exercise intervention followed by a 5-week behavioral program, (2) EG performed exercise intervention similar to EBG, and (3) control group (CG) did not receive any interventions. Step counts were measured based on the scores recorded by a pedometer while ESE was measured by a self-reported ESE scale. Results. Data analysis showed significant differences due to time effect (F(1,2) = 39.884, P < 0.01, and eta = .399); time and group interactions (F(2,60) = 112.683, P < 0.01, and eta = .790); and between group effect (F(2,60) = 12.524, P < 0.01, and eta = .295) for step counts. As for ESE, significant differences were also found for time effect (F(2,4) = 66.628, P < 0.05, and eta = .526); time and group interactions (F(2,60) = 4.562, P = 0.014, and eta = .132); and between-group effect (F(2,60) = 13.632, P < 0.05, and eta = .312). EBG presented with significantly higher mean changes for both step counts and ESE compared to other groups (all P < 0.05). Conclusion. This study suggests that the addition of a behavioral program is superior as compared to exercising alone on increasing exercise adherence and level of self-efficacy in older persons. PMID- 24489540 TI - Control of a Clonal Outbreak of Multidrug-Resistant Acinetobacter baumannii in a Hospital of the Basque Country after the Introduction of Environmental Cleaning Led by the Systematic Sampling from Environmental Objects. AB - Background. Between July 2009 and September 2010, an outbreak of multidrug resistant (MDR) Acinetobacter baumannii was detected in one critical care unit of a tertiary hospital in the Basque Country, involving 49 infected and 16 colonized patients. The aim was to evaluate the impact of environmental cleaning and systematic sampling from environmental objects on the risk of infection by MDR A. baumannii. Methods. After systematic sampling from environmental objects and molecular typing of all new MDR A. baumannii strains from patients and environmental isolates, we analyzed the correlation (Pearson's r) between new infected cases and positive environmental samples. The risk ratio (RR) of infection was estimated with Poisson regression. Results. The risk increased significantly with the number of positive samples in common areas (RR = 1.40; 95%CI = 0.99-1.94) and positive samples in boxes (RR = 1.19; 95%CI = 1.01-1.40). The number of cases also positively correlated with positive samples in boxes (r = 0.50; P < 0.05) and common areas (r = 0.29; P = 0.18). Conclusion. Once conventional measures have failed, environmental cleaning, guided by systematic sampling from environmental objects, provided the objective risk reduction of new cases and enabled the full control of the outbreak. PMID- 24489541 TI - Obesity-related metabolic syndrome and vascular complications. PMID- 24489543 TI - Prognosis of multifocal papillary thyroid carcinoma. AB - This study was to investigate the clinical features and therapeutic outcomes of multifocal papillary thyroid microcarcinoma (PTMC). A total of 2,418 papillary thyroid carcinoma (PTC) patients had undergone thyroidectomy in one medical center between 1977 and 2010. There were 483 (20.0%) diagnosed with multifocal PTC. The percentage of multifocal PTC was higher in PTMC patients (22.0%) than in non-PTMC patients (19.5%). Demographic and clinical characteristics of PTMC and multifocal PTC in PTC patients were traced. Multifocal PTC patients presented with smaller tumors at an older age, and a higher percentage underwent total or complete thyroidectomy. These patients also showed a higher incidence of postoperative disease progression than did unifocal PTC patients. Comparison of 483 patients with multifocal PTMC and non-PTMC tumors showed a higher incidence of postoperative disease progression in patients with non-PTMC; otherwise, there was no statistical difference in disease-specific and total mortality between these two groups. In conclusion, the incidence of multifocal PTMC was not lower than that of non-PTMC, and postoperative therapies were necessary for both multifocal PTMC and non-PTMC patients. PMID- 24489542 TI - Negative effects of high glucose exposure in human gonadotropin-releasing hormone neurons. AB - Metabolic disorders are often associated with male hypogonadotropic hypogonadism, suggesting that hypothalamic defects involving GnRH neurons may impair the reproductive function. Among metabolic factors hyperglycemia has been implicated in the control of the reproductive axis at central level, both in humans and in animal models. To date, little is known about the direct effects of pathological high glucose concentrations on human GnRH neurons. In this study, we investigated the high glucose effects in the human GnRH-secreting FNC-B4 cells. Gene expression profiling by qRT-PCR, confirmed that FNC-B4 cells express GnRH and several genes relevant for GnRH neuron function (KISS1R, KISS1, sex steroid and leptin receptors, FGFR1, neuropilin 2, and semaphorins), along with glucose transporters (GLUT1, GLUT3, and GLUT4). High glucose exposure (22 mM; 40 mM) significantly reduced gene and protein expression of GnRH, KISS1R, KISS1, and leptin receptor, as compared to normal glucose (5 mM). Consistent with previous studies, leptin treatment significantly induced GnRH mRNA expression at 5 mM glucose, but not in the presence of high glucose concentrations. In conclusion, our findings demonstrate a deleterious direct contribution of high glucose on human GnRH neurons, thus providing new insights into pathogenic mechanisms linking metabolic disorders to reproductive dysfunctions. PMID- 24489544 TI - Detection of TP53 R249 Mutation in Iranian Patients with Pancreatic Cancer. AB - The TP53 gene encodes tumor protein p53 which play a major role in the etiology of pancreatic cancer. The important role of codon 249 of TP53 for binding of p53 to its sequence-specific consensus site in DNA has been revealed by crystallography's studies, and mutation at this codon was detected in the plasma of some human cancers. The TP53 Mut assessor software within the International Agency for Research on Cancer (IARC) TP53 Database was performed to evaluate every possible mutation at codon 249. DNA was extracted from the plasma of 133 pancreatic cancer patients and 85 noncancer-bearing individuals. Exon 7 in TP53 was amplified, and mutation at R249 was identified by the endonuclease cleavage of HaeIII. The group of patients showed a frequency of 11% (22 of 133 samples) R249 mutation compared to 3.5% (3 of 85 samples) in the group of control which was significant (P = 0.03). This mutation demonstrated statistically significant association with pancreatic cancer risk in unadjusted odds ratio (OR: 3.74, 95% CI: 1.1-13.2; P = 0.041); however when adjusted for confounding factors, it was marginally significant because of lower control samples. These findings demonstrate that mutation at R249 of TP53 can be considered for increasing risk of pancreatic cancer that needs more research. PMID- 24489545 TI - Cancer Incidence and Mortality in a Cohort of US Blood Donors: A 20-Year Study. AB - Blood donors are considered one of the healthiest populations. This study describes the epidemiology of cancer in a cohort of blood donors up to 20 years after blood donation. Records from donors who participated in the Retroviral Epidemiology Donor Study (REDS, 1991-2002) at Blood Centers of the Pacific (BCP), San Francisco, were linked to the California Cancer Registry (CCR, 1991-2010). Standardized incidence ratios (SIR) were estimated using standard US 2000 population, and survival analysis used to compare all-cause mortality among donors and a random sample of nondonors with cancer from CCR. Of 55,158 eligible allogeneic blood donors followed-up for 863,902 person-years, 4,236 (7.7%) primary malignant cancers were diagnosed. SIR in donors was 1.59 (95% CI = 1.54,1.64). Donors had significantly lower mortality (adjusted HR = 0.70, 95% CI = 0.66-0.74) compared with nondonor cancer patients, except for respiratory system cancers (adjusted HR = 0.93, 95% CI = 0.82-1.05). Elevated cancer incidence among blood donors may reflect higher diagnosis rates due to health seeking behavior and cancer screening in donors. A "healthy donor effect" on mortality following cancer diagnosis was demonstrated. This population-based database and sample repository of blood donors with long-term monitoring of cancer incidence provides the opportunity for future analyses of genetic and other biomarkers of cancer. PMID- 24489547 TI - Clinically Significant Minor Blood Group Antigens amongst North Indian Donor Population. AB - Background. Racial differences in blood group antigen distribution are common and may result in striking and interesting findings. These differences in blood group antigen distribution are important due to their influence on the clinical practice of transfusion medicine. Study Design and Methods. This is a prospective study, involving 1000 healthy regular repeat voluntary blood donors associated with the department. The clinically significant minor blood group antigens of these donors were studied. Results. Out of 1000 healthy regular repeat voluntary blood donors, 93% were D positive and 2.8% were K positive. Amongst the Rh antigens, e was the most common (99%), followed by D (93%), C (85.1%), c (62.3%), and E (21.5%). Within the MNS blood group system, antigen frequency was M (88%), N (57.5%), S (57.8%), and s (87.5%). Within the Duffy blood group system, antigen frequency was Fy(a) (87.3%) and Fy(b) (58.3%). Conclusions. This data base will help us to prevent alloimmunisation in young females, pregnant women, and patients who are expected to require repeated transfusions in life by providing them with antigen matched blood. Antigen negative blood can also be made available without delay to already alloimmunized multitransfused patients. PMID- 24489546 TI - Missing links in antibody assembly control. AB - Fidelity of the humoral immune response requires that quiescent B lymphocytes display membrane bound immunoglobulin M (IgM) on B lymphocytes surface as part of the B cell receptor, whose function is to recognize an antigen. At the same time B lymphocytes should not secrete IgM until recognition of the antigen has occurred. The heavy chains of the secretory IgM have a C-terminal tail with a cysteine instead of a membrane anchor, which serves to covalently link the IgM subunits by disulfide bonds to form "pentamers" or "hexamers." By virtue of the same cysteine, unassembled secretory IgM subunits are recognized and retained (via mixed disulfide bonds) by members of the protein disulfide isomerase family, in particular ERp44. This so-called "thiol-mediated retention" bars assembly intermediates from prematurely leaving the cell and thereby exerts quality control on the humoral immune response. In this essay we discuss recent findings on how ERp44 governs such assembly control in a pH-dependent manner, shuttling between the cisGolgi and endoplasmic reticulum, and finally on how pERp1/MZB1, possibly as a co-chaperone of GRP94, may help to overrule the thiol-mediated retention in the activated B cell to give way to antibody secretion. PMID- 24489548 TI - Taxonomy and Polyphasic Characterization of Alkaline Amylase Producing Marine Actinomycete Streptomyces rochei BTSS 1001. AB - Actinomycetes isolated from marine sediments along the southeast coast of Bay of Bengal were investigated for amylolytic activity. Marine actinomycete BTSS 1001 producing an alkaline amylase was identified from marine sediment of Diviseema coast, Bay of Bengal. The isolate produced alkaline amylase with maximum amylolytic activity at pH 9.5 at 50 degrees C. The organism produced white to pale grey substrate mycelium and grayish aerial mycelium with pinkish brown pigmentation. A comprehensive study of morphological, physiological parameters, cultural characteristics, and biochemical studies was performed. The presence of iso-C15 : 0, anteiso-C15 : 0, iso-C16 : 0, and anteiso-C17 : 0 as the major cellular fatty acids, LL-diaminopimelic acid as the characteristic cell wall component, and menaquinones MK-9H(6) and MK-9H(8) as the major isoprenoid quinones is attributed to the strain BTSS 1001 belonging to the genus Streptomyces. Comparison of 16S rRNA gene sequences showed that strain BTSS 1001 exhibited the highest similarities to the type strains of Streptomyces rochei (99%), Streptomyces plicatus (99%), and Streptomyces enissocaesilis (99%). Using the polyphasic taxonomical approach and phenotypic characteristic studies, the isolate BTSS 1001 was characterized as marine actinomycete Streptomyces rochei. PMID- 24489549 TI - Biofilm Formation among Clinical and Food Isolates of Listeria monocytogenes. AB - Objective. A total of 725 Listeria monocytogenes isolates, 607 from various foods and 118 from clinical cases of listeriosis, were investigated concerning their ability to form biofilms, at 4 degrees C during 5 days and at 37 degrees C during 24 h. Methods. Biofilm production was carried out on polystyrene tissue culture plates. Five L. monocytogenes isolates were tested for biofilm formation after being exposed to acidic and osmotic stress conditions. Results. Significant differences (P < 0.01) between clinical and food isolates were observed. At 37 degrees C for 24 h, most food isolates were classified as weak or moderate biofilm formers whereas all the clinical isolates were biofilm producers, although the majority were weak. At 4 degrees C during 5 days, 65 and 59% isolates, from food and clinical cases, respectively, were classified as weak. After both sublethal stresses, at 37 degrees C just one of the five isolates tested was shown to be more sensitive to subsequent acidic exposure. However, at 4 degrees C both stresses did not confer either sensitivity or resistance. Conclusions. Significant differences between isolates origin, temperature, and sublethal acidic stress were observed concerning the ability to form biofilms. Strain, origin, and environmental conditions can determine the level of biofilm production by L. monocytogenes isolates. PMID- 24489550 TI - Prospective Zinc Solubilising Bacteria for Enhanced Nutrient Uptake and Growth Promotion in Maize (Zea mays L.). AB - Zinc (Zn) is one of the essential micronutrients required for optimum plant growth. Substantial quantity of applied inorganic zinc in soil is converted into unavailable form. Zinc solubilising bacteria are potential alternates for zinc supplement. Among 10 strains screened for Zn solubilisation, P29, P33, and B40 produced 22.0 mm clear haloes on solid medium amended with ZnCO3. Similarly, P17 and B40 showed 31.0 mm zone in ZnO incorporated medium. P29 and B40 showed significant release of Zn in broth amended with ZnCO3 (17 and 16.8 ppm) and ZnO (18 and 17 ppm), respectively. The pH of the broth was almost acidic in all the cases ranging from 3.9 to 6.1 in ZnCO3 and from 4.1 to 6.4 in ZnO added medium. Short term pot culture experiment with maize revealed that seed bacterization with P29 @ 10 g.kg(-1) significantly enhanced total dry mass (12.96 g) and uptake of N (2.268%), K (2.0%), Mn (60 ppm), and Zn (278.8 ppm). PMID- 24489552 TI - Anti-HPA-1b Mediated Posttransfusion Purpura: A Case Report. AB - Posttransfusion purpura (PTP) is an uncommon, but potentially fatal, transfusion reaction characterized by profound thrombocytopenia and bleeding. PTP is caused by alloimmunization to human platelet specific antigens following blood component transfusion. Although there is evidence of a wide serological spectrum of culprit antibodies implicated, Anti-human-platelet-antigen- (HPA-) 1a is the most common antibody in cases reported. We report a case of posttransfusion purpura in an African American. The patient was negative for HPA-1a antibodies, but anti-HPA-1b was identified with a platelet phenotype of HPA-1a/HPA-1a. Although less common, HPA-1b antibody may be an important consideration in posttransfusion purpura diagnosed in patients of African descent. PMID- 24489553 TI - Missed lung cancers on the scout view: do we look every time? AB - Scout views are digital radiographs obtained to aid planning of the subsequent computed tomography (CT) examination. Review of these scout views may provide additional information not demonstrated on the axial images, but such reviews may not necessarily be performed routinely, especially in the context of abdominopelvic CT studies. We illustrate the value of the scout images by presenting a series of representative cases of missed pulmonary neoplasms in five patients who originally underwent such examinations. PMID- 24489551 TI - Contemporary clinical management of the cerebral complications of preeclampsia. AB - The neurological complications of preeclampsia and eclampsia are responsible for a major proportion of the morbidity and mortality arising from these conditions, for women and their infants alike. This paper outlines the evidence base for contemporary management principles pertaining to the neurological sequelae of preeclampsia, primarily from the maternal perspective, but with consideration of fetal and neonatal aspects as well. It concludes with a discussion regarding future directions in the management of this potentially lethal condition. PMID- 24489554 TI - PEComa: A Perivascular Epithelioid Cell Tumor in the Liver-A Case Report and Review of the Literature. AB - Perivascular epithelioid cell tumors are soft tissue tumors that can occur in various locations in the body whose incidence is rising. Hepatic PEComas are quite rare and diagnosis involves positivity of Melan-A and HMB45 on immunohistochemistry. Usual treatment is surgery for benign tumors and chemotherapy including mTOR inhibitors for malignant tumors. Here we discuss the radiological and pathological diagnosis, evaluation, and management of a hepatic PEComa. We describe a 51-year-old patient who was diagnosed incidentally after unusual physical exam findings. PMID- 24489555 TI - Spontaneous rapid resolution of acute epidural hematoma in childhood. AB - Acute epidural hematoma is a critical emergency all around the world, and its aggressive diagnosis and treatment are of vital importance. Emergent surgical evacuation of the hematoma is known as standard management; however, conservative procedures are also used for small ones. Spontaneous rapid resolution of these hematomas has also been reported in eight pediatric cases. Various theories have been proposed to explain the underlying pathophysiology of this resolution. Herein, we are reporting a new pediatric case with spontaneously resolving acute epidural hematoma 12 hours after admission to the emergency room. PMID- 24489556 TI - 10 years later... PMID- 24489557 TI - New vaccines - which ones should we choose? PMID- 24489558 TI - Respiratory infection and otitis media visits in relation to pneumococcal conjugate vaccine use in Saskatchewan. AB - BACKGROUND: In Saskatchewan, pneumococcal conjugate vaccination (PCV) was offered to high-risk children in 2002 and to all infants in 2005. OBJECTIVE: To describe trends in the frequency of medical visits for lower respiratory tract infection (LRI) and otitis media (OM) in relation to PCV use during the period 1990 to 2008. METHODS: Statistics regarding the number of children covered by the health insurance plan, PCV administration, and medical visits with a diagnostic code associated with LRI and OM were provided by Saskatchewan Health. Monthly rates were analyzed using dynamic state space models. RESULTS: In all series, there was a marked seasonal cycle and some higher-than-expected winter peak values, possibly associated with epidemics of specific respiratory viruses. Three abrupt decreases in baseline rate were observed for LRI and the final one, in February 2007, could be related to the increased proportion of children vaccinated with PCV. There was no statistical correlation between PCV use and OM visit frequency. CONCLUSION: Many environmental, biological and administrative factors may influence health services use, and an effect of low magnitude of a particular vaccine pertaining to nonspecific outcomes could be obscured in time-series analyses. PMID- 24489559 TI - Reduction of central line-associated bloodstream infection rates in a neonatal intensive care unit after implementation of a multidisciplinary evidence-based quality improvement collaborative: A four-year surveillance. AB - BACKGROUND: The use of central venous catheters has permitted lifesaving treatment for critically ill neonates; however, the attributable mortality rate for central line-associated bloodstream infections (CLABSIs) has been estimated to be between 4% and 20%. In 2006/2007, the authors' neonatal intensive care unit (NICU) had a CLABSI rate that was nearly twofold higher than that reported by other Canadian NICUs. OBJECTIVE: To implement a quality improvement collaborative to reduce the incidence of neonatal CLABSI. METHODS: A retrospective observational study was performed to compare CLABSI in neonates admitted to the authors' level III NICU between August 2007 and March 2011. The entire study period was divided into four time periods to evaluate secular trends. A comprehensive catheter-related bloodstream infection prevention initiative was implemented in August 2007. The initiatives included staff education, standardization of skin preparation protocol, introduction of new antiseptic agents, implementation of central catheter insertion and maintenance checklists, reinforcement of the use of maximal sterile barrier precautions, and revision of the central catheter configuration and maintenance protocols. RESULTS: The median CLABSI rate of 7.9 per 1000 catheter days at the beginning of the study (period 1 [August 2007 to June 2008]) gradually decreased over the entire study period (P=0.034): period 2 (July 2008 to May 2009), 3.3 per 1000 catheter days; period 3 (June 2009 to April 2010), 2.6 per 1000 catheter days; and period 4 (May 2010 to March 2011), 2.2 per 1000 catheter days. CONCLUSION: A multidisciplinary evidence based quality improvement collaborative resulted in a significant reduction in the CLABSI rate. Continuous quality improvement measures are required to reduce catheter-related bloodstream infections among low-birth-weight infants. PMID- 24489560 TI - Evaluation of MALDI-TOF mass spectrometry and Sepsityper KitTM for the direct identification of organisms from sterile body fluids in a Canadian pediatric hospital. AB - Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) can be used to identify bacteria directly from positive blood and sterile fluid cultures. The authors evaluated a commercially available kit - the Sepsityper Kit (Bruker Daltonik, Germany) - and MALDI-TOF MS for the rapid identification of organisms from 80 flagged positive blood culture broths, of which 73 (91.2%) were blood culture specimens and seven (8.7%) were cerebrospinal fluid specimens, in comparison with conventional identification methods. Correct identification to the genus and species levels was obtained in 75 of 80 (93.8%) and 39 of 50 (78%) blood culture broths, respectively. Applying the blood culture analysis module, a newly developed software tool, improved the species identification of Gram-negative organisms from 94.7% to 100% and of Gram-positive organisms from 66.7% to 70%. MALDI-TOF MS is a promising tool for the direct identification of organisms cultured from sterile sites. PMID- 24489561 TI - Influenza immunization practices and policies for health care students in Canada. AB - BACKGROUND: Influenza vaccine is recommended for all health care providers including health care students. Little is known about how health care student programs provide information about influenza vaccination to their students, deliver vaccines and document their vaccination status. METHODS: A mixed-methods approach was used and included key informant interviews of program coordinators for health care student programs in Halifax (Nova Scotia) and a national survey of program coordinators of health care student programs across Canada. RESULTS: All 21 coordinators of programs that had students placed at the IWK Health Centre (Halifax, Nova Scotia) during the influenza season were interviewed. Surveys were completed by 93 (36.3%) of 256 eligible coordinators representing 134 different programs (response rate 52.3%). Most programs encouraged seasonal influenza vaccination but only 28 (20.9%) required it. None of the Halifax programs delivered influenza vaccine and most preferred a coordinated, centrally administered program. In contrast, many programs across Canada delivered influenza vaccine and did not desire a centralized process. CONCLUSION: There is considerable variability in the delivery of influenza vaccine to health care students across Canada. Coordinated programs may be desirable where delivery programs do not already exist. PMID- 24489562 TI - HIV-1 tropism testing and clinical management of CCR5 antagonists: Quebec review and recommendations. AB - HIV-1 tropism assays play a crucial role in determining the response to CCR5 receptor antagonists. Initially, phenotypic tests were used, but limited access to these tests prompted the development of alternative strategies. Recently, genotyping tropism has been validated using a Canadian technology in clinical trials investigating the use of maraviroc in both experienced and treatment-naive patients. The present guidelines review the evidence supporting the use of genotypic assays and provide recommendations regarding tropism testing in daily clinical management. PMID- 24489563 TI - 'Bobo-Newton syndrome': An unwanted gift from man's best friend. AB - Capnocytophaga canimorsus is a facultative Gram-negative bacillus that is typically a constituent of the oral flora of dogs and cats. It was first isolated by Bobo and Newton in 1976 from a man presenting with meningitis following a dog bite. Transmission to humans follows various animal-related injuries, which may be gross or subtle. C canimorsus can cause a spectrum of syndromes ranging from skin and soft tissue infection to invasive disease such as meningitis or endocarditis. The present article reports a case of C canimorsus meningitis in a patient with the classic risk factor of alcoholic liver cirrhosis. Clinical suspicion was confirmed by culture and genetic identification of the blood isolate. The present article reviews the Capnocytophaga genus, the clinical syndromes most commonly associated with this zoonotic organism, its laboratory identification and treatment. PMID- 24489564 TI - Artemisinin combination therapy can result in clinical failure if oral therapy is not directly observed. AB - Intravenous artesunate therapy is the first-line therapy for severe malaria, and is highly efficacious when used in combination with an oral partner drug such as doxycycline or atovaquone-proguanil. However, treatment failure occurs routinely with artesunate monotherapy due to the very short half-life of this drug. In North America, experience with artesunate is limited. With the pressure to discharge patients early, administration of the essential oral partner drug is often left to the discretion of the patient. Thus, treatment failure may be commonplace if nonadherence is a factor, as was observed in the case described in the present report. PMID- 24489566 TI - Letter to the editor. PMID- 24489568 TI - Comparison of clinical and epidemiological features of Shiga toxin-producing Escherichia coli O157 and non-O157 infections in British Columbia, 2009 to 2011. AB - INTRODUCTION: Shiga toxin-producing Escherichia coli (STEC) are major foodborne agents that have the potential to cause severe enteric illnesses and large outbreaks worldwide. Several studies found non-O157 infections to be clinically milder than O157 STEC infections. OBJECTIVE: To compare the clinical and epidemiological profiles of O157 and non-O157 STEC human infections in British Columbia (BC). METHODS: All STEC cases reported in BC from 2009 to 2011 by four local health authorities were included in the study. Cases were classified according to STEC serotype based on laboratory information. Information was gathered via case interview forms. Data analysis included the chi(2) test and Mann-Whitney test; P<0.05 was considered to be statistically significant. RESULTS: A total of 260 STEC cases were reported, including 154 (59.2%) O157 cases, 63 (24.2%) non-O157 cases and 43 (16.5%) STEC cases with no serotype identified. Hospitalization rate was higher and duration of hospitalization was significantly longer for O157 cases compared with non-O157 cases, but other clinical features were not significantly different. Patients with non-O157 infections were significantly more likely to have travelled outside Canada, less likely to report food exposure at social gatherings and more likely to consume bagged greens and cheese. DISCUSSION: O157 is the predominant O serotype in BC and appeared to be more clinically severe than non-O157 STEC infections. However, the true incidence and severity of non-O157 remain unknown due to our current inability to detect all non-O157 cases. The present study and the literature suggest the need to identify more predictive virulence factors because serotype does not consistently predict disease severity. PMID- 24489565 TI - CIHR Canadian HIV Trials Network Coinfection and Concurrent Diseases Core: Canadian guidelines for management and treatment of HIV/hepatitis C coinfection in adults. AB - BACKGROUND: Hepatitis C virus (HCV) coinfection occurs in 20% to 30% of Canadians living with HIV, and is responsible for a heavy burden of morbidity and mortality. HIV-HCV management is more complex due to the accelerated progression of liver disease, the timing and nature of antiretroviral and HCV therapy, mental health and addictions management, socioeconomic obstacles and drug-drug interactions between new HCV direct-acting antiviral therapies and antiretroviral regimens. OBJECTIVE: To develop national standards for the management of HCV-HIV coinfected adults in the Canadian context. METHODS: A panel with specific clinical expertise in HIV-HCV co-infection was convened by The CIHR HIV Trials Network to review current literature, existing guidelines and protocols. Following broad solicitation for input, consensus recommendations were approved by the working group, and were characterized using a Class (benefit verses harm) and Level (strength of certainty) quality-of-evidence scale. RESULTS: All HIV-HCV coinfected individuals should be assessed for HCV therapy. Individuals unable to initiate HCV therapy should initiate antiretroviral therapy to slow liver disease progression. Standard of care for genotype 1 is pegylated interferon and weight based ribavirin dosing plus an HCV protease inhibitor; traditional dual therapy for 24 weeks (for genotype 2/3 with virological clearance at week 4); or 48 weeks (for genotypes 2-6). Therapy deferral for individuals with mild liver disease may be considered. HIV should not be considered a barrier to liver transplantation in coinfected patients. DISCUSSION: Recommendations may not supersede individual clinical judgement. PMID- 24489569 TI - Macrolide use in the treatment of critically ill patients with pneumonia: Incidence, correlates, timing and outcomes. AB - BACKGROUND: Macrolide antibiotics are commonly used to treat pneumonia despite increasing antimicrobial resistance. Evidence suggests that macrolides may also decrease mortality in severe sepsis via immunomodulatory properties. OBJECTIVE: To evaluate the incidence, correlates, timing and mortality associated with macrolide-based treatment. METHODS: A population-based cohort of critically ill adults with pneumonia at five intensive care units in Edmonton, Alberta, was prospectively followed over two years. Data collected included disease severity (Acute Physiology and Chronic Health Evaluation [APACHE] II score), pneumonia severity (Pneumonia Severity Index score), comorbidities, antibiotic treatments at presentation and time to effective antibiotic. The independent association between macrolide-based treatment and 30-day all-cause mortality was examined using multivariable Cox regression. A secondary exploratory analysis examined time to effective antimicrobial therapy. RESULTS: The cohort included 328 patients with a mean Pneumonia Severity Index score of 116 and a mean APACHE II score of 17; 84% required invasive mechanical ventilation. Ninety-one (28%) patients received macrolide-based treatments, with no significant correlates of treatment except nursing home residence (15% versus 30% for nonresidents [P=0.02]). Overall mortality was 54 of 328 (16%) at 30 days: 14 of 91 (15%) among patients treated with macrolides versus 40 of 237 (17%) for nonmacrolides (adjusted HR 0.93 [95% CI 0.50 to 1.74]; P=0.8). Patients who received effective antibiotics within 4 h of presentation were less likely to die than those whose treatment was delayed (14% versus 17%; adjusted HR 0.50 [95% CI 0.27 to 0.94]; P=0.03). CONCLUSIONS: Macrolide-based treatment was not associated with lower 30 day mortality among critically ill patients with pneumonia, although receipt of effective antibiotic within 4 h was strongly predictive of survival. Based on these results, timely effective treatment may be more important than choice of antibiotics. PMID- 24489570 TI - Evaluation of MRSASelect (TM) chromogenic medium for the early detection of methicillin-resistant Staphylococcus aureus from blood cultures. AB - INTRODUCTION: Staphylococcus aureus bacteremia is associated with considerable morbidity and mortality. In theory, reducing the turnaround time in reporting of methicillin-resistant S aureus (MRSA) among patients with bactermia could assist with the rapid optimization of antimicrobial therapy. OBJECTIVE: To evaluate the sensitivity and specificity of MRSASelect (Bio-Rad Laboratories, USA), a chromogenic medium, in the early detection of MRSA from blood cultures growing Gram-positive cocci in clusters, and to confirm that routine use of this medium would, in fact, reduce turnaround time for MRSA identification. METHODS: The present study was conducted at three microbiology laboratories in Manitoba. Between April 2010 and May 2011, positive blood cultures with Gram-positive cocci in clusters visualized on Gram stain were subcultured to both MRSASelect and routine media. MRSA isolates were identified using conventional microbiological methods from routine media and using growth with the typical colony morphology (pink colony) on MRSASelect medium. RESULTS: A total of 490 blood cultures demonstrating Gram-positive cocci in clusters on Gram stain were evaluated. S aureus was recovered from 274 blood cultures, with 51 S aureus isolates (51 of 274 [18.6%]) identified as MRSA. MRSASelect medium had a sensitivity of 98%, a specificity of 100%, a positive predictive value of 100% and a negative predictive value of 99.8% for the recovery and identification of MRSA directly from positive blood culture bottles. In addition, use of MRSASelect medium was found to improve turnaround time in the detection of MRSA by almost 24 h relative to conventional methods. DISCUSSION: These data support the utility of MRSASelect medium for the rapid identification of MRSA from positive blood cultures. Further clinical studies are warranted to determine whether the improvement in turnaround time will result in a measurable reduction in suboptimal antimicrobial therapy and/or improvement in patient outcome. PMID- 24489572 TI - Magnetic resonance imaging findings in a case of congenital rubella encephalitis. PMID- 24489571 TI - Prevalence and incidence of antimicrobial-resistant organisms among hospitalized inflammatory bowel disease patients. AB - BACKGROUND: Patients with inflammatory bowel disease (IBD) experience frequent hospitalizations and use of immunosuppressive medications, which may predispose them to colonization with antimicrobial-resistant organisms (ARO). OBJECTIVE: To determine the prevalence of ARO colonization on admission to hospital and the incidence of infection during hospitalization among hospitalized IBD patients. METHODS: A chart review comparing the prevalence of colonization and incidence of infection with methicillin-resistant Staphylococcus aureus, vancomycin-resistant enterococci and extended-spectrum beta-lactamase-producing Enterobacteriaceae (ESBL) in hospitalized IBD patients with those of non-IBD controls was performed. RESULTS: On admission, there were no significant differences between IBD inpatients and controls in the prevalence of colonization of methicillin resistant S aureus (1.0% versus 1.2%; P=0.74), vancomycin-resistant enterococci (0.2% versus 0%; P=1.0) or ESBL (4.1% versus 5.5%; P=0.33). Pooling data from historical clinic-based cohorts, IBD patients were more likely than controls to have ESBL colonization (19% versus 6.6%; P<0.05). Antibiotic use on admission was associated with ESBL colonization among IBD inpatients (OR 4.2 [95% CI 1.4 to 12.6]). The incidence of ARO infections during hospitalization was not significantly different between IBD patients and controls. Among IBD patients who acquired ARO infections during hospitalizations, the mean time interval from admission to infection was shorter for those who were already colonized with ARO on admission. CONCLUSIONS: This particular population of hospitalized IBD patients was not shown to have a higher prevalence or incidence of ARO colonization or infection compared with non-IBD inpatients. PMID- 24489573 TI - Prediction of IL4 inducing peptides. AB - The secretion of Interleukin-4 (IL4) is the characteristic of T-helper 2 responses. IL4 is a cytokine produced by CD4+ T cells in response to helminthes and other extracellular parasites. It has a critical role in guiding antibody class switching, hematopoiesis and inflammation, and the development of appropriate effector T-cell responses. In this study, it is the first time an attempt has been made to understand whether it is possible to predict IL4 inducing peptides. The data set used in this study comprises 904 experimentally validated IL4 inducing and 742 noninducing MHC class II binders. Our analysis revealed that certain types of residues are preferred at certain positions in IL4 inducing peptides. It was also observed that IL4 inducing and noninducing epitopes differ in compositional and motif pattern. Based on our analysis we developed classification models where the hybrid method of amino acid pairs and motif information performed the best with maximum accuracy of 75.76% and MCC of 0.51. These results indicate that it is possible to predict IL4 inducing peptides with reasonable precession. These models would be useful in designing the peptides that may induce desired Th2 response. PMID- 24489574 TI - Immunomodulatory effect of bisphosphonate risedronate sodium on CD163+ arginase 1+ M2 macrophages: the development of a possible supportive therapy for angiosarcoma. AB - An imbalance of immunosuppressive cells and cytotoxic cells plays an important role in inhibiting the antitumor immune response of the tumor-bearing host. We previously reported the profiles of tumor infiltrating leukocytes in cutaneous angiosarcoma (AS) and suggested that a combination of docetaxel (DTX) with bisphosphonate risedronate sodium (RS) might be effective for MMP9-expressing AS by targeting immunosuppressive cells such as M2 macrophages. To further confirm the effect of this combination therapy, in this report we investigated the immunomodulatory effect of DTX and RS on CD163(+) arginase 1 (Arg1)(+) M2 macrophages in vitro. Interestingly, our present study demonstrated that DTX in combination with RS significantly upregulated the mRNA expression of CXCL10 on M2 macrophages and significantly decreased the mRNA expression of CCL17 and Arg1. Moreover, the production of CXCL10 and CXCL11 from M2 macrophages was significantly increased by DTX with RS though there was no effect of DTX with RS on the production of CCL5 and CCL17. Furthermore, DTX with RS significantly decreased the production of CCL18, which was previously reported to correlate with the severity and prognosis in cancer patients. Our present report suggests one of the possible mechanisms of DTX with RS in the supportive therapy for angiosarcoma. PMID- 24489576 TI - Immunology and the central nervous system. PMID- 24489575 TI - Persistence of Th17/Tc17 cell expression upon smoking cessation in mice with cigarette smoke-induced emphysema. AB - Th17 and Tc17 cells may be involved in the pathogenesis of chronic obstructive pulmonary disease (COPD), a disease caused predominantly by cigarette smoking. Smoking cessation is the only intervention in the management of COPD. However, even after cessation, the airway inflammation may be present. In the current study, mice were exposed to room air or cigarette smoke for 24 weeks or 24 weeks followed by 12 weeks of cessation. Morphological changes were evaluated by mean linear intercepts (Lm) and destructive index (DI). The frequencies of CD8(+)IL 17(+)(Tc17) and CD4(+)IL-17(+)(Th17) cells, the mRNA levels of ROR gamma and IL 17, and the levels of IL-8, TNF-alpha, and IFN-gamma in lungs or bronchoalveolar lavage fluid of mice were assayed. Here we demonstrated that alveolar enlargement and destruction induced by cigarette smoke exposure were irreversible and that cigarette smokeenhanced these T-cell subsets, and related cytokines were not significantly reduced after smoking cessation. In addition, the frequencies of Th17 and Tc17 cells in lungs of smoke-exposed mice and cessation mice were positively correlated with emphysematous lesions. More important, the frequencies of Tc17 cells were much higher than Th17 cells, and there was a significantly positive correlation between Th17 and Tc17. These results suggested that Th17/Tc17 infiltration in lungs may play a critical role in sustaining lung inflammation in emphysema. Blocking the abnormally increased numbers of Tc17 and Th17 cells may be a reasonable therapeutic strategy for emphysema. PMID- 24489577 TI - The role of cytokines in the functional activity of phagocytes in blood and colostrum of diabetic mothers. AB - Immune response changes induced by diabetes are a risk factor for infections during pregnancy and may modify the development of the newborn's immune system. The present study analyzed colostrum and maternal and cord blood of diabetic women to determine (1) the levels of the cytokines IFN- gamma and TGF- beta and (2) phagocytic activity after incubation with cytokines. Methods. Colostrum and maternal and cord blood samples were classified into normoglycemic (N = 20) and diabetic (N = 19) groups. Cytokine levels, superoxide release, rate of phagocytosis, bactericidal activity, and intracellular Ca(2+) release by phagocytes were analyzed in the samples. Irrespective of glycemic status, IFN- gamma and TGF- beta levels were not changed in colostrum and maternal and cord blood. In maternal blood and colostrum, superoxide release by cytokine-stimulated phagocytes was similar between the groups. Compared to spontaneous release, superoxide release was stimulated by IFN- gamma and TGF- beta in normoglycemic and diabetic groups. In the diabetic group, cord blood phagocytes incubated with IFN- gamma exhibited higher phagocytic activity in response to EPEC, and maternal blood exhibited lower microbicidal activity. These data suggest that diabetes interferes in maternal immunological parameters and that IFN- gamma and TGF- beta modulate the functional activity of phagocytes in the colostrum, maternal blood, and cord blood of pregnant diabetic women. PMID- 24489579 TI - Contrasting effects of systemic monocyte/macrophage and CD4+ T cell depletion in a reversible ureteral obstruction mouse model of chronic kidney disease. AB - Using a reversible UUO model (rUUO), we have demonstrated that C57BL/6 mice are susceptible to development of CKD after obstruction-mediated kidney injury while BALB/c mice are resistant. We hypothesized that selective systemic depletion of subpopulations of inflammatory cells during injury or repair might alter the development of CKD. To investigate the impact of modification of Th-lymphocytes or macrophage responses on development of CKD after rUUO, we used an anti-CD4 antibody (GK1.5) or liposomal clodronate to systemically deplete CD4(+) T cells or monocyte/macrophages, respectively, prior to and throughout the rUUO protocol. Flow cytometry and immunohistochemistry confirmed depletion of target cell populations. C57BL/6 mice treated with the GK1.5 antibody to deplete CD4(+) T cells had higher BUN levels and delayed recovery from rUUO. Treatment of C57BL/6 mice with liposomal clodronate to deplete monocyte/macrophages led to a relative protection from CKD as assessed by BUN values. Our results demonstrate that modulation of the inflammatory response during injury and repair altered the susceptibility of C57BL/6 mice to development of CKD in our rUUO model. PMID- 24489580 TI - Innate immunity and the role of the antimicrobial peptide cathelicidin in inflammatory skin disease. AB - Cathelicidin antimicrobial peptide is an important mediator of the innate immune response. In addition to its potent antimicrobial activity, cathelicidin has been shown to have chemoattractant and angiogenic properties. Recent research has demonstrated that, in addition to its aforementioned functions, cathelicidin plays an important role in the complex pathogenesis of several chronic inflammatory skin diseases. This review will present a concise overview of the role of cathelicidin in infection and in the development of atopic dermatitis, psoriasis, and rosacea. This understanding will direct future research efforts to identify therapeutic approaches that use cathelicidin as a novel drug itself, or aim to modify its expression and regulation. PMID- 24489578 TI - Hepatic expression of metallothionein I/II, glycoprotein 96, IL-6, and TGF- beta in rat strains with different susceptibilities to experimental autoimmune encephalomyelitis. AB - In a search of peripheral factors that could be responsible for the discrepancy in susceptibility to EAE in Albino Oxford (AO) and Dark Agouti (DA) rats, we estimated the expression of metallothioneins I/II (MT), heat shock protein-gp96, interleukin (IL)-6, and transforming growth factor (TGF)- beta in the livers of these animals. Rats were immunized with bovine brain homogenate (BBH) emulsified in complete Freund adjuvant (CFA) or only with CFA. Western blot and immunohistochemical analyses were done on day 12 after the immunization, as well as in intact rats. The data have shown that during the first attack of EAE only the EAE prone-DA rats markedly upregulated the hepatic MTs, gp96, IL-6, and TGF- beta . In contrast, AO rats had a significantly higher expression of MT I/II, IL 6, and TGF- beta in intact liver (P < 0,001), suggesting that the greater constitutive expression of these proteins contributed to the resistance of EAE. Besides, since previously we found that AO rats reacted on immunization by an early upregulation of TGF- beta on several hepatic structures (vascular endothelium, Kupffer cells, and hepatocytes), the data suggest that the specific hepatic microenvironment might contribute also to the faster recovery of these rats from EAE. PMID- 24489581 TI - The Association between Yang-Deficient Constitution and Clinical Outcome of Highly Active Antiretroviral Therapy on People Living with HIV. AB - Objective. To determine the association between Yang-Deficient Constitution and the clinical outcomes of HIV/AIDS patients who have initiated highly active antiretroviral therapy (HAART). Method. A total of 197 antiretroviral-naive adults who initiated HAART between 2009 and 2011 were recruited. The participants were asked to complete a questionnaire twice to assess their Yang-Deficient Constitution status before HAART. During the study, signs and symptoms and CD4 or CD8 T cell counts were recorded. Routine blood and biochemical tests were conducted. For the patients who were found to have infections, pathologic examination was performed. Statistical test of association of clinical attributes and demographic factors with Yang-Deficient Constitution was conducted. Result. Good test-retest reliability was observed for Yang-Deficient Constitution scoring. The median Yang-Deficient Constitution score of 142 eligible participants was 25. Female (score = 32.14, P < 0.05), hepatotoxicity (32.14, P < 0.1), nephrotoxicity (37.50, P < 0.1), total number of adverse events (P < 0.1), and mortality (39.29, P < 0.05) were associated with Yang-Deficient Consitution, while annual changes or nadir values of CD4 or CD8 T lymphocytes, and newly acquired infections after starting HAART were not. Mortality was also associated with total number of adverse events (P < 0.05), hepatotoxicity (P < 0.05), and nephrotoxicity (P < 0.05). Conclusion. Yang-Deficient Constitution score has a potential to be developed as a predictor for early HIV-related mortality and side effects. The interrelation and underlying mechanisms should be further investigated for evidence-based design of a more appropriate treatment strategy. PMID- 24489582 TI - Self-care, stress management, and primary care: from salutogenesis and health promotion to mind-body medicine. PMID- 24489583 TI - Spatially Nonlinear Interdependence of Alpha-Oscillatory Neural Networks under Chan Meditation. AB - This paper reports the results of our investigation of the effects of Chan meditation on brain electrophysiological behaviors from the viewpoint of spatially nonlinear interdependence among regional neural networks. Particular emphasis is laid on the alpha-dominated EEG (electroencephalograph). Continuous time wavelet transform was adopted to detect the epochs containing substantial alpha activities. Nonlinear interdependence quantified by similarity index S(X?Y), the influence of source signal Y on sink signal X, was applied to the nonlinear dynamical model in phase space reconstructed from multichannel EEG. Experimental group involved ten experienced Chan-Meditation practitioners, while control group included ten healthy subjects within the same age range, yet, without any meditation experience. Nonlinear interdependence among various cortical regions was explored for five local neural-network regions, frontal, posterior, right-temporal, left-temporal, and central regions. In the experimental group, the inter-regional interaction was evaluated for the brain dynamics under three different stages, at rest (stage R, pre-meditation background recording), in Chan meditation (stage M), and the unique Chakra focusing practice (stage C). Experimental group exhibits stronger interactions among various local neural networks at stages M and C compared with those at stage R. The intergroup comparison demonstrates that Chan-meditation brain possesses better cortical inter-regional interactions than the resting brain of control group. PMID- 24489584 TI - Statistical analysis of hie (cold sensation) and hiesho (cold disorder) in kampo clinic. AB - A cold sensation (hie) is common in Japanese women and is an important treatment target in Kampo medicine. Physicians diagnose patients as having hiesho (cold disorder) when hie disturbs their daily activity. However, differences between hie and hiesho in men and women are not well described. Hie can be of three types depending on body part where patients feel hie. We aimed to clarify the characteristics of patients with hie and hiesho by analyzing data from new patients seen at the Kampo Clinic at Keio University Hospital between 2008 and 2013. We collected information about patients' subjective symptoms and their severity using visual analogue scales. Of 4,016 new patients, 2,344 complained about hie and 524 of those were diagnosed with hiesho. Hie was most common in legs/feet and combined with hands or lower back, rather than the whole body. Almost 30% of patients with hie felt upper body heat symptoms like hot flushes. Cold sensation was stronger in hiesho than non-hiesho patients. Patients with hie had more complaints. Men with hiesho had the same distribution of hie and had symptoms similar to women. The results of our study may increase awareness of hiesho and help doctors treat hie and other symptoms. PMID- 24489585 TI - Triterpenoid Saponins Isolated from Platycodon grandiflorum Inhibit Hepatitis C Virus Replication. AB - Hepatitis C virus (HCV) infection is a major cause of liver disease, including cirrhosis and hepatocellular carcinoma. Due to significant adverse effects and emergence of resistant strains of currently developed anti-HCV agents, plant extracts have been considered to be potential sources of new bioactive compounds against HCV. The aim of this study was to evaluate the functional effects of triterpenoid saponins contained in the root extract of Platycodon grandiflorum (PG) on viral enzyme activities and replication in both HCV replicon cells and cell culture grown HCV- (HCVcc-) infected cells. Inhibitory activities of triterpenoid saponins from PG were verified by NS5B RNA-dependent RNA polymerase assay and were further confirmed in the context of HCV replication. Six triterpenoid saponins (platycodin D, platycodin D2, platycodin D3, deapioplatycodin D, deapioplatycodin D2, and platyconic acid A), PG saponin mixture (PGSM), were identified as active components exerting anti-HCV activity. Importantly, PGSM exerted synergistic anti-HCV activity in combination with either interferon- alpha or NS5A inhibitors. We demonstrated that combinatorial treatment of PGSM and IFN- alpha efficiently suppressed colony formation with significant reduction in drug resistant variant of HCV. These data suggest that triterpenoid saponin may represent a novel anti-HCV therapeutic agent. PMID- 24489586 TI - Marine invertebrate natural products for anti-inflammatory and chronic diseases. AB - The marine environment represents a relatively available source of functional ingredients that can be applied to various aspects of food processing, storage, and fortification. Moreover, numerous marine invertebrates based compounds have biological activities and also interfere with the pathogenesis of diseases. Isolated compounds from marine invertebrates have been shown to pharmacological activities and are helpful for the invention and discovery of bioactive compounds, primarily for deadly diseases like cancer, acquired immunodeficiency syndrome (AIDS), osteoporosis, and so forth. Extensive research within the last decade has revealed that most chronic illnesses such as cancer, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways that have been linked to inflammation. On the basis of their bioactive properties, this review focuses on the potential use of marine invertebrate derived compounds on anti-inflammatory and some chronic diseases such as cardiovascular disease, osteoporosis, diabetes, HIV, and cancer. PMID- 24489587 TI - Effects of Electroacupuncture on PGC-1 alpha Expression in Brown Adipose Tissue. AB - The inducible coactivator PGC-1 alpha plays master regulator in mitochondrial biogenesis and thermogenesis in brown adipose tissues (BATs). BAT is a natural antiobesity organ which dissipates chemical energy in the form of heat through specialized mitochondrial protein UCP-1. Eletroacupuncture (EA) has been widely used as an alternative treatment for obesity and its related disorders such as type 2 diabetes. The molecular mechanism of electroacupuncture on treatment of obesity is still unclear. We hypothesized that electroacupuncture induced PGC-1 alpha expression to increase the energy expenditure in BAT. Rats were randomly divided into control group and electroacupuncture treatment group. We investigated the effects of electroacupuncture at Zusanli (ST36) acupoint on the expressions of PGC-1 alpha and its associated genes in the BAT of rats using real time PCR and western blotting. We found that electroacupuncture effectively induces the expression of PGC-1 alpha and UCP-1 by 4-fold and 5-fold in the BAT of rats, respectively. Our results indicated that the molecular mechanism of electroacupuncture for the treatment of obesity may be, or at least partially, through induction of both PGC-1 alpha and UCP-1 expressions to increase energy expenditure in BAT. PMID- 24489588 TI - Evaluation of a seven-week web-based happiness training to improve psychological well-being, reduce stress, and enhance mindfulness and flourishing: a randomized controlled occupational health study. AB - Background. As distress in society increases, including work environments, individual capacities to compete with stress have to be strengthened. Objective. We examined the impact of a web-based happiness training on psychological and physiological parameters, by self-report and objective means, in an occupational health setting. Methods. Randomized controlled trial with 147 employees. Participants were divided into intervention (happiness training) and control groups (waiting list). The intervention consisted of a seven-week online training. Questionnaires were administered before, after, and four weeks after training. The following scales were included: VAS (happiness and satisfaction), WHO-5 Well-being Index, Stress Warning Signals, Freiburg Mindfulness Inventory, Recovery Experience Questionnaire, and Flourishing Scale. Subgroup samples for saliva cortisol and alpha-amylase determinations were taken, indicating stress, and Attention Network Testing for effects on attention regulation. Results. Happiness (P = 0.000; d = 0.93), satisfaction (P = 0.000; d = 1.17), and quality of life (P = 0.000; d = 1.06) improved; perceived stress was reduced (P = 0.003; d = 0.64); mindfulness (P = 0.006; d = 0.62), flourishing (P = 0.002; d = 0.63), and recovery experience (P = 0.030; d = 0.42) also increased significantly. No significant differences in the Attention Network Tests and saliva results occurred (intergroup), except for one saliva value. Conclusions. The web-based training can be a useful tool for stabilizing health/psychological well-being and work/life balance. PMID- 24489589 TI - Mixed-Methods Research in a Complex Multisite VA Health Services Study: Variations in the Implementation and Characteristics of Chiropractic Services in VA. AB - Maximizing the quality and benefits of newly established chiropractic services represents an important policy and practice goal for the US Department of Veterans Affairs' healthcare system. Understanding the implementation process and characteristics of new chiropractic clinics and the determinants and consequences of these processes and characteristics is a critical first step in guiding quality improvement. This paper reports insights and lessons learned regarding the successful application of mixed methods research approaches-insights derived from a study of chiropractic clinic implementation and characteristics, Variations in the Implementation and Characteristics of Chiropractic Services in VA (VICCS). Challenges and solutions are presented in areas ranging from selection and recruitment of sites and participants to the collection and analysis of varied data sources. The VICCS study illustrates the importance of several factors in successful mixed-methods approaches, including (1) the importance of a formal, fully developed logic model to identify and link data sources, variables, and outcomes of interest to the study's analysis plan and its data collection instruments and codebook and (2) ensuring that data collection methods, including mixed-methods, match study aims. Overall, successful application of a mixed-methods approach requires careful planning, frequent trade offs, and complex coding and analysis. PMID- 24489590 TI - Impact of colored light on cardiorespiratory coordination. AB - Background. Light exposure to the eye can influence different physiological functions, for example, the suprachiasmatic nucleus (SCN). By affecting the autonomic nervous system, the SCN may influence the heart rate variability (HRV). Standardized colored light exposure alters HRV but the results are inconsistent. In this study we investigated the effects of nonstandardized red light (approx. 640 nm) and blue (approx. 480 nm) light (approx. 50 lx) on cardiorespiratory coordination and HRV. Methods. 17 healthy subjects (7 males, age: 26.5 +/- 6.2 years) were exposed to the following sequence (10 minutes each): daylight-red light-daylight-blue light-daylight. Red and blue lights were created by daylight passing through colored glass panes. Spectral measures of HRV (LF: low frequency, HF: high frequency oscillations, and sympathovagal balance LF/HF) and measures of cardiorespiratory coordination (HRR: heart respiration ratio, PCR: phase coordination ratio) were analyzed. Results. The LF component increased and the HF component decreased after red light. Consequently, LF/HF increased after red light. Furthermore, during red light HRR and PCR confined to 4 : 1, that is, 4 heartbeats during one respiratory cycle. Conclusion. Nonstandardized red and blue lights are able to alter the autonomic control reflected by HRV as well as cardiorespiratory coordination. PMID- 24489591 TI - A randomized controlled neurophysiological study of a chinese chan-based mind body intervention in patients with major depressive disorder. AB - Our previous studies have reported the therapeutic effects of 10-session Chinese Chan-based Dejian mind-body interventions (DMBI) in reducing the intake of antidepressants, improving depressive symptoms, and enhancing the attentional abilities of patients with depression. This study aims to explore the possible neuroelectrophysiological mechanisms underlying the previously reported treatment effects of DMBI in comparison with those of cognitive behavioral therapy (CBT). Seventy-five age-, gender-, and education-matched participants with depression were randomly assigned to receive either CBT or DMBI or placed on a waitlist. Eyes-closed resting EEG data were obtained individually before and after 10 weeks. After intervention, the DMBI group demonstrated significantly enhanced frontal alpha asymmetry (an index of positive mood) and intra- and interhemispheric theta coherence in frontoposterior and posterior brain regions (an index of attention). In contrast, neither the CBT nor the waitlist group showed significant changes in EEG activity patterns. Furthermore, the asymmetry and coherence indices of the DMBI group were correlated with self-reported depression severity levels and performance on an attention test, respectively. The present findings provide support for the effects of a Chinese Chan-based mind body intervention in fostering human brain states that can facilitate positive mood and an attentive mind. PMID- 24489592 TI - Andrographolide, a Novel NF- kappa B Inhibitor, Induces Vascular Smooth Muscle Cell Apoptosis via a Ceramide-p47phox-ROS Signaling Cascade. AB - Atherosclerosis is linked with the development of many cardiovascular complications. Abnormal proliferation of vascular smooth muscle cells (VSMCs) plays a crucial role in the development of atherosclerosis. Accordingly, the apoptosis of VSMCs, which occurs in the progression of vascular proliferation, may provide a beneficial strategy for managing cardiovascular diseases. Andrographolide, a novel nuclear factor- kappa B inhibitor, is the most active and critical constituent isolated from the leaves of Andrographis paniculata. Recent studies have indicated that andrographolide is a potential therapeutic agent for treating cancer through the induction of apoptosis. In this study, the apoptosis-inducing activity and mechanisms in andrographolide-treated rat VSMCs were characterized. Andrographolide significantly induced reactive oxygen species (ROS) formation, p53 activation, Bax, and active caspase-3 expression, and these phenomena were suppressed by pretreating the cells with N-acetyl-L-cysteine, a ROS scavenger, or diphenylene iodonium, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase (Nox) inhibitor. Furthermore, p47phox, a Nox subunit protein, was phosphorylated in andrographolide-treated rat VSMCs. However, pretreatment with 3-O-methyl-sphingomyelin, a neutral sphingomyelinase inhibitor, significantly inhibited andrographolide-induced p47phox phosphorylation as well as Bax and active caspase-3 expression. Our results collectively demonstrate that andrographolide-reduced cell viability can be attributed to apoptosis in VSMCs, and this apoptosis-inducing activity was associated with the ceramide-p47phox-ROS signaling cascade. PMID- 24489593 TI - Anti-Inflammatory Effects and Mechanisms of Fatsia polycarpa Hayata and Its Constituents. AB - Fatsia polycarpa, a plant endemic to Taiwan, is an herbal medicine known for treating several inflammation-related diseases, but its biological function needs scientific support. Thus, the anti-inflammatory effects and mechanisms of the methanolic crude extract (MCE) of F. polycarpa and its feature constituents, that is, brassicasterol (a phytosterol), triterpenoids 3 alpha -hydroxyolean-11,13(18) dien-28-oic acid (HODA), 3 alpha -hydroxyolean-11-en-28,13 beta -olide (HOEO), fatsicarpain D, and fatsicarpain F, were investigated. MCE and HOEO, but not brassicasterol, dose-dependently inhibited lipopolysaccharide- (LPS-)induced expression of inducible nitric oxide synthase and cyclooxygenase-2 in RAW 264.7 macrophage line, whereas HODA, fatsicarpain D and fatsicarpain F were toxic to RAW cells. Additionally, MCE and HOEO suppressed LPS-induced production of nitric oxide, prostaglandin E2, and interleukin-1 beta and interfered with LPS-promoted activation of the inhibitor kappa B kinase (IKK)/nuclear factor- kappa B (NF- kappa B) pathway, and that of the mitogen-activated protein kinases (MAPKs) extracellular signal regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38. In animal tests, MCE and HOEO effectively ameliorated 12-O tetradecanoylphorobol-13 acetate- (TPA-)induced ear edema of mice. Thus, MCE of F. polycarpa exhibited an obvious anti-inflammatory activity in vivo and in vitro that likely involved the inhibition of the IKK/NF- kappa B pathway and the MAPKs, which may be attributed by triterpenoids such as HOEO. PMID- 24489594 TI - Xuesaitong soft capsule (chinese patent medicine) for the treatment of unstable angina pectoris: a meta-analysis and systematic review. AB - Objective. To provide a systematic review to evaluate the effectiveness and safety of Xuesaitong soft capsule (XST) in treating unstable angina (UA). Methods. An extensive search of 6 medical databases was performed up to August 2013. Randomized controlled trials (RCTs) involving XST alone or combined with conventional drugs versus conventional drugs were included. A meta-analysis of reduction of angina symptoms and electrocardiogram (ECG) improvement was performed to evaluate the effects of XST on UA. Results. After researching, a total of 6 RCTs with 716 participants were included. Our review showed that XST combined with conventional drugs had significant effect on relieving angina symptoms (RR: 1.14 [1.07, 1.22]; P = 0.0001) and improving ECG (RR: 1.26 [1.12, 1.42]; P = 0.0001) compared with conventional drugs alone. Conclusions. XST appears to have beneficial effects on improvement of ECG, reduction of angina symptoms, and decreasing the frequency and duration of angina attack in participants with UA. However, the findings should be interpreted with caution due to the poor methodological quality of the included trials. PMID- 24489595 TI - High-speed detector for time-resolved diffraction studies. AB - There are a growing number of high brightness synchrotron sources that require high-frame-rate detectors to provide the time-scales required for performing time resolved diffraction experiments. We report on the development of a very high frame rate CMOS X-ray detector for time-resolved muscle diffraction and time resolved solution scattering experiments. The detector is based on a low afterglow scintillator, provides a megapixel resolution with frame rates of up to 120,000 frames per second, an effective pixel size of 64 um, and can be adapted for various X-ray energies. The paper describes the detector design and initial results of time-resolved diffraction experiments on a synchrotron beamline. PMID- 24489596 TI - Coping during pregnancy: a systematic review and recommendations. AB - Extensive evidence documents that prenatal maternal stress predicts a variety of adverse physical and psychological health outcomes for the mother and baby. However, the importance of the ways that women cope with stress during pregnancy is less clear. We conducted a systematic review of the English-language literature on coping behaviours and coping styles in pregnancy using PsycInfo and PubMed to identify 45 cross-sectional and longitudinal studies involving 16,060 participants published between January 1990 and June 2012. Although results were often inconsistent across studies, the literature provides some evidence that avoidant coping behaviours or styles and poor coping skills in general are associated with postpartum depression, preterm birth and infant development. Variability in study methods including differences in sample characteristics, timing of assessments, outcome variables and measures of coping styles or behaviours may explain the lack of consistent associations. To advance the scientific study of coping in pregnancy, we call attention to the need for a priori hypotheses and greater use of pregnancy-specific, daily process, and skills-based approaches. There is promise in continuing this area of research, particularly in the possible translation of consistent findings to effective interventions, but only if the conceptual basis and methodological quality of research improve. PMID- 24489597 TI - Characterizing protein crystal contacts and their role in crystallization: rubredoxin as a case study. AB - The fields of structural biology and soft matter have independently sought out fundamental principles to rationalize protein crystallization. Yet the conceptual differences and the limited overlap between the two disciplines have thus far prevented a comprehensive understanding of the phenomenon to emerge. We conduct a computational study of proteins from the rubredoxin family that bridges the two fields. Using atomistic simulations, we characterize the protein crystal contacts, and accordingly parameterize patchy particle models. Comparing the phase diagrams of these schematic models with experimental results enables us to critically examine the assumptions behind the two approaches. The study also reveals features of protein-protein interactions that can be leveraged to crystallize proteins more generally. PMID- 24489600 TI - Implementation of a low-cost mobile devices to support medical diagnosis. AB - Medical imaging has become an absolutely essential diagnostic tool for clinical practices; at present, pathologies can be detected with an earliness never before known. Its use has not only been relegated to the field of radiology but also, increasingly, to computer-based imaging processes prior to surgery. Motion analysis, in particular, plays an important role in analyzing activities or behaviors of live objects in medicine. This short paper presents several low-cost hardware implementation approaches for the new generation of tablets and/or smartphones for estimating motion compensation and segmentation in medical images. These systems have been optimized for breast cancer diagnosis using magnetic resonance imaging technology with several advantages over traditional X ray mammography, for example, obtaining patient information during a short period. This paper also addresses the challenge of offering a medical tool that runs on widespread portable devices, both on tablets and/or smartphones to aid in patient diagnostics. PMID- 24489601 TI - The MATCHIT automaton: exploiting compartmentalization for the synthesis of branched polymers. AB - We propose an automaton, a theoretical framework that demonstrates how to improve the yield of the synthesis of branched chemical polymer reactions. This is achieved by separating substeps of the path of synthesis into compartments. We use chemical containers (chemtainers) to carry the substances through a sequence of fixed successive compartments. We describe the automaton in mathematical terms and show how it can be configured automatically in order to synthesize a given branched polymer target. The algorithm we present finds an optimal path of synthesis in linear time. We discuss how the automaton models compartmentalized structures found in cells, such as the endoplasmic reticulum and the Golgi apparatus, and we show how this compartmentalization can be exploited for the synthesis of branched polymers such as oligosaccharides. Lastly, we show examples of artificial branched polymers and discuss how the automaton can be configured to synthesize them with maximal yield. PMID- 24489599 TI - Investigation on cardiovascular risk prediction using physiological parameters. AB - Cardiovascular disease (CVD) is the leading cause of death worldwide. Early prediction of CVD is urgently important for timely prevention and treatment. Incorporation or modification of new risk factors that have an additional independent prognostic value of existing prediction models is widely used for improving the performance of the prediction models. This paper is to investigate the physiological parameters that are used as risk factors for the prediction of cardiovascular events, as well as summarizing the current status on the medical devices for physiological tests and discuss the potential implications for promoting CVD prevention and treatment in the future. The results show that measures extracted from blood pressure, electrocardiogram, arterial stiffness, ankle-brachial blood pressure index (ABI), and blood glucose carry valuable information for the prediction of both long-term and near-term cardiovascular risk. However, the predictive values should be further validated by more comprehensive measures. Meanwhile, advancing unobtrusive technologies and wireless communication technologies allow on-site detection of the physiological information remotely in an out-of-hospital setting in real-time. In addition with computer modeling technologies and information fusion. It may allow for personalized, quantitative, and real-time assessment of sudden CVD events. PMID- 24489602 TI - Automated conduction velocity analysis in the electrohysterogram for prediction of imminent delivery: a preliminary study. AB - BACKGROUND: Analysis of the electrohysterogram (EHG) is a promising diagnostic tool for preterm delivery. For the introduction in the clinical practice, analysis of the EHG should be reliable and automated to guarantee reproducibility. STUDY GOAL: Investigating the feasibility of automated analysis of the EHG conduction velocity (CV) for detecting imminent delivery. MATERIALS AND METHODS: Twenty-two patients presenting with uterine contractions (7 preterm) were included. An EHG was obtained noninvasively using a 64-channel high-density electrode grid. Contractions were selected based on the estimated intrauterine pressure derived from the EHG, the tocodynamometer, and maternal perception. Within the selected contractions, the CV vector was identified in two dimensions. RESULTS: Nine patients delivered within 24 hours and were classified as a labor group. 64 contractions were analyzed; the average amplitude of the CV vector was significantly higher for the labor group, 8.65 cm/s +/- 1.90, compared to the nonlabor group, 5.30 cm/s +/- 1.47 (P < 0.01). CONCLUSION: The amplitude of the CV is a promising parameter for predicting imminent (preterm) delivery. Automated estimation of this parameter from the EHG signal is feasible and should be regarded as an important prerequisite for future clinical studies and applications. PMID- 24489603 TI - Machine learning approaches: from theory to application in schizophrenia. AB - In recent years, machine learning approaches have been successfully applied for analysis of neuroimaging data, to help in the context of disease diagnosis. We provide, in this paper, an overview of recent support vector machine-based methods developed and applied in psychiatric neuroimaging for the investigation of schizophrenia. In particular, we focus on the algorithms implemented by our group, which have been applied to classify subjects affected by schizophrenia and healthy controls, comparing them in terms of accuracy results with other recently published studies. First we give a description of the basic terminology used in pattern recognition and machine learning. Then we separately summarize and explain each study, highlighting the main features that characterize each method. Finally, as an outcome of the comparison of the results obtained applying the described different techniques, conclusions are drawn in order to understand how much automatic classification approaches can be considered a useful tool in understanding the biological underpinnings of schizophrenia. We then conclude by discussing the main implications achievable by the application of these methods into clinical practice. PMID- 24489605 TI - New advances in erectile technology. AB - New discoveries and technological advances in medicine are rapid. The role of technology in the treatment of erectile dysfunction (ED) will be widened and more options will be available in the years to come. These erectile technologies include external penile support devices, penile vibrators, low intensity extracorporeal shockwave, tissue engineering, nanotechnology and endovascular technology. Even for matured treatment modalities for ED, such as vacuum erectile devices and penile implants, there is new scientific information and novel technology available to improve their usage and to stimulate new ideas. We anticipate that erectile technologies may revolutionize ED treatment and in the very near future ED may become a curable condition. PMID- 24489604 TI - Sequential use of novel therapeutics in advanced prostate cancer following docetaxel chemotherapy. AB - In the last three years, five novel treatments have been shown to improve survival in metastatic castration-resistant prostate cancer (CRPC). These novel treatments have distinct mechanisms of action: tubulin-binding chemotherapy (cabazitaxel); immunotherapy (sipuleucel-T); CYP-17 inhibition (abiraterone); androgen receptor (AR) blockade (enzalutamide); and radioisotope therapy (radium 223). For a number of years, docetaxel was the only treatment with a proven survival benefit for patients with CRPC. Therefore, somewhat artificially, three treatment spaces for drug development in CRPC have emerged: pre-docetaxel; docetaxel combinations; and post-docetaxel. For patients progressing after docetaxel-based chemotherapy, treatment options available outside of clinical trials now include abiraterone, cabazitaxel and enzalutamide. Prospective data on how to best use these novel agents sequentially are not available. Clinicians face the difficult task of choosing between treatment options for individual patients to maximize patient benefit. Treatment evaluation in patients with CRPC remains challenging due to the predominance of bone metastatic disease and the lack of validated surrogate markers for survival. This review summarizes the data available with regards to sequencing of the novel treatments for CRPC. PMID- 24489606 TI - Blue-light cystoscopy in the evaluation of non-muscle-invasive bladder cancer. AB - Bladder carcinoma is the most common malignancy of the urinary tract. Two distinct groups can be identified: non-muscle-invasive bladder carcinoma (NMIBC) and muscle-invasive bladder carcinoma. At initial resection about 75-85% of the patients will be diagnosed with NMIBC. This subgroup has a recurrence rate up to 70-80%, and a subsequent chance of disease progression. This means that patients with NMIBC require adequate treatment and thorough follow up. This high recurrence rate also means that apparently current diagnosis and treatment can be improved. It is thought that photodynamic diagnosis, by the use of a photosensitizing drug and blue-light cystoscopy, can improve the detection of tumor and therefore affect outcome for patients with NMIBC. In this paper we will discuss the role of blue-light cystoscopy in NMIBC in different aspects of the disease by reviewing the latest literature. PMID- 24489607 TI - Experience with botulinum toxin type A in the treatment of neurogenic detrusor overactivity in clinical practice. AB - Control of the lower urinary tract is a complex, multilevel process that involves both the peripheral and central nervous system. Neurogenic lower urinary tract dysfunction (LUTD) is a widespread chronic illness that impairs millions of people worldwide. Neurogenic LUTD has a major impact on quality of life, affecting emotional, social, sexual, occupational and physical aspects of daily life, and in addition to the debilitating manifestations for patients, it also imposes a substantial economic burden on every healthcare system. First-line treatment for neurogenic LUTD includes antimuscarinics and some form of catheterization, preferably intermittent self-catheterization. However, the treatment effect is often unsatisfactory, so that other options have to be considered. Moreover, neurogenic LUTD is a challenge because all available treatment modalities (i.e. conservative, minimally invasive and invasive therapies) may fail. In recent years, botulinum neurotoxin type A (BoNT/A) treatment has been shown to be an effective pharmacological therapy option in patients refractory to antimuscarinic and neurogenic detrusor overactivity (NDO). Several studies have shown that BoNT/A injection significantly reduces detrusor muscle overactivity. Also BoNT/A treatment of NDO has revealed a significant improvement of lower urinary tract function with regard to reduced urinary incontinence, reduced detrusor pressure, increased bladder capacity and improved quality of life in NDO. PMID- 24489608 TI - The Link between Mother and Adolescent Substance Use: Intergenerational Findings from the British Cohort Study. AB - The objective of this study was to identify mother, family, and individual factors associated with adolescent alcohol, tobacco, and marijuana use using mother and child self-reports. Adolescents aged 12-15 (N=276) and their mothers who were participants in the British Cohort Study (BCS; born 1970) were both surveyed when mothers were 34 years old. Predictors included mother's substance use as well as characteristics of the child (gender, age, conduct problems) and family (social class, two-parent family, parent-adolescent conflict). Outcome variables were adolescent alcohol, cigarette, and marijuana use. Child characteristics were predictive, with older children more likely to engage in all behaviors. After controlling for other predictors, mothers' current drinking frequency and problems (i.e., CAGE 1+) predicted adolescent ever and sometimes/regular drinking; mothers' marijuana use was a marginally significant predictor of adolescent marijuana use. Results suggest that mothers' substance use is an important component of adolescent use, even after accounting for characteristics of the child and the intergenerational family context. PMID- 24489610 TI - Sarcoidois: is it only a mimicker of primary rheumatic disease? A single center experience. AB - BACKGROUND: Sarcoidosis is known as a T helper 1 lymphocyte (Th1-Ly) mediated disease which can imitate or sometimes accompany many primary rheumatic diseases. The purpose of this study is to share the clinical, demographic and laboratory data of patients presenting with rheumatologic manifestations and diagnosed with sarcoidosis. METHODS: A total of 42 patients (10 men) were included in the study. The patients were admitted to the rheumatology outpatient clinic for the first time with different rheumatic complaints between November 2011 and May 2013 and were diagnosed with sarcoidosis after relevant tests. Clinical, demographic, laboratory, radiological and histological data of these patients were collected during the 18-month follow-up period and then analyzed. RESULTS: Mean patient age was 45.2 years (20-70 years) and mean duration of disease was 3.5 years (1 month 25 years). Evaluation of system and organ involvement revealed that 20 (47.6%) patients had erythema nodosum, 3 (7.1%) had uveitis, 1 (2.3%) had myositis, 1 (2.3%) had neurosarcoidosis, 32 (76.2%) had arthritis and 40 (95.2%) had arthralgia. Of the 32 patients with arthritis, 28 (87.5%) had involvement of the ankle, 3 (9.4%) had involvement of the knee and 1 (3.2%) had involvement of the wrist. No patient had cardiac involvement. Thoracic computed tomography scan showed stage 1, 2, 3 and 4 sarcoidosis in 12 (28.5%), 22 (52.4%), 4 (9.5%) and 4 (9.5%) patients, respectively. Histopathology of sarcoidosis was verified by endobronchial ultrasound, mediastinoscopy and skin and axillary biopsy of lymphadenopathies, which revealed noncaseating granulomas. Laboratory tests showed elevated serum angiotensin-converting enzyme in 15 (35.7%) patients, elevated serum calcium level in 6 (14.2%) patients and elevated serum 1,25 dihydroxyvitamin D concentrations in 2 (4.7%) patients. Serological tests showed antinuclear antibody positivity in 12 (28.5%) patients, rheumatoid factor positivity in 7 (16.6%) patients and anticyclic citrullinated antibody positivity in 2 (4.8%) patients. CONCLUSION: Sarcoidosis can imitate or accompany many primary rheumatic diseases. Sarcoidosis should be considered not simply as an imitator but as a primary rheumatic pathology mediated by Th1-Ly. New studies are warranted on this subject. PMID- 24489609 TI - The important role of CNS facilitation and inhibition for chronic pain. AB - Multiple studies have demonstrated that the pain experience among individuals is highly variable. Even under circumstances where the tissue injuries are similar, individual pain experiences may vary drastically. However, this individual difference in pain sensitivity is not only related to sensitivity of peripheral pain receptors, but also to variability in CNS pain processing. Peripheral impulses derived from tissue receptors undergo modification in dorsal horn neurons that can either result in inhibition or facilitation of pain. Such influences are particularly apparent in inflammation where not only peripheral, but also central, pain modulatory mechanisms can significantly increase nociceptive pain. Emotional state, level of anxiety, attention and distraction, memories, stress, fatigue and many other factors can either increase or reduce the pain experience. Increasing evidence suggests that 'bottom-up' and 'top-down' modulatory circuits within the spinal cord and brain play an important role in pain processing, which can profoundly affect the experience of pain. PMID- 24489611 TI - Advances and challenges in the diagnosis and treatment of polymyalgia rheumatica. AB - Polymyalgia rheumatica (PMR) is a common inflammatory condition that often affects people over the age of 50 years. Characteristic symptoms are shoulder and hip girdle pain and prolonged morning stiffness. Markers of inflammation are often elevated. Clinicians are often faced with the challenge of distinguishing PMR from other conditions, particularly rheumatoid arthritis and spondyloarthropathy that can mimic symptoms of PMR in older people. Additionally, there is an association between PMR and giant cell arteritis, a common large vessel vasculitis which also affects people over the age of 50 years. Imaging of the large vessels in asymptomatic patients with PMR often reveals findings of subclinical vasculitis. Presently, there are no tests that are specific for the diagnosis of PMR and clinicians rely on a combination of history, physical examination, laboratory tests and imaging studies to make a diagnosis. A recent undertaking by the European League Against Rheumatism/American College of Rheumatology has led to the publication of provisional classification criteria of PMR. Ultrasonography, which is being increasingly used by rheumatologists, can greatly aid in the diagnosis of PMR and often shows changes of synovitis and tenosynovitis. Treatment consists of low doses of glucocorticoids which are associated with morbidity. Evaluation of newer biologic therapies targeting inflammatory cytokines is underway. Despite treatment, relapses are common. PMID- 24489613 TI - Estimation of angiotensin peptides in biological samples by LC/MS method. AB - The low abundance of angiotensin peptides in biological tissues such as the kidney cortex, adipose tissue, urine and plasma makes their detection and quantification a challenge. A few available methods used to quantify these peptides involve lengthy processes of sample preparation and are hardly quantitative. Here, we report a mass spectrometry approach for quantifying angiotensin peptides [Ang II, Ang-(1-7)] in the kidney cortex, epididymal white adipose tissue (eWAT), urine and plasma of male mice. Tissue homogenates, urine and plasma samples were solid-phase extracted with C18 Sep-Pak cartridges and eluted off proteinaceous compounds. These extracted peptide samples were separated on C18 column with a linear acetonitrile gradient and detected by Q-ToF mass analyzer in ESI+-MS ion mode based on their retention time, accurate mass measurement of peptides, the isotope pattern of doubly charged molecular ion, and quantitation of peak area (or ion count) when referencing to the angiotensin peptide standards. The lower limit of quantitation for each angiotensin peptide was 10 pgmg-1 with the percent recovery at 100.6%. The intra-batch precision for Ang-(1-7) and Ang II were 24.0 and 12.7%, accuracy 84.0-123.0% and 100.2-116.0% respectively. Using this method, we determined the levels of Ang II and Ang-(1-7) in the kidney cortex, eWAT, urine and plasma. Quantification of angiotensin peptides could help target subtle therapeutics changes against pathophysiological conditions such as obesity, kidney disease and hypertension. PMID- 24489612 TI - Targeting the synovial angiogenesis as a novel treatment approach to osteoarthritis. AB - Synovitis is a key feature in osteoarthritis and is associated with symptom severity. Synovial membrane inflammation is secondary to cartilage degradation which occurs in the early stage and is located adjacent to cartilage damage. This inflammation is characterized by the invasion and activation of macrophages and lymphocytes, the release in the joint cavity of large amounts of pro-inflammatory and procatabolic mediators, and by a local increase of synovial membrane vascularity. This latter process plays an important role in the chronicity of the inflammatory reaction by facilitating the invasion of the synovium by immune cells. Therefore, synovial membrane angiogenesis represents a key target for the treatment of osteoarthritis. This paper is a narrative review of the literature referenced in PubMed during the past 5 years. It addresses in particular three questions. What are the mechanisms involved in synovium blood vessels invasion? Are current medications effective in controlling blood vessels formation and invasion? What are the perspectives of research in this area? PMID- 24489614 TI - Analysis of Cooperative Behavior in Multiple Kinesins Motor Protein Transport by Varying Structural and Chemical Properties. AB - Intracellular transport is a fundamental biological process during which cellular materials are driven by enzymatic molecules called motor proteins. Recent optical trapping experiments and theoretical analysis have uncovered many features of cargo transport by multiple kinesin motor protein molecules under applied loads. These studies suggest that kinesins cooperate negatively under typical transport conditions, although some productive cooperation could be achieved under higher applied loads. However, the microscopic origins of this complex behavior are still not well understood. Using a discrete-state stochastic approach we analyze factors that affect the cooperativity among kinesin motors during cargo transport. Kinesin cooperation is shown to be largely unaffected by the structural and mechanical parameters of a multiple motor complex connected to a cargo, but much more sensitive to biochemical parameters affecting motor-filament affinities. While such behavior suggests the net negative cooperative responses of kinesins will persist across a relatively wide range of cargo types, it is also shown that the rates with which cargo velocities relax in time upon force perturbations are influenced by structural factors that affect the free energies of and load distributions within a multiple kinesin complex. The implications of these later results on transport phenomena where loads change temporally, as in the case of bidirectional transport, are discussed. PMID- 24489616 TI - Chronic Pain in a Biracial Cohort of Young Women. AB - This is a longitudinal study of a large US biracial community cohort of 732 young women - 50% African-American and 50% Caucasian - specifically investigating incidence, remission, and progression of, as well as factors associated with common chronic pains (back, head, face, chest and abdomen). The results show back, head and abdominal pains were the most common, severe and persistent pains. Facial pain, although less common and severe, was the only pain presenting significant racial differences with Caucasians having higher prevalence, incidence and persistence; incidence per 1000 person-years was 58 for Caucasians and 18 for African-Americans while remission per 1000 person-years was 107 for Caucasians and 247 for African-Americans (p<0.05). Risk factors associated with incidence (I) differed from those associated with persistence(P), perhaps due to the young age and shorter pain duration in this population. Face pain incidence, but not persistence for example, was associated with student status, fatigue, perceived stress and general health. Depression does not seem to be associated with any of these pains. However, increased number of existing pain sites was related to subsequent increase chance of developing new pain (I) or maintaining the existing pain (P). PMID- 24489615 TI - Single Nucleotide Polymorphism (SNP) Detection and Genotype Calling from Massively Parallel Sequencing (MPS) Data. AB - Massively parallel sequencing (MPS), since its debut in 2005, has transformed the field of genomic studies. These new sequencing technologies have resulted in the successful identification of causal variants for several rare Mendelian disorders. They have also begun to deliver on their promise to explain some of the missing heritability from genome-wide association studies (GWAS) of complex traits. We anticipate a rapidly growing number of MPS-based studies for a diverse range of applications in the near future. One crucial and nearly inevitable step is to detect SNPs and call genotypes at the detected polymorphic sites from the sequencing data. Here, we review statistical methods that have been proposed in the past five years for this purpose. In addition, we discuss emerging issues and future directions related to SNP detection and genotype calling from MPS data. PMID- 24489617 TI - Dissociation Among Inhibitory Control Mechanisms in Two Cases With Frontal vs. Non-frontal Damage. PMID- 24489618 TI - Regularized Multivariate Regression for Identifying Master Predictors with Application to Integrative Genomics Study of Breast Cancer. AB - In this paper, we propose a new method remMap - REgularized Multivariate regression for identifying MAster Predictors - for fitting multivariate response regression models under the high-dimension-low-sample-size setting. remMap is motivated by investigating the regulatory relationships among different biological molecules based on multiple types of high dimensional genomic data. Particularly, we are interested in studying the influence of DNA copy number alterations on RNA transcript levels. For this purpose, we model the dependence of the RNA expression levels on DNA copy numbers through multivariate linear regressions and utilize proper regularization to deal with the high dimensionality as well as to incorporate desired network structures. Criteria for selecting the tuning parameters are also discussed. The performance of the proposed method is illustrated through extensive simulation studies. Finally, remMap is applied to a breast cancer study, in which genome wide RNA transcript levels and DNA copy numbers were measured for 172 tumor samples. We identify a trans-hub region in cytoband 17q12-q21, whose amplification influences the RNA expression levels of more than 30 unlinked genes. These findings may lead to a better understanding of breast cancer pathology. PMID- 24489638 TI - Extended viral shedding of a low pathogenic avian influenza virus by striped skunks (Mephitis mephitis). AB - BACKGROUND: Striped skunks (Mephitis mephitis) are susceptible to infection with some influenza A viruses. However, the viral shedding capability of this peri domestic mammal and its potential role in influenza A virus ecology are largely undetermined. METHODOLOGY/PRINCIPAL FINDINGS: Striped skunks were experimentally infected with a low pathogenic (LP) H4N6 avian influenza virus (AIV) and monitored for 20 days post infection (DPI). All of the skunks exposed to H4N6 AIV shed large quantities of viral RNA, as detected by real-time RT-PCR and confirmed for live virus with virus isolation, from nasal washes and oral swabs (maximum <= 10(6.02) PCR EID50 equivalent/mL and <= 10(5.19) PCR EID50 equivalent/mL, respectively). Some evidence of potential fecal shedding was also noted. Following necropsy on 20 DPI, viral RNA was detected in the nasal turbinates of one individual. All treatment animals yielded evidence of a serological response by 20 DPI. CONCLUSIONS/SIGNIFICANCE: These results indicate that striped skunks have the potential to shed large quantities of viral RNA through the oral and nasal routes following exposure to a LP AIV. Considering the peri-domestic nature of these animals, along with the duration of shedding observed in this species, their presence on poultry and waterfowl operations could influence influenza A virus epidemiology. For example, this species could introduce a virus to a naive poultry flock or act as a trafficking mechanism of AIV to and from an infected poultry flock to naive flocks or wild bird populations. PMID- 24489639 TI - Knowledge-guided robust MRI brain extraction for diverse large-scale neuroimaging studies on humans and non-human primates. AB - Accurate and robust brain extraction is a critical step in most neuroimaging analysis pipelines. In particular, for the large-scale multi-site neuroimaging studies involving a significant number of subjects with diverse age and diagnostic groups, accurate and robust extraction of the brain automatically and consistently is highly desirable. In this paper, we introduce population-specific probability maps to guide the brain extraction of diverse subject groups, including both healthy and diseased adult human populations, both developing and aging human populations, as well as non-human primates. Specifically, the proposed method combines an atlas-based approach, for coarse skull-stripping, with a deformable-surface-based approach that is guided by local intensity information and population-specific prior information learned from a set of real brain images for more localized refinement. Comprehensive quantitative evaluations were performed on the diverse large-scale populations of ADNI dataset with over 800 subjects (55 ~ 90 years of age, multi-site, various diagnosis groups), OASIS dataset with over 400 subjects (18 ~ 96 years of age, wide age range, various diagnosis groups), and NIH pediatrics dataset with 150 subjects (5 ~ 18 years of age, multi-site, wide age range as a complementary age group to the adult dataset). The results demonstrate that our method consistently yields the best overall results across almost the entire human life span, with only a single set of parameters. To demonstrate its capability to work on non-human primates, the proposed method is further evaluated using a rhesus macaque dataset with 20 subjects. Quantitative comparisons with popularly used state-of-the-art methods, including BET, Two-pass BET, BET-B, BSE, HWA, ROBEX and AFNI, demonstrate that the proposed method performs favorably with superior performance on all testing datasets, indicating its robustness and effectiveness. PMID- 24489640 TI - Multidimensional single-cell analysis of BCR signaling reveals proximal activation defect as a hallmark of chronic lymphocytic leukemia B cells. AB - PURPOSE: Chronic Lymphocytic Leukemia (CLL) is defined by a perturbed B-cell receptor-mediated signaling machinery. We aimed to model differential signaling behavior between B cells from CLL and healthy individuals to pinpoint modes of dysregulation. EXPERIMENTAL DESIGN: We developed an experimental methodology combining immunophenotyping, multiplexed phosphospecific flow cytometry, and multifactorial statistical modeling. Utilizing patterns of signaling network covariance, we modeled BCR signaling in 67 CLL patients using Partial Least Squares Regression (PLSR). Results from multidimensional modeling were validated using an independent test cohort of 38 patients. RESULTS: We identified a dynamic and variable imbalance between proximal (pSYK, pBTK) and distal (pPLCgamma2, pBLNK, ppERK) phosphoresponses. PLSR identified the relationship between upstream tyrosine kinase SYK and its target, PLCgamma2, as maximally predictive and sufficient to distinguish CLL from healthy samples, pointing to this juncture in the signaling pathway as a hallmark of CLL B cells. Specific BCR pathway signaling signatures that correlate with the disease and its degree of aggressiveness were identified. Heterogeneity in the PLSR response variable within the B cell population is both a characteristic mark of healthy samples and predictive of disease aggressiveness. CONCLUSION: Single-cell multidimensional analysis of BCR signaling permitted focused analysis of the variability and heterogeneity of signaling behavior from patient-to-patient, and from cell-to cell. Disruption of the pSYK/pPLCgamma2 relationship is uncovered as a robust hallmark of CLL B cell signaling behavior. Together, these observations implicate novel elements of the BCR signal transduction as potential therapeutic targets. PMID- 24489641 TI - Effects of cadmium and mercury on the upper part of skeletal muscle glycolysis in mice. AB - The effects of pre-incubation with mercury (Hg(2+)) and cadmium (Cd(2+)) on the activities of individual glycolytic enzymes, on the flux and on internal metabolite concentrations of the upper part of glycolysis were investigated in mouse muscle extracts. In the range of metal concentrations analysed we found that only hexokinase and phosphofructokinase, the enzymes that shared the control of the flux, were inhibited by Hg(2+) and Cd(2+). The concentrations of the internal metabolites glucose-6-phosphate and fructose-6-phosphate did not change significantly when Hg(2+) and Cd(2+) were added. A mathematical model was constructed to explore the mechanisms of inhibition of Hg(2+) and Cd(2+) on hexokinase and phosphofructokinase. Equations derived from detailed mechanistic models for each inhibition were fitted to the experimental data. In a concentration-dependent manner these equations describe the observed inhibition of enzyme activity. Under the conditions analysed, the integral model showed that the simultaneous inhibition of hexokinase and phosphofructokinase explains the observation that the concentrations of glucose-6-phosphate and fructose-6 phosphate did not change as the heavy metals decreased the glycolytic flux. PMID- 24489642 TI - A general method for site specific fluorescent labeling of recombinant chemokines. AB - Chemokines control cell migration in many contexts including development, homeostasis, immune surveillance and inflammation. They are also involved in a wide range of pathological conditions ranging from inflammatory diseases and cancer, to HIV. Chemokines function by interacting with two types of receptors: G protein-coupled receptors on the responding cells, which transduce signaling pathways associated with cell migration and activation, and glycosaminoglycans on cell surfaces and the extracellular matrix which organize and present some chemokines on immobilized surface gradients. To probe these interactions, imaging methods and fluorescence-based assays are becoming increasingly desired. Herein, a method for site-specific fluorescence labeling of recombinant chemokines is described. It capitalizes on previously reported 11-12 amino acid tags and phosphopantetheinyl transferase enzymes to install a fluorophore of choice onto a specific serine within the tag through a coenzyme A-fluorophore conjugate. The generality of the method is suggested by our success in labeling several chemokines (CXCL12, CCL2, CCL21 and mutants thereof) and visualizing them bound to chemokine receptors and glycosaminoglycans. CXCL12 and CCL2 showed the expected co-localization on the surface of cells with their respective receptors CXCR4 and CCR2 at 4 degrees C, and co-internalization with their receptors at 37 degrees C. By contrast, CCL21 showed the presence of large discrete puncta that were dependent on the presence of both CCR7 and glycosaminoglycans as co receptors. These data demonstrate the utility of this labeling approach for the detection of chemokine interactions with GAGs and receptors, which can vary in a chemokine-specific manner as shown here. For some applications, the small size of the fluorescent adduct may prove advantageous compared to other methods (e.g. antibody labeling, GFP fusion) by minimally perturbing native interactions. Other advantages of the method are the ease of bacterial expression, the versatility of labeling with any maleimide-fluorophore conjugate of interest, and the covalent nature of the fluorescent adduct. PMID- 24489643 TI - Recent observations of human-induced asymmetric effects on climate in very high altitude area. AB - Like urban heat islands (UHI), human-induced land degradation (HLD) is a phenomenon attributed to human activities, but this phenomenon occurs in non urban areas. Although a large body of work has demonstrated that land-cover change influences local climate systems, little work has been done on separating the impact of HLD from naturally-occurring fluctuations in very high-altitude areas. We developed an innovative NDVI-difference method in order to evaluate HLD effects upon the climate system in the central Tibet Plateau. The results show that the minimum temperature increased at a significantly faster pace than the maximum temperature in the growing season at HLD meteorological stations, but this was reversed at stations with natural forces only. Further analysis revealed that abrupt changes of minimum temperature occurred five years earlier and amplitudes of these changes were 1.4 times larger than at stations with natural forces only. Therefore, our results complement other evidence that points to the fact that local effects from UHI contribute to climatic asymmetry observed between minimum and maximum temperature trends. Accordingly, we stress the need for consideration of non-urban factors from anthropogenic activities, such as human-induced land degradation, in understanding these asymmetric diurnal changes. PMID- 24489644 TI - Periodontal disease bacteria specific to tonsil in IgA nephropathy patients predicts the remission by the treatment. AB - BACKGROUND: Immunoglobulin (Ig)A nephropathy (IgAN) is the most common form of primary glomerulonephritis in the world. Some bacteria were reported to be the candidate of the antigen or the pathogenesis of IgAN, but systematic analysis of bacterial flora in tonsil with IgAN has not been reported. Moreover, these bacteria specific to IgAN might be candidate for the indicator which can predict the remission of IgAN treated by the combination of tonsillectomy and steroid pulse. METHODS AND FINDINGS: We made a comprehensive analysis of tonsil flora in 68 IgAN patients and 28 control patients using Denaturing gradient gel electrophoresis methods. We also analyzed the relationship between several bacteria specific to the IgAN and the prognosis of the IgAN. Treponema sp. were identified in 24% IgAN patients, while in 7% control patients (P = 0.062). Haemophilus segnis were detected in 53% IgAN patients, while in 25% control patients (P = 0.012). Campylobacter rectus were identified in 49% IgAN patients, while in 14% control patients (P = 0.002). Multiple Cox proportional-hazards model revealed that Treponema sp. or Campylobactor rectus are significant for the remission of proteinuria (Hazard ratio 2.35, p = 0.019). There was significant difference in remission rates between IgAN patients with Treponema sp. and those without the bacterium (p = 0.046), and in remission rates between IgAN patients with Campylobacter rectus and those without the bacterium (p = 0.037) by Kaplan Meier analysis. Those bacteria are well known to be related with the periodontal disease. Periodontal bacteria has known to cause immune reaction and many diseases, and also might cause IgA nephropathy. CONCLUSION: This insight into IgAN might be useful for diagnosis of the IgAN patients and the decision of treatment of IgAN. PMID- 24489645 TI - Reaction time and mortality from the major causes of death: the NHANES-III study. AB - OBJECTIVE: Studies examining the relation of information processing speed, as measured by reaction time, with mortality are scarce. We explored these associations in a representative sample of the US population. METHODS: Participants were 5,134 adults (2,342 men) aged 20-59 years from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-94). RESULTS: Adjusted for age, sex, and ethnic minority status, a 1 SD slower reaction time was associated with a raised risk of mortality from all-causes (HR = 1.25, 95% CI 1.12, 1.39) and cardiovascular disease (CVD) (HR = 1.36, 95% CI 1.17, 1.58). Having 1 SD more variable reaction time was also associated with greater risk of all-cause (HR = 1.36, 95% CI 1.19, 1.55) and CVD (HR = 1.50, 95% CI 1.33, 1.70) mortality. No associations were observed for cancer mortality. The magnitude of the relationships was comparable in size to established risk factors in this dataset, such as smoking. INTERPRETATION: Alongside better-established risk factors, reaction time is associated with increased risk of premature death and cardiovascular disease. It is a candidate risk factor for all-cause and cause specific mortality. PMID- 24489646 TI - Numerical magnitude affects temporal memories but not time encoding. AB - Previous research has suggested that the perception of time is influenced by concurrent magnitude information (e.g., numerical magnitude in digits, spatial distance), but the locus of the effect is unclear, with some findings suggesting that concurrent magnitudes such as space affect temporal memories and others suggesting that numerical magnitudes in digits affect the clock speed during time encoding. The current paper reports 6 experiments in which participants perceived a stimulus duration and then reproduced it. We showed that though a digit of a large magnitude (e.g., 9), relative to a digit of a small magnitude (e.g., 2), led to a longer reproduced duration when the digits were presented during the perception of the stimulus duration, such a magnitude effect disappeared when the digits were presented during the reproduction of the stimulus duration. These findings disconfirm the account that large numerical magnitudes accelerate the speed of an internal clock during time encoding, as such an account incorrectly predicts that a large numerical magnitude should lead to a shorter reproduced duration when presented during reproduction. Instead, the findings suggest that numerical magnitudes, like other magnitudes such as space, affect temporal memories when numerical magnitudes and temporal durations are concurrently held in memory. Under this account, concurrent numerical magnitudes have the chance to influence the memory of the perceived duration when they are presented during perception but not when they are presented at the reproduction stage. PMID- 24489647 TI - Facial EMG responses to emotional expressions are related to emotion perception ability. AB - Although most people can identify facial expressions of emotions well, they still differ in this ability. According to embodied simulation theories understanding emotions of others is fostered by involuntarily mimicking the perceived expressions, causing a "reactivation" of the corresponding mental state. Some studies suggest automatic facial mimicry during expression viewing; however, findings on the relationship between mimicry and emotion perception abilities are equivocal. The present study investigated individual differences in emotion perception and its relationship to facial muscle responses - recorded with electromyogram (EMG)--in response to emotional facial expressions. N degrees = degrees 269 participants completed multiple tasks measuring face and emotion perception. EMG recordings were taken from a subsample (N degrees = degrees 110) in an independent emotion classification task of short videos displaying six emotions. Confirmatory factor analyses of the m. corrugator supercilii in response to angry, happy, sad, and neutral expressions showed that individual differences in corrugator activity can be separated into a general response to all faces and an emotion-related response. Structural equation modeling revealed a substantial relationship between the emotion-related response and emotion perception ability, providing evidence for the role of facial muscle activation in emotion perception from an individual differences perspective. PMID- 24489648 TI - Effectiveness of a worksite mindfulness-related multi-component health promotion intervention on work engagement and mental health: results of a randomized controlled trial. AB - OBJECTIVES: The aim of the present study was to evaluate the effectiveness of a worksite mindfulness-related multi-component health promotion intervention on work engagement, mental health, need for recovery and mindfulness. METHODS: In a randomized controlled trial design, 257 workers of two research institutes participated. The intervention group (n = 129) received a targeted mindfulness related training, followed by e-coaching. The total duration of the intervention was 6 months. Data on work engagement, mental health, need for recovery and mindfulness were collected using questionnaires at baseline and after 6 and 12 months follow-up. Effects were analyzed using linear mixed effect models. RESULTS: There were no significant differences in work engagement, mental health, need for recovery and mindfulness between the intervention and control group after either 6- or 12-months follow-up. Additional analyses in mindfulness related training compliance subgroups (high and low compliance versus the control group as a reference) and subgroups based on baseline work engagement scores showed no significant differences either. CONCLUSIONS: This study did not show an effect of this worksite mindfulness-related multi-component health promotion intervention on work engagement, mental health, need for recovery and mindfulness after 6 and 12 months. TRIAL REGISTRATION: Netherlands Trial Register NTR2199. PMID- 24489649 TI - Phenotyping of human melanoma cells reveals a unique composition of receptor targets and a subpopulation co-expressing ErbB4, EPO-R and NGF-R. AB - Malignant melanoma is a life-threatening skin cancer increasingly diagnosed in the western world. In advanced disease the prognosis is grave. Growth and metastasis formation in melanomas are regulated by a network of cytokines, cytokine-receptors, and adhesion molecules. However, little is known about surface antigens and target expression profiles in human melanomas. We examined the cell surface antigen profile of human skin melanoma cells by multicolor flow cytometry, and compared their phenotype with 4 melanoma cell lines (A375, 607B, Mel-Juso, SK-Mel28). Melanoma cells were defined as CD45-/CD31- cells co expressing one or more melanoma-related antigens (CD63, CD146, CD166). In most patients, melanoma cells exhibited ErbB3/Her3, CD44/Pgp-1, ICAM-1/CD54 and IGF-1 R/CD221, but did not express CD20, ErbB2/Her2, KIT/CD117, AC133/CD133 or MDR 1/CD243. Melanoma cell lines were found to display a similar phenotype. In most patients, a distinct subpopulation of melanoma cells (4-40%) expressed the erythropoietin receptor (EPO-R) and ErbB4 together with PD-1 and NGF-R/CD271. Both the EPO-R+ and EPO-R- subpopulations produced melanoma lesions in NOD/SCID IL-2Rgamma(null) (NSG) mice in first and secondary recipients. Normal skin melanocytes did not express ErbB4 or EPO-R, but expressed a functional KIT receptor (CD117) as well as NGF-R, ErbB3/Her3, IGF-1-R and CD44. In conclusion, melanoma cells display a unique composition of surface target antigens and cytokine receptors. Malignant transformation of melanomas is accompanied by loss of KIT and acquisition of EPO-R and ErbB4, both of which are co-expressed with NGF-R and PD-1 in distinct subfractions of melanoma cells. However, expression of EPO-R/ErbB4/PD-1 is not indicative of a selective melanoma-initiating potential. PMID- 24489650 TI - The cellular basis for biocide-induced fluorescein hyperfluorescence in mammalian cell culture. AB - Clinical examination of the ocular surface is commonly carried out after application of sodium fluorescein in both veterinary and medical practice by assessing the resulting 'staining'. Although localized intensely stained regions of the cornea frequently occur after exposure to 'adverse' clinical stimuli, the cell biology underlying this staining is unknown, including whether intense fluorescein staining indicates the presence of damaged cells. Ocular exposure to certain contact lens multipurpose solutions (MPS) gives rise to intense fluorescein staining referred to as solution induced corneal staining (SICS), and we have made use of this phenomenon with Vero and L929 cell culture models to investigate the fundamental biology of fluorescein interactions with cells. We found that all cells take up fluorescein, however a sub-population internalize much higher levels, giving rise to brightly staining 'hyperfluorescent' cells within the treated cultures, which contain fluorescein throughout the cell cytoplasm and nucleus. The numbers of these hyperfluorescent cells are significantly increased after exposure to MPS associated with SICS. Surprisingly, hyperfluorescent cells did not show higher levels of staining with propidium iodide, a marker of lysed cells. Consistently, treatment with the cytolytic toxin benzalkonium chloride resulted in almost all cells staining with propidium iodide, and the complete abolition of fluorescein hyperfluorescence. Finally we found that internalization of fluorescein and its loss from treated cells both require cellular activity, as both processes were halted after incubation at 4 degrees C. We conclude that fluorescein hyperfluorescence can be replicated in three diverse cell cultures, and is increased by MPS-treatment, as occurs clinically. The process involves the concentration of fluorescein by a sub population of cells that are active, and does not occur in lysed cells. Our data suggest that corneal staining in the clinic reflects active living cells, and is not directly caused by dead cells being produced in response to adverse clinical stimuli. PMID- 24489651 TI - TFPI1 mediates resistance to doxorubicin in breast cancer cells by inducing a hypoxic-like response. AB - Thrombin and hypoxia are important players in breast cancer progression. Breast cancers often develop drug resistance, but mechanisms linking thrombin and hypoxia to drug resistance remain unresolved. Our studies using Doxorubicin (DOX) resistant MCF7 breast cancer cells reveals a mechanism linking DOX exposure with hypoxic induction of DOX resistance. Global expression changes between parental and DOX resistant MCF7 cells were examined. Westerns, Northerns and immunocytochemistry were used to validate drug resistance and differentially expressed genes. A cluster of genes involved in the anticoagulation pathway, with Tissue Factor Pathway Inhibitor 1 (TFPI1) the top hit, was identified. Plasmids overexpressing TFPI1 were utilized, and 1% O2 was used to test the effects of hypoxia on drug resistance. Lastly, microarray datasets from patients with drug resistant breast tumors were interrogated for TFPI1 expression levels. TFPI1 protein levels were found elevated in 3 additional DOX resistant cells lines, from humans and rats, indicating evolutionarily conservation of the effect. Elevated TFPI1 in DOX resistant cells was active, as thrombin protein levels were coincidentally low. We observed elevated HIF1alpha protein in DOX resistant cells, and in cells with forced expression of TFPI1, suggesting TFPI1 induces HIF1alpha. TFPI1 also induced c-MYC, c-SRC, and HDAC2 protein, as well as DOX resistance in parental cells. Growth of cells in 1% O2 induced elevated HIF1alpha, BCRP and MDR-1 protein, and these cells were resistant to DOX. Our in vitro results were consistent with in vivo patient datasets, as tumors harboring increased BCRP and MDR-1 expression also had increased TFPI1 expression. Our observations are clinically relevant indicating that DOX treatment induces an anticoagulation cascade, leading to inhibition of thrombin and the expression of HIF1alpha. This in turn activates a pathway leading to drug resistance. PMID- 24489652 TI - Epidemiology of spinal cord injuries and risk factors for complete injuries in Guangdong, China: a retrospective study. AB - BACKGROUND: Spinal cord injuries are highly disabling and deadly injuries. Currently, few studies focus on non-traumatic spinal cord injuries, and there is little information regarding the risk factors for complete injuries. This study aims to describe the demographics and the injury characteristics for both traumatic and non-traumatic spinal cord injuries and to explore the risk factors for complete spinal cord injuries. METHODS: A retrospective study was performed by reviewing the medical records of 3,832 patients with spinal cord injuries who were first admitted to the sampled hospitals in Guangdong, China. The demographics and injury characteristics of the patients were described and compared between the different groups using the chi-square test. Logistic regression was conducted to analyze the risk factors for complete spinal cord injuries. RESULTS: The proportion of patients increased from 7.0% to 14.0% from 2003 to 2011. The male-to-female ratio was 3.0 ? 1. The major cause of spinal cord injuries was traffic accidents (21.7%). Many of the injured were workers (36.2%), peasants (22.8%), and unemployed people (13.9%); these occupations accounted for 72.9% of the total sample. A multivariate logistic regression model revealed that the OR (95% CI) for male gender compared to female gender was 1.25 (1.07-1.89), the OR (95%CI) for having a spinal fracture was 1.56 (1.35-2.60), the OR (95%CI) for having a thoracic injury was 1.23 (1.10-2.00), and the OR (95%CI) for having complications was 2.47 (1.96-3.13). CONCLUSION: The proportion of males was higher than the proportion of females. Workers, peasants and the unemployed comprised the high-risk occupational categories. Male gender, having a spinal fracture, having a thoracic injury, and having complications were the major risk factors for a complete injury. We recommend that preventive measures should focus on high-risk populations, such as young males. PMID- 24489653 TI - Ras effector mutant expression suggest a negative regulator inhibits lung tumor formation. AB - Lung cancer is currently the most deadly malignancy in industrialized countries and accounts for 18% of all cancer-related deaths worldwide. Over 70% of patients with non-small cell lung cancer (NSCLC) are diagnosed at a late stage, with a 5 year survival below 10%. KRAS and the EGFR are frequently mutated in NSCLC and while targeted therapies for patients with EGFR mutations exist, oncogenic KRAS is thus far not druggable. KRAS activates multiple signalling pathways, including the PI3K/Akt pathway, the Raf-Mek-Erk pathway and the RalGDS/Ral pathway. Lung specific expression of BrafV600E, the most prevalent BRAF mutation found in human tumors, results in Raf-Mek-Erk pathway activation and in the formation of benign adenomas that undergo widespread senescence in a Cre-activated Braf mouse model (Braf(CA)). However, oncogenic KRAS expression in mice induces adenocarcinomas, suggesting additional KRAS-activated pathways cooperate with sustained RAF-MEK ERK signalling to bypass the oncogene-induced senescence proliferation arrest. To determine which KRAS effectors were responsible for tumor progression, we created four effector domain mutants (S35, G37, E38 and C40) in G12V-activated KRAS and expressed these alone or with BrafV600E in mouse lungs... The S35 and E38 mutants bind to Raf proteins but not PI3K or RalGDS; the G37 mutant binds to RalGDS and not Raf or PI3K and the C40 mutant is specific to PI3K. We designed lentiviral vectors to code for Cre recombinase along with KRAS mutants (V12, V12/S35, V12/G37, V12/E38 or V12/C40) or EGFP as a negative control.. These lentiviruses were used to infect Braf(CA) and wild-type mice. Surprisingly there was a significant decrease in tumor number and penetrance with each KRAS effector domain mutant relative to controls, suggesting that KRAS directly activates effectors with tumor suppressive functions. PMID- 24489655 TI - Spin-lattice distribution MRI maps nigral pathology in progressive supranuclear palsy (PSP) during life: a pilot study. AB - An MRI biomarker for Parkinsonism has long been sought, but almost all attempts at conventional field strengths have proved unsatisfactory, since patients and controls are not separated. The exception is Spin-Lattice Distribution MRI (SLD MRI), a technique which detects changes in the substantia nigra (SN) due to changes in the spin-lattice relaxation time, T1. This easily separates patients with Parkinson's disease (PD) from control subjects at 1.5 Tesla, suggesting that it may be sensitive to presymptomatic disease. SLD-MRI demonstrates a topography of signal change within the SN which is the same as the known topography of pathological change, where the lateral portions of the nucleus are more affected than the medial. In a further step towards its validation, we apply SLD-MRI to a disease control, Progressive Supranuclear Palsy (PSP), the most common of the atypical forms of Parkinsonism. In PSP the topography of pathological change in the SN is reversed. We therefore hypothesized that PSP would show a topography of SLD-MRI signal change in the SN that is the reverse of PD (i.e. the medial portion is more affected than the lateral). All 7 patients showed such a topography of MR signal, and all patients were separated from control subjects. Although this is a step toward validation of SLD-MRI with respect to sensitivity and disease specificity, nevertheless we stress that this is a pilot project only. Validation will only be possible when comparing larger cohorts of PSP, PD and control subjects. PMID- 24489654 TI - Discovery of a small molecule agonist of phosphatidylinositol 3-kinase p110alpha that reactivates latent HIV-1. AB - Combination antiretroviral therapy (cART) can effectively suppress HIV-1 replication, but the latent viral reservoir in resting memory CD4(+) T cells is impervious to cART and represents a major barrier to curing HIV-1 infection. Reactivation of latent HIV-1 represents a possible strategy for elimination of this reservoir. In this study we describe the discovery of 1,2,9,10-tetramethoxy 7H-dibenzo[de,g]quinolin-7-one (57704) which reactivates latent HIV-1 in several cell-line models of latency (J89GFP, U1 and ACH-2). 57704 also increased HIV-1 expression in 3 of 4 CD8(+)-depleted blood mononuclear cell preparations isolated from HIV-1-infected individuals on suppressive cART. In contrast, vorinostat increased HIV-1 expression in only 1 of the 4 donors tested. Importantly, 57704 does not induce global T cell activation. Mechanistic studies revealed that 57704 reactivates latent HIV-1 via the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. 57704 was found to be an agonist of PI3K with specificity to the p110alpha isoform, but not the p110beta, delta or gamma isoforms. Taken together, our work suggests that 57704 could serve as a scaffold for the development of more potent activators of latent HIV-1. Furthermore, it highlights the involvement of the PI3K/Akt pathway in the maintenance of HIV-1 latency. PMID- 24489656 TI - Deconvolution of serum cortisol levels by using compressed sensing. AB - The pulsatile release of cortisol from the adrenal glands is controlled by a hierarchical system that involves corticotropin releasing hormone (CRH) from the hypothalamus, adrenocorticotropin hormone (ACTH) from the pituitary, and cortisol from the adrenal glands. Determining the number, timing, and amplitude of the cortisol secretory events and recovering the infusion and clearance rates from serial measurements of serum cortisol levels is a challenging problem. Despite many years of work on this problem, a complete satisfactory solution has been elusive. We formulate this question as a non-convex optimization problem, and solve it using a coordinate descent algorithm that has a principled combination of (i) compressed sensing for recovering the amplitude and timing of the secretory events, and (ii) generalized cross validation for choosing the regularization parameter. Using only the observed serum cortisol levels, we model cortisol secretion from the adrenal glands using a second-order linear differential equation with pulsatile inputs that represent cortisol pulses released in response to pulses of ACTH. Using our algorithm and the assumption that the number of pulses is between 15 to 22 pulses over 24 hours, we successfully deconvolve both simulated datasets and actual 24-hr serum cortisol datasets sampled every 10 minutes from 10 healthy women. Assuming a one-minute resolution for the secretory events, we obtain physiologically plausible timings and amplitudes of each cortisol secretory event with R (2) above 0.92. Identification of the amplitude and timing of pulsatile hormone release allows (i) quantifying of normal and abnormal secretion patterns towards the goal of understanding pathological neuroendocrine states, and (ii) potentially designing optimal approaches for treating hormonal disorders. PMID- 24489657 TI - Antarctic climate change: extreme events disrupt plastic phenotypic response in Adelie penguins. AB - In the context of predicted alteration of sea ice cover and increased frequency of extreme events, it is especially timely to investigate plasticity within Antarctic species responding to a key environmental aspect of their ecology: sea ice variability. Using 13 years of longitudinal data, we investigated the effect of sea ice concentration (SIC) on the foraging efficiency of Adelie penguins (Pygoscelis adeliae) breeding in the Ross Sea. A 'natural experiment' brought by the exceptional presence of giant icebergs during 5 consecutive years provided unprecedented habitat variation for testing the effects of extreme events on the relationship between SIC and foraging efficiency in this sea-ice dependent species. Significant levels of phenotypic plasticity were evident in response to changes in SIC in normal environmental conditions. Maximum foraging efficiency occurred at relatively low SIC, peaking at 6.1% and decreasing with higher SIC. The 'natural experiment' uncoupled efficiency levels from SIC variations. Our study suggests that lower summer SIC than currently observed would benefit the foraging performance of Adelie penguins in their southernmost breeding area. Importantly, it also provides evidence that extreme climatic events can disrupt response plasticity in a wild seabird population. This questions the predictive power of relationships built on past observations, when not only the average climatic conditions are changing but the frequency of extreme climatic anomalies is also on the rise. PMID- 24489658 TI - Rule-based category learning in children: the role of age and executive functioning. AB - Rule-based category learning was examined in 4-11 year-olds and adults. Participants were asked to learn a set of novel perceptual categories in a classification learning task. Categorization performance improved with age, with younger children showing the strongest rule-based deficit relative to older children and adults. Model-based analyses provided insight regarding the type of strategy being used to solve the categorization task, demonstrating that the use of the task appropriate strategy increased with age. When children and adults who identified the correct categorization rule were compared, the performance deficit was no longer evident. Executive functions were also measured. While both working memory and inhibitory control were related to rule-based categorization and improved with age, working memory specifically was found to marginally mediate the age-related improvements in categorization. When analyses focused only on the sample of children, results showed that working memory ability and inhibitory control were associated with categorization performance and strategy use. The current findings track changes in categorization performance across childhood, demonstrating at which points performance begins to mature and resemble that of adults. Additionally, findings highlight the potential role that working memory and inhibitory control may play in rule-based category learning. PMID- 24489659 TI - Deficiency of CCAAT/enhancer binding protein-epsilon reduces atherosclerotic lesions in LDLR-/- mice. AB - The CCAAT/enhancer binding proteins (C/EBPs) are transcription factors involved in hematopoietic cell development and induction of several inflammatory mediators. C/EBPepsilon is expressed only in myeloid cells including monocytes/macrophages. Atherosclerosis is an inflammatory disorder of the vascular wall and circulating immune cells such as monocytes/macrophages. Mice deficient in the low density lipoprotein (LDL) receptor (Ldlr-/-) fed on a high cholesterol diet (HCD) show elevated blood cholesterol levels and are widely used as models to study human atherosclerosis. In this study, we generated Ldlr and Cebpe double-knockout (llee) mice and compared their atherogenic phenotypes to Ldlr single deficient (llEE) mice after HCD. Macrophages from llee mice have reduced lipid uptake by foam cells and impaired phagokinetic motility in vitro compared to macrophages from llEE mice. Also, compared to llEE mice, llee mice have alterations of lipid metabolism, and reduced atheroma and obesity, particularly the males. Peritoneal macrophages of llee male mice have reduced mRNA expression of FABP4, a fatty acid binding protein implicated in atherosclerosis. Overall, our study suggests that the myeloid specific factor C/EBPepsilon is involved in systemic lipid metabolism and that silencing of C/EBPepsilon could decrease the development of atherosclerosis. PMID- 24489660 TI - Virulent and avirulent strains of Toxoplasma gondii which differ in their glycosylphosphatidylinositol content induce similar biological functions in macrophages. AB - Glycosylphosphatidylinositols (GPIs) from several protozoan parasites are thought to elicit a detrimental stimulation of the host innate immune system aside their main function to anchor surface proteins. Here we analyzed the GPI biosynthesis of an avirulent Toxoplasma gondii type 2 strain (PTG) by metabolic radioactive labeling. We determined the biological function of individual GPI species in the PTG strain in comparison with previously characterized GPI-anchors of a virulent strain (RH). The GPI intermediates of both strains were structurally similar, however the abundance of two of six GPI intermediates was significantly reduced in the PTG strain. The side-by-side comparison of GPI-anchor content revealed that the PTG strain had only ~ 34% of the protein-free GPIs as well as ~ 70% of the GPI-anchored proteins with significantly lower rates of protein N glycosylation compared to the RH strain. All mature GPIs from both strains induced comparable secretion levels of TNF-alpha and IL-12p40, and initiated TLR4/MyD88-dependent NF-kappaBp65 activation in macrophages. Taken together, these results demonstrate that PTG and RH strains differ in their GPI biosynthesis and possess significantly different GPI-anchor content, while individual GPI species of both strains induce similar biological functions in macrophages. PMID- 24489662 TI - Background coloration of squamous epithelium in esophago-pharyngeal squamous cell carcinoma: what causes the color change? AB - OBJECTIVES: This study aims to clarify the cause of background coloration in the epithelia between each dilated intra papillary capillary loop in esophago pharyngeal squamous cell carcinoma. DESIGN: This is a single center retrospective study including 124 patients with 160 lesions who underwent esophagogastroduodenoscopy in Nagasaki University Hospital from September 2007 to March 2012; a detailed comparison between endoscopic images and pathology was performed. Immunohistological assessment using anti-human hemoglobin antibody (anti-Hb Ab) was performed to verify the presence of hemoglobin (Hb) component in the cancer cells. Real-time polymerase chain reaction (RT-PCR) and in situ hybridization (ISH) on Hb-beta mRNA were performed to assess the production of Hb component within the cancer cells. RESULTS: A strong positivity for anti-Hb Ab was observed in the squamous cell carcinoma area, whereas non-cancerous mucosa showed no immunopositivity for Hb. The concordance rate between anti-Hb Ab immunoreactivity and the presence of BC was as high as 80.9%. The amount of Hb beta mRNA expression was three times higher in cancer tissues compared with the surrounding non-cancerous mucosa. ISH images showed that the expression exclusively occurred in cancer cells, indicating that Hb is probably produced within cancer cells. CONCLUSIONS: The background coloration observed is partly due to an extravascular component of Hb. RT-PCR and ISH analyses indicate that Hb is produced within cancer cells. PMID- 24489661 TI - Integrated genomic and epigenomic analysis of breast cancer brain metastasis. AB - The brain is a common site of metastatic disease in patients with breast cancer, which has few therapeutic options and dismal outcomes. The purpose of our study was to identify common and rare events that underlie breast cancer brain metastasis. We performed deep genomic profiling, which integrated gene copy number, gene expression and DNA methylation datasets on a collection of breast brain metastases. We identified frequent large chromosomal gains in 1q, 5p, 8q, 11q, and 20q and frequent broad-level deletions involving 8p, 17p, 21p and Xq. Frequently amplified and overexpressed genes included ATAD2, BRAF, DERL1, DNMTRB and NEK2A. The ATM, CRYAB and HSPB2 genes were commonly deleted and underexpressed. Knowledge mining revealed enrichment in cell cycle and G2/M transition pathways, which contained AURKA, AURKB and FOXM1. Using the PAM50 breast cancer intrinsic classifier, Luminal B, Her2+/ER negative, and basal-like tumors were identified as the most commonly represented breast cancer subtypes in our brain metastasis cohort. While overall methylation levels were increased in breast cancer brain metastasis, basal-like brain metastases were associated with significantly lower levels of methylation. Integrating DNA methylation data with gene expression revealed defects in cell migration and adhesion due to hypermethylation and downregulation of PENK, EDN3, and ITGAM. Hypomethylation and upregulation of KRT8 likely affects adhesion and permeability. Genomic and epigenomic profiling of breast brain metastasis has provided insight into the somatic events underlying this disease, which have potential in forming the basis of future therapeutic strategies. PMID- 24489663 TI - Climate change increases reproductive failure in Magellanic penguins. AB - Climate change is causing more frequent and intense storms, and climate models predict this trend will continue, potentially affecting wildlife populations. Since 1960 the number of days with >20 mm of rain increased near Punta Tombo, Argentina. Between 1983 and 2010 we followed 3496 known-age Magellanic penguin (Spheniscus magellanicus) chicks at Punta Tombo to determine how weather impacted their survival. In two years, rain was the most common cause of death killing 50% and 43% of chicks. In 26 years starvation killed the most chicks. Starvation and predation were present in all years. Chicks died in storms in 13 of 28 years and in 16 of 233 storms. Storm mortality was additive; there was no relationship between the number of chicks killed in storms and the numbers that starved (P = 0.75) or that were eaten (P = 0.39). However, when more chicks died in storms, fewer chicks fledged (P = 0.05, R(2) = 0.14). More chicks died when rainfall was higher and air temperature lower. Most chicks died from storms when they were 9 23 days old; the oldest chick killed in a storm was 41 days old. Storms with heavier rainfall killed older chicks as well as more chicks. Chicks up to 70 days old were killed by heat. Burrow nests mitigated storm mortality (N = 1063). The age span of chicks in the colony at any given time increased because the synchrony of egg laying decreased since 1983, lengthening the time when chicks are vulnerable to storms. Climate change that increases the frequency and intensity of storms results in more reproductive failure of Magellanic penguins, a pattern likely to apply to many species breeding in the region. Climate variability has already lowered reproductive success of Magellanic penguins and is likely undermining the resilience of many other species. PMID- 24489664 TI - Fully automated segmentation of the pons and midbrain using human T1 MR brain images. AB - PURPOSE: This paper describes a novel method to automatically segment the human brainstem into midbrain and pons, called labs: Landmark-based Automated Brainstem Segmentation. LABS processes high-resolution structural magnetic resonance images (MRIs) according to a revised landmark-based approach integrated with a thresholding method, without manual interaction. METHODS: This method was first tested on morphological T1-weighted MRIs of 30 healthy subjects. Its reliability was further confirmed by including neurological patients (with Alzheimer's Disease) from the ADNI repository, in whom the presence of volumetric loss within the brainstem had been previously described. Segmentation accuracies were evaluated against expert-drawn manual delineation. To evaluate the quality of LABS segmentation we used volumetric, spatial overlap and distance-based metrics. RESULTS: The comparison between the quantitative measurements provided by LABS against manual segmentations revealed excellent results in healthy controls when considering either the midbrain (DICE measures higher that 0.9; Volume ratio around 1 and Hausdorff distance around 3) or the pons (DICE measures around 0.93; Volume ratio ranging 1.024-1.05 and Hausdorff distance around 2). Similar performances were detected for AD patients considering segmentation of the pons (DICE measures higher that 0.93; Volume ratio ranging from 0.97-0.98 and Hausdorff distance ranging 1.07-1.33), while LABS performed lower for the midbrain (DICE measures ranging 0.86-0.88; Volume ratio around 0.95 and Hausdorff distance ranging 1.71-2.15). CONCLUSIONS: Our study represents the first attempt to validate a new fully automated method for in vivo segmentation of two anatomically complex brainstem subregions. We retain that our method might represent a useful tool for future applications in clinical practice. PMID- 24489665 TI - Structural and diffusion property alterations in unaffected siblings of patients with obsessive-compulsive disorder. AB - Disrupted white matter integrity and abnormal cortical thickness are widely reported in the pathophysiology of obsessive-compulsive disorder (OCD). However, the relationship between alterations in white matter connectivity and cortical thickness in OCD is unclear. In addition, the heritability of this relationship is poorly understood. To investigate the relationship of white matter microstructure with cortical thickness, we measure fractional anisotropy (FA) of white matter in 30 OCD patients, 19 unaffected siblings and 30 matched healthy controls. Then, we take those regions of significantly altered FA in OCD patients compared with healthy controls to perform fiber tracking. Next, we calculate the fiber quantity in the same tracts. Lastly, we compare cortical thickness in the target regions of those tracts. Patients with OCD exhibited decreased FA in cingulum, arcuate fibers near the superior parietal lobule, inferior longitudinal fasciculus near the right superior temporal gyrus and uncinate fasciculus. Siblings showed reduced FA in arcuate fibers near the superior parietal lobule and anterior limb of internal capsule. Significant reductions in both fiber quantities and cortical thickness in OCD patients and their unaffected siblings were also observed in the projected brain areas when using the arcuate fibers near the left superior parietal lobule as the starting points. Reduced FA in the left superior parietal lobule was observed not only in patients with OCD but also in their unaffected siblings. Originated from the superior parietal lobule, the number of fibers was also found to be decreased and the corresponding cortical regions were thinner relative to controls. The linkage between disrupted white matter integrity and the abnormal cortical thickness may be a vulnerability marker for OCD. PMID- 24489666 TI - Decisions among the undecided: implicit attitudes predict future voting behavior of undecided voters. AB - Implicit attitudes have been suggested as a key to unlock the hidden preferences of undecided voters. Past research, however, offered mixed support for this hypothesis. The present research used a large nationally representative sample and a longitudinal design to examine the predictive utility of implicit and explicit attitude measures in the 2008 U.S. presidential election. In our analyses, explicit attitudes toward candidates predicted voting better for decided than undecided voters, but implicit candidate attitudes were predictive of voting for both decided and undecided voters. Extending our examination to implicit and explicit racial attitudes, we found the same pattern. Taken together, these results provide convergent evidence that implicit attitudes predict voting about as well for undecided as for decided voters. We also assessed a novel explanation for these effects by evaluating whether implicit attitudes may predict the choices of undecided voters, in part, because they are neglected when people introspect about their confidence. Consistent with this idea, we found that the extremity of explicit but not implicit attitudes was associated with greater confidence. These analyses shed new light on the utility of implicit measures in predicting future behavior among individuals who feel undecided. Considering the prior studies together with this new evidence, the data seem to be consistent that implicit attitudes may be successful in predicting the behavior of undecided voters. PMID- 24489667 TI - Impact of uncertainties in exposure assessment on estimates of thyroid cancer risk among Ukrainian children and adolescents exposed from the Chernobyl accident. AB - The 1986 accident at the Chernobyl nuclear power plant remains the most serious nuclear accident in history, and excess thyroid cancers, particularly among those exposed to releases of iodine-131 remain the best-documented sequelae. Failure to take dose-measurement error into account can lead to bias in assessments of dose response slope. Although risks in the Ukrainian-US thyroid screening study have been previously evaluated, errors in dose assessments have not been addressed hitherto. Dose-response patterns were examined in a thyroid screening prevalence cohort of 13,127 persons aged <18 at the time of the accident who were resident in the most radioactively contaminated regions of Ukraine. We extended earlier analyses in this cohort by adjusting for dose error in the recently developed TD 10 dosimetry. Three methods of statistical correction, via two types of regression calibration, and Monte Carlo maximum-likelihood, were applied to the doses that can be derived from the ratio of thyroid activity to thyroid mass. The two components that make up this ratio have different types of error, Berkson error for thyroid mass and classical error for thyroid activity. The first regression-calibration method yielded estimates of excess odds ratio of 5.78 Gy( 1) (95% CI 1.92, 27.04), about 7% higher than estimates unadjusted for dose error. The second regression-calibration method gave an excess odds ratio of 4.78 Gy(-1) (95% CI 1.64, 19.69), about 11% lower than unadjusted analysis. The Monte Carlo maximum-likelihood method produced an excess odds ratio of 4.93 Gy(-1) (95% CI 1.67, 19.90), about 8% lower than unadjusted analysis. There are borderline significant (p = 0.101-0.112) indications of downward curvature in the dose response, allowing for which nearly doubled the low-dose linear coefficient. In conclusion, dose-error adjustment has comparatively modest effects on regression parameters, a consequence of the relatively small errors, of a mixture of Berkson and classical form, associated with thyroid dose assessment. PMID- 24489668 TI - An ribonuclease T2 family protein modulates Acinetobacter baumannii abiotic surface colonization. AB - Acinetobacter baumannii is an emerging bacterial pathogen of considerable medical concern. The organism's transmission and ability to cause disease has been associated with its propensity to colonize and form biofilms on abiotic surfaces in health care settings. To better understand the genetic determinants that affect biomaterial attachment, we performed a transposon mutagenesis analysis of abiotic surface-colonization using A. baumannii strain 98-37-09. Disruption of an RNase T2 family gene was found to limit the organism's ability to colonize polystyrene, polypropylene, glass, and stainless steel surfaces. DNA microarray analyses revealed that in comparison to wild type and complemented cells, the RNase T2 family mutant exhibited reduced expression of 29 genes, 15 of which are predicted to be associated with bacterial attachment and surface-associated motility. Motility assays confirmed that RNase T2 mutant displays a severe motility defect. Taken together, our results indicate that the RNase T2 family protein identified in this study is a positive regulator of A. baumannii's ability to colonize inanimate surfaces and motility. Moreover, the enzyme may be an effective target for the intervention of biomaterial colonization, and consequently limit the organism's transmission within the hospital setting. PMID- 24489669 TI - Predicting the risk of suicide by analyzing the text of clinical notes. AB - We developed linguistics-driven prediction models to estimate the risk of suicide. These models were generated from unstructured clinical notes taken from a national sample of U.S. Veterans Administration (VA) medical records. We created three matched cohorts: veterans who committed suicide, veterans who used mental health services and did not commit suicide, and veterans who did not use mental health services and did not commit suicide during the observation period (n = 70 in each group). From the clinical notes, we generated datasets of single keywords and multi-word phrases, and constructed prediction models using a machine-learning algorithm based on a genetic programming framework. The resulting inference accuracy was consistently 65% or more. Our data therefore suggests that computerized text analytics can be applied to unstructured medical records to estimate the risk of suicide. The resulting system could allow clinicians to potentially screen seemingly healthy patients at the primary care level, and to continuously evaluate the suicide risk among psychiatric patients. PMID- 24489671 TI - Powerlaw: a Python package for analysis of heavy-tailed distributions. AB - Power laws are theoretically interesting probability distributions that are also frequently used to describe empirical data. In recent years, effective statistical methods for fitting power laws have been developed, but appropriate use of these techniques requires significant programming and statistical insight. In order to greatly decrease the barriers to using good statistical methods for fitting power law distributions, we developed the powerlaw Python package. This software package provides easy commands for basic fitting and statistical analysis of distributions. Notably, it also seeks to support a variety of user needs by being exhaustive in the options available to the user. The source code is publicly available and easily extensible. PMID- 24489670 TI - Disruption of TgPHIL1 alters specific parameters of Toxoplasma gondii motility measured in a quantitative, three-dimensional live motility assay. AB - T. gondii uses substrate-dependent gliding motility to invade cells of its hosts, egress from these cells at the end of its lytic cycle and disseminate through the host organism during infection. The ability of the parasite to move is therefore critical for its virulence. T. gondii engages in three distinct types of gliding motility on coated two-dimensional surfaces: twirling, circular gliding and helical gliding. We show here that motility in a three-dimensional Matrigel-based environment is strikingly different, in that all parasites move in irregular corkscrew-like trajectories. Methods developed for quantitative analysis of motility parameters along the smoothed trajectories demonstrate a complex but periodic pattern of motility with mean and maximum velocities of 0.58 +/- 0.07 um/s and 2.01 +/- 0.17 um/s, respectively. To test how a change in the parasite's crescent shape might affect trajectory parameters, we compared the motility of Deltaphil1 parasites, which are shorter and wider than wild type, to the corresponding parental and complemented lines. Although comparable percentages of parasites were moving for all three lines, the Deltaphil1 mutant exhibited significantly decreased trajectory lengths and mean and maximum velocities compared to the parental parasite line. These effects were either partially or fully restored upon complementation of the Deltaphil1 mutant. These results show that alterations in morphology may have a significant impact on T. gondii motility in an extracellular matrix-like environment, provide a possible explanation for the decreased fitness of Deltaphil1 parasites in vivo, and demonstrate the utility of the quantitative three-dimensional assay for studying parasite motility. PMID- 24489672 TI - The association of cardioprotective medications with pneumonia-related outcomes. AB - INTRODUCTION: Little research has examined whether cardiovascular medications, other than statins, are associated with improved outcomes after pneumonia. Our aim was to examine the association between the use of beta-blockers, statins, angiotensin converting enzyme (ACE) inhibitors, and angiotensin II receptor blockers (ARBs) with pneumonia-related outcomes. MATERIALS AND METHODS: We conducted a retrospective population-based study on male patients >= 65 years of age hospitalized with pneumonia and who did not have pre-existing cardiac disease. Our primary analyses were multilevel regression models that examined the association between cardiovascular medication classes and either mortality or cardiovascular events. RESULTS: Our cohort included 21,985 patients: 22% died within 90 days of admission, and 22% had a cardiac event within 90 days. The cardiovascular medications studied that were associated with decreased 90-day mortality included: statins (OR 0.70, 95% CI 0.63-0.77), ACE inhibitors (OR 0.82, 95% CI 0.74-0.91), and ARBs (OR 0.58, 95% CI 0.44-0.77). However, none of the medications were significantly associated with decreased cardiovascular events. DISCUSSION: While statins, ACE inhibitors, and ARBs, were associated with decreased mortality, there was no significant association with decreased CV events. These results indicate that this decreased mortality is unlikely due to their potential cardioprotective effects. PMID- 24489673 TI - Increased risk of non-fatal myocardial infarction following testosterone therapy prescription in men. AB - BACKGROUND: An association between testosterone therapy (TT) and cardiovascular disease has been reported and TT use is increasing rapidly. METHODS: We conducted a cohort study of the risk of acute non-fatal myocardial infarction (MI) following an initial TT prescription (N = 55,593) in a large health-care database. We compared the incidence rate of MI in the 90 days following the initial prescription (post-prescription interval) with the rate in the one year prior to the initial prescription (pre-prescription interval) (post/pre). We also compared post/pre rates in a cohort of men prescribed phosphodiesterase type 5 inhibitors (PDE5I; sildenafil or tadalafil, N = 167,279), and compared TT prescription post/pre rates with the PDE5I post/pre rates, adjusting for potential confounders using doubly robust estimation. RESULTS: In all subjects, the post/pre-prescription rate ratio (RR) for TT prescription was 1.36 (1.03, 1.81). In men aged 65 years and older, the RR was 2.19 (1.27, 3.77) for TT prescription and 1.15 (0.83, 1.59) for PDE5I, and the ratio of the rate ratios (RRR) for TT prescription relative to PDE5I was 1.90 (1.04, 3.49). The RR for TT prescription increased with age from 0.95 (0.54, 1.67) for men under age 55 years to 3.43 (1.54, 7.56) for those aged >= 75 years (p trend = 0.03), while no trend was seen for PDE5I (p trend = 0.18). In men under age 65 years, excess risk was confined to those with a prior history of heart disease, with RRs of 2.90 (1.49, 5.62) for TT prescription and 1.40 (0.91, 2.14) for PDE5I, and a RRR of 2.07 (1.05, 4.11). DISCUSSION: In older men, and in younger men with pre-existing diagnosed heart disease, the risk of MI following initiation of TT prescription is substantially increased. PMID- 24489674 TI - Automatic conversational scene analysis in children with Asperger syndrome/high functioning autism and typically developing peers. AB - Individuals with Asperger syndrome/High Functioning Autism fail to spontaneously attribute mental states to the self and others, a life-long phenotypic characteristic known as mindblindness. We hypothesized that mindblindness would affect the dynamics of conversational interaction. Using generative models, in particular Gaussian mixture models and observed influence models, conversations were coded as interacting Markov processes, operating on novel speech/silence patterns, termed Steady Conversational Periods (SCPs). SCPs assume that whenever an agent's process changes state (e.g., from silence to speech), it causes a general transition of the entire conversational process, forcing inter-actant synchronization. SCPs fed into observed influence models, which captured the conversational dynamics of children and adolescents with Asperger syndrome/High Functioning Autism, and age-matched typically developing participants. Analyzing the parameters of the models by means of discriminative classifiers, the dialogs of patients were successfully distinguished from those of control participants. We conclude that meaning-free speech/silence sequences, reflecting inter-actant synchronization, at least partially encode typical and atypical conversational dynamics. This suggests a direct influence of theory of mind abilities onto basic speech initiative behavior. PMID- 24489675 TI - Emergence of small-world anatomical networks in self-organizing clustered neuronal cultures. AB - In vitro primary cultures of dissociated invertebrate neurons from locust ganglia are used to experimentally investigate the morphological evolution of assemblies of living neurons, as they self-organize from collections of separated cells into elaborated, clustered, networks. At all the different stages of the culture's development, identification of neurons' and neurites' location by means of a dedicated software allows to ultimately extract an adjacency matrix from each image of the culture. In turn, a systematic statistical analysis of a group of topological observables grants us the possibility of quantifying and tracking the progression of the main network's characteristics during the self-organization process of the culture. Our results point to the existence of a particular state corresponding to a small-world network configuration, in which several relevant graph's micro- and meso-scale properties emerge. Finally, we identify the main physical processes ruling the culture's morphological transformations, and embed them into a simplified growth model qualitatively reproducing the overall set of experimental observations. PMID- 24489676 TI - The role of calpain-myosin 9-Rab7b pathway in mediating the expression of Toll like receptor 4 in platelets: a novel mechanism involved in alpha-granules trafficking. AB - Toll-like receptors (TLRs) plays a critical role in innate immunity. In 2004, Aslam R. and Shiraki R. first determined that murine and human platelets express functional TLRs. Additionally, Andonegui G. demonstrated that platelets express TLR4, which contributes to thrombocytopenia. However, the underlying mechanisms of TLR4 expression by platelets have been rarely explored until now. The aim of this study was to identify the mechanism of TLR4 expression underlying thrombin treatment. The human washed platelets were used in this study. According to flowcytometry and western blot analysis, the surface levels of TLR4 were significantly enhanced in thrombin-activated human platelets and decreased by TMB 8, calpeptin, and U73122, but not Y27632 (a Rho-associated protein kinase ROCK inhibitor) indicating that thrombin-mediated TLR4 expression was modulated by PAR/PLC pathway, calcium and calpain. Co-immunoprecipitation (co-IP) assay demonstrated that the interaction between TLR4 and myosin-9 (a substrate of calpain) was regulated by calpain; cleavage of myosin-9 enhanced TLR4 expression in thrombin treated platelets. Transmission electron microscope data indicated that human platelets used alpha-granules to control TLR4 expression; the co-IP experiment suggested that myosin-9 did not coordinate with Rab7b to negatively regulate TLR4 trafficking in thrombin treated platelets. In summary, phospholipase Cgamma-calpain-myosin 9-Rab7b axis was responsible for the mechanism underlying the regulation of TLR4 containing alpha-granules trafficking in thrombin-stimulated platelets, which was involved in coagulation. PMID- 24489677 TI - Monitoring repair of UV-induced 6-4-photoproducts with a purified DDB2 protein complex. AB - Because cells are constantly subjected to DNA damaging insults, DNA repair pathways are critical for genome integrity [1]. DNA damage recognition protein complexes (DRCs) recognize DNA damage and initiate DNA repair. The DNA-Damage Binding protein 2 (DDB2) complex is a DRC that initiates nucleotide excision repair (NER) of DNA damage caused by ultraviolet light (UV) [2]-[4]. Using a purified DDB2 DRC, we created a probe ("DDB2 proteo-probe") that hybridizes to nuclei of cells irradiated with UV and not to cells exposed to other genotoxins. The DDB2 proteo-probe recognized UV-irradiated DNA in classical laboratory assays, including cyto- and histo-chemistry, flow cytometry, and slot-blotting. When immobilized, the proteo-probe also bound soluble UV-irradiated DNA in ELISA like and DNA pull-down assays. In vitro, the DDB2 proteo-probe preferentially bound 6-4-photoproducts [(6-4)PPs] rather than cyclobutane pyrimidine dimers (CPDs). We followed UV-damage repair by cyto-chemistry in cells fixed at different time after UV irradiation, using either the DDB2 proteo-probe or antibodies against CPDs, or (6-4)PPs. The signals obtained with the DDB2 proteo probe and with the antibody against (6-4)PPs decreased in a nearly identical manner. Since (6-4)PPs are repaired only by nucleotide excision repair (NER), our results strongly suggest the DDB2 proteo-probe hybridizes to DNA containing (6 4)PPs and allows monitoring of their removal during NER. We discuss the general use of purified DRCs as probes, in lieu of antibodies, to recognize and monitor DNA damage and repair. PMID- 24489678 TI - Mortality trends observed in population-based surveillance of an urban slum settlement, Kibera, Kenya, 2007-2010. AB - BACKGROUND: We used population based infectious disease surveillance to characterize mortality rates in residents of an urban slum in Kenya. METHODS: We analyzed biweekly household visit data collected two weeks before death for 749 cases who died during January 1, 2007 to December 31, 2010. We also selected controls matched by age, gender and having a biweekly household visit within two weeks before death of the corresponding case and compared the symptoms reported. RESULTS: The overall mortality rate was 6.3 per 1,000 person years of observation (PYO) (females: 5.7; males: 6.8). Infant mortality rate was 50.2 per 1000 PYOs, and it was 15.1 per 1,000 PYOs for children <5 years old. Poisson regression indicates a significant decrease over time in overall mortality from (6.0 in 2007 to 4.0 in 2010 per 1000 PYOs; p<0.05) in persons >= 5 years old. This decrease was predominant in females (7.8 to 5.7 per 1000 PYOs; p<0.05). Two weeks before death, significantly higher prevalence for cough (OR = 4.7 [95% CI: 3.7-5.9]), fever (OR = 8.1 [95% CI: 6.1-10.7]), and diarrhea (OR = 9.1 [95% CI: 6.4-13.2]) were reported among participants who died (cases) when compared to participants who did not die (controls). Diarrhea followed by fever were independently associated with deaths (OR = 14.4 [95% CI: 7.1-29.2]), and (OR = 11.4 [95% CI: 6.7-19.4]) respectively. CONCLUSIONS: Despite accessible health care, mortality rates are high among people living in this urban slum; infectious disease syndromes appear to be linked to a substantial proportion of deaths. Rapid urbanization poses an increasing challenge in national efforts to improve health outcomes, including reducing childhood mortality rates. Targeting impoverished people in urban slums with effective interventions such as water and sanitation interventions are needed to achieve national objectives for health. PMID- 24489679 TI - Untreated sleep-disordered breathing: links to aging-related decline in sleep dependent memory consolidation. AB - BACKGROUND: Increasing age is associated with a decline in cognition and motor skills, while at the same time exacerbating one's risk of developing obstructive sleep apnea (OSA). OSA-related cognitive deficits are highly prevalent and can affect various memory systems including overnight memory consolidation on a motor sequence task. Thus, the aim of our study was to examine the effect of aging on sleep-dependent motor memory consolidation in patients with and without OSA. METHODS: We studied 44 patients (19-68 years) who had been referred by a physician for a baseline polysomnography (PSG) evaluation. Based on their PSG, patients were assigned either to the OSA group (AHI>5/h), or control (Non-OSA) group (AHI<5/h). All subjects performed the Psychomotor Vigilance Task (PVT) and the Motor Sequence Learning Task (MST) in the evening and again in the morning after their PSG. RESULTS: Despite similar learning in the evening, OSA subjects showed significantly less overnight improvement on the MST, both for immediate (OSA -2.7% +/- 2.8% vs. controls 12.2% +/- 3.5%; p = 0.002) and plateau improvement (OSA 4.9% +/- 2.3% vs. controls 21.1%+/- 4.0%; p = 0.001). Within the OSA group, there was a significant negative correlation between overnight MST improvement and age (r(2) = 0.3; p = 0.01), an effect that was not observed in the Non-OSA group (r(2) = 0.08; p = 0.23). CONCLUSIONS: Consistent with previous research, healthy sleepers demonstrated a higher degree of sleep-dependent overnight improvement on the MST, an effect not mitigated by increasing age. However, the presence of untreated obstructive sleep apnea is associated with an aging-related cognitive deficit, otherwise not present in individuals without OSA. As other research has linked the presence of OSA to a higher likelihood of developing dementia, future studies are necessary to examine if the inhibition of memory consolidation is tied to the onset of neurodegenerative disease. PMID- 24489680 TI - Magnetic resonance evaluation of multiple myeloma at 3.0 Tesla: how do bone marrow plasma cell percentage and selection of protocols affect lesion conspicuity? AB - PURPOSE: To compare various pulse sequences in terms of percent contrast and contrast-to-noise ratio (CNR) for detection of focal multiple myeloma lesions and to assess the dependence of lesion conspicuity on the bone marrow plasma cell percent (BMPC%). MATERIALS AND METHODS: Sagittal T1-weighted FSE, fat-suppressed T2-weighted FSE (FS- T2 FSE), fast STIR and iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) imaging of the lumbar spine were performed (n = 45). Bone marrow (BM)-focal myeloma lesion percent contrast and CNR were calculated. Spearman rank correlation coefficients were obtained between percent contrast, CNR and BMPC%. Percent contrasts and CNRs were compared among the three imaging sequences. RESULTS: BM-focal lesion percent contrasts, CNRs and BMPC% showed significant negative correlations in the three fat-suppression techniques. Percent contrast and CNRs were significantly higher for FS- T2 FSE than for STIR (P<0.01, P<0.05, respectively), but no significant differences were found among the three fat-suppression methods in the low tumor load BM group. CONCLUSION: The higher BMPC% was within BM, the less conspicuous the focal lesion was on fat-suppressed MRI. The most effective protocol for detecting focal lesions was FS- T2 FSE. In the high tumor load BM group, no significant differences in lesion conspicuity were identified among the three fat suppression techniques. PMID- 24489682 TI - Adaptation of Musca domestica L. field population to laboratory breeding causes transcriptional alterations. AB - BACKGROUND: The housefly, Musca domestica, has developed resistance to most insecticides applied for its control. Expression of genes coding for detoxification enzymes play a role in the response of the housefly when encountered by a xenobiotic. The highest level of constitutive gene expression of nine P450 genes was previously found in a newly-collected susceptible field population in comparison to three insecticide-resistant laboratory strains and a laboratory reference strain. RESULTS: We compared gene expression of five P450s by qPCR as well as global gene expression by RNAseq in the newly-acquired field population (845b) in generation F1, F13 and F29 to test how gene expression changes following laboratory adaption. Four (CYP6A1, CYP6A36, CYP6D3, CYP6G4) of five investigated P450 genes adapted to breeding by decreasing expression. CYP6D1 showed higher female expression in F29 than in F1. For males, about half of the genes accessed in the global gene expression were up-regulated in F13 and F29 in comparison with the F1 population. In females, 60% of the genes were up-regulated in F13 in comparison with F1, while 33% were up-regulated in F29. Forty potential P450 genes were identified. In most cases, P450 gene expression was decreased in F13 flies in comparison with F1. Gene expression then increased from F13 to F29 in males and decreased further in females. CONCLUSION: The global gene expression changes massively during adaptation to laboratory breeding. In general, global expression decreased as a result of laboratory adaption in males, while female expression was not unidirectional. Expression of P450 genes was in general down regulated as a result of laboratory adaption. Expression of hexamerin, coding for a storage protein was increased, while gene expression of genes coding for amylases decreased. This suggests a major impact of the surrounding environment on gene response to xenobiotics and genetic composition of housefly strains. PMID- 24489681 TI - Crystal structures of HIV-1 gp120 envelope glycoprotein in complex with NBD analogues that target the CD4-binding site. AB - Efforts to develop therapeutic agents that inhibit HIV-1 entry have led to the identification of several small molecule leads. One of the most promising is the NBD series, which binds within a conserved gp120 cavity and possesses para halogen substituted aromatic rings, a central oxalamide linker, and a tetramethylpiperidine moiety. In this study, we characterized structurally the interactions of four NBD analogues containing meta-fluoro substitution on the aromatic ring and various heterocyclic ring replacements of the tetramethylpiperidine group. The addition of a meta-fluorine to the aromatic ring improved surface complementarity and did not alter the position of the analogue relative to gp120. By contrast, heterocyclic ring replacements of the tetramethylpiperidine moiety exhibited diverse positioning and interactions with the vestibule of the gp120 cavity. Overall, the biological profile of NBD congeners was modulated by ligand interactions with the gp120-cavity vestibule. Herein, six co-crystal structures of NBD-analogues with gp120 provide a structural framework for continued small molecule-entry inhibitor optimization. PMID- 24489684 TI - A new titanosaurian sauropod from the Hekou Group (Lower Cretaceous) of the Lanzhou-Minhe Basin, Gansu Province, China. AB - Increased excavation of dinosaurs from China over the last two decades has enriched the record of Asian titanosauriform sauropods. However, the relationships of these sauropods remain contentious, and hinges on a few well preserved taxa, such as Euhelopus zdanskyi. Here we describe a new sauropod, Yongjinglong datangi gen. nov. et sp. nov., from the Lower Cretaceous Hekou Group in the Lanzhou Basin of Gansu Province, northwestern China. Yongjinglong datangi is characterized by the following unique combination of characters, including seven autapomorphies: long-crowned, spoon-shaped premaxillary tooth; axially elongate parapophyses on the cervical vertebra; very deep lateral pneumatic foramina on the lateral surfaces of the cervical and cranial dorsal vertebral centra; low, unbifurcated neural spine fused with the postzygapophyses to form a cranially-pointing, triangular plate in a middle dorsal vertebra; an "XI"-shaped configuration of the laminae on the arches of the middle dorsal vertebrae; a very long scapular blade with straight cranial and caudal edges; and a tall, deep groove on the lateral surface of the distal shaft of the radius. The new specimen shares several features with other sauropods: a pronounced M. triceps longus tubercle on the scapula and ventrolaterally elongated parapophyses in its cervical vertebra as in Euhelopodidae. Based on phylogenetic analyses Yongjinglong datangi is highly derived within Titanosauria, which suggests either a remarkable convergence with more basal titanosauriform sauropods in the Early Cretaceous or a retention of plesiomorphic features that were lost in other titanosaurians. The morphology and remarkable length of the scapulocoracoid reveal an unusual relationship between the shoulder and the middle trunk: the scapulocoracoid spans over half of the length of the trunk. The medial, notch shaped coracoid foramen and the partially fused scapulocoracoid synostosis suggest that the specimen is a subadult individual. This specimen sheds new light on the diversity of Early Cretaceous Titanosauriformes in China. PMID- 24489683 TI - Humor as a reward mechanism: event-related potentials in the healthy and diseased brain. AB - Humor processing involves distinct processing stages including incongruity detection, emotional response, and engagement of mesolimbic reward regions. Dysfunctional reward processing and clinical symptoms in response to humor have been previously described in both hypocretin deficient narcolepsy-cataplexy (NC) and in idiopathic Parkinson disease (PD). For NC patients, humor is the strongest trigger for cataplexy, a transient loss of muscle tone, whereas dopamine deficient PD-patients show blunted emotional responses to humor. To better understand the role of reward system and the various contributions of hypocretinergic and dopaminergic mechanisms to different stages of humor processing we examined the electrophysiological response to humorous and neutral pictures when given as reward feedback in PD, NC and healthy controls. Humor compared to neutral feedback demonstrated modulation of early ERP amplitudes likely corresponding to visual processing stages, with no group differences. At 270 ms post-feedback, conditions showed topographical and amplitudinal differences for frontal and left posterior electrodes, in that humor feedback was absent in PD patients but increased in NC patients. We suggest that this effect relates to a relatively early affective response, reminiscent of increased amygdala response reported in NC patients. Later ERP differences, corresponding to the late positive potential, revealed a lack of sustained activation in PD, likely due to altered dopamine regulation in reward structures in these patients. This research provides new insights into the temporal dynamics and underlying mechanisms of humor detection and appreciation in health and disease. PMID- 24489685 TI - Keap1 cysteine 288 as a potential target for diallyl trisulfide-induced Nrf2 activation. AB - Diallyl sulfide, diallyl disulfide, and daillyl trisulfide (DATS) are major volatile components of garlic oil. In this study, we assessed their relative potency in inducing antioxidant enzyme expression. Among the three organosulfur compounds, DATS was found to be most potent in inducing heme oxygenase-1 (HO-1) and NAD(P)H: quinone oxidoreductase-1 (NQO1) in human gastric epithelial (AGS) cells. Furthermore, DATS administration by gavage increased the expression of HO 1 and NQO1 in C57BL/6 mouse stomach. Treatment with DATS increased the accumulation of nuclear factor-erythroid-2-related factor-2 (Nrf2) in the nucleus of cultured AGS cells and in mouse stomach in vivo. The DATS-induced expression of HO-1 and NQO1 was abrogated in the cells transiently transfected with Nrf2 siRNA or in the embryonic fibroblasts from Nrf2-null mice, indicating that Nrf2 is a key mediator of the cytoprotective effects of DATS. Pretreatment of AGS cells with N-acetylcysteine or dithiothreitol attenuated DATS-induced nuclear localization of Nrf2 and the expression of HO-1 and NQO1. Cysteine-151, -273 and 288 of Kelch-like ECH-associated protein-1 (Keap1), a cytosolic repressor of Nrf2, have been considered to act as a redox sensor and play a role in Nrf2 activation. To determine whether DATS could inactivate Keap1 through thiol modification, we established cell lines constitutively expressing wild type-Keap1 or three different mutant constructs in which cysteine-151, -273, or -288 of Keap1 was replaced with serine by retroviral gene transfer. DATS failed to activate Nrf2, and to induce expression of HO-1 and NQO1 only in Keap1-C288S mutant cells. LC-ESI-MS/MS analysis of recombinant Keap1 treated with DATS revealed that the peptide fragment containing Cys288 gained a molecular mass of 72.1 Da equivalent to the molecular weight of mono-allyl mono-sulfide. Taken together, these findings suggest that DATS may directly interact with the Cys288 residue of Keap1, which partly accounts for its ability to induce Nrf2 activation and upregulate defensive gene expression. PMID- 24489686 TI - A tale of two "forests": random forest machine learning AIDS tropical forest carbon mapping. AB - Accurate and spatially-explicit maps of tropical forest carbon stocks are needed to implement carbon offset mechanisms such as REDD+ (Reduced Deforestation and Degradation Plus). The Random Forest machine learning algorithm may aid carbon mapping applications using remotely-sensed data. However, Random Forest has never been compared to traditional and potentially more reliable techniques such as regionally stratified sampling and upscaling, and it has rarely been employed with spatial data. Here, we evaluated the performance of Random Forest in upscaling airborne LiDAR (Light Detection and Ranging)-based carbon estimates compared to the stratification approach over a 16-million hectare focal area of the Western Amazon. We considered two runs of Random Forest, both with and without spatial contextual modeling by including--in the latter case--x, and y position directly in the model. In each case, we set aside 8 million hectares (i.e., half of the focal area) for validation; this rigorous test of Random Forest went above and beyond the internal validation normally compiled by the algorithm (i.e., called "out-of-bag"), which proved insufficient for this spatial application. In this heterogeneous region of Northern Peru, the model with spatial context was the best preforming run of Random Forest, and explained 59% of LiDAR-based carbon estimates within the validation area, compared to 37% for stratification or 43% by Random Forest without spatial context. With the 60% improvement in explained variation, RMSE against validation LiDAR samples improved from 33 to 26 Mg C ha(-1) when using Random Forest with spatial context. Our results suggest that spatial context should be considered when using Random Forest, and that doing so may result in substantially improved carbon stock modeling for purposes of climate change mitigation. PMID- 24489687 TI - Comparison of corneal epithelial and stromal thickness distributions between eyes with keratoconus and healthy eyes with corneal astigmatism >= 2.0 D. AB - PURPOSE: To identify corneal epithelial- and stromal-thickness distribution patterns in keratoconus using spectral-domain optical coherence tomography (SD OCT). PATIENTS AND METHODS: We analyzed SD-OCT findings in 20 confirmed cases of keratoconus (group 1) and in 20 healthy subjects with corneal astigmatism >= 2 D (group 2). Epithelial and stromal thicknesses were measured at 11 strategic locations along the steepest and flattest meridians, previously located by corneal topography. Vertical mirrored symmetry superimposition was used in the statistical analysis. RESULTS: The mean maximum keratometry measurements in groups 1 and 2 were 47.9 +/- 2.9 D (range, 41.8-52.8) and 45.6 +/- 1.1 D (range, 42.3-47.5), respectively, with mean corneal cylinders of 3.3 +/- 2.2 D (range, 0.5-9.5) and 3.6 +/- 1.2 D (range, 2.0-6.4), respectively. The mean epithelial thickness along the steepest meridian in group 1 was the lowest (37.4 +/- 4.4 um) at 1.2 mm inferotemporally and the highest (59.3 +/- 4.4 um) at 1.4 mm supranasally from the corneal vertex. There was only a small deviation in thickness along the steepest meridian in group 2, as well as along the flattest meridians in both groups. The stromal thickness distribution in the two groups was similar to the epithelial, while the stromal thickness was generally lower in group 1 than in group 2. CONCLUSIONS: SD-OCT provides details about the distribution of corneal epithelial and stromal thicknesses. The epithelium and stroma in keratoconic eyes were thinner inferotemporally and thicker supranasally compared with control eyes. The distribution pattern was more distinct in epithelium than in stroma. This finding may help improve the early diagnosis of keratoconus. TRIAL REGISTRATION: ClinicalTrials.gov NCT02023619. PMID- 24489688 TI - An high-throughput in vivo screening system to select H3K4-specific histone demethylase inhibitors. AB - BACKGROUND: Histone demethylases (HDMs) have a prominent role in epigenetic regulation and are emerging as potential therapeutic cancer targets. The search for small molecules able to inhibit HDMs in vivo is very active but at the present few compounds were found to be specific for defined classes of these enzymes. METHODOLOGY/PRINCIPAL FINDINGS: In order to discover inhibitors specific for H3K4 histone demethylation we set up a screening system which tests the effects of candidate small molecule inhibitors on a S.cerevisiae strain which requires Jhd2 demethylase activity to efficiently grow in the presence of rapamycin. In order to validate the system we screened a library of 45 structurally different compounds designed as competitive inhibitors of alpha ketoglutarate (alpha-KG) cofactor of the enzyme, and found that one of them inhibited Jhd2 activity in vitro and in vivo. The same compound effectively inhibits human Jumonji AT-Rich Interactive Domain (JARID) 1B and 1D in vitro and increases H3K4 tri-methylation in HeLa cell nuclear extracts (NEs). When added in vivo to HeLa cells, the compound leads to an increase of tri-methyl-H3K4 (H3K4me3) but does not affect H3K9 tri-methylation. We describe the cytostatic and toxic effects of the compound on HeLa cells at concentrations compatible with its inhibitory activity. CONCLUSIONS/SIGNIFICANCE: Our screening system is proved to be very useful in testing putative H3K4-specific HDM inhibitors for the capacity of acting in vivo without significantly altering the activity of other important 2-oxoglutarate oxygenases. PMID- 24489689 TI - Landmarking the brain for geometric morphometric analysis: an error study. AB - Neuroanatomic phenotypes are often assessed using volumetric analysis. Although powerful and versatile, this approach is limited in that it is unable to quantify changes in shape, to describe how regions are interrelated, or to determine whether changes in size are global or local. Statistical shape analysis using coordinate data from biologically relevant landmarks is the preferred method for testing these aspects of phenotype. To date, approximately fifty landmarks have been used to study brain shape. Of the studies that have used landmark-based statistical shape analysis of the brain, most have not published protocols for landmark identification or the results of reliability studies on these landmarks. The primary aims of this study were two-fold: (1) to collaboratively develop detailed data collection protocols for a set of brain landmarks, and (2) to complete an intra- and inter-observer validation study of the set of landmarks. Detailed protocols were developed for 29 cortical and subcortical landmarks using a sample of 10 boys aged 12 years old. Average intra-observer error for the final set of landmarks was 1.9 mm with a range of 0.72 mm-5.6 mm. Average inter observer error was 1.1 mm with a range of 0.40 mm-3.4 mm. This study successfully establishes landmark protocols with a minimal level of error that can be used by other researchers in the assessment of neuroanatomic phenotypes. PMID- 24489690 TI - Ants use partner specific odors to learn to recognize a mutualistic partner. AB - Regulation via interspecific communication is an important for the maintenance of many mutualisms. However, mechanisms underlying the evolution of partner communication are poorly understood for many mutualisms. Here we show, in an ant lycaenid butterfly mutualism, that attendant ants selectively learn to recognize and interact cooperatively with a partner. Workers of the ant Pristomyrmex punctatus learn to associate cuticular hydrocarbons of mutualistic Narathura japonica caterpillars with food rewards and, as a result, are more likely to tend the caterpillars. However, the workers do not learn to associate the cuticular hydrocarbons of caterpillars of a non-ant-associated lycaenid, Lycaena phlaeas, with artificial food rewards. Chemical analysis revealed cuticular hydrocarbon profiles of the mutualistic caterpillars were complex compared with those of non ant-associated caterpillars. Our results suggest that partner-recognition based on partner-specific chemical signals and cognitive abilities of workers are important mechanisms underlying the evolution and maintenance of mutualism with ants. PMID- 24489691 TI - Deep imaging: how much of the proteome does current top-down technology already resolve? AB - Effective proteome analyses are based on interplay between resolution and detection. It had been claimed that resolution was the main factor limiting the use of two-dimensional gel electrophoresis. Improved protein detection now indicates that this is unlikely to be the case. Using a highly refined protocol, the rat brain proteome was extracted, resolved, and detected. In order to overcome the stain saturation threshold, high abundance protein species were excised from the gel following standard imaging. Gels were then imaged again using longer exposure times, enabling detection of lower abundance, less intensely stained protein species. This resulted in a significant enhancement in the detection of resolved proteins, and a slightly modified digestion protocol enabled effective identification by standard mass spectrometric methods. The data indicate that the resolution required for comprehensive proteome analyses is already available, can assess multiple samples in parallel, and preserve critical information concerning post-translational modifications. Further optimization of staining and detection methods promises additional improvements to this economical, widely accessible and effective top-down approach to proteome analysis. PMID- 24489692 TI - XRCC1 Arg399Gln polymorphism confers risk of breast cancer in American population: a meta-analysis of 10846 cases and 11723 controls. AB - BACKGROUND: In the X-ray repair cross-complementing group 1 (XRCC1) gene, a polymorphism, Arg399Gln (rs25487), has been shown to change neoconservative amino acid and thus result in alternation of DNA repair capacity. Numerous studies have investigated the association between Arg399Gln and breast cancer risk in the American population, but yielding inconsistent results. This study aimed to clarify the role of this polymorphism in susceptibility to breast cancer. METHODS: Literatures were searched in multiple databases including PubMed, Springer Link, Ovid, EBSCO and ScienceDirect databases up to April 2013. A comprehensive meta-analysis was conducted to estimate the overall odds ratio (OR), by integrating data from 18 case control studies of 10846 cases and 11723 controls in the American population. RESULTS: Overall, significant association was observed between the Arg399Gln polymorphism and breast cancer risk under the random-effects model (OR for dominant model = 1.12, 95% CI: 1.02-1.24, P heterogeneity = 0.003; OR for additive model = 1.07, 95% CI: 1.01-1.14, P heterogeneity = 0.017). Further sensitivity analysis supported the robust stability of this current result by showing similar ORs before and after removal of a single study. CONCLUSIONS: This meta-analysis suggests that the XRCC1 Arg399Gln polymorphism may significantly contribute to susceptibility of breast cancer in the American population. PMID- 24489693 TI - Impact of ABCB1 and CYP2B6 genetic polymorphisms on methadone metabolism, dose and treatment response in patients with opioid addiction: a systematic review and meta-analysis. AB - BACKGROUND: Genetic variability may influence methadone metabolism, dose requirements, and risk of relapse. OBJECTIVES: To determine whether the CYP2B6*6 or ABCB1 (rs1045642) polymorphisms are associated with variation in methadone response (plasma concentration, dose, or response to treatment). METHODS: Two independent reviewers searched Medline, EMBASE, CINAHL, PsycINFO, and Web of Science databases. We included studies that reported methadone plasma concentration, methadone response, or methadone dose in relation to the CYP2B6*6 or ABCB1 polymorphisms. RESULTS: We screened 182 articles and extracted 7 articles for inclusion in the meta-analysis. Considerable agreement was observed between the two independent raters on the title (kappa, 0.82), abstract (kappa, 0.43), and full text screening (kappa, 0.43). Trough (R) methadone plasma concentration was significantly higher in CYP2B6*6 homozygous carriers when compared to non-carriers (standardized mean difference [SMD] = 0.53, 95% confidence interval [CI], 0.05-1.00, p = 0.03) with minimal heterogeneity (I(2) = 0%). Similarly, trough (S) methadone plasma concentration was higher in homozygous carriers of the *6 haplotype when compared to non-carriers, (SMD = 1.44, 95% CI 0.27-2.61, p = 0.02) however significant heterogeneity was observed (I(2) = 69%). Carriers of the CYP2B6*6 haplotype were not found to be significantly different from non-carriers with respect to dose or response to treatment. We found no significant association between the ABCB1 polymorphism and the trough (R), (S) plasma concentrations, methadone dose, or methadone response. CONCLUSION: Although the number of studies included and sample size were modest, this is the first meta analysis to show participants homozygous for the CYP2B6*6 genotype have higher trough (R) and (S) methadone plasma concentrations, suggesting that methadone metabolism is significantly slower in *6 homozygous carriers. PMID- 24489694 TI - Detection of cell carcinogenic transformation by a quadruplex DNA binding fluorescent probe. AB - Cancer can be easily treated when found early. A probe capable of detecting cell transformation may increase the success rate of early diagnosis of cancer. In this report we have tested the ability of a fluorescent, quadruplex DNA binding probe, 3,6-bis(1-methyl-4- vinylpyridinium) carbazole diiodide (BMVC), to detect cell transformation in vitro. BMVC was applied to living cells in several different models of cell transformation, and the fluorescence signals of BMVC were measured. The degrees of cell transformation in these models were characterized by alterations in cellular morphological phenotype and subcellular organization. When BMVC probes were applied, the number of BMVC-positive cells increased in accordance with the degree of transformation. BMVC was capable of significantly detecting formation of foci, increased cellular motility, cell proliferation, cell apoptosis, anchorage-independent growth, and increased invasiveness of transformed cells. These results demonstrate the ability of BMVC probes to detect cell transformation and indicate that BMVC is of promise for use as a probe in early cancer detection. PMID- 24489695 TI - Determinants of public attitudes to genetically modified salmon. AB - The objective of this paper is to assess the attitude of Malaysian stakeholders to genetically modified (GM) salmon and to identify the factors that influence their acceptance of GM salmon using a structural equation model. A survey was carried out on 434 representatives from various stakeholder groups in the Klang Valley region of Malaysia. Public attitude towards GM salmon was measured using self-developed questionnaires with seven-point Likert scales. The findings of this study have confirmed that public attitudes towards GM salmon is a complex issue and should be seen as a multi-faceted process. The most important direct predictors for the encouragement of GM salmon are the specific application-linked perceptions about religious acceptability of GM salmon followed by perceived risks and benefits, familiarity, and general promise of modern biotechnology. Encouragement of GM salmon also involves the interplay among other factors such as general concerns of biotechnology, threatening the natural order of things, the need for labeling, the need for patenting, confidence in regulation, and societal values. The research findings can serve as a database that will be useful for understanding the social construct of public attitude towards GM foods in a developing country. PMID- 24489696 TI - Cross-site comparison of land-use decision-making and its consequences across land systems with a generalized agent-based model. AB - Local changes in land use result from the decisions and actions of land-users within land systems, which are structured by local and global environmental, economic, political, and cultural contexts. Such cross-scale causation presents a major challenge for developing a general understanding of how local decision making shapes land-use changes at the global scale. This paper implements a generalized agent-based model (ABM) as a virtual laboratory to explore how global and local processes influence the land-use and livelihood decisions of local land users, operationalized as settlement-level agents, across the landscapes of six real-world test sites. Test sites were chosen in USA, Laos, and China to capture globally-significant variation in population density, market influence, and environmental conditions, with land systems ranging from swidden to commercial agriculture. Publicly available global data were integrated into the ABM to model cross-scale effects of economic globalization on local land-use decisions. A suite of statistics was developed to assess the accuracy of model-predicted land use outcomes relative to observed and random (i.e. null model) landscapes. At four of six sites, where environmental and demographic forces were important constraints on land-use choices, modeled land-use outcomes were more similar to those observed across sites than the null model. At the two sites in which market forces significantly influenced land-use and livelihood decisions, the model was a poorer predictor of land-use outcomes than the null model. Model successes and failures in simulating real-world land-use patterns enabled the testing of hypotheses on land-use decision-making and yielded insights on the importance of missing mechanisms. The virtual laboratory approach provides a practical framework for systematic improvement of both theory and predictive skill in land change science based on a continual process of experimentation and model enhancement. PMID- 24489697 TI - Starvation increases insulin sensitivity and reduces juvenile hormone synthesis in mosquitoes. AB - BACKGROUND: The interactions between the insulin signaling pathway (ISP) and juvenile hormone (JH) controlling reproductive trade-offs are well documented in insects. JH and insulin regulate reproductive output in mosquitoes; both hormones are involved in a complex regulatory network, in which they influence each other and in which the mosquito's nutritional status is a crucial determinant of the network's output. Previous studies reported that the insulin-TOR (target of rapamacyn) signaling pathway is involved in the nutritional regulation of JH synthesis in female mosquitoes. The present studies further investigate the regulatory circuitry that controls both JH synthesis and reproductive output in response to nutrient availability. METHODS: We used a combination of diet restriction, RNA interference (RNAi) and insulin treatments to modify insulin signaling and study the cross-talk between insulin and JH in response to starvation. JH synthesis was analyzed using a newly developed assay utilizing fluorescent tags. CONCLUSIONS: Our results reveal that starvation decreased JH synthesis via a decrease in insulin signaling in the corpora allata (CA). Paradoxically, starvation-induced up regulation of insulin receptor transcripts and therefore "primed" the gland to respond rapidly to increases in insulin levels. During this response to starvation the synthetic potential of the CA remained unaffected, and the gland rapidly and efficiently responded to insulin stimulation by increasing JH synthesis to rates similar to those of CA from non starved females. PMID- 24489698 TI - L1cam is crucial for cell locomotion and terminal translocation of the Soma in radial migration during murine corticogenesis. AB - L1cam (L1) is a cell adhesion molecule associated with a spectrum of human neurological diseases, the most well-known being X-linked hydrocephalus. Although we recently demonstrated that L1 plays an important role in neuronal migration during cortical histogenesis, the mechanisms of delayed migration have still not been clarified. In this study, we found that cell locomotion in the intermediate zone and terminal translocation in the primitive cortical zone (PCZ) were affected by L1-knockdown (L1-KD). Time-lapse analyses revealed that L1-KD neurons produced by in utero electroporation of shRNA targeting L1 (L1-shRNAs) molecules showed decreased locomotion velocity in the intermediate zone, compared with control neurons. Furthermore, L1-KD neurons showed longer and more undulated leading processes during translocation through the primitive cortical zone. The curvature index, a quantitative index for curvilinearity, as well as the length of the leading process, were increased, whereas the somal movement was decreased in L1-KD neurons during terminal translocation in the PCZ. These results suggest that L1 has a role in radial migration of cortical neurons. PMID- 24489699 TI - Twitter: a good place to detect health conditions. AB - With the proliferation of social networks and blogs, the Internet is increasingly being used to disseminate personal health information rather than just as a source of information. In this paper we exploit the wealth of user-generated data, available through the micro-blogging service Twitter, to estimate and track the incidence of health conditions in society. The method is based on two stages: we start by extracting possibly relevant tweets using a set of specially crafted regular expressions, and then classify these initial messages using machine learning methods. Furthermore, we selected relevant features to improve the results and the execution times. To test the method, we considered four health states or conditions, namely flu, depression, pregnancy and eating disorders, and two locations, Portugal and Spain. We present the results obtained and demonstrate that the detection results and the performance of the method are improved after feature selection. The results are promising, with areas under the receiver operating characteristic curve between 0.7 and 0.9, and f-measure values around 0.8 and 0.9. This fact indicates that such approach provides a feasible solution for measuring and tracking the evolution of health states within the society. PMID- 24489701 TI - Do birds select habitat or food resources? Nearctic-neotropic migrants in northeastern Costa Rica. AB - Nearctic-neotropic migrant birds need to replenish energy reserves during stopover periods to successfully complete their semiannual movements. In this study we used linear models to examine the habitat use of 11 migrant species in northeastern Costa Rica to better understand the influence of food and structural resources on the presence of birds during stopover periods. Our models indicated that frugivorous migrants primarily used food abundance, while insectivorous migrants chiefly used vegetation structure as cues for habitat use during stopover. In addition to habitat use models, we documented fruiting plant phenology and found a general relationship between migrant arrival and the timing of ripe fruit availability. Our results suggest that insectivorous migrants probably rely on structural features when using habitat because it may be inherently difficult to assess cryptic-arthropod availability during a short period of time in a novel habitat, such as stopover periods. PMID- 24489700 TI - Structural insights into complexes of glucose-regulated Protein94 (Grp94) with human immunoglobulin G. relevance for Grp94-IgG complexes that form in vivo in pathological conditions. AB - While the mechanism by which Grp94 displays its chaperone function with client peptides in the cell has been elucidated extensively, much less is known about the nature and properties of how Grp94 can engage binding to proteins once it is exposed on the cell surface or liberated in the extra-cellular milieu, as occurs in pathological conditions. In this work, we wanted to investigate the molecular aspects and structural characteristics of complexes that Grp94 forms with human IgG, posing the attention on the influence that glycosylation of Grp94 might have on the binding capacity to IgG, and on the identification of sites involved in the binding. To this aim, we employed both native, fully glycosylated and partially glycosylated Grp94, and recombinant, non-glycosylated Grp94, as well as IgG subunits, in different experimental conditions, including the physiological setting of human plasma. Regardless of the species and type, Grp94 engages a similar, highly specific and stable binding with IgG that involves sites located in the N-terminal domain of Grp94 and the hinge region of whole IgG. Grp94 does not form stable complex with Fab, F(ab)2 or Fc. Glycosylation turns out to be an obstacle to the Grp94 binding to IgG, although this negative effect can be counteracted by ATP and spontaneously also disappears in time in a physiological setting of incubation. ATP does not affect at all the binding capacity of non glycosylated Grp94. However, complexes that native, partially glycosylated Grp94 forms with IgG in the presence of ATP show strikingly different characteristics with respect to those formed in absence of ATP. Results have relevance for the mechanism regulating the formation of stable Grp94-IgG complexes in vivo, in the pathological conditions associated with the extra-cellular location of Grp94. PMID- 24489702 TI - Economic support to patients in HIV and TB grants in rounds 7 and 10 from the global fund to fight AIDS, tuberculosis and malaria. AB - People with TB and/or HIV frequently experience severe economic barriers to health care, including out-of-pocket expenses related to diagnosis and treatment, as well as indirect costs due to loss of income. These barriers can both aggravate economic hardship and prevent or delay diagnosis, treatment and successful outcome, leading to increased transmission, morbidity and mortality. WHO, UNAIDS and the ILO argue that economic support of various kinds is essential to enable vulnerable people to protect themselves from infection, avoid delayed diagnosis and treatment, overcome barriers to adherence, and avert destitution. This paper analyses successful country proposals to the Global Fund to Fight AIDS, Tuberculosis and Malaria that include economic support in Rounds 7 and 10; 36 and 20 HIV and TB grants in Round 7 and 32 and 26, respectively, in Round 10. Of these, up to 84 percent included direct or indirect economic support for beneficiaries, although the amount constituted a very small proportion of the total grant. In TB grants, the objectives of economic support were generally clearly stated, and focused on mechanisms to improve treatment uptake and adherence, and the case was most clearly made for MDR-TB patients. In HIV grants, the objectives were much broader in scope, including mitigation of adverse economic and social effects of HIV and its treatment on both patients and families. The analysis shows that economic support is on the radar for countries developing Global Fund proposals, and a wide range of economic support activities are in place. In order to move forward in this area, the wealth of country experience that exists needs to be collated, assessed and disseminated. In addition to trials, operational research and programme evaluations, more precise guidance to countries is needed to inform evidence-based decision about activities that are cost-effective, affordable and feasible. PMID- 24489703 TI - First Clarkforkian equivalent Land Mammal Age in the latest Paleocene basal Sparnacian facies of Europe: fauna, flora, paleoenvironment and (bio)stratigraphy. AB - The Paleocene-Eocene Thermal Maximum (PETM) is correlated with the first occurrences of earliest modern mammals in the Northern Hemisphere. The latest Paleocene Clarkforkian North American Land Mammal Age, that has yielded rodents and carnivorans, is the only exception to this rule. However, until now no pre PETM localities have yielded modern mammals in Europe or Asia. We report the first Clarkforkian equivalent Land Mammal Age in the latest Paleocene deposits of the basal Sparnacian facies at Rivecourt, in the north-central part of the Paris Basin. The new terrestrial vertebrate and macroflora assemblages are analyzed through a multidisciplinary study including sedimentologic, stratigraphic, isotopic, and palynological aspects in order to reconstruct the paleoenvironment and to evaluate biochronologic and paleogeographic implications. The mammals are moderately diverse and not abundant, contrary to turtles and champsosaurs. The macroflora is exceptional in preservation and diversity with numerous angiosperms represented by flowers, fruits, seeds and wood preserved as lignite material, revealing an abundance of Arecaceae, Betulaceae, Icacinaceae, Menispermaceae, Vitaceae and probably Cornaceae. Results indicate a Late Paleocene age based on carbon isotope data, palynology and vertebrate occurrences such as the choristoderan Champsosaurus, the arctocyonid Arctocyon, and the plesiadapid Plesiadapis tricuspidens. However, several mammal species compare better with the earliest Eocene. Among these, the particular louisinid Teilhardimys musculus, also recorded from the latest Paleocene of the Spanish Pyrenees, suggests a younger age than the typical MP6 reference level. Nevertheless, the most important aspect of the Rivecourt fauna is the presence of dental remains of a rodent and a "miacid" carnivoran, attesting to the presence of two modern mammalian orders in the latest Paleocene of Europe. Interestingly, these two groups are also the only modern groups recorded from the latest Paleocene of North America, making Rivecourt the first direct equivalent to the Clarkforkian Land Mammal Age outside of North America. PMID- 24489704 TI - Testing the prognostic accuracy of the updated pediatric sepsis biomarker risk model. AB - BACKGROUND: We previously derived and validated a risk model to estimate mortality probability in children with septic shock (PERSEVERE; PEdiatRic SEpsis biomarkEr Risk modEl). PERSEVERE uses five biomarkers and age to estimate mortality probability. After the initial derivation and validation of PERSEVERE, we combined the derivation and validation cohorts (n = 355) and updated PERSEVERE. An important step in the development of updated risk models is to test their accuracy using an independent test cohort. OBJECTIVE: To test the prognostic accuracy of the updated version PERSEVERE in an independent test cohort. METHODS: Study subjects were recruited from multiple pediatric intensive care units in the United States. Biomarkers were measured in 182 pediatric subjects with septic shock using serum samples obtained during the first 24 hours of presentation. The accuracy of PERSEVERE 28-day mortality risk estimate was tested using diagnostic test statistics, and the net reclassification improvement (NRI) was used to test whether PERSEVERE adds information to a physiology-based scoring system. RESULTS: Mortality in the test cohort was 13.2%. Using a risk cut off of 2.5%, the sensitivity of PERSEVERE for mortality was 83% (95% CI 62-95), specificity was 75% (68-82), positive predictive value was 34% (22-47), and negative predictive value was 97% (91-99). The area under the receiver operating characteristic curve was 0.81 (0.70-0.92). The false positive subjects had a greater degree of organ failure burden and longer intensive care unit length of stay, compared to the true negative subjects. When adding PERSEVERE to a physiology-based scoring system, the net reclassification improvement was 0.91 (0.47-1.35; p<0.001). CONCLUSIONS: The updated version of PERSEVERE estimates mortality probability reliably in a heterogeneous test cohort of children with septic shock and provides information over and above a physiology-based scoring system. PMID- 24489705 TI - Association study to evaluate FoxO1 and FoxO3 gene in CHD in Han Chinese. AB - BACKGROUND: Coronary heart disease (CHD) is one of the leading causes of mortality and morbidity in China. Genetic factors that predispose individuals to CHD are unclear. In the present study, we aimed to determine whether the variation of FoxOs, a novel genetic factor associated with longevity, was associated with CHD in Han Chinese populations. METHODS: 1271 CHD patients and 1287 age-and sex-matched controls from Beijing and Harbin were included. We selected four tagging single nucleotide polymorphisms (SNPs) of FoxO1 (rs2755209, rs2721072, rs4325427 and rs17592371) and two tagging SNPs of FoxO3 (rs768023 and rs1268165). And the genotypes of these SNPs were determined in both CHD patients and non-CHD controls. RESULTS: For population from Beijing, four SNPs of FoxO1 and two SNPs of FoxO3 were found not to be associated with CHD (p>0.05). And this was validated in the other population from Harbin (p>0.05). After combining the two geographically isolated case-control populations, the results showed that the six SNPs did not necessarily predispose to CHD in Han Chinese(p>0.05). In stratified analysis according to gender, the history of smoking, hypertension, diabetes mellitus, hyperlipidemia and the metabolic syndrome, we further explored that neither the variants of FoxO1 nor the variants of FoxO3 might be associated with CHD (p>0.05). CONCLUSION: The variants of FoxO1 and FoxO3 may not increase the prevalence of CHD in Han Chinese population. PMID- 24489706 TI - Network oscillations drive correlated spiking of ON and OFF ganglion cells in the rd1 mouse model of retinal degeneration. AB - Following photoreceptor degeneration, ON and OFF retinal ganglion cells (RGCs) in the rd-1/rd-1 mouse receive rhythmic synaptic input that elicits bursts of action potentials at ~ 10 Hz. To characterize the properties of this activity, RGCs were targeted for paired recording and morphological classification as either ON alpha, OFF alpha or non-alpha RGCs using two-photon imaging. Identified cell types exhibited rhythmic spike activity. Cross-correlation of spike trains recorded simultaneously from pairs of RGCs revealed that activity was correlated more strongly between alpha RGCs than between alpha and non-alpha cell pairs. Bursts of action potentials in alpha RGC pairs of the same type, i.e. two ON or two OFF cells, were in phase, while bursts in dissimilar alpha cell types, i.e. an ON and an OFF RGC, were 180 degrees out of phase. This result is consistent with RGC activity being driven by an input that provides correlated excitation to ON cells and inhibition to OFF cells. A2 amacrine cells were investigated as a candidate cellular mechanism and found to display 10 Hz oscillations in membrane voltage and current that persisted in the presence of antagonists of fast synaptic transmission and were eliminated by tetrodotoxin. Results support the conclusion that the rhythmic RGC activity originates in a presynaptic network of electrically coupled cells including A2s via a Na(+)-channel dependent mechanism. Network activity drives out of phase oscillations in ON and OFF cone bipolar cells, entraining similar frequency fluctuations in RGC spike activity over an area of retina that migrates with changes in the spatial locus of the cellular oscillator. PMID- 24489707 TI - Astrocytes modulate the polarization of CD4+ T cells to Th1 cells. AB - T-cell characteristics are dynamic and influenced by multiple factors. To test whether cells and the environment in the central nervous system (CNS) can influence T-cells, we tested if culturing mouse CD4(+) T-cells on mouse primary astrocytes, compared with standard feeder cells, modified T-cell polarization to Th1 and Treg subtypes. Astrocytes supported the production of Th1 cells and Tregs, which was diminished by inflammatory activation of astrocytes, and glutamate accumulation that may result from impaired glutamate uptake by astrocytes strongly promoted Th1 production. These results demonstrate that astrocytes and the environment in the CNS have the capacity to regulate T-cell characteristics. PMID- 24489708 TI - Effects of chicory/perennial ryegrass swards compared with perennial ryegrass swards on the performance and carcass quality of grazing beef steers. AB - An experiment investigated whether the inclusion of chicory (Cichorium intybus) in swards grazed by beef steers altered their performance, carcass characteristics or parasitism when compared to steers grazing perennial ryegrass (Lolium perenne). Triplicate 2-ha plots were established with a chicory/ryegrass mix or ryegrass control. Forty-eight Belgian Blue-cross steers were used in the first grazing season and a core group (n = 36) were retained for finishing in the second grazing season. The experiment comprised of a standardisation and measurement period. During standardisation, steers grazed a ryegrass/white clover pasture as one group. Animals were allocated to treatment on the basis of liveweight, body condition and faecal egg counts (FEC) determined 7 days prior to the measurement period. The measurement period ran from 25 May until 28 September 2010 and 12 April until 11 October 2011 in the first and second grazing year. Steers were weighed every 14 days at pasture or 28 days during housing. In the first grazing year, faecal samples were collected for FEC and parasite cultures. At the end of the first grazing year, individual blood samples were taken to determine O. ostertagi antibody and plasma pepsinogen levels. During winter, animals were housed as one group and fed silage. In the second grazing year, steers were slaughtered when deemed to reach fat class 3. Data on steer performance showed no differences in daily live-weight gain which averaged 1.04 kg/day. The conformation, fat grade and killing out proportion of beef steers grazing chicory/ryegrass or ryegrass were not found to differ. No differences in FEC, O. ostertagi antibody or plasma pepsinogen levels of beef steers grazing either chicory/ryegrass or ryegrass were observed. Overall, there were no detrimental effects of including chicory in swards grazed by beef cattle on their performance, carcass characteristics or helminth parasitism, when compared with steers grazing ryegrass. PMID- 24489710 TI - Prevalence of hypertension and associated factors in an indigenous community of central Brazil: a population-based study. AB - OBJECTIVE: The aim of the present study was to assess the prevalence of hypertension and cardiovascular risk factors among the native indigenous of Jaguapiru village in Dourados, Mato Grosso do Sul, Brazil. METHOD: A cross sectional, population-based study was conducted with adult indigenous aged 18 years or more. The subjects' blood pressure was measured twice, and the mean of the two measurements was calculated. Body weight, height, capillary blood glucose and waist circumference were measured. Pregnant women, individuals using glucocorticoids, and non-indigenous villagers and their offspring were excluded. Multivariate regression analyses were conducted on the socio-demographic and clinical independent variables. Interactions between independent variables were also tested. RESULTS: We included 1,608 native indigenous eligible to the research. The prevalence of hypertension was 29.5% (95% CI: 27-31.5), with no significant difference between the genders. For both men and women, diastolic hypertension was more common than systolic hypertension. The prevalence of hypertension was higher among obese, diabetic, and older participants, as well as those who consumed alcohol, had a lower educational level, or had a family history of hypertension. There was no association between hypertension and tobacco smoking or family income. CONCLUSION: Hypertension among the indigenous from Jaguapiru village was similar to the prevalence in the Brazilians, but may have a more negative effect in such disadvantaged population. The associated factors we found can help drawing prevention policies. PMID- 24489709 TI - ENDOGLIN is dispensable for vasculogenesis, but required for vascular endothelial growth factor-induced angiogenesis. AB - ENDOGLIN (ENG) is a co-receptor for transforming growth factor-beta (TGF-beta) family members that is highly expressed in endothelial cells and has a critical function in the development of the vascular system. Mutations in Eng are associated with the vascular disease known as hereditary hemorrhagic telangiectasia type l. Using mouse embryonic stem cells we observed that angiogenic factors, including vascular endothelial growth factor (VEGF), induce vasculogenesis in embryoid bodies even when Eng deficient cells or cells depleted of Eng using shRNA are used. However, ENG is required for the stem cell-derived endothelial cells to organize effectively into tubular structures. Consistent with this finding, fetal metatarsals isolated from E17.5 Eng heterozygous mouse embryos showed reduced VEGF-induced vascular network formation. Moreover, shRNA mediated depletion and pharmacological inhibition of ENG in human umbilical vein cells mitigated VEGF-induced angiogenesis. In summary, we demonstrate that ENG is required for efficient VEGF-induced angiogenesis. PMID- 24489711 TI - MR scanner systems should be adequately characterized in diffusion-MRI of the breast. AB - Breast imaging represents a relatively recent and promising field of application of quantitative diffusion-MRI techniques. In view of the importance of guaranteeing and assessing its reliability in clinical as well as research settings, the aim of this study was to specifically characterize how the main MR scanner system-related factors affect quantitative measurements in diffusion-MRI of the breast. In particular, phantom acquisitions were performed on three 1.5 T MR scanner systems by different manufacturers, all equipped with a dedicated multi-channel breast coil as well as acquisition sequences for diffusion-MRI of the breast. We assessed the accuracy, inter-scan and inter-scanner reproducibility of the mean apparent diffusion coefficient measured along the main orthogonal directions () as well as of diffusion-tensor imaging (DTI) derived mean diffusivity (MD) measurements. Additionally, we estimated spatial non-uniformity of (NU) and MD (NUMD) maps. We showed that the signal to-noise ratio as well as overall calibration of high strength diffusion gradients system in typical acquisition sequences for diffusion-MRI of the breast varied across MR scanner systems, introducing systematic bias in the measurements of diffusion indices. While and MD values were not appreciably different from each other, they substantially varied across MR scanner systems. The mean of the accuracies of measured and MD was in the range [-2.3%,11.9%], and the mean of the coefficients of variation for and MD measurements across MR scanner systems was 6.8%. The coefficient of variation for repeated measurements of both and MD was < 1%, while NU and NUMD values were <4%. Our results highlight that MR scanner system-related factors can substantially affect quantitative diffusion-MRI of the breast. Therefore, a specific quality control program for assessing and monitoring the performance of MR scanner systems for diffusion-MRI of the breast is highly recommended at every site, especially in multicenter and longitudinal studies. PMID- 24489712 TI - QTL dissection of Lag phase in wine fermentation reveals a new translocation responsible for Saccharomyces cerevisiae adaptation to sulfite. AB - Quantitative genetics and QTL mapping are efficient strategies for deciphering the genetic polymorphisms that explain the phenotypic differences of individuals within the same species. Since a decade, this approach has been applied to eukaryotic microbes such as Saccharomyces cerevisiae in order to find natural genetic variations conferring adaptation of individuals to their environment. In this work, a QTL responsible for lag phase duration in the alcoholic fermentation of grape juice was dissected by reciprocal hemizygosity analysis. After invalidating the effect of some candidate genes, a chromosomal translocation affecting the lag phase was brought to light using de novo assembly of parental genomes. This newly described translocation (XV-t-XVI) involves the promoter region of ADH1 and the gene SSU1 and confers an increased expression of the sulfite pump during the first hours of alcoholic fermentation. This translocation constitutes another adaptation route of wine yeast to sulfites in addition to the translocation VIII-t-XVI previously described. A population survey of both translocation forms in a panel of domesticated yeast strains suggests that the translocation XV-t-XVI has been empirically selected by human activity. PMID- 24489713 TI - Weight bias internalization scale: psychometric properties and population norms. AB - OBJECTIVE: Internalizing the pervasive weight bias commonly directed towards individuals with overweight and obesity, co-occurs with increased psychopathology and impaired quality of life. This study sought to establish population norms and psychometric properties of the most widely used self-report questionnaire, the Weight Bias Internalization Scale (WBIS), in a representative community sample. DESIGN AND METHODS: In a survey of the German population, N = 1158 individuals with overweight and obesity were assessed with the WBIS and self-report measures for convergent validation. RESULTS: Item analysis revealed favorable item-total correlation of all but one WBIS item. With this item removed, item homogeneity and internal consistency were excellent. The one-factor structure of the WBIS was confirmed using confirmatory factor analysis. Convergent validity was shown through significant associations with measures of depressive and somatoform symptoms. The WBIS contributed to the explanation of variance in depressive and somatoform symptoms over and above body mass index. Higher WBIS scores were found in women than in men, in individuals with obesity than in individuals with overweight, and in those with lower education or income than those with higher education or income. Sex-specific norms were provided. CONCLUSIONS: The results showed good psychometric properties of the WBIS after removal of one item. Future research is warranted on further indicators of reliability and validity, for example, retest reliability, sensitivity to change, and prognostic validity. PMID- 24489714 TI - Patient retention, clinical outcomes and attrition-associated factors of HIV infected patients enrolled in Zimbabwe's National Antiretroviral Therapy Programme, 2007-2010. AB - BACKGROUND: Since establishment of Zimbabwe's National Antiretroviral Therapy (ART) Programme in 2004, ART provision has expanded from <5,000 to 369,431 adults by 2011. However, patient outcomes are unexplored. OBJECTIVE: To determine improvement in health status, retention and factors associated with attrition among HIV-infected patients on ART. METHODS: A retrospective review of abstracted patient records of adults >= 15 years who initiated ART from 2007 to 2009 was done. Frequencies and medians were calculated for rates of retention in care and changes in key health status outcomes at 6, 12, 24 and 36 months respectively. Cox proportional hazards models were used to determine factors associated with attrition. RESULTS: Of the 3,919 patients, 64% were female, 86% were either WHO clinical stage III or IV. Rates of patient retention at 6, 12, 24 and 36 months were 90.7%, 78.1%, 68.8% and 64.4%, respectively. After ART initiation, median weight gains at 6, 12, and 24 months were 3, 4.5, and 5.0 kgs whilst median CD4+ cell count gains at 6, 12 and 24 months were 122, 157 and 279 cells/uL respectively. Factors associated with an increased risk of attrition included male gender (AHR 1.2; 95% CI, 1.1-1.4), baseline WHO stage IV (AHR 1.7; 95% CI, 1.1-2.6), lower baseline body weight (AHR 2.0; 95% CI, 1.4-2. 8) and accessing care from higher level healthcare facilities (AHR 3.5; 95% 1.1-11.2). CONCLUSIONS: Our findings with regard to retention as well as clinical and immunological improvements following uptake of ART, are similar to what has been found in other settings. Factors influencing attrition also mirror those found in other parts of sub-Saharan Africa. These findings suggest the need to strengthen earlier diagnosis and treatment to further improve treatment outcomes. Whilst decentralisation improves ART coverage it should be coupled with strategies aimed at improving patient retention. PMID- 24489715 TI - Efficacy of a low-cost bubble CPAP system in treatment of respiratory distress in a neonatal ward in Malawi. AB - BACKGROUND: Respiratory failure is a leading cause of neonatal mortality in the developing world. Bubble continuous positive airway pressure (bCPAP) is a safe, effective intervention for infants with respiratory distress and is widely used in developed countries. Because of its high cost, bCPAP is not widely utilized in low-resource settings. We evaluated the performance of a new bCPAP system to treat severe respiratory distress in a low resource setting, comparing it to nasal oxygen therapy, the current standard of care. METHODS: We conducted a non randomized convenience sample study to test the efficacy of a low-cost bCPAP system treating newborns with severe respiratory distress in the neonatal ward of Queen Elizabeth Central Hospital, in Blantyre, Malawi. Neonates weighing >1,000 g and presenting with severe respiratory distress who fulfilled inclusion criteria received nasal bCPAP if a device was available; if not, they received standard care. Clinical assessments were made during treatment and outcomes compared for the two groups. FINDINGS: 87 neonates (62 bCPAP, 25 controls) were recruited. Survival rate for neonates receiving bCPAP was 71.0% (44/62) compared with 44.0% (11/25) for controls. 65.5% (19/29) of very low birth weight neonates receiving bCPAP survived to discharge compared to 15.4% (1/13) of controls. 64.6% (31/48) of neonates with respiratory distress syndrome (RDS) receiving bCPAP survived to discharge, compared to 23.5% (4/17) of controls. 61.5% (16/26) of neonates with sepsis receiving bCPAP survived to discharge, while none of the seven neonates with sepsis in the control group survived. INTERPRETATION: Use of a low-cost bCPAP system to treat neonatal respiratory distress resulted in 27% absolute improvement in survival. The beneficial effect was greater for neonates with very low birth weight, RDS, or sepsis. Implementing appropriate bCPAP devices could reduce neonatal mortality in developing countries. PMID- 24489716 TI - Nitrosonifedipine ameliorates the progression of type 2 diabetic nephropathy by exerting antioxidative effects. AB - Diabetic nephropathy (DN) is the major cause of end-stage renal failure. Oxidative stress is implicated in the pathogenesis of DN. Nitrosonifedipine (NO NIF) is a weak calcium channel blocker that is converted from nifedipine under light exposure. Recently, we reported that NO-NIF has potential as a novel antioxidant with radical scavenging abilities and has the capacity to treat vascular dysfunction by exerting an endothelial protective effect. In the present study, we extended these findings by evaluating the efficacy of NO-NIF against DN and by clarifying the mechanisms of its antioxidative effect. In a model of type 2 DN (established in KKAy mice), NO-NIF administration reduced albuminuria and proteinuria as well as glomerular expansion without affecting glucose metabolism or systolic blood pressure. NO-NIF also suppressed renal and systemic oxidative stress and decreased the expression of intercellular adhesion molecule (ICAM)-1, a marker of endothelial cell injury, in the glomeruli of the KKAy mice. Similarly, NO-NIF reduced albuminuria, oxidative stress, and ICAM-1 expression in endothelial nitric oxide synthase (eNOS) knockout mice. Moreover, NO-NIF suppressed urinary angiotensinogen (AGT) excretion and intrarenal AGT protein expression in proximal tubular cells in the KKAy mice. On the other hand, hyperglycemia-induced mitochondrial superoxide production was not attenuated by NO-NIF in cultured endothelial cells. These findings suggest that NO-NIF prevents the progression of type 2 DN associated with endothelial dysfunction through selective antioxidative effects. PMID- 24489717 TI - A1M/alpha1-microglobulin protects from heme-induced placental and renal damage in a pregnant sheep model of preeclampsia. AB - Preeclampsia (PE) is a serious pregnancy complication that manifests as hypertension and proteinuria after the 20(th) gestation week. Previously, fetal hemoglobin (HbF) has been identified as a plausible causative factor. Cell-free Hb and its degradation products are known to cause oxidative stress and tissue damage, typical of the PE placenta. A1M (alpha1-microglobulin) is an endogenous scavenger of radicals and heme. Here, the usefulness of A1M as a treatment for PE is investigated in the pregnant ewe PE model, in which starvation induces PE symptoms via hemolysis. Eleven ewes, in late pregnancy, were starved for 36 hours and then treated with A1M (n = 5) or placebo (n = 6) injections. After injections, the ewes were re-fed and observed for additional 72 hours. They were monitored for blood pressure, proteinuria, blood cell distribution and clinical and inflammation markers in plasma. Before termination, the utero-placental circulation was analyzed with Doppler velocimetry and the kidney glomerular function was analyzed by Ficoll sieving. At termination, blood, kidney and placenta samples were collected and analyzed for changes in gene expression and tissue structure. The starvation resulted in increased amounts of the hemolysis marker bilirubin in the blood, structural damages to the placenta and kidneys and an increased glomerular sieving coefficient indicating a defect filtration barrier. Treatment with A1M ameliorated these changes without signs of side effects. In conclusion, A1M displayed positive therapeutic effects in the ewe starvation PE model, and was well tolerated. Therefore, we suggest A1M as a plausible treatment for PE in humans. PMID- 24489719 TI - Assessment of the reporting quality of randomized controlled trials on treatment of coronary heart disease with traditional chinese medicine from the chinese journal of integrated traditional and Western medicine: a systematic review. AB - BACKGROUND: Due to language limitations, little is known about the reporting quality of randomized clinical trials (RCTs) on the treatment of coronary heart disease (CHD) with traditional Chinese medicine (TCM) in Chinese Journal of Integrated Traditional and Western Medicine (CJITWM). OBJECTIVE: In this study, we utilized the CONSORT 2010 statement to understand the reporting quality of RCTs on CHD with TCM from the CJITWM. METHODS: The China National Knowledge Infrastructure (CNKI) electronic database was searched for CJITWM RCTs on the treatment of CHD with TCM, published between January 1, 2006 and December 31, 2011. We excluded articles reported as "animal studies," "topic review," "diagnostic test," "editorials," or "others." The CONSORT checklist was applied to evaluate the reporting quality of all eligible articles by two independent authors after extensive discussion. Each item was graded as either "yes" or "no" depending on whether the authors had reported it or not. RESULTS: We identified 21 articles meeting our inclusion criteria. The percentage of 11 of the 37 items was 4.8 ~ 95.2%, 14 of the 37 items were reported in all included articles, while 12 items were not mentioned at all. The average reporting percentage for the "title and abstract" section was 52.4%, for the "introduction" section 100.0%, for the "methods" section 45.4%, for the "results" section 57.1%, for the "discussion" section 79.4%, and for the "other information" section 17.5%. CONCLUSION: In general, the reviewed RCTs were not consistent with the CONSORT 2010 statement. Authors should adhere to the CONSORT statement in reporting RCTs; editorial departments may consider the CONSORT statement as a guideline and should instruct authors to write manuscripts, and reviewers to judge them according to CONSORT statutes. PMID- 24489718 TI - Prdm8 regulates the morphological transition at multipolar phase during neocortical development. AB - Here, we found that the PR domain protein Prdm8 serves as a key regulator of the length of the multipolar phase by controlling the timing of morphological transition. We used a mouse line with expression of Prdm8-mVenus reporter and found that Prdm8 is predominantly expressed in the middle and upper intermediate zone during both the late and terminal multipolar phases. Prdm8 expression was almost coincident with Unc5D expression, a marker for the late multipolar phase, although the expression of Unc5D was found to be gradually down-regulated to the point at which mVenus expression was gradually up-regulated. This expression pattern suggests the possible involvement of Prdm8 in the control of the late and terminal multipolar phases, which controls the timing for morphological transition. To test this hypothesis, we performed gain- and loss-of-function analysis of neocortical development by using in utero electroporation. We found that the knockdown of Prdm8 results in premature change from multipolar to bipolar morphology, whereas the overexpression of Prdm8 maintained the multipolar morphology. Additionally, the postnatal analysis showed that the Prdm8 knockdown stimulated the number of early born neurons, and differentiated neurons located more deeply in the neocortex, however, majority of those cells could not acquire molecular features consistent with laminar location. Furthermore, we found the candidate genes that were predominantly utilized in both the late and terminal multipolar phases, and these candidate genes included those encoding for guidance molecules. In addition, we also found that the expression level of these guidance molecules was inhibited by the introduction of the Prdm8 expression vector. These results indicate that the Prdm8-mediated regulation of morphological changes that normally occur during the late and terminal multipolar phases plays an important role in neocortical development. PMID- 24489720 TI - Dominant effects of the diet on the microbiome and the local and systemic immune response in mice. AB - Outside the nutrition community the effects of diet on immune-mediated diseases and experimental outcomes have not been appreciated. Investigators that study immune-mediated diseases and/or the microbiome have overlooked the potential of diet to impact disease phenotype. We aimed to determine the effects of diet on the bacterial microbiota and immune-mediated diseases. Three different laboratory diets were fed to wild-type mice for 2 weeks and resulted in three distinct susceptibilities to dextran sodium sulfate (DSS)-induced colitis. Examination of the fecal microbiota demonstrated a diet-mediated effect on the bacteria found there. Broad-spectrum antibiotics disturbed the gut microbiome and partially eliminated the diet-mediated changes in DSS susceptibility. Dietary changes 2 days after DSS treatment were protective and suggested that the diet-mediated effect occurred quickly. There were no diet-mediated effects on DSS susceptibility in germ-free mice. In addition, the diet-mediated effects were evident in a gastrointestinal infection model (Citrobacter rodentium) and in experimental autoimmune encephalomyelitis. Taken together, our study demonstrates a dominant effect of diet on immune-mediated diseases that act rapidly by changing the microbiota. These findings highlight the potential of using dietary manipulation to control the microbiome and prevent/treat immune-mediated disease. PMID- 24489721 TI - Acute thiopurine overdose: analysis of reports to a National Poison Centre 1995 2013. AB - Literature regarding acute human toxicity of thiopurines is limited to a handful of case reports. Our objectives were to describe all cases of overdose with thiopurines reported to the Swiss Toxicological Information Centre between 1995 2013. A retrospective analysis was performed to determine circumstances, magnitude, management and outcome of overdose with these substances. A total of 40 cases (14 paediatric) were reported (azathioprine, n = 35; 6-mercaptopurine, n = 5). Of these, 25 were with suicidal intent, 12 were accidental and 3 were iatrogenic errors. The magnitude of overdose ranged from 1.5 to 43 (median 8) times the usual dose in adults. Twelve cases (30%) had attributable symptoms. The majority of these were minor and included gastrointestinal complaints and liver function test and blood count abnormalities. Symptoms were experienced by patients who took at least 1.5-times their usual daily thiopurine dose. Overdoses over two or more consecutive days, even if of modest size, were less well tolerated. One case of azathioprine and allopurinol co-ingestion over consecutive days led to agranulocytosis. Decontamination measures were undertaken in 11 cases (10 activated charcoal, 1 gastric lavage) and these developed fewer symptoms than untreated patients. This study shows that acute overdoses with thiopurines have a favourable outcome in the majority of cases and provides preliminary evidence that gastrointestinal decontamination with activated charcoal may reduce symptom development after overdose of these substances if patients present to medical services soon after ingestion. PMID- 24489723 TI - Lower extremity amputations in persons with and without diabetes in Italy: 2001 2010. AB - OBJECTIVE: To analyze hospitalization for lower extremity amputations (LEAs) and amputee rates in persons with and without diabetes in Italy. RESEARCH DESIGN AND METHODS: All patients with LEAs in the period 2001-2010 were identified analyzing the National Hospital Discharge Record database. For each year, amputee and hospitalization rates for LEAs were calculated either for persons with diabetes or without. Time trend for major and minor amputations were analysed. RESULTS: From 2001 to 2010 a mean annual number of 11,639 individuals underwent a lower extremity amputation: 58.6% had diabetes accounting for 60.7% of total hospitalizations. In 2010, the crude amputee rate for LEAs was 20.4 per 100,000 inhabitants: 247.2 for 100.000 persons with diabetes, and 8.6 for those without diabetes. Having diabetes was associated to an increased risk of amputation (Poisson estimated RR 10.9, 95%CI 9.4-12.8). Over the whole period, a progressive reduction of amputee rates was observed for major amputations either among persons with diabetes (-30.7%) or without diabetes (-12.5%), while the rates of minor amputations increased progressively (+22.4%) among people without diabetes and were nearly stable in people with diabetes (-4.6%). A greater number of minor amputations were performed among persons with than without diabetes: in 2010, the minor-to-major ratio among persons with diabetes (2.5) was more than twice than in those without diabetes (1.0). CONCLUSIONS: The nationwide analyses confirm a progressive reduction of hospitalization and amputee rates for major LEAs, suggesting an earlier and more diffuse approach aimed at limb salvage. PMID- 24489722 TI - Cigarette smoke toxins deposited on surfaces: implications for human health. AB - Cigarette smoking remains a significant health threat for smokers and nonsmokers alike. Secondhand smoke (SHS) is intrinsically more toxic than directly inhaled smoke. Recently, a new threat has been discovered - Thirdhand smoke (THS) - the accumulation of SHS on surfaces that ages with time, becoming progressively more toxic. THS is a potential health threat to children, spouses of smokers and workers in environments where smoking is or has been allowed. The goal of this study is to investigate the effects of THS on liver, lung, skin healing, and behavior, using an animal model exposed to THS under conditions that mimic exposure of humans. THS-exposed mice show alterations in multiple organ systems and excrete levels of NNAL (a tobacco-specific carcinogen biomarker) similar to those found in children exposed to SHS (and consequently to THS). In liver, THS leads to increased lipid levels and non-alcoholic fatty liver disease, a precursor to cirrhosis and cancer and a potential contributor to cardiovascular disease. In lung, THS stimulates excess collagen production and high levels of inflammatory cytokines, suggesting propensity for fibrosis with implications for inflammation-induced diseases such as chronic obstructive pulmonary disease and asthma. In wounded skin, healing in THS-exposed mice has many characteristics of the poor healing of surgical incisions observed in human smokers. Lastly, behavioral tests show that THS-exposed mice become hyperactive. The latter data, combined with emerging associated behavioral problems in children exposed to SHS/THS, suggest that, with prolonged exposure, they may be at significant risk for developing more severe neurological disorders. These results provide a basis for studies on the toxic effects of THS in humans and inform potential regulatory policies to prevent involuntary exposure to THS. PMID- 24489724 TI - High selection pressure promotes increase in cumulative adaptive culture. AB - The evolution of cumulative adaptive culture has received widespread interest in recent years, especially the factors promoting its occurrence. Current evolutionary models suggest that an increase in population size may lead to an increase in cultural complexity via a higher rate of cultural transmission and innovation. However, relatively little attention has been paid to the role of natural selection in the evolution of cultural complexity. Here we use an agent based simulation model to demonstrate that high selection pressure in the form of resource pressure promotes the accumulation of adaptive culture in spite of small population sizes and high innovation costs. We argue that the interaction of demography and selection is important, and that neither can be considered in isolation. We predict that an increase in cultural complexity is most likely to occur under conditions of population pressure relative to resource availability. Our model may help to explain why culture change can occur without major environmental change. We suggest that understanding the interaction between shifting selective pressures and demography is essential for explaining the evolution of cultural complexity. PMID- 24489725 TI - Removal of micrometer size morphological defects and enhancement of ultraviolet emission by thermal treatment of Ga-doped ZnO nanostructures. AB - Mixed morphologies of Ga-doped Zinc Oxide (ZnO) nanostructures are synthesized by vapor transport method. Systematic scanning electron microscope (SEM) studies of different morphologies, after periodic heat treatments, gives direct evidence of sublimation. SEM micrographs give direct evidence that morphological defects of nanostructures can be removed by annealing. Ultra Violet (UV) and visible emission depends strongly on the annealing temperatures and luminescent efficiency of UV emission is enhanced significantly with each subsequent heat treatment. X-Ray diffraction (XRD) results suggest that crystal quality improved by annealing and phase separation may occur at high temperatures. PMID- 24489726 TI - The effect of three different (-135 degrees C) whole body cryotherapy exposure durations on elite rugby league players. AB - BACKGROUND: Whole body cryotherapy (WBC) is the therapeutic application of extreme cold air for a short duration. Minimal evidence is available for determining optimal exposure time. PURPOSE: To explore whether the length of WBC exposure induces differential changes in inflammatory markers, tissue oxygenation, skin and core temperature, thermal sensation and comfort. METHOD: This study was a randomised cross over design with participants acting as their own control. Fourteen male professional first team super league rugby players were exposed to 1, 2, and 3 minutes of WBC at -135 degrees C. Testing took place the day after a competitive league fixture, each exposure separated by seven days. RESULTS: No significant changes were found in the inflammatory cytokine interleukin six. Significant reductions (p<0.05) in deoxyhaemoglobin for gastrocnemius and vastus lateralis were found. In vastus lateralis significant reductions (p<0.05) in oxyhaemoglobin and tissue oxygenation index (p<0.05) were demonstrated. Significant reductions (p<0.05) in skin temperature were recorded. No significant changes were recorded in core temperature. Significant reductions (p<0.05) in thermal sensation and comfort were recorded. CONCLUSION: Three brief exposures to WBC separated by 1 week are not sufficient to induce physiological changes in IL-6 or core temperature. There are however significant changes in tissue oxyhaemoglobin, deoxyhaemoglobin, tissue oxygenation index, skin temperature and thermal sensation. We conclude that a 2 minute WBC exposure was the optimum exposure length at temperatures of -135 degrees C and could be applied as the basis for future studies. PMID- 24489727 TI - The self-liking brain: a VBM study on the structural substrate of self-esteem. AB - Abundant evidence suggests that self-esteem is an important personality resource for emotion regulation in response to stressful experiences. It was thus hypothesized that the relative grey matter volume of brain regions involved in responding to and coping with stress is related to individual differences in trait self-esteem. Using structural magnetic resonance imaging of 48 healthy adults in conjunction with voxel-based morphometry and diffeomorphic anatomical registration using exponentiated lie algebra (VBM-DARTEL), positive associations between self-esteem and regional grey matter volume were indeed found in the anterior cingulate cortex (ACC), right lateral prefrontal cortex (LPFC), right hippocampus, and left hypothalamus. In addition, self-esteem positively covaried with grey matter volume in the right temporo-parietal junction (TPJ), which has been implicated in pride and theory of mind. The results suggest that persons with low self-esteem have reduced grey matter volume in brain regions that contribute to emotion/stress regulation, pride, and theory of mind. The findings provide novel neuroanatomical evidence for the view that self-esteem constitutes a vital coping resource. PMID- 24489728 TI - Hypoxia increases gefitinib-resistant lung cancer stem cells through the activation of insulin-like growth factor 1 receptor. AB - Accumulating evidence indicates that a small population of cancer stem cells (CSCs) is involved in intrinsic resistance to cancer treatment. The hypoxic microenvironment is an important stem cell niche that promotes the persistence of CSCs in tumors. Our aim here was to elucidate the role of hypoxia and CSCs in the resistance to gefitinib in non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutation. NSCLC cell lines, PC9 and HCC827, which express the EGFR exon 19 deletion mutations, were exposed to high concentration of gefitinib under normoxic or hypoxic conditions. Seven days after gefitinib exposure, a small fraction of viable cells were detected, and these were referred to as "gefitinib-resistant persisters" (GRPs). CD133, Oct4, Sox2, Nanog, CXCR4, and ALDH1A1-all genes involved in stemness-were highly expressed in GRPs in PC9 and HCC827 cells, and PC9 GRPs exhibited a high potential for tumorigenicity in vivo. The expression of insulin-like growth factor 1 (IGF1) was also upregulated and IGF1 receptor (IGF1R) was activated on GRPs. Importantly, hypoxic exposure significantly increased sphere formation, reflecting the self renewal capability, and the population of CD133- and Oct4-positive GRPs. Additionally, hypoxia upregulated IGF1 expression through hypoxia-inducible factor 1alpha (HIF1alpha), and markedly promoted the activation of IGF1R on GRPs. Knockdown of IGF1 expression significantly reduced phosphorylated IGF1R expressing GRPs under hypoxic conditions. Finally, inhibition of HIF1alpha or IGF1R by specific inhibitors significantly decreased the population of CD133- and Oct4-positive GRPs, which were increased by hypoxia in PC9 and HCC827 cells. Collectively, these findings suggest that hypoxia increased the population of lung CSCs resistant to gefitinib in EGFR mutation-positive NSCLC by activating IGF1R. Targeting the IGF1R pathway may be a promising strategy for overcoming gefitinib resistance in EGFR mutation-positive NSCLC induced by lung CSCs and microenvironment factors such as tumor hypoxia. PMID- 24489729 TI - Mycobacteria bypass mucosal NF-kB signalling to induce an epithelial anti inflammatory IL-22 and IL-10 response. AB - The mechanisms by which mycobacteria subvert the inflammatory defence to establish chronic infection remain an unresolved question in the pathogenesis of tuberculosis. Using primary epithelial cells, we have analysed mycobacteria induced epithelial signalling pathways from activation of TLRs to cytokine secretion. Mycobacterium bovis bacilli Calmette-Guerin induced phosphorylation of glycogen synthase kinase (GSK)3 by PI3K-Akt in the signalling pathway downstream of TLR2 and TLR4. Mycobacteria did not suppress NF-kappaB by activating the peroxisome proliferator-activated receptor gamma. Instead the pro-inflammatory NF kappaB was bypassed by mycobacteria induced GSK3 inhibition that promoted the anti-inflammatory transcription factor CREB. Mycobacterial infection did not thus induce mucosal pro-inflammatory response as measured by TNFalpha and IFNgamma secretion, but led to an anti-inflammatory IL-10 and IL-22 production. Apart from CREB, MAP3Ks p38 and ERK1/2 activated the transcription factor AP-1 leading to IL 6 production. Interestingly, blocking of TLR4 before infection decreased epithelial IL-6 secretion, but increased the CREB-activated IL-10 production. Our data indicate that mycobacteria suppress epithelial pro-inflammatory production by suppressing NF-kappaB activation thereby shifting the infection towards an anti-inflammatory state. This balance between the host immune response and the pathogen could determine the outcome of infection. PMID- 24489730 TI - Small activating RNA restores the activity of the tumor suppressor HIC-1 on breast cancer. AB - HIC-1 is a gene that is hypermethylated in cancer, and commonly downregulated in human breast cancer. However, the precise mechanisms and molecular pathways regulated by HIC-1 remain unclear. We assessed HIC-1 expression on a tissue microarray containing 80 cases of breast cancer. We also analyzed its biological function by restoring HIC-1 expression using 5-aza-2' deoxycytidine (5-CdR) and small-activating RNAs for the reversal of HIC-1 tumor suppressive effects on MCF 7 and MDA-MB-231 cell lines. An Agilent Q44h global expressing microarray was probed after restoring the expression of HIC-1. Data demonstrated that HIC-1 expression was reduced significantly in breast cancer tissues. HIC-1 immunohistochemistry resulted in mean staining scores in cancer tissue and normal ductal epithelia of 3.54 and 8.2, respectively (p<0.01). 5-CdR partially reversed HIC-1 expression, and modulated cell growth and apoptosis. dsHIC1-2998, an saRNA, showed activating efficacy in breast cancer cells. A group of differentially expressed genes were characterized by cDNA microarray. Upon saRNA treatment, genes upregulated included those involved in immune activation, cell cycle interference, the induction of apoptosis, anti-metastasis, and cell differentiation. Downregulated genes included oncogenes and those that play roles in cell invasion, cell growth, and cell division. Our findings may provide valuable resources not only for gene functional studies, but also for potential clinical applications to develop novel drug targets. PMID- 24489731 TI - Ischemic acute kidney injury perturbs homeostasis of serine enantiomers in the body fluid in mice: early detection of renal dysfunction using the ratio of serine enantiomers. AB - The imbalance of blood and urine amino acids in renal failure has been studied mostly without chiral separation. Although a few reports have shown the presence of D-serine, an enantiomer of L-serine, in the serum of patients with severe renal failure, it has remained uncertain how serine enantiomers are deranged in the development of renal failure. In the present study, we have monitored serine enantiomers using a two-dimensional HPLC system in the serum and urine of mice after renal ischemia-reperfusion injury (IRI), known as a mouse model of acute kidney injury. In the serum, the level of D-serine gradually increased after renal IRI in parallel with that of creatinine, whereas the L-serine level decreased sharply in the early phase after IRI. The increase of D-serine was suppressed in part by genetic inactivation of a D-serine-degrading enzyme, D amino acid oxidase (DAO), but not by disruption of its synthetic enzyme, serine racemase, in mice. Renal DAO activity was detected exclusively in proximal tubules, and IRI reduced the number of DAO-positive tubules. On the other hand, in the urine, D-serine was excreted at a rate nearly triple that of L-serine in mice with sham operations, indicating that little D-serine was reabsorbed while most L-serine was reabsorbed in physiological conditions. IRI significantly reduced the ratio of urinary D-/L-serine from 2.82 +/- 0.18 to 1.10 +/- 0.26 in the early phase and kept the ratio lower than 0.5 thereafter. The urinary D-/L serine ratio can detect renal ischemia earlier than kidney injury molecule-1 (KIM 1) or neutrophil gelatinase-associated lipocalin (NGAL) in the urine, and more sensitively than creatinine, cystatin C, or the ratio of D-/L-serine in the serum. Our findings provide a novel understanding of the imbalance of amino acids in renal failure and offer a potential new biomarker for an early detection of acute kidney injury. PMID- 24489732 TI - Malaria and helminth co-infections in school and preschool children: a cross sectional study in Magu district, north-western Tanzania. AB - BACKGROUND: Malaria, schistosomiasis and soil transmitted helminth infections (STH) are important parasitic infections in Sub-Saharan Africa where a significant proportion of people are exposed to co-infections of more than one parasite. In Tanzania, these infections are a major public health problem particularly in school and pre-school children. The current study investigated malaria and helminth co-infections and anaemia in school and pre-school children in Magu district, Tanzania. METHODOLOGY: School and pre-school children were enrolled in a cross-sectional study. Stool samples were examined for Schistosoma mansoni and STH infections using Kato Katz technique. Urine samples were examined for Schistosoma haematobium using the urine filtration method. Blood samples were examined for malaria parasites and haemoglobin concentrations using the Giemsa stain and Haemoque methods, respectively. PRINCIPAL FINDINGS: Out of 1,546 children examined, 1,079 (69.8%) were infected with one or more parasites. Malaria-helminth co-infections were observed in 276 children (60% of all children with P. falciparum infection). Malaria parasites were significantly more prevalent in hookworm infected children than in hookworm free children (p = 0.046). However, this association was non-significant on multivariate logistic regression analysis (OR = 1.320, p = 0.064). Malaria parasite density decreased with increasing infection intensity of S. mansoni and with increasing number of co-infecting helminth species. Anaemia prevalence was 34.4% and was significantly associated with malaria infection, S. haematobium infection and with multiple parasite infections. Whereas S. mansoni infection was a significant predictor of malaria parasite density, P. falciparum and S. haematobium infections were significant predictors of anaemia. CONCLUSIONS/SIGNIFICANCE: These findings suggest that multiple parasite infections are common in school and pre-school children in Magu district. Concurrent P. falciparum, S. mansoni and S. haematobium infections increase the risk of lower Hb levels and anaemia, which in turn calls for integrated disease control interventions. The associations between malaria and helminth infections detected in this study need further investigation. PMID- 24489733 TI - Accurate data processing improves the reliability of Affymetrix gene expression profiles from FFPE samples. AB - Formalin fixed paraffin-embedded (FFPE) tumor specimens are the conventionally archived material in clinical practice, representing an invaluable tissue source for biomarkers development, validation and routine implementation. For many prospective clinical trials, this material has been collected allowing for a prospective-retrospective study design which represents a successful strategy to define clinical utility for candidate markers. Gene expression data can be obtained even from FFPE specimens with the broadly used Affymetrix HG-U133 Plus 2.0 microarray platform. Nevertheless, important major discrepancies remain in expression data obtained from FFPE compared to fresh-frozen samples, prompting the need for appropriate data processing which could help to obtain more consistent results in downstream analyses. In a publicly available dataset of matched frozen and FFPE expression data, the performances of different normalization methods and specifically designed Chip Description Files (CDFs) were compared. The use of an alternative CDFs together with fRMA normalization significantly improved frozen-FFPE sample correlations, frozen-FFPE probeset correlations and agreement of differential analysis between different tumor subtypes. The relevance of our optimized data processing was assessed and validated using two independent datasets. In this study we demonstrated that an appropriate data processing can significantly improve the reliability of gene expression data derived from FFPE tissues using the standard Affymetrix platform. Tools for the implementation of our data processing algorithm are made publicly available at http://www.biocut.unito.it/cdf-ffpe/. PMID- 24489735 TI - Pre-dialysis systolic blood pressure-variability is independently associated with all-cause mortality in incident haemodialysis patients. AB - Systolic blood pressure variability is an independent risk factor for mortality and cardiovascular events. Standard measures of blood pressure predict outcome poorly in haemodialysis patients. We investigated whether systolic blood pressure variability was associated with mortality in incident haemodialysis patients. We performed a longitudinal observational study of patients commencing haemodialysis between 2005 and 2011 in East Anglia, UK, excluding patients with cardiovascular events within 6 months of starting haemodialysis. The main exposure was variability independent of the mean (VIM) of systolic blood pressure from short gap, pre-dialysis blood pressure readings between 3 and 6 months after commencing haemodialysis, and the outcome was all-cause mortality. Of 203 patients, 37 (18.2%) patients died during a mean follow-up of 2.0 (SD 1.3) years. The age and sex-adjusted hazard ratio (HR) for mortality was 1.09 (95% confidence interval (CI) 1.02-1.17) for a one-unit increase of VIM. This was not altered by adjustment for diabetes, prior cardiovascular disease and mean systolic blood pressure (HR 1.09, 95% CI 1.02-1.16). Patients with VIM of systolic blood pressure above the median were 2.4 (95% CI 1.17-4.74) times more likely to die during follow-up than those below the median. Results were similar for all measures of blood pressure variability and further adjustment for type of dialysis access, use of antihypertensives and absolute or variability of fluid intake did not alter these findings. Diastolic blood pressure variability showed no association with all cause mortality. Our study shows that variability of systolic blood pressure is a strong and independent predictor of all-cause mortality in incident haemodialysis patients. Further research is needed to understand the mechanism as this may form a therapeutic target or focus for management. PMID- 24489734 TI - Effect of the learning climate of residency programs on faculty's teaching performance as evaluated by residents. AB - BACKGROUND: To understand teaching performance of individual faculty, the climate in which residents' learning takes place, the learning climate, may be important. There is emerging evidence that specific climates do predict specific outcomes. Until now, the effect of learning climate on the performance of the individual faculty who actually do the teaching was unknown. OBJECTIVES: THIS STUDY: (i) tested the hypothesis that a positive learning climate was associated with better teaching performance of individual faculty as evaluated by residents, and (ii) explored which dimensions of learning climate were associated with faculty's teaching performance. METHODS AND MATERIALS: We conducted two cross-sectional questionnaire surveys amongst residents from 45 residency training programs and multiple specialties in 17 hospitals in the Netherlands. Residents evaluated the teaching performance of individual faculty using the robust System for Evaluating Teaching Qualities (SETQ) and evaluated the learning climate of residency programs using the Dutch Residency Educational Climate Test (D-RECT). The validated D-RECT questionnaire consisted of 11 subscales of learning climate. Main outcome measure was faculty's overall teaching (SETQ) score. We used multivariable adjusted linear mixed models to estimate the separate associations of overall learning climate and each of its subscales with faculty's teaching performance. RESULTS: In total 451 residents completed 3569 SETQ evaluations of 502 faculty. Residents also evaluated the learning climate of 45 residency programs in 17 hospitals in the Netherlands. Overall learning climate was positively associated with faculty's teaching performance (regression coefficient 0.54, 95% confidence interval: 0.37 to 0.71; P<0.001). Three out of 11 learning climate subscales were substantially associated with better teaching performance: 'coaching and assessment', 'work is adapted to residents' competence', and 'formal education'. CONCLUSIONS: Individual faculty's teaching performance evaluations are positively affected by better learning climate of residency programs. PMID- 24489736 TI - MC1R genotype and plumage colouration in the zebra finch (Taeniopygia guttata): population structure generates artefactual associations. AB - Polymorphisms at the melanocortin-1 receptor (MC1R) gene have been linked to coloration in many vertebrate species. However, the potentially confounding influence of population structure has rarely been controlled for. We explored the role of the MC1R in a model avian system by sequencing the coding region in 162 zebra finches comprising 79 wild type and 83 white individuals from five stocks. Allelic counts differed significantly between the two plumage morphs at multiple segregating sites, but these were mostly synonymous. To provide a control, the birds were genotyped at eight microsatellites and subjected to Bayesian cluster analysis, revealing two distinct groups. We therefore crossed wild type with white individuals and backcrossed the F1s with white birds. No significant associations were detected in the resulting offspring, suggesting that our original findings were a byproduct of genome-wide divergence. Our results are consistent with a previous study that found no association between MC1R polymorphism and plumage coloration in leaf warblers. They also contribute towards a growing body of evidence suggesting that care should be taken to quantify, and where necessary control for, population structure in association studies. PMID- 24489737 TI - Semantic particularity measure for functional characterization of gene sets using gene ontology. AB - BACKGROUND: Genetic and genomic data analyses are outputting large sets of genes. Functional comparison of these gene sets is a key part of the analysis, as it identifies their shared functions, and the functions that distinguish each set. The Gene Ontology (GO) initiative provides a unified reference for analyzing the genes molecular functions, biological processes and cellular components. Numerous semantic similarity measures have been developed to systematically quantify the weight of the GO terms shared by two genes. We studied how gene set comparisons can be improved by considering gene set particularity in addition to gene set similarity. RESULTS: We propose a new approach to compute gene set particularities based on the information conveyed by GO terms. A GO term informativeness can be computed using either its information content based on the term frequency in a corpus, or a function of the term's distance to the root. We defined the semantic particularity of a set of GO terms Sg1 compared to another set of GO terms Sg2. We combined our particularity measure with a similarity measure to compare gene sets. We demonstrated that the combination of semantic similarity and semantic particularity measures was able to identify genes with particular functions from among similar genes. This differentiation was not recognized using only a semantic similarity measure. CONCLUSION: Semantic particularity should be used in conjunction with semantic similarity to perform functional analysis of GO-annotated gene sets. The principle is generalizable to other ontologies. PMID- 24489738 TI - A morpho-density approach to estimating neural connectivity. AB - Neuronal signal integration and information processing in cortical neuronal networks critically depend on the organization of synaptic connectivity. Because of the challenges involved in measuring a large number of neurons, synaptic connectivity is difficult to determine experimentally. Current computational methods for estimating connectivity typically rely on the juxtaposition of experimentally available neurons and applying mathematical techniques to compute estimates of neural connectivity. However, since the number of available neurons is very limited, these connectivity estimates may be subject to large uncertainties. We use a morpho-density field approach applied to a vast ensemble of model-generated neurons. A morpho-density field (MDF) describes the distribution of neural mass in the space around the neural soma. The estimated axonal and dendritic MDFs are derived from 100,000 model neurons that are generated by a stochastic phenomenological model of neurite outgrowth. These MDFs are then used to estimate the connectivity between pairs of neurons as a function of their inter-soma displacement. Compared with other density-field methods, our approach to estimating synaptic connectivity uses fewer restricting assumptions and produces connectivity estimates with a lower standard deviation. An important requirement is that the model-generated neurons reflect accurately the morphology and variation in morphology of the experimental neurons used for optimizing the model parameters. As such, the method remains subject to the uncertainties caused by the limited number of neurons in the experimental data set and by the quality of the model and the assumptions used in creating the MDFs and in calculating estimating connectivity. In summary, MDFs are a powerful tool for visualizing the spatial distribution of axonal and dendritic densities, for estimating the number of potential synapses between neurons with low standard deviation, and for obtaining a greater understanding of the relationship between neural morphology and network connectivity. PMID- 24489739 TI - A method for the evaluation of image quality according to the recognition effectiveness of objects in the optical remote sensing image using machine learning algorithm. AB - Objective and effective image quality assessment (IQA) is directly related to the application of optical remote sensing images (ORSI). In this study, a new IQA method of standardizing the target object recognition rate (ORR) is presented to reflect quality. First, several quality degradation treatments with high resolution ORSIs are implemented to model the ORSIs obtained in different imaging conditions; then, a machine learning algorithm is adopted for recognition experiments on a chosen target object to obtain ORRs; finally, a comparison with commonly used IQA indicators was performed to reveal their applicability and limitations. The results showed that the ORR of the original ORSI was calculated to be up to 81.95%, whereas the ORR ratios of the quality-degraded images to the original images were 65.52%, 64.58%, 71.21%, and 73.11%. The results show that these data can more accurately reflect the advantages and disadvantages of different images in object identification and information extraction when compared with conventional digital image assessment indexes. By recognizing the difference in image quality from the application effect perspective, using a machine learning algorithm to extract regional gray scale features of typical objects in the image for analysis, and quantitatively assessing quality of ORSI according to the difference, this method provides a new approach for objective ORSI assessment. PMID- 24489740 TI - Cluster subcutaneous allergen specific immunotherapy for the treatment of allergic rhinitis: a systematic review and meta-analysis. AB - BACKGROUND: Although allergen specific immunotherapy (SIT) represents the only immune- modifying and curative option available for patients with allergic rhinitis (AR), the optimal schedule for specific subcutaneous immunotherapy (SCIT) is still unknown. The objective of this study is to systematically assess the efficacy and safety of cluster SCIT for patients with AR. METHODS: By searching PubMed, EMBASE and the Cochrane clinical trials database from 1980 through May 10th, 2013, we collected and analyzed the randomized controlled trials (RCTs) of cluster SCIT to assess its efficacy and safety. RESULTS: Eight trials involving 567 participants were included in this systematic review. Our meta-analysis showed that cluster SCIT have similar effect in reduction of both rhinitis symptoms and the requirement for anti-allergic medication compared with conventional SCIT, but when comparing cluster SCIT with placebo, no statistic significance were found in reduction of symptom scores or medication scores. Some caution is required in this interpretation as there was significant heterogeneity between studies. Data relating to Rhinoconjunctivitis Quality of Life Questionnaire (RQLQ) in 3 included studies were analyzed, which consistently point to the efficacy of cluster SCIT in improving quality of life compared to placebo. To assess the safety of cluster SCIT, meta-analysis showed that no differences existed in the incidence of either local adverse reaction or systemic adverse reaction between the cluster group and control group. CONCLUSION: Based on the current limited evidence, we still could not conclude affirmatively that cluster SCIT was a safe and efficacious option for the treatment of AR patients. Further large-scale, well-designed RCTs on this topic are still needed. PMID- 24489741 TI - Influence of hydroxyl group position and temperature on thermophysical properties of tetraalkylammonium hydroxide ionic liquids with alcohols. AB - In this work, we have explored the thermophysical properties of tetraalkylammonium hydroxide ionic liquids (ILs) such as tetrapropylammonium hydroxide (TPAH) and tetrabutylammonium hydroxide (TBAH) with isomers of butanol (1-butanol, 2-butanol and 2-methyl-2-propanol) within the temperature range 293.15-313.15 K, with interval of 5 K and over the varied concentration range of ILs. The molecular interactions between ILs and butanol isomers are essential for understanding the function of ILs in related measures and excess functions are sensitive probe for the molecular interactions. Therefore, we calculated the excess molar volume (V(E) ) and the deviation in isentropic compressibility (Deltakappas ) using the experimental values such as densities (rho) and ultrasonic sound velocities (u) that are measured over the whole compositions range at five different temperatures (293.15, 298.15, 303.15, 308.15 and 313.15 K) and atmospheric pressure. These excess functions were adequately correlated by using the Redlich-Kister polynomial equation. It was observed that for all studied systems, the V(E) and Deltakappas values are negative for the whole composition range at 293.15 K. And, the excess function follows the sequence: 2 butanol>1-butanol>2-methyl-2-propanol, which reveals that (primary or secondary or tertiary) position of hydroxyl group influence the magnitude of interactions with ILs. The negative values of excess functions are contributions from the ion dipole interaction, hydrogen bonding and packing efficiency between the ILs and butanol isomers. Hence, the position of hydroxyl group plays an important role in the interactions with ILs. The hydrogen bonding features between ILs and alcohols were analysed using molecular modelling program by using HyperChem 7. PMID- 24489742 TI - Dichromatic colour vision in wallabies as characterised by three behavioural paradigms. AB - Despite lacking genetic evidence of a third cone opsin in the retina of any Australian marsupial, most species tested so far appear to be trichromatic. In the light of this, we have re-examined colour vision of the tammar wallaby which had previously been identified as a dichromat. Three different psychophysical tests, based on an operant conditioning paradigm, were used to confirm that colour perception in the wallaby can be predicted and conclusively explained by the existence of only two cone types. Firstly, colour-mixing experiments revealed a Confusion Point between the three primary colours of a LCD monitor that can be predicted by the cone excitation ratio of the short- and middle-wavelength sensitive cones. Secondly, the wavelength discrimination ability in the wallaby, when tested with monochromatic stimuli, was found to be limited to a narrow range between 440 nm and 500 nm. Lastly, an experiment designed to test the wallaby's ability to discriminate monochromatic lights from a white light provided clear evidence for a Neutral Point around 485 nm where discrimination consistently failed. Relative colour discrimination seemed clearly preferred but it was possible to train a wallaby to perform absolute colour discriminations. The results confirm the tammar wallaby as a dichromat, and so far the only behaviourally confirmed dichromat among the Australian marsupials. PMID- 24489743 TI - Attention Deficit/Hyperactivity Disorder symptoms and cognitive abilities in the late-life cohort of the PATH through life study. AB - Attention Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder that has not been well studied in older adults. In this study we examined relationships between ADHD symptoms and cognitive ability and compared them between middle-age (MA; 48-52 years) and older-age (OA; 68-74 years) adults sampled from the same population. ADHD, mood disorder symptoms and cognitive abilities were assessed in a large population-based sample (n = 3443; 50% male). We measured current ADHD symptoms using the adult ADHD Self-Report Scale (ASRS), which we found to have the same underlying structure in both cohorts. Older adults reported significantly lower levels of ADHD symptoms and 2.2% of the OA cohort scored equal or above the ASRS cut-off score of 14 (which has been previously associated with ADHD diagnosis) compared with 6.2% of MA adults. Symptom levels were not significantly different between males and females. Using multi-group structural equation modelling we compared ADHD symptom-cognitive performance relationships between the two age groups. Generally higher ADHD symptoms were associated with poorer cognitive performance in the MA cohort. However, higher levels of inattention symptoms were associated with better verbal ability in both cohorts. Surprisingly, greater hyperactivity was associated with better task-switching abilities in older adults. In the OA cohort ADHD symptom cognition relationships are indirect, mediated largely through the strong association between depression symptoms and cognition. Our results suggest that ADHD symptoms decrease with age and that their relationships with co-occurring mood disorders and cognitive performance also change. Although symptoms of depression are lower in older adults, they are much stronger predictors of cognitive performance and likely mediate the effect of ADHD symptoms on cognition in this age group. These results highlight the need for age-appropriate diagnosis and treatment of comorbid ADHD and mood disorders. PMID- 24489744 TI - Wolves are better imitators of conspecifics than dogs. AB - Domestication is thought to have influenced the cognitive abilities of dogs underlying their communication with humans, but little is known about its effect on their interactions with conspecifics. Since domestication hypotheses offer limited predictions in regard to wolf-wolf compared to dog-dog interactions, we extend the cooperative breeding hypothesis suggesting that the dependency of wolves on close cooperation with conspecifics, including breeding but also territory defense and hunting, has created selection pressures on motivational and cognitive processes enhancing their propensity to pay close attention to conspecifics' actions. During domestication, dogs' dependency on conspecifics has been relaxed, leading to reduced motivational and cognitive abilities to interact with conspecifics. Here we show that 6-month-old wolves outperform same aged dogs in a two-action-imitation task following a conspecific demonstration. While the wolves readily opened the apparatus after a demonstration, the dogs failed to solve the problem. This difference could not be explained by differential motivation, better physical insight of wolves, differential developmental pathways of wolves and dogs or a higher dependency of dogs from humans. Our results are best explained by the hypothesis that higher cooperativeness may come together with a higher propensity to pay close attention to detailed actions of others and offer an alternative perspective to domestication by emphasizing the cooperativeness of wolves as a potential source of dog-human cooperation. PMID- 24489745 TI - Diversity and spatial structure of belowground plant-fungal symbiosis in a mixed subtropical forest of ectomycorrhizal and arbuscular mycorrhizal plants. AB - Plant-mycorrhizal fungal interactions are ubiquitous in forest ecosystems. While ectomycorrhizal plants and their fungi generally dominate temperate forests, arbuscular mycorrhizal symbiosis is common in the tropics. In subtropical regions, however, ectomycorrhizal and arbuscular mycorrhizal plants co-occur at comparable abundances in single forests, presumably generating complex community structures of root-associated fungi. To reveal root-associated fungal community structure in a mixed forest of ectomycorrhizal and arbuscular mycorrhizal plants, we conducted a massively-parallel pyrosequencing analysis, targeting fungi in the roots of 36 plant species that co-occur in a subtropical forest. In total, 580 fungal operational taxonomic units were detected, of which 132 and 58 were probably ectomycorrhizal and arbuscular mycorrhizal, respectively. As expected, the composition of fungal symbionts differed between fagaceous (ectomycorrhizal) and non-fagaceous (possibly arbuscular mycorrhizal) plants. However, non fagaceous plants were associated with not only arbuscular mycorrhizal fungi but also several clades of ectomycorrhizal (e.g., Russula) and root-endophytic ascomycete fungi. Many of the ectomycorrhizal and root-endophytic fungi were detected from both fagaceous and non-fagaceous plants in the community. Interestingly, ectomycorrhizal and arbuscular mycorrhizal fungi were concurrently detected from tiny root fragments of non-fagaceous plants. The plant-fungal associations in the forest were spatially structured, and non-fagaceous plant roots hosted ectomycorrhizal fungi more often in the proximity of ectomycorrhizal plant roots. Overall, this study suggests that belowground plant-fungal symbiosis in subtropical forests is complex in that it includes "non-typical" plant-fungal combinations (e.g., ectomycorrhizal fungi on possibly arbuscular mycorrhizal plants) that do not fall within the conventional classification of mycorrhizal symbioses, and in that associations with multiple functional (or phylogenetic) groups of fungi are ubiquitous among plants. Moreover, ectomycorrhizal fungal symbionts of fagaceous plants may "invade" the roots of neighboring non-fagaceous plants, potentially influencing the interactions between non-fagaceous plants and their arbuscular-mycorrhizal fungal symbionts at a fine spatial scale. PMID- 24489746 TI - When money is not enough: awareness, success, and variability in motor learning. AB - When performing a skill such as throwing a dart, many different combinations of joint motions suffice to hit the target. The motor system adapts rapidly to reduce bias in the desired outcome (i.e., the first-order moment of the error); however, the essence of skill is to produce movements with less variability (i.e., to reduce the second-order moment). It is easy to see how feedback about success or failure could sculpt performance to achieve this aim. However, it is unclear whether the dimensions responsible for success or failure need to be known explicitly by the subjects, or whether learning can proceed without explicit awareness of the movement parameters that need to change. Here, we designed a redundant, two-dimensional reaching task in which we could selectively manipulate task success and the variability of action outcomes, whilst also manipulating awareness of the dimension along which performance could be improved. Variability was manipulated either by amplifying natural errors, leaving the correlation between the executed movement and the visual feedback intact, or by adding extrinsic noise, decorrelating movement and feedback. We found that explicit, binary, feedback about success or failure was only sufficient for learning when participants were aware of the dimension along which motor behavior had to change. Without such awareness, learning was only present when extrinsic noise was added to the feedback, but not when task success or variability was manipulated in isolation; learning was also much slower. Our results highlight the importance of conscious awareness of the relevant dimension during motor learning, and suggest that higher-order moments of outcome signals are likely to play a significant role in skill learning in complex tasks. PMID- 24489747 TI - Effectiveness and cost effectiveness of oral pre-exposure prophylaxis in a portfolio of prevention programs for injection drug users in mixed HIV epidemics. AB - BACKGROUND: Pre-exposure prophylaxis with oral antiretroviral treatment (oral PrEP) for HIV-uninfected injection drug users (IDUs) is potentially useful in controlling HIV epidemics with a significant injection drug use component. We estimated the effectiveness and cost effectiveness of strategies for using oral PrEP in various combinations with methadone maintenance treatment (MMT) and antiretroviral treatment (ART) in Ukraine, a representative case for mixed HIV epidemics. METHODS AND FINDINGS: We developed a dynamic compartmental model of the HIV epidemic in a population of non-IDUs, IDUs who inject opiates, and IDUs in MMT, adding an oral PrEP program (tenofovir/emtricitabine, 49% susceptibility reduction) for uninfected IDUs. We analyzed intervention portfolios consisting of oral PrEP (25% or 50% of uninfected IDUs), MMT (25% of IDUs), and ART (80% of all eligible patients). We measured health care costs, quality-adjusted life years (QALYs), HIV prevalence, HIV infections averted, and incremental cost effectiveness. A combination of PrEP for 50% of IDUs and MMT lowered HIV prevalence the most in both IDUs and the general population. ART combined with MMT and PrEP (50% access) averted the most infections (14,267). For a PrEP cost of $950, the most cost-effective strategy was MMT, at $520/QALY gained versus no intervention. The next most cost-effective strategy consisted of MMT and ART, costing $1,000/QALY gained compared to MMT alone. Further adding PrEP (25% access) was also cost effective by World Health Organization standards, at $1,700/QALY gained. PrEP alone became as cost effective as MMT at a cost of $650, and cost saving at $370 or less. CONCLUSIONS: Oral PrEP for IDUs can be part of an effective and cost-effective strategy to control HIV in regions where injection drug use is a significant driver of the epidemic. Where budgets are limited, focusing on MMT and ART access should be the priority, unless PrEP has low cost. PMID- 24489748 TI - Selecting essential information for biosurveillance--a multi-criteria decision analysis. AB - The National Strategy for Biosurveillance defines biosurveillance as "the process of gathering, integrating, interpreting, and communicating essential information related to all-hazards threats or disease activity affecting human, animal, or plant health to achieve early detection and warning, contribute to overall situational awareness of the health aspects of an incident, and to enable better decision-making at all levels." However, the strategy does not specify how "essential information" is to be identified and integrated into the current biosurveillance enterprise, or what the metrics qualify information as being "essential". The question of data stream identification and selection requires a structured methodology that can systematically evaluate the tradeoffs between the many criteria that need to be taken in account. Multi-Attribute Utility Theory, a type of multi-criteria decision analysis, can provide a well-defined, structured approach that can offer solutions to this problem. While the use of Multi Attribute Utility Theoryas a practical method to apply formal scientific decision theoretical approaches to complex, multi-criteria problems has been demonstrated in a variety of fields, this method has never been applied to decision support in biosurveillance.We have developed a formalized decision support analytic framework that can facilitate identification of "essential information" for use in biosurveillance systems or processes and we offer this framework to the global BSV community as a tool for optimizing the BSV enterprise. To demonstrate utility, we applied the framework to the problem of evaluating data streams for use in an integrated global infectious disease surveillance system. PMID- 24489750 TI - Experience of offering HIV rapid testing to at-risk patients in community health centers in eight Chinese cities. AB - OBJECTIVE: To explore the feasibility of offering HIV counseling and testing in community health centers (CHCs) and to provide evidence for the HIV/AIDS response in China. METHODS: Forty-two CHCs were selected from the eight cities that participated in the study. Rapid testing was mainly provided to: clients seeking HIV testing and counseling (HTC); outpatients with high-risk behavior of contracting HIV; inpatients and outpatients of key departments. Aggregate administrative data were collected in CHCs and general hospitals and differences between the two categories were compared. RESULTS: There were 23,609 patients who underwent HIV testing, accounting for 0.37% of all estimated clinic visits at the 42 sites (0.03%-4.35% by site). Overall, positive screening prevalence was 0.41% (95% confidence interval [CI] 0.33%-0.49%, range 0.00%-0.98%), which is higher than in general hospitals (0.17%). The identification efficiency was 0.22% (95% CI: 0.16%-0.27%) in pilot CHCs, 3.5 times higher than in general hospitals (0.06%) (Chi square test = 95.196, p<0.001). The percentage of those receiving confirmatory tests among those who screened positive was slightly lower in CHCs (73.7%) than in general hospitals (80.1%) (Chi-square test = 17.472, p<0.001). Composition of clients mobilized for testing was consistent with the usage of basic public health and medical services in CHCs. The rate of patients testing HIV positive was higher among patients from key CHC departments (0.68%) than among high-risk Voluntary Counseling and Testing (VCT) clients (0.56%), those participating in outreach activities (0.41%), pregnant women (0.05%), and surgical patients (0.00%). CONCLUSION: This project demonstrates that providing HIV testing services for patients who exhibit high risk behavior has a high HIV case detection rate and that CHCs have the capacity to integrate HTC into routine work. It provides concrete evidence supporting the involvement of CHCs in the expansion of HIV/AIDS testing and case finding. PMID- 24489749 TI - Inducible, dose-adjustable and time-restricted reconstitution of STAT1 deficiency in vivo. AB - Signal transducer and activator of transcription (STAT) 1 is a key player in interferon (IFN) signaling, essential in mediating host defense against viruses and other pathogens. STAT1 levels are tightly regulated and loss- or gain-of function mutations in mice and men lead to severe diseases. We have generated a doxycycline (dox) -inducible, FLAG-tagged Stat1 expression system in mice lacking endogenous STAT1 (i.e. Stat1(ind) mice). We show that STAT1 expression depends on the time and dose of dox treatment in primary cells and a variety of organs isolated from Stat1(ind) mice. In bone marrow-derived macrophages, a fraction of the amount of STAT1 present in WT cells is sufficient for full expression of IFN induced genes. Dox-induced STAT1 established protection against virus infections in primary cells and mice. The availability of the Stat1(ind) mouse model will enable an examination of the consequences of variable amounts of STAT1. The model will also permit the study of STAT1 dose-dependent and reversible functions as well as of STAT1's contributions to the development, progression and resolution of disease. PMID- 24489751 TI - Role of toxin zeta and starvation responses in the sensitivity to antimicrobials. AB - A fraction of otherwise antimicrobial-sensitive Bacillus subtilis cells, called persisters, are phenotypically tolerant of antimicrobial treatment. We report that, independently of B. subtilis' growth phase, transient zeta toxin expression induces a dormant state and alters cellular responses so that cells are more sensitive to antimicrobials with different modes of action. This outcome is modulated by fine tuning (p)ppGpp and GTP levels: i) in the presence of low "dysregulated" (p)ppGpp levels (as in relA (-) cells) hyper-tolerance to both toxin and antimicrobials was observed; ii) physiological or low (p)ppGpp levels (as in the wild-type, sasA (-), sasB (-) and relA (-) sasA (-) context) show a normal toxin and antimicrobial tolerance; and iii) lower levels (in relA (-) sasB (-)) or absence of (p)ppGpp (in the relA (-) sasA (-) sasB (-) context), in concert with elevated GTP levels, potentiate the efficacy of both toxin and antimicrobial action, rendering tolerance vulnerable to eradication. PMID- 24489753 TI - Selection of genetic and phenotypic features associated with inflammatory status of patients on dialysis using relaxed linear separability method. AB - Identification of risk factors in patients with a particular disease can be analyzed in clinical data sets by using feature selection procedures of pattern recognition and data mining methods. The applicability of the relaxed linear separability (RLS) method of feature subset selection was checked for high dimensional and mixed type (genetic and phenotypic) clinical data of patients with end-stage renal disease. The RLS method allowed for substantial reduction of the dimensionality through omitting redundant features while maintaining the linear separability of data sets of patients with high and low levels of an inflammatory biomarker. The synergy between genetic and phenotypic features in differentiation between these two subgroups was demonstrated. PMID- 24489752 TI - Bovine pericardium patch wrapping intestinal anastomosis improves healing process and prevents leakage in a pig model. AB - Failure of intestinal anastomosis is a major complication following abdominal surgery. Biological materials have been introduced as reinforcement of abdominal wall hernia in contaminated setting. An innovative application of biological patch is its use as reinforcement of gastrointestinal anastomosis. The aim of study was to verify whether the bovine pericardium patch improves the healing of anastomosis, when in vivo wrapping the suture line of pig intestinal anastomosis, avoiding leakage in the event of deliberately incomplete suture. Forty-three pigs were randomly divided: Group 1 (control, n = 14): hand-sewn ileo-ileal and colo colic anastomosis; Group 2 (n = 14): standard anastomosis wrapped by pericardium bovine patch; Group 3 (n = 1) and 4 (n = 14): one suture was deliberately incomplete and also wrapped by patch in the last one. Intraoperative evaluation, histological, biochemical, tensiometric and electrophysiological studies of intestinal specimens were performed at 48 h, 7 and 90 days after. In groups 2 and 4, no leak, stenosis, abscess, peritonitis, mesh displacement or shrinkage were found and adhesion rate decreased compared to control. Biochemical studies showed mitochondrial function improvement in colic wrapped anastomosis. Tensiometric evaluations suggested that the patch preserves the colic contractility similar to the controls. Electrophysiological results demonstrated that the patch also improves the mucosal function restoring almost normal transport properties. Use of pericardium bovine patch as reinforcement of intestinal anastomosis is safe and effective, significantly improving the healing process. Data of prevention of acute peritonitis and leakage in cases of iatrogenic perforation of anastomoses, covered with patch, is unpublished. PMID- 24489754 TI - Adverse events profile of PrePex a non-surgical device for adult male circumcision in a Ugandan urban setting. AB - BACKGROUND: Safe Male Circumcision is a proven approach for partial HIV prevention. Several sub Saharan African countries have plans to reach a prevalence of 80% of their adult males circumcised by 2015. These targets require out of ordinary organization, demand creation, timely execution and perhaps the use of SMC devices. OBJECTIVE: To profile Adverse Events rate and acceptance of PrePex, a non surgical device for adult male circumcision. METHODS: A prospective study, conducted at International Hospital Kampala, Uganda, between August and October 2012. Ethical approval was obtained from Uganda National Council of Science and Technology. RESULTS: Of 1,040 men received to undergo SMC, 678 opted for PrePex, 36 were excluded at an initial physical examination screening. 642 were enrolled and consented, and another 17 were excluded before device placement. 625 underwent the procedure. Average age was 24 years (+/- 7). Twelve moderate AEs occurred among 10 participants 12/625, (1.9%). These were all reversible. Five had device displacement, one had an everted foreskin; five had bleeding after the device was removed and one had voiding difficulties. The majority (279 out of 300) of men interviewed complained of some pain within the week of placement. Mean pain score at device placement (using visual analogue scale) was 0.5, at device removal 4.5 and within 2 min of removal the pain score was 1.4. Over 70% of the devices were placed and removed by non-physician clinicians. Presented with a choice, 60% of men chose PrePex over surgical SMC. Close to 90% would recommend the device to their friends. Odour from the necrotic skin was a concern. Removals done 1-2 days earlier than day 7 were beneficial and conferred no extra risk. CONCLUSION: AEs of a moderate or severe nature associated with PrePex were low and reversible. PrePex is feasible for mass safe male circumcision scaling up. PMID- 24489755 TI - Recommendations for the empirical treatment of complicated urinary tract infections using surveillance data on antimicrobial resistance in the Netherlands. AB - BACKGROUND: Complicated urinary tract infections (c-UTIs) are among the most common nosocomial infections and a substantial part of the antimicrobial agents used in hospitals is for the treatment of c-UTIs. Data from surveillance can be used to guide the empirical treatment choices of clinicians when treating c-UTIs. We therefore used nation-wide surveillance data to evaluate antimicrobial coverage of agents for the treatment of c-UTI in the Netherlands. METHODS: We included the first isolate per patient of urine samples of hospitalised patients collected by the Infectious Disease Surveillance Information System for Antibiotic Resistance (ISIS-AR) in 2012, and determined the probability of inadequate coverage for antimicrobial agents based on species distribution and susceptibility. Analyses were repeated for various patient groups and hospital settings. RESULTS: The most prevalent bacteria in 27,922 isolates of 23,357 patients were Escherichia coli (47%), Enterococcus spp. (14%), Proteus mirabilis (8%), and Klebsiella pneumoniae (7%). For all species combined, the probability of inadequate coverage was <5% for amoxicillin or amoxicillin-clavulanic acid combined with gentamicin and the carbapenems. When including gram-negative bacteria only, the probability of inadequate coverage was 4.0%, 2.7%, 2.3% and 1.7%, respectively, for amoxicillin, amoxicillin-clavulanic acid, a second or a third generation cephalosporin in combination with gentamicin, and the carbapenems (0.4%). There were only small variations in results among different patient groups and hospital settings. CONCLUSIONS: When excluding Enterococcus spp., considered as less virulent, and the carbapenems, considered as last-resort drugs, empirical treatment for c-UTI with the best chance of adequate coverage are one of the studied beta-lactam-gentamicin combinations. This study demonstrates the applicability of routine surveillance data for up-to-date clinical practice guidelines on empirical antimicrobial therapy, essential in patient care given the evolving bacterial susceptibility. PMID- 24489756 TI - COPA and SLC4A4 are required for cellular entry of arginine-rich peptides. AB - Cell-penetrating peptides (CPPs) have gained attention as promising tools to enable the delivery of various molecules in a non-invasive manner. Among the CPPs, TAT and poly-arginine have been extensively utilized in numerous studies for the delivery of functional proteins, peptides, and macromolecules to analyze cellular signaling. However, the molecular mechanisms of cellular entry remain largely unknown. Here, we applied siRNA library screening to identify the regulatory genes for the cellular entry of poly-arginine peptide based on microscopic observation of the entry of fluorescent peptides in siRNA-treated cells. In this screening, we identified the cell membrane gene SLC4A4 and the trafficking regulator gene COPA, which also plays an important role in early endosome maturation. These results demonstrated that cellular entry of poly arginine requires at least two different steps, probably binding on the cell surface and endosomal entry. The identification of genes for cellular entry of poly-arginine provides insights into its mechanisms and should further aid in the development of highly efficient cell-penetrating peptides. PMID- 24489757 TI - Ultrasound molecular imaging of secreted frizzled related protein-2 expression in murine angiosarcoma. AB - Angiosarcoma is a biologically aggressive vascular malignancy with a high metastatic potential. In the era of targeted medicine, knowledge of specific molecular tumor characteristics has become more important. Molecular imaging using targeted ultrasound contrast agents can monitor tumor progression non invasively. Secreted frizzled related protein 2 (SFRP2) is a tumor endothelial marker expressed in angiosarcoma. We hypothesize that SFRP2-directed imaging could be a novel approach to imaging the tumor vasculature. To develop an SFRP2 contrast agent, SFRP2 polyclonal antibody was biotinylated and incubated with streptavidin-coated microbubbles. SVR angiosarcoma cells were injected into nude mice, and when tumors were established the mice were injected intravenously with the SFRP2 -targeted contrast agent, or a control streptavidin-coated contrast agent. SFRP2 -targeted contrast agent detected tumor vasculature with significantly more signal intensity than control contrast agent: the normalized fold-change was 1.6 +/- 0.27 (n = 13, p = 0.0032). The kidney was largely devoid of echogenicity with no significant difference between the control contrast agent and the SFRP2-targeted contrast agent demonstrating that the SFRP2-targeted contrast agent was specific to tumor vessels. Plotting average pixel intensity obtained from SFRP2-targeted contrast agent against tumor volume showed that the average pixel intensity increased as tumor volume increased. In conclusion, molecularly-targeted imaging of SFRP2 visualizes angiosarcoma vessels, but not normal vessels, and intensity increases with tumor size. Molecular imaging of SFRP2 expression may provide a rapid, non-invasive method to monitor tumor regression during therapy for angiosarcoma and other SFRP2 expressing cancers, and contribute to our understanding of the biology of SFRP2 during tumor development and progression. PMID- 24489759 TI - Dominance of sterilization and alternative choices of contraception in India: an appraisal of the socioeconomic impact. AB - BACKGROUND: The recent decline in fertility in India has been unprecedented especially in southern India, where fertility is almost exclusively controlled by means of permanent contraceptive methods, mainly female sterilization, which constitutes about two-thirds of overall contraceptive use. Many Indian women undergo sterilization at relatively young ages as a consequence of early marriage and childbearing in short birth intervals. This research aims to investigate the socioeconomic factors determining the choices for alternative contraceptive choices against the dominant preference for sterilization among married women in India. METHODS: Data for this study are drawn from the 2005-06 National Family Health Surveys focusing on a sample of married women who reported having used a method of contraception in the five years preceding the survey. A multilevel multinomial logit regression is used to estimate the impact of socioeconomic factors on contraceptive choices, differentiating temporary modern or traditional methods versus sterilization. FINDINGS: Religious affiliation, women's education and occupation had overarching influence on method choices amongst recent users. Muslim women were at higher odds of choosing a traditional or modern temporary method than sterilization. Higher level of women's education increased the odds of modern temporary method choices but the education effect on traditional method choices was only marginally significant. Recent users belonging to wealthier households had higher odds of choosing modern methods over sterilization. Exposure to family planning messages through radio had a positive effect on modern and traditional method choices. Community variations in method choices were highly significant. CONCLUSION: The persistent dominance of sterilization in the Indian family planning programme is largely determined by socioeconomic conditions. Reproductive health programmes should address the socioeconomic barriers and consider multiple cost-effective strategies such as mass media to promote awareness of modern temporary methods. PMID- 24489758 TI - Allele distributions at hybrid incompatibility loci facilitate the potential for gene flow between cultivated and weedy rice in the US. AB - The accumulation of independent mutations over time in two populations often leads to reproductive isolation. Reproductive isolation between diverging populations may be reinforced by barriers that occur either pre- or postzygotically. Hybrid sterility is the most common form of postzygotic isolation in plants. Four postzygotic sterility loci, comprising three hybrid sterility systems (Sa, s5, DPL), have been recently identified in Oryza sativa. These loci explain, in part, the limited hybridization that occurs between the domesticated cultivated rice varieties, O. sativa spp. japonica and O. sativa spp. indica. In the United States, cultivated fields of japonica rice are often invaded by conspecific weeds that have been shown to be of indica origin. Crop weed hybrids have been identified in crop fields, but at low frequencies. Here we examined the possible role of these hybrid incompatibility loci in the interaction between cultivated and weedy rice. We identified a novel allele at Sa that seemingly prevents loss of fertility in hybrids. Additionally, we found wide compatibility type alleles at strikingly high frequencies at the Sa and s5 loci in weed groups, and a general lack of incompatible alleles between crops and weeds at the DPL loci. Our results suggest that weedy individuals, particularly those of the SH and BRH groups, should be able to freely hybridize with the local japonica crop, and that prezygotic factors, such as differences in flowering time, have been more important in limiting weed-crop gene flow in the past. As the selective landscape for weedy rice changes due to increased use of herbicide resistant strains of cultivated rice, the genetic barriers that hinder indica japonica hybridization cannot be counted on to limit the flow of favorable crop genes into weeds. PMID- 24489762 TI - The economics of dementia-care mapping in nursing homes: a cluster-randomised controlled trial. AB - BACKGROUND: Dementia-care mapping (DCM) is a cyclic intervention aiming at reducing neuropsychiatric symptoms in people with dementia in nursing homes. Alongside an 18-month cluster-randomized controlled trial in which we studied the effectiveness of DCM on residents and staff outcomes, we investigated differences in costs of care between DCM and usual care in nursing homes. METHODS: Dementia special care units were randomly assigned to DCM or usual care. Nurses from the intervention care homes received DCM training, a DCM organizational briefing day and conducted the 4-months DCM-intervention twice during the study. A single DCM cycle consists of observation, feedback to the staff, and action plans for the residents. We measured costs related to health care consumption, falls and psychotropic drug use at the resident level and absenteeism at the staff level. Data were extracted from resident files and the nursing home records. Prizes were determined using the Dutch manual of health care cost and the cost prices delivered by a pharmacy and a nursing home. Total costs were evaluated by means of linear mixed-effect models for longitudinal data, with the unit as a random effect to correct for dependencies within units. RESULTS: 34 units from 11 nursing homes, including 318 residents and 376 nursing staff members participated in the cost analyses. Analyses showed no difference in total costs. However certain changes within costs could be noticed. The intervention group showed lower costs associated with outpatient hospital appointments over time (p = 0.05) than the control group. In both groups, the number of falls, costs associated with the elderly-care physician and nurse practitioner increased equally during the study (p<0.02). CONCLUSIONS: DCM is a cost-neutral intervention. It effectively reduces outpatient hospital appointments compared to usual care. Other considerations than costs, such as nursing homes' preferences, may determine whether they adopt the DCM method. TRIAL REGISTRATION: Dutch Trials Registry NTR2314. PMID- 24489761 TI - The molecular chaperone binding protein BiP prevents leaf dehydration-induced cellular homeostasis disruption. AB - BiP overexpression improves leaf water relations during droughts and delays drought-induced leaf senescence. However, whether BiP controls cellular homeostasis under drought conditions or simply delays dehydration-induced leaf senescence as the primary cause for water stress tolerance remains to be determined. To address this issue, we examined the drought-induced transcriptomes of BiP-overexpressing lines and wild-type (WT) lines under similar leaf water potential (psiw) values. In the WT leaves, a psiw reduction of -1.0 resulted in 1339 up-regulated and 2710 down-regulated genes; in the BiP-overexpressing line 35S::BiP-4, only 334 and 420 genes were induced and repressed, respectively, at a similar leaf psiw = -1.0 MPa. This level of leaf dehydration was low enough to induce a repertory of typical drought-responsive genes in WT leaves but not in 35S::BiP-4 dehydrated leaves. The responders included hormone-related genes, functional and regulatory genes involved in drought protection and senescence associated genes. The number of differentially expressed genes in the 35S::BiP-4 line approached the wild type number at a leaf psiw = -1.6 MPa. However, N-rich protein (NRP)- mediated cell death signaling genes and unfolded protein response (UPR) genes were induced to a much lower extent in the 35S::BiP-4 line than in the WT even at psiw = -1.6 MPa. The heatmaps for UPR, ERAD (ER-associated degradation protein system), drought-responsive and cell death-associated genes revealed that the leaf transcriptome of 35S::BiP-4 at psiw = -1.0 MPa clustered together with the transcriptome of well-watered leaves and they diverged considerably from the drought-induced transcriptome of the WT (psiw = -1.0, -1.7 and -2.0 MPa) and 35S::BiP-4 leaves at psiw = -1.6 MPa. Taken together, our data revealed that BiP-overexpressing lines requires a much higher level of stress (psiw = -1.6 MPa) to respond to drought than that of WT (psiw = -1.0). Therefore, BiP overexpression maintains cellular homeostasis under water stress conditions and thus ameliorates endogenous osmotic stress. PMID- 24489763 TI - Comprehensive analysis to improve the validation rate for single nucleotide variants detected by next-generation sequencing. AB - Next-generation sequencing (NGS) has enabled the high-throughput discovery of germline and somatic mutations. However, NGS-based variant detection is still prone to errors, resulting in inaccurate variant calls. Here, we categorized the variants detected by NGS according to total read depth (TD) and SNP quality (SNPQ), and performed Sanger sequencing with 348 selected non-synonymous single nucleotide variants (SNVs) for validation. Using the SAMtools and GATK algorithms, the validation rate was positively correlated with SNPQ but showed no correlation with TD. In addition, common variants called by both programs had a higher validation rate than caller-specific variants. We further examined several parameters to improve the validation rate, and found that strand bias (SB) was a key parameter. SB in NGS data showed a strong difference between the variants passing validation and those that failed validation, showing a validation rate of more than 92% (filtering cutoff value: alternate allele forward [AF] >= 20 and AF<80 in SAMtools, SB<-10 in GATK). Moreover, the validation rate increased significantly (up to 97-99%) when the variant was filtered together with the suggested values of mapping quality (MQ), SNPQ and SB. This detailed and systematic study provides comprehensive recommendations for improving validation rates, saving time and lowering cost in NGS analyses. PMID- 24489760 TI - Telomere length shows no association with BRCA1 and BRCA2 mutation status. AB - This study aimed to determine whether telomere length (TL) is a marker of cancer risk or genetic status amongst two cohorts of BRCA1 and BRCA2 mutation carriers and controls. The first group was a prospective set of 665 male BRCA1/2 mutation carriers and controls (mean age 53 years), all healthy at time of enrollment and blood donation, 21 of whom have developed prostate cancer whilst on study. The second group consisted of 283 female BRCA1/2 mutation carriers and controls (mean age 48 years), half of whom had been diagnosed with breast cancer prior to enrollment. TL was quantified by qPCR from DNA extracted from peripheral blood lymphocytes. Weighted and unweighted Cox regressions and linear regression analyses were used to assess whether TL was associated with BRCA1/2 mutation status or cancer risk. We found no evidence for association between developing cancer or being a BRCA1 or BRCA2 mutation carrier and telomere length. It is the first study investigating TL in a cohort of genetically predisposed males and although TL and BRCA status was previously studied in females our results don't support the previous finding of association between hereditary breast cancer and shorter TL. PMID- 24489764 TI - Spiegelzymes(r) mirror-image hammerhead ribozymes and mirror-image DNAzymes, an alternative to siRNAs and microRNAs to cleave mRNAs in vivo? AB - With the discovery of small non-coding RNA (ncRNA) molecules as regulators for cellular processes, it became intriguing to develop technologies by which these regulators can be applied in molecular biology and molecular medicine. The application of ncRNAs has significantly increased our knowledge about the regulation and functions of a number of proteins in the cell. It is surprising that similar successes in applying these small ncRNAs in biotechnology and molecular medicine have so far been very limited. The reasons for these observations may lie in the high complexity in which these RNA regulators function in the cells and problems with their delivery, stability and specificity. Recently, we have described mirror-image hammerhead ribozymes and DNAzymes (Spiegelzymes(r)) which can sequence-specifically hydrolyse mirror-image nucleic acids, such as our mirror-image aptamers (Spiegelmers) discovered earlier. In this paper, we show for the first time that Spiegelzymes are capable of recognising complementary enantiomeric substrates (D-nucleic acids), and that they efficiently hydrolyse them at submillimolar magnesium concentrations and at physiologically relevant conditions. The Spiegelzymes are very stable in human sera, and do not require any protein factors for their function. They have the additional advantages of being non-toxic and non-immunogenic. The Spiegelzymes can be used for RNA silencing and also as therapeutic and diagnostic tools in medicine. We performed extensive three-dimensional molecular modelling experiments with mirror-image hammerhead ribozymes and DNAzymes interacting with D-RNA targets. We propose a model in which L/D-double helix structures can be formed by natural Watson-Crick base pairs, but where the nucleosides of one of the two strands will occur in an anticlinal conformation. Interestingly enough, the duplexes (L-RNA/D-RNA and L-DNA/D-RNA) in these models can show either right- or left-handedness. This is a very new observation, suggesting that molecular symmetry of enantiomeric nucleic acids is broken down. PMID- 24489766 TI - Preoperative measurement of breast cancer overestimates tumor size compared to pathological measurement. AB - BACKGROUND: Tumor size is one of the most important factors in making clinical and pathological assessment of breast cancer. In the present study, we aimed to determine whether the preoperative measurement of tumor size, by imaging modalities, deviate from the postoperative pathological measurement in breast cancer. PATIENTS AND METHODS: 1296 patients diagnosed with invasive ductal breast carcinoma (IDC) during 2007 and 2009 were involved. Pre- and postoperative measurements of tumor size were compared using paired t-test and Chi-square test. RESULTS: The mean maximum diameters of tumors by imaging modalities and pathology were 27.9 mm and 22.4 mm, respectively. There was a statistically significant difference of 5.5 mm (95% CI: 4.7-6.2, p<0.001) between them. The discordance between pre- and post-surgical measurements of tumor size had significant effect on choosing surgery type, causing less application of breast conserving therapy (p<0.0001). CONCLUSION: Compared to pathological size, preoperative measurement by imaging modalities tends to overestimate tumor size. These differences could have implications in the treatment of patients with breast cancer. PMID- 24489765 TI - RNA interference depletion of the Halloween gene disembodied implies its potential application for management of planthopper Sogatella furcifera and Laodelphax striatellus. AB - Sogatella furcifera and Laodelphax striatellus are economically important rice pests in China by acting as vectors of several rice viruses, sucking the phloem sap and blocking the phloem vessels. Ecdysteroid hormone 20-hydroxyecdysone regulates insect development and reproduction. A cytochrome P450 monooxygenase CYP302A1 (22-hydroxylase), encoded by the Halloween gene disembodied (dib), plays a critical role in ecdysteroidogenesis. The objective of this study is to test whether dib genes are potential targets for RNA interference-based management of S. furcifera and L. striatellus. We cloned and characterized Sfdib and Lsdib. The open reading frame regions of dib genes were generated and used for designing and constructing dsRNA fragments. Experiments were conducted using oral delivery of dsdib to investigate the effectiveness of RNAi in S. furcifera and L. striatellus nymphs. Real-time quantitative reverse transcriptase-PCR analysis demonstrated that continuous ingestion of dsdib at the concentration of 0.01, 0.05 and 0.50 mg/ml diminished Sfdib expression levels by 35.9%, 45.1% and 66.2%, and ecdysone receptor (SfEcR) gene mRNA levels by 34.0%, 36.2% and 58.5% respectively in S. furcifera, and decreased Lsdib expression level by 18.8%, 35.8% and 56.7%, and LsEcR mRNA levels by 25.2%, 46.8% and 68.8% respectively in L. striatellus. The reduction in dib and EcR transcript abundance resulted in observable phenotypes. The development of nymphs was impaired and the survival was negatively affected. Our data will enable the development of new insect control strategies and functional analysis of vital genes in S. furcifera and L. striatellus nymphs. PMID- 24489767 TI - Body height, estimated cerebrospinal fluid pressure and open-angle glaucoma. The Beijing Eye Study 2011. AB - PURPOSE: To examine potential associations between body height, cerebrospinal fluid pressure (CSFP), trans-lamina cribrosa pressure difference (TLCPD) and prevalence of open-angle glaucoma (OAG) in a population-based setting. METHODS: The population-based Beijing Eye Study 2011 included 3468 individuals with a mean age of 64.6 +/- 9.8 years (range:50-93 years). A detailed ophthalmic examination was performed. Based on a previous study with lumbar cerebrospinal fluid pressure (CSFP) measurements, CSFP was calculated as CSFP[mmHg] = 0.44 * Body Mass Index[kg/m(2)] + 0.16 * Diastolic Blood Pressure[mmHg]-0.18 * Age[Years]-1.91. RESULTS: Data of IOP and CSFP were available for 3353 (96.7%) subjects. Taller body height was associated with higher CSFP (P<0.001; standardized correlation coefficient beta:0.13; regression coefficient B:0.29; 95% confidence interval (CI):0.25,0.33) after adjusting for male gender, urban region of habitation, higher educational level, and pulse rate. If TLCPD instead of CSFP was added, taller body height was associated with lower TLCPD (P<0.001;beta:-0.10;B: 0.20;95%CI:-0.25,-0.15). Correspondingly, higher CSFP was associated with taller body height (P = 0.003;beta:0.02;B:0.01;95%CI:0.00,0.02), after adjusting for age, gender, body mass index, pulse, systolic blood pressure, and blood concentration of cholesterol. If IOP was added to the model, higher CSFP was associated with higher IOP (P<0.001;beta:0.02;B:0.02;95%CI:0.01,0.03). TLCPD was associated with lower body height (P = 0.003;beta:-0.04;B -0.02,95%CI:-0.04, 0.01) after adjusting for age, body mass index, systolic blood pressure, pulse, blood concentrations of triglycerides, axial length, central corneal thickness, corneal curvature radius, and anterior chamber depth. Adding the prevalence of OAG to the multivariate analysis revealed, that taller body height was associated with a lower OAG prevalence (P = 0.03;beta:-0.03;B:-1.20;95%CI:-2.28,-0.12) after adjusting for educational level and gender. CONCLUSIONS: Taller body height was associated with higher CSFP and lower TLCPD (and vice versa), after adjusting for systemic and ocular parameters. Parallel to the associations between a higher prevalence of glaucoma with a lower CSFP or higher TLCPD, taller body height was associated with a lower prevalence of OAG. PMID- 24489768 TI - Probing oral microbial functionality--expression of spxB in plaque samples. AB - The Human Oral Microbiome Database (HOMD) provides an extensive collection of genome sequences from oral bacteria. The sequence information is a static snapshot of the microbial potential of the so far sequenced species. A major challenge is to connect the microbial potential encoded in the metagenome to an actual function in the in vivo oral biofilm. In the present study we took a reductionist approach and identified a considerably conserved metabolic gene, spxB to be encoded by a majority of oral streptococci using the HOMD metagenome information. spxB encodes the pyruvate oxidase responsible for the production of growth inhibiting amounts of hydrogen peroxide (H2O2) and has previously been shown as important in the interspecies competition in the oral biofilm. Here we demonstrate a strong correlation of H2O2 production and the presence of the spxB gene in dental plaque. Using Real-Time RT PCR we show that spxB is expressed in freshly isolated human plaque samples from several donors and that the expression is relative constant when followed over time in one individual. This is the first demonstration of an oral community encoded gene expressed in vivo suggesting a functional role of spxB in oral biofilm physiology. This also demonstrates a possible strategy to connect the microbial potential of the metagenome to its functionality in future studies by identifying similar highly conserved genes in the oral microbial community. PMID- 24489769 TI - Genes belonging to the insulin and ecdysone signaling pathways can contribute to developmental time, lifespan and abdominal size variation in Drosophila americana. AB - Even within a single genus, such as Drosophila, cases of lineage-specific adaptive evolution have been found. Therefore, the molecular basis of phenotypic variation must be addressed in more than one species group, in order to infer general patterns. In this work, we used D. americana, a species distantly-related to D. melanogaster, to perform an F2 association study for developmental time (DT), chill-coma recovery time (CRT), abdominal size (AS) and lifespan (LS) involving the two strains (H5 and W11) whose genomes have been previously sequenced. Significant associations were found between the 43 large indel markers developed here and DT, AS and LS but not with CRT. Significant correlations are also found between DT and LS, and between AS and LS, that might be explained by variation at genes belonging to the insulin and ecdysone signaling pathways. Since, in this F2 association study a single marker, located close to the Ecdysone receptor (EcR) gene, explained as much as 32.6% of the total variation in DT, we performed a second F2 association study, to determine whether large differences in DT are always due to variation in this genome region. No overlapping signal was observed between the two F2 association studies. Overall, these results illustrate that, in D. americana, pleiotropic genes involved in the highly-conserved insulin and ecdysone signaling pathways are likely responsible for variation observed in ecologically relevant phenotypic traits, although other genes are also involved. PMID- 24489770 TI - Long-term alteration of intestinal microbiota in patients with ulcerative colitis by antibiotic combination therapy. AB - Previous work has demonstrated that intestinal bacteria, such as Fusobacterium varium (F. varium), contribute to the clinical activity in ulcerative colitis (UC); thus, an antibiotic combination therapy (amoxicillin, tetracycline, and metronidazole (ATM)) against F. varium can induce and maintain UC remission. Therefore, we investigated whether ATM therapy induces a long-term alteration of intestinal microbiota in patients with UC. Patients with UC were enrolled in a multicenter, randomized, double-blind, placebo-controlled study. Biopsy samples at the beginning of the trial and again at 3 months after treatment completion were randomly obtained from 20 patients. The terminal restriction fragment length polymorphism (T-RFLP) in mucosa-associated bacterial components was examined to assess the alteration of the intestinal microbiota. Profile changes of T-RFLP in mucosa-associated bacterial components were found in 10 of 12 patients in the treatment group and in none of 8 in the placebo group. Dice similarity coefficients using the unweighted pair group method with arithmetic averages (Dice-UPGMA) confirmed that the similarity of mucosal microbiota from the descending colon was significantly decreased after the ATM therapy, and this change was maintained for at least 3 months. Moreover, at 3 months after treatment completion, the F. varium/beta-actin ratio, examined by real-time PCR using nested PCR products from biopsy samples, was reduced less than 40% in 8 of 12 treated patients, which was higher, but not significantly, than in 4 of 8 patients in the placebo group. Together, these results suggest that ATM therapy induces long-term alterations in the intestinal microbiota of patients with UC, which may be associated, at least in part, with clinical effects of the therapy. PMID- 24489771 TI - What are the effects of teaching evidence-based health care (EBHC)? Overview of systematic reviews. AB - BACKGROUND: An evidence-based approach to health care is recognized internationally as a key competency for healthcare practitioners. This overview systematically evaluated and organized evidence from systematic reviews on teaching evidence-based health care (EBHC). METHODS/FINDINGS: We searched for systematic reviews evaluating interventions for teaching EBHC to health professionals compared to no intervention or different strategies. Outcomes covered EBHC knowledge, skills, attitudes, practices and health outcomes. Comprehensive searches were conducted in April 2013. Two reviewers independently selected eligible reviews, extracted data and evaluated methodological quality. We included 16 systematic reviews, published between 1993 and 2013. There was considerable overlap across reviews. We found that 171 source studies included in the reviews related to 81 separate studies, of which 37 are in more than one review. Studies used various methodologies to evaluate educational interventions of varying content, format and duration in undergraduates, interns, residents and practicing health professionals. The evidence in the reviews showed that multifaceted, clinically integrated interventions, with assessment, led to improvements in knowledge, skills and attitudes. Interventions improved critical appraisal skills and integration of results into decisions, and improved knowledge, skills, attitudes and behaviour amongst practicing health professionals. Considering single interventions, EBHC knowledge and attitude were similar for lecture-based versus online teaching. Journal clubs appeared to increase clinical epidemiology and biostatistics knowledge and reading behavior, but not appraisal skills. EBHC courses improved appraisal skills and knowledge. Amongst practicing health professionals, interactive online courses with guided critical appraisal showed significant increase in knowledge and appraisal skills. A short workshop using problem-based approaches, compared to no intervention, increased knowledge but not appraisal skills. CONCLUSIONS: EBHC teaching and learning strategies should focus on implementing multifaceted, clinically integrated approaches with assessment. Future rigorous research should evaluate minimum components for multifaceted interventions, assessment of medium to long term outcomes, and implementation of these interventions. PMID- 24489772 TI - The personal human oral microbiome obscures the effects of treatment on periodontal disease. AB - Periodontitis is a progressive disease of the periodontium with a complex, polymicrobial etiology. Recent Next-Generation Sequencing (NGS) studies of the microbial diversity associated with periodontitis have revealed strong, community level differences in bacterial assemblages associated with healthy or diseased periodontal sites. In this study, we used NGS approaches to characterize changes in periodontal pocket bacterial diversity after standard periodontal treatment. Despite consistent changes in the abundance of certain taxa in individuals whose condition improved with treatment, post-treatment samples retained the highest similarity to pre-treatment samples from the same individual. Deeper phylogenetic analysis of periodontal pathogen-containing genera Prevotella and Fusobacterium found both unexpected diversity and differential treatment response among species. Our results highlight how understanding interpersonal variability among microbiomes is necessary for determining how polymicrobial diseases respond to treatment and disturbance. PMID- 24489773 TI - Pivoting between calmodulin lobes triggered by calcium in the Kv7.2/calmodulin complex. AB - Kv7.2 (KCNQ2) is the principal molecular component of the slow voltage gated M channel, which strongly influences neuronal excitability. Calmodulin (CaM) binds to two intracellular C-terminal segments of Kv7.2 channels, helices A and B, and it is required for exit from the endoplasmic reticulum. However, the molecular mechanisms by which CaM controls channel trafficking are currently unknown. Here we used two complementary approaches to explore the molecular events underlying the association between CaM and Kv7.2 and their regulation by Ca(2+). First, we performed a fluorometric assay using dansylated calmodulin (D-CaM) to characterize the interaction of its individual lobes to the Kv7.2 CaM binding site (Q2AB). Second, we explored the association of Q2AB with CaM by NMR spectroscopy, using (15)N-labeled CaM as a reporter. The combined data highlight the interdependency of the N- and C-lobes of CaM in the interaction with Q2AB, suggesting that when CaM binds Ca(2+) the binding interface pivots between the N lobe whose interactions are dominated by helix B and the C-lobe where the predominant interaction is with helix A. In addition, Ca(2+) makes CaM binding to Q2AB more difficult and, reciprocally, the channel weakens the association of CaM with Ca(2+). PMID- 24489774 TI - Circulating tumor cells: clinically relevant molecular access based on a novel CTC flow cell. AB - BACKGROUND: Contemporary cancer diagnostics are becoming increasing reliant upon sophisticated new molecular methods for analyzing genetic information. Limiting the scope of these new technologies is the lack of adequate solid tumor tissue samples. Patients may present with tumors that are not accessible to biopsy or adequate for longitudinal monitoring. One attractive alternate source is cancer cells in the peripheral blood. These rare circulating tumor cells (CTC) require enrichment and isolation before molecular analysis can be performed. Current CTC platforms lack either the throughput or reliability to use in a clinical setting or they provide CTC samples at purities that restrict molecular access by limiting the molecular tools available. METHODOLOGY/PRINCIPAL FINDINGS: Recent advances in magetophoresis and microfluidics have been employed to produce an automated platform called LiquidBiopsy(r). This platform uses high throughput sheath flow microfluidics for the positive selection of CTC populations. Furthermore the platform quantitatively isolates cells useful for molecular methods such as detection of mutations. CTC recovery was characterized and validated with an accuracy (<20% error) and a precision (CV<25%) down to at least 9 CTC/ml. Using anti-EpCAM antibodies as the capture agent, the platform recovers 78% of MCF7 cells within the linear range. Non specific recovery of background cells is independent of target cell density and averages 55 cells/mL. 10% purity can be achieved with as low as 6 CTCs/mL and better than 1% purity can be achieved with 1 CTC/mL. CONCLUSIONS/SIGNIFICANCE: The LiquidBiopsy platform is an automated validated platform that provides high throughput molecular access to the CTC population. It can be validated and integrated into the lab flow enabling CTC enumeration as well as recovery of consistently high purity samples for molecular analysis such as quantitative PCR and Next Generation Sequencing. This tool opens the way for clinically relevant genetic profiling of CTCs. PMID- 24489775 TI - Molecular evolution of multiple-level control of heme biosynthesis pathway in animal kingdom. AB - Adaptation of enzymes in a metabolic pathway can occur not only through changes in amino acid sequences but also through variations in transcriptional activation, mRNA splicing and mRNA translation. The heme biosynthesis pathway, a linear pathway comprised of eight consecutive enzymes in animals, provides researchers with ample information for multiple types of evolutionary analyses performed with respect to the position of each enzyme in the pathway. Through bioinformatics analysis, we found that the protein-coding sequences of all enzymes in this pathway are under strong purifying selection, from cnidarians to mammals. However, loose evolutionary constraints are observed for enzymes in which self-catalysis occurs. Through comparative genomics, we found that in animals, the first intron of the enzyme-encoding genes has been co-opted for transcriptional activation of the genes in this pathway. Organisms sense the cellular content of iron, and through iron-responsive elements in the 5' untranslated regions of mRNAs and the intron-exon boundary regions of pathway genes, translational inhibition and exon choice in enzymes may be enabled, respectively. Pathway product (heme)-mediated negative feedback control can affect the transport of pathway enzymes into the mitochondria as well as the ubiquitin-mediated stability of enzymes. Remarkably, the positions of these controls on pathway activity are not ubiquitous but are biased towards the enzymes in the upstream portion of the pathway. We revealed that multiple-level controls on the activity of the heme biosynthesis pathway depend on the linear depth of the enzymes in the pathway, indicating a new strategy for discovering the molecular constraints that shape the evolution of a metabolic pathway. PMID- 24489777 TI - Therapeutic role of ursolic acid on ameliorating hepatic steatosis and improving metabolic disorders in high-fat diet-induced non-alcoholic fatty liver disease rats. AB - BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is one of the most prevalent liver diseases around the world, and is closely associated with obesity, diabetes, and insulin resistance. Ursolic acid (UA), an ubiquitous triterpenoid with multifold biological roles, is distributed in various plants. This study was conducted to investigate the therapeutic effect and potential mechanisms of UA against hepatic steatosis in a high-fat diet (HFD)-induced obese non-alcoholic fatty liver disease (NAFLD) rat model. METHODOLOGY/PRINCIPAL FINDINGS: Obese NAFLD model was established in Sprague-Dawley rats by 8-week HFD feeding. Therapeutic role of UA was evaluated using 0.125%, 0.25%, 0.5% UA supplemented diet for another 6 weeks. The results from both morphologic and histological detections indicated that UA significantly reversed HFD-induced hepatic steatosis and liver injury. Besides, hepatic peroxisome proliferator activated receptor (PPAR)-alpha was markedly up-regulated at both mRNA and protein levels by UA. Knocking down PPAR-alpha significantly inhibited the anti steatosis role of UA in vitro. HFD-induced adverse changes in the key genes, which participated in hepatic lipid metabolism, were also alleviated by UA treatment. Furthermore, UA significantly ameliorated HFD-induced metabolic disorders, including insulin resistance, inflammation and oxidative stress. CONCLUSIONS/SIGNIFICANCE: These results demonstrated that UA effectively ameliorated HFD-induced hepatic steatosis through a PPAR-alpha involved pathway, via improving key enzymes in the controlling of lipids metabolism. The metabolic disorders were accordingly improved with the decrease of hepatic steatosis. Thereby, UA could be a promising candidate for the treatment of NAFLD. PMID- 24489778 TI - Experimental evidence of threat-sensitive collective avoidance responses in a large wild-caught herring school. AB - Aggregation is commonly thought to improve animals' security. Within aquatic ecosystems, group-living prey can learn about immediate threats using cues perceived directly from predators, or from collective behaviours, for example, by reacting to the escape behaviours of companions. Combining cues from different modalities may improve the accuracy of prey antipredatory decisions. In this study, we explored the sensory modalities that mediate collective antipredatory responses of herring (Clupea harengus) when in a large school (approximately 60,000 individuals). By conducting a simulated predator encounter experiment in a semi-controlled environment (a sea cage), we tested the hypothesis that the collective responses of herring are threat-sensitive. We investigated whether cues from potential threats obtained visually or from the perception of water displacement, used independently or in an additive way, affected the strength of the collective avoidance reactions. We modified the sensory nature of the simulated threat by exposing the herring to 4 predator models differing in shape and transparency. The collective vertical avoidance response was observed and quantified using active acoustics. The combination of sensory cues elicited the strongest avoidance reactions, suggesting that collective antipredator responses in herring are mediated by the sensory modalities involved during threat detection in an additive fashion. Thus, this study provides evidence for magnitude-graded threat responses in a large school of wild-caught herring which is consistent with the "threat-sensitive hypothesis". PMID- 24489779 TI - Food sources for Ruditapes philippinarum in a coastal lagoon determined by mass balance and stable isotope approaches. AB - The relationship between the food demand of a clam population (Ruditapes philippinarum (Adams & Reeve 1850)) and the isotopic contributions of potential food sources (phytoplankton, benthic diatoms, and organic matter derived from the sediment surface, seagrass, and seaweeds) to the clam diet were investigated. In particular, we investigated the manner in which dense patches of clams with high secondary productivity are sustained in a coastal lagoon ecosystem (Hichirippu Lagoon) in Hokkaido, Japan. Clam feeding behavior should affect material circulation in this lagoon owing to their high secondary productivity (ca. 130 g C m(-2) yr(-1)). Phytoplankton were initially found to constitute 14-77% of the clam diet, although phytoplankton nitrogen content (1.79-4.48 kmol N) and the food demand of the clam (16.2 kmol N d(-1)) suggest that phytoplankton can constitute only up to 28% of clam dietary demands. However, use of isotopic signatures alone may be misleading. For example, the contribution of microphytobenthos (MPB) were estimated to be 0-68% on the basis of isotopic signatures but was subsequently shown to be 35 +/- 13% (mean +/- S.D.) and 64 +/- 4% (mean +/- S.D.) on the basis of phytoplankton biomass and clam food demand respectively, suggesting that MPB are the primary food source for clams. Thus, in the present study, the abundant MPB in the subtidal area appear to be a key food source for clams, suggesting that these MPB may sustain the high secondary production of the clam. PMID- 24489776 TI - An evaluation of HIV elite controller definitions within a large seroconverter cohort collaboration. AB - BACKGROUND: Understanding the mechanisms underlying viral control is highly relevant to vaccine studies and elite control (EC) of HIV infection. Although numerous definitions of EC exist, it is not clear which, if any, best identify this rare phenotype. METHODS: We assessed a number of EC definitions used in the literature using CASCADE data of 25,692 HIV seroconverters. We estimated proportions maintaining EC of total ART-naive follow-up time, and disease progression, comparing to non-EC. We also examined HIV-RNA and CD4 values and CD4 slope during EC and beyond (while ART naive). RESULTS: Most definitions classify ~ 1% as ECs with median HIV-RNA 43-903 copies/ml and median CD4>500 cells/mm(3). Beyond EC status, median HIV-RNA levels remained low, although often detectable, and CD4 values high but with strong evidence of decline for all definitions. Median % ART-naive time as EC was >= 92% although overlap between definitions was low. EC definitions with consecutive HIV-RNA measurements <75 copies/ml with follow-up >= six months, or with 90% of measurements <400 copies/ml over >= 10 year follow-up preformed best overall. Individuals thus defined were less likely to progress to endpoint (hazard ratios ranged from 12.5-19.0 for non-ECs compared to ECs). CONCLUSIONS: ECs are rare, less likely to progress to clinical disease, but may eventually lose control. We suggest definitions requiring individuals to have consecutive undetectable HIV-RNA measurements for >= six months or otherwise with >90% of measurements <400 copies/ml over >= 10 years be used to define this phenotype. PMID- 24489780 TI - Activation and inhibition of TMEM16A calcium-activated chloride channels. AB - Calcium-activated chloride channels (CaCC) encoded by family members of transmembrane proteins of unknown function 16 (TMEM16) have recently been intensely studied for functional properties as well as their physiological roles as chloride channels in various tissues. One technical hurdle in studying these channels is the well-known channel rundown that frequently impairs the precision of electrophysiological measurements for the channels. Using experimental protocols that employ fast-solution exchange, we circumvented the problem of channel rundown by normalizing the Ca(2+)-induced current to the maximally activated current obtained within a time period in which the channel rundown was negligible. We characterized the activation of the TMEM16A-encoded CaCC (also called ANO1) by Ca(2+), Sr(2+), and Ba(2+), and discovered that Mg(2+) competes with Ca(2+) in binding to the divalent-cation binding site without activating the channel. We also studied the permeability of the ANO1 pore for various anions and found that the anion occupancy in the pore-as revealed by the permeability ratios of these anions-appeared to be inversely correlated with the apparent affinity of the ANO1 inhibition by niflumic acid (NFA). On the other hand, the NFA inhibition was neither affected by the degree of the channel activation nor influenced by the types of divalent cations used for the channel activation. These results suggest that the NFA inhibition of ANO1 is likely mediated by altering the pore function but not through changing the channel gating. Our study provides a precise characterization of ANO1 and documents factors that can affect divalent cation activation and NFA inhibition of ANO1. PMID- 24489781 TI - The role of marital status in the association between benzodiazepines, psychotropics and injurious road traffic crashes: a register-based nationwide study of senior drivers in Sweden. AB - BACKGROUND: Among senior drivers, benzodiazepines (BZDs) have a documented effect on the risk of road traffic crashes (RTCs). It remains unclear however if BZDs play the same role when considering marital status. Therefore, we aimed to investigate the role of marital status in the association between BZD use and injurious RTCs among senior drivers. METHODS: Matched case-control study based on five national Swedish registers (n = 154 225). Cases comprised the first non alcohol-related injurious RTC sustained by drivers aged 50-80 years from July 2005 to December 2009 and controls included registered residents with a valid license who did not crash during that period. Four controls were matched to each case by sex, age and place of residence. Conditional logistic regression analysis for injurious RTC was performed with adjustment for occupation and number of medications. The main exposure was dispensation of BZDs, alone or in combination with other psychotropic medications, 1-30 days prior to the crash date stratified by marital status. RESULTS: BZD use, alone or in combination with other psychotropic medications, increased the risk of being involved in an RTC (BZD only: adjusted OR: 1.26, 95% CI: 1.17-1.36; BZDs and other psychotropics: adjusted OR: 1.25, 95% CI: 1.12-1.41). Compared to married drivers, those divorced (1.48, 1.43-1.53) and widowed (1.54; 1.45-1.63) had higher adjusted ORs. Marital status modified the association between BZDs and RTCs, particularly among younger male drivers. CONCLUSIONS: Both BZDs and marital status independently affect the risk for senior drivers to be involved in an RTC. However, marital status plays a role in the association between BZD use and RTCs and this may have implications for targeting risk populations for RTCs among senior drivers. PMID- 24489782 TI - Genomic evolution of 11 type strains within family Planctomycetaceae. AB - The species in family Planctomycetaceae are ideal groups for investigating the origin of eukaryotes. Their cells are divided by a lipidic intracytoplasmic membrane and they share a number of eukaryote-like molecular characteristics. However, their genomic structures, potential abilities, and evolutionary status are still unknown. In this study, we searched for common protein families and a core genome/pan genome based on 11 sequenced species in family Planctomycetaceae. Then, we constructed phylogenetic tree based on their 832 common protein families. We also annotated the 11 genomes using the Clusters of Orthologous Groups database. Moreover, we predicted and reconstructed their core/pan metabolic pathways using the KEGG (Kyoto Encyclopedia of Genes and Genomes) orthology system. Subsequently, we identified genomic islands (GIs) and structural variations (SVs) among the five complete genomes and we specifically investigated the integration of two Planctomycetaceae plasmids in all 11 genomes. The results indicate that Planctomycetaceae species share diverse genomic variations and unique genomic characteristics, as well as have huge potential for human applications. PMID- 24489783 TI - 3 beta-hydroxysteroid-Delta 24 reductase (DHCR24) protects neuronal cells from apoptotic cell death induced by endoplasmic reticulum (ER) stress. AB - 3beta-Hydroxysteroid-Delta24 reductase (DHCR24) is an endoplasmic reticulum (ER) localized multifunctional enzyme that possesses anti-apoptotic and cholesterol synthesizing activities. Accumulating evidence suggests that ER stress is involved in the pathogenesis of neurodegenerative disease. In this study, we investigated whether DHCR24 may function as a neuroprotective protein under ER stress. Neuroblastoma N2A cells were infected with adenovirus expressing myc tagged DHCR24 (Ad-DHCR24) or lacZ (Ad-lacZ, serving as a control) and subjected to ER-stress, induced with Tunicamycin (TM). Cells infected with Ad-DHCR24-myc were resistant to TM-induced apoptosis, and showed weaker level of caspase-12 activity. These cells also exhibited lower levels of Bip and CHOP proteins than Ad-LacZ-infected cells. Moreover, a stronger and rapid activation of PERK, and a prolonged activation of JNK and p38 were observed in Ad-LacZ-infected cells. The generation of intracellular reactive oxygen species from ER stress was also diminished by the overexpression of DHCR24. Additionally, intracellular cholesterol level was also elevated in the Ad-DHCR24-infected cells, accompanied by a well-organized formation of caveolae (cholesterol-rich microdomain) on the plasma membrane, and improved colocalization of caveolin-1 and insulin-like growth factor 1 receptor. These results demonstrated for the first time that DHCR24 could protect neuronal cells from apoptosis induced by ER stress. PMID- 24489784 TI - Sex and genetic factors determine osteoblastic differentiation potential of murine bone marrow stromal cells. AB - Sex and genetic factors determine skeletal mass, and we tested whether bone histomorphometric parameters were sexually dimorphic in femurs from 1 to 6 month old C57BL/6 mice. Trabecular bone volume declined more rapidly in female mice than in male littermates because of enhanced bone resorption. Although bone formation was not different between sexes, female mice exhibited a higher number of osteoblasts than male littermates, suggesting that osteoblasts from female mice may have a reduced ability to form bone. To determine the impact of sex on osteoblastogenesis, we investigated the potential for osteoblastic differentiation of bone marrow stromal cells from C57BL/6, Friend leukemia virus B (FVB), C3H/HeJ and BALB/c mice of both sexes. Bone marrow stromal cells from female FVB, C57BL/6 and C3H/HeJ mice exhibited lower Alpl and Osteocalcin expression and alkaline phosphatase activity, and formed fewer mineralized nodules than cells from male littermates. Proliferative capacity was greater in cells from male than female C57BL/6, but not FVB, mice. Sorting of bone marrow stromal cells from mice expressing an alpha-Smooth muscle actin-green fluorescent protein transgene, revealed a higher yield of mesenchymal stem cells in cultures from male mice than in those from female littermates. Sex had a modest impact on osteoblastic differentiation of mesenchymal stem cells. To determine the influence of sex and genetic factors on osteoblast function, calvarial osteoblasts were harvested from C57BL/6, FVB, C3H/HeJ and BALB/c mice. Alpl expression and activity were lower in osteoblasts from C57BL/6 and C3H/HeJ, but not FVB or BALB/c, female mice than in cells from littermates. Sex had no effect on osteoclastogenesis of bone marrow cultures of C57BL/6 mice, but osteoblasts from female mice exhibited higher Rankl and lower Opg expression than cells from male littermates. In conclusion, osteoblastogenesis is sexually dimorphic and influenced by genetic factors. PMID- 24489785 TI - Ocean warming, more than acidification, reduces shell strength in a commercial shellfish species during food limitation. AB - Ocean surface pH levels are predicted to fall by 0.3-0.4 pH units by the end of the century and are likely to coincide with an increase in sea surface temperature of 2-4 degrees C. The combined effect of ocean acidification and warming on the functional properties of bivalve shells is largely unknown and of growing concern as the shell provides protection from mechanical and environmental challenges. We examined the effects of near-future pH (ambient pH 0.4 pH units) and warming (ambient temperature +4 degrees C) on the shells of the commercially important bivalve, Mytilus edulis when fed for a limited period (4-6 h day(-1)). After six months exposure, warming, but not acidification, significantly reduced shell strength determined as reductions in the maximum load endured by the shells. However, acidification resulted in a reduction in shell flex before failure. Reductions in shell strength with warming could not be explained by alterations in morphology, or shell composition but were accompanied by reductions in shell surface area, and by a fall in whole-body condition index. It appears that warming has an indirect effect on shell strength by re-allocating energy from shell formation to support temperature-related increases in maintenance costs, especially as food supply was limited and the mussels were probably relying on internal energy reserves. The maintenance of shell strength despite seawater acidification suggests that biomineralisation processes are unaffected by the associated changes in CaCO3 saturation levels. We conclude that under near-future climate change conditions, ocean warming will pose a greater risk to shell integrity in M. edulis than ocean acidification when food availability is limited. PMID- 24489786 TI - Non-invasive determination of left ventricular workload in patients with aortic stenosis using magnetic resonance imaging and Doppler echocardiography. AB - Early detection and accurate estimation of aortic stenosis (AS) severity are the most important predictors of successful long-term outcomes in patients. Current clinical parameters used for evaluation of the AS severity have several limitations including flow dependency. Estimation of AS severity is specifically challenging in patients with low-flow and low transvalvular pressure gradient conditions. A proper diagnosis in these patients needs a comprehensive evaluation of the left ventricle (LV) hemodynamic loads. This study has two objectives: (1) developing a lumped-parameter model to describe the ventricular-valvular-arterial interaction and to estimate the LV stroke work (SW); (2) introducing and validating a new index, the normalized stroke work (N-SW), to assess the global hemodynamic load imposed on the LV. N-SW represents the global hemodynamic load that the LV faces for each unit volume of blood ejected. The model uses a limited number of parameters which all can be measured non-invasively using current clinical imaging modalities. The model was first validated by comparing its calculated flow waveforms with the ones measured using Cardiovascular Magnetic Resonance (CMR) in 49 patients and 8 controls. A very good correlation and concordance were found throughout the cycle (median root mean square: 12.21 mL/s) and between the peak values (r = 0.98; SEE = 0.001, p<0.001). The model was then used to determine SW using the parameters measured with transthoracic Doppler echocardiography (TTE) and CMR. N-SW showed very good correlations with a previously-validated index of global hemodynamic load, the valvular arterial impedance ([Formula: see text]), using data from both imaging modalities (TTE: r = 0.82, SEE = 0.01, p<0.001; CMR: r = 0.74, SEE = 0.01, p<0.001). Furthermore, unlike , N-SW was almost independent from variations in the flow rate. This study suggests that considering N-SW may provide incremental diagnostic and prognostic information, beyond what standard indices of stenosis severity and provide, particularly in patients with low LV outflow. PMID- 24489787 TI - Model steatogenic compounds (amiodarone, valproic acid, and tetracycline) alter lipid metabolism by different mechanisms in mouse liver slices. AB - Although drug induced steatosis represents a mild type of hepatotoxicity it can progress into more severe non-alcoholic steatohepatitis. Current models used for safety assessment in drug development and chemical risk assessment do not accurately predict steatosis in humans. Therefore, new models need to be developed to screen compounds for steatogenic properties. We have studied the usefulness of mouse precision-cut liver slices (PCLS) as an alternative to animal testing to gain more insight into the mechanisms involved in the steatogenesis. To this end, PCLS were incubated 24 h with the model steatogenic compounds: amiodarone (AMI), valproic acid (VA), and tetracycline (TET). Transcriptome analysis using DNA microarrays was used to identify genes and processes affected by these compounds. AMI and VA upregulated lipid metabolism, whereas processes associated with extracellular matrix remodelling and inflammation were downregulated. TET downregulated mitochondrial functions, lipid metabolism, and fibrosis. Furthermore, on the basis of the transcriptomics data it was hypothesized that all three compounds affect peroxisome proliferator activated receptor (PPAR) signaling. Application of PPAR reporter assays classified AMI and VA as PPARgamma and triple PPARalpha/(beta/delta)/gamma agonist, respectively, whereas TET had no effect on any of the PPARs. Some of the differentially expressed genes were considered as potential candidate biomarkers to identify PPAR agonists (i.e. AMI and VA) or compounds impairing mitochondrial functions (i.e. TET). Finally, comparison of our findings with publicly available transcriptomics data showed that a number of processes altered in the mouse PCLS was also affected in mouse livers and human primary hepatocytes exposed to known PPAR agonists. Thus mouse PCLS are a valuable model to identify early mechanisms of action of compounds altering lipid metabolism. PMID- 24489788 TI - Dealing with target uncertainty in a reaching control interface. AB - Prosthetic devices need to be controlled by their users, typically using physiological signals. People tend to look at objects before reaching for them and we have shown that combining eye movements with other continuous physiological signal sources enhances control. This approach suffers when subjects also look at non-targets, a problem we addressed with a probabilistic mixture over targets where subject gaze information is used to identify target candidates. However, this approach would be ineffective if a user wanted to move towards targets that have not been foveated. Here we evaluated how the accuracy of prior target information influenced decoding accuracy, as the availability of neural control signals was varied. We also considered a mixture model where we assumed that the target may be foveated or, alternatively, that the target may not be foveated. We tested the accuracy of the models at decoding natural reaching data, and also in a closed-loop robot-assisted reaching task. The mixture model worked well in the face of high target uncertainty. Furthermore, errors due to inaccurate target information were reduced by including a generic model that relied on neural signals only. PMID- 24489789 TI - Protein synthesis dependence of growth cone collapse induced by different Nogo-A domains. AB - BACKGROUND: The protein Nogo-A regulates axon growth in the developing and mature nervous system, and this is carried out by two distinct domains in the protein, Nogo-A-Delta20 and Nogo-66. The differences in the signalling pathways engaged in axon growth cones by these domains are not well characterized, and have been investigated in this study. METHODOLOGY/PRINCIPAL FINDINGS: We analyzed growth cone collapse induced by the Nogo-A domains Nogo-A-Delta20 and Nogo-66 using explanted chick dorsal root ganglion neurons growing on laminin/poly-lysine substratum. Collapse induced by purified Nogo-A-Delta20 peptide is dependent on protein synthesis whereas that induced by Nogo-66 peptide is not. Nogo-A-Delta20 induced collapse is accompanied by a protein synthesis-dependent rise in RhoA expression in the growth cone, but is unaffected by proteasomal catalytic site inhibition. Conversely Nogo-66-induced collapse is inhibited ~ 50% by proteasomal catalytic site inhibition. CONCLUSION/SIGNIFICANCE: Growth cone collapse induced by the Nogo-A domains Nogo-A-Delta20 and Nogo-66 is mediated by signalling pathways with distinguishable characteristics concerning their dependence on protein synthesis and proteasomal function. PMID- 24489790 TI - Artificial evolution by viability rather than competition. AB - Evolutionary algorithms are widespread heuristic methods inspired by natural evolution to solve difficult problems for which analytical approaches are not suitable. In many domains experimenters are not only interested in discovering optimal solutions, but also in finding the largest number of different solutions satisfying minimal requirements. However, the formulation of an effective performance measure describing these requirements, also known as fitness function, represents a major challenge. The difficulty of combining and weighting multiple problem objectives and constraints of possibly varying nature and scale into a single fitness function often leads to unsatisfactory solutions. Furthermore, selective reproduction of the fittest solutions, which is inspired by competition-based selection in nature, leads to loss of diversity within the evolving population and premature convergence of the algorithm, hindering the discovery of many different solutions. Here we present an alternative abstraction of artificial evolution, which does not require the formulation of a composite fitness function. Inspired from viability theory in dynamical systems, natural evolution and ethology, the proposed method puts emphasis on the elimination of individuals that do not meet a set of changing criteria, which are defined on the problem objectives and constraints. Experimental results show that the proposed method maintains higher diversity in the evolving population and generates more unique solutions when compared to classical competition-based evolutionary algorithms. Our findings suggest that incorporating viability principles into evolutionary algorithms can significantly improve the applicability and effectiveness of evolutionary methods to numerous complex problems of science and engineering, ranging from protein structure prediction to aircraft wing design. PMID- 24489791 TI - Multifactorial likelihood assessment of BRCA1 and BRCA2 missense variants confirms that BRCA1:c.122A>G(p.His41Arg) is a pathogenic mutation. AB - Rare exonic, non-truncating variants in known cancer susceptibility genes such as BRCA1 and BRCA2 are problematic for genetic counseling and clinical management of relevant families. This study used multifactorial likelihood analysis and/or bioinformatically-directed mRNA assays to assess pathogenicity of 19 BRCA1 or BRCA2 variants identified following patient referral to clinical genetic services. Two variants were considered to be pathogenic (Class 5). BRCA1:c.4484G> C(p.Arg1495Thr) was shown to result in aberrant mRNA transcripts predicted to encode truncated proteins. The BRCA1:c.122A>G(p.His41Arg) RING-domain variant was found from multifactorial likelihood analysis to have a posterior probability of pathogenicity of 0.995, a result consistent with existing protein functional assay data indicating lost BARD1 binding and ubiquitin ligase activity. Of the remaining variants, seven were determined to be not clinically significant (Class 1), nine were likely not pathogenic (Class 2), and one was uncertain (Class 3).These results have implications for genetic counseling and medical management of families carrying these specific variants. They also provide additional multifactorial likelihood variant classifications as reference to evaluate the sensitivity and specificity of bioinformatic prediction tools and/or functional assay data in future studies. PMID- 24489793 TI - Attentional control via parallel target-templates in dual-target search. AB - Simultaneous search for two targets has been shown to be slower and less accurate than independent searches for the same two targets. Recent research suggests this 'dual-target cost' may be attributable to a limit in the number of target templates than can guide search at any one time. The current study investigated this possibility by comparing behavioural responses during single- and dual target searches for targets defined by their orientation. The results revealed an increase in reaction times for dual- compared to single-target searches that was largely independent of the number of items in the display. Response accuracy also decreased on dual- compared to single-target searches: dual-target accuracy was higher than predicted by a model restricting search guidance to a single target template and lower than predicted by a model simulating two independent single target searches. These results are consistent with a parallel model of dual target search in which attentional control is exerted by more than one target template at a time. The requirement to maintain two target-templates simultaneously, however, appears to impose a reduction in the specificity of the memory representation that guides search for each target. PMID- 24489792 TI - Interferon-gamma induces expression of MHC class II on intestinal epithelial cells and protects mice from colitis. AB - Immune responses against intestinal microbiota contribute to the pathogenesis of inflammatory bowel diseases (IBD) and involve CD4(+) T cells, which are activated by major histocompatibility complex class II (MHCII) molecules on antigen presenting cells (APCs). However, it is largely unexplored how inflammation induced MHCII expression by intestinal epithelial cells (IEC) affects CD4(+) T cell-mediated immunity or tolerance induction in vivo. Here, we investigated how epithelial MHCII expression is induced and how a deficiency in inducible epithelial MHCII expression alters susceptibility to colitis and the outcome of colon-specific immune responses. Colitis was induced in mice that lacked inducible expression of MHCII molecules on all nonhematopoietic cells, or specifically on IECs, by continuous infection with Helicobacter hepaticus and administration of interleukin (IL)-10 receptor-blocking antibodies (anti-IL10R mAb). To assess the role of interferon (IFN)-gamma in inducing epithelial MHCII expression, the T cell adoptive transfer model of colitis was used. Abrogation of MHCII expression by nonhematopoietic cells or IECs induces colitis associated with increased colonic frequencies of innate immune cells and expression of proinflammatory cytokines. CD4(+) T-helper type (Th)1 cells - but not group 3 innate lymphoid cells (ILCs) or Th17 cells - are elevated, resulting in an unfavourably altered ratio between CD4(+) T cells and forkhead box P3 (FoxP3)(+) regulatory T (Treg) cells. IFN-gamma produced mainly by CD4(+) T cells is required to upregulate MHCII expression by IECs. These results suggest that, in addition to its proinflammatory roles, IFN-gamma exerts a critical anti inflammatory function in the intestine which protects against colitis by inducing MHCII expression on IECs. This may explain the failure of anti-IFN-gamma treatment to induce remission in IBD patients, despite the association of elevated IFN-gamma and IBD. PMID- 24489794 TI - Utilization of CDX2 expression in diagnosing pancreatic ductal adenocarcinoma and predicting prognosis. AB - CDX2, a master transcriptional regulator of intestinal cell differentiation and survival, has been used as a marker to indicate colorectal lineage in adenocarcinomas of unknown origin. Pancreatic ductal adenocarcinoma (PDAC) is one of the most common causes for adenocarcinomas of unknown origin, but CDX2 expression in pancreatic disease remains unclear. In this study, we systemically and extensively investigated the expression and role of CDX2 in PDAC. We reported that CDX2 expression is weak and heterogeneous is all normal pancreas and chronic pancreatitis. It is largely expressed in epithelial-lining cells of pancreatic ducts including main ducts, inter-lobular ducts, intra-lobular ducts, intercalated ducts and centroacinar cells, but not in acinar cells or islet cells. CDX2 expression is down regulated during the transformation process from PanIN to PDAC. Only one third of PDACs retain some degree of CDX2 expression, and this group of PDACs have reduced median survival time compared to that of CDX2 negative group (308 days vs. 586 days, p = 0.0065). Metastatic PDACs remain similar expression pattern to that of the primary sites. Our study clearly demonstrates CDX2 expression in pancreatic diseases including PDAC, which is practically important when CDX2 is used to establish the primary sites of adenocarcinomas of unknown origin. In addition, our study also provides CDX2 as a prognostic marker for PDAC and implicates an important role of CDX2 in the development of normal pancreas and PDAC. PMID- 24489795 TI - Urine microRNA as potential biomarkers of autosomal dominant polycystic kidney disease progression: description of miRNA profiles at baseline. AB - BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is clinically heterogenic. Biomarkers are needed to predict prognosis and guide management. We aimed to profile microRNA (miRNA) in ADPKD to gain molecular insight and evaluate biomarker potential. METHODS: Small-RNA libraries were generated from urine specimens of ADPKD patients (N = 20) and patients with chronic kidney disease of other etiologies (CKD, N = 20). In this report, we describe the miRNA profiles and baseline characteristics. For reference, we also examined the miRNA transcriptome in primary cultures of ADPKD cyst epithelia (N = 10), normal adult tubule (N = 8) and fetal tubule (N = 7) epithelia. RESULTS: In primary cultures of ADPKD kidney cells, miRNA cistrons mir-143(2) (9.2-fold), let-7i(1) (2.3-fold) and mir-3619(1) (12.1-fold) were significantly elevated compared to normal tubule epithelia, whereas mir-1(4) members (19.7-fold), mir-133b(2) (21.1-fold) and mir 205(1) (3.0-fold) were downregulated (P<0.01). Expression of the dysregulated miRNA in fetal tubule epithelia resembled ADPKD better than normal adult cells, except let-7i, which was lower in fetal cells. In patient biofluid specimens, mir 143(2) members were 2.9-fold higher in urine cells from ADPKD compared to other CKD patients, while expression levels of mir-133b(2) (4.9-fold) and mir-1(4) (4.4 fold) were lower in ADPKD. We also noted increased abundance mir-223(1) (5.6 fold), mir-199a(3) (1.4-fold) and mir-199b(1) (1.8-fold) (P<0.01) in ADPKD urine cells. In ADPKD urine microvesicles, miR-1(2) (7.2-fold) and miR-133a(2) (11.8 fold) were less abundant compared to other CKD patients (P<0.01). CONCLUSIONS: We found that in ADPKD urine specimens, miRNA previously implicated as kidney tumor suppressors (miR-1 and miR-133), as well as miRNA of presumed inflammatory and fibroblast cell origin (miR-223/miR-199), are dysregulated when compared to other CKD patients. Concordant with findings in the primary tubule epithelial cell model, this suggests roles for dysregulated miRNA in ADPKD pathogenesis and potential use as biomarkers. We intend to assess prognostic potential of miRNA in a followup analysis. PMID- 24489796 TI - Peace-making in marsupials: the first study in the red-necked wallaby (Macropus rufogriseus). AB - The issue of reconciliation has been widely investigated in many eutherian mammal species. Nevertheless, no data are available for marsupial mammals. Indeed, the majority of reports focus on group dynamics from an ecological and reproductive perspective, but no study has investigated them from a social point of view. We observed the red-necked wallaby colony (Macropus rufogriseus) hosted at the Tierparc Zoo Berlin (Germany) and collected data on aggressive and post-conflict interactions between group members. We found that the phenomenon of reconciliation is present in the study species (mean group CCT 27.40% +/- 8.89% SE). Therefore, we demonstrated, for the first time, the occurrence of reconciliation in a gregarious marsupial mammal. Post-conflict reunion was not affected by the relationship quality between individuals (friendship or kinship) but it was fine-tuned according to the aggression intensity. For example, low intensity conflicts were reconciled whereas high intensity ones were not. Reconciliation reduced anxiety-related scratching in both of the former opponents and limited further attacks towards the victim during the post-conflict period. These findings suggest that the red-necked wallaby, like many eutherian species, can evaluate the costs of reconciliation and engage in peace-making behavior in the right contexts, in order to maximize its pay-offs. PMID- 24489797 TI - Ethnic differences in the incidence of hypertension among rural Chinese adults: results from Liaoning Province. AB - BACKGROUND: This study was conducted to examine the differences in the incidence of hypertension and associated risk factors between Mongolian and Han populations in northeast China. METHODS: A population-based sample of 4753 Mongolian subjects and 20,247 Han subjects aged >= 35 years and free from hypertension at baseline were followed from 2004-2006 to 2010. Incident hypertension was defined as systolic blood pressure >= 140 mmHg, diastolic blood pressure >= 90 mmHg, or current use of antihypertensive medication. RESULTS: During mean 4.3 years follow up, a total of 8779 individuals developed hypertension. The age-adjusted incidence of hypertension for Mongolian subjects was 12.64 per 100 person-years, for Han subjects was 9.77 per 100 person-years (P<0.05). The incidence of hypertension was positively correlated with age, physical activity, drinking, body mass index (BMI), family of hypertension and prehypertension in the Han population. In the Mongolian population, hypertension was positively correlated with age, physical activity, education level, drinking, BMI, prehypertension and family history of hypertension. The rates of awareness, treatment and control of hypertension for newly developed cases among both Han and Mongolian populations were low. (36.5% vs. 42.3%, 13.1% vs. 18.2%, 0.7% vs. 1.3%, P<0.05, respectively). CONCLUSIONS: The incidence rate of hypertension is higher in the Mongolian populations than that in the Han populations, and hypertension in both ethnic populations was associated with similar risk factors. Our results suggest that most newly-diagnosed cases of hypertension are not adequately treated. Improvements in hypertension prevention and control programs in rural China are urgently needed. PMID- 24489798 TI - The potential role of increasing the release of mouse beta- defensin-14 in the treatment of osteomyelitis in mice: a primary study. AB - Mammalian beta-defensins are small cationic peptides that have been implicated in mediating innate immune defenses against microbial infection. Mouse beta-defensin 14 (MBD-14), based on structural and functional similarities, appears to be an ortholog of human beta-defensin-3 (HBD-3). Previous studies identified signaling pathway p38 mitogen-activated protein kinase (MAPK) that contributed to the expression of MBD-14 in mouse osteoblasts upon contacted with methicillin resistance Staphylococcus aureus (MRSA) supernatant, which provided a theoretical basis as a promising therapeutic target in the treatment of intramedullary infection with MRSA in vivo. In this study, the medullary cavities of tibiae were contaminated with MRSA 10(3) colony forming units and different doses of p38 MAPK agonists anisomycin were followed as group III or IV in 30 mice. Fifteen animals that received phosphate- buffered saline served as group II and 15 mice were not contaminated with MRSA and received phosphate-buffered saline served as controls (group I). Follow-up was 7 days. In day 1, day 4 and day 7 postoperatively, infection was evaluated by blood routine, microbiological and histological analyses after sacrifice. All animals of group II developed microbiological and histological signs of infection. Histological signs of infection, white blood counts and cultures of group III and IV showed significantly reduced bacterial growth compared to cultures of group II. Simultaneously, different doses of anisomycin significantly induced the expression of osteoblast-associated genes, including alkaline phosphatase, osteocalcin and collagen type I. In addition, the expression of HBD-3 in human interfacial membranes around infected periprosthetic joint by staphylococcus contaminated was evaluated, and the expression pattern changed with significant induction of HBD-3 in infected periprosthetic joint compared with aseptic loosening under inflammatory conditions. Our primary study indicated that the potential antibacterial role of increased MBD-14 in the osteomyelitis mouse model. PMID- 24489799 TI - Does the cosmopolitan diatom Gomphonema parvulum (Kutzing) Kutzing have a biogeography? AB - Diatom cultures of the G. parvulum species complex were established from seven different sites in the Faroe Islands, Sweden, Germany, Mexico and Korea, and were studied in detail. Eight morphodemes were identified which corresponded to the descriptions of the cosmopolitan taxon G. parvulum (Kutzing) Kutzing sensu lato: its nominate variety (var. parvulum), G. parvulum var. exilissimum Grunow and G. parvulum f. saprophilum Lange-Bertalot & Reichardt, G. [parvulum var.] lagenula Kutzing plus four unidentifiable morphodemes. The concatenated analysis of the sequences of the markers 18SV4, rbcL, and ITS as well as morphological data resulted in a separation of four taxa based on their biogeography in Mexico, Korea, central Continental Europe and Northern Atlantic Europe. Mantel tests showed a significant correlation between molecular and geographical distances. The diagnoses of two taxa, G. parvulum sensu stricto, and G. lagenula, were emended, G. saprophilum elevated to species rank and epitypes designated. One species was newly described. PMID- 24489800 TI - Comparative transcriptome of wild type and selected strains of the microalgae Tisochrysis lutea provides insights into the genetic basis, lipid metabolism and the life cycle. AB - The applied exploitation of microalgae cultures has to date almost exclusively involved the use of wild type strains, deposited over decades in dedicated culture collections. Concomitantly, the concept of improving algae with selection programs for particular specific purposes is slowly emerging. Studying since a decade an economically and ecologically important haptophyte Tisochrysis lutea (Tiso), we took advantage of the availability of wild type (Tiso-Wt) and selected (Tiso-S2M2) strains to conduct a molecular variations study. This endeavour presented substantial challenges: the genome assembly was not yet available, the life cycle unknown and genetic diversity of Tiso-Wt poorly documented. This study brings the first molecular data in order to set up a selection strategy for that microalgae. Following high-throughput Illumina sequencing, transcriptomes of Tiso Wt and Tiso-S2M2 were de novo assembled and annotated. Genetic diversity between both strains was analyzed and revealed a clear conservation, while a comparison of transcriptomes allowed identification of polymorphisms resulting from the selection program. Of 34,374 transcripts, 291 were differentially expressed and 165 contained positional polymorphisms (SNP, Indel). We focused on lipid over accumulation of the Tiso-S2M2 strain and 8 candidate genes were identified by combining analysis of positional polymorphism, differential expression levels, selection signature and by study of putative gene function. Moreover, genetic analysis also suggests the existence of a sexual cycle and genetic recombination in Tisochrysis lutea. PMID- 24489801 TI - Dlx1 and Rgs5 in the ductus arteriosus: vessel-specific genes identified by transcriptional profiling of laser-capture microdissected endothelial and smooth muscle cells. AB - Closure of the ductus arteriosus (DA) is a crucial step in the transition from fetal to postnatal life. Patent DA is one of the most common cardiovascular anomalies in children with significant clinical consequences especially in premature infants. We aimed to identify genes that specify the DA in the fetus and differentiate it from the aorta. Comparative microarray analysis of laser captured microdissected endothelial (ECs) and vascular smooth muscle cells (SMCs) from the DA and aorta of fetal rats (embryonic day 18 and 21) identified vessel specific transcriptional profiles. We found a strong age-dependency of gene expression. Among the genes that were upregulated in the DA the regulator of the G-protein coupled receptor 5 (Rgs5) and the transcription factor distal-less homeobox 1 (Dlx1) exhibited the highest and most significant level of differential expression. The aorta showed a significant preferential expression of the Purkinje cell protein 4 (Pcp4) gene. The results of the microarray analysis were validated by real-time quantitative PCR and immunohistochemistry. Our study confirms vessel-specific transcriptional profiles in ECs and SMCs of rat DA and aorta. Rgs5 and Dlx1 represent novel molecular targets for the regulation of DA maturation and closure. PMID- 24489802 TI - Overexpression of rice NAC gene SNAC1 improves drought and salt tolerance by enhancing root development and reducing transpiration rate in transgenic cotton. AB - The SNAC1 gene belongs to the stress-related NAC superfamily of transcription factors. It was identified from rice and overexpressed in cotton cultivar YZ1 by Agrobacterium tumefaciens-mediated transformation. SNAC1-overexpressing cotton plants showed more vigorous growth, especially in terms of root development, than the wild-type plants in the presence of 250 mM NaCl under hydroponic growth conditions. The content of proline was enhanced but the MDA content was decreased in the transgenic cotton seedlings under drought and salt treatments compared to the wild-type. Furthermore, SNAC1-overexpressing cotton plants also displayed significantly improved tolerance to both drought and salt stresses in the greenhouse. The performances of the SNAC1-overexpressing lines under drought and salt stress were significantly better than those of the wild-type in terms of the boll number. During the drought and salt treatments, the transpiration rate of transgenic plants significantly decreased in comparison to the wild-type, but the photosynthesis rate maintained the same at the flowering stage in the transgenic plants. These results suggested that overexpression of SNAC1 improve more tolerance to drought and salt in cotton through enhanced root development and reduced transpiration rates. PMID- 24489803 TI - Link community detection using generative model and nonnegative matrix factorization. AB - Discovery of communities in complex networks is a fundamental data analysis problem with applications in various domains. While most of the existing approaches have focused on discovering communities of nodes, recent studies have shown the advantages and uses of link community discovery in networks. Generative models provide a promising class of techniques for the identification of modular structures in networks, but most generative models mainly focus on the detection of node communities rather than link communities. In this work, we propose a generative model, which is based on the importance of each node when forming links in each community, to describe the structure of link communities. We proceed to fit the model parameters by taking it as an optimization problem, and solve it using nonnegative matrix factorization. Thereafter, in order to automatically determine the number of communities, we extend the above method by introducing a strategy of iterative bipartition. This extended method not only finds the number of communities all by itself, but also obtains high efficiency, and thus it is more suitable to deal with large and unexplored real networks. We test this approach on both synthetic benchmarks and real-world networks including an application on a large biological network, and compare it with two highly related methods. Results demonstrate the superior performance of our approach over competing methods for the detection of link communities. PMID- 24489804 TI - Sarcopenia as a determinant of blood pressure in older Koreans: findings from the Korea National Health and Nutrition Examination Surveys (KNHANES) 2008-2010. AB - BACKGROUND: Blood pressure (BP) is directly and causally associated with body size in the general population. Whether muscle mass is an important factor that determines BP remains unclear. OBJECTIVE: To investigate whether sarcopenia is associated with hypertension in older Koreans. PARTICIPANTS: We surveyed 2,099 males and 2,747 females aged 60 years or older. MEASUREMENTS: Sarcopenia was defined as an appendicular skeletal muscle mass divided by body weight (ASM/Wt) that was <1 SD below the gender-specific mean for young adults. Obesity was defined as a body mass index (BMI) >= 25 kg/m(2). Subjects were divided into four groups based on presence or absence of obesity or sarcopenia. Hypertension was defined as a systolic BP (SBP) >= 140 mmHg, a diastolic BP (DBP) >= 90 mmHg, or a self-reported current use of antihypertensive medications. RESULTS: The overall prevalence of hypertension in the four groups was as follows 49.7% for non-obese non-sarcopenia, 60.9% for non-obese sarcopenia, 66.2% for obese non-sarcopenia and 74.7% for obese sarcopenia. After adjustment for age, gender, regular activity, current smoking and alcohol use, the odds ratio (OR) for having hypertension was 1.5 (95% confidence interval (CI) = 1.23-1.84) in subjects in the non-obese sarcopenia group, 2.08 (95% CI = 1.68-2.57) in the obese non sarcopenia group and 3.0 (95% CI = 2.48-3.63) in the obese sarcopenia group, compared with the non-obese non-sarcopenia group (p for trend <0.001). Controlling further for body weight and waist circumference did not change the association between hypertension and sarcopenia. The association between sarcopenia and hypertension was more robust in the subjects with diabetes mellitus. CONCLUSION: Body composition beyond BMI has a considerable impact on hypertension in elderly Koreans. Subjects with sarcopenic obesity appear to have a greater risk of hypertension than simply obese or sarcopenia subjects. PMID- 24489805 TI - Juvenile hormone biosynthesis gene expression in the corpora allata of honey bee (Apis mellifera L.) female castes. AB - Juvenile hormone (JH) controls key events in the honey bee life cycle, viz. caste development and age polyethism. We quantified transcript abundance of 24 genes involved in the JH biosynthetic pathway in the corpora allata-corpora cardiaca (CA-CC) complex. The expression of six of these genes showing relatively high transcript abundance was contrasted with CA size, hemolymph JH titer, as well as JH degradation rates and JH esterase (jhe) transcript levels. Gene expression did not match the contrasting JH titers in queen and worker fourth instar larvae, but jhe transcript abundance and JH degradation rates were significantly lower in queen larvae. Consequently, transcriptional control of JHE is of importance in regulating larval JH titers and caste development. In contrast, the same analyses applied to adult worker bees allowed us inferring that the high JH levels in foragers are due to increased JH synthesis. Upon RNAi-mediated silencing of the methyl farnesoate epoxidase gene (mfe) encoding the enzyme that catalyzes methyl farnesoate-to-JH conversion, the JH titer was decreased, thus corroborating that JH titer regulation in adult honey bees depends on this final JH biosynthesis step. The molecular pathway differences underlying JH titer regulation in larval caste development versus adult age polyethism lead us to propose that mfe and jhe genes be assayed when addressing questions on the role(s) of JH in social evolution. PMID- 24489807 TI - Interoceptive focus shapes the experience of time. AB - The perception of time is a fundamental part of human experience. Recent research suggests that the experience of time emerges from emotional and interoceptive (bodily) states as processed in the insular cortex. Whether there is an interaction between the conscious awareness of interoceptive states and time distortions induced by emotions has rarely been investigated so far. We aimed to address this question by the use of a retrospective time estimation task comparing two groups of participants. One group had a focus on interoceptive states and one had a focus on exteroceptive information while watching film clips depicting fear, amusement and neutral content. Main results were that attention to interoceptive processes significantly affected subjective time experience. Fear was accompanied with subjective time dilation that was more pronounced in the group with interoceptive focus, while amusement led to a quicker passage of time which was also increased by interoceptive focus. We conclude that retrospective temporal distortions are directly influenced by attention to bodily responses. These effects might crucially interact with arousal levels. Sympathetic nervous system activation affecting memory build-up might be the decisive factor influencing retrospective time judgments. Our data substantially extend former research findings underscoring the relevance of interoception for the effects of emotional states on subjective time experience. PMID- 24489806 TI - Effects of nitric oxide on neuromuscular properties of developing zebrafish embryos. AB - Nitric oxide is a bioactive signalling molecule that is known to affect a wide range of neurodevelopmental processes. However, its functional relevance to neuromuscular development is not fully understood. Here we have examined developmental roles of nitric oxide during formation and maturation of neuromuscular contacts in zebrafish. Using histochemical approaches we show that elevating nitric oxide levels reduces the number of neuromuscular synapses within the axial swimming muscles whilst inhibition of nitric oxide biosynthesis has the opposite effect. We further show that nitric oxide signalling does not change synapse density, suggesting that the observed effects are a consequence of previously reported changes in motor axon branch formation. Moreover, we have used in vivo patch clamp electrophysiology to examine the effects of nitric oxide on physiological maturation of zebrafish neuromuscular junctions. We show that developmental exposure to nitric oxide affects the kinetics of spontaneous miniature end plate currents and impacts the neuromuscular drive for locomotion. Taken together, our findings implicate nitrergic signalling in the regulation of zebrafish neuromuscular development and locomotor maturation. PMID- 24489808 TI - Assessment of the AquaCrop model for use in simulation of irrigated winter wheat canopy cover, biomass, and grain yield in the North China Plain. AB - Improving winter wheat water use efficiency in the North China Plain (NCP), China is essential in light of current irrigation water shortages. In this study, the AquaCrop model was used to calibrate, and validate winter wheat crop performance under various planting dates and irrigation application rates. All experiments were conducted at the Xiaotangshan experimental site in Beijing, China, during seasons of 2008/2009, 2009/2010, 2010/2011 and 2011/2012. This model was first calibrated using data from 2008/2009 and 2009/2010, and subsequently validated using data from 2010/2011 and 2011/2012. The results showed that the simulated canopy cover (CC), biomass yield (BY) and grain yield (GY) were consistent with the measured CC, BY and GY, with corresponding coefficients of determination (R(2)) of 0.93, 0.91 and 0.93, respectively. In addition, relationships between BY, GY and transpiration (T), (R(2) = 0.57 and 0.71, respectively) was observed. These results suggest that frequent irrigation with a small amount of water significantly improved BY and GY. Collectively, these results indicate that the AquaCrop model can be used in the evaluation of various winter wheat irrigation strategies. The AquaCrop model predicted winter wheat CC, BY and GY with acceptable accuracy. Therefore, we concluded that AquaCrop is a useful decision making tool for use in efforts to optimize wheat winter planting dates, and irrigation strategies. PMID- 24489809 TI - Trace elemental imaging of rare earth elements discriminates tissues at microscale in flat fossils. AB - The interpretation of flattened fossils remains a major challenge due to compression of their complex anatomies during fossilization, making critical anatomical features invisible or hardly discernible. Key features are often hidden under greatly preserved decay prone tissues, or an unpreparable sedimentary matrix. A method offering access to such anatomical features is of paramount interest to resolve taxonomic affinities and to study fossils after a least possible invasive preparation. Unfortunately, the widely-used X-ray micro computed tomography, for visualizing hidden or internal structures of a broad range of fossils, is generally inapplicable to flattened specimens, due to the very high differential absorbance in distinct directions. Here we show that synchrotron X-ray fluorescence spectral raster-scanning coupled to spectral decomposition or a much faster Kullback-Leibler divergence based statistical analysis provides microscale visualization of tissues. We imaged exceptionally well-preserved fossils from the Late Cretaceous without needing any prior delicate preparation. The contrasting elemental distributions greatly improved the discrimination of skeletal elements material from both the sedimentary matrix and fossilized soft tissues. Aside content in alkaline earth elements and phosphorus, a critical parameter for tissue discrimination is the distinct amounts of rare earth elements. Local quantification of rare earths may open new avenues for fossil description but also in paleoenvironmental and taphonomical studies. PMID- 24489811 TI - IVUS validation of patient coronary artery lumen area obtained from CT images. AB - AIMS: Accurate computed tomography (CT)-based reconstruction of coronary morphometry (diameters, length, bifurcation angles) is important for construction of patient-specific models to aid diagnosis and therapy. The objective of this study is to validate the accuracy of patient coronary artery lumen area obtained from CT images based on intravascular ultrasound (IVUS). METHODS AND RESULTS: Morphometric data of 5 patient CT scans with 11 arteries from IVUS were reconstructed including the lumen cross sectional area (CSA), diameter and length. The volumetric data from CT images were analyzed at sub-pixel accuracy to obtain accurate vessel center lines and CSA. A new center line extraction approach was used where an initial estimated skeleton in discrete value was obtained using a traditional thinning algorithm. The CSA was determined directly without any circular shape assumptions to provide accurate reconstruction of stenosis. The root-mean-square error (RMSE) for CSA and diameter were 16.2% and 9.5% respectively. CONCLUSIONS: The image segmentation and CSA extraction algorithm for reconstruction of coronary arteries proved to be accurate for determination of vessel lumen area. This approach provides fundamental morphometric data for patient-specific models to diagnose and treat coronary artery disease. PMID- 24489810 TI - Sodium current reduction unmasks a structure-dependent substrate for arrhythmogenesis in the normal ventricles. AB - BACKGROUND: Organ-scale arrhythmogenic consequences of source-sink mismatch caused by impaired excitability remain unknown, hindering the understanding of pathophysiology in disease states like Brugada syndrome and ischemia. OBJECTIVE: We sought to determine whether sodium current (INa) reduction in the structurally normal heart unmasks a regionally heterogeneous substrate for the induction of sustained arrhythmia by premature ventricular contractions (PVCs). METHODS: We conducted simulations in rabbit ventricular computer models with 930 unique combinations of PVC location (10 sites) and coupling interval (250-400 ms), INa reduction (30 or 40% of normal levels), and post-PVC sinus rhythm (arrested or persistent). Geometric characteristics and source-sink mismatch were quantitatively analyzed by calculating ventricular wall thickness and a newly formulated 3D safety factor (SF), respectively. RESULTS: Reducing INa to 30% of its normal level created a substrate for sustained arrhythmia induction by establishing large regions of critical source-sink mismatch (SF<1) for ectopic wavefronts propagating from thin to thick tissue. In the same simulations but with 40% of normal INa, PVCs did not induce reentry because the volume of tissue with SF<1 was >95% smaller. Likewise, when post-PVC sinus activations were persistent instead of arrested, no ectopic excitations initiated sustained reentry because sinus activation breakthroughs engulfed the excitable gap. CONCLUSION: Our new SF formulation can quantify ectopic wavefront propagation robustness in geometrically complex 3D tissue with impaired excitability. This novel methodology was applied to show that INa reduction precipitates source-sink mismatch, creating a potent substrate for sustained arrhythmia induction by PVCs originating near regions of ventricular wall expansion, such as the RV outflow tract. PMID- 24489812 TI - High levels of BCOX1 expression are associated with poor prognosis in patients with invasive ductal carcinomas of the breast. AB - This study was to examine the breast cancer-overexpressed gene 1 (BCOX1) expression in invasive ductal carcinomas (IDC) of the breast and its value in the prognosis of the disease. The levels of BCOX1 expression in 491 paired IDC and surrounding non-tumor breast tissues as well as 40 paired fresh specimens were evaluated by tissue microarray, immunohistochemistry and quantitative RT-PCR. The potential associations of high BCOX1 expression with clinicopathological variables and the overall survival of these patients were analyzed. The relative levels of BCOX1 mRNA transcripts in the IDC breast tissues were significantly higher than that in the corresponding non-tumor tissues (P = 0.005). The anti BCOX1 was predominantly stained in the cytoplasm of breast tissue cells and the levels of BCOX1 expression in the majority of breast cancer tissues were obviously higher than that in the corresponding non-tumor breast tissues. High levels of BCOX1 expression were found in 59.5% (292/491) of breast cancer tissues. The high BCOX1 expression was significantly associated with high histological grade (P = 0.037), positive expression of human epidermal growth factor receptor 2 (HER2, P = 0.031) and triple negative breast cancer (P = 0.027). The high BCOX1 expression in breast cancers was significantly associated with a shorter overall survival of these patients (P = 0.023), particularly in patients with triple negative breast cancer (P = 0.005). Therefore, the high BCOX1 expression may serve as a novel marker of poor prognosis and a potential therapeutic target for patients with IDC of the breast. PMID- 24489813 TI - The course of asthma in young adults: a population-based nine-year follow-up on asthma remission and control. AB - BACKGROUND: Only few longitudinal studies on the course of asthma among adults have been carried out. OBJECTIVE: The aim of the present prospective study, carried out between 2000 and 2009 in Italy, is to assess asthma remission and control in adults with asthma, as well as their determinants. METHODS: All the subjects with current asthma (21-47 years) identified in 2000 in the Italian Study on Asthma in Young Adults in 6 Italian centres were followed up. Asthma remission was assessed at follow-up in 2008-2009 (n = 214), asthma control at baseline and follow-up. Asthma remission and control were related to potential determinants by a binomial logistic and a multinomial logistic model. Separate models for remission were used for men and women. RESULTS: The estimate of the proportion of subjects who were in remission was 29.7% (95%CI: 14.4%;44.9%). Men who were not under control at baseline had a very low probability of being in remission at follow-up (OR = 0.06; 95%CI:0.01;0.33) when compared to women (OR = 0.40; 95%CI:0.17;0.94). The estimates of the proportion of subjects who were under control, partial control or who were not under control in our sample were 26.3% (95%CI: 21.2;31.3%), 51.6% (95%CI: 44.6;58.7%) and 22.1% (95%CI: 16.6;27.6%), respectively. Female gender, increasing age, the presence of chronic cough and phlegm and partial or absent asthma control at baseline increased the risk of uncontrolled asthma at follow-up. CONCLUSION: Asthma remission was achieved in nearly 1/3 of the subjects with active asthma in the Italian adult population, whereas the proportion of the subjects with controlled asthma among the remaining subjects was still low. PMID- 24489814 TI - Broad shifts in gene expression during early postnatal life are associated with shifts in histone methylation patterns. AB - During early postnatal life, extensive changes in gene expression occur concomitantly in multiple major organs, indicating the existence of a common core developmental genetic program. This program includes hundreds of growth-promoting genes that are downregulated with age in liver, kidney, lung, and heart, and there is evidence that this component of the program drives the widespread decline in cell proliferation that occurs in juvenile life, as organs approach adult sizes. To investigate epigenetic changes that might orchestrate this program, we performed chromatin immunoprecipitation-promoter tiling array to assess temporal changes in histone H3K4 and H3K27 trimethylation (me3) at promoter regions throughout the genome in kidney and lung, comparing 1- to 4-wk old mice. We found extensive genome-wide shifts in H3K4me3 and H3K27me3 occurring with age in both kidney and lung. The number of genes with concordant changes in the two organs was far greater than expected by chance. Temporal changes in H3K4me3 showed a strong, positive association with changes in gene expression, assessed by microarray, whereas changes in H3K27me3 showed a negative association. Gene ontology analysis indicated that shifts in specific histone methylation marks were associated with specific developmental functions. Of particular interest, genes with decreases in H3K4me3 with age in both organs were strongly implicated in cell cycle and cell proliferation functions. Taken together, the findings suggest that the common core developmental program of gene expression which occurs in multiple organs during juvenile life is associated with a common core developmental program of histone methylation. In particular, declining H3K4me3 is strongly associated with gene downregulation and occurs in the promoter regions of many growth-regulating genes, suggesting that this change in histone methylation may contribute to the component of the genetic program that drives juvenile body growth deceleration. PMID- 24489815 TI - Young children understand the normative implications of future-directed speech acts. AB - Much recent research has shown that the capacity for mental time travel and temporal reasoning emerges during the preschool years. Nothing is known so far, however, about young children's grasp of the normative dimension of future directed thought and speech. The present study is the first to show that children from age 4 understand the normative outreach of such future-directed speech acts: subjects at time 1 witnessed a speaker make future-directed speech acts about/towards an actor A, either in imperative mode ("A, do X!") or as a prediction ("the actor A will do X"). When at time 2 the actor A performed an action that did not match the content of the speech act at time 1, children identified the speaker as the source of a mistake in the prediction case, and the actor as the source of the mistake in the imperative case and leveled criticism accordingly. These findings add to our knowledge about the emergence and development of temporal cognition in revealing an early sensitivity to the normative aspects of future-orientation. PMID- 24489816 TI - Longitudinal strain is a marker of microvascular obstruction and infarct size in patients with acute ST-segment elevation myocardial infarction. AB - OBJECTIVES: We assessed the value of speckle tracking imaging performed early after a first ST-segment elevation myocardial infarction (STEMI) in order to predict infarct size and functional recovery at 3-month follow-up. METHODS: 44 patients with STEMI who underwent revascularization within 12 h of symptom onset were prospectively enrolled. Echocardiography was performed 3.9 +/- 1.2 days after myocardial reperfusion, assessing circumferential (CGS), radial (RGS), and longitudinal global (GLS) strains. Late gadolinium-enhanced cardiac magnetic imaging (CMR), for assessing cardiac function, infarct size, and microvascular obstruction (MVO), was conducted 5.6 +/- 2.5 days and 99.4 +/- 4.6 days after myocardial reperfusion. RESULTS: GLS was evaluable in 97% of the patients, while CGS and RGS could be assessed in 85%. Infarct size significantly correlated with GLS (R = 0.601, p<0.001), RGS (R = -0.405, p = 0.010), CGS (R = 0.526, p = 0.001), ejection fraction (R = -0.699, p<0.001), wall motion score index (WMSI) (R = 0.539, p = 0.001), and left atrial volume (R = 0.510, p<0.001). Baseline ejection fraction and GLS were independent predictors of 3-month infarct size. MVO mass significantly correlated with GLS (R = 0.376, p = 0.010), WMSI (R = 0.387, p = 0.011), and ejection fraction (R = -0.389, p = 0.011). In multivariate analysis, GLS was the only independent predictor of MVO mass (p = 0.015). Longitudinal strain >-6.0% within the infarcted area exhibited 96% specificity and 61% sensitivity for predicting the persistence of akinesia (>= 3 segments) at 3-month follow-up. CONCLUSIONS: Speckle-tracking strain imaging performed early after a STEMI is easy-to-use as a marker for persistent akinetic territories at 3 months. In addition, GLS correlated significantly with MVO and final infarct size, both parameters being relevant post-MI prognostic factors, usually obtained via CMR. PMID- 24489817 TI - Mathematical modeling of renal tubular glucose absorption after glucose load. AB - A partial differential Progressive Tubular Reabsorption (PTR) model, describing renal tubular glucose reabsorption and urinary glucose excretion following a glucose load perturbation, is proposed and fitted to experimental data from five subjects. For each subject the Glomerular Filtration Rate was estimated and both blood and urine glucose were sampled following an Intra-Venous glucose bolus. The PTR model was compared with a model representing the conventional Renal Threshold Hypothesis (RTH). A delay bladder compartment was introduced in both formulations. For the RTH model, the average threshold for glycosuria varied between 9.90 +/- 4.50 mmol/L and 10.63 +/- 3.64 mmol/L (mean +/- Standard Deviation) under different hypotheses; the corresponding average maximal transport rates varied between 0.48 +/- 0.45 mmol/min (86.29 +/- 81.22 mg/min) and 0.50 +/- 0.42 mmol/min (90.62 +/- 76.15 mg/min). For the PTR Model, the average maximal transports rates varied between 0.61 +/- 0.52 mmol/min (109.57 +/ 93.77 mg/min) and 0.83 +/- 0.95 mmol/min (150.13 +/- 171.85 mg/min). The time spent by glucose inside the tubules before entering the bladder compartment varied between 1.66 +/- 0.73 min and 2.45 +/- 1.01 min. The PTR model proved much better than RTH at fitting observations, by correctly reproducing the delay of variations of glycosuria with respect to the driving glycemia, and by predicting non-zero urinary glucose elimination at low glycemias. This model is useful when studying both transients and steady-state glucose elimination as well as in assessing drug-related changes in renal glucose excretion. PMID- 24489818 TI - Transcriptomic analysis of flower development in wintersweet (Chimonanthus praecox). AB - Wintersweet (Chimonanthus praecox) is familiar as a garden plant and woody ornamental flower. On account of its unique flowering time and strong fragrance, it has a high ornamental and economic value. Despite a long history of human cultivation, our understanding of wintersweet genetics and molecular biology remains scant, reflecting a lack of basic genomic and transcriptomic data. In this study, we assembled three cDNA libraries, from three successive stages in flower development, designated as the flower bud with displayed petal, open flower and senescing flower stages. Using the Illumina RNA-Seq method, we obtained 21,412,928, 26,950,404, 24,912,954 qualified Illumina reads, respectively, for the three successive stages. The pooled reads from all three libraries were then assembled into 106,995 transcripts, 51,793 of which were annotated in the NCBI non-redundant protein database. Of these annotated sequences, 32,649 and 21,893 transcripts were assigned to gene ontology categories and clusters of orthologous groups, respectively. We could map 15,587 transcripts onto 312 pathways using the Kyoto Encyclopedia of Genes and Genomes pathway database. Based on these transcriptomic data, we obtained a large number of candidate genes that were differentially expressed at the open flower and senescing flower stages. An analysis of differentially expressed genes involved in plant hormone signal transduction pathways indicated that although flower opening and senescence may be independent of the ethylene signaling pathway in wintersweet, salicylic acid may be involved in the regulation of flower senescence. We also succeeded in isolating key genes of floral scent biosynthesis and proposed a biosynthetic pathway for monoterpenes and sesquiterpenes in wintersweet flowers, based on the annotated sequences. This comprehensive transcriptomic analysis presents fundamental information on the genes and pathways which are involved in flower development in wintersweet. And our data provided a useful database for further research of wintersweet and other Calycanthaceae family plants. PMID- 24489819 TI - Influence of musical training on understanding voiced and whispered speech in noise. AB - This study tested the hypothesis that the previously reported advantage of musicians over non-musicians in understanding speech in noise arises from more efficient or robust coding of periodic voiced speech, particularly in fluctuating backgrounds. Speech intelligibility was measured in listeners with extensive musical training, and in those with very little musical training or experience, using normal (voiced) or whispered (unvoiced) grammatically correct nonsense sentences in noise that was spectrally shaped to match the long-term spectrum of the speech, and was either continuous or gated with a 16-Hz square wave. Performance was also measured in clinical speech-in-noise tests and in pitch discrimination. Musicians exhibited enhanced pitch discrimination, as expected. However, no systematic or statistically significant advantage for musicians over non-musicians was found in understanding either voiced or whispered sentences in either continuous or gated noise. Musicians also showed no statistically significant advantage in the clinical speech-in-noise tests. Overall, the results provide no evidence for a significant difference between young adult musicians and non-musicians in their ability to understand speech in noise. PMID- 24489820 TI - Investigation of intramolecular dynamics and conformations of alpha-, beta- and gamma-synuclein. AB - The synucleins are a family of natively unstructured proteins consisting of alpha , beta-, and gamma-synuclein which are primarily expressed in neurons. They have been linked to a wide variety of pathologies, including neurological disorders, such as Parkinson's disease (alpha-synuclein) and dementia with Lewy bodies (alpha- and beta-synuclein), as well as various types of cancers (gamma synuclein). Self-association is a key pathological feature of many of these disorders, with alpha-synuclein having the highest propensity to form aggregates, while beta-synuclein is the least prone. Here, we used a combination of fluorescence correlation spectroscopy and single molecule Forster resonance energy transfer to compare the intrinsic dynamics of different regions of all three synuclein proteins to investigate any correlation with putative functional or dysfunctional interactions. Despite a relatively high degree of sequence homology, we find that individual regions sample a broad range of diffusion coefficients, differing by almost a factor of four. At low pH, a condition that accelerates aggregation of alpha-synuclein, on average smaller diffusion coefficients are measured, supporting a hypothesis that slower intrachain dynamics may be correlated with self-association. Moreover, there is a surprising inverse correlation between dynamics and bulkiness of the segments. Aside from this observation, we could not discern any clear relationship between the physico chemical properties of the constructs and their intrinsic dynamics. This work suggests that while protein dynamics may play a role in modulating self association or interactions with other binding partners, other factors, particularly the local cellular environment, may be more important. PMID- 24489821 TI - The response of Antarctic sea ice algae to changes in pH and CO2. AB - Ocean acidification substantially alters ocean carbon chemistry and hence pH but the effects on sea ice formation and the CO2 concentration in the enclosed brine channels are unknown. Microbial communities inhabiting sea ice ecosystems currently contribute 10-50% of the annual primary production of polar seas, supporting overwintering zooplankton species, especially Antarctic krill, and seeding spring phytoplankton blooms. Ocean acidification is occurring in all surface waters but the strongest effects will be experienced in polar ecosystems with significant effects on all trophic levels. Brine algae collected from McMurdo Sound (Antarctica) sea ice was incubated in situ under various carbonate chemistry conditions. The carbon chemistry was manipulated with acid, bicarbonate and bases to produce a pCO2 and pH range from 238 to 6066 uatm and 7.19 to 8.66, respectively. Elevated pCO2 positively affected the growth rate of the brine algal community, dominated by the unique ice dinoflagellate, Polarella glacialis. Growth rates were significantly reduced when pH dropped below 7.6. However, when the pH was held constant and the pCO2 increased, growth rates of the brine algae increased by more than 20% and showed no decline at pCO2 values more than five times current ambient levels. We suggest that projected increases in seawater pCO2, associated with OA, will not adversely impact brine algal communities. PMID- 24489822 TI - Revealing individual signatures of human T cell CDR3 sequence repertoires with Kidera Factors. AB - The recent development of High Throughput Sequencing technologies has enabled an individual's TCR repertoire to be efficiently analysed at the nucleotide level. However, with unique clonotypes ranging in the tens of millions per individual, this approach gives a surfeit of information that is difficult to analyse and interpret in a biological context and gives little information about TCR structural diversity. Using publicly available TCR CDR3 sequence data, we analysed TCR repertoires by converting the encoded CDR3 amino acid sequences into Kidera Factors, a set of orthogonal physico-chemical properties that reflect protein structure. This approach enabled the TCR repertoire from different individuals to be distinguished and demonstrated the close similarity of the repertoire in different samples from the same individual. PMID- 24489823 TI - Resource availability and spatial heterogeneity control bacterial community response to nutrient enrichment in lakes. AB - The diversity and composition of ecological communities often co-vary with ecosystem productivity. However, the relative importance of productivity, or resource abundance, versus the spatial distribution of resources in shaping those ecological patterns is not well understood, particularly for the bacterial communities that underlie most important ecosystem functions. Increasing ecosystem productivity in lakes has been shown to influence the composition and ecology of bacterial communities, but existing work has only evaluated the effect of increasing resource supply and not heterogeneity in how those resources are distributed. We quantified how bacterial communities varied with the trophic status of lakes and whether community responses differed in surface and deep habitats in response to heterogeneity in nutrient resources. Using ARISA fingerprinting, we found that bacterial communities were more abundant, richer, and more distinct among habitats as lake trophic state and vertical heterogeneity in nutrients increased, and that spatial resource variation produced habitat specific responses of bacteria in response to increased productivity. Furthermore, changes in communities in high nutrient lakes were not produced by turnover in community composition but from additional taxa augmenting core bacterial communities found in lower productivity lakes. These data suggests that bacterial community responses to nutrient enrichment in lakes vary spatially and are likely influenced disproportionately by rare taxa. PMID- 24489824 TI - Investigating and correcting plasma DNA sequencing coverage bias to enhance aneuploidy discovery. AB - Pregnant women carry a mixture of cell-free DNA fragments from self and fetus (non-self) in their circulation. In recent years multiple independent studies have demonstrated the ability to detect fetal trisomies such as trisomy 21, the cause of Down syndrome, by Next-Generation Sequencing of maternal plasma. The current clinical tests based on this approach show very high sensitivity and specificity, although as yet they have not become the standard diagnostic test. Here we describe improvements to the analysis of the sequencing data by reducing GC bias and better handling of the genomic repeats. We show substantial improvements in the sensitivity of the standard trisomy 21 statistical tests, which we measure by artificially reducing read coverage. We also explore the bias stemming from the natural cleavage of plasma DNA by examining DNA motifs and position specific base distributions. We propose a model to correct this fragmentation bias and observe that incorporating this bias does not lead to any further improvements in the detection of fetal trisomy. The improved bias corrections that we demonstrate in this work can be readily adopted into existing fetal trisomy detection protocols and should also lead to improvements in sub chromosomal copy number variation detection. PMID- 24489826 TI - From ugly duckling to swan: unexpected identification from cell-SELEX of an anti Annexin A2 aptamer targeting tumors. AB - BACKGROUND: Cell-SELEX is now widely used for the selection of aptamers against cell surface biomarkers. However, despite negative selection steps using mock cells, this method sometimes results in aptamers against undesirable targets that are expressed both on mock and targeted cells. Studying these junk aptamers might be useful for further applications than those originally envisaged. METHODOLOGY/PRINCIPAL FINDINGS: Cell-SELEX was performed to identify aptamers against CHO-K1 cells expressing human Endothelin type B receptor (ETBR). CHO-K1 cells were used for negative selection of aptamers. Several aptamers were identified but no one could discriminate between both cell lines. We decided to study one of these aptamers, named ACE4, and we identified that it binds to the Annexin A2, a protein overexpressed in many cancers. Radioactive binding assays and flow cytometry demonstrated that the aptamer was able to bind several cancer cell lines from different origins, particularly the MCF-7 cells. Fluorescence microscopy revealed it could be completely internalized in cells in 2 hours. Finally, the tumor targeting of the aptamer was evaluated in vivo in nude mice xenograft with MCF-7 cells using fluorescence diffuse optical tomography (fDOT) imaging. Three hours after intravenous injection, the aptamer demonstrated a significantly higher uptake in the tumor compared to a scramble sequence. CONCLUSIONS/SIGNIFICANCE: Although aptamers could be selected during cell-SELEX against other targets than those initially intended, they represent a potential source of ligands for basic research, diagnoses and therapy. Here, studying such aptamers, we identify one with high affinity for Annexin A2 that could be a promising tool for biomedical application. PMID- 24489825 TI - HIV-1 Nef down-modulates C-C and C-X-C chemokine receptors via ubiquitin and ubiquitin-independent mechanism. AB - Human and Simian Immunodeficiency virus (HIV-1, HIV-2, and SIV) encode an accessory protein, Nef, which is a pathogenesis and virulence factor. Nef is a multivalent adapter that dysregulates the trafficking of many immune cell receptors, including chemokine receptors (CKRs). Physiological endocytic itinerary of agonist occupied CXCR4 involves ubiquitinylation of the phosphorylated receptor at three critical lysine residues and dynamin-dependent trafficking through the ESCRT pathway into lysosomes for degradation. Likewise, Nef induced CXCR4 degradation was critically dependent on the three lysines in the C-terminal -SSLKILSKGK- motif. Nef directly recruits the HECT domain E3 ligases AIP4 or NEDD4 to CXCR4 in the resting state. This mechanism was confirmed by ternary interactions of Nef, CXCR4 and AIP4 or NEDD4; by reversal of Nef effect by expression of catalytically inactive AIP4-C830A mutant; and siRNA knockdown of AIP4, NEDD4 or some ESCRT-0 adapters. However, ubiquitinylation dependent lysosomal degradation was not the only mechanism by which Nef downregulated CKRs. Agonist and Nef mediated CXCR2 (and CXCR1) degradation was ubiquitinylation independent. Nef also profoundly downregulated the naturally truncated CXCR4 associated with WHIM syndrome and engineered variants of CXCR4 that resist CXCL12 induced internalization via an ubiquitinylation independent mechanism. PMID- 24489827 TI - Dietary Enterococcus faecium NCIMB 10415 and zinc oxide stimulate immune reactions to trivalent influenza vaccination in pigs but do not affect virological response upon challenge infection. AB - Swine influenza viruses (SIV) regularly cause significant disease in pigs worldwide. Since there is no causative treatment of SIV, we tested if probiotic Enterococcus (E.) faecium NCIMB 10415 or zinc (Zn) oxide as feed supplements provide beneficial effects upon SIV infection in piglets. Seventy-two weaned piglets were fed three different diets containing either E. faecium or different levels of Zn (2500 ppm, Zn(high); 50 ppm, Zn(low)). Half of the piglets were vaccinated intramuscularly (VAC) twice with an inactivated trivalent SIV vaccine, while all piglets were then infected intranasally with H3N2 SIV. Significantly higher weekly weight gains were observed in the E. faecium group before virus infection, and piglets in Zn(high) and E. faecium groups gained weight after infection while those in the control group (Zn(low)) lost weight. Using ELISA, we found significantly higher H3N2-specific antibody levels in the E. faecium+VAC group 2 days before and at the day of challenge infection as well as at 4 and 6 days after challenge infection. Higher hemagglutination inhibition (HI) titers were also observed in the Zn(high)+VAC and E. faecium+VAC groups at 0, 1 and 4 days after infection. However, there were no significant differences in virus shedding and lung lesions between the dietary groups. Using flow cytometry analysis significantly higher activated T helper cells and cytotoxic T lymphocyte percentages in the PBMCs were detected in the Zn(high) and E. faecium groups at single time points after infection compared to the Zn(low) control group, but no prolonged effect was found. In the BAL cells no influence of dietary supplementation on immune cell percentages could be detected. Our results suggest that feeding high doses of zinc oxide and particularly E. faecium could beneficially influence humoral immune responses after vaccination and recovery from SIV infection, but not affect virus shedding and lung pathology. PMID- 24489828 TI - Rapid clinical assessment to facilitate the triage of adults with falciparum malaria, a retrospective analysis. AB - BACKGROUND: Most adults dying from falciparum malaria will die within 48 hours of their hospitalisation. An essential component of early supportive care is the rapid identification of patients at greatest risk. In resource-poor settings, where most patients with falciparum malaria are managed, decisions regarding patient care must frequently be made using clinical evaluation alone. METHODS: We retrospectively analysed 4 studies of 1801 adults with severe falciparum malaria to determine whether the presence of simple clinical findings might assist patient triage. RESULTS: If present on admission, shock, oligo-anuria, hypo- or hyperglycaemia, an increased respiratory rate, a decreased Glasgow Coma Score and an absence of fever were independently predictive of death. The variables were used to construct a simple clinical algorithm. When applied to the 1801 patients, this algorithm's positive predictive value for survival to 48 hours was 99.4 (95% confidence interval (CI) 97.8-99.9) and for survival to discharge 96.9% (95% CI 94.3-98.5). In the 712 patients receiving artesunate, the algorithm's positive predictive value for survival to 48 hours was 100% (95% CI 97.3-100) and to discharge was 98.5% (95% CI 94.8-99.8). CONCLUSIONS: Simple clinical findings are closely linked to the pathophysiology of severe falciparum malaria in adults. A basic algorithm employing these indices can facilitate the triage of patients in settings where intensive care services are limited. Patients classified as low risk by this algorithm can be safely managed initially on a general ward whilst awaiting senior clinical review and laboratory data. PMID- 24489829 TI - HIV-1 genetic characteristics and transmitted drug resistance among men who have sex with men in Kunming, China. AB - BACKGROUND: Yunnan has been severely affected by HIV/AIDS in China. Recently, the reported prevalence of HIV-1 among men who have sex with men (MSM) in Yunnan was high in China. To monitor dynamic HIV-1 epidemic among Yunnan MSM, HIV-1 genetic characteristics and transmitted drug resistance (TDR) were investigated. METHODS: Blood samples from 131 newly HIV-1 diagnosed MSM were continuously collected at fixed sites from January 2010 to December 2012 in Kunming City, Yunnan Province. Partial gag, pol and env genes were sequenced. Phylogenetic, evolutionary and genotypic drug resistance analyses were performed. RESULTS: Multiple genotypes were identified among MSM in Kunming, including CRF01_AE (64.9%), CRF07_BC (25.2%), unique recombinant forms (URFs, 5.3%), subtype B (3.1%) and CRF08_BC (1.5%). CRF01_AE and CRF07_BC were the predominant strains. The mean of genetic distance within CRF01_AE were larger than that within CRF07_BC. The estimated introducing time of CRF01_AE in Yunnan MSM (1996.9) is earlier than that of CRF07_BC (2002.8). In this study, subtype B was first identified in Yunnan MSM. CRF08_BC seems to be the distinctive strain in Yunnan MSM, which was seldom found among MSM outside Yunnan. The proportion of URFs increased, which further contributed to genetic diversity among MSM. Strikingly, genetic relatedness was found among these strains with MSM isolates from multiple provinces, which suggested that a nationwide transmission network may exist. TDR-associated mutations were identified in 4.6% individuals. The multivariate analysis revealed that non-native MSM and divorced/widowed MSM were independently associated with a higher TDR rate. CONCLUSION: This work revealed diverse HIV-1 genetics, national transmission networks and a baseline level of TDR in MSM. These findings enhance our understanding of the distribution and evolution of HIV-1 in MSM, and are valuable for developing HIV prevention strategies for MSM. PMID- 24489830 TI - Give what you get: capuchin monkeys (Cebus apella) and 4-year-old children pay forward positive and negative outcomes to conspecifics. AB - The breadth of human generosity is unparalleled in the natural world, and much research has explored the mechanisms underlying and motivating human prosocial behavior. Recent work has focused on the spread of prosocial behavior within groups through paying-it-forward, a case of human prosociality in which a recipient of generosity pays a good deed forward to a third individual, rather than back to the original source of generosity. While research shows that human adults do indeed pay forward generosity, little is known about the origins of this behavior. Here, we show that both capuchin monkeys (Cebus apella) and 4-year old children pay forward positive and negative outcomes in an identical testing paradigm. These results suggest that a cognitively simple mechanism present early in phylogeny and ontogeny leads to paying forward positive, as well as negative, outcomes. PMID- 24489832 TI - He votes or she votes? Female and male discursive strategies in Twitter political hashtags. AB - In this paper, we conduct a study about differences between female and male discursive strategies when posting in the microblogging service Twitter, with a particular focus on the hashtag designation process during political debate. The fact that men and women use language in distinct ways, reverberating practices linked to their expected roles in the social groups, is a linguistic phenomenon known to happen in several cultures and that can now be studied on the Web and on online social networks in a large scale enabled by computing power. Here, for instance, after analyzing tweets with political content posted during Brazilian presidential campaign,we found out that male Twitter users, when expressing their attitude toward a given candidate, are more prone to use imperative verbal forms in hashtags, while female users tend to employ declarative forms. This difference can be interpreted as a sign of distinct approaches in relation to other network members: for example, if political hashtags are seen as strategies of persuasion in Twitter, imperative tags could be understood as more overt ways of persuading and declarative tags as more indirect ones. Our findings help to understand human gendered behavior in social networks and contribute to research on the new fields of computer-enabled Internet linguistics and social computing, besides being useful for several computational tasks such as developing tag recommendation systems based on users' collective preferences and tailoring targeted advertising strategies, among others. PMID- 24489831 TI - Mechanisms of metabonomic for a gateway drug: nicotine priming enhances behavioral response to cocaine with modification in energy metabolism and neurotransmitter level. AB - Nicotine, one of the most commonly used drugs, has become a major concern because tobacco serves as a gateway drug and is linked to illicit drug abuse, such as cocaine and marijuana. However, previous studies mainly focused on certain genes or neurotransmitters which have already been known to participate in drug addiction, lacking endogenous metabolic profiling in a global view. To further explore the mechanism by which nicotine modifies the response to cocaine, we developed two conditioned place preference (CPP) models in mice. In threshold dose model, mice were pretreated with nicotine, followed by cocaine treatment at the dose of 2 mg/kg, a threshold dose of cocaine to induce CPP in mice. In high dose model, mice were only treated with 20 mg/kg cocaine, which induced a significant CPP. (1)H nuclear magnetic resonance based on metabonomics was used to investigate metabolic profiles of the nucleus accumbens (NAc) and striatum. We found that nicotine pretreatment dramatically increased CPP induced by 2 mg/kg cocaine, which was similar to 20 mg/kg cocaine-induced CPP. Interestingly, metabolic profiles showed considerable overlap between these two models. These overlapped metabolites mainly included neurotransmitters as well as the molecules participating in energy homeostasis and cellular metabolism. Our results show that the reinforcing effect of nicotine on behavioral response to cocaine may attribute to the modification of some specific metabolites in NAc and striatum, thus creating a favorable metabolic environment for enhancing conditioned rewarding effect of cocaine. Our findings provide an insight into the effect of cigarette smoking on cocaine dependence and the underlying mechanism. PMID- 24489833 TI - Association between the PARP1 Val762Ala polymorphism and cancer risk: evidence from 43 studies. AB - BACKGROUND: Poly (ADP-ribose) polymerase-1 (PARP-1) plays critical roles in the detection and repair of damaged DNA, as well as cell proliferation and death. Numerous studies have examined the associations between PARP1 Val762Ala (rs1136410 T>C) polymorphism and cancer susceptibility; nevertheless, the findings from different research groups remain controversial. METHODS: We searched literatures from MEDLINE, EMBASE and CBM pertaining to such associations, and then calculated pooled odds ratio (OR) and 95% confidence interval (CI) by using random-effects model. The false-positive report probability (FPRP) analysis was used to confirm the validity of significant findings. Moreover, potential effects of rs1136410 variants on PARP1 mRNA expression were analyzed for three ethnicities by combining data from HapMap (genotype) and SNPexp (mRNA expression). RESULTS: The final meta-analysis incorporated 43 studies, consisting of 17,351 cases and 22,401 controls. Overall, our results did not suggest significant associations between Ala variant (Ala/Ala or Ala/Val genotype) and cancer risk. However, further stratification analysis showed significantly increased risk for gastric cancer (Ala/Ala vs. Val/Val: OR = 1.56, 95% CI = 1.01-2.42, Ala/Val vs. Val/Val: OR = 1.34, 95% CI = 1.14-1.58, dominant model: OR = 1.41, 95% CI = 1.21-1.65 and Ala vs. Val: OR = 1.29, 95% CI = 1.07-1.55). On the contrary, decreased risk for brain tumor (Ala/Val vs. Val/Val: OR = 0.77, 95% CI = 0.68-0.87, dominant model: OR = 0.77, 95% CI = 0.68 0.87 and Ala vs. Val: OR = 0.82, 95% CI = 0.74-0.91). Additionally, we found that the Ala carriers had a significantly increased risk in all models for Asians. Our mRNA expression data provided further biological evidence to consolidate this finding. CONCLUSIONS: Despite some limitations, this meta-analysis found evidence for an association between the PAPR1 Val762Ala and cancer susceptibility within gastric cancer, brain tumor and Asian subgroups. PMID- 24489834 TI - Regulation of ethanol-related behavior and ethanol metabolism by the Corazonin neurons and Corazonin receptor in Drosophila melanogaster. AB - Impaired ethanol metabolism can lead to various alcohol-related health problems. Key enzymes in ethanol metabolism are alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH); however, neuroendocrine pathways that regulate the activities of these enzymes are largely unexplored. Here we identified a neuroendocrine system involving Corazonin (Crz) neuropeptide and its receptor (CrzR) as important physiological regulators of ethanol metabolism in Drosophila. Crz-cell deficient (Crz-CD) flies displayed significantly delayed recovery from ethanol-induced sedation that we refer to as hangover-like phenotype. Newly generated mutant lacking Crz Receptor (CrzR(01) ) and CrzR-knockdown flies showed even more severe hangover-like phenotype, which is causally associated with fast accumulation of acetaldehyde in the CrzR(01) mutant following ethanol exposure. Higher levels of acetaldehyde are likely due to 30% reduced ALDH activity in the mutants. Moreover, increased ADH activity was found in the CrzR(01) mutant, but not in the Crz-CD flies. Quantitative RT-PCR revealed transcriptional upregulation of Adh gene in the CrzR(01) . Transgenic inhibition of cyclic AMP dependent protein kinase (PKA) also results in significantly increased ADH activity and Adh mRNA levels, indicating PKA-dependent transcriptional regulation of Adh by CrzR. Furthermore, inhibition of PKA or cAMP response element binding protein (CREB) in CrzR cells leads to comparable hangover-like phenotype to the CrzR(01) mutant. These findings suggest that CrzR-associated signaling pathway is critical for ethanol detoxification via Crz-dependent regulation of ALDH activity and Crz-independent transcriptional regulation of ADH. Our study provides new insights into the neuroendocrine-associated ethanol-related behavior and metabolism. PMID- 24489835 TI - Comparative genomic analysis reveals 2-oxoacid dehydrogenase complex lipoylation correlation with aerobiosis in archaea. AB - Metagenomic analyses have advanced our understanding of ecological microbial diversity, but to what extent can metagenomic data be used to predict the metabolic capacity of difficult-to-study organisms and their abiotic environmental interactions? We tackle this question, using a comparative genomic approach, by considering the molecular basis of aerobiosis within archaea. Lipoylation, the covalent attachment of lipoic acid to 2-oxoacid dehydrogenase multienzyme complexes (OADHCs), is essential for metabolism in aerobic bacteria and eukarya. Lipoylation is catalysed either by lipoate protein ligase (LplA), which in archaea is typically encoded by two genes (LplA-N and LplA-C), or by a lipoyl(octanoyl) transferase (LipB or LipM) plus a lipoic acid synthetase (LipA). Does the genomic presence of lipoylation and OADHC genes across archaea from diverse habitats correlate with aerobiosis? First, analyses of 11,826 biotin protein ligase (BPL)-LplA-LipB transferase family members and 147 archaeal genomes identified 85 species with lipoylation capabilities and provided support for multiple ancestral acquisitions of lipoylation pathways during archaeal evolution. Second, with the exception of the Sulfolobales order, the majority of species possessing lipoylation systems exclusively retain LplA, or either LipB or LipM, consistent with archaeal genome streamlining. Third, obligate anaerobic archaea display widespread loss of lipoylation and OADHC genes. Conversely, a high level of correspondence is observed between aerobiosis and the presence of LplA/LipB/LipM, LipA and OADHC E2, consistent with the role of lipoylation in aerobic metabolism. This correspondence between OADHC lipoylation capacity and aerobiosis indicates that genomic pathway profiling in archaea is informative and that well characterized pathways may be predictive in relation to abiotic conditions in difficult-to-study extremophiles. Given the highly variable retention of gene repertoires across the archaea, the extension of comparative genomic pathway profiling to broader metabolic and homeostasis networks should be useful in revealing characteristics from metagenomic datasets related to adaptations to diverse environments. PMID- 24489836 TI - CD163 expression was associated with angiogenesis and shortened survival in patients with uniformly treated classical Hodgkin lymphoma. AB - BACKGROUND: Recent studies have reported the prognostic value of tissue associated magrophages (TAMs) in classical Hodgkin lymphoma (cHL). In addition, TAMs are implicated in the tumor angiogenesis. In this study, we examined the prognostic relevance of TAMs in relation to vascular endothelial growth factor (VEGF) expression and angiogenesis in uniformly treated cases of cHL. METHODS: Diagnostic tissue from 116 patients with ABVD-treated cHL was evaluated retrospectively by immunohistochemical analysis for CD68, CD163 and VEGF expression and for CD31 expression as a measure of microvessel density (MVD). RESULTS: High CD163 expression (>= 35% of cellularity) correlated with VEGF expression (Pearson's Chi-square test, P = 0.008) and MVD (Spearman correlation coefficient 0.310, P<0.001). High CD163 expression was associated with inferior event-free survival (EFS, P = 0.005) and overall survival (OS, P<0.001) in univariate analysis. In multivariate analysis, high CD163 expression was strongly associated with inferior EFS (P = 0.043) and OS (P = 0.008). Patients with high MVD had a lower OS than those with low MVD, but the difference was not significant (P = 0.071, respectively). While high expression of CD68 was also associated with inferior EFS (P = 0.007), it showed no correlation with VEGF or MVD. CONCLUSIONS: Our data confirms that CD163 expression provides independent prognostic information in cHL. The correlation of CD163 with VEGF expression and MVD suggests the role of CD163-positive cells in tumor angiogenesis of cHL. PMID- 24489837 TI - Loss of connectivity in cancer co-expression networks. AB - Differential gene expression profiling studies have lead to the identification of several disease biomarkers. However, the oncogenic alterations in coding regions can modify the gene functions without affecting their own expression profiles. Moreover, post-translational modifications can modify the activity of the coded protein without altering the expression levels of the coding gene, but eliciting variations to the expression levels of the regulated genes. These considerations motivate the study of the rewiring of networks co-expressed genes as a consequence of the aforementioned alterations in order to complement the informative content of differential expression. We analyzed 339 mRNAomes of five distinct cancer types to find single genes that presented co-expression patterns strongly differentiated between normal and tumor phenotypes. Our analysis of differentially connected genes indicates the loss of connectivity as a common topological trait of cancer networks, and unveils novel candidate cancer genes. Moreover, our integrated approach that combines the differential expression together with the differential connectivity improves the classic enrichment pathway analysis providing novel insights on putative cancer gene biosystems not still fully investigated. PMID- 24489838 TI - Virus pathotype and deep sequencing of the HA gene of a low pathogenicity H7N1 avian influenza virus causing mortality in Turkeys. AB - Low pathogenicity avian influenza (LPAI) viruses of the H7 subtype generally cause mild disease in poultry. However the evolution of a LPAI virus into highly pathogenic avian influenza (HPAI) virus results in the generation of a virus that can cause severe disease and death. The classification of these two pathotypes is based, in part, on disease signs and death in chickens, as assessed in an intravenous pathogenicity test, but the effect of LPAI viruses in turkeys is less well understood. During an investigation of LPAI virus infection of turkeys, groups of three-week-old birds inoculated with A/chicken/Italy/1279/99 (H7N1) showed severe disease signs and died or were euthanised within seven days of infection. Virus was detected in many internal tissues and organs from culled birds. To examine the possible evolution of the infecting virus to a highly pathogenic form in these turkeys, sequence analysis of the haemagglutinin (HA) gene cleavage site was carried out by analysing multiple cDNA amplicons made from swabs and tissue sample extracts employing Sanger and Next Generation Sequencing. In addition, a RT-PCR assay to detect HPAI virus was developed. There was no evidence of the presence of HPAI virus in either the virus used as inoculum or from swabs taken from infected birds. However, a small proportion (<0.5%) of virus carried in individual tracheal or liver samples did contain a molecular signature typical of a HPAI virus at the HA cleavage site. All the signature sequences were identical and were similar to HPAI viruses collected during the Italian epizootic in 1999/2000. We assume that the detection of HPAI virus in tissue samples following infection with A/chicken/Italy/1279/99 reflected amplification of a virus present at very low levels within the mixed inoculum but, strikingly, we observed no new HPAI virus signatures in the amplified DNA analysed by deep-sequencing. PMID- 24489839 TI - Accounting for sampling error when inferring population synchrony from time series data: a Bayesian state-space modelling approach with applications. AB - BACKGROUND: Data collected to inform time variations in natural population size are tainted by sampling error. Ignoring sampling error in population dynamics models induces bias in parameter estimators, e.g., density-dependence. In particular, when sampling errors are independent among populations, the classical estimator of the synchrony strength (zero-lag correlation) is biased downward. However, this bias is rarely taken into account in synchrony studies although it may lead to overemphasizing the role of intrinsic factors (e.g., dispersal) with respect to extrinsic factors (the Moran effect) in generating population synchrony as well as to underestimating the extinction risk of a metapopulation. METHODOLOGY/PRINCIPAL FINDINGS: The aim of this paper was first to illustrate the extent of the bias that can be encountered in empirical studies when sampling error is neglected. Second, we presented a space-state modelling approach that explicitly accounts for sampling error when quantifying population synchrony. Third, we exemplify our approach with datasets for which sampling variance (i) has been previously estimated, and (ii) has to be jointly estimated with population synchrony. Finally, we compared our results to those of a standard approach neglecting sampling variance. We showed that ignoring sampling variance can mask a synchrony pattern whatever its true value and that the common practice of averaging few replicates of population size estimates poorly performed at decreasing the bias of the classical estimator of the synchrony strength. CONCLUSION/SIGNIFICANCE: The state-space model used in this study provides a flexible way of accurately quantifying the strength of synchrony patterns from most population size data encountered in field studies, including over-dispersed count data. We provided a user-friendly R-program and a tutorial example to encourage further studies aiming at quantifying the strength of population synchrony to account for uncertainty in population size estimates. PMID- 24489840 TI - Frozen cord blood hematopoietic stem cells differentiate into higher numbers of functional natural killer cells in vitro than mobilized hematopoietic stem cells or freshly isolated cord blood hematopoietic stem cells. AB - Adoptive natural killer (NK) cell therapy relies on the acquisition of large numbers of NK cells that are cytotoxic but not exhausted. NK cell differentiation from hematopoietic stem cells (HSC) has become an alluring option for NK cell therapy, with umbilical cord blood (UCB) and mobilized peripheral blood (PBCD34(+)) being the most accessible HSC sources as collection procedures are less invasive. In this study we compared the capacity of frozen or freshly isolated UCB hematopoietic stem cells (CBCD34(+)) and frozen PBCD34(+) to generate NK cells in vitro. By modifying a previously published protocol, we showed that frozen CBCD34(+) cultures generated higher NK cell numbers without loss of function compared to fresh CBCD34(+) cultures. NK cells generated from CBCD34(+) and PBCD34(+) expressed low levels of killer-cell immunoglobulin-like receptors but high levels of activating receptors and of the myeloid marker CD33. However, blocking studies showed that CD33 expression did not impact on the functions of the generated cells. CBCD34(+)-NK cells exhibited increased capacity to secrete IFN-gamma and kill K562 in vitro and in vivo as compared to PBCD34(+) NK cells. Moreover, K562 killing by the generated NK cells could be further enhanced by IL-12 stimulation. Our data indicate that the use of frozen CBCD34(+) for the production of NK cells in vitro results in higher cell numbers than PBCD34(+), without jeopardizing their functionality, rendering them suitable for NK cell immunotherapy. The results presented here provide an optimal strategy to generate NK cells in vitro for immunotherapy that exhibit enhanced effector function when compared to alternate sources of HSC. PMID- 24489841 TI - NIMH Project Accept (HPTN 043): results from in-depth interviews with a longitudinal cohort of community members. AB - INTRODUCTION: NIMH Project Accept (HPTN 043) is a community- randomized trial to test the safety and efficacy of a community-level intervention designed to increase testing and lower HIV incidence in Tanzania, Zimbabwe, South Africa and Thailand. The evaluation design included a longitudinal study with community members to assess attitudinal and behavioral changes in study outcomes including HIV testing norms, HIV-related discussions, and HIV-related stigma. METHODS: A cohort of 657 individuals across all sites was selected to participate in a qualitative study that involved 4 interviews during the study period. Baseline and 30-month data were summarized according to each outcome, and a qualitative assessment of changes was made at the community level over time. RESULTS: Members from intervention communities described fewer barriers and greater motivation for testing than those from comparison communities. HIV-related discussions in intervention communities were more grounded in personal testing experiences. A change in HIV-related stigma over time was most pronounced in Tanzania and Zimbabwe. Participants in the intervention communities from these two sites attributed community-level changes in attitudes to project specific activities. DISCUSSION: The Project Accept intervention was associated with more favorable social norms regarding HIV testing, more personal content in HIV discussions in all study sites, and qualitative changes in HIV-related stigma in two of five sites. PMID- 24489842 TI - Cervical cancer cells with positive Sox2 expression exhibit the properties of cancer stem cells. AB - BACKGROUND: Although Sox2 expression has been found in several types of cancer, it has not yet been used to identify or isolate CSCs in somatic carcinoma. METHODS: SiHa and C33A cells stably transfected with a plasmid containing human Sox2 transcriptional elements driving the enhanced green fluorescent protein (EGFP) reporter were sorted into the Sox2-positive and the Sox2-negative populations by FACS, and Sox2 expression was detected by western blot and immunohistochemistry. The differentiation, self-renewal and tumor formation abilities, as well as the expression of the stemness and the EMT related genes of the Sox2-positive and the Sox2-negative cervical cancer cells were characterized in vitro and in vivo. RESULTS: A pSox2/EGFP system was used to separate the Sox2 positive and the Sox2-negative cells from cervical cancer cell lines, SiHa and C33A cells. Compared with the Sox2-negative cells, the Sox2-positive SiHa and C33A cells exhibited greater capacities for self-renewal, differentiation and tumor formation. Furthermore, Sox2-positive SiHa and C33A cells expressed higher levels of stemness-related genes, such as Sox2/Bmi-1/Oct4/ALDH1, and EMT-related genes, such as vimentin/snail/beta-catenin. Taken together, all these results indicated that cells expressing endogenous Sox2 are CSCs in cervical carcinomas. CONCLUSION: This study is the first to establish a functional link between endogenous Sox2 expression and CSCs in cervical carcinomas. Additionally, this study demonstrated that it is feasible to develop a tool to isolate CSCs from somatic tumors based on the expression of the endogenous nuclear protein Sox2 instead of cell surface markers. PMID- 24489843 TI - Architectural design drives the biogeography of indoor bacterial communities. AB - BACKGROUND: Architectural design has the potential to influence the microbiology of the built environment, with implications for human health and well-being, but the impact of design on the microbial biogeography of buildings remains poorly understood. In this study we combined microbiological data with information on the function, form, and organization of spaces from a classroom and office building to understand how design choices influence the biogeography of the built environment microbiome. RESULTS: Sequencing of the bacterial 16S gene from dust samples revealed that indoor bacterial communities were extremely diverse, containing more than 32,750 OTUs (operational taxonomic units, 97% sequence similarity cutoff), but most communities were dominated by Proteobacteria, Firmicutes, and Deinococci. Architectural design characteristics related to space type, building arrangement, human use and movement, and ventilation source had a large influence on the structure of bacterial communities. Restrooms contained bacterial communities that were highly distinct from all other rooms, and spaces with high human occupant diversity and a high degree of connectedness to other spaces via ventilation or human movement contained a distinct set of bacterial taxa when compared to spaces with low occupant diversity and low connectedness. Within offices, the source of ventilation air had the greatest effect on bacterial community structure. CONCLUSIONS: Our study indicates that humans have a guiding impact on the microbial biodiversity in buildings, both indirectly through the effects of architectural design on microbial community structure, and more directly through the effects of human occupancy and use patterns on the microbes found in different spaces and space types. The impact of design decisions in structuring the indoor microbiome offers the possibility to use ecological knowledge to shape our buildings in a way that will select for an indoor microbiome that promotes our health and well-being. PMID- 24489844 TI - Straw mulching reduces the harmful effects of extreme hydrological and temperature conditions in citrus orchards. AB - Extreme weather conditions with negative impacts can strongly affect agricultural production. In the Danjiangkou reservoir area, citrus yields were greatly influenced by cold weather conditions and drought stress in 2011. Soil straw mulching (SM) practices have a major effect on soil water and thermal regimes. A two-year field experiment was conducted to evaluate whether the SM practices can help achieve favorable citrus fruit yields. Results showed that the annual total runoff was significantly (P<0.05) reduced with SM as compared to the control (CK). Correspondingly, mean soil water storage in the top 100 cm of the soil profile was increased in the SM as compared to the CK treatment. However, this result was significant only in the dry season (Jan to Mar), and not in the wet season (Jul to Sep) for both years. Interestingly, the SM treatment did not significantly increase citrus fruit yield in 2010 but did so in 2011, when the citrus crop was completely destroyed (zero fruit yield) in the CK treatment plot due to extremely low temperatures during the citrus overwintering stage. The mulch probably acted as an insulator, resulting in smaller fluctuations in soil temperature in the SM than in the CK treatment. The results suggested that the small effects on soil water and temperature changes created by surface mulch had limited impact on citrus fruit yield in a normal year (e.g., in 2010). However, SM practices can positively impact citrus fruit yield in extreme weather conditions. PMID- 24489845 TI - Diabetes mellitus and the risk of Alzheimer's disease: a nationwide population based study. AB - OBJECTIVES: Possible association between diabetes mellitus (DM) and Alzheimer's disease (AD) has been controversial. This study used a nationwide population based dataset to investigate the relationship between DM and subsequent AD incidence. METHODS: Data were collected from Taiwan's National Health Insurance Research Database, which released a cohort dataset of 1,000,000 randomly sampled people and confirmed it to be representative of the Taiwanese population. We identified 71,433 patients newly diagnosed with diabetes (age 58.74 +/- 14.02 years) since January 1997. Using propensity score, we matched them with 71,311 non-diabetic subjects by time of enrollment, age, gender, hypertension, hyperlipidemia, and previous stroke history. All the patients were followed up to December 31, 2007. The endpoint of the study was occurrence of AD. RESULTS: Over a maximum 11 years of follow-up, diabetic patients experienced a higher incidence of AD than non-diabetic subjects (0.48% vs. 0.37%, p<0.001). After Cox proportional hazard regression model analysis, DM (hazard ratio [HR], 1.76; 95% confidence interval [CI], 1.50-2.07, p<0.001), age (HR, 1.11; 95% CI, 1.10-1.12, p<0.001), female gender (HR, 1.24; 95% CI, 1.06-1.46, p=0.008), hypertension (HR, 1.30; 95% CI, 1.07-1.59, p=0.01), previous stroke history (HR, 1.79; 95% CI, 1.28 2.50, p<0.001), and urbanization status (metropolis, HR, 1.32; 95% CI, 1.07-1.63, p=0.009) were independently associated with the increased risk of AD. Neither monotherapy nor combination therapy with oral antidiabetic medications were associated with the risk of AD after adjusting for underlying risk factors and the duration of DM since diagnosis. However, combination therapy with insulin was found to be associated with greater risk of AD (HR, 2.17; 95% CI, 1.04-4.52, p=0.039). CONCLUSION: Newly diagnosed DM was associated with increased risk of AD. Use of hypoglycemic agents did not ameliorate the risk. PMID- 24489846 TI - ICAM-1-based rabies virus vaccine shows increased infection and activation of primary murine B cells in vitro and enhanced antibody titers in-vivo. AB - We have previously shown that live-attenuated rabies virus (RABV)-based vaccines infect and directly activate murine and human primary B cells in-vitro, which we propose can be exploited to help develop a single-dose RABV-based vaccine. Here we report on a novel approach to utilize the binding of Intracellular Adhesion Molecule-1 (ICAM-1) to its binding partner, Lymphocyte Function-associated Antigen-1 (LFA-1), on B cells to enhance B cell activation and RABV-specific antibody responses. We used a reverse genetics approach to clone, recover, and characterize a live-attenuated recombinant RABV-based vaccine expressing the murine Icam1 gene (rRABV-mICAM-1). We show that the murine ICAM-1 gene product is incorporated into virus particles, potentially exposing ICAM-1 to extracellular binding partners. While rRABV-mICAM-1 showed 10-100-fold decrease in viral titers on baby hamster kidney cells compared to the parental virus (rRABV), rRABV-mICAM 1 infected and activated primary murine B cells in-vitro more efficiently than rRABV, as indicated by significant upregulation of CD69, CD40, and MHCII on the surface of infected B cells. ICAM-1 expression on the virus surface was responsible for enhanced B cell infection since pre-treating rRABV-mICAM-1 with a neutralizing anti-ICAM-1 antibody reduced B cell infection to levels observed with rRABV alone. Furthermore, 100-fold less rRABV-mICAM-1 was needed to induce antibody titers in immunized mice equivalent to antibody titers observed in rRABV immunized mice. Of note, only 10(3) focus forming units (ffu)/mouse of rRABV mICAM-1 was needed to induce significant anti-RABV antibody titers as early as five days post-immunization. As both speed and potency of antibody responses are important in controlling human RABV infection in a post-exposure setting, these data show that expression of Icam1 from the RABV genome, which is then incorporated into the virus particle, is a promising strategy for the development of a single-dose RABV vaccine that requires only a minimum of virus. PMID- 24489847 TI - Stability of microbiota facilitated by host immune regulation: informing probiotic strategies to manage amphibian disease. AB - Microbial communities can augment host immune responses and probiotic therapies are under development to prevent or treat diseases of humans, crops, livestock, and wildlife including an emerging fungal disease of amphibians, chytridiomycosis. However, little is known about the stability of host-associated microbiota, or how the microbiota is structured by innate immune factors including antimicrobial peptides (AMPs) abundant in the skin secretions of many amphibians. Thus, conservation medicine including therapies targeting the skin will benefit from investigations of amphibian microbial ecology that provide a model for vertebrate host-symbiont interactions on mucosal surfaces. Here, we tested whether the cutaneous microbiota of Panamanian rocket frogs, Colostethus panamansis, was resistant to colonization or altered by treatment. Under semi natural outdoor mesocosm conditions in Panama, we exposed frogs to one of three treatments including: (1) probiotic - the potentially beneficial bacterium Lysinibacillus fusiformis, (2) transplant - skin washes from the chytridiomycosis resistant glass frog Espadarana prosoblepon, and (3) control - sterile water. Microbial assemblages were analyzed by a culture-independent T-RFLP analysis. We found that skin microbiota of C. panamansis was resistant to colonization and did not differ among treatments, but shifted through time in the mesocosms. We describe regulation of host AMPs that may function to maintain microbial community stability. Colonization resistance was metabolically costly and microbe treated frogs lost 7-12% of body mass. The discovery of strong colonization resistance of skin microbiota suggests a well-regulated, rather than dynamic, host-symbiont relationship, and suggests that probiotic therapies aiming to enhance host immunity may require an approach that circumvents host mechanisms maintaining equilibrium in microbial communities. PMID- 24489848 TI - MASP-1 induces a unique cytokine pattern in endothelial cells: a novel link between complement system and neutrophil granulocytes. AB - Microbial infection urges prompt intervention by the immune system. The complement cascade and neutrophil granulocytes are the predominant contributors to this immediate anti-microbial action. We have previously shown that mannan binding lectin-associated serine protease-1 (MASP-1), the most abundant enzyme of the complement lectin pathway, can induce p38-MAPK activation, NFkappaB signaling, and Ca(2+)-mobilization in endothelial cells. Since neutrophil chemotaxis and transmigration depends on endothelial cell activation, we aimed to explore whether recombinant MASP-1 (rMASP-1) is able to induce cytokine production and subsequent neutrophil chemotaxis in human umbilical vein endothelial cells (HUVEC). We found that HUVECs activated by rMASP-1 secreted IL 6 and IL-8, but not IL-1alpha, IL-1ra, TNFalpha and MCP-1. rMASP-1 induced dose dependent IL-6 and IL-8 production with different kinetics. rMASP-1 triggered IL 6 and IL-8 production was regulated predominantly by the p38-MAPK pathway. Moreover, the supernatant of rMASP-1-stimulated HUVECs activated the chemotaxis of neutrophil granulocytes as an integrated effect of cytokine production. Our results implicate that besides initializing the complement lectin pathway, MASP-1 may activate neutrophils indirectly, via the endothelial cells, which link these effective antimicrobial host defense mechanisms. PMID- 24489849 TI - Improving predictions of protein-protein interfaces by combining amino acid specific classifiers based on structural and physicochemical descriptors with their weighted neighbor averages. AB - Protein-protein interactions are involved in nearly all regulatory processes in the cell and are considered one of the most important issues in molecular biology and pharmaceutical sciences but are still not fully understood. Structural and computational biology contributed greatly to the elucidation of the mechanism of protein interactions. In this paper, we present a collection of the physicochemical and structural characteristics that distinguish interface-forming residues (IFR) from free surface residues (FSR). We formulated a linear discriminative analysis (LDA) classifier to assess whether chosen descriptors from the BlueStar STING database (http://www.cbi.cnptia.embrapa.br/SMS/) are suitable for such a task. Receiver operating characteristic (ROC) analysis indicates that the particular physicochemical and structural descriptors used for building the linear classifier perform much better than a random classifier and in fact, successfully outperform some of the previously published procedures, whose performance indicators were recently compared by other research groups. The results presented here show that the selected set of descriptors can be utilized to predict IFRs, even when homologue proteins are missing (particularly important for orphan proteins where no homologue is available for comparative analysis/indication) or, when certain conformational changes accompany interface formation. The development of amino acid type specific classifiers is shown to increase IFR classification performance. Also, we found that the addition of an amino acid conservation attribute did not improve the classification prediction. This result indicates that the increase in predictive power associated with amino acid conservation is exhausted by adequate use of an extensive list of independent physicochemical and structural parameters that, by themselves, fully describe the nano-environment at protein-protein interfaces. The IFR classifier developed in this study is now integrated into the BlueStar STING suite of programs. Consequently, the prediction of protein-protein interfaces for all proteins available in the PDB is possible through STING_interfaces module, accessible at the following website: (http://www.cbi.cnptia.embrapa.br/SMS/predictions/index.html). PMID- 24489850 TI - Gene duplication and phenotypic changes in the evolution of mammalian metabolic networks. AB - Metabolic networks attempt to describe the complete suite of biochemical reactions available to an organism. One notable feature of these networks in mammals is the large number of distinct proteins that catalyze the same reaction. While the existence of these isoenzymes has long been known, their evolutionary significance is still unclear. Using a phylogenetically-aware comparative genomics approach, we infer enzyme orthology networks for sixteen mammals as well as for their common ancestors. We find that the pattern of isoenzymes copy-number alterations (CNAs) in these networks is suggestive of natural selection acting on the retention of certain gene duplications. When further analyzing these data with a machine-learning approach, we found that that the pattern of CNAs is also predictive of several important phenotypic traits, including milk composition and geographic range. Integrating tools from network analyses, phylogenetics and comparative genomics both allows the prediction of phenotypes from genetic data and represents a means of unifying distinct biological disciplines. PMID- 24489851 TI - The impact of healthy parenting as a protective factor for posttraumatic stress disorder in adulthood: a case-control study. AB - BACKGROUND: Early life social adversity can influence stress response mechanisms and is associated with anxious behaviour and reductions in callosal area later in life. OBJECTIVE: To evaluate the association between perceptions of parental bonding in childhood/adolescence, hypothalamic-pituitary-adrenal (HPA) axis response, and callosal structural integrity in adult victims of severe urban violence with and without PTSD. METHODS: Seventy-one individuals with PTSD and 62 without the disorder were assessed with the Parental Bonding Instrument (PBI). The prednisolone suppression test was administered to assess cortisol levels, and magnetic resonance imaging was used to assess the total area of the corpus callosum (CC), as well as the areas of callosal subregions. RESULTS: The PBI items related to the perception of 'not having a controlling mother' (OR 4.84; 95%CI [2.26-10.3]; p=0.01), 'having a caring father' (OR 2.46; 95'%CI [1.18 5.12]; p=0.02), and 'not having controlling parents' (OR 2.70; 95%CI [1.10-6.63]; p=0.04) were associated with a lower risk of PTSD. The PTSD group showed a blunted response to the prednisolone suppression test, with lower salivary cortisol levels upon waking up (p=0.03). Individuals with PTSD had smaller total CC area than those without the disorder, but these differences were not statistically significant (e-value =0.34). CONCLUSIONS: Healthy parental bonding, characterized by the perception of low parental control and high affection, were associated with a lower risk of PTSD in adulthood, suggesting that emotional enrichment and the encouragement of autonomy are protective against PTSD in adulthood. PMID- 24489852 TI - NMR spectroscopic and bioinformatic analyses of the LTBP1 C-terminus reveal a highly dynamic domain organisation. AB - Proteins from the LTBP/fibrillin family perform key structural and functional roles in connective tissues. LTBP1 forms the large latent complex with TGFbeta and its propeptide LAP, and sequesters the latent growth factor to the extracellular matrix. Bioinformatics studies suggest the main structural features of the LTBP1 C-terminus are conserved through evolution. NMR studies were carried out on three overlapping C-terminal fragments of LTBP1, comprising four domains with characterised homologues, cbEGF14, TB3, EGF3 and cbEGF15, and three regions with no homology to known structures. The NMR data reveal that the four domains adopt canonical folds, but largely lack the interdomain interactions observed with homologous fibrillin domains; the exception is the EGF3-cbEGF15 domain pair which has a well-defined interdomain interface. (15)N relaxation studies further demonstrate that the three interdomain regions act as flexible linkers, allowing a wide range of motion between the well-structured domains. This work is consistent with the LTBP1 C-terminus adopting a flexible "knotted rope" structure, which may facilitate cell matrix interactions, and the accessibility to proteases or other factors that could contribute to TGFbeta activation. PMID- 24489853 TI - Efficient decoding of 2D structured illumination with linear phase stepping in X ray phase contrast and dark-field imaging. AB - The ability to map the phase distribution and lateral coherence of an x-ray wavefront offers the potential for imaging the human body through phase contrast, without the need to deposit significant radiation energy. The classic means to achieve this goal is structured illumination, in which a periodic intensity modulation is introduced into the image, and changes in the phase distribution of the wavefront are detected as distortions of the modulation pattern. Two dimensional periodic patterns are needed to fully characterize a transverse wavefront. Traditionally, the information in a 2D pattern is retrieved at high resolution by acquiring multiple images while shifting the pattern over a 2D matrix of positions. Here we describe a method to decode 2D periodic patterns with single-axis phase stepping, without either a loss of information or increasing the number of sampling steps. The method is created to reduce the instrumentation complexity of high-resolution 2D wavefront sensing in general. It is demonstrated with motionless electromagnetic phase stepping and a flexible processing algorithm in x-ray dark-field and phase contrast imaging. PMID- 24489854 TI - beta-Arrestin interacts with the beta/gamma subunits of trimeric G-proteins and dishevelled in the Wnt/Ca(2+) pathway in xenopus gastrulation. AB - beta-Catenin independent, non-canonical Wnt signaling pathways play a major role in the regulation of morphogenetic movements in vertebrates. The term non canonical Wnt signaling comprises multiple, intracellularly divergent, Wnt activated and beta-Catenin independent signaling cascades including the Wnt/Planar Cell Polarity and the Wnt/Ca(2+) cascades. Wnt/Planar Cell Polarity and Wnt/Ca(2+) pathways share common effector proteins, including the Wnt ligand, Frizzled receptors and Dishevelled, with each other and with additional branches of Wnt signaling. Along with the aforementioned proteins, beta-Arrestin has been identified as an essential effector protein in the Wnt/beta-Catenin and the Wnt/Planar Cell Polarity pathway. Our results demonstrate that beta-Arrestin is required in the Wnt/Ca(2+) signaling cascade upstream of Protein Kinase C (PKC) and Ca(2+)/Calmodulin-dependent Protein Kinase II (CamKII). We have further characterized the role of beta-Arrestin in this branch of non-canonical Wnt signaling by knock-down and rescue experiments in Xenopus embryo explants and analyzed protein-protein interactions in 293T cells. Functional interaction of beta-Arrestin, the beta subunit of trimeric G-proteins and Dishevelled is required to induce PKC activation and membrane translocation. In Xenopus gastrulation, beta-Arrestin function in Wnt/Ca(2+) signaling is essential for convergent extension movements. We further show that beta-Arrestin physically interacts with the beta subunit of trimeric G-proteins and Dishevelled, and that the interaction between beta-Arrestin and Dishevelled is promoted by the beta/gamma subunits of trimeric G-proteins, indicating the formation of a multiprotein signaling complex. PMID- 24489855 TI - Community-wide health risk assessment using geographically resolved demographic data: a synthetic population approach. AB - BACKGROUND: Evaluating environmental health risks in communities requires models characterizing geographic and demographic patterns of exposure to multiple stressors. These exposure models can be constructed from multivariable regression analyses using individual-level predictors (microdata), but these microdata are not typically available with sufficient geographic resolution for community risk analyses given privacy concerns. METHODS: We developed synthetic geographically resolved microdata for a low-income community (New Bedford, Massachusetts) facing multiple environmental stressors. We first applied probabilistic reweighting using simulated annealing to data from the 2006-2010 American Community Survey, combining 9,135 microdata samples from the New Bedford area with census tract level constraints for individual and household characteristics. We then evaluated the synthetic microdata using goodness-of-fit tests and by examining spatial patterns of microdata fields not used as constraints. As a demonstration, we developed a multivariable regression model predicting smoking behavior as a function of individual-level microdata fields using New Bedford-specific data from the 2006-2010 Behavioral Risk Factor Surveillance System, linking this model with the synthetic microdata to predict demographic and geographic smoking patterns in New Bedford. RESULTS: Our simulation produced microdata representing all 94,944 individuals living in New Bedford in 2006-2010. Variables in the synthetic population matched the constraints well at the census tract level (e.g., ancestry, gender, age, education, household income) and reproduced the census-derived spatial patterns of non-constraint microdata. Smoking in New Bedford was significantly associated with numerous demographic variables found in the microdata, with estimated tract-level smoking rates varying from 20% (95% CI: 17%, 22%) to 37% (95% CI: 30%, 45%). CONCLUSIONS: We used simulation methods to create geographically-resolved individual-level microdata that can be used in community-wide exposure and risk assessment studies. This approach provides insights regarding community-scale exposure and vulnerability patterns, valuable in settings where policy can be informed by characterization of multi-stressor exposures and health risks at high resolution. PMID- 24489856 TI - Generation of human induced pluripotent stem (Ips) cells in serum- and feeder free defined culture and TGF-Beta1 regulation of pluripotency. AB - Human Embryonic Stem cells (hESCs) and human induced Pluripotent Stem cells (hiPSCs) are commonly maintained on inactivated mouse embryonic fibroblast as feeder cells in medium supplemented with FBS or proprietary replacements. Use of culture medium containing undefined or unknown components has limited the development of applications for pluripotent cells because of the relative lack of knowledge regarding cell responses to differentiating growth factors. In addition, there is no consensus as to the optimal formulation, or the nature of the cytokine requirements of the cells to promote their self-renewal and inhibit their differentiation. In this study, we successfully generated hiPSCs from human dental pulp cells (DPCs) using Yamanaka's factors (Oct3/4, Sox2, Klf4, and c-Myc) with retroviral vectors in serum- and feeder-free defined culture conditions. These hiPSCs retained the property of self-renewal as evaluated by the expression of self-renewal marker genes and proteins, morphology, cell growth rates, and pluripotency evaluated by differentiation into derivatives of all three primary germ layers in vitro and in vivo. In this study, we found that TGF-beta1 increased the expression levels of pluripotency markers in a dose-dependent manner. However, increasing doses of TGF-beta1 suppressed the growth rate of hiPSCs cultured under the defined conditions. Furthermore, over short time periods the hiPSCs cultured in hESF9 or hESF9T exhibited similar morphology, but hiPSCs maintained in hESF9 could not survive beyond 30 passages. This result clearly confirmed that hiPSCs cultured in hESF9 medium absolutely required TGF beta1 to maintain pluripotency. This simple serum-free adherent monoculture system will allow us to elucidate the cell responses to growth factors under defined conditions and can eliminate the risk might be brought by undefined pathogens. PMID- 24489857 TI - Moving away from exhaustion: how core self-evaluations influence academic burnout. AB - BACKGROUND: Academic burnout refers to students who have low interest, lack of motivation, and tiredness in studying. Studies concerning how to prevent academic burnout are rare. OBJECTIVE: The present study aimed to investigate the impact of core self-evaluations on the academic burnout of university students, and mainly focused on the confirmation of the mediator role of life satisfaction. METHODS: A total of 470 university students accomplished the core self-evaluation scale, Satisfaction with Life, and academic burnout scale. RESULTS: Both core self evaluations and life satisfaction were significantly correlated with academic burnout. Structural equation modeling indicated that life satisfaction partially mediated the relationship between core self-evaluations and academic burnout. CONCLUSIONS: Core self-evaluations significantly influence academic burnout and are partially mediated by life satisfaction. PMID- 24489858 TI - Quantitative analysis of protein and gene expression in salivary glands of Sjogren's-like disease NOD mice treated by bone marrow soup. AB - BACKGROUND: Bone marrow cell extract (termed as BM Soup) has been demonstrated to repair irradiated salivary glands (SGs) and restore saliva secretion in our previous study. In the present study, we aim to investigate if the function of damaged SGs in non-obese diabetic (NOD) mice can be restored by BM Soup treatment and the molecular alterations associated with the treatment. METHODS: Whole BM cells were lysed and soluble intracellular contents ("BM Soup") were injected I.V. into NOD mice. Tandem mass tagging with 2-D liquid chromatography-mass spectrometry was used to quantify proteins in the submandibular glands (SMGs) between untreated and BM Soup-treated mice. Quantitative PCR was used to identify genes with altered expression in the treated mice. RESULTS BM SOUP: restored salivary flow rates to normal levels and significantly reduced the focus scores of SMGs in NOD mice. More than 1800 proteins in SMG cells were quantified by the proteomic approach. Many SMG proteins involved in inflammation and apoptosis were found to be down-regulated whereas those involved in salivary gland biology and development/regeneration were up-regulated in the BM Soup-treated mice. qPCR analysis also revealed expression changes of growth factors and cytokines in the SMGs of the treated NOD mice. CONCLUSION: BM Soup treatment is effective to restore the function of damaged SGs in NOD mice. Through gene/protein expression analysis, we have found that BM Soup treatment might effectuate via inhibiting apoptosis, focal adhesion and inflammation whereas promoting development, regeneration and differentiation of the SG cells in NOD mice. These findings provide important insights on the potential mechanisms underlying the BM Soup treatment for functional restoration of damaged SGs in NOD mice. Additional studies are needed to further confirm the identified target genes and their related signaling pathways that are responsible for the BM Soup treatment. PMID- 24489859 TI - Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, stimulates hepatic autophagy and lipid clearance. AB - Epigallocatechin gallate (EGCG) is a major polyphenol in green tea that has been shown to have anti-inflammatory, anti-cancer, anti-steatotic effects on the liver. Autophagy also mediates similar effects; however, it is not currently known whether EGCG can regulate hepatic autophagy. Here, we show that EGCG increases hepatic autophagy by promoting the formation of autophagosomes, increasing lysosomal acidification, and stimulating autophagic flux in hepatic cells and in vivo. EGCG also increases phosphorylation of AMPK, one of the major regulators of autophagy. Importantly, siRNA knockdown of AMPK abrogated autophagy induced by EGCG. Interestingly, we observed lipid droplet within autophagosomes and autolysosomes and increased lipid clearance by EGCG, suggesting it promotes lipid metabolism by increasing autophagy. In mice fed with high-fat/western style diet (HFW; 60% energy as fat, reduced levels of calcium, vitamin D3, choline, folate, and fiber), EGCG treatment reduces hepatosteatosis and concomitantly increases autophagy. In summary, we have used genetic and pharmacological approaches to demonstrate EGCG induction of hepatic autophagy, and this may contribute to its beneficial effects in reducing hepatosteatosis and potentially some other pathological liver conditions. PMID- 24489860 TI - Effects of reusing baseline volumes of interest by applying (non-)rigid image registration on positron emission tomography response assessments. AB - OBJECTIVES: Reusing baseline volumes of interest (VOI) by applying non-rigid and to some extent (local) rigid image registration showed good test-retest variability similar to delineating VOI on both scans individually. The aim of the present study was to compare response assessments and classifications based on various types of image registration with those based on (semi)-automatic tumour delineation. METHODS: Baseline (n = 13), early (n = 12) and late (n = 9) response (after one and three cycles of treatment, respectively) whole body [(18)F]fluoro 2-deoxy-D-glucose positron emission tomography/computed tomography (PET/CT) scans were acquired in subjects with advanced gastrointestinal malignancies. Lesions were identified for early and late response scans. VOI were drawn independently on all scans using an adaptive 50% threshold method (A50). In addition, various types of (non-)rigid image registration were applied to PET and/or CT images, after which baseline VOI were projected onto response scans. Response was classified using PET Response Criteria in Solid Tumors for maximum standardized uptake value (SUV(max)), average SUV (SUV(mean)), peak SUV (SUV(peak)), metabolically active tumour volume (MATV), total lesion glycolysis (TLG) and the area under a cumulative SUV-volume histogram curve (AUC). RESULTS: Non-rigid PET based registration and non-rigid CT-based registration followed by non-rigid PET based registration (CTPET) did not show differences in response classifications compared to A50 for SUV(max) and SUV(peak), however, differences were observed for MATV, SUV(mean), TLG and AUC. For the latter, these registrations demonstrated a poorer performance for small lung lesions (<2.8 ml), whereas A50 showed a poorer performance when another area with high uptake was close to the target lesion. All methods were affected by lesions with very heterogeneous tracer uptake. CONCLUSIONS: Non-rigid PET- and CTPET-based image registrations may be used to classify response based on SUV(max) and SUV(peak). For other quantitative measures future studies should assess which method is valid for response evaluations by correlating with survival data. PMID- 24489861 TI - Genetic variants in PCSK1 gene are associated with the risk of coronary artery disease in type 2 diabetes in a Chinese Han population: a case control study. AB - BACKGROUND: Insulin and glucagon-like peptide 1 (GLP-1), converted by proprotein convertase 1 (PC1/3) from proinsulin and proglucagon, are associated with type 2 diabetes (T2DM) and coronary artery disease (CAD). The aim of this study is to investigate the association of PCSK1 gene, which encodes PC1/3, with the risk of CAD in Chinese patients with T2DM. METHODS: We selected and genotyped 5 haplotype tagging single nucleotide polymorphisms (SNPs) at PCSK1 gene (across 39873bp locus) in a case-control study of Chinese Han population involving 425 diabetic patients (62.1% male, mean age 63.2 years) with CAD as positive cases and 258 diabetic patients (44.2% male, mean age 62.0 years) without CAD as controls. RESULTS: The allele frequencies at rs3811951 were significantly different between cases and controls (30.7% vs. 37.2%), with the allele G associated with decreased risk for CAD (OR = 0.75, 95% CI = 0.59-0.94, p = 0.013). In recessive inheritance mode, the carriers of GG had a lower risk (OR = 0.50, 95%CI = 0.31-0.82, p = 0.005), even after adjusted for gender, age, BMI and smoking (OR = 0.43, 95%CI = 0.24-0.77, p = 0.004). The carriers of the minor allele A at rs156019 had a higher risk (OR = 1.66, 95%CI = 1.10-2.50, p = 0.016 after adjustment) in dominant inheritance mode. The SNP rs6234 was also significantly associated with CAD risk in women, with the carriers of the minor allele G at rs6234 associated with a reduced CAD risk in recessive inheritance mode (OR = 0.42, 95% CI = 0.18 0.95, p = 0.036 after adjustment). CONCLUSIONS: Our results found that common genetic variants in PCSK1 were associated with CAD in Chinese patients with T2DM. PMID- 24489862 TI - Modulation of synaptic vesicle exocytosis in muscle-dependent long-term depression at the amphibian neuromuscular junction. AB - We have labeled recycling synaptic vesicles at the somatic Bufo marinus neuromuscular junction with the styryl dye FM2-10 and provide direct evidence for refractoriness of exocytosis associated with a muscle activity-dependent form of long-term depression (LTD) at this synapse. FM2-10 dye unloading experiments demonstrated that the rate of vesicle exocytosis from the release ready pool (RRP) of vesicles was more than halved in the LTD (induced by 20 min of low frequency stimulation). Recovery from LTD, observed as a partial recovery of nerve-evoked muscle twitch amplitude, was accompanied by partial recovery of the refractoriness of RRP exocytosis. Unexpectedly, paired pulse plasticity, another routinely used indicator of presynaptic forms of synaptic plasticity, was unchanged in the LTD. We conclude that the LTD induces refractoriness of the neuromuscular vesicle release machinery downstream of presynaptic calcium entry. PMID- 24489863 TI - BRCA2 and TP53 collaborate in tumorigenesis in zebrafish. AB - Germline mutations in the tumor suppressor genes BRCA2 and TP53 significantly influence human cancer risk, and cancers from humans who inherit one mutant allele for BRCA2 or TP53 often display loss of the wildtype allele. In addition, BRCA2-associated cancers often exhibit mutations in TP53. To determine the relationship between germline heterozygous mutation (haploinsufficiency) and somatic loss of heterozygosity (LOH) for BRCA2 and TP53 in carcinogenesis, we analyzed zebrafish with heritable mutations in these two genes. Tumor-bearing zebrafish were examined by histology, and normal and neoplastic tissues were collected by laser-capture microdissection for LOH analyses. Zebrafish on a heterozygous tp53(M214K) background had a high incidence of malignant tumors. The brca2(Q658X) mutation status determined both the incidence of LOH and the malignant tumor phenotype. LOH for tp53 occurred in the majority of malignant tumors from brca2 wildtype and heterozygous mutant zebrafish, and most of these were malignant peripheral nerve sheath tumors. Malignant tumors in zebrafish with heterozygous mutations in both brca2 and tp53 frequently displayed LOH for both genes. In contrast, LOH for tp53 was uncommon in malignant tumors from brca2 homozygotes, and these tumors were primarily undifferentiated sarcomas. Thus, carcinogenesis in zebrafish with combined mutations in tp53 and brca2 typically requires biallelic mutation or loss of at least one of these genes, and the specific combination of inherited mutations influences the development of LOH and the tumor phenotype. These results provide insight into cancer development associated with heritable BRCA2 and TP53 mutations. PMID- 24489864 TI - Effects of parental omega-3 fatty acid intake on offspring microbiome and immunity. AB - The "Western diet" is characterized by increased intake of saturated and omega-6 (n-6) fatty acids with a relative reduction in omega-3 (n-3) consumption. These fatty acids can directly and indirectly modulate the gut microbiome, resulting in altered host immunity. Omega-3 fatty acids can also directly modulate immunity through alterations in the phospholipid membranes of immune cells, inhibition of n-6 induced inflammation, down-regulation of inflammatory transcription factors, and by serving as pre-cursors to anti-inflammatory lipid mediators such as resolvins and protectins. We have previously shown that consumption by breeder mice of diets high in saturated and n-6 fatty acids have inflammatory and immune modulating effects on offspring that are at least partially driven by vertical transmission of altered gut microbiota. To determine if parental diets high in n 3 fatty acids could also affect offspring microbiome and immunity, we fed breeding mice an n-3-rich diet with 40% calories from fat and measured immune outcomes in their offspring. We found offspring from mice fed diets high in n-3 had altered gut microbiomes and modestly enhanced anti-inflammatory IL-10 from both colonic and splenic tissue. Omega-3 pups were protected during peanut oral allergy challenge with small but measurable alterations in peanut-related serologies. However, n-3 pups displayed a tendency toward worsened responses during E. coli sepsis and had significantly worse outcomes during Staphylococcus aureus skin infection. Our results indicate excess parental n-3 fatty acid intake alters microbiome and immune response in offspring. PMID- 24489865 TI - A conceptual framework for healthy eating behavior in ecuadorian adolescents: a qualitative study. AB - OBJECTIVE: The objective of this study was to identify factors influencing eating behavior of Ecuadorian adolescents - from the perspective of parents, school staff and adolescents - to develop a conceptual framework for adolescents' eating behavior. STUDY DESIGN: Twenty focus groups (N=144 participants) were conducted separately with adolescents aged 11-15 y (n (focus groups)=12, N (participants)=80), parents (n=4, N=32) and school staff (n=4, N=32) in rural and urban Ecuador. A semi-structured questioning route was developed based on the 'Attitude, Social influences and Self-efficacy' model and the socio-ecological model to assess the relevance of behavioral and environmental factors in low- and middle-income countries. Two researchers independently analyzed verbatim transcripts for emerging themes, using deductive thematic content analysis. Data were analyzed using NVivo 8. RESULTS: All groups recognized the importance of eating healthily and key individual factors in Ecuadorian adolescents' food choices were: financial autonomy, food safety perceptions, lack of self-control, habit strength, taste preferences and perceived peer norms. Environmental factors included the poor nutritional quality of food and its easy access at school. In their home and family environment, time and convenience completed the picture as barriers to eating healthily. Participants acknowledged the impact of the changing socio-cultural environment on adolescents' eating patterns. Availability of healthy food at home and financial constraints differed between settings and socio-economic groups. CONCLUSION: Our findings endorse the importance of investigating behavioral and environmental factors that influence and mediate healthy dietary behavior prior to intervention development. Several culture specific factors emerged that were incorporated into a conceptual framework for developing health promotion interventions in Ecuador. PMID- 24489866 TI - Long-term oral administration of hop flower extracts mitigates Alzheimer phenotypes in mice. AB - Coincident with the expanding population of aged people, the incidence of Alzheimer disease (AD) is rapidly increasing in most advanced countries. At present, no effective prophylactics are available. Among several pathological mechanisms proposed for AD, the "amyloid hypothesis" has been most widely accepted, in which accumulation or deposition of Abeta is considered to be the initial event. Thus, prevention of Abeta production would be an ideal strategy for the treatment or prevention of AD. Abeta is produced via the proteolytic cleavage of its precursor protein, APP (amyloid precursor protein), by two different enzymes, beta and gamma-secretases. Indeed, inhibitors against either or both enzymes have been developed and tested for clinical efficacy. Based on the "amyloid hypothesis", we developed a luciferase-based screening method to monitor gamma-secretase activity, screened more than 1,600 plant extracts, most of which have long been used in Chinese medicine, and observed that Hop extracts significantly inhibit Abeta production in cultured cells. A major component of the inhibitory activity was purified, and its chemical identity was determined by NMR to be Garcinielliptone HC. In vivo, oral administration of Hop extracts to AD model mice decreased Abeta depositions in the cerebral cortex of the parietal lobe, hippocampus, and artery walls (amyloid angiopathy) in the brains. In a Morris water maze test, AD model mice that had daily consumed Hop extracts in their drinking water showed significant mitigation of memory impairment at ages of 9 and 12 months. Moreover, in the open field test oral administration of Hop extracts also prevented an emotional disturbance that appeared in the AD mice at 18 months. Despite lifelong consumption of Hop extracts, no deleterious side effects were observed at any age. These results support the "amyloid hypothesis", and indicate that Hop extract is a promising candidate for an effective prophylactic for AD. PMID- 24489867 TI - Assessing intraspecific variation in effective dispersal along an altitudinal gradient: a test in two Mediterranean high-mountain plants. AB - BACKGROUND: Plant recruitment depends among other factors on environmental conditions and their variation at different spatial scales. Characterizing dispersal in contrasting environments may thus be necessary to understand natural intraspecific variation in the processes underlying recruitment. Silene ciliata and Armeria caespitosa are two representative species of cryophilic pastures above the tree line in Mediterranean high mountains. No explicit estimations of dispersal kernels have been made so far for these or other high-mountain plants. Such data could help to predict their dispersal and recruitment patterns in a context of changing environments under ongoing global warming. METHODS: We used an inverse modelling approach to analyse effective seed dispersal patterns in five populations of both Silene ciliata and Armeria caespitosa along an altitudinal gradient in Sierra de Guadarrama (Madrid, Spain). We considered four commonly employed two-dimensional seedling dispersal kernels exponential-power, 2Dt, WALD and log-normal. KEY RESULTS: No single kernel function provided the best fit across all populations, although estimated mean dispersal distances were short (<1 m) in all cases. S. ciliata did not exhibit significant among population variation in mean dispersal distance, whereas significant differences in mean dispersal distance were found in A. caespitosa. Both S. ciliata and A. caespitosa exhibited among-population variation in the fecundity parameter and lacked significant variation in kernel shape. CONCLUSIONS: This study illustrates the complexity of intraspecific variation in the processes underlying recruitment, showing that effective dispersal kernels can remain relatively invariant across populations within particular species, even if there are strong variations in demographic structure and/or physical environment among populations, while the invariant dispersal assumption may not hold for other species in the same environment. Our results call for a case-by-case analysis in a wider range of plant taxa and environments to assess the prevalence and magnitude of intraspecific dispersal variation. PMID- 24489868 TI - Is anterior cervical discectomy and fusion superior to corpectomy and fusion for treatment of multilevel cervical spondylotic myelopathy? A systemic review and meta-analysis. AB - OBJECTIVE: Both anterior cervical discectomy with fusion (ACDF) and anterior cervical corpectomy with fusion (ACCF) are used to treat cervical spondylotic myelopathy (CSM), however, there is considerable controversy as to whether ACDF or ACCF is the optimal treatment for this condition. To compare the clinical outcomes, complications, and surgical trauma between ACDF and ACCF for the treatment of CSM, we conducted a meta-analysis. METHODS: We conducted a comprehensive search in MEDLINE, EMBASE, PubMed, Google Scholar and Cochrane databases, searching for relevant controlled trials up to July 2013 that compared ACDF and ACCF for the treatment of CSM. We performed title and abstract screening and full-text screening independently and in duplicate. A random effects model was used for heterogeneous data; otherwise, a fixed effect model was used to pool data, using mean difference (MD) for continuous outcomes and odds ratio (OR) for dichotomous outcomes. RESULTS: Of 2157 citations examined, 15 articles representing 1372 participants were eligible. Overall, there were significant differences between the two treatment groups for hospital stay (M = -5.60, 95% CI = -7.09 to -4.11), blood loss (MD = -151.35, 95% CI = -253.22 to -49.48), complications (OR = 0.50, 95% CI = 0.35 to 0.73) and increased lordosis of C2-C7 (MD = 3.70, 95% CI = 0.96 to 6.45) and fusion segments angles (MD = 3.38, 95% CI = 2.54 to 4.22). However, there were no significant differences in the operation time (MD = -9.34, 95% CI = -42.99 to 24.31), JOA (MD = 0.24, 95% CI = -0.10 to 0.57), VAS (MD = -0.06, 95% CI = -0.81 to 0.70), NDI (MD = -1.37, 95% CI = -3.17 to 0.43), Odom criteria (OR = 0.88, 95% CI = 0.60 to 1.30) or fusion rate (OR = 1.17, 95% CI = 0.34 to 4.11). CONCLUSIONS: Based on this meta-analysis, although complications and increased lordosis are significantly better in the ACDF group, there is no strong evidence to support the routine use of ACDF over ACCF in CSM. PMID- 24489869 TI - Supported palladium nanoparticles synthesized by living plants as a catalyst for Suzuki-Miyaura reactions. AB - The metal accumulating ability of plants has previously been used to capture metal contaminants from the environment; however, the full potential of this process is yet to be realized. Herein, the first use of living plants to recover palladium and produce catalytically active palladium nanoparticles is reported. This process eliminates the necessity for nanoparticle extraction from the plant and reduces the number of production steps compared to traditional catalyst palladium on carbon. These heterogeneous plant catalysts have demonstrated high catalytic activity in Suzuki coupling reactions between phenylboronic acid and a range of aryl halides containing iodo-, bromo- and chloro- moieties. PMID- 24489870 TI - A preliminary study of viral metagenomics of French bat species in contact with humans: identification of new mammalian viruses. AB - The prediction of viral zoonosis epidemics has become a major public health issue. A profound understanding of the viral population in key animal species acting as reservoirs represents an important step towards this goal. Bats harbor diverse viruses, some of which are of particular interest because they cause severe human diseases. However, little is known about the diversity of the global population of viruses found in bats (virome). We determined the viral diversity of five different French insectivorous bat species (nine specimens in total) in close contact with humans. Sequence-independent amplification, high-throughput sequencing with Illumina technology and a dedicated bioinformatics analysis pipeline were used on pooled tissues (brain, liver and lungs). Comparisons of the sequences of contigs and unassembled reads provided a global taxonomic distribution of virus-related sequences for each sample, highlighting differences both within and between bat species. Many viral families were present in these viromes, including viruses known to infect bacteria, plants/fungi, insects or vertebrates, the most relevant being those infecting mammals (Retroviridae, Herpesviridae, Bunyaviridae, Poxviridae, Flaviviridae, Reoviridae, Bornaviridae, Picobirnaviridae). In particular, we detected several new mammalian viruses, including rotaviruses, gammaretroviruses, bornaviruses and bunyaviruses with the identification of the first bat nairovirus. These observations demonstrate that bats naturally harbor viruses from many different families, most of which infect mammals. They may therefore constitute a major reservoir of viral diversity that should be analyzed carefully, to determine the role played by bats in the spread of zoonotic viral infections. PMID- 24489871 TI - A novel malaria vaccine candidate antigen expressed in Tetrahymena thermophila. AB - Development of effective malaria vaccines is hampered by the problem of producing correctly folded Plasmodium proteins for use as vaccine components. We have investigated the use of a novel ciliate expression system, Tetrahymena thermophila, as a P. falciparum vaccine antigen platform. A synthetic vaccine antigen composed of N-terminal and C-terminal regions of merozoite surface protein-1 (MSP-1) was expressed in Tetrahymena thermophila. The recombinant antigen was secreted into the culture medium and purified by monoclonal antibody (mAb) affinity chromatography. The vaccine was immunogenic in MF1 mice, eliciting high antibody titers against both N- and C-terminal components. Sera from immunized animals reacted strongly with P. falciparum parasites from three antigenically different strains by immunofluorescence assays, confirming that the antibodies produced are able to recognize parasite antigens in their native form. Epitope mapping of serum reactivity with a peptide library derived from all three MSP-1 Block 2 serotypes confirmed that the MSP-1 Block 2 hybrid component of the vaccine had effectively targeted all three serotypes of this polymorphic region of MSP-1. This study has successfully demonstrated the use of Tetrahymena thermophila as a recombinant protein expression platform for the production of malaria vaccine antigens. PMID- 24489872 TI - Useless hearing in male Emblemasoma auditrix (Diptera, Sarcophagidae)--a case of intralocus sexual conflict during evolution of a complex sense organ? AB - Sensory modalities typically are important for both sexes, although sex-specific functional adaptations may occur frequently. This is true for hearing as well. Consequently, distinct behavioural functions were identified for the different insect hearing systems. Here we describe a first case, where a trait of an evolutionary novelty and a highly specialized hearing organ is adaptive in only one sex. The main function of hearing of the parasitoid fly Emblemasoma auditrix is to locate the host, males of the cicada species Okanagana rimosa, by their calling song. This task is performed by female flies, which deposit larvae into the host. We show that male E. auditrix possess a hearing sense as well. The morphology of the tympanal organ of male E. auditrix is rather similar to the female ear, which is 8% broader than the male ear. In both sexes the physiological hearing threshold is tuned to 5 kHz. Behavioural tests show that males are able to orient towards the host calling song, although phonotaxis often is incomplete. However, despite extensive observations in the field and substantial knowledge of the biology of E. auditrix, no potentially adaptive function of the male auditory sense has been identified. This unique hearing system might represent an intralocus sexual conflict, as the complex sense organ and the behavioural relevant neuronal network is adaptive for only one sex. The correlated evolution of the sense organ in both sexes might impose substantial constraints on the sensory properties of the ear. Similar constraints, although hidden, might also apply to other sensory systems in which behavioural functions differ between sexes. PMID- 24489873 TI - Spatial ecology of bacteria at the microscale in soil. AB - Despite an exceptional number of bacterial cells and species in soils, bacterial diversity seems to have little effect on soil processes, such as respiration or nitrification, that can be affected by interactions between bacterial cells. The aim of this study is to understand how bacterial cells are distributed in soil to better understand the scaling between cell-to-cell interactions and what can be measured in a few milligrams, or more, of soil. Based on the analysis of 744 images of observed bacterial distributions in soil thin sections taken at different depths, we found that the inter-cell distance was, on average 12.46 um and that these inter-cell distances were shorter near the soil surface (10.38 um) than at depth (>18 um), due to changes in cell densities. These images were also used to develop a spatial statistical model, based on Log Gaussian Cox Processes, to analyse the 2D distribution of cells and construct realistic 3D bacterial distributions. Our analyses suggest that despite the very high number of cells and species in soil, bacteria only interact with a few other individuals. For example, at bacterial densities commonly found in bulk soil (10(8) cells g(-1) soil), the number of neighbours a single bacterium has within an interaction distance of ca. 20 um is relatively limited (120 cells on average). Making conservative assumptions about the distribution of species, we show that such neighbourhoods contain less than 100 species. This value did not change appreciably as a function of the overall diversity in soil, suggesting that the diversity of soil bacterial communities may be species-saturated. All in all, this work provides precise data on bacterial distributions, a novel way to model them at the micrometer scale as well as some new insights on the degree of interactions between individual bacterial cells in soils. PMID- 24489874 TI - Body mass index and breast cancer defined by biological receptor status in pre menopausal and post-menopausal women: a multicenter study in China. AB - BACKGROUND: Few studies have investigated the association between body mass index (BMI) and breast cancer with consideration to estrogen/progesterone/human epidermal growth factor type 2 receptor status (ER/PR/HER2) in the breast tissue among Chinese pre- and post-menopausal women. METHODS: Four thousand two hundred and eleven breast cancer patients were selected randomly from seven geographic regions of China from 1999 to 2008. Demographic data, risk factors, pathologic features, and biological receptor status of cases were collected from the medical charts. Chi-square test, fisher exact test, rank-correlation analysis, and multivariate logistic regression model were adopted to explore whether BMI differed according to biological receptor status in pre- and post-menopausal women. RESULTS: Three thousand two hundred and eighty one eligible cases with BMI data were included. No statistically significant differences in demographic characteristics were found between the cases with BMI data and those without. In the rank-correlation analysis, the rates of PR+ and HER2+ were positively correlated with increasing BMI among post-menopausal women (rs BMI, PR+=0.867, P=0.001; rs BMI, HER2+ =0.636, P=0.048), but the ER+ rates did not vary by increasing BMI. Controlling for confounding factors, multivariate logistic regression models with BMI<24 kg/m(2) as the reference group were performed and found that BMI >= 24 kg/m(2) was only positively correlated with PR+ status among post-menopausal breast cancer cases (adjusted OR=1.420, 95% CI: 1.116-1.808, Wald=8.116, P=0.004). CONCLUSIONS: Post-menopausal women with high BMI (>= 24 kg/m(2)) have a higher proportion of PR+ breast cancer. In addition to effects mediated via the estrogen metabolism pathway, high BMI might increase the risk of breast cancer by other routes, which should be examined further in future etiological mechanism studies. PMID- 24489875 TI - Temporal constraints of behavioral inhibition: relevance of inter-stimulus interval in a Go-Nogo task. AB - The capacity to inhibit prepotent and automatic responses is crucial for proper cognitive and social development, and inhibitory impairments have been considered to be key for some neuropsychiatric conditions. One of the most used paradigms to analyze inhibitory processes is the Go-Nogo task (GNG). This task has been widely used in psychophysical and cognitive EEG studies, and more recently in paradigms using fMRI. However, a technical limitation is that the time resolution of fMRI is poorer than that of the EEG technique. In order to compensate for these temporal constraints, it has become common practice in the fMRI field to use longer inter-stimulus intervals (ISI) than those used in EEG protocols. Despite the noticeable temporal differences between these two techniques, it is currently assumed that both approaches assess similar inhibitory processes. We performed an EEG study using a GNG task with both short ISI (fast-condition, FC, as in EEG protocols) and long ISI (slow-condition, SC, as in fMRI protocols). We found that in the FC there was a stronger Nogo-N2 effect than in the SC. Moreover, in the FC, but not in the SC, the number of preceding Go trials correlated positively with the Nogo-P3 amplitude and with the Go trial reaction time; and negatively with commission errors. In addition, we found significant topographical differences for the Go-P3 elicited in FC and SC, which is interpreted in terms of different neurotransmitter dynamics. Taken together, our results provide evidence that frequency of stimulus presentation in the GNG task strongly modulates the behavioral response and the evoked EEG activity. Therefore, it is likely that short-ISI EEG protocols and long-ISI fMRI protocols do not assess equivalent inhibitory processes. PMID- 24489876 TI - Accelerometer-determined physical activity and its comparison with the International Physical Activity Questionnaire in a sample of Nigerian adults. AB - INTRODUCTION: Accurate assessment of physical activity to identify current levels and changes within the population is dependent on the precision of the measurement tools. The aim of this study was to compare components of physical activity measured with an adapted version of the International Physical Activity Questionnaire (Hausa IPAQ-SF) and the accelerometer in a sample of Nigeria adults. METHODS: One hundred and forty-four participants (Mean age = 32.6 +/- 9.9 years, 40.3% women) in a cross-sectional study wore an accelerometer for seven consecutive days and completed the Hausa IPAQ-SF questionnaire on the eighth day. Total physical activity, time spent in moderate-to-vigorous activity (MVPA) and sedentary time assessed by Hausa IPAQ-SF and accelerometer were compared. The absolute and criterion- related validity of the Hausa IPAQ-SF was assessed by Bland-Altman analysis and Spearman Correlation Coefficients, respectively. Specificity and sensitivity were calculated to classify individuals according to the global standard guideline for sufficient physical activity. RESULTS: Compared with the accelerometer, higher time in MVPA and total physical activity were reported on the Hausa IPAQ-SF (p<0.001), while low to moderate correlations (Rs = 0.03-0.38) were found between the two methods. The 95% limits of agreement were wide between methods for total physical activity (-23019 to 20375 METmin.d(-1)) and sedentary time (-510 to 150 min.d(-1)). The sensitivity (76.2%) of Hausa IPAQ SF to identify insufficiently active people was good, but its specificity (33.3%) to correctly classify sufficiently active people was low. CONCLUSIONS: The Hausa IPAQ-SF overestimated components of physical activity among Nigerian adults, and demonstrated poor to moderate evidence of absolute and criterion validity. Further evaluation of IPAQ and other self-report physical activity instruments in other Africa populations could enhance accurate evaluation of physical activity data in the region countries. PMID- 24489877 TI - New material of Beelzebufo, a hyperossified frog (Amphibia: Anura) from the late cretaceous of Madagascar. AB - The extant anuran fauna of Madagascar is exceptionally rich and almost completely endemic. In recent years, many new species have been described and understanding of the history and relationships of this fauna has been greatly advanced by molecular studies, but very little is known of the fossil history of frogs on the island. Beelzebufo ampinga, the first named pre-Holocene frog from Madagascar, was described in 2008 on the basis of numerous disarticulated cranial and postcranial elements from the Upper Cretaceous (Maastrichtian) Maevarano Formation of Madagascar. These specimens documented the presence of a hyperossified taxon that differed strikingly from extant Malagasy frogs in its large size and heavy coarse cranial exostosis. Here we describe and analyse new, articulated, and more complete material of the skull, vertebral column, and hind limb, as well as additional isolated elements discovered since 2008. MUCT scans allow a detailed understanding of both internal and external morphology and permit a more accurate reconstruction. The new material shows Beelzebufo to have been even more bizarre than originally interpreted, with large posterolateral skull flanges and sculptured vertebral spine tables. The apparent absence of a tympanic membrane, the strong cranial exostosis, and vertebral morphology suggest it may have burrowed during seasonally arid conditions, which have been interpreted for the Maevarano Formation from independent sedimentological and taphonomic evidence. New phylogenetic analyses, incorporating both morphological and molecular data, continue to place Beelzebufo with hyloid rather than ranoid frogs. Within Hyloidea, Beelzebufo still groups with the South American Ceratophryidae thus continuing to pose difficulties with both biogeographic interpretations and prior molecular divergence dates. PMID- 24489878 TI - Allo-reactivity of mesenchymal stem cells in rhesus macaques is dose and haplotype dependent and limits durable cell engraftment in vivo. AB - The emerging paradigm that MSCs are immune privileged has fostered the use of "off-the-shelf" allogeneic MSC-based therapies in human clinical trials. However, this approach ignores studies in experimental animals wherein transplantation of MSCs across MHC boundaries elicits measurable allo-immune responses. To determine if MSCs are hypo-immunogeneic, we characterized the immune response in rhesus macaques following intracranial administration of allogeneic vs. autologous MSCs. This analysis revealed unambiguous evidence of productive allo-recognition based on expansion of NK, B and T cell subsets in peripheral blood and detection of allo-specific antibodies in animals administered allogeneic but not autologous MSCs. Moreover, the degree of MHC class I and II mismatch between the MSC donor and recipient significantly influenced the magnitude and nature of the allo immune response. Consistent with these findings, real-time PCR analysis of brain tissue from female recipients administered varying doses of male, allogeneic MSCs revealed a significant inverse correlation between MSC engraftment levels and cell dose. Changes in post-transplant neutrophil and lymphocyte counts also correlated with dose and were predictive of overall MSC engraftment levels. However, secondary antigen challenge failed to elicit a measurable immune response in allogeneic recipients. Finally, extensive behavior testing of animals revealed no main effect of cell dose on motor skills, social development, or temperament. Collectively, these data indicate that allogeneic MSCs are weakly immunogenic when transplanted across MHC boundaries in rhesus macaques and this negatively impacts durable engraftment levels. Therefore the use of unrelated donor MSCs should be carefully evaluated in human patients. PMID- 24489879 TI - Mapping organelle motion reveals a vesicular conveyor belt spatially replenishing secretory vesicles in stimulated chromaffin cells. AB - How neurosecretory cells spatially adjust their secretory vesicle pools to replenish those that have fused and released their hormonal content is currently unknown. Here we designed a novel set of image analyses to map the probability of tracked organelles undergoing a specific type of movement (free, caged or directed). We then applied our analysis to time-lapse z-stack confocal imaging of secretory vesicles from bovine Chromaffin cells to map the global changes in vesicle motion and directionality occurring upon secretagogue stimulation. We report a defined region abutting the cortical actin network that actively transports secretory vesicles and is dissipated by actin and microtubule depolymerizing drugs. The directionality of this "conveyor belt" towards the cell surface is activated by stimulation. Actin and microtubule networks therefore cooperatively probe the microenvironment to transport secretory vesicles to the periphery, providing a mechanism whereby cells globally adjust their vesicle pools in response to secretagogue stimulation. PMID- 24489880 TI - Signals of climate change in butterfly communities in a Mediterranean protected area. AB - The European protected-area network will cease to be efficient for biodiversity conservation, particularly in the Mediterranean region, if species are driven out of protected areas by climate warming. Yet, no empirical evidence of how climate change influences ecological communities in Mediterranean nature reserves really exists. Here, we examine long-term (1998-2011/2012) and short-term (2011-2012) changes in the butterfly fauna of Dadia National Park (Greece) by revisiting 21 and 18 transects in 2011 and 2012 respectively, that were initially surveyed in 1998. We evaluate the temperature trend for the study area for a 22-year-period (1990-2012) in which all three butterfly surveys are included. We also assess changes in community composition and species richness in butterfly communities using information on (a) species' elevational distributions in Greece and (b) Community Temperature Index (calculated from the average temperature of species' geographical ranges in Europe, weighted by species' abundance per transect and year). Despite the protected status of Dadia NP and the subsequent stability of land use regimes, we found a marked change in butterfly community composition over a 13 year period, concomitant with an increase of annual average temperature of 0.95 degrees C. Our analysis gave no evidence of significant year-to-year (2011-2012) variability in butterfly community composition, suggesting that the community composition change we recorded is likely the consequence of long-term environmental change, such as climate warming. We observe an increased abundance of low-elevation species whereas species mainly occurring at higher elevations in the region declined. The Community Temperature Index was found to increase in all habitats except agricultural areas. If equivalent changes occur in other protected areas and taxonomic groups across Mediterranean Europe, new conservation options and approaches for increasing species' resilience may have to be devised. PMID- 24489881 TI - Identification and validation of miRNAs associated with the resistance of maize (Zea mays L.) to Exserohilum turcicum. AB - Northern leaf blight, caused by the fungus Exserohilum turcicum (Pass.), is a major disease of maize (Zea mays L.). MicroRNAs (miRNAs) have been recently reported as gene expression regulators related to several stress responses; however, evidence of the role of miRNAs in plant response to biotic stresses is limited. In this study, the miRNA expression patterns in maize in response to E. turcicum stress were investigated using a plant miRNA microarray platform. A total of 118 miRNAs were detected in mock- and E. turcicum-inoculated leaves. Among these miRNAs, miR530, miR811, miR829, and miR845 were identified as new miRNAs in maize through a homology-based approach. The secondary structures and putative targets of these miRNAs were also predicted. In addition, four miRNAs were differentially regulated in response to E. turcicum: miR811, miR829, miR845, and miR408. The functional annotation of the predicted targets indicated that these stress-responsive miRNAs regulate metabolic, morphologic, and physiologic adaptations in maize seedlings at the post-transcriptional level. Four targets were negatively correlated with their corresponding miRNAs (miR811, miR829, and miR408). Furthermore, we have demonstrated for the first time that miR811 and miR829 confers a high degree of resistance to E. turcicum, which can be used in maize breeding programs. PMID- 24489882 TI - Progesterone treatment shows benefit in a pediatric model of moderate to severe bilateral brain injury. AB - PURPOSE: Controlled cortical impact (CCI) models in adult and aged Sprague-Dawley (SD) rats have been used extensively to study medial prefrontal cortex (mPFC) injury and the effects of post-injury progesterone treatment, but the hormone's effects after traumatic brain injury (TBI) in juvenile animals have not been determined. In the present proof-of-concept study we investigated whether progesterone had neuroprotective effects in a pediatric model of moderate to severe bilateral brain injury. METHODS: Twenty-eight-day old (PND 28) male Sprague Dawley rats received sham (n = 24) or CCI (n = 47) injury and were given progesterone (4, 8, or 16 mg/kg per 100 g body weight) or vehicle injections on post-injury days (PID) 1-7, subjected to behavioral testing from PID 9-27, and analyzed for lesion size at PID 28. RESULTS: The 8 and 16 mg/kg doses of progesterone were observed to be most beneficial in reducing the effect of CCI on lesion size and behavior in PND 28 male SD rats. CONCLUSION: Our findings suggest that a midline CCI injury to the frontal cortex will reliably produce a moderate TBI comparable to what is seen in the adult male rat and that progesterone can ameliorate the injury-induced deficits. PMID- 24489883 TI - On the characterization of intermediates in the isodesmic aggregation pathway of hen lysozyme at alkaline pH. AB - Protein aggregation leading to formation of amyloid fibrils is a symptom of several diseases like Alzheimer's, type 2 diabetes and so on. Elucidating the poorly understood mechanism of such phenomena entails the difficult task of characterizing the species involved at each of the multiple steps in the aggregation pathway. It was previously shown by us that spontaneous aggregation of hen-eggwhite lysozyme (HEWL) at room temperature in pH 12.2 is a good model to study aggregation. Here in this paper we investigate the growth kinetics, structure, function and dynamics of multiple intermediate species populating the aggregation pathway of HEWL at pH 12.2. The different intermediates were isolated by varying the HEWL monomer concentration in the 300 nM-0.12 mM range. The intermediates were characterized using techniques like steady-state and nanosecond time-resolved fluorescence, atomic force microscopy and dynamic light scattering. Growth kinetics of non-fibrillar HEWL aggregates were fitted to the von Bertalanffy equation to yield a HEWL concentration independent rate constant (k = (6.6 +/- 0.6) * 10(-5) s(-1)). Our results reveal stepwise changes in size, molecular packing and enzymatic activity among growing HEWL aggregates consistent with an isodesmic aggregation model. Formation of disulphide bonds that crosslink the monomers in the aggregate appear as a unique feature of this aggregation. AFM images of multiple amyloid fibrils emanating radially from amorphous aggregates directly confirmed that on-pathway fibril formation was feasible under isodesmic polymerization. The isolated HEWL aggregates are revealed as polycationic protein nanoparticles that are robust at neutral pH with ability to take up non-polar molecules like ANS. PMID- 24489885 TI - Combining telephone surveys and fishing catches self-report: the French sea bass recreational fishery assessment. AB - Fisheries statistics are known to be underestimated, since they are mainly based on information about commercial fisheries. However, various types of fishing activities exist and evaluating them is necessary for implementing effective management plans. This paper assesses the characteristics and catches of the French European sea bass recreational fishery along the Atlantic coasts, through the combination of large-scale telephone surveys and fishing diaries study. Our results demonstrated that half of the total catches (mainly small fish) were released at sea and that the mean length of a kept sea bass was 46.6 cm. We highlighted different patterns of fishing methods and type of gear used. Catches from boats were greater than from the shore, both in abundance and biomass, considering mean values per fishing trip as well as CPUE. Spearfishers caught the highest biomass of sea bass per fishing trip, but the fishing rod with lure was the most effective type of gear in terms of CPUE. Longlines had the highest CPUE value in abundance but not in biomass: they caught numerous but small sea bass. Handlines were less effective, catching few sea bass in both abundance and biomass. We estimated that the annual total recreational sea bass catches was 3,173 tonnes of which 2,345 tonnes were kept. Since the annual commercial catches landings were evaluated at 5,160 tonnes, recreational landings represent 30% of the total fishing catches on the Atlantic coasts of France. Using fishers' self reports was a valuable way to obtain new information on data-poor fisheries. Our results underline the importance of evaluating recreational fishing as a part of the total amount of fisheries catches. More studies are critically needed to assess overall fish resources caught in order to develop effective fishery management tools. PMID- 24489884 TI - Genome-wide association study of proneness to anger. AB - BACKGROUND: Community samples suggest that approximately 1 in 20 children and adults exhibit clinically significant anger, hostility, and aggression. Individuals with dysregulated emotional control have a greater lifetime burden of psychiatric morbidity, severe impairment in role functioning, and premature mortality due to cardiovascular disease. METHODS: With publically available data secured from dbGaP, we conducted a genome-wide association study of proneness to anger using the Spielberger State-Trait Anger Scale in the Atherosclerosis Risk in Communities (ARIC) study (n = 8,747). RESULTS: Subjects were, on average, 54 (range 45-64) years old at baseline enrollment, 47% (n = 4,117) were male, and all were of European descent by self-report. The mean Angry Temperament and Angry Reaction scores were 5.8 +/- 1.8 and 7.6 +/- 2.2. We observed a nominally significant finding (p = 2.9E-08, lambda = 1.027 - corrected pgc = 2.2E-07, lambda = 1.0015) on chromosome 6q21 in the gene coding for the non-receptor protein-tyrosine kinase, Fyn. CONCLUSIONS: Fyn interacts with NDMA receptors and inositol-1,4,5-trisphosphate (IP3)-gated channels to regulate calcium influx and intracellular release in the post-synaptic density. These results suggest that signaling pathways regulating intracellular calcium homeostasis, which are relevant to memory, learning, and neuronal survival, may in part underlie the expression of Angry Temperament. PMID- 24489886 TI - The empirical analysis of cigarette tax avoidance and illicit trade in Vietnam, 1998-2010. AB - Illicit trade carries the potential to magnify existing tobacco-related health care costs through increased availability of untaxed and inexpensive cigarettes. What is known with respect to the magnitude of illicit trade for Vietnam is produced primarily by the industry, and methodologies are typically opaque. Independent assessment of the illicit cigarette trade in Vietnam is vital to tobacco control policy. This paper measures the magnitude of illicit cigarette trade for Vietnam between 1998 and 2010 using two methods, discrepancies between legitimate domestic cigarette sales and domestic tobacco consumption estimated from surveys, and trade discrepancies as recorded by Vietnam and trade partners. The results indicate that Vietnam likely experienced net smuggling in during the period studied. With the inclusion of adjustments for survey respondent under reporting, inward illicit trade likely occurred in three of the four years for which surveys were available. Discrepancies in trade records indicate that the value of smuggled cigarettes into Vietnam ranges from $100 million to $300 million between 2000 and 2010 and that these cigarettes primarily originate in Singapore, Hong Kong, Macao, Malaysia, and Australia. Notable differences in trends over time exist between the two methods, but by comparison, the industry estimates consistently place the magnitude of illicit trade at the upper bounds of what this study shows. The unavailability of annual, survey-based estimates of consumption may obscure the true, annual trend over time. Second, as surveys changed over time, estimates relying on them may be inconsistent with one another. Finally, these two methods measure different components of illicit trade, specifically consumption of illicit cigarettes regardless of origin and smuggling of cigarettes into a particular market. However, absent a gold standard, comparisons of different approaches to illicit trade measurement serve efforts to refine and improve measurement approaches and estimates. PMID- 24489887 TI - A conversion formula for comparing pulse oximeter desaturation rates obtained with different averaging times. AB - OBJECTIVE: The number of desaturations determined in recordings of pulse oximeter saturation (SpO2) primarily depends on the time over which values are averaged. As the averaging time in pulse oximeters is not standardized, it varies considerably between centers. To make SpO2 data comparable, it is thus desirable to have a formula that allows conversion between desaturation rates obtained using different averaging times for various desaturation levels and minimal durations. METHODS: Oxygen saturation was measured for 170 hours in 12 preterm infants with a mean number of 65 desaturations <90% per hour of arbitrary duration by using a pulse oximeter in a 2-4 s averaging mode. Using 7 different averaging times between 3 and 16 seconds, the raw red-to-infrared data were reprocessed to determine the number of desaturations (D). The whole procedure was carried out for 7 different minimal desaturation durations (>= 1, >= 5, >= 10, >= 15, >= 20, >= 25, >= 30 s) below SpO2 threshold values of 80%, 85% or 90% to finally reach a conversion formula. The formula was validated by splitting the infants into two groups of six children each and using one group each as a training set and the other one as a test set. RESULTS: Based on the linear relationship found between the logarithm of the desaturation rate and the logarithm of the averaging time, the conversion formula is: D2 = D1 (T2/T1)(c), where D2 is the desaturation rate for the desired averaging time T2, and D1 is the desaturation rate for the original averaging time T1, with the exponent c depending on the desaturation threshold and the minimal desaturation duration. The median error when applying this formula was 2.6%. CONCLUSION: This formula enables the conversion of desaturation rates between different averaging times for various desaturation thresholds and minimal desaturation durations. PMID- 24489888 TI - Glioma cell proliferation controlled by ERK activity-dependent surface expression of PDGFRA. AB - Increased PDGFRA signaling is an essential pathogenic factor in many subtypes of gliomas. In this context the cell surface expression of PDGFRA is an important determinant of ligand sensing in the glioma microenvironment. However, the regulation of spatial distribution of PDGFRA in glioma cells remains poorly characterized. Here, we report that cell surface PDGFRA expression in gliomas is negatively regulated by an ERK-dependent mechanism, resulting in reduced proliferation of glioma cells. Glioma tumor tissues and their corresponding cell lines were isolated from 14 patients and analyzed by single-cell imaging and flow cytometry. In both cell lines and their corresponding tumor samples, glioma cell proliferation correlated with the extent of surface expression of PDGFRA. High levels of surface PDGFRA also correlated to high tubulin expression in glioma tumor tissue in vivo. In glioma cell lines, surface PDGFRA declined following treatment with inhibitors of tubulin, actin and dynamin. Screening of a panel of small molecule compounds identified the MEK inhibitor U0126 as a potent inhibitor of surface PDGFRA expression. Importantly, U0126 inhibited surface expression in a reversible, dose- and time-dependent manner, without affecting general PDGFRA expression. Treatment with U0126 resulted in reduced co-localization between PDGFRA and intracellular trafficking molecules e.g. clathrin, RAB11 and early endosomal antigen-1, in parallel with enhanced co-localization between PDGFRA and the Golgi cisternae maker, Giantin, suggesting a deviation of PDGFRA from the endosomal trafficking and recycling compartment, to the Golgi network. Furthermore, U0126 treatment in glioma cells induced an initial inhibition of ERK1/2 phosphorylation, followed by up-regulated ERK1/2 phosphorylation concomitant with diminished surface expression of PDGFRA. Finally, down regulation of surface PDGFRA expression by U0126 is concordant with reduced glioma cell proliferation. These findings suggest that manipulation of spatial expression of PDGFRA can potentially be used to combat gliomas. PMID- 24489890 TI - Alternatives to conventional evaluation of rideability in horse performance tests: suitability of rein tension and behavioural parameters. AB - Rideability, i.e. the ease and comfort with which a horse can be ridden, is considered to be one of the most important traits in riding horses. However, at present rideability is evaluated rather subjectively in breeding horse performance tests. The aim of the present study was to evaluate the role horse behaviour as well as degree and quality of rein tension might play in judges' evaluation of horses' rideability. Mares (n=33) and stallions (n=13) from two different mare- and one stallion-testing station were observed twice during their performance test dressage training. During these rides, rein tension was measured continuously, and frequency of behaviour patterns such as head-tossing, tail swishing, and snorting was recorded. Rein tension parameters showed reasonable repeatabilities within horse-rider pairs (e.g. mean rein tension: r(2)=0.61 +/- 0.11; variance of rein tension: r(2)=0.52 +/- 0.14). Regression analysis revealed that a larger proportion of variance in rideability scores could be explained by maximum (17%), mean (16%) and variance (15%) of rein tension compared to horses' or riders' behavioural parameters (tail-swishing: 5% and rider's use of hands: 5%, respectively). According to mixed model analysis, rideability scores dropped (all P<0.05) with increasing mean, maximum and variability in rein tension (e.g. 0.37 +/- 0.14 scores per additional 10 Newton in mean tension). However, mean rein tension differed between testing stations (P<0.0001) ranging between 9.1 +/- 1.6 N in one station and 21.7 +/- 1.3 N in another station. These results indicate that quantity and consistency of rein tension is either directly or indirectly an important factor for judges to derive rideability scores. Given the importance of rein tension parameters to both rider comfort and horse welfare, potentially, measurements of rein tension along with behaviour observations assessing the quality of rein contact (e.g. distinguishing a light contact from attempts to evade contact) might be used to make the assessment of rideability more impartial. PMID- 24489889 TI - Genome-wide identification and characterization of RBR ubiquitin ligase genes in soybean. AB - RBR (RING1-IBR-RING2) proteins play an important role in protein ubiquitination and are involved in many cellular processes. Recent studies showed plant RBR genes were induced by abiotic and biotic stresses. However, detailed studies on RBR genes in the important oil crop, soybean (Glycine max (L.) Merr.), is still lacking. Here we performed a genome-wide search and identified 24 RBR domain containing genes from the soybean genome sequence and cloned 11 of them. Most soybean RBR proteins contain a highly conserved RBR supra-domain. Phylogenetic analyses indicated all 24 soybean RBR proteins are most related to the RBR proteins from Phaseolus vulgaris, and could be classified into seven groups including Ariadne A, Ariadne B, ARA54, Plant IIA, Plant IIB, Plant IIC, and Helicase. Tandem duplication and block duplication were found among the Ariadne B and Plant IIC group of soybean RBR genes. Despite the conserved RBR supra-domain, there are extensive variations in the additional protein motifs and exon-intron structures between different groups, which indicate they might have diverse functions. Most soybean RBR proteins are predicted to localize in nucleus, and four of them were experimentally confirmed by GFP fusion proteins. Soybean RBR genes are broadly expressed in many tissue types with a little more abundant in the roots and flowers than leaves, stems, and seeds. The expression of GmRTRTP3 (Plant IIB) and GmRTRTP5 (Plant IIC) are induced by NaCl treatment, which suggests these RBR genes might be involved in soybean response to abiotic stresses. PMID- 24489891 TI - The feeding tube of cyst nematodes: characterisation of protein exclusion. AB - Plant parasitic nematodes comprise several groups; the most economically damaging of these are the sedentary endoparasites. Sedentary endoparasitic nematodes are obligate biotrophs and modify host root tissue, using a suite of effector proteins, to create a feeding site that is their sole source of nutrition. They feed by withdrawing host cell assimilate from the feeding site though a structure known as the feeding tube. The function, composition and molecular characteristics of feeding tubes are poorly characterised. It is hypothesised that the feeding tube facilitates uptake of host cell assimilate by acting as a molecular sieve. Several studies, using molecular mass as the sole indicator of protein size, have given contradictory results about the exclusion limits of the cyst nematode feeding tube. In this study we propose a method to predict protein size, based on protein database coordinates in silico. We tested the validity of these predictions using travelling wave ion mobility spectrometry--mass spectrometry, where predictions and measured values were within approximately 6%. We used the predictions, coupled with mass spectrometry, analytical ultracentrifugation and protein electrophoresis, to resolve previous conflicts and define the exclusion characteristics of the cyst nematode feeding tube. Heterogeneity was tested in the liquid, solid and gas phase to provide a comprehensive evaluation of three proteins of particular interest to feeding tube size exclusion, GFP, mRFP and Dual PI. The data and procedures described here could be applied to the design of plant expressed defence compounds intended for uptake into cyst nematodes. We also highlight the need to assess protein heterogeneity when creating novel fusion proteins. PMID- 24489892 TI - Comparative analysis reveals distinct and overlapping functions of Mef2c and Mef2d during cardiogenesis in Xenopus laevis. AB - The family of vertebrate Mef2 transcription factors is comprised of four members named Mef2a, Mef2b, Mef2c, and Mef2d. These transcription factors are regulators of the myogenic programs with crucial roles in development of skeletal, cardiac and smooth muscle cells. Mef2a and Mef2c are essential for cardiac development in mice. In Xenopus, mef2c and mef2d but not mef2a were recently shown to be expressed during cardiogenesis. We here investigated the function of Mef2c and Mef2d during Xenopus laevis cardiogenesis. Knocking down either gene by corresponding antisense morpholino oligonucleotides led to profound heart defects including morphological abnormalities, pericardial edema, and brachycardia. Marker gene expression analyses and rescue experiments revealed that (i) both genes are required for proper cardiac gene expression, (ii) Mef2d can compensate for the loss of Mef2c but not vice versa, and (iii) the gamma domain of Mef2c is required for early cardiac development. Taken together, our data provide novel insights into the function of Mef2 during cardiogenesis, highlight evolutionary differences between species and might have an impact on attempts of direct reprogramming. PMID- 24489893 TI - A Ser252Trp mutation in fibroblast growth factor receptor 2 (FGFR2) mimicking human Apert syndrome reveals an essential role for FGF signaling in the regulation of endochondral bone formation. AB - A S252W mutation of fibroblast growth factor receptor 2 (FGFR2), which is responsible for nearly two-thirds of Apert syndrome (AS) cases, causes retarded development of the skeleton and skull malformation resulting from premature fusion of the craniofacial sutures. We utilized a Fgfr2(+/S252W) mouse (a knock in mouse model mimicking human AS) to demonstrate decreased bone mass due to reduced trabecular bone volume, reduced bone mineral density, and shortened growth plates in the long bones. In vitro bone mesenchymal stem cells (BMSCs) culture studies revealed that the mutant mice showed reduced BMSC proliferation, a reduction in chondrogenic differentiation, and reduced mineralization. Our results suggest that these phenomena are caused by up-regulation of p38 and Erk1/2 phosphorylation. Treatment of cultured mutant bone rudiments with SB203580 or PD98059 resulted in partial rescue of the bone growth retardation. The p38 signaling pathway especially was found to be responsible for the retarded long bone development. Our data indicate that the S252W mutation in FGFR2 directly affects endochondral ossification, resulting in growth retardation of the long bone. We also show that the p38 and Erk1/2 signaling pathways partially mediate the effects of the S252W mutation of FGFR2 on long bone development. PMID- 24489894 TI - Aurin tricarboxylic acid protects against red blood cell hemolysis in patients with paroxysmal nocturnal hemoglobinemia. AB - OBJECTIVES: Paroxysmal nocturnal hemoglobinemia (PNH) is a rare but serious condition characterized by complement-mediated red blood cell (RBC) hemolysis and episodic thrombotic attack. It results from decay accelerating factor (CD55), and protectin (CD59), becoming attached to RBC and other cell surfaces. Absence of these protective proteins leaves such cells vulnerable to self attack at the C3 convertase and membrane attack complex (MAC) stages of complement activation. We have previously reported that aurin tricarboxylic acid (ATA) is an orally effective agent that selectively blocks complement activation at the C3 convertase stage as well as MAC formation at the C9 insertion stage. DESIGN AND METHODS: We used a CH50 assay method and western blot analysis to investigate the vulnerability to complement attack of PNH RBCs compared with normal RBCs. Zymosan was used as the activator of normal serum and PNH serum. ATA was added to the sera to determine the concentration necessary to protect the RBCs from lysis by the zymosan-activated sera. RESULTS: We found that erythrocytes from PNH patients on long term treatment with eculizumab were twice as vulnerable as normal erythrocytes to lysis induced by complement activated serum. Western blot data showed the presence of both C3 and C5 convertases on the PNH patient erythrocyte membranes. These data indicate persistent vulnerability of PNH erythrocytes to complement attack due to deficiencies in CD55 and CD59. ATA, when added to serum in vitro, protected PNH erythrocytes from complement attack, restoring their resistance to that of normal erythrocytes. CONCLUSIONS: We conclude that ATA, by protecting PNH erythrocytes from their decay accelerating factor (CD55) and protectin (CD59) deficiencies, may be an effective oral treatment in this disorder. PMID- 24489895 TI - Productively infected murine Kaposi's sarcoma-like tumors define new animal models for studying and targeting KSHV oncogenesis and replication. AB - Kaposi's sarcoma (KS) is an AIDS-defining cancer caused by the KS-associated herpesvirus (KSHV). KS tumors are composed of KSHV-infected spindle cells of vascular origin with aberrant neovascularization and erythrocyte extravasation. KSHV genes expressed during both latent and lytic replicative cycles play important roles in viral oncogenesis. Animal models able to recapitulate both viral and host biological characteristics of KS are needed to elucidate oncogenic mechanisms, for developing targeted therapies, and to trace cellular components of KS ontogeny. Herein, we describe two new murine models of Kaposi's sarcoma. We found that murine bone marrow-derived cells, whether established in culture or isolated from fresh murine bone marrow, were infectable with rKSHV.219, formed KS like tumors in immunocompromised mice and produced mature herpesvirus-like virions in vivo. Further, we show in vivo that the histone deacetylase (HDAC) inhibitor suberoylanilide hydroxamic acid (SAHA/Vorinostat) enhanced viral lytic reactivation. We propose that these novel models are ideal for studying both viral and host contributions to KSHV-induced oncogenesis as well as for testing virally-targeted antitumor strategies for the treatment of Kaposi's sarcoma. Furthermore, our isolation of bone marrow-derived cell populations containing a cell type that, when infected with KSHV, renders a tumorigenic KS-like spindle cell, should facilitate systematic identification of KS progenitor cells. PMID- 24489896 TI - Design and optimization of PLGA-based diclofenac loaded nanoparticles. AB - Drug based nanoparticle (NP) formulations have gained considerable attention over the past decade for their use in various drug formulations. NPs have been shown to increase bioavailability, decrease side effects of highly toxic drugs, and prolong drug release. Nonsteroidal anti-inflammatory drugs such as diclofenac block cyclooxygenase expression and reduce prostaglandin synthesis, which can lead to several side effects such as gastrointestinal bleeding and renal insufficiency. The aim of this study was to formulate and characterize diclofenac entrapped poly(lactide-co-glycolide) (PLGA) based nanoparticles. Nanoparticles were formulated using an emulsion-diffusion-evaporation technique with varying concentrations of poly vinyl alcohol (PVA) (0.1, 0.25, 0.5, or 1%) or didodecyldimethylammonium bromide (DMAB) (0.1, 0.25, 0.5, 0.75, or 1%) stabilizers centrifuged at 8,800 rpm or 12,000 rpm. The resultant nanoparticles were evaluated based on particle size, zeta potential, and entrapment efficacy. DMAB formulated NPs showed the lowest particle size (108 +/- 2.1 nm) and highest zeta potential (-27.71 +/- 0.6 mV) at 0.1 and 0.25% respectively, after centrifugation at 12,000 rpm. Results of the PVA based NP formulation showed the smallest particle size (92.4 +/- 7.6 nm) and highest zeta potential (-11.14 +/- 0.5 mV) at 0.25% and 1% w/v, respectively, after centrifugation at 12,000 rpm. Drug entrapment reached 77.3 +/- 3.5% and 80.2 +/- 1.2% efficiency with DMAB and PVA formulations, respectively. The results of our study indicate the use of DMAB for increased nanoparticle stability during formulation. Our study supports the effective utilization of PLGA based nanoparticle formulation for diclofenac. PMID- 24489897 TI - Whole-genome quantitative trait locus mapping reveals major role of epistasis on yield of rice. AB - Although rice yield has been doubled in most parts of the world since 1960s, thanks to the advancements in breeding technologies, the biological mechanisms controlling yield are largely unknown. To understand the genetic basis of rice yield, a number of quantitative trait locus (QTL) mapping studies have been carried out, but whole-genome QTL mapping incorporating all interaction effects is still lacking. In this paper, we exploited whole-genome markers of an immortalized F2 population derived from an elite rice hybrid to perform QTL mapping for rice yield characterized by yield per plant and three yield component traits. Our QTL model includes additive and dominance main effects of 1,619 markers and all pair-wise interactions, with a total of more than 5 million possible effects. The QTL mapping identified 54, 5, 28 and 4 significant effects involving 103, 9, 52 and 7 QTLs for the four traits, namely the number of panicles per plant, the number of grains per panicle, grain weight, and yield per plant. Most identified QTLs are involved in digenic interactions. An extensive literature survey of experimentally characterized genes related to crop yield shows that 19 of 54 effects, 4 of 5 effects, 12 of 28 effects and 2 of 4 effects for the four traits, respectively, involve at least one QTL that locates within 2 cM distance to at least one yield-related gene. This study not only reveals the major role of epistasis influencing rice yield, but also provides a set of candidate genetic loci for further experimental investigation. PMID- 24489898 TI - Quantitative assessment of common genetic variants on FOXE1 and differentiated thyroid cancer risk. AB - Forkhead box E1 encodes the transcription factor FOXE1 (or TTF-2), which together with Homeobox protein NKX2-1, PAX8 and HHEX, are pivotal proteins required for thyroid gland formation, differentiation and function. Recently, genome-wide association studies have identified FOXE1 as a thyroid cancer (TC) susceptibility gene in populations of European descent. After that, a number of studies reported that the rs965513, rs1867277, and rs71369530 polymorphism in FOXE1 has been implicated in TC risk. However, the causal variants remain unknown. To derive a more precise estimation of the relationship, a meta-analysis of 9,828 TC cases and 109,995 controls from 14 case-control studies was performed. Overall, significant results were observed for rs965513 (OR=1.71, 95% CI: 1.59-1.85, P<10( 5)), rs1867277 (OR=1.64, 95% CI: 1.51-1.78, P<10(-5)) and rs71369530 (OR=2.01, 95% CI: 1.66-2.44, P<10(-5)) polymorphism. In the subgroup analysis by ethnicity, we found that rs965513 polymorphism confer high risk for Caucasians with per allele OR of 1.80 (95% CI: 1.69-1.92, P<10(-5)) compared to East Asians of 1.35 (95% CI: 1.09-1.67, P=0.006). There was strong evidence of heterogeneity, which largely disappeared after stratification by ethnicity. In the subgroup analysis by sample size, and study design, significantly increased risks were found for the polymorphism. In conclusion, this meta-analysis demonstrated that common variations of FOXE1 are a risk factor associated with increased TC susceptibility. PMID- 24489899 TI - The incidence and types of medication errors in patients receiving antiretroviral therapy in resource-constrained settings. AB - PURPOSE: This study assessed the incidence and types of medication errors, interventions and outcomes in patients on antiretroviral therapy (ART) in selected HIV treatment centres in Nigeria. METHODS: Of 69 health facilities that had program for active screening of medication errors, 14 were randomly selected for prospective cohort assessment. All patients who filled/refilled their antiretroviral medications between February 2009 and March 2011 were screened for medication errors using study-specific pharmaceutical care daily worksheet (PCDW). All potential or actual medication errors identified, interventions provided and the outcomes were documented in the PCDW. Interventions included pharmaceutical care in HIV training for pharmacists amongst others. Chi-square was used for inferential statistics and P<0.05 indicated statistical significance. RESULTS: Of 6,882 participants, 67.0% were female and 93.5% were aged >= 15 years old. The participants had 110,070 medications filling/refilling visits, average (+/- SD) of 16.0 (+/- 0.3) visits per patient over the observation period. Patients were followed up for 9172.5 person-years. The number of drug items dispensed to participants was 305,584, average of 2.8 (+/- 0.1) drug items per patient. The incidence rate of medication errors was 40.5 per 100 person-years. The occurrence of medication errors was not associated with participants' sex and age (P>0.05). The major medications errors identified were 26.4% incorrect ART regimens prescribed; 19.8% potential drug-drug interaction or contraindication present; and 16.6% duration and/or frequency of medication inappropriate. Interventions provided included 67.1% cases of prescriber contacted to clarify/resolve errors and 14.7% cases of patient counselling and education; 97.4% of potential/actual medication error(s) were resolved. CONCLUSION: The incidence rate of medication errors was somewhat high; and majority of identified errors were related to prescription of incorrect ART regimens and potential drug-drug interactions; the prescriber was contacted and the errors were resolved in majority of cases. Active screening for medication errors is feasible in resource-limited settings following a capacity building intervention. PMID- 24489900 TI - Characterisation of host growth after infection with a broad-range freshwater cyanopodophage. AB - Freshwater cyanophages are poorly characterised in comparison to their marine counterparts, however, the level of genetic diversity that exists in freshwater cyanophage communities is likely to exceed that found in marine environments, due to the habitat heterogeneity within freshwater systems. Many cyanophages are specialists, infecting a single host species or strain; however, some are less fastidious and infect a number of different host genotypes within the same species or even hosts from different genera. Few instances of host growth characterisation after infection by broad host-range phages have been described. Here we provide an initial characterisation of interactions between a cyanophage isolated from a freshwater fishing lake in the south of England and its hosts. Designated PhiMHI42, the phage is able to infect isolates from two genera of freshwater cyanobacteria, Planktothrix and Microcystis. Transmission Electron Microscopy and Atomic Force Microscopy indicate that PhiMHI42 is a member of the Podoviridae, albeit with a larger than expected capsid. The kinetics of host growth after infection with PhiMHI42 differed across host genera, species and strains in a way that was not related to the growth rate of the uninfected host. To our knowledge, this is the first characterisation of the growth of cyanobacteria in the presence of a broad host-range freshwater cyanophage. PMID- 24489902 TI - Combining epidemiologic and biostatistical tools to enhance variable selection in HIV cohort analyses. AB - BACKGROUND: Variable selection is an important step in building a multivariate regression model for which several methods and statistical packages are available. A comprehensive approach for variable selection in complex multivariate regression analyses within HIV cohorts is explored by utilizing both epidemiological and biostatistical procedures. METHODS: Three different methods for variable selection were illustrated in a study comparing survival time between subjects in the Department of Defense's National History Study and the Atlanta Veterans Affairs Medical Center's HIV Atlanta VA Cohort Study. The first two methods were stepwise selection procedures, based either on significance tests (Score test), or on information theory (Akaike Information Criterion), while the third method employed a Bayesian argument (Bayesian Model Averaging). RESULTS: All three methods resulted in a similar parsimonious survival model. Three of the covariates previously used in the multivariate model were not included in the final model suggested by the three approaches. When comparing the parsimonious model to the previously published model, there was evidence of less variance in the main survival estimates. CONCLUSIONS: The variable selection approaches considered in this study allowed building a model based on significance tests, on an information criterion, and on averaging models using their posterior probabilities. A parsimonious model that balanced these three approaches was found to provide a better fit than the previously reported model. PMID- 24489901 TI - Roles of PPARgamma/NF-kappaB signaling pathway in the pathogenesis of intrahepatic cholestasis of pregnancy. AB - BACKGROUND: Intrahepatic cholestasis of pregnancy (ICP) is the most prevalent pregnancy specific liver disease. However, the pathogenesis and etiology of ICP is poorly understood. AIM: To assess the expression of peroxisome proliferator activated receptorgamma (PPARgamma) and nuclear factor kappa B (NF-kappaB) in placenta and HTR-8/SVneo cell, and evaluate the serum levels of cytokines, bile acids, hepatic function and lipids in control and ICP patients and the fetal outcome, in order to explore the role of PPARgamma/NF-kappaB signaling pathway in the possible mechanism of ICP. METHODS: Clinical data of the pregnant women were collected and serum levels of cytokines, bile acids, hepatic function and lipids were measured. Expressions of PPARgamma and NF-kappaB in placenta and HTR-8/SVneo cell were determined. The new-born information was collected to demonstrate the relationship between PPARgamma/NF-kappaB signaling pathway and ICP. RESULTS: The serum levels of bile acids, hepatic function, triglycerides (TG), total cholesterol (TC), IL-6, IL-12 and TNF-alpha in ICP group were significantly increased (P<0.01), and serum level of IL-4 was significantly decreased (P<0.01). PPARgamma and NF-kappaB staining were found in the membrane and cytoplasm of placental trophoblast cell. The expression of PPARgamma and NF-kappaB were significantly higher in ICP group and taurocholate acid (TCA) treated HTR-8/SVneo cell (P<0.01). The new-born information in severe ICP group were significantly different as compared to that in control group (P<0.05), and part of information in mild ICP group were also difference to that in control group (P<0.05). CONCLUSIONS: The higher expressions of PPARgamma and NF-kappaB in ICP placenta and TCA treated HTR-8/SVneo cell, together with the abnormal serum levels of cytokines, might induced by the imbalance of inflammatory and immune reaction, and then disturb placental bile acid and serum lipids transportation, finally result in fatal cholestasis which probably be one of the mechanism of ICP. PMID- 24489903 TI - Coexistence of low coral cover and high fish biomass at Farquhar Atoll, Seychelles. AB - We report a reef ecosystem where corals may have lost their role as major reef engineering species but fish biomass and assemblage structure is comparable to unfished reefs elsewhere around the world. This scenario is based on an extensive assessment of the coral reefs of Farquhar Atoll, the most southern of the Seychelles Islands. Coral cover and overall benthic community condition at Farquhar was poor, likely due to a combination of limited habitat, localized upwelling, past coral bleaching, and cyclones. Farquhar Atoll harbors a relatively intact reef fish assemblage with very large biomass (3.2 t ha(-1)) reflecting natural ecological processes that are not influenced by fishing or other local anthropogenic factors. The most striking feature of the reef fish assemblage is the dominance by large groupers, snappers, and jacks with large (>1 m) potato cod (Epinephelus tukula) and marbled grouper (E. polyphekadion), commonly observed at many locations. Napoleon wrasse (Cheilinus undulatus) and bumphead parrotfish (Bolbometopon muricatum) are listed as endangered and vulnerable, respectively, but were frequently encountered at Farquhar. The high abundance and large sizes of parrotfishes at Farquhar also appears to regulate macroalgal abundance and enhance the dominance of crustose corallines, which are a necessary condition for maintenance of healthy reef communities. Overall fish biomass and biomass of large predators at Farquhar are substantially higher than other areas within the Seychelles, and are some of the highest recorded in the Indian Ocean. Remote islands like Farquhar Atoll with low human populations and limited fishing pressure offer ideal opportunities for understanding whether reefs can be resilient from global threats if local threats are minimized. PMID- 24489904 TI - Chronic oxidative stress increases growth and tumorigenic potential of MCF-7 breast cancer cells. AB - Accumulating evidence suggests that exposures to elevated levels of either endogenous estrogen or environmental estrogenic chemicals are associated with breast cancer development and progression. These natural or synthetic estrogens are known to produce reactive oxygen species (ROS) and increased ROS has been implicated in both cellular apoptosis and carcinogenesis. Though there are several studies on direct involvement of ROS in cellular apoptosis using short term exposure model, there is no experimental evidence to directly implicate chronic exposure to ROS in increased growth and tumorigenicity of breast cancer cells. Therefore, the objective of this study was to evaluate the effects of chronic oxidative stress on growth, survival and tumorigenic potential of MCF-7 breast cancer cells. MCF-7 cells were exposed to exogenous hydrogen peroxide (H2O2) as a source of ROS at doses of 25 uM and 250 uM for acute (24 hours) and chronic period (3 months) and their effects on cell growth/survival and tumorigenic potential were evaluated. The results of cell count, MTT and cell cycle analysis showed that while acute exposure inhibits the growth of MCF-7 cells in a dose-dependent manner, the chronic exposure to H2O2-induced ROS leads to increased cell growth and survival of MCF-7 cells. This was further confirmed by gene expression analysis of cell cycle and cell survival related genes. Significant increase in number of soft agar colonies, up-regulation of pro metastatic genes VEGF, WNT1 and CD44, whereas down-regulation of anti-metastatic gene E-Cadherin in H2O2 treated MCF-7 cells observed in this study further suggests that persistent exposure to oxidative stress increases tumorigenic and metastatic potential of MCF-7 cells. Since many chemotherapeutic drugs are known to induce their cytotoxicity by increasing ROS levels, the results of this study are also highly significant in understanding the mechanism for adaptation to ROS induced toxicity leading to acquired chemotherapeutic resistance in breast cancer cells. PMID- 24489905 TI - Sunscreen for fish: co-option of UV light protection for camouflage. AB - Many animals change their body pigmentation according to illumination of their environment. In aquatic vertebrates, this reaction is mediated through aggregation or dispersion of melanin-filled vesicles (melanosomes) in dermal pigment cells (melanophores). The adaptive value of this behavior is usually seen in camouflage by allowing the animal to visually blend into the background. When exposed to visible light from below, however, dark-adapted zebrafish embryos at the age of 2 days post fertilization (dpf) surprisingly display dispersal instead of aggregation of melanosomes, i.e. their body coloration becomes dark on a bright background. Melanosomes of older embryos and early larvae (3-5 dpf) on the other hand aggregate as expected under these conditions. Here we provide an explanation to this puzzling finding: Melanosome dispersion in larvae 3 dpf and older is efficiently triggered by ultraviolet (UV) light, irrespective of the visual background, suggesting that the extent of pigmentation is a trade-off between threats from predation and UV irradiation. The UV light-induced dispersion of melanosomes thereby is dependent on input from retinal short wavelength-sensitive (SWS) cone photoreceptors. In young embryos still lacking a functional retina, protection from UV light predominates, and light triggers a dispersal of melanosomes via photoreceptors intrinsic to the melanophores, regardless of the actual UV content. In older embryos and early larvae with functional retinal photoreceptors in contrast, this light-induced dispersion is counteracted by a delayed aggregation in the absence of UV light. These data suggest that the primary function of melanosome dispersal has evolved as a protective adaption to prevent UV damage, which was only later co-opted for camouflage. PMID- 24489906 TI - Novel marker for the onset of frontotemporal dementia: early increase in activity dependent neuroprotective protein (ADNP) in the face of Tau mutation. AB - Tauopathy, a major pathology in Alzheimer's disease, is also found in ~50% of frontotemporal dementias (FTDs). Tau transcript, a product of a single gene, undergoes alternative splicing to yield 6 protein species, each with either 3 or 4 microtubule binding repeat domains (tau 3R or 4R, associated with dynamic and stable microtubules, respectively). While the healthy human brain shows a 1/1 ratio of tau 3R/4R, this ratio may be dramatically changed in the FTD brain. We have previously discovered that activity-dependent neuroprotective protein (ADNP) is essential for brain formation in the mouse, with ADNP+/- mice exhibiting tauopathy, age-driven neurodegeneration and behavioral deficits. Here, in transgenic mice overexpressing a mutated tau 4R species, in the cerebral cortex but not in the cerebellum, we showed significantly increased ADNP expression (~3 fold transcripts) in the cerebral cortex of young transgenic mice (~disease onset), but not in the cerebellum, as compared to control littermates. The transgene-age-related increased ADNP expression paralleled augmented dynamic tau 3R transcript level compared to control littermates. Blocking mutated tau 4R transgene expression resulted in normalization of ADNP and tau 3R expression. ADNP was previously shown to be a member of the SWItch/Sucrose NonFermentable (SWI/SNF) chromatin remodeling complex. Here, Brahma (Brm), a component of the SWI/SNF complex regulating alternative splicing, showed a similar developmental expression pattern to ADNP. Immunoprecipitations further suggested Brm-ADNP interaction coupled to ADNP - polypyrimidine tract-binding protein (PTB) associated splicing factor (PSF)-binding, with PSF being a direct regulator of tau transcript splicing. It should be noted that although we have shown a correlation between levels of ADNP and tau isoform expression three months of age, we are not presenting evidence of a direct link between the two. Future research into ADNP/tau relations is warranted. PMID- 24489907 TI - Rift Valley fever virus incorporates the 78 kDa glycoprotein into virions matured in mosquito C6/36 cells. AB - Rift Valley fever virus (RVFV), genus Phlebovirus, family Bunyaviridae is a zoonotic arthropod-borne virus able to transition between distant host species, causing potentially severe disease in humans and ruminants. Viral proteins are encoded by three genomic segments, with the medium M segment coding for four proteins: nonstructural NSm protein, two glycoproteins Gn and Gc and large 78 kDa glycoprotein (LGp) of unknown function. Goat anti-RVFV polyclonal antibody and mouse monoclonal antibody, generated against a polypeptide unique to the LGp within the RVFV proteome, detected this protein in gradient purified RVFV ZH501 virions harvested from mosquito C6/36 cells but not in virions harvested from the mammalian Vero E6 cells. The incorporation of LGp into the mosquito cell line - matured virions was confirmed by immune-electron microscopy. The LGp was incorporated into the virions immediately during the first passage in C6/36 cells of Vero E6 derived virus. Our data indicate that LGp is a structural protein in C6/36 mosquito cell generated virions. The protein may aid the transmission from the mosquitoes to the ruminant host, with a possible role in replication of RVFV in the mosquito host. To our knowledge, this is a first report of different protein composition between virions formed in insect C6/36 versus mammalian Vero E6 cells. PMID- 24489908 TI - Prenatal and childhood growth, and hospitalization for alcohol use disorders in adulthood: the Helsinki birth cohort study. AB - BACKGROUND: Small birth size - an indicator of a sub-optimal prenatal environment - and variation in growth after birth have been associated with non-communicable diseases in later life. We tested whether birth size or growth in childhood associated with the risk of hospital admission for alcohol use disorders (AUDs) from early to late adulthood. METHODS: The sample comprised 6544 men and 6050 women born between 1934 and 1944 in Helsinki, Finland. Data on anthropometric measures were extracted from medical records and diagnoses of AUD from the Finnish Hospital Discharge Register and Causes of Death Register covering a 40 year period from 1969 to 2008. RESULTS: Altogether 171 women (2.8%) and 657 men (10.0%) were diagnosed at a hospital with AUD. After adjusting for major confounders, shorter length at birth, shorter height up to two years of age, and lower weight at two years associated with hospitalization for AUD in women. In men, slower growth in height, particularly from 2 to 7 years, and slower weight gain from 7 to 11 years as well as shorter height and lower weight at 7 and 11 years associated with a diagnosis of AUD in men. CONCLUSIONS: Pre- and postnatal growth associates with the risk for AUD later in life differently in women than in men: the fetal period and infancy seem to be the sensitive periods for women, whereas those for men the occur from toddlerhood onwards. PMID- 24489909 TI - BOR-syndrome-associated Eya1 mutations lead to enhanced proteasomal degradation of Eya1 protein. AB - Mutations in the human EYA1 gene have been associated with several human diseases including branchio-oto (BO) and branchio-oto-renal (BOR) syndrome, as well as congenital cataracts and ocular anterior segment anomalies. BOR patients suffer from severe malformations of the ears, branchial arches and kidneys. The phenotype of Eya1-heterozygous mice resembles the symptoms of human patients suffering from BOR syndrome. The Eya1 gene encodes a multifunctional protein that acts as a protein tyrosine phosphatase and a transcriptional coactivator. It has been shown that Eya1 interacts with Six transcription factors, which are also required for nuclear translocation of the Eya1 protein. We investigated the effects of seven disease-causing Eya1 missense mutations on Eya1 protein function, in particular cellular localization, ability to interact with Six proteins, and protein stability. We show here that the BOR-associated Eya1 missense mutations S454P, L472R, and L550P lead to enhanced proteasomal degradation of the Eya1 protein in mammalian cells. Moreover, Six proteins lead to a significant stabilization of Eya1, which is caused by Six-mediated protection from proteasomal degradation. In case of the mutant L550P, loss of interaction with Six proteins leads to rapid protein degradation. Our observations suggest that protein destabilization constitutes a novel disease causing mechanism for Eya1. PMID- 24489910 TI - Snail contributes to the maintenance of stem cell-like phenotype cells in human pancreatic cancer. AB - Snail, a potent repressor of E-cadherin expression, plays a key role in epithelial-to-mesenchymal transition (EMT) in epithelial cancer. Recently, EMT and stemness programs are found linked together. In the current study, the expression of Snail and its contribution to cancer stem cell (CSC) marker expression, invasiveness, self-renewal, clonogenicity, and tumorigenicity of pancreatic cancer cells were studied. Our results showed that Snail was highly expressed in CSC(high) cell line Panc-1. Stable, short hairpin RNA (shRNA) mediated Snail knockdown decreased invasion in Panc-1 cells, in line with increased E-cadherin expression and its translocation from the nucleus to the membrane. Snail silencing in Panc-1 also inhibited CSC marker ALDH expression, together with decreased sphere and colony forming capacity, which was highly consistent with the expression of stem cell associated transcription factors like Sox2 and Oct4. In mouse xenograft models, knockdown of Snail led to a reduced number of tumor-bearing mice and a reduced average size of tumors, which had a stronger membrane staining of E-cadherin and lighter staining of Oct4. Collectively, these findings implicate Snail is required for the maintenance of stem cell-like phenotype in pancreatic cancer, and inhibition of Snail could be an efficient strategy to treat pancreatic cancer by targeting CSCs. PMID- 24489911 TI - Inhibition of the K+ channel K(Ca)3.1 reduces TGF-beta1-induced premature senescence, myofibroblast phenotype transition and proliferation of mesangial cells. AB - OBJECTIVE: K(Ca)3.1 channel participates in many important cellular functions. This study planned to investigate the potential involvement of K(Ca)3.1 channel in premature senescence, myofibroblast phenotype transition and proliferation of mesangial cells. METHODS & MATERIALS: Rat mesangial cells were cultured together with TGF-beta1 (2 ng/ml) and TGF-beta1 (2 ng/ml) + TRAM-34 (16 nM) separately for specified times from 0 min to 60 min. The cells without treatment served as controls. The location of K(Ca)3.1 channels in mesangial cells was determined with Confocal laser microscope, the cell cycle of mesangial cells was assessed with flow cytometry, the protein and mRNA expression of K(Ca)3.1, alpha-smooth muscle actin (alpha-SMA) and fibroblast-specific protein-1 (FSP-1) were detected with Western blot and RT-PCR. One-way analysis of variance (ANOVA) and Student Newman-Keuls-q test (SNK-q) were used to do statistical analysis. Statistical significance was considered at P<0.05. RESULTS: Kca3.1 channels were located in the cell membranes and/or in the cytoplasm of mesangial cells. The percentage of cells in G0-G1 phase and the expression of K(ca)3.1, alpha-SMA and FSP-1 were elevated under the induction of TGF-beta1 when compared to the control and decreased under the induction of TGF-beta1+TRAM-34 when compared to the TGF-beta1 induced (P<0.05 or P<0.01). CONCLUSION: Targeted disruption of K(Ca)3.1 inhibits TGF-beta1-induced premature aging, myofibroblast-like phenotype transdifferentiation and proliferation of mesangial cells. PMID- 24489912 TI - A low gastric pH mouse model to evaluate live attenuated bacterial vaccines. AB - The low pH of the stomach serves as a barrier to ingested microbes and must be overcome or bypassed when delivering live bacteria for vaccine or probiotic applications. Typically, the impact of stomach acidity on bacterial survival is evaluated in vitro, as there are no small animal models to evaluate these effects in vivo. To better understand the effect of this low pH barrier to live attenuated Salmonella vaccines, which are often very sensitive to low pH, we investigated the value of the histamine mouse model for this application. A low pH gastric compartment was transiently induced in mice by the injection of histamine. This resulted in a gastric compartment of approximately pH 1.5 that was capable of distinguishing between acid-sensitive and acid-resistant microbes. Survival of enteric microbes during gastric transit in this model directly correlated with their in vitro acid resistance. Because many Salmonella enterica serotype Typhi vaccine strains are sensitive to acid, we have been investigating systems to enhance the acid resistance of these bacteria. Using the histamine mouse model, we demonstrate that the in vivo survival of S. Typhi vaccine strains increased approximately 10-fold when they carried a sugar-inducible arginine decarboxylase system. We conclude that this model will be a useful for evaluating live bacterial preparations prior to clinical trials. PMID- 24489913 TI - Opportunity or orientation? Who uses urban parks and why. AB - There is growing recognition that interactions with nature provide many desirable human well-being outcomes, yet increasing urbanization is degrading the quality and quantity of nature experiences. Thus, it has become increasingly important to understand how and why urban dwellers interact with nature. Studies of urban green space use have largely focused on the availability and ease of access to green space, suggesting that greater opportunities to experience such space will lead to increased use. However, a growing literature emphasizes the potential for an individual's nature orientation to affect their interaction with green space. Here we measure the importance of both opportunity and orientation factors in explaining urban park use. An urban lifestyle survey was deployed across Brisbane, Australia in November 2012 to assess patterns of green space use. Participants (n=1479) were asked to provide information on demographics, private yard use, park visitations in the past week, and their orientation toward nature. About 60% of those surveyed had visited a park in the past week, and while this park user population had significantly greater nearby park coverage (within a 250 m radius; p=0.006), a much stronger determinant of visitation was their higher nature orientation (p<0.00001), suggesting that while both opportunity and orientation are important drivers for park visitation, nature orientation is the primary effect. Park users also spent significantly more time in their yards than non-park users (p<0.00001), suggesting that yard use does not necessarily compensate for lower park use. Park users with stronger nature orientation (i) spent more time in their yard, (ii) traveled further to green spaces, and (iii) made longer visits than park visitors with weaker nature orientation. Overall, our results suggest that measures to increase people's connection to nature could be more important than measures to increase urban green space availability if we want to encourage park visitation. PMID- 24489914 TI - Early-life exposure to benzo[a]pyrene increases mutant frequency in spermatogenic cells in adulthood. AB - Children are vulnerable to environmental mutagens, and the developing germline could also be affected. However, little is known about whether exposure to environmental mutagens in childhood will result in increased germline mutations in subsequent adult life. In the present study, male transgenic lacI mice at different ages (7, 25 and 60 days old) were treated with a known environmental mutagen (benzo[a]pyrene, B[a]P) at different doses (0, 50, 200 or 300 mg/kg body weight). Mutant frequency was then determined in a meiotic cell type (pachytene spermatocyte), a post-meiotic cell type (round spermatid) and epididymal spermatozoa after at least one cycle of spermatogenesis. Our results show that 1) mice treated with B[a]P at 7 or 25 days old, both being pre-adult ages, had significantly increased mutant frequencies in all spermatogenic cell types tested when they were 60 days old; 2) spermatogenic cells from mice treated before puberty were more susceptible to B[a]P-associated mutagenesis compared to adult mice; and 3) unexpectedly, epididymal spermatozoa had the highest mutant frequency among the spermatogenic cell types tested. These data show that pre adult exposure to B[a]P increases the male germline mutant frequency in young adulthood. The data demonstrate that exposure to environmental genotoxins at different life phases (e.g., pre-adult and adult) can have differential effects on reproductive health. PMID- 24489915 TI - Mindfulness, acceptance and catastrophizing in chronic pain. AB - OBJECTIVES: Catastrophizing is often the primary target of the cognitive behavioral treatment of chronic pain. Recent literature on acceptance and commitment therapy (ACT) suggests an important role in the pain experience for the concepts mindfulness and acceptance. The aim of this study is to examine the influence of mindfulness and general psychological acceptance on pain-related catastrophizing in patients with chronic pain. METHODS: A cross-sectional survey was conducted, including 87 chronic pain patients from an academic outpatient pain center. RESULTS: The results show that general psychological acceptance (measured with the AAQ-II) is a strong predictor of pain-related catastrophizing, independent of gender, age and pain intensity. Mindfulness (measured with the MAAS) did not predict levels of pain-related catastrophizing. DISCUSSION: Acceptance of psychological experiences outside of pain itself is related to catastrophizing. Thus, acceptance seems to play a role in the pain experience and should be part of the treatment of chronic pain. The focus of the ACT treatment of chronic pain does not necessarily have to be on acceptance of pain per se, but may be aimed at acceptance of unwanted experiences in general. Mindfulness in the sense of "acting with awareness" is however not related to catastrophizing. Based on our research findings in comparisons with those of other authors, we recommend a broader conceptualization of mindfulness and the use of a multifaceted questionnaire for mindfulness instead of the unidimensional MAAS. PMID- 24489916 TI - Laparoscopic versus open hepatectomy with or without synchronous colectomy for colorectal liver metastasis: a meta-analysis. AB - BACKGROUND: To compare short-term and long-term results of colorectal patients undergoing laparoscopic and open hepatectomy. Moreover, outcomes of laparoscopic versus open procedures for simultaneous primary colorectal tumor and liver metastasis resection were compared. METHODS: A systematic search was conducted in the PubMed and EmBase databases (until Oct. 22. 2013) with no limits. Bibliographic citation management software (EndNote X6) was used for extracted literature management. Quality assessment was performed according to a modification of the Newcastle-Ottawa Scale. The data were analyzed using Review Manager (Version 5.1), and sensitivity analysis was performed by sequentially omitting each study. RESULTS: Finally, 14 studies, including a total of 975 CLM (colorectal liver metastasis) patients, compared laparoscopic with open hepatectomy. 3 studies of them, including a total of 107 CLM patients, compared laparoscopic with open procedures for synchronous hepatectomy and colectomy. Laparoscopic hepatectomy was associated with a significantly less blood loss, shorter hospitalization time, and less operative transfusion rate. In addition, lower hospital morbidity rate (OR=0.57, 95%CI:0.42-0.78, P=0.0005) and better R0 resection (OR=2.44, 95%CI:1.21-4.94, P=0.01) were observed in laparoscopic hepatectomy. For long-term outcomes, there were no significant differences between two surgical procedures on recurrence and overall survival. In comparison of synchronous hepatectomy and colectomy, laparoscopic procedure displayed shorter hospitalization (MD = -3.40, 95%CI:-4.37-2.44, P<0.00001) than open procedure. Other outcomes, including surgical time, estimated blood loss, hospital morbidity, and overall survival did not differ significantly in the comparison. CONCLUSIONS: Laparoscopic hepatectomy with or without synchronous colectomy are acceptable for selective CLM patients. We suggest standard inclusion criteria of CLM patients be formulated. PMID- 24489917 TI - A strategic interaction model of punishment favoring contagion of honest behavior. AB - The punishment effect on social behavior is analyzed within the strategic interaction framework of Cellular Automata and computational Evolutionary Game Theory. A new game, called Social Honesty (SH), is proposed. The SH game is analyzed in spatial configurations. Probabilistic punishment is used as a dishonesty deterrence mechanism. In order to capture the intrinsic uncertainty of social environments, payoffs are described as random variables. New dynamics, with a new relation between punishment probability and punishment severity, are revealed. Punishment probability proves to be more important than punishment severity in guiding convergence towards honesty as predominant behavior. This result is confirmed by empirical evidence and reported experiments. Critical values and transition intervals for punishment probability and severity are identified and analyzed. Clusters of honest or dishonest players emerge spontaneously from the very first rounds of interaction and are determinant for the future dynamics and outcomes. PMID- 24489918 TI - The role of fusion in ant chromosome evolution: insights from cytogenetic analysis using a molecular phylogenetic approach in the genus mycetophylax. AB - Among insect taxa, ants exhibit one of the most variable chromosome numbers ranging from n = 1 to n = 60. This high karyotype diversity is suggested to be correlated to ants diversification. The karyotype evolution of ants is usually understood in terms of Robertsonian rearrangements towards an increase in chromosome numbers. The ant genus Mycetophylax is a small monogynous basal Attini ant (Formicidae: Myrmicinae), endemic to sand dunes along the Brazilian coastlines. A recent taxonomic revision validates three species, Mycetophylax morschi, M. conformis and M. simplex. In this paper, we cytogenetically characterized all species that belongs to the genus and analyzed the karyotypic evolution of Mycetophylax in the context of a molecular phylogeny and ancestral character state reconstruction. M. morschi showed a polymorphic number of chromosomes, with colonies showing 2n = 26 and 2n = 30 chromosomes. M. conformis presented a diploid chromosome number of 30 chromosomes, while M. simplex showed 36 chromosomes. The probabilistic models suggest that the ancestral haploid chromosome number of Mycetophylax was 17 (Likelihood framework) or 18 (Bayesian framework). The analysis also suggested that fusions were responsible for the evolutionary reduction in chromosome numbers of M. conformis and M. morschi karyotypes whereas fission may determines the M. simplex karyotype. These results obtained show the importance of fusions in chromosome changes towards a chromosome number reduction in Formicidae and how a phylogenetic background can be used to reconstruct hypotheses about chromosomes evolution. PMID- 24489919 TI - Insulin-like growth factor 1 receptor is a prognostic factor in classical Hodgkin lymphoma. AB - The interaction between the tumor cells in classical Hodgkin lymphoma (cHL) and the microenvironment includes aberrant activity of receptor tyrosine kinases. In this study we evaluated the expression, functionality and prognostic significance of Insulin-like growth factor-1 receptor (IGF-1R) in cHL. IGF-1R was overexpressed in 55% (44/80) of cHL patients. Phosphorylated IGF-1R was detectable in a minority of the IGF-1R positive tumor cells. The overall survival (OS, 98%) and 5-year progression-free survival (PFS, 93%) was significantly higher in IGF-1R positive cHL patients compared to IGF-1R negative patients (OS 83%, p = .029 and PFS 77%, p = .047, respectively). Three cHL cell lines showed expression of IGF-1R, with strong staining especially in the mitotic cells and expression of IGF-1. IGF-1 treatment had a prominent effect on the cell growth of L428 and L1236 cells and resulted in an increased phosphorylation of IGF1R, Akt and ERK. Inhibition of IGF-1R with cyclolignan picropodophyllin (PPP) decreased cell growth and induced a G2/M cell cycle arrest in all three cell lines. Moreover, a decrease in pCcd2 and an increase in CyclinB1 levels were observed which is consistent with the G2/M cell cycle arrest. In conclusion, IGF-1R expression in HRS cells predicts a favorable outcome, despite the oncogenic effect of IGF-1R in cHL cell lines. PMID- 24489920 TI - Sequential treatment with cytarabine and decitabine has an increased anti leukemia effect compared to cytarabine alone in xenograft models of childhood acute myeloid leukemia. AB - The current interest in epigenetic priming is underpinned by the belief that remodelling of the epigenetic landscape will sensitise tumours to subsequent therapy. In this pre-clinical study, paediatric AML cells expanded in culture and primary AML xenografts were treated with decitabine, a DNA demethylating agent, and cytarabine, a frontline cytotoxic agent used in the treatment of AML, either alone or in combination. Sequential treatment with decitabine and cytarabine was found to be more effective in reducing tumour burden than treatment with cytarabine alone suggesting that the sequential delivery of these agents may a have real clinical advantage in the treatment of paediatric AML. However we found no evidence to suggest that this outcome was dependent on priming with a hypomethylating agent, as the benefits observed were independent of the order in which these drugs were administered. PMID- 24489921 TI - Activity-dependent adenosine release may be linked to activation of Na(+)-K(+) ATPase: an in vitro rat study. AB - In the brain, extracellular adenosine increases as a result of neuronal activity. The mechanisms by which this occurs are only incompletely understood. Here we investigate the hypothesis that the Na(+) influxes associated with neuronal signalling activate the Na(+)-K(+) ATPase which, by consuming ATP, generates intracellular adenosine that is then released via transporters. By measuring adenosine release directly with microelectrode biosensors, we have demonstrated that AMPA-receptor evoked adenosine release in basal forebrain and cortex depends on extracellular Na(+). We have simultaneously imaged intracellular Na(+) and measured adenosine release. The accumulation of intracellular Na(+) during AMPA receptor activation preceded adenosine release by some 90 s. By removing extracellular Ca(2+), and thus preventing indiscriminate neuronal activation, we used ouabain to test the role of the Na(+)-K(+) ATPase in the release of adenosine. Under conditions which caused a Na(+) influx, brief applications of ouabain increased the accumulation of intracellular Na(+) but conversely rapidly reduced extracellular adenosine levels. In addition, ouabain greatly reduced the amount of adenosine released during application of AMPA. Our data therefore suggest that activity of the Na(+)-K(+) ATPase is directly linked to the efflux of adenosine and could provide a universal mechanism that couples adenosine release to neuronal activity. The Na(+)-K(+) ATPase-dependent adenosine efflux is likely to provide adenosine-mediated activity-dependent negative feedback that will be important in many diverse functional contexts including the regulation of sleep. PMID- 24489922 TI - Activation of a chimeric Rpb5/RpoH subunit using library selection. AB - Rpb5 is a general subunit of all eukaryotic RNA polymerases which consists of a N terminal and a C-terminal domain. The corresponding archaeal subunit RpoH contains only the conserved C-terminal domain without any N-terminal extensions. A chimeric construct, termed rp5H, which encodes the N-terminal yeast domain and the C-terminal domain from Pyrococcus furiosus is unable to complement the lethal phenotype of a yeast rpb5 deletion strain (Deltarpb5). By applying a random mutagenesis approach we found that the amino acid exchange E197K in the C terminal domain of the chimeric Rp5H, either alone or with additional exchanges in the N-terminal domain, leads to heterospecific complementation of the growth deficiency of Deltarpb5. Moreover, using a recently described genetic system for Pyrococcus we could demonstrate that the corresponding exchange E62K in the archaeal RpoH subunit alone without the eukaryotic N-terminal extension was stable, and growth experiments indicated no obvious impairment in vivo. In vitro transcription experiments with purified RNA polymerases showed an identical activity of the wild type and the mutant Pyrococcus RNA polymerase. A multiple alignment of RpoH sequences demonstrated that E62 is present in only a few archaeal species, whereas the great majority of sequences within archaea and eukarya contain a positively charged amino acid at this position. The crystal structures of the Sulfolobus and yeast RNA polymerases show that the positively charged arginine residues in subunits RpoH and Rpb5 most likely form salt bridges with negatively charged residues from subunit RpoK and Rpb1, respectively. A similar salt bridge might stabilize the interaction of Rp5H-E197K with a neighboring subunit of yeast RNA polymerase and thus lead to complementation of Deltarpb5. PMID- 24489923 TI - The root extract of the medicinal plant Pelargonium sidoides is a potent HIV-1 attachment inhibitor. AB - Global HIV-1 treatment would benefit greatly from safe herbal medicines with scientifically validated novel anti-HIV-1 activities. The root extract from the medicinal plant Pelargonium sidoides (PS) is licensed in Germany as the herbal medicine EPs(r)7630, with numerous clinical trials supporting its safety in humans. Here we provide evidence from multiple cell culture experiments that PS extract displays potent anti-HIV-1 activity. We show that PS extract protects peripheral blood mononuclear cells and macrophages from infection with various X4 and R5 tropic HIV-1 strains, including clinical isolates. Functional studies revealed that the extract from PS has a novel mode-of-action. It interferes directly with viral infectivity and blocks the attachment of HIV-1 particles to target cells, protecting them from virus entry. Analysis of the chemical footprint of anti-HIV activity indicates that HIV-1 inhibition is mediated by multiple polyphenolic compounds with low cytotoxicity and can be separated from other extract components with higher cytotoxicity. Based on our data and its excellent safety profile, we propose that PS extract represents a lead candidate for the development of a scientifically validated herbal medicine for anti-HIV-1 therapy with a mode-of-action different from and complementary to current single molecule drugs. PMID- 24489924 TI - Glucose-induced glucagon-like Peptide 1 secretion is deficient in patients with non-alcoholic fatty liver disease. AB - BACKGROUND & AIMS: The incretins glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are gastrointestinal peptide hormones regulating postprandial insulin release from pancreatic beta-cells. GLP-1 agonism is a treatment strategy in Type 2 diabetes and is evaluated in Non-alcoholic fatty liver disease (NAFLD). However, the role of incretins in its pathophysiology is insufficiently understood. Studies in mice suggest improvement of hepatic steatosis by GLP-1 agonism. We determined the secretion of incretins after oral glucose administration in non-diabetic NAFLD patients. METHODS: N=52 patients (n=16 NAFLD and n=36 Non-alcoholic steatohepatitis (NASH) patients) and n=50 matched healthy controls were included. Standardized oral glucose tolerance test was performed. Glucose, insulin, glucagon, GLP-1 and GIP plasma levels were measured sequentially for 120 minutes after glucose administration. RESULTS: Glucose induced GLP-1 secretion was significantly decreased in patients compared to controls (p<0.001). In contrast, GIP secretion was unchanged. There was no difference in GLP-1 and GIP secretion between NAFLD and NASH subgroups. All patients were insulin resistant, however HOMA2-IR was highest in the NASH subgroup. Fasting and glucose-induced insulin secretion was higher in NAFLD and NASH compared to controls, while the glucose lowering effect was diminished. Concomitantly, fasting glucagon secretion was significantly elevated in NAFLD and NASH. CONCLUSIONS: Glucose-induced GLP-1 secretion is deficient in patients with NAFLD and NASH. GIP secretion is contrarily preserved. Insulin resistance, with hyperinsulinemia and hyperglucagonemia, is present in all patients, and is more severe in NASH compared to NAFLD. These pathophysiologic findings endorse the current evaluation of GLP-1 agonism for the treatment of NAFLD. PMID- 24489925 TI - The role of matrix metalloproteinase in the intimal sarcoma-like cells derived from endarterectomized tissues from a chronic thromboembolic pulmonary hypertension patient. AB - Sarcoma-like cells (SCLs) were derived from endarterectomized tissue of a single chronic thromboembolic pulmonary hypertension (CTEPH) patient during incubation of those thrombi at second passage as described at our previous report. These cells had malignant potential, with an increased expression of matrix metalloproteinase-14 (MMP-14), leading to tumor emboli within pulmonary arteries in in vivo studies. The purpose of this study was to perform a more detailed evaluation of the characteristics of SCLs, and to elucidate the role of the increased expression of MMP-14 expression in the growth and death of these cells. In order to elucidate the characteristics of SCLs and to confirm the protein expression of MMP-14, three-dimentional culture, invasion assays, a Western blot analysis and immunohistochemical studies were performed. To examine the role of MMP-14 in tumorigenesis, the metalloproteinase inhibitor, batimastat, was administered to SCID mice which were subcutaneously injected with SCLs. Those mice were sacrificed on day 14 and the tumor volume was evaluated. A Western blot analysis showed the increased expression of MMP-14 in comparison to the expression in lung adenocarcinoma cells (A549). Immunohistochemistry showed that SCLs were positive for vimentin, MMP-14, MMP-2 and CD44. However, endothelial markers, such as CD31 and von Willebrand factor (vWF), were negative. The in vivo studies demonstrated that batimastat could suppress the growth of the subcutaneous tumors formed by the SCLs. This study suggested that MMPs had critical roles on the pathological activities of SCLs and that batimastat might have anti-proliferative and anti-invasive effects on these cells. PMID- 24489926 TI - PolyC-binding protein 1 interacts with 5'-untranslated region of enterovirus 71 RNA in membrane-associated complex to facilitate viral replication. AB - Enterovirus 71 (EV71) is one causative agent of hand, foot, and mouth disease (HFMD), which may lead to severe neurological disorders and mortality in children. EV71 genome is a positive single-stranded RNA containing a single open reading frame (ORF) flanked by 5'-untranslated region (5'UTR) and 3'UTR. The 5'UTR is fundamentally important for virus replication by interacting with cellular proteins. Here, we revealed that poly(C)-binding protein 1 (PCBP1) specifically binds to the 5'UTR of EV71. Detailed studies indicated that the RNA binding K-homologous 1 (KH1) domain of PCBP1 is responsible for its binding to the stem-loop I and IV of EV71 5'UTR. Interestingly, we revealed that PCBP1 is distributed in the nucleus and cytoplasm of uninfected cells, but mainly localized in the cytoplasm of EV71-infected cells due to interaction and co localization with the viral RNA. Furthermore, sub-cellular distribution analysis showed that PCBP1 is located in ER-derived membrane, in where virus replication occurred in the cytoplasm of EV71-infected cells, suggesting PCBP1 is recruited in a membrane-associated replication complex. In addition, we found that the binding of PCBP1 to 5'UTR resulted in enhancing EV71 viral protein expression and virus production so as to facilitate viral replication. Thus, we revealed a novel mechanism in which PCBP1 as a positive regulator involved in regulation of EV71 replication in the host specialized membrane-associated replication complex, which provides an insight into cellular factors involved in EV71 replication. PMID- 24489927 TI - Genome-scale NAD(H/(+)) availability patterns as a differentiating feature between Saccharomyces cerevisiae and Scheffersomyces stipitis in relation to fermentative metabolism. AB - Scheffersomyces stipitis is a yeast able to ferment pentoses to ethanol, unlike Saccharomyces cerevisiae, it does not present the so-called overflow phenomenon. Metabolic features characterizing the presence or not of this phenomenon have not been fully elucidated. This work proposes that genome-scale metabolic response to variations in NAD(H/(+)) availability characterizes fermentative behavior in both yeasts. Thus, differentiating features in S. stipitis and S. cerevisiae were determined analyzing growth sensitivity response to changes in available reducing capacity in relation to ethanol production capacity and overall metabolic flux span. Using genome-scale constraint-based metabolic models, phenotypic phase planes and shadow price analyses, an excess of available reducing capacity for growth was found in S. cerevisiae at every metabolic phenotype where growth is limited by oxygen uptake, while in S. stipitis this was observed only for a subset of those phenotypes. Moreover, by using flux variability analysis, an increased metabolic flux span was found in S. cerevisiae at growth limited by oxygen uptake, while in S. stipitis flux span was invariant. Therefore, each yeast can be characterized by a significantly different metabolic response and flux span when growth is limited by oxygen uptake, both features suggesting a higher metabolic flexibility in S. cerevisiae. By applying an optimization-based approach on the genome-scale models, three single reaction deletions were found to generate in S. stipitis the reducing capacity availability pattern found in S. cerevisiae, two of them correspond to reactions involved in the overflow phenomenon. These results show a close relationship between the growth sensitivity response given by the metabolic network and fermentative behavior. PMID- 24489928 TI - Analysis of global gene expression in Brachypodium distachyon reveals extensive network plasticity in response to abiotic stress. AB - Brachypodium distachyon is a close relative of many important cereal crops. Abiotic stress tolerance has a significant impact on productivity of agriculturally important food and feedstock crops. Analysis of the transcriptome of Brachypodium after chilling, high-salinity, drought, and heat stresses revealed diverse differential expression of many transcripts. Weighted Gene Co Expression Network Analysis revealed 22 distinct gene modules with specific profiles of expression under each stress. Promoter analysis implicated short DNA sequences directly upstream of module members in the regulation of 21 of 22 modules. Functional analysis of module members revealed enrichment in functional terms for 10 of 22 network modules. Analysis of condition-specific correlations between differentially expressed gene pairs revealed extensive plasticity in the expression relationships of gene pairs. Photosynthesis, cell cycle, and cell wall expression modules were down-regulated by all abiotic stresses. Modules which were up-regulated by each abiotic stress fell into diverse and unique gene ontology GO categories. This study provides genomics resources and improves our understanding of abiotic stress responses of Brachypodium. PMID- 24489929 TI - A systematic review and meta-analysis of unilateral versus bilateral pedicle screw fixation in transforaminal lumbar interbody fusion. AB - BACKGROUND: Transforaminal lumbar interbody fusion (TLIF) has become one of the most widely used procedures for lumbar spinal disorders. However, it is still unclear whether TLIF with unilateral pedicle screw (PS) fixation is as effective as that with bilateral PS fixation. We performed a meta-analysis of the literatures and aimed to gain a better understanding of whether TLIF with unilateral PS fixation was safe and effective for lumbar diseases. METHODOLOGY/PRINCIPAL FINDINGS: We systematically searched Ovid, Springer, and Medline databases for relevant randomized controlled trials (RCTs) that compared the clinical and radiological outcomes of unilateral versus bilateral PS fixation in TLIF. Risk of bias in included studies was assessed using the Cochrane Risk of Bias tool. We generated pooled risk ratios or weighted mean differences across studies. According to our predefined inclusion criteria, seven RCTs with a total of 441 patients were included in this study. Baseline characteristics were similar between the unilateral and bilateral groups. Our meta-analysis showed that no significant difference was detected between the two groups in terms of postoperative clinical function, fusion status, reoperation rate, complication rate, and hospital stay (p>0.05). Pooled estimates revealed that the unilateral group was associated with significantly reduced implant cost, operative time and blood loss (p<0.05). CONCLUSIONS/SIGNIFICANCES: Our meta-analysis suggested TLIF with unilateral PS fixation was as safe and effective as that with bilateral PS fixation for lumbar diseases in selected patients. Despite these findings, our meta-analysis was based on studies with small sample size and different study characteristics that might lead to the inconsistent results such as various functional outcomes among the included studies. Therefore, high-quality randomized controlled trials with larger sample size are also needed to further clarify these issues and to provide the long-term outcomes. PMID- 24489930 TI - Natural variation in the strength and direction of male mating preferences for female pheromones in Drosophila melanogaster. AB - Many animal species communicate using chemical signals. In Drosophila, cuticular hydrocarbons (CHCs) are involved in species and sexual identification, and have long been thought to act as stimulatory pheromones as well. However, a previous study reported that D. melanogaster males were more attracted to females that were lacking CHCs. This surprising result is consistent with several evolutionary hypotheses but is at odds with other work demonstrating that female CHCs are attractive to males. Here, we investigated natural variation in male preferences for female pheromones using transgenic flies that cannot produce CHCs. By perfuming females with CHCs and performing mate choice tests, we found that some male genotypes prefer females with pheromones, some have no apparent preference, and at least one male genotype prefers females without pheromones. This variation provides an excellent opportunity to further investigate the mechanistic causes and evolutionary implications of divergent pheromone preferences in D. melanogaster males. PMID- 24489931 TI - The cost and cost-effectiveness of scaling up screening and treatment of syphilis in pregnancy: a model. AB - BACKGROUND: Syphilis in pregnancy imposes a significant global health and economic burden. More than half of cases result in serious adverse events, including infant mortality and infection. The annual global burden from mother-to child transmission (MTCT) of syphilis is estimated at 3.6 million disability adjusted life years (DALYs) and $309 million in medical costs. Syphilis screening and treatment is simple, effective, and affordable, yet, worldwide, most pregnant women do not receive these services. We assessed cost-effectiveness of scaling-up syphilis screening and treatment in existing antenatal care (ANC) programs in various programmatic, epidemiologic, and economic contexts. METHODS AND FINDINGS: We modeled the cost, health impact, and cost-effectiveness of expanded syphilis screening and treatment in ANC, compared to current services, for 1,000,000 pregnancies per year over four years. We defined eight generic country scenarios by systematically varying three factors: current maternal syphilis testing and treatment coverage, syphilis prevalence in pregnant women, and the cost of healthcare. We calculated program and net costs, DALYs averted, and net costs per DALY averted over four years in each scenario. Program costs are estimated at $4,142,287 - $8,235,796 per million pregnant women (2010 USD). Net costs, adjusted for averted medical care and current services, range from net savings of $12,261,250 to net costs of $1,736,807. The program averts an estimated 5,754 - 93,484 DALYs, yielding net savings in four scenarios, and a cost per DALY averted of $24 - $111 in the four scenarios with net costs. Results were robust in sensitivity analyses. CONCLUSIONS: Eliminating MTCT of syphilis through expanded screening and treatment in ANC is likely to be highly cost-effective by WHO defined thresholds in a wide range of settings. Countries with high prevalence, low current service coverage, and high healthcare cost would benefit most. Future analyses can be tailored to countries using local epidemiologic and programmatic data. PMID- 24489932 TI - Health care service utilization among patients with bladder pain syndrome/interstitial cystitis in a single payer healthcare system. AB - BACKGROUND: This study aims to investigate the differences in the utilization of healthcare services between patients with bladder pain syndrome/interstitial cystitis (BPS/IC) and patients without using a population-based database in Taiwan. METHODS: This study comprised of 350 patients with BPS/IC and 1,750 age matched controls. Healthcare resource utilization was evaluated in the one-year follow-up period as follows: number of outpatient visits and inpatient days, and the mean costs of outpatient and inpatient treatment. A multivariate regression analysis was used to evaluate the relationship between BPS/IC and total costs of health care services. RESULTS: For urological services, patients with BPS/IC had a significantly higher number of outpatient visits (2.5 vs. 0.2, p<0.001) as well as significantly higher outpatient costs ($US166 vs. $US6.8, p<0.001) than the controls. For non-urologic services, patients with BPS/IC had a significantly high number of outpatient visits (35.0 vs. 21.3, p<0.001) as well as significantly higher outpatient cots ($US912 vs. $US675, p<0.001) as compared to the controls. Overall, patients with BPS/IC had 174% more outpatient visits and 150% higher total costs than the controls. Multiple-regression-analyses also showed that the patients with BPS/IC had significantly higher total costs for all healthcare services than the controls. CONCLUSIONS: This study found that patients with BPS/IC have a significantly higher number of healthcare related visits, and have significantly higher healthcare related costs than age-matched controls. The high level of healthcare services utilization accrued with BPS/IC was not necessarily exclusive for BPS/IC, but may have also been associated with medical co-morbidities. PMID- 24489933 TI - A20 is critical for the induction of Pam3CSK4-tolerance in monocytic THP-1 cells. AB - A20 functions to terminate Toll-like receptor (TLR)-induced immune response, and play important roles in the induction of lipopolysacchride (LPS)-tolerance. However, the molecular mechanism for Pam3CSK4-tolerance is uncertain. Here we report that TLR1/2 ligand Pam3CSK4 induced tolerance in monocytic THP-1 cells. The pre-treatment of THP-1 cells with Pam3CSK4 down-regulated the induction of pro-inflammatory cytokines induced by Pam3CSK4 re-stimulation. Pam3CSK4 pre treatment also down-regulated the signaling transduction of JNK, p38 and NF kappaB induced by Pam3CSK4 re-stimulation. The activation of TLR1/2 induced a rapid and robust up-regulation of A20, suggesting that A20 may contribute to the induction of Pam3CSK4-tolerance. This hypothesis was proved by the observation that the over-expression of A20 by gene transfer down-regulated Pam3CSK4-induced inflammatory responses, and the down-regulation of A20 by RNA interference inhibited the induction of tolerance. Moreover, LPS induced a significant up regulation of A20, which contributed to the induction of cross-tolerance between LPS and Pam3CSK4. A20 was also induced by the treatment of THP-1 cells with TNF alpha and IL-1beta. The pre-treatment with TNF-alpha and IL-1beta partly down regulated Pam3CSK4-induced activation of MAPKs. Furthermore, pharmacologic inhibition of GSK3 signaling down-regulated Pam3CSK4-induced A20 expression, up regulated Pam3CSK4-induced inflammatory responses, and partly reversed Pam3CSK4 pre-treatment-induced tolerance, suggesting that GSK3 is involved in TLR1/2 induced tolerance by up-regulation of A20 expression. Taken together, these results indicated that A20 is a critical regulator for TLR1/2-induced pro inflammatory responses. PMID- 24489934 TI - IKK2 inhibition attenuates laser-induced choroidal neovascularization. AB - Choroidal neovascularization (CNV) is aberrant angiogenesis associated with exudative age-related macular degeneration (AMD), a leading cause of blindness in the elderly. Inflammation has been suggested as a risk factor for AMD. The IKK2/NF-kappaB pathway plays a key role in the inflammatory response through regulation of the transcription of cytokines, chemokines, growth factors and angiogenic factors. We investigated the functional role of IKK2 in development of the laser-induced CNV using either Ikk2 conditional knockout mice or an IKK2 inhibitor. The retinal neuronal tissue and RPE deletion of IKK2 was generated by breeding Ikk2(-/flox) mice with Nestin-Cre mice. Deletion of Ikk2 in the retina caused no obvious defect in retinal development or function, but resulted in a significant reduction in laser-induced CNV. In addition, intravitreal or retrobulbar injection of an IKK2 specific chemical inhibitor, TPCA-1, also showed similar inhibition of CNV. Furthermore, in vitro inhibition of IKK2 in ARPE-19 cells significantly reduced heat shock-induced expression of NFKBIA, IL1B, CCL2, VEGFA, PDGFA, HIF1A, and MMP-2, suggesting that IKK2 may regulate multiple molecular pathways involved in laser-induced CNV. The in vivo laser-induced expression of VEGFA, and HIF1A in RPE and choroidal tissue was also blocked by TPCA-1 treatment. Thus, IKK2/NF-kappaB signaling appears responsible for production of pro-inflammatory and pro-angiogenic factors in laser-induced CNV, suggesting that this intracellular pathway may serve as an important therapeutic target for aberrant angiogenesis in exudative AMD. PMID- 24489935 TI - Genome-wide mapping of furfural tolerance genes in Escherichia coli. AB - Advances in genomics have improved the ability to map complex genotype-to phenotype relationships, like those required for engineering chemical tolerance. Here, we have applied the multiSCale Analysis of Library Enrichments (SCALEs; Lynch et al. (2007) Nat. Method.) approach to map, in parallel, the effect of increased dosage for >10(5) different fragments of the Escherichia coli genome onto furfural tolerance (furfural is a key toxin of lignocellulosic hydrolysate). Only 268 of >4,000 E. coli genes (~ 6%) were enriched after growth selections in the presence of furfural. Several of the enriched genes were cloned and tested individually for their effect on furfural tolerance. Overexpression of thyA, lpcA, or groESL individually increased growth in the presence of furfural. Overexpression of lpcA, but not groESL or thyA, resulted in increased furfural reduction rate, a previously identified mechanism underlying furfural tolerance. We additionally show that plasmid-based expression of functional LpcA or GroESL is required to confer furfural tolerance. This study identifies new furfural tolerant genes, which can be applied in future strain design efforts focused on the production of fuels and chemicals from lignocellulosic hydrolysate. PMID- 24489936 TI - Corals like it waxed: paraffin-based antifouling technology enhances coral spat survival. AB - The early post-settlement stage is the most sensitive during the life history of reef building corals. However, few studies have examined the factors that influence coral mortality during this period. Here, the impact of fouling on the survival of newly settled coral spat of Acropora millepora was investigated by manipulating the extent of fouling cover on settlement tiles using non-toxic, wax antifouling coatings. Survival of spat on coated tiles was double that on control tiles. Moreover, there was a significant negative correlation between percentage cover of fouling and spat survival across all tiles types, suggesting that fouling in direct proximity to settled corals has detrimental effects on early post-settlement survival. While previous studies have shown that increased fouling negatively affects coral larval settlement and health of juvenile and adult corals, to the best of our knowledge, this is the first study to show a direct relationship between fouling and early post-settlement survival for a broadcast spawning scleractinian coral. The negative effects of fouling on this sensitive life history stage may become more pronounced in the future as coastal eutrophication increases. Our results further suggest that targeted seeding of coral spat on artificial surfaces in combination with fouling control could prove useful to improve the efficiency of sexual reproduction-based coral propagation for reef rehabilitation. PMID- 24489937 TI - Treatment with pyranopyran-1, 8-dione attenuates airway responses in cockroach allergen sensitized asthma in mice. AB - Chronic allergic asthma is characterized by Th2-typed inflammation, and contributes to airway remodeling and the deterioration of lung function. Viticis Fructus (VF) has long been used in China and Korea as a traditional herbal remedy for treating various inflammatory diseases. Previously, we have isolated a novel phytochemical, pyranopyran-1, 8-dione (PPY), from VF. This study was conducted to evaluate the ability of PPY to prevent airway inflammation and to attenuate airway responses in a cockroach allergen-induced asthma model in mice. The mice sensitized to and challenged with cockroach allergen were treated with oral administration of PPY. The infiltration of total cells, eosinophils and lymphocytes into the BAL fluid was significantly inhibited in cockroach allergen induced asthma mice treated with PPY (1, 2, or 10 mg/kg). Th2 cytokines and chemokine, such as IL-4, IL-5, IL-13 and eotaxin in BAL fluid were also reduced to normal levels following treatment with PPY. In addition, the levels of IgE were also markedly suppressed after PPY treatment. Histopathological examination demonstrated that PPY substantially inhibited eosinophil infiltration into the airway, goblet cell hyperplasia and smooth muscle hypertrophy. Taken together, these results demonstrate that PPY possesses a potent efficacy on controlling allergic asthma response such as airway inflammation and remodeling. PMID- 24489938 TI - Sodium ferulate inhibits neointimal hyperplasia in rat balloon injury model. AB - BACKGROUND/AIM: Neointimal formation after vessel injury is a complex process involving multiple cellular and molecular processes. Inhibition of intimal hyperplasia plays an important role in preventing proliferative vascular diseases, such as restenosis. In this study, we intended to identify whether sodium ferulate could inhibit neointimal formation and further explore potential mechanisms involved. METHODS: Cultured vascular smooth muscle cells (VSMCs) isolated from rat thoracic aorta were pre-treated with 200 umol/L sodium ferulate for 1 hour and then stimulated with 1 umol/L angiotensin II (Ang II) for 1 hour or 10% serum for 48 hours. Male Sprague-Dawley rats subjected to balloon catheter insertion were administrated with 200 mg/kg sodium ferulate (or saline) for 7 days before sacrificed. RESULTS: In presence of sodium ferulate, VSMCs exhibited decreased proliferation and migration, suppressed intracellular reactive oxidative species production and NADPH oxidase activity, increased SOD activation and down-regulated p38 phosphorylation compared to Ang II-stimulated alone. Meanwhile, VSMCs treated with sodium ferulate showed significantly increased protein expression of smooth muscle alpha-actin and smooth muscle myosin heavy chain protein. The components of Notch pathway, including nuclear Notch-1 protein, Jagged-1, Hey-1 and Hey-2 mRNA, as well as total beta-catenin protein and Cyclin D1 mRNA of Wnt signaling, were all significantly decreased by sodium ferulate in cells under serum stimulation. The levels of serum 8-iso-PGF2alpha and arterial collagen formation in vessel wall were decreased, while the expression of contractile markers was increased in sodium ferulate treated rats. A decline of neointimal area, as well as lower ratio of intimal to medial area was observed in sodium ferulate group. CONCLUSION: Sodium ferulate attenuated neointimal hyperplasia through suppressing oxidative stress and phenotypic switching of VSMCs. PMID- 24489939 TI - Association of matrix metalloproteinase-3 -1171(5A>6A) polymorphism with cancer risk: a meta-analysis of 41 studies. AB - BACKGROUND AND OBJECTIVE: Evidence has shown that matrix metalloproteinases-3 (MMP3) is important for cancer progression. Recent studies about the association between the -1171(5A>6A) polymorphism in MMP3 promoter region and cancer risk have yielded conflicting results. METHODOLOGY/PRINCIPAL FINDINGS: We performed a meta-analysis of 41 studies including 11112 cases and 11091 controls to determine whether the -1171(5A>6A) polymorphism of MMP3 was associated with cancer risk. We assessed the strength of association and performed sub-group analyses by cancer types, ethnicity, smoking status, genotyping method, source of controls and sample size. The pooled results revealed that no significant association of the 1171(5A>6A) polymorphism with overall cancer risk in any of four models. Further sub-group analysis revealed that individuals with the 6A allele had lower risk of gastrointestinal cancer in two models: heterozygote comparison (6A/5A vs. 5A/5A: OR=0.74, 95%CI: 0.60-0.91; I(2)=1.9%), and dominant model (6A/6A+6A/5A vs. 5A/5A: OR=0.77, 95%CI: 0.64-0.94; I(2)=29.0%). Additionally, the associations were significant in Asian populations for three models: homozygote comparison (6A/6A vs. 5A/5A, OR=0.68, 95%CI: 0.52-0.90; I(2)=26.7%), heterozygote comparison (6A/5A vs. 5A/5A: OR=0.75, 95%CI: 0.58-0.98; I(2)=0.0%), and dominant model (6A/6A+6A/5A vs. 5A/5A: OR=0.69, 95%CI: 0.54-0.88; I(2)=0.5%). It was noteworthy that we had a contrary finding in non-smokers: the variant 6A/6A homozygote might statistically increase cancer risk compared with 6A/5A+5A/5A genotype (OR=1.92, 95%CI: 1.25 2.96; I(2)=72.7%). CONCLUSION: This meta-analysis suggests that the -1171(5A>6A) polymorphism in MMP3 promoter region is not associated with overall cancer risk, but it may contribute to decreased cancer risk in Asian population when compared with Caucasian population and significantly reduce the risk of gastrointestinal cancer. PMID- 24489941 TI - Functional traits differ between cereal crop progenitors and other wild grasses gathered in the Neolithic fertile crescent. AB - The reasons why some plant species were selected as crops and others were abandoned during the Neolithic emergence of agriculture are poorly understood. We tested the hypothesis that the traits of Fertile Crescent crop progenitors were advantageous in the fertile, disturbed habitats surrounding early settlements and in cultivated fields. We screened functional traits related to competition and disturbance in a group of grass species that were increasingly exploited by early plant gatherers, and that were later domesticated (crop progenitors); and in a set of grass species for which there is archaeological evidence of gathering, but which were never domesticated (wild species). We hypothesised that crop progenitors would have greater seed mass, growth rate, height and yield than wild species, as these traits are indicative of greater competitive ability, and that crop progenitors would be more resilient to defoliation. Our results show that crop progenitors have larger seed mass than wild species, germinate faster and have greater seedling size. Increased seed size is weakly but positively correlated with a higher growth rate, which is primarily driven by greater biomass assimilation per unit leaf area. Crop progenitors also tend to have a taller stature, greater grain yield and higher resilience to defoliation. Collectively, the data are consistent with the hypothesis that adaptations to competition and disturbance gave crop progenitors a selective advantage in the areas surrounding early human settlements and in cultivated environments, leading to their adoption as crops through processes of unconscious selection. PMID- 24489943 TI - Study on risk factors for severe hand, foot and mouth disease in China. AB - BACKGROUND: Epidemics of HFMD are elevated every year globally, especially in mainland China. The disease now presents as an increasing threat to public health worldwide. METHODS: Five hundred and seventy-one EV71-infected HFMD patients in Beijing You'an Hospital were grouped by disease severity: Mild (no severe complication) (n=221), and Severe group (complicated with brainstem encephalitis (BE), and/or pulmonary edema (PE) (n=350)). Clinical and laboratory findings and levels of 7 serum cytokines were analyzed. RESULTS: Univariate analysis showed that (RR)>26/min (p<0.001), age<4 yo (p=0.001), GLU>8.3 mmol/L (p=0.008), CL<98 mmol/L (p=0.026), and WBC>1.2 * 10(9)/L (p=0.040) were associated with severe cases. Results of multivariate analysis indicated five independent risk factors (RR>26/min (p<0.001), Age<4 yo (p<0.001), GLU>8.3 mmol/L (p=0.011), LYM>40% (p=0.010), and ALT>40 U/L (p=0.045)). In addition to single-factor analysis, we further analyzed the use of different combinations of risk factors. "GLU>8.3 and CL<98 and RR>26" (confidence ration (CR)=100%) is the top indicator, followed by "ALT>40 and LYM>40% and RR>26 and Age<4 yo" (CR=92.9%). Serum levels of IL-2, IL 4, IL-10, IFNgamma, GM-CSF, and TNFalpha were higher in severe cases than in mild cases. A new evaluation scoring system by scoring each risk factor 1 and independent risk factor 2 was developed for early identification of severe HFMD cases. CONCLUSIONS: Five independent risk factors, along with indicative combinations of risk factors, for severe cases were identified, and a scoring system was created to facilitate the use of indicators for early medical intervention. PMID- 24489942 TI - Chemical and genetic validation of the statin drug target to treat the helminth disease, schistosomiasis. AB - The mevalonate pathway is essential in eukaryotes and responsible for a diversity of fundamental synthetic activities. 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) is the rate-limiting enzyme in the pathway and is targeted by the ubiquitous statin drugs to treat hypercholesterolemia. Independent reports have indicated the cidal effects of statins against the flatworm parasite, S. mansoni, and the possibility that SmHMGR is a useful drug target to develop new statin-based anti-schistosome therapies. For six commercially available statins, we demonstrate concentration- and time-dependent killing of immature (somule) and adult S. mansoni in vitro at sub-micromolar and micromolar concentrations, respectively. Cidal activity trends with statin lipophilicity whereby simvastatin and pravastatin are the most and least active, respectively. Worm death is preventable by excess mevalonate, the product of HMGR. Statin activity against somules was quantified both manually and automatically using a new, machine learning-based automated algorithm with congruent results. In addition, to chemical targeting, RNA interference (RNAi) of HMGR also kills somules in vitro and, again, lethality is blocked by excess mevalonate. Further, RNAi of HMGR of somules in vitro subsequently limits parasite survival in a mouse model of infection by up to 80%. Parasite death, either via statins or specific RNAi of HMGR, is associated with activation of apoptotic caspase activity. Together, our genetic and chemical data confirm that S. mansoni HMGR is an essential gene and the relevant target of statin drugs. We discuss our findings in context of a potential drug development program and the desired product profile for a new schistosomiasis drug. PMID- 24489940 TI - Childhood sexual abuse and the development of recurrent major depression in Chinese women. AB - BACKGROUND: Our prior study in Han Chinese women has shown that women with a history of childhood sexual abuse (CSA) are at increased risk for developing major depression (MD). Would this relationship be found in our whole data set? METHOD: Three levels of CSA (non-genital, genital, and intercourse) were assessed by self-report in two groups of Han Chinese women: 6017 clinically ascertained with recurrent MD and 5983 matched controls. Diagnostic and other risk factor information was assessed at personal interview. Odds ratios (ORs) were calculated by logistic regression. RESULTS: We confirmed earlier results by replicating prior analyses in 3,950 new recurrent MD cases. There were no significant differences between the two data sets. Any form of CSA was significantly associated with recurrent MD (OR 4.06, 95% confidence interval (CI) [3.19-5.24]). This association strengthened with increasing CSA severity: non-genital (OR 2.21, 95% CI 1.58-3.15), genital (OR 5.24, 95% CI 3.52-8.15) and intercourse (OR 10.65, 95% CI 5.56-23.71). Among the depressed women, those with CSA had an earlier age of onset, longer depressive episodes. Recurrent MD patients those with CSA had an increased risk for dysthymia (OR 1.60, 95%CI 1.11-2.27) and phobia (OR 1.41, 95%CI 1.09-1.80). Any form of CSA was significantly associated with suicidal ideation or attempt (OR 1.50, 95% CI 1.20-1.89) and feelings of worthlessness or guilt (OR 1.41, 95% CI 1.02-2.02). Intercourse (OR 3.47, 95%CI 1.66-8.22), use of force and threats (OR 1.95, 95%CI 1.05-3.82) and how strongly the victims were affected at the time (OR 1.39, 95%CI 1.20-1.64) were significantly associated with recurrent MD. CONCLUSIONS: In Chinese women CSA is strongly associated with recurrent MD and this association increases with greater severity of CSA. Depressed women with CSA have some specific clinical traits. Some features of CSA were associated with greater likelihood of developing recurrent MD. PMID- 24489944 TI - Single-kernel ionomic profiles are highly heritable indicators of genetic and environmental influences on elemental accumulation in maize grain (Zea mays). AB - The ionome, or elemental profile, of a maize kernel can be viewed in at least two distinct ways. First, the collection of elements within the kernel are food and feed for people and animals. Second, the ionome of the kernel represents a developmental end point that can summarize the life history of a plant, combining genetic programs and environmental interactions. We assert that single-kernel based phenotyping of the ionome is an effective method of analysis, as it represents a reasonable compromise between precision, efficiency, and power. Here, we evaluate potential pitfalls of this sampling strategy using several field-grown maize sample sets. We demonstrate that there is enough genetically determined diversity in accumulation of many of the elements assayed to overcome potential artifacts. Further, we demonstrate that environmental signals are detectable through their influence on the kernel ionome. We conclude that using single kernels as the sampling unit is a valid approach for understanding genetic and environmental effects on the maize kernel ionome. PMID- 24489945 TI - What influences the association between previous and future crashes among cyclists? A propensity score analysis. AB - BACKGROUND: It is known that experience of a previous crash is related to incidence of future crashes in a cohort of New Zealand cyclists. This paper investigated if the strength of such association differed by crash involvement propensity and by the need for medical care in the previous crash. METHODS: The Taupo Bicycle Study involved 2590 adult cyclists recruited in 2006 and followed over a median period of 4.6 years through linkage to four national databases. The crash involvement propensity was estimated using propensity scores based on the participants' demographic, cycling and residential characteristics. Cox regression modelling for repeated events was performed with multivariate and propensity score adjustments. Analyses were then stratified by quintiles of the propensity score. RESULTS: A total of 801 (31.0%) participants reported having experienced at least one bicycle crash in the twelve months prior to the baseline survey. They had a higher risk of experiencing crash events during follow-up (hazard ratio (HR): 1.43; 95% CI: 1.28, 1.60) but in the stratified analysis, this association was significant only in the highest two quintiles of the propensity score where the likelihood of having experienced a crash was more than 33%. The association was stronger for previous crashes that had received medical care (HR 1.63; 95% CI: 1.41, 1.88) compared to those that had not (HR 1.30; 95% CI: 1.14, 1.49). CONCLUSIONS: Previous crash experience increased the risk of future crash involvement in high-risk cyclists and the association was stronger for previous crashes attended medically. What distinguishes the high risk group warrants closer investigation, and the findings indicate also that health service providers could play an important role in prevention of bicycle crash injuries. PMID- 24489946 TI - Dietary patterns and depressive symptoms over time: examining the relationships with socioeconomic position, health behaviours and cardiovascular risk. AB - INTRODUCTION: Recent research suggests that diet quality influences depression risk; however, a lack of experimental evidence leaves open the possibility that residual confounding explains the observed relationships. The aim of this study was to document the cross-sectional and longitudinal associations between dietary patterns and symptoms of depression and to undertake a detailed examination of potential explanatory factors, particularly socioeconomic circumstances, in the diet-depression relationship. METHODS: Data were drawn from the Personality and Total Health (PATH) Through Life Study, a longitudinal community study following three age cohorts (20+; 40+; 60+yrs) from south-eastern Australia over three assessment periods (n=3663). Regression analyses evaluated the cross-sectional and longitudinal relationships between dietary patterns, depressive symptoms, age, detailed measures of socioeconomic circumstances, other health behaviours, and cardiovascular risk factors. RESULTS: The lowest tertile of prudent (healthy) dietary pattern and the highest tertile of western (unhealthy) dietary pattern were associated with an increased likelihood of depressive symptoms. However, these contemporaneous associations were explained by adjustment for detailed measures of socioeconomic circumstances and physical activity. In prospective analyses, lower scores on the healthy dietary pattern and higher scores on the unhealthy dietary pattern independently predicted increased depressive symptoms across time, before and after adjustment for potential confounders and baseline depressive symptoms, but only for those in the oldest cohort. Dietary patterns did not explain the relationship between socioeconomic position and depressive symptoms. CONCLUSION: The results of this study confirm that the relationship between habitual dietary intake and depressive symptoms is somewhat explained by socioeconomic circumstances and other health behaviours, but suggest that long term exposure to unhealthy dietary habits independently predisposes to depression over the lifecourse. PMID- 24489947 TI - IL-4 suppresses the responses to TLR7 and TLR9 stimulation and increases the permissiveness to retroviral infection of murine conventional dendritic cells. AB - Th2-inducing pathological conditions such as parasitic diseases increase susceptibility to viral infections through yet unclear mechanisms. We have previously reported that IL-4, a pivotal Th2 cytokine, suppresses the response of murine bone-marrow-derived conventional dendritic cells (cDCs) and splenic DCs to Type I interferons (IFNs). Here, we analyzed cDC responses to TLR7 and TLR9 ligands, R848 and CpGs, respectively. We found that IL-4 suppressed the gene expression of IFNbeta and IFN-responsive genes (IRGs) upon TLR7 and TLR9 stimulation. IL-4 also inhibited IFN-dependent MHC Class I expression and amplification of IFN signaling pathways triggered upon TLR stimulation, as indicated by the suppression of IRF7 and STAT2. Moreover, IL-4 suppressed TLR7- and TLR9-induced cDC production of pro-inflammatory cytokines such as TNFalpha, IL-12p70 and IL-6 by inhibiting IFN-dependent and NFkappaB-dependent responses. IL-4 similarly suppressed TLR responses in splenic DCs. IL-4 inhibition of IRGs and pro-inflammatory cytokine production upon TLR7 and TLR9 stimulation was STAT6 dependent, since DCs from STAT6-KO mice were resistant to the IL-4 suppression. Analysis of SOCS molecules (SOCS1, -2 and -3) showed that IL-4 induces SOCS1 and SOCS2 in a STAT6 dependent manner and suggest that IL-4 suppression could be mediated by SOCS molecules, in particular SOCS2. IL-4 also decreased the IFN response and increased permissiveness to viral infection of cDCs exposed to a HIV based lentivirus. Our results indicate that IL-4 modulates and counteracts pro inflammatory stimulation induced by TLR7 and TLR9 and it may negatively affect responses against viruses and intracellular parasites. PMID- 24489948 TI - Incidence and risk of cardiotoxicity associated with bortezomib in the treatment of cancer: a systematic review and meta-analysis. AB - BACKGROUND: We conducted a systematic review and meta-analysis to clarify the incidence and risk of cardiotoxicity associated with bortezomib in cancer patients. METHODS: Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to July 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating bortezomib in cancer patients with adequate data on cardiotoxicity. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS: A total of 5718 patients with a variety of malignancies from 25 clinical trials were included in our analysis. The incidence of all-grade and high-grade cardiotoxicity associated with bortezomib was 3.8% (95%CI: 2.6-5.6%) and 2.3% (1.6-3.5%), with a mortality of 3.0% (1.4-6.5%). Patients treated with bortezomib did not significantly increase the risk of all-grade (OR 1.15, 95%CI: 0.82-1.62, p=0.41) and high-grade (OR 1.13, 95%CI: 0.58-2.24, p=0.72) cardiotoxicity compared with patients treated with control medication. Sub-group analysis showed that the incidence of cardiotoxicity varied with tumor types, treatment regimens and phases of trials. No evidence of publication bias was observed. CONCLUSIONS: The use of bortezomib does not significantly increase the risk of cardiotoxicity compared to control patients. Further studies are recommended to investigate this association and risk differences among different tumor types, treatment regimens and phases of trials. PMID- 24489949 TI - Complementation of essential yeast GPI mannosyltransferase mutations suggests a novel specificity for certain Trypanosoma and Plasmodium PigB proteins. AB - The glycosylphosphatidylinositol (GPI) anchor is an essential glycolipid that tethers certain eukaryotic proteins to the cell surface. The core structure of the GPI anchor is remarkably well conserved across evolution and consists of NH2 CH2-CH2-PO4-6Manalpha1,2Manalpha1,6Manalpha1,4-GlcNalpha1,6-myo-inositol-PO4 lipid. The glycan portion of this structure may be modified with various side branching sugars or other compounds that are heterogeneous and differ from organism to organism. One such modification is an alpha(1,2)-linked fourth mannose (Man-IV) that is side-branched to the third mannose (Man-III) of the trimannosyl core. In fungi and mammals, addition of Man-III and Man-IV occurs by two distinct Family 22 alpha(1,2)-mannosyltransferases, Gpi10/PigB and Smp3/PigZ, respectively. However, in the five protozoan parasite genomes we examined, no genes encoding Smp3/PigZ proteins were observed, despite reports of tetramannosyl GPI structures (Man4-GPIs) being produced by some parasites. In this study, we tested the hypothesis that the Gpi10/PigB proteins produced by protozoan parasites have the ability to add both Man-III and Man-IV to GPI precursors. We used yeast genetics to test the in vivo specificity of Gpi10/PigB proteins from several Plasmodium and Trypanosoma species by examining their ability to restore viability to Saccharomyces cerevisiae strains harboring lethal defects in Man-III (gpi10Delta) or Man-IV (smp3Delta) addition to GPI precursor lipids. We demonstrate that genes encoding PigB enzymes from T. cruzi, T. congolense and P. falciparum are each capable of separately complementing essential gpi10Delta and smp3Delta mutations, while PIGB genes from T. vivax and T. brucei only complement gpi10Delta. Additionally, we show the ability of T. cruzi PIGB to robustly complement a gpi10Delta/smp3Delta double mutant. Our data suggest that certain Plasmodium and Trypanosoma PigB mannosyltransferases can transfer more than one mannose to GPI precursors in vivo, and suggest a novel biosynthetic mechanism by which Man4-GPIs may be synthesized in these organisms. PMID- 24489950 TI - Neisseria gonorrhoeae modulates iron-limiting innate immune defenses in macrophages. AB - Neisseria gonorrhoeae is a strict human pathogen that causes the sexually transmitted infection termed gonorrhea. The gonococcus can survive extracellularly and intracellularly, but in both environments the bacteria must acquire iron from host proteins for survival. However, upon infection the host uses a defensive response by limiting the bioavailability of iron by a number of mechanisms including the enhanced expression of hepcidin, the master iron regulating hormone, which reduces iron uptake from the gut and retains iron in macrophages. The host also secretes the antibacterial protein NGAL, which sequesters bacterial siderophores and therefore inhibits bacterial growth. To learn whether intracellular gonococci can subvert this defensive response, we examined expression of host genes that encode proteins involved in modulating levels of intracellular iron. We found that N. gonorrhoeae can survive in association (tightly adherent and intracellular) with monocytes and macrophages and upregulates a panel of its iron-responsive genes in this environment. We also found that gonococcal infection of human monocytes or murine macrophages resulted in the upregulation of hepcidin, NGAL, and NRAMP1 as well as downregulation of the expression of the gene encoding the short chain 3-hydroxybutyrate dehydrogenase (BDH2); BDH2 catalyzes the production of the mammalian siderophore 2,5-DHBA involved in chelating and detoxifying iron. Based on these findings, we propose that N. gonorrhoeae can subvert the iron-limiting innate immune defenses to facilitate iron acquisition and intracellular survival. PMID- 24489951 TI - Comparison of sugars, iridoid glycosides and amino acids in nectar and phloem sap of Maurandya barclayana, Lophospermum erubescens, and Brassica napus. AB - BACKGROUND: Floral nectar contains sugars and amino acids to attract pollinators. In addition, nectar also contains different secondary compounds, but little is understood about their origin or function. Does nectar composition reflect phloem composition, or is nectar synthesized and/or modified in nectaries? Studies where both, the nectar as well as the phloem sap taken from the same plant species were analyzed in parallel are rare. Therefore, phloem sap and nectar from different plant species (Maurandya barclayana, Lophospermum erubescens, and Brassica napus) were compared. METHODOLOGY AND PRINCIPAL FINDINGS: Nectar was collected with microcapillary tubes and phloem sap with the laser-aphid-stylet technique. The nectar of all three plant species contained high amounts of sugars with different percentages of glucose, fructose, and sucrose, whereas phloem sap sugars consisted almost exclusively of sucrose. One possible reason for this could be the activity of invertases in the nectaries. The total concentration of amino acids was much lower in nectars than in phloem sap, indicating selective retention of nitrogenous solutes during nectar formation. Nectar amino acid concentrations were negatively correlated with the nectar volumes per flower of the different plant species. Both members of the tribe Antirrhineae (Plantaginaceae) M. barclayana and L. erubescens synthesized the iridoid glycoside antirrhinoside. High amounts of antirrhinoside were found in the phloem sap and lower amounts in the nectar of both plant species. CONCLUSIONS/SIGNIFICANCE: The parallel analyses of nectar and phloem sap have shown that all metabolites which were found in nectar were also detectable in phloem sap with the exception of hexoses. Otherwise, the composition of both aqueous solutions was not the same. The concentration of several metabolites was lower in nectar than in phloem sap indicating selective retention of some metabolites. Furthermore, the existence of antirrhinoside in nectar could be based on passive secretion from the phloem. PMID- 24489952 TI - Targeted methylation of the epithelial cell adhesion molecule (EpCAM) promoter to silence its expression in ovarian cancer cells. AB - The Epithelial Cell Adhesion Molecule (EpCAM) is overexpressed in many cancers including ovarian cancer and EpCAM overexpression correlates with decreased survival of patients. It was the aim of this study to achieve a targeted methylation of the EpCAM promoter and silence EpCAM gene expression using an engineered zinc finger protein that specifically binds the EpCAM promoter fused to the catalytic domain of the Dnmt3a DNA methyltransferase. We show that transient transfection of this construct increased the methylation of the EpCAM promoter in SKOV3 cells from 4-8% in untreated cells to 30%. Up to 48% methylation was observed in stable cell lines which express the chimeric methyltransferase. Control experiments confirmed that the methylation was dependent on the fusion of the Zinc finger and the methyltransferase domains and specific for the target region. The stable cell lines with methylated EpCAM promoter showed a 60-80% reduction of EpCAM expression as determined at mRNA and protein level and exhibited a significantly reduced cell proliferation. Our data indicate that targeted methylation of the EpCAM promoter could be an approach in the therapy of EpCAM overexpressing cancers. PMID- 24489953 TI - Novel quantitative autophagy analysis by organelle flow cytometry after cell sonication. AB - Autophagy is a dynamic process of bulk degradation of cellular proteins and organelles in lysosomes. Current methods of autophagy measurement include microscopy-based counting of autophagic vacuoles (AVs) in cells. We have developed a novel method to quantitatively analyze individual AVs using flow cytometry. This method, OFACS (organelle flow after cell sonication), takes advantage of efficient cell disruption with a brief sonication, generating cell homogenates with fluorescently labeled AVs that retain their integrity as confirmed with light and electron microscopy analysis. These AVs could be detected directly in the sonicated cell homogenates on a flow cytometer as a distinct population of expected organelle size on a cytometry plot. Treatment of cells with inhibitors of autophagic flux, such as chloroquine or lysosomal protease inhibitors, increased the number of particles in this population under autophagy inducing conditions, while inhibition of autophagy induction with 3 methyladenine or knockdown of ATG proteins prevented this accumulation. This assay can be easily performed in a high-throughput format and opens up previously unexplored avenues for autophagy analysis. PMID- 24489954 TI - Phospholipase C and diacylglycerol mediate olfactory responses to amino acids in the main olfactory epithelium of an amphibian. AB - The semi-aquatic lifestyle of amphibians represents a unique opportunity to study the molecular driving forces involved in the transition of aquatic to terrestrial olfaction in vertebrates. Most amphibians have anatomically segregated main and vomeronasal olfactory systems, but at the cellular and molecular level the segregation differs from that found in mammals. We have recently shown that amino acid responses in the main olfactory epithelium (MOE) of larval Xenopus laevis segregate into a lateral and a medial processing stream, and that the former is part of a vomeronasal type 2 receptor expression zone in the MOE. We hypothesized that the lateral amino acid responses might be mediated via a vomeronasal-like transduction machinery. Here we report that amino acid-responsive receptor neurons in the lateral MOE employ a phospholipase C (PLC) and diacylglycerol mediated transduction cascade that is independent of Ca(2+) store depletion. Furthermore, we found that putative transient receptor potential (TRP) channel blockers inhibit most amino acid-evoked responses in the lateral MOE, suggesting that ion channels belonging to the TRP family may be involved in the signaling pathway. Our data show, for the first time, a widespread PLC- and diacylglycerol dependent transduction cascade in the MOE of a vertebrate already possessing a vomeronasal organ. PMID- 24489955 TI - Citrus sinensis annotation project (CAP): a comprehensive database for sweet orange genome. AB - Citrus is one of the most important and widely grown fruit crop with global production ranking firstly among all the fruit crops in the world. Sweet orange accounts for more than half of the Citrus production both in fresh fruit and processed juice. We have sequenced the draft genome of a double-haploid sweet orange (C. sinensis cv. Valencia), and constructed the Citrus sinensis annotation project (CAP) to store and visualize the sequenced genomic and transcriptome data. CAP provides GBrowse-based organization of sweet orange genomic data, which integrates ab initio gene prediction, EST, RNA-seq and RNA-paired end tag (RNA PET) evidence-based gene annotation. Furthermore, we provide a user-friendly web interface to show the predicted protein-protein interactions (PPIs) and metabolic pathways in sweet orange. CAP provides comprehensive information beneficial to the researchers of sweet orange and other woody plants, which is freely available at http://citrus.hzau.edu.cn/. PMID- 24489956 TI - Post-mating interactions and their effects on fitness of female and male Echinothrips americanus (Thysanoptera: Thripidae), a new insect pest in China. AB - Post-mating, sexual interactions of opposite sexes differ considerably in different organisms. Post-mating interactions such as re-mating behavior and male harassment can affect the fitness of both sexes. Echinothrips americanus is a new insect pest in Mainland China, and little is known about its post-mating interactions. In this study, we observed re-mating frequency and male harassment frequency and their effects on fitness parameters and offspring sex ratios of E. americanus females. Furthermore, we tested the impact of mating and post-mating interactions on fitness parameters of males. Our results revealed that the re mating frequency in female adults was extremely low during a 30-day period. However, post-mating interactions between females and males, consisting mainly of male harassment and female resistance, did occur and significantly reduced female longevity and fecundity. Interestingly, increased access to males did not affect the ratio of female offspring. For males, mating dramatically reduced their longevity. However, post-mating interactions with females had no effects on the longevity of mated males. These results enrich our basic knowledge about female and male mating and post-mating behaviors in this species and provide important information about factors that may influence population regulation of this important pest species. PMID- 24489957 TI - Divergence of acoustic signals in a widely distributed frog: relevance of inter male interactions. AB - Divergence of acoustic signals in a geographic scale results from diverse evolutionary forces acting in parallel and affecting directly inter-male vocal interactions among disjunct populations. Pleurodema thaul is a frog having an extensive latitudinal distribution in Chile along which males' advertisement calls exhibit an important variation. Using the playback paradigm we studied the evoked vocal responses of males of three populations of P. thaul in Chile, from northern, central and southern distribution. In each population, males were stimulated with standard synthetic calls having the acoustic structure of local and foreign populations. Males of both northern and central populations displayed strong vocal responses when were confronted with the synthetic call of their own populations, giving weaker responses to the call of the southern population. The southern population gave stronger responses to calls of the northern population than to the local call. Furthermore, males in all populations were stimulated with synthetic calls for which the dominant frequency, pulse rate and modulation depth were varied parametrically. Individuals from the northern and central populations gave lower responses to a synthetic call devoid of amplitude modulation relative to stimuli containing modulation depths between 30-100%, whereas the southern population responded similarly to all stimuli in this series. Geographic variation in the evoked vocal responses of males of P. thaul underlines the importance of inter-male interactions in driving the divergence of the acoustic traits and contributes evidence for a role of intra-sexual selection in the evolution of the sound communication system of this anuran. PMID- 24489958 TI - Qualichem in vivo: a tool for assessing the quality of in vivo studies and its application for bisphenol A. AB - In regulatory toxicology, quality assessment of in vivo studies is a critical step for assessing chemical risks. It is crucial for preserving public health studies that are considered suitable for regulating chemicals are robust. Current procedures for conducting quality assessments in safety agencies are not structured, clear or consistent. This leaves room for criticism about lack of transparency, subjective influence and the potential for insufficient protection provided by resulting safety standards. We propose a tool called "Qualichem in vivo" that is designed to systematically and transparently assess the quality of in vivo studies used in chemical health risk assessment. We demonstrate its use here with 12 experts, using two controversial studies on Bisphenol A (BPA) that played an important role in BPA regulation in Europe. The results obtained with Qualichem contradict the quality assessments conducted by expert committees in safety agencies for both of these studies. Furthermore, they show that reliance on standardized guidelines to ensure scientific quality is only partially justified. Qualichem allows experts with different disciplinary backgrounds and professional experiences to express their individual and sometimes divergent views-an improvement over the current way of dealing with minority opinions. It provides a transparent framework for expressing an aggregated, multi-expert level of confidence in a study, and allows a simple graphical representation of how well the study integrates the best available scientific knowledge. Qualichem can be used to compare assessments of the same study by different health agencies, increasing transparency and trust in the work of expert committees. In addition, it may be used in systematic evaluation of in vivo studies submitted by industry in the dossiers that are required for compliance with the REACH Regulation. Qualichem provides a balanced, common framework for assessing the quality of studies that may or may not be following standardized guidelines. PMID- 24489960 TI - Incontinentia pigmenti: learning disabilities are a fundamental hallmark of the disease. AB - Studies suggest that genetic factors are associated with the etiology of learning disabilities. Incontinentia Pigmenti (IP, OMIM#308300), which is caused by mutations of the IKBKG/NEMO gene, is a rare X-linked genomic disorder (1:10000/20:000) that affects the neuroectodermal tissues. It always affects the skin and sometimes the hair, teeth, nails, eyes and central nervous system (CNS). Data from IP patients demonstrate the heterogeneity of the clinical phenotype; about 30% have CNS manifestations. This extreme variability suggests that IP patients might also have learning disabilities. However, no studies in the literature have evaluated the cognitive profile of IP patients. In fact, the learning disability may go unnoticed in general neurological analyses, which focus on major disabling manifestations of the CNS. Here, we investigated the neuropsychological outcomes of a selected group of IP-patients by focusing on learning disabilities. We enrolled 10 women with IP (7 without mental retardation and 3 with mild to severe mental retardation) whose clinical diagnosis had been confirmed by the presence of a recurrent deletion in the IKBKG/NEMO gene. The participants were recruited from the Italian patients' association (I.P.A.SS.I. Onlus). They were submitted to a cognitive assessment that included the Wechsler Adult Intelligence scale and a battery of tests examining reading, arithmetic and writing skills. We found that 7 patients had deficits in calculation/arithmetic reasoning and reading but not writing skills; the remaining 3 had severe to mild intellectual disabilities. Results of this comprehensive evaluation of the molecular and psychoneurological aspects of IP make it possible to place "learning disabilities" among the CNS manifestations of the disease and suggest that the IKBKG/NEMO gene is a genetic determinant of this CNS defect. Our findings indicate the importance of an appropriate psychoneurological evaluation of IP patients, which includes early assessment of learning abilities, to prevent the onset of this deficit. PMID- 24489959 TI - Simvastatin impairs growth hormone-activated signal transducer and activator of transcription (STAT) signaling pathway in UMR-106 osteosarcoma cells. AB - Recent studies have demonstrated that statins reduce cell viability and induce apoptosis in various types of cancer cells. The molecular mechanisms underlying these effects are poorly understood. The JAK/STAT pathway plays an important role in the regulation of proliferation and apoptosis in many tissues, and its deregulation is believed to be involved in tumorigenesis and cancer. The physiological activation of STAT proteins by GH is rapid but transient in nature and its inactivation is regulated mainly by the expression of SOCS proteins. UMR 106 osteosarcoma cells express a GH-responsive JAK2/STAT5 signaling pathway, providing an experimental model to study the influence of statins on this system. In this study we investigated the actions of simvastatin on cell proliferation, migration, and invasion on UMR-106 cells and examined whether alterations in GH stimulated JAK/STAT/SOCS signaling may be observed. Results showed that treatment of osteosarcoma cells with simvastatin at 3 to 10 uM doses decreases cell proliferation, migration, and invasion in a time- and dose-dependent manner. At the molecular level, although the mechanisms used by simvastatin are not entirely clear, the effect of the statin on the reduction of JAK2 and STAT5 phosphorylation levels may partially explain the decrease in the GH-stimulated STAT5 transcriptional activity. This effect correlated with a time- and dose dependent increase of SOCS-3 expression levels in cells treated with simvastatin, a regulatory role that has not been previously described. Furthermore, the finding that simvastatin is capable of inducing SOCS-3 and CIS genes expression shows the potential of the JAK/STAT pathway as a therapeutic target, reinforcing the efficacy of simvastatin as chemotherapeutic drug for the treatment of osteosarcoma. PMID- 24489961 TI - Naturally occurring mutations in the nonstructural region 5B of hepatitis C virus (HCV) from treatment-naive Korean patients chronically infected with HCV genotype 1b. AB - The nonstructural 5B (NS5B) protein of the hepatitis C virus (HCV) with RNA dependent RNA polymerase (RdRp) activity plays a pivotal role in viral replication. Therefore, monitoring of its naturally occurring mutations is very important for the development of antiviral therapies and vaccines. In the present study, mutations in the partial NS5B gene (492 bp) from 166 quasispecies of 15 genotype-1b (GT) treatment-naive Korean chronic patients were determined and mutation patterns and frequencies mainly focusing on the T cell epitope regions were evaluated. The mutation frequency within the CD8+ T cell epitopes was significantly higher than those outside the CD8+ T cell epitopes. Of note, the mutation frequency within predicted CD4+ T cell epitopes, a particular mutational hotspot in Korean patients was significantly higher than it was in patients from other areas, suggesting distinctive CD4+ T cell-mediated immune pressure against HCV infection in the Korean population. The mutation frequency in the NS5B region was positively correlated with patients with carrier-stage rather than progressive liver disease (chronic hepatitis, liver cirrhosis and hepatocellular carcinoma). Furthermore, the mutation frequency in four codons (Q309, A333, V338 and Q355) known to be related to the sustained virological response (SVR) and end of treatment response (ETR) was also significantly higher in Korean patients than in patients from other areas. In conclusion, a high degree of mutation frequency in the HCV GT-1b NS5B region, particularly in the predicted CD4+ T cell epitopes, was found in Korean patients, suggesting the presence of distinctive CD4+ T cell pressure in the Korean population. This provides a likely explanation of why relatively high levels of SVR after a combined therapy of pegylated interferon (PEG-IFN) and ribavirin (RBV) in Korean chronic patients with GT-1b infections are observed. PMID- 24489962 TI - C26 cancer-induced muscle wasting is IKKbeta-dependent and NF-kappaB-independent. AB - Existing data suggest that NF-kappaB signaling is a key regulator of cancer induced skeletal muscle wasting. However, identification of the components of this signaling pathway and of the NF-kappaB transcription factors that regulate wasting is far from complete. In muscles of C26 tumor bearing mice, overexpression of dominant negative (d.n.) IKKbeta blocked muscle wasting by 69% and the IkappaBalpha-super repressor blocked wasting by 41%. In contrast, overexpression of d.n. IKKalpha or d.n. NIK did not block C26-induced wasting. Surprisingly, overexpression of d.n. p65 or d.n. c-Rel did not significantly affect muscle wasting. Genome-wide mRNA expression arrays showed upregulation of many genes previously implicated in muscle atrophy. To test if these upregulated genes were direct targets of NF-kappaB transcription factors, we compared genome wide p65 binding to DNA in control and cachectic muscle using ChIP-sequencing. Bioinformatic analysis of ChIP-sequencing data from control and C26 muscles showed very little p65 binding to genes in cachexia and little to suggest that upregulated p65 binding influences the gene expression associated with muscle based cachexia. The p65 ChIP-seq data are consistent with our finding of no significant change in protein binding to an NF-kappaB oligonucleotide in a gel shift assay, no activation of a NF-kappaB-dependent reporter, and no effect of d.n.p65 overexpression in muscles of tumor bearing mice. Taken together, these data support the idea that although inhibition of IkappaBalpha, and particularly IKKbeta, blocks cancer-induced wasting, the alternative NF-kappaB signaling pathway is not required. In addition, the downstream NF-kappaB transcription factors, p65 and c-Rel do not appear to regulate the transcriptional changes induced by the C26 tumor. These data are consistent with the growing body of literature showing that there are NF-kappaB-independent substrates of IKKbeta and IkappaBalpha that regulate physiological processes. PMID- 24489963 TI - On the reproducibility of TCGA ovarian cancer microRNA profiles. AB - Dysregulated microRNA (miRNA) expression is a well-established feature of human cancer. However, the role of specific miRNAs in determining cancer outcomes remains unclear. Using Level 3 expression data from the Cancer Genome Atlas (TCGA), we identified 61 miRNAs that are associated with overall survival in 469 ovarian cancers profiled by microarray (p<0.01). We also identified 12 miRNAs that are associated with survival when miRNAs were profiled in the same specimens using Next Generation Sequencing (miRNA-Seq) (p<0.01). Surprisingly, only 1 miRNA transcript is associated with ovarian cancer survival in both datasets. Our analyses indicate that this discrepancy is due to the fact that miRNA levels reported by the two platforms correlate poorly, even after correcting for potential issues inherent to signal detection algorithms. Corrections for false discovery and microRNA abundance had minimal impact on this discrepancy. Further investigation is warranted. PMID- 24489964 TI - Earlier diagnosis of invasive fusariosis with Aspergillus serum galactomannan testing. AB - Cross-reactivity of Fusarium species with serum galactomannan antigen (GMI) test has been observed. We sought to evaluate if GMI could help to early diagnose invasive fusariosis and to monitor treatment response. We reviewed the records of all patients with invasive fusariosis between 2008 and 2012 in three Brazilian hospitals. We selected patients who had at least 1 GMI test within 2 days before or after the date of the first clinical manifestation of fusariosis, and analyzed the temporal relationship between the first positive GMI test and the date of the diagnosis of invasive fusariosis, and the kinetics of GMI in relation to patients' response to treatment. We also selected 18 controls to determine the sensitivity and specificity of the test. Among 18 patients, 15 (83%) had at least one positive GMI (median 4, range 1-15). The sensitivity and specificity of was 83% and 67%, respectively. GMI was positive before the diagnosis of invasive fusariosis in 11 of the 15 cases (73%), at a median of 10 days (range 3-39), and after the diagnosis in 4 cases. GMI became negative in 8 of the 15 patients; 3 of these 8 patients (37.5%) were alive 90 days after the diagnosis of fusariosis compared with 2 of 7 (29%) who did not normalize GMI (p = 1.0). GMI is frequently positive in invasive fusariosis, and becomes positive before diagnosis in most patients. These findings may have important implications for the choice of antifungal therapy in settings with high prevalence of invasive fusariosis. PMID- 24489965 TI - Neuro-anatomical evidence indicating indirect modulation of macrophages by vagal efferents in the intestine but not in the spleen. AB - BACKGROUND: Electrical stimulation of the vagus nerve suppresses intestinal inflammation and normalizes gut motility in a mouse model of postoperative ileus. The exact anatomical interaction between the vagus nerve and the intestinal immune system remains however a matter of debate. In the present study, we provide additional evidence on the direct and indirect vagal innervation of the spleen and analyzed the anatomical evidence for neuroimmune modulation of macrophages by vagal preganglionic and enteric postganglionic nerve fibers within the intestine. METHODS: Dextran conjugates were used to label vagal preganglionic (motor) fibers projecting to the small intestine and spleen. Moreover, identification of the neurochemical phenotype of the vagal efferent fibers and enteric neurons was performed by immunofluorescent labeling. F4/80 antibody was used to label resident macrophages. RESULTS: Our anterograde tracing experiments did not reveal dextran-labeled vagal fibers or terminals in the mesenteric ganglion or spleen. Vagal efferent fibers were confined within the myenteric plexus region of the small intestine and mainly endings around nNOS, VIP and ChAT positive enteric neurons. nNOS, VIP and ChAT positive fibers were found in close proximity of intestinal resident macrophages carrying alpha7 nicotinic receptors. Of note, VIP receptors were found on resident macrophages located in close proximity of VIP positive nerve fibers. CONCLUSION: In the present study, we show that the vagus nerve does not directly interact with resident macrophages in the gut or spleen. Instead, the vagus nerve preferentially interacts with nNOS, VIP and ChAT enteric neurons located within the gut muscularis with nerve endings in close proximity of the resident macrophages. PMID- 24489966 TI - Serum CXCL16 as a novel marker of renal injury in type 2 diabetes mellitus. AB - BACKGROUND: Soluble C-X-C chemokine ligand 16 (CXCL16), a scavenger receptor for oxidized low density lipoprotein, has been shown to promote atherogenic effects in vivo and to predict long-term mortality in acute coronary syndrome. The aim of this study was to explore the association of circulating CXCL16 levels with diabetic subjects with and without renal disease. METHODOLOGY/PRINCIPAL FINDINGS: One hundred twenty Chinese subjects, which included patients with type 2 diabetes mellitus (T2DM), diabetic nephropathy (DN), and CKD, as well as healthy controls, were enrolled in this study. Serum CXCL16 levels were examined by immunoassay and other clinical biochemical parameters were tested based on standard methods. Our results indicated that, HDL and LDL cholesterol levels are significantly different in DN but not in T2D patients in comparison with healthy subjects. On the other hand, Serum CXCL16 levels were significantly increased in DN subjects compared with age and gender matched healthy and T2DM subjects (p<0.05 respectively). However, no significant changes in serum CXCL16 levels were found between T2DM and healthy subjects. Furthermore, serum CXCL16 concentration negatively correlated with estimated glomerular filtrate rate, creatinine clearance rate and blood albumin, and positively with 24 h proteinuria, blood urea nitrogen (BUN), creatinine, and uric acid after adjusting for age, gender and BMI in subjects with DN. Multiple stepwise regression analyses indicated that serum CXCL16 levels were independently associated with serum 24 h proteinuria, and BUN (p<0.05 respectively). CONCLUSION: Serum CXCL16 may be an indicator of renal injury in subjects with T2DM. Understanding the exact mechanism of elevated CXCL16 in subjects with DN requires further study. PMID- 24489967 TI - Startle auditory stimuli enhance the performance of fast dynamic contractions. AB - Fast reaction times and the ability to develop a high rate of force development (RFD) are crucial for sports performance. However, little is known regarding the relationship between these parameters. The aim of this study was to investigate the effects of auditory stimuli of different intensities on the performance of a concentric bench-press exercise. Concentric bench-presses were performed by thirteen trained subjects in response to three different conditions: a visual stimulus (VS); a visual stimulus accompanied by a non-startle auditory stimulus (AS); and a visual stimulus accompanied by a startle auditory stimulus (SS). Peak RFD, peak velocity, onset movement, movement duration and electromyography from pectoralis and tricep muscles were recorded. The SS condition induced an increase in the RFD and peak velocity and a reduction in the movement onset and duration, in comparison with the VS and AS condition. The onset activation of the pectoralis and tricep muscles was shorter for the SS than for the VS and AS conditions. These findings point out to specific enhancement effects of loud auditory stimulation on the rate of force development. This is of relevance since startle stimuli could be used to explore neural adaptations to resistance training. PMID- 24489968 TI - Genetic distinctiveness of the Herdwick sheep breed and two other locally adapted hill breeds of the UK. AB - There is considerable interest in locally adapted breeds of livestock as reservoirs of genetic diversity that may provide important fitness traits for future use in agriculture. In marginal areas, these animals contribute to food security and extract value from land unsuitable for other systems of farming. In England, close to 50% of the national sheep flock is farmed on grassland designated as disadvantaged areas for agricultural production. Many of these areas are in the uplands, where some native breeds of sheep continue to be commercially farmed only in highly localised geographical regions to which they are adapted. This study focuses on three of these breeds, selected for their adaptation to near identical environments and their geographical concentration in regions close to one another. Our objective has been to use retrotyping, microsatellites and single nucleotide polymorphisms to explore the origins of the breeds and whether, despite their similar adaptations and proximity, they are genetically distinctive. We find the three breeds each have a surprisingly different pattern of retrovirus insertions into their genomes compared with one another and with other UK breeds. Uniquely, there is a high incidence of the R0 retrotype in the Herdwick population, characteristic of a primitive genome found previously in very few breeds worldwide and none in the UK mainland. The Herdwick and Rough Fells carry two rare retroviral insertion events, common only in Texels, suggesting sheep populations in the northern uplands have a historical association with the original pin-tail sheep of Texel Island. Microsatellite data and analyses of SNPs associated with RXFP2 (horn traits) and PRLR (reproductive performance traits) also distinguished the three breeds. Significantly, an SNP linked to TMEM154, a locus controlling susceptibility to infection by Maedi Visna, indicated that all three native hill breeds have a lower than average risk of infection to the lentivirus. PMID- 24489969 TI - New mechanisms to explain the effects of added lactose fines on the dispersion performance of adhesive mixtures for inhalation. AB - Fine excipient particles or 'fines' have been shown to improve the dispersion performance of carrier-based formulations for dry powder inhalation. Mechanistic formulation studies have focussed mainly on explaining this positive effect. Previous studies have shown that higher drug contents may cause a decrease in dispersion performance, and there is no reason why this should not be true for fines with a similar shape, size and cohesiveness as drug particles. Therefore, the effects on drug detachment of 'fine lactose fines' (FLF, X50 = 1.95 um) with a similar size and shape as micronised budesonide were studied and compared to those of 'coarse lactose fines' (CLF, X50 = 3.94 um). Furthermore, interactions with the inhalation flow rate, the drug content and the mixing order were taken into account. The observed effects of FLF are comparable to drug content effects in that the detached drug fraction was decreased at low drug content and low flow rates but increased at higher flow rates. At high drug content the effects of added FLF were negligible. In contrast, CLF resulted in higher detached drug fractions at all flow rates and drug contents. The results from this study suggest that the effects of fines may be explained by two new mechanisms in addition to those previously proposed. Firstly, fines below a certain size may increase the effectiveness of press-on forces or cause the formation of strongly coherent fine particle networks on the carrier surface containing the drug particles. Secondly, when coarse enough, fines may prevent the formation of, or disrupt such fine particle networks, possibly through a lowering of their tensile strength. It is recommended that future mechanistic studies are based on the recognition that added fines may have any effect on dispersion performance, which is determined by the formulation and dispersion conditions. PMID- 24489971 TI - Plant responses to extreme climatic events: a field test of resilience capacity at the southern range edge. AB - The expected and already observed increment in frequency of extreme climatic events may result in severe vegetation shifts. However, stabilizing mechanisms promoting community resilience can buffer the lasting impact of extreme events. The present work analyzes the resilience of a Mediterranean mountain ecosystem after an extreme drought in 2005, examining shoot-growth and needle-length resistance and resilience of dominant tree and shrub species (Pinus sylvestris vs Juniperus communis, and P. nigra vs J. oxycedrus) in two contrasting altitudinal ranges. Recorded high vegetative-resilience values indicate great tolerance to extreme droughts for the dominant species of pine-juniper woodlands. Observed tolerance could act as a stabilizing mechanism in rear range edges, such as the Mediterranean basin, where extreme events are predicted to be more detrimental and recurrent. However, resistance and resilience components vary across species, sites, and ontogenetic states: adult Pinus showed higher growth resistance than did adult Juniperus; saplings displayed higher recovery rates than did conspecific adults; and P. nigra saplings displayed higher resilience than did P. sylvestris saplings where the two species coexist. P. nigra and J. oxycedrus saplings at high and low elevations, respectively, were the most resilient at all the locations studied. Under recurrent extreme droughts, these species-specific differences in resistance and resilience could promote changes in vegetation structure and composition, even in areas with high tolerance to dry conditions. PMID- 24489970 TI - Therapeutic effect of intravenous infusion of perfluorocarbon emulsion on LPS induced acute lung injury in rats. AB - Acute lung injury (ALI) and its more severe form, acute respiratory distress syndrome (ARDS) are the leading causes of death in critical care. Despite extensive efforts in research and clinical medicine, mortality remains high in these diseases. Perfluorocarbon (PFC), a chemical compound known as liquid ventilation medium, is capable of dissolving large amounts of physiologically important gases (mainly oxygen and carbon dioxide). In this study we aimed to investigate the effect of intravenous infusion of PFC emulsion on lipopolysaccharide (LPS) induced ALI in rats and elucidate its mechanism of action. Forty two Wistar rats were randomly divided into three groups: 6 rats were treated with saline solution by intratracheal instillation (control group), 18 rats were treated with LPS by intratracheal instillation (LPS group) and the other 18 rats received PFC through femoral vein prior to LPS instillation (LPS+PFC group). The rats in the control group were sacrificed 6 hours later after saline instillation. At 2, 4 and 6 hours of exposure to LPS, 6 rats in the LPS group and 6 rats in LPS+PFC group were sacrificed at each time point. By analyzing pulmonary pathology, partial pressure of oxygen in the blood (PaO2) and lung wet-dry weight ratio (W/D) of each rat, we found that intravenous infusion of PFC significantly alleviated acute lung injury induced by LPS. Moreover, we showed that the expression of pulmonary myeloperoxidase (MPO), intercellular adhesion molecule-1 (ICAM-1) of endothelial cells and CD11b of polymorphonuclear neutrophils (PMN) induced by LPS were significantly decreased by PFC treatment in vivo. Our results indicate that intravenous infusion of PFC inhibits the infiltration of PMNs into lung tissue, which has been shown as the core pathogenesis of ALI/ARDS. Thus, our study provides a theoretical foundation for using intravenous infusion of PFC to prevent and treat ALI/ARDS in clinical practice. PMID- 24489972 TI - Urinary concentration of monocyte chemoattractant protein-1 in idiopathic glomerulonephritis: a long-term follow-up study. AB - BACKGROUND: Monocyte chemoattractant protein-1 (MCP-1), which is up regulated in kidney diseases, is considered a marker of kidney inflammation. We examined the value of urine MCP-1 in predicting the outcome in idiopathic glomerulonephritis. METHODS: Between 1993 and 2004, 165 patients (68 females) diagnosed with idiopathic proteinuric glomerulopathy and with serum creatinine <150 umol/L at diagnosis were selected for the study. Urine concentrations of MCP-1 were analyzed by ELISA in early morning spot urine samples collected on the day of the diagnostic kidney biopsy. The patients were followed until 2009. The progression rate to end-stage kidney disease was calculated using Kaplan-Meier survival analysis. End-stage kidney disease (ESKD) was defined as the start of kidney replacement therapy during the study follow-up time. RESULTS: Patients with proliferative glomerulonephritis had significantly higher urinary MCP-1 excretion levels than those with non-proliferative glomerulonephritis (p<0.001). The percentage of patients whose kidney function deteriorated significantly was 39.0% in the high MCP-1 excretion group and 29.9% in the low MCP-1 excretion group. However, after adjustment for confounding variables such as glomerular filtration rate (GFR) and proteinuria, there was no significant association between urine MCP-1 concentration and progression to ESKD, (HR=1.75, 95% CI=0.64-4.75, p=0.27). CONCLUSION: Our findings indicate that progression to end-stage kidney disease in patients with idiopathic glomerulopathies is not associated with urine MCP-1 concentrations at the time of diagnosis. PMID- 24489973 TI - Phosphite protects Fagus sylvatica seedlings towards Phytophthora plurivora via local toxicity, priming and facilitation of pathogen recognition. AB - Phytophthora plurivora causes severe damage on Fagus sylvatica and is responsible for the extensive decline of European Beech throughout Europe. Unfortunately, no effective treatment against this disease is available. Phosphite (Phi) is known to protect plants against Phytophthora species; however, its mode of action towards P. plurivora is still unknown. To discover the effect of Phi on root infection, leaves were sprayed with Phi and roots were subsequently inoculated with P. plurivora zoospores. Seedling physiology, defense responses, colonization of root tissue by the pathogen and mortality were monitored. Additionally the Phi concentration in roots was quantified. Finally, the effect of Phi on mycelial growth and zoospore formation was recorded. Phi treatment was remarkably efficient in protecting beech against P. plurivora; all Phi treated plants survived infection. Phi treated and infected seedlings showed a strong up regulation of several defense genes in jasmonate, salicylic acid and ethylene pathways. Moreover, all physiological parameters measured were comparable to control plants. The local Phi concentration detected in roots was high enough to inhibit pathogen growth. Phi treatment alone did not harm seedling physiology or induce defense responses. The up-regulation of defense genes could be explained either by priming or by facilitation of pathogen recognition of the host. PMID- 24489974 TI - Preparation of artificial plasma membrane mimicking vesicles with lipid asymmetry. AB - Lipid asymmetry, the difference in lipid distribution across the lipid bilayer, is one of the most important features of eukaryotic cellular membranes. However, commonly used model membrane vesicles cannot provide control of lipid distribution between inner and outer leaflets. We recently developed methods to prepare asymmetric model membrane vesicles, but facile incorporation of a highly controlled level of cholesterol was not possible. In this study, using hydroxypropyl-alpha-cyclodextrin based lipid exchange, a simple method was devised to prepare large unilamellar model membrane vesicles that closely resemble mammalian plasma membranes in terms of their lipid composition and asymmetry (sphingomyelin (SM) and/or phosphatidylcholine (PC) outside/phosphatidylethanolamine (PE) and phosphatidylserine (PS) inside), and in which cholesterol content can be readily varied between 0 and 50 mol%. We call these model membranes "artificial plasma membrane mimicking" ("PMm") vesicles. Asymmetry was confirmed by both chemical labeling and measurement of the amount of externally-exposed anionic lipid. These vesicles should be superior and more realistic model membranes for studies of lipid-lipid and lipid-protein interaction in a lipid environment that resembles that of mammalian plasma membranes. PMID- 24489975 TI - Intracellular biosynthesis and removal of copper nanoparticles by dead biomass of yeast isolated from the wastewater of a mine in the Brazilian Amazonia. AB - In this study was developed a natural process using a biological system for the biosynthesis of nanoparticles (NPs) and possible removal of copper from wastewater by dead biomass of the yeast Rhodotorula mucilaginosa. Dead and live biomass of Rhodotorula mucilaginosa was used to analyze the equilibrium and kinetics of copper biosorption by the yeast in function of the initial metal concentration, contact time, pH, temperature, agitation and inoculum volume. Dead biomass exhibited the highest biosorption capacity of copper, 26.2 mg g(-1), which was achieved within 60 min of contact, at pH 5.0, temperature of 30 degrees C, and agitation speed of 150 rpm. The equilibrium data were best described by the Langmuir isotherm and Kinetic analysis indicated a pseudo-second-order model. The average size, morphology and location of NPs biosynthesized by the yeast were determined by scanning electron microscopy (SEM), energy dispersive X-ray spectroscopy (EDS) and transmission electron microscopy (TEM). The shape of the intracellularly synthesized NPs was mainly spherical, with an average size of 10.5 nm. The X-ray photoelectron spectroscopy (XPS) analysis of the copper NPs confirmed the formation of metallic copper. The dead biomass of Rhodotorula mucilaginosa may be considered an efficiently bioprocess, being fast and low-cost to production of copper nanoparticles and also a probably nano-adsorbent of this metal ion in wastewater in bioremediation process. PMID- 24489976 TI - Monitoring the Electrochemical Processes in the Lithium-Air Battery by Solid State NMR Spectroscopy. AB - A multi-nuclear solid-state NMR approach is employed to investigate the lithium air battery, to monitor the evolution of the electrochemical products formed during cycling, and to gain insight into processes affecting capacity fading. While lithium peroxide is identified by 17O solid state NMR (ssNMR) as the predominant product in the first discharge in 1,2-dimethoxyethane (DME) based electrolytes, it reacts with the carbon cathode surface to form carbonate during the charging process. 13C ssNMR provides evidence for carbonate formation on the surface of the carbon cathode, the carbonate being removed at high charging voltages in the first cycle, but accumulating in later cycles. Small amounts of lithium hydroxide and formate are also detected in discharged cathodes and while the hydroxide formation is reversible, the formate persists and accumulates in the cathode upon further cycling. The results indicate that the rechargeability of the battery is limited by both the electrolyte and the carbon cathode stability. The utility of ssNMR spectroscopy in directly detecting product formation and decomposition within the battery is demonstrated, a necessary step in the assessment of new electrolytes, catalysts, and cathode materials for the development of a viable lithium-oxygen battery. PMID- 24489977 TI - New Approaches to Treating Cardiac Cachexia in the Older Patient. AB - Congestive heart failure (CHF) is a leading cause of morbidity and mortality in the elderly, accounting for more hospitalizations than any other condition. Advanced stages of congestive heart failure can be associated with serious complications such as cardiac cachexia (defined here as unintentional weight loss of more than 6% in 6 months). Cardiac cachexia and the associated progressive weight loss are sometimes overlooked by older patients, their families and care providers. A delay in the diagnosis can result in further loss of vital organ tissue, progressive weakness, fall-related injuries and even long-term care institutionalization and/or death. During the past several years, researchers have begun to broaden their understanding of this common, morbid and often fatal condition, and these findings will help to characterize the features that assist in its diagnosis, minimize its exacerbation, delay the progressive decline, and educate clinicians about the potential management options. PMID- 24489978 TI - Magnified Effects of Changes in NIH Research Funding Levels. AB - What happens within the university-based research enterprise when a federal funding agency abruptly changes research grant funding levels, up or down? We use simple difference equation models to show that an apparently modest increase or decrease in funding levels can have dramatic effects on researchers, graduate students, postdocs, and the overall research enterprise. The amplified effect is due to grants lasting for an extended period, thereby requiring the majority of funds available in one year to pay for grants awarded in previous years. We demonstrate the effect in various ways, using National Institutes of Health data for two situations: the historical doubling of research funding from 1998 to 2003 and the possible effects of "sequestration" in January 2013. We posit human responses to such sharp movements in funding levels and offer suggestions for amelioration. PMID- 24489979 TI - The Role of Peers and Parents in Predicting Alcohol Consumption among Chilean Youth. AB - This study estimated marginal associations of parent- and peer-related measures to examine the different patterns of lifetime ever-use and frequency of alcohol consumption among adolescents in Santiago, Chile (N=918). Probit and negative binomial models were applied to predict the probability of ever-use and the average number of drinks consumed in the past 30 days. Results supported the profound role of peer-relationships in the development of youth drinking behavior. Particularly, peer pressure seemed more important in predicting alcohol ever-use than the frequency of drinking. Simultaneously, parents, especially fathers, played a crucial protective role. Policies aimed at preventing various drinking patterns may be more effective if they not only focus on the targeted adolescents, but also reach out to peers and parents. PMID- 24489980 TI - Public Diplomacy in Prime Time: Exploring the Potential of Entertainment Education in International Public Diplomacy. AB - Can stories succeed where traditional forms of diplomacy have faltered? This study examined whether a primetime drama could impact American viewers' knowledge, attitudes, and behavior with respect to U.S. foreign policy and funding by surveying 173 viewers of an episode of Law & Order: SVU ("Witness"). Additionally, this study sought to uncover which theoretical construct - involvement with a specific character or involvement with the narrative more generally (transportation) - best predicted impact. The fictional character in question was Nardelie, a woman forced to flee the Democratic Republic of the Congo after repeated rape by militias vying for "conflict minerals," so named because control of these valuable minerals has triggered numerous conflicts. Separate regression analyses suggested a positive relationship between impact of the storyline and both theoretical constructs. However, when both constructs were entered into a single regression, involvement with Nardelie was the stronger predictor of knowledge (e.g., conflict minerals, sexual violence, and asylum issues) and current or future behavior (i.e., discussing global health) while transportation was the stronger predictor of attitudes (i.e., support for aid). This suggests that, while correlated, these constructs do not completely overlap. Implications of these results and the use of entertainment education in public diplomacy are discussed. PMID- 24489981 TI - Imaging of Myocardial Oxidative Metabolism in Heart Failure. AB - Metabolic imaging has a potential for better understanding of pathophysiology of heart failure. C-11 acetate is taken up by the heart, rapidly converted to acetylCoA and readily metabolized to C-11 CO2 through TCA cycle with oxidative phosphorylation. Thus, the myocardial turnover rate of this tracer is tightly correlated with its clearance of C-11 CO2, reflecting overall oxidative metabolism. The heart relies on aerobic oxidative substrate for the generation of ATP, which is required to maintain its contractile function. The progression to heart failure is associated with a gradual decline in the activity of mitochondrial respiratory pathways, leading to diminished capacity for ATP production. The work metabolic index can also be estimated by the combination of C-11 acetate PET and hemodynamics by echocardiography, the metabolic index is a significant marker to understand the pathophysiology of heart failure as well as myocardial oxidative metabolism. PMID- 24489982 TI - Cardiac Cell Tracking with MRI Reporter Genes: Welcoming a New Field. AB - Research into cell therapy based cardiac repair and regeneration has experienced explosive growth over the last decade, however further progress is hindered by an inability to serially and non-invasively image cell survival and fate decisions following implantation. Recent advances in magnetic resonance imaging (MRI) reporter gene techniques have enabled in vivo imaging of cell survival, proliferation, migration, and differentiation, however this has mostly been performed in stationary tissues. A small series of recent studies has examined the possibility of using MRI reporter genes to track the survival of cells injected into the heart following myocardial infarction. In this review, we seek to frame the emerging field of MRI reporter gene based cardiac cell tracking within the larger framework of the needs of cardiac regeneration therapy and the more established field of MRI cell tracking. While initial studies have demonstrated a promising ability to track the viability and proliferation of cells used for cell therapy, the ultimate goal of MR reporter gene imaging in the heart remains the ability to simultaneously correlate cell fate decisions with additional measures of structural and functional recovery. PMID- 24489983 TI - Tanshinol attenuates the deleterious effects of oxidative stress on osteoblastic differentiation via Wnt/FoxO3a signaling. AB - There is now increasing evidence which suggests a pivotal role for oxidative stress in the development and progression of osteoporosis. We confirm herein the protective effects of natural antioxidant Tanshinol against oxidative stress in osteoblastic differentiation and the underlying mechanism. Our results show that hydrogen peroxide (H2O2) leads to accumulation of reactive oxygen species (ROS), decrease in cell viability, cell cycle arrest and apoptosis in a caspase-3 dependent manner, and inhibition of osteoblastic differentiation. Tanshinol reverses these deleterious consequence triggered by oxidative stress. Moreover, under the condition of oxidative stress, Tanshinol suppresses the activation of FoxO3a transcription factor and expressions of its target genes Gadd45a and catalase (CAT) and simultaneously counteracts the inhibition of Wnt signalling and expressions of target genes Axin2, alkaline phosphatase (ALP), and Osteoprotegerin (OPG). The findings are further consolidated using FoxO3a siRNA interference and overexpression of Tcf4. The results illustrate that Tanshinol attenuates oxidative stress via down-regulation of FoxO3a signaling, and rescues the decrease of osteoblastic differentiation through upregulation of Wnt signal under oxidative stress. The present findings suggest that the beneficial effects of Tanshinol may be adopted as a novel therapeutic approach in recently recognized conditions of niche targeting osteoporosis. PMID- 24489984 TI - Antioxidants supplementation in elderly cardiovascular patients. AB - Supplementation with antioxidants and its benefit-risk relationship have been largely discussed in the elderly population. We evaluated whether antioxidants supplementation improved the biochemical profile associated with oxidative metabolism in elderly cardiovascular patients. Patients (n = 112) received daily supplementation with alpha-TP 400 mg, beta-carotene 40 mg, and vitamin C 1000 mg for 2 months (treatment). Plasma concentrations of alpha-tocopherol (alpha-TP), beta-carotene (betaC), ubiquinol-10 (QH-10), glutathione, and thiobarbituric acid reactive substances (TBARS) were determined before and after treatment. Response to treatment was dependent on pretreatment alpha-TP and betaC levels. Increase in alpha-TP and betaC levels was observed only in patients with basal levels <18 MUM for alpha-TP (P < 0.01) and <0.30 MUM for betaC (P < 0.02). Ubiquinol-10, glutathione, and TBARS were unaffected by treatment: QH-10 (+57%, F(1,110) = 3.611, P < 0.06, and N.S.), glutathione (+21%, F(1,110) = 2.92, P < 0.09, and N.S.), and TBARS (-29%, F(1,110) = 2.26, P < 0.14, and N.S.). Treatment reduced oxidative metabolism: 5.3% versus 14.6% basal value (F(1,110) = 9.21, P < 0.0003). Basal TBARS/alpha-TP ratio was higher in smokers compared to nonsmokers: 0.11 +/- 0.02 versus 0.06 +/- 0.01 (F(32,80) = 1.63, P < 0.04). Response to antioxidant supplementation was dependent on basal plasma levels of alpha-TP and betaC. Smoking status was strongly associated with atherosclerotic cardiovascular disease and high TBARS/alpha-TP ratio (lipid peroxidation). PMID- 24489985 TI - The effect of submaximal exercise preceded by single whole-body cryotherapy on the markers of oxidative stress and inflammation in blood of volleyball players. AB - The aim of the study was to determine the effect of single whole-body cryotherapy (WBC) session applied prior to submaximal exercise on the activity of antioxidant enzymes, the concentration of lipid peroxidation products, total oxidative status, and the level of cytokines in blood of volleyball players. The study group consisted of 18 male professional volleyball players, who were subjected to extremely cold air (-130 degrees C) prior to exercise performed on cycloergometer. Blood samples were taken five times: before WBC, after WBC procedure, after exercise preceded by cryotherapy (WBC exercise), and before and after exercise without WBC (control exercise). The activity of catalase statistically significantly increased after control exercise. Moreover, the activity of catalase and superoxide dismutase was lower after WBC exercise than after control exercise (P < 0.001). After WBC exercise, the level of IL-6 and IL 1beta was also lower (P < 0.001) than after control exercise. The obtained results may suggest that cryotherapy prior to exercise may have some antioxidant and anti-inflammatory properties. The relations between the level of studied oxidative stress and inflammatory markers may testify to the contribution of reactive oxygen species in cytokines release into the blood system in response to exercise and WBC. PMID- 24489987 TI - Vernonia condensata Baker (Asteraceae): a promising source of antioxidants. AB - The present study evaluated the antioxidant potential of Vernonia condensata Baker (Asteraceae). Dried and powdered leaves were exhaustively extracted with ethanol by static maceration followed by partition to obtain the hexane, dichloromethane, ethyl acetate, and butanol fractions. Total phenols and flavonoids contents were determined through spectrophotometry and flavonoids were identified by HPLC-DAD system. The antioxidant activity was assessed by DPPH radical scavenging activity, TLC-bioautography, reducing power of Fe(+3), phosphomolybdenum, and TBA assays. The total phenolic content and total flavonoids ranged from 0.19 to 23.11 g/100 g and from 0.13 to 4.10 g/100 g, respectively. The flavonoids apigenin and luteolin were identified in the ethyl acetate fraction. The IC50 of DPPH assay varied from 4.28 to 75.10 ug/mL and TLC bioautography detected the antioxidant compounds. The reducing power of Fe(+3) was 19.98 to 336.48 MUg/mL, while the reaction with phosphomolybdenum ranged from 13.54% to 32.63% and 56.02% to 135.00% considering ascorbic acid and rutin as reference, respectively. At 30 mg/mL, the ethanolic extract and fractions revealed significant effect against lipid peroxidation. All these data sustain that V. condensata is an important and promising source of bioactive substances with antioxidant activity. PMID- 24489986 TI - Inhibition of nuclear Nox4 activity by plumbagin: effect on proliferative capacity in human amniotic stem cells. AB - Human amniotic fluid stem cells (AFSC) with multilineage differentiation potential are novel source for cell therapy. However, in vitro expansion leads to senescence affecting differentiation and proliferative capacities. Reactive oxygen species (ROS) have been involved in the regulation of stem cell pluripotency, proliferation, and differentiation. Redox-regulated signal transduction is coordinated by spatially controlled production of ROS within subcellular compartments. NAD(P)H oxidase family, in particular Nox4, has been known to produce ROS in the nucleus; however, the mechanisms and the meaning of this function remain largely unknown. In the present study, we show that Nox4 nuclear expression (nNox4) increases during culture passages up to cell cycle arrest and the serum starvation causes the same effect. With the decrease of Nox4 activity, obtained with plumbagin, a decline of nuclear ROS production and of DNA damage occurs. Moreover, plumbagin exposure reduces the binding between nNox4 and nucleoskeleton components, as Matrin 3. The same effect was observed also for the binding with phospho-ERK, although nuclear ERK and P-ERK are unchanged. Taken together, we suggest that nNox4 regulation may have important pathophysiologic effects in stem cell proliferation through modulation of nuclear signaling and DNA damage. PMID- 24489988 TI - Resveratrol: why is it a promising therapy for chronic kidney disease patients? AB - Resveratrol, a phenolic compound found in various plants, including grapes, berries, and peanuts, shows promise for the treatment of cancer, aging, type 2 diabetes, and cardiovascular diseases. Resveratrol can promote transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) activation, increase the expression level of SIRT-1, which is a sirtuin family protein, and reduce mTOR pathway signaling. This compound has anti-inflammatory properties in that it inhibits or antagonizes the nuclear factor-kappaB (NF-kappaB) activity, which is a redox-sensitive transcription factor that coordinates the inflammatory response. Inflammation and oxidative stress, which are common features in patients with chronic kidney disease (CKD), are interrelated and associated with cardiovascular disease and the progression of CKD itself. Because of the modulation of the mechanisms involved in the inflammatory-oxidative stress cycle, resveratrol could play an important role in controlling CKD-related metabolic derangements. Although resveratrol supplementation in theory is a promising therapy in this patient group, there are no studies evaluating its effects. Thus, the present review aims to describe the role of resveratrol in inflammation and oxidative stress modulation and its possible benefits to patients with CKD. PMID- 24489989 TI - The elusive and controversial roles of estrogen and progesterone receptors in human endometriosis. AB - Endometriosis is a complex and challenging disease that involves aberrant adhesion, growth, and progression of endometrial tissues outside of the uterine cavity, and there is evidence to suggest that estrogen plays a key role in its development and progression. Numerous in vivo clinical studies have described the ectopic expression and regulation of estrogen receptor (ER) and progesterone receptor (PR) in the different types of endometriosis compared to normal or eutopic endometrium. However, we have noticed that conflicting and contradictory results have been presented in terms of ER subtype (ERalpha and ERbeta) and PR isoform (PRA and PRB) expression. Both ER and PR are transcription factors and ER/PR-mediated responses depend on the coordinated, opposing, and compensatory functions of ER subtypes and PR isoforms. Moreover, analysis of the uterine phenotypes of ERalpha/ERbeta and PRA/PRB knockout mice indicates that different ER subtypes and PR isoforms mediate distinct responses to steroid hormones and play different roles in uterine function. In this review, we outline studies that have elucidated the molecules and signaling pathways that are linked to ER and/or PR signaling pathways in the development and progression of endometriosis. PMID- 24489990 TI - Lost in translation: animal models and clinical trials in cancer treatment. AB - Due to practical and ethical concerns associated with human experimentation, animal models have been essential in cancer research. However, the average rate of successful translation from animal models to clinical cancer trials is less than 8%. Animal models are limited in their ability to mimic the extremely complex process of human carcinogenesis, physiology and progression. Therefore the safety and efficacy identified in animal studies is generally not translated to human trials. Animal models can serve as an important source of in vivo information, but alternative translational approaches have emerged that may eventually replace the link between in vitro studies and clinical applications. This review summarizes the current state of animal model translation to clinical practice, and offers some explanations for the general lack of success in this process. In addition, some alternative strategies to the classic in vivo approach are discussed. PMID- 24489991 TI - Transplantation of Fas-deficient or wild-type neural stem/progenitor cells (NPCs) is equally efficient in treating experimental autoimmune encephalomyelitis (EAE). AB - Studies have shown that neural stem/progenitor cell (NPC) transplantation is beneficial in experimental autoimmune encephalomyelitis (EAE), an established animal model of multiple sclerosis (MS). It is unclear whether NPCs have the ability to integrate into the host CNS to replace lost cells or if their main mechanism of action is via bystander immunomodulation. Understanding the mechanisms by which NPCs exert their beneficial effects as well as exploring methods to increase post-transplantation survival and differentiation is critical to advancing this treatment strategy. Using the EAE model and Fas-deficient (lpr) NPCs, we investigated the effects of altering the Fas system in NPC transplantation therapy. We show that transplantation of NPCs into EAE mice ameliorates clinical symptoms with greater efficacy than sham treatments regardless of cell type (wt or lpr). NPC transplantation via retro-orbital injections significantly decreased inflammatory infiltrates at the acute time point, with a similar trend at the chronic time point. Both wt and lpr NPCs injected into mice with EAE were able to home to sites of CNS inflammation in the periventricular brain and lumbar spinal cord. Both wt and lpr NPCs have the same capacity for inducing apoptosis of Th1 and Th17 cells, and minimal numbers of NPCs entered the CNS. These cells did not express terminal differentiation markers, suggesting that NPCs exert their effects mainly via bystander peripheral immunomodulation. PMID- 24489992 TI - Anti-CD39 and anti-CD73 antibodies A1 and 7G2 improve targeted therapy in ovarian cancer by blocking adenosine-dependent immune evasion. AB - The ectonucleotidases CD39 and CD73 degrade ATP to adenosine which inhibits immune responses via the A2A adenosine receptor (ADORA2A) on T and NK cells. The current study investigates the potential therapeutic use of the specific anti CD39- and anti CD73-antibodies A1 (CD39) and 7G2 (CD73) as these two ectonucleotidases are overexpressed in ovarian cancer (OvCA). As expected, NK cell cytotoxicity against the human ovarian cancer cell lines OAW-42 or SK-OV-3 was significantly increased in the presence of A1 or 7G2 antibody. While this might partly be due to antibody-dependent cell-mediated cytotoxicity, a luciferase-dependent assay for quantifying biologically active adenosine further showed that A1 and 7G2 can inhibit CD39 and CD73-dependent adenosine-generation. In turn, the reduction in adenosine levels achieved by addition of A1 and 7G2 to OAW-42 or SK-OV-3 cells was found to de-inhibit the proliferation of CD4(+) T cells in coculture with OvCA cells. Likewise, blocking of CD39 and CD73 on OvCA cells via A1 and 7G2 led to an increased cytotoxicity of alloreactive primed T cells. Thus, antibodies like A1 and 7G2 could improve targeted therapy in ovarian cancer not only by specifically labeling overexpressed antigens but also by blocking adenosine-dependent immune evasion in this immunogenic malignancy. PMID- 24489993 TI - Decreased expression of stromal estrogen receptor alpha and beta in prostate cancer. AB - BACKGROUND: Recently there has been an increased interest in the role of tumor associated stroma in prostate tumorigenesis, but little is known about the respective roles of stomal ERalpha and ERbeta in prostate cancer (PCa). This study characterizes the expression patterns of ERalpha and ERbeta in tumor associated stroma in association with various clinicopathological factors of importance in PCa prognosis and treatment. DESIGN: Immunohistochemistry was performed using antibodies against ERalpha and ERbeta to characterize their expression patterns in PCa tissue. Stromal ER levels (ERalpha and ERbeta) on tissue sections (n=47), were compared between tumor associated stroma and adjacent benign associated stroma. Immunohistochemistry was also performed on a PCa tissue microarray (TMA) (n=177) to correlate stromal expression with various clinicopathological parameters. The levels of ER nuclear expression were scored semi-quantitatively. RESULTS: The expression levels of both ERalpha and ERbeta were significantly lower in tumor-associated stroma than stroma surrounding benign prostatic glands on the same tissue section (ERalpha: p<0.01; ERbeta: p=0.01). When correlated with clinicopathological factors, the level of ERalpha expression in tumor-associated stroma showed a positive correlation with Gleason score (R(2)=0.8638). The expression of ERalpha was higher in PCa with advanced tumor stage (p=0.05) and not significantly different in extraprostatic extension (p>0.05). The level of ERbeta expression in tumor-associated stroma was decreased in patients older than 60 years compared to younger patients (p=0.01). CONCLUSION: This study demonstrates significant down-regulation of ERalpha and ERbeta expression in the tumor-associated stroma of PCa. However, the level of ERalpha expression in tumor-associated stroma shows a positive correlation with cancer differentiation and tumor stage. PMID- 24489994 TI - MRI and ultrasonography detection of cervical lymph node metastases in differentiated thyroid carcinoma before reoperation. AB - OBJECTIVE: The purpose of this study was to compare the diagnostic capabilities of magnetic resonance imaging (MRI) and ultrasonography (US) for cervical lymph nodal metastases in differentiated thyroid carcinoma (DTC) before reoperation. MATERIAL AND METHOD: From June 2011 to May 2013, preoperative MRI and ultrasound data were collected from differentiated thyroid cancer patients who underwent a reoperation. The following characteristics were assessed: the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of MRI and US. The MRI and ultrasound findings were correlated with the histological diagnosis after reoperation. RESULTS: One hundred and thirty-eight cases were included in the analysis. 88.4% (122/138) of which had evidence of residual thyroid cancer tissue or metastatic nodal involvement at final histology. Lymph nodal metastases were confirmed in the central compartment in 76.42% (81/106) of patients and in lateral compartment in 73.28% (85/116) of patients. The sensitivity, specificity and accuracy of MRI VS US for detecting central compartment metastases was 75% VS 41.67% (P=0.04), 90.91% VS 100% (P=1) and 80% VS 60% (P=0.618), respectively; For detecting lateral compartment metastases was 83.33% VS 77.78% (P=1), 25% VS 50% (P=0.606) and 65.38% VS 69.23% (P=1), respectively. There was statistically significant difference between the sensitivity of MRI and ultrasound for diagnose of central compartment metastases. The MRI features with the greatest correlation with positive lymph nodal metastases were fusion and enhancing lesions. The ultrasound features with the greatest correlation with positive lymph nodal metastases were hypoechoic and microcalcifications. CONCLUSION: MRI is more sensitive than ultrasonography in detecting central compartment metastases in papillary thyroid carcinoma. There is no significant difference in diagnosis of lateral neck node metastases between MRI and US. PMID- 24489995 TI - Nuclear localization of catalytically active MMP-2 in endothelial cells and neurons. AB - From microscopic organelles and sub-cellular domains to the level of whole tissues, organs, and body parts, living organisms must continuously maintain and renovate structural components. Matrix metalloproteinases (MMPs) comprise a family of over two dozen Zn-dependent endopeptidases thought to be primary effectors of extracellular tissue renewal and remodeling processes. Endogenous inhibitors, particularly the tissue inhibitors of MMPs (TIMPs), counteract MMP-2 proteolytic activity, but also participate in conversion of several pro-MMPs to proteolytically active forms. Numerous pathologies are characterized by imbalances in activities of MMPs relative to TIMPs. MMPs are synthesized and stored in cytoplasmic domains prior to secretion or expression in cell surface associated form. Several proteases have been identified in cell nuclei, but their functions, regulation, and substrates remain largely unknown. Here we showed that the catalytically active gelatinase MMP-2 is expressed in nuclei of endothelial cells and neurons, but not in glial or Schwannoma cell lines, in a pattern resembling nuclear speckles, and colocalizes with TIMP-1. PMID- 24489996 TI - Surgical treatment for endometrioma does not increase clinical pregnancy rate or live birth/ongoing pregnancy rate after fresh IVF/ICSI treatment. AB - The impact of surgical treatment for endometrioma prior to assisted reproductive treatment (ART) on pregnancy outcomes remains controversy. The aim of this study is to investigate whether surgery provides benefits in subsequent ART outcomes. We retrospectively analyzed the data of 292 patients who underwent their first attempted IVF/ICSI treatment at fertility center in a university hospital, from 2011 to 2013. The primary outcomes included clinical pregnancy rate (CPR), live birth/ongoing pregnancy rate (LB/OPR). Although patients with no history of surgery and with visual endometriomas during IVF/ICSI treatment had fewer antral follicles (9.3+/-4.9 vs. 11.0+/-5.3, P=0.046), and required higher dosage of gonadotropin (3122.8+/-1118.1 vs. 2741.7+/-1096.0, P=0.043) when compared to patients who underwent surgery for endometriomas and without visual endometriomas during IVF/ICSI, the CPR and LB/OPR was not significantly affected (OR=0.771, 95%CI=0.398-1.495, and OR=1.043, 95%CI=0.526-2.069, respectively). In conclusion, surgical treatment does not significantly improve pregnancy outcomes in patients who plan to take IVF/ICSI treatment. PMID- 24489997 TI - Preclinical evaluation of an O(6)-methylguanine-DNA methyltransferase siRNA/liposome complex administered by convection-enhanced delivery to rat and porcine brains. AB - The main determinant of glioblastoma (GBM) resistance to temozolomide (TMZ) is thought to be O(6)-methylguanine-DNA methyltransferase (MGMT), which is a DNA repair enzyme that removes alkyl groups from the O(6)-position of guanine. Previously, we reported that a MGMT-siRNA/cationic liposome complex exerted a clear synergistic antitumor effect in combination with TMZ. Translation to a clinical setting might be desirable for reinforcing the efficacy of TMZ therapy for GBM. In this study, we aim to evaluate the safety of MGMT-siRNA/cationic liposome complexes and determine whether the convection-enhanced delivery of these complexes is suitable for clinical use by undertaking preclinical testing in laboratory animals. No significant adverse events were observed in rats receiving infusions of MGMT-siRNA/cationic liposome complex directly into the brain with or without TMZ administration. A pig which received the complex administered by CED also showed no evidence of neurological dysfunction or histological abnormalities. However, the complex did not appear to achieve effective distribution by CED in either the rat or the porcine brain tissue. Considering these results together, we concluded that insufficient distribution of cationic liposomes was achieved for tumor treatment by CED. PMID- 24489998 TI - Project Salud: Using community-based participatory research to culturally adapt an HIV prevention intervention in the Latino migrant worker community. AB - Despite the unique and challenging circumstances confronting Latino migrant worker communities in the U.S., debate still exists as to the need to culturally adapt evidence-based interventions for dissemination with this population. Project Salud adopted a community-based participatory research model and utilized focus group methodology with 83 Latino migrant workers to explore the relevance of culturally adapting an evidence-based HIV prevention intervention to be disseminated within this population. Findings from this study indicate that, despite early reservations, Latino migrant workers wanted to participate in the cultural adaptation that would result in an intervention that was culturally relevant, respectful, responsive to their life experiences, and aligned with their needs. This study contributes to the cultural adaptation/fidelity debate by highlighting the necessity of exploring ways to develop culturally adapted interventions characterized by high cultural relevance without sacrificing high fidelity to the core components that have established efficacy for evidence-based HIV prevention interventions. PMID- 24489999 TI - Development of a Comprehensive Osteochondral Allograft MRI Scoring System (OCAMRISS) with Histopathologic, Micro-Computed Tomography, and Biomechanical Validation. AB - OBJECTIVE: To describe and apply a semi-quantitative MRI scoring system for multi feature analysis of cartilage defect repair in the knee by osteochondral allografts, and to correlate this scoring system with histopathologic, micro computed tomography (MUCT), and biomechanical reference standards using a goat repair model. DESIGN: Fourteen adult goats had two osteochondral allografts implanted into each knee: one in the medial femoral condyle (MFC) and one in the lateral trochlea (LT). At 12 months, goats were euthanized and MRI was performed. Two blinded radiologists independently rated nine primary features for each graft, including cartilage signal, fill, edge integration, surface congruity, calcified cartilage integrity, subchondral bone plate congruity, subchondral bone marrow signal, osseous integration, and presence of cystic changes. Four ancillary features of the joint were also evaluated, including opposing cartilage, meniscal tears, synovitis, and fat-pad scarring. Comparison was made with histological and MUCT reference standards as well as biomechanical measures. Interobserver agreement and agreement with reference standards was assessed. Cohen's kappa, Spearman's correlation, and Kruskal-Wallis tests were used as appropriate. RESULTS: There was substantial agreement (kappa>0.6, p<0.001) for each MRI feature and with comparison against reference standards, except for cartilage edge integration (kappa=0.6). There was a strong positive correlation between MRI and reference standard scores (rho=0.86, p<0.01). OCAMRISS was sensitive to differences in outcomes between the types of allografts. CONCLUSIONS: We have described a comprehensive MRI scoring system for osteochondral allografts and have validated this scoring system with histopathologic and MUCT reference standards as well as biomechanical indentation testing. PMID- 24490000 TI - U.S. Mental Health Policy: Addressing the Neglect of Asian Americans. AB - Although Asian Americans are proportionally the fastest-growing ethnic group in the United States, federal mental health policies have neglected their special needs. U.S. federal mental health policy has shifted in the past 50 years from an emphasis on increasing accessibility to treatment to improving the quality of care and focusing on the brain as the basis of mental illness. However, the mental health needs of Asian Americans have been a relatively low priority. Myths about Asian Americans that have led to the general neglect of their mental health needs are that they: (a) are a small group; (b) are a successful group and do not experience problems; and (c) do not experience mental health disparities. Nevertheless, Asian Americans are a significant proportion of the population which experiences acculturative stress and discrimination that are often associated with psychopathology. However, Asian Americans who experience psychopathology are less likely than other groups to use mental health services. Political efforts must be made to get Asian Americans into positions of leadership and power in which they can make decisions about mental health policy priorities. PMID- 24490001 TI - Who will Benefit from a Wide-Scale Introduction of Vaginal Microbicides in Developing Countries? AB - Vaginal microbicides (VMB) are currently among the few biomedical interventions designed to help women reduce their risk of acquiring HIV infection. However, the microbicide containing antiretroviral (ARV-VMB) may lead to the development of antiretroviral resistance and could paradoxically become more beneficial to men at the population level. We developed a mathematical model to study the impact of a wide-scale population usage of VMB in a heterosexual population. Gender ratios of prevented infections and prevalence reduction are evaluated in 63 different intervention schedules including continuous and interrupted ARV-VMB use by HIV positive women. The influence of different factors on population-level benefits is also studied through Monte Carlo simulations using parameters sampled from primary ranges representative of developing countries. Our analysis indicates that women are more likely than men to benefit from ARV-VMB use since 78-80% of the total 63,000 simulations investigated (under different parameter sets) showed a female advantage whether benefit is measured as cumulative number of infections prevented, the percentage of cumulative infections prevented, or the expected reduction in prevalence. Stratified analysis by scenarios indicates that the likelihood of a male advantage with respect to the fractions of prevented infections varies from 6% to 49% among the scenarios. It is substantial only if the risk of systemic absorption and development of resistance to ARV-VMB is high and the HIV-positive women use VMB indefinitely without interruption. Therefore, the use of ARV-VMB, with successful control measures restricting usage by HIV positive women, is still very much a female prevention tool. PMID- 24490002 TI - Computation-guided discovery of influenza endonuclease inhibitors. AB - Influenza is a global human health threat, and there is an immediate need for new antiviral therapies to circumvent the limitations of vaccination and current small molecule therapies. During viral transcription, influenza incorporates the 5'-end of the host cell's mRNA in a process that requires the influenza endonuclease. Based on recently published endonuclease crystalized structures, a three-dimensional pharmacophore was developed and used to virtually screen 450,000 compounds for influenza endonuclease inhibitors. Of 264 compounds tested in a FRET-based endonuclease-inhibition assay, 16 inhibitors (IC50 <50 MUM) that span 5 molecular classes novel to this endonuclease were found (6.1% hit rate). To determine cytotoxicity and antiviral activity, subsequent cellular assays were performed. Two compounds suppress viral replication with negligible cell toxicity. PMID- 24490003 TI - Quenching Dynamics of Ultraviolet-Light Perception by UVR8 Photoreceptor. AB - UVR8 is a recently discovered UV-B photoreceptor with a homodimer as the active state. UV-B perception of an interfacial tryptophan (W285) causes dissociation of the dimer into two functional monomers. Here, we investigate the molecular mechanism behind UV perception by W285 in UVR8. We observed a significant quenching dynamics in about 150 ps within the interfacial four-tryptophan cluster and an unusual resonance energy transfer from the other ten tryptophans to the tryptophan cluster in 1-2 nanoseconds to enhance functional efficiency. With mutation of W285 to F, the quenching dynamics is highly suppressed in this intact mutant dimer and the overall fluorescence intensity dramatically increases by a factor of 6, indicating W285 as a dominant quencher. These results reveal a unique energy transfer mechanism for efficient UV perception and the critical functional role of W285 for primary quenching dynamics for initiating dimer dissociation to trigger the function. PMID- 24490004 TI - Streptococcus gordonii glucosyltransferase promotes biofilm interactions with Candida albicans. AB - BACKGROUND: Candida albicans co-aggregates with Streptococcus gordonii to form biofilms and their interactions in mucosal biofilms may lead to pathogenic synergy. Although the functions of glucosyltransferases (Gtf) of Mutans streptococci have been well characterized, the biological roles of these enzymes in commensal oral streptococci, such as S. gordonii, in oral biofilm communities are less clear. OBJECTIVE: The objective of this work was to explore the role of GtfG, the single Gtf enzyme of S. gordonii, in biofilm interactions with C. albicans. DESIGN: Biofilms were grown under salivary flow in flow cells in vitro, or under static conditions in 96 well plates. A panel of isogenic S. gordonii CH1 gtfG mutants and complemented strains were co-inoculated with C. albicans strain SC5314 to form mixed biofilms. Biofilm accretion and binding interactions between the two organisms were tested. Biofilms were quantified using confocal microscopy or the crystal violet assay. RESULTS: The presence of GtfG enhanced dual biofilm accretion, and sucrose supplementation further augmented dual biofilm formation, pointing to a role of newly synthesized glucans. GtfG also promoted binding to C. albicans preformed biofilms. Soluble alpha-1,6-glucans played a role in these interactions since: 1) a strain producing only soluble glucans (CH107) formed robust dual biofilms under conditions of salivary flow; and 2) the dual biofilm was susceptible to enzymatic breakdown by dextranase which specifically degrades soluble alpha-1,6-glucans. CONCLUSION: Our work identified a novel molecular mechanism for C. albicans and S. gordonii biofilm interactions, mediated by GtfG. This protein promotes early biofilm binding of S. gordonii to C. albicans which leads to increased accretion of streptococcal cells in mixed biofilms. We also showed that soluble glucans, with alpha-1,6-linkages, promoted inter-generic adhesive interactions. PMID- 24490005 TI - Relation between EDSS and monosymptomatic or polysymptomatic onset in clinical manifestations of multiple sclerosis in Babol, northern Iran. AB - BACKGROUND: Polysymptomatic or monosymptomatic patients of multiple sclerosis (MS) at the onset of the disease may influence the natural course of the disease. The purpose of this study was to determine the prognostic effect of the expanded disability status scale (EDSS) of patients with MS with polysymptomatic or monosymptomatic onset of the disease. METHODS: From 2001 to 2011, 263 patients with definitive diagnosis of MS were investigated in Shahid Beheshti Teaching Hospital in Babol, Iran. These patients were assessed regarding mono-or poly symptoms at the beginning of their disease. MRI of brain and spinal cord was done for all cases. These cases were evaluated every three months interval. EDSS of each patient at the beginning of their disease and then yearly were evaluated and registered. RESULTS: One hundred sixty-one subjects (61.2%) were monosymptomatic and 102 (38.8%) were polysymptomatic at the onset of their disease. The mean age of patients with monosymptomatic onset was 26.81+84 while in polysymptomatic was 26.35+7.7 years (P=0.656). Sex, place of residence and marriage statusbetween these two groups were equal. The mean EDSS in monosymptomatic and polysymptomatic patients were 1.37+/-0.64 and 2.16+/-0.714, respectively (P=0.0001). After the initiation of treatment, reduction of EDSS was seen in both groups but after the reduction in the first year, an increase of EDSS was seen in both groups. But there was no significant difference in the increase of EDSS in both groups. CONCLUSION: The results showed that the mean EDSS in monosymptomatic was lower than the polysymptomatic patients before treatment, but after treatment, this value does not differ in the increase of EDSS. PMID- 24490006 TI - Silymarin in treatment of non-alcoholic steatohepatitis: A randomized clinical trial. AB - BACKGROUND: No pharmacologic agents have been approved for the treatment of non alcoholic steatohepatitis (NASH) that is common in our region. The present study was designed to evaluate the efficacy of silymarin, a known herbal drug, in the treatment of NASH. METHODS: This clinical-trial study was conducted on 64 patients with NASH who were randomly divided as case group (33) and control group (31). Abdominal sonography and persistent elevation in levels of aspartate aminotransferase (AST) and alanine aminotransferase (ALT) more than 1.2 times of the upper normal limit within the last six months were selected as inclusion criteria. They were advised to take low-fat, low carbohydrate diet, do regular sport activity to lose weight up to 4 Kg. Patients in the case group received 210 mg/day silymarin orally for 8 weeks and those in the control group received placebo. After 8 weeks, the patients were reevaluated and their AST and ALT levels were measured. This study was registered in the Iranian Registry of Clinical Trial (www.irct.ir) with registration number ID: IRCT201202159018N1. RESULTS: The mean age of patients in case and control groups was 43.6+/-8.3 and 39.4+/-10.5 years, respectively. Their BMI were 27.4+/-1.7 and 27.5+/-1.9, respectively. Their weights were also 79+/-9.2 and 76.9+/-9.5 kg, respectively. Serum concentrations of ALT were 91.3+/-21.3 and 38.4+/-11.8 in case group before and after the study respectively, whiles the figures were 84.6+/-23.3 and 52.3+/ 29 in the control group (P=0.026). The same trend was seen for AST (P=0.038). CONCLUSION: The patients who had taken silymarin experienced more notable fall in hepatic enzymes. PMID- 24490007 TI - Clinical manifestations of right ventricle involvement in inferior myocardial infarction. AB - BACKGROUND: Early diagnosis of right ventricle (RV) involvement in inferior myocardial infarction (Inf MI) is very critical. This study was performed to evaluate the clinical findings of Inf MI with or without RV infarction. METHODS: From September 2010 to September 2012, 195 patients with definite diagnosis of Inf MI were evaluated in the Department of Cardiology, in Babol, north of Iran. The presence or absence of right ventricular infarction was evaluated by ST elevation in preicordial V3R-V4R leads. Chest pain (CP), changes in electrocardiography (ECG), serum level of Troponin T (TnT), decreased level of consciousness, hypotension, and jugular vein prominence (JVP) in patients with and without RV involvement were noted. RESULTS: One hundred forty eight (95 males and 53 females) and 47 (31 males and 16 females) cases developed Inf MI without and with RV infarction, respectively. The mean age of the patients with and without RV infarction were 60.59+/-12.9 and 60.9+/-12.2 years, respectively (P=0.883). CP, decreased consciousness, hypotension, and JVP were seen in 147 (99.3%), 1 (0.7%), 1 (0.7%) and 1 (0.7%) patients without RV involvement and in 44 (93.6%), 9 (19.1%), 27 (54.4%) and 9 (19.1) in RV involvement, respectively (p<0.05). No significant differences were seen in ThT enzymes and ECG changes. CONCLUSION: The results show that chest pain, decrease of consciousness, hypotension, JVP prominence are more frequent in inferior MI with RV involvement patients. PMID- 24490008 TI - Association between serum uric acid level and diabetic peripheral neuropathy (A case control study). AB - BACKGROUND: The role of uric acid is well known for the development of nephropathy and retinopathy in diabetic patients. The aim of this study was to evaluate the serum uric acid levels in patients with or without diabetic neuropathy (DPN). METHODS: Forty-two patients with DPN (case group) and 42 patients without DPN (control group) matched with regard to age, gender, body mass index (BMI) and duration of their disease were entered into the study. The diagnosis of DPN was based on the nerve conduction studies on sural, peroneal and tibial nerves in lower limbs. Serum uric acid was measured in these two groups. RESULTS: The mean age of the patients in the case group was 54.6+/-6.9 and in the control group was 55.8+/-5.8 years (p=0.389). The demographic characteristics of the patients in these two groups were equal, but only the history of diabetic foot ulcer was higher in patients with DPN (p<0.05). The mean serum uric acid was 4.70+/-0.96 in diabetic patients with DPN and 4.36+/-0.89 mg/dl in patients without DPN (p=0.019). CONCLUSION: The results show the higher level of serum uric acid level in diabetic patients with diabetic neuropathy. Further studies are required to determine the role of uric acid in the development and progression of DPN. PMID- 24490009 TI - Frequency of odontogenic periradicular lesions in diabetic patients. AB - BACKGROUND: Diabetic patients are more prone to oral infections and periradicular lesions due to changes in their immune system and qualitative and quantitative changes in normal flora of their mouth. The aim of this study was to evaluate the frequency of periradicular lesions in diabetic patients in Babol, North of Iran. METHODS: From October 2011 to March 2012, 135 diabetic patients who referred to the Iranian Diabetes Society - Babol Branch and Endocrinology Clinic of Babol University of Medical Sciences were studied. The demographic features as well as the duration of the diagnosis of diabetes (> 48 months was called long term and < 48 months short term) is the quality of control of their diabetes. For all the patients, panoramic and periapical radiography were performed for the presence of any radicular radiolucent lesions. Vitality test has been done for the recorded teeth except for the root treated ones and periodontal involvement necrotic teeth. The data were collected and analyzed. RESULTS: Periradicular lesions were seen on 90.37% of the patients. The frequency of periradicular lesions in long term patients was 85 (94.4%) and in short term was 37 (82.2%) (p=0.023). The mean of teeth with periradicular lesions in long and short term diabetic patients was 2.63+/-2.23 and 2.11+/-1.79, respectively (p=0.174). CONCLUSION: The results show that the frequency of periradicular lesions in diabetic patients is higher in long-term diabetic patients than the short-term diabetic patients. PMID- 24490010 TI - The effect of fennel (Foeniculum vulgare) gel 3% in decreasing hair thickness in idiopathic mild to moderate hirsutism, A randomized placebo controlled clinical trial. AB - BACKGROUND: Hirsutism is a common symptom presenting to primary care endocrinologists, gynecologists, and dermatologists. Management is usually a long and troublesome process. This study was designed to evaluate the effect of fennel topical gel on mild to moderate idiopathic hirsutism. METHODS: The randomized, double-blind, placebo-controlled clinical trial was carried out from 2009 to 2011, in Sari, Iran. Forty four women with mild to moderate idiopathic hirsutism were randomly divided to case and control groups, each group included 22 cases. The case group received fennel gel 3% and the control group received placebo. The effect of fennel gel 3% was defined as reduction of thickness of facial hair in micrometer by microscope in comparison with placebo. Measurements were performed at zero time and 24 weeks after treatment. This study was registered in the Iranian Registry of Clinical Trial (www.irct.ir) with registration number 138901213672N1. RESULTS: The mean age of patients was 26.9+/-6.7 and 25.6+/-4.3 years in case and control groups, respectively. Hair thickness was similar between the two groups before intervention. The hair thickness reduced from 97.9+/-31.5 to 75.6+/-26.7 micron in patients receiving fennel gel after 24 weeks (P<0.001). Four patients complained of itching (3 in case group) and 4 patients complained of irritation and itching (3 in case group). However, this difference was not statistically significant. CONCLUSION: The study indicated that fennel gel 3% is effective in decreasing hair thickness in women with idiopathic mild to moderate hirsutism. PMID- 24490011 TI - Bacterial entropathogens and antimicrobial susceptibility in children with acute diarrhea in Babol, Iran. AB - BACKGROUND: Infectious diarrhea is one of common cause of children diarrhea causing mortality and morbidity worldwide. This study was performed to identify the common bacteria and their antimicrobial susceptibility in children with diarrhea. METHODS: Children under 14 years old with acute diarrhea who referred to Amirkola Children's Hospital, Mazandaran, North of Iran, were enrolled during the summer and fall of 2009. From each patient, two fecal specimens were collected. Samples were cultured and bacterial isolation was done by conventional methods. Antimicrobial susceptibility was identified by disk diffusion and micro dilution methods. RESULTS: One hundred-seventy two patients with the mean age of 41.8+/-37.6 months were evaluated. The bacteria were isolated in 48 (27.9%) cases. The most common isolated bacteria was E.coli and then shigella in both bloody and nonbloody diarrheal patients. There was a significant difference between bacteria positive specimens and WBC in stool smear (p=0.003). All isolated shigella were susceptible to Ceftizoxime and ciprofloxacin and were resistant to Cefixime. Resistant to Nalidixic acid was seen in 14% of them. CONCLUSION: The results show that E.coli was the most frequently isolated pathogen in children with bloody and nonbloody diarrhea. Ceftizoxime is a good antibiotic for shigellosis in children in our area but Cefixime is not appropriate. PMID- 24490012 TI - Clinical profile of classical Fever of unknown origin (FUO). AB - BACKGROUND: The etiology of fever of unknown origin (FUO) may differ from different countries. This study was conducted to evaluate the etiology of FUO in patients attending SKIMS, a tertiary care teaching hospital, at Srinagar, Kashmir, India. METHODS: From July 2010 to September 2012, this study was done to examine the profile of patients with FUO. The classic FUO was defined as three outpatient visits or three days in the hospital without elucidation of cause of fever. Infectious agents, collagen vascular diseases and hematological malignancies as well as other etiologies were investigated when appropriate. The data were collected and analyzed. RESULTS: A total of 91 cases (62 males and 29 females), with age ranging from 16 to 80 years were investigated. The mean duration of fever before hospitalization was 26+/-4 days. The etiology of FUO was delineated in (66%) of cases, whereas, (25%) remained undiagnosed. Most common group of FUO was that of infectious diseases (44%) followed by collagen vascular diseases and malignancies (12 % each). Amongst the infection group, brucellosis and salmonellosis comprised the majority of cases (25% each). CONCLUSION: Infections are the most common cause of FUO followed by collagen vascular diseases in our region. PMID- 24490013 TI - Status of Vitamin-D in diabetic patients. AB - BACKGROUND: Vitamin D (vit D) deficiency has been found to have an inverse relationship with the occurrence of type-2 diabetes mellitus (DM). The aim of this study was to assess the vit D level in type-2 diabetic patients. METHODS: One hundred-twenty DM patients selected as case group and 120 healthy individuals as control group were investigated in this study from October 2011 to September 2012 in Shahid Beheshti and Ayatollah Rouhani teaching hospital in Babol, North of Iran. Both groups were matched regarding age and gender. Serum levels of 25(OH)-vitamin D were measured in both groups. The data were collected and analyzed. RESULTS: The mean age of the case group was 51.2+/-7.98 and in control group was 50.6+/-7.73 years. The mean concentration of vit D in the case group was 18.7+/-10.2 and in the control group was 24.6+/-13.5 ng/dl (p=0.002). The mean concentration of vit D in male subjects in both groups were equal but in women with diabetes was lower than the healthy women (19.3+/-11.9 versus 27.03+/ 10.28 ng/dl, respectively) (p=0.0001). In diabetic patient vit D level was deficient in 77 (64.2%), insufficient in 30 (25%) and sufficient in 13 (10.3%) patients. In the healthy group, these parameters were seen in 44 (36.6%), in 46 (38.4%) and in 30 (25%) patients. CONCLUSION: The results show that vit D concentration was significantly lower in diabetic patients than the healthy individuals. Although the mean concentration of vit D in males in both groups was equal but in the women with diabetes was lower than the healthy women. PMID- 24490015 TI - Alendronate-Related Femoral Fracture in a premenopausal glucocorticoid treated patient. AB - BACKGROUND: Alendronate is a bisphosphonate that is approved to reduce bone loss in glucocorticoid treated patients. In this paper, we present a case of femoral fracture following the use of Alendronate. CASE PRESENTATION: A- 46 year old woman who was a known case of hemolytic anemia has been treated by prednisolone (with different doses from 7.5 to 75 mg/day), calcium-D 500 mg/day and alendronate 70 mg/week for 3 years. Despite improvement of bone density, she experienced a low truama femoral shaft fracture. CONCLUSION: This case shows a rare complication of treatment by alendronate. It may be needed to evaluate patients with long term usage of bisphosphonates for cortical thickness. PMID- 24490014 TI - Meigs' syndrome with elevated serum CA125 in a case of ovarian fibroma /thecoma. AB - BACKGROUND: CA125 levels in Meig's syndrome can increase or be normal which an unusual laboratory condition is. In this paper, we present a case of Meigs' syndrome associated with increased CA125 level due to ovarian fibroma / thecoma. CASE PRESENTATION: A 50-year old Iranian woman presented with fever, abdominal pain and distention and in imaging assessment, a 90*109 mm heterogeneous pelvic mass with free abdominopelvic fluid was reported. Pleural effusion was detected in CXR. Aspiration of ascetic fluid showed no evidence of malignancy. CA125 level was greater than 600 IU/mL. The patient went under laparotomy in which a 120*100 mm mass was detected in her left adnexa attached to colon, bowels and bottom of pelvis. Histology reported ovarian fibro/ thecoma. The mass was resected and after that, the symptoms disappeared and CA125 level reached to 15 IU/mL. The patient had no problem after 18 months of follow up. CONCLUSION: Meigs' syndrome should be considered at the differential diagnosis for a patient with pelvic mass, pleural effusion and ascites with normal cytology, increased CA125 levels. PMID- 24490016 TI - Nasal tuberculosis in a 56 year old woman. AB - BACKGROUND: Nasal tuberculosis (NTB) is rare, but it can be caused by either a pulmonary disease or a retrograde involvement of the nose by lupus vulgaris of the facial skin. In this study, we present a case of NTB with an ulcerative lesion in her left nasal cavity. CASE PRESENTATION: A 56 years old woman presented with an ulcerative lesion in her left nasal cavity. The patient exhibited no clinical evidence of any systemic diseases. Peripheral leucocyte count (CBC) was normal but erythrocyte sedimentation rate was elevated. Mantoux' test elicited 25 mm reaction after 72 hr. Chest x-ray was normal. Pathological evaluation of the lesion revealed the caseating granulomas, epithelioid cells, lymphocytes, and a few giant cells. These findings suggested a diagnosis of tuberculosis. The patient was cured after 6 months treatment with standard regimen of tuberculosis. CONCLUSION: Although, nasal tuberculosis is rare, it should be considered in the differential diagnosis of patients with chronic nasal symptoms and ulcerative lesions of the nose. PMID- 24490017 TI - Circadian variation in onset of stroke in a university Hospital in Babol, North of Iran. PMID- 24490018 TI - Health Education still needs the Knowledge level and Attitude of Male Students about HIV/AIDS. PMID- 24490020 TI - Bosutinib in the treatment of patients with Philadelphia chromosome-positive (Ph+) chronic myelogenous leukemia: an overview. AB - Bosutinib is an orally bioavailable SRC/ABL tyrosine kinase inhibitor with activity against all phases of resistant chronic myeloid leukemia that do not express the T315I or V299L ABL kinase domain mutations. Bosutinib has a unique toxicity profile that is manageable. This paper provides an overview of bosutinib, covering pharmacodynamics and pharmacokinetic properties, results of treatment in newly diagnosed and previously treated chronic myeloid leukemia patients, as well as common side effects. PMID- 24490019 TI - Rituximab is associated with improved survival in Burkitt lymphoma: a retrospective analysis from two US academic medical centers. AB - BACKGROUND: Burkitt lymphoma (BL) is a rare, highly aggressive B-cell malignancy treated most successfully with brief-duration, high-intensity chemotherapeutic regimens. The benefit of the addition of rituximab to these regimens remains uncertain. We sought to examine the effectiveness of chemotherapy with and without rituximab in patients with BL. METHODS: This study is a retrospective cohort study of all adult patients with BL diagnosed and treated with modern, dose-intense chemotherapeutic regimens from 1998-2008 at two tertiary care institutions. All cases were confirmed by application of WHO 2008 criteria by hematopathologists. Medical records were reviewed for patient-, disease-, and treatment- related factors as well as treatment response and survival. Factors associated with survival were analyzed using Cox proportional hazards modeling. RESULTS: A total of 35 patients were analyzed: 18 patients received rituximab with chemotherapy (R-chemo) and 17 received chemotherapy (chemo) alone. The median age was 42 (range 20-74 years); 57% were male; 71% had Ann Arbor Stage IV disease; 33% had central nervous system involvement; 78% had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. R-chemo was associated with significantly longer overall survival (OS) than chemo alone (5 year OS 70% and 29%, respectively, p = 0.040). On multivariate regression analysis, poor performance status and central nervous system involvement were associated with poorer survival. CONCLUSIONS: The addition of rituximab to chemotherapy was associated with improved OS in patients with Burkitt lymphoma. Poor performance status and central nervous system involvement were prognostically significant on multivariate analysis. PMID- 24490021 TI - Liposomal vincristine for relapsed or refractory Ph-negative acute lymphoblastic leukemia: a review of literature. AB - Acute lymphoblastic leukemia (ALL) is a heterogeneous group of hematologic malignancies that arise from clonal proliferation of immature lymphoid cells in the bone marrow, peripheral blood and other organs. There are approximately 3000 new adult cases diagnosed every year in the United States with a 5-year overall survival ranging from 22% to 50%. Most adult patients with ALL who achieve a complete response will ultimately relapse and for this subset of patients the only hope of curative therapy is successful re-induction to achieve a complete response followed by allogeneic transplant. Conventional vincristine has been used in all phases of ALL therapy but its efficacy is limited by cumulative toxicity, typically neuropathic in nature. Historically, the dose of conventional vincristine has been capped at 2 mg to avoid severe neurotoxicity. Liposomal vincristine [as vincristine sulfate liposomal injection (VSLI)] constitutes encapsulating vincristine in a sphingomyelin/cholesterol envelope. This process is thought to enhance drug delivery to the target tissues, decrease neurotoxicity by reducing the percentage of free drug in the plasma and therefore results in increased efficacy with acceptable toxicity. Results from recent trials using VSLI in the setting of relapsed/refractory Ph-negative ALL have been encouraging. VSLI as salvage monotherapy has been successful in inducing complete responses in a minority of adults with relapsed/refractory ALL so that they can be bridged to stem-cell transplantation. Rigorous post-approval testing needs to be conducted to clarify its utility in the clinic. PMID- 24490022 TI - Cytochrome P450-Catalyzed Insertion of Carbenoids into N-H Bonds. AB - Expanding nature's catalytic repertoire to include reactions important in synthetic chemistry will open new opportunities for 'green' chemistry and biosynthesis. We demonstrate enzyme-catalyzed insertion of carbenoids into N-H bonds. This type of bond disconnection, which has no counterpart in nature, can be mediated by variants of the cytochrome P450 from Bacillus megaterium. The N-H insertion reaction takes place in water, provides the desired products in 26-83% yield, forms the single addition product exclusively, and does not require slow addition of the diazo component. PMID- 24490024 TI - Editorial. PMID- 24490025 TI - Comparison of the effects of Sertindole and Olanzapine on Cognition (SEROLA): a double-blind randomized 12-week study of patients diagnosed with schizophrenia. AB - OBJECTIVE: To assess the cognitive effects of sertindole and olanzapine in patients diagnosed with schizophrenia. Cognition was the primary outcome of the study. METHOD: This was a 12-week double-blinded randomized clinical controlled trial. Participants were randomized to either 16-24 mg of sertindole or 10-20 mg of olanzapine. RESULTS: The study had a low recruitment rate (N = 9) and was terminated before the expected number of patients was reached. No significant differences between groups were found at study end on any of the 32 cognitive subtests. A simple sign test did not show any of the comparator drugs trending towards being superior on the majority of tests. Mean change on Positive and Negative Syndrome Scale (PANSS) total and PANSS subscales from baseline to end of study were not significantly different between treatment groups. Similar results on cognition and PANSS was seen on completers and last observation carried forward analysis. CONCLUSION: In this study we did not find any significant differences between sertindole or olanzapine on PANSS subscales or neurocognitive tests in a population consisting of patients diagnosed with schizophrenia. PMID- 24490026 TI - SMARTS (Systematic Monitoring of Adverse events Related to TreatmentS): The development of a pragmatic patient-completed checklist to assess antipsychotic drug side effects. AB - OBJECTIVES: Antipsychotic drug side effects are common and can cause stigmatisation, decreased quality of life, poor adherence, and secondary morbidity and mortality. Systematic assessment of anticipated side effects is recommended as part of good clinical care, but is uncommon in practice and patients may not spontaneously report side effects. We aimed to develop a simple patient-completed checklist to screen systematically for potential antipsychotic side effects. METHODS: The SMARTS checklist was developed over a series of group meetings by an international faculty of 12 experts (including psychiatrists, a general physician and a psychopharmacologist) based on their clinical experience and knowledge of the literature. The emphasis is on tolerability (i.e. assessment of side effects that 'trouble' the patient) as subjective impact of side effects is most relevant to medication adherence. The development took account of feedback from practising psychiatrists in Europe, the Middle East and Africa, a process that contributed to face validity. RESULTS: The SMARTS checklist assesses whether patients are currently 'troubled' by 11 well-established potential antipsychotic side effects. Patients provide their responses to these questions by circling relevant side effects. An additional open question enquires about any other possible side effects. The checklist has been translated into Italian and Turkish. CONCLUSIONS: The SMARTS checklist aims to strike a balance between brevity and capturing the most common and important antipsychotic side effects. It is appropriate for completion by patients prior to a clinical consultation, for example, in the waiting room. It can then form the focus for a more detailed clinical discussion about side effects. It can be used alone or form part of a more comprehensive assessment of antipsychotic side effects including blood tests and a physical examination when appropriate. The checklist assesses current problems and can be used longitudinally to assess change. PMID- 24490027 TI - Difference of perceptions and evaluation of cognitive dysfunction in major depressive disorder patients across psychiatrists internationally. AB - BACKGROUND: Many studies have suggested that major depressive disorder (MDD) is often associated with cognitive dysfunction. Despite this, guidance addressing assessment of cognitive dysfunction in MDD is lacking. The aim of this study was to examine psychiatrists' perceptions and evaluation of cognitive dysfunction in routine practice in MDD patients across different countries. METHOD: A total of 61 psychiatrists in the US, Germany, France, Spain, Hong Kong, and Australia participated in an online survey about perceptions of cognitive dysfunction in MDD patients, evaluation of cognition and instruments used in cognitive evaluation. RESULTS: Most psychiatrists reportedly relied on patient history interviews for cognitive evaluation (83% in France and approximately 60% in the USA, Germany, Australia and Hong Kong). The remainder used a cognitive instrument or a combination of cognitive instrument and patient history interview for assessment. Of those using instruments for cognitive assessment, only nine named instruments that were appropriate for cognitive evaluation. The remainder reported other clinical measures not intended for cognitive evaluation. CONCLUSIONS: Overall, psychiatrists in routine clinical practice value the assessment of cognitive in MDD. However, there is a lack of standardization in these assessments and misconceptions regarding proper assessment. PMID- 24490028 TI - Olanzapine, weight change and metabolic effects: a naturalistic 12-month follow up. AB - OBJECTIVE: Olanzapine is an atypical antipsychotic drug used to treat schizophrenia. Some of the adverse effects related to its use are obesity, hyperlipidemia, type 2 diabetes and hypertension, which may result in development of metabolic syndrome. This study aimed to investigate a possible increase in some anthropometric and biochemical parameters, and the existence of any correlation between them in Brazilian patients with schizophrenia treated with olanzapine in the mid term. METHODS: Thirty subjects with schizophrenia were evaluated, 16 women and 14 men, aged between 18 and 47 years. All patients underwent blood collection and anthropometric measurements at four different times during 12 months of follow up; thus each patient was his or her own control. RESULTS: Evaluation of some anthropometric measurements showed significant differences when comparing the mean values obtained in each of the different data collection times (p < 0.05). However, the biochemical indicators of development of metabolic syndrome measured in our study did not show the same rate of increment, with only the total cholesterol and glucose levels presenting statistically significant changes (p < 0.05), but without the same magnitude of weight change. CONCLUSION: We conclude that medium-term treatment with olanzapine promoted a substantial weight gain and increased visceral fat, while the metabolic profile did not show the same magnitude of change, suggesting a dissociation between weight gain and blood parameters, despite the severe weight gain observed among subjects evaluated. PMID- 24490029 TI - The influence and changes in the dosages of concomitantly used psychotropic drugs associated with the discontinuation of donepezil in severe Alzheimer's disease with behavioral and psychological symptoms on dementia: a preliminary open-label trial. AB - OBJECTIVE: We investigated the influence on behavioral and psychological symptoms on dementia (BPSD) and the changes in the dosages of concomitant psychotropic drugs associated with the discontinuation of donepezil in patients with severe Alzheimer's disease (AD) who developed BPSD during donepezil therapy. METHODS: The subjects were 44 inpatients who had been diagnosed with AD according to the Diagnostic and Statistical Manual of Mental Disorders IV (DSM-IV). The outcome measures assessed were BPSD and cognitive function. BPSD was assessed using the Neuropsychiatric Inventory (NPI) and cognitive function was assessed using the Mini Mental Examination (MMSE). The changes in the dosages of concomitant psychotropic drugs were also assessed. RESULTS: Significant decreases were found in the donepezil treatment discontinuation group in the following NPI total score and two NPI subscales (agitation and irritability), but no significant differences were seen between the donepezil treatment discontinuation group and the control group. Furthermore, the mean changes from baseline in the risperidone equivalent dose and the diazepam equivalent dose were hardly changed in the donepezil treatment discontinuation group. CONCLUSION: The results of this study suggest that the discontinuation of donepezil treatment in patients with AD with BPSD may afford superior efficacy and may make it possible to not increase the dosage of other psychotropic drugs. PMID- 24490030 TI - High-dose prazosin for the treatment of post-traumatic stress disorder. AB - Patients with post-traumatic stress disorder (PTSD) are frequently symptomatic despite being on medications currently approved by the US Food and Drug Administration for PTSD. There is evidence to support the notion that prazosin is effective for PTSD nightmares. However, PTSD-related nightmares often do not resolve completely on a low dose of prazosin. The capacity of prazosin to treat daytime symptoms of PTSD which are distressing to patients has not been well studied. Clinicians are reluctant to increase the dose of prazosin due to side effect concerns. To date, the highest reported dose of prazosin used for PTSD is 16 mg daily. We illustrate two case reports using high-dose (up to 30 and 45 mg) prazosin for PTSD with comorbid treatment-resistant mood disorders. We report that high-dose prazosin was safe, tolerable and effective for PTSD in adults. To our knowledge, this is the first case series to highlight the importance of using high-dose prazosin for the treatment of PTSD. In patients with partial response to currently available medications for PTSD, greater utilization of high-dose prazosin for the management of PTSD may lead to better outcomes. PMID- 24490031 TI - A manic episode in a patient with stable bipolar disorder triggered by intranasal mometasone furoate. PMID- 24490032 TI - Baclofen in the management of cannabis dependence syndrome. AB - Cannabis is the most commonly used illicit drug in the world. However, only few studies have shown the efficacy of pharmacologic agents in targeting cannabis withdrawal symptoms or reducing the reinforcing effects of cannabis. Baclofen has been shown to reduce cannabis withdrawal symptoms and the subjective effects of cannabis. We think that the clinical utility of baclofen for cannabis dependence is a reasonable approach. A case report using baclofen is presented and provides preliminary support for the use of baclofen in the management of cannabis dependence. PMID- 24490033 TI - Memantine in the management of affective recurrences of bipolar disorders after the discontinuation of long-term lithium treatment: three case histories. PMID- 24490036 TI - Rectal cancer: do protons have prospects? PMID- 24490034 TI - Targeting hypoxia in the leukemia microenvironment. AB - The bone marrow (BM) microenvironment regulates survival and maintenance of normal hematopoietic stem cells. Within the endosteal niche, hypoxia has an essential role in maintenance of the primitive quiescent hematopoietic stem cell. We and others have demonstrated that in the context of hematologic malignancies the BM is highly hypoxic, and that progression of the disease is associated with expansion of hypoxic niches and stabilization of the oncogenic HIF-1alpha. This review will provide an overview of the normal and leukemic BM microenvironment with a special emphasis on pathological hypoxia including the development of hypoxia-activated prodrugs and their applicability in hematological malignancies. PMID- 24490035 TI - Quantitative Fluorescence Assays Using a Self-Powered Paper-Based Microfluidic Device and a Camera-Equipped Cellular Phone. AB - Fluorescence assays often require specialized equipment and, therefore, are not easily implemented in resource-limited environments. Herein we describe a point of-care assay strategy in which fluorescence in the visible region is used as a readout, while a camera-equipped cellular phone is used to capture the fluorescent response and quantify the assay. The fluorescence assay is made possible using a paper-based microfluidic device that contains an internal fluidic battery, a surface-mount LED, a 2-mm section of a clear straw as a cuvette, and an appropriately-designed small molecule reagent that transforms from weakly fluorescent to highly fluorescent when exposed to a specific enzyme biomarker. The resulting visible fluorescence is digitized by photographing the assay region using a camera-equipped cellular phone. The digital images are then quantified using image processing software to provide sensitive as well as quantitative results. In a model 30 min assay, the enzyme beta-D-galactosidase was measured quantitatively down to 700 pM levels. This Communication describes the design of these types of assays in paper-based microfluidic devices and characterizes the key parameters that affect the sensitivity and reproducibility of the technique. PMID- 24490037 TI - Protons offer reduced bone marrow, small bowel, and urinary bladder exposure for patients receiving neoadjuvant radiotherapy for resectable rectal cancer. AB - BACKGROUND: To assess the potential benefit of proton therapy (PT) over photon therapy, we compared 3-dimensional conformal radiotherapy (3DCRT), intensity modulated radiotherapy (IMRT), and PT plans in patients undergoing neoadjuvant chemoradiation for resectable rectal cancer at our institution. METHODS: Eight consecutive patients with resectable (T2-T3) rectal cancers underwent 3DCRT, IMRT, and 3-dimensional conformal PT treatment planning. Initial target volumes (PTV1) were contoured using the Radiation Therapy Oncology Group anorectal atlas guidelines. Boost target volumes (PTV2) consisted of the gross rectal tumor plus a uniform 2-cm expansion. Plans delivered 45 Gray (Gy) or Cobalt Gray Equivalent (CGE) to the PTV1 and a 5.4-Gy (CGE) boost to the PTV2. Ninety-five percent of the PTVs received 100% of the target dose and 100% of the PTVs received 95% of the target dose. Standard normal-tissue constraints were utilized. Wilcoxon paired t-tests were performed to compare various dosimetric points between the 3 plans for each patient. RESULTS: All plans met all normal-tissue constraints and were isoeffective in terms of PTV coverage. The proton plans offered significantly reduced median normal-tissue exposure over the 3DCRT and IMRT plans with respect to pelvic bone marrow at the V5Gy, V10Gy, V15Gy, and V20Gy levels and the small bowel space at the V10Gy and V20Gy levels. The proton plans also offered significantly reduced median normal-tissue exposure over the 3DCRT plans with respect to the small bowel at the V30Gy and V40Gy levels and the urinary bladder at the V40Gy level. CONCLUSIONS: By reducing bone marrow exposure, PT may reduce the acute hematologic toxicity of neoadjuvant chemoradiation and increase the likelihood of uninterrupted chemotherapy delivery. Bone marrow sparing may also facilitate the delivery of salvage chemotherapy for patients who subsequently develop hematogenous metastasis. Reduced small bowel exposure using PT may also reduce toxicity and possibly facilitate the use of more-aggressive chemotherapy with radiotherapy. PMID- 24490038 TI - Fourth versus eighth week surgery after neoadjuvant radiochemotherapy in T3-4/N0+ rectal cancer: Istanbul R-01 study. AB - BACKGROUND AND PURPOSE: The optimum duration between neoadjuvant radiochemotherapy and transmesorectal excision in locally advanced rectal cancer has not been defined yet. This randomized study was designed to compare the efficacy of four-week versus eight-week delay before surgery. METHODS: One hundred and fifty-three patients with locally advanced low- or mid-rectum rectal adenocarcinoma were included in this single center prospective randomized trial. Patients were assigned to receive surgical treatment after either four weeks or eight weeks of delay after chemoradiotherapy. Patients were followed for local recurrence and survival, and surgical specimens were examined for pathological staging and circumferential margin positivity. RESULTS: 4-week and 8-week groups did not differ with regard to lateral surgical margin positivity (9.2% vs. 5.1%, P=0.33, respectively), pathological tumor regression rate (P=0.90), overall survival (5-year, 76.5% vs. 74.2%, P=0.60) and local recurrence rate (11.8% vs. 10.3%, 0.77). Overall survival was better in patients with negative surgical margins (78.8% vs. 53.0%, P=0.04). Local recurrence rate was significantly higher among patients with positive surgical margin (28.5% vs. 9.3%, P=0.02). CONCLUSIONS: Intentional prolongation of the chemoradiotherapy-surgery interval does not seem to improve clinical outcomes of patients with locally advanced rectal cancer. Surgical margin positivity seems to be more important with this regard. PMID- 24490039 TI - Clinicopathological features and survival outcomes of primary signet ring cell and mucinous adenocarcinoma of colon: retrospective analysis of VACCR database. AB - BACKGROUND: Signet ring cell carcinoma (SRCC) accounts for less than 1% of all colon cancers. We examined the clinicopathological features and prognosis of signet ring cell and mucinous adenocarcinoma (MCC) of colon. METHODS: A total of 206 patients diagnosed with SRCC from 1995 to 2009 were identified from the VA Central Cancer Registry (VACCR) database. Age, race, histology, grade, lymph node status, stage and type of treatment received data were collected. RESULTS: Out of 206 patients, 173 (84%) were white, 31 (15%) were black, and 2 patients were listed as unknown. Median age of diagnosis was 67 years as compared to 70 years for both mucinous cell (MCC) and non-mucinous adenocarcinoma (NMCC) of colon. Pathological T-stages were as follows: T1 =3%, T2 =5%, T3 =34%, T4 =26%, and unknown 32%. Of the total, 22.3% were located in cecum, 7.7% in appendix, 21.8% in ascending colon, 7.7% in hepatic flexure of colon, 11% in transverse colon, 2.9% in splenic flexure 4.4% in descending colon, and 15.5% in sigmoid colon. 46.5% were lymph node positive, 21% were lymph node negative, and 32.5% were unknown. SRCC were in general poorly differentiated tumors (57%), small proportion of patients included were well-differentiated tumors with focal signet ring cell pathology (10%) and in 33% grade was unknown. Among stage 3 patients, 34% patients received only surgery while 64% received surgery with adjuvant chemotherapy and 2% received chemotherapy alone. The stage specific 5-year survivals for SRCC, MCC and NMCC were--Stage I: 100%, 61%, and 41% respectively (P<0.0001); Stage II: 42%, 58% and 32% respectively (P<0.0001); Stage III: 19%, 41% and 47% respectively (P=0.0002); Stage IV: 1.5%, 7% and 31% respectively (P<0.0001). Median survival of SRCC compared to NMCC was 18.6 vs. 46 months (P<0.0001) and mucinous cell adenocarcinoma versus NMCC was 47.8 and 46 months (P=0.63) respectively. CONCLUSIONS: SRCC of colon has poor survival rates compared to other histological subtypes. SRCC presents at an earlier age, has higher tumor grade and advanced stage at diagnosis when compared to mucinous and NMCC of colon. Due to rarity of this disease further prospective multi-institute studies are required for in-depth understanding of this disease. PMID- 24490040 TI - HER2 status in Barrett's esophagus & esophageal cancer: a meta analysis. AB - BACKGROUND: The oncogenic potential of the Human Epidermal Growth Factor Receptor 2 (HER2) is well known in the context of breast cancer however; its relationship with the development of Barrett's Esophagus (BE) and Esophageal Cancer (EC) is unclear. The aim of this meta-analysis was to determine the overall prevalence and survival of HER2+ in BE & EC. PATIENTS AND METHODS: Several databases were searched including article reference lists. Inclusion criteria required that studies measured HER2 positivity in subjects with BE or EC. RESULTS: 33 studies were included in the meta-analysis (10 BE & 23 EC studies). The prevalence of HER2+ was found to be 24% (95% CI: 15-36%) in BE and 26% (95% CI: 19-34%) in EC. Squamous cell carcinoma (SCC) had a higher ER of 32% (95% CI: 20-48%) in comparison with adenocarcinoma (ADC) with an ER of 21% (95% CI: 14-32%). Sub group analyses showed a high geographical variance, Asia was found to be the highest prevalent area with an ER 42% (95% CI: 22-64%). The difference in survival rate between groups HER2- & HER2+ was found to be 7 months. CONCLUSIONS: Our results highlight a high prevalence of HER2+ in subjects with adenocarcinoma. HER2+ appears to decrease the survival time of EC patients. PMID- 24490041 TI - Laparoscopic rectal resection versus open rectal resection with minilaparotomy for invasive rectal cancer. AB - BACKGROUND: The minilaparotomy approach is technically feasible for the resection of rectal cancer in selected patients with rapid postoperative recovery and small incision. The study aimed to compare the clinical and oncological outcomes of minilaparotomy and laparoscopic approaches in patients with rectal cancer. METHODS: The 122 included patients with rectal cancer were assigned to either minilaparotomy group (n=65) or laparoscopic group (n=57) which ran from January 2005 to January 2008. Clinical characteristics, perioperative outcomes, postoperative and long-term complications, pathological results and survival rates were compared between the groups. RESULTS: The demographic data of the two groups were similar. The time to normal diet (P=0.024) and the hospital stay (P=0.043) were less in the laparoscopic group than that in the minilaparotomy group. Compared with the minilaparotomy group, the mean operation time was significantly longer [low anterior resection (LAR), P=0.030; abdominoperineal resection (APR), P=0.048] and the direct costs higher for laparoscopic group (P<0.001). The morbidity and mortality were comparable between the two groups. Local recurrence was similar (5.3% laparoscopic, 1.5% minilaparotomy, P=0.520). The 5-year overall and disease-free survival rates were also similar (overall survival is 87.1% in laparoscopic group, and 82.5%in minilaparotomy group, P=0.425; disease-free survival is 74.2% in the laparoscopic group, and 71.4% in mini- laparotomy group, P=0.633). CONCLUSIONS: The minilaparotomy approach was similarly safe and oncologically equivalent to laparoscopic approach for patients with rectal cancer. At the expense of a longer operative time and higher cost, laparoscopic surgery was associated with faster postoperative recovery. PMID- 24490042 TI - Impact of treatment modality and number of lesions on recurrence and survival outcomes after treatment of colorectal cancer liver metastases. AB - BACKGROUND: Ablative strategies have been used to treat and facilitate hepatic resection (HR) in patients with otherwise unresectable colorectal liver metastases (CLM). We evaluated the efficacy of HR, concomitant HR and ablation and isolated ablation on recurrence and survival outcomes after treatment of CLM in patients with 1-4 and >=5 lesions, respectively. METHODS: A retrospective review of a prospectively collected hepatobiliary surgery database was performed on patients who underwent treatment for isolated CLM between 1990 and 2010. Pre operative and treatment characteristics were compared between patients who underwent HR, concomitant HR and ablation and ablation alone. The impact of treatment modality on survival and recurrence outcomes was determined. RESULTS: A total of 701 patients met inclusion criteria; 550 patients (78%) had 1-4 lesions and 151 patients (22%) had >=5 lesions. Overall median survival for the entire cohort was 35 months with 5- and 10-year survival of 33% and 20%, respectively. Overall median and 5-year recurrence-free survival (RFS) was 13 months and 21%, respectively. For patients with 1-4 lesions, median survival was 37 months with 5 year survival of 36%. Stratified by procedure type, 5-year survival was 41% in patients who underwent HR, 35% in patients who underwent concomitant HR and ablation and 13% in patients who underwent ablation alone (P<0.001). For patients with >=5 lesions, median survival was 28 months with 5-year survival of 23% without difference between treatment groups (P=0.078). CONCLUSIONS: HR appears to be the most effective strategy for patients with 1-4 lesions. When >=5 lesions are present, ablative strategies are useful in facilitating HR in otherwise unresectable patients. PMID- 24490043 TI - Gefitinib and celecoxib in advanced metastatic gastrointestinal tumors: a pilot feasibility study. AB - BACKGROUND: This pilot, open-label study examined the safety and tolerability (primary objective) and efficacy (secondary objective) of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, in combination with celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, in patients with advanced or refractory gastrointestinal (GI) tumors of epithelial origin. METHODS: Patients were administered gefitinib (250 mg/day) plus celecoxib (400 mg twice daily). In the event of toxicity, dose interruptions were permitted and a single celecoxib dose reduction was allowed. RESULTS: Thirty patients (median age 60 years) with primary colorectal (25 patients), pancreatic (3 patients), esophageal (1 patient), or gall bladder (1 patient) tumors were recruited, 29 of whom had received prior chemotherapy. Adverse events (AEs) were generally mild and consisted mainly of acne, diarrhea, and nausea. Few severe AEs were noted. There were no withdrawals or deaths due to AEs. Dose reductions for celecoxib were reported for five patients, in three cases due to toxicity. Stable disease was confirmed in 12 patients (40%), with progressive disease in 18 patients (60%). CONCLUSIONS: After study completion, safety issues relating to the long-term use of COX-2 inhibitors have been raised. However, in this pilot study, the combination of gefitinib and celecoxib was generally well tolerated in patients with advanced GI cancer. PMID- 24490045 TI - Complete response and prolonged disease-free survival in a patient with recurrent duodenal adenocarcinoma treated with bevacizumab plus FOLFOX6. AB - Small bowel adenocarcinoma is an uncommon gastrointestinal malignancy with limited data on effective chemotherapy in the adjuvant setting, as well as for advanced disease. We present a case report of a patient with recurrent duodenal adenocarcinoma after resection and adjuvant chemotherapy who experienced a complete response to bevacizumab with oxaliplatin and 5FU (FOLFOX) followed by bevacizumab/capecitabine maintenance therapy for 2 years. The patient continues to be disease-free 8 years after his recurrence. This case highlights the potential of vascular endothelial growth factor (VEGF) inhibitors to enhance chemotherapeutic regimens for advanced small bowel adenocarcinoma. PMID- 24490044 TI - Forthcoming prognostic markers for esophageal cancer: a systematic review and meta-analysis. AB - BACKGROUND: The incidence of esophageal cancer is rising, and survival rates remain poor. This meta-analysis summarizes five molecular mechanisms of disease progression, which are related to prognosis. PATIENTS AND METHODS: A systematic search was conducted using MEDLINE, PubMed, EMBASE, Current Contents Connect, Cochrane library, Google Scholar, Science Direct, and Web of Science. Original data was abstracted from each study and used to calculate a pooled event rate and 95% confidence interval (95% CI). RESULTS: Our analysis included five octamer binding transcription factor 4 (OCT4) studies (564 patients), six sex determining region Y-box 2 (SOX2) studies (336 patients), five oestrogen receptor (ER) studies (367 patients), seven MET or MNNG HOS Transforming gene (c-Met) studies (1,015 patients) and six insulin like growth factor receptor studies (764 patients). Incidence of OCT4 in SCC was 53.60% (95% CI: 0.182-0.857) and the overall hazard ratio for poor clinic outcome was 2.9 (95% CI: 1.843-4.565). The incidence of SOX2 in SCC was 69.2% (95% CI: 0.361-0.899) however, was associated with significant heterogeneity of 90.94%. The prevalence of Oestrogen receptor alpha and beta in SCC were 37.90% (95% CI: 0.317-0.444) and 67.20% (95% CI: 0.314 0.901) respectively. The prevalence of MET in EAC was 33.20% (95% CI: 0.031 0.884) and the incidence of insulin-like growth factor-1 receptor (IGF-1R) in EAC was 67.70% (95% CI: 0.333-0.898). CONCLUSIONS: Our results show that the status of ER, OCT4 and SOX2 expression correlates with the unfavourable prognosis in patients with esophageal squamous cell carcinoma (ESCC). This study also highlights the potential impact of the IGF-1R on the biology of EAC and the expression of Met was recognised as a significant prognostic factor. Our data supports the concept of IGF axis, ER, Met, OCT4 and SOX2 inhibition as (neo-) adjuvant treatment. PMID- 24490046 TI - Long-term survival in an advanced gastric cancer patient treated with cetuximab in association with FOLFIRI: a case report. AB - In December 2004, a 52-year-old woman with metastatic gastric cancer was enrolled in the phase II clinical trial FOLCETUX, receiving cetuximab at an initial dose of 400 mg/m(2) i.v. followed by weekly doses of 250 mg/m(2), irinotecan 180 mg/m(2) i.v. on day 1, LFA 100 mg/m(2) i.v. followed by 5-FU 400 mg/m(2) i.v. bolus and 600 mg/m(2) i.v. 22-h continuous infusion on days 1 and 2 every two weeks, to a total of 17 cycles. CT and PET-CT performed after six weeks treatment failed to show any residual disease, with complete radiological response in accord to RECIST criteria and complete metabolic response. A total of 24 maintenance administrations with cetuximab alone (250 mg/m(2) weekly) were performed, as foreseen by the protocol in responders. In November 2012 a clinical, radiological (CT) and metabolic (PET-CT) patient examination proved negative for recurrent disease, signifying 95 months' progression free survival. PMID- 24490047 TI - Total gastrectomy with isoperistaltic jejunal interposition flap for symptomatic management of gastric polyposis from familial adenomatous polyposis. AB - Patients with familial adenomatous polyposis (FAP) oftentimes have extracolonic polyps. The patient discussed in this case report had innumerable gastric polyps which were significantly affecting his ability to tolerate oral intake and his overall nutrition. Medical management was not sufficiently controlling his symptoms; therefore we proceeded with surgical intervention. We discuss the use of a total gastrectomy with an Isoperistaltic jejunal interposition flap for the symptomatic management of gastric polyposis. We describe the technique used and benefits to this specific procedure when it comes to long term outcome, complications, and monitoring. PMID- 24490049 TI - Durable response with a combination of imatinib and sorafenib in KIT exon 17 mutant gastrointestinal stromal tumor. AB - Imatinib, a selective KIT tyrosine-kinase inhibitor is considered standard first line therapy in metastatic gastrointestinal stromal tumors (GISTs). However, up to 40-50% of patients develop resistance to imatinib resulting in progression of disease. Other kinase inhibitors such as sunitinib, and most recently regorafenib have been approved as second and third line options respectively. Sorafenib has also been used following progression on standard therapies. Here we present the case of a patient with stage IV GIST of the rectum who had a rare exon 17 mutation treated prior to the approval of regorafenib. Therapy initially consisted of single agent imatinib, followed by sunitinib then sorafenib. Following continued progression of disease, the patient went on to develop stable disease for close to two years on a combination of sorafenib and imatinib. PMID- 24490048 TI - Palliative radiation therapy for primary gastric melanoma. AB - INTRODUCTION: Primary gastric melanoma is an exceedingly rare cause of upper gastrointestinal bleeding (GI bleeding). Prior reports of primary gastric melanoma have mostly been treated with surgery with utilization of radiation therapy being unreported. Radiation therapy has been used to palliate bleeding of other cancers including lung, bladder, cervix, and more recently primary gastric cancers. CASE PRESENTATION: This case documents an 87-year-old male who presented with fatigue and melena, and was found to have severe anemia. Endoscopy with biopsy revealed an isolated focus of melanoma. After discharge, he presented two days later and was found to have continued bleeding. Because he was deemed a poor surgical candidate he elected to undergo palliative radiation therapy for bleeding control. DISCUSSION: The diagnosis of primary verses metastatic melanoma is a topic of debate. Case reports of patients with no known extra-gastric primary have undergone surgical treatment with varying outcomes. Patients with metastatic gastric melanoma have relied on chemotherapy and radiation in addition to surgery, with radiation being used in the palliative setting. The use of radiation to control bleeding in other cancers including primary gastric adenocarcinoma has been previously studied. This case documents the utilization of radiation therapy in bleeding due to primary gastric melanoma. CONCLUSIONS: Radiation therapy can provide adequate bleeding palliation in patients with primary gastric melanoma. PMID- 24490050 TI - Eculizumab therapy for gemcitabine induced hemolytic uremic syndrome: case series and concise review. PMID- 24490051 TI - Surgical and radiation therapy management of recurrent anal melanoma. AB - BACKGROUND: Melanoma of the anorectal mucosa is a rare but highly aggressive tumor. Its presenting symptoms are frequently confused with hemorrhoids, thereby causing a delay in diagnosis. Anorectal melanoma carries with it a very poor prognosis. There is a paucity of data investigating management options for anorectal melanoma, and even fewer data reporting recurrent or refractory cases. CASE PRESENTATION: This case documents a 41-year-old female with a long history of hemorrhoids presenting with anorectal discharge. She was incidentally found have anorectal melanoma following surgical resection. Systemic diagnostic work-up demonstrated PET-avid lymphadenopathy in her right groin. She underwent right groin dissection. However, seven months later she recurred in her right groin and a new recurrent mass was found in her pelvis. She underwent a second groin dissection and resection of the pelvic recurrence. This was followed by a course of hypofractionated radiation therapy then systemic immunotherapy. DISCUSSION: Surgery has been the mainstay of treatment. However, the extent of surgery has been the topic of investigation. Historically, radical resections have been performed but they result in high rates of post-operative morbidity. Newer studies have compared radical resection with wide local excisions and found comparable outcomes. Anorectal melanoma is frequently a systemic disease. The ideal systemic therapy regimen has not yet been determined but numerous studies show a benefit to multi-agent treatments. Radiation therapy is typically given in the post-operative or palliative setting. CONCLUSIONS: Anorectal mucosal melanoma is a very rare but aggressive disease with a poor prognosis. The overall treatment goal should strive to optimize quality of life and tumor control while minimizing treatment-related morbidities. PMID- 24490052 TI - Revisiting the Fundamentals in the Design and Control of Nanoparticulate Colloids in the Frame of Soft Chemistry. AB - This review presents thoughts on some of the fundamental features of conceptual models applied in the design of fine particles in the frames of colloid and soft chemistry. A special emphasis is placed on the limitations of these models, an acknowledgment of which is vital in improving their intricacy and effectiveness in predicting the outcomes of the corresponding experimental settings. Thermodynamics of self-assembly phenomena illustrated on the examples of protein assembly and micellization is analyzed in relation to the previously elaborated thesis that each self-assembly in reality presents a co-assembly, since it implies a mutual reorganization of the assembling system and its immediate environment. Parameters used in the design of fine particles by precipitation are discussed while referring to solubility product, various measures of supersaturation levels, induction time, nucleation and crystal growth rates, interfacial energies, and the Ostwald-Lussac law of phases. Again, the main drawbacks and inadequacies of using the aforementioned parameters in tailoring the materials properties in a soft and colloidal chemical setting were particularly emphasized. The basic and practical limitations of zeta-potential analyses, routinely used to stabilize colloidal dispersions and initiate specific interactions between soft chemical entities, were also outlined. The final section of the paper reiterates the unavoidable presence of practical qualitative models in the design and control of nanoparticulate colloids, which is supported by the overwhelming complexity of quantitative relationships that govern the processes of their formation and assembly. PMID- 24490053 TI - The natural history of biopsy-negative rejection after heart transplantation. AB - Purpose. The most recent International Society for Heart and Lung Transplantation (ISHLT) biopsy scale classifies cellular and antibody-mediated rejections. However, there are cases with acute decline in left ventricular ejection fraction (LVEF <= 45%) but no evidence of rejection on biopsy. Characteristics and treatment response of this biopsy negative rejection (BNR) have yet to be elucidated. Methods. Between 2002 and 2012, we found 12 cases of BNR in 11 heart transplant patients as previously defined. One of the 11 patients was treated a second time for BNR. Characteristics and response to treatment were noted. Results. 12 cases (of 11 patients) were reviewed and 11 occurred during the first year after transplant. 8 cases without heart failure symptoms were treated with an oral corticosteroids bolus and taper or intravenous immunoglobulin. Four cases with heart failure symptoms were treated with thymoglobulin, intravenous immunoglobulin, and intravenous methylprednisolone followed by an oral corticosteroids bolus and taper. Overall, 7 cases resulted in return to normal left ventricular function within a mean of 14 +/- 10 days from the initial biopsy. Conclusion. BNR includes cardiac dysfunction and can be a severe form of rejection. Characteristics of these cases of rejection are described with most cases responding to appropriate therapy. PMID- 24490054 TI - Bevacizumab for CRVO Associated CME: Effect of Timing and Frequency of Injections on Final Visual Outcome. AB - Purpose. Injection of anti-VEGF antibody into the vitreous body is a well established treatment for ischemic central retinal vein occlusion (CRVO) associated macular edema. Various treatment regimens regarding the timing, number, and frequency of injections have been proposed. Methods. We reviewed the medical records of 68 patients treated by intravitreal bevacizumab (Avastin) injections for macular edema due to CRVO. We examined final visual acuity six months following the last injection in relation to injection policy (one primary injection followed by subsequent injections based on anatomical response versus a prescheduled protocol of one injection per month for the first 3 months) and in relation to the time lapsing from CRVO diagnosis to the first injection. Results. Mean visual acuity improved more for patients treated by a protocol of 3 prescheduled injections than for those treated with one primary injection. Improvement in mean visual acuity was greater for patients who received their first injection within the first month than those treated after 3 months (P < 0.01). Conclusion. A protocol of three prescheduled injections of bevacizumab, starting within one month of a CRVO event, was associated with better visual outcome compared to single injection and/or treatment starting more than 3 months following the time of diagnosis. PMID- 24490057 TI - Autoimmunity diseases of the skin. PMID- 24490056 TI - Severe skin forms of psoriasis in black africans: epidemiological, clinical, and histological aspects related to 56 cases. AB - Bacground. Psoriasis is an erythematosquamous dermatosis of chronic development. In sub-Saharan Africa, few studies have been focused on complicated forms of psoriasis. Objective. The aim is to describe epidemiological, clinical, and histological features of severe skin forms of psoriasis in Cote d'Ivoire. Material and Methods. The study was both cross-sectional and descriptive, that focused on patient admitted to the dermatology unit for complicated psoriasis, from January 1st, 1986, to December 31th, 2007. Results. Fifty-six patients admitted to hospital for severe skin forms of psoriasis were recorded and included in our study over 7.503 patients hospitalized during the study period. They represented 0.75% of cases. The average age was 39.6 +/- 3.3 years. There were 49 male (87.5%) and 7 female patients (12.5%) with a sex ratio of 7. At socioprofessional level, 48 patients (87.5%) were from category 1. Patients' history was dominated by the psoriasis vulgaris. Physical and general signs were dominated by itching (58.9%). The three severe skin forms were observed with predominant erythrodermic psoriasis (60.7%). Fifteen patients (34.9%) were HIV positive. Conclusion. Severe skin forms of psoriasis are rare in our setting. But in the quarter of HIV-positive patients, they are dominated by the erythrodermic psoriasis. PMID- 24490055 TI - Expression Analysis of Sugarcane Aquaporin Genes under Water Deficit. AB - The present work is a pioneer study specifically addressing the aquaporin transcripts in sugarcane transcriptomes. Representatives of the four aquaporin subfamilies (PIP, TIP, SIP, and NIP), already described for higher plants, were identified. Forty-two distinct aquaporin isoforms were expressed in four HT SuperSAGE libraries from sugarcane roots of drought-tolerant and -sensitive genotypes, respectively. At least 10 different potential aquaporin isoform targets and their respective unitags were considered to be promising for future studies and especially for the development of molecular markers for plant breeding. From those 10 isoforms, four (SoPIP2-4, SoPIP2-6, OsPIP2-4, and SsPIP1 1) showed distinct responses towards drought, with divergent expressions between the bulks from tolerant and sensitive genotypes, when they were compared under normal and stress conditions. Two targets (SsPIP1-1 and SoPIP1-3/PIP1-4) were selected for validation via RT-qPCR and their expression patterns as detected by HT-SuperSAGE were confirmed. The employed validation strategy revealed that different genotypes share the same tolerant or sensitive phenotype, respectively, but may use different routes for stress acclimation, indicating the aquaporin transcription in sugarcane to be potentially genotype-specific. PMID- 24490058 TI - Safety and efficacy of glucomannan for weight loss in overweight and moderately obese adults. AB - BACKGROUND: Few safe and effective dietary supplements are available to promote weight loss. We evaluated the safety and efficacy of glucomannan, a water-soluble fiber supplement, for achieving weight loss in overweight and moderately obese individuals consuming self-selected diets. METHODS: Participants were randomly assigned to take 1.33 grams of glucomannan or identically looking placebo capsules with 236.6 mL (8 ounces) of water one hour before breakfast, lunch, and dinner for 8 weeks. The primary efficacy outcome was change in body weight after 8 weeks. Other efficacy outcomes were changes in body composition, hunger/fullness, and lipid and glucose concentrations. Safety outcomes included gastrointestinal symptoms/tolerance and serum liver enzymes and creatinine levels. RESULTS: A total of 53 participants (18-65 years of age; BMI 25-35 kg/m2) were enrolled and randomized. The two groups did not differ with respect to baseline characteristics and compliance with the study supplement. At 8 weeks, there was no significant difference between the glucomannan and placebo groups in amount of weight loss (-.40 +/- .06 and -.43 +/- .07, resp.) or other efficacy outcomes or in any of the safety outcomes. CONCLUSIONS: Glucomannan supplements administered over 8 weeks were well tolerated but did not promote weight loss or significantly alter body composition, hunger/fullness, or lipid and glucose parameters. This trial is registered with NCT00613600. PMID- 24490060 TI - Nutrition Therapy in the Transition between Hospital and Home: An Investigation of Barriers. AB - Aims and Objectives. This study aimed to investigate barriers for nutrition therapy in the transition between hospital and home and hereby to identify areas for potential improvements. Background. Though the focus on nutritional risk is improving in hospital, there seems to be less effort to maintain or even improve nutritional status after discharge and during the rehabilitation period. Design. Qualitative focus group interviews. Methods. Semistructured focus group interviews with experienced multiprofessional staff from hospital, home care, nursing homes, and general practise. The study was done in the county of Aalborg with about 280.000 inhabitants regarding homecare and general practise as well as Aalborg University Hospital, Denmark. Results. Interviews were generated with 41 professionals from hospital, general practise, and home care. Barriers identified between settings included the following aspects: economic, organisation, and education. The impression of professionals was that few patients are discharged with nutrition therapy, compared to who could benefit from nutrition therapy after discharge. Most often, reasons were a short in-hospital stay and lack of knowledge and interest. Moreover, lack of clinical guidelines throughout all settings, time consumption, lack of transparency regarding economy and workflows, and lack of assistance from experts regarding complicated nutritional problems were identified. Conclusions. Many barriers were found in hospital as well as in the community and general practise. These were most often practical as well as organizational. Improvements of clinical guidelines and instructions and improvement of knowledge and communication at all levels are needed. Relevance to Clinical Practise. This study emphasizes that responsibility needs to be taken for patients whom are still at nutritional risk at discharge, and even before hospitalization. Nurses and doctors in and outside hospital are in need of improved knowledge, standard care plans, and instructions. PMID- 24490059 TI - Towards health in all policies for childhood obesity prevention. AB - The childhood obesity epidemic can be best tackled by means of an integrated approach, which is enabled by integrated public health policies, or Health in All Policies. Integrated policies are developed through intersectoral collaboration between local government policy makers from health and nonhealth sectors. Such intersectoral collaboration has been proved to be difficult. In this study, we investigated which resources influence intersectoral collaboration. The behavior change wheel framework was used to categorize motivation-, capability-, and opportunity-related resources for intersectoral collaboration. In-depth interviews were held with eight officials representing 10 non-health policy sectors within a local government. Results showed that health and non-health policy sectors did not share policy goals, which decreased motivation for intersectoral collaboration. Awareness of the linkage between health and nonhealth policy sectors was limited, and management was not involved in creating such awareness, which reduced the capability for intersectoral collaboration. Insufficient organizational resources and structures reduced opportunities for intersectoral collaboration. To stimulate intersectoral collaboration to prevent childhood obesity, we recommend that public health professionals should reframe health goals in the terminology of nonhealth policy sectors, that municipal department managers should increase awareness of public health in non-health policy sectors, and that flatter organizational structures should be established. PMID- 24490061 TI - Predictors of health-related quality of life in outpatients with cirrhosis: results from a prospective cohort. AB - Background. Cirrhosis may lead to a poor health-related quality of life (HRQOL), which should be taken into consideration when addressing the cirrhotic outpatient. Methods. Prospective cohort study evaluating predictors of HRQOL in outpatients with cirrhosis. Patients with overt hepatic encephalopathy at baseline were excluded. HRQOL was evaluated at baseline using the six point Chronic Liver Disease Questionnaire. Predictors of low quality of life scores (<4 points) and mortality were analyzed using multivariable logistic regression. Results. In total, 92 patients were included (mean age 61 years, 59% male). Nineteen patients died (mean duration of follow-up 20 months). The mean Child Pugh score was 6.9. Twenty percent had a poor HRQOL judged by the Chronic Liver Disease Questionnaire score and 45% had covert hepatic encephalopathy. The only predictors of poor HRQOL were the Child-Pugh score (beta=0.45;P = 0.013), nonalcoholic etiology of cirrhosis (beta=-2.34;P = 0.009), and body mass index (beta=-0.20;P = 0.023). The body mass index predicted poor HRQOL independently of the presence of ascites and albumin level. Conclusions. The body mass index was associated with a low HRQOL. This suggests that malnutrition may be an important target in the management of patients with cirrhosis. PMID- 24490062 TI - Involvement of Differential Relationship between HCV Replication and Hepatic PRR Signaling Gene Expression in Responsiveness to IFN-Based Therapy. AB - Aim. To gain an insight into the effect of HCV replication-associated interference with the IFN system on hepatic mRNA expression involved in IFN production. Methods. Relative mRNA expression of TLR3/RIG-I signaling genes involved in IFN- beta production was correlated with positive- and negative strand HCV RNAs in pretreatment liver tissues responsive and nonresponsive to peginterferon and ribavirin for chronic hepatitis C genotype 1. Treatment response was analyzed for per protocol population at weeks 12 (n = 45) and 24 (n = 40) and at 24 weeks aftertreatment (n = 38). Results. HCV replication had no relation to the expression of TLR3, RIG-I, TRIF, IPS-1, IRF3, and IFN- beta mRNAs in responders. In striking contrast, positive- and/or negative-strand HCV showed positive correlations with TLR3, RIG-I, TRIF, IPS-1, and IRF3 mRNAs in week-12 nonresponders; with RIG-I, TRIF, IPS-1, and IRF3 mRNAs in week-24 nonresponders; and with TLR3, RIG-I, and IRF3 mRNAs in posttreatment nonresponders. Thus mRNA expression of TLR3/RIG-I signaling genes was increased in relation to viral replication in nonresponders. Conclusions. The findings in IFN nonresponders may imply a host feedback response to severe impairment of the IFN system associated with HCV replication. PMID- 24490063 TI - Harmonic scalpel versus conventional haemostasis in neck dissection: a prospective randomized study. AB - PURPOSE: The aim of this prospective randomized trial was to compare operative factors, postoperative outcomes, and surgical complications of neck dissection (ND) when using the harmonic scalpel (HS) versus conventional haemostasis (CH) (classic technique of tying and knots, resorbable ligature, and bipolar diathermy). MATERIALS AND METHODS: Sixty-one patients who underwent ND with primary head and neck cancer (HNSCC) resection were enrolled in this study and were randomized into two homogeneous groups: CH (conventional haemostasis with classic technique of tying and knots, resorbable ligature, and bipolar diathermy) and HS (haemostasis with harmonic scalpel). Outcomes of the study included operative time, intraoperative blood loss, drainage volume, postoperative pain, hospital stay, and incidence of intraoperative and postoperative complications. RESULTS: The use of the HS reduced significantly the operating time, the intraoperative blood loss, the postoperative pain, and the volume of drainage. No significant difference was observed in mean hospital stay and perioperative, and postoperative complications. CONCLUSION: The HS is a reliable and safe tool for reducing intraoperative blood loss, operative time, volume of drainage and postoperative pain in patients undergoing ND for HNSCC. Multicenter randomized studies need to be done to confirm the advantages of this technique and to evaluate the cost-benefit ratio. PMID- 24490064 TI - Supraclavicular artery flap for head and neck oncologic reconstruction: an emerging alternative. AB - AIM: Head and Neck oncologic resections often leave complex defects which are challenging to reconstruct. The need of the hour is a versatile flap which has the advantages of both a regional flap (viz. reliable and easy to harvest) and a free flap (thin, pliable with good colour match). In this a study we assessed the usefulness of the supraclavicular artery flap in head and neck oncologic defects. MATERIALS AND METHOD: The flap was used as a pedicled fasciocutanous and was based on the transverse supraclavicular artery. We assessed this reconstructive option for complications as well as its and functional out comes. RESULTS: Eleven cases underwent supraclavicular artery flap between 20011-2012 of which 5 were males and 6 females. Mean defect size was 5 cm * 6 cm. Nine donor sites were closed primarily and 1 required split skin grafting. We encountered one complete flap loss which was attributed to a band of constricting skin bridge over the vascular pedicle in a defect involving lateral third of midface. Two patient developed pharyngeocutaneous fistula (without flap loss) out of 3 patients who underwent augmentation pharyngoplasty post Near total laryngectomy. CONCLUSION: Supra clavicular artery flap is a thin versatile, reliable, easy to harvest, with good cosmetic and functional outcome at both ends (recipient and donor) for reconstructing head and neck oncologic defects. PMID- 24490065 TI - Analysis of maternal and child health indicators in an area at parana state, Brazil. AB - The aim of this study was to analyze maternal and child health indicators and infant mortality rate (IMR) at the cities located at the 18th Health Division (HD) in Parana State, Brazil. In this ecological study we analyzed all live births and infant deaths which occurred from 2000 to 2009 at the 18th HD, collecting data from the Mortality Information Database and the Live Births Information Database. The variables assessed were grouped into maternal, pregnancy and delivery, and neonatal variables. The analysis was conducted using the mean percentage of each variable and the IMR calculated for both periods: from 2000 to 2004 and from 2005 to 2009. The IMR was reduced considerably, following Brazil's and Parana State's trend. Maternal indicators went down regarding the mean percentage of teenage mothers and low education, whereas they went up regarding mother with 35 years old or older and mothers without a partner. Pregnancy indicators showed increased prematurity and cesarean birth. Neonatal indicators raised in black/brown skin color and low birth weights percentages. This study provides a better understanding of maternal and child health in the cities located at the 18th HD, supplying grounds to plan actions regarding the real needs of each specific city. PMID- 24490066 TI - Standardization of laparoscopic pelvic examination: a proposal of a novel system. AB - Objective. Laparoscopic pelvic assessment is often performed in a nonstandardized fashion depending on the surgeon's discretion. Reporting anatomic findings is inconsistent and lesions in atypical locations may be missed. We propose a method for systematic pelvic assessment based on anatomical landmarks. Design. Retrospective analysis. Setting. Tertiary care academic medical center. Intervention. We applied this system to operative reports of 540 patients who underwent diagnostic or operative laparoscopy for unexplained infertility between 2006 and 2012. The pelvis was divided into 2 midline zones (zone I and II) and right and left lateral zones (zone III and IV). All reports were evaluated for the comprehensiveness of description with respect to normal findings or pathology for each zone. Results. Of 540 surgeries, all reports commented on the uterus, tubes, and ovaries (100%), but only 17% (n = 93, 95% CI: 13.8-20.2) commented on the dome of the bladder and the anterior cul-de-sac. 24% (n = 130, 95% CI: 20.4 27.6) commented on the posterior cul-de-sac, and 5% (n = 29, 95% CI: 3.2-6.8) commented on the pelvic sidewall. Overall, 6% (n = 34, 95% CI: 4-8) reported near complete documentation of the pelvic zones. Conclusion. Implementation of a systematic approach for laparoscopic pelvic examination will enhance the diagnostic accuracy and provide better communication between care providers. In the absence of pelvic pathology, we recommend a minimum of 6 photographs of the 6 pelvic zones. PMID- 24490067 TI - Comparison of Postoperative Analgesic Effect of Dexamethasone and Fentanyl Added to Lidocaine through Axillary Block in Forearm Fracture. AB - Aim. Regional analgesia has been introduced as better analgesic technique compared to using systemic analgesic agents, and it may decrease the adverse effects of them and increase the degree of satisfaction. Several additives have been suggested to enhance analgesic effect of local anesthetic agents such as opioids and steroids. We designed this randomized double-blind controlled study to compare the analgesic efficacy of the dexamethasone and fentanyl added to lidocaine using axillary block in patients undergoing operation of forearm fracture. Materials and Methods. Seventy-eight patients 20-60 years old were recruited in a prospective, double-blinded, randomized way. Axillary block was performed in the three groups by using 40 mL lidocaine and 2 mL distilled water (L group), 40 mL lidocaine and 2 mL dexamethasone (LD group), and 40 mL lidocaine and 2 mL fentanyl (LF group). The onset time of sensory and motor block, duration of sensory and motor block, the total analgesic dose administered during 6 hours after the surgery, and hemodynamic variables were recorded. Results. The duration of sensory and motor block was significantly longer in LD group compared to other groups (P < 0.001). Similarly, the total analgesic consumption in LD group was smaller compared to other groups (P < 0.001). Comparison of hemodynamic consequences of axillary block and surgery failed to reveal any statistically significant differences between all groups. Conclusion. Addition of dexamethasone to lidocaine significantly prolonged the duration of analgesia compared with fentanyl/lidocaine mixture or lidocaine alone using axillary block in patients undergoing forearm fracture surgery. This trial is registered with IRCT2012120711687N1. PMID- 24490068 TI - Feasibility and merits of performing preclinical imaging on clinical radiology and nuclear medicine systems. AB - Aim. Researchers have limited access to systems dedicated to imaging small laboratory animals. This paper aims to investigate the feasibility and merits of performing preclinical imaging on clinical systems. Materials and Methods. Scans were performed on rat and mouse models of diseases or injuries on four radiology systems, tomosynthesis, computed tomography (CT), positron emission tomography/computed tomography (PET-CT), and Magnetic Resonance Imaging (MRI), based on the availability at the author's institute. Results. Tomosysthesis delineated soft tissue anatomy and hard tissue structure with superb contrast and spatial resolution at minimal scan time and effort. CT allowed high resolution volumetric visualization of bones. Molecular imaging with PET was useful for detecting cancerous tissue in mouse but at the expense of poor resolution. MRI depicted abnormal or intervened tissue at quality and resolution sufficient for experimental studies. The paper discussed limitations of the clinical systems in preclinical imaging as well as challenges regarding the need of additional gadgets, modifications, or upgrades required for longitudinally scanning animals under anesthesia while monitoring their vital signs. Conclusion. Clinical imaging technologies can potentially make cost-effective and efficient contributions to preclinical efforts in obtaining anatomical, structural, and functional information from the underlying tissue while minimally compromising the data quality in certain situations. PMID- 24490069 TI - Application of a Simple In-House PCR-SSP Technique for HLA-B* 27 Typing in Spondyloarthritis Patients. AB - Background. Microlymphocytotoxicity (MLCT) and flowcytometry (FC) are the conventional serological methods to detect HLA-B* 27. Due to some disadvantages in these methods, most of the HLA laboratories have now switched over to molecular methods. Molecular techniques based on commercial kits are expensive; as such many laboratories with limited funds in developing countries cannot afford these techniques. Aims. Our main aim was to standardize a simple inexpensive in-house PCR-SSP technique for HLA-B* 27 typing. Materials and Methods. Sequence Specific primers were designed to amplify all the subtypes of B* 27 using IMGT-HLA sequence database. Accuracy was checked by retyping of 90 PCR-SSOP typed controls. Results. The presence of 149 bp specific band with control band on 2% agarose gel showed B* 27 positivity. No discrepancies were found when compared with PCR-SSOP results. The frequency of HLA-B* 27 was found to be significantly increased (68.75% versus 4.40%, O.R 46.909: P value 6.62E - 32) among 700 SpA patients as compared to controls. Clinically, 54% of patients had polyarticular arthritis with SI joints involvement (68%) and restricted spine flexion (60%). Conclusion. In-house PCR-SSP technique is very simple and inexpensive technique to detect B* 27 allele, which was strongly associated with SpA patients from Western India. PMID- 24490070 TI - QTc Prolongation in Patients Acutely Admitted to Hospital for Psychosis and Treated with Second Generation Antipsychotics. AB - QTc interval prolongation is a side effect of several antipsychotic drugs, with associated risks of torsade de pointes arrhythmias and sudden cardiac death. There is an ongoing debate of whether or not electrocardiogram (ECG) assessments should be mandatory in patients starting antipsychotic drugs. To investigate QTc prolongation in a clinically relevant patient group 171 adult patients acutely admitted to an emergency ward for psychosis were consecutively recruited. ECGs were recorded at baseline and then at discharge or after 6 weeks at the latest (discharge/6 weeks), thus reflecting the acute phase treatment period. The mean QTc interval was 421.1 (30.4) ms at baseline and there was a positive association between the QTc interval and the agitation score whereas the QTc interval was inversely associated with the serum calcium level. A total of 11.6% had abnormally prolonged QTc intervals and another 14.3% had borderline prolongation. At discharge/6 weeks, the corresponding proportions were reduced to 4.2% and 5.3%, respectively. The reduction of the proportion with prolonged QTc intervals reached statistical significance (chi-square exact test: P = 0.046). The finding of about one-quarter of the patients with borderline or prolonged QTc intervals could indicate mandatory ECG recordings in this population. This trial is registered with ClinicalTrials.gov ID: NCT00932529. PMID- 24490071 TI - The Effects of Antipsychotics on Prolactin Levels and Women's Menstruation. AB - Introduction. Typical and atypical antipsychotic agent is currently used for treatment in the majority of patients with psychotic disorders. The aim of this review is to assess antipsychotic induced hyperprolactinaemia and the following menstrual dysfunction that affects fertility, quality of life, and therapeutic compliance of women. Method. For this purpose, Medline, PsychInfo, Cochrane library, and Scopus databases were accessed, with a focus on the publication dates between 1954 and 2012. Research of references was also performed and 78 studies were retrieved and used for the needs of this review. Results. A summary of several antipsychotics as well as frequency rates and data on hyperprolactinaemia and menstrual disorders for different agent is presented. Conclusion. Diverse prevalence rates of hyperprolactinaemia and menstrual abnormalities have been found about each medication among different studies. Menstruation plays an important role for women, thus, understanding, careful assessment, and management of hyperprolactinaemia could enhance their lives, especially when dealing with women that suffer from a psychotic disorder. PMID- 24490072 TI - The Pathways to the First Contact with Mental Health Services among Patients with Schizophrenia in Lagos, Nigeria. AB - There is increasing evidence that delay in the commencement of treatment, following the onset of schizophrenia, may be related to the pathways patients navigate before accessing mental health care. Therefore, insight into the pattern and correlates of pathways to mental care of patients with schizophrenia may inform interventions that could fast track their contact with mental health professionals and reduce the duration of untreated psychosis. This study assessed the pathways to mental health care among patients with schizophrenia (n = 138), at their first contact with mental health services at the Federal Neuro Psychiatric Hospital Yaba Lagos, Nigeria. Traditional and religious healers were the first contact for the majority (69%) of the patients. Service users who first contacted nonorthodox healers made a greater number of contacts in the course of seeking help, eventuating in a longer duration of untreated psychosis (P < 0.001). However, the delay between the onset of psychosis and contact with the first point of care was shorter in patients who patronized nonorthodox practitioners. The findings suggest that collaboration between orthodox and nonorthodox health services could facilitate the contact of patients with schizophrenia with appropriate treatment, thereby reducing the duration of untreated psychosis. The need for public mental health education is also indicated. PMID- 24490073 TI - Periodontal proteomics: wonders never cease! AB - Proteins are vital parts of living organisms, as they are integral components of the physiological metabolic pathways of cells. Periodontal tissues comprise multicompartmental groups of interacting cells and matrices that provide continuous support, attachment, proprioception, and physical protection for the teeth. The proteome map, that is, complete catalogue of the matrix and cellular proteins expressed in alveolar bone, cementum, periodontal ligament, and gingiva, is to be explored for more in-depth understanding of periodontium. The ongoing research to understand the signalling pathways that allow cells to divide, differentiate, and die in controlled manner has brought us to the era of proteomics. Proteomics is defined as the study of all proteins including their relative abundance, distribution, posttranslational modifications, functions, and interactions with other macromolecules, in a given cell or organism within a given environment and at a specific stage in the cell cycle. Its application to periodontal science can be used to monitor health status, disease onset, treatment response, and outcome. Proteomics can offer answers to critical, unresolved questions such as the biological basis for the heterogeneity in gingival, alveolar bone, and cemental cell populations. PMID- 24490074 TI - Five decades with polyunsaturated Fatty acids: chemical synthesis, enzymatic formation, lipid peroxidation and its biological effects. AB - I have been involved in research on polyunsaturated fatty acids since 1964 and this review is intended to cover some of the most important aspects of this work. Polyunsaturated fatty acids have followed me during my whole scientific career and I have published a number of studies concerned with different aspects of them such as chemical synthesis, enzymatic formation, metabolism, transport, physical, chemical, and catalytic properties of a reconstructed desaturase system in liposomes, lipid peroxidation, and their effects. The first project I became involved in was the organic synthesis of [1-(14)C] eicosa-11,14-dienoic acid, with the aim of demonstrating the participation of that compound as a possible intermediary in the biosynthesis of arachidonic acid "in vivo." From 1966 to 1982, I was involved in several projects that study the metabolism of polyunsaturated fatty acids. In the eighties, we studied fatty acid binding protein. From 1990 up to now, our laboratory has been interested in the lipid peroxidation of biological membranes from various tissues and different species as well as liposomes prepared with phospholipids rich in PUFAs. We tested the effect of many antioxidants such as alpha tocopherol, vitamin A, melatonin and its structural analogues, and conjugated linoleic acid, among others. PMID- 24490075 TI - Innate and Adaptive Responses to Heat Shock Proteins in Behcet's Disease. AB - Behcet's disease (BD) is a systemic, chronic inflammatory disorder with both innate and adaptive immune responses. Heat shock proteins (HSP) are highly conserved molecules in different species with scavenger activity and involved in correct folding of newly synthesized proteins. T and B cell responses against HSPs are observed in BD patients in both alphabeta and gammadelta T-cell populations. 60-kD HSP (HSP60) is also shown to be recognized by pattern recognition receptors such as toll-like receptors (TLR) and is suggested to be an endogenous "danger" signal to the immune system with rapid inflammatory cytokine releases and enhancement of adaptive Th1-type responses. Elucidating the exact role of HSPs in BD pathogenesis might pave the way to less toxic therapeutic approaches to BD, such as antibacterial therapies and immunomodulation. PMID- 24490077 TI - A Comparison of Tumor Biology in Primary Ductal Carcinoma In Situ Recurring as Invasive Carcinoma versus a New In Situ. AB - Introduction. About half of all new ipsilateral events after a primary ductal carcinoma in situ (DCIS) are invasive carcinoma. We studied tumor markers in the primary DCIS in relation to type of event (invasive versus in situ). Methods. Two hundred and sixty-six women with a primary DCIS from two source populations, all with a known ipsilateral event, were included. All new events were regarded as recurrences. Patient and primary tumor characteristics (estrogen receptor (ER), progesterone receptor (PR), HER2, EGFR, and Ki67) were evaluated. Logistic regression was used to calculate odd ratios and 95% confidence intervals in univariate and multivariate analyses. Results. One hundred and thirty-six of the recurrences were invasive carcinoma and 130 were in situ. The recurrence was more often invasive if the primary DCIS was ER+ (OR 2.5, 95% CI 1.2-5.1). Primary DCIS being HER2+ (OR 0.5, 95% CI 0.3-0.9), EGFR+ (OR 0.4, 95% CI 0.2-0.9), and ER95 /HER2+ (OR 0.2, 95% CI 0.1-0.6) had a lower risk of a recurrence being invasive. Conclusions. In this study, comparing type of recurrence after a DCIS showed that the ER-/HER2+ tumors were related to a recurrence being a new DCIS. And surprisingly, tumors being ER+, HER2-, and EGFR- were related to a recurrence being invasive cancer. PMID- 24490078 TI - Clinically diagnosed insomnia and risk of all-cause and diagnosis-specific disability pension: a nationwide cohort study. AB - Background. Insomnia and disability pension are major health problems, but few population-based studies have examined the association between insomnia and risk of disability pension. Methods. We conducted a prospective nationwide cohort study based on Swedish population-based registers including all 5,028,922 individuals living in Sweden on December 31, 2004/2005, aged 17-64 years, and not on disability or old age pension. Those having at least one admission/specialist visit with a diagnosis of disorders of initiating and maintaining sleep (insomnias) (ICD-10: G47.0) during 2000/2001-2005 were compared to those with no such inpatient/outpatient care. All-cause and diagnosis-specific incident disability pension were followed from 2006 to 2010. Incidence rate ratios (IRRs) and 95% confidence intervals (CIs) were estimated by Cox regression. Results. In models adjusted for prior sickness absence, sociodemographic factors, and inpatient/specialized outpatient care, associations between insomnia and increased risks of all-cause disability pension (IRR 1.35, 95% CI 1.09-1.67) and disability pension due to mental diagnoses (IRR 1.86, 95% CI 1.38-2.50) were observed. After further adjustment for insomnia medications these associations disappeared. No associations between insomnia and risk of disability pension due to cancer, circulatory, or musculoskeletal diagnoses were observed. Conclusion. Insomnia seems to be positively associated with all-cause disability pension and disability pension due to mental diagnoses. PMID- 24490076 TI - Skewed Helper T-Cell Responses to IL-12 Family Cytokines Produced by Antigen Presenting Cells and the Genetic Background in Behcet's Disease. AB - Behcet's disease (BD) is a multisystemic inflammatory disease and is characterized by recurrent attacks on eyes, brain, skin, and gut. There is evidence that skewed T-cell responses contributed to its pathophysiology in patients with BD. Recently, we found that Th17 cells, a new helper T (Th) cell subset, were increased in patients with BD, and both Th type 1 (Th1) and Th17 cell differentiation signaling pathways were overactivated. Several researches revealed that genetic polymorphisms in Th1/Th17 cell differentiation signaling pathways were associated with the onset of BD. Here, we summarize current findings on the Th cell subsets, their contribution to the pathogenesis of BD and the genetic backgrounds, especially in view of IL-12 family cytokine production and pattern recognition receptors of macrophages/monocytes. PMID- 24490079 TI - Role of sugar and sugar substitutes in dental caries: a review. AB - Dental caries is a chronic disease which can affect us at any age. The term "caries" denotes both the disease process and its consequences, that is, the damage caused by the disease process. Dental caries has a multifactorial aetiology in which there is interplay of three principal factors: the host (saliva and teeth), the microflora (plaque), and the substrate (diet), and a fourth factor: time. The role of sugar (and other fermentable carbohydrates such as highly refined flour) as a risk factor in the initiation and progression of dental caries is overwhelming. Whether this initial demineralization proceeds to clinically detectable caries or whether the lesion is remineralized by plaque minerals depends on a number of factors, of which the amount and frequency of further sugars consumption are of utmost importance. This paper reviews the role of sugar and sugar substitutes in dental caries. PMID- 24490080 TI - Knowledge, Beliefs, and Psychosocial Effect of Acne Vulgaris among Saudi Acne Patients. AB - Objective. This study was conducted to assess the knowledge, beliefs, and psychosocial effect of acne vulgaris among acne patients attending referral dermatology clinic in Al-Khobar city. Material and Methods. A cross-sectional study was conducted on all Saudi acne patients (males and females) attending referral dermatology clinic in Al-Khobar Governmental Hospital. The data were collected by using a structured self-administered questionnaire. Results. Like other studies conducted before, we found that 58.33% of our sample have poor knowledge about factors that affect acne vulgaris with a significant correlation with both age and gender (P = 0.012 and P = 0.031, resp.). There was significant association of reporting affected social activities with age and educational level (P = 0.023 and P = 0.013, resp.). Variation between both genders regarding reporting feeling stressed due to acne was significant (P = 0.001). The majority of our sample sought medical advice after one year. The most commonly used treatment for acne vulgaris before seeking medical help was peeling products. The majority of our patients thought that acne needs no treatment by physicians. Doctors' treatment is considered guaranteed and safe by the vast majority of our patients. Conclusion. This study showed that knowledge about acne is still insufficient among acne patients. PMID- 24490081 TI - Effects of glucose control and variability on endothelial function and repair in adolescents with type 1 diabetes. AB - Background. Endothelial dysfunction and increased inflammation are precursors of cardiovascular disease in type 1 diabetes (T1D) and occur even in adolescents with T1D. The goal of this study was to determine the relationship of endothelial dysfunction to various measures of glycemia. Research Design and Methods. Forearm blood flow (FBF, venous occlusion plethysmography) was measured before and after 5 min of upper arm vascular occlusion in 17 adolescents with uncomplicated type 1 diabetes. Endothelial function was assessed as postocclusion FBF and forearm vascular resistance (FVR, mean arterial pressure/FBF). Fasting glucose, 72 hour mean glucose and standard deviation from continuous glucose monitoring, hemoglobin A1c, and hemoglobin A1c by duration area under the curve were used to assess immediate, short-term, and intermediate- and long-term glycemia. Results. Postocclusion FBF (r = -0.53, P = 0.030) negatively correlated and postocclusion FVR positively correlated (r = 0.52, P = 0.031) with hemoglobin A1c levels. FVR was positively associated with log 3 day mean glucose (r = 0.55, P = 0.027). Postocclusion FBF (2.8 +/- 1.1 versus 3.4 +/- 0.5 mL/dL/min, mean +/- SE, P = 0.084) tended to be lower and FVR (31.4 +/- 10.4 versus 23.9 +/- 4.4 mmHg dL min/mL, P = 0.015) was significantly higher in subjects with hemoglobin A1c above the median (8.3%) compared to those with lower hemoglobin A1c levels. Conclusions. These results demonstrate that poor intermediate-term glycemic control is associated with impaired endothelial function. PMID- 24490082 TI - Comparative Effects of Phosphoenolpyruvate, a Glycolytic Intermediate, as an Organ Preservation Agent with Glucose and N-Acetylcysteine against Organ Damage during Cold Storage of Mouse Liver and Kidney. AB - We evaluated the usefulness of phosphoenolpyruvate (PEP), a glycolytic intermediate with antioxidative and energy supplementation potentials, as an organ preservation agent. Using ex vivo mouse liver and kidney of a static cold storage model, we compared the effects of PEP against organ damage and oxidative stress during cold preservation with those of glucose or N-acetylcysteine (NAC). Lactate dehydrogenase (LDH) leakage, histological changes, and oxidative stress parameters (measured as thiobarbituric acid reactive substance and glutathione content) were determined. PEP (100 mM) significantly prevented an increase in LDH leakage, histological changes, such as tubulonecrosis and vacuolization, and changes in oxidative stress parameters during 72 h of cold preservation in mouse liver. Although glucose (100 mM) partly prevented LDH leakage and histological changes, no effects against oxidative stress were observed. By contrast, NAC inhibited oxidative stress in the liver and did not prevent LDH leakage or histological changes. PEP also significantly prevented kidney damage during cold preservation in a dose-dependent manner, and the protective effects were superior to those of glucose and NAC. We suggest that PEP, a functional carbohydrate with organ protective and antioxidative activities, may be useful as an organ preservation agent in clinical transplantation. PMID- 24490083 TI - Histological quantification of angiogenesis after focal cerebral infarction: a systematic review. AB - Ischemic stroke is a leading cause of disability, and current treatments to improve recovery are limited. Part of the natural recovery process after brain injury is angiogenesis. The formation of new blood vessels around the infarct appears to be important for restoration of adequate perfusion to allow for healing of brain tissue. Many potential restorative treatments may affect, and be affected by, angiogenesis, so accurate quantification of this outcome is needed. We performed a systematic review of histological methods to quantify angiogenesis after cerebral infarction. We found reports of the use of a variety of histological and general and immunostaining techniques in conjunction with a variety of analysis methods. We found no direct comparison studies and concluded that more research is needed to optimize the assessment of this important stroke outcome. PMID- 24490084 TI - Attitudes of Implanting Physicians about Cardiac Rhythm Management Devices and Their Features. AB - Modern cardiac rhythm management systems have become increasingly complex. The decision on which specific system to implant in a given patient often rests with the implanting physician. We conducted a multiple-choice survey to assess the opinions and preferences of cardiologists and electrophysiologists who implant and follow cardiac rhythm management systems. Reliability and battery longevity were viewed as the most important characteristics in device selection. Patient characteristics which most affected device choice were pacing indication and life expectancy. Remote technology was used in 47% of pacemaker patients, 64% of ICD patients, and 65% of CRT-D patients, with wireless (radiofrequency) remote patient monitoring associated with higher patient compliance rates (74% versus 64%, resp.). Wireless remote patient management with alerts for atrial tachyarrhythmias was felt to be important by 76% of respondents. When choosing an MR-conditional device, physicians deemed patients with prior orthopedic problems, a history of cancer, or neurological disorders to be more likely to require a future MRI. Device longevity and reliability remain the most important factors which influence device selection. Wireless remote patient monitoring with alerts is considered increasingly important when choosing a specific cardiac rhythm management system to implant. PMID- 24490086 TI - Radiobiological framework for the evaluation of stereotactic radiosurgery plans for invasive brain tumours. AB - This study presents a radiobiological formalism for the evaluation of the treatment plans with respect to the probability of controlling tumours treated with stereotactic radiosurgery accounting for possible infiltrations of malignant cells beyond the margins of the delineated target. Treatments plans devised for three anaplastic astrocytoma cases were assumed for this study representing cases with different difficulties for target coverage. Several scenarios were considered regarding the infiltration patterns. Tumour response was described in terms of tumour control probability (TCP) assuming a Poisson model taking into account the initial number of clonogenic cells and the cell survival. The results showed the strong impact of the pattern of infiltration of tumour clonogens outside the delineated target on the outcome of the treatment. The treatment plan has to take into account the existence of the possible microscopic disease around the visible lesion; otherwise the high gradients around the target effectively prevent the sterilisation of the microscopic spread leading to low probability of control, in spite of the high dose delivered to the target. From this perspective, the proposed framework offers a further criterion for the evaluation of stereotactic radiosurgery plans taking into account the possible infiltration of tumour cells around the visible target. PMID- 24490085 TI - Esophageal Cancer, the Topmost Cancer at MTRH in the Rift Valley, Kenya, and Its Potential Risk Factors. AB - Esophageal cancer at Moi Teaching and Referral Hospital (MTRH) is the leading cancer in men with a poor prognosis. A case control study (n = 159) aimed at the histology type, gender, and risk indicators was carried out at MTRH. Mantel Haenszel chi-square and logistic regression were employed for analysis. Squamous cell carcinoma was the common histological type occurring in the middle third portion of the oesophagus. The occurrence of the cancer in males was 1.4 times that of females. The mean age was 56.1 yrs. Low socioeconomic, smoking, snuff use, alcohol, tooth loss, cooking with charcoal and firewood, hot beverage, and use of mursik were independently associated with esophageal cancer (P < 0.05). Using logistic regression adjusted for various factors, alcohol consumption was associated with the increased risk of esophageal cancer. AHR was 0.45 and 95% CI: 0.205-0.985, P = 0.046. A societal component of low socioeconomic conditions, a lifestyle component with specific practices such as the consumption of mursik, chang'aa, busaa, snuff, smoking, hot tea, poor oral hygiene, and an environmental component with potential exposure to high levels of nitrosamines, passive smoking, and cooking with coal, could be involved. The increase in experts at MTRH capable of diagnosing could be responsible for the increase in reporting this neoplasm. PMID- 24490087 TI - Buried penis: evaluation of outcomes in children and adults, modification of a unified treatment algorithm, and review of the literature. AB - Introduction. Buried penis is a difficult condition to manage in children and adults and conveys significant physical and psychological morbidity. Surgery is often declined due to morbid obesity, forcing patients to live in disharmony for years until the desired weight reduction is achieved. No single operative technique fits all. We present our experience and surgical approach resulting in an improved algorithm unifying the treatment of adults and children. Methods. We conducted a retrospective analysis of patients treated for buried penis between 2011 and 2012. All patients underwent penile degloving and basal anchoring. Penile shaft coverage was achieved with skin grafts. Suprapubic lipectomies were performed on adult patients. Results. Nine patients were identified: four children and five obese adults. Average postoperative stay was three days for children and five for adults. Three adults were readmitted with superficial wound problems. One child had minor skin breakdown. All patients were pleased with their outcomes. Conclusion. Buried penis is a complex condition, and treatment should be offered by services able to deal with all aspects of reconstruction. Obesity in itself should not delay surgical intervention. Local and regional awareness is essential to manage expectations in these challenging patients aspiring to both aesthetic and functional outcomes. PMID- 24490088 TI - Noninvasive strategies to optimise brain plasticity: from basic research to clinical perspectives. PMID- 24490089 TI - Inadvertent Subdural Injection during Cervical Transforaminal Epidural Steroid Injection. AB - Serious complications following cervical epidural steroid injection are rare. Subdural injection of local anesthetic and steroid represents a rare but potentially life threatening complication. A patient presented with left sided cervical pain radiating into the left upper extremity with motor deficit. MRI showed absent lordosis with a broad left paramedian disc-osteophyte complex impinging the spinal cord at C5-6. During C5-6 transforaminal epidural steroid injection contrast in AP fluoroscopic view demonstrated a subdural contrast pattern. The needle was withdrawn slightly and repositioned. Normal lateral epidural and nerve root contrast pattern was subsequently obtained and injection followed with immediate improvement in radicular symptoms. There were no postoperative complications on subsequent clinic follow-up. The subdural space is a potential space between the arachnoid and dura mater. As the subdural space is larger in the cervical region, there may be an elevated potential for inadvertent subdural injection. Needle placement in the cervical subdural space during transforaminal injection is uncommon. Failure to identify aberrant needle entry within the cervical subdural space may result in life threatening complications. We recommend initial injection of a limited volume of contrast agent to detect inadvertent subdural space placement. PMID- 24490090 TI - Restoration of strip crown with a resin-bonded composite cement in early childhood caries. AB - Background. Early childhood caries is a widely prevalent disease throughout the world. It is necessary to treat this condition in early childhood; however, child behavior management may be particularly challenging during treatment. To overcome this challenge, we used Carigel to remove caries and RelyX Unicem resin cement for strip crown restoration. It not only has the desired aesthetic effect but is also more effective for primary teeth, which are used for a shorter period than permanent teeth are. Case Presentation. We report a case of three pediatric patients with early childhood caries, in whom caries was removed by using Carigel to avoid the risk of pulpal exposure associated with high-speed handpieces. Subsequently, aesthetic restoration was performed using strip crown with RelyX Unicem self-adhesive resin cement. Conclusion. RelyX Unicem has the following advantages: (1) not requiring have any special skills for the dentist for performing the procedure, (2) decreased occurrence of bubbles during injection of the cement, and (3) overall short duration of the procedure. Thus, it is appropriate for the treatment of pediatric patients whose behavior is difficult to manage. However, further studies are required in order to establish the use of RelyX Unicem as a stable restorative material in early childhood caries. PMID- 24490091 TI - Replacement of missing anterior teeth in a patient with chronic mouth breathing and tongue thrusting. AB - The loss of anterior teeth has serious functional, esthetic disabilities, in addition to compromising the patients' quality of life. Various etiologies can be attributed to the anterior tooth loss, including trauma, caries, and periodontal diseases. The chronic mouth breathing due to nasal adenoids is known to enhance the gingival and periodontal diseases. The dental literature proves the association of nasal breathing, tongue thrusting, and anterior open bite. Arch shape and tooth position are primarily determined by the equilibrium of the forces from tongue and perioral musculature. Increased force from tongue musculature in the tongue thrusting patient leads to flaring of anterior teeth, making them susceptible for periodontal and traumatic tooth loss. Replacement of the anterior teeth in this patient will also help in restoration of anterior guidance, which is critical for the health of temporomandibular joint, posterior teeth, and musculature. PMID- 24490092 TI - Pyogenic Liver Abscess, Bacteremia, and Meningitis with Hypermucoviscous Klebsiella pneumoniae: An Unusual Case Report in a Human T-Cell Lymphotropic Virus Positive Patient of Caribbean Origin in the United States. AB - Pyogenic liver abscess (PLA) is a potentially fatal disease. Klebsiella pneumoniae (K. pneumoniae) has replaced Escherichia coli (E. coli) as the predominant causative organism for pyogenic liver abscess. Over the years a unique form of community-acquired invasive K. pneumoniae infection of the liver has been well described in Southeast Asia. This has recently been linked to a virulent hypermucoviscous K. pneumoniae phenotype and to a specific genotype, rmpA positive. To our knowledge, we report the first case of PLA with bacteremia and meningitis in a Guyanese patient with the presence of rmpA-positive K. pneumoniae with laboratory evidence in North America. PMID- 24490093 TI - Unusual presentation of vivax malaria with anaemia, thrombocytopenia, jaundice, renal disturbance, and melena: a report from malang, a nonendemic area in indonesia. AB - Most of the complications of malaria such as anaemia, thrombocytopenia, jaundice, and renal failure are commonly found in Plasmodium falciparum malaria, but the incidence of severe and complicated vivax malaria tends to be increasing. We report two cases of severe Plasmodium vivax malaria from Malang, a nonendemic area in Indonesia. Patients exhibited anaemia, thrombocytopenia, jaundice, renal disturbance, and melena. Microscopic peripheral blood examination and amplification of parasite 18s rRNA by polymerase chain reaction showed the presence of P. vivax and absence of P. falciparum. All patients responded well to antimalarial drugs. PMID- 24490094 TI - Cisplatin and short-term 5-Fluorouracil infusion for paraneoplastic microangiopathic hemolytic anemia in gastric cancer: a case report and review of the literature. AB - Microangiopathic hemolytic anemia is a rare paraneoplastic syndrome accompanying adenocarcinoma of the stomach. We report on a patient presenting with anemia due to a combination of severe hemolysis and tumour bleeding, where the combination of cisplatin and 5-fluorouracil in a short course infusional regimen led to a complete response of the hematologic abnormalities in the first line setting. Relapse was successfully treated with second line docetaxel; however the response was relatively short-lived. Overall survival was 16 months from diagnosis, which compares favourably to the survival of other reported cases. The chemotherapy regimens used in previously reported similar cases are reviewed. We suggest that a regimen based on bolus 5-fluorouracil, possibly with a platinum, should be investigated as a possible regimen of choice. PMID- 24490095 TI - A rare case with a solitary fibrous tumour of the colon and an epithelioid angiomyolipoma of the kidney. AB - Solitary fibrous tumour is a soft tissue tumour composed of a subset of fibroblast-like cells and frequently needs immunohistochemical staining for final diagnosis. Epithelioid angiomyolipoma is a variant of angiomyolipoma but characterized by the absence of both adipocytes and abnormal blood vessels. We introduce a very rare case with the combination of these two tumours. A Japanese female patient without significant symptom was hospitalized and operated due to multiple uterine leiomyomas. During the operation, the surgeons found another tumour attaching to serosa of sigmoid colon. This tumour was resected and interpreted as solitary fibrous tumour, suspicious of malignancy. After 13 months of treatment, she was hospitalized again due to hematuria. The doctors detected a tumour in her right kidney. After consultation, laparoscopic right nephrectomy was done. The pathological result of this tumour was epithelioid angiomyolipoma. This is the first report on this very rare combination of tumours with extensive immunohistochemical demonstration of both tumours. Hereby, we review clinical information and histopathological findings together with discussion on each tumour. PMID- 24490096 TI - An atraumatic femoral fracture in a patient with rheumatoid arthritis and osteoporosis treated with denosumab. AB - Osteoporosis is responsible for a significant burden both individually and socially, but is readily treated with antiresorptive agents and mineral supplementation. However, long-term usage of these agents, notably bisphosphonates, is rarely associated with atypical fractures. Denosumab is a monoclonal antibody that reduces osteoclast activity and thus increases bone mineral density. In this case report, we present a 78-year-old woman with a background of rheumatoid arthritis and osteoporosis who presented with an atypical diaphyseal femoral fracture. PMID- 24490097 TI - Fatal paraneoplastic embolisms in both circulations in a patient with poorly differentiated neuroendocrine tumour. AB - Arterial embolism with lower limb ischemia is a rare manifestation of paraneoplastic hypercoagulability in cancer patients. We report a unique case of fatal thromboembolism involving both circulations associated with a poorly differentiated neuroendocrine tumor of the lung with rapid progress despite high doses of unfractioned heparin and review the current literature on anticoagulative regimen in tumour patients. PMID- 24490098 TI - Occult Bacteraemia and Aortic Graft Infection: A Wolf in Sheep's Clothing. AB - We report a case of late-onset aortic prosthetic vascular graft infection. We stress the importance of maintaining a high index of suspicion for any patient presenting with fever on the background of in situ prosthetic material. We present the difficulties in managing these extremely complicated, often life and limb threatening infections and suggest that a multidisciplinary team approach, involving specialist centre referral, may be key to success. We highlight the difficulties in diagnosing late-onset PVGI, where presentation can be subacute with subtle signs and confusing microbiology. In this case the presentation was pyrexia of unknown origin with multiple positive blood cultures isolating a variety of gut-associated organisms; a wolf in sheep's clothing. PMID- 24490099 TI - Heart failure 2013. PMID- 24490100 TI - Do gender and race/ethnicity influence acute myocardial infarction quality of care in a hospital with a large Hispanic patient and provider representation? AB - Background. Disparities in acute myocardial infarction (AMI) care for women and minorities have been extensively reported in United States but with limited information on Hispanics. Methods. Medical records of 287 (62%) Hispanic and 176 (38%) non-Hispanic white (NHW) patients and 245 women (53%) admitted with suspected AMI to a southern California nonprofit community hospital with a large Hispanic patient and provider representation were reviewed. Baseline characteristics, outcomes (mortality, CATH, PCI, CABG, and use of pertinent drug therapy), and medical insurance were analyzed according to gender, Hispanic and NHW race/ethnicity when AMI was confirmed. For categorical variables, 2 * 2 chi square analysis was conducted. Odds ratio and 95% confidence interval for outcomes adjusted for gender, race/ethnicity, cardiovascular risk factors, and insurance were obtained. Results. Women and Hispanics had similar drug therapy, CATH, PCI, and mortality as men and NHW when AMI was confirmed (n = 387). Hispanics had less private insurance than NHW (31.4% versus 56.3%, P < 0.001); no significant differences were found according to gender. Conclusions. No differences in quality measures and outcomes were found for women and between Hispanic and NHW in AMI patients admitted to a facility with a large Hispanic representation. Disparities in medical insurance showed no influence on these findings. PMID- 24490101 TI - Influence of a medium-impact exercise program on health-related quality of life and cardiorespiratory fitness in females with subclinical hypothyroidism: an open label pilot study. AB - Objective. To examine the influence of a medium-impact exercise program (MIEP) on health-related quality of life (HRQoL) and cardiorespiratory fitness (VO2max) in females with subclinical hypothyroidism (sHT). Materials and Methods. We selected 17 sedentary women with sHT (mean age: 43.1 (standard deviation: 9.7) years). Participants carried out an MIEP consisting of 3 weekly sessions of 60 minutes during 12 weeks. Before and after the exercise program HRQoL was assessed by the SF-12v2 questionnaire, and VO2max was evaluated by Rockport walk test. Results. After the 12-week intervention, the participants that performed an MIEP showed improvements in HRQoL in most domains, particularly the vitality domain by 7 points, the social functioning domain by 10 points, the mental health domain by 7 points, and the mental component summary by 7 points. One of the four domains within the physical component summary (general health domain) showed significant effect of the exercise intervention: 6 points. Moreover, the participants that performed exercise showed a higher VO2max (28%; P < 0.01). Conclusion. After 12 weeks of medium-impact exercise program, there were remarkable improvements in HRQoL in most domains. Moreover, this exercise program proved to have a positive influence on cardiorespiratory fitness. PMID- 24490102 TI - Awareness and Utilization of Affordable Medicine Facility-Malaria among Caregivers of Under-Five Children in Ibadan North-West Local Government Area, Oyo State. AB - Introduction. Distribution of Affordable Medicine Facility-malaria Artemisinin Combination Therapies (AMFm-ACTs) started in Nigeria in 2011, but its use at community level has not been documented. Methods. Four hundred seventy-eight caregivers whose under-five children had fever within two weeks prior to the survey were selected using cluster sampling technique. Information on sociodemographic characteristics, treatment seeking for malaria, and awareness and use of AMFm-ACTs was collected using an interviewer administered questionnaire. Result. More than half of the respondents (51.2%) bought AMFm-ACTs without prescription. Awareness of AMFm was low as only 9.1% has heard about the programme. Overall, 29.2% used AMFm-ACTs as their first line choice of antimalarial drug. On bivariate analysis age, group (25-34 years), public servants, respondents with tertiary education, respondents with high socioeconomic status, respondents with poor knowledge of symptoms of malaria, awareness of AMFm-ACTs, availability of AMFm-ACTs, and sources of drug were significantly associated with utilization of AMFm-ACTs (P < 0.05). Logistic regression demonstrated that only people who were aware of AMFM-ACTs predicted its use (AOR: 0.073; CI: 0.032-0.166; P < 0.001). Conclusion. Interventions which targeted at raising awareness of AMFm-ACTs among people at risk of malaria are advocated for implementation. PMID- 24490103 TI - Clinical Manifestations, Treatment, and Outcome of Hospitalized Patients with Plasmodium vivax Malaria in Two Indian States: A Retrospective Study. AB - This was a retrospective study done on 110 patients hospitalized with P. vivax malaria in three medical college hospitals, one in the union territory of Chandigarh and the other two in Gujarat, that is, Ahmedabad and Surat. The clinical presentation, treatment, and outcome were recorded. As per WHO criteria for severity, 19 of 110 patients had severe disease-six patients had clinical jaundice with hepatic dysfunction, three patients had severe anemia, three had spontaneous bleeding, two had acute respiratory distress syndrome, and one had cerebral malaria, hyperparasitemia, renal failure, circulatory collapse, and metabolic acidosis. All patients with severe P. vivax malaria survived, but one child with cerebral malaria had neurological sequelae. There was wide variation in the antimalarial treatment received at the three centres. Plasmodium vivax malaria can no longer be considered a benign condition. WHO guidelines for treatment of P. vivax malaria need to be reinforced. PMID- 24490105 TI - Evaluation of salt influence on sugar consumption by suspension cells based on spectroscopic analysis. AB - The influence of metal salt on sugar consumption by suspension cells in food models constructed by a sugar and salt aqueous solution was investigated based on mid-infrared spectroscopic analysis. The contaminated suspension cells in the food model could be detected using the spectral feature change that measured the present spectrum subtracted in the initial spectrum. The cells were prepared for growth and although the cell did not grow under the induction period, the cell activation (start of sugar metabolism) was detected on the subtracted spectral behavior before the cell growth. The rough grasp of the spectral change behavior is useful for the high-throughput spectroscopic method to detect the contaminated cell activation. Furthermore, the detailed sugar consumption kinetics of the cells was also investigated based on the spectroscopic method. The kind of added salt in the food model influenced the cell activation and the potassium ions play an important role in the plant cells. The living cells activity in fresh food may act to prevent microbial contamination and to suppress the growth of the contaminated microorganism. Both the simple and detailed analyses based on the spectroscopic method presented in this study might be useful for risk management of food. PMID- 24490104 TI - Nutrition, inflammation, and acute pancreatitis. AB - Acute pancreatitis is acute inflammatory disease of the pancreas. Nutrition has a number of anti-inflammatory effects that could affect outcomes of patients with pancreatitis. Further, it is the most promising nonspecific treatment modality in acute pancreatitis to date. This paper summarizes the best available evidence regarding the use of nutrition with a view of optimising clinical management of patients with acute pancreatitis. PMID- 24490106 TI - Several affinity tags commonly used in chromatographic purification. AB - Affinity tags have become powerful tools from basic biological research to structural and functional proteomics. They were widely used to facilitate the purification and detection of proteins of interest, as well as the separation of protein complexes. Here, we mainly discuss the benefits and drawbacks of several affinity or epitope tags frequently used, including hexahistidine tag, FLAG tag, Strep II tag, streptavidin-binding peptide (SBP) tag, calmodulin-binding peptide (CBP), glutathione S-transferase (GST), maltose-binding protein (MBP), S-tag, HA tag, and c-Myc tag. In some cases, a large-size affinity tag, such as GST or MBP, can significantly impact on the structure and biological activity of the fusion partner protein. So it is usually necessary to excise the tag by protease. The most commonly used endopeptidases are enterokinase, factor Xa, thrombin, tobacco etch virus, and human rhinovirus 3C protease. The proteolysis features of these proteases are described in order to provide a general guidance on the proteolytic removal of the affinity tags. PMID- 24490107 TI - Imaging of cardiac valves by computed tomography. AB - This paper describes "how to" examine cardiac valves with computed tomography, the normal, diseased valves, and prosthetic valves. A review of current scientific literature is provided. Firstly, technical basics, "how to" perform and optimize a multislice CT scan and "how to" interpret valves on CT images are outlined. Then, diagnostic imaging of the entire spectrum of specific valvular disease by CT, including prosthetic heart valves, is highlighted. The last part gives a guide "how to" use CT for planning of transcatheter aortic valve implantation (TAVI), an emerging effective treatment option for patients with severe aortic stenosis. A special focus is placed on clinical applications of cardiac CT in the context of valvular disease. PMID- 24490108 TI - Genetics of proteasome diseases. AB - The proteasome is a large, multiple subunit complex that is capable of degrading most intracellular proteins. Polymorphisms in proteasome subunits are associated with cardiovascular diseases, diabetes, neurological diseases, and cancer. One polymorphism in the proteasome gene PSMA6 (-8C/G) is associated with three different diseases: type 2 diabetes, myocardial infarction, and coronary artery disease. One type of proteasome, the immunoproteasome, which contains inducible catalytic subunits, is adapted to generate peptides for antigen presentation. It has recently been shown that mutations and polymorphisms in the immunoproteasome catalytic subunit PSMB8 are associated with several inflammatory and autoinflammatory diseases including Nakajo-Nishimura syndrome, CANDLE syndrome, and intestinal M. tuberculosis infection. This comprehensive review describes the disease-related polymorphisms in proteasome genes associated with human diseases and the physiological modulation of proteasome function by these polymorphisms. Given the large number of subunits and the central importance of the proteasome in human physiology as well as the fast pace of detection of proteasome polymorphisms associated with human diseases, it is likely that other polymorphisms in proteasome genes associated with diseases will be detected in the near future. While disease-associated polymorphisms are now readily discovered, the challenge will be to use this genetic information for clinical benefit. PMID- 24490111 TI - Maternal Dietary Patterns during Third Trimester in Association with Birthweight Characteristics and Early Infant Growth. AB - Our analysis examined the impact of maternal dietary patterns and lifestyle factors on markers of fetal growth, specifically birthweight and size for gestational age (small- (SGA) or large-for-gestational age (LGA)). The Infant Feeding Practices Study II, a prospective cohort study, surveyed pregnant women during their 3rd trimester, of which a subgroup (n = 893) completed a food frequency questionnaire. Maternal dietary patterns were evaluated by diet scores (Alternative Healthy Eating Index for Pregnancy and alternate Mediterranean diet) and by carbohydrate quality (glycemic index and glycemic load). Poisson regression with robust standard errors was used to examine the relative risk of SGA and separately LGA, with dietary patterns and other lifestyle factors. Linear regression was used to determine the association of birthweight and early infant growth with better dietary patterns. Relative risk of SGA and LGA was not associated with dietary patterns. Birthweight and infant growth were not associated with maternal diet. Smoking, however, increased the risk of delivering an SGA infant (RR = 2.92, 95% CI: 1.58-5.39), while higher prepregnancy BMI increased the risk of delivering an LGA infant (RR = 1.06, 95% CI: 1.03-1.09). Future studies are needed to evaluate whether deficiencies in more specific maternal dietary nutrients play a role in fetal growth. PMID- 24490112 TI - Impact of maternal prenatal stress on growth of the offspring. AB - Unperturbed fetal development is essential for future health of an individual. Previous studies have linked diseases of aging to harmful alterations that happen during fetal development. Given the significant long-term impact that intrauterine environment has on an individual's life, it was hypothesized that maternal stress during pregnancy will have negative effects on the offspring's prenatal and postnatal growth. To test this, twenty-eight female and seven male Wistar rats (Rattus norvegicus) were purchased and bred to produce 176 offspring. During pregnancy, dams were randomly divided into four groups (n=7, per group) and immobilization stress induced as follows; Group 1 (GW1): immobilization stress on days 1-7 of pregnancy, Group 2 (GW2): on days 8-14, Group 3 (GW3): on days 15-21, Group 4 (Controls): left undisturbed. Maternal cortisol hormone, food intake, and weight gain were monitored during pregnancy. Pups were raised under normal laboratory conditions and sacrificed at ages: 4, 8, 12, and 16 weeks to determine the effect of prenatal stress. At necropsy, the tibia was removed and processed for histology. Differences among groups were determined by T-test or analysis of variance (ANOVA). Linear regression analysis was performed to establish the relationship between stress in utero and indicators of bone development in offspring. P values <= 0.05 were considered significant. Cortisol hormone levels in controls were lower than those of stressed animals. Stressed dams consumed 12.5% less food per day compared to controls. Animals in GW1 and GW2 gained less weight during pregnancy but had larger litters than did GW3 or the control group. Offspring born to GW3 were heavier compared to all other groups. GW3 offspring had a higher rate of bone formation. In conclusion, stress during pregnancy resulted in increased cortisol and reduced food intake in mothers, but faster growth and higher weight gain in offspring compared to controls. PMID- 24490113 TI - Up-regulating telomerase and tumor suppressors: focusing on anti-aging interventions at the population level. AB - Most human populations are undergoing a demographic transition regarding their age structure. This transition is reflected in chronic non-communicable diseases featuring among the main contributors to burden of disease. Considering that the aging process is a major risk factor for such conditions, understanding the mechanisms underlying aging and age-related diseases is critical to develop strategies to impact human health at population and/or individual-levels. Two different aspects of aging process (namely, telomere shortening and DNA damage accumulation) were shown to interact in positively impacting mice median survival. However, strategies aimed at translating such knowledge into actual human health benefits have not yet been discussed. In this manuscript, we present potential exposures that are suited for population-level interventions, and contextualize the roles of population (based on behavioral exposures) and individual-level (based on small-molecule administration) anti-aging interventions in different levels of disease prevention. We suggest that exposures such as moderate wine consumption, reducing calorie intake and active lifestyle are potentially useful for primordial and primary prevention, while small-molecules that activate telomerase and/or tumor suppression responses are more suited for secondary and tertiary prevention (although important for primary prevention in specific population subgroups). We also indicate the need of studying the impacts, on aging and age-related diseases, of different combinations of these exposures in well-conducted randomized controlled trials, and propose Mendelian randomization as a valuable alternative to gather information in human populations regarding the effects of potential anti-aging interventions. PMID- 24490110 TI - Mammalian tribbles homologs at the crossroads of endoplasmic reticulum stress and Mammalian target of rapamycin pathways. AB - In 2000, investigators discovered Tribbles, a Drosophila protein that coordinates morphogenesis by inhibiting mitosis. Further work has delineated Xenopus (Xtrb2), Nematode (Nipi-3), and mammalian homologs of Drosophila tribbles, which include TRB1, TRB2, and TRB3. The sequences of tribbles homologs are highly conserved, and despite their protein kinase structure, to date they have not been shown to have kinase activity. TRB family members play a role in the differentiation of macrophages, lymphocytes, muscle cells, adipocytes, and osteoblasts. TRB isoforms also coordinate a number of critical cellular processes including glucose and lipid metabolism, inflammation, cellular stress, survival, apoptosis, and tumorigenesis. TRB family members modulate multiple complex signaling networks including mitogen activated protein kinase cascades, protein kinase B/AKT signaling, mammalian target of rapamycin, and inflammatory pathways. The following review will discuss metazoan homologs of Drosophila tribbles, their structure, expression patterns, and functions. In particular, we will focus on TRB3 function in the kidney in podocytes. This review will also discuss the key signaling pathways with which tribbles proteins interact and provide a rationale for developing novel therapeutics that exploit these interactions to provide better treatment options for both acute and chronic kidney disease. PMID- 24490114 TI - Emerging candidate biomarkers for Parkinson's disease: a review. AB - Parkinson's disease is a chronic neurodegenerative disorder leading to progressive motor impairment affecting more than 1% of the over-65 population. In spite of considerable progress in identifying the genetic and biochemical basis of PD, to date the diagnosis remains clinical and disease-modifying therapies continue to be elusive. A cornerstone in recent PD research is the investigation of biological markers that could help in identifying at-risk population or to track disease progression and response to therapies. Although none of these parameters has been validated for routine clinical practice yet, however some biochemical candidates hold great promise for application in PD patients, especially in the early stages of disease, and it is likely that in the future the diagnosis of PD will require a combination of genetic, imaging and laboratory data. In this review we discuss the most interesting biochemical markers for PD (including the "-omics" techniques), focusing on the methodological challenges in using ex vivo blood/CSF/tissue-based biomarkers and suggesting alternative strategies to overcome the difficulties that still prevent their actual use. PMID- 24490109 TI - Hox targets and cellular functions. AB - Hox genes are a group of genes that specify structures along the anteroposterior axis in bilaterians. Although in many cases they do so by modifying a homologous structure with a different (or no) Hox input, there are also examples of Hox genes constructing new organs with no homology in other regions of the body. Hox genes determine structures though the regulation of targets implementing cellular functions and by coordinating cell behavior. The genetic organization to construct or modify a certain organ involves both a genetic cascade through intermediate transcription factors and a direct regulation of targets carrying out cellular functions. In this review I discuss new data from genome-wide techniques, as well as previous genetic and developmental information, to describe some examples of Hox regulation of different cell functions. I also discuss the organization of genetic cascades leading to the development of new organs, mainly using Drosophila melanogaster as the model to analyze Hox function. PMID- 24490115 TI - Is Emotional Working Memory Training a New Avenue of AD Treatment? A review. AB - Emotional working memory training is a new area of research. In this study, we review a series of recent works describing a range of emotional working memory interventions that go from training single affective working memory function to teaching emotion regulation strategies. Generally speaking, research to date has established that emotional working memory may be preserved in Alzheimer's disease. However, much work remains to be done in clarifying what aspects of affective domain is preserved, and testing short- and long-term effects of the trainings as well as their generalization to everyday affective functioning. We conclude by offering suggestions about the development of emotional working memory training for Alzheimer's patients. PMID- 24490116 TI - Quality and innovations for caring hospitalized older persons in the unites States. AB - Older persons are occasionally acutely ill and their hospitalizations frequently end up with complications and adverse outcomes. Medicare from U.S. federal government's payment resource for older persons is facing financial strain. Medicare highlights both cost-saving and high quality of care while older persons are hospitalized. Several health policy changes were initiated to achieve Medicare's goals. In response to Medicare's health policy changes, U.S. hospital environments have been changed and these resulted in hospital quality measurements' improvement. American seniors are facing the challenges during and around their hospital care. Several innovative measures are suggested to overcome these challenges. PMID- 24490117 TI - New nucleophilic mechanisms of ros-dependent epigenetic modifications: comparison of aging and cancer. AB - It has been shown that ROS (reactive oxygen species, superoxide and hydrogen peroxide) regulate major epigenetic processes, DNA methylation and histone acetylation, although the mechanism of ROS action (ROS signaling) is still unknown. Both DNA methylation and histone acetylation are nucleophilic processes and therefore ROS signaling through typical free radical processes, for example hydrogen atom abstraction is impossible. However, being "super-nucleophile" superoxide can participate in these reactions. Now we propose new nucleophilic mechanisms of DNA methylation and histone modification. During DNA methylation superoxide can deprotonate the cytosine molecule at C-5 position and by this accelerate the reaction of DNA with the positive-charged intermediate S-adenosyl L-methionine (SAM). Superoxide can also deprotonate histone N-terminal tail lysines and accelerate the formation of their complexes with acetyl-coenzyme A (AcCoA), the supplier of acetyl groups. In cancer cells ROS enhance DNA methylation causing the silencing of tumor suppressor and antioxidant genes and enhancing the proliferation of cancer cells under condition of oxidative stress. ROS signaling in senescent cells probably causes DNA hypomethylation although there are insufficient data for such proposal. PMID- 24490119 TI - Cyanobacterial aldehyde deformylase oxygenation of aldehydes yields n-1 aldehydes and alcohols in addition to alkanes. AB - Aldehyde-deformylating oxygenase (ADO) catalyzes O2-dependent release of the terminal carbon of a biological substrate, octadecanal, to yield formate and heptadecane in a reaction that requires external reducing equivalents. We show here that ADO also catalyzes incorporation of an oxygen atom from O2 into the alkane product to yield alcohol and aldehyde products. Oxygenation of the alkane product is much more pronounced with C9-10 aldehyde substrates, so that use of nonanal as the substrate yields similar amounts of octane, octanal, and octanol products. When using doubly-labeled [1,2-13C]-octanal as the substrate, the heptane, heptanal and heptanol products each contained a single 13C-label in the C-1 carbons atoms. The only one-carbon product identified was formate. [18O]-O2 incorporation studies demonstrated formation of [18O]-alcohol product, but rapid solvent exchange prevented similar determination for the aldehyde product. Addition of [1-13C]-nonanol with decanal as the substrate at the outset of the reaction resulted in formation of [1-13C]-nonanal. No 13C-product was formed in the absence of decanal. ADO contains an oxygen-bridged dinuclear iron cluster. The observation of alcohol and aldehyde products derived from the initially formed alkane product suggests a reactive species similar to that formed by methane monooxygenase (MMO) and other members of the bacterial multicomponent monooxygenase family. Accordingly, characterization by EPR and Mossbauer spectroscopies shows that the electronic structure of the ADO cluster is similar, but not identical, to that of MMO hydroxylase component. In particular, the two irons of ADO reside in nearly identical environments in both the oxidized and fully reduced states, whereas those of MMOH show distinct differences. These favorable characteristics of the iron sites allow a comprehensive determination of the spin Hamiltonian parameters describing the electronic state of the diferrous cluster for the first time for any biological system. The nature of the diiron cluster and the newly recognized products from ADO catalysis hold implications for the mechanism of C-C bond cleavage. PMID- 24490118 TI - Evidence for gender differences in cognition, emotion and quality of life in Parkinson's disease? AB - A number of gender differences have been documented in the incidence and symptomatology of the second most common age-related neurodegenerative disorder, idiopathic Parkinson's disease (PD). Overall, previous reports suggest a less frequent incidence and a more benign phenotype in women mainly in Western populations, which is thought to be mediated by estrogens in particular in early stages of the disease. Not only motor symptoms seem to underlie gender effects, but also non-motor symptoms such as psychiatric and cognitive impairments, which can often precede motor manifestation. However, reliable results for gender differences in PD in particular of cognitive function and emotion processing, having a major impact on quality of life, are lacking. Moreover, studies investigating gender effects in PD in these areas have revealed highly heterogeneous results. The present review summarizes findings of currently available studies on gender effects on neuropsychological tests covering major cognitive domains, emotion processing as well as quality of life in patients with PD. Overall, the occurrence of cognitive impairment in PD seems to be associated with male gender, though inconsistent results were shown in cognitive screening tests. Regarding emotion recognition, men with PD were found to be less accurate than women with PD at identifying fearful expressions, whereas vice versa results appeared in healthy subjects. Lower quality of life and greater disability were reported by women compared to men with PD, which corresponds with the results in healthy subjects. Several disease-specific mediators as well as the question of a general gender and age-related effect as observed in healthy individuals are discussed. Increased knowledge on possible gender effects in PD would provide an enhanced insight in underlying pathological mechanisms, and has potential implications for the diagnosis and treatment of PD. PMID- 24490120 TI - Scientific Rigor Recommendations for Optimizing the Clinical Applicability of Translational Research. AB - The approval of new therapies to treat neurodegenerative disease conditions by the Food and Drug administration (FDA) has been hindered by many failed clinical trials, which were based upon "significant" efficacy in preclinical or translational studies. Additional problems during drug development related to significant adverse events and unforeseen toxicity have also hampered drug development. Recent reviews of preclinical data suggests that many studies have over-estimated efficacy due to poor or inadequate study design, exclusion of important data (negative or neutral) and lack of study randomization and blinding. This article describes in detail a set of recommendations to improve the quality of science being conducted in laboratories worldwide, with the goal of documenting in the peer-reviewed literature, including Journal of Neurology and Neurophysiology, the scientific basis for the continued development of specific strategies to treat neurodegenerative diseases such as Stroke, Alzheimer's disease, Huntington's disease, Parkinson's disease, Spinal cord injury, and Amyotrophic lateral sclerosis. The minimum recommendations for effective translational research include the need for model justification, study group randomization and blinding, power analysis calculations, appropriate statistical analysis of all data sets, and a conflict of interest statement by investigators. It will also be beneficial to demonstrate reproducible efficacy in multiple species and in studies done by independent laboratories. PMID- 24490121 TI - Linear birefringence magnitude of artificial self-assembled DNA crystals. AB - We determine the linear birefringence magnitude, i.e. the difference between refractive indexes along the extraordinary and ordinary axes, of artificial uniaxial DNA crystals assembled with the so-called DNA tile approach. Based on the ellipsometric measurements, the birefringence magnitude is between 0.001 and 0.0018 in the visible and near infrared range. Besides being of fundamental interest, the optical properties of DNA crystals are crucial in the design of novel photonic nanostuctures. PMID- 24490122 TI - Frequency and Quality of Social Networking Among Young Adults: Associations With Depressive Symptoms, Rumination, and Corumination. AB - Two studies examined associations between social networking and depressive symptoms among youth. In Study 1, 384 participants (68% female; mean age = 20.22 years, SD = 2.90) were surveyed. In Study 2, 334 participants (62% female; M age = 19.44 years, SD = 2.05) were surveyed initially and 3 weeks later. Results indicated that depressive symptoms were associated with quality of social networking interactions, not quantity. There was some evidence that depressive rumination moderated associations, and both depressive rumination and corumination were associated with aspects of social networking usage and quality. Implications for understanding circumstances that increase social networking, as well as resulting negative interactions and negative affect are discussed. PMID- 24490123 TI - Faithful Experimental Models of Human Mycobacterium Tuberculosis Infection. PMID- 24490124 TI - Supramolecular Polymers Formed by ABC Miktoarm Star Peptides. AB - We report here the design and synthesis of an ABC miktoarm star peptide connecting through a lysine junction a short peptide sequence and two hydrophobic but immiscible blocks (a hydrocarbon and a fluorocarbon). The designed molecule can self-assemble into one-dimensional nanostructures with a great diversity of kinetically evolving morphologies in aqueous solution, while molecules that contain only one of the two hydrophobic blocks form structurally similar filaments. We believe the rich assembly behavior and morphological evolution are a direct reflection of the molecular frustration present within the filament core as a result of the in-compatibility of the fluorocarbon and hydrocarbon segments. Our finding opens new opportunities for creating complex supramolecular polymers through the architecture design of small molecular building units. PMID- 24490125 TI - Oxysterols recruit tumor-supporting neutrophils within the tumor microenvironment: The many facets of tumor-derived oxysterols. AB - By binding to the liver X receptor (LXR), oxysterols inhibit the expression of chemokine (C-C motif) receptor 7 (CCR7), hence impairing the migration of dendritic cells to secondary lymphoid organs and inhibiting antitumor immune responses. We have recently identified a new tumor-supporting activity of oxysterols, which recruit neutrophils within tumor microenvironment by a chemokine (C-X-C motif) receptor 2 (CXCR2)-dependent, LXR-independent mechanism. PMID- 24490126 TI - Overcoming intrinsic inhibitory pathways to augment the antineoplastic activity of adoptively transferred T cells: Re-tuning your CAR before hitting a rocky road. AB - Effector T cells become rapidly inactivated after antigen exposure due to extracellular as well as intrinsic signals. We have recently demonstrated that the deletion of diacylglycerol kinases, intrinsic inhibitors of T-cell signaling, enhances the activity of adoptively transferred T cells expressing a chimeric antigen receptor (CAR) specific for a tumor-associated antigen. PMID- 24490127 TI - Local immunomodulation for cancer therapy: Providing treatment where needed. AB - In murine models of cancer, we have achieved efficient systemic activation of tumor-specific T cells by the local administration of a CTLA4-blocking antibody at low doses. Using a slow-release formulation, we could drastically lower the serum levels of the antibody, hence decreasing adverse effects and the risk of autoimmune reactions, without losing systemic efficacy. PMID- 24490128 TI - Human Plasma-Derived, Nanofiltered, C1-Inhibitor Concentrate (Cinryze(r)), a Novel Therapeutic Alternative for the Management of Hereditary Angioedema Resulting from C1-Inhibitor Deficiency. AB - Hereditary angioedema resulting from the deficiency of the C1 inhibitor (HAE-C1 INH) is a rare, but potentially life-threatening disorder characterized by paroxysmal episodes of subcutaneous or submucosal edema. Early diagnosis is essential. Management is aimed at the prompt elimination of full-fledged attacks, as well as at the prevention of edematous episodes. The most straightforward means for therapy is supplementation with the deficient C1-INH protein. Placebo controlled and open clinical studies have established that nanofiltered, human C1 INH concentrate, Cinryze(r) (ViroPharma Inc., Exton, PA, USA) (C1-INHCi), administered in 1,000 U doses is an effective and safe remedy for edematous episodes of HAE-C1-INH, regardless of the localization of the attack. Clinical manifestations rapidly improve and then resolve completely following treatment with this medicinal product. Additionally, C1-INHCi is also appropriate for pre procedural or for routine prophylaxis. The administration of 1,000 U C1-INHCi before the (dental, surgical, or interventional diagnostic) procedure reduced the incidence of edematous episodes compared with placebo, and this reduction proved significant during routine prophylaxis with the administration of this dose every 3-4 days. Relapses did not occur, and repeated dosing had no influence on the efficacy of the preparation. Patients also tolerated treatment with C1-INHCi well. The safety of this preparation was confirmed by the absence of viral transmission as well as by the lack of antibody formation against C1-INH during treatment. Nowadays, C1-INHCi for intravenous use is the only medicinal product indicated both for the prevention and management of edematous attacks. PMID- 24490129 TI - Review: Modulation of striatal neuron activity by cyclic nucleotide signaling and phosphodiesterase inhibition. AB - The cyclic nucleotides cAMP and cGMP are common signaling molecules synthesized in neurons following the activation of adenylyl or guanylyl cyclase. In the striatum, the synthesis and degradation of cAMP and cGMP is highly regulated as these second messengers have potent effects on the activity of striatonigral and striatopallidal neurons. This review will summarize the literature on cyclic nucleotide signaling in the striatum with a particular focus on the impact of cAMP and cGMP on the membrane excitability of striatal medium-sized spiny output neurons (MSNs). The effects of non-selective and selective phosphodiesterase (PDE) inhibitors on membrane activity and synaptic plasticity of MSNs will also be reviewed. Lastly, this review will discuss the implications of the effects PDE modulation on electrophysiological activity of striatal MSNs as it relates to the treatment of neurological disorders such as Huntington's and Parkinson's disease. PMID- 24490130 TI - NFkappaB mediates cisplatin resistance through histone modifications in head and neck squamous cell carcinoma (HNSCC). AB - Cisplatin-based chemotherapy is the standard treatment of choice for head and neck squamous cell carcinoma (HNSCC). The efficiency of platinum-based therapies is directly influenced by the development of tumor resistance. Multiple signaling pathways have been linked to tumor resistance, including activation of nuclear factor kappa B (NFkappaB). We explore a novel mechanism by which NFkappaB drives HNSCC resistance through histone modifications. Post-translational modification of histones alters chromatin structure, facilitating the binding of nuclear factors that mediate DNA repair, transcription, and other processes. We found that chemoresistant HNSCC cells with active NFkappaB signaling respond to chemotherapy by reducing nuclear BRCA1 levels and by promoting histone deacetylation (chromatin compaction). Activation of this molecular signature resulted in impaired DNA damage repair, prolonged accumulation of histone gammaH2AX and increased genomic instability. We found that pharmacological induction of histone acetylation using HDAC inhibitors prevented NFkappaB-induced cisplatin resistance. Furthermore, silencing NFkappaB in HNSCC induced acetylation of tumor histones, resulting in reduced chemoresistance and increased cytotoxicity following cisplatin treatment. Collectively, these findings suggest that epigenetic modifications of HNSCC resulting from NFkappaB-induced histone modifications constitute a novel molecular mechanism responsible for chemoresistance in HNSCC. Therefore, targeted inhibition of HDAC may be used as a viable therapeutic strategy for disrupting tumor resistance caused by NFkappaB. PMID- 24490131 TI - Functional characterization of WalRK: A two-component signal transduction system from Bacillus anthracis. AB - Two-component signal transduction systems (TCS), consisting of a sensor histidine protein kinase and its cognate response regulator, are an important mode of environmental sensing in bacteria. Additionally, they have been found to regulate virulence determinants in several pathogens. Bacillus anthracis, the causative agent of anthrax and a bioterrorism agent, harbours 41 pairs of TCS. However, their role in its pathogenicity has remained largely unexplored. Here, we show that WalRK of B. anthracis forms a functional TCS which exhibits some species specific functions. Biochemical studies showed that domain variants of WalK, the histidine kinase, exhibit classical properties of autophosphorylation and phosphotransfer to its cognate response regulator WalR. Interestingly, these domain variants also show phosphatase activity towards phosphorylated WalR, thereby making WalK a bifunctional histidine kinase/phosphatase. An in silico regulon determination approach, using a consensus binding sequence from Bacillus subtilis, provided a list of 30 genes that could form a putative WalR regulon in B. anthracis. Further, electrophoretic mobility shift assay was used to show direct binding of purified WalR to the upstream regions of three putative regulon candidates, an S-layer protein EA1, a cell division ABC transporter FtsE and a sporulation histidine kinase KinB3. Our work lends insight into the species specific functions and mode of action of B. anthracis WalRK. PMID- 24490133 TI - Control of reactive oxygen species (ROS) production through histidine kinases in Aspergillus nidulans under different growth conditions. AB - Sensor histidine kinases (HKs) are important factors that control cellular growth in response to environmental conditions. The expression of 15 HKs from Aspergillus nidulans was analyzed by quantitative real-time PCR under vegetative, asexual, and sexual growth conditions. Most HKs were highly expressed during asexual growth. All HK gene-disrupted strains produced reactive oxygen species (ROS). Three HKs are involved in the control of ROS: HysA was the most abundant under the restricted oxygen condition, NikA is involved in fungicide sensing, and FphA inhibits sexual development in response to red light. Phosphotransfer signal transduction via HysA is essential for ROS production control. PMID- 24490132 TI - Ebselen induces reactive oxygen species (ROS)-mediated cytotoxicity in Saccharomyces cerevisiae with inhibition of glutamate dehydrogenase being a target. AB - Ebselen is a synthetic, lipid-soluble seleno-organic compound. The high electrophilicity of ebselen enables it to react with multiple cysteine residues of various proteins. Despite extensive research on ebselen, its target molecules and mechanism of action remains less understood. We performed biochemical as well as in vivo experiments employing budding yeast as a model organism to understand the mode of action of ebselen. The growth curve analysis and FACS (florescence activated cell sorting) assays revealed that ebselen exerts growth inhibitory effects on yeast cells by causing a delay in cell cycle progression. We observed that ebselen exposure causes an increase in intracellular ROS levels and mitochondrial membrane potential, and that these effects were reversed by addition of antioxidants such as reduced glutathione (GSH) or N-acetyl-l-cysteine (NAC). Interestingly, a significant increase in ROS levels was noticed in gdh3 deleted cells compared to wild-type cells. Furthermore, we showed that ebselen inhibits GDH function by interacting with its cysteine residues, leading to the formation of inactive hexameric GDH. Two-dimensional gel electrophoresis revealed protein targets of ebselen including CPR1, the yeast homolog of Cyclophilin A. Additionally, ebselen treatment leads to the inhibition of yeast sporulation. These results indicate a novel direct connection between ebselen and redox homeostasis. PMID- 24490134 TI - Understanding the mechanism of glucose-induced relief of Rgt1-mediated repression in yeast. AB - The yeast Rgt1 repressor inhibits transcription of the glucose transporter (HXT) genes in the absence of glucose. It does so by recruiting the general corepressor complex Ssn6-Tup1 and the HXT corepressor Mth1. In the presence of glucose, Rgt1 is phosphorylated by the cAMP-activated protein kinase A (PKA) and dissociates from the HXT promoters, resulting in expression of HXT genes. In this study, using Rgt1 chimeras that bind DNA constitutively, we investigate how glucose regulates Rgt1 function. Our results show that the DNA-bound Rgt1 constructs repress expression of the HXT1 gene in conjunction with Ssn6-Tup1 and Mth1, and that this repression is lifted when they dissociate from Ssn6-Tup1 in high glucose conditions. Mth1 mediates the interaction between the Rgt1 constructs and Ssn6-Tup1, and glucose-induced downregulation of Mth1 enables PKA to phosphorylate the Rgt1 constructs. This phosphorylation induces dissociation of Ssn6-Tup1 from the DNA-bound Rgt1 constructs, resulting in derepression of HXT gene expression. Therefore, Rgt1 removal from DNA occurs in response to glucose but is not necessary for glucose induction of HXT gene expression, suggesting that glucose regulates Rgt1 function by primarily modulating the Rgt1 interaction with Ssn6-Tup1. PMID- 24490135 TI - The role of Importin-betas in the maintenance and lineage commitment of mouse embryonic stem cells. AB - Members of the Importin-beta family recognize nuclear localization signals (NLS) and nuclear export signals (NES). These proteins play important roles in various nucleocytoplasmic transport processes in cells. Here, we examined the expression patterns of 21 identified Importin-beta genes in mouse embryonic stem cells (mESCs), mouse embryonic fibroblast (MEF) and mESCs differentiated into neural ectoderm (NE) or mesoendoderm (ME). We observed striking differences in the Importin-beta mRNA expression levels within these cell types. We also found that knockdown of selected Importin-beta genes led to suppression of Nanog, and altered the balance of Oct4/Sox2 expression ratio, which is important for NE/ME lineage choice. Furthermore, we demonstrated that knockdown of XPO4, RanBP17, RanBP16, or IPO7 differentially affected the lineage selection of differentiating mESCs. More specifically, knockdown of XPO4 selectively stimulated the mESC differentiation towards definitive endoderm, while concomitantly inhibiting NE differentiation. RanBP17 knockdown also promoted endodermal differentiation with no effect on NE differentiation. RanBP16 knockdown caused differentiation into ME, while IPO7 knockdown inhibited NE differentiation, without obvious effects on the other lineages. Collectively, our results suggest that Importin-betas play important roles in cell fate determination processes of mESCs, such as in the maintenance of pluripotency or selection of lineage during differentiation. PMID- 24490136 TI - Ancestral mutations as a tool for solubilizing proteins: The case of a hydrophobic phosphate-binding protein. AB - Stable and soluble proteins are ideal candidates for functional and structural studies. Unfortunately, some proteins or enzymes can be difficult to isolate, being sometimes poorly expressed in heterologous systems, insoluble and/or unstable. Numerous methods have been developed to address these issues, from the screening of various expression systems to the modification of the target protein itself. Here we use a hydrophobic, aggregation-prone, phosphate-binding protein (HPBP) as a case study. We describe a simple and fast method that selectively uses ancestral mutations to generate a soluble, stable and functional variant of the target protein, here named sHPBP. This variant is highly expressed in Escherichia coli, is easily purified and its structure was solved at much higher resolution than its wild-type progenitor (1.3 versus 1.9 A, respectively). PMID- 24490138 TI - DHEA supplementation in ovariectomized rats reduces impaired glucose-stimulated insulin secretion induced by a high-fat diet. AB - Dehydroepiandrosterone (DHEA) and the dehydroepiandrosterone sulfate (DHEA-S) are steroids produced mainly by the adrenal cortex. There is evidence from both human and animal models suggesting beneficial effects of these steroids for obesity, diabetes mellitus, hypertension, and osteoporosis, conditions associated with the post-menopausal period. Accordingly, we hypothesized that DHEA supplementation in ovariectomized (OVX) female rats fed a high-fat diet would maintain glucose induced insulin secretion (GSIS) and pancreatic islet function. OVX resulted in a 30% enlargement of the pancreatic islets area compared to the control rats, which was accompanied by a 50% reduction in the phosphorylation of AKT protein in the pancreatic islets. However, a short-term high-fat diet induced insulin resistance, accompanied by impaired GSIS in isolated pancreatic islets. These effects were reversed by DHEA treatment, with improved insulin sensitivity to levels similar to the control group, and with increased serine phosphorylation of the AKT protein. These data confirm the protective effect of DHEA on the endocrine pancreas in a situation of diet-induced overweight and low estrogen concentrations, a phenotype similar to that of the post-menopausal period. PMID- 24490137 TI - Integrated mRNA and microRNA transcriptome sequencing characterizes sequence variants and mRNA-microRNA regulatory network in nasopharyngeal carcinoma model systems. AB - Nasopharyngeal carcinoma (NPC) is a prevalent malignancy in Southeast Asia among the Chinese population. Aberrant regulation of transcripts has been implicated in many types of cancers including NPC. Herein, we characterized mRNA and miRNA transcriptomes by RNA sequencing (RNASeq) of NPC model systems. Matched total mRNA and small RNA of undifferentiated Epstein-Barr virus (EBV)-positive NPC xenograft X666 and its derived cell line C666, well-differentiated NPC cell line HK1, and the immortalized nasopharyngeal epithelial cell line NP460 were sequenced by Solexa technology. We found 2812 genes and 149 miRNAs (human and EBV) to be differentially expressed in NP460, HK1, C666 and X666 with RNASeq; 533 miRNA-mRNA target pairs were inversely regulated in the three NPC cell lines compared to NP460. Integrated mRNA/miRNA expression profiling and pathway analysis show extracellular matrix organization, Beta-1 integrin cell surface interactions, and the PI3K/AKT, EGFR, ErbB, and Wnt pathways were potentially deregulated in NPC. Real-time quantitative PCR was performed on selected mRNA/miRNAs in order to validate their expression. Transcript sequence variants such as short insertions and deletions (INDEL), single nucleotide variant (SNV), and isomiRs were characterized in the NPC model systems. A novel TP53 transcript variant was identified in NP460, HK1, and C666. Detection of three previously reported novel EBV-encoded BART miRNAs and their isomiRs were also observed. Meta analysis of a model system to a clinical system aids the choice of different cell lines in NPC studies. This comprehensive characterization of mRNA and miRNA transcriptomes in NPC cell lines and the xenograft provides insights on miRNA regulation of mRNA and valuable resources on transcript variation and regulation in NPC, which are potentially useful for mechanistic and preclinical studies. PMID- 24490139 TI - The VTLISFG motif in the BH1 domain plays a significant role in regulating the degradation of Mcl-1. AB - Mcl-1 is a member of the Bcl-2 family protein; its degradation is required for the initiation of apoptosis. The mechanism, however, is not yet clearly known. Previously, it was reported that Mcl-1 is degraded through the ubiquitination mediated pathway and the PEST domain is the motif responsible for promoting this degradation. We found evidence that this may not be true. We generated several Mcl-1 deletion mutants and examined their effects on protein stability. Deletion of the PEST domain did not prevent the degradation of Mcl-1 during apoptosis. The BH1 domain, but not the PEST, BH3 or BH2 domain, exhibited a short half-life. A peptide named "F3" (VTLISFG) in the C-terminus of the BH1 domain appears to be critical for the rapid turnover of Mcl-1. Deletion of F3 from GFP-Mcl-1-DeltaPEST retarded the degradation of this mutant. F3 appeared to be the minimum functional sequence of the degradation motif, since deletion of a single residue was sufficient to abrogate its short half-life. Fusion of F3 with p32 resulted in the degradation of p32 during UV-induced apoptosis, while wild type p32 was not affected. Taken together, these findings suggest that F3 (VTLISFG), instead of PEST, is the major motif responsible for the degradation of Mcl-1 during apoptosis. PMID- 24490140 TI - A novel cell-penetrating peptide derived from WT1 enhances p53 activity, induces cell senescence and displays antimelanoma activity in xeno- and syngeneic systems. AB - The Wilms tumor protein 1 (WT1) transcription factor has been associated in malignant melanoma with cell survival and metastasis, thus emerging as a candidate for targeted therapy. A lysine-arginine rich peptide, WT1-pTj, derived from the ZF domain of WT1 was evaluated as an antitumor agent against A2058 human melanoma cells and B16F10-Nex2 syngeneic murine melanoma. Peptide WT1-pTj quickly penetrated human melanoma cells and induced senescence, recognized by increased SA-beta-galactosidase activity, enhanced transcriptional activity of p53, and induction of the cell cycle inhibitors p21 and p27. Moreover, the peptide bound to p53 and competed with WT1 protein for binding to p53. WT1-pTj treatment led to sustained cell growth suppression, abrogation of clonogenicity and G2/M cell cycle arrest. Notably, in vivo studies showed that WT1-pTj inhibited both the metastases and subcutaneous growth of murine melanoma in syngeneic mice, and prolonged the survival of nude mice challenged with human melanoma cells. The 27 amino acid cell-penetrating WT1-derived peptide, depends on C(3) and H(16) for effective antimelanoma activity, inhibits proliferation of WT1-expressing human tumor cell lines, and may have an effective role in the treatment of WT1 expressing malignancies. PMID- 24490141 TI - Graphene-based contrast agents for photoacoustic and thermoacoustic tomography. AB - In this work, graphene nanoribbons and nanoplatelets were investigated as contrast agents for photoacoustic and thermoacoustic tomography (PAT and TAT). We show that oxidized single-and multi-walled graphene oxide nanoribbons (O-SWGNRs, O-MWGNRs) exhibit approximately 5-10 fold signal enhancement for PAT in comparison to blood at the wavelength of 755 nm, and approximately 10-28% signal enhancement for TAT in comparison to deionized (DI) water at 3 GHz. Oxidized graphite microparticles (O-GMPs) and exfoliated graphene oxide nanoplatelets (O GNPs) show no significant signal enhancement for PAT, and approximately 12-29% signal enhancement for TAT. These results indicate that O-GNRs show promise as multi-modal PAT and TAT contrast agents, and that O-GNPs are suitable contrast agents for TAT. PMID- 24490142 TI - Probing the GnRH receptor agonist binding site identifies methylated triptorelin as a new anti-proliferative agent. AB - D-amino acid substitutions at glycine postion 6 in GnRH-I decapeptide can possess super-agonist activity and enhanced in vivo pharmacokinetics. Agonists elicit growth-inhibition in tumorigenic cells expressing the GnRH receptor above threshold levels. However, new agonists with modified properties are required to improve the anti-proliferative range. Effects of residue substitutions and methylations on tumourigenic HEK293[SCL60] and WPE-1-NB26-3 prostate cells expressing the rat GnRH receptor were compared. Peptides were ranked according to receptor binding affinity, induction of inositol phosphate production and cell growth-inhibition. Analogues possessing D-Trp6 (including triptorelin), D-Leu6 (including leuprolide), D-Ala6, D-Lys6, or D-Arg6 exhibited agonist and anti proliferative activity. Residues His5 or His5,Trp7,Tyr8, corresponding to residues found in GnRH-II, were tolerated, with retention of sub-nanomolar/low nanomolar binding affinities and EC50s for receptor activation and IC50s for cell growth-inhibition. His5D-Arg6-GnRH-I exhibited reduced binding affinity and potency, effective in the mid-nanomolar range. However, all GnRH-II-like analogues were less potent than triptorelin. By comparison, three methylated-Trp6 triptorelin variants showed differential binding, receptor activation and anti proliferation potency. Significantly, 5-Methyl-DL-Trp6-Triptorelin was equipotent to triptorelin. Subsequent studies should determine whether pharmacologically enhanced derivatives of triptorelin can be developed by further alkylations, without substitutions or cleavable cytotoxic adducts, to improve the extent of growth-inhibition of tumour cells expressing the GnRH receptor. PMID- 24490143 TI - A Bayesian Hierarchical Model for Relating Multiple SNPs within Multiple Genes to Disease Risk. AB - A variety of methods have been proposed for studying the association of multiple genes thought to be involved in a common pathway for a particular disease. Here, we present an extension of a Bayesian hierarchical modeling strategy that allows for multiple SNPs within each gene, with external prior information at either the SNP or gene level. The model involves variable selection at the SNP level through latent indicator variables and Bayesian shrinkage at the gene level towards a prior mean vector and covariance matrix that depend on external information. The entire model is fitted using Markov chain Monte Carlo methods. Simulation studies show that the approach is capable of recovering many of the truly causal SNPs and genes, depending upon their frequency and size of their effects. The method is applied to data on 504 SNPs in 38 candidate genes involved in DNA damage response in the WECARE study of second breast cancers in relation to radiotherapy exposure. PMID- 24490144 TI - Oxygen Consumption at 30 W of Exercise Is Surrogate for Peak Oxygen Consumption in Evaluation of Cardiorespiratory Fitness in Young-Adult African-American Females. AB - Body mass index (BMI) is negatively correlated with cardiorespiratory fitness, measured by maximal or peak oxygen consumption (VO2peak). VO2peak measurements require heavy aerobic exercise to near exhaustion which increases the potential for adverse cardiovascular events. This study tests the hypothesis that VO2 measured at a fixed submaximal workload of 30 W is a surrogate for VO2peak. We studied 42 normotensive African-American female university students, 18-25 years of age. We measured VO2peak, blood pressure, and VO2 at a 30 W exercise workload and computed BMI. We found significant negative correlations between BMI and VO2peak (r = -0.41, P < 0.01) and between BMI and VO2 at 30 W (r = -0.53, P < 0.001). Compared to VO2peak, VO2 at 30 W increased the significance of the negative correlation with BMI. The heart rate-systolic pressure product at 30 W was positively correlated with BMI (r = 0.36, P < 0.01) and negatively correlated with VO2peak (r = -0.38, P < 0.001). The positive correlation between BMI and the heart rate-systolic pressure product and the greater negative correlation between VO2 and BMI at 30 W of exercise than that at exercise to fatigue suggest that normalized measurements of VO2 at the fixed exercise workload of 30 W could be useful surrogates for measurements of VO2peak. PMID- 24490145 TI - Triceps innervation pattern: implications for triceps nerve to deltoid nerve transfer. AB - There are multiple nerve branches supplying the triceps. Traditionally, the nerve to the long head of triceps is utilized for nerve transfer to neurotize the deltoid muscle in patients with brachial plexus injuries. However, no anatomical studies were done to investigate which triceps nerve would be preferred for nerve transfer. This anatomical study was carried out to describe the innervation pattern of the triceps muscle to investigate the preferred triceps nerve for nerve transfer. Twenty-five cadaveric arms were dissected. The long head of the triceps received a single branch in 23 cases (92%) and double branches in 2 cases (8%) only. The medial head had a single branch in 22 cases (88%) and double branches in 3 cases (12%). The lateral head was the most bulky one and received more than one branch in all cases (100%), ranging from 2 to 5 branches. The transfer of the most proximal branch to the lateral head of the triceps seems to be the most preferred choice for deltoid muscle innervation. PMID- 24490146 TI - The influence of comorbidities on outcomes of pulmonary rehabilitation programs in patients with COPD: a systematic review. AB - INTRODUCTION: Chronic obstructive pulmonary disease (COPD) is associated with comorbidities such as cardiovascular disease, metabolic disease, osteoporosis, and anxiety and/or depression. Although pulmonary rehabilitation programs are proven to be beneficial in patients with COPD, it is unclear whether comorbidities influence pulmonary rehabilitation outcomes. The aim of the present review was to investigate to what extent the presence of comorbidities can affect pulmonary rehabilitation outcomes. METHODS: The systematic literature search (Pubmed, EMBASE, and PEDro) resulted in 4 articles meeting the inclusion criteria. The odds ratios (95% confidence intervals) of the logistic regression analyses, with comorbidities as independent variables and pulmonary rehabilitation outcomes (dyspnea, functional exercise capacity, and quality of life) as dependent variables, were used for data extraction. RESULTS: Patients with anxiety and/or depression less likely improve in dyspnea. Osteoporosis is associated with less improvements in functional exercise capacity, while cardiovascular disease does not seem to negatively impact on this outcome. Patients with cardiovascular comorbidity will experience less positive changes in quality of life. CONCLUSION: Evidence from literature suggests that comorbidities can have a negative influence on pulmonary rehabilitation outcomes. Screening for comorbidities in pulmonary rehabilitation settings seems useful to readdress the right patients for individually tailored pulmonary rehabilitation. PMID- 24490147 TI - Clinical profile and outcome of Japanese encephalitis in children admitted with acute encephalitis syndrome. AB - Japanese encephalitis (JE) is an arthropod borne viral disease. Children are most commonly affected in Southeast Asian region showing symptoms of central nervous system with several complications and death. The clinical characteristics and outcomes in pediatric JE patients hospitalized with acute encephalitis syndrome (AES) are still poorly understood. A prospective study was conducted in pediatric ward of Assam Medical College Hospital to evaluate the clinical profile and outcome of JE in children. A total of 223 hospitalized AES cases were enrolled during March to December 2012. Serum and cerebro spinal fluids were tested for presence of JE specific IgM antibody. 67 (30%) were found to be JE positive. The most common presenting symptoms in JE patients were fever (100%), altered sensorium (83.58%), seizure (82.08%), headache (41.79%), and vomiting (29.85%). Signs of meningeal irritation were present in 55.22% of cases. Around 40.29%, JE patients had GCS <= 8. Among the JE patients, 14.7% died before discharge. The complete recoveries were observed in 63.9% of cases, while 21.3% had some sort of disability at the time of discharge. JE is still a major cause of AES in children in this part of India. These significant findings thus seek attentions of the global community to combat JE in children. PMID- 24490148 TI - Microbial assessment and prevalence of foodborne pathogens in natural cheeses in Japan. AB - The production and consumption of domestic natural cheese in Japan is increasing year by year. More than ninety percent of domestic natural cheese is produced in Hokkaido region of Japan, while information on its quality and safety related to foodborne pathogens is limited. To assess the microbiological safety of domestic natural cheese, a total of 126 natural cheese samples produced in Hokkaido were collected from December, 2012, to July, 2013. In addition to standard plate count (SPC) and coliform counts, the prevalence study of three pathogens (Listeria monocytogenes, pathogenic Escherichia coli, and Salmonella spp.) was performed on each sample. Real-time PCR and matrix-assisted laser desorption-ionization time of-flight mass spectrometer methods were employed for identification of presumptive pathogens. Coliform was detected in 25 samples (19.8%) with a minimum of 25 cfu/g and a maximum of more than 3.0 * 10(6) cfu/g. Salmonella spp. and L. monocytogenes were not isolated from any of the samples. Only one sample (0.80%) showed positive PCR amplification for ipaH gene suggesting possible contamination of enteroinvasive E. coli or Shigella in this product. Overall results indicate that natural cheeses produced in Hokkaido region were satisfactory microbiological quality according to existing international standards. PMID- 24490149 TI - Multiclass prediction with partial least square regression for gene expression data: applications in breast cancer intrinsic taxonomy. AB - Multiclass prediction remains an obstacle for high-throughput data analysis such as microarray gene expression profiles. Despite recent advancements in machine learning and bioinformatics, most classification tools were limited to the applications of binary responses. Our aim was to apply partial least square (PLS) regression for breast cancer intrinsic taxonomy, of which five distinct molecular subtypes were identified. The PAM50 signature genes were used as predictive variables in PLS analysis, and the latent gene component scores were used in binary logistic regression for each molecular subtype. The 139 prototypical arrays for PAM50 development were used as training dataset, and three independent microarray studies with Han Chinese origin were used for independent validation (n = 535). The agreement between PAM50 centroid-based single sample prediction (SSP) and PLS-regression was excellent (weighted Kappa: 0.988) within the training samples, but deteriorated substantially in independent samples, which could attribute to much more unclassified samples by PLS-regression. If these unclassified samples were removed, the agreement between PAM50 SSP and PLS regression improved enormously (weighted Kappa: 0.829 as opposed to 0.541 when unclassified samples were analyzed). Our study ascertained the feasibility of PLS regression in multi-class prediction, and distinct clinical presentations and prognostic discrepancies were observed across breast cancer molecular subtypes. PMID- 24490150 TI - Degradation of diuron by Phanerochaete chrysosporium: role of ligninolytic enzymes and cytochrome P450. AB - The white-rot fungus Phanerochaete chrysosporium was investigated for its capacity to degrade the herbicide diuron in liquid stationary cultures. The presence of diuron increased the production of lignin peroxidase in relation to control cultures but only barely affected the production of manganese peroxidase. The herbicide at the concentration of 7 MU g/mL did not cause any reduction in the biomass production and it was almost completely removed after 10 days. Concomitantly with the removal of diuron, two metabolites, DCPMU [1-(3,4 dichlorophenyl)-3-methylurea] and DCPU [(3,4-dichlorophenyl)urea], were detected in the culture medium at the concentrations of 0.74 MU g/mL and 0.06 MU g/mL, respectively. Crude extracellular ligninolytic enzymes were not efficient in the in vitro degradation of diuron. In addition, 1-aminobenzotriazole (ABT), a cytochrome P450 inhibitor, significantly inhibited both diuron degradation and metabolites production. Significant reduction in the toxicity evaluated by the Lactuca sativa L. bioassay was observed in the cultures after 10 days of cultivation. In conclusion, P. chrysosporium can efficiently metabolize diuron without the accumulation of toxic products. PMID- 24490151 TI - Molecular modeling of lectin-like protein from Acacia farnesiana reveals a possible anti-inflammatory mechanism in Carrageenan-induced inflammation. AB - Acacia farnesiana lectin-like protein (AFAL) is a chitin-binding protein and has been classified as phytohaemagglutinin from Phaseolus vulgaris (PHA). Legume lectins are examples for structural studies, and this family of proteins shows a remarkable conservation in primary, secondary, and tertiary structures. Lectins have ability to reduce the effects of inflammation caused by phlogistic agents, such as carrageenan (CGN). This paper explains the anti-inflammatory activity of AFAL through structural comparison with anti-inflammatory legume lectins. The AFAL model was obtained by molecular modeling and molecular docking with glycan and carrageenan were performed to explain the AFAL structural behavior and biological activity. Pisum sativum lectin was the best template for molecular modeling. The AFAL structure model is folded as a beta sandwich. The model differs from template in loop regions, number of beta strands and carbohydrate binding site. Carrageenan and glycan bind to different sites on AFAL. The ability of AFAL binding to carrageenan can be explained by absence of the sixth beta strand (posterior beta sheets) and two beta strands in frontal region. AFAL can inhibit pathway inflammatory process by carrageenan injection by connecting to it and preventing its entry into the cell and triggers the reaction. PMID- 24490152 TI - Effect of brief daily resistance training on occupational neck/shoulder muscle activity in office workers with chronic pain: randomized controlled trial. AB - PURPOSE: This study investigates the acute and longitudinal effects of resistance training on occupational muscle activity in office workers with chronic pain. METHODS: 30 female office workers with chronic neck and shoulder pain participated for 10 weeks in high-intensity elastic resistance training for 2 minutes per day (n = 15) or in control receiving weekly email-based information on general health (n = 15). Electromyography (EMG) from the splenius and upper trapezius was recorded during a normal workday. RESULTS: Adherence to training and control interventions were 86% and 89%, respectively. Compared with control, training increased isometric muscle strength 6% (P < 0.05) and decreased neck/shoulder pain intensity by 40% (P < 0.01). The frequency of periods with complete motor unit relaxation (EMG gaps) decreased acutely in the hours after training. By contrast, at 10-week follow-up, training increased average duration of EMG gaps by 71%, EMG gap frequency by 296% and percentage time below 0.5%, and 1.0% EMGmax by 578% and 242%, respectively, during the workday in m. splenius. CONCLUSION: While resistance training acutely generates a more tense muscle activity pattern, the longitudinal changes are beneficial in terms of longer and more frequent periods of complete muscular relaxation and reduced pain. PMID- 24490153 TI - Pharmacological intervention of nicotine dependence. AB - Nicotine dependence is a major cause of mortality and morbidity all over the world. Various medications have been tried to treat nicotine dependence including nicotine replacement therapy, bupropion, and varenicline. A newer venture to nicotine dependence treatment is a nicotine vaccine which is yet to get footsteps in common practice. The present review assimilates various pharmacotherapeutic measures to address nicotine dependence. However, it is to be noted that psychological interventions, when combined with pharmacotherapy, offer the greatest benefits to the patients. PMID- 24490154 TI - Construction and immunogenicity of DNA vaccines encoding fusion protein of porcine IFN- lambda 1 and GP5 gene of porcine reproductive and respiratory syndrome virus. AB - Porcine reproductive and respiratory syndrome virus (PRRSV) has been mainly responsible for the catastrophic economic losses in pig industry worldwide. The commercial vaccines only provide a limited protection against PRRSV infection. Thus, the focus and direction is to develop safer and more effective vaccines in the research field of PRRS. The immune modulators are being considered to enhance the effectiveness of PRRSV vaccines. IFN- lambda1 belongs to type III interferon, a new interferon family. IFN- lambda1 is an important cytokine with multiple functions in innate and acquired immunity. In this study, porcine IFN- lambda1 (PoIFN- lambda1) was evaluated for its adjuvant effects on the immunity of a DNA vaccine carrying the GP5 gene of PRRSV. Groups of mice were immunized twice at 2 week interval with 100 MU g of the plasmid DNA vaccine pcDNA3.1-SynORF5, pcDNA3.1 PoIFN- lambda1-SynORF5, and the blank vector pcDNA3.1, respectively. The results showed that pcDNA3.1-PoIFN- lambda1-SynORF5 can significantly enhance GP5 specific ELISA antibody, PRRSV-specific neutralizing antibody, IFN- gamma level, and lymphocyte proliferation rather than the responses induced by pcDNA3.1 SynORF5. Therefore, type III interferon PoIFN- lambda1 could enhance the immune responses of DNA vaccine of PRRSV, highlighting the potential value of PoIFN- lambda1 as a molecular adjuvant in the prevention of PRRSV infection. PMID- 24490155 TI - Antioxidant and toxicity studies of 50% methanolic extract of Orthosiphon stamineus Benth. AB - The present study evaluated the antioxidant activity and potential toxicity of 50% methanolic extract of Orthosiphon stamineus (Lamiaceae) leaves (MEOS) after acute and subchronic administration in rats. Superoxide radical scavenging, hydroxyl radical scavenging, and ferrous ion chelating methods were used to evaluate the antioxidant properties of the extract. In acute toxicity study, single dose of MEOS, 5000 mg/kg, was administered to rats by oral gavage, and the treated rats were monitored for 14 days. While in the subchronic toxicity study, MEOS was administered orally, at doses of 1250, 2500, and 5000 mg/kg/day for 28 days. From the results, MEOS showed good superoxide radical scavenging, hydroxyl radical scavenging, ferrous ion chelating, and antilipid peroxidation activities. There was no mortality detected or any signs of toxicity in acute and subchronic toxicity studies. Furthermore, there was no significant difference in bodyweight, relative organ weight, and haematological and biochemical parameters between both male and female treated rats in any doses tested. No abnormality of internal organs was observed between treatment and control groups. The oral lethal dose determined was more than 5000 mg/kg and the no-observed-adverse-effect level (NOAEL) of MEOS for both male and female rats is considered to be 5000 mg/kg per day. PMID- 24490156 TI - Poly-s-nitrosated albumin as a safe and effective multifunctional antitumor agent: characterization, biochemistry and possible future therapeutic applications. AB - Nitric oxide (NO) is a ubiquitous molecule involved in multiple cellular functions. Inappropriate production of NO may lead to disease states. To date, pharmacologically active compounds that release NO within the body, such as organic nitrates, have been used as therapeutic agents, but their efficacy is significantly limited by unwanted side effects. Therefore, novel NO donors with better pharmacological and pharmacokinetic properties are highly desirable. The S nitrosothiol fraction in plasma is largely composed of endogenous S-nitrosated human serum albumin (Mono-SNO-HSA), and that is why we are testing whether this albumin form can be therapeutically useful. Recently, we developed SNO-HSA analogs such as SNO-HSA with many conjugated SNO groups (Poly-SNO-HSA) which were prepared using chemical modification. Unexpectedly, we found striking inverse effects between Poly-SNO-HSA and Mono-SNO-HSA. Despite the fact that Mono-SNO-HSA inhibits apoptosis, Poly-SNO-HSA possesses very strong proapoptotic effects against tumor cells. Furthermore, Poly-SNO-HSA can reduce or perhaps completely eliminate the multidrug resistance often developed by cancer cells. In this review, we forward the possibility that Poly-SNO-HSA can be used as a safe and effective multifunctional antitumor agent. PMID- 24490157 TI - Radiobiology of radiosurgery for the central nervous system. AB - According to Leksell radiosurgery is defined as "the delivery of a single, high dose of irradiation to a small and critically located intracranial volume through the intact skull." Before its birth in the early 60s and its introduction in clinical therapeutic protocols in late the 80s dose application in radiation therapy of the brain for benign and malignant lesions was based on the administration of cumulative dose into a variable number of fractions. The rationale of dose fractionation is to lessen the risk of injury of normal tissue surrounding the target volume. Radiobiological studies of cell culture lines of malignant tumors and clinical experience with patients treated with conventional fractionated radiotherapy helped establishing this radiobiological principle. Radiosurgery provides a single high dose of radiation which translates into a specific toxic radiobiological response. Radiobiological investigations to study the effect of high dose focused radiation on the central nervous system began in late the 50s. It is well known currently that radiobiological principles applied for dose fractionation are not reproducible when single high dose of ionizing radiation is delivered. A review of the literature about radiobiology of radiosurgery for the central nervous system is presented. PMID- 24490158 TI - The use of fiber-reinforced scaffolds cocultured with Schwann cells and vascular endothelial cells to repair rabbit sciatic nerve defect with vascularization. AB - To explore the feasibility of biodegradable fiber-reinforced 3D scaffolds with satisfactory mechanical properties for the repair of long-distance sciatic nerve defect in rabbits and effects of vascularized graft in early stage on the recovery of neurological function, Schwann cells and vascular endothelial cells were cocultured in the fiber-reinforced 3D scaffolds. Experiment group which used prevascularized nerve complex for the repair of sciatic nerve defect and control group which only cultured with Schwann cells were set. The animals in both groups underwent electromyography to show the status of the neurological function recovery at 4, 8, and 16 weeks after the surgery. Sciatic nerve regeneration and myelination were observed under the light microscope and electron microscope. Myelin sheath thickness, axonal diameter, and number of myelinated nerve fiber were quantitatively analyzed using image analysis system. The recovery of foot ulcer, the velocity of nerve conduction, the number of regenerating nerve fiber, and the recovery of ultrastructure were increased in the experimental group than those in the control group. Prevascularized tissue engineered fiber-reinforced 3D scaffolds for the repair of sciatic nerve defects in rabbits can effectively promote the recovery of neurological function. PMID- 24490160 TI - Diversity and seasonal impact of Acanthamoeba species in a subtropical rivershed. AB - This study evaluated the presence of Acanthamoeba species in the Puzih River watershed, which features typical subtropical monsoon climate and is located just above the Tropic of Cancer in Taiwan. The relationship between the seasonal and geographical distributions of Acanthamoeba species in this rivershed was also investigated. Acanthamoeba species were detected in water samples using the amoebal enrichment culture method and confirmed by PCR. A total of 136 water samples were included in this study, 16 (11.7%) of which contained Acanthamoeba species. Samples with the highest percentage of Acanthamoeba (32.4%) were obtained during the summer season, mainly from upstream areas. The identified species in the four seasons included Acanthamoeba palestinensis (T2), Acanthamoeba sp. IS2/T4 (T4), Acanthamoeba lenticulata (T5), Acanthamoeba hatchetti (T11), Acanthamoeba healyi (T12), and Acanthamoeba jacobsi (T15). The most frequently identified Acanthamoeba genotype was T4 (68.7%). Acanthamoeba genotype T4 is responsible for Acanthamoeba keratitis and should be considered for associated human health risk potential in the rivershed. PMID- 24490159 TI - Novel strategies for the treatment of chondrosarcomas: targeting integrins. AB - Chondrosarcomas are a heterogeneous group of malignant bone tumors that are characterized by the production of cartilaginous extracellular matrix. They are the second most frequently occurring type of bone malignancy. Surgical resection remains the primary mode of treatment for chondrosarcomas, since conventional chemotherapy and radiotherapy are largely ineffective. Treatment of patients with high-grade chondrosarcomas is particularly challenging, owing to the lack of effective adjuvant therapies. Integrins are cell surface adhesion molecules that regulate a variety of cellular functions. They have been implicated in the initiation, progression, and metastasis of solid tumors. Deregulation of integrin expression and/or signaling has been identified in many chondrosarcomas. Therefore, the development of new drugs that can selectively target regulators of integrin gene expression and ligand-integrin signaling might hold great promise for the treatment of these cancers. In this review, we provide an overview of the current understanding of how growth factors, chemokines/cytokines, and other inflammation-related molecules can control the expression of specific integrins to promote cell migration. We also review the roles of specific subtypes of integrins and their signaling mechanisms, and discuss how these might be involved in tumor growth and metastasis. Finally, novel therapeutic strategies for targeting these molecules will be discussed. PMID- 24490162 TI - Scope of nursing care in Polish intensive care units. AB - INTRODUCTION: The TISS-28 scale, which may be used for nursing staff scheduling in ICU, does not reflect the complete scope of nursing resulting from varied cultural and organizational conditions of individual systems of health care. AIM: The objective of the study was an attempt to provide an answer to the question what scope of nursing care provided by Polish nurses in ICU does the TISS-28 scale reflect? MATERIAL AND METHODS: The methods of working time measurement were used in the study. For the needs of the study, 252 hours of continuous observation (day-long observation) and 3.697 time-schedule measurements were carried out. RESULTS: The total nursing time was 4125.79 min. (68.76 hours), that is, 60.15% of the total working time of Polish nurses during the period analyzed. Based on the median test, the difference was observed on the level of chi(2) = 16945.8,P < 0.001 between the nurses' workload resulting from performance of activities qualified into the TISS-28 scale and load resulting from performance of interventions within the scopes of care not considered in this scale in Polish ICUs. CONCLUSIONS: The original version of the TISS-28 scale does not fully reflect the workload among Polish nurses employed in ICUs. PMID- 24490163 TI - HGF accelerates wound healing by promoting the dedifferentiation of epidermal cells through beta1-integrin/ILK pathway. AB - Skin wound healing is a critical and complex biological process after trauma. This process is activated by signaling pathways of both epithelial and nonepithelial cells, which release a myriad of different cytokines and growth factors. Hepatocyte growth factor (HGF) is a cytokine known to play multiple roles during the various stages of wound healing. This study evaluated the benefits of HGF on reepithelialization during wound healing and investigated its mechanisms of action. Gross and histological results showed that HGF significantly accelerated reepithelialization in diabetic (DB) rats. HGF increased the expressions of the cell adhesion molecules beta1-integrin and the cytoskeleton remodeling protein integrin-linked kinase (ILK) in epidermal cells in vivo and in vitro. Silencing of ILK gene expression by RNA interference reduced expression of beta1-integrin, ILK, and c-met in epidermal cells, concomitantly decreasing the proliferation and migration ability of epidermal cells. beta1-Integrin can be an important maker of poorly differentiated epidermal cells. Therefore, these data demonstrate that epidermal cells become poorly differentiated state and regained some characteristics of epidermal stem cells under the role of HGF after wound. Taken together, the results provide evidence that HGF can accelerate reepithelialization in skin wound healing by dedifferentiation of epidermal cells in a manner related to the beta1 integrin/ILK pathway. PMID- 24490164 TI - Toward personalized cell therapies by using stem cells 2013. PMID- 24490161 TI - Deregulation of the miRNAs expression in cervical cancer: human papillomavirus implications. AB - MicroRNAs (miRNAs) are a class of small non coding RNAs of 18-25 nucleotides in length. The temporal or short-lived expression of the miRNAs modulates gene expression post transcriptionally. Studies have revealed that miRNAs deregulation correlates and is involved with the initiation and progression of human tumors. Cervical cancer (CC) displays notably increased or decreased expression of a large number of cellular oncogenic or tumor suppressive miRNAs, respectively. However, understanding the potential role of miRNAs in CC is still limited. In CC, the high-risk human papillomaviruses (HR-HPVs) infection can affect the miRNAs expression through oncoprotein E6 and E7 that contribute to viral pathogenesis, although other viral proteins might also be involved. This deregulation in the miRNAs expression has an important role in the hallmarks of CC. Interestingly, the miRNA expression profile in CC can discriminate between normal and tumor tissue and the extraordinary stability of miRNAs makes it suitable to serve as diagnostic and prognostic biomarkers of cancer. In this review, we will summarize the role of the HR-HPVs in miRNA expression, the role of miRNAs in the hallmarks of CC, and the use of miRNAs as potential prognostic biomarkers in CC. PMID- 24490165 TI - Seroprevalence of St. Louis encephalitis virus and West Nile virus (Flavivirus, Flaviviridae) in horses, Uruguay. AB - St. Louis encephalitis virus (SLEV) and West Nile virus (WNV) belong to the Japanese encephalitis antigenic complex (Flavivirus genus, Flaviviridae family). They show antigenic close relationships and share many similarities in their ecology. Both are responsible for serious human diseases. The aim of this study was to investigate the presence of neutralizing antibodies to these viruses in horses from Uruguay. To do this, 425 horse sera were collected in 2007 and analyzed by plaque reduction neutralization tests. As a result, 205 sera (48.2%) were found positive for SLEV, with titers ranging between 10 and 80. Two sera remained inconclusive, since they showed low titers to WNV and SLEV (10 and 20), not allowing us to demonstrate activity of WNV in our territory. This is the first report of circulation of SLEV in horses in Uruguay. PMID- 24490168 TI - Application of systems biology and bioinformatics methods in biochemistry and biomedicine. PMID- 24490166 TI - Interleukin 1-beta, interleukin-1 receptor antagonist, and interleukin 18 in children with acute spontaneous urticaria. AB - Very little is known about the role of interleukin-1beta (IL-1beta) and interleukin-18 (IL-18) in urticaria. MATERIAL AND METHODS: Serum levels of IL 1beta, IL-1 receptor antagonist (IL-1RA), and IL-18 were measured in 56 children with urticaria and in 41 healthy subjects. RESULTS: Serum IL-1beta did not differ between children with acute urticaria and controls. Children with single episode of urticaria had higher levels of IL-1RA and IL-18 than healthy subjects. In children with single episode of urticaria, level of IL-1RA correlated with C reactive protein (CRP), D-dimer, and IL-1beta levels. In subjects with recurrence of urticaria IL-1RA was positively correlated with WBC and D-dimer levels. No correlation of cytokine levels and urticaria severity scores (UAS) in all children with urticaria was observed. In children with single episode of urticaria UAS correlated with CRP level. In the group with single episode of urticaria and in children with symptoms of upper respiratory infection, IL-1RA and IL-18 levels were higher than in controls. The former was higher than in noninfected children with urticaria. In conclusion, this preliminary study documents that serum IL-1RA and IL-18 levels are increased in some children with acute urticaria. However further studies are necessary to define a pathogenic role of IL-1beta, IL-1RA, and IL-18 in urticaria. PMID- 24490167 TI - GRIN2B gene and associated brain cortical white matter changes in bipolar disorder: a preliminary combined platform investigation. AB - Abnormalities in glutamate signaling and glutamate toxicity are thought to be important in the pathophysiology of bipolar disorder (BD). Whilst previous studies have found brain white matter changes in BD, there is paucity of data about how glutamatergic genes affect brain white matter integrity in BD. Based on extant neuroimaging data, we hypothesized that GRIN2B risk allele is associated with reductions of brain white matter integrity in the frontal, parietal, temporal, and occipital regions and cingulate gyrus in BD. Fourteen patients with BD and 22 healthy controls matched in terms of age, gender and handedness were genotyped using blood samples and underwent diffusion tensor imaging. Compared to G allele, brain FA values were significantly lower in BD patients with risk T allele in left frontal region (P = 0.001), right frontal region (P = 0.002), left parietal region (P = 0.001), left occipital region (P = 0.001), right occipital region (P < 0.001), and left cingulate gyrus (P = 0.001). Further elucidation of the interactions between different glutamate genes and their relationships with such structural, functional brain substrates will enhance our understanding of the link between dysregulated glutamatergic neurotransmission and neuroimaging endophenotypes in BD. PMID- 24490169 TI - Comparison of neurologic and radiographic outcomes with Solitaire versus Merci/Penumbra systems for acute stroke intervention. AB - BACKGROUND AND PURPOSE: The Solitaire Flow Restoration was approved by the FDA in 2012 for mechanical thrombolysis of proximal occlusion of intracranial arteries. To compare the Solitaire FR device and the Merci/Penumbra (previously FDA approved) systems in terms of safety, clinical outcomes, and efficacy including radiographic brain parenchymal salvage. METHODS: Thirty-one consecutive patients treated with the Solitaire and 20 patients with comparable baseline characteristics treated with Merci or Penumbra systems were included in the study. Primary outcome measures included recanalization rate and modified Rankin Scale score at followup. Secondary outcomes included length of procedure, incidence of symptomatic intracranial hemorrhage, 90-day mortality, and radiographic analysis of percentage area salvage. RESULTS: Compared with the Merci/Penumbra group, the Solitaire group showed a statistically significant improvement in favorable outcomes (mRS <= 2) (69% versus 35%, P = 0.03) and symptomatic ICH rate (0 versus 15%, P = 0.05) with a trend towards higher recanalization rates (93.5% versus 75%, P = 0.096) and shorter length of procedure (58.5 min versus 70.8 min, P = 0.08). Radiographic comparison also showed a significantly larger area of salvage in the Solitaire group (81.9% versus 71.9%, P = 0.05). CONCLUSION: Our study suggests that the Solitaire system allows faster, safer, and more efficient thrombectomy than Merci or Penumbra systems. PMID- 24490170 TI - Suppression of osteopontin functions by levocetirizine, a histamine H1 receptor antagonist, in vitro. AB - OBJECTIVES: Osteopontin (OPN), a multifunctional glycoprotein secreted from a wide variety of cells after inflammatory stimulation, is well accepted to contribute to the development of allergic diseases. However, the influence of histamine H1 receptor antagonists (antihistamines) on OPN functions is not well understood. The present study was undertaken to examine the influence of antihistamines on OPN functions in vitro. METHODS: Human nasal epithelial cells (5 * 10(5) cells) were stimulated with 250 ng/mL OPN in the presence of either desloratadine (DL), fexofenadine (FEX), or levocetirizine (LCT). The levels of OPN, GM-CSF, Eotaxin, and RANTES in 24 h culture supernatants were examined by ELISA. The influence of LCT on mRNA expression and transcription factor activation in cells were also examined by real-time RT-PCR and ELISA, respectively. KEY FINDINGS: The antihistamines examined significantly suppressed the production of GM-CSF, Eotaxin, and RANTES from cells after OPN stimulation. LCT also exhibited the suppression of mRNA expression for chemokines and transcription factor, NF- kappa B and AP-1, activation, which were increased by the stimulation of cells with OPN. CONCLUSIONS: The suppressive activity of LCT on OPN functions on nasal epithelial cells may be responsible for the attenuating effect of the agent on allergic diseases. PMID- 24490171 TI - Atrophy and primary somatosensory cortical reorganization after unilateral thoracic spinal cord injury: a longitudinal functional magnetic resonance imaging study. AB - The effects of traumatic spinal cord injury (SCI) on the changes in the central nervous system (CNS) over time may depend on the dynamic interaction between the structural integrity of the spinal cord and the capacity of the brain plasticity. Functional magnetic resonance imaging (fMRI) was used in a longitudinal study on five rhesus monkeys to observe cerebral activation during upper limb somatosensory tasks in healthy animals and after unilateral thoracic SCI. The changes in the spinal cord diameters were measured, and the correlations among time after the lesion, structural changes in the spinal cord, and primary somatosensory cortex (S1) reorganization were also determined. After SCI, activation of the upper limb in S1 shifted to the region which generally dominates the lower limb, and the rostral spinal cord transverse diameter adjacent to the lesion exhibited obvious atrophy, which reflects the SCI-induced changes in the CNS. A significant correlation was found among the time after the lesion, the spinal cord atrophy, and the degree of contralateral S1 reorganization. The results indicate the structural changes in the spinal cord and the dynamic reorganization of the cerebral activation following early SCI stage, which may help to further understand the neural plasticity in the CNS. PMID- 24490172 TI - Sphingosine-1-phosphate-mediated mobilization of hematopoietic stem/progenitor cells during intravascular hemolysis requires attenuation of SDF-1-CXCR4 retention signaling in bone marrow. AB - Sphingosine-1-phosphate (S1P) is a crucial chemotactic factor in peripheral blood (PB) involved in the mobilization process and egress of hematopoietic stem/progenitor cells (HSPCs) from bone marrow (BM). Since S1P is present at high levels in erythrocytes, one might assume that, by increasing the plasma S1P level, the hemolysis of red blood cells would induce mobilization of HSPCs. To test this assumption, we induced hemolysis in mice by employing phenylhydrazine (PHZ). We observed that doubling the S1P level in PB from damaged erythrocytes induced only a marginally increased level of mobilization. However, if mice were exposed to PHZ together with the CXCR4 blocking agent, AMD3100, a robust synergistic increase in the number of mobilized HSPCs occurred. We conclude that hemolysis, even if it significantly elevates the S1P level in PB, also requires attenuation of the CXCR4-SDF-1 axis-mediated retention in BM niches for HSPC mobilization to occur. Our data also further confirm that S1P is a major chemottractant present in plasma and chemoattracts HSPCs into PB under steady state conditions. However, to egress from BM, HSPCs first have to be released from BM niches by blocking the SDF-1-CXCR4 retention signal. PMID- 24490173 TI - Cone beam computed tomographic analysis of the shape, height, and location of the mandibular lingula in a population of children. AB - OBJECTIVES: This is the first study to identify and classify the different morphological shapes of the mandibular lingula (ML) in children using cone-beam computed tomography (CBCT). MATERIAL AND METHODS: A retrospective study was performed to evaluate the shape, height, and location of the ML in relation to the surrounding structures using CBCT images of mandibles obtained from 269 children. The shape of the ML was classified into triangular, truncated, nodular, or assimilated types. The location was determined by five distances. The height of the lingula was also measured from the lingular tip to the mandibular foramen. RESULTS: A nodular shape of the ML was most commonly found (48.3%, n = 260) followed by truncated (23.4%, n = 126), assimilated (14.4%, n = 78), and triangular (13.7%, n = 74). The mean distance of ML from the anterior and posterior borders of mandibular ramus was 13.3 +/- 2.3 mm and 10.2 +/- 1.6 mm, respectively. In the majority of the mandibles studied, the ML was located above the occlusal plane. CONCLUSION: The present study provides new information to the literature concerning the shape, height, and location of the lingula in a Turkish pediatric population. This finding may assist clinicians to localize the lingula and avoid intraoperative complications. PMID- 24490174 TI - In vitro antiophidian mechanisms of Hypericum brasiliense choisy standardized extract: quercetin-dependent neuroprotection. AB - The neuroprotection induced by Hypericum brasiliense Choisy extract (HBE) and its main active polyphenol compound quercetin, against Crotalus durissus terrificus (Cdt) venom and crotoxin and crotamine, was enquired at both central and peripheral mammal nervous system. Cdt venom (10 MUg/mL) or crotoxin (1 MUg/mL) incubated at mouse phrenic nerve-diaphragm preparation (PND) induced an irreversible and complete neuromuscular blockade, respectively. Crotamine (1 MUg/mL) only induced an increase of muscle strength at PND preparations. At mouse brain slices, Cdt venom (1, 5, and 10 MUg/mL) decreased cell viability. HBE (100 MUg/mL) inhibited significantly the facilitatory action of crotamine (1 MUg/mL) and was partially active against the neuromuscular blockade of crotoxin (1 MUg/mL) (data not shown). Quercetin (10 MUg/mL) mimicked the neuromuscular protection of HBE (100 MUg/mL), by inhibiting almost completely the neurotoxic effect induced by crotoxin (1 MUg/mL) and crotamine (1 MUg/mL). HBE (100 MUg/mL) and quercetin (10 MUg/mL) also increased cell viability in mice brain slices. Quercetin (10 MUg/mL) was more effective than HBE (100 MUg/mL) in counteracting the cell lysis induced by Cdt venom (1 and 10 MUg/mL, resp.). These results and a further phytochemical and toxicological investigations could open new perspectives towards therapeutic use of Hypericum brasiliense standardized extract and quercetin, especially to counteract the neurotoxic effect induced by snake neurotoxic venoms. PMID- 24490175 TI - In vitro wound healing potential and identification of bioactive compounds from Moringa oleifera Lam. AB - Moringa oleifera Lam. (M. oleifera) from the monogeneric family Moringaceae is found in tropical and subtropical countries. The present study was aimed at exploring the in vitro wound healing potential of M. oleifera and identification of active compounds that may be responsible for its wound healing action. The study included cell viability, proliferation, and wound scratch test assays. Different solvent crude extracts were screened, and the most active crude extract was further subjected to differential bioguided fractionation. Fractions were also screened and most active aqueous fraction was finally obtained for further investigation. HPLC and LC-MS/MS analysis were used for identification and confirmation of bioactive compounds. The results of our study demonstrated that aqueous fraction of M. oleifera significantly enhanced proliferation and viability as well as migration of human dermal fibroblast (HDF) cells compared to the untreated control and other fractions. The HPLC and LC-MS/MS studies revealed kaempferol and quercetin compounds in the crude methanolic extract and a major bioactive compound Vicenin-2 was identified in the bioactive aqueous fraction which was confirmed with standard Vicenin-2 using HPLC and UV spectroscopic methods. These findings suggest that bioactive fraction of M. oleifera containing Vicenin-2 compound may enhance faster wound healing in vitro. PMID- 24490176 TI - Severe cutaneous and neurologic toxicity in melanoma patients during vemurafenib administration following anti-PD-1 therapy. AB - Immune checkpoint inhibitors such as ipilimumab and targeted BRAF inhibitors have dramatically altered the landscape of melanoma therapeutics over the past few years. Agents targeting the programmed cell death-1/ligand (PD-1/PD-L1) axis are now being developed and appear to be highly active clinically with favorable toxicity profiles. We report two patients with BRAF V600E mutant melanoma who were treated with anti-PD-1 agents as first-line therapy without significant toxicity, followed by vemurafenib at disease progression. Both patients developed severe hypersensitivity drug eruptions with multi-organ injury early in their BRAF inhibitor treatment course. One patient subsequently developed acute inflammatory demyelinating polyneuropathy (AIDP) and the other developed anaphylaxis upon low-dose vemurafenib rechallenge. Further investigation of the immune response during combination or sequences of melanoma therapeutics is warranted. Furthermore, clinicians should maintain a high index of suspicion for these toxicities when vemurafenib is administered following an anti-PD-1 agent. PMID- 24490178 TI - NLRC5/CITA: a novel regulator of class I major histocompatibility complex genes. PMID- 24490177 TI - Temperature matters! And why it should matter to tumor immunologists. AB - A major goal of cancer immunology is to stimulate the generation of long-lasting, tumor antigen-specific immune responses that recognize and destroy tumor cells. This article discusses advances in thermal medicine with the potential to improve cancer immunotherapy. Accumulating evidence indicates that survival benefits are accorded to individuals who achieve an increase in body temperature (i.e. fever) following infection. Furthermore, accumulating evidence indicates that physiological responses to hyperthermia impact the tumor microenvironment through temperature-sensitive check-points that regulate tumor vascular perfusion, lymphocyte trafficking, inflammatory cytokine expression, tumor metabolism, and innate and adaptive immune function. Nevertheless, the influence of thermal stimuli on the immune system, particularly the antitum or immune response, remains incompletely understood. In fact, temperature is still rarely considered as a critical variable in experimental immunology. We suggest that more attention should be directed to the role of temperature in the regulation of the immune response and that thermal therapy should be tested in conjunction with immunotherapy as a multi-functional adjuvant that modulates the dynamics of the tumor microenvironment. PMID- 24490180 TI - Children are not small adults. PMID- 24490179 TI - An Integrated Approach to Diabetes Prevention: Anthropology, Public Health, and Community Engagement. AB - Diabetes is an enormous public health problem with particular concern within Hispanic communities and among individuals with low wealth. However, attempts to expand the public health paradigm to include social determinants of health rarely include analysis of social and contextual factors considered outside the purview of health research. As a result, conceptualization of the dynamics of diabetes health disparities remains shallow. We argue that using a holistic anthropological lens has the potential to offer insights regarding the nature of the interface between broader social determinants, health outcomes and health disparity. In a primarily Hispanic, immigrant community in Albuquerque, New Mexico, we conducted a mixed methods study that integrates an anthropological lens with a community engaged research design. Our data from focus groups, interviews, a survey and blood sampling demonstrate the need to conceptualize social determinants more broadly, more affectively and more dynamically than often considered. These results highlight a need to include, in addition to individual-level factors that are traditionally the focus of public health and more innovative structural factors that are currently in vogue, an in-depth, qualitative exploration of local context, social environment, and culture, and their interactions and intersectionality, as key factors when considering how to achieve change. The discussion presented here offers a model for culturally situated and contextually relevant scientific research. This model achieves the objectives and goals of both public health and anthropology while providing valuable insights and mechanisms for addressing health disparity such as that which exists in relation to diabetes among Hispanic immigrants in New Mexico. Such an approach has implications for how research projects are designed and conceptualizing social determinants more broadly. The discussion presented provides insights with relevance for both disciplines. PMID- 24490181 TI - All-polyethylene tibial components in octogenarians: survivorship, performance, and cost. AB - The ideal recipient for an all-polyethylene tibial (APT) component continues to be controversial. Several recent randomized clinical studies have demonstrated clinical efficacy of APT when compared to metal backed tibial (MBT) components in relation to survival and clinical outcomes measures, particularly in an elderly population. In this retrospective series, 166 knees in 130 patients (age > 80 years) received an APT component. Average follow-up for the living and deceased was 5.7 and 5.2 years, respectively. There were no APT failures at the time of most recent follow-up. Knee Society function score improved from 30 to 48. Almost all respondents reported either good or excellent satisfaction with their outcome. The average cost savings of using APT instead of MBT component can be substantial. We believe octogenarian patients represent the ideal population for an APT component, that functional outcomes and satisfaction levels will be acceptable to those patients, and that the component will outlast the remaining life of the patient while also potentially providing a substantial cost savings, compared with the cost of MBT components. PMID- 24490182 TI - Cost estimates of biologic implants among orthopedic surgeons. AB - The use and development of biologic implants such as autogenous bone grafts and bone morphogenetic proteins (BMPs) remain on the rise in orthopedic surgery. Apart from the differences in efficacies seen between the different methods, there is also a difference in the cost associated with each. We generated a questionnaire inquiring about current use of osteobiologics and cost perceptions, and distributed it to 30 orthopedic surgeons. When answers were compared to operating room pricing data from each institution, surgeons grossly over and underestimated the costs associated with each of the osteobiologics in the questionnaire. More than 25% of those questioned did not know the cost of the osteobiologics they had used in the last 3 months. Furthermore, none of the participating institutions had a committee with physician participation concerning the use of these techniques. As the use and cost of osteobiologics by orthopedic surgeons continues to increase, so should the importance of educating those surgeons on the financial outcomes so as to assuage extraneous and unnecessary economic ramifications. PMID- 24490183 TI - Subacute superior patellar pole sleeve fracture. AB - Patellar fractures are uncommon, representing 1% of pediatric fractures. Most of these injuries are sleeve avulsions of the inferior pole. Sleeve avulsion of the superior pole is rare, with only 14 cases reported in the English-language literature. These injuries occur in adolescents after forced knee flexion or direct anterior blow. Radiographs may reveal patella baja, anterior tilt, and suprapatellar calcifications. Ultrasound and magnetic resonance imaging (MRI) can confirm the diagnosis. We present a subacute superior pole sleeve fracture in a 15-year-old boy who sustained a left knee injury. Initial radiographs were negative. Ten days later, the patient returned with hemarthrosis and suprapatellar calcification. MRIs were read as "distal quadriceps tendon tear." Twenty-three days after the injury, the patient presented with a limp, palpable quadriceps tendon gap, and inability to maintain a straight leg raise. A superior pole sleeve fracture was repaired surgically the following day. An understanding of the injury demographics and radiological findings associated with superior pole sleeve fractures can prevent missed diagnosis of a rare injury. We review the literature for injury demographics, operative and nonoperative treatment methods, and outcomes. PMID- 24490184 TI - Symptomatic hip impingement due to exostosis associated with supra-acetabular pelvic external fixator pin. AB - Expedient stabilization of unstable pelvic fractures has been shown to significantly reduce morbidity and mortality in the polytrauma patient. Application of a pelvic external fixator is one of the methods used to provide effective pelvic stability. However, pelvic external fixators are not without drawbacks. While pin tract infections and pin loosening are frequent complications, we describe a unique complication consisting of the formation of a symptomatic exostosis at the supra-acetabular pin site in a 35-year-old male with a pelvic fracture. To our knowledge this is the first description of hip impingement due to reactive bone formation secondary to a supra-acetabular pelvic external fixation pin. The impinging bone was completely excised utilizing the anterior approach to the hip. A 40 degrees improvement in the patient's hip flexion range of motion was noted after exostosis excision. PMID- 24490185 TI - Total knee arthroplasty with concurrent femoral and tibial osteotomies in osteogenesis imperfecta. AB - Three total knee arthroplasties (TKA) with concurrent femoral and/or tibial osteotomies in 2 patients with osteogenesis imperfecta were performed from 2004 to 2009. The 2 patients were followed for a mean of 6 years. One patient with concurrent TKA, and femoral and tibial osteotomies developed a nonunion of the tibial site that responded to open reduction and internal fixation with iliac crest bone graft. The second patient underwent right TKA with bi-level tibial osteotomies, which healed uneventfully, allowing pain free, unassisted ambulation. The same patient then elected to undergo left TKA with bi-level tibial osteotomies. Intraoperatively he sustained a minor tibial plateau fracture requiring the use of a stemmed component and postoperatively, he developed a nonunion at the proximal site and valgus malunion of the distal site. Revision of fixation was performed at both osteotomy sites, and both healed within 3 months. Both patients are now pain free and ambulate without assistance. PMID- 24490187 TI - Prediction of semitendinosus and gracilis tendon lengths and diameters for double bundle ACL reconstruction. AB - Although double bundle anterior cruciate ligament (ACL) reconstruction with hamstring autograft tendons has been reported frequently, some patients may not have enough semitendinosus and gracilis tissue to make satisfactory diameter and length grafts or allow secure graft fixation. The purpose of this study was to evaluate double bundle ACL reconstruction feasibility with hamstring autograft tendons and correlate this feasibility with patient height, weight, and body mass index (BMI). One hundred consecutive patients undergoing ACL reconstruction with hamstring autograft tendons were evaluated. Preoperative height, weight, and BMI were documented for each patient. Our team measured semitendinosus and gracilis tendon lengths intraoperatively. Graft diameters were measured after doubling each tendon. Three double bundle ACL reconstruction techniques were defined that were felt to allow satisfactory graft diameters and lengths, and that would allow secure fixation of the grafts. There were moderate correlations between patient height and graft lengths and diameters. There were poor correlations between patient weight and BMI, and graft lengths and diameters. The likelihood of having enough semitendinosus and gracilis tendon tissue for double bundle ACL reconstruction was 57%, 39%, and 88% for each of the 3 described technique constructs respectively. PMID- 24490188 TI - Low velocity gunshot wounds result in significant contamination regardless of ballistic characteristics. AB - Controversy exists among the orthopedic community regarding the treatment of gunshot injuries. No consistent treatment algorithm exists for treatment of low energy gunshot wound (GSW) trauma. The purpose of this study was to critically examine the wound contamination following low velocity GSW based upon bullet caliber and clothing fiber type found within the injury track. Four types of handguns were fired at ballistic gel from a 10-foot distance. Various clothing materials were applied (denim, cotton, polyester, and wool) circumferentially around the tissue agar in a loose manor. A total of 32 specimens were examined. Each caliber handgun was fired a minimum of 5 times into a gel. Regardless of bullet caliber there was gross contamination of the entire bullet track in 100% of specimens in all scenarios and for all fiber types. Furthermore, as would be expected, the degree of contamination appeared to increase as the size of the bullet increased. Low velocity GSWs result in significant contamination regardless of bullet caliber and jacket type. Based upon our results further investigation of low velocity GSW tracks is warranted. Further clinical investigation should focus on the degree to which debridement should be undertaken. PMID- 24490189 TI - A comparison of acetate and digital templating for hip resurfacing. AB - This study sought to determine whether templating for metal-on-metal hip resurfacing is more accurate with digital or acetate methodology. The medical records of 102 consecutive patients who underwent hip resurfacing at our institution were retrospectively reviewed. Records lacking preoperative radiographs that included a magnification-establishing marker were excluded, leaving 78 records for study. Two investigators independently prepared acetate and digital templates of the preoperative radiographs, which had been calibrated to 120% magnification, to predict femoral and acetabular component size. Accuracy was measured by comparing the predicted component sizes to the surgically implanted component sizes. Digital templating was more accurate than acetate templating in predicting hip resurfacing component size when measuring accuracy of templates by the absolute error of predicted component sizes (femoral, P < .001; acetabular, P = .002), and by the prediction of components to +/-1 size difference (femoral, P = .001; acetabular, P = .002). Experience of the templating surgeon did not correlate with templating accuracy for acetate or digital templating. Although acetate templating is often regarded as the "gold standard" in preoperative planning, data from the current study shows that digital technology can be used for accurate preoperative templating prior to hip resurfacing procedures. PMID- 24490190 TI - A case of malignant transformation of myositis ossificans. AB - A 49-year-old white man presented for evaluation of an enlarging left distal thigh mass with increasing pain over the last several months. The mass was first noticed 11 years prior to this presentation. During his initial examination, the patient was diagnosed with myositis ossificans and had a partial resection of the mass to improve knee function. His current examination revealed a low grade parosteal osteosarcoma arising from pre-existing mature heterotopic ossification. To our knowledge, no reported cases of secondary parosteal osteosarcoma arising from myositis ossificans have been reported in the literature; only a few reports of malignant transformation of myositis ossificans were found. PMID- 24490191 TI - Family or career-must we choose? PMID- 24490192 TI - Patterns of costs and spending among orthopedic surgeons across the United States: a national survey. AB - Due to rising medical costs, the purpose of this study was to investigate the spending patterns of orthopedic surgeons across the United States and the financial implications of such behavior. Overall, 2,000 randomly chosen orthopedic surgeons from the American Academy of Orthopedic Surgeons (AAOS) were invited to answer web-based surveys on their utilization of healthcare resources; 1,214 (61%) completed the survey. There was a significant difference (P < .001) in monthly expenditure based on 8 domains of orthopedic care for the average orthopedist: x-ray costs were $7,536, computed tomography costs were $2,340, magnetic resonance imaging costs were $14,975, ultrasound costs were $686, laboratory test costs were $969, specialty referral costs were $1,389, biopsy costs were $1,314, and hospital admission costs were $6,808. Significant differences in monthly expenditure existed based on orthopedist practice setting (P < .001), subspecialty (P < .001), gender (P < .001), and age (P < .001). Demographics with the highest monthly spending included orthopedic private group setting ($36,278), orthopedic oncology subspecialty ($41,795), male gender ($33,843), and age 50 to 59 ($35,559). The average monthly expenditure for orthopedists nationally was calculated to be $33,436 per physician. Given there are approximately 20,400 practicing orthopedists, the annual United States expenditure in orthopedic surgery was calculated to be $8.2 billion. Orthopedic spending is a significant component of national healthcare expenditure. PMID- 24490193 TI - [Health politics and the Scientific Societies]. PMID- 24490194 TI - [Vascular emergencies, contemporary reflections]. PMID- 24490195 TI - Remote cardiac ischemic conditioning: underlying mechanisms and clinical applications. AB - Despite a significant improvement in the care of acute coronary disease, mortality and morbidity remain important. One explanation for this lies in the fact that the very coronary reperfusion may paradoxically result in additional myocardial injury, through the so-called ischemia-reperfusion injury, partially mitigating the beneficial effects of myocardial reperfusion. Over the past two decades, numerous pharmacological interventions (such as the use of antioxidants, anti-inflammatory, magnesium, glucose/insulin/potassium, rapid normalization of pH) were studied in order to prevent ischemia-reperfusion injury. Despite the promising results obtained in animal experiments, attempts to transpose these results to humans, and consequently to clinical practice, have been disappointing. On the other hand, cardiac ischemic conditioning is an intervention that has produced positive results. Ischemic conditioning refers to the protection induced by short periods of ischemia followed by reperfusion, prior to a major ischemic event. Ischemic stimulus can be applied before (pre conditioning), during (per-conditioning) or after (post-conditioning) the major ischemic event. An important finding regarding cardiac ischemic conditioning, was that protection could be induced remotely, introducing the concept of remote ischemic conditioning. In this paper, we proposed to review the mechanisms underlying remote ischemic cardiac conditioning and the possible clinical applications, considering more specifically pre and per-conditioning. PMID- 24490196 TI - [Quality of life evaluation of the patients and parents satisfaction after Nuss procedure in the management of Pectus Excavatum]. AB - Pectus Excavatum is the most common congenital deformity of the chest. Although Pectus Excavatum can be associated with heart or lung problems, the main indication for surgical correction of this congenital anomaly is the body image dissatisfaction. The Nuss technique is a minimally invasive procedure that allows the placement of an intrathoracic prosthetic convex bar, previously bended, which mobilize the sternum anteriorly. The aim of this study was to evaluate the degree of satisfaction of the patients and parents after the application of the Nuss technique using the Pectus Excavatum Evaluation Questionnaire. All parameters of psychosocial character - self-image, difficulties in exposing the chest, frustration, sadness, social isolation and ridicule - found a statistically significant improvement after surgical correction of Pectus Excavatum from the perspective of patients and their parents. There was not a marked improvement and consensus regarding the overall physical performance of patients. Which is understandable, since, theoretically, the physical deformity is not responsible for significant limitations on exertion. The current surgical correction of Pectus Excavatum by the Nuss technique allows obtaining aesthetic results of the chest with the resolution of the main problems with body image. Increase awareness of health issues for psychosocial and physical factors which might be involved in this kind of deformities is important, especially when there is a satisfactory solution. PMID- 24490197 TI - [Motor evoked potentials in thoracoabdominal aortic surgery]. AB - Thoracoabdominal aortic disease (aneurysm or dissection) has increased in recent decades. Surgery is the curative treatment but is associated to high perioperative morbidity and mortality risks. Paraplegia is one of the most severe complications, whose incidence has decreased significantly with the implementation of spinal cord protection strategies. No single method or combination of methods has proven to be fully effective in preventing paraplegia. This review is intended to analyse the scientific evidence available on the role of intraoperative monitoring with motor evoked potentials in the neurological outcome of patients undergoing thoracoabdominal aortic surgery. An online search (PubMed) was conducted. Relevant references were selected and reviewed. Intraoperative monitoring with motor evoked potentials (MEP) allows early detection of ischemic events and a targeted intervention to prevent the development of spinal cord injury, significantly reducing the incidence of postoperative paraplegia. MEP monitoring may undergo several intraoperative interferences which may compromise their interpretation. Neuromuscular blockade is the main limiting factor of anesthetic origin. It is essential to strike a balance between monitoring conditions and surgical and anesthetic needs as well as to evaluate the risks and benefits of the technique for each patient. MEP monitoring improves neurological outcome when integrated in a multidisciplinary strategy which must include multiple protective mechanisms that should be tailored to each hospital reality. PMID- 24490198 TI - [Surgical management of a spontaneous dissection of the celiac axis caused by fibromuscular dysplasia. First clinical report]. AB - The clinical case of a 46 years old male is reported, who complained of a sudden and sharp epigastric pain, with no other accompanying symptoms or signs. The patient was evaluated in the emergency department of a local hospital and the clinical and laboratory analysis excluded the occurrence of a common acute abdominal pathology. A CT and an angio CT study disclosed a spontaneous dissection and aneurismal dilatation of the celiac axis, along its extension. The patient underwent surgical management, consisting in the resection and prosthetic replacement of the celiac axis and the pathological studies of the specimen revealed a fibromuscular dysplasia, which seems to be, according to the literature, an exceptional situation, never reported before, thus justifying its publication and dissemination. PMID- 24490199 TI - [Aortic vascular anomalies and Kommerell's diverticulum, an imagiologic diagnosis]. AB - Aortic vascular anomalies are complex anatomic entities requiring often complex and problematic surgical approaches. The authors report the clinical case of a Kommerell's diverticulum and right-sided aortic arch. Right-sided aortic arch is an uncommon congenital defect of the aorta and it is rare in the setting of an otherwise normal heart. A right-sided aortic arch was described more than two centuries ago. Several classifications of these anomalies have been proposed on the basis of the arrangement of the arch vessels, relationships with the esophagus, or the presence of congenital heart anomalies. In the adult population, a right-sided aortic arch is often asymptomatic, unless aneurismal disease develops. This usually occurs at the level of the take-off of an aberrant left subclavian artery and is known as a Kommerell's diverticulum. In spite of its rarity, this condition is clinically relevant due to the mortality associated with rupture, morbidity caused by compression of mediastinal structures, and complexity of surgery. PMID- 24490200 TI - [Endovascular management of a ruptured pseudoaneurysm of a rectal artery]. AB - A 22-years old male patient, with a history of renovascular hypertension, was evaluated in the emergency department for abdominal pain of acute onset, interpreted as acute appendicitis. During surgery, we identified an extensive haemoperitoneum which required conversion to laparotomy without identifying focal hemorrhage. A peri-operative angiography disclosed a parietal irregularity of the upper rectal artery, without active bleeding. The patient remained stable until the 15th postoperative day, when there was clinical deterioration and hemoglobin decrease. Angio-CT revealed the presence of an upper rectal artery pseudoaneurysm with an extensive retroperitoneal and organized hematoma. The patient was proposed for surgical correction which was not carried out due to extensive inflammatory and fibrotic changes, being referred for endovascular exclusion, performed by selective catheterization and coil embolization. The procedure went without complications. Catheterization was performed upstream and downstream of the pseudoaneurysm, with microcatheter, and embolization performed with coils. Control angiography showed no filling of the aneurysm. The patient remained asymptomatic after the procedure, with clinical and analytical stability. Inferior mesenteric artery primary pseudoaneurysms are rare but potentially fatal, with formal indication for treatment, given the risks of free rupture. The use of endovascular techniques allows a minimally invasive approach, with exclusion of the PA, with high rates of primary success. Doubts remain regarding the functionality of the involved organ and long-term recurrence rates; therefore high importance is given to proper follow-up of these patients. PMID- 24490201 TI - [Bockenheimer's syndrome. A clinical report]. AB - The authors report the clinical case of a 12-year-old boy with an extensive superficial venous network in almost every area of the body, present since birth and worsening in recent months, with the occurence of superficial venous thrombosis. No other changes on physical examination were noted, no symptoms and no analytical or imaging findings were found. Histological examination of the lesions revealed ectatic superficial veins without any proliferation of endothelial cells and the amount of elastin in the walls of these veins was decreased. The patient was diagnosed as a Bockenheimer's syndrome. The main features of this rare syndrome are described and discussed. PMID- 24490202 TI - [Contained rupture of pseudo-aneurysms of the internal carotid artery in a case of Behcet's disease]. PMID- 24490204 TI - Design of two and three input molecular logic gates using non-Watson-Crick base pairing-based molecular beacons. AB - This study presents a single, resettable, and sensitive molecular beacon (MB) used to operate molecular-scale logic gates. The MB consists of a random DNA sequence, a fluorophore at the 5'-end, and a quencher at the 3'-end. The presence of Hg(2+), Ag(+), and coralyne promoted the formation of stable T-Hg(2+)-T, C Ag(+)-C, and A2-coralyne-A2 coordination in the MB probe, respectively, thereby driving its conformational change. The metal ion or small molecule-mediated coordination of mismatched DNA brought the fluorophore and the quencher into close proximity, resulting in collisional quenching of fluorescence between the two organic dyes. Because thiol can bind Hg(2+) and remove it from the T-Hg(2+)-T based MB, adding thiol to a solution of the T-Hg(2+)-T-based MB allowed the fluorophore and the quencher to be widely separated. A similar phenomenon was observed when replacing Hg(2+) with Ag(+). Because Ag(+) strongly binds to iodide, cyanide, and cysteine, they were capable of removing Ag(+) from the C Ag(+)-C-based MB, restoring the fluorescence of the MB. Moreover, the fluorescence of the A2-coralyne-A2-based MB could be switched on by adding polyadenosine. Using these analytes as inputs and the MB as a signal transducer, we successfully developed a series of two-input, three-input, and set-reset logic gates at the molecular level. PMID- 24490205 TI - [Not Available]. PMID- 24490206 TI - Noakes misses the point. PMID- 24490207 TI - Noakes' low-carbohydrate, high-fat diet: call for evidence. PMID- 24490208 TI - A laboratorian's experience of implementing multiple point-of-care testing in HIV antiretroviral treatment clinics in South Africa. PMID- 24490209 TI - Pretenders to the throne of affordable healthcare? PMID- 24490210 TI - Discovery Health's take on Regulation 8. PMID- 24490211 TI - RWOPS- light at the end of a dusty tunnel? PMID- 24490212 TI - Partnering up to get Eastern Cape healthcare delivery working. PMID- 24490213 TI - Retraction notice to "Long term toxicity of a Roundup herbicide and a Roundup tolerant genetically modified maize" [Food Chem. Toxicol. 50 (2012) 4221-4231]. PMID- 24490214 TI - South Africa's scientists honoured as global lifesavers. PMID- 24490215 TI - Obesity-a modern pandemic: the burden of disease. PMID- 24490216 TI - Obesity in children and adolescents. A critical review. PMID- 24490217 TI - Developmental origins of obesity and non-communicable disease. PMID- 24490218 TI - Epigenetics of obesity and weight loss. PMID- 24490219 TI - [Non-pharmacological treatment of obesity]. PMID- 24490220 TI - [Pharmacological treatment of obesity]. PMID- 24490221 TI - Obesity and type 2 diabetes in renal pathology. PMID- 24490223 TI - The healthy weight debate: does it apply to weight loss in obesity? PMID- 24490222 TI - Adipose tissue lipases and lipolysis. PMID- 24490224 TI - Obesity and the future. New problems and new solutions. PMID- 24490225 TI - Metabolic surgery for obesity: a critical account. PMID- 24490226 TI - Adipose tissue expandability, lipotoxicity and the metabolic syndrome. PMID- 24490228 TI - Traumatic injury induces changes in the expression of the serotonin 1A receptor in the spinal cord of lampreys. AB - After spinal cord injury (SCI) in mammals, the loss of serotonin coming from the brainstem reduces the excitability of motor neurons and leads to a compensatory overexpression of serotonin receptors. Despite the key role of the serotonin receptor 1a in the control of locomotion, little attention has been put in the study of this receptor after SCI. In contrast to mammals, lampreys recover locomotion after a complete SCI, so, studies in this specie could help to understand events that lead to recovery of function. Here, we showed that in lampreys there is an acute increase in the expression of the serotonin 1A receptor transcript (5-ht1a) after SCI and a few weeks later expression levels go back to normal rostrally and caudally to the lesion. Overexpression of the 5-ht1a in rostral levels after SCI has not been reported in mammals, suggesting that this could be part of the plastic events that lead to the recovery of function in lampreys. The analysis of changes in 5-ht1a expression by zones (periventricular region and horizontally extended grey matter) showed that they followed the same pattern of changes detected in the spinal cord as a whole, with the exception of the caudal periventricular layer, where no significant differences were observed between control and experimental animals at any time post lesion. This suggests that different molecular signals act on the periventricular cells of the rostral and caudal regions to injury site and thus affecting their response to the injury in terms of expression of the 5-ht1a. PMID- 24490230 TI - [Not Available]. PMID- 24490229 TI - Quantification of the interrelationships of receptor pharmacologies within a tricyclic privileged structural scaffold through application of modified forward selection. AB - Many neuropsychiatric drugs interact with more than one molecular target, and therapeutic indices might be improved by prospectively designing compounds with profiles optimized against a combination of targets. The dibenzo-epine scaffold is considered a privileged structure, and this scaffold has been explored rigorously in the search for potential novel neuropharmacologic treatments. Members of this chemical class are known to interact with many receptors and transporters, particularly those of the biogenic amine class. In this study, four points of diversity within a dibenzo-epine scaffold were varied systematically and the pharmacologic profiles of the compounds were assessed across 14 receptors and transporters thought to be important to clinical profiles of efficacy and safety. The resulting data were analyzed using a modified forward selection linear regression procedure, thus revealing potential pharmacophoric relationships of the assessed targets within this chemical class. The results highlight a strong covariance across numerous targets. Moreover, the outcome quantifies the innately problematic issue of prospectively designing compounds with defined affinities across multiple targets. Finally, an exploration of the correspondence of binding affinities to in vitro functional activity reveals an additional layer of complexity central to prospectively designing compounds to engage multiple targets. The apparent relatedness of the 5-HT(2a) and D2 activities suggests that the structural pharmacophores of these receptors overlap more closely with each other than with members of their respective families. PMID- 24490227 TI - Phosphodiesterase 10A inhibitor MP-10 effects in primates: comparison with risperidone and mechanistic implications. AB - Phosphodiesterase 10A (PDE10A) is highly expressed in striatal medium spiny neurons of both the direct and indirect output pathways. Similar to dopamine D2 receptor antagonists acting on indirect pathway neurons, PDE10A inhibitors have shown behavioral effects in rodent models that predict antipsychotic efficacy. These findings have supported the clinical investigation of PDE10A inhibitors as a new treatment for schizophrenia. However, PDE10A inhibitors and D2 antagonists differ in effects on direct pathway and other neurons of the basal ganglia, indicating that these two drug classes may have divergent antipsychotic efficacy and side effect profile. In the present study, we compare the behavioral effects of the selective PDE10A inhibitor MP-10 to those of the clinical standard D2 antagonist risperidone in rhesus monkeys using a standardized motor disability scale for parkinsonian primates and a newly designed "Drug Effects on Nervous System" scale to assess non-motor effects. Behavioral effects of MP-10 correlated with its plasma levels and its regulation of metabolic activity in striatal and cortical regions as measured by FDG-PET imaging. While MP-10 and risperidone broadly impacted similar behavioral domains in the primate, their effects had a different underlying basis. MP-10-treated animals retained the ability to respond but did not engage tasks, whereas risperidone-treated animals retained the motivation to respond but were unable to perform the intended actions. These findings are discussed in light of what is currently known about the modulation of striatal circuitry by these two classes of compounds, and provide insight into interpreting emerging clinical data with PDE10A inhibitors for the treatment of psychotic symptoms. PMID- 24490231 TI - Hierarchical prediction and context adaptive coding for lossless color image compression. AB - This paper presents a new lossless color image compression algorithm, based on the hierarchical prediction and context-adaptive arithmetic coding. For the lossless compression of an RGB image, it is first decorrelated by a reversible color transform and then Y component is encoded by a conventional lossless grayscale image compression method. For encoding the chrominance images, we develop a hierarchical scheme that enables the use of upper, left, and lower pixels for the pixel prediction, whereas the conventional raster scan prediction methods use upper and left pixels. An appropriate context model for the prediction error is also defined and the arithmetic coding is applied to the error signal corresponding to each context. For several sets of images, it is shown that the proposed method further reduces the bit rates compared with JPEG2000 and JPEG-XR. PMID- 24490232 TI - Role of endorectal prostate MRI in patients with initial suspicion of prostate cancer. AB - PURPOSE: To evaluate the role of conventional endorectal prostate MRI in patients with initial suspicion of prostate cancer. MATERIALS AND METHODS: Ethics board approval was received for this retrospective study of 87 men who underwent 1.5 Tesla conventional prostate MRI with a combination of endorectal and body phased array coils for suspected prostate cancer before their first systematic 12-core TRUS-guided biopsy. Three radiologists independently analyzed the images, dividing the prostate into 12 regions corresponding to the biopsy scheme and scoring each region for the presence of prostate cancer on a 5-point scale. Results were analyzed by prostate region. ROC analysis was done and descriptive statistics were calculated. The negative predictive value, specificity, sensitivity and positive predictive value were calculated using dichotomized scores (benign tissue = scores of 1 and 2; malignant tissues = scores of 3, 4, and 5). RESULTS: Biopsy revealed cancer in 47/87 patients (26 low-grade [Gleason score 6]; 21 high-grade [Gleason score >= 3 + 4]), and 184/1044 cores (77 low grade and 107 high-grade) with a median of 3 positive cores per cancer patient (range 1 - 12). The areas under ROC curves were 0.65 - 0.67 for cancer detection by region overall and 0.75 - 0.76 for the detection of high-grade cancer by region. Statistic figures for the detection of all cancers/high-grade cancers by region were as follows: negative predictive value, 87.4 - 88.2 %/92.6 - 93.1 %; specificity, 72.3 - 79.4 %/71.5 - 79.8 %; sensitivity, 49.5 - 54.8 %/62.6 - 69.2 %; and positive predictive value, 29.3 - 34.0 %/29.4 - 34.7 %. CONCLUSION: In patients with suspected prostate cancer, negative MRI findings indicate the absence of high-grade prostate cancer on subsequent TRUS-guided 12-core biopsy with high probability. However, agreement between conventional 1.5-T endorectal prostate MRI and systematic 12-core TRUS-guided biopsy for the detection of prostate cancer appears to be moderate. PMID- 24490233 TI - Whole-brain perfusion CT using a toggling table-technique to predict final infarct volume in acute ischemic stroke. AB - PURPOSE: To evaluate how accurately final infarct volume in acute ischemic stroke can be predicted with perfusion CT (PCT) using a 64-MDCT unit and the toggling table technique. MATERIALS AND METHODS: Retrospective analysis of 89 patients with acute ischemic stroke who underwent CCT, CT angiography (CTA) and PCT using the "toggling table" technique within the first three hours after symptom onset. In patients with successful thrombolytic therapy (n = 48) and in those without effective thrombolytic therapy (n = 41), the infarct volume and the volume of the penumbra on PCT were compared to the infarct size on follow-up images (CT or MRI) performed within 8 days. The feasibility of complete infarct volume prediction by 8 cm cranio-caudal coverage was evaluated. RESULTS: The correlation between the volume of hypoperfusion on PCT defined by cerebral blood volume reduction and final infarct volume was strongest in patients with successful thrombolytic therapy with underestimation of the definite infarct volume by 8.5 ml on average. The CBV map had the greatest prognostic value. In patients without successful thrombolytic therapy, the final infarct volume was overestimated by 12.1 ml compared to the MTT map on PCT. All infarcts were detected completely. There were no false-positive or false-negative results. CONCLUSION: Using PCT and the "toggling table" technique in acute stroke patients is helpful for the rapid and accurate quantification of the minimal final infarct and is therefore a prognostic parameter which has to be evaluated in further studies to assess its impact on therapeutic decision. PMID- 24490234 TI - MR-guided HIFU treatment of symptomatic uterine fibroids using novel feedback regulated volumetric ablation: effectiveness and clinical practice. AB - PURPOSE: To evaluate a novel feedback-regulated volumetric sonication method in MRguided HIFU treatment of symptomatic uterine fibroids. MATERIALS AND METHODS: 27 fibroids with an average volume of 124.9 +/- 139.8 cc in 18 women with symptomatic uterine fibroids were ablated using the new HIFU system Sonalleve (1.5 TMR system Achieva, Philips). 21 myomas in 13 women were reevaluated 6 months later. Standard (treatment) cells (TC) and feedback-regulated (feedback) cells (FC) with a diameter of 4, 8, 12, and 16 mm were used and compared concerning sonication success, diameter of induced necrosis, and maximum achieved temperature. The non-perfused volume ratio (NPV related to myoma volume) was quantified. The fibroid volume was measured before, 1 month, and 6 months after therapy. Symptoms were quantified using a specific questionnaire (UFS-QoL). RESULTS: In total, 205 TC and 227 FC were applied. The NPV ratio was 23 +/- 15 % (2 - 55). The TC were slightly smaller than intended (-3.9 +/- 52 %; range, -100 81), while the FC were 20.1 +/- 25.3 % bigger (p = 0.02). Feedback mechanism is less diversifying in diameter (p < 0.001). Overall, the FC correlate well with the planned treatment diameter (r = 0.79), other than the TC (r = 0.38). Six months after therapy, the fibroid volume was reduced by 45 +/- 21 % (5 - 100) (p = 0.001). The symptoms decreased significantly (p = 0.001). No serious adverse events were recorded. CONCLUSION: Use of volumetric sonication leads to homogenous heating and sufficient necrosis. It is a safe and effective therapy for treating symptomatic uterine fibroids. Successful sonication of feedback cells leads to more contiguous necrosis in diameter PMID- 24490235 TI - Interobserver agreement in mr enterography for diagnostic assessment in patients with Crohn's disease. AB - PURPOSE: To evaluate the extent to which MRE can be used as an observer independent, objective imaging method for the diagnosis and evaluation of CD with respect to the detection of inflammatory changes of the small bowel and lymphadenopathy as diagnostic criterion and bowel distension as a quality criterion. MATERIALS AND METHODS: MRE scans of 84 patients (42 female, median age 37 years) were evaluated independently by 4 experienced radiologists. Analysis of inflammatory changes of the bowel wall, lymphadenopathy and adequate bowel distension was conducted separately for the jejunum, ileum and terminal ileum. The Kendall's W-test was used for the statistical comparison of concordance. RESULTS: In a total of 55 patients, inflammatory activity of the bowel wall was detected and MRE was found to have a high interobserver reproducibility concerning inflammatory changes of the intestinal wall (Kendall's W 0.527 - 0.823). Concerning lymphadenopathy (31 cases, 36.9 %), a low to moderate consensus could be shown with a Kendall's W value of 0.402 - 0.505. For the assessment of adequate bowel distension, a moderate concordance between the operators could be found (Kendall's W 0.497 - 0.581). CONCLUSION: MRE has proven high interobserver agreement with respect to the diagnosis of inflammatory disease activity of the bowel as a diagnostic criterion in patients with CD. Concerning adequate bowel distension as a quality criterion of the examination itself and lymphadenopathy as a diagnostic criterion, moderate interobserver agreement could be found. This is thought to have a rather small effect on the diagnostic significance and conclusiveness of the method in the daily routine. PMID- 24490236 TI - Cue-centered treatment for youth exposed to interpersonal violence: a randomized controlled trial. AB - This study provides preliminary evidence of the feasibility and efficacy of the Stanford cue-centered treatment for reducing posttraumatic stress, depression, and anxiety in children chronically exposed to violence. Sixty-five youth aged 8 17 years were recruited from 13 schools. Participants were randomly assigned to cue-centered treatment or a waitlist control group. Assessments were conducted at 4 discrete time points. Self-report measures assessed youth symptoms of posttraumatic stress disorder (PTSD), anxiety, and depression.Self-report ratings of caregiver anxiety and depression as well as caregiver report of child PTSD were also obtained. Therapists evaluated participants' overall symptom improvement across treatment sessions. Hierarchal linear modeling analyses showed that compared to the waitlist group, the cue-centered treatment group had greater reductions in PTSD symptoms both by caregiver and child report, as well as caregiver anxiety. Cue-centered treatment, a hybrid trauma intervention merging diverse theoretical approaches, demonstrated feasibility,adherence, and efficacy in treating youth with a history of interpersonal violence. PMID- 24490237 TI - Magnetic resonance imaging-based diagnosis of congenital ureterocele. PMID- 24490238 TI - [Incidental finding of a paraganglioma - a "colibri" in differential diagnosis]. PMID- 24490239 TI - [Lung infarction--a diagnostic challenge in the oncologic patient?]. PMID- 24490240 TI - [Ultrasonography is very helpful for diagnosis in children]. PMID- 24490241 TI - [Gastrointestinal bleeding - accurate localization and detection by dual source CT scan]. PMID- 24490242 TI - Moderating effects of a postdisaster intervention on risk and resilience factors associated with posttraumatic stress disorder in Chinese children. AB - This study is an evaluation of a psychosocial intervention involving child and adolescent survivors of the 2008 Sichuan China earthquake. Sociodemographics, earthquake-related risk exposure, resilience using the Connor-Davidson Resilience Scale, and posttraumatic stress disorder (PTSD) using the UCLA-PTSD Index were collected from 1,988 intervention participants and 2,132 controls. Mean resilience scores and the odds of PTSD did not vary between groups. The independent factors for risk and resilience and the dependent variable, PTSD, in the measurement models between control and intervention groups were equivalent. The structural model of risk and 2 resilience factors on PTSD was examined and found to be unequivalent between groups. In contrast to controls, risk exposure (B = -0.32, p <.001) in the intervention group was negatively associated with PTSD. Rational thinking (B = -0.48, p < .001), a resilience factor, was more negatively associated with PTSD in the intervention group. The second resilience factor explored, self-awareness, was positively associated with PTSD in both groups (B = 0.46 for controls, p < .001, and B = 0.69 for intervention, p < .001). Results highlight the need for more cross-cultural research in resilience theory to develop culturally appropriate interventions and evaluation measures. PMID- 24490243 TI - [Early prediction of successful neoadjuvant chemotherapy response]. PMID- 24490244 TI - [Evidence of coronary heart disease: automatic or manual?]. PMID- 24490245 TI - Empirical support for the definition of a complex trauma event in children and adolescents. AB - Complex trauma events have been defined as chronic, interpersonal traumas that begin early in life (Cook, Blaustein, Spinazzola, & van der Kolk, 2003). The complex trauma definition has been examined in adults, as indicated by the Diagnostic and Statistical Manual of Mental Disorders (4th ed.; DSM-IV) field trial; however, this research was lacking in child populations. The symptom presentations of complexly traumatized children were contrasted with those exposed to other, less severe trauma ecologies that met 1 or 2 features of the complex trauma definition. Included in this study were 346 treatment-seeking children and adolescents (ages 3-18 years) who had experienced atraumatic event. Results indicated that child survivors of complex trauma presented with higher levels of generalized behavior problems and trauma-related symptoms than those who experienced (a) acute noninterpersonal trauma, (b) chronic interpersonal trauma that begins later in life, and (c) acute interpersonal trauma. Greater levels of behavioral problems were observed in children exposed to complex trauma as compared to those who experienced a traumatic event that begins early in life. These results provide support for the complex trauma event definition and suggest the need for a complex trauma diagnostic construct for children and adolescents. PMID- 24490246 TI - [Prostatitis vs. prostate cancer - distinction by MRI]. PMID- 24490247 TI - Sociodemographic risk, developmental competence, and PTSD symptoms in young children exposed to interpersonal trauma in early life. AB - Young children are disproportionately exposed to interpersonal trauma (maltreatment, witnessing intimate partner violence [IPV]) and appear particularly susceptible to negative sequelae. Little is known about the factors influencing vulnerability to traumatic stress responses and other negative outcomes in early life. This study examined associations among interpersonal trauma exposure, sociodemographic risk, developmental competence, and posttraumatic stress disorder (PTSD) symptoms in 200 children assessed from birth to first grade via standardized observations, record reviews, and maternal and teacher interviews. More severe PTSD symptoms were predicted by greater trauma exposure (r = .43), greater sociodemographic risk (r = .22), and lower developmental competence (rs=-.31 and -.54 for preschool and school-age developmental competence, respectively). Developmental competence partially mediated the association between trauma exposure and symptoms. Trauma exposure fully mediated the association between sociodemographic risk and symptoms. Neither sociodemographic risk nor developmental competence moderated trauma exposure effects on symptoms. The findings suggest that (a)exposure to maltreatment and IPV has additive effects on posttraumatic stress risk in early life, (b) associations between sociodemographic adversity and poor mental health may be attributable to increased trauma exposure in disadvantaged populations, and (c) early exposures have a negative cascade effect on developmental competence and mental health. PMID- 24490248 TI - [Cancer Diagnosis - 18F-sodiumfluorid/18F-FDG-PET/CT shows promising results. ]. PMID- 24490249 TI - [Arterial hypertension - neurovascular compression as cause?]. PMID- 24490250 TI - Deployment risk and resilience inventory-2 (DRRI-2): an updated tool for assessing psychosocial risk and resilience factors among service members and veterans. AB - The Deployment Risk and Resilience Inventory (DRRI) is a widely used instrument for assessing deployment-related risk and resilience factors among war veterans. A revision of this instrument was recently undertaken to enhance the DRRI's applicability across a variety of deployment-related circumstances and military subgroups. The resulting suite of 17 distinct DRRI-2 scales is the product of a multiyear psychometric endeavor that involved (a) focus groups with Operation Enduring Freedom/Operation Iraqi Freedom (OEF/OIF) veterans to inform an assessment of the content validity of original DRRI measures, (b) examination of item and scale characteristics of revised scales in a national sample of 469 OEF/OIF veterans, and (c) administration of refined scales to a second national sample of 1,046 OEF/OIF veterans to confirm their psychometric quality. Both classical test theory and item response theory analytical strategies were applied to inform major revisions, which included updating the coverage of warfare related stressors, expanding the assessment of family factors throughout the deployment cycle, and shortening scales. Finalized DRRI-2 scales demonstrated strong internal consistency reliability and criterion-related validity. The DRRI 2 can be applied to examine the role that psychosocial factors play in post deployment health and inform interventions aimed at reducing risk and enhancing resilience among war veterans. PMID- 24490251 TI - [Hepatocellular carcinoma - correlation between signal intensity on MRI and degree of differentiation?]. PMID- 24490252 TI - Thinking about trauma: the unique contributions of event centrality and posttraumatic cognitions in predicting PTSD and posttraumatic growth. AB - Researchers have been investigating possible pathways to negative (posttraumatic stress disorder [PTSD]) and positive (posttraumatic growth [PTG]) reactions to trauma in recent decades. Two cognitive constructs, event centrality and posttraumatic cognitions, have been implicated to uniquely predict PTSD symptoms in an undergraduate sample. The current pair of studies attempted to (a) replicate this finding in an undergraduate sample, (b) replicate this finding in a treatment-seeking sample, and (c) explore whether these 2 cognitive constructs uniquely predict PTG. The first study consisted of 500 undergraduate students, whereas the second study consisted of 53 treatment-seeking clients. Results indicated both posttraumatic cognitions and event centrality uniquely predicted PTSD in the undergraduate (R(2) = .46) and treatment-seeking samples (R(2) = .46). These 2 cognitive constructs also predicted PTG in the undergraduate sample (R(2) = .37), but only posttraumatic cognitions predicted PTG in the treatment seeking sample (R(2) = .17). The relationships between PTG varied, depending on whether PTG for high or low event-centrality events were assessed. The original model was supported within both populations for PTSD symptoms, and its extension to PTG was supported within the treatment-seeking sample. These results underscore cognitive and narrative factors in the progression of trauma. PMID- 24490253 TI - ["Certification of Jewish physicians will expire 30 September 1938" - 75 years ago the National Socialism lawmakers withdrew the state professional licensure of physicians]. PMID- 24490254 TI - The bidirectional dyadic association between tendency to forgive, self-esteem, social support, and PTSD symptoms among terror-attack survivors and their spouses. AB - This study examined the dyadic association of terror attack survivors' and spouses' internal resources, tendency to forgive (self, others,and situational forgiveness), self-esteem, and the external resource of social support, as associated with victims' and spouses' posttraumatic stress disorder (PTSD) symptoms, using the actor-partner interdependence model. Based on lists by the One Family organization in Israel, 108 couples participated in the study. The study results demonstrate that in the dyad relationship, survivors' tenden cyto forgive others and social support relate both to survivors' decreased levels of PTSD symptom severity (beta = -.20, p = .021;beta =-.55 p < .001) and spouses' decreased levels of PTSD symptom severity (beta =-.21, p = .015; beta =-.27, p = . 004), whereas spouses' self-esteem relates to both spouses' and survivors' decreased levels of PTSD symptom severity (beta =-.57, p < .001; beta =-.14, p = .041).The findings underscore the role of the survivor-spouse unit by highlighting the dyad relationship of internal and external resources as associated with both survivors' and spouses' PTSD symptoms. Theoretical and clinical implications of the findings are discussed. PMID- 24490255 TI - [Evaluating the methodologic quality of systematic reviews and meta-analyses. AMSTAR (A Measurement Tool for the Assessment of Multiple Systematic Reviews]. PMID- 24490256 TI - Role of preprocedural computed tomography in transcatheter aortic valve implantation. AB - Transcatheter aortic valve implantation (TAVI) is currently considered an acceptable alternative for the treatment of patients with severe aortic stenosis and a high perioperative risk or a contraindication for open surgery. The benefit of TAVI significantly outweighs the risk of the procedure in patients requiring treatment that are not suitable for open surgery, and leads to a lower mortality in the one-year follow-up. The absence of a direct view of the aortic root and valve remains a challenge for the transcatheter approach. While direct inspection of the aortic valve during open surgery allows an adequate prosthesis choice, it is crucial for TAVI to know the individual anatomical details prior to the procedure in order to assure adequate planning of the procedure and proper prosthesis choice and patient selection. Among the imaging modalities available for the evaluation of patients prior to TAVI, computed tomography (CT) plays a central role in patient selection. CT reliably visualizes the dimensions of the aortic root and allows a proper choice of the prosthesis size. The morphology of the access path and relevant comorbidities can be assessed. The present review summarizes the current state of knowledge regarding the value of CT in the evaluation of patients prior to TAVI. CT plays a central role in patient selection and planning prior to TAVI. CT reliably detects the dimensions of the aortic root including the size of the aortic annulus, the degree of valve calcification and the morphology of the access routes. KEY POINTS: CT plays a central role in patient selection and planning prior to TAVI. CT reliably detects the dimensions of the aortic root including the size of the aortic annulus, the degree of valve calcification and the morphology of the access routes. CT provides a more accurate measurement of the aortic annulus than 2D TEE and CT is the only imaging modality that allows a risk assessment for paravalvular leakages based on the calcification of the aortic valve. PMID- 24490257 TI - Whole-body-MR-diffusion weighted imaging in oncology. AB - The clinical implementation of whole body diffusion weighted imaging (WB-DWI) for tumor-detection, -characterization and therapy monitoring is well underway. The method is fast, robust and combined with its wide availability on modern MRI scanners, it has a vast potential clinical impact. Owing to the high tumor to background contrast, its main application areas are simple detection of tumor suspicious lesions (primary tumor, recurrence, and metastasis), tumor grading and therapy monitoring.WB-DWI has a strong diagnostic potential regarding the evaluation of bone marrow and its diseases and as thus, tumor detection and therapy monitoring of bone metastasis is of particular interest. The assessment of a lymphatic tumor spreading is constricted. One of the major hurdles that still hamper the wide clinical application of WB-DWI is a lack of standardization of measurement parameters that limit the comparability. of current research results. KEY POINTS: Owing to the high tumor to background contrast WB-DWI allows fast assessment of tumor distribution and total tumor burden. WB-DWI allows therapy monitoring. WB-DWI is widely available. PMID- 24490258 TI - Radiofrequency ablation of osteoid osteomas: analgesia and patient satisfaction in long-term follow-up. AB - PURPOSE: To review the long term clinical outcomes in the treatment of osteoid osteoma (OO) using radiofrequency ablation (RFA). MATERIALS AND METHODS: Our retrospective study included 59 patients who were treated in the period from April 2001 to December 2012 due to a symptomatic OO using RFA. Here, the occurrence of complications and postoperative recurrence, as well as postoperative patient satisfaction were examined. Patients satisfaction was assessed by means of a telephone interview with the visual analogue scale (VAS). RESULTS: Mean follow-up was 50 months (2 -116 months). The average size of the nidus was 6mm (range 2 - 14 mm). After initial radiofrequency ablation 11.8 % (7/59) of patient showed a recurrence of symptoms. Symptoms could successfully be treated by a second ablation in 5 patients. Assisted success rate was therefore 96.6 % (57/59). The complication rate was 5.1 % (2 major and one minor complication). Furthermore we report a very high patient satisfaction and acceptance of therapy. CONCLUSION: RFA is a very successful therapy of symptomatic OOs with a high patient satisfaction. KEY POINTS: Osteoid osteomas (OO) are rare benign bone tumors of the childhood and adolescence. Treatment of OOs with minimal-invasive radiofrequency ablation (RFA) shows a high patient satisfaction. RFA is by now the standard therapy of symptomatic OOs. PMID- 24490259 TI - [Procedures requiring pre-approval according to the radiology diagnosis and therapy agreement]. PMID- 24490260 TI - Guest editorial for special section on BSB 2012. PMID- 24490261 TI - Man versus microbe: warfare at its worst. PMID- 24490262 TI - Retraction. PMID- 24490263 TI - Governing NAPNAP. PMID- 24490266 TI - Doxycycline for stabilization of abdominal aortic aneurysms: a randomized trial. AB - BACKGROUND: Doxycycline inhibits formation and progression of abdominal aortic aneurysms (AAAs) in preclinical models of the disease, but it is unclear whether and how this observation translates to humans. OBJECTIVE: To test whether doxycycline inhibits AAA progression in humans. DESIGN: Randomized, placebo controlled, double-blind trial. (Dutch Trial Registry: NTR 1345) SETTING: 14 Dutch hospitals. PATIENTS: 286 patients with small AAAs between October 2008 and June 2011. INTERVENTION: Daily dose of 100 mg of doxycycline (n = 144) or placebo (n = 142) for 18 months. MEASUREMENTS: The primary outcome measure was aneurysm growth at 18 months, as estimated by repeated single-observer ultrasonography. Secondary outcomes included growth at 6 and 12 months and the need for elective surgery. RESULTS: Mean aneurysm diameter (approximately 43 mm) and other baseline characteristics were similar in both groups. Doxycycline treatment was associated with increased aneurysm growth (4.1 mm in the doxycycline group vs. 3.3 mm in the placebo group at 18 months; difference, 0.8 mm [95% CI, 0.1 to 1.4 mm]; P = 0.016 mm). Twenty-one patients receiving doxycycline and 22 patients receiving placebo had elective surgical repair (Kaplan-Meier estimates were 16.1% for those receiving doxycycline and 16.5% for those receiving placebo; difference, -0.4% [CI, -9.3% to 8.5%]; P = 0.83). Time to repair was similar in the groups (P = 0.92). LIMITATIONS: This study focuses on patients with small AAAs. As such, whether the data can be extrapolated to larger AAAs (>55 mm) is unclear. The high number of elective repairs (n = 43) was unanticipated. Moreover, the study did not follow patients who withdrew because of an adverse effect. CONCLUSION: This trial found that 18 months of doxycycline therapy did not reduce aneurysm growth and did not influence the need for AAA repair or time to repair. PRIMARY FUNDING SOURCE: The Netherlands Organisation for Health Research and Development, and the NutsOhra Fund. PMID- 24490267 TI - The role of palliative care in medical education. PMID- 24490265 TI - Long-term multivitamin supplementation and cognitive function in men: a randomized trial. AB - BACKGROUND: Despite widespread use of multivitamin supplements, their effect on cognitive health-a critical issue with aging-remains inconclusive. To date, no long-term clinical trials have studied multivitamin use and cognitive decline in older persons. OBJECTIVE: To evaluate whether long-term multivitamin supplementation affects cognitive health in later life. DESIGN: Randomized, double-blind, placebo-controlled trial of a multivitamin from 1997 to 1 June 2011. The cognitive function substudy began in 1998. Up to 4 repeated cognitive assessments by telephone interview were completed over 12 years. (ClinicalTrials.gov: NCT00270647) SETTING: The Physicians' Health Study II. PATIENTS: 5947 male physicians aged 65 years or older. INTERVENTION: Daily multivitamin or placebo. MEASUREMENTS: A global composite score averaging 5 tests of global cognition, verbal memory, and category fluency. The secondary end point was a verbal memory score combining 4 tests of verbal memory, which is a strong predictor of Alzheimer disease. RESULTS: No difference was found in mean cognitive change over time between the multivitamin and placebo groups or in the mean level of cognition at any of the 4 assessments. Specifically, for the global composite score, the mean difference in cognitive change over follow-up was -0.01 SU (95% CI, -0.04 to 0.02 SU) when treatment was compared with placebo. Similarly, cognitive performance did not differ between the multivitamin and placebo groups on the secondary outcome, verbal memory (mean difference in cognitive change over follow-up, -0.005 SU [CI, -0.04 to 0.03 SU]). LIMITATION: Doses of vitamins may be too low or the population may be too well-nourished to benefit from a multivitamin. CONCLUSION: In male physicians aged 65 years or older, long-term use of a daily multivitamin did not provide cognitive benefits. PRIMARY FUNDING SOURCE: National Institutes of Health, BASF, Pfizer, and DSM Nutritional Products. PMID- 24490268 TI - Enough is enough: Stop wasting money on vitamin and mineral supplements. PMID- 24490269 TI - Abdominal aortic aneurysm: still no pill. PMID- 24490270 TI - Chronic nandrolone administration induces dysfunction of the reward pathway in rats. AB - Data in animal models and surveys in humans have revealed psychiatric complications of long-term anabolic androgenic steroid abuse. However, the neurobiochemical mechanisms behind the observed behavioral changes are poorly understood. The aim of the present study was to investigate the effects of nandrolone decanoate on emotional behavior and neurochemical brain alterations in gonadally intact male rats. The behavioral reactivity to the elevated plus maze and the social interaction test was used to assess anxiety-related symptoms, and the sucrose preference test was used to evaluate anhedonia. Dopaminergic, serotonergic and noradrenergic transmissions were also evaluated in selected brain areas. The chronic administration of nandrolone, at 5 mg kg(-1) injected daily for 4 weeks, induced the loss of sweet taste preference, a sign of anhedonia and dysfunction of the reward pathway. The behavioral outcomes were accompanied by reductions in the dopamine, serotonin and noradrenaline contents in the nucleus accumbens. Alterations in the time spent in the open arms and in the social interaction test were not found, suggesting that nandrolone did not induce an anxiogenic profile. No differences were revealed between the experimental groups in the amygdala in terms of the neurotransmitters measured. Our data suggest that nandrolone-treated rats have a depressive, but not anxiogenic-like, profile, accompanied by brain region-dependent changes in dopaminergic, serotonergic and noradrenergic neurotransmission. As anabolic androgenic steroid dependence is plausibly the major form of worldwide substance dependence that remains largely unexplored, it should be highlighted that our data could contribute to a better understanding of the altered rewards induced by nandrolone treatment and to the development of appropriate treatments. PMID- 24490264 TI - Oral high-dose multivitamins and minerals after myocardial infarction: a randomized trial. AB - BACKGROUND: Whether high-dose multivitamins are effective for secondary prevention of atherosclerotic disease is unknown. OBJECTIVE: To assess whether oral multivitamins reduce cardiovascular events and are safe. DESIGN: Double blind, placebo-controlled, 2 x 2 factorial, multicenter, randomized trial. (ClinicalTrials.gov: NCT00044213) SETTING: 134 U.S. and Canadian academic and clinical sites. PATIENTS: 1708 patients aged 50 years or older who had myocardial infarction (MI) at least 6 weeks earlier and had serum creatinine levels of 176.8 mol/L (2.0 mg/dL) or less. INTERVENTION: Patients were randomly assigned to an oral, 28-component, high-dose multivitamin and multimineral mixture or placebo. MEASUREMENTS: The primary end point was time to total death, recurrent MI, stroke, coronary revascularization, or hospitalization for angina. RESULTS: The median age was 65 years, and 18% of patients were women. The qualifying MI occurred a median of 4.6 years (interquartile range [IQR], 1.6 to 9.2 years) before enrollment. Median follow-up was 55 months (IQR, 26 to 60 months). Patients received vitamins for a median of 31 months (IQR, 13 to 59 months) in the vitamin group and 35 months (IQR, 13 to 60 months) in the placebo group (P = 0.65). Totals of 645 (76%) and 646 (76%) patients in the vitamin and placebo groups, respectively, completed at least 1 year of oral therapy (P = 0.98), and 400 (47%) and 426 (50%) patients, respectively, completed at least 3 years (P = 0.23). Totals of 394 (46%) and 390 (46%) patients in the vitamin and placebo groups, respectively, discontinued the vitamin regimen (P = 0.67), and 17% of patients withdrew from the study. The primary end point occurred in 230 (27%) patients in the vitamin group and 253 (30%) in the placebo group (hazard ratio, 0.89 [95% CI, 0.75 to 1.07]; P = 0.21). No evidence suggested harm from vitamin therapy in any category of adverse events. LIMITATION: There was considerable nonadherence and withdrawal, limiting the ability to draw firm conclusions (particularly about safety). CONCLUSION: High-dose oral multivitamins and multiminerals did not statistically significantly reduce cardiovascular events in patients after MI who received standard medications. However, this conclusion is tempered by the nonadherence rate. PRIMARY FUNDING SOURCE: National Institutes of Health. PMID- 24490271 TI - Miracle on 39th Street. PMID- 24490272 TI - Summaries for patients. High-dose multivitamins and minerals after a heart attack. PMID- 24490273 TI - Summaries for patients. Does long-term multivitamin supplementation help cognitive function in men? PMID- 24490274 TI - Vitamin D and calcium supplementation to prevent fractures in adults. PMID- 24490275 TI - Methylprednisolone injections for the carpal tunnel syndrome. PMID- 24490276 TI - Methylprednisolone injections for the carpal tunnel syndrome. PMID- 24490277 TI - "Metal-free" catalytic oxygen reduction reaction on heteroatom- doped graphene is caused by trace metal impurities. AB - The oxygen reduction reaction (ORR) is of high industrial importance. There is a large body of literature showing that metal-based catalytic nanoparticles (e.g. Co, Mn, Fe or hybrid Mn/Co-based nanoparticles) supported on graphene act as efficient catalysts for the ORR. A significant research effort is also directed to the so-called "metal-free" oxygen reduction reaction on heteroatom-doped graphene surfaces. While such studies of the ORR on nonmetallic heteroatom-doped graphene are advertised as "metal-free" there is typically no sufficient effort to characterize the doped materials to verify that they are indeed free of any trace metal. Here we argue that the claimed "metal-free" electrocatalysis of the oxygen reduction reaction on heteroatom-doped graphene is caused by metallic impurities present within the graphene materials. PMID- 24490278 TI - [Spinal marrow development in Japanese quail embryos and chicklings in the spaceflight environment]. AB - Results of studying spinal marrow histogenesis in age varying Japanese quail embryos and chicklings whose embryonic development took place in microgravity are presented. Histological comparison of spinal cords showed retardation of morphogenetic development, lumber spine especially, in the group of flight embryos manifested as incomplete proliferative activity during migration processes and nervous cell differentiation. Like on earth, in space microgravity chicklings also hatched on day 17 of embryogenesis. Multiform marrow changes in space chicklings were a nervous cells reaction to the functional state of organism in the micro-g environment. PMID- 24490279 TI - [Light microscopy of statocyst cell elements from Helix lucorum (space experiment aboard the orbital station "MIR")]. AB - Statocyst epithelial lining of terrestrial pulmonary snail Helix lucorum is a spatially arranged structure consisting of 13 cell ensembles. Each ensemble has a sensory cell surrounded by companion cells. The sensory cell on the anterior statocyst pole is star-shaped due to multiple protoplasmatic protrusions on its body. The remaining 12 polygon-shaped cells form 3 tires along the statocyst internal perimeter: anterior, middle or equatorial and posterior. There are 4 cells in each tire. Topography of every sensory cell on the statocyst internal surface was described as well as cell nuclei size and form, nucleoli number and patterns of cytoplasm vacuolization. Space free of sensory cells is occupied by supporting or intercalary cells. Exposure to space microgravity over 40, 43, 102 and 135 days aboard the orbital station MIR affected morphology of the sensory cells. Specifically, this appeared as reductions in cell height and, consequently, extension of the statocyst cavity internal diameter and volume in the space-flown snails. PMID- 24490280 TI - [Spatial orientation of pilot using a cockpit exterior surveillance system]. AB - Spatial orientation of pilots using a cockpit exterior surveillance system was tested in real nighttime helicopter flights. Major factors complicating adequate spatial orientation and provoking visual illusions in pilots are lack of information for spatial depth (relation) perception in two-dimensional TV images altering their position along the horizontal and vertical lines of trajectory and simultaneous piloting and target search-identification operations. Reliability of pilot's spatial orientation could be improved by displaying on the exterior imaging screen also relevant flight navigation parameters. PMID- 24490281 TI - [Psychophysiological correlates of individual styles of professional operator's work]. AB - One of the prioritized objectives of psychophysiological support for long duration space missions is to strengthen professional reliability of cosmonauts. Operator's reliability is dependent as on skillfulness, so individual work style. PILOT-1 and VIRTU methods were used to study individual psychological characteristics and operator's strategy during project MARS500. The established two individual work styles (IWSs), i.e. control and search, reflect different types of reacting to stress. Combined analysis of these data and results of the "Mirror coordinograph" test showed invariance of IWSs no matter whether a task is complicated or simple. Operators demonstrating the "control" strategy are characterized by high initial mobilization readiness. Their reliability demands great physiological resources (high "cost"). Initial mobilization and physiological "cost" are lower in operators demonstrating the "search" work style. Dependent on the level of mobilization and motivation, their efficacy, in terms of quality and reliability specifically, is unstable in nature. PMID- 24490282 TI - [Evaluation of acoustic effectiveness of personnel protectors from extra-aural exposure to aviation noise]. AB - Purpose of the investigation was to validate testing acoustic effectiveness of a personnel vest-like protector (PP) from extra-aural exposure to aviation noise. Levels of aviation noise for PP testing were determined through calculation. Vest effectiveness in protecting from acoustic vibration generated by high-intensity aviation noise was evaluated both in laboratory and field tests. For comparison analysis, PP was also tested with a dummy exposed on a special tester, i.e. acoustic interferometer. PMID- 24490283 TI - [Morphofunctional evaluation of different parts of the cerebral cortex after ionizing radiation exposure]. AB - The investigation has the aim to compare reactions of phylogenetically different parts of the brain cortex to single and fractionated irradiation by 1 Gy. The focus is primarily laid on unveiling the morphological stage of radiation-induced changes in the cortex. A hundred of 100 nubilous male rats with the body mass of 200-230 g were subject to whole-body uniform single and fractionated gamma irradiation (total dose absorption over 5 days) with MeV spectrum 1.2 at 1 Gy (dose rate--50 cGy/h). Sampling of cortex motoria secundaria, cortex prelimbicus, hippocampus fields CA1-CA4, dentate fascia and cortex piriformis was conducted in a day, 6, 12 and 18 months after exposure. Brain sections were fixated in 10% formalin solution and then embedded in paraffin. Paraffin sections were stained by Karachi hematoxylin-eosin for review and Nissl methylene blue for cytoarchitectonics studies. In samples of every animal, 300 neurocytes were counted with careful examination of distinct changes in cell form, uniformity of cytoplasm staining, level of nucleus and nucleolus differentiation and Nissl substance basophilia. Late reparation of damaged neurocytes was observed after fractionated irradiation. Evidence of changes and time of compensation of damaged neurocytes correlate with method of irradiation, length of post-irradiation period and phylogenetic age of the cortex. PMID- 24490284 TI - [Cytogenetic investigations of mice marrow cells after isolated chronic exposure to radiation and chemical factors, and combined sequential exposure to these factors]. AB - The article presents data on chromosomal aberrations in bone marrow cells of mice following isolated exposure to gamma-radiation and chemical factor within the existing MPCs for piloted spacecraft, and also combined sequential exposure in the ranges predicted for interplanetary missions. In the event of chronic exposure the relative number of chromosomal aberrations goes up till reaching plateau and is governed strictly by the mathematical dependence on effective residual gamma-dose and effective damage of organism from inhaled chemical factor. Sequential exposure to the radiation and chemical factors within the ranges specified for orbital and remote space missions caused a tangible reduction of the speed of cytogenetic damages reparation in postexposure period which may be interpreted as depletion of the body reserve and compensatory recovery potential. PMID- 24490285 TI - [Effect of a mineral organic complex on mice radioresistance]. AB - Experiments showed that drinking water supplemented with a complex of 12 microelements and organic acids stimulates body mass gain and strengthening of radioresistance in mice. Obviously, availability of water with the mineral and organic complex before and after irradiation was the factor in survival of a part of mice exposed to the absolutely lethal dose (7.6 Gy from gamma-quanta 60Co) and reduction of chromosomal aberrations rate in bone marrow cells in consequence of nonlethal (1 Gy) irradiation. PMID- 24490286 TI - [Light-isotope water as a therapeutic agent for acute radiation disease]. AB - Eighty outbred CD-I male and female mice (initial body mass of 31-34 g) and 40 male Wistar rats (initial body mass of 280-360 g) were randomly distributed into the experimental and control groups by sex and body mass. According to the results of experiments, consumption of rectified light-isotope water over 30 days immediately after irradiation by gamma-quanta 60Co at 5 Gy and 6.5 Gy can increase survivability rate significantly, accelerate hemopoiesis recovery and prevent body mass loss in irradiated animals. Therefore, light-isotope water can be considered as an effective agent for treatment of the bone marrow syndrome. PMID- 24490287 TI - [Two-week magnetic deprivation does not alter rheologic parameters of rat's erythrocytes]. AB - Purpose of the work was to explore likelihood of impairment of erythrocytes deformation and aggregation properties in a compensated magnetic field of the Earth. It was shown that complete magnetic deprivation does not alter rat's hemorheology substantially. Stress-related changes were found neither in blood nor adrenals of the animals. PMID- 24490289 TI - [Development of a minerals supply system for plants in a conveyor-type space greenhouse]. AB - The paper presents ideas of optimizing the mineral nutrition system for salad crops in a space greenhouse. Experiments showed that to use mineral-saturated fiber ionite BIONA-V3 as an artificial soil will require to upmass a lot of expandable materials because of low specific content of nutrients. An additionally mineralized fiber soil makes possible to reduce mass of ionite in 5.6 times and volume in 28 times. The proposed mineral supply system is composed of two enrichment catridges with granulated ionite BIONA-V3 and slow-releasing fertilizer Osmocote 114-14-4, and a controller of irrigation water electric conduction stabilizer. Tests showed that this system provides sufficient mineral nutrition to plants and can be recommended for in-flight testing. PMID- 24490288 TI - [Investigation of the copper content in blood serum and its ultrafiltrate in the conditions of experimental space flight simulation]. AB - In experiment MARS-500 on remote space flight simulation, atomic emission spectral analysis with inductively coupled argon plasma was used to measure serum copper and its ultrafiltration fraction. It was shown that, in contrast to baseline data, the Cu serum level varied within the normal physiological boundaries throughout the entire simulation experiment. These variations were sync in all the serum samples. In several periods in the experiment reductions in serum Cu within the baseline range were equivalent to simultaneous reductions in ceruloplasmin. Amount of the free Cu (ultrafiltration) fraction, i.e. not bound to proteins in blood serum, was constant at all times. Since the simulation experiment is not a perfect analogy of space flight because of nonreproducibility of some factors, ionizing radiation specifically, we should take into consideration shifts in the serum copper balance caused by the action of space radiation on human organism. Radiation-induced imbalance is not only a marker of disturbed oxidase function of blood but also points to a mechanism of potential pathological outcome of toxic excessive copper accumulated in the brain, liver and kidney. PMID- 24490290 TI - [84th Congress of Aerospace Medical Association (AsMA)]. PMID- 24490291 TI - [Effectiveness of implementing sociopsychological, medicoengineering and ergonomic recommendations in aviation and space exploration]. PMID- 24490292 TI - [Expression and significance of lymphocytes in chronic rhinosinusitis]. AB - OBJECTIVE: To investigate the B lymphocytes(CD20) and T-lymphocyte subsets (CD4, CD8) expression and clinical significance in chronic rhinosinusitis. METHOD: Immunohistochemical technique was applied to detect the expression of the B lymphocytes (CD20), helper T lymphocytes (CD4) and the cytotoxic T lymphocyte (CD8) in 15 patients with chronic rhinosinusitis without nasal polyps group (CRSsNP). 12 patients of chronic nasal sinusitis with nasal polyp (CRSwNP), 7 cases of recurrent CRSwNP group and 13 patients with inferior turbinate mucosa in the control group. The Mann-Whitney U test was used to analyze CD)20, CD4 and CD8 between the experimental groups and the control group. One- Way ANOVA was used to compare the lymphocyte infiltration between the experiment groups. RESULT: Patients with CRS had higher infiltration of the B lymphocytes (CD20) and T lymphocyte subsets (CD4, CD88) than the patients of the control group (P < 0.05). The expression of T lymphocyte subsets (CD4, CD8) in CRSwNP and recurrent CRSwNP groups was significantly higher than in CRSsNP (P < 0.05). The expression of CD4 in the recurrent CRSwNP group was obviously higher than that in CRSsNP and CRSwNP (P < 0.01). CONCLUSION: The B lymphocytes, helper T cells and cytotoxic T cells have the high expression in CRS groups, which involved with the formation of inflammation. Furthermore nasal polyps are closely related to T lymphocyte infiltration. PMID- 24490293 TI - [Negative T-waves--always pathologic?]. PMID- 24490295 TI - [Diabetics on intensive care unit: increased glucose values are positive]. PMID- 24490294 TI - [Common mechanism: ketamine, propofol and sevoflurane]. PMID- 24490296 TI - [Analgesia for painful patient transfer]. PMID- 24490297 TI - [ARDS postoperatively: what conditions are essential?]. PMID- 24490298 TI - [Shouldering heavy responsibilities on prevention and treatment of hepatitis C]. PMID- 24490299 TI - [Present situation of hepatitis C virus antiviral therapy and application prospects of small molecule drugs in our country]. PMID- 24490300 TI - [The relevant factors and strategies related efficacy with standard of care in chronic hepatitis C treatment naive patients]. PMID- 24490301 TI - [Achieve a higher cure rate via standardized antiviral therapy for chronic hepatitis C]. PMID- 24490302 TI - [How to improve the efficacy of antiviral therapy on patients with hepatitis C related cirrhosis]. PMID- 24490304 TI - [The relevant factors and principles of therapy to relapse chronic hepatitis C]. PMID- 24490305 TI - [Discussions on treatment failure causes and principles of chronic hepatitis C patients]. PMID- 24490303 TI - [Current perspectives on antiviral therapy in hepatitis C-infected patients with decompensated cirrhosis]. PMID- 24490306 TI - [Recommendations for the clinical application of transient elastography in liver fibrosis assessment]. PMID- 24490307 TI - [Distribution of HBV genotypes and clinical characteristics of HBV-related hepatocellular carcinoma patients in Deyang District, Sichuan Province]. PMID- 24490308 TI - [The difference of anti-virus effect between different modified antisense oligonucleotides in vitro]. PMID- 24490309 TI - [Current advances in the understanding of HBeAg relation to immune tolerance]. PMID- 24490310 TI - Author's reply: To PMID 23793318. PMID- 24490311 TI - Authors' reply. PMID- 24490312 TI - Authors' reply. PMID- 24490313 TI - Disproportionality in safety warnings: the AVMA responds. PMID- 24490314 TI - Authors' reply. PMID- 24490315 TI - Authors' reply. PMID- 24490316 TI - [Application of custom casting separate post-and-core crown restorations of titanium in molar defects with low occlusogingival distance]. AB - PURPOSE: To evaluate the clinical effect of custom casting separate post-and-core crown restorations of titanium in residual molar roots and crows with low occlusogingival distance. METHODS: Twenty-two residual roots and crowns with low occlusogingival distance were involved in the study. The root canals were prepared according to their natural directions without concerning about the common path of insertion and then the preparation of abutment teeth were made following the routine clinical procedure. Accurate impression was taken with silicone to fabricate the custom casting separate post-and-core crown restorations of Ti. The two parts were cemented together with resin cement. RESULTS: All the 22 fixed restorations were found to be with good retention and without looseness, falling off or breaking off of the roots.They all used normally for 6-30 months. CONCLUSIONS: Custom casting separate post-and-core crown of Ti is a better prosthetic restoration for molar residual root and crown with low occlusogingival distance. PMID- 24490317 TI - Perception of inter-professional education (IPE) among laypersons in a Japanese rural area. AB - Many overseas healthcare researchers have advocated the importance of inter professional education (IPE). However, to what extent laypersons, who reside in Japanese rural areas, understand IPE is not well known. To clarify this issue, we interviewed laypersons regarding their perception of IPE. We selected one rural area in Japan, where over 40% of the residents were more than 65 years old. Participants, who had an interest in their community healthcare system, were nominated. Semi-structured interviews of approximately 60 minutes were performed and topics focused on were: 1. laypersons' perception of IPE, 2. laypersons' views on educating future medical professions, and 3. what laypersons could contribute to the educating of future medical professionals. Nine participants (58 to 88 years, 1 female and 8 males, mean 76 years) took part. We found three common themes among the interviewees. These were: 1. little knowledge about IPE, 2. positive attitudes towards educating future medical professionals, 3. original ideas concerning how to educate medical professionals. We also found that laypersons in this rural region did not fully understand IPE. As one potential educational method, we should promote IPE involving laypersons. For future study, we plan to explore medical professionals' opinions, and compare them with those of laypersons'. PMID- 24490318 TI - A framework to aid VNA implementation. PMID- 24490319 TI - Advancing imaging informatics: Looking at the leading edge in accessibility of images across the medical enterprise. PMID- 24490320 TI - Getting out of the compliance mindset: doing more with data security. Leading healthcare organizations have tackled the growing issue of data security through different technologies. PMID- 24490321 TI - Guiding I.T. strategy. At the helm of the vast Cleveland Clinic, CIO C. Martin Harris, M.D. reflects on next steps. Interview by Mark Hagland. PMID- 24490322 TI - Delivering data in real time. How Martin's Point Health Care has leveraged its data for effective population health management. PMID- 24490323 TI - The real-world experiences of Medicare ACOs. Executives of three medical groups discuss their experiences and the challenges of being part of the Medicare accountable care program. PMID- 24490324 TI - Discharged with a recording. How Cullman Regional is optimizing readmissions work. PMID- 24490325 TI - Staying on top. Using business intelligence to improve quality of care. PMID- 24490326 TI - Paying it forward. The different styles and many benefits of the mentoring process. PMID- 24490327 TI - [Clinical guidelines for diagnosing, treatment and monitoring patients with testicular cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. AB - Testicular tumors are the most common solid tumors in men between 15 and 34 years of age. The worldwide incidence of these tumors has doubled in the past 40 years. Germ cell tumors comprise 95% of malignant tumors arising in the testes and they are classified either as seminoma or nonseminoma. Testicular cancers have a high cure rates even in disseminated stage of the disease. The chemotherapy mostly contributed to these results but surgery is an inevitable part of successful treatment. In a significant number of these patients treatment algorithms with minimum side effects are designed with the intention to maintain same cure rates as previously used, more aggressive therapy. The following text presents the clinical guidelines in order to standardize the procedures and criteria for diagnosis, management, treatment and follow-up of patients with testicular cancer in Republic of Croatia. PMID- 24490329 TI - [Clinical guidelines for diagnosing, treatment and monitoring patients with prostate cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. AB - Prostate adenocarcinoma is the second most common solid neoplasm in male population in Croatia. It rarely causes symptoms unless it is advanced. The finding of PSA rise is the most common reason for diagnostic workout. Treatment plan is based on TNM classification, Gleason score and PSA. Clinically localized disease is successfully treated by radical prostatectomy or radiotherapy with or without hormonal therapy. Locally advanced disease is treated with radiotherapy and hormonal therapy. Metastatic disease can be controlled for many years by androgen deprivation. For castration resistant disease appropriate treatment is chemotherapy or secondary hormonal therapy. The following paper presents the clinical guidelines in order to standardize procedures and criteria for the diagnosis, management, management, treatment and monitoring of patients with prostate cancer in the Republic of Croatia. PMID- 24490328 TI - [Clinical guidelines for diagnosing, treatment and monitoring patients with bladder cancer--Croatian Oncology Society and Croatian Urology Society, Croatian Medical Association]. AB - Urothelial cancer is the most common bladder cancer. Hematuria is the most common presenting symptom in patients with bladder cancer. The most common diagnostics of bladder cancer is performed by transurethral resection of bladder after which pathohistological diagnosis is set. It is necessary to determine whether the cancer penetrated in muscle layer (muscle-invasive cancer) or not (muscle noninvasive cancer). Decision on therapeutic modality depends on the clinical stage of disease and on prognostic and risk factors. For muscle non-invasive bladder cancer transurethral resection is preferred with or without intravesical instillation of Bacillus Calmette-Guerin (BCG). For invasive cancer the method of choice is radical cystectomy. Radiotherapy is used in radical and palliative purposes. Metastatic disease is most frequently treated by chemotherapy metotrexate/vinblastine/doxorubicine/cisplatin (MVAC) or gemcitabine/cisplatin (GC). The purpose of this article is to present clinical recommendations to set standards of procedures and criteria in diagnostics, treatment and follow up of patients with bladder cancer in the Republic of Croatia. PMID- 24490330 TI - [Parathyroid hormone values in thyroid gland surgeries by harmonic scalpel and by conventional methods]. AB - We have examined if there are any differences in intraoperative and early postoperative concentrations of parathyroid hormone between the first group of patients, who had thyroidectomy surgery performed by harmonic scalpel, and the second group of patients operated on by standard techniqes with the use of electrocoagulation and ligature as primary hemostatic procedures. All the patients having total thyroidectomy had their blood taken in four measurement points; immediately after the induction anesthesia, 10 minutes after the first thyroid gland lobe removal, 10 minutes after total thyroid gland removal and 24 hours after the surgery. The blood samples were used to determine concentrations of the parathyroid hormone by an immunoradiometric test. The concentration comparison of parathyroid hormone between the first and the second group has not shown statistically significant difference for any of the four measurement points. The concentration comparison of parathyroid hormone within the same groups in relation to preoperational values (the first measurement point) has shown that in both groups the parathyroid hormone concentration, in all three post-incision measurement points, has been significantly lower in relation to the concentration measured before the surgery (p < 0.0005). PMID- 24490331 TI - [Communication with surgical patients of older age on the internet]. AB - A growing interest of general population to seek health information on the Internet and a growing body of health websites have been well documented in the recent health literature. Moreover, the Internet has become a popular mode of communication between healthcare providers and patients. This has resulted in many efforts to set specific quality guidelines for development of information for patients on the Internet, including different aspects of access to health information. This paper presents results of a study that explored the structure of information sources of surgical patients. Analysis of patient profiles shows that older patients rarely sought surgical information on the Internet, and mostly relied on communication with their doctors. This paper discusses various options of how to make this medium more attractive to patients and how to use the rich experience of the older patient generations to improve the quality of doctor patient communication. PMID- 24490333 TI - [Acute-on-chronic liver failure (ACLF)--a new entity in hepatology?]. AB - Recently, acute-on-chronic liver failure has been recognized as a specific and unique clinical form of liver failure (usually related to acute insult) in patients with previously known or unknown compensated chronic liver disease. Its main feature is the reversibility, and high short-mortality due to multiorgan failure (MOF) in the absence of liver support system devices and/or liver transplantation. This article aims to introduce the definition and better understanding of this newly developed and unique profile of liver failure. PMID- 24490332 TI - [A report of rarely observed resistance pattern to carbapenems in a clinical isolate of Enterobacter cloacae]. AB - The paper reports on the emergence of strain in which Enterobacter cloacae has demonstrated an unusual form of resistance to carbapenems mediated by enzyme IMI 1, class A beta-lactamase. The strain was isolated from a wound swab in the patient who had a surgical wound infection previously treated with meropenem. Limited choice of antibiotics that can treat infections caused by these pathogens indicates the necessity of accurate identification of multiple resistant gram negative microorganisms and mechanisms of their resistance. Recognition of multiresistant gram-negative microorganisms emphasizes the importance of continuous microbiological monitoring of patients, especially in intensive care units. In the investigated institution there was no secondary spread of this strain. Identifying new mechanisms of resistance will be helpful to clinicians in selection of targeted therapy, while important for efficient prevention of spreading infections caused by multiple resistant microorganisms. PMID- 24490334 TI - [Passive smoking--active killer]. AB - Although still not perceived in this way, passive smoking is a public health issue of great importance. World Health Organization estimates that as a result of passive exposure to tobacco smoke each year 600,000 people die, of which 165,000 children. There are 33% of men, 35% of women and 40% of children who do not smoke, but are exposed to second hand smoke, and still only 11% of the world population is protected by adequate smoke-free legislation. Scientific literature provides evidence that passive exposure to tobacco smoke can result in numerous adverse health effects: asthma and allergies, respiratory infections and (middle) ear infections, cancers of various localization, accelerated atherosclerosis and cardiovascular diseases, retardation of growth and development in children, and in pregnancy it can lead to congenital anomalies and premature birth as well as lower body weight and length of the child. Certainly, the scariest consequence of all is sudden infant death syndrome, also called "death in the crib". Smoke-free policies have proven their effectiveness, but while implementing the laws, it is necessary to raise public awareness of the hazards of, both active and passive, exposure to tobacco smoke. PMID- 24490335 TI - [40 years of neurological intensive care in Croatia]. AB - On the 40 year anniversary of the foundation of the first Neurological intensive therapy unit (ICU) in Zagreb, Croatia and in the region, the author recalls circumstances which stipulated its realization. The process lasted several years, from the proposal in 1968, starting working in provisional conditions in 1971- acquiring experience, and normal functioning in the newly adapted rooms in 1974. Paying tribute to personalities who supported and participated in the advances of this process, the author informs that at the First Congress of Intensive Care (London, 1974) his report on Zagreb Neurological intensive therapy unit was the only one in neurology. The basic principles of therapy are nowadays the standard in the neurological departments, enabling better recovery from stroke, neurological ailment with high mortality. Positive development brought to the realization of the concept of comprehensive care for cerebrovascular patients, including prevention, early intensive therapy and neurological restoration measures after stroke. PMID- 24490336 TI - [Homans' sign in Croatian literature]. PMID- 24490337 TI - [Perioperative intensive-medical investigations regarding compatibility of the ketamine-azaperone-general anesthesia in pigs]. AB - was observed. Perioperatively oxygen saturation was persistently high and mean arterial pressure was steady, too. An additional Ketamine administration caused a short tachycardia during operation. After restoration of total mobility, respiratory and heart rate stayed within the reference ranges again. All EMG values in between those caused by pain stimuli were significantly below the borderline of a muscle activity in conformity with a clinically visible complete muscle relaxation. Cortisol increased simultaneously with Ketamine and Azaperone before operation, but it remained at this level until the end of the determinations, parallel to the course of Norketamine, close to the maximum before anesthesia. The complex intensive-medical monitoring confirms that under real surgical conditions the counter-regulatory effects of both drugs equalize the respective cardiovascular and respiratory side effects. It is concluded also that the increase of cortisol is likely to be more a side effect of Ketamine/Norketamine than the expression of distress by surgical interventions or by wake-up reactions, and that an intoxication by additional Ketamine dosage or motoric disorders (i.e., catalepsis) can be excluded as undesired side effects of both drugs. PMID- 24490338 TI - Analysis of BVDV isolates and factors contributing to virus transmission in the final stage of a BVDV eradication program in lower Austria. AB - The BVDV eradication program in Lower Austria according to the Swedish model started in 1997 as a voluntary strategy and became obligatory for all herd owners in 2004. In this paper we analyse BVDV isolates found in PI animals of the last infected cattle farms at the genetic level and describe possible risk factors for virus transmission in the final stage of the BVDV eradication program in Lower Austria, where only five infected herds were identified in 2010. Viral isolates from 23 farms on which PI animals had been detected in 2009 (n = 10), 2010 (n = 5), 2008 (n = 5) and in 2006 (n = 3) were analysed at a genetic level at the 5' UTR. All isolates analysed by phylogenetic analysis fall into five BVDV-1 subgenotypes, i.e., b, e, f, g, and h. No new subgenotypes were identified when compared to isolates analysed at the beginning of the BVDV eradication program. The phylogenetic analysis also revealed three groups of herds with genetically identical isolates; the first group comprised two herds, the second seven herds and the third four herds. Analysis of several factors such as distance between herds, purchase of cattle, work of farmers, veterinarians, assistants of milk recording associations and animal carriers indicated the latter as the most critical factor for transmitting the same viruses. Seven herds of two groups of identical BVDV isolates were served by the same cattle carrier, six herds shared the veterinarian and five herds had the same assistant of the milk recording association who could be the risk factor for the introduction of BVDV into the herd. The analysis helped to stop virus transmission. Therefore, from early 2012 up to now, no new infection has occurred in Lower Austria. The results indicated that biosecurity is a very important factor to prevent the spreading of viruses in the final stage of the BVDV eradication program. PMID- 24490339 TI - [Two years BVD ear notch samples diagnostics--results from 16 districts of Lower Saxony]. AB - Since June 1st 2010 all calves in Lower Saxony are tested by ear notch samples for the presence of Bovine Virus Diarrhea (BVD) Virus based on the Lower Saxony BVDV-regulation. Since January 1st 2011 the new German BVDV-act requires an examination of the calves in the first 6 months of their life. In the Institute for Animal Health of LUFA Nord-West 1000-2000 ear notch samples originating from 16 rural districts are tested daily. In the period from June 1st 2010 to May 31st 2012 a total of 524,214 tissue samples were examined by an antigen ERNS ELISA. In case of low positive results the tests were verified by PCR. 2454 ear notch samples (0.47%) were from persistently with BVDV infected calves (PI-calves) coming from 763 farms (10.2% of the participating farms). In the first seven months of the eradication program 0.75% of the tested samples were positive. This number decreased in the year 2011 to 0.52%. In the first 5 months of 2012, only 0.18% of the ear notch samples tested positive. PMID- 24490340 TI - [Estimation of the financial reserves required by livestock disease compensation funds for rebates in the course of disease outbreaks using the example of Saxony Anhalt (Germany)]. AB - With certain restrictions, the federal states of Germany are obligated to financially compensate livestock owners for animal losses due to livestock diseases. If livestock disease compensation funds demand contributions from livestock owners for certain species in order to pay compensations, the federal states have to pay only one half of the rebate. The remaining 50% has to be financed through reserves of the respective compensation fund built up with the contributions. But there is no reference on how to calculate such financial reserves. Therefore, for the livestock disease compensation fund of Saxony-Anhalt (Germany), an attempt was made to estimate the required reserves.To this end, expert opinions concerning the expected number of affected holdings in potential outbreaks of different diseases were collected. In a conservative approach, assuming these diseases occur in parallel within a single year, overall costs as well as individual costs for altogether 25 categories and subcategories of livestock species were stochastically modeled.The 99.9th percentile of the resulting frequency distribution of the overall costs referred to a financial volume of about 23 million euro. Thus, financial reserves of 11,5 million euro were recommended to the livestock disease compensation fund. PMID- 24490341 TI - [Implementation and results of the EU-wide baseline studies on the prevalence of Salmonella spp. in slaughter and breeding pigs in Austria]. AB - The Member States of the European Union are following a common strategy on the control of Salmonella and other foodborne pathogens (Anonym, 2003). Within that framework baseline studies on the most relevant animal populations have been carried out. This paper describes the implementation and the results of the baseline studies on Salmonella spp. in slaughter and breeding pigs in Austria. A total of 647 slaughter pigs were sampled in 28 slaughterhouses between October 2006 and September 2007. Samples were taken from the ileocaecal lymphnodes to detect infection in pigs and from the surface of the carcasses to detect contamination. Out of the 617 datasets included in the final analysis, Salmonella prevalences of 2% in lymphnodes and 1.1% on the carcass surface were observed. S. Derby, S. Enteritidis and S. Typhimurium were the three most frequently identified serovars. In an additional study, a total of 252 holdings with breeding pigs has been sampled between January and December combined multiplier herds. Respectively prevalences of 5, 8, 5, 3 and 9.1% were obtained, with S. Typhimurium being the most frequently isolated serovar. Overall, compared to neighbouring Member States a rather low prevalence of Salmonella spp. in pigs was documented for Austria, in particular in slaughter pigs.The serovar distribution seemed to be similar throughout the pig populations, some also being represented in Austrian human isolates. Contamination of feed seems to play a minor role considering the overall low prevalence, but nevertheless has to be taken into account in any future control or monitoring strategy for Salmonella spp. in pigs. PMID- 24490342 TI - Listeria monocytogenes in retailed raw chicken meat in Turkey. AB - The objectives of this study were, to find the prevalence and antimicrobial resistance of L. monocytogenes from a total of 116 chicken meat samples including 50 carcasses and 66 meat parts marketed in Turkey between 2008 and 2009 using immunomagnetic separation (IMS) based cultivation technique, to detect the hlyA gene for the verification of the isolates by PCR, and to identify the genoserotypes of the L. monocytogenes isolates by multiplex PCR assay. In the study, 51 L. monocytogenes colonies were isolated from 34 (29.3%) chicken meat samples (eleven [22.0%] carcasses and 23 [34.8%] pieces of meat) by IMS based cultivation technique and confirmed by PCR. According to the multiplex PCR results, all the 51 isolates were identified as genoserotype IIa (1/2a or 3a). L. monocytogenes isolates were also tested for their susceptibility to eight antibiotic (gentamicin, vancomycin, chloramphenicol, streptomycin, tetracycline, ampicillin, penicillin G, erythromycin) agents using the disk diffusion method. 14 isolates (27.45%) were susceptible to all eight antimicrobials drugs tested and the remaining 37 isolates (72.54%) were resistant to gentamicin (one isolate, 1.96%), vancomycin (four isolates, 7.84%), penicillin G (six isolates, 11.76%), streptomycin (nine isolates, 17.64%; resistant or intermediate), tetracycline (seven isolates, 13.72%) and ampicillin (six isolates, 11.76%). This study showed that antimicrobial resistance is not highly prevalent in L. monocytogenes isolated from chicken carcasses and pieces of meat. The presence of L. monocytogenes in chicken samples suggests an importance of this pathogen in chicken. PMID- 24490343 TI - [The resistance status of gastrointestinal strongyles against anthelmintics in three Estonian sheep flocks]. AB - Poor efficacy of anthelmintic drugs in sheep due to infections with resistant gastrointestinal strongyles is reported worldwide. The aim of this pilot study was to gain an insight into the current situation of anthelmintic efficacy in Estonian sheep flocks. From September to November 2012, faecal egg count reduction tests (FECRT) were carried out in three Estonian sheep farms, evaluating the efficacy of albendazole and ivermectin. Individual faecal samples were taken at the day of treatment and 10 to 14 days later and examined by a modified McMaster technique. Anthelmintic treatment was carried out with ivermectin (Bimectin 10 mg/ml, Bimeda Chemicals Export) subcutaneously with a dose rate of 0.2 mg/kg of body weight in the IVM group (n = 20 animals/farms 1 and 2; n = 5 for farm 3) or albendazol (Endospec 10%, Bimeda Chemicals Export) orally in the dose of 5 mg/kg of body weight in the ALB group (n = 20 animals/ farm); animals in the control group (n = 20 animals for farms 1 and 3, n = 18 for farm 2) were left untreated. The FECRT was carried out according to the WAAVP guidelines. On farm 1 the efficacy of albendazole and ivermectin was reduced with 66% and 65% FECR, respectively. With a FECR of 26% the results of farm 2 showed a pronounced albendazole resistance while ivermectin was still sufficiently efficient (99% reduction). Farm 3 showed nearly 100% efficacy of albendazole and ivermectin, but earlier problems with high endoparasite burden and mortality may indicate a possible developing albendazole resistance which could not be detected with the FECRT yet. The results of this study show that in Estonia resistance against benzimidazoles and macrocyclic lactones does occur, indicating that close countrywide monitoring is advisable. PMID- 24490344 TI - Properties of an Arcanobacterium haemolyticum strain isolated from a donkey. AB - The present study was designed to characterize phenotypically and genotypically an Arcanobacterium haemolyticum strain (A. haemolyticum P646) isolated from a purulent nasal discharge of a donkey. A. haemolyticum P646 showed, compared to sheep blood, an enhanced hemolytic reaction on rabbit blood agar, a synergistic CAMP-like reaction with Streptococcus agalactiae and Rhodococcus equi as indicator strains, a reverse CAMP reaction in the zone of Staphylococcus aureus beta-hemolysin and the typical biochemical properties of this species. The species identity could be confirmed by MALDI-TOF MS analysis, by sequencing the 16S rDNA and glyceraldehyde-3-phosphate dehydrogenase encoding gene gap and by amplification of A. haemolyticum specific parts of 16S-23S rDNA intergenic spacer region and 23S rDNA. A. haemolyticum P646 and the reference strain A. haemolyticum DSM 20595 were further characterized by amplification of the putative virulence genes encoding arcanolysin, phospholipase D, hemolysin A, CAMP factor family protein, a collagen binding protein and two neuraminidases which were present for A. haemolyticum DSM 20595. A. haemolyticum P646 showed a comparable gene spectrum but was negative for the genes encoding collagen binding protein and neuraminidase H. To our knowledge, the present study is the first phenotypic and genotypic characterization of an A. haemolyticum strain isolated from a donkey. PMID- 24490346 TI - [Phenotypic trends and breeding values for canine congenital sensorineural deafness in Dalmatian dogs]. AB - In the present study, breeding values for canine congenital sensorineural deafness, the presence of blue eyes and patches have been predicted using multivariate animal models to test the reliability of the breeding values for planned matings. The dataset consisted of 6669 German Dalmatian dogs born between 1988 and 2009. Data were provided by the Dalmatian kennel clubs which are members of the German Association for Dog Breeding and Husbandry (VDH). The hearing status for all dogs was evaluated using brainstem auditory evoked potentials. The reliability using the prediction error variance of breeding values and the realized reliability of the prediction of the phenotype of future progeny born in each one year between 2006 and 2009 were used as parameters to evaluate the goodness of prediction through breeding values. All animals from the previous birth years were used for prediction of the breeding values of the progeny in each of the up-coming birth years. The breeding values based on pedigree records achieved an average reliability of 0.19 for the future 1951 progeny. The predictive accuracy (R2) for the hearing status of single future progeny was at 1.3%. Combining breeding values for littermates increased the predictive accuracy to 3.5%. Corresponding values for maternal and paternal half-sib groups were at 3.2 and 7.3%. The use of breeding values for planned matings increases the phenotypic selection response over mass selection. The breeding values of sires may be used for planned matings because reliabilities and predictive accuracies for future paternal progeny groups were highest. PMID- 24490345 TI - Causes of death in calves with experimentally induced bovine neonatal pancytopenia (BNP). AB - The objective of this study was to identify the different causes of death in calves affected with bovine neonatal pancytopenia (BNP). A total of 51 precolostral calves were fed with colostrum from cows which had lost at least one calf after parturition due to BNP in previous lactations. Clinical BNP could be induced in 71% (36/51) and subclinical BNP in 20% (10/51) of the calves. 9% (5/51) of the calves stayed BNP-unaffected despite challenging with the same mixed colostrum and approved passive transfer of colostral antibodies. The case fatality rate in BNP-affected cases was 83% (38/46). In the 38 lethal BNP-cases gross-pathological and histopathological examinations were performed. BNP-induced haemorrhagic anaemia was the cause of death in 18 calves (47%). 19 of these lethal cases (50%) died due to infectious diseases, especially due to pneumonia, enteritis and septicaemia. One calf died due to severe enteritis and exsiccosis without any signs of BNP (3%). In conclusion, anaemia as the consequence of haemorrhages was the most prevalent cause of death in BNP-affected calves, however, BNP has been approved to increase the lethality of common infectious neonatal diseases. PMID- 24490347 TI - [Salter-harris fractures in dogs and cats considering problems in radiological reports--a retrospective analysis of 245 cases between 1997 and 2012]. AB - To identify typical trauma patterns or frequent radiological pitfalls that could help a radiologists in their daily routine, a retrospective study of Salter Harris fractures in dogs and cats was performed. Radiographs obtained in the period 1991-2012 of 288 fractures in 245 patients with suspected injuries affecting growth plates in the appendicular skeleton were retrieved from the imaging archive. The femur was the bone most frequently affected (46.5%), followed by the humerus (19.8%), tibia (13.5%) and radius (11.8%). The distal growth plate was in all bones more often involved than the proximal growth plate (79.5% vs. 20.5%). The frequency of Salter-Harris fractures was 39.9% type I, 37.8% type II, 3.1% type III and 19.1% type IV. In dogs the most common physeal fracture was a type IV fracture of the of the distal femur. Radiographically, physeal fractures were recognized by at least two Roentgen signs, including change in opacity, displacement of the epiphysis or the Thurston-Holland sign. On the basis of the review, the original radiographic reports of 44/288 fractures were considered erroneous regarding the incorrect Salter Harris grouping. In 5/44 instances, the radiological examination had technical deficiencies that may have contributed to the errors, including 3 with oblique projections. Minimal variations in the projection was evident in the majority of reviewed cases. Measures to help optimize radiographic reports will be discussed. PMID- 24490348 TI - [Malaria from control to elimination in China: transition of goal, strategy and interventions]. AB - The Malaria Elimination Action Plan has been launched in China since 2010, to pursue the goal of national wide malaria elimination by 2020. To ensure the achievement of the goal, the strategy and interventions should be transited from control to elimination, based on the better understanding of malaria elimination. In this article, we delineate the difference between malaria control and elimination phase, and explain the importance of transition of the goal, strategy and interventions from control to elimination, also decrypt the background, definition, critical points and challenges of China's current malaria elimination strategy and interventions, to improve health workers' understanding and implementation of national elimination program at different levels, and eventually impact the progress of national elimination program. PMID- 24490349 TI - [The changes of hydrological regime in Poyang Lake after runs of Three Gorges Project and its impact on prevalence of schistosomiasis in the lake region]. AB - OBJECTIVE: To clarify new features of hydrological regime in the Poyang Lake after runs of the Three Gorges Project and its impact on the prevalence of schistosomiasis in this region. METHODS: It is collected information of Three Gorges Project, average daily water level from 2002 to 2012 at Duchang hydrological station in Poyang Lake and the data of prevalence and control of schistosomiasis in 12 endemic counties along the lake. It was analyzed the trends of prevalence of schistosomiasis under the changed condition of hydrologic situation. RESULTS: Effects of impoundment of Three Gorges reservoir running on water level of Poyang Lake are mainly shown in: Water levels of the lake are suppressed throughout the year which was characterized by high water level in flood season dropped, lower water level appeared in the spring, water withdrew earlier and quicker in the fall and to an even lower level in dry season. After impoundment of Three Gorges Project, infection rate of Schistosomajaponica in human and in bovine decreased by 92.65% and 76.37% respectively in endemic areas around the lake. The density of Oncomelania snails decreased by 94.21%. Prevalent of schistosomiasis in this region showed a significant downward trend. CONCLUSIONS: After runs of the Three Gorges Project, regularized changes hydrologic conditions has taken place in Poyang Lake which is characterized by lower water level and thus might lead to lower density of Oncomelania snails on marshlands and reducing of prevalence of schistosomiasis. Significant strengthening of schistosomiasis control efforts might also contributed to the stable and low level of prevalence of schistosomiasis in the region. PMID- 24490350 TI - [Establishment and application of rapid assessment system of environment with high transmission risk of schistosomiasis in marshland and lake regions II establishment and application of measures for field survey]. AB - OBJECTIVE: To establish the measures of schistosomiasis field survey and evaluate the efficacy of their application according to the content of indexes of rapid assessment system to high transmission risks in schistosomiasis endemic areas of lake regions. METHODS: In 2012, based on the analysis of Oncomelania hupensis snail situation, and schistosomiasis epidemic data of human and cattle from 2008 2010, 60 villages from Hunan, Hubei, Jiangxi and Anhui provinces were selected and investigated, and the content of the investigation included the field feces, snail status, and epidemic situation of human and cattle. The systemic sampling was applied for snail investigation; the feces collected from snail investigation field were examined by the hatching test (3 bottles for 1 sample). A cluster random sampling was carried out with more than 300 people in each village. By using the hatching test (3 bottles for 1 sample) , the human stool examination was carried out for the identification of the infected persons who were positive in the immunity test screening. The hatching test was applied for cattle of all the villages (3 bottles for 1 sample). RESULTS: A total of 65 field feces spots were surveyed in 60 villages, field feces were found in 78.46% (51/65) of spots, and the positive rate of field feces was 1.07% (9/842). There were 73.33% (44,160)of villages with cattle, and the largest amount cattle with 329 was found in Wufeng Village, Jiangxi Province. The cattle infection rate was 1.5 1% (4,913,242) in 3242 investigated cattle. The highest cattle infection rate was 4% in Tongxin Village, Jiangxi Province. The population of 47 099 was surveyed, the infection rate was 0.77% (364/47 099), and the highest was 4.37% in Xumuchang Village, Hunan Province. The infection rate was 0 in 43.33% (26/60) of villages. No acute schistosomiasis cases were reported in all the villages in 2011 and 2012. Totally, 77 snail spots in 60 villages were investigated, and 51 spots were marshland and 26 spots were ditches. The schistosome-infected snails were detected in 5.88% (3/51 )of the marshland spots and the living snails were found in 80.39%(41/51) of the spots. The highest density of living snails was 3.20/0.1 m2 in Xumuchang Village, Hunan Province. The average density of infected snails was 0.00045/0.1 m2 (4/8942). The infected snail spots were distributed in Liujiadi Village and Liuhe Village of Hubei Province, and Jiangkou Village of Anhui Province. No infected snails were detected in 26 ditches spots. The living snails were detected in 53.85% (14/26) of the ditches spots. The highest average density of living snails was 3.76/0.1 m2 in Huakou Village, Hubei Province. CONCLUSIONS: The measures of field survey for rapid assessment system of high transmission risks in schistosomiasis endemic areas of lake regions are established and applied with scientific, impersonal and rapid characteristics. PMID- 24490351 TI - [Establishment and application of quality control system for detection of schistosomiasis in Jiangsu Province I ability of serological detection among county-level personnel]. AB - OBJECTIVE: To evaluate the ability for serological screening of schistosomiasis among county-level personnel, so as to provide the evidence for establishing the quality control system of field detection of schistosomiasis. METHODS: The standard serum panel was prepared for the quality assessment of schistosomiasis diagnostic capability, and detected by county-level personnel in the endemic field simultaneously using single-blind method. The rates of coincidence, misdiagnosis and missed diagnosis were calculated compared with the standard results. RESULTS: Totally 780 samples of standard serum were detected in 26 counties, and showed 134 positive and 646 negative samples. The rates of coincidence, misdiagnosis and missed diagnosis were 95.13%, 1.28% and 19.23%, respectively, and there was a significant difference between the detection results and the standard results (chi2 = 11.6053, P = 0.0007). Among the 26 counties investigated, the misdiagnosis occurred in 5 counties (19.23%) and missed diagnosis occurred in 21 counties (80.77%). The misdiagnosis rate and missed diagnosis rate of serological screening of schistosomiasis were 0-2.08% and 16.67%-33.33% in beach, hilly, water net and marshland endemic areas, respectively, and no significant differences were found in the misdiagnosis rate and the missed diagnosis rate among various types of endemic areas (chi2 = 1.590 and 1.757, P = 0.6671 and 0.6244). The rates of misdiagnosis and the missed diagnosis were 1.14% and 1.39%, and 18.18% and 20.00% in the schistosomiasis transmission-controlled and the schistosomiasis transmission-interrupted areas, respectively, and no significant differences were found in the misdiagnosis rate and missed diagnosis rate between the schistosomiasis transmission-controlled and transmission-interrupted areas (chi2 = 0.008 and 0.001, P = 0.931 and 0.974). CONCLUSIONS: The missed diagnosis is a major cause for the reduction of quality of schistosomiasis detection at the county level in Jiangsu Province, and the coincidental detection of schistosomiasis with standard serum in the field is one of effective approaches for the control of the quality of schistosomiasis detection. PMID- 24490352 TI - [Retrospective investigation on changes of endemic situation before and after reaching criteria of schistosomiasis transmission controlled or interrupted in hilly endemic areas of Jiangxi Province]. AB - OBJECTIVE: To investigate the changing rules of schistosomiasis endemic situation before and after reaching the criteria of schistosomiasis transmission controlled or interrupted in hilly endemic areas of Jiangxi Province, so as to provide the evidence for reformulating the criteria of schistosomiasis control and eradication in the future. METHODS: In the hilly areas of schistosomiasis endemic in Jiangxi Province, 2 counties where the transmission has been interrupted and 1 county where the transmission has been controlled were selected and investigated with the retrospective research method. The endemic detailed data were collected and recorded 10 years before reaching the criteria of transmission interrupted/controlled, and several years after reaching the criteria (ending in 2008), and then a database was established. The changing rules of endemic situation before and after reaching the criteria of transmission interrupted/controlled were analyzed and compared. RESULTS: After reaching the criteria of transmission controlled, in the 3 counties, Guangfen, Shangrao and Dean, the declined rates of areas with Oncomelania hupensis snails were 96.79%, 98.99%, and 99.77% respectively. The snail density maintained a lower level, and 95% of infected persons and cattle were cured. The average time from transmission controlled to the transmission interrupted was 17 years in Guangfen County and 26 years in Dean County. However, in Shangrao County, the snail situation rebounded due to the snail re-found and spread although the schistosomiasis morbidity of population/animals maintained stably. CONCLUSIONS: After reaching the criteria of transmission interrupted/controlled, the remained snails were easy to re-find and spread under some certain condition, which is one of main obstacles for reaching the criteria of transmission interrupted. In an isolated snail unit, if the snail area and snail density are controlled in a very low level, it is still difficult to transmit and spread schistosomiasis even if there exist infectious sources. PMID- 24490353 TI - [Analysis of epidemic situation of schistosomiasis at Kongqing Village in Jurong City, 2012]. AB - OBJECTIVE: To understand the epidemic situation of schistosomiasis and control effect in mountainous regions in Jurong City. METHODS: According to the "Schistosomiasis Prevention and Control Practices" and the "Schistosomiasis Monitoring Work Program in Jiangsu Province", the density of Oncomelania hupensis snails, and the infection rates of residents and animals were investigated and the results were analyzed statistically. RESULTS: The area with snails was 8150 m2, and the snail density was 0.14 snial/0.1 m2. The positive rate of schistosomiasis serological tests was 3.2% in the residents, and the infection rate was 0 in animals. CONCLUSION: The epidemic situation of schistosomiasis in the mountainous regions of Jurong City presents a low prevalence, but the surveillance is still needed. PMID- 24490354 TI - [Mid-term evaluation on schistosomiasis control effect in Lushan earthquake stricken areas in Sichuan Province]. AB - OBJECTIVE: To evaluate the effect of schistosomiasis control in Lushan earthquake stricken areas in Sichuan Province, so as to provide the evidence for formulating appropriate measures for schistosomiasis prevention and control. METHODS: According to the data of historical schistosomiasis prevalence, 5 villages were selected as research sites and field investigations were conducted. RESULTS: The average density of Oncomelania hupensis snails was 0.41 snails/0.1 m2, and there were no schistosome-infected snails. There were no acute schistosomiasis cases in these five villages. For local residents, the health education leaflets were more suitable than warning signs, and for migrant population, they were more concerned about the warning signs. CONCLUSION: After the implementation of effective prevention and control works, the epidemic risks of schistosomiasis have been controlled. However, the health education, surveillance, and prevention measures for schistosomiasis still need to be persisted in. PMID- 24490355 TI - [Preparation and molluscicidal effect of 5% niclosamide ethanolamine granules]. AB - OBJECTIVE: To explore the preparation of 5% niclosamide ethanolamine granules and evaluate its molluscicidal effect. METHODS: The optimal formula was obtained by the selection of wetting agents, dispersants, adhesives and carriers. The molluscicidal effect of 5% niclosamide ethanolamine granules was measured by the spray methods in the laboratory and field. RESULTS: The mixed 5% niclosamide ethanolamine, 0.2% sodium lauryl sulfate, and 1% alkylphenol sulfonic polyxyethylene ether sulfonate were crushed by gas flow, and then mixed with 93.7% quartz sand and 0.1% polyvinyl alcohol water solution, drying to 5% niclosamide ethanolamine granules. The density, bulk density, and moisture of 5% niclosamide ethanolamine granules were 1.4 g/ml, 1.3 g/ml, and 2.4%, respectively, and the hot storage stability was qualified. Under the lab condition, the death rates of Oncomelania hupensis snails sprayed with 0.5 g/m2 (7 d) or 1.0 g/m2 (1 d) of 5% niclosamide ethanolamine granules were higher than 95%. In the field, the death rates of the snails sprayed with 0.5 g/m2 (7 d) or 1.0 g/m2 (1 d) were higher than 85%. CONCLUSION: There is a high molluscicidal effect of 5% niclosamide ethanolamine granules and it is suitable for field application. PMID- 24490356 TI - [Survey on newly-developed advanced schistosomiasis patients in schistosomiasis transmission-interrupted areas]. AB - OBJECTIVE: To understand the status of newly-developed advanced schistosomiasis patients in schistosome transmission-interrupted areas. METHODS: The newly diagnosed advanced schistosomiasis patients confirmed by professionals at province and county levels according to the available standards were investigated. Their detailed epidemiology history and present signs/ symptoms were surveyed, and the relevant medical examinations were performed. RESULTS: There were 75 patients including 22 males and 53 females. The average age was (70.0 +/- 7.0) years and they were all infected with schistosome previously. They received anti-schistosome therapy (mean 1.85 times) and stool examinations (mean 26.24 times) continuously from 1976 to 1985, and the results of stool examination were all negative. In majority of the patients' resident areas, the last time that Oncomelania hupensis snails were found was 1976, and the latest was 1983. During this period, no patients were up to the diagnostic criteria of advanced schistosomiasis after multiple examinations, and they were diagnosed as advanced cases between 2008 and 2011. The survey indicated that liver fibrosis was found in all the patients with 82.7% showing grad III pathological change, 90.7% of them had splenomegaly, 20.0% had ascites, and 22.7% had portal vein broadening. The mean value of enzyme indexes of liver function was 31.81 U/L (ALT), 53.19 U/L (AST) and 89.28 U/L (gamma-GT), and the positive rate was 21.3%, 49.3% and 57.3%, respectively. As for the fibrosis indexes, the positive rate of HA, LN, C VI and P III P was 73.3%, 13.3%, 17.3% and 9.3%, respectively, and the mean value of HA was 3 times higher than that of the upper limit of normal standard. Conclusions Newly-developed advanced schistosomiasis patients are those who were dignosed and cured parasitologically but progressed pathologically without any chance of re infection. Anti-fibrosis therapy is necessary as the patients show considerable progressive liver fibrosis. PMID- 24490357 TI - [Field evaluation of a novel plant molluscicide "Luo-wei" against Oncomelania hupensis snails II molluscicidal effect in the field of lake areas in Hanchuan City, Hubei Province]. AB - OBJECTIVE: To evaluate the effect of a novel plant molluscicide "Luo-wei" (Tea seed distilled saponins, TDS) against Oncomelania hupensis in the field of lake areas in Hanchuan City, Hubei Province. METHODS: Immersing experiment and spraying experiment were carried out in 5 ditches and a beach land respectively in Hanchuan City, Hubei Province to compare the molluscicidal effects among 4% TDS, 50% wettable powder of niclosamide ethanolamine salt (WPN), and 26% suspension concentrate of metaldehyde and niclosamide (MNSC) by different dosages and time. The chi2 test or Fish's exact test was used to examine the differences of snail death rates among them. RESULTS: After 72 h of immersing experiment, the snail death rates in the 2.5 g/m3 TDS group, 3.0 g/m3 TDS group, 2.0 g/m3 WPN group and 2.0 g/m3 MNSC group were 99.33%, 100%, 100%, and 100%, respectively, and there was no significant difference among them (P > 0.05). By the end of 15 d after the spraying experiments, the snail death rates were 91.86% in the 2.0 g/m2 MNSC group, 90.26% in the 5.0 g/m2 TDS group, 87.45% in the 2 g/m2 WPN group, and 86.10% in the 3 g/m2 TDS group. The differences between the 5.0 g/m2 TDS group and 2.0 g/m2 MNSC group, as well as the 3.0 g/m2 TDS group and the 2.0 g/m2 WPN group had no statistical significance (both P > 0.05). CONCLUSIONS: The molluscicidal effect of TDS is similar to that of WPN or MNSC. The recommended dosage of TDS is 2.5 g/m3 for immersing or 5 g/ m2 for spraying in the field. PMID- 24490358 TI - [Distribution characteristics, trend and control strategy of Oncomelania hupensis snails in Wuhu City from 1997 to 2012]. AB - OBJECTIVE: To understand the emerging and re-emerging trend of Oncomelania hupensis snails in Wuhu City from 1997 to 2012, so as to provide the evidence for developing schistosomiasis control strategy. METHODS: A retrospective survey was conducted. The emerging and re-emerging snail areas were investigated in various years, water systems, settings and countries (districts) based on the historical snail survey results. RESULTS: The accumulative emerging snail area from 1996 to 2007 was 3479.42 hm2, which was mainly found in marshland areas; while the accumulative re-emerging snail area was 1648.08 hm2, which was mainly concentrated on the inland areas. The longest duration from snail re-emergence to snail elimination was 26 years, and the majority of the duration ranged from 3 to 12 years. CONCLUSION: It seems impossible to avoid snail emergence and re emergence in Wuhu City, which is closely associated with the natural environment and the implementation of schistosomiasis control measures. PMID- 24490359 TI - [Effects of soluble egg antigen and adult worm antigen of Schistosoma japonicum on differentiation of effector B cells of mice]. AB - OBJECTIVE: To observe the differentiation ability of effector B cells induced by soluble egg antigen (SEA) and soluble adult worm antigen (SWAP) of Schistosoma japonicum. METHODS: The mouse spleen mononuclear cells and CDl9+ B cells sorted by beadg were stimulated by SEA, SWAP and lipopolysaccharide (LPS), respectively. The ratios of CD19+ IL-6+ cells and CD19+ IFN-gamma+ cells were analyzed by flow cytometry after 72 hours. At the same time, the cytokines IL-6 and IFN-gamma levels in the cultured supernatants were detected by ELISA. The mouse was immunized with the mixture of SEA or SWAP or LPS and the incomplete Freund' s adjuvant for three times, respectively. The mouse spleen mononuclear cells were isolated at the seventh day after the last immunization. The ratios of CD19+ IL 6+ cells and CD19 IFN-gama+ cells were analyzed, and the cytokines IL-6 and IFN gamma+ levels in the culture supernatants were detected. RESULTS: The ratio of CD19 IL-6+ cells in spleen mononuclear cells and splenic B cells was significantly increased in the groups stimulated by SEA and LPS (P < 0.05), and the cytokines IL-6 level in the CD193 cells culture supernatants were significantly increased (P < 0.01). Furthermore, the ratio of CD19+ IL-6+ cells and the cytokines IL-6 level were significantly increased in the SEA immunized group (P < 0.01). SWAP could induce a significantly higher ratio of the CD19+ IFN gamma+ cells in spleen cells, instead of in splenic CD19+ B cells (P < 0.05). The CD19+ IFN-gamma+ cells and the cytokine IFN-gamma level in the culture supernatants in the SWAP immunized group were significantly higher than those in the SEA and PBS immunized groups (P C 6.01). CONCLUSIONS: SEA preferentially induces the increase of CDl9+ IL-6+ cells in mouse spleen cells; while SWAP preferentially induces the CD19 + IFN-gamma+ cells' production of mouse spleen cells, depending on the effects of other immune cells. PMID- 24490360 TI - [Effect of comprehensive measures on schistosomiasis control in an aquaculture zone]. AB - OBJECTIVE: To evaluate the effect of comprehensive measures on the control of schistosomiasis in an aquaculture zone, so as to provide the evidence for formulating the schistosomiasis control strategy in special environments. METHODS: From 2003 to 2012, the comprehensive control measures including individual prevention, detection and treatment of schistosomiasis patients, environmental modification, and health education were implemented in an aquaculture zone of Luyang Lake, Jiangdu District of Yangzhou City, Jiangsu Province. The changes in human morbidity of schistosomiasis and the status of Oncomelania snails were investigated annually. RESULTS: No acute infection of Schistosoma japonicum was detected for successive 10 years, and only 5 cases of chronic infection were found in the latest 5 years in the aquaculture zone. Since 2007, no snail habitats were found. CONCLUSIONS: The comprehensive control measures are effective. PMID- 24490361 TI - [Field evaluation of a novel plant molluscicide "Luo-wei" against the snail Oncomelania hupensis III molluscicidal effect by spraying method in hilly regions]. AB - OBJECTIVE: To evaluate the molluscicidal effect of a novel plant molluscicide "Luo-wei" (Tea-seed distilled saponins, TDS) against Oncomelania httpensis in billy regions. METHODS: The molluscicidal effect of TDS at a dose of 5 g/m2 by the spraying method against Oncomelania snails was assessed in a setting with a high snail density in Husban Village, Jiangning District of Nanjing City, and the effect was compared with that of 50% wettable powder of niclosamide ethanolamine salt (WPN) at a dose of 2 gIm2 at different time after spraying. RESULTS: Afterl, 3, 7 and 15 day (days) of the spraying experiment, the snail death rates of the TDS group were 56.47%, 57.32%, 90.58% and 93.41% respectively, while those of the WPN group were 49.22%, 53.37%, 95.92% and 97.26%, respectively. The differences between the rates of the 2 groups 1, 7, 15 day (days) after the spraying were statistically significant (all P < 0.05). Fifteen days after the spraying, the density of living snails reduced from 20.30 +/- 16.20 snails/0.1 m2 and 23.67 +/- 21.22 snails/0.1 m2 to 2.28 +/- 2.17 snails/0.1 m2 and 1.27 +/- 0.76 snailsl0.1 m2 in the TDS group and WPN group, respectively, with the reduction rates of 88.77% and 94.63%, respectively. CONCLUSION: TDS can be used as an alternative molluscicide for the control of Oncornelania snails in hilly areas, which deserves further popularization. PMID- 24490362 TI - [Follow-up of chronic filariasis patients in Jinshan District, Shanghai from 2009 to 2011]. AB - OBJECTIVE: To understand the prognosis of chronic filariasis patients who were nursed with the care methods recommended by WHO in Jinshan District, Shanghai. METHODS: The chronic filariasis patients who were nursed with the care methods recommended by WHO were followed up in Jinshan District from 2009 to 2011. The patients of Level 1 were followed up once a year; the patients of Level 2 and Level 3 were followed up twice a year. All the results were recorded into the standard questionnaires and analyzed statistically. RESULTS: By the end of 2011, there were 264 chronic filariasis patients, including 106 males and 158 females. There were 201 patients aged between 70 and 85 years old, accounting for 76.14% of the patients. Lymphedema was the most common symptom in the patients and 76.51% of the patients had it. From 2009 to 2011, the conducting rates of sanitary cleaning the limbs, elevation of the limbs, and exercises were 89.02%, 83.71% and 72.08%, respectively. The improvement rates were 6.54%, 10.95% and 14.77% each year, which had a statistically significant difference (chi2 = 18.359, P < 0.01). CONCLUSION: The care methods of chronic filariasis patients recommend by WHO really benefit the relief of lymphedema, and should be popularized. PMID- 24490363 TI - [Lysozyme activities of Oncomelania hupensis in different seasons and ages of snails]. AB - OBJECTIVE: To explore the relationship between the lysozyme activities of Oncomelania hupensis snails among different seasons, and the difference of the lysozyme activities among the different ages of the snails. METHODS: The homogenate soft tissues of O. hupensis were dissolved with Tris-HCl-TritonX-114 buffer and concentrated, and the enzyme was extracted by centrifugation. RESULTS: There were significant differences of lysozyme activities among different seasons (Spring, Summer, Autumn, Winter) with the results of 71.33 +/- 4.16 U/mg, 93.67 +/- 7.10 U/mg, 150.33 +/- 10.01 U/mg, 358 +/- 35.38 U/mg,respectively (F = 144.455, P < 0.01). There were also significant differences of the activities between two age groups (adults and young snails) with the results of 93.67 +/- 7.10 U/mg and 69.33 +/- 5.03 U/mg,respectively (t = 4.845, P < 0.05). CONCLUSION: There are significant differences of the lysozyme activities among different seasons and ages of snails, and the highest lysozyme activity is in winter. The lysozyme activity of adult snails is higher than that of the youth. PMID- 24490364 TI - [Molluscicidal effects of nano-silver biological molluscicide and niclosamide]. AB - OBJECTIVE: To evaluate the molluscicidal effect of a novel nano-silver biological molluscicide in the field and its toxicity to other aquatic organisms. METHODS: A marshland of the Qiupu River was selected as the study site. Four 1 m3 pools were excavated. Four groups, including 300 g/m3 and 600 g/m3 nano-silver biological molluscicide groups, a 2 g/m3 50% niclosamide group, and a natural water (control) group were assigned to the four pools which had 100 Oncomelania hupensis snails and 100 crucian seedlings. The molluscicidal effects and toxicity to the aquatic organisms were observed. RESULTS: The snail death rates were 100% and crucian seedling death rates were 6% in the 600 g/m3 nano-silver biological molluscicide group and 300 g/m3 nano-silver biological molluscicide group in 7 days and 14 days. The snail death rate was 100% in the niclosamide group in 7 days, and the crucian seedling death rate was 100% in the niclosamide group in 3 days. The snail death rates were 7% and 14% in the control group in 7 and 14 days respectively, and the crucian seedling death rate was 22% in the control group. CONCLUSIONS: The novel nano-silver biological molluscicide possesses an excellent molluscicidal capability and non-toxicity to the other aquatic organisms. Therefore, it may become a new, efficient and environment-friendly bio molluscicide for extensive application. PMID- 24490365 TI - [Effects of different prevention and control measures on schistosomiasis prevalence in different limnetic regions]. AB - OBJECTIVE: To compare the schistosomiasis control effects of the comprehensive control measures based on infectious resources control and the conventional control measures, so as to provide the evidence for improving prevention and control strategies. METHODS: In the Hanbei River basin, the comprehensive control measures based on infectious resources control (conventional measures plus grazing prohibition in the marshland, machine instead of cattle, and marshland development, and so on) were carned out, and in the Nanzhi River basin, the conventional control measures were performed. The schistosomiasis epidemic data were collected, analyzed and compared from 2004 to 2011. RESULTS: In 2004, the infection rate of the populations and cattle in Nanzhi River basin was lower than that in the Hanbei River basin. From 2004 to 2011, the Oncomelania hupensis snail frame occurrence rate and the average density of living snails in the Nanzhi River basin was lower than that in the non-ploughing marshland and preventing wave woods of the Hanbei River basin, and there were schistosome infected snails in the Nanzhi River basin. From 2008 to 2010, there were no infected snails in the non-ploughing marshland of the Hanbei River basin. From 2007, the cattle have been eliminated in the Hanbei River basin. From 2007 to 2011, there were no infected snails in the preventing wave woods of the Hanbei River, but there were schistosome infected cattle found by stool examinations every year in the Nanzhi River basin. From 2004 to 2011, the infection rates of population presented downward trends in the two river basins, but the downward trend was more significant in the Hanbei River basin than in the Nanzhi River basin. CONCLUSION: The conventional control measures and comprehensive control measures based on infectious resources control are both effective, but the latter is more effective. PMID- 24490366 TI - [Qualitative research of self-management behavior in patients with advanced schistosomiasis]. AB - OBJECTIVE: To explore the self-management behavior of patients with advanced schistosomiasis, so as to provide the evidence for improving clinical nursing. METHODS: A total of 18 patients with advanced schistosomiasis were interviewed in depth by using a semi structured interview method. The results were analyzed with Miles and Huberman content analysis method. RESULTS: Most of the patients with advanced schistosomiasis had self-management control behavior and were cooperated with medical assistance because of their seriously illness. Based on data analysis, the symptom management, follow-up management, a healthy lifestyle, medication awareness, and emotional management were obtained. CONCLUSION: The patients with advanced schistosomiasis have self management control behavior. Health care workers should promote the patients, their families and social people to participate in the self-management behavior of advanced schistosomiasis patients. PMID- 24490368 TI - [Analysis of malaria situation in Quanzhou City, 1963-2012]. AB - OBJECTIVE: To understand the situation of malaria in Quanzhou City for 50 years, so as to provide the evidence for eliminating malaria. METHODS: The data of epidemic situation of malaria and intermediary surveillance were collected and analyzed statistically from 1963 to 2012. RESULTS: The incidence of malaria has been periodically increased, but seasonal distribution was not obvious. The incidence in economically developed areas was significantly lower than that in the slow economic development areas. The patients were mainly young adults, and the careers were mainly the farmer, worker and migrant worker. The vivax malaria was the main type and the main vector was Anopheles minimus. The incidence of malaria has been less than 1/100,000 since 1997. From 2004, all of the patients were imported, mainly came from Africa and Southeast Asia. CONCLUSIONS: After more than 50 years' comprehensive prevention and treatment, the incidence of malaria has been maintained at a low level. We should strengthen the control and management of imported malaria, and consolidate the achievements in malaria prevention, so as to achieve the aim of malaria elimination. PMID- 24490367 TI - [Cost-effectiveness of schistosomiasis comprehensive control in Lushan County from 2007 to 2012]. AB - OBJECTIVE: To evaluate the cost-effectiveness of comprehensive control strategy which mainly controls the schistosomiasis infection source in Lushan County from 2007 to 2012. METHODS: The data of the schistosomiasis endemic, Oncomelania hupensis snail status, control technology, and funding were collected and analyzed statistically in the endemic villages of Lushan County from 2007 to 2012. RESULTS: The schistosome infection rate of the residents decreased from 0.04% in 2007 to 0 in 2012. The numbers of advanced schistosomiasis patients decreased from 128 in 2007 to 121 in 2012. No acute schistosomiasis patients were found. The average density of living snails decreased from 0.06 snial/0.1 m2 to 0.05 snail/0.1 m2, with the decreased rate of 16.67%, and no schistosome infected snails were found. However, the snail area increased from 15.84 hm2 in 2007 to 52.12 hm2 in 2012, with the rise rate of 229.04%. The year per capita was 200.48 yuan, the cost of the infection rate decreasing by 1% was 949,900 yuan, and the cost of living snail density decreasing by 1% was 5,698,200 yuan. CONCLUSION: The cost-effectiveness of comprehensive control strategy which mainly controls the schistosomiasis infection source is relatively good in Lushan County from 2007 to 2012. PMID- 24490369 TI - [Effect of nursing intervention on improving quality of life of patients with advanced schistosomiasis]. AB - OBJECTIVE: To evaluate the effect of nursing intervention on the quality of life of patients with advanced schistosomiasis. METHODS: A total of 226 cases of advanced schistosomiasis were randomly divided into a control group and an experimental group (113 cases each). The patients in the control group received the conventional nursing, while the patients in the experimental group received the conventional nursing plus other interventions such as the health education, psychological counseling and diet guidance. The complications and scores of life quality of the patients in the 2 groups were observed and compared. RESULTS: The awareness of knowledge about the disease improved from 67.7% to 98.9%, the incidence of complications decreased from 28.3% to 13.3%, and the scores of life quality improved significantly in the experimental group, which were much better than those in the control group. CONCLUSION: The nursing intervention on the quality of life of patients with advanced schistosomiasis is effective. PMID- 24490370 TI - [Surveillance of echinococcosis in Liyang City from 2008 to 2012]. AB - OBJECTIVE: To investigate the Echinococcus infection of people and domestic animals in Liyang City, so as to provide the evidence for the establishment of control measures of echinococcosis. METHODS: The formerly confirmed cases and clue cases were investigated. The Echinococcus antibody in serum of children aged from 7 to 12 years old and adults in key towns and control towns was detected with ELISA, and the antigen in fecal samples of dogs in key towns was also detected. B ultrasound was applied to examine the ELISA positive cases, family member and the neighbored people around them. The sheep in the market were dissected and examined for Echinococcus. RESULTS: The Echinococcus antibody positive rates were 0.93% and 0.52% in children and adults, respectively. The Echinococcus antigen positive rate was 0.95% in dogs. There were no significant difference between the positive rates of the children and adults (CHI2 = 2.124, P > 0.05). No cases were found by ultrasonic examination and no Echinococcus infection was found in the sheep. CONCLUSION: The people with Echinococcus antibody in serum and dogs with antigen in their feces are found in the surveillance of echinococcosis, therefore, there exists the complete chain of transmission in local. Thus, in the prevention and control work for the disease, the monitoring of dog feces, quarantine of sheep from other regions, as well as the population health education in key areas should be strengthened. PMID- 24490371 TI - [Establishment and application of imported falciparum malaria control system in Yangzhou City]. AB - To aim at the characteristics of epidemic situation that the imported falciparum malaria cases increased year by year in Yangzhou City, an imported falciparum malaria control system was established. This control system was based on enhancing the management of returned labor service export persons from falciparum malaria endemic areas, the active medical remind service, the diagnostic capability and health education, and the cooperation of medical personnel and patients, and also avoiding diagnosis delay and misdiagnosis and promoting the treatment in time so as to decrease the serious patients and prevent them from death. After the application of the control system, there were 164 imported falciparum malaria cases from the returned persons of labor service export. The time from the attack of the disease to the diagnosis confirmed decreased from 6.8 days before the application of the system to 2.7 days after the application, and the rate of serious patients was 1.8% and there were no death cases. PMID- 24490372 TI - [Evolution of schistosomiasis control and prevention strategies in hilly regions with schistosomiasis endemic in China]. AB - This article expatiates the epidemiological characteristics, the evolution process of control and prevention strategies and measures in hilly regions with schistosomiasis endemic, especially the research progress and obstacle factors existed in the implementation process of the comprehensive strategy focused on controlling infection source, aiming at providing references for the hilly regions to reach transmission interrupted standard. PMID- 24490373 TI - [Wetland protection and Oncomelania hupensis control]. AB - The wetland is the unique ecosystem that is formed by the interaction between water and land on the earth surface. At present, the wetland ecology and wetland protection is becoming a more and more attention. Oncomelania hupensis is also a wetland creature that is the only snail host for spreading schistosomiasis japonica. The chemical drugs and environmental modification are usually used to the snail control in the schistosomiasis prevention and control. These control measures have different degrees of influence on wetland ecology. In order to meet the requirements of wetland protection, and to strengthen the research of the snail control appropriate technologies on wetland, this paper expounds the influence of different types of wetlands on Oncomelania and the influence of the snail control on wetland ecology. This paper also discusses the countermeasures of snail control of wetlands. PMID- 24490374 TI - [Endemic situation of schistosomiasis after transmission-interrupted in debao county: a 25-year surveillance]. AB - OBJECTIVE: To understand the dynamics of schistosomiasis prevalent factors after the transmission interruption in Debao Country, so as to provide the evidence for establishing a control strategy. METHODS: By using the system sample method combined with environmental sample method, the Oncomelania hupensis snail situation was surveyed through the general survey, round survey and selection check. Schistosomiasis cases were detected from local population and floating population by serological tests and stool tests. RESULTS: Four residual snail foci were found in a village from 1988 to 1991, covering an area of 1024 m2, and 853 snails were dissected but no positive snail was discovered. No schistosomiasis patient was detected among 42,641 persons. No positive was found from 3165 cattle and 2063 wild mice. CONCLUSION: The schistosomiasis situation is stable in Debao County, but the surveillance of schistosomiasis still should be continued. PMID- 24490375 TI - [Progress in researches on active constituents and molluscicidal activity of Sapium sebiferum]. AB - Sapium sebiferum contains a variety of organic acids, flavonoids and phenolic substances, which were linked with the functions of poisoning Oncomelania. Sapium sebiferum is a good plant material of inhibiting Oncomelania. This paper reviews the variety, resources and active ingredients of Sapium sebiferum, and the researches of Sapium sebiferum inhibiting Oncomelania, and forecasts the development of Sapium sebiferum as an inhibiting Oncomelania forest in order to provide the evidence for its penetrating research and development. PMID- 24490376 TI - [Sequential implementing farmland consolidation and replacing cattle with machine to control schistosomiasis]. AB - OBJECTIVE: To evaluate the schistosomiasis control effect of sequential farmland consolidation and replacing bovine with machine. METHODS: Two farmlands of Qianjiang City were selected as experimental districts, and the sequential implementing farmland consolidation and replacing bovine with machine were carried out. The schistosomiasis epidemic situation was observed continuously. RESULTS: From 2008 to 2012, the human schistosome infection rate decreased by 78.90%, in which the seropositive rate decreased by 47.88% (chi2 = 368.58, P < 0.01) and the stool positive rate decreased by 55.88% (chi2 = 29.92, P < 0.01). The schistosome infection rate of cattle was 2.54% in 2008, but from 2009, there were no cattle in the area. The Oncomelania snail area decreased by 54.78%, and the rate of frames with living snails and the mean density of living snails decreased by 76.49% and 72.63% (chi2 = 11.34, 12.86, P < 0.01) respectively. Since 2009, no infected snails were found. CONCLUSION: The sequential implementing farmland consolidation and replacing cattle with machine can effectively control the transmission of schistosomiasis. PMID- 24490377 TI - [Epidemic monitoring of schistosomiasis in Huangchang Village, Shashi District, from 2005 to 2010]. AB - OBJECTIVE: To understand the changes of epidemic situation of schistosomiasis in Shashi District, Jingzhou City. METHODS: From 2005 to 2010, each year, from April to May, thestatus of Oncomelania snails were investigate by using the systematic sampling approach; in October, the inhabitants aged over 6 years were screened by indirect hemagglutination assay (IHA) and the positive persons received the etiological examination (Kato-Katz technique). All the farm cattle in pens were examined by using the plastic cup jacking hatching method. The data of control measures, and the nature and society data were collected annually. All the data were analyzed systematically. RESULTS: From 2005-2010, the positive rate of blood tests was from 16.47% to 26.84%, assuming an ascend trend; the positive rate of stool examinations was from 2.13% to 4.44%, assuming a downward trend; the infection rate of cattle was from 1.56% to 18.00%, assuming a downward trend in volatility. The area with snails, the appearance rate of frames with living snails, and the average density of living snails assumed ascend trends. CONCLUSION: The prevalence of schistosomiasis presents a downward trend in volatility, and the snail status assumes a ascend trend. Therefore, the prevention and control measures still should be strengthened. PMID- 24490378 TI - [Effect of land consolidation project on detention of Oncomelania hupensis snails in flood at Yangtze River beach]. AB - OBJECTIVE: To explore the effect of land consolidation project on the detention of Oncomelania hupensis snails in the flood at the Yangtze River beach. METHODS: The land consolidation project including removing wild willow groves, cutting the high and filling the low, and improving the slope was carried out at the Yangtze River beach in 2011, and the status of snails was investigated before and after the project, respectively, at the end of the flood season. RESULTS: Before the project (2010), at the end of the flood season, the rate of the frames with snails was 96.5% and the snail density was 3.655/0.1 m2. After the project (2012), at the end of the flood season in the same area, the rate of the frames with snails was 2.0% and the snail density was 0.015/0.1 m2 (chi2 = 357.29, P < 0.01). CONCLUSION: The land consolidation has a significant effect on the detention of snails in the flood at the Yangtze River beach. PMID- 24490379 TI - [Surveillance of intestinal nematode infections in Nanjing City from 2008 to 2012]. AB - OBJECTIVE: To understand the intestinal nematode infection status of Nanjing City, so as to provide the evidence for formulating the preventive strategy and measures. METHODS: The eggs of intestinal nematodes were detected by Kato-Katz technique in population and eggs of Enterobius vermicularis were detected in children and low-grade primary school students by the transparent adhesive tape anal swab method. RESULTS: The fecal specimens from 45,645 individuals were tested, and of those, 167 were found to be infected with intestinal nematodes. The total infection rate was 0.36%, and the infection rates of Ascaris lumbricoides, hookworm, and Trichuris trichiura were 0.18%, 0.03%, and 0.15%, respectively. Totally 43,356 children and low-grade primary school students were surveyed for Enterobius vermicularis infection, and the infection rate was 0.31%. CONCLUSION: The prevalence of intestinal nematodes of population is low in Nanjing City. However, we still need to strengthen health education and regular monitoring. PMID- 24490380 TI - [A clinical study on lamivudine treatment for advanced schistosomisis with chronic B hepatits]. AB - OBJECTIVE: to explore the clinical effect of LVD on patients with advanced schistosomiasis with chronic B hepatitis and on the course of disease development. METHODS: A total of 58 patients with advanced schistosomiasis with chronic B hepatitis were enrolled and randomly divided into the treatment group (30 cases) and the control group (28 cases).patients in the treatment group received routinet colligative treatment and LVD 100 mg daily, while patients in the control group received routinet colligative treatment only.All the patients were followed up for 36 +/- 3 months. RESULTS: The mortality rate was 13.33% vs. 55.56% in the treatment and control (P < 0.01). The patients whose Child-Pugh score decreased by more than 2 were 89.2% vs. 62.3% (P < 0.05). After treatment the serum ALT TBIL levels dropped, the serum albumin level increased and The improvement of liver function in the treatment group was better than that in the control group(P < 0.01). The HBeAg and HBV-DNA negutive rate in the treatment group were higher than those in the control (P < 0.01). The HBV-DNA negative rate in thetreatment group was 93.3% at the end of 12 weekes. The rate of YMDD mutations was 6.7%, 23.3% and 40% in the treatment group at the end of 48 , 96 and 144 weeks. LVD and ADV can inhibit virus replication and the relative stability liver function remained the same in most YMDD mutation patients. CONCLUSION: LVD can inhibit virus replication rapidly and improveliver function, prevent exacerbation in patients with advanced schistosomiasis with chronic B hepatitis, LVD and ADV can inhibit virus replication and improve liver function in most YMDD mutation patients. PMID- 24490381 TI - [Epidemiological status of human intestinal nematodiasis in Yangzhou City, Jiangsu Province]. AB - OBJECTIVE: To understand the current epidemiological status of human intestinal nematodiasis. METHODS: Fresh feces of subjects were collected and the ova of intestinal nematodes were detected by Kato-Katz technique. Enterobius vermicularis was detected by the cellophane anal swab method. RESULTS: A total of 21 persons were ova positive among the 5666 subjects with 0.37% infection rate, and 51 persons were Enterobius vermicularis positive among 13,713 subjects with 0.37% infection rate. It was deducted that there were about 20,000 people infected with intestinal nematodes in Yangzhou City. CONCLUSION: There are some people infected with intestinal nematodes. Therefore, health education and surveillance of intestinal nematode infections still need to be strengthened PMID- 24490382 TI - [Epidemic situation of acute schistosomiasis in Nanchang City of Jiangxi Province from 2005 to 2012]. AB - OBJECTIVE: To understand the endemic regulation of acute schistosomiasis in Nanchang City of Jiangxi Province from 2005 to 2012 so as to provide the reference for policy-making of schistosomiasis control. METHODS: The data of acute schistosomiasis were collected and analyzed with the descriptive epidemiology method in Nanchang City from 2005 to 2012. RESULTS: A total of 52 acute schistosomiasis cases were reported in Nanchang City from 2005 to 2012. The morbidity of acute schistosomiasis was 0.003 46% in 2005, and it was 0 in 2012. The morbidity of acute schistosomiasis in different years was significant different (chi2 = 61.077, P < 0.01). The duration of incidence was from May to November, but the peak of the incidence was July. The sex ratio between males and females was 4.78:1 (43:9, chi2 = 22.231, P < 0.01). The ages of cases showed double humps, namely the 6-15 years' group and 30-40 years' group. Most of the acute cases were farmers (65.38%), students (25.00%), and fishermen (3.85%). Fishing and swimming were the main infection ways, with the infection rates of 63.46% and 26.92%, respectively. CONCLUSION: The susceptible populations are peasants and young students; therefore, we should strengthen health education for these high-risk groups. PMID- 24490383 TI - [Clinical observation on abnormal glucose metabolism of cirrhosis of different classified child-pugh in schistosomiasis patients]. AB - OBJECTIVE: To study the abnormal glucose metabolism of cirrhosis of different classified Child-Pugh in schistosomiasis patients. METHODS: A total of 90 schistosomiasis patients with different classified Child-Pugh cirrhosis were investigated for their fasting blood glucose (FBG), 2-hour blood glucose (2hBG), 3-hour blood glucose (3hBG), free insulin (FINS), insulin release index (IRI) and insulin resistance index (IRI). RESULTS: With the increasing of classified Child Pugh, the abnormal glucose metabolism of the 90 schistosome cirrhosis patients aggravates, but most of FBS was normal or increases slightly. There was only one female patient in 7 patients with diabetes mellitus of liver. CONCLUSION: The ratio of abnormal glucose metabolism of schistosomiasis cirrhosis patients is less, and most of them are younger males. PMID- 24490384 TI - [Clinical experience on treating Toxoplasma gondii infection during pregnancy by using acetyl spiramycin combined with azithromycin]. AB - OBJECTIVE: To explore an effective therapy for pregnant Toxoplasma gondii infection by using acetyl spiramycin combined with azithromycin. METHODS: ELISA and PCR were used to diagnose and evaluate the therapy efficiency to toxoplasmosis in pregnant women. RESULTS: The serological test showed that the positive rates of specific antibodies IgM and IgG to Toxoplasma gondii in 285 pregnant women were 1.05% (3/285) and 5.97% (17/285), respectively. All the 3 cases of serum IgM positive pregnant women received the amniotic fluid PCR tests for Toxoplasma gondii DNA and 2 were positive, and they received spiramycin combined with azithromycin. After the therapy, their serum IgM antibody specific to Toxoplasma gondii and positive amniotic fluid PCR test for Toxoplasma gondii DNA turned to be negative. CONCLUSION: Acetyl spiramycin in combination with azithromycin is effective in the treatment of pregnant toxoplasmosis. PMID- 24490385 TI - [Endemic status of schistosomiasis in People's Republic of China in 2012]. AB - This report showed the endemic status of schistosomiasis in P. R. China at national level in 2012. By the end of 2012, the total number of schistosomiasis japonica cases were estimated to be 240597, with a decrease of 16.12% compared with that in 2011. Meanwhile, thirteen acute cases were reported. Compared with 2011, 10.34% more advanced schistosomiasis patients were treated (22988) in 2012. Nationally, around 368741.67 hm2 were found to be infested with Oncomelania hupensis snails by the end of 2012, among which 46.71 hm2 were newly reported. Moreover, 1 189829 cattle were estimated to be raised in epidemic regions with 0.52% of them being infected with Schistosoma japonicum, which experienced a reduction of 23.53% compared with that in 2011. PMID- 24490386 TI - [Views for research development of control of parasitic diseases]. AB - With the social and technological development, new understandings have been emerged for the research development of the control of parasitic diseases. The present review argues that: the traditional point of view for the control of parasitic diseases, eliminating parasites/media, should be updated. For the long term interests of science and human perspective, biological diversity, including the parasite biodiversity, and ecological environment should be paid much more attention during the control of parasitic diseases. The leading role of society, economy and culture should be fully developed in the control of parasitic diseases with the progress of scientific and technology, to find a final way of sustainable development in the control of parasitic diseases. PMID- 24490387 TI - [Obstacle factors in implementation of integrated schistosomiasis prevention and control strategies with emphasis on infectious source in hilly endemic regions]. AB - OBJECTIVE: To analyze the main obstacles existing in the implementation of integrated schistosomiasis prevention and control strategies with emphasis on infection source in hilly endemic regions, and to find out the current priority issues in schistosomiasis prevention and control, so as to provide the evidence for further solutions. METHODS: Two typical hilly schistosomiasis endemic regions in Sichuan Province, including Pujiang County of Chengdu City and Dongpo District of Meishan City, were selected as research areas. A framework of obstacle factors in the implementation of integrated schistosomiasis prevention and control strategies with emphasis on infectious source in hilly endemic regions was built by literature review, and the management and technical personnel who worked on schistosomiasis prevention and control in eight different industries (health, agriculture, forestry and so on) and five levels (provincial, city, county, township and village levels) were investigated by questionnaires in the way of nominal group. RESULTS: One hundred and fifty-three management and technical personnel in different industries and different levels were investigated. The questionnaire recovery rate (experts' positive coefficient) was 100%. The results showed that the first four problems needing to be concerned in the implementation of integrated schistosomiasis prevention and control strategies with emphasis on infection source were eliminating Oncomelania hupensis snails by projects, health education, examination and treatment for schistosomiasis persons, and harmless treatment of night-soil and safe water supply. The focuses of two counties in the implementation of integrated strategy measures were different. The harmless treatment of night-soil and safe water supply was the most important measure in Pujiang County, while the elimination of snails by projects was the most in Dong po District. CONCLUSIONS: As the differences in the situation of epidemic areas and the existed condition of the prevention and treatment progress, the comprehensive schistosomiasis control measures should be adjusted according to the local conditions in the implementation of integrated schistosomiasis prevention and control strategies with emphasis on infection source. PMID- 24490388 TI - [Effect of environmental change in marshland after implementation of Three Gorges Reservoir Project on schistosomiasis in Jiangsu Province]. AB - OBJECTIVE: To investigate the effect of environmental change in marshland after the implementation of the Three Gorges Reservoir Project on schistosomiasis in Jiangsu Province. METHODS: The hydrologic data of Nanjing City in Jiangsu section of the Yangtze River, and the data regarding the marshlands, the snail status and schistosomiasis morbidity in areas adjacent to the Yangtze River in Jiangsu Province were collected, and field snail surveys were performed in typical marshlands. RESULTS: Following the implementation of the Three Gorges Reservoir Project, the water level in Nanjing section of the Yangtze River appeared a year dependent gradual decline tendency. The mean peak water level on January to March, 2012 (spring) increased by 0.41 m as compared to that before the construction of the project in 2002, while the peak water level on April to December, 2012 decreased by 0.32 m as compared to that before the construction of the project in 2002. The endemic situation of schistosomiasis showed a decline tendency in areas adjacent to the Yangtze River in Jiangsu Province. The area with infected snails along the Yangtze River was 0, the positive rates of serological tests and parasitological tests of the population were 0.73% and 0.004%, respectively in 2012. CONCLUSIONS: Both the schistosomiasis morbidity and snail status appear a decline tendency in areas adjacent to the Yangtze River along the lower reaches of the Yangtze River, Jiangsu Province after the implementation of the Three Gorges Reservoir Project. PMID- 24490389 TI - [Construction of platform of Schistosoma japonicum infection real-time monitoring and early warning along Yangtze River]. AB - OBJECTIVE: To construct a platform for Schistosoma japonicum infection real-time monitoring and early warning in marshlands along the Yangtze River. METHODS: The data of the status of Oncomelania hupensis snails, schistosomiasis endemic situation, marshland environment status, and other basic information were collected and analyzed comprehensively in marshlands along the Yangtze River in Jiangsu Province, and a schistosomiasis endemic situation electronic map was established. Through the GPS and 3G technology, the short messaging service (SMS) alerts were sent to the fishermen when they entered the areas of different schistosomiasis endemic levels in real-time. RESULTS: The SMS alerts reminded the fishermen to adopt the suitable interventions to reduce or avoid the schistosome infection. In addition, the data of moving track of mobile phones of fishermen, and the examination and treatment of schistosomiasis at each monitoring point were collected and analyzed comprehensively and then systematic analysis reports of schistosomiasis situation prediction, early warning, related evaluation, etc. were created in real-time. CONCLUSION: The platform for Schistosoma japonicum infection real-time monitoring and early warning in marshlands along the Yangtze River has a certain application value for schistosomiasis prevention and control work of Jiangsu Province and even whole country. PMID- 24490390 TI - [Relationship between changes of herbaceous plants and Oncomelania hupensis snail distribution under walnut forest of inhibition of snails in mountainous regions of Yunnan Province]. AB - OBJECTIVE: To explore the relationship between the changes of herbaceous plants and Oncomelania hupensis snail distribution under the walnut forest of inhibition of snails in mountainous regions of Yunnan Province. METHODS: The experimental field was established at Sanying Village of Eryuan County, Yunnan Province, where the "Flourishing Forest and Controlling Snails Project" was implemented. The different stand ages (2, 4, 6, 8, 10 years)of walnut forest in experimental groups were selected based on the method of space replacing time, and the non stocked land was served as a control group. The growth of forest, change of snails, number, biomass, overcast, height of the herbaceous plant and the soil moisture were investigated. RESULTS: The crown closure of 6-year-old walnut forest of inhibition of snails was 0.65. There were 11 species of herbaceous plant belonging to 11 genera, 6 families in 10-year-old forest and its crown closure was 0.77. Compared with the control group, the numbers of families, genera, and species of the 10-year-old forest were decreased by 64.71%, 69.44%, and 77.08%, and the biomass, overcast, and height of it decreased by 12.63%, 19%, and 22.18%, respectively. The soil moisture content (0-20 cm) monthly changes were increased obviously with the increase of stand age. There were no snails besides the control group and 2-year-old walnut forest. Compare with the control group, the occurrence rate of frames with living snails in the 2-year-old walnut forest was decreased by 50%, which was 1.25%. The density of living snails was decreased by 60.16%. CONCLUSIONS: The construction of walnut forest of inhibition of snails in mountainous regions of Yunnan Province are suitable for controlling the growth of herbaceous plants and altering the environment of snails. If the coalescence intercropped with crops is carried out, it is not only beneficial to the construction of good ecological environment, but also improves the utilization efficiencies of land, light, and thermal resource, and the income of peasants. PMID- 24490392 TI - [Development and assessment of Schistosoma japonicum antibody test kit (IHA)]. AB - OBJECTIVE: To develop a Schistosoma japonicum antibody test kit (IHA). METHODS: According to the requirement of Good Manufacturing Practice (GMP) and Quality Control (QC) of drugs, the components of kit as well as its preparation method and procedure were studied, and the test kit was assembled and its diagnostic effect was assessed. RESULTS: The sensitivity and specificity were up to 94.49% and 97.14% when testing the serum samples of chronic schistosomiasis patients and normal serum samples by the kit, respectively. The Youden Index of the Kit was 0.92. The cross reaction rates with paragonimus and trichina were 15.00% and 10.00%, respectively. Compared with ELISA and another IHA kit produced by An'Ji company which were used to test schistosome antibody in residents of endemic areas at the same time, the coincident rates of the developed kit were 93.06% and 92.25%, respectively. CONCLUSION: The IHA kit for Schistosomajaponicum antibody has a high sensitivity and specificity, and has the value of application and popularization in the field. PMID- 24490391 TI - [Effect of a novel plant molluscicide "Luo-wei" against Oncomelania hupensis in plateau mountain areas]. AB - OBJECTIVE: To evaluate the effect of a novel plant molluscicide, 4%"Luo-wei" (Tea seed distilled saponins, TDS) against Oncomelania hupensis snails in plateau mountain areas in Yunnan Province. METHODS: The immersing and spraying experiments were carried out in the ditches and grassland of Xiaolian Administrative Village in Heqing County, Yunnan Province, to assess the molluscicidal effect of 4% TDS comparing with 50% wettable powder of niclosamide ethanolamine salt (WPN) in different environments and time. RESULTS: After immersion for 24, 48 h and 72 h, the snail death rates were 70.67%, 87.33% and 98.67% in the TDS group, whereas being 77.33%, 96.67% and 100.00% in the WPN group, respectively. The differences of the death rates between the two groups 24 h and 72 h after immersing were not statistically significant ( chi2(24h) =1.73, chi2(72h) = 2.01, both P values > 0.05). Seven days after the immersing experiments, the occurrence rate of frames with living snails and the death rate of snails were 20.00% and 93.03% in the TDS group, while those were 13.33% and 95.76% in the WPN group, and there were no significant differences of the 2 indexes between the 2 groups ( chi(2)(Occurrence rate) = 2.27, chi(2)(Death rate) = 0.94, all P values > 0.05). After spraying for 1, 3, 7 d and 15 d, in both groups, the occurrence rates of frames with living snails and the average densities of living snails gradually declined, while the death rates of snails gradually increased with the extension of time. There were no statistically significant differences of the above 3 indexes between the 2 groups (all P values > 0.05). Fifteen days after the spraying experiment, the occurrence rate of frames with living snails and the adjusted death rate of snails were 15.00% and 87.39% in the TDS group and those were 16.67% and 89.32% in the WPN group, respectively. CONCLUSION: The molluscicidal effect of TDS is satisfying in plateau mountain areas, and the molluscicide is worthy of further extension and application. PMID- 24490393 TI - [Population genetic study of Oncomelania hupensis from three provinces in lower reaches of Yangtze River]. AB - OBJECTIVE: To analyze the population genetic structure and genetic diversity of Oncomelania hupensis population from Jiangxi, Anhui and Jiangsu provinces along the lower reaches of the Yangzte River in order to explore the application values of rDNA-ITS molecular markers in the surveillance of snail dispersal. METHODS: The samples about 9 species of O. hupensis snails were collected separately from Jiangxi, Anhui and Jiangsu provinces, and their genomes were extracted, then the partial gene of rDNA-ITS was amplified, cloned and sequenced. Next, the population genetic diversity parameters, including Fixation index (F(st)), genetic distance, and genetic variation were calculated. By using the neighbor joining method, the family map was constructed based on the haplotype. RESULTS: A total of 78 haplotypes among 93 sequences were acquired from 9 populations. The average haplotype diversity and nucleotide diversity of 9 populations were 0.988 and 0.012 88, respectively, which showed that the genetic diversity level of O. hupensis snail population was high. The variation was found mainly among the samples, the genetic distances between populations were ranged from 0.001 6 to 0.002 3, which showed a higher degree of genetic differentiation among snail populations. The family map showed that all the haploid types could be divided into three major branches. CONCLUSIONS: The genetic diversity of O. hupensis population in Jiangxi, Anhui and Jiangsu provinces along the lower reaches of the Yangtze River mainly exists among individuals, and there are no obvious genetic differences among populations. The application of rDNA-ITS molecular markers in surveillance of snail dispersal is worth further discussing. PMID- 24490394 TI - [Effect of Pulsatilla chinensis (Bunge) Regel saponins against juvenile and adult Schistosoma japonicum in vitro]. AB - OBJECTIVE: To explore the effect of Pulsatilla chinensis (Bunge) Regel saponins (PRS) against juvenile and adult Schistosoma japonicum and to compare its efficacy with praziquantel (PZQ) in vitro. METHODS: 3 h, 7 d, 14 d schistosomula and 42 d adult schistosomes were incubated with 0, 1, 5, 10, 20 and 30 microg/ml PRS for 4, 24, 48 and 72 hours, then the states of them were observed. The changes of the surface of S. japonicum incubated with 30 microg/ml PRS and PZQ within 4 hours were observed by a scanning electron microscope. RESULTS: The sensitivity of 3 h, 7 d, 14 d schistosomula and adults of S. japonicum to 1, 5, 10, 20, 30 microg/ml PRS displayed a time and dose dependence. All the worms died in 30 microg/ml PRS after 4 hours. The dead worm body appeared a gray-white color accompanied with their altered morphogenesis and opaque body. The tegumental surface of adults with different degrees of damages was observed by the electron microscope within 4 hours affected by PRS in vitro. CONCLUSIONS: The effects of PRS against S. japonicum in different developmental stages in vitro show that PRS may eventually have a therapeutic potential in the treatment or prevention of S. japonicum infection and is expected to become a new anti-schistosome drug. PMID- 24490395 TI - [Killing effect of exogenous NO on cercariae of Schistosoma japonicum in vitro]. AB - OBJECTIVE: To explore the killing effects of exogenous NO on the cercariae of Schistosoma japonicum in vitro and the blocking effects of NO inhibitors. METHODS: The cercariae of S. japonicum were collected from naturally infected snails, and then formulated into a 1000 cercariae/ml suspension with RPMI 1640 medium. The relationship between the killing effects and doses of exogenous NO on cercariae were investigated through the suspension with different concentrations of NO generating agents (SNP) and negative control (without SNP). On the other hand, the blocking effects were also investigated through the suspensions being added 2.00 mmol/L SNP and four different NO inhibitors, Hb, FeSO4, L-cyst, L-arg and their combination. Additionally, the appropriate positive(2.00 mmol/L SNP) and negative controls (without NO generating agent) were used. RESULTS: The mortality rates of cercariae were (8.3 +/- 1.1)%, (6.26 +/- 2.3)%, and (9.3 +/- 1.0)% in the SNP 0.06, 0.1 and 0.2 mmol/L groups, respectively, and there were no statistically significant differences between the blank control group and the above-mentioned three groups, respectively (P > 0.05). The mortality rates of cercariae were(23.5 +/- 3.9)%, (46.0 +/- 1.1)%, and (59.4 +/- 0.5)% in the SNP 0.50, 1.00 and 2 mmol/L groups, respectively, and there were statistically significant differences between the blank control group and the above-mentioned groups, respectively (P < 0.05). The mortality rates of cercariae were (30.1 +/- 1.2)%, (45.1 +/- 1.4)%, (31.1 +/- 1.3)%, (34.2 +/- 3.1)%, (47.8 +/- 2.0)%, (49.1 +/- 0.6)%, and (44.2 +/- 0.1)% in the 2.00 mmol/L SNP suspensions which were added of Hb, FeSO4, L-cyst, L-arg, FeSO4+L-cyst, FeSO4+L-arg, FeSO4+L-arg+L-cyst, respectively. Compared with the 2.00 mmol/L SNP suspension, the mortality rates of the above-mentioned groups declined, and there were statistically significant differences (P < 0.05). CONCLUSION: There are killing effects of exogenous NO on the cercariae of S. japonicum in vitro, and four different NO inhibitors, Hb, FeSO4, L-cyst, L-arg and their combinations have some different degrees of blocking effects. PMID- 24490396 TI - [Investigation on infection sources of schistosomiasis in mountainous regions, Nanjian County, Yunnan Province]. AB - OBJECTIVE: To understand the types of schisotsome infection sources and their roles in schistosomiasis transmission in mountainous endemic regions in Yunnan Province, so as to provide the evidence for implementing the comprehensive control measures based on infection source control. METHODS: Two villages of typical mountainous regions in Nanjian County were chosen for field investigation. The Oncomelania hupensis snail status was surveyed by the methods of systematic and environmental sampling. The infections of schistosomiasis were surveyed in residents with the indirect haemagglutination and the hatching method, in livestock with the hatching method and in wild animals with the anatomical method and the hatching method. The distribution and pollution status of wild faeces were investigated in the snail environments nearby villages or with livestock frequent activities. The positives of schistosomiasis in wild faeces were tested with the hatching method. The pollution index of wild feces was calculated. RESULTS: A total of 533.56 hm2 were investigated in two villages, and the area with snails was 16.52 hm2. The rate of frame with snails was 1.03%, the average density of snails was 0.07 snails/0.1 m2, and no positive snails were found. The positive rate of blood examinations of population was 1.61%, but no persons were positive with the hatching method. The infection rates were 0.90%, and 0.62% in cattle and equus, respectively, and there were no positives in other livestock. Totally 472 piles of wild feces of 6 species (human, cattle, equus, goat, pig and dog) distributed in the investigation areas, and among them, the densities of wild feces of cattle, equus, and dog were 7.2, 4.3 piles/hm2, and 2.1 piles/hm2 respectively, being relatively higher than others. The hatching positive rates of wild faeces of cattle, equus, and dog were 2.27% (3/132), 2.63% (2/76), and 3.70% (1/27), respectively. The relative pollution indexes of wild faeces of cattle, equus, and dog were 80.68%, 15.89%, and 3.43%, respectively. CONCLUSIONS: After schistosomiasis transmission is controlled, the potential epidemic factors still remain in the mountainous endemic regions of schistosomiasis in Yunnan Province. The cattle are still the most infection source of schistosomiasis, but equus and dog as infection sources should be not neglected. We should extend the investigation and monitor scope of the infection sources, and carry out scientific and feasible control technique and management measures. PMID- 24490397 TI - [Epidemiological analysis of malaria prevalence in Shandong Province in 2012]. AB - OBJECTIVE: To understand the characteristics of malaria prevalence and epidemic in Shandong Province in 2012 so as to provide the evidence for improving the work of the elimination of malaria. METHODS: The epidemiological data of malaria cases collected from the Disease Surveillance Information Reporting System of Chinese Center for Disease Control and Prevention were analyzed with the descriptive epidemiological method for epidemiological characteristics of malaria. RESULTS: A total of 93 malaria cases were reported in Shandong Province in 2012 with the incidence of 0.097 per 100 thousand, with a reduction of 19.83% as compared to 2011. There were 93 imported cases which decreased by 4.12% compared with 97 cases in 2011 and it was the first year that there was no local infection. Jining, Qingdao and Weihai cities reported more cases, with 62.37% (58/93) of the total number of the whole province. Totally 93.55% of malaria cases were imported from Africa, most from Equatorial Guinea, Nigeria and Angola. There were 3 cases of imported ovale malaria firstly reported. CONCLUSIONS: There were no local malaria cases reported in Shandong Province in 2012, but the imported malaria prevention and control was still not optimistic. In order to achieve the goal of malaria elimination in Shandong Province, it needs to continue to strengthen epidemic management, professional training and work supervision, strengthen management, advocacy and detection on the floating population, and explore multisectoral coordination mechanisms. PMID- 24490398 TI - [Field evaluation of a novel plant molluscicide "Luo-wei" against Oncomelania hupensis IV molluscicidal effect in field of river beach in Dongzhi County, Anhui Province]. AB - OBJECTIVE: To evaluate the field effect of the plant molluscicide "Luo-wei" (tea seed distilled saponins, TDS) against the snail Oncomelania hupensis in the river beach in Anhui Province. METHODS: The immersing and spraying experiments were carried out in the river beach in Dongzhi County, Anhui Province, to assess the molluscicidal effect of 4% TDS comparing with 50% wettable powder of niclosamide ethanolamine salt (WPN). The chi(2) test or Fish's exact test was used to examine the differences between or among the molluscicidal effects by different environments, molluscicides, application methods, or days after the intervention. Meanwhile, the cost-effectiveness of the two molluscicides was analyzed. RESULTS: After 1, 2 , 3 d and 7 d of the immersion, the snail death rates in both TDS group and WPN group increased gradually, the snail death rates in the two groups after immersing for 7 d were 94.62% and 99.24%, respectively, and there was no significant difference between them ( chi(2) = 3.30, P > 0.05). After 1 , 3 , 7 d and 15 d of spraying, the snail death rates were 70.82%, 79.75%, 85.11% and 91.65% in the TDS group, and 77.71%, 84.27%, 91.90% and 95.58% in the WPN group, respectively, and the differences among the snail death rates of the two groups at each time point were statistically significant (all P values < 0.05). The costs of spraying were 316.71 yuan per 100 m2 for TDS and 309.71 for WPN. CONCLUSIONS: The molluscicidal effect of TDS has reached the requirements of national standard on nature source pesticides in the river beach of the middle and lower reaches of the Yangtze River. It is necessary to further evaluate its cost-effectiveness in large-scale field experiments in the future. PMID- 24490399 TI - [Analysis of malaria epidemic situation in Shantou City from 1992 to 2012]. AB - OBJECTIVE: To understand the epidemic characteristics, regular pattern and trend of malaria in Shantou City, Guangdong Province. METHODS: The historical data of malaria were collected and analyzed by the descriptive epidemiological methods in Shantou City from 1992 to 2012. RESULTS: A total of 556 malaria cases were reported in Shantou City from 1992 to 2012, with the annually incidence of 0.056 cases per 10 thousand. After 2003, no secondary cases and local outbreak of malaria occurred. The ratio of male to female was 3.34: 1, and 82.73% of the patients were aged from 15 to 45 years. The peasants (including workers from the village) and factory workers most easily suffered from malaria with a proportion of 39.21% and 18.35%, respectively. Nevertheless there was an exception in some year. CONCLUSION: There is still some reported cases of malaria each year in Shantou City, therefore, we should continue to strengthen the preventive and monitoring measures. PMID- 24490401 TI - [Effect of execution of Global Fund Malaria Project in Suining County]. AB - OBJECTIVE: To evaluate the effect of the execution of the Global Fund Malaria Project in Suining County. METHODS: The data of malaria information and the execution of the Global Fund Malaria Project in Suining County from 2006 to 2012 were collected and analyzed statistically. RESULTS: From 2006 to 2012, 215 confirmed malaria cases were reported, including 213 cases of vivax malaria and 2 cases of falciparum malaria. With the implementation of the Global Fund Malaria Project, the malaria cases decreased from 37 cases in 2006 to 1 case in 2012, and the incidence decreased from 0.28/10000 to 0.01/10000 with the decline rate of 96.43%. CONCLUSION: The implementation of the Global Fund Malaria Project plays a significant role on malaria control in Suining County. PMID- 24490400 TI - [Comparison of molluscicidal effects of two snail control methods with plastic film covering in hilly regions]. AB - OBJECTIVE: To evaluate and compare the molluscicidal effects of colorless and black plastic film covering methods against Oncomelania hupensis snails in hilly regions. METHODS: A hilly setting with high snail density was selected as the study area, and three groups including the colorless plastic film covering method, black plastic film covering method and control were designed. The snail surveys were conducted 1, 3, 7, 15 days and 30 days in each group following plastic film covering, and the mortality of snails and reduction of snail density were investigated. The air temperature, soil surface temperature in the control group, as well as the soil surface temperature and the temperatures 5 cm and 15 cm under the soil within the film were recorded. RESULTS: The mortality rates of snails were 36.84%, 78.94%, 95.92%, 100.00% and 99.45% 1, 3, 7, 15 days and 30 days following colorless plastic film covering, respectively, and the snail density after 30 days of covering reduced by 99.36% as compared to that before covering, while the mortality rates of snails were 10.08%, 8.94%, 6.11%, 26.15% and 49.32% 1, 3, 7, 15 days and 30 days following black plastic film covering, respectively, and the snail density after 30 days of covering reduced by 58.10% as compared to that before covering. There were significant differences in the 1 , 3-, 7-, 15-day and 30-day snail mortality rates between the colorless and black film covering groups (all P values <0.01), and a significant difference was detected in the snail density between the two groups 30 days after the film covering (P < 0.001). In addition, the speed, amplitude and duration of the rise in the soil surface temperature within the colorless film were all greater than those within the black film. CONCLUSION: The short-term molluscicidal effect of the colorless plastic film covering method is significantly superior to that of the black plastic film covering method in summer in hilly regions. PMID- 24490402 TI - [Survey of distribution of Enterobius vermicularis infection of children in Huadu District, Guangzhou City]. AB - OBJECTIVE: To understand the status of Enterobius vermicularis infection of children in Huadu District, Guangzhou City so as to provide the evidence for improving the control work. METHODS: In 2012, 24 kindergartens and 24 primary schools were selected as survey sites by the stratified random sampling method and 200 or more children aged below 10 years per site were investigated for the Enterobius vermicularis infection by the cellophane tape method. The relevant influencing factors (environment conditions, sanitary facilities and management system, and health habits of families and individuals) were surveyed with questionnaire, and all the data were analyzed statistically with the Excel software. RESULTS: From September to December, 2012, totally 9 777 children were investigated and 760 ones were detected with Enterobius vermicularis infection (7.77%). With a school as the unit, the highest infection rate reached to 33.82% (69/204). The infection rate in urban areas was 4.63% (195/ 4 213), and the rate in villages was 10.15% (760/5 546) ( chi2 =102.126, P <0.01). The infection rate of preschool children was 3.51% (1 70/4 840) and the rate of school children was 11.95% (590/4 973), and the latter was much higher than the former (chi2 =242.732, P < 0.01). The infection rates of the male and the female were 7.44% (412/5 537) and 8.21% (348/4, 240) respectively ( chi2 = 1.969, P > 0.05). The survey of relevant influencing factors showed that the conditions of the kindergartens were better than those in the primary schools, and the conditions in the urban areas were better than those in the villages. CONCLUSIONS: The Enterobius vermicularis infection of children in Huadu District is high. The control key points should be put on the schools with poor sanitary facilities and environment conditions in villages and urban areas. PMID- 24490403 TI - [Clinical characteristics of 32 cases of tsutsugamushi disease in Suqian Municipality]. AB - OBJECTIVE: To understand the clinical characteristics of tsutsugamushi disease in Suqian Municipality, Jiangsu Province so as to guide the diagnosis and treatment of this disease. METHODS: The clinical data of 32 patients diagnosed as tsutsugamushi disease in our hospital during the past 2 years were analyzed retrospectively. RESULTS: Tsutsugamushi disease occurred frequently between August and December. All the 32 patients had the history of contacting grass and brushwood, and all of them showed the signs of pyrexia, eschar, ulcer, swelling of lymph nodes and rash. Liver damages were observed in 30 cases (93.75%). Pulmonary imaging changes were observed in 14 cases (43.75%). Heart damages were noticed in 9 cases (28.13%). Kidney damages were noticed in 6 cases (18.75%). One case was complicated by multiple organ dysfunction syndromes (MODS) and disseminated intravascular coagulation (DIC). The OX19 and OX2 antigen agglutination reaction of bacillus proteus were negative in all the cases. The OXK antigen agglutination reaction of bacillus proteus was positive in 6 cases (18.75%). Among 32 cases, 24 cases were misdiagnosed in the first visiting clinic. The misdiagnosis rate of the initial diagnosis of this disease reached as high as 75%. Azithromycin was effective. The curative rate was 96.88% and the mortality was 3.13% (1 case). CONCLUSIONS: Clinical characteristics of tsutsugamushi disease are complicated, and it is commonly complicated with liver damages. The Weil-Felix test is not very important to initial diagnosis for tsutsugamushi disease in local. For patients as fever with unknown origin (FUO) and with the liver damage, the diagnosis of tsutsugamushi disease should be reminded. PMID- 24490404 TI - [Optimization of time of artificial population schistosome infected Oncomelania hupensis snails]. AB - OBJECTIVE: To explore the optimizational time of artificial population schistosome infected Oncomelania hupensis snails. METHODS: Under laboratory conditions, the snails were infected with the miracidia of Schistosoma japonicum for 2 h, 3 h and 4 h respectively, and the death rates and the infection rates of the snails, and the quantities of cercariae of each group were observed 60-120 d after the infection, and all the data observed were analyzed to get the optimizational time of artificial population schistosome infected snails. RESULTS: Of the 3 h group, the snail infection rate was the highest and the mortality was the lowest among the 3 groups (P<0.05). The average number of cercariae of the 3 h group was higher than that of the 2 h group (P<0.05), while there was no statistical difference between the 3 h group and the 4h group (P>0.05). CONCLUSION: Under laboratory conditions, the optimizational time is 3 h in artificial population schistosome infected O. hupensis snails. PMID- 24490405 TI - [Surveillance of endemic situation of schistosomiasis in Gaoyou sections in east route of South-to-North Water Diversion Project before water transfer]. AB - OBJECTIVE: To understand the endemic situation of schistosomiasis and the distribution of Oncomelania hupensis snails in Gaoyou sections in the east route of the South-to-North Water Diversion Project before water transfer. METHODS: The Grand Canal, the Sanyang River and the range of 3 kilometers of both sides of the rivers were chosen as the surveillance area in the Gaoyou sections in the east route of the South-to-North Water Diversion Project, and the Gaoyou Lake area adjacent to the east route was also chosen as the surveillance area. The human and livestock schistosomiasis and Oncomelania hupensis snails were monitored by the conventional method. Three underwater snail surveillance sites were set up in the Grand Canal and the Sanyang River respectively, and the net salvage method and the method of attracting snails with rice straw curtains were used to survey the snails underwater in the surveillance sites. RESULTS: The schistosome infected snails, the human and livestock schistosomiasis were not found in the Gaoyou sections in the east route of the South-to-North Water Diversion Project from 2006 to 2012. The snail areas were on the decline in the Grand Canal. The snail was not found in the Sanyang River. A total of 270 kg floatage was refloated and 720 pieces of rice straw curtains were placed in the surveillance sites, and there were no snails in the floatage and the rice straw curtains. CONCLUSION: There is no evidence showing that the snails spread to northward in the Gaoyou sections in the east route of the South-to-North Water Diversion Project. PMID- 24490406 TI - [Survey of the number of eggs in Taenia asiatica gravid proglottids in Dali Prefecture of Yunnan Province]. AB - OBJECTIVE: To observe the number of eggs in the gravid proglottids of Taenia asiatica. METHODS: Twenty gravid proglottids at each end of two adults of T. asiatica were digested by 1% pepsin. Then, the collected eggs were observed and counted by a microscope. RESULTS: The number of eggs in each gravid proglottid were not the same, with the maximum of 132 500, minimum of 44 180, and the average number of 90 051, and there was a significant difference among the different gravid proglottids (t = -3.487, P = 0.003). CONCLUSION: The number of eggs in different gravid proglottids of T. asiatica is evidently different. PMID- 24490407 TI - [Splenectomy and esophagogastric devascularization for advanced schistosomiasis with cavernous transformation of portal vein]. AB - OBJECTIVE: To explore a surgical treatment of advanced schistosomiasis with cavernous transformation of the portal vein. METHOD: The clinical data of 18 patients who suffered from advanced schistosomiasis with cavernous transformation of the portal vein were collected and analyzed retrospectively in the Affiliated Xiangyue Hospital of Hunan Institute of Parasitic Diseases. RESULTS: Two cases were undertaken the endoscopic variceal ligation, and the upper gastrointestinal bleeding happened 32 months and 40 months after the treatment respectively, and they received the splenectomy and esophagogastric devascularization again; 16 cases were undertaken the splenectomy and esophagogastric devascularization. During the follow-up of 6-72 months, no esophageal and gastric varices were found. CONCLUSION: Splenectomy and esophagogastric devascularization is effective in the treatment of advanced schistosomiasis with cavernous transformation of the portal vein. PMID- 24490408 TI - [Surveillance of schistosomiasis endemic situation in Jingzhou City in 2011]. AB - OBJECTIVE: To understand the endemic situation of schistosomiasis in monitoring sites of Jingzhou City in 2011. METHODS: According to the monitoring scheme of the schistosomiasis in Hubei Province, the schistosomiasis endemic situation in human, farm cattle and Oncomelania snails were investigated in 64 monitoring sites of Jingzhou City in 2011 and the results were analyzed statistically. RESULTS: In the 64 monitoring sites, the average schistosome infection rate of residents was 1.48%, and the rate in residents aged 50 years or over was highest. There was no case of acute schistosomiasis infection. There were 170 cases of advanced schistosomiasis. The average infection rate of farm cattle was 1.38%. Among the 3 034.03 hm2 area with snails, the area with schistosome infected snails was 25.65 hm2. The average density of living snails was 0.74 snails/0.1 m2, while the average density of infected snails was 0.000 6 snails/0.1 m2. The infection rate of snails was 0.08%. CONCLUSION: The endemic situation of schistosomiasis in Jingzhou City in 2011 is relatively stable, but the infection rate of farm cattle is higher. Therefore, the preventive measures still should be enhanced. PMID- 24490409 TI - [Changes of historical Paragonimus metacercaria infection rates of freshwater crabs in Yongjia County]. AB - OBJECTIVE: To understand the changes of Paragonimus metacercaria infection rates of freshwater crabs in Paragonimus endemic areas and explore the causes in Yongjia County, Zhejiang Province, China. METHODS: A field investigation was carried out. The freshwater crabs were collected and the metacercaria were separated from the crabs. The infection rates, infectiosities and infection indexes were calculated and the results were vertically compared with the historical findings. The causes of the changes were discussed. RESULTS: Compared with those in 1980, the average infection rate in original endemic areas decreased from 59.71% to 21.50% (P < 0.05), while the infection density decreased from 1.09/g to 0.23/g (P < 0.05). The infection index decreased obviously. In Hesheng Village, it decreased from 4.05 to 0.01 (P < 0.01), in Wuchi Village, it was from 37.90 to 2.91 (P <0.01), and in Daruoyan Scinic area,it was from 5.85 to 0.03 (P < 0.01). Two endemic areas disappeared but two new endemic areas (Sihai Village and Sunshan Village) were found, and in Sunshan Village, the metacercaria infection rate was 100%, the infection density and infection index were 21.30/g and 3 402.68 respectively, which meant it was a super high endemic focus. CONCLUSION: The Paragonimus metacercaria infection rate in crabs is lower than before in Yongjia County, but some super high epidemic focus of paragonimiasis still exists. Therefore, we still should strengthen the control measures. PMID- 24490410 TI - [Investigation on status of Oncomelania hupensis in schistosomiasis transmission interrupted areas of Huangshan City]. AB - OBJECTIVE: To explore a new monitoring method for schistosomiasis transmission interrupted areas, so as to evaluate the monitoring results in counties (districts) to improve the quality. METHODS: Specialized technicians were selected as survey teams to investigate the status of Oncomelania hupensis snails with the random sampling method combined with environmental sampling method every year from 1997 to 2013. RESULTS: From 1997 to 2013, 118 villages of 38 townships of 21 counties were investigated for the snail status, and there were 18 environments with snails in 10 townships of 7 counties. The snail area was 10.91 hm2. CONCLUSION: There are still small snail areas. Therefore, the snail monitoring should still be strengthened by specialized technicians. PMID- 24490411 TI - [Brief discussion on experiences from laboratory certification and accreditation on detection of parasitic diseases]. AB - The laboratory certification and accreditation is the development trend of domestic and international laboratories. The National Institute for Parasitic Diseases, Chinese Center for Disease Control and Prevention passed through the site assessment in September 2012 successfully, 26 items in 8 fields declared were all adopted. This article summarizes some work experiences during carrying out the laboratory certification and accreditation. PMID- 24490412 TI - [Experience of improving achievements of skill competitions of parasitic diseases]. AB - This paper summarizes the experiences of improving the performance of skill competitions of parasitic diseases through reviewing several national and provincial races. PMID- 24490413 TI - [Progress in researches of molecular mechanism of schistosome cercariae infection]. AB - Schistosome cercariae must penetrate skin as an initial step to successfully infect the final host. Proteolytic enzymes secreted from the acetabular glands of cercariae contribute significantly to the invasion process. Nowadays, the researches of molecular mechanism of schistosome infection mainly focus on the cercarial secretions including serine protease and cysteine protease. Previous researches already showed that Schistosoma mansoni penetrates the skin mainly depend on cercarial elastease secreted by cercariae while Schistosoma japonicum penetrates the skin chiefly by cathepsin B2. The illustration of molecular mechanism of schistosome cecariae infection will accelerate the identification of novel vaccines and drug targets. PMID- 24490414 TI - [Study on morphological and functional characterization of hemocytes in snails]. AB - Snails are the intermediate host of Schistosoma and they play an important role in the transmission of schistosomiasis. The snails in different areas present various susceptibilities, which are related to the different hemocytes in the snails. There is not a common standard in the classification of hemocytes, and generally the hemocytes are divided into two categories: a granulocyte and a hyalinocyte. The granulocyte plays an important role in immunization, while hyalinocyte shows a less effect. Besides, soluble factors may also play a role in immunization. PMID- 24490415 TI - [Effect of sand buried on elimination of Oncomelania hupensis snails in marshland along Yangtze River in Jiangdu District, Jiangsu Province]. AB - OBJECTIVE: To evaluate the effect of sand buried on the elimination of Oncomelania snails in the marshland along the Yangtze River downstream. METHODS: The areas along the Yangtze River were chosen as the investigated objects in Jiangdu District, Jiangsu Province. The datum review and field investigations were used to observe the change of snail area after the sand buried. RESULTS: There were 11 sand buried projects along the Yangtze River in Jiangdu District, Jiangsu Province. The snail areas decreased by 93.73% after the sand buried. CONCLUSION: The sand buried is an effective method of snail control in the marshland along the Yangtze River. This method can be combined with economic construction and development projects for popularization and application. PMID- 24490416 TI - [Investigation on intestinal nematode infections of rural people in Jiangning District, Nanjing City]. AB - OBJECTIVE: To understand the prevalence of intestinal nematodiasis in rural people in Jiangning District, Nanjing City, so as to provide the evidence for the establishment of the control programs of the disease. METHODS: The residents and primary and secondary school students aged above 6 years in Tongshan Township, Jiangning District were selected as investigation objectives, and the Kato-Katz technique was used to detect the intestinal nematode eggs in feces of them. RESULTS: Four hundred and ten villagers were detected, and the infection rates of Ascaris lumbricoides and hookworm were 5.12% and 0.98%, respectively. Meanwhile, 407 students were detected, and the infection rates of Ascaris lumbricoides and Fasciolopsis buski were 1.72% and 0.25%, respectively. The infection rates of intestinal nematodes in villagers and students were 6.10% and 1.97%, respectively, and the difference between them were statistically significant (chi2 =8.997, P < 0.05). CONCLUSIONS: The infection rate of intestinal nematodes in rural population of Jiangning District, Nanjing City has decreased obviously, and the rate is higher in villagers than in students. Therefore, the control work in the future should put emphasis on villagers. PMID- 24490417 TI - [Effect of health education intervention in schools of Yanrui Town, Yushan County]. AB - OBJECTIVE: To evaluate the effect of a new mode of health education in schools. METHODS: In the Zhaiqian Primary School, Yanrui Town, Yushan County in a hilly schistosomiasis endemic area, a new mode of health education intervention, i. e. "rewards and punishment + advise others by using one's experience + teachers' participation" was carried out, and the knowledge, attitude and practice of schistosomiasis prevention of the pupils, and the schistosome infection rates of the pupils were investigated and the results were analyzed and compared before and after the intervention. RESULTS: Among 204 pupils investigated, the awareness rate of schistosomiasis prevention knowledge increased from 26.47% before the intervention to 86.76% and 99.51% one and two years after the intervention, respectively; the rate of correct attitude increased from 17.04% to 73.04% and 100%, respectively; the rate of the infested water contact decreased from 83.33% to 26.96% and 0, respectively; the schistosome infection rate decreased from 2.94% to 0.49% and 0, respectively. CONCLUSION: The health education of schistosomiasis prevention in schools is necessary, and the new mode of health education, "rewards and punishment + advise others by using one's experience + teachers' participation" is effective in the prevention from schistosome infection in pupils. PMID- 24490418 TI - [Effect of health education on prevention from schistosome infection in engineering construction workers in Poyang Lake area]. AB - OBJECTIVE: To evaluate the effect of health education on prevention from schistosome infection in engineering construction workers in Poyang Lake area. METHODS: The workers for constructing "De Chang" highway in Poyang Lake area were divided randomly into an experiment group and a control group, "health education + protective skill training" was carried out in the experiment group, whereas, no intervention was implemented in the control group. RESULTS: In the experiment group, the awareness rates of schistosomiasis control knowledge were 7.96% and 96.39% before and after the intervention, respectively; the rates of contacting infested water were 100% and 1.77% pre- and post-intervention, respectively; the work protective rates increased from zero before the intervention to 100% after the intervention; there was no person infected with schistosome after the intervention. However, in the control group, all the indexes above-mentioned had no significant changes. CONCLUSION: The intervention model "health education + protective skill training", can effectively prevent from schistosome infection in engineering construction workers in Poyang Lake area. PMID- 24490419 TI - Talking about the taboo. PMID- 24490420 TI - Gay blood drive attempts to change FDA policy. PMID- 24490421 TI - Out: The climate has changed for gay and lesbian physicians. PMID- 24490422 TI - View from the Hotel California. is it possible to rehabilitate Minnesota's most serious sex offenders? PMID- 24490423 TI - Falling through the cracks. Health insurance policies increasingly include coverage for treatments related to gender dysphoria, but gaps remain. PMID- 24490424 TI - Can we talk about sex? Seven things physicians need to know about sex and the older adult. PMID- 24490425 TI - An ethic for working in Haiti. PMID- 24490426 TI - Fancy. PMID- 24490427 TI - A few minutes with Carol Falkowski, Minnesota's foremost drug abuse expert (interview by Dan Hauser). PMID- 24490428 TI - Physicians need help in the courts. PMID- 24490429 TI - Promoting sexual health. PMID- 24490430 TI - Toward better care for lesbian, gay, bisexual and transgender patients. AB - Studies have shown that the health status of lesbian, gay, bisexual and transgender (LGBT) people generally is worse than that of the population as a whole. This is in part because these individuals have not been well-served by the health care establishment. This article describes ways physicians can begin to better care for this population and provides tips for making practices more welcoming to LGBT patients. PMID- 24490432 TI - [Drug approvals - Epilogue and Outlook]. PMID- 24490431 TI - Sex matters for personalized care. AB - The basic biological variable that distinguishes half the population from the other, sex, is rarely considered integral to the development of personalized treatment strategies. Yet sex is a fundamental aspect of human physiology. This article reviews evidence showing how sex influences patient outcomes and identifies ways to facilitate evidence-, sex-based approaches to patient care. PMID- 24490433 TI - [Hand, foot and mouth disease--more than a harmless "childhood disease"]. AB - Hand, foot and mouth disease (HFMD) is a highly contagious, world-wide distributed viral illness that affects predominantly children. It is caused by several enteroviruses, such as coxsackieviruses A6, A10, A16 and enterovirus 71. In most cases, HFMD follows a benign and self-limiting course. After an incubation period of 3 to 10 days, fever and sore throat, the first symptoms of the disease, appear. A few days later, maculopapular or vesicular eruptions form on the palms and soles as well as in the oral cavity. Since the year 2000, several large HFMD outbreaks have been reported in many Asian regions such as China, Malaysia and Vietnam. In some of these outbreaks, high incidences of severe progressive HFMD forms with some fatalities were observed. Such diseases have been caused primarily by enterovirus 71 strains and were characterized frequently by sudden onset of fever, encephalitis/meningitis and severe respiratory symptoms such as pulmonary edema. Further severe neurological and cardiac complications have also been observed during these outbreaks. Recently, some HFMD outbreaks caused by the coxsackievirus A6 have been reported in several parts of the world. These illnesses also affected adults and were characterized by more severe symptoms of "classical" HFMD. In addition, outbreaks of coxsackievirus-A6-associated HFMD in many countries were associated with onychomadesis, with the loss of nails occurring up to two months after initial symptoms. Treatment of "classical" HFMD is usually symptomatic, a generally recommended antiviral therapy does not exist. In severe HFMD cases, suitable treatment also encompasses mechanical ventilation, as well as the additional application of antiviral agents such as ribavirin. In the last years, several novel agents with good in vitro and in vivo activity against enteroviruses have been developed. A vaccine against HFMD is not yet available. PMID- 24490434 TI - [Food supplements in primary prevention--methodological aspects]. AB - The terms "evidence" or "evidence-based medicine" (EBM) dominate the current biomedical debate. When asked about the usefulness of nutritional supplements, increasingly reliable studies and "evidence-based" recommendations are demanded. However, usually, it remains unclear what is meant by "evidence" and "evidence based medicine". The aim of the current paper is to clarify and explain why continuous designed evaluation instruments, proofing the efficacy of pharmacological active compounds, cannot be applied without modifications to prove the benefits of nutrients. The focus bases on the following questions: (a) What does evidence-based medicine exactly means and how does it differ from non evidence-based medicine? (b) What is the meaning of "evidence" and "evidence based statements"? (c) What types of studies are suitable for securing evidence? (d) How can be drawn summarizing conclusions from various, sometimes divergent, results of single studies? (e) Which specific characteristics must be considered in the nutrition context? PMID- 24490435 TI - [Cancer in old age]. PMID- 24490436 TI - [AMTS and MM - Quo vadis, clinical pharmacy?]. PMID- 24490437 TI - [Interleukin 17, a promising target for the treatment of psoriasis]. PMID- 24490438 TI - [In impaired ability to drive action is needed]. PMID- 24490439 TI - [Subcutaneous Rituximab is effective and safe]. PMID- 24490440 TI - Cough. PMID- 24490441 TI - Combating cough--etiopathogenesis. PMID- 24490442 TI - Diagnostic approach to cough. PMID- 24490443 TI - Current drugs for the treatment of dry cough. AB - Cough is one of the commonest symptoms of respiratory tract infections and is a frequent problem encountered in general practice as well as in hospital practice. A wide range of disease processes may present with cough and definitive treatment depends on identifying the cause and diagnosis. Specific treatment of the cause should control the cough, but this may not occur in all cases and in a sizeable proportion of patients, no associated cause can be found. An increased sensitivity of the cough reflex can be observed in patients with dry cough. Symptomatic relief must be considered when the cough interferes with the patient's daily activities and this is effectively treated with antitussive preparations which are available as combinations of codeine or dextromethorphan with antihistamines, decongestants and expectorants Antitussives are used for effective symptomatic relief of dry or non-productive cough. First generation antihistamines like chlorpheniramine and centrally acting opioid derivatives like codeine are often used alone or in combination in the management of nonspecific cough. Sedation caused by these is valuable, particularly if the cough is disturbing the sleep. Although there is extensive experimental data on single agent antitussives and antitussive combinations, there is a major paucity of published literature on these combinations in nonspecific cough. Treatment of dry cough remains a challenge in some patients and this article reviews the scope of the current drugs and combination of Codeine and Chlorpheniramine in the effective management of dry cough. PMID- 24490444 TI - Future drugs for the treatment of dry cough. AB - Cough is a commonly frequent debilitating symptom that is often viewed as an intractable problem. However, specialist cough clinics report very high success rate, in the order of 90%.6 The key to successful management is to establish a diagnosis and treat the cause. Idiopathic cough is rare and commonly misdiagnosed, because of the failure to recognize that cough is often caused from sites outside the airway. Asthma, gastric reflux and rhinitis are common causes from three different anatomical areas and the realms of different specialists. This problem is complicated by the frequently atypical presentation of patients with cough. Thus, patients with cough-predominant asthma may not exhibit bronchoconstriction, and patients with reflux-associated cough may have no associated reflux symptoms such as heartburn. Hence, this warrants a detailed history and evaluation to reach a diagnosis for successful treatment. The following article aims to provide a framework for a logical approach, for patients with this highly disabling symptom. PMID- 24490445 TI - Gastro-oesophageal reflux and cough. AB - Gastro-oesophageal reflux, either singly or in association with postnasal drip and/or asthma is considered to be a cause of chronic cough. The amount and nature of gastro-oesophageal reflux however is often normal with acid suppression having very little, if any therapeutic effect in these patients. This review examines the challenges posed when exploring the reflux-cough link, and discusses the merits and limitations of the proposed mechanisms of reflux leading to cough. PMID- 24490446 TI - Role of bronchodilators in management of cough. PMID- 24490447 TI - Role of mucolytics in wet cough. PMID- 24490448 TI - Chronic cough. AB - Chronic cough is often viewed as a difficult clinical problem. It can be physically and psychologically debilitating, occasionally leading to serious complications. Although there are many etiologies, an organized approach including focused history and physical examination, directed testing in select cases, and treatment trials lead to accurate, safe, and cost-effective diagnoses in most patients. Additional symptomatic treatment is frequently beneficial. Occasionally, diagnostic dilemmas, treatment failures, or more serious causative disorders necessitate referral for further testing and management. PMID- 24490449 TI - [Another milestone for Nursing Care Research in the diffusion of scientific nursing knowledge]. PMID- 24490450 TI - [Communication among hospital leaders]. AB - New management styles imposed on hospital institutions in recent years, have fundamentally changed the organization of the latter. Many texts discuss the consequences, specifically on the field of communication. The aim of this study was to understand the real impact of new management methods on communication by managers in hospital, but also on care teams in termes of satisfaction and/or stress. This two-year study was conducted among 900 executives in hospitals in Western Switzerland using a mixed methodology. A first phase of questionnaires highlighted the problematic areas, while a second phase in the form of organized group interviews in each hospital, had the objective of achieving a better understanding of the relationship between management and communication. The latter proved to be particularly significant in terms of results, and this is the one we focused on in this article.These results indeed show that a crucial role is given to communication by carers, and, at the same time a lessening of the time devoted to relationships, both among peers and with patients. Frustration then arises, which is not without consequences both for the management of patients and the institutions themselves. It is by means of these results that awareness is raised of the omnipresence of communication at all levels and the major advantages that positive dynamic supports. And, on the contrary, of the serious problems which may arise from management practice that do not give due importance to the dimension of communication, present in all sectors of the hospital. PMID- 24490451 TI - [The role of spirituality in nursing care: a literature review]. AB - Spirituality addresses the need to give meaning to life events and is characterized by the relationship with oneself, others and the universe. This article aims to provide an overview of the empirical knowledge, and the prevailing thoughts about spirituality in nursing and suggest perspectives for future directions. The literature review was conducted using the main databases; 36 articles, published between 2008-2013, were selected. The themes covered include the definitions of the spirituality, the spiritual care and the spiritual well-being. Spirituality differs from, yet is not opposed to religion and takes different forms in multicultural and secular societies. Cancer incites existential questions and impacts quality of life, and spiritual well-being is recognized as a good indicator of quality of life for people living with cancer. Professional caregivers are concerned about the needs and spiritual well-being of their patients and often consider interventions to address them. This article reflects the depth of thought and research in nursing and touches on both discipline-specific and interdisciplinary issues. PMID- 24490452 TI - [Prolonged pain in neonates: retrospective analysis]. AB - INTRODUCTION: Infants hospitalised in neonatology are inevitably exposed to pain repeatedly. Premature infants are particularly vulnerable, because they are hypersensitive to pain and demonstrate diminished behavioural responses to pain. They are therefore at risk of developing short and long-term complications if pain remains untreated. CONTEXT: Compared to acute pain, there is limited evidence in the literature on prolonged pain in infants. However, the prevalence is reported between 20 and 40 %. OBJECTIVE: This single case study aimed to identify the bio-contextual characteristics of neonates who experienced prolonged pain. METHODS: This study was carried out in the neonatal unit of a tertiary referral centre in Western Switzerland. A retrospective data analysis of seven infants' profile, who experienced prolonged pain ,was performed using five different data sources. RESULTS: The mean gestational age of the seven infants was 32weeks. The main diagnosis included prematurity and respiratory distress syndrome. The total observations (N=55) showed that the participants had in average 21.8 (SD 6.9) painful procedures that were estimated to be of moderate to severe intensity each day. Out of the 164 recorded pain scores (2.9 pain assessment/day/infant), 14.6 % confirmed acute pain. Out of those experiencing acute pain, analgesia was given in 16.6 % of them and 79.1 % received no analgesia. CONCLUSION: This study highlighted the difficulty in managing pain in neonates who are exposed to numerous painful procedures. Pain in this population remains underevaluated and as a result undertreated.Results of this study showed that nursing documentation related to pain assessment is not systematic.Regular assessment and documentation of acute and prolonged pain are recommended. This could be achieved with clear guidelines on the Assessment Intervention Reassessment (AIR) cyclewith validated measures adapted to neonates. The adequacy of pain assessment is a pre-requisite for appropriate pain relief in neonates. PMID- 24490453 TI - [Advanced nursing practice: vision in Switzerland]. AB - To meet the challenges related to the development of health problems taking into account the development of knowledge, several innovations in care are being implemented. Among these, advanced nursing roles and increased interprofessional collaboration are considered as important features in Switzerland. Although the international literature provides benchmarks for advanced roles, it was considered essential to contextualize these in order to promote their application value in Switzerland. Thus, from 79 statements drawn from the literature, 172 participants involved in a two-sequential phases study only kept 29 statements because they considered they were relevant, important and applicable in daily practice. However, it is important to point out that statements which have not been selected at this stage to describe advanced practice cannot be considered irrelevant permanently. Indeed, given the emergence of advanced practice in western Switzerland, it is possible that a statement judged not so relevant at this moment of the development of advanced practice, will be considered as such later on. The master's program in nursing embedded at the University of Lausanne and the University of Applied Sciences Western Switzerland was also examined in the light of these statements. It was concluded that all the objectives of the program are aligned with the competencies statements that were kept. PMID- 24490454 TI - [Urinary incontinence in hospitalized geriatric patients : is it really a priority for nurses?]. AB - INTRODUCTION: urinary incontinence (UI) is a phenomenon with high prevalence in hospitalized elderly patients, effecting up to 70% of patients requiring long term care. However, despite the discomfort it causes and its association with functional decline, it seems to be given insufficient attention by nurses in geriatric care. OBJECTIVES: to assess the prevalence of urinary incontinence in geriatric patients at admission and the level of nurse involvement as characterized by the explicit documentation of UI diagnosis in the patient's record, prescription of nursing intervention, or nursing actions related to UI. METHODS: cross-sectional retrospective chart review. One hundred cases were randomly selected from those patients 65 years or older admitted to the geriatric ward of a university hospital. The variables examined included: total and continence scores on the Measure of Functional Independence (MIF), socio demographic variables, presence of a nursing diagnosis in the medical record, prescription of or documentation of a nursing intervention related to UI. RESULTS: the prevalence of urinary incontinence was 72 % and UI was positively correlated with a low MIF score, age and status of awaiting placement. Of the examined cases, nursing diagnosis of UI was only documented in 1.4 % of cases, nursing interventions were prescribed in 54 % of cases, and at least one nursing intervention was performed in 72 % of cases. The vast majority of the interventions were palliative. DISCUSSION: the results on the prevalence of IU are similar to those reported in several other studies. This is also the case in relation to nursing interventions. In this study, people with UI were given the same care regardless of their MIF score MIF, age or gender. One limitation of this study is that it is retrospective and therefore dependent on the quality of the nursing documentation. CONCLUSIONS: this study is novel because it examines UI in relation to nursing interventions. It demonstrates that despite a high prevalence of UI, the general level of concern for nurses remains relatively low. Individualized care is desirable and clinical innovations must be developed for primary and secondary prevention of UI during hospitalization. PMID- 24490455 TI - [The "sandwich generation" in Switzerland : a better understanding of factors linked with perceived health for health promotion]. AB - The so-called < Sandwich Generation > (SG) is characterized by concurrent and competing professional, familial, and informal caregiving workloads. These stressors pose potential health risks. However, the current knowledge about SG characteristics and perceived state of health are insufficient to allow occupational health nurses to develop evidence-based interventions designed for health promotion. We aimed to describe this population and examine the relationships between these coexisting workloads and their perceived health. This study is based on a descriptive, correlational design. Employees of a Swiss public administration completed an electronic questionnaire. Of 844 respondents, 23 % are SG members. Ages of frailed parents or parents-in-law, co-residence with the latters, children still living at home predict that employees could be members of the SG. Perceived physical health status of SG members is rated better than mental health status. The heterogeneity of SG is reflected in three clusters. Finally, physical health score is the only that differs from the other health scores adjusting for clusters and sex. This study provides a foundation for developing preventive interventions targeting the SG. PMID- 24490456 TI - [Ethics of care and masculinity: the case of men who choose the nursing profession]. AB - The ethic of care formulated in 1982 by C. Gilligan states that men and women do not have the same moral concerns. This work had as main objective to determine moral concerns of men who choose to be pediatric nurse, a female occupation (in France, 1,3% of men reported in 2010 among nurses specialized in pediatric care). POPULATION AND METHOD: population was composed of a non-representative sample of male pediatric nurses recruited from the next. Methodology consisted in a qualitative survey in the form of face-to-face interviews by a single female investigator. RESULTS: I I men were interviewed between January and Mai 2013. Analysis of the interviews showed that, although they announce classical nursing and masculine values, moral concerns that characterize the ethic of care were present in almost of them ( 10 out of 11). DISCUSSION: the main feature of this work was that the investigator met happy health professionals. It is therefore suggested that it is explained by the fact that this group of men combine, in an apparently harmonious way, moral concerns traditionally assigned to men and women. PMID- 24490457 TI - [Practices surrounding developmental care: exploration of barriers and remedy strategies suggested by the experts]. AB - Developmental care represents a new approach in care promoting a harmonious development of the premature baby. Although this approach is increasingly common,the recommended behaviors for these cares are not sufficiently adopted by the neonatal nurses.This research aims to explore the barriers the neonatal nurses encounter when adopting the practices surrounding developmental care and the strategies that need to be implemented in order to overcome these barriers. In order to achieve this, semi-directed interviews based on open questions have been held with experts in the field, and were analyzed with a qualitative approach.This results in multiple barriers (mainly difficulties to redefine the role of the nurse) and a large amount of strategies to overcome these barriers with individual, organizational and institutional levers.To reach a larger individualization of the care for the premature infant, it is ultimately important to invest every level by suggesting an individual and a collective reflexive practice but also by raising awareness of each tier for developmental care. PMID- 24490458 TI - [The Citizen Accompaniment Project for Community Integration for people with traumatic brain injury: a step towards resilience?]. AB - INTRODUCTION: most people with a traumatic brain injury (TBI) live with physical, sensory, or psychological sequelae that affect their day-to-day functioning and prevent them from performing their regular activities. CONTEXT: a Citizen Accompaniment for Community Integration project (APIC) was implemented for people with TBI to fulfill the lack of access to resources and gives them support to redefine their life projects. OBJECTIVES: this study's aim is to evaluate the APIC's impacts on the participants' wellbeing and their ability to participate in recreational and day-to-day living activities. METHODS: it uses a mixed research design of multiple case studies supported by a participative and collaborative research approach. Qualitative and quantitative datas were collected from 9 participants with TBI in 2 stages, at the beginning of the APIC after 6 months and at the end, after 12 months, using semi-structured interviews. RESULTS: this study shows the APIC's positive impacts in the development of the participant's autonomy and satisfaction with their social participation. DISCUSSION AND CONCLUSION: it tends to reveal that the APIC is a safe space for experimentation, founded on a reciprocal relationship between accompanied and accompanier, and promoting the commitment to the resilience process. PMID- 24490459 TI - [Supporting preceptor skills development with a forum discussion]. AB - The success of nursing students in clinical settings is significantly influenced by the nurse's preparation level of the preceptor's role. It is therefore essential to create and make available training activities that prepares and support the development of these skills in clinical settings. Among the significant benefits to participate in preceptorship training activities, the satisfaction of feeling better prepared and to share experiences with colleagues is well recognized. Thus, the online environment allows the creation of programs that encourage exchanges and discussions in addition to promote a social learning space. This article presents the implementation of an online training activity to support the development of preceptors skills in clinical settings with nursing students. The results of this clinical experience revealed several constraints to the involvement of nurses in this activity and enhanced the importance of an organizational partnership between the institution and the clinical environment to overcome these constraints. PMID- 24490460 TI - [Electrocardiogram in the cardiovascular rare diseases]. AB - Electrocardiography is a method which can not be replaced by any other examination in arrhythmias. It also plays a crucial role in the diagnosis of arrhythmic rare diseases by providing not only diagnostic data, but also paving the way for treatment. This article presents some characteristic examples of ECG in arrhythmic rare diseases (i.e., polimorphic ventricular tachycardia, Brugada syndrome, Coumela syndrome, nonreentrant supraventricular tachycardia with double ventricular response). PMID- 24490461 TI - [Quality of life in patients after anti-arrhythmic devices implantation]. AB - THE AIM OF STUDY: To assess changes in quality of life in patients with advanced heart failure before ICD or CRTD implantation and after 6 months follow-up period. MATERIAL AND METHODS: The quality of life study was performed in group consisting of 98 patients (69 male, mean age 70.4 +/- 8.60 years), who underwent CRTD implantation (48 patients, 33 male, mean age 70.6 +/- 9.12 years) or ICD implantation (50 patients, 36 male, mean age 70.3 +/- 8.16 years) before the procedure and after 6 months of follow-up. Inclusion criteria were as follows: patients with indications to ICD or CRTD implantation, complete quality of life questionnaires before the procedure and after 6 months follow-up, lack of diagnosed dementia. The quality of life assessment was performed using patient's self-assessment with SF-36 and DASI questionnaires. Patients' self-assessment, NYHA class and ejection fraction was compared before the implantation and after 6 months. Additionally, co-morbidities and experiencing of high voltage therapy were analyzed. RESULTS: In the whole group after 6 months NYHA class improved from mean 2.9 +/- 0.5 to 2.3 +/- 0.84, p < 0.001; in CRTD group from mean 3.0 +/- 0.62 to 2.3 +/- 0.95, p < 0.001; in ICD group from mean 2.9 +/- 0.35 to 2.2 +/- 0.74, p < 0.001. In the whole group after 6 months ejection fraction improved from mean 27.7 +/- 6.92 to 31.0 +/- 7.23%, p < 0.001; in CRTD group from mean 25.3 +/- 7.85 to 32.4 +/- 8.98%, p < 0.001; in ICD group there was no significant improvement of ejection fraction. After CRTD implantation improvement of quality of life was achieved in SF36 and DASI questionnaires. There was no significant improvement in ICD group. DASI index is deteriorated by device's interventions (cardioversions) (regression index=3.45, odds ratio OR = 31.5, 95% confidence interval OR = 8.2-121, p < 0.001) and presence of permanent atrial fibrillation (regression index = 1,243, odds ratio OR = 3.45, 95% confidence interval OR = 1.03-11.7, p < 0.042). SF36 index is deteriorated by presence of kidney failure (regression index = 1.91, odds ratio OR = 6.74, 95% confidence interval OR = 1.75 26, p < 0.005) and permanent atrial fibrillation (regression index = 2.27, odds ratio OR = 9.7, 95% confidence interval OR = 3.1-29.6, p < 0.001). CONCLUSIONS: Cardiac resynchronization therapy (CRTD) improves quality of life, NYHA class and left ventricle ejection fraction. Implantable cardioverter-defibrillator (ICD) does not significantly improve quality of life, NYHA class or left ventricle ejection fraction. Only in the CRTD group a significant positive correlation between changes in DASI and SF36 indexes and left ventricle ejection fraction was achieved. Experiencing cardioversion/defibrillation from implantable device and co morbidities (diabetes mellitus, arterial hypertension, kidney failure, permanent atrial fibrillation) significantly deteriorate patients' self assessment of quality of life. PMID- 24490462 TI - [Analysis of state costs of the social security benefits provided to the insured presenting with lung cancer and pulmonary diseases caused by external factors]. AB - Lung cancer and pneumoconioses constitute two serious problems of contemporary medicine and a public health system. THE AIM: To analyze the costs associated with social security benefits provided to the insured presenting with lung cancer and pulmonary diseases (including pneumoconioses) caused by external factors. MATERIAL AND METHODS: The analysis was based on the data obtained from the Department of Statistics and Actuarial Forecasts of the Social Insurance Institution (SlI) in Warsaw. Structural diversity of the costs of the separate benefits available within the national health insurance system has been considered. Based on the data available in Poland costs associated with the incidence of lung cancer and pneumoconiosis were assessed taking into account sex and age of the insured as well as the administrative division of Poland. Additionally, mortality rates from the selected pulmonary diseases were analyzed. RESULTS: Costs of the pensions paid to the insured presenting with lung cancer amount to 81.11% of the total social security costs associated with these diseases, while the sick leave money paid to the insured lung cancer patients equal to 15.5% of the total costs. In the insured women, costs of the pensions paid due to occupational pulmonary diseases (predominantly pneumoconioses) constitute 41.1% and in the insured men--11.5% of the total 'occupational' pensions. CONCLUSIONS: Although the maximal incidence of lung cancer occurs in both men and women above their retirement ages the costs of the work incapacity pensions paid to lung cancer patients still exceed 81% of the total social security costs associated with these diseases. In the insured women, the cost of pensions paid due to occupational pulmonary diseases, most of which are pneumoconioses, ranks first among the costs of 'occupational' pensions received by these subjects, while in the insured men the respective cost ranks third (after injuries plus intoxications and cardiovascular diseases) among their 'occupational' pensions. Moreover, the results of the performed analyses indicate that data on the social insurance money allow to comprehensively evaluate the health status of the insured men and women as well as their quality of life and therapeutical, rehabilitational and prophylactic needs. These data can and should, therefore, be utilized in both clinical practice and for accomplishment of the public health tasks. PMID- 24490463 TI - [Verification of the effectiveness of the dietary supplementation in infertility treatment]. AB - Fertility problems are observed in a growing number of couples in many countries, including Poland. The treatment of infertile couple should be comprehensive and apart from medical procedures also other factors affecting fertility potential should be taken into account. There is increasing evidence that a properly balanced diet and/or administration of specifically composed supplements may increase the chances of conceiving both naturally as well as in result of assisted reproductive techniques. THE AIM OF STUDY: Preliminary verification of the effectiveness of vitamin preparation to improve the quality of semen and the number of pregnancies achieved. MATERIAL AND METHODS: In total 28 infertile couples were included to the study. Within 6 months from the start of diet supplementation seminological studies and the assessment of getting pregnant have been conducted. RESULTS: The consumption of vitamin and mineral ingredients improves sperm quality and increases pregnancy rate. CONCLUSIONS: Dietary supplement may help to conceive by increasing the number and improving sperm motility. PMID- 24490464 TI - [Evaluate the influence of psychosocial factors on sexuality soldiers participating in the Polish Military Contingent in Afghanistan]. AB - Sexual health problems of stabilization missions soldiers, contrary to other specific populations, have not been fully studied. However, effects of being in a war zone have been thoroughly investigated. Modern warfare soldier experiences stress related not only to life and health threat but also to separation from loved ones. Anxiety and depression as adaptive disorders, rarer posttraumatic disorder were diagnosed in participants of stabilization missions. These disorders as well as not diagnosed dysfunctions may have impact on sexual health. THE AIM OF STUDY: To assess the selected psychosocial factors on sexuality of veterans of Polish Military Contingent (PMC) in Afghanistan. MATERIAL AND METHODS: The study was carried out on 68 soldiers, participants of stabilization mission in Afghanistan. The following diagnostic tools were used: sexual history related to military service specificity was taken, IIEF questionnaire, Mell-Krat Scale for Men, scale of sexual pathology in men, questionnaire: 'Self-esteem on relationship with a partner'. RESULTS: According to the investigated individuals, taking part in a military mission did not increase present or trigger new problems in sex life. The examined soldiers were satisfied with their sexual activity, assessed themselves as good lovers and claimed to be perceived so by their partners. CONCLUSIONS: The results of the study show that taking part in Polish Military Contingent seems to have had no negative effect on veterans sex life. Majority of the investigated veterans assessed well the relationship with a wife/partner as well as satisfaction from sexual activity and were aware of being well assessed by a wife/partner with reference to sexual activity. PMID- 24490465 TI - [Effect of post-traumatic disorders of the victims and causes of traffic accidents in the early stages of treatment]. AB - Poland is a country in which every year there is a lot of motor vehicle accidents, number of victims is one of the highest in European union. Helping patients after motor vehicle accidents should base on cooperation of doctors and psychologists because holistic approach to patient enables rapid and effective rehabilitation. THE AIM OF STUDY: To show connection between physical damage cause in motor vehicle accident with mental trauma, which increase on process of full recovery. MATERIAL AND METHODS: There were 31 victims who were involved in motor vehicle accidents not more than one month ago. In the second group there were people who was never involved in motor vehicle accident. The procedure consisted on filling demographic questionnaire, state traite anxety inventory and aqute stress disorder questionnare. In the second part of the research was to accomplish the emotional Stroop task, which based on selecting the name of the color of a word, which was on the screen. There were two types of the words: negative related to motor vehicle accident and neutral. RESULTS: Participants from the research group had higher level of anxiety than participants from control group and they had significantly longer reaction time in particular on words associated to accident, which could be the signal of problems with cognitive processes because of the anxiety. Furthermore participants with head injuries and upper limbs (whitout dominant limb) have had longer reaction times in Stroop test than participants with leg injuries, it indicating on higher level of anxiety and feeling of insecurity. CONCLUSIONS: It should be noted that looking on a character an range of a injuries, role that participant attend in accident (victims have more emotional disturbance), because it could determinate rate of recovery and the way communication with the patient. PMID- 24490466 TI - [Steroid-resistant nephrotic syndrome complicated with severe Streptococcus pneumonlae peritonitis in a 10-year-old girl--case report]. AB - Primary bacterial peritonitis is a rare complication of idiopathic nephrotic syndrome (INS) in children, found in 1.5-3.7% cases. The 10-year-old girl was admitted with INS relapse: generalized edema, proteinuria 630 mg/kg/24 h, hypoalbuminemia 1.8 g/dL, hypogammaglobulinemia 74.0 mg/dL (n: 618-1537 mg/dL), GFR 71.6 mL/min/1.73 m2. She was treated with prednisone 60 mg/24 h. On 5th day severe pain, fever, CRP (15.5 mg/dL) and leukocytosis (19.5 tys/mm3) rise occurred. On 6th day due to suspicion of peritonitis, laparotomy was performed and 400 mL of suppurative exudate was evacuated (Streptococcus pneumoniae was cultured). Postoperative course was complicated with acute kidney injury (GFR 47.7 mL/min/ 1.73 m2), lung edema, arterial hypertension, and separation of the layers of a surgical wound. The patient was treated with: imipenem (9 days), vancomycine i.v. (4 days)/p.o. (11 days) (Clostridium difficile toxin present in stool), fluconazole (14 days), 20% albumins, furosemide, labetalole, cyclosporine A (started on 56th day after the operation due to secondary steroid-resistance of INS). The remission was achieved after 7 days of cyclosporine A treatment. Authors suggest that children with nephrotic syndrome belong to high-risk group of invasive pneumococcal disease, therefore they require careful implementation of mandatory immunization schedule. Peritonitis is a rare and still dangerous infectious complication of nephrotic syndrome in children. PMID- 24490467 TI - [Butamyrate citrate in cough controlling]. AB - The cough as one of the main symptoms of respiratory infections in the most cases is carried out in children and adults using preparations without a prescription (OTC--over-the-counter) and cold medications (CCMs). Their efficacy and safety have not been fully confirmed. In turn, the administration of drugs that inhibit cough by acting on the central nervous system requires adherence to dosage. Codeine as the main standard of the cough suppressants is not always effective. Used for many years butamyrate citrate is highly effective and complete safety. The number and quality of the side effects after application of this preparation is small and is not limited especially in pediatrics. Conducted research on new drugs that inhibit cough are very promising. PMID- 24490468 TI - [Lymphoedema--diagnosis and treatment]. AB - Lymphoedema is a common complication of oncological treatment. Various methods of imaging are used in its diagnosing and monitoring. However, presently lymphoscintigraphy has become the golden standard. A physical examination and detailed medical history also play a very important role. There are still no effective methods of prevention and treatment of lymphoedema in spite of medical progress. The treatment requires a multidisciplinary approach with the use of various methods of physiotherapy (pressure therapy, pneumatic pumps and electric high-voltage treatment), pharmacology and surgery. Patient's education and suitable physical exercises are also significant. PMID- 24490469 TI - [Kawasaki disease in children: epidemiology, clinical symptoms, diagnostics and treatment]. AB - Kawasaki disease is a multisystem inflammatory disease of small- and medium-sized blood vessels with acute and self limiting course. It occurs most frequently in children under five years of age and is characterized by high fever lasting more than five days, conjunctivitis, stomatitis, edema of hands or feet erythema of the palms and soles, epidermic desquamation of the fingers and toes, polymorphic rush and cervical lymphadenopathy. Such symptoms from other organs as cholestatic jaundice, inflammation and hydrops of the gallbladder, pancreatitis, hepatitis and traits of acute abdomen can also be present. The most serious complications of Kawasaki disease are coronary aneurysms. The principal treatment of the disease is intravenous infusion of immunoglobulin and aspirin. Prompt diagnosis with echocardiogram and the treatment with immunoglobulins before 10th day after the first symptoms improve prognosis and diminish life threatening complication such as coronary arteries aneurysms. PMID- 24490470 TI - [Hypertensive crisis in children and adolescents]. AB - Hypertensive crisis is a sudden rise in blood pressure above 99 c. for sex, age and height +5 mm Hg. Depending on patient's symptoms, hypertensive crisis can be divided into hypertensive emergency severe arterial hypertension with target organ insufficiency and/r damage (central nervous system, heart, kidney, eye), and hypertensive urgency - severe arterial hypertension without target organ insufficiency and damage with non-specific symptoms like: headaches, vertigo, nasal bleeding, nausea, and vomiting. The most common causes of hypertensive crisis in neonates and infants are renal artery thrombosis, broncho-pulmonary dysplasia, and coarctation of aorta; in older children - kidney diseases and renal artery stenosis. In neonates and infants symptoms of cardiac failure predominate, whereas in older children symptoms from central nervous system (headaches, nausea, vomiting, changes in level of consciousness, seizures, focal deficits). Hypertensive crisis is treated with fast- and short-acting medications; 25% reduction of blood pressure within first 8 hours is recommended, with complete normalization within 24-48 hours. Hypertensive emergency should be treated with intravenous agents (labetalol, hydralazine, nicardipine, and sodium nitroprusside), hypertensive urgency with intravenous or oral agents like nifedipine, isradipine, clonidine and minoxidil. Nicardipine is a first-choice medication in neonates. PMID- 24490471 TI - [The problem of Clostridium dlfficile infection in children with inflammatory bowel disease]. AB - The last decade has seen a significant increase in the incidence of diseases related to infection by Clostridium difficile (Clostridium difficile-associated disease--CDAD) in the U.S.A., Canada and European countries, which is probably due to the widespread environmental hipervirulent C. difficile strain NAP 1 / BI / 027. Those particularly affected by CDAD are patients with inflammatory bowel disease (IBD) who observed more severe infections, prolonged hospital stay, higher risk of complications and higher mortality. C. difficile infection can cause or mimic the symptoms of exacerbation of IBD. For this reason, all patients with exacerbations of IBD in the differential diagnosis should be considered a C. difficile infection. Patients with IBD often found non-antibiotic treatment of CDAD or previous hospitalisations. Young people with IBD are also more likely to get CDAD. It is necessary to conduct further studies in patients of the adult population and children with IBD in order to not only determine the effect of CDI on the course of inflammatory bowel disease, but also to determine the epidemiology, risk factors, and the most effective treatments for these patients. PMID- 24490472 TI - [Prolonged-release drug formulations for parenteral administration. Part l. Suspensions and oily solutions for injection]. AB - The article presents description of the most important parenteral forms, which release an active substance in sustained manner. Technological and biopharmaceutical information is supplemented with examples of commercial products, currently registered in Poland. Mechanism of drug release from the dosage form and duration of the process, role of other excipients and characteristics of certain medicinal products is presented. The information about suspensions and oily solutions for injection is summarized. Owing to specific chemical modifications and selection of suitable excipients, it was possible to develop these types of medicinal products for some antibiotics, hormones, antipsychotics and cytostatics. These formulations, after subcutaneous or intramuscular injection, release the active substances even for several weeks allowing to reduce the frequency of drug administration and finally help to improve patient's compliance. Here also the modified time course of insulin products achieved by selection of appropriate suspension form or insulin analogue is discussed. PMID- 24490473 TI - [Controversies around diet proteins]. AB - Critical theories regarding proteins of anima origin are still and still popularized, though they are ungrounded from scientific point of view. Predominance of soya proteins over the animal ones in relation to their influence on calcium metabolism, bone break risk or risk of osteoporosis morbidity has not been confirmed in any honest, reliable research experiment. Statement, that sulphur amino acids influence disadvantageously on calcium metabolism of human organism and bone status, is completely groundless, the more so as presence of sulphur amino acids in diet (animal proteins are their best source) is the condition of endogenic synthesis of glutathione, the key antioxidant of the organism, and taurine stimulating brain functioning. Deficiency of proteins in the diet produce weakness of intellectual effectiveness and immune response. There is no doubt that limitation of consumption of animal proteins of standard value is not good for health. PMID- 24490474 TI - [Radiation-induced neuropathy]. AB - Radiation-induced neuropathy is commonly observed among oncological patients. Radiation can affect the nervous tissue directly or indirectly by inducing vasculopathy or dysfunction of internal organs. Symptoms may be mild and reversible (e.g., pain, nausea, vomiting, fever, drowsiness, fatigue, paresthesia) or life-threatening (cerebral oedema, increased intracranial pressure, seizures). Such complications are clinically divided into peripheral (plexopathies, neuropathies of spinal and cranial nerves) and central neuropathy (myelopathy, encephalopathy, cognitive impairment). The degree of neuronal damages primarily depends on the total and fractional radiation dose and applied therapeutic methods. The conformal and megavoltage radiotherapy seems to be the safeties ones. Diagnostic protocol includes physical examination, imaging (in particular magnetic resonance), electromyography, nerve conduction study and sometimes histological examination. Prevention and early detection of neurological complications are necessary in order to prevent a permanent dysfunction of the nervous system. Presently their treatment is mostly symptomatic, but in same cases a surgical intervention is required. An experimental and clinical data indicates some effectiveness of different neuroprotective agents (e.g. anticoagulants, vitamin E, hyperbaric oxygen, pentoxifylline, bevacizumab, methylphenidate, donepezil), which should be administered before and/or during radiotherapy. PMID- 24490475 TI - [Contemporary pharmacological methods of treating hirsutism]. AB - Hirsutism is a symptom of excessive androgen secretion in women, which in recent years is becoming more common. It is a problem of physical, mental and social background and patients always require application of an appropriate therapy Today's medicine offers a wide variety of treatments for the disease, each of which has a different efficiency. This article describes the pharmacological treatment of hirsutism using, among others: antiandrogenic drugs, corticosteroids and oral contraceptives. We performed an extensive literature looking for articles dealing with various forms of hirsutism treatment, most important items were selected and compiled in this work. Modem medicine distinguishes many forms of hirsutism treatment. A very important form of treatment for this condition is the use of pharmacological agents. Their diversity allows optimal adjustment of therapy to the requirements and needs of the patient. Drug therapy is effective, however, in most cases also requires a dermatological treatment. PMID- 24490476 TI - [Hyponatremia]. AB - Hyponatremia is defined as plasma concentration of sodium lower than 135 mmol/L. It usually does not reflect a true sodium deficiency, but rather free water retention caused by vasopressin hypersecretion, with hypoosmolality of body fluids. Hyponatremia may be caused by different diseases and pathological conditions, such as: hypovolemia, hypothyroidism, adrenal insufficiency, syndrome of inappropriate antidiuretic hormone secretion (SIADH), congestive heart failure, hepatic cirrhosis, and adverse drug reactions. Neurological symptoms of hyponatremia result from brain edema, and depend on the rate of sodium concentration decrease and degree of the disorder. The treatment includes elimination of free water, most often through volume expansion, water restriction in SIADH or deficient hormones supplementation. The rate of correction of sodium concentration in chronic and profound hyponatremia should not exceed 10 mmol/L during the first 24 hours, and 18 mmol/L during the first 48 hours. Overly rapid correction of natremia may result in irreversible demyelinating damage of the central nervous system. PMID- 24490477 TI - [Hypernatremia]. AB - Presentation contains practical approach to the relatively common clinical problem of hypernatremia The main causes of the hypernatremia, its relationships with water balance, and its symptoms are shortly discussed, followed by diagnostic and therapeutic recommendations. PMID- 24490478 TI - [Potassium homeostasis]. AB - Potassium is a main cation in the intracellular compartment, with nearly 80% of stores being present in muscles, liver, bone and red blood cells. Intracellular potassium concentration is about 140-150 mmol/l in contrast to more than 30 times lower extracellular levels (3.5-5.0 mmol/l).This transmembrane gradient is crucial for maintenance of the membrane resting potential and neuro muscularfunctioning, including the heart. In this review the physiological regulation of potassium balance is shortly reviewed to set a background for understanding its disorders. PMID- 24490479 TI - [Hypokalemia]. AB - Hypokalemia, defined as a less than 3.5 mmol/I serum potassium, is probably the most common electrolyte abnormality in clinical practice. It is usually well tolerated but, if severe, it can be life-threatening. However, even mild or moderate hypokalemia increases the risks of morbidity and mortality in patients with cardiovascular disease. When hypokalemia is identified, the underlying cause should be established and the disorder immediately treated. PMID- 24490480 TI - [Hiperkalemia]. AB - Hyperkalemia is a common and potentially lethal clinical problem. It may be caused by several drugs, especially those which target the renin-angiotensin- aldosterone system, inability of kidney to excrete potassium, a shift of these ions into the extracellular fluid, or a combination of those mechanisms. It can be also spurious, caused by hemolysis after blood drawing. In the article the conditions associated with hyperkalemia, its diagnosis and the management are reviewed. PMID- 24490481 TI - [Calcium homeostasis]. AB - There is approximately 1000-1500 g of calcium in the human body, 98-99% of this being in the form of hydroxyapatite in bone. Serum ionized calcium is tightly regulated through a complex interplay of parthormone (PTH), calcitriol (1.25(OH)2,D), and ionized calcium itself, acting through their receptors mostly in parathyroids, intestine, bone and kidney. In the review role of those factors and organs in calcium homeostasis is shortly discussed. PMID- 24490482 TI - [Hypocalcemia]. AB - Hypocalcemia is often clinical problem. The levels of total serum calcium below 2.15 mmol/L (<8.6 mg/dl) and ionized calcium below 1.15 mmol/L (4.6 mg/dl) are considered to be consistent with hypocalcemia. The major factor that influence the hypocalcemia is low parathyroid hormone. Clinical manifestations are different: ranging from few, if any, in case of mild hypocalcemia, to life threatening, when hypocalcemia is severe or acute. Classic clinical manifestation is tetany: open or latent. The treatment varies with its severity and the underlying cause. Recommendations contains the administration of calcium and vitamin D. PMID- 24490483 TI - [Hypercalcemia]. AB - Hypercalcemia defined as serum calcium >2.62 mmol/l (10.5 mg/dl) is a relatively common clinical problem. Malignancy and primary hyperparathyroidism remain its leading causes. The clinical symptoms depend on the degree and duration of the disorder. Hypercalcemia can affect different organs or systems. The therapy involves saline hydration, loop diuretics, antiresorptive drugs (calcitonin, bisphophonates), steroids. In severe hypercalcemia hemodialysis may be necessary. PMID- 24490484 TI - [Magnesium homeostasis]. AB - Magnesium is the second most prevalent intracellular cation, which plays a critical role in many cellular processes, essential for life, especially for neuromuscular functioning, cardiovascular health and normal bone formation. Its homeostasis is tightly regulated by a dynamic interplay between intestinal absorption and renal excretion. Additionally, it is controlled through the reservoir in bone tissue. This review summarizes shortly the current knowledge of magnesium homeostasis important for the practitioner to better understand it's disorders. PMID- 24490485 TI - [Magnesium homeostasis disorders: hypomagnesemia]. AB - Physiologically, magnesium plays an essential role in bone formation, neuromuscular stability and muscle contraction, and the consequences of its altered homeostasis may be serious. Magnesium deficiency and hypomagnesemia are common and under-recognized problems, which can cause a variety of symptoms and can also affect the other cations metabolism. In this review causes, clinical picture and management of hypomagnesemia and magnesium deficiency are discussed. PMID- 24490486 TI - [Magnesium homeostasis disorders: hypermagnesemia]. AB - Hypermagnesemia, defined as a plasma total magnesium concentration greater than 1.2 mmol/l, is much less common than hypomagnesemia, however it may be also life threatening. In this review causes, clinical presentation and treatment of hypermagnesemia is shortly reviewed. PMID- 24490487 TI - [Diuretics]. AB - Diuretics are an important class of medicine used to treat a wide variety of acute and chronic conditions, like: heart failure, hypertension and renal diseases. They act by increasing urinary excretion of water, sodium, and some others electrolytes, at different sites in the nephron. In this paper the mechanisms of action, use, dosing and adverse effects of the commonly used diuretics are reviewed. PMID- 24490488 TI - [Polyuria]. AB - Polyuria has been defined as an urine output exceeding 3 I/day in adults and 2 I/m2/day in children. The most common causes are: psychogenic polydipsia, diabetes insipidus (central and nephrogenic), chronic kidney disease and uncontrolled diabetes mellitus. The article focuses on diagnostic approach to a patient with polyuria. PMID- 24490489 TI - [Alkalosis]. AB - An elevation of arterial blood pH called alkalosis remains an underestimated condition in hospitalized patients. Serious alkalosis can be associated with high risk of death. The disorder can be caused by increased concentration of bicarbonate (metabolic alkalosis) or decreased concentration of carbon dioxide (respiratory alkalosis). In most cases of metabolic alkalosis it is generated by vomiting or diuretic use, whereas respiratory alkalosis is provoked by hyperventilation associated with respiratory or neurological disorder. Maintenance of metabolic alkalosis is possible only in patients with impaired renal base excretion which is most often produced by hypochloremia. In both respiratory and metabolic alkaloses treatment depends on the underlying factor. In hyperventilation syndrome is based on behavioral therapy. In most cases of metabolic alkalosis the administration of sodium and potassium chloride forms a substantial part of therapy. PMID- 24490490 TI - [Recombinant soluble CD40 ligand enhances Wogonin-induced antitumor activity]. AB - OBJECTIVE: To investigate the effect of recombinant soluble CD40 ligand (rsCD40L) on Wogonin mediated antitumor activity in cancer cells and the underlying molecular mechanisms. METHODS: Cell death was detected based on the release of lactate dehydrogenase (LDH) using a cytotoxicity detection kit. For morphological study of cell death, cells were stained with 50 microg/mL of acridine orange and 50 microg/mL of ethidium bromide and observed and photographed under a fluorescence microscope. Activation of apoptosis pathway was evaluated by Western blot. The effects of pan-caspase inhibitor Z-VAD-FMK and tumor necrosis factor alpha (TNF-alpha) neutralizing antibody on cell death induced by rsCD40L and Wogonin co-treatment were also investigated. RESULTS: rsCD40L significantly enhanced Wogonin-induced cell death of ovarian cancer cells SKOV3. A dose dependent synergism was found with a fixed rsCD40L dose (1 microg/mL) and increased concentrations of Wogonin (5 micromol/L-15 micromol/L). rsCD40L and Wogonin co-treated cells showed typical apoptotic morphologies and enhanced activation of caspases pathway. As expected, the pan-caspase inhibitor Z-VAD-FMK inhibited synergistic cell death of rsCD40L and Wogonin co-treated SKOV3 cells. Interestingly, the TNF-alpha neutralizing antibody that blocks TNF-alpha binding to its receptor also significantly suppressed the cell death enhancing effect, indicating that autocrine TNF-alpha played a role of sensitization. CONCLUSION: rscCD40L sensitizes cancer cells to wogonin-mediated apoptosis, which may involve autocrine of TNF-alpha, and the combination of rsCD40L and Wogonin may have a potential for cancer therapy. PMID- 24490492 TI - [Effects of Jiaweisinisan dispersion on content and gene expression of gastric tissue GASR and jejunal tissue VIPR2 of physical and mental stress model rat]. AB - OBJECTIVE: To observe the effects of Jiaweisini dispersion (JWSNS) on the ultrastructure of gastric mucosa, the content and gene expression of gastric antrum tissue gastrin receptor (GASR) and jejunal tissue vasoactive intestinal peptide receptor 2 (VIPR2) in chronic stress gastric ulcer rats, and to elucidate its mechanism. METHODS: 60 Wistar rats were randomly divided into normal group, model group, JWSNS large, medium, small dose groups, and omeprazole group, 10 rats in each group. Chronic stress method was used to establish the stress ulcer rat model. The every rat in JWSNS small, medium, large dose groups were gavaged with 0.25, 0.5, 1.0 g/ mL Chinese medicine Decoction on 2 mL respectively daily, rats in omeprazole group were gavaged with 0.3 mg/mL omeprazole solution on 2 mL daily, rats in normal group and model group were gavaged 2 mL NS daily. After modeling was end, transmission electron microscopy (TEM) was used to observe gastric mucosa cells and intercellular connections changes of ultrastructure of glandular stomach area and immunohistochemical method and Real time-PCR method were used to detect the protein content and gene expression changes of gastric antrum tissue GASR and jejunal tissue cell VIPR2. RESULTS: TEM observation demonstrated that in the normal group the gastric mucosa epithelial cells connected compact, cell membrane integrity, cell nuclear shape and size was normal; in model group rats the gastric mucosal cells were severely damaged; the rats in the rest treatment groups were better than those in the model group in different degree. After The treatment of JWSNS and omeprazole, the expression of GASR protein and mRNA in gastric antrum tissue were increased when compared with that of model group (P < 0.05), the expression of VIPR2 protein and mRNA in the jejunum tissue were lower than that of the model group (P < 0.05). The expression of GASR, VIPR2 protein and mRNA in the JWSNS large dose group was closed to the normal group with no significant difference (P > 0.05). And compared with omeprazole group and JWSNS small dose group, expression of GASR protein and mRNA in high dose group rats were increased (P < 0.05), and expression of VIPR2 protein and mRNA were decreased (P < 0.05). CONCLUSION: JWSNS can significantly improve microscopic pathologic morphology of the gastric mucosa cell in gastric ulcer of chronic stress rats models, and can through two aspects of inhibiting damage factor and enhancing defense factor to adjust the content and gene expression of gastric tissue GASR and jejunal tissue VIPR2. PMID- 24490491 TI - [Regulatory effects and associated mechanisms of miR-130a molecules on cisplatin resistance in ovarian cancer A2780 cell lines]. AB - OBJECTIVE: To determine the regulatory effects and associated mechanisms of miR 130a on cisplatin resistance in ovarian cancer A2780 cell lines (including cisplatin sensitive A2780s and its resistant A2780/DDP cells). METHODS: A2780s and A2780/DDP cells were divided into four groups, and treated with lipo2000 (Lip), miR-negative (miR-NC) control, miR-130a-mimics (miR-130a-M increasing the expression of miR-130a and the agent), and miR-130a-inhibitor (miR-130a-I downregulating miR-130a expression), respectively. The proliferation of cells and their sensitivity to cisplatin were detected by MTT assay. RT-PCR and western blot were performed to examine the levels of MDR1, PTEN mRNA and proteins. RESULTS: The expressions of MDR1 mRNA and P-gp in the A2780/DDP cells were significantly higher than those in the A2780s cells. However, no differences in the expressions of PTEN mRNA and proteins were detected between the two cell lines. Over-expressions of miR-130a had no effect on cell proliferation, but increased the resistance of the cells to cisplatin and up-regulated the expressions of MDR1 mRNA and P-gp in both cell lines. Down-regulated miR-130a did not affect cell proliferations, but enhanced the sensitivity of the cells to cisplatin, inhibited the expressions of MDR1 mRNA and P-gp and increased the expression of PTEN proteins. CONCLUSION: MiR-130a expression may be associated with cisplatin resistance of ovarian cancer cells. MiR-130a inhibitor can reverse the cisplatin resistance by upregulating the expression of PTEN proteins and down regulating P-gp in A2780 cell lines. MiR-130 may become a new potential target of genetic therapy for cisplatin-resistant ovarian cancers. PMID- 24490493 TI - [Influence of EphA2 siRNA transfection on the biological behavior of human ovarian carcinoma cell]. AB - OBJECTIVE: To explore EphA2 siRNA transfection and its influence on the biological behavior of human ovarian carcinoma cells. METHODS: One pairs of siRNA was synthesized and transfected into the human ovarian carcinoma cell line SKOV3. Observation of the transfection efficiency through the fluorescence inverted microscope was followed by the evaluation of expression of EphA2 protein using Western blot. The effects of EphA2 siRNA on proliferation of SKOV3 cells were observed by drawing cell growth curves and measuring cloning efficiency, and the adhesion and invasion of SKOV3 were detected by cell adhesion assay and Matrigel boyden chamber method respectively. RESULTS: After successful transfection, a large number of fluorescent particles were observed under the fluorescence inverted microscope. The expression of EphA2 protein was obviously suppressed by EphA2 siRNA (P < 0.05). The cell proliferation, adhesiveness and invasiveness were significantly inhibited (P < 0.05). However, no changes in colony-forming efficiency were observed (P > 0.05). CONCLUSION: Down-regulation of EphA2 gene by EphA2 siRNA in SKOV3 cell line showed retardation of cell growth, proliferation and partial reversion of the malignant phenotype, including the ability of adhesion and invasion. EphA2 may be a new and potent target of gene therapy in ovarian carcinoma. PMID- 24490494 TI - [The effect of RABEX-5 downregulation on the chemosensitivity of human breast cancer cells]. AB - OBJECTIVE: To investigate the changes in sensitivity to anthracycline and taxanes of human breast cancer cells after RABEX-5 downregulated. METHODS: By constructing a lentiviral vector for RNA interference (RNAi) of RABEX-5 gene and transfected into human breast cancer cell line MCF-7 to silence the express of RABEX-5. Real-time PCR and Western blot were used to detect the silencing effect. The changes in sensitivity to chemotherapeutic drugs of MCF-7/RNAi and its negative control cell lines MCF-7/vector were detected by CCK-8 reagent. RESULTS: Compared with MCF-7 cell and MCF-7/vector cell, the expression of RABEX-5 mRNA and protein was downregulated in MCF-7/RNAi cells. The sensitivity to epirubicin was reduced after downregulating the expression of RABEX-5, the 50% inhibition concentration (IC50) of MCF-7/RNAi [(3.590 0 +/- 0.228 69) microg/mL] was higher than that of MCF-7/Vvector [(1.193 3 +/- 0.187 71) microg/mL, P < 0.05]; while the same effect was not found in docetaxel group, the IC50 were (11.162 7 +/- 0.210 26) microg/mL and (10.536 7 +/- 0.430 97) microg/mL, respectively (P > 0.05). CONCLUSION: Downregulation of RABEX-5 can induce chemoresistance to epirubicin in human breast cancer cell MCF-7; while its effect on sensitivity to docetaxel is not significant. This study can provide a theoretical basis for future research RABEX-5 in the individualized treatment of breast cancer. PMID- 24490495 TI - [The change of alpha cell mass and its mechanism with diabetic progress]. AB - OBJECTIVE: To explore the change of a cell mass and its mechanism with diabetic progress. METHODS: Diabetic mice were killed by exsanguinations after 4, 12 and 20 weeks of diabetes, respectively. Indirect double immunofluorescences for Insulin/Ki67, or BrdU, Cleaved-Caspase 3, TUNEL were used to evaluate pancreatic alpha cell mass, regeneration and apoptosis of a cells. Indirect triple immunofluorescences for Glucagon/ Neurogenin 3/MafA and Western blot analysis for Neurogenin 3 were used to determine neogenesis of pancreatic alpha cells. RESULTS: Pancreatic alpha cell mass was gradually increased with diabetic progress. It was significantly different from that of controls. There weren't any proliferation and apoptosis of alpha cell during diabetes, however, many Neurogenin 3+ cells appeared in the pancreatic islets of diabetic mice, and most of them were co-stained with MafA and Glucagon. CONCLUSION: Pancreatic alpha cell mass is gradually increased with diabetic progress. It seems to be strongly associated with neogenesis of pancreatic alpha cells. PMID- 24490496 TI - [Influence of siRNA-mediated PPARgamma gene knockdown on insulin resistance induced by myocardial ischemia-reperfusion in rats]. AB - OBJECTIVE: To observe the influenece of siRNA-mediated PPARgamma gene knockdown on insulin resistance induced by myocardial ischemia-reperfusion in adult rats. METHOD: The targeting PPARgamma siRNA was synthesized. The myocardial cells of adult rats were isolated and cultured. They were divided into four groups: IRI group, siRNA-PPARgamma group, empty group and blank control group. Two groups of rat cardiac cells were transfected with PPARgamma-targeting siRNA (siRNA PPARgamma group), or empty small interfering RNA (NC group), respectively. Real time quantitive PCR was performed to detect the mRNA levels of PPARgamma and GLUT 4. PPARgamma protein expression level was determined with Western blot test. The uptake rate of glucose was determined by the isotope tracer method. RESULT: The PPARgamma mRNA and protein expression of IRI group were significantly higher than those in blank control group (P < 0.05). The PPARgamma mRNA and protein expression of siRNA-PPARgamma group were significantly less than those in blank control and IRI group (P < 0.01). There was no significant difference in the PPARgamma mRNA and protein expression between the blank group and IRI group. The mRNA expression of GLUT-4 in blank control was no significant difference at each time point. The mRNA expression of GLUT-4 in IRI group was significantly less at 0 min, but increased gradually over the following time point. Finally, The mRNA expression of GLUT-4 in IRI group restored the same level as blank control. There was no significant difference in the GLUT-4 mRNA expression between the empty group and IRI group. The GLUT-4 mRNA expression in siRNA-PPARgamma group was significantly less than that in IRI group or NC group (P < 0.05), and recovered more slowly than IRI group. After given insulin, The uptake rate of glucose in siRNA-PPARgamma group was significantly less at each time point compared with those in IRI group (P < 0.05), declined by 49.78%, 38.94%, 18.61%, 11.54% at 0 min, 15 min, 1 h, 2 h, respectively. At 6 h time point, the uptake rate of glucose in siRNA-PPARgamma group reached the same level as IRI group. There was no significant difference was observed in the uptake rate of glucose between the empty group and IRI group. CONCLUSION: The siRNA-mediated PPARgamma gene knockdown may enhance the myocardial insulin resistance. The molecular mechanisms that trigger myocardial cell insulin resistance might because the silence of PPARgamma expression decreasing the expression of GLUT-4 and decline its transportation from cytoplasm to membrane. PMID- 24490498 TI - [Preliminary study of apoptotic inhibition and its molecular mechanism of dexamethasone on cisplatin-induced human lung adenocarcinoma cell line SPCA/I]. AB - OBJECTIVE: To study the apoptotic inhibition and its molecular mechanism of dexamethasone (Dex) on cisplatin (CDDP)-induced human lung adenocarcinoma cells. METHODS: The human lung adenocarcinoma cell The human lung adenocarcinoma cell line, SPCA/I, was pre-cultured in vitro for 24 hours with Dex in different concentration and then different concentration of CDDP was added. The cells were cultured for another 48 hours. The survival rate of the cells was determined by MTT colorimetry. The appototic rate of SPCA/I cells measured by flow cytometer. Using 1 micromol/ L Dex to stimulate the SPCA/I cells RNAs of the cells at different time points (1 h, 2 h, 4 h, 6 h, 12 h) were extracted respectively. Semi-quantitative RT-PCR technology was used to detect the expression of the serum and glucocorticoid-induced kinase (SGK-1) and mitogen-activated protein kinase phosphatase-1(MKP-1) in SPCA/I cells. Simultaneously the glucocorticoid receptor (GR) of the SPCA/I cell line cells were measured by using biotin-labeled anti-glucocorticoid receptor antibody with immunohistochemistry assay. RESULTS: SPCA/I cells showed resistance to CDDP-induced apoptosis while pre-cultured with Dex and the resistance intensity was Dex concentration-dependent. After Dex stimulating the SPCA/I cells, SGK-1 expressed increased and reached the peak at 12 h. But the expression of MKP-1 was not detected. Immunohistochemistry results showed that upregulated GR in SPCA/I cells after stimulation with Dex. The number of intracellular GR was significantly higher than that of control group. CONCLUSION: The experimental results in vitro demonstrated that Dex inhibits apoptosis on CDDP-induced human lung adenocarcinoma cell line, SPCA/I. This anti apoptosis effect might due to Dex increasing the expression of SGK-1, an anti apoptotic protein, in its downstream signal pathway through the increasement of intracellular GR of SPCA/I cells. PMID- 24490497 TI - [Effect of recombinant adenovirus carrying NLS-RARalpha gene on the proliferation of HL-60 cell and the differentiation of HL-60 cells induced by ATRA and relevant mechanism]. AB - OBJECTIVE: To explore the effect and mechanism of recombined adenovirus carrying NLS-RARalpha gene on proliferation of HL-60 cells and the differentiation of HL 60 cells induced by ATRA. METHODS: HL-60 cells was infected with Ad-NLS-RARalpha and control virus Ad-KZ. The efficiency of infection was detected by FCM. The mRNA and protein levels of NLS-RARalpha were assessed by Real-time PCR (RT-PCR) and Western blot, respectively. MTT assay were applied to determine proliferation of HL-60 cells. Cell surface differentiation antigen CD11b of infected HL-60 cell induced by ATRA was examined by FCM. The mRNA and protein levels of C-MYC of infected HL-60 cell induced by ATRA were determined by Real-time PCR (RT-PCR) and Western blot assay. RESULTS: The efficiency of infection of Ad-NLS-RARalpha and Ad-KZ on HL-60 cell was 70%-80%. The mRNA and protein levels of NLS-RARalpha gene of HL-60 cells which infected with Ad-NLS-RARalpha were both obviously higher than that of the cells which infected with Ad-KZ and non-infected (P < 0.05). The proliferation ability of HL-60 cell infected with Ad-NLS-RARalpha was significantly increased (P < 0.05). The level of CD11b of HL-60 cell infected with Ad-NLS-RARalpha and induced by ATRA was clearly decreased than control groups (P < 0.05). The mRNA and protein levels of C-MYC gene of HL-60 cells infected with Ad-NLS-RARalpha and induced by ATRA were both obviously higher than that of the cells which infected with Ad-KZ and non-infected (P < 0.05). CONCLUSION: The recombined adenovirus Ad-NLS-RARalpha can increase the proliferation ability of HL-60 cell, and inhibit the differentiation of HL-60 cell through reduce the expression level of C-MYC gene. PMID- 24490499 TI - [The role of T helper 17 cells of synovial fluid in rheumatoid arthritis]. AB - OBJECTIVE: To investigate the role of Th17 cells of synovial fluid (SF)in the pathogenesis of rheumatoid arthritis (RA). METHODS: RA patients with knee synovial fluid (n = 15) and healthy volunteers (n = 15) were enrolled. The amounts of Th17 cells in peripheral blood and SF were measured by flow cytometry. Since there was no SF in healthy control, only the amounts of Th17 cells in peripheral blood were measured. The correlation between the amounts of SF Th17 cells and clinical inflammatory parameters was evaluated. Retinoic acid-related orphan receptor gammat (RORgammat), interleukin-17 (IL-17) gene expression in lymphocytes were assessed by real-time PCR. RESULTS: The percentages of Th17 cells in SF from RA patients (1.89 +/- 0.88)% were significantly higher than that in paired PB from RA patients (1.03 +/- 0.57)% and that in PB from healthy controls (0.35 +/- 0.18)%; (2) The frequency of Th17 cells in SF from RA patients correlated positively with serum CRP (r = 0.519, P = 0.047); (3) The mRNA levels of RORgammat and IL-17 were increased in SF lymphocyte population from RA patients compared to paired PB from RA patients and healthy controls (P < 0.01). CONCLUSION: Increases of Th17 cells in synovial fluid of patients with RA patients might attribute to the difference between local joint inflammation and systemic inflammation, and participates in joint damage. PMID- 24490500 TI - [Functional analysis of VicK kinase activity in Streptococcus mutans]. AB - OBJECTIVE: To investigate the regulatory function on physiology and virulence of VicK kinase activity in Streptococcus mutans. METHODS: PCR ligation mutagenesis was used to construct a vicK knock-out mutant, and kinase activity abolished VicK was expressed by a streptococcal vector in this vicK null mutant. Colony morphology, overnight culture, biofilm formation and gene expression involved in biofilm formation were analyzed. Delta VicK, strains harboring a complemented wild-type vicK, and a vector without insert were used as controls. RESULTS: Colonies of VicK(H217A) were smoother and more elevated than that of wild-type UA159 and complementary strain SMCVicK; cells from VicK(H217A) overnight culture coaggregated on the bottom of glass tubes; no obvious alteration was observed in VicK(H217A) biofilm; expressions of gbpB, ftf, gtfD were repressed while gtfB/C were up-regulated (P < 0.05). CONCLUSION: VicK kinase activity is important for maintaining normal growth, biofilm formation and expression of genes involved in biofilm formation in Streptococcus mutans. PMID- 24490501 TI - [Expression of SSB following early myocardial ischemia in rats]. AB - OBJECTIVE: To investigate the expression of Sjogren's syndrome antigen B (SSB) gene and SSB protein in the early ischemic myocardium in rats. METHODS: Adult healthy Sprague-Dawley rats were randomly divided into groups of operation [myocardial ischemia (MI) and non-ischemia (NI)], non-operation (NO) and sham operation (SO) (n = 6 for MI and NI; n = 4 for NO and SO). According to time of ischemia, it was then divided into groups of 0 min, 15 min, 30 min, 60 min, 120 min, and 240 min. The expression of SSB gene in the myocardium was examined by real-time PCR, and the expression of SSB protein was examined by Western blot and immunofluorescence staining. RESULTS: The expressions of SSB gene was down regulated at early stage of ischemia. There was significant difference between 0 min and 120 min at the level of expression of SSB gene in MI group, so did that between 120 min group and NO group (P < 0.05). The expression of SSB protein at 60 min after ischemia was significantly decreased compared with that in the group of 0 min (P < 0.05). The expression of SSB protein in NI groups was significantly higher than that in MI groups at the time of 60 min and 120 min after myocardial ischemia (P < 0.05). Additionally, the expression of SSB protein was mainly located in the myocardial nucleus, myocardial plasma, and plasma membrane of partial myocardiocytes according to the result of immunofluorescence staining. CONCLUSION: SSB may participate in pathophysiologic regulation process in myocardial cells at the early stage of myocardial ischemia in rats. PMID- 24490502 TI - [Preliminary study on the expression of cystatin C in primary liver cancer]. AB - OBJECTIVE: To preliminarily investigate the expression of cysteine proteinase inhibitors C (cystatin C) in primary hepatic carcinoma. METHODS: Hepatic tissue samples and peripheral blood samples were collected from 41 cases of primary hepatic carcinoma, 24 cases of cirrhosis and 40 cases of normal control. To primary hepatic carcinoma, three kinds of hepatic tissue samples were harvested, including carcinoma tissue, adjacent non-tumor tissue, and distant normal tissue. The expression levels of cystatin C in hepatic samples and blood samples were measured by immunohistochemistry method and latex enhanced immune turbidimetric method respectively, and the differences of cystatin C expressions were compared in primary hepatic cancer, cirrhosis, and normal control. Furthermore, the relationships of cystatin C expression with tumor size, intrahepatic metastasis, serum AFP level were studied with correlation analysis. RESULTS: The expression of cystatin C was positive, in primary hepatic carcinoma. Part of adjacent non tumor tissue, and distant normal tissue and cirrhosis tissues had some degree of cyctatin C expression. Wilcoxon test showed that the differences of cyctatin C expression in different hepatic tissues were statistics significance (P < 0.01). The proportion of positive cell, staining intensity, and the product of these two was: carcinoma tissues > adjacent non-tumor tissues> cirrhosis tissues > distant normal tissue. Compared with normal control, primary hepatic carcinoma and cirrhosis both had higher serum cystatin C level (P < 0.001), but there was no difference between hepatic carcinoma and cirrhosis (P = 0.769). The correlation analysis showed that the level of serum cystatin C was not related to serum AFP, tumor size, or intrahepatic metastasis. CONCLUSION: The expression of cystatin C in primary hepatic carcinoma is higher than that of adjacent non-tumor tissue, distant normal tissue, and cirrohsis tissue. The serum cystatin C level of primary hepatic carcinoma is higher than that of normal control. PMID- 24490503 TI - [Effects of retinoic acid on the expression of Cx43 and its gap juncion intercellular communication function in testicular cancer cell]. AB - OBJECTIVE: To investigate the effects of retinoic acid (RA) on the expression of Cx43 and its gap junction intercellular communication function in testicular cancer cells. METHODS: Cultured testicular cancer cells I-10 were treated with different concentration of RA (2.5, 5.0,10.0 micromol/L). The expression of Cx43 in 1-10 cells was detected by Western blot, and the distribution and location of Cx43 on cellular membrane was studied with immunofluorescence assay. Parachute assay was used to detect the function of gap junction intercellular communication composed of Cx43 in 1-10 cells. RESULTS: RA (2.5, 5.0, 10.0 micromol/L) markedly increased the expression of Cx43 in I-10 cells, the enhancement ratios were 43.14% +/- 2.1%, 58.09% +/- 1.8%, 143.13% +/- 1.6%, respectively. The result of immunofluorescence assay showed that RA (2.5, 5.0, 10.0 micromol/L) obviously increased the level of Cx43 located on the cellular membrane of I-10 cells. The result of parachute assay demonstrated that RA (2.5,5.0,10.0 gmol/L) could enhance the intercellular dye coupling through gap junction, the enhancement ratios were 26.1% +/- 2.3%, 63.3% +/- 1.6%, 140.5% +/- 3.4%, respectively. CONCLUSION: RA could enhance the gap junction intercellular communication by increasing the expression of Cx43 in I-10 cells. PMID- 24490504 TI - [Effect of paclitaxel on platelet aggregation induced by adenosine diphosphate in vitro]. AB - OBJECTIVE: To investigate the effect of paclitaxel on platelet aggregation induced by adenosine diphosphate (ADP) in vitro. METHODS: Platelet suspension was incubated with paclitaxel in different concentrations (0 ng/mL, 0.01 ng/mL, 0.1 ng/mL, 1 ng/mL, 10 ng/mL, 100 ng/mL, 1 000 ng/mL), then the maximal extent of platelet aggregation was determined under the conditions of the best ADP concentration and the best incubation time. RESULTS: Under the condition of 10 micromol/L ADP and incubated for 10 min, with the increase of paclitaxel concentration, the effect of paclitaxel on platelet aggregation induced by ADP elevated accordingly, and the differences among the different concentration groups were statistically significant (P < 0.05). CONCLUSION: Paclitaxel can enhance ADP-induced platelet aggregation in a concentration-dependent manner in vitro. PMID- 24490506 TI - [Histological changes after the recontruction of tongue defect with rectus abdominis musculoperitoneal flap]. AB - OBJECTIVE: To observe the cellular morphological and histological changes of the reconstructed tongue defect by rectus abdominis musculoperitoneal flap of dogs with or without nerve. METHODS: 12 Beagle dogs were randomly divided into two groups. Group A made rectus abdominis musculoperitoneal flap with the intercostal nerve while group B without the intercostal nerve. Nerve anastomosis was performed in Group A while not in Group B in the repairment. 12 weeks later, the length, width, surface area and cellular morphology and histological changes of the two transfer flaps were observed. RESULTS: The length, width, surface area of transplanted rectus abdominis musculoperitoneal flaps in group A were greater than those in Group B, and the differences were statistically significant at 12th week (P < 0.01). The microscope study found that the transplanted rectus abdominis musculoperitoneal flaps of group A had part of muscle fiber atrophy with some connective and adipose tissue, loose muscle fiber arrangement, while the transplanted rectus abdominis musculoperitoneal flaps of Group B had muscle cells atrophy with some adipocyte. The structure of muscle cells in Group A was basically normal, but it was disorder in Group B. The type II muscle fibers of Group B was atrophy and substituted by a lot of connective tissue. CONCLUSION: After tongue defect reconstructed by rectus abdominis musculoperitoneal flap with nerve, the changes of muscle fibers could be similar to tongue muscles, providing a basis for the dynamic recovery of the tongue. PMID- 24490505 TI - [Effect of human umbilici mesenchymal stromal cells implantation on the BDNF expression in diabetic foot rats]. AB - OBJECTITVE: To investigate the effect of human umbilici mesenchymal cells (HUMSCs) implantation on the brain derived neurotrophic factor (BDNF) expression in diabetic foot rats. METHODS: SD rats were divided into three groups (n = 12): normal group, diadetic foot model group and HUMSC treatment group. Diabetic foot model in rats was established, then prepared HUMSC were implanted on the diabetic foot ulcers in rats, and control ones were administrated with saline only. The area of ulceration, sensory function, BDNF expression and its localization were determined by using morphology, physiological function measurement, RT-PCR and immunohistochemistry assay. RESULT: Siglificantly decreased area of ulceration in diabetic foot rats of HUMSC implantation group was observed. This was simultaneously companied with the sensory function improvement (P < 0.05). RT-PCR showed that BDNF mRNA expression was significantly up regulated (P < 0.05). BDNF immunstaining was located in epithelia tissue and the protein level of BDNF was markedly increased (P < 0.05). CONCLUSION: HUMSC implantation maybe an effective strategy on the treatment of ulceration in diabetic foot rats, and the possible mechanism may involve in BDNF expression. PMID- 24490507 TI - [The changes of skin barrier of patients with different facial dermatitis and the comparison of CE and KLK5]. AB - OBJECTIVE: To study the clinical symptoms and the condition of skin barrier of different facial dermatitis. METHODS: The patients with facial dermatitis were divided into 4 groups based on their diagnosis: hormone-dependent dermatitis (HDD) group, sensitive skin (SS) group, cosmetic intolerance (CI) group and normal control group. All patients received the evaluation on clinical symptoms with measuring scale, measurements of stratum corneum water content (SCWC), sebum, pH, trans-epidermal water loss (TEWL) and blood flow. The skin scales were collected for the measurements of the ratio of immature cornified envelope (CE) via immunofluorescence and the concentration of kallikrein 5 (KLK5) via enzyme linked immunosorbent assay. RESULTS: There were total 146 patients included (HDD 38, SS 53, CI 15, control group 30), most of them had their symptoms evaluated as moderate to severe. Compared with the control, the disease groups had lower SCWC and sebum (P < 0.05), higher pH, TEWL and blood flow (P < 0.05), higher ratio of immature CE (P = 0.011) and lower concentration of KLK5 (P = 0.000); while these parameters among the disease groups did not show statistical significant difference. CONCLUSION: There is no difference in the clinical symptoms and the condition of skin barrier between facial dermatitis with different inducements. The growth of CE may be inhibited and the concentration of KLK5 decreases in facial dermatitis. PMID- 24490508 TI - [The value of different obese criteria for the assessment of insulin resistance in women with polycystic ovary syndrome]. AB - OBJECTIVE: To investigate the value of three different obese criteria: body mass index (BMI), waist circumference (WC) and visceral fat area (VAA, CT measurement) in the evaluation of polycystic overy syndrome (PCOS) with insulin resistance. METHODS: There were 300 cases of PCOS included in this study. According to the three criteria, there were 210 cases of abdominal obesity (WC > or = 80 cm), and 90 cases of nonabdominal obesity (WC < 80 cm); 97 cases of overall obesity (BMI > or = 25 kg/m2), and 203 cases of non-overall obese (BMI < 25 kg/m2); 198 cases of visceral obesity (VAA > or = 80 cm2), and 102 cases non-visceral obesity (VAA < 80 cm2). Fasting plasma glucose (FPG) and fasting insulin (FINS) were detected, and HOMA-IR index was calculated; analyze the detection rate of the three criteria in the diagnosis of obese PCOS patients and insulin resistance. The serum levels of sex hormones, thyroid hormones, and plasma total cortisol (PTC) were measured as well. RESULTS: (1) The levels of blood hormone (including LH/FSH), thyroid hormone, PTC, fasting blood glucose were no significant differences between groups (P > 0.05), while the weight and fasting insulin were significantly difference between groups (P < 0.05) in three different obese. (2) The detection rates of obese PCOS patients in three criteria: overall obesity was 32.33% (97/300), abdominal obesity was 70.00% (210/300), visceral obesity was 66.00% (198/300). Compared to WC and VAA, BMI had the lowest detection rate of obesity, the differences were statistically significant (P < 0.05), while the detection rates of obesity in VAA and WC were no significant difference (P > 0.05). (3) The detection rates of insulin resistance in BMI,WC,VAA were respectively 38.60% (83/215), 85.11% (183/215), 69.77% (150/215), the differences were significant (P < 0.05). (4) The misdiagnosis rates of insulin resistance in BMI, WC,VAA were 61.40% (132/215), 14.88% (32/215), 30. 23% (65/215) respectively, and the differences were statistically significant (P < 0.05). CONCLUSION: There was obviously insufficient of BMI in screening obesity, WCmay has more advantages than BMI and VAA in the assessment of insulin resistance in obese PCOS patients. PMID- 24490509 TI - [Clinical features and epidemiological trend of diabetic ketosis in patients admitted to West China Hospital]. AB - OBJECTIVE: To evaluate the clinical features and epidemiological trend of diabetes ketosis (DK) in patients admitted to West China Hospital. METHODS: We reviewed medical records of diabetic patients with DK who were admitted to West China Hospital from 1997 to 2005. Their clinical and laboratory data were analysed with SAS 9.0. RESULTS: From 1997 to 2005, the proportion of diabetic patients with DK increased by 0.12% annually. The proportion of provoked DK patients (who had a clinically evident precipitating factor) in those with DK remained stable; whereas the proportion of T1D patients in those with DK declined by 2.00% annually and the proportion of ketosis prone obesity diabetes (KPD) in those with DK increased by 2.27% annually. The KPD patients displayed a striking male predominance (2.31:1, male:female) and were diagnosed at an older age compared with those with T1D [(46.3 +/- 12.9) yr. vs. (28.9 +/- 14.7) yr.]. The KPD patients were more likely to have a strong family history of diabetes and a better beta-cell function reserve, and be accompanied with dyslipidemia (52.7%), hypertension (23.3%), fatty liver (10.1%) and hyperuricemia/gout (8. 5%) compared with those with T1D. CONCLUSION: In recent years the proportion of KPD patients in the hospitalized DK patients is increasing. With different characteristics compared with typical T1D, KPD might belong to a subgroup of T2D. PMID- 24490510 TI - [Blood lipid, glucose and uric acid in people with subclinical hypothyroidism]. AB - OBJECTIVE: To investigate the changes of blood lipid, fasting blood glucose and blood uric acid and its clinical significance in people with subclinical hypothyroidism. METHODS: Body mass index (BMI), thyroid stimulating hormone (TSH), free triiodothyronine (FT3), free tetraiodothyronine (FT4), total cholesterol (TC), triglyceride (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), fasting blood glucose (FBG) and uric acid (UA) were measured and compared in 356 people with subclinical hypothyroidism and 331 health people (controls). RESULTS: Compared to the control group, people with subclinical hypothyroidism had higher levels of BMI, TSH, TC, LDL-C, TG, FBG, UA (P < 0.05) and non-significant decrease of HDL-C (P > 0.05). The level of TSH was positively correlated with TC (r = 0.254), LDL-C (r = 0.110), TG (r = 0.218), BMI (r = 0.119) and FBG (r = 0.210) (P < 0.05). The level of HDL-C was not correlated with TSH (P > 0.05). CONCLUSION: Thyroid dysfunction may have an effect on the metabolism of blood lipid, FBG and UA. PMID- 24490511 TI - [Development of a quality of working life scale (QWL7-32)]. AB - OBJECTIVE: To develop a simple structured scale measuring quality of working life (QWL) from the perspective of occupational health and safety. METHODS: We identified the dimensions and items of QWL through literature review, brainstorming and expert panel discussions, and developed a pre-test questionnaire. The pre-test questionnaire was tested in school teachers and revised accordingly. The QWL Scale was eventually validated in 516 The school teachers in Chengdu. We examined the validity and reliability of the final scale (QWL7-32). RESULTS: exploratory factor analysis extracted seven factors with an eigenvalue greater than 1. Those seven factors contributed to 60.1% of the total variance. The confirmatory factor Analysis endorsed the seven factor model. The seven-dimension scale had good convergent validity and discriminant validity. The Cronbach's alpha coefficients of the QWL7-32 scale and all its seven dimensions were around or higher than 0.70 (P < 0.01). The test-retest correlation coefficients of the scale and all its seven dimensions were close to or greater than 0.60 (P < 0.01). CONCLUSION: The QWL7-32 scale has acceptable validity and reliability. It measures QWL in a comprehensive, specific and accurate way, and can be used as an instrument for assessing QWL. PMID- 24490512 TI - [Hot issues on the treatment of severe acute pancreatitis by Integrated Traditional Chinese and Western Medicine]. AB - Severe acute pancreatitis (SAP) is recognized as critical refractory disease. The case fatality rate of SAP is as high as 36%-50%. Although significant progress has been achieved on the treatment of severe acute pancreatitis (SAP) by Integrated Traditional Chinese Medicine (TCM) and Western Medicine (WM), there still exist some difficulties hindering the further improvement of therapeutic efficacy. The hot issues includes: unconfirmative curative effects and diverse treatment principles, complicated predictive scoring systems and inaccurate markers for the severity stratification, unproved new therapeutic tools and controversial methods waiting more high qualified evidence, unclarified mechanism of Integrated TCM and WM. In order to overcome the difficulties, we aim to launch the clinical pathway of Integrated TCM and WM, to strengthen the unity of multidisciplinary cooperation. We also need to keep the efforts on screening the markers for early evaluation and prediction of disease severity, improving the diagnosis and treatment, exploring the mechanism of Traditional Chinese Medicine in treating SAP with more high quality basic and clinical research. Based on these efforts, we could provide better treatments and prognosis for SAP patients. PMID- 24490513 TI - [Health economic evaluation of clinical pathway of traditional Chinese medicine in the treatment of mild acute pancreatitis]. AB - OBJECTIVE: To evaluate the health economic value clinical pathway (CP) of traditional Chinese medicine in the treatment of mild acute pancreatitis (MAP). METHODS: Ninty one patients with MAP were enrolled prospectively in TCM clinical pathway group from June 2012 to February 2013, while the data of 80 MAP patients who were treated without TCM clinical pathway from June 2011 to May 2012, were analyzed retrospectively as control group. The health economic evaluation data used for the two groups comparison included: average length of stay, hospitalization expenses (total hospitalization expenses, total treatment cost, TCM treatment cost, herbal fees, medicine fees, and nursing care cost), as well as the usage of antibiotics/somatostatin, the release time of abdominal pain, the time of re-feeding, and patient satisfaction. RESULTS: There were no significant statistical differences in demographics, etiology, Ranson and Balthazar CT scores between the two groups (P > 0.05). Compared with non-CP group, the usage of antibiotics and somatostatin, the release time of abdominal pain, the time of re feeding and patient satisfaction were all improved significantly in CP group (P < 0.05). The average length of stay in CP group was shorter than that of non-CP group (P < 0.05). Total hospitalization expenses [yen (11,089.89 +/- 4,318.29) vs. yen (8,960.34 +/- 4,328.91)], medicine fees [yen (6,563.80 +/- 2,743.87) vs. yen (3,988.28 +/- 2,128.10)] and nursing care cost [yen (110.51 +/- 37.24) vs. yen (93.32 +/- 35.20)] were all reduced in CP group, while TCM treatment cost [yen (609.59 +/- 624.42) vs. (968.29 +/- 769.68)] and herbal fees [yen (162.72 +/ 135.13) vs. yen (303.49 +/- 149.90)] were increased (P < 0.05). There was no significant statistical difference in total treatment cost between the two groups (P > 0.05). CONCLUSION: TCM clinical pathway of MAP can not only ensure the therapeutic effects, but also shorten the average length of stay, reduce medical cost and increase patient satisfaction. PMID- 24490514 TI - [The value of different scoring systems for computed tomography in predicting pancreatic pseudocyst in severe acute pancreatitis]. AB - OBJECTIVE: To evaluate the value of several Computed Tomograph (CT) scoring systems in predicting the development of acute pancreatic pseudocyst (PPC) in severe acute pancreatitis (SAP) during early One hundred and sixty-two patients with SAP were retrospectively observed and subjected to stage. METHODS clinical, laboratory, and radiology investigation from October 2007 to December 2010. Three different CT scoring systems including CT severity index (CTSI), Modified CT severity index (MCTSI) and Extrapancreatic Inflammation on CT score (EPIC), were used for the determine of PPC, while the predictive values of these three Forty eight patients CT scoring systems in the presence of PPC were analyzed by the ROC curve. RESULTS: (29.6%) were observed the formation of PPC. The scores of CTSI, MCTSI, EPIC and the occurrence rate of ascites in PPC group were significantly higher than those in non-PPC group with One-way ANOVA analysis. Among the three CT scoring systems, EPIC score showed a larger area under ROC curve (AUC = 0.914) than CTSI (AUC = 0.674) and MCTSI (AUC = 0.72) did. CONCLUSION: EPIC scoring system has better prediction of PPC in SAP patients than CTSI and MCTSI. PMID- 24490515 TI - [Clinical study on different admission serum glucose levels in patients with severe acute pancreatitis]. AB - OBJECTIVE: To investigate the clinical characteristics, prognosis effects and management of different admission serum glucose levels in patients with severe acute pancreatitis (SAP). METHODS: A retrospective analysis involving a total of 218 patients with SAP and have serum glucose > or = 6.1 mmol/L at admission during the period from August 1, 2005 to December 31, 2007 was enrolled based on the coding data in West China hospital. They were divided into 3 groups according to admission glucose levels of 6.1-11.1 mmol/L (n = 115), 11.2-16.7 mmol/L (n = 71), and > 16.7 mmol/L (n = 32) respectively. Patients' demographic characteristics, clinical parameters, various scoring systems, the ICU transfer rate during early phase and the mortality, infection rate and operation transfer rate during later phase were obtained and calculated. RESULTS: The pulse and respire frequency, the levels of serum lactate dehydrogenase (LDH), blood urea nitrogen (BUN), creatinine (Crea) and scores on the Ranson Criteria, Acute Physiology and Chronic Health Evaluation II (APACHE II) at admission, APACHE II and Balthazar's Computed Tomography Severity Index (CTSI) within 72 hours increased in sequence according to mild, moderate and severe hyperglycemic group (P < 0.01). Whereas the concentration of serum Ca2+ was lower than that in the mild elevated serum glucose group (P < 0.01). In the 3 groups, the early single organ failure rates were elevated in turn (P < 0.01) and the multi-organ failure rates were 16.5%, 45.1% and 50.0% (P < 0.01) respectively. Simultaneously, the ICU transfer rates were 10.4%, 26.8% and 34.4%, while the mortality in the 3 groups were 7.8%, 16.9% and 40.6% respectively, which were statistically significant (P < 0.01). CONCLUSION: The findings of the study suggest that admission elevated glucose is an indicator of organ failure and poor prognosis of SAP. PMID- 24490516 TI - [Effects of micron Chinese herbal Liu-He-Dan ointment on inflammation and oxidative stress in rats with acute pancreatitis]. AB - OBJECTIVE: To evaluate the effects of micron Chinese herbal Liu-He-Dan ointment (MLHD) on inflammation and oxidative stress in rats with acute pancreatitis (AP). METHODS: Eighteen SD rats were randomized into three groups: normal group (n = 6), AP group (n = 6) and MLHD group (n = 6). The rat model of AP was induced by intra-peritoneal injection of 150 g/L L-arginine with dosage of 2.0 mg/g twice within 2 hours. As control, the normal rats were injected the same amount of saline. The MLHD was applied to the abdomen area of the AP rats in MLHD group for 72 h. The serum and pancreas of the rats were obtained. The level of amylase, TNF alpha, IL-6, IL-10 in serum and SOD, MDA in the pancreas were detected and quantified. RESULTS: Compared with AP group, the serum levels of amylase, TNF alpha, IL-6, IL-10 were significantly decreased in MLHD group (P < 0.05). And the SOD in pancreas increased significantly (P < 0.05), but a decreasing trend of MDA level in MLHD group (P > 0.05) was observed. The serum level of the pathological score of pancreas in treatment group were similar to that in the model group (P > 0.05). CONCLUSION: Micron Liu-He-Dan ointment may have therapeutic and protective effects on AP by antioxidation and alleviating inflammatory response. PMID- 24490517 TI - [Effects of electro-acupuncture at Zusanli point on gastric and intestinal blood flow in rats with acute necrotizing pancreatitis]. AB - OBJECTIVE: To investigate the effects of electro-acupuncture (EA) at Zusanli point on gastric and intestinal blood flow and serum endothelin-1(ET-1), nitricoxide(NO), thromboxaneB2 (TXB2), 6-keto-prostaglandin F1alpha (6-K PGF1alpha) in rats with acute necrotizing pancreatitis (ANP). METHODS: Thirty-six male Sprague Dawley (SD) rats were randomly divided into sham operation (sham), ANP and EA groups (n = 12). ANP model was induced by retrograde injection of 5% sodium taurocholate into pancreaticobiliary. EA was applied to Zusanli for 30 min at 2 h and 6 h after the operation in EA group. Gastric and intestinal mucosal blood flow was measured by laser doppler flowmetry (LDF) at 12 h and 24 h after operation, while the levels of serum ET-1, NO, TXB2 and 6-K-PGF1alpha were detected. RESULTS: The gastric and intestinal blood flow in ANP rats were significantly lower than those in the sham group (P < 0.05), but those of EA groups were higher than those in ANP groups (P < 0.05). The serum ET-1, NO and ET 1/NO levels in ANP group were increased when compared with SO group (P < 0.05). After the electro-acupuncture treatment at Zusanli point, the levels of ET-1, NO and ET-1/N were decreased, and there were significant differences of ET-1 (at 12 h, 24 h), NO (at 12 h) and ET-1/NO (at 24 h) between EA and ANP group (P < 0.05). The levels of serum TXB2, 6-K-PGF1alpha and TXB2/6-K-PGF1alpha in ANP group were also increased (P < 0.05), but those in EA group were decreased, and there were significant differences of TXB2 (at 12 h, 24 h), 6-K-PGF1alpha (at 12 h) and TXB2/6-K-PGF1alpha (at 24 h) compared with ANP groups (P < 0.05). CONCLUSION: Electro-acupuncture at Zusanli point can significantly improve the gastric and intestinal mucosa blood flow in ANP rats, which may be related to the regulation of serum ET-1, NO, TXB2, 6-K-PGF1alpha. PMID- 24490518 TI - [Primary culture and identification of rat glomerular podocytes]. AB - OBJECTIVE: To establish an easy and feasible method for primary culture and identification of rat glomerular podocytes. METHODS: Glomeruli from Sprague Dawley (SD) rats weighing 60-100 gram were isolated by the method of different size combination of screen. Isolated glomeruli were appropriately digested with 2 g/L type IV collagenase and cultured in 25 cm2 plastic flask coated with rat tail collagen in K1-3T3 medium with ITS-X (containing insulin-transferrin-selenium). Subculture of primary cultured epithelial cells was performed at 9-10 days after implantation of collagenase digested glomeruli. Podocytes were identified by the morphology study with scanning electron microscope and inverted microscope, as well as the immunohistochemistry staining (SP methods) study for the expression of keratin, desmin and Wilms' tumor suppressor-1 (WT-1). RESULTS: Epithelial cells outgrowth from isolated glomeruli appeared after 3 days primary culture and grew to confluence with cobblestone-appearance at 9-10 days. These cobblestone cells were subcultured at this point and gradually conversed into large, flat arborized cells with well-developed processes and microvilli. These arborized cells were negative expression with desmin staining and showed positive expression of cytokeratin and WT-1, which indicated that they were podocytes. CONCLUSION: Implantating collagenase digested-glomeruli is an easy and feasible method for primary culture of rat glomerular podocytes. WT-1 may serve as a good marker to identify rat glomerular podocytes. PMID- 24490519 TI - [Intraoperative transesophageal echocardiography in robotic perimembranous ventricular septal defect repair]. AB - OBJECTIVE: To explore the role of intraoperative transesophageal echocardiography (TEE) in robotic perimembranous ventricular septal defect (VSD) repair. METHODS: A retrospective analysis was conducted with intraoperative TEE data of 18 consecutive patients who underwent robotic perimembranous VSD repair from January 2009 to August 2012. (1) Before cardiopulmonary bypass (CPB), TEE was performed to document the anatomic types, numbers, and the size of VSD. The procedures were predetermined by the surgeon according to TEE information. (2) During the establishment of peripheral CPB, TEE was used to guide the placement of cannulae in inferior vena cava (IVC), superior vena cava (SVC), and ascending aorta (AAO). (3) After weaning from CPB, TEE was conducted to evaluate the effect of the procedure. RESULTS: (1) Accuracy of TEE was 100% for diagnosing the anatomic types of VSD. All the surgical procedures were performed based on the predetermined information. (2) Under TEE guidance, all the cannulae in the SVC, IVC and AAO were located in correct positions. (3) In all patients, TEE confirmed successful VSD repair. CONCLUSION: TEE is a useful tool in the assessment of robotic perimembranous VSD repair. PMID- 24490520 TI - [Surgery for patients with hepatocellular carcinoma and inferior vena cava tumor thrombus]. AB - OBJECTIVE: To investigate the surgical procedure, safety and efficacy of liver resection with inferior vena cava (IVC) thrombectomy in the treatment of the patients with hepatocellular carcinoma (HCC) and IVC tumor thrombus. METHODS: A retrospective study was conducted to analyze the data of 10 patients with HCC and IVC tumor thrombus undergoing liver resection and thrombectomy was analyzed. The surgical procedure included two parts, firstly the involving liver lobes were transected using the anterior approach without pedicle clamping, then the tumor thrombus were removed from the IVC under total hepatic vascular exclusion (THVE). RESULTS: All lesions and tumor thrombus were successfully removed. The mean operation and THVE time were 202 and 22 minutes respectively. The mean intraoperative blood loss was 1,463 mL and the mean postoperative hospital stay was 12 days. One patient died of hepatic and renal function failure within 30 days after surgery. Hepatic insufficiency was seen in four cases and was successfully treated. The rest experienced uneventful postoperative recovery course. One patient died in the perioperative period and the rest had the postoperative life span ranging from 3 months to 19 months. CONCLUSION: Hepatocellular carcinoma with IVC tumor thrombus is not a contraindication for surgery. Liver resection combined with IVC thrombectomy can be safely performed. PMID- 24490521 TI - [Using carboxymethl starch sodium solution for the treatment of children with cough variation asthma]. AB - OBJECTIVE: To analysis the clinical characteristics of children with cough variation asthma (CVA) who received treatments with Carboxymethl starch sodium solution and inhaled Glucocorticoid budesonide. METHODS: A total of 96 children with CVA were divided into two group randomly. The control group (n = 49) received inhaled budesonide treatment (500 microg/times in 1-5 years old children, 1 mg/times and 2 times/day in 6-14 years old children over a 12 week period). The children in treatment group (n = 47) were given carboxymethl starch sodium solution (3 mL/times in 1-3 years old children, 5 mL/times in 4-7 years old children, 7 mL/times in 8-14 years old children, 3 times/day) in addition to the inhaled budesonide treatment. Observations were made on clinical therapeutic effects, cough score and the level of IgE 4 weeks, 8 weeks and 12 weeks after the treatments, respectively. Recurrence rate and adverse reactions were investigated. RESULTS: Compared with the control group, the treatment group had significantly improved clinical characteristics after 8 weeks and 12 weeks of treatments (P < 0.05), and reduced cough scores after 4 weeks, 8 weeks and 12 weeks of treatments (P< 0.05). The IgE level of the children in the treatment group was significantly lower than the controls after 12 weeks of treatments (P < 0.05). The treatment group also had significantly lower recurrence rate and adverse reactions than the controls (P < 0.05). CONCLUSION: Carboxymethl starch sodium solution can boost the clinical efficiency of inhaled budesonide in the treatment of children with cough variant asthma. It is safe and effectual. PMID- 24490522 TI - [Thinking in treatment of lumbar intervertebral disc herniation under endoscope with minimally invasive spine surgery technique]. PMID- 24490523 TI - [Treatment of lumbar intervertebral disc herniation and sciatica with percutaneous transforaminal endoscopic technique]. AB - OBJECTIVE: To analyze the clinical effects of percutaneous transforaminal endoscopic technique in treating lumbar intervertebral disc herniation and sciatica. METHODS: From June 2011 to January 2012,the clinical data of 46 patients with lumbar intervertebral disc herniation and sciatica underwent percutaneous transforaminal endoscopic technique were retrospectively analyzed. There were 28 males and 18 females,ranging in age from 11 to 77 years old with an average of (39.7_ 15.3) years old,20 cases were L5S1 and 26 cases were L4,5. All patients had the symptoms such as lumbago and sciatica and their straight-leg raising test were positive. Straight-leg raising test of patients were instantly repeated after operation;operative time,volume of blood loss,complication, length of stay and duration of back to work or daily life were recorded. The clinical effects were assessed according to the VAS,JOA and JOABPEQ score. RESULTS: All operations were successful,postoperative straight-leg raising test were all negative. Operative time,volume of blood loss,length of stay,duration of back to work or daily life,follow-up time were (93.0+/-28.0) min, (20.0+/-9.0)ml, (3.1+/ 1.5) d, (11.6+/-4.2) d, (13.9+/-1.6) months,respectively. VAS score of lumbar before operation and at the 1st and 3rd,6th,12th month after operation were 5.3+/ 1.2,1.9+/-1.1,1.0+/-0.8,0.9+/-0.8,0.8+/-0.6,respectively;VAS score of leg before operation and at the 1st and 3rd,6th,12th month after operation were 7.2+ 1.2,0.8+/-1.2,0.5+/-0.8,0.5+/-0.8,0.3+/-0.8,respectively. Five factors of JOABPEQ score,including lumbar pain,lumbar function, locomotor activity,social life viability and mental status,were respectively 27.0+/-30.6,37.3+/-27.4,38.5+/ 26.6,33.0+/-13.7,55.4+/-19.0 before operation and 83.6+/-24.8,89.4+/-15.7,87.0+/ 17.9,58.4+/-14.6,79.5+/-13.4 at final follow-up. Preoperative and postoperative JOA score were 9.1+/-2.6 and 27.3+/- 1.7, respectively. The postoperative VAS,JOA and JOABPEQ score had significantly improved (P<0.05). CONCLUSION: Percutaneous transforaminal endoscopic technique is safe and effective method in treating lumbar disc herniation and sciatica,it can fleetly relieve pain and the patient can recover daily life and work after treatment. PMID- 24490524 TI - [Treatment of senile lumbar nerve root canal stenosis with micro-endoscope discectomy]. AB - OBJECTIVE: To investigate the indication, surgical techniques and clinical effect of micro-endoscope discectomy (MED)in treating senile lumbar nerve root canal stenosis. METHODS: From March 2007 to October 2010,56 patients with lumbar nerve root canal stenosis were treated with discectomy and decompression through micro endoscope. There were 38 males and 18 females,aged 61 to 76 years old with an average of (64.53+/-4.43) years old. Course of disease was from 6 months to 15 years. According to JOA 29 score system,the function was evaluatd before and after operation,including subjective symptom, objective sign and bladder function. At 1,3,6,12 months after operation, according to X-rays examination to analyze, the clinical effects were analyzed. RESULTS: Fifty-one patients were followed up from 1 to 12 months. At 1,3,6,12 months after operation,JOA score improved from preoperative 13.46+/-2.02 to 23.13+/-1.86,23.54+/-2.39,24.66+/ 1.57,24.83+/-1.74,respectively;and the rate of excellent and good was 83.92% ,90.74%,95.42% ,92.15% ,respectively. There was statistical significance in JOA score between preoperative and final follow-up (P<0.05). No lumbar instability sign was found by X-rays examination. CONCLUSION: Nerve root canal decompression through micro-endoscope discectomy for the treatment of senile lumbar nerve root canal stenosis is an effective procedure,which has the advantages of less traumatic,rapid recovery,but selection of indication and accurate operation are main keys. PMID- 24490525 TI - [Treatment of the recurrent lumbar disc herniation:a comparison between endoscopic surgery and open surgery]. AB - OBJECTIVE: To compare the clinical effect,advantages and disadvantages of endoscopic surgery and open surgery in treating the recurrent lumbar disc herniation. METHODS: From August 2008 to December 2010,the data of 35 patients with recurrent lumbar disc herniation were retrospectively analyzed. The patients were divided into endoscopic surgery group and open surgery group according to operative methods. Fourteen patients in endoscopic surgery group were treated with transforaminal lumbar interbody fusion by micro-endoscopic discectomy (MED) and the other 21 patients in open surgery the group were treated with posterior lumbar interbody fusion by open surgery. All patients were fixed by vertebral pedicle screw. The operation time,volume of bleeding and drainage after operation,analgesic dosage and time in bed after operation were observed. Visual Analogue Scale(VAS),Japanese Orthopedic Association(JOA)and Chinese Oswestry Disability Index(CODI) were used to evaluate the clinical effects before and after operation. RESULTS: There was no significant difference in operation time between two groups(P>0.05). Volume of bleeding and drainage after operation,analgesic dosage and time in bed after operation,VAS score in endoscopic surgery group was less than that of open surgery group (P<0.01). All patients were followed up for 1 year. There was no significant difference in JOA between two groups (P>0.05). CODI in endoscopic surgery group was better than that of open surgery group (P<0.01). CONCLUSION: Both operative methods can obtain good clinical effects,but the transforaminal lumbar interbody fusion operation by micro-endoscopic discectomy (MED) has advantage of less traumatic and less pain,better functional recovery,it is a first choice in treating the recurrent lumbar disc herniation. PMID- 24490526 TI - [Treatment of lumbar intervertebral disc herniation with coblation combined with ozone nucleus pulposus ablation]. AB - OBJECTIVE: To compare the clinical effects between coblation combined with ozone nucleus pulposus ablation and single radiofrequency ablation of nucleus pulposus in treating a simple segment inclusive lumbar intervertebral disc herniation. METHODS: From June 2009 to June 2011,33 patients with lumbar intervertebral disc herniation were treated with coblation combined with ozone nucleus pulposus ablation (group A),including 19 males and 14 females,ranging in age from 20 to 60 years old with an average of (40.4+/-8.8) years old,in the course of disease from 12 to 38 months with an average of (19.9+/-5.8) months;31 patients were treated with single radiofrequency ablation of nucleus pulposus(group B),ineluding 18 males and 13 females,ranging in age from 20 to 60 years old with an average of (39.8+/-7.3) years old,in the course of disease from 12 to 48 months with an average of (19.2+/-8.1) months. Visual analogue score(VAS) and JOA score system was respectively used to evaluate pain and function after operation. RESULTS: All patients were followed up more than 1 year. No injuries of nerve root and cauda equina nerve,infection were found. There was no significant difference in VAS score between two groups at 1 month after operation (P>0.05),but at 12 months after operation,VAS score of group A was better than that of group B (P<0.05). There was no significant difference in JOA score between two groups at 12 months after operation (P>0.05). According to the functional improvement rate to evaluate the clinical effects,in group A,9 cases got excellent results, 21 good,3 fair;and in group B,6 excellent,18 good,7 fair. Clinical effects of group A was better than that of group B (P<0.05). CONCLUSION: Clinical effects of coblation combined with ozone nucleus pulposus ablation is better in treating a simple segment inclusive lumbar intervertebral disc herniation. PMID- 24490527 TI - [Treatment of monteggia fractures of type II with manipulation reduction and plaster external fixation]. PMID- 24490528 TI - [Percutaneous kyphoplasty for the treatment of senior patient with acute and chronic osteoporotic vertebral compression fractures]. AB - OBJECTIVE: To discuss the clinical effects of percutaneous kyphoplasty (PKP) for acute and chronic osteoporotic vertebral compression fractures (OVCF). METHODS: From June 2006 to October 2011,42 senior patients with OVCF were treated with PKP. There were 5 males and 37 females,ranging in age from 60 to 86 years old with an average of (73.3+/-7.5) years old. The patients were divided into two groups (acute group and chronic group) according to the course,MRI and whether or not undergoing systematically conservative. VAS and ADL scoring systems were used to evaluate the pain and daily activities. X-ray was used to evaluate the vertebral height restoration rate and the kyphosis correction rate. RESULTS: All patients were followed up from 10 to 64 months with an average of 17 months. At 1 week and 6 months after operation in two groups, VAS and ADL scores decreased significantly (P<0.05) ;VAS and ADL scores at 6 months after operation were higher than at 1 week after operation (P>0.05). But the improvement rates of the pain and daily activities of acute group were better than that of chronic group (P<0.05). At 1 week after operation,the restoration rate of anterior and middle vertebral height,the kyphotic correction rate in acute group were better than that of chronic group (P<0.05). CONCLUCSION: Using PKP to treat both acute and chronic osteoporotic vertebral compression fractures can get good effects,but acute patients can obtain better effects than chronic patients,it has obviously advantages of relieving pain,correcting kyphotic angle,recovering vertebral height. PMID- 24490529 TI - [Treatment of senile osteoporotic vertebral compression fractures with percutaneous kyphoplasty under local anesthesia]. AB - OBJECTIVE: To evaluate the clinical outcomes of percutaneous kyphoplasty (PKP) in treating senile osteoporotic vertebral compression fractures under local anesthesia. METHODS: From May 2007 to May 2010,129 patients with osteoporotic vertebral compression fractures were treated with PKP under local anesthesia. There were 47 males and 82 females, ranging in age from 61 to 92 years old,with an average of 73.7 years old,including 88 segments of thoracic vertebrae and 101 segments of lumbar vertebrae. Visual analogue scale (VAS),height of vertebral body,Cobb's angle were evaluated before and after operation. RESULTS: Operations were performed successfully in all patients and these patients were followed up from 24 to 60 months with an average of 34.2 months. Preoperative,postoperative two weeks and at final follow-up,VAS score was 7.9+/-2.5,2.8+/-1.8,3.0+/ 2.2,respectively;Cobb angle was (28.3+/-13.7)degree, (16.2+/-9.8)degree, (19.1+/ 10.3)degree, respectively. There was significant difference between postoperative and preoperative, and between at final follow up and preoperative (P<0.05). The height of vertebral body obtained partial recovery. Bone cement leakage occurred in 23 vertebrae (with proportion of 17.8%) during operation,among one patient with temporary clinical symptom of radiculalgia. All lumbago obtained obviously anesis after operation, 1 case complicated with respiratory depression and recovered after resuscitation; 1 case complicated with intestinal obstruction and improved after treatment, 1 case complicated with fracture separation of vertebral body by bone cement, and 4 cases complicated with fracture of adjacent vertebral body. CONCLUSION: Percutaneous vertebral kyphoplasty is an effective method for treatment of senile osteoporotic vertebral compression fractures,which can expeditiously relieve pain and effectively recovery height of vertebral body and Cobb angle,it has advantages of minimal invasive. The results of short and mid-term follow-up were satisfactory, long-term follow-up is still needed. Correctly choosing the operative indication and improving surgical technique may avoid complications, especially bone cement leakage which is the most frequent complication. PMID- 24490530 TI - [Treatment of atlantoaxial hemangioma with vertebroplasty through anterior approach]. AB - OBJECTIVE: To investigate the diagnostic and therapeutic experience for the atlantoaxial hemangioma with vertebral plasty through anterior approach. METHODS: From January 2005 to April 2012,6 cases were initially diagnosed as atlantoaxial hemangioma under MRI,and treated with vertebroplasty through anterior approach. There were 2 males and 4 females ranging in age from 35 to 67 years old with an average of 49 years old. Six patients were followed up by out-patient clinic or telephone after operation for 6 months,and WHO standard clinical effects were used to assesse pain degree. RESULTS: All the hemangioma were confirmed by puncture. The mean operative time and injection amount of bone cement were 58 min and 2.6 ml,repectively. Postoperative X-ray or CT scan showed that the bone cement filled focus satisfactorily. All patients were followed up from 6 to 48 months with average of 28 months. According to the pain degree of WHO standard, 2 cases got partly relief and 4 got completely relief and up to final follow-up,the results were still stable. CONCLUSION: Treatment of atlantoaxial hemangioma with vertebroplasty through anterior approach is a safe and effective method. And correct puncture, adequate injection time and volume of bone cement are keys to successful. PMID- 24490531 TI - [Treatment of intertrochanteric fractures over age of 80 years old patients with proximal femur intramedullary nail]. AB - OBJECTIVE: To explore the clinical effects of proximal femur intramedullary nail (PFNA) in treating intertrochanteric fracture in elderly patients. METHODS: From January,2008 to December,2010,the data of 86 elderly patients (aged, 80 to 93 years) with intertrochanteric fracture who underwent internal fixation were retrospectively analyzed. Of them, 54 patients (22 males and 32 females) were treated with close reduction and PFNA internal fixation(PFNA group),and 32 patients (12 males and 20 females) were treated with open reduction and nail plate internal fixation (control group). Operation time, volume of blood loss, postoperative complications, time of hospitalization and bone union, hip function were compared between two groups. RESULTS: All patients were followed up more than 2 years. Operation time, volume of blood loss, postoperative complications,time of hospitalization in PFNA group were less than that of control group (P<0.01). There was no significant difference in time of bone union between two groups (P>0.05). According to Harris score to evaluate the function of hip joint, PFNA group was better than that of control group (P<0.01). CONCLUSION: Treatment of elderly patients with intertrochanteric fractures with PFNA internal fixations can obtain satisfactory results, the method is better than that of traditional method. PMID- 24490532 TI - [Clinical natural development in human meniscus injury]. AB - OBJECTIVE: To investigate the changes of clinic and wound edge of the meniscus without treatment in order to provide a theoretical basis for clinical treatment. METHODS: From January 2001 to December 2011,68 patients with knee injury without diagnosis and treatment were selected in the study. According to clinical symptoms (pain,interlocking,instability, etc.) and knee MRI,32 patients were diagnosed as meniscus injury and underwent the arthroscopy. Total meniscectomy was performed in 32 cases on account of impossible repair of the meniscus. There were 21 males and 11 females,ranging in age from 15 to 49 years old with an average age of 25 years old,with an average time from diagnosis to arthroscopy for 46 weeks. Observation indexes included 1Preoperative and postoperative Lysholm scores of knee. 2Position,type and status of injury by arthroscopy. 3Observation of histology. With the procedure as follow: tissue samples were taken from different positions of the edge of the meniscus wound,and were divided into two parts. One part of sample was fixed with formalin, sliced with paraffin imbedding,and observed under an electron microscope after HE staining,and the other part of the sample was fixed with glutaraldehyde of 3%,sliced with ethoxyline imbedding ,and observed under an electron microscope after Lead Citrate staining. RESULTS: Thirty-two patients were followed up more than one year. There was significant differences in Lysholm scores bewteen preoperative and postoperative 3 months (t=15.6,P<0.01). Arthroscopy showed typical differences in 28 cases between the middle and the two ends of the wound edge and atypical differences in 4 cases. Light microscope showed typical manifestations in 26 cases, a few epithelioid cells could been seen fat the middle of the wound edge as well as cells tissue healing (such as fibroblasts) at the junction of each end,and atypical manifestations in 2 cases. Electron microscope showed typical manifestation in 25 cases and atypical manifestations in 3 cases. Typical manifestations in electron microscope showed the atrophic state tions in 25 cases and atypical manifestations in 3 cases. Typical manifestations electron microscope showed the atrophic state of nuclei and kytoplasm of cell (isogenous cells and epithelioid cells) at the middle of the wound edge; at the either junction of the wound edge, the fibroblasts exhibited an enlarged volume with many protuberances; the nuclei also increased in size, and the cytoplasm contained major rough endoplasmic reticulum, free ribosomes and Golgi complex; chondrocytes were round or oval with a large,round nucleus ; a large amount of rough endoplasmic reticulum and many free ribosomes could be observed in the cytoplasm;cartilage lacunae were observed surrounding chondrocytes. CONCLUSION: Weight loading activities with meniscus injury without treatment or before healing will increase the length of the wound and aggravate clinical symptoms. These findings indicate that early diagnosis and treatment combined with timely and effective immobilization is a key to the healing of meniscus injury and avoiding further surgery. The recent clinical effect of total meniscectomy is satisfacory in treating impossible repair meniscus. PMID- 24490533 TI - [Construction of lentivirus vector containing human LIM mineralization protein-1 (LMP-1) and its expression in rat bone mesenchymal stem cells]. AB - OBJECTIVE: To construct a recombiant lentivirus vector of human LMP-1 and detect the expression of LMP-1 in infected rat bone mesenchymal stem cells. METHODS: LMP 1 gene from the cDNA library were extracted by Polymerase Chain Reaction (PCR). The LMP-1 genes were connected into lentiviral vectors pGC-FU-EGFP which was linearized by Age I enzyme to produce recombiant lentivirus vector called as pGC FU-LMP-1-EGFP,then packaged by 293T cells. The virus supernant congtaining LV-LMP 1-EGFP was harvested, concentrated and titrated. The rat BMSCs were transfected with recombiant lentivirus LV-LMP-1-EGFP at the most appropriate MOI. The mRNA and protein expression of LMP-1 were detected by RT-PCR and Western blot. RESULTS: 1LV-LMP-1I-EGFP was recombined successfully and the titer reached 2x108TU/ml. 2The efficiency of infection was 93.5% ,which was get after LV-LMP-1 EGFP infected rat BMSCs at the most appropriate MOI=100. The expression of LMP-1 gene was confirmed by RT-PCR and Western blot. CONCLUSION: Lentivirus vector containing human LMP-1 gene is constructed successfully,which can transfected efficiently into rat BMSCs,and the infected rat BMSCs can effectively express LMP 1. PMID- 24490534 TI - [Analysis of chronergy for treatment of spinal cord injury with the allogeneic bone mesenchymal stem cells (BMscs) transplantation in rats]. AB - OBJECTIVE: To observe the change of behavior, pathological change of the spinal cord,and expression of brain-derived neurotrophic factor (BDNF) and brain-derived neurotrophic factor (NGF) on rats with spinal cord injury in order to explore the optimal time of BMSCs transplantation. METHODS: Eighty health SD rats were randomly divided into 8 groups (group A,B,C,D,E,F,G,H), 10 rats in each group. According to the modified Allen method,the rat model of spinal cord injury was built. Group A as non-injured group only exposed the spinal cord but not result in blast injury. BMSCs of vitro culture were respectively infunded the region of spinal cord injury in group C, D, E, F, G, H (as transplantation groups) at the 0 h, 6 h, 24 h,3 d,5 d,7 d after model made. Group B as single model group was infunded the equal cell culture fluid. BBB score was used to evaluate the function of spinal cord at the 1st,2nd and 4th weeks after injury. The morphological changes of the tissue of spinal cord injury were observed by HE stain and the expression of BDNF and NGF were detected by Elisa method at the 4th weeks after BMSCs transplantation. RESULTS: In non-injured group,BBB score was highest than that of other 7 groups at the 1st, 2nd and 4th weeks after injury (P<0.01). There was no significant difference in BBB score between single model group and transplantation groups at the 1st week after BMSCs transplantation (P>0.05). BBB score in transplantation groups were higher than that of single model group at the 2nd and 4th weeks after BMSCs transplantation (P<0.05). At the 2nd week after injury, BBB score from high to low was group F,E,G,D,H,C,but there was no significant difference among the groups (P>0.05). At the 4th week after injury,there was significant differences in BBB score between group F and other transplantation groups (group C,D,E,G,H)(P0.05). The levels of BDNF and NGF in group F was highest at the 4th week after BMSCs transplantation (P<0.05). In non-injured group,HE staining showed the struction of spinal cord was clear and complete,no neutrophil was found. But in other 7 groups,HE staining showed obviously oedema at local tissue,juncture of gray and white matter was undefined,and different gliocyte proliferation and inflammatory cell infiltrate cound be found. CONCLUSION: Allogeneic BMSCs transplantation is effective to stimulate the recovery of spinal cord function in rats with spinal cord injury,and the optimal time of BMSCs transplantation maybe at the 3 d after injury. PMID- 24490535 TI - [Issues in the diagnosis and treatment of cervical spondylosis]. PMID- 24490536 TI - [Early treatment of postoperative pyogenic infection in patients with lumbar disc diseases]. AB - OBJECTIVE: To explore the etiopathogenisis, diagnosis and early treatment of postoperative pyogenic infection in patients with lumbar disc diseases. METHODS: From March 2009 to March 2012,7 patients with postoperative pyogenic infection were retrospectivly analyzed. There were 6 males and 1 female,ranging in age from 42 to 62 years old,with an average of 46.5 years old. Among 7 cases,outside the spinal canal suppurative infection occurred in 6 cases and inside the spinal canal infection in 1 case and with temporary paralysis. All the patients were treated with continuous saline lavage-drainage of low pressure impulse during operation. Unitive sensitive antibiotics were applied for 4-6 weeks after operation until CRP and ESR completely normal or the biochemistry and routine examination of the cerebrospinal fluid completely normal for the patients with intracranial pyogenic infection. RESULTS: All the 7 cases obtained recovery and the length of stay was for 2-3 months. No remnant symptoms of nervous system were found at the leave hospital. CONCLUSION: Postoperative pyogenic infection in patients with lumbar disc diseases is an emergency,and easily results in misdiagnosis in clinic. So the early diagnosis is very important. Early debridement is the only measure to retrieve the life of patient,continuous saline lavage-drainage of low pressure impulse may remove the remnant focus of the deep soft tissue space,and removel of the internal fixation can ensure the postoperative pyogenic infection completely control. PMID- 24490537 TI - [Analysis of diagnosis and treatment of Segond fracture]. AB - OBJECTIVE: To investigate the clinical characteristics of Segond fracture and its operative method and opportunity. METHODS: From June 2008 to December 2011, arthroscopic exploration was performed in 16 patients with Segond fracture. Six patients were explored at 1 week after injury ,their anterior cruciate ligament were broken completely combined with meniscus injury. Ten patients were explored at 8-10 weeks after injury, 4 patients with anterior and posterior cruciate ligament breakage completely, 4 patients with anterior cruciate ligament breakage completely,and 2 patients with anterior cruciate ligament breakage incompletely,among 10 cases, 8 cases of anterior cruciate ligament breakage completely combined with meniscus injury, 1 case of anterior cruciate ligament breakage incompletely without obviously meniscus injury, 1 case combined with fibular head fracture and lateral collateral ligament injury. All broken cruciate ligaments were rebuilt after arthroscopic exploration and meniscus injuries were sutured in 5 cases. Clinical effects were evaluated according to Lysholm Gillquist scoring of knee joint function. RESULTS: Six patients were operated at 1 week after injury,their knee joint swelled obviously at 3 days after operation,unloaded blood oozing by joint puncture,and out-of-bed activity with assistance at the I week after operation. Other 10 patients were operated at 8-10 weeks after injury,no knee joint obviously swelled,no blood oozing was found by joint puncture ,and out-of-bed activity with assistance at 3 days after operation. All patients were followed up from 12 to 50 months with an average of 24 months. Postoperative Lysholm-Gillquist scoring of all patients were higher than preoperative and recovered well. CONCLUSION: Segond fractures often associated with anterior cruciate ligament breakage and meniscus injury,it is important that early detection for treatment. The best time of cruciate ligament rebuilding and meniscus repairing may be at 8-10 weeks after injury. PMID- 24490538 TI - [Tuberculosis of synovial membrane at greater trochanter of femur combined with bone destruction:a case report]. PMID- 24490539 TI - [Comparison of three measurements of lower extremity length during total hip arthroplasthy]. AB - OBJECTIVE: To analyze the accuracy of three measurements of lower extremity length during total hip arthroplasty(THA),and explore the causes that influence the accuracy. METHODS: From January 2010 to January 2013,145 patients underwent THA were retrospectively analyzed. There were 66 males and 79 females,ranging in age from 48 to 89 years with an average of 66.7 years. Their lower extremities were measured by three methods during operation,among them,31 cases with reference method of contralaterallegs (A method) ,63 cases with measurement method of Kirschner wire location (B method), and other 51 cases with measurement method of anatomical landmark (C method). The accuracy of the three measurements and the incidence rate of length inequality of lower extremity were analyzed. RESULTS: All patients were followed up,there was no significant differences in the operation time and the intraoperative blood loss among three groups. The difference of lower extremity length with A,B,C method were respectively (8.7+/ 5.7),(3.1+/-2.6), (5.6+/-5.3) mm after operation; there were significant difference between any two groups. The accuracy of three methods from high to low were respectively B,C,A method. The incidence rate of length inequality of lower extremity with A, B, C method were respectively 32.3%, 1.6%, 11.8%, the incidence rate with A method was higher than that other two methods ; and there was no significant difference between B method and C method. CONCLUSION: The measurement method of Kirschner wire location has the best accuracy in the three methods and the measurement method of anatomical landmark is the second. The measurement method of Kirschner wire location is recommended in all THA except for the patients with femoral neck fracture. And the measurement method of anatomical landmark can be used in the patients with femoral neck fracture. PMID- 24490540 TI - [Comparison between pavlik harness and bryant traction for femoral shaft fractures in infants]. AB - OBJECTIVE: To compare clinical effects between Pavlik harness and Bryant traction in treating femoral shaft fractures in infants,including the time of hospitalization, expense of treatment, complications,time of bone union. METHODS: From May 2005 to August 2010,the clinical data of 42 infants with femoral shaft fractures were retrospectively analyzed. Among the patients, 23 cases were treated with Pavlik harness(Pavlik harness group),there were 14 males and 9 females,ranging in age from 1 to 12 months with an average of (5.5+/-2.4) months,including upper 1/3 segment of 16 cases and middle segment of 7 cases; transverse fracture of 18 cases and oblique fracture of 5 cases. The other 19 patients were treated with Bryant traction (Bryant traction group),there were 15 males and 4 females,ranging in age from 2 to 12 months with an average of (6.7+/ 2.8) months,including upper 1/3 segment of 13 cases and middle segment of 6 cases;transverse fracture of 12 cases and oblique fracture of 7 cases. The time of hospitalization,expense of treatment,complications,time of bone union were analyzed in the patients. RESULTS: All patients were followed up with an average of 25.3 months (ranging from 19 to 30) in Pavlik harness group and 23.7 months (ranging from 17 to 28) in Bryant traction group. Time of hospitalization, expense of treatment in Pavlik harness group were respectively (0.4+/-0.7) d, (2147.7+/-64.9) yuan; and in Bryant traction group were respectively(27.1+/-2.2) d, (2741.3+/-227.6) yuan;there was significant difference between two groups(P<0.05). No complication was found in Pavlik harness group and 8 cases complicated with skin hydroa in Bryant traction group, there was significant difference between two groups (P<0.05). Time of bone union,difference of both lower extremities in Pavlik harness group were respectively (4.1+/-0.3)weeks, (6.3+/-4.1) mm;and in Bryant traction group were respectively (3.9+/-0.3) weeks, (7.6 +/-4.3) mm; 20 cases got bone healing in Pavlik harness group and 18 cases got bone healing in Bryant traction group;there was no significant difference between two groups (P>0.05). CONCLUSION: Compared with Bryant traction method,Pavlik harness method has obvious advantages in time of hospitalization, expense of treatment, complications in treating femoral shaft fractures in infants. PMID- 24490541 TI - [Revision after a failed anterior internal fixation use the anterior transpedicular screw fixation:a case report]. PMID- 24490542 TI - [Progress on cervical anterior transpedicular screw fixators for lower cervical vertebrae]. AB - Compared with the traditional anterior and posterior operation,anterior transpedicular screw fixation (ATPS) has many advantages of hiomechanics, relative safety. Both problems of decompression and reconstruction can be resolved only through an anterior approach. A rather peculiar anatomic channel was used in ATPS, but no special tools was used in system supporting for anterior pedicle screw to place,so the indications of ATPS of lower cervical vertebrae is relatively narrow,it cannot replace of traditional anterior and posterior surgery. Problems of accurately inserting screws and the development of internal fixation device about ATPS is a hot spot of current research and a future direction. In recent years,many scholars have systematically studied the technique, and applied it in clinic gradually and achieved good effects. In order to improve the level of application,recent articles were analyzed retrospectively in this paper,and the studies of anatomy,biomechanical and clinical application of ATPS were reviewed. PMID- 24490543 TI - [Progress on treatment of osteoporotic vertebral compression fracture]. AB - Osteoporosis vertebral compression fractures seriously affect the life and health of the elderly,indicating the elderly life health begin to decline. Therefore, aggressive treatment is particularly important. Traditional surgical method,such as laminectomy and internal fixation has large trauma,more blood loss and high failure rate. However, conservative treatment cannot early reduce pain symptoms and improve functional status,it can lead delayed union and severe ossification and form chronic OVCF,make more difficult to treat. In treatment of vertebral body fracture,there was a new way with the development of minimally invasive spinal surgery technology. Percutaneous vertebroplasty and percutaneous kyphoplasty has become the commonly used method in treating OVCF. With rapid and significant analgesic effect,vertebral body height recovered ideally, the patients can early load activities and preoperative complications is rare. Effective rehabilitation exercise is also important in treating OVCF by surgery at the same time. PMID- 24490544 TI - [Advance in studies on anti-tumor mechanism of matrine]. AB - Matrine is one of the main active components extracted from Sophora flavescens, S. subprostrata and S. alopecuroides. In recent years, its anti-tumor activity has attracted wide attention. According to studies, matrine shows the anti-tumor effect through multiple channels such as inducing apoptosis and autophagy of cancer cells, arresting cell cycle, inhibiting tumor cell migration, angiogenesis and NF-kappaB, as well as the synergistic effect with chemotherapeutics. Along with the further studies on matrine's anti-tumor mechanism, it has a broad prospect for development and application in tumor clinical treatment. PMID- 24490545 TI - [Research progress of Ypsilandra thibetica, a medicinal plant of Liliaceae]. AB - Ypsilandra thibetica belongs to the family Liliaceae. Its whole plant has the medicinal functions of heat-clearing and detoxifying, relieving congestion and other effects, and is used as the folk medicine to cure scrofula, dysuria embolism and other symptoms. Previous chemical studies revealed that its major and active ingredient is steroidal saponin. Up to now, more than fifty steroidal saponins, mainly composed of spirostan and furostanol types, have been described. Pharmacological and clinical studies have demonstrated that Y. thibetica has anti tumor, uterine contractions, hemostatic and antibacterial activities, in particular for the treatment of a variety of gynecological hemorrhagic diseases. In an effort to provide references for the advanced research and development of this species, this paper summarized the research progress on its pharmacognosy, including botany and authentication, its isolated secondary metabolites, biological activities and pharmacological applications. In addition, some advantages of this species which could be potentially used as a substitute for Paridis Rhizoma, one of ingredients of the well-known drug "Yunnan Baiyao", together with the future prospect are also briefly included. PMID- 24490546 TI - [Spatial structure and geographic distribution of major active component in medical herb Dipsacus asperoides population]. AB - To study the spatial structure and geographic distribution of major active components in medical herb Dipsacus asperoides population, in Guizhou province, the author obtained the asperosaponin VI content among 38 D. asperoides population points. Using spatial statistic and traditional statistic, the spatial variation pattern has been found. Combining the environment variables, it is tried to reveal the geographic distribution rules between group of major active component in medical herb D. asperoides population and group of environmental factors. The results show: the spatial structure of major active component in medical herb D. asperoides population is randomly distributed in global space, but has two aggregation points which have a high positive correlation in local space; environmental factors value for group of major active component in medical herb D. asperoides population has a large difference in the interior-group, but environmental factors value has a small difference in inter-group. PMID- 24490547 TI - [Regulation effects of intracellular and extracellular Ca2+ on biosynthesis of rosmarinic acid induced by salicylic acid in young seedlings of Salvia miltiorrhiza]. AB - OBJECTIVE: To investigate the effect of intracellular and extracellular Ca2+ on the biosynthesis of rosmarinic acid (RA) induced by salicylic acid in young seedlings of Salvia miltiorrhiza. METHOD: Young seedlings of S. miltiorrhiza were used to select an optimal concentration of salicylic acid (SA), and then use the optimal concentration of SA to investigate the effects of extracellular Ca2+ channel inhibitors Verapamil, LaCl3, intracelluar calmodulin antagonist TFP and intracelluar Ca2+ channel inhibitors LiCl on the biosynthesis of RA and related enzymes. RESULT: SA increased the accumulation of RA and the activities of PAL and TAT, especially the SA of 2 mmol x L(-1) after 24 h. SA improved the accumulation of RA to (40.51 +/- 2.16) mg x g(-1), which was 1.97 times than that of control, and the activities of PAL, TAT were 1.42 times and 1.29 times than those of the control. However, Vp, LaCl3, TFP, LiCl inhibited the effects of SA evidently. CONCLUSION: Ca2+ plays a key role in the regulation of the induction process. PMID- 24490548 TI - [Differences of Cynomorium songaricum seed quality and mutual parasitism in different host plants]. AB - In natural conditions, fully ripe Cynomorium songaricum seeds parasitize in Nitraria tangutorum or N. sphaerocarpa or N. sibirica or Zygophyllum xanthoxylom and Peganum harmala, were used in this study to research the morphological characteristics, embryo rate, seed viability, 1 000-grain weight, purity, water content and the seeds of different host parasitic relationship with each other. The results showed that the morphology, color and surface characteristics of the C. songaricum seeds are very similar in different hosts. According to the seed morphology can not be judged on its host. For the host to N. tangutorum or Peganum harmala or N. sibirica, we should choose the round hole screen less than 0.923 1 mm and larger than 1.066 2 mm to cleaning seeds. For the C. songaricum seeds parasitic in N. sphaerocarpa, the choice of slightly less than 0.926 1 mm and larger than 0.985 3 mm round hole screen to cleaning. For the parasitic seeds in Z. xanthoxylom, less than 0.751 3 mm and slightly larger than 1.035 3 mm round hole screen could be used. Highy significant correlation was found among the morphological indexes in C. songaricum seeds (P < 0.01). Morphological indexes and 1 000-grain weight were significantly correlated (0.01 < P < 0.05), but with the seed viability and the embryo rate were not found significant correlation. Grain weight is not related with the seed viability and the Fully mature C. songaricum seed viability is high and water content is low. The difference of the habitats and the host plants should be considered in the seed quality assessment and classification. The C. songaricum seeds on host plants are not selective, and the C. songaricum seeds from the host plants could be parasitized in other host plants. PMID- 24490549 TI - [Screening for virulence strains of Metarhizium against Dorysthenes hydropicus pascoes]. AB - OBJECTIVE: The aim of the present study was to screen the Metarhizium strains with high virulence against the larvae of Dorysthenes hydropicus, a serious pest of Citrus grandis. METHOD: Thirty six strains of Metarhiziums were isolated from the soil of C. grandis GAP base and collected from other institutions, and the pathogenicity of these strains against 1st instar larvae of D. hydropicus was detected at concentration of 1 x 10(8) conidia/g. The high violence strains against D. hydropicus were cultivated in sabouraud dextrose yeast medium at first, then transfer to rice grain. And the sporulations of these violent strains against D. hydropicus were detected. RESULT: Twenty-eight strains showed virulence against D. hydropicus by preliminary study, and 7 strains of them were collected for further study, 6 of the 7 showed high virulence, the highest cadaver rate was higher than 74%. The conidia production of strain 1 and strain 4 were 2.35 +/- 0. 25 (1 x 10(9) conidia/g), 2.21 +/- 0.27 (1 x 10(9) conidia/g), respectively, showed significantly higher than other strains. CONCLUSION: Strain 1 and strain 4 of the 36 Metarhiziums strains showed high virulence against D. hydropicus, and the highest sporulation ability, so they have a best application prospect. PMID- 24490550 TI - [Comparative study on four major active compounds of Sanvitalia procumbens and Chrysanthemum morifolium cv 'Hangju' and 'Gongju']. AB - The contents of chlorogenic acid, 3,5-O-caffeoylquinic acid, galuteolin and quercitrin in Sanvitalia procumbens and Chrysanthemum morifolium cv. 'Hangju' and 'Gongju' were determined by RP-HPLC. The main active ingredient of S. procumbens was similar to C. morifolium cv. 'Hangju' and 'Gongju'. The content varied significantly. The contents of chlorogenic acid, quercitrin and galuteolin in S. procumbens were 7.46, 46.58, 26.01 mg x g(-1), respectively, and they were the highest among the samples. The content of 3,5-O-caffeoylquinic acid in C. morifolium cv. 'Hangju' was 14.70 mg x g(-1), it was the highest among the samples. The data of the study provide a basis for further research and development of S. procumbens. PMID- 24490551 TI - [Cloning and expression analysis of HSP70 gene from Dendrobium officinale under low temperature stress]. AB - OBJECTIVE: To investigate HSP70 gene expression from Dendrobium officinale under low temperature stress, which will provide the molecular biological foundation for breeding the low temperature resistant strain. METHOD: HSP70 gene full length cDNA was cloned by rapid amplification of cDNA ends (RACE) on the basis of HSP70 gene fragment sequences, and the structure and function of HSP70 gene were deduced. The expression of HSP70 under low temperature stress was detected by RT PCR. RESULT: The full length of HSP70 gene cDNA was 2 296 bp containing a 1 944 bp open reading frame (ORF) that encoded a protein of 647 amino acids. Its amino acids sequence had typical HSP70 characteristics and high homology with other plant's HSP70. Cold stress expression analysis showed that expression of the HSP70 gene could be induced by low temperature. CONCLUSION: The HSP70 gene of D. officinale was successfully cloned and reported for the first time which proved that the expression could be induced by low temperature. The cloning of HSP70 gene provides a stable foundation for further study of D. officinale cultivation and the breeding of the cold resistance strains. PMID- 24490552 TI - [Analysis on influential factors of Chinese medicinal herb growers' willingness to use green pesticides: evidence on Panax notoginseng production areas in Wenshan, Yunnan province]. AB - The purpose of the article is to apply a binary logistic model to analyze the major factors, which influence Chinese medicinal herb growers' willingness to use green pesticides by using survey data collected in Wenshan, Yunnan Province. The results indicate that, output per capita, average pesticide cost per mu, cognition of pesticide residues, expectations on Panax notoginseng prices, cognition of pesticides' effect of pests control, cognition of P. notoginseng prices of low pesticide residues have a significant influence on growers' willingness to use green pesticides. According to the analysis above, some proposals for enhancing Chinese medicinal herb growers' willingness to use green pesticides are put forward, such as, moving toward the intensive planting systems, fetching down the pieces of green pesticides, emphasizing and propagating the advantages of green pesticides, keeping the prices of Chinese medicinal herb running at steady rates. PMID- 24490553 TI - [Change of Chinese chrysanthemi flos from different producing areas in storage]. AB - To observe and analyze the character change of Chinese Chrysanthemi Flos from different producing areas in the same storage conditions, and provide certain reference to the study of storage method and storage time of Chrysanthemi Flos. METHOD: Different species of Chrysanthemi Flos were collected from the whole country at the same period, stored in the same nature conditions for three years. The change on worm situation, mildew degree, flower shape, color and appearance character were ovserved. RESULT: The degree of worm and mildew situation of different regions of Chrysanthemi Flos was: Qiju < Hangju < Gongju < Chuju < Jiju = Huaiju = Damaya chrysanthemum. Among three cultivar species of Hangju, 'Huju' was the best preserved, following by 'Xiaobaiju', the worst was 'Dabaiju'. After the storage, the degree of worm situation of Gongju was different. The degree of worm situation of Chuju and Qiju were related to the process methods. CONCLUSION: The storage changes of Chrysanthemi Flos were related to the regions, specise, process methods, geography location and harvest time, etc. Different specises of Chrysanthemi Flos had different storage time. PMID- 24490554 TI - [Research on common laws during membrane enrichment of six herbal volatile oils- physicochemical property and fingerprint similarity]. AB - Membrane enrichment process of Chinese medicine volatile oil is green, practical and has a good application prospects. Schizonepetae Herba et al. six chinese medicine oily water were filtrated with polyvinylidene fluoride (PVDF) membrane with MWCO 70 000, at 40 degrees C, 0.1 MPa and 150 r x min(-1), common laws of physicochemical property of six oily water and fingerprint similarity between original and preserved oil were studied during membrane enrichment. Results were as follows: pH was gradually reduced to the minimum; conductivity firstly became larger, then smaller until 0; viscosity gradually increased to a maximum; surface tension gradually decreased to a minimum; turbidity firstly gradually increased, then reduced to a minimum; density gradually decreased to a minimum, but the change trend was opposite for Acori Tatarinowii Rhizoma with heavy oil; salinity was 0. In the end, pH reached a maximum and density reached a maximum (contrary for Acori Tatarinowii Rhizoma) and the other physicochemical property values reached a minimum for the last permeate. Fingerprint similarity between original and enriched volatile oil was above 90%. The above results provided data support and theoretical basis for the industrialization of membrane enrichment volatile oil technology. PMID- 24490555 TI - [Study on preparation of deoxyrhaponti-beta-cyclodextrin super-molecular inclusion complex and performance of inclusion complex]. AB - To prepare beta-cyclodextrin (beta-CD)-deoxyrhaponti inclusion complex by the homogeneous method, and characterize the inclusion complex with ultraviolet visible spectrum and fluorescence spectroscopy, in order to determine the inclusion rate, the ratio of subject-object, the binding constant of supra molecular system and the thermodynamic function. The results showed that the designed method was so rational that the inclusion complex was successfully prepared. The ultraviolet-visible spectrophotometry method was adoptedto determine the inclusion rate of 38%, and the ratio of subject-object of 2: 1. The thermodynamic parameters of this inclusion complex: deltaH(0), deltaS(0) was all smaller than zero, which indicated that the main acting forces generated by the inclusion complex were hydrogen bonding and Vander Waals' force. deltaG(0) < 0 and deltaG(0) were directly proportional to the reaction temperature, which suggested that the reaction would spontaneously increase with the temperature rise. The polarization fluorescence method was used to quantitatively prove the non-covalent inclusion complex generated during the interaction between beta-CD interacting with DES. The results could also provide reference for studies on cyclodextrin supra-molecular system. PMID- 24490556 TI - [Correlation between dissolution in vitro and absorption in vivo of chuanping sustained release tablets]. AB - OBJECTIVE: To investigate the correlation between dissolution in vitro and absorption in vivo of Chuanping sustained release tablets. METHOD: The ephedrine, pseudoephedrine were chosen as marker components, dissolution in vitro of Chuanping sustained release tablets in the different pH were tested by the rotating basket method and HPLC; urine drug levels were determined by HPLC and absorption fractions were calculated according to Wagner-Nelson's formula and deconvolution technique. RESULT: The linear regressive equation between the absorption percentage in vivo F and accumulative release percentage in vitro of Chuanping sustained release tablets was established as F(ephedrine) = 1.572 5f 20. 729 (R2 = 0.974 5); F(pseudoephedrine) = 1.237f-0.147 6 (R2 = 0.959 5). CONCLUSION: The results suggested that there was fine correlation between the absorption percentage in vivo and the accumulative release percentage in vitro of Chuanping sustained release tablets. PMID- 24490557 TI - [Preparation of cinnamomi cortex oil microspheres based on porous silicon dioxide and its property characterizations]. AB - To determine the optimum process for preparing Cinnamomi Cortex oil microspheres based on porous silicon dioxide. After porous silica dioxide adsorbed Cinnamomi Cortex oil, Cinnamomi Cortex oil microspheres were prepared by the dropping method, with sodium alginate as the skeleton materials. The preparation process was optimized through the L(9) (3(4)) orthogonal test design, with microspheres diameter, distribution, drug loading capacity and entrapment efficiency as the indexes. The cinnamon volatile oil microspheres were characterized by scanning election microscope (SEM), thermogravimetric analysis (TGA), and infrared (IR) spectroscopy. An in vitro drug release experiment was conducted. The results showed that the microspheres prepared with the optimal process parameters were in good shape, even in size and good in dispersibility, with an average diameter of 1.61 mm, an average drug loading capacity of 32.85%, an entrapment efficiency of 94.79%. The maximum drug release capacity reached 72.6%, 95.0%, 97.4%, respectively, under pH 4.0, 6.8, 7.4 in 6 hours. Meanwhile, microsphere generation was tested by IR, TGA and other methods. The established optimum process for preparing Cinnamomi Cortex oil microspheres was proved to be stable and practical. PMID- 24490558 TI - [Optimization of supercritical fluid extraction of bioactive components in Ligusticum chuanxiong by orthogonal array design]. AB - With the yields of ferulic acid, coniferylferulate, Z-ligustilide, senkyunolide A, butylidenephthalide, butylphthalide, senkyunolide I, senkyunolide H, riligustilide, levistolide A, and total pharmacologically active ingredient as evaluation indexes, the extraction of Ligusticum chuanxiong by supercritical fluid technology was investigated through an orthogonal experiment L9 (3(4)). Four factors, namely temperature, pressure, flow rate of carbon dioxide, co solvent concentration of the supercritical fluid, were investigated and optimized. Under the optimized conditions, namely 65 degrees C of temperature, 35 MPa of pressure, 1 L x min(-1) of CO2 flow rate, 8% of co-solvent concetration, supercritical fluid extraction could achieve a better yield than the conventional reflux extraction using methanol. And the supercritical fluid extraction process was validated to be stable and reliable. PMID- 24490559 TI - [Study on determination method for components in monocrotalinum liposomes and their entrapment efficiency]. AB - To establish an HPLC method for determining components in monocrotalinum liposomes. The results showed a good linear relationship in monocrotalinum liposomes within the concentration range between 1.6-102.4 mg x L(-1) (r = 0.999 8), with RSDs of intra-day precision, inter-day precision, stability and reproducibility of 0.61%, 0.92%, 1.7%, 1.6%, respectively. The recovery rate of monocrotaline was (99.96 +/- 0.50)%. These data indicated that the HPLC method could accurately determine components in monocrotalinum liposomes. Meanwhile, the microcolumn centrifugation method was established to determine the entrapment efficiency of components in monocrotalinum liposomes. As a result, the recovery rate and the blank liposome recovery of free components were (94.44 +/- 0.77)%, (95.86 +/- 0.68 )%, respectively. According to the parallel determination of the entrapment efficiency of three monocrotaline liposomes, their RSD was 4.0%. The data indicated that the microcolumn centrifugation method was an accurate and feasible method for determining the entrapment efficiency of monocrotaline liposomes. PMID- 24490560 TI - [Verification of processing theory of "reducing ketone and dryness, and increasing ester and effect" for bran-fried atractylodes]. AB - We previously proposed the processing theory of "reducing ketone and dryness, and increasing ester and effect" for bran-fried atractylodes, and made a preliminary study. To further verify the science and rationality of the theory, we determined the changes in the content of atractylenolide I, II, III and atractylon in atractylodes after and before being fried with bran, in order to compare the effect of raw and bran-fried atractylodes on the water intake and urination in rats in this study. The effect of raw and bran-fried atractylodes on the content of four gastrointestinal hormones and two neurotransmitters in serum was observed in an attempt to verify the science and rationality the processing theory of "reducing ketone and dryness, and increasing ester and effect" for bran-fried atractylodes. PMID- 24490561 TI - [Study on fingerprint of xiaochaihu granules sold in the market]. AB - To establish a fingerprint of Xiaochaihu granules sold in the market with HPLC method, and study fingerprints of Xiaochaihu granules produced by different manufacturers and in different batches of the same manufacturer. Seven major index components were identified for the first time. The established method provided an all-around analysis on the quality assessment of Xiaochaihu granules. PMID- 24490562 TI - [Study on fingerprint of shengxuening tablets]. AB - To establish a method for studying fingerprint of Shengxuening tablets. With chlorin e6 as the reference substance, SHISEIDO Capcell-pak C18 (4.6 mm x 250 mm, 5 microm) analytical column was adopted and eluted with 0.2% formic acid ( containing 20 mmol x L(-1) TBAB) (A) and acetonitrile-methanol-acetone (50: 50: 5) (B). The detection wavelength was set 392 nm. The volume flow rate was 1.0 mL x min(-1). The temperature of column was 45 degrees C. Totally 10 common peaks were indicated on the HPLC fingerprint, with RSDs for variable retention values in common peaks below 0.50%. UPLC/DAD/Q-TOF-MS xevo G2 Q-TOF LC/MS was adopted to preliminarily indentify six chromatographic peaks. The main ingredient in Shengxuening tablets was ferrous derivative, which was mainly composed of Fe chlorin p6, Fe chlorin e6 and Fe isochlorin e4. PMID- 24490563 TI - [Chemical constituents from roots of Psammosilene tunicoides]. AB - Three compounds, including a new one (1), were isolated from the roots of Psammosilene tunicoides. Based on analysis of NMR data as well as their physical and chemical properties, their structures were elucidated as 3,3'-(4,5 dimethoxynaphthalene-2,7-diyl) bis (1-nitropropan-1-one) (1), alpha-spinasterol-3 O-beta-D-glucopyranoside (2) and alpha-spinasteryl-3-O-beta-D-glucoside-6'-O palmitate(3). Compounds 2 and 3 were isolated from this genus for the first time. PMID- 24490564 TI - [Studies on biotransformation of chemical constituents of tongmai formula by human intestinal flora]. AB - To study the chemical constituents in Tongmai formula (TMF) after biotransformation by human intestinal flora (HIF), water extract of TMF was anaerobically incubated with HIF at 37 degrees C. Column chromatographic methods over silica gel, Sephadex LH-20 and semi-preparative high-performance liquid chromatography as well as recrystallization were used to isolate and purify the chemical constituents in TMF after biotransformation by HIF. The chemical structures of isolated compounds were identified on the basis of MS and NMR data. Twenty-six compounds were obtained and identified as phenylpropionic acid (1), 6" O-acetylpuerarin (2), formononetin(3), daidzein(4), p-hydroxyphenylpropionic acid (5), 3-indolepropionic acid (6), genistein (7), isoformononetin (8), isoononin (9), a mixture of (-)-puerol B-2"-O-glucopyranoside (10a) and (+) -puerol B-2"-O glucopyranoside (10b), 8-hydroxydaidzein (11), puerol A (12), 3'-methoxy-6"-O acetylpuerarin (13), 6"-O-acetyldaidzin (14), 3'-methoxydaidzin (15), puerol B (16), 3-methyluracil (17), genistin (18), daidzin (19), 3'-methoxypuerarin (20), mirificin (21), swertiamarin (22) , daidzein-7, 4'-O-glucoside (23), adenine (24), 3'-hydroxypuerarin (25), and puerarin (26). After biotransformation by HIF, the glycosides in TMF were transformed into aglycone and/or less glycosyl compounds along with some hydroxylation and demethylation reactions. Therefore, the glycosides in the TMF are the pro-drug. PMID- 24490565 TI - [Non-alkaloid components from Sophora flavescens]. AB - Five compounds were obtained from the stems and leaves of Sophora flavescens Ait. and ten compounds were obtained from the roots of S. flavescens by various chromatography methods including silica gel column chromatography and preparative HPLC. Their structures were identified on the basis of spectroscopic methods including 1H-NMR, 13C-NMR and ESI-MS, as corchionoside C (1), syringing (2), 2' deoxythymidin (3), coniferin (4), benzyl O-beta-D-glucopyranoside (5), piscidic acid (6), trifolirhizin (7), kurarinone (8), trifolirhizin-6'-monoacetate (9), sophoraflavanone G (10), isoxanthohumol (11), noranhydroicaritin (12), 4' methoxyisoflavone-7-O-beta-D-apiofuranosyl-(1 --> 6)-beta-D-glucopyranoside (13), kushenol O (14) and 6"-beta-D-xylopyranosylgenistin (15). Compounds 1-6 were isolated from the Sophora genus for the first time. PMID- 24490566 TI - [Chemical constituents from leaves of Aglaia testicularis]. AB - To study the chemical constituents from the leaves of Aglaia testicularis. The methanol extract was isolated and purified by silica gel, Sephadex LH-20 and preparative HPLC. Their chemical structures were elucidated by MS and spectral data (1H, 13C-NMR). Seven compounds were isolated from the leaves and identified as dasyclamide (1), aglamide A (2), aglamide B (3), aglamide C (4), aglamide D (5), aglaroxin A 1-O-acetate (6), and 3'-methoxyaglaroxin A 1-0-acetate (7). All compounds were isolated from this plant for the first time. PMID- 24490567 TI - [Research on chemical fingerprint chromatograms of Sinopodophyllum hexandrum]. AB - OBJECTIVE: To study the HPLC fingerprint of Sinopodophylli Fructus, compare the major chemical differences in fruit of Sinopodophyllum hexandrum as well as the roots and rhizomas of S. hexandrum, and provide scientific evidence for clinical application and quality control. METHOD: HPLC fingerprint method was used to analyze 12 fruits of S. hexandrum. A total of 20 common peaks were confirmed, and 12 peaks in the HPLC fingerprint were identified. Furthermore, similarity evaluation method and clustering analysis method were introduced to compare HPLC chromatograms, between fruits and underground parts. RESULT: In this paper, quercetin-3-O-beta-D-glucopyranosid, kaempferol-3-O-beta-D-glucopyranoside, 8 prenylquercetin and 8-prenylquercetin 3-methyl ether were firstly reported in Sinopodophylli Fructus. Among the existing fingerprint research, a total of 11 peaks were identified for the first time, containing 9 flavonoids and 2 lignans. The chemical constituents differed significantly in different medicinal parts of S. hexandrum. Prenylflavonoid compounds were the main constituents of Sinopodophylli Fructus. However, podophyllotoxin, flavonoids with simple substituent groups and flavonoid glycosides were the major ingredients in the roots and rhizomas of S. hexandrum. CONCLUSION: This method can be used for the quality control of Sinopodophylli Fructus and the roots and rhizomas of S. hexandrum. It has provided a reference for the pharmacodynamic differences of the two different parts. PMID- 24490568 TI - [Determination of aflatoxin B1, B2, G1, G2 in armeniacae semen amarum by high performance liquid chromatography-tandem mass spectrometry]. AB - A simple, rapid and cost-effective high-performance liquid chromatography-tandem mass spectrometry (LC-MS/ MS) method was established for simultaneous determination of aflatoxins (AFB1, AFB2, AFG1, AFG2) in Armeniacae Semen Amarum and the application was performance in 11 samples collected from different markets, medical stores and hospitals. The sample was extracted with 84% acetonitrile/water and 250 microL extraction was directly injected into a LC MS/MS system without further purification procedure after being redissolved with methanol. The LC separation was performed on a C18 column with a linear gradient elution program of 4 mmol x L(-1) NH4 Ac-0.1% formic acid solution and menthol as the mobile phase. Selected reaction monitoring (SRM) was used for selective determination of the four aflatoxins on a triple quadruple mass spectrometer, which was operated in positive ionization modes. All the four aflatoxins showed a good linear relationship with r > 0.999 0, the average recoveries were between 87.88% and 102.9% and the matrix effect was ranged from 90.71% to 99.30% in low, intermediate and high levels. Furthermore, the higher recovery was obtained by the method reported in this study, comparing to the cleanup procedure with the Mycosep 226 purification column. Eleven samples collected were detected and the contamination levels of the AFB1 were between 1.590-2.340 microg x kg(-1) and the AF (B1 + B2 + G1 + G2) was ranged from 2.340 to 3.340 microg x kg(-1). In summary, the developed method was suitable to detect and screen AFB1, AFB2, AFG1, AFG2 in Armeniacae Semen Amarum. PMID- 24490569 TI - [Effect of euodiae fructus on hepatic energy metabolism-related mechanisms of reserpine-induced asthenia cold syndrome rats]. AB - OBJECTIVE: To discuss the effect of Euodiae Fructus on hepatic energy metabolism related mechanisms of mitochondria of hepatic tissues of asthenia cold syndrome rats. METHOD: Rats were subcutaneously injected with Reserpine to establish the model. After the oral administration with Euodiae Fructus for 12 d, the oxygen electrode method was adopted to determine the respiration efficiency. The expressions of Cox4, Atp5b, Ucp2,Pgc-1alpha, Nrf1, Tfam mRNA were assayed by using RT-PCR method. RESULT: Euodiae Fructus 4.2 g x kg(-1) could obviously increase ST3 and RCR of asthenia cold syndrome rats, and expressions of Cox4, Ucp2 Nrf1 mRNA. It could also increase expressions of Atp5b and Pgc-1alpha mRNA, but with no statistical significance. No obvious change was observed in Tfam mRNA expression. Euodiae Fructus 4.2 g x kg(-1) could significantly increase ST3 and RCR of asthenia cold syndrome rats and Pgc-1alpha mRNA and Nrf1 mRNA expressions, and significantly decrease P/O, with no obvious impact on Cox4, AtpSb, Ucp2, Tfam mRNA expressions. CONCLUSION: Euodiae Fructus can promote mitochondrial respiratory function and oxidative phosphorylation efficiency by improving Pgc 1alpha mRNA and Nrf1 mRNA expressions and regulating Cox4 and Atp5b mRNA in mitochondrial respiratory chain. It can also strengthen mitochondrial uncoupling respiration and add heat production by activating Ucp2 mRNA expression in liver. PMID- 24490570 TI - [Study on antagonistic effect of liangxue huayu recipe on endoplasmic reticulum stress-induced L02 hepatocyte apoptosis and its mechanism]. AB - Endoplasmic reticulum stress (ERS) is a new pathway inducing cell apoptosis that has been discovered in recent years. This study focused on the protective effect of Liangxue Huayu recipe (LHR) on tumor necrosis factor-alpha (TNF-alpha) and D GalN-induced hepatocyte apoptosis. It found that TNF-alpha and D-GalN could obviously inhibit hepatocyte proliferation, induce cell apoptosis, and significantly increase free calcium ions in cytoplasms, as well as protein expressions of ERS apoptosis-related signal molecules phosphorylated PERK, phosphorylated elF2alpha, cleaved Caspase-12, GRP78 and CHOP. After the administration of LHR of different concentrations, compared with the TNF alpha/GalN injury group, LHR could significantly alleviated L02 hepatocyte proliferation, decreased cell apoptosis, inhibited growth of intracytoplasmic free calcium content, and gradually reduced the protein expressions of phosphorylated PERK, phosphorylated elF2alpha, cleaved Caspase-12, GRP78 and CHOP. These findings indicated that LHR has the inhibitory effect on TNF-alpha and D-GalN-induced hepatocyte apoptosis. Its mechanism may be related to down regulation of ERS apoptosis-related signal molecules phosphorylated PERK, phosphorylated elF2alpha, cleaved Caspase-12, GRP78 and CHOP that maintain calcium homeostasis in endoplasmic reticulum. PMID- 24490571 TI - [Study on inhibitory effect of aqueous extract of Taxus chinensis var. mairei on growth of A549 lung cancer xenografts in nude mice and its mechanism]. AB - OBJECTIVE: To study the effect of aqueous extract of Taxus chinensis var. mairei (AETC) on the growth of A549 lung cancer xenografts in nude mice and its mechanism. METHOD: The A549 lung cancer xenograft model was established, and then randomly divided into the control group, and low, middle and high dose AETC experiment groups. After 24 hours, they were orally administered with normal saline and drugs of the same volume for seven weeks. The length and width of the xenografts were measured every three days, and the xenograft growth curve was drawn. The nude mice were sacrificed after the administration for seven weeks, and their xenografts were collected to cultivate the anti-tumor rate. Real-time PCR and Western-blot were adopted to detect mRNA and protein levels. RESULT: All of AETC experiment groups showed a significant anti-tumor effect (P < 0.05). Compared with the control group, each experimental group showed notable reduction in EGFR and Survivin mRNA in xenograft tissues (P < 0.05), with no significant change in VEGF mRNA level. The analysis on gray value ratio showed that EGFR mRNA were down-regulated (P < 0.05) in xenograft tissues in all experimental groups, but with no statistical significance in difference, and Survivin and p-EGFR were significantly down-regulated. CONCLUSION: AETC has not significant effect on angiogenesis, but may have the inhibitory effect on xenograft growth by inhibiting Survivin protein and EGFR phosphorylation. PMID- 24490572 TI - [Analgesic effect of CQM on prosopalgia model rats and its impact on exciting amino acid neurotransmitters]. AB - OBJECTIVE: To observe the analgesic effect of CQM on photochemically-induced prosopalgia model rats, and discuss its impact on the exciting amino acid neurotransmitter-glutamate (Glu). METHOD: Male SD rats were randomly divided into the sham operation group and the prosopalgia group. And the latter was subdivided into the model group, the gabapentin group (100 mg kg(-1)), and the CQM low-dose (35 mg x kg(-1)) and CQM high-dose (70 mg x kg(-1)) groups. The mechanical allodynia test was adopted to evaluate the pain behavior of rats, and reflect the efficacy with the mechanical withdrawal thresholds. The rat striatum extra cellular fluid was collected by brain micro-dialysis. The Glu level of samples was measured by high performance liquid chromatography-fluorescene detector (HPLC FLD). RESULT: Compared to the control group, the threshold of the mechanical allodynia of the IoN injury group was decreased significantly (P < 0.05), and the concentration of Glu was increased dramatically (P < 0.05). Compared to the model group, the mechanical allodynia of photochemically-induced prosopalgia model rats increased significantly (P < 0.01), with a notable increase in brain Glu concentration (P < 0.05). Compared with the model group, all of mechanical withdrawal thresholds increased. Among them, the CQM high-dose group showed a remarkably growth at three time points (P < 0.05), with the maximum up to (23 +/- 7.3) g. And the gabapentin group showed a remarkably growth at two time points (P < 0.05), with the maximum up to (20.5 +/- 9.2) g. All of the drug groups showed significantly lower Glu concentrations in rat brains than the model group (P < 0.05). CONCLUSION: CQM can ease the mechanical allodynia of photochemically induced prosopalgia model rats. Its analgesic effect may be related to the decrease of Glu concentrations in striatum extra-cellular fluid. PMID- 24490573 TI - [Effect of Dendrobium officinale granule on long-term-alcohol-induced hypertension rats]. AB - OBJECTIVE: To observe the effect of Dendrobium officinale granule (DOG) on symptoms, blood pressure and serum biochemical indexes of long-term-alcohol induced hypertension rats. METHOD: The alcohol-induced hypertension rat model was established by feeding alcohol drink to normal rats (the alcohol volume fraction increases from 5% to 22%). Since the 4th week, DOG was administered for 32 weeks, once everyday. During the experiment, body weight, kinematic parameters (locomotor activities, grip strength, duration of vertigo) and blood pressures (systolic blood pressure, diastolic blood pressure and mean blood pressure) were detected regularly. On the 28th and 32nd weeks, blood samples were collected to determine serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), uric acid (UA), creatinine (Cr), cholesterol (CH) and triglycerides (TG). RESULT: (1) Sign: The DOG-administered group showed reduction in the duration of vertigo and increase in appetite, body weight, locomotor activities and grip strength. (2) Blood pressure: The DOG-administered group showed significant decrease in blood pressure since the 8th week. (3) Biochemical indexes: The DOG-administered group showed notable decrease in serum ALT, AST, ALP, Cr, UA, TG level, but without significant change in TC level. CONCLUSION: The long-term administration of DOG can relieve alcohol-induced hypertension, while alleviating general signs, liver and kidney injuries and abnormal blood fat biochemical indexes. PMID- 24490574 TI - [Primary study of skin wound healing in rats for Loropetalum chinens]. AB - OBJECTIVE: Cutaneous wound is a common health problem of humans. Loropetalum chinens, a medicinal plant, is widely used to treat wounds among the people. The research aims to observe whether L. chinens can promote the rats' wounds healing process, isolate the extracts primarily and commit the wound healing selection, which provide work basis for wound healing research of L. chinens. METHOD: First we analyzed the possible components with HC-MS/MS, then committed our wound healing experiments for L. chinens in the rat incision wound model and excision wound model, which are commonly used worldwide. After that, we carried on the preliminary isolation of the L. chinens and we screened the heal-promoting effects of the isolations in incision wound model. RESULT: L. chinens significantly accelerates the wound healing of rat's skin, shortens the healing period, enhances the healing intensity and promotes the cell proliferation and blood vessels formation around the wounds. The isolations, which are petroleum ether layer, ethyl acetate layer and n-butyl alcohol layer, exert heal-promoting effects. It indicates that the possible morphon that promotes wound healing may exist in these three components, with small polar. CONCLUSIONS: L. chinens possesses strong wound healing promoting effects, and the active constituent, with small polar, exists in petroleum ether layer, ethyl acetate layer and n butyl alcohol layer, and we should focus on these three layers when carrying on further studies. PMID- 24490575 TI - [Study on intestinal absorption of formononetin in Millettia nitita var. hirsutissima in rats]. AB - To use the single-pass intestine perfusion (SPIP) model and HPLC to determine the concentration of formononetin, the effect of quality concentrations of formononetin, different intestinal segments and P-glycoprotein inhibitor on intestinal absorption of formononetin, in order to observe the intestinal absorption mechanism of formononetin from Millettia nitita var. hirsutissima in rats. The experimental results showed that the qulaity concentration of formononetin in the perfusate had no significant effect on the absorption rate constant (K(a)) and the apparent absorption coefficient (P(app)); K(a) and P(app) of formononetin in duodenum, jejunum and ileum showed no significant difference. However, K(a) was significantly higher than that in colon (P < 0.05), with significant difference between that in intestinum tenue and colon. P-glycoprotein inhibitor verapamil showed significant difference in K(a) and P(app) in intestinal segments (P < 0.05). This indicated that the absorption mechanism of formononein in rat intestinal tracts passive diffusion, without any saturated absorption. Formononein is absorbed well in all intestines. Their absorption windows were mainly concentrated in the intestinum tenue, without specific absorption sites. Formononein may be the substrate of P-glycoprotein. PMID- 24490576 TI - [Evaluate activating blood circulation and dissipating blood stasis effect mechanism of foshousan on acute blood stasis rats on basis of metabolomic approach]. AB - Ice water bath and subcutaneous injection of adrenaline were used to establish the acute blood stasis model of rats. Ultra-performance liquid chromatography/quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS) was used to study the urine metabolic changes of acute blood stasis rats. Potential biomarkers were selected by variable importance projection, and identified on basis of MS information and databases. The metabolic pathways were predicted via MetPA database. To study the effect of Foshousan on endogenous metabolites of acute blood stasis model rats, find potential biomarkers, and explore the effect mechanism of Foshousan on activating blood circulation and dissipating blood stasis. Eleven potential biomarkers were identified with multivariate statistical analysis of urine metabolite profiles, and which also were used to explain the phenylalanine metabolism, tryptophan metabolism and sphingolipid metabolism. Those disturbed metabolic pathways in acute blood stasis rats could be regulated closely to normal state after Foshousan administration. Metabolomics has a bright prospect in the efficacy evaluation and effect mechanism elucidation of the traditional Chinese medicines. PMID- 24490577 TI - [Effect of Jiangzhi Kangyanghua mixture on high-sensitivity C-reactive protein and vascular endothelial functions of hypertension patients]. AB - To observe the effect of Jiangzhikangyanghua Mixture on high-sensitivity CRP (hs CRP) and vascular endothelial functions of essential hypertension (EH) patients. In this study, 72 cases of out-patients with EH were selected from department of cardiology of Wujin hospital of traditional Chinese Medicine, and randomly divided into the control group (n= 36, amlodipine 5 mg qd + valsartan 80 mg qd) and the test group (n =36 amlodipine 5 mg qd + valsartan 80 mg qd + Jiangzhikangyanghua mixture 20 mL tid). The contents of hs-CRP, ET-1 and NO were measured before and after treatment for two months. The result showed that the contents of hs-CRP, ET-1 in both groups reduced (P <0. 05) , while the test group show a more significant reduction than the control group (P <0. 05). After the treatment, the content of NO raised in both group, while the test group show a more significant increase than that of the control group (P <0. 05). This study indicated that Jiangzhi Kangyanghua mixture could reduce the contents of hs-CRP and ET-1 and raise NO of EH patients. PMID- 24490578 TI - [Study on relations between characteristics of traditional chinese medicine body constitutions and syndromes in COPD patients]. AB - The specific theoretical system of traditional Chinese medicine(TCM) body constitutions had beening gradually founded, which showed TCM body constitutions comprehensively and introduced the clinical treatment. According to TCM body constitutions, it was benefit to recognize and prevent diseases through investigating the susceptible body and discussing the relation between constitutions and syndromes, and since TCM body constitutions leaded the characteristic of susceptibility and tendency of diseases and the body was stable but changed later. TCM body constitutions of 498 COPDs were diagnosed by questionnaires and the relation between the constitutions and syndromes were analyzed. The result showed that the constitutions of Qi asthenia, of phlegm dampness and of damp-heat were common constitutions in COPDs. There was a significant correlation between TCM body constitutions and syndromes. Thus, during different period of COPD taking the treatment of adjusting the constitutions especially biased constitutions and combining "recognizing constitutions" and "recognizing syndromes" are benefit to increase the effect of prevention and treatment, and are significant to decrease the incidence and prevalence. PMID- 24490579 TI - [Discussion on strengthening yin of chinese herbs with bitter-flavor clinical traditional Chinese pharmacology noun terminology standardization research]. AB - Clinical traditional Chinese pharmacology is the subject that study of basic theory of traditional Chinese medicine, property of Chinese materia medica and clinical application. The study on the standardization research of the terminology of clinical traditional Chinese pharmacology is an important premise and foundation to standardization, modernization and internationalization, informationization construction of clinical traditional Chinese pharmacology and is also the important content of the subject construction. To provide some exploring ideas for clinical traditional Chinese pharmacology noun terminology standardization, this article elaborates the concept of strengthening Yin with bitter-flavor herbs in several aspects, such as connotation and the historical origin, the clinical application in the traditional, modern clinic application, and the modern basic research and so on. PMID- 24490581 TI - Exceeding the limit in solar energy conversion with multiple excitons. PMID- 24490580 TI - [Varieties, functions and clinical applications of Chishao and Baishao: a literature review]. AB - According to Chinese Pharmacopoeia (2010ed), Chishao,Paeoniae Radix Rubra and Baishao,Paeoniae Radix Alba are both from the root of Paeonia lactiflora Pall. In recent years, it is known from the studies that Chishao and Baishao must have the resemblance in the chemical composition, but the differences have related to the ecological environment and the processing methods, this makes their functions be different, athough they derive from the same original plants. This review explores the material basis and functions differences based on the analysis of the relationship in Chishao and Baishao on characteristic index function and the genetic background and the analysis of the clinical and pharmacological effects. It may provide more scientific data for identification and establishment of new quality control methods of the Paeoniae Radix Alba and Paeoniae Radix Rubra in the future. PMID- 24490582 TI - High relative environmental humidity is associated with diabetes among elders living in Mediterranean islands. AB - BACKGROUND: Climate variation has long been studied in relation to human health. The aim of the present work was to evaluate the relationship between environmental humidity, and air temperature with the prevalence of diabetes, among elderly islanders. METHODS: During 2005-2011, 1959 elderly (aged 65 to 100 years) individuals from 13 Mediterranean islands were enrolled. Socio demographic, clinical and lifestyle factors were assessed using standard procedures. Diabetes was defined as fasting blood glucose levels > 125 mg/dl. Relative environmental humidity was measured as a percentage of air moisture and mean daily temperature in degrees Celsius. RESULTS: For the present analysis 713 men (74 +/- 7 years) and 596 women (73 +/- 7 years) with complete data were studied; 27% of both men and women had diabetes. The prevalence of diabetes was 42% in the elders living in high relative humidity areas (i.e., >70%) as compared with 24% among those living at low relative humidity residential areas (p < 0.001). After adjusting for age, sex and mean temperature, an increase in the area's relative humidity by 1 degree, increased the likelihood of having diabetes by 12% (OR = 1.12, 95% CI 1.05 to 1.20). No significant association was observed between mean temperature and diabetes (OR = 0.97, 95% CI 0.74, 1.26). CONCLUSIONS: A considerable proportion of elderly, especially those living in high relative humidity areas, had diabetes. Further research is needed to confirm this observation and to understand the underlying mechanisms. PMID- 24490584 TI - Analysis of blood gases, serum fat and serum protein: a new approach to estimate survival chances of stranded Harbor seal (Phoca vitulina) pups from the German North Sea. AB - BACKGROUND: Facing numerous challenges, such as illness, storms or human disturbance, some harbor seal (Phoca vitulina) pups lose contact to their dams and are found abandoned along the North Sea coast. In Schleswig-Holstein, pups with the prospect of surviving rehabilitation are admitted to the Seal Center Friedrichskoog. Despite elaborate clinical health assessments on admission, including differential hematology, in 2010, 17% of 108 admitted pups did not survive the first 20 days. The death rate during the years 2006 and 2009 varied between 9 and 19%. To broaden the spectrum of variables which could be predictive for survival, blood gas and serum analyses were performed for 99 pups using venous blood. Variables included total CO2, pH, partial CO2, HCO3-, base excess and anion gap as well as glucose, urea nitrogen, sodium, potassium and chloride. Moreover, total serum protein and fat (triglyceride) concentrations were measured for all pups on admission. RESULTS: Repeated measurements of 12 randomly selected individuals revealed a significant (p = 0.002) positive influence of time in rehabilitation on triglyceride concentrations. This trend probably shows the improvement of the pups' nutritional status as a consequence of the shift from milk replacer formula to fish. No such positive influence was detected for total protein concentrations though. Hematologic values, including blood gases, were not predictive for survival. CONCLUSIONS: For the first time blood gas values are reported in this study for a large sample size (N = 99) of seal pups (regardless of their health status). The ranges and medians calculated from the data can serve as a stepping stone towards the establishment of reference values for neonate harbor seals. However, future investigations on the development of blood gases in harbor seals with different health conditions and ages over time are necessary to allow for a better understanding of acid-base regulation in harbor seals. PMID- 24490585 TI - Conserved immunogens in prime-boost strategies for the next-generation HIV-1 vaccines. AB - INTRODUCTION: Effective vaccines are the best solution for stopping the spread of HIV/AIDS and other infectious diseases. Their development and in-depth understanding of pathogen-host interactions rely on technological advances. AREAS COVERED: Rational vaccine development can be effectively approached by conceptual separation of, on one hand, design of immunogens from improving their presentation to the immune system and, on the other, induction of antibodies from induction of killer CD8(+) T cells. The biggest roadblock for many vaccines is the pathogens' variability. This is best tackled by focusing both antibodies and T cells on the functionally most conserved regions of proteins common to many variants, including escape mutants. For vectored vaccines, these 'universal' subunit immunogens are most efficiently delivered using heterologous prime-boost regimens, which can be further optimised by adjuvantation and route of delivery. EXPERT OPINION: Development of vaccines against human diseases has many features in common. Acceleration of vaccine discovery depends on basic research and new technologies. Novel strategies should be safely, but rapidly tested in humans. While out-of-the-box thinking is important, vaccine success largely depends on incremental advances best achieved through small, systematic, iterative clinical studies. Failures are inevitable, but the end rewards are huge. The future will be exciting. PMID- 24490586 TI - How evidence-based workforce planning in Australia is informing policy development in the retention and distribution of the health workforce. AB - BACKGROUND: Australia's health workforce is facing significant challenges now and into the future. Health Workforce Australia (HWA) was established by the Council of Australian Governments as the national agency to progress health workforce reform to address the challenges of providing a skilled, innovative and flexible health workforce in Australia. HWA developed Australia's first major, long-term national workforce projections for doctors, nurses and midwives over a planning horizon to 2025 (called Health Workforce 2025; HW 2025), which provided a national platform for developing policies to help ensure Australia's health workforce meets the community's needs. METHODS: A review of existing workforce planning methodologies, in concert with the project brief and an examination of data availability, identified that the best fit-for-purpose workforce planning methodology was the stock and flow model for estimating workforce supply and the utilisation method for estimating workforce demand. Scenario modelling was conducted to explore the implications of possible alternative futures, and to demonstrate the sensitivity of the model to various input parameters. Extensive consultation was conducted to test the methodology, data and assumptions used, and also influenced the scenarios selected for modelling. Additionally, a number of other key principles were adopted in developing HW 2025 to ensure the workforce projections were robust and able to be applied nationally. RESULTS: The findings from HW 2025 highlighted that a 'business as usual' approach to Australia's health workforce is not sustainable over the next 10 years, with a need for co-ordinated, long-term reforms by government, professions and the higher education and training sector for a sustainable and affordable health workforce. The main policy levers identified to achieve change were innovation and reform, immigration, training capacity and efficiency and workforce distribution. CONCLUSION: While HW 2025 has provided a national platform for health workforce policy development, it is not a one-off project. It is an ongoing process where HWA will continue to develop and improve health workforce projections incorporating data and methodology improvements to support incremental health workforce changes. PMID- 24490587 TI - Introduction to ion channels and disease. PMID- 24490588 TI - Avidity-controlled delivery of angiogenic peptides from injectable molecular recognition hydrogels. AB - Peptide mimics of growth factors represent an emerging class of therapeutic drugs due to high biological specificity and relative ease of synthesis. However, maintaining efficacious therapeutic dosage at the therapy site has proven challenging owing to poor intestinal permeability and short circulating half lives in the blood stream. In this work, we present the affinity immobilization and controlled release of QK, a vascular endothelial growth factor (VEGF) mimetic peptide, from an injectable mixing-induced two-component hydrogel (MITCH). The MITCH system is crosslinked by reversible interactions between WW domains and complementary proline-rich peptide modules. Fusion of the QK peptide to either one or two units of the proline-rich sequence creates bifunctional peptide conjugates capable of specific binding to MITCH while preserving their angiogenic bioactivity. Presenting two repeats of the proline-rich sequence increases the binding enthalpy 2.5 times due to avidity effects. Mixing of the drug conjugates with MITCH components results in drug encapsulation and extended release at rates consistent with the affinity immobilization strength. Human umbilical vein endothelial cells (HUVECs) treated with the soluble drug conjugates exhibit morphogenetic events of VEGF receptor 2 signal transduction followed by cell migration and organization into networks characteristic of early angiogenesis. In a three-dimensional model where HUVECs were cultured as spheroids in a matrix of collagen and fibronectin, injection of drug-releasing MITCH resulted in significantly more cell outgrowth than drugs injected in saline. This ability to sustain local drug availability is ideal for therapeutic angiogenesis applications, where spatiotemporal control over drug distribution is a key requirement for clinical success. PMID- 24490590 TI - Electrowetting-induced droplet detachment from hydrophobic surfaces. AB - Detachment of droplets from solid surfaces is a basic and crucial process in practical applications such as heat transfer and digital microfluidics. In this study, electrowetting actuations with square pulse signals are employed to detach droplets from a hydrophobic surface. The threshold voltage for droplet detachment is obtained both experimentally and theoretically to find that it is almost constant for various droplet volumes ranging from 0.4 to 10 MUL. It is also found that droplets can be detached more easily when the width of applied pulse is well matched to the spreading time (i.e., the time to reach the maximum spread diameter). When the droplet is actuated by a double square pulse, the threshold voltage is reduced by ~20% from that for a single square pulse actuation. Finally, by introducing an interdigitated electrode system, it is demonstrated that droplets can be detached from the solid bottom surface without using a top needle electrode. PMID- 24490589 TI - Direct validation of aptamers as powerful tools to image solid tumor. AB - Visualization of cancer cells requires distinguishing malignant from normal cells by objective criteria with high specificity. For several years, tumor markers expressed on the surface of cancer cells have been characterized as cancer signatures, and their labeling with specific imaging probes has revolutionized cancer diagnosis. This specific labeling is also an important tool in surgery tumor ablation. The present study considers the tumor labeling potential of an aptamer that specifically recognizes the epithelial cancer biomarker mucin1 (MUC1). This anti-MUC1 aptamer was investigated in vitro in a three-dimensional (3D) environment and compared to an anti-MUC1 antibody for its capacity to visualize cancer cells. Multicellular spheroids of breast cancer MCF-7 cells were used as tumor models and anti-MUC1 fluorescent aptamer and antibody were visualized by fluorescence imaging. Results showed that the antibodies interacted only with cells located on the surface of the spheroid, whereas the anti-MUC1 aptamers were able to penetrate inside these 3D tumor models and thereafter internalized into the cancer cells. Due to their lack of immunogenicity and their facility to be chemically modified, aptamers may replace advantageously the use of antibodies in diagnosis based on imaging setup thanks to their specific detection of cancer cells without invasive surgical procedures or during clinical intraoperative intervention. PMID- 24490591 TI - Metal-free oxidative amidation of 2-oxoaldehydes: a facile access to alpha ketoamides. AB - A novel and efficient method for the synthesis of alpha-ketoamides, employing a dimethyl sulfoxide (DMSO)-promoted oxidative amidation reaction between 2 oxoaldehydes and amines under metal-free conditions is presented. Furthermore, mechanistic studies supported an iminium ion-based intermediate as a central feature of reaction wherein C1-oxygen atom of alpha-ketoamides is finally derived from DMSO. PMID- 24490592 TI - The Vibrio cholerae diguanylate cyclase VCA0965 has an AGDEF active site and synthesizes cyclic di-GMP. AB - BACKGROUND: Diguanylate cyclases (DGCs) regulate biofilm formation and motility in bacteria by synthesizing the second messenger cyclic di-GMP (c-di-GMP) in response to environmental stimuli. DGC enzymatic activity is believed to be dependent on the presence of a GG(D/E)EF active site motif, however approximately 25% of known DGCs contain a degenerate active site. The Vibrio cholerae protein VCA0965 contains an AGDEF active site and is presumed to be an inactive DGC. RESULTS: Ectopic expression of VCA0965 in V. cholerae causes a 3-fold reduction in flagellar-based motility. Additionally, an RXXD allosteric inhibition mutant of VCA0965 strongly inhibited motility and stimulated biofilm formation. This activity was lost when the active site of VCA0965 was mutated to AGDAF, suggesting that VCA0965 synthesizes c-di-GMP. In support of this, ectopic expression of VCA0965 and VCA0965 containing a mutation in its RXXD motif significantly increased the intracellular c-di-GMP levels in V. cholerae and Escherichia coli. Furthermore, we found that purified VCA0965 was able to synthesize c-di-GMP in vitro. Systematic mutation of the first amino acid in the AGDEF motif of VCA0965 revealed that glycine, methionine, and histidine also produced an active DGC capable of inhibiting motility and increasing the intracellular concentration of c-di-GMP in V. cholerae. CONCLUSIONS: Based on these results, we conclude that VCA0965 is capable of c-di-GMP synthesis and that the first amino acid of the GG(D/E)EF motif is more tolerant of substitutions than currently appreciated. PMID- 24490593 TI - Analysis of As- and Hg-species in metal-resistant oral bacteria, by imaging ToF SIMS. AB - Bacterial strains were isolated from the oral cavity of healthy volunteers and grown in the presence of Hg-ions (1-10 ppm) or arsenate ions at concentrations of 0.1-1.0%. To elucidate how bacteria take up and transform toxic metals inside the cells, we performed ion imaging and depth profiling with time-of-flight secondary ion mass spectrometry (ToF-SIMS). This analysis relies on the use of a pulsed ion beam to ionize surface molecules that can be extracted into a time-of-flight mass spectrometer. By combining the pulsed ion beam with another ion beam in direct current (DC) mode, depth profiles are obtained as a result of consecutive removal of surface layers. The spatial resolution of the depth profile along the y-axis is in the range of a few nanometres, and the spatial resolution along the x- and z-axes is in the MUm range. The ToF-SIMS analysis was performed on crude biofilms of bacteria air-dried at aluminium foil surfaces, allowing subcellular resolution along the y-axis. The mercury ions were found transformed to methylmercury preferably in the periplasmic space, and the arsenate ions were found reduced to arsenite inside the cells, close to the cell membrane. The data are discussed in relation to current concepts in bacterial resistance to metals and antibiotics. PMID- 24490594 TI - Role of propolis on biochemical parameters in kidney and heart tissues against L NAME induced oxidative injury in rats. AB - Nitric oxide (NO), produced by endothelial NO synthase, is recognised as a central antiinflammatory and antiatherogenic principle in the vasculature. Epidemiological and clinical studies have demonstrated that a growing list of natural products, as components of the daily diet or phytomedical preparations, may improve vascular function by enhancing NO bioavailability. In this article, we investigated antioxidant effects of propolis on biochemical parameters in kidney and heart tissues of acute NO synthase inhibited rats by Nomega-nitro-l arginine methyl ester (l-NAME). There was increase (p < 0.001) in the activities of catalase and malondialdehyde levels in the l-NAME treatment groups when compared with control rats, but NO levels were decreased in both kidney and heart tissues. There were statistically significant changes (p < 0.001) in these parameters of l-NAME + propolis treated rats as compared with l-NAME-treated group. In summary, propolis may influence endothelial NO production. PMID- 24490596 TI - Climate change and regulation of hepatotoxin production in Cyanobacteria. AB - Harmful, bloom-forming cyanobacteria (CyanoHABs) are occurring with increasing regularity in freshwater and marine ecosystems. The most commonly occurring cyanobacterial toxins are the hepatotoxic microcystin and nodularin. These cyclic hepta- and pentapeptides are synthesised nonribosomally by the gene products of the toxin gene clusters mcy and nda, respectively. Understanding of the regulation of hepatotoxin production is incomplete, although there is strong evidence supporting the roles of iron, light, higher nitrate availability and inorganic carbon in modulating microcystin levels. The majority of these studies have focused on the unicellular freshwater, microcystin-producing strain of Microcystis aeruginosa, with little attention being paid to terrestrial or marine toxin producers. This review intends to investigate the regulation of microcystin and nodularin production in unicellular and filamentous diazotrophic cyanobacteria against the background of changing climate conditions. Special focus is given to diazotrophic filamentous cyanobacteria, for example Nodularia spumigena, capable of regulating their nitrogen levels by actively fixing dinitrogen. By combining data from significant studies, an overall scheme of the regulation of toxin production is presented, focussing specifically on nodularin production in diazotrophs against the background of increasing carbon dioxide concentrations and temperatures envisaged under current climate change models. Furthermore, the risk of sustaining and spreading CyanoHABs in the future ocean is evaluated. PMID- 24490597 TI - From linear 'dogma' and trastuzumab-emtansine to future transcriptional circuitry based drug discovery for breast cancer. PMID- 24490598 TI - Tenth anniversary of bevacizumab in colorectal cancer: has it fulfilled its promise? PMID- 24490599 TI - Sequential therapies in castration-resistant prostate cancer. PMID- 24490601 TI - Cancer healthcare: change is the only constant. AB - Ben Holland speaks to Francesca Lake, Managing Commissioning Editor: Ben Holland is a nationally known expert on oncology-specific consulting solutions in the USA. Over the past decade, he has led consulting projects for some of the most prestigious hospitals and cancer centers in the USA, including California's Cedars-Sinai Health System (CA, USA), Roswell Park Cancer Institute in New York (NY, USA), Carolinas HealthCare System (NC, USA) and Providence Health Care in Washington state (USA). He frequently speaks at some of the most well-attended conferences in the country, including those presented by the Association of Community Cancer Centers and the Association of Cancer Executives, and has recently published articles in the Journal of Oncology Practice. As Kurt Salmon's National Director of Cancer Services, Holland will lead the global management consulting firm's oncology service line. PMID- 24490595 TI - Adverse events in IBD: to stop or continue immune suppressant and biologic treatment. AB - Crohn's disease and ulcerative colitis affect an increasing number of patients. A variety of medical options exist for the treatment of these diseases including immune suppressants and biologic therapies. Unfortunately, these agents are associated with adverse events ranging from mild nuisance symptoms to potentially life-threatening complications including infections and malignancies. This review discusses adverse events associated with azathioprine, mercaptopurine, and methotrexate as well as anti-TNF-alpha and anti-integrin antibodies. In addition, adverse events associated with combination therapy are discussed as are clinical scenarios in which it may be reasonable to discontinue or de-escalate drug therapy. It is the responsibility of the treating gastroenterologist to effectively communicate the benefits and risks of therapy with patients; this review offers strategies that may assist providers in communicating risk with patients in addition to offering our perspective on whether modification or cessation of therapy can be considered. PMID- 24490602 TI - Efficacy of solubilized vemurafenib administered via nasogastric tube. AB - Until only a few years ago, there was only one truly effective therapy for patients with metastatic melanoma. While long-term remission could be achieved in some patients, toxicities associated with high-dose IL-2 were significant. New insight related to molecular pathways of tumor cells indicated that an activating mutation of BRAF can be found in approximately 50-60% of all patients with melanoma. Proof-of-concept demonstrated in clinical trials of a drug targeting mutant BRAF led to the approval of vemurafenib by the US FDA in August 2011. Supplied in an oral dosage form, we provide an alternative method of administering vemurafenib in a patient unable to take anything by mouth. PMID- 24490603 TI - A tumor of the uterine cervix with a complex histology in a Peutz-Jeghers syndrome patient with genomic deletion of the STK11 exon 1 region. AB - Patients with Peutz-Jeghers syndrome (PJS) have a risk of complicating malignant tumors, including cancer of the uterine cervix. Mutations in the STK11 gene have been identified as being responsible for PJS. However, the genotype-phenotype correlation in PJS is poorly understood, especially with respect to malignant tumors. Here, we report a detailed analysis of a case of a cervical tumor in a PJS patient showing a large genomic deletion in exon 1 of STK11 without human papillomavirus infection. Histological examination revealed a complex histology consisting of three components: lobular endocervical gland hyperplasia (LEGH), minimal deviation adenocarcinoma (MDA) and mucinous adenocarcinoma. Immunohistochemistry for STK11 was positive in the LEGH and MDA components, while that of the mucinous adenocarcinoma stained very faintly. These findings support a close relationship among LEGH, MDA and mucinous adenocarcinoma and imply that inactivation of STK11 may occur during progression from MDA to mucinous adenocarcinoma. PMID- 24490604 TI - Bosutinib treatment for Philadelphia chromosome-positive leukemias. AB - The SRC-ABL inhibitor bosutinib is one of the five tyrosine kinase inhibitors currently approved for the treatment of Philadelphia chromosome-positive leukemias. Bosutinib has shown activity against all phases of resistant chronic myeloid leukemia that do not harbor the T315I or V299L ABL kinase domain mutations. Bosutinib is overall well tolerated; transient diarrhea is the most common side effect. This article summarizes the pharmacokinetics, pharmacodynamics, safety and efficacy of bosutinib for the treatment of Philadelphia chromosome-positive leukemias. PMID- 24490605 TI - Enobosarm (GTx-024, S-22): a potential treatment for cachexia. AB - Muscle loss and wasting occurs with aging and in multiple disease states including cancer, heart failure, chronic obstructive pulmonary disease, end-stage liver disease, end-stage renal disease and HIV. Cachexia is defined as a multifactorial syndrome that is associated with anorexia, weight loss and increased catabolism, with increased morbidity and mortality. Currently no therapy is approved for the treatment or prevention of cachexia. Different treatment options have been suggested but many have proven to be ineffective or associated with adverse events. Nonsteroidal selective androgen receptor modulators (SARMs) are a new class of anabolic agents that bind the androgen receptor and exhibit tissue selectivity. Enobosarm (GTx-024, S-22) is a recently developed SARM, developed by GTx, Inc. (TN, USA), which has been tested in Phase I, II and III trials with promising results in terms of improving lean body mass and measurements of physical function and power. Enobosarm has received fast track designation by the US FDA and results from the Phase III trials POWER1 and POWER2 will help determine approval for use in the prevention and treatment of muscle wasting in patients with non-small-cell lung cancer. This article provides an introduction to enobosarm as a new therapeutic strategy for the prevention and treatment of cachexia. A review of the literature was performed using search terms 'cachexia', 'sarcopenia', 'SARM', 'enobosarm' and 'GTx-024' in September 2013 using multiple databases as well as online resources. PMID- 24490606 TI - Prognostic impact of the inclusion of uPA/PAI-1 tumor levels in the current adjuvant treatment decision-making for early breast cancer. AB - AIMS: Following the introduction of new adjuvant therapies we wanted to reappraise the prognostic and predictive value of uPA/PAI-1 in early breast cancer. PATIENTS & METHODS: This monocentric retrospective study included 652 patients who had curative surgery between 2006 and 2011 and adjuvant treatment decision-making, taking into account uPA/PAI-1 tumor levels. RESULTS: uPA and PAI 1 levels were associated with classical clinicopathological parameters and adjuvant chemotherapy decision, but not with peritumoral vascular invasion (PVI; also known as peritumoral vascular emboli). HER2 overexpression, PVI and uPA/PAI 1 levels were not significantly associated with relapse-free survival in univariate analysis. In multivariate analysis, T stage, N stage and progesterone receptors were the only independent relapse-free survival predictive factors. CONCLUSION: The absence of an association between uPA/PAI-1 and PVI allows their concomitant consideration in adjuvant treatment discussion. The overall good prognosis of patients with high uPA/PAI-1 levels might be linked to the uPA/PAI-1 predictive value and the inclusion of these parameters in adjuvant guidelines. PMID- 24490607 TI - Crizotinib inhibits migration and expression of ID1 in MET-positive lung cancer cells: implications for MET targeting in oncology. AB - AIMS: ID1 is an important component of the MET-SRC signaling pathway, which is a regulator of cell migration and invasion. We hypothesized that the ALK/MET inhibitor crizotinib inhibits migration via MET-SRC-ID1, rather than ALK. MATERIALS & METHODS: We used ALK fusion-positive and -negative lung cancer cell lines; crizotinib, PHA-665752, and saracatinib, and stable transfection with shMET. We performed western blotting for p-ALK, ALK, p-MET, MET, p-SRC, SRC and ID1, and quantitative real-time PCR for ID1. RESULTS: Crizotinib decreased p-MET, p-SRC and ID1 levels in ALK- and or MET-positive cell lines and inhibited cell migration. Knockdown of MET was comparable with the effect of crizotinib. CONCLUSION: The effects of crizotinib on ID1 expression and cancer cell migration were associated with the presence of activated MET, rather than ALK fusion. PMID- 24490609 TI - Eribulin mesylate in heavily pretreated metastatic breast cancer patients: current practice in an Italian community hospital. AB - AIM: The aim of this study is to report on the activity and safety of eribulin mesylate in a representative number of pretreated metastatic breast cancer (MBC) patients in current practice. Eribulin mesylate, a new microtubule inhibitor, is approved as monotherapy for the treatment of patients with locally advanced breast cancer or MBC who have progressed after at least two chemotherapeutic regimens for advanced disease. PATIENTS & METHODS: From February to October 2012, 27 MBC patients, previously treated with anthracyclines and taxanes, were treated with 1.4 mg/m(2) intravenous infusion of eribulin mesylate at a community hospital. RESULTS: Eight (30%) patients achieved partial response, one achieved complete response and three achieved stable disease. Median duration of response was 2.5 months (95% CI: 1.6-5.7; range: 1.3-5.7). Median overall survival was 8 months (95% CI: 6.1-9.7; range: 0.6-9.9). Reported adverse events were grade 1-2 asthenia (83%), peripheral sensory neuropathy (48%), nausea (37%) and neutropenia (30%). CONCLUSION: Our retrospective analysis of a clinical practice experience supports the evidence that eribulin mesylate has clinical activity and provides acceptable benefit to heavily pretreated MBC. PMID- 24490608 TI - Randomized Phase II trial of nintedanib, afatinib and sequential combination in castration-resistant prostate cancer. AB - AIMS: The aim of this article was to evaluate afatinib (BIBW 2992), an ErbB family blocker, and nintedanib (BIBF 1120), a triple angiokinase inhibitor, in castration-resistant prostate cancer patients. PATIENTS & METHODS: Patients were randomized to receive nintedanib (250 mg twice daily), afatinib (40 mg once daily [q.d.]), or alternating sequential 7-day nintedanib (250 mg twice daily) and afatinib (70 mg q.d. [Combi70]), which was reduced to 40 mg q.d. (Combi40) due to adverse events. The primary end point was progression-free rate at 12 weeks. RESULTS: Of the 85 patients treated 46, 20, 16 and three received nintedanib, afatinib, Combi40 and Combi70, respectively. At 12 weeks, the progression-free rate was 26% (seven out of 27 patients) for nintedanib, and 0% for afatinib and Combi40 groups. Two patients had a >=50% decline in PSA (nintedanib and the Combi40 groups). The most common drug-related adverse events were diarrhea, nausea, vomiting and lethargy. CONCLUSION: Nintedanib and/or afatinib demonstrated limited anti-tumor activity in unselected advanced castration resistant prostate cancer patients. PMID- 24490610 TI - Acute gastrointestinal toxicity after robotic stereotactic ablative radiotherapy for treatment of metastatic gynecological malignancies. AB - AIMS: The aim of this study was to assess acute and subacacute gastrointestinal toxicity after fractionated stereotactic ablative radiotherapy (SABR) in women having recurrent gynecological cancers in the upper abdomen. MATERIALS & METHODS: In total, 34 women underwent upper abdominal SABR (24 Gy/three divided 8 Gy consecutive daily doses) using a robotic Cyberknife(r) (Accuray, CA, USA) platform. Volumes of the duodenum receiving 10% increments of the prescription dose were associated to post-therapy gastrointestinal toxicities using binary logistic regression analyses. RESULTS: Median clinical follow-up was 10 months. In total, 14 (41%) of the 34 women manifested grade 2 or higher post-therapy gastrointestinal adverse events. The duodenal volume, receiving 80% of a 24-Gy dose, was significantly associated with gastrointestinal toxicity (p = 0.03). However, in a multivariate analysis, only patient age at SABR adjusted the odds of experiencing gastrointestinal toxicity (p = 0.02). CONCLUSION: The duodenal volume receiving 80% of 24 Gy dose may be associated with gastrointestinal toxicity from upper abdominal SABR. PMID- 24490611 TI - BMI and lymph node ratio may predict clinical outcomes of gastric cancer. AB - AIM: BMI and the lymph node (LN) ratio can affect short- and long-term outcomes of patients with gastric cancer. PATIENTS & METHODS: This study includes 104 consecutive patients with gastric adenocarcinoma who underwent curative gastrectomy divided in two groups: overweight group (group A) and normal weight group (group B). RESULTS: We found that 53.4% of our patients were overweight (group A). The overall rate of postoperative complications was 16.3%, while mortality was 1%. Statistical analyses revealed that postoperative morbidity was significantly higher in group A (p < 0.05). Long-term survival was significantly higher in group B. Cox regression showed a statistically significant correlation between higher BMI and poor long-term survival after curative gastrectomy. Multivariate analysis has identified age and the LN ratios as independent prognostic factors of survival. CONCLUSION: In this retrospective analysis, BMI and LN ratio were independently associated with survival in patients with gastric cancer. Further studies are needed to confirm our findings. PMID- 24490612 TI - Epidemiology, clinical manifestations, risk reduction and treatment strategies of jaw osteonecrosis in cancer patients exposed to antiresorptive agents. AB - Osteonecrosis of the jaws (ONJ) is an adverse side event of bisphosphonates and denosumab, antiresorptive agents that effectively reduce the incidence of skeletal-related events in patients with metastatic bone cancer and multiple myeloma. Available data suggest that 0-27.5% of individuals exposed to antiresorptive agents can develop ONJ. There is increasing evidence that avoidance of surgical trauma and infection to the jawbones can minimize the risk of ONJ, but there are still a significant number of individuals who develop ONJ in the absence of these risk factors. Bone necrosis is almost irreversible and there is no definitive cure for ONJ with the exclusion, in certain cases, of surgical resection. However, most ONJ individuals are affected by advanced incurable cancer and are often managed with minimally invasive nonsurgical interventions in order to control jawbone infections and painful symptoms. This article summarizes current knowledge of ONJ epidemiology, manifestations, risk reduction and therapeutic strategies. Further research is needed in order to determine individual predisposition to ONJ and clarify the effectiveness of available treatments. PMID- 24490613 TI - Safety considerations for transplanting cryopreserved ovarian tissue to restore fertility in female patients who have recovered from Ewing's sarcoma. AB - Ewing's sarcoma (EWS) is a highly malignant cancer in children, adolescents and young adults. The chemotherapy required to treat female EWS patients may cause primary ovarian insufficiency and infertility as a side effect. Cryopreservation of ovarian tissue before the start of chemotherapy can potentially preserve fertility. When the patient has been cured and primary ovarian insufficiency has developed, transplantation of frozen/thawed ovarian tissue can restore ovarian function. The tissue is usually collected before chemotherapy is initiated, and malignant cells may contaminate the stored ovarian tissue, potentially causing recrudescence of the original cancer after transplantation. The risk of EWS metastasizing to the ovary is probably low but has not been studied in great detail. This review describes the available evidence on the risk of malignant cell contamination in the ovaries of EWS patients and presents a new case of malignant cells in an ovarian biopsy from a girl with EWS. PMID- 24490614 TI - Dissecting signaling pathways in hepatocellular carcinoma: new perspectives in medical therapy. AB - Prognosis of patients with advanced hepatocellular carcinoma (HCC) is poor and is largely influenced by associated liver comorbidities. Moreover, effective treatment alternatives are limited; with the exception of the multitargeted inhibitor sorafenib, established options in the treatment of advanced HCC no longer amenable with ablative or locoregional procedures are lacking. In light of the limited efficacy of chemotherapy in this setting, great efforts have been made in the definition of targetable molecular pathways with a central role in the progression of HCC. Targeting angiogenesis, growth factor receptors, intracellular transduction pathways, or mechanisms of gene-expression regulation represents the main way to improve patient outcome. At the same time, identifying clinical and biological factors, which may help selecting patients with higher chances of benefit, is essential in order to hasten drug development and maximize treatment efficacy. PMID- 24490615 TI - ALK-positive cancer: still a growing entity. AB - Since the discovery of ALK-positive anaplastic large-cell lymphoma in 1994 many other types of tumors showing ALK expression were disclosed. They form a heterogeneous group, including lung, renal and soft tissue tumors. The biological function of ALK, its role in carcinogenesis and impact exerted on the clinical outcome have been studied by many research groups. New drugs specifically dedicated for ALK inhibition, for example, crizotinib, have been synthesized and have become a viable treatment option for ALK-positive lung adenocarcinoma, and potentially for other ALK-positive cancers. This review summarizes the current state of knowledge concerning ALK-positive neoplasms, focusing on the clinical aspects of the subject. PMID- 24490616 TI - Women's experiences and health care-seeking practices in relation to uterine prolapse in a hill district of Nepal. AB - BACKGROUND: Although uterine prolapse (UP) occurs commonly in Nepal, little is known about the physical health and care-seeking practices of women with UP. This study aimed to explore women's experiences of UP and its effect on daily life, its perceived causes, and health care-seeking practices. METHODS: Using a convenience sampling method, we conducted 115 semi-structured and 16 in-depth interviews with UP-affected women during September-December 2012. All interviews occurred in outreach clinics in villages of the Dhading district. RESULTS: Study participants were 23-82 years of age. Twenty-four percent were literate, 47.2% had experienced a teenage pregnancy, and 29% had autonomy to make healthcare decisions. Most participants (>85%) described the major physical discomforts of UP as difficulty with walking, standing, working, sitting, and lifting. They also reported urinary incontinence (68%) bowel symptoms (42%), and difficulty with sexual activity (73.9%). Due to inability to perform household chores or fulfill their husband's sexual desires, participants endured humiliation, harassment, and torture by their husbands and other family members, causing severe emotional stress. Following disclosure of UP, 24% of spouses remarried and 6% separated from the marital relationship. Women perceived the causes of UP as unsafe childbirth, heavy work during the postpartum period, and gender discrimination. Prior to visiting these camps some women (42%) hid UP for more than 10 years. Almost half (48%) of participants sought no health care; 42% ingested a herb and ate nutritious food. Perceived barriers to accessing health care included shame (48%) and feeling that care was unnecessary (12.5%). Multiple responses (29%) included shame, inability to share, male service provider, fear of stigma and discrimination, and perceiving UP as normal for childbearing women. CONCLUSIONS: UP adversely affects women's daily life and negatively influences their physical, mental, and social well-being. The results of our study are useful to generate information on UP symptoms and female health care seeking practices. Our findings can be helpful for effective development of UP awareness programs to increase service utilization at early stages of UP and thereby might contribute to both primary and secondary prevention of UP. PMID- 24490618 TI - PFClust: an optimised implementation of a parameter-free clustering algorithm. AB - BACKGROUND: A well-known problem in cluster analysis is finding an optimal number of clusters reflecting the inherent structure of the data. PFClust is a partitioning-based clustering algorithm capable, unlike many widely-used clustering algorithms, of automatically proposing an optimal number of clusters for the data. RESULTS: The results of tests on various types of data showed that PFClust can discover clusters of arbitrary shapes, sizes and densities. The previous implementation of the algorithm had already been successfully used to cluster large macromolecular structures and small druglike compounds. We have greatly improved the algorithm by a more efficient implementation, which enables PFClust to process large data sets acceptably fast. CONCLUSIONS: In this paper we present a new optimized implementation of the PFClust algorithm that runs considerably faster than the original. PMID- 24490617 TI - Generation of disease-specific induced pluripotent stem cells from patients with rheumatoid arthritis and osteoarthritis. AB - INTRODUCTION: Since the concept of reprogramming mature somatic cells to generate induced pluripotent stem cells (iPSCs) was demonstrated in 2006, iPSCs have become a potential substitute for embryonic stem cells (ESCs) given their pluripotency and "stemness" characteristics, which resemble those of ESCs. We investigated to reprogram fibroblast-like synoviocytes (FLSs) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA) to generate iPSCs using a 4-in 1 lentiviral vector system. METHODS: A 4-in-1 lentiviral vector containing Oct4, Sox2, Klf4, and c-Myc was transduced into RA and OA FLSs isolated from the synovia of two RA patients and two OA patients. Immunohistochemical staining and real-time PCR studies were performed to demonstrate the pluripotency of iPSCs. Chromosomal abnormalities were determined based on the karyotype. SCID-beige mice were injected with iPSCs and sacrificed to test for teratoma formation. RESULTS: After 14 days of transduction using the 4-in-1 lentiviral vector, RA FLSs and OA FLSs were transformed into spherical shapes that resembled embryonic stem cell colonies. Colonies were picked and cultivated on matrigel plates to produce iPSC lines. Real-time PCR of RA and OA iPSCs detected positive markers of pluripotency. Immunohistochemical staining tests with Nanog, Oct4, Sox2, Tra-1 80, Tra-1-60, and SSEA-4 were also positive. Teratomas that comprised three compartments of ectoderm, mesoderm, and endoderm were formed at the injection sites of iPSCs. Established iPSCs were shown to be compatible by karyotyping. Finally, we confirmed that the patient-derived iPSCs were able to differentiate into osteoblast, which was shown by an osteoimage mineralization assay. CONCLUSION: FLSs derived from RA and OA could be cell resources for iPSC reprogramming. Disease- and patient-specific iPSCs have the potential to be applied in clinical settings as source materials for molecular diagnosis and regenerative therapy. PMID- 24490619 TI - Validation of a previous day recall for measuring the location and purpose of active and sedentary behaviors compared to direct observation. AB - PURPOSE: Gathering contextual information (i.e., location and purpose) about active and sedentary behaviors is an advantage of self-report tools such as previous day recalls (PDR). However, the validity of PDR's for measuring context has not been empirically tested. The purpose of this paper was to compare PDR estimates of location and purpose to direct observation (DO). METHODS: Fifteen adult (18-75 y) and 15 adolescent (12-17 y) participants were directly observed during at least one segment of the day (i.e., morning, afternoon or evening). Participants completed their normal daily routine while trained observers recorded the location (i.e., home, community, work/school), purpose (e.g., leisure, transportation) and whether the behavior was sedentary or active. The day following the observation, participants completed an unannounced PDR. Estimates of time in each context were compared between PDR and DO. Intra-class correlations (ICC), percent agreement and Kappa statistics were calculated. RESULTS: For adults, percent agreement was 85% or greater for each location and ICC values ranged from 0.71 to 0.96. The PDR-reported purpose of adults' behaviors were highly correlated with DO for household activities and work (ICCs of 0.84 and 0.88, respectively). Transportation was not significantly correlated with DO (ICC = -0.08). For adolescents, reported classification of activity location was 80.8% or greater. The ICCs for purpose of adolescents' behaviors ranged from 0.46 to 0.78. Participants were most accurate in classifying the location and purpose of the behaviors in which they spent the most time. CONCLUSIONS: This study suggests that adults and adolescents can accurately report where and why they spend time in behaviors using a PDR. This information on behavioral context is essential for translating the evidence for specific behavior-disease associations to health interventions and public policy. PMID- 24490620 TI - Characterization of the glutathione S-transferase gene family through ESTs and expression analyses within common and pigmented cultivars of Citrus sinensis (L.) Osbeck. AB - BACKGROUND: Glutathione S-transferases (GSTs) represent a ubiquitous gene family encoding detoxification enzymes able to recognize reactive electrophilic xenobiotic molecules as well as compounds of endogenous origin. Anthocyanin pigments require GSTs for their transport into the vacuole since their cytoplasmic retention is toxic to the cell. Anthocyanin accumulation in Citrus sinensis (L.) Osbeck fruit flesh determines different phenotypes affecting the typical pigmentation of Sicilian blood oranges. In this paper we describe: i) the characterization of the GST gene family in C. sinensis through a systematic EST analysis; ii) the validation of the EST assembly by exploiting the genome sequences of C. sinensis and C. clementina and their genome annotations; iii) GST gene expression profiling in six tissues/organs and in two different sweet orange cultivars, Cadenera (common) and Moro (pigmented). RESULTS: We identified 61 GST transcripts, described the full- or partial-length nature of the sequences and assigned to each sequence the GST class membership exploiting a comparative approach and the classification scheme proposed for plant species. A total of 23 full-length sequences were defined. Fifty-four of the 61 transcripts were successfully aligned to the C. sinensis and C. clementina genomes. Tissue specific expression profiling demonstrated that the expression of some GST transcripts was 'tissue-affected' and cultivar specific. A comparative analysis of C. sinensis GSTs with those from other plant species was also considered. Data from the current analysis are accessible at http://biosrv.cab.unina.it/citrusGST/, with the aim to provide a reference resource for C. sinensis GSTs. CONCLUSIONS: This study aimed at the characterization of the GST gene family in C. sinensis. Based on expression patterns from two different cultivars and on sequence-comparative analyses, we also highlighted that two sequences, a Phi class GST and a Mapeg class GST, could be involved in the conjugation of anthocyanin pigments and in their transport into the vacuole, specifically in fruit flesh of the pigmented cultivar. PMID- 24490621 TI - Effects of Tai Chi exercise on blood pressure and plasma levels of nitric oxide, carbon monoxide and hydrogen sulfide in real-world patients with essential hypertension. AB - Objective was to investigate the effects of Tai Chi exercise on nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S) levels, and blood pressure (BP) in patients with essential hypertension (EH). EH patients were assigned to the Tai Chi exercise group (HTC, n = 24), and hypertension group (HP, n = 16) by patients' willingness. Healthy volunteers matched for age and gender were recruited as control (NP, n = 16). HTC group performed Tai Chi (60 min/d, 6 d/week) for 12 weeks. Measurements (blood glucose, cholesterol, NO, CO, H2S and BP) were obtained at week 0, 6, and 12. SBP, MAP, and low-density lipoprotein cholesterol levels decreased, and high-density lipoprotein cholesterol levels increased by week 12 in the HTC group (all p < 0.05 versus baseline). Plasma NO, CO, and H2S levels in the HTC group were increased after 12 weeks (all p < 0.05 versus baseline). SBP, DBP and MAP levels were significantly lower in the HTC than in the HP group (all p < 0.05). However, no changes were observed in the HP and NP groups. Correlations were observed between changes in SBP and changes in NO, CO and H2S (r = -0.45, -0.51 and -0.46, respectively, all p < 0.05), and between changes in MAP and changes in NO, CO and H2S (r = -0.36, -0.45 and -0.42, respectively, all p < 0.05). In conclusion, Tai Chi exercise seems to have beneficial effects on BP and gaseous signaling molecules in EH patients. However, further investigation is required to understand the exact mechanisms underlying these observations, and to confirm these results in a larger cohort. PMID- 24490622 TI - Religious socialization in African American families: the relative influence of parents, grandparents, and siblings. AB - The family is the principal context for religious and spiritual socialization. Although religion remains a central force in the lives of most African Americans, research has failed to explore the role and impact of family on religious socialization within this population. This study addresses that gap in the literature by (1) exploring adults' perceptions of the influence of their parents, grandparents, and siblings on their religious and spiritual lives, and (2) examining the extent to which those perceptions are associated with subjective religiosity, subjective spirituality, religious importance, and commitment to religious socialization among a community sample of urban-residing African American adults in the Midwest and Northeast (N = 319). Findings revealed that, on average, parents, grandparents, and siblings positively influenced adults' religious commitment and values. However, mothers had the greatest positive influence on these outcomes. Religious commitment and values were differentially associated with family members as a function of the generation and gender of the family member. The implications of these findings are discussed. PMID- 24490623 TI - Highly electroconductive mesoporous graphene nanofibers and their capacitance performance at 4 V. AB - We report the fabrication of one-dimensional highly electroconductive mesoporous graphene nanofibers (GNFs) by a chemical vapor deposition method using MgCO3.3H2O fibers as the template. The growth of such a unique structure underwent the first in situ decomposition of MgCO3.3H2O fibers to porous MgO fibers, followed by the deposition of carbon on the MgO surface, the removal of MgO by acidic washing, and the final self-assembly of wet graphene from single to double layer in drying process. GNFs exhibited good structural stability, high surface area, mesopores in large amount, and electrical conductivity 3 times that of carbon nanotube aggregates. It, used as an electrode in a 4 V supercapacitor, exhibited high energy density in a wide range of high power density and excellent cycling stability. The short diffusion distance for ions of ionic liquids electrolyte to the surface of GNFs yielded high surface utilization efficiency and a capacitance up to 15 MUF/cm(2), higher than single-walled carbon nanotubes. PMID- 24490626 TI - Persistence to oral 5-aminosalicylate therapy for inflammatory bowel disease in Australia. AB - Aminosalicylate (5-ASA) is effective treatment for inflammatory bowel diseases (IBDs) but requires continuous maintenance therapy. This study determines persistence of 5-ASA in IBD using national population-based data for Australia from 2002 to 2011 with follow up for 36 months. Non-persistence was defined as failing to fill a prescription for 3 months. Of 12,592 patients those initiated on non-sulphasalazine 5-ASA (2917) had significantly higher persistence (P < 0.001) than those on sulphasalazine (9675). Persistence for sulphasalazine and non-sulphasalazine 5-ASA initiation was 22.3% and 28.5% at 12-months, and 11.9% and 16.2% at 24-months. Sulphasalazine poor persistence continued despite intra class switch to another 5-ASA. Patients receiving immunomodulator co-therapy had higher persistence (P < 0.001). National population-based data identified persistence to 5-ASA to be low but significantly lower when sulphasalazine is the initial drug. Physicians should stress the importance of long-term 5-ASA therapy as overall drug efficacy especially the 5-ASA chemo-prophylactic benefits may be reduced by non-persistence. PMID- 24490627 TI - Lupus clinical development: will belimumab's approval catalyse a new paradigm for SLE drug development? AB - INTRODUCTION: Systemic lupus erythematosus (SLE) is a diverse autoimmune disease affecting many different organ systems. Although disease manifestations are varied across the lupus population, the widespread presence of autoantibodies indicates that SLE immunopathology involves B-cell dysregulation. Belimumab, a human anti-B-cell activating factor (BLyS) monoclonal antibody, was invented by Human Genome Sciences and co-developed with GlaxoSmithKline and became, in 2011, the first new therapy approved for SLE patients in over 50 years. AREAS COVERED: Belimumab approval represents a milestone as a new treatment for a subset of SLE patients and also a window onto the continued unmet need for many patients suffering from this diverse disease. This paper analyses the drugs and clinical trials of industry-sponsored development programs to profile the current SLE landscape and to consider how belimumab is shaping the future of SLE drug development. EXPERT OPINION: Our analysis demonstrates that the belimumab clinical program created a model for improvements in study designs that is reflected in ongoing clinical trials sponsored by a broad range of companies. Additional BLyS inhibitors, with distinctive targeting characteristics, are now in late stage development. A broad range of drugs with other mechanisms of action are also under investigation in Phase II - III trials, some of which are focused on the underserved lupus nephritis population. PMID- 24490625 TI - Chemistry of bridged lactams and related heterocycles. PMID- 24490628 TI - Vocal local versus pharmacological treatments for pain management in tubal ligation procedures in rural Kenya: a non-inferiority trial. AB - BACKGROUND: Vocal local (VL) is a non-pharmacological pain management technique for gynecological procedures. In Africa, it is usually used in combination with pharmacological analgesics. However, analgesics are associated with side-effects, and can be costly and subject to frequent stock-outs, particularly in remote rural settings. We compared the effectiveness of VL + local anesthesia + analgesics (the standard approach), versus VL + local anesthesia without analgesics, on pain and satisfaction levels for women undergoing tubal ligations in rural Kenya. METHODS: We conducted a site-randomised non-inferiority trial of 884 women receiving TLs from 40 Marie Stopes mobile outreach sites in Kisii and Machakos Districts. Twenty sites provided VL + local anesthesia + analgesics (control), while 20 offered VL + local anesthesia without additional analgesics (intervention). Pain was measured using a validated 11-point Numeric Rating Scale; satisfaction was measured using 11-point scales. RESULTS: A total of 461 women underwent tubal ligations with VL + local anesthesia, while 423 received tubal ligations with VL + local anesthesia + analgesics. The majority were aged >=30 years (78%), and had >3 children (99%). In a multivariate analysis, pain during the procedure was not significantly different between the two groups. The pain score after the procedure was significantly lower in the intervention group versus the control group (by 0.40 points; p = 0.041). Satisfaction scores were equally high in both groups; 96% would recommend the procedure to a friend. CONCLUSION: VL + local anesthesia is as effective as VL + local anesthesia + analgesics for pain management during tubal ligation in rural Kenya. Avoiding analgesics is associated with numerous benefits including cost savings and fewer issues related to the maintenance, procurement and monitoring of restricted opioid drugs, particularly in remote low-resource settings where these systems are weak. TRIAL REGISTRATION: Pan-African Clinical Trials Registry PACTR201304000495942. PMID- 24490629 TI - Straining graphene using thin film shrinkage methods. AB - Theoretical works suggest the possibility and usefulness of strain engineering of graphene by predicting remarkable properties, such as Dirac cone merging, bandgap opening and pseudo magnetic field generation. However, most of these predictions have not yet been confirmed because it is experimentally difficult to control the magnitude and type (e.g., uniaxial, biaxial, and so forth) of strain in graphene devices. Here we report two novel methods to apply strain without bending the substrate. We employ thin films of evaporated metal and organic insulator deposited on graphene, which shrink after electron beam irradiation or heat application. These methods make it possible to apply both biaxial strain and in plane isotropic compressive strain in a well-controlled manner. Raman spectroscopy measurements show a clear splitting of the degenerate states of the G-band in the case of biaxial strain, and G-band blue shift without splitting in the case of in-plane isotropic compressive strain. In the case of biaxial strain application, we find out the ratio of the strain component perpendicular to the stretching direction is at least three times larger than what was previously observed, indicating that shrinkage of the metal or organic insulator deposited on graphene induces both tensile and compressive strain in this atomically thin material. Our studies present for the first time a viable way to apply strain to graphene without the need to bend the substrate. PMID- 24490630 TI - Enantioselective synthesis of triarylmethanes by chiral imidodiphosphoric acids catalyzed Friedel-Crafts reactions. AB - The first enantioselective synthesis of pyrrolyl-substituted triarylmethanes has been accomplished using a novel imidodiphosphoric acid catalyst, which is derived from two (R)-BINOL frameworks with different 3,3'-substituents. This strategy was also expanded to the synthesis of bis(indolyl)-substituted triarylmethanes with high enantioselectivities, which could only be obtained with moderate ee values in previous reports. These two efficient Friedel-Crafts alkylation processes feature low catalyst loading, broad functional group compatibilities, and the potential to provide practical pathways for the synthesis of enantioenriched bioactive triarylmethanes. PMID- 24490632 TI - Chitosan/alkylethoxy carboxylates: a surprising variety of structures. AB - In this work, we present a comprehensive structural characterization of long-term stable complexes formed by biopolycation chitosan and oppositely charged nonaoxyethylene oleylether carboxylate. These two components are attractive for many potential applications, with chitosan being a bioderived polymer and the surfactant being ecologically benign and mild. Experiments were performed at different mixing ratios Z (ratio of the nominal charges of surfactant/polyelectrolyte) and different pH values such that the degree of ionization of the surfactant is largely changed whereas that of chitosan is only slightly affected. The structural characterization was performed by combining static and dynamic light scattering (SLS and DLS) and small-angle neutron scattering (SANS) to cover a large structural range. Highly complex behavior is observed, with three generic structures formed that depend on pH and the mixing ratio, namely, (i) a micelle-decorated network at low Z and pH, (ii) rodlike complexes with the presence of aligned micelles at medium Z and pH, and (iii) compacted micellar aggregates forming a supraaggregate surrounded by a chitosan shell at high Z and pH. Accordingly, the state of aggregation in these mixtures can be tuned structurally over quite a range only by rather small changes in pH. PMID- 24490631 TI - Decreased plasma levels of soluble CD18 link leukocyte infiltration with disease activity in spondyloarthritis. AB - INTRODUCTION: Spondyloarthritis (SpA) comprises a group of diseases often associated with HLA-B27 and characterized by inflammation of the entheses and joints of the axial skeleton. The inflammatory process in SpA is presumably driven by innate immune cells but is still poorly understood. Thus, new tools for monitoring and treating inflammation are needed. The family of CD18 integrins is pivotal in guiding leukocytes to sites of inflammation, and CD18 hypomorphic mice develop a disease resembling SpA. Previously, we demonstrated that altered soluble CD18 (sCD18) complexes in the blood and synovial fluid of patients with arthritis have anti-inflammatory functions. Here, we study the mechanisms for these alterations and their association with SpA disease activity. METHODS: Plasma levels of sCD18 in a study population with 84 patients with SpA and matched healthy controls were analyzed with a time-resolved immunoflourometric assay (TRIFMA). Binding of sCD18 to endothelial cells and fibroblast-like synoviocytes (FLSs) was studied with confocal microscopy. Shedding of CD18 from peripheral blood mononuclear cells (PBMCs) was studied with flow cytometry and TRIFMA. RESULTS: Plasma levels of sCD18 were decreased in patients with SpA compared with healthy volunteers (P <0.001), and the lowest levels were in the HLA-B27-positive subgroup (P <0.05). In a multiple regression model, the sCD18 levels exhibited an inverse correlation with the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) (P <0.05), the level of morning stiffness (P <0.05), the Bath Ankylosing Spondilitis Metrology Index (P <0.05), the physician global assessment score (P <0.01), and the sacroiliac magnetic resonance imaging activity score (P <0.05). The mechanisms for these changes could be simulated in vitro. First, sCD18 in plasma adhered to inflammation-induced intercellular adhesion molecule 1 (ICAM-1) on endothelial cells and FLS, indicating increased consumption. Second, CD18 shedding from SpA PBMCs correlated inversely with the BASDAI (P <0.05), suggesting insufficient generation. CD18 was shed primarily from intermediate CD14++ CD16+ monocytes, supporting the view that alterations in innate immunity can regulate the inflammatory processes in SpA. CONCLUSIONS: Taken together, the failure of patients with SpA to maintain adequate sCD18 levels may reflect insufficient CD18 shedding from monocytes to counterbalance the capture of sCD18 complexes to inflammation-induced ICAM-1. This could increase the availability of ICAM-1 molecules on the endothelium and in the synovium, facilitating leukocyte migration to the entheses and joints and aggregating disease activity. PMID- 24490633 TI - Hygrocins C-G, cytotoxic naphthoquinone ansamycins from gdmAI-disrupted Streptomyces sp. LZ35. AB - Six hygrocins, polyketides of ansamycin class, were isolated from the gdmAI disrupted Streptomyces sp. LZ35. The planar structure of hygrocins C-E (1-3) was determined by one-dimensional and two-dimensional NMR spectroscopy and high resolution mass spectrometry. They are derivatives of hygrocin A but differ in the configuration at C-2 and the orientation of the C-3,4 double bond. Hygrocin F(4) and G(5) were shown to be isomers of hygrocin C (1) and B (6), respectively, due to the different alkyl oxygen participating in the macrolide ester linkage. Hygrocins C, D, and F were found to be toxic to human breast cancer MDA-MB-431 cells (IC50 = 0.5, 3.0, and 3.3 MUM, respectively) and prostate cancer PC3 cells (IC50 = 1.9, 5.0, and 4.5 MUM, respectively), while hygrocins B, E, and G were inactive. PMID- 24490634 TI - Strepsesquitriol, a rearranged zizaane-type sesquiterpenoid from the deep-sea derived actinomycete Streptomyces sp. SCSIO 10355. AB - Strepsesquitriol, a new caged sesquiterpene, was isolated from Streptomyces sp. SCSIO 10355. Its absolute structure was established as (1R,2R,4S,5S,8S,10S) 4,9,9,10-tetramethyl-2,5,10-trihydroxytricyclo[6.2.1.0(1,5)]undecane by NMR analysis and a theoretical optical rotation derived from quantum-chemical calculations. It showed moderate inhibitory activity against lipopolysaccharide induced TNFalpha production in RAW264.7 macrophages. PMID- 24490636 TI - Defective black TiOTiO2 synthesized via anodization for visible-light photocatalysis. AB - Defective TiO(2-x) was synthesized via a facile anodization technique. Electron paramagnetic resonance spectra confirmed the presence of oxygen vacancy, which extended the photon-absorbance deeply into the visible-light region. By stripping off the nanotubes on top, a hexagonally dimpled layer of black TiO(2-x) was exposed and exhibited remarkable photocatalytic activity. PMID- 24490635 TI - Reducing mortality in hip fracture patients using a perioperative approach and "Patient- Centered Medical Home" model: a prospective cohort study. AB - BACKGROUND: Hip fracture patients experience high morbidity and mortality rates in the first post-operative year after discharge. We compared mortality, utilization, costs, pain and function between two prospective cohorts of hip fracture patients, both managed with identical perioperative protocols and one group subsequently managed via a "Patient-Centered Medical Home" (PCMH) primary care management model. METHODS: We analyzed 6 and 12-month outcomes from two matched cohorts of patients who were surgically treated for hip fracture from January 1, 2010 to June 30, 2011 at two hospitals (n = 194). Controls did not receive PCMH and were matched to cases on surgery date, sex, age, and comorbidities. Mortality and healthcare utilization were the primary outcomes studied, with medical costs, quality of life, pain and function at 12 months assessed as secondary outcomes in a subgroup. Survival analysis, regression and Student-t testing were used with p < 0.05 considered significant. RESULTS: At 6 months, PCMH patients had significantly lower mortality than patients receiving standard care (11% vs. 26%, p < 0.01). At 12 months, a difference persisted (23% vs. 30%, p = 0.12) but was no longer statistically significant. Mean quality of life scores were similar (0.73 vs. 0.76, p = 0.49) and Harris Hip score was slightly improved for PCMH (73 vs. 64, p = 0.04). Mean costs per patient per month were lower for PCMH but not significantly different ($69 vs. $141, p = 0.20 for pharmacy costs; $1212 vs. $1452, p = 0.45 for non-pharmacy costs). CONCLUSIONS: Patients receiving aggressive post-discharge care from a PCMH program showed significant benefits in terms of reduced mortality at 6 months, with similar costs and functional outcomes at 12 months. PCMH was not shown to improve all outcomes studied, but these results suggest that ongoing Medical Home management can have some benefit for patients without negatively impacting function or cost. PMID- 24490637 TI - Lotus tenuis x L. corniculatus interspecific hybridization as a means to breed bloat-safe pastures and gain insight into the genetic control of proanthocyanidin biosynthesis in legumes. AB - BACKGROUND: Proanthocyanidins (PAs) are secondary metabolites that strongly affect plant quality traits. The concentration and the structure of these metabolites influence the palatability and nutritional value of forage legumes. Hence, modulating PAs in the leaves of forage legumes is of paramount relevance for forage breeders worldwide. The lack of genetic variation in the leaf PA trait within the most important forage species and the difficulties in engineering this pathway via the ectopic expression of regulatory genes, prompted us to pursue alternative strategies to enhance this trait in forage legumes of agronomic interest. The Lotus genus includes forage species which accumulate PAs in edible organs and can thus be used as potential donor parents in breeding programs. RESULTS: We recovered a wild, diploid and PA-rich population of L. corniculatus and crossed with L. tenuis. The former grows in an alkaline-salty area in Spain while the latter is a diploid species, grown extensively in South American pastures, which does not accumulate PAs in the herbage. The resulting interspecific hybrids displayed several traits of outstanding agronomic relevance such as rhizome production, PA levels in edible tissues sufficient to prevent ruminal bloating (around 5 mg of PAs/g DW), biomass production similar to the cultivated parent and potential for adaptability to marginal lands. We show that PA levels correlate with expression levels of the R2R3MYB transcription factor TT2 and, in turn, with those of the key structural genes of the epicatechin and catechin biosynthetic pathways leading to PA biosynthesis. CONCLUSIONS: The L. tenuis x L. corniculatus hybrids, reported herein, represent the first example of the introgression of the PA trait in forage legumes to levels known to provide nutritional and health benefits to ruminants. Apart from PAs, the hybrids have additional traits which may prove useful to breed forage legumes with increased persistence and adaptability to marginal conditions. Finally, our study suggests the hybrids and their progeny are an invaluable tool to gain a leap forward in our understanding of the genetic control of PA biosynthesis and tolerance to stresses in legumes. PMID- 24490639 TI - An outbreak of pyrimethamine toxicity in patients with ischaemic heart disease in Pakistan. AB - We investigated an outbreak of darkening of skin, bleeding from multiple sites, leucopenia and thrombocytopenia in ischaemic heart disease patients. Case patients were defined as patients who had received medicines from the pharmacy of Punjab Institute of Cardiology between 1 December 2011 and 12 January 2012 and who developed any one of the following: darkening of skin, bleeding from any site, thrombocytopenia and leucopenia. Clinical and drug-related data were abstracted. All 664 case patients had received iso-sorbide-mono-nitrate contaminated with about 50 mg of pyrimethamine, and 151 (23%) died. The median age of 117 patients admitted at Jinnah Hospital Lahore was 57 years (range, 37 100) and 92 (79%) were male. The median time from intake of medicine to presentation was 37 days (range 13-72). Symptoms and signs included bleeding (in 95% of the patients), skin hyperpigmentation (in 61%), diarrhoea (in 53%) and abdominal pain (in 48%). At presentation, the median white cell count was 2.3 * 10(9) /L (range, 0.1 * 10(9) -16.0 * 10(9) ), the median hemoglobin concentration was 109 g/L (range 58-169) and the median platelet count was 18 * 10(9) /L (range, 0 * 10(9) -318 * 10(9) ). Bone marrow examination revealed trileneage dysplasia and severe megaloblastosis. The predictors of mortality included presentation prior to 15 January 2012, age more than 57 years, hypotension and leukocyte count less than 1.5 * 10(9) /L. None of the patients who died received Calcium folinate because all deaths occurred prior to contaminant identification. We describe an outbreak of pyrimethamine toxicity in ischaemic heart disease patients receiving medicines from a single pharmacy due to accidental contamination of iso-sorbide mono-nitrate tablets at industrial level. Late recognition of illness resulted in high mortality. PMID- 24490638 TI - Population-based studies of myocardial hypertrophy: high resolution cardiovascular magnetic resonance atlases improve statistical power. AB - BACKGROUND: Cardiac phenotypes, such as left ventricular (LV) mass, demonstrate high heritability although most genes associated with these complex traits remain unidentified. Genome-wide association studies (GWAS) have relied on conventional 2D cardiovascular magnetic resonance (CMR) as the gold-standard for phenotyping. However this technique is insensitive to the regional variations in wall thickness which are often associated with left ventricular hypertrophy and require large cohorts to reach significance. Here we test whether automated cardiac phenotyping using high spatial resolution CMR atlases can achieve improved precision for mapping wall thickness in healthy populations and whether smaller sample sizes are required compared to conventional methods. METHODS: LV short-axis cine images were acquired in 138 healthy volunteers using standard 2D imaging and 3D high spatial resolution CMR. A multi-atlas technique was used to segment and co-register each image. The agreement between methods for end diastolic volume and mass was made using Bland-Altman analysis in 20 subjects. The 3D and 2D segmentations of the LV were compared to manual labeling by the proportion of concordant voxels (Dice coefficient) and the distances separating corresponding points. Parametric and nonparametric data were analysed with paired t-tests and Wilcoxon signed-rank test respectively. Voxelwise power calculations used the interstudy variances of wall thickness. RESULTS: The 3D volumetric measurements showed no bias compared to 2D imaging. The segmented 3D images were more accurate than 2D images for defining the epicardium (Dice: 0.95 vs 0.93, P<0.001; mean error 1.3 mm vs 2.2 mm, P<0.001) and endocardium (Dice 0.95 vs 0.93, P<0.001; mean error 1.1 mm vs 2.0 mm, P<0.001). The 3D technique resulted in significant differences in wall thickness assessment at the base, septum and apex of the LV compared to 2D (P<0.001). Fewer subjects were required for 3D imaging to detect a 1 mm difference in wall thickness (72 vs 56, P<0.001). CONCLUSIONS: High spatial resolution CMR with automated phenotyping provides greater power for mapping wall thickness than conventional 2D imaging and enables a reduction in the sample size required for studies of environmental and genetic determinants of LV wall thickness. PMID- 24490640 TI - Preparation and properties of calcium-silicate filled resins for dental restoration. Part I: chemical-physical characterization and apatite-forming ability. AB - OBJECTIVE: The aim of this study was to measure dimensional changes due to hygroscopic expansion and the bioactivity of two experimental methacrylate-based dental adhesives either incorporating Bioglass 45S5 (3-E&RA/BG) or MTA (3 E&RA/WMTA). MATERIALS AND METHODS: 3-E&RA/BG, 3-E&RA/WMTA and a control filler free resin blend (3-E&RA) were formulated from commercially available monomers. Water sorption (WS) and solubility (SL) behaviour were evaluated by weighing material disks at noted intervals; the relationship between degree of hydration and the glass transition temperature (Tg) was investigated by using differential scanning calorimetry (DSC). In vitro apatite-forming ability as a function of soaking time in phosphate-containing solutions was also determined. Kruskal Wallis analysis of variance (ANOVA) was used to evaluate differences between groups for maximum WS, SL, net water uptake and the percentage change in Tg values. Post-ANOVA pair-wise comparisons were conducted using Mann-Whitney-U tests. RESULTS: 3-E&RA/BG and 3-E&RA/WMTA exhibited values of maximum WS and net water uptake that were significantly higher when compared to 3-E&RA. However, no statistically significant differences were observed in terms of SL between all the adhesives. The addition of the Bioglass 45S5 and MTA to the 3-E&RA showed no reduction of the Tg after 60 days of storage in deionized water. ATR Fourier Transform Infrared Spectroscopy (ATR-FTIR) of the filled resin disks soaked in DPBS for 60 days showed the presence of carbonate ions in different chemical phases. CONCLUSION: Dentine bonding agents comprising calcium-silicates are not inert materials in a simulated oral environment and apatite formation may occur in the intra-oral conditions. CLINICAL SIGNIFICANCE: A bioactive dental material which forms apatite on the surface would have several benefits including closure of gaps forming at the resin-dentine interface and potentially better bond strength over time (less degradation of bond). PMID- 24490641 TI - Influence of ceramic thickness and type on micromechanical properties of light cured adhesive bonding agents. AB - OBJECTIVE: The aim of this study was to evaluate the micromechanical properties of different adhesive bonding agents when polymerized through ceramics. MATERIALS AND METHODS: Sixty sound extracted human third molars were selected and the crowns were sectioned perpendicular to the long axis in order to obtain dentin slices to be bonded with one of the following adhesives: Syntac/Heliobond (Ivoclar-Vivadent) or Adper-Scotchbond-1XT (3M-ESPE). The adhesives were cured by using a LED-unit (Bluephase(r), Ivoclar Vivadent) with three different curing times (10 s, 20 s and 30 s) under two ceramics (IPS-e.max-Press, Ivoclar Vivadent; IPS-Empress(r)CAD, Ivoclar-Vivadent) of different thicknesses (0 mm, 0.75 mm, 2 mm). Thirty groups were included, each containing 60 measurements. Micromechanical properties (Hardness, HV; indentation modulus, E; and creep, Cr) of the adhesives were measured with an automatic microhardness indenter (Fisherscope H100C, Germany). Data were statistically analyzed by using one-way ANOVA and Tukey's post-hoc test, as well as a multivariate analysis to test the influence of the study parameters (SPSS 18.0). RESULTS: Significant differences were observed between the micromechanical properties of the adhesives (p < 0.05). The ceramic type showed the highest effect on HV (Partial-eta squared (eta(2)) = 0.109) of the tested adhesives, while E (eta(2) = 0.275) and Cr (eta(2) = 0.194) were stronger influenced by the adhesive type. Ceramic thickness showed no effect on the E and Cr of the adhesives. CONCLUSIONS: The adhesive bonding agents used in this study performed well by curing through different thicknesses of ceramics. The micromechanical properties of the adhesives were determined by the adhesive type and were less influenced by ceramic type and curing time. PMID- 24490642 TI - Preparation and properties of calcium-silicate filled resins for dental restoration. Part II: Micro-mechanical behaviour to primed mineral-depleted dentine. AB - OBJECTIVE: Evaluating microtensile bond strength (MUTBS) and Knoop micro-hardness (KHN) of resin bonded-dentine interfaces created with two methacrylate-based systems either incorporating Bioglass 45S5 (3-E&RA/BG) or MTA (3-E&RA/WMTA). MATERIALS AND METHODS: Solvated resins (50% ethanol/50% co-monomers) were used as primers while their neat counterparts were filled with the two calcium-silicate compounds. Application of neat resin adhesive with no filler served as control (3 E&RA). MUTBS, KHN analysis and confocal tandem scanning microscopy (TSM) micropermeability were carried out after 24 h and 10 months of storage in phosphate buffer solution (DPBS). Scanning electron microscopy (SEM) was also performed after debonding. RESULTS: High MUTBS values were achieved in all groups after 24 h of DPBS storage. On the contrary, solely the specimens created using 3 E&RA/BG and 3-E&RA/WMTA agents showed no significant reduction in terms of MUTBS even after 10 months in DPBS; similarly, they did not restore the average superficial micro-hardness to the level of sound dentine, but maintained unchanged KHN values, and no statistical decrease was found following 10 months of DPBS storage. The only statistically significant changes occurred in the resin dentine interfaces bonded with 3-E&RA that were subjected to a reduction of both MUTBS and KHN values with ageing. In terms of micropermeability, adverse results were obtained with 3-E&RA while 3-E&RA/BG and 3-E&RA/WMTA demonstrated a beneficial effect after prolonged DPBS storage. CONCLUSION: Calcium-silicate filled composite resins performed better than a current etch-and-rinse adhesive and had a therapeutic/protective effect on the micro-mechanical properties of mineral-depleted resin-dentine interfaces. CLINICAL SIGNIFICANCE: The incorporation of calcium-silicates into dental restorative and bonding agents can create more biomimetic (life-like) restorations. This will not only enable these materials to mimic the physical characteristics of the tooth structure, but will also stabilize and protect the remaining dental hard tissues. PMID- 24490643 TI - Left ventricular diastolic function evaluated by the E/e' ratio is impaired in patients with masked uncontrolled hypertension. AB - BACKGROUND: Masked uncontrolled hypertension (MUH), defined as controlled office blood pressure (BP) but uncontrolled out-of-office BP in treated hypertensives, is a risk factor for cardiovascular disease. We tested the hypothesis that MUH is associated with a greater degree of diastolic dysfunction than controlled hypertension (CH) or uncontrolled hypertension (UH). METHODS AND RESULTS: We studied 299 treated patients who had at least one cardiovascular risk factor (age, 63 +/- 10 years; male sex, 43%), consisting of 94 (31.4%) patients with UH, 46 (15.4%) with MUH, 56 (18.7%) with treated white-coat hypertension (WCH), and 103 (34.4%) with CH. We performed office and home BP monitoring, electrocardiography, echocardiography and blood tests. Diastolic dysfunction was defined as an E-wave to e'-wave (E/e') ratio >=8 measured by Doppler echocardiography. The value of E/e' was higher in the MUH (8.3 +/- 2.7) and UH (8.3 +/- 2.7) groups than in the CH group (7.3 +/- 2.3; p = 0.08, p = 0.02, respectively). In multivariable analysis, MUH was associated with a significantly higher likelihood of diastolic dysfunction than CH (odds ratio 2.90 versus CH, p < 0.01) after adjusting for significant covariates. CONCLUSIONS: MUH and UH were associated with a greater degree of diastolic dysfunction than CH. Even in treated patients, out-of-office BP is important to stratify the risk of cardiovascular disease. PMID- 24490644 TI - Irrational health beliefs predict adherence to cardiac rehabilitation: a pilot study. AB - OBJECTIVE: Cardiac rehabilitation (CR) is routinely prescribed for patients with cardiovascular disease (CVD), but data indicate that 20% to 50% of patients do not adhere to CR. Studies have focused on the impact of depression on CR adherence, but results have been equivocal. Irrational health beliefs are related to adherence among diabetes patients, but have not been examined among cardiac patients. This study examined depression and irrational health beliefs as predictors of CR adherence. METHOD: Sixty-one participants (30% female; mean age = 59.9 +/- 11.8; 72% Caucasian), recruited at the outset of an outpatient CR program, completed a baseline questionnaire including measures of depression and irrational health beliefs. CR adherence was defined as the percentage of CR exercise sessions completed. Pearson correlations and analysis of variance determined demographic factors related to adherence. Hierarchical regression analyses examined irrational health beliefs and depression as predictors of CR adherence. RESULTS: Older age (p < .05) and higher income (p < .05) were associated with better CR adherence, but CR adherence was lower among African Americans than Caucasians (p < .01). Depression was not related to adherence (p = .78), but irrational health beliefs predicted CR adherence, after controlling for race/ethnicity, income, and age (beta = -.290, DeltaR2 = .074, DeltaF[1,55] = 5.50, p < .05). CONCLUSIONS: Irrational health beliefs predicted CR adherence but depression did not. Thus, poorer adherence to CR was associated with endorsing beliefs that are not based in medical evidence. PMID- 24490645 TI - Social contagion of vasovagal reactions in the blood collection clinic: a possible example of mass psychogenic illness. AB - OBJECTIVE: Observing or hearing about illness in another person can lead to reports of similar symptoms. Reports can occasionally be widespread. However, it has been difficult to document whether this is the result of genuine illness or the expression of anxiety with physical terminology. This study examined the effects of being able to see another blood donor experience vasovagal symptoms. METHODS: Data were collected in mobile university blood collection clinics. Bedside research assistants coded whether the donor was able or not able to see another donor being treated for vasovagal symptoms. Dependent variables included subjective vasovagal symptoms indicated on the Blood Donation Reactions Inventory (BDRI) and the need for treatment oneself. Given the population of inexperienced donors, many (26% of the 1,209 participants) were able to see another donor treated for symptoms. RESULTS: Being able to see another donor treated was associated with higher scores on the BDRI and an increased likelihood of treatment for vasovagal symptoms oneself. However, this was limited to non-first time blood donors, perhaps because of higher levels in first-time donors (ceiling effects) or greater attention to the environment in less "overwhelmed" repeat donors. In general, donors who were able to see another react rated themselves as less relaxed and had smaller increases in heart rate. During the 2-year follow up, first-time donors who were able to see another react were slower to return to give blood again. CONCLUSIONS: Seeing another donor being treated for symptoms contributed to the vasovagal process in many donors. This environment provides a useful context to study social influences on symptoms and illness. PMID- 24490646 TI - Perceived control reduces mortality risk at low, not high, education levels. AB - OBJECTIVE: Both higher levels of educational attainment and a strong sense of control over one's life independently predict better health and longevity. Evidence also suggests that these 2 factors may combine in multiplicative ways to influence subjective reports of health. METHOD: In the Midlife in the United States (MIDUS) national sample (N = 6,135; age = 25 to 75 years), we tested whether stronger beliefs of control over one's life would moderate the effect of education on 14-year mortality risk. RESULTS: Proportional hazards modeling indicated that both current levels of education and control beliefs were associated with lower risk of dying, over and above childhood socioeconomic level. In addition, there was a significant interaction between education and control beliefs. Among those low in education, higher control beliefs were associated with a decreased mortality risk. However, at greater levels of education, control beliefs were not associated with mortality risk. This effect remained after adjusting for potential confounding variables, including health behaviors, depressed affect, and general health (chronic illnesses, functional limitations, and self-rated health). CONCLUSIONS: These findings demonstrate the importance of individual perceptions of control in buffering the mortality risk associated with educational disadvantage. PMID- 24490647 TI - The influence of social adjustment on normative and risky health behaviors in emerging adults with spina bifida. AB - OBJECTIVE: To understand the rates of normative and risky health behaviors and the influence of prior and current social adjustment on health risk behaviors in emerging adults with spina bifida (SB). METHOD: These data are part of a larger longitudinal study of youth with SB; at ages 18-19, 50 emerging adults with SB and 60 typically developing (TD) youth participated. Social adjustment was measured at ages 12/13, 14/15, 16/17, and 18/19. Substance use and sexual activity were self-reported by emerging adults. RESULTS: The SB group reported similar frequencies (i.e., number of days in the previous month) of cigarette and marijuana use. Fewer individuals with SB reported initiation of both alcohol use (i.e., ever used) and sexual activity (i.e., ever had sex) compared to TD peers. The SB group also reported less frequent alcohol use and fewer sexual partners. Better social adjustment during early adolescence (ages 12/13) predicted more frequent alcohol use and a greater number of sexual partners for all youth. Social adjustment also mediated the effect of group status on health risk behaviors. CONCLUSIONS: Emerging adults with SB lag behind TD peers in terms of normative initiation of alcohol use and sexual activity. However, this population participates in some risky health behaviors at similar rates compared to their TD peers (e.g., smoking). Youths' health risk behaviors may be influenced by their level of social adjustment. A challenge for future interventions for this population will be finding methods of improving social functioning without increasing the rate of health risk behavior. PMID- 24490649 TI - Salinity affects compositional traits of epibacterial communities on the brown macroalga Fucus vesiculosus. AB - Epibiotic biofilms have the potential to control major aspects of the biology and ecology of their hosts. Their composition and function may thus be essential for the health of the host. We tested the influence of salinity on the composition of epibacterial communities associated with the brown macroalga Fucus vesiculosus. Algal individuals were incubated at three salinities (5, 19, and 25) for 14 days and nonliving reference substrata (stones) were included in the experiment. Subsequently, the composition of their surface-associated bacterial communities was analyzed by 454 pyrosequencing of 16S rRNA gene sequences. Redundancy analysis revealed that the composition of epiphytic and epilithic communities significantly differed and were both affected by salinity. We found that 5% of 2494 epiphytic operational taxonomic units at 97% sequence similarity were responsible for the observed shifts. Epibacterial alpha-diversity was significantly lower at salinity 5 but did not differ between substrata. Our results indicate that salinity is an important factor in structuring alga associated epibacterial communities with respect to composition and/or diversity. Whether direct or indirect mechanisms (via altered biotic interactions) may have been responsible for the observed shifts is discussed. PMID- 24490648 TI - Combining self-affirmation with implementation intentions to promote fruit and vegetable consumption. AB - OBJECTIVE: The current study tested whether self-affirmation in the context of a threatening health message helps promote a health behavior (fruit and vegetable consumption) over a 3-month period, and whether adding a manipulation to support the translation of intentions into behavior (an implementation intentions induction) enhances the impact of self-affirmation. METHODS: Participants (N = 332, 71% women) reported their baseline consumption and were randomly assigned to condition in a 2 (self-affirmation: yes, no) * 2 (implementation intentions: formed, not formed) between-subjects factorial design. They completed a self affirmation/control task and then read a health communication advising eating at least 5 portions of fruit and vegetables daily. Next participants reported intentions for behavior change, after which they formed/did not form relevant implementation intentions. Consumption was measured again 7 days and 3 months postintervention. RESULTS: Self-affirmed (vs. nonaffirmed) participants reported eating more fruit and vegetables at both follow-ups. Forming (vs. not forming) implementation intentions was also beneficial for consumption. At 7 days, there was also a significant self-affirmation * implementation intentions interaction: consumption was highest when self-affirmed participants also formed implementation intentions. CONCLUSIONS: The present study offers new evidence concerning the impact and durability of self-affirmation on health behaviors and the role of implementation intentions in enhancing the impact of self affirmation. PMID- 24490650 TI - Ultrafast charge- and energy-transfer dynamics in conjugated polymer: cadmium selenide nanocrystal blends. AB - Hybrid nanocrystal-polymer systems are promising candidates for photovoltaic applications, but the processes controlling charge generation are poorly understood. Here, we disentangle the energy- and charge-transfer processes occurring in a model system based on blends of cadmium selenide nanocrystals (CdSe-NC) with poly[2-methoxy-5-(3',7'-dimethyloctyloxy)-1,4-phenylene vinylene] (MDMO-PPV) using a combination of time-resolved absorption and luminescence measurements. The use of different capping ligands (n-butylamine, oleic acid) as well as thermal annealing allows tuning of the polymer-nanocrystal interaction. We demonstrate that energy transfer from MDMO-PPV to CdSe-NCs is the dominant exciton quenching mechanism in nonannealed blends and occurs on ultrafast time scales (<1 ps). Upon thermal annealing electron transfer becomes competitive with energy transfer, with a transfer rate of 800 fs independent of the choice of the ligand. Interestingly, we find hole transfer to be much less efficient than electron transfer and to extend over several nanoseconds. Our results emphasize the importance of tuning the organic-nanocrystal interaction to achieve efficient charge separation and highlight the unfavorable hole-transfer dynamics in these blends. PMID- 24490652 TI - Branching out from the bisabolyl cation. Unifying mechanistic pathways to barbatene, bazzanene, chamigrene, chamipinene, cumacrene, cuprenene, dunniene, isobazzanene, iso-gamma-bisabolene, isochamigrene, laurene, microbiotene, sesquithujene, sesquisabinene, thujopsene, trichodiene, and widdradiene sesquiterpenes. AB - Quantum chemical calculations on the transformation of the bisabolyl cation into an array of sesquiterpenes (iso-gamma-bisabolene, trichodiene, cuprenene, laurene, isochamigrene, chamigrene, chamipinene, sesquithujene, sesquisabinene, microbiotene, dunniene, cumacrene, isobazzanene, bazzanene, barbatene, widdradiene, and thujopsene) are described. The bisabolyl cation is the hub of a complicated web of carbocations involved in the construction of diverse and complex molecular architectures present in a large number of Nature's sesquiterpenoids. The results of quantum chemical calculations on the multitude of rearrangements described herein provide reasonable answers to several persistent mechanistic questions in the world of terpene biosynthesis and also provide examples of general reactivity principles for terpene-forming (and other) carbocation rearrangements. PMID- 24490651 TI - Gut microbiome phenotypes driven by host genetics affect arsenic metabolism. AB - Large individual differences in susceptibility to arsenic-induced diseases are well-documented and frequently associated with different patterns of arsenic metabolism. In this context, the role of the gut microbiome in directly metabolizing arsenic and triggering systemic responses in diverse organs raises the possibility that gut microbiome phenotypes affect the spectrum of metabolized arsenic species. However, it remains unclear how host genetics and the gut microbiome interact to affect the biotransformation of arsenic. Using an integrated approach combining 16S rRNA gene sequencing and HPLC-ICP-MS arsenic speciation, we demonstrate that IL-10 gene knockout leads to a significant taxonomic change of the gut microbiome, which in turn substantially affects arsenic metabolism. PMID- 24490653 TI - Celiac disease: the search for adjunctive or alternative therapies. AB - Celiac disease is a widespread disorder caused by intolerance to gluten, a common protein in food. Currently, a life-long gluten-free diet is the only available treatment for patients with celiac disease. However, adherence to gluten-free diet is difficult due to the widespread use of wheat-derived gluten in the food industry. Therefore, there is a pressing need for the development of novel non dietary therapies. In this article, we will review several promising strategies focusing on reducing gluten immunogenicity or sequestering to gluten prevent its uptake by the intestinal epithelium. Other possible treatment strategies that will be reviewed include the suppression of the adaptive immune response, permeability modulation and the use of systemic T-cell or cytokine blockers. PMID- 24490654 TI - Design and discovery of soluble epoxide hydrolase inhibitors for the treatment of cardiovascular diseases. AB - INTRODUCTION: Cardiovascular diseases are a leading cause of death in developed countries. Increasing evidence shows that the alteration in the normal functions of the vascular endothelium plays a major role in the development of cardiovascular diseases. However, specific agents designed to prevent endothelial dysfunction and related cardiovascular complications are still lacking. One emerging strategy is to increase the bioavailability of epoxyeicosatrienoic acids (EETs), synthesized by cytochrome P450 epoxygenases from arachidonic acid. EETs are endothelium-derived hyperpolarising and relaxing factors and display attractive anti-inflammatory and metabolic properties. Genetic polymorphism studies in humans, and experiments in animal models of diseases, have identified soluble epoxide hydrolase (sEH), the major enzyme involved in EET degradation, as a potential pharmacological target. AREAS COVERED: This review presents EET pathway and its functions and summarises the data supporting the development of sEH inhibitors for the treatment of cardiovascular and metabolic diseases. Furthermore, the authors present the different chemical families of sEH inhibitors developed and their effects in animal models of cardiovascular and metabolic diseases. EXPERT OPINION: Several generations of sEH inhibitors have now been designed to treat endothelial dysfunction and cardiovascular complications for a variety of diseases. The safety of these drugs remains to be carefully investigated, particularly in relation to carcinogenesis. The increasing knowledge of the biological role of each of the EET isomers and of their metabolites may improve their pharmacological profile. This, in turn, could potentially lead to the identification of new pharmacological agents that achieve the cellular effects needed without the deleterious side effects. PMID- 24490655 TI - Comparison of the interfacial activity between homogeneous and Janus gold nanoparticles by pendant drop tensiometry. AB - The interfacial activity of 3.5 nm homogeneous (HPs) and amphiphilic Janus gold nanoparticles (JPs) was characterized by pendant drop tensiometry for water/air and water/decane interfaces. This technique requires a smaller quantity of nanoparticles than the traditional Langmuir balance technique. The direct deposition at the interface of the nanoparticles dispersed in a spreading solvent also requires smaller quantities of sample than does adsorption from the bulk. From the growing and shrinking of the pendant drops, the interfacial activity of the nanoparticles can be evaluated and compared within a wide range of area per particle. In this work, the JPs exhibited a higher interfacial activity than did the HPs in all cases. A hard disk model fits the piecewise compression isotherm of the HPs, yet this model underestimates the interactions between the JPs adsorbed at the interface. PMID- 24490656 TI - Identification and characterization of locus-specific methylation patterns within novel loci undergoing hypermethylation during breast cancer pathogenesis. AB - INTRODUCTION: Despite similar clinical and pathological features, large numbers of breast cancer patients experience different outcomes of the disease. This, together with the fact that the incidence of breast cancer is growing worldwide, emphasizes an urgent need for identification of new biomarkers for early cancer detection and stratification of patients. METHODS: We used ultrahigh-resolution microarrays to compare genomewide methylation patterns of breast carcinomas (n = 20) and nonmalignant breast tissue (n = 5). Biomarker properties of a subset of discovered differentially methylated regions (DMRs) were validated using methylation-sensitive high-resolution melting (MS-HRM) in a case-control study on a panel of breast carcinomas (n = 275) and non-malignant controls (n = 74). RESULTS: On the basis of microarray results, we selected 19 DMRs for large-scale screening of cases and controls. Analysis of the screening results showed that all DMRs tested displayed significant gains of methylation in the cancer tissue compared to the levels in control tissue. Interestingly, we observed two types of locus-specific methylation, with loci undergoing either predominantly full or heterogeneous methylation during carcinogenesis. Almost all tested DMRs (17 of 19) displayed low-level methylation in nonmalignant breast tissue, independently of locus-specific methylation patterns in cases. CONCLUSIONS: Specific loci can undergo either heterogeneous or full methylation during carcinogenesis, and loci hypermethylated in cancer frequently show low-level methylation in nonmalignant tissue. PMID- 24490658 TI - A palladium-catalyzed methylenation of olefins using halomethylboronate reagents. AB - Methylenation of electron-rich olefins is a highly challenging reaction, for which we have developed a new methodology exploiting Pd-catalysis and halomethylboronate reagents, the latter replacing diazomethane and zinc carbenoids as methylene donors. Optimization of the reaction for norbornene and extension to several other olefins are reported, with reasonable-to-excellent yields of cyclopropanes in combination with beta-H elimination products. Several mechanisms are plausible for this methylenation reaction. PMID- 24490657 TI - Isoquercitrin activates the AMP-activated protein kinase (AMPK) signal pathway in rat H4IIE cells. AB - BACKGROUND: Isoquercitrin, a flavonoid compound that is widely distributed in medicinal and dietary plants, possesses many biological activities, including inhibition of adipocyte differentiation. In this study, we investigated the effect of isoquercitrin on lipid accumulation and its molecular mechanisms in rat hepatoma H4IIE cells. METHODS: To investigate the effect of isoquercitrin on lipid accumulation, H4IIE cells were induced by FFA and the total lipid levels were detected by Oil Red O staining. Furthermore, The protein levels of AMPK and acetyl-CoA carboxylase (ACC), the gene expressions of transcriptional factor, lipogenic genes, and adiponectin receptor 1 (AdipoR1) were analyzed by Western blotting and quantitative real-time PCR. To further confirm the pathway of isoquercitrin-mediated hepatic lipid metabolism, H4IIE cells were treated with an AMPK inhibitor and AdipoR1 siRNA. RESULTS: Isoquercitrin significantly enhances AMPK phosphorylation, downregulates sterol regulatory element binding protein transcription factor 1 (SREBP-1) and fatty acid synthase (FAS) gene expressions. Pretreatment with AMPK inhibitor, significantly decreased the AMPK phosphorylation and increased FAS expression stimulated by isoquercitrin. Isoquercitrin might also upregulate the expression of AdipoR1 dose-dependently via AMPK in the presence of an AMPK inhibitor and AdipoR1 siRNA. CONCLUSIONS: Isoquercitrin appears to regulate AMPK activation, thereby enhancing AdipoR1 expression, suppressing SREBP-1 and FAS expressions, and resulting in the regulation of lipid accumulation. These results suggest that isoquercitrin is a novel dietary compound that can be potentially be used to prevent lipid metabolic disorder and nonalcoholic fatty liver disease. PMID- 24490660 TI - Aldehydes and ketones formation: copper-catalyzed aerobic oxidative decarboxylation of phenylacetic acids and alpha-hydroxyphenylacetic acids. AB - Aromatic aldehydes or ketones from copper catalyzed aerobic oxidative decarboxylation of phenylacetic acids and alpha-hydroxyphenylacetic acids have been synthesized. This reaction combined decarboxylation, dioxygen activation, and C-H bond oxidation steps in a one-pot protocol with molecular oxygen as the sole terminal oxidant. This reaction represents a novel decarboxylation of an sp(3)-hybridized carbon and the use of a benzylic carboxylic acid as a source of carbonyl compounds. PMID- 24490659 TI - Organizing person-centred care in paediatric diabetes: multidisciplinary teams, long-term relationships and adequate documentation. AB - BACKGROUND: Type 1 diabetes is one of the most frequent long-term endocrine childhood disorders and the Swedish National Diabetes Register for children states that adolescents (12-18 years) constitute the most vulnerable patient group in terms of metabolic control. The aim of this study was to examine how a multidisciplinary team functions when caring for adolescents with type 1 diabetes. METHODS: Qualitative interviews were performed with 17 health professionals at a Paediatric Diabetes Care Unit in a Swedish university hospital. The interviews were analysed to gain insight into a multidisciplinary care team's experiences of various organizational processes and circumstances related to the provision of person-centred paediatric diabetes care. RESULTS: Building long-term relationships with adolescents, the establishment of a multidisciplinary care team and ensuring adequate documentation are vital for the delivery of person-centred care (PCC). Furthermore, a PCC process and/or practice requires more than the mere expression of person-centred values. The contribution of this study is that it highlights the necessity of facilitating and safeguarding the organization of PCC, for which three processes are central: 1. Facilitating long-term relationships with adolescents and their families; 2. Facilitating multi-professional teamwork; and 3. Ensuring adequate documentation. CONCLUSION: Three processes emerged as important for the functioning of the multidisciplinary team when caring for adolescents with type 1 diabetes: building a long-term relationship, integrating knowledge by means of multidisciplinary team work and ensuring adequate documentation. This study demonstrates the importance of clearly defining and making use of the specific role of each team member in the paediatric diabetes care unit (PDCU). Team members should receive training in PCC and a PCC approach should form the foundation of all diabetes care. Every adolescent suffering from type 1 diabetes should be offered individual treatment and support according to her/his needs. However, more research is required to determine how a PCC approach can be integrated into adolescent diabetes care, and especially how PCC education programmes for team members should be implemented. PMID- 24490661 TI - Editorial for the virtual issue on quantum molecular magnets. PMID- 24490662 TI - Ligand effects on the oxidative addition of halogens to (dpp-nacnac(R))Rh(phdi). AB - The treatment of (dpp-nacnac(R))Rh(phdi) {(dpp-nacnac(R))(-) = CH[C(R)(N (i)Pr2C6H3)]2(-); R = CH3, CF3; phdi = 9,10-phenanthrenediimine} with X2 oxidants afforded octahedral rhodium(III) products in the case of X = Cl and Br. The octahedral complexes exhibit well-behaved cyclic voltammograms in which a two electron reduction is observed to regenerate the initial rhodium(I) complex. When treated with I2, (dpp-nacnac(CH3))Rh(phdi) produced a square pyramidal eta(1)-I2 complex, which was characterized by NMR and UV-vis spectroscopies, mass spectrometry, and X-ray crystallography. The more electron poor complex (dpp nacnac(CF3))Rh(phdi) reacted with I2 to give a mixture of two products that were identified by (1)H NMR spectroscopy as a square pyramidal eta(1)-I2 complex and an octahedral diiodide complex. Reaction of the square pyramidal (dpp nacnac(CH3))Rh(I2)(phdi) with HBF4 resulted in protonation of the (dpp nacnac(CH3))(-) backbone to provide an octahedral rhodium(III) diiodide species. These reactions highlight the impact that changes in the electron-withdrawing nature of the supporting ligands can have on the reactivity at the metal center. PMID- 24490663 TI - Risk factors for death from pandemic influenza in 1918-1919: a case-control study. AB - BACKGROUND: Despite the persisting threat from future influenza pandemics, much is still unknown about the risk factors for death from such events, and especially for the 1918-1919 influenza pandemic. METHODS: A case-control study was performed to explore possible risk factors for death from pandemic influenza among New Zealand military personnel in the Northern Hemisphere in 1918-1919 (n = 218 cases, n = 221 controls). Data were compiled from a Roll-of-Honour dataset, a dataset of nearly all military personnel involved in the war and archived individual records. RESULTS: In the fully adjusted multivariable model, the following were significantly associated with increased risk of death from pandemic influenza: age (25-29 years), pre-pandemic hospitalisations for a chronic condition (e.g. tuberculosis), relatively early year of military deployment, a relatively short time from enlistment to foreign service, and having a larger chest size (e.g. adjusted odds ratio for 90-99 cm versus <90 cm was 2.45; 95% CI=1.47-4.10). There were no significant associations in the fully adjusted model with military rank, occupational class at enlistment, and rurality at enlistment. CONCLUSIONS: This is one of the first published case-control studies of mortality risk factors for the 1918-1919 influenza pandemic. Some of the findings are consistent with previous research on risk factors (such as chronic conditions and age groups), but others appear more novel (e.g., larger chest size). As all such historical analyses have limitations, there is a need for additional studies in other settings as archival World War One records become digitalised. PMID- 24490664 TI - 2.45-GHz microwave irradiation adversely affects reproductive function in male mouse, Mus musculus by inducing oxidative and nitrosative stress. AB - Electromagnetic radiations are reported to produce long-term and short-term biological effects, which are of great concern to human health due to increasing use of devices emitting EMR especially microwave (MW) radiation in our daily life. In view of the unavoidable use of MW emitting devices (microwaves oven, mobile phones, Wi-Fi, etc.) and their harmful effects on biological system, it was thought worthwhile to investigate the long-term effects of low-level MW irradiation on the reproductive function of male Swiss strain mice and its mechanism of action. Twelve-week-old mice were exposed to non-thermal low-level 2.45-GHz MW radiation (CW for 2 h/day for 30 days, power density = 0.029812 mW/cm(2) and SAR = 0.018 W/Kg). Sperm count and sperm viability test were done as well as vital organs were processed to study different stress parameters. Plasma was used for testosterone and testis for 3beta HSD assay. Immunohistochemistry of 3beta HSD and nitric oxide synthase (i-NOS) was also performed in testis. We observed that MW irradiation induced a significant decrease in sperm count and sperm viability along with the decrease in seminiferous tubule diameter and degeneration of seminiferous tubules. Reduction in testicular 3beta HSD activity and plasma testosterone levels was also noted in the exposed group of mice. Increased expression of testicular i-NOS was observed in the MW-irradiated group of mice. Further, these adverse reproductive effects suggest that chronic exposure to nonionizing MW radiation may lead to infertility via free radical species-mediated pathway. PMID- 24490665 TI - Magnetism in single metalloorganic complexes formed by atom manipulation. AB - The magnetic properties of molecular structures can be tailored by chemical synthesis or bottom-up assembly at the atomic scale. We used scanning tunneling microscopy to study charge and spin transfer in individual complexes of transition metals with the charge acceptor, tetracyanoethylene (TCNE). The complexes were formed on a thin insulator, Cu2N on Cu(100), by manipulation of individual atoms and molecules. The Cu2N layer decouples the complexes from Cu electron density, enabling direct imaging of the TCNE molecular orbitals as well as spin-flip inelastic electron tunneling spectroscopy. Results were obtained at low temperature down to 1 K and in magnetic fields up to 7 T in order to resolve splitting of spin states in the complexes. We also performed spin-polarized density functional theory calculations to compare with the experimental data. Our results indicate that charge transfer to TCNE leads to a change in spin magnitude, Kondo resonance, and magnetic anisotropy for the metal atoms. PMID- 24490666 TI - Fungal succession in an in-vessel composting system characterized using 454 pyrosequencing. AB - Fungi are known to have an important role in the composting process as degraders of recalcitrant materials such as cellulose and lignin. Previous attempts to study the diversity and succession of fungi in compost systems have relied on the use of culture-dependent analyses and low-resolution DNA-fingerprinting techniques, lacking the necessary depth to analyse such a rich ecosystem. In this study, 454 pyrosequencing was used to characterize the fungal community composition at the different stages of an in-vessel composting process. A complex succession of fungi was revealed, with 251 fungal OTUs identified throughout the monitoring period. The Ascomycota were the dominant phylum (82.5% of all sequences recovered), followed by the Basidiomycota (10.4%) and the subphylum Mucoromycotina (4.9%). In the starting materials and early stages of the process, yeast species from the Saccharomycetales were abundant, while in latter stages and in the high temperature regions of the pile, fungi from the orders Eurotiales, Sordariales, Mucorales, Agaricales and Microascales were the most prominent. This study provides an improved understanding of the fungal diversity occurring during the composting of municipal solid waste, and this knowledge can lead to the development of more efficient composting practices and a better evaluation of the end-product quality. PMID- 24490667 TI - Ultrafast synthesis of yolk-shell and cubic NiO Nanopowders and application in lithium ion batteries. AB - A continuous one-pot method was employed to synthesize yolk-shell and single crystalline cubic NiO powders in a few seconds. Submicrometer-sized NiO yolk shell particles were prepared by spray pyrolysis at 900 degrees C. Single crystalline cubic NiO nanopowders were prepared by one-pot flame spray pyrolysis from NiO vapors. Particle surface areas of the yolk-shell and single-crystalline cubic NiO powders as obtained using the Brunauer-Emmett-Teller method were 8 and 5 m(2) g(-1), respectively. The mean crystallite sizes of the yolk-shell structured and cubic NiO powders were 50 and 80 nm, respectively. The yolk-shell and single-crystalline cubic NiO powders delivered discharge capacities of 951 and 416 mA h g(-1), respectively, after 150 cycles, and the corresponding capacity retentions measured after the first cycle were 106 and 66%, respectively. The yolk-shell-structured NiO powders showed rate performance better than that of the single-crystalline cubic NiO nanopowders. Even at a high current density of 1 A g(-1), the discharge capacity of the yolk-shell-structured NiO powders was as high as 824 mA h g(-1) after 50 cycles, in which the current densities were increased stepwise. PMID- 24490668 TI - Continuing excellence for chemical research in toxicology. PMID- 24490671 TI - Chronic diuretic therapy attenuates renal BOLD magnetic resonance response to an acute furosemide stimulus. AB - BACKGROUND: Blood Oxygen Level Dependent (BOLD) magnetic resonance (MR) is a novel imaging tool that detects changes in tissue oxygenation. Increases in renal oxygenation in response to a standard 20 mg intravenous furosemide stimulus have been evaluated to assess kidney viability in patients with renal artery stenosis (RAS). The effect of prior exposure to furosemide on the ability of BOLD MR techniques to evaluate renal function is unknown.This study tested the hypothesis that chronic loop diuretic therapy is associated with attenuated responses in renal tissue oxygenation as measured by BOLD MR with an acute 20 mg intravenous furosemide stimulus in participants undergoing evaluation for RAS. METHODS: Thirty-eight participants referred for evaluation of RAS were recruited for this study. We examined renal cortical and medullary BOLD signal (T2*) intensities before and after a 20 mg intravenous furosemide stimulus. Additionally, we measured changes in renal artery blood flow using phase contrast techniques. RESULTS: After controlling for covariates age, race, gender, diabetes, glomerular filtration rate, body mass index, and stenosis severity, daily oral furosemide dose was an independent, negative predictor of renal medullary T2* response (p=0.01) to a standard 20 mg intravenous furosemide stimulus. Stenosis severity and ethnicity were also significant independent predictors of changes in T2* signal intensity in response to an acute furosemide challenge. Changes in renal blood flow in response to acute furosemide administration were correlated with changes in T2* in the renal cortex (r=0.29, p=0.03) but not the medulla suggesting changes in renal medullary oxygenation were not due to reduced renal medullary blood flow. CONCLUSIONS: Chronic furosemide therapy attenuates BOLD MR responses to an acute furosemide stimulus in patients with RAS being evaluated for renal artery revascularization procedures. Thus, patients who are chronically administered loop diuretics may need a different dosing strategy to accurately detect changes in renal oxygenation with BOLD MR in response to a furosemide stimulus. PMID- 24490672 TI - Status of drug development for the prevention and treatment of osteoporosis. AB - INTRODUCTION: The metabolic bone disease osteoporosis is a growing health and health-economic problem worldwide. Bisphosphonates are the most widely used antiresorptive medication and the de facto gold standard in fracture prophylaxis all over the world, in conjunction with calcium and vitamin D supplementation. Several new medications for the treatment of postmenopausal osteoporosis are in the pipeline. AREAS COVERED: The authors present the most recent studies on new and current antiresorptive as well as anabolic drugs. Specifically, the authors present the current knowledge on drugs directed against cathepsin K and sclerostin as well as the new pathways of interest from preclinical studies. EXPERT OPINION: New scientific results have identified novel signaling pathways as potential targets for future development of anti-osteoporotic drugs. The treatments close to marketing at the moment are odanacatib and romosozumab and these are both promising new medications based on bone mineral density results, safety profile and administration. Theoretically, romosozumab may hold the potential to be a drug to 'cure' even advanced stages of osteoporosis with short term treatment. However, safety, fracture data and cost are key elements that will determine the extent of use. PMID- 24490673 TI - Estimating time-to-onset of adverse drug reactions from spontaneous reporting databases. AB - BACKGROUND: Analyzing time-to-onset of adverse drug reactions from treatment exposure contributes to meeting pharmacovigilance objectives, i.e. identification and prevention. Post-marketing data are available from reporting systems. Times to-onset from such databases are right-truncated because some patients who were exposed to the drug and who will eventually develop the adverse drug reaction may do it after the time of analysis and thus are not included in the data. Acknowledgment of the developments adapted to right-truncated data is not widespread and these methods have never been used in pharmacovigilance. We assess the use of appropriate methods as well as the consequences of not taking right truncation into account (naive approach) on parametric maximum likelihood estimation of time-to-onset distribution. METHODS: Both approaches, naive or taking right truncation into account, were compared with a simulation study. We used twelve scenarios for the exponential distribution and twenty-four for the Weibull and log-logistic distributions. These scenarios are defined by a set of parameters: the parameters of the time-to-onset distribution, the probability of this distribution falling within an observable values interval and the sample size. An application to reported lymphoma after anti TNF- alpha treatment from the French pharmacovigilance is presented. RESULTS: The simulation study shows that the bias and the mean squared error might in some instances be unacceptably large when right truncation is not considered while the truncation-based estimator shows always better and often satisfactory performances and the gap may be large. For the real dataset, the estimated expected time-to-onset leads to a minimum difference of 58 weeks between both approaches, which is not negligible. This difference is obtained for the Weibull model, under which the estimated probability of this distribution falling within an observable values interval is not far from 1. CONCLUSIONS: It is necessary to take right truncation into account for estimating time-to-onset of adverse drug reactions from spontaneous reporting databases. PMID- 24490674 TI - Corticosterone-activated mineralocorticoid receptor contributes to salt-induced sympathoexcitation in pressure overload mice. AB - Abstract We previously reported that pressure overload (PO) activates the hypothalamic mineralocorticoid receptor (MR) and angiotensin II type 1 receptor (AT1R). Moreover, salt intake further activates the hypothalamic MR and AT1R, resulting in salt-induced sympathoexcitation. However, the mechanism underlying this pathway activation in response to a high salt intake remains unknown. Although the role of aldosterone is extensively examined as a ligand for MR, corticosterone is able to bind to MR. Therefore, we hypothesized that corticosterone contributes to salt-induced sympathoexcitation in PO-mice. Four weeks after aortic banding to produce PO-mice, or a sham operation for controls, the mice were fed a high-salt diet for an additional 4 weeks. Compared to Sham mice, the expression levels of hypothalamic MR, serum glucocorticoid-induced kinase 1 (a marker of MR activity) and AT1R increased in PO-mice. Salt intake further increased the expression levels of these proteins only in PO-mice with the increases in sympathetic activity evaluated on the basis of the excretion of 24-h urinary norepinephrine excretion. Bilateral adrenalectomy or the intraperitoneal infusion of metyrapone, a corticosterone synthase inhibitor, attenuated salt-induced sympathoexcitation via inhibition of the hypothalamic MR and AT1R activity. These adrenalectomy-induced alterations disappeared after corticosterone replacement therapy. We also found decreased expression levels of 11beta-hydroxysteroid dehydrogenase type 2, suggesting that corticosterone is apt to bind to MR. These results indicate that salt intake in PO-mice causes sympathoexcitation via, at least in part, corticosterone-induced MR and AT1R activation in the hypothalamus. PMID- 24490675 TI - Editorial 2014. PMID- 24490676 TI - Syphilitic uveitis. PMID- 24490677 TI - Vitreoretinal lymphoma versus uveitis: cytokine profile and correlations. AB - PURPOSE: To compare the cytokine spectrum of vitreoretinal lymphoma to uveitis and correlate cytokine concentrations with disease activity. METHODS: Retrospective case series of 10 patients with vitreoretinal lymphoma and 7 patients with uveitis. Aqueous humor concentration of IFN-gamma, TNF-alpha, TNF beta, IL-1ra, IL-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12, IL-13, IL-17, MCP-1, G-CSF, GM-CSF, and VEGF-A was determined using a bead-based assay (Luminex). Variance between groups, correlation coefficients, and longitudinal behavior of cytokines were analyzed. RESULTS: No statistically significant difference in cytokines was found when comparing groups. IL-10 was positively correlated with IL-6 and MCP-1. IL-6 was positively correlated with G-CSF, IL 1ra, IL-8, and IL-10. A relationship between concentration of any cytokine, aside from IL-10, and disease activity was not found. CONCLUSION: IL-10 and IL-6 are good immunologic markers to be used as complementary diagnostic tools. IL-10 is the only IL that could be used for monitoring purposes. PMID- 24490678 TI - Clinically meaningful change: false positives in the estimation of individual change. AB - In applied research as well as in clinical practice, it is common to evaluate the change that patients experience as a consequence of the treatment they receive. Various methods designed to evaluate this change are reviewed in this study. This review has focused on a specific aspect that has not been given proper attention: the false positive rate. For this reason, a nonchange situation was simulated (pre-post design with no differences between pre and post) and the behavior of 8 different methods was evaluated in this scenario. Different distributions as well as different sample sizes were simulated. A thousand samples were created for each simulated condition. The percentage of times each method detected a change was obtained in order to evaluate the behavior of the selected methods. Because the simulated situation is a nonchange one, any change alert was considered as a false positive. Out of the 8 evaluated methods, the standardized individual difference and the confidence intervals of linear regression are the ones with the best performance. The remaining methods fail to correctly identify and reject sampling random fluctuations. In most cases there is a tendency to consider changes that respond only to random variations as statistically reliable. However, a simple modification related in reliability estimation allows a considerable improvement in the behavior of some methods. PMID- 24490679 TI - Do maladaptive behaviors exist at one or both ends of personality traits? AB - In the Diagnostic and Statistical Manual of Mental Disorders (5th ed.; American Psychiatric Association, 2013) personality disorder trait model, maladaptive behavior is located at one end of continuous scales. Widiger and colleagues, however, have argued that maladaptive behavior exists at both ends of trait continua. We propose that the role of evaluative variance differentiates these two perspectives and that once evaluation is isolated, maladaptive behaviors emerge at both ends of nonevaluative trait dimensions. In Study 1, we argue that evaluative variance is worthwhile to measure separately from descriptive content because it clusters items by valence regardless of content (e.g., lazy and workaholic; apathetic and anxious; gullible and paranoid; timid and hostile, etc.), which is unlikely to describe a consistent behavioral style. We isolate evaluation statistically (Study 2) and at the time of measurement (Study 3) to show that factors unrelated to valence evidence maladaptive behavior at both ends. We argue that nonevaluative factors, which display maladaptive behavior at both ends of continua, may better approximate ways in which individuals actually behave. PMID- 24490680 TI - Autism detection in early childhood (ADEC): reliability and validity data for a Level 2 screening tool for autistic disorder. AB - The Autism Detection in Early Childhood (ADEC; Young, 2007) was developed as a Level 2 clinician-administered autistic disorder (AD) screening tool that was time-efficient, suitable for children under 3 years, easy to administer, and suitable for persons with minimal training and experience with AD. A best estimate clinical Diagnostic and Statistical Manual of Mental Disorders (4th ed., text rev.; DSM-IV-TR; American Psychiatric Association, 2000) diagnosis of AD was made for 70 children using all available information and assessment results, except for the ADEC data. A screening study compared these children on the ADEC with 57 children with other developmental disorders and 64 typically developing children. Results indicated high internal consistency (alpha = .91). Interrater reliability and test-retest reliability of the ADEC were also adequate. ADEC scores reliably discriminated different diagnostic groups after controlling for nonverbal IQ and Vineland Adaptive Behavior Composite scores. Construct validity (using exploratory factor analysis) and concurrent validity using performance on the Autism Diagnostic Observation Schedule (Lord et al., 2000), the Autism Diagnostic Interview-Revised (Le Couteur, Lord, & Rutter, 2003), and DSM-IV-TR criteria were also demonstrated. Signal detection analysis identified the optimal ADEC cutoff score, with the ADEC identifying all children who had an AD (N = 70, sensitivity = 1.0) but overincluding children with other disabilities (N = 13, specificity ranging from .74 to .90). Together, the reliability and validity data indicate that the ADEC has potential to be established as a suitable and efficient screening tool for infants with AD. PMID- 24490681 TI - Examining the factor structures of the five facet mindfulness questionnaire and the self-compassion scale. AB - The five facet mindfulness questionnaire (FFMQ; Baer, Smith, Hopkins, Krietemeyer, & Toney, 2006) and the self-compassion scale (SCS; Neff, 2003) are widely used measures of mindfulness and self-compassion in mindfulness-based intervention research. The psychometric properties of the FFMQ and the SCS need to be independently replicated in community samples and relevant clinical samples to support their use. Our primary aim was to establish the factor structures of the FFMQ and SCS in individuals with recurrent depression in remission, since mindfulness-based cognitive therapy (MBCT) was developed as a treatment for preventing depressive relapse. In order to determine the consistency across populations, we examined the factor structures of the FFMQ and SCS in 3 samples: (1) a convenience sample of adults, (2) a sample of adults who practice meditation, and (3) a sample of adults who suffer from recurrent depression and were recruited to take part in a trial of MBCT. Confirmatory factor analyses (CFAs) showed that a 4-factor hierarchical model of the FFMQ best fits the community sample and the clinical sample but that a 5-factor hierarchical model of the FFMQ best fits the meditator sample. CFA did not endorse the SCS 6-factor hierarchical structure in any of the 3 samples. Clinicians and researchers should be aware of the psychometric properties of the FFMQ to measure mindfulness when comparing meditators and nonmeditators. Further research is needed to develop a more psychometrically robust measure of self-compassion. PMID- 24490682 TI - Dimensional latent structure of somatic symptom reporting in two representative population studies: results from taxometric analyses. AB - Somatoform disorders are characterized by somatic symptoms that suggest a medical condition when such a condition is not present. Recently, Thomas and Locke (2010) and Jasper, Hiller, Rist, Bailer, and Witthoft (2012) found that the latent status of somatic symptom reporting may be best viewed from a dimensional perspective in a student, primary care, and an epilepsy-monitoring-unit setting using the Minnesota Multiphasic Personality Inventory-2-Restructured Form Somatic Complaints (RC1) Scale and Patient Health Questionnaire (PHQ-15). To determine whether the latent status of somatic symptom reporting is dimensional in general population samples and across other measures, we analyzed the latent status of somatic symptom reporting in 2 large general German population samples using the PHQ-15 and Screening for Somatoform Symptoms (SOMS-7; N1 = 2,469; N2 = 2,434). We applied 3 popular taxometric methods: MAXEIG, MAMBAC, and L-Mode. In both samples, the analyses indicated a dimensional solution. Hence, the latent structure of somatic symptom reporting encompasses differences in degree rather than kind. Implications of the dimensional latent status of somatoform disorders regarding assessment and causality are discussed. PMID- 24490683 TI - CT colonography: does it satisfy the necessary criteria for a colorectal screening test? PMID- 24490685 TI - Substrate biasing effect on the physical properties of reactive RF-magnetron sputtered aluminum oxide dielectric films on ITO glasses. AB - High dielectric constant (high-k) Al2O3 thin films were prepared on ITO glasses by reactive RF-magnetron sputtering at room temperature. The effect of substrate bias on the subband structural, morphological, electrode/Al2O3 interfacial and electrical properties of the Al2O3 films is systematically investigated. An optical method based on spectroscopic ellipsometry measurement and modeling is adopted to probe the subband electronic structure, which facilitates us to vividly understand the band-tail and deep-level (4.8-5.0 eV above the valence band maximum) trap states. Well-selected substrate biases can suppress both the trap states due to promoted migration of sputtered particles, which optimizes the leakage current density, breakdown strength, and quadratic voltage coefficient of capacitance. Moreover, high porosity in the unbiased Al2O3 film is considered to induce the absorption of atmospheric moisture and the consequent occurrence of electrolysis reactions at electrode/Al2O3 interface, as a result ruining the electrical properties. PMID- 24490684 TI - Effectiveness of the 2010 and 2011 Southern Hemisphere trivalent inactivated influenza vaccines against hospitalization with influenza-associated acute respiratory infection among Thai adults aged >= 50 years. AB - BACKGROUND: Inactivated influenza vaccine (IIV) effectiveness has been evaluated among older adults in high-income countries, but data on IIV effectiveness in low and middle-income countries remain sparse. We conducted a test-negative case control analysis to estimate 2010 and 2011 trivalent IIV effectiveness against hospitalization with influenza-associated acute respiratory infection (ARI) among persons aged >= 50 years in rural Thailand. METHODS: During 2010-2011, active surveillance for ARI hospitalization was conducted in two provinces; patients were tested for influenza viruses by real-time RT-PCR. Vaccination status was obtained from vaccine registries. Case and control patients were patients with nasopharyngeal swabs positive and negative for influenza viruses, respectively. Vaccine effectiveness (VE) was estimated for the 6 months after vaccination began. Logistic regression was used to evaluate the association between case status and vaccination while adjusting for age, province, medical conditions, and time. RESULTS: During 2010-2011, there were 1545 patients with ARI, of whom 279 (18%) were influenza-positive case patients and 1266 (82%) were influenza negative control patients. Of the 279 case patients, 247 (89%) had influenza A and 32 (11%) had influenza B. Fourteen of 279 (5%) case patients and 108 of 1266 (9%) control patients were vaccinated against influenza. The unadjusted IIV effectiveness against hospitalization with influenza-associated ARI was 43% (95% CI: 0-68%); adjusted VE was 47% (95% CI: 5-71%). CONCLUSION: The 2010 and 2011 IIVs were moderately effective against hospitalization with influenza-associated ARI among Thais aged >= 50 years, but IIV coverage was low. Additional efforts are warranted in Thailand to improve IIV uptake in this target group. PMID- 24490686 TI - Characterization of polymorphic microsatellite loci in the Antarctic krill Euphausia superba. AB - BACKGROUND: The Antarctic krill, Euphausia superba is a pelagic crustacean, abundant in high-density swarms (10,000 - 30,000 ind/m2) with a circumpolar distribution and a key role in the food web of the Southern Ocean. Only three EST derived microsatellite markers have been used in previous genetic studies, hence we developed additional highly polymorphic microsatellite markers to allow robust studies of the genetic variability and population differentiation within this species. FINDINGS: The microsatellite markers described here were obtained through an enriched genomic library, followed by 454 pyrosequencing. A total of 10 microsatellite markers were tested in 32 individuals from the Antarctic Peninsula. One of the tested loci was fixed for one allele while the other was variable. Of the remaining nine markers, seven showed no departure from Hardy Weinberg equilibrium. The mean number of alleles was 14.9. CONCLUSIONS: These markers open perspectives for population genetic studies of this species to unravel genetic structure, dispersal and population biology, vital information for future conservation. PMID- 24490687 TI - Specific alkylation of human telomere repeat sequences by a tandem-hairpin motif of pyrrole-imidazole polyamides with indole-seco-CBI. AB - We designed and synthesized a tandem-hairpin motif of pyrrole (P)-imidazole (I) polyamide 1-(chloromethyl)-5-hydroxy-1,2-dihydro-3H-benz[e]indole (seco-CBI) conjugates (1) that targets the human telomere repeat sequence 5'-d(CCCTAA)n-3'. As a control, conjugate 2 (hairpin PI polyamide with seco-CBI), which also targets the human telomere repeat sequence, was synthesized. High-resolution denaturing polyacrylamide gel electrophoresis (PAGE) using 5' Texas Red-labeled 219-bp DNA fragments revealed the outstandingly high sequence selectivity of 1, with no mismatch alkylation. Furthermore, an evaluation performed in human cancer cell lines demonstrated that conjugate 1 has low cytotoxicity compared with conjugate 2. In addition, a cell-staining analysis indicated that conjugate 1 induced apoptosis moderately by DNA damage. This study demonstrated that conjugate 1 can be used as an effective alkylator for telomere repeat sequences or as an apoptotic inducer. PMID- 24490688 TI - Genome-wide analysis links emerin to neuromuscular junction activity in Caenorhabditis elegans. AB - BACKGROUND: Laminopathies are diseases characterized by defects in nuclear envelope structure. A well-known example is Emery-Dreifuss muscular dystrophy, which is caused by mutations in the human lamin A/C and emerin genes. While most nuclear envelope proteins are ubiquitously expressed, laminopathies often affect only a subset of tissues. The molecular mechanisms underlying these tissue specific manifestations remain elusive. We hypothesize that different functional subclasses of genes might be differentially affected by defects in specific nuclear envelope components. RESULTS: Here we determine genome-wide DNA association profiles of two nuclear envelope components, lamin/LMN-1 and emerin/EMR-1 in adult Caenorhabditis elegans. Although both proteins bind to transcriptionally inactive regions of the genome, EMR-1 is enriched at genes involved in muscle and neuronal function. Deletion of either EMR-1 or LEM-2, another integral envelope protein, causes local changes in nuclear architecture as evidenced by altered association between DNA and LMN-1. Transcriptome analyses reveal that EMR-1 and LEM-2 are associated with gene repression, particularly of genes implicated in muscle and nervous system function. We demonstrate that emr 1, but not lem-2, mutants are sensitive to the cholinesterase inhibitor aldicarb, indicating altered activity at neuromuscular junctions. CONCLUSIONS: We identify a class of elements that bind EMR-1 but do not associate with LMN-1, and these are enriched for muscle and neuronal genes. Our data support a redundant function of EMR-1 and LEM-2 in chromatin anchoring to the nuclear envelope and gene repression. We demonstrate a specific role of EMR-1 in neuromuscular junction activity that may contribute to Emery-Dreifuss muscular dystrophy in humans. PMID- 24490691 TI - Synthesis, structure, photophysics, and a DFT study of phosphorescent C*N?N- and C?N?N-coordinated platinum complexes. AB - The reaction of N,N-diphenyl-2,2'-bipyridin-6-amine (L1) and N,N-diphenyl-6-(1H pyrazol-1-yl)pyridin-2-amine (L2) with K2PtCl4 produced C*N(?)N-coordinated cycloplatinated compounds with a five-six fused metallacycle 1a and 2a, respectively, which were then converted into their phenylacetylide derivatives 1b and 2b, respectively. Similar reactions starting from 2-phenyl-6-(1H-pyrazol-1 yl)pyridine (L3) produced C(?)N(?)N-coordinated platinum complexes 3a and 3b with a five-five-fused metallacycle. The structures of 1a, 1b, 2b, 3a, and 3b were determined by X-ray crystallography. The C*N(?)N-coordinated platinum complexes are closer to a square geometry, whereas the C(?)N(?)N-coordinated complexes display a nearly perfect planar geometry. The pi...pi interactions were revealed in the crystal packing for 1a, 2b, and 3a with a pi...pi contact of 3.450, 3.422, and 3.414 A, respectively. Two conformers were revealed in the crystal structure of 2b, one with the phenyl ring of the phenylacetylide being approximately parallel with the coordination plane and the other with the phenyl ring being approximately perpendicular to the coordination plane. Both 1a and 1b are weakly emissive in the red region. Complexes 2a and 3a are also weakly emissive, but their acetylide derivatives 2b and 3b emitted strongly green light at room temperature with quantum yields of 43 and 62%, respectively. DFT/TDDFT calculations were performed to elucidate the nature of their electronic transitions. The calculations suggested that lowest singlet and triplet excited states are characteristic of a mixed state involving one or more charge-transfer transitions such as ILCT, MLCT, and LLCT. PMID- 24490690 TI - Oxidation of biologically relevant chalcogenones and their Cu(I) complexes: insight into selenium and sulfur antioxidant activity. AB - Hydroxyl radical damage to DNA causes disease, and sulfur and selenium antioxidant coordination to hydroxyl-radical-generating Cu(+) is one mechanism for their observed DNA damage prevention. To determine how copper binding results in antioxidant activity, biologically relevant selone and thione ligands and Cu(+) complexes of the formula [Tpm*Cu(L)](+) [Tpm* = tris(3,5 dimethylpyrazolyl)methane; L = N,N'-dimethylimidazole selone or thione] were treated with H2O2 and the products analyzed by (1)H, (13)C{(1)H}, and (77)Se{(1)H} NMR spectroscopy, mass spectrometry, and X-ray crystallography. Upon H2O2 treatment, selone and thione binding to Cu(+) prevents oxidation to Cu(2+); instead, the chalcogenone ligand is oxidized. Thus, copper coordination by sulfur and selenium compounds can provide targeted sacrificial antioxidant activity. PMID- 24490692 TI - Temperature initiated P-polymerization in solid [Cd3Cu]CuP10. AB - [Cd3Cu]CuP10, a polyphosphide containing adamantine-analogue [P10] unit undergoes a solid-state polymerization to form [P6] rings and tubular [P26] polymer units at elevated temperatures. This reaction represents the rare case of a polyphosphide polymerization in the solid state. The formation of such a polymeric unit starting from a molecular precursor is the first evidence of the general possibility to perform a bottom-up route to the well-known tubular polyphosphide units of elemental phosphorus in a solid material. Temperature dependent X-ray powder diffraction experiments substantiate the solid phase transformation of [Cd3Cu]CuP10 starting at 550 degrees C to the polymerized form via an additional intermediate step. A single crystal structure determination of the quenched product at room temperature was performed to evaluate the structural properties and the resulting polyphosphide units. The full polymerization and decomposition mechanism has been analyzed by thermogravimetric experiments and subsequent X-ray powder phase analyses. The present [P26] polymer unit represents a former unseen one-dimensional cut-out of the two-dimensional polyphosphide substructure of Ag3P11 and can be directly related to the tubular polyphosphide substructures of violet or fibrous phosphorus. PMID- 24490693 TI - A MnII6MnIII6 single-strand molecular wheel with a reuleaux triangular topology: synthesis, structure, magnetism, and DFT studies. AB - The use of the anion of 3-methyl-1,3,5-pentanetriol (mpt(3-)) in manganese carboxylate chemistry has afforded the new Mn(II/III)12 cluster [Mn(II)6Mn(III)6(mpt)6(CH3CO2)12(py)6].3CH3CN (1.3CH3CN). Complex 1 was isolated in moderate yield by the reaction of Mn(CH3CO2)2.4H2O and H3mpt in a 2.6:1 molar ratio in a solvent mixture of acetonitrile and pyridine. The structure of 1 consists of alternating [Mn(II)2(CH3CO2)3(py)](+) and [Mn(III)2(MU OR)2(CH3CO2)(py)](3+) dimeric units (three of each dimer), linked at each end by two alkoxo and one acetate bridges; the mpt(3-) ligands adopt the eta(2):eta(2):eta(2):MU4 coordination mode. The overall metal topology of this new Mn12 wheel resembles a guitar plectrum, or a Reuleaux triangle. Complex 1 displays an unprecedented structural topology, being the first example of a Mn(II)6Mn(III)6 wheel constructed from alternating homovalent dimers and the only known Mn12 loop with the trigonal symmetry of a Reuleaux triangle (all other reported loops were ellipsoids). Variable-temperature, solid-state direct- and alternating-current magnetization studies were carried out on complex 1, revealing the presence of antiferromagnetic exchange interactions between the metal ions in the molecule, which lead to a spin ground-state value S = 0; the exchange coupling parameters J were calculated using density functional theory employing a hybrid B3LYP functional. PMID- 24490696 TI - Tempol attenuates atherosclerosis associated with metabolic syndrome via decreased vascular inflammation and NADPH-2 oxidase expression. AB - Oxidative stress is an important factor in the generation of vascular injury in atherosclerosis. Chronic administration of fructose in rodents is able to facilitate oxidative damage. In the present study we evaluated the role of Tempol, a superoxide dismutase mimetic, on the effect of high fructose intake in apolipoprotein E-deficient (ApoE-KO) mice. Rodents were fed with fructose overload (FF, 10% w/v) for 8 weeks and treated with Tempol 1 mg/kg/day the latest 4 weeks. Tempol revert the pro-oxidant effects caused by FF, diminished lipid peroxidation and impaired vascular NADPH oxidase system through the downregulation of p47phox expression in the vascular wall. Tempol inhibited the expression of vascular adhesion molecule 1 (VCAM-1) in aorta and reduced the development of atheroma plaques. Our results indicate that tempol attenuates oxidative stress by interfering with the correct assembly of Nox2 oxidase complex in the vascular wall and is able to reduce atherosclerosis. Thus tempol represents a potential therapeutic target for preventing risk factors associated with metabolic syndrome. PMID- 24490697 TI - Preparation, characterization, and properties of hollow Janus particles with tailored shapes. AB - As compared to the traditional solid Janus particles, the hollow Janus particles have inspired growing interests due to their diverse potential applications. Herein, the novel hollow Janus particles with elephant trunk-like and acorn-like shapes were prepared by seed emulsion polymerization. In contrast to traditional template methods, the hollow structure was obtained during the preparation by one step swelling method. The shapes and internal structures of hollow Janus particles were confirmed, and the compositions were identified too. Some critical influences on the morphology control were investigated, that is, the surface modification, the amount of surfactant, and cross-linking agent concentrations. It was inferred that the balance of hydrophilicity and hydrophobicity and the effective phase separation were important for preparing the hollow Janus particles with tailored shapes. Finally, amphiphilic properties of hollow Janus particles were demonstrated by emulsifying oil-water mixture. PMID- 24490698 TI - Selective ionic transport through tunable subnanometer pores in single-layer graphene membranes. AB - We report selective ionic transport through controlled, high-density, subnanometer diameter pores in macroscopic single-layer graphene membranes. Isolated, reactive defects were first introduced into the graphene lattice through ion bombardment and subsequently enlarged by oxidative etching into permeable pores with diameters of 0.40 +/- 0.24 nm and densities exceeding 10(12) cm(-2), while retaining structural integrity of the graphene. Transport measurements across ion-irradiated graphene membranes subjected to in situ etching revealed that the created pores were cation-selective at short oxidation times, consistent with electrostatic repulsion from negatively charged functional groups terminating the pore edges. At longer oxidation times, the pores allowed transport of salt but prevented the transport of a larger organic molecule, indicative of steric size exclusion. The ability to tune the selectivity of graphene through controlled generation of subnanometer pores addresses a significant challenge in the development of advanced nanoporous graphene membranes for nanofiltration, desalination, gas separation, and other applications. PMID- 24490699 TI - Microbial diversities (16S and 18S rRNA gene pyrosequencing) and environmental pathogens within drinking water biofilms grown on the common premise plumbing materials unplasticized polyvinylchloride and copper. AB - Drinking water (DW) biofilm communities influence the survival of opportunistic pathogens, yet knowledge about the microbial composition of DW biofilms developed on common in-premise plumbing material is limited. Utilizing 16S and 18S rRNA gene pyrosequencing, this study characterized the microbial community structure within DW biofilms established on unplasticized polyvinyl chloride (uPVC) and copper (Cu) surfaces and the impact of introducing Legionella pneumophila (Lp) and Acanthamoeba polyphaga. Mature (> 1 year old) biofilms were developed before inoculation with sterilized DW (control, Con), Lp, or Lp and A. polyphaga (LpAp). Comparison of uPVC and Cu biofilms indicated significant differences between bacterial (P = 0.001) and eukaryotic (P < 0.01) members attributable to the unique presence of several family taxa: Burkholderiaceae, Characeae, Epistylidae, Goniomonadaceae, Paramoebidae, Plasmodiophoridae, Plectidae, Sphenomonadidae, and Toxariaceae within uPVC biofilms; and Enterobacteriaceae, Erythrobacteraceae, Methylophilaceae, Acanthamoebidae, and Chlamydomonadaceae within Cu biofilms. Introduction of Lp alone or with A. polyphaga had no effect on bacterial community profiles (P > 0.05) but did affect eukaryotic members (uPVC, P < 0.01; Cu, P = 0.001). Thus, established DW biofilms host complex communities that may vary based on substratum matrix and maintain consistent bacterial communities despite introduction of Lp, an environmental pathogen. PMID- 24490701 TI - Nanostructured liquid-crystalline particles for drug delivery. AB - INTRODUCTION: Nanostructured lyotropic liquid crystal particles (LLC NPs) have proven to be extremely useful tools for applications in drug delivery. These structured nanoparticles are formed by amphiphilic molecules and contain internal water channels, which are not in contact with external water, and where polar drugs can situate; on the other hand, apolar drugs can be loaded in the lipophilic part of the structure and the amphiphilic drugs can locate at the polar/apolar interfaces. AREAS COVERED: A revision of the most relevant results published in the field of LLC NPs has been made. The first section discusses the most common compounds used in these nanoparticles and their preparation and characterization. A summary of recent and relevant results including the composition and type of nanoparticles used, the illness treated, the administration via and some special features in each case have been summarized in a table. EXPERT OPINION: LLC NPs are highly versatile drug delivery systems, which can be applied by topical, oral and intravenous treatments. Especially relevant is their use for the release of anticancer drugs, biomolecules and vaccines. Nevertheless a number of critical points need to be solved in order to attain practical applications. PMID- 24490703 TI - What is the impact of primary care model type on specialist referral rates? A cross-sectional study. AB - BACKGROUND: Several new primary care models have been implemented in Ontario, Canada over the past two decades. These practice models differ in team structure, physician remuneration, and group size. Few studies have examined the impact of these models on specialist referrals. We compared specialist referral rates amongst three primary care models: 1) Enhanced Fee-for-service, 2) Capitation- Non-Interdisciplinary (CAP-NI), 3) Capitation - Interdisciplinary (CAP-I). METHODS: We conducted a cross-sectional study using health administrative data from primary care practices in Ontario from April 1st, 2008 to March 31st, 2010. The analysis included all family physicians providing comprehensive care in one of the three models, had at least 100 patients, and did not have a prolonged absence (eight consecutive weeks). The primary outcome was referral rate (# of referrals to all medical specialties/1000 patients/year). A multivariable clustered Poisson regression analysis was used to compare referral rates between models while adjusting for provider (sex, years since graduation, foreign trained, time in current model) and patient (age, sex, income, rurality, health status) characteristics. RESULTS: Fee-for-service had a significantly lower adjusted referral rate (676, 95% CI: 666-687) than the CAP-NI (719, 95% confidence interval (CI): 705-734) and CAP-I (694, 95% CI: 681-707) models and the interdisciplinary CAP-I group had a 3.5% lower referral rate than the CAP-NI group (RR = 0.965, 95% CI: 0.943-0.987, p = 0.002). Female and Canadian-trained physicians referred more often, while female, older, sicker and urban patients were more likely to be referred. CONCLUSIONS: Primary care model is significantly associated with referral rate. On a study population level, these differences equate to 111,059 and 37,391 fewer referrals by fee-for-service versus CAP-NI and CAP-I, respectively - a difference of $22.3 million in initial referral appointment costs. Whether a lower rate of referral is more appropriate or not is not known and requires further investigation. Physician remuneration and team structure likely account for the differences; however, further investigation is also required to better understand whether other organizational factors associated with primary care model also impact referral. PMID- 24490704 TI - Tolerance and osteointegration of TricOs(TM)/MBCP((r)) in association with fibrin sealant in mastoid obliteration after canal wall-down technique for cholesteatoma. AB - CONCLUSION: The TricOsTM/MBCP((r)) and fibrin sealant composite was a convenient, effective, and well-tolerated material for mastoid cavity filling and immediate reconstruction of the external auditory meatus after cholesteatoma surgery with canal wall down (CWD). OBJECTIVE: To assess the tolerance and osteointegration of a bone graft substitute, TricOsTM/MBCP((r)), in association with fibrin sealant for filling the mastoid cavity after cholesteatoma surgery using the CWD technique. METHODS: In this prospective observational study 57 patients with cholesteatoma suitable for CWD were recruited from April 2006 to April 2008 and followed up for 1 year. The mastoid cavity was filled with TricOsTM/MBCP((r)) followed by immediate reconstruction of the external auditory meatus covered with fascia temporalis and/or cartilage. The main outcome was skin tolerance assessed by a novel weighted score emphasizing long-term results. The typical weighted reference score was 1.67; skin tolerance was considered acceptable if 75% of patients had a score <= 1.67. Secondary outcomes were otorrhea and/or otalgia, hearing, and osteointegration assessed through computed tomography scanning at 12 months. RESULTS: Forty-one patients had a complete follow-up; 34 (82.3%) patients achieved the main end point with scores <= 1.67. Otorrhea decreased postoperatively. No otalgia interfering with daily tasks was reported. Ossicular reconstruction was carried out in 29 patients. Absence of cochlear toxicity was confirmed by unimpaired bone conduction. Preoperative and postoperative speech audiometry results were similar. No serious adverse events were observed. Osteointegration was satisfactory with hyperdensity or intermediate density in 95% of patients at 12 months. PMID- 24490705 TI - Effect of telmisartan on VEGF-induced and VEGF-independent angiogenic responsiveness of coronary endothelial cells in normal and streptozotocin (STZ) induced diabetic rats. AB - Telmisartan possesses endothelial protective effects due to angiotensin II type 1 receptor antagonist, peroxisome proliferator-activated receptor gamma (PPARgamma) agonist and antioxidant action. Therefore, our objective was to study effect of telmisartan on angiogenic responsiveness of coronary endothelial cells (cECs) of normal and diabetic rats. Male Wistar rats were divided into six groups, normal rats, diabetic rats 30 d. (30 days after administration of STZ), diabetic rats 60 ds. (60 days after administration of STZ), telmisartan-treated normal rats (2 mg/kg, p.o., for 15 days before isolation of hearts), telmisartan-treated diabetic rats 30 ds, and telmisartan-treated diabetic rats 60 ds. Each group was further divided into two subgroups, sham rat hearts and ischemia-reperfused rat hearts. After isolation of cEC from each subgroup, angiogenic responsiveness and nitric oxide releasing properties were studied using chorioallantoic membrane (CAM) assay and Griess method, respectively. cEC of normal rats showed significant increase in angiogenic responsiveness in presence of vascular endothelial growth factor (VEGF) but not in absence of it. This activity was attenuated by pretreatment of cEC with l-NAME, wortmannin and chelerythrine. Diabetes and ischemia reperfusion injury suppressed angiogenic responsiveness of cEC. Telmisartan treatment showed significant increase in VEGF-induced angiogenic responsiveness and nitric oxide releasing properties of cECs of all subgroups as compared to their respective non-treated subgroups. These effects of telmisartan were significantly inhibited by pretreatment of cECs with L-NAME and wortmannin but not with chelerythrine. Our data suggest that telmisartan improves VEGF induced coronary angiogenic activity in normal and diabetic rats via stimulation of PI3K/eNOS/NO pathway. PMID- 24490707 TI - Anatabine significantly decreases nicotine self-administration. AB - Nicotine addiction is associated with many lethal disorders (cancer, cardiovascular and pulmonary disease), and more effective medications to aid smoking cessation are urgently needed. Anatabine is 1 of the most abundant minor tobacco alkaloids, but relatively little is known about its interactions with the abuse-related effects of nicotine. The acute effects of anatabine or saline on nicotine- and food-maintained responding were examined in 7 rhesus monkeys (Macaca mulatta). Nicotine (0.01 mg/kg/inj, base) and banana-flavored food pellets (1 g) were available under a second-order schedule (FR 2 [VR 16:S]). Anatabine or saline injections were administered 15 min before the 11:00 a.m. food self-administration session began. Anatabine (0.18-3.2 mg/kg, IM) dose dependently reduced nicotine self-administration (0.01 mg/kg/inj) (p = .036 0.0003). Food-maintained responding was decreased only at the highest dose of anatabine (3.2 mg/kg; p = .003). Each monkey returned to baseline levels of nicotine self-administration after anatabine treatment, and there was no evidence of catheter malfunction. Next, the effects of anatabine and saline on the nicotine dose-effect curve (0.001-0.1 mg/kg/inj) were evaluated. Anatabine (0.32 and 1.0 mg/kg, IM) decreased the peak of the nicotine dose-effect curve (p < .001 - p < .0001), with no significant effect on food-maintained responding. The abuse liability of anatabine also was examined, and monkeys did not self-administer anatabine (0.0032-0.32 mg/kg/inj) above saline levels. These findings are consistent with anatabine's effects on nicotine self-administration in rats (Caine et al., 2014). These data suggest that anatabine could be an effective agonist medication for treatment of nicotine addiction. PMID- 24490706 TI - The role of smoking inflexibility/avoidance in the relation between anxiety sensitivity and tobacco use and beliefs among treatment-seeking smokers. AB - Recent scholarly attention has focused on explicating the nature of tobacco use among anxiety-vulnerable smokers. Anxiety sensitivity (fear of aversive internal anxiety states) is a cognitive-affective individual difference factor related to the development and maintenance of anxiety symptoms and disorders and various smoking processes. The present study examined the cross-sectional associations between anxiety sensitivity and a range of cognitive and behavioral smoking processes, and the mediating role of the tendency to respond inflexibly and with avoidance in the presence of smoking-related distress (i.e., avoidance and inflexibility to smoking [AIS]) in such relations. Participants (n = 466) were treatment-seeking daily tobacco smokers recruited as part of a larger tobacco cessation study. Baseline (pretreatment) data were utilized. Self-report measures were used to assess anxiety sensitivity, AIS, and 4 criterion variables: barriers to smoking cessation, quit attempt history, severity of problematic symptoms reported in past quit attempts, and mood-management smoking expectancies. Results indicated that anxiety sensitivity was indirectly related to greater barriers to cessation, greater number of prior quit attempts and greater mood-management smoking expectancies through the tendency to respond inflexibly/avoid to the presence of distressing smoking-related thoughts, feelings, and internal sensations; but not severity of problems experienced while quitting. The present findings suggest AIS may be an explanatory mechanism between anxiety sensitivity and certain smoking processes. PMID- 24490708 TI - Nicotine-like behavioral effects of the minor tobacco alkaloids nornicotine, anabasine, and anatabine in male rodents. AB - Tobacco use is associated with lethal diseases in an estimated 440,000 persons in the United States each year (Centers for Disease Control and Prevention, 2005). Successful smoking quit-rates are estimated at 5%-8%, even though a quarter of those attempts included use of smoking-cessation aids (Messer et al., 2008; Henningfield et al., 2009). Current projections are that 16% of the U.S. population-35 million people-will still smoke in 2025, thus more effective smoking-cessation aids are urgently needed (Pollock et al., 2009). The minor tobacco alkaloids may be promising candidates, but further research is necessary (Hoffman & Evans, 2013). Accordingly, we systematically evaluated the minor tobacco alkaloids nornicotine, anabasine, and anatabine using assays of behavioral tolerability, nicotine withdrawal, nicotine discrimination, and nicotine self-administration in male rodents. At doses that were well tolerated, all 3 minor alkaloids dose-dependently engendered robust substitution for a nicotine discriminative stimulus in mice (0.32 mg/kg, IP), and anabasine attenuated nicotine withdrawal. When the ED50 dose of each alkaloid was administered in combination with nicotine, the discriminative stimulus effects of nicotine were not enhanced by any of the alkaloids, and anatabine blunted nicotine's effects. In drug self-administration studies, only nornicotine was self-administered by rats that self-administered nicotine intravenously; anabasine and anatabine had no reinforcing effects. Moreover, prior administration of each of the minor tobacco alkaloids dose-dependently decreased nicotine self-administration. Collectively these results suggest that the minor tobacco alkaloids may substitute for the subjective effects of nicotine and attenuate withdrawal and craving without the abuse liability of nicotine. PMID- 24490709 TI - Acute and chronic administration of a low-dose combination of topiramate and ondansetron reduces ethanol's reinforcing effects in male alcohol preferring (P) rats. AB - Topiramate (a GABA/glutamate modulator) and ondansetron (a serotonin-3 antagonist) have shown promise as treatments for alcohol use disorders (AUDs), although efficacy is modest/variable for both medications. We recently showed in animal models of consumption and relapse that acute treatment with a combination of these medications was more efficacious than either alone. To determine whether the mechanism for its beneficial effects is through modulation of ethanol's reinforcing effects, we measured the effect of this combination in male alcohol preferring (P) rats (N = 22) responding for ethanol under a progressive-ratio (PR) schedule. Low doses, which either do not affect (ondansetron; 0.001 mg/kg) or only modestly affect (topiramate; 10 mg/kg) alcohol-related behaviors on their own, were selected in an attempt to maximize their combined efficacy while minimizing potential side effects. In addition to acute treatment (1 day), the effects of chronic administration (10 days) were examined in an attempt to model human treatment approaches. The effects of the combination were compared with the low dose of topiramate alone hypothesizing that the combination would be more efficacious than topiramate alone. Although both topiramate and the combination similarly reduced PR responding for ethanol following acute treatment and during the initial phase of chronic treatment (Days 1-5), after repeated administration (Days 6-10), only the combination produced a sustained reduction in ethanol maintained responding. These results suggest an advantage of the combination over topiramate alone at producing a sustained reduction in ethanol's reinforcing effects following prolonged treatment, and lend further support for its use as a potential treatment for AUDs. PMID- 24490710 TI - Craving as an alcohol use disorder symptom in DSM-5: an empirical examination in a treatment-seeking sample. AB - Craving has been added as an alcohol use disorder (AUD) symptom in DSM-5 but relatively few nosological studies have directly examined the empirical basis for doing so. The current study investigated the validity of craving as an AUD symptom in a sample of heavy drinking treatment-seeking individuals. Using a semistructured clinical interview, individuals (N = 104; 62% male) were assessed for symptoms of DSM-IV AUD. The extent to which individuals endorsed pathological levels of craving in comparison with other AUD symptoms was investigated as was the association between craving and several aspects of problematic alcohol involvement. Factor analysis was utilized to examine whether craving and other AUD symptoms comprised a unidimensional syndrome. Results indicated that craving was significantly positively correlated with AUD severity, quantitative indices of drinking, and adverse consequences of alcohol abuse. In terms of frequency of endorsement, craving was present in 47% of the sample and was the 8th most frequent of the 12 symptoms evaluated. When considered with the DSM-IV AUD criteria, craving aggregated with other symptoms to form a unidimensional syndrome. Extending previous findings from epidemiological samples, these data suggest that, in a clinical sample, many relevant aspects of craving aggregate to form a diagnostic criterion that functions similarly to other AUD symptoms and is related to diverse aspects of alcohol-related impairment. PMID- 24490711 TI - DSM-5 gambling disorder: prevalence and characteristics in a substance use disorder sample. AB - The fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) replaced the fourth edition's (DSM-IV) diagnosis of Pathological Gambling (PG) with Gambling Disorder (GD). GD differs from PG in that it requires 4 rather than 5 criteria for diagnosis and excludes the "Illegal Acts" criterion. We examined the prevalence of GD and its characteristics and validity in a substance use disorder (SUD) sample. Participants (N = 6,613) in genetic studies of substance dependence underwent a semistructured psychiatric interview. Individuals who reported ever having gambled $10 at least monthly (n = 1,507) were the focus of the analyses. Approximately one third of acknowledged gamblers (n = 563; 8.5% of the total sample) received PG (DSM-IV) and GD (DSM-5) diagnoses and 678 (10.3% of the total) received only a DSM-5 diagnosis, representing an increase of 20.4% relative to DSM-IV. Although the 3 groups were comparable demographically, the DSM-5-Only group was intermediate between the other 2 groups on the prevalence of comorbid SUDs, the distribution of DSM-IV PG criteria endorsed, and the types of gambling reported. Multinomial logistic regression analysis showed that the DSM-5-Only group was more likely than the No-Diagnosis group and less likely than the Both-Diagnoses group to acknowledge a gambling problem. In conclusion, there was a high prevalence of PG in this SUD sample. Analysis of non-DSM variables suggested that the increased sensitivity of the DSM 5 GD diagnosis successfully identifies a broader set of individuals with clinically significant gambling-related problems. Prospective studies of individuals with GD are needed to validate this finding. PMID- 24490713 TI - Predictors of detection of alcohol use episodes using a transdermal alcohol sensor. AB - The objective of this investigation was to establish the ability of the Secure Continuous Remote Alcohol Monitoring (SCRAM) alcohol sensor to detect different levels of self-reported alcohol consumption, and to determine whether gender and body mass index, alcohol dependence, bracelet version, and age of bracelet influenced detection of alcohol use. Heavy drinking adults (N = 66, 46% female) wore the SCRAM for 1-28 days and reported their alcohol use in daily Web-based surveys. Participant reports of alcohol use were matched with drinking episodes identified from bracelet readings. On days when bracelets were functional, 690 drinking episodes were reported and 502 of those episodes (72.8%) were detected using sensor data. Using generalized estimating equations, we found no gender differences in detection of reported drinking episodes (77% for women, 69% for men). In univariate analyses, at the level of fewer than 5 drinks, women's episodes were more likely to be detected, likely because of the significantly higher transdermal alcohol concentration levels of these episodes, whereas at the level of 5 or more drinks, there was no gender difference in detection (92.6% for women, 93.4% for men). In multivariable analyses, no variables other than number of drinks significantly predicted alcohol detection. In summary, the SCRAM sensor is very good at detecting 5 or more drinks; performance of the monitor below this level was better among women because of their higher transdermal alcohol concentration levels. Individual person characteristics and bracelet features were not related to detection after number of drinks was included. Minimal bracelet malfunctions were noted. PMID- 24490712 TI - Employment-based abstinence reinforcement following inpatient detoxification in HIV-positive opioid and/or cocaine-dependent patients. AB - Employment-based reinforcement interventions have been used to promote abstinence from drugs among chronically unemployed injection drug users. The current study used an employment-based reinforcement intervention to promote opioid and cocaine abstinence among opioid and/or cocaine-dependent, HIV-positive participants who had recently completed a brief inpatient detoxification. Participants (n = 46) were randomly assigned to an abstinence and work group that was required to provide negative urine samples in order to enter the workplace and to earn incentives for work (n = 16), a work-only group that was permitted to enter the workplace and to earn incentives independent of drug use (n = 15), and a no voucher control group that did not receive any incentives for working (n = 15) over a 26-week period. The primary outcome was urinalysis-confirmed opioid, cocaine, and combined opioid/cocaine abstinence. Participants were 78% male and 89% African American. Results showed no significant between-groups differences in urinalysis-verified drug abstinence or HIV risk behaviors during the 6-month intervention. The work-only group had significantly greater workplace attendance, and worked more minutes per day when compared to the no-voucher group. Several features of the study design, including the lack of an induction period, setting the threshold for entering the workplace too high by requiring immediate abstinence from several drugs, and increasing the risk of relapse by providing a brief detoxification that was not supported by any continued pharmacological intervention, likely prevented the workplace from becoming established as a reinforcer that could be used to promote drug abstinence. However, increases in workplace attendance have important implications for adult training programs. PMID- 24490714 TI - Influenza vaccination coverage in children with inflammatory bowel disease. AB - The aim of this study was to evaluate the influenza vaccination status among paediatric patients with inflammatory bowel disease (IBD) in Poland. This was a questionnaire-based study. 242 patients with IBD and 142 controls were enrolled in the study. Of patients with IBD, 7.8% received an influenza vaccine, compared to 18.3% of controls (P = 0.0013). There were no statistically significant differences in time from IBD diagnosis, disease activity and in drugs, between vaccinated and non-vaccinated IBD children. In conclusion, the data of our study demonstrate an alarmingly poor influenza vaccination status in the majority of children with IBD. Therefore, there is an unmet need to implement better influenza vaccination strategies for this group of patients. PMID- 24490715 TI - Worst-case scenario intubation of laryngeal granuloma: a case report. AB - BACKGROUND: Intubation of patients with laryngeal granulomas on the vocal folds are sometimes difficult to manage because of potential airway obstruction. Laryngeal granulomas usually have flexible stalks where they attach to the vocal folds. We report a worst-case scenario of dislocation of the laryngeal granuloma during induction of anaesthesia. CASE PRESENTATION: We present a case of laryngeal granulomas on the posterior vocal fold. A 20-year-old woman had an approximately 10-mm tumour in the laryngeal arytenoid region. Manual ventilation resulted in the tumour lodging in the subglottis and the inflated cuff of the intubation tube successfully returned it to its original position during tube withdrawal. Images were obtained using an Airway Scope(r) (Hoya-Pentax, Tokyo, Japan) and a video laryngoscope. CONCLUSION: In our case, the tumour was benign and relatively small in size; therefore, we did not select tracheotomy as an airway management strategy. The case had a granulomatous tumour arising from the posterior vocal folds on the right side, and the tumour was very flexible. To promptly gain control of the airway in such a case using direct laryngoscopy, thus avoiding tracheotomy, other strategies are suggested, such as bronchoscopic visualization with awake or semi-awake intubation. PMID- 24490716 TI - Advances in cervical cancer pharmacotherapies. AB - While widely employed in the management of cervical cancer, the overall utility of systemic anti-neoplastic agents in this clinical setting is quite modest. Cisplatin, the single most studied agent, is currently administered concurrently with external beam radiation as a component of "standard-of-care" in the management of locally advanced cervical cancer. Cisplatin (or carboplatin) combined with paclitaxel is the most commonly utilized regimen in the metastatic/recurrent disease setting (assuming the absence of evidence the cancer is resistant to platinum agents). Recently reported phase 3 trial data have demonstrated that the addition of bevacizumab to either a cisplatin/paclitaxel or paclitaxel/topotecan chemotherapy regimen improves overall survival in metastatic/recurrent cervical cancer. PMID- 24490717 TI - Genetic ancestry of participants in the National Children's Study. AB - BACKGROUND: The National Children's Study (NCS) is a prospective epidemiological study in the USA tasked with identifying a nationally representative sample of 100,000 children, and following them from their gestation until they are 21 years of age. The objective of the study is to measure environmental and genetic influences on growth, development, and health. Determination of the ancestry of these NCS participants is important for assessing the diversity of study participants and for examining the effect of ancestry on various health outcomes. RESULTS: We estimated the genetic ancestry of a convenience sample of 641 parents enrolled at the 7 original NCS Vanguard sites, by analyzing 30,000 markers on exome arrays, using the 1000 Genomes Project superpopulations as reference populations, and compared this with the measures of self-reported ethnicity and race. For 99% of the individuals, self-reported ethnicity and race agreed with the predicted superpopulation. NCS individuals self-reporting as Asian had genetic ancestry of either South Asian or East Asian groups, while those reporting as either Hispanic White or Hispanic Other had similar genetic ancestry. Of the 33 individuals who self-reported as Multiracial or Non-Hispanic Other, 33% matched the South Asian or East Asian groups, while these groups represented only 4.4% of the other reported categories. CONCLUSIONS: Our data suggest that self-reported ethnicity and race have some limitations in accurately capturing Hispanic and South Asian populations. Overall, however, our data indicate that despite the complexity of the US population, individuals know their ancestral origins, and that self-reported ethnicity and race is a reliable indicator of genetic ancestry. PMID- 24490718 TI - Control of nanomorphology in all-polymer solar cells via assembling nanoaggregation in a mixed solution. AB - The formation of interconnected phase-separated domains on sub-20 nm length scale is a key requirement for all-polymer solar cells (all-PSCs) with high efficiency. Herein, we report the application of crystalline poly(3-hexylthiophene) (P3HT) nanowires via an O-dichlorobenzene/hexane mixed solution blended with poly{(9,9 dioctylfluorenyl-2,7-diyl)-alt-[4,7-bis(3-hexylthiophen-5-yl)-2,1,3 benzothiadiazole]-2',2"-diyl} (F8TBT) for the first time. The nanomorphology of P3HT:F8TBT all-PSCs can be controlled by P3HT nanowires. The improved film morphology leads to enhanced light absorption, exciton dissociation, and charge transport in all-PSCs, as confirmed by ultraviolet-visible absorption spectra, X ray diffraction, transmission electron microscopy, atomic force microscopy, and time-resolved photoluminescence spectra. The P3HT nanowire:F8TBT all-PSCs could achieve a power conversion efficiency of 1.87% and a Voc of 1.35 V, both of which are the highest values for P3HT:F8TBT all-PSCs. This work demonstrates that the semiconductor nanowires fabricated by the mixed solvents method is an efficient solution process approach to controlling the nanomorphology of all-PSCs. PMID- 24490719 TI - Noble-gas difluoride complexes of mercury(II): the syntheses and structures of Hg(OTeF5)2.1.5NgF2 (Ng = Xe, Kr) and Hg(OTeF5)2. AB - The synthesis of high-purity Hg(OTeF5)2 has resulted in its structural characterization in the solid state by Raman spectroscopy and single-crystal X ray diffraction (XRD) and in solution by (19)F NMR spectroscopy. The crystal structure of Hg(OTeF5)2 (-173 degrees C) consists of discrete Hg(OTeF5)2 units having gauche-conformations that interact through long Hg---O and Hg---F intramolecular contacts to give a chain structure. The Lewis acidity of Hg(OTeF5)2 toward NgF2 (Ng = Xe, Kr) was investigated in SO2ClF solvent and shown to form stable coordination complexes with NgF2 at -78 degrees C. Both complexes were characterized by low-temperature Raman spectroscopy (-155 degrees C) and single-crystal XRD. The complexes are isostructural and are formulated as Hg(OTeF5)2.1.5NgF2. The Hg(OTeF5)2 units of Hg(OTeF5)2.1.5NgF2 also have gauche conformations and are linked through bridging NgF2 molecules, also resulting in chain structures. These complexes represent the only examples of coordination compounds where NgF2 coordinates to mercury in a neutral covalent compound and the only example of mercury coordinated to KrF2. Moreover, the Hg(OTeF5)2.1.5KrF2 complex is the only KrF2 complex known to contain a bridging KrF2 ligand. Energy minimized gas-phase geometries and vibrational frequencies for the model compounds, [Hg(OTeF5)2]3 and [Hg(OTeF5)2]3.2NgF2, were obtained and provide good approximations of the local environments of Hg(OTeF5)2 and NgF2 in the crystal structures of Hg(OTeF5)2 and Hg(OTeF5)2.1.5NgF2. Assignments of the Raman spectra of Hg(OTeF5)2 and Hg(OTeF5)2.1.5NgF2 are based on the calculated vibrational frequencies of the model compounds. Natural bond orbital analyses provided the associated bond orders, valencies, and natural population analysis charges. PMID- 24490721 TI - Tunable charge transport in single-molecule junctions via electrolytic gating. AB - We modulate the conductance of electrochemically inactive molecules in single molecule junctions using an electrolytic gate to controllably tune the energy level alignment of the system. Molecular junctions that conduct through their highest occupied molecular orbital show a decrease in conductance when applying a positive electrochemical potential, and those that conduct though their lowest unoccupied molecular orbital show the opposite trend. We fit the experimentally measured conductance data as a function of gate voltage with a Lorentzian function and find the fitting parameters to be in quantitative agreement with self-energy corrected density functional theory calculations of transmission probability across single-molecule junctions. This work shows that electrochemical gating can directly modulate the alignment of the conducting orbital relative to the metal Fermi energy, thereby changing the junction transport properties. PMID- 24490720 TI - Factors associated with quality of services for marginalized groups with mental health problems in 14 European countries. AB - BACKGROUND: Different service characteristics are known to influence mental health care delivery. Much less is known about the impact of contextual factors, such as the socioeconomic circumstances, on the provision of care to socially marginalized groups.The objectives of this work were to assess the organisational characteristics of services providing mental health care for marginalized groups in 14 European capital cities and to explore the associations between organisational quality, service features and country-level characteristics. METHODS: 617 services were assessed in two highly deprived areas in 14 European capital cities. A Quality Index of Service Organisation (QISO) was developed and applied across all sites. Service characteristics and country level socioeconomic indicators were tested and related with the Index using linear regressions and random intercept linear models. RESULTS: The mean (standard deviation) of the QISO score (minimum = 0; maximum = 15) varied from 8.63 (2.23) in Ireland to 12.40 (2.07) in Hungary. The number of different programmes provided was the only service characteristic significantly correlated with the QISO (p < 0.05). The national Gross Domestic Product (GDP) was inversely associated with the QISO. Nearly 15% of the variance of the QISO was attributed to country-level variables, with GDP explaining 12% of this variance. CONCLUSIONS: Socioeconomic contextual factors, in particular the national GDP are likely to influence the organisational quality of services providing mental health care for marginalized groups. Such factors should be considered in international comparative studies. Their significance for different types of services should be explored in further research. PMID- 24490722 TI - Helicobacter pylori infection is associated with advanced colorectal neoplasia. PMID- 24490723 TI - Tribute to Takeshi Oka. PMID- 24490727 TI - Publications of Takeshi Oka. PMID- 24490724 TI - My 45 years of astrochemistry: memoirs of Takeshi Oka. PMID- 24490728 TI - Changes in membrane organization upon spontaneous insertion of 2-hydroxylated unsaturated fatty acids in the lipid bilayer. AB - Recent research regarding 2-hydroxylated fatty acids (2OHFAs) showed clear evidence of their benefits in the treatment of cancer, inflammation, and neurodegenerative disorders such as Alzheimer's disease. Monolayer compressibility isotherms and isothermal titration calorimetry of 2OHFA (C18-C22) in phosphatidylcholine/phosphatidylethanolamine/sphingomyelin/cholesterol (1:1:1:1 mole ratio), a mixture that mimics the composition of mammalian plasma membrane, were performed to assess the membrane binding capacity of 2OHFAs and their natural, nonhydroxylated counterparts. The results show that 2OHFAs are surface-active substances that bind membranes through exothermic, spontaneous processes. The main effects of 2OHFAs are a decrease in lipid order, with a looser packing of the acyl chains, and a decreased dipole potential, regardless of the 2OHFAs' relative affinity for the lipid bilayer. The strongest effects are usually observed for 2-hydroxyarachidonic (C20:4) acid, and the weakest one, for 2-hydroxydocosahexaenoic acid (C22:6). In addition, 2OHFAs cause increased hydration, except in gel-phase membranes, which can be explained by the 2OHFA preference for membrane defects. Concerning the membrane dipole potential, the magnitude of the reduction induced by 2OHFAs was particularly marked in the liquid-ordered (lo) phase (cholesterol/sphingomyelin-rich) membranes, those where order reduction was the smallest, suggesting a disruption of cholesterol sphingolipid interactions that are responsible for the large dipole potential in those membranes. Moreover, 2OHFA effects were larger than for both lo and ld phases separately in model membranes with liquid disordered (ld)/lo coexistence when both phases were present in significant amounts, possibly because of the facilitating effect of ld/lo domain interfaces. The specific and marked changes induced by 2OHFAs in several membrane properties suggest that the initial interaction with the membrane and subsequent reorganization might constitute an important step in their mechanisms of action. PMID- 24490729 TI - Poly(A)-binding proteins: structure, domain organization, and activity regulation. AB - RNA-binding proteins are of vital importance for mRNA functioning. Among these, poly(A)-binding proteins (PABPs) are of special interest due to their participation in virtually all mRNA-dependent events that is caused by their high affinity for A-rich mRNA sequences. Apart from mRNAs, PABPs interact with many proteins, thus promoting their involvement in cellular events. In the nucleus, PABPs play a role in polyadenylation, determine the length of the poly(A) tail, and may be involved in mRNA export. In the cytoplasm, they participate in regulation of translation initiation and either protect mRNAs from decay through binding to their poly(A) tails or stimulate this decay by promoting mRNA interactions with deadenylase complex proteins. This review presents modern notions of the role of PABPs in mRNA-dependent events; peculiarities of regulation of PABP amount in the cell and activities are also discussed. PMID- 24490730 TI - Chemistry enters nucleic acids biology: enzymatic mechanisms of RNA modification. AB - Modified nucleotides are universally conserved in all living kingdoms and are present in almost all types of cellular RNAs, including tRNA, rRNA, sn(sno)RNA, and mRNA and in recently discovered regulatory RNAs. Altogether, over 110 chemically distinct RNA modifications have been characterized and localized in RNA by various analytical methods. However, this impressive list of known modified nucleotides is certainly incomplete, mainly due to difficulties in identification and characterization of these particular residues in low abundance cellular RNAs. In DNA, modified residues are formed by both enzymatic reactions (like DNA methylations, for example) and by spontaneous chemical reactions resulting from oxidative damage. In contrast, all modified residues characterized in cellular RNA molecules are formed by specific action of dedicated RNA modification enzymes, which recognize their RNA substrate with high specificity. These RNA-modification enzymes display a great diversity in terms of the chemical reaction and use various low molecular weight cofactors (or co-substrates) in enzymatic catalysis. Depending on the nature of the target base and of the co substrate, precise chemical mechanisms are used for appropriate activation of the base and the co-substrate in the enzyme active site. In this review, we give an extended summary of the enzymatic mechanisms involved in formation of different methylated nucleotides in RNA, as well as pseudouridine residues, which are almost universally conserved in all living organisms. Other interesting mechanisms include thiolation of uridine residues by ThiI and the reaction of guanine exchange catalyzed by TGT. The latter implies the reversible cleavage of the N-glycosidic bond in order to replace the initially encoded guanine by an aza guanosine base. Despite the extensive studies of RNA modification and RNA modification machinery during the last 20 years, our knowledge on the exact chemical steps involved in catalysis of RNA modification remains very limited. Recent discoveries of radical mechanisms involved in base methylation clearly demonstrate that numerous possibilities are used in Nature for these difficult reactions. Future studies are certainly required for better understanding of the enzymatic mechanisms of RNA modification, and this knowledge is crucial not only for basic research, but also for development of new therapeutic molecules. PMID- 24490731 TI - Molecular chaperone GroEL/ES: unfolding and refolding processes. AB - Molecular chaperones are a special class of heat shock proteins (Hsp) that assist the folding and formation of the quaternary structure of other proteins both in vivo and in vitro. However, some chaperones are complex oligomeric proteins, and one of the intriguing questions is how the chaperones fold. The representatives of the Escherichia coli chaperone system GroEL (Hsp60) and GroES (Hsp10) have been studied most intensively. GroEL consists of 14 identical subunits combined into two interacting ring-like structures of seven subunits each, while the co chaperone GroES interacting with GroEL consists of seven identical subunits combined into a dome-like oligomeric structure. In spite of their complex quaternary structure, GroEL and GroES fold well both in vivo and in vitro. However, the specific oligomerization of GroEL subunits is dependent on ligands and external conditions. This review analyzes the literature and our own data on the study of unfolding (denaturation) and refolding (renaturation) processes of these molecular chaperones and the effect of ligands and solvent composition. Such analysis seems to be useful for understanding the folding mechanism not only of the GroEL/GroES complex, but also of other oligomeric protein complexes. PMID- 24490732 TI - AGR2, ERp57/GRP58, and some other human protein disulfide isomerases. AB - This review considers the major features of human proteins AGR2 and ERp57/GRP58 and of other members of the protein disulfide isomerase (PDI) family. The ability of both AGR2 and ERp57/GRP58 to catalyze the formation of disulfide bonds in proteins is the parameter most important for assigning them to a PDI family. Moreover, these proteins and also other members of the PDI family have specific structural features (thioredoxin-like domains, special C-terminal motifs characteristic for proteins localized in the endoplasmic reticulum, etc.) that are necessary for their assignment to a PDI family. Data demonstrating the role of these two proteins in carcinogenesis are analyzed. Special attention is given to data indicating the presence of biomarker features in AGR2 and ERp57/GRP58. It is now thought that there is sufficient reason for studies of AGR2 and ERp57/GRP58 for possible use of these proteins in diagnosis of tumors. There are also prospects for studies on AGR2 and ERp57/GRP58 leading to developments in chemotherapy. Thus, we suppose that further studies on different members of the PDI family using modern postgenomic technologies will broaden current concepts about functions of these proteins, and this will be helpful for solution of urgent biomedical problems. PMID- 24490733 TI - Hydroxylamine derivatives for regulation of spermine and spermidine metabolism. AB - The biogenic polyamines spermine, spermidine, and their precursor putrescine are present in micro-to-millimolar concentrations in all cell types and are vitally important for their normal growth. High intracellular content of spermine and spermidine determines the multiplicity of the cellular functions of the polyamines. Many of these functions are not well characterized at the molecular level, ensuring the ongoing development of this field of biochemistry. Tumor cells have elevated polyamine level if compared with normal cells, and this greatly stimulates the search for new opportunities to deplete the intracellular pool of spermine and spermidine resulting in decrease in cell growth and even cell death. O-Substituted hydroxylamines occupy their own place among chemical regulators of the activity of the enzymes of polyamine metabolism. Varying the structure of the alkyl substituent made it possible to obtain within one class of chemical compounds highly effective inhibitors and regulators of the activity of all the enzymes of putrescine, spermine and spermidine metabolism (with the exception of FAD-dependent spermine oxidase and acetylpolyamine oxidase), effectors of the polyamine transport system, and even actively transported in cells "proinhibitor" of ornithine decarboxylase. Some principles for the design of specific inhibitors of these enzymes as well as the peculiarities of cellular effects of corresponding O-substituted hydroxylamines are discussed. PMID- 24490734 TI - Human cardiac troponin complex. Structure and functions. AB - Troponin complex is a component of skeletal and cardiac muscle thin filaments. It consists of three subunits - troponin I, T, and C, and it plays a crucial role in muscle activity, connecting changes in intracellular Ca2+ concentration with generation of contraction. In spite of more than 40 years of studies, many aspects of troponin functioning are still not completely understood, and several models describing the mechanism of muscle contraction exist. Being a key factor in the regulation of cardiac muscle contraction, troponin complex is utilized in medicine as a target for some cardiotonic drugs used in the treatment of heart failure. A number of mutations in troponin subunits are associated with development of different types of cardiomyopathy. Moreover, for the last 25 years cardiac isoforms of troponin I and T have been widely used for immunochemical diagnostics of pathologies associated with cardiomyocyte death (myocardial infarction, myocardial trauma, and others). This review summarizes the existing evidence on the structure and function of troponin complex subunits, their role in the regulation of cardiac muscle contraction, and their clinical applications. PMID- 24490735 TI - Hypochlorous acid as a precursor of free radicals in living systems. AB - Hypochlorous acid (HOCl) is produced in the human body by the family of mammalian heme peroxidases, mainly by myeloperoxidase, which is secreted by neutrophils and monocytes at sites of inflammation. This review discusses the reactions that occur between HOCl and the major classes of biologically important molecules (amino acids, proteins, nucleotides, nucleic acids, carbohydrates, lipids, and inorganic substances) to form free radicals. The generation of such free radical intermediates by HOCl and other reactive halogen species is accompanied by the development of halogenative stress, which causes a number of socially important diseases, such as cardiovascular, neurodegenerative, infectious, and other diseases usually associated with inflammatory response and characterized by the appearance of biomarkers of myeloperoxidase and halogenative stress. Investigations aimed at elucidating the mechanisms regulating the activity of enzyme systems that are responsible for the production of reactive halogen species are a crucial step in opening possibilities for control of the development of the body's inflammatory response. PMID- 24490736 TI - Mitochondrial production of reactive oxygen species. AB - Numerous biochemical studies are aimed at elucidating the sources and mechanisms of formation of reactive oxygen species (ROS) because they are involved in cellular, organ-, and tissue-specific physiology. Mitochondria along with other cellular organelles of eukaryotes contribute significantly to ROS formation and utilization. This review is a critical account of the mitochondrial ROS production and methods for their registration. The physiological and pathophysiological significance of the mitochondrially produced ROS are discussed. PMID- 24490737 TI - Noncatalytic nucleotide binding sites: properties and mechanism of involvement in ATP synthase activity regulation. AB - ATP synthases (FoF1-ATPases) of chloroplasts, mitochondria, and bacteria catalyze ATP synthesis or hydrolysis coupled with the transmembrane transfer of protons or sodium ions. Their activity is regulated through their reversible inactivation resulting from a decreased transmembrane potential difference. The inactivation is believed to conserve ATP previously synthesized under conditions of sufficient energy supply against unproductive hydrolysis. This review is focused on the mechanism of nucleotide-dependent regulation of the ATP synthase activity where the so-called noncatalytic nucleotide binding sites are involved. Properties of these sites varying upon free enzyme transition to its membrane-bound form, their dependence on membrane energization, and putative mechanisms of noncatalytic site mediated regulation of the ATP synthase activity are discussed. PMID- 24490738 TI - Structural studies on photosystem II of cyanobacteria. AB - Photosynthesis is one of the most important chemical processes in the biosphere responsible for the maintenance of life on Earth. Light energy is converted into energy of chemical bonds in photoreaction centers, which, in particular, include photosystem II (PS II). PS II is a multisubunit pigment-protein complex located in the thylakoid membrane of cyanobacteria, algae and plants. PS II realizes the first stage of solar energy conversion that results in decomposition of water to molecular oxygen, protons, and bound electrons via a series of consecutive reactions. During recent years, considerable progress has been achieved in determination of the spatial structures of PS II from various cyanobacteria. In the present review, we outline the current state of crystallographic studies on PS II. PMID- 24490739 TI - Biocatalytic synthesis of conducting polymers and prospects for its application. AB - Enzymatic methods of synthesis of conducting polymers, physicochemical properties of the resulting products, and mechanisms of the reactions are considered. The enzymes involved in oxidative polymerization of monomers are briefly characterized. Examples of practical application of enzymatically synthesized conducting polymers are given. PMID- 24490740 TI - Antiaggregation activity of chaperones and its quantification. AB - Methods for the quantitative estimation of the antiaggregation activity of protein chaperones (first of all, small heat shock proteins) and chemical chaperones including amino acids, carbohydrates, polyamines, and cyclodextrins are discussed. Based on analysis of the plots of light scattering intensity or apparent optical absorption versus time, formulas for calculation of initial rate of aggregation of protein substrate and lag period on kinetic curves of aggregation were derived. Possible determination of the stoichiometry of chaperone-protein substrate complex from the dependence of the initial rate of aggregation on the ratio of protein chaperone/protein substrate concentrations is discussed. To characterize efficiency of the protective action of chemical chaperones, the [L]0.5 value can be used ([L]0.5 is the concentration of a chemical chaperone at which twofold decrease in the initial rate of aggregation occurs). Methods for quantitative estimation of the combined protective action of chaperones are discussed. PMID- 24490743 TI - Lasers as an approach for promoting drug delivery via skin. AB - INTRODUCTION: Using lasers can be an effective drug permeation-enhancement approach for facilitating drug delivery into or across the skin. The controlled disruption and ablation of the stratum corneum (SC), the predominant barrier for drug delivery, is achieved by the use of lasers. The possible mechanisms of laser assisted drug permeation are the direct ablation of the skin barrier, optical breakdown by a photomechanical wave and a photothermal effect. It has been demonstrated that ablative approaches for enhancing drug transport provide some advantages, including increased bioavailability, fast treatment time, quick recovery of SC integrity and the fact that skin surface contact is not needed. In recent years, the concept of using laser techniques to treat the skin has attracted increasing attention. AREAS COVERED: This review describes recent developments in using nonablative and ablative lasers for drug absorption enhancement. This review systematically introduces the concepts and enhancement mechanisms of lasers, highlighting the potential of this technique for greatly increasing drug absorption via the skin. Lasers with different wavelengths and types are employed to increase drug permeation. These include the ruby laser, the erbium:yttrium-gallium-garnet laser, the neodymium-doped yttrium-aluminum-garnet laser and the CO2 laser. Fractional modality is a novel concept for promoting topical/transdermal drug delivery. The laser is useful in enhancing the permeation of a wide variety of permeants, such as small-molecule drugs, macromolecules and nanoparticles. EXPERT OPINION: This potential use of the laser affords a new treatment for topical/transdermal application with significant efficacy. Further studies using a large group of humans or patients are needed to confirm and clarify the findings in animal studies. Although the laser fluence or output energy used for enhancing drug absorption is much lower than for treatment of skin disorders and rejuvenation, the safety of using lasers is still an issue. Caution should be used in optimizing the feasible conditions of the lasers in balancing the effectiveness of permeation enhancement and skin damage. PMID- 24490744 TI - Phylogenetic analysis of parasitic trematodes of the genus Euclinostomum found in Trichopsis and Betta fish. AB - Many species of fish in the world are infected with digenean trematodes belonging to the genera Clinostomum and Euclinostomum. In this study, metacercariae, identified as Euclinostomum sp. on the basis of morphological characteristics and molecular data, were taken from 3 osphronemid fish- Trichopsis vittata , Trichopsis schalleri, and Betta imbellis, in Thailand. Phylogenetic analysis based on a mitochondrial gene (cytochrome c oxidase subunit I) and 2 nuclear genes (18S rDNA and ITS-internal transcribed spacer) of these Euclinostomum parasites indicated a clear distinction from those belonging to the Clinostomum genus. These are the first records of partial mitochondrial and nuclear DNA sequences of an Euclinostomum sp. PMID- 24490742 TI - Modulation of inflammation in transgenic models of Alzheimer's disease. AB - Over the past decade the process of inflammation has been a focus of increasing interest in the Alzheimer's disease (AD) field, not only for its potential role in neuronal degeneration but also as a promising therapeutic target. However, recent research in this field has provided divergent outcomes, largely due to the use of different models and different stages of the disease when the investigations have been carried out. It is now accepted that microglia, and possibly astrocytes, change their activation phenotype during ageing and the stage of the disease, and therefore these are important factors to have in mind to define the function of different inflammatory components as well as potential therapies. Modulating inflammation using animal models of AD has offered the possibility to investigate inflammatory components individually and manipulate inflammatory genes in amyloid precursor protein and tau transgenics independently. This has also offered some hints on the mechanisms by which these factors may affect AD pathology. In this review we examine the different transgenic approaches and treatments that have been reported to modulate inflammation using animal models of AD. These studies have provided evidence that enhancing inflammation is linked with increases in amyloid-beta (Abeta) generation, Abeta aggregation and tau phosphorylation. However, the alterations on tau phosphorylation can be independent of changes in Abeta levels by these inflammatory mediators. PMID- 24490745 TI - Cardiovascular risks and benefits with oral drugs for Type 2 diabetes mellitus. AB - Type 2 diabetes mellitus affects approximately 321 million people worldwide. It is estimated that about half of these patients will die from cardiovascular complications. In spite of these statistics, medications for diabetes are approved based not on outcomes, but on surrogate markers such as blood glucose or glycosylated hemoglobin. In recent years, however, the safety of diabetes medications has come under scrutiny, and more studies are being undertaken to determine the effect(s) of the medications on actual outcomes. In this review the authors review available study results for all of the currently approved classes of oral medications for Type 2 diabetes, and discuss the possible mechanisms for the findings. More studies are necessary for many of these classes, however, to make definitive recommendations regarding their cardiovascular effects. PMID- 24490746 TI - Primary care quality improvement from a practice facilitator's perspective. AB - BACKGROUND: Practice facilitation has proven to be effective at improving care delivery. Practice facilitators are healthcare professionals who work with and support other healthcare providers. To the best of our knowledge, very few studies have explored the perspective of facilitators. The objective of this study was to gain insight into the barriers that facilitators face during the facilitation process and to identify approaches used to overcome these barriers to help practices move towards positive change. METHODS: We conducted semi structured interviews with four practice facilitators who worked with 84 primary care practices in Eastern Ontario, Canada over a period of five years (2007 2012). The transcripts were analyzed independently by three members of the research team using an open coding technique. A qualitative data analysis using immersion/crystallization technique was applied to interpret the interview transcripts. RESULTS: Common barriers identified by the facilitators included accessibility to the practice (e.g., difficulty scheduling meetings, short meetings), organizational behaviour (team organization, team conflicts, etc.), challenges with practice engagement (e.g., lack of interest, lack of trust), resistance to change, and competing priorities. To help practices move towards positive change the facilitators had to tailor their approach, integrate themselves, be persistent with practices, and exhibit flexibility. CONCLUSIONS: The consensus on redesigning and transforming primary care in North America and around the world is rapidly growing. Practice facilitation has been pivotal in materializing the transformation in the way primary care practices deliver care. This study provides an exclusive insight into facilitator approaches which will assist the design and implementation of small- and large-scale facilitation interventions. PMID- 24490747 TI - Vapor-phase polymerization of nanofibrillar poly(3,4-ethylenedioxythiophene) for supercapacitors. AB - Nanostructures of the conducting polymer poly(3,4-ethylenedioxythiophene) with large surface areas enhance the performance of energy storage devices such as electrochemical supercapacitors. However, until now, high aspect ratio nanofibers of this polymer could only be deposited from the vapor-phase, utilizing extrinsic hard templates such as electrospun nanofibers and anodized aluminum oxide. These routes result in low conductivity and require postsynthetic template removal, conditions that stifle the development of conducting polymer electronics. Here we introduce a simple process that overcomes these drawbacks and results in vertically directed high aspect ratio poly(3,4-ethylenedioxythiophene) nanofibers possessing a high conductivity of 130 S/cm. Nanofibers deposit as a freestanding mechanically robust film that is easily processable into a supercapacitor without using organic binders or conductive additives and is characterized by excellent cycling stability, retaining more than 92% of its initial capacitance after 10,000 charge/discharge cycles. Deposition of nanofibers on a hard carbon fiber paper current collector affords a highly efficient and stable electrode for a supercapacitor exhibiting gravimetric capacitance of 175 F/g and 94% capacitance retention after 1000 cycles. PMID- 24490748 TI - Electrical switch to the resonant magneto-phonon effect in graphene. AB - We report a comprehensive study of the tuning with electric fields of the resonant magneto-exciton optical phonon coupling in gated graphene. For magnetic fields around B ~ 25 T that correspond to the range of the fundamental magneto phonon resonance, the electron-phonon coupling can be switched on and off by tuning the position of the Fermi level in order to Pauli block the two fundamental inter-Landau level excitations. The effects of such a profound change in the electronic excitation spectrum are traced through investigations of the optical phonon response in polarization resolved magneto-Raman scattering experiments. We report on the observation of a splitting of the phonon feature with satellite peaks developing at particular values of the Landau level filling factor on the low or on the high energy side of the phonon, depending on the relative energy of the discrete electronic excitation and of the optical phonon. Shifts of the phonon energy as large as +/-60 cm(-1) are observed close to the resonance. The intraband electronic excitation, the cyclotron resonance, is shown to play a relevant role in the observed spectral evolution of the phonon response. PMID- 24490749 TI - Prevalence of malnutrition and associated risk factors among adult visceral leishmaniasis patients in Northwest Ethiopia: a cross sectional study. AB - BACKGROUND: Visceral leishmaniasis (VL) causes considerable morbidity and mortality in Ethiopia. Data on the prevalence and associated risk factors on malnutrition among VL patients in Ethiopia are scarce. This study aimed to assess the prevalence of malnutrition and its associated risk factor among VL patients in Northwest Ethiopia. METHODS: An institution-based cross-sectional study was conducted from June to September 2012 at four leishmaniasis treatment sites in Northwest Ethiopia. Four hundred and three adult VL patients were enrolled in the study. Malnutrition was defined as a body mass index (BMI) <= 18.5 kg/m2. The data collected from the VL patients included sex, age, residence, occupation, weight, height, laboratory results (HIV, hemoglobin, intestinal parasites). Multivariate logistic regression model was used to determine the strength of association between malnutrition and associated risk factors. RESULTS: Among 403 adult VL patients 385 (95.5%) were malnourished. Twenty eight percent (n = 113), 30.3% (n = 122), and 37.2% (n = 150) were mildly, moderately and severely malnourished, respectively. The prevalence of intestinal parasitic infection was 47.6% (n = 192) and it was associated with malnutrition (P = 0.01). The prevalence of VL-HIV co-infection was 10.4% (n = 42). Hook worm, Giardia intestinalis and Ascaris lumbircoides were the leading prevalent intestinal parasites. Factors such as age, sex, residence, occupation, HIV status and anemia were not associated with severe malnutrition. CONCLUSIONS: The prevalence of malnutrition in VL patients was very high and it was associated with intestinal parasitic infections. Therefore, screening of severely malnourished VL patients for intestinal parasitic infections during admission is recommended. PMID- 24490750 TI - The effect of hospital mergers on long-term sickness absence among hospital employees: a fixed effects multivariate regression analysis using panel data. AB - BACKGROUND: Hospitals are merging to become more cost-effective. Mergers are often complex and difficult processes with variable outcomes. The aim of this study was to analyze the effect of mergers on long-term sickness absence among hospital employees. METHODS: Long-term sickness absence was analyzed among hospital employees (N = 107 209) in 57 hospitals involved in 23 mergers in Norway between 2000 and 2009. Variation in long-term sickness absence was explained through a fixed effects multivariate regression analysis using panel data with years-since-merger as the independent variable. RESULTS: We found a significant but modest effect of mergers on long-term sickness absence in the year of the merger, and in years 2, 3 and 4; analyzed by gender there was a significant effect for women, also for these years, but only in year 4 for men. However, men are less represented among the hospital workforce; this could explain the lack of significance. CONCLUSIONS: Mergers has a significant effect on employee health that should be taken into consideration when deciding to merge hospitals. This study illustrates the importance of analyzing the effects of mergers over several years and the need for more detailed analyses of merger processes and of the changes that may occur as a result of such mergers. PMID- 24490753 TI - Surface-initiated polymerization from barium titanate nanoparticles for hybrid dielectric capacitors. AB - A phosphonic acid is used as a surface initiator for the growth of polystyrene and polymethylmethacrylate (PMMA) from barium titanate (BTO) nanoparticles through atom transfer radical polymerization with activators regenerated by electron transfer. This results in the barium titanate cores embedded in the grafted polymer. The one-component system, PMMA-grafted-BTO, achieves a maximum extractable energy density of 2 J/cm(3) at a field strength of ~220 V/MUm, which exhibits a 2-fold increase compared to that of the composite without covalent attachment or the neat polymer. Such materials have potential applications in hybrid capacitors due to the high permittivity of the nanoparticles and the high breakdown strength, mechanical flexibility, and ease of processability due to the organic polymer. The synthesis, processing, characterization, and testing of the materials in capacitors are discussed. PMID- 24490751 TI - Respiratory viral infections among hospitalized adults: experience of a single tertiary healthcare hospital. AB - BACKGROUND: Following the 2009 H1N1 pandemic, there have been a large number of studies focusing on the epidemiology and outcomes of influenza A infection; however, there have been fewer studies focused on other respiratory viral infections. OBJECTIVES: To define the epidemiology and outcomes of non-influenza respiratory viral infections in hospitalized adults. PATIENTS/METHODS: Data on all patients >=18 years of age with a positive molecular respiratory viral assay who were hospitalized at a single tertiary healthcare system in Chicago, IL, from retrospectively collected and analyzed. RESULTS: Over the study period, 503 of 46 024 (1.1%) admitted patients had a positive RVP result. Human rhinovirus was the most commonly detected virus followed by influenza A, human metapneumovirus, respiratory syncytial virus, and parainfluenza virus, adenovirus, and influenza B, respectively. Infection in immunocompromised patients was associated with a higher rate of progression to pneumonia and death. CONCLUSIONS: Non-influenza respiratory viral infections are commonly detected among adults admitted to the hospital and can cause serious illness. The data can inform the prioritization of research into novel antiviral therapies for these infections. PMID- 24490752 TI - Aging of blood can be tracked by DNA methylation changes at just three CpG sites. AB - BACKGROUND: Human aging is associated with DNA methylation changes at specific sites in the genome. These epigenetic modifications may be used to track donor age for forensic analysis or to estimate biological age. RESULTS: We perform a comprehensive analysis of methylation profiles to narrow down 102 age-related CpG sites in blood. We demonstrate that most of these age-associated methylation changes are reversed in induced pluripotent stem cells (iPSCs). Methylation levels at three age-related CpGs--located in the genes ITGA2B, ASPA and PDE4C- were subsequently analyzed by bisulfite pyrosequencing of 151 blood samples. This epigenetic aging signature facilitates age predictions with a mean absolute deviation from chronological age of less than 5 years. This precision is higher than age predictions based on telomere length. Variation of age predictions correlates moderately with clinical and lifestyle parameters supporting the notion that age-associated methylation changes are associated more with biological age than with chronological age. Furthermore, patients with acquired aplastic anemia or dyskeratosis congenita--two diseases associated with progressive bone marrow failure and severe telomere attrition--are predicted to be prematurely aged. CONCLUSIONS: Our epigenetic aging signature provides a simple biomarker to estimate the state of aging in blood. Age-associated DNA methylation changes are counteracted in iPSCs. On the other hand, over-estimation of chronological age in bone marrow failure syndromes is indicative for exhaustion of the hematopoietic cell pool. Thus, epigenetic changes upon aging seem to reflect biological aging of blood. PMID- 24490754 TI - Comparison of subclinical left and right ventricular systolic dysfunction in non dipper and dipper hypertensives: impact of isovolumic acceleration. AB - Abstract Objectives: To evaluate subclinical left ventricular and right ventricular systolic impairment in dipper and non-dipper hypertensives by using isovolumic acceleration. METHODS: About 45 normotensive healthy volunteers (20 men, mean age 43 +/- 9 years), 45 dipper (27 men, mean age 45 +/- 9 years) and 45 non-dipper (25 men, 47 +/- 7 years) hypertensives were enrolled. Isovolumic acceleration was measured by dividing the peak myocardial isovolumic contraction velocity by isovolumic acceleration time. RESULTS: Non-dippers indicated lower left ventricular (2.2 +/- 0.4 m/s(2) versus 2.8 +/- 1.0 m/s(2), p < 0.01) and right ventricular isovolumic acceleration values (2.8 +/- 0.8 m/s(2) versus 3.5 +/- 1.0 m/s(2), p = 0.012) compared with dippers. Left ventricular mass index (p = 0.001), interventricular septal thickness (p = 0.002) and myocardial performance index (p < 0.001) were negatively correlated with left ventricular isovolumic acceleration. Left ventricular septal thickness (p = 0.002), mass index (p = 0.001) and right ventricular myocardial performance index (p < 0.001) were negatively correlated with right ventricular isovolumic acceleration. CONCLUSION: The present study demonstrates that non-dipper hypertensives have increased left and right ventricular subclinical systolic dysfunction compared with dippers. Isovolumic acceleration is the only echocardiographic parameter in predicting this subtle impairment. PMID- 24490755 TI - MD and NMR analyses of choline and TMA binding to duplex DNA: on the origins of aberrant sequence-dependent stability by alkyl cations in aqueous and water-free solvents. AB - It has been known for decades that alkylammonium ions, such as tetramethyl ammonium (TMA), alter the usual correlation between DNA GC-content and duplex stability. In some cases it is even possible for an AT-rich duplex to be more stable than a GC-rich duplex of the same length. There has been much speculation regarding the origin of this aberration in sequence-dependent DNA duplex stability, but no clear resolution. Using a combination of molecular dynamics simulations and NMR spectroscopy we demonstrate that choline (2-hydroxy-N,N,N trimethylethanaminium) and TMA are preferentially localized in the minor groove of DNA duplexes at A.T base pairs and these same ions show less pronounced localization in the major groove compared to what has been demonstrated for alkali and alkali earth metal ions. Furthermore, free energy calculations show that single-stranded GC-rich sequences exhibit more favorable solvation by choline than single-stranded AT-rich sequences. The sequence-specific nature of choline and TMA binding provides a rationale for the enhanced stability of AT rich sequences when alkyl-ammonium ions are used as the counterions of DNA. Our combined theoretical and experimental study provides one of the most detailed pictures to date of cations localized along DNA in the solution state, and provides insights that go beyond understanding alkyl-ammonium ion binding to DNA. In particular, because choline and TMA bind to DNA in a manner that is found to be distinct from that previously reported for Na(+), K(+), Mg(2+), and Ca(2+), our results reveal the important but underappreciated role that most other cations play in sequence-specific duplex stability. PMID- 24490757 TI - Condensation on surface energy gradient shifts drop size distribution toward small drops. AB - During dropwise condensation from vapor onto a cooled surface, distributions of drops evolve by nucleation, growth, and coalescence. Drop surface coverage dictates the heat transfer characteristics and depends on both drop size and number of drops present on the surface at any given time. Thus, manipulating drop distributions is crucial to maximizing heat transfer. On earth, manipulation is achieved with gravity. However, in applications with small length scales or in low gravity environments, other methods of removal, such as a surface energy gradient, are required. This study examines how chemical modification of a cooled surface affects drop growth and coalescence, which in turn influences how a population of drops evolves. Steam is condensed onto a horizontally oriented surface that has been treated by silanization to deliver either a spatially uniform contact angle (hydrophilic, hydrophobic) or a continuous radial gradient of contact angles (hydrophobic to hydrophilic). The time evolution of number density and associated drop size distributions are measured. For a uniform surface, the shape of the drop size distribution is unique and can be used to identify the progress of condensation. In contrast, the drop size distribution for a gradient surface, relative to a uniform surface, shifts toward a population of small drops. The frequent sweeping of drops truncates maturation of the first generation of large drops and locks the distribution shape at the initial distribution. The absence of a shape change indicates that dropwise condensation has reached a steady state. Previous reports of heat transfer enhancement on chemical gradient surfaces can be explained by this shift toward smaller drops, from which the high heat transfer coefficients in dropwise condensation are attributed to. Terrestrial applications using gravity as the primary removal mechanism also stand to benefit from inclusion of gradient surfaces because the critical threshold size required for drop movement is reduced. PMID- 24490756 TI - Comprehensive analysis of protein N-glycosylation sites by combining chemical deglycosylation with LC-MS. AB - Glycosylation is one of the most important protein modifications in biological systems. It plays a critical role in protein folding, trafficking, and stability as well as cellular events such as immune response and cell-to-cell communication. Aberrant protein glycosylation is correlated with several diseases including diabetes, cancer, and infectious diseases. The heterogeneity of glycans makes comprehensive identification of protein glycosylation sites very difficult by MS because it is challenging to match mass spectra to peptides that contain different types of unknown glycans. We combined a chemical deglycosylation method with LC-MS-based proteomics techniques to comprehensively identify protein N glycosylation sites in yeast. On the basis of the differences in chemical properties between the amide bond of the N-linkage and the glycosidic bond of the O-linkage of sugars, O-linked sugars were removed and only the innermost N-linked GlcNAc remained, which served as a mass tag for MS analysis. This chemical deglycosylation method allowed for the identification of 555 protein N glycosylation sites in yeast by LC-MS, which is 46% more than those obtained from the parallel experiments using the Endo H cleavage method. A total of 250 glycoproteins were identified, including 184 membrane proteins. This method can be extensively used for other biological samples. PMID- 24490758 TI - Amorphous solid dispersion with increased gastric solubility in tandem with oral disintegrating tablets: a successful approach to improve the bioavailability of atorvastatin. AB - CONTEXT: Serious efforts have been made to overcome the bioavailability problems of ever increasing number of poorly soluble drugs, including atorvastatin (ATO); however, enhancing its gastric solubility has not received much attention. OBJECTIVES: To improve the bioavailability of ATO by increasing its gastric solubility in a stable oral disintegration tablet (ODT) formulation. MATERIALS AND METHODS: Amorphous solid dispersion (ASD) of ATO with Eudragit(r) EPO was used as API in ODT formulation. Characterization using Differential scanning calorimetry, Powder X-ray diffraction, Fourier transform infrared drug-polymer interaction simulated by molecular modeling, solubility, dissolution and stability studies together with in vivo evaluation. RESULTS AND DISCUSSION: In ASD there was uniform distribution of drug in the polymer and it retained the amorphous nature without any chemical interactions except the possibility of hydrogen bond formation, with substantially higher gastric solubility. The dissolution profile of the ODT containing ASD was significantly improved >90% within 15 min compared with 25% of plain ATO formulation. In vivo results showed an overall enhancement in the apparent bioavailability (83% and 434% more than Lipitor(r) and plain amorphous ATO tablets, respectively). Combining the ASD with ODT presents a reliable solution to overcome the low solubility and bioavailability problems of ATO in a simple, robust and cost effective formulation. PMID- 24490759 TI - Paediatric end-stage renal disease in a tertiary hospital in South West Nigeria. AB - BACKGROUND: Children and adolescents with end-stage renal disease (ESRD) in sub Saharan Africa may have the worst outcomes globally. Barriers to management include late presentation, poor socioeconomic conditions, absence of medical insurance, limited diagnostic facilities and non-availability of chronic renal replacement therapy (RRT). Our study was to determine the incidence, aetiology, management and outcomes of paediatric ESRD in a tertiary hospital in Nigeria. METHODS: A retrospective case review of paediatric ESRD at the University College Hospital Ibadan, Nigeria, over 8 years, from January 2005 to December 2012. RESULTS: 53 patients (56.6% male), median age 11 (inter quartile range 8.5-12) years were studied. Mean annual incidence of ESRD in Ibadan for children aged 14 years and below was 4 per million age related population (PMARP) while for those aged 5-14 years it was 6.0 PMARP. Glomerulonephritis was the cause in 41 (77.4%) patients amongst whom, 29 had chronic glomerulonephritis and 12 had nephrotic syndrome. Congenital anomalies of the kidneys and urinary tract (CAKUT) accounted for 11 (21.2%) cases, posterior urethral valves being the most common. Acute haemodialysis, acute peritoneal dialysis or a combination of these were performed in 33 (62.3%), 6 (11.3%) and 4 (7.5%) patients respectively. Median survival was 47 days and in-hospital mortality was 59%. CONCLUSIONS: Incidence of paediatric ESRD in Ibadan is higher than previous reports from sub-Saharan Africa. Glomerulonephritis, and then CAKUT are the most common causes. Mortality is high, primarily due to lack of resources. Preventive nephrology and chronic RRT programmes are urgently needed. PMID- 24490761 TI - Highly efficient synthesis of polysubstituted pyrroles via four-component domino reaction. AB - A highly efficient, catalyst-free synthesis of polysubstituted pyrroles by means of a novel four-component domino reaction of an arylglyoxal monohydrate, an aniline, a dialkyl but-2-ynedioate, and malononitrile is reported. This transformation proceeded via a 6,6a-dihydrofuro[2,3-b]pyrrole as the key intermediate. PMID- 24490762 TI - A pilot clinical trial of intravesical mitomycin-C and external deep pelvic hyperthermia for non-muscle-invasive bladder cancer. AB - PURPOSE: This paper aims to evaluate the safety and heating efficiency of external deep pelvic hyperthermia combined with intravesical mitomycin C (MMC) as a novel therapy for non-muscle-invasive bladder cancer (NMIBC). MATERIALS AND METHODS: We enrolled subjects with bacillus Calmette-Guerin (BCG) refractory NMIBC to an early phase clinical trial of external deep pelvic hyperthermia (using a BSD-2000 device) combined with MMC. Bladders were heated to 42 degrees C for 1 h during intravesical MMC treatment. Treatments were given weekly for 6 weeks, then monthly for 4 months. Heating parameters, treatment toxicity, and clinical outcomes were systematically measured. RESULTS: Fifteen patients were enrolled on the clinical trial. Median age was 66 years and 87% were male. Median European Organisation for Research and Treatment of Cancer (EORTC) recurrence and progression scores were 6 and 8, respectively. The full treatment course was attained in 73% of subjects. Effective bladder heating was possible in all but one patient who could not tolerate the supine position due to lung disease. Adverse events were all minor (grade 2 or less) and no systemic toxicity was observed. The most common adverse effects were Foley catheter pain (40%), abdominal discomfort (33%), chemical cystitis symptoms (27%), and abdominal skin swelling (27%). With a median follow-up of 3.18 years, 67% experienced another bladder cancer recurrence (none were muscle invasive) and 13% experienced an upper tract recurrence. CONCLUSIONS: External deep pelvic hyperthermia using the BSD-2000 device is a safe and reproducible method of heating the bladder in patients undergoing intravesical MMC. The efficacy of this treatment modality should be explored further in clinical trials. PMID- 24490760 TI - CX3CR1 deficiency suppresses activation and neurotoxicity of microglia/macrophage in experimental ischemic stroke. AB - BACKGROUND: Chemokine (C-X3-C motif) ligand 1 (CX3CL1)/ CX3C chemokine receptor 1 (CX3CR1) signaling is important in modulating the communication between neurons and resident microglia/migrated macrophages in the central nervous system (CNS). Although CX3CR1 deficiency is associated with an improved outcome following ischemic brain injury, the mechanism of this observation is largely unknown. The aim of this study was to investigate how CX3CR1 deficiency influences microglia/macrophage functions in the context of its protection following brain ischemia. METHODS: Wild-type (WT) and CX3CR1-deficient (CX3CR1-/-) mice were subjected to transient middle cerebral artery occlusion (MCAO) and reperfusion. The ischemic brain damage was monitored by rodent high-field magnetic resonance imaging. Neurological deficit was assessed daily. Neuronal apoptotic death and reactive oxygen species (ROS) production were analyzed by immunostaining and live imaging. Activation/inflammatory response of microglia/macrophage were assessed using immunohistochemistry, flow cytometry, 5-bromo-2-deoxyuridine labeling, cytokine ELISA, and real-time PCR. RESULTS: CX3CR1-/- mice displayed significantly smaller infarcts and less severe neurological deficits compared to WT controls, following MCAO. In addition, CX3CR1-/- MCAO mice displayed fewer apoptotic neurons and reduced ROS levels. Impaired CX3CR1 signaling abrogated the recruitment of monocyte-derived macrophages from the periphery, suppressed the proliferation of CNS microglia and infiltrated macrophage, facilitated the alternative activation (M2 state) of microglia/macrophages, and attenuated their ability to synthesize and release inflammatory cytokines. CONCLUSION: Our results suggest that inhibition of CX3CR1 signaling could function as a therapeutic modality in ischemic brain injury, by reducing recruitment of peripheral macrophages and expansion/activation of CNS microglia and macrophages, resulting in protection of neurological function. PMID- 24490763 TI - Drug-in-cyclodextrin-in-liposomes: a promising delivery system for hydrophobic drugs. AB - INTRODUCTION: Recently, the entrapment of hydrophobic drugs in the form of water soluble drug-cyclodextrin (CD) complex in liposomes has been investigated as a new strategy to combine the relative advantages of CDs and liposomes into one system, namely drug-in-CD-in-liposome (DCL) systems. AREAS COVERED: For DCLs preparation, an overall understanding of the interaction between CDs and lipid components of liposomes is necessary and valuable. The present article reviews the preparation, characterization and application of DCLs, especially as antitumor or transdermal carriers. Double-loading technique, an interesting strategy to control release and increase drug-loading capacity, is also discussed. EXPERT OPINION: DCL approach can be useful in increasing drug solubility and vesicles stability, in controlling the in vivo fate of hydrophobic drugs and in avoiding burst release of drug from the vesicles. To obtain stable DCL, the CDs should have a higher affinity to drug molecules compared with liposomal membrane lipids. DCLs prepared by double-loading technique seem to be a suitable targeted drug delivery system because they have a fast onset action with prolonged drug release process and the significantly enhanced drug-loading capacity. In particular, DCLs are suitable for the delivery of hydrophobic drugs which also possess volatility. PMID- 24490765 TI - Using high-density DNA methylation arrays to profile copy number alterations. AB - The integration of genomic and epigenomic data is an increasingly popular approach for studying the complex mechanisms driving cancer development. We have developed a method for evaluating both methylation and copy number from high density DNA methylation arrays. Comparing copy number data from Infinium HumanMethylation450 BeadChips and SNP arrays, we demonstrate that Infinium arrays detect copy number alterations with the sensitivity of SNP platforms. These results show that high-density methylation arrays provide a robust and economic platform for detecting copy number and methylation changes in a single experiment. Our method is available in the ChAMP Bioconductor package: http://www.bioconductor.org/packages/2.13/bioc/html/ChAMP.html. PMID- 24490766 TI - Risk conferred by tagged SNPs of AGT gene in causing susceptibility to essential hypertension. AB - Abstract Introduction: AGT gene harbors several variants of which 21 are found to be in high linkage disequilibrium as per Hapmap database. Studies delineating the importance of these tagged SNPs are very limited and lacking from Indian population. In the present study, we evaluated the contribution of four tagged SNPs namely, g.6635G > A, g.6506G > A, g.12840G > A, and g.13828T > C at AGT locus along with the analyses of haplotype and epistatic interactions in causing susceptibility to essential hypertension (EHT). METHODS: About 215 hypertensives and 230 normotensives were genotyped for selected tagged SNPs using PCR-RFLP method. RESULTS: Significant association was obtained for g.6635G > A and g.6506G > A polymorphisms wherein GG homozygotes for both the markers were at risk for developing the condition. g.13828T > C polymorphism specially, female heterozygotes (TC) were found to be at increased risk for EHT. Haplotype GGGC was found to have a significant protective effect (p = 0.0059). Markers g.6506G > A and g.12840G > A resulted in the creation of new enhancer sites thereby affecting splicing process. CONCLUSION: The present report is the first one in the literature showing general- and gender-specific association of g.6506G > A and g.13828T > C polymorphisms, respectively, with EHT. However, further studies for replication of present observations are warranted from other populations and other parts of India. PMID- 24490767 TI - Characteristics and service use of participants in a large consumer-operated service agency. AB - OBJECTIVE: Administrative data were used to examine the demographic and service use characteristics of participants in a large consumer-operated agency in New York City (NYC). METHOD: Demographic characteristics for all consumer-operated agency participants in 2011 (N = 3,296) were compared with data from the 2011 Office of Mental Health Patient Characteristics Survey (N = 87,131). RESULTS: Consumer-operated participants were more likely to be male and diagnosed with a mood disorder, and less likely to be Latino/a than public mental health recipients. "Advocacy" and "Self-Help Services" were used by 80% of service recipients, and lengths-of-stay averaged less than 6 months. CONCLUSIONS AND IMPLICATIONS FOR PRACTICE: Self-help services were the most common consumer operated service used in NYC. Given the demographic differences noted, consumer operated service providers may need to take additional steps to engage women, Latinos, and persons diagnosed with schizophrenia-spectrum disorders to reach the full range of public mental health consumers. PMID- 24490764 TI - Inhibition of autophagy enhances the effects of the AKT inhibitor MK-2206 when combined with paclitaxel and carboplatin in BRAF wild-type melanoma. AB - This study investigates the mechanism of action behind the long-term responses (12-16 months) of two BRAF WT melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. Although single agent MK-2206 inhibited phospho-AKT signaling, it did not impact in vitro melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin was cytotoxic in long-term colony formation and 3D spheroid assays, and induced autophagy. Autophagy was initially protective with autophagy inhibitors and deletion of ATG5 found to enhance cytotoxicity. Although prolonged autophagy induction (>6 days) led to caspase-dependent apoptosis, drug resistant clones still emerged. Autophagy inhibition enhanced the cell death response through reactive oxygen species and could be reversed by anti-oxidants. We demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma and show that an autophagy inhibitor may prevent resistance to these drugs. PMID- 24490768 TI - Adaptation and psychometric assessment of the Hebrew version of the Recovery Promoting Relationships Scale (RPRS). AB - Recovery is supported by relationships that are characterized by human centeredness, empowerment and a hopeful approach. The Recovery Promoting Relationships Scale (RPRS; Russinova, Rogers, & Ellison, 2006) assesses consumer provider relationships from the consumer perspective. Here we present the adaptation and psychometric assessment of a Hebrew version of the RPRS. The RPRS was translated to Hebrew (RPRS-Heb) using multiple strategies to assure conceptual soundness. Then 216 mental health consumers were administered the RPRS Heb as part of a larger project initiative implementing illness management and recovery intervention (IMR) in community settings. Psychometric testing included assessment of the factor structure, reliability, and validity using the Hope Scale, the Working Alliance Inventory, and the Recovery Assessment Scale. The RPRS-Heb factor structure replicated the two factor structures found in the original scale with minor exceptions. Reliability estimates were good: Cronbach's alpha for the total scale was 0.94. An estimate of 0.93 for the Recovery Promoting Strategies factor, and 0.86 for the Core Relationship. Concurrent validity was confirmed using the Working Alliance Scale (rp = .51, p < .001) and the Hope Scale (rp = .43, p < .001). Criterion validity was examined using the Recovery Assessment Scale (rp = .355, p < .05). The study yielded a 23-item RPRS Heb version with a psychometrically sound factor structure, satisfactory reliability, and concurrent validity tested against the Hope, Alliance, and Recovery Assessment scales. Outcomes are discussed in the context of the original scale properties and a similar Dutch initiative. The RPRS-Heb can serve as a valuable tool for studying recovery promoting relationships with Hebrew speaking population. PMID- 24490769 TI - Randomized trials of PCIs versus CABG surgery: why coronary stenting should remain the first choice of revascularization in non-diabetic patients and why the controversy is still present in diabetics. AB - Knowing the best revascularization option for diabetic patients with multiple vessel disease is a challenge without a definitive answer. There have been several randomized clinical trials and subsequent meta-analyses comparing current available technology trying to reach an exhaustive conclusion; comparisons between coronary artery bypass grafts and bare-metal stents, coronary artery bypass grafts and first generation drug-eluting stents and, most recently, first generation versus latest generation drug-eluting stents generated some interesting results. Information provided by pooled data from some of the most important randomized clinical cardiology trials from the last two decades have produced surprising results. The authors analyze these data to discuss the best therapeutic procedures for each patient. PMID- 24490770 TI - Control of surface wettability using tripodal light-activated molecular motors. AB - Monolayers of fluorinated light-driven molecular motors were synthesized and immobilized on gold films in an altitudinal orientation via tripodal stators. In this design the functionalized molecular motors are not interfering and preserve their rotary function on gold. The wettability of the self-assembled monolayers can be modulated by UV irradiation. PMID- 24490772 TI - High-contrast terahertz wave modulation by gated graphene enhanced by extraordinary transmission through ring apertures. AB - Gate-controllable transmission of terahertz (THz) radiation makes graphene a promising material for making high-speed THz wave modulators. However, to date, graphene-based THz modulators have exhibited only small on/off ratios due to small THz absorption in single-layer graphene. Here we demonstrate a ~50% amplitude modulation of THz waves with gated single-layer graphene by the use of extraordinary transmission through metallic ring apertures placed right above the graphene layer. The extraordinary transmission induced ~7 times near-filed enhancement of THz absorption in graphene. These results promise complementary metal-oxide-semiconductor compatible THz modulators with tailored operation frequencies, large on/off ratios, and high speeds, ideal for applications in THz communications, imaging, and sensing. PMID- 24490773 TI - Chronic irreducible dislocation of the proximal interphalangeal joint of the fifth toe: a case report. AB - BACKGROUND: Traumatic dislocation of the interphalangeal of the fifth toe is an unusual foot injury. CASE PRESENTATION: We report the case of a 47-year-old woman who sustained a minor foot injury for more than 30 years, resulting in chronic, irreducible dislocation of the proximal interphalangeal joint of the fifth toe. The affected proximal interphalangeal joint was accessed via a dorsal incision over the unstable interphalangeal joint. It was found that the interposed interphalangeal joint capsule and attenuated lateral collateral ligament were reconstructed, and it was stabilized by temporary insertion of a Kirschner wire. The affected joint was found to be stable, well-positioned and pain-free at the 12-month post-surgical check-up. CONCLUSION: This unusual presentation of a chronic joint dislocation responded favorably to open reduction, soft tissue reconstruction and restabilization of the affected joint. It is suggested that this approach will provide a good and functional outcome even in cases of very long-standing joint injury. PMID- 24490774 TI - Metal selenides as a new class of electrocatalysts for quantum dot-sensitized solar cells: a tale of Cu(1.8)Se and PbSe. AB - The development of a Pt-free, highly active electrocatalyst for a counter electrode (CE) is vital to the construction of highly efficient quantum dot sensitized solar cells (QDSSCs). As an alternative to Pt, the use of various metal sulfides, such as Cu2S, CoS, and PbS, has been successfully demonstrated; however, the studies on the utilization of non-sulfide materials have been scarcely reported. In this regard, we examined eight different types of binary metal selenides as new candidate materials, and found that the electrocatalytic activity of Cu1.8Se and PbSe toward polysulfide reduction was superior to that of Pt. In depth investigation into these two materials further revealed that, while the electrocatalytic activity of both metal selenides surpasses that of Pt, the long-term utilization of the PbSe CE is hindered by the formation of PbO on the surface of PbSe, which is attributed to the instability of PbSe under air. Unlike PbSe, Cu1.8Se was found to be chemically stable with a polysulfide electrolyte and was even better than Cu2S, a commonly used CE material for QDSSCs. Using the Cu1.8Se CE, we obtained a power conversion efficiency of 5.0% for CdS/CdSe sensitized solar cells, which was an efficiency almost twice that obtained from Pt CE. This work provides a new application for metal selenides, which have been traditionally utilized as sensitizers for QDSSCs. PMID- 24490777 TI - C-Terminal acetylene derivatized peptides via silyl-based alkyne immobilization. AB - A new Silyl-based Alkyne Modifying (SAM)-linker for the synthesis of C-terminal acetylene-derivatized peptides is reported. The broad scope of this SAM2-linker is illustrated by manual synthesis of peptides that are side-chain protected, fully deprotected, and disulfide-bridged. Synthesis of a 14-meric (KLAKLAK)2 derivative by microwave-assisted automated SPPS and a one-pot cleavage click procedure yielding protected 1,2,3-triazole peptide conjugates are also described. PMID- 24490775 TI - Effects of fluid overload on heart rate variability in chronic kidney disease patients on hemodialysis. AB - BACKGROUND: While fluid overload (FO) and alterations in the autonomic nervous system (ANS) such as hypersympathetic activity, are known risk factors for cardiovascular morbidity and mortality in patients on chronic hemodialysis (HD), their relationship has not been thoroughly studied. METHODS: In this observational study involving 69 patients on chronic HD, FO was assessed by whole body bioimpedance measurements before the midweek HD session and ANS activity reflected by Heart Rate Variability (HRV) was measured using 24-hour Holter electrocardiogram recordings starting before the same HD treatment. In total, 13 different HRV indices were analyzed, comprising a mixture of time domain, frequency domain and complexity parameters. A correlation analysis was performed between the HRV indices and hydration status indices. Successively, patients were retrospectively assigned to a high FO (H, FO > 2.5 L) or low FO (L, FO <= 2.5 L) group and these were further compared also after stratification by diabetes mellitus. Finally, a small number of patients without diabetes with significant and persistent FO were followed up for 3 months post-study to investigate how normalization of fluid status affects HRV. RESULTS: SDANN, VLF, LZC and HF% parameters significantly correlate with FO (correlation coefficients were respectively r = -0.40, r = -0.37, r = -0.28 and r = 0.26, p-value < 0.05). Furthermore, LF% and LF/HF were inversely correlated with hydration status (correlation coefficients were respectively r = -0.31 and r = -0.33, p-value < 0.05). These results indicate an association between FO and reduced HRV, higher parasympathetic activation and reduced sympathetic response to the HD session. Indeed, group H tended to have lower values of SDANN, VLF and LZC, and higher values of HF% than patients in the L group. Finally, there was a trend towards lower LF% measured during the last 30 minutes of HD for the H group versus the L group. Reduction in FO achieved over 3 months by implementation of a strict fluid management plan resulted in an increase of HRV. CONCLUSIONS: Our results suggest that depressed HRV is associated with fluid overload and that normalization of hydration status is accompanied by improved HRV. PMID- 24490776 TI - Feasibility study on measuring selected proteins in malignant melanoma tissue by SRM quantification. AB - Currently there are no clinically recognized molecular biomarkers for malignant melanoma (MM) for either diagnosing disease stage or measuring response to therapy. The aim of this feasibility study was to develop targeted selected reaction monitoring (SRM) assays for identifying candidate protein biomarkers in metastatic melanoma tissue lysate. In a pilot study applying the SRM assay, the tissue expression of nine selected proteins [complement 3 (C3), T-cell surface glycoprotein CD3 epsilon chain E (CD3E), dermatopontin, minichromosome maintenance complex component (MCM4), premelanosome protein (PMEL), S100 calcium binding protein A8 (S100A8), S100 calcium binding protein A13 (S100A13), transgelin-2 and S100B] was quantified in a small cohort of metastatic malignant melanoma patients. The SRM assay was developed using a TSQ Vantage triple quadrupole mass spectrometer that generated highly accurate peptide quantification. Repeated injection of internal standards spiked into matrix showed relative standard deviation (RSD) from 6% to 15%. All nine target proteins were identified in tumor lysate digests spiked with heavy peptide standards. The multiplex SRM peptide assay panel was then measured and quantified on a set of frozen MM tissue samples obtained from the Malignant Melanoma Biobank collected in Lund, Sweden. All nine proteins could be accurately quantified using the new SRM assay format. This study provides preliminary data on the heterogeneity of biomarker expression within MM patients. The S100B protein, which is clinically used as the pathology identifier of MM, was identified in 9 out of 10 MM tissue lysates. The use of the targeted SRM assay provides potential advancements in the diagnosis of MM that can aid in future assessments of disease in melanoma patients. PMID- 24490778 TI - Synthesis of trifluoromethylated isoxazolidines: 1,3-dipolar cycloaddition of nitrosoarenes, (trifluoromethyl)diazomethane, and alkenes. AB - Isoxazolidines have proven to be important substrates in synthetic organic chemistry. Limited examples in the literature that provide trifluoromethylated versions of these compounds have prompted us to investigate a 1,3-dipolar cycloaddition route providing access to N-functionalized isoxazolidines containing a trifluoromethyl group. Thus, a 1,3-dipolar cycloaddition of nitrosoarenes, (trifluoromethyl)diazomethane, and alkenes was developed. The starting materials can be synthesized from easy to handle and accessible reagents. The reaction proved to be tolerant of a variety of electron-deficient alkenes and nitrosoarenes. PMID- 24490779 TI - Concise synthesis of reduced propionates by stereoselective reductions combined with the Kobayashi reaction. AB - A concise and straightforward synthesis of 2,4,6-trimethyloctanoates was established by using the sequence of the vinylogous Mukaiyama aldol reaction and regio- and stereoselective reduction reactions. All isomers were obtained selectively in a few steps. The short step synthesis of septoriamycin A, an antimalarial and antileishmanial agent, has been achieved by this methodology. PMID- 24490781 TI - Human leucocyte antigen frequency in a miscegenated population presenting with seborrhoeic dermatitis. PMID- 24490782 TI - Synthesis of selenazoles by in situ cycloisomerization of propargyl selenoamides using oxygen-selenium exchange reaction. AB - Herein, we describe an approach toward selenazole preparation based on the cycloisomerization of propargyl selenoamides. The selenoamides were synthesized in situ using the Ishihara reagent with spontaneous cyclization to form the 2,5 disubstituted selenazoles. Heterocylcles 9a-j were prepared using readily available starting materials, and yields ranged from moderate to good (20-80%). Methylselenazole 9a could be transformed into a bromomethyl derivative 13 using NBS. The intermediate 13 would provide a more versatile building block for further derivatizations, e.g., the cyanide 14. PMID- 24490783 TI - Cardiovascular impact of obstructive sleep apnea: does gender matter? AB - Obstructive sleep apnea (OSA) is a common disease characterized by recurrent upper airway obstruction, intermittent hypoxemia and sleep fragmentation. OSA is considered to be predominantly a disease of obese middle-aged men, and it is generally accepted that this disorder is at least twice more common in men than in women. Consistent evidence suggests that OSA is independently associated with cardiovascular risk; however, a significant proportion of the evidence relates to men with OSA. In this brief editorial, we will discuss if markers of cardiovascular risk and cardiovascular events observed in OSA are modulated by gender. We will then examine the evidence regarding the impact of OSA treatment on cardiovascular events in men and women. PMID- 24490784 TI - Microvascular dysfunction in the course of metabolic syndrome induced by high-fat diet. AB - BACKGROUND: Metabolic syndrome (MetS) is associated with increased risk of cardiovascular disease (CVD). One important feature underlying the pathophysiology of many types of CVD is microvascular dysfunction. Although components of MetS are themselves CVD risk factors, the risk is increased when the syndrome is considered as one entity. We aimed to characterize microvascular function and some of its influencing factors in the course of MetS development. METHODS: Development of MetS in C57BL/6 mice on a high-fat diet (HFD, 51% of energy from fat) was studied. The initial phase of MetS (I-MetS) was defined as the first 2 weeks of HFD feeding, with the fully developed phase occurring after 8 weeks of HFD. We characterized these phases by assessing changes in adiposity, blood pressure, and microvascular function. All data are presented as mean +/- standard error (SEM). Differences between cumulative dose-response curves of myograph experiments were calculated using non-linear regression analysis. In other experiments, comparisons between two groups were made with Student's t test. Comparisons between more than two groups were made using one-way ANOVA with Tukey post-hoc test. A probability value <0.05 was considered statistically significant. RESULTS: I-MetS mice presented with weight gain, blood pressure elevation, and microvascular dysfunction characterized by augmented vasoconstriction. This finding, contrary to those in mice with fully developed MetS, was not associated with endothelial dysfunction, insulin resistance, or systemic inflammation. In the initial phase, perivascular adipose tissue showed no sign of inflammation and had no influence on the pattern of vasoconstriction. These findings suggest that the onset of hypertension in MetS is strongly influenced by vascular smooth muscle cell dysfunction and independent of important factors known to influence microvascular function and consequently blood pressure levels. CONCLUSION: We identified in I-MetS the occurrence of isolated augmented vasoconstriction along with blood pressure elevation, but not the presence of classical MetS components known to influence microvascular function. These findings increase our understanding of the pathophysiology of CVD risk associated with MetS. PMID- 24490785 TI - Hockey Concussion Education Project, Part 2. Microstructural white matter alterations in acutely concussed ice hockey players: a longitudinal free-water MRI study. AB - OBJECT: Concussion is a common injury in ice hockey and a health problem for the general population. Traumatic axonal injury has been associated with concussions (also referred to as mild traumatic brain injuries), yet the pathological course that leads from injury to recovery or to long-term sequelae is still not known. This study investigated the longitudinal course of concussion by comparing diffusion MRI (dMRI) scans of the brains of ice hockey players before and after a concussion. METHODS: The 2011-2012 Hockey Concussion Education Project followed 45 university-level ice hockey players (both male and female) during a single Canadian Interuniversity Sports season. Of these, 38 players had usable dMRI scans obtained in the preseason. During the season, 11 players suffered a concussion, and 7 of these 11 players had usable dMRI scans that were taken within 72 hours of injury. To analyze the data, the authors performed free-water imaging, which reflects an increase in specificity over other dMRI analysis methods by identifying alterations that occur in the extracellular space compared with those that occur in proximity to cellular tissue in the white matter. They used an individualized approach to identify alterations that are spatially heterogeneous, as is expected in concussions. RESULTS: Paired comparison of the concussed players before and after injury revealed a statistically significant (p < 0.05) common pattern of reduced free-water volume and reduced axial and radial diffusivities following elimination of free-water. These free-water-corrected measures are less affected by partial volumes containing extracellular water and are therefore more specific to processes that occur within the brain tissue. Fractional anisotropy was significantly increased, but this change was no longer significant following the free-water elimination. CONCLUSIONS: Concussion during ice hockey games results in microstructural alterations that are detectable using dMRI. The alterations that the authors found suggest decreased extracellular space and decreased diffusivities in white matter tissue. This finding might be explained by swelling and/or by increased cellularity of glia cells. Even though these findings in and of themselves cannot determine whether the observed microstructural alterations are related to long-term pathology or persistent symptoms, they are important nonetheless because they establish a clearer picture of how the brain responds to concussion. PMID- 24490787 TI - The role of dialect density in nonword repetition performance: an examination with at-risk African American preschool children. AB - The Nonword Repetition Task (NRT) is considered to be a less-biased language measure for children from cultural minority groups. In the current study, we examined NRT performance of 50 at-risk, preschool-age children who spoke African American English (AAE). In addition to the NRT, measures included AAE dialect density and several standardised language tests. The primary aim was to determine significant contributors to NRT performance. We hypothesised that the language measures would significantly contribute to NRT performance while dialect density would be an insignificant contributor. Contrary to our predictions, dialect density was a unique and significant predictor of NRT performance (in addition to phonological awareness), while the language measures were not significant predictors. The current findings cast doubt on categorising the NRT as a less biased language assessment for AAE-speaking preschoolers; however, the NRT may have potential as a screener for identifying preschoolers at risk for delays in literacy acquisition. PMID- 24490786 TI - Discovery of human sORF-encoded polypeptides (SEPs) in cell lines and tissue. AB - The existence of nonannotated protein-coding human short open reading frames (sORFs) has been revealed through the direct detection of their sORF-encoded polypeptide (SEP) products. The discovery of novel SEPs increases the size of the genome and the proteome and provides insights into the molecular biology of mammalian cells, such as the prevalent usage of non-AUG start codons. Through modifications of the existing SEP-discovery workflow, we discover an additional 195 SEPs in K562 cells and extend this methodology to identify novel human SEPs in additional cell lines and human tissue for a final tally of 237 new SEPs. These results continue to expand the human genome and proteome and demonstrate that SEPs are a ubiquitous class of nonannotated polypeptides that require further investigation. PMID- 24490788 TI - A combined model of sensory and cognitive representations underlying tonal expectations in music: from audio signals to behavior. AB - Listeners' expectations for melodies and harmonies in tonal music are perhaps the most studied aspect of music cognition. Long debated has been whether faster response times (RTs) to more strongly primed events (in a music theoretic sense) are driven by sensory or cognitive mechanisms, such as repetition of sensory information or activation of cognitive schemata that reflect learned tonal knowledge, respectively. We analyzed over 300 stimuli from 7 priming experiments comprising a broad range of musical material, using a model that transforms raw audio signals through a series of plausible physiological and psychological representations spanning a sensory-cognitive continuum. We show that RTs are modeled, in part, by information in periodicity pitch distributions, chroma vectors, and activations of tonal space--a representation on a toroidal surface of the major/minor key relationships in Western tonal music. We show that in tonal space, melodies are grouped by their tonal rather than timbral properties, whereas the reverse is true for the periodicity pitch representation. While tonal space variables explained more of the variation in RTs than did periodicity pitch variables, suggesting a greater contribution of cognitive influences to tonal expectation, a stepwise selection model contained variables from both representations and successfully explained the pattern of RTs across stimulus categories in 4 of the 7 experiments. The addition of closure--a cognitive representation of a specific syntactic relationship--succeeded in explaining results from all 7 experiments. We conclude that multiple representational stages along a sensory-cognitive continuum combine to shape tonal expectations in music. PMID- 24490789 TI - On the ability to inhibit thought and action: general and special theories of an act of control. AB - Response inhibition is an important act of control in many domains of psychology and neuroscience. It is often studied in a stop-signal task that requires subjects to inhibit an ongoing action in response to a stop signal. Performance in the stop-signal task is understood as a race between a go process that underlies the action and a stop process that inhibits the action. Responses are inhibited if the stop process finishes before the go process. The finishing time of the stop process is not directly observable; a mathematical model is required to estimate its duration. Logan and Cowan (1984) developed an independent race model that is widely used for this purpose. We present a general race model that extends the independent race model to account for the role of choice in go and stop processes, and a special race model that assumes each runner is a stochastic accumulator governed by a diffusion process. We apply the models to 2 data sets to test assumptions about selective influence of capacity limitations on drift rates and strategies on thresholds, which are largely confirmed. The model provides estimates of distributions of stop-signal response times, which previous models could not estimate. We discuss implications of viewing cognitive control as the result of a repertoire of acts of control tailored to different tasks and situations. PMID- 24490790 TI - The perception of probability. AB - We present a computational model to explain the results from experiments in which subjects estimate the hidden probability parameter of a stepwise nonstationary Bernoulli process outcome by outcome. The model captures the following results qualitatively and quantitatively, with only 2 free parameters: (a) Subjects do not update their estimate after each outcome; they step from one estimate to another at irregular intervals. (b) The joint distribution of step widths and heights cannot be explained on the assumption that a threshold amount of change must be exceeded in order for them to indicate a change in their perception. (c) The mapping of observed probability to the median perceived probability is the identity function over the full range of probabilities. (d) Precision (how close estimates are to the best possible estimate) is good and constant over the full range. (e) Subjects quickly detect substantial changes in the hidden probability parameter. (f) The perceived probability sometimes changes dramatically from one observation to the next. (g) Subjects sometimes have second thoughts about a previous change perception, after observing further outcomes. (h) The frequency with which they perceive changes moves in the direction of the true frequency over sessions. (Explaining this finding requires 2 additional parametric assumptions.) The model treats the perception of the current probability as a by product of the construction of a compact encoding of the experienced sequence in terms of its change points. It illustrates the why and the how of intermittent Bayesian belief updating and retrospective revision in simple perception. It suggests a reinterpretation of findings in the recent literature on the neurobiology of decision making. PMID- 24490791 TI - Factorial comparison of working memory models. AB - Three questions have been prominent in the study of visual working memory limitations: (a) What is the nature of mnemonic precision (e.g., quantized or continuous)? (b) How many items are remembered? (c) To what extent do spatial binding errors account for working memory failures? Modeling studies have typically focused on comparing possible answers to a single one of these questions, even though the result of such a comparison might depend on the assumed answers to both others. Here, we consider every possible combination of previously proposed answers to the individual questions. Each model is then a point in a 3-factor model space containing a total of 32 models, of which only 6 have been tested previously. We compare all models on data from 10 delayed estimation experiments from 6 laboratories (for a total of 164 subjects and 131,452 trials). Consistently across experiments, we find that (a) mnemonic precision is not quantized but continuous and not equal but variable across items and trials; (b) the number of remembered items is likely to be variable across trials, with a mean of 6.4 in the best model (median across subjects); (c) spatial binding errors occur but explain only a small fraction of responses (16.5% at set size 8 in the best model). We find strong evidence against all 6 documented models. Our results demonstrate the value of factorial model comparison in working memory. PMID- 24490793 TI - Quality by design approach for formulation, evaluation and statistical optimization of diclofenac-loaded ethosomes via transdermal route. AB - The objective of this study was to fabricate and understand ethosomal formulations of diclofenac (DF) for enhanced anti-inflammatory activity using quality by design approach. DF-loaded ethosomal formulations were prepared using 4 * 5 full-factorial design with phosphatidylcholine:cholesterol (PC:CH) ratios ranging between 50:50 and 90:10, and ethanol concentration ranging between 0% and 30% as formulation variables. These formulations were characterized in terms of physicochemical properties and skin permeation kinetics. The interaction of formulation variables had a significant effect on both physicochemical properties and permeation kinetics. The results of multivariate regression analysis illustrated that vesicle size and elasticity of ethosomes were the dominating physicochemical properties affecting skin permeation, and could be suitably controlled by manipulation of formulation variables to optimize the formulation and enhance the skin permeation of DF-loaded ethosomes. The optimized formulation had ethanol concentration of 22.9% and PC:CH ratio of 88.4:11.6, with vesicle size of 144 +/- 5 nm, zeta potential of -23.0 +/- 3.76 mV, elasticity of 2.48 +/- 0.75 and entrapment efficiency of 71 +/- 4%. Permeation flux for the optimized formulation was 12.9 +/- 1.0 ug/h cm(2), which was significantly higher than the drug-loaded conventional liposome, ethanolic or aqueous solution. The in vivo study indicated that optimized ethosomal hydrogel exhibited enhanced anti inflammatory activity compared with liposomal and plain drug hydrogel formulations. PMID- 24490795 TI - Adhesion of gels by silica particle. AB - In this study, a method for achieving adhesion between two positively charged gels with high mechanical strength was developed. By utilizing a silica particle dispersion as a binder, the gels easily adhered to each other and remained stable for up to 11 days when immersed in aqueous solution. The adhesion force between the two positively charged semi-interpenetrating network gels with the silica particle was measured to be up to approximately 20 kPa, which is around 10 times larger than that with a charged polymer-rich liquid as a cross-linker (approximately 1.5 kPa). It was demonstrated that the adhesion force was a result of two types of interactions: an electrostatic attractive force between the cationic gel surface and hydrogen bonding among the silica particles. In addition, it was shown that the adhesion force was dependent on solution pH, which was attributed to changes in the charge of the silica particles. PMID- 24490796 TI - Imputation of non-genotyped individuals based on genotyped relatives: assessing the imputation accuracy of a real case scenario in dairy cattle. AB - BACKGROUND: Imputation of genotypes for ungenotyped individuals could enable the use of valuable phenotypes created before the genomic era in analyses that require genotypes. The objective of this study was to investigate the accuracy of imputation of non-genotyped individuals using genotype information from relatives. METHODS: Genotypes were simulated for all individuals in the pedigree of a real (historical) dataset of phenotyped dairy cows and with part of the pedigree genotyped. The software AlphaImpute was used for imputation in its standard settings but also without phasing, i.e. using basic inheritance rules and segregation analysis only. Different scenarios were evaluated i.e.: (1) the real data scenario, (2) addition of genotypes of sires and maternal grandsires of the ungenotyped individuals, and (3) addition of one, two, or four genotyped offspring of the ungenotyped individuals to the reference population. RESULTS: The imputation accuracy using AlphaImpute in its standard settings was lower than without phasing. Including genotypes of sires and maternal grandsires in the reference population improved imputation accuracy, i.e. the correlation of the true genotypes with the imputed genotype dosages, corrected for mean gene content, across all animals increased from 0.47 (real situation) to 0.60. Including one, two and four genotyped offspring increased the accuracy of imputation across all animals from 0.57 (no offspring) to 0.73, 0.82, and 0.92, respectively. CONCLUSIONS: At present, the use of basic inheritance rules and segregation analysis appears to be the best imputation method for ungenotyped individuals. Comparison of our empirical animal-specific imputation accuracies to predictions based on selection index theory suggested that not correcting for mean gene content considerably overestimates the true accuracy. Imputation of ungenotyped individuals can help to include valuable phenotypes for genome-wide association studies or for genomic prediction, especially when the ungenotyped individuals have genotyped offspring. PMID- 24490797 TI - Development of chloroplast simple sequence repeats (cpSSRs) for the intraspecific study of Gracilaria tenuistipitata (Gracilariales, Rhodophyta) from different populations. AB - BACKGROUND: Gracilaria tenuistipitata is an agarophyte with substantial economic potential because of its high growth rate and tolerance to a wide range of environment factors. This red seaweed is intensively cultured in China for the production of agar and fodder for abalone. Microsatellite markers were developed from the chloroplast genome of G. tenuistipitata var. liui to differentiate G. tenuistipitata obtained from six different localities: four from Peninsular Malaysia, one from Thailand and one from Vietnam. Eighty G. tenuistipitata specimens were analyzed using eight simple sequence repeat (SSR) primer-pairs that we developed for polymerase chain reaction (PCR) amplification. FINDINGS: Five mononucleotide primer-pairs and one trinucleotide primer-pair exhibited monomorphic alleles, whereas the other two primer-pairs separated the G. tenuistipitata specimens into two main clades. G. tenuistipitata from Thailand and Vietnam were grouped into one clade, and the populations from Batu Laut, Middle Banks and Kuah (Malaysia) were grouped into another clade. The combined dataset of these two primer-pairs separated G. tenuistipitata obtained from Kelantan, Malaysia from that obtained from other localities. CONCLUSIONS: Based on the variations in repeated nucleotides of microsatellite markers, our results suggested that the populations of G. tenuistipitata were distributed into two main geographical regions: (i) populations in the west coast of Peninsular Malaysia and (ii) populations facing the South China Sea. The correct identification of G. tenuistipitata strains with traits of high economic potential will be advantageous for the mass cultivation of seaweeds. PMID- 24490799 TI - Drug safety evaluation of ropinirole prolonged release. AB - INTRODUCTION: The need for multiple administrations and a difficult titration schedule has always represented a limit in the use of dopamine agonists in the treatment of early Parkinson's disease. To avoid these problems, Ropinirole prolonged release (RPR), a non-ergoline dopamine receptor agonist that can be taken once a day, has been formulated. The prolonged release formulation has higher patient compliance due to a simpler and fastest titration schedule; the once-a-day administration makes this molecule especially suitable for young Parkinsonian patients who are still working and having an active lifestyle. AREAS COVERED: In this paper, we will review ropinirole's mechanism of action including pharmacokinetics and pharmacodynamic data and the results of the main clinical studies in early and advanced PD patients. We will also discuss safety data shown during the experimental phase and after RPR commercialization. This article reviews the use of RPR in early and advanced Parkinsonian patients. Medical literature on the use of RPR in Parkinson's disease was identified using MEDLINE and the reference lists of published articles. EXPERT OPINION: RPR is effective in the treatment of patients with early Parkinson's disease; in advanced Parkinsonian patients, the amount of daily off-time significantly decreases, improving the mean on time. RPR has also demonstrated to be effective in ameliorating the quality of sleep without increasing the occurrence of daily sleepiness and nocturnal psychosis. RPR was generally well tolerated in both early and advanced Parkinsonian patients. PMID- 24490798 TI - Anti-inflammatory properties of a novel peptide interleukin 1 receptor antagonist. AB - BACKGROUND: Interleukin 1 (IL-1) is implicated in neuroinflammation, an essential component of neurodegeneration. We evaluated the potential anti-inflammatory effect of a novel peptide antagonist of IL-1 signaling, Ilantide. METHODS: We investigated the binding of Ilantide to IL-1 receptor type I (IL-1RI) using surface plasmon resonance, the inhibition of Il-1beta-induced activation of nuclear factor kappaB (NF-kappaB) in HEK-Blue cells that contained an IL-1beta sensitive reporter, the secretion of TNF-alpha in macrophages, protection against IL-1-induced apoptosis in neonatal pancreatic islets, and the penetration of Ilantide through the blood-brain barrier using competitive enzyme-linked immunosorbent assay (ELISA). We studied the effects of the peptide on social behavior and memory in rat models of lipopolysaccharide (LPS)- and amyloid induced neuroinflammation, respectively, and its effect in a rat model of experimental autoimmune enchephalomyelitis. RESULTS: Ilantide bound IL-1RI, inhibited the IL-1beta-induced activation of NF-kappaB, and inhibited the secretion of TNF-alpha in vitro. Ilantide protected pancreatic islets from apoptosis in vitro and reduced inflammation in an animal model of arthritis. The peptide penetrated the blood-brain barrier. It reduced the deficits in social activity and memory in LPS- and amyloid-treated animals and delayed the development of experimental autoimmune enchephalomyelitis. CONCLUSIONS: These findings indicate that Ilantide is a novel and potent IL-1RI antagonist that is able to reduce inflammatory damage in the central nervous system and pancreatic islets. PMID- 24490801 TI - Assembly of the TgrB1-TgrC1 cell adhesion complex during Dictyostelium discoideum development. AB - In Dictyostelium discoideum, TgrB1 and TgrC1 are partners of a heterophilic cell adhesion system. To investigate its assembly process, the split GFP complementation assay was used to track the oligomeric status of both proteins. The ability of TgrC1 to form cis-homodimers spontaneously was demonstrated by fluorescence complementation studies and confirmed by chemical cross-linking. In contrast, TgrB1 failed to form cis-homodimers in the absence of TgrC1. Treatment of cell aggregates with antibodies against TgrB1 or TgrC1 did not affect TgrC1 dimerization, but inhibited TgrB1 dimer formation, suggesting that TgrB1 cis homodimerization is dependent on trans-interaction with TgrC1. When TgrB1 and TgrC1 conjugated with the complementary halves of GFP were co-expressed in cells, cis-heterodimers were not detected. However, weak FRET signals were detected in cells expressing TgrB1-RFP and TgrC1-GFP, suggesting that TgrB1 dimers and TgrC1 dimers were arranged juxtapose to each other in the adhesion complex. The results of the present study suggest that the assembly process is initiated upon trans interaction of monomeric TgrB1 with TgrC1 homodimers on adjacent cells, which triggers the formation of TgrB1 dimers. The homodimerization of TgrB1 in turn induces the clustering of TgrB1 and TgrC1, and the coalescence of TgrB1-TgrC1 clusters results in the formation of large adhesion complexes. PMID- 24490802 TI - Simple synthesis of mesoporous carbon nanofibers with hierarchical nanostructure for ultrahigh lithium storage. AB - In this study, a simple and reproducible synthesis strategy was developed to fabricate mesoporous carbon nanofibers (MCNFs) by using dual hard templates, a porous anodic aluminum oxide (AAO) membrane, and colloidal silica (Ludox TM-40). By using commercial templates, and removing AAO and the silica simultaneously, the synthesis procedures for MCNFs are greatly simplified without the need for separate preparation or the removal of templates in sequence. With phenol resin as a carbon precursor, the as-prepared MCNFs material reveals not only high surface area and mesoporous volume but also hierarchical nanostructure composed of hollow macrochannels derived from the AAO template, large mesopores (ca. 22 nm) from the removal of silica particles and micropores from the carbonization of phenol resin. Such unique surface and structural characteristics could provide a large quantity of active sites for Li storage and facilitate fast mass transport. Moreover, a one-dimensional (1D) carbon nanofiber (CNF) nanostructure favors fast electron transfer. The as-prepared MCNF anode demonstrates ultrahigh lithium storage capacity particularly at high rates, which is much higher than that reported for the commercial graphite and also significantly higher than other nanostructured carbon materials, such as ordered mesoporous carbon CMK-3 and ordered multimodal porous carbon (OMPC). PMID- 24490800 TI - A retrospective comparative exploratory study on two methylentetrahydrofolate reductase (MTHFR) polymorphisms in esophagogastric cancer: the A1298C MTHFR polymorphism is an independent prognostic factor only in neoadjuvantly treated gastric cancer patients. AB - BACKGROUND: Methylentetrahydrofolate reductase (MTHFR) plays a major role in folate metabolism and consequently could be an important factor for the efficacy of a treatment with 5-fluorouracil. Our aim was to evaluate the prognostic and predictive value of two well characterized constitutional MTHFR gene polymorphisms for primarily resected and neoadjuvantly treated esophagogastric adenocarcinomas. METHODS: 569 patients from two centers were analyzed (gastric cancer: 218, carcinoma of the esophagogastric junction (AEG II, III): 208 and esophagus (AEG I): 143). 369 patients received neoadjuvant chemotherapy followed by surgery, 200 patients were resected without preoperative treatment. The MTHFR C677T and A1298C polymorphisms were determined in DNA from peripheral blood lymphozytes. Associations with prognosis, response and clinicopathological factors were analyzed retrospectively within a prospective database (chi-square, log-rank, cox regression). RESULTS: Only the MTHFR A1298C polymorphisms had prognostic relevance in neoadjuvantly treated patients but it was not a predictor for response to neoadjuvant chemotherapy. The AC genotype of the MTHFR A1298C polymorphisms was significantly associated with worse outcome (p = 0.02, HR 1.47 (1.06-2.04). If neoadjuvantly treated patients were analyzed based on their tumor localization, the AC genotype of the MTHFR A1298C polymorphisms was a significant negative prognostic factor in patients with gastric cancer according to UICC 6th edition (gastric cancer including AEG type II, III: HR 2.0, 95% CI 1.3-2.0, p = 0.001) and 7th edition (gastric cancer without AEG II, III: HR 2.8, 95% CI 1.5 5.7, p = 0.003), not for AEG I. For both definitions of gastric cancer the AC genotype was confirmed as an independent negative prognostic factor in cox regression analysis. In primarily resected patients neither the MTHFR A1298C nor the MTHFR C677T polymorphisms had prognostic impact. CONCLUSIONS: The MTHFR A1298C polymorphisms was an independent prognostic factor in patients with neoadjuvantly treated gastric adenocarcinomas (according to both UICC 6th or 7th definitions for gastric cancer) but not in AEG I nor in primarily resected patients, which confirms the impact of this enzyme on chemotherapy associated outcome. PMID- 24490803 TI - Regio- and stereoselective aminopentadienylation of carbonyl compounds. AB - A simple and robust protocol is detailed for the preparation of enantioenriched alpha-substituted (1,4-pentadien-3-yl)amine derivatives. The methodology involves the addition of an in situ formed pentadienyl indium reagent to chiral tert butylsulfinimines, previously formed in the same pot. The addition takes place with excellent gamma-regio- and diastereoselectivity for a wide range of carbonyl compounds, including alpha-unsubstituted aldehydes and methyl alkyl ketones. The catalytic hydrogenation of the sulfinamines obtained provides a convenient access to chiral alpha-substituted (3-pentyl)amines. The hydroboration-oxidation of the alpha-(1,4-pentadien-3-yl)amine derivatives, followed by a cyclization under Mitsunobu conditions, takes place with an excellent diastereoselectivity governed by the chiral sulfinyl group. PMID- 24490804 TI - Electroluminescence from graphene quantum dots prepared by amidative cutting of tattered graphite. AB - Size-controlled graphene quantum dots (GQDs) are prepared via amidative cutting of tattered graphite. The power of this method is that the size of the GQDs could be varied from 2 to over 10 nm by simply regulating the amine concentration. The energy gaps in such GQDs are narrowed down with increasing their size, showing colorful photoluminescence from blue to brown. We also reveal the roles of defect sites in photoluminescence, developing long-wavelength emission and reducing exciton lifetime. To assess the viability of the present method, organic light emitting diodes employing our GQDs as a dopant are first demonstrated with the thorough studies in their energy levels. This is to our best knowledge the first meaningful report on the electroluminescence of GQDs, successfully rendering white light with the external quantum efficiency of ca. 0.1%. PMID- 24490805 TI - Predicting the electrochemical behavior of lithium nitrite in acetonitrile with quantum chemical methods. AB - Electrolyte stability is an essential prerequisite for the successful development of a rechargeable organic electrolyte Li-O2 battery. Lithium nitrate (LiNO3) salt was employed in our previous work because it was capable of stabilizing a solid electrolyte interphase on the Li anode. The byproduct of this process is lithium nitrite (LiNO2), the fate of which in a Li-O2 battery is unknown. In this work, we employ density functional theory and coupled-cluster calculations combined with an implicit solvation model for neutral molecules and a mixed cluster/continuum model for single ions to understand the chemical and electrochemical behavior of LiNO2 in acetonitrile (AN). The redox potentials of oxygenated nitrogen compounds predicted in this study are in excellent agreement with the experimental results (the average accuracy is 0.10 V). Theoretical calculations suggest that the reaction between the nitrite ion and its first oxidation product, nitrogen dioxide (NO2), in AN solution proceeds via the initial formation of a trans-ONO-NO2 dimer that is subject to autoionization and the subsequent reaction of produced nitrosyl ion (NO(+)) with NO2(-). Good agreement between experimental and simulated cyclic voltammograms for electrochemical oxidation of LiNO2 in AN provides support to the proposed mechanism of coupled electrochemical and chemical reactions. The results suggest a possible mechanism of regeneration of LiNO3 in electrolyte in the presence of oxygen, which is uniquely possible under charging conditions in a Li-O2 battery. PMID- 24490806 TI - Phenylalanine-free taste-masked orodispersible tablets of fexofenadine hydrochloride: development, in vitro evaluation and in vivo estimation of the drug pharmacokinetics in healthy human volunteers. AB - CONTEXT: Fexofenadine hydrochloride (FXD) is a slightly soluble, bitter-tasting, drug having an oral bioavailability of 35%. The maximum plasma concentration is reached 2.6 h (T(max)) post-dose. OBJECTIVE: Developing taste-masked FXD orodispersible tablets (ODTs) to increase extent of drug absorption and reduce Tmax. METHODS: Taste masking was achieved via solid dispersion (SD) with chitosan (CS) or sodium alginate (ALG). Fourier transform infrared spectroscopy, differential scanning calorimetry and X-ray diffraction were performed to identify physicochemical interactions and FXD crystallinity. Taste-masked FXD ODTs were developed via addition of superdisintegrants (croscarmellose sodium or sodium starch glycolate, 5% and 10%, w/w) or sublimable agents (camphor, menthol or thymol; 10% and 20%, w/w) to FXD-SDs. ODTs were evaluated for weight variation, drug-content, friability, wetting, disintegration and drug release. Camphor-based (20%, w/w) FXD-ODT (F12) was optimized (F23) by incorporation of a more hydrophilic lubricant (Pruv((r))), visualized via scanning electron microscopy and evaluated for FXD pharmacokinetics in healthy volunteers relative to Allegra((r)) tablets. RESULTS: Based on gustatory sensation test, FXD-CS (1:1) and FXD-ALG (1:0.5) SDs were selected. Taste-masked FXD-ODTs had appropriate physicochemical properties. Drug release profiles of F23 and the phenylalanine containing Allegra((r)) ODT were similar (f(2) = 96). Pores were observed following camphor sublimation. The pharmacokinetic studies proved F23 ability to increase extent of FXD absorption and reduce T(max). PMID- 24490807 TI - Experimental and theoretical investigation of the distance dependence of localized surface plasmon coupled Forster resonance energy transfer. AB - The distance dependence of localized surface plasmon (LSP) coupled Forster resonance energy transfer (FRET) is experimentally and theoretically investigated using a trilayer structure composed of separated monolayers of donor and acceptor quantum dots with an intermediate Au nanoparticle layer. The dependence of the energy transfer efficiency, rate, and characteristic distance, as well as the enhancement of the acceptor emission, on the separations between the three constituent layers is examined. A d(-4) dependence of the energy transfer rate is observed for LSP-coupled FRET between the donor and acceptor planes with the increased energy transfer range described by an enhanced Forster radius. The conventional FRET rate also follows a d(-4) dependence in this geometry. The conditions under which this distance dependence is valid for LSP-coupled FRET are theoretically investigated. The influence of the placement of the intermediate Au NP is investigated, and it is shown that donor-plasmon coupling has a greater influence on the characteristic energy transfer range in this LSP-coupled FRET system. The LSP-enhanced Forster radius is dependent on the Au nanoparticle concentration. The potential to tune the characteristic energy transfer distance has implications for applications in nanophotonic devices or sensors. PMID- 24490808 TI - Total synthesis of (-)-18-epi-peloruside A: an alkyne linchpin strategy. AB - A convergent synthetic route toward cytotoxic agent peloruside A that hinges on the use of an alkyne linchpin to assemble the natural product is described. Other highlights of this synthesis include an asymmetric desymmetrization reaction of a 1,3-diol, a one-pot conversion of a dibromoolefin to a stereodefined enone, and a diastereoselective aldol condensation. Misassignment of the absolute stereochemistry of the C18 stereocenter in our synthesis provided the natural product epimeric at the C18 ethyl stereocenter. PMID- 24490809 TI - The DPP-4 inhibitor sitagliptin attenuates the progress of atherosclerosis in apolipoprotein-E-knockout mice via AMPK- and MAPK-dependent mechanisms. AB - BACKGROUND: The dipeptidyl peptidase-4 inhibitor sitagliptin, a new anti-diabetic medicine, is effective in treating type 2 diabetes mellitus by increasing the activation and duration of action of glucagon-like peptide-1. Since atherosclerosis is the main pathological feature of diabetic cardiovascular complications, it is important to investigate the anti-atherosclerotic effect of sitagliptin and explore the relevant mechanisms. METHODS: Male apolipoprotein-E knockout mice were randomly divided into two groups and fed either high-fat diet (HFD) or HFD plus sitagliptin at a concentration of 0.3% for 16 weeks. Body weight, food intake, blood glucose, serum lipids and adhesion molecules were measured. The atherosclerotic plaque area and its histological composition were analyzed using Sudan staining and immunohistochemistry. The expression of inflammatory cytokines (monocyte chemoattractant protein (MCP)-1 and interleukin (IL)-6) and the activation of AMP-activated protein kinase (AMPK) and mitogen activated protein kinase (MAPK) in the aortas were determined using quantitative polymerase chain reaction and western blot, respectively. RESULTS: Mice treated with sitagliptin developed fewer atherosclerotic plaques than the control group (7.64 +/- 1.98% vs 12.91 +/- 1.15%, p < 0.001), particularly in the aortic arch and abdominal aorta, where plaques were decreased 1.92- and 2.74-fold, respectively (p < 0.05 and p < 0.01). Sitagliptin significantly reduced the content of collagen fiber in plaques 1.2-fold (p < 0.05). Moreover, sitagliptin significantly reduced the expression of monocyte chemoattractant protein-1 and interleukin-6 in the aorta (p < 0.01 and p < 0.05), as well as the serum levels of soluble vascular cell adhesion molecule-1 and P-selectin (both p < 0.05). In addition, Sitagliptin induced phosphorylation of AMPK and Akt (p < 0.05 and p < 0.01), while suppressed phosphorylation of p38 and extracellular signal-regulated kinase (Erk) 1/2 (p < 0.05 and p < 0.01) in aortas. CONCLUSIONS: Our present study indicates that sitagliptin can reduce the area of the atherosclerotic lesion, possibly by regulating the AMPK and MAPK pathways and then reducing leukocyte -endothelial cell interaction and inflammation reactions. These actions are independent of weight loss and glucose-reducing effects. PMID- 24490810 TI - Determinants of modern contraceptive utilization among married women of reproductive age group in North Shoa Zone, Amhara Region, Ethiopia. AB - BACKGROUND: Ethiopia is the second most populous country in Africa with high fertility and fast population growth rate. It is also one of the countries with high maternal and child mortality rate in sub-Saharan Africa Family planning is a crucial strategy to halt the fast population growth, to reduce child mortality and improve maternal health (Millennium Development Goal 4 and 5). Therefore, this study aimed to assess the prevalence and determinants of modern contraceptive utilization among married women of reproductive age group. METHODS: A community based cross-sectional study was conducted from August 15 to September 1, 2010 among married women aged 15-49 years in Debre Birhan District. Multistage sampling technique was used to select a total of 851 study participants. A pre tested structured questionnaire was used for gathering data. Bivariate and multivariate logistic regression analyses were performed using SPSS version 16.0 statistical package. RESULTS: Modern contraceptive prevalence rate among currently married women was 46.9%. Injectable contraceptives were the most frequently used methods (62.9%), followed by intrauterine device (16.8%), pills (14%), norplant (4.3%), male condom (1.2%) and female sterilization (0.8%). Multiple logistic regression model revealed that the need for more children (AOR 9.27, 95% CI 5.43-15.84), husband approve (AOR 2.82, 95% CI 1.67-4.80), couple's discussion about family planning issues (AOR 7.32, 95% CI 3.60-14.86). Similarly, monthly family income and number of living children were significantly associated with the use of modern contraceptives. CONCLUSION: Modern contraceptive use was high in the district. Couple's discussion and husband approval of contraceptives use were significantly associated with the use of modern contraceptives. Therefore, district health office and concerned stakeholders should focus on couples to encourage communication and male involvement for family planning. PMID- 24490811 TI - In vitro diagnosis of Hymenoptera venom allergy and further development of component resolved diagnostics. AB - For most people Hymenoptera stings result in transient and bothersome local inflammatory responses characterized by pain, itching, redness and swelling. In contrast, for those presenting an IgE-mediated allergic reaction, a re-sting may cause life-threatening reactions. In such patients, correct diagnosis is an absolute prerequisite for effective management, i.e. venom-specific immunotherapy. Generally, identification of the offending insect involves a detailed history along with quantification of venom-specific IgE antibodies and venom skin tests. Unfortunately, due to uncertainties associated with both tests, correct diagnosis is not always straightforward. This review summarizes the potentials and limitations of the various in vitro tests that are currently being used in the diagnosis of Hymenoptera venom allergy. Particular attention is paid to the potential of novel cellular tests such as basophil activation tests and component-resolved diagnosis with recombinant venom allergens in the diagnostic approach of patients with difficult diagnosis, i.e. cases in whom traditional venom specific IgE and skin tests yield equivocal or negative results. Finally, this review also covers the recent discoveries in the field of proteome research of Hymenoptera venoms and the selection of cell types for recombinant allergens production. PMID- 24490812 TI - Thermoregulated formation and disintegration of cationic block copolymer vesicles: fluorescence resonance energy transfer study. AB - Formation and disintegration of self-assembled nanostructures in response to external stimuli are important phenomena that have been widely explored for a variety of biomedical applications. In this contribution, we report the thermally triggered assembly of block copolymer molecules in aqueous solution to form vesicles (polymersomes) and their disassembly on reduction of temperature. A new thermoresponsive diblock copolymer of poly(N-isopropylacrylamide) poly((3 methacrylamidopropyl)trimethylammonium chloride) (PNIPA-b-PMAPTAC) was synthesized by reversible addition-fragmentation chain transfer technique. The solution properties and self-assembling behavior of the block copolymer molecules were studied by turbidimetry, temperature-dependent proton nuclear magnetic resonance, fluorescence spectroscopy, dynamic light scattering, and transmission electron microscopy. Fluorescence resonance energy transfer studies between coumarin-153 (C-153, donor) and rhodamine 6G (R6G, acceptor) have been performed by steady-state and picosecond-resolved fluorescence spectroscopy to probe the structural and dynamic heterogeneity of the vesicles. The occurrence of efficient energy transfer was evident from the shortening of donor lifetime in the presence of the acceptor. The capability of the vesicles to encapsulate both hydrophobic and hydrophilic molecules and release them in response to decrease in temperature makes them potentially useful as drug delivery vehicles. PMID- 24490813 TI - Role of Toll-like receptors in diabetic nephropathy. AB - Diabetic nephropathy is the leading cause of kidney failure and its increasing prevalence and incidence has imposed global socio-economic stress on healthcare systems worldwide. Although historically considered a metabolic disorder, recent studies have established that inflammatory responses are central to the pathogenesis of diabetic nephropathy. TLRs (Toll-like receptors) are a family of pattern recognition receptors responsible for the initiation of inflammatory and immune responses. The regulation of TLR2 and TLR4 have been implicated in the pathogenesis of various kidney diseases, and emerging evidence shows their involvement in the perpetuation of inflammation in the diabetic kidney. The present review focuses on the relative contributions of TLR2 and TLR4 in recognizing endogenous ligands relevant to diabetic nephropathy and their subsequent activation of NF-kappaB (nuclear factor kappaB), which results in the synthesis and secretion of pro-inflammatory cytokines and chemokines. Moreover, we discuss the pro-inflammatory signalling pathways of TLR2 and TLR4, in which their interruption or blockade may prove to be important therapeutic targets, potentially translated into clinical treatments for diabetic nephropathy. Currently, inhibitors to TLR2 and TLR4 are undergoing clinical trials in various inflammatory models of disease, but none in patients with diabetic nephropathy. Given the existing literature, there is a fundamental necessity to undertake trials in patients with diabetic nephropathy with a focus on renal end points. PMID- 24490815 TI - Neutrophilic eccrine hidradenitis in a patient with Crohn's disease and azathioprine hypersensitivity syndrome. PMID- 24490814 TI - The central renin-angiotensin system and sympathetic nerve activity in chronic heart failure. AB - CHF (chronic heart failure) is a multifactorial disease process that is characterized by overactivation of the RAAS (renin-angiotensin-aldosterone system) and the sympathetic nervous system. Both of these systems are chronically activated in CHF. The RAAS consists of an excitatory arm involving AngII (angiotensin II), ACE (angiotensin-converting enzyme) and the AT1R (AngII type 1 receptor). The RAAS also consists of a protective arm consisting of Ang-(1-7) [angiotensin-(1-7)], the AT2R (AngII type 2 receptor), ACE2 and the Mas receptor. Sympatho-excitation in CHF is driven, in large part, by an imbalance of these two arms, with an increase in the AngII/AT1R/ACE arm and a decrease in the AT2R/ACE2 arm. This imbalance is manifested in cardiovascular-control regions of the brain such as the rostral ventrolateral medulla and paraventricular nucleus in the hypothalamus. The present review focuses on the current literature that describes the components of these two arms of the RAAS and their imbalance in the CHF state. Moreover, the present review provides additional evidence for the relevance of ACE2 and Ang-(1-7) as key players in the regulation of central sympathetic outflow in CHF. Finally, we also examine the effects of exercise training as a therapeutic strategy and the molecular mechanisms at play in CHF, in part, because of the ability of exercise training to restore the balance of the RAAS axis and sympathetic outflow. PMID- 24490816 TI - Molecular phylogeny of Salmo of the western Balkans, based upon multiple nuclear loci. AB - BACKGROUND: Classification of species within the genus Salmo is still a matter of discussion due to their high level of diversity and to the low power of resolution of mitochondrial (mt)DNA-based phylogeny analyses that have been traditionally used in evolutionary studies of the genus. We apply a new marker system based on nuclear (n)DNA loci to present a novel view of the phylogeny of Salmo representatives and we compare it with the mtDNA-based phylogeny. METHODS: Twenty-two nDNA loci were sequenced for 76 individuals of the brown trout complex: Salmo trutta (Danubian, Atlantic, Adriatic, Mediterranean and Duero mtDNA lineages), Salmo marmoratus (marble trout), Salmo obtusirostris (softmouth trout), and Salmo ohridanus (Ohrid belvica or belushka). Sequences were phylogenetically analyzed using maximum-likelihood and Bayesian Inference methods. The divergence time of the major clades was estimated using the program BEAST. RESULTS: The existence of five genetic units i.e. S. salar, S. ohridanus, S. obtusirostris, S. marmoratus and the S. trutta complex, including its major phylogenetic lineages was confirmed. Contrary to previous observations, S. obtusirostris was found to be sister to the S. trutta complex and the S. marmoratus clade rather than to the S. ohridanus clade. Reticulate evolution of S. obtusirostris was confirmed and a time for its pre-glacial origin suggested. S. marmoratus was found to be a separate species as S. trutta and S. obtusirostris. Relationships among lineages within the S. trutta complex were weakly supported and remain largely unresolved. CONCLUSIONS: Nuclear DNA-based results showed a fairly good match with the phylogeny of Salmo inferred from mtDNA analyses. The comparison of nDNA and mtDNA data revealed at least four cases of mitochondrial-nuclear DNA discordance observed that were all confined to the Adriatic basin of the Western Balkans. Together with the well-known extensive morphological and genetic variability of Balkan trouts, this observation highlights an interesting and variegated evolutionary history of Salmo in this area. PMID- 24490817 TI - Diabetes mellitus suppresses hemodialysis-induced increases in tear fluid secretion. AB - BACKGROUND: Hemodialysis is essential for the survival of patients suffering from chronic renal failure. However, in diabetics the incidence of dry eye disease is higher than in non-diabetic individuals. Accordingly, we evaluated if this difference is attributable to different effects of hemodialysis on basal tear fluid secretion. METHODS: A modified Schirmer's eye test determined if hemodialysis improved basal tear secretion rates in 36 diabetic and non-diabetic patients undergoing hemodialysis. RESULTS: Basal tear secretion was invariant in diabetic patients whereas in non-diabetic individuals this process increased. CONCLUSION: In non-diabetic patients, autonomic neuropathy appears to be less severe and somewhat reversible since only in these individuals hemodialysis improved basal tear fluid secretion. This difference may be a factor contributing to the lower incidence of dry eye disease in non-diabetic patients. PMID- 24490818 TI - Metacognition of multitasking: How well do we predict the costs of divided attention? AB - Risky multitasking, such as texting while driving, may occur because people misestimate the costs of divided attention. In two experiments, participants performed a computerized visual-manual tracking task in which they attempted to keep a mouse cursor within a small target that moved erratically around a circular track. They then separately performed an auditory n-back task. After practicing both tasks separately, participants received feedback on their single task tracking performance and predicted their dual-task tracking performance before finally performing the 2 tasks simultaneously. Most participants correctly predicted reductions in tracking performance under dual-task conditions, with a majority overestimating the costs of dual-tasking. However, the between-subjects correlation between predicted and actual performance decrements was near 0. This combination of results suggests that people do anticipate costs of multitasking, but have little metacognitive insight on the extent to which they are personally vulnerable to the risks of divided attention, relative to other people. PMID- 24490819 TI - Endoplasmic reticulum stress induced by zinc oxide nanoparticles is an earlier biomarker for nanotoxicological evaluation. AB - Zinc oxide nanoparticles (ZnO NPs) have been widely used in cosmetics and sunscreens, advanced textiles, self-charging and electronic devices; the potential for human exposure and the health impact at each stage of their manufacture and use are attracting great concerns. In addition to pulmonary damage, nanoparticle exposure is also strongly correlated with the increase in incidences of cardiovascular diseases; however, their toxic potential remains largely unclear. Herein, we investigated the cellular responses and endoplasmatic reticulum (ER) stress induced by ZnO NPs in human umbilical vein endothelial cells (HUVECs) in comparison with the Zn2+ ions and CeO2 NPs. We found that the dissolved zinc ion was the most significant factor for cytotoxicity in HUVECs. More importantly, ZnO NPs at noncytotoxic concentration, but not CeO2 NPs, can induce significant cellular ER stress response with higher expression of spliced xbp-1, chop, and caspase-12 at the mRNA level, and associated ER marker proteins including BiP, Chop, GADD34, p-PERK, p-eIF2alpha, and cleaved Caspase-12 at the protein levels. Moreover, ER stress was widely activated after treatment with ZnO NPs, while six of 84 marker genes significantly increased. ER stress response is a sensitive marker for checking the interruption of ER homeostasis by ZnO NPs. Furthermore, higher dosage of ZnO NPs (240 MUM) quickly rendered ER stress response before inducing apoptosis. These results demonstrate that ZnO NPs activate ER stress-responsive pathway and the ER stress response might be used as an earlier and sensitive end point for nanotoxicological study. PMID- 24490820 TI - Statin use and the risk of breast cancer: a population-based case-control study. AB - OBJECTIVE: The aim of this study was to investigate whether the use of statins was associated with breast cancer risk. BACKGROUND: Experimental studies have shown that statins have potential protective effects against cancer. METHODS: We conducted a population-based case-control study in Taiwan. Cases consisted of all patients who were aged 50 years and older and had a first-time diagnosis of breast cancer for the period between 2004 and 2011. The controls were matched to cases by age, sex and index date. Adjusted odds ratios (ORs) and 95% CIs were estimated by using multiple logistic regression. RESULTS: We examined 565 breast cancer cases and 2260 controls. The unadjusted OR for any statin prescription was 1.19 (95% CI = 0.95 - 1.49) and the adjusted OR was 1.13 (95% CI = 0.84 - 1.51). Compared with no use of statins, the adjusted ORs were 1.02 (95% CI = 0.61 - 1.69) for the group with cumulative defined daily doses (DDDs) below 44.67 DDDs, 1.21 (95% CI = 0.83 - 1.76) for the group with cumulative dose between 44.68 DDDs and 308 DDDs, and 1.10 (95% CI = 0.66 - 1.83) for the group with the highest cumulative dose (> 308 DDDs). CONCLUSIONS: The present data do not provide evidence to support either beneficial or harmful associations between statin use and breast cancer risk. PMID- 24490821 TI - Intensity dependence of the excited state lifetimes and triplet conversion yield in the Fenna-Matthews-Olson antenna protein. AB - The Fenna-Matthews-Olson (FMO) protein is a soluble light-harvesting, bacteriochlorophyll a (BChl a) containing antenna complex found in green sulfur bacteria. We have measured time-resolved fluorescence and transient absorption at variable laser intensities at 298 and 77 K using FMO protein from Chlorobaculum tepidum prepared in both oxidizing and reducing environments. Fitting of the spectroscopic data shows that high laser intensities (i.e., above 10(13) photons * cm(-2) delivered per laser pulse) distort the intrinsic decay processes in this complex. At high laser intensities, both oxidized and reduced FMO samples behave similarly, exhibiting high levels of singlet-singlet annihilation. At lower laser intensities, the reduced protein mainly displays a singlet excited state lifetime of 2 ns, although upon oxidation, a 60 ps lifetime dominates. We also demonstrate that the apparent quantum yield of singlet-triplet intersystem crossing in the reduced FMO complex is ~11% in the most favorable low laser intensities, with this yield decreasing and the probability of singlet-singlet annihilation yield increasing as laser intensity increases. After correcting for stimulated emission effects in the experiments, the actual maximum triplet yield is calculated to be ~27%. Experiments at 77 K demonstrate that BChl a triplet states in FMO are localized on pigments no. 4 or 3, the lowest energy pigments in the complex. This study allows for a discussion of how BChl triplets form and evolve on the picosecond-to-nanosecond time scale, as well as whether triplet conversion is a physiologically relevant process. PMID- 24490823 TI - Biaxially mechanical tuning of 2-D reversible and irreversible surface topologies through simultaneous and sequential wrinkling. AB - Controlled buckling is a facile means of structuring surfaces. The resulting ordered wrinkling topologies provide surface properties and features desired for multifunctional applications. Here, we study the biaxially dynamic tuning of two dimensional wrinkled micropatterns under cyclic mechanical stretching/releasing/restretching simultaneously or sequentially. A biaxially prestretched PDMS substrate is coated with a stiff polymer deposited by initiated chemical vapor deposition (iCVD). Applying a mechanical release/restretch cycle in two directions loaded simultaneously or sequentially to the wrinkled system results in a variety of dynamic and tunable wrinkled geometries, the evolution of which is investigated using in situ optical profilometry, numerical simulations, and theoretical modeling. Results show that restretching ordered herringbone micropatterns, created through sequential release of biaxial prestrain, leads to reversible and repeatable surface topography. The initial flat surface and the same wrinkled herringbone pattern are obtained alternatively after cyclic release/restretch processes, owing to the highly ordered structure leaving no avenue for trapping irregular topological regions during cycling as further evidenced by the uniformity of strains distributions and negligible residual strain. Conversely, restretching disordered labyrinth micropatterns created through simultaneous release shows an irreversible surface topology whether after sequential or simultaneous restretching due to creation of irregular surface topologies with regions of highly concentrated strain upon formation of the labyrinth which then lead to residual strains and trapped topologies upon cycling; furthermore, these trapped topologies depend upon the subsequent strain histories as well as the cycle. The disordered labyrinth pattern varies after each cyclic release/restretch process, presenting residual shallow patterns instead of achieving a flat state. The ability to dynamically tune the highly ordered herringbone patterning through mechanical stretching or other actuation makes these wrinkles excellent candidates for tunable multifunctional surfaces properties such as reflectivity, friction, anisotropic liquid flow or boundary layer control. PMID- 24490822 TI - Inhibition of HSP90 attenuates porcine reproductive and respiratory syndrome virus production in vitro. AB - BACKGROUND: Porcine reproductive and respiratory syndrome virus (PRRSV) infection leads to substantial economic losses to the swine industry worldwide. However, no effective countermeasures exist to combat this virus infection so far. The most common antiviral strategy relies on directly inhibiting viral proteins. However, this strategy invariably leads to the emergence of drug resistance due to the error-prone nature of viral ploymerase. Targeting cellular proteins required for viral infection for developing new generation of antivirals is gaining concern. Recently, heat shock protein 90 (HSP90) was found to be an important host factor for the replication of multiple viruses and the inhibition of HSP90 showed significant antiviral effects. It is thought that the inhibition of HSP90 could be a promising broad-range antiviral approach. However, the effects of HSP90 inhibition on PRRSV infection have not been evaluated. In the current research, we tried to inhibit HSP90 and test whether the inhibition affect PRRSV infection. METHODS: We inhibit the function of HSP90 with two inhibitors, geldanamycin (GA) and 17- allylamono-demethoxygeldanamycin (17-AAG), and down-regulated the expression of endogenous HSP90 with specific small-interfering RNAs (siRNAs). Cell viability was measured with alamarBlue. The protein level of viral N was determined by western blotting and indirect immunofluorescence (IFA). Besides, IFA was employed to examine the level of viral double-stranded RNA (dsRNA). The viral RNA copy number and the level of IFN-beta mRNA were determined by quantitative real-time PCR (qRT-PCR). RESULTS: Our results indicated that both HSP90 inhibitors showed strong anti-PRRSV activity. They could reduce viral production by preventing the viral RNA synthesis. These inhibitory effects were not due to the activation of innate interferon response. In addition, we observed that individual knockdown targeting HSP90alpha or HSP90beta did not show dramatic inhibitory effect. Combined knockdown of these two isoforms was required to reduce viral infection. CONCLUSIONS: Our results shed light on the possibility of developing potential therapeutics targeting HSP90 against PRRSV infection. PMID- 24490824 TI - 2-Aminopyridines via reaction of pyridine N-oxides and activated isocyanides. AB - A practical and efficient method for the synthesis of substituted 2 aminopyridines from pyridine N-oxides is reported. Yields of purified, isolated products of up to 84% are observed for the one-pot, two-step process. The reaction involves an in situ deprotection of an isolable N-formylaminopyridine intermediate and facilitates the synthesis of 2-aminopyridines for which other methods fail. PMID- 24490825 TI - Total antioxidant capacity and phenolic content of the Brazilian diet: a real scenario. AB - The present study aimed to estimate the total dietary antioxidant capacity (TDAC) taken in by the Brazilian population. For analysis, the 36 most consumed foods in Brazil were evaluated. The foods were prepared according to their usual form of consumption and submitted to in vitro digestion. The daily intake of phenolics and flavonoids was estimated to be 2.31 +/- 0.12 g and 374.12 +/- 18.17 mg, respectively. The TDAC, evaluated as the ferric-reducing antioxidant power and as the trolox equivalent antioxidant capacity, was 10.3 and 9.4 mmol/d, respectively. The beverages, especially coffee, followed by beans, rice and salt bread were the most important sources of antioxidants. The average intake of phenolics and flavonoids of the Brazilian diet was comparatively higher than that estimated for several other countries. However, the contribution of fruits and vegetables to the phenolic intake and TDAC was minimal (4-6%). PMID- 24490826 TI - Risk factors and health during pregnancy among women previously exposed to sexual violence. AB - OBJECTIVE: To determine whether women exposed to sexual violence in adolescence or adulthood are at increased risk of adverse maternal characteristics during subsequent pregnancies. DESIGN: Register-based cohort study. SETTING: Iceland. POPULATION: We identified 586 women who attended a Rape Trauma Service (RTS) between 1993 and 2008 and all subsequent births of these women up to April 2011 (n = 915). These pregnancies were compared with 1641 randomly selected pregnancies of women who had not attended the RTS and who gave birth during the same calendar month. METHODS: Information on maternal smoking, body mass index and illicit drug use was obtained from maternal charts. We used Poisson regression to obtain multivariable adjusted relative risks (aRR) with 95% CI contrasting prevalence of outcomes in the two groups. MAIN OUTCOME MEASURES: Characteristics and risk factors during pregnancy, including maternal smoking, body mass index, weight gain during pregnancy, illicit drug use. RESULTS: Compared with unexposed women, sexually assaulted women were younger and more often primiparous in subsequent pregnancy, more likely not to be employed (7.8% vs. 4.3%; aRR 2.42, 95% CI 1.49-3.94), not cohabiting (45.6% vs. 14.2%; aRR 2.15, 95% CI 1.75-2.65), smokers (45.4% vs. 13.5%; aRR 2.68, 95% CI 2.25-3.20), and more likely to have used illicit drugs during pregnancy (3.4% vs. 0.4%; aRR 6.27, 95% CI 2.13-18.43). Exposed primiparas were more likely to be obese (15.5% vs. 12.3%; aRR 1.56, 95% CI 1.15-2.12). CONCLUSIONS: Women with a history of sexual violence are more likely to have risk factors during pregnancy that may affect maternal health and fetal development. PMID- 24490827 TI - Intravenous immunoglobulin in systemic capillary leak syndrome: a case report and review of literature. AB - The systemic capillary leak syndrome (SCLS) is a rare condition characterized by unexplained episodic attacks of systemic capillary hyperpermeability accompanied by hypoalbuminemia, hemoconcentration and edema. Treatment of the acute phase is supportive, focusing on adequate fluid resuscitation. Many agents have been used to prevent acute attacks, including corticosteroids, beta2-agonists (aminophylline, theophylline, or terbutaline), infliximab, thalidomide and intravenous immunoglobulin (IVIg). beta2-agonists were the first-line maintenance therapy until a few years ago. In more recent years, IVIg became common first line prophylactic therapy in most patients with benefits at the dose of 2 g/kg once a month. We report the case of a 49-year-old man with SCLS treated successfully with a lower dose of IVIg (1 g/kg monthly) in the maintenance phase. He presented no acute episodes in a follow-up of 28 months. We describe prophylactic treatments for SCLS in literature and compare our patient to another 18 who received IVIg in follow-up. PMID- 24490828 TI - Development and characterization of itraconazole-loaded solid lipid nanoparticles for ocular delivery. AB - The purpose of this study was to investigate the feasibility of entrapping water insoluble drug itraconazole into solid lipid nanoparticles (SLNs) for topical ocular delivery. The drug-loaded SLNs were prepared from stearic acid and palmitic acid using different concentrations of polyvinyl alcohol employed as emulsifier. SLNs were prepared by the melt-emulsion sonication and low temperature-solidification method and characterized for particle size, zeta potential, drug loading and drug entrapment efficiency. The mean particle size of SLNs prepared with stearic acid ranged from 139 to 199 nm, while the SLNs prepared with palmitic acid had particle size in the range of 126-160 nm. The SLNs were spherical in shape. Stearic acid-SLNs showed higher entrapment of drug compared with palmitic acid-SLNs. Differential scanning calorimetry (DSC) and X ray diffraction measurements showed decrease in crystallinity of drug in the SLN formulations. The modified Franz-diffusion cell and freshly excised goat corneas were used to test drug corneal permeability. Permeation of itraconazole from stearic acid-SLNs was higher than that obtained with palmitic acid-SLNs. The SLNs showed clear zone of inhibition against Aspergillus flavus indicating antimicrobial efficacy of formulations. PMID- 24490829 TI - Dynamical properties of self-assembled surfactant-based mixtures: triggering of one-dimensional anomalous diffusion in bis(2-ethylhexyl)phosphoric acid/n octylamine systems. AB - The dynamic features of bis(2-ethylhexyl)phosphoric acid (HDEHP)/n-octylamine (NOA) mixtures have been investigated as a function of the NOA mole fraction and temperature by (1)H NMR spectroscopy and rheometry. All data consistently suggest a composition-induced glass-forming behavior. The microscopic factors responsible for this behavior have been highlighted and have been explained in terms of driving forces given by HDEHP-to-NOA proton transfer, the tendency of the resulting species to establish H bonds and to spatially segregate the alkyl chains. The study sheds light on the molecular mechanism responsible for the peculiar behavior of transport properties in such systems and furnishes basic knowledge to be used to design novel materials with planned physicochemical properties. PMID- 24490830 TI - Generalized pustular psoriasis caused by deficiency of interleukin-36 receptor antagonist successfully treated with granulocyte and monocyte adsorption apheresis. PMID- 24490832 TI - Immunosuppression abrogates resistance of young rabbits to Rabbit Haemorrhagic Disease (RHD). AB - Rabbit Haemorrhagic Disease (RHD) is caused by a calicivirus (RHDV) that kills 90% of infected adult European rabbits within 3 days. Remarkably, young rabbits are resistant to RHD. We induced immunosuppression in young rabbits by treatment with methylprednisolone acetate (MPA) and challenged the animals with RHDV by intramuscular injection. All of these young rabbits died within 3 days of infection due to fulminant hepatitis, presenting a large number of RHDV-positive dead or apoptotic hepatocytes, and a significant seric increase in cytokines, features that are similar to those of naive adult rabbits infected by RHDV. We conclude that MPA-induced immunosuppression abrogates the resistance of young rabbits to RHD, indicating that there are differences in the innate immune system between young and adult rabbits that contribute to their distinct resistance/susceptibility to RHDV infection. PMID- 24490833 TI - Case report: an atypical peripapillary uveal melanoma. AB - BACKGROUND: The treatment of uveal melanoma has seen a shift towards eye conserving treatments. Efforts have been made towards the identification of patients at high risk of metastatic disease with the use of prognostic fine needle biopsy, Monosomy 3 a risk factor for metastatic death thought to occur early in the development of uveal melanoma. CASE PRESENTATION: We report a case in which an atypical optic nerve lesion was found to be a peripapillary primary uveal melanoma with distinct non-pigmented and pigmented halves on gross dissection and corresponding disomy 3 and monosomy 3 halves. The tumour demonstrated rapid growth with apparent transformation from disomy 3 to monosomy 3. CONCLUSIONS: These are clinical features that challenge the current concepts of the cytogenetic pathogenesis of uveal melanoma and demonstrate the potential problems and limitations of prognostic fine needle biopsy and molecular classifications. PMID- 24490831 TI - Recent advances in in vivo applications of intein-mediated protein splicing. AB - Intein-mediated protein splicing has become an essential tool in modern biotechnology. Fundamental progress in the structure and catalytic strategies of cis- and trans-splicing inteins has led to the development of modified inteins that promote efficient protein purification, ligation, modification and cyclization. Recent work has extended these in vitro applications to the cell or to whole organisms. We review recent advances in intein-mediated protein expression and modification, post-translational processing and labeling, protein regulation by conditional protein splicing, biosensors, and expression of trans genes. PMID- 24490834 TI - Disease management patterns for postmenopausal women in Europe with hormone receptor-positive, human epidermal growth factor receptor-2 negative advanced breast cancer. AB - BACKGROUND: International guidelines for hormone-receptor-positive (HR(+)), human epidermal growth factor receptor-2 negative (HER2(-)) advanced breast cancer (BC) recommend sequential lines of hormonal therapy (HT), and only recommend chemotherapy for patients with extensive visceral involvement or rapidly progressive disease. This study evaluated actual physician-reported treatments for advanced BC in Europe. METHODS: We conducted a retrospective chart review of 355 postmenopausal women with HR(+), HER2(-) advanced BC who progressed on >=1 line of HT (adjuvant or advanced) and completed >=1 line of chemotherapy (advanced). Treatment choice was evaluated for each line of therapy. RESULTS: Of 355 patients, 111 (31%) received first-line chemotherapy, whereas 218 (61%) and 26 (7%) switched from HT to chemotherapy in second and third line, respectively. More patients receiving first-line HT had bone metastases (73% vs 27% chemotherapy). Patients treated with first-line chemotherapy had more brain (12% vs 3% HT) or extensive liver (13% vs 6% HT) metastases. Subgroup analysis of 188 patients who received first-line HT and had de novo advanced BC or relapsed/recurrent disease more than 1 year after adjuvant therapy found that the majority (89%; n = 167) of these patients switched to chemotherapy in second line. However, among these 167 patients, 27% had no significant changes in metastases between first and second line. Among the 73% of patients who had significant changes in metastases, 20% had no brain metastases or extensive visceral disease. CONCLUSIONS: Our study suggests that the guideline-recommended use of multiple HT lines is open to interpretation and that optimal treatment for European postmenopausal women with HR(+), HER2(-) advanced BC who responded to HT may not be achieved. PMID- 24490836 TI - Reusable floating-electrode sensor for the quantitative electrophysiological monitoring of a nonadherent cell. AB - We report a reusable floating-electrode sensor based on aligned semiconducting single-walled carbon nanotubes for the quantitative monitoring of the electrophysiological responses from a nonadherent cell. This method allowed us to monitor and distinguish the real-time responses from normal and small-cell lung cancer (SCLC) cells to the addition of nicotine. The difference was attributed to the overexpressed nicotinic acetylcholine receptors (nAChRs) in the SCLC cells. The sensor was also utilized to monitor the effect of various drugs on the cells. The treatment with inhibitors such as genistin or daidzein was found to reduce Ca(2+) influx in SCLC cells. Moreover, tamoxifen, though known as the antiestrogen compound, was found to only partly block the binding of daidzein to nAChRs. Significantly, the activities of multiple individual cells could be measured repeatedly using a single sensor device, enabling statistically meaningful measurements without errors from the device-to-device variations of the sensor characteristics. This capability of the quantitative monitoring of nonadherent cells should be a major breakthrough for electrophysiology research and various biomedical applications such as drug screening and therapeutic monitoring. PMID- 24490837 TI - A botryane metabolite with a new hexacyclic skeleton from an entomogenous fungus Hypocrea sp. AB - Hypocrolide A (1), a botryane metabolite with a new hexacyclic skeleton, was isolated from cultures of the entomogenous fungus Hypocrea sp. The proposed structure was confirmed by X-ray crystallography using Cu Kalpha radiation. The mixed-biogenetic skeleton could be derived from the hypothetical precursors related to coumarin and dihydrobotrydiol, and the latter may be derived from the coisolated 10-oxodehydrodihydrobotrydial (2) or a similar analogue. PMID- 24490835 TI - Assessment of the cardiovascular safety of saxagliptin in patients with type 2 diabetes mellitus: pooled analysis of 20 clinical trials. AB - BACKGROUND: It is important to establish the cardiovascular (CV) safety profile of novel antidiabetic drugs. METHODS: Pooled analyses were performed of 20 randomized controlled studies (N = 9156) of saxagliptin as monotherapy or add-on therapy in patients with type 2 diabetes mellitus (T2DM) as well as a subset of 11 saxagliptin + metformin studies. Adjudicated major adverse CV events (MACE; CV death, myocardial infarction [MI], and stroke) and investigator-reported heart failure were assessed, and incidence rates (IRs; events/100 patient-years) and IR ratios (IRRs; saxagliptin/control) were calculated (Mantel-Haenszel method). RESULTS: In pooled datasets, the IR point estimates for MACE and individual components of CV death, MI, and stroke favored saxagliptin, but the 95% CI included 1. IRR (95% CI) for MACE in the 20-study pool was 0.74 (0.45, 1.25). The Cox proportional hazard ratio (95% CI) was 0.75 (0.46, 1.21), suggesting no increased risk of MACE in the 20-study pool. In the 11-study saxagliptin + metformin pool, the IRR for MACE was 0.93 (0.44, 1.99). In the 20-study pool, the IRR for heart failure was 0.55 (0.27, 1.12). CONCLUSIONS: Analysis of pooled data from 20 clinical trials in patients with T2DM suggests that saxagliptin is not associated with an increased CV risk. PMID- 24490838 TI - Assessment of machine learning reliability methods for quantifying the applicability domain of QSAR regression models. AB - The vastness of chemical space and the relatively small coverage by experimental data recording molecular properties require us to identify subspaces, or domains, for which we can confidently apply QSAR models. The prediction of QSAR models in these domains is reliable, and potential subsequent investigations of such compounds would find that the predictions closely match the experimental values. Standard approaches in QSAR assume that predictions are more reliable for compounds that are "similar" to those in subspaces with denser experimental data. Here, we report on a study of an alternative set of techniques recently proposed in the machine learning community. These methods quantify prediction confidence through estimation of the prediction error at the point of interest. Our study includes 20 public QSAR data sets with continuous response and assesses the quality of 10 reliability scoring methods by observing their correlation with prediction error. We show that these new alternative approaches can outperform standard reliability scores that rely only on similarity to compounds in the training set. The results also indicate that the quality of reliability scoring methods is sensitive to data set characteristics and to the regression method used in QSAR. We demonstrate that at the cost of increased computational complexity these dependencies can be leveraged by integration of scores from various reliability estimation approaches. The reliability estimation techniques described in this paper have been implemented in an open source add-on package ( https://bitbucket.org/biolab/orange-reliability ) to the Orange data mining suite. PMID- 24490840 TI - Fabrication of complex free-standing nanostructures with concave and convex curvature via the layer-by-layer approach. AB - We report on the fabrication of unprecedented free-standing complex polymeric nanoobjects, which possess both concave and convex curvatures, by exploiting the layer-by-layer (LBL) deposition of polyelectrolytes. In a combined top down/bottom-up replication approach pore diameter-modulated anodic aluminum oxide (AAO) templates, fabricated by temperature modulation hard anodization (TMHA), were replicated with multilayers of poly(styrene sulfonate) (PSS) and poly(allylamine hydrochloride) (PAH) to yield open nanotubes with diameters in the wide and narrow segments of 210 and 150 nm, respectively. To obtain stable pore diameter-modulated nanopores, which possess segment lengths between 1 and 5 MUm and 5 and 10 MUm in the narrow and wide pore portion, respectively, conventional hard anodization of aluminum was followed by a subsequent temperature-modulated anodization. After removing the backside aluminum electrode, silanizing the aluminum oxide, and passivating the exposed membrane surface with a thin layer of gold, PSS and PAH were deposited alternatingly to yield LBL multilayers. For optimized LBL multilayer thicknesses and compactness, established in separate experiments on silicon substrates and nanoporous AAO with straight pores, free-standing polymeric nanoobjects with concave and convex curvatures, were obtained. These were stable for wall thickness to pore diameter ratios of >=0.08. PMID- 24490839 TI - Hockey Concussion Education Project, Part 1. Susceptibility-weighted imaging study in male and female ice hockey players over a single season. AB - OBJECT: Concussion, or mild traumatic brain injury (mTBI), is a commonly occurring sports-related injury, especially in contact sports such as hockey. Cerebral microbleeds (CMBs), which appear as small, hypointense lesions on T2* weighted images, can result from TBI. The authors use susceptibility-weighted imaging (SWI) to automatically detect small hypointensities that may be subtle signs of chronic and acute damage due to both subconcussive and concussive injury. The goal was to investigate how the burden of these hypointensities changes over time, over a playing season, and postconcussion, in comparison with subjects who did not suffer a medically observed and diagnosed concussion. METHODS: Images were obtained in 45 university-level adult male and female ice hockey players before and after a single Canadian Interuniversity Sports season. In addition, 11 subjects (5 men and 6 women) underwent imaging at 72 hours, 2 weeks, and 2 months after concussion. To identify subtle changes in brain tissue and potential CMBs, nonvessel clusters of hypointensities on SWI were automatically identified, and a hypointensity burden index was calculated for all subjects at the beginning of the season (BOS), the end of the season (EOS), and at postconcussion time points (where applicable). RESULTS: A statistically significant increase in the hypointensity burden, relative to the BOS, was observed for male subjects with concussions at the 2-week postconcussion time point. A smaller, nonsignificant rise in the burden for female subjects with concussions was also observed within the same time period. There were no significant changes in burden for nonconcussed subjects of either sex between the BOS and EOS time points. However, there was a statistically significant difference in the burden between male and female subjects in the nonconcussed group at both the BOS and EOS time points, with males having a higher burden. CONCLUSIONS: This method extends the utility of SWI from the enhancement and detection of larger (> 5 mm) CMBs, which are often observed in more severe cases of TBI, to cases involving smaller lesions in which visual detection of injury is difficult. The hypointensity burden metric proposed here shows statistically significant changes over time in the male subjects. A smaller, nonsignificant increase in the burden metric was observed in the female subjects. PMID- 24490841 TI - Integrative neuromuscular training and sex-specific fitness performance in 7-year old children: an exploratory investigation. AB - CONTEXT: Integrative neuromuscular training (INT) has successfully enhanced physical fitness and reduced abnormal biomechanics, which appear to decrease injury rates in adolescent female athletes. If not addressed at the proper time, low levels of physical fitness and abnormal mechanics may predispose female athletes to an increased risk of musculoskeletal injuries. OBJECTIVES: To evaluate sex-specific effects of INT on selected measures of health- and skill related fitness in children during physical education (PE). DESIGN: Cohort study. SETTING: Public primary school. PATIENTS OR OTHER PARTICIPANTS: Forty children (16 boys, 24 girls; age = 7.6 +/- 0.3 years, height = 124.5 +/- 6.4 cm, mass = 29.5 +/- 7.6 kg) from 2 second-grade PE classes. INTERVENTION(S): The classes were randomized into the PE-plus-INT group (10 boys, 11 girls) or the control group (6 boys, 13 girls) that participated in traditional PE. The INT was performed 2 times per week during the first approximately 15 minutes of each PE class and consisted of body weight exercises. MAIN OUTCOME MEASURE(S): Push-up, curl-up, standing long jump, single-legged hop, single-legged balance, sit-and reach flexibility test, shuttle run, and 0.8-km run. RESULTS: At baseline, the boys demonstrated higher levels of performance in most of the fitness measurements as evidenced by greater performance on the push-up, standing long jump, single-legged hop, shuttle run, and 0.8-km run (P < .05). In the evaluation of the training effects, we found intervention effects in the girls for enhanced INT-induced gains in performance relative to the control group on the curl-up, long jump, single-legged hop, and 0.8-km run (P < .05) after controlling for baseline. Boys did not demonstrate similar adaptations from the INT program (P >= .05). CONCLUSIONS: These data indicate that INT is an effective and time efficient addition to PE for enhancing motor skills and promoting physical activity in children. Seven-year-old girls appeared to be more sensitive to the effects of INT than 7-year-old boys. Future research is warranted to confirm these effects in larger cohorts of children. PMID- 24490842 TI - Examining the effectiveness of psychological strategies on physiologic markers: evidence-based suggestions for holistic care of the athlete. AB - CONTEXT: Current holistic rehabilitation blends both physical and psychological techniques. However, validation of the usefulness of psychological strategies is limited in the literature. OBJECTIVE: To quantify the effects of psychological strategies on both physiologic (salivary cortisol) and subjective assessments of stress. DESIGN: Randomized controlled clinical trial. SETTING: Laboratory. PATIENTS OR OTHER PARTICIPANTS: A total of 97 college-aged students (age = 20.65 +/- 4.38 years), most with little to no experience with psychological strategies. INTERVENTION(S): A 15-minute script via an iPod led the participant through visual imagery (cognitive relaxation) or deep breathing exercises (somatic relaxation) cues. The control group listened to 15 minutes of ambient nature sounds. MAIN OUTCOME MEASURE(S): Two samples (pretest, posttest) of salivary cortisol were analyzed using an enzyme immunoassay kit; the average was used for statistical analysis. Descriptive statistics and correlations were conducted to examine group differences in time of day, salivary cortisol, sex, Stress-O-Meter values, and Perceived Stress Scale scores. RESULTS: Salivary cortisol levels were lower in the treatment group than the control group (F2,97 = 15.62, P < .001). Females had higher scores on both the pretest Stress-O-Meter (5.15 +/- 1.796) and the Perceived Stress Scale (18.31 +/- 5.833) than males (4.25 +/- 1.741 and 15.272 +/- 5.390, respectively). CONCLUSIONS: Both cognitive and somatic relaxation strategies reduced cortisol levels. Participants who received verbal guidance achieved a larger cortisol reduction. However, the change in cortisol level was uncorrelated with the change in report of acute stress; females reported higher levels of stress. Clinical implications include attention to sex when assessing stress and providing coping skills during the rehabilitation process. PMID- 24490843 TI - Disinhibitory interventions and voluntary quadriceps activation: a systematic review. AB - OBJECTIVE: To determine the effects of various therapeutic interventions on increasing voluntary quadriceps muscle activation. BACKGROUND: Decreased voluntary quadriceps activation is commonly associated with knee injury. Recently, research has focused on developing specific disinhibitory interventions to improve voluntary quadriceps activation; yet, it remains unknown which interventions are most effective in promoting this improvement. DATA SOURCES: We searched Web of Science from January 1, 1965 through September 27, 2012, using the key words quadriceps activation and transcutaneous electrical nerve stimulation, transcranial magnetic stimulation, cryotherapy, focal joint cooling, joint mobilization, joint mobilisation, joint manipulation, manual therapy, and neuromuscular electrical stimulation. STUDY SELECTION: Studies evaluating the effect of disinhibitory interventions on volitional quadriceps activation were used in our review. Standardized effect sizes (Cohen d) and 95% confidence intervals (CIs) were calculated from voluntary quadriceps activation means and standard deviations measured at baseline and at all available postintervention time points from each study. DATA SYNTHESIS: Ten studies were grouped into 5 categories based on intervention type: manual therapy (4 studies), transcutaneous electrical nerve stimulation (2 studies), cryotherapy (2 studies), neuromuscular electrical stimulation (2 studies), and transcranial magnetic stimulation (1 study). Transcutaneous electrical nerve stimulation demonstrated the strongest immediate effects (d = 1.03; 95% CI = 0.06, 1.92) and long-term effects (d = 1.93; 95% CI = 0.91, 2.83). Cryotherapy (d = 0.76; 95% CI = -0.13, 1.59) and transcranial magnetic stimulation (d = 0.54; 95% CI = -0.33, 1.37) had moderate immediate effects in improving voluntary quadriceps activation, whereas manual therapy (d = 0.38; 95% CI = -0.35, 1.09) elicited only weak immediate effects. Neuromuscular electrical stimulation produced weak negative to strong positive effects (range of d values = -0.50 to 1.87) over a period of 3 weeks to 6 months. CONCLUSIONS: Transcutaneous electrical nerve stimulation demonstrated the strongest and most consistent effects in increasing voluntary quadriceps activation and may be the best disinhibitory intervention for improving the same. PMID- 24490844 TI - Integrating ReSET with glycosyl iodide glycosylation in step-economy syntheses of tumor-associated carbohydrate antigens and immunogenic glycolipids. AB - Carbohydrates mediate a wide range of biological processes, and understanding these events and how they might be influenced is a complex undertaking that requires access to pure glycoconjugates. The isolation of sufficient quantities of carbohydrates and glycolipids from biological samples remains a significant challenge that has redirected efforts toward chemical synthesis. However, progress toward complex glycoconjugate total synthesis has been slowed by the need for multiple protection and deprotection steps owing to the large number of similarly reactive hydroxyls in carbohydrates. Two methodologies, regioselective silyl exchange technology (ReSET) and glycosyl iodide glycosylation have now been integrated to streamline the synthesis of the globo series trisaccharides (globotriaose and isoglobotriaose) and alpha-lactosylceramide (alpha-LacCer). These glycoconjugates include tumor-associated carbohydrate antigens (TACAs) and immunostimulatory glycolipids that hold promise as immunotherapeutics. Beyond the utility of the step-economy syntheses afforded by this synthetic platform, the studies also reveal a unique electronic interplay between acetate and silyl ether protecting groups. Incorporation of acetates proximal to silyl ethers attenuates their reactivity while reducing undesirable side reactions. This phenomenon can be used to fine-tune the reactivity of silylated/acetylated sugar building blocks. PMID- 24490845 TI - Discontinued drug projects in the respiratory therapeutic area during 2012. AB - During 2012, a number of respiratory drug projects and individual agents were discontinued, for a variety of reasons, including toxicity, lack of efficacy, commercial re-evaluation and change in corporate focus. These included three antagonists of chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2), which had been evaluated in allergic respiratory disease and (in one case) chronic obstructive pulmonary disease (COPD), and other agents intended for the treatment of asthma, COPD, pulmonary hypertension and lung fibrosis. These have been reviewed against the background of a general reduction in respiratory research by the pharmaceutical industry. PMID- 24490846 TI - The influence of social power on weight perception. AB - Three studies explored whether social power affects the perception of physical properties of objects, testing the hypothesis that the powerless find objects to be heavier than the powerful do. Correlational findings from Study 1 revealed that people with a low personal sense of power perceived loaded boxes to be heavier than people with a high personal sense of power perceived them to be. In Study 2, experimentally manipulated power indicated that participants in the powerless condition judged the boxes to be heavier than did participants in the powerful condition. Study 3 further indicated that lacking power actively influences weight perception relative to a neutral control condition, whereas having power does not. Although much research on embodied perception has shown that various physiological and psychosocial resources influence visual perception of the physical environment, this is the first demonstration suggesting that power, a psychosocial construct that relates to the control of resources, changes the perception of physical properties of objects. PMID- 24490847 TI - MAGELLAN: a cognitive map-based model of human wayfinding. AB - In an unfamiliar environment, searching for and navigating to a target requires that spatial information be acquired, stored, processed, and retrieved. In a study encompassing all of these processes, participants acted as taxicab drivers who learned to pick up and deliver passengers in a series of small virtual towns. We used data from these experiments to refine and validate MAGELLAN, a cognitive map-based model of spatial learning and wayfinding. MAGELLAN accounts for the shapes of participants' spatial learning curves, which measure their experience based improvement in navigational efficiency in unfamiliar environments. The model also predicts the ease (or difficulty) with which different environments are learned and, within a given environment, which landmarks will be easy (or difficult) to localize from memory. Using just 2 free parameters, MAGELLAN provides a useful account of how participants' cognitive maps evolve over time with experience, and how participants use the information stored in their cognitive maps to navigate and explore efficiently. PMID- 24490849 TI - Pressure tuning of electron attachment to benzoquinones in nonpolar fluids: continuous adjustment of free energy changes. AB - Changing pressure from 1 to 2500 bar continuously tunes free energy changes for electron attachment to molecules in nonpolar liquids by nearly 0.3 eV. Rate constants for electron attachment to substituted benzoquinones were determined over an extended free energy range of nearly 1 eV by a combination of solute, pressure, temperature, and use of solvents with differing energies of the quasifree electron, V0: tetramethylsilane (TMS) and 2,2,4-trimethylpentane (TMP). The rates of attachment to both benzoquinone (BQ) and 2,5-dichlorobenzoquinone in TMS increase as the pressure increases to 2500 bar, while in TMP the rates are higher but change little with pressure; the rate of attachment to fluoranil in TMS is similarly high at 1 bar but decreases with increasing pressure. Together the observed rate constants can be qualitatively interpreted to yield a rate vs free energy relation having both normal and Marcus inverted region behavior. Because the electron attachment reactions yield excited states, quantitative interpretation of the free energy dependence requires knowledge of the excited state energies. The electron enters the second lowest pi* orbital to form a pi* pi* excited state, which quickly relaxes to the lower n-pi* excited state. The rate of attachment to this excited state is low when the free energy of reaction, DeltaG degrees , is positive and increases as DeltaG degrees decreases until near -0.2 eV, after which the rate decreases. While excited state energies are uncertain, reasonable estimates are obtained from absorption, excitation, and fluorescence spectra of the product radical anions measured here. The results are modeled using Marcus theory with inclusion of a high frequency molecular vibration. PMID- 24490850 TI - Ionic-liquid-based proton conducting membranes for anhydrous H2/Cl2 fuel-cell applications. AB - An ionic-liquid-doped poly(benzimidazole) (PBI) proton-conducting membrane for an anhydrous H2/Cl2 fuel cell has been proposed. Compared with other ionic liquids, such as imidazole-type ionic liquids, diethylmethylammonium trifluoromethanesulfonate ([dema][TfO]) showed better electrode reaction kinetics (H2 oxidation and Cl2 reduction reaction at platinum) and was more suitable for a H2/Cl2 fuel cell. PBI polymer and [dema][TfO] were compatible with each other, and the hybrid membranes exhibited high stability and good ionic conductivity, reaching 20.73 mS cm(-1) at 160 degrees C. We also analyzed the proton-transfer mechanism in this ionic-liquid-based membrane and considered that both proton hopping and diffusion mechanisms existed. In addition, this composite electrolyte worked well in a H2/Cl2 fuel cell under non-water conditions. This work would give a good path to study the novel membranes for anhydrous H2/Cl2 fuel-cell application. PMID- 24490848 TI - Emotion and language: valence and arousal affect word recognition. AB - Emotion influences most aspects of cognition and behavior, but emotional factors are conspicuously absent from current models of word recognition. The influence of emotion on word recognition has mostly been reported in prior studies on the automatic vigilance for negative stimuli, but the precise nature of this relationship is unclear. Various models of automatic vigilance have claimed that the effect of valence on response times is categorical, an inverted U, or interactive with arousal. In the present study, we used a sample of 12,658 words and included many lexical and semantic control factors to determine the precise nature of the effects of arousal and valence on word recognition. Converging empirical patterns observed in word-level and trial-level data from lexical decision and naming indicate that valence and arousal exert independent monotonic effects: Negative words are recognized more slowly than positive words, and arousing words are recognized more slowly than calming words. Valence explained about 2% of the variance in word recognition latencies, whereas the effect of arousal was smaller. Valence and arousal do not interact, but both interact with word frequency, such that valence and arousal exert larger effects among low frequency words than among high-frequency words. These results necessitate a new model of affective word processing whereby the degree of negativity monotonically and independently predicts the speed of responding. This research also demonstrates that incorporating emotional factors, especially valence, improves the performance of models of word recognition. PMID- 24490851 TI - Seroprevalence survey of avian influenza A (H5) in wild migratory birds in Yunnan Province, Southwestern China. AB - BACKGROUND: Highly pathogenic avian influenza virus (HPAIV) is a highly contagious disease which is a zoonotic pathogen of significant economic and public health concern. The outbreaks caused by HPAIV H5N1 of Asian origin have caused animal and human disease and mortality in several countries of Southeast Asia, such as Bangladesh, Cambodia, China, India, Indonesia, Laos, Myanmar, Thailand and Viet Nam. For the first time since 1961, this HPAIV has also caused extensive mortality in wild birds and has sparked debate of the role wild birds have played in the spread of this virus. Other than confirmed mortality events, little is known of this virus in wild birds. There is no report on the seroprevalence of avian influenza H5 infection in wild migratory birds in Yunnan Province. In this study we examined live wild birds in Yunnan Province for H5 specific antibody to better understand the occurrence of this disease in free living birds. METHODS: Sera from 440 wild birds were collected from in Kunming and Northern Ailaoshan of Yunnan Province, Southwestern China, and assayed for H5 antibodies using the hemagglutination inhibition (HI) assays. RESULTS: The investigation revealed that the seroprevalence of avian influenza H5 was as following: Ciconiiformes 2.6%, Strigiformes 13.04%, Passeriformes 20%, Cuculiformes 21.74%, Gruiformes 0%, Columbiformes 0%, Charadriiformes 0% and Coraciiformes 0%. Statistical analyses showed that there was a significant difference of prevalence between the orders (P < 0.01). Specific avian influenza H5 antibodies were detected in 23 of 440 (5.23%) sera. Mean HI titer 23 positive sera against H5 were 5.4 log2. CONCLUSIONS: The results of the present survey indicated that the proportion of wild birds had previously infected AIV H5 at other times of the year. To our knowledge, this is the first seroprevalence report of avian influenza H5 infection in wild migratory birds in China' s southwestern Yunnan Province. The results of the present survey have significant public health concerns. PMID- 24490852 TI - Linkages of biomarkers of zinc with cognitive performance and taste acuity in adolescent girls. AB - A cross-sectional study (n = 403) was conducted to examine the relationship of plasma zinc (PZ) and erythrocyte zinc (EZ) levels with cognitive performance and taste acuity for salt in Indian adolescent girls. PZ, EZ and hemoglobin were estimated in schoolgirls (10-16 years). Cognitive performance was assessed by simple-reaction-time (SRT), recognition-reaction-time (RRT), visual-memory, Raven's Progressive Matrices (RPM) test. Taste acuity was determined by recognition-thresholds-for-salt (RTS) using 10 different salt concentrations. Low PZ (<0.7 mg/l) and EZ (<8 ug/g of packed cells) were observed in 72% and 23.6% of girls, respectively. PZ and EZ were negatively associated with SRT (r = -0.41, 0.34), RRT (r = -0.49, -0.4), and positively with Memory (r = 0.43, 0.34) and RPM (r = 0.39, 0.31; p < 0.05) and remained significant after adjusting for socio demographic factors and hemoglobin. RTS was impaired in 18.3% girls and significantly correlated with EZ (r = -0.31, p < 0.05). Zinc deficiency in adolescent girls was associated with poor cognition and taste function implying need for improving their dietary zinc intakes. PMID- 24490853 TI - Amyloid-based immunotherapy for Alzheimer's disease in the time of prevention trials: the way forward. AB - Both active and passive anti-beta-amyloid (Abeta) immunotherapies for the treatment of Alzheimer's disease (AD) have demonstrated clearance of brain Abeta deposits. Among passive immunotherapeutics, two Phase III clinical trials in mild to-moderate AD patients with bapineuzumab, a humanized monoclonal antibody directed at the N-terminal sequence of Abeta, were disappointing. Also solanezumab, directed at the mid-region of Abeta, failed in two Phase III trials in mild-to-moderate AD. Another Phase III trial with solanezumab is ongoing in mildly affected AD patients based on encouraging results in this subgroup. Second generation active Abeta vaccines (CAD106, ACC-001, and Affitope AD02) and new passive anti-Abeta immunotherapies (gantenerumab and crenezumab) have been developed and are under clinical testing. These new anti-Abeta immunotherapies are being tested in prodromal AD, in presymptomatic subjects with AD-related mutations, or in asymptomatic subjects at risk of developing AD. These primary and secondary prevention trials will definitely test the Abeta cascade hypothesis of AD. PMID- 24490854 TI - Clinimetric properties of sitting balance measures for children with cerebral palsy: a systematic review. AB - Assessment of sitting balance in children and youth with cerebral palsy (CP) is critical in order to design appropriate interventions to enhance activities and participation. This systematic review synthesized research evidence on the reliability, validity, responsiveness to change, and clinical utility of sitting balance measures for children and youth with CP. A two-tiered search in August 2012 using nine peer-reviewed electronic databases yielded nine articles with relevant information on seven clinical measures. Four of seven clinical measures: the Pediatric Reach Test (PRT), Sitting Assessment for Children with Neuromotor Dysfunction (SACND), Segmental Assessment of Trunk Control (SATCo), and Trunk Control Measurement Scale (TCMS), demonstrate acceptable overall applicability (at least one study supporting clinical utility, reliability, and validity) and are thus recommended for use in practice. Ongoing research on responsiveness to change, however, is warranted to support validity for outcomes measurement. PMID- 24490855 TI - Biological sex themed section: incorporating the female dimension into cardiovascular pharmacology. PMID- 24490857 TI - Methyl jasmonate sensitizes human bladder cancer cells to gambogic acid-induced apoptosis through down-regulation of EZH2 expression by miR-101. AB - BACKGROUND AND PURPOSE: Gambogic acid (GA) and methyl jasmonate (MJ) are increasingly being recognized as novel natural anticancer compounds. Here, we investigated the antitumour effects of GA in combination with MJ on human bladder cancer cells. EXPERIMENTAL APPROACH: Cell viability was detected by cell counting kit-8 assay. Cell apoptosis was assessed by Hoechst 33258 staining and flow cytometry. Protein levels were determined by immunoblotting and expressions of mRNA and miRNAs by RT-PCR. Differential expressions of a group of downstream genes were identified using microarray analysis. KEY RESULTS: MJ significantly sensitized bladder cancer cells to GA-induced growth inhibition and apoptosis while sparing normal fibroblasts. MJ enhanced GA-induced activation of caspase-3 and caspase-9, and down-regulated the expression of XIAP. Furthermore, treatment of bladder cancer cells with a combination of GA and MJ induced synergistic inhibition of the enhancer of zeste homologue 2 (EZH2) expression, whereas miR 101 expression was up-regulated. Conversely, knockdown of miR-101 restored this decreased expression of EZH2 and suppressed the inhibitory effect of GA and MJ on the growth of bladder cancer cells. Microarray analysis showed that genes closely associated with bladder cancer development were significantly down-regulated by GA and MJ. In a s.c. xenograft mouse model of human bladder carcinoma, the combination of GA and MJ exerted an increased antitumour effect compared with GA alone. CONCLUSION AND IMPLICATIONS: MJ sensitizes bladder cancer cells to GA induced apoptosis by down-regulating the expression of EZH2 induced by miR-101. Thus, the combination of selective anti-cancer agents MJ and GA could provide a novel strategy for treating human bladder cancer. PMID- 24490858 TI - Thromboxane receptor hyper-responsiveness in hypoxic pulmonary hypertension requires serine 324. AB - BACKGROUND AND PURPOSE: Dysregulation of the thromboxane A2 (TP) receptor, resulting in agonist hypersensitivity and hyper-responsiveness, contributes to exaggerated vasoconstriction in the hypoxic pulmonary artery in neonatal persistent pulmonary hypertension. We previously reported that hypoxia inhibits TP receptor phosphorylation, causing desensitization. Hence, we examined the role of PKA-accessible serine residues in determining TP receptor affinity, using site directed mutational analysis. EXPERIMENTAL APPROACH: Vasoconstriction to a thromboxane mimetic and phosphorylation of TP receptor serine was examined in pulmonary arteries from neonatal swine with persistent pulmonary hypertension and controls. Effects of hypoxia were determined in porcine and human TP receptors. Human TPalpha serines at positions 324, 329 and 331 (C-terminal tail) were mutated to alanine and transiently expressed in HEK293T cells. Saturation binding and displacement kinetics of a TP antagonist and agonist were determined in porcine TP, wild-type human TPalpha and all TP mutants. Agonist-elicited calcium mobilization was determined for each TP mutant, in the presence of a PKA activator or inhibitor, and in hypoxic and normoxic conditions. KEY RESULTS: The Ser324A mutant was insensitive to PKA activation and hypoxia, had a high affinity for agonist and increased agonist-induced calcium mobilization. Ser329A was no different from wild-type TP receptors. Ser331A was insensitive to hypoxia and PKA with a decreased agonist-mediated response. CONCLUSIONS AND IMPLICATIONS: In hypoxic pulmonary hypertension, loss of site-specific phosphorylation of the TP receptor causes agonist hyper-responsiveness. Ser324 is the primary residue phosphorylated by PKA, which regulates TP receptor-agonist interactions. Ser331 mutation confers loss of TP receptor-agonist interaction, regardless of PKA activity. PMID- 24490859 TI - Corticotropin-releasing factor (CRF) receptor-1 is involved in cardiac noradrenergic activity observed during naloxone-precipitated morphine withdrawal. AB - BACKGROUND AND PURPOSE: The negative affective states of withdrawal involve the recruitment of brain and peripheral stress circuitry [noradrenergic activity, induction of the hypothalamic-pituitary-adrenocortical (HPA) axis and activation of heat shock proteins (Hsps)]. Corticotropin-releasing factor (CRF) pathways are important mediators in the negative symptoms of opioid withdrawal. We performed a series of experiments to characterize the role of the CRF1 receptor in the response of stress systems to morphine withdrawal and its effect in the heart using genetically engineered mice lacking functional CRF1 receptors. EXPERIMENTAL APPROACH: Wild-type and CRF1 receptor-knockout mice were treated with increasing doses of morphine. Precipitated withdrawal was induced by naloxone. Plasma adrenocorticotropic hormone (ACTH) and corticosterone levels, the expression of myocardial Hsp27, Hsp27 phosphorylated at Ser82, membrane (MB)- COMT, soluble (S) COMT protein and NA turnover were evaluated by RIA, immunoblotting and HPLC. KEY RESULTS: During morphine withdrawal we observed an enhancement of NA turnover in parallel with an increase in mean arterial blood pressure (MAP) and heart rate (HR) in wild-type mice. In addition, naloxone-precipitated morphine withdrawal induced an activation of HPA axis and Hsp27. The principal finding of the present study was that plasma ACTH and corticosterone levels, MB-COMT, S-COMT, NA turnover, and Hsp27 expression and activation observed during morphine withdrawal were significantly inhibited in the CRF1 receptor-knockout mice. CONCLUSION AND IMPLICATIONS: Our results demonstrate that CRF/CRF1 receptor activation may contribute to stress-induced cardiovascular dysfunction after naloxone precipitated morphine withdrawal and suggest that CRF/CRF1 receptor pathways could contribute to cardiovascular disease associated with opioid addiction. PMID- 24490860 TI - The electromechanical window is no better than QT prolongation to assess risk of Torsade de Pointes in the complete atrioventricular block model in dogs. AB - BACKGROUND AND PURPOSE: The electromechanical window (EMW), the interval between the end of the T-wave and the end of the left ventricular pressure (LVP) curve, has recently been proposed as a predictor of risk of Torsade de Pointes (TdP) in healthy animals, whereby a negative EMW (mechanical relaxation earlier than repolarization) after drug administration indicates an increased TdP risk. The aims of this study were to assess (i) the effect of the ventricular remodelling in the canine chronic, complete atrioventricular block (CAVB) model on EMW; (ii) the effect of the I(Kr) -blocker dofetilide on EMW; and (iii) the correlation of EMW with TdP inducibility. EXPERIMENTAL APPROACH: Our 11 year database of experiments of CAVB in dogs under general anaesthesia was reviewed and experiments included if ECG and LVP were recorded simultaneously at spontaneous rhythm. In total, 89 experiments in 44 dogs were appropriate and were analysed. KEY RESULTS: During normally conducted sinus rhythm or acute atrioventricular block, EMW was positive. During CAVB, EMW was decreased to negative values. Dofetilide further reduced EMW before inducing repetitive TdP in 82% of the experiments. However, subclassification into inducible and non-inducible dogs revealed no difference in EMW. Analysis of the components of EMW revealed that the observed changes in EMW were solely caused by QT prolongation. CONCLUSIONS AND IMPLICATIONS: In the canine CAVB model, ventricular remodelling and I(Kr) block by dofetilide are associated with negative EMW values, but this reflects QT prolongation, and implies that the EMW lacks specificity to predict dofetilide induced TdP. PMID- 24490861 TI - Exendin-4 decreases liver inflammation and atherosclerosis development simultaneously by reducing macrophage infiltration. AB - BACKGROUND AND PURPOSE: The aetiology of inflammation in the liver and vessel wall, leading to non-alcoholic steatohepatitis (NASH) and atherosclerosis, respectively, shares common mechanisms including macrophage infiltration. To treat both disorders simultaneously, it is highly important to tackle the inflammatory status. Exendin-4, a glucagon-like peptide-1 (GLP-1) receptor agonist, reduces hepatic steatosis and has been suggested to reduce atherosclerosis; however, its effects on liver inflammation are underexplored. Here, we tested the hypothesis that exendin-4 reduces inflammation in both the liver and vessel wall, and investigated the common underlying mechanism. EXPERIMENTAL APPROACH: Female APOE*3-Leiden.CETP mice, a model with human-like lipoprotein metabolism, were fed a cholesterol-containing Western-type diet for 5 weeks to induce atherosclerosis and subsequently treated for 4 weeks with exendin 4. KEY RESULTS: Exendin-4 modestly improved dyslipidaemia, but markedly decreased atherosclerotic lesion severity and area (-33%), accompanied by a reduction in monocyte adhesion to the vessel wall (-42%) and macrophage content in the plaque (-44%). Furthermore, exendin-4 reduced hepatic lipid content and inflammation as well as hepatic CD68+ (-18%) and F4/80+ (-25%) macrophage content. This was accompanied by less monocyte recruitment from the circulation as the Mac-1+ macrophage content was decreased (-36%). Finally, exendin-4 reduced hepatic chemokine expression in vivo and suppressed oxidized low-density lipoprotein accumulation in peritoneal macrophages in vitro, effects dependent on the GLP-1 receptor. CONCLUSIONS AND IMPLICATIONS: Exendin-4 reduces inflammation in both the liver and vessel wall by reducing macrophage recruitment and activation. These data suggest that exendin-4 could be a valuable strategy to treat NASH and atherosclerosis simultaneously. PMID- 24490864 TI - Regiodivergent synthesis of 1- and 2-arylsulfonyl 1,3-dienes. AB - In the course of a study of the alkoxyallylation of allenic sulfones through the use of pi-allylpalladium chemistry, we discovered an isomerization of allenic sulfones to arylsulfonyl 1,3-dienes. Under conditions of palladium catalysis in the presence of acids such as acetic acid, allenic sulfones are converted to 1 arylsulfonyl 1,3-dienes. On the other hand, nucleophilic catalysis using triphenylphosphine in the presence of a proton shuttle yields 2-arylsulfonyl 1,3 dienes. Thus, either regioisomer of the arylsulfonyl diene can be prepared at will based on changes in reaction conditions. PMID- 24490856 TI - Perivascular fat, AMP-activated protein kinase and vascular diseases. AB - Perivascular adipose tissue (PVAT) is an active endocrine and paracrine organ that modulates vascular function, with implications for the pathophysiology of cardiovascular disease (CVD). Adipocytes and stromal cells contained within PVAT produce mediators (adipokines, cytokines, reactive oxygen species and gaseous compounds) with a range of paracrine effects modulating vascular smooth muscle cell contraction, proliferation and migration. However, the modulatory effect of PVAT on the vascular system in diseases, such as obesity, hypertension and atherosclerosis, remains poorly characterized. AMP-activated protein kinase (AMPK) regulates adipocyte metabolism, adipose biology and vascular function, and hence may be a potential therapeutic target for metabolic disorders such as type 2 diabetes mellitus (T2DM) and the vascular complications associated with obesity and T2DM. The role of AMPK in PVAT or the actions of PVAT have yet to be established, however. Activation of AMPK by pharmacological agents, such as metformin and thiazolidinediones, may modulate the activity of PVAT surrounding blood vessels and thereby contribute to their beneficial effect in cardiometabolic diseases. This review will provide a current perspective on how PVAT may influence vascular function via AMPK. We will also attempt to demonstrate how modulating AMPK activity using pharmacological agents could be exploited therapeutically to treat cardiometabolic diseases. PMID- 24490862 TI - Chronic blockade of angiotensin AT1 receptors improves cardinal symptoms of metabolic syndrome in diet-induced obesity in rats. AB - BACKGROUND AND PURPOSE: AT1 receptor antagonists decrease body weight gain in models of murine obesity. However, fewer data are available concerning the anti obesity effects of these antagonists, given as a treatment after obesity had been established. EXPERIMENTAL APPROACH: In spontaneously hypertensive rats, obesity was established by cafeteria diet (CD) feeding for 19 weeks. Rats were then were treated with telmisartan (8 mg.kg-1.d-1) or amlodipine (10 mg.kg-1.d-1; serving as blood pressure control) or telmisartan + amlodipine (2 + 10 mg.kg-1.d-1; to control for dose-dependency) for 17 weeks. Rats receiving only chow (C(chow)) or CD-fed rats treated with vehicle (C(CD)) served as controls. KEY RESULTS: The CD feeding induced obesity, hyperphagia, hyperlipidaemia, and leptin and insulin resistance. Telmisartan reduced the CD-induced increase in body weight and abdominal fat mass. Whereas energy intake was higher rather than lower, the respiratory ratio was lower. After telmisartan, leptin-induced energy intake was reduced and respiratory ratio was increased compared with C(CD) rats. Telmisartan also decreased plasma levels of triglycerides, free fatty acids and low-density lipoprotein. Amlodipine alone or the combination telmisartan + amlodipine did not affect body weight and eating behaviour. Telmisartan, but not amlodipine and telmisartan + amlodipine, improved glucose utilization. The decrease in BP reduction was almost the same in all treatment groups. CONCLUSIONS AND IMPLICATIONS: Telmisartan exerted anti-obesity effects and restored leptin sensitivity, given as a treatment to rats with obesity. Such effects required high doses of telmisartan and were independent of the decrease in blood pressure. PMID- 24490863 TI - The cognition-enhancing activity of E1R, a novel positive allosteric modulator of sigma-1 receptors. AB - BACKGROUND AND PURPOSE: Here, we describe the in vitro and in vivo effects of (4R,5S)-2-(5-methyl-2-oxo-4-phenyl-pyrrolidin-1-yl)-acetamide (E1R), a novel positive allosteric modulator of sigma-1 receptors. EXPERIMENTAL APPROACH: E1R was tested for sigma receptor binding activity in a [3H](+)-pentazocine assay, in bradykinin (BK)-induced intracellular Ca2+ concentration ([Ca2+](i)) assays and in an electrically stimulated rat vas deferens model. E1R's effects on cognitive function were tested using passive avoidance (PA) and Y-maze tests in mice. A selective sigma-1 receptor antagonist (NE-100), was used to study the involvement of the sigma-1 receptor in the effects of E1R. The open-field test was used to detect the effects of E1R on locomotion. KEY RESULTS: Pretreatment with E1R enhanced the selective sigma-1 receptor agonist PRE-084's stimulating effect during a model study employing electrically stimulated rat vasa deferentia and an assay measuring the BK-induced [Ca2+](i) increase. Pretreatment with E1R facilitated PA retention in a dose-related manner. Furthermore, E1R alleviated the scopolamine-induced cognitive impairment during the PA and Y-maze tests in mice. The in vivo and in vitro effects of E1R were blocked by treatment with the selective sigma-1 receptor antagonist NE-100. E1R did not affect locomotor activity. CONCLUSION AND IMPLICATIONS: E1R is a novel 4,5-disubstituted derivative of piracetam that enhances cognition and demonstrates efficacy against scopolamine-induced cholinergic dysfunction in mice. These effects are attributed to its positive modulatory action on the sigma-1 receptor and this activity may be relevant when developing new drugs for treating cognitive symptoms related to neurodegenerative diseases. PMID- 24490865 TI - Response of different nitrospira species to anoxic periods depends on operational do. AB - The exploitation of a lag phase in nitrate production after anoxic periods is a promising approach to suppress nitrite oxidizing bacteria, which is crucial for implementation of the combined partial nitritation-anammox process. An in-depth study of the actual lag phase in nitrate production after short anoxic periods was performed with varied temperatures and air flow rates. In monitored batch experiments, biomass from four different full-scale partial nitritation-anammox plants was subjected to anoxic periods of 5-60 min. Ammonium and the nitrite that was produced were present to reproduce reactor conditions and enable ammonium and nitrite oxidation at the same time. The lag phase observed in nitrite oxidation exceeded the lag phase in ammonium oxidation after anoxic periods of more than 15 20 min. Lower temperatures slowed down the conversion rates but did not affect the lag phases. The operational oxygen concentration in the originating full scale plants strongly affected the length of the lag phase, which could be attributed to different species of Nitrospira spp. detected by DGGE and sequencing analysis. PMID- 24490866 TI - Mild cognitive impairment: a concept and diagnostic entity in need of input from neuropsychology. AB - This virtual issue consists of studies previously published in the Journal of the International Neuropsychological Society and selected on the basis of their content related to one of the most highly researched concepts in behavioral neurology and neuropsychology over the past decade: mild cognitive impairment (MCI). The reliance on cognitive screening measures, staging-based rating scales, and limited neuropsychological testing in diagnosing MCI across most research studies may miss individuals with subtle cognitive declines or mis-diagnose MCI in those who are otherwise cognitively normal on a broader neuropsychological battery of tests. The assembled articles highlight the perils of relying on these conventional criteria for MCI diagnosis and reveal how the reliability of diagnosis is improved when sound neuropsychological approaches are adopted. When these requirements are met, we illustrate with a second series of articles that neuropsychological measures associate strongly with biomarkers and often reflect pathology beyond or instead of typical AD distributions. The final set of articles reveal that people with MCI demonstrate mild but identifiable functional difficulties, and a challenge for neuropsychology is how to incorporate this information to better define MCI and distinguish it from early dementia. Neuropsychology is uniquely positioned to improve upon the state of the science in MCI research and practice by providing critically important empirical information on the specific cognitive domains affected by the predominant neurodegenerative disorders of late life as well as on the diagnostic decision making strategies used in studies. When such efforts to more comprehensively assess neuropsychological functions are undertaken, better characterizations of spared and impaired cognitive and functional abilities result and lead to more convincing associations with other biomarkers as well as to prediction of clinical outcomes. PMID- 24490867 TI - Interfacial tension of complex coacervated mussel adhesive protein according to the Hofmeister series. AB - Complex coacervation is a liquid-liquid phase separation in a colloidal system of two oppositely charged polyelectrolytes or colloids. The interfacial tension of the coacervate phase is the key parameter for micelle formation and interactions with the encapsulating material. However, the relationship between interfacial tensions and various salt solutions is poorly understood in complex coacervation. In the present work, the complex coacervate dynamics of recombinant mussel adhesive protein (MAP) with hyaluronic acid (HA) were determined in the presence of Hofmeister series salt ions. Using measurements of absorbance, hydrodynamic diameter, capillary force, and receding contact angle in the bulk phase, the interfacial tensions of complex coacervated MAP/HA were determined to be 0.236, 0.256, and 0.287 mN/m in 250 mM NaHCOO, NaCl, and NaNO3 solutions, respectively. The sequences of interfacial tensions and contact angles of the complex coacervates in the presence of three sodium salts with different anions were found to follow the Hofmeister ordering. The tendency of interfacial tension between the coacervate and dilute phases in the presence of different types of Hofmeister salt ions could provide a better understanding of Hofmeister effects on complex coacervated materials based on the protein-polysaccharide system. This information can also be utilized for microencapsulation and adsorption by controlling intramolecular interactions. In addition, the injection molding dynamics of mussel byssus formation was potentially explained based on the measured interfacial tension of coacervated MAP. PMID- 24490868 TI - Biochemical and structural analysis of the hyperpolarization-activated K(+) channel MVP. AB - In contrast to the majority of voltage-gated ion channels, hyperpolarization activated channels remain closed at depolarizing potentials and are activated at hyperpolarizing potentials. The basis for this reverse polarity is thought to be a result of differences in the way the voltage-sensing domain (VSD) couples to the pore domain. In the absence of structural data, the molecular mechanism of this reverse polarity coupling remains poorly characterized. Here we report the characterization of the structure and local dynamics of the closed activation gate (lower S6 region) of MVP, a hyperpolarization-activated potassium channel from Methanococcus jannaschii, by electron paramagnetic resonance (EPR) spectroscopy. We show that a codon-optimized version of MVP has high expression levels in Escherichia coli, is purified as a stable tetramer, and exhibits expected voltage-dependent activity when reconstituted in liposomes. EPR analysis of the mid to lower S6 region revealed positions exhibiting strong spin-spin coupling, indicating that the activation gate of MVP is closed at 0 mV. A comparison of local environmental parameters along the activation gate for MVP and KcsA indicates that MVP adopts a different closed conformation. These structural details set the stage for future evaluations of reverse electromechanical coupling in MVP. PMID- 24490869 TI - A comparison of hydration effect on body fluid and temperature regulation between Malaysian and Japanese males exercising at mild dehydration in humid heat. AB - BACKGROUND: This study investigated the effect of hydration differences on body fluid and temperature regulation between tropical and temperate indigenes exercising in the heat. METHODS: Ten Japanese and ten Malaysian males with matched physical characteristics (height, body weight, and peak oxygen consumption) participated in this study. Participants performed exercise for 60 min at 55% peak oxygen uptake followed by a 30-min recovery at 32 degrees C and 70% relative air humidity with hydration (4 times each, 3 mL per kg body weight, 37 degrees C) or without hydration. Rectal temperature, skin temperature, heart rate, skin blood flow, and blood pressure were measured continuously. The percentage of body weight loss and total sweat loss were calculated from body weight measurements. The percentage change in plasma volume was estimated from hemoglobin concentration and hematocrit. RESULTS: Malaysian participants had a significantly lower rectal temperature, a smaller reduction in plasma volume, and a lower heart rate in the hydrated condition than in the non-hydrated condition at the end of exercise (P <0.05), whereas Japanese participants showed no difference between the two hydration conditions. Hydration induced a greater total sweat loss in both groups (P <0.05), and the percentage of body weight loss in hydrated Malaysians was significantly less than in hydrated Japanese (P <0.05). A significant interaction between groups and hydration conditions was observed for the percentage of mean cutaneous vascular conductance during exercise relative to baseline (P <0.05). CONCLUSIONS: The smaller reduction in plasma volume and percentage body weight loss in hydrated Malaysians indicated an advantage in body fluid regulation. This may enable Malaysians to reserve more blood for circulation and heat dissipation and thereby maintain lower rectal temperatures in a hydrated condition. PMID- 24490870 TI - Autophagic response in the Rabbit Hemorrhagic Disease, an animal model of virally induced fulminant hepatic failure. AB - The Rabbit Hemorrhagic Disease Virus (RHDV) induces a severe disease that fulfils many requirements of an animal model of fulminant hepatic failure. However, a better knowledge of molecular mechanisms contributing to liver damage is required, and it is unknown whether the RHDV induces liver autophagy and how it relates to apoptosis. In this study, we attempted to explore which signalling pathways were involved in the autophagic response induced by the RHDV and to characterize their role in the context of RHDV pathogenesis. Rabbits were infected with 2 * 104 hemmaglutination units of a RHDV isolate. The autophagic response was measured as presence of autophagic vesicles, LC3 staining, conversion of LC3-I to autophagosome-associated LC3-II and changes in expression of beclin-1, UVRAG, Atg5, Atg12, Atg16L1 and p62/SQSTM1. RHDV-triggered autophagy reached a maximum at 24 hours post-infection (hpi) and declined at 30 and 36 hpi. Phosphorylation of mTOR also augmented in early periods of infection and there was an increase in the expression of the endoplasmic reticulum chaperones BiP/GRP78, CHOP and GRP94. Apoptosis, measured as caspase-3 activity and expression of PARP-1, increased significantly at 30 and 36 hpi in parallel to the maximal expression of the RHDV capsid protein VP60. These data indicate that RHDV infection initiates a rapid autophagic response, perhaps in an attempt to protect liver, which associates to ER stress development and is independent from downregulation of the major autophagy suppressor mTOR. As the infection continues and the autophagic response declines, cells begin to exhibit apoptosis. PMID- 24490871 TI - A pedometer based physical activity self-management program for children and adolescents with physical disability - design and methods of the StepUp study. AB - BACKGROUND: Physical activity affords a wide range of physiological and psychological benefits for children and adolescents, yet many children with physical disabilities are insufficiently active to achieve these benefits. The StepUp program is a newly developed 6-week pedometer-based self-management program for children and adolescents with physical disability. Participants use a pedometer to undertake a 6-week physical activity challenge, with personalised daily step count goals set in consultation with a physiotherapist. The study aims to evaluate the effectiveness of the StepUp program, using a randomised control trial design. METHODS/DESIGN: A target sample of 70 young people with physical disabilities (aged 8-17 years, ambulant with or without aid, residing in Adelaide) will be recruited. Participants will be randomly allocated to either intervention or control following completion of baseline assessments. Assessments are repeated at 8 weeks (immediately post intervention) and 20 weeks (12 weeks post intervention). The primary outcome is objective physical activity determined from 7 day accelerometry, and the secondary outcomes are exercise intention, physical self-worth, quality of life and fatigue. Analyses will be undertaken on an intention-to-treat basis using random effects mixed modelling. DISCUSSION: This study will provide information about the potential of a low-touch and low cost physical activity intervention for children and adolescents with cerebral palsy. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry (ANZCTR): ACTRN12613000023752. PMID- 24490872 TI - The feasibility, patterns of use and acceptability of using mobile phone text messaging to improve treatment adherence and post-treatment review of children with uncomplicated malaria in western Kenya. AB - BACKGROUND: Trials evaluating the impact of mobile phone text-messaging to support management of acute diseases, such as malaria, are urgently needed in Africa. There has been however a concern about the feasibility of interventions that rely on access to mobile phones among caregivers in rural areas. To assess the feasibility and inform development of an intervention to improve adherence to malaria medications and post-treatment review, mobile phone network, access, ownership and use among caregivers in western Kenya was assessed. METHODS: A cross-sectional survey based on outpatient exit interviews was undertaken among caregivers of children with malaria at four trial facilities. The main outcomes were proportions of caregivers that have mobile signal at home; have access to mobile phones; are able to read; and use text-messaging. Willingness to receive text-message reminders was also explored. Descriptive analyses were performed. RESULTS: Of 400 interviewed caregivers, the majority were female (93.5%), mothers of the sick children (87.8%) and able to read (97.3%). Only 1.7% of caregivers were without any education. Nearly all (99.8%) reported access to a mobile signal at home. 93.0% (site range: 89-98%) had access to a mobile phone within their household while 73.8% (site range: 66-78%) possessed a personal phone. Among caregivers with mobile phone access, 93.6% (site range: 85-99%) used the phone to receive text-messages. Despite only 19% having electricity at home nearly all (99.7%) caregivers reported that they would be able to have permanent phone access to receive text-messages in the next 28 days. Willingness to receive text message reminders was nearly universal (99.7%) with 41.7% of caregivers preferring texts in English, 32.3% in Kiswahili and 26.1% in Dholuo. CONCLUSIONS: Despite concerns that the feasibility of text-messaging interventions targeting caregivers may be compromised in rural high malaria risk areas in Kenya, very favourable conditions were found with respect to mobile network, access and ownership of phones, use of text-messaging and minimum literacy levels required for successful intervention delivery. Moreover, there was a high willingness of caregivers to receive text-message reminders. Impact evaluations of carefully tailored text-messaging interventions targeting caregivers of children with malaria are timely and justified. PMID- 24490873 TI - Nanocenter directors gather from around the world. PMID- 24490876 TI - The military and its potential role in malaria elimination. PMID- 24490875 TI - Facing the truth about nanotechnology in drug delivery. AB - Nanotechnology in drug delivery has been manifested into nanoparticles that can have unique properties both in vitro and in vivo, especially in targeted drug delivery to tumors. Numerous nanoparticle formulations have been designed and tested to great effect in small animal models, but the translation of the small animal results to clinical success has been limited. Successful translation requires revisiting the meaning of nanotechnology in drug delivery, understanding the limitations of nanoparticles, identifying the misconceptions pervasive in the field, and facing inconvenient truths. Nanoparticle approaches can have real impact in improving drug delivery by focusing on the problems at hand, such as enhancing their drug loading capacity, affinity to target cells, and spatiotemporal control of drug release. PMID- 24490877 TI - Update: malaria, U.S. Armed Forces, 2013. AB - U.S. service members are at risk of acquiring malaria infection when they are present in endemic areas because of long term duty assignments, participation in shorter term contingency operations, or personal travel. The numbers of cases among service members in 2012 (n=40) and 2013 (n=30) were the lowest reported during the past ten years. In 2013 over one-third of cases were attributed to service in Afghanistan (n=11) and six cases were linked to Africa. Nine cases were caused by Plasmodium vivax; eight cases were caused by P. falciparum; and one-third were reported as "unspecified" malaria. Malaria was reported from 21 different medical facilities in the United States, Afghanistan, Germany, Italy, Japan, Korea, and Cuba. The relatively low numbers of cases in 2012 and 2013 could reflect a decrease in the number of troops who served in endemic areas, improved or increased use of chemoprophylaxis and personal protective equipment, and changes in environmental factors that may influence the numbers and distribution of infected mosquitoes. Providers of care to military members should be knowledgeable regarding, and vigilant for, clinical presentations of malaria outside of endemic areas. PMID- 24490879 TI - Surveillance snapshot: self-reported malaria prophylaxis compliance among U.S. service members with diagnosed malaria, 2008-2013. PMID- 24490878 TI - Report of two cases of vivax malaria in U.S. soldiers and a review of malaria in the Republic of Korea. AB - This report describes two cases of vivax malaria in U.S. Army soldiers who acquired their infections at a training area in the Republic of Korea during 2012, but developed symptoms and were diagnosed more than six months later, long after they had returned to the United States. The report provides a historical perspective regarding the epidemiology of temperate climate vivax malaria, particularly in Korea, and relevant aspects of malaria prevention and control. PMID- 24490880 TI - Images in health surveillance: dengue and chikungunya virus vectors and prevention. PMID- 24490881 TI - Intensive care utilization among nursing home residents with advanced cognitive and severe functional impairment. AB - BACKGROUND: Dementia is a progressive terminal illness which requires decisions around aggressiveness of care. OBJECTIVE: The study objective was to examine the rate of intensive care unit (ICU) utilization and its regional variation among persons with both advanced cognitive and severe functional impairment. METHODS: We utilized the Minimum Data Set (MDS) to identify a cohort of decedents between 2000 and 2007 who (1) were in a nursing home (NH) 120 days prior to death and (2) had an MDS assessment indicating advanced cognitive and functional impairment as identified by cognitive performance scale (CPS) >=5 and total dependence or extensive assistance in seven activities of daily living (ADLs). ICU utilization in the last 30 days of life was determined from Medicare claims files. A multivariate logistic regression model examined the likelihood of ICU admission in 2007 versus 2000 adjusting for sociodemographics, orders to limit life sustaining treatment, and health status. RESULTS: Among 474,829 Medicare NH residents with advanced cognitive impairment followed during 2000-2007, we observed an increase in ICU utilization from 6.1% in 2000 to 9.5% in 2007. After adjustment for sociodemographic characteristics, orders to limit life sustaining treatment, and measures of health status, the likelihood of a resident being admitted to an ICU was higher in 2007 compared to 2000 (adjusted odds ratio [OR] 1.71, 95% CI 1.60-1.81). Additionally, substantial regional variation was noted in ICU utilization, from 0.82% in Montana to 22% in the District of Columbia. CONCLUSIONS: Even among patients with advanced cognitive and functional impairment, ICU utilization in the last 30 days increased and varied by geographic region. PMID- 24490882 TI - Specificity of regulatory T cells that modulate vascular inflammation. AB - Intravenous immunoglobulin therapy (IVIG) is the treatment of choice for many immune-mediated diseases, yet its mechanisms of action are incompletely elucidated. We investigated the possibility that IVIG played a direct role in the expansion of regulatory T cells (Treg) that recognize the heavy chain constant region of immunoglobulin G (Fc) as a mechanism for the recovery of Kawasaki disease (KD), a T cell mediated pediatric vasculitis of the coronary arteries. We successfully generated Fc-specific Treg clones from sub-acute KD subjects that did not develop arterial complications after IVIG and defined an unusual functional phenotype: Fc-specific Treg secrete IL-10 and small amounts of IL-4 but not TGF-beta. Antigen presentation studies demonstrated that these Treg clones can be activated by autologous B cells that express IgG on their cell surface in the absence of exogenous Fc. The IgG molecule has to be canonically processed and presented by autologous MHC molecules to be recognized by Treg. In support of the importance of this novel Treg population in downsizing vascular inflammation, KD patients with dilated coronary arteries or aneurysms despite IVIG treatment failed to expand Fc-specific Treg. Our results point to a specificity of a previously un-described Treg population for the clinical benefit provided by IVIG therapy in children. PMID- 24490883 TI - Targeting metastatic castration-resistant prostate cancer: mechanisms of progression and novel early therapeutic approaches. AB - INTRODUCTION: Advances in clinical research have led to official approval of several new treatments for metastatic prostate cancer in the last three years: sipuleucel-T, cabazitaxel, abiraterone acetate, radium-223 and enzalutamide. Although these agents have all been shown to improve overall survival in randomized Phase III trials, metastatic castration-resistant prostate cancer (mCRPC) remains incurable. AREAS COVERED: First, the review summarizes the current literature on the biology of mCRPC. The emerging data are increasing our understanding of the mechanisms that underlie the pathogenesis of castrate resistance and where future treatment might be headed. In the second part of the review, the authors assess the future directions in disease therapy. Indeed, novel selected therapeutic approaches, including novel agents and combinatorial therapies, are showing promising early results. EXPERT OPINION: Targeting different molecular pathways in combination with immunotherapy can be a promising direction in metastatic castration prostate cancer treatment. However, several challenges still exist including elucidating the optimal use and sequencing of these new agents. There are also challenges in both the design and the interpretation of the results from clinical trials. PMID- 24490884 TI - Nanostructuring of iron surfaces by low-energy helium ions. AB - The behavior of iron surfaces under helium plasma exposure is investigated as a function of surface temperature, plasma exposure time, and He ion flux. Different surface morphologies are observed for a large process parameter range and discussed in terms of temperature-related surface mechanisms. Surface modification is observed under low-He ion flux (in the range of 10(20) m(-2) s( 1)) irradiation, whereas fiberlike iron nanostructures are formed by exposing the surface to a high flux (in the range of 10(23) m(-2) s(-1)) of low-energy He ions at surface temperatures of 450-700 degrees C. The effects of surface temperature and plasma exposure time on nanostructures are studied. The results show that surface processing by high-flux low-energy He ion bombardment provides a size controlled nanostructuring on iron surfaces. PMID- 24490885 TI - Advances in magnetic resonance: from stem cells to catalytic surfaces. PMID- 24490887 TI - Copper-catalyzed domino addition/double cyclization: an approach to polycyclic benzimidazole derivatives. AB - An efficient and versatile method for the assembly of novel polycyclic benzimidazole derivatives has been developed by Cu-catalyzed domino addition/double cyclization reactions. A wide variety of polycyclic benzimidazole derivatives, which might be used as synthetic medicines and functional materials, were successfully assembled from bis-(o-haloaryl)carbodiimides. Unexpected N methylated benzo[4,5]imidazo[1,2-a]indoles can also be selectively assembled. Multibonds and polycyclic moieties were conveniently formed in one pot during these domino processes. PMID- 24490888 TI - Effects of daily intake of yoghurt enriched with bioactive components on chronic stress responses: a double-blinded randomized controlled trial. AB - Chronic stress has a negative influence on health. The aim was to determine stress reducing effects of yoghurt enriched with bioactive components as compared to normal yoghurt. High-trait anxiety individuals (n = 67) aged 18-63 years participated in a randomized, placebo-controlled, double-blinded intervention with parallel groups. They received either yoghurt enriched with alpha lactalbumin, casein tripeptides and B vitamins (active) or isoenergetic standard yoghurt (control). To detect changes in psychological and physiological stress, State-Trait Anxiety Inventory, Profile of Mood States, salivary cortisol, inflammatory markers, blood pressure, heart rate variability (HRV) and actigraphy were monitored. We observed higher ratings of vigor (p = 0.047) and reduced feeling of inefficiency (p = 0.048) in the active group. HRV (baseline adjusted mean 49.1 +/- 2.3 ms) and recovery index (106.6 +/- 33.4) were higher in the active group than in controls (42.5 +/- 2.2 ms and 80.0 +/- 29.3) (p = 0.046 and p = 0.02, respectively). In conclusion, daily intake of yoghurt enriched with bioactive components may aid in stress coping. PMID- 24490890 TI - Ethnic and racial identity during adolescence and into young adulthood: an integrated conceptualization. AB - Although ethnic and racial identity (ERI) are central to the normative development of youth of color, there have been few efforts to bring scholars together to discuss the theoretical complexities of these constructs and provide a synthesis of existing work. The Ethnic and Racial Identity in the 21st Century Study Group was assembled for this purpose. This article provides an overview of the interface of ERI with developmental and contextual issues across development, with an emphasis on adolescence and young adulthood. It proposes a metaconstruct to capture experiences that reflect both individuals' ethnic background and their racialized experiences in a specific sociohistorical context. Finally, it presents milestones in the development of ERI across developmental periods. PMID- 24490891 TI - Ethnic and racial identity in adolescence: implications for psychosocial, academic, and health outcomes. AB - The construction of an ethnic or racial identity is considered an important developmental milestone for youth of color. This review summarizes research on links between ethnic and racial identity (ERI) with psychosocial, academic, and health risk outcomes among ethnic minority adolescents. With notable exceptions, aspects of ERI are generally associated with adaptive outcomes. ERI are generally beneficial for African American adolescents' adjustment across all three domains, whereas the evidence is somewhat mixed for Latino and American Indian youth. There is a dearth of research for academic and health risk outcomes among Asian American and Pacific Islander adolescents. The review concludes with suggestions for future research on ERI among minority youth. PMID- 24490892 TI - Methodological issues in ethnic and racial identity research with ethnic minority populations: theoretical precision, measurement issues, and research designs. AB - This article takes stock of research methods employed in the study of racial and ethnic identity with ethnic minority populations. The article is presented in three parts. The first section reviews theories, conceptualizations, and measurement of ethnic and racial identity (ERI) development. The second section reviews theories, conceptualizations, and measurement of ERI content. The final section reviews key methodological and analytic principles that are important to consider for both ERI development and content. The article concludes with suggestions for future research addressing key methodological limitations when studying ERI. PMID- 24490893 TI - Feeling good, happy, and proud: a meta-analysis of positive ethnic-racial affect and adjustment. AB - One point of intersection in ethnic and racial identity research is the conceptual attention paid to how positively youth feel about their ethnicity or race, or positive ethnic-racial affect. This article reports results of a series of meta-analyses based on 46 studies of this dimension and psychosocial, academic, and health risk outcomes among ethnic and racial minority youth. The overall pattern of results suggests that positive ethnic-racial affect exhibited small to medium associations (r range = |.11| to |.37|) with depressive symptoms, positive social functioning, self-esteem, well-being, internalizing, externalizing, academic achievement, academic attitudes, and health risk outcomes. Implications for theory and research about the role of positive ethnic racial affect among youth growing up in an increasingly diverse society are discussed. PMID- 24490895 TI - Malaria indicator survey 2009, South Sudan: baseline results at household level. AB - BACKGROUND: South Sudan has borne the brunt of years of chronic warfare and probably has the highest malaria burden in sub-Saharan Africa. Malaria is the leading cause of morbidity and mortality in the country. This nationally representative survey aimed to provide data on malaria indicators at household level across the country. METHODS: In 2009, data were collected using a two-stage random cluster sample of 2,797 households in 150 census enumeration areas during a Malaria Indicator Survey (MIS) in South Sudan. The survey determined parasite and anaemia prevalence in vulnerable population groups and evaluated coverage, use and access to malaria control services. Standardized Roll Back Malaria Monitoring and Evaluation Reference Group (RBM-MERG) MIS household and women's questionnaires were adapted to the local situation and used for collection of data that were analysed and summarized using descriptive statistics. RESULTS: The results of this survey showed that 59.3% (95% CI: 57.5-61.1) of households owned at least one mosquito net. The proportion of the population with access to an ITN in their household was 49.7% (95% CI: 48.2-51.2). The utilization of insecticide treated nets was low; 25.3% (95% CI: 23.9-26.7) for children under five (U5) and 35.9% (95% CI: 31.9-40.2) of pregnant women (OR: 1.66 (1.36-2.01); P =0.175). Prevalence of infection was 24.5% (95% CI: 23.0-26.1) in children U5 and 9.9% (95% CI: 7.4-13.1) in pregnant women. About two thirds (64%) of children U5 and 46% of pregnant women were anaemic. Only 2% of households were covered by indoor residual spraying (IRS) the previous year. Data shows that 58% reported that malaria is transmitted by mosquitoes, 34% mentioned that the use of mosquito nets could prevent malaria, 41% knew the correct treatment for malaria, and 52% of the children received treatment at a health facility. CONCLUSION: The observed high malaria prevalence could be due to low levels of coverage and utilization of interventions coupled with low knowledge levels. Therefore, access and utilization of malaria control tools should be increased through scaling up coverage and improving behaviour change communication. PMID- 24490896 TI - Extending World Health Organization weight-for-age reference curves to older children. AB - BACKGROUND: For ages 5-19 years, the World Health Organization (WHO) publishes reference charts based on 'core data' from the US National Center for Health Statistics (NCHS), collected from 1963-75 on 22,917 US children. To promote the use of body mass index in older children, weight-for-age was omitted after age 10. Health providers have subsequently expressed concerns about this omission and the selection of centiles. We therefore sought to extend weight-for-age reference curves from 10 to 19 years by applying WHO exclusion criteria and curve fitting methods to the core NCHS data and to revise the choice of displayed centiles. METHODS: WHO analysts first excluded ~ 3% of their reference population in order to achieve a "non-obese sample with equal height". Based on these exclusion criteria, 314 girls and 304 boys were first omitted for 'unhealthy' weights-for height. By applying WHO global deviance and information criteria, optimal Box-Cox power exponential models were used to fit smoothed weight-for-age centiles. Bootstrap resampling was used to assess the precision of centile estimates. For all charts, additional centiles were included in the healthy range (3 to 97%), and the more extreme WHO centiles 0.1 and 99.9% were dropped. RESULTS: In addition to weight-for-age beyond 10 years, our charts provide more granularity in the centiles in the healthy range -2 to +2 SD (3-97%). For both weight and BMI, the bootstrap confidence intervals for the 99.9th centile were at least an order of magnitude wider than the corresponding 50th centile values. CONCLUSIONS: These charts complement existing WHO charts by allowing weight-for-age to be plotted concurrently with height in older children. All modifications followed strict WHO methodology and utilized the same core data from the US NCHS. The additional centiles permit a more precise assessment of normal growth and earlier detection of aberrant growth as it crosses centiles. Elimination of extreme centiles reduces the risk of misclassification. A complete set of charts is available at the CPEG web site (http://cpeg-gcep.net). PMID- 24490897 TI - Cauda equina syndrome. AB - Questions from patients about pain conditions and analgesic pharmacotherapy and responses from authors are presented to help educate patients and make them more effective self-advocates. The topics addressed in this issue are cauda equina syndrome, a dysfunction of the nerves in the spinal canal, and its symptoms, diagnosis, and treatment. PMID- 24490898 TI - Beyond the "coffee ring": re-entrant ordering in an evaporation-driven self assembly in a colloidal suspension on a substrate. AB - We study the phenomenon of evaporation-driven self-assembly of a colloid suspension of silica microspheres in the interior region and away from the rim of the droplet on a glass plate. In view of the importance of achieving a large area, monolayer assembly, we first realize a suitable choice of experimental conditions, minimizing the influence of many other competing phenomena that usually complicate the understanding of fundamental concepts of such self assembly processes in the interior region of a drying droplet. Under these simplifying conditions to bring out essential aspects, our experiments unveil an interesting competition between ordering and compaction in such drying systems in analogy to an impending glass transition. We establish a re-entrant behavior in the order-disorder phase diagram as a function of the particle density, such that there is an optimal range of the particle density to realize the long-range ordering. The results are explained with the help of simulations and phenomenological theory. PMID- 24490899 TI - The role of innate and lymphoid IL-22-producing cells in the immunopathology of primary Sjogren's syndrome. AB - In primary Sjogren's syndrome (pSS) a complex of interconnections between epithelial barrier, innate and adaptive immunity occurs. IL-22 is a pleiotropic cytokine that in pSS may be placed at the intersection of the adaptive and innate branches of immunity. Some evidence suggests that, in pSS, IL-22 may play a prominent pro-inflammatory role driving the early phase of tissue and systemic inflammation and participating in the self-perpetuation of disease. Despite contradictory data in literature about the role of NK cells in pSS, recent data also suggest an important contribution of this subset of cells of the innate immune system in the development and perpetuation of inflammation. Here, we discuss the role of IL-22 in the pathogenesis of pSS and in epithelial barrier function. PMID- 24490900 TI - Nitrogen-containing bisphosphonates inhibit RANKL- and M-CSF-induced osteoclast formation through the inhibition of ERK1/2 and Akt activation. AB - BACKGROUND: Bisphosphonates are an important class of antiresorptive drugs used in the treatment of metabolic bone diseases. Recent studies have shown that nitrogen-containing bisphosphonates induced apoptosis in rabbit osteoclasts and prevented prenylated small GTPase. However, whether bisphosphonates inhibit osteoclast formation has not been determined. In the present study, we investigated the inhibitory effect of minodronate and alendronate on the osteoclast formation and clarified the mechanism involved in a mouse macrophage like cell lines C7 and RAW264.7. RESULTS: It was found that minodronate and alendronate inhibited the osteoclast formation of C7 cells induced by receptor activator of NF-kappaB ligand and macrophage colony stimulating factor, which are inhibited by the suppression of geranylgeranyl pyrophosphate (GGPP) biosynthesis. It was also found that minodronate and alendronate inhibited the osteoclast formation of RAW264.7 cells induced by receptor activator of NF-kappaB ligand. Furthermore, minodronate and alendornate decreased phosphorylated extracellular signal-regulated kinase 1/2 (ERK1/2) and Akt; similarly, U0126, a mitogen protein kinase kinase 1/2 (MEK1/2) inhibitor, and LY294002, a phosphatidylinositol 3 kinase (PI3K) inhibitor, inhibited osteoclast formation. CONCLUSIONS: This indicates that minodronate and alendronate inhibit GGPP biosynthesis in the mevalonate pathway and then signal transduction in the MEK/ERK and PI3K/Akt pathways, thereby inhibiting osteoclast formation. These results suggest a novel effect of bisphosphonates that could be effective in the treatment of bone metabolic diseases, such as osteoporosis. PMID- 24490901 TI - Prediction of ecotoxicity of heavy crude oil: contribution of measured components. AB - A prediction model for estimating the ecotoxicity of the water-accommodated fraction (WAF) and water-soluble fraction (WSF) of heavy crude oil is proposed. Iranian heavy crude oil (IHC), one of the major components of the Hebei Spirit oil spill in Korea in 2007, was used as a model crude oil for the preparation of the WAF and the WSF. Luminescence inhibition of Vibrio fischeri was chosen as the model ecotoxicity test for evaluating the baseline toxicity of aromatic hydrocarbons in the IHC. The measured concentration of each chemical species in WAF and WSF agreed well with the predicted soluble concentration calculated using Raoult's law from the measured amount in the IHC. This indicates that the toxic potential of an oil mixture can be evaluated from the dissolved concentration of each species, which in turn, may be predicted from the composition of the crude or weathered oils. In addition, the contribution of each species in the mixture to the apparent luminescence inhibition by the WAF and the WSF was assessed using a concentration-addition model. The relative contributions of benzene, toluene, ethylbenzene, xylenes (BTEX), polycyclic aromatic hydrocarbons (PAHs), and alkylated PAHs in luminescence inhibition were estimated to be 76%, 2%, and 21%, respectively. It was further identified that C3- and C4-naphthalenes were the most important aromatic hydrocarbons responsible for baseline toxicity. This indicates that alkylated PAHs would be the major components of oil-spill residue. Further research is needed to evaluate the fate and ecotoxicity of alkylated PAHs. PMID- 24490902 TI - Lupin protein isolate versus casein modifies cholesterol excretion and mRNA expression of intestinal sterol transporters in a pig model. AB - BACKGROUND: Lupin proteins exert hypocholesterolemic effects in man and animals, although the underlying mechanism remains uncertain. Herein we investigated whether lupin proteins compared to casein modulate sterol excretion and mRNA expression of intestinal sterol transporters by use of pigs as an animal model with similar lipid metabolism as humans, and cellular cholesterol-uptake by Caco 2 cells. METHODS: Two groups of pigs were fed cholesterol-containing diets with either 230 g/kg of lupin protein isolate from L. angustifolius or 230 g/kg casein, for 4 weeks. Faeces were collected quantitatively over a 5 d period for analysis of neutral sterols and bile acids by gas chromatographically methods. The mRNA abundances of intestinal lipid transporters were analysed by real-time RT-PCR. Cholesterol-uptake studies were performed with Caco-2 cells that were incubated with lupin conglutin gamma, phytate, ezetimibe or albumin in the presence of labelled [4-14C]-cholesterol. RESULTS: Pigs fed the lupin protein isolate revealed lower cholesterol concentrations in total plasma, LDL and HDL than pigs fed casein (P < 0.05). Analysis of faeces revealed a higher output of cholesterol in pigs that were fed lupin protein isolate compared to pigs that received casein (+57.1%; P < 0.05). Relative mRNA concentrations of intestinal sterol transporters involved in cholesterol absorption (Niemann-Pick C1-like 1, scavenger receptor class B, type 1) were lower in pigs fed lupin protein isolate than in those who received casein (P < 0.05). In vitro data showed that phytate was capable of reducing the uptake of labelled [4-14C]-cholesterol into the Caco 2 cells to the same extend as ezetimibe when compared to control (-20.5% vs. 21.1%; P < 0.05). CONCLUSIONS: Data reveal that the cholesterol-lowering effect of lupin protein isolate is attributable to an increased faecal output of cholesterol and a reduced intestinal uptake of cholesterol. The findings indicate phytate as a possible biofunctional ingredient of lupin protein isolate. PMID- 24490903 TI - Application of docking and QM/MM-GBSA rescoring to screen for novel Myt1 kinase inhibitors. AB - Identification of compounds that can bind to a target protein with high affinity is a nontrivial task in structure-based drug design. Several approaches ranging from simple scoring methods to more computationally demanding methods are usually applied for this purpose. In the current work, we used ligand docking in combination with QM/MM-GBSA, MM-GBSA, and MM-PBSA rescoring to discriminate between active and inactive Myt1 kinase inhibitors. Results show that QM/MM-GBSA rescoring performs better than normal docking scores or MM-GBSA rescoring in classifying active and inactive inhibitors. We also applied QM/MM-GBSA rescoring to estimate the binding affinities of compounds from different virtual screening runs. To prove our approach and to confirm its predictive power, a few compounds which were predicted to be active were purchased and experimentally tested. Among the five selected compounds, three showed significant inhibition of recombinant Myt1. PD-173952, which yielded a favorable QM/MM-GBSA binding free energy, showed a K(i) value of 8.1 nM. In addition, two compounds, PD-180970 and saracatinib, showed inhibition at the low micromolar level. Thus, the developed protocol might be useful for further virtual screening experiments to better discriminate between active and inactive compounds and to further optimize the identified hits. PMID- 24490904 TI - How pH modulates the reactivity and selectivity of a siderophore-associated flavin monooxygenase. AB - Flavin-containing monooxygenases (FMOs) catalyze the oxygenation of diverse organic molecules using O2, NADPH, and the flavin adenine dinucleotide (FAD) cofactor. The fungal FMO SidA initiates peptidic siderophore biosynthesis via the highly selective hydroxylation of L-ornithine, while the related amino acid L lysine is a potent effector of reaction uncoupling to generate H2O2. We hypothesized that protonation states could critically influence both substrate selective hydroxylation and H2O2 release, and therefore undertook a study of SidA's pH-dependent reaction kinetics. Consistent with other FMOs that stabilize a C4a-OO(H) intermediate, SidA's reductive half reaction is pH independent. The rate constant for the formation of the reactive C4a-OO(H) intermediate from reduced SidA and O2 is likewise independent of pH. However, the rate constants for C4a-OO(H) reactions, either to eliminate H2O2 or to hydroxylate L-Orn, were strongly pH-dependent and influenced by the nature of the bound amino acid. Solvent kinetic isotope effects of 6.6 +/- 0.3 and 1.9 +/- 0.2 were measured for the C4a-OOH/H2O2 conversion in the presence and absence of L-Lys, respectively. A model is proposed in which L-Lys accelerates H2O2 release via an acid-base mechanism and where side-chain position determines whether H2O2 or the hydroxylation product is observed. PMID- 24490905 TI - An overview of recent developments in the treatment of heart failure: update from the ESC Congress 2013. AB - The European Society of Cardiology held their annual congress in Amsterdam between the 31st of August and 4 September 2013 to discuss the latest developments in the field. The meeting included an update of the latest treatments currently under investigation for the treatment of heart failure. Updates were provided on the RELAX-AHF study that had, for the first time, demonstrated an improvement in post-discharge outcome in patients with acute heart failure treated with seralaxin. The meeting also gave the opportunity to highlight the latest goings on from the promising agent omecamtiv mecarbil as shown in the ATOMIC-AHF study. Indeed, its unique inotropic effect showed a potential to improve dyspnea without increasing myocardial oxygen consumption. Other presentations at the meeting included: a recent study evaluating ultrafiltration in the treatment of acute HF with renal impairment and the effects of the vasodilator cinaciguat. The unremarkable results from the recent ASTRONAUT study with aliskiren were also touched upon. It is important to note that while the data from seralaxin and omecamtiv mecarbil has been promising, the long term benefits of these therapies in heart failure still need to be evaluated. The authors also highlight the need for these promising agents to be further evaluated in women and other ethnic groups. PMID- 24490906 TI - DNA fingerprinting in zoology: past, present, future. AB - In 1962, Thomas Kuhn famously argued that the progress of scientific knowledge results from periodic 'paradigm shifts' during a period of crisis in which new ideas dramatically change the status quo. Although this is generally true, Alec Jeffreys' identification of hypervariable repeat motifs in the human beta-globin gene, and the subsequent development of a technology known now as 'DNA fingerprinting', also resulted in a dramatic shift in the life sciences, particularly in ecology, evolutionary biology, and forensics. The variation Jeffreys recognized has been used to identify individuals from tissue samples of not just humans, but also of many animal species. In addition, the technology has been used to determine the sex of individuals, as well as paternity/maternity and close kinship. We review a broad range of such studies involving a wide diversity of animal species. For individual researchers, Jeffreys' invention resulted in many ecologists and evolutionary biologists being given the opportunity to develop skills in molecular biology to augment their whole organism focus. Few developments in science, even among the subsequent genome discoveries of the 21st century, have the same wide-reaching significance. Even the later development of PCR-based genotyping of individuals using microsatellite repeats sequences, and their use in determining multiple paternity, is conceptually rooted in Alec Jeffreys' pioneering work. PMID- 24490907 TI - Life is pretty meaningful. AB - The human experience of meaning in life is widely viewed as a cornerstone of well being and a central human motivation. Self-reports of meaning in life relate to a host of important functional outcomes. Psychologists have portrayed meaning in life as simultaneously chronically lacking in human life as well as playing an important role in survival. Examining the growing literature on meaning in life, we address the question "How meaningful is life, in general?" We review possible answers from various psychological sources, some of which anticipate that meaning in life should be low and others that it should be high. Summaries of epidemiological data and research using two self-report measures of meaning in life suggest that life is pretty meaningful. Diverse samples rate themselves significantly above the midpoint on self-reports of meaning in life. We suggest that if meaning in life plays a role in adaptation, it must be commonplace, as our analysis suggests. PMID- 24490908 TI - Disposable electrochemical aptasensor array by using in situ DNA hybridization inducing silver nanoparticles aggregate for signal amplification. AB - Nanomaterials as tracing tags have been widely used in biosensors with high sensitivity and selectivity. In this work, a signal amplification electrochemical aptamer sensing strategy for the detection of protein was designed by combining the hybridization-inducing aggregate of DNA-functionalized silver nanoparticles (AgNPs) and differential pulse stripping voltammetry (DPSV) detection. The multiprobes containing hybridization DNA and aptamers were anchored onto the silver nanoparticles. The protein assay was prepared through the immobilization of capture aptamer that specifically recognizes platelet-derived growth factor (PDGF-BB) on gold nanoparticles modified screen-printed electrode (SPE) array. After a sandwich-type reaction, two kinds of DNA-modified AgNPs were simultaneously added on the electrode surface for specifically recognizing PDGF BB and forming the AgNPs aggregate caused by in situ hybridization of DNA. Compared to the signal-labeled tag, the tracing aggregate tags showed a strong electroactivity for signal amplification through stripping detection of silver after preoxidation. By using the hybridization-inducing aggregate as electrochemical readouts, the sensor showed wide linear range and low detection limit. The hybridization-inducing AgNPs aggregate were further used as tracing tags in multiplied proteins assays for PDGF-BB and thrombin by using the SPE array chip as sensing platform. The cross-talk between different aptamer-modified electrodes on the same array was avoided because of the advantage of labeled AgNPs. The array detection was also applied in the logic gate operation. The proposed method described here is ideal for multianalytes determination in clinical diagnostics with good analytical performance. PMID- 24490909 TI - The acceptability of humor between palliative care patients and health care providers. AB - BACKGROUND: Humor frequently occurs in palliative care environments; however, the acceptability of humor, particularly between patients and health care providers has not been previously examined. OBJECTIVES: To explore the importance and acceptability of humor to participants who are patients in a palliative care context, the study determines if demographics are correlated with the degree of acceptability, and examines the acceptance of humor by patients with advanced illness when interacting with nurses or physicians. METHODS: One hundred participants admitted to a palliative care unit or residential hospice were surveyed. Basic demographic data were collected, as well as responses on a five point Likert scale to a variety of questions regarding the participants' attitudes about humor before and after their illness and the acceptability of humor in a palliative setting. Participants were also given the opportunity to comment freely on the topic of humor and the palliative experience. RESULTS: A large majority of participants valued humor highly both prior to (77%) and during (76%) their illness experience. Despite this valuation, the frequency of laughter in their daily lives diminished significantly as patients' illness progressed. Most participants remembered laughing with a nurse (87%) and a doctor (67%) in the week prior to the survey, and found humor with their doctors (75%) and nurses appropriate (88%). CONCLUSION: The vast majority of participants found humorous interactions with their health care providers acceptable and appropriate, and this may indicate a opportunity for enhanced and more effective end-of-life care in the future. PMID- 24490910 TI - Tailoring assembly of reduced graphene oxide nanosheets to control gas barrier properties of natural rubber nanocomposites. AB - Self-assembling of reduced graphene oxide platelets, as a tailored interconnected network within a natural rubber matrix, is proposed as a mean for obtaining nanocomposites with improved gas barrier, as compared to neat natural rubber. Interestingly, this nanocomposite structure results to be much more effective than homogeneous dispersion of graphene platelike particles, even at low graphene loadings. Such behavior is interpreted on the grounds of a theoretical model describing permeability of heterogeneous systems specifically accounting for self segregated graphene morphology. PMID- 24490911 TI - Evaluation of a multiplex real-time PCR method for detecting shiga toxin producing Escherichia coli in beef and comparison to the U.S. Department of Agriculture Food Safety and Inspection Service Microbiology laboratory guidebook method. AB - The "top-six" non-O157 Shiga toxin-producing Escherichia coli (STEC) serogroups (O26, O45, O103, O111, O121, and O145) most frequently associated with outbreaks and cases of foodborne illnesses have been declared as adulterants in beef by the U.S. Department of Agriculture Food Safety and Inspection Service (FSIS). Regulatory testing in beef began in June 2012. The purpose of this study was to evaluate the DuPont BAX System method for detecting these top six STEC strains and strains of E. coli O157:H7. For STEC, the BAX System real-time STEC suite was evaluated, including a screening assay for the stx and eae virulence genes and two panel assays to identify the target serogroups: panel 1 detects O26, O111, and O121, and panel 2 detects O45, O103, O145. For E. coli O157:H7, the BAX System real-time PCR assay for this specific serotype was used. Sensitivity of each assay for the PCR targets was >=1.23 * 10(3) CFU/ml in pure culture. Each assay was 100% inclusive for the strains tested (20 to 50 per assay), and no cross-reactivity with closely related strains was observed in any of the assays. The performance of the BAX System methods was compared with that of the FSIS Microbiology Laboratory Guidebook (MLG) methods for detection of the top six STEC and E. coli O157:H7 strains in ground beef and beef trim. Generally, results of the BAX System method were similar to those of the MLG methods for detecting non O157 STEC and E. coli O157:H7. Reducing or eliminating novobiocin in modified tryptic soy broth (mTSB) may improve the detection of STEC O111 strains; one beef trim sample inoculated with STEC O111 produced a negative result when enriched in mTSB with 8 mg/liter novobiocin but was positive when enriched in mTSB without novobiocin. The results of this study indicate the feasibility of deploying a panel of real-time PCR assay configurations for the detection and monitoring of the top six STEC and E. coli O157:H7 strains in beef. The approach could easily be adapted for additional multiplex assays should regulations expand to include other O serogroups or virulence genes. PMID- 24490912 TI - Absence of internalization of Escherichia coli O157:H7 into germinating tissue of field-grown leafy greens. AB - Both growth chamber and field studies were conducted to investigate the potential for Escherichia coli O157:H7 to be internalized into leafy green tissue when seeds were germinated in contaminated soil. Internalized E. coli O157:H7 was detected by enrichment in both spinach (Spinacia oleracea L.) and lettuce (Lactuca sativa L.) seedlings when seeds were germinated within the growth chamber in autoclaved and nonautoclaved soil, respectively, contaminated with E. coli O157:H7 at 2.0 and 3.8 log CFU/g, respectively. Internalized E. coli O157:H7 populations could be detected by enumeration within leafy green tissues either by increasing the pathogen levels in the soil or by autoclaving the soil. Attempts to maximize the exposure of seed to E. coli O157:H7 by increasing the mobility of the microbe either through soil with a higher moisture content or through directly soaking the seeds in an E. coli O157:H7 inoculum did not increase the degree of internalization. Based on responses obtained in growth chamber studies, internalization of E. coli O157:H7 surrogates (natural isolates of Shiga toxin negative E. coli O157:H7 or recombinant [stx- and eae-negative] outbreak strains of E. coli O157:H7) occurred to a slightly lesser degree than did internalization of the virulent outbreak strains of E. coli O157:H7. The apparent lack of internalized E. coli O157:H7 when spinach and lettuce were germinated from seed in contaminated soil (ca. 3 to 5 log CFU/g) in the field and the limited occurrence of surface contamination on the seedlings suggest that competition from indigenous soil bacteria and environmental stresses were greater in the field than in the growth chamber. On the rare occasion that soil contamination with E. coli O157:H7 exceeded 5 log CFU/g in a commercial field, this pathogen probably would not be internalized into germinating leafy greens and/or would not still be present at the time of harvest. PMID- 24490913 TI - Growth of Escherichia coli O157:H7 and Listeria monocytogenes in packaged fresh cut romaine mix at fluctuating temperatures during commercial transport, retail storage, and display. AB - Temperature abuse during commercial transport and retail sale of leafy greens negatively impacts both microbial safety and product quality. Consequently, the effect of fluctuating temperatures on Escherichia coli O157:H7 and Listeria monocytogenes growth in commercially-bagged salad greens was assessed during transport, retail storage, and display. Over a 16-month period, a series of time temperature profiles for bagged salads were obtained from five transportation routes covering four geographic regions (432 profiles), as well as during retail storage (4,867 profiles) and display (3,799 profiles). Five different time temperature profiles collected during 2 to 3 days of transport, 1 and 3 days of retail storage, and 3 days of retail display were then duplicated in a programmable incubator to assess E. coli O157:H7 and L. monocytogenes growth in commercial bags of romaine lettuce mix. Microbial growth predictions using the Koseki-Isobe and McKellar-Delaquis models were validated by comparing the root mean square error (RMSE), bias, and the acceptable prediction zone between the laboratory growth data and model predictions. Monte Carlo simulations were performed to calculate the probability distribution of microbial growth from 8,122,127,472 scenarios during transport, cold room storage, and retail display. Using inoculated bags of retail salad, E. coli O157:H7 and L. monocytogenes populations increased a maximum of 3.1 and 3.0 log CFU/g at retail storage. Both models yielded acceptable RMSEs and biases within the acceptable prediction zone for E. coli O157:H7. Based on the simulation, both pathogens generally increased <2 log CFU/g during transport, storage, and display. However, retail storage duration can significantly impact pathogen growth. This large-scale U.S. study the first using commercial time/temperature profiles to assess the microbial risk of leafy greens-should be useful in filling some of the data gaps in current risk assessments for leafy greens. PMID- 24490914 TI - Selection of process conditions by risk assessment for apple juice pasteurization by UV-heat treatments at moderate temperatures. AB - The effect of bactericidal UV-C treatments (254 nm) on Escherichia coli O157:H7 suspended in apple juice increased synergistically with temperature up to a threshold value. The optimum UV-C treatment temperature was 55 degrees C, yielding a 58.9% synergistic lethal effect. Under these treatment conditions, the UV-heat (UV-H55 degrees C) lethal variability achieving 5-log reductions had a logistic distribution (alpha = 37.92, beta = 1.10). Using this distribution, UV H55 degrees C doses to achieve the required juice safety goal with 95, 99, and 99.9% confidence were 41.17, 42.97, and 46.00 J/ml, respectively, i.e., doses higher than the 37.58 J/ml estimated by a deterministic procedure. The public health impact of these results is that the larger UV-H55 degrees C dose required for achieving 5-log reductions with 95, 99, and 99.9% confidence would reduce the probability of hemolytic uremic syndrome in children by 76.3, 88.6, and 96.9%, respectively. This study illustrates the importance of including the effect of data variability when selecting operational parameters for novel and conventional preservation processes to achieve high food safety standards with the desired confidence level. PMID- 24490915 TI - Verotoxigenic Escherichia coli: costs of illness in Canada, including long-term health outcomes. AB - The main objective of this study was to provide cost estimates of human Escherichia coli O157 infection to facilitate future assessment of the benefits and costs of alternative preventive strategies to reduce illness. We investigated the costs of illness to Canadians from primary human infection by verotoxigenic E. coli O157 (also called Shiga toxin-producing E. coli O157) using data from the National Notifiable Diseases Registry. We used relative risk information from peer-reviewed publications to estimate the burden of illness and associated costs for eight long-term health outcomes. National estimates of the number of cases (mean and 5th and 95th percentiles), associated costs, and a rank correlation test to identify which outcomes were associated with the highest per capita costs were calculated. An estimated 22,344 cases of primary infections occur in Canada annually, costing $26.7 million. There are 37,867 additional on-going long-term health outcomes costing $377.2 million each year. Our analysis indicated that the annual cost for primary and long-term illness is $403.9 million. The analysis supports evaluation of alternative control and prevention measures and the development and implementation of policy and practices aimed at safe food production. PMID- 24490916 TI - Counts, serovars, and antimicrobial resistance phenotypes of Salmonella on raw chicken meat at retail in Colombia. AB - The objective of this study was to determine Salmonella counts, serovars, and antimicrobial-resistant phenotypes on retail raw chicken carcasses in Colombia. A total of 301 chicken carcasses were collected from six departments (one city per department) in Colombia. Samples were analyzed for Salmonella counts using the most-probable-number method as recommended by the U.S. Department of Agriculture, Food Safety Inspection Service protocol. A total of 378 isolates (268 from our previous study) were serotyped and tested for antimicrobial susceptibility. The overall Salmonella count (mean log most probable number per carcass +/- 95% confidence interval) and prevalence were 2.1 (2.0 to 2.3) and 37%, respectively. There were significant differences (P < 0.05) by Salmonella levels (i.e., counts and prevalence) by storage temperature (i.e., frozen, chilled, or ambient), retail store type (wet markets, supermarkets, and independent markets), and poultry company (chicken produced by integrated or nonintegrated company). Frozen chicken had the lowest Salmonella levels compared with chicken stored at other temperatures, chickens from wet markets had higher levels than those from other retail store types, and chicken produced by integrated companies had lower levels than nonintegrated companies. Thirty-one Salmonella serovars were identified among 378 isolates, with Salmonella Paratyphi B tartrate-positive (i.e., Salmonella Paratyphi B dT+) the most prevalent (44.7%), followed by Heidelberg (19%), Enteritidis (17.7%), Typhimurium (5.3%), and Anatum (2.1%). Of all the Salmonella isolates, 35.2% were resistant to 1 to 5 antimicrobial agents, 24.6% to 6 to 10, and 33.9% to 11 to 15. Among all the serovars obtained, Salmonella Paratyphi B dT+ and Salmonella Heidelberg were the most antimicrobial resistant. Salmonella prevalence was determined to be high, whereas cell numbers were relatively low. These data can be used in developing risk assessment models for preventing the transmission of Salmonella from chicken to humans in Colombia. PMID- 24490917 TI - Prevalence, characteristics, and antimicrobial resistance patterns of Salmonella in retail pork in Jiangsu province, eastern China. AB - Salmonella is commonly isolated from raw pork and is a leading cause of foodborne illness. Because China has the highest rate of pork consumption and the largest number of pig breeding facilities in the world, an epidemiological analysis of Salmonella species from pork in China is warranted. In this study, pork samples (n = 1,096) were collected from 20 major free markets in four cities of Jiangsu province from August 2010 to December 2012. A total of 163 Salmonella isolates were recovered from 154 Salmonella-positive samples. Among 14 Salmonella serovars identified, Derby (47.9%) was most prevalent, followed by Typhimurium (10.4%), Meleagridis (9.2%), Anatum (8.6%), and London (6.7%). Antimicrobial sensitivity testing revealed that 134 (82.2%) of the isolates were resistant to at least one antimicrobial agent, and 41 (25.2%) were resistant to more than three antimicrobials. The highest resistance was to tetracycline (66.3% of isolates) followed by ampicillin (39.9%), trimethoprim-sulfamethoxazole (31.3%), and nalidixic acid (30.1%). Multilocus sequence typing analysis revealed 14 sequence type (ST) patterns; ST40 was the most common (77 isolates) followed by ST64 (19 isolates). Our research revealed a high prevalence of Salmonella in retail pork. Diversity among the Salmonella isolates was high in terms of serovar and genotype, and multidrug resistance was prevalent. Multilocus sequence type was generally associated with serovar and provided a reliable prediction of the most common Salmonella serovars. PMID- 24490918 TI - High-salt preadaptation of Vibrio parahaemolyticus enhances survival in response to lethal environmental stresses. AB - Adaptation to changing environmental conditions is an important strategy for survival of foodborne bacterial pathogens. Vibrio parahaemolyticus is a gram negative seafoodborne enteric pathogen found in the marine environment both free living and associated with oysters. This pathogen is a moderate halophile, with optimal growth at 3% NaCl. Among the several stresses imposed upon enteric bacteria, acid stress is perhaps one of the most important. V. parahaemolyticus has a lysine decarboxylase system responsible for decarboxylation of lysine to the basic product cadaverine, an important acid stress response system in bacteria. Preadaptation to mild acid conditions, i.e., the acid tolerance response, enhances survival under lethal acid conditions. Because of the variety of conditions encountered by V. parahaemolyticus in the marine environment and in oyster postharvest facilities, we examined the nature of the V. parahaemolyticus acid tolerance response under high-salinity conditions. Short preadaptation to a 6% salt concentration increased survival of the wild-type strain but not that of a cadA mutant under lethal acid conditions. However, prolonged exposure to high salinity (16 h) increased survival of both the wild-type and the cadA mutant strains. This phenotype was not dependent on the stress response sigma factor RpoS. Although this preadaptation response is much more pronounced in V. parahaemolyticus, this characteristic is not limited to this species. Both Vibrio cholerae and Vibrio vulnificus also survive better under lethal acid stress conditions when preadapted to high-salinity conditions. High salt both protected the organism against acid stress and increased survival under -20 degrees C cold stress conditions. High-salt adaptation of V. parahaemolyticus strains significantly increases survival under environmental stresses that would otherwise be lethal to these bacteria. PMID- 24490919 TI - Gene transcription patterns of pH- and salt-stressed Listeria monocytogenes cells in simulated gastric and pancreatic conditions. AB - A Listeria monocytogenes subgenomic array, targeting 54 genes involved in the adhesion, adaptation, intracellular life cycle, invasion, and regulation of the infection cycle was used to investigate the gene expression patterns of acid- and salt-stressed Listeria cells after exposure to conditions similar to those in gastric and pancreatic fluids. Three L. monocytogenes strains, one laboratory reference strain (EGDe) and two food isolates (wild strain 12 isolated from milk and wild strain 3 isolated from fermented sausage), were used during the studies. Differences in the expressed genes were observed between the gastric and pancreatic treatments and also between the serotypes. Increased transcripts were observed of the genes belonging to the adaptation and regulation group for serotype 4b (strain 12) and to the invasion and regulation group for serotype 1/2a (strain EGDe). Interestingly, no significantly differentially expressed genes were found for serotype 3c (strain 3) in most cases. The genes related to adaptation (serotype 1/2a) and to intracellular life cycle and invasion (serotype 4b) were down-regulated in order to cope with the hostile environment of the gastric and pancreatic fluids. These findings may provide experimental evidence for the dominance of serotypes 1/2a and 4b in clinical cases of listeriosis and for the sporadic occurrence of serotype 3c. PMID- 24490920 TI - Antimicrobial activity of Hibiscus sabdariffa aqueous extracts against Escherichia coli O157:H7 and Staphylococcus aureus in a microbiological medium and milk of various fat concentrations. AB - Hibiscus sabdariffa L. calyces are widely used in the preparation of beverages. The calyces contain compounds that exhibit antimicrobial activity, yet little research has been conducted on their possible use in food systems as antimicrobials. Aqueous extracts prepared from the brand "Mi Costenita" were sterilized by membrane filtration (0.22-MUm pore size) or autoclaving (121 degrees C, 30 min) and tested for antimicrobial activity against the foodborne pathogens Escherichia coli O157:H7 strains ATCC 43894 and Cider and Staphylococcus aureus strains SA113 and ATCC 27708 in a microbiological medium and ultrahigh-temperature-processed milk with various fat percentages. Extracts heated by autoclaving exhibited greater activity than did filtered extracts in a microbiological medium. Against E. coli, results of 20 mg/ml filtered extract were not different from those of the control, whereas autoclaved extracts reduced viable cells ca. 3 to 4 log CFU/ml. At 60 mg/ml, both extracts inactivated cells after 24 h. There were reduced populations of both strains of S. aureus (ca. 2.7 and 3 log CFU/ml, respectively) after 24 h of incubation in 40 mg/ml filtered extracts. When grown in autoclaved extracts at 40 mg/ml, both strains of S. aureus were inactivated after 9 h. Autoclaved extracts had decreased anthocyanin content (2.63 mg/liter) compared with filtered extracts (14.27 mg/liter), whereas the phenolic content (48.7 and 53.8 mg/g) remained similar for both treatments. Autoclaved extracts were then tested for activity in milk at various fat concentrations (skim [<0.5%], 1%, 2%, and whole [>3.25%]) against a 1:1 mixture of the two strains of E. coli O157:H7 and a 1:1 mixture of the two strains of S. aureus. Extracts at 40 mg/ml inactivated S. aureus after 168 h in skim and whole milk, and E. coli was inactivated after 96 h in 60 mg/ml extract in all fat levels. These findings show the potential use of Hibiscus extracts to prevent the growth of pathogens in foods and beverages. PMID- 24490921 TI - Efficacy of commercial natural antimicrobials alone and in combinations against pathogenic and spoilage microorganisms. AB - Microbial control strategies are needed in the food industry to prevent foodborne illnesses and outbreaks and prolong product shelf life. The aim of this study was to investigate and compare the efficacy of the commercial natural antimicrobials white mustard essential oil (WMEO), citrus flavonoid and acid blend (CFAB), olive extract (OE), Nisaplin (a compound containing nisin), and lauric arginate (LAE) alone and in combinations against foodborne pathogens and spoilage microorganisms. MICs of individual and combined antimicrobials against Escherichia coli, Salmonella Enteritidis, Enterobacter aerogenes, Bacillus cereus, Listeria monocytogenes, and Staphylococcus aureus were determined at pH 6.0 and 25 degrees C. WMEO was most effective against B. cereus and S. aureus, with MICs of 250 and 500 mg/liter, respectively. CFAB inhibited all tested microorganisms, requiring only 12 to 35 mg/liter for gram-positive bacteria. For OE, 2,000 mg/liter was needed to achieve microbial inhibition. Nisaplin at 400 to 1,200 mg/liter inhibited only gram-positive bacteria. LAE was effective at low concentrations and required only 20 to 50 mg/liter to inhibit all tested microorganisms. When WMEO was combined with other antimicrobials, the effects were usually additive except for WMEO plus Nisaplin and WMEO+OE, which had synergistic activity against L. monocytogenes and Salmonella Enteritidis, respectively. An antagonistic effect was observed for WMEO+CFAB against E. aerogenes. For WMEO+LAE+CFAB, additive antimicrobial effects were noted against all strains tested except S. aureus, where a synergistic effect occurred. These findings suggest that these commercial natural antimicrobials have potential to enhance food safety by inhibiting foodborne pathogens and extending product shelf life. PMID- 24490922 TI - Thermal inactivation of human norovirus surrogates in spinach and measurement of its uncertainty. AB - Leafy greens, including spinach, have potential for human norovirus transmission through improper handling and/or contact with contaminated water. Inactivation of norovirus prior to consumption is essential to protect public health. Because of the inability to propagate human noroviruses in vitro, murine norovirus (MNV-1) and feline calicivirus (FCV-F9) have been used as surrogates to model human norovirus behavior under laboratory conditions. The objectives of this study were to determine thermal inactivation kinetics of MNV-1 and FCV-F9 in spinach, compare first-order and Weibull models, and measure the uncertainty associated with the process. D-values were determined for viruses at 50, 56, 60, 65, and 72 degrees C in 2-ml vials. The D-values calculated from the first-order model (50 to 72 degrees C) ranged from 0.16 to 14.57 min for MNV-1 and 0.15 to 17.39 min for FCV-9. Using the Weibull model, the tD for MNV-1 and FCV-F9 to destroy 1 log (D ~ 1) at the same temperatures ranged from 0.22 to 15.26 and 0.27 to 20.71 min, respectively. The z-values determined for MNV-1 were 11.66 +/- 0.42 degrees C using the Weibull model and 10.98 +/- 0.58 degrees C for the first-order model and for FCV-F9 were 10.85 +/- 0.67 degrees C and 9.89 +/- 0.79 degrees C, respectively. There was no difference in D- or z-value using the two models (P > 0.05). Relative uncertainty for dilution factor, personal counting, and test volume were 0.005, 0.0004, and ca. 0.84%, respectively. The major contribution to total uncertainty was from the model selected. Total uncertainties for FCV-F9 for the Weibull and first-order models were 3.53 to 7.56% and 11.99 to 21.01%, respectively, and for MNV-1, 3.10 to 7.01% and 13.14 to 16.94%, respectively. Novel and precise information on thermal inactivation of human norovirus surrogates in spinach was generated, enabling more reliable thermal process calculations to control noroviruses. The results of this study may be useful to the frozen food industry in designing blanching processes for spinach to inactivate or control noroviruses. PMID- 24490923 TI - Use of blue-greenish yellow fluorescence test on feeds and its association with aflatoxin M1 contamination in bulk tank milk. AB - The objectives of this study were to use the blue-greenish yellow fluorescence (BY) test for aflatoxin M1 (AFM1) contamination in bulk milk and to examine the association between AFM1 contamination and environmental and feed management factors. The study was conducted March to May of 2011 with samples from 82 small holder dairy farms belonging to a single dairy cooperative in Chiang Mai province, Thailand. On the day of milk sample collection, samples of all feed used for milking cows and data on feed characteristics, feed management, and environmental factors also were collected at each farm. High-performance liquid chromatography was used to determine AFM1 concentrations in milk samples, and samples with AFM1 concentrations above the limit of detection were considered AFM1 contaminated. Fisher's exact tests were used to determine the association between AFM1 contamination in milk and farm management factors, feed management factors, and fungal contamination in feeds (as determined with the BY test). A multilevel logistic regression model was used to create the final model of factors associated with AFM1 contamination in milk. Feeds with fungal contamination (as determined by the BY test), high levels of cracked particles of commercial concentrate pellets, sunlight in the feed storage room, storage of commercial concentrates on the farm for more than 1 month, and more than 5% difference in relative humidity between the feed storage room and the barn holding lactating cows were associated with AFM1 contamination in milk. The BY test was useful for screening cattle feed for fungal contamination, and the results of this test in conjunction with other factors can be used to monitor and prevent AFM1 contamination in milk on small holder dairy farms. PMID- 24490924 TI - Development and model testing of antemortem screening methodology to predict required drug withholds in heifers. AB - A simple, cow-side test for the presence of drug residues in live animal fluids would provide useful information for tissue drug residue avoidance programs. This work describes adaptation and evaluation of rapid screening tests to detect drug residues in serum and urine. Medicated heifers had urine, serum, and tissue biopsy samples taken while on drug treatment. Samples were tested by rapid methods and high-performance liquid chromatography (HPLC). The adapted microbial inhibition method, kidney inhibition swab test, was useful in detecting sulfadimethoxine in serum, and its response correlated with the prescribed withdrawal time for the drug, 5 to 6 days posttreatment. The lateral flow screening method for flunixin and beta-lactams, adapted for urine, was useful in predicting flunixin in liver detected by HPLC, 96 h posttreatment. The same adapted methods were not useful to detect ceftiofur in serum or urine due to a lack of sensitivity at the levels of interest. These antemortem screening test studies demonstrated that the method selected, and the sampling matrix chosen (urine or serum), will depend on the drug used and should be based on animal treatment history if available. The live animal tests demonstrated the potential for verification that an individual animal is free of drug residues before sale for human consumption. PMID- 24490925 TI - Microbiological quality and safety assessment of the Rwandan milk and dairy chain. AB - Milk is a valuable and nutritious food product that can partially fulfill the rising food demand of the growing African population. The microbiological status of milk and derived products was assessed throughout the milk and dairy chain in Rwanda by enumeration of the total mesophilic count, coliforms, and Staphylococcus aureus and detection of Salmonella and Listeria monocytogenes. The quality of raw milk was satisfactory for the majority of samples, but 5.2% contained Salmonella. At the processing level, the total mesophilic count and coliform numbers indicated ineffective heat treatment during pasteurization or postpasteurization contamination. Increasing bacterial counts were observed along the retail chain and could be attributed to insufficient temperature control during storage. Milk and dairy products sold in milk shops were of poor and variable microbiological quality in comparison with the pasteurized milk sold in supermarkets. In particular, the microbiological load and pathogen prevalence in cheese were unacceptably high. PMID- 24490926 TI - Validation of receptor-binding assays to detect antibiotics in goat's milk. AB - The suitability of different receptor-binding assays to detect antibiotics in raw goat's milk was investigated. Detection capability of most beta-lactams and tetracyclines assessed applying the Betastar Combo, the SNAP Betalactam, the SNAP Tetracycline, and the Twinsensor tests was at or below maximum residue limits established by European legislation. Regarding test specificity, cross-reactions with antibiotics other than beta-lactams and tetracyclines were not found, and no false-positive results were obtained for the Betastar Combo and the SNAP tests when bulk samples of goat's milk were analyzed. For the Twinsensor test, the false-positive rate was 1%. The performance of the Betastar Combo and the SNAP tests was practically unaffected by the milk quality parameters using individual samples of goat's milk collected at points throughout the entire lactation period (false-positive rate, <=5%). However, a larger number of positive results were obtained by the Twinsensor test in this type of milk sample (>10%), especially in the last weeks of lactation. Interferences related to the use of the preservative azidiol were not observed in any case. Neither were any significant differences found in relation to the interpretation method (visual versus instrumental) applied. In general, the response of the Betastar Combo, SNAP, and Twinsensor tests was optimal for the analysis of bulk caprine milk; thus, they may be used to monitor milk for the presence of beta-lactam and tetracycline residues in quality control programs. PMID- 24490927 TI - Comparing real-time and conventional PCR to culture-based methods for detecting and quantifying Escherichia coli O157 in cattle feces. AB - Detection of Escherichia coli O157 in cattle feces has traditionally used culture based methods; PCR-based methods have been suggested as an alternative. We aimed to determine if multiplex real-time (mq) or conventional PCR methods could reliably detect cattle naturally shedding high (>=10(4) CFU/g of feces) and low (~10(2) CFU/g of feces) concentrations of E. coli O157. Feces were collected from pens of feedlot cattle and evaluated for E. coli O157 by culture methods. Samples were categorized as (i) high shedders, (ii) immunomagnetic separation (IMS) positive after enrichment, or (iii) culture negative. DNA was extracted pre- and postenrichment from 100 fecal samples from each category (high shedder, IMS positive, culture negative) and subjected to mqPCR and conventional PCR assays based on detecting three genes, rfbE, stx1, and stx2. In feces from cattle determined to be E. coli O157 high shedders by culture, 37% were positive by mqPCR prior to enrichment; 85% of samples were positive after enrichment. In IMS positive samples, 4% were positive by mqPCR prior to enrichment, while 43% were positive after enrichment. In culture-negative feces, 7% were positive by mqPCR prior to enrichment, and 40% were positive after enrichment. The proportion of high shedder-positive and culture-positive (high shedder and IMS) samples were significantly different from mqPCR-positive samples before and after enrichment (P < 0.01). Similar results were observed for conventional PCR. Our data suggest that mqPCR and conventional PCR are most useful in identifying high shedder animals and may not be an appropriate substitute to culture-based methods for detection of E. coli O157 in cattle feces. PMID- 24490928 TI - Potential Interactions between Salmonella enterica and Ralstonia solanacearum in tomato plants. AB - Over the past decade, the Eastern Shore of Virginia (ESV) has been implicated in at least four outbreaks of salmonellosis associated with tomato, all originating from the same serovar, Salmonella enterica serovar Newport. In addition to Salmonella Newport contamination, the devastating plant disease bacterial wilt, caused by the phytopathogen Ralstonia solanacearum, threatens the sustainability of ESV tomato production. Bacterial wilt is present in most ESV tomato fields and causes devastating yield losses each year. Although the connection between bacterial wilt and tomato-related salmonellosis outbreaks in ESV is of interest, the relationship between the two pathogens has never been investigated. In this study, tomato plants were root dip inoculated with one of four treatments: (i) 8 log CFU of Salmonella Newport per ml, (ii) 5 log CFU of R. solanacearum per ml, (iii) a coinoculation of 8 log CFU of Salmonella Newport per ml plus 5 log CFU of R. solanacearum per ml, and (iv) sterile water as control. Leaf, stem, and fruit samples were collected at the early-green-fruit stage, and S. enterica contamination in the internal tissues was detected. S. enterica was recovered in 1.4 and 2.9% of leaf samples from plants inoculated with Salmonella Newport only and from plants coinoculated with Salmonella Newport plus R. solanacearum, respectively. S. enterica was recovered from 1.7 and 3.5% of fruit samples from plants inoculated with Salmonella Newport only and from plants coinoculated with Salmonella Newport plus R. solanacearum, respectively. There were significantly more stem samples from plants coinoculated with Salmonella Newport plus R. solanacearum that were positive for S. enterica (18.6%) than stem samples collected from plants inoculated with Salmonella Newport only (5.7%). Results suggested that R. solanacearum could influence S. enterica survival and transportation throughout the internal tissues of tomato plants. PMID- 24490929 TI - Low-cost monitoring of Campylobacter in poultry houses by air sampling and quantitative PCR. AB - The present study describes the evaluation of a method for the quantification of Campylobacter by air sampling in poultry houses. Sampling was carried out in conventional chicken houses in Poland, in addition to a preliminary sampling in Denmark. Each measurement consisted of three air samples, two standard boot swab fecal samples, and one airborne particle count. Sampling was conducted over an 8 week period in three flocks, assessing the presence and levels of Campylobacter in boot swabs and air samples using quantitative real-time PCR. The detection limit for air sampling was approximately 100 Campylobacter cell equivalents (CCE)/m3. Airborne particle counts were used to analyze the size distribution of airborne particles (0.3 to 10 MUm) in the chicken houses in relation to the level of airborne Campylobacter. No correlation was found. Using air sampling, Campylobacter was detected in the flocks right away, while boot swab samples were positive after 2 weeks. All samples collected were positive for Campylobacter from week 2 through the rest of the rearing period for both sampling techniques, although levels 1- to 2-log CCE higher were found with air sampling. At week 8, the levels were approximately 10(4) and 10(5) CCE per sample for boot swabs and air, respectively. In conclusion, using air samples combined with quantitative real-time PCR, Campylobacter contamination could be detected earlier than by boot swabs and was found to be a more convenient technique for monitoring and/or to obtain enumeration data useful for quantitative risk assessment of Campylobacter. PMID- 24490930 TI - Prevalence, antimicrobial susceptibility, and enterotoxin gene detection of Staphylococcus aureus isolates in ready-to-eat foods in Shaanxi, People's Republic of China. AB - Various ready-to-eat (RTE) foods are becoming increasingly popular in the world and could be easily contaminated with various microorganisms including certain pathogens. A total of 342 RTE food samples, including 32 cooked meats, 123 vegetable salads, 26 boiled peanuts, 109 cold noodles, and 52 dried tofu samples, were collected in Shaanxi Province, People's Republic of China, during the period of July to October 2012 and screened for Staphylococcus aureus. All S. aureus isolates were characterized by antimicrobial susceptibility and PCR for detecting nine enterotoxin genes (sea to sej). Overall, 25.4% of samples were positive for S. aureus, including 10 (31.3%) cooked meats, 34 (27.6%) salad vegetables, 6 (23.1%) boiled peanuts, 20 (18.3%) cold noodles, and 17 (32.7%) dried tofu samples. Of the isolated S. aureus organisms, 98.4% were resistant to at least one antimicrobial agent and 58.6% to three or more antimicrobials. Resistance to erythromycin (78.1%) and tetracycline (40.6%) was most frequently detected, while all isolates were sensitive to vancomycin and amikacin. Moreover, 55.5% of isolates were positive for one or more enterotoxin genes. The genes sed (25.8%) and sea (19.5%) were commonly detected among the isolates; seg, sei, and sej were not found. Our findings indicate that RTE foods in Shaanxi were contaminated with S. aureus isolates that harbored multiple toxin genes and exhibited multiple-drug resistance. Appropriated hygienic measures should be taken by producers, retailers, and consumers to reduce the risk posed by S. aureus in RTE foods. PMID- 24490931 TI - Presence of Mycobacterium avium subspecies and hepatitis E virus in raw meat products. AB - Meat and meat products may be the source of various pathogenic and potentially pathogenic agents for humans. We ascertained the occurrence of Mycobacterium avium subsp. paratuberculosis, subsp. avium, and subsp. hominissuis, and hepatitis E virus in retail raw meat products. The DNA of at least one of the target M. avium subspecies was detected in 26 (29.2%) of 89 analyzed samples of meat products. Fourteen (15.7%), 1 (1.1%), and 17 (19.1%) samples contained the DNA of Mycobacterium avium subsp. paratuberculosis, subsp. avium, and subsp. hominissuis, respectively. The number of mycobacterial cells per gram of meat products determined by real-time quantitative PCR ranged from 1.15 * 10(2) to 6.97 * 10(3). Mycobacterium chitae and Mycobacterium nonchromogenicum were isolated from three (3.4%) samples. Culture examination was not positive for any M. avium subspecies. Hepatitis E virus RNA was not detected in any of the samples. PMID- 24490932 TI - Inactivation of Alicyclobacillus acidoterrestris spores in apple and orange juice concentrates by gamma irradiation. AB - The objective of this study was to evaluate the effect of different concentrations of reconstituted apple and orange juice on reduction of Alicyclobacillus acidoterrestris spores by gamma irradiation. Spores of A. acidoterrestris were inoculated into three concentrations of apple (18, 36, and 72 degrees Brix) and orange (11, 33, and 66 degrees Brix) juice and subjected to five radiation doses (1, 3, 5, 7, and 10 kGy). No significant reductions (P > 0.05) in spores were observed after the 1-kGy treatment for all apple and orange concentrations. Spores in 18, 36, and 72 degrees Brix apple juice concentrates subjected to 10 kGy were reduced to 4.34, 3.9, and 3.84 log CFU/ml, respectively. Similar results were observed for orange juice. When 10 kGy was applied to 11 degrees Brix orange juice, populations of spores were reduced by 5 log CFU/ml. The reduction of spores in 33 and 66 degrees Brix orange juice concentrates exposed to 10-kGy gamma irradiation was 4.54 and 3.85 log CFU/ml, respectively. Juice concentration did not affect (P > 0.05) the number of surviving A. acidoterrestris spores from the same kGy treatment. Gamma irradiation treatment did not change the pH or water activity of the juice (P > 0.05). PMID- 24490933 TI - Response to Sakamoto et al. PMID- 24490934 TI - pi-Complexation in nickel-catalyzed cross-coupling reactions. AB - The kinetic isotope effect (KIE) is used to experimentally elucidate the first irreversible step in oxidative addition reactions of a zerovalent nickel catalyst to a set of haloarene substrates. Halogenated o-methylbenzene, dimethoxybenzene, and thiophene derivatives undergo intramolecular oxidative addition through irreversible pi-complexation. Density functional theory computations at the B3LYP D3/TZ2P-LANL2TZ(f)-LANL08d level predict eta(2)-bound pi-complexes are generally stable relative to a solvated catalyst plus free substrate and that ring-walking of the Ni(0) catalyst and intramolecular oxidative addition are facile in these intermediates. PMID- 24490936 TI - Sex identification and PIT-tagging: tools and prospects for studying intersexual differences in freshwater fishes. AB - This study evaluated a technique to allow the long-term monitoring of individual fishes of known sex in the wild using sex confirmation in close proximity to the reproductive period combined with individual tagging. Hundreds of partially migratory roach Rutilus rutilus were tagged with passive integrated transponders (PIT) following sex determination in spring and various performance measures were compared with fish tagged outside the reproductive period in autumn. Short-term survival was >95% for R. rutilus sexed and tagged under natural field conditions. Total length (LT ) did not affect the probability of survival within the size range tagged (119-280 mm), nor were there differences in timing of migration the following season between individuals sexed and tagged in spring and individuals tagged in autumn (i.e. outside the reproductive period). Also, a similar per cent of R. rutilus sexed and tagged in spring and tagged in autumn migrated the following season (34.5 and 34.7%). Moreover, long-term recapture data revealed no significant differences in body condition between R. rutilus individuals sexed and tagged in spring, individuals tagged in autumn and unmanipulated individuals. The observed sex ratio of recaptured fish did not differ from the expected values of equal recapture rates between males and females. Hence, there is no observable evidence for an adverse effect of tagging close to the reproductive period and therefore this method is suitable for studying intersexual differences and other phenotypic traits temporarily expressed during reproduction at the individual level in fishes. PMID- 24490935 TI - Molecular cloning and expression of a C-type lectin-like protein from orange spotted grouper Epinephelus coioides. AB - A C-type lectin-like protein (Ec-CTLP) was cloned from the grouper Epinephelus coioides. The full-length cDNA of Ec-CTLP was composed of 905 bp with a 522 bp open reading frame that encodes a 174-residue protein. The putative amino acid sequence of Ec-CTLP contains a signal peptide of 19 residues at the N-terminus and a CLECT domain from Cys43 to Arg169 and a conserved imperfect WND (Trp-Asn Asp) motif. The homologous identity of deduced amino acid sequences is from 32 to 42% with other fishes. The expression of Ec-CTLP was differently upregulated in E. coioides spleen (germline stem) cells after being challenged at 16 and 4 degrees C. Intracellular localization revealed that Ec-CTLP was distributed only in the cytoplasm. Recombinant Ec-CTLP (rEc-CTLP) was expressed in Escherichia coli BL21 (DE3) and purified for mouse Mus musculus anti-Ec-CTLP serum preparation. The rEc-CTLP fusion protein does not possess haemagglutinating activity, but improves survival from frozen bacteria. The survival of bacteria (including gram-negative E. coli and gram-positive Staphylococcus aureus) was positively correlated with the concentration of the rEc-CTLP. These findings can provide clues to help understand the probable C-type lectin in marine fish innate immunity. PMID- 24490937 TI - Redescription of Chlorophthalmus corniger, a senior synonym of Chlorophthalmus bicornis (Family: Chlorophthalmidae). AB - Chlorophthalmus corniger is redescribed on the basis of recently collected specimens. The species is redefined as a species of Chlorophthalmus with the lower jaw terminating in a distinctly projecting horizontal plate with strong, spine-like processes directed forward from the plate's corners; body silvery grey, with numerous minute black spots and traces of broad darker crossbars; base of anterior dorsal fin spines and distal parts of dorsal fins black; adipose fin tiny with numerous black spots; caudal fin black; 3.5 scales above lateral line; three rows of cheek scales; head very large, 34.3-40.1% standard length (LS ); eye large, 29.8-40.8% head length (LH ); pectoral fin long, extending to beyond dorsal fin base, 21.7-26.2% LS . Chlorophthalmus bicornis is a junior synonym of C. corniger based on the examination of the type series of both species. It is confined to the northern half of the Indian Ocean, reliably recorded from Somalia and the Gulf of Aden to southern Java, Indonesia, at depths between 200 and 500 m. A lectotype and three paralectotypes were designated for C. corniger. DNA barcodes for Indian species of Chlorophthalmus were generated. PMID- 24490938 TI - Mitochondrial phylogeography of a Beringian relict: the endemic freshwater genus of blackfish Dallia (Esociformes). AB - Mitochondrial genetic variability among populations of the blackfish genus Dallia (Esociformes) across Beringia was examined. Levels of divergence and patterns of geographic distribution of mitochondrial DNA lineages were characterized using phylogenetic inference, median-joining haplotype networks, Bayesian skyline plots, mismatch analysis and spatial analysis of molecular variance (SAMOVA) to infer genealogical relationships and to assess patterns of phylogeography among extant mitochondrial lineages in populations of species of Dallia. The observed variation includes extensive standing mitochondrial genetic diversity and patterns of distinct spatial segregation corresponding to historical and contemporary barriers with minimal or no mixing of mitochondrial haplotypes between geographic areas. Mitochondrial diversity is highest in the common delta formed by the Yukon and Kuskokwim Rivers where they meet the Bering Sea. Other regions sampled in this study host comparatively low levels of mitochondrial diversity. The observed levels of mitochondrial diversity and the spatial distribution of that diversity are consistent with persistence of mitochondrial lineages in multiple refugia through the last glacial maximum. PMID- 24490940 TI - Experimental and computational study of BODIPY dye-labeled cavitand dynamics. AB - Understanding the distance distribution and dynamics between moieties attached to the walls of a resorcin[4]arene cavitand, which is switchable between an expanded kite and a contracted vase form, might enable the use of this molecular system for the study of fundamental distance-dependent interactions. Toward this goal, a combined experimental and molecular dynamics (MD) simulation study on donor/acceptor borondipyrromethene (BODIPY) dye-labeled cavitands present in the vase and kite forms was performed. Direct comparison between anisotropy decays calculated from MD simulations with experimental fluorescence anisotropy data showed excellent agreement, indicating that the simulations provide an accurate representation of the dynamics of the system. Distance distributions between the BODIPY dyes were established by comparing time-resolved Forster resonance energy transfer experiments and MD simulations. Fluorescence intensity decay curves emulated on the basis of the MD trajectories showed good agreement with the experimental data, suggesting that the simulations present an accurate picture of the distance distributions and dynamics in this molecular system and provide an important tool for understanding the behavior of extended molecular systems and designing future applications. PMID- 24490944 TI - A new view through Alberti's window. AB - In his famous treatise on perspective, Alberti compared picture perception with looking through a window. Although Alberti himself was more concerned with picture production than perception, the window metaphor is still widely used to describe picture perception. By performing depth perception experiments, we investigated whether Alberti's hypothesis makes sense in a geometrical fashion. If pictures are regarded as windows, the locus of objects with equal depth should be similar for pictorial and real space-ideally, spherical. Furthermore, if the loci of equidistance are indeed similar for real and pictorial space, their difference should be flat. We designed two experiments to investigate this claim. In the first experiment, a pairwise depth comparison task was used to compute the global perceived depth structure of a complex scene. We found that perception of the real space is more accurate and less ambiguous than pictorial space. More interestingly, we found that the relative differences between these two spaces (locus of relative equidistance) are curved, which contradicts the window hypothesis. In the second experiment, we wanted to measure the absolute locus of equidistance that we believed was diagnostic for the difference between real and pictorial space perception. We found that under normal circumstances, the distribution of equally perceived depths is curved in real space, and relatively flat in pictorial space. However, we also found exceptions. For example, viewing real space with one eye yielded similar results as normal pictorial space perception. We conclude that Alberti's hypothesis needs a revision. PMID- 24490943 TI - Pharmacokinetic evaluation of topical calcineurin inhibitors for treatment of allergic conjunctivitis. AB - INTRODUCTION: Topical calcineurin (Cn) inhibitors delivered via ophthalmic drop is emerging as a potential treatment for severe, immune-mediated forms of allergic conjunctivitis, such as vernal keratoconjunctivitis, atopic keratoconjunctivitis and giant papillary conjunctivitis. AREAS COVERED: This article is based on a comprehensive literature search, with information taken from meta-analyses, systematic reviews, treatment guidelines and clinical studies in children and adults. The articles that have been selected evaluate the use of topical Cn inhibitors and their role in the treatment of allergic conjunctivitis. EXPERT OPINION: Ophthalmic topical Cn inhibitors have been shown to be safe for short-term use, with minimal systemic absorption and toxicity. For patients with severe, refractory forms of allergic conjunctivitis, topical Cn inhibitors offer a promising treatment option and an alternative to steroidal therapies. The safety profile and efficacy data for topical cyclosporine are more robust compared to that of tacrolimus and pimecrolimus, although larger trials will be needed for all three agents. With more randomized controlled trials involving larger sample sizes and long-term follow-up to establish both efficacy and safety, ophthalmic Cn inhibitors offer exciting treatment possibilities for the prevention of morbidity associated with refractory allergic conjunctivitis. PMID- 24490942 TI - A manual-based individual therapy to improve metacognition in schizophrenia: protocol of a multi-center RCT. AB - BACKGROUND: Metacognitive dysfunction has been widely recognized as a feature of schizophrenia. As it is linked with deficits in several aspects of daily life functioning, improvement of metacognition may lead to improvement in functioning. Individual psychotherapy might be a useful form of treatment to improve metacognition in patients with schizophrenia; multiple case reports and a pilot study show promising results. The present study aims to measure the effectiveness of an individual, manual-based therapy (Metacognitive Reflection and Insight Therapy, MERIT) in improving metacognition in patients with schizophrenia. We also want to examine if improvement in metacognitive abilities is correlated with improvements in aspects of daily life functioning namely social functioning, experience of symptoms, quality of life, depression, work readiness, insight and experience of stigma. METHODS/DESIGN: MERIT is currently evaluated in a multicenter randomized controlled trial. Thirteen therapists in six mental health institutions in the Netherlands participate in this study. Patients are randomly assigned to either MERIT or the control condition: treatment as usual (TAU). DISCUSSION: If proven effective, MERIT can be a useful addition to the care for schizophrenia patients. The design brings along some methodological difficulties, these issues are addressed in the discussion of this paper. TRIAL REGISTRATION: Current Controlled Trials: ISRCTN16659871. PMID- 24490945 TI - Target selection bias transfers across different response actions. AB - Target selection is biased by recent experience. For example, a selected target feature may be stored in memory and bias selection on future trials, such that objects matching that feature are "primed" for selection. In the present study, we examined the role of action history in selection biases. Participants searched for a uniquely colored object. Pretrial cues indicated whether participants should respond with a keypress or a reach movement. If the representation of the feature that biases selection is critically bound with its associated action, we would expect priming effects to be restricted to cases where both the response mode and target color are repeated. However, we found that responses to the target were faster when the target color was repeated, even when the response switched from a reach to a keypress, or vice versa. Priming effects were even observed after "no-go" trials in which a response was withheld, and priming effects transferred across response modes when eye movement recordings ensured that participants did not saccade to the target. These results demonstrate that target features are represented in memory separately from their associated actions and can bias selection on subsequent trials even when a different mode of action output is required. PMID- 24490946 TI - Broadly tuned face representation in older adults assessed by categorical perception. AB - Studies of face recognition in older adults (60 years of age and older) report increases in false alarms over younger adults (usually 18-30 years of age), but no age differences in hits. To examine this phenomenon, we compared older and younger adults in categorical perception of faces. We hypothesized that face representations in older adults would be broadly tuned, resulting in overlapping representations, manifested by a shallower slope in identity categorization than in younger adults, and age-related reductions in the advantage for between categories, as compared with within-category, face discrimination. We morphed faces to change linearly from one identity to another. We used familiar or unfamiliar faces in separate conditions to examine the role of familiarity. Categorical perception was assessed in an identity-classification task and a discrimination task. Older adults showed a shallower slope and poorer discrimination compared with younger adults, and both groups exhibited better performance with familiar than unfamiliar faces. Enhanced discriminability for between-categories as compared with within-category faces was seen for both familiar and unfamiliar faces in younger adults, but only for familiar faces in older adults. The more broadly tuned representations of unfamiliar faces in older adults may lead to misidentification and greater false alarms for unfamiliar faces, but not for familiar faces. PMID- 24490947 TI - A magnocellular contribution to conscious perception via temporal object segmentation. AB - The human visual system is continuously confronted with dynamic visual input. One challenge that the visual system must solve, therefore, is recognizing when two distinct objects have appeared at a given location despite their brief presentation and rapid succession, that is, temporal object segmentation. Here we examined the role of magnocellular neurons in this process. We measured temporal object segmentation via object substitution masking (OSM), which reflects the failure to distinguish the target and mask as distinct objects through time. We isolated the selective role of magnocellular neurons by comparing performance under conditions of pulsed luminance pedestals, which are designed to saturate the magnocellular response, with that in a steady-pedestal condition that leaves both magnocellular and parvocellular channels available to process the target. Across two experiments, we found that OSM magnitude was enhanced under pulsed pedestal conditions, in which the magnocellular response was impaired. This indicates that magnocellular neurons contribute to temporal object segmentation. Given that temporal object segmentation has consequences for which stimuli are consciously perceived, this demonstrates a functional mechanism via which magnocellular neurons contribute to determining the contents conscious perception. Implications for models of specialization of dorsal and ventral cortical streams are discussed. PMID- 24490949 TI - The effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus. AB - OBJECTIVE: To assess the effect of ginger consumption on glycemic status, lipid profile and some inflammatory markers in patients with type 2 diabetes mellitus. METHODS: In a double-blinded, placebo-controlled clinical trial, 70 type 2 diabetic patients were enrolled. They allocated randomly into ginger group and control group. They consumed 1600 mg ginger versus 1600 mg wheat flour placebo daily for 12 weeks. Serum sugar, lipids, CRP, PGE2 and TNFalpha were measured before and after intervention. RESULTS: Ginger reduced fasting plasma glucose, HbA1C, insulin, HOMA, triglyceride, total cholesterol, CRP and PGE2 significantly compared with placebo group (p < 0.05). There were no significant differences in HDL, LDL and TNFalpha between two groups (p > 0.05). CONCLUSION: Ginger improved insulin sensitivity and some fractions of lipid profile, and reduced CRP and PGE2 in type 2 diabetic patients. Therefore ginger can be considered as an effective treatment for prevention of diabetes complications. PMID- 24490950 TI - PCBs are associated with altered gene transcript profiles in arctic Beluga Whales (Delphinapterus leucas). AB - High trophic level arctic beluga whales (Delphinapterus leucas) are exposed to persistent organic pollutants (POP) originating primarily from southern latitudes. We collected samples from 43 male beluga harvested by Inuvialuit hunters (2008-2010) in the Beaufort Sea to evaluate the effects of POPs on the levels of 13 health-related gene transcripts using quantitative real-time polymerase chain reaction. Consistent with their role in detoxification, the aryl hydrocarbon receptor (Ahr) (r(2) = 0.18, p = 0.045 for 2008 and 2009) and cytochrome P450 1A1 (Cyp1a1) (r(2) = 0.20, p < 0.001 for 2008 and 2009; r(2) = 0.43, p = 0.049 for 2010) transcripts were positively correlated with polychlorinated biphenyls (PCBs), the dominant POP in beluga. Principal Components Analysis distinguished between these two toxicology genes and 11 other genes primarily involved in growth, metabolism, and development. Factor 1 explained 56% of gene profiles, with these latter 11 gene transcripts displaying greater abundance in years coinciding with periods of low sea ice extent (2008 and 2010). delta(13)C results suggested a shift in feeding ecology and/or change in condition of these ice edge-associated beluga whales during these two years. While this provides insight into the legacy of PCBs in a remote environment, the possible impacts of a changing ice climate on the health of beluga underscores the need for long-term studies. PMID- 24490951 TI - Fragment-based lead discovery and design. AB - Fragment-based lead discovery and design has and continues to show increasing promise in drug discovery. In this article, the current state of the art in terms of hot-spot characterization, fragment screening techniques, and fragment-based design is discussed. Three overall fragment-based lead generation strategies are explored and involve the chemical biology characterization of biological targets via fragment screening, fragment screening as a complementary approach to high throughput screening of drug-like compounds, and direct fragment-based drug discovery, respectively. The evolution and development of fragment libraries is described. With an emphasis on computational approaches and the strategies applied at AstraZeneca, the review illustrates how integration of data from one regime can inform the design of experiments in the other, ultimately leading to the discovery of high quality chemical matter. PMID- 24490952 TI - Is drop-out from obesity treatment a predictable and preventable event? AB - BACKGROUND: Attrition is an important but understudied issue that plays a vital role in the successful treatment of obesity. To date, most studies focusing on attrition rates and/or its predictors have been based on pretreatment data routinely collected for other purposes. Our study specifically aims at identifying the predictors of drop-out focusing on empirically or theoretically based factors. METHODS: We conducted a retrospective observational study in an academic outpatient clinical nutrition service in Pavia, Italy. We examined a total of 98 adult obese patients (36 males, 62 females) who underwent a 6-month dietary behavioral weight-loss treatment at our Center. Pre-treatment and treatment-related variables were collected or calculated from clinical charts in order to discriminate those subjects who completed treatment from those who abandoned it before its completion. Multivariable regression analysis was used to identify the independent predictors of drop-out. RESULTS: The drop-out rates were 21% at 1 month and 57% at 6 months. Compared with completers, noncompleters were significantly younger in terms of age at first dieting attempt (24.0 +/- 10.7 vs. 31.3 +/- 11.2 years, P = 0.005), had lower diastolic blood pressure (87.8 +/- 9.7 vs. 92.7 +/- 11.4 mmHg, P = 0.022), had a lower baseline body fat percentage (38.5 +/- 6.4 vs. 41.2 +/- 4.4% weight, P = 0.015), and had a lower percentage of early weight loss (-1.8 +/- 1.8% vs. -3.1 +/- 2.1%, P = 0.035). Moreover, noncompleters significantly differed from completers with regard to type of referral (34.1% vs. 53.3% sent by a physician, P = 0.036) and SCL-90 anger hostility subscale (0.83 +/- 0.72 vs. 0.53 +/- 0.51, P = 0.022). A multivariable logistic regression analysis including pre-treatment variables showed that body fat percentage (P = 0.030) and SCL-90 anger-hostility subscale (P = 0.021) were independently associated with attrition. In a multivariable model considering both pre-treatment and treatment-related factors, attrition was found to be independently related to the age at first dieting attempt (P = 0.016) and the achievement of early weight loss (P = 0.029). CONCLUSIONS: Our data confirm that psychopathological tracts, early dieting attempts, and a poor initial treatment response are key independent predictors of drop-out from obesity treatment. PMID- 24490953 TI - A different world? The transition experiences of newly qualified children's nurses taking up first destination posts within children's community nursing teams in England. AB - The concept of transition is of fundamental concern to those seeking to prepare, recruit, and retain newly qualified staff. The pioneering work of researchers such as Kramer (1974) who explored the transition experiences of nurses has transcended international boundaries (Whitehead & Holmes, 2011) to influence the educational preparation of nurses worldwide. However, much of what we know about the transition experiences of newly qualified nurses is based on research with adult nurses and in the acute care settings. This article outlines the findings from a qualitative study about the experiences of a group of newly qualified children's nurses in England who had taken up first destination posts in community children's nursing teams at a time when such posts were novel, and had previously been met with some resistance. Data were collected using semi structured interviews and fieldwork observation, and analyzed using a combination of thematic analysis (Braun & Clarke, 2006) and the framework approach (Ritchie & Lewis 2003; Smith & Firth 2011). The findings are outlined under the broad headings of "Shadowing," "The Visits," and "Emerging Identity" and support previous research that highlights how good formal support and the physical presence of a preceptor is valued by newly qualified nurses since it reduces occupational stress. However, the study also highlights the downside of such support which occurred because some accepted practices inadvertently reduced confidence and therefore inhibited a smooth transition. The ideal transition experience therefore necessitated a more individual approach, allowing for different rates of progression. The primary care environment allowed for such individuality which may account for the significant finding that the nurses in this study did not report feelings of reality shock (Kramer, 1974) as experienced by those in acute care settings. The study therefore highlights how the development of a new professional identity as a community children's nurse is not just dependent on the actions of the newly qualified nurse, but also of those with whom they work. PMID- 24490954 TI - Antibody epitopes on g protein-coupled receptors mapped with genetically encoded photoactivatable cross-linkers. AB - We developed a strategy for creating epitope maps of monoclonal antibodies (mAbs) that bind to G protein-coupled receptors (GPCRs) containing photo-cross-linkers. Using human CXC chemokine receptor 4 (CXCR4) as a model system, we genetically incorporated the photolabile unnatural amino acid p-azido-l-phenylalanine (azF) at various positions within extracellular loop 2 (EC2). We then mapped the interactions of the azF-CXCR4 variants with mAb 12G5 using targeted loss-of function studies and photo-cross-linking in whole cells in a microplate-based format. We used a novel variation of a whole cell enzyme-linked immunosorbent assay to quantitate cross-linking efficiency. 12G5 cross-linked primarily to residues 184, 178, and 189 in EC2 of CXCR4. Mapping of the data to the crystal structure of CXCR4 showed a distinct mAb epitope footprint with the photo-cross linked residues clustered around the loss-of-function sites. We also used the targeted photo-cross-linking approach to study the interaction of human CC chemokine receptor 5 (CCR5) with PRO 140, a humanized mAb that inhibits human immunodeficiency virus-1 cellular entry, and 2D7. The mAbs produced distinct cross-linking patterns on EC2 of CCR5. PRO 140 cross-linked primarily to residues 174 and 175 at the amino-terminal end of EC2, and 2D7 cross-linked mainly to residues 170, 176, and 184. These results were mapped to the recent crystal structure of CCR5 in complex with maraviroc, showing cross-linked residues at the tip of the maraviroc binding crevice formed by EC2. As a strategy for mapping mAb epitopes on GPCRs, our targeted photo-cross-linking method is complementary to loss-of-function mutagenesis results and should be especially useful for studying mAbs with discontinuous epitopes. PMID- 24490956 TI - Function and clinical relevance of kallikrein-related peptidases and other serine proteases in gynecological cancers. AB - Gynecological cancers, including malignant tumors of the ovaries, the endometrium and the cervix, account for approximately 10% of tumor-associated deaths in women of the Western world. For screening, diagnosis, prognosis, and therapy response prediction, the group of enzymes known as serine (Ser-)proteases show great promise as biomarkers. In the present review, following a summary of the clinical facts regarding malignant tumors of the ovaries, the endometrium and the cervix, and characterization of the most important Ser-proteases, we thoroughly review the current state of knowledge relating to the use of proteases as biomarkers of the most frequent gynecological cancers. Within the Ser-protease group, the kallikrein-related peptidase (KLK) family, which encompasses a subgroup of 15 members, holds particular promise, with some acting via a tumor-promoting mechanism and others behaving as protective factors. Further, the urokinase-type plasminogen activator (uPA) and its inhibitor PAI-1 (plasminogen activator inhibitor-1) seem to play an unfavorable role in gynecological tumors, while down regulation of high-temperature requirement proteins A 1, 2 and 3 (HtrA1,2,3) is associated with malignant disease and cancer progression. Expression/activity levels of other Ser-proteases, including the type II transmembrane Ser-proteases (TTSPs) matriptase, hepsin (TMPRSS1), and the hepsin-related protease (TMPRSS3), as well as the glycosyl-phosphatidylinositol (GPI)-anchored Ser-proteases prostasin and testisin, may be of clinical relevance in gynecological cancers. In conclusion, proteases are a rich source of biomarkers of gynecological cancer, though the enzymes' exact roles and functions merit further investigation. PMID- 24490955 TI - Upregulation of cystathionine-beta-synthetase expression contributes to inflammatory pain in rat temporomandibular joint. AB - BACKGROUND: Hydrogen sulfide (H2S), an endogenous gaseotransmitter/modulator, is becoming appreciated that it may be involved in a wide variety of processes including inflammation and nociception. However, the role for H2S in nociceptive processing in trigeminal ganglion (TG) neuron remains unknown. The aim of this study was designed to investigate whether endogenous H2S synthesizing enzyme cystathionine-beta-synthetase (CBS) plays a role in inflammatory pain in temporomandibular joint (TMJ). METHODS: TMJ inflammatory pain was induced by injection of complete Freund's adjuvant (CFA) into TMJ of adult male rats. Von Frey filaments were used to examine pain behavioral responses in rats following injection of CFA or normal saline (NS). Whole cell patch clamp recordings were employed on acutely isolated TG neurons from rats 2 days after CFA injection. Western blot analysis was carried out to measure protein expression in TGs. RESULTS: Injection of CFA into TMJ produced a time dependent hyperalgesia as evidenced by reduced escape threshold in rats responding to VFF stimulation. The reduced escape threshold was partially reversed by injection of O-(Carboxymethyl) hydroxylamine hemihydrochloride (AOAA), an inhibitor for CBS, in a dose-dependent manner. CFA injection led to a marked upregulation of CBS expression when compared with age-matched controls. CFA injection enhanced neuronal excitability as evidenced by depolarization of resting membrane potentials, reduction in rheobase, and an increase in number of action potentials evoked by 2 and 3 times rheobase current stimulation and by a ramp current stimulation of TG neurons innervating the TMJ area. CFA injection also led to a reduction of IK but not IA current density of TG neurons. Application of AOAA in TMJ area reduced the production of H2S in TGs and reversed the enhanced neural hyperexcitability and increased the IK currents of TG neurons. CONCLUSION: These data together with our previous report indicate that endogenous H2S generating enzyme CBS plays an important role in TMJ inflammation, which is likely mediated by inhibition of IK currents, thus identifying a specific molecular mechanism underlying pain and sensitization in TMJ inflammation. PMID- 24490957 TI - Guidelines for the practice and performance of manipulation under anesthesia. AB - BACKGROUND: There are currently no widely accepted guidelines on standards for the practice of chiropractic or manual therapy manipulation under anesthesia, and the evidence base for this practice is composed primarily of lower-level evidence. The purpose of this project was to develop evidence-informed and consensus-based guidelines on spinal manipulation under anesthesia to address the gaps in the literature with respect to patient selection and treatment protocols. METHODS: An expert consensus process was conducted from August-October 2013 using the Delphi method. Panelists were first provided with background literature, consisting of three review articles on manipulation under anesthesia. The Delphi rounds were conducted using the widely-used and well-established RAND-UCLA consensus process methodology to rate seed statements for their appropriateness. Consensus was determined to be reached if 80% of the 15 panelists rated a statement as appropriate. Consensus was reached on all 43 statements in two Delphi rounds. RESULTS: The Delphi process was conducted from August-October 2013. Consensus was reached on recommendations related to all aspects of manipulation under anesthesia, including patient selection; diagnosis and establishing medical necessity; treatment and follow-up procedures; evaluation of response to treatment; safety practices; appropriate compensation considerations; and facilities, anesthesia and nursing standards. CONCLUSIONS: A high level of agreement was achieved in developing evidence-informed recommendations about the practice of chiropractic/manual therapy manipulation under anesthesia. PMID- 24490958 TI - Research-based insights into increasing the global supply and affordability of donor milk. PMID- 24490959 TI - Inflammatory bowel disease and demyelination: more than just a coincidence? AB - Infliximab and other anti-TNF-alpha agents have been implicated for drug-induced demyelination in patients with inflammatory bowel diseases (IBDs). We evaluated existing data from MEDLINE and EMBASE and conducted a narrative review to investigate further the aforementioned association. Our literature search highlighted 34 case reports, 3 case-control studies, 1 prospective and 7 retrospective cohort studies published in English. Available data suggest that IBD patients can manifest demyelinating events in both central and peripheral nervous system, however, they are still insufficient to conclude whether anti-TNF alpha therapies are an independent risk factor for demyelination. Prospective cohort studies with internal control groups are needed to estimate the true incidence of demyelinating disorders in patients with IBD and to elucidate if anti-TNF-alpha therapy increases further the risk of demyelination. PMID- 24490960 TI - Malondialdehyde mediates oxidized LDL-induced coronary toxicity through the Akt FGF2 pathway via DNA methylation. AB - BACKGROUND: Oxidized LDL (oxLDL) is involved in the development of atherosclerotic heart disease through a mechanism that is not fully understood. In this study, we examined the role of malondialdehyde (MDA), an important oxidative stress epitope of oxLDL, in mediating coronary endothelial cytotoxicity. RESULTS: Human coronary artery endothelial cells (HCAECs) were treated with oxLDL in the presence or absence of antibody against MDA (anti-MDA) or apoB100 (anti-apoB100). In HCAECs treated with oxLDL (100 MUg/ml) alone, DNA synthesis, cell viability, and expression of prosurvival fibroblast growth factor 2 (FGF2) were significantly reduced (P < 0.01 vs phosphate buffered saline treated cells). These inhibitory effects of oxLDL were significantly attenuated in HCAECs cotreated with anti-MDA (0.15 MUg/ml; P < 0.05 vs oxLDL-treated cells), but not in those cotreated with anti-apoB100. When we tested the effects of a panel of signal transduction modifiers on the signal transduction pathways of MDA in oxLDL-treated HCAECs, we found that MDA-induced cytotoxicity was mediated partly through the Akt pathway. Using a reporter gene assay, we identified an oxLDL-response element in the FGF2 promoter that was responsible for the transcriptional repression of FGF2 by oxLDL. The results of bisulfite genomic DNA sequencing showed that in HCAECs treated with oxLDL, the GC-rich promoter of FGF2 was heavily methylated at cytosine residues, whereas cotreatment with anti-MDA markedly reduced oxLDL-induced FGF2 promoter methylation. CONCLUSION: OxLDL disrupts the growth and survival of HCAECs through an MDA-dependent pathway involving methylation of the FGF2 promoter and repression of FGF2 transcription. This novel epigenetic mechanism of oxLDL may underlie its atherogenicity in patients with atherosclerotic cardiovascular disease. PMID- 24490961 TI - WExplore: hierarchical exploration of high-dimensional spaces using the weighted ensemble algorithm. AB - As most relevant motions in biomolecular systems are inaccessible to conventional molecular dynamics simulations, algorithms that enhance sampling of rare events are indispensable. Increasing interest in intrinsically disordered systems and the desire to target ensembles of protein conformations (rather than single structures) in drug development motivate the need for enhanced sampling algorithms that are not limited to "two-basin" problems, and can efficiently determine structural ensembles. For systems that are not well-studied, this must often be done with little or no information about the dynamics of interest. Here we present a novel strategy to determine structural ensembles that uses dynamically defined sampling regions that are organized in a hierarchical framework. It is based on the weighted ensemble algorithm, where an ensemble of copies of the system ("replicas") is directed to new regions of configuration space through merging and cloning operations. The sampling hierarchy allows for a large number of regions to be defined, while using only a small number of replicas that can be balanced over multiple length scales. We demonstrate this algorithm on two model systems that are analytically solvable and examine the 10 residue peptide chignolin in explicit solvent. The latter system is analyzed using a configuration space network, and novel hydrogen bonds are found that facilitate folding. PMID- 24490962 TI - Minimizing fouling at hydrogenated conical-tip carbon electrodes during dopamine detection in vivo. AB - In this paper, physically small conical-tip carbon electrodes (~2-5 MUm diameter and ~4 MUm axial length) were hydrogenated to develop a probe capable of withstanding fouling during dopamine detection in vivo. Upon hydrogenation, the resultant hydrophobic sp(3) carbon surface deters adsorption of amphiphilic lipids, proteins, and peptides present in extracellular fluid and hence minimizes electrode fouling. These hydrogenated carbon electrodes showed a 35% decrease in sensitivity but little change in the limit of detection for dopamine over a 7-day incubation in a synthetic laboratory solution containing 1.0% (v/v) caproic acid (a lipid), 0.1% (w/v) bovine serum albumin and 0.01% (w/v) cytochrome C (both are proteins), and 0.002% (w/v) human fibrinopeptide B (a peptide). Subsequently, during dopamine detection in vivo, over 70% of the dopamine oxidation current remained after the first 30 min of a 60-min experiment, and at least 50% remained over the next half-period at the hydrogenated carbon electrodes. On the basis of these results, an initial average electrode surface fouling rate of 1.2% min(-1) was estimated, which gradually declined to 0.7% min(-1). These results support minimal fouling at hydrogenated carbon electrodes applied to dopamine detection in vivo. PMID- 24490963 TI - Do high-commitment work systems affect creativity? A multilevel combinational approach to employee creativity. AB - In this article, some information about the data used in the article and a citation were not included. The details of the corrections are provided.] This study uses 3-level, 2-wave time-lagged data from a random sample of 55 high technology firms, 238 teams, and 1,059 individuals in China to investigate a multilevel combinational model of employee creativity. First, we hypothesize that firm (macrolevel) high-commitment work systems are conducive to individual (microlevel) creativity. Furthermore, we hypothesize that this positive crosslevel main impact may be combined with middle-level (mesolevel) factors, including team cohesion and team task complexity, such that the positive impact of firm high-commitment work systems on individual creativity is stronger when team cohesion is high and the team task more complex. The findings from random coefficient modeling analyses provide support for our hypotheses. These sets of results offer novel insight into how firms can use macrolevel and mesolevel contextual variables in a systematic manner to promote employee creativity in the workplace, despite its complex nature. PMID- 24490964 TI - Victimization of high performers: the roles of envy and work group identification. AB - Drawing from victim precipitation, social comparison, and identity theories, this study develops and tests an integrative model of the victimization of high performing employees. We examine envy as an explanatory mechanism of the victimization of high performers from fellow group members and propose work group identification as a moderator of this envy mechanism. Study 1, in a sample of 4,874 university staff employees in 339 work groups, supports the proposition that high performers are more likely to be targets of victimization. In Study 2, multisource data collected at 2 time points (217 employees in 67 work groups in 3 organizations), supports the proposition that high performers are more likely to be targets of victimization because of fellow group members' envy, and work group identification mitigates the mediated relationship. PMID- 24490965 TI - Comparative evaluation of three situational judgment test response formats in terms of construct-related validity, subgroup differences, and susceptibility to response distortion. AB - As a testing method, the efficacy of situational judgment tests (SJTs) is a function of a number of design features. One such design feature is the response format. However, despite the considerable interest in SJT design features, there is little guidance in the extant literature as to which response format is superior or the conditions under which one might be preferable to others. Using an integrity-based SJT measure administered to 31,194 job applicants, we present a comparative evaluation of 3 response formats (rate, rank, and most/least) in terms of construct-related validity, subgroup differences, and score reliability. The results indicate that the rate-SJT displayed stronger correlations with the hypothesized personality traits; weaker correlations with general mental ability and, consequently, lower levels of subgroup differences; and higher levels of internal consistency reliability. A follow-up study with 492 college students (Study 2; details of which are presented in the online supplemental materials) also indicates that the rate response format displayed higher levels of internal consistency and retest reliability as well as favorable reactions from test takers. However, it displayed the strongest relationships with a measure of response distortion, suggesting that it is more susceptible to this threat. Although there were a few exceptions, the rank and most/least response formats were generally quite similar in terms of several of the study outcomes. The results suggest that in the context of SJTs designed to measure noncognitive constructs, the rate response format appears to be the superior, preferred response format, with its main drawback being that it is susceptible to response distortion, although not any more so than the rank response format. PMID- 24490966 TI - [Are we all on the same temporal page? The moderating effects of temporal team cognition on the polychronicity diversity-team performance relationship]. AB - Integrating research on polychronicity, team diversity, and team cognition, we hypothesized that shared temporal cognition (overlapping knowledge) and temporal transactive memory systems (differentiated knowledge) would moderate the effects of polychronicity diversity on team performance. Results from 71 teams in an Indian organization revealed opposing moderating effects in that shared temporal cognition attenuated, but temporal transactive memory systems amplified, the negative effects of polychronicity diversity on team performance. Shared temporal cognition also exerted a strong, positive effect on team performance. Study results provide support for the continued examination of polychronicity diversity and temporal team cognition. PMID- 24490967 TI - Fired up or burned out? How developmental challenge differentially impacts leader behavior. AB - Leadership development research has largely drawn on experiential and enactive learning theories to explore the positive effects of developmental challenge on leaders. In contrast, we examined potential positive and negative effects of developmental challenge (i.e., challenging job assignments) on leader behavior through an alternative theoretical lens--transactional stress theory. We predicted, on one hand, that developmental challenge may be associated with higher leader engagement and transformational leadership behavior; however, developmental challenge also has the potential to be associated with higher leader emotional exhaustion and laissez-faire leadership behavior. We further proposed that leadership self-efficacy (LSE) moderates these potential effects of developmental challenge and helps explain why leaders react either positively or negatively to developmental challenge. We tested our hypotheses in a sample of 153 leaders and 631 direct reports at a Fortune 500 company. Findings supported positive relationships among developmental challenge, leader engagement, and transformational leadership. However, we also found support for significant relationships among developmental challenge, emotional exhaustion, and laissez faire leadership. Additionally, leaders lower in LSE were more likely to encounter the negative effects of developmental challenge by experiencing increased emotional exhaustion and displaying laissez-faire leadership behaviors. Our study contributes to theory and practice by elucidating a "dark side" of developmental challenge, identifying LSE as a moderator of the negative effects of developmental challenge, identifying antecedents of transformational and laissez-faire leadership behaviors, and investigating demands and stress in leadership roles. PMID- 24490968 TI - Don't fear the reaper: trait death anxiety, mortality salience, and occupational health. AB - Despite multiple calls for research, there has been little effort to incorporate topics regarding mortality salience and death anxiety into workplace literature. As such, the goals of the current study were to (a) examine how trait differences in death anxiety relate to employee occupational health outcomes and (b) examine how death anxiety might exacerbate the negative effects of mortality salience cues experienced at work. In Study 1, we examined how death anxiety affected nurses in a multitime point survey. These results showed that trait death anxiety was associated with increased burnout and reduced engagement and that death anxiety further exacerbated the relationship between mortality salience cues (e.g., dealing with injured and dying patients) and burnout. These results were replicated and extended in Study 2, which examined the impact of death anxiety in firefighters. In this multitime point study, death anxiety related to burnout, engagement, and absenteeism. The results further showed that death anxiety moderated the relationship between mortality cues and burnout, where people high in trait death anxiety experience higher levels of burnout as a result of mortality cues than people lower in death anxiety. Across the 2 studies, despite differences in the methods (e.g., time lag; measures), the effect sizes and the form of the significant interactions were quite similar. Overall, these results highlight the importance of understanding death anxiety in the workplace, particularly in occupations where mortality salience cues are common. We discuss recommendations, such as death education and vocational counseling, and provide some avenues for future research. PMID- 24490969 TI - Supervisor support: does supervisor support buffer or exacerbate the adverse effects of supervisor undermining? AB - Empirical investigations concerning the interplay between supervisor support and supervisor undermining behaviors and their effects on employees yielded contradictory findings, with some studies suggesting that support buffers the adverse effects of undermining, and others suggesting that support exacerbates these adverse effects. Seeking to explain such contradictory findings, we integrate uncertainty-management perspectives with coping theory to posit that relational uncertainty is inherent in the mixture of supervisor support and undermining. Hence, whether supervisor support buffers or exacerbates the adverse effects of supervisor undermining on employee health and well-being depends on factors pertaining to employee ability to resolve and manage such relational uncertainty. Specifically, we hypothesize a buffering effect for employees with high self-esteem and high quality of work life, and an exacerbating effect for employees with low self-esteem and low quality of work life. Analyses of 2-wave data collected from a probability stratified sample of U.S. Air Force personnel supported our predictions. Two supplementary studies of the U.S. military replicated our core findings and demonstrated its practical significance. PMID- 24490970 TI - Translational pain biomarkers in the early development of new neurotherapeutics for pain management. AB - Translation of the analgesic efficacy of investigational neurotherapeutics from pre-clinical pain models into clinical trial phases is associated with a high risk of failure. Application of human pain biomarkers in early stages of clinical trials can potentially enhance the rate of successful translation, which would eventually reduce both length and costs of drug development after the pre clinical stage. Human pain biomarkers are based on the standardized activation of pain pathways followed by the assessment of ongoing and paroxysmal pain, plus evoked responses which can be applied to healthy individuals and patients prior to and after pharmacological interventions. This review discusses the rationality and feasibility of advanced human pain biomarkers in early phases of drug development for pain management which is still an unmet medical need. PMID- 24490972 TI - Electron-beam nanopatterning and spectral modulation of organic molecular light emitting single crystals. AB - The nanopatterning of light-emitting molecular crystals with semiconducting properties can be crucial for the development of future optoelectronic and nanoelectronic devices based on organic materials. In this respect, electron-beam writing is a powerful tool to realize patterns at the nanoscale, but it is still rarely applied to active organic materials. Here, sub-100-nm-scale nanopatterning is performed on the surface of quaterthiophene monocrystals by direct maskless electron-beam writing. Gratings are produced on organic crystals with periods ranging from 80 nm to 1 MUm and single-line lateral dimensions ranging from 20 to 500 nm, with electron-beam exposure doses between 100 and 1500 MUC/cm(2). The morphological and texturing properties of the pattern are discussed, together with the interaction mechanisms between the electron beam and the crystal. The resulting modulation of the light emission is consistent with Bragg scattering from the patterned periodic features. PMID- 24490973 TI - Macrophage migration inhibitory factor is a novel determinant of cigarette smoke induced lung damage. AB - Cigarette smoke (CS) is the most common cause of chronic obstructive pulmonary diseases (COPD), including emphysema. CS exposure impacts all cell types within the airways and lung parenchyma, causing alveolar tissue destruction through four mechanisms: (1) oxidative stress; (2) inflammation; (3) protease-induced degradation of the extracellular matrix; and (4) enhanced alveolar epithelial and endothelial cell (EC) apoptosis. Studies in human pulmonary ECs demonstrate that macrophage migration inhibitory factor (MIF) antagonizes CS-induced apoptosis. Here, we used human microvascular ECs, an animal model of emphysema (mice challenged with chronic CS), and patient serum samples to address both the capacity of CS to alter MIF expression and the effects of MIF on disease severity. We demonstrate significantly reduced serum MIF levels in patients with COPD. In the murine model, chronic CS exposure resulted in decreased MIF mRNA and protein expression in the intact lung. MIF deficiency (Mif(-/-)) potentiated the toxicity of CS exposure in vivo via increased apoptosis of ECs, resulting in enhanced CS-induced tissue remodeling. This was linked to MIF's capacity to protect against double-stranded DNA damage and suppress p53 expression. Taken together, MIF appears to antagonize CS-induced toxicity in the lung and resultant emphysematous tissue remodeling by suppressing EC DNA damage and controlling p53 mediated apoptosis, highlighting a critical role of MIF in EC homeostasis within the lung. PMID- 24490975 TI - Virtual screening of LPXTG competitive SrtA inhibitors targeting signal transduction mechanism in Bacillus anthracis: a combined experimental and theoretical study. AB - Members of the sortase enzyme super family decorate the surfaces of Bacillus anthracis cell wall with proteins that play key roles in microbial pathogenesis and its biofilm formation. Bacillus anthracis Sortase-A (Ba-SrtA) is a potential target for new therapeutics as it is required for B. anthracis survival and replication within macrophages. An understanding of the binding site pocket and substrate recognition mechanism by SrtA enzymes may serve to be beneficial in the rational development of sortase inhibitors. Here, the LPXTG signal peptide-based competitive inhibitors are screened against the Ba-SrtA and compounds with reasonable inhibition, specificity, and mechanisms of inactivation of SrtA have been covered. The screened compounds are experimentally validated against the phylogenetically similar Gram-positive pathogen B. cereus. In situ microscopic visualizations suggest that these screened compounds showed the microbial and biofilm inhibitory activity against B. cereus. It facilitates the further development of these molecules into useful anti-infective agents to treat infections caused by B. anthracis and other Gram-positive pathogens. These results provide insight into basic design principles for generating new clinically relevant lead molecules. It also provides an alternative strategy where a screened ligand molecule can be used in combination to battle increasingly against the Gram-positive pathogens. PMID- 24490974 TI - Compensating for the absence of selenocysteine in high-molecular weight thioredoxin reductases: the electrophilic activation hypothesis. AB - Mammalian thioredoxin reductase (TR) is a pyridine disulfide oxidoreductase that uses the rare amino acid selenocysteine (Sec) in place of the more commonly used amino acid cysteine (Cys). Selenium is a Janus-faced element because it is both highly nucleophilic and highly electrophilic. Cys orthologs of Sec-containing enzymes may compensate for the absence of a Sec residue by making the active site Cys residue more (i) nucleophilic, (ii) electrophilic, or (iii) reactive by increasing both S-nucleophilicity and S-electrophilicity. It has already been shown that the Cys ortholog TR from Drosophila melanogaster (DmTR) has increased S-nucleophilicity [Gromer, S., Johansson, L., Bauer, H., Arscott, L. D., Rauch, S., Ballou, D. P., Williams, C. H., Jr., Schrimer, R. H., and Arner, E. S (2003) Active sites of thioredoxin reductases: Why selenoproteins? Proc. Natl. Acad. Sci. U.S.A. 100, 12618-12623]. Here we present evidence that DmTR also enhances the electrophilicity of Cys490 through the use of an "electrophilic activation" mechanism. This mechanism is proposed to work by polarizing the disulfide bond that occurs between Cys489 and Cys490 in the C-terminal redox center by the placement of a positive charge near Cys489. This polarization renders the sulfur atom of Cys490 electron deficient and enhances the rate of thiol/disulfide exchange that occurs between the N- and C-terminal redox centers. Our hypothesis was developed by using a strategy of homocysteine (hCys) for Cys substitution in the Cys-Cys redox dyad of DmTR to differentiate the function of each Cys residue. The results show that hCys could substitute for Cys490 with little loss of thioredoxin reductase activity, but that substitution of hCys for Cys489 resulted in a 238-fold reduction in activity. We hypothesize that replacement of Cys489 with hCys destroys an interaction between the sulfur atom of Cys489 and His464 crucial for the proposed electrophilic activation mechanism. This electrophilic activation serves as a compensatory mechanism in the absence of the more electrophilic Sec residue. We present an argument for the importance of S electrophilicity in Cys orthologs of selenoenzymes. PMID- 24490976 TI - Comparison of the antifungal efficacy of terbinafine hydrochloride and ciclopirox olamine containing formulations against the dermatophyte Trichophyton rubrum in an infected nail plate model. AB - Onychomycosis is a fungal infection mostly induced by dermatophytes such as Trichophyton rubrum. Due to slow nail growth, the treatment takes 3-9 months depending on the nail size and infected area. Hence, high efficacy of the active ingredient without systemic side effects is of major interest. To test the efficacy of an antifungal formulation, an appropriate in vitro model reflecting the in vivo situation as close as possible is required. In this study, a variety of antifungal formulations, i.e., commercial ones (Ciclopoli and Lamisil cream), those used in compounding pharmacies (Pentravan) as well as poloxamer 407-based systems, have been evaluated in an infected nail plate model. The active pharmaceutical ingredients (APIs) were ciclopirox olamine and terbinafine hydrochloride. The poloxamer 407-based formulations consisted of poloxamer 407, double distilled water, propylene glycol, isopropyl alcohol, medium chain triglycerides and either 1% ciclopirox olamine or 1% terbinafine hydrochloride as API, respectively. Former studies have shown high permeation rates of terbinafine hydrochloride from similar poloxamer 407-based formulations with dimethyl isosorbide instead of propylene glycol. The present contribution shows superior inhibition of T. rubrum growth from poloxamer 407-based formulations in comparison to the commercial Lamisil cream. Moreover, poloxamer 407-based formulations were equally effective as the nail lacquer Ciclopoli even though the poloxamer formulations contained only 1% of the drug instead of 8% in the marketed lacquer. Poloxamer 407-based systems containing ciclopirox olamine proved to be about as effective as similar terbinafine hydrochloride systems. PMID- 24490977 TI - Overcoming recruitment barriers revealed high readiness to participate and low dropout rate among people with schizophrenia in a randomized controlled trial testing the effect of a Guided Self-Determination intervention. AB - BACKGROUND: Recruitment is one of the most serious challenges in performing randomized controlled trials. Often clinical trials with participants diagnosed with schizophrenia are terminated prematurely because of recruitment challenges resulting in a considerable waste of resources in the form of time, funding, and the participants' efforts. Dropout rates in schizophrenia trials are also high.Recruitment challenges are often due to patients not wanting to participate in research but can also be due to clinicians' concerns regarding individuals diagnosed with schizophrenia as participants in research. This paper reports how overcoming recruitment challenges not related to patients revealed high readiness to take part and low dropout rates in a one year long randomized controlled trial testing Guided Self-Determination (GSD) among outpatients with schizophrenia receiving treatment in Assertive Outreach Teams in the northern part of Denmark. METHODS: GSD is a shared decision-making and mutual problem-solving method using reflection sheets, which was developed in diabetes care and adjusted for this study and utilized by patients with schizophrenia. Descriptive data on strategies to overcome recruitment challenges were derived from notes and observations made during the randomized controlled trial testing of GSD in six outpatient teams. RESULTS: Three types of recruitment challenges not related to patients were identified and met during the trial: 1) organizational challenges, 2) challenges with finding eligible participants and 3) challenges with having professionals invite patients to participate. These challenges were overcome through: 1) extension of time, 2) expansion of the clinical recruitment area and 3) encouragement of professionals to invite patients to the study. Through overcoming these challenges, we identified a remarkably high patient-readiness to take part (101 of 120 asked accepted) and a low dropout rate (8%). CONCLUSION: Distinction between recruitment challenges was important in discovering the readiness among patients with schizophrenia to take part in and complete a trial with the GSD-intervention. PMID- 24490978 TI - Diabetic characteristics and alveolar bone loss in streptozotocin- and streptozotocin-nicotinamide-treated rats with periodontitis. AB - BACKGROUND AND OBJECTIVE: Experimental models showing variable diabetic status are necessary to understand the relationship between diabetes and periodontitis. The streptozotocin (STZ)-induced diabetes model allows control of diabetic status by nicotinamide (NA), which protects against STZ-induced beta-cell necrosis. Therefore, we compared diabetic characteristics and alveolar bone loss in STZ- and STZ-NA-treated rats with periodontitis. MATERIAL AND METHODS: STZ-treated rats were generated by intravenous (IV) administration of STZ (50 mg/kg). STZ-NA treated rats were induced by intraperitoneal administration of NA (270 mg/kg) 15 min before IV administration of STZ (65 mg/kg). Periodontitis was induced by ligature around the left mandibular first molar 1 wk after injection. Blood glucose level, glucose tolerance and serum insulin levels were determined at day 0 and/or 20 after ligature. At day 20, tibia bone loss was assessed using micro computed tomography and hematoxylin and eosin staining. Alveolar bone loss was histologically measured as the distance of the cementoenamel junction to the alveolar bone crest in distal and the percentage of periodontal ligament area in the first molar furcation, respectively. The number of inflammatory cells, receptor activator of nuclear factor kappa-B ligand (RANKL)-positive cells and the area of osteoid were determined. RESULTS: In STZ-treated rats, obvious hyperglycemia over 300 mg/dL and severe body weight loss were observed. The insulin level was approximately 14% compared to that of control rats. STZ-NA treated rats were impaired in glucose tolerance compared to control rats; however, body weight and insulin levels were not significantly different. Tibia bone loss was increased in STZ-treated rats, but significant change was not observed in STZ-NA-treated rats compared to control rats. In ligatured teeth, alveolar bone loss was increased in both STZ- and STZ-NA-treated rats compared to control rats. Alveolar bone loss, the number of inflammatory cells and RANKL positive cells in STZ-treated rats were greater than in STZ-NA-treated rats. The area of osteoid decreased in STZ-treated rats compared to control, but not STZ-NA treated rats. CONCLUSION: These results indicate that STZ- and STZ-NA-treated rats exhibit diabetic characteristics similar to type 1 diabetes mellitus and a pre-diabetic state, respectively. In addition, alveolar bone loss in response to periodontitis and tibia loss depend on diabetic status. Diabetic status-dependent bone remodeling imbalance and inflammation could affect the alveolar bone loss in the two models. Both STZ- and STZ-NA-treated rats may be useful to investigate differences in periodontitis sensitivity associated with diabetic status and to develop therapeutic agents for periodontitis in patients with diabetes. PMID- 24490979 TI - Hybrid soft computing systems for electromyographic signals analysis: a review. AB - Electromyographic (EMG) is a bio-signal collected on human skeletal muscle. Analysis of EMG signals has been widely used to detect human movement intent, control various human-machine interfaces, diagnose neuromuscular diseases, and model neuromusculoskeletal system. With the advances of artificial intelligence and soft computing, many sophisticated techniques have been proposed for such purpose. Hybrid soft computing system (HSCS), the integration of these different techniques, aims to further improve the effectiveness, efficiency, and accuracy of EMG analysis. This paper reviews and compares key combinations of neural network, support vector machine, fuzzy logic, evolutionary computing, and swarm intelligence for EMG analysis. Our suggestions on the possible future development of HSCS in EMG analysis are also given in terms of basic soft computing techniques, further combination of these techniques, and their other applications in EMG analysis. PMID- 24490980 TI - A mixed-methods observational study of human milk sharing communities on Facebook. AB - OBJECTIVES: The Food and Drug Administration discourages the casual sharing of human milk because of the risk of pathogen transmission. No information is currently available on the prevalence of this practice. The purpose of this mixed methods observational study is to describe the size and activity of online milk sharing communities. MATERIALS AND METHODS: Data for 3 months were extracted from nine public Facebook pages that facilitate the exchange of human milk. The numbers of participants, interactions, and comments were analyzed. RESULTS: We observed 954 individuals participating in milk sharing. The number of interactions per individual ranged from none to 16 (mean, 1.74 +/- 1.65). Top reasons that participants requested milk included "lactation problems" (69.4%) and "child health problems" (48.5%). Nearly half of donors were offering 100 ounces or more, which is the minimum to be eligible to donate to nonprofit milk banks. CONCLUSIONS: Milk sharing networks in the United States are active, with thousands of individuals participating in the direct exchange of raw human milk. Public health issues include increasing the supply of pasteurized donor milk for fragile infants, increasing breastfeeding support, and helping milk sharing families appropriately manage risks. PMID- 24490981 TI - Visible-light-induced chemoselective deboronative alkynylation under biomolecule compatible conditions. AB - Here, we report a visible-light-induced deboronative alkynylation reaction, which is redox-neutral and works with primary, secondary and tertiary alkyl trifluoroborates or boronic acids to generate aryl, alkyl and silyl substituted alkynes. This reaction is highly chemoselective and performs well on substrates containing alkenes, alkynes, aldehydes, ketones, esters, nitriles, azides, aryl halides, alkyl halides, alcohols, and indoles, with no detectable occurrence of side reactions. The mechanism of this novel C(sp(3))-C(sp) bond coupling reaction was investigated by luminescence quenching, radical trapping, on-off light, and (13)C-isotopic-labeling experiments. This reaction can be performed in neutral aqueous conditions, and it is compatible with amino acids, nucleosides, oligosaccharides, nucleic acids, proteins, and cell lysates. PMID- 24490982 TI - Mathematical models for skin toxicology. AB - INTRODUCTION: Our skin is exposed daily to substances; many of these are neutral and safe but others are potentially harmful. In order to estimate the degree of toxicity and damage to skin tissues when exposed to harmful substances, skin toxicology studies are required. If these studies are coupled with suitably designed mathematical models, they can provide a powerful tool that allows appropriate interpretation of data. This work reviews mathematical models that can be employed in skin toxicology studies. AREAS COVERED: Two types of mathematical models and their suitability for assessing skin toxicology are covered in this review. The first is focused on predicting penetration rate through the skin from a solute's physicochemical properties, while the second type of models transport processes in skin layers using appropriate equations with the specific aim of predicting the concentration of a given solute in viable skin tissues. EXPERT OPINION: Mathematical models are an important tool for accurate valuation of skin toxicity experiments, estimation of skin toxicity and for developing new formulations for skin disease therapy. Comprehensive mathematical models of drug transport in skin, especially those based on more physiologically detailed mechanistic considerations of transport processes, are required to further enhance their role in assessing skin toxicology. PMID- 24490983 TI - Rapid allergen inactivation using atmospheric pressure cold plasma. AB - Allergies have become a global problem, and effective control is greatly needed. Here, the inactivation effects of the atmospheric pressure cold plasma (APCP) on aerosolized allergens including Der p 1, Der f 1, Asp f 1, Alt a 1, and Can f 1 as well as those from indoor and outdoor environments were investigated. The effectiveness of the APCP treatment was further studied using blood sera from the allergen sensitized humans. In addition, the allergen samples were also analyzed using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE). Results revealed that the APCP was highly effective in reducing the allergenicity of both lab-prepared and environmental allergen aerosols. The airborne reductions were shown to range from 30% for Der p 1 to 80% for Can f 1 allergen for 0.12 s exposure. Allergnicity tests showed that the APCP treated Asp f 1 allergens caused 50% less binding with IgEs in the blood sera compared to the control. The observed allergenicity loss was due to hydroxyl radicals produced by the plasma device. The results from SDS-PAGE showed that the plasma treatment resulted in decreased size of the Asp f 1 allergen. The developed technology holds great promise in combating the allergic diseases. PMID- 24490984 TI - Commentary: two-stage surgery for hidradenitis suppurativa: staged artificial dermis and skin grafting. PMID- 24490985 TI - Commentary: treatment and prevention of surgical scars: to bruise or not to bruise is no longer the question, but rather who pays for the treatment. PMID- 24490986 TI - Clear cell hidradenocarcinoma mimicking pyogenic granuloma after repeated surgical excision. PMID- 24490987 TI - Potential cardiovascular implications of Sea Buckthorn berry consumption in humans. AB - Diets rich in fruits and vegetables have been correlated with decreased risks of cardiovascular disease. Particularly, berry consumption has been associated with reductions in cardiovascular risk. Despite the range of potentially beneficial phytochemical components (vitamins, polyphenols, carotenoids, and fatty acids), there is little evidence underpinning the cardiovascular effects of sea buckthorn (SB) berries. The purpose of this review is to evaluate the benefits of SB consumption on cardiovascular health in human trials. Only six human studies were found, which examine the effect of SB berries on cardiovascular outcomes (i.e., lipid metabolism, platelet aggregation, and inflammation). Although there appears to be an inverse association between SB consumption and cardiovascular risk factors, the evidence is still scarce and the results are inconsistent. In addition, limitations in study design made it difficult to form firm conclusions. More "high-quality" human clinical trials are needed in order to establish the cardio-protective benefits of SB berries. PMID- 24490990 TI - Structural and topological control on physical properties of arsenic selenide glasses. AB - The structures of Ge-doped arsenic selenide glasses with Se contents varying between 25 and 90 at. % are studied using a combination of high-resolution, two dimensional (77)Se nuclear magnetic resonance (NMR) and Raman spectroscopy. The results indicate that, in contrast to the conventional wisdom, the compositional evolution of the structural connectivity in Se-excess glasses does not follow the chain-crossing model, and chemical order is likely violated with the formation of a small but significant fraction of As-As bonds. The addition of As to Se results in a nearly random cross-linking of Se chains by AsSe3 pyramids, and a highly chemically ordered network consisting primarily of corner-shared AsSe3 pyramids is formed at the stoichiometric composition. Further increase in As content, up to 40 at. % Se, results in the formation of a significant fraction of As4Se3 molecules with As-As homopolar bonds, and consequently the connectivity and packing efficiency of the network decrease and anharmonic interactions increase. Finally, in the highly As-rich region with <40 at. % Se, the relative concentration of the As4Se3 molecules decreases rapidly and large clusters of As atoms connected via Se-Se-As and As-Se-As linkages dominate. These three composition regions with distinct structural characteristics and the corresponding mixing entropy of the Se environments are reflected in the appearance of multiple extrema in the compositional variation of a wide range of physical properties of these glasses, including density, glass transition temperature, thermal expansivity, and fragility. PMID- 24490988 TI - Effect of triptolide on reproduction of female lesser bandicoot rat, Bandicota bengalensis. AB - Triptolide has been reported to cause antifertility in male rats and mice. However, studies on female rats have been limited. Present study was aimed to evaluate the effects of triptolide on reproduction of wild female rodent pest species, Bandicota bengalensis. Feeding of bait containing 0.1, 0.15 and 0.2% triptolide for a period of 15 days in bi-choice resulted in per day ingestion of 17.37, 23.54 and 27.49 mg/kg body weight of triptolide, respectively. Examination of vaginal smear of all the rats revealed a significant (p <= 0.05) increase in duration of estrous cycle due to increase in durations of metestrous and diestrous stages in rats of treated groups. Autopsy of rats after 15 and 30 days of treatment withdrawal revealed significant (p <= 0.05) reduction in weights of uterus and ovaries, non-significant reduction in weights of liver and levels of estradiol and progesterone and significant (p <= 0.05) reduction in levels of urea and BUN and increase in levels of plasma proteins, ALT, AST, ALP, ACP and LDH in rats of treated groups compared to untreated group. There was no significant (p <= 0.05) effect of treatment on body weight. Triptolide treatment affected the histomorphology of uterus by causing a decrease in lumen and columnar cell height and number of uterine glands and ovary by increasing the number of atretic follicles and decreasing the number of developing follicles. The present study suggests triptolide to be a strong candidate affecting reproduction of female B. bengalensis. PMID- 24490991 TI - Subtle clinical signs of a meningioma in an adult: a case report. PMID- 24490992 TI - Advancements in understanding the mechanisms of symptomatic lacunar ischemic stroke: translation of knowledge to prevention strategies. AB - Symptomatic lacunar ischemic stroke (25% of all brain infarctions) results from occlusion of a single penetrating artery by microatheromas or lipohyalinosis and rarely from an intracranial atheromatous branch disease. Recurrent lacunar stroke may be associated with more severe clinical features and has been involved in producing lacunar state and vascular subcortical dementia. In the first multicenter randomized clinical trial (SPS3) focused on stroke prevention among patients with recent lacunar stroke, the addition of clopidogrel to aspirin not only did not reduced significantly the risk of recurrent stroke, but also increased significantly the likelihood of hemorrhage and fatal outcome. If lacunar stroke is primarily non-atherothromboembolic, secondary prevention aimed at preventing atheroma progression may not be very effective. The efficacy of drugs that improve endothelial function in lacunar stroke patients remains to be studied in the future. PMID- 24490993 TI - Discovery of bioluminogenic probes for aminopeptidase N imaging. AB - To find an approach that can image the hydrolysis activity of aminopeptidase N (APN) both in vitro and in vivo, three bioluminescent probes have been well designed and synthesized herein. All of them can be recognized and hydrolyzed by APN to produce bioluminescence emission in the presence of firefly luciferase. To the best of our knowledge, they are the first bioluminescent probes for imaging APN in deep tissues and living animals. PMID- 24490997 TI - Addressing viral hepatitis in Pakistan: not all is gloom and doom. PMID- 24490994 TI - Age differences in the impact of forced swimming test on serotonin transporter levels in lateral septum and dorsal raphe. AB - BACKGROUND: Forced swimming test (FST) is an animal model which evaluates behavioral despair and the effect of antidepressants such as the selective serotonin reuptake inhibitors; the FST modifies the expression of some receptors related to antidepressant response, but it is not known whether serotonin transporter (SERT), their main target, is affected by this test in animals of different ages. Antidepressant response has shown age-dependent variations which could be associated with SERT expression. The aim of the present study was to analyze changes in the SERT immunoreactivity (SERT-IR) in dorsal raphe and lateral septum of male rats from different age groups with or without behavioral despair induced by their exposure to the FST, since these two structures are related to the expression of this behavior. METHODS: Prepubertal (24 PN), pubertal (40 PN), young adult (3-5 months) and middle-aged (12 months) male rats were assigned to a control group (non-FST) or depressed group (FST, two sessions separated by 24 h). Changes in SERT-IR in dorsal raphe and lateral septum were determined with immunofluorescence. RESULTS: Pubertal and middle-aged rats showed higher levels of immobility behavior compared to prepubertal rats on the FST. SERT-IR showed an age-dependent increase followed by a moderate decrease in middle-aged rats in both structures; a decreased in SERT-IR in lateral septum and dorsal raphe of pubertal rats was observed after the FST. CONCLUSIONS: Age differences were observed in the SERT-IR of structures related to behavioral despair; SERT expression was modified by the FST in lateral septum and dorsal raphe of pubertal rats. PMID- 24490996 TI - LeMAPK1, LeMAPK2, and LeMAPK3 are associated with nitric oxide-induced defense response against Botrytis cinerea in the Lycopersicon esculentum fruit. AB - Nitric oxide (NO) and mitogen-activated protein kinases (MAPKs) are signal molecules involved in the disease resistance of plants. To investigate the role of tomato MAPKs in the NO-mediated defense response, mature green tomatoes (Lycopersicon esculentum Mill. cv. Qian-xi) were treated with a MAPKs inhibitor (1,4-diamino-2,3-dicyano-1,4-bis(o-amino-phenylmercapto) butadiene (U0126)), NO donor sodium nitroprusside (SNP), and SNP plus U0126. Treatment with U0126 increased the incidence of disease and size of lesion areas in the tomato fruits after being inoculated with Botrytis cinerea. NO enhanced the resistance of the tomato fruits against Botrytis cinerea invasion and the activities of nitric oxide synthase, Chitinase, beta-1,3-glucanase, polyphenol oxidase, and phenylalanine ammonia-lyase. However, the effects of NO on disease resistance were weakened by the MAPKs inhibitor. Meanwhile, the relative expression of LeMAPK1, LeMAPK2, and LeMAPK3 in the (SNP + U0126)-treated fruits was lower than that in the SNP-treated fruits. The results suggest that LeMAPK1/2/3 are involved in NO-induced disease resistance of tomato fruits against Botrytis cinerea. PMID- 24490998 TI - Trans-radial primary percutaneous coronary intervention in ST-elevation myocardial infarction. AB - OBJECTIVE: To study the effect of trans-radial approach (TRA) on achievement of a door-to-balloon time (DBT) of 2 90 minutes in primary PCI percutaneous Coronary intervention (PPCI) for ST-elevation myocardial infarction (STEMI). STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Armed Forces Institute of Cardiology - National Institute of Heart Diseases (AFIC -NIHD), Rawalpindi, from October 2011 to August 2012. METHODOLOGY: Systems goal for door-to-balloon time (DBT - time elapsed between first medical contact and restoration of flow in the infarct related artery [IRA]) was set at < 90 minutes. Procedural success was defined as restoration of TIMI 3 flow in the IRA with less than 30% residual stenosis and discharge from hospital. Non-infarct related arteries were not treated. Bleeding episodes were defined by TIMI definitions. RESULTS: For vascular access for PPCI in a total of 207 patients, TRA was 91.3% (n = 189), transfemoral approach (TFA) 6.3% (n = 13) and brachial 2.4% (n = 5). Males represented 90.3% of cases and 7% were females. Mean age was 55 +/- 10.86 years. Procedural success rate was 97.1%. Mean DBT was 54.1 minutes. DBT was less 2 60 and 90 minutes in 75% and 94.2% of patients respectively. DBT 2 89.50 minutes was achieved in 90% of patients. The difference in DBT between the different access groups was not markedly different between the three groups. There were 6 (2.9%) in-hospital deaths and no major bleeds. CONCLUSION: TRA for PPCI poses no hindrance to achieving a DBT of < 90 minutes in PPCI for STEMI. Furthermore, the in-hospital mortality rates are acceptable and within rational limits. PMID- 24490999 TI - Parathyroid hormone measurement in prediction of hypocalcaemia following thyroidectomy. AB - OBJECTIVE: To determine the risk of postthyroidectomy hypocalcaemia by measuring parathyroid hormone (PTH) level after thyroidectomy. STUDY DESIGN: Cross sectional study. PLACE AND DURATION OF STUDY: Baqiyatallah Hospital, Tehran, Iran, from March 2008 to July 2010. METHODOLOGY: All included patients were referred for total or near bilateral thyroidectomy. Serum Calcium (Ca) and PTH levels were measured before and 24 hours after surgery. In low Ca cases or development of hypocalcaemia symptoms, daily monitoring of Ca levels were continued. Data were analyzed using SPSS 20 software (SPSS, Chicago, IL, USA). A p-value less than 0.05 were considered statistically significant. To assess the standard value of useful predictive factors, we used receiver operating characteristic (ROC) curves. RESULTS: Of total 99 patients who underwent bilateral thyroidectomy, 47 patients (47.5%) developed hypocalcaemia, out of them, 12 (25.5%) became symptomatic while 2 patients developed permanent hypoparathyroidism. After surgery, mean rank of PTH level within the normocalcaemic and hypocalcaemic patients was 55.34 and 44.1 respectively, p=0.052. Twenty four hours after surgery, 62% drop in PTH was associated with 83.3% of symptomatic hypocalcaemic. For diagnosis of symptomatic hypocalcaemia, 62% PTH drop had sensitivity and specificity were 83.3% and 90.80%. The area under the ROC curve for the PTH postoperative and PTH drop for diagnostic symptomatic hypocalcaemia were 0.835 and 0.873 respectively. CONCLUSION: Measuring PTH levels after 24 hours postthyroidectomy is not reliable factor for predicting hypocalcaemia itself. For predicting the risk of hypocalcaemia after thyroidectomy it is more reliable to measure the serum PTH level before and after operation and compare the reduction level of percentage of PTH drop for predicting the risk of hypocalcaemia. PMID- 24491000 TI - Polypropylene suture versus skin staples for securing mesh in lichtenstein inguinal hernioplasty. AB - OBJECTIVE: To compare polypropylene suture and skin staples for securing mesh in Lichtenstein inguinal hernioplasty in terms of mean operating time and postoperative pain. STUDY DESIGN: Randomized clinical trial. PLACE AND DURATION OF STUDY: Surgical Ward, Combined Military Hospital, Kharian, from August 2011 to February 2012. METHODOLOGY: All individuals fulfilling inclusion criteria underwent elective Lichtenstein inguinal hernioplasty as admitted patients, under spinal anaesthesia and with aseptic measures. In group 1, during the operation, mesh fixation was done with 2/0 polypropylene suture and skin was closed with subcuticular 2/0 polypropylene suture whereas in group 2, the anchorage of mesh was done with skin staples and skin was closed with staples from the same stapler. Mean operative time and postoperative pain, assessed on a visual analog score, were compared between the groups. RESULTS: The overall postoperative pain was lower (p = 0.026) when staples were used to anchor mesh. Moreover, operative time was also lower (37.42 +/- 2.69 minutes) in staple group versus (42.44 +/- 2.55 minutes in polypropylene group). CONCLUSION: Mean operating time and postoperative pain is less in securing mesh with skin staples as compared to polypropylene suture in Lichtenstein inguinal hernioplasty. PMID- 24491001 TI - Generation of hepatocyte-like cells from human induced pluripotent stem (iPS) cells by co-culturing embryoid body cells with liver non-parenchymal cell line TWNT-1. AB - OBJECTIVE: To generate a homogeneous population of patient-specific hepatocyte like cells (HLCs) from human iPS cells those show the morphologic and phenotypic properties of primary human hepatocytes. STUDY DESIGN: An experimental study. PLACE AND DURATION OF STUDY: Department of Surgery, Okayama University, Graduate School of Medicine, Japan, from April to December 2011. METHODOLOGY: Human iPS cells were generated and maintained on ES qualified matrigel coated plates supplemented with mTeSR medium or alternatively on mitotically inactivated MEF feeder layer in DMEM/F12 medium containing 20% KOSR, 4ng/ml bFGF-2, 1 x 10-4 M 2 mercaptoethanol, 1 mmol/L NEAA, 2mM L-glutamine and 1% penicillin-streptomycin. iPS cells were differentiated to HLCs by sequential culture using a four step differentiation protocol: (I) Generation of embryoid bodies (EBs) in suspension culture; (II) Induction of definitive endoderm (DE) from 2 days old EBs by growth in human activin-A (100 ng/ml) and basic fibroblasts growth factor (bFGF2) (100 ng/ml) on matrigel coated plates; (III) Induction of hepatic progenitors by co culture with non-parenchymal human hepatic stellate cell line (TWNT-1); and (IV) Maturation by culture in dexamethasone. Characterization was performed by RT-PCR and functional assays. RESULTS: The generated HLCs showed microscopically morphological phenotype of human hepatocytes, expressed liver-specific genes (ASGPR, Albumin, AFP, Sox17, Fox A2), secreted human liver-specific proteins such as albumin, synthesized urea and metabolized ammonia. CONCLUSION: Functional HLCs were generated from human iPS cells, which could be used for autologus hepatocyte transplantation for liver failure and as in vitro model for determining the metabolic and toxicological properties of drug compounds. PMID- 24491002 TI - Comparison of the histological and serological parameters of patients with hepatitis delta virus in active and inactive hepatitis B virus carriers. AB - OBJECTIVE: To assess the histological and serological parameters of patients with hepatitis delta virus (HDV) in active HBV versus inactive HBV carriers. STUDY DESIGN: An observational study. PLACE AND DURATION OF STUDY: Medical Unit IV at Liaquat University Hospital, Jamshoro, Sindh, from June 2008 to September 2011. METHODOLOGY: This study included 49 consecutive inactive HBV carriers who were HBsAg-positive, HBV DNA-negative, anti-D antibody-positive, and HDV RNA-positive, as well as 277 patients with active HBV who were HBsAg-positive, anti- HDV antibody-positive, HDV RNA-positive, and demonstrated > 20,000 IU/mL HBV DNA and > 2 (ULN) serum glutamic pyruvic transaminase (SGPT). Informed consent was obtained from each patient. Liver biopsies were obtained and the staging of fibrosis was performed according to the METAVIR scoring system. Continuous variables such as age, SGPT, platelet count, and the HBV DNA level were computed as the mean +/- standard deviation. Categorical variables such as gender and stage of fibrosis are expressed as percentages. All data were processed using SPSS version 16. RESULTS: This study included 49 patients in an inactive HBV group. Fibrosis stage 0 was observed in 37 (75.5%) patients and 12 (24.5%) were stage 1. Among the 277 patients with active disease, fibrosis stage 0 was present in 7 (2.5%) patients, stage 1 in 31 (11.2%) patients, stage 2 in 172 (62.1%) patients, stage 3 in 44 (15.9%) patients and stage 4 in 23 (8.3%) patients. CONCLUSION: HDV in active HBV carriers is severe on its initial presentation and requires prompt treatment whereas in inactive HBV carriers demonstrates an indolent course. PMID- 24491003 TI - Detection of genes for superantigen toxins in methicillin-resistant Staphylococcus aureus clinical isolates in Karachi. AB - OBJECTIVE: To detect genes for enterotoxins, exfoliative and toxic shock syndrome toxins in Staphylococcus aureus (S. aureus) strains isolated from clinical specimens. STUDY DESIGN: Cross-sectional observational study. PLACE AND DURATION OF STUDY: Department of Molecular Genetics, Dr. Ziauddin Hospital, Karachi, from January to December 2010. METHODOLOGY: Two hundred and ninety eight S. aureus clinical isolates were obtained from various clinical samples received at Dr. Ziauddin Hospital, Karachi. Out of these, 115 were detected as methicillin resistant (MRSA) by cefoxitin disk diffusion test showing a prevalence rate of 38.6%. Detection of individual toxin genes was performed by Polymerase Chain Reaction (PCR) by using only one primer pair for each tube. Uniplex primers were preferred as multiplex primers are longer in base pairs and have the potential for cross reaction due to non-specific binding and increase in optimization time. RESULTS: The possession of a single gene or more than a single gene in MRSA isolates was found in 61.73% of clinical samples; the highest number was found in pus swab, followed by sputum, blood, urethral swab, and urine. The prevalence of toxin genes was higher in MRSA as compared to methicillin sensitive (MSSA) isolates (19.12%). CONCLUSION: PCR detects strains possessing toxin genes independent of their expression. The possession of genes for super-antigens seems to be a frequent and habitual trait of S. aureus more so in MRSA. PMID- 24491004 TI - High affinity IgE-Fc receptor alpha and gamma subunit interactions. AB - OBJECTIVE: To explore the relationships between the subunits (alpha, beta and gamma) of the high affinity IgE receptor (Fc&RI) and its ability to mediate transmembrane signaling. STUDY DESIGN: Experimental study. PLACE AND DURATION OF STUDY: Department of Molecular Biology and Biotechnology, University of Sheffield, UK, from 2008 to 2009. METHODOLOGY: The approach employed was to create a chimera (human alphagammagamma) using the extracellular (EC) domain of the human high affinity IgE receptor. The alpha subunit (huFc&RIalpha) of IgE receptor was spliced onto the rodent gamma TM and cytoplasmic domain (CD). This was transfected into the Rat Basophilic Leukemia cell line in order to assess the possibility of selectively activating cells transfected with this single pass construct for antigen induced mediator release. RESULTS: The RBLs cell lines transfected with the huFc&RIalpha/gamma/gamma cDNA constructs were assessed for the cell surface expression of the huFc&RIalpha subunit and the response to the antigenic stimulus by looking for degranulation and intracellular Ca2+ mobilisation. The results obtained showed the absence of huFc&RIalpha subunit expression on the surface of transfected cells as seen by flowcytometric studies, beta-hexosaminidase assays and intracellular calcium mobilisation studies. CONCLUSION: In the present study the grounds for non-expression of huFc&RIalpha/gamma/gamma cDNA remains elusive but may be due to the fact that the human-rodent chimeric receptors are assembled differently than the endogenous rodent receptors as seen in study in which COS 7 cells were transfected with human/rat chimeric complexes. PMID- 24491005 TI - Zinc supplement in reduction of relapses in children with steroid sensitive nephrotic syndrome. AB - OBJECTIVE: To determine whether Zinc supplementation could reduce relapse rate in children with nephrotic syndrome. STUDY DESIGN: Randomized-controlled trial. PLACE AND DURATION OF STUDY: National Institute of Child-Health and The Kidney Centre, Karachi, from January 2008 to June 2009. METHODOLOGY: Sixty nephrotic children aged 2 - 15 years were selected. Baseline data including age, number of infections and relapses during pre and post study one year were recorded. Randomization was done to divide into Zinc group (Zg) to receive Zinc versus placebo (Pg) for 6 months. Relapses and infections were treated with standard therapy. T-test and chi-square tests were used to compare the mean values and proportions respectively with significance at p < 0.05. RESULTS: Among 60 children, 54 completed trial (Zg = 25, Pg = 29). Forty (74%) were males and 14 (26%) females. Mean age, pre study relapses and Zinc level in the two groups were similar. Overall, infections and relapses were observed in 43 (79.62%) and 17 cases (31.48%) respectively. There was no significant difference in frequency of infections and mean infection rate in Zg (20, 80% and 1.92 +/- 1.47) compared to Pg (23, 79.3% and 2 +/- 1.53, p = 0.950). Relapses occurred in 7 (28%) in Zg compared to 10 (34%) in Pg which was not significant (p = 0.609). Mean infection and relapse rate per patient per year (PPPY) in Zg was 1.92 +/- 1.47and 1.14 +/- 0.37 compared to 2 +/- 1.53 and1.3 +/- 0.48 in Pg respectively (p=0.846, 0.464). Pre study relapses in two groups were similar (Zg vs. Pg = 96 vs. 96.6%) whereas post study relapses in Zg were lower (7, 28%) compared to Pg (10, 34.5%). Post study mean relapse rate in Zg was 1.14 +/- 0.37 PPPY compared to 2.71 +/- 1.11 in pre study (p = 0.005). In Pg, post study mean relapse rate PPPY was 1.30 +/- 0.48 compared to 1.70 +/- 0.48 in pre study period (p = 0.037). Relapse rate reduction was 43% after Zinc supplementation compared to 27% reduction in placebo. Metallic taste was observed in 10% of cases. CONCLUSION: Zinc supplementation was helpful in reducing relapses in nephrotic syndrome. PMID- 24491007 TI - Fronto-orbital advancement and total calvarial remodelling for craniosynostosis. AB - OBJECTIVE: To describe the results of fronto-orbital advancement and remodelling for craniosynostosis in children. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Plastic Surgery, Combined Military Hospital, Rawalpindi, from June 2009 to June 2012. METHODOLOGY: All the patients with cranial suture synostosis operated were included in the study. Those patients who were lost to follow-up were excluded. Variables considered were age, gender, type of synostosis, intracranial pressure, and history of previous surgeries for the same problem. Outcome measures were studied in terms of improvement of skull measurements (anteroposterior and bicoronal), duration of surgery, hospital stay, blood transfusions, complications and parents satisfaction. RESULTS: A total of 36 patients were included in the study. Male to female ratio was 3:1. The age ranged from 5 to 54 months. Thirty two patients presented with non-syndromic and four with syndromic craniosynostosis. Fronto orbital advancement and total calvarial remodelling was done in 26 and 10 patients respectively. There was improvement in the skull measurements and the parents were satisfied in all cases with the skull shape. Complications occurred in 11.1% including chest and wound infection and one death. CONCLUSION: Fronto-orbital advancement and remodelling is an effective procedure for the correction of craniosynostosis, however, individual cases may require other procedures like total calvarial remodelling. PMID- 24491006 TI - Rota virus Diarrhea in Hospitalized Children. AB - OBJECTIVE: To determine the frequency and clinical features of Rota virus diarrhea in children presenting in a tertiary care hospital. STUDY DESIGN: A cross-sectional, observational study. PLACE AND DURATION OF STUDY: National Institute of Child Health, Karachi, from January to June 2007. METHODOLOGY: A total of three hundred children of either gender aged 1 month to 5 years, who presented with diarrhea of < 7 days as a primary illness were enrolled. Children with bloody diarrhea or nosocomial gastroenteritis acquired during hospitalization for other disease were not included. Detection of Rota virus in stool was done by enzyme linked immunoassay. RESULTS: Out of 300 children, 188 (63%) tested positive and 112 (37%) tested negative for Rota virus. Positive Rota virus cases in 7 - 12 months of age was (n = 34, 18.08%). Overall, 151 (80.3%) children with Rota virus were less than 3 years old. 182 (60.7%) had fever, 118 (39.3%) had vomiting and 156 (82.9%) children had both fever and vomiting. CONCLUSION: This study shows that Rota virus is a common organism causing diarrhea in children less than 3 years of age. There is a need to incorporate Rota virus vaccine in the national EPI program to decrease the disease burden as highlighted in this study. PMID- 24491008 TI - The Pittsburgh Sleep Quality Index: validation of the Urdu translation. AB - OBJECTIVE: To translate and validate the Pittsburgh Sleep Quality Index (PSQI), a standardized self-administered questionnaire for the assessment of subjective sleep quality into the Urdu language. STUDY DESIGN: Validation study. PLACE AND DURATION OF STUDY: Mayo Hospital, Lahore, from March to April 2012. METHODOLOGY: The PSQI was translated into Urdu following standard guidelines. The final Urdu version (PSQI-U) was administered to 200 healthy volunteers comprising medical students, nursing staff and doctors. Inter-item correlation was assessed by calculating Cronbach alpha. Correlation of component scores with global score was assessed by calculating Spearman correlation coefficient. Correlation between global PSQI-U scores at baseline with global scores for each PSQI-U and PSQI-E at 4-week interval was evaluated by calculating Spearman correlation coefficient. Moreover, scores on individual items of the scale at baseline were compared with respective scores after 4-week by t-test. RESULTS: One hundred and eighty five (185) participants completed the PSQI-U at baseline. The Cronbach alpha for PSQI U was 0.56. Scores on individual components of the PSQI-U and composite scores were all highly correlated with each other (all p-values < 0.01). Composite scores for PSQI-U at baseline and PSQI-E at 4-week interval were also highly correlated with each other (Spearman correlation coefficient 0.74, p-value < 0.01) indicating good linguistic interchangeability. Composite scores for PSQI-U at baseline and at 4-week interval were positively correlated with each other (Spearman correlation coefficient 0.70, p < 0.01) indicating good test-retest reliability. CONCLUSION: The PSQI-U is a valid and reliable instrument for the assessment of sleep quality. It shows good linguistic interchangeability and test retest reliability in comparison to the original English version when applied to individuals who speak the Urdu language. The PSQI-U can be a tool either for clinical management or research. PMID- 24491009 TI - Fetomaternal outcome in acute hepatitis e. AB - OBJECTIVE: To determine fetomaternal outcome in pregnant women with acute hepatitis E in terms of pregnancy outcome and perinatal mortality. STUDY DESIGN: Case series. PLACE AND DURATION OF STUDY: Department of Obstetrics and Gynecology, Sir Ganga Ram Hospital, Lahore, from July 2012 to March 2013. METHODOLOGY: Serum samples of 38 patients who presented with jaundice in pregnancy were collected to detect hepatitis E IgM antibodies. Demographics, pregnancy outcome and perinatal mortality was noted in hepatitis E positive cases with cause of complications. Cases with jaundice due solely to any other cause were excluded. RESULTS: Twenty five patients had acute hepatitis E with coexistent acute hepatitis A in 1(4%) patient. Their mean age was 25 years and mean gravidity was 2. Among them, 10 (40%) patients were primigravida followed by gravida two in 7 (28%) cases. Twenty four (96%) patients presented in third trimester of pregnancy and in 1 (4%) pregnancy ended in second trimester missed miscarriage. The mean gestational age was 32 weeks. Twenty one (84%) babies were born alive, among them 18 (86%) were preterm. Perinatal mortality was 26%; contributed by intrauterine deaths and early neonatal deaths in 3 (14%) cases each. Total maternal deaths were 5 (20%), 4 (80%) in postpartum period and 1 (20%) in antepartum period due to fulminant hepatic failure in all cases. CONCLUSION: Prematurity in newborns and fulminant hepatic failure in mothers are major cause of poor fetomaternal outcome in acute hepatitis E in pregnancy. PMID- 24491010 TI - Comparison of obstetric outcome in terms of the risk of low birth weight, preterm delivery, cesarean section rate and anemia in primigravid adolescents and older primigravida. AB - OBJECTIVE: To compare the obstetric outcome in terms of risk of low birth weight, preterm delivery, cesarean section rate and anemia in primigravid adolescents and older primigravida. STUDY DESIGN: Cohort study. PLACE AND DURATION OF STUDY: Department of Obstetrics and Gynaecology, Sir Ganga Ram Hospital, Lahore, from July to December 2012. METHODOLOGY: Three hundred primigravid women presenting to department of obstetrics and gynecology of Sir Ganga Ram Hospital, Lahore, having live singleton pregnancy, including 150 adolescents (2 19 years) and 150 adults (3 20 years) were studied. Obstetric outcome in terms of gestational age at delivery, infant's birth weight, presence of anemia and cesarean section rate was compared between two groups. Results were analyzed using Statistical Package for Social Sciences (SPSS) version 16. Chi-square test was applied with 0.05 as level of significance. RESULTS: The mean age of adolescent subjects was 17.3 + 1.5 years and of adults 25.6 + 3.4 years. Mean gestational age at delivery was similar in two groups (39.2 weeks and 39.4 weeks, p = 0.37). Adolescents were more likely to have a preterm delivery (11.2% vs. 4.9%, p = 0.04) and low birth weight infants (19.3% vs. 8.2%, p = 0.005) than adults. Adolescents were more likely to be anemic (46% vs. 32%, p = 0.01) than adults. However, cesarean section rate was not statistically different between two groups. CONCLUSION: This study showed that primiparous adolescents have significantly higher risk of adverse pregnancy outcomes such as preterm delivery, low birth weight infants and anemia as compared to adult primiparas. PMID- 24491011 TI - Correlation of hyponatremia with hepatic encephalopathy and severity of liver disease. AB - OBJECTIVE: To assess the frequency of low serum sodium levels and to correlate it with the severity of liver disease and hepatic encephalopathy (HE) in patients coming to the tertiary care hospital. STUDY DESIGN: Observational study. PLACE AND DURATION OF STUDY: Shifa International Hospital, Islamabad, from January 2011 to January 2012. METHODOLOGY: A total of 202 patients with hepatic encephalopathy and chronic liver disease had serum sodium measured. The HE was graded according to the West Haven classification (4 grades). Relationship of hyponatremia was correlated with severity grade of encephalopathy using Spearman rank correlation test. RESULTS: Out of 202 patients, 62 (30.7%) patients had serum sodium less than 130 meq/l. Out of 202, HE was present in 69 (34.15%) patients and out of these, 38 had grade III-IV HE and 31 had grade I - II HE. Out of 69 patients with HE 57 had sodium less than 135 (p < 0.001). CONCLUSION: Hyponatremia was a common feature in patients with cirrhosis and its severity increased with the severity of liver disease. The existence of serum sodium concentration < 135 mmol/L was associated with greater frequency of hepatic encephalopathy compared with patients with serum sodium concentration > 135 mmol/L. PMID- 24491012 TI - Pityriasis alba with poliosis. AB - Pityriasis alba is a skin disease, commonly seen in children and young adults. This case presents the ocular association of this disease in a 10 years old Pakistani male. Ocular features in this case were poliosis, tilted disc, high myopia and chorioretinal degeneration. Tilted discs and high myopia can be coincidental but poliosis and decreased pigment in retinal pigment epithelium are closely related with the hypopigmentation seen in this disease. PMID- 24491013 TI - Lichen scrofulosorum presenting as pyrexia of unknown origin. AB - Cutaneous tuberculosis forms a subset of extra pulmonary tuberculosis. It accounts for about 1.5% of all the cases of extrapulmonary tuberculosis. Lichen Scrofulosorum is a rare form of cutaneous tuberculosis. It is usually seen in children or young adults and an important marker of occult tuberculosis. Usually, the eruption appears in children and adolescents with strong immune sensitivity to Mycobacterium tuberculosis and consists of tiny follicular papules. Underlying systemic involvement is more common in children, compared with adults. We report a case of 3 years old boy who was investigated for pyrexia of unknown origin and finally diagnosed as Lichen Scrofulosorum associated with tuberculous lymphadenitis of mediastinal lymph nodes. A skin biopsy showed extensive tuberculoid granulomas surrounding hair follicles which were consistent with the diagnosis of Lichen Scrofulosorum. The child was treated with antitubercular drugs and it showed improvement within 2 weeks of starting treatment with resolution of skin lesions. PMID- 24491014 TI - Isolated pneumomediastinum following laparoscopic cholecystectomy: an unpredictable situation. AB - Pneumomediastinum is a clinical event characterized by the presence of air in the mediastinum. Often a result of physical trauma, this condition results from air escaping from the respiratory airway and moving into the mediastinal cavity. Although rare, it can also develop following abdominal laparoscopic surgical procedures. Diagnosis is commonly made by visualizing a radiolucent airline in the mediastinum and/or surrounding the heart following a chest X-ray radiography or a thoracic CT scan. This case study describes the diagnosis, treatment and follow-up of a 51 years old female patient who developed pneumomediastinum following a laparoscopic cholecystectomy. PMID- 24491015 TI - Spinal cystic schwannoma: an MRI evaluation. AB - Spinal cystic schwannomas are a very rare entity and have been reported in only a few case reports in literature; its diagnosis and management has remained a challenge. This study reviewed the results of magnetic resonance imaging (MRI) of 12 patients (7 men and 5 women; aged 37 - 67 years; mean age: 52.75 years) with pathologically proven cystic schwannoma of the spine and discussed their differential diagnosis. All patients underwent surgery at our institutions between June 2000 and April 2012. MRI showed well-delineated intradural and extramedullary lesion of iso- to low signal intensity on T1 weighted images, high signal intensity on T2 weighted images, and rim enhancement on contrast-enhanced images. A precise understanding of the MRI features of spinal schwannomas, especially the typical characteristic of enhancement, may help clinicians in their pre-operative diagnoses and surgical planning. PMID- 24491016 TI - Active disease in chronic hepatitis C patients with normal alanine aminotransferase. PMID- 24491017 TI - The cost associated with the supernatural explanation of the natural diseases: dual responsibility of the doctors. PMID- 24491019 TI - Apolipoprotein E increases cell association of amyloid-beta 40 through heparan sulfate and LRP1 dependent pathways. AB - The increased risk of Alzheimer's disease (AD) associated with specific apolipoprotein E (ApoE) isoforms appears to relate to altered amyloid-beta (Abeta) homeostasis. Clearance of Abeta from the brain is reduced in the presence of the AD-associated ApoE4 isoform, which may contribute to the accumulation of Abeta deposits in the parenchyma and vasculature. The low-density lipoprotein receptor-related protein 1 (LRP1) and heparan sulfate proteoglycans (HSPGs), both established ApoE receptors, are involved in Abeta uptake, with LRP1 additionally implicated in Abeta transcytosis across the blood-brain barrier. In this study, we detected the co-distribution of heparan sulfate (HS), ApoE and LRP1 in Abeta(1 40)-positive brain microvessels from individuals with Down's syndrome diagnosed with AD. In addition, ApoE was pulled-down from AD cerebrospinal fluid with anti Abeta antibodies. Using Chinese hamster ovary cells deficient in HS or LRP1, we found that ApoE increases cell association of Abeta in a HSPG- and LRP1-dependent manner; and further, ApoE processing is altered in the absence of cellular HS. These interactions may facilitate Abeta clearance from the brain, but if overwhelmed could contribute to Abeta accumulation and the pathogenesis of AD. PMID- 24491020 TI - Intrinsic motivation and extrinsic incentives jointly predict performance: a 40 year meta-analysis. AB - More than 4 decades of research and 9 meta-analyses have focused on the undermining effect: namely, the debate over whether the provision of extrinsic incentives erodes intrinsic motivation. This review and meta-analysis builds on such previous reviews by focusing on the interrelationship among intrinsic motivation, extrinsic incentives, and performance, with reference to 2 moderators: performance type (quality vs. quantity) and incentive contingency (directly performance-salient vs. indirectly performance-salient), which have not been systematically reviewed to date. Based on random-effects meta-analytic methods, findings from school, work, and physical domains (k = 183, N = 212,468) indicate that intrinsic motivation is a medium to strong predictor of performance (rho = .21-45). The importance of intrinsic motivation to performance remained in place whether incentives were presented. In addition, incentive salience influenced the predictive validity of intrinsic motivation for performance: In a "crowding out" fashion, intrinsic motivation was less important to performance when incentives were directly tied to performance and was more important when incentives were indirectly tied to performance. Considered simultaneously through meta-analytic regression, intrinsic motivation predicted more unique variance in quality of performance, whereas incentives were a better predictor of quantity of performance. With respect to performance, incentives and intrinsic motivation are not necessarily antagonistic and are best considered simultaneously. Future research should consider using nonperformance criteria (e.g., well-being, job satisfaction) as well as applying the percent-of-maximum-possible (POMP) method in meta-analyses. PMID- 24491021 TI - The pains and pleasures of parenting: when, why, and how is parenthood associated with more or less well-being? AB - The relationship between parenthood and well-being has become a hot topic among scholars, media, and general public alike. The research, however, has been mixed some studies indicate that parents are happier than nonparents, whereas others suggest the reverse. We suggest that the question of whether parents are more or less happy than their childless peers is not the most meaningful one. To reconcile the conflicting literature and expand understanding of the emotional experience of parenthood, we present a model of parents' well-being that describes why and how parents experience more or less happiness than nonparents (i.e., mediators of the link between parenthood and well-being). We then apply this model to explain when parents are more likely to experience more or less happiness (i.e., moderators of parents' well-being, such as parent age or child temperament). Supporting our model, we review 3 primary methodological approaches: studies comparing parents and nonparents, studies examining changes in well-being across the transition to parenthood, and studies comparing parents' experiences while with their children to their other daily activities. Our review suggests that the relationship between parenthood and well-being is highly complex. We propose that parents are unhappy to the extent that they encounter relatively greater negative emotions, magnified financial problems, more sleep disturbance, and troubled marriages. By contrast, when parents experience greater meaning in life, satisfaction of their basic needs, greater positive emotions, and enhanced social roles, they are met with happiness and joy. PMID- 24491022 TI - The effects of single-sex compared with coeducational schooling on students' performance and attitudes: a meta-analysis. AB - Proponents of single-sex (SS) education believe that separating boys and girls, by classrooms or schools, increases students' achievement and academic interest. In this article, we use meta-analysis to analyze studies that have tested the effects on students of SS compared with coeducational (CE) schooling. We meta analyzed data from 184 studies, representing the testing of 1.6 million students in Grades K-12 from 21 nations, for multiple outcomes (e.g., mathematics performance, mathematics attitudes, science performance, educational aspirations, self-concept, gender stereotyping). To address concerns about the quality of research designs, we categorized studies as uncontrolled (no controls for selection effects, no random assignment) or controlled (random assignment or controls for selection effects). Based on mixed-effects analyses, uncontrolled studies showed some modest advantages for single-sex schooling, for both girls and boys, for outcomes such as mathematics performance but not for science performance. Controlled studies, however, showed only trivial differences between students in SS versus CE, for mathematics performance (g = 0.10 for girls, 0.06 for boys) and science performance (g = 0.06 for girls, 0.04 for boys), and in some cases showed small differences favoring CE schooling (e.g., for girls' educational aspirations, g = -0.26). Separate analyses of U.S. studies yielded similar findings (e.g., for mathematics performance g = 0.14 for girls and 0.14 for boys). Results from the highest quality studies, then, do not support the view that SS schooling provides benefits compared with CE schooling. Claims that SS schooling is particularly effective for U.S. ethnic minority boys could not be tested due to the lack of controlled studies on this question. PMID- 24491023 TI - Intravitreal ranibizumab injection for idiopathic choroidal neovascularization in children. AB - We report two cases of idiopathic choroidal neovascularization (CNV) in pediatric patients treated with intravitreal ranibizumab injections (IVRs). A nine-year-old girl with decreased visual acuity in the left eye (20/100) was diagnosed with idiopathic CNV (case 1). The fluorescein angiography (FAG), indocyanine green angiography (ICG), and optical coherence tomography (OCT) revealed classic CNV. After two monthly IVRs, the visual acuity improved to 20/30 and stabilized without any adverse events. In case 2, a 10-year-old girl presented with decreased visual acuity (20/50) in the right eye. The OCT and FAG showed classic CNV. After one IVR, the visual acuity improved to 20/40 and the central foveal thickness was decreased. Visual acuity, FAG, ICG, OCT, serologic tests, and occurrence of ocular or systemic adverse events during follow-up were evaluated. During 14 and 12 months of follow-up for cases 1 and 2, respectively, no evidence of recurrence or adverse events were noted. PMID- 24491024 TI - Long-term effect of curcumin down-regulates expression of tumor necrosis factor alpha and interleukin-6 via modulation of E26 transformation-specific protein and nuclear factor-kappaB transcription factors in livers of lymphoma bearing mice. AB - Tumor necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6) are typical multifunctional proinflammatory cytokines involved actively in the regulation of immunity, hematopoiesis, inflammation and carcinogenesis. Coordinated regulation of these cytokines could be required for effective regulation of early phase inflammation and cancer progression. The present work was aimed to analyze the anti-carcinogenic action of curcumin on the expression of TNF-alpha and IL-6 even after withdrawal of treatment. Up-regulated expressions of TNF-alpha and IL-6 in terms of mRNA and protein levels in lymphoma bearing mice were significantly down regulated by curcumin as compared to normal. Electrophoretic mobility shift assay (EMSA) results revealed that curcumin reduced binding of nuclear protein with ETS and NF-kappaB binding elements of TNF-alpha and IL-6 promoters, respectively. The anti-carcinogenic effect of curcumin against lymphoma progression has been reported previously. In continuation, the present study suggests that the long term effect of curcumin may contribute to attenuate cancer progression via the down-regulation of TNF-alpha and IL-6 modulated by E26 transformation-specific protein (ETS) and nuclear factor-kappaB (NF-kappaB), respectively. PMID- 24491025 TI - Clinicopathologic characteristics and outcomes of patients experiencing severe pyrimethamine poisoning. PMID- 24491026 TI - Effectiveness and safety of thiotepa as conditioning treatment prior to stem cell transplant in patients with central nervous system lymphoma. AB - BACKGROUND: Thiothepa is a cytostatic agent used in managing solid malignancies, and also as conditioning treatment before hematopoietic stem cell transplantation [HSCT]. This systematic review summarizes evidence on its effectiveness and safety, in patients with central nervous system [CNS] lymphoma. METHODS: We searched 3 databases for clinical studies. When feasible, we performed meta analyses. RESULTS: We identified 13 eligible studies, none of which with a priori controls. So data synthesis focused on the 226 patients who received thiotepa. Based on pooled estimates, 75.9% of thiotepa-treated patients achieved a complete remission (95% confidence interval [CI] = 67.5-82.8), and 61.7% had a progression free survival for up to 125 months post-treatment (95% CI = 49.4-72.7). However, 25.5% relapsed, 24.6% experienced infection, and 13.2% experienced neurotoxicity. DISCUSSION: Thiotepa-based conditioning followed by HSCT may be effective in most CNS lymphoma patients, with a manageable toxicity profile. But adequately powered randomized trials are needed to better evaluate and isolate the effects of thiotepa. PMID- 24491027 TI - Safety and efficacy of high-dose cyclophosphamide, etoposide and ranimustine regimen followed by autologous peripheral blood stem cell transplant for patients with diffuse large B-cell lymphoma. AB - We retrospectively evaluated the safety and efficacy of high-dose chemotherapy consisting of cyclophosphamide, etoposide and ranimustine (CEM) with autologous peripheral blood stem cell transplant (PBSCT) in 55 adult patients with relapsed or high-risk de novo diffuse large B-cell lymphoma (DLBCL) or DLBCL associated with follicular lymphoma. This included 36 patients in the upfront setting in their first complete remission. The median follow-up of 42 patients surviving at the time of the analysis was 52 months (range 1-159). Relapse or disease progression after PBSCT was a frequent cause of death, but no therapy-related mortality associated with PBSCT was observed. The 5-year overall survival and progression-free survival were 70.6% (95% confidence interval [CI], 54.0-82.1) and 57.0% (95% CI, 39.5-71.2), respectively. Chronic renal impairment, therapy related myelodysplastic syndrome and prostate cancer were the major late complications. The CEM regimen is a tolerable, effective conditioning regimen for autologous PBSCT for DLBCL, with no therapy-related mortality observed. PMID- 24491028 TI - Long-term imatinib maintenance therapy for adult Philadelphia positive acute lymphoblastic leukemia. PMID- 24491029 TI - Physical chemical drug-drug interactions from drug discovery to registration: new opportunities for the pharmaceutical scientist to impact drug development. PMID- 24491030 TI - Direct kinetic study of OH and O3 formation in the reaction of CH3C(O)O2 with HO2. AB - The reaction between HO2 and CH3C(O)O2 has three exothermic product channels, forming OH (R3a), peracetic acid (R3b), and acetic acid plus O3 (R3c). The branching ratios of the OH- and ozone-forming reaction channels were determined using a combination of laser-induced fluorescence (LIF, for time-resolved OH concentration measurement) and transient absorption spectroscopy (TAS, for time resolved O3 concentration measurement) following pulsed laser generation of HO2 and CH3C(O)O2 from suitable precursors. TAS was also used to determine the initial concentration of the reactant peroxy radicals. The data were evaluated by numerical simulation using kinetic models of the measured concentration profiles; a Monte Carlo approach was used to estimate the uncertainties of the rate constants (k3) and branching ratios (alpha) thus obtained. The reaction channel forming OH (R3a) was found to be the most important with alpha3a = 0.61 +/- 0.09 and alpha3c = 0.16 +/- 0.08. The overall rate coefficient of the title reaction was found to be k3 = (2.1 +/- 0.4) * 10(-11) cm(3) molecule(-1) s(-1) for both HO2 and DO2. Use of DO2 resulted in an increase in alpha3a to 0.80 +/- 0.14. Comparison with former studies shows that OH formation via (R3) has been underestimated significantly to date. Possible reasons for these discrepancies and atmospheric implications are discussed. PMID- 24491031 TI - Oncogenic transformation of mesenchymal stem cells decreases Nrf2 expression favoring in vivo tumor growth and poorer survival. AB - BACKGROUND: The transcription factor Nrf2 is a key regulator of the cellular antioxidant response, and its activation by chemoprotective agents has been proposed as a potential strategy to prevent cancer. However, activating mutations in the Nrf2 pathway have been found to promote tumorigenesis in certain models. Therefore, the role of Nrf2 in cancer remains contentious. METHODS: We employed a well-characterized model of stepwise human mesenchymal stem cell (MSC) transformation and breast cancer cell lines to investigate oxidative stress and the role of Nrf2 during tumorigenesis. The Nrf2 pathway was studied by microarray analyses, qRT-PCR, and western-blotting. To assess the contribution of Nrf2 to transformation, we established tumor xenografts with transformed MSC expressing Nrf2 (n = 6 mice per group). Expression and survival data for Nrf2 in different cancers were obtained from GEO and TCGA databases. All statistical tests were two sided. RESULTS: We found an accumulation of reactive oxygen species during MSC transformation that correlated with the transcriptional down-regulation of antioxidants and Nrf2-downstream genes. Nrf2 was repressed in transformed MSC and in breast cancer cells via oncogene-induced activation of the RAS/RAF/ERK pathway. Furthermore, restoration of Nrf2 function in transformed cells decreased reactive oxygen species and impaired in vivo tumor growth (P = 0.001) by mechanisms that included sensitization to apoptosis, and a decreased hypoxic/angiogenic response through HIF-1alpha destabilization and VEGFA repression. Microarray analyses showed down-regulation of Nrf2 in a panel of human tumors and, strikingly, low Nrf2 expression correlated with poorer survival in patients with melanoma (P = 0.0341), kidney (P = 0.0203) and prostate (P = 0.00279) cancers. CONCLUSIONS: Our data indicate that oncogene-induced Nrf2 repression is an adaptive response for certain cancers to acquire a pro-oxidant state that favors cell survival and in vivo tumor growth. PMID- 24491032 TI - Liquiritigenin exhibits antitumour action in pituitary adenoma cells via Ras/ERKs and ROS-dependent mitochondrial signalling pathways. AB - OBJECTIVE: The purpose of this study was to investigate antitumour effects of liquiritigenin (LQ) on pituitary adenoma in in-vitro and in-vivo models. METHODS: The effects of LQ on cell viability, apoptosis rate, mitochondrial membrane potential (MMP), intracellular reactive oxygen species (ROS) level and various apoptosis-related mediators were examined in MMQ and GH3 cells that are derived from rat pituitary adenoma. Antitumour effect of LQ was also examined in the mouse model of GH3-xenografted tumour. KEY FINDINGS: LQ inhibited cell viability, caused G1 phase arrest and initiated apoptosis in both MMQ and GH3 cells. LQ dissipated MMP, increased intracellular ROS level and cytosol cytochrome C, and reduced the expression of Ras, B-cell lymphoma 2 and B-cell lymphoma-extra large. LQ also inhibited the activation of extracellular signalling-regulated kinases (ERKs) and the translocation of from cytoplasm to nucleus. LQ markedly reduced tumour size without affecting bodyweight in mice with GH3 cells xenograft. CONCLUSIONS: LQ effectively inhibits pituitary adenoma tumour growth and induces cell apoptotic death mainly via Ras/ERKs and ROS-dependent mitochondrial pathways, suggesting that LQ is a potential suppressor of pituitary adenoma. PMID- 24491033 TI - Paliperidone extended-release in patients with non-acute schizophrenia previously unsuccessfully treated with other oral antipsychotics. AB - OBJECTIVE: This study explores relevant outcomes with flexibly dosed paliperidone extended-release (ER) in a real-world design. RESEARCH DESIGN AND METHODS: Patients were recruited from 23 countries. Adults with non-acute schizophrenia (n = 1812), previously unsuccessfully treated with other oral antipsychotics, were transitioned to paliperidone ER and prospectively treated for 6 months. MAIN OUTCOME MEASURES: Primary efficacy outcome for patients switching for the main reason of lack of efficacy was >= 20% improvement in Positive and Negative Syndrome Scale (PANSS) total scores. For patients switching for main reasons other than lack of efficacy, primary outcome was non-inferiority in efficacy compared with the previous medication. RESULTS: Among the lack-of-efficacy group, 61% achieved a >= 20% improvement in PANSS total scores from baseline to endpoint. For switchers from other than the lack-of-efficacy group, efficacy maintenance after switching to paliperidone ER was confirmed. Clinically relevant and statistically significant symptomatic improvements occurred for each patient group based on main reason for switching. CONCLUSION: Paliperidone ER was well tolerated and associated with a meaningful clinical response in patients who switched from other oral antipsychotics, with insomnia and anxiety as most frequent side-effects. PMID- 24491034 TI - The positive outlook study- a randomised controlled trial evaluating the effectiveness of an online self-management program targeting psychosocial issues for men living with HIV: a study protocol. AB - BACKGROUND: The emergence of HIV as a chronic condition means that people living with HIV are required to take more responsibility for the self-management of their condition, including making physical, emotional and social adjustments. This paper describes the design and evaluation of Positive Outlook, an online program aiming to enhance the self-management skills of gay men living with HIV. METHODS/DESIGN: This study is designed as a randomised controlled trial in which men living with HIV in Australia will be assigned to either an intervention group or usual care control group. The intervention group will participate in the online group program 'Positive Outlook'. The program is based on self-efficacy theory and uses a self-management approach to enhance skills, confidence and abilities to manage the psychosocial issues associated with HIV in daily life. Participants will access the program for a minimum of 90 minutes per week over seven weeks. Primary outcomes are domain specific self-efficacy, HIV related quality of life, and outcomes of health education. Secondary outcomes include: depression, anxiety and stress; general health and quality of life; adjustment to HIV; and social support. Data collection will take place at baseline, completion of the intervention (or eight weeks post randomisation) and at 12 week follow-up. DISCUSSION: Results of the Positive Outlook study will provide information regarding the effectiveness of online group programs improving health related outcomes for men living with HIV. TRIAL REGISTRATION: ACTRN12612000642886. PMID- 24491036 TI - Pressure recording analytical method and bioreactance for stroke volume index monitoring during pediatric cardiac surgery. AB - BACKGROUND: It is currently uncertain which hemodynamic monitoring device reliably measures stroke volume and tracks cardiac output changes in pediatric cardiac surgery patients. OBJECTIVE: To evaluate the difference between stroke volume index (SVI) measured by pressure recording analytical method (PRAM) and bioreactance and their ability to track changes after a therapeutic intervention. METHODS: A single-center prospective observational cohort study in children undergoing cardiac surgery with cardiopulmonary bypass (CPB) was conducted. Twenty children below 20 kg with median (interquartile range) weight of 5.3 kg (4.1-7.8) and age of 6 months (3-20) were enrolled. Data were collected after anesthesia induction, at the end of CPB, before fluid administration and after fluid administration. Overall, median-IQR PRAM SVI values (23 ml.m(-2), 19-27) were significantly higher than bioreactance SVI (15 ml.m(-2), 12-25, P = 0.0001). Correlation (r(2) ) between the two methods was 0.15 (P = 0.0003). The mean difference between the measurements (bias) was 5.7 ml.m(-2) with a standard deviation of 9.6 (95% limits of agreement ranged from -13 to 24 ml.m(-2)). Percentage error was 91.7%. Baseline SVI appeared to be similar, but PRAM SVI was systematically greater than bioreactance thereafter, with the highest gap after the fluid loading phase: 13 (12-18) ml.m(-2) vs. 23 (19-25) ml.m(-2), respectively, P = 0.0013. A multivariable regression model showed that a significant independent inverse correlation with patients' body weight predicted the CI difference between the two methods after fluid challenge (beta coefficient -0.12, P = 0.013). CONCLUSIONS: Pressure recording analytical method and bioreactance provided similar SVI estimation at stable hemodynamic conditions, while bioreactance SVI values appeared significantly lower than PRAM at the end of CPB and after fluid replacement. PMID- 24491037 TI - Economic impact of human milk on medical charges of extremely low birth weight infants. PMID- 24491035 TI - Pattern recognition scavenger receptor A/CD204 regulates airway inflammatory homeostasis following organic dust extract exposures. AB - Exposure to agriculture organic dusts, comprised of a diversity of pathogen associated molecular patterns, results in chronic airway diseases. The multi functional class A macrophage scavenger receptor (SRA)/CD204 has emerged as an important class of pattern recognition receptors with broad ligand binding ability. The objective was to determine the role of SRA in mediating repetitive and post-inflammatory organic dust extract (ODE)-induced airway inflammation. Wild-type (WT) and SRA knockout (KO) mice were intra-nasally treated with ODE or saline daily for 3 weeks and immediately euthanized or allowed to recover for 1 week. Results show that lung histopathologic changes were increased in SRA KO mice as compared to WT following repetitive ODE exposures marked predominately by increased size and distribution of lymphoid aggregates. After a 1-week recovery from daily ODE treatments, there was significant resolution of lung injury in WT mice, but not SRA KO animals. The increased lung histopathology induced by ODE treatment was associated with decreased accumulation of neutrophils, but greater accumulation of CD4(+) T-cells. The lung cytokine milieu induced by ODE was consistent with a TH1/TH17 polarization in both WT and SRA KO mice. Overall, the data demonstrate that SRA/CD204 plays an important role in the normative inflammatory lung response to ODE, as evidenced by the enhanced dust-mediated injury viewed in the absence of this receptor. PMID- 24491038 TI - Predicting partition coefficients of Polyfluorinated and organosilicon compounds using polyparameter linear free energy relationships (PP-LFERs). AB - The environmental behavior, fate, and effects of polyfluorinated compounds (PFCs) and organosilicon compounds (OSCs) have received increasing attention in recent years. In this study, polyparameter linear free energy relationships (PP-LFERs) were evaluated for predicting partition coefficients of neutral PFCs and OSCs, using experimental data for fluorotelomer alcohols (FTOHs) and cyclic volatile methylsiloxanes (cVMS) reported in the literature and measured newly for this work. It was found that the recently proposed PP-LFER model that uses the McGowan characteristic volume (V), the logarithmic hexadecane-air partition coefficient (L), and three polar interaction descriptors can accurately describe partition coefficients of PFCs and OSCs. The prediction errors were <1 log unit when literature descriptors were used, and the errors were reduced to <0.2 log units on average by further optimization of the descriptors. Surprisingly, the conventional forms of PP-LFERs that include the excess molar refraction (E) sometimes led to substantial errors (>1 log unit) even with optimized parameters. The system parameters for octanol-water, air-water, octanol-air, oil-water, liposome-water, and organic carbon-water partition coefficients as well as the solute descriptors for FTOHs and cVMS were recalibrated in this work, which should provide even more reliable predictions of partition coefficients. The results also confirm the consistency of the published experimental partition coefficients for FTOHs and cVMS. PMID- 24491039 TI - The prospects and predicaments of intravenous rt-PA in childhood ischemic stroke. AB - One of the biggest conundrums in acute treatment of childhood arterial ischemic stroke is administration of intravenous recombinant tissue plasminogen activator. Although the benefit of this treatment is well-established in adults, the same effectiveness in children has not been demonstrated. Diversity of underlying causes of ischemic stroke in children and delay and uncertainty in diagnosis are some of the complexities that make intravenous thrombolysis elusive in this population. Physiological, pharmacological and developmental factors may also play roles in variable effect of intravenous recombinant tissue plasminogen activator in children. Current studies are aimed to determine the safety and efficacy of intravenous thrombolysis in carefully-selected children who would benefit the most from this procedure. PMID- 24491040 TI - Long-term mycophenolate monotherapy in human leukocyte antigen (HLA)-identical living-donor kidney transplantation. AB - Although recipients of a first HLA-identical living-donor kidney transplant seem to need less immunosuppression, there are no guideline recommendations for these patients, and few prospective trials are available. METHODS: We analyzed all PRA negative patients who received a first kidney transplant from an HLA-identical living donor. The patients received no antibody induction. An intraoperative bolus of 500 mg of methylprednisolone was administered. Then, steroid therapy was withdrawn within one week. Tacrolimus and mycophenolate treatment were started 3 days before transplantation with tacrolimus target levels of 4 to 8 ng/mL. In the absence of rejection, tacrolimus was withdrawn between 3 and 12 months post transplant to reach mycophenolate mofetil monotherapy of 2 g/day or equivalent. RESULTS: Six patients were treated with the above protocol. At last follow-up, graft and patient survival were 100%. MDRD glomerular filtration rates were 54, 60, and 62 mL/min at 3 months, 12 months and last follow-up, respectively. None of the patients developed PRA post-transplant. One episode of acute rejection Banff IA occurred 9 years after transplantation due to non-adherence with good outcome after treatment. The mean number of concomitant drugs given with mycophenolate was 2.6. Four patients needed antihypertensive drugs. CONCLUSION: Steroid-free de novo treatment and calcineurin-inhibitor weaning with mycophenolate monotherapy is feasible in first HLA-identical kidney transplantation from a living sibling. PMID- 24491041 TI - Surface dilution kinetics of phospholipase A(2) catalyzed lipid-bilayer hydrolysis. AB - Phospholipase A2 (PLA2) enzymes catalyze hydrolysis of phospholipids in membranes. Elucidation of the kinetics of interfacial enzymatic activity is best accomplished by investigating the interface substrate concentration dependence of the activity for which appropriate diluents are required. PLA2 is stereoselective toward the L_enantiomers of phospholipids. A novel approach employing D_phospholipids as diluents to perform surface dilution kinetic studies of PLA2 is presented. Activity of bee venom PLA2 at mixed L+D_DPPC (dipalmitoylphosphatidylcholine) bilayer interfaces was measured as a function of substrate L_DPPC mole fraction and vesicle concentration using a sensitive fluorescence assay. A model for interface enzymatic activity based on the three step kinetic scheme of (i) binding of PLA2 to the bilayer interface, (ii) binding of a lipid to PLA2 at the interface, and (iii) hydrolysis was applied to the hydrolysis data. Activity profiles showed that D_enantiomers also bind to the enzyme but resist hydrolysis. Activity dependences on vesicle and substrate concentrations could be disentangled, bringing resolution to an outstanding problem in membrane hydrolysis of separating the effects of the three steps. Individual values of the kinetic parameters of the model, including the vesicle PLA2 equilibrium dissociation constant of step (i), interface Michaelis-Menten Henri constant for L and D_DPPC of step (ii), and the rate constant for interface hydrolysis, step (iii), were obtained as solutions to equations resulting from fitting the model to the data. PMID- 24491043 TI - Role of CDH1 promoter polymorphism and DNA methylation in bladder carcinogenesis: a meta-analysis. AB - Increasing scientific evidences suggest that CDH1 gene promoter polymorphism and DNA methylation may contribute to the development and progression of bladder cancer, but many existing studies have yielded inconclusive results. This meta analysis aims to assess the role of CDH1 gene promoter polymorphism and methylation in bladder carcinogenesis. An extensive literature search for relevant studies was conducted in PubMed, Embase, Web of Science, Cochrane Library, and CBM databases from their inception through April 1, 2013. This meta analysis was performed using the STATA 12.0 software. The crude odds ratio with 95% confidence interval was calculated. Fifteen studies were included in this meta-analysis with a total of 824 bladder cancer patients and 818 healthy controls being assessed. Our meta-analysis revealed that the A variant of CDH1 160C/A polymorphism was associated with an increased risk of bladder cancer. Further analysis by pathological subtype indicated that patients with invasive carcinoma had a higher frequency of CDH1 -160A variant than those with superficial carcinoma. We analyzed the methylation frequency of CDH1 gene in 608 bladder cancer samples and 338 normal bladder samples. Our data strongly suggest that the CDH1 promoter methylation frequencies in bladder cancer tissues were greater than those in normal control tissues. In conclusion, our meta-analysis indicates that promoter polymorphism and methylation of CDH1 gene may be involved in the development and progression of bladder cancer. CDH1 gene promoter polymorphism and methylation might be promising biomarkers for the diagnosis and prognosis of bladder cancer. PMID- 24491042 TI - A network-assisted co-clustering algorithm to discover cancer subtypes based on gene expression. AB - BACKGROUND: Cancer subtype information is critically important for understanding tumor heterogeneity. Existing methods to identify cancer subtypes have primarily focused on utilizing generic clustering algorithms (such as hierarchical clustering) to identify subtypes based on gene expression data. The network-level interaction among genes, which is key to understanding the molecular perturbations in cancer, has been rarely considered during the clustering process. The motivation of our work is to develop a method that effectively incorporates molecular interaction networks into the clustering process to improve cancer subtype identification. RESULTS: We have developed a new clustering algorithm for cancer subtype identification, called "network-assisted co-clustering for the identification of cancer subtypes" (NCIS). NCIS combines gene network information to simultaneously group samples and genes into biologically meaningful clusters. Prior to clustering, we assign weights to genes based on their impact in the network. Then a new weighted co-clustering algorithm based on a semi-nonnegative matrix tri-factorization is applied. We evaluated the effectiveness of NCIS on simulated datasets as well as large-scale Breast Cancer and Glioblastoma Multiforme patient samples from The Cancer Genome Atlas (TCGA) project. NCIS was shown to better separate the patient samples into clinically distinct subtypes and achieve higher accuracy on the simulated datasets to tolerate noise, as compared to consensus hierarchical clustering. CONCLUSIONS: The weighted co-clustering approach in NCIS provides a unique solution to incorporate gene network information into the clustering process. Our tool will be useful to comprehensively identify cancer subtypes that would otherwise be obscured by cancer heterogeneity, using high-throughput and high-dimensional gene expression data. PMID- 24491045 TI - Label-free capacitive diagnostics: exploiting local redox probe state occupancy. AB - An electrode surface confined redox group contributes to a substantial potential dependent interfacial charging that can be sensitively probed and frequency resolved by impedance-derived capacitance spectroscopy. In utilizing the sensitivity of this charging fingerprint to redox group environment, one can seek to generate derived sensory configurations. Exemplified here through the generation of mixed molecular films comprising ferrocene and antibody receptors to two clinically important targets, the label-free methodology is able to report on human prostatic acid phosphatase (PAP), a tumor marker, with a limit of detection of 11 pM and C-reactive protein with a limit of detection of 28 pM. Both assays exhibit linear ranges encompassing those of clinical value. PMID- 24491046 TI - [Therapeutic effect and mechanism of Phoenix roebelenii pollen vaccine for treatment of mice with allergic rhinitis]. AB - OBJECTIVE: To apply Phoenix roebelenii pollen vaccine to murine models of allergic rhinitis and observe the pathological changes of allergic rhinitis in mice, and to study the efficacy and mechanism of the vaccine for the treatment of allergic rhinitis. METHODS: BALB/c mice models of allergic rhinitis were established by intraperitoneal injection, and then treated with immunotherapy of allergen vaccine by subcutaneous injection. The mice were examined for the levels of airway hyperresponsiveness by a noninvasive lung function detector, for the specific antibodies IgE and IgG2a in serum and cytokines by indirect ELISA, and for the pathological changes of ultrastructure of nasal mucosa of the mice by transmission electron microscopy before and after the treatment. RESULTS: After the immunotherapy, nasal symptoms and airway hyperresponsiveness of the mice were relieved. The level of specificity antibody IgG2a in serum was elevated, and IgE dropped significantly. In the culture supernatant of spleen cells, INF-gamma and IL-10 levels increased and the production of IL-4 decreased. CONCLUSION: The recombinant profilin of the Phoenix roebelenii pollen as vaccine has a certain therapeutic effect for the pollen allergic rhinitis, and it works maybe through promoting the transition of Th2 to Th1 and regulating the balance of helper T cells. PMID- 24491047 TI - [Construction and identification of H5 subtype avian influenza vaccine candidate based on flagellin]. AB - OBJECTIVE: To develop a novel H5 subtype avian influenza vaccine candidate based on flagellin. METHODS: HA1-2-fljB was amplified through splicing hemagglutinin gene fragment HA1-2 of A/Goose/Jiangsu/1/2000 H5N1 and Salmonella typhimurium II phase flagellin fljB gene by overlap PCR, and then the gene was inserted to pET32a(+) to construct the recombinant plasmid pET32a-HA1-2-fljB. The recombinant plasmid was transformed into E.coli BL21 (DE3) and was induced with IPTG. The expression of the fusion protein was identified by SDS-PAGE and Western blotting. The biological activity of the fusion protein was evaluated by stimulating HEK293 TLR5 cells. RESULTS: The recombinant plasmid pET32a-HA1-2-fljB was constructed. The fusion protein, whose relative molecule weight was about 100 000, had a good immunoreactivity. TLR5 bioassay demonstrated the flagellin part of the fusion protein could be recognized by TLR5 of HEK293-TLR5 cell line to secrete a higher level of IL-8 when compared with HA1-2 protein (P<0.01). CONCLUSION: The flagellin-based fusion protein HA1-2-fljB with TLR5 bioactivity was expressed correctly, and the results would establish a basis for the further research on avian influenza virus H5 vaccine. PMID- 24491048 TI - [Expression and identification of enterohemorrhagic Escherichia coli O157:H7 Shiga toxin1A subunit]. AB - OBJECTIVE: To express and identify enterohemorrhagic Escherichia coli (EHEC) O157:H7 Shiga toxin 1 A subunit (Stx1A). METHODS: Stx1A encoded gene was amplified from EHEC O157:H7 genome by PCR, confirmed by sequencing and cloned into vector pET-22b(+). The recombinant plasmid pET-22b(+)-Stx1A was transformed into E.coli BL21(DE3) which was induced by IPTG to express the target protein. After purified by AKTA(TM);-His affinity chromatography, the recombinant protein was identified by mass spectrometry. With the recombinant protein, BALB/c mice were immunized to develop the anti-sera and evaluate its specific reaction with the natural Stx1A by Western blotting. RESULTS: The Stx1A gene with a size of 945 bp was amplified and cloned into prokaryotic expression vector pET22b(+) to form pET-22b(+)-Stx1A. The recombinant protein was effectively expressed in E.coli BL21(DE3) and purified by 6*His-based affinity chromatography. The mass spectrometry analysis showed that the target protein was Stx1A. Western blotting demonstrated that its immunized sera could react specifically with the natural Stx1A. CONCLUSION: The EHEC O157:H7 Stx1A gene was successfully cloned and expressed, which laid a solid foundation for the following researches. PMID- 24491049 TI - [Over-expressed microRNA-7 inhibits the growth of human lung cancer cells via suppressing CGGBP1 expression]. AB - OBJECTIVE: To investigate the effect of microRNA-7 (miR-7) over-expression on the growth of human lung cancer cells in vivo and in vitro and explore its possible mechanism. METHODS: The eukaryotic expression vector of pcDNA3.1 encoding miR-7 (p-miR-7) was transiently transfected into human lung cancer 95D cells in vitro. The proliferation of cells was detected by MTT assay and colony formation assay. Moreover, the expressions of nuclear antigen Ki-67 and CGG binding protein 1 (CGGBP1) were detected by immunofluorescence assay. Human lung cancer model in nude mice was established. Next, p-miR-7 vector was directly injected into local tumor tissue. Then, tumor size was measured and the survival time of mice was observed. The expression level of miR-7 in the tumor tissue was determined by real-time PCR. Finally, the expressions of Ki-67 and CGGBP1 were detected by immunohistochemistry. RESULTS: Over-expression of miR-7 could significantly inhibit the growth of 95D cells in vitro (P<0.05), accompanied by the remarkably reduced expressions of Ki-67 and CGGBP1 (P<0.05). Moreover, compared with those in control group, the expression level of miR-7 increased significantly in p-miR 7 injected group (P<0.05). Meanwhile, the growth of tumors in injected group was slower than in the control group. Consistently, the survival time of mice was dramatically prolonged in p-miR-7 injected group (P<0.05). The expression levels of Ki-67 and CGGBP1 also remarkably decreased in tumor tissue (P<0.05). CONCLUSION: Over-expression of miR-7 could significantly inhibit the growth of human lung cancer cells in vivo and in vitro, which might be related to the down regulated expression of tumor growth-associated protein CGGBP1. PMID- 24491050 TI - [Dynamic changes of peripheral blood monocyte subsets after myocardial ischemia/reperfusion in rats]. AB - OBJECTIVE: To investigate the dynamic changes of monocyte subsets after myocardial ischemia/reperfusion (I/R) in rats and their correlations with myocardial repair after I/R injury. METHODS: Sixteen male Wistar rats were randomly divided into two groups: I/R group and sham group. Myocardial I/R was induced by left anterior descending coronary artery ligation for 45 min followed by permanent reperfusion. Peripheral blood was harvested from the tail vein to evaluate the dynamics of CD172a(+);CD43(low); and CD172a(+);CD43(high); monocyte subsets by flow cytometry at baseline and on day 1, 3, 5, 7 and 14 after I/R injury. Survival rats were sacrificed on day 30, and the hearts were prepared for the evaluation of collagen deposition (Masson's trichrome staining) and myocardial hypertrophy (wheat-germ agglutinin staining). RESULTS: In I/R group, there was a significant increase of CD172a(+);CD43(low); monocytes on day 1 compared with the baseline (P<0.05), followed by an increasing trend, which peaked on day 3 (P<0.01), and then underwent a gradual decreasing trend to the baseline on day 7. In sham group, a similar increasing trend of CD172a(+);CD43(low); monocytes was observed on day 1 (P<0.05) compared with the baseline, whereas this trend declined rapidly to the baseline level on day 3. The proportion of CD172a(+);CD43(low); in I/R group on day 3 was much higher than that in the sham group (P<0.01). There were no significant differences between the two groups at any other time points. A reciprocal change of CD172a(+);CD43(high); monocytes was observed during investigation. Cardiac pathological evaluation revealed that there was a significant reparative fibrosis in the infarct area (P<0.05) along with a significant myocardial hypertrophy in non-infarct area (P<0.01) in I/R group. Correlation analysis showed that the proportion of CD172a(+);CD43(low); monocytes on day 3, but not CD172a(+);CD43(high); monocytes, was positively correlated with the level of collagen deposition in the infarct area (r=0.86, P<0.05). CONCLUSION: The study demonstrates the dynamic profile of circulating monocyte subsets following myocardial I/R injury in rats, which indicates that the proinflammatory CD172a(+);CD43(low); monocytes might be a therapeutic target to attenuate myocardial I/R injury. PMID- 24491051 TI - [Preparation of recombinant adenovirus Ad5/F35 containing human WT1 and identification after recombinant adenovirus infected dendritic cells]. AB - OBJECTIVE: To construct recombinant adenovirus vector Ad5/F35 containing human WT1 (Wilms' tumor gene-1) and observe its expression in the dendritic cells (DCs) derived from the peripheral blood of patients with melanoma. METHODS: The two types of adenovirus vectors containing enhanced green fluorescence protein (EGFP), Ad5/F35-EGFP and Ad5-EGFP, were respectively infected into DCs. The EGFP expression was observed by fluorescent microscope. The adenovirus vector with the highest infection efficiency for the DCs was chosen to construct the recombinant adenoviral vector Ad5/F35-WT1, and WT1 expression in DCs was examined by immunohistochemistry and flow cytometry. RESULTS: Ad5/F35 adenovirus was the vector with the better infection efficiency. The recombinant adenovirus vector Ad5/F35-WT1 was successfully constructed with the infective titer of 1*10(8); IU/mL, which was proved effective in mediating the expression of WT1 in the DCs by immunohistochemistry and flow cytometry. CONCLUSION: The recombinant adenoviral vector Ad5/F35 containing human WT1 can transfer WT1 with effective expression into the DCs originally derived from the peripheral blood of patients with melanoma. PMID- 24491052 TI - [HIV-1gp120 injures neurons by alteration of neuronal expressions of NR2B and PSD 95]. AB - OBJECTIVE: To investigate the mechanisms underlying HIV-1 envelope glycoprotein 120 (gp120)-associated neurotoxicity on rat cortical neuronal cultures. METHODS: Experiments were carried out on primary cortical neuronal cultures prepared from fetal Sprague-Dawley fetal rats. Immunocytochemistry and Western blot techniques were employed to examine the changes of the expressions of N-methyl-D-asparate receptors 2B(NR2B) and postsynaptic density 95 (PSD-95) in cultured neurons in the presence and absence of gp120 in the culture media. Gp120-induced neurotoxicity was determined by MTT assay. RESULTS: MTT assay showed gp120 produced dose-dependent neuronal injury when added to the culture media and the gp120-induced neuronal injury was blocked by memantine, a specific NR2B receptor antagonist. Further studies revealed that gp120 induced neuronal injury by up regulation of NR2B and down-regulation of PSD-95 expressions in rat cortical neurons. CONCLUSION: These results demonstrated that gp120 injures neurons via an increase of NR2B and a decrease of PSD-95 expressions. The gp120-induced neuronal injury can be blocked by a specific NR2B receptor antagonist, suggesting NR2B may function as a potential target for the development of therapeutic strategies. PMID- 24491053 TI - [Honokiol inhibits the invasion and angiogenesis of U937 leukemia cells]. AB - OBJECTIVE: To investigate the inhibiting effect of Honokiol (HNK) on the invasion and angiogenesis in U937 leukemia cells and the molecular mechanism. METHODS: After treated with different concentrations of HNK, the growth inhibition rate of U937 cells was determined by MTT assay, and for the adhesion and invasion abilities were assessed using cell matrix adhesion technique and Transwell(TM); assay, respectively. VEGF, VEGFR1 and MMP-9 mRNA expression levels were detected by real-time quantitative RT-PCR (qRT-PCR). VEGF protein levels were determined by ELISA. RESULTS: HNK could significantly inhibit the proliferation of U937 cells in a time- and dose-dependent manner. The adhesion and invasion abilities of U937 cells were suppressed after treated with a low concentration of HNK. The expressions of VEGF, VEGFR1 and MMP-9 were down-regulated by HNK in a dose dependent manner. CONCLUSION: HNK can inhibit the invasion and angiogenesis of U937 cells via down-regulating VEGF, VEGFR1 and MMP-9 expressions. PMID- 24491054 TI - [Rosiglitazone inhibits human HepG2 cell proliferation via PI3K/PTEN/Akt signaling pathway]. AB - OBJECTIVE: To investigate the effects of rosiglitazone (ROZ) on proliferation and cell cycle of human hepatocellular carcinoma cell line HepG2 and explore the underlying mechanisms by detecting the related proteins. METHODS: After treated with ROZ of different concentrations, HepG2 cells were tested for the changes in the cell proliferation by MTT assay and in the cell cycle by flow cytometry. Western blotting and RT-PCR were performed to measure the expressions of PTEN, pAkt, S phase kinase associated protein 2 (Skp2) and P27(kip1); at protein and mRNA levels, respectively. RESULTS ROZ significantly inhibited HepG2 cell proliferation in a concentration-dependent and time-dependent manner (P<0.05). The proportion of HepG2 cells in G0/G1 phase increased, and that in S phase decreased significantly (P<0.05). ROZ reduced the expressions of pAkt and Skp2, and raised the expressions of PTEN and P27(kip1); in HepG2 cells (P<0.05). RT-PCR revealed that ROZ increased the expressions of PTEN mRNA, decreased the expressions of Skp2 mRNA, and had no effect on P27(kip1); mRNA. CONCLUSION: Our study demonstrated that ROZ could inhibit HepG2 cell proliferation and block G0/G1 phase, the mechanisms may be related to the regulation on the expressions of Skp2 and P27(kip1); through the PI3K/PTEN/Akt signaling pathway. PMID- 24491055 TI - [Protective effect of forsythiaside A on acute lung injure induced by lipopolysaccharide in mice]. AB - OBJECTIVE: To study the potential protective effect of monomer forsythiaside A (FA), a key component of traditional Chinese medicine, on acute lung injury induced by lipopolysaccharide (LPS) in mice and its possible mechanism. METHODS: The mouse model of acute lung injury was induced by LPS of 10 mg/kg, ip. The experiment was carried out in six groups: control group: without any treatment (n=8); acute lung injury model group: mice were given LPS at a dose of 10 mg/kg (n=8); antibody group: mice were given anti-TLR4/MD antibody (50 MUg/20 g body weight) 12 h before modeling (n=8); high-, medium- and low-dose FA groups: mice were respectively given FA at 80 mg/kg (n=8), 20 mg/kg (n=8) and 5 mg/kg (n=8). Mice in all FA treatment groups were given FA once a day till 7 days before modeling. Blood and lung tissue specimens were taken 4 h after modeling. Amount of endotoxin in plasma was measured by kinetic turbidimetric assay. Degree of lung damage was graded by HE staining. Expression of TLR4 at both mRNA and protein levels were measured by RT-PCR and Western blotting, respectively. Expressions of MyD88 and NF-kappaB were detected by immunohistochemistry. Content of TNF-alpha in serum was detected by ELISA. RESULTS: Compared with the control group, endotoxin and TNF-alpha in the model group significantly increased (P<0.01), with obvious pathological damages in lung tissue, such as thickened alveolar septum, hyperemia, edema and infiltration of a lot of neutrophils. Compared with the model group, FA groups presented significantly decreased endotoxin level (P<0.01), attenuated lung damages, down-regulated expressions of TLR4 mRNA and protein, MyD88 and NF-kappaB proteins in the lung (P<0.01), and significantly dropped TNF-alpha content in plasma (P<0.01). In addition, the protective effect of FA was dose dependent. CONCLUSION: FA has a protective effect on acute lung injury induced by LPS in mice. The mechanism may be related to the interference in LPS-TLR4-MyD88-NF-kappaB signaling pathway. PMID- 24491056 TI - [Effects of tanshinone IIA on the expressions of caspase-3, Akt and NF-kappaB in the brains of rat models of Alzheimer's disease]. AB - OBJECTIVE: To observe the effects of tanshinone IIA (Tan IIA) on the expressions of serine/threonine kinase Akt, nuclear factor kappaB (NF-kappaB) and caspase-3 in the brain tissues of rat models of Alzheimer's disease (AD). METHODS: Thirty male Sprague-Dawley rats were randomized into three groups (n=10 per group): Sham group, AD group, Tan IIA treatment group. The models of AD were established by injecting beta-amyloid (Abeta) into the hippocampus of rats. The location and expression level of Abeta1-16; was observed by immunofluorescence, the expression level of caspase-3 was detected by immunohistochemistry, and the expression levels of Akt and NF-kappaB were determined by immunohistochemistry and Western blotting. RESULTS: There was no Abeta1-16; detected in the control group, and the difference in the expression level of Abeta1-16; between AD group and Tan IIA treatment group was not significant statistically (P>0.05); The expression of Akt in AD group was lower than that in the control group and the Tan IIA treatment group, and the difference between AD group and the other two groups was of statistical significance (P<0.05). Conversely, compared with Tan IIA treatment group and sham group, the AD group was significantly higher in the expression levels of NF-kappaB and caspase-3 (P<0.05). CONCLUSION: Tan IIA can up-regulate the expression of Akt and inhibit the production of NF-kappaB and caspase-3 in the model rats with AD. PMID- 24491058 TI - [Expression of HPV16 E7 protein and preparation of its polyclonal antibody]. AB - OBJECTIVE: To prepare a prokaryotic expression vector carrying E7 protein of human papillomavirus (HPV) type 16 and a polyclonal antibody against it. METHODS: The HPV16 E7 gene was amplified by PCR from the tissue samples of cervical cancer and cloned into the pET21a(+) prokaryotic expression vector. The constructed pET21a(+)/HPV16 E7 recombinant plasmid was transformed into E.coli BL21(DE3) and induced by isopropyl beta-D-1-thiogalactopyranoside (IPTG). The recombinant protein of HPV16 E7 was purified by Ni-NTA affinity chromatography and confirmed by SDS-PAGE and Western blot analysis. To prepare the polyclonal antibody, the rabbits were immunized with the purified recombinant protein HPV16 E7. The titers of specific antibodies were detected by ELISA. The specificity activity was further detected by Western blotting and immunofluorescence analysis. RESULTS: HPV16 E7 recombinant protein was expressed and purified in the prokaryotic expression system. The polyclonal antibodies were produced in the rabbits immunized with the recombinant protein. The titer of specific antibodies was up to 1:30 000. Western blotting and immunofluorescence analysis indicated that the polyclonal antibody could specifically recognize the HPV16 E7 protein. CONCLUSION: HPV16 E7 recombinant protein was successfully expressed and its polyclonal antibody was prepared. PMID- 24491057 TI - [Dexamethasone induces PC12 cell apoptosis by down-regulating glucose uptake]. AB - OBJECTIVE: To observe the effects of dexamethasone (DEX) on rat PC12 chromaffin tumor cells and glucose uptake. METHODS: PC12 cells in vitro were randomized into normal control group, 10 and 100 MUmol/L DEX treated groups. MTT assay was used to determined the cell viability to evaluate the optimal concentration of DEX. Cell apoptosis was measured by DAPI fluorescence staining, mitochondrial membrane permeability transition pore (mPTP), activities of caspase-3 and caspase-9. Glucose oxidase and peroxidase (GOD-POD) assay was performed to detect the glucose consumption. Expression of glucose transporter 3 (GLUT-3) was detected by Western blotting. RESULTS: Compared with the control group, (10, 100) MUmol/L DEX significantly decreased cell vitality, caused apoptosis, and reduced the glucose uptake and GLUT-3 protein level (P<0.05). CONCLUSION: DEX can induce the apoptosis of PC12 cells, the mechanism of which may be related to inhibited GLUT 3 protein expression and glucose uptake. PMID- 24491059 TI - [Preparation of anti-HBsAg epitope monoclonal antibodies and establishment of a sandwich ELISA for HBV serotype detection]. AB - OBJECTIVE: To prepare the monoclonal antibodies against HBsAg epitopes and establish a sandwich ELISA system for HBV serotype detection. METHODS: The BALB/c mice were immunized with HBsAg subtype proteins. The hybridoma cells were cultured in serum-free medium after cell fusion and high throughput screening ELISA (HTS-ELISA). Monoclonal antibodies were purified with protein A. The specificity, affinity, isotype, and epitope of the mAbs were characterized respectively and the sandwich ELISA system was established. RESULTS: The titers of mouse anti-sera reached 1:10(5);. After the cell fusion and HTS-ELISA, the four hybridoma cell lines were obtained. The mAbs were purified and named #2-4, #18-23, #7-7, #56-71, respectively. The mAbs had a high affinity (over 10(9); L/mol). Indirect ELISA showed that #2-4, #18-23, #7-7 and #56-71 could recognize HBsAg "d, y, r, w" epitopes, respectively. The sandwich ELISA was established through using #3-11 (Anti-HBsAg "a" epitope) as the coating antibody while the HRP labeled mAb as the secondary antibody. The optimized sandwich ELISA was proved to have a good specificity by testing different antibody-antigen reactions. CONCLUSION: The mAbs against HBsAg epitopes we prepared had a good affinity and specificity. The sandwich ELISA for HBV serotype detection we established successfully provided a basis for HBV serotype detection and disease diagnosis. PMID- 24491060 TI - [Construction, expression and functional detection of fusion gene of CD80 extracellular region and anti-human CD33 scFv]. AB - OBJECTIVE: To construct and express the CD80 extracellular region-anti-human CD33 single chain fragment of variable region (ExCD80-CD33scFv) fusion gene, and detect the biological activity of the fusion protein. METHODS: Extracellular region of CD80 (ExCD80) was amplified and then linked with anti-CD33scFv using 403Aa-427Aa (hydrophilic fragments) in domain III of human serum albumin (HAS) as interlinker. The recombinant fusion gene was subcloned into the prokaryotic expression vector PET22b(+) and expressed in E.coli Rosetta (DE3) after induction by IPTG. The purified fusion protein was obtained after a series of purification steps including cell lysis, inclusion body solubilization, Ni(2+); metal affinity chromatography and protein refolding. The biological activity of the fusion protein was detected with indirect immunofluorescence technique. RESULTS: The ExCD80 (633bp) was amplified by PCR and 403aa-427aa from domain III of HAS as interlinker was synthesized correctly. SDS-PAGE and Western blotting demonstrated that ExCD80-CD33scFv fusion gene expression vector was successfully constructed and expressed in E.coli Rosetta (DE3). The relative molecular mass (Mr;) of the fusion protein was 55 000, which has human CD33-binding specificity after renaturation as shown by indirect immunofluorescence technique. CONCLUSION: Recombinant ExCD80-CD33scFv fusion gene was successfully constructed and expressed in E.coli Rosetta (DE3), which could provide a foundation for the future target therapy to the myeloid leukemia. PMID- 24491061 TI - [Correlation between DNA damage and EB virus infection in nasopharyngeal carcinoma]. AB - OBJECTIVE: To explore the correlation between the expression of phosphorylated histone H2AX (gamma-H2AX) and Epstein-Barr virus (EBV) infection in nasopharyngeal carcinoma (NPC) specimens, and to investigate the role and mechanism of EBV-induced DNA damage in NPC tumorigenesis and development in vitro. METHODS: We enrolled 50 cases of NPC and 20 cases of nasopharyngitis (NPI) specimens to test the expressions of gamma-H2AX and EBV latent membrane protein 1 (LMP1) by immunohistochemical method (IHC). And then in LMP1-negative samples, we detected the EBV-encoded RNA (EBER) using in situ hybridization. The gamma-H2AX level was detected in NPC cells CNE1 before and after EBV infection using Western blotting. RESULTS: gamma-H2AX was expressed in most NPC specimens (94%), which was much higher than that in NPI (40%), and EBV was presented in 94% of NPC but only 30% in NPI. Moreover, gamma-H2AX was positive in 97.9% of the EBV-positive specimens, which indicated the close correlation between gamma-H2AX expression and EBV infection (P<0.05). Finally, Western blotting showed that gamma-H2AX level significantly increased in CNE1 cells after EBV infection. CONCLUSION: This study demonstrated that an intimate connection existed between gamma-H2AX expression and EBV infection in NPC both in vivo and in vitro. EBV infection might induce DNA damage in CNE1 cells, which causes genome instability and initiates or promotes the tumorigenesis and development of NPC. PMID- 24491062 TI - [Correlation of HLA-DRB1 gene polymorphism and aplastic anemia in Xinjiang Han people]. AB - OBJECTIVE: To investigate the correlation between the human leukocyte antigen (HLA) DRB1 and the aplastic anemia (AA). METHODS: A total of 243 Han ethnic people in Xinjiang were enrolled for this study. Among them, 43 people were diagnosed as AA and the other 200 were healthy controls. All the blood samples of the 243 people were tested by polymerase chain reaction-sequence specific primer (PCR-SSP) DNA typing techniques. Then their allele frequencies were compared by the statistical analysis of x(2); test to study the correlation between the HLA DRB1 gene polymorphism and the AA in Xinjiang. RESULTS: The HLA-DRB1 allele frequency distributions in AA patients and healthy controls were similar, that was, DRB1*15 allele frequency was highest, while DRB1*4, DRB1*7, DRB1*9, DRB1*12 expressions were higher, and the lowest frequency was DRB1*17. The frequency of HLA-DRB1*8 allele in the AA group (13.73%) was significantly higher than that in healthy controls (6.99%) (OR=2.202, P<0.05). The frequency of HLA-DRB1*12, DRB1*14 alleles were lower in AA group than in healthy control group, but the difference was not statistically significant (P>0.05). However, compared with the healthy control group, the female AA patients had a lower frequency of HLA DRB1*12 allele (5.41% vs 10.00%, OR=0.2079, P<0.05) and the male AA cases had a lower HLA-DRB1*14 allele (2.11% vs 7.53%, OR=0.1403, P<0.05); The frequency of HLA-DRB1*15 allele in female AA patients was significantly higher than that in healthy control group (27.45% vs 14.56%, OR=2.433, P<0.05). CONCLUSION: The HLA DRB1*8 could be a susceptibility allele for AA. The HLA-DRB1*12 and the HLA DRB1*14 could be the antagonistic alleles for female and male AA patients, respectively. The HLA-DRB1*15 could be a susceptibility allele for the female AA patients. PMID- 24491063 TI - [Relationship between dendritic cell and microvessel density in clear cell renal cell carcinoma]. AB - OBJECTIVE: To investigate the relationship between the number and maturation of dendritic cell (DC) and microvessel density (MVD) in clear cell renal cell carcinoma (CCRCC). METHODS: CCRCC paraffin-embedded tissues and surrounding normal tissues were collected from 30 cases of CCRCC who underwent operations in No. 307 hospital of PLA during July, 2010 to January, 2013. Immunohistochemistry was used to detect the expressions of CD11c, MHC-II, and CD34 to analyze the relationship among them. RESULTS: The positive expression rate of CD11c in CCRCC tissues [(93.08+/-66.14)%] was higher than that in the surrounding tissues [(25.91+/-12.29)%]. MVD in CCRCC tissues (26.31+/-11.05) was significantly higher than that in the surrounding tissues (12.78+/-5.49). The permillage of MHC-II positive DC in CCRCC tissues [(9.65+/-3.61)%] was significantly lower than that in the surrounding tissues [(17.60+/-6.26)%]. There was a negative correlation between the MVD value and the expression of MHC-II; there was no correlation between the MVD and the expression of CD11c. Positive expressions of various indicators in CCRCC tissues were not related to patients' age, sex, and TNM classification. CONCLUSION: In CCRCC tissues, there were higher MVD and more DCs than in the surrounding tissues, yet there were less mature DCs. There was a negative correlation between the MVD and the maturation of DC. PMID- 24491064 TI - [A fast method for preparing the mouse germ cell slides]. AB - OBJECTIVE: To establish a new method of fast preparation of mouse germ cell slides for immunofluorescence assay. METHODS: Mice of different developing stages (at postnatal days 16, 21, 28 and 120) were treated with colchicine by intraperitoneal injection respectively, and 3 hours later, the testes were taken out and the tunica albuginea were removed. The seminiferous tubules were separated and minced into small pieces, resuspended with ice-cold PBS, and the cells were filtered and collected by centrifugation. After washed with ice-cold PBS for three times, the cells were treated with a hypotonic solution, fixed with 4% paraformaldehyde, and finally mounted onto the slides. To test the slide quality, the cells mounted on the slides were stained with DAPI, and immunofluorescence staining was performed using 21-day-old mouse slides. RESULTS: Stained with DAPI, the distribution of various germ cells was observed on each slide by the new method and the background was clear. According to the size and color of the cell nucleus, the types of germ cells could be recognized preliminarily. The types of germ cells on the slides were very different among 16 , 21-, 28- and 120-day-old mice, of which the slides from 28-day-old mice had the most types of germ cells. Immunofluorescence staining using 21-day-old mice slides revealed that the red- and green-fluorescence labeled target proteins were observed in spermatocytes, and the background was clear, suggesting the slides were suitable for immunofluorescence detection. CONCLUSION: A new method of fast preparing the mouse germ cell slides was successfully established, providing a foundation for the study on the process of spermatogenesis. PMID- 24491065 TI - Physical fitness training in Subacute Stroke (PHYS-STROKE)--study protocol for a randomised controlled trial. AB - BACKGROUND: Given the rising number of strokes worldwide, and the large number of individuals left with disabilities after stroke, novel strategies to reduce disability, increase functions in the motor and the cognitive domains, and improve quality of life are of major importance. Physical activity is a promising intervention to address these challenges but, as yet, there is no study demonstrating definite outcomes. Our objective is to assess whether additional treatment in the form of physical fitness-based training for patients early after stroke will provide benefits in terms of functional outcomes, in particular gait speed and the Barthel Index (co-primary outcome measures) reflecting activities of daily living (ADL). We will gather secondary functional outcomes as well as mechanistic parameters in an exploratory approach. METHODS/DESIGN: Our phase III randomised controlled trial will recruit 215 adults with moderate to severe limitations of walking and ADL 5 to 45 days after stroke onset. Participants will be stratified for the prognostic variables of "centre", "age", and "stroke severity", and randomly assigned to one of two groups. The interventional group receives physical fitness training delivered as supported or unsupported treadmill training (cardiovascular active aerobic training; five times per week, over 4 weeks; each session 50 minutes; total of 20 additional physical fitness training sessions) in addition to standard rehabilitation treatment. The control intervention consists of relaxation sessions (non-cardiovascular active; five times per week week, over 4 weeks; each session 50 minutes) in addition to standard rehabilitation treatment. Co-primary efficacy endpoints will be gait speed (in m/s, 10 m walk) and the Barthel Index (100 points total) at 3 months post-stroke, compared to baseline measurements. Secondary outcomes include standard measures of quality of life, sleep and mood, cognition, arm function, maximal oxygen uptake, and cardiovascular risk factors including blood pressure, pulse, waist-to-hip ratio, markers of inflammation, immunity and the insulin glucose pathway, lipid profile, and others. DISCUSSION: The goal of this endpoint blinded, phase III randomised controlled trial is to provide evidence to guide post-stroke physical fitness-based rehabilitation programmes, and to elucidate the mechanisms underlying this intervention. TRIAL REGISTRATION: Registered in ClinicalTrials.gov with the Identifier NCT01953549. PMID- 24491066 TI - Loss aversion and hypoxia: less loss aversion in oxygen-depleted environment. AB - Hypoxia, the deprivation of adequate oxygen supply, constitutes a direct threat to survival by disrupting cardiovascular or respiratory homeostasis and eliciting a respiratory distress. Although hypoxia has been shown to increase brain vulnerability and impair basic cognitive functions, only one study has examined its effect on decision-making. The present study examined the effect of mild hypoxia on individual's loss aversion, that is, the tendency to be more affected by losses than equal sized gains. A sample of 26 participants were asked to either accept or reject a series of mixed gambles once in an oxygen-depleted environment (14.1% oxygen concentration) and once in a normoxic environment (20.9% oxygen concentration). Each gamble involved a 50-50 chance of winning or losing specified amounts of money. Mild hypoxia decreased loss aversion: on average in the normoxic condition participants accepted gambles if the gain was at least 2.4 times as large as the loss, whereas in the oxygen-depleted condition participants accepted gambles if the gain was at least 1.7 times as large as the loss. Mild hypoxia may push individuals to be less cautious in daily decisions that involve a trade-off between a gain and a loss. PMID- 24491067 TI - Beyond weight reduction: improvements in quality of life after an intensive lifestyle intervention in subjects with severe obesity. AB - INTRODUCTION: We examined the effects of 10-14 weeks of inpatient intensive lifestyle intervention (ILI), including a minimum of 90 minutes of adapted physical activity 5 days/week, with regard to changes in quality of life and associations with weight loss in subjects with severe obesity. METHODS: A total of 100 severely obese subjects (BMI 42.6 +/- 5.3 kg/m(2); 42.7 +/- 10.6 years) were included. Quality of life was assessed by Binge Eating Scale, Hospital Anxiety, and Depression Scale, and SF- 36. The ILI group completed the questionnaires at inclusion, after 10-14 weeks and 12 months, and controls at inclusion and after 10-14 weeks. RESULTS: Compared to controls, self-reported binge eating (-6.4, P < 0.0001), anxiety (-1.7, P = 0.005), and depression (-3.0, P < 0.0001) were reduced, and physical (8.0, P < 0.0001) and mental (7.6, P < 0.0001) health increased in the ILI group. After 12 months, reduction in self reported binge eating (-7.2, P < 0.0001) and depression (-3.4, P < 0.0001) and increase in physical (8.9, P < 0.0001) and mental (3.6, P = 0.035) health were maintained. Decreased self-reported binge eating (beta = 0.555, P = 0.010) and increased physical health (beta = -0.554, P = 0.003) were associated with weight loss. CONCLUSION: ILI including a high volume of physical activity in subjects with severe obesity improved quality of life by favorable changes in self reported binge eating, depression, and mental and physical health. Improvements in binge eating and physical health were associated with weight loss. PMID- 24491068 TI - Small molecule inhibitors in the treatment of cerebral ischemia. AB - INTRODUCTION: Stroke is the world's second leading cause of death. Although recombinant tissue plasminogen activator is an effective treatment for cerebral ischemia, its limitations and ischemic stroke's complex pathophysiology dictate an increased need for the development of new therapeutic interventions. Small molecule inhibitors (SMIs) have the potential to be used as novel therapeutic modalities for stroke, since many preclinical and clinical trials have established their neuroprotective capabilities. AREAS COVERED: This paper provides a summary of the pathophysiology of stroke as well as clinical and preclinical evaluations of SMIs as therapeutic interventions for cerebral ischemia. Cerebral ischemia is broken down into four mechanisms in this article: thrombosis, ischemic insult, mitochondrial injury and immune response. Insight is provided into preclinical and current clinical assessments of SMIs targeting each mechanism as well as a summary of reported results. EXPERT OPINION: Many studies demonstrated that pre- or post-treatment with certain SMIs significantly ameliorated adverse effects from stroke. Although some of these promising SMIs moved on to clinical trials, they generally failed, possibly due to the poor translation of preclinical to clinical experiments. Yet, there are many steps being taken to improve the quality of experimental research and translation to clinical trials. PMID- 24491069 TI - Sequenced versus coordinated treatment for adolescents with comorbid depressive and substance use disorders. AB - OBJECTIVE: We evaluated 3 methods of integrating interventions for depression (Adolescent Coping With Depression Course; CWD) and substance use disorders (Functional Family Therapy; FFT), examining (a) treatment sequence effects on substance use and depression outcomes and (b) whether the presence of major depressive disorder (MDD) moderated effects. METHOD: Participants were 170 adolescents (ages 13-18; 22% female; 61% non-Hispanic White) with comorbid depressive disorder (54% MDD, 18% dysthymia) and substance use disorders who were randomized to (a) FFT followed by CWD (FFT/CWD), (b) CWD followed by FFT (CWD/FFT), or (c) coordinated FFT and CWD (CT). Acute treatment (24 treatment sessions provided over 20 weeks) and 6- and 12-month follow-up effects are presented for substance use (percentage of days of substance use; Timeline Followback) and depression (Children's Depression Rating Scale-Revised). RESULTS: FFT/CWD achieved better substance use outcomes than CT at posttreatment, and 6- and 12-month follow-ups; substance use effects for CWD/FFT were intermediate. For participants with baseline MDD, the CWD/FFT sequence resulted in lower substance use than either FFT/CWD or CT. Depressive symptoms decreased significantly in all 3 treatment sequences with no evidence of differential effectiveness during or following treatment. Attendance was lower for the second of both sequenced interventions. A large proportion of the sample received treatment outside the study, which predicted better outcomes in the follow-up. CONCLUSIONS: Depression reductions occurred early in all 3 treatment sequences. Of the examined treatment sequences, FFT/CWD appeared most efficacious for substance use reductions but addressing depression early in treatment may improve substance use outcomes in the presence of MDD. PMID- 24491070 TI - Emergency department predictors of posttraumatic stress reduction for trauma exposed individuals with and without an early intervention. AB - OBJECTIVE: Recent data have supported the use of an early exposure intervention to promote a reduction in acute stress and posttraumatic stress disorder (PTSD) symptoms after trauma exposure. The present study explored a comprehensive predictive model that included history of trauma exposure, dissociation at the time of the trauma and early intervention, and physiological responses (cortisol and heart rate) to determine which variables were most indicative of reduced PTSD symptoms for an early intervention or treatment as usual. METHOD: Participants (n = 137) were randomly assigned to the early intervention condition (n = 68) or assessment-only condition (n = 69) while receiving care at the emergency department of a Level 1 trauma center. Follow-up assessments occurred at 4 and 12 weeks posttrauma. RESULTS: Findings suggested that dissociation at the time of the 1st treatment session was associated with reduced response to the early intervention. No other predictors were associated with treatment response. For treatment as usual, cortisol levels at the time of acute care and dissociation at the time of the traumatic event were positively associated with PTSD symptoms. CONCLUSIONS: Dissociation at the time at which treatment starts may indicate poorer response to early intervention for PTSD. Similarly, dissociation at the time of the event was positively related to PTSD symptoms in those who received treatment as usual. PMID- 24491071 TI - Analyzing multiple outcomes in clinical research using multivariate multilevel models. AB - OBJECTIVE: Multilevel models have become a standard data analysis approach in intervention research. Although the vast majority of intervention studies involve multiple outcome measures, few studies use multivariate analysis methods. The authors discuss multivariate extensions to the multilevel model that can be used by psychotherapy researchers. METHOD AND RESULTS: Using simulated longitudinal treatment data, the authors show how multivariate models extend common univariate growth models and how the multivariate model can be used to examine multivariate hypotheses involving fixed effects (e.g., does the size of the treatment effect differ across outcomes?) and random effects (e.g., is change in one outcome related to change in the other?). An online supplemental appendix provides annotated computer code and simulated example data for implementing a multivariate model. CONCLUSIONS: Multivariate multilevel models are flexible, powerful models that can enhance clinical research. PMID- 24491072 TI - Randomized controlled trial of a Spring Break intervention to reduce high-risk drinking. AB - OBJECTIVE: Although recent studies have documented high-risk drinking occurring during Spring Break (SB), particularly on SB trips with friends, published intervention studies are few. In the present study, we evaluated the efficacy of event specific prevention strategies for reducing SB drinking among college students, compared to general prevention strategies and an assessment-only control group, as well as evaluated inclusion of peers in interventions and mode of intervention delivery (in-person vs. web). METHOD: Participants included 783 undergraduates (56.1% women; average age = 20.5 years) intending to go on a SB trip with friends as well as to drink heavily on at least 1 day of SB. Participants completed assessments prior to SB and were randomized to 1 of 5 intervention conditions: SB in-person Brief Alcohol Screening and Intervention for College Students (BASICS; Dimeff, Baer, Kivlahan, & Marlatt, 1999), SB web BASICS, SB in-person BASICS with friend, SB web BASICS with friend, general BASICS, or an attention control condition. Follow-up assessment was completed 1 week after SB. RESULTS: Although the SB web BASICS (with and without friends) and general BASICS interventions were not effective at reducing SB drinking, results indicated significant intervention effects for SB in-person BASICS in reducing SB drinking, particularly on trip days. Follow-up analyses indicated that change in descriptive norms mediated treatment effect and reductions in drinking, whereas SB drinking intentions and positive expectancies did not. CONCLUSIONS: Overall, results suggest that an in-person SB-specific intervention is effective at reducing SB drinking, especially during trips. In contrast, interventions that contain non-SB-related content, are web-based, or seek to involve friends may be less effective at reducing SB drinking. PMID- 24491073 TI - Extreme response style and symptom return after depression treatment: the role of positive extreme responding. AB - OBJECTIVE: Evidence linking extreme response style (ER) to depressive relapse has been mixed. One reason might be high levels of extreme responses that are positive in nature (ER-Ps) compared with those negative in nature (ER-Ns) at posttreatment. ER-Ps likely consist of both maladaptive "style" responses and adaptive "content" responses (i.e., legitimate denials of dysfunction). The composition of ER-Ps might confound measures of total extreme responding as well as conventional scores on cognitive questionnaires. In the current study, we assessed ER in a new sample by (a) disambiguating ER-Ps that reflect style from those that reflect content and (b) assessing the contribution of ER-Ps to the prediction of relapse/recurrence. METHOD: Responders (N = 104) to a randomized controlled trial of cognitive therapy versus medications for moderate to severe depression had an average age of 40 years (SD = 12), and they were 58% female, 38% married/cohabitating, and 85% Caucasian. ER variables were calculated using the Dysfunctional Attitudes Scale (DAS; Weissman, 1979), with ER-Ps categorized as either content or style responses. ER indices and DAS scores were used to predict symptom return over 2 years. RESULTS: No standard extreme responding variables (e.g., an index of total extreme responding) predicted symptom return, but higher relative levels of style ER-P predicted relapse/recurrence. Total DAS scores also predicted relapse/recurrence but only when high levels of style ER-P responses were controlled. CONCLUSIONS: ER-Ps, at least on the DAS, appear to contain indicators of both adaptive and maladaptive positive responses. Future research should attend to the valence of the extreme responses as well as to the content of extreme positive responses, which may reflect either healthy or unhealthy tendencies. PMID- 24491074 TI - Randomized controlled trial of a friendship skills intervention on adolescent depressive symptoms. AB - OBJECTIVE: The Resourceful Adolescent Program (RAP) is a universal, school-based intervention that has been found to produce small to medium effects in the reduction of adolescent depressive symptoms. In the present study, we evaluated the effectiveness of a friendship-building skills program--the Peer Interpersonal Relatedness (PIR) program--in producing larger effects when used in conjunction with RAP. METHOD: A cluster-randomized controlled trial was used to assign whole classrooms of adolescent participants recruited from Sydney secondary schools to 1 of 3 conditions: (a) RAP-PIR, (b) RAP-placebo, or (c) assessment-only waiting list control. Hierarchical linear modeling (HLM) was used to analyze the data. RESULTS: Across the intervention period, RAP did not significantly reduce depressive symptoms relative to those students not receiving this intervention. RAP followed by PIR did significantly reduce depressive symptoms relative to those students not receiving PIR. Across the 12-month follow-up, the between group reductions in depressive symptoms were no longer significant. At follow-up, participants in the RAP-PIR condition had achieved significant increases in their school-related life satisfaction and significant increases in social functioning with peers relative to their peers in the other conditions. CONCLUSION: The study provides preliminary support for the effectiveness of the PIR program in reducing depressive symptoms when used alongside RAP in the short term and in improving social adjustment and school-related life satisfaction in the longer term. Given the importance of social adjustment in adolescent mental well-being, the PIR program represents a potentially important addition to the prevention of depression in youth. PMID- 24491076 TI - Randomized controlled trial of a web-delivered personalized normative feedback intervention to reduce alcohol-related risky sexual behavior among college students. AB - OBJECTIVE: The purpose of this study was to evaluate the efficacy of personalized normative feedback (PNF) on college student alcohol-related risky sexual behavior (RSB). METHOD: In a randomized controlled trial, 480 (57.6% female) sexually active college students were stratified by gender and level of drinking and randomly assigned to an alcohol-only intervention, an alcohol-related RSB-only intervention, a combined alcohol and alcohol-related RSB intervention, or control. All assessment and intervention procedures were Web-based. RESULTS: Results indicated a significant reduction in drinking outcomes for the alcohol only and the combined alcohol and alcohol-related RSB interventions relative to control. Findings further demonstrated a significant reduction in alcohol-related RSB outcomes for the alcohol-related RSB only and the combined alcohol and alcohol-related RSB interventions relative to control. There were no significant intervention effects on alcohol-related negative consequences. These findings demonstrate that the combined alcohol and alcohol-related RSB intervention was the only intervention successful at reducing both drinking and alcohol-related RSB outcomes relative to control. There were no significant differences when comparing the combined alcohol and alcohol-related RSB intervention to the alcohol-only intervention or the alcohol-related RSB-only intervention. Finally, results suggested that the intervention effects on high-risk behaviors were mediated by reductions in descriptive normative perceptions. CONCLUSIONS: These findings demonstrate that PNF specific to drinking in sexual situations was needed to reduce alcohol-related RSB. Furthermore, this study highlights the potential utility of a brief intervention that can be delivered via the Internet to reduce high-risk drinking and alcohol-related RSB among college students. PMID- 24491075 TI - Mindfulness-oriented recovery enhancement for chronic pain and prescription opioid misuse: results from an early-stage randomized controlled trial. AB - OBJECTIVE: Opioid pharmacotherapy is now the leading treatment for chronic pain, a problem that affects nearly one third of the U.S. population. Given the dramatic rise in prescription opioid misuse and opioid-related mortality, novel behavioral interventions are needed. The purpose of this study was to conduct an early-stage randomized controlled trial of Mindfulness-Oriented Recovery Enhancement (MORE), a multimodal intervention designed to simultaneously target mechanisms underpinning chronic pain and opioid misuse. METHOD: Chronic pain patients (N = 115; mean age = 48 +/- 14 years; 68% female) were randomized to 8 weeks of MORE or a support group (SG). Outcomes were measured at pre- and posttreatment, and at 3-month follow-up. The Brief Pain Inventory was used to assess changes in pain severity and interference. Changes in opioid use disorder status were measured by the Current Opioid Misuse Measure. Desire for opioids, stress, nonreactivity, reinterpretation of pain sensations, and reappraisal were also evaluated. RESULTS: MORE participants reported significantly greater reductions in pain severity (p = .038) and interference (p = .003) than SG participants, which were maintained by 3-month follow-up and mediated by increased nonreactivity and reinterpretation of pain sensations. Compared with SG participants, participants in MORE evidenced significantly less stress arousal (p = .034) and desire for opioids (p = .027), and were significantly more likely to no longer meet criteria for opioid use disorder immediately following treatment (p = .05); however, these effects were not sustained at follow-up. CONCLUSIONS: Findings demonstrate preliminary feasibility and efficacy of MORE as a treatment for co-occurring prescription opioid misuse and chronic pain. (PsycINFO Database Record (c) 2014 APA, all rights reserved). PMID- 24491078 TI - Stepped care in the treatment of trichotillomania. AB - OBJECTIVE: There are effective treatments of trichotillomania (TTM), but access to expert providers is limited. This study tested a stepped care model aimed at improving access. METHOD: Participants were 60 (95% women, 75% Caucasian, 2% Hispanic) adults (M = 33.18 years) with TTM. They were randomly assigned to immediate versus waitlist (WL) conditions for Step 1 (10 weeks of web-based self help via StopPulling.com). After Step 1, participants chose whether to engage in Step 2 (8 sessions of in-person habit reversal training [HRT]). RESULTS: In Step 1, the immediate condition had a small (d = .21) but significant advantage, relative to WL, in reducing TTM symptom ratings by interviewers (masked to experimental condition but not to assessment point); there were no differences in self-reported TTM symptoms, alopecia, functional impairment, or quality of life. Step 1 was more effective for those who used the site more often. Stepped care was highly acceptable: Motivation did not decrease during Step 1; treatment satisfaction was high, and 76% enrolled in Step 2. More symptomatic patients self selected into HRT, and on average they improved significantly. Over one third (36%) made clinically significant improvement in self-reported TTM symptoms. Considering the entire stepped care program, participants significantly reduced symptoms, alopecia, and impairment, and increased quality of life. For quality of life and symptom severity, there was some relapse by 3-month follow-up. CONCLUSIONS: Stepped care is acceptable, and HRT was associated with improvement. Further work is needed to determine which patients with TTM can benefit from self help and how to reduce relapse. PMID- 24491077 TI - Social problem solving among depressed adolescents is enhanced by structured psychotherapies. AB - OBJECTIVE: Changes in adolescent interpersonal behavior before and after an acute course of psychotherapy were investigated as outcomes and mediators of remission status in a previously described treatment study of depressed adolescents. Maternal depressive symptoms were examined as moderators of the association between psychotherapy condition and changes in adolescents' interpersonal behavior. METHOD: Adolescents (n = 63, mean age = 15.6 years, 77.8% female, 84.1% White) engaged in videotaped interactions with their mothers before randomization to cognitive behavior therapy (CBT), systemic behavior family therapy (SBFT), or nondirective supportive therapy (NST) and after 12-16 weeks of treatment. Adolescent involvement, problem solving, and dyadic conflict were examined. RESULTS: Improvements in adolescent problem solving were significantly associated with CBT and SBFT. Maternal depressive symptoms moderated the effect of CBT, but not SBFT, on adolescents' problem solving; adolescents experienced increases in problem solving only when their mothers had low or moderate levels of depressive symptoms. Improvements in adolescents' problem solving were associated with higher rates of remission across treatment conditions, but there were no significant indirect effects of SBFT on remission status through problem solving. Exploratory analyses revealed a significant indirect effect of CBT on remission status through changes in adolescent problem solving, but only when maternal depressive symptoms at study entry were low. CONCLUSIONS: Findings provide preliminary support for problem solving as an active treatment component of structured psychotherapies for depressed adolescents and suggest one pathway by which maternal depression may disrupt treatment efficacy for depressed adolescents treated with CBT. PMID- 24491079 TI - A brief psychological intervention that reduces adolescent alcohol consumption. AB - OBJECTIVE: Alcohol consumption in adolescence is associated with problem drinking in later life, and there is a need to develop evidence-based interventions to reduce adolescent alcohol consumption. The aims of the present study were to test the ability of a very brief intervention based on self-affirmation theory to reduce alcohol consumption in a sample of adolescents and to examine potential mediators of the effects. METHOD: 67 adolescents were randomly allocated either to form a self-affirming implementation intention or to complete a distractor task. All participants were exposed to a threatening message concerning the health risks of alcohol consumption. The main outcome measure was subsequent alcohol intake, but message processing (operationalized as perceived threat and message derogation), behavioral intention, and self-efficacy were also measured as potential mediators. RESULTS: The intervention produced a significant decrease in alcohol consumption: Participants in the self-affirming implementation intention condition consumed 2.48 fewer grams of pure alcohol per day at the end of the study than adolescents who completed the distractor task. The effect was not mediated by perceived threat, message derogation, behavioral intention, or self-efficacy. CONCLUSIONS: The findings provide support for the efficacy of the self-affirming implementation intention for promoting health behavior change and extend previous research by testing an adolescent sample and observing longer term effects. Further research is needed to find out what mediates the effects of self-affirming implementation intentions on health behavior change. PMID- 24491080 TI - Expression and activation of toll-like receptor 3 and toll-like receptor 4 on human corneal epithelial and conjunctival fibroblasts. AB - BACKGROUND: Toll-like receptors (TLRs) are recognized as important contributors to the initiation and modulation of the inflammatory response in the eye. This study investigated the precise expression patterns and functionality of TLRs in human corneal epithelial cells (HCE) and in conjunctival fibroblasts (HCF). METHODS: The cell surface expression of TLRs 2-4, TLR7 and TLR9 in HCE and HCF was examined by flow cytometry with or without stimulation with lipopolysaccharide (LPS) or polyinosinic:polycytidylic acid (poly I:C). The mRNA expression of the TLRs was determined by real-time PCR. The protein content levels of interleukin (IL)-6, IL-8, IL-1beta and tumor necrosis factor-alpha (TNF alpha) were measured in HCE and HCF using multiplex fluorescent bead immunoassay (FBI). RESULTS: The surface expression of TLR3 and TLR4 was detected on both HCE and HCF. Following incubation with LPS, the percentage of HCE cells staining for TLR4 decreased from 10.18% to 0.62% (P < 0.001). Incubation with poly I:C lowered the percentage of HCE cells positive for TLR3 from 10.44% to 2.84% (P < 0.001). The mRNA expression of TLRs2, 4, 7 and 9 was detected in HCE only. Activation of HCE with LPS complex elicited protein secretion up to 4.51 +/- 0.85-fold higher levels of IL-6 (P < 0.05), 2.5 +/- 0.36-fold IL-8 (P > 0.05), 4.35 +/- 1.12-fold IL-1beta (P > 0.05) and 29.35 +/- 2.3-fold TNFalpha (P < 0.05) compared to cells incubated in medium. CONCLUSIONS: HCF and HCE both express TLRs that respond to specific ligands by increasing cytokine expression. Following activation, the surface expression of TLR3 and TLR4 on HCE is decreased, thus creating a negative feedback loop, mitigating the effect of TLR activation. PMID- 24491082 TI - Controlling melanoma at local and systemic levels: is a combination of ablative therapy and immunotherapy the way forward? PMID- 24491083 TI - Should we be moving from suppression to stimulation to deal with immunoparalysis in sepsis patients? PMID- 24491084 TI - Vaccines against neglected tropical diseases: promising interventions to rescue the poorest populations in the Americas. PMID- 24491081 TI - Predictors of long-term change of a physical activity promotion programme in primary care. AB - BACKGROUND: Further research is needed to improve the evidence regarding determinants of physical activity (PA) as a crucial step to plan higher effective intervention strategies. The goal of the present study is to identify socio demographic and clinical characteristics of primary care (PHC) insufficiently active patients that are associated with longitudinal changes in the level of physical activity. METHODS: Longitudinal analysis of baseline socio-demographic and clinical predictors of physical activity change in insufficiently active PHC patients who participated in a PA-promoting multi-centre randomized clinical trial conducted from October 2003 through March 2006. The primary outcome measure was the self-reported physical activity assessed with the 7-day Physical Activity Recall (PAR), at baseline, 6, 12 and 24 months. Baseline covariates included sex, age, social class, anthropometric measures and other cardiovascular risk factors or associated diseases (Diabetes, HTA, tobacco use, etc.), and stage of readiness to change PA. Generalized linear mixed models were used to estimate longitudinal association of studied variables on PA change over the three follow-up measurements. RESULTS: A total of 3691 patients (85% of the 4317 recruited in the trial) with at least one follow-up measurement were included in the longitudinal analysis. At baseline, analysed patients (mean age: 50.6 years; 64.6% women) devoted 34.7 minutes and 2.36 metabolic equivalent hours per week (MET.h/week) to moderate and vigorous physical activity. Older age, male gender, higher social class, lower BMI, diagnosis of diabetes or hypertension, and measurement season were significant predictors of PA longitudinal change. The effect of baseline readiness to change on PA dose was modified by time, showing a positive gradient in favour of those with more readiness to change that increases significantly at 12 and 24 months (p-value interaction < .0001). CONCLUSIONS: Identified baseline characteristics such as readiness to change and risk factors can guide physicians to prioritize time and intervention efforts for maximizing their impact on insufficiently active PHC patients. PMID- 24491086 TI - Interview: experiences targeting B cells for the treatment of multiple sclerosis. PMID- 24491087 TI - Influenza vaccination in immunocompromised patients: efficacy and safety. AB - Yearly administration of the influenza vaccine is the main strategy to prevent influenza in immunocompromised patients. Here, we reviewed the recent literature regarding the clinical significance of the influenza virus infection, as well as the immunogenicity and safety of the influenza vaccine in HIV-infected individuals, solid-organ and stem-cell transplant recipients and patients receiving biological agents. Epidemiological data produced during the 2009 influenza pandemic have confirmed that immunocompromised patients remain at high risk of influenza-associated complications, namely viral and bacterial pneumonia, hospitalization and even death. The immunogenicity of the influenza vaccine is overall reduced in immunocompromised patients, although a significant clinical protection from influenza is expected to be obtained with vaccination. Influenza vaccination is safe in immunocompromised patients. The efficacy of novel strategies to improve the immunogenicity to the vaccine, such as the use of adjuvanted vaccines, boosting doses and intradermal vaccination, needs to be validated in appropriately powered clinical trials. PMID- 24491088 TI - Immunotherapy targeting alpha-synuclein, with relevance for future treatment of Parkinson's disease and other Lewy body disorders. AB - Immunotherapy targeting alpha-synuclein has evolved as a potential therapeutic strategy for neurodegenerative diseases, such as Parkinson's disease, and initial studies on cellular and animal models have shown promising results. alpha synuclein vaccination of transgenic mice reduced the number of brain inclusions, whereas passive immunization studies demonstrated that antibodies against the C terminus of alpha-synuclein can pass the blood-brain barrier and affect the pathology. In addition, preliminary evidence suggests that transgenic mice treated with an antibody directed against alpha-synuclein oligomers/protofibrils resulted in reduced levels of such species in the CNS. The underlying mechanisms of immunotherapy are not yet fully understood, but may include antibody-mediated clearance of pre-existing aggregates, prevention of protein propagation between cells and microglia-dependent protein clearance. Thus, immunotherapy targeting alpha-synuclein holds promise, but needs to be further developed as a future disease-modifying treatment in Parkinson's disease and other alpha synucleinopathies. PMID- 24491089 TI - Antigen-specific therapy against type 1 diabetes: mechanisms and perspectives. AB - Type 1 diabetes (T1D) is an immune-mediated disease that occurs when the insulin producing beta-cells of the pancreatic islets are destroyed by an inflammatory process perpetuated by cells of the immune system. The logical approach to suppress T1D is to inactivate or eliminate the lymphocytes responsible for inducing inflammation and targeting the beta-cells. Antigen-specific approaches have been devised and were able to target inflammatory lymphocytes and induce apoptosis or block trafficking to pancreatic islets. Lack of costimulation, expansion of Tregs and bystander suppression are likely mechanisms by which antigen-specific treatments modulate pathogenic T cells. This strategy, however, while prevents the onset of T1D, could not overcome overt T1D, perhaps because of collateral damage to the islet vascular network. Recent developments indicate that donor endothelial stem cell precursors can repair the islets' vascular niche and assist antigen-specific therapy against overt T1D. PMID- 24491090 TI - Cancer-testis genes as candidates for immunotherapy in breast cancer. AB - Cancer-testis (CT) antigens are tumor-associated antigens attracting immunologists for their possible application in the immunotherapy of cancer. Several clinical trials have assessed their therapeutic potentials in cancer patients. Breast cancers, especially triple-negative cancers are among those with significant expression of CT genes. Identification of CT genes with high expression in cancer patients is the prerequisite for any immunotherapeutic approach. CT genes have gained attention not only for immunotherapy of cancer patients, but also for immunoprevention in high-risk individuals. Many CT genes have proved to be immunogenic in breast cancer patients suggesting the basis for the development of polyvalent vaccines. PMID- 24491092 TI - Emerging immunotherapy strategies in breast cancer. AB - Although immunogenicity is typically associated with renal cell carcinomas and melanoma, there are several compelling reasons why immune-based therapies should be explored in breast cancer. First, breast cancers express multiple putative tumor-associated antigens, such as HER-2 and MUC-1, which have been the successful focus of vaccine development over the past decade, translating into tumor-specific immune responses and, in some cases, clinical benefit. Second, passive immune strategies with anti-HER-2 antibodies, such as trastuzumab and pertuzumab, have led to survival benefits in breast cancer. Finally, the successes observed with novel immunotherapeutic strategies, such as immune checkpoint blockade and adoptive T-cell therapies in other malignancies, combined with a growing body of literature that supports an interplay between solid tumors and the immune system, indicate that these strategies have the potential to revolutionize the treatment of breast cancer. PMID- 24491091 TI - Immunosuppression following heart transplantation: prospects and challenges. AB - Immunosuppression after heart transplantation has significantly reduced the incidence of cellular rejection and improved patient outcomes with the routine use of calcineurin inhibitors. Antimetabolites and proliferation signal inhibitors add to the improvement in patient outcomes, particularly with respect to the reduced burden of cardiac allograft vasculopathy. Patients with antibody sensitization are potentially at higher risk of postoperative complications. Sensitized patients are undergoing heart transplantation with increased frequency, in part due to the emergence of ventricular assist device use as a bridge to heart transplantation. Despite improvements in immunosuppressive therapies, many challenges face physicians and patients, which will further refine and improve care of the post-heart transplant patient. PMID- 24491093 TI - The use of monoclonal antibodies to treat Castleman's disease. AB - Multicentric Castleman's disease (MCD) is a rare lymphoproliferative disorder presenting with heterogeneous clinical features and with a complex etiology. MCD incidence is increased in people living with HIV/AIDS when it is causally associated with Kaposi's sarcoma-associated herpes virus (KSHV). HIV-seronegative individuals present with either idiopathic or KSHV-associated MCD. Central to MCD pathology is altered expression and signaling of IL-6, which promotes B-cell proliferation and causes systemic manifestations. KSHV encodes a viral homolog of human IL-6, accounting for its role in MCD, while recent evidence shows an association between IL-6 receptor polymorphisms and idiopathic MCD. The increased understanding of mechanisms underlying the pathogenesis of MCD has guided the use of new monoclonal antibody therapies for treating this complex disorder. PMID- 24491094 TI - The complete mitochondrial genome of the common cutworm, Spodoptera litura (Lepidoptera: Noctuidade). AB - The complete mitochondrial genome (mitogenome) of Spodoptera litura (Lepidoptera: Noctuidae) was determined to be 15,374 bp (GenBank accession No. KF543065), including 13 protein-coding genes (PCGs), two rRNA genes, 22 tRNA genes and an A + T-rich region. It has the typical gene organization and order of mitogenomes from lepidopteran insects. The AT skew of this mitogenome was slightly positive and the nucleotide composition was also biased toward A + T nucleotides (81.03%). All PCGs were initiated by ATN codons, except for cytochrome c oxidase subunit 1 (cox1) gene which was initiated by CGA. Four of the 13 PCGs harbor the incomplete termination codon by T. All the tRNA genes displayed a typical clover-leaf structure of mitochondrial tRNA, with the exception of trnS1 (AGN). The A + T rich region of the mitogenome was 326 bp in length. PMID- 24491095 TI - Single nucleotide polymorphisms in the mitochondrial displacement loop region and outcome of malignant fibrous histiocytoma. AB - PURPOSE: Single nucleotide polymorphisms (SNPs) in the mitochondrial DNA displacement-loop (D-loop) region have been reported to be associated with cancer risk and disease outcome in several types of cancer. In this study, we investigated whether the SNPs in mitochondrial D-loop were associated with the outcome of malignant fibrous histiocytoma (MFH). EXPERIMENTAL DESIGN: The D-loop region of mtDNA was sequenced for 80 MFH patients. The 3 years survival curve were calculated with the Kaplan-Meier method and compared by the log-rank test at each SNP site, a multivariate survival analysis was also performed with the Cox proportional hazards method. RESULTS: The SNP sites of nucleotides 152T/C, 16,390G/A, 16,290C/T, 16,304T/C and the AC deletion at sites 523 and 524 were identified for prediction of post-operational survival by the log-rank test. In an overall multivariate analysis, the 16,290 and 16,390 alleles were identified as independent predictors of MFH outcome. The length of survival for patients with the rare allele 16,390A genotype was significantly shorter than that for patients with the frequent allele 16,390Gat the site 16,390. The same was seen for the rare allele 16,290T genotype when compared with matched allele 16,290C at the site 16,290 in MFH patients. CONCLUSIONS: These results suggested that SNPs in the D-loop are independent prognostic markers for patients with MFH. The analysis of genetic polymorphisms in the D-loop can help identify patient subgroups at higher risk of a poor disease outcome. PMID- 24491096 TI - The complete mitochondrial genome of the scuttle fly, Megaselia scalaris (Diptera: Phoridae). AB - More than 1400 scuttle flies species in worldwide comprise the Megaselia genus, the largest genus in the family Phoridae. The complete mitochondrial genome of Megaselia scalaris, a medically important entomology was sequenced for the first time. The 15,599 bp circular genome contains the 37 genes found in a typical Metazoan genome: 13 protein-coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. The mitochondrial genome also contains one non-coding A + T-rich region. The arrangement of the genes was identical with other insect. Each of the base composition on heavy strand was as follows A: 38.87%, G: 13.74%, C: 9.46%, T: 37.93% and the A + T content 76.80%. The mitochondrial genome of M. scalaris presented may be valuable for determining phylogenetic relationships within the order Diptera and especially for the family Phoridae. These sequences could also be used to select reliable molecular markers for species identification in forensic entomology. PMID- 24491097 TI - The complete mitochondrial genome of a cyprinid fish; Metzia longinasus (Teleostei, Cypriniformes). AB - The long polymerase chain reaction and primer walking method were applied for the sequencing of the complete mitochondrial genome sequence of a cyprinid species (Metzia longinasus) collected from the Hongshuihe River of the Pearl River drainage, Guangxi Province in China. It is 16,614 bp in length, containing 2 rRNA, 22 tRNA, 13 protein-coding genes and 1 control region generally found in most vertebrates. Most of the mitochondrial genes are encoded on the heavy strand except for eight tRNA and ND6 genes. The base composition of this genome was 31.9% A, 26.2%C, 26.2%T and 15.7%G, showing a lower level of G (15.7%) and a slighter AT bias (58.1%). This is the 2nd completely sequenced mitogenome from genus Metzia. The mtDNA sequence of M. longinasus shared 93% sequence similarity with that of M. formosae and it could contribute to a better solution of its phylogenetic position within cyprinid fishes based on the complete mitogenomic data. PMID- 24491098 TI - Phylogeny and genetic structure of Tunisians and their position within Mediterranean populations. AB - Tunisia is located at the crossroads of Europe, the Middle East and Sub-Saharan Africa. This position might lead to numerous waves of migrations, contributing to the current genetic landscape of Tunisians. In this study, we analyzed 815 mitochondrial DNA (mtDNA) sequences from Tunisia in order to characterize the mitochondrial DNA genetic structure of this region, to construct the processes for its composition and to compare it to other Mediterranean populations. To that end, additional 4206 mtDNA sequences were compiled from previous studies performed in African (1237), Near Eastern (231) and European (2738) populations. Both phylogenetic and statistical analyses were performed. This study confirmed the mosaic genetic structure of the Tunisian population with the predominance of the Eurasian lineages, followed by the Sub-Saharan and North African lineages. Among Tunisians, the highest haplogroup and haplotype diversity were observed in particular in the Capital Tunis. No significant differentiation was observed between both geographical (Northern versus Southern Tunisia) and different ethnic groups in Tunisia. Our results highlight the presence of outliers and most frequent unique sequences in Tunisia (10.2%) compared to 45 Mediterranean populations. Phylogenetic analysis showed that the majority of Tunisian localities were closer to North Africans and Near Eastern populations than to Europeans. The exception was found for Berbers from Jerba which are clustered with Sardinians and Valencians. PMID- 24491099 TI - The complete mitochondrial genome of the Huang Lang chicken. AB - Huang Lang chicken is the native breed of Hunan province in China. The complete mitochondrial (mt) genome sequence plays an important role in the accurate determination of phylogenetic relationships among metazoans. It is the first time that the complete mt genome sequence of the Huang Lang chicken was reported in this work, which was determined through the polymerase chain reaction-based method. The total length of the mitogenome is 16,786 bp, with the base composition of 30.25% for A, 23.71% for T, 32.53% for C and 13.51% for G, in the order C > A > T > G feature occurs in the Huang Lang chicken. It contains the typical structure, including two ribosomal RNA genes, 13 protein-coding genes, 22 transfer RNA genes and 1 non-coding control region (D-loop region). The complete mt genome sequence of the Huang Lang chicken provided an important data for further study on the genetic mechanism. PMID- 24491100 TI - DNA barcoding revises a misidentification on musk deer. AB - As an endangered animal group in China, musk deer (genus Moschus) have attracted the attention of deer biologists and wildlife conservationists. Clarifying the taxonomic status and distribution of musk deer species is important to determine the conservation status for each species and establish appropriate conservation strategies. There remains some uncertainty about the species determination of the musk deer in the Guandi Forest District of Shanxi Province, China. The musk deer in Shanxi would appear to represent an extension of the geographical distribution of either the Forest Musk Deer from the southwest or the Siberian Musk Deer from the northeast, or possibly both. The musk deer population in Shanxi Province provides an interesting and significant case to test the value of applying molecular methods to make a genetic species identification. In order to clarify the species status of the Shanxi musk deer, we sequenced 627 bp of the COI gene and ~723 bp of the D-loop gene in 12 musk deer samples collected from the Guandi Forest District, and the two reference samples collected from Sichuan. Genetic analyses from the data suggest that all of the samples from the Guandi Forest District are M. berezovskii rather than M. moschiferus. It is most likely that the most previous studies had wrong species identification. And it is the first time we use DNA barcoding to prove that Shanxi is a new distribution of M. berezovskii. PMID- 24491101 TI - Mitochondrial ATPase 6/8 genes to infer the population genetic structure of silver pomfret fish Pampus argenteus along the Indian waters. AB - Silver pomfret, Pampus argenteus is an economically important seafood species. The fishery resource of pomfret in Indian waters shows a dwindling catch since the last few years and the pomfrets caught were mostly undersized which calls for immediate attempts for management of resources. An accurate definition of population structure is important for management of this species. The genetic stock structure of P. argenteus distributed along Indian coast was identified using analysis of 842 bp of complete ATPase 6/8 genes of mitochondrial DNA. Altogether, 83 silver pomfret (P. argenteus) collected from 4 locations along Indian coast (Gujarat, Kerala, Tamil Nadu and West Bengal) were sequenced. Twenty four haplotypes were identified among 83 individuals with haplotype diversity (0.87) and nucleotide diversity (0.0025). The significant pair-wise FST and AMOVA values, between samples from West Bengal (east coast) and other locations along the west coast (Gujarat and Kerala) indicated the occurrence of distinct population structure in silver pomfret along the coast. PMID- 24491102 TI - Molecular phylogenetics of the glass frog Hyalinobatrachium orientale (Anura: Centrolenidae): evidence for Pliocene connections between mainland Venezuela and the island of Tobago. AB - The presence of Hyalinobatrachium orientale in Tobago and in northeastern Venezuela is puzzling as this species is unknown from the island of Trinidad, an island often hypothesized to be a stepping-stone for the mainland fauna to colonize Tobago. A period of extended isolation on Tobago could result in the Hyalinobatrachium population becoming distinct from the mainland H. orientale. Here, we use 12S and 16S rDNA gene fragments from nine H. orientale specimens from Tobago and the mainland to assess their relationship and taxonomy, as well as the tempo and mode of speciation. The results suggest H. orientale from Venezuela and Tobago are monophyletic and the two populations diverged about 3 million years ago. This estimate corresponds with the drier climate and lower sea levels of the Pliocene glaciation periods. We hypothesize that lower sea levels resulted in land-bridge formations connecting the mainland and Tobago, with a corridor of habitat allowing H. orientale to colonize Tobago to the west of Trinidad. PMID- 24491103 TI - The complete mitochondrial genome of natural Cobitis elongatoides (Cypriniformes: Cobitidae). AB - Cobitis elongatoides is a small sized freshwater fish species that is widely distributed in Europe, especially in Croatia. In this study, the complete mitochondrial genome of C. elongatoides is sequenced to be 16,540 bp in length, including 13 protein-coding genes, 2 ribosomal RNAs, 22 transfer RNAs, a control region and the origin of the light strand replication. The overall base composition of C. elongatoides in descending order is A 29.37%, T 28.53%, C 25.34%, and G 16.76%, with a slight A + T bias. The mitogenome sequence data may provide useful information to the population genetics analysis of C. elongatoides and the elucidation of evolutionary mechanisms in Cobitidae. PMID- 24491104 TI - Simple sequence repeats in bryophyte mitochondrial genomes. AB - Simple sequence repeats (SSRs) are thought to be common in plant mitochondrial (mt) genomes, but have yet to be fully described for bryophytes. We screened the mt genomes of two liverworts (Marchantia polymorpha and Pleurozia purpurea), two mosses (Physcomitrella patens and Anomodon rugelii) and two hornworts (Phaeoceros laevis and Nothoceros aenigmaticus), and detected 475 SSRs. Some SSRs are found conserved during the evolution, among which except one exists in both liverworts and mosses, all others are shared only by the two liverworts, mosses or hornworts. SSRs are known as DNA tracts having high mutation rates; however, according to our observations, they still can evolve slowly. The conservativeness of these SSRs suggests that they are under strong selection and could play critical roles in maintaining the gene functions. PMID- 24491105 TI - The complete mitochondrial genome of Mekongiella kingdoni (Uvarov, 1937) (Orthoptera: Acridoidea: Chrotogonidae). AB - The complete mitochondrial genome of Mekongiella kingdoni, which was collected from the Tibetan Plateau, is determined here. It is 15,932 bp in length and contains 73.1% AT. All M. kingdoni protein-coding sequences except for the cox1 start with a typical ATN codon. Instead, CCG, which is a rare but possible initiation codon, is located at the initiation context of cox1. The usual termination codons (TAA and TAG) and incomplete stop codons (TA or T) are found from 13 PCGs. All tRNA genes can be folded into the typical cloverleaf secondary structure, except trnS(AGN) due to the lacking of dihydrouridine arm. The sizes of the large and small ribosomal RNA genes are 1313 and 837 bp, respectively. The AT content of the A + T-rich region is 78.4%. PMID- 24491106 TI - The complete mitochondrial genome of the longhorn beetle, Massicus raddei. AB - We sequenced the complete mitochondrial genome of Massicus raddei, which is the first beetle sequenced in Cerambycinae to date. The complete mitochondrial genome is 15,585 bp in length with an A + T content of 71.82%, and contains 13 protein coding genes, 2 rRNAs, 22 tRNAs and a control region. The gene order and orientation are similar to that of typical insect species. These data will provide useful molecular information for phylogenetic relationships among the suborders of Coleoptera. By using 13 protein-coding genes as phylogenetic markers, the results support that the suborder Archostemata is a sister group to the remaining beetles and the most primitive suborder in any case; the suborder Myxophaga is sister to the suborder Adephaga. PMID- 24491107 TI - Phylogeographical structure in mitochondrial DNA of eggplant fruit and shoot borer, Leucinodes orbonalis Guenee (Lepidoptera: Crambidae) in South and Southeast Asia. AB - Leucinodes orbonalis is the most detrimental South and Southeast Asian insect pest of eggplant. To help reduce the impact of this pest, population genetic diversity and structure of L. orbonalis were examined in eight populations from six countries using mitochondrial cytochrome c oxidase subunit I DNA sequences. No correlation between genetic diversity and geographic distance was detected among populations. Low levels of haplotype and nucleotide diversities were observed in the Philippines population, suggesting recent colonization. No significant gene flow was found among local populations in different countries. The Vietnam population is highly differentiated, indicated by significant pairwise FST values, and may be ascribed to a new subspecies or race. India was confirmed to be the source of genetic variation in L. orbonalis populations. Our study showed that L. orbonalis formed subpopulations for each local region, and the corresponding pest management technology should be developed at the country scale. PMID- 24491108 TI - Is mitochondrial tRNA(Ser(UCN)) T7501C mutation associated with cardiovascular disease? AB - Mitochondrial DNA mutations are increasingly recognized as an important cause of cardiovascular diseases, point mutations in mitochondrial tRNA genes being the largest group among them. Most recently, mutation at position 7501 in mt tRNA(Ser(UCN)) gene has been reported to be associated with human cardiovascular diseases including cardiomyopathy, sudden cardiac death (SCD) and Tetralogy of Fallot (TOF). However, its direct pathogenic role remained poorly understood. In this study, we performed an extensive web-based search for the published resources concerning this association. Through the application of bioinformatics tool, we observed that this mutation altered the mt-tRNA(Ser(UCN)) secondary structure, in addition, evolutionary conservation analysis of this mutation indicated that this mutation is highly conserved between different species. Notably, the T7501C mutation belonging to human mitochondrial haplogroup U8a1a1, a rare subgroup of U8, was present only in European population and was absent in Han Chinese population. Taken together, our result indicated that the T7501C mutation may occur infrequently and was probably pathogenic in cardiovascular disease development. PMID- 24491109 TI - Commonly asked questions: imaging stroke and other types of neurovascular disorders. AB - The medical management of patients requiring imaging of the head is often complex. This is confounded by growth and development of neuroimaging technology. Summarizing established guidelines and provided answers to commonly asked questions about neurovascular imaging may aid in providing efficient medical care. Noncontrast head computed tomography (CT) is usually the first line in imaging because of its speed and wide-spread availability. More advanced techniques are reserved for more specific questions or when the CT head is non diagnostic. MRI is the modality of choice for indications that include chronic headache, pulsatile tinnitus, and cerebrovascular diseases including stroke in the subacute or chronic setting. The imaging of stroke is evolving and many advanced techniques including CT and magnetic resonance perfusion are playing an increasing role in diagnosis. Digital subtraction angiography is widely accepted as the gold standard for evaluation of vascular pathology including aneurysm, vascular malformations, Moyamoya syndrome, carotid stenosis and dissection; and offers treatment options. Alternatives such as MR angiography, MR venography, and CT angiography offer similar sensitivity and specificity to conventional digital subtraction angiography. Safety considerations are an important concern. When using iodinated and gadolinium contrast agents, there are potential complications including allergic reactions, lactic acidosis, and nephrogenic systemic fibrosis. Impaired renal function requires modification in the use of contrast during neuroimaging. Neuroimaging during pregnancy is also discussed. PMID- 24491110 TI - The New Phytologist Tansley Medals 2013. PMID- 24491111 TI - Connecting stomatal development and physiology. PMID- 24491112 TI - Deep thoughts on ectomycorrhizal fungal communities. PMID- 24491114 TI - Geographical and environmental gradients shape phenotypic trait variation and genetic structure in Populus trichocarpa. AB - * Populus trichocarpa is widespread across western North America spanning extensive variation in photoperiod, growing season and climate. We investigated trait variation in P. trichocarpa using over 2000 trees from a common garden at Vancouver, Canada, representing replicate plantings of 461 genotypes originating from 136 provenance localities. * We measured 40 traits encompassing phenological events, biomass accumulation, growth rates, and leaf, isotope and gas exchange based ecophysiology traits. With replicated plantings and 29,354 single nucleotide polymorphisms (SNPs) from 3518 genes, we estimated both broad-sense trait heritability (H(2)) and overall population genetic structure from principal component analysis. * Populus trichocarpa had high phenotypic variation and moderate/high H(2) for many traits. H(2) ranged from 0.3 to 0.9 in phenology, 0.3 to 0.8 in biomass and 0.1 to 0.8 in ecophysiology traits. Most traits correlated strongly with latitude, maximum daylength and temperature of tree origin, but not necessarily with elevation, precipitation or heat : moisture indices. Trait H(2) values reflected trait correlation strength with geoclimate variables. The population genetic structure had one significant principal component (PC1) which correlated with daylength and showed enrichment for genes relating to circadian rhythm and photoperiod. * Robust relationships between traits, population structure and geoclimate in P. trichocarpa reflect patterns which suggest that range-wide geographical and environment gradients have shaped its genotypic and phenotypic variability. PMID- 24491113 TI - OsPT2, a phosphate transporter, is involved in the active uptake of selenite in rice. AB - * Selenite is a predominant form of selenium (Se) available to plants, especially in anaerobic soils, but the molecular mechanism of selenite uptake by plants is not well understood. * ltn1, a rice mutant previously shown to have increased phosphate (Pi) uptake, was found to exhibit higher selenite uptake than the wild type in both concentration- and time-dependent selenite uptake assays. Respiratory inhibitors significantly inhibited selenite uptake in the wildtype and the ltn1 mutant, indicating that selenite uptake was coupled with H(+) and energy-dependent. Selenite uptake was greatly enhanced under Pi-starvation conditions, suggesting that Pi transporters are involved in selenite uptake. * OsPT2, the most abundantly expressed Pi transporter in the roots, is also significantly up-regulated in ltn1 and dramatically induced by Pi starvation. OsPT2-overexpressing and knockdown plants displayed significantly increased and decreased rates of selenite uptake, respectively, suggesting that OsPT2 plays a crucial role in selenite uptake. Se content in rice grains also increased significantly in OsPT2-overexpressing plants. * These data strongly demonstrate that selenite and Pi share similar uptake mechanisms and that OsPT2 is involved in selenite uptake, which provides a potential strategy for breeding Se-enriched rice varieties. PMID- 24491115 TI - The grapevine flagellin receptor VvFLS2 differentially recognizes flagellin derived epitopes from the endophytic growth-promoting bacterium Burkholderia phytofirmans and plant pathogenic bacteria. AB - * The role of flagellin perception in the context of plant beneficial bacteria still remains unclear. Here, we characterized the flagellin sensing system flg22 FLAGELLIN SENSING 2 (FLS2) in grapevine, and analyzed the flagellin perception in the interaction with the endophytic plant growth-promoting rhizobacterium (PGPR) Burkholderia phytofirmans. * The functionality of the grapevine FLS2 receptor, VvFLS2, was demonstrated by complementation assays in the Arabidopsis thaliana fls2 mutant, which restored flg22-induced H2O2 production and growth inhibition. Using synthetic flg22 peptides from different bacterial origins, we compared recognition specificities between VvFLS2 and AtFLS2. * In grapevine, flg22 triggered immune responses are conserved and led to partial resistance against Botrytis cinerea. Unlike flg22 peptides derived from Pseudomonas aeruginosa or Xanthomonas campestris, flg22 peptide derived from B. phytofirmans triggered only a small oxidative burst, weak and transient defense gene induction and no growth inhibition in grapevine. Although, in Arabidopsis, all the flg22 epitopes exhibited similar biological activities, the expression of VvFLS2 into the fls2 background conferred differential flg22 responses characteristic for grapevine. * These results demonstrate that VvFLS2 differentially recognizes flg22 from different bacteria, and suggest that flagellin from the beneficial PGPR B. phytofirmans has evolved to evade this grapevine immune recognition system. PMID- 24491117 TI - Observational study of perioperative behavior changes in children having teeth extracted under general anesthesia. AB - BACKGROUND: Perioperative behavioral disturbance is common in children. Negative behavior changes may be seen during induction of anesthesia, during recovery and following discharge home. There has been little research on this subject in the UK. OBJECTIVES: The aim of this study was to determine the incidence of behavioral changes within our institution and identify which children are at increased risk. METHODS: A prospective observational study of healthy children aged two to 12 undergoing elective dental extractions under general anesthesia. Assessments included: the child's and parent's state anxiety; anxiety and behavior during induction of anesthesia (modified Yale preoperative anxiety scale and the pediatric anesthesia behavior score); behavior in PACU (pediatric anesthesia emergence delirium [PAED] scale); behavior at home on postoperative days 1 and 7 (post hospitalization behavior questionnaire). Data were examined for associations and correlations. RESULTS: One hundred and two children with a median age of 6 years were recruited. Sixty-seven per cent exhibited high anxiety during induction of anesthesia, although only 3% demonstrated significant vocal or physical resistance. Thirteen per cent had a PAED score of 10 or more. Post hospitalization behavior changes were demonstrated by 52% of children on day 1 and 22% on day 7; and were associated with: a previous traumatic healthcare experience, male sex, and distress during induction of anesthesia. CONCLUSIONS: Perioperative behavioral disturbance is common in children undergoing anesthesia. Predicting which children are at increased risk may allow us to adapt the management of these children in order to minimize adverse behavior changes. PMID- 24491116 TI - RuBPCase activase (RCA) mediates growth-defense trade-offs: silencing RCA redirects jasmonic acid (JA) flux from JA-isoleucine to methyl jasmonate (MeJA) to attenuate induced defense responses in Nicotiana attenuata. AB - * RuBPCase activase (RCA), an abundant photosynthetic protein, is strongly down regulated in response to Manduca sexta's oral secretion (OS) in Nicotiana attenuata. RCA-silenced plants are impaired not only in photosynthetic capacity and growth, but also in jasmonic acid-isoleucine (JA-Ile) signaling, and herbivore resistance mediated by JA-Ile-dependent defense traits. These responses are consistent with a resource-based growth-defense trade-off. * As JA + Ile supplementation of OS restored wild-type (WT) levels of JA-Ile, defenses and resistance to M. sexta, but OS supplemented individually with JA or Ile did not, the JA-Ile deficiency of RCA-silenced plants could not be attributed to lower JA or Ile pools or JAR4/6 conjugating activity. Similar levels of JA-Ile derivatives after OS elicitation indicated unaltered JA-Ile turnover, and lower levels of other JA conjugates ruled out competition from other conjugation reactions. * RCA silenced plants accumulated more methyl jasmonate (MeJA) after OS elicitation, which corresponded to increased jasmonate methyltransferase (JMT) activity. RCA silencing phenocopies JMT overexpression, wherein elevated JMT activity redirects OS-elicited JA flux towards inactive MeJA, creating a JA sink which depletes JA Ile and its associated defense responses. * Hence, RCA plays an additional non photosynthetic role in attenuating JA-mediated defenses and their associated costs, potentially allowing plants to anticipate resource-based constraints on growth before they actually occur. PMID- 24491119 TI - Predictors of hospital surface contamination with Extended-spectrum beta lactamase-producing Escherichia coli and Klebsiella pneumoniae: patient and organism factors. AB - BACKGROUND: The role of the hospital environment in transmission of ESBL Klebsiella pneumoniae (ESBL-KP) and ESBL-Escherichia coli (ESBL-EC) is poorly defined. Recent data however suggest that in the hospital setting, ESBL-KP is more transmissible than ESBL-EC. We sought therefore to measure the difference in hospital contamination rates between the two species and to identify key risk factors for contamination of the hospital environment with these organisms. METHODS: We systematically sampled 8 surfaces in the rooms and bathrooms of adult patients colonized or infected with ESBL-EC or ESBL-KP throughout their hospital stay. Data were collected on factors potentially affecting contamination rates. Environmental contamination was defined as recovery of an ESBL-producing organism matching the source patient's isolate. Multivariate logistic regression analysis was performed at the level of the patient visit using generalized estimating equations to identify independent predictors of environmental contamination. RESULTS: 24 patients (11 with ESBL-KP, 11 ESBL-EC and 2 with both organisms) had 1104 swabs collected during 138 visits. The overall contamination rate was 3.4% (38/1104) and was significantly higher for ESBL-KP than ESBL-EC (5.4% versus 0.4%; p < 0.0001). After multivariate analysis, environmental contamination was found to be negatively associated with carbapenem exposure (OR 0.06 [95% CI 0.01 0.61]; p = 0.017) and positively associated with the presence of an indwelling urinary catheter (OR 6.12 [95% CI 1.23-30.37]; p = 0.027) and ESBL-KP in the source patient (OR 26.23 [95% CI 2.70-254.67]; p = 0.005). CONCLUSIONS: Contamination of the hospital environment with ESBL-producing Enterobacteriaceae (ESBL-E) is inversely associated with carbapenem exposure. Predictors of hospital contamination with ESBL-E include: indwelling urinary catheters and ESBL-KP. Rooms of patients with ESBL-KP have substantially higher contamination rates than those with ESBL-EC. This finding may help explain the apparently higher transmissibility of ESBL-KP in the hospital setting. PMID- 24491120 TI - Effects of single nucleotide polymorphism marker density on degree of genetic variance explained and genomic evaluation for carcass traits in Japanese Black beef cattle. AB - BACKGROUND: Japanese Black cattle are a beef breed whose meat is well known to excel in meat quality, especially in marbling, and whose effective population size is relatively low in Japan. Unlike dairy cattle, the accuracy of genomic evaluation (GE) for carcass traits in beef cattle, including this breed, has been poorly studied. For carcass weight and marbling score in the breed, as well as the extent of whole genome linkage disequilibrium (LD), the effects of equally spaced single nucleotide polymorphisms (SNPs) density on genomic relationship matrix (G matrix), genetic variance explained and GE were investigated using the genotype data of about 40,000 SNPs and two statistical models. RESULTS: Using all pairs of two adjacent SNPs in the whole SNP set, the means of LD (r2) at ranges 0 0.1, 0.1-0.2, 0.2-0.5 and 0.5-1 Mb were 0.22, 0.13, 0.10 and 0.08, respectively, and 25.7, 13.9, 10.4 and 6.4% of the r2 values exceeded 0.3, respectively. While about 90% of the genetic variance for carcass weight estimated using all available SNPs was explained using 4,000-6,000 SNPs, the corresponding percentage for marbling score was consistently lower. With the conventional linear model incorporating the G matrix, correlation between the genomic estimated breeding values (GEBVs) obtained using 4,000 SNPs and all available SNPs was 0.99 for carcass weight and 0.98 for marbling score, with an underestimation of the former GEBVs, especially for marbling score. CONCLUSIONS: The Japanese Black is likely to be in a breed group with a relatively high extent of whole genome LD. The results indicated that the degree of marbling is controlled by only QTLs with relatively small effects, compared with carcass weight, and that using at least 4,000 equally-spaced SNPs, there is a possibility of ranking animals genetically for these carcass traits in this breed. PMID- 24491121 TI - Carbon isotope ratio analysis of steroids by high-temperature liquid chromatography-isotope ratio mass spectrometry. AB - Generally, compound-specific isotope analysis of steroids is carried out by gas chromatography combined with isotope ratio mass spectrometry. Thus, a derivatization of the steroids prior to the measurement is compulsory, and a correction of the isotopic data is often necessary. To overcome this limitation, we present a new approach of high-temperature liquid chromatography coupled with photodiode array detection and isotope ratio mass spectrometry (HT-LC/PDA/IRMS) for the carbon isotope ratio analysis of unconjugated steroids. A steroid mixture containing 19-norandrosterone, testosterone, epitestosterone, androsterone, and 5beta-pregnane-3alpha,17alpha,20alpha-triol was fully separated on a C4 column under high-temperature elution with water as the sole eluent. The accuracy for isotope analysis (+/-0.5 0/00) was around 20 MUg g(-1) for testosterone, epitestosterone (79 ng steroid absolute on column), and 30 MUg g(-1) for 19 norandrosterone, androsterone, and 5beta-pregnane-3alpha,17alpha,20alpha-triol (119 ng steroid absolute on column). The applicability of the method was tested by measuring a pharmaceutical gel containing testosterone. With this work, the scope of LC/IRMS applications has been extended to nonpolar compounds. PMID- 24491122 TI - Mesalazine-probiotics beads for acetic acid experimental colitis: formulation and characterization of a promising new therapeutic strategy for ulcerative colitis. AB - BACKGROUND: Acetic acid ulcerative colitis (UC) is an experimental condition created due to intra-rectal administration of acetic acid which causes inflammation and ulceration in the lining of colon and rectum. In such condition, the colon cannot absorb liquid from the stools, resulting in larger volume of watery stools. Mesalazine is mainly used for the treatment of UC but suffers from the drawback of having poor bioavailability. UC is also characterized by alteration in colonic microflora. The present work was focused on delivering mesalazine along with probiotic, which would facilitate to refurbish customary growth of microflora. Mesalazine and probiotic were encapsulated in pectin beads with an aim to protect the drug from gastric environment and target to colonic region. METHODS: Pectin beads were prepared, formulation process was optimized for polymer concentration, drug concentration, cross-linking agent concentration. Formulation was characterized for surface morphology, in vitro drug release studies, determination of viable cell count, in vivo ulcer protective studies and stability studies. RESULTS: Average particle diameter of beads was ~1.44-1.72 mm. Drug entrapment efficiency was found to be optimal (78-79%). A sustained release of drug was observed for 5 h; nearly 60% of drug was released at the end of 10 h. Microbiological studies of probiotic showed best cell viability. In acetic acid induced UC model, Mesalazine-probiotic beads-treated group showed significant (p < 0.01) ulcer protection index with respect to free drug-treated group. CONCLUSION: In conclusion, mesalazine-probiotic loaded beads may serve as a useful colon specific drug delivery system for treatment of colitis. PMID- 24491123 TI - The biopsychosocial model of stress in adolescence: self-awareness of performance versus stress reactivity. AB - Extensive research among adults supports the biopsychosocial (BPS) model of challenge and threat, which describes relationships among stress appraisals, physiological stress reactivity, and performance; however, no previous studies have examined these relationships in adolescents. Perceptions of stressors as well as physiological reactivity to stress increase during adolescence, highlighting the importance of understanding the relationships among stress appraisals, physiological reactivity, and performance during this developmental period. In this study, 79 adolescent participants reported on stress appraisals before and after a Trier Social Stress Test in which they performed a speech task. Physiological stress reactivity was defined by changes in cardiac output and total peripheral resistance from a baseline rest period to the speech task, and performance on the speech was coded using an objective rating system. We observed in adolescents only two relationships found in past adult research on the BPS model variables: (1) pre-task stress appraisal predicted post-task stress appraisal and (2) performance predicted post-task stress appraisal. Physiological reactivity during the speech was unrelated to pre- and post-task stress appraisals and to performance. We conclude that the lack of association between post-task stress appraisal and physiological stress reactivity suggests that adolescents might have low self-awareness of physiological emotional arousal. Our findings further suggest that adolescent stress appraisals are based largely on their performance during stressful situations. Developmental implications of this potential lack of awareness of one's physiological and emotional state during adolescence are discussed. PMID- 24491124 TI - Spectroscopic study of firefly oxyluciferin in an enzymatic environment on the basis of stability monitoring. AB - To understand the influence of the enzyme microenvironment on the properties of the emitter oxyluciferin (OL) in firefly bioluminescence, we investigated the spectroscopic characteristics of OL in a complex with the enzyme luciferase formed in a consumed reaction mixture. By monitoring the in situ absorption spectra, we analyzed the enzymatic synthesis and the stability of OL in luciferase environment. The absorption spectra of OL in Photinus pyralis luciferase showed that the dominant form was neutral OL, probably the enol form, which emitted blue fluorescence (~450 nm). A monoanionic OL emitting green fluorescence (~560 nm) exhibited a weak pH-dependent equilibrium with the neutral enol-OL. The red-emitting form of OL was almost completely absent from the consumed reaction mixture. The peak wavelengths of the green and red emissions of the fluorescence and bioluminescence were similar, but the peak intensities, and hence the spectral shapes, differed greatly. The above characteristics were also found in the absorption and fluorescence spectra of OL in a complex with the H433Y mutant of Luciola cruciata luciferase, which catalyzes pH-independent red bioluminescence. Optical excitation could not reproduce the excited states of bioluminescence that was generated from the chemical reaction. The probable reason is that the chemical excited states formed from a keto-like transition state after decomposition of a dioxetanone intermediate, whereas the optical excited states were generated by exciting the neutral enol-OL. Different luciferases only influenced the chemical transition state during the bioluminescence reaction; they did not influence the ground states or optical excited states after the reaction. PMID- 24491125 TI - Brave new world: mental health experiences of Puerto Ricans, immigrant Latinos, and Brazilians in Massachusetts. AB - Depression and anxiety are of the most commonly occurring mental health disorders in the United States. Despite a variety of efficacious interventions for depression and anxiety, it is clear that ethnic minorities experience mental health care disparities in their access to mental health services and the quality of treatment they receive. Research indicates that Latino heterogeneity impacts access to depression and anxiety treatment. In addition, Brazilians are becoming an increasingly visible minority within the United States and are often depicted as Latinos. The current study sought to understand the role of acculturation and stigma in mental health symptom endorsement and treatment seeking among Puerto Ricans, immigrant Latinos, and Brazilians. A total of 250 self-identified Latinos and Brazilians were interviewed about their mental health symptom and treatment experience, acculturation, and stigma toward mental illness. Results indicated considerable variability across the three groups, with Puerto Ricans endorsing higher rates of depression and anxiety, as well as higher rates of treatment seeking, than either the immigrant Latinos or the Brazilians. Acculturation played a differential role in the endorsement of anxiety treatment seeking for Brazilians. Finally, although the three groups differed in the extent to which they experienced stigma about mental health issues, stigma did not predict symptom endorsement or treatment-seeking behavior for any of the three groups. These findings underscore the importance of attending to both between-groups and within-group differences in the mental health and mental health treatment experiences of different ethnic groups. PMID- 24491128 TI - The role of critical ethnic awareness and social support in the discrimination depression relationship among Asian Americans: path analysis. AB - This study used a path analytic technique to examine associations among critical ethnic awareness, racial discrimination, social support, and depressive symptoms. Using a convenience sample from online survey of Asian American adults (N = 405), the study tested 2 main hypotheses: First, based on the empowerment theory, critical ethnic awareness would be positively associated with racial discrimination experience; and second, based on the social support deterioration model, social support would partially mediate the relationship between racial discrimination and depressive symptoms. The result of the path analysis model showed that the proposed path model was a good fit based on global fit indices, chi2(2) = 4.70, p = .10; root mean square error of approximation = 0.06; comparative fit index = 0.97; Tucker-Lewis index = 0.92; and standardized root mean square residual = 0.03. The examinations of study hypotheses demonstrated that critical ethnic awareness was directly associated (b = .11, p < .05) with the racial discrimination experience, whereas social support had a significant indirect effect (b = .48; bias-corrected 95% confidence interval [0.02, 1.26]) between the racial discrimination experience and depressive symptoms. The proposed path model illustrated that both critical ethnic awareness and social support are important mechanisms for explaining the relationship between racial discrimination and depressive symptoms among this sample of Asian Americans. This study highlights the usefulness of the critical ethnic awareness concept as a way to better understand how Asian Americans might perceive and recognize racial discrimination experiences in relation to its mental health consequences. PMID- 24491127 TI - Racial discrimination, gender discrimination, and substance abuse among Latina/os nationwide. AB - This study investigates the relationship between discrimination and substance abuse among Latina/os, and further examines whether this relationship differs by gender and type of discrimination. Analyses focus on the Latina/o respondents (n = 1,039 men; n = 1,273 women) from the National Latino and Asian American Study carried out from 2002-2003. Outcomes were alcohol abuse and drug abuse measured using DSM-IV definitions and criteria. Additional covariates included immigrant characteristics and demographics. Analyses were completed using gender-stratified multinomial logistic regression. Men reported more discrimination (39.6% vs. 30.3%) and had higher prevalence of alcohol abuse (16.5% vs. 4.5%) and drug abuse (9.5% vs. 2.3%) than women. Discrimination was significantly associated with increased risk of alcohol abuse for women and increased risk of drug abuse for men. Men and women also varied in the types of discrimination (e.g., racial vs. gender) reported, and in the associations between these types of discrimination and substance abuse. These data indicate that discrimination is associated with different substance abuse outcomes between genders. Future research should consider the mechanisms that explain these differences. PMID- 24491130 TI - Academic stress and positive affect: Asian value and self-worth contingency as moderators among Chinese international students. AB - The theoretical model proposed by Berry and colleagues (Berry, 1997; Berry, Kim, Minde, & Mok, 1987) highlights the importance of identifying moderators in the acculturation process. Accordingly, the current study examined the Asian cultural value of family recognition through achievement (FRTA) and contingency of self worth on academic competence (CSW-AC) as moderators in the association between academic stress and positive affect among Chinese international students. A total of 370 Chinese international students completed online surveys. Results from a hierarchical regression indicated that while academic stress was negatively associated with positive affect, FRTA was positively associated with positive affect. In other words, those with high academic stress reported a lower level of positive affect. However, individuals who endorsed high levels of FRTA reported a higher level of positive affect. In addition, results also revealed a significant interaction between academic stress and CSW-AC on positive affect. Thus, the study's finding supported the moderator role of CSW-AC. Simple effect analyses were conducted to examine the significant interaction. The results showed that higher levels of CSW-AC strengthened the negative association between academic stress and positive affect but lower levels of CSW-AC did not. Future research directions and implications are discussed. PMID- 24491129 TI - Gender roles and acculturation: relationships with cancer screening among Vietnamese American women. AB - The aim of this study was to examine the influence of demographic variables and the interplay between gender roles and acculturation on breast and cervical cancer screening outcomes among Vietnamese American women. Convenience sampling was used to recruit 100 Vietnamese women from the Richmond, VA, metropolitan area. Women were recruited to participate in a larger cancer screening intervention. All participants completed measures on demographic variables, gender roles, acculturation, and cancer screening variables. Findings indicated that traditional masculine gender roles were associated with increased self efficacy for breast and cervical cancer screening. Higher levels of acculturation were associated with higher probability of having had a Papanicolaou test. In addition, acculturation moderated the relationship between traditional female gender roles and cancer screening variables. For highly acculturated women, higher levels of feminine gender roles predicted higher probability of having had a previous clinical breast exam and higher levels of self-efficacy for cervical cancer screening, while the opposite was true for lower acculturated women. The findings of this study indicate the important roles that sociodemographic variables, gender roles, and acculturation play in affecting health attitudes and behaviors among Vietnamese women. These findings also help to identify a potentially high-risk subgroup and existing gaps that need to be targeted by preventive interventions. PMID- 24491135 TI - Absolute and direct microRNA quantification using DNA-gold nanoparticle probes. AB - DNA-gold nanoparticle probes are implemented in a simple strategy for direct microRNA (miRNA) quantification. Fluorescently labeled DNA-probe strands are immobilized on PEGylated gold nanoparticles (AuNPs). In the presence of target miRNA, DNA-RNA heteroduplexes are formed and become substrate for the endonuclease DSN (duplex-specific nuclease). Enzymatic hydrolysis of the DNA strands yields a fluorescence signal due to diffusion of the fluorophores away from the gold surface. We show that the molecular design of our DNA-AuNP probes, with the DNA strands immobilized on top of the PEG-based passivation layer, results in nearly unaltered enzymatic activity toward immobilized heteroduplexes compared to substrates free in solution. The assay, developed in a real-time format, allows absolute quantification of as little as 0.2 fmol of miR-203. We also show the application of the assay for direct quantification of cancer related miR-203 and miR-21 in samples of extracted total RNA from cell cultures. The possibility of direct and absolute quantification may significantly advance the use of microRNAs as biomarkers in the clinical praxis. PMID- 24491134 TI - Movement as Medicine for Type 2 Diabetes: protocol for an open pilot study and external pilot clustered randomised controlled trial to assess acceptability, feasibility and fidelity of a multifaceted behavioural intervention targeting physical activity in primary care. AB - BACKGROUND: Physical activity (PA) and nutrition are the cornerstones of diabetes management. Several reviews and meta-analyses report that PA independently produces clinically important improvements in glucose control in people with Type 2 diabetes. However, it remains unclear what the optimal strategies are to increase PA behaviour in people with Type 2 diabetes in routine primary care. METHODS: This study will determine whether an evidence-informed multifaceted behaviour change intervention (Movement as Medicine for Type 2 Diabetes) targeting both consultation behaviour of primary healthcare professionals and PA behaviour in adults with Type 2 diabetes is both acceptable and feasible in the primary care setting. An open pilot study conducted in two primary care practices (phase one) will assess acceptability, feasibility and fidelity. Ongoing feedback from participating primary healthcare professionals and patients will provide opportunities for systematic adaptation and refinement of the intervention and study procedures. A two-arm parallel group clustered pilot randomised controlled trial with patients from participating primary care practices in North East England will assess acceptability, feasibility, and fidelity of the intervention (versus usual clinical care) and trial processes over a 12-month period. Consultation behaviour involving fidelity of intervention delivery, diabetes and PA related knowledge, attitudes/beliefs, intentions and self-efficacy for delivering a behaviour change intervention targeting PA behaviour will be assessed in primary healthcare professionals. We will rehearse the collection of outcome data (with the focus on data yield and quality) for a future definitive trial, through outcome assessment at baseline, one, six and twelve months. An embedded qualitative process evaluation and treatment fidelity assessment will explore issues around intervention implementation and assess whether intervention components can be reliably and faithfully delivered in routine primary care. DISCUSSION: Movement as Medicine for Type 2 Diabetes will address an important gap in the evidence-base, that is, the need for interventions to increase free living PA behaviour in adults with Type 2 diabetes. The multifaceted intervention incorporates an online accredited training programme for primary healthcare professionals and represents, to the best of our knowledge, the first of its kind in the United Kingdom. This study will establish whether the multifaceted behavioural intervention is acceptable and feasible in routine primary care. TRIAL REGISTRATION: Movement as Medicine for Type 2 Diabetes (MaMT2D) was registered with Current Controlled Trials on the 14th January 2012: ISRCTN67997502. The first primary care practice was randomised on the 5th October 2012. PMID- 24491136 TI - Organic free radicals in clathrate hydrates investigated by muon spin spectroscopy. AB - Very little is known about the behavior of free H atoms and small organic radicals inside clathrate hydrate structures despite the relevance of such species to combustion of hydrocarbon hydrates. Muonium is an H atom analog, essentially a light isotope of hydrogen, and can be used to probe the chemistry of H atoms and transient free radicals. We demonstrate the first application of muon spin spectroscopy to characterize radicals in clathrate hydrates. Atomic muonium was detected in hydrates of cyclopentane and tetrahydrofuran, and muoniated free radicals were detected in the hydrates of cyclopentene and 2,5 dihydrofuran, indicating rapid addition of muonium to the organic guest. Muon avoided level-crossing spectra of the radicals in hydrates are markedly different to those of the same radicals in pure organic liquids at the same temperature, and this can be explained by limited mobility of the enclathrated radicals, leading to anisotropy in the hyperfine interactions. PMID- 24491137 TI - Taking Healthy Steps: rationale, design and baseline characteristics of a randomized trial of a pedometer-based Internet-mediated walking program in veterans with chronic obstructive pulmonary disease. AB - BACKGROUND: Low levels of physical activity are common in patients with chronic obstructive pulmonary disease (COPD), and a sedentary lifestyle is associated with poor outcomes including increased mortality, frequent hospitalizations, and poor health-related quality of life. Internet-mediated physical activity interventions may increase physical activity and improve health outcomes in persons with COPD. METHODS/DESIGN: This manuscript describes the design and rationale of a randomized controlled trial that tests the effectiveness of Taking Healthy Steps, an Internet-mediated walking program for Veterans with COPD. Taking Healthy Steps includes an uploading pedometer, a website, and an online community. Eligible and consented patients wear a pedometer to obtain one week of baseline data and then are randomized on a 2:1 ratio to Taking Healthy Steps or to a wait list control. The intervention arm receives iterative step-count feedback; individualized step-count goals, motivational and informational messages, and access to an online community. Wait list controls are notified that they are enrolled, but that their intervention will start in one year; however, they keep the pedometer and have access to a static webpage. DISCUSSION: Participants include 239 Veterans (mean age 66.7 years, 93.7% male) with 155 randomized to Taking Healthy Steps and 84 to the wait list control arm; rural living (45.2%); ever-smokers (93.3%); and current smokers (25.1%). Baseline mean St. George's Respiratory Questionnaire Total Score was 46.0; 30.5% reported severe dyspnea; and the average number of comorbid conditions was 4.9. Mean baseline daily step counts was 3497 (+/- 2220).Veterans with COPD can be recruited to participate in an online walking program. We successfully recruited a cohort of older Veterans with a significant level of disability including Veterans who live in rural areas using a remote national recruitment strategy. TRIAL REGISTRATION: Clinical Trials.gov NCT01102777. PMID- 24491138 TI - Association of CDKN2A polymorphisms with the severity of cervical neoplasia in a Brazilian population. AB - Variants of p16(INK4a) and p14(ARF), encoded by the CDKN2A locus, may respond differently to the presence of human papillomavirus (HPV). We investigated the potential association of two CDKN2A polymorphisms, 500C > G (rs11515) and 540C > T (rs3088440), with cervical neoplasia in patients with cervical lesions and healthy controls (n = 492). Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), single-strand conformation polymorphism (SSCP) and/or DNA sequencing techniques were employed for genotyping. The 500G allele was found higher, whereas the 540T/T genotype was less frequent in patients with more severe lesions. The CDKN2A variants may have the potential to be markers for the management of patients with cervical neoplasia. PMID- 24491140 TI - Endoscopy-guided vitreoretinal surgery. AB - Vitreoretinal surgery has recently undergone remarkable developments. The introduction of micro-incision vitrectomy surgery using 25- and 23-gauge techniques has led to minimally invasive, faster, safer, and more accurate surgeries. Similarly, intraocular illumination and observation systems have advanced from light pipes to chandelier illumination, slit illumination, wide angle viewing systems, and intraocular endoscopes. Compared to observation via the cornea and optic media, vitreous surgery using an endoscope is extremely useful, as the endoscope is inserted directly into the eye, circumventing the difficulties of corneal clouding and small pupil diameters. Furthermore, there are no blind spots after surgery. We here discuss the advantages of intraocular endoscope use, the current state of endoscopy-guided vitreoretinal surgery, and its future prospects. PMID- 24491141 TI - Sleep problems and their effect in ADHD. AB - Sleep problems are common in attention-deficit/hyperactivity disorder (ADHD) to the extent that they mimic or exacerbate daytime symptoms expression. In this review, we advocate the need for a better understanding of sleep alterations in youths with ADHD and their impact on neurobehavioral functions including learning, memory and emotional regulation. An in-depth exploration of existing data showed that although extensively studied, the actual nature of sleep problems in ADHD and their effects on daytime behavior are still less well understood. Important issues, among which developmental changes in sleep architecture and role of subtle sleep electroencephalogram signatures, are generally neglected. Future research of sleep effects on behavior in ADHD would benefit from considering developmental aspects and links between brain activation patterns during sleep and wake. PMID- 24491139 TI - Self-assembled bionanostructures: proteins following the lead of DNA nanostructures. AB - Natural polymers are able to self-assemble into versatile nanostructures based on the information encoded into their primary structure. The structural richness of biopolymer-based nanostructures depends on the information content of building blocks and the available biological machinery to assemble and decode polymers with a defined sequence. Natural polypeptides comprise 20 amino acids with very different properties in comparison to only 4 structurally similar nucleotides, building elements of nucleic acids. Nevertheless the ease of synthesizing polynucleotides with selected sequence and the ability to encode the nanostructural assembly based on the two specific nucleotide pairs underlay the development of techniques to self-assemble almost any selected three-dimensional nanostructure from polynucleotides. Despite more complex design rules, peptides were successfully used to assemble symmetric nanostructures, such as fibrils and spheres. While earlier designed protein-based nanostructures used linked natural oligomerizing domains, recent design of new oligomerizing interaction surfaces and introduction of the platform for topologically designed protein fold may enable polypeptide-based design to follow the track of DNA nanostructures. The advantages of protein-based nanostructures, such as the functional versatility and cost effective and sustainable production methods provide strong incentive for further development in this direction. PMID- 24491142 TI - Potentially preventable hospitalisations: are they a useful marker of access to and experience of care in general practice among people with type 2 diabetes? AB - The aim of the present study was to explore access to and experience of care in general practice among patients admitted to hospital with a type 2 diabetes mellitus-related potentially preventable hospitalisation (PPH). Forty-eight patients admitted to two public hospitals in the north and west of Melbourne completed a survey and 13 patients were interviewed. Patients generally had long standing diabetes with multimorbidity and were relatively socioeconomically disadvantaged. Nearly two-thirds reported more than one hospital admission in the prior 12 months, and 74% of respondents were able to access theirpreferred general practitioner (GP) on either the same or next day. Emotional support, time and continuity of care with their GP were important to patients, but they recognised many patient barriers to optimal care, including self-management and social and economic factors. Patients that accessed specialist care perceived that GPs had limited role in their disease management. Although the patients in this study experienced good access to care, they also identified several factors that were arguably outside the scope of general practice management, indicating that their admissions to hospital may not have been avoidable. PMID- 24491143 TI - Watching the clock: endoplasmic reticulum-mediated control of circadian rhythms in cancer. AB - In the past 20 years both the circadian clock and endoplasmic reticulum (ER) stress signaling have emerged as major players in oncogenesis and cancer development. Although several lines of evidence have established functional links between these two molecular pathways, their interconnection and the subsequent functional implications in cancer development remain to be fully characterized. Herein, we provide an extensive review of the literature depicting the molecular connectivity linking ER stress signaling and the circadian clock and elaborate on the potential use of these functional interactions in cancer therapeutics. PMID- 24491144 TI - Deaths due to dengue fever at a tertiary care hospital in Lahore, Pakistan. AB - OBJECTIVE: We conducted this study to review deaths due to dengue fever (DF) during a large outbreak of DF in Lahore, Pakistan. METHODS: We reviewed deaths due to DF at Jinnah Hospital Lahore between August and November 2011. Clinical and laboratory data were abstracted. The 2011 World Health Organization Regional Office for South-East Asia (WHO SEARO) guidelines were used to classify the disease. RESULTS: Out of 128,634 probable DF patients who visited the outpatient department, 2313 patients were hospitalized; 1699 (73.3%) were male. RT-PCR was positive in 92 of 114 hospitalized patients (DENV-2 in 91 patients and DENV-3 in 1 patient). Sixty dengue-related deaths were reported; 41 (68.3%) were male. The mean age (+/- standard deviation) was 44 (+/- 20.5) y. The diagnosis at the time of presentation was DF in 5 (8.3%), dengue haemorrhagic fever without shock in 16 (26.6%), dengue shock syndrome in 20 (33%), and expanded dengue syndrome in 19 (31.7%) patients. Expanded dengue syndrome included encephalopathy in 12 (20%) patients, intracerebral bleed in 3 (5%), multiorgan failure in 3 (5%), and Guillain-Barre syndrome in 1 (1.6%). Twenty-nine (48.3%) patients had at least 1 comorbidity. CONCLUSION: Dengue shock syndrome and expanded dengue syndrome were the most common causes of death. PMID- 24491145 TI - De novo design of self-assembling foldamers that inhibit heparin-protein interactions. AB - A series of self-associating foldamers have been designed as heparin reversal agents, as antidotes to prevent bleeding due to this potent antithrombotic agent. The foldamers have a repeating sequence of Lys-Sal, in which Sal is 5-amino-2 methoxy-benzoic acid. These foldamers are designed to self-associate along one face of an extended chain in a beta-sheet-like interaction. The methoxy groups were included to form intramolecular hydrogen bonds that preclude the formation of very large amyloid-like aggregates, while the positively charged Lys side chains were introduced to interact electrostatically with the highly anionic heparin polymer. The prototype compound (Lys-Sal)4 carboxamide weakly associates in aqueous solution at physiological salt concentration in a monomer-dimer hexamer equilibrium. The association is greatly enhanced at either high ionic strength or in the presence of a heparin derivative, which is bound tightly. Variants of this foldamer are active in an antithrombin III-factor Xa assay, showing their potential as heparin reversal agents. PMID- 24491147 TI - The need for a peer physical examination policy within Australian medical schools. AB - BACKGROUND: Peer physical examinations (PPEs) are often used to enhance medical students' clinical examination skills. Previous research indicates that there are several issues of concern regarding PPEs suggesting that it is important to have a PPE policy in place to respond to these issues appropriately. However, it is unknown as to how many Australian medical schools actually have such a policy. AIMS: The aims of the present study were to enumerate how many Australian medical schools use PPEs and have a PPE policy. METHODS: Surveys were sent to all Australian medical schools. RESULTS: Our findings show that most Australian medical schools use PPEs, but none appear to have a thorough PPE policy. CONCLUSIONS: The findings of our study show that the majority of medical schools practise PPEs but do not have a policy. This in turn could lead to significant problems arising. PMID- 24491148 TI - Alistonitrine A, a caged monoterpene indole alkaloid from Alstonia scholaris. AB - Alistonitrine A, a new monoterpene indole alkaloid incorporating a third nitrogen atom, was isolated from the leaves of Alstonia scholaris and found to possess an unprecedented caged skeleton with a unique 6/5/6/5/5/6 ring system. Its structure and absolute configuration were established by extensive spectroscopic analyses and electron circular dichroism calculations. A plausible biogenetic pathway has been proposed for the biosynthesis of alistonitrine A from picrinine. PMID- 24491146 TI - Imaging evaluation of 5HT2C agonists, [(11)C]WAY-163909 and [(11)C]vabicaserin, formed by Pictet-Spengler cyclization. AB - The serotonin subtype 2C (5HT2C) receptor is an emerging and promising drug target to treat several disorders of the human central nervous system. In this current report, two potent and selective 5HT2C full agonists, WAY-163909 (2) and vabicaserin (3), were radiolabeled with carbon-11 via Pictet-Spengler cyclization with [(11)C]formaldehyde and used in positron emission tomography (PET) imaging. Reaction conditions were optimized to exclude the major source of isotope dilution caused by the previously unknown breakdown of N,N-dimethylformamide (DMF) to formaldehyde at high temperature under mildly acid conditions. In vivo PET imaging was utilized to evaluate the pharmacokinetics and distribution of the carbon-11 labeled 5HT2C agonists. Both radiolabeled molecules exhibit high blood brain barrier (BBB) penetration and nonspecific binding, which was unaltered by preadministration of the unlabeled agonist. Our work demonstrates that Pictet Spengler cyclization can be used to label drugs with carbon-11 to study their pharmacokinetics and for evaluation as PET radiotracers. PMID- 24491149 TI - Prescription drug misuse and gender. AB - In recent years, prescription drug misuse has become a serious public health issue. A number of studies in this area have identified females to be at an increased risk for prescription drug misuse during adolescence. Guided by Agnew's general strain theory, the current research examined the relationship between prescription drug misuse and gender during adolescence. We used data from the 2010 National Survey on Drug Use and Health, a sample representative of the non institutionalized population of the United States. Logistic regression models were estimated to examine the relationship between gender, prescription drug misuse, strain, and depression. The findings indicated that females were at an increased for prescription drug misuse. We also found support for general strain theory, as strain and depression were significantly related to prescription drug misuse. In addition, we found evidence that strain was gendered in that elements of general strain theory accounted for the relationship between prescription drug misuse and gender. PMID- 24491150 TI - Nicotine exposure, blood pressure, and inflammation in tobacco smokers and chewers in a rural community in Nepal. AB - Tobacco consumption is high amongst the people of Xxx. This study was carried out in 2011 in a rural community of Xxx, to compare pathological parameters associated with tobacco use in relation to nicotine metabolism between smokers, chewers, and a control group. A total of 216 volunteers provided blood and urine samples for testing nicotine metabolites, C-reactive protein, and cell counts. Data were analyzed using ANOVA, correlation, and t-tests using STATA. Differences in blood pressure amongst the groups indicate a role of smoking in preventing a rise in BP with age, likely attributable to a different mechanism of metabolism of tobacco constituents. PMID- 24491152 TI - Stimuli-responsivity of secondary structures of glycopolypeptides derived from poly(L-glutamate-co-allylglycine). AB - Copolypeptides containing L-glutamate and various amounts of either D-/DL-/L allylglycine or D-/DL-/L-(3-(beta-D-glucopyranosyl)thio)propylglycine defect units were studied by circular dichroism (CD) and infrared (FT-IR) spectroscopy according to their secondary structures in dependence of pH and temperature. All samples adopt random coil conformation at high pH and alpha-helix at low pH without evidence for beta-sheet formation. Folding into the alpha-helix structure is strongly affected by the number and configuration of allylglycine defects (which intrinsically stabilize beta-sheets). Helix folding is facilitated upon the attachment of D-glucopyranose to the L- (but not the D-) allylglycine units, which is attributed to a different secondary structure preference of the L-(3 (beta-D-glucopyranosyl)thio)propylglycine (L: random coil; D: beta-sheet) and a majority rule effect. PMID- 24491151 TI - Alcohol use among Hispanic early adolescents in the United States: an examination of behavioral risk and protective profiles. AB - Few studies have examined the behavioral and protective correlates of alcohol use among young Hispanics. Using a national sample (N = 7,606), logistic regression and latent profile analysis (LPA) are employed to examine the relationships between alcohol use, psychosocial factors, and externalizing behavior among Hispanics during early adolescence. Early drinkers are more likely to report truancy, fighting, smoking, and drug use. LPA results revealed a three class solution. Classes identified included: psychosocial risk (41.11%), moderate protection (39.44%), and highly religious (19.44%). Alcohol use is clearly associated with externalizing behavior; however, an important degree of psychosocial and behavioral heterogeneity nevertheless exists. PMID- 24491154 TI - Multiple major QTL lead to stable yield performance of rice cultivars across varying drought intensities. AB - BACKGROUND: Availability of irrigation water is becoming a major limiting factor in rice cultivation. Production in rainfed areas is affected in particular by drought events, as these areas are commonly planted to high-yielding drought susceptible rice (Oryza sativa L.) varieties. The use of bulk segregant analysis (BSA), taking grain yield (GY) as a selection criterion, has resulted in the identification of several large-effect QTL. A QTL mapping study was undertaken on a BC1F3:4 population developed from the cross IR55419-04/2*TDK1 with the aim of identifying large-effect QTL in the background of TDK1, a popular variety from Lao PDR. RESULTS: The study identified three QTL-qDTY3.1 (RM168-RM468), qDTY6.1 (RM586-RM217), and qDTY6.2 (RM121-RM541)-for grain yield under drought. qDTY3.1 and qDTY6.1, showed consistent effect across seasons under lowland drought-stress conditions while qDTY6.1 and qDTY6.2 showed effect under both upland and lowland drought conditions. The test of QTL effect, conducted through a QTL class analysis, showed the complimentary nature of qDTY3.1 and qDTY6.1. Both QTL showed specific patterns of effect across different maturity groups within the mapping population and higher stability for grain yield was seen across stress levels for lines with both QTLs as compared to those with single or no QTL. CONCLUSIONS: The study offers a clear understanding of large-effect QTL for grain yield under drought and their effect as individual QTL and in various combinations. The study also opens up an opportunity to develop a drought-tolerant version of TDK1 through marker-assisted backcross breeding and has led to a large-scale QTL pyramiding program aiming to combine these QTL with Sub1 in the background of TDK1 as recipient variety. PMID- 24491153 TI - Increased CD44s and decreased CD44v6 RNA expression are associated with better survival in myxofibrosarcoma patients: a pilot study. AB - BACKGROUND: New prognostic markers may be of value in determining survival and informing decisions of adjuvant treatment in the heterogeneous group of soft tissue sarcomas known as malignant fibrous sarcomas (MFS). Increased CD44 expression has been associated with a better outcome in cancers such as bladder tumors and could potentially relate to cell-cell interaction as a marker for potential invasion/metastasis. The aim of this pilot study was to determine if there is a correlation between the expression rate of CD44 in adult patients with MFS and clinical outcomes. METHODS: The clinical outcome of 34 adult MFS patients (19 males and 15 females, average age 62 years, median 63 years, range: 38-88 years) who underwent surgical treatment were evaluated. Twenty-five of these patients had additional adjuvant radiotherapy. Extracted RNA from sarcoma tissues was used to measure the transcripts of CD44s (standard form) and isoform expression.The pooled data for each variant of CD44 was divided in half at the median expression value into two equally sized groups (low and high). Survival modeling and multivariate analysis were used with these two groups to determine if there were differences in survival times and whether this was independent of known factors such as tumor stage/grade, patient age and resection margin status. RESULTS: High CD44s and low of CD44v6 expression significantly correlated with an improved outcome (P <0.05 and P <0.02, respectively) whereas CD44v8 and hCD44 (isoforms) did not. Differences in survival were apparent within 6-12 months of operation with >30% difference in survival between low/high expressions at 5 years. These finding were independent of the other measured MFS survival predictors, though the group was homogenous. CONCLUSIONS: High CD44s and low CD44v6 expression may be an independent predictor of improved survival in MFS patients in this pilot data. This is contrary to other MFS data, which did not account for the CD44 isoforms but is confirmed by data from other cancer types. Further investigation is needed to confirm CD44 isoform expression data as a relevant survival biomarker and whether it could be used to inform clinical decisions such as adjuvant therapy. PMID- 24491155 TI - Laser microdissection of paraffin embedded tissue as a tool to estimate the sialylation status of selected cell populations. AB - In vertebrates, sialic acids occur at the terminal end of glycans mediating numerous biological processes like cell differentiation or tumor metastasis. Consequently, the cellular sialylation status under healthy and pathological conditions is of high interest. Existing analytical strategies to determine sialylation patterns are mostly applied to tissue samples consisting of a mixture of different cell types. Alterations in the sialylation status in a distinct area of tissues or in a specific cell population may, therefore, be easily overlooked. Likewise, estimated variations in sialylation in tissue homogenates might be simply the result of a changed cell composition. To overcome these limitations, we employed laser microdissection to isolate defined cell types or functional subunits and cell populations of paraffin embedded specimens which represent the most abundant supply of human tissue associated with clinical records. For qualitative and quantitative estimation of the sialylation status, sialic acids were released, fluorescently labeled, and analyzed by an online high-performance liquid chromatography-electrospray ionization-mass spectrometry (HPLC-ESI-MS) system. As a proof of principle, this strategy was successfully applied to characterize the sialylation of the apical region of epididymal epithelial cells. Furthermore, it was possible to detect an impaired sialylation during kidney maturation in a transgenic mouse model, which was restricted to glomeruli, whereas no differences in sialylation were observed when whole kidney homogenates were used. Thus, starting from paraffin embedded tissue samples, the outlined approach offers a sensitive method to detect and quantify sialic acids on defined cell populations, which may be useful to explore novel sialic acid dependent roles during physiological and pathological processes. PMID- 24491156 TI - Six-cell penetrating peptide-based fusion proteins for siRNA delivery. AB - The siRNA deliveries, for the siRNA's high negative charge, short serum half life, poor cellular internalization, etc, are still the key barriers for its application in clinic. In this study, several cell penetrating peptide (CPP) and dsRNA binding domain (dsRBD)-based fusion proteins have been developed and screened as the siRNA vector. The siRNA binding ability was measured by the agarose gel retardation, the cell uptaking was characterized under fluorescence microscopy, and further more RNAi effect was evaluated on the endogenous (GAPDH, western blot) and exogenous (GFP, flow cytometry analysis) genes in HeLa cell. Finally, the cytotoxicity was assessed on HeLa cells using cell counting kit-8. The efficiency of siRNA delivery by the CPP-dsRBD fusion protein was the CPP and the dsRBD dependent. Three fusion proteins showed similar efficiency of siRNA delivery when comparing to Lipofectamine RNAi Max as the siRNA carrier. These results indicated that these CPP-dsRBD-based fusion proteins were promising candidates as siRNA carriers. PMID- 24491157 TI - Social jetlag negatively correlates with academic performance in undergraduates. AB - Discrepancies between sleep timing on workdays and weekends, also known as social jetlag (SJL), affect the majority of the population and have been found to be associated with increased health risk and health-impairing behaviors. In this study, we explored the relationship between SJL and academic performance in a sample of undergraduates of the Semmelweis University. We assessed SJL and other sleep-related parameters with the Munich ChronoType Questionnaire (MCTQ) (n = 753). Academic performance was measured by the average grade based on weekly test results as well as scores acquired on the final test (n = 247). The average mid sleep point on free days in the Hungarian sample fits well the regression line plotted for longitudes within the Central European Time Zone and chronotypes, confirming that sunlight has a major impact on chronotype. Multivariate analysis showed negative effect of SJL on the weekly average grade (p = 0.028, n = 247) during the lecture term with its highly regular teaching schedules, while this association disappeared in the exam period (p = 0.871, n = 247) when students had no scheduled obligations (lower SJL). We also analyzed the relationship between the time of the weekly tests and academic performance and found that students with later sleep times on free days achieved worse in the morning (p = 0.017, n = 129), while the inverse tendency was observed for the afternoon test-takers (p = 0.10, n = 118). We did not find significant association between academic performance and sleep duration or sleep debt on work days. Our data suggest that circadian misalignment can have a significant negative effect on academic performance. One possible reason for this misalignment is socially enforced sleep times. PMID- 24491159 TI - Dimerization of polycyclic aromatic hydrocarbons in soot nucleation. AB - A possible pathway of soot nucleation, in which localized pi electrons play an important role in binding the polycyclic aromatic hydrocarbon (PAH) molecules having multiradical characteristics to form stable polymer molecules through covalent bonds, is studied using density functional and semiempirical methods. Results show that the number of covalent bonds formed in the dimerization of two identical PAHs is determined by the radical character, and the sites to form bonds are related to the aromaticity of individual six-membered ring structure. It is further shown that the binding energy of dimerization increases linearly with the diradical character in the range relevant to soot nucleation. PMID- 24491161 TI - Polycystic ovary syndrome: what's in a name? PMID- 24491160 TI - Engineered nanoparticles interacting with cells: size matters. AB - With the rapid advancement of nanoscience and nanotechnology, detailed knowledge of interactions between engineered nanomaterials and cells, tissues and organisms has become increasingly important, especially in regard to possible hazards to human health. This review intends to give an overview of current research on nano bio interactions, with a focus on the effects of NP size on their interactions with live cells. We summarize common techniques to characterize NP size, highlight recent work on the impact of NP size on active and passive cellular internalization and intracellular localization. Cytotoxic effects are also discussed. PMID- 24491162 TI - Advanced glycation end-products: pathway of potentially significant pathophysiological and therapeutic relevance for metabolic syndrome in menopausal women. PMID- 24491164 TI - Introduction of team-based learning (TBL) at Kilimanjaro Christian Medical University College: experience with the ectoparasites module. AB - BACKGROUND: Contemporary teaching in sub-Saharan African medical schools is largely through didactic and problem-based approaches. These schools face challenges from burgeoning student numbers, severe faculty shortages, faculty without instruction in teaching methods and severe infrastructure inadequacies. Team-based learning (TBL) is a pedagogy which may be attractive because it spares faculty time. TBL was piloted in a module on ectoparasites at the Kilimanjaro Christian Medical University College (KCMU Co.). METHODS: TBL orientation began six weeks before starting the module. Students were issued background readings and individual and group readiness assessment tests, followed by module application, discussion and evaluation. At completion, student perceptions of TBL were assessed using a 5-point Likert scale evaluating six domains, with a score of 5 being most favourable. Strength of consensus measures (sCns) was applied. Final examination scores were compiled for 2011 (didactic) and 2012 (TBL). RESULTS: About 158 students participated in the module. The mean student scores across the six domains ranged from 4.2 to 4.5, with a high degree of consensus (range 85-90%). The final examination scores improved between 2011 and 2012. CONCLUSIONS: KCMU Co. student perceptions of TBL were very positive, and final exam grades improved. These observations suggest future promise for TBL applications at KCMU Co. and potentially other schools. PMID- 24491168 TI - 104th American Association For Cancer Research (AACR) annual meeting; breakthroughs in science and technology changing cancer care. PMID- 24491163 TI - Acute murine antigen-induced arthritis is not affected by disruption of osteoblastic glucocorticoid signalling. AB - BACKGROUND: The role of endogenous glucocorticoids (GC) in the initiation and maintenance of rheumatoid arthritis (RA) remains unclear. We demonstrated previously that disruption of GC signalling in osteoblasts results in a profound attenuation of K/BxN serum-induced arthritis, a mouse model of RA. To determine whether or not the modulation of the inflammatory response by osteoblasts involves T cells, we studied the effects of disrupted osteoblastic GC-signalling in the T cell-dependent model of antigen-induced arthritis (AIA). METHODS: Acute arthritis was induced in pre-immunised 11-week-old male 11beta-hydroxysteroid dehydrogenase type 2 transgenic (tg) mice and their wild-type (WT) littermates by intra-articular injection of methylated bovine serum albumine (mBSA) into one knee joint. Knee diameter was measured every 1-2 days until euthanasia on day 14 post injection. In a separate experiment, arthritis was maintained for 28 days by weekly reinjections of mBSA. Tissues were analysed by histology, histomorphometry and microfocal-computed tomography. Serum cytokines levels were determined by multiplex suspension array. RESULTS: In both short and long term experiments, arthritis developed in tg and WT mice with no significant difference between both groups. Histological indices of inflammation, cartilage damage and bone erosion were similar in tg and WT mice. Bone volume and turnover at the contralateral tibia and systemic cytokine levels were not different. CONCLUSIONS: Acute murine AIA is not affected by a disruption in osteoblastic GC signalling. These data indicate that osteoblasts do not modulate the T cell-mediated inflammatory response via a GC-dependent pathway. PMID- 24491169 TI - Highly stereoselective synthesis of (borylmethyl)cyclopropylamines by copper catalyzed aminoboration of methylenecyclopropanes. AB - A Cu-catalyzed aminoboration of 1-methylenecyclopropanes with bis(pinacolato)diboron and O-benzoyl-N,N-dialkylhydroxylamines has been developed. The Cu catalysis provides a rapid and concise access to (borylmethyl)cyclopropylamines in a highly regio- and diastereoselective manner. The products obtained can be useful building blocks for the synthesis of potential antidepressants, trans-2-arylcyclopropylamine derivatives. PMID- 24491170 TI - Healthy aging in a cross-sectional study of Australian men: what has sex got to do with it? AB - AIM: To identify lifestyle factors associated with healthy aging in middle-aged and older Australian men. METHODS: A cross-sectional, population-based, computer assisted telephone interview study explored self-reported health outcomes, and associated determinants for general and reproductive health (the Men in Australia Telephone Survey) in men aged 40 years and older (n = 5990). "Good health" was defined by self-reported health (excellent/very good) combined with absence of self-reported high blood pressure, heart disease, stroke, diabetes and depression symptoms. Categories of sexual activity frequency in the previous four weeks ranged from zero to 12+ times. RESULTS: "Good health" declined with increasing age with 17% of men over 70 years reporting "good health". In multivariable logistic regression models, significant inverse associations were found between modifiable lifestyle factors - both underweight and overweight/obesity, physical inactivity, smoking and high alcohol consumption - and "good health". Low-risk alcohol intake and living with a partner were positively associated with "good health". Sexual activity was also positively associated with "good health" (p < 0.001) with elevated odds ratios (ORs) for each category of frequency of sexual activity (1-4, 5-8, 9-12 or 12+ times in the past 4 weeks) relative to zero frequency (ORs 1.68 to 2.16). CONCLUSION: This study suggests that sexual activity is an important correlate of retaining good health in middle- and older aged men, independent of other behavioral determinants. PMID- 24491172 TI - Relationship between spin ordering, entropy, and anomalous lattice variation in Mn3Sn(1-epsilon)Si(epsilon)C(1-delta) compounds. AB - The crystal and magnetic structures of antiperovskite compounds Mn3SnC, Mn3Sn0.95C0.9, and Mn3Sn0.93Si0.07C0.94 were studied as a function of temperature and magnetic field by neutron powder diffraction. For Mn3SnC, the magnetic field induces a dramatic variation of antiferromagnetic moment and lattice parameter. Because of this spin-lattice coupling, the "square" antiferromagnetic (AFM) structure plays a key role in inducing a negative thermal expansion in the material. Moreover, the thermal expansion parameter is closely related to the rate of change of the AFM moment, which can be controlled by introducing vacancies or by doping. The variations of the AFM moment and lattice parameter in Mn3SnC with magnetic field make it possible to use the tunable properties for technical applications. PMID- 24491171 TI - Discovery of a potent stapled helix peptide that binds to the 70N domain of replication protein A. AB - Stapled helix peptides can serve as useful tools for inhibiting protein-protein interactions but can be difficult to optimize for affinity. Here we describe the discovery and optimization of a stapled helix peptide that binds to the N terminal domain of the 70 kDa subunit of replication protein A (RPA70N). In addition to applying traditional optimization strategies, we employed a novel approach for efficiently designing peptides containing unnatural amino acids. We discovered hot spots in the target protein using a fragment-based screen, identified the amino acid that binds to the hot spot, and selected an unnatural amino acid to incorporate, based on the structure-activity relationships of small molecules that bind to this site. The resulting stapled helix peptide potently and selectively binds to RPA70N, does not disrupt ssDNA binding, and penetrates cells. This peptide may serve as a probe to explore the therapeutic potential of RPA70N inhibition in cancer. PMID- 24491173 TI - Central line-associated bloodstream infections caused by Staphylococcus aureus in cancer patients: Clinical outcome and management. AB - BACKGROUND: There are limited data regarding clinical presentation and management of Staphylococcus aureus central line- associated bloodstream infection (CLABSI) in immunocompromised cancer patients. METHODS: In this review, we evaluated 299 patients with 304 episodes of S. aureus-CLABSI between 2005 and 2011. FINDINGS: By multivariate analysis, the major predictors of complicated S. aureus-CLABSI were septic shock, catheter site inflammation, presence of peripherally inserted central catheter, anti-cancer chemotherapy within 10 days, and persistent bacteremia beyond 72 hours (P <= 0.02). A total of 67% of the cases were defined as complicated. In the subset of patients who were uncomplicated on presentation, patients receiving antimicrobials >= 14 days had similar rates of relapse, attributable mortality, and development of complications compared to those receiving shorter-course therapy. By competing risk analysis, removal of the catheter within 3 days of the onset of bacteremia was associated with a lower relapse rate at 90 days (P = 0.024). INTERPRETATION: The majority of S. aureus CLABSI in cancer patients are complicated and require prolonged course of antimicrobial treatment. Early removal of the catheter within the first 3 days is associated with better course. In patients with prompt removal of the catheter and no evidence of a complicated course, treatment beyond 2 weeks may not be necessary. PMID- 24491175 TI - Gestalt principle use in college students, children with autism, toddlers (Homo sapiens), and cotton top tamarins (Saguinus oedipus). AB - The use of Gestalt principles of proximity, similarity, and closure to recognize objects by configural superiority was examined in college students, low- and high functioning children with autism, toddlers, and adult cotton top tamarin monkeys. At issue was whether the monkeys showed differences from humans in perceptual processing and whether they showed any similarities with clinical or developmental groups. The method required a pointing response to discriminate an odd item in a 4-item visual display. All subjects were trained to a high accuracy to point to the odd item before being tested with graphic stimuli that differentiated feature changes based on configural superiority. The results were that college students and high-functioning children with autism responded faster and more accurately to trials in which the odd item was easily noticed by the use of Gestalt principles and configural superiority. Toddlers also responded more accurately to the Gestalt trials, but without being faster at making the response. Low-functioning children with autism and tamarins showed no advantage to Gestalt trials but exhibited different processing styles. The implications of these findings to track the evolution of human perception and to develop a primate model for the perceptual deficits of autism are discussed. PMID- 24491176 TI - Biased hand use in captive emperor tamarins (Saguinus imperator). AB - Comparing forelimb use across primates can improve the understanding of the mechanisms and functions of brain asymmetry. We broadened the comparative framework by investigating hand use biases across spontaneous behaviors in 11 captive emperor tamarins of 2 family groups. We found a right preference across 58% of pooled unimanual bouts and 60% of all tasks. The maximum biases for a single task were 88% right-hand use and 78% left-hand use. On an individual basis, for most tasks, 6 tamarins preferred their right hand, 2 tamarins the left, and 2 animals were ambidextrous. Only a single tamarin did not switch between left and right hand bias according to task, but displayed a consistent right-hand bias. Our accompanying review of the 2 dozen previous callitrichid hand use studies confirms this picture. Across the board, these report hand preferences for single tasks. Task specialization is found in less than half of the studies, hand specialization in less than a third, whereas population level handedness is almost never reported. Importantly, right-hand use is preponderant, but very rarely consistent across tasks or subjects. This might be attributable to the fact that often-employed simple (food-reaching) tasks may not be coupled to a specialized hemisphere and therefore not constrain forelimb use. A better understanding of what causes directional forelimb use in callitrichids and other animals is currently hampered by a lack of standardized methods including measurement criteria, task difficulty, and social setting as well as a dearth of taxonomic diversity and field studies. PMID- 24491177 TI - Detection of dissolved CO(2) based on the aggregation of gold nanoparticles. AB - A sensitive colorimetric assay of dissolved CO2 (dCO2) was developed based on the plasmon shift of gold nanoparticles (AuNPs). A water-soluble random copolymer poly(dimethyl acrylamide-co-(N-amidino)ethyl acrylamide), or P(DMA-co-NAEAA), containing amidine groups was synthesized. In the presence of dCO2, the amidine groups in the NAEAA block protonate and convert the polymer from a neutral to a positive-charged state, hence triggering the negative-charged AuNPs to aggregate by the electrostatic interaction. The degree of AuNP aggregation is dependent on the charge density of polymer, which is related to dCO2 concentration. The aggregation of AuNPs results in a red shift of the AuNP plasmonic spectrum, or a color change from red to blue. In addition, dCO2 concentration can be quantitatively measured by the UV absorbance change of the AuNP solution. A linear relationship between 0.264 and 6.336 hPa of dCO2 with a limit of detection (LOD) of 0.04 hPa can be acquired. This is the first report to detect dCO2 using the optical properties of nanoparticles. PMID- 24491174 TI - Molecular adhesion between cartilage extracellular matrix macromolecules. AB - In this study, we investigated the molecular adhesion between the major constituents of cartilage extracellular matrix, namely, the highly negatively charged proteoglycan aggrecan and the type II/IX/XI fibrillar collagen network, in simulated physiological conditions. Colloidal force spectroscopy was applied to measure the maximum adhesion force and total adhesion energy between aggrecan end-attached spherical tips (end radius R ~ 2.5 MUm) and trypsin-treated cartilage disks with undamaged collagen networks. Studies were carried out in various aqueous solutions to reveal the physical factors that govern aggrecan collagen adhesion. Increasing both ionic strength and [Ca(2+)] significantly increased adhesion, highlighting the importance of electrostatic repulsion and Ca(2+)-mediated ion bridging effects. In addition, we probed how partial enzymatic degradation of the collagen network, which simulates osteoarthritic conditions, affects the aggrecan-collagen interactions. Interestingly, we found a significant increase in aggrecan-collagen adhesion even when there were no detectable changes at the macro- or microscales. It is hypothesized that the aggrecan-collagen adhesion, together with aggrecan-aggrecan self-adhesion, works synergistically to determine the local molecular deformability and energy dissipation of the cartilage matrix, in turn, affecting its macroscopic tissue properties. PMID- 24491178 TI - Confirmation of warfarin resistance of naturally occurring VKORC1 variants by coexpression with coagulation factor IX and in silico protein modelling. AB - BACKGROUND: VKORC1 has been identified some years ago as the gene encoding vitamin K epoxide reductase (VKOR) - the target protein for coumarin derivates like warfarin or phenprocoumon. Resistance against warfarin and other coumarin type anticoagulants has been frequently reported over the last 50 years in rodents due to problems in pest control as well as in thrombophilic patients showing variable response to anticoagulant treatment. Many different mutations have already been detected in the VKORC1 gene leading to warfarin resistance in rats, mice and in humans. Since the conventional in vitro dithiothreitol (DTT) driven VKOR enzymatic assay often did not reflect the in vivo status concerning warfarin resistance, we recently developed a cell culture-based method for coexpression of VKORC1 with coagulation factor IX and subsequent measurement of secreted FIX in order to test warfarin inhibition in wild-type and mutated VKORC1. RESULTS: In the present study, we coexpressed wild-type factor IX with 12 different VKORC1 variants which were previously detected in warfarin resistant rats and mice. The results show that amino acid substitutions in VKORC1 maintain VKOR activity and are associated with warfarin resistance. When we projected in silico the amino acid substitutions onto the published three-dimensional model of the bacterial VKOR enzyme, the predicted effects matched well the catalytic mechanism proposed for the bacterial enzyme. CONCLUSIONS: The established cell based system for coexpression of VKORC1 and factor IX uses FIX activity as an indicator of carboxylation efficiency. This system reflects the warfarin resistance status of VKORC1 mutations from anticoagulant resistant rodents more closely than the traditional DTT-driven enzyme assay. All mutations studied were also predicted to be involved in the reaction mechanism. PMID- 24491180 TI - Improvement of right ventricular function with transcatheter aortic valve implantation. AB - BACKGROUND AND AIM: It has been demonstrated that right ventricular systolic dysfunction develops soon after surgical aortic valve replacement (s-AVR). While the impact of s-AVR or TAVI on the function of the left ventricle has been studied with various imaging modalities, little is known about the impact on right ventricular function (RVF). In the current study, we evaluated the impact of TAVI on RVF using conventional echocardiography parameters. METHODS AND RESULTS: Echocardiography was performed prior to 24 h, 1 month and 6 months after TAVI. RVF was assessed using (1) tricuspid annular plane systolic excursion (TAPSE); (2) RV Tissue Doppler Imaging (S'); (3) right ventricular systolic pressure (RVSP); (4) Fractional area change (FAC); and (5) RV ejection fraction (RVEF). TAVI was performed through the subclavian artery in two patients and femoral artery in 48 patients with an Edwards Sapien XT valve. TAVI was performed on 50 patients between the dates of December 2012 and June 2013. After TAVI, a statistically significant improvement was observed for all parameters related to RVF (RVSP, RVEF, TAPSE, FAC, RVTDI S'). During the 1st and 6th months this statistically significant improvement continued in TAPSE and FAC, and there was no deterioration in RVSP, RVEF, and RVTDI S during the 1st month but a statistically significant improvement continued in the 6th month. CONCLUSION: RVF assessed by conventional echocardiography did not deteriorate after TAVI in early and midterm follow-up. Further, TAVI provides improvement of RVF and can safely and efficiently be performed in patients with impaired RVF. PMID- 24491181 TI - Cyclodextrin modulates the cytotoxic effects of chlorhexidine on microrganisms and cells in vitro. AB - Although several studies have shown that chlorhexidine (Cx) has bactericidal activity and exerts toxic effects on periodontal tissues a few studies evaluated mechanisms to reduce its adverse effects maintaining the antimicrobial properties. Therefore, the aim of the present study was to investigate the in vitro antimicrobial activity and cellular cytotoxicity of Cx included on cyclodextrins (Cd), alpha, beta or Hp-beta-cyclodextrins (Hp-beta-Cd). The influence of Cds was determined by increasing its molar rate 1:1 to 1:4 in relation with free Cx. The minimal inhibitory concentrations (MICs) for Candida albicans, Aggregatibacter actinomycetemcomitans actinomycemcomitans and Streptococcus mutans were determined. An ergosterol solubilization assay was carried out using the C. albicans model and osteoblasts, fibroblasts and tumoral Caco-2 cells for cytotoxicity assay. The antimicrobial activity results in a significant growth inhibition of C. albicans when it was treated with Cx:alpha-Cd complexes, whereas Cx:beta-Cd was more effective for A. actinomycetemcomitans, and Cx:Hp-beta-Cd complexes was for S. mutans when compared to the other complexes. The cytotoxicity for fibroblasts and osteoblasts decreased in relation with each kind of Cd been beta-Cd <= Hp-beta-Cd <= alpha-Cd. Although the Hp-beta Cd inclusion complexes had more severe effects on Caco-2 cells, all complexes exhibited less cytotoxicity than free Cx. The alpha-Cd, beta-Cd and Hp-beta-Cd increase the antimicrobial activity of Cx, but decrease its cytotoxic effects on mammalian cells. Taken together these findings suggest that cyclodextrins are a tool for modulation of effects of Cx. It could be useful to design Cx/Cd delivery systems with high efficacy and minimum cytotoxic effects. PMID- 24491179 TI - Hypoxia signaling pathways in cancer metabolism: the importance of co-selecting interconnected physiological pathways. AB - Both tumor hypoxia and dysregulated metabolism are classical features of cancer. Recent analyses have revealed complex interconnections between oncogenic activation, hypoxia signaling systems and metabolic pathways that are dysregulated in cancer. These studies have demonstrated that rather than responding simply to error signals arising from energy depletion or tumor hypoxia, metabolic and hypoxia signaling pathways are also directly connected to oncogenic signaling mechanisms at many points. This review will summarize current understanding of the role of hypoxia inducible factor (HIF) in these networks. It will also discuss the role of these interconnected pathways in generating the cancer phenotype; in particular, the implications of switching massive pathways that are physiologically 'hard-wired' to oncogenic mechanisms driving cancer. PMID- 24491182 TI - Kinetics and mechanism of the oxidation of pentathionate ion by chlorine dioxide in a slightly acidic medium. AB - The chlorine dioxide-pentathionate reaction has been studied at a slightly acidic medium by conventional UV-vis spectroscopy monitoring the absorbance at 430 nm. We have shown that pentathionate was oxidized to sulfate, but chlorate is also a marginal product of the reaction besides the chloride ion. The stoichiometry of the reaction can be established as a linear combination of two limiting stoichiometries under our experimental conditions. Kinetics of the reaction was found to be also complex because initial rate studies revealed that formal kinetic orders of both the hydrogen ion and chlorine dioxide is far from unity. Moreover, log-log plot of the initial rate against pentathionate concentration indicated a nonconstant formal kinetic order. We also observed a significant catalytic effect of chloride ion. Based on our observations and simultaneous evaluation of the kinetic curves, an 11-step kinetic model is obtained with 6 fitted rate coefficients. A relatively simple rate equation has also been derived and discussed. PMID- 24491183 TI - Surgical techniques for improving outcomes in pancreatic ductal adenocarcinoma. AB - Pancreatic ductal adenocarcinoma is a devastating disease with extremely poor survival despite patients undergoing potentially curative resections and improvements in chemotherapeutic agents. Surgery for operable cancer in the head of the pancreas typically involves an open pancreaticoduodenectomy with a post operative median survival of 21 months. Newer surgical techniques, however, aim to improve patient outcomes in terms of both their hospital experience and better oncological results. This article focuses on the evidence to date for some of these surgical techniques including laparoscopic and robotic surgery, the no touch technique, venous and arterial resection, intra-operative radiofrequency ablation and intra-operative irreversible electroporation. With the increased use of these techniques we hope to see better quality of life and survival for these patients. PMID- 24491184 TI - Temperature-dependent Raman spectroscopic evidence of and molecular mechanism for irreversible isomerization of beta-endosulfan to alpha-endosulfan. AB - Endosulfan (6,7,8, 9,10,10-hexachloro-1,5,5a,6,9,9a-hexahydro-6,9-methano-2,4,3 benzodioxathiepine-3-oxide) is a broad-spectrum, organochlorine insecticide used on numerous crops since the 1950s. It is has been identified as a persistent organic pollutant (POP) due to its persistence, bioaccumulation, long-range transport, and adverse effects to human health and aquatic ecosystems; it will be phased out in the United States in 2016. Endosulfan consists of two diastereomers, alpha and beta; alpha-endosulfan exists as two asymmetrical, twist chair enantiomers which interchange, while beta-endosulfan has a symmetrical chair conformation. beta-Endosulfan has been shown to isomerize to alpha endosulfan. Here we document the previously proposed isomerization mechanism using temperature-dependent Raman (TDR) spectroscopy. The bending frequencies in the fingerprint region were assigned to specific bonds. Changes in the signal intensity as a function of temperature were used to identify detailed ring movements and thus conversion of beta to alpha. These movements cannot occur simultaneously nor symmetrically, precluding conversion of alpha-endosulfan to beta-endosulfan. PMID- 24491186 TI - A novel approach to needs assessment in curriculum development: going beyond consensus methods. AB - BACKGROUND: Needs assessment should be the starting point for curriculum development. In medical education, expert opinion and consensus methods are commonly employed. AIM: This paper showcases a more practice-grounded needs assessment approach. METHODS: A mixed-methods approach, incorporating a national survey, practice audit, and expert consensus, was developed and piloted in thrombosis medicine; Phase 1: National survey of practicing consultants, Phase 2: Practice audit of consult service at a large academic centre and Phase 3: Focus group and modified Delphi techniques vetting Phase 1 and 2 findings. RESULTS: Phase 1 provided information on active curricula, training and practice patterns of consultants, and volume and variety of thrombosis consults. Phase 2's practice audit provided empirical data on the characteristics of thrombosis consults and their associated learning issues. Phase 3 generated consensus on a final curricular topic list and explored issues regarding curriculum delivery and accreditation. CONCLUSIONS: This approach offered a means of validating expert and consensus derived curricular content by incorporating a novel practice audit. By using this approach we were able to identify gaps in training programs and barriers to curriculum development. This approach to curriculum development can be applied to other postgraduate programs. PMID- 24491185 TI - A novel, bottom-up approach to promote evidence-based HIV prevention for people who inject drugs in Ukraine: protocol for the MICT ('Bridge') HIV prevention exchange project. AB - BACKGROUND: Ukraine has one of the most severe HIV epidemics in Eastern Europe, with an estimated 1.6% of the adult population living with the virus. Injection drug use accounts for 36% of new HIV cases. Nongovernmental organizations in Ukraine have little experience with effective, theory-based behavioral risk reduction interventions necessary to reduce the scope of the HIV epidemic among Ukrainians who inject drugs. This study seeks to promote the use of evidence based HIV prevention strategies among Ukrainian organizations working with drug users. METHODS/DESIGN: This study combines qualitative and quantitative methods to explore a model of HIV prevention intervention development and implementation that disseminates common factors of effective behavioral risk reduction interventions and enables service providers to develop programs that reflect their specific organizational contexts. Eight agencies, located in regions of Ukraine with the highest HIV and drug use rates and selected to represent key organizational context criteria (e.g., agency size, target population, experience with HIV prevention), will be taught common factors as the basis for intervention development. We will use qualitative methods, including interviews and observations, to document the process of intervention development and implementation at each agency. Using risk assessments with intervention participants, we will also assess intervention effectiveness.The primary outcome analyses will determine the extent to which agencies develop and implement an intervention for drug users that incorporates common factors of effective behavioral interventions. Effectiveness analyses will be conducted, and effect size of each intervention will be compared to that of published HIV prevention interventions for drug users with demonstrated effectiveness. This study will explore the role of organizational context on intervention development and implementation, including resource allocation decisions, problem-solving around intervention development, and barriers and facilitators to inclusion of common factors and delivery of a high quality intervention. DISCUSSION: This innovative approach to HIV prevention science dissemination and intervention development draws on providers' ability to quickly develop innovative programs and reach populations in greatest need of services. It has the potential to enhance providers' ability to use HIV prevention science to develop sustainable interventions in response to a rapidly changing epidemic. PMID- 24491187 TI - Global health education programming as a model for inter-institutional collaboration in interprofessional health education. AB - While global health (GH) opportunities have expanded at schools of medicine, nursing, and public health, few examples of interprofessional approaches to GH education have been described. The elective GH program at our university serves as an important opportunity for high-quality interprofessional education. We undertook a qualitative study to examine the experience of student, faculty and administrative leaders of the program. We used content analysis to code responses and analyze data. Among the leadership, key themes fell within the categories of interprofessional education, student-faculty collaboration, professional development, and practical considerations for the development of such programs. The principles described could be considered by institutions seeking to develop meaningful partnerships in an effort to develop or refine interprofessional global health education programs. PMID- 24491188 TI - Targeting homologous recombination-mediated DNA repair in cancer. AB - INTRODUCTION: DNA is the target of many traditional non-specific chemotherapeutic drugs. New drugs or therapeutic approaches with a more rational and targeted component are mandatory to improve the success of cancer therapy. The homologous recombination (HR) pathway is an attractive target for the development of inhibitors because cancer cells rely heavily on HR for repair of DNA double strand breaks resulting from chemotherapeutic treatments. Additionally, the discovery that poly(ADP)ribose polymerase-1 inhibitors selectively kill cells with genetic defects in HR has spurned an even greater interest in inhibitors of HR. AREAS COVERED: HR drives the repair of broken DNA via numerous protein mediated sequential DNA manipulations. Due to extensive number of steps and proteins involved, the HR pathway provides a rich pool of potential drug targets. This review discusses the latest developments concerning the strategies being explored to inhibit HR. Particular attention is given to the identification of small molecule inhibitors of key HR proteins, including the BRCA proteins and RAD51. EXPERT OPINION: Current HR inhibitors are providing the basis for pharmaceutical development of more potent and specific inhibitors to be applied in mono- or combinatorial therapy regimes, while novel targets will be uncovered by experiments aimed to gain a deeper mechanistic understanding of HR and its subpathways. PMID- 24491189 TI - New oral anticoagulants: are coagulation units still required? AB - Chronic antithrombotic therapy involves the use of anticoagulants, antiplatelets given either as monotherapy or in combination for the prevention of thrombotic complications. The most feared and sometimes fatal complication with this therapy is bleeding. It should be considered a "golden rule" that a drug or combination of drugs that maximizes efficiency (decreased thromboembolic risk) will probably be less safe (increased risk of bleeding), and this holds true either for single therapy or during combined therapy. The chances of bleeding indicated by risk tables can be useful but show only a snapshot, and the biological, social, environmental, and drug changes and therapeutic adherence also determine changes in the risk of thrombosis and bleeding. Bleeding is an eventuality that occurs in places of "locus minoris resistentiae," and the results of careful phase 3 studies thus cannot be completely predictive of outcomes when a medication is introduced on the pharmaceutical market. With the use of warfarin, the International Normalized Ratio (INR) that has been established to indicate adequately balanced therapy is between 2.0 and 3.0. With the new oral anticoagulants, the pharmaceutical companies emphasize that it is not necessary to monitor anticoagulant effects. In studies with different doses of new oral anticoagulants, however, incidence of clinically significant bleeding complications have been directly related to the doses. Therefore, therapeutic excesses can condition bleeding risk and therapeutic limitation can increase thrombotic risk, especially when short-acting drugs such as the new oral anticoagulants are used. Hence, it is imperative to establish an appropriate method for monitoring new oral anticoagulants, setting levels of safety and effectiveness through periodic dosage and monitoring of their anticoagulant effects. Therefore, we still recommend the use of anticoagulation units for monitoring during treatment with the new oral anticoagulants. PMID- 24491190 TI - The spectrum of eye disease in hospitalized adults living with HIV, 1995-2010. AB - Eye disease is a well-documented complication of HIV infection. Opportunistic infections generally comprised the majority of pre-antiretroviral therapy (ART) eye complications. With the introduction of ART, opportunistic infections diminished. However, early ART regimens were cumbersome regarding side effects and pill burden, making patient compliance difficult. Newer ART regimens are better tolerated and consist of fewer pills, theoretically making compliance easier and therapy more effective. The aim of this chart review study is to examine eye disease epidemiology in HIV patients as ART has evolved. We reviewed 222 admissions at Thomas Jefferson University Hospitals for 188 patients. These cases were divided into two groups. The first group was comprised of patients admitted from 1995 through 2003, while the second group consisted of patients admitted from 2003 to 2010. Eye disease epidemiology was compared between the two groups. Our study did note a significant decrease in eye diseases caused by opportunistic infections in the 2003-2010 patient group. Noninfectious eye disease is a significant complication in this group. PMID- 24491191 TI - Imminent danger? Probabilistic classification learning of threat-related information in obsessive-compulsive disorder. AB - A tendency to overestimate threat has been shown in individuals with OCD. We tested the hypothesis that this bias in judgment is related to difficulties in learning probabilistic associations between events. Thirty participants with OCD and 30 matched healthy controls completed a learning experiment involving 2 variants of a probabilistic classification learning task. In the neutral weather prediction task, rainy and sunny weather had to be predicted. In the emotional task danger of an epidemic from virus infection had to be predicted (epidemic prediction task). Participants with OCD were as able as controls to improve their prediction of neutral events across learning trials but scored significantly below healthy controls on the epidemic-prediction task. Lower performance on the emotional task variant was significantly related to a heightened tendency to overestimate threat. Biased information processing in OCD might thus hamper corrective experiences regarding the probability of threatening events. PMID- 24491192 TI - Parenting behaviors during risky driving by teens with attention deficit/hyperactivity disorder. AB - Parenting practices for teen drivers with ADHD were observed via a video monitor installed in vehicles. All teens had recently completed a driver education course and were in the driving permit stage of a graduated driver-licensing program. Parent behaviors were coded during drives when teens were driving safely and during drives when teens engaged in risky driving. The overall frequency of positive parenting strategies was low, regardless of whether teens drove safely or engaged in risky driving. Although the rate of negative feedback was also low, parents engaged in significantly more criticism and were rated by an observer to appear angrier when teens were driving in a risky manner. No other differences in parent behaviors associated with the quality of teen driving were observed. The inconsistencies between observed parenting behaviors and those parenting practices recommended as effective with teens with ADHD are discussed. The need for further research addressing effective strategies for teaching teens with ADHD to drive is highlighted. PMID- 24491195 TI - The gap between science and practice: how therapists make their clinical decisions. AB - Recent surveys have found that many patients are not receiving empirically supported treatments and that therapists may not update their knowledge of research. Studies have found that therapists prefer to use their clinical experience rather than research findings to improve their practice, although cognitive behavioral (CB) practitioners have been found to use research more frequently than therapists of other theoretical orientations. The organization in which therapists work has been shown to impact attitudes toward working practices, but studies have not examined whether workplace requirements to use research affect therapists' practice. Studies to date have mainly been conducted in North America. These findings may not be generalizable to the United Kingdom where there is a National Health Service (NHS), which requires the use of empirically supported treatments. The first part of this study aimed to investigate which factors were influential in therapists' choice of theoretical orientation and to see whether CB practitioners differed from other therapists in the factors that influenced their choice of theoretical orientation. The second part tested whether therapists' theoretical orientation or their workplace influenced the frequency with which they used research in their clinical decision making. The final part investigated whether being a CB practitioner or working in the NHS was associated with having a favorable attitude toward research. An online survey was sent to 4,144 psychological therapists in England; 736 therapists responded (18.5%). Therapists reported that research had little influence over their choice of theoretical orientation and clinical decision making compared to other factors, specifically clinical experience and supervision. CB practitioners and NHS therapists, regardless of their orientation, were significantly more likely to use research than other therapists and were more likely to have a positive attitude toward research. PMID- 24491193 TI - The premonitory urge to tic: measurement, characteristics, and correlates in older adolescents and adults. AB - In addition to motor and/or vocal tics, many individuals with Tourette syndrome (TS) or chronic tic disorder (CTD) report frequent, uncomfortable sensory phenomena that immediately precede the tics. To date, examination of these premonitory sensations or urges has been limited by inconsistent assessment tools. In this paper, we examine the psychometric properties of a nine-item self report measure, the Premonitory Urge to Tic Scale (PUTS) and examine the characteristics and correlates of the premonitory urge to tic in a clinical sample of 122 older adolescents and adults with TS or CTD. The PUTS demonstrated adequate internal consistency, temporal stability, and concurrent validity. Premonitory urges were endorsed by the majority of individuals. Most individuals reported some relief from the urges after completing a tic and being able to stop their tics even if only temporarily. Degree of premonitory urges was not significantly correlated with age, and we did not observe any gender differences. Degree of premonitory urges was significantly correlated with estimated IQ and tic severity, but not severity of comorbid obsessive-compulsive disorder or attention-deficit hyperactivity disorder. Also, it was not related to concomitant medication status. These findings represent another step forward in our understanding of the premonitory sensations associated with TS and CTD. PMID- 24491196 TI - Integrating the interpersonal psychological theory of suicide into the depression/suicidal ideation relationship: a short-term prospective study. AB - We examined the hypothesis that depressive symptoms are associated with increased beliefs about perceived burdensomeness and thwarted belongingness identified in the interpersonal psychological theory of suicide and that these beliefs are associated with changes in suicidal ideation. Participants with clinical levels of depressive symptoms (n=299) were selected from a larger group (n=508) and completed measures of depressive symptoms, perceived burdensomeness and thwarted belongingness, and suicidal ideation twice over a period of 2 months. Results of a structural equation model found that depressive symptoms were associated with increases in burdensomeness and lack of belonging, which were associated with suicidal ideation. Moreover, this hypothesized integrated model demonstrated a significantly better fit than an alternative model that assumed burdensomeness and lack of belonging were associated with changes in depressive symptoms, which were associated with suicidal ideation. Our findings suggest that the well established relationship between depressive symptoms and suicidal ideation is associated with changes in beliefs that one is a burden on others and lacks belonging. More generally, these results suggest that it may be fruitful to integrate theories of suicide risk to form a comprehensive model that can inform future research and clinical interventions. PMID- 24491194 TI - Partners' attributions for service members' symptoms of combat-related posttraumatic stress disorder. AB - The association of service members' combat-related PTSD with partners' distress is weaker when spouses/partners believe that service members experienced more traumatic events during deployment. Also, when simultaneously examining partners' perceptions of all PTSD symptoms, perceptions of reexperiencing symptoms (the symptoms most obviously connected to traumatic events) are significantly negatively related to distress in partners. These findings are consistent with the notion that partners may be less distressed if they make external, rather than internal, attributions for service members' symptoms. The present study explicitly tests this possibility. Civilian wives of active duty service members completed measures regarding their own marital satisfaction, their perceptions of service members' combat exposure during deployments, their perceptions of service members' symptoms of PTSD, and their attributions for those symptoms. External attributions were significantly positively associated with perceptions of combat exposure (rp=.31) and reexperiencing symptoms (beta=.33) and significantly negatively associated with perceptions of numbing/withdrawal symptoms (rp=-.22). In contrast, internal attributions were significantly negatively associated with perceptions of reexperiencing symptoms (beta=-.18) and significantly positively associated with perceptions of numbing/withdrawal symptoms (beta=.46). Internal attributions significantly moderated the negative association of PTSD symptoms with marital satisfaction, such that the association strengthened as internal attributions increased. These findings are the first explicit support for an attributional understanding of distress in partners of combat veterans. Interventions that alter partners' attributions may improve marital functioning. PMID- 24491197 TI - Discriminating clinical from nonclinical manifestations of test anxiety: a validation study. AB - Test anxiety, although being a very common, severe, and impairing psychological disorder, is not coded as a separate diagnosis in the DSM or ICD. In the present study we investigated whether the Test Anxiety Inventory can be used to discriminate clinical and subclinical levels of test anxiety by comparing patients who seek treatment for their test anxiety in an outpatient clinic with carefully matched students with normal test anxiety. The data from 47 test anxious patients as well as 41 healthy university students were examined. Results show that a cutoff score of >=80 in the Test Anxiety Inventory can discriminate the clinical group from the control students. The symptom pattern of test anxiety was very consistent in the clinical group regardless of the principal diagnosis allocated by the treating clinician. Comorbid depression did not affect the severity of test anxiety. The motivation to avoid failure was one of the most important differences between patients who sought help for their test anxiety and students with nonclinical levels of test anxiety. PMID- 24491199 TI - Internet-based mindfulness treatment for anxiety disorders: a randomized controlled trial. AB - Mindfulness-based interventions have proven effective for the transdiagnostic treatment of heterogeneous anxiety disorders. So far, no study has investigated the potential of mindfulness-based treatments when delivered remotely via the Internet. The current trial aims at evaluating the efficacy of a stand-alone, unguided, Internet-based mindfulness treatment program for anxiety. Ninety-one participants diagnosed with social anxiety disorder, generalized anxiety disorder, panic disorder, or anxiety disorder not otherwise specified were randomly assigned to a mindfulness treatment group (MTG) or to an online discussion forum control group (CG). Mindfulness treatment consisted of 96 audio files with instructions for various mindfulness meditation exercises. Primary and secondary outcome measures were assessed at pre-, posttreatment, and at 6-months follow-up. Participants of the MTG showed a larger decrease of symptoms of anxiety, depression, and insomnia from pre- to postassessment than participants of the CG (Cohen's d(between)=0.36-0.99). Within effect sizes were large in the MTG (d=0.82-1.58) and small to moderate in the CG (d=0.45-0.76). In contrast to participants of the CG, participants of the MTG also achieved a moderate improvement in their quality of life. The study provided encouraging results for an Internet-based mindfulness protocol in the treatment of primary anxiety disorders. Future replications of these results will show whether Web-based mindfulness meditation can constitute a valid alternative to existing, evidence based cognitive-behavioural Internet treatments. The trial was registered at ClinicalTrials.gov (NCT01577290). PMID- 24491198 TI - Changes in distress intolerance and treatment outcome in a partial hospital setting. AB - Despite the well-established role of distress intolerance (DI) in a wide range of psychological disorders, few studies have examined whether DI improves during treatment and whether these changes are associated with symptom outcomes. Patients (N=626) enrolled in a brief cognitive-behavioral partial hospital program completed pre- and posttreatment measures of DI. Results indicated that DI decreased significantly during treatment, with more than 30% of the sample exhibiting a reduction of more than 2 standard deviations from the sample mean. Women reported higher DI than men at baseline; however, there were no gender differences in changes in DI over time. Participants also completed a pre- and posttreatment measure of depression and a subset completed a measure of anxiety (n=167). DI was associated with more severe depression and anxiety at pre- and posttreatment, with participants who reported a decrease in DI also reporting lower depression and anxiety symptoms at post-treatment. These results further highlight the transdiagnostic relevance of DI and suggest that DI may be a relevant factor in treatment outcome for depression and anxiety. PMID- 24491200 TI - The sense of incompleteness as a motivator of obsessive-compulsive symptoms: an empirical analysis of concepts and correlates. AB - Contemporary models of obsessive-compulsive disorder emphasize the importance of harm avoidance (HA) and related dysfunctional beliefs as motivators of obsessive compulsive (OC) symptoms. Recently, there has been a resurgence of interest in Janet's (1908) concept of incompleteness (INC) as another potentially important motivator. Contemporary investigators define INC as the sense that one's actions, intentions, or experiences have not been properly achieved. Janet defined INC more broadly to include alexithymia, depersonalization, derealization, and impaired psychological mindedness. We conducted two studies to address four issues: (a) the clinical correlates of INC; (b) whether INC and HA are distinguishable constructs; (c) whether INC predicts OC symptoms after controlling for HA; and (d) the relative merits of broad versus narrow conceptualizations of INC. Study 1 was a meta-analysis of the clinical correlates of narrowly defined INC (16 studies, N=5,940). INC was correlated with all types of OC symptoms, and was more strongly correlated with OC symptoms than with general distress. Study 2 (N=534 nonclinical participants) showed that (a) INC and HA were strongly correlated but factor analytically distinguishable; (b) INC statistically predicted all types of OC symptoms even after controlling for HA; and (c) narrow INC was most strongly correlated with OC symptoms whereas broad INC was most strongly correlated with general distress. Although the findings are limited by being correlational in nature, they support the hypothesis that INC, especially in its narrow form, is a motivator of OC symptoms. PMID- 24491202 TI - Relationships among self, others, and persecutors in individuals with persecutory delusions: a repertory grid analysis. AB - The purpose of the current study was to examine the way individuals with persecutory delusions construe the self, others, and their main persecutor with reference to the constructs of malevolence and omnipotence, and examine the extent to which these interpersonal beliefs link to distress, self-esteem, and delusion conviction. Repertory grid methodology was used to explore interpersonal beliefs about malevolence and omnipotence in a sample (N=30) of individuals with current persecutory delusions (mean age 36.4 years; 62% male and 53% White). Participants also completed measures of emotional distress (depression and anxiety) and self-esteem. The findings suggested that persecutors were construed as more omnipotent and malevolent than both the self and others; others in turn were construed as more omnipotent and malevolent than the self. Beliefs about self as powerful were associated with lower anxiety, depression, and higher self esteem, and beliefs about persecutors' omnipotence predicted delusion conviction. As with voices, the concepts of power/omnipotence and malevolence/benevolence appear to be important constructs when seeking to understand the relationship between individuals and their perceived persecutors. These findings support working therapeutically with negative schematic beliefs about self, others, and persecutors, which is consistent with a person-based cognitive therapy model of distressing psychosis. PMID- 24491201 TI - The Driving Behavior Survey as a measure of behavioral stress responses to MVA related PTSD. AB - Numerous treatments are available that address the core symptoms of posttraumatic stress disorder (PTSD). However, there are a number of related behavioral stress responses that are not assessed with PTSD measures, yet these behavioral stress responses affect quality of life. The goal of the current study was to investigate whether a recently developed measure of behavioral stress response, the Driving Behavior Survey (DBS), was sensitive to change associated with treatment among a group of participants diagnosed with PTSD. The DBS indexes anxious driving behavior, which is frequently observed among individuals with motor vehicle accident-related PTSD. Participants (n=40) were racially diverse adults (M age=40.78, 63% women) who met diagnostic criteria for motor vehicle accident-related PTSD. Hierarchical linear modeling analyses indicated that participants who were assigned to a brief, exposure-based intervention displayed significant reductions on the DBS subscales relative to participants assigned to the wait-list control condition (r=.41-.43). Moreover, mediational analyses indicated that the observed reductions on the DBS subscales were not better accounted for by reductions in PTSD. Taken together, these findings suggest that the DBS subscales are sensitive to changes associated with PTSD treatment and can be used to augment outcome assessment in PTSD treatment trials. PMID- 24491206 TI - Reports from the award symposia hosted by the American Chemical Society, Division of Carbohydrate Chemistry at the 245th American Chemical Society National Meeting. AB - We would like to congratulate all of the award winners for the well deserved honor. The award symposia provided a snapshot of some of the state-of-the-art research at the interface between chemistry and biology in the glycoscience field. The presentations serve as prime examples of the increasing integration of chemical and biological research in the area of glycoscience and how tools of chemistry can be applied to answer interesting, important, and fundamental biological questions. We look forward to many more years of exciting developments in the chemistry and chemical biology of glycoscience and anticipate improved tools and approaches will drive major advances while also spurring interests in the wider field. PMID- 24491208 TI - Effects of formulation and operating variables on zanamivir dry powder inhalation characteristics and aerosolization performance. AB - Abstract The objective of this study was to investigate the influence of formulation and operating variables on the physical characteristics and aerosolization performance of zanamivir spary-dried powders for inhalation. Spray dried samples of zanamivir, zanamivir/mannitol and zanamivir/mannitol/leucine were prepared from their corresponding aqueous solutions under the same conditions to study the influence of the composition, and zanamivir/mannitol/leucine (1/1/3 by weight) formulation was used for investigation of the effect of the preparation process. Dry powders were characterized afterwards for different physical properties, including morphology, particle size, flowability, density and moisture absorption. The in vitro deposition was also evaluated after the aerosolization of powders at 100 L min( 1) via the Aerolizer(r) into a Next Generation Impactor (NGI). The highest FPF of 41.40 +/- 1.1% was obtained with a zanamivir/mannitol/leucine ratio of 1/1/3, which had an average Dg of 3.11 +/- 0.13 MUm and an angle of repose of 36 degrees ( )+/- 1. It was found that the influence of the preparation process on zanamivir spary-dried powders characteristics and aerosolization properties was relatively small, but the influence of the composition was relatively large. Optimization of DPI can be achieved by selecting the most appropriate formulation and preparation process. PMID- 24491207 TI - Retroperitoneal laparoscopic technique in treatment of complex renal stones: 75 cases. AB - BACKGROUND: In most hospitals, several options for the management of renal stones are available: shockwave lithotripsy, endourologic treatment, or surgery. Choice of treatment is based on the anatomic characteristics of the patient, and the location and size of the stones. In this study we assessed a retroperitoneal laparoscopic technique for treatment of complex renal stones. METHODS: Seventy five patients, including 53 men and 22 women with a mean age of 47.8 years (range 18-74 y), underwent retroperitoneal laparoscopy for the treatment of complex renal stones between July 2006 and November 2012 in our hospital. RESULTS: The retroperitoneal laparoscopic procedures for treatment of complex renal stones were completely successful in 73 cases, while 2 cases converted to open surgery. The operative time was 85-190 min with a mean of 96 min. The estimated blood lost was 20-400 mL with a mean of 80 mL. After the operation 7 patients experienced urinary leakage. Ultrasonography, x-ray of the kidney, ureter and bladder, and intravenous urography were reviewed at post-procedural follow-up at 6-82 months. No hydronephrosis aggravation was found, and there was no calculus recurrence. CONCLUSION: The merits of retroperitoneal laparoscopy for the treatment of complex renal stones include sparing the nephron, less bleeding, short hospitalization, quick postoperative recovery, and controllable procedure after training Success depends on the experience of surgeons and judicious selection of cases. PMID- 24491209 TI - Ruthenium porphyrin catalyzed three-component reaction of diazo compounds, nitrosoarenes, and alkynes: an efficient approach to multifunctionalized aziridines. AB - A ruthenium porphyrin catalyzed three-component reaction of diazo compounds, nitrosoarenes, and alkynes gives multifunctionalized aziridines in good to high yields and with moderate to high diastereoselectivity. PMID- 24491210 TI - Rapid Ni, Zn, and Cu ion-promoted alcoholysis of N,N-bis(2-picolyl)- and N,N bis((1H-benzimidazol-2-yl)methyl)-p-nitrobenzamides in methanol and ethanol. AB - The methanolysis and ethanolysis of the Ni(II), Zn(II), and Cu(II) complexes of N,N-bis(2-picolyl)-p-nitrobenzamide (1) and N,N-bis((1H-benzimidazol-2-yl)methyl) p-nitrobenzamide (2) were studied under pH-controlled conditions at 25 degrees C. Details of the mechanism were obtained from plots of the kobs values for the reaction under pseudo-first-order conditions as a function of [M2+]. Such plots give saturation kinetics for the Cu(II)-promoted reactions of 1 and 2 in both solvents, the Zn(II)-promoted reaction of 1 in methanol, and the Zn(II)- and Ni(II)-promoted reactions of 2 in methanol and ethanol. Logs of the maximal observed rate constants obtained from the latter plots, (kobs(max)), when plotted versus s(s)pH, are curved downward only for the Cu(II) complexes of 1 and 2 in both solvents and the Zn(II) complex of 1 in methanol. Despite differences in the metal-binding abilities and pKa values for formation of the active form, there is a common reaction mechanism, with the active form being 1:M(II):(-OR) and 2:M(II):(-OR), where M(II):(-OR) is the metal-bound alkoxide. The acceleration provided by the metal ion is substantial, being 10(14)-10(19) relative to the k2( OMe) value for the alkoxide-promoted alcoholysis of the uncomplexed amide. PMID- 24491211 TI - Genotype-environment interactions for quantitative traits in Korea Associated Resource (KARE) cohorts. AB - BACKGROUND: Due to the lack of statistical power and confounding effects of population structure in human population data, genotype-environment interaction studies have not yielded promising results and have provided only limited knowledge for exploring how genotype and environmental factors interact to in their influence onto risk. RESULTS: We analyzed 49 human quantitative traits in 7,170 unrelated Korean individuals on 326,262 autosomal single nucleotide polymorphisms (SNPs) collected from the KARE (Korean Association Resource) project, and we estimated the statistically significant proportion of variance that could be explained by genotype-area interactions in the supra-iliac skinfold thickness trait (hGE2 = 0.269 and P = 0.00032), which is related to abdominal obesity. Data suggested that the genotypes could have different effects on the phenotype (supra-iliac skinfold thickness) in different environmental settings (rural vs. urban areas). We then defined the genotype groups of individuals with similar genetic profiles based on the additive genetic relationships among individuals using SNPs. We observed the norms of reaction, and the differential phenotypic response of a genotype to a change in environmental exposure. Interestingly, we also found that the gene clusters responsible for cell-cell and cell-extracellular matrix interactions were enriched significantly for genotype area interaction. CONCLUSIONS: This significant heritability estimate of genotype environment interactions will lead to conceptual advances in our understanding of the mechanisms underlying genotype-environment interactions, and could be ultimately applied to personalized preventative treatments based on environmental exposures. PMID- 24491212 TI - Anxious solitude and the middle school transition: a diathesis * stress model of peer exclusion and victimization trajectories. AB - Consistent with a Diathesis * Stress model, it was hypothesized that anxious solitude (individual vulnerability) and the middle school transition (environmental stress) would jointly predict peer exclusion and victimization trajectories. Youth (N = 688) were followed from 3rd through 7th grade, with the middle school transition in 6th grade. Peer-reported peer exclusion and physical victimization trajectories across the middle school transition were modeled with piecewise growth curves. As expected, anxious solitude predicted elevated exclusion and victimization in both elementary and middle school. Nonetheless, exclusion and victimization declined after the transition on average, and anxious solitary youth versus average youth experienced greater relative declines. The pattern of results suggests that the collective renegotiation of peer relations after the transition, rather than posttransition decline in classroom emotional support, contributed to the posttransition decline in peer mistreatment. PMID- 24491213 TI - Cognitive control and language across the life span: does labeling improve reactive control? AB - How does cognitive control change with age, and what are the processes underlying these changes? This question has been extensively studied using versions of the task-switching paradigm, which allow participants to actively prepare for the upcoming task (Kray, Eber, & Karbach, 2008). Little is known, however, about age related changes in this ability across the life span when there is no opportunity to anticipate task goals. We examined the effect of 2 kinds of verbal self instruction-labeling either the task goal or the relevant feature of the stimulus on 2 components of cognitive control, goal setting and switching, in children, young adults, and older adults. All participants performed single-task blocks and mixed-task blocks (involving unpredictable switching between 2 tasks) in silent and labeling conditions. Participants categorized bidimensional stimuli either by picture or by color, depending on their spatial position in a 2-cell vertical grid. Response times revealed an inverted U shape in performance with age. These age differences were more pronounced for goal setting than for switching, thus generalizing results obtained in situations taping proactive control to this new context forcing reactive control. Further, differential age-related effects of verbalization were also obtained. Verbalizations were detrimental for young adults, beneficial for older adults, and had mixed effects in children. These differences are interpreted in terms of qualitative developmental changes in reactive goal-setting strategies. PMID- 24491214 TI - Comparing changes in late-life depressive symptoms across aging, disablement, and mortality processes. AB - Developmental processes are inherently time-related, with various time metrics and transition points being used to proxy how change is organized with respect to the theoretically underlying mechanisms. Using data from 4 Swedish studies of individuals aged 70-100+ (N = 453) who were measured every 2 years for up to 5 waves, we tested whether depressive symptoms (according to the Center for Epidemiologic Studies Depression Scale; Radloff, 1977) are primarily driven by aging-, disablement-, or mortality-related processes, as operationally defined by time-from-birth, time-to/from-disability-onset (1st reported impairment in Personal Activities of Daily Living; Katz, Ford, Moskowitz, Jackson, & Jaffe, 1963), and time-to-death metrics. Using an approach based on Akaike weights, we tested whether developmental trajectories (for each time metric) of depressive symptoms in late life are more efficiently described as a single continuous process or as a 2-phase process. Comparing fits of linear and multiphase growth models, we found that 2-phase models demonstrated better fit than did single phase models across all time metrics. Time-to-death and time-to/from-disability onset models provided more efficient descriptions of changes in depressive symptoms than did time-from-birth models, with time-to-death models representing the best overall fit. Our findings support prior research that late-life changes in depressive symptoms are driven by disablement and, particularly, mortality processes, rather than advancing chronological age. From a practical standpoint, time-to/from-disability-onset and, particularly, time-to-death metrics may provide better "base" models from which to examine changes in late-life depressive symptoms and determine modifiable risk and protective factors. Developmental researchers across content areas can compare age with other relevant time metrics to determine if chronological age or other processes drive the underlying developmental change in their construct of interest. PMID- 24491215 TI - Context differences in children's ingroup preferences. AB - Ingroup preferences when deciding who to include in 2 distinct intergroup contexts, gender and school affiliation, were investigated. Children and adolescents, in the 4th (9-10 years) and 8th (13-14 years) grades, chose between including someone in their group who shared their group norm (moral or conventional) or who shared their group membership (school affiliation or gender). With age, children displayed a greater ability to balance information about ingroup norms and group membership. Younger children were more likely to include an outgroup member who supported equal norms than were older children. Accompanying the choices made, there was a greater use of fairness reasoning in younger rather than older participants, and increased references to group identity and group functioning for school identification. There were no differences in ingroup preferences in the school and gender contexts for groups involving moral norms. Desires for equal allocation of resources trumped differences related to ingroup preference. For social-conventional norms, however, there was a greater ingroup preference in a school intergroup context than in a gender intergroup context. Thus, the results demonstrate the importance of context in the manifestation of ingroup preference and the increasing sophistication, with age, of children's and adolescents' group decision-making skills. PMID- 24491216 TI - CF3I synthesis catalyzed by activated carbon: a density functional theory study. AB - A revised reaction mechanism of CF3I synthesis catalyzed by activated carbon is investigated with quantum chemistry methods using density functional theory (DFT). The adsorption configurations of possible intermediates are carefully examined. The reaction pathway and related transition states are also analyzed. According to our calculations, first, the dehydrofluorination of CHF3 is catalyzed by -COOH groups, which possesses the highest barrier and is accordingly identified as the rate-determining step. Second, the difluorocarbene disproportionation over graphite (001) surface proceeds instead of dimerization. The next reaction steps involving the association of fluoromethine and trifluoromethyl, the fluorine abstractions between intermediates and the iodine abstractions by the desorbed CF3 and CF2CF3 from molecular iodine are also feasible over graphite (001) surfaces. It is also found that the coke deposition in experiments is due to the fluorine abstraction from fluoromethine. This revised mechanism is in agreement with available experimental data and our theoretical computations. PMID- 24491217 TI - Effect of wettability on sessile drop freezing: when superhydrophobicity stimulates an extreme freezing delay. AB - An increasing number of studies directed at supercooling water droplets on surfaces with different wettabilities have appeared in recent years. This activity has been stimulated by the recognition that water supercooling phenomena can be effectively used to develop methods for protecting outdoor equipment and infrastructure elements against icing and snow accretion. In this article, we discuss the nucleation kinetics of supercooled sessile water droplets on hydrophilic, hydrophobic, and superhydrophobic surfaces under isothermal conditions at temperatures of -8, -10, and -15 degrees C and a saturated water vapor atmosphere. The statistics of nucleation events for the ensembles of freezing sessile droplets is completed by the detailed analysis of the contact angle temperature dependence and freezing of individual droplets in a saturated vapor atmosphere. We have demonstrated that the most essential freezing delay is characteristic of the superhydrophobic coating on aluminum, with the texture resistant to contact with ice and water. This delay can reach many hours at T = 8 degrees C and a few minutes at -23 degrees C. The observed behavior is analyzed on the basis of different nucleation mechanisms. The dissimilarity in the total nucleation rate, detected for two superhydrophobic substrates having the same apparent contact angle of the water drop but different resistivities of surface texture to the contact with water/ice, is associated with the contribution of heterogeneous nucleation on external centers located at the water droplet/air interface. PMID- 24491218 TI - A monochromatic electrochemiluminescence sensing strategy for dopamine with dual stabilizers-capped CdSe quantum dots as emitters. AB - A promising electrochemiluminescence (ECL) sensing strategy was proposed with dual-stabilizers-capped CdSe quantum dots (QDs) as ECL emitters. The dual stabilizers-capped CdSe QDs were covalently immobilized onto p-aminobenzoic acid modified glass carbon electrode with ethylenediamine as a link molecule. This strategy can preserve the completely passivated surface states of dual stabilizers-capped CdSe QDs, so that the sensor demonstrated eye-visible greenish, band gap engineering and monochromatic ECL emission at 546 nm with a fwhm of 35 nm. Moreover, the proposed sensor could accurately quantify dopamine from 10.0 nM to 3.0 MUM with a detection limit of 3.0 nM in practical drug, human urine, and cerebrospinal fluid samples without any signal amplification techniques. This strategy is promising for developing ECL sensors with high sensitivity and spectral selectivity. PMID- 24491220 TI - A review of image-enhanced endoscopy in the evaluation of colonic polyps. AB - The practice of colonoscopy has changed considerably over the last decade. The growth of image-enhanced endoscopy have altered our concepts of how we perform colonoscopy. This article examines the evidence base behind these techniques and looks at where future research needs to be directed. PMID- 24491219 TI - Lipocalin-2, A-FABP and inflammatory markers in relation to flow-mediated vasodilatation in patients with essential hypertension. AB - Lipocalin families including lipocalin-2 and adipocyte fatty acid binding protein (A-FABP) were recently identified as novel adipokines to be associated with the cardiovascular risk variables of the metabolic syndrome. We evaluated the lipocalin-2 and A-FABP levels in 62 patients with essential hypertension (EHT) and 16 age-, gender- and body mass index-matched normotensive healthy subjects (NT). Furthermore, we evaluated the correlation between lipocalin-2, A-FABP levels, inflammatory markers including hsCRP and IL-10, and flow-mediated vasodilatation (FMD). In EHT, circulating lipocalin-2 levels were significantly higher than in NT (85.0 +/- 37.6 ng/ml versus 43.8 +/- 13.1 ng/ml, p < 0.001). However, A-FABP levels were not different between patients with EHT and NT. Serum lipocalin-2 levels were positively associated with SBP (r = 0.54, p < 0.001), DBP (r = 0.34, p = 0.003) and fasting glucose levels (r = 0.25, p = 0.032), On the other hand, circulating A-FABP levels were significantly associated with variables such as BMI, fasting insulin, insulin resistance index and hsCRP. Multiple linear regression analysis showed that mean arterial pressure was associated with fasting glucose, lipocalin-2 levels, age, BMI and hsCRP levels (R2= 0.456). However, circulating lipocalin-2 levels were not associated with FMD. In conclusion, lipocalin-2 levels were significantly higher in patients with EHT, and were independently associated with mean arterial pressure. PMID- 24491221 TI - Introducing a new measure for assessing self-efficacy in response to air pollution hazards for pregnant women. AB - A self-efficacy instrument should be condition-specific. There are several instruments for measuring self-efficacy, but none are air pollution-specific. This study aimed to develop a self-efficacy measure for assessing pregnant women's responses to air pollution hazards. A random sample of pregnant women aged between 18 and 35 years attending three prenatal care centers were entered into the study. Prenatal care centers randomly selected from a list of centers located in different geographical regions of Tehran, Iran. After careful consideration and performing content and face validity, a 4-item measure was developed and participants completed the questionnaire. Reliability was estimated using internal consistency and validity was assessed by performing confirmatory factor analysis (CFA) and known group comparison. In all 200 eligible pregnant women were studied. The mean age of participants was 26.9 (SD = 4.8) years and it was 27.9 (SD = 9.1) weeks for gestational age. The findings showed almost perfect results for both content validity ratio (CVR = 1) and content validity index (CVI = 1). The confirmatory factor analysis indicated a good fit to the data, and known group comparison revealed satisfying results. Internal consistency as measured by the Cronbach's alpha coefficient was found to be 0.74. In general, the findings suggest that this new generated scale is a reliable and valid specific measure of self-efficacy in response to air pollution hazards for pregnant women. However, further studies are needed to establish stronger psychometric properties for the questionnaire. PMID- 24491222 TI - In response: it's all about what is typical. PMID- 24491223 TI - Small patients, complex challenging cases: a reappraisal of the professional efforts in perinatal autopsies. PMID- 24491224 TI - Single nucleotide polymorphism (SNP) analysis used for the phylogeny of the Mycobacterium tuberculosis complex based on a pyrosequencing assay. AB - BACKGROUND: Different polymorphisms have been described as markers to classify the lineages of the Mycobacterium tuberculosis complex. The analysis of nine single nucleotide polymorphisms (SNPs) was used to describe seven SNPs cluster groups (SCGs). We attempted to classify those strains that could not been categorized into lineages by the genotyping methods used in the routine testing. RESULTS: The M. tuberculosis complex isolates collected in 2010 in our region were analysed. A new method based on multiplex-PCRs and pyrosequencing to analyse these SNPs was designed. For the pyrosequencing assay nine SNPs that defined the seven SCGs were selected from the literature: 1977, 74092, 105139, 232574, 311613, 913274, 2460626, 3352929 and gyrA95. In addition, SNPs in katG(463), mgtC(182), Ag85C(103) and RD(Rio) deletion were detected. CONCLUSIONS: This work has permitted to achieve a better classification of Aragonian strains into SCGs and in some cases, to assign strains to its certain lineage. Besides, the description of a new pattern shared by two isolates "SCG-6c" reinforces the interest of SNPs to follow the evolution of M. tuberculosis complex. PMID- 24491225 TI - Cembrane-type diterpenoids from the Chinese liverworts Chandonanthus hirtellus and C. birmensis. AB - Six new cembrane-type diterpenoids (1-6) were isolated from two species of Chandonanthus: Chandonanones A, B, and D-F (1, 2, and 4-6) were isolated from C. hirtellus, and chandonanones B, C, E, and F (2, 3, 5, and 6) from C. birmensis. Five known diterpenoids, (8E)-4alpha-acetoxy-12alpha,13alpha-epoxycembra-1(15),8 diene (7), isochandonanthone (8), chandonanthone (9), anadensin (10), and 2,10,14 triacetoxy-7,8,18,19-diepoxydolabell-3(E)-ene (11), were also obtained. The structures of the new metabolites were established by analyses of their spectroscopic data (1D NMR, 2D NMR, HRESIMS, and IR). The absolute configurations of compounds 1 and 2 were unequivocally confirmed using single-crystal X-ray diffraction analysis with Cu Kalpha radiation. Cytotoxicity tests of the isolated diterpenoids against seven cancer cell lines (DU145, PC3, A549, PC12, NCI-H292, NCI-H1299, and A172) revealed that some of the diterpenoids had weak activity. PMID- 24491226 TI - Developing the role of big data and analytics in health professional education. AB - As we capture more and more data about learners, their learning, and the organization of their learning, our ability to identify emerging patterns and to extract meaning grows exponentially. The insights gained from the analyses of these large amounts of data are only helpful to the extent that they can be the basis for positive action such as knowledge discovery, improved capacity for prediction, and anomaly detection. Big Data involves the aggregation and melding of large and heterogeneous datasets while education analytics involves looking for patterns in educational practice or performance in single or aggregate datasets. Although it seems likely that the use of education analytics and Big Data techniques will have a transformative impact on health professional education, there is much yet to be done before they can become part of mainstream health professional education practice. If health professional education is to be accountable for its programs run and are developed, then health professional educators will need to be ready to deal with the complex and compelling dynamics of analytics and Big Data. This article provides an overview of these emerging techniques in the context of health professional education. PMID- 24491227 TI - Synthesis and characterization of diverse Pt nanostructures in Nafion. AB - With the aid of TEM characterization, we describe two distinct Pt nanostructures generated via the electroless reduction of Pt(NH3)4(NO2)2 within Nafion. Under one set of conditions, we produce bundles of Pt nanorods that are 2 nm in diameter and 10-20 nm long. These bundled Pt nanorods, uniformly distributed within 5 MUm of the Nafion surface, are strikingly similar to the proposed hydrated nanomorphology of Nafion, and therefore strongly suggestive of Nafion templating. By altering the reaction environment (pH, reductant strength, and Nafion hydration), we can also generate nonregular polyhedron Pt nanoparticles that range in size from a few nanometers in diameter up to 20 nm. These Pt nanoparticles form a dense Pt layer within 100-200 nm from the Nafion surface and show a power-law dependence of particle size and distribution on the distance from the Nafion membrane surface. Control over the distribution and the type of Pt nanostructures in the surface region may provide a cost-effective, simple, and scaleable pathway for enhancing manufacturability, activity, stability, and utilization efficiency of Pt catalysts for electrochemical devices. PMID- 24491228 TI - Human steroid and oxysterol 7alpha-hydroxylase CYP7B1: substrate specificity, azole binding and misfolding of clinically relevant mutants. AB - Oxysterols and neurosteroids are important signaling molecules produced by monooxygenases of the cytochrome P450 family that realize their effect through nuclear receptors. CYP7B1 catalyzes the 6- or 7-hydroxylation of both steroids and oxysterols and thus is involved in the metabolism of neurosteroids and bile acid synthesis, respectively. The dual physiological role of CYP7B1 is evidenced from different diseases, liver failure and progressive neuropathy, caused by enzyme malfunction. Here we present biochemical characterization of CYP7B1 at the molecular level to understand substrate specificity and susceptibility to azole drugs. Based on our experiments with purified enzyme, the requirements for CYP7B1 hydroxylation of steroid molecules are as follows: C5 hydrogen in the alpha configuration (or double bond at C5), a polar group at C17, a hydroxyl group at C3, and the absence of the hydroxyl group at C20-C24 in the C27-sterol side chain. 21-hydroxy-pregnenolone was identified as a new substrate, and overall low activity toward pregnanes could be related to the increased potency of 7-hydroxy derivatives produced by CYP7B1. Metabolic conversion (deactivation) of oxysterols by CYP7B1 in a reconstituted system proceeds via two sequential hydroxylations. Two mutations that are found in patients with diseases, Gly57Arg and Phe216Ser, result in apo-P450 (devoid of heme) protein formation. Our CYP7B1 homology model provides a rationale for understanding clinical mutations and relatively broad substrate specificity for steroid hydroxylase. PMID- 24491231 TI - Electrochemical energy storage. PMID- 24491229 TI - Takotsubo cardiomyopathy and transient thyrotoxicosis during combination therapy with interferon-alpha and ribavirin for chronic hepatitis C. AB - BACKGROUND: Thyroid dysfunction is a common complication of chronic hepatitis C (CHC) and its therapy. Takotsubo cardiomyopathy (TCM) is a multifactorial, stress related cardiomyopathy, rarely reported in association with thyrotoxicosis. Simultaneous occurrence of TCM and thyrotoxicosis due to hepatitis C and its treatment has never been reported. CASE PRESENTATION: A 47-year-old woman was admitted for acute chest pain, dyspnea, palpitations and diaphoresis. She had been diagnosed with CHC and had undergone 7 months of IFNalpha and Ribavirin therapy. At admission electrocardiogram (ECG) showed ST segment elevation, negative T waves and troponin was elevated suggesting ST segment elevation myocardial infarction (STEMI). Echocardiography demonstrated left ventricular apical akinesia and ballooning, with a left ventricular ejection fraction (LVEF) of 35%. Contrast angiography showed normal epicardial coronaries, yet a ventriculogram revealed left ventricular apical ballooning, consistent with TCM. Cardiac MRI showed left ventricle apical ballooning and no late enhancement suggesting the absence of any edema, scar or fibrosis in the left myocardium. She was diagnosed with non-autoimmune destructive thyroiditis: TSH=0.001 mU/L, free T4=2.41 ng/dl, total T3=199 ng/dl and negative thyroid antibodies. The thyroid ultrasonography showed a diffuse small goiter, no nodules and normal vascularization of the parenchyma. Following supportive treatment she experienced a complete recovery after a few weeks and she successfully completed her antiviral treatment, with no thyroid or cardiovascular dysfunction ever since. In patients treated with IFNalpha for CHC, the prevalence of thyroid dysfunction varies between 2.5-45.3% of cases. TCM is a stress related cardiomyopathy characterized by elevated cardiac enzymes, normal coronary angiography and an acute, transient, left ventricular apical dysfunction that mimics myocardial infarction. Most of the patients survive the initial acute event, typically recover normal ventricular function within one to four weeks and have a favorable outcome, as was the case with our patient. Thyrotoxicosis induced stress cardiomyopathy is rare and has been mostly reported in association with Graves' disease, thyroid storm, thyrotoxicosis factitia or following radioiodine therapy for toxic multinodular goiter. CONCLUSION: Routine thyroid screening should be done in patients receiving IFN-alpha and Ribavirin for CHC and thyrotoxicosis should be considered as a possible and treatable underlying cause of TCM. PMID- 24491230 TI - Optimization of tomotherapy treatment planning for patients with bilateral hip prostheses. AB - BACKGROUND: To determine the effect of different imaging options and the most efficient imaging strategy for treatment planning of patients with hip prostheses. METHODS: The planning kilovoltage CT (kVCT) and daily megavoltage CT (MVCT) studies for three prostate cancer patients with bilateral hip prostheses were used for creating hybrid kVCT/MVCT image sets. Treatment plans were created for kVCT images alone, hybrid kVCT/MVCT images, and MVCT images alone using the same dose prescription and planning parameters. The resulting dose volume histograms were compared. The orthopedic metal artifact reduction (O-MAR) reconstruction tool for kVCT images and different MVCT options were investigated with a water tank fit with double hip prostheses. Treatment plans were created for all imaging options and calculated dose was compared with the one measured by a pin-point ion chamber. RESULTS: On average for three patients, the D35% for the bladder was 8% higher in plans based on MVCT images and 7% higher in plans based on hybrid images, compared to the plans based on kVCT images alone. Likewise, the D35% for the rectum was 3% higher than the kVCT based plan for both hybrid and MVCT plans. The average difference in planned D99% in the PTV compared to kVCT plans was 0.9% and 0.1% for MVCT and hybrid plans, respectively. For the water tank with hip prostheses phantom, the kVCT plan with O-MAR correction applied showed better agreement between the measured and calculated dose than the original image set, with a difference of -1.9% compared to 3.3%. The measured doses for the MVCT plans were lower than the calculated dose due to image size limitations. The best agreement was for the kVCT/MVCT hybrid plans with the difference between calculated and measured dose around 1%. CONCLUSION: MVCT image provides better visualization of patient anatomy and hybrid kVCT/MVCT study enables more accurate calculations using updated MVCT relative electron density calibration. PMID- 24491232 TI - Surgical technique and short-term outcome for experimental laparoscopic closure of the epiploic foramen in 6 horses. AB - OBJECTIVE: To describe a laparoscopic technique for, and short-term outcome after, closure of the epiploic foramen (EF) in horses. STUDY DESIGN: Descriptive, experimental study. ANIMALS: Healthy, adult horses (n = 6). METHODS: Laparoscopic portals to approach the EF were identified in standing horses. Under laparoscopic observation, the gastropancreatic fold and right lobe of the pancreas were grasped with Babcock forceps and secured to the caudate hepatic lobe using helical titanium coils to obliterate the EF. Surgical procedure time and intra- and postoperative complications were recorded. Serial analysis of select serum enzymes was used as an indication of involvement of the pancreas and liver. Closure was reevaluated at 4 weeks using repeat laparoscopy, and necropsy was performed immediately after. RESULTS: At initial surgery, EF closure was successful in all 6 horses; median surgical time was 40.5 minutes (range, 22-110 minutes). Serum gamma-glutamyl transferase (GGT) and sorbitol dehydrogenase (SDH) were not significantly altered by the surgical procedure; however, aspartate aminotransferase (AST) and amylase (AMY) were transiently increased. At repeat laparoscopic reevaluation, closure was complete in 5 horses, with partial closure of the EF observed in 1 horse. No complications related to the procedure were noted during or after surgery in any horse. CONCLUSIONS: EF closure in the standing horse can be accomplished without complications to the surrounding organs and vessels. PMID- 24491233 TI - Mechanical properties of canine patella-ligament-tibia segment. AB - OBJECTIVE: To test the ex vivo mechanical properties of canine patella-ligament tibia (PLT) segment and establish the relationship between donor size and PLT dimensions to the mechanical properties of PLT grafts. STUDY DESIGN: Ex vivo mechanical testing study. SAMPLE POPULATION: Canine PLT segments (n = 21 dogs; 42 PLT). METHODS: Morphometric measurements of PLT segments were taken from computed tomography (CT) images and compared with results obtained using calipers. PLT were tested to failure at a rate of 100% length/s. Mechanical properties and failure mode were recorded. RESULTS: PLT width and thickness (P < .001 for both) measured by calipers were significantly lower than those taken from CT images. Thirty-five (83%) specimens failed by avulsion fracture from the patella, 1 failed mid-ligament, and 6 failed by tibial fracture. Dog weight and PLT length had the strongest Pearson's r value when correlated with load at failure (r = 0.73, 0.81, respectively). CONCLUSION: Dog weight and PLT length were the best predictors of load at failure. PLT failure load of dogs weighing >25 kg were similar to those reported for the cranial cruciate ligament (CCL) suggesting that the PLT may be a suitable allograft for CCL replacement. PMID- 24491234 TI - Benefits of pre- and intraoperative planning for tibial plateau leveling osteotomy. AB - OBJECTIVE: To determine (1) if preoperative and intraoperative osteotomy planning increases the likelihood that a surgeon will achieve a centered osteotomy during tibial plateau leveling osteotomy (TPLO) and (2) if that centered osteotomy reduces the risk of tibial tuberosity (TT) fractures. STUDY DESIGN: Retrospective case series. ANIMALS: Dogs (n = 406) with cranial cruciate ligament that had TPLO (n = 468). METHODS: Medical records (2007-2010) and radiographs of dogs that had TPLO were reviewed. Osteotomies from Group A (pre and intra-operative planning) were compared to Group B (free-hand osteotomy only) investigating the influence of osteotomy planning as well as 21 other variables, looking for any other confounding variables that may also contribute to TT fractures. Data were analyzed with logistic regression and chi(2) analysis. RESULTS: Actual osteotomies were closer to the centered-osteotomy position in Group A than in Group B (P <= .01). TT fractures occurred in 20 cases (4.3% overall). Group A had 0 fractures out of 172 surgeries and Group B had 20 fractures out of 296 surgeries (6.8%). Five variables were found to increase the risk of TT fractures: lack of osteotomy planning, bilateral same-session surgeries, osteotomy gap, anti rotational pin location, and decreased tibial crest width at the insertion of the patellar ligament (P <= .05). CONCLUSIONS: Dogs that had osteotomy planning had a more centered osteotomy position and a reduced risk of developing TT factures. PMID- 24491235 TI - Cross-linked hyaluronic acid based gel and wound healing. PMID- 24491236 TI - Recycling of uranyl from contaminated water. AB - Many separation processes are related to the behavior of ions close to charged surfaces. In this work, we examine uranyl ions, which can be considered as rod like molecular ions with a spatially distributed charge, embedded in a system of like charged surfaces. The analysis of the system is based on an approximate field theory which is accurate from the weak to the strong electrostatic coupling regimes. The numerical results show that close to the charged surface the ions are oriented parallel to the surface, whereas at distances greater than half of the ion length, they are randomly oriented. Due to the restriction of the orientational degrees of freedom, the density of ions at the charged surface decreases to zero. For large surface charge densities, the force between like charged surfaces becomes attractive, as a result of charge correlations. The theoretical results are in good agreement with Monte Carlo simulation results. PMID- 24491237 TI - Rehospitalization to primary versus different facilities following abdominal aortic aneurysm repair. AB - OBJECTIVE: Reducing readmissions represents a unique opportunity to improve care and reduce health care costs and is the focus of major payers. A large number of surgical patients are readmitted to hospitals other than where the primary surgery was performed, resulting in clinical decisions that do not incorporate the primary surgeon and potentially alter outcomes. This study characterizes readmission to primary vs different hospitals after abdominal aortic aneurysm (AAA) repair and examines the implications with regard to mortality and cost. METHODS: Patients who underwent open or endovascular aneurysm repair for AAA were identified from the Centers for Medicare and Medicaid Services Chronic Conditions Warehouse, a random 5% national sample of Medicare beneficiaries from 2005 to 2009. Outcomes for patients who underwent AAA repair and were readmitted within 30 days of initial discharge were compared based on readmission location (primary vs different hospital). RESULTS: A total of 885 patients underwent AAA repair and were readmitted within 30 days. Of these, 626 (70.7%) returned to the primary facility, and 259 (29.3%) returned to a different facility. Greater distance from patient residence to the primary hospital was the strongest predictor of readmission to a different facility. Patients living 50 to 100 miles from the primary hospital were more likely to be readmitted to a different hospital compared with patients living <10 miles away (odds ratio, 8.50; P < .001). Patients with diagnoses directly related to the surgery (eg, wound infection) were more likely to be readmitted to the primary hospital, whereas medical diagnoses (eg, pneumonia and congestive heart failure) were more likely to be treated at a different hospital. There was no statistically significant difference in mortality between patients readmitted to a different or the primary hospital. Median total 30-day payments were significantly lower at different vs primary hospitals (primary, $11,978 vs different, $11,168; P = .04). CONCLUSIONS: Readmission to a different facility after AAA repair is common and occurs more frequently than for the overall Medicare population. Patients travelling a greater distance for AAA repair are more likely to return to different vs the primary hospital when further care is required. For AAA repair, quality healthcare may be achieved at marginally lower cost and with greater patient convenience for selected readmissions at hospitals other than where the initial procedure was performed. PMID- 24491238 TI - Dual antiplatelet therapy (clopidogrel and aspirin) is associated with increased all-cause mortality after carotid revascularization for asymptomatic carotid disease. AB - OBJECTIVE: Despite the established guidelines, there is not a clear consensus about how to manage antiplatelet therapy after carotid surgery. It is a common practice in vascular surgery to use the combination of aspirin and clopidogrel in the treatment of such patients. In this work, we analyzed the impact on long-term survival of antiplatelet therapy in patients treated for carotid stenosis at a single institution over a 10-year period. METHODS: Outcomes of 471 patients who underwent carotid intervention (1999-2008) were analyzed. Discharge prescription summaries were retrieved, and patients were divided into two groups according to their antiplatelet regimen: aspirin-only group and aspirin plus clopidogrel group. Only patients with a minimum of 30 days of confirmed antiplatelet therapy were included. All-cause mortality during follow-up represented the primary outcome, whereas stroke and bleeding at 30 days and during follow-up represented secondary end points. When local records were sparse, the Social Security Death Index was queried to confirm mortality. The International Classification of Diseases, 9th Revision (ICD-9 codes), was reviewed for treatment related to a bleeding condition. RESULTS: When divided by indication, there was an increased mortality rate in patients with asymptomatic carotid disease receiving dual antiplatelet therapy as compared with aspirin alone (47% vs 40%; P = .05). Patients with symptomatic carotid disease had a nonsignificant decrease in all cause mortality if they received dual antiplatelet therapy (38% vs 39%; P = .53). In a subgroup analysis, there was a significant increase in the rate of all-cause mortality among patients older than 75 years receiving dual antiplatelet therapy for asymptomatic carotid disease (82% vs 56%; P = .001), whereas there was a nonsignificant decrease in mortality in patients older than 75 years receiving dual antiplatelet therapy for symptomatic carotid disease (47% vs 63%; P = .50). There was no difference in secondary outcomes (stroke and bleeding) regardless of the indication or the antiplatelet therapy. CONCLUSIONS: In this retrospective, single-institution study, the use of dual antiplatelet therapy (aspirin plus clopidogrel) in patients intervened for asymptomatic carotid disease was related to increased all-cause mortality, whereas it did not significantly influence the outcome in patients with symptomatic carotid disease. PMID- 24491239 TI - Risk factors for readmission after lower extremity bypass in the American College of Surgeons National Surgery Quality Improvement Program. AB - OBJECTIVE: Readmission is associated with high mortality, morbidity, and cost. We used the American College of Surgeons National Surgery Quality Improvement Program (ACS-NSQIP) to determine risk factors for readmission after lower extremity bypass (LEB). METHODS: We identified all patients who received LEB in the 2011 ACS-NSQIP database. Multivariable logistic regression was used to assess independent predictors of 30-day readmission. We also identified our institutional contribution of LEB patients to the ACS-NSQIP from 2005 to 2011 to determine our institution's rate of readmission and readmission indications. RESULTS: Among 5018 patients undergoing LEB, ACS-NSQIP readmission analysis was performed on 4512, excluding those whose readmission data were unavailable, who suffered a death on index admission, or who remained in the hospital at 30 days. Overall readmission rate was 18%, and readmission rate of those with NSQIP captured complications was 8%. Multivariable predictors of readmission were dependent functional status (odds ratio [OR], 1.40; 95% confidence interval [CI], 1.08-1.79), dyspnea (OR, 1.28; 95% CI, 1.02-1.60), cardiac comorbidity (OR, 1.46; 95% CI, 1.16-1.84), dialysis dependence (OR, 1.44; 95% CI, 1.05-1.97), obesity (OR, 1.28; 95% CI, 1.07-1.53), malnutrition (OR, 1.42; 95% CI, 1.12-1.79), critical limb ischemia operative indication (OR, 1.40; 95% CI, 1.10-1.79), and return to the operating room on index admission (OR, 8.0; 95% CI, 6.68-9.60). The most common postdischarge complications occurring in readmitted patients included wound complications (55%), multiple complications (22%), and graft failure (5%). Our institutional data contributed 465 LEB patients to the ACS-NSQIP from 2005 to 2012, with an overall readmission rate of 14%. Unplanned readmissions related to the original LEB (related unplanned) made up 75% of cases. The remainder 25% included readmissions that were planned staged procedures related to the original LEB (related planned, 11%) and admissions for a completely unrelated reason (unrelated unplanned, 14%). The most common readmission indications included wound infection (37%) and graft failure (10%). Readmissions were attributable to NSQIP-captured postdischarge complications in 44% of cases, an additional 44% had a non-NSQIP-defined reason for readmission, and the remainder (12%) included patients admitted for complications described in NSQIP but not meeting strict NSQIP criteria. CONCLUSIONS: Readmissions are common after LEB. Optimization of select chronic conditions, closer follow-up of patients in poor health and those who required return to the operating room, and early detection of surgical site infections may improve readmission rates. Our finding that 25% of readmissions after LEB are not procedure related informs the broader discussion of how a readmission penalty affects vascular surgery in particular. PMID- 24491240 TI - Erythropoiesis stimulating agents (ESAs) for congestive heart failure: the red and the black. AB - CHF is a disease of high incidence and prevalence in the elderly. Anemia is associated with an increased mortality in these patients. Erythropoietin secretion is reduced in these patients due to complexed mechanisms. Although some improvement in quality of life has been shown when using ESAs it has not been found any decrement on mortality. Moreover, safety reports suggest an increased risk of thromboembolic event. Together with the high drug cost, the use of ESAs cannot be recommended for the treatment of CHF patients. PMID- 24491241 TI - Vascular endothelial growth factor, a novel and highly accurate pancreatic fluid biomarker for serous pancreatic cysts. AB - BACKGROUND: Mucinous pancreatic cysts (intraductal papillary mucinous neoplasm and mucinous cystic neoplasm) have the potential to progress to invasive pancreatic adenocarcinoma, presenting an opportunity for early detection, prevention, and cure. Serous cystic neoplasms (SCN) have no malignant potential, but can mimic mucinous pancreatic cysts on imaging. Therefore, identification of biomarkers that can distinguish between cystic lesions is critically important. We hypothesize that vascular endothelial growth factor (VEGF)-A levels in pancreatic fluid correlate with pathologic diagnosis. STUDY DESIGN: Pancreatic cyst/duct fluid samples were prospectively collected from patients undergoing pancreatic resection and correlated with surgical pathology. VEGF levels were detected by ELISA. VEGF-A and VEGF receptor 2 expression in pancreatic tissue was localized by immunohistochemistry. Genetic alterations of the von Hippel-Lindau gene were determined by targeted next-generation sequencing. RESULTS: Eighty seven patients met inclusion criteria for enrollment. Final pathologic diagnoses included pseudocyst (n = 9), SCN (n = 17), mucinous cystic neoplasm (n = 24), low/moderate grade intraductal papillary mucinous neoplasm (n = 16), high grade/invasive intraductal papillary mucinous neoplasm (n = 10), and pancreatic ductal adenocarcinoma (n = 11). VEGF-A was significantly upregulated in SCN cyst fluid compared with all other diagnoses (p < 0.0001). With a cut-off of 8,500 pg/mL, VEGF-A has 100% sensitivity and 97% specificity as an SCN biomarker. VEGF A and VEGF receptor 2 are overexpressed in SCN cyst tissue. VEGF-C was also significantly elevated in SCN cyst fluid (p < 0.0001). With a cut-off set at 200 pg/mL, VEGF-C identifies SCN with 100% sensitivity and 90% specificity. The presence of a von Hippel-Lindau mutation in SCN cyst tissue correlates with elevated cyst fluid VEGF levels. CONCLUSIONS: This is the first report of a cyst fluid protein biomarker that can positively identify SCN. The ability to distinguish SCN from premalignant/malignant pancreatic cysts can spare the cost and risk of surveillance and surgical intervention in select patients. PMID- 24491242 TI - Subscription to the Surgical Council on Resident Education web portal and qualifying examination performance. AB - BACKGROUND: The Surgical Council on Resident Education (SCORE) curriculum for general surgery was developed to guide surgery residents in the acquisition of knowledge for patient care. We hypothesized that residents in programs that subscribed to the SCORE web portal would perform better on the American Board of Surgery (ABS) Surgery Qualifying Examination (QE). STUDY DESIGN: Scaled scores and the percent passing the 2011 ABS Surgery QE for individual residents and programs were compared between programs that subscribed to the SCORE portal in 2010 to 2011 and those that did not subscribe. Regression analyses were performed to control for program QE percent passing from 2004 to 2008 (baseline performance), as well as demographic factors known to affect examination results. RESULTS: There were 200 programs and 893 residents that subscribed to the SCORE web portal and 33 programs with 139 residents that did not subscribe. Regression analysis comparing predicted 2011 mean program QE scores based on 2004 to 2008 results showed that subscribing programs had a substantial increase in mean scaled scores of 1.4 points (adjusted means of 81.5 and 80.1, respectively), controlling for the percentage of international medical graduates and program size (p = 0.048). Residents from SCORE portal subscribing programs had a QE percent passing that was 1.6% higher than nonsubscribing residents, and the mean percent passing was higher for subscribing programs (86.4% vs 82.7%), but neither difference was statistically significant. The SCORE subscription status did not correlate with program size, percent of international medical graduates, or baseline scale scores. CONCLUSIONS: There was a considerable improvement in mean QE scaled scores for residents in programs that initially subscribed to the SCORE web portal. The percent passing the QE showed a trend toward improvement for subscribing programs and their residents. This association is promising and deserves additional investigation. PMID- 24491243 TI - The concept of a composite perioperative quality index in kidney transplantation. AB - BACKGROUND: Public reporting of patient and graft outcomes in a national registry and close Centers for Medicare and Medicaid Services oversight has resulted in transplantation being a highly regulated surgical discipline. Despite this, transplantation surgery lacks comprehensive tracking and reporting of perioperative quality measures. Therefore, the aim of this study was to determine the association between a kidney transplantation centers' perioperative quality benchmarking and graft and patient outcomes. STUDY DESIGN: This was an analysis of 2011 aggregate data compiled from 2 national datasets that track outcomes from member hospitals and transplantation centers. The transplantation centers included in this study were composed of accredited US kidney transplantation centers that report data through the national registry and are associate members of the University HealthSystem Consortium. RESULTS: A total of 16,811 kidney transplantations were performed at 236 centers in the United States in 2011, of which 10,241 (61%) from 93 centers were included in the analysis. Of the 6 perioperative quality indicators, 3 benchmarked metrics were significantly associated with a kidney transplantation center's underperformance: mean ICU length of stay (C-statistic 0.731; p = 0.002), 30-day readmissions (C-statistic 0.697; p = 0.012) and in-hospital complications (C-statistic 0.785; p = 0.001). The composite quality index strongly correlated with inadequate center performance (C-statistic 0.854; p < 0.001, R(2) = 0.349). The centers in the lowest quartile of the quality index performed 2,400 kidney transplantations in 2011, which led to 2,640 more hospital days, 4,560 more ICU days, 120 more postoperative complications, and 144 more patients with 30-day readmissions, when compared with centers in the 3 higher-quality quartiles. CONCLUSIONS: An objective index of a transplantation center's quality of perioperative care is significantly associated with patient and graft survival. PMID- 24491246 TI - Macro vs micro level surgical quality improvement: a regional collaborative demonstrates the case for a national NSQIP initiative. AB - BACKGROUND: The Florida Surgical Care Initiative (FSCI) is a quality improvement collaborative of the American College of Surgeons National Surgical Quality Improvement Program (NSQIP) and the Florida Hospital Association. In the wake of a dramatic decrease in complications and cost documented over 15 months, we analyzed the semiannual measures reports (SAR) to determine whether this improvement was driven by specific institutions or was a global accomplishment by all participants. METHODS: Reports from NSQIP were analyzed to determine rank change of participants. Odds ratio (OR) of observed-to-expected incidence of the 4 FSCI outcomes (catheter-associated urinary tract infection [CAUTI], surgical site infection [SSI], colorectal, and surgery in patients older than 65 years) were used to assess individual and group performance. Data from SAR 2 (October 2011 to April 2012) were compared with data from SAR 3 (May to July 2012). Poorly performing hospitals were tracked to determine evidence of improvement. Individual facility performance was evaluated by determining proportion of hospitals showing improved rank across all measures. RESULTS: Fifty-four hospitals were evaluated. SAR 2 reported 28,112 general and vascular surgical cases; SAR 3 added 10,784 more. The proportion of institutions with OR < 1 for each measure did not change significantly. Only urinary tract infection and colorectal measures demonstrated increased number of hospitals with OR < 1. Each institution that was a significant negative outlier in SAR 2 demonstrated improvement. Three of 54 hospitals demonstrated improvement across all 4 measures. Of 15 hospitals with improved performance across 3 measures, all included elderly surgery. CONCLUSIONS: The increase in quality achieved across this population of surgical patients was the result of a quality assessment process driven by NSQIP rather than disproportionate improvement of some raising the bar for all. The NSQIP process, applied collaboratively across a population by committed institutions, produces dramatic results. PMID- 24491245 TI - Comparison of sentinel lymph node micrometastatic tumor burden measurements in melanoma. AB - BACKGROUND: Multiple methods have been proposed to classify the micrometastatic tumor burden in sentinel lymph nodes (SLN) for melanoma. The purpose of this study was to determine the classification scheme that best predicts nonsentinel node (NSN) metastasis, disease-free survival (DFS), and overall survival (OS). STUDY DESIGN: A single reviewer reanalyzed tumor-positive SLN from a multicenter, prospective clinical trial of patients with melanoma >= 1.0 mm Breslow thickness who underwent SLN biopsy. The following micrometastatic disease burden measurements were recorded: Starz classification, Dewar classification (microanatomic location), maximum diameter of the largest focus of metastasis, maximum tumor area, and sum of all diameters. Univariate and multivariate models and Kaplan-Meier analysis were used to evaluate each classification system. RESULTS: We reviewed 204 tumor-positive SLNs from 157 patients. On univariate analysis, all criteria except Starz classification were statistically significant risk factors for NSN metastasis. On multivariate analysis, including Breslow thickness, ulceration, age, sex, and NSN status, maximum diameter (using a cut off of 3 mm) was the only classification system that was an independent risk factor predicting DFS (hazard ratio 2.31, p = 0.0181) and OS (hazard ratio 3.53, p = 0.0005). By Kaplan-Meier analysis, DFS and OS were significantly different among groups using maximum diameter cut-offs of 1 and 3 mm. CONCLUSIONS: Maximum tumor diameter outperformed other measurements of metastatic tumor burden, including microanatomic tumor location (Dewar classification), Starz classification, maximum tumor area, and sum of all diameters for prediction of survival. Maximum tumor diameter is a simple method of assessing micrometastatic tumor burden that should be reported routinely. PMID- 24491247 TI - Overexpression of eukaryotic initiation factor 4E is correlated with increased risk for systemic dissemination in node-positive breast cancer patients. AB - BACKGROUND: Molecular events impact systemic dissemination. Overexpression of eukaryotic initiation factor 4E (eIF4E) has been shown to predict worse clinical outcomes in breast cancer. Node-positive breast cancer patients were specifically studied to determine if eIF4E elevation increases risk for systemic dissemination. STUDY DESIGN: Two hundred two node-positive breast cancer patients were prospectively accrued and treated with standardized treatment and surveillance protocol. Tumor eIF4E protein level was quantified by Western blots as x-fold over benign samples from noncancer patients. Primary end point was systemic metastasis. RESULTS: Systemic recurrence was detected in 22.2% of the low eIF4E group, 27.3% of the intermediate group, and 49% of the high group, at a median follow-up of 47 months. A greater risk for systemic metastasis was seen in the high eIF4E group compared with the low group (log-rank test, p = 0.0084). Patients in the high eIF4E group had a 1.5-fold (hazard ratio = 1.52; 95% CI, 1.07-2.17; p = 0.0206) higher risk for systemic metastasis than the low group. Sixty percent of the patients with high eIF4E were observed to have metastasis to multiple sites, compared with 50% in the intermediate group, and 14.5% in the low group (p = 0.02, Fisher's exact test). When patients were segregated based on nodal classification (N1, N2, and N3), eIF4E overexpression continued to be a predictor for systemic dissemination in patients with N1 disease. CONCLUSIONS: High eIF4E is correlated with an increased risk for systemic metastasis in node positive breast cancer patients. High eIF4E overexpression was associated with a higher incidence of metastasis to multiple sites. Therefore, high eIF4E overexpression appears to be a marker for molecular events that increases risk for systemic dissemination. PMID- 24491244 TI - Intraperitoneal chemotherapy for peritoneal surface malignancy: experience with 1,000 patients. AB - BACKGROUND: Peritoneal dissemination of abdominal malignancy (carcinomatosis) has a clinical course marked by bowel obstruction and death; it traditionally does not respond well to systemic therapy and has been approached with nihilism. To treat carcinomatosis, we use cytoreductive surgery (CS) with hyperthermic intraperitoneal chemotherapy (HIPEC). METHODS: A prospective database of patients has been maintained since 1992. Patients with biopsy-proven peritoneal surface disease were uniformly evaluated for, and treated with, CS and HIPEC. Patient demographics, performance status (Eastern Cooperative Oncology Group), resection status, and peritoneal surface disease were classified according to primary site. Univariate and multivariate analyses were performed. The experience was divided into quintiles and outcomes compared. RESULTS: Between 1991 and 2013, a total of 1,000 patients underwent 1,097 HIPEC procedures. Mean age was 52.9 years and 53.1% were female. Primary tumor site was appendix in 472 (47.2%), colorectal in 248 (24.8%), mesothelioma in 72 (7.2%), ovary in 69 (6.9%), gastric in 46 (4.6%), and other in 97 (9.7%). Thirty-day mortality rate was 3.8% and median hospital stay was 8 days. Median overall survival was 29.4 months, with a 5-year survival rate of 32.5%. Factors correlating with improved survival on univariate and multivariate analysis (p <= 0.0001 for each) were preoperative performance status, primary tumor type, resection status, and experience quintile (p = 0.04). For the 5 quintiles, the 1- and 5-year survival rates, as well as the complete cytoreduction score (R0, R1, R2a) have increased, and transfusions, stoma creations, and complications have all decreased significantly (p < .001 for all). CONCLUSIONS: This largest reported single-center experience with CS and HIPEC demonstrates that prognostic factors include primary site, performance status, completeness of resection, and institutional experience. The data show that outcomes have improved over time, with more complete cytoreduction and fewer serious complications, transfusions, and stomas. This was due to better patient selection and increased operative experience. Cytoreductive surgery with HIPEC represents a substantial improvement in outcomes compared with historical series, and shows that meaningful long-term survival is possible for selected carcinomatosis patients. Multi-institutional cooperative trials are needed to refine the use of CS and HIPEC. PMID- 24491248 TI - Pride attenuates nonconscious mimicry. AB - Positive affect has been associated with increased nonconscious mimicry-an association that is quite logical given ties between positive mood and desires for social bonding. Yet positive emotions vary with respect to function, leading to the prediction that not all positive states might similarly increase mimicry. Pride, due to its association with higher status and self-focus, could be expected to attenuate affiliative behaviors such as mimicry. Participants in the present study were induced to experience one of three affective states (neutral, pride, general positivity), after which they interacted with a confederate who expressed a specific, neutral nonverbal behavior (i.e., foot shaking). Supporting past research, participants experiencing general positive affect evidenced greater mimicry as compared to participants in a neutral mood. In accord with predictions, participants experiencing pride mimicked the confederate's behavior significantly less than did those experiencing general positive affect or a neutral state. Regression analyses also confirmed that increasing intensities of pride predicted decreasing mimicry. PMID- 24491249 TI - Conceptual and empirical strengths of the authentic/hubristic model of pride. AB - The authentic/hubristic (A/H) model of pride has been empirically supported by dozens of studies drawing on thousands of participants. The model involves four distinct components, most central of which is the finding that pride is not a unitary construct but rather is comprised of two distinct facets, referred to as authentic and hubristic pride. In the present article, we review the four critical components of the A/H model, and explain why Holbrook and colleagues' (2013) critique raises questions for one part of one of these components only-the attribution distinction between the two prides. We then raise questions for Holbrook and colleagues' alternative model of pride, and conclude by noting several convergences between the two perspectives. PMID- 24491250 TI - Further challenges to the "Authentic"/"Hubristic" model of pride: conceptual clarifications and new evidence. AB - The Authentic and Hubristic Pride Scales (AHPS) are the methodological core of an influential perspective on pride. The Authentic Pride (AP) scale purportedly measures a distinct facet of pride rooted in attributing success to effort (but not ability), and related to prestige (but not dominance). The Hubristic Pride (HP) scale purportedly measures a complementary facet rooted in attributing success to ability (but not effort), and related to dominance (but not prestige). In the target article, we presented evidence against both profiles. Here, we first examine the counterarguments raised in defense of both the AHPS and the related appraisal-tendency model, then present a new study confirming that AP is elicited by attributions of success to natural ability, and HP is elicited by attributions of success to causes outside the self. It is thus clear that the HP scale measures not pride, but rather evaluations of the self as overclaiming credit or excessively displaying pride. PMID- 24491251 TI - Editorial comment. PMID- 24491253 TI - Maximum likelihood model based on minor allele frequencies and weighted Max-SAT formulation for haplotype assembly. AB - Human haplotypes include essential information about SNPs, which in turn provide valuable information for such studies as finding relationships between some diseases and their potential genetic causes, e.g., for Genome Wide Association Studies. Due to expensiveness of directly determining haplotypes and recent progress in high throughput sequencing, there has been an increasing motivation for haplotype assembly, which is the problem of finding a pair of haplotypes from a set of aligned fragments. Although the problem has been extensively studied and a number of algorithms have already been proposed for the problem, more accurate methods are still beneficial because of high importance of the haplotypes information. In this paper, first, we develop a probabilistic model, that incorporates the Minor Allele Frequency (MAF) of SNP sites, which is missed in the existing maximum likelihood models. Then, we show that the probabilistic model will reduce to the Minimum Error Correction (MEC) model when the information of MAF is omitted and some approximations are made. This result provides a novel theoretical support for the MEC, despite some criticisms against it in the recent literature. Next, under the same approximations, we simplify the model to an extension of the MEC in which the information of MAF is used. Finally, we extend the haplotype assembly algorithm HapSAT by developing a weighted Max-SAT formulation for the simplified model, which is evaluated empirically with positive results. PMID- 24491254 TI - Modelling of cross-linked actin networks - Influence of geometrical parameters and cross-link compliance. AB - A major structural component of the cell is the actin cytoskeleton, in which actin subunits are polymerised into actin filaments. These networks can be cross linked by various types of ABPs (Actin Binding Proteins), such as Filamin A. In this paper, the passive response of cross-linked actin filament networks is evaluated, by use of a numerical and continuum network model. For the numerical model, the influence of filament length, statistical dispersion, cross-link compliance (including that representative of Filamin A) and boundary conditions on the mechanical response is evaluated and compared to experimental results. It is found that the introduction of statistical dispersion of filament lengths has a significant influence on the computed results, reducing the network stiffness by several orders of magnitude. Actin networks have previously been shown to have a characteristic transition from an initial bending-dominated to a stretching dominated regime at larger strains, and the cross-link compliance is shown to shift this transition. The continuum network model, a modified eight-chain polymer model, is evaluated and shown to predict experimental results reasonably well, although a single set of parameters cannot be found to predict the characteristic dependence of filament length for different types of cross-links. Given the vast diversity of cross-linking proteins, the dependence of mechanical response on cross-link compliance signifies the importance of incorporating it properly in models to understand the roles of different types of actin networks and their respective tasks in the cell. PMID- 24491255 TI - Evolving protein-protein interaction networks: A model based on duplication and mutation at different rates. AB - We present a model describing the evolution of protein-protein interaction networks. The model is based on gene duplication and mutation. Considering rates of gene duplication and mutation, the average node degree and cluster coefficient are calculated for different parameters. The predicted degree distribution and cluster coefficient are in good agreement with the observed statistical properties obtained from the analysis of the yeast proteome. PMID- 24491256 TI - Markov mean properties for cell death-related protein classification. AB - The cell death (CD) is a dynamic biological function involved in physiological and pathological processes. Due to the complexity of CD, there is a demand for fast theoretical methods that can help to find new CD molecular targets. The current work presents the first classification model to predict CD-related proteins based on Markov Mean Properties. These protein descriptors have been calculated with the MInD-Prot tool using the topological information of the amino acid contact networks of the 2423 protein chains, five atom physicochemical properties and the protein 3D regions. The Machine Learning algorithms from Weka were used to find the best classification model for CD-related protein chains using all 20 attributes. The most accurate algorithm to solve this problem was K*. After several feature subset methods, the best model found is based on only 11 variables and is characterized by the Area Under the Receiver Operating Characteristic Curve (AUROC) of 0.992 and the true positive rate (TP Rate) of 88.2% (validation set). 7409 protein chains labeled with "unknown function" in the PDB Databank were analyzed with the best model in order to predict the CD related biological activity. Thus, several proteins have been predicted to have CD-related function in Homo sapiens: 3DRX-involved in virus-host interaction biological process, protein homooligomerization; 4DWF-involved in cell differentiation, chromatin modification, DNA damage response, protein stabilization; 1IUR-involved in ATP binding, chaperone binding; 1J7D-involved in DNA double-strand break processing, histone ubiquitination, nucleotide-binding oligomerization; 1UTU-linked with DNA repair, regulation of transcription; 3EEC participating to the cellular membrane organization, egress of virus within host cell, class mediator resulting in cell cycle arrest, negative regulation of ubiquitin-protein ligase activity involved in mitotic cell cycle and apoptotic process. Other proteins from bacteria predicted as CD-related are 2G3V - a CAG pathogenicity island protein 13 from Helicobacter pylori, 4G5A - a hypothetical protein in Bacteroides thetaiotaomicron, 1YLK-involved in the nitrogen metabolism of Mycobacterium tuberculosis, and 1XSV - with possible DNA/RNA binding domains. The results demonstrated the possibility to predict CD-related proteins using molecular information encoded into the protein 3D structure. Thus, the current work demonstrated the possibility to predict new molecular targets involved in cell-death processes. PMID- 24491257 TI - The physiological role of hydrogen sulfide and beyond. AB - Hydrogen sulfide (H2S) has been considered to be a physiological mediator since the identification of endogenous sulfides in the mammalian brain. H2S is produced from L-cysteine by enzymes such as cystathionine beta-synthase (CBS), cystathionine gamma-lyase (CSE), 3-mercaptopyruvate sulfurtransferase (3MST), and cysteine aminotransferase (CAT). CSE and CAT are regulated by Ca(2+). At steady state low intracellular concentrations of Ca(2+), CSE and the 3MST/CAT pathway produce H2S. However, after intracellular concentrations of Ca(2+) increase in stimulated cells, the production of H2S by these enzymes decreases. We recently identified a fourth pathway, by which H2S is produced from D-cysteine by the enzymes D-amino acid oxidase (DAO) and 3MST. This pathway is mainly localized in the cerebellum and the kidney. The production of H2S from D-cysteine is 80 times more efficient than that from L-cysteine in the kidney, and the administration of D-cysteine to mice ameliorates renal ischemia-reperfusion injury more effectively than L-cysteine. These results suggest that D-cysteine might be used to treat renal diseases or even increase the success of kidney transplantation. We found that H2S-derived polysulfides exist in the brain and activate transient receptor potential ankyrin-1 (TRPA1) channels 300 times more potently than H2S. Although TRPA1 channels mediate sensory transduction and respond to a variety of stimuli, including cold temperature, pungent compounds and environmental irritants, their endogenous ligand(s) has not been identified. The sulfane sulfur of polysulfides is a reactive electrophile that is readily transferred to a nucleophilic protein thiolate to generate the protein persulfide or bound sulfane sulfur by sulfhydration (as referred to as sulfuration). The bound sulfane sulfur-producing activity of polysulfides is much greater than that of H2S. This review focuses on the physiological roles of H2S and H2S-derived polysulfides as signaling molecules. PMID- 24491258 TI - Protective effects of the total saponins from Dioscorea nipponica Makino against carbon tetrachloride-induced liver injury in mice through suppression of apoptosis and inflammation. AB - The present study was to investigate the effects and possible mechanisms of the total saponins from Dioscorea nipponica Makino (TSDN) against CCl4-induced hepato toxicity in mice. The mice were orally administrated with TSDN for seven days and then given CCl4 (0.3%, 10 ml/kg i.p.). The results showed that TSDN significantly attenuated the activities of ALT and AST, consistent with hematoxylin-eosin staining. The ALP levels and relative liver weight were significantly decreased by TSDN compared with model group. Moreover, TSDN dramatically decreased MDA, iNOS and NO levels, while the levels of GSH, GSH-Px and SOD were increased. Further investigations showed that TSDN inhibited CCl4-induced metabolic activation and CYP2E1 expression, down-regulated the levels of MAPKs phosphorylation, NF-kappaB, HMGB1, COX-2 as well as effectively suppressed the expressions of Caspase-3, Caspase-9, PARP and Bak. Quantitative real-time PCR assay demonstrated that TSDN obviously decreased the gene expressions of TNF-a, IL-1beta, IL-6, IL-10, Fas, FasL, Bax as well as modulated Bcl-2 mRNA level. This is the first time to report the protective actions of the TSDN against CCl4 induced liver damage in mice through suppression of inflammation and apoptosis. This natural product should be developed as a new drug for treatment of liver injury in future. PMID- 24491260 TI - Translating reference doses into allergen management practice: challenges for stakeholders. AB - Risk assessment describes the impact of a particular hazard as a function of dose and exposure. It forms the foundation of risk management and contributes to the overall decision-making process, but is not its endpoint. This paper outlines a risk analysis framework to underpin decision-making in the area of allergen cross contact. Specifically, it identifies challenges relevant to each component of the risk analysis: risk assessment (data gaps and output interpretation); risk management (clear and realistic objectives); and risk communication (clear articulation of risk and benefit). Translation of the outputs from risk assessment models into risk management measures must be informed by a clear understanding of the model outputs and their limitations. This will lead to feasible and achievable risk management objectives, grounded in a level of risk accepted by the different stakeholders, thereby avoiding potential unintended detrimental consequences. Clear, consistent and trustworthy communications actively involving all stakeholders underpin these objectives. The conclusions, integrating the perspectives of different stakeholders, offer a vision where clear, science-based benchmarks form the basis of allergen management and labelling, cutting through the current confusion and uncertainty. Finally, the paper recognises that the proposed framework must be adaptable to new and emerging evidence. PMID- 24491259 TI - Quantum mechanical studies of DNA and LNA. AB - Quantum mechanical (QM) methodology has been employed to study the structure activity relations of DNA and locked nucleic acid (LNA). The QM calculations provide the basis for construction of molecular structure and electrostatic surface potentials from molecular orbitals. The topologies of the electrostatic potentials were compared among model oligonucleotides, and it was observed that small structural modifications induce global changes in the molecular structure and surface potentials. Since ligand structure and electrostatic potential complementarity with a receptor is a determinant for the bonding pattern between molecules, minor chemical modifications may have profound changes in the interaction profiles of oligonucleotides, possibly leading to changes in pharmacological properties. The QM modeling data can be used to understand earlier observations of antisense oligonucleotide properties, that is, the observation that small structural changes in oligonucleotide composition may lead to dramatic shifts in phenotypes. These observations should be taken into account in future oligonucleotide drug discovery, and by focusing more on non RNA target interactions it should be possible to utilize the exhibited property diversity of oligonucleotides to produce improved antisense drugs. PMID- 24491261 TI - Burden of diseases estimates associated to different red meat cooking practices. AB - The burden of disease estimate has been performed for diseases attributable to nutritional deficiency, foodborne pathogens, the environment, infection and other factors. However, the burden of disease estimate attributable to different food processing practices has not been investigated before. The aim of this study is to compare the burden of disease estimate attributed to red meat consumption processed using different cooking practices. The red meat cooking practices were categorized into three: (A) barbecuing/grilling; (B) frying/broiling and (C) roasting/baking. The associated endpoints, affected population, intake and dose response data are obtained by literature survey. The selected endpoints are four types of cancer: colorectal, prostate, breast and pancreatic. The burden of disease per cooking practice, endpoint, sex and age is estimated in the Danish population, using disability adjusted life years (DALY) as a common health metric. The results reveal that the consumption of barbecued red meat is associated with the highest disease burden, followed by fried red meat and roasted red meat. The method used to quantify the difference in disease burden of different cooking practices can help to inform the consumer to make a choice on whether the benefit of a preferred cooking style is worth the associated health loss. PMID- 24491262 TI - Association between passive smoking and atopic dermatitis in dogs. AB - Onset of atopic dermatitis and occurrence of related skin lesions are influenced by various environmental factors in humans, and companion animals. Several studies have demonstrated an association between passive smoking and the development of atopic dermatitis in children. This association has never been investigated in the dog to our knowledge. We enrolled 161 dogs seen at dermatology and vaccination consultations over a six-month period for this study. Dog owners were asked to complete a questionnaire, to evaluate the exposure of the dog to tobacco smoke. The atopic or non-atopic status of the dog was assessed on the basis of Favrot's criteria (history, clinical examination and cutaneous cytology for Malassezia). Analysis of the data for the 161 dogs enrolled revealed a significant association between high levels of passive exposure to tobacco smoke (cigarette consumption divided by the area of the home) and the presence of atopic dermatitis in the dogs (OR, 4.38; 95% CI, 1.10-17.44; p=0.03; NNH (number needed to harm) 3, 95% CI 2-52). The prevalence of atopic dermatitis showed a slight, but non-significant association with breed predisposition. Dogs with high levels of exposure to tobacco smoke may have a higher risk of atopic dermatitis than non-exposed dogs. PMID- 24491263 TI - Effects of storage, processing and proteolytic digestion on microcystin-LR concentration in edible clams. AB - Accumulation of microcystin-LR (MC-LR) in edible aquatic organisms, particularly in bivalves, is widely documented. In this study, the effects of food storage and processing conditions on the free MC-LR concentration in clams (Corbicula fluminea) fed MC-LR-producing Microcystisaeruginosa (1*10(5) cell/mL) for four days, and the bioaccessibility of MC-LR after in vitro proteolytic digestion were investigated. The concentration of free MC-LR in clams decreased sequentially over the time with unrefrigerated and refrigerated storage and increased with freezing storage. Overall, cooking for short periods of time resulted in a significantly higher concentration (P<0.05) of free MC-LR in clams, specifically microwave (MW) radiation treatment for 0.5 (57.5%) and 1 min (59%) and boiling treatment for 5 (163.4%) and 15 min (213.4%). The bioaccessibility of MC-LR after proteolytic digestion was reduced to 83%, potentially because of MC-LR degradation by pancreatic enzymes. Our results suggest that risk assessment based on direct comparison between MC-LR concentrations determined in raw food products and the tolerable daily intake (TDI) value set for the MC-LR might not be representative of true human exposure. PMID- 24491264 TI - Microbial phenolic metabolites improve glucose-stimulated insulin secretion and protect pancreatic beta cells against tert-butyl hydroperoxide-induced toxicity via ERKs and PKC pathways. AB - Oxidative stress is accepted as one of the causes of beta cell failure in type 2 diabetes. Therefore, identification of natural antioxidant agents that preserve beta cell mass and function is considered an interesting strategy to prevent or treat diabetes. Recent evidences indicated that colonic metabolites derived from flavonoids could possess beneficial effects on various tissues. The aim of this work was to establish the potential anti-diabetic properties of the microbial derived flavonoid metabolites 3,4-dihydroxyphenylacetic acid (DHPAA), 2,3 dihydroxybenzoic acid (DHBA) and 3-hydroxyphenylpropionic acid (HPPA). To this end, we tested their ability to influence beta cell function and to protect against tert-butyl hydroperoxide-induced beta cell toxicity. DHPAA and HPPA were able to potentiate glucose-stimulated insulin secretion (GSIS) in a beta cell line INS-1E and in rat pancreatic islets. Moreover, pre-treatment of cells with both compounds protected against beta cell dysfunction and death induced by the pro-oxidant. Finally, experiments with pharmacological inhibitors indicate that these effects were mediated by the activation of protein kinase C and the extracellular regulated kinases pathways. Altogether, these findings strongly suggest that the microbial-derived flavonoid metabolites DHPAA and HPPA may have anti-diabetic potential by promoting survival and function of pancreatic beta cells. PMID- 24491265 TI - Thirteen week rodent feeding study with processed fractions from herbicide tolerant (DP-O73496-4) canola. AB - The potential health effects of meal and oil processed from seed of genetically modified (GM) canola plants (OECD unique identifier: DP-O73496-4; hereafter referred to as 73496 canola) containing an insert that expresses the GAT4621 protein conferring tolerance to nonselective herbicidal ingredient glyphosate were evaluated in a subchronic rodent feeding study. Sprague-Dawley rats (12/sex/group) were administered diets containing dehulled, defatted toasted canola meal (DH meal) and refined/bleached/deodorized canola oil (RBD oil) processed from seed of plants that were untreated (73496), sprayed in-field with glyphosate (73496GLY), the non-transgenic near-isogenic (091; control), or one of four commercially available non-GM reference canola varieties (45H72, 45H73, 46A65, 44A89). All diets were formulated as a modification of the standard laboratory chow PMI(r) Nutrition International, LLC Certified Rodent LabDiet(r) 5002 (PMI(r) 5002). DH canola meal and RBD canola oil replaced all commodity soybean fractions typically incorporated in PMI(r) 5002. No toxicologically significant differences were observed between the test and control groups in this study. The results reported herein support the conclusion that DH meal and RBD oil processed from seed of 73496 canola are as safe and nutritious as DH meal and RBD oil processed from seed of non-GM canola. PMID- 24491267 TI - Adjuvant therapy with bemiparin in patients with limited-stage small cell lung cancer: results from the ABEL study. AB - INTRODUCTION: The haemostatic system plays an important role in the process of cancer development and spread. Anticoagulants, mainly low molecular weight heparins, could prolong survival in cancer patients, particularly in patients with lung cancer, beyond prevention of thromboembolic events. METHODS: In a multicenter, investigator-initiated, open-label, randomized, sequential study, 38 patients with newly-diagnosed, limited-stage small-cell lung cancer were randomized to receive standard chemoradiotherapy or the same therapy plus 3,500 IU daily of bemiparin for a maximum of 26 weeks. The primary outcome was progression-free survival. RESULTS: The study was terminated early due to slow recruitment. Median progression-free survival was 272 days with chemoradiotherapy alone and 410 days in the bemiparin group; hazard ratio, 2.58 (95% confidence interval [CI], 1.15-5.80); p=0.022. Median overall survival was 345 days with chemoradiotherapy alone and 1133 days in the bemiparin group; hazard ratio, 2.96 (95% CI, 1.22-7.21); p=0.017. The rate of tumor response was similar in both study arms. There was no significant between-group difference in the rates of major bleeding. Toxicity related with the experimental treatment was minimal. CONCLUSION: The addition of bemiparin to first line therapy with chemoradiotherapy significantly increases survival in patients with newly diagnosed, limited-stage small-cell lung cancer. (Funded by the Instituto Cientifico y Tecnologico, University of Navarra. ClinicalTrials.gov identifier: NCT00324558). PMID- 24491268 TI - Spindle cell angiosarcoma almost exclusively made up of spindle cells. PMID- 24491269 TI - DCMDSM: a DICOM decomposed storage model. AB - OBJECTIVE: To design, build, and evaluate a storage model able to manage heterogeneous digital imaging and communications in medicine (DICOM) images. The model must be simple, but flexible enough to accommodate variable content without structural modifications; must be effective on answering query/retrieval operations according to the DICOM standard; and must provide performance gains on querying/retrieving content to justify its adoption by image-related projects. METHODS: The proposal adapts the original decomposed storage model, incorporating structural and organizational characteristics present in DICOM image files. Tag values are stored according to their data types/domains, in a schema built on top of a standard relational database management system (RDBMS). Evaluation includes storing heterogeneous DICOM images, querying metadata using a variable number of predicates, and retrieving full-content images for different hierarchical levels. RESULTS AND DISCUSSION: When compared to a well established DICOM image archive, the proposal is 0.6-7.2 times slower in storing content; however, in querying individual tags, it is about 48.0% faster. In querying groups of tags, DICOM decomposed storage model (DCMDSM) is outperformed in scenarios with a large number of tags and low selectivity (being 66.5% slower); however, when the number of tags is balanced with better selectivity predicates, the performance gains are up to 79.1%. In executing full-content retrieval, in turn, the proposal is about 48.3% faster. CONCLUSIONS: DCMDSM is a model built for the storage of heterogeneous DICOM content, based on a straightforward database design. The results obtained through its evaluation attest its suitability as a storage layer for projects where DICOM images are stored once, and queried/retrieved whenever necessary. PMID- 24491270 TI - Tory MP demands to know how government will recoup L10m in NHS "pay-offs". PMID- 24491271 TI - Treatment of ruptured blood blister-like aneurysms with flow diverter SILK stents. AB - INTRODUCTION: Blood blister-like aneurysms (BBAs) are fragile and difficult to treat. Routine surgical and endovascular treatment methods, such as clipping, clip wrapping, primary coiling, or stent assisted coiling, have relatively high morbidity and mortality rates. In this study, we report clinical and angiographic results for treatment of ruptured BBAs using flow diverter stents. METHODS: We retrospectively reviewed patients who presented with subarachnoid hemorrhages caused by rupture of BBAs and who were treated using flow diverter stents at three neurointervention centers between January 2009 and January 2013. Clinical and angiographic findings, together with the procedural data and follow-up results, are reported. RESULTS: 11 patients were identified in this study. BBAs were located on the supraclinoid internal carotid artery (nine patients) and basilar arteries (two patients). Eight patients were treated by implantation of a single flow diverter stent. Two flow diverter stents were telescopically deployed in each of three patients. The procedures were successful in all cases. No acute complications developed in any case. One patient who had an initial Hess-Hunt grade 4 died of septicemia 2 weeks after the procedure (9%). Another patient developed a minor stroke caused by parent artery thrombosis (9%). Control angiographies performed 3 and 6 months post stenting revealed complete occlusion of the aneurysms in all of the remaining nine patients (82%). 10 of the 11 patients (92%) had good clinical outcomes (modified Rankin Scale score <= 2). CONCLUSIONS: Implantation of flow diverter stents seems to be a safe and feasible alternative for treatment of ruptured BBAs. PMID- 24491272 TI - Blood glucose monitoring in the intensive care unit: toward defining bias and imprecision thresholds for (near) continuous sensors. PMID- 24491273 TI - Accurate fetal chromosome dosage determination by shotgun sequencing of maternal plasma DNA without PCR amplification during library preparation. PMID- 24491274 TI - Measurement of viscosity of highly viscous non-Newtonian fluids by means of ultrasonic guided waves. AB - In order to perform monitoring of the polymerisation process, it is necessary to measure viscosity. However, in the case of non-Newtonian highly viscous fluids, viscosity starts to be dependent on the vibration or rotation frequency of the sensing element. Also, the sensing element must possess a sufficient mechanical strength. Some of these problems may be solved applying ultrasonic measurement methods, however until now most of the known investigations were devoted to measurements of relatively low viscosities (up to a few Pas) of Newtonian liquids. The objective of the presented work is to develop ultrasonic method for measurement of viscosity of high viscous substances during manufacturing process in extreme conditions. For this purpose the method based on application of guided Lamb waves possessing the predominant component of in-plane displacements (the S0 and the SH0 modes) and propagating in an aluminium planar waveguide immersed in a viscous liquid has been investigated. The simulations indicated that in the selected modes mainly in-plane displacements are dominating, therefore the attenuation of those modes propagating in a planar waveguide immersed in a viscous liquid is mainly caused by viscosity of the liquid. The simulation results were confirmed by experiments. All measurements were performed in the viscosity standard Cannon N2700000. Measurements with the S0 wave mode were performed at the frequency of 500kHz. The SH0 wave mode was exited and used for measurements at the frequency of 580kHz. It was demonstrated that by selecting the particular mode of guided waves (S0 or SH0), the operation frequency and dimensions of the aluminium waveguide it is possible to get the necessary viscosity measurement range and sensitivity. The experiments also revealed that the measured dynamic viscosity is strongly frequency dependent and as a characteristic feature of non-Newtonian liquids is much lower than indicated by the standards. Therefore, in order to get the absolute values of viscosity in this case an additional calibration procedure is required. Feasibility to measure variations of high dynamic viscosities in the range of (20-25,000) Pas was theoretically and experimentally proved. The proposed solution differently from the known methods in principle is more mechanically robust and better fitted for measurements in extreme conditions. PMID- 24491275 TI - Polycystic ovarian syndrome and Cushing's syndrome: a persistent diagnostic quandary. AB - OBJECTIVE: To retrospectively review institutional records of female patients of reproductive age with Cushing's disease (CD) and determine if and how many had been previously diagnosed as having solely polycystic ovarian syndrome (PCOS). To determine whether clinical patterns might be useful in identifying appropriate candidates for hypercortisolism screening in women suspected of PCOS. STUDY DESIGN: The study included 50 patients with pathologically proven CD at Oregon Health & Science University, Northwest Pituitary Center between 2006 and 2011. Physical, clinical, and biochemical features for hypercortisolism were compared. RESULTS: Of 50 patients with pathologically proven CD, 26 were women of reproductive age. Of these, half had previously been diagnosed with and treated initially solely for PCOS. Hirsutism and menstrual abnormalities were more common in the group with an initial PCOS diagnosis than in the group with an initial CD diagnosis. CONCLUSIONS: Prolonged exposure to hypercortisolism has been linked with increased mortality and morbidity. Tests for hypercortisolism in all the PCOS cases we report led to an appropriate CD diagnosis. Future research should focus on when and which (if not all) women with suspected PCOS should be tested for hypercortisolism. PMID- 24491276 TI - Management of heterotopic cesarean scar pregnancy by repeated transvaginal ultrasonographic-guided aspiration with successful preservation of normal intrauterine pregnancy and complicated by arteriovenous malformation. PMID- 24491277 TI - The effect of maternal supine position on umbilical and cerebral blood flow indices. AB - OBJECTIVE: The brain sparing phenomenon in the fetus is a protective mechanism aimed at maintaining sufficient blood flow towards the brain during chronic or acute fetal stress, such as that caused by hypoxemia or utero-placental insufficiency. In this study we investigated whether the brain sparing effect can also be elicited by a physiological stress associated with maternal posture. Study design Twenty-three low-risk pregnant women participated in the study. Between 36 and 40 weeks' gestation, Doppler flow velocity waveforms were obtained from the fetal middle cerebral and the umbilical artery in the supine and the left lateral decubitus positions. Pulsatility index, systolic/diastolic index, and peak systolic velocities were measured and comparison was made between the left lateral and supine positions. RESULTS: The pulsatility index in the middle cerebral artery decreased from 1.78+/-0.27 in the left lateral decubitus position to 1.29+/-0.16 in supine position (p<0.0001). Peak systolic velocity decreased from 46.05+/-7.85cm/s to 39.43+/-7.95cm/s, respectively (p=0.001). The pulsatility index in the umbilical artery decreased from 0.89+/-0.13 in the left lateral position to 0.74+/-0.11 in the supine position (p<0.0001). CONCLUSIONS: This study demonstrates that the supine position in late pregnancy, causing aortic and venacaval compression, leads to brain auto-regulation that activates the brain sparing effect in the fetus. This protective mechanism, shown here for the first time to be linked to a physiological stress, may provide the basis for a novel approach in the assessment of fetal wellbeing. PMID- 24491278 TI - Respiratory sounds in healthy people: a systematic review. AB - BACKGROUND: There is a lack of systematised information on respiratory sounds of healthy people. This impairs health professionals from differentiating respiratory sounds of healthy people from people with respiratory diseases, which may affect patients' diagnosis and treatment. Therefore, this systematic review aimed to characterise respiratory sounds of healthy people. METHODS: The Web of knowledge, MEDLINE, EMBASE and SCOPUS databases were searched and studies using computerised analyses to detect/characterise respiratory sounds in healthy people were included. Data were extracted using a structured table-format. RESULTS: Sixteen cross-sectional studies assessing respiratory sounds in 964 subjects (aged 1 day-70 yrs) were included: 13 investigated normal respiratory sounds (frequency, intensity and amplitude) and 3 adventitious respiratory sounds (crackles and wheezes). The highest sound frequencies were observed at the trachea (inspiration: 447-1323 Hz; expiration: 206-540 Hz). Women (444-999 Hz) and infants (250-400 Hz) presented the highest frequencies at maximum power. Inspiratory sounds were more intense at the left posterior lower lobe (5.7-76.6 dB) and expiratory sounds at the trachea (45.4-85.1 dB). Nevertheless, studies establishing direct comparisons between inspiratory and expiratory sounds showed that inspiratory sounds presented the highest intensities (p < 0.001). Amplitude was higher at the left upper anterior chest (1.7 +/- 0.8 V) and lower at the right posterior lower lobe (1.2 +/- 0.7 V). Crackles were the adventitious respiratory sound most frequently reported. CONCLUSIONS: Respiratory sounds show different acoustic properties depending on subjects' characteristics, subjects' position, respiratory flow and place of recording. Further research with robust study designs, different populations and following the guidelines for computerised respiratory sound analysis are urgently needed to build evidence base. PMID- 24491279 TI - Designing protein function - macromolecular design. PMID- 24491280 TI - Importance of altered glycoprotein-bound N- and O-glycans for epithelial-to mesenchymal transition and adhesion of cancer cells. AB - Aberrant glycosylation of cell surface glycoproteins acquired during malignant progression is a common characteristic of human cancer cells. Several biological processes and molecular mechanisms relevant for tumour progression are accompanied by altered mRNA expression levels of certain glycosyltransferases resulting in unusual ratios of common glycoconjugates present in a cancer cell's glycocalyx or even in the development of unusual, cancer-characterizing carbohydrates. This mini-review aims to give a concise overview on the current knowledge of the functional relevance of altered O- and N-glycans during two critical steps of tumour progression: (I) epithelial-to-mesenchymal transition of primary tumour cells during intravasation and (II) adhesion of circulating tumour cells towards the vascular wall during extravasation at a distant metastatic site. Characteristic lectin binding patterns reflecting these glycosylation changes and the resulting prognostic impact of certain lectin binding sites in different neoplasias are reviewed as well. PMID- 24491281 TI - Characterisation and optimisation of organotypic oral mucosal models to study Porphyromonas gingivalis invasion. AB - Porphyromonas gingivalis is a Gram-negative, keystone pathogen in periodontitis that leads to tissue destruction and ultimately tooth loss. The organism is able to infect oral epithelial cells and two-dimensional (monolayer) cultures have been used to investigate this process. However, recently there has been interest in the use of three-dimensional, organotypic mucosal models to analyse infection. These models are composed of collagen-embedded fibroblasts overlain with multilayers of oral epithelial cells. In this study we report for the first time significant differences in the response of oral mucosal models to P. gingivalis infection when compared to monolayer cultures of oral epithelial cells. Intracellular survival (3-fold) and bacterial release (4-fold) of P. gingivalis was significantly increased in mucosal models compared with monolayer cultures, which may be due to the multi-layered nature and exfoliation of epithelial cells in these organotypic models. Furthermore, marked differences in the cytokine profile between infected organotypic models and monolayer cultures were observed, particularly for CXCL8 and IL6, which suggested that degradation of cytokines by P. gingivalis may be less pronounced in organotypic compared to monolayer cultures. These data suggest that use of oral mucosal models may provide a greater understanding of the host responses to P. gingivalis invasion than simple monolayer cultures. PMID- 24491282 TI - Angiosome-targeted lower limb revascularization for ischemic foot wounds: systematic review and meta-analysis. AB - OBJECTIVE: The efficacy of angiosome-targeted revascularization to achieve healing of ischemic tissue lesions of the foot and limb salvage is controversial. This issue has been investigated in this meta-analysis. METHODS: A systematic review of the literature and meta-analysis of data on angiosome-targeted lower limb revascularization for ischemic tissue lesions of the foot were performed. RESULTS: Nine studies reported on data of interest. No randomized controlled study was available. There were 715 legs treated by direct revascularization according to the angiosome principle and 575 legs treated by indirect revascularization. The prevalence of diabetes was >70% in each study group and three studies included only patients with diabetes. The risk of unhealed wound was significantly lower after direct revascularization (HR 0.64, 95% CI: 0.52 0.8, I2 0%, four studies included) compared with indirect revascularization. Direct revascularization was also associated with significantly lower risk of major amputation (HR 0.44, 95% CI: 0.26-0.75, I2 62%, eight studies included). Pooled limb salvage rates after direct and indirect revascularization were at 1 year 86.2% vs. 77.8% and at 2 years 84.9% vs. 70.1%, respectively. The analysis of three studies reporting only on patients with diabetes confirmed the benefit of direct revascularization in terms of limb salvage (HR 0.48, 95% CI: 0.31-0.75, I2 0%). CONCLUSIONS: The results of the present meta-analysis suggest that, when feasible, direct revascularization of the foot angiosome affected by ischemic tissue lesions may improve wound healing and limb salvage rates compared with indirect revascularization. Further studies of better quality and adjusted for differences between the study groups are needed to confirm the present findings. PMID- 24491283 TI - Ultrasound measurement for abdominal aortic aneurysm screening: a direct comparison of the three leading methods. AB - OBJECTIVES: Ultrasound (US) is non-invasive and cost-effective for screening abdominal aortic aneurysms (AAAs) but there is no universally accepted method to measure the aortic diameter. This study evaluates the accuracy, reproducibility, and repeatability of three methods: inner-to-inner (ITI), leading-to-leading edge (LTL), and outer-to-outer (OTO). The secondary objective of this study was to determine whether aneurysm size or grade of operator had any effect on either intra- or inter-observer variability. METHODS: Fifty static US images were measured by six assessors (2 vascular radiologists, 2 interventional radiology trainees, and 2 sonographers) on two separate occasions 6 weeks apart. Repeatability and reproducibility were calculated and compared with computed tomography (CT) as the gold standard. RESULTS: All three methods have high repeatability and reproducibility when static images are used. The inter-observer reproducibility coefficients between assessors were 0.48 cm, 0.35 cm, and 0.34 cm for ITI, LTL and OTO, respectively. The intra-observer repeatability coefficients between assessors were 0.30 cm, 0.20 cm, and 0.19 cm for ITI, LTL and OTO, respectively. The mean difference between CT and OTO, LTL, and ITI was 1 mm, 3 mm, and 5 mm, respectively (all underestimations) (p < .0001). CONCLUSIONS: US consistently underestimates aortic size when compared with CT, with ITI demonstrating the greatest underestimation (on average 5 mm). In the UK, this underestimation by the NHS Abdominal Aortic Aneurysm screening programme reduces the sensitivity of the screening test and may impact on the way in which vascular specialists interpret the findings of the screening programme. PMID- 24491284 TI - Commentary on " 'Real angiosome' assessment from peripheral tissue perfusion using tissue oxygen saturation (sto2) foot-mapping in patients with critical limb ischemia". PMID- 24491285 TI - Human-robot skills transfer interfaces for a flexible surgical robot. AB - In minimally invasive surgery, tools go through narrow openings and manipulate soft organs to perform surgical tasks. There are limitations in current robot assisted surgical systems due to the rigidity of robot tools. The aim of the STIFF-FLOP European project is to develop a soft robotic arm to perform surgical tasks. The flexibility of the robot allows the surgeon to move within organs to reach remote areas inside the body and perform challenging procedures in laparoscopy. This article addresses the problem of designing learning interfaces enabling the transfer of skills from human demonstration. Robot programming by demonstration encompasses a wide range of learning strategies, from simple mimicking of the demonstrator's actions to the higher level imitation of the underlying intent extracted from the demonstrations. By focusing on this last form, we study the problem of extracting an objective function explaining the demonstrations from an over-specified set of candidate reward functions, and using this information for self-refinement of the skill. In contrast to inverse reinforcement learning strategies that attempt to explain the observations with reward functions defined for the entire task (or a set of pre-defined reward profiles active for different parts of the task), the proposed approach is based on context-dependent reward-weighted learning, where the robot can learn the relevance of candidate objective functions with respect to the current phase of the task or encountered situation. The robot then exploits this information for skills refinement in the policy parameters space. The proposed approach is tested in simulation with a cutting task performed by the STIFF-FLOP flexible robot, using kinesthetic demonstrations from a Barrett WAM manipulator. PMID- 24491286 TI - Modelling diameter distributions of two-cohort forest stands with various proportions of dominant species: a two-component mixture model approach. AB - In recent years finite-mixture models have been employed to approximate and model empirical diameter at breast height (DBH) distributions. We used two-component mixtures of either the Weibull distribution or the gamma distribution for describing the DBH distributions of mixed-species, two-cohort forest stands, to analyse the relationships between the DBH components, age cohorts and dominant species, and to assess the significance of differences between the mixture distributions and the kernel density estimates. The data consisted of plots from the Swietokrzyski National Park (Central Poland) and areas close to and including the North Carolina section of the Great Smoky Mountains National Park (USA; southern Appalachians). The fit of the mixture Weibull model to empirical DBH distributions had a precision similar to that of the mixture gamma model, slightly less accurate estimate was obtained with the kernel density estimator. Generally, in the two-cohort, two-storied, multi-species stands in the southern Appalachians, the two-component DBH structure was associated with age cohort and dominant species. The 1st DBH component of the mixture model was associated with the 1st dominant species sp1 occurred in young age cohort (e.g., sweetgum, eastern hemlock); and to a lesser degree, the 2nd DBH component was associated with the 2nd dominant species sp2 occurred in old age cohort (e.g., loblolly pine, red maple). In two-cohort, partly multilayered, stands in the Swietokrzyski National Park, the DBH structure was usually associated with only age cohorts (two dominant species often occurred in both young and old age cohorts). When empirical DBH distributions representing stands of complex structure are approximated using mixture models, the convergence of the estimation process is often significantly dependent on the starting strategies. Depending on the number of DBHs measured, three methods for choosing the initial values are recommended: min.k/max.k, 0.5/1.5/mean, and multistart. For large samples (number of DBHs measured >= 80) the multistage method is proposed--for the two-component mixture Weibull or gamma model select initial values using the min.k/max.k (for k=1,5,10) and 0.5/1.5/mean methods, run the numerical procedure for each method, and when no two solutions are the same, apply the multistart method also. PMID- 24491287 TI - Traditional lateral ileostomy versus percutaneous ileostomy by exclusion probe for the protection of extraperitoneal colo-rectal anastomosis: the ALPPI (Anastomotic Leak Prevention by Probe Ileostomy) trial. A randomized controlled trial. AB - BACKGROUND: Low colo-rectal anastomoses have a relevant risk of leakage. The protective stomas (ileostomy or colostomy) have always been utilized to reduce the complications due to anastomotic leakage. The stoma not only causes relevant morbidity but also needs a second operation to be closed, with an added risk of complications. PURPOSE: For this reason we planed and carried out a temporary percutaneous ileostomy by a jejunal probe introduced in the distal ileum, that can be removed without a surgical procedure and with negligible complications. METHODS: The ALPPI trial is a randomized controlled, open, parallel, equivalence multicenter study. Patients undergoing elective laparoscopic or laparotomic surgery for rectal cancer with extraperitoneal anastomosis, will be randomly allocated to undergo either lateral ileostomy or percutaneous ileostomy by exclusion probe. RESULTS: The primary endpoint is the protection of the extraperitoneal colo-rectal anastomosis in terms of incidence of symptomatic and asymptomatic anastomotic leakages. The secondary endpoints are the evaluation of complications due to the placement and the removal of the exclusion probe for percutaneous ileostomy. CONCLUSIONS: The ALPPI trial is designed to provide the surgical community with an evidence based new technique in the protection of low colo-rectal anastomosis, alternative to the conventional stomas. TRIAL REGISTRATION: The ALPPI trial was approved by the Ethical Committee of Regional Public Health System of Umbria, Italy, (Protocol Number 28657/11/AV, study code RO-MA 01) and it is registered in the International Standard Randomised Controlled Trial Number (ISRCTN) Register with identification number ISRCTN99356919. PMID- 24491288 TI - Long-term follow-up of patients with GIST undergoing metastasectomy in the era of imatinib -- analysis of prognostic factors (EORTC-STBSG collaborative study). AB - BACKGROUND: Long-term complete remissions remain a rare exception in patients with metastatic gastrointestinal stromal tumors (GIST) treated with IM (imatinib). To date the therapeutic relevance of surgical resection of metastatic disease remains unknown except for the use in palliative intent. PATIENTS AND METHODS: We analyzed overall survival (OS) and progression-free survival (PFS) in consecutive patients with metastatic GIST who underwent metastasectomy and received IM therapy (n = 239). RESULTS: Complete resection (R0+R1) was achieved in 177 patients. Median OS was 8.7 y for R0/R1 and 5.3 y in pts with R2 resection (p = 0.0001). In the group who were in remission at time of resection median OS was not reached in the R0/R1 surgery and 5.1 y in the R2-surgery (p = 0.0001). Median time to relapse/progression after resection of residual disease was not reached in the R0/R1 and 1.9 years in the R2 group of patients, who were resected in response. No difference in mPFS was seen in patients progressing at time of surgery. CONCLUSIONS: Our analysis implicates possible long-term survival in patients in whom surgical complete remission can be achieved. Incomplete resection, including debulking surgery does not seem to prolong survival. Despite the retrospective character and likely selection bias, this analysis may help in decision making for surgical approaches in metastatic GIST. PMID- 24491289 TI - A comparison of diagnostic imaging modalities for colorectal liver metastases. AB - AIMS: The aims of this study were to compare the diagnostic performance of CT scan, MR liver, PET-CT and intra-operative ultrasound (IOUS) for the detection of liver metastases against the histopathological findings, and to compare PET-CT with CT for the detection of distant disease in metastatic colorectal cancer patients eligible for surgical treatment. METHODS: A prospective study was performed that measured concordance between the number and stage of metastatic lesions identified with various preoperative imaging modalities and histology of patients undergoing surgical treatment for CRLM. RESULTS: Compared with histopathology, concordance for the number of metastatic liver lesions was moderate for CT scan (K = 0.477, 95% CI: 0.28-0.66), moderate for MR scan (K = 0.574, 95% CI: 0.39-0.75), good for FDG PET-CT (K = 0.703, 95% CI: 0.52-0.87) and very good for IOUS (K = 0.904, 95% CI: 0.81-0.99). Additional CRLM were identified intraoperatively in six patients (9.1%) with IOUS and in 7.5% of the cases surgical strategy was changed according to the new intraoperative findings. The diagnosis of intra abdominal lymph node metastatic disease was made with PET CT only in nine patients (13.6%) DISCUSSION: Our study supports the recent recommendations of the Oncosurg Multidisciplinary International Consensus regarding the importance of high quality CT and MR in the staging of CRLM but provides further evidence for the added value of PET-CT, especially in detecting extrahepatic intra-abdominal metastatic disease that may be amenable to potentially curative resection. Despite these advances in preoperative staging, there still remains a role for IOUS in detecting additional metastases at the time of surgery. PMID- 24491290 TI - Acquired ichthyosis associated with primary cutaneous CD30+ lymphoproliferative disorders. PMID- 24491291 TI - Early dentine remineralisation: morpho-mechanical assessment. AB - OBJECTIVES: The purpose of this study was to evaluate some physical-mechanical and morphological changes of demineralised dentine at early stages of dentine remineralisation. METHODS: Extracted human third molars were sectioned to obtain dentine discs. After polishing the dentine surfaces, three groups were established: (1) untreated dentine - UD, (2) 37% phosphoric acid application for 15s (partially demineralised dentine - PDD) and (3) 10% phosphoric acid for 12h, at 25 degrees C (totally demineralised dentine - TDD). Five different remineralizing fluids were used for 30min: chlorhexidine (CHX), artificial saliva (AS), phosphated solution (PS), ZnCl2 and ZnO solutions. Atomic force microscopy (AFM) imaging/nano-indentation, surface nano-roughness and fibrils diameter were determined. X-ray diffraction (XRD), energy dispersive elemental analyses (EDX) and high resolution scanning electron microscopy analysis (HRSEM) were applied. RESULTS: PDD and TDD preserved some mineral contents. After demineralisation and immersion in all solutions, width of nanomechanical properties and fibrils was increased, and total nanoroughness was decreased. Peritubular and intertubular dentine were remineralised. CONCLUSION: Mineral exists in PA-demineralised dentine matrix and it is important since it may work as a constant site for further nucleation. The dentine surface remineralisation process may be stimulated as early as 30min in abiotic conditions, with a pH ranging from 7.0 to 7.5. CLINICAL SIGNIFICANCE: The existence of enzymes and remineralising factors within the dentine matrix may facilitate early dentine remineralisation under favourable conditions. This process should be stimulated by new reparative materials. PMID- 24491292 TI - Anodic microbial community diversity as a predictor of the power output of microbial fuel cells. AB - The relationship between the diversity of mixed-species microbial consortia and their electrogenic potential in the anodes of microbial fuel cells was examined using different diversity measures as predictors. Identical microbial fuel cells were sampled at multiple time-points. Biofilm and suspension communities were analysed by denaturing gradient gel electrophoresis to calculate the number and relative abundance of species. Shannon and Simpson indices and richness were examined for association with power using bivariate and multiple linear regression, with biofilm DNA as an additional variable. In simple bivariate regressions, the correlation of Shannon diversity of the biofilm and power is stronger (r=0.65, p=0.001) than between power and richness (r=0.39, p=0.076), or between power and the Simpson index (r=0.5, p=0.018). Using Shannon diversity and biofilm DNA as predictors of power, a regression model can be constructed (r=0.73, p<0.001). Ecological parameters such as the Shannon index are predictive of the electrogenic potential of microbial communities. PMID- 24491293 TI - Enhanced cellulase producing mutants developed from heterokaryotic Aspergillus strain. AB - A heterokaryon 28, derived through protoplast fusion between Aspergillus nidulans and Aspergillus tubingensis (Dal8), was subjected cyclic mutagenesis followed by selection on increasing levels of 2-deoxy glucose (2-DG) as selection marker. The derived deregulated cellulase hyper producing mutant '64', when compared to fusant 28, produced 9.83, 7.8, 3.2, 4.2 and 19.74 folds higher endoglucanase, beta-glucosidase, cellobiohydrolase, FPase and xylanase, respectively, under shake cultures. The sequence analysis of PCR amplified beta-glucosidase gene from wild and mutant showed nucleotide deletion/substitution. The mutants showed highly catalytic efficient beta-glucosidase as evident from low Km and high Vmax values. The expression profiling through zymogram analysis also indicated towards over-expression of cellulases. The up/down regulated expressed proteins observed through SDS-PAGE were identified by Peptide mass fingerprinting The cellulase produced by mutants in conjunction with cellulase free xylanase derived from Thermomyces lanuginosus was used for efficient utilization of alkali treated rice straw for obtaining xylo-oligosaccharides and ethanol. PMID- 24491294 TI - Achieving high lipid productivity of a thermotolerant microalga Desmodesmus sp. F2 by optimizing environmental factors and nutrient conditions. AB - The optimal conditions for cultivating the thermotolerant lipid-rich microalga Desmodesmus sp. F2 to achieve maximal lipid productivity were determined in this study. The conditions were light intensity, 700MUmol/m(2)s; temperature, 35 degrees C; cultivation nitrogen source, nitrate; initial nitrogen level, 6.6mM nitrogen. Carbon dioxide (2.5%, 0.2 vvm) was pumped into the cultures continuously. In the pre-optimized conditions, the maximal lipid productivity of this microalga was 113mg/L/d, which was raised to 263mg/L/d in the optimized conditions. This level of lipid productivity of microalgae is the highest ever reported in the literature. Fatty acid composition of the lipid produced by Desmodesmus sp. F2 in the optimal conditions was determined, in which C16 and C18 species accounted for 95% of the fatty acids. Saturated, monounsaturated and polyunsaturated fatty acids accounted for 38.9%, 33.1% and 22.6%, respectively. Based on the analysis, this lipid quality makes it a good feedstock for biodiesel production. PMID- 24491295 TI - Sequential acid and enzymatic hydrolysis in situ and bioethanol production from Gracilaria biomass. AB - Gracilaria sp., a red alga, was used as a feedstock for the production of bioethanol. Saccharification of Gracilaria sp. by sequential acid and enzyme hydrolysis in situ produced a high quality hydrolysate that ensured its fermentability to produce ethanol. The optimal saccharification process resulted in total 11.85g/L (59.26%) of glucose and galactose, Saccharomyces cerevisiae Wu Y2 showed a good performance on co-fermentability of glucose and galactose released in the hydrolysate from Gracilaria sp. The final ethanol concentrations of 4.72g/L (0.48g/g sugar consumed; 94% conversion efficiency) and the ethanol productivity 4.93g/L/d were achieved. 1g of dry Gracilaria can be converted to 0.236g (23.6%) of bioethanol via the processes developed. Efficient alcohol production by immobilized S. cerevisiae Wu-Y2 in batch and repeated batch fermentation was also demonstrated. The findings of this study revealed that Gracilaria sp. can be a potential feedstock in biorefinery for ethanol production. PMID- 24491296 TI - Does ovarian suspension following laparoscopic surgery for endometriosis reduce postoperative adhesions? An RCT. AB - STUDY QUESTION: Is temporary ovarian suspension following laparoscopic surgery for severe pelvic endometriosis an effective method for reducing the prevalence of postoperative ovarian adhesions? SUMMARY ANSWER: Temporary ovarian suspension for 36-48 h following laparoscopic treatment of severe endometriosis does not result in a significant reduction of postoperative ovarian adhesions. WHAT IS KNOWN ALREADY: Pelvic adhesions often develop following laparoscopic surgery for severe pelvic endometriosis. Adhesions can cause chronic pelvic pain and fertility problems compromising the success of treatment. Small observational studies suggested that temporary postoperative ovarian suspension to the abdominal wall may significantly reduce the prevalence of postoperative ovarian adhesions. STUDY DESIGN, SIZE, DURATION: This was a prospective within group comparison double-blind RCT. We recruited premenopausal women with severe pelvic endometriosis who required extensive laparoscopic surgery with preservation of the uterus and ovaries. Severity of the disease and eligibility for inclusion were determined at surgery. A total of 55 women were randomized to unilateral ovarian suspension for 36-48 h, 52 of which were included in the final analysis. Both ovaries were routinely suspended to the anterior abdominal wall during surgery. At the end of the operation, each woman was randomized to having only one ovary suspended postoperatively. The suture suspending the contralateral ovary was cut and a new transabdominal suture was inserted to act as a placebo. Both sutures were removed 36-48 h after surgery prior to discharge. Three months after surgery, all women attended for a detailed transvaginal ultrasound scan to assess ovarian mobility. Both the women and the ultrasound operators were blinded as to the side of postoperative ovarian suspension. The primary outcome was the prevalence of ovarian adhesions as described on ultrasound examination. Secondary outcomes were the severity of adhesions and the presence and intensity of postoperative pain. PARTICIPANTS/MATERIALS, SETTING, METHODS: All 55 participants had severe pelvic endometriosis confirmed at laparoscopy. As each participant had only one of their ovaries suspended at the end of surgery, they acted as their own control. MAIN RESULTS AND THE ROLE OF CHANCE: The median interval between ovarian suspension and postoperative scan was 99 days (interquartile range 68 114). There was no significant difference (P = 0.23) in the prevalence of postoperative ovarian adhesions between the suspended (20/52) and unsuspended (27/52) side (38.5 versus 51.9%) [odds ratio 0.56 (95% confidence interval 0.22 1.35)]. LIMITATIONS, REASONS FOR CAUTION: Ovaries were suspended postoperatively for 36-48 h. Longer suspension could result in lower prevalence of postoperative adhesions. WIDER IMPLICATIONS OF THE FINDINGS: The value of temporary ovarian suspension in women having surgery for mild-to-moderate endometriosis should be investigated further. The potential benefits of other adhesion prevention strategies, such as surgical barrier agents, in women undergoing surgical treatment for severe pelvic endometriosis should also be explored. STUDY FUNDING/COMPETING INTERESTS: E.S. received honoraria from Ethicon for provision of training to healthcare professionals and consultancy fees from Bayer. W.H. was supported by the research fund provided by the Gynaecology Ultrasound Centre, London UK. A.C. is on the advisory board for surgical innovations for which he receives an annual honorarium. A.C. also received support for courses and education from Storz and Johnson and Johnson and support for clinical nursing from Covidien and Lotus. The other authors declared no competing interests. TRIAL REGISTRATION NUMBER: Current Controlled Trials ISRCTN24242218. PMID- 24491297 TI - In vitro screening of embryos by whole-genome sequencing: now, in the future or never? AB - STUDY QUESTION: What are the analytical and clinical validity and the clinical utility of in vitro screening of embryos by whole-genome sequencing? SUMMARY ANSWER: At present there are still many limitations in terms of analytical and clinical validity and utility and many ethical questions remain. WHAT IS KNOWN ALREADY: Whole-genome sequencing of IVF/ICSI embryos is technically possible. Many loss-of-function mutations exist in the general population without serious effects on the phenotype of the individual. Moreover, annotations of genes and the reference genome are still not 100% correct. STUDY DESIGN, SIZE, DURATION: We used publicly available samples from the 1000 Genomes project and Complete Genomics, together with 42 samples from in-house research samples of parents from trios to investigate the presence of loss-of-function mutations in healthy individuals. PARTICIPANTS/MATERIALS, SETTING, METHODS: In the samples, we looked for mutations in genes that are associated with a selection of severe Mendelian disorders with a known molecular basis. We looked for mutations predicted to be damaging by PolyPhen and SIFT and for mutations annotated as disease causing in Human Genome Mutation Database (HGMD). MAIN RESULTS AND THE ROLE OF CHANCE: More than 40% of individuals who can be considered healthy have mutations that are predicted to be damaging in genes associated with severe Mendelian disorders or are annotated as disease causing. LIMITATIONS, REASONS FOR CAUTION: The analysis relies on current knowledge and databases are continuously updated to reflect our increasing knowledge about the genome. In the process of our analysis several updates were already made. WIDER IMPLICATIONS OF THE FINDINGS: At this moment it is not advisable to use whole-genome sequencing as a tool to set up health profiles to select embryos for transfer. We also raise some ethical questions that have to be addressed before this technology can be used for embryo selection. TRIAL REGISTRATION NUMBER: N/A. PMID- 24491298 TI - Reply: the danger of ignoring pregnancy and delivery rates in ART. PMID- 24491299 TI - The danger of ignoring pregnancy and delivery rates in ART. PMID- 24491300 TI - Air pollution and decreased semen quality: a comparative study of Chongqing urban and rural areas. AB - To investigate the association and effects of air pollution level on male semen quality in urban and rural areas, this study examines the outdoor concentrations of particulate matter (PM10), sulfur dioxide (SO2), nitrous dioxide (NO2) and semen quality outcomes for 1346 volunteers in both urban and rural areas in Chongqing, China. We found the urban area has a higher pollution level than the rural area, contrasted with better semen quality in the rural residents, especially for sperm morphology and computer assistant semen analysis (CASA) motility parameters. A multivariate linear regression analysis demonstrates that concentrations of PM10, SO2, and NO2 significantly and negatively are associated with normal sperm morphology percentage (P < 0.001) and sperm kinetic parameters. In conclusion, exposure to higher concentrations of PM10, SO2, and NO2 in urban ambient air may account for worse semen quality in urban males. PMID- 24491301 TI - Role of oncogenic K-Ras in cancer stem cell activation by aberrant Wnt/beta catenin signaling. AB - BACKGROUND: Adenomatous polyposis coli (APC) loss-of-function mutations and K-Ras gain-of-function mutations are common abnormalities that occur during the initiation and intermediate adenoma stages of colorectal tumorigenesis, respectively. However, little is known about the role these mutations play in cancer stem cells (CSCs) associated with colorectal cancer (CRC) tumorigenesis. METHODS: We analyzed tissue from CRC patients (n = 49) to determine whether K-Ras mutations contributed to CSC activation during colorectal tumorigenesis. DLD-1-K Ras-WT and DLD-1-K-Ras-MT cells were cultured and evaluated for their ability to differentiate, form spheroids in vitro, and form tumors in vivo. Interaction between APC and K-Ras mutations in colorectal tumorigenesis was evaluated using APC (Min/+)/K-Ras (LA2) mice and DLD-1-K-Ras-WT and DLD-1-K-Ras-MT cell xenografts. (n = 4) Group differences were determined by Student t test. All statistical tests were two-sided. RESULTS: The sphere-forming capability of DLD-1 K-Ras-MT cells was statistically significantly higher than that of DLD-1-K-Ras-WT cells (DLD-1-K-Ras-MT mean = 86.661 pixel, 95% confidence interval [CI] = 81.701 to 91.621 pixel; DLD-1-K-Ras-WT mean = 42.367 pixel, 95% CI = 36.467 to 48.267 pixel; P = .003). Moreover, both the size and weight of tumors from DLD-1-K-Ras MT xenografts were markedly increased compared with tumors from DLD-1-K-Ras-WT cells. Expression of the CSC markers CD44, CD133, and CD166 was induced in intestinal tumors from APC (Min/+)/K-Ras (LA2)mice, but not K-Ras (LA2) mice, indicating that APC mutation is required for CSC activation by oncogenic K-Ras mutation. CONCLUSIONS: K-Ras mutation activates CSCs, contributing to colorectal tumorigenesis and metastasis in CRC cells harboring APC mutations. Initial activation of beta-catenin by APC loss and further enhancement through K-Ras mutation induces CD44, CD133, and CD166 expression. PMID- 24491303 TI - KRAS and cancer stem cells in APC-mutant colorectal cancer. PMID- 24491304 TI - ALK1 as a novel therapeutic target for CD30+ T-anaplastic large cell lymphoma. PMID- 24491302 TI - Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. AB - Anaplastic lymphoma kinase (ALK)-positive lymphomas respond to chemotherapy, but relapses, which bear a poor prognosis, occur. Crizotinib inhibits ALK in vitro and in vivo and was administered as monotherapy to 11 ALK+ lymphoma patients who were resistant/refractory to cytotoxic therapy. The overall response rate was 10 of 11 (90.9%; 95% confidence interval [CI] = 58.7% to 99.8%). Disease status at the latest follow-up is as follows: four patients are in complete response (CR) (months >21, >30, >35, >40) under continuous crizotinib administration; 4 patients had progression of disease (months 1, 2, 2, 2); 1 patient obtained CR on crizotinib, received an allogeneic bone marrow transplant, and is in CR; 2 patients (treated before and/or after allogeneic bone marrow transplant) obtained and are still in CR but they have stopped crizotinib. Overall and progression free survival rates at 2 years are 72.7% (95% CI = 39.1% to 94.0%) and 63.7% (95% CI = 30.8% to 89.1%), respectively. ALK mutations conferring resistance to crizotinib in vitro could be identified in relapsed patients. Crizotinib exerted a potent antitumor activity with durable responses in advanced, heavily pretreated ALK+ lymphoma patients, with a benign safety profile. PMID- 24491305 TI - Endotoxin-induced experimental systemic inflammation in humans: a model to disentangle immune-to-brain communication. AB - Systemic inflammation is among the most prominent and most frequently observed responses of the immune system. Over the past decades, it has become clear that inflammatory cytokines not only affect immune and metabolic functions but also cause a wide range of behavioral and mood changes. Based on experimental findings in animals and observations in clinical populations it has been hypothesized that inflammation-induced neurocognitive changes contribute to the pathophysiology of neuropsychiatric diseases. However, since certain aspects of human behavior cannot be modeled in laboratory animals, there is a need for human models of systemic inflammation. In this review, we summarize recent studies employing administration of endotoxin as a model to induce transient systemic inflammation in healthy human subjects. PMID- 24491306 TI - Propensity-matched comparison of morbidity and costs of open and robot-assisted radical cystectomies: a contemporary population-based analysis in the United States. AB - BACKGROUND: Radical cystectomy (RC) is a morbid procedure associated with high costs. Limited population-based data exist on the complication profile and costs of robot-assisted RC (RARC) compared with open RC (ORC). OBJECTIVE: To evaluate morbidity and cost differences between ORC and RARC. DESIGN, SETTING, AND PARTICIPANTS: We conducted a population-based, retrospective cohort study of patients who underwent RC at 279 hospitals across the United States between 2004 and 2010. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Multivariable logistic and median regression was performed to evaluate 90-d mortality, postoperative complications (Clavien classification), readmission rates, length of stay (LOS), and direct costs. To reduce selection bias, we used propensity weighting with survey weighting to obtain nationally representative estimates. RESULTS AND LIMITATIONS: The final weighted cohort included 34 672 ORC and 2101 RARC patients. RARC use increased from 0.6% in 2004 to 12.8% in 2010. Major complication rates (Clavien grade >= 3; 17.0% vs 19.8%, p = 0.2) were similar between ORC and RARC (odds ratio [OR]: 1.32; p = 0.42). RARC had 46% decreased odds of minor complications (Clavien grade 1-2; OR: 0.54; p = 0.03). RARC had $4326 higher adjusted 90-d median direct costs (p = 0.004). Although RARC had a significantly shorter LOS (11.8 d vs 10.2 d; p = 0.008), no significant differences in room and board costs existed (p = 0.20). Supply costs for RARC were significantly higher ($6041 vs $3638; p < 0.0001). Morbidity and cost differences were not present among the highest-volume surgeons (>= 7 cases per year) and hospitals (>= 19 cases per year). Limitations include use of an administrative database and lack of oncologic characteristics. CONCLUSIONS: The use of RARC has increased between 2004 and 2010. Compared with ORC, RARC was associated with decreased odds of minor but not major complications and with increased expenditures attributed primarily to higher supply costs. Centralization of ORC and RARC to high-volume providers may minimize these morbidity and cost differences. PATIENT SUMMARY: Using a US population-based cohort, we found that robotic surgery for bladder cancer decreased minor complications, had no impact on major complications and was more costly than open surgery. PMID- 24491307 TI - The influence of prior abiraterone treatment on the clinical activity of docetaxel in men with metastatic castration-resistant prostate cancer. AB - BACKGROUND: Taxanes may partly mediate their effect in castration-resistant prostate cancer (CRPC) through disruption of androgen-receptor trafficking along microtubules. This raises the possibility of cross-resistance between androgen directed agents and docetaxel. OBJECTIVE: To evaluate docetaxel efficacy after abiraterone treatment in CRPC patients. DESIGN, SETTING, AND PARTICIPANTS: This was a single-institution, retrospective analysis in CRPC patients (N=119) who either received abiraterone before docetaxel (AD) (n=24) or did not receive abiraterone before docetaxel (docetaxel-only; n=95). Men initiated docetaxel between December 2007 (the date abiraterone was first used at our center) and May 2013. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary efficacy end points were prostate-specific antigen progression-free survival (PSA-PFS) and clinical/radiographic progression-free survival (PFS) on docetaxel. Differences between groups were assessed using univariate and multivariable analyses. RESULTS AND LIMITATIONS: Men in the AD group had a significantly higher risk for progression than those in the docetaxel-only group. Median PSA-PFS was 4.1 mo in the AD group and 6.7 mo in the docetaxel-only group (p=0.002). Median PFS was also shorter in the AD group (4.4 mo vs 7.6 mo; p=0.003). In multivariable analysis, prior abiraterone treatment remained an independent predictor of shorter PSA-PFS (hazard ratio [HR]: 3.48; 95% confidence interval [CI], 1.36 8.94; p=0.01) and PFS (HR: 3.62; 95% CI, 1.41-9.27; p=0.008). PSA declines >=50% were less frequent in the AD group (38% vs 63%; p=0.02). The small size and retrospective nature of this study may have introduced bias. CONCLUSIONS: Men receiving abiraterone before docetaxel were more likely to progress on docetaxel and less likely to achieve a PSA response than abiraterone-naive patients. Cross resistance between abiraterone and docetaxel may explain these findings; however, larger, more definitive studies are still needed to confirm this. PATIENT SUMMARY: We examined the efficacy of docetaxel in castration-resistant prostate cancer patients who either did or did not receive prior abiraterone. We found that men receiving abiraterone before docetaxel were less likely to achieve a PSA response and were more likely to progress sooner on docetaxel than abiraterone untreated patients. This may be due to cross-resistance. PMID- 24491309 TI - Novel tools to improve patient selection and monitoring on active surveillance for low-risk prostate cancer: a systematic review. AB - CONTEXT: Active surveillance (AS) is an alternative to initial radical treatment of low-risk prostate cancer (PCa). Current criteria for selection and follow-up incorrectly exclude some patients eligible for AS and misclassify some who actually harbour significant disease. Better prediction of cancer behaviour at diagnosis would allow less strict monitoring and may improve acceptance of AS. OBJECTIVE: To review and critically analyse the literature on the value of novel clinical tools for patient selection and monitoring on AS. EVIDENCE ACQUISITION: A comprehensive search of the PubMed database until July 10, 2013, was performed according to Preferred Reporting Items for Systematic Reviews and Meta-analysis statement guidelines. Studies assessing novel markers and diagnostics for patient selection for AS and follow-up during AS were included. Studies analysing only classic clinical parameters used in current protocols (prostate-specific antigen, prostate volume, number of (positive) prostate biopsies, percentage malignant tissue, Gleason score) were excluded. This review focuses only on the AS setting and not on predicting insignificant disease in general. EVIDENCE SYNTHESIS: Of 787 studies on AS, 30 were included in this review: 14 on magnetic resonance imaging (MRI), 5 on serum markers, 5 on urinary markers, 4 on histopathology markers, and 2 on germline genetic markers. Several of these markers improve the prediction of tumour volume, tumour grade, or time to active treatment. MRI has a high specificity for low-risk PCa; new serum markers are associated with unfavourable disease. In none of the studies was the new marker used as the primary decision tool. Long-term outcome measures such as mortality were not assessed. The definition of indolent PCa is disputable. CONCLUSIONS: Imaging and serum markers may improve future patient selection for AS and follow-up during AS. Prospective studies should aim to further evaluate the clinical utility of these new markers with respect to longer term outcomes of AS. PATIENT SUMMARY: We searched the literature for articles reporting new ways to safely monitor low risk prostate cancer for patients who have not had radical treatment. We found 30 articles. The most promising tools appear to be magnetic resonance imaging scans and various new blood markers. These may be used in the future within active surveillance regimens. PMID- 24491310 TI - Clinical practice guideline: acute otitis externa. AB - OBJECTIVE: This clinical practice guideline is an update and replacement for an earlier guideline published in 2006 by the American Academy of Otolaryngology Head and Neck Surgery Foundation. This update provides evidence-based recommendations to manage acute otitis externa (AOE), defined as diffuse inflammation of the external ear canal, which may also involve the pinna or tympanic membrane. The variations in management of AOE and the importance of accurate diagnosis suggest a need for updating the clinical practice guideline. The primary outcome considered in this guideline is clinical resolution of AOE. PURPOSE: The primary purpose of the original guideline was to promote appropriate use of oral and topical antimicrobials for AOE and to highlight the need for adequate pain relief. An updated guideline is needed because of new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group. The target patient is aged 2 years or older with diffuse AOE. Differential diagnosis will be discussed, but recommendations for management will be limited to diffuse AOE, which is almost exclusively a bacterial infection. This guideline is intended for primary care and specialist clinicians, including otolaryngologists-head and neck surgeons, pediatricians, family physicians, emergency physicians, internists, nurse practitioners, and physician assistants. This guideline is applicable in any setting in which patients with diffuse AOE would be identified, monitored, or managed. ACTION STATEMENTS: The development group made strong recommendations that (1) clinicians should assess patients with AOE for pain and recommend analgesic treatment based on the severity of pain and (2) clinicians should not prescribe systemic antimicrobials as initial therapy for diffuse, uncomplicated AOE unless there is extension outside the ear canal or the presence of specific host factors that would indicate a need for systemic therapy. The development group made recommendations that (1) clinicians should distinguish diffuse AOE from other causes of otalgia, otorrhea, and inflammation of the external ear canal; (2) clinicians should assess the patient with diffuse AOE for factors that modify management (nonintact tympanic membrane, tympanostomy tube, diabetes, immunocompromised state, prior radiotherapy); (3) clinicians should prescribe topical preparations for initial therapy of diffuse, uncomplicated AOE; (4) clinicians should enhance the delivery of topical drops by informing the patient how to administer topical drops and by performing aural toilet, placing a wick, or both, when the ear canal is obstructed; (5) clinicians should prescribe a non ototoxic preparation when the patient has a known or suspected perforation of the tympanic membrane, including a tympanostomy tube; and (6) clinicians should reassess the patient who fails to respond to the initial therapeutic option within 48 to 72 hours [corrected] to confirm the diagnosis of diffuse AOE and to exclude other causes of illness. PMID- 24491308 TI - Systematic review and meta-analysis of candidate gene association studies of lower urinary tract symptoms in men. AB - CONTEXT: Although family studies have shown that male lower urinary tract symptoms (LUTS) are highly heritable, no systematic review exists of genetic polymorphisms tested for association with LUTS. OBJECTIVE: To systematically review and meta-analyze studies assessing candidate polymorphisms/genes tested for an association with LUTS, and to assess the strength, consistency, and potential for bias among pooled associations. EVIDENCE ACQUISITION: A systematic search of the PubMed and HuGE databases as well as abstracts of major urologic meetings was performed through to January 2013. Case-control studies reporting genetic associations in men with LUTS were included. Reviewers independently and in duplicate screened titles, abstracts, and full texts to determine eligibility, abstracted data, and assessed the credibility of pooled associations according to the interim Venice criteria. Authors were contacted for clarifications if needed. Meta-analyses were performed for variants assessed in more than two studies. EVIDENCE SYNTHESIS: We identified 74 eligible studies containing data on 70 different genes. A total of 35 meta-analyses were performed with statistical significance in five (ACE, ELAC2, GSTM1, TERT, and VDR). The heterogeneity was high in three of these meta-analyses. The rs731236 variant of the vitamin D receptor had a protective effect for LUTS (odds ratio: 0.64; 95% confidence interval, 0.49-0.83) with moderate heterogeneity (I(2)=27.2%). No evidence for publication bias was identified. Limitations include wide-ranging phenotype definitions for LUTS and limited power in most meta-analyses to detect smaller effect sizes. CONCLUSIONS: Few putative genetic risk variants have been reliably replicated across populations. We found consistent evidence of a reduced risk of LUTS associated with the common rs731236 variant of the vitamin D receptor gene in our meta-analyses. PATIENT SUMMARY: Combining the results from all previous studies of genetic variants that may cause urinary symptoms in men, we found significant variants in five genes. Only one, a variant of the vitamin D receptor, was consistently protective across different populations. PMID- 24491311 TI - Treatment and survival disparities in lung cancer: the effect of social environment and place of residence. AB - OBJECTIVE: The purpose of this study was to measure the extent to which geographic residency status and the social environment are associated with disease stage at diagnosis, receipt of treatment, and five-year survival for patients diagnosed with non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: This study was a retrospective cohort study of the Georgia Comprehensive Cancer Registry (GCCR) for incident cases of NSCLC diagnosed in the state. Multilevel logistic models were employed for five outcome variables: unstaged and late stage disease at diagnosis; receipt of treatment (surgery, chemotherapy, and radiation); and survival following diagnosis. The social and geographical variables of interest were census tract (CT) poverty level, CT-level educational attainment, and CT-level geographic residency status. RESULTS: Compared to urban residents, rural and suburban residents had increased odds of unstaged disease (suburban OR=1.23, 95% CI: 1.11-1.37; rural OR=1.63, 95% CI: 1.45-1.83). In this study, rural participants had lower odds of receiving radiotherapy (OR=0.89, 95% CI: 0.82-0.96) and chemotherapy (OR=0.92, 95% CI: 0.85 0.99). Living in CTs with lower educational levels was associated with decreasing odds of receiving both surgery (lowest educational level OR=0.67, 95% CI: 0.59 0.75) and chemotherapy (lowest educational level OR=0.74, 95% CI: 0.68-0.81). Living in areas with higher concentration of deprivation (high level of deprivation HR=1.04, 95% CI: 1.01-1.09) and lower levels of education (lowest educational level HR=1.12, 95% CI: 1.07-1.17) was associated with poorer survival. Rural residents did not show poorer survival when treatment was controlled and they even presented a lower risk of death for early stage disease (HR=0.90, 95% CI: 0.82-0.99). CONCLUSION: This study concludes that where NSCLC patients live can, to some extent, explain treatment and prognostic disparities. Public health practitioners and policy makers should be cognizant of the importance of where people live and shift their efforts to improve lung cancer outcomes in rural areas and neighborhoods with concentrated poverty. PMID- 24491312 TI - Mouse and cockroach exposure in rural Arkansas Delta region homes. AB - BACKGROUND: Home characteristics and aeroallergen exposure in rural US children with asthma are poorly described. OBJECTIVE: To examine the relationship between cockroach and mouse allergen concentrations and home characteristics of children with asthma in the rural Arkansas Delta. METHODS: The home environments of rural children with asthma were examined using home environment questionnaire and home inspection. Bedroom and kitchen dust was analyzed for cockroach and mouse allergen concentrations. RESULTS: The median age of participants was 9 years, and 84% were African American. Most participants (78%) resided in single-family homes. Evidence of cockroaches was detected in 13% of homes and evidence of rodents was detected in 23% of homes. Detectable Bla g 1 was found in 58% of kitchens and 43% of bedrooms, Bla g 2 was detected in 37% of kitchens and 28% of bedrooms, and Mus m 1 was found in 81% of kitchens and 97% of bedrooms. Evidence of cockroaches in any room was associated with Bla g 1 concentrations of >=2 U/g (odds ratio 21.71, 95% confidence interval 4.26-118.39) and Bla g 2 concentrations of >=2 U/g (odds ratio 21.90 95% confidence interval 4.30-138.91). Multifamily vs single-family dwellings were more likely to have Bla g 2 concentrations of >=2 U/g (odds ratio 3.52, 95% confidence interval 1.0-11.82). Home characteristics were not associated with Mus m 1. CONCLUSION: Mouse and cockroach allergens were detected in most rural homes; however, concentrations were relatively low compared with those previously reported in inner-city homes. Few home characteristics predicted allergen concentrations. Further studies are needed to establish clinically relevant associations that might place rural children with asthma at risk for poor clinical outcomes. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00590304. PMID- 24491313 TI - Hallucinators find meaning in noises: pareidolic illusions in dementia with Lewy bodies. AB - By definition, visual illusions and hallucinations differ in whether the perceived objects exist in reality. A recent study challenged this dichotomy, in which pareidolias, a type of complex visual illusion involving ambiguous forms being perceived as meaningful objects, are very common and phenomenologically similar to visual hallucinations in dementia with Lewy bodies (DLB). We hypothesise that a common psychological mechanism exists between pareidolias and visual hallucinations in DLB that confers meaning upon meaningless visual information. Furthermore, we believe that these two types of visual misperceptions have a common underlying neural mechanism, namely, cholinergic insufficiency. The current study investigated pareidolic illusions using meaningless visual noise stimuli (the noise pareidolia test) in 34 patients with DLB, 34 patients with Alzheimer's disease and 28 healthy controls. Fifteen patients with DLB were administered the noise pareidolia test twice, before and after donepezil treatment. Three major findings were discovered: (1) DLB patients saw meaningful illusory images (pareidolias) in meaningless visual stimuli, (2) the number of pareidolic responses correlated with the severity of visual hallucinations, and (3) cholinergic enhancement reduced both the number of pareidolias and the severity of visual hallucinations in patients with DLB. These findings suggest that a common underlying psychological and neural mechanism exists between pareidolias and visual hallucinations in DLB. PMID- 24491314 TI - Quercetin inhibits AMPK/TXNIP activation and reduces inflammatory lesions to improve insulin signaling defect in the hypothalamus of high fructose-fed rats. AB - Fructose is a nutritional composition of fruits and honey. Its excess consumption induces insulin resistance-associated metabolic diseases. Hypothalamic insulin signaling plays a pivotal role in controlling whole-body insulin sensitivity and energy homeostasis. Quercetin, a natural flavonoid, has been reported to ameliorate high fructose-induced rat insulin resistance and hyperlipidemia. In this study, we investigated its regulatory effects on the hypothalamus of high fructose-fed rats. Rats were fed 10% fructose in drinking water for 10 weeks. After 4 weeks, these animals were orally treated with quercetin (50 and 100 mg/kg), allopurinol (5 mg/kg) and water daily for the next 6 weeks, respectively. Quercetin effectively restored high fructose-induced hypothalamic insulin signaling defect by up-regulating the phosphorylation of insulin receptor and protein kinase B. Furthermore, quercetin was found to reduce metabolic nutrient sensors adenosine monophosphate-activated protein kinase (AMPK) activation and thioredoxin-interacting protein (TXNIP) overexpression, as well as the glutamine glutamate cycle dysfunction in the hypothalamus of high fructose-fed rats. Subsequently, it ameliorated high fructose-caused hypothalamic inflammatory lesions in rats by suppressing the activation of hypothalamic nuclear factor kappaB (NF-kappaB) pathway and NOD-like receptor 3 (NLRP3) inflammasome with interleukin 1beta maturation. Allopurinol had similar effects. These results provide in vivo evidence that quercetin-mediated down-regulation of AMPK/TXNIP and subsequent inhibition of NF-kappaB pathway/NLRP3 inflammasome activation in the hypothalamus of rats may be associated with the reduction of hypothalamic inflammatory lesions, contributing to the improvement of hypothalamic insulin signaling defect in this model. Thus, quercetin with the central activity may be a therapeutic for high fructose-induced insulin resistance and hyperlipidemia in humans. PMID- 24491315 TI - Oleanolic and maslinic acid sensitize soft tissue sarcoma cells to doxorubicin by inhibiting the multidrug resistance protein MRP-1, but not P-glycoprotein. AB - The pentacyclic triterpenes oleanolic acid (OLA) and maslinic acid (MLA) are natural compounds present in many plants and dietary products consumed in the Mediterranean diet (e.g., pomace and virgin olive oils). Several nutraceutical activities have been attributed to OLA and MLA, whose antitumoral effects have been extensively evaluated in human adenocarcinomas, but little is known regarding their effectiveness in soft tissue sarcomas (STS). We assessed efficacy and molecular mechanisms involved in the antiproliferative effects of OLA and MLA as single agents or in combination with doxorubicin (DXR) in human synovial sarcoma SW982 and leiomyosarcoma SK-UT-1 cells. As single compound, MLA (10-100 MUM) was more potent than OLA, inhibiting the growth of SW982 and SK-UT-1 cells by 70.3 +/- 1.11% and 68.8 +/- 1.52% at 80 MUM, respectively. Importantly, OLA (80 MUM) or MLA (30 MUM) enhanced the antitumoral effect of DXR (0.5-10 MUM) by up to 2.3-fold. On the molecular level, efflux activity of the multidrug resistance protein MRP-1, but not of the P-glycoprotein, was inhibited. Most probably as a consequence, DXR accumulated in these cells. Kinetic studies showed that OLA behaved as a competitive inhibitor of substrate-mediated MRP-1 transport, whereas MLA acted as a non-competitive one. Moreover, none of both triterpenes induced a compensatory increase in MRP-1 expression. In summary, OLA or MLA sensitized cellular models of STS to DXR and selectively inhibited MRP-1 activity, but not its expression, leading to a higher antitumoral effect possibly relevant for clinical treatment. PMID- 24491316 TI - Emissions of polybrominated diphenyl ethers (PBDEs) in Zurich, Switzerland, determined by a combination of measurements and modeling. AB - Polybrominated diphenyl ethers (PBDEs) have been widely used as flame retardants but they are of concern and are currently being phased-out because of their environmentally hazardous properties and their potential to cause adverse health effects. We analyzed PBDEs in Zurich, Switzerland, and applied a multi-media environmental fate model to back-calculate the rate of PBDE emission to air. PBDE concentrations in ambient air were measured in summer 2010 and winter 2011 in the city center of Zurich. Concentrations were higher in summer (sum PBDEs 118-591 pg m(-3)) than in winter (sum PBDEs 17-151 pg m(-3)), and are on the upper end of concentrations reported in literature for urban sites with no point sources of PBDEs. The emissions derived from our measurements (summer: 53-165 MUg capita(-1) d(-1), winter: 25-112 MUg capita(-1) d(-1)) and extrapolated to annual emissions for Switzerland (114-406 kg a(-1)) lie in the middle of ranges reported on the basis of substance flow analyses and emission inventories. The difference between summer and winter emissions is small compared to the difference that would be expected from the temperature dependence of PBDE vapor pressure, which would be consistent with emissions occurring to a large extent from flame-proofed materials located indoors under nearly constant temperature conditions and/or emissions to air occurring by suspension of particles containing PBDEs. Compared to previous studies in Switzerland, concentrations and emissions of PBDEs appear to have increased during the last five years with an increasing contribution of decabromodiphenyl ether, despite the addition of PBDEs to national and international regulations. PMID- 24491317 TI - Formation of PBDD/F from PBDE in electronic waste in recycling processes and under simulated extruding conditions. AB - The increasing volumes of waste electrical and electronic equipment (WEEE) in Europe and developing economies demand for efficient disposal solutions. However, WEEE also contains toxic compounds and, therefore, there is a need for recycling technologies for WEEE that creates revenue without causing environmental harm. Among other fast developing economies, South Africa is tempting to make use of recycled plastic. Brominated flame retardants (BFRs) are additives used to protect plastic materials in electrical and electronic equipment (EEE) against ignition. Some BFRs are known persistent organic pollutants (POPs) and some BFRs can be transformed into highly toxic compounds such as polybrominated dibenzofurans and dioxins (PBDD/Fs). In this study, the contents of critical BFRs, i.e. polybrominated diphenyl ethers, and highly toxic PBDD/Fs were measured in WEEE material from Switzerland and South Africa. The formation of PBDD/Fs has been observed in two South African recycling processes and under controlled laboratory conditions. Total PBDE-contents in the South African and Swiss plastic waste varied between 1*10(3) and 7*10(6) MUg kg(-1). A few WEEE plastic fractions exceeded the RoHS limit of 1*10(6) MUg kg(-1) for PBDEs and thus they could not be used for recycling products without special treatment. The total content of ?PBDFs was around 1*10(3) MUg kg(-1). Such contents in materials do not pose a risk for consumer under normal conditions. Workers at recycling plants might be at risk. The measured formation rates of PBDFs were between 2*10(-5) and 2*10( 4)?PBDE(-1) min(-1). PMID- 24491319 TI - Mucus models to evaluate nanomedicines for diffusion. AB - In the fast-growing field of nanomedicine, mucus is often the first barrier encountered by drug products in the body, and can be the only barrier if it is not overcome by the drug delivery system. Thus, there is a need to design new nanomedicines that are able to diffuse easily across mucus to reach their pharmacological targets. In this design process, mucus diffusion studies are mandatory and have an important role in the selection of the best drug candidates. However, there is currently no standard procedure for diffusion studies across mucus. In this Foundation Review, we discuss the differences observed within mucus models and experimental protocols in diffusion studies, with an emphasis on nanomedicine diffusion. PMID- 24491320 TI - Breast cancer awareness campaign targets older women. PMID- 24491318 TI - Clinical and laboratory patterns during immune stimulation in hormone responsive metastatic breast cancer. AB - This study clarifies the relationship between clinical and laboratory patterns, in endocrine-responsive metastatic breast cancer patients treated with a cyclic beta-interferon and interleukin-2 sequence added to anti-estrogens. In 31 patients, a regular laboratory and immunological assessment was made. During clinical benefit, as opposed to progression, a significant increase in the total number of lymphocytes, CD4+, CD8+, NK cells, CRP and IL-12 was confirmed. Also, a significant CEA, TPA, CA15.3 decrease occurred 24-72h after interleukin-2 administration. At the progression, both basally and after interleukin-2 stimulation, the mean values of CD4+ plus CD25+ cells were more than twice higher than during clinical benefit, with a decrease of CD4+ plus CD8+ (Teffector)/CD4+CD25+ (Treg) ratio. Moreover, a significant increase for CEA and for all 3 markers (standardized values) was found 24-72h after interleukin-2 administration. In patients who survived less than 5years, the Treg cell increase occurred at a significantly shorter time interval than in those who survived longer than 5years (20 vs 45.5months, respectively; P=0.001). These data show laboratory evidence of the effect of immunotherapy as well as that of hormone resistance occuring concomitantly with a laboratory pattern compatible with immune inhibition. PMID- 24491322 TI - Chiral monolayer-protected Au-Pd bimetallic nanoclusters: effect of palladium doping on their chiroptical responses. AB - We present an effect of palladium doping on the chiroptical responses of optically active gold nanoclusters. Monolayer-protected Au-Pd bimetallic nanoclusters of 1.5-2.0 nm in diameter are synthesized by the reduction in mixtures of Au and Pd salts in the presence of chiral thiol, glutathione (GSH), and isolated by electrophoretic separation. For synthetic feed mole ratios of Au/Pd=3/1 and 1/1, the isolated nanocluster compounds have much higher Au/Pd ratios of ~8.4 (7.9-8.8) and ~5.1 (4.7-5.4), respectively. We find that circular dichroism (CD) offers a greater advantage in detecting a foreign atom doping in the nanocluster as compared to absorption spectroscopy; namely, there is a significant difference in Cotton effects between the Au-Pd bimetallic nanoclusters and the monometallic counterparts (Au or Pd nanoclusters), whereas almost no difference can be seen between them in the UV-vis absorption spectra. In the bimetallic nanoclusters, interestingly, their CD profiles are almost independent on the Pd dopant content. The X-ray photoelectron spectroscopy (XPS) reveals that Au atoms are predominated in the surface (including staples) layer of these Au-Pd nanoclusters, indicating a Pd(core)-Au(shell) (inverted core shell) structure, so the similarity in the CD responses observed would be due both to the predominance of Au in the outermost chiral surface structure and possession of their similar metal core configuration. PMID- 24491323 TI - Facile synthesis of core-shell CuO/Ag nanowires with enhanced photocatalytic and enhancement in photocurrent. AB - CuO nanowires were grown on Cu foil via a simple cost-effective wet-chemical route in large scales and used as templates for making silver-coated CuO (CuO/Ag) core-shell nanowires. The coverage of Ag shells on CuO nanowires was controlled by varying the concentration of Ag precursor. The structure, composition, morphology and optical properties of the synthesized core-shell CuO/Ag nanowires (CACs) were considered. The discussion on the growth process of CACs revealed the important role of Sn(2+). And, the novel structure enlarged the range of absorbed light and enhanced the absorption intensity of light. The CACs were evaluated for their ability to degrade methyl orange (MeO) solution under visible-light irradiation. The rate of degradation of the as-prepared CACs was more than 7 times faster than that of using pure CuO nanowires under solar light irradiation. Moreover, the incorporation of Ag shells at the surface causes a quenching of PL emissions and enhanced photocurrent of CuO nanowires. The mechanisms of enhanced photocatalytic activity, luminescence emission quenching, and photocurrent multiplication of the core-shell nanowires have been discussed. PMID- 24491321 TI - Development and validation of a brief dementia screening indicator for primary care. AB - BACKGROUND: Detection of "any cognitive impairment" is mandated as part of the Medicare annual wellness visit, but screening all patients may result in excessive false positives. METHODS: We developed and validated a brief Dementia Screening Indicator using data from four large, ongoing cohort studies (the Cardiovascular Health Study [CHS]; the Framingham Heart Study [FHS]; the Health and Retirement Study [HRS]; the Sacramento Area Latino Study on Aging [SALSA]) to help clinicians identify a subgroup of high-risk patients to target for cognitive screening. RESULTS: The final Dementia Screening Indicator included age (1 point/year; ages, 65-79 years), less than 12 years of education (9 points), stroke (6 points), diabetes mellitus (3 points), body mass index less than 18.5 kg/m(2) (8 points), requiring assistance with money or medications (10 points), and depressive symptoms (6 points). Accuracy was good across the cohorts (Harrell's C statistic: CHS, 0.68; FHS, 0.77; HRS, 0.76; SALSA, 0.78). CONCLUSIONS: The Dementia Screening Indicator is a simple tool that may be useful in primary care settings to identify high-risk patients to target for cognitive screening. PMID- 24491324 TI - Impact of particle size on interaction forces between ettringite and dispersing comb-polymers in various electrolyte solutions. AB - The inter-particle forces play a fundamental role for the flow properties of a particle suspension in response to shear stresses. In concrete applications, cement admixtures based on comb-polymers like polycarboxylate-ether-based superplasticizer (PCE) are used to control the rheological behavior of the fresh mixtures, as it is negatively impacted by certain early hydration products, like the mineral ettringite. In this work, dispersion forces due to PCE were measured directly at the surface of ettringite crystals in different electrolyte solutions by the means of atomic force microscopy (AFM) applying spherical and sharp silicon dioxide tips. Results show an effective repulsion between ettringite surface and AFM tips for solutions above the IEP of ettringite (pH~12) and significant attraction in solution at lower pH. The addition of polyelectrolytes in solution provides dispersion forces exclusively between the sharp tips (radius ~ 10 nm) and the ettringite surface, whereas the polymer layer at the ettringite surface results to be unable to disperse large colloidal probes (radius ~ 10 MUm). A simple modeling of the inter-particle forces explains that, for large particles, the steric hindrance of the studied PCE molecules is not high enough to compensate for the Van der Waals and the attractive electrostatic contributions. Therefore, in cement suspensions the impact of ettringite on rheology is probably not only related to the particle charge, but also related to the involved particle sizes. PMID- 24491325 TI - Effects of chemical mechanical planarization slurry additives on the agglomeration of alumina nanoparticles II: aggregation rate analysis. AB - The aggregation rate and mechanism of 150 nm alumina particles in 1mM KNO3 with various additives used in chemical mechanical planarization of copper were investigated. The pH of each suspension was ~8 such that the aggregation rate was slow enough to be measured and analyzed over ~120 min. In general, an initial exponential growth was observed for most suspensions indicating reaction-limited aggregation. After aggregate sizes increase to >500 nm, the rate followed a power law suggesting diffusion-limited aggregation. Stability ratios and fractal dimension numbers were also calculated to further elucidate the aggregation mechanism. PMID- 24491326 TI - Surface properties of Cu/La2O3 and its catalytic performance in the synthesis of glycerol carbonate and monoacetin from glycerol and carbon dioxide. AB - Cu/La2O3 catalysts with different Cu loadings were prepared by impregnation method and employed in the synthesis of glycerol carbonate and monoacetin from glycerol and CO2 in the presence of CH3CN. The interface between Cu and La2O3 and the structure of catalysts were characterized by XRD, TEM, H2-TPR, CO2-TPD, N2O chemisorptions, UV-vis DSR and XPS. Cu/La2O3 exhibited high catalytic activity for the conversion of glycerol to glycerol carbonate and monoacetin under mild reaction conditions. The effect of reaction parameters on the carbonylation of glycerol was also studied. CH3CN can break the thermodynamic limit of the reaction of glycerol with CO2 to glycerol carbonate through its hydrolysis. Over 2.3%Cu/La2O3 catalyst, the conversion of glycerol and the selectivity to glycerol carbonate and monoacetin were 33.4%, 45.4% and 52.9%, respectively (150 degrees C, 7.0 MPa, 12 h). The size effect of Cu nanoparticles and the basic property of the supports were also examined. The characterization results suggested that the Cu sizes and basic sites on Cu/La2O3 had significant effect on the conversion and selectivity in the carbonylation of glycerol. PMID- 24491327 TI - Effect of molecular desorption on the electronic properties of self-assembled polarizable molecular monolayers. AB - We investigated the interfacial electronic properties of self-assembled monolayers (SAM)-modified Au metal surface at elevated temperatures. We observed that the work functions of the Au metal surfaces modified with SAMs changed differently under elevated-temperature conditions based on the type of SAMs categorized by three different features based on chemical anchoring group, molecular backbone structure, and the direction of the dipole moment. The temperature-dependent work function of the SAM-modified Au metal could be explained in terms of the molecular binding energy and the thermal stability of the SAMs, which were investigated with thermal desorption spectroscopic measurements and were explained with molecular modeling. Our study will aid in understanding the electronic properties at the interface between SAMs and metals in organic electronic devices if an annealing treatment is applied. PMID- 24491328 TI - Effects of surfactants on the magnetic properties of iron oxide colloids. AB - Iron oxide nanoparticles are having been extensively investigated for several biomedical applications such as hyperthermia and magnetic resonance imaging. However, one of the biggest problems of these nanoparticles is their aggregation. Taking this into account, in this study the influence of three different surfactants (oleic acid, sodium citrate and Triton X-100) each one with various concentrations in the colloidal solutions stability was analyzed by using a rapid and facile method, the variation in the optical absorbance along time. The synthesized nanoparticles through chemical precipitation showed an average size of 9 nm and a narrow size distribution. X-ray diffraction pattern and Fourier Transform Infrared analysis confirmed the presence of pure magnetite. SQUID measurements showed superparamagnetic properties with a blocking temperature around 155 K. In addition it was observed that neither sodium citrate nor Triton X-100 influences the magnetic properties of the nanoparticles. On the other hand, oleic acid in a concentration of 64 mM decreases the saturation magnetization from 67 to 45 emu/g. Oleic acid exhibits a good performance as stabilizer of the iron oxide nanoparticles in an aqueous solution for 24h, for concentrations that lead to the formation of the double layer. PMID- 24491329 TI - Thiol-ene clickable hyaluronans: from macro-to nanogels. AB - The fabrication of hyaluronic acid (HA) nanogels using a thiol-ene reaction has been demonstrated. HA was modified with pentenoate groups and then cross-linked with poly(ethylene glycol)-bis(thiol) by exposure to UV light. The cross-linking density and thereby the rigidity of the obtained gels were precisely controlled by the degree of substitution of pentenoate-modified HA. Their swelling properties also depended on cross-linking density. To produce hydrogels at the nanoscale, hyaluronic acid precursors were solely confined inside liposomes before cross-linking and purified after cross-linking. The size of the resulting nanogels followed their swelling properties and was also affected by their cross linking density. Such bionanogels with tunable mechanical and swelling properties have potential in drug delivery. PMID- 24491330 TI - Effects of CMP slurry additives on the agglomeration of alumina nanoparticles 1: general aggregation rate behavior. AB - The aggregation behavior for 150 nm alumina particles suspended in 1 mM KNO3 solutions with various additives used in chemical mechanical planarization of copper was investigated. Three behaviors were observed: no aggregation, reversible aggregation where large agglomerates formed almost instantaneously, and steady aggregation where particle sizes grew over the duration of the measurement. In general steady aggregation occurred at high pH for all suspensions, while no aggregation occurred at acidic pH, except with suspensions with sodium dodecyl sulfate, where reversible aggregation was observed. No aggregation was observed at near neutral pH for all suspensions. Zeta potential and isoelectric points for each suspension were also measured. PMID- 24491331 TI - Heterojunction nanowires having high activity and stability for the reduction of oxygen: formation by self-assembly of iron phthalocyanine with single walled carbon nanotubes (FePc/SWNTs). AB - A self-assembly approach to preparing iron phthalocyanine/single-walled carbon nanotube (FePc/SWNT) heterojunction nanowires as a new oxygen reduction reaction (ORR) electrocatalyst has been developed by virtue of water-adjusted dispersing in 1-cyclohexyl-pyrrolidone (CHP) of the two components. The FePc/SWNT nanowires have a higher Fermi level compared to pure FePc (d-band center, DFT=-0.69 eV versus -0.87 eV, respectively). Consequently, an efficient channel for transferring electron to the FePc surface is readily created, facilitating the interaction between FePc and oxygen, so enhancing the ORR kinetics. This heterojunction-determined activity in ORR illustrates a new stratagem to preparing non-noble ORR electrocatalysts of significant importance in constructing real-world fuel cells. PMID- 24491332 TI - Adsorptive performance and catalytic activity of superparamagnetic Fe3O4@nSiO2@mSiO2 core-shell microspheres towards DDT. AB - Due to specific properties, core-shell Fe3O4@SiO2 and core-shell-shell Fe3O4@nSiO2@mSiO2 nanostructures have been extensively investigated for the contamination treatment of wastewater. However, these reported materials were usually used as advanced adsorbents or catalyst-supports. In this study, we demonstrate that magnetic mesoporous silica Fe3O4@nSiO2@mSiO2 microspheres can not only exhibit excellent adsorptive performance for removal of DDT (1,1,1 trichloro-2,2-bis(4-chlorophenyl) ethane) from aqueous media, but also display high catalytic activity. Over 97% of DDT could be quickly removed from aqueous media in 60 min. At 60 degrees C the DDE (1,1-dichloro-2,2-bis(4-chlorophenyl) ethylene) content increases greatly as DDT disappears completely, and is decomposed completely after thermal treatment at a relatively low temperature of 450 degrees C. The obtained magnetic mesoporous silica nanoparticles were characterized by X-ray diffraction, transmission electron microscopy, nitrogen adsorption-desorption measurements and vibrating sample magnetometer. The results indicate that Fe3O4@nSiO2@mSiO2 microspheres show strong superparamagnetism and have high specific surface area (577 m(2) g(-1)). PMID- 24491333 TI - Rational interface design of epoxy-organoclay nanocomposites: role of structure property relationship for silane modifiers. AB - Montmorillonite was modified by three silane surfactants with different functionalities to investigate the role of surfactant structure on the properties of a final epoxy-organoclay nanocomposite. N-aminopropyldimethylethoxysilane (APDMES), an aminated monofunctional silane, was chosen as a promising surfactant for several reasons: (1) it will bond to silica in montmorillonite, (2) it will bond to epoxide groups, and (3) to overcome difficulties found with trifunctional aminosilane bonding clay layers together and preventing exfoliation. A trifunctional and non-aminated version of APDMES, 3-aminopropyltriethoxysilane (APTES) and n-propyldimethylmethoxysilane (PDMMS), respectively, was also studied to provide comparison to this rationally chosen surfactant. APDMES and APTES were grafted onto montmorillonite in the same amount, while PDMMS was barely grafted (<1 wt%). The gallery spacing of APDMES organoclay was greater than APTES or PDMMS, but the final nanocomposite gallery spacing was not dependent on the surfactant used. Different concentrations of APDMES modified montmorillonite yielded different properties, as concentration decreased glass transition temperature increased, thermal stability increased, and the storage modulus decreased. Storage modulus, glass transition temperature, and thermal stability were more similar for epoxy-organoclay composites modified with the same concentration of silane surfactant, neat epoxy, and epoxy-montmorillonite nanocomposite. PMID- 24491334 TI - A generalized diffusion model for growth of nanoparticles synthesized by colloidal methods. AB - A nanoparticle growth model is developed to predict and guide the syntheses of monodisperse colloidal nanoparticles in the liquid phase. The model, without any a priori assumptions, is based on the Fick's law of diffusion, conservation of mass and the Gibbs-Thomson equation for crystal growth. In the limiting case, this model reduces to the same expression as the currently accepted model that requires the assumption of a diffusion layer around each nanoparticle. The present growth model bridges the two limiting cases of the previous model i.e. complete diffusion controlled and adsorption controlled growth of nanoparticles. Specifically, the results show that a monodispersion of nanoparticles can be obtained both with fast monomer diffusion and with surface reaction under conditions of small diffusivity to surface reaction constant ratio that results is growth 'focusing'. This comprehensive description of nanoparticle growth provides new insights and establishes the required conditions for fabricating monodisperse nanoparticles critical for a wide range of applications. PMID- 24491335 TI - Hydroxyl density affects the interaction of fibrinogen with silica nanoparticles at physiological concentration. AB - An increasing interest in the interaction between blood serum proteins and nanoparticles has emerged over the last years. In fact, this process plays a key role in the biological response to nanoparticles. The behavior of proteins at the biofluid/material interface is driven by the physico-chemical properties of the surface. However, much research is still needed to gain insight into the process at a molecular level. In this study, the effect of silanol density on the interaction of fibrinogen at physiological concentrations with silica nanoparticle/flat surfaces has been studied. Silica nanoparticles and silica wafers were modified and characterized to obtain a set of samples with different silanols density. The interaction with fibrinogen has been studied by evaluating the extent of coverage (bicinchoninic acid assay) and the irreversibility of adsorption (shift of the zeta potential). To clarify the molecular mechanism of fibrinogen/surface interactions, confocal micro-Raman spectroscopy (nanoparticles) and atomic force microscopy (wafers) were used. Finally the effect of fibrinogen on the agglomeration of nanoparticles has been evaluated by Flow Particle Image Analysis. The data reported here show that a minimal variation in the state of the silica surface modifies the adsorption behavior of fibrinogen, which appears mediated by a competition between protein/protein and protein/surface interactions. By comparing the data obtained on nanoparticles and silicon-supported silica layers, we found that hydrophilicity increases the tendency of fibrinogen molecules to interact with the surface rather than with other molecules, thus inhibiting fibrinogen self-assembly. This study contributes to the knowledge of the processes occurring at the surface/biological fluids interface, needed for the design of new biocompatible materials. PMID- 24491336 TI - Morphology modulation of SrTiO3/TiO2 heterostructures for enhanced photoelectrochemical performance. AB - Design and fabrication of nanoscale semiconductors with regulatable morphology or structure has attracted tremendous interest due to the dependency relationship between properties and architectures. Two types of SrTiO3/TiO2 nanocomposites with different morphologies and structures have been fabricated by controlling the kinetics of hydrothermal reactions. One is TiO2 nanotube arrays densely wrapped by SrTiO3 film and the other is SrTiO3 nanospheres distributed on the top region of TiO2 nanotube arrays, which has been firstly fabricated. It has been found that the photoelectrochemical performances of these heterostructures are crucially dominated by their architectures. Heterostructured SrTiO3/TiO2 nanotube arrays were fabricated by traditional method in the absence of NaOH and they exhibited higher photoelectrochemical performance than pure TiO2 nanotube arrays. However, the compact SrTiO3 coating film on the sidewalls of TiO2 nanotube arrays could inevitably destroy the tubular structures of TiO2 and thus go against the vectorial transport of electrons. Interestingly, when excess NaOH was added into the growth solution, SrTiO3 nanospheres would be rationally grafted on the top of TiO2 nanotube arrays, which could preserve the tubular structures of TiO2, and thus further improve the photoelectrochemical performance. PMID- 24491337 TI - A program for the fitting of Debye, Cole-Cole, Cole-Davidson, and Havriliak Negami dispersions to dielectric data. AB - The description and interpretation of dielectric spectroscopy data usually require the use of analytical functions, which include unknown parameters that must be determined iteratively by means of a fitting procedure. This is not a trivial task and much effort has been spent to find the best way to accomplish it. While the theoretical approach based on the Levenberg-Marquardt algorithm is well known, no freely available program specifically adapted to the dielectric spectroscopy problem exists to the best of our knowledge. Moreover, even the more general commercial packages usually fail on the following aspects: (1) allow to keep temporarily fixed some of the parameters, (2) allow to freely specify the uncertainty values for each data point, (3) check that parameter values fall within prescribed bounds during the fitting process, and (4) allow to fit either the real, or the imaginary, or simultaneously both parts of the complex permittivity. A program that satisfies all these requirements and allows fitting any superposition of the Debye, Cole-Cole, Cole-Davidson, and Havriliak-Negami dispersions plus a conductivity term to measured dielectric spectroscopy data is presented. It is available on request from the author. PMID- 24491338 TI - Synthesis and characterization of full interpenetrating structure mesoporous polycarbonate-silica spheres and p-phenylenediamine adsorption. AB - As a common used and hardly emulsified amorphous thermoplastic, the bisphenol-A polycarbonates were used as the polymer candidate to form a novel monodispersed sub-micrometer mesoporous polymer-silica spheres with full interpenetrating structure. The synthesis procedure was based on a modified sol-gel approach in which the polycarbonate was plasticized in advanced by the surfactant of polymer emulsion. The mesoporous spheres possess a perfect uniform particle size and the polymer-silica spheres are held together by permanent entanglement in three dimensions. The defined crystallization of the polycarbonate was occurred when it was entrapped in the silica laminated matrix due to the plasticizing effect of the surfactant, and directly affected the thermal stability of the mesoporous spheres. The specific surface areas and pore diameters of mesoporous sphere were affected by the mass content and crystallization behavior of the polycarbonate. The p-phenylenediamine was used as adsorbate to investigate the cationic organics adsorption ability of the mesoporous spheres. The results shown that the polycarbonate-silica possess a well adsorption capacity for p-phenylenediamine by virtue of two kinds of hydrogen bond, and the maximum adsorption capacity was nearly 7.5 times larger than that of the hollow mesoporous silica. PMID- 24491339 TI - Anti-fouling properties of microstructured surfaces bio-inspired by rice leaves and butterfly wings. AB - Material scientists often look to biology for new engineering solutions to materials science problems. For example, unique surface characteristics of rice leaves and butterfly wings combine the shark skin (antifouling) and lotus leaf (self-cleaning) effects, producing the so-called rice and butterfly wing effect. In this paper, we study antifouling properties of four microstructured surfaces inspired by rice leaves and fabricated with photolithography and hot embossing techniques. Anti-biofouling effectiveness is determined with bioassays using Escherichia coli whilst inorganic fouling with simulated dirt particles. Antifouling data are presented to understand the role of surface geometrical features resistance to fouling. Conceptual modeling provides design guidance when developing novel antifouling surfaces for applications in the medical, marine, and industrial fields. PMID- 24491340 TI - The effects of low-molecular-weight emulsifiers in O/W-emulsions on microviscosity of non-solidified oil in fat globules and the mobility of emulsifiers at the globule surfaces. AB - Electron Spin Resonance spectroscopy (ESR) was used to measure the mobility of the spin probe TEMPO in O/W-emulsions. This allowed determination of temperature dependent microviscosity of the liquid fraction in lipid globules. Six hydrogenated palm kernel oil (HPKO) based emulsions containing caseinate and different combinations of lactic acid ester of monoglyceride (LACTEM), unsaturated monoglycerides (GMU) or saturated monoglyceride (GMS) were studied. The non-solidified oil in emulsions made with LACTEM+GMU had a high microviscosity, whereas the emulsion made with GMS had a low microviscosity. Also the partitioning of TEMPO between the lipid and aqueous phases was found to be highly temperature dependent, most likely due to the change of solid fat content with temperature. This behaviour may mimic the partitioning of aroma compounds in emulsions. The spin probe 5-doxylstearic acid was used to study the mobility of the components at the lipid globule surfaces. At 5 degrees C all emulsions had a very low surface mobility. At 25 degrees C the mobility of the spin probe was found to be correlated to the surface protein load. Emulsions with GMU had a high protein surface coverage and low mobility of the spin probe on the droplet surfaces. Conversely, in presence of LACTEM and GMS, the protein surface loads decreased and high surface mobilities were observed. Based on these results it is argued that the high macroscopic viscosity and lipid agglomeration of emulsions containing GMU is due to a lipid globule-protein-network where the lipid globules are connected via caseinate. PMID- 24491341 TI - Manipulating surface ligands of copper sulfide nanocrystals: synthesis, characterization, and application to organic solar cells. AB - CuS NCs were synthesized via a facile sol-gel method without post-thermal treatment. The as-prepared CuS NCs were analyzed and confirmed by XRD, HR-TEM, EDS and XPS as hexagonal covellite CuS. The average diameter of the samples was about 3nm with narrow size distribution. CuS NCs can form a thin and smooth film without ligand-exchange that can be used as hole transport layer in organic solar cell. These hydrophilic CuS NCs with pyridine ligands can be exchanged with OAm and OA rapidly at room temperature and present hydrophobic characteristic, resulting in forming oil-soluble CuS NCs. This makes it possible tuning the surface property of CuS NCs and has the potential application for different fields. PMID- 24491342 TI - Removal of sulfamethoxazole sulfonamide antibiotic from water by high silica zeolites: a study of the involved host-guest interactions by a combined structural, spectroscopic, and computational approach. AB - Sulfonamide antibiotics are persistent pollutants present in surface and subsurface waters in both agricultural and urban environments. Sulfonamides are of particular concern in the environment because they are known to induce high levels of bacterial resistance. Adsorption of sulfamethoxazole sulfonamide antibiotic into three high silica zeolites (Y, mordenite, and ZSM-5) with pore opening sizes comparable to sulfamethoxazole dimensions is reported. Sulfamethoxazole was almost completely removed from water by zeolite Y and MOR in a few minutes. Adsorption onto ZSM-5 showed an increased kinetics with increasing temperature. Antibiotic sorption was largely irreversible with little antibiotic desorbed. Sulfamethoxazole incorporation and localization into the pore of each zeolite system was defined along with medium-weak and cooperative host-guest interactions in which water molecules play a certain role only in zeolite Y and mordenite. PMID- 24491343 TI - Mature beech trees (Fagus grandifolia; Fagaceae) are persistently clonal in coves and beech gaps in the Great Smoky Mountains. AB - PREMISE OF THE STUDY: Angiosperms frequently have mixed sexual and asexual reproductive strategies, which can have significant consequences for population and community structure. Many tree species respond to disturbance by vegetative sprouting over sexual reproduction, but the ability to do so varies within and among species and is poorly studied. We tested the hypothesis that root sprouting in Fagus grandifolia is more important in high-elevation beech forests (extreme environmental conditions), relative to lower-elevation cove hardwood forests (optimal environmental conditions), in Great Smoky Mountains National Park. METHODS: Four cove hardwood and two high-elevation beech gap forests were sampled. Fagus grandifolia trees were tagged, mapped, and genotyped at each site using six nuclear microsatellite loci. A subset of trees was cored to determine minimum ages of identified clonal lineages. Relationships between measures of clonal richness, diameter, forest type, and elevation were compared by nonparametric analyses. KEY RESULTS: Five of six sites were highly dependent on sprouting; one site was entirely dependent on reproduction by seed. Clonal richness did not differ significantly by forest type or elevation, but differed significantly from previously published work. Tree diameter was significant by elevation and significant between the present study and previously published work. CONCLUSIONS: The results of this study in the context of previously published work suggest that relatively recent recruits may be more likely to reflect both sexual and asexual strategies, whereas mature F. grandifolia may be more likely to be the result of persistent clonal lineages. PMID- 24491344 TI - The evolution of sex ratio differences and inflorescence architectures in Begonia (Begoniaceae). AB - PREMISE OF THE STUDY: A major benefit conferred by monoecy is the ability to alter floral sex ratio in response to selection. In monoecious species that produce flowers of a given sex at set positions on the inflorescence, floral sex ratio may be related to inflorescence architecture. We studied the loci underlying differences in inflorescence architecture between two monoecious Begonia species and related this to floral sex ratios. METHODS: We performed trait comparisons and quantitative trait locus (QTL) mapping in a segregating backcross population between Central American Begonia plebeja and B. conchifolia. We focused on traits related to inflorescence architecture, sex ratios, and other reproductive traits. KEY RESULTS: The inflorescence branching pattern of B. conchifolia was more asymmetric than B. plebeja, which in turn affects the floral sex ratio. Colocalizing QTLs of moderate effect influenced both the number of male flowers and the fate decisions of axillary meristems, demonstrating the close link between inflorescence architecture and sex ratio. Additional QTLs were found for stamen number (30% variance explained, VE) and pollen sterility (12.3% VE). CONCLUSIONS: One way in which Begonia species develop different floral sex ratios is through modifications of their inflorescence architecture. The potential pleiotropic action of QTL on inflorescence branching and floral sex ratios may have major implications for trait evolution and responses to selection. The presence of a single QTL of large effect on stamen number may allow rapid divergence for this key floral trait. We propose candidate loci for stamen number and inflorescence branching for future characterization. PMID- 24491345 TI - Contributions of the mechanical properties of major structural polysaccharides to the stiffness of a cell wall network model. AB - PREMISE OF THE STUDY: The molecular mechanisms regulating the expansive growth of the plant cell wall have yet to be fully understood. The recent development of a computational cell wall model allows quantitative examinations of hypothesized cell wall loosening mechanisms. METHODS: Computational cell wall network (CWN) models were generated using cellulose microfibrils (CMFs), hemicelluloses (HCs), and their interactions (CMF-HC). For each component, a range of stiffness values, representing various situations hypothesized as potential cell-wall-loosening mechanisms, were used in the calculation of the overall stiffness of the computational CWN model. Thus, a critical mechanism of the loosening of the primary cell wall was investigated using a computational approach by modeling the molecular structure. KEY RESULTS: The increase in the stiffness equivalent of the CMF-HC interaction results in an increase in the Young's modulus of the CWN. In the major growth direction, the CWN stiffness is most sensitive to the CMF-HC interaction (75%). HC stiffness contributes moderately (24%) to the change in the CWN stiffness, whereas the CMF contribution is marginal (1%). Minor growth direction exhibited a similar trend except that the contributions of CMFs and HCs are higher than for the major growth direction. CONCLUSIONS: The stiffness of the CMF-HC interaction is the most critical mechanical component in altering stiffness of the CWN model, which supports the hypothesized mechanism of expansin's role in efficient loosening of the plant cell wall by disrupting HC binding to CMFs. The comparison to experiments suggests additional load-bearing mechanisms in CMF-HC interactions. PMID- 24491346 TI - Clinicopathological features and treatment of uremic calciphylaxis: a case series. PMID- 24491347 TI - The experience of stroke survivors three months after being discharged home: A phenomenological investigation. AB - BACKGROUND: Stroke is the leading cause of disability in adults, and has a significant impact on individuals, families, and society. Returning home after a stroke represents a challenging experience for patients who struggle to adapt to their new life conditions. Although many studies have been conducted on stroke survivors, few studies have focused on the lived experience of patients at three months after they came home after rehabilitation. AIMS: The aim of this study was to describe the experience of stroke survivors three months after being discharged home from rehabilitation hospitals. METHOD: A phenomenological methodology was used to conduct the study. Participants were enrolled from rehabilitation hospitals in the cities of Rome and Naples. Interviews were conducted at the patients' house and data were analysed with a phenomenological approach FINDINGS: Fifteen stroke survivors were interviewed (mean age 70 years; 12 males). Five themes emerged from the phenomenological analysis of the interviews and the field notes: deeply changed life, vivid memory of the acute phase of the stroke, slowed lives, relief after recovering from stroke, being a burden for family members. CONCLUSIONS: The results of this study give an overview of the experience of stroke survivors three months after being discharged home. From a clinical perspective, health care providers need to provide more interventions to help survivors to cope better with life changes and encourage them to adapt to daily life limitations caused by stroke. Also, health care providers should improve support provided to family members of stroke patients. PMID- 24491348 TI - The effect of a supervised exercise training programme on sleep quality in recently discharged heart failure patients. AB - BACKGROUND: Sleep disturbances, including insomnia and sleep-disordered breathing, are a common complaint in people with heart failure and impair well being. Exercise training (ET) improves quality of life in stable heart failure patients. ET also improves sleep quality in healthy older patients, but there are no previous intervention studies in heart failure patients. AIM: The aim of this study was to examine the impact of ET on sleep quality in patients recently discharged from hospital with heart failure. METHODS: This was a sub-study of a multisite randomised controlled trial. Participants with a heart failure hospitalisation were randomised within six weeks of discharge to a 12-week disease management programme including exercise advice (n=52) or to the same programme with twice weekly structured ET (n=54). ET consisted of two one-hour supervised aerobic and resistance training sessions, prescribed and advanced by an exercise specialist. The primary outcome was change in Pittsburgh Sleep Quality Index (PSQI) between randomisation and week 12. RESULTS: At randomisation, 45% of participants reported poor sleep (PSQI>=5). PSQI global score improved significantly more in the ET group than the control group (-1.5+/ 3.7 vs 0.4+/-3.8, p=0.03). Improved sleep quality correlated with improved exercise capacity and reduced depressive symptoms, but not with changes in body mass index or resting heart rate. CONCLUSION: Twelve weeks of twice-weekly supervised ET improved sleep quality in patients recently discharged from hospital with heart failure. PMID- 24491349 TI - Effect of a reminder system using an automated short message service on medication adherence following acute coronary syndrome. AB - BACKGROUND: Medication non-adherence leads to a vast range of negative outcomes in patients with coronary artery disease. An automated web-based system managing short message service (SMS) reminders is a telemedicine approach to optimise adherence among patients who frequently forget to take their medications or miss the timing. AIM: This paper sought to investigate the effect of automated SMS based reminders on medication adherence in patients after hospital discharge following acute coronary syndrome (ACS). METHODS: An interventional study was conducted at a tertiary teaching hospital in Malaysia. A total of 62 patients with ACS were equally randomised to receive either automated SMS reminders before every intake of cardiac medications or only usual care within eight weeks after discharge. The primary outcome was adherence to cardiac medications. Secondary outcomes were the heart functional status, and ACS-related hospital readmission and death rates. RESULTS: There was a higher medication adherence level in the intervention group rather than the usual care group, (chi(2) (2)=18.614, p<0.001). The risk of being low adherent among the control group was 4.09 times greater than the intervention group (relative risk =4.09, 95% confidence interval (CI) 1.82-9.18). A meaningful difference was found in heart functional status between the two study groups with better results among patients who received SMS reminders, (chi(2) (1) = 16.957, p<0.001). CONCLUSION: An automated SMS-based reminder system can potentially enhance medication adherence in ACS patients during the early post-discharge period. PMID- 24491350 TI - Endogenous hyperinsulinemic hypoglycemia syndrome: surgical treatment. AB - BACKGROUND: The endogenous hyperinsulinemic hypoglicemia syndrome (EHHS) can be caused by an insulinoma, or less frequently, by nesidioblastosis in the pediatric population, also known as non insulinoma pancreatic hypoglycemic syndrome (NIPHS) in adults. The aim of this paper is to show the strategy for the surgical treatment of ehhs. MATERIAL AND METHODS: A total of 19 patients with a final diagnosis of insulinoma or NIPHS who were treated surgically from january 2007 until june 2012 were included. We describe the clinical presentation and preoperative work-up. Emphasis is placed on the surgical technique, complications and long-term follow-up. RESULTS: All patients had a positive fasting plasma glucose test. Preoperative localization of the lesions was possible in 89.4% of cases. The most frequent surgery was distal pancreatectomy with spleen preservation (9 cases). Three patients with insulinoma presented with synchronous metastases, which were treated with simultaneous surgery. There was no perioperative mortality and morbidity was 52.6%. Histological analysis revealed that 13 patients (68.4%) had benign insulinoma, 3 malignant insulinoma with liver metastases and 3 with a final diagnosis of SHPNI. Median follow-up was 20 months. All patients diagnosed with benign insulinoma or NIPHS had symptom resolution. CONCLUSION: The surgical treatment of EHHS achieves excellent long-term results in the control of hypoglucemic symptoms. PMID- 24491351 TI - EMTALA and patients with psychiatric emergencies: a review of relevant case law. AB - STUDY OBJECTIVE: Emergency department (ED) care for patients with psychiatric complaints has become increasingly challenging given recent nationwide declines in available inpatient psychiatric beds. This creates pressure to manage psychiatric patients in the ED or as outpatients and may place providers and institutions at risk for liability under the Emergency Medical Treatment and Labor Act (EMTALA). We describe the patient characteristics, disposition, and legal outcomes of EMTALA cases involving patients with psychiatric complaints. METHODS: Jury verdicts, settlements, and other litigation involving alleged EMTALA violations related to psychiatric patients between the law's enactment in 1986 and the end of 2012 were collected from 3 legal databases (Westlaw, Lexis, and Bloomberg Law). Details about the patient characteristics, disposition, and reasons for litigation were independently abstracted by 2 trained reviewers onto a standardized data form. RESULTS: Thirty-three relevant cases were identified. Two cases were decided in favor of the plaintiffs, 4 cases were settled, 10 cases had an unknown outcome, and 17 were decided in favor of the defendant institutions. Most patients in these 33 cases were men, had past psychiatric diagnoses, were not evaluated by a psychiatrist, and eventually committed or attempted suicide. The most frequently successful defense used by institutions was to demonstrate that their providers used a standard screening examination and did not detect an emergency medical condition that required stabilization. CONCLUSION: Lawsuits involving alleged EMTALA violations in the care of ED patients with psychiatric complaints are uncommon and rarely successful. PMID- 24491352 TI - The effects of Phalpha1beta, a spider toxin, calcium channel blocker, in a mouse fibromyalgia model. AB - This study investigated the effects of Phalpha1beta, pregabalin and diclofenac using an animal model of fibromyalgia (FM). Repeated administration of reserpine (0.25 mg/kg sc) once daily for three consecutive days significantly decreased thermal hyperalgesia, mechanical allodynia, and dopamine and serotonin content in the brain on the 4th day. Phalpha1beta and pregabalin treatment completely reverted the mechanical allodynia and thermal hyperalgesia induced by reserpine treatment on the 4th day, but diclofenac was ineffective. Reserpine treatment significantly increased the immobility time in the forced swim test, which is indicative of depression in the animals. Phalpha1beta, but not pregabalin, reduced the immobility time (56%), suggesting that Phalpha1beta may control persistent pathological pain in FM. PMID- 24491353 TI - Gymnopilins, a product of a hallucinogenic mushroom, inhibit the nicotinic acetylcholine receptor. AB - Gymnopilins are substances produced in fruiting bodies of the hallucinogenic mushroom, Gymnopilus junonius. Although, only a few biological effects of gymnopilins on animal tissues have been reported, it is believed that gymnopilins are a key factor of the G. junonius poisoning. In the present study, we found that gymnopilins inhibited ACh-evoked responses in neuronal cell line, PC12 cell, and determine the underlying mechanism. Gymnopilins were purified from wild fruiting bodies of G. junonius collected in Japan. Ca(2+)-imaging revealed that gymnopilins reduced the amplitude of ACh-evoked [Ca(2+)]i rises by about 50% and abolished the ACh responses remaining in the presence of atropine. Gymnopilins greatly reduced the amplitude of [Ca(2+)]i rises evoked by nicotinic ACh receptor agonists, 1,1-Dimethyl-4-phenylpiperazinium iodide (DMPP) and nicotine. In the whole-cell voltage clamp recording, gymnopilins inhibited the DMPP-evoked currents, but did not affect the voltage-gated Ca(2+) channel currents. These results indicate that gymnopilins directly act on nicotinic ACh receptors and inhibit their activity. This biological action of gymnopilins may be one of the causes of the G. junonius poisoning. PMID- 24491354 TI - Endometrial cysts within the liver: a rare entity and its differential diagnosis with mucinous cystic neoplasms of the liver. AB - Endometrial cysts within the liver are rare but can present as diagnostic challenges on small biopsies or frozen sections and may mimic mucinous cystic neoplasms (MCN) of the liver. Five cases of endometrial cysts and 6 cases of MCNs within the liver were collected. The clinicopathological, imaging, and immunohistochemical features were systematically reviewed and compared. The average size of the endometrial cysts was 8.3 cm. Four patients had a prior pelvic operation and coexisting endometriosis at other sites. All 5 cases of endometrial cysts had positive ER staining within both the epithelium and the stroma. PR was also positive in both epithelial and stromal cells in 4 cases. Four cases had additional immunostains performed, which all showed cytokeratin 19 and cytokeratin 7 positivity (only in epithelium) and CD10 positivity (only in stroma). alpha-Inhibin and calretinin were negative for both the epithelium and the stroma in all 4 cases. All 6 MCN cases (mean size, 11.1 cm) had positive ER, PR, and alpha-inhibin staining only in the stroma. ER and PR were positive in both the epithelium and stromal cells in endometrial cysts, whereas they were positive only in the stromal cells of MCNs. The stromal cells were CD10 positive and alpha-inhibin negative in endometrial cysts as opposed to the opposite staining pattern in MCNs. Awareness of this distinct staining pattern and the possibility of endometrial cysts in the liver can lead to accurate diagnoses and appropriate treatment modalities. PMID- 24491355 TI - Intratumoral heterogeneous amplification of ERBB2 and subclonal genetic diversity in gastric cancers revealed by multiple ligation-dependent probe amplification and fluorescence in situ hybridization. AB - A humanized monoclonal antibody against ERBB2 is used in neoadjuvant therapy for patients with gastric cancer. A critical factor in determining patient eligibility and predicting outcomes of this therapy is the intratumoral heterogeneity of ERBB2 amplification in gastric adenocarcinomas. The aims of this study are to assess the underlying mechanisms of intratumoral heterogeneity of ERBB2 amplification; to characterize the diversity of coamplified oncogenes such as EGFR, FGFR2, MET, MYC, CCND1, and MDM2; and to examine the usefulness of multiple ligation-dependent probe amplification (MLPA) in the semicomprehensive detection of these gene amplifications. A combined analysis of immunohistochemistry and fluorescence in situ hybridization revealed ERBB2 amplified cancer cells in 51 of 475 formalin-fixed, paraffin-embedded gastric adenocarcinomas. The fraction of amplification-positive cells in each tumor ranged from less than 10% to almost 100%. Intratumoral heterogeneity of ERBB2 amplification, defined as less than 50% of cancer cells positive for ERBB2 amplification, was found in 41% (21/51) of ERBB2-amplified tumors. The combined analysis of MLPA and fluorescence in situ hybridization revealed that ERBB2 was coamplified with EGFR in 7 tumors, FGFR2 in 1 tumor, and FGFR2 and MET in 1 tumor; however, the respective genes were amplified in mutually exclusive cells. Coamplified ERBB2 and MYC coexisted within single nuclei in 4 tumors, and one of these cases had suspected coamplification in the same amplicon of ERBB2 with MYC. In conclusion, the amplification status of ERBB2 and other genes can be obtained semicomprehensively by MLPA and could be useful to plan individualized molecularly targeted therapy against gastric cancers. PMID- 24491356 TI - Social construction and the evidence-based drug policy endeavour. AB - 'Evidence-based policy' has become the catch-cry of the drug policy field. A growing literature has been dedicated to better realising the goal of evidence based drug policy: to maximise the use of the best quality research to inform policy decision-making and help answer the question of 'what works'. Alternative accounts in the policy processes literature conceptualise policy activity as an ambiguous and contested process, and the role of evidence as being only marginally influential. Multiple participants jostle for influence and seek to define what may be regarded as a policy problem, how it may be appropriately addressed, which participants may speak authoritatively, and what knowledge(s) may be brought to bear. The question posited in this article is whether the conceptual shift offered by thinking about policy activity as a process of social construction may be valuable for beginning to explore different perspectives of the evidence-based drug policy endeavour. Within a constructionist account of policy, what counts as valid 'evidence' will always be a constructed notion within a dynamic system, based on the privileging and silencing of participants and discourse, and the contestation of those many positions and perspectives. The social construction account shifts our focus from the inherent value of 'evidence' for addressing 'problems' to the ways in which policy knowledge is made valid, by whom and in what contexts. As such, social construction provides a framework for critically analysing the ways in which 'policy-relevant knowledge' may not be a stable concept but rather one which is constructed through the policy process, and, through a process of validation, is rendered useful. We have limited knowledge in the drug policy field about how this happens; how ambiguity about the problems to be addressed, which voices should be heard, and what activities may be appropriate is contested and managed. By unpicking the values and assumptions which underlie drug policy processes, how problems are constructed and represented, and the ways in which different voices and knowledge(s) come to bear on that process, we may begin to see avenues for reform which may not at present seem obvious. PMID- 24491357 TI - Matrin 3 co-immunoprecipitates with the heat shock proteins glucose-regulated protein 78 (GRP78), GRP75 and glutathione S-transferase pi isoform 2 (GSTpi2) in thymoma cells. AB - Here, we report evidence that matrin 3 (MATR3), a highly conserved inner nuclear matrix phosphoprotein, whose function is largely unknown, interacts specifically with the heat shock proteins glucose-regulated protein 78 (GRP78), GRP75 and glutathione S-transferase pi isoform 2 (GSTpi2). Using immunoprecipitation experiments of lysates obtained from control and tributyltin oxide (TBTO)-treated thymoma cell line (EL4), we identified MATR3 and its partners by MS/MS analysis and confirmed by immunoblot. We also show that MATR3 undergoes degradation as reported before and that this cleavage process, which is inhibited by the broad spectrum caspase inhibitor, z-VAD-FMK, is more marked in TBTO-treated cells. Further, we found that the heat shock protein glucose-regulated protein 78 was downregulated in the TBTO-treated cells. The GRP78 protein is known to protect cells from apoptosis by complexing with procaspase 7 thereby preventing caspase activation cascade. By immunoblot analysis, we found that the levels of procaspases-3 and -7 were lower in TBTO-treated cells; in contrast, the level of p20, the active form of caspase 3, was relatively higher in the treated cells compared to that of control cells. We propose that the TBTO-mediated downregulation of GRP78 triggers the caspase cascade pathway leading to MATR3 degradation. PMID- 24491358 TI - Prevention of immunoglobulin G immobilization eliminates artifactual stimulation of dendritic cell maturation by intravenous immunoglobulin in vitro. AB - Intravenous immunoglobulin (IVIg), a therapeutic preparation containing pooled human immunoglobulin (Ig) G, has been suggested to inhibit differentiation and maturation of dendritic cells (DCs); however, controversies exist on this issue. We aimed to reinvestigate the effects of IVIg on human DC maturation and cytokine production, and to determine whether an artifactual determinant is involved in the observed effects. Human monocyte-derived DCs or freshly isolated blood myeloid DCs were cultured in the presence of IVIg in vitro, and the expression of maturation markers CD80, CD86, CD83, and Human Leukocyte Antigen-DR were determined by flow cytometry, whereas production of interleukin (IL)-12 and IL-10 was measured by enzyme-linked immunosorbent assay, and T-cell stimulatory capacity was determined in cocultures with allogeneic CD4(+) T cells. Interestingly, we observed that IVIg did not inhibit, but instead stimulated, spontaneous maturation and T-cell stimulatory ability of human DCs, while leaving lipopolysaccharide-induced DC maturation and cytokine production unaffected. Strikingly, prevention of IVIg binding to culture plate surface, or blocking of the activating Fcgamma receptor IIa on DC, abrogated the stimulatory effect of IVIg on costimulatory molecule expression and on T-cell stimulatory capacity of DCs, suggesting that IVIg activates DCs on IgG adsorption to the plastic surface. This study warrants for careful study design when performing cell culture studies with IVIg to prevent artifactual effects, and shows that IVIg does not modulate directly costimulatory molecule expression, cytokine production, or allogeneic T cell stimulatory capacity of human DCs. PMID- 24491359 TI - Bariatric surgery and childhood obesity. Preface. PMID- 24491360 TI - The multi-disciplinary approach to adolescent bariatric surgery. AB - The multi-disciplinary team is essential for the success of an adolescent bariatric surgical program. This article will describe the components of the team and their roles. Essential members include a pediatrician or pediatric subspecialist with an interest and expertise in adolescent obesity, a pediatric surgeon with bariatric expertise, or an adult bariatric surgeon with adolescent experience, adolescent/child psychologist, pediatric nutritionist, exercise physiologist or physical therapist, nursing support, and a patient coordinator. Some programs have found a social worker to be helpful as well. The function of the team members is more important than the title. A physical therapist may develop an activity program or a social worker may function as the coordinator. The whole team, led by the pediatric bariatrician, makes decisions concerning the selection of candidates for bariatric surgery. During team rounds, each patient is discussed and treatment decisions are made. PMID- 24491361 TI - Adolescent bariatric surgery program characteristics: the Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study experience. AB - The number of adolescents undergoing weight loss surgery (WLS) has increased in response to the increasing prevalence of severe childhood obesity. Adolescents undergoing WLS require unique support, which may differ from adult programs. The aim of this study was to describe institutional and programmatic characteristics of centers participating in Teen Longitudinal Assessment of Bariatric Surgery (Teen-LABS), a prospective study investigating safety and efficacy of adolescent WLS. Data were obtained from the Teen-LABS database, and site survey completed by Teen-LABS investigators. The survey queried (1) institutional characteristics, (2) multidisciplinary team composition, (3) clinical program characteristics, and (4) clinical research infrastructure. All centers had extensive multidisciplinary involvement in the assessment, pre-operative education, and post-operative management of adolescents undergoing WLS. Eligibility criteria and pre-operative clinical and diagnostic evaluations were similar between programs. All programs have well-developed clinical research infrastructure, use adolescent-specific educational resources, and maintain specialty equipment, including high weight capacity diagnostic imaging equipment. The composition of clinical team and institutional resources is consistent with current clinical practice guidelines. These characteristics, coupled with dedicated research staff, have facilitated enrollment of 242 participants into Teen-LABS. PMID- 24491362 TI - Laparoscopic Roux-en-Y gastric bypass in adolescents with morbid obesity- surgical aspects and clinical outcome. AB - In this paper, we address surgical aspects on bariatric surgery in adolescents from a nationwide Swedish study. Laparoscopic gastric bypass surgery was performed for 81 adolescents with morbid obesity (13-18 years), while 81 adolescents with obesity-matched by age, sex, and BMI received conventional care. Another comparison group was adults undergoing gastric bypass at the same institution during the same time period. This report addresses the 2-year clinical outcome and five-year surgical adverse event rate. Body weight decreased from 133 kg (SD = 22) at inclusion to 92 kg (SD = 17) after 1 year and was 89 (SD = 18) after 2 years (p < 0.001) representing a 32% (-35 to -30) weight loss after 2 years, corresponding to 76% (-81 to -71) excess weight loss. Weight loss was similar in the adult gastric bypass patients (-31%) while weight gain (+3%) was seen in the conventionally treated obese adolescents. Significant improvement in cardiovascular and metabolic risk factors and inflammation was seen after surgery. The treatment was generally well tolerated and quality of life improved significantly. The surgical adverse events included cholecystectomies (10%) and operations for internal hernia (9%) but no postoperative mortality. Adolescents undergoing laparoscopic gastric bypass surgery achieve similar weight loss to adults. Improvements in risk factors and quality of life were substantial. There were surgical complications similar to the adult group, which may be preventable. PMID- 24491363 TI - Laparoscopic adjustable gastric banding in adolescents. AB - Gastric band placement developed as a means of limiting the amount of solid food that enters the stomach, relying on the principle of reducing caloric intake by reducing food volume. By making it difficult for a patient to swallow a large bite of food, one ideally could learn to change eating behavior to take smaller bites and eat more slowly in order to avoid the unpleasant sensation of food backing up at the level of the restriction. Limiting intake should result in weight loss. This article reviews the history of gastric band surgery, the operation and follow-up care, complications associated with gastric banding, and results to date. PMID- 24491364 TI - Laparoscopic vertical sleeve gastrectomy for adolescents with morbid obesity. AB - Obesity is a worldwide epidemic, and surgical weight loss operations have been performed for over 20 years. Laparoscopic sleeve gastrectomy was first performed as part of the biliopancreatic diversion over 30 years ago. Recently, laparoscopic sleeve gastrectomy has led to excellent excess weight loss with limited morbidity, especially compared to Roux-en-Y gastric bypass. In adolescents, laparoscopic sleeve gastrectomy is an excellent option to provide excess weight loss and remission of comorbid conditions without long-term malabsorptive risks. PMID- 24491365 TI - Laparoscopic gastric plication in the morbidly obese adolescent patient. AB - Childhood obesity is a significant problem. Due in part to suboptimal weight loss with lifestyle intervention alone, bariatric surgery, combined with ongoing lifestyle changes, has become a favorable approach in adolescents with severe obesity and weight-related comorbidities and is associated with effective weight loss and reducing weight-related comorbidities. Laparoscopic greater curvature plication is a promising new bariatric surgical procedure that has been shown to be effective in adults with severe obesity but has not been evaluated in the adolescent population. Gastric plication may be a particularly attractive approach for the adolescent patient as it is potentially reversible, does not involve the surgical removal of tissue, and is without a significant malabsorptive component. Our team has obtained approval from our Institutional Review Board to perform a laparoscopic greater curvature plication on 30 adolescent patients with severe obesity and study its effect on weight loss, metabolic effects, and psychological functioning in the setting of a multidisciplinary program. Results of this study, including comprehensive clinical and psychological data collected over a 3.5-year span, will inform larger prospective investigations comparing the laparoscopic greater curvature plication and other bariatric operations in the adolescent population. PMID- 24491366 TI - Adolescent bariatric surgery: the Canadian perspective. AB - Canada faces a similar epidemic of obesity in their adolescent population as other Western countries. However, the development of programs to treat obesity and manage its sequelae has evolved in a unique way. This is in part due to differences in health care funding, population distribution, public demand, and availability of expertise and resources. In this article, we will describe the evolution of adolescent bariatric care in Canada and describe the current programs and future directions. The focus will be on the province of Ontario, the site of the first adolescent bariatric program in the country. PMID- 24491367 TI - Bariatric surgery in monogenic and syndromic forms of obesity. AB - Currently, no topic is more controversial in bariatric surgery than performing these procedures on children with monogenic and syndromic forms of obesity. The medical community and the caregivers of those patients are struggling to find a solution that can alleviate their suffering and save their life. In all forms of obesity, dieting and physical activity do not result in significant weight loss and is associated with a high rate of weight regain. Additionally, effective medical therapy is not available yet. While there is significant debate about the risks and benefits of bariatric surgery in the adolescent population, there is an increasing number of studies that demonstrate the success of this option for the appropriate patients. Similarly, our experience demonstrated the same success not only in normal children and adolescents but also in those with monogenic and syndromic form of obesity. PMID- 24491368 TI - Genetic modifiers of obesity and bariatric surgery outcomes. AB - Obesity is a highly heritable trait. While acute and chronic changes in body weight or obesity-related comorbidities are heavily influenced by environmental factors, there are still strong genomic modifiers that help account for inter subject variability in baseline traits and in response to interventions. This review is intended to provide an up-to-date overview of our current understanding of genetic influences on obesity, with emphasis on genetic modifiers of baseline traits and responses to intervention. We begin by reviewing how genetic variants can influence obesity. We then examine genetic modifiers of weight loss via different intervention strategies, focusing on known and potential modifiers of surgical weight loss outcomes. We will pay particular attention to the effects of patient age on outcomes, addressing the risks and benefits of adopting early intervention strategies. Finally, we will discuss how the field of bariatric surgery can leverage knowledge of genetic modifiers to adopt a personalized medicine approach for optimal outcomes across this widespread and diverse patient population. PMID- 24491369 TI - Nonalcoholic fatty liver disease and bariatric surgery in adolescents. AB - Obesity is a multi-organ system disease with underlying insulin resistance and systemic chronic inflammation. Nonalcoholic fatty liver disease (NAFLD) is a hepatic manifestation of the underlying metabolic dysfunction. This review provides a highlight of the current understanding of NAFLD pathogenesis and disease characteristics, with updates on the challenges of NAFLD management in obese and severely obese (SO) patients and recommendations for the pediatric surgeons' role in the care of SO adolescents. PMID- 24491370 TI - Synthesis of amphiphilic seleninic acid derivatives with considerable activity against cellular membranes and certain pathogenic microbes. AB - Selenium compounds play a major role in Biology, where they are often associated with pronounced antioxidant activity or toxicity. Whilst most selenium compounds are not necessarily hazardous, their often selective cytotoxicity is interesting from a biochemical and pharmaceutical perspective. We have synthesized a series of amphiphilic molecules which combine a hydrophilic seleninic acid head group - which at the same time serves as thiol-specific warhead - with a hydrophobic tail. These molecules possess a surface activity similar to the one of SDS, yet their biological activity seems to exceed by far the one of a simple surfactant (e.g. SDS) or seleninic acid (e.g. phenyl seleninic acid). Such compounds effectively haemolyse Red Blood Cells and exhibit pronounced activity against Saccharomyces cerevisiae. From a chemical perspective, the seleninic warheads are likely to attack crucial cysteine proteins of the cellular thiolstat. PMID- 24491371 TI - The phylogenetic position of the Loimoidae Price, 1936 (Monogenoidea: Monocotylidea) based on analyses of partial rDNA sequences and morphological data. AB - Phylogenetic analyses of partial sequences of 18S and 28S rDNA of some monogenoids, including monocotylids and a specimen of Loimosina sp. collected from a hammerhead shark off Brazil, indicated that the Loimoidae (as represented by the specimen of Loimosina sp.) represents an in-group taxon of the Monocotylidae. In all analyses, the Loimoidae fell within a major monocotylid clade including species of the Heterocotylinae, Decacotylinae, and Monocotylinae. The Loimoidae formed a terminal clade with two heterocotyline species, Troglocephalus rhinobatidis and Neoheterocotyle rhinobatis, for which it represented the sister taxon. The following morphological characters supported the clade comprising the Loimoidae, Heterocotylinae, Decacotylinae and Monocotylinae: single vagina present, presence of a narrow deep anchor root, and presence of a marginal haptoral membrane. The presence of cephalic pits was identified as a putative synapomorphy for the clade (Loimoidae (T. rhinobatidis, N. rhinobatis)). Although rDNA sequence data support the rejection of the Loimoidae and incorporating its species into the Monocotylidae, this action was not recommended pending a full phylogenetic analysis of morphological data. PMID- 24491372 TI - Pilot study for home monitoring of cough capacity in amyotrophic lateral sclerosis: A case series. AB - BACKGROUND: Cough capacity derangement is associated with a high risk of pulmonary complications in amyotrophic lateral sclerosis patients when cough assistance is not routinely performed at home. The primary aim of this study was to evaluate the feasibility of a long-term home based daily self-monitoring cough capacity. METHODS: Eighteen subjects were enrolled in a 9-month study at home. Changes in peak cough expiratory flow, oxygen saturation, respiratory discomfort and incidence of respiratory deterioration events were evaluated. In subjects presenting respiratory deterioration events, decline in the abovementioned respiratory variables was evaluated (#NCT00613899). RESULTS: During an average follow-up of 125+/-102 days, a total of 1175 measures were performed on 12 subjects. Mean compliance to proposed evaluations was 37+/-32% which worsened over time. Peak cough expiratory flow decreased by 15.08+/-32.43L/min monthly. Five subjects reported 6 episodes of respiratory deterioration events, after a mean period of 136+/-108 days. They had poor respiratory function and more years of disease. There was no difference in peak cough expiratory flow and its decline whether subjects presented respiratory deterioration events or not. In 4 subjects the respiratory discomfort score significantly worsened after respiratory deterioration events from 3.0+/-1.41 to 4.25+/-1.71. CONCLUSION: Daily self monitoring of peak cough expiratory flow, oxygen saturation and respiratory discomfort seems difficult to obtain because of poor adherence to measures; this protocol does not seem to add anything to current practice of advising on clinical derangements. Confirmatory larger studies are necessary. PMID- 24491373 TI - Monitoring equine visceral pain with a composite pain scale score and correlation with survival after emergency gastrointestinal surgery. AB - Recognition and management of equine pain have been studied extensively in recent decades and this has led to significant advances. However, there is still room for improvement in the ability to identify and treat pain in horses that have undergone emergency gastrointestinal surgery. This study assessed the validity and clinical application of the composite pain scale (CPS) in horses after emergency gastrointestinal surgery. Composite pain scores were determined every 4h over 3 days following emergency gastrointestinal surgery in 48 horses. Inter observer reliability was determined and another composite visceral pain score (numerical rating scale, NRS) was determined simultaneously with CPS scores. CPS scores had higher inter-observer reliability (r=0.87, K=0.84, P<0.001), compared to NRS scores (r=0.68, K=0.72, P<0.001). Horses that survived without complications had significantly lower CPS and NRS scores compared to horses that were euthanased or had to undergo re-laparotomy (P<0.001). Breed and the location in the intestinal tract (small or large intestine) did not influence pain scores. In conclusion, the use of the CPS improved objectivity of pain scoring in horses following emergency gastrointestinal surgery. High inter-observer reliability allows for comparisons between different observers. This will be of great benefit in larger veterinary hospitals where several attending clinicians are often involved in the care of each case. PMID- 24491374 TI - Promoting positive behavioral health: a non-pharmacologic toolkit for senior living communities. PMID- 24491375 TI - Effectiveness of MESNA on the success of cholesteatoma surgery. AB - IMPORTANCE: It is important that chronic otitis media with cholesteatoma be treated successfully in patients to protect them from having repeated surgeries with related surgical co-morbidities and hearing loss. OBJECTIVE: To evaluate the effectiveness of MESNA usage on the residual cholesteatoma rates of the patients who underwent surgery due to chronic otitis media with cholesteatoma. DESIGN: Retrospective single-institution study of a prospectively collected database. SETTING: Tertiary University Hospital. PARTICIPANTS: Nine hundred and thirty-four patients underwent surgery due to chronic otitis media between September 2000 and March 2012 by the same surgeon. One hundred and forty-one cases out of 934 patients were selected who had cholesteatoma for the study. These randomly selected 141 cases were divided into two groups as follows: I. Forty-six cases were applied MESNA (Sodium 2-mercaptoethanesulfonate) intraoperatively, and II. Ninety-five cases were not applied MESNA intraoperatively. The cases that were followed-up at least one year were included in this study. INTERVENTION: MESNA (Ureomitexan, MESNA, Baxter oncology, Germany) was diluted with saline (20% MESNA and 80% saline) that was applied, and then a waiting period of approximately 5 min followed to start to dissect cholesteatoma matrix. MAIN OUTCOMES AND MEASURES: Residual cholesteatoma rates between intraoperative MESNA, a disulfide bond breaking chemical agent, applied and MESNA non-applied cases in the postoperative follow-up period were compared for the success of the surgery. RESULTS: MESNA was used in 46 patients out of 141 cases intraoperatively. Twenty four of these patients underwent CWD (canal wall down), and twenty-two patients underwent CWU (canal wall up) mastoidectomy. For the other 95 subjects, 56 patients with CWD and 39 with CWU mastoidectomy, MESNA was not applied. Residual cholesteatoma rates were found to be significantly higher in MESNA non-applied group than MESNA applied group (p<0.05). Residual cholesteatoma rates between CWD and CWU mastoidectomy procedures were not statistically significant (p>0.05). CONCLUSIONS AND RELEVANCE: MESNA application that breaks disulfide bonds in the structure of the matrix in cholesteatoma surgery may assist the elimination of the disease, and increase surgical success by facilitating the elevation of the epithelium. Thereby, it causes a decrease in the possibility of remaining residual epithelium after surgery, which decreases the need for second-look surgery. TRIAL REGISTRATION: The retrospective research protocol was approved by the Inonu University Clinical Research Ethics Committee. REGISTRATION NUMBER: ......... PMID- 24491376 TI - Evaluation of alternative rapid thin layer chromatography systems for quality control of technetium-99m radiopharmaceuticals. AB - Whatman 3MMTM and Tec-ControlTM systems were evaluated as ITLC-SG alternatives for 99mTc-radiopharmaceuticals. They compare well in accuracy and reproducibility, and are faster and more convenient than ITLC-SG. Tec-ControlTM radiochemical purity values for 99mTc-sestamibi were more conservative than ITLC SG. Full solvent migration was not reproduced for 99mTc-tetrofosmin in Tec ControlTM, and for this Whatman 3MMTM is preferred. Developing times were 10-15 min, 7-9 min and ~1min for ITLC-SG, Whatman 3MMTM and Tec-ControlTM, respectively. Overall, Tec-ControlTM strips are preferred due to speed and ease of use. PMID- 24491377 TI - Revisiting scoliosis in the KNM-WT 15000 Homo erectus skeleton. AB - Owing to its completeness, the 1.5 million year old Nariokotome boy skeleton KNM WT 15000 is central for understanding the skeletal biology of Homo erectus. Nevertheless, since the reported asymmetries and distortions of Nariokotome boy's axial skeleton suggest adolescent idiopathic scoliosis, possibly associated with congenital skeletal dysplasia, it is questionable whether it still can be used as a reference for H. erectus. Recently, however, the presence of skeletal dysplasia has been refuted. Here, we present a morphological and morphometric reanalysis of the assertion of idiopathic scoliosis. We demonstrate that unarticulated vertebral columns of non-scoliotic and scoliotic individuals can be distinguished based on the lateral deviation of the spinous process, lateral and sagittal wedging, vertebral body torsion, pedicle thickness asymmetry, and asymmetry of superior and inferior articular facet areas. A principal component analysis of the overall asymmetry of all seven vertebral shape variables groups KNM-WT 15000 within non-scoliotic modern humans. There is, however, an anomaly of vertebrae T1 T2 that is compatible with a short left convex curve at the uppermost thoracic region, possibly due to injury or local growth dysbalance. Asymmetries of the facet joints L3-L5 suggest a local right convex curve in the lower lumbar region that probably resulted from juvenile traumatic disc herniation. This pattern is incompatible with adolescent idiopathic scoliosis or other types of scoliosis, including congenital, neuromuscular or syndromic scoliosis. It is, however, consistent with a recent reanalysis of the rib cage that did not reveal any asymmetry. Except for these possibly trauma-related anomalies, the Nariokotome boy fossil therefore seems to belong to a normal H. erectus youth without evidence for adolescent idiopathic scoliosis or other severe pathologies of the axial skeleton. PMID- 24491378 TI - Hyperostosis frontalis interna in a Neandertal from Marillac (Charente, France). AB - The site of Marillac (Charente, France) has yielded an important stratigraphic sequence containing numerous Neandertal remains (some of them with peri-mortem manipulations) from lithofacies 2 (Quina Mousterian). This level has been correlated with MIS 4 and is associated with a TL date of 57,600 +/- 4600 years BP (before present). The study of one of the cranial fragments (Marillac 3) revealed a grade 2 or Type B Hyperostosis frontalis interna (HFI), remodelling and altering the internal table of the thick frontal bone. This pathology has been analysed macroscopically together with radiography and sections made using a microscanner and a scanner. The development of the HFI is compared with published evidence for Sangiran 3 (Homo erectus), two other Neandertals (Forbes' Quarry and Shanidar 5), and several archaeological samples. Forbes' Quarry seems to display more advanced HFI than either Shanidar 5 or Marillac 3. The three Neandertals may be considered mature individuals (>=40 years) and it seems likely that the aetiology of this pathology may be associated with hormonal alterations, as has been suggested for past and extant populations. While the prevalence of HFI in contemporary post-menopausal women is well documented, the identification of HFI amongst males from several archaeological samples (Neanderthals, Ancient Egypt, Syrian Bronze Age or the Anasazi), with different stages of development, confirm that the pathology affected both sexes in past populations. Additional data and research are still needed to elucidate the etiopathogenesis of this illness and to better understand the relationship between environmental factors and their possible influences/consequences for the development of metabolic disorders in prehistoric populations. PMID- 24491379 TI - Correlation between nocturnal scratch behavior assessed by actigraphy and subjective/objective parameters in patients with atopic dermatitis. PMID- 24491380 TI - Criminality and suicide: a longitudinal Swedish cohort study. AB - OBJECTIVES: This study aimed to investigate whether violent and non-violent offending were related to elevated risk of suicide. We also investigated whether the risk was higher among those with repeated offences and how experiences of substance misuse and suicide attempt modified the relationship. DESIGN: A nationwide prospective cohort study. SETTING: A register study of 48 834 conscripted men in 1969/1970 in Sweden followed up during a 35-year period in official registers. PARTICIPANTS: A birth cohort of 48 834 men who were mandatory conscripted for military service in 1969/70 at the age of 18-20 years. Possible confounders were retrieved from psychological assessments at conscription and the cohort was linked to mortality and hospitalisation and crime records from 1970 onwards. Estimates of suicide risks were calculated as HR with 95% CIs using Cox proportional regression analyses with adjustment for potential confounding by family, psychological and behavioural factors including substance use and psychiatric disorders. RESULTS: Of the total cohort, 2671 (5.5%) persons died during the follow-up period. Of these, 615 (23%) persons died due to suicide. Non violent criminality was evident for 29% and violent criminality for 4.7% of all the participants. In the crude model, the violent offenders had nearly five times higher risk (HR=4.69, 3.56 to 6.19) to die from suicide and non-violent criminals had about two times higher risk (HR=2.08, 1.72 to 2.52). In the fully adjusted model, the HRs were still significant for suicide in the non-violent group. CONCLUSIONS: Experiences of violent or non-violent criminality were associated with increased risk of suicide. Comorbidity with alcohol and substance use and psychiatric disorders modified the risk, but the suicide risk remained significantly elevated for non-violent criminals. It is crucial to identify offenders and especially repeated offenders who also suffer from alcohol or substance misuse and psychiatric illness in clinical settings in order to prevent suicide. PMID- 24491382 TI - Access to the NHS by telephone and Internet during an influenza pandemic: an observational study. AB - OBJECTIVES: To examine use of a novel telephone and Internet service-the National Pandemic Flu Service (NPFS)-by the population of England during the 2009-2010 influenza pandemic. SETTING: National telephone and Internet-based service. PARTICIPANTS: Service available to population of England (n=51.8 million). PRIMARY AND SECONDARY OUTCOME MEASURES: Primary: service use rate, by week. Numbers and age-specific and sex-specific rates of population who: accessed service; were authorised to collect antiviral medication; collected antiviral medication; were advised to seek further face-to-face assessment. Secondary: daily mean contacts by hour; proportion using service by telephone/Internet. RESULTS: The NPFS was activated on 23 July 2009, operated for 204 days and assessed 2.7 million patients (5200 consultations/100 000 population). This was six times the number of people who consulted their general practitioner with influenza-like illness during the same period (823 consultations/100 000 population, rate ratio (RR)=6.30, 95% CI 6.28 to 6.32). Women used the service more than men (52.6 vs 43.4 assessments/1000 population, RR1 21, 95% CI 1.21 to 1.22). Among adults, use of the service declined with age (16-29 years: 74.4 vs 65 years+: 9.9 assessments/1000 population (RR 7.46 95% CI 7.41 to 7.52). Almost three-quarters of those assessed met the criteria to receive antiviral medication (1 807 866/2 488 510; 72.6%). Most of the people subsequently collected this medication, although more than one-third did not (n=646 709; 35.8%). Just over one-third of those assessed were advised to seek further face-to-face assessment with a practitioner (951 332/2 488 504; 38.2%). CONCLUSIONS: This innovative healthcare service operated at large scale and achieved its aim of relieving considerable pressure from mainstream health services, while providing appropriate initial assessment and management for patients. This offers proof-of concept for such a service that, with further refinement, England can use in future pandemics. Other countries may wish to adopt a similar system as part of their pandemic emergency planning. PMID- 24491383 TI - Enhanced styrene recovery from waste polystyrene pyrolysis using response surface methodology coupled with Box-Behnken design. AB - A work applied response surface methodology coupled with Box-Behnken design (RSM BBD) has been developed to enhance styrene recovery from waste polystyrene (WPS) through pyrolysis. The relationship between styrene yield and three selected operating parameters (i.e., temperature, heating rate, and carrier gas flow rate) was investigated. A second order polynomial equation was successfully built to describe the process and predict styrene yield under the study conditions. The factors identified as statistically significant to styrene production were: temperature, with a quadratic effect; heating rate, with a linear effect; carrier gas flow rate, with a quadratic effect; interaction between temperature and carrier gas flow rate; and interaction between heating rate and carrier gas flow rate. The optimum conditions for the current system were determined to be at a temperature range of 470-505 degrees C, a heating rate of 40 degrees C/min, and a carrier gas flow rate range of 115-140mL/min. Under such conditions, 64.52% WPS was recovered as styrene, which was 12% more than the highest reported yield for reactors of similar size. It is concluded that RSM-BBD is an effective approach for yield optimization of styrene recovery from WPS pyrolysis. PMID- 24491384 TI - Effect of increased axial rotation angle on bone mineral density measurements of the lumbar spine. AB - BACKGROUND CONTEXT: Osteoporosis frequently occurs in elderly people and is commonly associated with neuromuscular diseases or severe cerebral palsy. Osteoporosis can cause pain via compression fractures or secondary neurologic deficits; thus, accurate evaluation of bone mineral density (BMD) is essential for the prevention and treatment of osteoporosis. However, spinal axial rotation caused by scoliosis may affect the outcome of BMD tests, such that BMD measurements may be significantly greater than actual BMD in patients with severe scoliosis of the spine. PURPOSE: We investigated the effect of axial rotation angle on BMD measurements of the phantom spine. STUDY DESIGN/SETTING: Investigation for the effect of axial rotation with aluminum phantom spine. METHODS: A GE-Lunar Aluminum Spine Phantom was used to assess BMD. Bone mineral content (BMC), BMD, and cross-sectional area were measured 100 times at L1-L4 using a GE Lunar Prodigy Vision system. Dual-energy X-ray absorptiometry was performed at axial rotation angles of 0 degrees to 25 degrees (5 degrees intervals). RESULTS: Cross-sectional area decreased and BMD values increased as the axial rotation angle increased, whereas BMC did not change significantly. A fitting function was obtained to evaluate the relationships among axial rotation angle, cross-sectional area, and BMD. We obtained an equation to estimate BMD at L1-L4: 1.000-0.001674x+0.0001043x(2)-0.000005333x(3), where x denotes the axial rotation angle. We found that the observed BMD needed adjustment when the angle was more than 5 degrees . CONCLUSIONS: Bone mineral density values may be overestimated in patients with even slight (>5 degrees ) axial rotation. When osteoporosis is suspected in a clinical setting, the degree of axial rotation should be measured on a lumbar spine X-ray. PMID- 24491385 TI - Rigid gas-permeable contact lens-assisted cataract surgery in patients with severe keratoconus. AB - We describe rigid gas-permeable (RGP) contact lens-assisted cataract surgery in patients with severe keratoconus. During cataract surgery in cases with severe keratoconus, the intraocular images are distorted and visual perspective is lost because of irregular corneal astigmatism. Poor visibility can lead to complications, including posterior capsule rupture and corneal endothelial cell damage. To overcome these problems, an RGP contact lens was placed on the cornea in 2 cases. The image distortion decreased markedly, and the visual perspective improved. Intraocular manipulations such as irrigation/aspiration were performed safely. Improvement in transillumination led to good visualization of the anterior and posterior capsules. No intraoperative or postoperative complications developed in either case. This technique provided excellent visualization during cataract surgery in patients with severe keratoconus. PMID- 24491386 TI - Is visual short-term memory depthful? AB - Does visual short-term memory (VSTM) depend on depth, as it might be if information was stored in more than one depth layer? Depth is critical in natural viewing and might be expected to affect retention, but whether this is so is currently unknown. Cued partial reports of letter arrays (Sperling, 1960) were measured up to 700 ms after display termination. Adding stereoscopic depth hardly affected VSTM capacity or decay inferred from total errors. The pattern of transposition errors (letters reported from an uncued row) was almost independent of depth and cue delay. We conclude that VSTM is effectively two-dimensional. PMID- 24491387 TI - Direct observation of residents: a model for an assessment system. PMID- 24491388 TI - Insulin-like growth factor-I induces CLU expression through Twist1 to promote prostate cancer growth. AB - Clusterin (CLU) is cytoprotective molecular chaperone that is highly expressed in castrate-resistant prostate cancer (CRPC). CRPC is also characterized by increased insulin-like growth factor (IGF)-I responsiveness which induces prostate cancer survival and CLU expression. However, how IGF-I induces CLU expression and whether CLU is required for IGF-mediated growth signaling remain unknown. Here we show that IGF-I induced CLU via STAT3-Twist1 signaling pathway. In response to IGF-I, STAT3 was phosphorylated, translocated to the nucleus and bound to the Twist1 promoter to activate Twist1 transcription. In turn, Twist1 bound to E-boxes on the CLU promoter and activated CLU transcription. Inversely, we demonstrated that knocking down Twist1 abrogated IGF-I induced CLU expression, indicating that Twist1 mediated IGF-I-induced CLU expression. When PTEN knockout mice were crossed with lit/lit mice, the resultant IGF-I deficiency suppressed Twist1 as well as CLU gene expression in mouse prostate glands. Moreover, both Twist1 and CLU knockdown suppressed prostate cancer growth accelerated by IGF-I, suggesting the relevance of this signaling not only in an in vitro, but also in an in vivo. Collectively, this study indicates that IGF-I induces CLU expression through sequential activation of STAT3 and Twist1, and suggests that this signaling cascade plays a critical role in prostate cancer pathogenesis. PMID- 24491389 TI - End of the Joint National Committee heritage? PMID- 24491390 TI - Hypertension guidelines: political correctness trumping expertise? PMID- 24491391 TI - Response to Comment on optimal treatment for resistant hypertension: the missing data on pulse wave velocity. PMID- 24491392 TI - Comment on optimal treatment for resistant hypertension: the missing data on pulse wave velocity. PMID- 24491393 TI - Concentration, distribution, and human health risk assessment of endosulfan from a manufacturing facility in Huai'an, China. AB - Endosulfan concentrations and its distribution in air, soil, sediment and foodstuffs in the area surrounding a production facility in Huai'an, China were investigated because of its threats to the environment and human health. Air concentrations for endosulfan Iota, endosulfan II and endosulfan sulfate measured in this study were several orders of magnitude higher than those reported previously for this region. Surface soil concentration ranges of endosulfan I, endosulfan II, and endosulfan sulfate were greater than in sediment. Endosulfan II was the greatest contributor to total endosulfan concentrations in both surface sediment and soil followed by endosulfan sulfate and endosulfan Iota. However, a different concentration profile was observed in fish and crop samples, with endosulfan sulfate having the highest concentration followed by endosulfan I and endosulfan II. The concentration of Sigmaendosulfans (endosulfans Iota and II) in soil decreased rapidly with increasing distance from the plant by a factor of 10 within 45 km. Trace amounts of Sigmaendosulfans were observed in deep soil layers which implied that these compounds are transported through the leaching of pore water in soil. This demonstrated that emissions from the manufacturing facility can lead to ground water contamination in the area near the plant. A screening level human health risk assessment of Sigmaendosulfans based on the worst-case scenario was performed for people living in the vicinity of the manufacturing facility. The hazard indices were at least 2 orders of magnitude of <1, indicating no adverse health effects are likely to occur at current exposure levels, and the risk to human health is generally acceptable. PMID- 24491394 TI - Letter to the Editor regarding the paper by Aurilio et al., A meta-analysis of oestrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 discordance between primary breast cancer and metastases. PMID- 24491395 TI - Limited human epidermal growth factor receptor 2 discordance in metastatic breast cancer patients treated with trastuzumab, a population based study. AB - BACKGROUND: Accurate assessment of the human epidermal growth factor receptor 2 (HER2) in breast cancer is essential for proper treatment decisions. HER2 positivity confirmation rates in breast cancer trials by central testing pathology laboratories were reported to be approximately 85%. The aim of our study was to assess in a population based sample concordance of HER2 status in metastatic breast cancer (MBC) patients locally tested HER2 positive and treated with trastuzumab. Moreover cost-effectiveness of in situ hybridisation (ISH) in patients with an immunohistochemical score 3+ (IHC3+) was explored. METHODS: MBC patients treated between 2005 and 2009 with trastuzumab-based therapy in North East Netherlands were identified by a survey of hospital pharmacies. Primary tumour samples were retested centrally for HER2 status using 1 immunohistochemical (IHC) method and two methods using ISH on tissue micro arrays. Potential discordant patients were retested on whole tumour slides. HER2 positivity was defined as: (1) ISH amplification (according to American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) clinical practice Guideline Update) and (2) when ISH failed an IHC score of 3+. Cost effectiveness was estimated using potential ISH and treatment costs. RESULTS: HER2 status could be retested in 174 of 194 (90%) patients. The HER2 concordance rate was 87%. The 21 discordant patients were in the 67% due to primary HER2 testing with only IHC. Overall survival of HER2 discordant and concordant patients was not significantly different (18 versus 25months, p=0.131). Structural ISH in the case of IHC3+ has an estimated potential saving of ?87,710 per 100 patients. CONCLUSION: HER2 concordance in a population based study is comparable to those described in selected populations. Discordance is mostly due to testing with only IHC. ISH in the case of IHC3+ is cost-effective. PMID- 24491396 TI - The risk of vector-borne infections in sled dogs associated with existing and new endemic areas in Poland: Part 1: A population study on sled dogs during the racing season. AB - The achievements of sled dogs in competitions depend both on their training and on their health. Vector-borne infections may lead to anaemia, affect joints or heart muscle or even cause death. Between December 2009 and October 2010, one hundred and twenty six individual blood samples were collected from 26 sled dog kennels situated in different regions of Poland. The majority of samples were taken during the racing season (winter 2009/10). The prevalences of 3 vector borne infections- including 2 'old pathogens' Anaplasma phagocytophilum and Babesia canis, and 'new pathogen' Hepatozoon canis-were estimated in sled dogs using PCR and nested PCR. Additionally, 25 serum samples originating from a subset of 3 kennels situated in a tick-borne encephalitis (TBE) endemic area (Mazowiecki region), were tested for antibodies against the tick-borne encephalitis virus (TBEV). Because of the recently reported occurrence of Dirofilaria repens in Central Poland and that of fatal cases of unknown aetiology in two of the kennels, blood samples collected from dogs at these kennels in 2010 and in February-May 2013 and from two unaffected kennels were checked for evidence of presence of this parasite. Babesia canis DNA was detected in 11 sled dogs (4 with clinical babesiosis, 7 asymptomatic; 8.7%) inhabiting mainly endemic regions of Poland (9/11 cases). Three serum samples originating from one location tested positive for TBEV antibodies (total seroprevalence: 3/25=12%, local seroprevalence: 3/12=25%). The risk of TBEV infection was associated with previous B. canis infections. Dirofilaria repens DNA was detected in 15 dogs (44%). Prevalence was especially high in two sled dog kennels situated near Grodzisk Mazowiecki (50-57%). No blood samples tested positive for A. phagocytophilum or H. canis DNA. The present study has established that the prevalence of vector-borne pathogens in working sled dogs is significant in the endemic regions and has justified the important role of surveillance of reservoir hosts in the epidemiology of TBE. Our results emphasize the need for regular monitoring for the presence of D. repens. PMID- 24491397 TI - Targeted uptake of folic acid-functionalized iron oxide nanoparticles by ovarian cancer cells in the presence but not in the absence of serum. AB - Targeted delivery of nanoparticles to cells or tissues of interest is arguably the "holy grail" of nanomedicine. Using primary human macrophages and ovarian cancer cells, we evaluated the biocompatibility and specific targeting of folic acid (FA)-conjugated iron oxide nanoparticles with organic [poly(ethylene glycol), PEG] or inorganic (SiO2) intermediate surface coatings. Reduction of folate receptor-alpha expression using specific siRNA resulted in a significant decrease in cellular uptake of the SiO2-coated nanoparticles, but did not affect uptake of PEG-coated nanoparticles. Notably, specific (i.e. FA-dependent) uptake was observed only in the presence of serum proteins. The strategy presented here for receptor-mediated uptake of nanoparticles with pre-defined surface chemistry may enable targeting of nanoparticles for therapeutic and imaging applications. From the clinical editor: In this study the receptor specific uptake of folic acid-functionalized iron oxide nanoparticles was determined in ovarian cancer cells. It was found that the presence of serum proteins is an absolute requirement for the uptake of these nanoparticles. The described strategy for receptor-mediated uptake of nanoparticles with pre-defined surface chemistry may enable a better targeting of nanoparticles for additional therapeutic and imaging applications. PMID- 24491398 TI - The arrhythmogenic effect of self-assembling nanopeptide hydrogel scaffolds on neonatal mouse cardiomyocytes. AB - The chaotic spatial disarray due to extracellular matrix expansion disrupts cardiomyocytes interaction and causes arrhythmia. We hypothesized that disordered nanopeptide scaffolds can mimic the chaotic spatial disarray related to cardiac fibrosis and have arrhythmogenic effects on cardiomyocytes. Primary mouse cardiomyocytes were cultured in 2D traditional and 3D nanopeptide hydrogel scaffold systems. Cardiomyocytes in 3D scaffolds showed irregular spontaneous contractile activity as compared with 2D culture controls. Calcium fluorimetric imaging revealed that basal intracellular calcium level increased 1.42-fold in cardiomyocytes cultured in the 3D scaffold, in vitro. The mRNA levels of sarcoplasmic reticulum calcium transport ATPase, ryanodine 2 receptor and connexin 43 elevated 2.14-fold, 2.33-fold and 2.62-fold in 3D compared with 2D. Immunofluorescence imaging revealed lateralization of the distribution of connexin 43 in 3D group. These findings suggest that 3D hydrogel culture system provides a model for the development of cardiac dysrhythmia. These limitations should be considered during cardiac tissue engineering. FROM THE CLINICAL EDITOR: This team of scientists has established a unique 3D hydrogel culture system as a model for the development of cardiac dysrhythmia. PMID- 24491399 TI - Development of an automatic ROI setting program for input function determination in 99mTc-ECD non-invasive cerebral blood flow quantification. AB - Non-invasive quantitative measurements are useful for clinical study as these are simple and pain-free procedures. A new non-invasive semi-automatic quantitative measurement method, the improved brain uptake ratio (IBUR) method using (99m)Tc ECD SPECT, has recently been reported. If an automatic ROI setting algorithm could be developed to determine the input function for the IBUR method, analysis of regional cerebral blood flow (rCBF) can be completed within a few min without recourse to complex techniques, through a fully automatic rCBF analysis program. The purpose of this study was to develop an automatic input function determination program for (99m)Tc-ECD non-invasive cerebral blood flow quantification and to confirm the feasibility of use of this program. The images of 15 consecutive patients who underwent both (99m)Tc-ECD chest RI angiography and SPECT examinations were used for development of the automatic arterial input function program. The images of 69 consecutive patients were used for validation of the program. The coincidence ratio between the ROI automatic method and the manual setting method was 98%. The mean difference in the ROI location was +/-6.4 mm in the X direction and +/-8.6 mm in the Y direction. Individual rCBF values obtained using these independent techniques were also reasonably well correlated (r = 0.95). The total time for the IBUR analysis using the automatic method is 2 3 min as compared to 20-30 min for the current analysis method. This technique improves the throughput of nuclear medical examinations. PMID- 24491400 TI - Clinical implications of different calculation algorithms in breast radiotherapy: a comparison between pencil beam and collapsed cone convolution. AB - BACKGROUND: This investigation focused on the clinical implications of the use of the Collapsed Cone Convolution algorithm (CCC) in breast radiotherapy and investigated the dosimetric differences as respect to Pencil Beam Convolution algorithm (PBC). MATERIAL AND METHODS: 15 breast treatment plans produced using the PBC algorithm were re-calculated using the CCC algorithm with the same MUs. In a second step, plans were re-optimized using CCC algorithm with modification of wedges and beam weightings to achieve optimal coverage (CCCr plans). For each patient, dosimetric comparison was performed using the standard tangential technique (SWT) and a forward-planned IMRT technique (f-IMRT). RESULTS: The CCC algorithm showed significant increased dose inhomogeneity. Mean and minimum PTV doses decreased by 1.4% and 2.8% (both techniques). Mean V95% decreased to 83.7% and 90.3%, respectively for the SWT and f-IMRT. V95% was correlated to the ratio of PTV and lung volumes into the treatment field. The re-optimized CCCr plans achieved similar target coverage, but high-dose volume was significantly larger (V107%: 7.6% vs 2.3% (SWT), 7.1% vs 2.1% (f-IMRT). There was a significantly increase in the ipsilateral lung volume receiving low doses (V5 Gy: 31.3% vs 26.2% in SWT, 27.0% vs 23.0% in f-IMRT). MUs needed for PTV coverage in CCCr plans were higher by 3%. CONCLUSIONS: The PBC algorithm overestimated PTV coverage in terms of all important dosimetric metrics. If previous clinical experience are based on the use of PBC model, especially needed is discussion between medical physicists and radiation oncologists to fully understand the dosimetric changes. PMID- 24491401 TI - Depressive disorder, coronary heart disease, and stroke: dose-response and reverse causation effects in the Whitehall II cohort study. AB - BACKGROUND: Systematic reviews examining associations of depressive disorder with coronary heart disease and stroke produce mixed results. Failure to consider reverse causation and dose-response patterns may have caused inconsistencies in evidence. DESIGN: This prospective cohort study on depressive disorder, coronary heart disease, and stroke analysed reverse causation and dose-response effects using four 5-year and three 10-year observation cycles (total follow up 24 years) based on multiple repeat measures of exposure. METHODS: Participants in the Whitehall II study (n = 10,036, 31,395 person-observations, age at start 44.4 years) provided up to six repeat measures of depressive symptoms via the 30-item General Health Questionnaire (GHQ-30) and one measure via Center for Epidemiologic Studies Depression Scale (CES-D). The cohort was followed up for major coronary events (coronary death/nonfatal myocardial infarction) and stroke (stroke death/morbidity) through the national mortality register Hospital Episode Statistics, ECG-screening, medical records, and self-report questionnaires. RESULTS: GHQ-30 caseness predicted stroke over 0-5 years (age-, sex- and ethnicity-adjusted HR 1.60, 95% CI 1.1-2.3) but not over 5-10 years (HR 0.94, 95% CI 0.6-1.4). Using the last 5-year observation cycle, cumulative GHQ-30 caseness was associated with incident coronary heart disease in a dose-response manner (1 2 times a case: HR 1.12, 95% CI 0.7-1.7; 3-4 times: HR 2.06, 95% CI 1.2-3.7), and CES-D caseness predicted coronary heart disease (HR 1.81, 95% CI 1.1-3.1). CONCLUSIONS: There was evidence of a dose-response effect of depressive symptoms on risk of coronary heart disease. In contrast, prospective associations of depressive symptoms with stroke appeared to arise wholly or partly through reverse causation. PMID- 24491402 TI - A systematic review of yoga for heart disease. AB - BACKGROUND: This systematic review of randomized controlled trials (RCTs) aimed to evaluate the quality of evidence and the strength of recommendation for yoga as an ancillary intervention for heart disease. METHODS: Medline/PubMed, Scopus, the Cochrane Library, and IndMED were searched up to October 2013. Main outcome measures were mortality, nonfatal cardiac events, exercise capacity, health related quality of life, and modifiable cardiac risk factors. Risk of bias, quality of evidence, and the strength of the recommendation for or against yoga were assessed according to the Cochrane Collaboration and GRADE recommendations. RESULTS: Seven RCTs with 624 patients comparing yoga to usual care were included. For coronary heart disease (four RCTs), there was very low evidence for no effect on mortality, for a reduced number of angina episodes, and for increased exercise capacity, and low evidence for reduced modifiable cardiac risk factors. For heart failure (two RCTs), there was very low evidence for no effect on mortality, and low evidence for increased exercise capacity, and for no effect on health-related quality of life. For cardiac dysrhythmias treated with implantable cardioverter defibrillator (one RCT), there was very low evidence for no effect on mortality, and for improved quality, and low evidence for effects on nonfatal device-treated ventricular events. Three RCTs reported safety data and reported that no adverse events occurred. CONCLUSIONS: Based on the results of this review, weak recommendations can be made for the ancillary use of yoga for patients with coronary heart disease, heart failure, and cardiac dysrhythmia at this point. PMID- 24491403 TI - Effectiveness of the Heart Age tool for improving modifiable cardiovascular risk factors in a Southern European population: a randomized trial. AB - AIMS: To test whether communicating cardiovascular diseases (CVD) risk using a novel risk assessment tool (Heart Age) will be able to motivate a population to adopt healthier lifestyles and improve CVD risk profile over the use of a traditional percentage-based tool. METHODS: A single-blind randomized intervention study was carried out in a Caucasian population. A total of 3153 subjects were randomly allocated to one of three study groups: control (conventional medical advice was given to the subjects), Framingham REGICOR (10 year percentage risk score, calibrated to Spanish population was given to the subjects), or Heart Age group (Heart Age tool was administered to the subjects). Anthropometrical and metabolic parameters were measured and lifestyle habits were recorded at recruitment and 12-months post intervention. RESULTS: Both the Framingham REGICOR and the Heart Age intervention groups demonstrated significant decreases in their risk scores at post intervention compared to the control group, with the improvement being of a greater magnitude in the Heart Age group. No differences per gender were observed in the Heart Age group. CONCLUSIONS: Informing patients about their CVD risk expressed as the new Heart Age tool results in a reduction in their CVD risk higher than the one observed when the Framingham REGICOR risk score was used. PMID- 24491404 TI - Pachyonychia congenita in Japan: report of familial cases with a recurrent KRT16 mutation. PMID- 24491405 TI - Glaucarubinone and gemcitabine synergistically reduce pancreatic cancer growth via down-regulation of P21-activated kinases. AB - Pancreatic cancer is one of the most lethal of human malignancies. Nearly 100% cases of pancreatic cancer carry mutations in KRas. P-21-activated kinases (PAKs) are activated by and act downstream of KRas. Glaucarubinone, a natural product first isolated from the seeds of the tree Simarouba glauca, was originally developed as an antimalarial drug, and has more recently been recognised as an anticancer agent. The aims of this study were to determine whether glaucarubinone, alone or in combination with the front-line chemotherapeutic agent gemcitabine, would inhibit the growth of pancreatic cancer cells in vitro or in vivo and the mechanism involved. Growth of the human pancreatic cancer cell lines PANC-1 and MiaPaCa-2 was measured by (3)H-thymidine incorporation in vitro, and by volume as xenografts in SCID mice. The expression and activities of the two serine/threonine kinases PAK1 and PAK4, which are key regulators of cancer progression, were measured by Western blotting. Here we report that glaucarubinone decreased proliferation and migration of pancreatic cancer cells in vitro, and reduced their growth as xenografts in vivo. Treatment with glaucarubinone and gemcitabine reduced proliferation in vitro and tumor growth in vivo more than treatment with either glaucarubinone or gemcitabine alone. Treatment with glaucarubinone reduced PAK1 and PAK4 activities, which were further decreased by the combination of glaucarubinone and gemcitabine. These results indicate that glaucarubinone reduced pancreatic cancer cell growth at least in part via inhibition of pathways involving PAK1 and PAK4. The synergistic inhibition by glaucarubinone and gemcitabine observed both in vitro and in vivo suggests that glaucarubinone may be a useful adjunct to current regimes of chemotherapy. PMID- 24491406 TI - Recent advances in personalized colorectal cancer research. AB - Colorectal cancer is one of the most prevalent cancers and a leading cause ofcancer-related death. It is also curable if detected early. The prognosis for metastatic colorectal cancer remains poor and resistance to chemotherapy is still a major obstacle in effective treatment. While many patients do not clinically benefit from chemotherapy, others experience adverse reactions resulting in dose modifications or treatment withdrawal, thereby reducing treatment efficacy. Researchefforts attempt to identify reliable biomarkers which will guide clinicians in decision making, while matching suitable therapeutic regimens. We here review currently known molecular biomarkers used for the personalized treatment of colorectal cancer. PMID- 24491407 TI - Tailored therapeutic strategies for synovial sarcoma: receptor tyrosine kinase pathway analyses predict sensitivity to the mTOR inhibitor RAD001. AB - We examined efficacy of the mTOR inhibitor RAD001 to seek novel therapies for synovial sarcoma (SS). Although RAD001 had significant anti-tumor effects, its sensitivity differed among cell lines. Phospho-receptor tyrosine kinase (RTK) array analyses revealed c-MET phosphorylation in highly mTOR inhibitor-sensitive cells and PDGFRalpha (which induces intrinsic resistance to mTOR inhibitor) activation in less sensitive cells. Combined treatment with RAD001 and the PDGFR inhibitor pazopanib showed anti-tumor effects in xenograft models with less sensitive cells. Thus, evaluating activated RTKs in clinical samples may predict sensitivity to mTOR inhibitors, raising the possibility of a tailored therapy for SS. PMID- 24491408 TI - MicroRNA let-7 downregulates STAT3 phosphorylation in pancreatic cancer cells by increasing SOCS3 expression. AB - Although dispensable for normal pancreatic function, STAT3 signaling is frequently activated in pancreatic cancers. Consistent downregulation of expression of microRNA let-7 is also characteristic of pancreatic ductal adenocarcinoma (PDAC) biopsy specimens. We demonstrate in this study that re expression of let-7 in poorly-differentiated PDAC cell lines reduced phosphorylation/activation of STAT3 and its downstream signaling events and reduced the growth and migration of PDAC cells. Let-7 re-expression did not repress expression of STAT3 protein or its activator cytokine interleukin 6 (IL 6). However, let-7 re-expression enhanced cytoplasmic expression of suppressor of cytokine signaling 3 (SOCS3), which blocks STAT3 activation by JAK2. Our study thus identified a mechanism by which STAT3 signaling can be inhibited in pancreatic cancer cells by modifying let-7 expression. PMID- 24491409 TI - A comparison of the imaging characteristics and microregional distribution of 4 hypoxia PET tracers. AB - We compared the imaging characteristics and hypoxia selectivity of 4 hypoxia PET radiotracers ((18)F-fluoromisonidazole [(18)F-FMISO], (18)F-flortanidazole [(18)F HX4], (18)F-fluoroazomycin arabinoside [(18)F-FAZA], and (64)Cu-diacetyl-bis(N4 methylsemicarbazone) [(64)Cu-ATSM]) in a single murine xenograft tumor model condition using small-animal PET imaging and combined ex vivo autoradiography and fluorescence immunohistochemistry. METHODS: Nude mice bearing SQ20b xenograft tumors were administered 1 of 4 hypoxia PET tracers and images acquired 80-90 min after injection. Frozen sections from excised tumors were then evaluated for tracer distribution using digital autoradiography and compared with histologic markers of tumor hypoxia (pimonidazole, carbonic anydrase 9 [CA9]) and vascular perfusion (Hoechst 33342). RESULTS: The highest tumor uptake was observed with (64)Cu-ATSM (maximum standardized uptake values [SUV(max)], 1.26 +/- 0.13) and the lowest with (18)F-FAZA (SUVmax, 0.41 +/- 0.24). (18)F-FMISO and (18)F-HX4 had similar intermediate tumor uptake (SUV(max), 0.76 +/- 0.38 and 0.65 +/- 0.19, respectively). Digital autoradiographs of hypoxia tracer distribution were compared pixel by pixel with images of immunohistochemistry stains. The fluorinated nitroimidazoles all showed radiotracer uptake increasing with pimonidazole and CA9 staining. (64)Cu-ATSM showed the opposite pattern, with highest radiotracer uptake observed in regions with the lowest pimonidazole and CA9 staining. CONCLUSION: The fluorinated nitroimidazoles showed similar tumor distributions when compared with immunohistochemistry markers of hypoxia. Variations in tumor standardized uptake value and normal tissue distribution may determine the most appropriate clinical setting for each tracer. (64)Cu-ATSM showed the highest tumor accumulation and little renal clearance. However, the lack of correlation between (64)Cu-ATSM distribution and immunohistochemistry hypoxia markers casts some doubt on the hypoxia selectivity of (64)Cu-ATSM. PMID- 24491410 TI - Contrast-enhanced PET/MR imaging versus contrast-enhanced PET/CT in head and neck cancer: how much MR information is needed? AB - Considering PET/MR imaging as a whole-body staging tool, scan time restrictions in a single body area are mandatory for the cost-effective clinical operation of an integrated multimodality scanner setting. It has to be considered that (18)F FDG already acts as a contrast agent and that under certain circumstances MR contrast may not yield additional clinically relevant information. The concept of the present study was to understand which portions of the imaging information enhance the sensitivity and specificity of the hybrid examination and which portions are redundant. METHODS: One hundred fifty consecutive patients referred for primary staging or restaging of head and neck cancer underwent sequential whole-body (18)F-FDG PET with CT-based attenuation correction, contrast-enhanced (ce) CT, and conventional diagnostic MR imaging of the head and neck in a trimodality PET/CT-MR system. Assessed were image quality, lesion conspicuity, diagnostic confidence, and the benefit of additional coronal and sagittal imaging planes in cePET/CT, PET/MR imaging with only T2-weighted fat-suppressed images (T2w PET/MR imaging), and cePET/MR imaging. RESULTS: In 85 patients with at least 1 PET-positive lesion, 162 lesions were evaluated. Similar robustness was found for CT and MR image quality. T2w PET/MR imaging performed similarly to (metastatic lymph nodes) or better than (primary tumors) cePET/CT in the morphologic characterization of PET-positive lesions and permitted the diagnosis of necrotic or cystic lymph node metastasis without application of intravenous contrast medium. CePET/MR imaging yielded a higher diagnostic confidence for accurate lesion conspicuity (especially in the nasopharynx and in the larynx), infiltration of adjacent structures, and perineural spread. CONCLUSION: The results of the present study provide evidence that PET/MR imaging can serve as a legitimate alternative to PET/CT in the clinical workup of patients with head and neck cancers. Intravenous MR contrast medium may be applied only if the exact tumor extent or infiltration of crucial structures is of concern (i.e., preoperatively) or if perineural spread is anticipated. In early assessment of the response to therapy, in follow-up examinations, or in a whole-body protocol for non-head and neck tumors, T2w PET/MR imaging may be sufficient for coverage of the head and neck. The additional MR scanning time may instead be used for advanced MR techniques to increase the specificity of the hybrid imaging examination. PMID- 24491411 TI - Identification of endometrioid endometrial carcinoma-associated microRNAs in tissue and plasma. AB - OBJECTIVE: This study aimed to identify a set of endometrioid endometrial carcinoma EEC-associated microRNAs (miRNAs) in tissue and plasma, and evaluate their clinical significance. METHODS: A set of EEC-associated miRNAs in tissue and plasma was identified by next-generation sequencing (NGS), which could enable in-depth characterization of the global repertoire of miRNAs. RESULTS: NGS identified 11 candidate EEC-associated miRNAs. Quantitative reverse-transcriptase PCR identified 8 EEC-associated miRNAs in tissue (upregulated: miR-499, miR-135b, miR-205, downregulated: miR-10b, miR-195, miR-30a-5p, miR-30a-3p and miR-21). Expression of hsa-miR-499 in International Federation of Gynecology and Obstetrics (FIGO) Stage IA and Grade 1 tissues was significantly lower than in others (FIGO Stage IB or more advanced, and Grade 2 or 3). By receiver operating characteristic (ROC) curve analysis, compared with single EEC-associated miRNA, two miRNA signatures (miR135b/miR195 and miR135b/miR30a-3p) could distinguish between EEC and normal endometrial tissue samples yielding a high area under the curve (AUC) of 0.9835 [95% confidence interval (CI): 0.9677-1.0], and 0.9898 (95% CI: 0.9677-1.0), respectively. As possible non-invasive markers for EEC, four EEC associated miRNAs (increased level: miR-135b and miR-205, decreased-level: miR 30a-3p and miR-21) in plasma were identified. Circulating levels of three EEC associated miRNAs (miR-135b, miR-205 and miR-30a-3p) in plasma were significantly decreased after hysterectomy. ROC curves analysis revealed that miR-135b and miR 205 levels in plasma yielded AUCs of 0.9722 (95% CI: 0.913-1.0) and 1.0 (95% CI: 1.0-1.0), respectively. CONCLUSION: Measurement of tissue and plasma EEC associated miRNAs may be useful for early detection, diagnostic, and follow-up tests for EEC. PMID- 24491412 TI - HPV vaccine use among African American girls: qualitative formative research using a participatory social marketing approach. AB - OBJECTIVE: To generate recommendations for framing messages to promote HPV vaccination, specifically for African American adolescents and their parents who have not yet made a decision about the vaccine (the "Undecided" market segment). METHODS: Focus groups and interviews were conducted with African American girls ages 11-18 (N=34) and their mothers (N=31), broken into market segments based on daughter's vaccination status and mother's intent to vaccinate. RESULTS: Findings suggested that the HPV vaccine should be presented to "Undecided" mothers and adolescents as a routine vaccine (just like other vaccines) that helps prevent cancer. Within the "Undecided" segment, we identified two sub-segments based on barriers to HPV vaccination and degree of reluctance. The "Undecided/Ready If Offered" segment would easily accept HPV vaccine if given the opportunity, with basic information and a healthcare provider recommendation. The "Undecided/Skeptical" segment would need more in-depth information to allay concerns about vaccine safety, mistrust of drug companies, and recommended age. Some mothers and girls had the erroneous perception that girls do not need the vaccine until they become sexually active. African American adolescents and their mothers overwhelmingly thought campaigns should target both girls and boys for HPV vaccination. In addition, campaigns and messages may need to be tailored for pre-teens (ages 9-12) versus teens (ages 13-18) and their parents. CONCLUSIONS: Findings pointed to the need to "normalize" the perception of HPV vaccine as just another routine vaccine (e.g., part of pre-teen vaccine package). Findings can inform social marketing campaigns targeting Undecided or ethnically diverse families. PMID- 24491413 TI - Alternating hemiplegia of childhood with a de novo mutation in ATP1A3 and changes in SLC2A1 responsive to a ketogenic diet. AB - BACKGROUND: Alternating hemiplegia of childhood (AHC) is a rare condition characterized by an early onset of hemiplegic episodes and other paroxysmal or permanent neurological dysfunctions. Recently, mutations in the ATP1A3 gene have been identified as the causal mechanism of AHC. Regarding the differential diagnosis of AHC, glucose transporter 1 deficiency syndrome may be considered because these two disorders share some paroxystic and nonparoxystic features. PATIENT AND RESULTS: We report a typical case of AHC harboring a de novo mutation in the ATP1A3 gene, together with a duplication and insertion in the SLC2A1 gene who exhibited marked clinical improvement following ketogenic diet. CONCLUSION: Because the contribution of the SLC2A1 mutation to the clinical phenotype cannot be definitely demonstrated, the remarkable clinical response after ketogenic diet led us to the hypothesis that ketogenic diet might be effective in AHC as it provides an alternative energy source for the brain. PMID- 24491414 TI - Analgesic efficacy of caudal dexamethasone combined with ropivacaine in children undergoing orchiopexy. AB - BACKGROUND: Epidural administration of dexamethasone might reduce postoperative pain in adults. We evaluated whether a caudal block of 0.1 mg kg(-1) dexamethasone combined with ropivacaine improves analgesic efficacy in children undergoing day-case orchiopexy. METHODS: This randomized, double-blind study included 80 children aged 6 months to 5 yr who underwent day-case, unilateral orchiopexy. Patients received either 1.5 ml kg(-1) of 0.15% ropivacaine (Group C) or 1.5 ml kg(-1) of 0.15% ropivacaine in which dexamethasone of 0.1 mg kg(-1) was mixed (Group D) for caudal analgesia. Postoperative pain scores, rescue analgesic consumption, and side-effects were evaluated 48 h after operation. RESULTS: Postoperative pain scores at 6 and 24 h post-surgery were significantly lower in Group D than in Group C. Furthermore, the number of subjects who remained pain free up to 48 h after operation was significantly greater in Group D [19 of 38 (50%)] than in Group C [four of 37 (10.8%); P<0.001]. The number of subjects who received oral analgesic was significantly lower in Group D [11 of 38 (28.9%)] than in Group C [20 of 37 (54.1%); P=0.027]. Time to first oral analgesic administration after surgery was also significantly longer in Group D than in Group C (P=0.014). Adverse events after surgery including vomiting, fever, wound infection, and wound dehiscence were comparable between the two groups. CONCLUSIONS: The addition of dexamethasone 0.1 mg kg(-1) to ropivacaine for caudal block can significantly improve analgesic efficacy in children undergoing orchiopexy. Clinical trial registration NCT01604915. PMID- 24491415 TI - Relationship between retinal lesions and inward choroidal bulging in Vogt Koyanagi-Harada disease. AB - PURPOSE: To investigate the correlation between choroidal and retinal lesions in eyes with acute Vogt-Koyanagi-Harada disease (VKH) using optical coherence tomography (OCT) by using a new parameter, retinal pigment epithelium (RPE) undulation index, which quantitatively describes choroidal deformations. DESIGN: Retrospective, observational, cross-sectional study. METHODS: Spectral-domain OCT (SD OCT) and swept-source OCT images from a consecutive series of 42 eyes in 22 patients with acute VKH who underwent steroid therapy and 20 healthy eyes in 20 volunteers were analyzed retrospectively. Correlations between best-corrected visual acuity (BCVA), axial length change, and OCT parameters were examined. The RPE undulation index was defined as RPE line length to the total scan length ratio on a foveal-centered scan in the SD OCT image. RESULTS: Eyes with acute VKH showed increased RPE undulation index, choroidal thickness, and retinal thickness compared to normal subjects, which were reduced following steroidal treatment (P < .0001, P = .0003, and P < .0001, respectively). RPE undulation index was related to choroidal thickness (r = 0.624, P = .0043), retinal thickness (r = 0.483, P = .0028), and BCVA (r = 0.588, P = .0002). Meanwhile, no statistically significant relationship was observed between choroidal thickness and retinal thickness. Axial length changes were significantly correlated with both choroidal thickness (r = 0.842, P < .0001) and RPE undulation index (r = 0.600, P = .0139). CONCLUSIONS: This study demonstrated that the choroid was diffusely undulated and bulged inward in eyes with acute VKH. Correlations between RPE undulation index and choroid morphology, retinal thickness, and poor BCVA suggest that choroidal folding, quantified by RPE undulation index, is useful in assessing VKH disease severity. PMID- 24491416 TI - Acute corneal hydrops in keratoconus - new perspectives. AB - PURPOSE: To summarize the current concepts and recent literature regarding the epidemiology, pathogenesis, imaging modalities, and treatment of acute hydrops in keratoconus. DESIGN: Perspective. METHODS: Review and synthesis of selected literature, with interpretation and perspective. RESULTS: Acute corneal hydrops is an incompletely understood complication of keratoconus, characterized by marked corneal edema caused by a break in Descemet membrane, allowing aqueous to enter the corneal stroma and epithelium. Although usually self-limiting, with clinical signs of edema typically resolving after 3 months, it often leaves a vision-impairing scar, necessitating and expediting the need for corneal transplantation. Studies have identified risk factors for developing acute hydrops. Modern imaging modalities such as ultrasound biomicroscopy, anterior segment optical coherence tomography, and in vivo confocal microscopy have enlightened us to the microstructural changes that take place during acute hydrops, the factors that influence its duration, and sequelae. Newer treatment regimens have seen a reduction in the duration of corneal edema during acute hydrops, and have improved the survival of corneal grafts after transplantation for resolved hydrops. CONCLUSIONS: Effective management of acute corneal hydrops in keratoconus is based on recognizing and addressing the risk factors, treating the acute event effectively and promptly to reduce the duration of edema and its complications, and, ultimately, successful corneal transplantation with acceptable long-term graft survival rates. Improved in vivo imaging of the cornea during acute hydrops has led to an enhanced understanding of the pathogenesis and ultrastructural changes of the condition, and in turn has resulted in improved management of the disease. PMID- 24491418 TI - Macular choroidal thickness and volume of eyes with reticular pseudodrusen using swept-source optical coherence tomography. AB - PURPOSE: To investigate the choroidal thickness/volume of eyes with reticular pseudodrusen using high-penetration swept-source optical coherence tomography (SS OCT) and to evaluate the choroidal vasculature changes using en face images. DESIGN: Prospective cross-sectional study. METHODS: Thirty-eight eyes with reticular pseudodrusen and 14 normal eyes were studied with prototype SS-OCT. Eyes with reticular pseudodrusen were classified into 3 subgroups: eyes without late age-related macular degeneration (AMD) (Group1), eyes with neovascular AMD (Group2), and eyes with geographic atrophy (Group3). Mean regional choroidal thickness/volume measurements were obtained by 3-dimensional (3D) raster scanning. The choroidal vascular area was measured using en face images reconstructed from a 3D SS-OCT data set. RESULTS: Mean age and axial length did not differ between eyes with reticular pseudodrusen and normal eyes. The mean choroidal thickness and volume of each sector was significantly reduced in eyes with reticular pseudodrusen compared with normal eyes (P < .020 for all). Mean choroidal thickness and volume of each area showed no significant difference between the 3 groups; however, most of them showed decreased thickness compared with normal eyes. En face images through the choroid revealed narrow and sparse choroidal vessels in eyes with reticular pseudodrusen. The area of choroidal vasculature was significantly reduced in eyes with reticular pseudodrusen compared with normal eyes (P = .037). CONCLUSIONS: In eyes with reticular pseudodrusen, macular choroidal thickness/volume was reduced regardless of choroidal neovascularization/geographic atrophy. Thinned vessels in the choroid suggest choroidal involvement in the pathogenesis of reticular pseudodrusen. PMID- 24491419 TI - Acute generalized pustular psoriasis, von Zumbusch type, treated in the burn unit. A review of clinical features and new therapeutics. AB - Generalized pustular psoriasis (GPP) is an immune-mediated dermatologic condition that is characterized by a widespread eruption of sterile, subcorneal pustules. Cases of GPP may present to the burn intensive care unit (ICU), and they may be confused with toxic epidermal necrolysis (TEN) due to the generalized erythema and desquamation. GPP often benefits from admission to an ICU for management of fluid and electrolyte imbalances and for complications such as pneumonitis, renal dysfunction and sepsis. We present the case of a 42 year-old man who was transferred to the burn unit for presumed TEN where he was diagnosed with GPP and successfully treated with intravenous cyclosporine and supportive care. Our objective is to increase awareness of this condition in the critical care community, discuss clinical and laboratory findings, and to review the treatment guidelines published by the National Psoriasis Foundation in August 2012. We also discuss the latest reports utilizing biological response modifying drugs. PMID- 24491417 TI - Risk factors associated with reticular pseudodrusen versus large soft drusen. AB - PURPOSE: To investigate genetic, environmental, and systemic risk factors in prospectively identified subjects with the age-related macular degeneration (AMD) phenotypes of (1) reticular pseudodrusen without large soft drusen and (2) large soft drusen without reticular pseudodrusen. DESIGN: Prospective case-case comparison. METHODS: In a clinical practice setting, patients with AMD were sequentially screened using clinical examination and scanning laser ophthalmoscopy imaging to prospectively identify subjects (n = 73) with the phenotypes of (1) reticular pseudodrusen without large soft drusen (n = 30) or (2) large soft drusen without reticular pseudodrusen (n = 43). Subjects were genotyped for 2 alleles associated with AMD, age-related maculopathy susceptibility 2 (ARMS2) and complement factor H (CFH). A questionnaire was administered to collect history of smoking, hypertension, diabetes, and hyperlipidemia, as well as personal and family history of AMD. RESULTS: The reticular pseudodrusen group was older (median age 87 vs 81 years, P = .04) and had more female subjects (83.3% vs 48.8%, P = .003), later ages of AMD onset (83 vs 70 years, P = .0005), and a greater frequency of hypertension (76.7% vs 55.8%, P = .08). No significant differences were found in the distribution of the ARMS2 risk allele (P = .4) between the reticular pseudodrusen (homozygous = 20.0%; heterozygous = 56.7%) and large soft drusen (homozygous = 19.0%; heterozygous = 42.9%) phenotypes, or in the distribution of the CHF risk allele (P = .7) between the reticular pseudodrusen (homozygous = 26.7%; heterozygous = 56.7%) and large soft drusen (homozygous = 21.4%; heterozygous = 66.7%) phenotypes. CONCLUSIONS: The reticular pseudodrusen phenotype was associated with increased age, later age of AMD onset, and female sex. PMID- 24491420 TI - Protective role of extracellular catalase (KatA) against UVA radiation in Pseudomonas aeruginosa biofilms. AB - One of the more stressful factors that Pseudomonas aeruginosa must face in nature is solar UVA radiation. In this study, the protective role of KatA catalase in both planktonic cells and biofilms of P. aeruginosa against UVA radiation was determined by using the wild-type (PAO1) and an isogenic catalase deficient strain (katA). The katA strain was more sensitive than the wild-type, especially in the case of biofilms. Moreover, the wild-type biofilm was more resistant than its planktonic counterpart, but this was not observed in the katA strain. Striking KatA activity was detected in the matrix of katA(+) strains, and to our knowledge, this is the first report of this activity in the matrix of P. aeruginosa biofilms. Provision of bovine catalase or KatA to the matrix of a katA biofilm significantly increased its UVA tolerance, demonstrating that extracellular KatA is essential to optimal defense against UVA in P. aeruginosa biofilms. Efficiency of photocatalytic treatments using TiO2 and UVA was lower in biofilms than in planktonic cells, but KatA and KatB catalases seem not to be responsible for the higher resistance of the sessile cells to this treatment. PMID- 24491421 TI - In vitro and in vivo photoprotective/photochemopreventive potential of Garcinia brasiliensis epicarp extract. AB - The damaging effects of sunlight to the skin has triggered studies that involve the synthesis and extraction of organic compounds from natural sources that can absorb UV radiation, and studies on polyphenolic compounds with antioxidant and anti-inflammatory properties that can be used as photochemopreventive agents for reducing skin damage. We investigated the in vitro and in vivo photoprotective/photochemopreventive potential of Garcinia brasiliensis epicarp extract (GbEE). We evaluated the cell viability of L929 fibroblasts after UVB exposure using a quartz plate containing the extract solution or the GbEE formulation. The in vivo photoprotective effect of the GbEE formulation was evaluated by measuring the UVB damage-induced decrease in endogenous reduced glutathione (GSH), the increase in myeloperoxidase (MPO) activity and secretion of cytokines IL-1beta and TNF-alpha. The in vitro methodology using fibroblasts showed that the photoprotective properties of the GbEE solutions and 10% GbEE formulation were similar to the commercial sunscreen (SPF-15). In vivo results demonstrated of the GbEE formulation in decreasing UVB induced-damage such as GSH depletion, an increased in MPO activity and secretion of cytokines IL-1beta and TNF-alpha. The results showed that the extract has great potential for use as a sunscreen in topical formulations in addition to UV filters. PMID- 24491422 TI - Comorbid Abeta toxicity and stroke: hippocampal atrophy, pathology, and cognitive deficit. AB - Numerous clinical and epidemiological reports indicate that patients with history of vascular illness such as stroke are more likely to develop dementia as the clinical manifestation of Alzheimer's disease. However, there are little data regarding the pathologic mechanisms that link vascular risk factors to the factors associated with dementia onset. We provide evidence that suggests intriguing detrimental interactions between stroke and beta-amyloid (Abeta) toxicity in the hippocampus. Stroke was induced by unilateral striatal injection of endothelin-1, the potent vasoconstrictor. Abeta toxicity was modeled by bilateral intracerebroventricular injections of the toxic fragment Abeta. Gross morphologic changes in comorbid Abeta and stroke rats were enlargement of the lateral ventricles with concomitant shrinkage of the hippocampus. The hippocampus displayed a series of synergistic biochemical alterations, including microgliosis, deposition of Abeta precursor protein fragments, and cellular degeneration. In addition, there was bilateral induction of connexin43, reduced neuronal survival, and impaired dendritic development of adult-born immature neurons in the dentate gyrus of these rats compared with either rats alone. Behaviorally, there was impairment in the hippocampal-based discriminative fear conditioning to context task indicating learning and memory deficit. These results suggest an insight into the relationship between hippocampal atrophy, pathology, and functional impairment. Our work not only highlights the exacerbated pathology that emerges when Abeta toxicity and stroke occur comorbidly but also demonstrates that this comorbid rat model exhibits physiopathology that is highly characteristic of the human condition. PMID- 24491423 TI - Grounding models in empirical data of language socialisation: Comment on "Modelling language evolution: Examples and predictions" by Gong, Shuai and Zhang. PMID- 24491424 TI - The role of action semantics in action control: Comment on "Action semantics: A unifying conceptual framework for the selective use of multimodal and modality specific object knowledge" by Michiel van Elk, Hein van Schie and Harold Bekkering. PMID- 24491425 TI - Absence of tissue factor is characteristic of lymphoid malignancies of both T- and B-cell origin. AB - BACKGROUND: Thrombosis is a marker of poor prognosis in individuals with solid tumors. The expression of tissue factor (TF) on the cell surface membrane of malignant cells is a pivotal molecular link between activation of coagulation, angiogenesis, metastasis, aggressive tumor behavior and poor survival. Interestingly, thrombosis is associated with shortened survival in solid, but not in lymphoid neoplasias. OBJECTIVES: We sought to study whether the lack of impact of thrombosis on survival in lymphoid neoplasias could be due to a lack of tumor derived TF expression. METHODS: We analyzed TF gene (F3) expression in lymphoid (N=114), myeloid (N=49) and solid tumor (N=856) cell lines using the publicly available dataset from the Broad-Novartis Cancer Cell Line Encyclopedia (http://www.broadinstitute.org/ccle/home), and in 90 patient-derived lymphoma samples. TF protein expression was studied by immunohistochemistry (IHC). RESULTS: In sharp contrast to wide F3 expression in solid tumors (74.2%), F3 was absent in all low and high grade T- and B-cell lymphomas, and in most myeloid tumors, except for select acute myeloid leukemias with monocytic component. IHC confirmed the absence of TF protein in all indolent and high-grade B-cell (0/90) and T-cell (0/20) lymphomas, and acute leukemias (0/11). CONCLUSIONS: We show that TF in lymphomas does not derive from the malignant cells, since these do not express either F3 or TF protein. Therefore, it is unlikely that thrombosis in patients with lymphoid neoplasms is secondary to tumor-derived tissue factor. PMID- 24491426 TI - Effects of wastewater microalgae harvesting methods on polyhydroxybutyrate production. AB - Microalgae have gained considerable attention recently as a sustainable means to produce biofuels and bioproducts. It has previously been demonstrated that single strain microalgae can be harvested and processed through a wet lipid extraction procedure (WLEP). After WLEP processing, acetone, butanol, ethanol, and biodiesel can be produced, and growth of recombinant Escherichia coli can be achieved from the microalgae. This study demonstrates the application of different wastewater microalgae harvesting techniques and processing through WLEP on the production of polyhydroxybutyrate (PHB) by E. coli. The harvesting techniques include: cationic potato starch (CPS), cationic corn starch (CCS), aluminum sulfate, and centrifugation. The microalgae-based media were used to grow E. coli to ~10(13)CFU/mL and produce approximately 7.8% of dry cell weight as PHB. This study demonstrates the feasibility of harvesting wastewater algae to produce PHB and the potential for bioproduct generation. PMID- 24491427 TI - IFI16 mis-localization can be a contributing factor to hepatocellular carcinoma progression. AB - Hepatocellular carcinoma (HCC) is a highly deadly cancer, with usually drug resistance. However the mechanisms responsible for this phenomenon are poorly understood. Interferon-gamma inducible protein 16 (IFI16), a multifunctional protein, has roles in anti-proliferation, autophagy, cell senescence, anti inflammation, and DNA sensor to trigger innate immunity. IFI16 physiologically absents in adult healthy hepatocyte, but exists in liver cancer cells. Interestingly, increasing evidences suggest that dysregulation or/and loss of IFI16 function have a critical role in drug resistance and tumor progression. Furthermore, interaction with DNA or other protein depends on IFI16 localization. In our study, to our knowledge, we first showed that IFI16 is a chromatin-binding protein in four HCC cell lines with different TP53 genotype, but not in fetal liver cell line, L02 cells. However, the function of IFI16 subcellular localization has not been determined in HCC. Therefore, we present our study and theoretical basis and presume that chromatin-bounding localization of IFI16 is associated with HCC progression. If we are able to acetylate or/and delete NLS of IFI16 with activated-p53 restoration, we may offer an alternative for HCC therapy. PMID- 24491428 TI - 6R-l-erythro-5,6,7,8-tetrahydrobiopterin (BH4): a potential treatment for all symptom domains of schizophrenia. AB - Current psychopharmacological treatment of schizophrenia is suboptimal and the available antipsychotic medications have little or no effect on negative and cognitive symptom domains of the disorder. 6R-l-erythro-5,6,7,8 tetrahydrobiopterin (BH4) is a cofactor involved in the synthesis of dopamine, serotonin and nitric oxide which have all been implicated in the pathophysiology of schizophrenia. BH4 may potentiate dopaminergic neurotransmission via mechanisms independent of dopamine biosynthesis. BH4 may also potentiate NMDA neurotransmission through its cofactor effect on nitric oxide synthase (NOS). The hypothesis being advanced is that BH4 will be effective in treating all symptom domains of schizophrenia. The hypothesis is based on the findings of: (1) reduced BH4 levels in schizophrenia patients; (2) negative and cognitive symptoms of schizophrenia are related to reduced dopamine neurotransmission in some parts of the brain and BH4 may correct this abnormality by potentiating dopaminergic neurotransmission in these brain regions; (3) there is reduced cellular expression of neuronal NOS in certain brain regions of schizophrenia patients relative to healthy controls, an abnormality which may be corrected via BH4 cofactor effect on NOS; (4) there is increased neuroinflammation in schizophrenia, and BH4 may be anti-inflammatory; (5) schizophrenia is associated with hyperphenyalaninemia (which maybe neurotoxic) and BH4 has clinical utility in normalizing phenylalanine levels. Confirming this hypothesis would advance the knowledge of the pathophysiology of schizophrenia and also meet a significant treatment need in the overall management of this severe and chronic illness. PMID- 24491429 TI - Comprehensive DNA methylation analysis of human neuroblastoma cells treated with blonanserin. AB - Blonanserin is a second-generation antipsychotic drug for schizophrenia. The pharmacological actions of blonanserin are shown to be the antagonism of dopamine receptor 2 and serotonin receptors. However, its molecular mechanisms in brain cells have not been fully characterized. Accumulating evidence suggests that antipsychotic drugs and mood stabilizers show epigenetic effects on a wide range of genes in animal and cellular models. We performed genome-wide DNA methylation analysis targeting 479,814 CpG sites of cultured human neuroblastoma cells administered with blonanserin. We found that 3,057 CpG sites showed statistically significant changes in DNA methylation at two different doses of blonanserin (1.36 nM and 13.6 nM). These included hypermethylated CpG sites that were enriched in genes related to axonogenesis and cell morphogenesis involved in neuron differentiation. We also showed that the global effect on DNA methylome depends on the concentration of the drug. With a high dose of blonanserin, the overall methylation levels across all CpG sites significantly increased. These increases in DNA methylation were prominent in the CpG sites distant from promoter regions. We further examined DNA methylation changes in specific genes implicated for the actions of antipsychotic drugs, such as the dopamine receptor 2 (DRD2) gene and the serotonin receptor 2A (HTR2A) gene. We observed that CpG sites that were located within DRD2 and HTR2A genes were significantly hypermethylated by blonanserin. The DNA methylation changes induced by the treatment with blonanserin will be useful for understanding its pharmacological actions at the cellular level. PMID- 24491430 TI - Hippocampal cystathionine beta synthase in young and aged mice. AB - Cystathionine beta synthase (CBS) is the main contributor to the production of hydrogen sulfide (H2S) in the brain. Exogenously administered H2S has been reported to protect neurons against hypoxic injury, ischemia and LPS-induced neuro-inflammation and in the facilitating of long term potentiation (LTP). Dysregulation of CBS leads to different diseases, which all have mental retardation in common. Although multiple studies have implicated a link between the CBS/H2S pathway and neurodegeneration, no studies have been performed examining the pathway in healthy aging animals. We hypothesize that CBS/H2S pathway plays an important role in the protection of learning and memory functions in the brain at the level of the hippocampus. Thus, we studied a set of 8 young (4 months) and 14 aged (24 months (n=6) and 28 months (n=8)) C57Bl6 mice. The 24-month-old mice displayed a significant decrease of CBS immunoreactivity in the MoDG only, compared to 4-month-old mice. In 28-month-old mice, we observed a significant increase of CBS immunoreactivity in the MoDG, compared to 4-month-old mice. When comparing 28-month-old mice to 24-month-old mice, all areas showed a significant increase of CBS immunoreactivity. Thus, throughout aging, CBS expression is maintained in the hippocampus, and many other forebrain regions as well. Mice at the unusual age of 28 months even have a higher hippocampal CBS expression than young mice. Maintenance (and increase) of CBS levels may sustain memory and learning by precluding neuronal loss in areas of the hippocampus. PMID- 24491431 TI - Association of genetic variants with anti-tuberculosis drug induced hepatotoxicity: a high resolution melting analysis. AB - BACKGROUND: Tuberculosis (TB) treatment remains a challenge owing to the high incidence of drug induced hepatotoxicity (DIH). Apart from environmental factors, single nucleotide polymorphisms (SNPs) in drug metabolizing enzymes (DMEs), nuclear receptors (NRs) and transporter proteins (TPs) contribute to DIH. In the present study, we report known and novel SNPs in a total of seven genes of DMEs, NRs and TPs with high resolution melting (HRM) technique. METHODS: DNA samples of 185 TB patients of Western Indian population, of which 50 showed DIH, were analyzed. Grouping of the temperature-shifted difference plots obtained from the DNA melt curves enables identification of known and novel SNPs. Representative samples of each group were sequenced. RESULTS: We report 18 novel SNPs, of which 3 are in 5'-UTR, 14 in exonic and 1 in intronic region. Of the SNPs in exons, 7 non-synonymous, 3 synonymous and 4 deletion mutations were observed. Among the known SNPs, CYP2E1 wild-type, NAT2(*)5 mutant and NAT2(*)6 heterozygous genotypes were associated with DIH (p<0.05). Among the novel SNPs, group 2 of SLCO1B1 showed a significant association (p<0.05). CONCLUSIONS: While several SNPs showed borderline p values between 0.05 and 0.15, the confidence in association can be improved further by using larger data sets. PMID- 24491432 TI - [Deep brain recording and length of surgery in stereotactic and functional neurosurgery for movement disorders]. AB - OBJECTIVE: Our objectives were to study the length of multi-unit recordings (MURs) of brain activity in 20 years of movement disorder neurosurgeries and to determine the number of times in which it was necessary for the teams using single-unit recording (SUR) to explore all the electrode tracks in the simultaneously recorded sites (SRS). MATERIAL AND METHOD: This was a retrospective descriptive statistical analysis of MUR length on 4,296 tracks in 952 surgeries. The exclusion criteria were: tracks with fewer than 5 recorded signals, tracks that had a signal length different from the habitual 2s, or there being unusual situations not related to the MUR, as well as the first 20 surgeries of each surgical target. This yielded a total of 3,448 tracks in 805 surgeries. We also determined the number of the total 952 surgeries in which all the tracks in the SURs of the SRS were explored. RESULTS: The mean and its confidence interval (P=.05) of time per MUR track were 5.49+/-0.16min in subthalamic nucleus surgery, 8.82+/-0.24min in the medial or internal globus pallidus) and 18.51+/-1.31min in the ventral intermediate nucleus of the thalamus. For the total sum of tracks per surgery, in 75% of cases the total time was less than 39min in subthalamic nucleus, almost 42min in the medial or internal globus pallidus and less than 1h and 17min in ventral intermediate nucleus of the thalamus. All the tracks in the SUR SRS were explored in only 4.2% of the surgeries. CONCLUSIONS: The impact of MUR on surgical time is acceptable for this guide in objective localization for surgical targets, without having to use several simultaneous electrodes (not all indispensable in most of the cases). Consequently, there is less risk for the patient. PMID- 24491433 TI - The organization of prospective thinking: evidence of event clusters in freely generated future thoughts. AB - Recent research suggests that many imagined future events are not represented in isolation, but instead are embedded in broader event sequences-referred to as event clusters. It remains unclear, however, whether the production of event clusters reflects the underlying organizational structure of prospective thinking or whether it is an artifact of the event-cuing task in which participants are explicitly required to provide chains of associated future events. To address this issue, the present study examined whether the occurrence of event clusters in prospective thought is apparent when people are left to think freely about events that might happen in their personal future. The results showed that the succession of events participants spontaneously produced when envisioning their future frequently included event clusters. This finding provides more compelling evidence that prospective thinking involves higher-order autobiographical knowledge structures that organize imagined events in coherent themes and sequences. PMID- 24491434 TI - A broad assessment of theory of mind in adolescence: the complexity of mindreading. AB - The aim of this research was to provide an articulated assessment of several different ToM components, namely first- vs. third-person, egocentric vs. allocentric, and first- vs. second-order ToM, in preadolescence and adolescence. Our expectations for the sample of 80 juveniles that participated in the research were that: (1) ToM abilities would improve with age; (2) participants would perform better at first-person than at third-person tasks; (3) participants would perform better at first-order than at second-order tasks; (4) girls will perform systematically better than boys. We also explored possible differences in performance (5) in the allocentric vs. the egocentric perspectives as well as (6) in the comprehension of different types of mental states, namely desires, beliefs and positive and negative emotions. Overall our expectations were confirmed. Our data confirmed that all ToM aspects we investigated keep maturing during preadolescence and adolescence. PMID- 24491435 TI - Blocking of corticotrophin releasing factor receptor-1 during footshock attenuates context fear but not the upregulation of prepro-orexin mRNA in rats. AB - Hypothalamic neuropeptides called orexins (hypocretins) are well known for their roles in promoting arousal. Orexins have also been shown to play a role in fear and anxiety produced by the exposure of rats to an acute episode of moderately intense footshocks. Recent evidence indicates that stress activates orexin neurons through a corticotropin releasing factor (CRF) mechanism. In this study, we examined the effect of a CRF receptor-1 (CRF-R1) antagonist antalarmin (20mg/kg, i.p.) given before shock exposure on subsequent expression of contextual fear and the levels of prepro-orexin (ppOX) mRNA in the hypothalamus. Antalarmin decreased fear and ultrasonic vocalization expression to the shock context at 2 and 10 days after shock exposure. However, antalarmin did not prevent the increases in ppOX mRNA produced by the shock experience. This study provides evidence that blocking of CRF-R1 at the time of footshocks attenuates contextual fear. While an increase in the activity of the orexin system may contribute to fear, this activation does not appear to be sufficient for fear expression. PMID- 24491436 TI - Adolescent traumatic stress experience results in less robust conditioned fear and post-extinction fear cue responses in adult rats. AB - Early exposure to a traumatic event may produce lasting effects throughout the lifespan. Traumatic stress during adolescence may deliver a distinct developmental insult compared with more-often studied neonatal or juvenile traumatic stress paradigms. The present study describes the lasting effects of adolescent traumatic stress upon adulthood fear conditioning. Adolescent rats were exposed to a traumatic stressor (underwater trauma, UWT), then underwent fear conditioning during adulthood. Fear extinction was tested over five conditioned suppression extinction sessions three weeks later. The efficacies of two potential extinction-enhancing compounds, endocannabinoid reuptake inhibitor AM404 (10mg/kg) and M1 muscarinic positive allosteric modulator BQCA (10mg/kg), were also assessed. Finally, post-extinction fear responses were examined using a fear cue (light) as a prepulse stimulus. Rats traumatically stressed during adolescence showed blunted conditioned suppression on day 1 of extinction training, and AM404 reversed this effect. Post-extinction startle testing showed that fear conditioning eliminates prepulse inhibition to the light cue. Startle potentiation was observed only in rats without adolescent UWT exposure. AM404 and BQCA both ameliorated this startle potentiation, while BQCA increased startle in the UWT group. These results suggest that exposure to a traumatic stressor during adolescence alters developmental outcomes related to stress response and fear extinction compared to rats without adolescent traumatic stress exposure, blunting the adulthood fear response and reducing residual post-extinction fear expression. Efficacy of pharmacological interventions may also vary as a factor of developmental traumatic stress exposure. PMID- 24491437 TI - Diffuse plane normolipemic xanthoma associated with chronic myelomonocytic leukemia-1. PMID- 24491440 TI - Study of Methylene Blue adsorption on keratin nanofibrous membranes. AB - In this work, keratin nanofibrous membranes (mean diameter of about 220nm) were prepared by electrospinning and tested as adsorbents for Methylene Blue through batch adsorption tests. The adsorption capacity of the membranes was evaluated as a function of initial dye concentration, pH, adsorbent dosage, time and temperature. The adsorption capacity increased with increasing the initial dye concentration and pH, while it decreased with increasing the adsorbent dosage and temperature, indicating an exothermic process. The adsorption results indicated that the Langmuir isotherm fitted the experimental data better than the Freundlich and Temkin isotherm models. A mean free energy evaluated through the Dubinin-Radushkevich model of about 16kJmol(-1), indicated a chemisorption process which occurred by ion exchange. The kinetic data were found to fit the pseudo-second-order model better than the pseudo-first-order model. The obtained results suggest that keratin nanofibrous membranes could be promising candidates as dye adsorption filters. PMID- 24491439 TI - Photochemical decomposition of perfluorooctanoic acid mediated by iron in strongly acidic conditions. AB - The performance of a ferric ion mediated photochemical process for perfluorooctanoic acid (PFOA) decomposition in strongly acidic conditions of pH 2.0 was evaluated in comparison with those in weakly acidic conditions, pH 3.7 or pH 5.0, based on iron species composition and ferric ion regeneration. Complete decomposition of PFOA under UV irradiation was confirmed at pH 2.0, whereas perfluoroheptanoic acid (PFHpA) and other intermediates were accumulated in weakly acidic conditions. Iron states at each pH were evaluated using a chemical equilibrium model, Visual MINTEQ. The main iron species at pH 2.0 is Fe(3+) ion. Although Fe(3+) ion is consumed and is transformed to Fe(2+) ion by photochemical decomposition of PFOA and its intermediates, the produced Fe(2+) ion will change to Fe(3+) ion to restore chemical equilibrium. Continuous decomposition will occur at pH 2.0. However, half of the iron cannot be dissolved at pH 3.7. The main species of dissolved iron is Fe(OH)(2+). At pH 3.7 or higher pH, Fe(3+) ion will only be produced from the oxidation of Fe(2+) ion by hydroxyl radical produced by Fe(OH)(2+) under UV irradiation. These different mechanisms of Fe(3+) regeneration that prevail in strongly and weakly acidic conditions will engender different performances of the ferric ion. PMID- 24491438 TI - Essential role of the linear ubiquitin chain assembly complex in lymphoma revealed by rare germline polymorphisms. AB - Constitutive activation of NF-kappaB is a hallmark of the activated B cell-like (ABC) subtype of diffuse large B-cell lymphoma (DLBCL), owing to upstream signals from the B-cell receptor (BCR) and MYD88 pathways. The linear polyubiquitin chain assembly complex (LUBAC) attaches linear polyubiquitin chains to IkappaB kinase gamma, a necessary event in some pathways that engage NF-kappaB. Two germline polymorphisms affecting the LUBAC subunit RNF31 are rare among healthy individuals (~1%) but enriched in ABC DLBCL (7.8%). These polymorphisms alter RNF31 alpha-helices that mediate binding to the LUBAC subunit RBCK1, thereby increasing RNF31-RBCK1 association, LUBAC enzymatic activity, and NF-kappaB engagement. In the BCR pathway, LUBAC associates with the CARD11-MALT1-BCL10 adapter complex and is required for ABC DLBCL viability. A stapled RNF31 alpha helical peptide based on the ABC DLBCL-associated Q622L polymorphism inhibited RNF31-RBCK1 binding, decreased NF-kappaB activation, and killed ABC DLBCL cells, credentialing this protein-protein interface as a therapeutic target. SIGNIFICANCE: We provide genetic, biochemical, and functional evidence that the LUBAC ubiquitin ligase is a therapeutic target in ABC DLBCL, the DLBCL subtype that is most refractory to current therapy. More generally, our findings highlight the role of rare germline-encoded protein variants in cancer pathogenesis. PMID- 24491441 TI - Improving the treatment of non-aqueous phase TCE in low permeability zones with permanganate. AB - Treating dense non-aqueous phase liquids (DNAPLs) embedded in low permeability zones (LPZs) is a particularly challenging issue for injection-based remedial treatments. Our objective was to improve the sweeping efficiency of permanganate (MnO4(-)) into LPZs to treat high concentrations of TCE. This was accomplished by conducting transport experiments that quantified the penetration of various permanganate flooding solutions into a LPZ that was spiked with non-aqueous phase (14)C-TCE. The treatments we evaluated included permanganate paired with: (i) a shear-thinning polymer (xanthan); (ii) stabilization aids that minimized MnO2 rind formation and (iii) a phase-transfer catalyst. In addition, we quantified the ability of these flooding solutions to improve TCE destruction under batch conditions by developing miniature LPZ cylinders that were spiked with (14)C-TCE. Transport experiments showed that MnO4(-) alone was inefficient in penetrating the LPZ and reacting with non-aqueous phase TCE, due to a distinct and large MnO2 rind that inhibited the TCE from further oxidant contact. By including xanthan with MnO4(-), the sweeping efficiency increased (90%) but rind formation was still evident. By including the stabilization aid, sodium hexametaphosphate (SHMP) with xanthan, permanganate penetrated 100% of the LPZ, no rind was observed, and the percentage of TCE oxidized increased. Batch experiments using LPZ cylinders allowed longer contact times between the flooding solutions and the DNAPL and results showed that SHMP+MnO4(-) improved TCE destruction by ~16% over MnO4(-) alone (56.5% vs. 40.1%). These results support combining permanganate with SHMP or SHMP and xanthan as a means of treating high concentrations of TCE in low permeable zones. PMID- 24491443 TI - Effects of the oxidation degree of graphene oxide on the adsorption of methylene blue. AB - In this current work, a series of graphene oxides (GO) with different oxidation degrees (OD) was prepared using Hummer method. Fundamental adsorption behavior of the GO series for removal of methylene blue (MB) from aqueous solutions has been studied. The GO series shows an overall fast and pH-independent MB adsorption, which is even capable of removing trace levels of dye completely from very dilute solutions. Furthermore, the effects of the oxidation degree (OD) on MB adsorption behavior have been investigated systematically, indicating that the dye uptakes of GO exponentially increase with the increase of OD. Further study on the adsorption mechanism shows that adsorption behavior of GO would change from a Freundlich-type to a Langmuir-type adsorption as the OD increases. It may be due to both the enhanced exfoliation degree of the carbon planes in graphite caused by oxidation and the production of more active adsorption sites. The binding features of the MB loaded GO gradually change from MB molecule parallel stacking on graphite plane through hydrophobic pi-pi interaction to vertical standing via electrostatic interaction with increasing OD, resulting in a significant improvement of MB uptakes. In addition, the adsorption capacity of the regenerated GO has little loss until four cycles. PMID- 24491442 TI - Recycling indium from waste liquid crystal display panel by vacuum carbon reduction. AB - This study investigated the recovery of indium from waste liquid crystal display (LCD) panel using vacuum carbon-reduction. First of all, high purity In2O3 was investigated. The results indicated that indium can be reclaimed from In2O3 using vacuum carbon-reduction in thermodynamics and dynamics. The conditions of 1223K, 50wt% carbon addition, 30min, and 1Pa were confirmed as the optimal conditions for pure In2O3 and high purity indium could be selectively recovered on condensing zone. Based on this, the experiment of the recovery of indium from waste LCD power was performed. The best parameters were confirmed as 1223K and 1Pa with 30wt% carbon addition for 30min. The recovery rate of indium from LCD powder could reach to 90wt%. No hazardous materials produced in this process. Therefore, this technique provides the possibility of reutilization of LCD in an environmentally friendly way. PMID- 24491444 TI - Synthesis and site-directed fluorescence labeling of azido proteins using eukaryotic cell-free orthogonal translation systems. AB - Eukaryotic cell-free systems based on wheat germ and Spodoptera frugiperda insect cells were equipped with an orthogonal amber suppressor tRNA-synthetase pair to synthesize proteins with a site-specifically incorporated p-azido-l-phenylalanine residue in order to provide their chemoselective fluorescence labeling with azide reactive dyes by Staudinger ligation. The specificity of incorporation and bioorthogonality of labeling within complex reaction mixtures was shown by means of translation and fluorescence detection of two model proteins: beta glucuronidase and erythropoietin. The latter contained the azido amino acid in proximity to a signal peptide for membrane translocation into endogenous microsomal vesicles of the insect cell-based system. The results indicate a stoichiometric incorporation of the azido amino acid at the desired position within the proteins. Moreover, the compatibility of cotranslational protein translocation, including glycosylation and amber suppression-based incorporation of p-azido-l-phenylalanine within a cell-free system, is demonstrated. The presented approach should be particularly useful for providing eukaryotic and membrane-associated proteins for investigation by fluorescence-based techniques. PMID- 24491445 TI - Gold nanostructures for the multiplex detection of glucose-6-phosphate dehydrogenase gene mutations. AB - We describe a gold nanoparticle-based technique for the detection of single-base mutations in the glucose-6-phosphate dehydrogenase (G6PD) gene, a condition that can lead to neonatal jaundice and hemolytic anemia. The aim of this technique is to clearly distinguish different mutations frequently described within the Asian population from their wild-type counterparts and across different mutant variants. Gold nanoparticles of different sizes were synthesized, and each was conjugated with a single-strand DNA (ssDNA) sequence specific for a particular mutation in the G6PD gene. It was found that only mutant targets presented a characteristic band on the agarose gel, indicating the successful formation of dimeric nanostructures. No such dimer bands were observed for the wild-type targets. The difference in the relative dimer band levels allowed different mutant variants to be distinguished from one another. The technique was further validated using G6PD-deficient patient samples. This simple mutation detection method with direct result readout is amenable for rapid and mass screening of samples. PMID- 24491446 TI - Influence of atmospheric pressure on infrarenal abdominal aortic aneurysm rupture. AB - BACKGROUND: Meteorologic conditions have a significant impact on the occurrence of cardiovascular events. Previous studies have shown that abdominal aortic aneurysm rupture (AAAR) may be associated with atmospheric pressure, with conflicting results. Therefore, we aimed to further investigate the nature of the correlation between atmospheric pressure variations and AAAR. METHOD: Hospital admissions related to AAAR between 2005-2009 were assessed in 19 districts of metropolitan France and correlated with geographically and date-matched mean atmospheric pressures. In parallel and from 2005-2009, all fatal AAARs as reported by death certificates were assessed nationwide and correlated to local atmospheric pressures at the time of aortic rupture. RESULTS: Four hundred ninety four hospital admissions related to AAAR and 6,358 deaths nationwide by AAAR were identified between 2005-2009. Both in-hospital ruptures and aneurysm-related mortality had seasonal variations, with peak/trough incidences in January and June, respectively. Atmospheric pressure peaks occurred during winter. Univariate analysis revealed a significant association (P < 0.001) of high mean atmospheric pressure values and AAAR. After multivariate analysis, mean maximum 1-month prerupture atmospheric pressure had a persistent correlation with both in hospital relative risk (1.05 [95% confidence interval: 1.03-1.06]; P < 0.0001) and aneurysm rupture-related mortality relative risk (1.02 [95% confidence interval: 1.01-1.03]; P < 0.0001). CONCLUSION: The annual incidence of AAAR is nonhomogeneous with a peak incidence in winter, and is independently associated with mean maximum 1-month prerupture atmospheric pressure. PMID- 24491447 TI - Impact of hospital-acquired infection on long-term outcomes after endovascular and open abdominal aortic aneurysm repair. AB - BACKGROUND: We hypothesized that infectious complications after open surgery (OPEN) and endovascular repair (EVAR) of nonruptured abdominal aortic aneurysms (AAAs) negatively affected long-term outcomes. METHODS: Elective OPEN and EVAR cases were selected from 2005-2007 Medicare databases, and rates of postoperative infection, readmission, and longitudinal mortality were compared. RESULTS: Forty thousand eight hundred ninety-two EVARs and 16,669 OPEN AAA repairs were evaluated. Patients with OPEN developed infection during and after the index hospitalization (12.8% and 4.9%, respectively) more often than those who had undergone EVAR (3.2% and 3.9%, respectively; P < 0.0001 for both). Patients with hospital-acquired infection compared to noninfectious ones were more likely to die during the index hospitalization (odds ratio [OR]: 3.7 [95% confidence interval {CI}: 3.22-4.30]) and within 30 days after discharge (OR: 3.6 [95% CI: 2.83-4.45]). They also were more likely to be readmitted to the hospital during 30 days after index discharge (OR: 1.8 [95% CI: 1.63-1.94]). Index infections associated with the greatest readmission were urinary tract infection after OPEN and sepsis after EVAR. Hospital-acquired infection significantly increased the duration of hospital stay (14.2 +/- 13.2 vs 4.0 +/- 4.4 days; P < 0.0001) and total hospital charges ($133,070 +/- $136,100 vs $66,359 +/- $45,186; P < 0.0001). The most common infections to develop 30 days after initial discharge were surgical site infection after EVAR (1.27%) and urinary tract infection after OPEN (1.38%). CONCLUSION: Hospital-acquired infections had a dramatic effect by increasing hospital and 30-day mortality, readmission rates, and hospital resource use after AAA repair. Programs minimizing infectious complications may decrease future readmissions and mortality after AAA repair. PMID- 24491448 TI - Diagnostic imaging in carotid artery dissection: a case report and review of current modalities. AB - BACKGROUND: This case report presents the challenges associated with the existing screening modalities in the diagnosis of carotid artery dissection, and also reviews the diagnostic efficiency, limitations, and recent advances in imaging technology. CASE PRESENTATION: A 54-year-old man with blunt trauma and subsequent development of ischemic stroke and no clear initial evidence of carotid dissection with noninvasive screening, including magnetic resonance imaging, magnetic resonance angiography, and computed tomography angiography. CONCLUSIONS: Despite emerging noninvasive imaging techniques, conventional angiography should still be considered to establish a diagnosis of carotid artery dissection, particularly when other imaging modalities are negative or inconclusive but a high degree of clinical suspicion exists based on symptoms or mechanism of injury. PMID- 24491449 TI - The role of key genes and pathways involved in the tumorigenesis of Malignant Mesothelioma. AB - Malignant Mesothelioma (MM) is a very aggressive cancer with low survival rates and often diagnosed at an advanced stage. Several players have been implicated in the development of this cancer, such as asbestos, erionite and the simian virus 40 (SV40). Here, we have reviewed the involvement of erionite, SV40, as well as, the role of several genes (p16(INK4a), p14(ARF), NF2, LATS2, SAV, CTNNB1 and among others), the pathways (RAS, PI3K, Wnt, BCL and Hippo), and their respective roles in the development of MM. PMID- 24491450 TI - Reply of the authors. PMID- 24491451 TI - Luteal phase support for frozen embryo transfer cycles: intramuscular or vaginal progesterone? PMID- 24491452 TI - Value of antimullerian hormone as a prognostic indicator of in vitro fertilization outcome. AB - OBJECTIVE: To determine the predictive attributes of antimullerian hormone (AMH) in terms of oocyte yield, cycle cancellation, and pregnancy outcomes. DESIGN: Retrospective cohort. SETTING: Academic center. PATIENT(S): All patients initiating IVF at the Weill-Cornell Ronald O. Perelman and Claudia Cohen Center for Reproductive Medicine from April 2010 through January 2013. INTERVENTION(S): In vitro fertilization without preimplantation genetic testing. MAIN OUTCOME MEASURE(S): Number of oocytes retrieved, cycle cancellation, clinical and ongoing pregnancy, implantation, and miscarriage rates. RESULT(S): Antimullerian hormone was positively correlated with number of eggs retrieved. Number of oocytes retrieved increased with increasing AMH within each age group and diminished slightly within AMH groupings as age increased. Overall, AMH was significantly correlated with risk of cycle cancellation, with an area under the curve (AUC) of 0.74. Patients with undetectable AMH had a 13.3-fold increased risk of cancellation as compared with patients with an AMH >2.0 ng/mL. Antimullerian hormone had an AUC of 0.83 for prediction of three or fewer oocytes; undetectable AMH exhibited sensitivity and specificity of 21.1% and 98.2%, respectively, for three or fewer oocytes retrieved. Antimullerian hormone was less predictive of pregnancy, with AUCs ranging from 0.55 to 0.65. Even with undetectable AMH, 23.5% of patients <40 years old achieved live birth after transfer. CONCLUSION(S): Antimullerian hormone is a fairly robust metric for the prediction of cancellation and how many oocytes may be retrieved after stimulation but is a relatively poor test for prediction of pregnancy after any given treatment cycle. Patients with extremely low levels of AMH still can achieve reasonable treatment outcomes and should not be precluded from attempting IVF solely on the basis of an AMH value. PMID- 24491453 TI - The postreproductive salpingectomy. PMID- 24491454 TI - Daily physical activity and hot flashes in the Study of Women's Health Across the Nation (SWAN) Flashes Study. AB - OBJECTIVE: To examine the role of physical activity in menopausal hot flashes. DESIGN: Physiologic hot flash monitor and activity monitor over two 48-hour periods, with self-report in an electronic diary. SETTING: Community. PATIENT(S): 51 midlife women. INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): Physiologically detected hot flashes and reported hot flashes with and without physiologic corroboration. RESULT(S): Competing models conceptualize physical activity as a risk or protective factor for hot flashes, but few studies have examined this relationship prospectively using physiologic measures of hot flashes and physical activity. When physiologic hot flashes, reported hot flashes, and reported hot flashes without physiologic corroboration were related to activity changes using hierarchic generalized linear modeling, adjusting for potential confounders, hot flash reports without physiologic corroboration were more likely after activity increases, particularly among women with higher levels of depressive symptoms. No other types of hot flashes were related to physical activity. CONCLUSION(S): Acute increases in physical activity were associated with increased reporting of hot flashes that lacked physiologic corroboration, particularly among women with depressive symptoms. Clinicians should consider the role of symptom perception and reporting in relations between physical activity and hot flashes. PMID- 24491455 TI - Breast lymphoma combined with postoperative acute hematopoietic disorder in an immediate breast reconstruction patient. PMID- 24491456 TI - An alternative tendon lengthening technique. PMID- 24491457 TI - Supermicrosurgical free sensate intercostal artery perforator flap based on the lateral cutaneous branch for plantar reconstruction. AB - The use of an intercostal artery perforator (ICAP) flap has recently become popular in reconstructive surgery. We have developed a novel free sensate ICAP flap based on the lateral cutaneous branch (LCB) and applied it to a case with a plantar defect. To the best of our knowledge, this case is the first to describe a free sensate ICAP flap based on the LCB. This method has several advantages: (1) a sensate flap is possible because the LCB neurovascular bundle is consistently available; (2) the long neurovascular pedicle can be harvested in the supine position without the risk of pneumothorax; (3) the donor-site morbidity is low; and (4) conversion or combination with a superficial circumflex iliac artery perforator (SCIP) or a superficial inferior epigastric artery (SIEA) flap is readily possible. We believe that this method represents a new option for soft-tissue reconstruction. PMID- 24491460 TI - Potential alpha-glucosidase inhibitors from thermal transformation of (+) catechin. AB - Thermal transformation of the (+)-catechin (1) with heating processing afforded a new oxidation product, gambiriin D (2), along with catechin [6'-8]-catechin (3), and (+)-epicatechin (4). The structure of a new catechin dimer with C-C linkage was determined on the basis of spectroscopic data interpretation. The catechin dimers 2 and 3 exhibited significantly improved inhibitory activities against alpha-glucosidase, with IC50 values of 0.16+/-0.2 and 0.14+/-0.2MUM, respectively, when compared to parent (+)-catechin. Kinetic analysis showed that the two effective compounds 2 and 3 have noncompetitive modes of action. PMID- 24491458 TI - Temporal profile of fronto-striatal-limbic activity during implicit decisions in drug dependence. AB - BACKGROUND: Substance dependence is associated with impaired decision-making and altered fronto-striatal-limbic activity. Both greater and lesser brain activity have been reported in drug users compared to controls during decision-making. Inconsistent results might be explained by group differences in the temporal profile of the functional magnetic resonance imaging (fMRI) response. While most previous studies model a canonical hemodynamic response, a finite impulse response (FIR) model measures fMRI signal at discrete time points without assuming a temporal profile. We compared brain activity during decision-making and feedback in substance users and controls using two models: a canonical hemodynamic response function (HRF) and a FIR model. METHODS: 37 substance dependent individuals (SDI) and 43 controls performed event-related decision making during fMRI scanning. Brain activity was compared across group using canonical HRF and FIR models. RESULTS: Compared to controls, SDI were impaired at decision-making. The canonical HRF model showed that SDI had significantly greater fronto-striatal-limbic activity during decisions and less activity during feedback than controls. The FIR model confirmed greater activity in SDI during decisions. However, lower activity in SDI during feedback corresponded to a lower post-stimulus undershoot of the hemodynamic response. CONCLUSIONS: Greater activity in fronto-striatal-limbic pathways in SDI compared to controls is consistent with prior work, further supporting the hypothesis that abnormalities in these circuits underlie impaired decision-making. We demonstrate for the first time using FIR analysis that lower activity during feedback may simply reflect the tail end of the hemodynamic response to decision, the post-stimulus undershoot, rather than an actual difference in feedback response. PMID- 24491459 TI - Synthesis and biological evaluation of novel benzamide derivatives as potent smoothened antagonists. AB - A series of novel benzamide derivatives were prepared and evaluated using cell based measurements. Among these compounds, 10f significantly inhibited Hedgehog signaling and showed equivalent or more potency than GDC-0449 in different tests. Furthermore, compound 10f potently inhibited the proliferation of Daoy, a medulloblastoma cell line that is reported to be resistant to GDC-0449, which indicated a promising prospect in the treatment of Hedgehog signaling pathway related cancer in clinical trial. PMID- 24491461 TI - A radiogallium-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging. AB - We have developed a novel radiogallium (Ga)-DOTA-based bivalent peptidic ligand targeting a chemokine receptor, CXCR4, for tumor imaging. A CXCR4 imaging probe with two CXCR4 antagonists (Ac-TZ14011) on Ga-DOTA core, Ga-DOTA-TZ2, was synthesized, and the affinity and binding to CXCR4 was evaluated in CXCR4 expressing cells in vitro. The affinity of Ga-DOTA-TZ2 for CXCR4 was 20-fold greater than the corresponding monovalent probe, Ga-DOTA-TZ1. (67)Ga-DOTA-TZ2 showed the significantly higher accumulation in CXCR4-expressing tumor cells compared with (67)Ga-DOTA-TZ1, suggesting the bivalent effect enhances its binding to CXCR4. The incorporation of two CXCR4 antagonists to Ga-DOTA could be effective in detecting CXCR4-expressing tumors. PMID- 24491462 TI - [Suspension trauma: a form of positional asphyxia]. PMID- 24491463 TI - Systemic magnesium to improve quality of post-surgical recovery in outpatient segmental mastectomy: a randomized, double-blind, placebo-controlled trial. AB - BACKGROUND: It remains to be determined if perioperative systemic magnesium can improve postoperative quality of recovery of patients undergoing ambulatory procedures. The main objective of the current investigation was to evaluate the effect of systemic magnesium on postoperative quality of recovery in patients undergoing outpatient segmental mastectomies. METHODS: The study was a prospective randomized, double-blind, placebo-controlled, clinical trial. Female subjects were randomized to receive intravenous magnesium (MgSO4 50mg/kg in 100 mL of normal saline over 15 min before anesthesia induction, followed by an infusion of 15 mg/kg/hour) or the same volume of saline. The primary outcome was the Quality of Recovery 40 (QOR-40) questionnaire at 24 hours after surgery. RESULTS: 50 subjects were recruited and 46 completed the study. Patients in the magnesium group had better global Quality of Recovery scores compared with the saline group, with a median difference of 24 (99% CI, 3 to 33), P<0.001. After discharge from hospital, subjects in the magnesium group required less oral opioids, median (IQR) of 10 (0 to 20) (oral milligrams of morphine equivalents) than the saline group, 30 (20 to 40) (P<0.001). The postoperative systemic magnesium concentrations were substantially higher in the magnesium group, 1.25 +/- 0.28 mmol/L compared to control, 0.71 +/- 0.11 mmol/L, P<0.0001. Simple linear regression demonstrated a direct linear relationship between the postoperative systemic magnesium concentrations and 24 hour postoperative quality of recovery scores (P = 0.004), and also an inverse relationship with pain burden in the postoperative care unit (P = 0.01). CONCLUSIONS: Systemic magnesium improves postoperative quality of recovery in patients undergoing outpatient segmental mastectomy. Systemic magnesium is a safe, inexpensive, efficacious strategy to improve quality of recovery after ambulatory surgery. PMID- 24491464 TI - Rare POLG1 CAG variants do not influence Parkinson's disease or polymerase gamma function. AB - A recent meta-analysis suggested that rare CAG repeat variants in the gene that encodes polymerase gamma (POLG1) predispose individuals to develop Parkinson's disease (PD); alternative alleles were proposed to increase risk by 27%. In the current case-control study of 2255 Australians, we observed no statistical association between individuals possessing rare CAG repeat genotypes and PD (p=0.178); a subsequent meta-analysis of 2852 PD cases and 2833 controls was also non-significant (OR=1.085, p=0.124). Moreover, mitochondrial DNA synthesis (p=0.427) or Complex I activity (p=0.639) were not different in cells derived from individuals with different POLG1 genotypes. These data provide no evidence to suggest CAG repeat length in POLG1 affects PD susceptibility. PMID- 24491465 TI - Determining the anaerobic threshold in postpolio syndrome: comparison with current guidelines for training intensity prescription. AB - OBJECTIVES: To determine whether the anaerobic threshold (AT) can be identified in individuals with postpolio syndrome (PPS) using submaximal incremental exercise testing, and to compare current guidelines for intensity prescription in PPS with the AT. DESIGN: Cohort study. SETTING: Research laboratory. PARTICIPANTS: Individuals with PPS (N=82). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Power output, gas exchange variables, heart rate, and rating of perceived exertion (RPE) were measured in an incremental submaximal cycle ergometry test. Two independent observers identified the AT. Comparison of current guidelines for training intensity prescription in PPS (40%-60% heart rate reserve [HRR] or RPE of 12) with the AT was based on correlations between recommended heart rate and the heart rate at the AT. In addition, we determined the proportion of individuals that would have been recommended to train at an intensity corresponding to their AT. RESULTS: The AT was identified in 63 (77%) of the participants. Pearson correlation coefficients between the recommended heart rate and the heart rate at the AT were lower in cases of 40% HRR (r=.56) and 60% HRR (r=.50) than in cases of prescription based on the RPE (r=.86). Based on the RPE, 55% of the individuals would have been recommended to train at an intensity corresponding to their AT. This proportion was higher compared with 40% HRR (41%) or 60% HRR (18%) as criterion. CONCLUSIONS: The AT can be identified in most individuals with PPS offering an individualized target for aerobic training. If the AT cannot be identified (eg, because gas analysis equipment is not available), intensity prescription can best be based on the RPE. PMID- 24491466 TI - Is the long form of the Fugl-Meyer motor scale more responsive than the short form in patients with stroke? AB - OBJECTIVE: To compare the responsiveness of the Rasch-calibrated 37-item Fugl Meyer motor Scale with that of the 12-item Fugl-Meyer motor scale at both an individual and a group level. DESIGN: Repeated-measurements design. SETTING: Medical center. PARTICIPANTS: Patients (N=301) 14 days after stroke. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: 50-item Fugl-Meyer motor scale, 37-item Fugl-Meyer motor scale, and 12-item Fugl-Meyer motor scale. RESULTS: The patients were assessed with the original 50-item Fugl-Meyer motor scale 4 times, at 14, 30, 90, and 180 days after stroke onset. The patients' responses were used for estimating the Rasch scores of the 37-item Fugl-Meyer motor scale and 12-item Fugl-Meyer motor scale. The effect size, standardized response mean, and paired t test were used to compare the group-based responsiveness of the 3 forms (50-item Fugl-Meyer motor scale, 37-item Fugl-Meyer motor scale, 12-item Fugl-Meyer motor scale). Individual-level responsiveness was compared based on the significance of change between the 37-item Fugl-Meyer motor scale and 12-item Fugl-Meyer motor scale. Because up to 13 items of the 50-item Fugl-Meyer motor scale did not meet the Rasch model's assumptions, the significance of change of the 50-item Fugl-Meyer motor scale was not calculated. At the group level, the FM-37 and FM-12 Fugl-Meyer motor scale had sufficient and similar responsiveness. At the individual level, the FM-37 Fugl-Meyer motor scale detected more patients with significant improvement than the FM-12 Fugl-Meyer motor scale. The SC values and category distribution of the FM-37 Fugl-Meyer motor scale were significantly better than those of the FM-12 Fugl-Meyer motor scale (P<.001). CONCLUSIONS: Although the group-level responsiveness of the 12 item Fugl-Meyer motor scale was sufficient and very similar to that of the 37 item Fugl-Meyer motor scale, the 37-item Fugl-Meyer motor scale had better individual-level responsiveness. The 37-item Fugl-Meyer motor scale is suggested as an outcome measure for both clinicians and researchers. PMID- 24491467 TI - Is the association between healthy lifestyle behaviors and cardiovascular mortality modified by overweight status? The Japan Collaborative Cohort Study. AB - OBJECTIVE: To examine the modifying effects of overweight status on the association of healthy lifestyle behaviors with cardiovascular mortality in the Japanese population. METHODS: A community-based, prospective cohort of 18,730 men and 24,216 women aged 40-79 years without a history of cardiovascular disease (CVD) or cancer at baseline (1988-1990) was followed until 2009. Healthy lifestyle behaviors included intake of fruits, fish, and milk; exercise; avoidance of smoking; moderate alcohol intake; and moderate sleep duration. RESULTS: During the median of 19.3 years of follow-up, there were 2412 deaths from total CVD. Inverse associations between healthy lifestyle scores and mortality from stroke, total CVD, and coronary heart disease (CHD) were observed for non-overweight and overweight (body mass index >=25 kg/m2) individuals, although the association was weaker for overweight individuals. The multivariable hazard ratios (HRs, 95% confidence interval) of mortality from total CVD for the highest (6-7) versus the lowest (0-2) scores were 0.44 (0.37-0.54) for non overweight and 0.56 (0.39-0.81) for overweight individuals. Especially for CHD mortality, such association was more evident for non-overweight compared to that for overweight individuals. CONCLUSIONS: Our findings suggest that lifestyle modification may be beneficial in the prevention of cardiovascular mortality for persons who are and are not overweight. PMID- 24491468 TI - Pigeons exhibit contextual cueing to both simple and complex backgrounds. AB - Repeated pairings of a particular visual context with a specific location of a target stimulus facilitate target search in humans. We explored an animal model of this contextual cueing effect using a novel Cueing-Miscueing design. Pigeons had to peck a target which could appear in one of four possible locations on four possible color backgrounds or four possible color photographs of real-world scenes. On 80% of the trials, each of the contexts was uniquely paired with one of the target locations; on the other 20% of the trials, each of the contexts was randomly paired with the remaining target locations. Pigeons came to exhibit robust contextual cueing when the context preceded the target by 2s, with reaction times to the target being shorter on correctly-cued trials than on incorrectly-cued trials. Contextual cueing proved to be more robust with photographic backgrounds than with uniformly colored backgrounds. In addition, during the context-target delay, pigeons predominately pecked toward the location of the upcoming target, suggesting that attentional guidance contributes to contextual cueing. These findings confirm the effectiveness of animal models of contextual cueing and underscore the important part played by associative learning in producing the effect. This article is part of a Special Issue entitled: SQAB 2013: Contextual Con. PMID- 24491469 TI - Impact of sodium lactate and vinegar derivatives on the quality of fresh Italian pork sausage links. AB - Sodium lactate and acetic acid derivatives were evaluated for their impact on fresh Italian pork sausage using commercial trimmings. Analysis over storage included total plate count (TPC), TBARS, sensory analysis, cooking loss, pH, and color. Treatments included: (a) vinegar and sodium lactate mixture (V), (b) sodium lactate (S), (c) positive control with BHA/BHT (B) and (d) negative control, seasoning only (C). Treatments S and V had lower TPC (P<0.05) from days 5 to 14 when compared to B and C. TBARS values increased (P<0.05) for C, S, and V while B did not change (P>0.05) over time. While CIE a* surface values for redness generally decreased over storage time for all treatments, B maintained more redness. There were few major differences in descriptive sensory evaluation over time, but S and V precluded early onset of rancidity, oxidation and other off-flavors contrary to some of the analytical results. Of consumers tested, 85.6% rated all treatments between like slightly and like very much. PMID- 24491470 TI - Fetal exposure to nonsteroidal anti-inflammatory drugs and spontaneous abortions. AB - BACKGROUND: Spontaneous abortion is the most common complication of pregnancy. Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used during pregnancy. Published data are inconsistent regarding the risk of spontaneous abortion following exposure to NSAIDs. METHODS: We performed a historical cohort study involving all women who conceived between January 2003 and December 2009 and who were admitted for delivery or spontaneous abortion at Soroka Medical Center, Clalit Health Services, Israel. A computerized database of medication dispensation was linked with 2 computerized databases containing information on births and spontaneous abortions. We constructed time-varying Cox regression models and adjusted for maternal age, diabetes mellitus, hypothyroidism, obesity, hypercoagulation or inflammatory conditions, recurrent miscarriage, in vitro fertilization of the current pregnancy, intrauterine contraceptive device, ethnic background, tobacco use and year of admission. RESULTS: The cohort included 65,457 women who conceived during the study period; of these, 58,949 (90.1%) were admitted for a birth and 6508 (9.9%) for spontaneous abortion. A total of 4495 (6.9%) pregnant women were exposed to NSAIDs during the study period. Exposure to NSAIDs was not an independent risk factor for spontaneous abortion (nonselective cyclooxygenase [COX] inhibitors: adjusted hazard ratio [HR] 1.10, 95% confidence interval [CI] 0.99-1.22; selective COX-2 inhibitors: adjusted HR 1.43, 95% CI 0.79-2.59). There was no increased risk for specific NSAID drugs, except for a significantly increased risk with exposure to indomethacin (adjusted HR 2.8, 95% CI 1.70-4.69). We found no dose-response effect. INTERPRETATION: We found no increased risk of spontaneous abortion following exposure to NSAIDs. Further research is needed to assess the risk following exposure to selective COX-2 inhibitors. PMID- 24491471 TI - New tools to improve safety of electronic health records. PMID- 24491473 TI - Cyproterone acetate-ethinyl estradiol use in a 23-year-old woman with stroke. PMID- 24491474 TI - Ethics and legalities associated with independent medical evaluations. PMID- 24491476 TI - Researcher-participant confidentiality now a formal concept in Canadian law. PMID- 24491477 TI - New CMAJ policy on sharing data from clinical research. PMID- 24491478 TI - Canada opposes harm reduction policies for drug users. PMID- 24491479 TI - Quebec rejects mandatory university for nurses. PMID- 24491480 TI - Resilience in families raising children with disabilities and behavior problems. AB - The purpose of this study was to investigate the resilience displayed by families raising children with disabilities and behavior problems. The question is why do some families do well when others, exposed to similar stressors, struggle to keep their family life running? A stratified (by child age group) random sample of 538 families raising children with disabilities in Alberta, Canada took part. Participants completed the Family Life Survey, which incorporated measures of child behavior problems, social-ecological resources and family-level 'outcomes'. Families raising children with disabilities and behavior problems 'do well' under conditions of high social support and low financial hardship. In contrast, families with low levels of social support and high levels of financial hardship typically struggle, even when the number or intensity of child behavior problems is low. The study findings are consistent with the view that 'resilience' has more to do with the availability and accessibility of culturally relevant resources than with intrinsic, individual or family factors. With respect to family-level outcomes, strengthening social relationships and ameliorating financial hardship may be more important than behavior modification. PMID- 24491481 TI - [Paediatric Chagas in a non-endemic area]. AB - INTRODUCTION: Immigration has introduced new diseases into Spanish society, one of which is Chagas disease. Young women of childbearing age and children infected with Trypanosoma cruzi from endemic areas are at risk of developing the disease years later, and pregnant women can transmit the infection through the placenta. METHODS: Serological screening for anti-T.cruzi antibodies was performed on all immigrant children coming from a Chagas endemic area and seen in our Pathology Unit between 2003 and 2008, as well as on newborns of T.cruzi positive infected pregnant women coming from Latin America. Two ELISA tests were used (bioelisa Chagas Biokit(r) with recombinant antigens, and an 'in house' ELISA with crude antigen). Patients with sufficient sample were also screened by nested PCR (TCZ3/Z4). RESULTS: A total of 202 children, aged 1 day to 14 years old were included in the study, of whom 22 (10.8%) were diagnosed with asymptomatic infection, 5 of which were congenital as they were born in this country. All infected patients received treatment with benznidazole, with three of them currently with a serologically negative result after treatment. CONCLUSION: Chagas disease is a new imported paediatric disease that can affect children from endemic countries, but can also be acquired in our country by vertical transmission. Therefore, we believe that it is essential to perform serological screening on all children and pregnant women in the prenatal care from endemic areas, and provide specific treatment for those infected patients, given the good results observed in the paediatric population. PMID- 24491482 TI - Polio in syria. PMID- 24491483 TI - Pharmacophore model of the quercetin binding site of the SIRT6 protein. AB - SIRT6 is a histone deacetylase that has been proposed as a potential therapeutic target for metabolic disorders and the prevention of age-associated diseases. We have previously reported on the identification of quercetin and vitexin as SIRT6 inhibitors, and studied structurally related flavonoids including luteolin, kaempferol, apigenin and naringenin. It was determined that the SIRT6 protein remained active after immobilization and that a single frontal displacement could correctly predict the functional activity of the immobilized enzyme. The previous study generated a preliminary pharmacophore for the quercetin binding site on SIRT6, containing 3 hydrogen bond donors and one hydrogen bond acceptor. In this study, we have generated a refined pharmacophore with an additional twelve quercetin analogs. The resulting model had a positive linear behavior between the experimental elution time verses the fit values obtained from the model with a correlation coefficient of 0.8456. PMID- 24491484 TI - Longitudinal measurements of MRI-T2 in boys with Duchenne muscular dystrophy: effects of age and disease progression. AB - Duchenne muscular dystrophy (DMD) is characterized by an increased muscle damage and progressive replacement of muscle by noncontractile tissue. Both of these pathological changes can lengthen the MRI transverse proton relaxation time (T2). The current study measured longitudinal changes in T2 and its distribution in the lower leg of 16 boys with DMD (5-13years, 15 ambulatory) and 15 healthy controls (5-13years). These muscles were chosen to allow extended longitudinal monitoring, due to their slow progression compared with proximal muscles in DMD. In the soleus muscle of boys with DMD, T2 and the percentage of pixels with an elevated T2 (?2SD above control mean T2) increased significantly over 1year and 2years, while the width of the T2 histogram increased over 2years. Changes in soleus T2 variables were significantly greater in 9-13years old compared with 5-8years old boys with DMD. Significant correlations between the change in all soleus T2 variables over 2years and the change in functional measures over 2years were found. MRI measurement of muscle T2 in boys with DMD is sensitive to disease progression and shows promise as a clinical outcome measure. PMID- 24491485 TI - Hammersmith Functional Motor Scale and Motor Function Measure-20 in non ambulant SMA patients. AB - The aim of this prospective longitudinal multi centric study was to evaluate the correlation between the Hammersmith Functional Motor Scale and the 20 item version of the Motor Function Measure in non ambulant SMA children and adults at baseline and over a 12 month period. Seventy-four non-ambulant patients performed both measures at baseline and 49 also had an assessment 12 month later. At baseline the scores ranged between 0 and 40 on the Hammersmith Motor function Scale and between 3 and 45 on the Motor Function Measure 20. The correlation between the two scales was 0.733. The 12 month changes ranged between -11 and 4 for the Hammersmith and between -11 and 7 for the Motor Function Measure 20. The correlation between changes was 0.48. Our results suggest that both scales provide useful information although they appeared to work differently at the two extremes of the spectrum of abilities. The Hammersmith Motor Function Scale appeared to be more suitable in strong non ambulant patients, while the Motor Function Measures appeared to be more sensitive to capture activities and possible changes in the very weak patients, including more items capturing axial and upper limb activities. The choice of these measures in clinical trials should therefore depend on inclusion criteria and magnitude of expected changes. PMID- 24491486 TI - Myopathy with anti-signal recognition particle antibodies: clinical and histopathological features in Chinese patients. AB - Myopathy with anti-signal recognition particle antibodies (SRP) is generally thought to be immune-mediated necrotic myopathy in previous studies. We report the clinical and histopathological features of myopathy with anti-SRP antibodies in Chinese patients. Muscle biopsy and immunoblots for myositis antibodies were carried out in 123 patients with idiopathic inflammatory myopathy. Among them, 16 (13.0%) patients had anti-SRP antibodies. Age of onset ranged from 24 to 77 years, and the disease began insidiously. Fourteen of 16 patients presented with chronic progression of proximal limb weakness, with 6 having myalgia. Serum creatine kinase levels ranged from 400 to 9082 IU/L. Muscle biopsies showed necrotic and/or regenerative muscle fibers in all 16, infiltrates of lymphocytes in 11 and morphological features of muscular dystrophy in 7. Eleven patients showed focal or diffuse major histocompatibility complex class 1 expression in sarcolemma or cytoplasm of muscle fibers, with 9 showing deposition of membrane attack complex in necrotic muscle fibers and 2 around capillaries. These findings indicate that anti-SRP antibodies are most likely to be related to IMNM. Myopathy with anti-SRP antibodies is not infrequent in Chinese patients with idiopathic inflammatory myopathy. PMID- 24491487 TI - A novel missense mutation in POMT1 modulates the severe congenital muscular dystrophy phenotype associated with POMT1 nonsense mutations. AB - Mutations in POMT1 lead to a group of neuromuscular conditions ranging in severity from Walker-Warburg syndrome to limb girdle muscular dystrophy. We report two male siblings, ages 19 and 14, and an unrelated 6-year old female with early onset muscular dystrophy and intellectual disability with minimal structural brain anomalies and no ocular abnormalities. Compound heterozygous mutations in POMT1 were identified including a previously reported nonsense mutation (c.2167dupG; p.Asp723Glyfs*8) associated with Walker-Warburg syndrome and a novel missense mutation in a highly conserved region of the protein O mannosyltransferase 1 protein (c.1958C>T; p.Pro653Leu). This novel variant reduces the phenotypic severity compared to patients with homozygous c.2167dupG mutations or compound heterozygous patients with a c.2167dupG mutation and a wide range of other mutant POMT1 alleles. PMID- 24491488 TI - Immune regulatory activities of fowlicidin-1, a cathelicidin host defense peptide. AB - Appropriate modulation of immunity is beneficial in antimicrobial therapy and vaccine development. Host defense peptides (HDPs) constitute critically important components of innate immunity with both antimicrobial and immune regulatory activities. We previously showed that a chicken HDP, namely fowlicidin-1(6-26), has potent antibacterial activities in vitro and in vivo. Here we further revealed that fowl-1(6-26) possesses strong immunomodulatory properties. The peptide is chemotactic specifically to neutrophils, but not monocytes or lymphocytes, after injected into the mouse peritoneum. Fowl-1(6-26) also has the capacity to activate macrophages by inducing the expression of inflammatory mediators including IL-1beta, CCL2, and CCL3. However, unlike bacterial lipopolysaccharide that triggers massive production of inflammatory cytokines and chemokines, fowl-1(6-26) only marginally increased their expression in mouse RAW264.7 macrophages. Additionally, fowl-1(6-26) enhanced the surface expression of MHC II and CD86 on RAW264.7 cells, suggesting that it may facilitate development of adaptive immune response. Indeed, co-immunization of mice with chicken ovalbumin (OVA) and fowl-1(6-26) augmented both OVA-specific IgG1 and IgG2a titers, relative to OVA alone. We further showed that fowl-1(6-26) is capable of preventing a methicillin-resistant Staphylococcus aureus (MRSA) infection due to its enhancement of host defense. All mice survived from an otherwise lethal infection when the peptide was administered 1-2 days prior to MRSA infection, and 50% mice were protected if receiving the peptide 4 days before infection. Taken together, with a strong capacity to stimulate innate and adaptive immunity, fowl-1(6-26) may have potential to be developed as a novel antimicrobial and a vaccine adjuvant. PMID- 24491489 TI - Molecular cloning, expression and functional analysis of B-cell activating factor (BAFF) in yellow grouper, Epinephelus awoara. AB - B cell activating factor (BAFF), a ligand belonging to the tumor necrosis factor (TNF) family is critical to B cell survival, proliferation, maturation and immunoglobulin secretion. In this study, the yellow grouper (Epinephelus awoara) BAFF (designated EaBAFF) gene was cloned using RT-PCR and RACE (rapid amplification of cDNA ends) techniques. The full-length EaBAFF was 1442bp and contained an open reading frame of 780bp encoding a putative protein of 259 amino acids. Amino acids sequence comparison indicated that EaBAFF possessed the TNF signature. The soluble BAFF (EasBAFF) had been cloned into pET28a. SDS-PAGE and Western blotting analysis confirmed that the soluble fusion protein His-EasBAFF was efficiently expressed in Escherichia coli BL21 (DE3). In vitro, the WST-8 assay indicated that EasBAFF was not only able to promote the survival/proliferation of yellow grouper splenic lymphocytes but also able to promote the survival/proliferation of mouse splenic B cells. Our findings may provide valuable information for research into the immune system of E. awoara and EasBAFF may serve as a potential immunologic factor for enhancing immunological efficacy in fish. PMID- 24491491 TI - "Inside-in" or "inside-out"? The membrane topology of SLC41A1. AB - Membrane topology is an important parameter for understanding the function and regulation of any integral protein. This aspect of the NME SLC41A1 is currently under debate. The most probable model, which has been computer-predicted, exhibits ten TMh with both termini being oriented intracellularly. However, other freely accessible online prediction programs predict that SLC41A1 possesses eleven ("outside-in" configuration), nine ("outside-in" configuration), or eight ("inside-in" configuration) TMh. The consensus based on published experimental data acquired by independent research teams is that the N-terminal flanking region is located intracellularly. However, controversy remains about the orientation of the C-terminus, which has lately been proposed to be extracellular in peer-reviewed bibliography. Here, we performed split-ubiquitin functional assays with transgenic SLC41A1 fused N- or C-terminally to a Cub-LexA-VP16 reporter cassette. The bait constructs were co-expressed in S. cerevisiae st. NMY51 with positive recombinant membrane markers (Ost1, Fur4, Alg5, Tom20) tagged with NubI (or NubG). Ubiquitin could only be reconstituted if the reporter moiety was exposed to the cytosol. Functional reconstitution of ubiquitin was observed when SLC41A1 C-terminally tagged with Cub was co-expressed with NubI-tagged membrane markers, thereby, indicating a cytosolic orientation of the C-terminus of SLC41A1. Thus, our experimental data are in favor of the - the in silico analyses being strongly preferred - ten TMh model of SLC41A1 topology, with both termini being oriented intracellularly. PMID- 24491490 TI - Design, synthesis, and characterization of a 39 amino acid peptide mimic of the main immunogenic region of the Torpedo acetylcholine receptor. AB - We have designed a 39 amino acid peptide mimic of the conformation-dependent main immunogenic region (MIR) of the Torpedo acetylcholine receptor (TAChR) that joins three discontinuous segments of the Torpedo alpha-subunit, alpha(1-12), alpha(65 79), and alpha(110 - 115) with two GS linkers: This 39MIR-mimic was expressed in E. coli as a fusion protein with an intein-chitin-binding domain (IChBD) to permit affinity collection on chitin beads. Six MIR-directed monoclonal antibodies (mAbs) bind to this complex and five agonist/antagonist site directed mAbs do not. The complex of MIR-directed mAb-132A with 39MIR has a Kd of (2.11+/ 0.11)*10(-10)M, which is smaller than (7.13+/-1.20)*10(-10)M for the complex of mAb-132A with alpha(1-161) and about the same as 3.4*10(-10)M for that of mAb 132A with TAChR. Additionally, the 39MIR-IChBD adsorbs all MIR-directed antibodies (Abs) from an experimental autoimmune myasthenia gravis (EAMG) rat serum. Hence, the 39MIR-mimic has the potential to inactivate or remove pathogenic Torpedo MIR-directed Abs from EAMG sera and to direct a magic bullet to the memory B-cells that produce those pathogenic Abs. The hope is to use this as a guide to produce a mimic of the human MIR on the way to an antigen specific therapeutic agent to treat MG. PMID- 24491492 TI - Putative P1B-type ATPase from the bacterium Achromobacter xylosoxidans A8 alters Pb2+/Zn2+/Cd2+-resistance and accumulation in Saccharomyces cerevisiae. AB - PbtA, a putative P(1B)-type ATPase from the Gram-negative soil bacterium Achromobacter xylosoxidans A8 responsible for Pb(2+)/Zn(2+)/Cd(2+)-resistance in Escherichia coli, was heterologously expressed in Saccharomyces cerevisiae. When present in Zn(2+)- and Pb(2+)/Cd(2+)-hypersensitive S. cerevisiae strains CM137 and DTY168, respectively, PbtA was able to restore Zn(2+)- and Pb(2+)-resistant phenotype. At the same time, the increase of Pb, Zn, and Cd accumulation in yeast was observed. However, Cd(2+)-tolerance of the pbtA-bearing yeasts dramatically decreased. The PbtA-eGFP fusion protein was localized primarily in the tonoplast and also in the plasma membrane and the perinuclear region corresponding to the endoplasmic reticulum at later growth stages. This indicates that PbtA protein is successfully incorporated into membranes in yeasts. Since PbtA caused a substantial increase of Pb(2+)/Zn(2+)-resistance and accumulation in baker's yeast, we propose its further use for the genetic modification of suitable plant species in order to obtain an effective tool for the phytoremediation of sites polluted by toxic transition metals. PMID- 24491493 TI - Polysaccharides of Aloe vera induce MMP-3 and TIMP-2 gene expression during the skin wound repair of rat. AB - Polysaccharides are the main macromolecules of Aloe vera gel but no data about their effect on extracellular matrix (ECM) elements are available. Here, mannose rich Aloe vera polysaccharides (AVP) with molecular weight between 50 and 250 kDa were isolated and characterized. Open cutaneous wounds on the back of 45 rats (control and treated) were daily treated with 25mg (n=15) and 50 mg (n=15) AVP for 30 days. The levels of MMP-3 and TIMP-2 gene expression were analyzed using real time PCR. The levels of n-acetyl glucosamine (NAGA), n-acetyl galactosamine (NAGLA) and collagen contents were also measured using standard biochemical methods. Faster wound closure was observed at day 15 post wounding in AVP treated animals in comparison with untreated group. At day 10 post wounding, AVP inhibited MMP-3 gene expression, while afterwards MMP-3 gene expression was upregulated. AVP enhanced TIMP-2 gene expression, collagen, NAGLA and NAGA synthesis in relation to untreated wounds. Our results suggest that AVP has positive effects on the regulation of ECM factor synthesis, which open up new perspectives for the wound repair activity of Aloe vera polysaccharide at molecular level. PMID- 24491494 TI - Effect of chitosan-based edible coating on preservation of white shrimp during partially frozen storage. AB - Chitosan and chitooligosaccharides are preservatives with proven antibacterial activity, while glutathione has antioxidant activity. This study investigated the effects of chitosan coating combined with chitooligosaccharides and glutathione (0.8% glutathione+1% chitooligosaccharides+1% chitosan) on preservation of white shrimp (Penaeus vannamei) during partially frozen storage. Chitosan-based coating treatments effectively inhibited bacterial growth, reduced total volatile basic nitrogen and malondialdehyde, and basically maintained the sensory properties of white shrimp (P. vannamei) during partially frozen storage. Therefore, chitosan based edible coating combined with chitooligosaccharides and glutathione could be a promising antimicrobial and oxidant method to prevent metamorphism of white shrimp with extended shelf life. PMID- 24491496 TI - Computational approaches for analyzing the mechanics of atherosclerotic plaques: a review. AB - Vulnerable and stable atherosclerotic plaques are heterogeneous living materials with peculiar mechanical behaviors depending on geometry, composition, loading and boundary conditions. Computational approaches have the potential to characterize the three-dimensional stress/strain distributions in patient specific diseased arteries of different types and sclerotic morphologies and to estimate the risk of plaque rupture which is the main trigger of acute cardiovascular events. This review article attempts to summarize a few finite element (FE) studies for different vessel types, and how these studies were performed focusing on the used stress measure, inclusion of residual stress, used imaging modality and material model. In addition to histology the most used imaging modalities are described, the most common nonlinear material models and the limited number of models for plaque rupture used for such studies are provided in more detail. A critical discussion on stress measures and threshold stress values for plaque rupture used within the FE studies emphasizes the need to develop a more location and tissue-specific threshold value, and a more appropriate failure criterion. With this addition future FE studies should also consider more advanced strain-energy functions which then fit better to location and tissue-specific experimental data. PMID- 24491495 TI - Effects of mechanical properties and atherosclerotic artery size on biomechanical plaque disruption - mouse vs. human. AB - Mouse models of atherosclerosis are extensively being used to study the mechanisms of atherosclerotic plaque development and the results are frequently extrapolated to humans. However, major differences have been described between murine and human atherosclerotic lesions and the determination of similarities and differences between these species has been largely addressed recently. This study takes over and extends previous studies performed by our group and related to the biomechanical characterization of both mouse and human atherosclerotic lesions. Its main objective was to determine the distribution and amplitude of mechanical stresses including peak cap stress (PCS) in aortic vessels from atherosclerotic apoE(-/-) mice, in order to evaluate whether such biomechanical data would be in accordance with the previously suggested lack of plaque rupture in this model. Successful finite element analysis was performed from the zero stress configuration of aortic arch sections and mainly indicated (1) the modest role of atherosclerotic lesions in the observed increase in residual parietal stresses in apoE(-/-) mouse vessels and (2) the low amplitude of murine PCS as compared to humans. Overall, the results from the present study support the hypothesis that murine biomechanical properties and artery size confer less propensity to rupture for mouse lesions in comparison with those of humans. PMID- 24491497 TI - Young's modulus of canine vocal fold cover layers. AB - OBJECTIVES: The objective of this study was to measure the elastic modulus (Young's modulus) of canine vocal fold cover layers. STUDY DESIGN: Basic science study. METHODS: Cover layers from vocal folds of eight canine larynges were dissected. Cover layer samples from the mid-membranous, medial vocal fold surface area were used to measure material stiffness using a previously validated indentation method. Cover layers from two human larynges were also measured as control references. Superior and inferior medial cover layers were measured separately. A total of 15 superior medial surface and 17 inferior medial surface specimens from the canine and two and four specimens, respectively, from the human were tested. RESULTS: In the canine larynges, the mean Young's modulus of the superior medial surface was 4.2 kPa (range, 3.0-5.4 kPa; standard deviation [SD], 0.6 kPa) and of the inferior medial surface was 6.8 kPa (range, 5.4-8.5 kPa; SD, 0.8 kPa). Measurements on human cover samples were 5.0 kPa (range, 4.7 5.4 kPa; SD, 0.5 kPa) and 7.0 kPa (range, 6.7-7.3 kPa; SD, 0.3 kPa) for the superior medial and inferior medial surface, respectively. Human measurements were similar to the previously validated measurements. There was no difference between the stiffness measurements in the human and canine cover layer samples (P>0.05). CONCLUSIONS: The elastic stiffness (Young's modulus) of the canine and human vocal fold cover layers is similar. Findings support the use of canine larynx as an externally valid model to study voice production. PMID- 24491498 TI - Subglottic extramedullary plasmacytoma with light chain multiple myeloma masquerading as adult-onset asthma. AB - Extramedullary plasmacytoma (EMP) arises outside the bone marrow and can be associated with multiple myeloma (MM). A 55-year-old gentleman, who presented with dyspnea and expiratory wheeze, was diagnosed and treated for asthma. A subsequent relapse 6 months later prompted an Otolaryngology consult. Preliminary findings showed a benign-looking nodular lesion at the subglottis. Work-up at our institution revealed an Fludeoxyglucose (FDG) avid left subglottic lesion with multiple bone metastases on a Positron Emission Tomography / Computed Tomography (PET/CT). The patient underwent a panendoscopy and laser excision of the subglottic lesion with subglottic jet ventilation. Histology showed an EMP. Further work-up revealed the presence of kappa light chain MM with adverse cytogenetics. Patient was treated systemically with lenalidomide, bortezomib, and dexamethasone for four cycles with rapid improvement in his symptoms. We review the literature about EMP of the subglottis with MM. We present the first case of subglottic laryngeal EMP with MM managed via CO2 laser excision. PMID- 24491499 TI - Use of cepstral analyses for differentiating normal from dysphonic voices: a comparative study of connected speech versus sustained vowel in European Portuguese female speakers. AB - OBJECTIVE: The aim of this study was to investigate the use of cepstral peak prominence (CPP) and CPP-smoothed (CPPs) to differentiate dysphonic from nondysphonic voices, using two speech tasks: sustained vowel /a/ and connected speech. STUDY DESIGN: A retrospective study was based on data selected from an archival database of recorded voices. METHODS: Sixty age- and occupation-matched individuals (30 participants with dysphonia and 30 controls) were recorded producing the sustained vowel /a/ and reading the European Portuguese version of "The Story of Arthur the Rat." Recorded voices were analyzed acoustically by measuring CPP and CPPs and auditory-perceptual ratings were related to the acoustic measurements. RESULTS: For the sustained vowel, both CPP and CPPs measures were significantly different between dysphonic and control groups. For connected speech, only CPP values revealed significant differences between the two groups, both in direct and narrative speech. Acoustic measurements correlated with the auditory-perceptual classifications in both sustained vowel and connected speech, although the strongest correlation (0.6 < r < 0.7) was obtained between CPP and the perception of breathiness. CONCLUSIONS: The results of this study suggest that analysis of CPP and CPPs is a promising tool in clinical practice with European Portuguese speakers. PMID- 24491500 TI - Comparison of effects on voice of diode laser and cold knife microlaryngology techniques for vocal fold polyps. AB - AIM: To compare the effects on voice of endolaryngeal microsurgery (EMS) with cold instruments and a new method, "diode laser," for vocal fold polyps. PATIENTS AND METHODS: Fifty-one patients with vocal fold polyps suffering from dysphonia who were treated in the Erciyes University Department of Otolaryngology were included in the study. Voice analysis was performed in a soundproof room, holding the microphone 15 cm away from the patients' mouth and by recording a sustained [a] vowel for at least 10 seconds. Fundamental frequency (F0), Jitter, Shimmer, and noise-to-harmonic ratio (NHR) parameters were evaluated in terms of vocal analysis. All patients were asked for to fill in a questionnaire, after being informed about the voice handicap index (VHI). EMS was performed with a diode laser and cold knife on 26 and 25 patients, respectively. Patient follow-up was performed 8 weeks after surgery. Changes in F0, Jitter, Shimmer, and NHR values were measured and recorded. VHI was also completed and reassessed. RESULTS: There was a significant difference in each technique's VHI score between the preoperative and postoperative questionnaire (P < 0.001). Postoperatively, there was no significant difference in VHI scores between two groups (P > 0.05). There was a significant difference in voice analysis values measured preoperatively and at the postoperative controls for both groups (P < 0.05). Postoperatively, there was no significant difference in voice analysis values between two groups (P > 0.05). CONCLUSION: In the treatment of vocal polyps, EMS with both diode laser and traditional cold knife is effective. PMID- 24491501 TI - LPR: how different diagnostic tools shape the outcomes of treatment. AB - OBJECTIVE: To seek a deeper and more comprehensive understanding of two major diagnostic methods for laryngopharyngeal reflux by exploring whether and how differences exist before and after treatment between patients diagnosed by either Reflux Symptom Index (RSI) and Reflux Finding Score (RFS) or 24-hour pH monitoring. MATERIALS AND METHODS: Two groups of patients who confirmed laryngopharyngeal reflux disease (LPRD) by either a combination of RSI and RFS (Questionnaire group, 35 patients) or 24-hour multichannel intraluminal impedance (MII) pH monitoring (pH Group, 23 patients) were recruited. All patients were prescribed esomeprazole 20 mg twice a day for 1 month. RSI, RFS, and acoustic parameters before and after treatment were compared between the two groups. Intrinsic correlations involving multiple parameters were investigated as well. RESULTS: Except for excess throat mucus (P = 0.019) and subglottic edema (P = 0.042), most RSI and RFS items before treatment were not significantly different between the Questionnaire and pH Groups, and nearly all such items in both groups exhibited distinct remission after therapy (P < 0.05). Absolute value of remission in RSI after treatment was more prominent in pH Group than in the Questionnaire group (P = 0.007). Jitter (P = 0.252), shimmer (P = 0.815), and harmonics-to-noise ratio (P = 0.117) descended to normal value after treatment. Moderate to high levels of correlation were found between the patient's original status and the absolute value of remission in most items of RSI and RFS as well as voice parameters. CONCLUSION: The 24-hour MII pH monitoring and a combination of RSI and RFS are quite competitive with each other in selecting LPRD patients. Although treatment worked out on nearly all the symptoms, laryngeal images and voice parameters, 24-hour MII pH seems to be more promising in a greater symptom relief. The extent of relief that can take place in most of the measurements is considerably determined by their initial status. PMID- 24491502 TI - Office-based injection laryngoplasty for the management of unilateral vocal fold paralysis. AB - OBJECTIVE: Office-based injection laryngoplasty (OBIL) is a common method of addressing glottal insufficiency. This retrospective chart review identifies the demongraphics, laterality, technique, success rate, injectates, and complications of OBIL performed over a 3-year period at a single institution. STUDY DESIGN: Retrospective chart review. METHODS: All OBILs performed for the management of UVFP by the senior author over 3 years (2007-2009) were identified from billing records. The age, gender, laterality, underlying disease process, augmentation material, route of injection, and complications were recorded. RESULTS: Eighty two OBILs were attempted on 57 patients. The most common route of access was transoral (85.6%). All OBILs were able to be completed. Injectates used were hyaluronic acid derivatives (57.3%), calcium hydroxyapatite (16%), and Cymmetra (16.5%). Three complications (3.7%) occurred. Thirty percent of patients ultimately elected for thyroplasty or ansa reinnervation, 22% found their condition to self-resolve, 14% died, and 25% were lost to follow-up. CONCLUSIONS: Using a variety of approaches, OBIL is possible in almost all patients. The single surgeon transoral route using a rigid angled telescope and curved injection needle was the most commonly used approach. Multiple injectates can be used and have good safety records. The final disposition of patients may be variable and warrants further investigation. PMID- 24491503 TI - Calcium-calmodulin dependent protein kinase I from Macrobrachium nipponense: cDNA cloning and involvement in molting. AB - Calcium-calmodulin dependent protein kinase I is a component of a calmodulin dependent protein kinase cascade and involved in many physiological processes. The full-length cDNA of calcium-calmodulin dependent protein kinase I (MnCaMKI) was cloned from the freshwater prawn Macrobrachium nipponense and its expression pattern during the molt cycle and after eyestalk ablation is described. The full length cDNA of MnCaMKI is 3,262 bp in length and has an open reading frame (ORF) of 1,038 bp, encoding a 345 amino acid protein. The expression of MnCaMKI in three examined tissues was upregulated in the premolt stage of the molt cycle. Its expression was induced after eyestalk ablation (ESA): the highest expression level was reached 1 day after ESA in hepatopancreas, and 3 days after ESA in muscle. By dsRNA-mediated RNA interference assay, expression of MnCaMKI and ecydone receptor gene (MnEcR) was significantly decreased in prawns treated by injection of dsMnCaMKI, while expression of these two genes was also significantly decreased in prawns treated by injection of dsMnEcR, demonstrating a close correlation between the expression of these two genes. These results suggest that CaMKI in M. nipponense is involved in molting. PMID- 24491504 TI - Ensemble docking and molecular dynamics identify knoevenagel curcumin derivatives with potent anti-EGFR activity. AB - Epidermal growth factor receptor tyrosine kinase (EGFR-TK) is an attractive target for cancer therapy. Despite a number of effective EGFR inhibitors that are constantly expanding and different methods being employed to obtain novel compounds, the search for newer EGFR inhibitors is still a major scientific challenge. In the present study, a molecular docking and molecular dynamics investigation has been carried out with an ensemble of EGFR-TK structures against a synthetically feasible library of curcumin analogs to discover potent EGFR inhibitors. To resolve protein flexibility issue we have utilized 5 EGFR wild type crystal structures during docking as this gives improved possibility of identifying an active compound as compared to using a single crystal structure. We then identified five curcumin analogs representing different scaffolds that can serve as lead molecules. Finally, the 5 ns molecular dynamics simulation shows that knoevenagel condensate of curcumin specifically C29 and C30 can be used as starting blocks for developing effective leads capable of inhibiting EGFR. PMID- 24491505 TI - Transcriptional background of beef marbling - novel genes implicated in intramuscular fat deposition. AB - The purpose of this study was to identify novel marbling-related genes by comparison of the global gene expression in semitendinosus muscle of 15-month-old Limousin (LIM), Holstein-Friesian (HF) and Hereford (HER) bulls. Muscle of LIM was lean with low intramuscular fat (IMF) content (0.53%) unlike the marbled muscles of HER and HF characterized by higher amounts of IMF (1.10 and 0.81%, respectively). The comparison of muscle transcriptional profile between marbled and lean beef revealed significant differences in expression of 144 genes, presumably involved in consecutive stages of adipose tissue development, such as preadipocyte proliferation and differentiation, adipocyte maturation, lipid filling and lipid metabolism leading to increased IMF deposition and marbling development. Correlation coefficients and regression analysis for nine of them (gadd45a, pias3, ccrn4l, diras3, pou5f1, hoxa9, atp2a2 and pim1) validated by real-time qPCR confirmed their moderate-high correlation with IMF% and explained up to 70.5% of the total variability in IMF deposition in the bulls. PMID- 24491506 TI - Non-coding RNAs in cardiovascular ageing. AB - The increasing burden of ageing populations and their healthcare expenditure is a major challenge worldwide. Ageing is a complex disorder and can be defined as progressive decline in function with time leading to increased incidence of various cardiovascular, neurological and immunological diseases. The human genome comprises of many protein coding and even more non-coding RNA genes. MicroRNAs, a class of non-coding RNA, regulate the expression of multiple messenger RNAs post transcriptionally and are reported to be involved in crucial aspects of cell biology encompassing ageing. Recently, several studies have reported the regulation of microRNAs with ageing and microRNAs like miR-34 have emerged as critical regulator of ageing extending from Caenorhabditis elegans to mammals. Here, we summarize the reported role of microRNAs as well as long noncoding RNAs (lncRNAs) in the process of ageing with a special emphasis on cardiovascular ageing. PMID- 24491507 TI - "Treating the Whole Person with Autism: Care Across the Lifespan," Columbus, Ohio, July 26 to 27, 2013. PMID- 24491508 TI - Treating the whole person with autism: the proceedings of the Autism Speaks National Autism Conference. AB - The identification of autism spectrum disorders has increased dramatically over the past decade, with the latest estimates indicating prevalence as high as 1 in 54 boys. There is greater awareness of medical conditions that co-occur with autism and expansion of treatment options. Closer scrutiny has led to refinement of the diagnostic criteria, and there have been advances in genetics examining potential causal factors. Transition to adulthood is an area of growing concern, and professionals and families require guidance on this issue. This article summarizes the proceedings of the Autism Speaks conference on Treating the Whole Person with Autism: Care across the Lifespan. The conference was organized with the intent of providing a forum for both families and professionals to learn about the most current research in the field. Dr. Sue Swedo provides important background information regarding the changes in the diagnostic criteria for autism spectrum disorders. She particularly deals with the concerns of individuals and families that their autism diagnosis may change. Recommendations for genetic testing and its interpretation are provided by Dr. David Miller. His discussion helps make sense of the utility of genetic testing for ASD, along with demonstration of the complexity of determining which genetic factors are doing what and through which pathways. Dr. Jeremy Veenstra-VanderWeele provides useful background information on how medicines are initially identified and for what purpose and goes on to describe the present and future treatments in pharmacology. Medical issues are addressed by Dr. Paul Carbone, especially the coordination of comprehensive services through the medical home model of care. Dr. Julie Lounds Taylor concludes with guidance on preparation for adulthood, a topic of great importance to families as their child matures and for the professionals who will help guide this transition. PMID- 24491509 TI - Commentary. PMID- 24491510 TI - A porous tissue engineering scaffold selectively degraded by cell-generated reactive oxygen species. AB - Biodegradable tissue engineering scaffolds are commonly fabricated from poly(lactide-co-glycolide) (PLGA) or similar polyesters that degrade by hydrolysis. PLGA hydrolysis generates acidic breakdown products that trigger an accelerated, autocatalytic degradation mechanism that can create mismatched rates of biomaterial breakdown and tissue formation. Reactive oxygen species (ROS) are key mediators of cell function in both health and disease, especially at sites of inflammation and tissue healing, and induction of inflammation and ROS are natural components of the in vivo response to biomaterial implantation. Thus, polymeric biomaterials that are selectively degraded by cell-generated ROS may have potential for creating tissue engineering scaffolds with better matched rates of tissue in-growth and cell-mediated scaffold biodegradation. To explore this approach, a series of poly(thioketal) (PTK) urethane (PTK-UR) biomaterial scaffolds were synthesized that degrade specifically by an ROS-dependent mechanism. PTK-UR scaffolds had significantly higher compressive moduli than analogous poly(ester urethane) (PEUR) scaffolds formed from hydrolytically degradable ester-based diols (p < 0.05). Unlike PEUR scaffolds, the PTK-UR scaffolds were stable under aqueous conditions out to 25 weeks but were selectively degraded by ROS, indicating that their biodegradation would be exclusively cell-mediated. The in vitro oxidative degradation rates of the PTK URs followed first-order degradation kinetics, were significantly dependent on PTK composition (p < 0.05), and correlated to ROS concentration. In subcutaneous rat wounds, PTK-UR scaffolds supported cellular infiltration and granulation tissue formation, followed first-order degradation kinetics over 7 weeks, and produced significantly greater stenting of subcutaneous wounds compared to PEUR scaffolds. These combined results indicate that ROS-degradable PTK-UR tissue engineering scaffolds have significant advantages over analogous polyester-based biomaterials and provide a robust, cell-degradable substrate for guiding new tissue formation. PMID- 24491511 TI - Validation of the Premature Infant Pain Profile-Revised (PIPP-R). AB - OBJECTIVES: To examine the construct validity, inter-rater reliability, and feasibility of the Premature Infant Pain Profile-Revised in infants of varying gestational ages, diagnoses, and procedures. METHODS: A prospective cross-over study with infants in three gestational age groups (26-31, 32-36, and >=37 weeks) at three university-affiliated Neonatal Intensive Care Units in Canada. One hundred and ninety five bedside nurses and expert raters rated 202 hospitalized infants' pain during scheduled procedures using the measure. An expert rater and a nurse independently assessed infants' pain scores, using the Premature Infant Pain Profile-Revised, during 246 scheduled pairs of painful and non-painful procedures in the 202 infants. Nurses also completed a feasibility survey on using the measure in a clinical setting. To establish construct validity, pain scores were computed during painful and non-painful procedures. Inter-rater reliability between pain experts and nurses was calculated. A 5-point Likert scale was used to measure feasibility in terms of clarity, ease of use, and time to complete. RESULTS: Irrespective of gestational age, Premature Infant Pain Profile-Revised scores were significantly higher during painful procedures (mean 6.7 [SD 3.0]) compared to non-painful procedures (mean 4.8 [SD 2.9]). There was a high degree of correlation between nurses' and experts' ratings for painful (all R(2)=0.92, p<0.001) and non-painful (all R(2)=0.87, p<0.001) procedures. Mean scores on all feasibility indicators were equal to or higher than 3.8. DISCUSSION: The Premature Infant Pain Profile Revised has beginning construct validation, inter-rater reliability, and is considered feasible by clinicians. Concurrent validation studies should be considered. PMID- 24491512 TI - [Variability and opportunity costs among the surgical alternatives for breast cancer]. AB - OBJECTIVE: To analyze medical practice variation in breast cancer surgery (either inpatient-based or day-case surgery), by comparing conservative surgery (CS) plus radiotherapy vs. non-conservative surgery (NCS). We also analyzed the opportunity costs associated with CS and NCS. METHODS: We performed an observational study of age- and sex-standardized rates of CS and NCS, performed in 199 Spanish healthcare areas in 2008-2009. Costs were calculated by using two techniques: indirectly, by using All-Patients Diagnosis Related Groups (AP-DRG) based on hospital admissions, and directly by using full costing from the Spanish Network of Hospital Costs (SNHC) data. RESULTS: Standardized surgery rates for CS and NCS were 6.84 and 4.35 per 10,000 women, with variation across areas ranging from 2.95 to 3.11 per 10,000 inhabitants. In 2009, 9% of CS was performed as day-case surgery, although a third of the health care areas did not perform this type of surgery. Taking the SNHC as a reference, the cost of CS was estimated at 7,078 ? and that of NCS was 6,161 ?. Using AP-DRG, costs amounted to 9,036 ? and 8,526 ?, respectively. However, CS had lower opportunity costs than NCS when day-case surgery was performed frequently-more than 46% of cases (following SNHC estimates) or 23% of cases (following AP-DRG estimates). CONCLUSIONS: Day-case CS for breast cancer was found to be the best option in terms of opportunity-costs beyond a specific threshold, when both CS and NCS are elective. PMID- 24491513 TI - [The "neglect" of people infected with the human immunodeficiency virus who do not have "insurance": unfair and inefficient]. PMID- 24491514 TI - Adalimumab versus infliximab for the treatment of moderate to severe ulcerative colitis in adult patients naive to anti-TNF therapy: an indirect treatment comparison meta-analysis. AB - OBJECTIVE: To compare the efficacy of adalimumab and infliximab for the treatment of moderate to severe ulcerative colitis using indirect treatment comparison meta analysis. METHODS: A systematic review and Bayesian indirect treatment comparison meta-analyses were performed for seven patient-important clinical outcomes at 8 weeks and 52 weeks. Odds ratio (OR) estimates and associated 95% credible intervals (CrIs) were produced. RESULTS: Five eligible RCTs informed clinical remission, response, mucosal healing, quality of life, colectomy, serious adverse events, and discontinuation due to adverse events at 8 weeks and 52 weeks. At 8 weeks of induction therapy, clinical remission (OR=0.42, 95% CrI 0.17-0.97), clinical response (OR=0.45, 95% CrI 0.23-0.89) and mucosal healing (OR=0.46, 95% CrI 0.25-0.86) statistically favored infliximab. However, after 52 weeks of maintenance therapy OR estimates showed no significant difference between infliximab and adalimumab. For serious adverse events and discontinuations due to adverse events, adalimumab and infliximab were similar to placebo. Further, the indirect treatment comparison of adalimumab and infliximab yielded odds ratios close to 1.00 with wide credible intervals. CONCLUSION: The findings of this indirect treatment comparison meta-analysis suggest that both infliximab and adalimumab are superior to placebo in the treatment of moderate to moderately severe ulcerative colitis. While infliximab is statistically more effective than adalimumab in the induction of remission, response and mucosal healing at 8 weeks, infliximab and adalimumab are comparable in efficacy at 52 weeks of maintenance treatment. PMID- 24491515 TI - Adalimumab for Crohn's disease: long-term sustained benefit in a population-based cohort of 438 patients. AB - BACKGROUND AND AIMS: Adalimumab is an effective therapy for induction and maintenance of Crohn's disease. However, results in clinical trials don't necessarily reflect daily clinical practice. Therefore, we assessed real-life long-term clinical response to adalimumab in a large population-based cohort and identified clinical parameters affecting response METHODS: All consecutive patients in North-Holland that started adalimumab between 2003 and 2011 were included, of which medical charts were reviewed. Response to induction therapy was assessed after 3months. Sustained benefit of maintenance therapy was calculated from Kaplan-Meier survival tables depicting ongoing adalimumab treatment. Regression analyses were performed to identify factors predicting response to adalimumab therapy. RESULTS: In total 438 Crohn's patients started adalimumab with 92.5% response to the induction phase. After 1year 83.3% showed sustained benefit of maintenance treatment, followed by 74.0% after 2years. Nevertheless, one third of patients were in steroid-free remission at the end of their follow-up. Response to induction was negatively affected by longer disease duration (OR 1.05; p<0.01) and strictures (OR 3.73; p=0.04). Increased CRP levels predicted higher rates of initial response (OR 0.31; p<0.01). Concomitant thiopurines in the first 6months of adalimumab treatment decreased the risk to fail maintenance therapy (HR 0.69, p=0.05). Previous infliximab therapy did not affect response to adalimumab, however dose escalation was more often deemed necessary (p<0.01). CONCLUSION: Adalimumab was successful in the majority of patients, with 10% loss of response per subsequent year. Concomitant thiopurines might improve adalimumab maintenance treatment. PMID- 24491516 TI - Healthcare professionals' perceptions of fatigue experienced by people with IBD. AB - BACKGROUND AND AIMS: Fatigue is one of the top complaints of people with inflammatory bowel disease (IBD); however this is often not addressed in clinical consultations. This study aimed to gain an understanding of healthcare practitioners' (HCPs) perception of IBD fatigue as experienced by people with IBD. METHODS: Descriptive phenomenology was conducted with 20 HCPs who work with people with IBD. In-depth semi-structured interviews were audio recorded and transcribed verbatim. Colazzi's framework was used to analyse data. RESULTS: Three themes and several sub-themes were identified. The main themes were: the phenomenon of fatigue as perceived by HCPs; the impact of fatigue on patients' lives; and the methods used by HCPs to deal with fatigue. Fatigue was identified as an important, but difficult and frustrating, symptom to understand. HCPs reported that fatigue impacts on the emotional, private and public aspects of patients' functioning, however there were few methods suggested on how to assess and manage the fatigue. Many expressed frustration at not being able to help more. CONCLUSIONS: The study identified a gap in HCPs' knowledge and their understanding of the complexity of IBD fatigue and the full impact that IBD fatigue has on people's lives. There is a need for more research-generated evidence to enhance our understanding of the concept and the factors associated with IBD fatigue. Advances in the assessment and management of this complicated and poorly understood clinical symptom are needed in order to help enable HCPs to provide better quality care to people affected by IBD and IBD fatigue. PMID- 24491517 TI - IBD prevalence in Baltic states or just a guessing game? PMID- 24491518 TI - Brain stem hemorrhage due to cerebral amyloid angiopathy: the autopsy of a patient with Alzheimer's disease at a young age. AB - We report findings from an autopsy of a male in his 40s who died of a brain stem hemorrhage associated with cerebral amyloid angiopathy (CAA), senile plaques (SPs) and neurofibrillary tangles (NFTs), which are histopathological changes associated with Alzheimer's disease (AD). Our immunohistochemical study demonstrated amyloid beta (Abeta) deposition in the small cerebral arteries and SPs. Although hypertension (178/132 mmHg) was detected, the subject was not treated accordingly. CAA coupled with hypertension might have caused the intracerebral hemorrhage (ICH). PMID- 24491519 TI - Efficacy of automated three-dimensional image reconstruction of the femur from postmortem computed tomography data in morphometry for victim identification. AB - Besides conventional radiology, postmortem computed tomography (PM-CT) is nowadays widely used for victim identification in forensic routines to detect anatomical characteristics and specific pathologies as well as to estimate the stature and sex. A major advantage of PM-CT is virtual reconstruction of skeletal structures independent of the status of recovered remains. The present study investigated the efficacy of a recently provided automated analyzer to reconstruct three-dimensional (3-D) images using CT data for skeletal morphometry, measuring the whole bone mass volume of the femur (60 bones in 30 cases) as an index of reproducibility. Manual cursoring could reconstruct bilateral femurs with high reproducibility, showing mass volume fluctuations by repetition and between two independent observers of 0.2-2.1% and 3.5-6.7%, respectively, partly depending on the data analysis system, but was time consuming, while automated reconstruction was very rapid and highly reproducible virtually without detectable fluctuation; there was a high correlation between bone mass volumes reconstructed by manual and automated procedures (r=0.9976, p<0.0001). The reproducibility of the automated procedure was 98.64-100.81% in 5 cases scanned twice under the same CT conditions. Preliminary analysis showed a substantial correlation of the whole femur mass volume with the body height and a significant sex-related difference in the femur mass volume/body height ratio (males>females). These findings indicate the accuracy and practical feasibility of the automated procedure to reconstruct single bone 3-D CT images for virtual skeletal morphometry in victim identification. PMID- 24491520 TI - A longitudinal study of gait function and characteristics of gait disturbance in individuals with Alzheimer's disease. AB - Walking in daily life places high demands on the interplay between cognitive and motor functions. A well-functioning dual-tasking ability is thus essential for walking safely. The aims were to study longitudinal changes in gait function during single- and dual-tasking over a period of two years among people with initially mild AD (n=21). Data were collected on three occasions, twelve months apart. An optical motion capture system was used for three-dimensional gait analysis. Gait parameters were examined at comfortable gait speed during single tasking, dual-tasking naming names, and naming animals. The dual-task cost for gait speed was pronounced at baseline (names 26%, animals 35%), and remained so during the study period. A significant (p<0.05) longitudinal decline in gait speed and step length during single- and dual-tasking was observed, whereas double support time, step width and step height showed inconsistent results. Systematic visual examination of the motion capture files revealed that dual tasking frequently resulted in gait disturbances. Three main characteristics of such disturbances were identified: Temporal disturbance, Spatial disturbance and Instability in single stance. These aberrant gait performances may affect gait stability and increase the risk of falling. Furthermore, the observed gait disturbances can contribute to understanding and explaining previous reported gait variability among individuals with AD. However, the role that dual-task testing and aberrant dual-task gait performance play in the identification of individuals with early signs of cognitive impairment and in predicting fall risk in AD remains to be studied. PMID- 24491521 TI - Identification of gamma-interferon-inducible lysosomal thiol reductase (GILT) homologues in the fruit fly Drosophila melanogaster. AB - Gamma-interferon-inducible lysosomal thiol reductase (GILT) has been demonstrated to be involved in the immune response to bacterial challenge in various organisms. However, little is known about GILT function in innate immunity. Drosophila has been commonly used as a model for the study of the innate immune response of invertebrates. Here, we identify the CG9796, CG10157, and CG13822 genes of fruit fly Drosophila melanogaster as GILT homologues. All deduced Drosophila GILT coding sequences contained the major characteristic features of the GILT protein family: the GILT signature CQHGX2ECX2NX4C sequence and the active site CXXC or CXXS motif. The mRNA transcript levels of the Drosophila GILT genes were up-regulated after Gram-negative bacteria Escherichia coli DH5alpha infection. Moreover, a bacterial load assay showed that over-expression of Drosophila GILT in fat body or hemocytes led to a low bacterial colony number whereas knock-down of Drosophila GILT in fat body or hemocytes led to a high bacterial colony number when compared to a wild-type control. These results indicate that the Drosophila GILTs are very likely to play a role in the innate immune response upon bacterial challenge of Drosophila host defense. This study may provide the basis for further study on GILT function in innate immunity. PMID- 24491523 TI - Rapid and simple extraction of lipids from blood plasma and urine for liquid chromatography-tandem mass spectrometry. AB - A simple and fast lipid extraction method from human blood plasma and urine is introduced in this study. The effective lipid extraction from biological systems with a minimization of the matrix effect is important for the successful qualitative and quantitative analysis of lipids in liquid chromatography electrospray ionization-tandem mass spectrometry (LC-ESI-MS/MS). The method described here is based on the modification of the quick, easy, cheap, effective, rugged and safe (QuEChERS) extraction method, which was originally developed for pesticide residue analysis in food, for the purpose of isolating lipids from biological fluids. Applicability of QuEChERS method for lipids was evaluated by varying organic solvents for the extraction/partitioning of lipids in MgSO4/CH3COONa for the removal of water and by varying sorbents (primary secondary amines, graphitized carbon black, silica, strong anion exchange resins and C18 particles) for the dispersive solid-phase extraction (dSPE) step. This study shows that 2:1 (v/v) CHCl3/CH3OH is effective in the extraction/partitioning step and that 50mg of C18 particles (for 0.1mL plasma and 1mL of urine) are more suitable for sample cleanup for the dSPE step of the QuEChERS method. Matrix effects were calculated by comparing the recovery values of lipid standards spiked to both plasma and urine samples after extraction with those of the same standards in a neat solution using nanoflow LC-ESI-MS/MS, resulting in improved MS signals due to the decrease of the ion suppression compared to the conventional Folch method. The modified QuEChERS method was applied to lipid extracts from both human urine and plasma samples, demonstrating that it can be powerfully utilized for high-speed (<15min) preparation of lipids compared to the Folch method, with equivalent or slightly improved results in lipid identification using nLC-ESI-MS/MS. PMID- 24491522 TI - Utilization of zebrafish for intravital study of eukaryotic pathogen-host interactions. AB - Unique imaging tools and practical advantages have made zebrafish a popular model to investigate in vivo host-pathogen interactions. These studies have uncovered details of the mechanisms involved in several human infections. Until recently, studies using this versatile host were limited to viral and prokaryotic pathogens. Eukaryotic pathogens are a diverse group with a major impact on the human and fish populations. The relationships of eukaryote pathogens with their hosts are complex and many aspects remain obscure. The small and transparent zebrafish, with its conserved immune system and amenability to genetic manipulation, make it an exciting model for quantitative study of the core strategies of eukaryotic pathogens and their hosts. The only thing to do now is realize its potential for advancement of biomedical and aquaculture research. PMID- 24491524 TI - Engineering the allosteric properties of archaeal non-phosphorylating glyceraldehyde-3-phosphate dehydrogenases. AB - The archaeal non-phosphorylating glyceraldehyde-3-phosphate dehydrogenase (GAPN, EC 1.2.1.9) is a highly allosteric enzyme activated by glucose 1-phosphate (Glc1P). Recent kinetic analyses of two GAPN homologs from Sulfolobales show different allosteric behaviors toward the substrate glyceraldehyde-3-phosphate (GAP) and the allosteric effector Glc1P. In GAPN from Sulfolobus tokodaii (Sto GAPN), Glc1P-induced activation follows an increase in affinity for GAP rather than an increase in maximum velocity, whereas in GAPN from Sulfolobus solfataricus (Sso-GAPN), Glc1P-induced activation follows an increase in maximum velocity rather than in affinity for GAP. To explore the molecular basis of this difference between Sto-GAPN and Sso-GAPN, we generated 14 mutants and 2 chimeras. The analyses of chimeric GAPNs generated from regions of Sto-GAPN and Sso-GAPN indicated that a 57-residue module located in the subunit interface was clearly involved in their allosteric behavior. Among the point mutations in this modular region, the Y139R variant of Sto-GAPN no longer displayed a sigmoidal K-type-like allostery, but instead had apparent V-type allostery similar to that of Sso-GAPN, suggesting that the residue located in the center of the homotetramer critically contributes to the allosteric behavior. PMID- 24491525 TI - Four Cys residues in heterodimeric 2-oxoacid:ferredoxin oxidoreductase are required for CoA-dependent oxidative decarboxylation but not for a non-oxidative decarboxylation. AB - Heterodimeric 2-oxoacid:ferredoxin oxidoreductase (OFOR) from Sulfolobus tokodaii (StOFOR) has only one [4Fe-4S]2+ cluster, ligated by 4 Cys residues, C12, C15, C46, and C197. The enzyme has no other Cys. To elucidate the role of these Cys residues in holding of the iron-sulfur cluster in the course of oxidative decarboxylation of a 2-oxoacid, one or two of these Cys residues was/were substituted with Ala to yield C12A, C15A, C46A, C197A and C12/15A mutants. All the mutants showed the loss of iron-sulfur cluster, except the C197A one which retained some unidentified type of iron-sulfur cluster. On addition of pyruvate to OFOR, the wild type enzyme exhibited a chromophore at 320nm and a stable large EPR signal corresponding to a hydroxyethyl-ThDP radical, while the mutant enzymes did not show formation of any radical intermediate or production of acetyl-CoA, suggesting that the intact [4Fe-4S] cluster is necessary for these processes. The stable radical intermediate in wild type OFOR was rapidly decomposed upon addition of CoA in the absence of an electron acceptor. Non-oxidative decarboxylation of pyruvate, yielding acetaldehyde, has been reported to require CoA for other OFORs, but StOFOR catalyzed acetaldehyde production from pyruvate independent of CoA, regardless of whether the iron-sulfur cluster is intact [4Fe 4S] type or not. A comprehensive reaction scheme for StOFOR with a single cluster was proposed. PMID- 24491526 TI - Significant positive relationship between serum magnesium and muscle quality in maintenance hemodialysis patients. AB - BACKGROUND/AIMS: Serum magnesium (Mg) levels have been associated with muscle performance in the general population. We hypothesized that serum Mg would be associated with muscle quality in hemodialysis patients. METHODS: A total of 310 patients were examined (age: 58 +/- 12 years, hemodialysis duration: 6.4 +/- 6.0 years, 60.6% men, and 36.1% diabetics). Arm lean mass was measured by dual energy X-ray absorptiometry (DXA) on the dominant side. Arm muscle quality was defined as the ratio of the handgrip strength to the arm lean mass of the same side (kg/kg). RESULTS: Serum Mg was 1.15 +/- 0.16 mmol/L (2.8 +/- 0.4 mg/dL), being higher than the reference range of normal subjects. There was a significant negative correlation between muscle quality and age (r = -0.326, p<0.0001) and duration of hemodialysis (r = -0.253, p<0.0001). The muscle quality of the diabetics was significantly lower than that of the non-diabetics (p<0.001). There was a significant, positive correlation between muscle quality and serum Mg (r = 0.118, p<0.05), but not serum calcium or phosphate. In multiple regression analysis, age, gender, hemodialysis duration, diabetes, and serum Mg (beta = 0.129, p<0.05) were significantly and independently associated with muscle quality (R(2) = 0.298, p<0.0001). CONCLUSION: These results demonstrated that a lower serum Mg concentration was significantly associated with poor muscle quality in hemodialysis patients. Further studies are needed to explore the mechanism by which lower serum Mg affects muscle quality. PMID- 24491527 TI - Acoustic emission monitoring from a lab scale high shear granulator--a novel approach. AB - A new approach to the monitoring of granulation processes using passive acoustics together with precise control over the granulation process has highlighted the importance of particle-particle and particle-bowl collisions in acoustic emission. The results have shown that repeatable acoustic results could be obtained but only when a spray nozzle water addition system was used. Acoustic emissions were recorded from a transducer attached to the bowl and an airborne transducer. It was found that the airborne transducer detected very little from the granulation and only experienced small changes throughout the process. The results from the bowl transducer showed that during granulation the frequency content of the acoustic emission shifted towards the lower frequencies. Results from the discrete element model indicate that when larger particles are used the number of collisions the particles experience reduces. This is a result of the volume conservation methodology used in this study, therefore larger particles results in less particles. These simulation results coupled with previous theoretical work on the frequency content of an impacting sphere explain why the frequency content of the acoustic emissions reduces during granule growth. The acoustic system used was also clearly able to identify when large over-wetted granules were present in the system, highlighting its benefit for detecting undesirable operational conditions. High-speed photography was used to study if visual changes in the granule properties could be linked with the changing acoustic emissions. The high speed photography was only possible towards the latter stages of the granulation process and it was found that larger granules produced a higher magnitude of acoustic emission across a broader frequency range. PMID- 24491529 TI - Double layer paclitaxel delivery systems based on bioresorbable terpolymer with shape memory properties. AB - The growing interest in the bioresorbable polymers contributed to developing a number of commercially available controlled drug delivery systems. Due to a variety of drugs and their physicochemical properties, there is a necessity of choosing an appropriate drug carrier. Terpolymer with shape memory properties was used to obtain double layer matrices composed of drug free matrix and paclitaxel containing layer. The in vitro degradation and drug release study were conducted at 37 degrees C in PBS (pH 7.4). The investigated materials were characterized by GPC (gel permeation chromatography) and DSC (differential scanning calorimetry). HPLC (high-pressure liquid chromatography) was applied to analyze the amount of released paclitaxel. The main purpose of this work was to determine the usefulness of the studied terpolymer as an anti-restenotic drug vehicle. Based on the obtained results it was established that polymer's degradation proceeded regularly and provided even paclitaxel release profiles. Double layer systems allowed to modify the amount of released drug which may be considered while developing the self-expanding drug-eluting stents tailoring different clinical indications. PMID- 24491528 TI - An allergen-polymeric nanoaggregate as a new tool for allergy vaccination. AB - A recombinant hybrid composed of the two major allergens of the Parietaria pollen Par j 1 and Par j 2 has been generated by DNA recombinant technology (PjED). This hybrid was produced in E. coli at high levels of purity. Then, the engineered derivative has been combined with a synthetic polyaminoacidic derivative having a poly(hydroxyethyl)aspartamide (PHEA) backbone and bearing both butyryl groups (C4) and succinyl (S) moieties in the side chain (PHEA-C4-S). The allergen copolymer nanoaggregate was characterized by means of DLS, zeta potential, electrophoretic mobility and atom force microscopy analysis displaying the formation of a stable complex. Its safety has been proved in vitro on a murine cell line, human erythrocytes and basophils. Moreover, the formation of the complex did not alter the ability of the allergens to cross-link surface bound specific IgE demonstrating that the combination of an engineered hybrid with a copolymer did not interfere with its biological activity suggesting its employment as potential vaccine against Parietaria-induced allergies. PMID- 24491530 TI - Differences in physical chemistry and dissolution rate of solid particle aerosols from solution pressurised inhalers. AB - Solution composition alters the dynamics of beclomethasone diproprionate (BDP) particle formation from droplets emitted by pressurised metered dose inhalers (pMDIs). The hypothesis that differences in inhaler solutions result in different solid particle physical chemistry was tested using a suite of complementary calorimetric techniques. The atomisation of BDP-ethanol solutions from commercial HFA-pMDI produced aerodynamically-equivalent solid particle aerosols. However, differences in particle physico-chemistry (morphology and solvate/clathrate formation) were detected by differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and supported by hot stage microscopy (HSM). Increasing the ethanol content of the formulation from 8 to 12% (w/w), which retards the evaporation of propellant and slows the increase in droplet surface viscosity, enhanced the likelihood of particles drying with a smooth surface. The dissolution rate of BDP from the 12% (w/w) ethanol formulation-derived particles (63% dissolved over 120 min) was reduced compared to the 8% (w/w) ethanol formulation-derived particles (86% dissolved over 120 min). The addition of 0.01% (w/w) formoterol fumarate or 1.3% (w/w) glycerol to the inhaler solution modified the particles and reduced the BDP dissolution rate further to 34% and 16% dissolved in 120 min, respectively. These data provide evidence that therapeutic aerosols from apparently similar inhaler products, including those with similar aerodynamic performance, may behave non-equivalently after deposition in the lungs. PMID- 24491531 TI - The difficulties for a photolabile drug in topical formulations: the case of diclofenac. AB - Topical commercial formulations containing diclofenac (DC) were submitted to photostability tests, according to the international rules, showing a clear degradation of the drug. The degradation process was monitored by applying the multivariate curve resolution technique to the UV spectral data from samples exposed to stressing irradiation. This method was able to estimate the number of components evolved as well as to draw their spectra and concentration profiles. Three photoproducts (PhPs) were resolved by the analysis of photodegradation kinetics, according to two consecutive reactions with a mechanism postulated as DC>PhP1>PhP2 and PhP3. Photodegradation rate of DC in gel was found to be very fast, with a residual content of 90% only after 3.90 min under a radiant exposure of 450 Wm(-2). Because of a very slow skin uptake of DC, a prolonged time of exposure to light could lead to a significant decrease of drug available or the uptake of undesired photoproducts. New gel formulations were designed to increase the photostability of DC by incorporating chemical light-absorbers or entrapping the drug into cyclodextrin. Drug photostability resulted increased significantly in comparison with that of the commercial formulations. The gel containing the light-absorbers such as octisilate, octyl methoxycinnamate and a combination thereof showed a residual DC of 90% up to 12.22 min, 13.75 min and 15.71 min, respectively, under the same irradiation power. The best results were obtained by incorporating the drug in beta-cyclodextrin with a degradation of 10% after 25.01 min of light exposure. PMID- 24491532 TI - Sirt3 controls chromosome alignment by regulating spindle dynamics during mitosis. AB - Sirt3, one of mammalian sirtuins is a prominent mitochondrial deacetylase that controls mitochondrial oxidative pathways and the rate of reactive oxygen species. Sirt3 also regulates energy metabolism by deacetylating enzymes involved in the metabolic pathway related with lifespan. We report here a novel function of Sirt3 which was found to be involved in mitosis. Depletion of the Sirt3 protein generated unaligned chromosomes in metaphase which caused mitotic arrest by activating spindle assembly checkpoint (SAC). Furthermore, the shape and the amount of the spindles in Sirt3 depleted cells were abnormal. Microtubule (MT) polymerization also increased in Sirt3 depleted cells, suggesting that Sirt3 is involved in spindle dynamics. However, the level of acetylated tubulin was not increased significantly in Sirt3 depleted cells. The findings collectively suggest that Sirt3 is not a tubulin deacetylase but regulates the attachment of spindle MTs to the kinetochore and the subsequent chromosome alignment by increasing spindle dynamics. PMID- 24491533 TI - Jolkinolide B inhibits RANKL-induced osteoclastogenesis by suppressing the activation NF-kappaB and MAPK signaling pathways. AB - Osteoclasts together with osteoblasts play pivotal roles in bone remodeling. The unique function and ability of osteoclasts to resorb bone makes them critical in both normal bone homeostasis and pathologic bone diseases such as osteoporosis and rheumatoid arthritis. Thus, new compounds that may inhibit osteoclastogenesis and osteoclast function may be of great value in the treatment of osteoclast related diseases. In the present study, we examined the effect of jolkinolide B (JB), isolated from the root of Euphorbia fischeriana Steud on receptor activator of NF-kappaB ligand (RANKL)-induced osteoclast formation. We found that JB inhibited RANKL-induced osteoclast differentiation from bone marrow macrophages (BMMs) without cytotoxicity. Furthermore, the expression of osteoclastic marker genes, such as tartrate-resistant acid phosphatase (TRAP), cathepsin K (CtsK), and calcitonin receptor (CTR), was significantly inhibited. JB inhibited RANKL induced activation of NF-kappaB by suppressing RANKL-mediated IkappaBalpha degradation. Moreover, JB inhibited RANKL-induced phosphorylation of mitogen activated protein kinases (p38, JNK, and ERK). This study thus identifies JB as an inhibitor of osteoclast formation and provides evidence that JB might be an alternative medicine for preventing and treating osteolysis. PMID- 24491534 TI - Guanine nucleotide-binding protein subunit beta-2-like 1, a new Annexin A7 interacting protein. AB - We report for the first time that Guanine nucleotide-binding protein subunit beta 2-like 1 (RACK1) formed a complex with Annexin A7. Hca-F and Hca-P are a pair of syngeneic mouse hepatocarcinoma cell lines established and maintained in our laboratory. Our previous study showed that both Annexin A7 and RACK1 were expressed higher in Hca-F (lymph node metastasis >70%) than Hca-P (lymph node metastasis <30%). Suppression of Annexin A7 expression in Hca-F cells induced decreased migration and invasion ability. In this study, knockdown of RACK1 by RNA interference (RNAi) had the same impact on metastasis potential of Hca-F cells as Annexin A7 down-regulation. Furthermore, by co-immunoprecipitation and double immunofluorescence confocal imaging, we found that RACK1 was in complex with Annexin A7 in control cells, but not in the RACK1-down-regulated cells, indicating the abolishment of RACK1-Annexin A7 interaction in Hca-F cells by RACK1 RNAi. Taken together, these results suggest that RACK1-Annexin A7 interaction may be one of the means by which RACK1 and Annexin A7 influence the metastasis potential of mouse hepatocarcinoma cells in vitro. PMID- 24491535 TI - Recent advances in Phytosterol Oxidation Products. AB - Phytosterols and their oxidation products have become increasingly investigated in recent years with respect to their roles in diet and nutrition. We present a comprehensive review of recent literature on Phytosterol Oxidation Products (POP) identifying critical areas for future investigation. It is evident that POP are formed on food storage/preparation; are absorbed and found in human serum; do not directly affect cholesterol absorption; have evidence of atherogenicity and inflammation; have distinct levels of cytotoxicity; are implicated with high levels of oxidative stress, glutathione depletion, mitochondrial dysfunction and elevated caspase activity. PMID- 24491536 TI - Luminescence enhancement of the catalytic 19 kDa protein (KAZ) of Oplophorus luciferase by three amino acid substitutions. AB - To characterize the luminescence properties of nanoKAZ, a 16 amino acid substituted mutant of the catalytic 19kDa protein (KAZ) of Oplophorus luciferase, the effects of each mutated amino acid were investigated by site-specific mutagenesis. All 16 single substituted KAZ mutants were expressed in Escherichia coli cells and their secretory expressions in CHO-K1 cells were also examined using the signal peptide sequence of Gaussia luciferase. Luminescence activity of KAZ was significantly enhanced by single amino acid substitutions at V44I, A54I, or Y138I. Further, the triple mutant KAZ-V44I/A54I/Y138I, named eKAZ, was prepared and these substitutions synergistically enhanced luminescence activity, showing 66-fold higher activity than wild-KAZ and also 7-fold higher activity than nanoKAZ using coelenterazine as a substrate. Substrate specificity of eKAZ for C2- and/or C6-modified coelenterazine analogues was different from that of nanoKAZ, indicating that three amino acid substitutions may be responsible for the substrate recognition of coelenterazine to increase luminescence activity. In contrast, these substitutions did not stimulate protein secretion from CHO-K1 cells, suggesting that the folded-protein structure of KAZ might be different from that of nanoKAZ. PMID- 24491537 TI - Serine 83 in DosR, a response regulator from Mycobacterium tuberculosis, promotes its transition from an activated, phosphorylated state to an inactive, unphosphorylated state. AB - A sensor kinase, DosS, and its corresponding response regulator, DosR, constitute a two component system for regulating gene expression under hypoxic conditions in Mycobacterium tuberculosis. Among response regulators in M. tuberculosis, NarL has high sequence similarity to DosR, and autophosphorylated DosS transfers its phosphate group not only to DosR but also to NarL. Phosphorylated DosR is more rapidly dephosphorylated than phosphorylated NarL. DosR and NarL differ with respect to the amino acids at positions T+1 and T+2 around the phosphorylation sites in the N-terminal phosphoacceptor domain; NarL has S83 and Y84, whereas DosR has A90 and H91. A DosR S83A mutant shows prolonged phosphorylation. Structural comparison with a histidinol phosphate phosphatase suggests that the hydroxyl group of DosR S83 could play a role in activating the water molecule involved in the triggering of autodephosphorylation. PMID- 24491538 TI - Asymmetric spindle pole formation in CPAP-depleted mitotic cells. AB - CPAP is an essential component for centriole formation. Here, we report that CPAP is also critical for symmetric spindle pole formation during mitosis. We observed that pericentriolar material between the mitotic spindle poles were asymmetrically distributed in CPAP-depleted cells even with intact numbers of centrioles. The length of procentrioles was slightly reduced by CPAP depletion, but the length of mother centrioles was not affected. Surprisingly, the young mother centrioles of the CPAP-depleted cells are not fully matured, as evidenced by the absence of distal and subdistal appendage proteins. We propose that the selective absence of centriolar appendages at the young mother centrioles may be responsible for asymmetric spindle pole formation in CPAP-depleted cells. Our results suggest that the neural stem cells with CPAP mutations might form asymmetric spindle poles, which results in premature initiation of differentiation. PMID- 24491539 TI - Production of rhesus monkey cloned embryos expressing monomeric red fluorescent protein by interspecies somatic cell nuclear transfer. AB - Interspecies somatic cell nuclear transfer (iSCNT) is a promising method to clone endangered animals from which oocytes are difficult to obtain. Monomeric red fluorescent protein 1 (mRFP1) is an excellent selection marker for transgenically modified cloned embryos during somatic cell nuclear transfer (SCNT). In this study, mRFP-expressing rhesus monkey cells or porcine cells were transferred into enucleated porcine oocytes to generate iSCNT and SCNT embryos, respectively. The development of these embryos was studied in vitro. The percentage of embryos that underwent cleavage did not significantly differ between iSCNT and SCNT embryos (P>0.05; 71.53% vs. 80.30%). However, significantly fewer iSCNT embryos than SCNT embryos reached the blastocyst stage (2.04% vs. 10.19%, P<0.05). Valproic acid was used in an attempt to increase the percentage of iSCNT embryos that developed to the blastocyst stage. However, the percentages of embryos that underwent cleavage and reached the blastocyst stage were similar between untreated iSCNT embryos and iSCNT embryos treated with 2mM valproic acid for 24h (72.12% vs. 70.83% and 2.67% vs. 2.35%, respectively). These data suggest that porcine-rhesus monkey interspecies embryos can be generated that efficiently express mRFP1. However, a significantly lower proportion of iSCNT embryos than SCNT embryos reach the blastocyst stage. Valproic acid does not increase the percentage of porcine-rhesus monkey iSCNT embryos that reach the blastocyst stage. The mechanisms underling nuclear reprogramming and epigenetic modifications in iSCNT need to be investigated further. PMID- 24491540 TI - BmICE-2 is a novel pro-apoptotic caspase involved in apoptosis in the silkworm, Bombyx mori. AB - In this study we identified a potential pro-apoptotic caspase gene, Bombyx mori(B. mori)ICE-2 (BmICE-2) which encoded a polypeptide of 284 amino acid residues, including a (169)QACRG(173) sequence which surrounded the catalytic site and contained a p20 and a p10 domain. BmICE-2 expressed in Escherichia coli (E. coli) exhibited high proteolytic activity for the synthetic human initiator caspase-9 substrates Ac-LEHD-pNA, but little activity towards the effector caspase-3 substrates Ac-DEVD-pNA. When BmICE-2 was transiently expressed in BmN SWU1 silkworm B. mori cells, we found that the high proteolytic activity for Ac LEHD-pNA triggered caspase-3-like protease activity resulting in spontaneous cleavage and apoptosis in these cells. This effect was not replicated in Spodoptera frugiperda 9 cells. In addition, spontaneous cleavage of endogenous BmICE-2 in BmN-SWU1 cells could be induced by actinomycin D. These results suggest that BmICE-2 may be a novel pro-apoptotic gene with caspase-9 activity which is involved apoptotic processes in BmN-SWU1 silkworm B. mori cells. PMID- 24491541 TI - Genome-wide analysis of murine renal distal convoluted tubular cells for the target genes of mineralocorticoid receptor. AB - BACKGROUND AND OBJECTIVE: Mineralocorticoid receptor (MR) is a member of nuclear receptor family proteins and contributes to fluid homeostasis in the kidney. Although aldosterone-MR pathway induces several gene expressions in the kidney, it is often unclear whether the gene expressions are accompanied by direct regulations of MR through its binding to the regulatory region of each gene. The purpose of this study is to identify the direct target genes of MR in a murine distal convoluted tubular epithelial cell-line (mDCT). METHODS: We analyzed the DNA samples of mDCT cells overexpressing 3xFLAG-hMR after treatment with 10(-7)M aldosterone for 1h by chromatin immunoprecipitation with deep-sequence (ChIP-seq) and mRNA of the cell-line with treatment of 10(-7)M aldosterone for 3h by microarray. RESULTS: 3xFLAG-hMR overexpressed in mDCT cells accumulated in the nucleus in response to 10(-9)M aldosterone. Twenty-five genes were indicated as the candidate target genes of MR by ChIP-seq and microarray analyses. Five genes, Sgk1, Fkbp5, Rasl12, Tns1 and Tsc22d3 (Gilz), were validated as the direct target genes of MR by quantitative RT-qPCR and ChIP-qPCR. MR binding regions adjacent to Ctgf and Serpine1 were also validated. CONCLUSIONS: We, for the first time, captured the genome-wide distribution of MR in mDCT cells and, furthermore, identified five MR target genes in the cell-line. These results will contribute to further studies on the mechanisms of kidney diseases. PMID- 24491542 TI - Loss of AMP-activated protein kinase in X-linked adrenoleukodystrophy patient derived fibroblasts and lymphocytes. AB - X-Adrenoleukodystrophy (X-ALD) is a peroxisomal disorder characterized by accumulation of very-long-chain (VLC) fatty acids, which induces inflammatory disease and alterations in cellular redox, both of which are reported to play a role in the pathogenesis of the severe form of the disease (childhood cerebral ALD). While the mutation defect in ABCD1 gene is common to all forms of X-ALD it fails to account for the spectrum of phenotypic variability seen in X-ALD patients, strongly suggesting a role for as yet unidentified modifier gene(s). Here we report, for the first time, loss of AMP-activated protein kinase alpha1 (AMPKalpha1) in patient-derived fibroblasts and lymphocytes of the severe cerebral form of X-ALD (ALD), and not in the milder adrenomyeloneuropathy (AMN) form. Decrease in AMPK was observed at both protein and mRNA levels. AMPK loss in ALD patient-derived fibroblasts was associated with increased ubiquitination. Using the Seahorse Bioscience XF(e)96 Flux Analyzer for measuring the mitochondrial oxygen consumption and extracellular acidification rate we show that ALD patient-derived fibroblasts have a significantly lower "metabolic state" than AMN fibroblasts. Unstimulated ALD patient-derived lymphocytes had significantly higher proinflammatory gene expression. Selective AMPK loss represents a novel physiopathogenic factor in X-ALD disease mechanism. Strategies aimed at upregulating/recovering AMPK levels might have beneficial therapeutic effects in X-ALD. PMID- 24491544 TI - CD98hc regulates the development of experimental colitis by controlling effector and regulatory CD4(+) T cells. AB - CD4(+) T cell activation is controlled by signaling through the T cell receptor in addition to various co-receptors, and is also affected by their interactions with effector and regulatory T cells in the microenvironment. Inflammatory bowel diseases (IBD) are caused by the persistent activation and expansion of auto aggressive CD4(+) T cells that attack intestinal epithelial cells. However, the molecular basis for the persistent activation of CD4(+) T cells in IBD remains unclear. In this study, we investigated how the CD98 heavy chain (CD98hc, Slc3a2) affected the development of colitis in an experimental animal model. Transferring CD98hc-deficient CD4(+)CD25(-) T cells into Rag2(-/-) mice did not cause colitis accompanied by increasing Foxp3(+) inducible regulatory T cells. By comparison, CD98hc-deficient naturally occurring regulatory T cells (nTregs) had a decreased capability to suppress colitis induced by CD4(+)CD25(-) T cells, although CD98hc deficient mice did not have a defect in the development of nTregs. Blocking CD98hc with an anti-CD98 blocking antibody prevented the development of colitis. Our results indicate that CD98hc regulates the expansion of autoimmune CD4(+) T cells in addition to controlling nTregs functions, which suggests the CD98hc as an important target molecule for establishing strategies for treating colitis. PMID- 24491545 TI - Sexually dimorphic expression of the sex chromosome-linked genes cntfa and pdlim3a in the medaka brain. AB - In vertebrates, sex differences in the brain have been attributed to differences in gonadal hormone secretion; however, recent evidence in mammals and birds shows that sex chromosome-linked genes, independent of gonadal hormones, also mediate sex differences in the brain. In this study, we searched for genes that were differentially expressed between the sexes in the brain of a teleost fish, medaka (Oryzias latipes), and identified two sex chromosome genes with male-biased expression, cntfa (encoding ciliary neurotrophic factor a) and pdlim3a (encoding PDZ and LIM domain 3 a). These genes were found to be located 3-4 Mb from and on opposite sides of the Y chromosome-specific region containing the sex-determining gene (the medaka X and Y chromosomes are genetically identical, differing only in this region). The male-biased expression of both genes was evident prior to the onset of sexual maturity. Sex-reversed XY females, as well as wild-type XY males, had more pronounced expression of these genes than XX males and XX females, indicating that the Y allele confers higher expression than the X allele for both genes. In addition, their expression was affected to some extent by sex steroid hormones, thereby possibly serving as focal points of the crosstalk between the genetic and hormonal pathways underlying brain sex differences. Given that sex chromosomes of lower vertebrates, including teleost fish, have evolved independently in different genera or species, sex chromosome genes with sexually dimorphic expression in the brain may contribute to genus- or species-specific sex differences in a variety of traits. PMID- 24491543 TI - Genetic regulation of MUC1 expression by Helicobacter pylori in gastric cancer cells. AB - Helicobacter pylori infection of the stomach is associated with the development of gastritis, peptic ulcers, and gastric adenocarcinomas, but the mechanisms are unknown. MUC1 is aberrantly overexpressed by more than 50% of stomach cancers, but its role in carcinogenesis remains to be defined. The current studies were undertaken to identify the genetic mechanisms regulating H. pylori-dependent MUC1 expression by gastric epithelial cells. Treatment of AGS cells with H. pylori increased MUC1 mRNA and protein levels, and augmented MUC1 gene promoter activity, compared with untreated cells. H. pylori increased binding of STAT3 and MUC1 itself to the MUC1 gene promoter within a region containing a STAT3 binding site, and decreased CpG methylation of the MUC1 promoter proximal to the STAT3 binding site, compared with untreated cells. These results suggest that H. pylori upregulates MUC1 expression in gastric cancer cells through STAT3 and CpG hypomethylation. PMID- 24491546 TI - Phenethyl isothiocyanate sensitizes glioma cells to TRAIL-induced apoptosis. AB - Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) is a promising antitumor therapy. However, many cancer cells, including malignant glioma cells, tend to be resistant to TRAIL, highlighting the need for strategies to overcome TRAIL resistance. Here we show that in combination with phenethyl isothiocyanate (PEITC), exposure to TRAIL induced apoptosis in TRAIL-resistant glioma cells. Subtoxic concentrations of PEITC significantly potentiated TRAIL-induced cytotoxicity and apoptosis in glioma cells. PEITC dramatically upregulated DR5 receptor expression but had no effects on DR4 receptor. PEITC enhances TRAIL induced apoptosis through the downregulation of cell survival proteins and the upregulation of DR5 receptors through actions on the ROS-induced-p53. PMID- 24491547 TI - N-acetylglucosamine kinase, HXK1 contributes to white-opaque morphological transition in Candida albicans. AB - Morphological transition (yeast-hyphal and white-opaque) is an important biological process in the life cycle of pathogenic yeast, Candida albicans and is a major determinant of virulence. Earlier reports show that the amino sugar, N acetylglucosamine (GlcNAc) induces white to opaque switching in this pathogen. We report here a new contributor to this switching phenomenon, namely N acetylglucosamine kinase or HXK1, the first enzyme of the GlcNAc catabolic cascade. Microarray profile analysis of wild type vs. hxk1 mutant cells grown under switching inducing condition showed upregulation of opaque specific and cell wall specific genes along genes involved in the oxidative metabolism. Further, our qRT-PCR and immunoblot analysis revealed that the expression levels of Wor1, a master regulator of the white-opaque switching phenomenon remained unaltered during this HXK1 mediated transition. Thus the derepression of opaque specific gene expression observed in hxk1 mutant could be uncoupled to the expression of WOR1. Moreover, this regulation via HXK1 is independent of Ras1, a major regulator of morphogenetic transition and probably independent of MTL locus too. These results extend our understanding of multifarious roles of metabolic enzymes like Hxk1 and suggest an adaptive mechanism during host-pathogen interactions. PMID- 24491548 TI - Structural basis for the conserved binding mechanism of MDM2-inhibiting peptides and anti-apoptotic Bcl-2 family proteins. AB - The interaction between tumor suppressor p53 and the anti-apoptotic Bcl-2 family proteins serves a critical role in the transcription-independent apoptosis mechanism of p53. Our previous studies showed that an MDM2-inhibiting motif (residues 15-29) in the p53 transactivation domain (p53TAD) mediates the interaction with anti-apoptotic Bcl-2 family proteins. In this study, we provided structural models of the complexes between the MDM2-inhibiting p53TAD peptide and Mcl-1, Bcl-w, and Kaposi sarcoma-associated herpes virus (KSHV) Bcl-2 using NMR chemical shift perturbation data. The binding mode of the MDM2-inhibiting p53TAD peptide is highly conserved among the anti-apoptotic Bcl-2 family proteins despite their distinct specificities for pro-apoptotic Bcl-2 family proteins. We also identified the binding of a phage-display-derived MDM2-inhibiting peptide 12 1 to anti-apoptotic Bcl-XL protein by using NMR spectroscopy. The structural model of the Bcl-XL/12-1 peptide complex revealed that the conserved residues Phe4, Trp8, and Leu11 in the MDM2-inhibiting peptide fit into a hydrophobic cleft of Bcl-XL in a manner similar to that of pro-apoptotic Bcl-2 homology 3 (BH3) peptides. Our results shed light on the mechanism underlying dual-targeting of the FxxxWxxL-based alpha-helical motif to MDM2 and anti-apoptotic Bcl-2 family proteins for anticancer therapy. PMID- 24491549 TI - Short-term effects of 7-ketocholesterol on human adipose tissue mesenchymal stem cells in vitro. AB - Oxysterols comprise a very heterogeneous group derived from cholesterol through enzymatic and non-enzymatic oxidation. Among them, 7-ketocholesterol (7-KC) is one of the most important. It has potent effects in cell death processes, including cytoxicity and apoptosis induction. Mesenchymal stem cells (MSCs) are multipotent cells characterized by self-renewal and cellular differentiation capabilities. Very little is known about the effects of oxysterols in MSCs. Here, we describe the short-term cytotoxic effect of 7-ketocholesterol on MSCs derived from human adipose tissue. MSCs were isolated from adipose tissue obtained from two young, healthy women. After 24 h incubation with 7-KC, mitochondrial hyperpolarization was observed, followed by a slight increase in the level of apoptosis and changes in actin organization. Finally, the IC50 of 7-KC was higher in these cells than has been observed or described in other normal or cancer cell lines. PMID- 24491550 TI - Identification of an atypical calcium-dependent calmodulin binding site on the C terminal domain of GluN2A. AB - N-methyl-D-aspartate (NMDA) receptors are calcium-permeable ion channels assembled from four subunits that each have a common membrane topology. The intracellular carboxyl terminal domain (CTD) of each subunit varies in length, is least conserved between subunits, and binds multiple intracellular proteins. We defined a region of interest in the GluN2A CTD, downstream of well-characterized membrane-proximal motifs, that shares only 29% sequence similarity with the equivalent region of GluN2B. GluN2A (amino acids 875-1029) was fused to GST and used as a bait to identify proteins from mouse brain with the potential to bind GluN2A as a function of calcium. Using mass spectrometry we identified calmodulin as a calcium-dependent GluN2A binding partner. Equilibrium fluorescence spectroscopy experiments indicate that Ca(2+)/calmodulin binds GluN2A with high affinity (5.2+/-2.4 nM) in vitro. Direct interaction of Ca(2+)/calmodulin with GluN2A was not affected by disruption of classic sequence motifs associated with Ca(2+)/calmodulin target recognition, but was critically dependent upon Trp-1014. These findings provide new insight into the potential of Ca(2+)/calmodulin, previously considered a GluN1-binding partner, to influence NMDA receptors by direct association. PMID- 24491551 TI - Expression, purification and substrate specificities of 3-nitrotoluene dioxygenase from Diaphorobacter sp. strain DS2. AB - 3-Nitotoluene dioxygenase (3-NTDO) is the first enzyme in the degradation pathway of 3-nitrotoluene (3-NT) by Diaphorobacter sp. strain DS2. The complete gene sequences of 3-NTDO were PCR amplified from genomic DNA of Diaphorobacter sp., cloned, sequenced and expressed. The 3-NTDO gene revealed a multi component structure having a reductase, a ferredoxin and two oxygenase subunits. Clones expressing the different subunits were constructed in pET21a expression vector system and overexpressed in E. coli BL21(DE3) host. Each subunit was individually purified separately to homogeneity. The active recombinant enzyme was reconstituted in vitro by mixing all three purified subunits. The reconstituted recombinant enzyme could catalyse biotransformations on a variety of organic aromatics. PMID- 24491552 TI - Rck1 up-regulates pseudohyphal growth by activating the Ras2 and MAP kinase pathways independently in Saccharomyces cerevisiae. AB - Previously, we reported that Rck1 regulates Hog1 and Slt2 activities and affects MAP kinase activity in Saccharomyces cerevisiae. Recently, we found that Rck1 up regulates phospho-Kss1 and phospho-Fus3. Kss1 has been known as a component in the pseudohyphal growth pathway, and we attempted to identify the function of Rck1 in pseudohyphal growth. Rck1 up-regulated Ras2 at the protein level, not the transcriptional level. Additionally, FLO11 transcription was up-regulated by RCK1 over-expression. RCK1 expression was up-regulated during growth on SLAD+1% butanol medium. On nitrogen starvation agar plates, RCK1 over-expression induced pseudohyphal growth of colonies, and cells over-expressing RCK1 showed a filamentous morphology when grown in SLAD medium. Furthermore, 1-butanol greatly induced filamentous growth when RCK1 was over-expressed. Moreover, invasive growth was activated in haploid cells when RCK1 was over-expressed. The growth defect of cells observed on 1-butanol medium was recovered when RCK1 was over expressed. Interestingly, Ras2 and phospho-Kss1 were up-regulated by Rck1 independently. Together, these results suggest that Rck1 promotes pseudohyphal growth by activating Ras2 and Kss1 via independent pathways in S. cerevisiae. PMID- 24491553 TI - A novel fibrin(ogen)olytic trypsin-like protease from Chinese oak silkworm (Antheraea pernyi): purification and characterization. AB - A novel fibrin(ogen)olytic protease from Antheraea pernyi (important economically insect), named cocoonase, was isolated by a combination of ion-exchange chromatography and gel filtration. Furthermore, the characterization of cocoonase was investigated using fibrin(ogen)olytic, thrombolysis, and hemorrhagic assays. The NH2-terminal sequence (IVGGY SVTID KAPYQ) was established by Edman degradation. Based on the N-terminal sequencing, cocoonase cDNA has been cloned by means of RT-PCR and 5'RACE. It is composed of 261 amino acid residues and possesses the structural features of trypsin-like serine protease. The purified cocoonase showed specific esterase activity on N-beta-benzoyl-l-arginine ethyl (BAEE), and the kinetic constants, Km and Vmax were 2.577 * 10(-3)mol/L and 4.09 * 10(-3)MUmol/L/s, respectively. Cocoonase showed strong activities on both fibrin and fibrinogen, preferentially hydrolyzed Aalpha and Bbeta chains followed by gamma-chains of fibrinogen. Cocoonase exhibited a thrombolysis activity both in vitro (blood-clot lysis activity assay) and in vivo (carrageenan-induced thrombosis model). These findings indicate that A. pernyi cocoonase ia a novel fibrin(ogen)olytic enzyme and may have a potential clinical application as an antithrombotic agent. PMID- 24491554 TI - Association of bi-functional activity in the N-terminal domain of glycogen debranching enzyme. AB - Glycogen debranching enzyme (GDE) in mammals and yeast exhibits alpha-1,4 transferase and alpha-1,6-glucosidase activities within a single polypeptide chain and facilitates the breakdown of glycogen by a bi-functional mechanism. Each enzymatic activity of GDE is suggested to be associated with distinct domains; alpha-1,4-glycosyltransferase activity with the N-terminal domain and alpha-1,6-glucosidase activity with the C-terminal domain. Here, we present the biochemical features of the GDE from Saccharomyces cerevisiae using the substrate glucose(n)-beta-cyclodextrin (Gn-beta-CD). The bacterially expressed and purified GDE N-terminal domain (aa 1-644) showed alpha-1,4-transferase activity on maltotetraose (G4) and G4-beta-CD, yielding various lengths of (G)n. Surprisingly, the N-terminal domain also exhibited alpha-1,6-glucosidase activity against G1-beta-CD and G4-beta-CD, producing G1 and beta-CD. Mutational analysis showed that residues D535 and E564 in the N-terminal domain are essential for the transferase activity but not for the glucosidase activity. These results indicate that the N-terminal domain (1-644) alone has both alpha-1,4-transferase and the alpha-1,6-glucosidase activities and suggest that the bi-functional activity in the N-domain may occur via one active site, as observed in some archaeal debranching enzymes. PMID- 24491555 TI - In vivo consequences of cholesterol-24S-hydroxylase (CYP46A1) inhibition by voriconazole on cholesterol homeostasis and function in the rat retina. AB - Cholesterol 24S-hydroxylase (CYP46A1) converts cholesterol into 24S hydroxycholesterol in neurons and participates in cholesterol homeostasis in the central nervous system, including the retina. We aimed to evaluate the consequences of CYP46A1 inhibition by voriconazole on cholesterol homeostasis and function in the retina. Rats received daily intraperitoneal injections of voriconazole (60mg/kg), minocycline (22mg/kg), voriconazole plus minocycline, or vehicle during five consecutive days. The rats were submitted to electroretinography to monitor retinal functionality. Cholesterol and 24S hydroxycholesterol were measured in plasma, brain and retina by gas chromatography-mass spectrometry. The expression of CYP46A1, and GFAP as a marker for glial activation was analyzed in the retina and brain. Cytokines and chemokines were measured in plasma, vitreous, retina and brain. Voriconazole significantly impaired the functioning of the retina as exemplified by the reduced amplitude and increased latency of the b-wave of the electroretinogram, and altered oscillary potentials. Voriconazole decreased 24S-hydroxycholesterol levels in the retina. Unexpectedly, CYP46A1 and GFAP expression was increased in the retina of voriconazole-treated rats. ICAM-1 and MCP-1 showed significant increases in the retina and vitreous body. Minocycline did not reverse the effects of voriconazole. Our data highlighted the cross talk between retinal ganglion cells and glial cells in the retina, suggesting that reduced 24S hydroxycholesterol concentration in the retina may be detected by glial cells, which were consequently activated. PMID- 24491556 TI - The role of growth factors in maintenance of stemness in bone marrow-derived mesenchymal stem cells. AB - Mesenchymal stem cells (MSCs) are an active topic of research in regenerative medicine due to their ability to secrete a variety of growth factors and cytokines that promote healing of damaged tissues and organs. In addition, these secreted growth factors and cytokines have been shown to exert an autocrine effect by regulating MSC proliferation and differentiation. We found that expression of EGF, FGF-4 and HGF were down-regulated during serial passage of bone marrow-derived mesenchymal stem cells (BMSCs). Proliferation and differentiation potentials of BMSCs treated with these growth factors for 2 months were evaluated and compared to BMSCs treated with FGF-2, which increased proliferation of BMSCs. FGF-2 and -4 increased proliferation potentials at high levels, about 76- and 26-fold, respectively, for 2 months, while EGF and HGF increased proliferation of BMSCs by less than 2.8-fold. Interestingly, differentiation potential, especially adipogenesis, was maintained only by HGF treatment. Treatment with FGF-2 rapidly induced activation of AKT and later induced ERK activation. The basal level of phosphorylated ERK increased during serial passage of BMSCs treated with FGF-2. The expression of LC3-II, an autophagy marker, was gradually increased and the population of senescent cells was increased dramatically at passage 7 in non-treated controls. But FGF-2 and FGF-4 suppressed LC3-II expression and down-regulated senescent cells during long term (i.e. 2month) cultures. Taken together, depletion of growth factors during serial passage could induce autophagy, senescence and down-regulation of stemness (proliferation via FGF-2/-4 and differentiation via HGF) through suppression of AKT and ERK signaling. PMID- 24491557 TI - MiR-361-5p acts as a tumor suppressor in prostate cancer by targeting signal transducer and activator of transcription-6(STAT6). AB - Castration-resistant prostate cancer (CRPC), whose pathogenesis is known to be regulated by microRNAs (miRNAs), has a poor prognosis. In our present study, we found that the expression of miR-361-5p in CRPC was lower than in androgen dependent prostate cancer (ADPC), indicating that miR-361-5p may play an important role in the progression of ADPC to CRPC. The role of miR-361-5p in prostate cancer (PCa) has not been evaluated until date. Our findings suggest that miR-361-5p is a suppressor in CRPC. Signal transducer and activator of transcription-6 (STAT6), a direct target of miR-361-5p, enhances the expression of B-cell lymphoma-extra large (Bcl-xL), while miR-361-5p inhibits its expression through STAT6. Therefore, miR-361-5p has great clinical significance in preventing the malignant progression of PCa. PMID- 24491558 TI - Expression of Drosophila forkhead transcription factors during kidney development. AB - The Drosophila forkhead (Dfkh) family of transcription factors has over 40 family members. One Dfkh family member, BF2 (aka FoxD1), has been shown, by targeted disruption, to be essential for kidney development. In order to determine if other Dfkh family members were involved in kidney development and to search for new members of this family, reverse transcriptase polymerase chain reaction (RT PCR) was performed using degenerate primers of the consensus sequence of the DNA binding domain of this family and developing rat kidney RNA. The RT-PCR product was used to probe RNA from a developing rat kidney (neonatal), from a 20-day old kidney, and from an adult kidney. The RT-PCR product hybridized only to a developing kidney RNA transcript of ~2.3 kb (the size of BF2). A lambda gt10 mouse neonatal kidney library was then screened, using the above-described RT-PCR product as a probe. Three lambda phage clones were isolated that strongly hybridized to the RT-PCR probe. Sequencing of the RT-PCR product and the lambda phage clones isolated from the developing kidney library revealed Dfkh BF2. In summary, only Dfkh family member BF2, which has already been shown to be essential for nephrogenesis, was identified in our screen and no other candidate Dfkh family members were identified. PMID- 24491559 TI - Cobalt chloride induces neuronal differentiation of human mesenchymal stem cells through upregulation of microRNA-124a. AB - Human mesenchymal stem cells (hMSCs) are known to have the capacity to differentiate into various cell types, including neurons. To examine our hypothesis that miRNA was involved in neuronal differentiation of hMSCs, CoCl2, a hypoxia-mimicking agent was used to induce neuronal differentiation, which was assessed by determining the expression of neuronal markers such as nestin and Tuj1. Treatment of hMSCs with CoCl2 led to increased expression of miR-124a, a neuron-specific miRNA. HIF-1alpha silencing and JNK inhibition abolished CoCl2 induced miR-124a expression, suggesting that JNK and HIF-1alpha signals were required for the miR-124a expression induced by CoCl2 in hMSCs. Overexpression of miR-124a or CoCl2 treatment suppressed the expression of anti-neural proteins such as SCP1 and SOX9. Silencing of both SCP1 and SOX9 induced neuronal differentiation of hMSCs, indicating that suppression of miR-124a targets is important for CoCl2-induced neuronal differentiation of hMSCs. Knockdown of HIF 1alpha or inhibition of JNK restored the expression of SCP1 and SOX9 in CoCl2 treated cells. Inhibition of miR-124a blocked CoCl2-induced suppression of SCP1 and SOX9 and abolished CoCl2-induced neuronal differentiation of hMSCs. Taken together, we demonstrate that miR-124a is critically regulates CoCl2-induced neuronal differentiation of hMSCs by suppressing the expression of SCP1 and SOX9. PMID- 24491560 TI - Plant sterols in food: no consensus in guidelines. AB - Plant sterols are supplemented in foods to reduce cardiovascular risk. Randomized controlled trials show 2 g of plant sterols a day reduce serum cholesterol by about 10%. This reduction in serum cholesterol levels is achieved at the expense of increased serum plant sterol levels. Findings in patients with phytosterolemia, in experimental studies and in clinical trials have lead to speculations that plant sterols might be atherogenic. In view of emerging safety issues the role of plant sterols in cardiovascular prevention has become controversial. This review reflects the ongoing controversial scientific debate and points out recent developments in guidelines of national and international societies. PMID- 24491561 TI - Integration, visualization and analysis of human interactome. AB - Data integration and visualization are crucial to obtain meaningful hypotheses from the diversity of 'omics' fields and the large volume of heterogeneous and distributed data sets. In this review we focus on network analysis as a key technique to integrate, visualize and extrapolate relevant information from diverse data. We first describe challenges in integrating different types of data and then focus on systematically exploring network properties to gain insight into network function. We also describe the relationship between network structures and function of elements that form it. Next, we highlight the role of the interactome in connecting data derived from different experiments, and we stress the importance of network analysis to recognize interaction context specific features. Finally, we present an example integration to demonstrate the value of the network approach in cancer research, and highlight the importance of dynamic data in the specific context of signaling pathways. PMID- 24491562 TI - Oxysterols in the brain of the cholesterol 24-hydroxylase knockout mouse. AB - Oxysterols are oxidised forms of cholesterol or its precursors. In this study we utilised the cholesterol 24-hydroxylase knockout mouse (Cyp46a1-/-) to study the sterol and oxysterol content of brain. Despite a great reduction in the abundance of 24S-hydroxycholesterol, the dominant metabolite of cholesterol in wild type brain, no other cholesterol metabolite was found to quantitatively replace this oxysterol in the Cyp46a1-/- mouse. Only minor amounts of other side-chain oxysterols including 22R-, 24R-, 25- and (25R),26-hydroxycholesterols were detected. In line with earlier studies, levels of cholesterol were similar in Cyp46a1-/- and wild type animals. However, the level of the cholesterol precursor, desomsterol, and its parallel metabolite formed via a shut of the mevalonate pathway, 24S,25-epoxycholesterol, were reduced in the Cyp46a1-/- mouse. The reduction in abundance of 24S,25-epoxycholesterol is interesting in light of a recent report indicating that this oxysterol promotes dopaminergic neurogenesis. PMID- 24491563 TI - A cellular stress response (CSR) that interacts with NADPH-P450 reductase (NPR) is a new regulator of hypoxic response. AB - NADPH-P450 reductase (NPR) was previously found to contribute to the hypoxic response of cells, but the mechanism was not clarified. In this study, we identified a cellular stress response (CSR) as a new factor interacting with NPR by a yeast two-hybrid system. Overexpression of CSR enhanced the induction of erythropoietin and hypoxia response element (HRE) activity under hypoxia in human hepatocarcinoma cell lines (Hep3B), while knockdown of CSR suppressed them. This new finding regarding the interaction of NPR with CSR provides insight into the function of NPR in hypoxic response. PMID- 24491564 TI - Down regulated connexin26 at different postnatal stage displayed different types of cellular degeneration and formation of organ of Corti. AB - Connexin26 (Cx26) mutation is the most common cause for non-syndromic hereditary deafness. Different congenital Cx26 null mouse models revealed a profound hearing loss pattern and developmental defect in the cochlea. Our study aimed at establishing a Cx26 knocking down mouse model at different postnatal time points and to investigate the time course and pattern of the hearing loss and cell degeneration in these models. Morphologic changes were observed for 5 months to detect long-term diversities among these models. Depending on the time point when Cx26 expression was reduced, mild to profound hearing loss patterns were found in different groups. Malformed organ of Corti with distinct cell loss in middle turn was observed only in early Cx26 reduction group while mice in late Cx26 reduction group developed normal organ of Corti and only suffered a few hair loss in the basal turn. These results indicated that Cx26 may play essential roles in the postnatal maturation of the cochlea, and its role in normal hearing at more mature stage may be replaceable. PMID- 24491565 TI - Cadmium induces cytotoxicity in human bronchial epithelial cells through upregulation of eIF5A1 and NF-kappaB. AB - Cadmium (Cd) and Cd compounds are widely-distributed in the environment and well known carcinogens. Here, we report that in CdCl2-exposed human bronchial epithelial cells (BEAS-2B), the level of p53 is dramatically decreased in a time- and dose-dependent manner, suggesting that the observed Cd-induced cytotoxicity is not likely due to the pro-apoptotic function of p53. Therefore, this prompted us to further study the responsive pro-apoptotic factors by proteomic approaches. Interestingly, we identified that high levels (20 or 30 MUM) of Cd can significantly upregulate the protein levels of eukaryotic translation initiation factor 5A1 (eIF5A1) and redox-sensitive transcription factor NF-kappaB p65. Moreover, there is an enhanced NF-kappaB nuclear translocation as well as chromatin-binding in Cd-treated BEAS-2B cells. We also show that small interfering RNA-specific knockdown of eIF5A1 in Cd-exposed cells attenuated the Cd cytotoxicity, indicating the potential role of eIF5A1 in Cd cytotoxicity. As eIF5A1 is reported to be related with cell apoptosis but little is known about its transcriptional control, we hypothesize that NF-kappaB might likely modulate eIF5A1 gene expression. Notably, by bioinformatic analysis, several potential NF kappaB binding sites on the upstream promoter region of eIF5A1 gene can be found. Subsequent chromatin immunoprecipitation assay revealed that indeed there is enhanced NF-kappaB binding on eIF5A1 promoter region of Cd-treated BEAS-2B cells. Taken together, our findings suggest for the first time a regulatory mechanism for the pro-apoptotic protein eIF5A1 in which its level is possibly modulated by NF-kappaB in human lung cells. PMID- 24491566 TI - Efficient generation of genome-modified mice via offset-nicking by CRISPR/Cas system. AB - The mammalian zygote-mediated CRISPR/Cas system can efficiently generate targeted genome-modified animals. However, this system is limited by the risk of off target mutations. Here we show that offset-nicking by Cas9 nickase and paired gRNAs allows us to generate region deleted mice and targeted knock-in mice without off-target mutations. PMID- 24491567 TI - Possible involvement of PI3K-dependent pathways in the increased VEGF120 release from osteoblastic cells preloaded with palmitate in vitro. AB - It have been reported that abnormal bone metabolism often occurs in patients with type 2 diabetes, but the underlying mechanisms remain to be elucidated. In recent years dyslipidemia (hyperlipidemia) has been presumed to have an influence on bone metabolism. In addition, the involvements of VEGF and MCP-1 derived from osteoblasts in bone abnormal metabolism were also observed. Thus, we investigated the pathogenic mechanism of this abnormal bone metabolism, which is included in the regulation of VEGF and MCP-1 secretions from osteoblasts, by using UMR-106 osteosarcoma cells as an osteoblast cell model and treating them with palmitate in order to mimic a state of hyperlipidemia. Palmitate-preloaded cells showed the significant increase of VEGF120 release (1.8-fold vs. control cells, p<0.01). Moreover, the treatment with palmitate significantly increased VEGF-A mRNA with the maximal 2.5-fold upregulation at 12h after the treatment (p<0.01). However, MCP-1 release was not affected by palmitate. Moreover, the amplified VEGF120 secretion with palmitate was significantly decreased by the treatment with TLR4 antagonist or PI3K pathway inhibitors, LY294002 and wortmannin (p<0.01, respectively). On the other hand, the stimulation with TNF-alpha, which osteoclasts were able to release, significantly enhanced MCP-1 secretion (p<0.01), but had no effect on VEGF120. On the contrary IL-1beta amplified VEGF120 release (p<0.01), but not MCP-1. These results suggest that palmitate can increase VEGF120 release from UMR-106 osteosarcoma cells, which is accelerated at the transcriptional level, and this increase of VEGF120 release may be mediated though, at least partly, TLR4 and the PI3K pathways. In addition, we also verified that TNF-alpha and IL-1beta, which are considered to be derived from osteoclasts, amplified the secretions of MCP-1 and VEGF120 from UMR-106 cells, respectively. PMID- 24491568 TI - Acyl-chain remodeling of dioctanoyl-phosphatidylcholine in Saccharomyces cerevisiae mutant defective in de novo and salvage phosphatidylcholine synthesis. AB - A yeast strain, in which endogenous phosphatidylcholine (PC) synthesis is controllable, was constructed by the replacement of the promoter of PCT1, encoding CTP:phosphocholine cytidylyltransferase, with GAL1 promoter in a double deletion mutant of PEM1 and PEM2, encoding phosphatidylethanolamine methyltransferase and phospholipid methyltransferase, respectively. This mutant did not grow in the glucose-containing medium, but the addition of dioctanoyl phosphatidylcholine (diC8PC) supported its growth. Analyses of the metabolism of (13)C-labeled diC8PC ((methyl-(13)C)3-diC8PC) in this strain using electrospray ionization tandem mass spectrometry revealed that it was converted to PC species containing acyl residues of 16 or 18 carbons at both sn-1 and sn-2 positions. In addition, both acyl residues of (methyl-(13)C)3-diC8PC were replaced with 16:1 acyl chains in the in vitro reaction using the yeast cell extract in the presence of palmitoleoyl-CoA. These results indicate that PC containing short acyl residues was remodeled to those with acyl chains of physiological length in yeast. PMID- 24491569 TI - Crystal structure of cbbF from Zymomonas mobilis and its functional implication. AB - A phosphate group at the C1-atom of inositol-monophosphate (IMP) and fructose-1,6 bisphosphate (FBP) is hydrolyzed by a phosphatase IMPase and FBPase in a metal dependent way, respectively. The two enzymes are almost indiscernible from each other because of their highly similar sequences and structures. Metal ions are bound to residues on the beta1- and beta2-strands and one mobile loop. However, FBP has another phosphate and FBPases exist as a higher oligomeric state, which may discriminate FBPases from IMPases. There are three genes annotated as FBPases in Zymomonas mobilis, termed also cbbF (ZmcbbF). The revealed crystal structure of one ZmcbbF shows a globular structure formed by five stacked layers. Twenty five residues in the middle of the sequence form an alpha-helix and a beta strand, which occupy one side of the catalytic site. A non-polar Leu residue among them is protruded to the active site, pointing out unfavorable access of a bulky charged group to this side. In vitro assays have shown its dimeric form in solution. Interestingly, two beta-strands of beta1 and beta2 are disordered in the ZmcbbF structure. These data indicate that ZmcbbF might structurally belong to IMPase, and imply that its active site would be reorganized in a yet unreported way. PMID- 24491570 TI - Critical function of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in mouse spermatogenesis. AB - Small GTPase Rap1 has been implicated in the proper differentiation of testicular germ cells. In the present study, we investigated the functional significance of RA-GEF-2/Rapgef6, a guanine nucleotide exchange factor for Rap1, in testicular differentiation using mice lacking RA-GEF-2. RA-GEF-2 was expressed predominantly on the luminal side of the seminiferous tubules in wild-type mice. No significant differences were observed in the body weights or hormonal parameters of RA-GEF-2( )(/)(-) and wild-type mice. However, the testes of RA-GEF-2(-)(/)(-) male mice were significantly smaller than those of wild-type mice and were markedly atrophied as well as hypospermatogenic. The concentration and motility of epididymal sperm were also markedly reduced and frequently had an abnormal shape. The pregnancy rate and number of fetuses were markedly lower in wild-type females after they mated with RA-GEF-2(-)(/)(-) males than with wild-type males, which demonstrated the male infertility phenotype of RA-GEF-2(-)(/)(-) mice. Furthermore, a significant reduction and alteration were observed in the expression level and cell junctional localization of N-cadherin, respectively, in RA-GEF-2(-)(/)(-) testes, which may, at least in part, account for the defects in testicular differentiation and spermatogenesis in these mice. PMID- 24491571 TI - Augmenting podocyte injury promotes advanced diabetic kidney disease in Akita mice. AB - To determine if augmenting podocyte injury promotes the development of advanced diabetic nephropathy (DN), we created mice that expressed the enzyme cytosine deaminase (CD) specifically in podocytes of diabetic Akita mice (Akita-CD mice). In these mice, treatment with the prodrug 5-flucytosine (5-FC) causes podocyte injury as a result of conversion to the toxic metabolite 5-fluorouracil (5-FU). We found that treatment of 4-5 week old Akita mice with 5-FC for 5 days caused robust albuminuria at 16 and 20 weeks of age compared to 5-FC treated Akita controls, which do not express CD (Akita CTLs). By 20 weeks of age, there was a significant increase in mesangial expansion in Akita-CD mice compared to Akita CTLs, which was associated with a variable increase in glomerular basement membrane (GBM) width and interstitial fibrosis. At 20 weeks of age, podocyte number was similarly reduced in both groups of Akita mice, and was inversely correlated with the albuminuria and mesangial expansion. Thus, enhancing podocyte injury early in the disease process promotes the development of prominent mesangial expansion, interstitial fibrosis, increased GBM thickness and robust albuminuria. These data suggest that podocytes play a key role in the development of advanced features of diabetic kidney disease. PMID- 24491572 TI - Effect of gemfibrozil, rifampicin, or probenecid on the pharmacokinetics of the SGLT2 inhibitor empagliflozin in healthy volunteers. AB - BACKGROUND: Empagliflozin is a potent, oral, selective inhibitor of sodium glucose cotransporter 2 in development for the treatment of type 2 diabetes mellitus. OBJECTIVE: The goal of these studies was to investigate potential drug drug interactions between empagliflozin and gemfibrozil (an organic anion transporting polypeptide 1B1 [OATP1B1]/1B3 and organic anion transporter 3 [OAT3] inhibitor), rifampicin (an OATP1B1/1B3 inhibitor), or probenecid (an OAT3 and uridine diphosphate glucuronosyltransferase inhibitor). METHODS: Two open-label, randomized, crossover studies were undertaken in healthy subjects. In the first study, 18 subjects received the following in 1 of 2 randomized treatment sequences: a single dose of empagliflozin 25 mg alone and gemfibrozil 600 mg BID for 5 days with a single dose of empagliflozin 25 mg on the third day. In the second study, 18 subjects received a single dose of empagliflozin 10 mg, a single dose of empagliflozin 10 mg coadministered with a single dose of rifampicin 600 mg, and probenecid 500 mg BID for 4 days with a single dose of empagliflozin 10 mg on the second day in 1 of 6 randomized treatment sequences. RESULTS: In the gemfibrozil study, 11 subjects were male, mean age was 35.1 years and mean body mass index (BMI) was 23.47 kg/m(2). In the rifampicin/probenecid study, 10 subjects were male, mean age was 32.7 years and mean BMI was 23.03 kg/m(2). Exposure to empagliflozin was increased by coadministration with gemfibrozil (AUC0-infinity: geometric mean ratio [GMR], 158.50% [90% CI, 151.77-165.53]; Cmax: GMR, 115.00% [90% CI, 106.15-124.59]), rifampicin (AUC0-infinity: GMR, 135.20% [90% CI, 129.58-141.06]; Cmax: GMR, 175.14% [90% CI, 160.14-191.56]), and probenecid (AUC0-infinity: GMR, 153.47% [90% CI, 146.41-160.88]; Cmax: GMR, 125.60% [90% CI, 113.67-138.78]). All treatments were well tolerated. CONCLUSIONS: Increases in empagliflozin exposure were <2-fold, indicating that the inhibition of the OATP1B1/1B3, OAT3 transporter, and uridine diphosphate glucuronosyltransferases did not have a clinically relevant effect on empagliflozin exposure. No dose adjustments of empagliflozin were necessary when it was coadministered with gemfibrozil, rifampicin, or probenecid. ClinicalTrials.gov identifiers: NCT01301742 and NCT01634100. PMID- 24491573 TI - Suppression of antimicrobial peptide expression by ureaplasma species. AB - Ureaplasma species commonly colonize the adult urogenital tract and are implicated in invasive diseases of adults and neonates. Factors that permit the organisms to cause chronic colonization or infection are poorly understood. We sought to investigate whether host innate immune responses, specifically, antimicrobial peptides (AMPs), are involved in determining the outcome of Ureaplasma infections. THP-1 cells, a human monocytoid tumor line, were cocultured with Ureaplasma parvum and U. urealyticum. Gene expression levels of a variety of host defense genes were quantified by real-time PCR. In vitro antimicrobial activities of synthetic AMPs against Ureaplasma spp. were determined using a flow cytometry-based assay. Chromosomal histone modifications in host defense gene promoters were tested by chromatin immunoprecipitation (ChIP). DNA methylation status in the AMP promoter regions was also investigated. After stimulation with U. parvum and U. urealyticum, the expression of cell defense genes, including the AMP genes (DEFB1, DEFA5, DEFA6, and CAMP), was significantly downregulated compared to that of TNFA and IL-8, which were upregulated. In vitro flow cytometry-based antimicrobial assay revealed that synthetic peptides LL-37, hBD-3, and hBD-1 had activity against Ureaplasma spp. Downregulation of the AMP genes was associated with chromatin modification alterations, including the significantly decreased histone H3K9 acetylation with U. parvum infection. No DNA methylation status changes were detected upon Ureaplasma infection. In conclusion, AMPs have in vitro activity against Ureaplasma spp., and suppression of AMP expression might be important for the organisms to avoid this aspect of the host innate immune response and to establish chronic infection and colonization. PMID- 24491574 TI - PrtR homeostasis contributes to Pseudomonas aeruginosa pathogenesis and resistance against ciprofloxacin. AB - Pseudomonas aeruginosa is an opportunistic pathogen that causes acute and chronic infections in humans. Pyocins are bacteriocins produced by P. aeruginosa that are usually released through lysis of the producer strains. Expression of pyocin genes is negatively regulated by PrtR, which gets cleaved under SOS response, leading to upregulation of pyocin synthetic genes. Previously, we demonstrated that PrtR is required for the expression of type III secretion system (T3SS), which is an important virulence component of P. aeruginosa. In this study, we demonstrate that mutation in prtR results in reduced bacterial colonization in a mouse acute pneumonia model. Examination of bacterial and host cells in the bronchoalveolar lavage fluids from infected mice revealed that expression of PrtR is induced by reactive oxygen species (ROS) released by neutrophils. We further demonstrate that treatment with hydrogen peroxide or ciprofloxacin, known to induce the SOS response and pyocin production, resulted in an elevated PrtR mRNA level. Overexpression of PrtR by a tac promoter repressed the endogenous prtR promoter activity, and electrophoretic mobility shift assay revealed that PrtR binds to its own promoter, suggesting an autorepressive mechanism of regulation. A high level of PrtR expressed from a plasmid resulted in increased T3SS gene expression during infection and higher resistance against ciprofloxacin. Overall, our results suggest that the autorepression of PrtR contributes to the maintenance of a relatively stable level of PrtR, which is permissive to T3SS gene expression in the presence of ROS while increasing bacterial tolerance to stresses, such as ciprofloxacin, by limiting pyocin production. PMID- 24491575 TI - Protein kinase C mediates enterohemorrhagic Escherichia coli O157:H7-induced attaching and effacing lesions. AB - Enterohemorrhagic Escherichia coli serotype O157:H7 causes outbreaks of diarrhea, hemorrhagic colitis, and the hemolytic-uremic syndrome. E. coli O157:H7 intimately attaches to epithelial cells, effaces microvilli, and recruits F-actin into pedestals to form attaching and effacing lesions. Lipid rafts serve as signal transduction platforms that mediate microbe-host interactions. The aims of this study were to determine if protein kinase C (PKC) is recruited to lipid rafts in response to E. coli O157:H7 infection and what role it plays in attaching and effacing lesion formation. HEp-2 and intestine 407 tissue culture epithelial cells were challenged with E. coli O157:H7, and cell protein extracts were then separated by buoyant density ultracentrifugation to isolate lipid rafts. Immunoblotting for PKC was performed, and localization in lipid rafts was confirmed with an anti-caveolin-1 antibody. Isoform-specific PKC small interfering RNA (siRNA) was used to determine the role of PKC in E. coli O157:H7 induced attaching and effacing lesions. In contrast to uninfected cells, PKC was recruited to lipid rafts in response to E. coli O157:H7. Metabolically active bacteria and cells with intact lipid rafts were necessary for the recruitment of PKC. PKC recruitment was independent of the intimin gene, type III secretion system, and the production of Shiga toxins. Inhibition studies, using myristoylated PKCzeta pseudosubstrate, revealed that atypical PKC isoforms were activated in response to the pathogen. Pretreating cells with isoform-specific PKC siRNA showed that PKCzeta plays a role in E. coli O157:H7-induced attaching and effacing lesions. We concluded that lipid rafts mediate atypical PKC signal transduction responses to E. coli O157:H7. These findings contribute further to the understanding of the complex array of microbe-eukaryotic cell interactions that occur in response to infection. PMID- 24491576 TI - Mucosal immunization with recombinant fusion protein DnaJ-DeltaA146Ply enhances cross-protective immunity against Streptococcus pneumoniae infection in mice via interleukin 17A. AB - Pneumolysin (Ply) and its variants are protective against pneumococcal infections in animal models, and as a Toll-like receptor 4 agonist, pneumolysin has been reported to be a mucosal adjuvant. DnaJ has been approved as a useful candidate vaccine protein; we therefore designed novel fusion proteins of DnaJ with a form of Ply that has a deletion of A146 (DeltaA146Ply-DnaJ [the C terminus of DeltaA146Ply connected with the N terminus of DnaJ] and DnaJ-DeltaA146Ply [the C terminus of DnaJ connected with the N terminus of DeltaA146Ply]) to test whether they are protective against focal and lethal pneumococcal infections and their potential protective mechanisms. The purified proteins were used to intranasally immunize the animals without additional adjuvant. Immunization with DnaJ DeltaA146Ply or DnaJ plus DeltaA146Ply (Ply with a single deletion of A146) could significantly reduce S. pneumoniae colonization in the nasopharynx and lung relative with DnaJ alone. Additionally, we observed the best protection for DnaJ DeltaA146Ply-immunized mice after challenge with lethal doses of S. pneumoniae strains, which was comparable to that achieved by PPV23. Mice immunized with DnaJ DeltaA146Ply produced significantly higher levels of anti-DnaJ IgG in serum and secretory IgA (sIgA) in saliva than those immunized with DnaJ alone. The production of IL-17A was also striking in DnaJ-DeltaA146Ply-immunized mice. IL 17A knockout (KO) mice did not benefit from DnaJ-DeltaA146Ply immunization in colonization experiments, and sIgA production was impaired in IL-17A KO mice. Collectively, our results indicate a mucosal adjuvant potential for DeltaA146Ply and that, without additional adjuvant, DnaJ-DeltaA146Ply fusion protein exhibits extensive immune stimulation and is effective against pneumococcal challenges, properties which are partially attributed to the IL-17A-mediated immune responses. PMID- 24491577 TI - Role of Pht proteins in attachment of Streptococcus pneumoniae to respiratory epithelial cells. AB - Pneumococcal adherence to mucosal surfaces is a critical step in nasopharyngeal colonization, but so far few pneumococcal adhesins involved in the interaction with host cells have been identified. PhtA, PhtB, PhtD, and PhtE are conserved pneumococcal surface proteins that have proven promising as vaccine candidates. One suggested virulence function of Pht proteins is to mediate adherence at the respiratory mucosa. In this study, we assessed the role of Pht proteins in pneumococcal binding to respiratory epithelial cells. Pneumococci were incubated with human nasopharyngeal epithelial cells (Detroit-562) and lung epithelial cells (A549 and NCI-H292), and the proportion of bound bacteria was measured by plating viable counts. Strains R36A (unencapsulated), D39 (serotype 2), 43 (serotype 3), 4-CDC (serotype 4), and 2737 (serotype 19F) with one or more of the four homologous Pht proteins deleted were compared with their wild-type counterparts. Also, the effect of anti-PhtD antibodies on the adherence of strain 2737 to the respiratory epithelial cells was studied. Our results suggest that Pht proteins play a role in pneumococcal adhesion to the respiratory epithelium. We also found that antibody to PhtD is able to inhibit bacterial attachment to the cells, suggesting that antibodies against PhtD present at mucosal surfaces might protect from pneumococcal attachment and subsequent colonization. However, the relative significance of Pht proteins to the ability of pneumococci to bind in vitro to epithelial cells depends on the genetic background and the capsular serotype of the strain. PMID- 24491578 TI - The delta subunit of RNA polymerase guides promoter selectivity and virulence in Staphylococcus aureus. AB - In Gram-positive bacteria, and particularly the Firmicutes, the DNA-dependent RNA polymerase (RNAP) complex contains an additional subunit, termed the delta factor, or RpoE. This enigmatic protein has been studied for more than 30 years for various organisms, but its function is still not well understood. In this study, we investigated its role in the major human pathogen Staphylococcus aureus. We showed conservation of important structural regions of RpoE in S. aureus and other species and demonstrated binding to core RNAP that is mediated by the beta and/or beta' subunits. To identify the impact of the delta subunit on transcription, we performed transcriptome sequencing (RNA-seq) analysis and observed 191 differentially expressed genes in the rpoE mutant. Ontological analysis revealed, quite strikingly, that many of the downregulated genes were known virulence factors, while several mobile genetic elements (SaPI5 and prophage SA3usa) were strongly upregulated. Phenotypically, the rpoE mutant had decreased accumulation and/or activity of a number of key virulence factors, including alpha toxin, secreted proteases, and Panton-Valentine leukocidin (PVL). We further observed significantly decreased survival of the mutant in whole human blood, increased phagocytosis by human leukocytes, and impaired virulence in a murine model of infection. Collectively, our results demonstrate that the delta subunit of RNAP is a critical component of the S. aureus transcription machinery and plays an important role during infection. PMID- 24491579 TI - Enhanced interaction of Vibrio cholerae virulence regulators TcpP and ToxR under oxygen-limiting conditions. AB - Vibrio cholerae is the causative agent of the diarrheal disease cholera. The ability of V. cholerae to colonize and cause disease requires the intricately regulated expression of a number of virulence factors during infection. One of the signals sensed by V. cholerae is the presence of oxygen-limiting conditions in the gut. It has been shown that the virulence activator AphB plays a key role in sensing low oxygen concentrations and inducing the transcription of another key virulence activator, TcpP. In this study, we used a bacterial two-hybrid system to further examine the effect of oxygen on different virulence regulators. We found that anoxic conditions enhanced the interaction between TcpP and ToxR, identified as the first positive regulator of V. cholerae virulence genes. We further demonstrated that the TcpP-ToxR interaction was dependent on the primary periplasmic protein disulfide formation enzyme DsbA and cysteine residues in the periplasmic domains of both ToxR and TcpP. Furthermore, we showed that in V. cholerae, an interaction between TcpP and ToxR is important for virulence gene induction. Under anaerobic growth conditions, we detected ToxR-TcpP heterodimers, which were abolished in the presence of the reducing agent dithiothreitol. Our results suggest that V. cholerae may sense intestinal anoxic signals by multiple components to activate virulence. PMID- 24491580 TI - Type I interferons promote severe disease in a mouse model of lethal ehrlichiosis. AB - Human monocytic ehrlichiosis (HME) is caused by a tick-borne obligate intracellular pathogen of the order Rickettsiales. HME disease can range from mild to a fatal, toxic shock-like syndrome, yet the mechanisms regulating pathogenesis are not well understood. We define a central role for type I interferons (alpha interferon [IFN-alpha] and IFN-beta) in severe disease in a mouse model of fatal ehrlichiosis caused by Ixodes ovatus Ehrlichia (IOE). IFN alpha and IFN-beta were induced by IOE infection but not in response to a less virulent strain, Ehrlichia muris. The major sources of type I IFNs during IOE infection were plasmacytoid dendritic cells and monocytes. Mice lacking the receptor for type I IFNs (Ifnar deficient) or neutralization of IFN-alpha and IFN beta resulted in a reduced bacterial burden. Ifnar-deficient mice exhibited significantly increased survival after IOE infection, relative to that of wild type (WT) mice, that correlated with increased type II IFN (IFN-gamma) production. Pathogen-specific antibody responses were also elevated in Ifnar deficient mice, and this required IFN-gamma. Remarkably, increased IFN-gamma and IgM were not essential for protection in the absence of type I IFN signaling. The direct effect of type I IFNs on hematopoietic and nonhematopoietic cells was evaluated in bone marrow chimeric mice. We observed that chimeric mice containing Ifnar-deficient hematopoietic cells succumbed to infection early, whereas Ifnar deficient mice containing WT hematopoietic cells exhibited increased survival, despite having a higher bacterial burden. These data demonstrate that IFN-alpha receptor signaling in nonhematopoietic cells is important for pathogenesis. Thus, type I IFNs are induced during a rickettsial infection in vivo and promote severe disease. PMID- 24491582 TI - Delayed malignant transformation of petroclival meningioma to chondrosarcoma after stereotactic radiosurgery. AB - Stereotactic radiosurgery (SRS) is often used as adjuvant treatment for residual or recurrent tumor following microsurgical resection of posterior fossa meningiomas. SRS is associated with excellent rates of local control, however long-term complications remain unclear. Secondary malignancy is an often discussed but rarely described complication of SRS. We present a 56-year-old woman who underwent near total resection of a petroclival meningioma, followed by two episodes of SRS over the ensuing 8 years for local recurrence. She returned 14 years after initial diagnosis with neurologic deterioration and was found to have massive recurrence. Pathology was consistent with high-grade chondrosarcoma. The tumor continued to progress despite debulking and proton-beam therapy and the patient died of medical complications. To our knowledge this is the first report of malignant transformation of a meningioma to high-grade chondrosarcoma, further notable due to the remarkable clinical course and delayed presentation after initial surgery and radiosurgery. Though this may have been a de novo tumor, it is also possible that this represents a case of radiation-induced neoplasm. Although SRS continues to gain favor as a treatment modality, delayed malignant degeneration is a potential complication and physicians should counsel patients of this risk. PMID- 24491581 TI - Matrix metalloproteinase inhibition lowers mortality and brain injury in experimental pneumococcal meningitis. AB - Pneumococcal meningitis (PM) results in high mortality rates and long-lasting neurological deficits. Hippocampal apoptosis and cortical necrosis are histopathological correlates of neurofunctional sequelae in rodent models and are frequently observed in autopsy studies of patients who die of PM. In experimental PM, inhibition of matrix metalloproteinases (MMPs) and/or tumor necrosis factor (TNF)-converting enzyme (TACE) has been shown to reduce brain injury and the associated impairment of neurocognitive function. However, none of the compounds evaluated in these studies entered clinical development. Here, we evaluated two second-generation MMP and TACE inhibitors with higher selectivity and improved oral availability. Ro 32-3555 (Trocade, cipemastat) preferentially inhibits collagenases (MMP-1, -8, and -13) and gelatinase B (MMP-9), while Ro 32-7315 is an efficient inhibitor of TACE. PM was induced in infant rats by the intracisternal injection of live Streptococcus pneumoniae. Ro 32-3555 and Ro 32 7315 were injected intraperitoneally, starting at 3 h postinfection. Antibiotic (ceftriaxone) therapy was initiated at 18 h postinfection, and clinical parameters (weight, clinical score, mortality rate) were recorded. Myeloperoxidase activities, concentrations of cytokines and chemokines, concentrations of MMP-2 and MMP-9, and collagen concentrations were measured in the cerebrospinal fluid. Animals were sacrificed at 42 h postinfection, and their brains were assessed by histomorphometry for hippocampal apoptosis and cortical necrosis. Both compounds, while exhibiting disparate MMP and TACE inhibitory profiles, decreased hippocampal apoptosis and cortical injury. Ro 32-3555 reduced mortality rates and cerebrospinal fluid TNF, interleukin-1beta (IL-1beta) and collagen levels, while Ro 32-7315 reduced weight loss and cerebrospinal fluid TNF and IL-6 levels. PMID- 24491583 TI - The use of adenosine in the treatment of a high-flow vein of Galen malformation in an adult. AB - The treatment of high-flow vein of Galen aneurysmal malformations (VGAM) remains a therapeutic challenge for the neurosurgeon and the neurointerventionalist, as it is associated with high morbidity and mortality rates despite recent advances in open cranial surgery and interventional neuroradiology. A 37-year-old patient presented with a history of non-specific headaches. He had a history of heart failure since birth that was caused by an untreated VGAM. Intravenous boluses of adenosine were injected as an attempt to slow down the arteriovenous shunting of a VGAM prior to endovascular treatment. Adenosine can be a very useful adjunct in patients with extremely high arteriovenous shunting. n-butyl cyanoacrylate (n BCA) should be the embolic material of choice due to its quick polymerization and adhesive properties. PMID- 24491584 TI - Natural history and CT scan follow-up of subependymal giant cell tumors in tuberous sclerosis complex patients. AB - This study investigated whether subependymal giant cell tumors (SGCT) grow after the second decade in patients with tuberous sclerosis complex (TSC). In this retrospective longitudinal study all 214 TSC patients who had previously been in a single center cross-sectional study in 2007 were included. Institutional Review Board approval was obtained. In February 2012, the most recent contrast-enhanced CT scan of the brain since 2007 was reviewed for radiological signs of SGCT and, if present, the largest diameter was measured. The findings of the CT scans before 2007 were compared with the current findings. Of the 43 patients with radiological signs of SGCT in 2007 a follow-up CT scan was available for 34. Ten (29%) of these patients showed an increase in size of the SGCT. These 10 patients were on average 36 years old (median 34 years; range 26-50 years) and the average size of the SGCT was 17 mm (median 16 mm; range 11-29 mm), which corresponded to an average size increase of 5mm (median 4mm; range 2-8mm) after an average interval of 5 years (range 2-8 years). Of the 171 patients without radiological signs of SGCT in 2007 a follow-up CT scan was available for 138. Three (2%) of these patients showed radiological signs of SGCT on follow-up. These patients were 19, 23, and 41 years old and the SGCT was on average 13 mm (median 17 mm; range 4-19 mm). To conclude, in our cohort, CT scan demonstrated both growth of SGCT and development of new SGCT after the second decade of life in TSC patients. PMID- 24491585 TI - Thumb basal joint: Utilizing new technology for the treatment of a common problem. AB - New technology has the potential to greatly impact the medical field because it may lead to a greater quality of life, decreased pain, or increased function for our patients. This manuscript will discuss the introduction of one such advance in hand surgery and hand therapy. Utilizing the Mini-TightropeTM (Arthrex, Naples, FL) for suspension of the thumb metacarpal following trapeziectomy is a new technique for treating thumb carpometacarpal (CMC) arthritis. This technique is described as an example of the advantages of considering new techniques and technologies when treating established problems. This article discusses the responsibility of health professionals in considering the adoption of new technologies over current ones in the context of describing a new type of CMC suspensionplasty procedure. Further, a description of the surgical technique, the hand therapy postoperatively, and a case study to demonstrate some of the features of the Tightrope suspensionplasty procedure is presented. In the author's experience, the reduced healing time, reduced weeks of immobility, and fewer therapy visits following the procedure suggest that the Tightrope procedure should be considered as an option for patients needing thumb CMC arthroplasty. PMID- 24491587 TI - Critical issues facing the profession of radiology. PMID- 24491586 TI - Using smartphone applications as hand therapy interventions. AB - In the hand therapy clinic, smartphones can be used as an educational resource, to view a photo or video of a home exercise program, or as a method of electronically documenting progress related to healing from an injury. Smartphone applications may also serve as appropriate therapy interventions to address deficits often presenting with common hand injuries. For individuals with trapeziometacarpal arthrosis, gaming can encourage radial abduction range of motion and neuromuscular control required for joint stability. People with distal radius fractures may benefit from smartphone applications for range of motion and proprioceptive training. These treatments may assist with addressing client centered goals and be motivating in the current technology driven times. PMID- 24491588 TI - Out with the old, in with the new. PMID- 24491589 TI - Political polarization and the decline of power. PMID- 24491590 TI - An introduction to "business essentials". PMID- 24491591 TI - Understanding your physician contract. PMID- 24491592 TI - Cumulative radiation exposure estimates of hospitalized patients from radiological imaging. AB - PURPOSE: To examine the use of inpatient diagnostic imaging and image-guided procedures to estimate cumulative radiation exposure, radiation exposure based on imaging modality, and compare estimated doses based on patient demographics including age, gender, and diagnoses. METHODS: Two hundred consecutive hospitalized adult patients who underwent diagnostic imaging studies at 2 large, affiliated hospitals were identified, and every study in each patient's electronic record that took place during a single hospitalization was reviewed. Dose estimates were calculated for each CT, fluoroscopy, nuclear medicine, plain film, and interventional radiology study or procedure based on reported dose length product, published reference values, and conversion factors. Medical records were reviewed to determine patient gender, age, diagnoses, length of stay, admitting service, and time in an intensive care unit (ICU). RESULTS: Two hundred inpatients (46.5% male; mean age, 60.4 years) underwent 2,751 imaging studies (79.3% radiographs, 9.7% CT, 6.1% ultrasound, 2.5% interventional radiology, 2.2% MRI, 0.4% nuclear medicine). The mean dose estimate per patient was 14.8 milliSieverts (mSv) and the range was 0 mSv to 130.5 mSv. Mean cumulative dose estimates were significantly higher for patients whose hospitalizations included time in an ICU (17.9 mSv versus 11.3 mSv [P = .01]). CT examinations accounted for 82.1% of the total radiation dose estimate. Eleven patients (5.5%) received radiation dose estimates >= 50 mSv, including 2 >= 100 mSv. CONCLUSIONS: Of imaged inpatients, 62% underwent at least 1 CT and the majority (82.1%) of inpatient radiation exposure was attributable to CT examinations. Mean dose estimate was 14.8 mSv per patient; 5.5% of patients experienced estimated doses >= 50 mSv. PMID- 24491593 TI - Quality and safety as the spark for employee engagement. PMID- 24491594 TI - Portable wireless digital detectors: advantages and challenges. PMID- 24491595 TI - The business of radiology.... PMID- 24491596 TI - Genomic variability as a driver of plant-pathogen coevolution? AB - Pathogens apply one of the strongest selective pressures in plant populations. Understanding plant-pathogen coevolution has therefore been a major research focus for at least sixty years [1]. Recent comparative genomic studies have revealed that the genes involved in plant defense and pathogen virulence are among the most polymorphic in the respective genomes. Which fraction of this diversity influences the host-pathogen interaction? Do coevolutionary dynamics maintain variation? Here we review recent literature on the evolutionary and molecular processes that shape this variation, focusing primarily on gene-for gene interactions. In summarizing theoretical and empirical studies of the processes that shape this variation in natural plant and pathogen populations, we find a disconnect between the complexity of ecological interactions involving hosts and their myriad microbes, and the models that describe them. PMID- 24491597 TI - Advancing the management and control of typhoid fever: a review of the historical role of human challenge studies. AB - Typhoid infection causes considerable morbidity and mortality worldwide, particularly in settings where lack of clean water and inadequate sanitation facilitate disease spread through faecal-oral transmission. Improved understanding of the pathogenesis, immune control and microbiology of Salmonella Typhi infection can help accelerate the development of improved vaccines and diagnostic tests necessary for disease control. S. Typhi is a human-restricted pathogen; therefore animal models are limited in their relevance to human infection. During the latter half of the 20th century, induced human infection ("challenge") studies with S. Typhi were used effectively to assess quantitatively the human host response to challenge and to measure directly the efficacy of typhoid vaccines in preventing clinical illness. Here, the findings of these historic challenge studies are reviewed, highlighting the pivotal role that challenge studies have had in improving our understanding of the host pathogen interaction, and illustrating issues relevant to modern typhoid challenge model design. PMID- 24491600 TI - Ultrasound assisted synthesis of TiO2-WO3 heterostructures for the catalytic degradation of Tergitol (NP-9) in water. AB - TiO2-WO3 heterostructures were synthesized at room temperature, ambient pressure, and short reaction time via a sonochemical approach. TEM and EDX images show that the prepared TiO2-WO3 heterostructures consist of globular agglomerates (~250 nm in diameter) composed of very small (<5 nm) dense particles (WO3) dispersed inside the globules. The observed less intense monoclinic WO3 diffraction peak (around 2theta=22 degrees belonging to (001) plane) and the high intense hexagonal WO3 diffraction peak (around 2theta=28 degrees belonging to (200) plane) in XRD indicate that there may be phase transition occurring due to the formation of intimate bond between TiO2 and WO3. In addition, the formation of such new phase was also observed from Raman spectra with a new peak at 955 cm( 1), which is due to the symmetric stretching of W=O terminal. The catalytic activity of TiO2-WO3 heterostructures was tested for the degradation of wastewater pollutant containing Tergitol (NP-9) by a process combined with ozonation and it showed two-fold degradation rate compared with ozone process alone. PMID- 24491599 TI - Degradation of reactive, acid and basic textile dyes in the presence of ultrasound and rare earths [Lanthanum and Praseodymium]. AB - Degradation of five textile dyes, namely Reactive Red 141 (RR 141), Reactive Blue 21 (RB 21), Acid Red 114 (AR 114), Acid Blue 113 (AB 113) and Basic Violet 16 (BV 16) in aqueous solution has been carried out with ultrasound (US) and in combination with rare earth ions (La(3+) and Pr(3+)). Kinetic analysis of the data showed a pseudo-first order degradation reaction for all the dyes. The rate constant (k), half life (t1/2) and the process efficiency (phi) for various processes in degradation of dyes under different experimental conditions have been calculated. The influence of concentrations of dyes (16-40mg/L), pH (5, 7 and 9) and rare earth ion concentration (4, 12 and 20mg/L) on the degradation of dyes have also been studied. The degradation percentage increased with increasing rare earth amount and decreased with increasing concentration of dyes. Both horn and bath type sonicators were used at 20kHz and 250W for degradation. The sonochemical degradation rate of dyes in the presence of rare earths was related to the type of chromophoric groups in the dye molecule. Degradation sequence of dyes was further examined through LCMS and Raman spectroscopic techniques, which confirmed the sonochemical degradation of dyes to non-toxic end products. PMID- 24491598 TI - Pandemic H1N1 virus transmission and shedding dynamics in index case households of a prospective Vietnamese cohort. AB - OBJECTIVES: Influenza household transmission studies are required to guide prevention strategies but most passively recruit index cases that seek healthcare. We investigated A(H1N1)pdm09 transmission in a household-based cohort during 2009. METHODS: Health-workers visited 270 households weekly, and collected swabs from influenza-like-illness cases. If A(H1N1)pdm09 was RT-PCR-confirmed, all household members had symptoms assessed and swabs collected daily for 10-15 days. Viral RNA was quantified and sequenced and serology performed on pre pandemic sera. RESULTS: Index cases were detected in 20 households containing 81 people. 98.5% lacked A(H1N1)pdm09 neutralizing antibodies in pre-pandemic sera. Eleven (18.6%, 95% CI 10.7-30.4%) of 59 contacts were infected. Virus genetic diversity within households was negligible and less than between households. Index and secondary cases were distributed between mothers, daughters and sons, and had similar virus-RNA shedding and symptom dynamics. Fathers were rarely infected. Five secondary cases (45%) had no apparent symptoms and three shed virus before symptoms. Secondary infection was associated with index case wet cough (OR 1.56, 95% CI 1.22-1.99). CONCLUSIONS: In this cohort of A(H1N1)pdm09 susceptible persons, virus sequencing was capable of discriminating household from community transmission. Household transmission involved mothers and children but rarely fathers. Asymptomatic or pre-symptomatic shedding was common. PMID- 24491601 TI - Ultrasound assisted enzymatic conversion of non edible oil to methyl esters. AB - Conventional and ultrasound-assisted hydrolysis and subsequent esterification of Nagchampa oil under mild operating conditions have been investigated with an objective of intensification of methyl esters production using a sustainable approach. The effect of ratio of reactants, temperature, enzyme loading, pretreatment of enzyme (using ultrasonic irradiations) on the hydrolysis and esterification reaction has been studied. Optimum conditions for hydrolysis were observed to be 1:1 weight ratio of oil: water for Lip Z and 1:3 for Lip 2 enzymes, enzyme loading of 400 units for Lip Z and 800 mg for Lip 2 enzymes and reaction time of 6h. In the case of esterification reaction, optimum conditions obtained were oil to methanol molar ratio of 1:2, enzyme loading of 1000 mg and reaction time of 20 h. Use of pretreated enzyme (using ultrasonic irradiations) was found to increase the extent of esterification reaction from 75% to 92.5%. It was observed that use of ultrasound in the reaction significantly intensified the esterification reaction with time requirement reducing from 20 h for conventional stirring based approach to only about 7.5 h in the presence of ultrasound. The extent of esterification obtained with sonicated enzyme also increased to 96% from 75% with unsonicated enzyme. PMID- 24491602 TI - The influence of oral steroidal contraceptives on magnesium concentration in breast milk. AB - This study determined the total magnesium concentration in the breast milk of mothers that were using oral, steroidal contraceptives during lactation. The study involved two groups of breast-feeding mothers that were receiving oral contraception, and a control group of 15 breast-feeding mothers that did not receive oral contraception. The first group received a daily combination pill (levonorgestrel 0.15 mg + ethinylestradiol 0.03 mg); the second group received a daily mini-pill (progestin-only pill, containing norethindrone 0.35 mg). The total magnesium concentrations of plasma and breast milk were determined before the start of contraception and after 30 days of contraception. The results showed that after 30 days of contraception, the contraceptive drugs had not significantly modified the total breast milk magnesium concentration (1.16 +/- 0.11 mmol/L before treatment versus 1.01 +/- 0.12 mmol/L, in first group; 0.97 +/ 0.16 mmol/L before contraception versus 1.08 +/- 0.11 mmol/L, in the second group). There were no significant changes in the total magnesium concentration in the breast milk of the control group after the 30 days. In addition, the oral, steroidal contraceptives (pill and mini-pill) did not affect the total magnesium concentration in the plasma of lactating mothers. PMID- 24491603 TI - Invisible gorillas and red herrings: a response to Paley (2013). PMID- 24491604 TI - Effects of training and simulated combat stress on leg tourniquet application accuracy, time, and effectiveness. AB - The lower extremity tourniquet failure rate remains significantly higher in combat than in preclinical testing, so we hypothesized that tourniquet placement accuracy, speed, and effectiveness would improve during training and decline during simulated combat. Navy Hospital Corpsman (N = 89), enrolled in a Tactical Combat Casualty Care training course in preparation for deployment, applied Combat Application Tourniquet (CAT) and the Special Operations Forces Tactical Tourniquet (SOFT-T) on day 1 and day 4 of classroom training, then under simulated combat, wherein participants ran an obstacle course to apply a tourniquet while wearing full body armor and avoiding simulated small arms fire (paint balls). Application time and pulse elimination effectiveness improved day 1 to day 4 (p < 0.005). Under simulated combat, application time slowed significantly (p < 0.001), whereas accuracy and effectiveness declined slightly. Pulse elimination was poor for CAT (25% failure) and SOFT-T (60% failure) even in classroom conditions following training. CAT was more quickly applied (p < 0.005) and more effective (p < 0.002) than SOFT-T. Training fostered fast and effective application of leg tourniquets while performance declined under simulated combat. The inherent efficacy of tourniquet products contributes to high failure rates under combat conditions, pointing to the need for superior tourniquets and for rigorous deployment preparation training in simulated combat scenarios. PMID- 24491605 TI - Preliminary validation of the military low back pain questionnaire. AB - Soldiers must perform a variety of physical tasks that the civilian population does not. The Modified Oswestry Disability Index (M-ODI) is the most widely used measure of function in patients with low back pain but does not include military tasks. The Military Low Back Pain Questionnaire (MBQ) was developed by military Physical Therapists to include tasks such as wearing body armor. The purpose of this study was to provide preliminary evidence for the reliability, responsiveness, and validity of the MBQ in nondeployed Soldiers. The MBQ had good reliability compared to the M-ODI. The inter-rater correlation coefficient for the M-ODI was 0.79 and 0.75 for the MBQ. Cronbach's alpha was 0.75 and 0.85 for the M-ODI and MBQ, respectively. The minimal detectable change for the M-ODI was 21.03 and 22.97 for the MBQ. Responsiveness was assessed using a global rating of change; area under the curve for the M-ODI was 0.82 and 0.90 for the MBQ. The correlation between the M-ODI and the MBQ was r = 0.80 indicating good concurrent validity. The MBQ was as reliable as the M-ODI in an Army population. There were trends in the psychometrics suggesting the MBQ may be more sensitive to change than the M-ODI in this population. PMID- 24491606 TI - Safe lithium use in a non-psychiatric versus a psychiatric inpatient veterans affairs hospital setting: a retrospective assessment. AB - OBJECTIVE: This study examined practices for monitoring lithium in a non psychiatric versus psychiatric inpatient setting at a Veterans Affairs facility. METHODOLOGY: This retrospective chart review included veterans who had an active order of lithium during their non-psychiatric or psychiatric inpatient stay over the time period of January 2000 to September 2011. Chi-square tests were used for data analysis. Frequency of appropriate lithium monitoring was assessed using standards set by the National Institute for Clinical Excellence and British Association for Psychopharmacology guidelines for bipolar disorder. RESULTS: A total of 200 patients (100 for each group) were included in the final analysis. Psychiatric inpatients had more frequent serum lithium levels measured during inpatient stay (p = 0.0002), whereas nonpsychiatric patients had more frequent renal monitoring (p = 0.0001). Non-psychiatric patients were significantly more likely to have action taken upon abnormal safety assessments (p = 0.0075). CONCLUSIONS: Our results demonstrate significant differences between the non psychiatric and psychiatric inpatient settings in respect to monitoring lithium. The frequency of serum lithium level monitoring in both groups was below the level set by both the National Institute for Clinical Excellence and British Association for Psychopharmacology guidelines. Additionally, frequency of corrective measures in both settings was low, indicating a need for improvement in this area. PMID- 24491607 TI - Female veterans of Operations Enduring and Iraqi Freedom: status and future directions. AB - OBJECTIVES: The number of female veterans has increased four-fold over the past 20 years, yet the study of specific care for female veterans is lacking. Given our military's growing number of female veterans, this article aims to review historical and recent knowledge as well as define research priorities for treatment of the unique physical and mental health issues experienced by women who have served in Operations Enduring Freedom and Iraqi Freedom. METHODS: A literature review was performed of publications spanning the Vietnam War, Persian Gulf War, and Operation Iraqi Freedom and Operation Enduring Freedom periods to determine what health issues persist among female veterans. RESULTS: Female veterans historically report more reproductive and gynecological problems than the general population. They also potentially experience higher incidences of post-traumatic stress disorder and depression compared to male veterans, and overall exhibit a higher prevalence of several mental health disorders compared to the general population. CONCLUSIONS: The study of military trauma outcomes and treatments for female veterans as a distinct population continues to be lacking despite evidence that female veterans experience substantial disability from gynecological and mental health issues. Policy guiding attention to female veterans' health issues is needed. PMID- 24491608 TI - Reservists in a postconflict zone: deployment stressors and the deployment experience. AB - In postconflict zones, both aid and military personnel face chronic stress, including boredom, isolation, family separation, and difficult living conditions, plus the intra-organizational and interpersonal frictions found in all work settings. Australian Army reservists (N = 350) were surveyed during and after peacekeeping in the Solomon Islands. Most respondents reported having a positive experience (66%) and fewer reported their experience was neutral (16%) or negative (17%). The stressors reported by reservists predominately emanated from work-related sources rather than from separation or the operational environment. The discussion considers leadership factors, especially the role of organizational justice in deployed organizations, that may influence the deployment experience. PMID- 24491609 TI - Increasing engagement in evidence-based PTSD treatment through shared decision making: a pilot study. AB - Within the Veterans Health Administration, post-traumatic stress disorder (PTSD) treatment decisions are left to the patient and provider, allowing substantial variability in the way treatment decisions are made. Theorized to increase treatment engagement, shared decision-making interventions provide a standardized framework for treatment decisions. This study sought to develop (phase 1) and pilot test the feasibility and potential effectiveness (phase 2) of a brief shared decision-making intervention to promote engagement in evidence-based PTSD treatment. An initial version of the intervention was developed and then modified according to stakeholder feedback. Participants in the pilot trial were 27 Iraq and Afghanistan Veterans recruited during an intake assessment at a Veterans Affairs PTSD clinic. Participants randomized to the intervention condition (n = 13) participated in a 30-minute shared decision-making session, whereas patients randomized to the usual care condition (n = 14) completed treatment planning during their intake appointment, per usual clinic procedures. Among the 20 study completers, a greater proportion of participants in the intervention condition preferred an evidence-based treatment and received an adequate (>=9 sessions) dose of psychotherapy. Results provide preliminary support for the feasibility and potential effectiveness of the intervention and suggest that larger-scale trials are warranted. PMID- 24491610 TI - In-person and video-based post-traumatic stress disorder treatment for veterans: a location-allocation model. AB - Post-traumatic stress disorder (PTSD) is associated with poor health but there is a gap between need and receipt of care. It is useful to understand where to optimally locate in-person care and where video-based PTSD care would be most useful to minimize access to care barriers, care outside the Veterans Affairs system, and total costs. We developed a service location systems engineering model based on 2010 to 2020 projected care needs for veterans across New England to help determine where to best locate and use in-person and video-based care. This analysis determined specific locations and capacities of each type of PTSD care relative to patient home locations to help inform allocation of mental health resources. Not surprisingly Massachusetts, Connecticut, and Rhode Island are well suited for in-person care, whereas some rural areas of Maine, Vermont, and New Hampshire where in-patient services are infeasible could be better served by video-based care than external care, if the latter is even available. Results in New England alone suggest a potential $3,655,387 reduction in average annual total costs by shifting 9.73% of care to video-based treatment, with an average 12.6 miles travel distance for the remaining in-person care. PMID- 24491611 TI - Apparent comorbidity of bipolar disorder in a population with combat-related post traumatic stress disorder. AB - Combat is often associated with the diagnosis of post-traumatic stress disorder. Battle may also lead to other emotional extremes. Sometimes this is enough to meet criteria for a diagnosis of bipolar disorder (BPD), but it is open to debate if this is clinically appropriate. This study examined the rate of BPD, as assessed by structured interview, in combat veterans who clinicians believed met the criteria for post-traumatic stress disorder but not BPD. Structured interviews were conducted with 109 such participants. Close to 81% endorsed a history of a major depressive episode, 34.9% endorsed a history of manic episode, and 27.5% endorsed a history of a hypomanic episode. According to the interviews, 54.1% participants experienced BPD, including 34.9% who experienced BPD type I. Clinicians were aware of these results and observed the individuals for a prolonged period afterward, but the clinical diagnosis did not change to include BPD in any of these individuals. Future research is needed to establish reliable and valid methods to make a diagnosis of BPD in the presence of comorbid conditions and stressors and thus guide clinicians with better treatment options. PMID- 24491612 TI - Physical therapist vs. family practitioner knowledge of simple low back pain management in the U.S. Air Force. AB - The purpose of this study was to compare knowledge in managing low back pain (LBP) between physical therapists and family practice physicians. Fifty-four physical therapists and 130 family practice physicians currently serving in the U.S. Air Force completed standardized examinations assessing knowledge, attitudes, the usefulness of clinical practice guidelines, and management strategies for patients with LBP. Beliefs of physical therapists and family practice physicians about LBP were compared using relative risks and independent t tests. Scores related to knowledge, attitudes, and the usefulness of clinical practice guidelines were generally similar between the groups. However, physical therapists were more likely to recommend the correct drug treatments for patients with acute LBP compared to family practice physicians (85.2% vs. 68.5%; relative risk: 1.24 [95% confidence interval: 1.06-1.46]) and believe that patient encouragement and explanation is important (75.9% vs. 56.2%; relative risk: 1.35 [95% confidence interval: 1.09-1.67]). In addition, physical therapists showed significantly greater knowledge regarding optimal management strategies for patients with LBP compared to family practice physicians. The results of this study may have implications for health policy decisions regarding the utilization of physical therapists to provide care for patients with LBP without a referral. PMID- 24491613 TI - Mode of delivery trends by hospital type: an 18-year comparison of a military hospital with university and community hospitals. AB - OBJECTIVE: To determine the rate of mode of delivery over 18 years in a military teaching hospital as compared to university and community hospitals. METHODS: From January 1992 to December 2009, we retrospectively calculated yearly rates for mode of delivery from a military hospital, two university hospitals, a community hospital in South Carolina and all community hospitals in Arkansas. RESULTS: Over the 18-year period, 803,249 deliveries occurred from all hospitals. Overall the cesarean delivery rates have significantly increased across all practice models (22.7% + 0.9 versus 33.0% + 0.9, p = <0.001). The rate of increase has been greatest in university hospitals (21.8-37%) followed by community hospitals (26.7-32.9%) and the military hospital (19.6-29.2%). The rate of forceps-assisted deliveries has decreased dramatically across all practice models (11.6% + 1.3 versus 1.1% + 0.1, p = <0.001). The decline in forceps use was 6.4 to 1.1% in community hospital, 12.6 to 1.4% in university hospitals, and 15.7 to 0.9% in military hospitals. CONCLUSIONS: The overall cesarean delivery rate has increased in all practice models but less so in the military. Forceps deliveries have dramatically decreased overall especially in the military hospital. PMID- 24491614 TI - Aeromedical evacuation planning using geospatial decision-support. AB - In this study, we proffer an algorithmic, geospatial-based decision-support methodology that assists military decision-makers in determining which aeromedical evacuation (MEDEVAC) assets to launch after receiving an injury location, given knowledge only of terrain, aircraft location, and aircraft capabilities. The objective is for military medical planners to use this decision support tool (1) to improve real-time situational awareness by visualization of MEDEVAC coverage, showing which areas can be reached within established timelines; (2) to support medical planning by visualizing the impact of changes in the medical footprint to the MEDEVAC coverage; and (3) to support decision making by providing a time-sorted list of MEDEVAC asset packages to select from, given the location of the patients. This same geospatial-based decision tool can be used for proper emplacement of evacuation assets such that the theater is covered within a truly representative 1-hour response time. We conclude with a discussion of applicability of this tool in medical force structure planning. PMID- 24491615 TI - The 2009 A(H1N1) influenza pandemic in the French Armed Forces: epidemiological surveillance and operational management. AB - OBJECTIVE: The main objective of this study was to evaluate the contribution of a newly implemented daily surveillance system to the management of the 2009 A(H1N1) influenza pandemic by the military decision-makers at different levels in the French Department of Defence. METHODS: The study sample included all medical advisors in the Ministry of Defence and the French Armed Forces Staff and also the members of the specific committee dedicated to flu pandemic control. The variables studied were mental representation of epidemiology, relevance, usefulness, and real-time use of surveillance data using quantitative questionnaires and qualitative face-to-face semistructured interviews. RESULTS: Among the risk managers of the flu pandemic in the Armed Forces, 84% responded. The data generated by epidemiological surveillance were considered relevant and useful, and were reported as effectively used. On the basis of the information produced, concrete actions were planned and implemented in the French Armed Forces. CONCLUSION: In a pandemic situation involving low mortality, the daily monitoring of the disease did not target public health issues, but it was mainly used to assess the availability of the Armed Forces in real time. For the military staff, epidemiological surveillance represents an essential information tool for the conduct of operations. PMID- 24491616 TI - Evaluation of a prototype ration aimed at increasing caloric intake in a field environment. AB - Underconsumption is a common problem among militaries around the world. The purpose of this study was to review and modify the current field ration (FR) to encourage energy intake in the field. Military servicemen from the Singapore Armed forces (N = 232) were interviewed on their perception of the current FR. Based on their inputs, the FR was modified and subsequently evaluated by 434 military personnel undergoing field operations. Mean energy intakes of the servicemen measured through the daily collection of food wrappers were 1,651 +/- 842 kcal/day (6.9 +/- 3.5 MJ/day) and 1,237 +/- 802 kcal/day (5.2 +/- 3.4 MJ/day) for those on the modified (Test) and current (Control) FR, respectively. Surveys conducted at field sites indicated that servicemen in the Test group were less likely to skip meals and had higher desire to eat compared to those in the Control group. Factors that may have contributed to the higher energy intake include improved palatability and convenience, greater variety of food provided, and the higher nutrient density of the modified ration. The findings from this study have implications for future FR design. PMID- 24491617 TI - Medical activity in the Conventional Hospitalization Unit in Kabul NATO Role 3 Hospital: a 3-month-long experience. AB - INTRODUCTION: The main goal of the North Atlantic Treaty Organization role 3 hospital located in Kabul is to provide comprehensive medical services to troops engaged in Afghanistan. Nevertheless, it also provides care for Afghan National Security Forces and for Afghan and non-Afghan civilians. OBJECTIVES: To describe the patients admitted to the conventional hospitalization unit over a 3-month period, between June 29 and October 1, 2012. RESULTS: A total of 439 patients were admitted, for scheduled surgery, discharged from intensive care unit, or referred by emergency room and primary care physicians. Causes of hospitalization were diverse, particularly for nonscheduled admissions, with mainly war- and traffic-accident-related injuries for Afghan civilians and national security forces, and non-war- and non-traffic-accident-related trauma emergencies and gastroenteritis for non-Afghan patients. Suspected or confirmed cardiovascular diseases were a frequent cause of hospitalization and the leading cause of medical evacuation out of war zone for non-Afghan civilians. The patients admitted for war injuries were mainly Afghan civilians, of whom 36.6% were children and 44.7% had been injured by improvised explosive devices. CONCLUSION: Reasons of admission to the conventional hospitalization unit were numerous. Care provided to Afghan and non-Afghan civilians represented the main activity of this unit. PMID- 24491618 TI - Relationship between the 2.4-km run and multistage shuttle run test performance in military personnel. AB - In the United Kingdom, all branches of the armed forces use 2.4-km run time and/or the 20-m multistage shuttle run test (MSRT) to assess the aerobic fitness of their personnel. This study quantified the relationship between these two tests in 156 army recruits and officer cadets (100 men and 56 women) to ensure equivalence in the required aerobic fitness standards. The 2.4-km run was performed on surfaced roads and tracks around the training establishment and the MSRT in a gymnasium. Ordinary least product regression was used to describe the relationship between average 2.4-km running speed (km . h(-1)) and the total number of shuttles completed on the U.K. version of the MSRT (r = 0.91, p < 0.01), showing MSRT shuttles = (9.708*2.4-km run speed) - 52.56, with a standard error of prediction of approximately 8 shuttles or 0.8 km . h(-1). The British Army 2.4-km run biannual fitness assessment standard for young men of 10:30 min:s equates to a MSRT score of 82 shuttles (level 10 and 1 shuttle) and for young women of 13:00 min:s equates to 56 shuttles (level 7 and 6 shuttles), with a standard error of estimate of approximately 8 shuttles. PMID- 24491619 TI - Validity and reliability of bioelectrical impedance analysis and skinfold thickness in predicting body fat in military personnel. AB - Previous studies show that body composition is related to injury risk and physical performance in soldiers. Thus, valid methods for measuring body composition in military personnel are needed. The frequently used body mass index method is not a valid measure of body composition in soldiers, but reliability and validity of alternative field methods are less investigated in military personnel. Thus, we carried out test and retest of skinfold (SKF), single frequency bioelectrical impedance analysis (SF-BIA), and multifrequency bioelectrical impedance analysis measurements in 65 male and female soldiers. Several validated equations were used to predict percent body fat from these methods. Dual-energy X-ray absorptiometry was also measured, and acted as the criterion method. Results showed that SF-BIA was the most reliable method in both genders. In women, SF-BIA was also the most valid method, whereas SKF or a combination of SKF and SF-BIA produced the highest validity in men. Reliability and validity varied substantially among the equations examined. The best methods and equations produced test-retest 95% limits of agreement below +/-1% points, whereas the corresponding validity figures were +/-3.5% points. Each investigator and practitioner must consider whether such measurement errors are acceptable for its specific use. PMID- 24491620 TI - Cardiorespiratory responses induced by various military field tasks. AB - Typical military tasks include load carriage, digging, and lifting loads. To avoid accumulation of fatigue, it is important to know the energy expenditure of soldiers during such tasks. The purpose of this study was to measure cardiorespiratory responses during military tasks in field conditions. Unloaded (M1) and loaded (M2) marching, artillery field preparation (AFP), and digging of defensive positions (D) were monitored. 15 conscripts carried additional weight of military outfit (5.4 kg) during M1, AFP, and D and during M2 full combat gear (24.4 kg). Absolute and relative oxygen uptake (VO2) and heart rate (HR) of M1 (n = 8) were 1.5 +/- 0.1 L min(-1), 19.9 +/- 2.7 mL kg(-1) min(-1) (42 +/- 7% VO2max), and 107 +/- 8 beats min(-1) (55 +/- 3% HRmax), respectively. VO2 of M2 (n = 8) was 1.7 +/- 0.2 L min(-1), 22.7 +/- 3.4 mL kg(-1) min(-1) (47 +/- 6% VO2max) and HR 123 +/- 9 beats min(-1) (64 +/- 4% HRmax). VO2 of AFP (n = 5) and D (n = 6) were 1.3 +/- 0.3 L min(-1), 18.0 +/- 3.0 (37 +/- 6% VO2max), and 1.8 +/ 0.4 L min(-1), 24.3 +/- 5.1 mL kg(-1) min(-1) (51 +/- 9% VO2max), respectively. Corresponding HR values were 99 +/- 8 beats min(-1) (50 +/- 3% HRmax) and 132 +/- 10 beats min(-1) (68 +/- 4% HRmax), respectively. The mean work intensity of soldiers was close to 50% of their maximal aerobic capacity, which has been suggested to be maximal limit of intensity for sustained work. PMID- 24491621 TI - The effect of exercise on D-dimer levels. AB - OBJECTIVE: Many health care providers encounter patients with complaints of calf pain, swelling, chest pain, shortness of breath, and syncope after intense exercise. Unfortunately, these symptoms alone or in constellation could represent an underlying venous thromboembolism. A negative D-dimer can often exclude moderate-risk patients. We examined the change in D-dimer levels following strenuous exercise. METHODS: In a prospective study of 42 sailors, D-dimer levels were drawn before and after a workout that simulated the standardized Navy Physical Readiness Test. Data were analyzed using the Kruskal-Wallis and Kolmogorov-Smirnov tests. RESULTS: No significant change was found between pre- and postexercise levels. CONCLUSION: Findings indicate that neither level of conditioning, nor short, intense exercise affected D-dimer levels in participants who were considered extremely at low risk for thromboembolic disease. In essence, this allowed us to test the test, and therefore adds to our understanding of a screening tool used in the pursuit of a disease with significant consequence. PMID- 24491622 TI - Multiple complex penetrating cardiac injuries: role of civilian trauma in the education of the combat general surgeon. AB - OBJECTIVES: To use a case report of a complex cardiac injury case to illustrate how civilian trauma can be used to train combat general surgeons. CASE REPORT: We report the case of a 23-year-old man who suffered three penetrating injuries to the left ventricle (LV) after multiple stab wounds to left chest. On hospital arrival he was conversant, hemodynamically stable, oxygenating well, and without signs of cardiac tamponade. He deteriorated and required an urgent exploratory thoracotomy. Intraoperatively, 2-, 3.5-, and 5-cm stellate lacerations were discovered in the LV near the aortic root, of which, two were full thickness. A simple pledgeted horizontal mattress suture was not sufficient to repair the injuries. The repair ultimately required a running polypropylene suture to control the hemorrhage. The patient was awake on postoperative day 0 and discharged on postoperative day 12 without significant complication. CONCLUSIONS: This case illustrates several points for the combat surgeon. First, young men are able to tolerate catastrophic injuries, presenting with normal hemodynamics. Second, there are a variety of techniques to use when treating uncommon injuries. Finally, the surgeon needs the ability to improvise quickly and to apply surgical techniques to treat complex traumatic injuries successfully. PMID- 24491623 TI - Treatment of complex medical emergencies in a forward deployed setting: a case of out-of-hospital cardiac arrest. AB - The Joint Trauma System in Afghanistan, while designed for the care of injured patients, can provide timely, multimodal, coordinated care for nontraumatic medical emergencies as patients are evacuated from theater. To illustrate this, a case of out-of-hospital cardiac arrest is presented. The patient was able to receive all recommended components of postcardiac arrest care in a timely, coordinated manner at four different medical treatment facilities and while traveling over 8,600 miles with critical care provided en route. PMID- 24491624 TI - Use of CT-arthrography and ultrasound in ACL surgery during Operation Enduring Freedom in Afghanistan: a case report and practice recommendations. AB - The availability of magnetic resonance imaging is severely limited in a deployed environment. However, advanced imaging for diagnosis and treatment of musculoskeletal soft-tissue injuries in theater does exist. Computed tomography (CT), arthrography, and ultrasound are readily available at Role 2 and 3 Medical Treatment Facilities in Afghanistan in support of Operation Enduring Freedom. In this report, we describe a case using CT arthrogram and ultrasound to assist with the diagnosis, treatment, and follow-up of an anterior cruciate ligament reconstruction surgery performed at a Role 2E hospital at Camp Arena, Herat, Afghanistan on a coalition soldier. All physicians who treat musculoskeletal injuries in theater should be familiar with the musculoskeletal applications of ultrasound and CT arthrography. Finally, treatment of the local population and coalition soldiers who do not have access to magnetic resonance imaging will be improved with the knowledge and use of existing advanced imaging in a deployed and austere setting. PMID- 24491625 TI - Rash and elevated creatine kinase in a deployed soldier. AB - A 24-year-old active duty soldier was evacuated from Afghanistan to the United States after persistent upper respiratory tract infection. His course was complicated by an exfoliative rash, diffuse muscle aches, and elevated creatine kinase following trimethoprim-sulfamethoxazole exposure that persisted despite withdrawal of the medication. Dermatomyositis was strongly considered, but the patient had a negative muscle biopsy and had positive serologies for acute Epstein-Barr virus infection. We present a case of acute Epstein-Barr virus infection and possible trimethoprim-sulfamethoxazole reaction mimicking dermatomyositis. PMID- 24491626 TI - Poland's breast reconstruction with decellularized human dermal allograft. AB - The eponym of Poland's syndrome is given to a condition described by Sir Alfred Poland in 1941. The condition is characterized by a myriad of anomalies of the chest wall with multiple theories of its etiology. Usually, the patient that presents to the reconstructive breast surgeon is a female with some degree of abnormal development of her affected ipsilateral breast. Numerous options of breast reconstruction have been described in the literature for patients with Poland's breast anomalies. These include the use of autologous tissue, prosthetic material, or a combination of both. The use of dermal allograft for breast reconstruction in breast cancer has become extremely helpful and prevalent. Currently, the use of dermal allograft with the aid of the pectoralis major muscle is one of the most common techniques for breast reconstruction. However, with the absence of the pectoralis major muscle as is in the case of Poland's syndrome the utility of this technique is unknown. In this article the author describes the case of a patient with severe breast hypoplasia secondary to Poland's syndrome and the successful use of decellularized human dermal allograft only and a tissue expander, followed by postoperative adjustable mammary prosthesis. PMID- 24491627 TI - Rare open hallux interphalangeal joint dislocations sustained in combatives training: a case series. AB - Hallux interphalangeal joint dislocations are a very rare occurrence, and open medial dislocations of the hallux interphalangeal joint, to our knowledge, have not been previously reported in the literature. We report two open medial dislocations, one with fracture, that were sustained within a year of each other at the same military installation. Both patients presented were active duty soldiers that were involved in barefoot combatives and caught their hallux in the fold of the mats while simultaneously experiencing a "twisting force" applied to their foot by their combatives partner. Each soldier required surgical intervention and healed uneventfully, able to return to full activities in an average of 10 weeks with no residual pain. Two injuries of this rarity occurring with the same mechanism of injury within a year at the same military base raise concerns about the surface and shoegear being used for combatives training. The initial analysis of these two separate but similar cases points to the fact that injuries to the foot and toes may be reduced by using seamless mats and/or wearing closed-toed shoes (wrestling style) during combatives training. PMID- 24491628 TI - Idiopathic renal infarction in a previously healthy active duty soldier. AB - Renal infarction (RI) is rare, and usually occurs in patients with associated comorbidities. The majority of reported cases have presented with laboratory abnormalities, most notably leukocytosis and elevated lactate dehydrogenase (LDH). A 50-year-old active duty white male nonsmoker without medical history presented with flank pain. Urinalysis, complete blood count, LDH, and serum creatinine were normal. Contrast-enhanced computed tomography of the abdomen and pelvis showed a right-sided RI. The patient was admitted to the hospital and anticoagulated. Laboratory values remained normal, and a comprehensive workup failed to reveal an etiology for his RI. RI is rare, and affected patients often present with symptoms similar to more common conditions such as lumbago or nephrolithiasis. Elevated LDH may be a clue to the diagnosis, but unlike 92% of the reviewed cases, our patient presented with a normal value. This case suggests that clinicians should consider RI in patients with persistent symptoms for whom more common causes of flank pain have been excluded; including in nonsmoking patients without apparent risk factors for infarction who present with a normal LDH and no leukocytosis. PMID- 24491629 TI - Relationship between cognitive anxiety level and client variables at initial consultation for adults with hearing impairment. AB - The purpose of this study was to use the Cognitive Anxiety Scale (CAS) to investigate relationships between state-anxiety level (cognitive anxiety) and audiometric variables in adults with hearing impairment at their initial consultation. Thirty-five adults with hearing impairment who consulted an audiologist for the first time participated in this study. An interview to obtain information about cognitive anxiety was conducted prior to the audiological assessment. The results indicated that cognitive anxiety was significantly related to an ability to understand speech in noise. Further, cognitive anxiety and ability to understand speech in noise significantly contributed to the classification of hearing aid adopters and non-adopters. These results indicate that the measure of cognitive anxiety may have clinical applications in the future. LEARNING OUTCOMES: The reader will be able to: (1) discuss the relationship between anxiety and hearing impairment; (2) define cognitive anxiety; (3) state the relationship between cognitive anxiety and audiometric variables; (4) state the relationship between cognitive anxiety and the decision to adopt hearing aids; (5) identify signs of cognitive anxiety in adults with hearing impairment. PMID- 24491630 TI - Auditory-motor interactions in pediatric motor speech disorders: neurocomputational modeling of disordered development. AB - BACKGROUND/PURPOSE: Differentiating the symptom complex due to phonological-level disorders, speech delay and pediatric motor speech disorders is a controversial issue in the field of pediatric speech and language pathology. The present study investigated the developmental interaction between neurological deficits in auditory and motor processes using computational modeling with the DIVA model. METHOD: In a series of computer simulations, we investigated the effect of a motor processing deficit alone (MPD), and the effect of a motor processing deficit in combination with an auditory processing deficit (MPD+APD) on the trajectory and endpoint of speech motor development in the DIVA model. RESULTS: Simulation results showed that a motor programming deficit predominantly leads to deterioration on the phonological level (phonemic mappings) when auditory self monitoring is intact, and on the systemic level (systemic mapping) if auditory self-monitoring is impaired. CONCLUSIONS: These findings suggest a close relation between quality of auditory self-monitoring and the involvement of phonological vs. motor processes in children with pediatric motor speech disorders. It is suggested that MPD+APD might be involved in typically apraxic speech output disorders and MPD in pediatric motor speech disorders that also have a phonological component. Possibilities to verify these hypotheses using empirical data collected from human subjects are discussed. LEARNING OUTCOMES: The reader will be able to: (1) identify the difficulties in studying disordered speech motor development; (2) describe the differences in speech motor characteristics between SSD and subtype CAS; (3) describe the different types of learning that occur in the sensory-motor system during babbling and early speech acquisition; (4) identify the neural control subsystems involved in speech production; (5) describe the potential role of auditory self-monitoring in developmental speech disorders. PMID- 24491632 TI - Emotional stress and sympathetic activity: contribution of dorsomedial hypothalamus to cardiac arrhythmias. AB - Maintenance of homeostasis in normal or stressful situations depends upon mechanisms controlling autonomic activity. Central requirement for changes in sympathetic output resulting from emotional stress must be adjusted to the input signals from visceral sensory afferent (feedback response) for an optimum cardiovascular performance. There is a large body of evidence indicating that emotional stress can lead to cardiovascular disease. Reviewing the descending pathways from dorsomedial hypothalamus, a key region involved in the cardiovascular response to emotional stress, we discuss the interactions between mechanisms controlling the sympathetic output to the cardiovascular system and the possible implications in cardiovascular disease. PMID- 24491631 TI - Cell death in the central division of the medial preoptic nucleus of male and female lamb fetuses. AB - The medial preoptic area of the adult sheep contains an ovine sexually dimorphic nucleus (oSDN) that is larger and has more neurons in males than in females. In the lamb fetus, the nascent oSDN occupies the central division of the medial preoptic nucleus (MPNc) and consists of a cluster of cells that is organized by the action of testosterone during gestational days 60-90 of a 147 day term pregnancy. The current study sought to determine whether programmed cell death contributes to the emergence of the oSDN. Male and female lamb fetuses were euthanized at different ages spanning the period during which the oSDN is organized. The expression of the pro- and anti-apoptotic genes bcl-2 and bax, respectively, was measured by quantitative RT-PCR to assess possible sex differences in neuron vulnerability to programmed cell death. The appearance of DNA-fragmentation was detected by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and used to estimate the occurrence of apoptotic cell death. We found that bcl-2 and bax mRNA expression in the medial preoptic area of the developing lamb fetus decreased during the last half of the 147-day gestation. The ratio of bcl-2/bax gene expression was highest at gestational day 85 but was equivalent between males and females. TUNEL staining in the MPNc was very low and although it decreased significantly with age, it was not significantly different between sexes. These results using two different methods to assess cell death indicate that a sex difference in the incidence of cell death is not a primary mechanism leading to sexual differentiation of the oSDN. PMID- 24491633 TI - Morphine inhibits acid-sensing ion channel currents in rat dorsal root ganglion neurons. AB - Extracellular acidosis is a common feature in pain-generating pathological conditions. Acid-sensing ion channels (ASICs), pH sensors, are distributed in peripheral sensory neurons and participate in nociception. Morphine exerts potent analgesic effects through the activation of opioid receptors for various pain conditions. A cross-talk between ASICs and opioid receptors in peripheral sensory neurons has not been shown so far. Here, we have found that morphine inhibits the activity of native ASICs in rat dorsal root ganglion (DRG) neurons. Morphine dose dependently inhibited proton-gated currents mediated by ASICs in the presence of the TRPV1 inhibitor capsazepine. Morphine shifted the proton concentration response curve downwards, with a decrease of 51.4+/-3.8% in the maximum current response but with no significant change in the pH0.5 value. Another MU-opioid receptor agonist DAMGO induced a similar decrease in ASIC currents compared with morphine. The morphine inhibition of ASIC currents was blocked by naloxone, a specific opioid receptor antagonist. Pretreatment of forskolin, an adenylyl cyclase activator, or the addition of cAMP reversed the inhibitory effect of morphine. Moreover, morphine altered acid-evoked excitability of rat DRG neurons and decreased the number of action potentials induced by acid stimuli. Finally, peripheral applied morphine relieved pain evoked by intraplantar of acetic acid in rats. Our results indicate that morphine can inhibit the activity of ASICs via MU-opioid receptor and cAMP dependent signal pathway. These observations demonstrate a cross-talk between ASICs and opioid receptors in peripheral sensory neurons, which was a novel analgesic mechanism of morphine. PMID- 24491634 TI - Relative specificity: all substrates are not created equal. AB - A biological molecule, e.g., an enzyme, tends to interact with its many cognate substrates, targets, or partners differentially. Such a property is termed relative specificity and has been proposed to regulate important physiological functions, even though it has not been examined explicitly in most complex biochemical systems. This essay reviews several recent large-scale studies that investigate protein folding, signal transduction, RNA binding, translation and transcription in the context of relative specificity. These results and others support a pervasive role of relative specificity in diverse biological processes. It is becoming clear that relative specificity contributes fundamentally to the diversity and complexity of biological systems, which has significant implications in disease processes as well. PMID- 24491635 TI - Chemical constituents of Plectranthus amboinicus and the synthetic analogs possessing anti-inflammatory activity. AB - This study demonstrates that compounds 1-4 from an extract of Plectranthus amboinicus inhibit the binding of AP-1 to its consensus DNA sequence. Thymoquinone (5) was further identified as a nonpolar ingredient from the hexane extract of P. amboinicus to suppress the expression of lipopolysaccharide-induced tumor necrosis factor-alpha (TNF-alpha). We then synthesized 2-alkylidenyl-4 cyclopentene-1,3-diones as the designed biomimetics of thymoquinone, and found that compounds 8a, 8b and 8d were more potent TNF-alpha inhibitors. PMID- 24491636 TI - Taccalonolide microtubule stabilizers. AB - This review focuses on a relatively new class of microtubule stabilizers, the taccalonolides. The taccalonolides are highly oxygenated pentacyclic steroids isolated from plants of the genus Tacca. Originally identified in a cell-based phenotypic screen, the taccalonolides have many properties similar to other microtubule stabilizers. They increase the density of interphase microtubules, causing microtubule bundling, and form abnormal multi-polar mitotic spindles leading to mitotic arrest and, ultimately, apoptosis. However, the taccalonolides differ from other microtubule stabilizers in that they retain efficacy in taxane resistant cell lines and in vivo models. Binding studies with the newly identified, potent taccalonolide AJ demonstrated covalent binding to beta-tubulin at or near the luminal and/or pore taxane binding site(s) which stabilizes microtubule protofilaments in a unique manner as compared to other microtubule stabilizers. The isolation and semi-synthesis of 21 taccalonolides helped to identify key structure activity relationships and the importance of multiple regions across the taccalonolide skeleton for optimal biological potency. PMID- 24491637 TI - FicTrac: a visual method for tracking spherical motion and generating fictive animal paths. AB - Studying how animals interface with a virtual reality can further our understanding of how attention, learning and memory, sensory processing, and navigation are handled by the brain, at both the neurophysiological and behavioural levels. To this end, we have developed a novel vision-based tracking system, FicTrac (Fictive path Tracking software), for estimating the path an animal makes whilst rotating an air-supported sphere using only input from a standard camera and computer vision techniques. We have found that the accuracy and robustness of FicTrac outperforms a low-cost implementation of a standard optical mouse-based approach for generating fictive paths. FicTrac is simple to implement for a wide variety of experimental configurations and, importantly, is fast to execute, enabling real-time sensory feedback for behaving animals. We have used FicTrac to record the behaviour of tethered honeybees, Apis mellifera, whilst presenting visual stimuli in both open-loop and closed-loop experimental paradigms. We found that FicTrac could accurately register the fictive paths of bees as they walked towards bright green vertical bars presented on an LED arena. Using FicTrac, we have demonstrated closed-loop visual fixation in both the honeybee and the fruit fly, Drosophila melanogaster, establishing the flexibility of this system. FicTrac provides the experimenter with a simple yet adaptable system that can be combined with electrophysiological recording techniques to study the neural mechanisms of behaviour in a variety of organisms, including walking vertebrates. PMID- 24491638 TI - A modular hierarchical approach to 3D electron microscopy image segmentation. AB - The study of neural circuit reconstruction, i.e., connectomics, is a challenging problem in neuroscience. Automated and semi-automated electron microscopy (EM) image analysis can be tremendously helpful for connectomics research. In this paper, we propose a fully automatic approach for intra-section segmentation and inter-section reconstruction of neurons using EM images. A hierarchical merge tree structure is built to represent multiple region hypotheses and supervised classification techniques are used to evaluate their potentials, based on which we resolve the merge tree with consistency constraints to acquire final intra section segmentation. Then, we use a supervised learning based linking procedure for the inter-section neuron reconstruction. Also, we develop a semi-automatic method that utilizes the intermediate outputs of our automatic algorithm and achieves intra-segmentation with minimal user intervention. The experimental results show that our automatic method can achieve close-to-human intra segmentation accuracy and state-of-the-art inter-section reconstruction accuracy. We also show that our semi-automatic method can further improve the intra segmentation accuracy. PMID- 24491639 TI - Glucose-induced temporary visual recovery in primary open-angle glaucoma: a double-blind, randomized study. AB - PURPOSE: To investigate the effect of topical glucose on visual parameters in individuals with primary open-angle glaucoma (POAG). DESIGN: Double-blind, randomized, crossover study. PARTICIPANTS: Nondiabetic pseudophakic patients with definite POAG were recruited; 29 eyes of 16 individuals participated in study 1. A follow-up study (study 2) included 14 eyes of 7 individuals. INTERVENTION: Eyes were randomly allocated to receive 50% glucose or saline eye drops every 5 minutes for 60 minutes. MAIN OUTCOME MEASURES: The contrast sensitivity and best corrected logarithm of the minimum angle of resolution (logMAR). RESULTS: The 50% glucose reached the vitreous in pseudophakic but not phakic individuals. Glucose significantly improved the mean contrast sensitivity at 12 cycles/degree compared with 0.9% saline by 0.26 log units (95% confidence interval [CI], 0.13-0.38; P < 0.001) and 0.40 log units (95% CI, 0.17-0.60; P < 0.001) in the follow-up study. The intraocular pressure, refraction, and central corneal thickness were not affected by glucose; age was not a significant predictor of the response. CONCLUSIONS: Topical glucose temporarily improves psychophysical visual parameters in some individuals with POAG, suggesting that neuronal energy substrate delivery to the vitreous reservoir may recover function of "sick" retinal neurons. PMID- 24491640 TI - Macular corneal dystrophy: in vivo confocal and structural data. AB - OBJECTIVE: To demonstrate the corneal morphologic aspects obtained with in vivo confocal microscopy (CM) and light and electron microscopy of specimens obtained from the same patients with macular corneal dystrophy (MCD). DESIGN: Case series. PARTICIPANTS: Five consecutive patients affected by MCD undergoing penetrating keratoplasty (PK) in 1 eye. METHODS: The patients were examined with the slit lamp, optical pachymetry, and CM before undergoing PK. The corneal buttons were processed for light, transmission, and scanning electron microscopy. MAIN OUTCOME MEASURES: Corneal in vivo CM, corneal light, and electron microscopy. RESULTS: Confocal microscopy showed areas of altered reflectivity in basal epithelial cells, which appeared hyperreflective or completely white. In the anterior stroma, rectilinear hyperreflective areas were shown. The stroma was characterized by a granular appearance of both keratocytes and extracellular matrix. Dark striae of different length and orientation were present in the middle and posterior stroma. The corneal endothelium showed polymegethism and cells containing bright granules in their cytoplasm. The histopathologic study demonstrated areas of thickened Bowman's layer covered by an epithelium reduced in height. The Bowman's layer thickenings were due to the accumulation of free or vesiculated material of different electron density. The keratocytes showed intracytoplasmatic vesicles, whereas the extracellular matrix presented a large quantity of intercellular electron-lucent material and parallel lamellae with an undulated course. Occasional macrophages, filled with vesicles of granular filamentous material and evident podosomes, were observed. Descemet's membrane was formed by a normal anterior banded zone and a posterior nonbanded zone of honeycombed aspect. The endothelial cells showed a large number of intracytoplasmic vesicles. CONCLUSIONS: The structural changes observed with the histopathologic methods give an account and provide an explanation for the pathologic changes demonstrated by CM in the course of MCD. This may contribute to the understanding of in vivo imaging, allowing a better, noninvasive study of the disease evolution. PMID- 24491641 TI - Nationwide incidence of clinically diagnosed retinal vein occlusion in Korea, 2008 through 2011: preponderance of women and the impact of aging. AB - OBJECTIVE: This study aimed at defining the incidence and demographics of clinically diagnosed retinal vein occlusion (RVO) in Korea. DESIGN: Nationwide population-based retrospective study using data entered into the Korean national health claims database from 2007 through 2011. PARTICIPANTS: Data of the entire population of Korea (n = 47,990,761, based on the 2010 census) were analyzed. METHODS: The Korean national health claims database was analyzed to identify patients with RVO. Incident cases included individuals with no RVO claims in 2007, but with RVO claims in the years 2008 through 2011. The incidence rate of RVO was estimated for the entire Korean population. MAIN OUTCOME MEASURES: The person-time incidence rates of clinically diagnosed RVO in Korea, including the age- and gender-specific incidence rates, were estimated. RESULTS: A total of 92 730 RVO cases (56.4% in women) were identified. The incidence rate of clinically diagnosed RVO during the study period was 48.31 per 100,000 person-years (95% confidence interval [CI], 48.00-48.62). The incidence rate among men and women was 42.40 (95% CI, 41.99-42.81) and 54.14 (95% CI, 53.67-54.60) per 100,000 person-years, respectively (P < 0.001). The highest incidence of 214.92 per 100,000 person-years (95% CI, 211.29-218.56) was observed in the age group of 70 to 74 years (186.62 [95% CI, 181.46-191.78] and 236.25 [95% CI, 231.21-241.29] per 100,000 person-years for men and women aged 70 to 74 years, respectively). The incidence rate of RVO increased as the age of the population increased-more than doubling approximately every 10 years from the second to the seventh decade of life. Retinal vein occlusion occurred more often in men 30 to 54 years of age and in men older than 85 years, but was more common in women 55 to 84 years of age. CONCLUSIONS: This study reports the population-based RVO incidence in Korea. The RVO incidence increased exponentially as the age of the population increased, and the RVO incidence in women was 1.28 times higher than that in men. PMID- 24491642 TI - Three-year outcomes of individualized ranibizumab treatment in patients with diabetic macular edema: the RESTORE extension study. AB - OBJECTIVE: To evaluate long-term efficacy and safety profiles during 3 years of individualized ranibizumab treatment in patients with visual impairment due to diabetic macular edema (DME). DESIGN: Phase IIIb, multicenter, 12-month, randomized core study and 24-month open-label extension study. PARTICIPANTS: Of the 303 patients who completed the randomized RESTORE 12-month core study, 240 entered the extension study. METHODS: In the extension study, patients were eligible to receive individualized ranibizumab treatment as of month 12 guided by best-corrected visual acuity (BCVA) and disease progression criteria at the investigators' discretion. Concomitant laser treatment was allowed according to the Early Treatment Diabetic Retinopathy Study guidelines. Based on the treatments received in the core study, the extension study groups were referred to as prior ranibizumab, prior ranibizumab + laser, and laser. MAIN OUTCOME MEASURES: Change in BCVA and incidence of ocular and nonocular adverse events (AEs) over 3 years. RESULTS: Overall, 208 patients (86.7%) completed the extension study. In patients treated with ranibizumab during the core study, consecutive individualized ranibizumab treatment during the extension study led to an overall maintenance of BCVA and central retinal subfield thickness (CRST) observed at month 12 over the 2-year extension study (+8.0 letters, -142.1 MUm [prior ranibizumab] and +6.7 letters, -145.9 MUm [prior ranibizumab + laser] from baseline at month 36) with a median of 6.0 injections (mean, 6.8 injections; prior ranibizumab) and 4.0 (mean, 6.0 injections; prior ranibizumab + laser). In the prior laser group, a progressive BCVA improvement (+6.0 letters) and CRST reduction (-142.7 MUm) at month 36 were observed after allowing ranibizumab during the extension study, with a median of 4.0 injections (mean, 6.5 injections) from months 12 to 35. Patients in all 3 treatment groups received a mean of <3 injections in the final year. No cases of endophthalmitis, retinal tear, or retinal detachment were reported. The most frequently reported ocular and nonocular adverse effects over 3 years were cataract (16.3%) and nasopharyngitis (23.3%). Eight deaths were reported during the extension study, but none were suspected to be related to the study drug/procedure. CONCLUSIONS: Ranibizumab was effective in improving and maintaining BCVA and CRST outcomes with a progressively declining number of injections over 3 years of individualized dosing. Ranibizumab was generally well tolerated with no new safety concerns over 3 years. PMID- 24491644 TI - Cyto-/genotoxic effects of the ethanol extract of Chan Su, a traditional Chinese medicine, in human cancer cell lines. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Chan Su, an ethanolic extract from skin and parotid venom glands of the Bufo bufo gargarizans Cantor, is widely used as a traditional Chinese medicine for cancer therapy. Although the anti-cancer properties of Chan Su have been investigated, no information exists regarding whether Chan Su has genotoxic effects in cancer cells. The aim of the present study was to examine the cyto-/genotoxic effect of Chan Su in human breast carcinoma (MCF-7 cells), human lung carcinoma (A-549 cells), human T cell leukemia (Jurkat T cells), and normal human lymphocytes. MATERIALS AND METHODS: Effects on the viability of MCF-7, A-549, Jurkat T cells, and normal lymphocytes were evaluated by Trypan blue exclusion assays. The DNA content in the sub-G1 region was detected by propidium iodide (PI) staining and flow cytometry. The genotoxicity of Chan Su was assessed by single-cell gel electrophoresis (comet assay) and the cytokinesis-block micronucleus assay (CBMN assay). RESULTS: Chan Su significantly inhibited the viability of MCF-7, A-549, and Jurkat T cells dose dependently, but had no effect on normal human lymphocytes. Apoptotic death of the cancer cells was evident after treatment. Chan Su also induced genotoxicity in a dose-dependent manner, as indicated by the comet and cytokinesis-block micronucleus assays. CONCLUSIONS: These findings suggest that Chan Su can induce apoptotic death of, and exert genotoxic effects on, MCF-7, A-549, and Jurkat T cells. PMID- 24491646 TI - Heat stress impairs the nutritional metabolism and reduces the productivity of egg-laying ducks. AB - This research was conducted to determine the effect of heat stress on the nutritional metabolism and productivity of egg-laying shelducks. Healthy shelducks (n=120) in the early laying stage (uniform body weights and normal feed intakes) were randomly assigned to two identical climate chambers and exposed to constant high temperature (34 degrees C) or control temperature (23 degrees C) for 28d. The heat-exposed ducks had reduced feed intakes and laying rates (P<0.05), increased frequency of panting and spreading wings and dull featheration; egg weight, eggshell thickness and strength, and Haugh unit also decreased and malondialdehyde (MDA) content of egg yolk increased (P<0.05). Compared with the control ducks, the plasma concentrations of HCO3(-), phosphorus, glucose, thyroxine and activities of glutamic-pyruvic transaminase and glutamic oxaloacetic transaminase were decreased, while there were increased concentrations of corticosterone (P<0.05). The content of MDA and lactate in plasma and liver was greater in heat-exposed than in control ducks, but superoxide dismutase (SOD), glutathione peroxidase (GSH-Px), total antioxidant enzymes (T-AOC) activities and glutathione (GSH) contents were less. The expression of HSP70 gene expression in the liver was increased in heat-stressed ducks. The relative weight of oviduct, number of large ovarian follicles, length of the oviduct all decreased (P<0.05) in heat-treated ducks, as did expression of carbonic anhydrase and calcium binding protein genes in the shell gland as a result of heat stress. In summary, heat stress decreased the productivity of ducks, which related to reduced feed intake, protein synthesis, endocrine dysfunction, less antioxidant capacity, and derangement of calcium and phosphorous balance. PMID- 24491645 TI - Picralima nitida seeds suppress PGE2 production by interfering with multiple signalling pathways in IL-1beta-stimulated SK-N-SH neuronal cells. AB - ETHNOPHARMACOLOGICAL RELEVANCE: The dried seed of Picralima nitida is used in rheumatic fever and as an antipyretic in West Africa. In this study we have investigated the effects of an extract obtained from the seeds of Picralima nitida (PNE) on PGE2 production in IL-1beta-stimulated cells. MATERIALS AND METHODS: Prostaglandin E2 (PGE2) was measured in supernatants of IL-1beta stimulated SK-N-SH cells using enzyme immunoassay (EIA) for PGE2. In Cell ELISA and western blot were used to evaluate the effects of PNE on protein expressions of COX-2, mPGES-1, IkappaB and IKK. To determine the effect of the extract on NF kappaB transactivation, a reporter gene assay was carried out in HEK293 cells stimulated with TNFalpha. An ELISA was used to measure the roles of p38, ERK1/2 and JNK Mitogen Activated Protein Kinases (MAPKs) on anti-neuroinflammatory actions of PNE. RESULTS: Results show that PNE significantly inhibited PGE2 production, as well as COX-2 and mPGES-1 protein expressions in IL-1beta stimulated SK-N-SH cells. Molecular targeting experiments showed that PNE interfered with NF-kappaB signalling pathway through attenuation of TNFalpha stimulated NF-kappaB transcriptional activation in HEK 293 cells. Furthermore, IL 1beta-mediated phosphorylation of IkappaB and IKK were inhibited in SK-N-SH cells. PNE (50-200 MUg/ml) also produced significant inhibition of IL-1beta induced p38 MAPK phosphorylation in SK-N-SH cells. However, phosphorylation of ERK1/2 and JNK MAPKs were achieved at 100 and 200 MUg/ml of the extract. CONCLUSIONS: Taken together, these results clearly demonstrate that Picralima nitida suppresses PGE2 production by targeting multiple pathways involving NF kappaB and MAPK signalling in IL-1beta-stimulated SK-N-SH neuronal cells. PMID- 24491647 TI - Preoperative anxiety management, emergence delirium, and postoperative behavior. AB - Preoperative anxiolysis is important for children scheduled for surgery. The nature of the anxiety depends on several factors, including age, temperament, past hospitalizations, and socioeconomic and ethnic backgrounds. A panoply of interventions effect anxiolysis, including parental presence, distraction, and premedication, although no single strategy is effective for all ages. Emergence delirium (ED) occurs after the use of sevoflurane and desflurane in preschool aged children in the recovery room. Symptoms usually last approximately 15 minutes and resolve spontaneously. The Pediatric Anesthesia Emergence Delirium scale is used to diagnose ED and evaluate therapeutic interventions for ED such as propofol and opioids. PMID- 24491648 TI - Anesthesia and sedation outside the operating room. AB - The volume of pediatric invasive and noninvasive procedures outside the operating room continues to increase. The acuity and complexity of patient clinical condition has resulted in the expansion of the anesthesiologist's role in remote sites. The anesthesia provider must ensure patient safety by assuring appropriate patient preparation, having available required equipment for monitoring and rescue, planning careful sedation/anesthesia management, continuing vigilance and observation into the recovery phase, and requiring strict discharge criteria. A quality improvement program for the department of anesthesiology should review anesthetic and sedation outcomes of patients both inside and outside the operating room. PMID- 24491649 TI - Respiratory complications in the pediatric postanesthesia care unit. AB - This article focuses on common respiratory complications in the postanesthesia care unit (PACU). Approximately 1 in 10 children present with respiratory complications in the PACU. The article highlights risk factors and at-risk populations. The physiologic and pathophysiologic background and causes for respiratory complications in the PACU are explained and suggestions given for an optimization of the anesthesia management in the perioperative period. Furthermore, the recognition, prevention, and treatment of these complications in the PACU are discussed. PMID- 24491650 TI - Major surgical procedures in children with cerebral palsy. AB - There are 3 surgical procedures that patients with cerebral palsy (CP) undergo that may be considered major procedures: femoral osteotomies combined with pelvic osteotomies, spine fusion, and intrathecal baclofen pump implant for the treatment of spasticity. Many complications are known to occur at a higher rate in this population, and some may be avoided with prior awareness of the preoperative pathophysiology of the patient with CP. PMID- 24491651 TI - Challenges in pediatric neuroanesthesia: awake craniotomy, intraoperative magnetic resonance imaging, and interventional neuroradiology. AB - This article gives a review of 3 challenges in caring for children undergoing neurosurgical and neurointerventional procedures. Anesthesiologists may have experience with certain aspects of these situations but may not have extensive experience with each clinical setting. This review addresses issues with awake craniotomy, intraoperative magnetic resonance imaging, and neurointerventional procedures in children with neurologic disease. Familiarization with these complex clinical scenarios and their unique considerations allows the anesthesiologist to deliver optimal care and helps facilitate the best possible outcome for these patients. PMID- 24491652 TI - Neuromonitoring for scoliosis surgery. AB - The use of intraoperative neuromonitoring (IONM) during pediatric scoliosis repair has become commonplace to reduce the risk of potentially devastating postoperative neurologic deficits. IONM techniques include somatosensory evoked potentials, motor evoked potentials, electromyography, and intraoperative wake-up tests. Special considerations for scoliosis repair in pediatric patients include preexisting neurologic deficits and young patients with immature neural pathways in whom neurophysiologic monitoring may prove difficult or unreliable. PMID- 24491653 TI - Brain monitoring in children. AB - Applying scalp sensors in the operating theater, intensive care, or resuscitation scenarios to detect and monitor brain function is achievable, practical, and affordable. The modalities are complex and the output of the monitor needs careful interpretation. The monitor may have technical problems, and a single reading must be considered with caution. These monitors may have a use for monitoring trends in specific situations, but evidence does not support their widespread use. Nevertheless, research should continue to investigate their role. Future techniques and treatments may show that these monitors can monitor brain function and prevent harm. PMID- 24491654 TI - Anesthetic neurotoxicity. AB - All routinely utilized sedatives and anesthetics have been found neurotoxic in a wide variety of animal species, including non-human primates. Neurotoxic effects observed in animals include histologic evidence for apoptotic neuronal cell death and subsequent learning and memory impairment. Several cohort studies in neonates with significant comorbidities requiring surgical procedures early in life have also demonstrated abnormal neurodevelopmental outcomes. This article provides an overview of the currently available data from both animal experiments and human clinical studies regarding the effects of sedatives and anesthetics on the developing brain. PMID- 24491655 TI - The anesthetic management of children with pulmonary hypertension in the cardiac catheterization laboratory. AB - Children need cardiac catheterization to establish the diagnosis and monitor the response to treatment when undergoing drug therapy for the treatment of pulmonary arterial hypertension (PAH). Children with PAH receiving general anesthesia for cardiac catheterization procedures are at significantly increased risk of perioperative complications in comparison with other children. The most acute life-threatening complication is a pulmonary hypertensive crisis. It is essential that the anesthesiologist caring for these children understands the pathophysiology of the disease, how anesthetic medications may affect the patient's hemodynamics, and how to manage an acute pulmonary hypertensive crisis. PMID- 24491656 TI - Anesthesia and analgesia for pectus excavatum surgery. AB - The technique of choice for surgical correction of pectus excavatum is the Nuss procedure, a minimally invasive technique in which rigid metal bars are placed transthoracically beneath the sternum and costal cartilages until permanent remodeling of the chest wall has occurred. Intraoperatively, anesthesia focuses on three areas: the potential for catastrophic blood loss caused by perforation of large capacitance vessels and the heart, the potential for malignant arrhythmias, and the consequences of bilateral iatrogenic pneumothoraces. Postoperatively, analgesia is institutionally dependent and controversial, based on usage and type of regional anesthesia. The necessity of multimodal analgesic techniques creates a common ground across different hospital systems. PMID- 24491657 TI - Anesthesia for the child with cancer. AB - Children with cancer undergo a host of surgeries and procedures that require anesthesia during the various phases of the disease. A safe anesthetic plan includes consideration of the direct effects of tumor, toxic effects of chemotherapy and radiation therapy, the specifics of the surgical procedure, drug drug interactions with chemotherapy agents, pain syndromes, and psychological status of the child. This article provides a comprehensive overview of the anesthetic management of the child with cancer, focuses on a systems-based approach to the impact from both tumor and its treatment in children, and presents a discussion of the relevant anesthetic considerations. PMID- 24491658 TI - Anesthesia for craniofacial surgery in infancy. AB - Anesthetic management of infants undergoing craniofacial surgery can be challenging. Primary concerns for the anesthesiologist include blood loss and its management. The evolution of procedures to treat craniosynostosis has resulted in improvements in perioperative morbidity, including decreased blood loss and transfusion, shorter operations, and shorter hospital stays. An understanding of the procedures performed to treat craniosynostosis is necessary to provide optimal anesthetic management. Descriptions of current surgical techniques and approaches to anesthetic care are presented in this review. PMID- 24491659 TI - Pediatric obstructive sleep apnea. AB - Obstructive sleep apnea syndrome (OSAS) is a disorder of airway obstruction with multisystem implications and associated complications. OSAS affects children from infancy to adulthood and is responsible for behavioral, cognitive, and growth impairment as well as cardiovascular and perioperative respiratory morbidity and mortality. OSAS is associated commonly with comorbid conditions, including obesity and asthma. Adenotonsillectomy is the most commonly used treatment option for OSAS in childhood, but efforts are underway to identify medical treatment options. PMID- 24491660 TI - Ultrasound for regional anesthesia in children. AB - The use of regional anesthesia in children is increasing. Rapid advancement in the use of ultrasound guidance has allowed for a greater ease in performing peripheral regional anesthesia in pediatrics. Successful peripheral nerve blockade provides children with analgesia that will improve their operative experience. PMID- 24491661 TI - Perspectives on quality and safety in pediatric anesthesia. AB - Organizational culture underlies every improvement strategy; without a strong culture, a change, even if initially successful, is short lived. Changing culture and improving quality require commitment of leadership, and leaders must play an active and visible role to articulate the vision and create the proper environment. Quality-improvement projects require a consistent framework for outlining a process, identifying problems, and testing, evaluating, and implementing changes. Wake Up Safe is a patient safety organization that strives to use quality improvement to make anesthesia care safer. Root cause analysis is a methodology in safety analytics based on a sequence of events model of safety. PMID- 24491662 TI - A review of key topics in pediatric anesthesia patient care. PMID- 24491663 TI - Parkinsonism in fragile X-associated tremor/ataxia syndrome (FXTAS): revisited. AB - BACKGROUND: Parkinsonian features have been used as a minor diagnostic criterion for fragile X-associated tremor/ataxia syndrome (FXTAS). However, prior studies have examined parkinsonism (defined as having bradykinesia with at least rest tremor or postural instability) mostly in premutation carriers without a diagnosis of FXTAS. The current study was intended to elaborate this important aspect of the FXTAS spectrum, and to quantify the relationships between parkinsonism, FXTAS clinical staging and genetic/molecular measures. METHODS: Thirty eight (38) FXTAS patients and 10 age-matched normal controls underwent a detailed neurological examination that included all but one item (i.e. rigidity) of the motor section of the Unified Parkinson's Disease Rating Scale (UPDRS). RESULTS: The FXTAS patient group displayed substantially higher prevalence of parkinsonian features including body bradykinesia (57%) and rest tremor (26%), compared to the control group. Furthermore, parkinsonism was identified in 29% of FXTAS patients. Across all patients, body bradykinesia scores significantly correlated with FXTAS clinical stage, FMR1 mRNA level, and ataxic gait of cerebellar origin, while postural instability was associated with intention tremor. INTERPRETATION: Parkinsonian features in FXTAS appear to be characterized as bradykinesia concurrent with cerebellar gait ataxia, postural instability accompanied by intention tremor, and frequent rest tremor, representing distinctive patterns that highlight the need for further clinical studies including genetic testing for the FMR1 premutation. The association between FMR1 mRNA level and bradykinesia implicates pathophysiological mechanisms which may link FMR1 mRNA toxicity, dopamine deficiency and parkinsonism in FXTAS. PMID- 24491664 TI - Histopathological evaluation of horse serum-induced immune complex vasculitis in swine: implication to coronary artery lesions in Kawasaki disease. AB - BACKGROUND: Immune complex (IC) vasculitis can be experimentally induced in animal models by intravenous injection of horse serum (HS), and the findings of HS-induced IC vasculitis in swine were very similar to that of Kawasaki disease (KD). The IC mechanism may be involved in the pathogenesis of vasculitis in KD. Here, we studied the two-dimensional (2D) echocardiographic and histopathological findings of acute, subacute, and healing phases of vasculitis induced by two different types of HS, and the reproducibility of IC vasculitis in swine. METHODS AND RESULTS: Our study group consisted of 24 pure-bred landrace male piglets of 1.5-3 months of age. They were divided into three HS groups (n = 17), namely, Group A (n = 8) receiving gamma globulin-free HS, and Group B (n = 6) receiving donor herd HS, three doses at 5-day intervals, and Group C (n = 3) that received only one dose of donor herd HS on Day 1, and the saline group (n = 7) that received three doses of intravenous normal saline (NS) at 5-day intervals. The 2D echocardiography was performed every 3-4 days, and all piglets were killed for histopathological studies at different dates from Days 2 to Day 60. All the HS groups developed rashes and demonstrated significant dilation (54-150%) of coronary arteries in Groups A and B; when compared (p < 0.02) with 9-53% dilation in Group C and the saline group. Histopathological changes of test groups were asymmetric coronary vasculitis in various stages, whereas none of the piglets in the control group developed vasculitis. No significant difference in the echocardiographic and histopathological findings was observed among the piglets that received two types of HS. CONCLUSION: HS can induce IC vasculitis in swine. The rashes and 2D echocardiographic and histopathological studies of the acute to healing phases showed close similarities with KD, and it is concluded that swine may serve as a unique experimental model for IC vasculitis and for various therapeutic trials. PMID- 24491665 TI - A vibrational spectroscopic study of the phosphate mineral whiteite CaMn(++)Mg2Al2(PO4)4(OH)2.8(H2O). AB - Vibrational spectroscopy enables subtle details of the molecular structure of whiteite to be determined. Single crystals of a pure phase from a Brazilian pegmatite were used. The infrared and Raman spectroscopy were applied to compare the molecular structure of whiteite with that of other phosphate minerals. The Raman spectrum of whiteite shows an intense band at 972 cm(-1) assigned to the nu1PO4(3-) symmetric stretching vibrations. The low intensity Raman bands at 1076 and 1173 cm(-1) are assigned to the nu3PO4(3-) antisymmetric stretching modes. The Raman bands at 1266, 1334 and 1368 cm(-1) are assigned to AlOH deformation modes. The infrared band at 967 cm(-1) is ascribed to the PO4(3-)nu1 symmetric stretching vibrational mode. The infrared bands at 1024, 1072, 1089 and 1126 cm( 1) are attributed to the PO4(3-)nu3 antisymmetric stretching vibrations. Raman bands at 553, 571 and 586 cm(-1) are assigned to the nu4 out of plane bending modes of the PO4(3-) unit. Raman bands at 432, 457, 479 and 500 cm(-1) are attributed to the nu2 PO4 and H2PO4 bending modes. In the 2600 to 3800 cm(-1) spectral range, Raman bands for whiteite are found 3426, 3496 and 3552 cm(-1) are assigned to AlOH stretching vibrations. Broad infrared bands are also found at 3186 cm(-1). Raman bands at 2939 and 3220 cm(-1) are assigned to water stretching vibrations. Raman spectroscopy complimented with infrared spectroscopy has enabled aspects of the structure of whiteite to be ascertained and compared with that of other phosphate minerals. PMID- 24491666 TI - A novel fluorescent nano-chemosensor for Al(III) ions using a new macrocyclic receptor. AB - A novel macrocyclic chemosensor (L) has been synthesized and characterized by common spectroscopic methods. Spectral properties of fluorescent macrocycle L were studied either as solution in ethanol or as insoluble nanoparticles in aqueous buffer solution. The nano-chemosensors with size about 35nm were prepared by nanoprecipitation method. The influence of metal cations such as Na(+), K(+), Cs(+), Mg(2+), Ba(2+), Al(3+), Pb(2+), Cr(3+), Mn(2+), Fe(3+), Fe(2+), Co(2+), Ni(2+), Cu(2+), Zn(2+), Cd(2+), Hg(2+) and Ag(+) on the spectroscopic properties of nano-chemosensor (L) in aqueous buffer solution were investigated by means of emission spectrophotometry. The macrocycle was found to be as an effective fluorescence sensor for Al(3+) ions. PMID- 24491667 TI - Multi-spectroscopic analysis and molecular modeling on the interaction of curcumin and its derivatives with human serum albumin: a comparative study. AB - The comparative study about the interaction between curcumin and its derivatives (demothxycurcumin and bisdeoxycurcumin) with human serum albumin (HSA) has been carried out using multi-spectroscopic analysis and molecular modeling method. The characteristic of fluorescence quenching and the thermodynamic parameters have been studied by state emission fluorescence experiments under different temperatures with an interval of 6 K. Curcumin shows largest quenching constant and bisdeoxycurcumin shows the smallest at the temperature of 298 K. However, the quenching constant of curcumin drops quickly with the increase of temperature. Demothxycurcumin gives the largest quenching efficiency at the temperature of 310 K. An average distance of 6.7 nm for energy transfer has been determined based on forster resonance energy theory (FRET). The site competitive replacement experiments illustrate three compounds mainly binding on site I (Subdomain IIA) of the protein, and show tendency of binding on site II (Subdomain IIIA) with the removing of methoxyl groups. Circular dichroism spectra and Fourier transform infrared spectroscopy (FTIR) have been used to investigate the influence on protein secondary structure. Content of the alpha-helix increases at low concentrations of the compounds, while unfolding occurs at high concentrations. Docking simulation reveals possible mechanism for different quenching behavior and binding sites preferred by three compounds. The binding modes have effectively supported the conclusion of the experiments. PMID- 24491643 TI - A comparison of lamellar and penetrating keratoplasty outcomes: a registry study. AB - OBJECTIVES: To investigate changing patterns of practice of keratoplasty in Australia, graft survival, visual outcomes, the influence of experience, and the surgeon learning curve for endothelial keratoplasty. DESIGN: Observational, prospective cohort study. PARTICIPANTS: From a long-standing national corneal transplantation register, 13 920 penetrating keratoplasties, 858 deep anterior lamellar keratoplasties (DALKs), and 2287 endokeratoplasties performed between January 1996 and February 2013 were identified. METHODS: Kaplan-Meier functions were used to assess graft survival and surgeon experience, the Pearson chi-square test was used to compare visual acuities, and linear regression was used to examine learning curves. MAIN OUTCOME MEASURES: Graft survival. RESULTS: The total number of corneal grafts performed annually is increasing steadily. More DALKs but fewer penetrating grafts are being performed for keratoconus, and more endokeratoplasties but fewer penetrating grafts are being performed for Fuchs' dystrophy and pseudophakic bullous keratopathy. In 2012, 1482 grafts were performed, compared with 955 in 2002, translating to a requirement for 264 extra corneal donors across the country in 2012. Comparing penetrating grafts and DALKs performed for keratoconus over the same era, both graft survival (P <0.001) and visual outcomes (P <0.001) were significantly better for penetrating grafts. Survival of endokeratoplasties performed for Fuchs' dystrophy or pseudophakic bullous keratopathy was poorer than survival of penetrating grafts for the same indications over the same era (P <0.001). Visual outcomes were significantly better for penetrating grafts than for endokeratoplasties performed for Fuchs' dystrophy (P <0.001), but endokeratoplasties achieved better visual outcomes than penetrating grafts for pseudophakic bullous keratopathy (P <0.001). Experienced surgeons (>100 registered keratoplasties) achieved significantly better survival of endokeratoplasties (P <0.001) than surgeons who had performed fewer grafts (<100 registered keratoplasties). In the hands of experienced, high-volume surgeons, endokeratoplasty failures occurred even after 100 grafts had been performed. CONCLUSIONS: More corneal transplants, especially DALKs and endokeratoplasties, are being performed in Australia than ever before. Survival of DALKs and endokeratoplasties is worse than the survival of penetrating grafts performed for the same indications over the same timeframe. Many endokeratoplasties fail early, but the evidence for a surgeon learning curve is unconvincing. PMID- 24491668 TI - [History of chronic myeloid leukemia: a paradigm in the treatment of cancer]. AB - During two centuries, advances in medicine and medical research have helped to understand the pathophysiology of chronic myelogenous leukemia (CML). This hematologic malignancy is a unique model of oncogenesis where a single molecular hit, causing cell proliferation and survival, was identified. The chromosomal abnormality first highlighted by P. Nowell and D. Hungerford in 1960, and characterized as the reciprocal translocation t(9;22)(q34;q11), the Philadelphia chromosome, discovered in leukemic cells, by J. Rowley in 1973. At the end of the 20th century, the contribution of molecular biology techniques was crucial by the discovery of the BCR-ABL1 hybrid oncogene derived from the t(9;22), responsible for the translation of an aberrant protein tyrosine kinase. This BCR-ABL1 kinase deregulates signaling pathways that control normal cell cycle and survival in primitive hematopoietic cells and is thus responsible for malignant cell accumulation observed in CML. It was then only necessary to develop a targeted treatment adapted to this molecular hit. Recently, tyrosine kinase inhibitors, by their specific inhibitory activity of BCR-ABL, have revolutionized the treatment of CML, allowing rates of haematological, cytogenetic and molecular responses never seen to date, and has significantly improved the overall survival and the quality of life of patients. PMID- 24491669 TI - [Major advances in Oncology in 2013: the editorial board of the Bulletin du Cancer point of view]. AB - Many data are presented each year during the American Society of Clinical Oncology meeting and others international major meetings. This article is proposed by the editorial board of the Bulletin du Cancer as a synthesis of important new data. The purpose is to identify in these results those who may have an immediate impact on our clinical practices. PMID- 24491670 TI - [Management of enzalutamide, a new hormonal therapy]. AB - Enzalutamide (MDV3100) is a non-steroidal antiandrogen of second generation that has shown efficacy in metastatic castration-resistant prostate cancer (mCRPC). The study AFFIRM demonstrated a statistically significant increase in overall survival among patients who have progressed following a docetaxel chemotherapy. Based on these results, a marketing authorization for enzalutamide has been granted. The enzalutamide has been shown to be generally well tolerated. Other trials are underway to evaluate its earlier use in the management of mCRPC. A pivotal registration phase III study (PREVAIL) is ongoing to investigate the effectiveness of enzalutamide in patients who have not yet received chemotherapy. PMID- 24491671 TI - Incremental value of the en face view of the tricuspid valve by two-dimensional and three-dimensional echocardiography for accurate identification of tricuspid valve leaflets. AB - BACKGROUND: In this study, advanced postprocessing of three-dimensional echocardiographic (3DE) data sets was used to identify tricuspid valve (TV) leaflets in two-dimensional echocardiographic (2DE) views, and the feasibility of the subcostal view to obtain 2DE en face views of the TV, as an alternative imaging option to image reconstruction from 3DE imaging, was also tested. METHODS: In 155 consecutive patients, attempts were made to obtain the en face view of the TV by 2DE imaging (from the subcostal window) and by reconstruction from 3DE imaging. Using both in-house-developed and commercially available software for postprocessing of 3DE data, image planes from the standard 2DE views were reconstructed and TV leaflets identified in each view. RESULTS: With 2DE imaging, all TV leaflets could be visualized in 58% of patients, compared with 56% using 3DE imaging. In 30 patients (19%), en face views of the TV could be obtained only by 3DE imaging. The anterior leaflet was the largest one in 90% of patients, and the smallest leaflet was either the posterior (49%) or septal (41%) leaflet. In 12% of patients, the TV was either bicuspid or quadricuspid. In patients with pacemakers, the position of the right ventricular lead relative to the TV leaflets was readily determined using both imaging techniques. Visible TV leaflets varied in all standard 2DE views because of variability in image planes and leaflet morphology. CONCLUSIONS: High variability in TV leaflet anatomy and the dependence on transducer position do not allow schematic leaflet identification. All existing TV leaflet identification schemes are therefore only partially correct, and if correct leaflet identification is needed, the use of an en face view is recommended. PMID- 24491672 TI - Carotid artery and aortic stiffness evaluation in aortic stenosis. AB - BACKGROUND: In aortic stenosis (AS), the combination of risk factors can progressively lead to an increased arterial rigidity, which can be evaluated by the carotid artery and aortic stiffness (beta index). The aim of this study was to investigate the relationship between carotid and aortic beta index, left ventricular (LV) function, plasma brain natriuretic peptide (BNP) level, and symptoms in patients with AS. METHODS: Comprehensive echocardiography including Doppler tissue imaging of the mitral annulus was performed in 53 patients with AS (aortic valve area < 1.2 cm(2)) and preserved LV ejection fractions (>= 50%). Carotid beta index was automatically derived from ultrasound wall tracking of the right carotid artery. The mitral E/e' ratio was used to estimate LV filling pressures. RESULTS: Carotid beta index was higher in women than in men and was significantly correlated with age (P < .0001), diastolic arterial pressure (P = .046), pulse pressure (P = .006), and systemic arterial compliance (P = .001). Interestingly, carotid beta index was significantly correlated with E/e' ratio (P < .0001) and plasma BNP level (P = .011). In multivariate regression analysis, carotid beta index was an independent predictor of E/e' ratio (P < .0001) and of BNP level (P = .02). Moreover, carotid beta index was significantly higher in symptomatic patients (P = .009). Aortic beta index was significantly correlated with carotid beta index (P < .0001), E/e' ratio (P = .004), and BNP (P < .001) and was significantly higher in symptomatic patients (P = .037). CONCLUSIONS: In patients with moderate to severe AS and preserved LV ejection fractions, the presence of increased carotid artery and aortic stiffness, assessed using carotid and aortic beta index, is independently associated with elevated LV filling pressures, BNP level, and symptoms. PMID- 24491673 TI - Preliminary observations of prognostic value of left atrial functional reserve during dobutamine infusion in patients with dilated cardiomyopathy. AB - BACKGROUND: The importance of left atrial (LA) functional reserve in patients with depressed left ventricular function remains unclear. Thus, the aim of this study was to test the hypothesis that diminished augmentation of LA function during dobutamine stress might be associated with cardiovascular events in patients with dilated cardiomyopathy. METHODS: Eighty-four patients with dilated cardiomyopathy with a mean ejection fraction of 34 +/- 9% were retrospectively recruited, and LA strain was determined as the averaged global speckle-tracking longitudinal strain from apical four-chamber and two-chamber views during dobutamine stress (20 MUg/kg/min). The systolic component of LA strain was considered to reflect reservoir function, whereas the passive and active emptying components were considered to reflect passive and active emptying function, respectively. Event-free survival was tracked for 17 months. RESULTS: Multivariate Cox proportional-hazards analysis identified LA volume index (hazard ratio [HR], 1.060; P < .001) and beta-blocker use (HR, 0.048; P < .05) as the independent variables associated with cardiovascular events among the baseline parameters and changes in systolic LA strain (HR, 0.971; P = .02), in passive emptying LA strain (HR, 0.942; P < .001), and in left ventricular early diastolic strain rate (HR, 0.986; P = .03) under dobutamine as the variables among the functional reserve parameters. In sequential Cox models, a model based on clinical variables (chi(2) = 9.3) was improved by conventional echocardiographic parameters (chi(2) = 19.2, P = .012) and LA strain parameters at rest (chi(2) = 40.1, P = .005) and further improved by the addition of changes in LA strain parameters under dobutamine (chi(2) = 61.6, P < .001). CONCLUSIONS: The assessment of LA reservoir and passive emptying function during dobutamine stress provides important incremental prognostic value in patients with dilated cardiomyopathy. PMID- 24491674 TI - Editor's perspectives - March 2014. PMID- 24491675 TI - Impact of ostium secundum atrial septal defect closure on the resolution of falsely positive electrocardiographic criteria for myocardial scarring. AB - BACKGROUND: Electrocardiographic (ECG) Selvester QRS score criteria with false indication of anteroseptal scarring consistent with myocardial infarction have been found in patients with ostium secundum atrial septal defect (OS-ASD). The objective of this study was to evaluate ECGs pre and post percutaneous transcatheter OS-ASD closure to test the hypothesis that the falsely positive criteria for anteroseptal scar decline 1 day post procedure. METHODS: Patients (n = 34, mean age 48 +/- 17 years, 79% female) that underwent OS-ASD closure and had undergone pre procedure cardiac magnetic resonance imaging showing no left ventricular (LV) scarring were included in this study. ECGs pre and 1 day post procedure were assessed according to the QRS Selvester scoring system and compared. RESULTS: Mean Selvester score in anteroseptal regions pre procedure was 6.6 (0.0-6.8) % LV scar and decreased to 4.3 (0.0-6.0) % LV scar one day after the procedure (p = 0.01). Mean Selvester score in lateral regions pre procedure was 3.7 (0.0-3.0) %LV scar and decreased to 2.8 (0.0-0.0) % LV scar one day post procedure (p = 0.25). DISCUSSION: OS-ASD patients with falsely positive anteroseptal scar criteria by the Selvester QRS score pre procedure have a significant decrease in anteroseptal Selvester score 1 day post procedure. The falsely positive anteroseptal scar criteria did not completely resolve 1 day post procedure. Further studies are needed to investigate the relationship between ECG criteria for anteroseptal scar and right ventricular volume overload in late follow up. PMID- 24491676 TI - Clusianone, a naturally occurring nemorosone regioisomer, uncouples rat liver mitochondria and induces HepG2 cell death. AB - Clusianone is a member of the polycyclic polyprenylated acylphloroglucinol family of natural products; its cytotoxic mechanism is unknown. Clusianone is a structural isomer of nemorosone, which is a mitochondrial uncoupler and a well known cytotoxic anti-cancer agent; thus, we addressed clusianone action at the mitochondria and its potential cytotoxic effects on cancer cells. In the HepG2 hepatocarcinoma cell line, clusianone induced mitochondrial membrane potential dissipation, ATP depletion and phosphatidyl serine externalization; this later event is indicative of apoptosis induction. In isolated mitochondria from rat liver, clusianone promoted protonophoric mitochondrial uncoupling. This was evidenced by the dissipation of mitochondrial membrane potential, an increase in resting respiration, an inhibition of Ca(2+) influx, stimulation of Ca(2+) efflux in Ca(2+)-loaded mitochondria, a decrease in ATP and NAD(P)H levels, generation of ROS, and swelling of valinomycin-treated organelles in hyposmotic potassium acetate media. The cytotoxic and uncoupling actions of clusianone were appreciably less than those of nemorosone, likely due to the presence of an intra molecular hydrogen bond with the juxtaposed carbonyl group at the C15 position. Therefore, clusianone is capable of pharmacologically increasing the leakage of protons from the mitochondria and with favorable cytotoxicity in relation to nemorosone. PMID- 24491677 TI - NAD(+) administration decreases doxorubicin-induced liver damage of mice by enhancing antioxidation capacity and decreasing DNA damage. AB - One of the major obstacles for cancer treatment is the toxic side effects of anti cancer drugs. Doxorubicin (DOX) is one of the most widely used anti-cancer drugs, which produces significant toxic side effects on the heart and such organs as the liver. Because NAD(+) can decrease cellular or tissue damage under multiple conditions, we hypothesized that NAD(+) administration may decrease DOX-induced hepatotoxicity. In this study we tested this hypothesis by using a mouse model, showing that NAD(+) administration can significantly attenuate DOX-induced increase in serum glutamate oxaloacetate transaminase activity and decrease in liver weight. The NAD(+) administration also attenuated the DOX-induced increases in the levels of double-strand DNA (dsDNA) damage, TUNEL signals, and active caspase-3. Furthermore, our data has suggested that the NAD(+) administration could produce protective effects at least partially by restoring the antioxidation capacity of the liver, because NAD(+) administration can attenuate the decreases in both the GSH levels and the glutathione reductase activity of the DOX-treated liver, which could play a significant role in the DOX-induced hepatotoxicity. This finding has provided the first evidence indicating that NAD(+) is capable of increasing the antioxidation capacity of tissues. Collectively, our study has found that NAD(+) can significantly decrease DOX induced liver damage at least partially by enhancing antioxidation capacity and decreasing dsDNA damage. Because it can also selectively decrease tumor cell survival, NAD(+) may have significant merits over antioxidants for applying jointly with DOX to decrease the toxic side effects of DOX. PMID- 24491678 TI - Anti-inflammatory effects of genistein via suppression of the toll-like receptor 4-mediated signaling pathway in lipopolysaccharide-stimulated BV2 microglia. AB - Genistein, a principal soy isoflavone, has received considerable attention as a protein kinase inhibitor. Although some studies have demonstrated that genistein possesses anti-inflammatory effects, the molecular mechanisms of genistein mediated anti-inflammatory potential are unclear in microglial cells. In this study, we determined whether genistein attenuates pro-inflammatory responses in lipopolysaccharide (LPS)-stimulated BV2 microglia and attempted to establish the possible mechanisms. Our results indicated that genistein inhibited the production of nitric oxide (NO) and prostaglandin E2 at non-toxic concentrations by inhibiting inducible NO synthase and cyclooxygenase-2 expression. The increased release and expression of inflammatory cytokines, including interleukin 1beta, tumor necrosis factor-alpha, by LPS, were markedly reduced by genistein. Genistein also attenuated LPS-induced reactive oxygen species generation and LPS mediated nuclear translocation of nuclear factor-kappa B (NF-kappaB), associated with blocking degradation of the inhibitor of NF-kappaB-alpha. Furthermore, genistein potently suppressed binding of LPS to the microglial cell surface, indicating the antagonistic effect of genistein against toll like receptor 4 (TLR4), and inhibited LPS-induced TLR4 and myeloid differentiation factor 88 expression. In addition, blocking TLR4 signaling using the specific TLR4 signaling inhibitor CLI-095 increased the anti-inflammatory potential of genistein in BV2 microglia. Our data indicate that genistein may attenuate the initiation of intracellular signaling cascades by LPS through inhibiting NF kappaB activation by inhibiting the binding of LPS to TLR-4 on microglial cells. PMID- 24491679 TI - Autoantibodies to complement components in C3 glomerulopathy and atypical hemolytic uremic syndrome. AB - The alternative pathway of complement is implicated in the pathogenesis of several renal diseases, such as atypical hemolytic uremic syndrome, dense deposit disease and other forms of C3 glomerulopathy. The underlying complement defects include genetic and/or acquired factors, the latter in the form of autoantibodies. Because the autoimmune forms require a specific treatment, in part different from that of the genetic forms, it is important to detect the autoantibodies as soon as possible and understand their characteristics. In this overview, we summarize the types of anti-complement autoantibodies detected in such diseases, i.e. autoantibodies to factor H, factor I, C3b, factor B and those against the C3 convertases (C3 nephritic factor and C4 nephritic factor). We draw attention to newly described autoantibodies and their characteristics, and highlight similarities and differences in the autoimmune forms of these diseases. PMID- 24491680 TI - (33)S as a cooperative capturer for BNCT. AB - (33)S is a stable isotope of sulfur for which the emission of an alpha-particle is the dominant exit channel for neutron-induced reactions. In this work the enhancement of both the absorbed and the equivalent biologically weighted dose in a BNCT treatment with 13.5keV neutrons, due to the presence of (33)S, has been tested by means of Monte Carlo simulations. The kerma-fluence factors for the ICRU-4 tissue have been calculated using standard weighting factors. The simulations depend crucially on the scarce (33)S(n,alpha)(30)Si cross-section data. The presence of a high resonance at 13.5keV was established by previous authors providing discrepant resonance parameters. No experimental data below 10keV are available. All of this has motivated a proposal of experiment at the n_TOF facility at CERN. A setup was designed and tested in 2011. Some results of the successful test will be shown. The experiment is scheduled for the period November to December 2012. PMID- 24491681 TI - Intra-tumor distribution of metallofullerene using micro-particle induced X-ray emission (PIXE). AB - To clarify the intra tumor distribution of gadlinium containing fullerene (Gd@C82), micro particle induced X-ray emission (Micro-PIXE) analysis were performed. The tumor bearing BALB/c mice were injected Gd@C82 and subcutaneous tumors were taken from 48h after the intravenous injection. Using the Micro-PIXE method, we could visualize Gd intra tumor distribution. Therefore our results indicate the possibility that Micro-PIXE is useful technique for imaging the bioditribution of Gd, and Gd@C82 is potentially useful Gd carrier for NCT. PMID- 24491682 TI - Near-threshold (7)Li(p,n)(7)Be neutrons on the practical conditions using thick Li-target and Gaussian proton energies for BNCT. AB - The near threshold (7)Li(p,n)(7)Be neutrons generated by incident proton energy having Gaussian distribution with mean energies from 1.85 to 1.95MeV, were studied as a practical neutron source for BNCT wherein an RFQ accelerator and a thick Li-target are used. Gaussian energy distributions with the standard deviation of 0, 10, 20 and 40keV for mean proton energies from 1.85 to 1.95MeV were surveyed in 0.01MeV increments. A thick liquid Li-target whose dimensions were established in our previous experiments (i.e., 1mm-thick with 50mm width and 50mm length) was considered in this study. The suitable incident proton energy and physical dimensions of Pb layer which serves as a gamma absorber and a Polyethylene layer which is used as a BDE were surveyed by means of the concepts of TPD. Dose distribution were calculated by using MCNP5. A proton beam with mean energy of 1.92MeV and a Gaussian energy distribution with a standard deviation of 20keV at a current of 10mA was selected from the viewpoint of irradiation time and practically achievable proton current. The suitable thicknesses of Pb gamma absorber was estimated to be about 3cm. The estimated thickness of the polyethylene BDE was about 24mm for an ideal proton current of 13mA, and was 18mm for a practical proton current of 10mA. PMID- 24491684 TI - Foreword. PMID- 24491683 TI - Prospective validation of EuroSCORE II in patients undergoing cardiac surgery in Argentinean centres. AB - OBJECTIVES: The European System for Cardiac Operative Risk Evaluation II (EuroSCORE II) is an updated version of the original EuroSCORE that must be extensively validated. The objective was to prospectively evaluate the efficacy of EuroSCORE II in predicting the immediate results of cardiac surgery in Argentinean centres. METHODS: A prospective consecutive series of 503 adults who underwent cardiac surgery between January 2012 and April 2013 was studied. EuroSCORE II discrimination and accuracy were assessed in the overall cohort and in two surgically defined subgroups: isolated coronary artery bypass graft (CABG) surgery and non-CABG surgery. Additionally, a risk-adjusted cumulative sum control chart analysis was performed. RESULTS: In-hospital overall mortality rate was 4.17%, while the mortality rate predicted by the EuroSCORE II was 3.18% (P = 0.402). Receiver operating characteristic curve analysis demonstrated a good overall (area 0.856) and non-CABG subgroup (area 0.857) discrimination (P = 0.0001), while discrimination in the CABG subgroup was poorer (area 0.794, P = 0.014). The model showed good calibration in predicting in-hospital mortality, both overall (Hosmer-Lemeshow, P = 0.082) and for each subgroup (non-CABG, P = 0.308, and CABG, P = 0.150). CONCLUSIONS: EuroSCORE II reflects a better current surgical performance and offers a new quality standard to evaluate local outcomes. EuroSCORE showed an overall good discriminative capacity and calibration in this local population; nevertheless, the model performed optimally in non-CABG surgery and in highest-risk patients, underestimating in-hospital mortality in lowest-risk cases. The latter finding may be interpreted as an inadequate behaviour of the model, as a poor performance of surgeons or both. Larger prospective studies will elucidate this hypothesis. PMID- 24491685 TI - Effect of religious context on the content of visual hallucinations in individuals high in religiosity. AB - This study investigated the interaction between the current environment and personality factors associated with religiosity in determining the content of false perceptions (used as a model for hallucinations). A primed word-detection task was used to investigate the effect of a 'religious' context on false perceptions in individuals scoring highly on religiosity. After a subliminal prime, participants viewed letter strings, and stated any words that they saw. The prime and the actual words could have a religious connotation or not. Participants measuring high on religiosity were more likely to report false perceptions of a religious type than participants low on religiosity. It is suggested that context affects the content of false perceptions through the activation of stored beliefs and values, which vary between individuals, offering a mechanism for the effect of context on idiosyncratic content of hallucinations in schizophrenia. The effect of context and individual differences on false perception content in the current study provides possibilities for future work regarding the underlying nature of hallucinations and their treatment. PMID- 24491686 TI - Associations between polymorphisms of LSAMP gene and schizophrenia. AB - The purpose of this study was to explore relationships between single-nucleotide polymorphisms (SNPs) in the limbic system-associated membrane protein (LSAMP) gene and schizophrenia. Twenty-two SNPs were analysed in 127 unrelated schizophrenic patients and in 171 healthy controls. The results showed significant allelic and haplotypic associations between LSAMP gene and schizophrenia. PMID- 24491687 TI - The importance of distinguishing between the different eating disorders (sub)types when assessing emotion regulation strategies. AB - People with eating disorders (ED) have difficulties regulating their emotions adaptively. Little is known about differences and similarities between different types of ED and how these regulation difficulties relate to other emotional problems. The present study examines maladaptive (suppression) and adaptive (cognitive reappraisal) emotion regulation strategies in women with different ED and relationships with anxiety and depression levels. In 32 women with AN restrictive subtype (ANR), 32 with AN binge-purge subtype (ANBP), 30 with bulimia nervosa (BN), 29 with binge eating disorder (BED), and 64 healthy women, the ERQ (emotion regulation) as well as STAI-T (anxiety), BDI-SF (depression), and EDDS (eating pathology) were administered. Women across different ED subtypes were inclined to suppress emotions and lacked the capacity to reappraise emotions (except women with ANBP). Correlational relations of suppression and reappraisal with anxiety and depression levels differed across ED groups. Emotion regulation problems were found across ED subtypes. However, the types of emotion regulation problems, and the effect of coexisting other emotional problems such as anxiety and depression may differ across ED subtypes. These findings illustrate the importance to of considering ED subtypes in emotion regulation research rather than consider ED as a whole. PMID- 24491688 TI - Temperament and character and psychopathy in male conduct disordered offenders. AB - Adult male offenders with high psychopathy scores are characterized by high Novelty Seeking, low Harm Avoidance and low Cooperativeness; temperament and character traits that may moderate treatment outcomes. This is the first study to investigate if a similar profile is present in juveniles. One hundred and twenty two incarcerated juvenile male offenders who met the criteria for conduct disorder in the absence of current psychiatric disorder (e.g. psychosis, depression, anxiety) were rated on the Temperament and Character Inventory (TCI) and the Psychopathy Checklist: Youth Version (PCL: YV). PCL: YV total score was positively correlated with Novelty Seeking but negatively correlated with Cooperativeness and Harm Avoidance. Examination of the PCL: YV facets indicated a significant negative correlation between Harm Avoidance and PCL: YV Interpersonal and PCL: YV Antisocial; and Reward Dependence and Cooperativeness and PCL: YV Lifestyle/Behavioral. Relationships were primarily with lifestyle/behavioral and antisocial facets of psychopathy. The TCI profile resembles that seen in adult offenders and has implications for treatment as low cooperativeness and reward dependency are likely to be key responsivity factors that need to be addressed in treatment planning. PMID- 24491689 TI - The global health and economic burden of hospitalizations for heart failure: lessons learned from hospitalized heart failure registries. AB - Heart failure is a global pandemic affecting an estimated 26 million people worldwide and resulting in more than 1 million hospitalizations annually in both the United States and Europe. Although the outcomes for ambulatory HF patients with a reduced ejection fraction (EF) have improved with the discovery of multiple evidence-based drug and device therapies, hospitalized heart failure (HHF) patients continue to experience unacceptably high post-discharge mortality and readmission rates that have not changed in the last 2 decades. In addition, the proportion of HHF patients classified as having a preserved EF continues to grow and may overtake HF with a reduced EF in the near future. However, the prognosis for HF with a preserved EF is similar and there are currently no available disease-modifying therapies. HHF registries have significantly improved our understanding of this clinical entity and remain an important source of data shaping both public policy and research efforts. The authors review global HHF registries to describe the patient characteristics, management, outcomes and their predictors, quality improvement initiatives, regional differences, and limitations of the available data. Moreover, based on the lessons learned, they also propose a roadmap for the design and conduct of future HHF registries. PMID- 24491690 TI - What is current practice in offering debriefing services to post partum women and what are the perceptions of women in accessing these services: a critical review of the literature. AB - OBJECTIVE: the main research question is to describe current practice in offering debriefing services to post partum women and learn about the perceptions of women accessing these services. DESIGN: critical review of the literature using a meta ethnography approach. FINDINGS: 20 papers were identified. These included four surveys, three qualitative studies, one mixed methods study and three literature reviews. Nine randomised controlled trials (RCTs) provided additional information from alongside surveys and description of interventions. Two types of debriefing were identified: structured and unstructured. The more formal psychoanalytic forms took place within the RCTs whilst the unstructured discussion sessions commonly with midwives were identified in other research papers. In addition there is confusion amongst service providers about the nature of debriefing and what is delivered. Various aspects of providing a postnatal debriefing service were identified including the optimal timing, specific groups offered debriefing and the number of sessions offered. Postnatal debriefing enabled women to have their birth experiences validated by talking and being listened to and being provided with information. Finally from the limited literature identified relating to midwives' perceptions of postnatal debriefing there was an overall feeling from midwives that they considered it to be beneficial to women. KEY CONCLUSIONS: the findings of this literature review imply that women's responses to receiving postnatal debriefing are generally positive. This review has found that women appear to value talking and being listened to by a midwife following birth. They seem to have a strong need to have their story heard. This discussion also allows the women to have questions answered and information given where necessary. The whole process places a seal on a woman's birth experience which is validated. IMPLICATIONS FOR PRACTICE: although there is no evidence to suggest that postnatal debriefing reduces morbidity, women find the service of value. Maternity providers should consider offering a postnatal debriefing service to meet those needs in advance of further research in this area. PMID- 24491691 TI - Jagged1 is essential for osteoblast development during maxillary ossification. AB - Maxillary hypoplasia occurs due to insufficient maxillary intramembranous ossification, leading to poor dental occlusion, respiratory obstruction and cosmetic deformities. Conditional deletion of Jagged1 (Jag1) in cranial neural crest (CNC) cells using Wnt1-cre; Jagged1(f/f) (Jag1CKO) led to maxillary hypoplasia characterized by intrinsic differences in bone morphology and density using MUCT evaluation. Jag1CKO maxillas revealed altered collagen deposition, delayed ossification, and reduced expression of early and late determinants of osteoblast development during maxillary ossification. In vitro bone cultures on Jag1CKO mouse embryonic maxillary mesenchymal (MEMM) cells demonstrated decreased mineralization that was also associated with diminished induction of osteoblast determinants. BMP receptor expression was dysregulated in the Jag1CKO MEMM cells suggesting that these cells were unable to respond to BMP-induced differentiation. JAG1-Fc rescued in vitro mineralization and osteoblast gene expression changes. These data suggest that JAG1 signaling in CNC-derived MEMM cells is required for osteoblast development and differentiation during maxillary ossification. PMID- 24491692 TI - Inhibition of human neutrophils NEP activity, CD11b/CD18 expression and elastase release by 3,4-dihydroxyphenylethanol-elenolic acid dialdehyde, oleacein. AB - Polyphenols, such as oleacein (3,4-DHPEA-EDA; 3,4-dihydroxyphenylethanol-elenolic acid dialdehyde), are believed to play a role in the prevention of cardiovascular diseases. Due to an increase of neutrophil mediators in acute myocardial infarction the aim of this study was to establish the effect of oleacein on neutral endopeptidase (NEP) activity and other functions of human neutrophils, such as elastase, MMP-9 and IL-8 production. The effect on CD62L and CD11b/CD18 expression on neutrophils was also determined. Oleacein with a concentration of 100 MUM inhibited NEP activity, elastase, MMP-9 and IL-8 release from neutrophils by 77.7 +/- 2.7%, 21.3 +/- 7.8%, 22.7 +/- 4.2% and 25.2 +/- 5.6%, respectively. Oleacein with a concentration of 50 MUM suppressed CD11b/CD18 expression by 63.6 +/- 3.1% and to a lesser extent, increased CD62L expression by 27.3 +/- 8.3% on the surface of neutrophils, in comparison with stimulated cells. Oleacein by inhibiting NEP activity, adhesion molecules expression and elastase release might play a role in the protective effects of olive oil against endothelial injuries. PMID- 24491693 TI - Optimizing delivery systems for cationic biopolymers: competitive interactions of cationic polylysine with anionic kappa-carrageenan and pectin. AB - Polylysine is a cationic biopolymer with a strong antimicrobial activity against a wide range of microorganisms, however, its functional performance is influenced by its interactions with anionic biopolymers. We examined the stability of polylysine-pectin complexes in the presence of carrageenan, and vice versa. Polylysine-pectin or polylysine-carrageenan complexes were formed at mass ratios of 1:0 to 1:32 (pH 3.5), and then micro-electrophoresis, turbidity, microscopy, and isothermal titration calorimetry (ITC) were used to characterise them. Solutions containing polylysine-pectin complexes were slightly turbid and relatively stable to aggregation at high mass ratios, whereas those containing polylysine-carrageenan complexes were turbid and unstable to aggregation and precipitation. Pectin did not strongly interact with polylysine-carrageenan complexes, whereas carrageenan displaced pectin from polylysine-pectin complexes, which was attributed to differences in electrostatic attraction between polylysine, carrageenan, and pectin. These results have important implications for the design of effective antimicrobial delivery systems for foods and beverages. PMID- 24491694 TI - Fast and robust discrimination of almonds (Prunus amygdalus) with respect to their bitterness by using near infrared and partial least squares-discriminant analysis. AB - In this study, near-infrared spectroscopy (NIR) coupled to chemometrics is used to develop a fast, simple, non-destructive and robust method for discriminating sweet and bitter almonds (Prunus amygdalus) by the in situ measurement of the kernel surface without any sample pre-treatment. Principal component analysis (PCA) and partial least-squares discriminant analysis (PLS-DA) models were built to discriminate both types of almonds, obtaining high levels of sensitivity and specificity for both classes, with more than 95% of the samples correctly classified and discriminated. Moreover, the almonds were also analysed by Raman spectroscopy, the reference technique for this type of analysis, to validate and confirm the results obtained by NIR. PMID- 24491695 TI - Quantitative analysis of phenolic metabolites from different parts of Angelica keiskei by HPLC-ESI MS/MS and their xanthine oxidase inhibition. AB - Angelica keiskei is used as popular functional food stuff. However, quantitative analysis of this plant's metabolites has not yet been disclosed. The principal phenolic compounds (1-16) within A. keiskei were isolated, enabling us to quantify the metabolites within different parts of the plant. The specific quantification of metabolites (1-16) was accomplished by multiple reaction monitoring (MRM) using a quadruple tandem mass spectrometer. The limit of detection and limit of quantitation were calculated as 0.4-44 MUg/kg and 1.5-148 MUg/kg, respectively. Abundance and composition of these metabolites varied significantly across different parts of plant. For example, the abundance of chalcones (12-16) decreased as follows: root bark (10.51 mg/g)>stems (8.52 mg/g)>leaves (2.63 mg/g)>root cores (1.44 mg/g). The chalcones were found to be responsible for the xanthine oxidase (XO) inhibition shown by this plant. The most potent inhibitor, xanthoangelol inhibited XO with an IC50 of 8.5 MUM. Chalcones (12-16) exhibited mixed-type inhibition characteristics. PMID- 24491696 TI - Bioactive components, antioxidant and DNA damage inhibitory activities of honeys from arid regions. AB - Honey serves as a good source of natural antioxidants, which are effective in reducing the risk of occurrence of several diseases. This study was undertaken to address the limited knowledge regarding the polyphenolic content, antioxidant and DNA damage inhibitory activities of honeys produced in arid regions and compare them with well-recognized honeys from non-arid regions. Different types of honey were assessed for their contents of total phenolics, total flavonoids, and certain types of phenolic compounds. The antioxidant capacity of honey was evaluated by ferric-reducing/antioxidant power assay (FRAP), free radical scavenging activity (DPPH), nitric oxide (NO) radical-scavenging assay, total antioxidant activity, and DNA damage. Results clearly showed significant differences among honeys with all the evaluated parameters. Results also showed that one or more types of honey from arid regions contained higher levels of phenolic compounds, free radical-scavenging activities, or DNA damage inhibitory activities compared with the evaluated honeys from non-arid regions. PMID- 24491697 TI - Physicochemical and biochemical properties of honeys from arid regions. AB - This study was conducted to evaluate the quality of 11 honeys from arid regions for first time, and compare it with 5 different honeys from non-arid regions. Mean values obtained for physicochemical parameters were: pH 4.76 +/- 0.55; 17.32 +/- 1.8% moisture; 80.95 +/- 1.60 degrees Brix sugar; 69.05 +/- 4.41% total sugar; 413.81 +/- 178.48 MUS cm(-1) electrical conductivity; 17.58 +/- 7.68 meq/kg free acidity; 11.05 +/- 3.18 meq/kg lactonic acidity; 28.63 +/- 9.6 meq/kg total acidity; 12.66 +/- 20.39 mg/kg HMF; 0.58 +/- 0.03 water activity; and 0.98 +/- 0.62 colour intensity. Potassium was the major mineral (1760.54 +/- 685.24 mg/kg). All the samples showed considerable significant variations with reference to their physicochemical and biochemical properties, moreover, the total free amino acids and total carotenoids were 61.13 +/- 63.16 mg/100g and 4.07 +/- 10.05 MUg/100g respectively. Acrylamide was detected only in one sample at 2.39 +/- 0.22 MUg/kg. PMID- 24491698 TI - Evaluation of a modified QuEChERS method for analysis of mycotoxins in rice. AB - A simple and efficient QuEChERS (Quick, Easy, Cheap, Effective, Rugged, and Safe) sample preparation method was modified to provide good analytical results for 14 mycotoxins in rice. The method involved mixing sample with acidified aqueous acetonitrile, followed by salt-out liquid partitioning using MgSO4, NaCl, and citrate buffer salts. The extract was cleaned-up by dispersive solid-phase extraction with MgSO4, PSA, C18, and alumina-neutral. The analysis was performed using ultra-high performance liquid chromatography coupled to triple-quadrupole tandem mass spectrometry (UHPLC-MS/MS). Throughout the validation experiments, 70 98% overall recoveries were achieved with RSDs ? 7% for most analytes at concentrations 10-100 MUg kg(-1). Limit of detections were 0.5-15 MUg kg(-1). Inter-laboratory precision was performed by proficiency testing, |z|? 2 was considered satisfactory. We compared our modified QuEChERS method against sample preparation using an immunoaffinity column; the recovery and specificity were comparable for the two methods, but the QuEChERS approach was more time- and cost effective. PMID- 24491699 TI - Pinot Noir wine composition from different vine vigour zones classified by remote imaging technology. AB - The relationship between grapevine vigour and grape and wine composition was investigated in this study. Own-rooted Pinot Noir grapevines were grown in a commercial vineyard in Tasmania, Australia, with uniform vineyard management practices. Vine vigours were determined by plant cell density (PCD) obtained from aerial photography. As vine vigour decreased, total soluble solid in grapes, total phenolics and anthocyanins in wines increased, while titratable acidity and yield decreased. Wines from the ultra low vine vigour zone had the highest concentrations of esters and alcohols. Higher level of linalool, nerol, geraniol, vitispirane, and beta-ionone were observed in ultra low vigour and low vigour zones, but there was no obvious trend for citronellol and beta-damascenone. Principal component analysis and discriminant analysis of the volatiles illustrated the differences among wines from the four vine vigour zones. PMID- 24491700 TI - Competitive chemiluminescent enzyme immunoassay for vitamin B12 analysis in human milk. AB - Recent discoveries of matrix interferences by haptocorrin (HC) in human milk and serum show that past analyses of vitamin B12 in samples with high HC content might have been inaccurate (Lildballe et al., 2009; Carmel & Agrawal, 2012). We evaluated two competitive enzyme-binding immunoassays for serum/plasma (IMMULITE and SimulTRAC-SNB) for B12 analysis in human milk. B12-recovery rates (United States Environmental Protection Agency, 2007) were determined to be 78.9 +/- 9.1% with IMMULITE and 225 +/- 108% (range 116-553%) using SimulTRAC-SNB, most likely due to the presence of excess HC. HC-interferences were not observed with the IMMULITE assay, rendering previously reported mandatory HC-removal (Lildballe et al., 2009) unnecessary. Linearity continued at low B12-concentrations (24-193 pM; r(2)>0.985). Milk B12 concentrations from Bangladeshi women (72-959 pM) were significantly lower than those from California (154-933 pM; p<0.0001) showing IMMULITE's robustness against the complex milk matrix and its ability to measure low milk B12 concentrations. PMID- 24491701 TI - Development and validation of a duplex real-time PCR assay for the simultaneous detection of three mustard species (Sinapis alba, Brassica nigra and Brassica juncea) in food. AB - The paper presents a duplex real-time PCR assay for the simultaneous detection of three potentially allergenic mustard species commonly used in food: white mustard (Sinapis alba), black mustard (Brassica nigra) and brown mustard (Brassica juncea). White mustard is detected in the "green" and black/brown mustard in the "yellow" channel. The duplex real-time PCR assay does not show cross-reactivity with other Brassicaceae species including broccoli, cauliflower, radish and rapeseed. Low cross-reactivities (difference in the Ct value ? 11.91 compared with the positive control) were obtained with cumin, fenugreek, ginger, rye and turmeric. When applying 500 ng DNA per PCR tube, the duplex real-time PCR assay allowed the detection of white, black and brown mustard in brewed model sausages down to a concentration of 5mg/kg in 10 out of 10 replicates. The duplex real time PCR assay was applied to verify correct labelling of commercial foodstuffs. PMID- 24491702 TI - Particle-stabilizers modified from indica rice starches differing in amylose content. AB - Octenyl succinic anhydride (OSA) starches were prepared from four cultivars of native indica rice starches with amylose contents of 1.90%, 18.01%, 25.40% and 26.98% (w/w). The emulsion stability and microstructure of the oil-in-water Pickering emulsions (soybean oil/water, 1/2, v/v) stabilized by OSA starch particles were investigated. Results indicated that the average droplet sizes of the emulsions were in the range of 10-70 MUm, depending on starch cultivars. During 100 days of storage, the emulsions made from OSA starches (degree of substitution: 0.0287-0.0294) were stable. Optical microscopy showed that starch particles were accumulated at the oil-water interface in the form of a densely packed layer, which prevented the flocculation and coalescence of oil droplets by a steric mechanism. Moreover, the emulsification of particle-stabilizers was positively correlated with degree of substitution (P<0.01) but had no obvious correlation with amylose content and pasting properties. PMID- 24491703 TI - Characterisation of volatile compounds in a smoke flavouring from rice husk. AB - An aqueous smoke flavouring from rice husk was obtained on a laboratory scale. The volatile compounds were isolated by simultaneous steam distillation-solvent extraction and its identification and quantitative composition was studied by GC MS and GC-FID. A total of 93 compounds were isolated and 86 of them were positively identified. Major compounds (more than 5% GC area) were 2-furfural, phenol, 2-methoxyphenol, 4-ethyl-2-methoxyphenol, and 2,6-dimethoxyphenol. Application of aroma extract dilution analysis on the volatile fraction revealed that 2-methoxyphenol, 4-methyl-2-methoxyphenol, 2,6-dimethoxyphenol, 2-furfural, 2-acetylfuran, 3-methyl-1,2-cyclopentanedione, acetic acid, 5-methyl-2-furfural, 4-(2-propenyl)-2-methoxyphenol, 4-methyl-2,6-dimethoxyphenol, phenol, 2,6 dimethylphenol, 4-ethyl-2-methoxyphenol, 2-methylphenol were the most odour active compounds. PMID- 24491704 TI - Nondestructive determination of transgenic Bacillus thuringiensis rice seeds (Oryza sativa L.) using multispectral imaging and chemometric methods. AB - Crop-to-crop transgene flow may affect the seed purity of non-transgenic rice varieties, resulting in unwanted biosafety consequences. The feasibility of a rapid and nondestructive determination of transgenic rice seeds from its non transgenic counterparts was examined by using multispectral imaging system combined with chemometric data analysis. Principal component analysis (PCA), partial least squares discriminant analysis (PLSDA), least squares-support vector machines (LS-SVM), and PCA-back propagation neural network (PCA-BPNN) methods were applied to classify rice seeds according to their genetic origins. The results demonstrated that clear differences between non-transgenic and transgenic rice seeds could be easily visualized with the nondestructive determination method developed through this study and an excellent classification (up to 100% with LS-SVM model) can be achieved. It is concluded that multispectral imaging together with chemometric data analysis is a promising technique to identify transgenic rice seeds with high efficiency, providing bright prospects for future applications. PMID- 24491705 TI - N-3 fatty acid enriched eggs and production of egg yolk powders: an increased risk of lipid oxidation? AB - Lipid oxidation is generally favoured by thermal processing and long-term storage. Oxidised lipids can alter nutritional and sensorial properties of foods. As eggs are widely used in food industries in dried powder form, our aim was to determine whether compositional or processing parameters have an impact on lipid oxidation from the shell eggs up to the dried powders and subsequent storage. Two batches of shell eggs were processed: one issued from hens fed with a standard diet and another receiving a diet enriched in extruded linseed, rich in linolenic acid. The extent of lipid oxidation was evaluated by quantification of conjugated dienes (CD) and malondialdehyde (MDA), but also by assessment of tocopherols, lutein and zeaxanthin losses. Results highlighted the remarkable oxidative stability of control and enriched yolk powders as revealed by a moderate increase of the quantities of CD and MDA, the lack of oxidised cholesterol and small loss of alpha-tocopherol. PMID- 24491706 TI - Differential responses of B vitamins in black soybean seeds. AB - This study was aimed to determine the contents and the association of B vitamins from seeds of 10 black and one yellow soybean (Glycine max (L.) Merr.) varieties with either green or yellow cotyledon. Thiamine, flavin adenine dinucleotide (FAD), riboflavin and total riboflavin were found highest in 'Chengjakong', while flavin mononucleotide (FMN) was greatest in 'Mirang'. Nicotinic acid and total vitamin B3 were highest in 'Shingi' as a yellow soybean variety but pantothenic acid and pyridoxine contents were greatest in 'Tawon' and 'Mirang', respectively. These content variations of B vitamins directly reflected the wide segregation of soybean varieties on the principal component analysis (PCA) scores plot, indicating that these 4 soybean varieties appeared to be least associated with other soybean varieties based on the different responses of B vitamins. The results of cluster and correlation analyses presented that the cotyledon colour of soybean seed contributed to a variation of B vitamin contents. Overall, the results suggest that a wide range of B vitamin contents would be affected by genotypic factors alongside the difference of cotyledon colour. PMID- 24491707 TI - Nutritional characterisation and bioactive components of commercial carobs flours. AB - Food industry is interested in the utilisation of legume flours for the improvement the nutritional quality of cereal based foods. In this context, this research aimed at investigating the beneficial properties of different commercial carob seed flours -Ceratonia siliqua L.-. In particular, we determined chemical parameters (protein, fat, ash, soluble and insoluble fibre) by standard AOAC methods, lignans (secoisolariciresinol, lariciresinol, isolariciresinol, pinoresinol) by HPLC methods, the Total Polyphenol Content (TPC) by the Folin Ciocalteau method and the antioxidant properties by the FRAP assay. The carob germ flour and the raw carob seed flour reached the highest insoluble fibre, lignan and total polyphenols content and these results were matched by their antioxidant properties. Different carob flours showed a different distribution of the various lignans. PMID- 24491708 TI - Effect of ultra-high pressure homogenisation processing on phenolic compounds, antioxidant capacity and anti-glucosidase of mulberry juice. AB - In this study, the effects of ultra-high pressure homogenisation (UHPH) processing at 200 MPa for 1-3 successive passes (inlet temperatures at 4 degrees C) were compared with pasteurisation (95 degrees C, 1 min) processing on phenolic compounds, antioxidant capacity (ORAC value) and anti-glucosidase of mulberry juice. Compared with thermal pasteurisation processing, the more reductions in the anthocyanins, phenolic acids (gallic, protocatechuic, caffeic and p-coumaric acids, and a unknown hydroxycinnamic acid) and quercetin aglycone contents, as well as ORAC value were observed during UHPH processing of mulberry juice, whereas all reductions above during UHPH processing could be inhibited by adding ascorbic acid to mulberry juice. Besides, no significant change (p>0.05) in the alpha-glucosidase inhibitory activity was observed during UHPH processing of mulberry juice, but showed a 14% reduction in mulberry juice processed by thermal pasteurisation. PMID- 24491710 TI - Phenylalanine ammonia-lyase, flavanone 3beta-hydroxylase and flavonol synthase enzyme activity by a new in vitro assay method in berry fruits. AB - An HPLC method for the determination of phenylalanine ammonia-lyase, flavanone 3beta-hydroxylase and flavonol synthase enzyme activity is proposed. This method is based on the determination of the compounds produced and consumed on the enzymatic reaction in just one chromatographic analysis. Optimisation of the method considered kinetic studies to establish the incubation time to perform the assay. The method here described proved to be an interesting approach to measure the activities of the three enzymes simultaneously increasing the rapidity, selectivity and sensitivity over other exiting methods. The enzyme activity method developed was applied to strawberry, raspberry, blackberry, redcurrant and blackcurrant fruits. PMID- 24491709 TI - A multi-residue method for the determination of pesticides in tea using multi walled carbon nanotubes as a dispersive solid phase extraction absorbent. AB - A modified QuEChERS (quick, easy, cheap, effective, rugged and safe) method using multi-walled carbon nanotubes (MWCNTs) as a dispersive solid phase extraction (d SPE) absorbent was established for analysis of 78 pesticide residues in tea. A 6 mg MWCNT sample was selected as the optimised amount based on the distribution of pesticide recoveries and clean-up efficiency from 6 mL acetonitrile extracts. The matrix effects of the method were evaluated and matrix-matched calibration was recommended. The method was validated employing gas chromatography coupled to tandem mass spectrometry (GC-MS/MS) at the spiked concentration levels of 0.05, 0.1 and 0.15 mg kg(-1). For most of the targeted pesticides, the percent recoveries range from 70% to 120%, with relative standard deviations (RSDs) <20%. The linear correlation coefficients (r(2)) were higher than 0.99 at concentration levels of 0.025-0.500 mg kg(-1). In this study, MWCNTs were proved to be a promising d-SPE absorbent with excellent cleanup efficiency, which could be widely applied for the analysis of pesticide residues. PMID- 24491711 TI - Effect of high pressure processing on the conversion of dihydroxyacetone to methylglyoxal in New Zealand manuka (Leptospermum scoparium) honey and models thereof. AB - The effect of high pressure processing (HPP) on the conversion of dihydroxyacetone (DHA) to methylglyoxal (MGO) was examined in New Zealand manuka honey and models thereof. The objective was to confirm that previously reported increases of MGO with HPP treatment originated from conversion of DHA. RP-HPLC was used to quantify DHA, MGO and hydroxymethylfurfural (HMF) after derivatisation with O-(2,3,4,5,6-pentafluorobenzyl)hydroxylamine hydrochloride (PFBHA) or (in the case of MGO) separately with o-phenylenediamine (OPD). Fresh and stored manuka honey, clover honey with DHA added and artificial 26 honey with DHA added were subjected to nine different pressures and holding times and compared to untreated samples. There was no consistent trend of decrease in DHA or increase in MGO for any of the samples with any treatment. Samples showed random change generally within 5-10% of an untreated sample for MGO, DHA and HMF. HPP does not accelerate the conversion of DHA to MGO in honey. PMID- 24491712 TI - Solution behaviour and sweetness response of D-Mannitol at different temperatures. AB - The solution properties of d-Mannitol (DM) were studied to explore sweetness response and molecular interactions in aqueous solutions at different temperatures. The density (rho) and ultrasonic velocity (MU) were measured at 20 45 degrees C using density sound velocity metre (DSA 5000M). The results obtained were used to compute apparent and partial molar volume, apparent specific volumes, partial molar expansibility, apparent molar isentropic compressibility and compressibility hydration number. The partial molar volume (PhiV degrees ) indicates hydrophilic interactions dominating in aqueous solution of DM. The quality of taste has been determined from apparent specific volumes (ASV) data at 20-45 degrees C and 0.04-0.89 mol kg(-1).The apparent molar isentropic compressibility (PhiK(s)) and hydration number (nH) conferred pre-dominance of solute-solvent interactions, whereas partial molar expansibility (PhiE degrees ) and related standards predicted structure making behaviour of DM. This study may provide new insights in elucidation of mechanistic differences between sweeteners and their mode of interactions. PMID- 24491713 TI - Drought stress-induced compositional changes in tolerant transgenic rice and its wild type. AB - Comparing well-watered versus deficit conditions, we evaluated the chemical composition of grains harvested from wild-type (WT) and drought-tolerant, transgenic rice (Oryza sativa L.). The latter had been developed by inserting AtCYP78A7, which encodes a cytochrome P450 protein. Two transgenic Lines, '10B-5' and '18A-4', and the 'Hwayoung' WT were grown under a rainout shelter. After the harvested grains were polished, their levels of key components, including proximates, amino acids, fatty acids, minerals and vitamins were analysed to determine the effect of watering system and genotype. Drought treatment significantly influenced the levels of some nutritional components in both transgenic and WT grains. In particular, the amounts of lignoceric acid and copper in the WT decreased by 12.6% and 39.5%, respectively, by drought stress, whereas those of copper and potassium in the transgenics rose by 88.1-113.3% and 10.4-11.9%, respectively, under water-deficit conditions. PMID- 24491714 TI - Determination of melatonin and its isomer in foods by liquid chromatography tandem mass spectrometry. AB - This study aimed to develop a reliable analytical method for the determination of melatonin and its isomers in various food products. The method entails ethanol extraction of solid samples (or dilution of liquid samples) prior to liquid chromatography coupled to triple quadruple mass spectrometry (LC-MS/MS) analysis of target analytes. The method was in-house validated and successfully applied to various food matrices. Recovery of melatonin from different matrices were found to be 86.0 +/- 3.6%, 76.9 +/- 5.4%, 98.6 +/- 6.4%, and 67.0 +/- 4.5% for beer, walnut, tomato and sour cherry samples, respectively. No melatonin could be detected in black and green tea, sour cherry, sour cherry concentrate, kefir (a fermented milk drink) and red wine while the highest amount of melatonin (341.7 +/- 29.3 pg/g) was detected in crumb. The highest amounts of melatonin isomer were detected in yeast-fermented foods such as 170.7 +/- 29.9 ng/ml in red wine, 14.3 +/- 0.48 ng/ml in beer, and 15.7 +/- 1.4 ng/g in bread crumb. PMID- 24491715 TI - Effect of carbon dioxide enrichment on health-promoting compounds and organoleptic properties of tomato fruits grown in greenhouse. AB - The objective of the present study was to evaluate the effect of carbon dioxide (CO2) enrichment on the main health-promoting compounds and organoleptic characteristics of tomato (Solanum lycopersicum) fruits grown in greenhouse. The contents of health-promoting compounds, including lycopene, beta-carotene, and ascorbic acid, as well as the flavour, indicated by sugars, titrable acidity, and sugar/acid ratio, were markedly increased in CO2 enrichment fruits. Furthermore, CO2 enrichment significantly enhanced other organoleptic characteristics, including colour, firmness, aroma, and sensory attributes in tomato fruits. The results indicated that CO2 enrichment has potential in promoting the nutritional value and organoleptic characteristics of tomatoes. PMID- 24491716 TI - Impact of processing conditions on the kinetic of vitamin C degradation and 2 furoylmethyl amino acid formation in dried strawberries. AB - In this paper, a study on the usefulness of the determination of vitamin C together with indicators of the initial steps of Maillard reaction (2 furoylmethyl amino acids, 2-FM-AA) during the convective drying of strawberries has been carried out for the first time, paying special attention to the kinetics of degradation and formation, respectively, of both parameters. Formation of 2-FM AA of Lys, Arg and GABA and vitamin C loss increased with time and temperature following, respectively, a zero and first-order kinetics. As supported by its lower activation energy, 2-FM-GABA (55.9 kJ/mol) and 2-FM-Lys+2-FM-Arg (58.2 kJ/mol) were shown to be slightly more sensitive indicators than vitamin C (82.1 kJ/mol). The obtained results, together with a complementary study on the rehydration ability and sensorial attributes of samples, pointed out the suitability of the convective drying system to obtain dried strawberries of high nutritive quality and bioactivity and good consumer acceptance. PMID- 24491717 TI - Reduction of hexavalent chromium by digested oat bran proteins. AB - Hexavalent chromium (Cr(VI)) is associated with an increase in oxidative stress, such as DNA, lipid and protein oxidations. This study investigated, for the first time, the ability of digested food proteins to reduce Cr(VI) and scavenge free radicals. Protamex, an endopeptidase was used to digest oat bran protein isolates for 1, 2, 3, and 4h. The hydrolysates (1mg/ml) showed a maximum Cr(VI)-reducing activity of 5.4 +/- 0.4% and 44.6% at pH 7.4 and 3.0, respectively. The difference might be due to charge or conformation changes depending on the pH. The 2h hydrolysate possessed the highest O2(-) inhibition activity (57.4 +/- 5.1%), while the 1h hydrolysate had the highest HO inhibition (11.6 +/- 0.6%). A correlation (R(2)=0.82) was observed between the O2(-) scavenging activities of hydrolysates and their Cr(VI)-reducing activities at pH 3.0 only. Further investigations of the digested oat bran proteins are required to determine their ability to reduce Cr(VI) oxidative stress damage in vivo. PMID- 24491718 TI - Comparative analysis of surface wax in mature fruits between Satsuma mandarin (Citrus unshiu) and 'Newhall' navel orange (Citrus sinensis) from the perspective of crystal morphology, chemical composition and key gene expression. AB - Surface wax of mature Satsuma mandarin (Citrus unshiu) and 'Newhall' navel orange (Citrus sinensis) was analysed by crystal morphology, chemical composition, and gene expression levels. The epicuticular and total waxes of both citrus cultivars were mostly composed of aldehydes, alkanes, fatty acids and primary alcohols. The epicuticular wax accounted for 80% of the total wax in the Newhall fruits and was higher than that in the Satsuma fruits. Scanning electron microscopy showed that larger and more wax platelets were deposited on the surface of Newhall fruits than on the Satsuma fruits. Moreover, the expression levels of genes involved in the wax formation were consistent with the biochemical and crystal morphological analyses. These diversities of fruit wax between the two cultivars may contribute to the differences of fruit postharvest storage properties, which can provide important information for the production of synthetic wax for citrus fruits. PMID- 24491719 TI - Evaluation of seed chemical quality traits and sensory properties of natto soybean. AB - Natto is a popular soyfood in Japan, and the U.S. is the largest supplier of natto soybeans. However, information on natto seed chemical and sensory properties is very limited. The objectives of this study were to evaluate differences of seed chemical and sensory properties among natto types and determine heritability and correlation. A total of 15 small-seeded natto genotypes (three superior, nine moderate and three inferior) were evaluated for protein, oil, calcium, manganese, boron and sugar content and processed into a natto product to evaluate appearance, stickiness, flavor, texture and shelf-life. The superior natto group had a higher sugar content but lower protein plus oil, calcium, manganese and boron content than other two groups. Most seed quality traits exhibited high heritability. The natto sensory preference was positively correlated with sucrose and oil content, but negatively correlated with seed hardness, protein, protein plus oil, calcium, manganese, and boron contents. Selecting soybean lines with low protein, protein plus oil, calcium, manganese, and boron content while with high sucrose will be an effective approach for soybean breeding for natto production. PMID- 24491720 TI - Position of modifying groups on starch chains of octenylsuccinic anhydride modified waxy maize starch. AB - Octenylsuccinic anhydride (OSA)-modified starches with a low (0.018) and high (0.092) degree of substitution (DS) were prepared from granular native waxy maize starch in aqueous slurry. The position of OS substituents along the starch chains was investigated by enzyme hydrolysis followed by chromatographic analysis. Native starch and two OS starches with a low and high DS had beta-limit values of 55.9%, 52.8%, and 34.4%, respectively. The weight-average molecular weight of the beta-limit dextrin from the OS starch with a low DS was close to that of the beta limit dextrin from native starch but lower than that of the beta-limit dextrin from the OS starch with a high DS. Debranching of OS starches was incomplete compared with native starch. OS groups in the OS starch with a low DS were located on the repeat units near the branching points, whereas the OS substituents in the OS starch with a high DS occurred both near the branching points and the non-reducing ends. PMID- 24491721 TI - Evolution of total and individual capsaicinoids in peppers during ripening of the Cayenne pepper plant (Capsicum annuum L.). AB - The evolution of total capsaicinoids and the individual contents of the five major capsaicinoids: nordihydrocapsaicin, capsaicin, dihydrocapsaicin, homocapsaicin and homodihydrocapsaicin present in the Cayenne pepper (Capsicum annuum L.), during fruit ripening, has been established. Capsaicinoids begin to accumulate gradually in the peppers from the beginning of its development up to a maximum concentration (1,789 MUmol/Kg FW). From this time there is initially a sharp decrease in the total capsaicinoid content (32%), followed by a gradual decrease until day 80 of ripening. The two major capsaicinoids present in the Cayenne pepper are capsaicin and dihydrocapsaicin, which represent between 79% and 90%, respectively, of total capsaicinoids depending on fruit ripening. The relative content of capsaicin differs from the evolution of the other four capsaicinoids studied. PMID- 24491722 TI - Compositional differences in soybeans on the market: glyphosate accumulates in Roundup Ready GM soybeans. AB - This article describes the nutrient and elemental composition, including residues of herbicides and pesticides, of 31 soybean batches from Iowa, USA. The soy samples were grouped into three different categories: (i) genetically modified, glyphosate-tolerant soy (GM-soy); (ii) unmodified soy cultivated using a conventional "chemical" cultivation regime; and (iii) unmodified soy cultivated using an organic cultivation regime. Organic soybeans showed the healthiest nutritional profile with more sugars, such as glucose, fructose, sucrose and maltose, significantly more total protein, zinc and less fibre than both conventional and GM-soy. Organic soybeans also contained less total saturated fat and total omega-6 fatty acids than both conventional and GM-soy. GM-soy contained high residues of glyphosate and AMPA (mean 3.3 and 5.7 mg/kg, respectively). Conventional and organic soybean batches contained none of these agrochemicals. Using 35 different nutritional and elemental variables to characterise each soy sample, we were able to discriminate GM, conventional and organic soybeans without exception, demonstrating "substantial non-equivalence" in compositional characteristics for 'ready-to-market' soybeans. PMID- 24491723 TI - The fatty acid profile in different wheat cultivars depending on the level of contamination with microscopic fungi. AB - Analyses were conducted on 30 winter wheat samples growing under controlled conditions and following inoculation with fungi Fusarium culmorum. In inoculated samples the mean concentration of 30 analysed fatty acids was significantly higher in relation to the control and amounted to 1,396 mg/kg vs. 1,046 mg/kg in the control kernels. Recorded concentrations for individual cultivars were significantly correlated with the concentration of fungal biomass. Higher concentration in the control was recorded only for the acid trans C18:2n-6. It was also found that the acid profiles are characteristic of individual cultivars. Statistical analysis showed that trans C18:2n-6, C18:1, C18:3n-3 and C18:3n-6 were the acids with the greatest discriminatory power in distinguishing inoculated samples from the control. Discriminatory analysis separated individual cultivars into quality classes of winter wheat cultivars depending on the presence of a specific fatty acid profile. PMID- 24491724 TI - Active compounds and medicinal properties of Myrciaria genus. AB - The genus Myrciaria occurs in various Brazilian biomes. Its species contains several active components, including phenolic compounds, such as tannins, flavonoids, ellagic acid and anthocyanins. Biological activities reported for Myrciaria fruits and leaf and bark extracts include antioxidant, antibacterial and antifungal effects. This work aims to provide an overview of the active compounds of Myrciaria, highlighting its secondary metabolites and medicinal properties for stimulating new studies regarding this genus. PMID- 24491725 TI - Rootstock and fruit canopy position affect peach [Prunus persica (L.) Batsch] (cv. Rich May) plant productivity and fruit sensorial and nutritional quality. AB - The right combination of rootstock and training system is important for increased yield and fruit sensorial and nutritional homogeneity and quality with peach [Prunus persica (L.) Batsch]. We investigated the effects of rootstock and training system on these parameters, testing the effect of vigorous GF677 and weaker Penta rootstock on 'Rich May' peach cultivar. Fruit position effects regarding photosynthetically active radiation availability, along the canopy profile using the Y training system, were investigated. The positive relationships between total polyphenols content and antioxidant capacity according to canopy vigour and architecture were determined for the two scion/stock combinations. Changes in fruit epicarp colour and content of bioactive compounds were also determined. Lower-vigour trees from Penta rootstock grafting yielded larger fruit with improved skin overcolour, and greater total polyphenols content and antioxidant capacity. GF677 rootstock produced more vigorous trees with fruit with lower sensorial and nutritional parameters. Canopy position strongly affects fruit sensorial and nutritional qualities. These data define potential for improvements to peach production efficiency and fruit quality, particularly for southern Europe peach cultivation conditions. PMID- 24491726 TI - Low temperature conditioning reduces chilling injury while maintaining quality and certain bioactive compounds of 'Star Ruby' grapefruit. AB - In the current study, influence of storage temperature (11 and 2 degrees C) and low temperature conditioning (7 days at 16 degrees C before cold storage at 2 degrees C) on the bioactive compounds in 'Star Ruby' grapefruit (Citrus paradisi Macf.) were examined. Fruits stored at 11 degrees C showed no CI; while fruits stored at 2 degrees C showed highest CI. Conditioning treatment (CD) reduced the incidence of CI. Carotenoids and flavonoids were significantly higher after 16 weeks in fruits stored at 11 degrees C. Low temperature storage (2 degrees C and CD) helped to retain ascorbic acid for a longer period (12 weeks). Higher furocoumarins and taste scores along with less decay development were observed in CD fruits. Conditioning treatment can be utilized to reduce CI and to maintain taste and certain bioactive compounds of grapefruits during prolonged storage at low temperature. However, for a short storage period, 11 degrees C temperature is more effective. PMID- 24491727 TI - Low field nuclear magnetic resonance (LF-NMR) relaxometry in hake (Merluccius merluccius, L.) muscle after different freezing and storage conditions. AB - Low field NMR T2 transverse relaxation measurements were performed on muscle samples from sixty hake (Merluccius merluccius, L.). Fish fillets from hake stored in ice for 3 and 14 days were subjected to different freezing methods (air blast, liquid nitrogen or walk-in freezer) and storage conditions (-20 and -10 degrees C for 5 days, 8 and 18 weeks). Distribution analysis of T2 data of unfrozen muscle displayed a major band (T21), accounting for 90-92% of the total signal, with a relaxation time centred at 47-60 ms and a broad band with protons of higher mobility between 300 and 800 ms, accounting for 3-5% of the signal. Upon freezing, T21 became wider and an extra band appeared within the range 120 360 ms. Whereas no changes were detected at -20 degrees C, the T21 time constant decreased during frozen storage at -10 degrees C in a similar way for all three freezing methods. The relative abundance of T21 declined with storage time but differences were found as a function of freezing. Results are discussed in the light of morphological alterations and protein denaturation, and it is concluded that LF NMR relaxometry is sensitive to different freezing and frozen storage conditions which can have important implications for the quality of fish muscle. PMID- 24491728 TI - Isoflavones profiling of soybean [Glycine max (L.) Merrill] germplasms and their correlations with metabolic pathways. AB - The isoflavone diversity (44 varieties) of the soybean, Glycine max (L.) Merrill, from China, Japan, and Korea was examined by high-performance liquid chromatography. The profiles of 12 isoflavones identified from the grains were subjected to data-mining processes, including partial least-squares discriminant analysis (PLS-DA), Pearson's correlation analysis, and hierarchical clustering analysis (HCA). Although PLS-DA did not reveal significant differences among extracts of soybean from 3 countries, the results clearly show that the variation between varieties was low. The CS02554 variety was separate from the others in the first 2 principal components of PLS-DA. HCA of these phytochemicals resulted in clusters derived from closely related biochemical pathways. Daidzin, genistin, and glycitin contents were significantly correlated with their respective malonyl glycoside contents. Daidzein content correlated positively with genistein content (r=0.8189, P<0.0001). The CS02554 variety appears to be a good candidate for future breeding programs, as it contains high levels of isoflavone compounds. These results demonstrate the use of metabolite profiling combined with chemometrics as a tool for assessing the quality of food and identifying metabolic links in biological systems. PMID- 24491729 TI - Anti-fungal activity of Citrus reticulata Blanco essential oil against Penicillium italicum and Penicillium digitatum. AB - The chemical composition of Citrus reticulata Blanco essential oil was analysed using GC/MS. Monoterpene hydrocarbons (C10H16) constituted the majority (88.96%, w/w) of the total oil. The oils dose-dependently inhibited Penicillium italicum and Penicillium digitatum. The anti-fungal activity of the oils against P. italicum was attributed to citronellol, octanal, citral, decanal, nonanal, beta pinene, linalool, and gamma-terpinene, whereas anti-fungal activity against P. digitatum is attributed to octanal, decanal, nonanal, limonene, citral, gamma terpinene, linalool, and alpha-terpineol. The oils altered the hyphal morphology of P. italicum and P. digitatum by causing loss of cytoplasm and distortion of the mycelia. The oils significantly altered extracellular conductivity, the release of cell constituents, and the total lipid content of P. italicum and P. digitatum. The results suggest that C. reticulata Blanco essential oils generate cytotoxicity in P. italicum and P. digitatum by disrupting cell membrane integrity and causing the leakage of cell components. PMID- 24491730 TI - Total phenolics content and antioxidant capacities of microencapsulated blueberry anthocyanins during in vitro digestion. AB - The goal of this research was to investigate the change in phenolics content and antioxidant capacity of microencapsulated anthocyanins (ACNs) digested in vitro. Blueberry ACN microcapsules were prepared from two wall materials (whey protein isolate and gum arabic) and ACN powder, previously extracted with three solvent systems (acetonic, ethanolic, methanolic); this was then spray-dried. The physicochemical properties and release characteristics of the microcapsules were evaluated. Rehydrated gum arabic microcapsules retained more total ACNs but less ferric reducing power than did whey protein microcapsules. Ethanolic extracts retained most of the total ACNs while methanolic extracts possessed the highest antioxidant capacity. During in vitro digestion, gum arabic microcapsules had high release rates of phenolics with high antioxidant activity during the gastric phase. Whey protein microcapsules had comparably lower release rates but high antioxidant activity throughout digestion. PMID- 24491731 TI - Antioxidant-rich phytochemicals in miracle berry (Synsepalum dulcificum) and antioxidant activity of its extracts. AB - Miracle berry is known for its unique characteristic of modifying sour flavours to sweet. Twelve phenolics were identified and quantified in the miracle berry flesh at a level from 0.3 for kaempferol to 17.8 mg/100g FW for epicatechin. Lutein and alpha-tocopherol were also quantified at a level of 0.4 and 5.8 mg/100g FW, respectively. The TP and TF contents were 1448.3 GA and 9.9 QR mg Equiv/100g FW for the flesh, respectively, compared with 306.7 GA and 3.8 mg QR mg Equiv/100g FW of the seeds. The free radical scavenging and reducing percentage of the flesh extract was 96.3% and 32.5% in DPPH and ABTS assays, respectively. Additionally, the flesh extract had a high FRAP of 22.9 mmol/100g. It significantly inhibited the oxidation of PUFA in fish oil as well. Thus, miracle berry could also serve as an antioxidant-rich fruit to provide health promoting function. PMID- 24491732 TI - Concentration and particle size distribution of polycyclic aromatic hydrocarbons formed by thermal cooking. AB - The concentration and particle size distribution of 19 major polycyclic aromatic hydrocarbons (PAHs) emitted by thermal cooking were investigated. Corn, trout, beef, prawns, and pork were selected for grilling. The PAHs in the oil mist emitted when the food was grilled were collected according to particle size range and analysed by GC/MS. Much higher concentrations of PAHs were detected in the oil mist emitted by grilled pork, trout, and beef samples, which were rich in fat. The main components of the cooking exhaust were 3- and 4-ring PAHs, regardless of food type. The particle size distribution showed that almost all the PAHs were concentrated in particles with diameters of <0.43 MUm. For pork, the toxic equivalent of benzo[a]pyrene accounted for 50% of the PAHs in particles with diameters of <0.43 MUm. From these results, we estimated that >90% of the PAHs would reach the alveolar region of the lungs. PMID- 24491733 TI - The interaction of DNA with phytoferritin during iron oxidation. AB - Phytoferritin from legume seeds is considered an iron supplement with great potential. Phytoferritin co-exists with plastid DNA in amyloplasts of legume seed cells where Fe(2+) is oxidized into Fe(3+), followed by storage within the inner cavity of the protein. In this study, the interaction of plasmid DNA with black bean (Phaseolus vulgaris L.) seed ferritin (BSF) during iron oxidation was studied. Results indicated that iron ions facilitated formation of apoBSF aggregates at a high iron loading (>48 Fe(2+)/shell). Interestingly, the co existence of DNA and ferritin has a pronounced effect on iron uptake by ferritin. This view is confirmed by a pronounced increase in the rate of iron oxidation catalysed by apoBSF in the presence of DNA. On the other hand, the apoBSF exhibited a marked DNA-protective function against oxidative damage at a low loading of Fe(2+) (? 48 Fe(2+)/shell). However, outside this ratio, such an effect gradually decreased, because the added iron exceeded the iron binding capacity of ferritin. The current study advances the understanding of the interaction among multi-components in foodstuffs. PMID- 24491734 TI - Volatile fingerprint of Brazilian defective coffee seeds: corroboration of potential marker compounds and identification of new low quality indicators. AB - In the present work, the volatile profiles of green and roasted Brazilian defective coffee seeds and their controls were characterised, totalling 159 compounds. Overall, defective seeds showed higher number and concentration of volatile compounds compared to those of control seeds, especially pyrazines, pyrroles and phenols. Corroborating our previous results, butyrolactone and hexanoic acid, previously considered as potential defective seeds' markers, were observed only in raw and roasted defective seeds, respectively, and not in control seeds. New compounds were suggested as potential defective seeds' markers: hexanoic acid (for raw and roasted defective seeds in general), butyrolactone (for raw defective seeds in general), and 3-ethyl-2-methyl-1,3 hexadiene (for raw black seeds); beta-linalool and 2-butyl-3,5-dimethylpyrazine (for roasted defective seeds in general), and 2-pentylfuran (for roasted black seeds). Additional compounds suggested as low quality indicators were 2,3,5,6 tetramethylpyrazine,2,3-butanediol and 4-ethylguaiacol, beta-linalool, 2-,3 dimethylbutyl butanoate, 2-phenylethyl acetate, 2,3-butanedione, hexanedioic acid, guaiacol, 2,3-dihydro-2-methyl-1H-benzopyrrol, 3-methylpiperidine, 2 pentylpiperidine, 3-octen-2-one, 2-octenal, 2-pentylfuran and 2-butyl-3 methylpyrazine. PMID- 24491735 TI - Cytotoxicity and DNA damage properties of tert-butylhydroquinone (TBHQ) food additive. AB - Tert-butylhydroquinone (TBHQ) was tested for potential cytotoxicity and genotoxicity upon A549 lung cancer cells and Human Umbilical Vein Endothelial Cells (HUVEC). Cytotoxicity was evaluated by MTT assay and flow cytometry analysis, while genotoxicity was assessed in vitro by alkaline comet, DNA fragmentation and DAPI staining assays. TBHQ dose- and time-dependently decreased the growth of A549 and HUVEC cells. Flow cytometry analyses determined early and late apoptosis in the treated cells. Also, single strand DNA breaking has been observed through comet assay technique. In addition, morphology of DAPI stained cells and DNA fragmentation assay using gel electrophoresis showed clear fragmentation in the chromatin and DNA rings within the nucleus of cell's treated TBHQ. PMID- 24491736 TI - A new chemical criteria for white wine: the glutathione equivalent capacity. AB - The present work aimed at showing the interest in applying liquid chromatography with amperometric detection at a silver electrode (LC-EC-Ag) in order to record a chromatogram highly selective to non volatile aminothiols present in white wines. By integrating and summing the peak area of the aminothiols and by normalizing with respect to the peak area of an injected standard solution of glutathione (1 MUM) a new quantitative criteria for white wine characterization is proposed namely, the glutathione equivalent capacity (GEC). The LC setup uses a C18 column in isocratic mode and the analysis takes less than 4 min. The wine sample needs no sample treatment other than dilution with the mobile phase. This new methodology and concept is illustrated by the LC-EC-Ag analysis of several white wines of different origins especially Alsace Riesling wines and Riesling grape juice. It is anticipated that in addition to the determination of the GEC, the developed method may be of interest for establishing a white wine "signature" based on the chromatographic profile. PMID- 24491737 TI - Effect of two experimental diets (protein and lipid vegetable oil blends) on the volatile profile of Senegalese sole (Solea senegalensis Kaup, 1858) muscle. AB - The aim of this study was to determine differences among volatile compounds composition of Senegalese sole muscle fed with extruded diets containing different plant protein (PP) and vegetable oil (VO) sources. Two set of experiments were performed on growing sole. One growth trial used a control diet containing fish meal (FM) as the main protein source and different PP-based diets. Another growth trial compared a control diet containing fish oil (FO) as the main lipid source and different VO-based diets; after a period, all sole were fed with the FO diet. Results showed that the incorporation of PP sources up to 75% allowed the production of a similar content of major volatile compounds to the control diet. In VO-based diets, some significant differences were found in the levels of some volatile compounds in sole muscle; however, no significant differences were obtained through sensory evaluation. PMID- 24491738 TI - Identification of species of the Euterpe genus by rare earth elements using inductively coupled plasma mass spectrometry and linear discriminant analysis. AB - The acai (Euterpe oleracea Mart.) and jucara (Euterpe edulis Mart.) produce similar fruits which are rich in energy, minerals, vitamins and natural compounds with antioxidant and anti-inflammatory properties. Although the drink obtained from these species is similar, it is important to develop tools to establish the identity of the fruit species and growing regions. To assess claims of origin and for other purposes, we use multivariate analysis to investigate the differentiation of acai and jucara fruits based on rare earth element (REE) content determined by Inductively Coupled Plasma Mass Spectrometry. REE content, in particular Sm, Th, La, Pr, Gd, and especially Ce and Nd varied between species. PCA analysis was not efficient in differentiating acai from jucara fruit samples. In contrast, LDA analysis permitted a correct differentiation between species with a predictive ability of 83.3%. The methodology that we have applied confirms that REE can be used to differentiate between acai and jucara fruit samples and to identify their origin. PMID- 24491739 TI - Effect of high pressure high temperature processing on the volatile fraction of differently coloured carrots. AB - To get deeper insight into the effect of high pressure high temperature (HPHT) processing on the volatile fraction of carrots, differently coloured cultivars exhibiting orange, purple, red and yellow hues were investigated. The impact of HPHT sterilisation was compared with thermal sterilisation based on equivalent microbiological inactivation. The results of this study demonstrated HPHT sterilisation to exert a distinct effect on important chemical reactions in comparison to thermal sterilisation. A comprehensive integration of MS-based metabolomic fingerprinting (HS-SPME-GC-MS) and chemometric tools has been implemented as an untargeted multivariate screening tool to identify differences. In all carrot cultivars, two dominant discriminative quality-related reactions were found: oxidative degradation and the Maillard reaction. Regarding the first reaction, oxidative terpenes, free fatty acids and carotenoids degradation products were detected at higher levels after HPHT sterilisation. Regarding the latter reaction, HPHT sterilisation appeared to suppress the formation of Maillard and Strecker degradation products. PMID- 24491740 TI - Studies on the functional properties of protein concentrate of Kappaphycus alvarezii (Doty) Doty - an edible seaweed. AB - Protein concentrate (PC) of Kappaphycus alvarezii (cultivated on the West coast of India), was extracted and its functional properties were evaluated. The K. alvarezii PC contained 62.3 +/- 1.62% proteins. At pH 12, the nitrogen solubility of this PC was 58.72 +/- 1.68% in the presence of 0.5M NaCl. The emulsifying and foaming properties of this PC varied with time and pH. However, it formed remarkably stable emulsions with Jatropha oil after 720 min (i.e. E720=53.67 +/- 1.59). On the other hand, maximum foaming ability (53.33 +/- 2.31%) of the PC was recorded at pH 4.0. This PC had high oil (1.29 +/- 0.20 ml oil/g PC) and water absorption capacity (2.22 0.04 ml H2O/g PC). DSC analysis revealed thermal transitions at about 109.25 degrees C at neutral pH. The results obtained in this investigation suggest the suitability of K. alvarezii PC as an inexpensive source of protein; thus this PC could be incorporated into several value-added food products. PMID- 24491741 TI - Curcumin-beta-cyclodextrin inclusion complex: stability, solubility, characterisation by FT-IR, FT-Raman, X-ray diffraction and photoacoustic spectroscopy, and food application. AB - Curcumin was complexed with beta-CD using co-precipitation, freeze-drying and solvent evaporation methods. Co-precipitation enabled complex formation, as indicated by the FT-IR and FT-Raman techniques via the shifts in the peaks that were assigned to the aromatic rings of curcumin. In addition, photoacoustic spectroscopy and X-ray diffraction, with the disappearance of the band related to aromatic rings, by Gaussian fitting, and modifications in the spectral lines, respectively, also suggested complex formation. The possible complexation had an efficiency of 74% and increased the solubility of the pure colourant 31-fold. Curcumin-beta-CD complex exhibited a sunlight stability 18% higher than the pure colourant. This material was stable to pH variations and storage at -15 and 4 degrees C. With an isothermal heating at 100 and 150 degrees C for 2h, the material exhibited a colour retention of approximately 99%. The application of curcumin-beta-CD complex in vanilla ice creams intensified the colour of the products and produced a great sensorial acceptance. PMID- 24491742 TI - A "three-in-one" sample preparation method for simultaneous determination of B group water-soluble vitamins in infant formula using VitaFast((r)) kits. AB - VitaFast((r)) test kits designed for the microbiological assay in microtiter plate format can be applied to quantitative determination of B-group water soluble vitamins such as vitamin B12, folic acid and biotin, et al. Compared to traditional microbiological methods, VitaFast((r)) kits significantly reduce sample processing time and provide greater reliability, higher productivity and better accuracy. Recently, simultaneous determination of vitamin B12, folic acid and biotin in one sample is urgently required when evaluating the quality of infant formulae in our practical work. However, the present sample preparation protocols which are developed for individual test systems, are incompatible with simultaneous determination of several analytes. To solve this problem, a novel "three-in-one" sample preparation method is herein developed for simultaneous determination of B-group water-soluble vitamins using VitaFast((r)) kits. The performance of this novel "three-in-one" sample preparation method was systematically evaluated through comparing with individual sample preparation protocols. The experimental results of the assays which employed "three-in-one" sample preparation method were in good agreement with those obtained from conventional VitaFast((r)) extraction methods, indicating that the proposed "three-in-one" sample preparation method is applicable to the present three VitaFast((r)) vitamin test systems, thus offering a promising alternative for the three independent sample preparation methods. The proposed new sample preparation method will significantly improve the efficiency of infant formulae inspection. PMID- 24491743 TI - Establishment of the purity values of carbohydrate certified reference materials using quantitative nuclear magnetic resonance and mass balance approach. AB - This work described the assignment of purity values to six carbohydrate certified reference materials, including glucose, fructose, galactose, lactose, xylose and sucrose, according to the ISO Guides 34 and 35. The CRMs' purity values were assigned based on the weighted average of quantitative nuclear magnetic resonance method and mass balance approach with high resolution liquid chromatography - evaporative light scattering detection. All the six CRMs with following value amount fractions: glucose (GBW10062) at a certified purity P +/- U (k=2) of (0.99 +/- 0.005)%; fructose (GBW10063) at (0.99 +/- 0.005)%; galactose (GBW10064) at (0.99 +/- 0.007)%; lactose (GBW10065) at (0.99 +/- 0.008)%; xylose (GBW10066) at (0.99 +/- 0.007)% and sucrose (GBW10067) at (0.99 +/- 0.008)%, respectively were certified. The homogeneity of the CRMs was determined by an in-house validated liquid chromatographic method. Potential degradation during storage was also investigated and a shelf-life based on this value was established. PMID- 24491744 TI - Detection of argan oil adulteration with vegetable oils by high-performance liquid chromatography-evaporative light scattering detection. AB - Triacylglycerol profiles were selected as indicator of adulteration of argan oils to carry out a rapid screening of samples for the evaluation of authenticity. Triacylglycerols were separated by high-performance liquid chromatography evaporative light scattering detection. Different peak area ratios were defined to sensitively detect adulteration of argan oil with vegetable oils such as sunflower, soy bean, and olive oil up to the level of 5%. Based on four reference argan oils, mean limits of detection and quantitation were calculated to approximately 0.4% and 1.3%, respectively. Additionally, 19 more argan oil reference samples were analysed by high-performance liquid chromatography refractive index detection, resulting in highly comparative results. The overall strategy demonstrated a good applicability in practise, and hence a high potential to be transferred to routine laboratories. PMID- 24491745 TI - Various concentrations of erucic acid in mustard oil and mustard. AB - Erucic acid is a typical constituent of mustard or rape. Foodstuff with a high content of erucic acid is considered undesirable for human consumption because it has been linked to myocardial lipidosis and heart lesions in laboratory rats. As a result, several countries have restricted its presence in oils and fats. In this study, the erucic acid content in several mustard oils and prepared mustard samples from Germany and Australia was determined. Seven of nine mustard oil samples exceeded the permitted maximum levels established for erucic acid (range: 0.3-50.8%, limit: 5%). The erucic acid content in mustard samples (n=15) varied from 14% to 33% in the lipids. Two servings (i.e. 20 g) of the mustards with the highest erucic acid content already surpassed the tolerable daily intake established by Food Standards Australia New Zealand. However, a careful selection of mustard cultivars could lower the nutritional intake of erucic acid. PMID- 24491746 TI - Analysis of lysozyme in cheese samples by on-line combination of capillary zone electrophoresis and mass spectrometry. AB - Some methodological aspects of an on-line combination of capillary zone electrophoresis with mass spectrometric detection (CZE-QqQ-MS) were studied in this work as well as the possibilities of using this combination for analysis of the high-molecular mass compounds present in multi-component matrices. All experiments using an on-line combination of capillary electrophoresis with mass spectrometric detection were carried out in cationic mode in covalently-coated capillary. The optimised electrolyte system consisted of 100 mmol/L formic acid. Prior to the CZE-QqQ-MS analysis, an extraction of lysozyme from cheese samples using 1 mol/L of acetic acid was performed. The LOD was 3.6 mg lysozyme per kg and the LOQ was 10.9 mg lysozyme per kg. The concentration range of the lysozyme determined in four cheese samples analysed in this work was from 0.5 to 3.3g of lysozyme per kg. The values of the relative standard deviations thus obtained were from 4.6% to 9.3% depending on the cheese sample. PMID- 24491747 TI - High-resolution mass spectrometry applied to the study of metabolome modifications in various chicken tissues after amoxicillin administration. AB - The performance of high resolution accurate mass spectrometry (HRMS) operating in full scan MS mode was investigated for the quantitative determination of amoxicillin (AMX) as well as qualitative analysis of metabolomic profiles in tissues of medicated chickens. The metabolomic approach was exploited to compile analytical information on changes in the metabolome of muscle, kidney and liver from chickens subjected to a pharmacological program with AMX. Data consisting of m/z features taken throughout the entire chromatogram were extracted and filtered to be treated by Principal Component Analysis. As a result, it was found that medicated and non-treated animals were clearly clustered in distinct groups. Besides, the multivariate analysis revealed some relevant mass features contributing to this separation. In this context, recognizing those potential markers of each chicken class was a priority research for both metabolite identification and, obviously, evaluation of food quality and health effects associated to food consumption. PMID- 24491748 TI - Multi-element analysis of wines by ICP-MS and ICP-OES and their classification according to geographical origin in Slovenia. AB - Inductively coupled plasma mass spectrometry and optical emission were used to determine the multi-element composition of 272 bottled Slovenian wines. To achieve geographical classification of the wines by their elemental composition, principal component analysis (PCA) and counter-propagation artificial neural networks (CPANN) have been used. From 49 elements measured, 19 were used to build the final classification models. CPANN was used for the final predictions because of its superior results. The best model gave 82% correct predictions for external set of the white wine samples. Taking into account the small size of whole Slovenian wine growing regions, we consider the classification results were very good. For the red wines, which were mostly represented from one region, even-sub region classification was possible with great precision. From the level maps of the CPANN model, some of the most important elements for classification were identified. PMID- 24491749 TI - The role of oxygen in the liquid fermentation of wheat bran. AB - The extensive use of wheat bran as a food ingredient is limited due to its bitter taste and hard texture. To overcome these, some preprocessing methods, such as fermentation with yeast and lactic acid bacteria or enzymatic treatments have been proposed. The current work studied microbial communities, acidification, ethanol formation and metabolite profile of wheat bran fermented in either aerated or anaerobic conditions. In aerated conditions, yeasts grew better and the production of organic acids was smaller, and hence pH was higher. In anaerobic conditions, lactic acid bacteria and endogenous heterotrophic bacteria grew better. Aeration had a large effect on the sourdough metabolite profile, as analyzed by UPLC-qTOF-MS. Anaerobic conditions induced degradation of ferulic and caffeic acids, whereas the amount of sinapic acid increased. Aeration caused degradation of amino acids and hydroxycinnamic acid derivatives of polyamines. The results suggest that the control of oxygen could be used for tailoring the properties of bran sourdough. PMID- 24491750 TI - Biogenic amine accumulation in silver carp sausage inoculated with Lactobacillus plantarum plus Saccharomyces cerevisiae. AB - The effect of an amine-negative mixed starter culture (Lactobacillus plantarum ZY40 plus Saccharomyces cerevisiae JM19) on biogenic amine accumulation in fermented silver carp sausage was studied. Microbial counts, pH, titratable acid and free amino acids were also determined. Putrescine, cadaverine and tyramine were the main amines formed during sausage fermentation. The contents of putrescine and cadaverine were greatly reduced by the addition of L. plantarum ZY40 plus S. cerevisiae JM19, whereas tyramine accumulation was enhanced as compared to the control batch. Histamine and spermidine were not affected by the mixed starter culture, and their levels varied slightly throughout the fermentation. Besides, no positive correction between pH, free amino acid content and biogenic amine accumulation were found. PMID- 24491751 TI - High-throughput histamine analysis approach in an official control laboratory: analytical methods and four years fish products results. AB - A highly practical two-tier approach involving a screening and a confirmatory method was set up to efficiently test histamine in fish products in the frame of official controls. After their validation, the routine management of the two procedures was simplified as far as possible ensuring a strict quality data control and maximizing the cost-effectiveness. Accordingly five hundred and ninety batches of fish products (3129 determinations) sampled from the Italian authorities were successfully analyzed over a four year period (2008-2012). Only a small percentage of analysed batches (4.9%) was judged non-compliant. The examination of irregular cases (fish species, processing technology and storage practices) suggests important considerations in order to minimise the histamine risk for consumers. PMID- 24491752 TI - Feasibility of non-invasive detection of engineered nanoparticles in food mimicking matrices by Optical Coherence Tomography. AB - The study was dedicated towards the detection of Engineered Nanoparticles (ENPs) by means of Optical Coherence Tomography (OCT). Polymeric films were produced to mimic complex food matrices whereas gold nanorods (AuNRs) were embedded to act as ENPs. The straightforward coating application resulted in a sufficient film wetting, adhesion and homogenous AuNR distribution. Compared to food samples, these films are simpler and better defined. Such artefacts are therefore promising candidate materials for quality assurance and regulatory matters. The OCT investigations revealed a dependency of the measured signal intensity on the AuNR concentration in the film. The limit of detection for the setup and material was estimated to be -8 dB. This value corresponds to a ppm nanoparticle concentration being well below the concentration used in food additive applications. Thus, the findings indicate the potential of OCT to screen food/feed products for a number of ENPs. PMID- 24491753 TI - Optimization of pressurized liquid extraction of inositols from pine nuts (Pinus pinea L.). AB - Pressurized liquid extraction (PLE) has been used for the first time to extract bioactive inositols from pine nuts. The influence of extraction time, temperature and cycles of extraction in the yield and composition of the extract was studied. A quadratic lineal model using multiple linear regression in the stepwise mode was used to evaluate possible trends in the process. Under optimised PLE conditions (50 degrees C, 18 min, 3 cycles of 1.5 mL water each one) at 10 MPa, a noticeable reduction in extraction time and solvent volume, compared with solid liquid extraction (SLE; room temperature, 2h, 2 cycles of 5 mL water each one) was achieved; 5.7 mg/g inositols were extracted by PLE, whereas yields of only 3.7 mg/g were obtained by SLE. Subsequent incubation of PLE extracts with Saccharomyces cerevisiae (37 degrees C, 5h) allowed the removal of other co extracted low molecular weight carbohydrates which may interfere in the bioactivity of inositols. PMID- 24491754 TI - Proposal on the usage of conversion factors for fatty acids in fish and shellfish. AB - Different approaches for converting fatty acid (FA) data in fish and shellfish expressed as weight percent of total FA or of total lipid content (TL) to per 100g edible portion fresh weight (EP) are used. FAO/INFOODS studied on a dataset of 668 fish and shellfish firstly the impact on their FA and TL content per 100g EP using two fatty acid conversion factors, namely the factors published by Weihrauch et al. (XFAW) and Greenfield and Southgate (XFAGS), and secondly the usefulness of Sheppard factors (ShF), which convert fatty acid methyl esters to fatty acids. The data show that XFAW should be used as they are applicable to fish and shellfish and the resulting FA values are a continuous function of the TL content while applying a minimum TL value of 0.55 g/100 g EP even for lower TL values. This study showed that the use of ShF is not necessary for fish and shellfish as they do not influence fatty acid values significantly. PMID- 24491755 TI - Surveillance, epidemiology, and end results-based analysis of the impact of preoperative or postoperative radiotherapy on survival outcomes for T3N0 rectal cancer. AB - PURPOSE: Preoperative chemoradiation has been established as standard of care for T3/T4 node-positive rectal cancer. Recent work, however, has called into question the overall benefit of radiation for tumors with lower risk characteristics, particularly T3N0 rectal cancers. We retrospectively analyzed T3N0 rectal cancer patients and examined how outcomes differed according to the sequence of treatment received. METHODS: The Surveillance, Epidemiology, and End Results (SEER) database was used to analyze T3N0 rectal cancer cases diagnosed between 1998 and 2008. Treatment consisted of surgery alone (No RT), preoperative radiation followed by surgery (Neo-Adjuvant RT), or surgery followed by postoperative radiation (Adjuvant RT). Demographic and tumor characteristics of the three groups were compared using t-tests for the comparison of means. Survival information from the SEER database was utilized to estimate cause specific survival (CSS) and to generate Kaplan-Meier survival curves. Multivariate analysis (MVA) of features associated with outcomes was conducted using Cox proportional hazards regression models with Adjuvant RT, Neo-Adjuvant RT, No RT, histological grade, tumor size, year of diagnosis, and demographic characteristics as covariates. RESULTS: 10-Year CSS estimates were 66.1% (95% CI 62.3-69.6%; P=0.02), 73.5% (95% CI 68.9-77.5%; P=0.02), and 76.1% (95% CI 72.4 79.4%; P=0.02), for No RT, Neo-Adjuvant RT, and Adjuvant RT, respectively. On MVA, Adjuvant RT (HR=0.688; 95% CI, 0.578-0.819; P<0.001) was associated with significantly decreased risk for cancer death. By contrast, Neo-Adjuvant RT was not significantly associated with improved cancer survival (HR=0.863; 95% CI, 0.715-1.043; P=0.127). CONCLUSION: Adjuvant RT was associated with significantly higher CSS when compared with surgery alone, while the benefit of Neo-Adjuvant RT was not significant. This indicates that surgery followed by Adjuvant RT may still be an important treatment plan for T3N0 rectal cancer with potentially significant survival advantages over other treatment sequences. PMID- 24491756 TI - Nanostructuring carbon fibre probes for use in central venous catheters. AB - A carbon fibre probe is described which utilises the oxidation of an endogenous biomarker to provide diagnostic information on the condition of intravascular access lines. The probe surface was modified through anodic oxidation to provide a high selectivity towards urate which was used as a redox probe through which the pH could be determined. A Nernstian response (-60 mV/pH) was obtained which was free from the interference of other redox species common to biofluids. The electroanalytical performance of the probe has been optimised and the applicability of the approach demonstrated through testing the responses in whole blood. PMID- 24491757 TI - Direct determination of mercury in cosmetic samples by isotope dilution inductively coupled plasma mass spectrometry after dissolution with formic acid. AB - A new method was proposed for the accurate determination of mercury in cosmetic samples based on isotopic dilution (ID)-photochemical vapor generation (PVG) inductively coupled plasma mass spectrometry (ICP MS) measurement. Cosmetic samples were directly dissolved in formic acid solution and subsequently subjected to PVG for the reduction of mercury into vapor species following by ICP MS detection. Therefore, the risks of analyte contamination and loss were avoided. Highly enriched (201)Hg isotopic spike is added to cosmetics and the isotope ratios of (201)Hg/(202)Hg were measured for the quantitation of mercury. With ID calibration, the influences originating from sample matrixes for the determination of mercury in cosmetic samples have been efficiently eliminated. The effects of several experimental parameters, such as the concentration of the formic acid, and the flow rates of carrier gas and sample were investigated. The method provided good reproducibility and the detection limits were found to be 0.6 pg mL(-1). Finally, the developed method was successfully applied for the determination of mercury in six cosmetic samples and a spike test was performed to verify the accuracy of the method. PMID- 24491758 TI - Ultra-sensitive quantification of lysozyme based on element chelate labeling and capillary electrophoresis-inductively coupled plasma mass spectrometry. AB - In this study, an ultra-sensitive method for the quantification of lysozyme based on the Gd(3+) diethylenetriamine-N,N,N',N",N"-pentaacetic acid labeling and capillary electrophoresis-inductively coupled plasma mass spectrometry (CE-ICP MS) was described. The Gd(3+)-tagged lysozyme was effectively separated by capillary electrophoresis (CE) and sensitively determined by inductively coupled plasma mass spectrometry (ICP-MS). Based on the gadolinium-tagging and CE-ICP-MS, the lysozyme was determined within 12 min with an extremely low detection limit of 3.89 attomole (3.89*10(-11) mol L(-1) for 100 nL of sample injection) and a RSD<6% (n=5). The proposed method has been successfully used to detect lysozyme in saliva samples with a recovery of 91-106%, suggesting that our method is sensitive and reliable. The success of the present method provides a new potential for the biological assays and sensitive detection of low-abundant proteins. PMID- 24491759 TI - Glassy carbon electrodes sequentially modified by cysteamine-capped gold nanoparticles and poly(amidoamine) dendrimers generation 4.5 for detecting uric acid in human serum without ascorbic acid interference. AB - Glassy carbon electrodes (GCE) were sequentially modified by cysteamine-capped gold nanoparticles (AuNp@cysteamine) and PAMAM dendrimers generation 4.5 bearing 128-COOH peripheral groups (GCE/AuNp@cysteamine/PAMAM), in order to explore their capabilities as electrochemical detectors of uric acid (UA) in human serum samples at pH 2. The results showed that concentrations of UA detected by cyclic voltammetry with GCE/AuNp@cysteamine/PAMAM were comparable (deviation <+/-10%; limits of detection (LOD) and quantification (LOQ) were 1.7*10(-4) and 5.8*10(-4) mg dL(-1), respectively) to those concentrations obtained using the uricase-based enzymatic-colorimetric method. It was also observed that the presence of dendrimers in the GCE/AuNp@cysteamine/PAMAM system minimizes ascorbic acid (AA) interference during UA oxidation, thus improving the electrocatalytic activity of the gold nanoparticles. PMID- 24491760 TI - Electroanalytical quantification of total dsDNA extracted from human sample using, an ionic liquid modified, carbon nanotubes paste electrode. AB - Direct electrochemistry of dsDNA has been achieved by using an ionic liquid 1 butyl-4-methylpyridinium hexafluorophosphate modified carbon nanotubes paste electrode (IL-CNTPE). Oxidation peaks appeared at 0.93 and 1.26 V (vs. Ag/AgCl) on the IL- CNTPE after preconcentration of dsDNA in pH 5.0 acetate buffer, which were attributed to the oxidation of guanine and adenine residues on the dsDNA molecule structure. Based on the signal of guanine, under the optimal conditions, very low levels of dsDNA can be detected after 60s accumulation with detection limits of 0.249 mg L(-) 16 pM. Additionally, human DNA from a healthy volunteer is determined by use of the IL-CNTPE and it is found to be 40+/-2, 14 pM. PMID- 24491761 TI - Highly sensitive electrogenerated chemiluminescence biosensor in profiling protein kinase activity and inhibition using a multifunctional nanoprobe. AB - We presented a novel electrogenerated chemiluminescence (ECL) biosensor for monitoring the activity and inhibition of protein kinases based on signal amplification using enzyme-functionalized Au NPs nanoprobe. In this design, the biotin-DNA labeled glucose oxidase/Au NPs (GOx/Au NPs/DNA-biotin) nanoprobes, prepared by conjugating Au NPs with biotin-DNA and GOx, were bound to the biotinylated anti-phosphoserine labeled phosphorylated peptide modified electrode surface through a biotin-avidin interaction. The GOx assembled on the nanoprobe can catalyze glucose to generate H2O2 in the presence of O2 while the ECL reaction occurred in the luminol ECL biosensor. At a higher concentration of kinase, there are more nanoprobes on the electrode, which gives a higher amount of GOx at the electrode interface and thus higher electrocatalytic efficiency to the luminol ECL reaction. Therefore, the activity of protein kinases can be monitored by ECL with high sensitivity. Protein kinase A (PKA), an important enzyme in regulation of glycogen, sugar, and lipid metabolism in the human body, was used as a model to confirm the present proof-of-concept strategy. The as proposed biosensor presents high sensitivity, low detection limit of 0.013 U mL( 1), wide linear range (from 0.02 to 40 U mL(-1)), and excellent stability. Moreover, this biosensor can also be used for quantitative analysis of kinase inhibition. On the basis of the inhibitor concentration dependent ECL signal, the half-maximal inhibition value IC50 of ellagic acid, a typical PKA inhibitor, was estimated, which is in agreement with those obtained using the conventional kinase assay. The simple and sensitive biosensor is promising in developing a high-through assay of in vitro kinase activity and inhibitor screening for clinic diagnostic and drug development. PMID- 24491762 TI - Sulfite oxidase biosensors based on tetrathiafulvalene modified screen-printed carbon electrodes for sulfite determination in wine. AB - Screen-printed carbon electrodes have been modified with tetrathiafulvalene and sulfite oxidase enzyme for the sensitive and selective detection of sulfite. Amperometric experimental conditions were optimized taking into account the importance of quantifying sulfite in wine samples and the inherent complexity of these samples, particularly red wine. The biosensor responds to sulfite giving a cathodic current (at +200 mV vs screen-printed Ag/AgCl electrode and pH 6) in a wide concentration range, with a capability of detection of 6 MUM (alpha=beta=0.05) at 60 degrees C. The method has been applied to the determination of sulfite in white and red samples, with averages recoveries of 101.5% to 101.8%, respectively. PMID- 24491763 TI - Aptamer-based homogeneous protein detection using cucurbit[7]uril functionalized electrode. AB - A new strategy for homogeneous protein detection is developed based on a cucurbit[7]uril (CB[7]) functionalized electrode. The analytical procedure consists of the binding of target protein to its aptamer in the test solution, followed by an exonuclease-catalyzed digestion of methylene blue (MB) tag labeled DNA oligonucleotides. Since CB[7] molecules immobilized on the electrode may efficiently capture the released MB-labeled nucleotides, the MB tags are concentrated to the electrode surface and subsequently yield highly sensitive electrochemical signal, which is related to the concentration of the target protein. The method combines the host-guest properties of CB[7] with the immobilization-free homogeneous assay, providing a powerful tool for protein detection. Taking the detection of osteopontin as an example, the proposed method can have a linear response to the target protein in a range from 50 to 500 ng mL( 1) with a detection limit of 10.7 ng mL(-1). It can also show high specificity and good reproducibility, and can be used directly for the assay of osteopontin in serum samples. PMID- 24491764 TI - Determination of UV filters in both soluble and particulate fractions of seawaters by dispersive liquid-liquid microextraction followed by gas chromatography-mass spectrometry. AB - An analytical method to determine the total content (i.e., not only in the soluble fraction but also in the particulate one) of eight commonly used UV filters in seawater samples is presented for the first time. Dispersive liquid liquid microextraction (DLLME) is used as microextraction technique to pre concentrate the target analytes before their determination by gas chromatography mass spectrometry (GC-MS). In order to release the UV filters from the suspended particles an ultrasound treatment is performed before DLLME. The ultrasound treatment time was studied in order to achieve a quantitative lixiviation of the target analytes. The type and volume of both disperser and extraction solvent, the sample volume, the pH and the ionic strength involved in the DLLME have been optimized to provide the best enrichment factors. Under the optimized conditions, the method was successfully validated showing good linearity, enrichment factors between 112 and 263 depending on the analyte, limits of detection and quantification in the low ng L(-1) range (10-30 ng L(-1) and 33-99 ng L(-1), respectively) and good intra- and inter-day repeatability (RSD <15%). No significant matrix effects were found. Finally, the method was satisfactorily applied to the analysis of three seawater samples from different origin. Results showed significant amounts of UV filters in the particulate fraction that would have been ignored if only the soluble fraction had been considered. This fact shows that the UV filters are also accumulated in the suspended particles contained in water, what should be taken into account from an environmental standpoint. PMID- 24491765 TI - Development of a new green non-dispersive ionic liquid microextraction method in a narrow glass column for determination of cadmium prior to couple with graphite furnace atomic absorption spectrometry. AB - Easy and innovative non-dispersive ionic liquid based microextraction (NDILME) has been developed for preconcentration of trace level of cadmium (Cd) in aqueous real surface water samples prior to couple with graphite furnace atomic absorption spectrometry (GFAAS). A 200 cm long narrow glass column containing aqueous solution of standard/sample was used to increase phase transfer ratio by providing more contact area between two medium (aqueous and extractive), which drastically improve the recoveries of labile hydrophobic chelate of Cd ammonium pyrrolidinedithiocarbamate (APDC), into ionic liquid 1-butyl-3-methylimidazolium hexafluorophosphate [C4mim][PF6]. Different aspect of the desire method have been investigated and optimized. Under the optimized key experimental variables, limit of detection (LOD) and enhancement factor (EF) were achieved to be 0.5 ng L(-1) and 150, respectively. Reliability of the model method was checked by relative standard deviation (%RSD), which was found to be <5%. Validity and accuracy of the developed method was checked by analysis of certified reference water samples (SLRS-4 Riverine water) using standard addition method. Application of the model method was productively performed by analysis of Cd in real surface water samples (tap and sea). PMID- 24491766 TI - Immobilization of trypsin onto multifunctional meso-/macroporous core-shell microspheres: a new platform for rapid enzymatic digestion. AB - A simple, fast, efficient, and reusable microwave-assisted tryptic digestion system which was constructed by immobilization of trypsin onto porous core-shell Fe3O4@fTiO2 microspheres has been developed. The nanostructure with magnetic core and titania shell has multiple pore sizes (2.4 and 15.0 nm), high pore volume (0.25 cm(3) g(-1)), and large surface area (50.45 m(2) g(-1)). For the proteins, the system can realize fast and efficient microwave-assisted tryptic digestion. Various standard proteins (e.g., cytochrome c (cyt-c), myoglobin (MYO), beta lactoglobulin (beta-LG), and bovine serum albumin (BSA)) used can be digested in 45 s under microwave radiation, and they can be confidently identified by mass spectrometry (MS) analysis; even the concentration of substrate is as low as 5 ng MUL(-1). Furthermore, the system for the 45 s microwave-assisted tryptic digestion is still effective after the trypsin-immobilized microspheres have been reused for 5 times. Importantly, 1715 unique proteins from 10 MUg mouse brain proteins can be identified with high confidence after treatment of 45 s microwave assisted tryptic digestion. PMID- 24491767 TI - Development of stir-bar sorptive extraction-thermal desorption-gas chromatography mass spectrometry for the analysis of musks in vegetables and amended soils. AB - The aim of this study was to develop a sensitive and environment-friendly method based on stir-bar sorptive extraction (SBSE) followed by thermal desorption-gas chromatography-mass spectrometry (TD-GC-MS) to determine 8 synthetic musks (musk ambrette, musk ketone, celestolide, tonalide, galaxolide, phantolide, traseolide, and cashmeran) in vegetables (lettuce, carrot, and pepper) and amended soil samples. In a first step sorptive extraction was studied both in the headspace (HSSE) and in the immerse mode (SBSE). The best results were obtained in the immersion mode which was further studied. The influence of the main factors: methanol (20%) and NaCl addition (0%), extraction temperature (40 degrees C) and time (180 min), extraction solvent volume (9 mL) and stirring rate (600 rpm) on the efficiency of SBSE was evaluated by means of experimental designs. In the case of TD, desorption time (10 min), desorption temperature (300 degrees C), cryo-focusing temperature (-30 degrees C), vent flow (75 mL/min) and vent pressure (7.2 psi) were studied using both a fractioned factorial design and a central composite design (CCD). The method was validated in terms of apparent recoveries (AR%), method detection limits (MDLs) and precision at two different concentration levels. Although quantification using instrumental calibration rendered odd results in most of the cases, satisfactory recoveries (74-126%) were obtained in the case of matrix-matched calibration approach for all of the analytes and matrices studied at the two concentration levels evaluated. MDLs in the range of 0.01-0.8 ng/g and 0.01-1.1 ng/g were obtained for vegetables and amended soil samples, respectively. RSD values within 1-23% were obtained for all the analytes and matrices. Finally, the method was applied to the determination of musks in vegetable and amended soil samples. PMID- 24491768 TI - Analytical methodology for sampling and analysing eight siloxanes and trimethylsilanol in biogas from different wastewater treatment plants in Europe. AB - Siloxanes and trimethylsilanol belong to a family of organic silicone compounds that are currently used extensively in industry. Those that are prone to volatilisation become minor compounds in biogas adversely affecting energetic applications. However, non-standard analytical methodologies are available to analyse biogas-based gaseous matrixes. To this end, different sampling techniques (adsorbent tubes, impingers and tedlar bags) were compared using two different configurations: sampling directly from the biogas source or from a 200 L tedlar bag filled with biogas and homogenised. No significant differences were apparent between the two sampling configurations. The adsorbent tubes performed better than the tedlar bags and impingers, particularly for quantifying low concentrations. A method for the speciation of silicon compounds in biogas was developed using gas chromatography coupled with mass spectrometry working in dual scan/single ion monitoring mode. The optimised conditions could separate and quantify eight siloxane compounds (L2, L3, L4, L5, D3, D4, D5 and D6) and trimethylsilanol within fourteen minutes. Biogas from five waste water treatment plants located in Spain, France and England was sampled and analysed using the developed methodology. The siloxane concentrations in the biogas samples were influenced by the anaerobic digestion temperature, as well as the nature and composition of the sewage inlet. Siloxanes D4 and D5 were the most abundant, ranging in concentration from 1.5 to 10.1 and 10.8 to 124.0 mg Nm(-3), respectively, and exceeding the tolerance limit of most energy conversion systems. PMID- 24491769 TI - Investigation of endogenous corticosteroids profiles in human urine based on liquid chromatography tandem mass spectrometry. AB - The accurate and precise measurement of endogenous corticosteroids in urine is a powerful tool to understand the biochemical state in several diseases. In this study, a rapid, accurate, and sensitive method based on liquid chromatography tandem mass spectrometry (LC-MS/MS) for the quantification of 67 endogenous gluco and mineralo-corticosteroids and progestins has been developed and validated. Sample preparation, chromatographic separation, and mass spectrometric detection were optimized. Urine samples (0.5 mL) were hydrolyzed with beta-glucuronidase and the released analytes were extracted by liquid-liquid extraction. The chromatographic separation was performed in 20 min after redisolution of the extract. MS behavior of endogenous corticosteroids was evaluated in order to select the most specific precursor ion ([M+H](+), [M+NH4](+), or [M+H-nH2O](+)) for the detection. MS/MS determination was performed under selected reaction monitoring mode using electrospray ionization in positive mode. The method was shown to be linear (r>0.99) in the range of endogenous concentrations for all studied metabolites. Limits of detection (LOD) below 1 ng mL(-1) were typically obtained for analytes with a 3-oxo-4-ene structure whereas LODs below 15 ng mL( 1) were common for the rest of analytes. Recoveries were higher than 80% and intra-assay precisions below 20%, evaluated at three concentration levels, were found for most steroids. No significant or moderate matrix effect, ranging from 54 to 155%, was observed for most of the analytes. The applicability of the method was confirmed by analyzing 24h urine samples collected from twenty healthy volunteers and comparing the results with previously established normal ranges. The wide coverage of corticosteroid metabolism, together with short analysis time, low sample volume, simple sample preparation, and satisfactory quantitative results make this method useful for clinical purposes. PMID- 24491770 TI - A novel titanium dioxide-polydimethylsiloxane plate for phosphopeptide enrichment and mass spectrometry analysis. AB - The phosphorylation of proteins is a major post-translational modification that is required for the regulation of many cellular processes and activities. Mass spectrometry signals of low-abundance phosphorylated peptides are commonly suppressed by the presence of abundant non-phosphorylated peptides. Therefore, one of the major challenges in the detection of low-abundance phosphopeptides is their enrichment from complex peptide mixtures. Titanium dioxide (TiO2) has been proven to be a highly efficient approach for phosphopeptide enrichment and is widely applied. In this study, a novel TiO2 plate was developed by coating TiO2 particles onto polydimethylsiloxane (PDMS)-coated MALDI plates, glass, or plastic substrates. The TiO2-PDMS plate (TP plate) could be used for on-target MALDI-TOF analysis, or as a purification plate on which phosphopeptides were eluted out and subjected to MALDI-TOF or nanoLC-MS/MS analysis. The detection limit of the TP plate was ~10-folds lower than that of a TiO2-packed tip approach. The capacity of the ~2.5 mm diameter TiO2 spots was estimated to be ~10 MUg of beta-casein. Following TiO2 plate enrichment of SCC4 cell lysate digests and nanoLC-MS/MS analysis, ~82% of the detected proteins were phosphorylated, illustrating the sensitivity and effectiveness of the TP plate for phosphoproteomic study. PMID- 24491771 TI - Photochemical decoration of silver nanoparticles on magnetic microspheres as substrates for the detection of adenine by surface-enhanced Raman scattering. AB - In this work, silver nanoparticles (AgNPs) decorated magnetic microspheres (MMs) are prepared as surface-enhanced Raman scattering (SERS) substrate for the analysis of adenine in aqueous solutions. To prepare these substrates, magnetic particles were first synthesized by coprecipitation of Fe(II) and Fe(III) with ammonium hydroxide. A thin layer of cross-linked polymer was formed on these magnetic particles by polymerization through suspension of magnetic particles into a solution of divinyl benzene/methyl methacrylate. The resulted polymer protected magnetic particles are round in shape with a size of 80 MUm in diameter. To form AgNPs on these MMs, photochemical reduction method was employed and the factors in photochemical reduction method were studied and optimized for the preparation of highly sensitive and stable AgNPs on MMs substrates (abbreviated as AgMMs substrates). By dispersing the AgMMs in aqueous samples, cylindrical magnet was used to attract the AgMMs for SERS detections. The observed enhancement factor of AgMMs reached 7 orders in magnitude for detection of adenine with a detection limit approaching to few hundreds of nanomolar. PMID- 24491772 TI - Determination of dissolved organic matter based on UV-light induced reduction of ionic silver to metallic nanoparticles by humic and fulvic acids. AB - We describe a novel solution-based method for the determination of dissolved organic matter (DOM) relying on the formation of silver nanoparticles (AgNPs) via photo-stimulated reduction of silver ions by humic and fulvic acids. The method is based on natural driven formation of nanoscale materials yielding a direct relationship between DOM concentration and AgNPs formation. The aqueous dispersion of the formed AgNPs show strong and uniform UV-Vis absorption bands between 450 and 550 nm irrespectively of DOM nature and properties (i.e. humic or fulvic acids). The ensuing chromatic shift accompanying the appearance of the new absorption bands is easily conceivable by a simple spectrophotometer and the bare eye, holding great promise for the on-site, instrumental-free screening of DOM levels. Under the optimum experimental conditions the determination of DOM was successfully demonstrated to various water samples with high sensitivity (<1.0 mg L(-1)), satisfactory recoveries (87.5-123.5%) and reproducibility (5.87-6.73%). PMID- 24491773 TI - A 3,3'-dichlorobenzidine-imprinted polymer gel surface plasmon resonance sensor based on template-responsive shrinkage. AB - Molecularly imprinted polymer gel film on the gold substrate of a chip was prepared with minute amount of cross-linker for the fabrication of a surface plasmon resonance (SPR) sensor sensitive to 3,3'-dichlorobenzidine. The molecularly imprinted gel film was anchored on a gold chip by a surface-bound photo-radical initiator. The sensing of 3,3'-dichlorobenzidine is based on responsive shrinkage of the imprinted polymer gel film that is triggered by target binding. This change can improve the responsiveness of the imprinted SPR sensor to 3,3'-dichlorobenzidine. The molecularly imprinted polymer gel film was characterized with contact angle measurements, electrochemical impedance spectroscopy, cyclic voltammogram, swelling measurements and atomic force microscopy. The changes of SPR spectroscopy wavenumber shifts revealed that the imprinted gel sensing film can 'memorize' the binding of 3,3'-dichlorobenzidine compared to non-imprinted one. The imprinted gel-SPR sensor showed a linear response in the range of 9.0*10(-12) to 5.0*10(-10) mol L(-1) (R(2)=0.9998) for the detection of 3,3'-dichlorobenzidine, and it also exhibited high selectivity to 3,3'-dichlorobenzidine compared to its structurally related analogues. We calculated the detection limits to be 0.471 ng L(-1) for tap water and 0.772 ng kg(-1) for soil based on a signal to noise ratio of 3. The method showed good recoveries and precision for the samples spiked with 3,3'-dichlorobenzidine. This suggest that the imprinted gel-SPR sensing method can be used as a promising alternative for the detection of 3,3'-dichlorobenzidine. PMID- 24491774 TI - Locked nucleic acid/DNA chimeric aptamer probe for tumor diagnosis with improved serum stability and extended imaging window in vivo. AB - As promising molecular probes for in vivo tumor imaging, aptamers without modification remain problematic due to insufficient serum stability and unabiding imaging window. To address this problem, a novel locked nucleic acid (LNA)/DNA chimeric aptamer probe was developed through proper LNA incorporation and supplemented 3'-3'-thymidine (3'-3'-T) capping. TD05, a DNA aptamer against lymphoma Ramos cells, being used as the model, a series of modification strategies were designed and optimized with different positions, numbers and combinations. It was revealed that the combined use of LNA and 3'-3'-T had a synergistic effect, and with the increase of LNA substitution in stem region, the serum stability of TD05 was gradually enhanced while its affinity and specificity were perfectly maintained to Ramos cells. Particularly, TD05.6 with 7-base pair LNA substitution exhibited the significantly elevated detection stability half life from ~0.5 h of TD05 to 5-6h of TD05.6 for target cells in serum. Moreover, a much slower clearance rate in tumor-bearing mice was also observed for TD05.6, thus leading to the greatly extended tumor imaging window from <150 min of TD05 to >600 min of TD05.6. This strategy might be of great potentials to generate more aptamer probes that are stable and nuclease-resistant for tumor diagnosis in real biological systems. PMID- 24491775 TI - A ratiometric fluorescent probe for iron(III) and its application for detection of iron(III) in human blood serum. AB - A simple and versatile ratiometric fluorescent Fe(3+) detecting system, probe 1, was rationally developed based on the Fe(3+)-mediated deprotection of acetal reaction. Notably, this reaction was firstly employed to design fluorescent Fe(3+) probe. Upon treatment with Fe(3+), probe 1 showed ratiometric response, with the fluorescence spectra displaying significant red shift (up to 132 nm) and the emission ratio value (I522/I390) exhibiting approximately 2362-fold enhancement. In addition, the probe is highly sensitive (with the detection limit of 0.12 MUM) and highly selective to Fe(3+) over other biologically relevant metal ions. The sensing reaction product of the probe with Fe(3+) was confirmed by NMR spectra and mass spectrometry. TD-DFT calculation has demonstrated that the ratiometric response of probe 1 to Fe(3+) is due to the regulation of intramolecular charge transfer (ICT) efficiency. Moreover, the practical utility in fluorescence detection of Fe(3+) in human blood serum was also conducted, and probe 1 represents the first ratiometric fluorescent probe that can be used to monitor Fe(3+) level in human blood serum. Finally, probe 1 was further employed in living cell imaging with pancreatic cancer cells, in which it displayed low cytotoxicity, satisfactory cell permeability, and selective ratiometric response to Fe(3+). PMID- 24491776 TI - Aptamer-functionalized silver nanoparticles for scanometric detection of platelet derived growth factor-BB. AB - In this work, we reported a scanometric assay system based on the aptamer functionalized silver nanoparticles (apt-AgNPs) for detection of platelet-derived growth factor-BB (PDGF-BB) protein. The aptamer and ssDNA were bound with silver nanoparticles by self-assembly of sulfhydryl group at 5' end to form the apt AgNPs probe. The apt-AgNPs probe can catalyze the reduction of metallic ions in color agent to generate metal deposition that can be captured both by human eyes and a flatbed scanner. Two different color agents, silver enhancer solution and color agent 1 (10 mM HAuCl4+2 mM hydroquinone) were used to develop silver and gold shell on the surface of AgNPs separately. The results demonstrated that the formation of Ag core-Au shell structure had some advantages especially in the low concentrations. The apt-AgNPs probe coupled with color agent 1 showed remarkable superiority in both sensitivity and detection limit compared to the apt-AuNPs system. The apt-AgNPs system also produced a wider linear range from 1.56 ng mL( 1) to 100 ng mL(-1) for PDGF-BB with the detection limit lower than 1.56 ng mL( 1). The present strategy was applied to the determination of PDGF-BB in 10% serum, and the results showed that it had good specificity in complex biological media. PMID- 24491777 TI - A sensitive fluorescence anisotropy method for detection of lead (II) ion by a G quadruplex-inducible DNA aptamer. AB - Sensitive and selective detection of Pb(2+) is of great importance to both human health and environmental protection. Here we propose a novel fluorescence anisotropy (FA) approach for sensing Pb(2+) in homogeneous solution by a G-rich thrombin binding aptamer (TBA). The TBA labeled with 6 carboxytetramethylrhodamine (TMR) at the seventh thymine nucleotide was used as a fluorescent probe for signaling Pb(2+). It was found that the aptamer probe had a high FA in the absence of Pb(2+). This is because the rotation of TMR is restricted by intramolecular interaction with the adjacent guanine bases, which results in photoinduced electron transfer (PET). When the aptamer probe binds to Pb(2+) to form G-quadruplex, the intramolecular interaction should be eliminated, resulting in faster rotation of the fluorophore TMR in solution. Therefore, FA of aptamer probe is expected to decrease significantly upon binding to Pb(2+). Indeed, we observed a decrease in FA of aptamer probe upon Pb(2+) binding. Circular dichroism, fluorescence spectra, and fluorescence lifetime measurement were used to verify the reliability and reasonability of the sensing mechanism. By monitoring the FA change of the aptamer probe, we were able to real-time detect binding between the TBA probe and Pb(2+). Moreover, the aptamer probe was exploited as a recognition element for quantification of Pb(2+) in homogeneous solution. The change in FA showed a linear response to Pb(2+) from 10 nM to 2.0 MUM, with 1.0 nM limit of detection. In addition, this sensing system exhibited good selectivity for Pb(2+) over other metal ions. The method is simple, quick and inherits the advantages of aptamer and FA. PMID- 24491778 TI - On-bead fluorescent DNA nanoprobes to analyze base excision repair activities. AB - DNA integrity is constantly threatened by endogenous and exogenous agents that can modify its physical and chemical structure. Changes in DNA sequence can cause mutations sparked by some genetic diseases or cancers. Organisms have developed efficient defense mechanisms able to specifically repair each kind of lesion (alkylation, oxidation, single or double strand break, mismatch, etc). Here we report the adjustment of an original assay to detect enzymes' activity of base excision repair (BER), that supports a set of lesions including abasic sites, alkylation, oxidation or deamination products of bases. The biosensor is characterized by a set of fluorescent hairpin-shaped nucleic acid probes supported on magnetic beads, each containing a selective lesion targeting a specific BER enzyme. We have studied the DNA glycosylase alkyl-adenine glycosylase (AAG) and the human AP-endonuclease (APE1) by incorporating within the DNA probe a hypoxanthine lesion or an abasic site analog (tetrahydrofuran), respectively. Enzymatic repair activity induces the formation of a nick in the damaged strand, leading to probe's break, that is detected in the supernatant by fluorescence. The functional assay allows the measurement of DNA repair activities from purified enzymes or in cell-free extracts in a fast, specific, quantitative and sensitive way, using only 1 pmol of probe for a test. We recorded a detection limit of 1 MUg mL(-1) and 50 MUg mL(-1) of HeLa nuclear extracts for APE1 and AAG enzymes, respectively. Finally, the on-bead assay should be useful to screen inhibitors of DNA repair activities. PMID- 24491779 TI - Effect of redox label tether length and flexibility on sensor performance of displacement-based electrochemical DNA sensors. AB - This article summarizes the sensor performance of four electrochemical DNA sensors that exploit the recently developed displacement-replacement sensing motif. In the absence of the target, the capture probe is partially hybridized to the signaling probe at the distal end, positioning the redox label, methylene blue (MB), away from the electrode. In the presence of the target, the MB modified signaling probe is released; one type of probe is capable of assuming a stem-loop probe (SLP) conformation, whereas the other type adopts a linear probe (LP) conformation. Independent of the sensor architecture, all four sensors showed "signal-on" sensor behavior. Unlike the previous report, here we focused on elucidating the effect of the redox label tether length and flexibility on sensor sensitivity, specificity, selectivity, and reusability. For both SLP and LP sensors, the limit of detection was 10 pM for sensors fabricated using a signaling probe with three extra thymine (T3) bases linked to the MB label. A limit of detection of 100 pM was determined for sensors fabricated using a signaling probe with five extra thymine (T5) bases. The linear dynamic range was between 10 pM and 100 nM for the T3 sensors, and between 100 pM and 100 nM for the T5 sensors. When compared to the LP sensors, the SLP sensors showed higher signal enhancement in the presence of the full-complement target. More importantly, the SLP-T5 sensor was found to be highly specific; it is capable of discriminating between the full complement and single-base mismatch targets even when employed in undiluted blood serum. Overall, these results highlight the advantages of using oligo-T(s) as a tunable linker to control flexibility of the tethered redox label, so as to achieve the desired sensor response. PMID- 24491780 TI - Computational prediction and experimental selectivity coefficients for hydroxyzine and cetirizine molecularly imprinted polymer based potentiometric sensors. AB - In spite of the increasing usages number of molecularly imprinted polymers (MIPs) in many scientific applications, the theoretical aspects of participating intra molecular forces are not fully understood. This work investigates effects of the electrostatic force, the Mulliken charge and the role of cavity's backbone atoms on the selectivity of MIPs. Moreover, charge distribution, which is a computational parameter, was proposed for the prediction of the selectivity coefficients of MIP-based sensors. In the computational approaches and experimental study, methacrylic acid (MAA) was chosen as the functional monomer and ethylene glycol dimethacrylate (EGDMA) as the cross linker for hydroxyzine and cetirizine imprinted polymers. Ab initio, DFT B3LYP method was carried out on molecular optimization. With regard to results obtained from molecules optimization and hydrogen bonding properties, possible configurations of 1:n (n<=5) template/monomer complexes were designed and optimized. The binding energy for each complex in gas phase was calculated. Depending on the most stable configuration, hydroxyzine and cetirizine imprinted polymer models were designed. The calculations including the porogen were also investigated. The theoretical charge distributions for the template and some potential interfering molecules were calculated. The results showed a correlation between the selectivity coefficients and the theoretical charge distributions. The results surprisingly show that charge distribution based model was able to predict the selectivity coefficients of MIP based potentiometric sensors. PMID- 24491781 TI - Ligand displacement-induced fluorescence switch of quantum dots for ultrasensitive detection of cadmium ions. AB - This paper reports the construction of a simple CdTe quantum dots (QDs)-based sensor with 1,10-phenanthroline (Phen) as ligand, and the demonstration of a novel ligand displacement-induced fluorescence switch strategy for sensitive and selective detection of Cd(2+) in aqueous phase. The complexation of Phen at the surface quenches the green photoluminescence (PL) of QDs dominated by a photoinduced hole transfer (PHT) mechanism. In the presence of Cd(2+), the Phen ligands are readily detached from the surface of CdTe QDs, forming [Cd(Phen)2(H2O)2](2+) in solution, and as a consequence the PL of CdTe QDs switches on. The detection limit for Cd(2+) is defined as ~0.01 nM, which is far below the maximum Cd(2+) residue limit of drinking water allowed by the U.S. Environmental Protection Agency (EPA). Two consecutive linear ranges allow a wide determination of Cd(2+) from 0.02 nM to 0.6 MUM. Importantly, this CdTe QDs-based sensor features to distinctly discriminate between Cd(2+) and Zn(2+), and succeeds in real water samples. This extremely simple strategy reported here represents an attempt for the development of fluorescent sensors for ultrasensitive chemo/biodetection. PMID- 24491782 TI - Fluorescent recognition of deoxyribonucleic acids by a quantum dot/meso tetrakis(N-methylpyridinium-4-yl)porphyrin complex based on a photo induced electron-transfer mechanism. AB - We have developed a new fluorescent probe of thioglycolic acid (TGA)-capped CdTe quantum dots (QDs) complexed with a model drug, meso-tetrakis(N-methylpyridinium 4-yl)porphyrin (TMPyP) for detecting deoxyribonucleic acids (DNAs). This probe operates with an "Off-On" mode: TMPyP quenches the photoluminescence (PL) of QDs via a photo induced electron-transfer (PIET) process; the presence of DNA can break the QD/TMPyP complexation, interrupting the PIET process, and switch on the PL of QDs. Sensitive detection of DNA with the detection limit of 0.16 nM and a linear detection range of 0.25-6.0 nM are achieved. Importantly, this probe can be used to distinguish the binding modes of DNA-TMPyP interactions, exhibiting the DNA sequence-dependent PL recovery behaviors. The obtained binding constant for poly(dA).poly(dT) is ~3.30*10(7) L mol(-1), which is approximately one order of magnitude larger than those for native DNAs and poly(dG).poly(dC). Furthermore, the thymine bases preferential of the TMPyP-DNA interaction is proved by this probe. PMID- 24491783 TI - Heterogeneous nucleation for synthesis of sub-20nm ZnO nanopods and their application to optical humidity sensing. AB - We present a novel method for colloidal synthesis of one-dimensional ZnO nanopods by heterogeneous nucleation on zero-dimensional ZnO nanoparticle 'seeds'. Ultra small ZnO nanopods, multi-legged structures with sub-20 nm individual leg diameters, can be synthesized by hydrolysis of a Zn2+ precursor growth solution in presence of ~4 nm ZnO seeds under hydrothermal conditions via microwave assisted heating in as little as 20 min of reaction time. One-dimensional ZnO nanorods are initially generated in the reaction mixture by heterogeneous nucleation and growth along the [0001] direction of the ZnO crystal. Growth of one-dimensional nanorods subsequently yields to an 'attachment' and size-focusing phase where individual nanorods fuse together to form multi-legged nanopods having diameters ~15 nm. ZnO nanopods exhibit broad orange-red defect-related photoluminescence in addition to a near-band edge emission at 373 nm when excited above the band-gap at 350 nm. The defect-related photoluminescence of the ZnO nanopods has been applied towards reversible optical humidity sensing at room temperature. The sensors demonstrated a linear response between 22% and 70% relative humidity with a 0.4% increase in optical intensity per % change in relative humidity. Due to their ultra-small dimensions, ZnO nanopods exhibit a large dynamic range and enhanced sensitivity to changes in ambient humidity, thus showcasing their ability as a platform for optical environmental sensing. PMID- 24491784 TI - Photocured thiol-ene based optical fluorescence sensor for determination of gold(III). AB - This study describes the preparation and the characterization of a new thiol-ene based polymeric fluorescence sensor by photo initiated polymerization of trimethylolpropane tris(3-mercaptopropionate), 2-hydroxyethylacrylate, and 2,4,6 triallyloxy-1,3,5-triazine which are used as monomers and also a photo initiator (2,2-dimethoxy-2-phenylacetophenone) for its usage as optical sensor for gold ions. The thiol-ene based polymeric membrane sensor was characterized by using attenuated total reflectance-fourier transform infrared spectroscopy (ATR-FTIR) and scanning electron microscopy (SEM). The response characteristics of the sensors including dynamic range, pH effect, response time, and the effect of foreign ions were investigated. Fluorescence spectra showed that the excitation/emission maxima of the membrane were at 379/425 nm, respectively. PMID- 24491785 TI - Optical "Turn off" based selective detection and concomitant degradation of 2 chloroethyl ethyl sulfide (CEES) via Mg-porphyrazine complex immobilized on glass. AB - Covalently assembled monolayers (CAMs) of Mg-porphyrazine complex on glass and silicon substrates were fabricated and employed as "Turn off" sensor for ppm level detection and degradation of a sulfur mustard analogue: 2-chloroethyl ethyl sulfide (CEES). The detection process was read-out optically via an off-the-shelf UV/Vis spectrophotometer in transmission mode. Monolayer based sensor system was shown to be quite robust and stable, sufficiently accurate and reversible under given experimental conditions. Notably, the sensor system exhibited marked selectivity for CEES when exposed exclusively or in mix to different potent analytes. Moreover, action of KMnO4 on monolayer-CEES complex lead to CEES degradation and resetting of the sensor to its native state for reuse. PMID- 24491786 TI - Fingerprint detection and using intercalated CdSe nanoparticles on non-porous surfaces. AB - A fluorescent nanocomposite based on the inclusion of CdSe quantum dots in porous phosphate heterostructures, functionalized with amino groups (PPH-NH2@CdSe), was synthesized, characterized and used for fingerprint detection. The main scopes of this work were first to develop a friendly chemical powder for detecting latent fingerprints, especially in non-porous surfaces; their further intercalation in PPH structure enables not to spread the fluorescent nanoparticles, for that reason very good fluorescent images can be obtained. The fingerprints, obtained on different non-porous surfaces such as iron tweezers, mobile telephone screen and magnetic band of a credit card, treated with this powder emit a pale orange luminescence under ultraviolet excitation. A further image processing consists of contrast enhancement that allows obtaining positive matches according to the information supplied from a police database, and showed to be more effective than that obtained with the non-processed images. Experimental results illustrate the effectiveness of proposed methods. PMID- 24491787 TI - A competitive immunoassay for sensitive detection of small molecules chloramphenicol based on luminol functionalized silver nanoprobe. AB - Chloramphenicol (CHL) as a broad-spectrum antibiotic has a broad action spectrum against Gram-positive and Gram-negative bacteria, as well as anaerobes. The use of CHL is strictly restricted in poultry because of its toxic effect. However, CHL is still illegally used in animal farming because of its accessibility and low cost. Therefore, sensitive methods are highly desired for the determination of CHL in foodstuffs. The immunoassays based on labeling as an important tool have been reported for the detection of CHL residues in food-producing animals. However, most of the labeling procedures require multi-step reactions and purifications and thus they are complicated and time-consuming. Recently, in our previous work, luminol functionalized silver nanoparticles have been successfully synthesized, which exhibits higher CL efficiency than luminol functionalized gold nanoparticles. In this work, the new luminol functionalized silver nanoparticles have been used for the labeling of small molecules CHL for the first time and a competitive chemiluminescent immunoassay has been developed for the detection of CHL. Owing to the amplification of silver nanoparticles, high sensitivity for CHL could be achieved with a low detection limit of 7.6*10(-9) g mL(-1) and a wide linear dynamic range of 1.0*10(-8)-1.0*10(-6) g mL(-1). This method has also been successfully applied to determine CHL in milk and honey samples with a good recoveries (92% and 102%, 99% and 107% respectively), indicating that the method is feasible for the determination of CHL in real milk and honey samples. The labeling procedure is simple, convenient and fast, superior to previously reported labeling procedures. The immunoassay is also simple, fast, sensitive and selective. It is of application potential for the determination of CHL in foodstuffs. PMID- 24491788 TI - Combination of micropreparative solution isoelectric focusing and high performance liquid chromatography for differentiation of biofilm-positive and biofilm-negative Candida parapsilosis group from vascular catheter. AB - This study utilizes the high-performance liquid chromatography technique in combination with the new micropreparative solution isoelectric focusing fractionation on non-woven fabric strip for the characterization and differentiation of biofilm-positive and biofilm-negative forms of Candida parapsilosis sensu stricto on the basis of the changes in the composition of their cell-surface. Treatment of yeasts by boiling in distilled water relased surface substances from yeasts cells. Consequently, the optimized procedure has been used for fast identification of the highly pathogenic biofilm-positive Candida parapsilosis group in real clinical material - sonicate from vascular catheters. Moreover, the capillary isoelectric focusing was used as supporting and control technique. Obtained results suggest that this new method can be used to distinguish between biofilm-positive and negative forms of Candida parapsilosis sensu stricto. PMID- 24491789 TI - Direct accurate analysis of cysteinylated and glutathionylated precursors of 4 mercapto-4-methyl-2-pentanone and 3-mercaptohexan-1-ol in must by ultrahigh performance liquid chromatography coupled to mass spectrometry. AB - A direct method for the quantitative determination in grapes of four known precursors of the varietal aromas of the thiol character of wine has been optimized and validated. A small volume of centrifuged and filtered must is directly injected in the ultrahigh liquid performance chromatography coupled to mass spectrometry system (UHPLC-MS-MS). Must sugars and other early eluting polar compounds are diverted to the waste, not entering the ion source. Cysteinyl (CYS) and glutathionyl (GLU) precursors from 3-mercaptohexanol (3MH) and 4-mercapto-4 methylpentanone (4M4MP) are separated in 5 min rendering narrow peaks (W1/2<9s). No system performance degradation has been noticed in series of more than 200 injections. A standard addition procedure using the consecutive injection of a spiked sample made it possible to satisfactorily correct for matrix effects, with recoveries very close to 100% in all cases. Intermediate reproducibility was satisfactory (RSD between 1 and 10%), except for the glutathione-4-mercapto-4 methyl-2-pentanone (GLUMP) precursor, for which this value is around 20%. The limits of detection in real-must were below 1 MUg L(-1) for the precursors of the 4M4MP and for cysteine-3-mercaptohexan-1-ol (CYSMH) and glutathione-3 mercaptohexan-1-ol (GLUMH), 2 and 7 MUg L(-1), respectively, what is enough for the determination of these precursors in musts of any variety. PMID- 24491790 TI - Gas chromatography-mass spectroscopy optimization by computer simulation, application to the analysis of 93 volatile organic compounds in workplace ambient air. AB - GC-MS optimization method including both advantages from chromatographic separation and mass spectrometric detection was designed for a set of 93 volatile organic compounds. Only a few experiments were necessary to determine the thermodynamic retention parameters for all compounds on a RTX-VMS column. From these data, computer simulation was used in order to predict the retention times of the compounds in temperature programmed gas chromatography. Then, an automatic selection of ions from the NIST database was performed and compared to the optimum conditions (full separation of VOC). This simulation-selection procedure was used to screen a numerous set of GC and MS conditions in order to quickly design a GC-MS method whatever the set of compounds considered. PMID- 24491791 TI - Mulligan Concept manual therapy: standardizing annotation. AB - Quality technique documentation is integral to the practice of manual therapy, ensuring uniform application and reproducibility of treatment. Manual therapy techniques are described by annotations utilizing a range of acronyms, abbreviations and universal terminology based on biomechanical and anatomical concepts. The various combinations of therapist and patient generated forces utilized in a variety of weight-bearing positions, which are synonymous with Mulligan Concept, challenge practitioners existing annotational skills. An annotation framework with recording rules adapted to the Mulligan Concept is proposed in which the abbreviations incorporate established manual therapy tenets and are detailed in the following sequence of; starting position, side, joint/s, method of application, glide/s, Mulligan technique, movement (or function), whether an assistant is used, overpressure (and by whom) and numbers of repetitions or time and sets. Therapist or patient application of overpressure and utilization of treatment belts or manual techniques must be recorded to capture the complete description. The adoption of the Mulligan Concept annotation framework in this way for documentation purposes will provide uniformity and clarity of information transfer for the future purposes of teaching, clinical practice and audit for its practitioners. PMID- 24491792 TI - In an occupational health surveillance study, auxiliary data from administrative health and occupational databases effectively corrected for nonresponse. AB - OBJECTIVES: To show how reweighting can correct for unit nonresponse bias in an occupational health surveillance survey by using data from administrative databases in addition to classic sociodemographic data. STUDY DESIGN AND SETTING: In 2010, about 10,000 workers covered by a French health insurance fund were randomly selected and were sent a postal questionnaire. Simultaneously, auxiliary data from routine health insurance and occupational databases were collected for all these workers. To model the probability of response to the questionnaire, logistic regressions were performed with these auxiliary data to compute weights for correcting unit nonresponse. Corrected prevalences of questionnaire variables were estimated under several assumptions regarding the missing data process. The impact of reweighting was evaluated by a sensitivity analysis. RESULTS: Respondents had more reimbursement claims for medical services than nonrespondents but fewer reimbursements for medical prescriptions or hospitalizations. Salaried workers, workers in service companies, or who had held their job longer than 6 months were more likely to respond. Corrected prevalences after reweighting were slightly different from crude prevalences for some variables but meaningfully different for others. CONCLUSION: Linking health insurance and occupational data effectively corrects for nonresponse bias using reweighting techniques. Sociodemographic variables may be not sufficient to correct for nonresponse. PMID- 24491793 TI - Strengths and weaknesses of a stepped wedge cluster randomized design: its application in a colorectal cancer follow-up study. AB - OBJECTIVES: To determine the advantages and disadvantages of a stepped wedge design for a specific clinical application. STUDY DESIGN AND SETTING: The clinical application was a pragmatic cluster randomized surgical trial intending to find an increased percentage of curable recurrences in patients in follow-up after colorectal cancer. Advantages and disadvantages of the stepped wedge design were evaluated, and for this application, new advantages and disadvantages were presented. RESULTS: A main advantage of the stepped wedge design was that the intervention rolls out to all participants, motivating patients and doctors, and a large number of patients who were included in this study. The stepped wedge design increased the complexity of the data analysis, and there were concerns regarding the informed consent procedure. The repeated measurements may bring burden to patients in terms of quality of life, satisfaction, and costs. CONCLUSION: The stepped wedge design is a strong alternative for pragmatic cluster randomized trials. The known advantages hold, whereas most of the disadvantages were not applicable to this application. The main advantage was that we were able to include a large number of patients. Main disadvantages were that the informed consent procedure can be problematic and that the analysis of the data can be complex. PMID- 24491794 TI - Network geometry shows evidence sequestration for medical vs. surgical practices: treatments for basal cell carcinoma. AB - OBJECTIVES: Basal cell carcinoma (BCC) is the most common cancer with 2 million treatments per year with little evidence-based guidelines for treatment. There are three classes of interventions (surgical, destructive, and topical) for BCC, and this study aimed to determine whether there are preferences or avoidances in comparisons of different types of treatments for BCC in randomized controlled trials (RCTs). STUDY DESIGN AND SETTING: PubMed, Cochrane Central Registry of Clinical Trials, and ClinicalTrials.Gov were used to identify eligible published and registered ongoing RCTs. RESULTS: Fifty-five trials (42 published and 13 registered trials) were identified. Only one unpublished registered trial compared a topical vs. a surgical intervention, and only one trial compared a topical vs. a destructive intervention. Conversely, 44 of the 55 trials compared interventions within the same treatment class and 9 of 55 trials compared surgical vs. destructive interventions. In most trials, selection of same-class comparators was not necessitated by the type of BCC lesions (nonaggressive superficial or nodular vs. aggressive, infiltrative, morpheic BCCs, P = 0.155) or their location (face vs. nonfacial, P = 0.137). CONCLUSION: This is the first time that an evaluation of network geometry is applied to address issues of comparisons between different families of interventions that belong to different specialties and practices (medical vs. surgical). Previous evaluations of homophily have addressed different families of interventions, in which all interventions are medical (drugs) and performed in the same health-care settings. The noncommunicating bodies of evidence between medical and surgical interventions that we document highlight a problem of unnecessary sequestration of the evidence and the corresponding health-care practices. PMID- 24491795 TI - Tryptophan hydroxylase 2 (TPH2) gene polymorphisms and psychiatric comorbidities in temporal lobe epilepsy. AB - Psychiatric comorbidities are frequent in temporal lobe epilepsy (TLE). It is plausible that variance in serotonin-related genes is involved in the susceptibility of these associations. We report here the results on the association of tryptophan hydroxylase 2 (TPH2) gene polymorphisms with psychiatric comorbidities in TLE. A cohort study was conducted on 163 patients with TLE. We assessed the influence of the rs4570625 and rs17110747 polymorphisms in the TPH2 gene on psychiatric comorbidities in TLE. In patients with TLE, the presence of the T allele in the rs4570625 polymorphism was associated with psychotic disorders (OR=6.28; 95% CI=1.27-17.54; p=0.02), while the presence of the A allele in the rs17110747 polymorphism was associated with alcohol abuse (OR=20.33; 95% CI=1.60-258.46; p=0.02). Moreover, we identified male gender (OR=11.24; 95% CI=1.68-76.92; p=0.01) and family history of psychiatric disorder (OR=15.87; 95% CI=2.46-100; p=0.004) as factors also associated with alcohol abuse in TLE. Conversely, a family history of epilepsy was inversely associated with alcohol abuse (OR=0.03; 95% CI=0.001-0.60; p=0.02). Tryptophan hydroxylase 2 gene allele variants might be risk factors for psychiatric conditions in TLE. More specifically, we observed that the T allele in the rs4570625 polymorphism was associated with psychotic disorders, and the A allele in the rs17110747 TPH2 polymorphism was associated with alcohol abuse in patients with TLE. We believe that this study may open new research venues on the influence of the serotonergic system associated with psychiatric comorbidities in epilepsy. PMID- 24491796 TI - The effect of a novel cryoprotective agent, carboxylated epsilon-poly-L-lysine, on the developmental ability of re-vitrified mouse embryos at the pronuclear stage. AB - Transgenic animals are generally produced by microinjection of exogeneous DNA into embryos at the pronuclear (PN) stage. PN embryos also can be used for knockout animals because artificial nucleases such as zinc-finger nuclease or transcription activator-like effector nuclease are now available for modification of the targeted gene. If the embryos can be vitrified with multiple rounds, the remaining embryos without microinjection can be reused. In this study, we examined the developmental competence of repetitively vitrified mouse embryos at the PN stage using Cryotop. It was also examined whether a new cryoprotective agent (CPA), carboxylated epsilon-poly-l-lysine (COOH-PLL), is available for vitrification of mouse embryos. PN embryos were vitrified with dimethyl sulfoxide (DMSO) and ethylene glycol (EG) as CPAs. After warming, some embryos were re vitrified up to three times. The re-vitrification did not affect survival and in vitro developmental ability. PN embryos were also vitrified with COOH-PLL instead of DMSO up to three times. The embryos re-vitrified with COOH-PLL and EG also maintained high survival and developmental ability. However embryos vitrified with COOH-PLL and EG at three times significantly showed higher developmental ability (61.2+/-3.1%) than those vitrified with DMSO and EG at three times (44.2+/-2.7%) which was equivalent to that of fresh embryos (70.0+/-3.6%). Taken together, our results show that re-vitrification of mouse PN embryos did not have a detrimental effect on the in vitro and in vivo development of the embryos. In addition, COOH-PLL is available as a CPA for vitrification of mouse PN embryos. PMID- 24491797 TI - Efficacy and tolerability after 24 weeks of treatment with telaprevir, pegylated interferon and ribavirin in cirrhotic HIV-HCV coinfected subjects. AB - Efficacy and tolerability of telaprevir, pegylated interferon and ribavirin combination was assessed in 32 cirrhotic genotype 1 hepatitis C (HCV)-HIV coinfected patients. Undetectability of HCV-RNA was observed in 23/32 (71.9%) patients after 24 weeks. Treatment failure was observed in 9/32 subjects: four of them (45.5%) failed triple therapy due to virological rebound, while 5 patients (55.5%) experienced drug-related side effects driving to treatment interruption. These data suggest that telaprevir-containing triple therapy should be considered for treatment of genotype 1 HCV in HIV coinfected patients with liver cirrhosis, although a close vigilance is required because of potential drug-related side effects. PMID- 24491798 TI - Reduced glutamine synthetase activity plays a role in control of photosynthetic responses to high light in barley leaves. AB - The chloroplastic glutamine synthetase (GS, EC 6.3.1.2) activity was previously shown to be the limiting step of photorespiratory pathway. In our experiment, we examined the photosynthetic high-light responses of the GS2-mutant of barley (Hordeum vulgare L.) with reduced GS activity, in comparison to wild type (WT). The biophysical methods based on slow and fast chlorophyll fluorescence induction, P700 absorbance, and gas exchange measurements were employed. Despite the GS2 plants had high basal fluorescence (F0) and low maximum quantum yield (Fv/Fm), the CO2 assimilation rate, the PSII and PSI actual quantum yields were normal. On the other hand, in high light conditions the GS2 had much higher non photochemical quenching (NPQ), caused both by enhanced capacity of energy dependent quenching and disconnection of PSII antennae from reaction centers (RC). GS2 leaves also maintained the PSII redox poise (QA(-)/QA total) at very low level; probably this was reason why the observed photoinhibitory damage was not significantly above WT. The analysis of fast chlorophyll fluorescence induction uncovered in GS2 leaves substantially lower RC to antenna ratio (RC/ABS), low PSII/PSI ratio (confirmed by P700 records) as well as low PSII excitonic connectivity. PMID- 24491799 TI - CBP loss cooperates with PTEN haploinsufficiency to drive prostate cancer: implications for epigenetic therapy. AB - Despite the high incidence and mortality of prostate cancer, the etiology of this disease is not fully understood. In this study, we develop functional evidence for CBP and PTEN interaction in prostate cancer based on findings of their correlate expression in the human disease. Cbp(pc-/-);Pten(pc+/-) mice exhibited higher cell proliferation in the prostate and an early onset of high-grade prostatic intraepithelial neoplasia. Levels of EZH2 methyltransferase were increased along with its Thr350 phosphorylation in both mouse Cbp(-/-); Pten(+/-) and human prostate cancer cells. CBP loss and PTEN deficiency cooperated to trigger a switch from K27-acetylated histone H3 to K27-trimethylated bulk histones in a manner associated with decreased expression of the growth inhibitory EZH2 target genes DAB2IP, p27(KIP1), and p21(CIP1). Conversely, treatment with the histone deacetylase inhibitor panobinostat reversed this switch, in a manner associated with tumor suppression in Cbp(pc-/-);Pten(pc+/-) mice. Our findings show how CBP and PTEN interact to mediate tumor suppression in the prostate, establishing a central role for histone modification in the etiology of prostate cancer and providing a rationale for clinical evaluation of epigenetic-targeted therapy in patients with prostate cancer. PMID- 24491800 TI - Activation of the glutamate receptor GRM1 enhances angiogenic signaling to drive melanoma progression. AB - Glutamate-triggered signal transduction is thought to contribute widely to cancer pathogenesis. In melanoma, overexpression of the metabotropic glutamate receptor (GRM)-1 occurs frequently and its ectopic expression in melanocytes is sufficient for neoplastic transformation. Clinical evaluation of the GRM1 signaling inhibitor riluzole in patients with advanced melanoma has demonstrated tumor regressions that are associated with a suppression of the mitogen-activated protein kinase (MAPK) and phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) pathways. Together, these results prompted us to investigate the downstream consequences of GRM1 signaling and its disruption in more detail. We found that melanoma cells with enhanced GRM1 expression generated larger tumors in vivo marked by more abundant blood vessels. Media conditioned by these cells in vitro contained relatively higher concentrations of interleukin-8 and VEGF due to GRM1 mediated activation of the AKT-mTOR-HIF1 pathway. In clinical specimens from patients receiving riluzole, we confirmed an inhibition of MAPK and PI3K/AKT activation in posttreatment as compared with pretreatment tumor specimens, which exhibited a decreased density of blood vessels. Together, our results demonstrate that GRM1 activation triggers proangiogenic signaling in melanoma, offering a mechanistic rationale to design treatment strategies for the most suitable combinatorial use of GRM1 inhibitors in patients. PMID- 24491801 TI - UTX and MLL4 coordinately regulate transcriptional programs for cell proliferation and invasiveness in breast cancer cells. AB - Histone methyltransferases and demethylases reversibly modulate histone lysine methylation, which is considered a key epigenetic mark associated with gene regulation. Recently, aberrant regulation of gene expression by histone methylation modifiers has emerged as an important mechanism for tumorigenesis. However, it remains largely unknown how histone methyltransferases and demethylases coregulate transcriptional profiles for cancer cell characteristics. Here, we show that in breast cancer cells, the histone H3 lysine 27 (H3K27) demethylase UTX (also known as KDM6A) positively regulates gene expression programs associated with cell proliferation and invasion. The majority of UTX controlled genes, including a cohort of oncogenes and prometastatic genes, are coregulated by the H3K4 methyltransferase mixed lineage leukemia 4 (MLL4, also called ALR, KMT2D, and MLL2). UTX interacted with a C-terminal region of MLL4. UTX knockdown resulted in significant decreases in the proliferation and invasiveness of breast cancer cells in vitro and in a mouse xenograft model. Such defective cellular characteristics of UTX-depleted cells were phenocopied by MLL4 knockdown cells. UTX-catalyzed demethylation of trimethylated H3K27 and MLL4 mediated trimethylation at H3K4 occurred interdependently at cotarget genes of UTX and MLL4. Clinically, high levels of UTX or MLL4 were associated with poor prognosis in patients with breast cancer. Taken together, these findings uncover that coordinated regulation of gene expression programs by a histone methyltransferase and a histone demethylase is coupled to the proliferation and invasion of breast cancer cells. PMID- 24491802 TI - Noninvasive quantification of solid tumor microstructure using VERDICT MRI. AB - There is a need for biomarkers that are useful for noninvasive imaging of tumor pathophysiology and drug efficacy. Through its use of endogenous water, diffusion weighted MRI (DW-MRI) can be used to probe local tissue architecture and structure. However, most DW-MRI studies of cancer tissues have relied on simplistic mathematical models, such as apparent diffusion coefficient (ADC) or intravoxel incoherent motion (IVIM) models, which produce equivocal results on the relation of the model parameter estimate with the underlying tissue microstructure. Here, we present a novel technique called VERDICT (Vascular, Extracellular and Restricted Diffusion for Cytometry in Tumors) to quantify and map histologic features of tumors in vivo. VERDICT couples DW-MRI to a mathematical model of tumor tissue to access features such as cell size, vascular volume fraction, intra- and extracellular volume fractions, and pseudo diffusivity associated with blood flow. To illustrate VERDICT, we used two tumor xenograft models of colorectal cancer with different cellular and vascular phenotypes. Our experiments visualized known differences in the tissue microstructure of each model and the significant decrease in cell volume resulting from administration of the cytotoxic drug gemcitabine, reflecting the apoptotic volume decrease. In contrast, the standard ADC and IVIM models failed to detect either of these differences. Our results illustrate the superior features of VERDICT for cancer imaging, establishing it as a noninvasive method to monitor and stratify treatment responses. PMID- 24491803 TI - miR-28-5p promotes chromosomal instability in VHL-associated cancers by inhibiting Mad2 translation. AB - Chromosomal instability enables tumor development, enabled in part by aberrant expression of the mitotic checkpoint protein Mad2. Here we identify a novel regulatory mechanism for Mad2 expression involving miR-28-5p-mediated inhibition of Mad2 translation, and we demonstrate that this mechanism is triggered by inactivation of the tumor suppressor VHL, the most common event in clear cell renal cell carcinoma (ccRCC). In VHL-positive cancer cells, enhanced expression of miR-28-5p diminished Mad2 levels and promoted checkpoint weakness and chromosomal instability. Conversely, in checkpoint-deficient VHL-negative renal carcinoma cells, inhibition of miR-28-5p function restored Mad2 levels, mitotic checkpoint proficiency, and chromosomal stability. Notably, chromosome missegregation errors and aneuploidy that were produced in a mouse model of acute renal injury (as a result of kidney-specific ablation of pVHL function) were reverted in vivo also by genetic inhibition of miR-28-5p. Finally, bioinformatic analyses in human ccRCC associated loss of VHL with increased miR-28-5p expression and chromosomal instability. Together, our results defined miR-28-5p as a critical regulator of Mad2 translation and mitotic checkpoint function. By identifying a potential mediator of chromosomal instability in VHL-associated cancers, our work also suggests a novel microRNA-based therapeutic strategy to target aneuploid cells in VHL-associated cancers. PMID- 24491804 TI - The sex difference in haemoglobin levels in adults - mechanisms, causes, and consequences. AB - Men and women have different mean haemoglobin levels in health in venous blood - women have mean levels approximately 12% lower than men. A similar sex-related difference in haemoglobin levels in adult animals is found in many species of mammals, birds and reptiles, indicating that it is an important physiological phenomenon. It is probably a direct effect of sex hormones, both oestrogen and androgens, on erythropoiesis. However, since there is no difference in erythropoietin levels between the sexes, this effect most likely takes place in the kidney, rather than in the bone marrow. Oestrogens dilate and androgens constrict the renal microvasculature: dilation and vasoconstriction in vessels below 300 MUm in diameter respectively increase and decrease the haematocrit in blood in arterioles, capillaries and venules, altering the oxygen delivery per unit red cell mass, and providing a mechanism for varying the red cell mass without compensatory changes in erythropoiesis. PMID- 24491805 TI - Developmental co-expression and functional redundancy of tyrosine phosphatases with neurotrophin receptors in developing sensory neurons. AB - Receptor-type protein tyrosine phosphatases (RPTPs) have been implicated as direct or indirect regulators of neurotrophin receptors (TRKs). It remains less clear if and how such RPTPs might regulate TRK proteins in vivo during development. Here we present a comparative expression profile of RPTP genes and Trk genes during early stages of murine, dorsal root ganglion maturation. We find little if any specific, temporal mRNA co-regulation between individual RPTP and Ntrk genes between E12.5 and E14.5. Moreover, a double fluorescent in-situ hybridization and immunofluorescence study of seven Rptp genes with Ntrks revealed widespread co-expression of RPTPs in individual neurons, but no tight correlation with Trk expression profiles. No Rptp is expressed in 100% of Ntrk1 expressing neurons, whereas at least 6 RPTPs are expressed in 100% of Ntrk2- and Ntrk3-expressing neurons. An exception is Ptpro, which showed very selective expression. Short hairpin RNA suppression of Ptprf, Ptprs or Ptpro in primary, E13.5 DRG neurons did not alter TRK signalling. We therefore propose that TRK signalling may not be simply dependent on rate-limiting regulation by individual RPTP subtypes during sensory neuron development. Instead, TRK signalling has the potential to be buffered by concurrent inputs from several RPTPs in individual neurons. PMID- 24491806 TI - Advanced oxidation protein product level in children with chronic otitis media with effusion. AB - OBJECTIVE: To determine the level of advanced oxidation protein products (AOPPs) in children with chronic otitis media with effusion (COME), in an effort to elucidate the multifactorial etiology of this disease. METHODS: This study involved 25 COME patients and 30 healthy children (control group) recruited from the Ear, Nose and Throat (ENT) and Pediatric Departments, respectively, of the Haseki Research and Training Hospital. In the COME group, blood samples were collected before a middle ear operation, and middle ear fluid was sampled during the operation. Blood samples were also obtained from the control subjects. AOPP levels in the plasma and effusion fluid were measured by the spectrophotometric method. RESULTS: In the COME group, the mean AOPP levels in plasma and effusion fluid were 168.08 MUmol/l and 412.75 MUmol/l, respectively. In the control group, the mean plasma AOPP level was 141.54 MUmol/l. The plasma AOPP levels did not significantly differ between the COME and control groups (p>0.05). In the COME group, however, the effusion fluid AOPP level (412.75 +/- 204.54 MUmol/l) was significantly higher than the plasma AOPP level (168.08 +/- 68.45 MUmol/l; p<0.01). CONCLUSION: We found that AOPP levels were elevated in the effusion fluid, but not in the plasma, of COME patients. Thus, COME was associated with protein oxidation abnormalities. Oxidative stress may play a role in the etiopathogenesis of COME, and AOPPs may be used as markers of oxidative stress; however, further studies are required to confirm these findings. PMID- 24491807 TI - Eustachian tube opening measured by sonotubometry is poorer in adults with a history of past middle ear disease. AB - OBJECTIVE: Test the hypothesis that active Eustachian tube opening efficiency as measured by sonotubometry is higher in adults with no extant middle-ear disease and no history of previous otitis media (Group-1) when compared to adults with no middle-ear disease but a positive history for otitis media (Group-2). METHODS: Eustachian tube function for 1 ear of 33 otherwise healthy adult subjects, 16 assigned to Group-1 and 17 to Group-2, was tested by sonotubometry using a standard protocol. For each test, the sound envelopes for 3 swallows were abstracted independently by 2 observers from the data stream and 7 descriptive parameters related to sound envelope "shape" were calculated. Inter-relatedness among the values for the parameters was explored using correlation analysis. The contributions of swallow, observer and group to the variance in each parameter were evaluated for significance using a General Linear Model. RESULTS: The shape parameters reflecting envelope height, area and rise and fall rates were highly inter-correlated, but those reflecting envelope widths were not. There was no effect of "swallow" on any of the parameters; but there was a significant "observer" effect on all measures of envelope width, greater for observer-2, and a significant "group" effect for 5 of the 7 shape parameters, all greater in Group-1. CONCLUSIONS: Quantifiable measures of the sound signal "shape" recorded by sonotubometry during swallowing were significantly different between the 2 groups of subjects. This is interpretable as evidencing a more efficient Eustachian tube opening-function in adults with healthy middle ears who do not have a previous history of otitis media when compared to similar adults with a history of prior otitis media. Inefficient Eustachian tube function as children may not be completely resolved by adulthood increasing adult otitis media risk when Eustachian tube function is down-graded by extant upper respiratory diseases that provoke nasopharyngeal inflammation. PMID- 24491808 TI - Craniofacial modifications in Ivorian melanoderm children with chronic retronasal obstruction. AB - OBJECTIVE: To determine the influence of the chronic retro nasal airway obstruction on craniofacial morphology. METHODS: It was a case-control study which included fifty-eight melanoderm children aged from 3 to 6 years (31 males and 27 females), divided in 2 samples. A studied group of 29 habitual snorers presenting chronic retro nasal obstruction due to enlarged adenoid and a control group of 29 age matched children selected among patients consulting for routine evaluation. Patients who had used topical or systemic medication for the nose, as well as those who had undergone adenoidectomy were excluded from the study. Children were submitted to history taking then ENT and orthodontic examination. Linear and angular cephalometric measurements were used for craniofacial features evaluation. RESULTS: Significant craniofacial anomalies were found in patients presenting chronic retro nasal obstruction: shortened cranial base and mandibular plane length, widened cranio-cervical flexure, forwardness of hyoid bone, reduced nasopharyngeal airway space, widened of oropharyngeal and hypopharyngeal airway space. CONCLUSIONS: Our study suggests that craniofacial modifications due to chronic retro nasal obstruction lead to pharyngeal airway readjustment. Persistent retro nasal obstruction should be corrected early in life in order to avoid skeletal modifications appearance. PMID- 24491809 TI - Measuring socioeconomic health inequalities in presence of multiple categorical information. AB - While many of the measurement approaches in health inequality measurement assume the existence of a ratio-scale variable, most of the health information available in population surveys is given in the form of categorical variables. Therefore, the well-known inequality indices may not always be readily applicable to measure health inequality as it may result in the arbitrariness of the health concentration index's value. In this paper, we address this problem by changing the dimension in which the categorical information is used. We therefore exploit the multi-dimensionality of this information, define a new ratio-scale health status variable and develop positional stochastic dominance conditions that can be implemented in a context of categorical variables. We also propose a parametric class of population health and socioeconomic health inequality indices. Finally we provide a twofold empirical illustration using the Joint Canada/United States Surveys of Health 2004 and the National Health Interview Survey 2010. PMID- 24491810 TI - MEKK2 regulates focal adhesion stability and motility in invasive breast cancer cells. AB - MEK Kinase 2 (MEKK2) is a serine/threonine kinase that functions as a MAPK kinase kinase (MAP3K) to regulate activation of Mitogen-activated Protein Kinases (MAPKs). We recently have demonstrated that ablation of MEKK2 expression in invasive breast tumor cells dramatically inhibits xenograft metastasis, but the mechanism by which MEKK2 influences metastasis-related tumor cell function is unknown. In this study, we investigate MEKK2 function and demonstrate that silencing MEKK2 expression in breast tumor cell significantly enhances cell spread area and focal adhesion stability while reducing cell migration. We show that cell attachment to the matrix proteins fibronectin or Matrigel induces MEKK2 activation and localization to focal adhesions. Further, we reveal that MEKK2 ablation enhances focal adhesion size and frequency, thereby linking MEKK2 function to focal adhesion stability. Finally, we show that MEKK2 knockdown inhibits fibronectin-induced Extracellular Signal-Regulated Kinase 5 (ERK5) signaling and Focal Adhesion Kinase (FAK) autophosphorylation. Taken together, our results strongly support a role for MEKK2 as a regulator of signaling that modulates breast tumor cell spread area and migration through control of focal adhesion stability. PMID- 24491811 TI - Cellular interplay in pulmonary arterial hypertension: implications for new therapies. AB - Pulmonary arterial hypertension (PAH) is a complex and multifactorial disease characterized by vascular remodeling, vasoconstriction, inflammation and thrombosis. Although the available therapies have resulted in improvements in morbidity and survival, PAH remains a severe and devastating disease with a poor prognosis and a high mortality, justifying the need of novel therapeutic targets. An increasing number of studies have demonstrated that endothelial cells (ECs), smooth muscle cells (SMCs) and fibroblasts of the pulmonary vessel wall, as well as platelets and inflammatory cells have a role in PAH pathogenesis. This review aims to integrate the interplay among different types of cells, during PAH development and progression, and the impact of current therapies in cellular modulation. The interplay among endothelial cells, smooth muscle cells and fibroblasts present in pulmonary vessels wall, platelets and inflammatory cells is regulated by several mediators produced by these cells, contributing to the pathophysiologic features of PAH. Current therapies are mainly focused in the pulmonary vascular tone and in the endothelial dysfunction. However, once they have not been effective, novel therapies targeting other PAH features, such as inflammation and platelet dysfunction are emerging. Further understanding of the interplay among different vascular cell types involved in PAH development and progression can contribute to find novel therapeutic targets, decreasing PAH mortality and morbidity in the future. PMID- 24491812 TI - High risk association of IL-4 VNTR polymorphism with asthma in a North Indian population. AB - BACKGROUND: A case-control study was conducted to evaluate the role of IL-4 VNTR polymorphism in asthma that has been associated with various inflammatory diseases worldwide. This is the first case-control study conducted in India, investigating the role of IL-4 VNTR polymorphism in asthma pathogenesis. METHODS: A case-control study was performed with a total of 824 adult subjects, inducting 410 asthma patients and 414 healthy controls from North India. The genotypes were identified by polymerase chain reaction. RESULTS: Statistical analysis for the IL 4 VNTR polymorphism revealed that the Rp1 allele was significantly associated with asthma with OR=1.47, 95% CI (1.11-1.94) and p=0.005. The Rp1/Rp1 homozygous mutant genotype posed a high risk towards asthma with OR=2.39, 95% CI (0.96-6.14) and p=0.040. The Rp2/Rp1 heterozygous genotype also posed a risk towards asthma with OR=1.39, 95% CI (1.00-1.94) and p=0.040. Most of the phenotypic traits were significantly associated with the disease. CONCLUSIONS: IL-4 VNTR polymorphism is a high risk factor for asthma in the studied North Indian population. PMID- 24491813 TI - Interleukin-6 signal transduction and its role in hepatic lipid metabolic disorders. AB - Hepatic lipid dysregulation can lead to spectrum of metabolic disease conditions including metabolic syndrome (MS), fatty liver and diabetes. Liver lipids are regulated by a complex set of extra-hepatic and intra-hepatic factors including cellular cross-talk with variety of cells, inducing various cytokines. Interleukin 6(IL-6) is a pleiotropic cytokine that exerts both pro-inflammatory and anti-inflammatory effects on hepatic system through either JNK/STAT or ERK/MAPK signaling. Although, IL-6 has shown to protect the liver from fat storage in both rodent and human models and various IL-6(-/-) studies have supported this notion yet a question remains over its deleterious pro inflammatory effects on hepatocytes. IL-6 ability to produce reactive oxygen species (ROS) and subsequently disturb the hepatic lipid balance has created a conundrum. Furthermore, IL-6 has shown to behave differently under different disease states within hepatocytes and hence, modulating the hepatic lipids accordingly. This review deals with the role of IL-6 on hepatic lipid metabolism and analyzes various data presented on this topic. PMID- 24491815 TI - Cofactor assisted enzymatic catalysis. PMID- 24491814 TI - "It was an overwhelming thing": parents' needs after infant diagnosis with congenital adrenal hyperplasia. AB - This study characterizes the experiences and expressed needs of parents following diagnosis of their newborn with congenital adrenal hyperplasia (CAH). Six parents (four mothers and two fathers) were interviewed about how they learned about CAH and its management, followed by qualitative data analysis. Coding of transcripts revealed several themes, including health communication problems, a lack of medical home and decision support, and a desire for parent-to-parent social support. Findings have implications for how family-centered health care is delivered following an unexpected newborn diagnosis. PMID- 24491817 TI - The evolutionary history of vertebrate cranial placodes II. Evolution of ectodermal patterning. AB - Cranial placodes are evolutionary innovations of vertebrates. However, they most likely evolved by redeployment, rewiring and diversification of preexisting cell types and patterning mechanisms. In the second part of this review we compare vertebrates with other animal groups to elucidate the evolutionary history of ectodermal patterning. We show that several transcription factors have ancient bilaterian roles in dorsoventral and anteroposterior regionalisation of the ectoderm. Evidence from amphioxus suggests that ancestral chordates then concentrated neurosecretory cells in the anteriormost non-neural ectoderm. This anterior proto-placodal domain subsequently gave rise to the oral siphon primordia in tunicates (with neurosecretory cells being lost) and anterior (adenohypophyseal, olfactory, and lens) placodes of vertebrates. Likewise, tunicate atrial siphon primordia and posterior (otic, lateral line, and epibranchial) placodes of vertebrates probably evolved from a posterior proto placodal region in the tunicate-vertebrate ancestor. Since both siphon primordia in tunicates give rise to sparse populations of sensory cells, both proto placodal domains probably also gave rise to some sensory receptors in the tunicate-vertebrate ancestor. However, proper cranial placodes, which give rise to high density arrays of specialised sensory receptors and neurons, evolved from these domains only in the vertebrate lineage. We propose that this may have involved rewiring of the regulatory network upstream and downstream of Six1/2 and Six4/5 transcription factors and their Eya family cofactors. These proteins, which play ancient roles in neuronal differentiation were first recruited to the dorsal non-neural ectoderm in the tunicate-vertebrate ancestor but subsequently probably acquired new target genes in the vertebrate lineage, allowing them to adopt new functions in regulating proliferation and patterning of neuronal progenitors. PMID- 24491816 TI - The c-Ski family member and transcriptional regulator Corl2/Skor2 promotes early differentiation of cerebellar Purkinje cells. AB - Purkinje cells (PCs) provide the primary output from the cerebellar cortex, which controls movement and posture, and loss of PCs causes severe cerebellar dysfunction. The mechanisms underlying cell fate determination and early differentiation of PC remain largely unknown. Here we show that the c-Ski family member and transcriptional regulator Corl2 is required for correct differentiation of PCs. In Corl2 knock-out embryos, initial PC specification appeared largely normal, but in a subset of presumptive PCs generated near the ventral border of the PC domain, cell fate choice was compromised and cells showed a mixed identity expressing the interneuron marker Pax2 as well. Additionally, selection and maintenance of the transmitter phenotype was compromised in most developing PCs in the mutants. During later differentiation steps, induction of PC marker genes was significantly suppressed, suggesting that maturation was delayed in the absence of Corl2. Consistently, defects in migration, cell polarization and dendrite formation were observed in mutant PCs, although their axonal trajectories appeared normal. These phenotypes closely resembled those of mutants for Rora, an essential regulator of PC differentiation. However, Rora expression was not significantly changed in the Corl2 mutants, indicating that Corl2 does not simply act upstream of Rora to promote PC differentiation. ChIP experiments revealed that Corl2 bound to the promoter regions of several PC-selective genes, which are also known to be direct downstream targets of RORalpha. Altogether, our results identified a novel regulatory program of PC differentiation involving Corl2, which might cooperate with the RORalpha pathway. PMID- 24491818 TI - Yap1, transcription regulator in the Hippo signaling pathway, is required for Xenopus limb bud regeneration. AB - The Hippo signaling pathway is conserved from insects to mammals and is important for multiple processes, including cell proliferation, apoptosis and tissue homeostasis. Hippo signaling is also crucial for regeneration, including intercalary regeneration, of the whole body in the flatworm and of the leg in the cricket. However, its role in vertebrate epimorphic regeneration is unknown. Therefore, to identify principles of regeneration that are conserved among bilaterians, we investigated the role of Hippo signaling in the limb bud regeneration of an anuran amphibian, Xenopus laevis. We found that a transcription factor, Yap1, an important downstream effector of Hippo signaling, is upregulated in the regenerating limb bud. To evaluate Yap1's function in limb bud regeneration, we made transgenic animals that expressed a dominant-negative form of Yap under a heat-shock promoter. Overexpression of a dominant-negative form of Yap in tadpoles reduced cell proliferation, induced ectopic apoptosis, perturbed the expression domains of limb-patterning genes including hoxa13, hoxa11, and shh in the regenerating limb bud. Transient expression of a dominant negative Yap in transgenic tadpoles also caused limb bud regeneration defects, and reduced intercalary regeneration. These results indicate that Yap1 has a crucial role in controlling the limb regenerative capacity in Xenopus, and suggest that the involvement of Hippo signaling in regeneration is conserved between vertebrates and invertebrates. This finding provides molecular evidence that common principles underlie regeneration across phyla, and may contribute to the development of new therapies in regenerative medicine. PMID- 24491820 TI - Autoimmunity: from black water fever to regulatory function. AB - Autoimmunity is a field that has only been around for a little over a century. Initially, it was thought that autoimmunity could not happen, that the body would never turn on itself (i.e. "horror autotoxicus"). It was only around the First World War that autoimmunity was recognized as the pathogenesis of various diseases, including rheumatoid arthritis. The discovery of Compound E led to successful treatment of patients with autoimmune diseases, but it was not till later that the adverse effects of this class of drugs were elucidated. The "modern" age of autoimmunity began around 1945 with the description of blackwater fever, and most of the subsequent research on hemolytic anemia and the role of an autoantibody in its pathogenesis led to a description of the anti-globulin reaction. The lupus erythematous (LE) cell was recognized in the mid-1940s by Hargreaves. His research carried on into the 1960s. Rheumatoid factor was also first described in the 1940s as yet another serum factor with activity against globulin-coated sheep red blood cells. The concept of autoimmunity really gained a foothold in the 1950s, when autoimmune thyroid disease and idiopathic thrombocytopenia were first described. Much has happened since then, and our understanding of autoimmunity has evolved now to include mechanisms of apoptosis, signaling pathway derangements, and the discovery of subsets of T cells with regulatory activity. The modern day study of autoimmunity is a fascinating area of research, and full understanding of the pathogenesis of autoimmune diseases is far from being completely elucidated. PMID- 24491819 TI - Neural crest and placode interaction during the development of the cranial sensory system. AB - In the vertebrate head, the peripheral components of the sensory nervous system are derived from two embryonic cell populations, the neural crest and cranial sensory placodes. Both arise in close proximity to each other at the border of the neural plate: neural crest precursors abut the future central nervous system, while placodes originate in a common preplacodal region slightly more lateral. During head morphogenesis, complex events organise these precursors into functional sensory structures, raising the question of how their development is coordinated. Here we review the evidence that neural crest and placode cells remain in close proximity throughout their development and interact repeatedly in a reciprocal manner. We also review recent controversies about the relative contribution of the neural crest and placodes to the otic and olfactory systems. We propose that a sequence of mutual interactions between the neural crest and placodes drives the coordinated morphogenesis that generates functional sensory systems within the head. PMID- 24491822 TI - Diagnosis and classification of central nervous system vasculitis. AB - Central nervous system vasculitis is one of the foremost diagnostic challenges in rheumatology. It results in inflammation and destruction of the vasculature within the CNS. When vasculitis is confined to brain, meninges or spinal cord, it is referred to as primary angiitis of the CNS. Secondary CNS vasculitis occurs in the setting of a systemic vasculitis, auto-inflammatory or infectious disease. Prompt and accurate diagnosis of CNS vasculitis is essential to prevent irreversible brain damage, and to secure precise treatment decisions. Progressive debilitating and unexplained neurological deficits, associated with abnormal cerebrospinal fluid is the typical picture of the disease. Biopsy of the brain remains the gold standard diagnostic test. The differential diagnosis of CNS vasculitis is highly diverse with a broad array of mimics at the clinical, radiographic and angiographic levels. PMID- 24491821 TI - IL-10-producing regulatory B cells induced by IL-33 (Breg(IL-33)) effectively attenuate mucosal inflammatory responses in the gut. AB - Regulatory B cells (Breg) have attracted increasing attention for their roles in maintaining peripheral tolerance. Interleukin 33 (IL-33) is a recently identified IL-1 family member, which leads a double-life with both pro- and anti inflammatory properties. We report here that peritoneal injection of IL-33 exacerbated inflammatory bowel disease in IL-10-deficient (IL-10(-/-)) mice, whereas IL-33-treated IL-10-sufficient (wild type) mice were protected from the disease induction. A phenotypically unconventional subset(s) (CD19(+)CD25(+)CD1d(hi)IgM(hi)CD5(-)CD23(-)Tim-1(-)) of IL-10 producing Breg-like cells (Breg(IL-33)) was identified responsible for the protection. We demonstrated further that Breg(IL-33) isolated from these mice could suppress immune effector cell expansion and functions and, upon adoptive transfer, effectively blocked the development of spontaneous colitis in IL-10(-/-) mice. Our findings indicate an essential protective role, hence therapeutic potential, of Breg(IL-33) against mucosal inflammatory disorders in the gut. PMID- 24491823 TI - International consensus criteria for the diagnosis of Raynaud's phenomenon. AB - Vasoconstriction accompanied by changes in skin color is a normal physiologic response to cold. The distinction between this normal physiology and Raynaud's phenomenon (RP) has yet to be well characterized. In anticipation of the 9th International Congress on Autoimmunity, a panel of 12 RP experts from 9 different institutes and four different countries were assembled for a Delphi exercise to establish new diagnostic criteria for RP. Relevant investigators with highly cited manuscripts in Raynaud's-related research were identified using the Web of Science and invited to participate. Surveys at each stage were administered to participants via the on-line SurveyMonkey software tool. The participants evaluated the level of appropriateness of statements using a scale of 1 (extremely inappropriate) through 9 (extremely appropriate). In the second stage, panel participants were asked to rank rewritten items from the first round that were scored as "uncertain" for the diagnosis of RP, items with significant disagreement (Disagreement Index > 1), and new items suggested by the panel. Results were analyzed using the Interpercentile Range Adjusted for Symmetry (IPRAS) method. A 3-Step Approach to diagnose RP was then developed using items the panelists "agreed" were "appropriate" diagnostic criteria. In the final stage, the panel was presented with the newly developed diagnostic criteria and asked to rate them against previous models. Following the first two iterations of the Delphi exercise, the panel of 12 experts agreed that 36 of the items were "appropriate", 12 items had "uncertain" appropriateness, and 13 items were "inappropriate" to use in the diagnostic criteria of RP. Using an expert committee, we developed a 3-Step Approach for the diagnosis of RP and 5 additional criteria for the diagnosis of primary RP. The committee came to an agreement that the proposed criteria were "appropriate and accurate" for use by physicians to diagnose patients with RP. PMID- 24491824 TI - Taking stock -- what is known about suicide in Sri Lanka: a systematic review of diverse literature. AB - BACKGROUND: Suicide is and has been a major public health problem in Sri Lanka and has generated a wide range of literature. AIMS: This review aimed to systematically appraise what is known about suicide in Sri Lanka. The patterns and content of articles were examined and recommendations for further research proposed. METHOD: The paper describes the systematic search, retrieval, and quality assessment of studies. Thematic analysis techniques were applied to the full text of the articles to explore the range and extent of issues covered. RESULTS: Local authors generated a large body of evidence of the problem in early studies. The importance of the method of suicide, suicidal intention, and the high incidence of suicide were identified as key foci for publications. Neglected areas have been policy and health service research, gender analysis, and contextual issues. CONCLUSION: The literature reviewed has produced a broad understanding of the clinical factors, size of the problem, and social aspects. However, there remains limited evidence of prevention, risk factors, health services, and policy. A wide range of solutions have been proposed, but only regulation of pesticides and improved medical management proved to be effective to date. PMID- 24491825 TI - Gender differences in deliberate self-poisoning in Hungary: analyzing the effect of precipitating factors and their relation to depression. AB - BACKGROUND: The suicide rate in Hungary is one of the highest in the European Union, with a male-female ratio of 3.55:1. Suicide rates correlate positively with suicide attempts, for which depression is the most frequent underlying disorder. AIMS: The aim of this qualitative study was to examine gender differences in suicide attempts, with a focus on the effect of precipitating factors on depression. METHOD: Semistructured interviews were conducted among 150 suicide attempters. Data on circumstances, reason, and method of attempt were recorded. Patients completed the Shortened Beck Depression Inventory, the Beck Hopelessness Scale, the Sense of Coherence Scale, and the Social Support Questionnaire. RESULTS: Interpersonal conflict was found to be the most frequent precipitating factor. There were significant gender differences in depressive symptoms among patients with interpersonal conflicts. We found differences in depressive symptoms according to presence or absence of interpersonal conflicts among men, but not among women. Male suicide attempters who indicated interpersonal conflicts had lower levels of depression. CONCLUSION: Depressive symptoms are frequent among suicide attempters. However, a subgroup of male attempters reporting interpersonal conflicts are characterized by a lower level of depression. This subgroup of attempters would probably not be detected with depression screening programs and may have an unmet need for other forms of screening and prevention. PMID- 24491826 TI - Policy oscillation is overshooting. AB - A majority of approximate dynamic programming approaches to the reinforcement learning problem can be categorized into greedy value function methods and value based policy gradient methods. The former approach, although fast, is well known to be susceptible to the policy oscillation phenomenon. We take a fresh view to this phenomenon by casting, within the context of non-optimistic policy iteration, a considerable subset of the former approach as a limiting special case of the latter. We explain the phenomenon in terms of this view and illustrate the underlying mechanism with artificial examples. We also use it to derive the constrained natural actor-critic algorithm that can interpolate between the aforementioned approaches. In addition, it has been suggested in the literature that the oscillation phenomenon might be subtly connected to the grossly suboptimal performance in the Tetris benchmark problem of all attempted approximate dynamic programming methods. Based on empirical findings, we offer a hypothesis that might explain the inferior performance levels and the associated policy degradation phenomenon, and which would partially support the suggested connection. Finally, we report scores in the Tetris problem that improve on existing dynamic programming based results by an order of magnitude. PMID- 24491827 TI - Genotype*environment interaction QTL mapping in plants: lessons from Arabidopsis. AB - Plant growth and development are influenced by the genetic composition of the plant (G), the environment (E), and the interaction between them (G*E). To produce suitable genotypes for multiple environments, G*E should be accounted for and assessed in plant-breeding programs. Here, we review the genetic basis of G*E and its consequence for quantitative trait loci (QTL) mapping in biparental and genome-wide association (GWA) mapping populations. We also consider the implications of G*E for understanding plant fitness trade-offs and evolutionary ecology. PMID- 24491828 TI - Maternal work and children's diet, activity, and obesity. AB - Mothers' work hours are likely to affect their time allocation towards activities related to children's diet, activity and well-being. For example, mothers who work more may be more reliant on processed foods, foods prepared away from home and school meal programs for their children's meals. A greater number of work hours may also lead to more unsupervised time for children that may, in turn, allow for an increase in unhealthy behaviors among their children such as snacking and sedentary activities such as TV watching. Using data on a national cohort of children, we examine the relationship between mothers' average weekly work hours during their children's school years on children's dietary and activity behaviors, BMI and obesity in 5th and 8th grade. Our results are consistent with findings from the literature that maternal work hours are positively associated with children's BMI and obesity especially among children with higher socioeconomic status. Unlike previous papers, our detailed data on children's behaviors allow us to speak directly to affected behaviors that may contribute to the increased BMI. We show that children whose mothers work more consume more unhealthy foods (e.g. soda, fast food) and less healthy foods (e.g. fruits, vegetables, milk) and watch more television. Although they report being slightly more physically active, likely due to organized physical activities, the BMI and obesity results suggest that the deterioration in diet and increase in sedentary behaviors dominate. PMID- 24491829 TI - Ureibacillus defluvii sp. nov., isolated from a thermophilic microbial fuel cell. AB - A thermophilic bacterium, designated DX-1T, was isolated from the anode biofilm of a microbial fuel cell (MFC). Cells of strain DX-1T were oxidase-positive, catalase-positive and Gram-staining-negative. The strain was found to be rod shaped and non-motile and to produce subterminal spores. The strain was able to grow with NaCl at concentrations ranging from 0 to 6 %, at temperatures of 25-60 degrees C (optimum 55 degrees C) and pH 6.0-8.0 (optimum pH 7.0). Phylogenetic analyses based on 16S rRNA gene sequences showed that strain DX-1T formed a cluster with Ureibacillus thermosphaericus DSM 10633T (96.9% 16S rRNA sequence similarity), Ureibacillus composti DSM 17951T (95.8%), Ureibacillus thermophilus DSM 17952T (95.7%) and Ureibacillus terrenus DSM 12654T (95.3%). The G+C content of the genomic DNA was 40.4 mol%. The major quinone was MK-7, the peptidoglycan type was L-Lys<-D-Asp, and the major cellular fatty acids (>5%) were iso-C16:0 and iso-C14:0. The polar lipids consisted of phosphatidylglycerol, diphosphatidylglycerol and phospholipids of unknown composition. Based on phenotypic characteristics, chemotaxonomic features and results of phylogenetic analyses, the strain was determined to represent a distinct novel species of the genus Ureibacillus, and the name proposed for the novel species is Ureibacillus defluvii sp. nov., with type strain DX-1T (=CGMCC 1.12358T=KCTC 33127T). PMID- 24491830 TI - Luteimicrobium xylanilyticum sp. nov., isolated from the gut of a long-horned beetle, Massicus raddei. AB - A novel strain, designated W-15(T), was isolated from the gut of a long-horned beetle, Massicus raddei, collected in South Korea. Phylogenetic analysis based on 16S rRNA gene sequences revealed that the strains belonged to the suborder Micrococcineae. Strain W-15(T) was most closely related to Luteimicrobium album RI148-Li105(T) (97.9 % similarity). Strain W-15(T) was Gram-stain-positive, rod- and coccus-shaped and non-motile. Growth was observed at 15-37 degrees C, at pH 4.5-8.5 and in the presence of 0-5.0 % NaCl. The cell-wall peptidoglycan of the strain was A4alpha (l-Lys-d-Ser-d-Asp). The major menaquinone present in this strain was MK-8 (H2) and the major cellular fatty acids were anteiso-C15 : 0, iso C16 : 0, iso-C15 : 0 and anteiso-C17 : 0. The major polar lipids were diphosphatidylglycerol, phosphatidylinositol, an unknown lipid, an unknown phospholipid and an unknown phosphoglycolipid. The G+C content of genomic DNA of the strain was 73.8 mol%. On the basis of evidence from our polyphasic taxonomic study, strain W-15(T) is classified as representing a novel species in the suborder Micrococcineae, for which the name Luteimicrobium xylanilyticum sp. nov. is proposed. The type strain of this species is strain W-15(T) ( = KCTC 19882(T) = JCM 18090(T)). PMID- 24491831 TI - Critical Incident Stress Management (CISM) in complex systems: cultural adaptation and safety impacts in healthcare. AB - In complex systems, such as hospitals or air traffic control operations, critical incidents (CIs) are unavoidable. These incidents can not only become critical for victims but also for professionals working at the "sharp end" who may have to deal with critical incident stress (CIS) reactions that may be severe and impede emotional, physical, cognitive and social functioning. These CIS reactions may occur not only under exceptional conditions but also during every-day work and become an important safety issue. In contrast to air traffic management (ATM) operations in Europe, which have readily adopted critical incident stress management (CISM), most hospitals have not yet implemented comprehensive peer support programs. This survey was conducted in 2010 at the only European general hospital setting which implemented CISM program since 2004. The aim of the article is to describe possible contribution of CISM in hospital settings framed from the perspective of organizational safety and individual health for healthcare professionals. Findings affirm that daily work related incidents also can become critical for healthcare professionals. Program efficiency appears to be influenced by the professional culture, as well as organizational structure and policies. Overall, findings demonstrate that the adaptation of the CISM program in general hospitals takes time but, once established, it may serve as a mechanism for changing professional culture, thereby permitting the framing of even small incidents or near misses as an opportunity to provide valuable feedback to the system. PMID- 24491832 TI - Computational principles of microcircuits for visual object processing in the macaque temporal cortex. AB - Understanding the principles of neuronal computation that underlie our cognitive abilities is a fundamental goal of neuroscience. Microcircuits are thought to be computational units embedded in a brain-wide neuronal network. Recent progress in experimental and analytical techniques has enabled the exploration of information flow in operating microcircuits of behaving monkeys. Accumulating evidence demonstrates that crucial transformations of neuronal codes for the representation and memory retrieval of visual objects occur in cortical microcircuits. Particularly, microcircuit comparisons across cortical areas provide novel principles for object processing, in which precursor codes for object features are constructed in a lower-order area before prevalence in a higher-order area. We review recent findings on microcircuit operations in macaque temporal cortex that enable object processing, and discuss future research directions. PMID- 24491833 TI - Editorial overview - virus entry: towards reality - refining models of virus entry. PMID- 24491834 TI - Gene expression in teratogenic exposures: a new approach to understanding individual risk. AB - The phenomenon of partial or incomplete penetrance is common to many paradigms of exposure to teratogens, where only some of the exposed individuals exhibit developmental defects. We here argue that the most widely used experimental approaches in reproductive toxicology do not take partial penetrance into account, and are thus likely to miss differences between affected and unaffected individuals that contribute to susceptibility for teratogenesis. We propose that focus on the variation between exposed individuals could help to discover factors that may play a causative role for abnormal developmental processes that occur with incomplete penetrance. PMID- 24491835 TI - Amperometric glucose biosensor based on layer-by-layer films of microperoxidase 11 and liposome-encapsulated glucose oxidase. AB - An important step in several bioanalytical applications is the immobilization of biomolecules. Accordingly, this procedure must be carefully chosen to preserve their biological structure and fully explore their properties. For this purpose, we combined the versatility of the layer-by-layer (LbL) method for the immobilization of biomolecules with the protective behavior of liposome encapsulated systems to fabricate a novel amperometric glucose biosensor. To obtain the biosensing unit, an LbL film of the H2O2 catalyst polypeptide microperoxidase-11 (MP-11) was assembled onto an indium-tin oxide (ITO) electrode followed by the deposition of a liposome-encapsulated glucose oxidase (GOx) layer. The biosensor response toward glucose detection showed a sensitivity of 0.91+/-0.09 (MUA/cm2)/mM and a limit of detection (LOD) of 8.6+/-1.1 MUM, demonstrating an improved performance compared to similar biosensors with a single phospholipid-liposome or even containing a non-encapsulated GOx layer. Finally, glucose detection was also performed in a zero-lactose milk sample to demonstrate the potential of the biosensor for food analysis. PMID- 24491836 TI - Adaptation of the Halobacterium salinarum ssp. NRC-1 gene deletion system for modification of chromosomal loci. AB - The model archaeon Halobacterium salinarum ssp. NRC-1 is an excellent system for the study of archaeal molecular biology. Unlike many other archaea, its only special growth requirement is high levels of sodium chloride and other salts; it requires neither high-temperature incubation nor anaerobic environments. Additionally, there are a number of well-developed post-genomic tools available, including whole-genome microarrays and a ura3-based gene deletion system. While some tools are available for protein expression, a system for measurement and purification of protein expressed from native promoters is lacking. We have adapted the established H. salinarum gene deletion system for this purpose, and have used this to place 8*-histidine tags on either the carboxyl or amino terminus of the protein encoded by the chromosomal rfa3 gene. To demonstrate the utility of this approach, we used Western blot analysis to determine levels of the Rfa3 protein under different conditions. This system provides another powerful molecular tool for studies of native protein expression and for simple protein purification in H. salinarum. PMID- 24491837 TI - Rapid and simple colorimetric method for the quantification of AI-2 produced from Salmonella Typhimurium. AB - The aim of this study was to evaluate the feasibility of Fe(III) ion reduction for the simple and rapid quantification of autoinducer-2 (AI-2) produced from bacteria using Salmonella Typhimurium as a model. Since the molecular structure of AI-2 is somewhat similar to ascorbic acid it was expected that AI-2 would also act as a reducing agent and reduce Fe(III) ions in the presence of 1,10 phenanthroline to form the colored [(o-phen)3 Fe(II)]SO4 ferroin complex that could be quantified colorimetrically. In support of this, colony rinses and cell free supernatants from cultures of all tested AI-2 producing strains, but not the AI-2 negative Sinorhizobium meliloti, formed a colored complex with a lambdamax of 510nm. The OD510 values of these culture supernatants or colony rinses were in broad agreement with the % activity observed in the same samples using the standard Vibrio harveyi bioluminescence assay for AI-2 detection, and with previously reported results. This methodology could potentially be developed as an alternative method for the simple and rapid quantification of AI-2 levels produced in bacterial cultures. PMID- 24491838 TI - A salicylate-based small molecule HS-Cm exhibits immunomodulatory effects and inhibits dipeptidyl peptidase-IV activity in human T cells. AB - Activated T cells are key players in chronic inflammatory diseases, including atherosclerosis. Salicylates, like aspirin, display not only anti-inflammatory, anti-thrombotic, anti-atherosclerotic activities, but also immunomodulatory effects in T cells at high dosages. Here, we aimed to identify potent immunomodulators for T cells through cell-based screening from a mini-library of 300 salicylate-based small molecules, and elucidate the mechanisms. Human peripheral blood T cells were isolated from buffy coat. Phorbol 12-myristate 13 acetate plus ionomycin (P/I) was used to stimulate T cells. Cytokine production was measured by enzyme-linked immunosorbent assays. T cell activation markers were determined by flow cytometry. The activation of transcription factors and kinases was analyzed by western blotting, electrophoretic mobility shift assay, or kinase assay. Through library screening, we identified a small molecule named HS-Cm [C13H9ClFNO2; N-(4-chloro-2-fluorophenyl)-2-hydroxybenzamide] that exhibited potent immunomodulatory effects on T cells with low cytotoxicity. In P/I-stimulated T cells, HS-Cm inhibited the production of interleukin-2, tumor necrosis factor-alpha, and interferon-gamma and suppressed the expression of surface activation markers CD25, CD69, and CD71, but not CD45RO. HS-Cm down regulated DNA-binding activities of activator protein-1 and nuclear factor-kappa B, but not nuclear factor of activated T-cells, through inhibiting c-Jun N terminal kinase/p38 and inhibitor of kappaB alpha (IkappaBalpha) kinase (IKK)/IkappaBalpha pathways, respectively. On the basis of structure-activity relationship, HS-Cm exerted considerable inhibition of dipeptidyl-peptidase IV/CD26 activity in T cells. Our results suggested that the small molecule HS-Cm exhibiting immunomodulatory effects on T cells may be useful for therapeutics in chronic inflammatory diseases, like atherosclerosis, diabetes and autoimmune arthritis. PMID- 24491839 TI - Effects of (-)-epicatechin on a diet-induced rat model of cardiometabolic risk factors. AB - Overweight and obesity have been associated with increase in cardiometabolic risk. Therapeutics include lifestyle changes and/or pharmacologic agents. However, such interventions are often limited by poor compliance and/or significant side effects. The consumption of certain dietary products, such as cocoa, exerts positive effects on cardiometabolic risk factors. (-)-Epicatechin (EPI), the most abundant flavonoid in cacao has been reported to replicate such effects. However its mechanisms of action have not been fully elucidated.In a rat model of high-fat diet-induced obesity and its associated cardiometabolic risk factors, we administered 1mg/kg of EPI, by gavage, for 2 weeks. Endpoints included weight-gain, glycemia, triglyceridemia, and systolic blood pressure. We also assessed food intake and fecal excretion. Mitochondrial function and structure related proteins were measured by Westerns.Obesity, hyperglycemia, hypertriglyceridemia, and systolic hypertension were developed after the administration of the high-fat diet for five weeks. EPI significantly decreased the rate of weight gain, glycemia and hypertriglyceridemia. The ratio between energy intake and excretion was not significantly modified by treatment. EPI restored the obesity-induced decreases in the levels of skeletal muscle and abdominal tissue sirtuins (SIRTs), peroxisome proliferator-activated receptor coactivator (PGC-1alpha), mitofilin, transcription factor A mitochondrial (TFAM), uncoupling protein 1 (UCP1), and deiodinase.EPI treatment yielded beneficial effects on high fat diet-induced endpoints thus may be considered as a potential agent for the treatment of obesity and its cardiometabolic associated abnormalities. Mechanism of action may be attributed to the modulation of cellular/mitochondrial function, thus improving overall metabolism. PMID- 24491840 TI - Dinitrosyl iron complexes with glutathione suppress experimental endometriosis in rats. AB - Dinitrosyl iron complexes (DNIC) with glutathione exert a cytotoxic effect on endometrioid tumours in rats with surgically induced experimental endometriosis. Intraperitoneal treatment of rats (Group 1) with DNIC (12.5MUmoles/kg, daily, for 12 days), beginning with day 4 after the surgical operation (implantation of two 2mm-thick uterine fragments onto the abdominal wall) followed by 14-day keeping of animals on a standard feeding schedule (without medication) resulted in complete inhibition of the growth of endometrioid implants (EMI) in the majority of experimental animals. The ratio of mean EMI volumes in control and experimental rats of Group 1 was 14:1. In Group 2 rats, the use of a similar treatment protocol 4 weeks after surgery changed this ratio to 1.4:1. Noteworthy, the decrease of this ratio was irrelevant to deceleration of EMI growth at later periods after surgery. The histopathological analysis of EMI samples from experimental rats of Group 2 demonstrated complete disappearance of endometrial cysts suggesting a cytotoxic effect of DNIC on the tumours. The data obtained demonstrate that DNIC with glutathione and, probably, with other thiol-containing ligands hold considerable promise in the design of drugs for treating endometriosis in female patients. PMID- 24491841 TI - pH and glutathion-responsive hydrogel for localized delivery of paclitaxel. AB - pH and glutathion (GSH)- responsive nanogels (NGs) based on poly-N isopropylacrilamide (NIPA), N-hydroxyethyl acrylamide (HEAA) and tert-butyl 2 acrylamidoethyl carbamate (2AAECM) were synthesized by a microemulsion polymerization method using N, N'-cystaminebisacrylamide (CBA) as a crosslinking agent and evaluated for passive targeting of paclitaxel (PTX). Physicochemical characterizations of unloaded and PTX-loaded NGs, such as particle size, morphology, encapsulation efficiency and in vitro PTX release were also assessed. Electron microscopy techniques (SEM and TEM) as well as dynamic light scattering (DLS) analysis showed nanosized spherical hydrogels. FTIR spectra confirmed the synthesis of nanogels by free radical polymerization among vinyl groups of monomers. In vitro release was analyzed by high-performance liquid chromatography (HPLC) and differences between two NG formulations were obtained. Nanogels released almost 64% of PTX after 50h at GSH concentrations equivalent to that in the cellular cytosol, whereas less PTX was released from NGs at pH and GSH levels similar to plasma. Cellular uptake and cytotoxicity were also demonstrated by using coumarin-6 and MTT assays, respectively, for three tumor cell lines (MCF7, HeLa and T47D). Cellular uptake assays revealed rapid uptake within 2h and intracellular accumulation of coumarin-6-loaded nanogels after 48 h incubation. MTT assays showed changes in cell viability at different concentrations of PTX formulations, as well as pure PTX (10 MUM, 20 MUM and 30 MUM). To investigate PTX effect on cell viability, changes in cell cycle were examined by flow cytometry and a G2/M cell arrest was demonstrated. Overall, synthesized nanogels may be used as potential carriers for hydrophobic anticancer drugs. PMID- 24491842 TI - Synthesis of gold nanoparticles with glycosides: synthetic trends based on the structures of glycones and aglycones. AB - A new, room temperature synthetic method for gold nanoparticles from auric acid with glycosides as reducing agents in aqueous NaOH is presented. As a mechanistic study of the oxidation sites on the glycosides, eight sugar-containing reductants (glycoside, glucose, glucuronic acid) have been tested in the synthesis of gold nanoparticles to determine their trends based on the structures of glycones and aglycones. As a result of the comparison among the eight sugar-containing reductants, it was determined that C-6 of glycosides is oxidized to a carboxylic acid during the reduction of auric acid. To detect the oxidized compounds of the glycosides, the reaction mixtures were monitored by (13)C NMR. Among the eight sugar-containing reductants, phenyl beta-D-glucoside generated the highest synthetic yield of mono-dispersed, round gold nanoparticles (13.15+/-1.30 nm, 99.7% yield). PMID- 24491843 TI - Structural characterization of polysaccharides expressed by Burkholderia oklahomensis E0147. AB - Burkholderia oklahomensis E0147 is a US isolated bacterium believed to express a similar O-antigen to type A structure of the highly pathogenic species, Burkholderia pseudomallei. Both species are genetically closely related. Lipopolysaccharide was collected from E0147 and structurally characterized to test this hypothesis. Glycosyl composition and linkage analyses in conjunction with 1D and 2D (1)H and (13)C NMR spectroscopy showed that the O-antigen was a repeating disaccharide with the following structure: [3)-beta-D-Glcp-(1->3)-2OAc alpha-L-6dTalp-(1->]n NMR spectroscopy also revealed the presence of a co extracted exopolysaccharide previously described in B. pseudomallei, with the structure: [3)-2OAc-beta-D-Galp-(1->4)-alpha-D-Galp-(1->3)-beta-D-Galp-(1->5) beta-D-Kdop-(2->]n. PMID- 24491844 TI - Protecting-group-free O-glysosidation using p-toluenesulfonohydrazide and glycosyl chloride donors. AB - A range of N'-glycosylsulfonohydrazides (GSHs) display good reactivity but poor stereoselectivity in protecting-group-free O-glycosidations when a moderate excess of the model acceptor n-decanol is employed. This stable, readily-accessed class of donor may be more tractable for the glycosylation of non-volatile acceptors than Fischer's glycosidation conditions. It is possible to generate unprotected glycosyl chlorides from GSHs in situ. In an effort to find conditions to improve glycosidation stereoselectivity, methanolysis of unprotected glucosyl chloride under halide-ion exchange conditions was examined. Relative to its tetra O-benzyl analogue, this donor displays moderate, inverted stereoselectivity and a significantly faster reaction rate. PMID- 24491845 TI - Synthesis of sulfonamide-conjugated glycosyl-amino acid building blocks. AB - The efficient synthesis of novel glycoconjugate amino acid building blocks wherein the amino acid and carbohydrate moieties are linked via a sulfonamide functional group is reported. The general reaction sequence consists of coupling a glycosyl thioacetate to an amino acid methyl ester followed by oxidation and deprotection of the carbohydrate moiety. We demonstrate the synthesis of derivatives from a range of amino acids, with reaction at either the alpha-amino group of amino acid precursors or the sidechain epsilon-amino group of lysine precursors. PMID- 24491846 TI - Reconstructing a complex central facial defect with a multiple-folding radial forearm flap. AB - The central face is the dominant feature of humans. A complex central facial defect can severely affect a person's appearance and function and can pose significant challenges for reconstructive surgeons. The aims and principles of central facial reconstruction are to achieve adequate function and esthetics. This report describes the case of a 45-year-old man who was bitten in the central face by a wild boar. A free radial forearm flap was designed as a multiple folding flap that was divided into several portions. The folded portions of the flap were used to reconstruct the nasal mucosa, oral mucosa, and upper lip defects and provided the lining for an eventual staged nasal reconstruction. The patient achieved good functional recovery and had a good esthetic outcome. PMID- 24491847 TI - New TASER injuries: lacrimal canaliculus laceration and ethmoid bone fracture. AB - The TASER is a non-lethal conducted electrical weapon intended to incapacitate a person. The growing use of the TASER has resulted in an increased risk of injuries, including those to the face. We report a case of lacrimal canaliculus laceration and ethmoid bone fracture caused by an extra penetration (XP) TASER X26 dart. A 35-year-old was subdued with a TASER head shot; the probe was discharged into the left medial canthus without causing any ocular lesions. A computed tomography scan revealed the probe to be embedded in the left nasolacrimal duct and showed a displaced ethmoid fracture. The barbed dart had sectioned the inferior lacrimal canaliculus without electrifying the lesion. This case expands the knowledge of injuries that may occur as a result of the use of this device and the management of peri-ocular TASER injuries. PMID- 24491848 TI - Histomorphometric evaluation of the effect of systemic and topical ozone on alveolar bone healing following tooth extraction in rats. AB - The aim of this study was to investigate the effects of systemic and topical ozone applications on alveolar bone healing following tooth extraction. One hundred and twelve male Wistar rats were divided into eight groups of 14 rats each; seven groups were experimental (A-G) and one formed the control group (K). The experimental groups were further divided into two sub-groups, with seven rats in each - sacrificed on days 14 and 28 (subgroups 1 and 2). The maxillary right central incisors were extracted under general anaesthesia following the administration of local anaesthesia. After sacrifice, semi-serial histological sections were prepared, and mineralized and trabecular bone and osteoid and osteoblast surfaces were measured. Measurements of the trabecular bone showed statistically higher values in the groups treated with systemic ozone (D(2): 50.01 +/- 2.12; E(2): 49.03 +/- 3.03; F(2): 48.76 +/- 2.61; G(2): 50.24 +/- 3.37) than in the groups that underwent topical ozone administration (A(2): 46.01 +/- 3.07; B(2): 46.79 +/- 3.09; C(2): 47.07 +/- 2.12; P = 0.030 (G(2)-A(2), G(2) B(2), G(2)-C(2))). Within the limitations of the current study, it may be concluded that postoperative long-term systemic ozone application can accelerate alveolar bone healing following extraction. However, additional studies are required to clarify the effects of the different ozone applications on new bone formation. PMID- 24491850 TI - Reply to the comments on "a study of the phosphate mineral kapundaite NaCa(Fe(3+))4(PO4)4(OH)3.5(H2O) using SEM/EDX and vibrational spectroscopic methods" by Frost et al. (2014). PMID- 24491849 TI - A study of van der Waals complexes of 1,2-dichloroethane in paraffin oil by FTIR spectroscopy and ab initio calculations. AB - Weak molecular interactions of 1,2-dichloroethane dissolved in paraffin oil were investigated by FTIR spectroscopy. Occurrence of isosbestic points in the spectra along with the factor analysis showed that DCE?DCE dimers are formed in solutions at DCE concentrations between 7 and 15 vol.%. It was found that both trans and gauche conformers are involved in the complexation, forming a tg-dimer. From the spectra collected at 200-222 K, the complexation enthalpy was determined: -4.2+/ 0.4 kcal mol(-1). The equilibrium geometry of tg-dimer and the vibrational frequencies were determined from the density functional calculations performed at B3LYP/6-311++G(d,p) and 6-31G(d,p) levels. The C-C bonds of the two molecules involved in tg-dimers were found to be oriented nearly perpendicular to each other. The complexation energy calculated using 6-31G(d,p) and 6-311++G(d,p) basis sets was found to be -1.59 and -1.52 kcal mol(-1), respectively. PMID- 24491851 TI - How about watching others? Observation of error-related feedback by others in autism spectrum disorders. AB - Research indicates that individuals with autism spectrum disorders (ASD) may have a reduced ability to utilize performance feedback to regulate their behavior; however, it is unclear to what degree alterations in the environmental context affect feedback processing and contribute to the symptoms of ASD. We utilized the observational FRN (oFRN), an event-related potential (ERP) component that putatively indexes feedback processing while observing feedback directed toward another person, to examine the influence of motivational and social demands on feedback processing in ASD. High-density electroencephalogram recordings were collected from 38 youth with ASD and 31 control participants similar on age and IQ while they observed a confederate performing a modified Eriksen Flanker task. Participants were instructed to count the confederate's errors and were told that they would be awarded based on performance: the confederate would either earn points for the participant or herself. Both groups showed robust oFRN activity on traditional scalp-electrode waveforms and waveforms identified using temporospatial principal components analysis. Amplitude of oFRN did not differentiate groups. Results remained non-significant when comparing medicated to non-medicated participants. There were no significant correlations between oFRN amplitudes, autism symptom severity, and anxiety symptoms. Findings suggest that the social context of the task and motivational significance of the confederate's performance did not limit feedback processing in ASD. Future research in which the context is manipulated further is warranted to determine whether increased environmental complexity influences feedback processing in ASD. PMID- 24491852 TI - Generalized lapse of responding in trait impulsivity indicated by ERPs: The role of energetic factors in inhibitory control. AB - Impaired inhibitory control is one of the still debated underlying mechanisms of trait impulsivity. The Cognitive Energetic Model accounts for the role of energetic factors mediating task performance. The aim of the present study was to compare inhibitory control functions of adults with high and low impulsivity by using a modified Eriksen flanker task. Adults were classified as impulsive (n=15) and control (n=15) participants based on the Barratt Impulsiveness Scale. Flanker trials had three levels of required effort manipulated by visual degradation. We analyzed RT, accuracy, and ERPs time-locked to the flanker stimuli. Reaction time of impulsive participants was generally slower than that of controls', but accuracy was similar across groups. N2c showed that monitoring of response conflict was modulated by task requirements independent of impulsivity. The P3 latency was delayed in the impulsive group indicating slower stimulus evaluation. The P3 amplitude was reduced in the control group for moderately degraded incongruent trials suggesting that the attentional resources were employed less. The Lateralized Readiness Potential (LRP) peaked later in the impulsive group irrespective of experimental effects. The amplitude of the positive-going LRP recorded in the incongruent condition was comparable across groups, but the latency was delayed partly supporting a stronger susceptibility to stimulus interference of impulsive participants. Their delayed incongruent negative-going LRP reflected a weaker response inhibition and a slower correct response organization. In conclusion, impaired inhibitory functions in impulsivity could not be unequivocally demonstrated, but we found a generalized lapse of motor activation. PMID- 24491853 TI - Targeting hydrogen sulfide as a promising therapeutic strategy for atherosclerosis. AB - Physiological concentrations of nitric oxide (NO) and carbon monoxide (CO) have multiple protective effects in the cardiovascular system. Recent studies have implicated hydrogen sulfide (H2S) as a new member of vasculoprotective gasotransmitter family, behaving similarly to NO and CO. H2S has been demonstrated to inhibit multiple key aspects of atherosclerosis, including atherogenic modification of LDL, monocytes adhesion to the endothelial cells, macrophage-derived foam cell formation and inflammation, smooth muscle cell proliferation, neointimal hyperplasia, vascular calcification, and thrombogenesis. H2S also decreases plasma homocysteine levels in experimental animal models. In the human body, H2S production is predominantly catalyzed by cystathionine-beta-synthase (CBS) and cystathionine gamma-lyase (CSE). CSE is the primary H2S-producing enzyme in the vasculature. Growing evidence suggests that atherosclerosis is associated with vascular CSE/H2S deficiency and that H2S supplementation by exogenous H2S donors (such as NaHS and GYY4137) attenuates, and H2S synthesis suppression by inhibitors (such as D, L-propargylglycine) aggravates the development of atherosclerotic plaques. However, it remains elusive whether CSE deficiency plays a causative role in atherosclerosis. A recent study (Circulation. 2013; 127: 2523-2534) demonstrates that decreased endogenous H2S production by CSE genetic deletion accelerates atherosclerosis in athero-prone ApoE-/- mice, pinpointing that endogenously produced H2S by CSE activation may be of benefit in the prevention and treatment of atherosclerosis. This study will facilitate the development of H2S-based pharmaceuticals with therapeutic applications in atherosclerosis-related cardiovascular diseases. PMID- 24491854 TI - Serum potassium levels and long-term post-discharge mortality in acute myocardial infarction. PMID- 24491855 TI - Different dietary fatty acids are associated with blood lipids in healthy South African men and women: the PURE study. AB - BACKGROUND: Preliminary data from the baseline Prospective Urban Rural Epidemiology (PURE) study in South Africa indicated a higher prevalence of dyslipidemia than previous South African studies. The intake of specific individual dietary fatty acids may affect blood lipids differently than sub groups of fat (i.e. polyunsaturated fatty acids). We investigated the dietary intake of different individual fatty acids and their associations with blood lipids, in relation to urbanization and gender. METHODS: Cross-sectional data analysis within the PURE baseline study of healthy subjects (n=1950, 35-70 years) from rural and urban areas. Dietary data were collected and blood lipid analysis performed. RESULTS: Intake of individual fatty acids was significantly higher in urban than rural dwellers. However, the intake of n-3 PUFAs was below recommendations in all groups. Total cholesterol and LDL were higher in females than in males, with no rural-urban differences. Intake of alpha-linolenic acid (ALA) was positively associated with total cholesterol (beta=0.143) and triglycerides (beta=0.256) in males. The risk for having elevated LDL also increased with increased intake of ALA (OR 1.49, 95% CI 1.04, 2.14) in males. In females, arachidonic acid and eicosapentaenoic acid (EPA) were positively associated with total cholesterol and arachidonic acid was also positively associated with LDL, whereas docosahexaenoic acid was negatively associated with total cholesterol and LDL. CONCLUSIONS: These results suggest that specific individual dietary fatty acids may affect blood lipids in males differently than in females irrespective of rural or urban dwelling. The positive association between ALA and total cholesterol and triglycerides in males is a concern, because current advice aims to improve the dietary linoleic acid to ALA ratio by increasing ALA intake. PMID- 24491856 TI - Effects of Nepsilon-carboxymethyl-Lysine on ERS-mediated apoptosis in diabetic atherosclerosis. PMID- 24491857 TI - Clinical characteristics of atrial fibrillation detected by implanted devices and its association with ICD therapy. PMID- 24491858 TI - Multiple recanalized images of thrombotic occlusion 19 years after percutaneous coronary intervention: insights from optical coherence tomography and intravascular ultrasound. PMID- 24491859 TI - Are ischemic stunning, conditioning, and "takotsubo" different sides to the same coin? PMID- 24491860 TI - First ad hoc bioresorbable vascular scaffold bench test: a glimpse into percutaneous bifurcation interventions. PMID- 24491861 TI - Sudden death after sustained restraint following self-administration of the designer drug alpha-pyrrolidinovalerophenone. PMID- 24491862 TI - Platelets in Kawasaki patients: two different populations with different mitochondrial functions. PMID- 24491863 TI - Elevated fasting serum insulin level predicts future development of hypertension. AB - BACKGROUND: Studies have investigated clinical association between fasting insulin level and hypertension. However, it is still debatable whether elevated fasting insulin actually increases the risk of hypertension with the passage of time. Thus, this study was aimed at investigating the association between baseline fasting insulin level and the development of hypertension. METHODS: 25,062 normotensive, non-diabetic Korean men participating in a medical health check-up program were followed up from 2005 until 2010. They were divided into 4 groups according to baseline fasting insulin levels (first quartile-fourth quartile). The incidence of hypertension was compared among 4 groups, and Cox proportional hazards model was used to determine if hypertension was associated with higher baseline fasting insulin level. RESULTS: The incidence of hypertension increased according to the baseline fasting insulin level (first quartile: 13.3%, second quartile: 15.4%, third quartile: 17.5%, fourth quartile: 23.2%, P<0.001). Even after adjusting for multiple covariates, the HRs (95% CI) for hypertension were higher for the second (1.12; 0.96-1.31), third (1.39; 1.20 1.62) and fourth quartile group (1.75; 1.51-2.03), compared to the first quartile group, respectively (P for trend<0.001). CONCLUSION: The risk of hypertension was in proportion to the baseline fasting insulin level. In addition, hyperinsulinemia was an independent risk factor for the future development of hypertension. These findings suggest the value of fasting insulin level as an early predictor of hypertension. PMID- 24491865 TI - Treatment failure of low molecular weight heparin bridging therapy after implantation of a permanent pacemaker. PMID- 24491864 TI - Long-term outcome of transitory "reversible" complete atrio-ventricular block unrelated to myocardial ischemia. PMID- 24491866 TI - Obesity paradox in female patients after stent implantation for carotid artery disease. PMID- 24491867 TI - The clinical correlates and prognostic impact of QRS prolongation in patients with dilated cardiomyopathy: a single-center cohort study. PMID- 24491868 TI - Renal sympathetic denervation for resistant hypertension in a child after aortic coarctation surgery. PMID- 24491869 TI - Large compressive proximal pseudoaneurysm after ascending-to-descending aortic bypass in a 62 year-old patient with severe aortic coarctation: first reported case. PMID- 24491870 TI - Cardioautonomic instability following a sports-related concussion in a 20-year old male. PMID- 24491871 TI - Giant left atrium in a patient with prosthetic mitral valve. PMID- 24491872 TI - Supravalvular aortic stenosis as a non-syndromic familial disease. Relevance of familial screening. PMID- 24491873 TI - Effects of exercise training on behavioral and emotional problems in adolescents with tetralogy of Fallot or a Fontan circulation: a randomized controlled trial. PMID- 24491874 TI - Heated water-based exercise training reduces 24-hour ambulatory blood pressure levels in resistant hypertensive patients: a randomized controlled trial (HEx trial). AB - BACKGROUND: Regular exercise is an effective intervention to decrease blood pressure (BP) in hypertension, but no data are available concerning the effects of heated water-based exercise (HEx). This study examines the effects of HEx on BP in resistant hypertensive patients. METHODS: This is a parallel, randomized controlled trial. 125 nonconsecutive sedentary patients with resistant hypertension from a hypertension outpatient clinic in a university hospital were screened; 32 patients fulfilled the study requirements. The training was performed for 60-minute sessions in a heated pool (32 degrees C), three times a week for 12 weeks. The HEx protocol consisted of callisthenic exercises and walking inside the pool. The control group was asked to maintain habitual activities. The main outcome measure was change in mean 24-hour ambulatory BP (ABPM). RESULTS: 32 patients (HEx n=16; control n=16) were randomized; none were lost to follow-up. Office BPs decreased significantly after heated water exercise (36/12 mmHg). HEx decreased 24-hour systolic (from 137+/-23 to 120+/-12 mmHg, p=0.001) and diastolic BPs (from 81+/-13 to 72+/-10 mmHg, p=0.009); daytime systolic (from 141+/-24 to 120+/-13 mmHg, p<0.0001) and diastolic BPs (from 84+/ 14 to 73+/-11 mmHg, p=0.003); and nighttime systolic (from 129+/-22 to 114+/-12 mmHg, p=0.006) and diastolic BPs (from 74+/-11 to 66+/-10 mmHg, p<0.0001). The control group after 12 weeks significantly increased in 24-hour systolic and diastolic BPs, and daytime and nighttime diastolic BPs. CONCLUSION: HEx reduced office BPs and 24-hour ABPM levels in resistant hypertensive patients. These effects suggest that HEx may be a potential new therapeutic approach in these patients. PMID- 24491875 TI - Efficacy of bepridil to prevent ventricular fibrillation in severe form of early repolarization syndrome. PMID- 24491876 TI - Predictors for permanent pacemaker implantation after core valve implantation in patients without preexisting ECG conduction disturbances: the role of a new echocardiographic index. PMID- 24491877 TI - Cardiac autonomic dysfunction after aortic surgery. PMID- 24491878 TI - Competing endogenous RNA network in pulmonary arterial hypertension. PMID- 24491879 TI - Neuroglobin expression and oxidant/antioxidant balance after graded traumatic brain injury in the rat. AB - Neuroglobin is a neuron-specific hexacoordinated globin capable of binding various ligands, including O2, NO, and CO, the biological function of which is still uncertain. Various studies seem to indicate that neuroglobin is a neuroprotective agent when overexpressed, acting as a potent inhibitor of oxidative and nitrosative stress. In this study, we evaluated the pathophysiological response of the neuroglobin gene and protein expression in the cerebral tissue of rats sustaining traumatic brain injury of differing severity, while simultaneously measuring the oxidant/antioxidant balance. Two levels of trauma (mild and severe) were induced in anesthetized animals using the weight drop model of diffuse axonal injury. Rats were then sacrificed at 6, 12, 24, 48, and 120 h after traumatic brain injury, and the gene and protein expression of neuroglobin and the concentrations of malondialdehyde (as a parameter representative of reactive oxygen species-mediated damage), nitrite + nitrate (indicative of NO metabolism), ascorbate, and glutathione (GSH) were determined in the brain tissue. Results indicated that mild traumatic brain injury, although causing a reversible increase in oxidative/nitrosative stress (increase in malondialdehyde and nitrite + nitrate) and an imbalance in antioxidants (decrease in ascorbate and GSH), did not induce any change in neuroglobin. Conversely, severe traumatic brain injury caused an over nine- and a fivefold increase in neuroglobin gene and protein expression, respectively, as well as a remarkable increase in oxidative/nitrosative stress and depletion of antioxidants. The results of this study, showing a lack of effect in mild traumatic brain injury as well as asynchronous time course changes in neuroglobin expression, oxidative/nitrosative stress, and antioxidants in severe traumatic brain injury, do not seem to support the role of neuroglobin as an endogenous neuroprotective antioxidant agent, at least under pathophysiological conditions. PMID- 24491880 TI - Effects of combined lipoic acid and pyridoxine on albuminuria, advanced glycation end-products, and blood pressure in diabetic nephropathy. AB - This study was designed to investigate the effects of combined administration of lipoic acid and pyridoxine on albuminuria, oxidative stress, blood pressure, serum advanced glycation end-products, nitric oxide (NO), and endothelin-1 in patients with diabetic nephropathy. Thirty-four patients were randomly assigned to either a supplement group or a placebo group. The patients in the supplement group received 800 mg lipoic acid and 80 mg pyridoxine daily for 12 weeks, whereas the placebo group received corresponding placebos. Urinary albumin, serum malondialdehyde (MDA), and systolic blood pressure decreased significantly in the supplement group compared to the placebo group (p < 0.05). Serum NO increased in the supplement group compared to the placebo group (p < 0.05). Serum pentosidine and carboxymethyl lysine decreased significantly in the supplement group at the end of week 12 compared to baseline (p < 0.05). No statistically significant differences were observed between the two groups in mean changes of serum endothelin-1, glucose, and diastolic blood pressure. The present study indicates that combined administration of lipoic acid and pyridoxine improves albuminuria in patients with diabetic nephropathy by reducing oxidative stress, advanced glycation end-products, and systolic blood pressure. The reduction in microalbuminuria may be of benefit in retarding the progression of diabetic nephropathy. PMID- 24491881 TI - C677T methylenetetrahydrofolate reductase and plasma homocysteine levels among Thai vegans and omnivores. AB - Hyperhomocysteinemia among vegetarians and vegans is caused mostly by vitamin B12 deficiency. A C-to-T mutation in the methylenetetrahydrofolate reductase (MTHFR) gene results in a thermolabile MTHFR, which may affect homocysteine (Hcy) levels. The importance of this gene mutation among populations depends on the T allele frequency. Blood Hcy, vitamin B12, folate, vitamin B6, and MTHFR C677T mutation status were determined in 109 vegans and 86 omnivores aged 30 - 50 years. The vegans had significantly higher Hcy levels than the omnivores, geometric means (95 % CI) 19.2 (17.0 - 21.7) umol/L vs. 8.53 (8.12 - 8.95) umol/L, p < 0.001. A C to-T mutation in the vegans increased plasma Hcy, albeit insignificantly; geometric means 18.2 umol/L, 20.4 umol/L, and 30.0 umol/L respectively in CC, CT, and TT MTHFR genotypes. There was also a significant decrease in serum folate; geometric means 12.1 ng/mL, 9.33 ng/mL, and 7.20 ng/mL respectively, in the CC, CT, and TT mutants, p = 0.006, and particularly, in the TT mutant compared with the CC wild type, 7.20 ng/mL vs. 12.1 ng/mL, p = 0.023. These findings were not seen in the omnivores. It was concluded that hyperhomocysteinemia is prevalent among Thai vegans due to vitamin B12 deficiency. C-to-T MTHFR mutation contributes only modestly to the hyperhomocysteinemia. PMID- 24491882 TI - Vitamin D, an essential nutrient with versatile functions in nearly all organs. AB - For decades, vitamin D has been known to be essential in the development, function, and maintenance of healthy bones through the regulation of calcium homeostasis throughout life. Sufficient vitamin D prevents the occurrence of rickets in children and osteomalacia in adults. The adequate nutritional intake of vitamin D and calcium are the basis for the prevention and management of osteoporosis, a disease producing brittle bones that are prone to fractures. Vitamin D has been implicated in the regulation of neuromuscular function and in reducing the risk of falls, a major cause of bone fractures. Thus vitamin D may be a central component of musculoskeletal health through its beneficial effects on muscle function and bone stability. The action of vitamin D by the active metabolite 1,25-dihydroxyvitamin D [1,25(OH)2D], however, is not limited to its endocrine function in bone metabolism. The active metabolite behaves as a hormone and binds to the vitamin D receptor (VDR) present in nearly all tissues of the human body. In addition, the 1-alpha-hydroxylase enzyme is present not only in the kidney but also in many other organs. Both vitamin and enzyme exert their biological effects via paracrine/autocrine actions related to cardiovascular disease, diabetes, cancer, and the immune system. Thus vitamin D may show favorable effects in many organs and play a significant role in the maintenance of general health. PMID- 24491883 TI - Protective effects of vitamin E on chemotherapy-induced peripheral neuropathy: a meta-analysis of randomized controlled trials. AB - PURPOSE: This study aimed to investigate the neuroprotective effects of vitamin E for preventing chemotherapy-induced peripheral neuropathy (CIPN). METHODS: A comprehensive search from 1973 through July 2011 identified randomized controlled trials (RCTs) that reported the preventive effects of vitamin E on CIPN. The relative risk (RR) of CIPN with vitamin E supplementation, compared with placebo, was assessed with the Bayesian random effect model and expressed as RR with a 95 % credible-interval (CrI). Bayesian outcome probabilities were calculated as the probability (P) of RR < 1. RESULTS: Five RCTs, involving 319 patients, were identified. Upon pooling these RCTs, vitamin E supplementation (300 - 600 mg/day) had a significant effect on CIPN prevention (RR 0.43; 95 % CrI 0.10 - 1.00, P = 97.5 %). Subgroup analysis by chemotherapeutic agent type was only available for cisplatin and showed that vitamin E supplementation significantly reduced the incidence of CIPN (RR 0.26; 95 % CrI 0.06 - 0.89, P = 98.1 %). Furthermore, there were no adverse effects caused by vitamin E supplementation in any of the RCTs. CONCLUSION: Available data included in this meta-analysis show that vitamin E supplementation might significantly prevent CIPN. Currently, however, the data are insufficient to confidently conclude the true value. Large-scale, rigorously designed RCTs are needed to confirm the role of vitamin E supplementation in CIPN prevention. PMID- 24491884 TI - Quantification of isotope-labeled and unlabeled folates and folate catabolites in urine samples by stable isotope dilution assay. AB - Dual-label stable isotope dilution assays for the simultaneous quantification of isotopologic folates in clinical samples offer the perspective for differentiating between unlabeled folates from endogenous body pools and administered [13C5]-labeled folates from a test dose when performing bioavailability trials. In contrast to intact folates, this methodology could hitherto not be applied to the quantification of the folate catabolites, p aminobenzoyl glutamate and p-acetamidobenzoyl glutamate. In this study, [2H4]-p aminobenzoyl glutamate, [2H4]-p-acetamidobenzoyl glutamate, and unlabeled p acetamidobenzoyl glutamate were synthesized. The synthesis of the [2H4]-labeled compounds started at unlabeled p-aminobenzoic acid. For the formation of p acetamidobenzoyl glutamate, p-aminobenzoyl glutamate was acetylated. The new substances were applied successfully in stable isotope dilution assays for the simultaneous quantification of the [13C5]-labeled and unlabeled folate catabolites, p-aminobenzoyl glutamate and p-acetamidobenzoyl glutamate, along with the predominant folate vitamers in urine. The assays were based on clean-up by strong anion exchange followed by liquid chromatography-tandem mass spectrometry detection. Assay sensitivity was sufficient to detect the folate catabolites in physiologic concentrations. The limit of detection was below 0.4 and 0.3 nmol/100 g for p-aminobenzoyl glutamate isotopologues and p acetamidobenzoyl glutamate isotopologues in urine, respectively. The successful synthesis of [2H4]-p-aminobenzoyl glutamate, [2H4]-p-acetamidobenzoyl glutamate, and unlabeled p-acetamidobenzoyl glutamate and the implementation of these substances in stable isotope dilution assays allows dual-label designs that provide a more detailed insight into human folate metabolism. PMID- 24491885 TI - Quantification of vitamin A in fortified rapeseed, groundnut and soya oils using a simple portable device: comparison to high performance liquid chromatography. AB - Vitamin A deficiency is still one of the major public health problems in least developed countries. Fortification of vegetable oils is a strategy implemented worldwide to prevent this deficiency. For a fortification program to be effective, regular monitoring is necessary to control food quality in the producing units. The reference methods for vitamin A quantification are expensive and time-consuming. A rapid method should be useful for regular assessment of vitamin A in the oil industry. A portable device was compared to high-performance liquid chromatography (HPLC) for three plant oils (rapeseed, groundnut, and soya). The device presented a good linearity from 3 to 30 mg retinol equivalents per kg (mg RE.kg- 1). Its limits of detection and quantification were 3 mg RE.kg- 1 for groundnut and rapeseed oils and 4 mg RE.kg- 1 for soya oil. The intra-assay precision ranged from 1.48 % to 3.98 %, considered satisfactory. Accuracy estimated by the root mean squares error ranged from 3.99 to 5.49 and revealed a lower precision than HPLC (0.4 to 2.25). Although it offers less precision than HPLC, the device estimates quickly the vitamin A content of the tested oils from 3 or 4 to 15 mg RE.kg- 1. PMID- 24491886 TI - The challenge of setting appropriate intake recommendations for vitamin E: considerations on status and functionality to define nutrient requirements. AB - The main function of vitamin E is to protect against scavenging of reactive oxygen species; it is the primary protective agent against lipid peroxidation. Overt vitamin E deficiency is present only in patients with severe malnutrition and certain chronic diseases. The latest Recommended Dietary Allowance for vitamin E is based on the correlation between hydrogen peroxide-induced erythrocyte lysis and plasma alpha-tocopherol concentrations (Institute of Medicine, United States), or the prevention of lipid peroxidation (National Nutrition Societies of Germany, Austria and Switzerland, D-A-CH). According to the current recommendations, the reference plasma concentration for vitamin E is 12 - 46 umol/L (daily intake of 15 - 30 mg alpha-tocopherol equivalents). Epidemiological studies suggest a beneficial effect of vitamin E on cardiovascular health at a plasma concentration of 30 umol/L (a daily intake of ~ 50 IU). Vitamin E is also an important micronutrient for maintaining the immune system, especially in the elderly. A workshop was organized with the main objective to propose a concept for developing markers of status, functionality, and health in the field of nutritional research, in order to define desirable vitamin E requirements in healthy individuals. PMID- 24491887 TI - Presence of glyceraldehyde-derived advanced glycation end-products in the liver of insulin-resistant mice. AB - Insulin resistance is a fundamental feature of metabolic disorders such as metabolic syndrome. The formation of advanced glycation end-products (AGEs) is increased in patients with hyperglycemia, which results in the loss of protein function. Therefore, considerable attention has been paid to the pathological significance of AGEs in diseases associated with insulin resistance. We previously demonstrated that all-trans-retinoic acid (ATRA) ameliorated insulin resistance in mice that were fed a high-fat, high-fructose (HFHFr) diet. However, it is unclear whether the HFHFr diet increases the production of AGEs in the liver, and whether ATRA affects this production. In the present study, we investigated the production of glyceraldehyde-derived AGEs (Glycer-AGEs) in the liver of HFHFr diet-induced insulin-resistant mice using an antibody against Glycer-AGEs. We noted a remarkable formation of Glycer-AGEs with estimated molecular weights of approximately 265, 282, and 312 kDa in the liver of the insulin-resistant mice; however, the production of Glycer-AGEs was limited in the control. In accordance with previous observations, these Glycer-AGEs in mice disappeared after treatment with ATRA. These results suggest that hepatic Glycer AGEs can be useful markers for the diagnosis and therapeutic evaluation of insulin resistance and may play a pathological role in the development of insulin resistance. PMID- 24491888 TI - Effective management of hemoptysis via endobronchial application of Ankaferd hemostat. AB - Hemoptysis is symptomatic of potentially serious and life-threatening chest disease and requires urgent evaluation and treatment. The aim of this study was to evaluate the hemostatic efficacy of endobronchial application of Ankaferd Blood Stopper((r)) (ABS) solution in patients with hemoptysis. This retrospective study included 20 patients with hemoptysis in whom endobronchial ABS was applied in 25 bronchoscopic procedures. Endobronchial application of ABS was successful in 23 of the 25 bronchoscopic procedures. ABS application was repeated due to recurrent bleeding in 4 patients. This is the first case series demonstrating the endobronchial application of ABS, a novel hemostatic agent, effective in the management of bleeding, especially in local endobronchial malignant lesions. Bronchoscopic ABS application may be an alternative supportive therapeutic method in cases of uncontrolled hemoptysis. PMID- 24491889 TI - Pulmonary embolism and concomitant paradoxical embolism. A case report. AB - Although patent foramen ovale is a relatively common disease, the presence of paradoxical embolism is a rare clinical condition, representing less than 2% of arterial ischemias. We report the case of a 55-year-old male diagnosed with massive pulmonary embolism and paradoxical embolism in the right arm, secondary to patent foramen ovale. We also highlight some uncertainties in the diagnosis and treatment of patients with paradoxical embolism. PMID- 24491890 TI - [Cystathionine gamma-lyase]. AB - gamma-Cystathionase (CTH, EC: 4.4.1.1), an enzyme widely distributed in the world of prokaryotic and eukaryotic organisms, catalyzes the formation and transformations of sulfane sulfur-containing compounds and plays a pivotal role in the L-cysteine desulfuration pathway. Human, tetrameric CTH is composed of two dimers and each monomer binds pyridoxal phosphate (PLP). The gene, located on the short arm of chromosome 1, consists of 13 exons and 12 introns. As a result of alternative splicing, three isoforms of human CTH arise. Analysis of genetic variations of the CTH encoding gene showed a large number of polymorphisms. A decrease of the expression of CTH entails a drop in the level of cysteine , glutathione (GSH), taurine and hydrogen sulfide (H2S) in the cells and, more importantly, leads to cystathioninuria. H2S, endogenously formed by CTH, affects the vasodilation and regulation of blood pressure. CTH knockout mice have decreased levels of H2S, hypertension, and reduced capacity for vascular endothelium relaxation. Overexpression of the gene encoding CTH in the cells leads to increased production of H2S. H2S plays a role in protection of neurons against oxidative stress, and stimulates an increase in gamma-glutamylcysteine synthetase and thereby an increase in the level of GSH. Sulfurtransferases, including CTH, can locally prevent oxidative stress due to reversible oxidation of - SH groups in the presence of increased levels of reactive oxygen species, and reduction in the presence of GSH and/or reduced thioredoxin. PMID- 24491891 TI - [Mitogen-activated protein kinases in atherosclerosis]. AB - Intracellular signalling cascades, in which MAPK (mitogen-activated protein kinases) intermediate, are responsible for a biological response of a cell to an external stimulus. MAP kinases, which include ERK1/2 (extracellular signalling regulated kinase), JNK (c-Jun N-terminal kinase) and p 38 MAPK, regulate the activity of many proteins, enzymes and transcription factors and thus have a wide spectrum of biological effects. Many basic scientific studies have defined numerous details of their pathway organization and activation. There are also more and more studies suggesting that individual MAP kinases probably play an important role in the pathogenesis of atherosclerosis. They may mediate inflammatory processes, endothelial cell activation, monocyte/macrophage recruitment and activation, smooth muscle cell proliferation and T-lymphocyte differentiation, all of which represent crucial mechanisms involved in pathogenesis of atherosclerosis. The specific inhibition of an activity of the respective MAP kinases may prove a new therapeutic approach to attenuate atherosclerotic plaque formation in the future. In this paper, we review the current state of knowledge concerning MAP kinase-dependent cellular and molecular mechanisms underlying atherosclerosis. PMID- 24491892 TI - Antibacterial activity of selected glass ionomer cements. AB - INTRODUCTION: The aim of the paper was to determine the antibacterial activity of four glass ionomer cements against bacteria of the genera Streptococcus and Lactobacillus. MATERIAL AND METHODS: Four capsulated glass ionomer cements were applied in the study: Fuji Triage (GC), Fuji IX (GC), Ketac Molar (3M Espe) and Ketac Silver (3M Espe). Four standard bacterial strains were used to assess the antibacterial activity of the studied cements: Streptococcus mutans, S. sanguis, S. salivarius and Lactobacillus casei. The antibacterial activity was determined by the agar diffusion method. The bacterial suspension was spread with a cotton swab on TSA plates. For each material six wells (7 mm diameter, 5 mm deep) were made with a cork borer. Each well was then filled with freshly prepared cements. The results were obtained by measuring the bacterial growth inhibition zone after 1, 2, 3 and 7 days. RESULTS: Fuji Triage cement inhibited the growth of all bacterial strains. Fuji IX cement demonstrated the most potent antibacterial activity against S. sanguis. Ketac Molar showed antibacterial activity against S. sanguis and S. salivarius, whereas Ketac Silver was efficient against S. mutans as well. Neither of the Ketac cements inhibited growth of the standard L. casei strain. DISCUSSION: Antibacterial activity of glass ionomer cements has attracted the interest of scientists in recent years. Most authors, including us, carried out experiments using the agar diffusion method and demonstrated antibacterial activity of glass ionomer cements. Different antibacterial activity of glass ionomer cements, observed in our study and studies of other authors, depended on the evaluated cement, bacterial strain and period of evaluation. PMID- 24491893 TI - [Amylin under examination. Fibrillogenic polypeptide hormone of the pancreas]. AB - In patients or animals affected by type 2 diabetes mellitus (DM2, non-insulin dependent diabetes mellitus [NIDDM]) some pathological deposits, called amyloid, are observed among cells of islets of Langerhans. Among other constituents, deposits consist of an insoluble, fibrillar form of peptide neurohormone called amylin, produced by pancreatic beta cells. It is thought that formation of fibrillar deposits of misfolded and aggregated peptide is highly toxic to beta cells and leads to cell dysfunction, cell loss, pancreas destruction and progress of the disease. This relatively small 37-amino acid peptide constitutes a serious scientific, research and to some extent a medical problem. This article presents amylin as a hormone, neurohormone and as a fibrillating molecule which participates in amyloid deposit formation in human and animal pancreas. The role of some amino acids important for fibril formation has been highlighted. PMID- 24491894 TI - [Role of Th17 lymphocytes in pathogenesis of colorectal cancer]. AB - Colorectal cancer (CRC) is estimated to be the first leading cause of death from cancer among men and women in the EU. Every year in Poland, 15,254 cases of CRC are diagnosed, and 10,501 patients die of the disease, making it the second leading cause of death from cancer. In more than 90% of cases, the disease begins as adenomatous polyps with epithelial dysplasia as a common feature. Inflammatory bowel diseases (IBD), a group of chronic inflammatory diseases of the gastrointestinal tract characterized by remissions and relapses, constitute an independent risk factor of CRC development. CRC developing in IBD patients, however, has features distinct from sporadic cancer, suggesting the influence of unique factors. The high risk of CRC in IBD patients probably results from chronic inflammation. In most cases, neoplastic lesions arise within the inflamed gastrointestinal mucosa during the process of re-epithelization, which is a healing response to ulceration. The recently discovered Th17 lymphocytes, which demonstrate strong pro-inflammatory capabilities, might link the two diseases. Th17 lymphocytes produce a number of pro-inflammatory cytokines, such as interleukin (IL)-17A, IL-17F, IL-21, IL-22 and tumor necrosis factor (TNF)-a, and play a key role in mucosal defense against various pathogens. Numerous observations suggest that Th17 lymphocytes are involved in pathogenesis of different autoimmune diseases and pathologic inflammatory states. Mounting evidence suggests that Th17 cells contribute to the pathogenesis of IBD and CRC. However, their precise role in both diseases is unknown. PMID- 24491895 TI - [Microbiological diagnosis of infections caused by Campylobacter jejuni and Campylobacter coli in humans]. AB - Campylobacter jejuni and Campylobacter coli are Gram-negative, microaerophilic bacteria which are worldwide in distribution, causing a zoonotic disease in humans called campylobacteriosis. These infections are mainly caused by eating contaminated food products, most often improperly prepared poultry meat. Campylobacteriosis usually takes the form of gastroenteritis, or inflammation of the intestines, and the characteristic symptoms are watery-mucous diarrhea often with the presence of blood in stool, nausea, vomiting, abdominal pain and fever. The epidemiological data suggest that in Europe, as well as in North America, bacteria of the genus Campylobacter, especially C. jejuni and C. coli, are the most commonly isolated pathogens in infections of the gastrointestinal tract in humans. Epidemiological data indicate that these organisms are a much more common cause of acute diarrhea, mostly in young children, than Salmonella and Yersinia. The lack of specific symptoms makes the diagnosis of campylobacteriosis necessary to carry out specialized microbiological diagnostics. Because so far these studies are performed in our country only in a few laboratories, the overwhelming number of cases of campylobacteriosis are not recorded in Polish epidemiological statistics. The purpose of this paper is to discuss issues related to the microbiological diagnosis of infections caused by C. jejuni and C. coli. It also describes the basic epidemiological and clinical data, as well as current treatment of campylobacteriosis. PMID- 24491896 TI - [The role of vascular endothelial growth factor in inflammatory processes]. AB - The vascular endothelial growth factor (VEGF) is produced by different types of cells and has a major role in both, physiological and pathological angiogenesis. On the one hand VEGF is a strong mitotic and chemotactic factor for the endothelial cells, stimulating thus formation of new vessels, while on the other, it enhances the vascular endothelium permeability of the existing blood vessels which contributes to development and persistence of the inflammatory conditions. In the latter its activity is by 50 000 times higher than that of histamine. VEGF facilitates formation of oedema and leukocyte migration from the circulation to the site of inflammation. VEGF is also important in remodeling of the extracellular matrix. Moreover, it has an important significance in regulation of the immunological response, therefore plays a role in autoaggressive phenomena as well as immediate- and delayed-type hypersensitivity. Its role in the pathogenesis of immunological and inflammatory diseases, including allergy, asthma and different skin disorders has been indicated. PMID- 24491897 TI - TGF-beta1 and granulocyte elastase in the evaluation of activity of inflammatory bowel disease. A pilot study. AB - INTRODUCTION: The aim was to assess the usefulness of TGF-beta1 and elastase in the evaluation of activity of ulcerative colitis (UC) and Crohn's disease (CD). MATERIAL AND METHODS: 32 patients diagnosed with UC, 31 with CD and 30 healthy volunteers were enrolled in this study. Diagnosis of the disease was confirmed by videocolonoscopy and histopathological evaluation of intestinal biopsies. Disease activity was assessed by use of the Mayo Scoring System for Assessment of Ulcerative Colitis Activity in UC patients and by CDAI in CD patients. hsCRP was determined by the immunonephelometric method, TGF-beta1 and elastase plasma concentration by ELISA. The results of the study were analyzed using Statistica and R statistical language. RESULTS: In UC a positive correlation between disease activity and platelet level, hsCRP and TGF-beta1 concentration was noted. Elastase concentration in UC patients was significantly higher than in CD, but there was no correlation with the activity of the disease. In CD patients we observed a positive correlation between disease activity and leukocytes, platelet levels and elastase concentration, and a very low correlation with hsCRP and TGF beta1. DISCUSSION: Determination of TGF-beta1 can be used for evaluation of inflammatory activity in UC and it is connected with elevated concentrations of CRP and platelets. To a lower extent TGF-beta1 can also be used for evaluation of inflammatory activity in CD. Examination of elastase concentration may be useful in the assessment of CD activity. Plasma elastase concentration may be helpful in UC and CD differentiation. The preliminary results of this investigation seem promising; nevertheless, more studies are necessary. PMID- 24491898 TI - [Bioactive lipids in kidney physiology and pathophysiology]. AB - Lipids not only have structural functions, but also play an important role as signaling and regulatory molecules and participate in many cellular processes such as proliferation, differentiation, migration, and apoptosis. Bioactive lipids act both as extracellular mediators, which are associated with receptors on the surface of cells, and intracellular mediators triggering different signal pathways. They are present and active in physiological conditions, and are also involved in the pathogenesis of inflammation, asthma, cancer, diabetes, and hypertension. Bioactive lipids such as derivatives of arachidonic acid and sphingolipids have an important role in renal development, physiology and in many renal diseases. Some of them are potential indicators of kidney damage degree and/or function of the transplanted kidneys. PMID- 24491899 TI - [The role of gut microbiota in the pathogenesis of obesity]. AB - Obesity is a disease that develops as a result of long-term positive energy balance. In recent years, the influence of gut microflora composition, as a potential factor affecting the energy balance and contributing to fat accumulation, has been studied. It seems that bacteria can affect host energy balance through several mechanisms, such as increased fermentation of undigested polysaccharides and obtaining extra energy from the portion of food, reduced expression of FIAF (fasting-induced adipocyte factor) in the enterocytes with inhibitory activity towards intestinal lipoprotein lipase, and the increased release of peptide YY that slows the intestinal motility. It is also believed that changes in the composition of gut microflora may be one of the factors that induce systemic microinflammation in the obese, an important link in the pathogenesis of obesity related complications, including dyslipidaemia, hypertension and type 2 diabetes. However, the results of previous studies are inconclusive. Many of them have been carried out in an animal model and were not confirmed in studies involving humans. These discrepancies may be due to different composition of the diet, distinct physiological gut microflora and the methodology used in these studies. The present article reviews the current literature on the potential role of gut microflora in the pathogenesis of obesity. PMID- 24491900 TI - [Endothelial dysfunction in patients with primary hypertension and hyperhomocysteinemia]. AB - It is widely accepted that endothelial dysfunction is the basis of the development of cardiovascular diseases, including hypertension. With regard to hypertension, endothelial dysfunction is concerned mainly with impaired vascular expansion; however, it is also related to the intensity of the development of atherosclerosis and thrombosis. Among the factors that cause damage to the endothelium, along with classic risk factors, is hyperhomocysteinemia. Hyperhomocysteinemia promotes the formation of oxygen radicals, lowering the oxidation-reduction potential, adversely affects the biosynthesis and function of vasodilator factors in the vascular wall, contributes to the inhibition of endothelial cell division with intense myocyte proliferation and migration, and impairs production of extracellular matrix components in the vascular wall. In addition, high levels of homocysteine and its derivatives contribute to the modification of LDL and HDL particles, inflammation and disorders in coagulation and fibrinolysis. Biochemical effects of the impact of hyperhomocysteinemia on endothelium can lead to damage of endothelial cells, dysfunction of diastolic function of vessels and reduction of their flexibility through its influence on vascular wall remodeling. These changes lead to an increase in blood pressure, strengthening the development of hypertension and target organ damage in patients with this disease. PMID- 24491901 TI - [Carbon monoxide in human physiology--its role in the gastrointestinal tract]. AB - Carbon monoxide (CO) is produced endogenously in the body as a byproduct of heme degradation catalyzed by the action of heme oxygenase (HO) enzymes. An inducible form, HO-1, responds to many factors such as oxidative stress, hypoxia, heme, bacterial endotoxins, proinflammatory cytokines and heavy metals. HO-2 is constitutively expressed under basal conditions in most human tissues including brain and gonads. Recent data show that CO is a gaseous mediator with multidirectional biological activity. It is involved in maintaining cellular homeostasis and many physiological and pathophysiological processes. CO shares many properties with another established vasodilatator and neurotransmitter - nitric oxide (NO). Both CO and NO are involved in neural transmission, modulation of blood vessel function and inhibition of platelet aggregation. The binding to guanylate cyclase, stimulation of the production of cGMP, activation of Ca2+ dependent potassium channels and stimulation of mitogen-activated protein kinases are well known cellular targets of CO action. Since CO is nowadays a subject of extensive investigation in many centers worldwide, the aim of the present study was to present the role of CO in various aspects of human physiology with special focus on its activity in the gastrointestinal tract. PMID- 24491902 TI - Influence of polyphenol extract from evening primrose (Oenothera paradoxa) seeds on human prostate and breast cancer cell lines. AB - There is growing interest in plant polyphenols which exhibit pleiotropic biological activities, including anti-inflammatory, antioxidant, and anticancer effects. The objective of our study was to evaluate the influence of an evening primrose extract (EPE) from defatted seeds on viability and invasiveness of three human cell lines: PNT1A (normal prostate cells), DU145 (prostate cancer cells) and MDA-MB-231 (breast cancer cells). The results revealed that after 72 h of incubation the tested extract reduced the viability of DU 145 and MDA-MB-231 with IC50 equal to 14.5 MUg/mL for both cell lines. In contrast, EPE did not inhibit the viability of normal prostate cells. Furthermore, EPE reduced PNT1A and MDA-MB 231 cell invasiveness; at the concentration of 21.75 MUg/mL the suppression of invasion reached 92% and 47%, respectively (versus control). Additionally, zymographic analysis revealed that after 48 h of incubation EPE inhibited metalloproteinase-2 (MMP-2) and metalloproteinase-9 (MMP-9) activities in a dose dependent manner. For PNT1A the activities of MMP-2 and MMP-9 decreased 4- and 2 fold, respectively, at EPE concentration of 29 MUg/mL. In the case of MDA-MB-231 and DU 145 the decrease in MMP-9 activity at EPE concentration of 29 MUg/mL was 5.5-fold and almost 1.9-fold, respectively. In conclusion, this study suggests that EPE may exhibit antimigratory, anti-invasive and antimetastatic potential towards prostate and breast cancer cell lines. PMID- 24491903 TI - Photodynamic therapy in head and neck cancer. AB - Photodynamic therapy (PDT) is a special type of treatment involving the use of a photosensitizer or a photosensitizing agent along with a special type of light, which, combined together, induces production of a form of oxygen that is used to kill surrounding cells in different areas of the human body. Specification of the head and neck region requires different approaches due to the surrounding of vital structures. PDT can also be used to treat cells invaded with infections such as fungi, bacteria and viruses. The light beam placed in tumor sites activates locally applied drugs and kills the cancer cells. Many studies are taking place in order to invent better photosensitizers, working on a larger scale and to treat deeply placed and larger tumors. It seems that PDT could be used as an alternative surgical treatment in some tumor types; however, all clinicians should be aware that the surgical approach is still the treatment of choice. PDT is a very accurate and effective therapy, especially in early stages of head and neck squamous cell carcinomas (HNSCC), and can greatly affect surgical outcomes in cancerous patients. We present a detailed review about photosensitizers, their use, and therapeutic advantages and disadvantages. PMID- 24491904 TI - Modulation of NF-kB transcription factor activation by Molluscum contagiosum virus proteins. AB - Molluscum contagiosum virus is a human and animal dermatotropic pathogen, which causes a severe disease in immunocompromised individuals. MCV belongs to the Poxviridae family whose members exert immunomodulatory effects on the host antiviral response. Poxviruses interfere with cell signaling pathways that lead to the activation of nuclear factor kB, a pleiotropic transcription factor which is crucial for regulation of the immune response, the cell cycle and apoptosis. In resting cells, NF-kappaB is present in the cytoplasm, where it is associated with inhibitor kappaB. Upon stimulation by activators, such as proinflammatory cytokines and bacterial or viral products, the inhibitory protein undergoes phosphorylation and proteasomal degradation. NF-kappaB, in turn, translocates to the nucleus, where it regulates the transcription of various genes that are essential for processes mentioned above. Since poxviruses replicate exclusively in the cell cytoplasm, NF-kB became a good target for poxviral immunomodulation. MCV encodes various proteins which interfere with the signaling pathways that lead to the activation of NF-kappaB. Ligand inhibitor encoded by MCV, MC54, binds interleukin-18 and inhibits interferon-gamma production. Other MCV proteins, MC159 and MC160, belong to intracellular inhibitors of NF-kappaB and are members of viral FLICE-inhibitory proteins (vFLIPs). MC159 protein encoded by MCV was shown to inhibit apoptosis of virus-infected cells. Such interactions serve immune evasion and are responsible for the persistence of MCV. PMID- 24491905 TI - Prevention of influenza infection--a Polish perspective. AB - Influenza is a viral respiratory illness that causes high morbidity and significant mortality in humans. Costs associated with influenza in terms of human suffering are immeasurable and the economic costs are very high. Every year, according to the World Health Organization (WHO), 5-25% of the global population suffers from infection with influenza and influenza-like viruses and between 500 thousand and one million individuals of all ages die from multiple organ complications, irrespective of the geographic location. Influenza vaccination is still neglected and the percentage of the global population vaccinated remains low. The first authorization for the use of influenza vaccines in humans was issued in 1941. Currently, many varieties of influenza vaccine are available, containing either fragments of inactivated influenza virus or live vaccine which consists of attenuated virus. The influenza vaccine is most often developed in chick embryos or less frequently in tissue culture such as MDCK and Vero. A variety of inactivated vaccines are registered in Poland. Due to the mutability of the virus, it is not yet possible to develop a universal vaccine, nor can the disease be eradicated; however, prevention is possible by inoculating the greatest percentage of the global population. According to the WHO, Poland is in the penultimate position in Europe in terms of the percentage of the population vaccinated. In the last epidemic season of 2012/2013 only 3.75% of the Polish population was immunized. PMID- 24491906 TI - [Mechanisms of osteoporosis development in patients with rheumatoid arthritis]. AB - Rheumatoid arthritis (RA) is progressive, chronic, autoimmune, systemic connective tissue disease. It affects 0,5-1% population. RA manifests as inflammation of symmetrical mainly small and medium joints with synovial hypertrophy, extra-articular lesions and systemic complications. Depending on intensity and duration of RA in imaging studies the patients demonstrate narrowing of articular fissures, presence of geodes, erosions, subluxations and/or synostoses. Progressive bone mass loss in the joint involved by the morbid process and in the entire skeleton was also described. Local (periarticular) osteoporosis is linked to the presence of cytokines and growth factors, which regulate reciprocal interactions between osteoclasts, osteoblasts and immune system cells. In the inflamed joint accumulate synoviocytes of fibroblast phenotype, synoviocytes of macrophage phenotype, antigen presenting cells, lymphocytes T, activated lymphocytes B, plasma cells and neutrophils. Increased expression of receptor activator of nuclear factor kappaB (RANKL), macrophage colony stimulating factor (M-CSF), presence of TNFalpha, IL-1, IL-6, IL-7, IL-17 influences pathological loss of bone mass. Rheumatoid arthritis is an important risk factor of generalised osteoporosis and fractures, involved in FRAX (fracture risk assessment) algorythm. Generalised osteoporosis in patients with RA has a multifactorial aetiology. Its development reflects effects of both: factors linked to the disease (presence of proinflammatory cytokines, disability of the patients, applied therapy) and classical risk factors of osteoporosis (e.g. advanced age, sex, post-menopausal period, genetic predisposition, low peak bone mass, low body weight, deficiency of calcium and vitamin D, tobacco smoking). PMID- 24491907 TI - [From precursor to reprogrammed cells: evolution of cardiomyoplasty]. AB - Myocardial infarction is underoxygenation-driven limited necrosis of heart tissues which results in elimination of ca. 0.5 to 1 billion spontaneously contracting cardiomyocytes (CM). Since the ability of human heart to regenerate is limited, efforts have been undertaken to increase the number of cardiomyocytes in post-infarction myocardium. Theoretically, such proposals might involve transplantation of 1) skeletal myoblasts and cardiomyocytes, or 2) progenitor/stem cells, theoretically capable of differentiating into cardiomyocytes, or 3) pluripotent cells such as embryonal stem cells (ESC) and induced pluripotent stem cells (iPSC) differentiating into cardiomyocytes. The efforts to increase CM could also involve 4) in situ reprogramming of fibroblasts into active cardiomyocyte-like cells, or 5) stimulating in situ proliferation of cardiomyocytes using pharmacological agents. Only three proposals merit closer scrutiny (2, 4 and 5). However, preclinical and clinical data have demonstrated weak ability of progenitor cells to differentiate (proposal 2). Nevertheless, transplanted cell-induced paracrine effects accompanying such therapy do improve functioning of the damaged heart muscle. The proposals that would permit the number of CM to be increased include in situ reprogramming of fibroblasts into active cardiomyocytes (proposal 4), as well as in situ stimulation of quiescent cardiomyocytes' proliferation (proposal 5). It appears that an optimized therapeutic solution (increasing left ventricular ejection fraction and decreasing the post-infarct scar) might combine agents stimulating paracrine effects and reprogramming of fibroblasts. PMID- 24491909 TI - Interferon gamma peptidomimetic targeted to hepatic stellate cells ameliorates acute and chronic liver fibrosis in vivo. AB - Hepatic stellate cells play a crucial role in the pathogenesis of hepatic fibrosis. Thus, pharmacological inhibition of pro-fibrotic activities of these cells might lead to an effective therapy for this disease. Among the potent anti fibrotics, interferon gamma (IFNgamma), a proinflammatory cytokine, is highly efficacious but it failed in clinical trials due to the poor efficacy and multiple adverse effects attributed to the ubiquitous IFNgamma receptor (IFNgammaR) expression. To resolve these drawbacks, we chemically synthesized a chimeric molecule containing (a) IFNgamma signaling peptide (IFNgamma peptidomimetic, mimgamma) that retains the agonistic activities of IFNgamma but lacks an extracellular receptor recognition sequence for IFNgammaR; coupled via heterobifunctional PEG linker to (b) bicyclic platelet derived growth factor beta receptor (PDGFbetaR)-binding peptide (BiPPB) to induce internalization into the stellate cells that express PDGFbetaR. The synthesized targeted IFNgamma peptidomimetic (mimgamma-BiPPB) was extensively investigated for its anti fibrotic and adverse effects in acute and chronic CCl4-induced liver fibrosis models in mice. Treatment with mimgamma-BiPPB, after the onset of disease, markedly inhibited both early and established hepatic fibrosis as reflected by a reduced intrahepatic alpha-SMA, desmin and collagen-I mRNA expression and protein levels. While untargeted mimgamma and BiPPB had no effect, and native IFNgamma only induced a moderate reduction. Additionally, no off-target effects, e.g. systemic inflammation, were found with mimgamma-BiPPB, which were substantially observed in mice treated with native IFNgamma. The present study highlights the beneficial effects of a novel BiPPB mediated cell-specific targeting of IFNgamma peptidomimetic to the disease-inducing cells and therefore represents a highly potential therapeutic approach to treat fibrotic diseases. PMID- 24491908 TI - Tardive dyskinesia in relation to estimated dopamine D2 receptor occupancy in patients with schizophrenia: analysis of the CATIE data. AB - OBJECTIVE: The objective of this study was to evaluate the relationship between antipsychotic-induced tardive dyskinesia (TD) and estimated dopamine D2 receptor occupancy levels in patients with schizophrenia, using the dataset from the Clinical Antipsychotic Trials in Intervention Effectiveness (CATIE). METHODS: The dataset from 218 subjects (risperidone, N=78; olanzapine, N=100; ziprasidone, N=40) who presented with a score of zero on the Abnormal Involuntary Movement Scale (AIMS) at baseline in Phase 1 of the CATIE study, and remained for >=6months, was used. Peak and trough dopamine D2 receptor occupancy levels on the day of the AIMS assessment at the endpoint were estimated from plasma antipsychotic concentrations, using population pharmacokinetic analysis and our D2 prediction model. The estimated dopamine D2 receptor occupancy levels were compared between patients who presented an AIMS score of >=2 at endpoint and those with a score of zero, using the Mann-Whitney U test. RESULTS: Estimated dopamine D2 receptor occupancy levels at trough were significantly higher in subjects who developed involuntary movements (N=23) than those who did not (N=195) (71.7+/-14.4% vs. 64.3+/-19.3%, p<0.05) while no significant difference was found in the estimated peak D2 receptor occupancy between them (75.4+/-8.7% vs. 72.1+/-9.9%, p=0.07). When the analyses were separately conducted for the three drugs, there were no significant differences in estimated peak or trough D2 occupancy although the values were consistently numerically higher among those developing involuntary movements. CONCLUSION: Greater dopamine D2 receptor blockade with antipsychotics at trough might increase the risk of tardive involuntary movements although this finding needs to be replicated in larger trials. PMID- 24491910 TI - A chondromimetic microsphere for in situ spatially controlled chondrogenic differentiation of human mesenchymal stem cells. AB - Human mesenchymal stem cells (hMSCs) have been identified as a viable cell source for cartilage tissue engineering. However, to undergo chondrogenic differentiation hMSCs require growth factors, in particular members of the transforming growth factor beta (TGF-beta) family. While in vitro differentiation is feasible through continuous supplementation of TGF-beta3, mechanisms to control and drive hMSCs down the chondrogenic lineage in their native microenvironment remain a significant challenge. The release of TGF-beta3 from an injectable microsphere composed of the cartilage-associated extracellular matrix molecule hyaluronan represents a readily translatable approach for in situ differentiation of hMSCs for cartilage repair. In this study, chondromimetic hyaluronan microspheres were used as a growth factor delivery source for hMSC chondrogenesis. Cellular compatibility of the microspheres (1.2 and 14.1 MUm) with hMSCs was shown and release of TGF-beta3 from the most promising 14.1 MUm microspheres to control differentiation of hMSCs was evaluated. Enhanced accumulation of cartilage-associated glycosaminoglycans by hMSCs incubated with TGF-beta3-loaded microspheres was seen and positive staining for collagen type II and proteoglycan confirmed successful in vitro chondrogenesis. Gene expression analysis showed significantly increased expression of the chondrocyte-associated genes, collagen type II and aggrecan. This delivery platform resulted in significantly less collagen type X expression, suggesting the generation of a more stable cartilage phenotype. When evaluated in an ex vivo osteoarthritic cartilage model, implanted hMSCs with TGF-beta3-loaded HA microspheres were detected within cartilage fibrillations and increased proteoglycan staining was seen in the tissue. In summary, data presented here demonstrate that TGF-beta3 bound hyaluronan microspheres provide a suitable delivery system for induction of hMSC chondrogenesis and their use may represent a clinically feasible tissue engineering approach for the treatment of articular cartilage defects. PMID- 24491911 TI - Evaluation of the accuracy of smartphone medical calculation apps. AB - BACKGROUND: Mobile phones with operating systems and capable of running applications (smartphones) are increasingly being used in clinical settings. Medical calculating applications are popular mhealth apps for smartphones. These include, for example, apps that calculate the severity or likelihood of disease based clinical scoring systems, such as determining the severity of liver disease, the likelihood of having a pulmonary embolism, and risk stratification in acute coronary syndrome. However, the accuracy of these apps has not been assessed. OBJECTIVE: The objective of this study was to evaluate the accuracy of smartphone-based medical calculation apps. METHODS: A broad search on Google Play, BlackBerry World, and the iTunes App Store was conducted to find medical calculation apps for smartphones. The list of apps was narrowed down based on inclusion and exclusion criteria focusing on functions thought to be relevant by a panel of general internists (number of functions =13). Ten case values were inputted for each function and were compared to manual calculations. For each case, the correct answer was assigned a score of 1. A score for the 10 cases was calculated based on the accuracy of the results for each function on each app. RESULTS: We tested 14 apps and 13 functions for each app if that function was available. We conducted 10 cases for each function for a total of 1240 tests. Most functions tested on the apps were accurate in their results with an overall accuracy of 98.6% (17 errors in 1240 tests). In all, 6 of 14 (43%) apps had 100% accuracy. Although 11 of 13 (85%) functions had perfect accuracy, there were issues with 2 functions: the Child-Pugh scores and Model for End-Stage Liver Disease (MELD) scores on 8 apps. Approximately half of the errors were clinically significant resulting in a significant change in prognosis (8/17, 47%). CONCLUSIONS: The results suggest that most medical calculating apps provide accurate and reliable results. The free apps that were 100% accurate and contained the most functions desired by internists were CliniCalc, Calculate by QxMD, and Medscape. When using medical calculating apps, the answers will likely be accurate; however, it is important to be careful when calculating MELD scores or Child-Pugh scores on some apps. Despite the few errors found, greater scrutiny is warranted to ensure full accuracy of smartphone medical calculator apps. PMID- 24491912 TI - C-type lectin receptor SIGNR1 expressed on peritoneal phagocytic cells with an immature dendritic cell-like phenotype is involved in uptake of oligomannose coated liposomes and subsequent cell maturation. AB - The mannose-binding C-type lectin receptor SIGNR1 appears to be a structural and functional murine homologue of human DC-SIGN, but expression of SIGNR1 and its function in induction of immune responses in dendritic cell (DC) lineages remains unclear. In this study, we demonstrated expression and function of SIGNR1 on mouse peritoneal phagocytic cells with an immature DC-like phenotype. Analysis of these cells with a series of cell lineage markers indicated that CD11b(+)F4/80(-) phagocytic cells expressed costimulatory molecules, the DC marker CD83, and MHC class II, suggesting an immature DC-like phenotype. These immature peritoneal DC like cells expressed low levels of SIGNR1, in addition to another mannose-binding C-type lectin, CD206. The immature peritoneal DC-like cells ingested oligomannose or Lewis antigen-coated liposomes in vitro through SIGNR1. Following in vitro uptake of oligomannose-coated liposomes, SIGNR1, but not CD206, disappeared rapidly from the surface of the cells. In response to in vitro uptake of OMLs, the peritoneal DC-like cells matured with increasing expression of CD11c, CD86, and MHC class II. Thus, low levels of SIGNR1 expressed on mouse peritoneal phagocytic cells with an immature DC-like phenotype are primarily involved in uptake of mannose- or fucose-decorated particles, and this uptake leads to cell maturation. PMID- 24491913 TI - Inhibition of Notch signaling leads to increased intracellular ROS by up regulating Nox4 expression in primary HUVECs. AB - The essential roles of Notch pathway in angiogenesis have been reported for years. However, how Notch pathway plays its role in regulating endothelial cells remains largely unknown. In this study we found that blockade of Notch signaling with a gamma-secretase inhibitor increased reactive oxygen species (ROS) in primary human umbilical vein endothelial cells (HUVECs) under both normaxic and ischemia/reperfusion (I/R) conditions. Abruption of ROS generation with ROS scavengers or specific inhibitors of ROS production in HUVECs abolished Notch blockade-induced HUVEC proliferation, migration and adhesion, suggesting that the regulation of Notch pathway on endothelial cell behavior is at least partially dependent on its down-regulation of ROS level. We further showed that the enhanced generation of ROS after blocking Notch signal was accompanied by augmented expression of Nox4, which led to increased phosphorylation of VEGFR2 and ERK in HUVECs. In summary, our results have shown that Notch signaling regulates ROS generation by suppressing Nox4, and further modulates endothelial cell proliferation, migration and adhesion. PMID- 24491914 TI - Enhancing lipid productivity by co-cultivation of Chlorella sp. U4341 and Monoraphidium sp. FXY-10. AB - To improve lipid productivity, co-cultivation of Chlorella sp. U4341 and Monoraphidium sp. FXY-10 for lipid production was studied. Compared with mono cultivations, co-cultivation of the two microalgae significantly increased the accumulation of total biomass and total lipid yield, and enhanced the lipid productivity (29.52 mg L(-1) d(-1)). Fatty acid compositions significantly varied in different cultivations. The content of C18 fatty acids in co-cultivation significantly increased, especially for oleic acid (32.45%) and linolenic acid (10.03%) compared with that in mono-cultivation. Moreover, high saturated and monounsaturated fatty acids (55.85%) were obtained in co-cultivation, which suggests their potential as a biodiesel feedstock. PMID- 24491915 TI - Analysis of the correlation between dipeptides and taste differences among soy sauces by using metabolomics-based component profiling. AB - Characterizing the relationships between the components and taste differences among soy sauces can help evaluate and improve the quality of soy sauces. Although previous studies have reported that certain taste-active dipeptides, the relationships between taste differences and dipeptides of soy sauces are unknown. Therefore, our objective in this study was to investigate the correlations between the dipeptides and the taste differences among soy sauces. To analyze the dipeptides, we constructed an analytical method using liquid chromatography/tandem mass spectrometry (LC/MS/MS) in multiple reaction monitoring mode. Based on this method, we detected 237 dipeptides, the largest number ever detected in soy sauce research. Next, orthogonal projections to latent structures regressions were performed. The data matrix of components, including dipeptides and other low-molecular-weight hydrophilic components obtained from gas chromatography/mass spectrometry (GC/MS), served as explanatory variables (366 in total), whereas a sensory data matrix obtained using quantitative descriptive analysis served as the response variable. The accuracy of models for the sweetness and saltiness differences constructed using the LC/MS/MS and GC/MS data matrix were higher than did models constructed using only the GC/MS data matrix. As a result of investigation of the correlation between the dipeptides and taste differences among soy sauces by using variable importance in the projection (VIP) score, many dipeptides showed the high correlation with taste differences. Specifically, Ile-Gln, Pro-Lys, Ile-Glu, Thr Phe, and Leu-Gln showed the high VIP score on sweet differences. This study is the first report that reveals the correlations between the dipeptides and taste differences among soy sauces. PMID- 24491916 TI - Anaphylactic shock caused by sting of crown-of-thorns starfish (Acanthaster planci). AB - A 40s-year-old woman with previous history of injury due to contact with crown-of thorns starfish, Acanthaster planci, was stung on the right middle finger. After immediately losing consciousness, she died 13 h after injury despite intensive medical treatment. Examination of the respiratory system revealed narrowing due to severe edema of the laryngopharynx, as well as alveolar hemorrhage, eosinophilic infiltration, and extensive neutrophil and eosinophil aggregation in the intravascular lumen of the lungs. Examination of the liver revealed severe diffuse hepatocellular necrosis and extremely high levels of liver transaminases, indicating severe liver damage. Based on these findings, we concluded that she had died from anaphylactic shock induced by circulation of crown-of-thorns starfish venom in the bloodstream. Injurious contact with the spine of the crown of-thorns starfish can cause severe symptoms as well as systematic reactions, including anaphylaxis. To our knowledge, this is the first case of anaphylactic shock or death caused by human contact with the crown-of-thorns starfish reported in the English-language literature. Although rare, anaphylaxis due to injury by marine animals is potentially fatal. Saving lives requires providing education regarding prevention and enabling prompt response to possible anaphylaxis, including preparation of adrenaline for auto-injection. PMID- 24491917 TI - A novel receptor cross-talk between the ATP receptor P2Y2 and formyl peptide receptors reactivates desensitized neutrophils to produce superoxide. AB - Neutrophils express several G-protein coupled receptors (GPCRs) and they cross regulate each other. We described a novel cross-talk mechanism in neutrophils, by which signals generated by the receptor for ATP (P2Y2) reactivate desensitized formyl peptide receptors (FPRs) so that these ligand-bound inactive FPRs resume signaling. At the signaling level, the cross-talk was unidirectional, i.e., P2Y2 ligation reactivated FPR, but not vice versa and was sensitive to the phosphatase inhibitor calyculinA. Further, we show that the cross talk between P2Y2 and FPR bypassed cytosolic Ca(2+) transients and did not rely on the actin cytoskeleton. In summary, our data demonstrate a novel cross-talk mechanism that results in reactivation of desensitized FPRs and, an amplification of the neutrophil response to ATP. PMID- 24491919 TI - MDMA induces cardiac contractile dysfunction through autophagy upregulation and lysosome destabilization in rats. AB - The underlying mechanisms of cardiotoxicity of 3,4 methylenedioxymethylamphetamine (MDMA, "ecstasy") abuse are unclear. Autophagy exerts either adaptive or maladaptive effects on cardiac function in various pathological settings, but nothing is known on the role of autophagy in the MDMA cardiotoxicity. Here, we investigated the mechanism through which autophagy may be involved in MDMA-induced cardiac contractile dysfunction. Rats were injected intraperitoneally with MDMA (20mg/kg) or saline. Left ventricular (LV) echocardiography and LV pressure measurement demonstrated reduction of LV systolic contractility 24h after MDMA administration. Western blot analysis showed a time-dependent increase in the levels of microtubule-associated protein light chain 3-II (LC3-II) and cathepsin-D after MDMA administration. Electron microscopy showed the presence of autophagic vacuoles in cardiomyocytes. MDMA upregulated phosphorylation of adenosine monophosphate-activated protein kinase (AMPK) at Thr172, mammalian target of rapamycin (mTOR) at Thr2446, Raptor at Ser792, and Unc51-like kinase (ULK1) at Ser555, suggesting activation of autophagy through the AMPK-mTOR pathway. The effects of autophagic inhibitors 3 methyladenine (3-MA) and chloroquine (CQ) on LC3-II levels indicated that MDMA enhanced autophagosome formation, but attenuated autophagosome clearance. MDMA also induced release of cathepsins into cytosol, and western blotting and electron microscopy showed cardiac troponin I (cTnI) degradation and myofibril damage, respectively. 3-MA, CQ, and a lysosomal inhibitor, E64c, inhibited cTnI proteolysis and improved contractile dysfunction after MDMA administration. In conclusion, MDMA causes lysosome destabilization following activation of the autophagy-lysosomal pathway, through which released lysosomal proteases damage myofibrils and induce LV systolic dysfunction in rat heart. PMID- 24491920 TI - The dynamic spindle matrix. AB - Chromosome segregation during mitosis is mediated by the mitotic spindle, a structure composed of microtubules associated with a variety of proteins. Additionally, a distinct biochemical milieu, the 'spindle matrix', has long been proposed to assist this process and recent work provided compelling evidence for its existence in living animal cells. Here we focus on the dynamic properties of such a matrix, highlighting its roles in the spatial and temporal control of mitotic fidelity in respect to recent findings in different systems. Based on these findings and on theoretical principles behind molecular crowding, we challenge the idea of the spindle matrix as one functional entity and propose that some observed phenomena associated with this elusive structure could simply be a consequence of intrinsic cellular architecture and cytoplasmic 'compartmentalization' during mitosis. PMID- 24491918 TI - HIV-1 stimulates nuclear entry of amyloid beta via dynamin dependent EEA1 and TGF beta/Smad signaling. AB - Clinical evidence indicates increased amyloid deposition in HIV-1-infected brains, which contributes to neurocognitive dysfunction in infected patients. Here we show that HIV-1 exposure stimulates amyloid beta (Abeta) nuclear entry in human brain endothelial cells (HBMEC), the main component of the blood-brain barrier (BBB). Treatment with HIV-1 and/or Abeta resulted in concurrent increase in early endosomal antigen-1 (EEA1), Smad, and phosphorylated Smad (pSmad) in nuclear fraction of HBMEC. A series of inhibition and silencing studies indicated that Smad and EEA1 closely interact by influencing their own nuclear entry; the effect that was attenuated by dynasore, a blocker of GTP-ase activity of dynamin. Importantly, inhibition of dynamin, EEA1, or TGF-beta/Smad effectively attenuated HIV-1-induced Abeta accumulation in the nuclei of HBMEC. The present study indicates that nuclear uptake of Abeta involves the dynamin-dependent EEA1 and TGF-beta/Smad signaling pathways. These results identify potential novel targets to protect against HIV-1-associated dysregulation of amyloid processes at the BBB level. PMID- 24491921 TI - Estimating the correlation between concentrations of two species of bacteria with censored microbial testing data. AB - Indicator organisms, such as generic Escherichia coli (GEC) and coliforms, can be used to measure changes in microbial contamination during the production of food products. Large and consistent reductions in the concentration of these organisms demonstrates an effective and well-controlled production process. Nevertheless, it is unclear to what degree concentrations of indicator organisms are related to pathogenic organisms such as Campylobacter and Salmonella on a sample-by-sample basis. If a strong correlation exists between the concentrations of different organisms, then the monitoring of indicator organisms would be a cost-effective surrogate for the measurement of pathogenic organisms. Calculating the correlation between the concentrations of an indicator and pathogenic organism is complicated because microbial testing datasets typically contain a large proportion of censored observations (i.e., samples where the true concentration is not observable, with nondetects and samples that are only screen-test positive being examples). This study proposes a maximum likelihood estimator that can be used to estimate the correlation between the concentrations of indicator and pathogenic organisms. An example based on broiler chicken rinse samples demonstrates modest, but significant positive correlations between the concentration of the indicator organism GEC when compared to the concentration of both Campylobacter and Salmonella. A weak positive correlation was also observed between concentrations of Campylobacter and Salmonella, but it was not statistically significant. PMID- 24491922 TI - Avian influenza vaccines against H5N1 'bird flu'. AB - H5N1 avian influenza viruses (AIVs) have spread widely to more than 60 countries spanning three continents. To control the disease, vaccination of poultry is implemented in many of the affected countries, especially in those where H5N1 viruses have become enzootic in poultry and wild birds. Recently, considerable progress has been made toward the development of novel avian influenza (AI) vaccines, especially recombinant virus vector vaccines and DNA vaccines. Here, we will discuss the recent advances in vaccine development and use against H5N1 AIV in poultry. Understanding the properties of the available, novel vaccines will allow for the establishment of rational vaccination protocols, which in turn will help the effective control and prevention of H5N1 AI. PMID- 24491926 TI - Simultaneous determination of morphine, codeine and 6-acetyl morphine in human urine and blood samples using direct aqueous derivatisation: validation and application to real cases. AB - Opiates play a relevant role in forensic toxicology and their assay in urine or blood is usually performed for example in workplace drug-testing or toxicological investigation of drug impaired driving. The present work describes two new methods for detecting morphine, codeine and 6-monoacethyl morphine in human urine or blood using a single step derivatisation in aqueous phase. Propyl chloroformate is used as the dramatizing agent followed by liquid-liquid extraction and gas-chromatography-mass spectroscopy to detect the derivatives. The methods have been validated both for hydrolysed and unhydrolysed urine. For hydrolysed urine, the LOD and LOQ were 2.5ng/ml and 8.5ng/ml for codeine, and 5.2ng/ml and 15.1ng/ml for morphine, respectively. For unhydrolysed urine, the LOD and LOQ were 3.0ng/ml and 10.1ng/ml for codeine, 2.7ng/ml and 8.1ng/ml for morphine, 0.8ng/ml and 1.5ng/ml for 6-monoacetyl morphine, respectively. In blood, the LOD and LOQ were 0.44ng/ml and 1.46ng/ml for codeine, 0.29ng/ml and 0.98ng/ml for morphine, 0.15ng/ml and 0.51ng/ml for 6-monoacetyl morphine, respectively. The validated methods have been applied to 50 urine samples and 40 blood samples (both positive and negative) and they can be used in routine analyses. PMID- 24491927 TI - Drug and cell encapsulation: alternative delivery options for the treatment of malignant brain tumors. AB - Malignant brain tumors including glioblastoma are incurable cancers. Over the last years a number of promising novel treatment approaches have been investigated including the application of inhibitors of receptor tyrosine kinases and downstream targets, immune-based therapies and anti-angiogenic agents. Unfortunately so far the major clinical trials in glioblastoma patients did not deliver clear clinical benefits. Systemic brain tumor therapy is seriously hampered by poor drug delivery to the brain. Although in glioblastoma, the blood brain barrier is disrupted in the tumor core, the major part of the tumor is largely protected by an intact blood brain barrier. Active cytotoxic compounds encapsulated into liposomes, micelles, and nanoparticles constitute novel treatment options because they can be designed to facilitate entry into the brain parenchyma. In the case of biological therapeutics, encapsulation of therapeutic cells and their implantation into the surgical cavity represents another promising approach. This technology provides long term release of the active compound at the tumor site and reduces side effects associated with systemic delivery. The proof of principle of encapsulated cell factories has been successfully demonstrated in experimental animal models and should pave the way for clinical application. Here we review the challenges associated with the treatment of brain tumors and the different encapsulation options available for drugs and living cells, with an emphasis on alginate based cell encapsulation technology. PMID- 24491928 TI - Remote monitoring of implantable cardioverter defibrillators. PMID- 24491929 TI - Creatine kinase-MB assessed in patients with acute myocardial infarction correlates with cardiac magnetic resonance infarct size at 6-month follow up. AB - INTRODUCTION: There are still only limited data concerning the use of creatine kinase-MB (CKMB) values for predicting infarct size in long-term follow up in patients with ST-segment elevation myocardial infarction (STEMI) who have undergone primary percutaneous coronary intervention (PCI). The aim of this study was to analyze the correlation between CKMB and both infarct size and left ventricular function during a 6-month follow up. METHODS: In a cohort of 68 patients with STEMI treated with PCI, serial CKMB assessment was performed at baseline and at 6, 12, 18, 24 and 48 hours after PCI. The area under the curve (AUC) of CKMB was calculated. Cardiac magnetic resonance (CMR) parameters were assessed at 6 months. RESULTS: All CKMB single time-point values, AUC CKMB, and CKMB maximal value after primary PCI were correlated with CMR infarct size and left ventricular function, but a high correlation (r>0.7) was found only for CKMB at 6 hours, CKMB at 12 hours, CKMB AUC, CKMB maximal value, and CMR infarct size (r=0.71, r=0.73, r=0.72, r=0.75, respectively, p<0.001 for all). CONCLUSIONS: CKMB assessment is a good predictor of infarct size at 6 months in patients with STEMI treated with PCI. The CKMB value at a single time point 12 hours after PCI is a good predictor of infarct size at 6 months, comparable to serial assessment parameters such as AUC CKMB and CKMB maximal value. PMID- 24491930 TI - Genes and genetic variations involved in the development of hypertension: focusing on a Greek patient cohort. AB - INTRODUCTION: Essential hypertension (HTN) is a multifactorial disease involving environmental, genetic and other factors. Over the past years, genetic studies of essential HTN have increased dramatically but the molecular mechanisms involved are still unknown. As part of a research program coordinated by Boston university (USA), we studied the role of various genes and single nucleotide polymorphisms (SNPs) in the inheritance or the onset of HTN in African-American, Caucasian American and Greek families. METHODS: Among 128 Greek families with a history of HTN, we studied 1474 people. Of the total examined, 273 men and 286 women were hypertensive. Based on 410 DNA samples from the hypertensive subjects, different SNPs were examined. An overall meta-analysis of the results from the Greek families, as well as a comparison with the 2 other groups (African-Americans and Caucasian-Americans), was performed. RESULTS: We report SNPs that are associated with the inheritance of HTN and are located either at the promoters of N methyltransferase and catalase genes, or within the coding region of NEDD4L ubiquitin ligase gene, or SNPs in mitochondrial DNA of hypertensive probands. Furthermore, we clarified the role of hereditary predisposition in the development of HTN, showing that the presence of maternal HTN was significantly higher in African-Americans and Greeks compared to Caucasian-Americans (81.7%, 84.8%, and 65%), while the paternal HTN showed no such difference (50%, 48.3% and 44.9%), respectively. CONCLUSIONS: Although genetic factors that were correlated with HTN were identified, it was not possible to identify a single gene that should be targeted for the treatment of HTN. Nevertheless, the important role of the maternal hereditary predisposition to HTN in the Greek patients and the responsible genetic factors involved should be further examined. PMID- 24491931 TI - Upgrading pacemaker to cardiac resynchronization therapy: an option for patients with chronic right ventricular pacing and heart failure. AB - INTRODUCTION: Long-term pacing from the right ventricle (RV) has been shown to induce a deleterious effect on left ventricular function. Cardiac resynchronization therapy (CRT) is an established treatment for heart failure (HF) patients. The purpose of this study was to assess the benefit from upgrading to CRT in chronically RV-paced patients with a low left ventricular ejection fraction (LVEF<35%). METHODS: Thirty-seven HF patients (age 71.4 +/- 7.7, 26 male), who fulfilled CRT indications, were included. Study subjects had undergone VVI or DDD pacemaker implantation 6.1 +/- 5.7 years earlier and were referred to our centre because of worsened clinical condition or a depleted battery. Patients were assessed at baseline and six months after CRT. Evaluation included NYHA classification, functional capacity assessed by six-minute walk test (6 MWT), hospitalization rate and echocardiographic assessment. RESULTS: Biventricular pacing was possible in 34 of the 37 cases (91.7%) who had their device upgraded to CRT-P (n=8) or to CRT-D (n=26). After the implementation of CRT the patients showed a noteworthy clinical improvement. Average NYHA class changed from 3.3 +/- 0.6 to 2.5 +/- 0.9 (p<0.001), 6 MWT performance increased from 246 +/- 105 m to 321 +/- 101 m (p<0.001), while six-month hospitalization rate dropped from 1.4 +/ 1 to 0.7 +/- 0.8 admissions (p<0.001). LVEF increased from 26.3 +/- 5.4% to 31.4 +/- 6.7% (p<0.001) and left ventricular end-systolic volume changed from 134.3 +/ 46 mL to 111.9 +/- 41.1 mL (p<0.001). A reduction in QRS duration by 28 ms (p<0.001) was also noted. CONCLUSIONS: RV-paced patients should be closely monitored, and upgrade to CRT should be considered promptly if they develop moderate or severe HF. PMID- 24491932 TI - Association between mediterranean diet and non-fatal cardiovascular events, in the context of anxiety and depression disorders: a case/case-control study. AB - INTRODUCTION: The aim of this study was to investigate the effect of the Mediterranean diet on the likelihood of having a non-fatal cardiovascular outcome, taking into account anxiety and depression status. METHODS: This was a case-control study with individual matching by age and sex. During 2009-2010, 1000 participants were enrolled; 250 were consecutive patients with a first acute coronary syndrome (ACS), 250 were consecutive patients with a first ischemic stroke, and 500 were population-based control subjects, one-for-one matched to the patients by age and sex. Among other characteristics, adherence to the Mediterranean diet was assessed by the MedDietScore, anxiety was assessed with the Spielberger State-Trait Anxiety Inventory form Y-2, while depressive symptomatology was evaluated by the Zung Depression Rating Scale. RESULTS: Higher adherence to the Mediterranean diet was associated with a lower likelihood of ACS and ischemic stroke, even after adjusting for anxiety or depression (ACS: OR=0.92, 95%CI 0.87-0.98 and 0.93, 0.88-0.98, respectively; ischemic stroke: 0.91, 0.84-0.98 and 0.90, 0.83-0.97, respectively). For both ACS and stroke patients, anxiety and depression were associated with a higher likelihood of ACS and stroke. When stratifying for depression or anxiety status, the Mediterranean diet remained a significantly protective factor only for people with low levels of depression and anxiety for ACS, and only for people with low levels of anxiety, as far as stroke was concerned. CONCLUSION: Anxiety and depression seem to play a mediating role in the protective relationship between adherence to the Mediterranean diet and the likelihood of developing cardiovascular events. PMID- 24491933 TI - Eighteen years' experience applying old and current strategies in the pre participation cardiovascular screening of athletes. AB - INTRODUCTION: Cardiovascular pre-participation screening (PPS) is recommended for the identification of athletes at risk for sudden cardiac death. However, there is currently no universally accepted screening protocol. METHODS: Two distinct PPS strategies were studied in a large cohort of Greek athletes (5 to 39 years old): PPS I, with routine 12-lead ECG and echo, in addition to personal and family history, and physical examination; and PPS II, without routine echo. PPS I (12,353 athletes) was performed from 1992 to 2002, and PPS II (9852 athletes) from 2003 to 2010. RESULTS: "Abnormal" findings were observed in 49.3% of the athletes (49.6% in PPS I and 48.9% in PPS II, p=0.299). Most of them were age- or exercise-related. Further evaluation was recommended for 8.3% of the athletes. Finally, 39 athletes (22 from PPS I) were excluded from competitive sports. Hypertrophic cardiomyopathy was found in 7 athletes. Other abnormalities were: dilated cardiomyopathy; complete heart block; coronary artery disease; Wolf Parkinson-White syndrome; and severe hypertension. The ECG played a critical role in the exclusion of 13 athletes, compared to only one for echo. Both PPS methods revealed an almost equal incidence of findings. CONCLUSIONS: We suggest that the routine use of ECG alone is sufficient for the successful screening of athletes. PMID- 24491934 TI - Transradial catheterization, a critical review with comparison between right and left access: insight into the clinical applicability of each approach. PMID- 24491935 TI - The role of the angiosome model in percutaneous intravascular and surgical reperfusion treatment of peripheral artery disease of the lower limbs. PMID- 24491936 TI - Sequential spontaneous coronary dissection/mural haematoma within all three coronary arteries over a nine-year period. PMID- 24491937 TI - Myocardial infarction caused by coronary artery dissection due to blunt injury: is thromboaspiration an appropriate treatment? AB - The present study reports a case of myocardial infarction (MI) resulting from blunt trauma-induced coronary artery injury. After falling from a 5-meter-tall building, a man suffered multiple fractures of the arms and legs. Percutaneous coronary intervention (PCI) was performed 48 hours after successful repair of the limb fractures. Coronary angiography revealed an occlusion of the left anterior descending artery, without significant lesions of other arteries. Intravascular ultrasound showed obvious signs of coronary artery dissection at the calcium point of the intimal layer, intramural hematoma, and intimal stripping. The intimal lesion itself may have been responsible for the MI, by causing mechanical obstruction. Use of a thrombectomy device to remove the thrombus caused coronary artery spasm and no blood flow. Sodium nitroprusside and tirofiban were injected into the coronary artery three times, and the coronary blood flow was restored. The patient was again returned to the care unit. One week later, balloon angioplasty without thromboaspiration was performed, and a rapamycin-eluting stent was placed at the point of the intimal lesion. The patient was discharged uneventfully 7 days after stent placement. The patient was asymptomatic and doing well at the outpatient follow-up visit 1 year after PCI. PMID- 24491938 TI - Iatrogenic left main coronary artery dissection and intramural hematoma caused by diagnostic transradial cardiac catheterization. AB - The growing use of the transradial approach for percutaneous coronary interventions has been shown to decrease the risk of major vascular complications. However, in this case report we describe a iatrogenic left main dissection during diagnostic coronary catheterization, which remains a rare, but still life-threatening condition. The adjunctive use of intravascular ultrasound may assist in the accurate diagnosis and treatment process. PMID- 24491939 TI - Antegrade approach to stumpless chronic total occlusion of ostial left anterior descending artery: first using a side branch cutting technique. AB - The approach to a chronic total occlusion (CTO) still remains one of the most technical challenges in percutaneous coronary intervention (PCI). CTO lesions with a blunt entry point, calcification, and failure of a previous approach, are the independent predictors of CTO-PCI failure. Here we report a successful antegrade approach for reattempted CTO-PCI of a left anterior descending artery (LAD) with unknown, calcified ostium. We used a novel side branch cutting technique, combined with intravascular ultrasound-guided wiring and parallel wire techniques. Considering the ramus artery as a side branch and dilating it with a cutting balloon was a crucial part of the strategy for achieving overall procedural success using this approach. This is the first report describing a side branch cutting technique in CTO-PCI. The combined application of multiple antegrade techniques, using the latest devices, might provide an effective and safe approach for complex CTO-PCI. PMID- 24491940 TI - Urinary neutrophil gelatinase-associated lipocalin as a predictor of acute kidney injury after transcatheter aortic valve implantation. PMID- 24491941 TI - Anticoagulation treatment in patients with atrial fibrillation and results of the RAFTING study. PMID- 24491942 TI - Cholesterol: "targeting" the enemy. PMID- 24491943 TI - New frontiers in interventional cardiology: from the past to the future. PMID- 24491944 TI - An autopsy case of microencephaly, bizarre putaminal lesion, and cerebellar atrophy with heart and liver diseases. AB - We reported a 64-year-old autopsy case, showing a unique combination of disorders in visceral organs and brain. She had developmental delay, microencephaly, and facial dysmorphism. She developed sick sinus syndrome and liver cirrhosis. There were no abnormalities in laboratory tests for congenital metabolic errors or anomaly syndromes, including activities of lysosomal enzymes, isoelectric focusing of serum transferrin or array comparative genomic hybridization. She died of cardiorespiratory failure. At autopsy she showed liver cirrhosis and mesangial proliferation. The brain weighed 710 g. Bizarre putaminal changes were found, in which the size of area of putamen in coronal sections was small, aberrant fiber running was increased, and immunoreactivity for tyrosine hydroxylase was reduced. Loss of Purkinje cells was found throughout the cerebellar cortex. She had unreported combination of developmental delay, facial dysmorphism, small brain, bizarre putaminal lesion, cerebellar atrophy, cardiac disease, liver cirrhosis and renal disease. Although the exact cause of disease still remains to be investigated, it will be a clue for the establishment of new disease entity to accumulate subjects having the similar phenotype. PMID- 24491945 TI - Epilepsy with myoclonic absences in siblings. AB - BACKGROUND: Epilepsy with myoclonic absences (EMAs) is a distinct form of childhood epilepsy characterized by a peculiar seizure type that identifies this condition. PURPOSE: To describe the clinical, electroencephalographic features, treatment strategies and outcome in this first case series of two siblings with normal intelligence presenting with EMAs. MATERIALS AND METHODS: Both siblings underwent video-polygraphic investigations (simultaneous recording of electroencephalogram [EEG] and electromyogram [EMG] from deltoids), high resolution magnetic resonance imaging (MRI), karyotyping, neuropsychological evaluation and language assessment. RESULTS: Both the children had a mean age of onset of prototype seizures by 3.5 years. Myoclonic absences (MAs) were characterized by rhythmic, bilateral, synchronous, symmetric 3-Hz spike-wave discharges, associated with EMG myoclonic bursts at 3 Hz, superimposed on a progressively increasing tonic muscle contraction. The interictal EEG showed a normal background activity with bursts of generalized spike and waves (SWs) as well as rare focal SWs independently over bilateral temporal and frontal regions. Increase in the seizure frequency from 5 to 100/day was observed due to use of carbamazepine and phenobarbitone which decreased with its withdrawal and introduction of valproate. Though lamotrigine was given as an add on to valproate, it did not benefit them and was therefore replaced by topiramate at 3.5 mg/kg/day which has maintained them on remission at one year follow up. CONCLUSIONS: Recognition of this ictal pattern allows identification and differentiation of EMAs from other seizure types. Idiopathic and symptomatic EMAs need to be differentiated from childhood absence epilepsy with myoclonia. MAs are worsened by drugs like carbamazepine while valproate either alone or in combination with topiramate (preferred to lamotrigine) gives excellent outcome. PMID- 24491946 TI - Relational stressors as predictors for repeat aggressive and self-harming incidents in child and adolescent psychiatric inpatient settings. AB - This study examined whether relational stressors such as psychosocial stressors, the therapist's absence and a change of therapist are associated with repeat aggressive or self-harming incidents in child and adolescent psychiatric inpatient care. The study data were derived from critical incident reports and chart reviews of 107 inpatients. In multinomial regression analysis, patients with repeat aggressive or self-harming incidents were compared with patients with single incidents. Results suggested that a higher number of psychosocial stressors and a change of therapist, but not the therapist's absence are predictors for repeat aggressive and self-harming incidents. There was a high prevalence of therapist's absence during both, single and repeat, incidents. Repeat aggressive incidents were common in male children and adolescents with disruptive behavior disorders. Repeat self-harming incidents were common in adolescent females with trauma-related disorders. Patients with repeat aggressive or self-harming incidents had a higher number of abnormal intrafamilial relationships and acute life events than patients with single incidents. Interventions to reduce a change of therapist should in particular target children and adolescents with a higher number of psychosocial stressors and/or a known history of traumatic relational experiences. After a first incident, patients should have a psychosocial assessment to evaluate whether additional relational support is needed. PMID- 24491947 TI - A cross-national study to compare the knowledge, attitudes, perceptions of sexually transmitted diseases and the sexual risk behaviors of Latino adolescents. AB - BACKGROUND: Adolescents are at high risk of acquiring sexually transmitted diseases (STDs). However, little is known about differences in knowledge and risk behaviors across nationalities. The objective of this study was to assess and compare the knowledge and perceptions of STDs and the sexual risk behaviors in Latino adolescents in the United States (US) and the Dominican Republic (DR). METHODS: A survey was administered to 364 high school students after obtaining parental consent. The questionnaire asked about demographics, sources of STD information, risk behaviors, and knowledge of syphilis, gonorrhea, and human immunodeficiency virus (HIV). Mean percentage scores were calculated to compare correct responses by nationality, gender, and sexual activity. Predictors of self reported high risk sexual behavior were identified by multivariable logistic regression analysis. RESULTS: In all, 242 (66%) US and 122 (34%) DR students were interviewed. Of these, 52% were males. Median age was 15 years (range, 13-18). Sexual activity was reported by 40% of the participants and did not differ by gender (p=0.43) or national origin (p=0.53), although it was greater for adolescents older than 15 years of age (60% vs. 35%, p<0.001). US students identified abstinence as an effective STD prevention method more often than their counterparts (p=<0.001). Knowledge of specific STDs was higher in girls (p=0.002) and Dominicans (p=0.003). Predictors of high risk behavior were male gender (OR25) when the membranes were dried. On this basis, two H2O2-biosensing systems were developed based on the biofunctionalization of the glass fiber inserts either with cytochrome c or horseradish peroxidase (HRP) and the analytical performances were systematically compared with the corresponding bioassay in solution. The efficiency of the absorbance-enhancement approach was particularly clear in the case of the cytochrome c-based biosensor with a sensitivity gain of 40 folds and wider dynamic range. Therefore, the developed strategy represents a promising way to convert standard colorimetric bioassays into optical biosensors with improved sensitivity. PMID- 24491963 TI - Core/shell nanoparticles in biomedical applications. AB - Nanoparticles have several exciting applications in different areas and biomedial field is not an exception of that because of their exciting performance in bioimaging, targeted drug and gene delivery, sensors, and so on. It has been found that among several classes of nanoparticles core/shell is most promising for different biomedical applications because of several advantages over simple nanoparticles. This review highlights the development of core/shell nanoparticles based biomedical research during approximately past two decades. Applications of different types of core/shell nanoparticles are classified in terms of five major aspects such as bioimaging, biosensor, targeted drug delivery, DNA/RNA interaction, and targeted gene delivery. PMID- 24491964 TI - Lymphangioma circumscriptum, angiokeratoma, or superficial vascular ectasia with epithelial hyperplasia? AB - We report a case of lymphangioma circumscriptum (cavernous lymphangioma with epithelial hyperplasia) in a 12-year-old girl, presenting as a papillary tumor on the right dorsal side of her tongue. Microscopic examination found cavernous vascular channels lined by a single layer of CD31(+), podoplanin-positive, CD34( ) endothelial cells that occupied the papillary lamina propria and were accompanied by epithelial hyperplasia. A review of the literature on oral vascular tumors with epithelial hyperplasia, namely, lymphangioma circumscriptum and angiokeratoma, provided information that draws into question the use of these terms. PMID- 24491965 TI - Optogenetic inhibition of chemically induced hypersynchronized bursting in mice. AB - Synchronized activity is common during various physiological operations but can culminate in seizures and consequently in epilepsy in pathological hyperexcitable conditions in the brain. Many types of seizures are not possible to control and impose significant disability for patients with epilepsy. Such intractable epilepsy cases are often associated with degeneration of inhibitory interneurons in the cortical areas resulting in impaired inhibitory drive onto the principal neurons. Recently emerging optogenetic technique has been proposed as an alternative approach to control such seizures but whether it may be effective in situations where inhibitory processes in the brain are compromised has not been addressed. Here we used pharmacological and optogenetic techniques to block inhibitory neurotransmission and induce epileptiform activity in vitro and in vivo. We demonstrate that NpHR-based optogenetic hyperpolarization and thereby inactivation of a principal neuronal population in the hippocampus is effectively attenuating seizure activity caused by disconnected network inhibition both in vitro and in vivo. Our data suggest that epileptiform activity in the hippocampus caused by impaired inhibition may be controlled by optogenetic silencing of principal neurons and potentially can be developed as an alternative treatment for epilepsy. PMID- 24491967 TI - Assessment of in vitro human dermal absorption studies on pesticides to determine default values, opportunities for read-across and influence of dilution on absorption. AB - Dermal absorption is an integral part of non-dietary human safety risk assessments for agrochemicals. Typically, dermal absorption data for agrochemical active substances are generated from the undiluted formulation concentrate and its spray dilutions. European Food Safety Authority (EFSA) guidance, which combines highly conservative default values, very limited opportunities for read across from existing data and other overly conservative conclusions, was the driver for this assessment. To investigate the reliability of the EFSA guidance, a homogeneous data-set of 190 GLP and OECD guideline compliant in vitro human skin studies, chosen to match the test method preferred by EU data requirements, was evaluated. These studies represented a wide range of active substances, formulation types, and concentrations. In alignment with EFSA guidance on human exposure assessment, a conservative estimate of absorption (95th percentile) was chosen to define defaults, which were also based on the EFSA worst-case assumption that all material in skin, excluding the first two tape strips, is absorbed. The analysis supports dermal absorption defaults of 6% for liquid concentrates, 2% for solid concentrates, and 30% for all spray dilutions, irrespective of the active substance concentration. Relatively high dermal absorption values for organic solvent-based formulations, compared to water-based or solid concentrates, support their use as worst-case surrogate data for read across to other formulation types. The current review also shows that dermal absorption of sprays does not increase linearly with increasing dilution, and provides a novel, science-based option for extrapolation from existing data. PMID- 24491966 TI - Contributions of signaling by dopamine neurons in dorsal striatum to cognitive behaviors corresponding to those observed in Parkinson's disease. AB - Although the cardinal features of Parkinson's disease (PD) are motor symptoms, PD also causes cognitive deficits including cognitive flexibility and working memory, which are strongly associated with prefrontal cortex (PFC) functions. Yet, early stage PD is not characterized by pathology in the PFC but by a loss of dopaminergic (DA) projections from the substantia nigra to the dorsal striatum. Moreover, the degree to which PD symptoms can be ascribed to the loss of DA alone or to the loss of DA neurons is unknown. We addressed these issues by comparing mouse models of either chronic DA depletion or loss of DA projections to the dorsal striatum. We achieved equal levels of striatal DA reduction in both models which ranged from mild (~25%) to moderate (~60%). Both models displayed DA concentration-dependent reductions of motor function as well as mild deficits of cognitive flexibility and working memory. Interestingly, whereas both motor function and cognitive flexibility were more severely impaired after mild ablation of DA neurons as compared to mild loss of DA alone, both models had equal deficits after moderate loss of DA. Our results confirm contributions of nigro-striatal dopamine signaling to cognitive behaviors that are affected in early stage PD. Furthermore, our findings suggest that the phenotype after ablation of DA neurons accrues from factors beyond the mere loss of DA. PMID- 24491968 TI - Mode of action analysis for liver tumors from oral 1,4-dioxane exposures and evidence-based dose response assessment. AB - 1,4-Dioxane is found in consumer products and is used as a solvent in manufacturing. Studies in rodents show liver tumors to be consistently reported after chronic oral exposure. However, there were differences in the reporting of non-neoplastic lesions in the livers of rats and mice. In order to clarify these differences, a reread of mouse liver slides from the 1978 NCI bioassay on 1,4 dioxane in drinking water was conducted. This reread clearly identified dose related non-neoplastic changes in the liver; specifically, a dose-related increase in the hypertrophic response of hepatocytes, followed by necrosis, inflammation and hyperplastic hepatocellular foci. 1,4-Dioxane does not cause point mutations, DNA repair, or initiation. However, it appears to promote tumors and stimulate DNA synthesis. Using EPA Guidelines (2005), the weight of the evidence suggests that 1,4-dioxane causes liver tumors in rats and mice through cytotoxicity followed by regenerative hyperplasia. Specific key events in this mode of action are identified. A Reference Dose (RfD) of 0.05mg/kgday is proposed to protect against regenerative liver hyperplasia based on a benchmark dose (BMD) approach. Based on this RfD, a maximum contaminant level goal of 350MUg/L is proposed using a default relative source contribution for water of 20%. PMID- 24491969 TI - Cap buckling as a potential mechanism of atherosclerotic plaque vulnerability. AB - Plaque rupture in atherosclerosis is the primary cause of potentially deadly coronary events, yet about 40% of ruptures occur away from the plaque cap shoulders and cannot be fully explained with the current biomechanical theories. Here, cap buckling is considered as a potential destabilizing factor which increases the propensity of the atherosclerotic plaque to rupture and which may also explain plaque failure away from the cap shoulders. To investigate this phenomenon, quasistatic 2D finite element simulations are performed, considering the salient geometrical and nonlinear material properties of diverse atherosclerotic plaques over the range of physiological loads. The numerical results indicate that buckling may displace the location of the peak von Mises stresses in the deflected caps. Plaque buckling, together with its deleterious effects is further observed experimentally in plaque caps using a physical model of deformable mock coronary arteries with fibroatheroma. Moreover, an analytical approach combining quasistatic equilibrium equations with the Navier-Bresse formulas is used to demonstrate the buckling potential of a simplified arched slender cap under intraluminal pressure and supported by foundations. This analysis shows that plaque caps - calcified, fibrotic or cellular - may buckle in specific undulated shapes once submitted to critical loads. Finally, a preliminary analysis of intravascular ultrasonography recordings of patients with atherosclerotic coronary arteries corroborates the numerical, experimental and theoretical findings and shows that various plaque caps buckle in vivo. By displacing the sites of high stresses in the plaque cap, buckling may explain the atherosclerotic plaque cap rupture at various locations, including cap shoulders. PMID- 24491971 TI - Tournay's description of anisocoria on lateral gaze: reaction, myth, or phenomenon? AB - The year 1917 witnessed the opening of a great debate in neuro-ophthalmology, with Tournay's description of a phenomenon thought to be universal: anisocoria in lateral gaze, due to mydriasis of the abducting pupil and a minor miosis of the fellow one. Through many publications, this phenomenon was soon assessed and confirmed to be physiologic, while the cause of the pupil reaction in lateral gaze was extensively discussed. Cases of abolition and reversal of the phenomenon were also reported in specific clinical situations, such as neurosyphilis, and its study became part of the neuro-ophthalmologic examination. Publications on the phenomenon declined after 1934, with only one publication appearing between 1934 and 1974 (1957). In 1974, the demise of the Tournay phenomenon was secured after 2 pupillographic studies showed it to be rare and marginal. This story is reviewed. Hypotheses are proposed in order to help unfold the controversy; anisocoria in lateral gaze should not be regarded as a myth, nor does it--or only rarely--correspond to a pupil reaction, or noumenon: it can usually be accounted for by a specific optical distortion (apparent without real anisocoria) and hence fits the Kantian definition of a phenomenon. An understanding of Tournay phenomenon is therefore of current relevance to the examination of the pupils to avoid misinterpretation of observed changes in the pupil. PMID- 24491970 TI - Aldehyde dehydrogenase variation enhances effect of pesticides associated with Parkinson disease. AB - OBJECTIVE: The objective of this study was to determine whether environmental and genetic alterations of neuronal aldehyde dehydrogenase (ALDH) enzymes were associated with increased Parkinson disease (PD) risk in an epidemiologic study. METHODS: A novel ex vivo assay was developed to identify pesticides that can inhibit neuronal ALDH activity. These were investigated for PD associations in a population-based case-control study, the Parkinson's Environment & Genes (PEG) Study. Common variants in the mitochondrial ALDH2 gene were genotyped to assess effect measure modification (statistical interaction) of the pesticide effects by genetic variation. RESULTS: All of the metal-coordinating dithiocarbamates tested (e.g., maneb, ziram), 2 imidazoles (benomyl, triflumizole), 2 dicarboxymides (captan, folpet), and 1 organochlorine (dieldrin) inhibited ALDH activity, potentially via metabolic byproducts (e.g., carbon disulfide, thiophosgene). Fifteen screened pesticides did not inhibit ALDH. Exposures to ALDH-inhibiting pesticides were associated with 2- to 6-fold increases in PD risk; genetic variation in ALDH2 exacerbated PD risk in subjects exposed to ALDH-inhibiting pesticides. CONCLUSION: ALDH inhibition appears to be an important mechanism through which environmental toxicants contribute to PD pathogenesis, especially in genetically vulnerable individuals, suggesting several potential interventions to reduce PD occurrence or slow or reverse its progression. PMID- 24491972 TI - Wilbrand knee. AB - Wilbrand and Saenger(1) studied optic chiasms after unilateral enucleation, noting inferonasal crossing fibers curved anteriorly into the contralateral optic nerve (Wilbrand knee; figure, A). This explains contralateral superotemporal visual field defects (junctional scotomas) with optic nerve lesions at the chiasmal junction. However, Wilbrand knee may be an enucleation artifact.(2) The anisotropic light-reflecting properties of myelinated axons permitted imaging of normal human chiasms. Thin sections (25 um) were illuminated and digitally imaged from 3 incident angles. Each of the images was pseudocolored (red, green, or blue) and merged, revealing an anomalously oriented fiber tract (appearing white) that reversed direction at the optic nerve-chiasm junction, found in inferior (figure, C) but not in superior sections (figure, B), consistent with Wilbrand and Saenger's original description. PMID- 24491973 TI - Identification of a novel risk variant in the FUS gene in essential tremor. PMID- 24491974 TI - Propofol-related infusion syndrome heralding a mitochondrial disease: case report. PMID- 24491976 TI - Clinical reasoning: a 76-year-old man remaining comatose after cardiopulmonary resuscitation. AB - A 76-year-old man was admitted to the hospital after having a "cardiac arrest" while riding his bicycle and subsequently falling into a canal. Thirty minutes after the accident, he was resuscitated by an ambulance crew. They detected a ventricular tachycardia, which responded to defibrillation. Thereafter, there was a sinus bradycardia, which was treated with atropine and adrenaline. After 30 minutes of resuscitation, there was return of spontaneous circulation (ROSC). At admission to our hospital, the patient was comatose, with a body temperature of 30 degrees C and Glasgow Coma Scale score (GCS) of E1M1V1. According to protocol for presumed acute hypoxic ischemic encephalopathy, he was started on therapeutic hypothermia. The body temperature of the patient was kept at 32 degrees C to 34 degrees C for 24 hours. A few hours after starting hypothermia, twitches around the eyes and mouth were noticed and a neurology consultation was requested. Neurologic examination during hypothermia and under sedation showed a deeply comatose patient with intact pupillary reaction to light bilaterally and present oculocephalic reflex. He had multifocal random twitching movements involving the face, arms, and legs. These shock-like movements were found to increase by external stimuli. PMID- 24491977 TI - Pearls & Oy-sters: chronic mumps meningoencephalitis with low CSF glucose and acute hydrocephalus in an adult. AB - Chronic lymphocytic meningoencephalitis with low glucose and increased adenosine deaminase (ADA) levels in the CSF together with hydrocephalus represents a diagnostic challenge of varied etiology and only seldom is due to a viral (mumps) infection. PMID- 24491978 TI - Teaching neuroimages: "subarachnoid hemorrhage" from decreased contrast elimination after therapeutic hypothermia. PMID- 24491979 TI - Simplifying the complexity of resistance heterogeneity in metastasis. AB - The main goal of treatment regimens for metastasis is to control growth rates, not eradicate all cancer cells. Mathematical models offer methodologies that incorporate high-throughput data with dynamic effects on net growth. The ideal approach would simplify, but not over-simplify, a complex problem into meaningful and manageable estimators that predict the response of a patient to specific treatments. We explore here three fundamental approaches with different assumptions concerning resistance mechanisms in which the cells are categorized into either discrete compartments or described by a continuous range of resistance levels. We argue in favor of modeling resistance as a continuum, and demonstrate how integrating cellular growth rates, density-dependent versus exponential growth, and intratumoral heterogeneity improves predictions concerning the resistance heterogeneity of metastases. PMID- 24491981 TI - Classic and cutting-edge strategies for the management of early pregnancy loss. AB - There are few conditions in medicine associated with more heartache to patients than recurrent pregnancy loss (RPL). The management of early RPL is a formidable clinical challenge for physicians. Great strides have been made in characterizing the incidence and diversity of this heterogeneous disorder, and a definite cause of pregnancy loss can be established in more than half of couples after a thorough evaluation. In this review, current data are evaluated and a clear roadmap is provided for the evaluation and treatment of RPL. PMID- 24491980 TI - Polycystin-1: a master regulator of intersecting cystic pathways. AB - Autosomal dominant polycystic kidney disease (ADPKD) is the most common potentially lethal monogenic disorder, with more than 12 million cases worldwide. The two causative genes for ADPKD, PKD1 and PKD2, encode protein products polycystin-1 (PC1) and polycystin-2 (PC2 or TRPP2), respectively. Recent data have shed light on the role of PC1 in regulating the severity of the cystic phenotypes in ADPKD, autosomal recessive polycystic kidney disease (ARPKD), and isolated autosomal dominant polycystic liver disease (ADPLD). These studies showed that the rate for cyst growth was a regulated trait, a process that can be either sped up or slowed down by alterations in functional PC1. These findings redefine the previous understanding that cyst formation occurs as an 'on-off' process. Here, we review these and other related studies with an emphasis on their translational implications for polycystic diseases. PMID- 24491982 TI - Research methodology in recurrent pregnancy loss. AB - The aim of this article is to highlight pitfalls in research methodology that may explain why studies in recurrent pregnancy loss (RPL) often provide very divergent results. It is hoped that insight into this issue may help clinicians decide which published studies are the most valid. It may help researchers to eliminate methodological flaws in future studies, which may hopefully come to some kind of agreement about the usefulness of diagnostic tests and treatments in RPL. PMID- 24491983 TI - The evolving role of genetics in reproductive medicine. AB - As medicine has evolved over the last century, medical genetics has grown from nonexistence to one of the most visible aspects of how we understand and treat disease. This increased role of genetics within medicine will only increase in the coming years, and its role in reproductive medicine will be significant. Genetics has emerged as a primary focus of research with translational applications within reproductive medicine. The aim of this article is to outline the applications of genetics currently available, and how these technologies can provide a positive impact on patient care. PMID- 24491984 TI - Uterine factors. AB - Uterine anomalies are one of the most common parental causes of recurrent pregnancy loss, occurring in about 19% of patients. Congenital uterine anomalies are most likely caused by HOX gene mutations, although the mechanism is probably polygenic. There are no known environmental causes other than estrogenic endocrine disruptors such as diethylstilbestrol. Acquired uterine anomalies may result from uterine trauma (adhesions) or benign growths of the myometrium (fibroids) or endometrium (polyps). Although randomized controlled trials are lacking, surgical treatment is recommended for repair of uterine septa, and for removal of severe adhesions and submucosal fibroids, especially if no other causes are identified. PMID- 24491985 TI - Mid-trimester pregnancy loss. AB - Mid-trimester pregnancy loss (MTL) occurs between 12 and 24 weeks' gestation. The true incidence of this pregnancy complication is unknown, because research into MTL in isolation is scarce, although the estimated incidence has been noted to be 2% to 3% of pregnancies. A comprehensive preconceptual screening protocol is recommended, because the cause for an MTL may be present in isolation or combined (dual pathology), and is often heterogeneous. Patients with a history of MTL are at an increased risk of future miscarriage and preterm delivery. This risk is increased further depending on the number of associative factors diagnosed. PMID- 24491986 TI - Endocrine basis for recurrent pregnancy loss. AB - Common endocrinopathies are a frequent contributor to spontaneous and recurrent miscarriage. Although the diagnostic criteria for luteal phase defect (LPD) is still controversial, treatment of patients with both recurrent pregnancy loss and LPD using progestogen in early pregnancy seems beneficial. For patients who are hypothyroid, thyroid hormone replacement therapy along with careful monitoring in the preconceptual and early pregnancy period is associated with improved outcome. Women with polycystic ovary syndrome (PCOS) have an increased risk of pregnancy loss. Management of PCOS with normalization of weight or metformin seems to reduce the risk of pregnancy loss. PMID- 24491987 TI - Antiphospholipid antibody syndrome. AB - Antiphospholipid antibodies (aPLs) are acquired antibodies directed against negatively charged phospholipids. Obstetric antiphospholipid antibody syndrome (APS) is diagnosed in the presence of certain clinical features in conjunction with positive laboratory findings. Obstetric APS is one of the most commonly identified causes of recurrent pregnancy loss. Thus, obstetric APS is distinguished from APS in other organ systems where the most common manifestation is thrombosis. Several pathophysiologic mechanisms of action of aPLs have been described. This article discusses the diagnostic and obstetric challenges of obstetric APS, proposed pathophysiologic mechanisms of APS during pregnancy, and the management of women during and after pregnancy. PMID- 24491988 TI - Inherited thrombophilias and adverse pregnancy outcomes: a review of screening patterns and recommendations. AB - Historically, much controversy has existed regarding the association of inherited thrombophilias with adverse pregnancy outcomes. The current guidelines do not recommend screening unless a personal history of venous thromboembolism is present, but the authors' survey of physician screening patterns has suggested that up to 40% of physicians may screen contrary to the current guidelines. This article summarizes the existing evidence for each inherited thrombophilia and reviews the current guidelines. PMID- 24491989 TI - Recurrent miscarriage clinics. AB - A recurrent miscarriage clinic offers specialist investigation and treatment of women with recurrent first- and second-trimester miscarriages. Consultant-led clinics provide a dedicated and focused service to couples who have experienced at least two prior miscarriages. The best treatment strategy for couples with recurrent miscarriage is to discuss a treatment plan for a future pregnancy. Evidence-based up-to-date guidelines are required to reduce ineffective management of recurrent miscarriage couples, including overdiagnostics and underdiagnostics. Scientific research is necessary to study the effectiveness of new interventions, to study patient preferences, and to evaluate health care and costs or other outcomes. PMID- 24491990 TI - Unexplained recurrent pregnancy loss. AB - Women with unexplained recurrent pregnancy loss (RPL) represent a highly heterogeneous group of patients. Past studies have investigated systemic endocrine and immunologic mechanisms as potential causes for pregnancy loss in unexplained RPL, while exciting new work has focused on spermatozoal, embryonic, and endometrial characteristics to explain the regulation of implantation and subsequent pregnancy loss. In the clinical and research context, stratification of women with unexplained RPL according to whether they have a high probability of pathologic status will help select women who are most appropriate for further investigation and potential future treatment. PMID- 24491991 TI - Recurrent first trimester pregnancy loss. Foreword. PMID- 24491992 TI - Recurrent pregnancy loss. PMID- 24491993 TI - Comparison of CT and MRI artefacts from coils and vascular plugs used for portal vein embolization. AB - PURPOSE: To retrospectively analyze the degree of artefacts in CT and MRI scans caused by coils and vascular plugs used for portal vein embolization (PVE). MATERIALS AND METHODS: All patients who underwent PVE between July 2011 and December 2012 and received either plug or coil embolization additional to particle embolization were retrospectively analyzed. Artefacts causes by embolization materials were measured in CT and MRI scans following PVE. RESULTS: The sum of the artefact diameters caused from coils was significantly higher in CT (188.3 +/- 26.1 mm) than in MRI T1 (50.5 +/- 6.5 mm) or T2 imaging (39.5 +/- 9.7 mm) (P<0.05). In MRI, the diameter in T1 and T2 sequences did not differ significantly (P=0.977). The sum of the artefact diameters from vascular plugs in MRI T1 sequences (62.5 +/- 8.7 mm) was significantly higher than in CT (46.6 +/- 4.8 mm; P<0.05) and MRI T2 sequences (52.8 +/- 3.8 mm; P<0.05). CONCLUSION: PVE with particles and vascular plug causes significantly fewer artefacts than PVE with particles and coils on CT scans following embolization, which can be important in the event of vascular complications or in follow-up scans, should the patient become unresectable. PMID- 24491994 TI - Outcome of vesicourethral anastomosis after robot-assisted laparoscopic radical prostatectomy: A 6-year experience in Taiwan. AB - BACKGROUND/PURPOSE: The use of a da Vinci robotic system may improve the outcome of urological surgery. This study reports 6 years of experience with vesicourethral anastomosis (VUA) following robot-assisted laparoscopic radical prostatectomy (RALP) performed in Taichung Veterans General Hospital, Taichung, Taiwan. METHODS: A total of 350 patients who underwent RALP by a single surgeon were reviewed. We followed Dr Patel's RALP procedure with minor modifications. VUA was checked with 120 mL and 200 mL saline in sequence. The urinary bladder was then pressed with endoscopic instruments. If a VUA leak was detected, it was sutured immediately. An 18-French silicon Foley's catheter was inserted and removed 7-14 days after RALP. Preoperative characteristics and perioperative complications were assessed. RESULTS: Overall, 332 (94.85%) patients were without any leakage in the first step of the challenge, eight of whom had leakage in the second step. After repair, all were free from leakage. The other 18 patients had leakage in the first step of the challenge (5.14%). After repair, 12 patients were without leakage in the second step. However, one patient had urine leakage postoperatively. The other six patients had leakage in the second step. After repair, two patients were free from leakage, but the remaining four suffered from persistent minor urine leakage postoperatively. The urine leakage rate after RALP was 1.43% (5/350). The potential urine leakage after bladder challenge and endoscopic instruments pressing could be minimized to 0.29% (1/346). CONCLUSION: VUA leakage after RALP is rare. Intraoperative VUA challenge is simple and feasible compared to postoperative retrograde cystography. PMID- 24491995 TI - Using high-performance liquid chromatography with UV detector to quantify exhaled leukotriene B4 level in nonatopic adults. AB - This study aimed to evaluate the feasibility of the chemical method to analyze exhaled breath condensate (EBC) leukotriene B4 (LTB4) level in humans. High performance liquid chromatography with a UV detector was applied to quantify the inflammatory biomarker. The LTB4 concentration in the concentrated pooled EBC samples was 1.19 ng/MUL, and the average LTB4 concentration of each EBC sample was 15.38 ng/MUL. This analytical technique was feasible to evaluate the levels of inflammatory mediators such as LTB4 in human EBCs without any complicated sample pretreatment processes. PMID- 24491996 TI - Trps1 is associated with the multidrug resistance of osteosarcoma by regulating MDR1 gene expression. AB - Multidrug resistance (MDR) is a significant clinical problem in the chemotherapy of osteosarcoma and has been linked to the cellular expression of several multidrug-efflux transporters such as MDR1/P-gp. Our inhibition of the transcription factor Trps1 led to repression of MDR1/P-gp while its overexpression resulted in upregulation of MDR1/P-gp. Flow cytometric analysis suggested Trps1 increased the release of several anti-cancer drugs, thus decreasing their accumulation. Immunohistochemical analysis of clinical samples indicated that the expression of Trps1 directly correlated with MDR1/P-gp. Trps1 inhibited TGFbeta-1 and directly bound to the MDR1 promoter. Our data demonstrate a role for Trps1 in the regulation of MDR1 expression in osteosarcoma. PMID- 24491997 TI - Synthetic crowding agent dextran causes excluded volume interactions exclusively to tracer protein apoazurin. AB - To understand protein biophysics in crowded cellular environments, researchers often use synthetic polymers as 'crowding agents' in vitro. The idea is that these agents will occupy space and reproduce the in vivo scenario in terms of excluded volume. However, recent work has challenged this concept and pointed out that attractive interactions between protein and crowding agent will provide an enthalpic contribution to the overall effect on protein thermodynamics. Here we use a typical synthetic crowding agent and a well-studied model protein to demonstrate in a window of 50K that the presence of dextran 20 affects apoazurin by steric repulsion. PMID- 24491998 TI - Transcriptional control of RfaH on polysialic and colanic acid synthesis by Escherichia coli K92. AB - The transcriptional antiterminator RfaH promotes transcription of long operons encoding surface cell components important for the virulence of Escherichiacoli pathogens. In this paper, we show that RfaH enhanced kps expression for the synthesis of group 2 polysialic acid capsule in E. coli K92. In addition, we demonstrate for the first time that RfaH promotes cps expression for the synthesis of colanic acid, a cell wall component with apparently no role on pathogenicity. Finally, we show a novel RfaH requirement for growth at low temperatures. PMID- 24491999 TI - The dark sides of amyloid in Alzheimer's disease pathogenesis. AB - Although widely explored, the pathogenesis of Alzheimer's disease (AD) has yet to be cleared. Over the past twenty years the so call amyloid cascade hypothesis represented the main research paradigm in AD pathogenesis. In spite of its large consensus, the proposed role of beta-amyloid (Abeta) remain to be elucidated. Many evidences are starting to cast doubt on Abeta as the primary causative factor in AD. For instance, Abeta is deposited in the brain following many different kinds of injury. Also, concentration of Abeta needed to induce toxicity in vitro are never reached in vivo. In this review we propose an amyloid independent interpretation of several AD pathogenic features, such as synaptic plasticity, endo-lysosomal trafficking, cell cycle regulation and neuronal survival. PMID- 24492000 TI - EGF induces efficient Cx43 gap junction endocytosis in mouse embryonic stem cell colonies via phosphorylation of Ser262, Ser279/282, and Ser368. AB - Gap junctions (GJs) traverse apposing membranes of neighboring cells to mediate intercellular communication by passive diffusion of signaling molecules. We have shown previously that cells endocytose GJs utilizing the clathrin machinery. Endocytosis generates cytoplasmic double-membrane vesicles termed annular gap junctions or connexosomes. However, the signaling pathways and protein modifications that trigger GJ endocytosis are largely unknown. Treating mouse embryonic stem cell colonies - endogenously expressing the GJ protein connexin43 (Cx43) - with epidermal growth factor (EGF) inhibited intercellular communication by 64% and activated both, MAPK and PKC signaling cascades to phosphorylate Cx43 on serines 262, 279/282, and 368. Upon EGF treatment Cx43 phosphorylation transiently increased up to 4-fold and induced efficient (66.4%) GJ endocytosis as evidenced by a 5.9-fold increase in Cx43/clathrin co-precipitation. PMID- 24492001 TI - Peripherally administrated prions reach the brain at sub-infectious quantities in experimental hamsters. AB - The mechanisms implicated in prion infection and tissue distribution are not completely understood. In this study we investigated the levels of 263K prions in brain and spleen of Syrian hamsters few days after intra-peritoneal challenge. For this purpose we utilized the PMCA technology which permits to detect as little as few PrP(Sc) molecules. Our results show that peripherally administered prions directly reach the brain, although at levels below the minimum necessary to produce disease. PrP(Sc) remains in the brain several days after administration suggesting inefficient clearance or early replication. Understanding the fate of the infectious agent after administration and its uptake in different organs and fluids may provide useful information to develop strategies to minimize further spreading of prion diseases. PMID- 24492002 TI - VRK1 interacts with p53 forming a basal complex that is activated by UV-induced DNA damage. AB - DNA damage immediate cellular response requires the activation of p53 by kinases. We found that p53 forms a basal stable complex with VRK1, a Ser-Thr kinase that responds to UV-induced DNA damage by specifically phosphorylating p53. This interaction takes place through the p53 DNA binding domain, and frequent DNA contact mutants of p53, such as R273H, R248H or R280K, do not disrupt the complex. UV-induced DNA damage activates VRK1, and is accompanied by phosphorylation of p53 at Thr-18 before it accumulates. We propose that the VRK1 p53 basal complex is an early-warning system for immediate cellular responses to DNA damage. PMID- 24492003 TI - Functional analysis of the C-terminal region of the vacuolar cadmium-transporting rice OsHMA3. AB - Rice OsHMA3 is a vacuolar cadmium (Cd) transporter belonging to the P1B-ATPase family and has a long (273aa) C-terminal region. We analyzed the function of the region related to Cd using the transgenic Arabidopsis Col-0 ecotype, which is sensitive to Cd. The OsHMA3 variant containing a truncated (58aa) C-terminal region did not confer Cd tolerance, whereas an OsHMA3 variant containing a longer truncated (105aa) C-terminal region conferred Cd tolerance to transgenic Arabidopsis. We conclude that the C-terminal region, particularly the region containing the first 105aa, has an important role in OsHMA3 activity. PMID- 24492004 TI - A small portion of plastid transcripts is polyadenylated in the flagellate Euglena gracilis. AB - Euglena gracilis possesses secondary plastids of green algal origin. In this study, E. gracilis expressed sequence tags (ESTs) derived from polyA-selected mRNA were searched and several ESTs corresponding to plastid genes were found. PCR experiments failed to detect SL sequence at the 5'-end of any of these transcripts, suggesting plastid origin of these polyadenylated molecules. Quantitative PCR experiments confirmed that polyadenylation of transcripts occurs in the Euglena plastids. Such transcripts have been previously observed in primary plastids of plants and algae as low-abundance intermediates of transcript degradation. Our results suggest that a similar mechanism exists in secondary plastids. PMID- 24492005 TI - H3K9 histone methyltransferase G9a-mediated transcriptional activation of p21. AB - We report that H3K9 HMTase G9a activates transcription of the cell cycle regulatory gene, p21, in p53-null H1299 cells. Positive regulation of p21 by G9a is independent of its HMTase activity. We demonstrate that G9a upregulates p21 via interaction with PCAF, and provide evidence that the activating complex is recruited to the p21 promoter upon DNA damage-inducing agent etoposide treatment. Our study suggests that G9a decreases proliferation and cell viability by increasing the level of p21-mediated apoptosis. Our results suggest that G9a functions as a coactivator for p21 transcription, and directs cells to undergo apoptosis. PMID- 24492006 TI - Dissection of the role of p62/Sqstm1 in activation of Nrf2 during xenophagy. AB - Upon infection of a cell by Salmonella, p62/Sqstm1 assembles on the microbes; simultaneously, p62/Sqstm1 is phosphorylated at Ser351, leading to inactivation of Keap1, which is responsible for degrading Nrf2. Thus, cytoprotective Nrf2 targets are induced at the same time that autophagosomes entrap the microbes (xenophagy). However, the detailed role of p62/Sqstm1 during xenophagy has remained unclear. Here we show that translocation of p62/Sqstm1 to invasive Salmonella precedes Ser351 phosphorylation. Furthermore, in addition to Ser351 phosphorylation, oligomerization of p62/Sqstm1 is also required for localization of Keap1 onto microbes, which is followed by Nrf2 activation. Our data reveal the sequential dynamics of p62/Sqstm1 in response to bacterial infection. PMID- 24492007 TI - Structure and closure of connexin gap junction channels. AB - Connexin gap junctions comprise assembled channels penetrating two plasma membranes for which gating regulation is associated with a variety of factors, including voltage, pH, Ca(2+), and phosphorylation. Functional studies have established that various parts of the connexin peptides are related to channel closure and electrophysiology studies have provided several working models for channel gating. The corresponding structural models supporting these findings, however, are not sufficient because only small numbers of closed connexin structures have been reported. To fully understand the gating mechanisms, the channels should be visualized in both the open and closed states. Electron crystallography and X-ray crystallography studies recently revealed three dimensional structures of connexin channels in a couple of states in which the main difference is the conformation of the N-terminal domain, which have helped to clarify the structure in regard to channel closure. Here the closure models for connexin gap junction channels inferred from structural and functional studies are described in the context of each domain of the connexin protein associated with gating modulation. PMID- 24492008 TI - End-binding protein 1 (EB1) up-regulation is an early event in colorectal carcinogenesis. AB - End-binding protein (EB1) is a microtubule protein that binds to the tumor suppressor adenomatous polyposis coli (APC). While EB1 is implicated as a potential oncogene, its role in cancer progression is unknown. Therefore, we analyzed EB1/APC expression at the earliest stages of colorectal carcinogenesis and in the uninvolved mucosa ("field effect") of human and animal tissue. We also performed siRNA-knockdown in colon cancer cell lines. EB1 is up-regulated in early and field carcinogenesis in the colon, and the cellular/nano-architectural effect of EB1 knockdown depended on the genetic context. Thus, dysregulation of EB1 is an important early event in colon carcinogenesis. PMID- 24492010 TI - Domain isolation, expression, purification and proteolytic activity of the metalloprotease PrtV from Vibrio cholerae. AB - The metalloprotease PrtV from Vibrio cholerae serves an important function for the bacteria's ability to invade the mammalian host cell. The protein belongs to the family of M6 proteases, with a characteristic zinc ion in the catalytic active site. PrtV constitutes a 918 amino acids (102 kDa) multidomain pre-pro protein that so far has only been expressed in V. cholerae. Structural studies require high amounts of soluble protein with high purity. Previous attempts for recombinant expression have been hampered by low expression and solubility of protein fragments. Here, we describe results from parallel cloning experiments in Escherichia coli where fusion tagged constructs of PrtV fragments were designed, and protein products tested for expression and solubility. Of more than 100 designed constructs, three produced protein products that expressed well. These include the N-terminal domain (residues 23-103), the PKD1 domain (residues 755 839), and a 25 kDa fragment (residues 581-839). The soluble fusion proteins were captured with Ni2+ affinity chromatography, and subsequently cleaved with tobacco etch virus protease. Purification protocols yielded ~10-15 mg of pure protein from 1L of culture. Proper folding of the shorter domains was confirmed by heteronuclear NMR spectra recorded on 15N-labeled samples. A modified protocol for the native purification of the secreted 81 kDa pro-protein of PrtV is provided. Proteolytic activity measurements suggest that the 37 kDa catalytic metalloprotease domain alone is sufficient for activity. PMID- 24492009 TI - A 10-year follow-up of a population-based study of people with multiple sclerosis in Stockholm, Sweden: changes in health-related quality of life and the value of different factors in predicting health-related quality of life. AB - BACKGROUND: Health-related quality of life (HRQL) in people with multiple sclerosis (PwMS) is negatively affected compared to that of the general population. Cognitive impairment and depressive symptoms have been shown to predict worse HRQL in a short-term perspective. Considering the progressive nature of MS, it is essential to include the long-term (10 years) perspective of HRQL in PwMS. OBJECTIVES: The aim of this 10-year follow-up of a population-based sample of PwMS was to explore changes in and the predictive value of personal factors, degree of MS disability, depressive symptoms and cognitive impairment on HRQL. METHODS: Data on personal and disease-specific factors, mood, and cognitive function was collected. Data on HRQL was collected, seen as a health profile with the Sickness Impact Profile, as a health index with the EuroQol 5D and as a single global question with the EQ Visual Analog Scale. RESULTS: HRQL worsened over 10 years according to the health profile (Sickness Impact Profile Total and its physical dimension) and according to the health index. The effect sizes were small. HRQL assessed with the single global question remained unchanged. Depressive symptoms and cognitive impairment predicted worse HRQL. CONCLUSION: In a 10-year perspective the HRQL with regard to its physical domain or when seen as a total health profile tends to get worse in PwMS. Yet, HRQL with regard to its psychosocial domain and with regard to PwMS' self-rated health, remains stable. There is a potential for health-care professionals to decrease the impact of modifiable factors on HRQL in PwMS by identifying those with depressive symptoms and/or cognitive impairment and initiating evidence-based treatment as well as meeting the need for environmental facilitators aiming at reducing disability. PMID- 24492011 TI - Cloning, expression and mutational studies of a trypsin inhibitor that retains activity even after cyanogen bromide digestion. AB - A winged bean trypsin inhibitor (WbTI-2) of molecular mass ~20kDa, has been cloned and expressed in Escherichiacoli with full activity like the one from seed protein. It completely inhibits trypsin at an enzyme:inhibitor molar ratio of 1:2. PCR with cDNA and genomic DNA using same primers produced about 550 base pair product, which indicated it to be an intronless gene. Through site-directed mutagenesis, the Arg64 has been confirmed as the P1 residue. For the presence of five methionine residues in WbTI-2, cyanogen bromide (CNBr) digestion was carried out. Out of three fragments the one (about 65% of original size) containing the reactive site loop retained 50% activity. PMID- 24492012 TI - [Epidemiological characteristics and clinical features of black African subject's resistant hypertension]. AB - INTRODUCTION: Few studies in sub-Saharan Africa were interested in resistant hypertension. The objectives of this study were to determine the frequency of resistant hypertension in hypertensive black African population, and to describe its clinical and therapeutic features. PATIENTS AND METHODS: From May 1, 2010 to May 31, 2012, we included consecutively hypertensive followed in two hospitals in the city of Ouagadougou, under antihypertensive treatment at optimum dose and observant. Patients whose blood pressure was uncontrolled despite a triple antihypertensive therapy at the optimal dose including a diuretic associated with dietary measures have received ambulatory blood pressure monitoring. Following this examination, patients whose blood pressure was >=135/85mmHg during the day and/or >=120/70mmHg at night were considered resistant hypertension. We investigated the cardiovascular risk factors as well as target organ damages. We combined spironolactone 50mg in treatment when absence of contra-indication appreciated the evolution of blood pressure under this treatment. The measurement of plasma renin activity was not performed. Statistical analysis was performed using SPSS Version 17 for Windows. RESULTS: We included 692 patients with 14.6% of resistant hypertension. The average age of patients was 54.8+/-11.1years in the general population, 56.5+/-11.8years in the subgroup of non-resistant hypertension and 64.2+/-5.4years in the subgroup of resistant hypertension. The symptoms were represented by headache (11.9%), dizziness (9.9%) and chest pain (8.9%). Modifiable cardiovascular risk factors were dominated by dyslipidemia, diabetes and obesity/overweight. These risk factors were significantly more frequent in the subgroup of resistant hypertension. The global cardiovascular risk was high in 24.9% of cases in the general population, 22.5% in the subgroup of non-resistant hypertension and 38.6% in the subgroup of resistant hypertension. The target organ damages were significantly more frequent in the same subgroup of resistant hypertension. After addition of spironolactone, 21.8% of resistant hypertensive patients were controlled. CONCLUSION: This study shows that resistant hypertension is common in black Africans. It is mostly subjects of the sixth decade, with limited economic income and living in rural areas. In the absence of contra-indication, spironolactone contributed to decrease the morbidity of this pathology. PMID- 24492013 TI - DNA vaccines encoding altered peptide ligands for SSX2 enhance epitope-specific CD8+ T-cell immune responses. AB - Plasmid DNA serves as a simple and easily modifiable form of antigen delivery for vaccines. The USDA approval of DNA vaccines for several non-human diseases underscores the potential of this type of antigen delivery method as a cost effective approach for the treatment or prevention of human diseases, including cancer. However, while DNA vaccines have demonstrated safety and immunological effect in early phase clinical trials, they have not consistently elicited robust anti-tumor responses. Hence many recent efforts have sought to increase the immunological efficacy of DNA vaccines, and we have specifically evaluated several target antigens encoded by DNA vaccine as treatments for human prostate cancer. In particular, we have focused on SSX2 as one potential target antigen, given its frequent expression in metastatic prostate cancer. We have previously identified two peptides, p41-49 and p103-111, as HLA-A2-restricted SSX2-specific epitopes. In the present study we sought to determine whether the efficacy of a DNA vaccine could be enhanced by an altered peptide ligand (APL) strategy wherein modifications were made to anchor residues of these epitopes to enhance or ablate their binding to HLA-A2. A DNA vaccine encoding APL modified to increase epitope binding elicited robust peptide-specific CD8+ T cells producing Th1 cytokines specific for each epitope. Ablation of one epitope in a DNA vaccine did not enhance immune responses to the other epitope. These results demonstrate that APL encoded by a DNA vaccine can be used to elicit increased numbers of antigen specific T cells specific for multiple epitopes simultaneously, and suggest this could be a general approach to improve the immunogenicity of DNA vaccines encoding tumor antigens. PMID- 24492014 TI - Carrier priming or suppression: understanding carrier priming enhancement of anti polysaccharide antibody response to conjugate vaccines. AB - INTRODUCTION: With the availability of newer conjugate vaccines, immunization schedules have become increasingly complex due to the potential for unpredictable immunologic interference such as 'carrier priming' and 'carrier induced epitopic suppression'. Carrier priming refers to an augmented antibody response to a carbohydrate portion of a glycoconjugate vaccine in an individual previously primed with the carrier protein. This review aims to provide a critical evaluation of the available data on carrier priming (and suppression) and conceptualize ways by which this phenomenon can be utilized to strengthen vaccination schedules. METHODS: We conducted this literature review by searching well-known databases to date to identify relevant studies, then extracted and synthesized the data on carrier priming of widely used conjugate polysaccharide vaccines, such as, pneumococcal conjugate vaccine (PCV), meningococcal conjugate vaccine (MenCV) and Haemophilus influenzae type b conjugate vaccines (HibV). RESULTS: We found evidence of carrier priming with some conjugate vaccines, particularly HibV and PCV, in both animal and human models but controversy surrounds MenCV. This has implications for the immunogenicity of conjugate polysaccharide vaccines following the administration of tetanus-toxoid or diphtheria-toxoid containing vaccine (such as DTP). CONCLUSION: Available evidence supports a promising role for carrier priming in terms of maximizing the immunogenicity of conjugate vaccines and enhancing immunization schedule by making it more efficient and cost effective. PMID- 24492015 TI - School-based vaccination of young US males: impact of health beliefs on intent and first dose acceptance. AB - Little is known about adolescent males and their parents with respect to intent and first dose uptake of the human papillomavirus (HPV) vaccine outside of primay care settings. The purpose of this study was to evaluate potential predictors of parental intent to vaccinate (study was conducted in November 2010-December 2012) and of first dose uptake of HPV vaccine among a sample of young adolescent males, 11-15 years of age, who received care at a school-based health center (SBHC). We also examined intent as a potential mediator of the relationships between predictors (health beliefs and perceived spousal agreement) and vaccination. Slightly more than half (n=135 of 249) of parents reported an intention to vaccinate and 28% (n=69) of males received their first dose of the HPV vaccine. Two of three health beliefs were significantly associated with both intention and uptake as was perceived spousal agreement. We found intention to vaccinate was a partial mediatator between the perceived benefits of HPV vaccine and first dose acceptance. We also determined that intent was a strong mediator between both general immunization benefits and perceived spousal agreement and first dose uptake. While vaccine uptake was lower than expected, particularly considering that many barriers to vaccine initiation were eliminated because of the SBHC setting, this rate is higher than in traditional settings. After controlling for intent, only perceived benefits of the HPV vaccine remained a significant predictor of first dose acceptance. PMID- 24492016 TI - Refusal of oral polio vaccine in northwestern Pakistan: a qualitative and quantitative study. AB - BACKGROUND: Refusal of the oral polio vaccine (OPV) is a difficulty faced by the Polio Eradication Initiative (PEI) in multiple endemic areas, including the Khyber Pakhtunkhwa Province (KPP), Pakistan. In 2007, we investigated community perceptions of the OPV and estimated the prevalence of OPV refusal in three districts in Swat Valley, KPP, a polio-endemic area. METHODS: Qualitative data concerning community perceptions were collected by focus group discussions among lady health workers (LHWs) and mothers with children <1 year old and by key informant interviews with local health managers and officials. Quantitative data collection followed using a questionnaire survey of 200 LHWs and a cluster sampling survey of 210 mothers (per district) with children <1 year old. RESULTS: The qualitative assessments identified the grounded theory of OPV refusal involving facts known by the residents that are related to the OPV (too frequent OPV campaigns, an OPV boycott in northern Nigeria in 2003 and that birth control is viewed as is against Islam), the local interpretations of these facts (perceptions that OPV contained birth control or pork, that OPV was a foreign/central plot against Muslims, and that the vaccination was against the Hadith and the fate determined by God) and different manifestations of OPV refusal. Among the three districts studied, the proportion of LHWs who encountered OPV refusal ranged from 0 to 33%, whereas among the districts, the proportions of mothers unwilling to give OPV to their children ranged from 0.5 to 5.7%. Refusal of other injectable vaccines was almost equally prevalent for reasons that were very similar. CONCLUSIONS: The PEI needs to reflect local value system in the path to polio eradication in the studied districts in the Swat Valley. The religious and cultural values as well as the interpretation of the international political situation are of particular importance. PMID- 24492017 TI - A novel HCN4 mutation, G1097W, is associated with atrioventricular block. AB - BACKGROUND: Loss-of-function mutations in the HCN4 gene have been shown to be associated with sinus dysfunction, but there are no reports on HCN4-mediated atrioventricular (AV) block. A novel missense HCN4 mutation G1097W was identified in a 69 year-old Japanese male with AV block, and we characterized the functional consequences of If-like channels reconstituted with the heterozygous HCN4 mutation. METHODS AND RESULTS: Wild-type (WT) HCN4 or/and HCN4-G1097W were expressed in a heterologous cell expression system. A functional assay using a whole-cell patch-clamp demonstrated that the mutant If-like currents were activated at more negative voltages compared to WT currents, while they retained the sensitivity to changes in intracellular cyclic adenosine monophosphate (cAMP) levels. Co-expression of G1097W with WT channels showed dominant-negative effects, including a reduction in peak currents and a negative voltage shifting on reconstituted currents. CONCLUSIONS: The HCN4-G1097W mutant channels displayed a loss-of-function type modulation on cardiac If channels and thus could predispose them to AV nodal dysfunction. These data provide a novel insight into the genetic basis for the AV block. PMID- 24492019 TI - Novel pathways and products from 2-keto acids. AB - Since traditional chemical processes are non-renewable and environmentally unfriendly, biosynthesis is emerging as an attractive alternative for the production of advanced biofuels, chemicals, pharmaceuticals and polymers. Cost competitive biomanufacturing requires the design of metabolic pathways that can achieve high production yields and rates. Recent advances in natural amino acid production have motivated the use of 2-ketoacid intermediates for the production of important chemicals. These 2-ketoacids undergo a wide range of efficient biochemical reactions leading to an array of industrially useful products. In this review, recently developed novel pathways based on 2-ketoacids will be described along with representative examples. PMID- 24492018 TI - Use of antihypertensive medications and diagnostic tests among privately insured adolescents and young adults with primary versus secondary hypertension. AB - PURPOSE: To compare the use of antihypertensive medications and diagnostic tests among adolescents and young adults with primary versus secondary hypertension. METHODS: We conducted retrospective cohort analysis of claims data for adolescents and young adults (12-21 years of age) with >=3 years of insurance coverage (>=11 months/year) in a large private managed care plan during 2003-2009 with diagnosis of primary hypertension or secondary hypertension. We examined their use of antihypertensive medications and identified demographic characteristics and the presence of obesity-related comorbidities. For the subset receiving antihypertensive medications, we examined their diagnostic test use (echocardiograms, renal ultrasounds, and electrocardiograms). RESULTS: The study sample included 1,232 adolescents and young adults; 84% had primary hypertension and 16% had secondary hypertension. The overall prevalence rate of hypertension was 2.6%. One quarter (28%) with primary hypertension had one or more antihypertensive medications, whereas 65% with secondary hypertension had one or more antihypertensive medications. Leading prescribers of antihypertensives for subjects with primary hypertension were primary care physicians (80%), whereas antihypertensive medications were equally prescribed by primary care physicians (43%) and sub-specialists (37%) for subjects with secondary hypertension. CONCLUSIONS: The predominant hypertension diagnosis among adolescents and young adults is primary hypertension. Antihypertensive medication use was higher among those with secondary hypertension compared with those with primary hypertension. Further study is needed to determine treatment effectiveness and patient outcomes associated with differential treatment patterns used for adolescents and young adults with primary versus secondary hypertension. PMID- 24492020 TI - Transmission of Dientamoeba fragilis: pinworm or cysts? AB - Recently, conflicting evidence has been published on the mode of transmission of the trichomonad Dientamoeba fragilis. Detection of D. fragilis DNA inside Enterobius vermicularis eggs agrees with the prediction of Dobell in 1940 that the eggs of a nematode act as a vector for transmission. However, the identification of a cyst stage of D. fragilis in the stool of rodents infected with a human isolate has also been reported, and this implies a life cycle similar to those of most other intestinal protistan parasites. Herein we discuss the recent data, identify gaps in the experimental evidence, and propose a method for determining which view of the life cycle of this organism is correct. PMID- 24492021 TI - Direct and indirect associations between social anxiety and nicotine dependence and cessation problems: multiple mediator analyses. AB - INTRODUCTION: Little empirical work has evaluated why socially anxious smokers are especially vulnerable to more severe nicotine dependence and cessation failure. Presumably, these smokers rely on cigarettes to help them manage their chronically elevated negative affect elicited by a wide array of social contexts. METHODS: The current study examined the direct and indirect effects of social anxiety cross-sectionally in regard to a range of smoking processes among 466 treatment-seeking smokers. Negative affect and negative affect reduction motives were examined as mediators of the relations of social anxiety with nicotine dependence and cessation problems. RESULTS: Social anxiety was directly and robustly associated with perceived barriers to smoking cessation and problems experienced during past quit attempts. Social anxiety was also associated with greater nicotine dependence and smoking inflexibility indirectly through negative affect and negative affect smoking motives. Negative affect and smoking to reduce negative affect mediated these relations. CONCLUSIONS: These findings document the important role of negative affect and negative affect reduction motives in the relationships of social anxiety with nicotine dependence and cessation problems. PMID- 24492022 TI - Effectiveness of combined therapy with angiotensin-converting enzyme inhibitors and statins in reducing mortality in diabetic patients with critical limb ischemia: an observational study. AB - AIMS: To investigate the effect of combined treatment with angiotensin-converting enzyme inhibitors (ACE) and statins on mortality in diabetic patients with critical limb ischemia (CLI). METHODS: Prospective observational study of 553 consecutive diabetic patients admitted because of CLI followed for a mean of 2.2 years. All patients underwent peripheral revascularization and antithrombotic therapy was prescribed or continued and therapy with statin and ACE was recorded. Mortality from any cause was assessed and Kaplan-Meier analyses were performed to compare the relationship between survival and recorded variables. RESULTS: One hundred thirty-nine patients did not have therapy with statin or an ACE, 78 had therapy with statin without ACE, 164 had therapy with ACE without statin and 172 patients had therapy with both statin and ACE. One hundred thirty-six patients died, 45/139 with neither statin nor ACE, 40/164 with ACE only, 26/78 with statin only, and 25/172 with both statin and ACE. Multivariate analysis confirmed the independent role of age, history of stroke, renal insufficiency and dialysis. Combined treatment with ACE and statin appeared to have a protective role. CONCLUSIONS: In patients with diabetes and CLI mortality after two years is high. Life expectancy was better in patients receiving combined therapy with ACE and statin but not with therapy with only a statin or an ACE. PMID- 24492023 TI - Testosterone regulates the density of dendritic spines in the male preoptic area. AB - Male-typical behavior is dependent on testosterone. Castrated males gradually stop mating and engaging in sexual behaviors. Castrates treated with testosterone regain motivation and sex behaviors over time. Although this effect is well characterized, the specific mechanisms by which testosterone treatment recovers sexual behaviors remain unknown. The medial preoptic area (MPOA) is a likely site for testosterone's action on copulation. The integrity of the area is essential for the expression of male sex behavior; and the MPOA is densely populated with receptors for gonadal steroids. Moreover testosterone appears to regulate synaptic efficacy in the MPOA. Exposure to sexually relevant stimuli stimulates the MPOA but only in the presence of circulating testosterone. Sites afferent to the area respond to similar exposure independent of the hormonal milieu suggesting that testosterone mediates communication between the MPOA and its afferents. The protracted time course suggests that the effects of steroidal manipulation are mediated by structural changes. The present experiment evaluated this hypothesis by comparing dendritic spine density among Syrian hamsters that were castrated, castrated and treated with testosterone, or were left gonadally intact. Brains were sectioned and stained using the rapid Golgi stain protocol (FD Neurotechnologies, Baltimore), and the spine density, dendrite length, and the number of branches were compared among groups. Intact and testosterone replaced animals had more spines and greater spine density but did not differ in dendrite length and branching from castrated animals. These results suggest that existing dendrites increase the number of spines available for synapse formation but do not extend their dendrites in response to testosterone treatment. PMID- 24492024 TI - Effects of housing condition and early corticosterone treatment on learned features of song in adult male zebra finches. AB - Early developmental stress can have long-term physiological and behavioral effects on an animal. Developmental stress and early corticosterone (Cort) exposure affect song quality in many songbirds. Early housing condition can act as a stressor and affect the growth of nestlings and adult song, and improvements in housing condition can reverse adverse effects of early stress exposure in rodents. However, little is known about this effect in songbirds. Therefore, we took a novel approach to investigate if housing condition can modify the effects of early Cort exposure on adult song in male zebra finches. We manipulated early housing conditions to include breeding in large communal flight cages (FC; standard housing condition; with mixed-sex and mix-aged birds) versus individual breeding cages (IBC, one male-female pair with small, IBC-S, or large clutches, IBC-L) in post-hatch Cort treated male birds. We found that Cort treated birds from IBC-S have higher overall song learning scores (between tutor and pupil) than from FC but there is no difference between these groups in the No-Cort treated birds. When examining the effects of Cort within each housing condition, overall song learning scores decreased in Cort treated birds from flight cages but increased in birds from IBC-S compared to controls. Likewise, the total number of syllables and syllable types increased significantly in Cort treated birds from IBC-S, but decreased in FC-reared birds though this effect was not statistically significant. These findings suggest that the effects of early Cort treatment on learned features of song depend on housing condition. PMID- 24492025 TI - Antimicrobial susceptibility of Gram-negative organisms isolated from patients hospitalized in intensive care units in United States and European hospitals (2009-2011). AB - Treatment of infections in the intensive care unit (ICU) represents a great challenge, especially those caused by Gram-negative organisms. Rapid introduction of appropriate antimicrobial therapy is crucial to reduce mortality; resistance rates in the ICU can be elevated due to antimicrobial selection pressure. We evaluated the antimicrobial susceptibility patterns of Gram-negative bacteria isolated from patients hospitalized in ICUs (ICU patients). The isolates were consecutively collected as part of the SENTRY Antimicrobial Surveillance Program from January 2009 to December 2011 and tested for susceptibility to multiple antimicrobial agents at a central laboratory by reference broth microdilution methods. Antimicrobial susceptibility results for 5989 bacterial isolates from ICU patients (3445 from the United States [USA] and 2544 from Europe [EU]) were analyzed and compared to those of 17,244 organisms from non-ICU patients (9271 from USA and 7973 from EU). Escherichia coli, Klebsiella spp., and Pseudomonas aeruginosa were the most frequently isolated organisms from ICU patients, followed by Enterobacter spp., Serratia spp., Haemophilus influenzae, Acinetobacter spp., and Proteus mirabilis. Susceptibility rates were generally lower among ICU isolates compared to non-ICU organisms. E. coli isolates from ICU patients exhibited elevated extended-spectrum beta-lactamase (ESBL)-phenotype rates (13.7% in USA and 16.6% in EU); furthermore, only amikacin (90.5-94.8% susceptibility), colistin (99.8-100.0% inhibited at <=2 MUg/mL), imipenem (95.5 96.0%), meropenem (95.4-95.8%), and tigecycline (96.3-98.0%) exhibited good activity against Klebsiella spp. ESBL-phenotype rates have increased among both E. coli and Klebsiella spp. from ICU patients in the USA and in Europe, with the most noticeable increase among Klebsiella spp. from Europe (from 27.5% in 2009 to 41.8% in 2011; P = 0.015 and odds ratio = 0.89 [95% confidence interval, 1.13 3.18]). Meropenem susceptibility among Klebsiella spp. improved slightly in the USA but decreased markedly in Europe from 100.0% in 2009 to 89.7% in 2011. Only colistin (99.4% susceptible) and amikacin (97.3% in USA and 84.9% in EU) exhibited good activity against P. aeruginosa strains from ICU patients. The greatest differences in susceptibility rates between P. aeruginosa strains from ICU and non-ICU patients were observed for the anti-pseudomonal beta-lactams, such as ceftazidime, meropenem, and piperacillin/tazobactam. The results of this study (101 medical centers) highlight major antimicrobial coverage problems and trends in antimicrobial resistance for USA and EU ICU patient isolates. PMID- 24492026 TI - Development of a tick-borne encephalitis serodiagnostic ELISA using recombinant Fc-antigen fusion proteins. AB - Current diagnostic tests for tick-borne encephalitis virus (TBEV) infections require high-biosafety facilities for antigen preparation and can cross-react with other flaviviruses. There is, therefore, a need to develop safe, inexpensive serodiagnostic tools with high specificity and sensitivity. In this study, a recombinant plasmid that expresses the membrane and envelope (E) proteins of TBEV fused to the Fc domain of rabbit IgG was constructed and expressed in mammalian cells. The E-Fc proteins were secreted as soluble homodimers, which retained reactivity with anti-TBEV and anti-rabbit IgG antibodies. The E-Fc proteins were then used to develop an enzyme-linked immunosorbent assay (ELISA) to detect TBEV antibodies in rodent and human sera. Compared with the neutralization test, the ELISA had over 90% sensitivity and specificity. In addition, the assay showed no cross-reactivity with Japanese encephalitis virus antibodies. These findings suggest that the E-Fc ELISA may be a useful tool for TBEV serodiagnosis. PMID- 24492027 TI - [Usefulness of measuring serum procalcitonin levels by immunochromatographic assay in febrile neutropenia]. AB - In order to clarify the usefulness of measuring procalcitonin (PCT) values under the extreme condition called febrile neutropenia (FN), PCT was measured with immunochromatographic assay (ICA) and electro-chemi-luminescence immunoassay (ECLIA) at two time points: upon FN occurrence and 12 to 24 hours after FN occurrence, and correlations and associations between the two methods were reviewed. A strong correlation between the ICA and ECLIA results was observed when Spearman's rank correlation coefficient was 0.878, and the association was also demonstrated by Fisher's direct test since P=4.68*10(-10). Special equipment is not required, the operations are simple, and the ICA method currently adopted by many facilities can be used as the standard method even for the clinical condition known as FN. PMID- 24492028 TI - [Picture in clinical hematology no. 69--Case of asymptomatic limbic leukoencephalopathy due to methotrexate therapy]. PMID- 24492029 TI - [Preface--Special editions of The Japanese Journal of Clinical Hematology regarding "Future prospects of clinical hematology"]. PMID- 24492030 TI - [Overview on recent therapeutic strategy for hematologic disorders of erythrocyte]. PMID- 24492031 TI - [Recent issues and prospects of the treatment of aplastic anemia]. PMID- 24492032 TI - [Myelodysplastic syndromes: treatment strategy up-to-date]. PMID- 24492033 TI - [Current therapeutic strategy for hemolytic anemia: paroxysmal nocturnal hemoglobinuria]. PMID- 24492034 TI - [Overview--Recent therapeutic strategy for hematologic disorders of bone marrow]. PMID- 24492035 TI - [Current therapy for acute myeloid leukemia and acute promyelocytic leukemia]. PMID- 24492036 TI - [Chronic myeloid leukemia: up-to-date management]. PMID- 24492037 TI - [Management strategy for BCR-ABL negative myeloproliferative neoplasms]. PMID- 24492038 TI - [Overview--Recent therapeutic strategy for blood coagulation disorders]. PMID- 24492039 TI - [Treatment of acquired inhibitors of coagulation factors]. PMID- 24492040 TI - [Recent therapeutic strategy for disseminated intravascular coagulation]. PMID- 24492041 TI - [Pathogenesis and management of immune thrombocytopenia]. PMID- 24492042 TI - [Recent therapeutic strategy for thrombotic thrombocytopenic purpura]. PMID- 24492043 TI - [Single institution experience of HLA-haploidentical hematopoietic stem cell transplantation for children: current problems and perspective]. AB - HLA-haploidentical 2 or 3-loci mismatched families are alternative donors for high-risk patients without HLA-matched donors. We retrospectively reviewed our case series of HLA-halpoidentical hematopoietic stem cell transplantations (haplo HSCTs). Between Jul 2005 and Dec 2012, 25 patients (median age, 8 y; 13 ALL, 8 AML, 4 others) received haplo-HSCTs because of a worsening prognosis (i.e. induction failure, non-CR, or relapse after prior HSCT). Disease status was CR in 8 and non-CR in 17 patients. The 17 patients received myeloablative conditioning, while the 8 were given reduced-intensity conditioning because of their conditions (e.g. early relapse after prior HSCT). ATG was not administered in all but 3 patients. Tacrolimus and sMTX were used for prophylaxis GVHD and steroids were immediately given to prevent the onset of aGVHD. The 3-year OS and EFS were 35.6+/-10.0% and 31.3+/-10.1%, respectively (median follow-up, 49 mo); 14 patients died of their primary disease. Grade 3-4 aGVHD occurred in 7 patients, 2 of whom died of grade 4 aGVHD. Eleven patients had extensive cGVHD. While 4 of the 8 CR patients remained in CR, only 4 of the 17 non-CR patients achieved long term CR (survival time, 6-89 mo). Haplo-HSCT was tolerable with strict control of infections and GVHD. However, further strategies for non-CR patients appear to be required. PMID- 24492044 TI - [Successful treatment with high-dose methotrexate/cytarabine regimen in a patient in SMILE regimen-resistant extranodal natural killer/T-cell lymphoma]. AB - A 28-year-old man complained of pain in the oral mucosa and pharynx in March 2011, and then developed fever and generalized swelling of the cheek. In March 2012, a gum biopsy led to a diagnosis of extranodal natural killer/T-cell lymphoma (ENKL). (18)F-FDG-PET revealed significant uptake in the mouth, tonsils, jawbone, shoulder blade, humerus, ilium, femur, and spleen. After two courses of the SMILE (dexamethasone, methotrexate (MTX), ifosfamide, L-asparaginase, etoposide) regimen, the response was stable disease. However, a high-dose MTX/cytarabine (MA) regimen was effective. After three courses of the MA regimen, a partial response was achieved. Then, allogeneic bone marrow transplantation from an unrelated donor was performed. At 10 months after transplantation, there was no sign of recurrence. Although the optimal treatment for ENKL refractory to the SMILE regimen has yet to be established, our case suggests the MA regimen to be a potentially effective treatment option. PMID- 24492045 TI - [Hydroxyurea (hydroxycarbamide)-induced hepatic dysfunction confirmed by drug induced lymphocyte stimulation test]. AB - A 62-year-old man with refractory leukemia transformed from myelodysplastic syndrome was placed on hydroxyurea (hydroxycarbamide) at a daily dose of 500 mg. Because of insufficient cytoreductive efficacy, the dose was increased to 1,500 mg five days later. Eight days after the initiation of hydroxyurea, the patient started complaining of chills, fever, and vomiting. Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) were markedly elevated to 5,098 and 3,880 IU/l from 44 and 59 IU/l in one day, respectively. Tests for hepatitis viruses were all negative. With the discontinuation of hydroxyurea, AST and ALT returned to their former levels within two weeks. A drug-induced lymphocyte stimulation test for hydroxyurea was positive with a stimulating index of 2.0. Hepatic dysfunction has been recognized as one of the side effects of hydroxyurea. However, there have been only a limited number of reports demonstrating drug allergy to have a role in hepatic dysfunction accompanied by fever and gastrointestinal symptoms. The findings of our case strongly suggest that all presentations could be explained by drug allergy. Physicians should be mindful of the potential for acute and severe hepatic dysfunction due to allergic reaction against hydroxyurea. PMID- 24492046 TI - [Intestinal bleeding in patients with chronic myelogenous leukemia treated with tyrosine kinase inhibitors]. AB - Tyrosine kinase inhibitors (TKIs) are highly effective in the treatment of chronic myelogenous leukemia (CML), but there have been a few adverse event reports describing gastrointestinal bleeding. We clinically analyzed two patients who developed intestinal bleeding during the administration of TKIs for CML. Platelet counts of both patients were normal. The patients showed endoscopic findings characterized by mildly hemorrhagic mucosa. The imatinib patient was diagnosed by capsule endoscopy of the small intestine, and required frequent blood transfusions. The dasatinib patient showed occult bleeding due to CD8 positive colitis. We should adequately recognize that gastrointestinal bleeding may occur during the administration of TKIs. PMID- 24492049 TI - Cyprinid herpesvirus-2 causing mass mortality in goldfish: applying electron microscopy to histological samples for diagnostic virology. AB - In June 2013, a major fish kill of adult goldfish Carassius auratus occurred in Runnemede Lake, New Jersey, USA: an estimated 3000 to 5000 fish died within ~5 d. Necropsy of 4 moribund fish revealed severely pale gills, and histopathology showed type I and II fusion of the gills, diffuse necrosis of hematopoietic tissue in anterior and posterior kidney, and multifocal necrosis of the spleen. Within necrotic areas, pyknosis and enlarged nuclei with marginalized chromatin were observed. Cyprinid herpesvirus-2, the etiological agent for herpesviral hematopoietic necrosis disease, was confirmed in all 4 fish using PCR. We assessed the efficacy of identifying herpesviral infections (viral morphogenesis and cellular ultrastructure) using transmission electron microscopy (TEM) when applied to tissues fixed in 10% neutral buffered formalin (NBF) and tissue that was removed from paraffin blocks. Both sample types could be used to detect the virus within cells at similar concentrations. Tissues reprocessed from 10% NBF contained all the known stages of viral morphogenesis including empty capsids, capsids with an inner linear concentric density, capsids with an electron-dense core, and in the cytoplasm, mature capsids containing an envelope. Paraffin embedded tissues showed similar stages, but viral capsids with an inner linear concentric density were rare and mature enveloped virions were not observed. In previously paraffin-embedded tissues, cellular membranes were not preserved, making identification of cell types and organelles difficult, whereas membrane preservation was good in tissues processed from 10% NBF. The results demonstrated that routinely fixed and paraffin-embedded samples can be successfully utilized to diagnose herpesviruses, and formalin-fixed tissue could be used to describe viral morphogenesis by TEM, making this a useful and reliable method for diagnostic virology when other samples are not available. PMID- 24492050 TI - Antibiotic uptake by cultured Atlantic cod leucocytes and effect on intracellular Francisella noatunensis subsp. noatunensis replication. AB - The granuloma disease caused by Francisella noatunensis subsp. noatunensis in farmed Atlantic cod has not been successfully treated by use of antibacterials, even when antibacterial resistance testing indicates a sufficient effect. The reason for this treatment failure may be the intracellular existence of the bacteria within immune cells, mainly macrophages. To investigate the effect of antibacterials on intracellular Francisella replication, we established a protocol for the detection of drugs within Atlantic cod immune cells using high performance liquid chromatography (HPLC). When the uptake and intracellular concentrations of oxolinic acid and flumequine were analysed in isolated adherent head kidney leucocytes (HKLs) by HPLC, we found that uptake was rapid and the intracellular concentrations reflected the extracellular exposure concentrations. To investigate the effect of the antibacterial compounds on intracellular bacterial replication, adherent HKLs experimentally infected with the bacteria were analysed using flow cytometry and intracellular labelling of bacteria by specific antibodies. We found that flumequine did not inhibit intracellular bacterial replication. Unexpectedly, the results indicated that the intracellularly effiacy of the drug was reduced. The HPLC method used proved to be highly applicable for accurate determination of intracellular drug concentrations. When combined with sensitive and specific flow cytometry analyses for identification and measurement of intracellular bacterial replication, we suggest that this approach can be very valuable for the design of antibacterial treatments of intracellular pathogens. PMID- 24492051 TI - Edwardsiella piscicida identified in the Southeastern USA by gyrB sequence, species-specific and repetitive sequence-mediated PCR. AB - A new Edwardsiella taxon was recently described from fishes of Europe and Asia. Phenotypically similar to E. tarda, extensive genetic and phenotypic characterization determined this new strain does not belong to any established Edwardsiella taxa, leading to the adoption of a new taxon, E. piscicida. Concurrent research in the USA also identified 2 genetically distinct taxa within the group of organisms traditionally classified as E. tarda. Comparisons of gyrB sequences between US isolates and E. piscicida from Europe and Asia identified several US isolates with >99.6% similarity to the gyrB sequence of the E. piscicida type strain (ET883) but <87% similarity to the E. tarda type strain (ATCC #15947). A discriminatory PCR was developed for the identification of E. tarda and 2 genetic variants of E. piscicida (E. piscicida and E. piscicida-like species). Using these PCR assays, a survey was conducted of 44 archived bacterial specimens from disease case submissions to the Aquatic Research and Diagnostic Laboratory (Stoneville, MS, USA) between 2007 and 2012. All 44 isolates, originally identified phenotypically and biochemically as E. tarda, were identified as E. piscicida by PCR. Repetitive sequence-mediated PCR (rep-PCR) analysis of these archived specimens suggests they are largely homogenous, similar to what has been observed for E. ictaluri. The gyrB sequence data, coupled with the E. piscicida specific-PCR and rep-PCR data, confirms that E. piscicida has been isolated from fish disease cases in the southeastern USA. Moreover, our survey data suggests E. piscicida may be more prevalent in catfish aquaculture than E. tarda. PMID- 24492052 TI - In vitro growth of the microsporidian Heterosporis saurida in the eel kidney EK-1 cell line. AB - Heterosporis saurida is an intracellular microsporidian that infects lizardfish Saurida undosquamis. Although some attempts have been introduced to clarify microsporidian host-pathogen interactions, development of novel strategies to combat fish diseases is still needed. Here we present an in vitro cultivation model for fish microsporidia based on an eel kidney cell line (EK-1), which is susceptible to infection by H. saurida. Spores were isolated from infected lizardfish and used to inoculate EK-1 cells. H. saurida were propagated in the eel kidney EK-1 cell line and detected by immunofluorescence. Developmental stages of H. saurida were seen in EK-1 cells by transmission electron microscopy. Identity of the parasite was confirmed by partial sequencing of the 16S rDNA gene. Our cell culture model provides a valuable means to explore molecular and immunological events and will facilitate development of effective treatment strategies. PMID- 24492053 TI - Seasonal monitoring of Kudoa yasunagai from sea water and aquaculture water using quantitative PCR. AB - Kudoid myxozoans pose serious chronic problems in marine fisheries by causing pathological damage to host fish, reducing the market value of infected fish and potentially threatening public health. Kudoa yasunagai is a cosmopolitan parasite that infects the brains of various marine fishes, including important aquaculture species. We developed a quantitative PCR assay to detect K. yasunagai in sea water, and we used it to monitor abundance of the parasite in the environment and in culture through spring and winter. Quantitative PCR detected K. yasunagai DNA from sea water, with the lowest reliable threshold of 162 copies 28S rDNA l-1. Parasite DNA was detected sporadically in sea water throughout the study period of May through December 2012. The highest level of detected DNA occurred in mid December (winter), at 117180 copies-equivalent to an estimate of over 200 myxospores l-1. Parasite DNA was generally not detected in August or September, the period with the highest water temperature. The reason for this observation is unknown, but the timing of parasite development may play a role. The amount of detected DNA was not different between unfiltered culture water and water filtered through a high-speed fiber filtration system. This result and the past incidence of high infection rate of fish reared in filtered water indicate that the mechanical removal of K. yasunagai from culture water is difficult. Detecting the precise onset and time window of infection in host fish will be an important step in the development of measures to control this economically important parasite. PMID- 24492054 TI - Occurrence of tumour (odontoma) in marine fish Sphyraena jello from the southeast coast of India. AB - We examined the occurrence of odontoma in the marine fish Sphyraena jello sourced from 3 different landing centers (Cuddalore, Parangipettai and Nagapattinam) in Tamil Nadu (southeast India). A total of 19783 fishes were examined for odontoma presence, of which 2393 were affected with odontoma. The overall prevalence was 12.1% among the 3 stations. Fish landed at Parangipettai showed the highest peak prevalence of odontoma (16.8%) during the pre-monsoon, followed by Nagapatinam (9.1%) during summer 2011. The tumour lengths in premaxilla, supermaxilla and dentary bone were 1.1-3.6, 1.4-5.9 and 1.2-4.1 cm, respectively, and tumour widths were 0.3-1.9, 0.7-3.1 and 0.5-1.9 cm. Higher prevalence (0.206%) of tongue tumour along with odontoma was observed at Nagapattinam whereas it was lower (0.162%) at Cuddalore. Odontoma histopathology showed dense fibrous tissue with fine teeth roots. TEM analysis showed virus-like particles associated with odontoma. Radiography of the odontoma showed that the tumour masses were bony in nature and tissues were merged with upper and lower jaw. PMID- 24492055 TI - Gastrointestinal parasites of bottlenose dolphins Tursiops truncatus from the extreme Southwestern Atlantic, with notes on diet composition. AB - We surveyed the gastrointestinal tracts of 6 bottlenose dolphins Tursiops truncatus from Patagonia to check for helminth parasites and characterize dolphin diet. All dolphins harbored parasites (6477 helminths). We recorded 7 species, including nematodes Anisakis simplex s.l., Pseudoterranova decipiens, acanthocephalans Corynosoma cetaceum, C. australe, and digeneans Braunina cordiformis, Pholeter gastrophilus and Synthesium tursionis. Among the gastric helminths, the most prevalent species were C. cetaceum and A. simplex while C. australe and S. tursionis inhabited the intestine at low prevalence. This is the first report of C. australe and P. decipiens in bottlenose dolphins. Regarding diet, 5 stomachs contained food remains (consisting of 103 prey items). The most important prey species were Geotria australis and Stromateus brasiliensis, but their role in parasite transmission is unclear. At the community level, the gastrointestinal parasite community of T. truncatus was depauperate and strongly overlapped the community described for pelagic dolphins inhabiting Patagonia, suggesting a strong local influence in shaping helminth communities. Nevertheless, these observations are at odds with the notion that oceanic cetaceans have comparatively poorer helminth fauna than neritic species such as bottlenose dolphins, due to the lower likelihood of parasite exchange. PMID- 24492056 TI - Clinicoimmunopathologic findings in Atlantic bottlenose dolphins Tursiops truncatus with positive Chlamydiaceae antibody titers. AB - Sera from free-ranging Atlantic bottlenose dolphins Tursiops truncatus inhabiting the Indian River Lagoon (IRL), Florida, and coastal waters of Charleston (CHS), South Carolina, USA, were tested for antibodies to Chlamydiaceae as part of a multidisciplinary study of individual and population health. A suite of clinicoimmunopathologic variables was evaluated in Chlamydiaceae-seropositive dolphins (n = 43) and seronegative healthy dolphins (n = 83). Fibrinogen, lactate dehydrogenase, amylase, and absolute numbers of neutrophils, lymphocytes, and basophils were significantly higher, and serum bicarbonate, total alpha globulin, and alpha-2 globulin were significantly lower in dolphins with positive Chlamydiaceae titers compared with seronegative healthy dolphins. Several differences in markers of innate and adaptive immunity were also found. Concanavalin A-induced T lymphocyte proliferation, lipopolysaccharide-induced B lymphocyte proliferation, and granulocytic phagocytosis were significantly lower, and absolute numbers of mature CD 21 B lymphocytes, natural killer cell activity and lysozyme concentration were significantly higher in dolphins with positive Chlamydiaceae antibody titers compared to seronegative healthy dolphins. Additionally, dolphins with positive Chlamydiaceae antibody titers had significant increases in ELISA antibody titers to Erysipelothrix rhusiopathiae. These data suggest that Chlamydiaceae infection may produce subclinical clinicoimmunopathologic perturbations that impact health. Any potential subclinical health impacts are important for the IRL and CHS dolphin populations, as past studies have indicated that both dolphin populations are affected by other complex infectious and neoplastic diseases, often associated with immunologic perturbations and anthropogenic contaminants. PMID- 24492057 TI - Role of Crassicauda sp. in natural mortality of pantropical spotted dolphins Stenella attenuata: a reassessment. AB - Evaluating the effect of parasites on population size is essential for designing management and conservation plans of wild animal populations. Although knowledge in this area is scarce in cetaceans, current evidence suggests that species of the nematode genus Crassicauda may play an important regulatory role in some populations. In the present study, a semiparametric regression technique was applied to a previously published dataset to re-examine the role of Crassicauda sp. in natural mortality of pantropical spotted dolphins Stenella attenuata. The resulting model indicated parasite-induced mortality at ages between 6.5 and 9 yr and at roughly 12 yr. The maximum mortality estimates obtained could represent 2 to 4% of natural mortality in dolphins 6 to 8 yr old. This estimate is substantially smaller than previously published values, but in contrast with previous research, our model provides clear statistical evidence for parasite induced mortality because the bootstrapped 95% confidence intervals of the estimated mortality rates excluded the 0 value. We also evaluated, through simulations, how potential sampling biases of infected dolphins could overestimate parasite-induced mortality. Small differences in sampling selectivity between infected and uninfected animals could substantially reduce the mortality estimates. However, the simulated models also supported the notion of statistically significant mortality in juvenile dolphins. Given that dolphins older than 16 yr were poorly represented in the dataset, further research is needed to establish whether Crassicauda sp. causes meaningful mortality for population dynamics among adult individuals. PMID- 24492058 TI - Menstrual-cycle dependent fluctuations in ovarian hormones affect emotional memory. AB - The hormones progesterone and estradiol modulate neural plasticity in the hippocampus, the amygdala and the prefrontal cortex. These structures are involved in the superior memory for emotionally arousing information (EEM effects). Therefore, fluctuations in hormonal levels across the menstrual cycle are expected to influence activity in these areas as well as behavioral memory performance for emotionally arousing events. To test this hypothesis, naturally cycling women underwent functional magnetic resonance imaging during the encoding of emotional and neutral stimuli in the low-hormone early follicular and the high hormone luteal phase. Their memory was tested after an interval of 48 h, because emotional arousal primarily enhances the consolidation of new memories. Whereas overall recognition accuracy remained stable across cycle phases, recognition quality varied with menstrual cycle phases. Particularly recollection-based recognition memory for negative items tended to decrease from early follicular to luteal phase. EEM effects for both valences were associated with higher activity in the right anterior hippocampus during early follicular compared to luteal phase. Valence-specific modulations were found in the anterior cingulate, the amygdala and the posterior hippocampus. Current findings connect to anxiolytic actions of estradiol and progesterone as well as to studies on fear conditioning. Moreover, they are in line with differential networks involved in EEM effects for positive and negative items. PMID- 24492059 TI - Pulmonary arterioplasty with decellularized allogeneic patches. AB - BACKGROUND: Decellularized allogeneic nonvalved pulmonary artery patches for arterioplasty are a relatively new option compared with cryopreserved allogeneic, crosslinked xenogeneic bioprosthetic or synthetic materials. This study examines the midterm experience with a new decellularized allogeneic patch for congenital cardiac reconstructions. METHODS: For this prospective postmarket approval, nonrandomized, inclusive observational study, we collected data on a consecutive cohort of 108 patients with cardiovascular reconstructions using 120 decellularized allogeneic pulmonary artery patches (MatrACELL; LifeNet Health, Inc, Virginia Beach, VA) between September 2009 and December 2012. One hundred of the patches were used for pulmonary arterioplasties. Two patients were lost early to follow-up and excluded from subsequent survival and durability analyses. Data included demographics, surgical outcomes, subsequent reoperations, and catheter reinterventions. These variables were also collected for an immediately preceding retrospective consecutive cohort of 100 patients with 101 pulmonary arterioplasty patches who received classical cryopreserved pulmonary artery allografts (n=59 patches and patients) or synthetic materials (n=41 patients with 42 patches) for pulmonary arterioplasties between 2006 and 2009. RESULTS: In 106 patients with 118 decellularized patches, there were no device-related serious adverse events, no device failures, and no evidence of calcifications on chest roentgenograms. In contrast, the prior comparative pulmonary arterioplasty cohort of 100 patients experienced an overall 14.0% patch failure rate requiring device-related reoperations (p<0.0001) at mean duration of 194+/-104 days (range, 25 to 477 days). CONCLUSIONS: The intermediate-term data obtained in this study suggest favorable performance by decellularized pulmonary artery patches, with no material failures or reoperations provoked by device failure. PMID- 24492060 TI - Reliability of readmission rates as a hospital quality measure in cardiac surgery. AB - BACKGROUND: Recent policy interventions have reduced payments to hospitals with higher-than-predicted risk-adjusted readmission rates. However, whether readmission rates reliably discriminate deficiencies in hospital quality is uncertain. We sought to determine the reliability of 30-day readmission rates after cardiac operations as a measure of hospital performance and evaluate the effect of hospital caseload on reliability. METHODS: We examined national Medicare beneficiaries undergoing coronary artery bypass graft operations for 2006 to 2008 (n=244,874 patients, n=1,210 hospitals). First, we performed multivariable logistic regression examining patient factors to calculate a risk adjusted readmission rate for each hospital. We then used hierarchical modeling to estimate the reliability of this quality measure for each hospital. Finally, we determined the proportion of total variation attributable to three factors: true signal, statistical noise, and patient factors. RESULTS: A median of 151 (25% to 75% interquartile range, 79 to 265) coronary artery bypasses were performed per hospital during the 3-year period. The median risk-adjusted 30-day readmission rate was 17.6% (25% to 75% interquartile range, 14.4% to 20.8%). Of the variation in readmission rates, 55% was explained by measurement noise, 4% could be attributed to patient characteristics, and the remaining 41% represented true signal in readmission rates. Only 53 hospitals (4.4%) achieved a proficient level of reliability exceeding 0.70. To achieve this reliability, 599 cases were required during the 3-year period. In 33.7% of hospitals, a moderate degree of reliability exceeding 0.5 was achieved, which required 218 cases. CONCLUSIONS: The vast majority of hospitals do not achieve a minimum acceptable level of reliability for 30-day readmission rates. Despite recent enthusiasm, readmission rates are not a reliable measure of hospital quality in cardiac surgery. PMID- 24492061 TI - Percutaneous lead dysfunction in the HeartMate II left ventricular assist device. AB - BACKGROUND: The incidence of percutaneous lead failure among patients supported with a HeartMate II left ventricular assist device is unknown. METHODS: All HeartMate II left ventricular assist device driveline dysfunctions reported to Thoratec Corporation were retrospectively reviewed. The location and severity of driveline failures and their association with adverse clinical outcomes were examined. Also, the effect of design modifications was evaluated. RESULTS: Between 2004 and October 2012, 12,969 HeartMate II pumps were implanted worldwide. The incidence of percutaneous lead dysfunction was 1,418 events occurring in 1,198 pumps (9.2% of pumps) over a cumulative support period of 13,932 patient-years (maximum, 8 years). Lead failure was mostly in the externalized part of the cable (87.2%). Lead dysfunction was managed by clamshell reinforcement of the external connector strain relief or by tape or silicone cable reinforcement in 76% of cases. Mortality or significant morbidity, including pump exchange or urgent transplant, or more complex cable repair occurred in 2.3% of all implanted pumps. The cumulative incidence of lead failures leading to major adverse clinical events has decreased with two lead design revisions: at 18 months postimplantation, the incidence was 6.2%+/-1.2% for the original design versus 2.2%+/-0.5% for the latest design change introduced in 2010 (log-rank p<0.001). CONCLUSIONS: Lead failures remain an important factor in the durability of left ventricular assist devices during long term support. Most lead failures in the HeartMate II occurred in the externalized portion of the driveline, suggesting lead fatigue. The incidence of both internal and external lead failures has diminished since 2004 with improvements in lead design. PMID- 24492062 TI - "Prophylactic" tricuspid repair for functional tricuspid regurgitation. AB - BACKGROUND: The optimal management of functional tricuspid regurgitation (FTR) in the setting of mitral valve operations remains controversial. The objective of this study is to compare the outcomes of congestive heart failure patients who underwent a prophylactic tricuspid operation for FTR as a component of their initial mitral valve procedure with those who underwent a redo tricuspid operation at a later date for residual FTR. METHODS: Patients with FTR repaired as a redo operation between 2004 and 2012 were identified. These patients were propensity-matched 1:2 with contemporaneous patients with FTR or tricuspid dilatation who underwent tricuspid repair at the same time as mitral valve repair. Demographic information, postoperative complications, and short-term and long-term mortality rates were compared between groups. RESULTS: There were 21 patients treated with redo tricuspid valve repair matched with 42 patients treated prophylactically. There were 3 deaths at 30 days in the redo group (14%), compared with zero in the prophylactic group (p=0.03). Overall long-term mortality in the redo group was 29% (6 of 21), with a mean 31 months of follow up, but was only 14% (6 of 42) in the prophylactic group, with a mean 25 months of follow-up. Kaplan-Meier long-term survival analysis did not reveal a difference between groups (log-rank p=0.37) once the perioperative period was survived. CONCLUSIONS: Redo tricuspid valve repair for residual FTR can be performed with acceptable short-term and long-term mortality. However, treatment of FTR at the time of the initial intervention should be considered, because it is safe and effective. A randomized, controlled trial of prophylactic tricuspid operation for FTR at the time of the mitral operation may be warranted. PMID- 24492063 TI - Outcomes of pediatric out-of-hospital cardiac arrest. PMID- 24492064 TI - Lifestyle and dietary risk factors for peripheral artery disease. AB - Peripheral artery disease (PAD) usually refers to ischemia of the lower limb vessels. Currently, the estimated number of cases in the world is 202 million. PAD is the third leading cause of atherosclerotic cardiovascular morbidity. The measurement of the ankle-brachial index (ABI) is recommended as a first-line noninvasive test for screening and diagnosis of PAD. An ABI <0.90 is an independent predictor of cardiovascular events and this measurement is useful to identify patients at moderate to high risk of cardiovascular disease. However, there is insufficient evidence to assess the benefits and harms of screening for PAD with the ABI in asymptomatic adults. Lifestyle modifications, including smoking cessation, dietary changes and physical activity, are currently the most cost-effective interventions. Inverse associations with PAD have been reported for some subtypes of dietary fats, fiber, antioxidants (vitamins E and C), folate, vitamins B6, B12 and D, flavonoids, and fruits and vegetables. A possible inverse association between better adherence to the Mediterranean diet and the risk of symptomatic PAD has also been reported in a large randomized clinical trial. Therefore, a Mediterranean-style diet could be effective in the primary and secondary prevention of PAD, although further experimental studies are needed to better clarify this association. (Circ J 2014; 78: 553-559). PMID- 24492065 TI - Discolored blood and blood components: a dilemma for transfusion specialists. AB - BACKGROUND AND OBJECTIVES: It is not uncommon in transfusion practice to see blood/components with abnormal colored plasma. The present study was conducted to identify and determine the etiology of blood and/or blood components showing altered color. MATERIAL AND METHODS: The present study was conducted in the Department of Transfusion Medicine, Government Medical College and Hospital, Chandigarh over a period of seven months. All the blood units/components having an abnormal appearance were segregated as: 1. Green discoloration. 2. Yellow discoloration. 3. Bright cherry red color. 4. Lipemic plasma. The donor's history was carefully evaluated and relevant investigations were done depending on discoloration. RESULTS: Seventeen units out of 7370 (0.23%) donations showed discoloration. In 3 units the plasma was green, 5 units were yellow, in 3 units PRBC/WB unit was bright cherry red and in the remaining 6 units the plasma was lipemic. Total bilirubin of all the 5 donors with yellowish plasma ranged from 1.6 to 2.3mg/dl. The hemoglobin and hematocrit of two out of three donors with cherry red discoloration of PRBC/WB was low. All the donors with lipemic plasma gave history of intake of fatty meal prior to donating blood. CONCLUSION: The existing rules prohibit issue of blood and blood components if the plasma is abnormal in color. Our study showed that many of the discolored units could have been safely transfused but further larger studies are required to confirm the safety of recipients receiving such units. PMID- 24492066 TI - Blood group antigens frequencies in Kabul, Afghanistan. PMID- 24492067 TI - The makings of a good human norovirus surrogate. AB - Norovirus is undoubtedly a leading cause of acute gastroenteritis. A large limitation to the study of human norovirus is the lack of consensus research using norovirus surrogates. Over two decades of research have included vast comparisons of norovirus surrogates within the Calicivirus family. A discussion on the continued use of norovirus surrogates includes use of surrogates to adequately assess environmental persistence and food preservation technologies. Choice of proper surrogate may be influenced by a myriad of issues, including ease of propagation, genetic similarities, and binding properties. While it remains impossible to routinely culture human norovirus in vitro the continued use of a variety of norovirus surrogates remains crucial to facilitate an understanding of norovirus in order to reduce the public health impact of the disease. PMID- 24492068 TI - Fibroblast-mediated pathways in cardiac hypertrophy. AB - Under normal physiological conditions, cardiac fibroblasts are the primary producers of extracellular matrix and supply a mechanical scaffold for efficacious heart contractions induced by cardiomyocytes. In the hypertrophic heart, cardiac fibroblasts provide a pivotal contribution to cardiac remodeling. Many growth factors and extracellular matrix components secreted by cardiac fibroblasts induce and modify cardiomyocyte hypertrophy. Recent evidence revealed that cardiomyocyte-cardiac fibroblast communications are complex and multifactorial. Many growth factors and molecules contribute to cardiac hypertrophy via different roles that include induction of hypertrophy and the feedback hypertrophic response, fine-tuning of adaptive hypertrophy, limitation of left ventricular dilation, and modification of interstitial changes. This review focuses on recent work and topics and provides a mechanistic insight into cardiomyocyte-cardiac fibroblast communication in cardiac hypertrophy. This article is part of a Special Issue entitled "Myocyte-Fibroblast Signalling in Myocardium ". PMID- 24492069 TI - Single neuron dynamics and computation. AB - At the single neuron level, information processing involves the transformation of input spike trains into an appropriate output spike train. Building upon the classical view of a neuron as a threshold device, models have been developed in recent years that take into account the diverse electrophysiological make-up of neurons and accurately describe their input-output relations. Here, we review these recent advances and survey the computational roles that they have uncovered for various electrophysiological properties, for dendritic arbor anatomy as well as for short-term synaptic plasticity. PMID- 24492070 TI - The healthy population-high disability paradox. PMID- 24492071 TI - Building maps from maps in primary visual cortex. AB - Neurons in the visual system respond to more complex and holistic features at each new stage of processing. Often, these features are organized into continuous maps. Could there be a fundamental link between continuous maps and functional hierarchies? Here, we review recent studies regarding V1 maps providing some of the most noteworthy advances in our understanding of how and why maps exist. In particular, we focus on the common theme that some maps are inherited from the input of parallel pathways, which are then intimately linked to the emergence of new functional properties and their corresponding maps. These results on V1 maps may prove to be a unifying framework for hierarchical representations in the visual cortex. PMID- 24492072 TI - Molecular guidance of retinotopic map development in the midbrain. AB - Topographic maps are utilized in many sensory and motor systems to efficiently transfer information between brain regions. The retina's projection to the superior colliculus has served as a model for the identification of molecular cues and mechanistic strategies by which topographic maps are formed. Evidence from both in vitro and in vivo studies points to graded cell surface cues playing a central role, but support for axon-axon competition and selective degeneration have also been advanced recently. In combination with mathematical models, these studies suggest that topographic maps are established using a complex combination of strategies to ensure precise connectivity. PMID- 24492073 TI - Neural maps in the electrosensory system of weakly electric fish. AB - The active electrosense of weakly electric fish is evolutionarily and developmentally related to passive electrosensation and the lateral line system. It shows the most highly differentiated topographic maps of the receptor array of all these senses. It is organized into three maps in the hindbrain that are, in turn, composed of columns, each consisting of six pyramidal cell classes. The cells in each column have different spatiotemporal processing properties yielding a total of 18 topographic representations of the body surface. The differential filtering by the hindbrain maps is used by superimposed maps in the multi-layered midbrain electrosensory region to extract specific stimulus features related to communication and foraging. At levels beyond the midbrain, topographic mapping of the body surface appears to be lost. PMID- 24492074 TI - From cortical modules to memories. AB - Many sensory features are topographically mapped in the mammalian cortex. In each case, features of the external world are systematically represented across the cortical area in a topographic manner, providing a complete representation of stimulus space. The cortex in turn utilizes sets of functionally specific, connected neurons to extract behaviorally relevant features from the incoming sensory information. This organization is perhaps best exemplified by the classical cortical column. The degree to which such networks also exist in high end association cortices has been unclear. Recently it was shown that the grid map of the entorhinal cortex is organized in a modular fashion. Here, we review the key features of the grid modules and the extent to which the grid modules resemble functional arrangements in other areas of cortex. PMID- 24492076 TI - Mapping odor valence in the brain of flies and mice. AB - Why are some odors perceived as pleasant while others are not? We review current research on how pleasant and unpleasant odors, that is, odors with positive or negative valence, are processed in the brain of flies and mice. We conclude that in mice pleasant and unpleasant odors are detected via three olfactory subsystems with only one being fully dedicated to unpleasant odors, while the others detect both good and bad odors. Correspondingly, so far no clear segmentation into regions processing exclusively pleasant or unpleasant odors has been identified in the mouse brain. The situation is different in flies, where most odors are sensed via the antenna. Already at the antennal lobe level, that is, the first processing center for olfactory input, odorants seem to be categorized as pleasant or unpleasant. We furthermore discuss why animals at all should make a decision based on olfaction, and why a straightforward and fast processing of odorant valence might be important for survival and reproduction. PMID- 24492075 TI - A mouse model of higher visual cortical function. AB - During sensory experience, the retina transmits a diverse array of signals to the brain, which must be parsed to generate meaningful percepts that can guide decisions and actions. Decades of anatomical and physiological studies in primates and carnivores have revealed a complex parallel and hierarchical organization by which distinct visual features are distributed to, and processed by, different brain regions. However, these studies have been limited in their ability to dissect the circuit mechanisms involved in the transformation of sensory inputs into complex cortical representations and action patterns. Multiple groups have therefore pushed to explore the organization and function of higher visual areas in the mouse. Here we review the anatomical and physiological findings of these recent explorations in mouse visual cortex. These studies find that sensory input is processed in a diverse set of higher areas that are each interconnected with specific limbic and motor systems. This hierarchical and parallel organization is consistent with the multiple streams that have been found in the higher visual areas of primates. We therefore propose that the mouse visual system is a useful model to explore the circuits underlying the transformation of sensory inputs into goal-directed perceptions and actions. PMID- 24492077 TI - Multisensory maps in parietal cortex. AB - Parietal cortex has long been known to be a site of sensorimotor integration. Recent findings in humans have shown that it is divided up into a number of small areas somewhat specialized for eye movements, reaching, and hand movements, but also face-related movements (avoidance, eating), lower body movements, and movements coordinating multiple body parts. The majority of these areas contain rough sensory (receptotopic) maps, including a substantial multisensory representation of the lower body and lower visual field immediately medial to face VIP. There is strong evidence for retinotopic remapping in LIP and face centered remapping in VIP, and weaker evidence for hand-centered remapping. The larger size of the functionally distinct inferior parietal default mode network in humans compared to monkeys results in a superior and medial displacement of middle parietal areas (e.g., the saccade-related LIP's). Multisensory superior parietal areas located anterior to the angular gyrus such as AIP and VIP are less medially displaced relative to macaque monkeys, so that human LIP paradoxically ends up medial to human VIP. PMID- 24492078 TI - Cellular, columnar and modular organization of spatial representations in medial entorhinal cortex. AB - Spatial discharge patterns in medial entorhinal cortex consist of grid, head direction, border and spatial-band cells. These firing patterns differ from the single-peaked fields of hippocampal place cells, in that they have well-defined geometries and extend throughout the available space. Such discharge properties could contribute to a metric representation of space. Both functional and anatomical evidence point to principal cell diversity, modularity and columnar organization, but linking entorhinal anatomy and physiology remains challenging. Layer 2 microcircuits consist of pyramidal neurons and a stellate cell network, which lacks recurrent excitation and is coupled by disynaptic inhibition. Intracellular recordings showed that periodic, grid-like firing emerges from depolarization ramps, whereas theta-oscillations determine spike timing. Interference with various inputs to entorhinal cortex abolishes grid activity, often without concomitant loss of hippocampal place activity. PMID- 24492079 TI - New perspectives on the owl's map of auditory space. AB - A map of sound direction was found in the owl's midbrain more than three decades ago. This finding suggested that the brain reconstructs spatial coordinates to represent them. Subsequent research elucidated the variables used to compute the map. Here we provide a review of the processes leading to its emergence and an updated perspective on how and what information is represented. PMID- 24492080 TI - Speech map in the human ventral sensory-motor cortex. AB - The study of spatial maps of the ventral sensory-motor cortex (vSMC) dates back to the earliest cortical stimulation studies. This review surveys a number of recent and historical reports of the features and function of spatial maps within vSMC towards the human behavior of speaking. Representations of the vocal tract, like other body parts, are arranged in a somatotopic fashion within ventral SMC. This region has unique features and connectivity that may give insight into its specialized function in speech production. New methods allow us to probe further into the functional role of this organization by studying the spatial dynamics of vSMC during natural speaking in humans. PMID- 24492081 TI - Neural maps for target range in the auditory cortex of echolocating bats. AB - Computational brain maps as opposed to maps of receptor surfaces strongly reflect functional neuronal design principles. In echolocating bats, computational maps are established that topographically represent the distance of objects. These target range maps are derived from the temporal delay between emitted call and returning echo and constitute a regular representation of time (chronotopy). Basic features of these maps are innate, and in different bat species the map size and precision varies. An inherent advantage of target range maps is the implementation of mechanisms for lateral inhibition and excitatory feedback. Both can help to focus target ranging depending on the actual echolocation situation. However, these maps are not absolutely necessary for bat echolocation since there are bat species without cortical target-distance maps, which use alternative ensemble computation mechanisms. PMID- 24492082 TI - Microcircuit dynamics of map plasticity in barrel cortex. AB - Functional reorganization of the whisker map in rodent barrel cortex has long served as a model for cortical plasticity following changes in sensory experience. Given the heterogeneity of neuronal response properties in neocortex, it has remained unclear how individual neurons in the cortical microcircuit are affected. Novel in vivo imaging and electrophysiology methods allow longitudinal recording of the same neurons' functional properties and therefore have the critical ability to resolve the direction and dynamics of change as plasticity progresses. Tracking sensory responsiveness before and after whisker trimming has uncovered diverse effects in individual neurons, suggesting that longitudinal recording will be essential for elucidating plasticity mechanisms within cortical microcircuits. PMID- 24492083 TI - Neural maps in insect versus vertebrate auditory systems. AB - The convergent evolution of hearing in insects and vertebrates raises the question about similarity of the central representation of sound in these distant animal groups. Topographic representations of spectral, spatial and temporal cues have been widely described in mammals, but evidence for such maps is scarce in insects. Recent data on insect sound encoding provides evidence for an early integration of sound parameters to form highly-specific representation that predict behavioral output. In mammals, new studies investigating neural representation of perceptual features in behaving animals allow asking similar questions. A comparative approach may help in understanding principles underlying the formation of perceptual categories and behavioral plasticity. PMID- 24492084 TI - Motor maps and the cortical control of movement. AB - The brain's cortical maps serve as a macroscopic framework upon which additional levels of detail can be overlaid. Unlike sensory maps generated by measuring the brain's responses to incoming stimuli, motor maps are made by directly stimulating the brain itself. To understand the significance of motor maps and the functions they represent, it is necessary to consider the relationship between the natural operation of the motor system and the pattern of activity evoked in it by artificial stimulation. We review recent findings from the study of the cortical motor system and new insights into the control of movement based on its mapping within cortical space. PMID- 24492085 TI - Neural maps versus salt-and-pepper organization in visual cortex. AB - Theoretical neuroscientists have long been intrigued by the spatial patterns of neuronal selectivities observed in the visual cortices of many mammals, including primates. While theoretical studies have contributed significantly to our understanding of how the brain learns to see, recent experimental discoveries of the spatial irregularity of visual response properties in the rodent visual cortex have prompted new questions about the origin and functional significance of cortical maps. Characterizing the marked differences of cortical design principles among species and comparing them may provide us with a deeper understanding of primate and non-primate vision. PMID- 24492086 TI - Single neuron and population coding of natural sounds in auditory cortex. AB - The auditory system drives behavior using information extracted from sounds. Early in the auditory hierarchy, circuits are highly specialized for detecting basic sound features. However, already at the level of the auditory cortex the functional organization of the circuits and the underlying coding principles become different. Here, we review some recent progress in our understanding of single neuron and population coding in primary auditory cortex, focusing on natural sounds. We discuss possible mechanisms explaining why single neuron responses to simple sounds cannot predict responses to natural stimuli. We describe recent work suggesting that structural features like local subnetworks rather than smoothly mapped tonotopy are essential components of population coding. Finally, we suggest a synthesis of how single neurons and subnetworks may be involved in coding natural sounds. PMID- 24492087 TI - The development of the hippocampal neural representation of space. AB - The hippocampal formation (HF) contains a neural representation of the environment, based on the activity of several classes of neurons whose firing is tuned to an animal's position and orientation in space. Recently, work has begun on understanding when and how this neural map of space emerges during development. Different classes of spatially tuned neurons emerge at different ages, some of them very early during development, before animals have started exploring their environment. The developmental timeline thus far uncovered has yielded insights into both the mechanisms of the ontogeny of the neural code for space, as well as how this system functions in the adult. PMID- 24492088 TI - Olfactory maps, circuits and computations. AB - Sensory information in the visual, auditory and somatosensory systems is organized topographically, with key sensory features ordered in space across neural sheets. Despite the existence of a spatially stereotyped map of odor identity within the olfactory bulb, it is unclear whether the higher olfactory cortex uses topography to organize information about smells. Here, we review recent work on the anatomy, microcircuitry and neuromodulation of two higher order olfactory areas: the piriform cortex and the olfactory tubercle. The piriform is an archicortical region with an extensive local associational network that constructs representations of odor identity. The olfactory tubercle is an extension of the ventral striatum that may use reward-based learning rules to encode odor valence. We argue that in contrast to brain circuits for other sensory modalities, both the piriform and the olfactory tubercle largely discard any topography present in the bulb and instead use distributive afferent connectivity, local learning rules and input from neuromodulatory centers to build behaviorally relevant representations of olfactory stimuli. PMID- 24492089 TI - Retinal ganglion cell maps in the brain: implications for visual processing. AB - Everything the brain knows about the content of the visual world is built from the spiking activity of retinal ganglion cells (RGCs). As the output neurons of the eye, RGCs include ~20 different subtypes, each responding best to a specific feature in the visual scene. Here we discuss recent advances in identifying where different RGC subtypes route visual information in the brain, including which targets they connect to and how their organization within those targets influences visual processing. We also highlight examples where causal links have been established between specific RGC subtypes, their maps of central connections and defined aspects of light-mediated behavior and we suggest the use of techniques that stand to extend these sorts of analyses to circuits underlying visual perception. PMID- 24492091 TI - The evolutionary masquerade: genetic and epigenetic contributions to the neocortex. AB - The neocortex is a defining feature of the mammalian brain and its expansion is one of the hallmarks of human evolution. Given the complexity of human behavior, it is tempting to think that as a species humans are exclusive compared to other animals. However, comparative studies indicate that human brains follow the same rules of construction and that alterations to the human neocortex take a similar form as in other mammals. Studies from a number of disciplines indicate that many of the morphological specializations associated with the vocal tract, ear and hand were present in early hominins and thus our ancestors had the capacity for speech, language and sophisticated manual abilities, yet much of modern human behavior evolved very recently. In this review, we discuss the possibility that phenotypic changes in modern human brains and behavior may have been mediated by epigenetic mechanisms that allowed for context dependent changes to the cortical phenotype. Further, we consider whether these epigenetic mechanisms may be more readily engaged in humans than in other species in order to rapidly meet the demands of a dynamic environment. We suggest that perhaps it is the extent to which the neocortex incorporates these context dependent alterations that distinguishes humans from other mammals. PMID- 24492090 TI - Auditory map plasticity: diversity in causes and consequences. AB - Auditory cortical maps have been a long-standing focus of studies that assess the expression, mechanisms, and consequences of sensory plasticity. Here we discuss recent progress in understanding how auditory experience transforms spatially organized sound representations at higher levels of the central auditory pathways. New insights into the mechanisms underlying map changes have been achieved and more refined interpretations of various map plasticity effects and their consequences in terms of behavioral corollaries and learning as well as other cognitive aspects have been offered. The systematic organizational principles of cortical sound processing remain a key aspect in studying and interpreting the role of plasticity in hearing. PMID- 24492093 TI - [A synergistic combination for the French laboratory medicine...]. PMID- 24492094 TI - [Biological diagnosis of pheochromocytoma in 2014]. AB - Pheochromocytomas and/or paragangliomas are rare, heterogeneous tumors of the chromaffin cells. Thirty percent of the patients presented with these diseases in a hereditary context. The biological diagnosis relies on the identification of excessive secretion of the metanephrines which are more sensitive and specific than those of catecholamines. The published recommendations give the opportunity to choose between the metanephrines in sera or urines. The concentrations of the free plasmatic metanephrines reflect the ongoing production of tumor. They are little sensitive to the renal failure. The gold standard method to measure the free metaphrines in plasma is the LC-MS/MS chromatography. This is the technical event that we use since 2008, and we relate our experience. PMID- 24492092 TI - Role of emergent neural activity in visual map development. AB - The initial structural and functional development of visual circuits in reptiles, birds, and mammals happens independent of sensory experience. After eye opening, visual experience further refines and elaborates circuits that are critical for normal visual function. Innate genetic programs that code for gradients of molecules provide gross positional information for developing nerve cells, yet much of the cytoarchitectural complexity and synaptogenesis of neurons depends on calcium influx, neurotransmitter release, and neural activity before the onset of vision. In fact, specific spatiotemporal patterns of neural activity, or 'retinal waves', emerge amidst the development of the earliest connections made between excitable cells in the developing eye. These patterns of spontaneous activity, which have been observed in all amniote retinae examined to date, may be an evolved adaptation for species with long gestational periods before the onset of functional vision, imparting an informational robustness and redundancy to guide development of visual maps across the nervous system. Recent experiments indicate that retinal waves play a crucial role in the development of interconnections between different parts of the visual system, suggesting that these spontaneous patterns serve as a template-matching mechanism to prepare higher-order visually associative circuits for the onset of visuomotor learning and behavior. Key questions for future studies include determining the exact sources and nature of spontaneous activity during development, characterizing the interactions between neural activity and transcriptional gene regulation, and understanding the extent of circuit connectivity governed by retinal waves within and between sensory motor systems. PMID- 24492095 TI - [Customizing dosage drugs what contribution in therapeutic drug monitoring?]. AB - Drug response is often variable from an individual to another: the same dose of drug administered to different patients could cause variable pharmacological effects in nature and intensity. Those effects are often the result of variability in drugs pharmacokinetics (absorption, distribution, metabolism and elimination) which alter their bioavailability. In fact, two factors should be taken into account: the disease(s) from which the patient suffers, and the associated drugs, because many drug interactions may alter their pharmacokinetics causing consequently quite enough of different therapeutic effects. The choice of the assay of the drug subject in monitoring is crucial, it allows quantifying the in vivo dose of the drug and the quality of compliance thereof, the pharmacokinetic characteristics allows the clinician to adjust the dosage by different approaches so that plasma concentrations are included in the therapeutic range. Therapeutic monitoring aims to increase clinical efficacy and to minimize toxicity. PMID- 24492096 TI - [Genomic medicine: the new way of thinking medicine present and future--Part two]. AB - New sequencing techniques are revolutionizing medical practice as its applications are numerous and considerable. We are living a technological turning point in molecular medicine. Indeed, thanks to these new machines, this technological leap allowed us to analyse the human genome with an elarged or even a total view. Genome analysis has applications in all medical fields from now on. Gene analysis in parallel with personalized therapy help in prolonged survival or even cures in some cancers or other diseases. Genetics is progressively arriving in every field of clinical practice. A new way of thinking clinics is born. This publication describes in its main lines these new applications, their problems and their challenges for geneticists as much as for other practitioners in the medical fields. PMID- 24492097 TI - [The external quality assessment schemes for lead in blood organized by the French national agency for medicine and health product safety: a synthesis of 15 years of activity]. AB - In 1992, at the request of the French labor ministry following questions on the ability of medical biology laboratories to satisfactorily measure blood lead level (PbB), a national PbB quality control came into being. Only in 1996 did this external quality control include a number of laboratories sufficient to allow for a significant retrospective evaluation. After fifteen years (1996 2011), The French National Agency for Medicines and Health Products Safety wished to exploit the database collected. The number of participating laboratories went down from 73 to 41. On the other hand, the key finding pertained to the highly improved performance of the laboratories, which was associated with a spread decrease of the results over the entire range of tested PbBs (9 to 700 MUg/L). Since 2006, we have observed increasing use of the inductively coupled plasma with mass spectrometry and decreasing use of electrothermal atomic absorption spectrometry. Provided that they rely on identical metrology expertise, the two analytical techniques lead to results on all the tested concentrations that are not statistically different. PMID- 24492098 TI - [Inter-observes agreement of Ishak and Metavir scores in histological evaluation of chronic viral hepatitis B and C]. AB - Many classification systems are currently used for histological evaluation of the severity of chronic viral hepatitis, including the Ishak and Metavir scores, but there is not a consensus classification. The objective of this work was to study the intra and inter-observers agreement of these two scores in the histopathological analysis of liver biopsies in patients with chronic viral hepatitis B or C. Fifty nine patients were included in the study, 26 had chronic hepatitis C and 33 had chronic hepatitis B. To investigate the inter-observers agreement, the liver biopsies were analyzed separately by two pathologists without prior consensus reading. The two pathologists conducted then a consensual reading before reviewing all cases independently. Cohen's kappa coefficient was calculated and in case of asymmetry Spearman's rho coefficient. Before the consensus reading, the agreement was moderate for the analysis of histological activity with both scores (Metavir: kappa=0.41, Ishak: rho=0.58). For the analysis of fibrosis, the agreement was good with both scores (Metavir: kappa=0.61, Ishak: rho=0.86). The consensus reading has improved the reproducibility of the activity that has become good with both scores (Metavir: kappa=0.77, Ishak: rho=0.76). For fibrosis improvement was observed with the Ishak score which agreement became excellent (kappa=0.81). In conclusion, we recommend in routine practice, a combined score: Metavir for activity and Ishak for fibrosis and to make a double reading for each biopsy. PMID- 24492099 TI - [WHIM syndrome: presumptive diagnosis based on myelokathexis on bone marrow smear]. AB - The WHIM syndrome is a rare congenital immunodeficiency disorder characterized by human papillomavirus (HPV)-induced warts, hypogammaglobulinemia, bacterial infections and myelokathexis. Myelokathexis refers to abnormal retention of mature neutrophils in the bone marrow leading to severe neutropenia. We report the case of a 20 year old man presenting with chronic and severe neutropenia since early childhood without established diagnosis. He was addressed for chronic parodontal disease treatment. Examination of bone marrow smear showed morphological abnormalities of mature neutrophils strongly suggestive of myelokathexis. Diagnosis of WHIM syndrome was confirmed by molecular analysis: a nonsense mutation was identified in the gene encoding CXCR4, the CXCL12 (or SDF 1) chemokine receptor which notably controls cell adhesion to the marrow stroma and thereby regulates mature leukocytes release from the bone marrow. Treatment of the disease usually consists in prophylactic anti-infective measures including intravenous immunoglobulins administration, oral antibiotic prophylaxis and more recently HPV vaccination. Long term G-CSF therapy did not show any significant efficiency in preventing recurrent infections. The use of specific CXCR4 antagonist is being currently evaluated. PMID- 24492100 TI - [Acute myeloid leukemia with t(8;21): unusual cytological presentation and immunophenotype]. AB - We report the case of a 20 years old woman with unusual acute myeloid leukemia t(8;21). Cytological, phenotypic and cytogenetic investigations showed a divergence from those of the literature as well as data for the last 12 LA to t(8;21) supported in the service. PMID- 24492101 TI - [Does bilirubin interfere with capillary electrophoresis of serum proteins?]. AB - Capillary electrophoresis of serum proteins is a fast, reliable and simple technique, but many interference exist. The objective of our work is to study the interference of bilirubin on this technique; 70 icteric sera were analysed on Capillarys TM (Sebia). A second electrophoresis was performed on 40 samples after bilirubin photodegradation. The bilirubin and serum proteins were determinated respectively by Jendrassik and Grof and biuret methods on Konelab 20i TM (Thermo Electron Corporation). We found abnormal spreading of the albumin fraction of the anode side wich constitute sometimes an isolated fraction in the traditional area of pre-albumin migration. This fraction varies from 2.0 +/- 2.0% (0.0 to 7.3%) or 0.98 +/- 1.53 g/L (0 to 5.3 g/L) and it seems to be related to the direct bilirubin since, following overloading sera with a solution of bilirubin, no further fraction was recovered. An average decrease of bilirubin after photodegradation of 58 +/- 17% (26-89%) is followed by a decrease in the same order 64 +/- 38% (10-100%) of the additional fraction. Acetate cellulose electrophoresis of the same samples showed no variation. The high bilirubin levels seem modify slightly the electrophoretic profile. However the impact of the interference on the interpretation of electrophoretic trace is negligible. PMID- 24492102 TI - Markedly increased vitamin B12 concentration due to immunological interference. PMID- 24492103 TI - [Accreditation by COFRAC according to NF EN ISO 15189 for biological analysis using chemical or CE non labelled reagents?]. PMID- 24492104 TI - Micro-CT evaluation of the effectiveness of the combined use of rotary and hand instrumentation in removal of Resilon. AB - This study compares the effectiveness of ProTaper rotary files with ProTaper retreatment and K-files in the removal of Resilon or gutta percha (GP) from canals filled either by cold lateral condensation or thermal obturation using micro-CT. Ninety-six teeth were prepared using ProTaper files and allocated into four groups (n=24): Group-1 was filled with GP/AH-Plus and Group-2 with Resilon/RealSeal using cold lateral condensation. Group-3 was filled with GP/AH Plus and Group-4 with Resilon/RealSeal using System B and Obtura II. The roots were scanned by micro-CT. Each group was divided into two subgroups (n=12): A, retreated using ProTaper files and B, using ProTaper retreatment and K-files. The roots were scanned to calculate the volume of the remaining material. With thermal obturation, roots filled with Resilon had significantly more remaining material than GP. Obturation using thermal technique resulted in significantly less remaining material than cold condensation except Resilon retreated using ProTaper retreatment and K-files. PMID- 24492105 TI - Proliferation and adhesion capability of human gingival fibroblasts onto zirconia, lithium disilicate and feldspathic veneering ceramic in vitro. AB - Human gingival fibroblasts (HGFs) were cultured onto CAD/CAM zirconia (Group A), CAD/CAM zirconia after polishing (Group B), CAD/CAM lithium disilicate after polishing (Group C), and feldspathic ceramic (Group D) to evaluate their proliferation and adhesion potential. After 3 h, HGF adhesion was similar in all groups. Later, HGFs closely adhered to surfaces, particularly onto groups B, C and D, acquiring an elongated shape. Proliferation assay showed no differences in cell viability among the groups after 24 h, while significant increase was shown after 72 h in Groups B and C. After 24 h, similar Collagen I levels were found in all groups, while after 72 h Groups B and C revealed a deep reduction in respect to the 24 h level. In vitro, HGF behavior may reflect variability in soft tissue response to different surface materials for prosthetic restorations, and support that polished zirconia is able to achieve a better integration in vivo in respect to the other materials. PMID- 24492106 TI - Effect of fabrication process on the bond strength between silicone elastomer and acrylic resin for maxillofacial prosthesis. AB - This study evaluated the effects of the fabrication process on tensile bond strength between maxillofacial silicone elastomer and acrylic resin. A common maxillofacial silicone elastomer (VST-50), two primers (Sofreliner primer and R SI-LINE Plasticbond), and two acrylic resins (Unifast III and Palapress Vario) were selected. Silicone elastomer between primed acrylic resin plates were polymerized using a metal flask mold or a flaskless stone mold. Bond strength of the specimens was measured by a tensile test and analyzed using two-way analysis of variance (ANOVA) with Tukey's honest significant difference test. All fracture surfaces showed interfacial fracture. Both the fabrication process and the primer acrylic resin combination affected bond strength, and two-way ANOVA indicated a significant interaction. Bond strength was generally greater when silicone elastomer was polymerized using a flaskless stone mold. PMID- 24492107 TI - The effect of Er:YAG laser and different surface conditioning procedures on microtensile bond strength of the fissure sealant containing amorphous calcium phosphate after artificial aging. AB - The present study aimed to compare post-aging microtensile values of fissure sealant(FS) containing amorphous calcium phosphate(ACP) with or without bonding after various enamel-etching methods. The buccal enamel surfaces of teeth were prepared and divided into five main groups according to enamel etching (Group 1; acid-etching, Group 2; air-abrasion, Group 3; 2W, Group 4; 3W, and Group 5; 4W of Er:YAG laser). Each main group was subdivided as with(Subgroup B) or without(Subgroup A) a bonding system. We applied FS-containing ACP to etched enamel surfaces. All specimens were aged by Thermocycling and water bath. We then measured microtensile bond strengths and analyzed data with two-way ANOVA and Tukey's tests. We found a statistically significant difference between Group 1 and Group 2, between Subgroup B of Group 5 and Subgroups B of all other groups, and between Subgroups A and Subgroups B of all main groups (p<0.01). Er:YAG laser etching may be an alternative enamel etching method to acid-etching for ACP containing FS. PMID- 24492108 TI - The influence of heat treatment on the mechanical properties of Ni-Ti file materials. AB - The purpose of this study was to investigate the influence of heat treatment on the mechanical properties of Ni-Ti file materials. Ni-Ti wire (1.00 mm o) was processed into a conical shape with 0.30-mm diameter tip and 0.06 taper. Specimens were heated for 30 min at 300, 400, 450, 500 or 600 degrees C. Non heated specimens were used as controls. DSC, a cantilever-bending test and cyclic fatigue test were performed. Ms and Af for groups 400 and 450 were higher than those for others (p<0.05). The load/deflection ratios of groups 400, 450 and 500 were lower than that of group 600 (p<0.05). The bending load values at 2.0-mm deflection of groups 400, 450 and 500 were lower than those of group 300 and the control group (p<0.05). The NCFs of groups 400, 450 and 500 exceeded that of group 600(p<0.05). Changes in flexibility with heat treatment could improve the cyclic fatigue properties of Ni-Ti instruments. PMID- 24492109 TI - Evaluation of adhesion of reline resins to the thermoplastic denture base resin for non-metal clasp denture. AB - This study aimed to evaluate the tensile and transverse bond strength of chairside reline resins (Tokuyama Rebase II, Mild Rebaron LC) to a thermoplastic acrylic resin (Acrytone) used for non metal clasp denture. The results were compared with those of a conventional heat polymerized acrylic resin (Paladent 20) and a thermoplastic polyamide resin (Biotone). The failure sites were examined by scanning electron microscopy to evaluate the mode of failure. As results, the bond strength of reline resins to a thermoplastic acrylic resin was similar to the value of a conventional heat polymerized acrylic resin. However, thermoplastic polyamide resin showed the lowest value. The results of this study indicated that a thermoplastic acrylic resin for non metal clasps denture allows chairside reline and repair. It was also found that the light-polymerized reline resin had better bond strength than the autopolymerizing reline resin in relining for a conventional heat polymerized acrylic resin and a thermoplastic acrylic resin. PMID- 24492110 TI - Influence of thin carbonate-containing apatite coating with molecular precursor method to zirconia on osteoblast-like cell response. AB - The influence of a thin carbonate-containing hydroxyapatite (CA) coating to tetragonal zirconia polycrystal (TZP) on osteoblastlike cell response was investigated. TZP disks were subjected to blasting and acid etching. Thin CA coatings were deposited by the molecular precursor method (TZP-CA). Initial cell adhesion of mouse osteoblast-like cells MC3T3-E1 was enhanced, and marked progress of actin filaments was observed on TZP-CA compared to on TZP. After 3, 5 or 7 days, cell proliferation on TZP-CA was significantly higher than that on TZP. Alkaline phosphatase activity was slightly lower on TZP-CA than on TZP at 7 days, and no difference was observed at 14 or 21 days. At 28 days incubation, collagenous fibers with mineral precipitants accompanied by phosphorous and amino groups were observed. These results indicate that thin CA coating with molecular precursor method offers promise as a means of enhancing cell response, particularly initial adhesion and proliferation of MC3T3-E1 cells. PMID- 24492111 TI - Optical coherence tomography examination of the effect of S-PRG filler extraction solution on the demineralization of bovine enamel. AB - The purpose of this study was to determine the effect of PRG filler extraction solution on the demineralization of enamel using optical coherence tomography (OCT). Bovine enamel was treated with lactic acid buffer solution and then placed in artificial saliva (De group). In the second group, specimens were stored in PRG filler extraction solution followed by immersion in lactic acid buffer solution (PRG group). In the control group, specimens were simply stored in artificial saliva. From the OCT image, the peak intensity (dB) and width at (1/e(2)) were obtained, and the integrated value was calculated. The data were analyzed using Tukey-Kramer tests (alpha=0.05). There was a slight but significant increase in the integrated value observed for the control group, and a slight but significant decrease in the value observed for the De group. For the PRG group, integrated values were doubled after seven days from the start of the experiment. PMID- 24492112 TI - Effect of dentinal tubule orientation on the modulus of elasticity of resin infiltrated demineralized dentin. AB - The effect of tubule orientation of dentin on the elastic modulus of resin infiltrated dentin was evaluated. Rectangular cylindricalshaped dentin specimens with their long axis parallel to and perpendicular to dentinal tubules were prepared from extracted premolars. Twenty-five mineralized specimens of each orientation were evaluated. The remaining specimens were then demineralized. The demineralized specimens and the demineralized following by infiltration with one of these adhesives; Optibond Solo Plus, Single Bond 2 or Prime & Bond NT, from each orientation were evaluated (25 specimens per group). The tubular orientation only affected the elastic modulus of mineralized dentin. The highest elastic modulus was observed for the mineralized dentin when the tensile force was applied parallel to the direction of tubules. The elastic modulus of demineralized dentin was the lowest. The adhesive resins increased the elastic modulus of demineralized dentin, but the differences among the three were insignificant. PMID- 24492113 TI - Effects of bleaching agents on surface roughness of filling materials. AB - The aim of this study was to use a non-tactile optical measurement system to assess the effects of three bleaching agents' concentrations on the surface roughness of dental restoration materials. Two composites (Grandio, Venus) and one glass ionomer cement (Ketac Fil Plus) were used in this in vitro study. Specimens were treated with three different bleaching agents (16% and 22% carbamide peroxide (Polanight) and 38% hydrogen peroxide (Opalescence Boost)). Surface roughness was measured with an optical profilometer (Infinite Focus G3) before and after the bleaching treatment. Surface roughness increased in all tested specimens after bleaching treatment (p<0.05). Our in vitro study showed that dental bleaching agents influenced the surface roughness of different restoration materials, and the restoration material itself was shown to have an impact on alteration susceptibility. There seemed to be no clinical relevance in case of an optimal finish. PMID- 24492114 TI - Genotoxicity and cytotoxicity of mineral trioxide aggregate and calcium enriched mixture cements on L929 mouse fibroblast cells. AB - Mineral trioxide aggregate (MTA) has shown good biocompatibility in several studies. In the present study, the genotoxic and cytotoxic effects of calcium enriched mixture (CEM) were evaluated compared with MTA using MTT and single-cell gel (comet) assays with serial ascending concentrations (0 to 1,000 ug/mL) of tested materials. Cytotoxicity data indicated that there is no significant difference between CEM and MTA at all concentrations except for the full concentration (1,000 ug/mL); CEM had lower cytotoxicity. Genotoxic effects were more evident with CEM at concentrations of 15.6 and 250 ug/mL; however, was less than that of MTA at concentrations of 500 and 1,000 ug/mL. The cytotoxicity and genotoxicity effects of the two experimental groups generally increased with consistency. Under the conditions of this study, CEM is biocompatible in terms of cyto- and genotoxicity. It appears to be an alternative to MTA as an endodontic biomaterial offering several advantages. PMID- 24492115 TI - Effects of acidic sodium fluoride-treated, commercially pure titanium on periodontal pathogens and rat bone marrow cells. AB - The purpose of the present study was to clarify the potentiality of acidic fluoride solution in treating peri-implantitis. We examined bactericidal activity of fluoride solution against periodontal pathogens; and evaluated the effects of fluoride on titanium, and the effects on cell proliferation and differentiation of rat bone marrow cells on the fluoride-treated titanium. Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis were used to determine minimal inhibitory concentration (MIC) and shorttime exposure. The cells were seeded on the titanium surface with or without fluoride treatment. Then, cellular proliferation, differentiation and mineral deposition were analyzed. The MIC values for A. actinomycetemcomitans and P. gingivalis were 225 and 900 ppm F(-), respectively. In short-time exposure test, both bacterial strains exhibited a significant decrease in a concentrationdependent manner. Cell proliferation and mineral deposition were significantly increased on the fluoride-treated surface. Within the limitation of this study, acidic sodium fluoride solution has the potentiality in treating peri-implantitis. PMID- 24492116 TI - Dental zirconia can be etched by hydrofluoric acid. AB - The surface morphology and crystal structure change of dental zirconia after hydrofluoric acid (HF) etching were evaluated. Four groups of sintered zirconia specimens were 1) control group, 2) immersion in 9.5%HF at 25 degrees C for 1, 2, 3, or 24 h, 3) immersion in 9.5%HF at 80 degrees C for 1, 3, 5, or 30 min and 4) immersion in 48%HF at 25 degrees C for 30 or 60 min. The specimens were evaluated under SEM and XRD. The SEM analysis revealed changes in surface topography for all the HF-etched zirconia specimens. The irregularities surface increased with increasingly longer immersion times and higher etching solution temperatures. The XRD analysis of the HFetched zirconia specimens revealed the presence of a crystalline monoclinic phase along with a tetragonal form. It was concluded HF can etch dental zirconia ceramic, creating micro-morphological changes. Tetragonal-to-monoclinic phase transformation was induced on the etched zirconia surface. PMID- 24492117 TI - Evaluation of the staining potential of a caries infiltrant in comparison to other products. AB - In this study, we evaluated in vitro the staining susceptibility of an infiltration resin (Icon, DMG, Hamburg, Germany) and compared it with several marketed bonding systems. Fifty 1-mm-thick disk-shaped specimens were prepared for Icon and for each bonding material. Initial specimen color was assessed by a spectrophotometer. Specimens in each group were then randomly divided into five sub-groups and stored in an incubator at 37C in the dark for 60 days. Groups 4 and 5 were used as negative controls by being stored dry and in tap water respectively. Test groups were stored in (1) coffee, (2) tea, or (3) red wine. After 60 days of storage, new spectrophotometric measurements were performed and dE (color difference) was calculated to determine color change. Icon showed higher staining susceptibility. The clinician should be aware of the staining potential of infiltration resins over time. PMID- 24492118 TI - Effect of accelerated aging on the bonding performance of fluoridated adhesive resins. AB - The purpose of this study was to investigate the dentin bond durability of a one step, fluoride-containing, glass ionomer-based adhesive system, Reactmer Bond (RB), and that of a two-step, fluoride-containing, self-etch adhesive system, Clearfil Protect Bond (CPB). Enamel was removed from the occlusal surfaces of teeth, and flat dentin surfaces were entirely covered with a composite resin following the application of an adhesive material (n=10). After specimens were sectioned into rectangular sticks of 0.87 +/- 0.03 mm(2), the sticks were randomly assigned into two accelerated aging time period groups: 1 week or 1 year. Microtensile bond strengths were determined. Bond strength of RB increased significantly after 1 year (1 week=27.80 +/- 10.57 MPa versus 1 year=36.93 +/- 14.38 MPa) (p<0.05). In contrast, there was no significant difference in bond strength between the two time periods for CPB (1 week=51.74 +/- 17.8 MPa versus 1 year=56.03 +/- 18.85 MPa) (p>0.05). Both fluoride-containing adhesives seemed to demonstrate reliable bonding performance after 1 year of accelerated aging in water. PMID- 24492119 TI - Influence of composition on the adhesive strength and initial viscosity of denture adhesives. AB - To investigate the effect of composition on the initial viscosity and adhesive strength between denture adhesives and the denture base. Two types of water soluble polymers (methoxy ethylene maleic anhydride copolymer [PVM-MA] and sodium carboxymethyl cellulose [CMC]) were used. Samples were divided into three groups. Group 1 contained only PVM-MA; Group 2 contained only CMC; and Group 3 contained PVM-MA and CMC. The initial viscosity and adhesive strength were measured. For Group 1, the initial viscosity increased significantly as PVM-MA content increased. The adhesive strength of Group 1 lasted longer than Group 2. The adhesive strength of Group 3 varied greatly. The ratio of CMC and PVM-MA has a significant effect on the initial viscosity and adhesive strength of denture adhesives. Our results suggest that it is possible to improve the durability of a denture adhesive by combining different water-soluble polymers. PMID- 24492120 TI - Polymerization shrinkage, flexural and compression properties of low-shrinkage dental resin composites. AB - This study evaluated the polymerization shrinkage, flexural and compressive properties of low-shrinkage resin composites. For the study, four methacrylate based and one silorane-based resin composites were light cured using three different light-curing units (LCUs) and their polymerization shrinkage, flexural (strength (FS) and modulus (FM)) and compressive (strength (CS) and modulus (CM)) properties were evaluated. Data were statistically analyzed using ANOVA and a post-hoc Tukey test. The polymerization shrinkage ranged approximately 7.6-14.2 MUm for 2-mm thick specimens depending on the resin product and LCU. Filtek LS showed the least shrinkage while the rest shrank approximately 13.2-14.2 MUm. However, Filtek LS showed the greatest shrinkage difference for the used LCUs. FS and CS of the tested specimens ranged 96.2-152.1 MPa and 239.2-288.4 MPa, respectively, depending on the resin product and LCU. The highest and lowest FS and FM were recorded for the methacrylate-based resin composites. Among the specimens, Filtek LS showed the lowest CS and CM. PMID- 24492121 TI - Effect of gold deposition onto titanium on the adsorption of alkanethiols as the protein linker functionalizing the metal surface. AB - A new method to enhance the biofunctionalization of Ti materials was developed by the immersion of Au-sputtered titanium plates into a solution of alkanethiol with a carboxy group end (HS-C11-COOH). X-ray photoelectron spectroscopy (XPS) analysis showed that the gold content increased with the Au sputtering time and reached over 98 at% after 100 s. The content of the characteristic alkanethiol elements (S, C, and O) in the immersed Ti specimens increased with the Au sputtering time, which indicates that the binding of alkanethiol molecules is enhanced by the Au modification on the Ti surface. Qualitative analysis of XPS (Au-S, COO(-), and OH(-) species) and FTIR spectra (peaks assignable to an aliphatic carboxylic acid) for the sample after immersion also supported this. A strong positive correlation between the S and Au content confirms that Au sputtering is an effective method to control the alkanethiol treatment of Ti substrates. PMID- 24492122 TI - Visualization study on distortion of a metal frame by polymerization shrinkage and thermal contraction of resin. AB - Three types of metal specimens (ring-shaped, plate-shaped, and a simulated anterior arch) for distortion observations were made from Au-Ag-Pd-Cu alloy. Distortion due to polymerization shrinkage and thermal contraction of a heat curing acrylic resin containing 4-META (4-methacryloyloxyethyl trimellitate anhydride, 4-META resin) could be visualized for the ring-shaped specimen, which showed increasing distortion of the metal frame upon adhesion of the resin to the outer metal surface. Distortion of the plateshaped specimen adhering to 4-META resin decreased with increasing thickness of the cured resin. The distortion of the metal frame simulating an anterior arch of a six-unit bridge with a facing composite resin showed that the curvature of the metal frame was larger after curing of the facing composite resin. However, it recovered most of its original curvature with an associated increase in the number of cracks between the crowns after trimming the resin to a tooth profile. PMID- 24492123 TI - Effect of mesoporous silica nanoparticles on dentinal tubule occlusion: an in vitro study using SEM and image analysis. AB - The occlusion of dentinal tubules is considered to be an effective strategy to treat dentin hypersensitivity. This in vitro study introduced mesoporous silica nanoparticles (MSNs) for tubular occlusion to achieve deeper sealing. Further, MSNs with independently encapsulated calcium and phosphates (as calcium and phosphate sources) (Ca(2+)/PO4(3-)@MSNs) were introduced to achieve improved efficacy of tubular occlusion and remineralization. MSNs or Ca(2+)/PO4(3-)@MSNs were proportionally mixed with distilled water to make their respective desensitizing slurries, which were used to treat dentin surfaces. The efficacy of tubular occlusion was evaluated using scanning electron microscopy (SEM) images and an image analyzer, and compared with that achieved with Green-Or -a commonly used densitizer. The results demonstrated that both MSNs and Ca(2+)/PO4(3-)@MSNs almost completely occluded dentinal tubules and formed a deeper seal which penetrated about 105 MUm deep into the dentinal tubules. Significant differences in tubular occlusion were observed between Green-Or densitizer and MSNs or Ca(2+)/PO4(3-)@MSNs. The novel MSNs-based nanomaterials showed great potential as a treatment option for dentin hypersensitivity. PMID- 24492124 TI - Effect of ultraviolet light irradiation period on bond strengths between fiber reinforced composite post and core build-up composite resin. AB - The aim of the present study was to characterize the effects of the ultraviolet light (UV) irradiation period on the bond strength of fiber-reinforced composite (FRC) posts to core build-up resin. Three types of FRC posts were prepared using polymethyl methacrylate, urethane dimethacrylate, and epoxy resin. The surfaces of these posts were treated using UV irradiation at a distance of 15 mm for 0 to 600 s. The pull-out bond strength was measured and analyzed with the Dunnett's comparison test (alpha=0.05). The bond strengths of the post surfaces without irradiation were 6.9 to 7.4 MPa; those after irradiation were 4.2 to 26.1 MPa. The bond strengths significantly increased after 15 to 120-s irradiation. UV irradiation on the FRC posts improved the bond strengths between the FRC posts and core build-up resin regardless of the type of matrix resin. PMID- 24492126 TI - Retraction: A three-dimensional finite element analysis of the effects of restorative materials and post geometry on stress distribution in mandibular molar tooth restored with post-core crown. PMID- 24492125 TI - Hybrid effects of zirconia nanoparticles with aluminum borate whiskers on mechanical properties of denture base resin PMMA. AB - The aim of this study was to investigate the hybrid effects of ZrO2 nanoparticles (nano-ZrO2) and aluminum borate whiskers (ABWs) on flexural strength and surface hardness of denture base resin, polymethyl methacrylate (PMMA). Both nano-ZrO2 and ABWs were modified by silane coupling agent (Z6030) before being mixed with PMMA. Various amounts of silanized nano-ZrO2 and ABWs were mixed with PMMA to prepare ZrO2-ABW/PMMA composites. Flexural strength and surface hardness were evaluated using three- point bending test and Vickers hardness test respectively. Fractured surfaces were also observed by scanning electron microscopy (SEM). The mechanical behaviors of silanized ZrO2-ABW/PMMA composites were significantly improved. Flexural strength reached a maximum value of 108.01 +/- 5.54 MPa when 2 wt% of nano-ZrO2 was mixed with ABWs at a ZrO2/ABW ratio of 1:2, amounting to an increase of 52% when compared with pure PMMA. Surface hardness achieved a maximum value of 22.50 +/- 0.86 MPa when 3 wt% of nano-ZrO2 was mixed with ABWs at the same ZrO2/ABW ratio, which was an increase of 27% when compared with pure PMMA. PMID- 24492127 TI - Retraction: In vitro osteoinduction of human mesenchymal stem cells in biomimetic surface modified titanium alloy implants. PMID- 24492128 TI - Retraction: Morinda citrifolia leaves enhance osteogenic differentiation and mineralization of human periodontal ligament cells. PMID- 24492130 TI - A new comprehensive cochlear implant questionnaire for measuring quality of life after sequential bilateral cochlear implantation. AB - OBJECTIVE: To develop a comprehensive cochlear implant questionnaire (CCIQ) as a tool for assessing changes in quality of life (QoL) after receiving a second cochlear implant (CI2) and to correlate the QoL with speech perception changes after CI2. STUDY DESIGN: Retrospective case series with planned data collection. SETTING: Academic cochlear implant center. PATIENTS: Ninety-eight English speaking adults who received CI2 between 2000 and 2011. INTERVENTION: CCIQ is a 28-item, 5-point Likert-scale questionnaire that assesses the physical and psychosocial benefits of CI2. MAIN OUTCOME MEASURES: Test-retest reliability and Cronbach's alpha internal consistency were used to assess the reliability of the CCIQ. Speech perception was tested using CNC and HINT. RESULTS: Fifty-four patients completed the CCIQ, and 26 were retested. Respondents reported a subjective improvement in all domains. Test-retest reliability was satisfactory, with 64% of items achieving an intraclass correlation coefficient of greater than 0.6. Internal consistency reliability was excellent for the overall measure and was satisfactory for 6 of 9 subdomains. Speech perception data were available for 22 patients. Average CNC scores improved 13 +/- 16%, and HINT scores improved 42 +/- 16%. No statistically significant correlation was found between QoL scores and audiometric data or duration of CI2 use. CONCLUSION: Our preliminary data indicate that this CCIQ is a promising tool in assessing QoL specific to CI2 patients. Overall, patients reported improved QoL, independent of speech perception scores. Further refinements of the questionnaire with larger patient numbers are needed to strengthen the CCIQ. PMID- 24492129 TI - Rare variants in BMP2 and BMP4 found in otosclerosis patients reduce Smad signaling. AB - HYPOTHESIS: Genetic variation in BMP2 and BMP4 found in otosclerosis patients result in altered Smad signaling. BACKGROUND: Otosclerosis is a common form of adult-onset conductive hearing loss resulting from abnormal bone remodeling of the bony labyrinth that surrounds the inner ear. Both genetic and environmental factors are implicated in the disease, yet very little is known about its pathogenesis. The evidence for a genetic component has been established through family-based linkage and population-based association studies. Previously, members of the TGF-beta superfamily of genes have been associated with otosclerosis. METHODS: Sequencing of BMP2 and BMP4 coding regions was performed to identify common and rare variation in German otosclerosis patients compared with controls. Functional analyses of rare variation in the patient cohort were conducted by exposing an osteosarcoma cell line to conditioned media containing either wild type or variant forms of BMP2 or BMP4 and analyzing Smad1/5/8 phosphorylation. RESULTS: Although no significant association with common variation in these 2 genes was detected, there were 8 singleton variants identified in the German population. Of the 4 coding variants found solely in otosclerosis patients, two--BMP4(N150K) and BMP2(K357-R396del)--were found to decrease Smad1/5/8 signaling. CONCLUSION: Rare variants in BMP2 and BMP4 are not a major genetic component in the otosclerosis population. However, those with functional affect showed decreased Smad signaling. Further analysis of Smad signaling molecules should be performed to determine if these pathways in combination are a major contributor to otosclerosis, which could lead to additional treatment options for otosclerosis patients. PMID- 24492131 TI - Cochlear implantation in Meniere's disease patients. AB - OBJECTIVE: A significant portion of the Meniere's disease (MD) population will ultimately have severe-to-profound hearing loss in their affected ear. When this occurs bilaterally or when a patient has poor hearing in the contralateral ear, these patients may meet criteria for cochlear implantation (CI). Here, we describe our institution's CI outcomes in MD patients. STUDY DESIGN: Retrospective chart and literature review. SETTING: Tertiary referral center. PATIENTS: Twenty-one patients with either bilateral MD or unilateral MD who underwent CI in their ear affected with MD. INTERVENTION(S): Cochlear implantation. MAIN OUTCOME MEASURE(S): Postoperative speech perception. RESULTS: Results for the MD patients were also compared with a standard sample of 178 adult recipients implanted with newest generation technology. Collapsing across status of MD activity, there was a significant difference between the MD CNC word recognition scores and that of the standard sample (43.2 versus 59.1%, p = 0.02). When separating the MD patients into groups according to the status of disease activity, those with active MD achieved scores that were not significantly different from the standard sample (55.7 versus 59.1%, p = 0.94), although those without active MD were significantly different from the standard group (38.2 versus, p = 0.002). Patients undergoing surgical or ablative procedures for their MD symptoms had statistically significant improvement in their CI hearing outcomes compared with those who did not (CNC words: p = 0.014; CNC phonemes: p = 0.035). Six patients had persistent vertiginous symptoms of MD before CI. After CI, 2 had complete resolution of vertigo, 3 had subjective improvement in their symptoms, and 1 noticed no change. CONCLUSION: Meniere's disease patients' hearing outcomes seem to be worse than the general CI population. However, those with active MD perform similarly to the general CI population. PMID- 24492132 TI - Feasibility of using EMG for early detection of the facial nerve during robotic direct cochlear access. AB - HYPOTHESIS: Facial nerve monitoring can be used synchronous with a high-precision robotic tool as a functional warning to prevent of a collision of the drill bit with the facial nerve during direct cochlear access (DCA). BACKGROUND: Minimally invasive direct cochlear access (DCA) aims to eliminate the need for a mastoidectomy by drilling a small tunnel through the facial recess to the cochlea with the aid of stereotactic tool guidance. Because the procedure is performed in a blind manner, structures such as the facial nerve are at risk. Neuromonitoring is a commonly used tool to help surgeons identify the facial nerve (FN) during routine surgical procedures in the mastoid. Recently, neuromonitoring technology was integrated into a commercially available drill system enabling real-time monitoring of the FN. The objective of this study was to determine if this drilling system could be used to warn of an impending collision with the FN during robot-assisted DCA. MATERIALS AND METHODS: The sheep was chosen as a suitable model for this study because of its similarity to the human ear anatomy. The same surgical workflow applicable to human patients was performed in the animal model. Bone screws, serving as reference fiducials, were placed in the skull near the ear canal. The sheep head was imaged using a computed tomographic scanner and segmentation of FN, mastoid, and other relevant structures as well as planning of drilling trajectories was carried out using a dedicated software tool. During the actual procedure, a surgical drill system was connected to a nerve monitor and guided by a custom built robot system. As the planned trajectories were drilled, stimulation and EMG response signals were recorded. A postoperative analysis was achieved after each surgery to determine the actual drilled positions. RESULTS: Using the calibrated pose synchronized with the EMG signals, the precise relationship between distance to FN and EMG with 3 different stimulation intensities could be determined for 11 different tunnels drilled in 3 different subjects. CONCLUSION: From the results, it was determined that the current implementation of the neuromonitoring system lacks sensitivity and repeatability necessary to be used as a warning device in robotic DCA. We hypothesize that this is primarily because of the stimulation pattern achieved using a noninsulated drill as a stimulating probe. Further work is necessary to determine whether specific changes to the design can improve the sensitivity and specificity. PMID- 24492133 TI - Type 1 allergy-induced endolymphatic hydrops and the suppressive effect of H1 receptor antagonist (olopatadine hydrochloride). AB - OBJECTIVE: To investigate whether endolymphatic hydrops (EH) is experimentally induced by type 1 (or immediate) hypersensitivity allergic reaction and to investigate the inhibitory action of a histamine H(1)-receptor antagonist (olopatadine hydrochloride [OLO-Hy]) on allergic EH induced by systemic immune challenge with 2,4-dinitrophenylated-Ascaris (DNP-As). METHODS: The experimental animals were actively sensitized with DNP-As twice at a 4-week interval and were provoked by an injection of DNP-BSA including DNP-As 1 week after the second sensitization. The OLO-Hy (+) group received oral administration of OLO-Hy (30 mg/kg) 1 hour before the provocation, whereas the OLO-Hy (-) group received distilled water. The temporal bones in all animals were light microscopically examined to assess the degree of EH quantitatively and the expression of degranulated mast cells in the endolymphatic sac. RESULTS: Endolymphatic hydrops was observed 1, 6, 12, and 24 hours after the last sensitization in the OLO-Hy ( ) group but was not observed in the OLO-Hy (+) group. Quantitative analysis of the increase ratios (IRs) of the cross-sectional area of the scala media revealed that the IRs of the OLO-Hy (-) group were significantly greater compared with those of the control group (p < 0.001). There was also a significant difference in the IRs between the OLO-Hy (-) and OLO-Hy (+) groups (p < 0.001). CONCLUSION: The systemic sensitization with DNP-As produced allergy-induced experimental EH by type 1 hypersensitivity allergic reaction, and the development of this EH was prevented by histamine H(1)-receptor antagonists. PMID- 24492134 TI - Pseudo-spontaneous and head-shaking nystagmus in horizontal canal benign paroxysmal positional vertigo. AB - OBJECTIVES: To determine the characteristics and diagnostic value of pseudo spontaneous and head-shaking nystagmus (HSN) in benign paroxysmal positional vertigo involving the horizontal semicircular canal (HC-BPPV). STUDY DESIGN: Retrospective case series review. METHODS: After excluding 19 patients with canal paresis, abnormal head impulse test, recent history of peripheral or central vestibular disorders, or poor cooperation, we retrospectively recruited 127 patients with HC-BPPV from January 2009 to July 2012. The patients included 69 geotropic and 58 apogeotropic types. We analyzed the pattern of pseudo spontaneous nystagmus and HSN according to the lesion side. RESULTS: Pseudo spontaneous nystagmus was observed in 87 (87/127, 68.5%) patients, both in geotropic (46/69, 66.7%) and apogeotropic (41/58, 70.7%) types without difference in the prevalence between the types (p = 0.627). Pseudo-spontaneous nystagmus beat more to the lesion side in apogeotropic type (28/41, 68.3%, p = 0.028) but in either direction without directional preponderance in geotropic type (p = 0.659). Of the 90 patients who underwent horizontal head-shaking, 27 (30.0%) showed HSN that was more common in apogeotropic than in geotropic type (22/44 [50.0%] versus 5/46 [10.9%], p < 0.001). Patients with apogeotropic HC-BPPV showed predominantly contralesional HSN (19/22 [86.4%], p = 0.001), whereas patients with geotropic type did not show any directional preponderance of HSN (contralesional in 2 and ipsilesional in 3). CONCLUSION: HSN is more common and mostly contralesional in apogeotropic HC-BPPV. HSN may be a lateralizing sign in apogeotropic HC-BPPV. Different prevalence and patterns of HSN in apogeotropic and geotropic HC-BPPV suggest dissimilar cupular dynamics in those disorders. PMID- 24492135 TI - Squamous cell carcinoma of the temporal bone: clinical outcomes from radical surgery and postoperative radiotherapy. AB - OBJECTIVE: To review the treatment of squamous carcinoma of the temporal bone at a regional skull base unit for the period 1982-2012. STUDY DESIGN: Retrospective case review. SETTING: Tertiary referral center. PATIENTS: Sixty patients with primary squamous carcinoma of the temporal bone. INTERVENTIONS: Multidisciplinary team approach including surgical resection, reconstruction, and postoperative radiotherapy. MAIN OUTCOME MEASURES: Disease-specific survival, overall survival. RESULTS: The 5-year disease-specific survival for the whole cohort was 44% (CI, 37%-51%). Multivariable analysis revealed nodal status, poorly differentiated squamous cell histology, and carotid involvement to be poor prognostic indicators. CONCLUSION: Although the survival figures in this series are comparable with the best outcomes from other units, our experience would suggest improvements can still be achieved by reconsidering the selection of patients for neck dissection and temperomandibular joint excision in early stage disease. We also conclude that postoperative radiotherapy should be delivered to all patients, including surgical salvage cases who may have received previous irradiation. Finally, the minority of patients with poor prognostic features should be offered a more palliative therapeutic approach. PMID- 24492136 TI - Observation of regenerated fungiform taste buds after severing the chorda tympani nerve using confocal laser scanning microscopy in vivo. AB - OBJECTIVE: To evaluate whether regenerated fungiform taste buds after severing the chorda tympani nerve can be detected by confocal laser scanning microscopy in vivo. STUDY DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Six patients with a normal gustatory function (Group 1), 9 patients with taste function recovery after severing the CTN (Group 2), and 5 patients without taste function recovery (Group 3) were included. In Groups 2 and 3, canal wall up (closed) tympanoplasty or canal wall down with canal reconstruction tympanoplasty was performed in all patients. INTERVENTION: Diagnostic. MAIN OUTCOME MEASURES: The severed nerves were readapted or approximated on the temporalis muscle fascia used to reconstruct the eardrum during surgery. Preoperative and postoperative gustatory functions were assessed using electrogustometry. Twelve to 260 months after severing the CTN, the surface of the midlateral region of the tongue was observed with a confocal laser microscope. RESULTS: EGM thresholds showed no response 1 month after surgery in all patients of Groups 2 and 3. In Group 2, EGM thresholds showed recovery 1 to 2 years after surgery and before confocal microscopy (-1.3 +/- 6.5 dB). There was a significant difference between Group 1 (-5.7 +/- 2.0 dB; p < 0.01) and Group 2. In Group 3, EGM thresholds showed no response for more than 2 years. In the control group (Group 1), 0 to 16 taste buds were observed in each FP, and 55 (79.7%) of 69 FP contained at least 1 taste bud. The mean number of taste bud per papilla was 3.7 +/- 3.6. In patients with a recovered taste function (Group 2), 0 to 8 taste buds were observed in each FP. In this group, 54 (56.2%) of 94 FP contained at least 1 taste bud. The mean number of taste bud per papilla was 2.0 +/- 2.2 (p < 0.01). In Group 3, without recovery, the FP was atrophied, and no taste bud was observed. CONCLUSION: Regenerated fungiform taste bud could be observed in vivo using confocal laser scanning microscopy, indicating that regenerated taste bud can be detected without biopsy. PMID- 24492137 TI - Letter to the editor : about the paper: Nehne J., Saliba I. - bilateral simultaneous caloric test for superior semicicular canal evaluation 2011; 32: 1473-1479. PMID- 24492138 TI - Reply to the letter about the "bilateral simultaneous caloric test for superior semicircular canal evaluation". PMID- 24492139 TI - Is cartilage interposition required for ossiculoplasty with titanium prostheses? AB - OBJECTIVE: To demonstrate that cartilage interposition between the head of a titanium prosthesis and the tympanic membrane is not necessary to prevent extrusion. STUDY DESIGN: Retrospective review. SETTING: District general hospital. PATIENTS: A retrospective review of 73 ears in patients aged between 5.9 and 64.5 years, which had an ossiculoplasty performed using a titanium prosthesis between the stapes footplate or stapes head and the tympanic membrane. INTERVENTIONS: Use of Spiggle and Theis two part, shortenable titanium PORP and TORP and Grace Alto titanium TORP and PORP. MAIN OUTCOME MEASURES: Number of extruded prostheses. Audiometric results. RESULTS: Five extrusions occurred in 4 patients, follow-up between 6 and 98 months. Extrusions were related to retraction of the tympanic membrane around the prosthesis. Audiometric results compared favorably with other ossiculoplasty techniques. CONCLUSION: The titanium head of the Spiggle and Theis and Grace Alto titanium prostheses interact well with the undersurface of the tympanic membrane in patients with favorable middle ear conditions. In our experience, cartilage interposition is not mandatory. PMID- 24492140 TI - Active middle ear implants in patients undergoing subtotal petrosectomy: long term follow-up. AB - OBJECTIVE: In 2009, we had introduced the active middle ear implant (aMEI) round window coupling in patients undergoing a subtotal petrosectomy and reported our first results. In the current study, we evaluated the long-term firmness of the vibranting floating mass transducer (FMT) within the round window niche, the long term audiologic results and the patient's perspective of wearing the speech processor over time. PATIENTS AND INTERVENTION: Of 10 patients, 6 female and 1 male patients (age range from 30 to 71 yr) had undergone subtotal petrosectomy with aMEI round window vibroplasty and were available for a long-term follow-up. Indications were recurrent or chronic ear infections with preserved inner ear function and inability for ossicular chain reconstruction. A thin piece of fascia was placed between the FMT and the round window membrane once the round window niche had been enlarged by drilling. The operative cavity was filled with fat and a muscle flap in all cases. MAIN OUTCOME MEASURES: Audiologic evaluations included pre- and postoperative pure-tone audiometry, Freiburger syllable and numeric tests. All patients underwent preoperative computed tomographic (CT) scans and magnetic resonance imaging (MRI) examination. Postoperative follow-up included CT scans at 1 and preferentially 3 to 5 years to confirm the correct positioning of the FMT and the complete removal of the underlaying pathology. Subjective benefit was rated by the Glasgow Hearing Aid Benefit Profile. RESULTS: There were no immediate postoperative complications. CT scans confirmed the correct and durable positioning of the FMT. Audiometric tests revealed a stable and adequate functional gain in all patients with limited adjustments over time. Subjective rating reached a high satisfaction score, and all patients remained long-term implant users. One patient developed a skin necrosis over the implant because of excessive pressure exerted by the retaining magnet of the headpiece. Revision was performed using local skin flaps with preservation of the functioning implant. CONCLUSION: Our radiologic, audiometric, and subjective data show stable long-term results of round window vibroplasty in patients undergoing subtotal petrosectomy, and we continue to recommend this treatment option instead of another mastoid revision procedure. PMID- 24492141 TI - High-dose chemotherapy with autologous stem cell transplantation for elderly patients with relapsed/refractory diffuse large B cell lymphoma: a nationwide retrospective study. AB - The number of elderly patients with diffuse large B cell lymphoma (DLBCL) continues to increase but the data regarding autologous stem cell transplantation (ASCT) for elderly patients are limited. We analyzed 484 patients, ages 60 years or over, diagnosed with relapsed/refractory DLBCL who received ASCT from 1993 to 2010 in the Japan Society for Hematopoietic Cell Transplantation database. Median age was 64 years (range, 60 to 78). To evaluate the impact of age at ASCT, patients were classified into 3 groups: those between the ages of 60 to 64, 65 to 69, and 70 years or over. Overall nonrelapse mortality (NRM) at day 100, 1 year, and 2 years was 4.1%, 5.9% and 7.7%, respectively. NRM did not significantly differ among age groups (P = .60). Two-year progression-free survival (PFS) and overall survival (OS) were 48% and 58%, respectively. PFS and OS were significantly longer in patients 60 to 64 years old; however, the survival rate was acceptable even in those 70 or over, with a 2-year OS of 46%. ASCT is feasible in selected elderly patients and age alone should not be a contraindication for ASCT. Eligibility should be individualized and identification of a subset of elderly patients at high risk of treatment-related morbidity or mortality warrants investigation. PMID- 24492142 TI - Preparative regimen dosing for hematopoietic stem cell transplantation in patients with chronic hepatic impairment: analysis of the literature and recommendations. AB - Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. Transplant has been associated with high treatment-related morbidity and mortality, therefore limiting its usefulness in patients with baseline liver dysfunction. In the event that a patient with hepatic insufficiency is selected for HSCT, dosage adjustments may be considered; however, no reliable endogenous biomarkers can serve as a guide for adjustments. There is no clear standard or guideline for how to approach these patients, and most adjustments are made empirically on the basis of expert opinion. This article offers practical advice and outlines our personal approaches to provide dosing recommendations for commonly-used preparative agents in the setting of hepatic impairment with the aim to optimize dosing for this patient population. PMID- 24492143 TI - Allogeneic hematopoietic cell transplantation may alleviate the negative prognostic impact of monosomal and complex karyotypes on patients with acute myeloid leukemia. AB - Monosomal karyotype (MK) and complex karyotype (CK) are well known to be associated with a very poor clinical outcome in patients with acute myeloid leukemia (AML). However, whether or not the prognostic impact of MK and CK remains relevant for patients who have undergone allogeneic hematopoietic cell transplantation (allo-HCT) is still unclear. We retrospectively analyzed the status of MK and CK, as well as other clinical laboratory features, in 148 allo HCT AML patients at our institution and correlated with their event-free survival (EFS) and overall survival (OS) after transplantation. MK and CK were identified in 14 (9%) and 19 (13%) cases, respectively. On univariate analysis, only age (>=60 years) and WBC count (>=15 * 10(9)/L) were significant adverse predictors for EFS (P < .001 and P = .017, respectively) and OS (P = .002 and P = .021, respectively). MK, CK, and other relevant parameters analyzed did not affect the clinical outcome. Multivariable analysis confirmed that both older age and high WBC count were independent prognostic factors for a shorter OS (P = .001 and P = .003, respectively) and a shorter EFS (P < .001 and P = .001, respectively). Our results indicate that neither MK nor CK are high-risk factors in AML patients undergoing allo-HCT. PMID- 24492145 TI - No impact of total or myeloid Cd34+ cell numbers on neutrophil engraftment and transplantation-related mortality after allogeneic pediatric bone marrow transplantation. AB - Although the influence of transplanted bone marrow (BM) CD34+ cells on neutrophil engraftment (NE) and transplantation outcomes has been discussed controversially, thresholds between 2 and 4 * 10(6)/kg CD34+ cells are commonly accepted. This has substantial consequences for a donor in terms of BM volume to be collected, which frequently covers up to 15 to 20 mL/kg. As the BM CD34+ compartment contains varying fractions of CD34+/CD19+ B lymphoid progenitors, we tested the hypothesis that the infused CD34+/CD45dim/CD19-/CD10- myeloid stem cells might reliably predict NE in 94 children who received BM from 37 HLA-identical sibling donors (MSD) and 57 matched unrelated donors after myeloablative conditioning. The grafts contained a median of 3.6 * 10(6)/kg total CD34+ cells, which consisted of a median of 73% myeloid CD34+ cells and 27% B lymphoid progenitors. Grafts from donors <15 years old yielded significantly lower myeloid fractions compared with grafts from older donors (P < .001). All patients achieved sustained NE after median 20 (range, 11 to 40) days. By multivariate analysis, neither the number of total CD34+ cells (P = .605) nor of myeloid CD34+ cells (P = .981) correlated with NE, whereas transplantation from MSD (hazard ratio [HR] 3.51; P = .019) and the administration of granulocyte colony-stimulating factor (HR 2.24; P = .002) remained independent factors associated with earlier NE. Furthermore, neither total nor myeloid CD34+ cell quantities were associated with incidences of severe infections before NE (P = .271 and P = .132) or transplantation-related mortality (TRM) at day +100 (P = .294 and P = .490). Taking into account that the number of transplanted total CD34+ or myeloid CD34+ cells does not seem to have a relevant impact on time to NE, sepsis rates, or TRM, the need of certain threshold cell numbers should be revisited, at least for pediatric MSD. PMID- 24492144 TI - Metagenomic analysis of the stool microbiome in patients receiving allogeneic stem cell transplantation: loss of diversity is associated with use of systemic antibiotics and more pronounced in gastrointestinal graft-versus-host disease. AB - Next-generation sequencing of the hypervariable V3 region of the 16s rRNA gene isolated from serial stool specimens collected from 31 patients receiving allogeneic stem cell transplantation (SCT) was performed to elucidate variations in the composition of the intestinal microbiome in the course of allogeneic SCT. Metagenomic analysis was complemented by strain-specific enterococcal PCR and indirect assessment of bacterial load by liquid chromatography-tandem mass spectrometry of urinary indoxyl sulfate. At the time of admission, patients showed a predominance of commensal bacteria. After transplantation, a relative shift toward enterococci was observed, which was more pronounced under antibiotic prophylaxis and treatment of neutropenic infections. The shift was particularly prominent in patients that developed subsequently or suffered from active gastrointestinal (GI) graft-versus-host disease (GVHD). The mean proportion of enterococci in post-transplant stool specimens was 21% in patients who did not develop GI GVHD as compared with 46% in those that subsequently developed GI GVHD and 74% at the time of active GVHD. Enterococcal PCR confirmed predominance of Enterococcus faecium or both E. faecium and Enterococcus faecalis in these specimens. As a consequence of the loss of bacterial diversity, mean urinary indoxyl sulfate levels dropped from 42.5 +/- 11 MUmol/L to 11.8 +/- 2.8 MUmol/L in all post-transplant samples and to 3.5 +/- 3 MUmol/L in samples from patients with active GVHD. Our study reveals major microbiome shifts in the course of allogeneic SCT that occur in the period of antibiotic treatment but are more prominent in association with GI GVHD. Our data indicate early microbiome shifts and a loss of diversity of the intestinal microbiome that may affect intestinal inflammation in the setting of allogeneic SCT. PMID- 24492146 TI - Editorial transition. PMID- 24492147 TI - Commentary on Berlin et al. PMID- 24492148 TI - Commentary on Berlin et al. PMID- 24492151 TI - Application of food waste based diets in polyculture of low trophic level fish: effects on fish growth, water quality and plankton density. AB - Food waste was collected from local hotels and fish feed pellets were produced for a 6 months long field feeding trial. Three types of fish feed pellets (control diet: Jinfeng(r) 613 formulated feed, contains mainly fish meal, plant product and fish oil; Diet A: food waste based diet without meat and 53% cereal; Diet B: food waste based diet with 25% meat and 28% cereal) were used in polyculture fish ponds to investigate the growth of fish (grass carp, bighead and mud carp), changes in water quality and plankton density. No significant differences in the levels of nitrogen and phosphorous compounds of water body were observed between 3 fish ponds after the half-year feeding trial, while pond receiving Diet A had the highest density of plankton. The food waste combination of Diet B seems to be a better formulation in terms of the overall performance on fish growth. PMID- 24492152 TI - The impact of water temperature on water quality indexes in north of Liaodong Bay. AB - The north of Liaodong Bay is one of the most severely polluted areas in Bohai Sea. Because the self-purification capacity from the sea water exchange process is limited, the pollutants from the land and river sources cannot be completed degraded and an obviously contaminated zone was formed in the north of Liaodong Bay. Therefore the self-purification capacity from biological process is essential for maintaining ecosystem balance. Marine heterotrophic bacteria play an important role in degradation of the dissolved organic matters and constitution of the primary production in the coastal areas. The shift of water temperature between winter and summer is about 28 degrees C in the north of Liaodong Bay, which causes changes in the self-purification capacity of the sea area. Certain indexes of water quality in Liaodong Bay were investigated in order to detect how these indexes response to the changing of water temperature. The experimental results show that COD, DO and the concentration of fecal coliform vary a little with the changing of water temperature; TBC increases dramatically when the water temperature is over 16 degrees C; and TBC in summer is 30 times more than that in winter. By this study, the paper provides a reference to assess the environmental purification capacity of the sea area during different seasons. PMID- 24492153 TI - Uptake and biological effects of synthetic glucocorticoids in common carp (Cyprinus carpio). AB - Uptake and biological effects of synthetic glucocorticoids (GCs) were analyzed using common carp (Cyprinus carpio). Fish were exposed to clobetasol propionate (CP) or clobetasone butyrate (CB) individually or in mixture at 1 MUg L(-1) for 21 days. Bioconcentration factor (BCF) of CB was calculated as 100, and BCF of CP was less than 16. No effects were found in fish erythrocyte and leukocyte numbers and serum glucose levels after exposure to the selected GCs. On the other hand, serum concentrations of free amino acids significantly increased in GC-exposed groups. Thus, exposures to synthetic GCs at relatively low concentrations seemed to cause enhancement of protein degradation and subsequent increase of serum free amino acids without a corresponding increase in serum glucose levels, an effect which might be related to partial induction of gluconeogenesis by GC. PMID- 24492154 TI - The PAH level, distribution and composition in surface sediments from a Mediterranean lagoon: the Marano and Grado Lagoon (Northern Adriatic Sea, Italy). AB - The Marano and Grado Lagoon is one of the best conserved transitional environment in the whole Mediterranean area. On the other hand, it suffers from industrial, agricultural and fisheries activities, which could have an important impact on its environmental quality. With the application of the WFD, the sediment chemical status was investigated. In this work, 16 polycyclic aromatic hydrocarbons included by the US EPA within the priority pollutants were considered. PAHs values ranged from non-detectable to 1056 ng g(-1) showing the highest contamination close to the Aussa-Corno River mouth, which received the industrial inputs. The contamination level was comparable to that observed in low contaminated sites of the Mediterranean region, and lower than the adjacent Gulf of Trieste. The ratios of selected PAHs congeners pointed out the prevalence of pyrolitic sources. Moreover, the application of the ERL/ERM displayed an environment, which should not have a potential biological impact. PMID- 24492155 TI - Comparison of common persistent organic pollutants (POPs) in flounder (Platichthys flesus) from the Vistula (Poland) and Douro (Portugal) River estuaries. AB - Groups of flounder (Platichthys flesus) females were collected in 2011 from the Vistula River and the Duoro River estuaries and corresponding reference sites in the southern Baltic Sea and Portuguese coast of the Atlantic Ocean to measure and compare the levels and profiles of polychlorinated biphenyls (PCBs), organochlorine pesticides (OCPs), and polybrominated diphenyl ethers (PBDEs). The estuaries' sediments were also investigated. Several differences were found in the POPs between the estuaries and between the two marine regions, which were highlighted by PCA. The Vistula River estuary POPs, significantly higher than in the Douro River estuary, were dominated by DDTs followed by PCBs. PBDEs levels, indifferent between the estuaries, were relatively low. The POP levels in flounder and sediment evaluated against environmental assessment criteria (EACs) indicated that none of the measured contaminants for which EAC had been established exceeded the criterion, except for CB-118 in flounder from the Vistula River estuary. PMID- 24492156 TI - Addressing health literacy through clear health communication: a training program for internal medicine residents. AB - OBJECTIVE: To develop, pilot, and test the effectiveness of a clear health communication curriculum to improve resident knowledge, attitudes, and skills regarding health literacy. METHODS: Thirty-one internal medicine residents participated in a small group curriculum that included didactic teaching, practice with a standardized patient, and individualized feedback on videotaped encounters with real patients. Outcomes were assessed using a pre-post survey and a communication skills checklist. RESULTS: Mean knowledge scores increased significantly from 60.3% to 77.6% (p<0.001). Residents also reported increased familiarity with the concept of health literacy (mean response 3.2 vs. 4.5 on a 5 point scale), importance placed on health literacy (4.2 vs. 4.9), frequency of considering health literacy in patient care (3.3 vs. 4.0), and confidence in communicating with low literacy patients (3.3 vs. 4.1) (all p<0.001). Use of plain language increased significantly from 33% to 86% (p=0.023). There were nonsignificant increases in the use of teach-back (0-36%, p=0.116) and encouraging questions (0-14%, p=0.502). CONCLUSION: Training in clear health communication improves resident knowledge, attitudes, and skills regarding health literacy. PRACTICE IMPLICATIONS: The increased use of clear health communication techniques can significantly improve the care and outcomes of vulnerable patients with limited health literacy. PMID- 24492157 TI - Modifiable risk factors for adherence to adjuvant endocrine therapy among breast cancer patients. AB - OBJECTIVE: Breast cancer incidence and mortality are declining due to improvements in early detection and treatment. One advance in treatment is the development of adjuvant endocrine therapy (AET) for women with hormone receptor positive breast cancer. Despite strong evidence linking AET to better health outcomes, AET adherence continues to be suboptimal. This study tests the hypothesis that patient beliefs about medication mediate the relationship between frequency of physician communication and AET adherence. METHODS: This cross sectional study utilizes data from patient self-report and medical chart abstraction (N=200). Survey measures included frequency of physician communication, patient beliefs about medicine, AET adherence, and demographic characteristics. RESULTS: Necessity beliefs mediated the relationship between frequency of physician communication and medication adherence (necessity beliefs beta=.18, p<.05; physician communication beta=.13, p>.05). There was no evidence of medication concerns mediating the relationship between frequency of physician communication and medication adherence. CONCLUSION: More frequent physician communication that shapes what patients believe about AET importance may be associated with greater AET adherence; however, frequent physician communication that shapes patient concerns about side effects may not be associated with greater AET adherence. PRACTICE IMPLICATIONS: Research is needed to enhance understanding of the type of physician communication that is most consistently associated with patient beliefs about medication and AET adherence. PMID- 24492158 TI - General practitioners' and psychiatrists' responses to emotional disclosures in patients with depression. AB - OBJECTIVE: To investigate general practitioners' (GPs') and psychiatrists' responses to emotional disclosures in consultations with patients with depression. METHODS: Thirteen patient consultations with GPs and 17 with psychiatrists were video-recorded and then analyzed using conversation analysis (CA). RESULTS: Psychiatrists responded to patients' emotional disclosures by attempting to clarify symptoms, by rational argumentation, or by offering an interpretation of the emotions from their own perspectives. GPs responded by claiming to understand the emotions or by formulating the patients' statements, but without further exploring the emotions. CONCLUSION: GPs displayed a greater engagement with patients' emotions than psychiatrists. Their approach could be described as empathic, corresponding to a mentalizing stance. The different approaches taken by psychiatrists could represent conceptual differences and might affect fruitful interdisciplinary work. Psychiatric nurses' responses to patients' emotions must also be studied to complete our knowledge from psychiatry. PRACTICE IMPLICATIONS: Experiences from training in mentalization could be used to develop physicians' empathic or mentalizing approach. As most patients with depression are treated in primary care, developing GPs' mentalizing capacity instead of offering didactic training could have a substantial effect in the population. PMID- 24492160 TI - Molecular mechanism underlying the renoprotective action of vitamin D. PMID- 24492159 TI - Patient preferences and performance bias in a weight loss trial with a usual care arm. AB - OBJECTIVES: This qualitative study examines performance bias, i.e. unintended differences between groups, in the context of a weight loss trial in which a novel patient counseling program was compared to usual care in general practice. METHODS: 14/381 consecutive interviewees (6 intervention group, 8 control group) within the CAMWEL (Camden Weight Loss) effectiveness trial process study were asked about their engagement with various features of the research study and a thematic content analysis undertaken. RESULTS: Decisions to participate were interwoven with decisions to change behavior, to the extent that for many participants the two were synonymous. The intervention group were satisfied with their allocation. The control group spoke of their disappointment at having been offered usual care when they had taken part in the trial to access new forms of help. Reactions to disappointment involved both movements toward and away from behavior change. CONCLUSION: There is a prima facie case that reactions to disappointment may introduce bias, as they lead the randomized groups to differ in ways other than the intended experimental contrast. PRACTICE IMPLICATIONS: In depth qualitative studies nested within trials are needed to understand better the processes through which bias may be introduced. PMID- 24492161 TI - Mitral valve repair. AB - Mitral valve repair is the gold standard treatment for mitral regurgitation. The history of mitral valve repair and its refinement in terms of the technique used will show the evolution of this surgical technique. The standard technique we use for mitral valve repair is described, and the outcomes we have observed over the past 4 decades are presented. PMID- 24492163 TI - Transient constrictive pericarditis following cardiac surgery. AB - Transient constrictive pericarditis (CP) is quite rare, with only a few reports presented. Herein, we report 2 cases of transient CP following cardiac surgery. Case 1 was an 80-year-old man who underwent repair of a left ventricular free wall rupture, while Case 2 was a 69-year-old woman who underwent a conventional aortic valve implantation procedure. In both cases, constrictive features developed about 2 weeks after surgery, which were treated successfully by administrations of non-steroidal anti-inflammatory drugs (NSAIDs). Prior to performing a pericardiectomy, NSAID administration should be considered for affected patients who are hemodynamically stable. PMID- 24492162 TI - Phase I trial of cisplatin, pemetrexed, and imatinib mesylate in chemonaive patients with unresectable malignant pleural mesothelioma. AB - BACKGROUND: We conducted a phase I trial of cisplatin/pemetrexed/imatinib mesylate, an oral platelet-derived growth factor receptor (PDGFR) inhibitor, in chemonaive patients with malignant pleural mesothelioma (MPM). METHODS: A standard 3 + 3 dose-escalating trial was used with the end points of maximum tolerated dose (MTD), response rate, survival, safety/toxicity, and tumor PDGFR levels. RESULTS: Seventeen patients with MPM were enrolled. The most common (any grade) side effects were nausea, fatigue, hypomagnesemia, and anemia. The MTD was established at dose level 3 (imatinib 600 mg) with a dose-limiting toxicity (DLT) of nausea and vomiting. The median progression-free survival (PFS) was 7.9 months and the median overall survival (OS) was 8.8 months. Patients with a sarcomatoid subtype had worse PFS (P = .01) and OS (P = .009), whereas they had a better Eastern Cooperative Oncology Group performance status (ECOG PS) of 0-1 predicted for improved OS (P = .001) and PFS (P = .013). The 6 patients who completed all 6 treatment cycles had better OS (P = .006); the median PFS was 9.6 months and the OS was 22.4 months. In the translational studies, 14 patients had adequate tumor tissue that could be assessed for immunohistochemical (IHC) analysis and fluorescence in situ hybridization (FISH). Patients with higher than median p PDGFRalpha IHC expression had a better OS (P = .013). When assessed as a continuous variable, higher p-PDGFRalpha in tumor cells correlated with an improved OS (P = .045). None of the other 4 IHC biomarkers were predictive or prognostic for survival. Twelve patients had successful PDGFRB FISH results, but none met the criteria of >= 4 copies of the PDGFRB gene; thus a correlation with clinical outcomes could not be done. CONCLUSION: The cisplatin/pemetrexed/imatinib mesylate combination had clinical benefit in some patients with MPM but was not well tolerated. Further investigation into alternative antiangiogenic agents, including PDGFRalpha inhibitors, is warranted. PMID- 24492164 TI - Does gefitinib have effects on EGFR mutation-positive thymoma? -Case report of thymoma recurrence. AB - A 56-year-old woman heavily pretreated for a thymoma was referred to our hospital with recurrence. Following additional surgery, the tumor recurred again in the left thoracic cavity. Because of previous multiple operations and repeated chemotherapies, the patient was considered unable to tolerate additional surgery or chemotherapy. After we obtained positive evidence of epidermal growth factor receptor (EGFR) mutation, she was administrated gefitinib for 3 months. Although immunohistochemistry findings showed that the tumor was EGFR positive, gefitinib therapy led no reduction of the tumor size. After undergoing immunotherapy, the patient suffered from repeated occurrences of pneumonia, and died from respiratory failure. PMID- 24492166 TI - Pleomorphic carcinoma showing rapid growth, multiple metastases, and intestinal perforation. AB - Pleomorphic carcinoma is a rare and very aggressive subtype of lung cancer that tends to grow rapidly and invade adjacent structures. Here we report a case of pleomorphic carcinoma with rapid growth, multiple metastases, and intestinal perforation. A 46-year-old man was admitted to our hospital because of lung abscess. Several antibiotics were administered for 2 weeks, but his condition did not improve. F18-fluorodeoxyglucose positron emission tomography revealed high uptake in the right lung, stomach, and pancreas. CT-fluoroscopic lung biopsy was performed, and a diagnosis of pleomorphic carcinoma was made. His performance status worsened each day, and the lung tumor grew within 1 month. In addition, sudden severe abdominal pain and tenderness developed 10 days after lung biopsy. He was diagnosed with gastrointestinal perforation, and he underwent surgery. However, he died 2 weeks after the surgery. Autopsy revealed the presence of an enormous tumor in the right lung and multiple metastases in the stomach, duodenum, intestine, bilateral kidneys, pancreas, gallbladder, right adrenal gland and thyroid. PMID- 24492165 TI - Successful repair of a syphilitic aortic arch aneurysm accompanied by serious cerebral infarction. AB - We present a 52-year-old male with a syphilitic aortic arch aneurysm accompanied by relevant extensive cerebral infarction. He was admitted to a local hospital for sudden loss of consciousness, where he was diagnosed with serious cerebral infarction. During his treatment, a multilocular aortic arch aneurysm involving the arch vessels was found incidentally. He was transferred to our hospital for surgical treatment. A preoperative routine laboratory test for syphilis was highly positive, which suggested that the aneurysm was likely caused by syphilis and the cerebral infarction was also induced by the involvement of syphilitic aortitis or arteritis. After 2 weeks of antibiotic therapy for syphilis, total arch replacement was performed successfully using meticulous brain protection with antegrade selective cerebral perfusion and deep hypothermia. He recovered without any further cerebral deficits. The pathological examination of the surgical specimen showed some characteristic changes of syphilitic aortitis. PMID- 24492167 TI - Nodular metastatic lung tumor from thyroid carcinoma. AB - Pulmonary metastases from thyroid cancer usually present with a micronodular or miliary pattern throughout both lungs; pulmonary metastasis with nodules measuring 10 mm in diameter is very rare. We herein present a 74-year-old woman with a history of papillary thyroid cancer treated surgically 17 years previously who presented with pulmonary metastatic nodules measuring 15 mm in diameter on chest radiography. If a pulmonary nodule or nodules are encountered in a patient with a history of thyroid cancer, though very rare, the possibility that it is a metastasis must be borne in mind. PMID- 24492168 TI - Co-existence of severe coarctation of the aorta and aortic valve stenosis in a 65 year-old woman: a case report. AB - Coarctation of the aorta is usually diagnosed and corrected early in life. Survival to more than 60 years of age of a patient with unrepaired coarctation of the aorta is extremely unusual, and the optimal management strategies for such patients are controversial. We describe the case of a woman who was first diagnosed as having coarctation of the aorta and aortic valve stenosis at the age of 65 years and underwent successful aortic valve replacement. PMID- 24492169 TI - Surgical thrombectomy for right heart thrombus with acute aortic dissection. AB - An 81-year-old female complaining of severe back pain was admitted to hospital and diagnosed with acute type A aortic dissection with a thrombosed false lumen. Aggressive antihypertensive therapy was selected. On day 8, computed tomography showed pulmonary artery thrombus, and transthoracic echocardiography showed a 76*70 mm worm-like floating right heart thrombus. Thrombolytic therapy is reported to be the optimal treatment for patients with pulmonary embolism and floating right heart thrombus, but is contraindicated in acute aortic dissection. The patient underwent surgical thrombectomy, which revealed thrombus entrapped in the Chiari network. An inferior vena cava filter was placed. The patient recovered uneventfully and was discharged home after initiation of warfarin therapy. PMID- 24492170 TI - Hybrid one-stage repair using a sutureless telescoped stent graft fixation for ruptured multiple thoracic aortic aneurysms. AB - We report the case of a 58-year-old man who underwent emergency one-stage hybrid repair for multiple thoracic aortic aneurysms involving giant arch and ruptured descending aortic aneurysms. Retrograde thoracic endovascular aortic repair for the ruptured descending aortic aneurysm was first performed to stabilize the hemodynamics. Then, a total arch replacement with an open stent graft, which was inserted into the previous stent graft of the descending aorta in a sutureless telescoped fashion, was performed without any technical problems. This procedure may be one useful therapeutic option for multiple thoracic aortic aneurysms, especially for emergency cases requiring one-stage repair. PMID- 24492171 TI - Thoracoscopic lobectomy as salvage surgery for local recurrence of non-small cell lung cancer after carbon ion radiotherapy in an initially operable patient. AB - Carbon ion radiotherapy (CIRT) for patients with early-stage non-small cell lung cancer (NSCLC) has recently provided favorable local control with very few toxic reactions. Because CIRT for NSCLC has been mostly performed for elderly or inoperable patients, salvage surgery for NSCLC after CIRT has rarely been reported. We describe a case of complete thoracoscopic right upper lobectomy with mediastinal lymphadenectomy performed as salvage surgery for local recurrence of stage IA NSCLC after CIRT in an initially operable patient who had refused surgery 27 months previously. Pleural adhesions caused by CIRT were localized to the pulmonary apex and the central pulmonary structures were intact at the time of the salvage surgery, which allowed us to successfully perform thoracoscopic lobectomy without any complications. Thus, salvage surgery for NSCLC after CIRT may be feasible in an initially operable patient, as CIRT appears to be unlikely to cause any difficulties in the salvage surgery. PMID- 24492172 TI - Primary pulmonary mucinous (colloid) adenocarcinoma with postoperative bone metastasis. AB - We describe rare primary pulmonary mucinous (colloid) adenocarcinoma in an 80 year-old man. Chest computed tomography revealed a lobulated, well-defined nodule with a diameter of 3.2 cm in the right middle lobe. Transbronchial biopsy via endobronchial ultrasound with a guide sheath did not uncover malignancy. Right middle lobectomy proceeded because the tumor was located close to the pulmonary hilum. Macroscopically, the cut surface of the nodule comprised a well demarcated area of somewhat transparent granular aggregates and a yellow-white gelatinous substance. Computed tomography findings of a solitary metastatic lesion in the left fifth costal head 28 months thereafter were consistent with those of a mucin rich tumor, which was effectively treated by radiotherapy. PMID- 24492173 TI - Pulmonary resection for lung cancer in nonagenarians: a report of five cases. AB - Lung cancer surgery in octogenarians has already become common in Japan due to the high proportion of elderly people and the progress in perioperative management, including anesthesia and video-assisted thoracic surgery. However, there have been few reports about the surgical treatment of lung cancer in nonagenarians. Five cases (mean age: 91.2 years; 3 men, 2 women) of non-small cell lung cancer in nonagenarians in whom pulmonary resection was performed are reported. All were adenocarcinomas; three were clinical stage IA, and two were IB. Three patients underwent lobectomy, and two underwent wedge resection. Mediastinal lymph node dissection was omitted in all patients. There were no fatal postoperative complications. During follow-up, one patient died due to fatal arrhythmia, and one patient who underwent wedge resection had local recurrence, but the others are alive in good condition. Pulmonary resection of lung cancer is possible for highly selected, nonagenarian patients without lymph node metastasis. PMID- 24492174 TI - Midterm outcomes of chordal cutting in combination with downsized ring annuloplasty for ischemic mitral regurgitation. AB - PURPOSE: We describe midterm outcomes after division of secondary chords (chordal cutting) combined with downsized ring annuloplasty for ischemic mitral regurgitation (IMR). METHODS: We compared the clinical outcomes in patients who underwent chordal cutting with downsized ring annuloplasty (CC-group, n = 15) and those who underwent conventional ring annuloplasty only (Conventional-group, n = 35) for IMR. Follow-up was complete in all patients. The median follow-up time was 4.1 years. RESULTS: Thirty-day mortality was 0% in CC-group and 20% in Conventional-group. The overall survival rate at 5-year was 80.8% +/- 12.6% in CC group and 61.7% +/- 8.4% in Conventional-group (Log-rank, p = 0.145). The freedom rate from valve-related events at 5 year was 84.6% +/- 10.0% in CC-group and 65.3% +/- 10.1% in Conventional-group (Log-rank, p = 0.213). Recurrence of severe mitral regurgitation was revealed in 3 patients of CC-group. Preoperative tenting height was the significant predictor of mitral regurgitation recurrence. In CC group, the mean left ventricular ejection fraction was 38.0% +/- 14.0%, which was similar to the preoperative value of 40.0% +/- 13.2% (p = 0.349). CONCLUSIONS: Chordal cutting with downsized ring annuloplasty for IMR is a simple method and provides satisfactory early outcomes. However, it carries with high recurrence of MR especially for patients with high tenting height. PMID- 24492175 TI - Spinal epidural hematoma during anticoagulant therapy for pulmonary embolism: postoperative complications in a patient with lung cancer. AB - Spinal epidural hematoma (SEH) is rare but causes neurological disorders. Rapid diagnosis and treatment maximize neurological recovery. We present the case of SEH after lung cancer surgery under epidural and general anesthesia. A 64-year old man underwent right upper lobectomy. Pulmonary embolism occurred on postoperative day 2. Anticoagulant therapy with fondaparinux and warfarin was started 2 hours after epidural catheter removal and he gradually recovered. On postoperative day 13, the level of prothrombin time-international normalized ratio reached 1.47 and fondaparinux administration was stopped. The next day, he developed back pain and paraplegia, and magnetic resonance imaging revealed a mass between Th4 and Th7 compressing the spinal cord. Emergency decompression laminectomy and hematoma evacuation were performed. After 2.5 months of rehabilitation, he regained almost all motor function and sensation. Late after epidural anesthesia, attention should be paid to possible SEH even though appropriate anticoagulant therapy had been initiated after epidural catheter removal. PMID- 24492176 TI - Study of adipose tissue-derived mesenchymal stem cells transplantation for rats with dilated cardiomyopathy. AB - BACKGROUND: Increasing evidences indicated that adipose-derived mesenchymal stem cells (ADMSCs) can stay survive, then gradually proliferate and differentiate into myocardial cells after transplanted into damaged areas and improve function of heart. METHODS: In this article, ADMSCs were isolated from adipose tissue of Wistar rats and cultured. When treated with 5-azacytidine (5-aza), ADMSCs were differentiated into myocardial cells, then we implant these cells into myocardium of rats of DCM to observe cell population and differentiation and compare cardiac function and hemodynamics changes before and after transplantation. RESULTS: The expression of Cardiac-specific markers indicated that ADMSCs which were isolated from adipose tissue of Wistar rats can differentiate into various cell types. Meanwhile, the treatment group displayed a higher level of LVESP, left ventricular intraventricular pressure (+dP/dt max), left ventricular intraventricular pressure (-dP/dt max) and left ventricular EF (%) than the control group. Altogether, these results indicate that heart systolic and diastolic function of rats of DCM was significantly improved meanwhile ventricular dilatation remodeling was inhibited after ADMSCs transplantation. CONCLUSIONS: Therefore, this research provides an experimental basis for further clinical application of ADMSCs transplantation for the treatment of DCM and non ischemic HF. PMID- 24492177 TI - Factors for sac size change of abdominal aortic aneurysm after endovascular repair. AB - OBJECTIVES: Factor(s) affecting the sac size of an abdominal aortic aneurysm (AAA) after endovascular aneurysm repair (EVAR) remain unclear. We compared the diameter of the aneurysm sac at one year after surgery with the preoperative diameter using CT images. METHODS: Patients who underwent EVAR at Juntendo University Hospital were involved. According to the size change in treated lesions of the aorta, patients were categorized into the following 3 groups: shrink (<5 mm of reduction), enlarge (>5 mm of expansion), and no change (size change within 5 mm). The patients' background, laboratory data, devices used, medications, anatomical characteristics, and presence/absence of postoperative endoleaks were examined. RESULTS: Of the 68 consecutive patients, 23 were excluded. Seventeen patients were classified into the shrink group, 28 patients into the no change group, and no patients into the enlarge group. Patients with higher thrombotic area rate on the preoperative AAA tended to present AAA sac shrinkage (p = 0.05). No other variables affected the size change in this study. In addition, the existence of an endoleak suggested the interference of sac shrinkage. CONCLUSIONS: The higher AAA thrombotic area rate tended to associate with AAA sac shrinkage. PMID- 24492178 TI - Are octogenarians in good condition after cardiac valvular surgery? AB - PURPOSE: With the aging of society in developed countries and advances in surgical technology in recent years, surgery is increasing in elderly patients. When performing surgery in older patients, both surgical outcomes and the maintenance of postoperative quality of life (QOL) are important issues. This study investigated surgical outcomes and postoperative QOL in octogenarians who underwent cardiac valvular surgery. METHODS AND RESULTS: Fifty-nine (16 males) octogenarians (80-89 years old, mean age, 82.4 +/- 2.4 years) underwent cardiac valvular surgery between August 1999 and June 2011. A QOL questionnaire, which included the Barthel Index (BI), Fillenbaum Instrumental Activities of Daily Living (FIADL), and the Vitality Index (VI), was sent to all survivors. Kaplan Meier analysis was used to assess survival. Hospital mortality was 1.6% (1 patient). The 3-, 5-, and 7-year survival rates were 81.2%, 75.4%, and 67.8%, respectively. The BI showed that 87.5% of patients did not require caregiving, the FIADL showed that 32.5% were highly independent, and the VI showed that 87.5% were motivated to live. CONCLUSIONS: Short-term outcomes were satisfactory, with low complication and mortality rates. Mid-term outcomes showed maintenance of the minimal required ADL and good motivation for living. However, independence in social activities was decreased, suggesting the need for comprehensive social support. PMID- 24492179 TI - Single-incision thoracoscopic surgery for spontaneous pneumothorax using multi degrees of freedom forceps. AB - PURPOSE: The objective of this study was to assess the perioperative results of a single-incision approach using multi-DOF forceps for spontaneous pneumothorax, in comparison with the traditional 3-port approach. METHODS: Between May 2012 and June 2013, 44 patients with spontaneous pneumothorax underwent SITS, and their clinical characteristics and perioperative results were evaluated. We then compared those who had undergone SITS (SITS group) with those who had undergone traditional 3-port surgery before the study period (3-port group). RESULTS: The two groups were similar in terms of mean patient age and pneumothorax laterality (p = 0.81, 0.38), but the proportion of male patients was higher in the 3-port group than in the SITS group (p = 0.0026). Operation time in the SITS group (52.4 min) was longer than in the 3-port group (35.9 min, p <0.0001). The duration of postoperative drainage and hospital stay did not differ significantly between the groups (p = 0.19, 0.075). Although 14 of the 56 SITS patients (25%) showed mild adhesion in the pleural cavity, none required conversion to a 3-port approach. The bullous region in two or three lobes was resected in 23 patients (41%). CONCLUSIONS: SITS using multi-DOF forceps is a useful approach for treatment of spontaneous pneumothorax in selected patients. PMID- 24492181 TI - Bone: Diagnostic blood test for osteoporosis moves a step closer. PMID- 24492182 TI - Obesity: A complex role for adipose tissue macrophages. PMID- 24492180 TI - The 'omics' of adrenocortical tumours for personalized medicine. AB - Pan-genomic analyses of genetic and epigenetic alterations and gene expression profiles are providing important new insights into the pathogenesis and molecular classification of cancers. The technologies and methods used for these studies are rapidly diversifying and improving. The use of such methodologies for the analysis of adrenocortical tumours has revealed clear transcriptomic (mRNA and microRNA expression profiles), epigenomic (DNA methylation profiles) and genomic (DNA mutations and chromosomal alterations) differences between benign and malignant tumours. Interestingly, genomic studies of adrenal cancers have also identified subtypes of malignant tumours, which demonstrate distinct patterns of molecular alterations and are associated with different clinical outcomes. These discoveries have created the opportunity for classifying adrenocortical tumours on the basis of molecular analyses. Following these genomic studies, efforts to develop new molecular tools that improve diagnosis and prognostication of patients with adrenocortical tumours have also been made. This Review describes the progress that has been made towards classification of adrenocortical tumours to date based on key genomic approaches. In addition, the potential for the development and use of various molecular tools to personalize the management of patients with adrenocortical tumours is discussed. PMID- 24492183 TI - Blood storage duration and morbidity and mortality in children undergoing cardiac surgery. A retrospective analysis. AB - BACKGROUND: Blood transfusion is frequently required in children undergoing cardiac surgery and is associated with altered postoperative outcome. This may be due to alterations in red blood cell properties related to the storage process. OBJECTIVE: To evaluate the effect of blood storage duration on postoperative morbidity and mortality in children undergoing cardiac surgery. DESIGN: A retrospective review of a paediatric cardiac surgery database. SETTING: Department of Anaesthesiology, Queen Fabiola Children's University Hospital, Brussels, Belgium. PARTICIPANTS: Children transfused with one or two units of blood in the perioperative period. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Storage duration was used to allocate children to the Group 'Young' or the Group 'Old' (cut-off = 7 days). The primary endpoint was a composite based on the incidence of hospital mortality and/or the incidence of at least one organ failure. RESULTS: From 1014 children in the database, 570 were included in the final analysis. One hundred and eighteen patients were included in the Group 'Young' [median (interquartile range, IQR) storage duration 6 (5 to 7) days] and 452 in the Group 'Old' [storage duration 14 (11 to 19) days]. No difference was found in mortality, length of ICU stay, mechanical ventilation duration, postoperative infection and major organ dysfunction. Duration of storage used as a continuous variable did not influence the incidence of the composite endpoint when evaluated by univariate or multivariate logistic regression analyses. CONCLUSION: Red blood cell storage duration did not influence postoperative morbidity and mortality in paediatric cardiac surgery patients transfused with one or two units of blood. PMID- 24492184 TI - A chicken in every pot-a pediatric intensivist in every unit/all the time?*. PMID- 24492185 TI - Parental perspectives of donation after circulatory determination of death in children: have we really investigated the heart of the matter?*. PMID- 24492186 TI - Neutrophil gelatinase-associated lipocalin-can it predict the future?*. PMID- 24492187 TI - Searching the right way to treat neonatal abstinence syndrome*. PMID- 24492188 TI - Prolonged propofol infusions in critically ill children: are we ready for a large controlled study?*. PMID- 24492189 TI - Anticoagulation monitoring during extracorporeal membrane oxygenation: is anti factor Xa assay (heparin level) a better test?*. PMID- 24492190 TI - Posttraumatic stress and technology: do extracorporeal membrane oxygenation programs have an ethical obligation to provide ongoing psychological support for parents?*. PMID- 24492191 TI - Respiratory rate criteria for pediatric systematic inflammatory response syndrome. PMID- 24492192 TI - The authors reply. PMID- 24492193 TI - Acute respiratory distress syndrome in children: is there any evidence to use surfactant? PMID- 24492194 TI - The authors reply. PMID- 24492195 TI - Nasal high-flow therapy and aerosol delivery: a difficult target to achieve? PMID- 24492196 TI - The authors reply. PMID- 24492197 TI - Bugs, hosts and ICU environment: countering pan-resistance in nosocomial microbiota and treating bacterial infections in the critical care setting. AB - ICUs are areas where resistance problems are the largest, and these constitute a major problem for the intensivist's clinical practice. Main resistance phenotypes among nosocomial microbiota are (i) vancomycin-resistance/heteroresistance and tolerance in grampositives (MRSA, enterococci) and (ii) efflux pumps/enzymatic resistance mechanisms (ESBLs, AmpC, metallo-betalactamases) in gramnegatives. These phenotypes are found at different rates in pathogens causing respiratory (nosocomial pneumonia/ventilator-associated pneumonia), bloodstream (primary bacteremia/catheter-associated bacteremia), urinary, intraabdominal and surgical wound infections and endocarditis in the ICU. New antibiotics are available to overcome non-susceptibility in grampositives; however, accumulation of resistance traits in gramnegatives has led to multidrug resistance, a worrisome problem nowadays. This article reviews microorganism/infection risk factors for multidrug resistance, suggesting adequate empirical treatments. Drugs, patient and environmental factors all play a role in the decision to prescribe/recommend antibiotic regimens in the specific ICU patient, implying that intensivists should be familiar with available drugs, environmental epidemiology and patient factors. PMID- 24492199 TI - Blockade of Notch signaling ameliorates murine collagen-induced arthritis via suppressing Th1 and Th17 cell responses. AB - Recent studies have demonstrated that Notch signaling is critically involved in the regulation of immune response and contributes to autoimmune pathogenesis. Here, Notch signaling was found to be activated in CD4(+) T cells and synovial tissue from collagen-induced arthritis mice. In vivo administration of the gamma secretase inhibitor N-[N-(3,5-difluorophenacetyl-l-alanyl)]-S-phenylglycine t butyl ester (DAPT) substantially reduced the severity of arthritic symptoms and joint damage in collagen-induced arthritis mice. Notably, DAPT treatment significantly suppressed Th1- and Th17-cell responses in spleen and lymph nodes and reduced IFN-gamma and IL-17 levels in plasma. In polarization culture, DAPT treatment markedly reduced Th17 cell expansion from naive T cells, whereas fusion protein of the Notch receptor ligand delta-like 3 significantly increased the frequency and absolute number of Th17 cells. These results suggest a novel therapeutic strategy for treatment of human rheumatoid arthritis by targeting Notch signaling using gamma-secretase inhibitors. PMID- 24492198 TI - Increased severity of tuberculosis in Guinea pigs with type 2 diabetes: a model of diabetes-tuberculosis comorbidity. AB - Impaired glucose tolerance and type 2 diabetes were induced in guinea pigs to model the emerging comorbidity of Mycobacterium tuberculosis infection in diabetic patients. Type 2 diabetes mellitus was induced by low-dose streptozotocin in guinea pigs rendered glucose intolerant by first feeding a high fat, high-carbohydrate diet before M. tuberculosis exposure. M. tuberculosis infection of diabetic guinea pigs resulted in severe and rapidly progressive tuberculosis (TB) with a shortened survival interval, more severe pulmonary and extrapulmonary pathology, and a higher bacterial burden compared with glucose intolerant and nondiabetic controls. Compared with nondiabetics, diabetic guinea pigs with TB had an exacerbated proinflammatory response with more severe granulocytic inflammation and higher gene expression for the cytokines/chemokines interferon-gamma, IL-17A, IL-8, and IL-10 in the lung and for interferon-gamma, tumor necrosis factor-alpha, IL-8, and monocyte chemoattractant protein-1 in the spleen. TB disease progression in guinea pigs with impaired glucose tolerance was similar to that of nondiabetic controls in the early stages of infection but was more severe by day 90. The guinea pig model of type 2 diabetes-TB comorbidity mimics important features of the naturally occurring disease in humans. This model will be beneficial in understanding the complex pathogenesis of TB in diabetic patients and to test new strategies to improve TB and diabetes control when the two diseases occur together. PMID- 24492201 TI - Ammonia-oxidation as an engine to generate nitrous oxide in an intensively managed calcareous fluvo-aquic soil. AB - We combine field observations, microcosm, stoichiometry, and molecular and stable isotope techniques to quantify N2O generation processes in an intensively managed low carbon calcareous fluvo-aquic soil. All the evidence points to ammonia oxidation and linked nitrifier denitrification (ND) being the major processes generating N2O. When NH4(+)-based fertilizers are applied the soil will produce high N2O peaks which are inhibited almost completely by adding nitrification inhibitors. During ammonia oxidation with high NH4(+) concentrations (>80 mg N kg(-1)) the soil matrix will actively consume oxygen and accumulate high concentrations of NO2(-), leading to suboxic conditions inducing ND. Calculated N2O isotopomer data show that nitrification and ND accounted for 35-53% and 44 58% of total N2O emissions, respectively. We propose that slowing down nitrification and avoiding high ammonium concentrations in the soil matrix are important measures to reduce N2O emissions per unit of NH4(+)-based N input from this type of intensively managed soil globally. PMID- 24492200 TI - Increasing dietary selenium elevates reducing capacity and ERK activation associated with accelerated progression of select mesothelioma tumors. AB - To study the effect of the micronutrient selenium on malignant mesothelioma (MM) progression, we cultured four different MM cell lines in media containing increasing amounts of sodium selenite (30, 50, and 80 nmol/L). Increasing selenium levels increased density-dependent proliferation and mobility for CRH5 and EKKH5 but not AB12 and AK7. Comparing these cell lines revealed that extracellular regulated kinase (ERK) phosphorylation was sensitive to a selenium increase in CRH5 and EKKH5 but not AB12 and AK7 cells. Stable expression of a dominant-negative mutant ERK eliminated the effects of increasing selenium. Because ERK is redox sensitive, we compared the MM cell lines in terms of glutathione levels and the capacity to reduce exogenous hydrogen peroxide. Increasing selenium levels led to higher glutathione and reducing capacity in CRH5 and EKKH5 but not AB12 and AK7. The reducing agent N-acetylcysteine eliminated the effects of selenium on ERK activation, proliferation, and mobility. Mice fed diets containing increasing levels of selenium (0.08, 0.25, and 1.0 ppm) showed increased tumor progression for CRH5 but not AB12, MM cells, and in vivo N-acetylcysteine treatment eliminated these effects. These data suggest that the effects of dietary selenium on MM tumor progression depend on the arising cancer cells' redox metabolism, and the tumors able to convert increased selenium into a stronger reducing capacity actually benefit from increased selenium intake. PMID- 24492204 TI - A comparison of the irritant and allergenic properties of antiseptics. AB - Over recent years, interest in the use of antiseptics has been reinforced as these molecules are not concerned by the problem of bacterial resistance. Whereas the in vitro efficacy of antiseptics has been well-studied, much less is known regarding their irritant and allergenic properties. This review provides an update on the comparative irritant and allergenic properties of commonly-used antiseptics in medicine nowadays. All antiseptics have irritant properties, especially when they are misused. Povidone-iodine has an excellent profile in terms of allergenicity. Allergic contact dermatitis is uncommon but is often misdiagnosed by practitioners, who confuse allergy and irritation. Chlorhexidine has been incriminated in some cases of allergic contact dermatitis; it is considered a relatively weak allergen, although it may rarely cause immunological contact urticaria and even life-threatening anaphylaxis. Octenidine is considered a safe and efficient antiseptic when used for superficial skin infections, however, aseptic tissue necrosis and chronic inflammation have been reported following irrigation of penetrating hand wounds. Polihexanide is an uncommon contact allergen as regards irritant and/or allergic contact dermatitis but cases of anaphylaxis have been reported. Considering the data available comparing the irritant and allergenic properties of major antiseptics currently in use, it should be acknowledged that all antiseptics may induce cutaneous side-effects. The present article reviews the most recent safety data that can guide consumers' choice. PMID- 24492205 TI - Blending effect of 6,13-bis(triisopropylsilylethynyl) pentacene-graphene composite layers for flexible thin film transistors with a polymer gate dielectric. AB - Solution processible poly(4-vinylphenol) is employed as a transistor dielectric material for low cost processing on flexible substrates at low temperatures. A 6,13-bis (triisopropylsilylethynyl) (TIPS) pentacene-graphene hybrid semiconductor is drop cast to fabricate bottom-gate and bottom-contact field effect transistor devices on flexible and glass substrates under an ambient air environment. A few layers of graphene flakes increase the area in the conduction channel, and form bridge connections between the crystalline regions of the semiconductor layer which can change the surface morphology of TIPS pentacene films. The TIPS pentacene-graphene hybrid semiconductor-based organic thin film transistors (OTFTs) cross-linked with a poly(4-vinylphenol) gate dielectric exhibit an effective field-effect mobility of 0.076 cm(2) V(-1) s(-1) and a threshold voltage of -0.7 V at V(gs) = -40 V. By contrast, typical TIPS pentacene shows four times lower mobility of 0.019 cm(2) V(-1) s(-1) and a threshold voltage of 5 V. The graphene/TIPS pentacene hybrids presented in this paper can enhance the electrical characteristics of OTFTs due to their high crystallinity, uniform large-grain distribution, and effective reduction of crystal misorientation of the organic semiconductor layer, as confirmed by x-ray diffraction spectroscopy, atomic force microscopy, and optical microscopy studies. PMID- 24492202 TI - Structural basis of efficient contagion: measles variations on a theme by parainfluenza viruses. AB - A quartet of attachment proteins and a trio of fusion protein subunits play the cell entry concert of parainfluenza viruses. While many of these viruses bind sialic acid to enter cells, wild type measles binds exclusively two tissue specific proteins, the lymphatic receptor signaling lymphocytic activation molecule (SLAM), and the epithelial receptor nectin-4. SLAM binds near the stalk head junction of the hemagglutinin. Nectin-4 binds a hydrophobic groove located between blades 4 and 5 of the hemagglutinin beta-propeller head. The mutated vaccine strain hemagglutinin binds in addition the ubiquitous protein CD46, which explains attenuation. The measles virus entry concert has four movements. Andante misterioso: the virus takes over the immune system. Allegro con brio: it rapidly spreads in the upper airway's epithelia. 'Targeting' fugue: the versatile orchestra takes off. Presto furioso: the virus exits the host with thunder. Be careful: music is contagious. PMID- 24492206 TI - Determination of dynamic changes in the nature and biosynthesis of glycome of wt and rd1 mice retinae by lectin microarray analysis. PMID- 24492203 TI - Theoretical frameworks for multiscale modeling and simulation. AB - Biomolecular systems have been modeled at a variety of scales, ranging from explicit treatment of electrons and nuclei to continuum description of bulk deformation or velocity. Many challenges of interfacing between scales have been overcome. Multiple models at different scales have been used to study the same system or calculate the same property (e.g., channel conductance). Accurate modeling of biochemical processes under in vivo conditions and the bridging of molecular and subcellular scales will likely soon become reality. PMID- 24492207 TI - Targeting host pathways to block HSV-1 at the cornea. PMID- 24492209 TI - Characterization of facial paresis in hemifacial microsomia. AB - OBJECTIVE: To provide an overview of the incidence, characteristics, and proposed etiologic mechanisms of facial paresis in patients with manifestations of hemifacial microsomia. DATA SOURCES: PubMed database for English-language studies with no date restrictions. REVIEW METHODS: A comprehensive literature review was performed identifying all studies that discussed incidence, characterization, or etiologic mechanisms for facial paresis in hemifacial microsomia/oculo-auriculo vertebral spectrum. CONCLUSIONS: This review supports that the prevalence of facial weakness in the spectrum of hemifacial microsomia/oculo-auriculo-vertebral spectrum ranges from 10% to 45%. Most of these patients have involvement of all facial nerve branches or lower branches only. The most commonly involved single nerve branch has yet to be described. The 2 most common associated anomalies involve the mandible and auricle. Dysmorphogeneisis of the temporal bone and its effects on the facial nerve are most likely implicated in the cause of facial weakness. IMPLICATIONS FOR PRACTICE: There is a wide variety of facial nerve presentations seen within oculo-auriculo-vertebral spectrum for which the exact etiologic mechanism is unclear. Through a better understanding of the presentation and etiology surrounding facial paresis in hemifacial microsomia, improved treatment options may be offered in the management of the facial weakness. PMID- 24492208 TI - Clinical practice guideline: acute otitis externa executive summary. AB - The American Academy of Otolaryngology--Head and Neck Surgery Foundation (AAO HNSF) has published a supplement to this issue featuring the updated Clinical Practice Guideline: Acute Otitis Externa, as a supplement to Otolaryngology-Head and Neck Surgery. To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 8 recommendations developed address appropriate diagnosis of acute otitis externa (AOE) and the use of oral and topical antimicrobials and highlight the need for adequate pain relief. An updated guideline is needed due to new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group. PMID- 24492211 TI - The failure of screening and treating as a malaria elimination strategy. PMID- 24492212 TI - [Progress for the revival after the Fukushima nuclear plant accident to date]. PMID- 24492213 TI - [Assessment and control of health risk caused by the radiological accident at the TEPCO Fukushima Daiichi nuclear power plant]. AB - The accident at the Tokyo Electric Power Company (TEPCO) Fukushima Daiichi nuclear power plant on March 11, 2011, released a large amount of radioactive materials resulting in the radioactive contamination of a wide area of eastern Japan. Residents of the Fukushima prefecture experienced various unavoidable damages and fear of radiation effects on their health. A reliable communication of accurate risk assessment for residents is required as a countermeasure aimed at the reconstruction of Fukushima. Here, the current status of individual dose estimation and the issues relating to the radiation risk perception are discussed. PMID- 24492214 TI - [Terrestrial environmental dynamics of radioactive nuclides released by the Fukushima nuclear accident]. AB - Research into environmental dynamics of radioactive nuclides released by the Fukushima nuclear accident, especially radiocesium (137)Cs (half-life, 30.1 years), is highly focused especially on diffusion processes of radiocesium into ecosystems, which is high-priority knowledge. Because of relatively sparse knowledge about the reallocation of radiocesium contained in organic matter in terrestrial ecosystems, the effects of diffused rediocesium into ecosystem cannot be accurately estimated. In this article, the terrestrial environmental dynamics of radiocesium mainly in the processes of plant uptake and the possibility of release from plants will be discussed. Plants uptake minerals from soil and these minerals are likewise ingested by animals that feed on plants, including humans. Therefore one of the main gateways of radiocesium into ecosystem is via plants. From the viewpoint of human dietary consumption, rice contamination with radiocesium has been energetically investigated and useful data are accumulating. Processes of radiocesium uptake mechanisms by plants are being researched using legumes, e.g. soybean. Speculation on the possibility of radiocesium release into forest atmosphere via plant activity will be introduced. PMID- 24492215 TI - [Transport processes of Fukushima derived radioactivity in the Pacific Ocean]. AB - Before the Fukushima Nuclear Power Plant 1 (FNPP1) accident, environmental (137)Cs was already detectable originating from nuclear weapon tests conducted in the late 1950s and early 1960s. In the western North Pacific Ocean, (90)Sr and (137)Cs activities in surface water were 10-100 Bqm(-3) in the late 1950s and early 1960s, then this parameter decreased gradually; (137)Cs activity in surface water subsequently decreased to around a few Bq m(-3). After the FNPP1 accident, (137)Cs and (134)Cs were released into the North Pacific Ocean by two pathways, direct discharge from the Fukushima NPP1 accident site and atmospheric deposition off Honshu Islands of Japan, east and northeast of the site. High-density observations of (137)Cs and (134)Cs in the surface water were carried out by 17 VOS cruises and several research vessel cruises between April 2011 and March 2012. The main body of radioactive surface plume of which activity exceeded 10 Bqm(-3) traveled along 40 degrees N, and reached the International Date Line in March 2012, 1 year after the accident. The radioactive plume was confined along 40 degrees N when the plume reached the International Date Line. Zonal speed of the radioactive plume was estimated to be about 8 cm s(-1), which is consistent with zonal speeds derived by Argo floats at the region. PMID- 24492216 TI - [Effect of ionizing radiation on the living body]. AB - Since the Fukushima nuclear plant accident following the great East Japan earthquake on March 11, 2011, we have been warned to be careful about possible radiation exposure almost every day in newspapers and on TV. Radioactive iodine ((131)I) and cesium ((134)Cs, (137)Cs) produced by nuclear reactions were released into the air during and after the accident, and have been scattered by the winds in Tohoku and in the Kanto district. Even today, 2 years after the accident, there is great public concern about possible pollution of foodstuffs and fishery products with radioactive cesium, not only in Japan, but also in other countries. On the other hand, decontamination work has been proceeding, including removal of contaminated soil near the accident site. Since the accident, many media reports have continued to tell us only that current dose levels of radiation are not dangerous to human health. But, many people are not satisfied with such vague statements, and want to understand the situation in more detail. So, it is important to provide basic education about the effects of radiation to the general public. I am a professor of the Department of Radiation Biosciences at Tokyo University of Science, and so I am very familiar with radiation and its dangers. So, in my lecture today, we would like to explain the effects of radiation and put the present situation into perspective, so that people will better understand the risks, and not be unnecessarily afraid. PMID- 24492217 TI - [What should the radiation education in Japan in the future be like?]. AB - In respect to policy and involvement in social cognition of Advanced Science and Technology, people desire to recognize the scientific understanding and social understanding hierarchically and simultaneously. However, the understandings of some sciences and technologies are dependent on the amount of information given and how easy it is to understand it. Nuclear power and radiation are a typical example of such sciences and technologies because their advantages and disadvantages are clear. On the other hand, the Fukushima Nuclear Plant Accident that occurred in March 2011 caused the myth about the safety and security of nuclear power to collapse. Concerns about nuclear power and radiation increased abruptly after the accident. Also the scientific understanding of 'nuclear power' and radiation increased. The content and level of radiation education was highly significant than before the accident. However, it is essential to propose a more detailed explanation for people that are concerned about radioactive contamination of food and also for people living in areas that still have relatively high dose of radioactive material. Although some technical problems such as the influences on the human body by low-dose exposure remain unresolved, not only specialists on nuclear power and radiation, but also the persons that have studied the radiation are desired to explain radiation for familiar people. As a result, in Japan, the learning of individuals spread to society because the Japanese are highly interested in nuclear power and radiation and the understanding of historical background. PMID- 24492218 TI - [Team-based learning (TBL) brings active and complementary learning--practice and outcomes in pharmacy education]. PMID- 24492219 TI - [Team-based learning (TBL) in the interdisciplinary lecture]. AB - We conducted team-based learning (TBL) with interdisciplinary lectures as a part of "Introduction to Pharmacy", divided among the pharmacy department's six pharmacist education curricula in the first semester. The interdisciplinary lecture is led by seven lecturers, each specializing in one area: cell biology, biochemistry, chemistry, public health pharmacology, pharmacokinetics, and clinical science. This lecture's purpose is to demonstrate to the students that all field subjects relate to each other and they must learn the basic science subjects to understand pharmaceutical sciences. The TBL contents have two themes, "cancer" and "aspirin", each of which had two lectures, each 90 minutes long and were conducted using TBL as expansive learning. On receiving knowledge of a wide range of fields in one lecture, a small number of students indicated that they were unable to understand the contents very well. However, in the questionnaire about TBL, many students reported "I have understood" and "I have enjoyed studying" using TBL, especially group readiness assessment test (GRAT). By incorporating TBL, they reported "increasing eagerness to learn pharmacy". Overall, students seem to have accepted TBL favorably, but they still find peer review difficult. We believe that their discomfort with peer review results from their unfamiliarity in evaluating others, and the time before the evaluation is short because TBL is conducted only twice. PMID- 24492220 TI - [Introduction of team-based learning to the pharmacy experiential practice course for first-year pharmacy students]. AB - In recent years, the number of high school graduates has decreased, whereas the number of new pharmacy schools has increased substantially. Therefore, pharmacy schools these days accommodate students from diverse backgrounds in terms of basic knowledge, study skills, and/or their motivation to be pharmacists. To address this issue, we developed a mandatory 10-day course named "Pharmacy experiential practice" for the first-year students. The program trains students in basic pharmacy calculation skills and communication skills, and provides an insight into how these skills can be applied in actual pharmacy practice. The program includes 5 themes, namely, "Compounds", "Solutions", "Infusions", "Nutrition" and "Communication". Each theme, except "Communication", was conducted for 2 days 3 hour calculation practice in class and 3 hour pharmacy experiential practice each day. In the calculation class, we introduced team based learning, which enhanced the students for interactive learning in the classes. In the pharmacy experiential practices, the students were trained not only to apply their calculation skills to pharmacy practice in each theme, but also to understand the importance of basic science knowledge in strengthening the foundations for their calculation skills. Course evaluation showed that students experienced the effectiveness of interactive study and that they realized the importance of pharmacy practice and the basic sciences that they had learnt. Some students commented that their motivation to become pharmacists increased after this course. PMID- 24492221 TI - [Practical chemistry education provided by team-based learning (TBL) and peer evaluation]. AB - Learning chemistry is cumulative: basic knowledge and chemical calculation skills are required to gain understanding of higher content. However, we often suffer from students' lack of learning skills to acquire these concepts. One of the reasons is the lack of adequate training in the knowledge and skills of chemistry, and one of the reasons for this lack is the lack of adequate evaluation of training procedures and content. Team-based learning (TBL) is a strong method for providing training in the knowledge and skills of chemistry and reaffirms the knowledge and skills of students of various levels. In our faculty, TBL exercises are provided for first-year students concurrently with lectures in physical chemistry and analytical chemistry. In this study, we researched the adoption of a peer evaluation process for this participatory learning model. Questionnaires taken after TBL exercises in the previous year showed a positive response to TBL. Further, a questionnaire taken after TBL exercises in the spring semester of the current year also yielded a positive response not only to TBL but also to peer evaluation. In addition, a significant correlation was observed between the improvement of students' grades in chemistry classes and the feeling the percentage (20%) of peer evaluation in overall evaluation low (logistic regression analysis, p=0.022). On the basis of the findings, we argue that TBL provides a generic, practical learning environment including an effective focus on learning strategy and evaluation of knowledge, skills, and attitudes, and studies on the educational effects of TBL and peer evaluation. PMID- 24492222 TI - [Front line of combating counterfeit medicines, globally and locally]. PMID- 24492223 TI - [Analysis and identification of illegal constituents in health food products implicitly advertizing tonic or slimming effect in the National Institute of Health Sciences in Japan]. AB - With the prefectural governments' aid of the purchase, the Division of Pharmacognosy, Phytochemistry and Narcotics, National Institute of Health Sciences (NIHS) successively has surveyed illegal constituents in health food products implicitly advertizing tonic or slimming effect since the fiscal year of 2002 (slimming type) or 2003 (tonic type). The average numbers of the analyzed products per year are about 100 (slimming type) and 150 (tonic type), respectively. We also continuously distribute standards of authentic samples of several illegal components such as N-nitrosofenfluramine (NFF) and sildenafil (SIL) to prefectural institutes and the average gross number per year is about 140. In the case of slimming type, the fact that the products containing NFF were widely sold in Japanese markets in 2002 is well known. In addition, phenolphthalein, fenfluramine, sibtramine, desdimethylsibtramine, orlistat, mazindol, Rhubarb, Senna Leaf, etc. have been found as illegal constituents. In the tonic type products, we have identified more than 20 synthetic compounds relating to the erectile dysfunction (ED) treatment drugs, SIL, vardenafil and tadalafil (TDF). Since 2005, their synthetic intermediates and the patented but non-approved PDE5 inhibitors also have been found. It should be noted that TDF was found in the shells of capsule in 2009 and that mutaprodenafil was found as pro-drug type illegal component in 2010. In this report identification method of these illegal constituents is briefly described and then analytical trend in this decade is reviewed. PMID- 24492224 TI - [Anti-counterfeit activities of pharmaceutical companies in Japan: for patient safety]. AB - Global spread of counterfeit medicines is an imminent threat for the patients' safety. Although major targets of counterfeits are still erectile dysfunction (ED) drugs in the industrialized countries, including Japan, anti-cancer agents and some medicines for metabolic syndromes are also being counterfeited and circulated to the market mainly through the Internet. Due to the global expansion of the business, pharmaceutical companies based in Japan are suffering from the damage of counterfeits, illegal sales including diversion, and thefts, which have never been experienced in the conventional domestic market. We, pharmaceutical companies, must be responsible for the prevention of the prevalence because our mission is to deliver effective and safe medicine to patients. For this end, we are taking necessary actions including, 1. Forestalling counterfeit, falsification and illicit trade: Measures to prevent counterfeiting are taken by introducing anti-counterfeit technologies to the packaging and tablets on a risk basis. It is also important to establish supply chain security on a global scale. 2. Finding out counterfeits and cooperating crackdown: We are conducting market and internet surveillances when high risk products are sold in high risk markets. The outcome of the criminal investigation is reported to authorities and police if necessary. 3. Conducting educational campaign to medical staff or patients: For example, four companies which manufacture and sell ED drug in Japan are collaboratively continuing activities to raise the awareness of the danger of Internet purchase. To deliver effective and safe medicines stably and globally, pharmaceutical companies extend comprehensive measures against counterfeit and illicit trading. PMID- 24492225 TI - [Counterfeit medicines--Japan and the world]. AB - Circulating counterfeit medicines in the market is a public health threat. Counterfeit medicines become common problem, not only in developing countries, but also in industrialised countries, as internet has made them more accessible. In Japan, the recent survey on the medicines purchased through on-line pharmacy (targeting Japanese consumers) showed that the majority of erectile dysfunction (ED) medicines imported by individuals in Japan were counterfeit version. The survey of Japanese consumers, who privately imported medicines through on-line pharmacy, indicated that 16% of these consumers experienced adverse events associated with these products. Not only that it is just fake brand, but fake medicines may even cause health hazard. The counterfeit version of Avastin recently detected in the United States became a serious threat for those who desperately need these medicines for life-threatening disease. The Japanese regulatory authorities have provided risk information of counterfeit medicines to general public, as well as monitored on-line pharmacies and conducted enforcement action where necessary. However, more resources of compliance activity should be allocated to respond to the situation of growing threats of counterfeit medicines. Purchasing medicines from abroad through unauthorised channel is the major source of counterfeit medicines. It is essential to prevent circulation of counterfeit medicines through international collaboration of various regulatory authorities. To address these problems, the World Health Organization (WHO) has launched a new Member States Mechanism (MSM) to build network of the authorities. Also, INTERPOL (ICPO) initiated globally concerted enforcement actions (Operation Pangea) against pharmaceutical crime as well as built partnership with pharmaceutical industry to create Pharmaceutical Crime Programme. It is also necessary to prevent consumers encountering counterfeit medicines and to prevent health hazard. The Ministry of Health, Labour and Welfare (MHLW) has been actively involved in prevention and educational activities such as public awareness campaign. MHLW started anti-counterfeit medicines and new psychoactive substance project from February 2013, which centrally collects information about counterfeit medicines, in particular, and provides the risk information more effectively to the public. Japanese Government will work together with international community and contribute to combating counterfeiting through public and private partnership. PMID- 24492226 TI - [Role of pharmacists and student pharmacists in educating and providing advice about over the counter (OTC) medications]. AB - The role of pharmacists in self-medication is to provide informed and objective advice on medicines and their use, and to promote the concept of pharmaceutical care. In 2012, the teaching of medicines and their use was started in junior high schools, and pharmacists should be providing samples and the example package inserts, and/or giving lessons in cooperation with teachers. In this article, a number of examples of how to do this will be shared. In 2009, the Pharmaceutical Affairs Law was revised and the role of pharmacists being key figures in supplying medicines was significantly increased. Pharmacists should have a professional obligation to provide advice about self-medication and medicines for self-medication. We introduced some approaches for student pharmacists to enhance the self-medication leading ability. 1) Problem-based learning, and combination learning of basic problems and clinical topics for 1st-year students, 2) An e learning system to provide objective information about medicines, and 3) A case study system to cultivate pharmacists and student pharmacists who can contribute to providing advice about the safe use of over the counter (OTC) medicines. PMID- 24492227 TI - [Base in four types of lidocaine preparation (formulated in hospital)]. AB - PL cream (combination of lidocaine and procaine) was launched on the market in April 2012 in Japan. We investigated differences in the anesthetic effect by employing two types of base: Carbopol and methylcellulose. Electron microscopy showed a distinct difference in appearance: densely-scattered, fine particles for Carbopol and sparse, large particles for methylcellulose. Accordingly, the extensibility of the cream was significantly greater at 4 and 25 degrees centigrade for methylcellulose, but was greater at 34 degrees centigrade for Carbopol. The steady flow viscosity (1 s(-1)) was greater for the Carbopol than methylcellulose base. The difference in the cutaneous permeability between the two bases increased over time: the methylcellulose base was removed at 90 min after application and, 30 min later, showed a significant difference. These results suggest that the methylcellulose base has a superior anesthetic effect in clinical settings. PMID- 24492228 TI - [Study for the revision of analytical method for tris (2,3-dibromopropyl) phosphate with restriction in textiles]. AB - The official analytical method for tris(2,3-dibromopropyl)phosphate (TDBPP), which is banned from use in textile products by the "Act on Control of Household Products Containing Harmful Substances", requires revision. This study examined an analytical method for TDBPP by GC/MS using a capillary column. Thermal decomposition of TDBPP was observed by GC/MS measurement using capillary column, unlike in the case of gas chromatography/flame photometric detector (GC/FPD) measurement based on a direct injection method using a capillary megabore column. A quadratic curve, Y=2572X(1.416), was obtained for the calibration curve of GC/FPD in the concentration range 2.0-100 MUg/mL. The detection limit was 1.0 MUg/mL under S/N=3. The reproducibility for repetitive injections was satisfactory. A pretreatment method was established using methanol extraction, followed by liquid-liquid partition and purification with a florisil cartridge column. The recovery rate of this method was ~100%. TDBPP was not detected in any of the five commercial products that this study analyzed. To understand the cause of TDBPP decomposition during GC/MS (electron ionization; EI) measurement using capillary column, GC/MS (chemical ionization; CI), GC/FPD, and gas chromatography/flame ionization detector (GC/FID) measurements were conducted. It was suggested that TDBPP might thermally decompose both during GC injection, especially through a splitless injection method, and in the column or ion sources. To attempt GC/MS measurement, an injection part comprising quartz liner was used and the column length was halved (15 m); thus, only one peak could be obtained. PMID- 24492229 TI - [Trends and antimicrobial susceptibilities of clinical methicillin-resistant Staphylococcus aureus isolates in Fukuoka University Chikushi Hospital 2008 2012]. AB - The aim of this study was to investigate the trends and antimicrobial susceptibilities of methicillin-resistant Staphylococcus aureus (MRSA) clinical isolates from outpatients and inpatients from April 2008 to March 2013 at Fukuoka University Chikushi Hospital. The proportion of MRSA among the S. aureus isolates from outpatients was stable over the study period, however, that from inpatients gradually decreased (p=0.026). There was no difference in the susceptibility to anti-MRSA agents between MRSA isolates from outpatients and inpatients, however, the susceptibilities to fosfomycin (FOM), minocycline (MINO), levofloxacin, erythromycin and clindamycin were higher in MRSA isolates from outpatients than from inpatients (48.6% vs. 35.6%, 56.1% vs. 40.1%, 38.2% vs. 4.9%, 16.2% vs. 3.9% and 18.5% vs. 4.5%, respectively, p<0.01). The susceptibility to FOM improved in MRSA from both outpatients and inpatients over time (p<0.05). In MRSA isolates from inpatients, the susceptibility to FOM and gentamicin increased significantly over the study period (p=0.023 and p=0.010, respectively), while, the susceptibility to MINO tended to decrease (p=0.094). The rate of MRSA isolates which were susceptible to more than two non-beta-lactam antibiotics was significantly higher in outpatients than in inpatients (24.5% vs. 47.4%, p<0.01), however, this rate increased significantly during the study period only in inpatients, with a rate of 12.2% in 2008 and 53.1% in 2012 (p<0.01). In conclusion, our findings indicate a changing antimicrobial susceptibility of MRSA isolates, especially to non-beta-lactam antibiotics. The determination of the prevalence and antimicrobial susceptibilities of MRSA clinical isolates will help physicians to select the initial empirical treatment. PMID- 24492230 TI - [Research on the forecasting of trends in demand for pharmacists 2011-2035]. AB - The first crop of pharmacists graduating from 6-year programs in pharmaceutical l education arrived in April 2012, and it will be important to incorporate new factors when predicting future trends in supply and demand for pharmacists. If we project supply given an exam pass rate of 75%, the supply of pharmacists will increase for the next 10 years or so if the number of exam takers is about 10000, and no decrease in the total number of pharmacists is expected until 2035. At pharmacies, a high degree of demand for the services of pharmacists can be expected to result from increases in the number of elderly patients and the number of patients receiving prescriptions, together with expanded accommodation of home health care, if the proportion of prescriptions that are actually filled up to 70%. At hospitals, demand has been projected to increase over the short term, owing to such factors as the trend toward having a resident pharmacist in each ward, advances in team medicine, and the spread of outpatient chemotherapy. Given the rising enrollment quotas for schools of pharmacy, and if the current supply and demand for pharmacists are maintained, we cannot rule out the possibility that pharmacists will come to be in excess supply within a 10-year horizon if the number of unemployed continues to decrease and the employment rate continues to improve along with changes in economic conditions and the consciousness of graduates of the 6-year programs. PMID- 24492231 TI - [Examination of the cause of changing solution color by mixing aminophylline and dopamine, the compatibility of which was indicated by the supplier]. AB - A case in which aminophylline solution was administered to a patient with congestive heart failure is reported and the problems caused by administration were solved by subsequent experiments. Dopamine solution was added from the side route using a mechanical pump, and mixed with aminophylline solution in the main route. Furosemide was administered after clamping and flushing the main route according to the supplier's information that indicated the compatibility of dopamine and aminophylline. However, the aminophylline solution turned black in color 3 h after furosemide administration. Several examinations were carried out to clarify the cause of the incompatibility in this case. The results showed that solutions with all possible combinations, including aminophylline and dopamine, turned black at 24 h after mixing, and the UV absorption at 430 nm increased from 0 to 0.28. UV absorption of the mixed solution increased in a dopamine dose dependent manner in the range of 1.5-12 mg. When aminophylline was added to physiological saline or hypotonic electrolyte solution, the pH of each solution increased. These results suggested that degradation of dopamine to a melanin-like polymer under alkaline conditions caused the change in color of the solution. It is presumed that dopamine was inappropriately injected into aminophylline solution as the route was clamped tightly to shut out furosemide contamination. Aminophylline and dopamine are often co-administered to patients in critical condition. Thus, even if compatibility of aminophylline with dopamine is indicated by the supplier, they should be administered through separate routes. PMID- 24492232 TI - [Evaluation of the association between the use of oral anti-hyperglycemic agents and hypoglycemia in Japan by data mining of the Japanese Adverse Drug Event Report (JADER) database]. AB - Hypoglycemia due to treatment with oral anti-hyperglycemic agents (OHAs) is a major clinical problem in patients with type 2 diabetes mellitus. The aim of the present study was to evaluate the risk of hypoglycemia due to OHA use by using the Japanese Adverse Drug Event Report (JADER) database. To this end, reports of hypoglycemia events included in the JADER database between 2004 and 2012 were analyzed by calculating the reporting odds ratio (OR). The Medical Dictionary for Regulatory Activities Preferred Terms was used to identify hypoglycemia; 254392 reports were found in the JADER database, of which 13269 were excluded because the age and sex of the patient were not reported. Finally, 241123 reports were analyzed. Among OHAs, sulfonylureas showed the highest adjusted OR (adjusted OR, 10.13; 95% confidence interval, 9.08-11.26). The adjusted ORs for meglitinides, biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors were significantly lower than that of sulfonylureas. The adjusted OR of meglitinides (3.17; 95% confidence interval, 2.23-4.36) was significantly higher than that of alpha-glucosidase inhibitors or thiazolidinedione. We observed no difference between the adjusted ORs for biguanide, thiazolidinedione, alpha-glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors. Data mining of the JADER database was useful for analyzing OHA-associated hypoglycemia events. The results of our study suggested a low risk of hypoglycemia associated with biguanide, thiazolidinedione, alpha glucosidase inhibitors, and dipeptidyl peptidase-4 inhibitors in clinical practice. PMID- 24492233 TI - Degradation of chlorofluorocarbons using granular iron and bimetallic irons. AB - Degradation of trichlorofluoromethane (CFC11) and 1,1,2-trichloro-1,2,2 trifluoroethane (CFC113) by granular iron and bimetallic (nickel- or palladium enhanced) irons was studied in flow-through column tests. Both compounds were rapidly degraded, following pseudo-first-order kinetics with respect to the parent compounds. The average pseudo-first-order rate constants for CFC11 were similar among different materials, except for palladium-enhanced iron (PdFe), in which the rate of degradation was about two times faster than for the other materials. In the case of CFC113, the rate constants for bimetallic irons were about two to three times greater than for the regular iron material. The smaller than expected differences in degradation rate constants of chlorofluorocarbons (CFCs) between regular iron and bimetallic irons suggested little, if any, catalytic effect of the bimetallic materials in the initial degradation step. Subsequent degradation steps involved catalytic hydrogenation, however, playing a significant role in further degradation of reaction intermediates. The degradation intermediates and final products of CFC11 and CFC113 suggested that degradation proceeded through hydrogenolysis and alpha/beta-elimination in the presence of regular iron (Fe) and nickel-enhanced iron (NiFe). Even though there is only minor benefit in the use of bimetallic iron in terms of degradation kinetics of the parent CFCs, enhanced degradation rates of intermediates such as chlorotriflouroethene (CTFE) in subsequent reaction steps could be beneficial. PMID- 24492234 TI - Technology: SMRT move? PMID- 24492236 TI - Genome stability: Chromosome correction through reprogramming. PMID- 24492237 TI - Prognostic significance of the Ki67 scoring categories in breast cancer subgroups. AB - BACKGROUND: Immunohistochemical (IHC) expression of Ki67 has a prognostic and predictive value for breast cancer, and the IHC Ki67 labeling index is estimated by counting the number of positive and negative cells. It has not been clarified whether IHC Ki67 estimated using a semiquantitative scoring system has a prognostic value. We aimed to estimate the usefulness of scoring categories of IHC Ki67 as a prognostic factor for breast cancer subgroups. PATIENTS AND METHODS: We retrospectively identified patients in the Tokai University breast cancer database for whom IHC Ki67 data were available between January 1, 2000 and December 31, 2010. Survival curves were calculated using the Kaplan-Meier method and compared using the log-rank test. RESULTS: Of the 1331 primary breast cancer patients included in the study, In patients with estrogen receptor (ER)-positive and HER2-negative tumors (n = 971), high and intermediate Ki67 scores were associated with poorer relapse-free survival than low Ki67 scores (P < .001 and P = .002, respectively). Furthermore, in the multivariate analyses of this subgroup, progression-free survival (PFS) was significantly longer in patients with low Ki67 scores than in patients with high Ki67 scores (hazard ratio, 0.387; 95% confidence interval, 0.233-0.643; P < .001). In the multivariate analyses, the Ki67 score was not significantly associated with PFS in the ER-positive and HER2-positive, ER-negative and HER2-positive, or ER-negative and HER2-negative subgroups. CONCLUSION: Our data demonstrated that low, intermediate, and high Ki67 scores have a prognostic value in breast cancer patients with ER-positive and HER2-negative tumors. PMID- 24492238 TI - Agreement of corneal epithelial profiles produced by automated segmentation of SD OCT images having different optical resolutions. AB - OBJECTIVE: Using a custom-developed segmentation algorithm, agreement of corneal epithelial thickness profile measurements between two spectral domain optical coherence tomography (SD-OCT) systems was assessed. METHODS: Eighteen left eyes (18 subjects; mean+/-standard deviation; age, 23.2+/-0.9 years) were imaged twice on nonconsecutive days by a custom-built ultra-high resolution OCT (UHR-OCT) system and a commercial RTVue OCT system. A segmentation algorithm based on axial gradient information and a shortest path search was developed to measure corneal epithelial thickness profiles from the SD-OCT images. RESULTS: There was good correlation between the automated and manual segmentation positions of the epithelium. The epithelial thickness differences between automated and manual segmentations by the UHR-OCT and RTVue OCT systems were 0.4+/-0.3 MUm and 1.1+/ 0.5 MUm, respectively. The intraclass correlation coefficients (ICCs) and coefficients of repeatability for repeated UHR-OCT measurements of epithelial thickness were 0.90+/-0.05 MUm and 1.44+/-0.01 MUm, respectively. For RTVue OCT, the ICCs and coefficients of repeatability were 0.88+/-0.04 MUm and 2.16+/-0.01 MUm, respectively. The epithelial thickness measured by RTVue OCT was 1.1+/-0.2 MUm greater than that by UHR-OCT (P<0.05, paired t test), and ICC for the agreement between the 2 systems was 0.85+/-0.06. The average 95% limit of agreement was -1.67 to 3.79 MUm. CONCLUSIONS: For images of different qualities from both SD-OCT systems, the custom-developed automated segmentation of the corneal epithelium had good repeatability for thickness profile measurements. The accurate and precise algorithm also demonstrated good agreement of epithelial thickness profile measurements between the two SD-OCT systems. PMID- 24492239 TI - Tear function evaluation in candidates of corneal laser refractive surgery for myopia. AB - OBJECTIVE: To assess the tear function in a young to middle age myopic population and finding possible associations of abnormal tear function with gender and age. METHODS: Dry eye workup was conducted in patients undergoing screening for myopic laser keratorefractive surgery. All patients completed the McMonnies dry eye questionnaire (MQ) and also underwent evaluation of the fluorescein break-up time (FBUT) and the Schirmer tests with anesthesia (STA). Patients with contraindications for keratorefractive surgery or any condition interfering with tear function were excluded from the database. RESULTS: In this prospective study, we evaluated 655 eyes of 216 women and 116 men with a mean age of 27.3+/ 6.1 years. Results of right eyes only are reported. The FBUT and STA were abnormal in 30.8% (95% confidence interval [CI]: 25.7-35.8) and 14.6% (95% CI 10.7-18.4) of cases, respectively. According to MQ scores, 15.9% (95% CI: 11.8 20.0) of patients showed abnormal results. In the assessment of abnormal cases, MQ scores were significantly higher (P<0.001) and FBUT was significantly lower in women (P=0.003) and older ages. Abnormal STA results were not significantly correlated with age or gender. CONCLUSION: In an otherwise normal population seeking keratorefractive surgery for myopia, some cases may demonstrate abnormal tear functions, especially women and older ages. A timely diagnosis and treatment can help avoid complications related to such abnormalities after refractive surgery. PMID- 24492235 TI - The impact of whole-genome sequencing on the reconstruction of human population history. AB - Examining patterns of molecular genetic variation in both modern-day and ancient humans has proved to be a powerful approach to learn about our origins. Rapid advances in DNA sequencing technology have allowed us to characterize increasing amounts of genomic information. Although this clearly provides unprecedented power for inference, it also introduces more complexity into the way we use and interpret such data. Here, we review ongoing debates that have been influenced by improvements in our ability to sequence DNA and discuss some of the analytical challenges that need to be overcome in order to fully exploit the rich historical information that is contained in the entirety of the human genome. PMID- 24492240 TI - Field-effect transistors based on cubic indium nitride. AB - Although the demand for high-speed telecommunications has increased in recent years, the performance of transistors fabricated with traditional semiconductors such as silicon, gallium arsenide, and gallium nitride have reached their physical performance limits. Therefore, new materials with high carrier velocities should be sought for the fabrication of next-generation, ultra-high speed transistors. Indium nitride (InN) has attracted much attention for this purpose because of its high electron drift velocity under a high electric field. Thick InN films have been applied to the fabrication of field-effect transistors (FETs), but the performance of the thick InN transistors was discouraging, with no clear linear-saturation output characteristics and poor on/off current ratios. Here, we report the epitaxial deposition of ultrathin cubic InN on insulating oxide yttria-stabilized zirconia substrates and the first demonstration of ultrathin-InN-based FETs. The devices exhibit high on/off ratios and low off current densities because of the high quality top and bottom interfaces between the ultrathin cubic InN and oxide insulators. This first demonstration of FETs using a ultrathin cubic indium nitride semiconductor will thus pave the way for the development of next-generation high-speed electronics. PMID- 24492241 TI - Response to Emanuele. PMID- 24492242 TI - Challenging the central dogma of skin photobiology: are proteins more important than DNA? PMID- 24492244 TI - Observation of allylic rearrangement in water-rich reaction. AB - Allylic rearrangement or the migration of a double bond from its original position in the carbon skeleton to an adjacent site was observed when 3,4,5,6 tetrahydrophthalate was hydrolyzed in a basic solution and in the presence of Co(ii) and Mn(ii) under hydrothermal conditions. PMID- 24492243 TI - Patched 1 and patched 2 redundancy has a key role in regulating epidermal differentiation. AB - The Patched 1 (Ptch1) receptor has a pivotal role in inhibiting the activity of the Hedgehog (Hh) pathway and is therefore critical in preventing the onset of many human developmental disorders and tumor formation. However, the functional role of the mammalian Ptch2 paralogue remains elusive, particularly the extent to which it contributes to regulating the spatial and temporal activity of Hh signaling. Here we demonstrate in three independent mouse models of epidermal development that in vivo ablation of both Ptch receptors results in a more severe phenotype than loss of Ptch1 alone. Our studies indicate that concomitant loss of Ptch1 and Ptch2 activity inhibits epidermal lineage specification and differentiation. These results reveal that repression of Hh signaling through a dynamic Ptch regulatory network is a crucial event in lineage fate determination in the skin. In general, our findings implicate Ptch receptor redundancy as a key issue in elucidating the cellular origin of Hh-induced tumors. PMID- 24492245 TI - Emerging Adulthood: Developmental Period Facilitative of the Addictions. AB - Following adolescence and prior to young adulthood is a life developmental period that has been referred to as "emerging adulthood." This period of life involves an extended duration of learning and experimentation before settling into a career and stable relationship. Risky behaviors may be most tolerated or even promoted during emerging adulthood. Various substance and behavioral addictions are most likely to be realized during this period. Understanding what differentiates emerging adults that develop or do not develop full-blown addictions will assist in the creation of more efficacious prevention and cessation programs. PMID- 24492246 TI - The Impact of Market Orientation on Patient Safety Climate Among Hospital Nurses. AB - Improving market orientation and patient safety have become the key concerns of nursing management. For nurses, establishing a patient safety climate is the key to enhancing nursing quality. This study explores how market orientation affects the climate of patient safety among hospital nurses. We proposed adopting a cross sectional research design and using questionnaires to collect responses from nurses working in two Taiwanese hospitals. Three-hundred and forty-three valid samples were obtained. Multiple regression and path analyses were conducted to test the study. Market orientation was defined as the combination of customer orientation, competitor orientation, and interfunctional coordination. Customer orientation directly affects the climate of patient safety. Although the findings only supported Hypothesis 1, competitor orientation and interfunctional coordination positively affected the patient safety climate through the mediating effects of hospital support for staff. Health care managers could encourage nurses to adopt customer-oriented perspectives to enhance their nursing care. In addition, to enhance competitor orientation, interfunctional coordination, and the patient safety climate, hospital managers could strengthen their support for staff members. PMID- 24492247 TI - Photofragmentation spectroscopy of cold protonated aromatic amines in the gas phase. AB - The electronic spectra of cold protonated aromatic amines: anilineH(+) C6H5 NH3(+), benzylamineH(+) C6H5-CH2-NH3(+) and phenylethylamineH(+) C6H5-(CH2)2 NH3(+) have been investigated experimentally in a large spectral domain and are compared to those of their hydroxyl homologues. In the low energy region, the electronic spectra are similar to their neutral analogues, which reveals the pipi* character of their first excited state. A second transition is observed from 0.4 to 1 eV above the origin band, which is assigned to the excitation of the pisigma* state. In these protonated amine molecules, there is a competition between different fragmentation channels, some being specific to UV excitation i.e., not observed in low-energy collision induced dissociation experiments. Besides, for one amine a drastic change in the fragmentation branching ratio is observed within a very short energy range that reveals the complex excited state dynamics and fragmentation processes. The experimental observations can be rationalized using a simple qualitative model, the pipi*-pisigma* model [A. L. Sobolewski, W. Domcke, C. Dedonder-Lardeux and C. Jouvet, Phys. Chem. Chem. Phys., 2002, 4, 1093-1100], which predicts that the excited state dynamics is controlled by the crossing between the pipi* excited state and a pisigma* state repulsive along the XH (X being O or N) coordinate. PMID- 24492249 TI - Hybrid nanoparticle-nanoline plasmonic cavities as SERS substrates with gap controlled enhancements and resonances. AB - We present hybrid nanoline-nanoparticle plasmonic substrates which allow easily achievable sub-5 nm gaps and a possibility of large-area fabrication. These substrates--based on plasmonic nanocavities formed by arrays of plasmonic nanoparticle (NP) dimers lying inside periodic metal nanolines (NLs)--can be used as tunable surface enhanced Raman scattering (SERS) substrates due to the tunability of cavity modes in the gap regions. Theoretical studies were conducted, using finite difference time domain (FDTD) modeling, to understand the plasmon resonance tunability as a function of gaps in these hybrid plasmonic substrates. The gaps forming the nanocavities include those between nanolines and nanoparticles (NL-NP) and between two nanoparticles (NP-NP). Our analysis reveals that these gaps play a combined role in tuning the resonance wavelength and the magnitude of electromagnetic field enhancement. Moreover, distinct structure dependent plasmon resonance peaks are present in addition to material-dependent resonance peaks characteristic to the metal involved. Replacing the spherical particle arrays inside the nanolines with nanorod arrays revealed the possibility of tuning the plasmon resonance in the near-infrared regime. This indicates that there is a possibility of tuning the plasmon resonance wavelength to any region of the visible or near-infrared spectrum by changing the size or shape of the particles assembled inside these plasmonic nanolines. PMID- 24492250 TI - Ethylenediamine-modified oriented MCM-41 at the electrode surface, cobalt adsorption ability and electrochemical performance. AB - Mesoporous silica thin films (MCM-41) functionalized with ethylenediamine groups were electrochemically fabricated on electrode surfaces. These ligand functionalized film were a promising matrix for the immobilization of cobalt ions and preparation of cobalt complexes covalently bound to the MCM-41 support. The constructed MCM-41 were characterized by TEM, EDS and TGA analysis. This method yields uniform thin films with hexagonal mesochannels aligned and accessible to electrode surface. Well-defined electrode responses were, therefore, observed for the anchored complexes which made the electrochemical analysis of the structure possible as well. Voltammetric studies revealed the reactivity of the covalently bound complexes differed significantly from the dissolved ones. The anchored complexes preferred to be in their oxidized form which inhibits formation of oxygen adducts. The covalently bound complexes had relatively good leaching stability with good catalytic performance towards hydrogen peroxide reduction. PMID- 24492248 TI - Increasing FcgammaRIIa affinity of an FcgammaRIII-optimized anti-EGFR antibody restores neutrophil-mediated cytotoxicity. AB - Antibody-dependent cell-mediated cytotoxicity (ADCC) has been suggested as an essential mechanism for the in vivo activity of cetuximab, an epidermal growth factor receptor (EGFR)-targeting therapeutic antibody. Thus, enhancing the affinity of human IgG1 antibodies to natural killer (NK) cell-expressed FcgammaRIIIa by glyco- or protein-engineering of their Fc portion has been demonstrated to improve NK cell-mediated ADCC and to represent a promising strategy to improve antibody therapy. However, human polymorphonuclear (PMN) effector cells express the highly homologous FcgammaRIIIb isoform, which is described to be ineffective in triggering ADCC. Here, non-fucosylated or protein engineered anti-EGFR antibodies with optimized FcgammaRIIIa affinities demonstrated the expected benefit in NK cell-mediated ADCC, but did not mediate ADCC by PMN, which could be restored by FcgammaRIIIb blockade. Furthermore, eosinophils and PMN from paroxysmal nocturnal hemoglobinuria patients that expressed no or low levels of FcgammaRIIIb mediated effective ADCC with FcgammaRIII-optimized anti-EGFR antibody. Additional experiments with double FcgammaRIIa/FcgammaRIII-optimized constructs demonstrated enhanced PMN-mediated ADCC compared with single FcgammaRIII-optimized antibody. In conclusion, our data demonstrate that FcgammaRIIIb engagement impairs PMN-mediated ADCC activity of FcgammaRIII-optimized anti-EGFR antibodies, while further optimization of FcgammaRIIa binding significantly restores PMN recruitment. PMID- 24492251 TI - Health information preferences among Hispanic/Latino immigrants in the U.S. rural Midwest. AB - We investigated whether length of residence and other socio-demographic factors affect how rural Hispanic/Latino immigrants in the U.S. prefer to receive general health information. As part of a federally-funded participatory research project, we surveyed 894 adult Hispanics who were recruited through schools, community based organizations (CBO) and faith-based organizations (FBO) in six rural communities of Illinois. Data suggest that workshops in Spanish at community settings are the most preferred health information strategy and home visits the least. Preference for these two strategies decreased significantly in the second generation, while preference for mailed printed materials increased. We further explored the role of length of residence in the U.S. on 'in-person' and 'impersonal' health information preferences controlling for other relevant socio demographic factors finding that first generation and less educated Hispanic immigrants' prefer 'in-person' strategies. These findings suggest that rural health organizations and practitioners should implement not only culturally appropriate but also acculturation-sensitive approaches to address Hispanic/Latino immigrants' specific health information needs. PMID- 24492253 TI - Lifespan of effector memory CD4+ T cells determined by replication-incompetent integrated HIV-1 provirus. AB - OBJECTIVE: Determining the precise lifespan of human T-cell is challenging due to the inability of standard techniques to distinguish between dividing and dying cells. Here, we measured the lifespan of a pool of T cells that were derived from a single cell 'naturally' labelled with a single integrated clone of a replication-incompetent HIV-1 provirus. DESIGN/METHODS: Utilizing a combination of techniques, we were able to sequence/map an integration site of a unique provirus with a stop codon at position 42 of the HIV-1 protease. In-vitro reconstruction of this provirus into an infectious clone confirmed its inability to replicate. By combining cell separation and integration site-specific PCR, we were able to follow the fate of this single provirus in multiple T-cell subsets over a 20-year period. As controls, a number of additional integrated proviruses were also sequenced. RESULTS: The replication-incompetent HIV-1 provirus was solely contained in the pool of effector memory CD4 T cells for 17 years. The percentage of the total effector memory CD4 T cells containing the replication incompetent provirus peaked at 1% with a functional half-life of 11.1 months. In the process of sequencing multiple proviruses, we also observed high levels of lethal mutations in the peripheral blood pool of proviruses. CONCLUSION: These data indicate that human effector memory CD4 T cells are able to persist in vivo for more than 17 years without detectably reverting to a central memory phenotype. A secondary observation is that the fraction of the pool of integrated HIV-1 proviruses capable of replicating may be considerably less than the 12% currently noted in the literature. PMID- 24492254 TI - Chaperone and protease functions of LON protease 2 modulate the peroxisomal transition and degradation with autophagy. AB - Balancing repair and degradation is essential for maintaining organellar and cellular homeostasis. Peroxisomes are ubiquitous organelles in eukaryotic cells that play pivotal roles in cell survival. However, the quality control mechanism used to maintain peroxisomes is unclear. Here, we demonstrate that LON protease 2 (LON2), which is encoded by ABERRANT PEROXISOME MORPHOLOGY 10 (APEM10), is responsible for the functional transition of peroxisomes with autophagy. The Arabidopsis apem10 mutant displayed accelerated peroxisome degradation and a dramatically reduced number of peroxisomes. LON2 deficiency caused enhanced peroxisome degradation by autophagy, and peroxisomal proteins accumulated in the cytosol due to a decrease in the number of peroxisomes. We also show the proteolytic consequence of LON2 for the degradation of peroxisomal proteins, and we demonstrated that unnecessary proteins are eliminated by LON2- and autophagy dependent degradation pathways during the functional transition of peroxisomes. LON2 plays dual roles as an ATP-dependent protease and a chaperone. We show that the chaperone domain of LON2 is essential for the suppression of autophagy, whereas its peptidase domain interferes with this chaperone function, indicating that intramolecular modulation between the proteolysis and chaperone functions of LON2 regulates degradation of peroxisomes by autophagy. PMID- 24492252 TI - PharmGKB summary: very important pharmacogene information for UGT1A1. PMID- 24492255 TI - Isolation and phenotypic characterization of Lotus japonicus mutants specifically defective in arbuscular mycorrhizal formation. AB - Several symbiotic mutants of legume plants defective in nodulation have also been shown to be mutants related to arbuscular mycorrhizal (AM) symbiosis. The origin of the AM symbiosis can be traced back to the early land plants. It has therefore been postulated that the older system of AM symbiosis was partially incorporated into the newer system of legume-rhizobium symbiosis. To unravel the genetic basis of the establishment of AM symbiosis, we screened about 34,000 plants derived from ethyl methanesulfonate (EMS)-mutagenized Lotus japonicus seeds by microscopic observation. As a result, three lines (ME778, ME966 and ME2329) were isolated as AM-specific mutants that exhibit clear AM-defective phenotypes but form normal effective root nodules with rhizobial infection. In the ME2329 mutant, AM fungi spread their hyphae into the intercellular space of the cortex and formed trunk hyphae in the cortical cells, but the development of fine branches in the arbuscules was arrested. The ME2329 mutant carried a nonsense mutation in the STR-homolog gene, implying that the line may be an str mutant in L. japonicus. On the ME778 and ME966 mutant roots, the entry of AM fungal hyphae was blocked between two adjacent epidermal cells. Occasionally, hyphal colonization accompanied by arbuscules was observed in the two mutants. The genes responsible for the ME778 and ME966 mutants were independently located on chromosome 2. These results suggest that the ME778 and ME966 lines are symbiotic mutants involved in the early stage of AM formation in L. japonicus. PMID- 24492256 TI - High-throughput transcriptome analysis of the leafy flower transition of Catharanthus roseus induced by peanut witches'-broom phytoplasma infection. AB - Peanut witches'-broom (PnWB) phytoplasma are obligate bacteria that cause leafy flower symptoms in Catharanthus roseus. The PnWB-mediated leafy flower transitions were studied to understand the mechanisms underlying the pathogen host interaction; however, our understanding is limited because of the lack of information on the C. roseus genome. In this study, the whole-transcriptome profiles from healthy flowers (HFs) and stage 4 (S4) PnWB-infected leafy flowers of C. roseus were investigated using next-generation sequencing (NGS). More than 60,000 contigs were generated using a de novo assembly approach, and 34.2% of the contigs (20,711 genes) were annotated as putative genes through name-calling, open reading frame determination and gene ontology analyses. Furthermore, a customized microarray based on this sequence information was designed and used to analyze samples further at various stages of PnWB infection. In the NGS profile, 87.8% of the genes showed expression levels that were consistent with those in the microarray profiles, suggesting that accurate gene expression levels can be detected using NGS. The data revealed that defense-related and flowering gene expression levels were altered in S4 PnWB-infected leafy flowers, indicating that the immunity and reproductive stages of C. roseus were compromised. The network analysis suggested that the expression levels of >1,000 candidate genes were highly associated with CrSVP1/2 and CrFT expression, which might be crucial in the leafy flower transition. In conclusion, this study provides a new perspective for understanding plant pathology and the mechanisms underlying the leafy flowering transition caused by host-pathogen interactions through analyzing bioinformatics data obtained using a powerful, rapid high-throughput technique. PMID- 24492257 TI - Aphidicolin-induced nuclear elongation in tobacco BY-2 cells. AB - Plant nuclei are known to differentiate into various shapes within a single plant. However, little is known about the mechanisms of nuclear morphogenesis. We found that nuclei of tobacco BY-2 cells were highly elongated on long-term treatment with 5 mg l-1 aphidicolin, an inhibitor of DNA polymerase alpha. In aphidicolin-treated cells, the nuclear length was correlated with the cell length. During culture in the presence of aphidicolin, the nuclei were elongated in parallel with cell elongation. Nuclear elongation was inhibited by the inhibition of cell elongation with 2,6-dichlorobenzonitrile, a cellulose synthesis inhibitor. However, cell elongation induced in the auxin-depleted medium in the absence of aphidicolin did not cause nuclear elongation, indicating that cell elongation alone is not sufficient for nuclear elongation. Treatment with either latrunculin B or propyzamide inhibited the aphidicolin-induced nuclear elongation, indicating that both actin filaments and microtubules (MTs) are required for nuclear elongation. Observations using BY-YTHCLR2 cells, in which actin filaments, MTs and nuclei were simultaneously visualized, revealed that the longitudinally arranged MT bundles associated with the nucleus play an important role in nuclear elongation, and that actin filaments affect the formation of these MT bundles. In aphidicolin-treated cells, the nuclear DNA contents of the elongated nuclei exceeded 4C, and the nuclear length was highly correlated with the nuclear DNA content. In cells treated with 50 mg l-1 aphidicolin, cells were elongated and nucleus-associated longitudinal MT bundles were formed, but the nuclear DNA contents did not exceed 4C and the nuclei did not elongate. These results indicate that an increase in the nuclear DNA content above 4C is also required for nuclear elongation. PMID- 24492258 TI - Abscisic acid suppresses hypocotyl elongation by dephosphorylating plasma membrane H(+)-ATPase in Arabidopsis thaliana. AB - Plasma membrane H(+)-ATPase is thought to mediate hypocotyl elongation, which is induced by the phytohormone auxin through the phosphorylation of the penultimate threonine of H(+)-ATPase. However, regulation of the H(+)-ATPase during hypocotyl elongation by other signals has not been elucidated. Hypocotyl elongation in etiolated seedlings of Arabidopsis thaliana was suppressed by the H(+)-ATPase inhibitors vanadate and erythrosine B, and was significantly reduced in aha2-5, which is a knockout mutant of the major H(+)-ATPase isoform in etiolated seedlings. Application of the phytohormone ABA to etiolated seedlings suppressed hypocotyl elongation within 30 min at the half-inhibitory concentration (4.2 uM), and induced dephosphorylation of the penultimate threonine of H(+)-ATPase without affecting the amount of H(+)-ATPase. Interestingly, an ABA-insensitive mutant, abi1-1, did not show ABA inhibition of hypocotyl elongation or ABA-induced dephosphorylation of H(+)-ATPase. This indicates that ABI1, which is an early ABA signaling component through the ABA receptor PYR/PYL/RCARs (pyrabactin resistance/pyrabactin resistance 1-like/regulatory component of ABA receptor), is involved in these responses. In addition, we found that the fungal toxin fusiccocin (FC), an H(+)-ATPase activator, induced hypocotyl elongation and phosphorylation of the penultimate threonine of H(+)-ATPase, and that FC-induced hypocotyl elongation and phosphorylation of H(+)-ATPase were significantly suppressed by ABA. Taken together, these results indicate that ABA has an antagonistic effect on hypocotyl elongation through, at least in part, dephosphorylation of H(+)-ATPase in etiolated seedlings. PMID- 24492259 TI - Transcriptional silencing of Arabidopsis endogenes by single-stranded RNAs targeting the promoter region. AB - Transcriptional gene silencing (TGS) of transgenes by promoter-related RNAs has been known for more than a decade. However, the effectiveness and efficiency of silencing of endogenes by single-stranded and inverted repeat (IR) RNA/silencers remain unclear. Here, we demonstrated that a single-stranded antisense (AS) silencer targeting the promoter region can efficiently silence four Arabidopsis endogenes, with comparable efficiency to an IR silencer. In the case of Too Many Mouths (TMM), single-stranded silencers generated mainly 24 nt small RNAs (smRNAs), whereas IR silencers produced a higher proportion of 21-23 nt smRNAs. Heavy CG, CHG and CHH methylations were detected on the TMM promoter in silenced plant lines. We also demonstrated that the silencing and DNA methylation of the TMM promoter was dependent on the presence of the silencer. Chromatin immunoprecipitation (ChIP) assays showed that DNA methylation was accompanied by formation of repressive chromatin structures. Our results suggest that single stranded silencer transcripts are converted to double-stranded RNA to enter the RdRM (RNA-directed DNA methylation) pathway for TGS of endogenes. PMID- 24492260 TI - Evaluation of the activity of ertapenem against gonococcal isolates exhibiting a range of susceptibilities to cefixime. AB - OBJECTIVES: There is a need for new or alternative antimicrobial agents for the treatment of gonorrhoea as antimicrobial resistance emerges to current therapies. The aim was to investigate the activity of ertapenem against isolates of Neisseria gonorrhoeae with decreased susceptibility to cefixime. METHODS: A panel of 52 clinical isolates and 10 control strains of N. gonorrhoeae were selected to represent a range of susceptibilities to cefixime. Susceptibility testing was performed using the methodology used for the Gonococcal Resistance to Antimicrobials Surveillance Programme (GRASP). The isolates were typed by N. gonorrhoeae multi-antigen sequence typing (NG-MAST). RESULTS: The isolates comprised 42 different molecular types as defined by NG-MAST. The susceptibility of the clinical isolates to ertapenem was similar to that of cefixime, with a Pearson's correlation coefficient of R = 0.89. The MIC90 and MIC50 values of ertapenem were 0.25 and 0.12 mg/L, respectively, while those of cefixime were 0.12 and 0.06 mg/L, respectively. However, these isolates were more susceptible to ceftriaxone than ertapenem, with a Pearson's correlation coefficient of R = 0.65 and ceftriaxone MIC90 and MIC50 values of 0.03 and 0.016 mg/L, respectively. The isolates that were least susceptible to ertapenem were all non-producers of penicillinase. However, one isolate that was highly resistant to cefixime and ceftriaxone was more susceptible to ertapenem than either cefixime or ceftriaxone. CONCLUSIONS: This study has shown that ertapenem is not a suitable alternative for first-line treatment for gonorrhoea but that it may be useful for the treatment of highly resistant infections. PMID- 24492261 TI - Population pharmacokinetic modelling of total and unbound cefazolin plasma concentrations as a guide for dosing in preterm and term neonates. AB - OBJECTIVES: Cefazolin is frequently administered for antimicrobial prophylaxis and treatment of infections. In neonates, pharmacokinetic observations are limited and dosing regimens variable. The aim of this study was to describe the pharmacokinetics of cefazolin in neonates based on total and unbound concentrations to optimize cefazolin dosing. METHODS: Thirty-six neonates [median birth body weight 2720 (range 540-4200) g, current body weight (cBW) 2755 (830 4200) g and postnatal age (PNA) 9 (1-30) days] receiving intravenous cefazolin (50 mg/kg/8 h) were included. Based on 119 total and unbound plasma concentrations, a population pharmacokinetic analysis with a covariate analysis was performed. Monte Carlo simulations were performed aiming for unbound concentrations above an MIC of 8 mg/L (>60% of the time) in all patients. RESULTS: A one-compartment pharmacokinetic model was developed in which total and unbound concentrations were linked by maximum protein binding (Bmax) of 136 mg/L and a dissociation constant (KD) for cefazolin protein binding of 46.5 mg/L. cBW was identified as covariate for volume of distribution (V), bBW and PNA for clearance and albumin plasma concentration for Bmax, explaining 50%, 58% and 41% of inter-individual variability in V, clearance and Bmax, respectively. Based on Monte Carlo simulations, a body weight- and PNA-adapted dosing regimen that resulted in similar exposure across different weight and age groups was proposed. CONCLUSIONS: A neonatal pharmacokinetic model taking into account total and unbound cefazolin concentrations with saturable plasma protein binding was identified. As cBW and PNA were the most important covariates, these may be used for individualized dosing in neonates. PMID- 24492263 TI - Your important role in transitions, chronic care, and the increasing complexity as we live longer! PMID- 24492262 TI - Segmental helical motions and dynamical asymmetry modulate histidine kinase autophosphorylation. AB - Histidine kinases (HKs) are dimeric receptors that participate in most adaptive responses to environmental changes in prokaryotes. Although it is well established that stimulus perception triggers autophosphorylation in many HKs, little is known on how the input signal propagates through the HAMP domain to control the transient interaction between the histidine-containing and ATP binding domains during the catalytic reaction. Here we report crystal structures of the full cytoplasmic region of CpxA, a prototypical HK involved in Escherichia coli response to envelope stress. The structural ensemble, which includes the Michaelis complex, unveils HK activation as a highly dynamic process, in which HAMP modulates the segmental mobility of the central HK alpha-helices to promote a strong conformational and dynamical asymmetry that characterizes the kinase active state. A mechanical model based on our structural and biochemical data provides insights into HAMP-mediated signal transduction, the autophosphorylation reaction mechanism, and the symmetry-dependent control of HK kinase/phosphatase functional states. PMID- 24492265 TI - A system-wide innovation in transition services: transforming the home care liaison role. AB - This article describes how a provincial health authority in Canada improved patient care and staff satisfaction by transforming the role of home care (HC) liaison. The transformation focused on clearly defining the role, function and reporting structure, and identifying which healthcare providers could fill the liaison role. The transformation included adoption of transition best practices, leveraging an electronic referral system, creation of an interprofessional team, standardization of tools/orientation, and strong evaluation metrics, centralizing decision making, and developing a process for streaming referrals. The authors identify key success factors that made the transformation possible, as well as challenges and work that remains to sustain the change. PMID- 24492266 TI - Applying research into practice: a guide to determine the next palliative home care nurse visit. AB - Beyond their own family caregivers, home healthcare nurses play a pivotal role in caring for those dying at home. However, deciding the timing of the next visit for these patients and their families is not straightforward. The Palliative Care: Determining Next Home Care Nurse Visit decision guide supports clinicians in their decision-making process of planning visits to most effectively meet the needs and goals of patients and families during the final months of life. PMID- 24492268 TI - Reducing the fear of falling through a community evidence-based intervention. AB - Falls and the fear of falling are major health concerns among older adults. The purpose of this study was to assess the effects of an evidence-based fall prevention program on the fear of falling and health-related quality of life among community-dwelling elders. The program consisted of 6 classes that covered topics such as risk factors for falls, balance exercises, medications, safe footwear, and home safety. Of those elders who were most fearful at baseline, the fall prevention program decreased their fear of falling and improved 1 dimension of their health-related quality of life. PMID- 24492270 TI - The interdisciplinary approach to the implementation of a diabetes home care disease management program. AB - Diabetes is a national epidemic and a leading cause of hospitalizations in the United States. Home care agencies need to be able to provide effective Diabetes Disease Management to help prevent avoidable hospitalizations and assist patients to live a good quality of life. This article describes one organization's journey toward providing patients with better diabetes care resulting in an improved quality of life. PMID- 24492272 TI - Effectiveness of wound, ostomy, and continence nurses on agency-level wound and incontinence outcomes in home care. AB - PURPOSE: The purpose of this study was to describe the prevalence, incidence, and effectiveness of home health care (HHC) agencies' services with and without a WOC nurse related to wounds, incontinence, and urinary tract infection (UTI) patient outcomes. SUBJECTS AND SETTING: There were 449,243 episodes of care from a national convenience sample of 785 HHC agencies representing nonmaternity patients who were aged 18 years or older and receiving skilled home health services between October 1, 2008, and December 31, 2009. DESIGN: This study employed descriptive and comparative designs for data collection and analysis. We analyzed data from HHC agencies' electronic health records and conducted an Internet-based survey of HHC agencies. INSTRUMENTS: Data for this study were documented by HHC clinicians using the Outcome and Assessment Information Set. An Internet survey identified if a WOC nurse provided care or consultations within an HHC agency. RESULTS: The majority of HHC agencies (88.5%) had some influence of a WOC nurse. The incidence of wounds, incontinence, and UTIs was higher for agencies with no WOC nurse. Home health care agencies with WOC nurses had significantly better improvement outcomes for pressure ulcers, lower extremity ulcers, surgical wounds, urinary incontinence, bowel incontinence, and UTIs as well as significantly better stabilization outcomes for these outcomes except lower extremity ulcers. Virtually all patients in HHC agencies with and without a WOC nurse had stabilization of their lower extremity ulcers. CONCLUSIONS: Findings of this study suggest that influence of a WOC nurse is effective in achieving several important positive outcomes of HHC agencies' services for wounds, incontinence, and UTIs. PMID- 24492273 TI - Establishing a value-based community partnership: a best-practice approach. PMID- 24492274 TI - Alzheimer's be not proud. PMID- 24492275 TI - Pancreatitis: Is TPIAT the answer for treatment of chronic pancreatitis? PMID- 24492276 TI - The emerging roles of microvesicles in liver diseases. AB - Microvesicles (MVs) are extracellular vesicles released by virtually all cells, under both physiological and pathological conditions. They contain lipids, proteins, RNAs and microRNAs and act as vectors of information that regulate the function of target cells. This Review provides an overview of the studies assessing circulating MV levels in patients with liver diseases, together with an insight into the mechanisms that could account for these changes. We also present a detailed analysis of the implication of MVs in key processes of liver diseases. MVs have a dual role in fibrosis as certain types of MVs promote fibrolysis by increasing expression of matrix metalloproteinases, whereas others promote fibrosis by stimulating processes such as angiogenesis. MVs probably enhance portal hypertension by contributing to intrahepatic vasoconstriction, splanchnic vasodilation and angiogenesis. As MVs can modulate vascular permeability, vascular tone and angiogenesis, they might contribute to several complications of cirrhosis including hepatic encephalopathy, hepatopulmonary syndrome and hepatorenal syndrome. Several results also suggest that MVs have a role in hepatocellular carcinoma. Although MVs represent promising biomarkers in patients with liver disease, methods of isolation and subsequent analysis must be standardized. PMID- 24492277 TI - Neurogastroenterology: Ageing, ENS senescence and gastrointestinal motility. PMID- 24492278 TI - HCC therapies--lessons learned. AB - The antiangiogenic multikinase inhibitor sorafenib was the first systemic agent to demonstrate a significant improvement in the overall survival of patients with advanced hepatocellular carcinoma (HCC), thereby introducing molecularly-targeted therapy in a therapeutic field of unmet needs. However, survival benefits for patients on sorafenib treatment are modest in clinical practice and advancing the field is far more challenging than initially anticipated. Molecular and clinical heterogeneity diminishes signals of potential activity in unselected populations, and underlying liver cirrhosis seals the fate of many novel targeted agents by causing relevant toxicity and mortality. The failure of subsequent randomized controlled phase III trials underscores the urgent need to identify the driver targets and to develop matched active agents with manageable toxicities in specific phase I studies in patients with cirrhosis. Refinement of phase II-III trial designs with a biomarker-enriched patient-selection process and stratification according to prognostic baseline factors is indispensable to prevent another 5-year vain endeavour in systemic therapy of HCC. PMID- 24492279 TI - Helicobacter pylori infection: Helicobacter pylori induces changes in regulatory T cells. PMID- 24492280 TI - Topical review: locking plate technology in foot and ankle surgery. AB - The use of locking plate technology in foot and ankle surgery has increased over the last decade. Reported applications include fracture repair, deformity correction, and arthrodesis. There is limited evidence, however, to guide clinicians with regard to the appropriate and optimal use of this technology. This work aims to examine the current biomechanical and clinical evidence comparing locking construct technology to other forms of fixation in the field of foot and ankle surgery. PMID- 24492281 TI - Modulation of PI3K-LXRalpha-dependent lipogenesis mediated by oxidative/nitrosative stress contributes to inhibition of HCV replication by quercetin. AB - There is experimental evidence that some antioxidant flavonoids show therapeutic potential in the treatment of hepatitis C through inhibition of hepatitis C virus (HCV) replication. We examined the effect of treatment with the flavonols quercetin and kaempferol, the flavanone taxifolin and the flavone apigenin on HCV replication efficiency in an in vitro model. While all flavonoids studied were able to reduce viral replication at very low concentrations (ranging from 0.1 to 5 MUM), quercetin appeared to be the most effective inhibitor of HCV replication, showing a marked anti-HCV activity in replicon-containing cells when combined with interferon (IFN)alpha. The contribution of oxidative/nitrosative stress and lipogenesis modulation to inhibition of HCV replication by quercetin was also examined. As expected, quercetin decreased HCV-induced reactive oxygen and nitrogen species (ROS/RNS) generation and lipoperoxidation in replicating cells. Quercetin also inhibited liver X receptor (LXR)alpha-induced lipid accumulation in LXRalpha-overexpressing and replicon-containing Huh7 cells. The mechanism underlying the LXRalpha-dependent lipogenesis modulatory effect of quercetin in HCV-replicating cells seems to involve phosphatidylinositol 3-kinase (PI3K)/AKT pathway inactivation. Thus, inhibition of the PI3K pathway by LY294002 attenuated LXRalpha upregulation and HCV replication mediated by lipid accumulation, showing an additive effect when combined with quercetin. Inactivation of the PI3K pathway by quercetin may contribute to the repression of LXRalpha-dependent lipogenesis and to the inhibition of viral replication induced by the flavonol. Combined, our data suggest that oxidative/nitrosative stress blockage and subsequent modulation of PI3K-LXRalpha-mediated lipogenesis might contribute to the inhibitory effect of quercetin on HCV replication. PMID- 24492282 TI - Increased expression of c-Jun in nonalcoholic fatty liver disease. AB - Overnutrition is the major cause of nonalcoholic fatty liver disease (NAFLD) and its advanced form nonalcoholic steatohepatitis (NASH). We aimed to develop and characterize a murine model, which resembles both the pathology and nutritional situation, of NASH patients in Western societies. Mice were fed with a NASH inducing diet (ND) containing sucrose, cholesterol and fats rich in saturated fatty acids in a composition, which mimics Western food. After 12 weeks, ND-fed mice revealed obesity and impaired glucose tolerance. In the liver, ND-feeding led to marked steatosis, hepatocellular damage, inflammation and beginning fibrosis. Transcriptome-wide gene expression analysis and search for over represented transcription factor target sites among the differentially expressed genes identified activator protein-1 (AP-1) as the most likely factor to cause the transcriptional changes in ND livers. Combining differentially expressed gene and protein-protein interaction network analysis identified c-Jun as hub in the largest connected deregulated sub-network in ND livers. Accordingly, ND livers revealed c-Jun-phosphorylation and nuclear translocation. Moreover, hepatic c-Jun expression was enhanced in ND-fed mice. Combined tissue microarray technology and immunohistochemical analysis confirmed enhanced hepatic c-Jun levels in NAFLD patients, which correlated with inflammation, and notably, with the degree of hepatic steatosis. In summary, our new mouse model shows important pathological changes also found in human NASH and indicates c-Jun/AP-1 activation as critical regulator of hepatic alterations. Abundance of c-Jun in NAFLD likely facilitates development and progression of NASH. PMID- 24492283 TI - Activation of platelet-activating factor receptor exacerbates renal inflammation and promotes fibrosis. AB - Platelet-activating factor (PAF) is a lipid mediator with important pro inflammatory effects, being synthesized by several cell types including kidney cells. Although there is evidence of its involvement in acute renal dysfunction, its role in progressive kidney injury is not completely known. In the present study, we investigated the role of PAF receptor (PAFR) in an experimental model of chronic renal disease. Wild-type (WT) and PAFR knockout (KO) mice underwent unilateral ureter obstruction (UUO), and at kill time, urine and kidney tissue was collected. PAFR KO animals compared with WT mice present: (a) less renal dysfunction, evaluated by urine protein/creatinine ratio; (b) less fibrosis evaluated by collagen deposition, type I collagen, Lysyl Oxidase-1 (LOX-1) and transforming growth factor beta (TGF-beta) gene expression, and higher expression of bone morphogenetic protein 7 (BMP-7) (3.3-fold lower TGF-beta/BMP-7 ratio); (c) downregulation of extracellular matrix (ECM) and adhesion molecule-related machinery genes; and (d) lower levels of pro-inflammatory cytokines. These indicate that PAFR engagement by PAF or PAF-like molecules generated during UUO potentiates renal dysfunction and fibrosis and might promote epithelial-to mesenchymal transition (EMT). Also, early blockade of PAFR after UUO leads to a protective effect, with less fibrosis deposition. In conclusion, PAFR signaling contributes to a pro-inflammatory environment in the model of obstructive nephropathy, favoring the fibrotic process, which lately will generate renal dysfunction and progressive organ failure. PMID- 24492284 TI - Thioredoxin-interacting protein mediates dysfunction of tubular autophagy in diabetic kidneys through inhibiting autophagic flux. AB - Thioredoxin-interacting protein (TXNIP) expression is ubiquitous and is induced by a variety of cellular stresses, including high intracellular glucose. TXNIP is associated with activation of oxidative stress and tubulointerstitial fibrosis in diabetic nephropathy. Autophagy is a major pathway that delivers damaged proteins and organelles to lysosomes to maintain cellular homeostasis. This study aimed to investigate the dysregulation of autophagy and the regulation of TXNIP on autophagy in renal proximal tubular cells (PTCs) under diabetic conditions. The formation of autophagosomes was measured using transmission electron microscopy, and LC3-II, and the effectiveness of autophagic clearance was determined by p62 expression in diabetic kidney and in human PTCs exposed to high glucose (HG). The results collectively demonstrated increased expression of TXNIP, LC3/LC3-II and p62 in renal tubular cells of mice with diabetic nephropathy and in cultured human PTCs exposed to HG (30 mM/l) for 48 h compared with control. The formation of autophagic vacuoles was increased in HG-induced cells. Furthermore, silencing of TXNIP by siRNA transfection reduced autophagic vacuoles and the expression of LC3-II and p62 in human PTCs exposed to HG compared with control and partially reversed the accumulation of LC3-II and p62 induced by bafilomycin A1 (50 nM/l), a pharmacological inhibitor of autophagy which blocks the fusion of autophagosomes with lysosomes and impairs the degradation of LC3-II and p62. Collectively, these results suggest that hyperglycemia leads to dysfunction of autophagy in renal tubular cells and decreases autophagic clearance. HG-induced overexpression of TXNIP may contribute to the dysfunction of tubular autophagy in diabetes. PMID- 24492285 TI - Correlation of BAG-3 and heat shock protein 70 with CD30 expression in T-cell lymphomas. AB - T-cell lymphomas are aggressive lymphomas with decreased prognosis and resistance to therapy. BAG-3 and heat shock protein 70 (HSP70) function in chemotherapeutic resistance and cellular survival. Expression of BAG-3 has not been investigated in T cell lymphomas. We investigated fifty cases including benign, systemic and cutaneous T cell lymphomas. Benign T cells were negative for BAG-3 and HSP70 immunohistochemical staining. BAG-3 expression correlated with increased HSP70 expression in a subset of systemic T cell lymphoma cases co-expressing the CD30 antigen. Correlation between BAG-3, HSP70 and CD30 expression was not seen in cutaneous T cell lymphoma cases. However, these cases showed a significant increase in BAG-3 staining when compared to CD30 negative systemic T cell lymphoma cases. The differential protein expression profile of BAG-3 and HSP70 may indicate a specific role for these proteins and the ubiquitin-proteasome system/autophagy in T cell lymphomas which may help guide future targeted therapy. PMID- 24492286 TI - Changes in hospitalizations for pneumonia after universal vaccination with pneumococcal conjugate vaccines 7/13 valent and haemophilus influenzae type b conjugate vaccine in a Pediatric Referral Hospital in Uruguay. AB - BACKGROUND: In 1994, Uruguay included Haemophilus influenzae b (Hib) conjugated vaccine in a 3 + 1 schedule. In March 2008, 7-valent pneumococcal conjugate vaccines (PCV7) was included in a 2 +1 schedule. In 2010, 13-valent PCV replaced PCV7. Catch-up immunization was offered. The aim of this study was to describe the etiology of community-acquired pneumonia (CAP) in children 0-14 years of age hospitalized at the Hospital Pediatrico-Centro Hospitalario Pereira Rossell between 2003 and 2012. METHODS: Annual hospitalization rates (per 10,000 discharges) for CAP and bacterial-confirmed CAP in children 0-14 years of age was described prior PCV7 vaccination (2003-2007), during the year of implementation of PCV7 (2008) and after the introduction of PCV7 (2009-2012). Data regarding age, strains isolated from pleural fluid and/or blood, vaccination status, pneumococcal and H. influenzae serotypes were obtained from Hospital Pediatrico Centro Hospitalario Pereira Rossell databases and vaccination records. RESULTS: Hospitalization rates for CAP and pneumococcal CAP between prevaccine years and the last year after introduction of vaccination with PCV (2012) significantly decreased by 78.1% and 92.4%, respectively. Significant reduction for 13-valent PCV vaccine serotypes and significant increase for nonvaccine serotypes was observed. A decrease in Staphylococcus aureus pneumonia was observed. Hospitalization rates for H. influenzae CAP remain stable before and after pneumococcal vaccination. CONCLUSIONS: Three years after PCV7/13 introduction into the routine vaccination schedule, there was a rapid and significant reduction in rates of CAP and P-CAP. An increase of etiology of CAP by other agents was not observed. PMID- 24492287 TI - 3-Bromopyruvate induces apoptosis in breast cancer cells by downregulating Mcl-1 through the PI3K/Akt signaling pathway. AB - The hexokinase inhibitor 3-bromopyruvate (3-BrPA) can inhibit glycolysis in tumor cells to reduce ATP production, resulting in apoptosis. However, as 3-BrPA is an alkylating agent, its cytotoxic action may be induced by other molecular mechanisms. The results presented here reveal that 3-BrPA-induced apoptosis is caspase independent. Further, 3-BrPA induces the generation of reactive oxygen species in MDA-MB-231 cells, leading to mitochondria-mediated apoptosis. These results suggest that caspase-independent apoptosis may be induced by the generation of reactive oxygen species. In this study, we also demonstrated that 3 BrPA induces apoptosis through the downregulation of myeloid cell leukemia-1 (Mcl 1) in MDA-MB-231 breast cancer cells. The results of Mcl-1 knockdown indicate that Mcl-1 plays an important role in 3-BrPA-induced apoptosis. Further, the upregulation of Mcl-1 expression in 3-BrPA-treated MDA-MB-231 cells significantly increases cell viability. In addition, 3-BrPA treatment resulted in the downregulation of p-Akt, suggesting that 3-BrPA may downregulate Mcl-1 through the phosphoinositide-3-kinase/Akt pathway. These findings indicate that 3-BrPA induces apoptosis in breast cancer cells by downregulating Mcl-1 through the phosphoinositide-3-kinase/Akt signaling pathway. PMID- 24492288 TI - High-density metallic nano-emitter arrays and their field emission characteristics. AB - We report the fabrication and field emission properties of high-density nano emitter arrays with on-chip electron extraction gate electrodes and up to 10(6) metallic nanotips that have an apex curvature radius of a few nanometers and a the tip density exceeding 10(8) cm(-2). The gate electrode was fabricated on top of the nano-emitter arrays using a self-aligned polymer mask method. By applying a hot-press step for the polymer planarization, gate-nanotip alignment precision below 10 nm was achieved. Fabricated devices exhibited stable field electron emission with a current density of 0.1 A cm(-2), indicating that these are promising for applications that require a miniature high-brightness electron source. PMID- 24492289 TI - Engineering multivalent antibodies to target heregulin-induced HER3 signaling in breast cancer cells. AB - The use of antibodies in therapy and diagnosis has undergone an unprecedented expansion during the past two decades. This is due in part to innovations in antibody engineering that now offer opportunities for the production of "second generation" antibodies with multiple specificities or altered valencies. The targeting of individual components of the human epidermal growth factor receptor (HER)3-PI3K signaling axis, including the preferred heterodimerization partner HER2, is known to have limited anti-tumor effects. The efficacy of antibodies or small molecule tyrosine kinase inhibitors (TKIs) in targeting this axis is further reduced by the presence of the HER3 ligand, heregulin. To address these shortcomings, we performed a comparative analysis of two distinct approaches toward reducing the proliferation and signaling in HER2 overexpressing tumor cells in the presence of heregulin. These strategies both involve the use of engineered antibodies in combination with the epidermal growth factor receptor (EGFR)/HER2 specific TKI, lapatinib. In the first approach, we generated a bispecific anti-HER2/HER3 antibody that, in the presence of lapatinib, is designed to sequester HER3 into inactive HER2-HER3 dimers that restrain HER3 interactions with other possible dimerization partners. The second approach involves the use of a tetravalent anti-HER3 antibody with the goal of inducing efficient HER3 internalization and degradation. In combination with lapatinib, we demonstrate that although the multivalent HER3 antibody is more effective than its bivalent counterpart in reducing heregulin-mediated signaling and growth, the bispecific HER2/HER3 antibody has increased inhibitory activity. Collectively, these observations provide support for the therapeutic use of bispecifics in combination with TKIs to recruit HER3 into complexes that are functionally inert. PMID- 24492290 TI - Preclinical characterization of an anti-methamphetamine monoclonal antibody for human use. AB - Ch-mAb7F9, a human-mouse chimeric monoclonal antibody (mAb) designed to bind (+) methamphetamine (METH) with high affinity and specificity, was produced as a treatment medication for METH abuse. In these studies, we present the preclinical characterization that provided predictive evidence that ch-mAb7F9 may be safe and effective in humans. In vitro ligand binding studies showed that ch-mAb7F9 is specific for and only binds its target ligands (METH, (+)-amphetamine, and 3,4 methylenedioxy-N-methylamphetamine) with high affinity. It did not bind endogenous neurotransmitters or other medications and was not bound by protein C1q, thus it is unlikely to stimulate in vivo complement-dependent cytotoxicity. Isothermal titration calorimetry potency studies showed that METH binding by ch mAb7F9 is efficient. Pharmacokinetic studies of METH given after ch-mAb7F9 doses in rats demonstrated the in vivo application of these in vitro METH-binding characteristics. While METH had little effect on ch-mAb7F9 disposition, ch-mAb7F9 substantially altered METH disposition, dramatically reducing the volume of distribution and clearance of METH. The elimination half-life of METH was increased by ch-mAb7F9, but it was still very fast compared with the elimination of ch-mAb7F9. Importantly, the rapid elimination of unbound METH combined with previous knowledge of mAb:target ligand binding dynamics suggested that ch-mAb7F9 binding capacity regenerates over time. This finding has substantial therapeutic implications regarding the METH doses against which ch-mAb7F9 will be effective, on the duration of ch-mAb7F9 effects, and on the safety of ch-mAb7F9 in METH users who use METH while taking ch-mAb7F9. These results helped to support initiation of a Phase 1a study of ch-mAb7F9. PMID- 24492291 TI - Sortase-catalyzed in vitro functionalization of a HER2-specific recombinant Fab for tumor targeting of the plant cytotoxin gelonin. AB - We report on the preparation of a new type of immunotoxin via in vitro ligation of the alphaHer2 antigen binding fragment (Fab) of the clinically-validated antibody trastuzumab to the plant toxin gelonin, employing catalysis by the bacterial enzyme sortase A (SrtA). The alphaHer2 Fab was fused with the extended SrtA recognition motif LPET?GLEH 6 at the C-terminus of its heavy chain, thereby preventing interference with antigen binding, while the toxin was equipped with a Gly 2 sequence at its N-terminus, distant to the catalytically active site in the C-terminal region. Site-specific in vitro transpeptidation led to a novel antibody-toxin conjugate wherein gelonin had effectively replaced the Fc region of a conventional (monomerized) immunoglobulin. After optimization of reaction conditions and incubation time, the resulting Fab-Gelonin ligation product was purified to homogeneity in a two-step procedure by means of Strep-Tactin affinity chromatography--utilizing the Strep-tag II appended to gelonin--and size exclusion chromatography. Binding activity of the immunotoxin for the Her2 ectodomain was indistinguishable from the unligated Fab as measured by real-time surface plasmon resonance spectroscopy. Specific cytotoxic potency of Fab-Gelonin was demonstrated against two Her2-positive cell lines, resulting in EC 50 values of ~1 nM or lower, indicating a 1000-fold enhanced cell-killing activity compared with gelonin itself. Thus, our strategy provides a convenient route to the modular construction of functional immunotoxins from Fabs of established tumor specific antibodies with gelonin or related proteotoxins, also avoiding the elevated biosafety levels that would be mandatory for the direct biotechnological preparation of corresponding fusion proteins. PMID- 24492292 TI - The ErbB2-targeting antibody trastuzumab and the small-molecule SRC inhibitor saracatinib synergistically inhibit ErbB2-overexpressing gastric cancer. AB - The anti-ErbB2 antibody trastuzumab has shown significant clinical benefits in ErbB2-overexpressing breast and gastric cancer, but resistance to the drug is common. Here, we investigated the antitumor activity of the combination of trastuzumab and the SRC inhibitor saracatinib in ErbB2-overexpressing trastuzumab resistant gastric cancer. The ErbB2-overexpressing human gastric cancer cell line NCI-N87 was treated with trastuzumab to obtain the trastuzumab-resistant cell line NCI-N87R. The NCI-N87R cell line showed a marked increase in SRC activity and ErbB signaling compared with the NCI-N87 cell line. Our data demonstrated that trastuzumab plus saracatinib was much more potent than either agent alone in reducing the phosphorylation of ErbB3 and AKT in both NCI-N87 and NCI-N87R gastric cancer cell lines. Trastuzumab and saracatinib synergistically inhibited the in vitro growth of NCI-N87 and NCI-N87R cell lines. Further data showed that combination therapy of trastuzumab with saracatinib resulted in a significant benefit over either agent alone in both NCI-N87 and NCI-N87R xenograft models, suggesting its potential use for treating ErbB2-overexpressing gastric cancer. PMID- 24492293 TI - Hybridization-based antibody cDNA recovery for the production of recombinant antibodies identified by repertoire sequencing. AB - High-throughput sequencing of the antibody repertoire is enabling a thorough analysis of B cell diversity and clonal selection, which may improve the novel antibody discovery process. Theoretically, an adequate bioinformatic analysis could allow identification of candidate antigen-specific antibodies, requiring their recombinant production for experimental validation of their specificity. Gene synthesis is commonly used for the generation of recombinant antibodies identified in silico. Novel strategies that bypass gene synthesis could offer more accessible antibody identification and validation alternatives. We developed a hybridization-based recovery strategy that targets the complementarity determining region 3 (CDRH3) for the enrichment of cDNA of candidate antigen specific antibody sequences. Ten clonal groups of interest were identified through bioinformatic analysis of the heavy chain antibody repertoire of mice immunized with hen egg white lysozyme (HEL). cDNA from eight of the targeted clonal groups was recovered efficiently, leading to the generation of recombinant antibodies. One representative heavy chain sequence from each clonal group recovered was paired with previously reported anti-HEL light chains to generate full antibodies, later tested for HEL-binding capacity. The recovery process proposed represents a simple and scalable molecular strategy that could enhance antibody identification and specificity assessment, enabling a more cost efficient generation of recombinant antibodies. PMID- 24492294 TI - High-throughput screening for developability during early-stage antibody discovery using self-interaction nanoparticle spectroscopy. AB - The discovery of monoclonal antibodies (mAbs) that bind to a particular molecular target is now regarded a routine exercise. However, the successful development of mAbs that (1) express well, (2) elicit a desirable biological effect upon binding, and (3) remain soluble and display low viscosity at high concentrations is often far more challenging. Therefore, high throughput screening assays that assess self-association and aggregation early in the selection process are likely to yield mAbs with superior biophysical properties. Here, we report an improved version of affinity-capture self-interaction nanoparticle spectroscopy (AC-SINS) that is capable of screening large panels of antibodies for their propensity to self-associate. AC-SINS is based on concentrating mAbs from dilute solutions around gold nanoparticles pre-coated with polyclonal capture (e.g., anti-Fc) antibodies. Interactions between immobilized mAbs lead to reduced inter-particle distances and increased plasmon wavelengths (wavelengths of maximum absorbance), which can be readily measured by optical means. This method is attractive because it is compatible with dilute and unpurified mAb solutions that are typical during early antibody discovery. In addition, we have improved multiple aspects of this assay for increased throughput and reproducibility. A data set comprising over 400 mAbs suggests that our modified assay yields self-interaction measurements that are well-correlated with other lower throughput assays such as cross interaction chromatography. We expect that the simplicity and throughput of our improved AC-SINS method will lead to improved selection of mAbs with excellent biophysical properties during early antibody discovery. PMID- 24492295 TI - Preclinical evaluation of 89Zr-labeled anti-CD44 monoclonal antibody RG7356 in mice and cynomolgus monkeys: Prelude to Phase 1 clinical studies. AB - RG7356 is a humanized antibody targeting the constant region of CD44. RG7356 was radiolabeled with (89)Zr for preclinical evaluations in tumor xenograft-bearing mice and normal cynomolgus monkeys to enable study of its biodistribution and the role of CD44 expression on RG7356 uptake. Studies with (89)Zr-RG7356 were performed in mice bearing tumor xenografts that differ in the level of CD44 expression (CD44(+) or CD44(-)) and RG7356 responsiveness (resp or non-resp): MDA MB-231 (CD44(+), resp), PL45 (CD44(+), non-resp) and HepG2 (CD44(-), non-resp). Immuno-PET whole body biodistribution studies were performed in normal cynomolgus monkeys to determine normal organ uptake after administration of a single dose. At 1, 2, 3, and 6 days after injection, (89)Zr-RG7356 uptake in MDA-MB-231 (CD44(+), resp) xenografts was nearly constant and about 9 times higher than in HepG2 (CD44(-), non-resp) xenografts (range 27.44 +/- 12.93 to 33.13 +/- 7.42% ID/g vs. 3.25 +/- 0.38 to 3.90 +/- 0.58% ID/g). Uptake of (89)Zr-RG7356 was similar in MDA-MB-231 (CD44(+), resp) and PL45 (CD44(+), non-resp) xenografts. Studies in monkeys revealed antibody uptake in spleen, salivary glands and bone marrow, which might be related to the level of CD44 expression. (89)Zr-RG7356 uptake in these normal organs decreased with increasing dose levels of unlabeled RG7356. (89)Zr-RG7356 selectively targets CD44(+) responsive and non-responsive tumors in mice and CD44(+) tissues in monkeys. These studies indicate the importance of accurate antibody dosing in humans to obtain optimal tumor targeting. Moreover, efficient binding of RG7356 to CD44(+) tumors may not be sufficient in itself to drive an anti-tumor response. PMID- 24492296 TI - ARGX-110, a highly potent antibody targeting CD70, eliminates tumors via both enhanced ADCC and immune checkpoint blockade. AB - Overexpression of CD70 has been documented in a variety of solid and hematological tumors, where it is thought to play a role in tumor proliferation and evasion of immune surveillance. Here, we describe ARGX-110, a defucosylated IgG1 monoclonal antibody (mAb) that selectively targets and neutralizes CD70, the ligand of CD27. ARGX-110 was generated by immunization of outbred llamas. The antibody was germlined to 95% human identity, and its anti-tumor efficacy was tested in several in vitro assays. ARGX-110 binds CD70 with picomolar affinity. In depletion studies, ARGX-110 lyses tumor cells with greater efficacy than its fucosylated version. In addition, ARGX-110 demonstrates strong complement dependent cytotoxicity and antibody-dependent cellular phagocytosis activity. ARGX-110 inhibits signaling of CD27, which results in blocking of the activation and proliferation of Tregs. In a Raji xenograft model, administration of the fucosylated version of ARGX-110 resulted in a prolonged survival at doses of 0.1 mg/kg and above. The pharmacokinetics of ARGX-110 was tested in cynomolgus monkeys; the calculated half-life is 12 days. In conclusion, ARGX-110 is a potent blocking mAb with a dual mode of action against both CD70-bearing tumor cells and CD70-dependent Tregs. This antibody is now in a Phase 1 study in patients with advanced malignancies expressing CD70 (NCT01813539). PMID- 24492298 TI - 9th annual European Antibody Congress, November 11-13, 2013, Geneva, Switzerland. AB - The annual European Antibody Congress (EAC) has traditionally been the key event for updates on critical scientific advances in the antibody field, and 2013 was no exception. Organized by Terrapinn, the well-attended meeting featured presentations on considerations for developing antibodies and antibody-like therapeutics, with separate tracks for antibody-drug conjugates, naked antibodies, and multispecific antibodies or protein scaffolds. The overall focus of the EAC was current approaches to enhance the functionality of therapeutic antibodies or other targeted proteins, with the ultimate goal being improvement of the safety and efficacy of the molecules as treatments for cancer, immune mediated disorders and other diseases. Roundtable discussion sessions gave participants opportunities to engage in group discussions with industry leaders from companies such as Genmab, Glenmark Pharmaceuticals, MedImmune, Merrimack Pharmaceuticals, and Pierre Fabre. As the 2013 EAC was co-located with the World Biosimilar Congress, participants also received an update on European Medicines Agency guidelines and thoughts on the future direction and development of biosimilar antibodies in the European Union. PMID- 24492297 TI - A new class of bispecific antibodies to redirect T cells for cancer immunotherapy. AB - Various constructs of bispecific antibodies (bsAbs) to redirect effector T cells for the targeted killing of tumor cells have shown considerable promise in both preclinical and clinical studies. The single-chain variable fragment (scFv)-based formats, including bispecific T-cell engager (BiTE) and dual-affinity re targeting (DART), which provide monovalent binding to both CD3 on T cells and to the target antigen on tumor cells, can exhibit rapid blood clearance and neurological toxicity due to their small size (~55 kDa). Herein, we describe the generation, by the modular DOCK-AND-LOCKTM) (DNLTM) method, of novel T-cell redirecting bispecific antibodies, each comprising a monovalent anti-CD3 scFv covalently conjugated to a stabilized dimer of different anti-tumor Fabs. The potential advantages of this design include bivalent binding to tumor cells, a larger size (~130 kDa) to preclude renal clearance and penetration of the blood brain barrier, and potent T-cell mediated cytotoxicity. These prototypes were purified to near homogeneity, and representative constructs were shown to provoke the formation of immunological synapses between T cells and their target tumor cells in vitro, resulting in T-cell activation and proliferation, as well as potent T-cell mediated anti-tumor activity. In addition, in vivo studies in NOD/SCID mice bearing Raji Burkitt lymphoma or Capan-1 pancreatic carcinoma indicated statistically significant inhibition of tumor growth compared with untreated controls. PMID- 24492299 TI - In vitro affinity maturation of a natural human antibody overcomes a barrier to in vivo affinity maturation. AB - Antibodies isolated from human donors are increasingly being developed for anti infective therapeutics. These antibodies undergo affinity maturation in vivo, minimizing the need for engineering of therapeutic leads for affinity. However, the affinities required for some therapeutic applications may be higher than the affinities of the leads obtained, requiring further affinity maturation in vitro. To improve the neutralization potency of natural human antibody MSL-109 targeting human cytomegalovirus (CMV), we affinity matured the antibody against the gH/gL glycoprotein complex. A phage display library where most of the six complementary determining regions (CDRs) were allowed to vary in only one amino acid residue at a time was used to scan for mutations that improve binding affinity. A T55R mutation and multiple mutations in position 53 of the heavy chain were identified that, when present individually or in combination, resulted in higher apparent affinities to gH/gL and improved CMV neutralization potency of Fab fragments expressed in bacterial cells. Three of these mutations in position 53 introduced glycosylation sites in heavy chain CDR 2 (CDR H2) that impaired binding of antibodies expressed in mammalian cells. One high affinity (KD<10 pM) variant was identified that combined the D53N and T55R mutations while avoiding glycosylation of CDR H2. However, all the amino acid substitutions identified by phage display that improved binding affinity without introducing glycosylation sites required between two and four simultaneous nucleotide mutations to avoid glycosylation. These results indicate that the natural human antibody MSL-109 is close to a local affinity optimum. We show that affinity maturation by phage display can be used to identify and bypass barriers to in vivo affinity maturation of antibodies imposed by glycosylation and codon usage. These constraints may be relatively prevalent in human antibodies due to the codon usage and the amino acid sequence encoded by the natural human repertoire. PMID- 24492300 TI - Generation of human single-chain variable fragment antibodies specific to dengue virus non-structural protein 1 that interfere with the virus infectious cycle. AB - Severe forms of dengue virus (DENV) infection frequently cause high case fatality rate. Currently, there is no effective vaccine against the infection. Clinical cases are given only palliative treatment as specific anti-DENV immunotherapy is not available and it is urgently required. In this study, human single-chain variable fragment (HuScFv) antibodies that bound specifically to the conserved non-structural protein-1 (NS1) of DENV and interfered with the virus replication cycle were produced by using phage display technology. Recombinant NS1 (rNS1) of DENV serotype 2 (DENV2) was used as antigen in phage bio-panning to select phage clones that displayed HuScFv from antibody phage display library. HuScFv from two phagemid transformed E. coli clones, i.e., clones 11 and 13, bound to the rNS1 as well as native NS1 in both secreted and intracellular forms. Culture fluids of the HuScFv11/HuScFv13 exposed DENV2 infected cells had significant reduction of the infectious viral particles, implying that the antibody fragments affected the virus morphogenesis or release. HuScFv epitope mapping by phage mimotope searching revealed that HuScFv11 bound to amino acids 1-14 of NS1, while the HuScFv13 bound to conformational epitope at the C-terminal portion of the NS1. Although the functions of the epitopes and the molecular mechanism of the HuScFv11 and HuScFv13 require further investigations, these small antibodies have high potential for development as anti-DENV biomolecules. PMID- 24492301 TI - Combined glyco- and protein-Fc engineering simultaneously enhance cytotoxicity and half-life of a therapeutic antibody. AB - While glyco-engineered monoclonal antibodies (mAbs) with improved antibody dependent cell-mediated cytotoxicity (ADCC) are reaching the market, extensive efforts have also been made to improve their pharmacokinetic properties to generate biologically superior molecules. Most therapeutic mAbs are human or humanized IgG molecules whose half-life is dependent on the neonatal Fc receptor FcRn. FcRn reduces IgG catabolism by binding to the Fc domain of endocytosed IgG in acidic lysosomal compartments, allowing them to be recycled into the blood. Fc engineered mAbs with increased FcRn affinity resulted in longer in vivo half-life in animal models, but also in healthy humans. These Fc-engineered mAbs were obtained by alanine scanning, directed mutagenesis or in silico approach of the FcRn binding site. In our approach, we applied a random mutagenesis technology (MutaGenTM) to generate mutations evenly distributed over the whole Fc sequence of human IgG1. IgG variants with improved FcRn-binding were then isolated from these Fc-libraries using a pH-dependent phage display selection process. Two successive rounds of mutagenesis and selection were performed to identify several mutations that dramatically improve FcRn binding. Notably, many of these mutations were unpredictable by rational design as they were located distantly from the FcRn binding site, validating our random molecular approach. When produced on the EMABling((r)) platform allowing effector function increase, our IgG variants retained both higher ADCC and higher FcRn binding. Moreover, these IgG variants exhibited longer half-life in human FcRn transgenic mice. These results clearly demonstrate that glyco-engineering to improve cytotoxicity and protein-engineering to increase half-life can be combined to further optimize therapeutic mAbs. PMID- 24492302 TI - Evaluation of human pancreatic RNase as effector molecule in a therapeutic antibody platform. AB - Human antibody-ribonuclease (RNase) fusion proteins, referred to as immunoRNases, have been proposed as an alternative to heterologous immunotoxins, without their immunogenicity and unspecific toxicity issues. In this study, we investigated if human pancreatic RNase will be suitable as effector component in a therapeutic antibody development platform. We generated several fusion proteins consisting of tumor-specific human immunoglobulins (IgGs) and human pancreatic RNase. Transient mammalian cell production was efficient and IgG-RNases were purified to homogeneity. Antigen binding was comparable to the parental antibodies and RNase catalytic activity was retained even in the presence of 50-fold molar excess of human cytosolic RNase inhibitor (RI). Serum stability, cell binding and internalization of IgG-RNases were comparable to the parental IgGs. Despite these promising properties, none of the IgG-RNases revealed significant inhibition of tumor cell growth in vitro even when targeting different antigens putatively employing different endocytotic pathways. The introduction of different linkers containing endosomal protease cleavage sites into the IgG-RNase did not enhance cytotoxicity. Similarly, RI evasive human pancreatic RNase variants mediated only small inhibiting effects on tumor cell growth at high concentrations, potentially reflecting inefficient cytosolic translocation. Taken together, human pancreatic RNase and variants did not prove to be generally suitable as effector component for a therapeutic antibody drug development platform. PMID- 24492303 TI - Comparative reactivity of human IgE to cynomolgus monkey and human effector cells and effects on IgE effector cell potency. AB - BACKGROUND: Due to genetic similarities with humans, primates of the macaque genus such as the cynomolgus monkey are often chosen as models for toxicology studies of antibody therapies. IgE therapeutics in development depend upon engagement with the FcepsilonRI and FcepsilonRII receptors on immune effector cells for their function. Only limited knowledge of the primate IgE immune system is available to inform the choice of models for mechanistic and safety evaluations. METHODS: The recognition of human IgE by peripheral blood lymphocytes from cynomolgus monkey and man was compared. We used effector cells from each species in ex vivo affinity, dose-response, antibody-receptor dissociation and potency assays. RESULTS: We report cross-reactivity of human IgE Fc with cynomolgus monkey cells, and comparable binding kinetics to peripheral blood lymphocytes from both species. In competition and dissociation assays, however, human IgE dissociated faster from cynomolgus monkey compared with human effector cells. Differences in association and dissociation kinetics were reflected in effector cell potency assays of IgE-mediated target cell killing, with higher concentrations of human IgE needed to elicit effector response in the cynomolgus monkey system. Additionally, human IgE binding on immune effector cells yielded significantly different cytokine release profiles in each species. CONCLUSION: These data suggest that human IgE binds with different characteristics to human and cynomolgus monkey IgE effector cells. This is likely to affect the potency of IgE effector functions in these two species, and so has relevance for the selection of biologically-relevant model systems when designing pre-clinical toxicology and functional studies. PMID- 24492304 TI - Development of neutralizing scFv-Fc against botulinum neurotoxin A light chain from a macaque immune library. AB - Botulinum toxins (BoNTs) are among the most toxic substances on earth, with serotype A toxin being the most toxic substance known. They are responsible for human botulism, a disease characterized by flaccid muscle paralysis that occurs naturally through food poisoning or the colonization of the gastrointestinal tract by BoNT-producing clostridia. BoNT has been classified as a category A agent by the Centers for Disease Control, and it is one of six agents with the highest potential risk of use as bioweapons. Human or human-like neutralizing antibodies are thus required for the development of anti-botulinum toxin drugs to deal with this possibility. In this study, Macaca fascicularis was hyperimmunized with a recombinant light chain of BoNT/A. An immune phage display library was constructed and, after multistep panning, several scFv with nanomolar affinities that inhibited the endopeptidase activity of BoNT/A1 in vitro as scFv-Fc, with a molar ratio (ab binding site:toxin) of up to 1:1, were isolated. The neutralization of BoNT/A-induced paralysis by the SEM120-IID5, SEM120-IIIC1 and SEM120-IIIC4 antibodies was demonstrated in mouse phrenic nerve-hemidiaphragm preparations with the holotoxin. The neutralization observed is the strongest ever measured in the phrenic nerve-hemidiaphragm assay for BoNT/A1 for a monoclonal antibody. Several scFv-Fc inhibiting the endopeptidase activity of botulinum neurotoxin A were isolated. For SEM120-IID5, SEM120-IIIC1, and SEM120 IIIC4, inhibitory effects in vitro and protection against the toxin ex vivo were observed. The human-like nature of these antibodies makes them promising lead candidates for further development of immunotherapeutics for this disease. PMID- 24492305 TI - The effect of the neonatal Fc receptor on human IgG biodistribution in mice. AB - The neonatal Fc receptor (FcRn) plays a pivotal role in IgG homeostasis, i.e., it salvages IgG antibodies from lysosomal degradation following fluid-phase pinocytosis, thus preventing rapid systemic elimination of IgG. Recombinant therapeutic antibodies are typically composed of human or humanized sequences, and their biodistribution, or tissue distribution, is often studied in murine models, although, the effect of FcRn on tissue distribution of human IgG in rodents has not been investigated. In this report, an (125)I-labeled human IgG1 antibody was studied in both wild type C57BL/6 (WT) and FcRn knockout (KO) mice. Total radioactivity in both plasma and tissues (0-96hr post-dose) was measured by gamma-counting. Plasma exposure of human IgG1 were significantly lower in FcRn KO mice, which is consistent with the primary function of FcRn. Differences in biodistribution of human IgG to selected tissues were also observed. Among the tissue examined, the fat, skin and muscle showed a decrease in tissue-to-blood (T/B) exposure ratio of human IgG1 in FcRn KO mice comparing to the WT mice, while the liver, spleen, kidney, and lung showed an increase in the T/B exposure ratio in FcRn KO mice. A time-dependent change in the T/B ratios of human IgG1 was also observed for many tissues in FcRn KO mice. These results suggest that, in addition to its role in IgG elimination, FcRn may also play a role in antibody biodistribution. PMID- 24492306 TI - Multiplexed screening of natural humoral immunity identifies antibodies at fine specificity for complex and dynamic viral targets. AB - Viral entry targets with therapeutic neutralizing potential are subject to multiple escape mechanisms, including antigenic drift, immune dominance of functionally irrelevant epitopes, and subtle variations in host cell mechanisms. A surprising finding of recent years is that potent neutralizing antibodies to viral epitopes independent of strain exist, but are poorly represented across the diverse human population. Identifying these antibodies and understanding the biology mediating the specific immune response is thus difficult. An effective strategy for meeting this challenge is to incorporate multiplexed antigen screening into a high throughput survey of the memory B cell repertoire from immune individuals. We used this approach to discover suites of cross-clade antibodies directed to conformational epitopes in the stalk region of the influenza A hemagglutinin (HA) protein and to select high-affinity anti-peptide antibodies to the glycoprotein B (gB) of human cytomegalovirus. In each case, our screens revealed a restricted VH and VL germline usage, including published and previously unidentified gene families. The in vivo evolution of paratope specificity with optimal neutralizing activity was understandable after correlating biological activities with kinetic binding and epitope recognition. Iterative feedback between antigen probe design based on structure and function information with high throughput multiplexed screening demonstrated a generally applicable strategy for efficient identification of safe, native, finely tuned antibodies with the potential for high genetic barriers to viral escape. PMID- 24492307 TI - Lorvotuzumab mertansine, a CD56-targeting antibody-drug conjugate with potent antitumor activity against small cell lung cancer in human xenograft models. AB - Lorvotuzumab mertansine (LM) is an antibody-drug conjugate composed of a humanized anti-CD56 antibody, lorvotuzumab, linked via a cleavable disulfide linker to the tubulin-binding maytansinoid DM1. CD56 is expressed on most small cell lung cancers (SCLC), providing a promising therapeutic target for treatment of this aggressive cancer, which has a poor five-year survival rate of only 5 10%. We performed immunohistochemical staining on SCLC tumor microarrays, which confirmed that CD56 is expressed at high levels on most (~74%) SCLC tumors. Conjugation of lorvotuzumab with DM1 did not alter its specific binding to cells and LM demonstrated potent target-dependent cytotoxicity against CD56-positive SCLC cells in vitro. The anti-tumor activity of LM was evaluated against SCLC xenograft models in mice, both as monotherapy and in combination with platinum/etoposide and paclitaxel/carboplatin. Dose-dependent and antigen specific anti-tumor activity of LM monotherapy was demonstrated at doses as low as 3 mg/kg. LM was highly active in combination with standard-of-care platinum/etoposide therapies, even in relatively resistant xenograft models. LM demonstrated outstanding anti-tumor activity in combination with carboplatin/etoposide, with superior activity over chemotherapy alone when LM was used in combinations at significantly reduced doses (6-fold below the minimally efficacious dose for LM monotherapy). The combination of LM with carboplatin/paclitaxel was also highly active. This study provides the rationale for clinical evaluation of LM as a promising novel targeted therapy for SCLC, both as monotherapy and in combination with chemotherapy. PMID- 24492308 TI - 3D modeling and characterization of the human CD115 monoclonal antibody H27K15 epitope and design of a chimeric CD115 target. AB - The humanized monoclonal antibody H27K15 specifically targets human CD115, a type III tyrosine kinase receptor involved in multiple cancers and inflammatory diseases. Binding of H27K15 to hCD115 expressing cells inhibits the functional effect of colony-stimulating factor-1 (CSF-1), in a non-competitive manner. Both homology modeling and docking programs were used here to model the human CD115 extracellular domains, the H27K15 variable region and their interaction. The resulting predicted H27K15 epitope includes mainly the D1 domain in the N terminal extracellular region of CD115 and some residues of the D2 domain. Sequence alignment with the non-binding murine CD115, enzyme-linked immunosorbent assay, nuclear magnetic resonance spectroscopy and affinity measurements by quartz crystal microbalance revealed critical residues of this epitope that are essential for H27K15 binding. A combination of computational simulations and biochemical experiments led to the design of a chimeric CD115 carrying the human epitope of H27K15 in a murine CD115 backbone that is able to bind both H27K15 as well as the murine ligands CSF-1 and IL-34. These results provide new possibilities to minutely study the functional effects of H27K15 in a transgenic mouse that would express this chimeric molecule. PMID- 24492310 TI - A novel approach for simultaneous sensing of urea and glucose by SPR based optical fiber multianalyte sensor. AB - A novel design is presented for the sensing of urea and glucose simultaneously by surface plasmon resonance (SPR) based optical fiber multianalyte sensor using gel entrapment technique in a fluid for biomedical applications. Sensing surfaces are prepared by coating of different metals and high index dielectric over-layers (silver and silicon in channel 1 and copper and tin-oxide in channel 2) over two small and well separated unclad portions of an optical fiber. Enzymes urease and glucose oxidase are immobilized over respective surfaces using gel entrapment method for the sensing of urea and glucose, respectively. Wavelength interrogation technique is used for the calibration of the sensor. The concentration of urea and glucose are selected in the range 0-180 mM and 0-260 mg dl(-1), respectively, to mimic the physiological range of urea and glucose in human blood. Mixed solutions of urea and glucose with varying concentrations are prepared in buffer solution for the calibration of the sensor. The resonance wavelengths are determined corresponding to two channels responding independently to the interaction of analytes in solution on sensing channels. It is observed that the resonance wavelengths in the case of both the sensing channels decrease with the increasing concentrations of urea and glucose in solutions. The sensor gives 8.51 nm and 13.04 nm total shifts in resonance wavelength for 0 mM to 180 mM urea and 0 mg dl(-1) to 260 mg dl(-1) glucose concentrations in a sample, respectively. The advantages of the present sensor are cascaded design with multiple sensing channels on a single platform, inexpensive, simultaneous sensing of two parameters, possibility of online monitoring and remote sensing. PMID- 24492309 TI - HER2 monoclonal antibodies that do not interfere with receptor heterodimerization mediated signaling induce effective internalization and represent valuable components for rational antibody-drug conjugate design. AB - The human epidermal growth factor receptor (HER)2 provides an excellent target for selective delivery of cytotoxic drugs to tumor cells by antibody-drug conjugates (ADC) as has been clinically validated by ado-trastuzumab emtansine (Kadcyla(TM)). While selecting a suitable antibody for an ADC approach often takes specificity and efficient antibody-target complex internalization into account, the characteristics of the optimal antibody candidate remain poorly understood. We studied a large panel of human HER2 antibodies to identify the characteristics that make them most suitable for an ADC approach. As a model toxin, amenable to in vitro high-throughput screening, we employed Pseudomonas exotoxin A (ETA') fused to an anti-kappa light chain domain antibody. Cytotoxicity induced by HER2 antibodies, which were thus non-covalently linked to ETA', was assessed for high and low HER2 expressing tumor cell lines and correlated with internalization and downmodulation of HER2 antibody-target complexes. Our results demonstrate that HER2 antibodies that do not inhibit heterodimerization of HER2 with related ErbB receptors internalize more efficiently and show greater ETA'-mediated cytotoxicity than antibodies that do inhibit such heterodimerization. Moreover, stimulation with ErbB ligand significantly enhanced ADC-mediated tumor kill by antibodies that do not inhibit HER2 heterodimerization. This suggests that the formation of HER2/ErbB heterodimers enhances ADC internalization and subsequent killing of tumor cells. Our study indicates that selecting HER2 ADCs that allow piggybacking of HER2 onto other ErbB receptors provides an attractive strategy for increasing ADC delivery and tumor cell killing capacity to both high and low HER2 expressing tumor cells. PMID- 24492311 TI - Association between prehospital vitamin D status and hospital-acquired Clostridium difficile infections. AB - OBJECTIVE: To investigate whether preadmission 25-hydroxyvitamin D (25(OH)D) levels are associated with the risk of hospital-acquired Clostridium difficile infection (HACDI). MATERIALS AND METHODS: Our retrospective cohort study focused on 568 adult patients from 2 Boston teaching hospitals between August 1993 and November 2006. All patients had 25(OH)D levels measured before hospitalization and were at risk for HACDI (defined as the presence of C difficile toxin A or B in stool samples obtained >48 hours after hospitalization). We performed multivariable regression analyses to test the association of prehospital 25(OH)D levels with HACDI while adjusting for clinically relevant covariates. RESULTS: In these 568 patients, mean (SD) 25(OH)D level was 19 (12) ng/mL, and 11% of patients met criteria for incident HACDI. Following adjustment for age, sex, race (nonwhite vs white), patient type (medical vs surgical), and Deyo-Charlson index, patients with 25(OH)D levels <10 ng/mL had higher odds of HACDI (odds ratio [OR], 2.90; 95% confidence interval [CI], 1.01-8.34) compared with patients with 25(OH)D levels >=30 ng/mL. When patients with HACDI were analyzed relative to a larger patient cohort without HACDI (n = 5047), those with 25(OH)D levels <10 ng/mL (OR, 4.96; 95% CI, 1.84-13.38) and 10-19.9 ng/mL (OR, 3.36; 95% CI, 1.28 8.85) had higher adjusted odds of HACDI compared with patients with 25(OH)D levels >=30 ng/mL. CONCLUSIONS: In our cohort of adult patients, vitamin D status before hospital admission was inversely associated with the risk of developing HACDI. These data support the need for randomized, controlled trials to test the role of vitamin D supplementation to prevent HACDI. PMID- 24492312 TI - Whey Peptide-Based Formulas With omega-3 Fatty Acids Are Protective in Lipopolysaccharide-Mediated Sepsis. AB - BACKGROUND: Sepsis and septic shock syndrome are among the leading causes of death in critically ill patients. Lipopolysaccharide (LPS) released by bacteria within the colon may translocate across a compromised epithelium, leading to oxidative stress, inflammation, sepsis, and eventually death. METHODS: We examined the effects of a whey-based enteral formula high in cysteine (antioxidant precursor) and the addition of omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), against a mouse model of LPS-induced sepsis. Mice were fed either a whey-based diet with EPA-DHA (PAF), a whey-based diet without EPA-DHA (PSTD), or a casein-based control diet (CONT). RESULTS: Mice fed PAF or PSTD were protected against LPS-induced weight loss. Whey-based diets suppressed inflammatory cytokine release and oxidative stress damage. Furthermore, PAF and PSTD were able to inhibit autophagy, a mechanism in which the cell recycles damaged organelles. These anti-inflammatory and antioxidative effects of PSTD and PAF resulted in decreased liver inflammation and intestinal damage and promoted protective microbiota within the intestines. CONCLUSIONS: These data suggest a clinical role for whey peptide-based diets in promoting healing and recovery in critically ill patients. PMID- 24492313 TI - DUOX2 and DUOXA2 form the predominant enzyme system capable of producing the reactive oxygen species H2O2 in active ulcerative colitis and are modulated by 5 aminosalicylic acid. AB - BACKGROUND: NADPH oxidase-derived reactive oxygen species, such as H2O2, are part of the intestinal innate immune system but may drive carcinogenesis through DNA damage. We sought to identify the predominant enzyme system capable of producing H2O2 in active ulcerative colitis and assess whether it is affected by 5 aminosalicylic acid (5-ASA). METHODS: We studied human mucosal biopsies by expression arrays, quantitative real-time polymerase chain reaction for NADPH oxidase family members, in situ hybridization (DUOX2 and DUOXA2) and immunofluorescence for DUOX, 8-OHdG (DNA damage), and gammaH2AX (DNA damage response) and sought effects of 5-ASA on ex vivo cultured biopsies and cultured rectal cancer cells. RESULTS: DUOX2 with maturation partner DUOXA2 forms the predominant system for H2O2 production in human colon and is upregulated in active colitis. DUOX2 in situ is exclusively epithelial, varies between and within individual crypts, and increases near inflammation. 8-OHdG and gammaH2AX were observed in damaged crypt epithelium. 5-ASA upregulated DUOX2 and DUOXA2 levels in the setting of active versus quiescent disease and altered DUOX2 expression in cultured biopsies. Ingenuity pathway analysis confirmed that inflammation status and 5-ASA increase expression of DUOX2 and DUOXA2. An epithelial cell model confirmed that cultured cancer cells expressed DUOX protein and produced H2O2 in response to hypoxia and 5-ASA exposure. CONCLUSIONS: Both DUOX2 and DUOXA2 expression are involved specifically in inflammation and are regulated on a crypt-by-crypt basis in ulcerative colitis tissues. Synergy between inflammation, hypoxia, and 5-ASA to increase H2O2 production could explain how 5-ASA supports innate defense, although potentially increasing the burden of DNA damage. PMID- 24492314 TI - Primary ischial osteosarcoma occupying the pelvic cavity in a Japanese Black cow. AB - A 10-year-old Japanese Black cow presented with a swelling of the right femur, and a hard, large mass occupied the pelvic cavity. The mass strongly adhered to the visceral surface of the ischium and had posteriorly invaded among the right femoral muscles. Histologically, the mass was composed of neoplastic osteoblasts and exhibited osteoid and immature trabecular bone production. In the region where the mass adhered to the ischium, neoplastic cells were continuously proliferating into the medullary cavity. Tumor emboli were observed in the small vessels of the femoral muscles and lungs. Based on these findings, the mass was diagnosed as an osteosarcoma and considered to have arisen from the ischium. PMID- 24492315 TI - A feline case of hepatic neuroendocrine carcinoma with gastrin immunoreactivity. AB - A 5-year-old castrated Japanese domestic cat was presented with persistent vomiting. Ultrasound examinations revealed many masses only in the liver, and the fine needle aspiration was performed. Cytologically, polygonal or oval shaped tumor cells forming rosette and cord-like patterns were demonstrated, and then, the hepatic lesions were diagnosed as neuroendocrine carcinoma tentatively. The cat died one month after admission and was necropsied. Histopathologically, the tumor cells of the hepatic mass were arranged in typical rosette and cord-like structures. They were considerably uniform in size with hyperchromatic round nuclei and eosinophilic cytoplasm. Most of tumor cells were immunopositive for chromogranin A, and some were positive for gastrin. The findings indicate the possibility that the present case was a gastrin-producing neuroendocrine carcinoma. PMID- 24492317 TI - Factors affecting the implementation and use of electronic templates for histopathology cancer reporting. PMID- 24492316 TI - Faster speciation and reduced extinction in the tropics contribute to the Mammalian latitudinal diversity gradient. AB - The increase in species richness from the poles to the tropics, referred to as the latitudinal diversity gradient, is one of the most ubiquitous biodiversity patterns in the natural world. Although understanding how rates of speciation and extinction vary with latitude is central to explaining this pattern, such analyses have been impeded by the difficulty of estimating diversification rates associated with specific geographic locations. Here, we use a powerful phylogenetic approach and a nearly complete phylogeny of mammals to estimate speciation, extinction, and dispersal rates associated with the tropical and temperate biomes. Overall, speciation rates are higher, and extinction rates lower, in the tropics than in temperate regions. The diversity of the eight most species-rich mammalian orders (covering 92% of all mammals) peaks in the tropics, except that of the Lagomorpha (hares, rabbits, and pikas) reaching a maxima in northern-temperate regions. Latitudinal patterns in diversification rates are strikingly consistent with these diversity patterns, with peaks in species richness associated with low extinction rates (Primates and Lagomorpha), high speciation rates (Diprotodontia, Artiodactyla, and Soricomorpha), or both (Chiroptera and Rodentia). Rates of range expansion were typically higher from the tropics to the temperate regions than in the other direction, supporting the "out of the tropics" hypothesis whereby species originate in the tropics and disperse into higher latitudes. Overall, these results suggest that differences in diversification rates have played a major role in shaping the modern latitudinal diversity gradient in mammals, and illustrate the usefulness of recently developed phylogenetic approaches for understanding this famous yet mysterious pattern. PMID- 24492318 TI - Layered double hydroxide (LDH) derived catalysts for simultaneous catalytic removal of soot and NO(x). AB - Nitrogen oxides (NO(x)) and soot which come from vehicle engine exhausts cause serious environmental pollution and human health problems. Recently, the catalytic purification technology, particularly the simultaneous catalytic removal of soot and NO(x), has received more and more attention. For this technology, the key is to develop highly efficient and robust catalysts. Due to the unique chemical and structural properties of layered double hydroxides (LDHs), LDH-derived catalysts have shown great potential, and much effort has been devoted to this type of catalyst. In this manuscript, we reviewed the latest progress in the LDH derived catalysts by classifying the LDH precursors according to the number of metals into binary, ternary, and quaternary, and discussed their advantages and disadvantages in detail. We hope that this review paper could provide a clearer picture of this topic and theoretical support for its better development. PMID- 24492319 TI - DFT study on the reaction mechanism of the ring closing enyne metathesis (RCEYM) catalyzed by molybdenum alkylidene complexes. AB - The ring closing enyne metathesis reaction (RCEYM) catalyzed by molybdenum based monoalkoxy pyrrolyl Schrock type catalysts has been studied by means of DFT (B3LYP-D) calculations. The two potential active alkylidene species as well as the three proposed reaction mechanisms (ene-then-yne, endo-yne-then-ene and exo yne-then-ene) have been taken into account. Moreover, the influence on the exo- and endo- selectivity of the reactant substituents has also been explored. Results show that, in contrast to what is found for RCEYM processes catalyzed by Ru-based catalysts, the metallacyclobutene is a very short-living reaction intermediate that can be present in two isomeric forms (trigonal bipyramid (TBP) coordination around the metal center and square based pyramid (SPY) coordination). These two isomers are directly involved in the reaction mechanism, and the ring opening takes place from the SPY species. Moreover and regardless of the nature of the reacting metal-alkylidene, the yne-then-ene pathways (endo- or exo-) are computed to present significantly lower energy barriers than the ene then-yne pathway and thus the latter is computed not to take place. Finally, the exo-/endo- selectivity is predicted to highly depend on the sterics of the two carbon ends of the alkyne fragment. In this way, the carbon bearing the largest group prefers to interact with the carbon end of the metal-alkylidene. This places the bulkiest groups as far away as possible from the metal fragment and overall leads to a generally lower energy barrier for the metallacyclobutene formation, the key step in defining the exo-/endo- selectivity. PMID- 24492320 TI - Glomerular disease: increased complexity of the glomerular extracellular matrix. PMID- 24492322 TI - Pharmacology: NHERF3 regulates MRP4-mediated efflux of drug molecules in the kidneys. PMID- 24492321 TI - Noncardiovascular mortality in CKD: an epidemiological perspective. AB - Patients with chronic kidney disease (CKD) have increased risk of all-cause mortality; the elevated cardiovascular mortality in patients with end-stage renal disease is particularly well documented. Lately, the increased noncardiovascular mortality in these patients has gained particular attention. In this article, both cardiovascular and noncardiovascular mortality in CKD are discussed, with specific attention paid to studies that provide details of noncardiovascular causes of death. Examples are provided of several cardiovascular risk factors that also seem to be associated with noncardiovascular mortality, including levels of fetuin-A, troponin T, and C-reactive protein, as well as vitamin D deficiency and proteinuria. Potential pathophysiological mechanisms (such as inflammatory reactions and the uraemic milieu) that might explain the increased cardiovascular and noncardiovascular mortality in CKD are also discussed. Future research should not only focus on preventing cardiovascular mortality, but also on studying noncardiovascular mortality and the potential link between causal pathways of cardiovascular mortality and noncardiovascular mortality in CKD. PMID- 24492323 TI - B-cell receptor pathway inhibitors affect CD20 levels and impair antitumor activity of anti-CD20 monoclonal antibodies. PMID- 24492324 TI - Myelodysplastic/myeloproliferative neoplasms, unclassifiable (MDS/MPN, U): natural history and clinical outcome by treatment strategy. PMID- 24492325 TI - Effect of electrolyte constituents on the motion of ionic species and recombination kinetics in dye-sensitized solar cells. AB - The dynamic motion of ions in electrolyte solutions and its effect on recombination was investigated by the heterodyne transient grating method in addition to transient absorption and transient photocurrent methods in dye sensitized solar cells. Realignment of ionic species at the electrode/electrolyte interface was observed after the electron injection in TiO2 on the order of MUs. The process was affected by the total quantity of ionic species as well as cation species in the electrolyte. The recombination processes of the electrons were also affected by the constituents; the probability of the electron-electrolyte recombination decreased with decrease in I2 concentration; the dominant recombination process changed from the electron-electrolyte to the electron-dye recombination by decreasing I(-) concentration. It is concluded that sufficient I(-) is necessary for the suppression of the electron-dye recombination and that sufficient I2 is necessary for an efficient redox cycle, while low concentration of I3(-) ions at the electrolyte/TiO2 interface is preferable to suppress the electron-electrolyte recombination. The effect of the cation size in an electrolyte solution on the charge dynamics was also investigated, and it was revealed that the steric hindrance of cations changed the penetration of ionic species into the nanoporous dye/TiO2 electrode, causing a change in the electrostatic properties at the interface. The cation dependence indicated that the presence of large-sized cations suppressed the electron-electrolyte recombination by disturbing the approach of I3(-) paired with the cations. PMID- 24492327 TI - No monitor is an island: depth of anesthesia involves the whole patient. PMID- 24492326 TI - Preclinical toxicity screening of intrathecal oxytocin in rats and dogs. AB - BACKGROUND: Anatomic, physiologic, and behavioral studies in animals suggest that spinally released oxytocin should produce analgesia in humans and may also protect from chronic pain after injury. In this article, the authors report preclinical toxicity screening of oxytocin for intrathecal delivery. METHODS: Intrathecal oxytocin, 11 MUg (6 U) or vehicle, was injected intrathecally in 24 rats, followed by frequent behavioral assessment and histologic examination of spinal contents 2 or 14 days after injection. In three dogs, a range of intrathecal oxytocin doses (18 to 550 MUg in 0.5 ml) was injected followed by physiologic, biochemical, and behavioral assessments. Ten dogs were then randomized to receive five daily injections of intrathecal oxytocin, 550 MUg in 0.5 ml, or vehicle with similar assessments and, necropsy and histologic analysis were conducted 2 days later. RESULTS: In rats, intrathecal oxytocin resulted in transient scratching and itching behaviors, without other differences from vehicle. There was no behavioral, gross anatomic, or histologic evidence of neurotoxicity. Dose ranging in dogs suggested mild effects on motor tone, blood pressure, and heart rate at the 550 MUg dose. Repeated boluses in dogs did not produce behavioral, biochemical, neurological, gross anatomic, or histologic evidence of neurotoxicity. CONCLUSIONS: Substances, including natural neurotransmitters, may be toxic when administered in pharmacologic doses in the spinal cord. This preclinical toxicity screen in two species suggests that bolus injections of oxytocin in concentrations up to 1,100 MUg/ml are unlikely to cause neurotoxicity. The authors also support cautious clinical application of intrathecal oxytocin under regulatory supervision. PMID- 24492328 TI - Designing self-organized nanopatterns on Si by ion irradiation and metal co deposition. AB - Dot and ripple nanopatterns on Si surfaces with defined symmetry and characteristic dot spacings of 50-70 nm were created by 1 keV Ar ion irradiation at normal incidence and simultaneous co-deposition of Fe atoms at grazing incidence. Fe was continuously supplied from different sputter targets surrounding the Si substrate, leading to a steady-state Fe content in the near surface region of the substrates. The pattern formation is self-organized, most probably caused by ion-induced phase separation. Patterns were analyzed with atomic force microscopy and the Fe content in the irradiated layer was measured with Rutherford backscattering. The symmetries of the produced patterns are isotropic, four-fold symmetric, three-fold symmetric and various types of two fold symmetric patterns, depending on the geometrical arrangement of the sputter targets. Pattern formation was studied for a steady-state coverage of Fe between 0.5 and 3.3 * 10(15) Fe cm(-2). The threshold coverage for the onset of pattern formation is about 0.5-1 * 10(15) Fe cm(-2). The coherence length of the patterns is comparable to the average dot spacing. Nevertheless, the autocorrelation analysis reveals a residual long-range periodicity of some patterns. The dot spacing can be adjusted between about 20 nm and several hundred nm depending on the ion species and ion energy. PMID- 24492329 TI - Giant up-conversion efficiency of InGaAs quantum dots in a planar microcavity. AB - Self-assembled InGaAs quantum dots (QDs) were fabricated inside a planar microcavity with two vertical cavity modes. This allowed us to excite the QDs coupled to one of the vertical cavity modes through two propagating cavity modes to study their down- and up-converted photoluminescence (PL). The up-converted PL increased continuously with the increasing temperature, reaching an intensity level comparable to that of the down-converted PL at ~120 K. This giant efficiency in the up-converted PL of InGaAs QDs was enhanced by about 2 orders of magnitude with respect to a similar structure without cavity. We tentatively explain the enhanced up-converted signal as a direct consequence of the modified spontaneous emission properties of the QDs in the microcavity, combined with the phonon absorption and emission effects. PMID- 24492330 TI - Identification and characterization of a Trypanosoma congolense 46 kDa protein as a candidate serodiagnostic antigen. AB - Trypanosoma congolense is a major livestock pathogen in Africa, causing large economic losses with serious effects on animal health. Reliable serodiagnostic tests are therefore urgently needed to control T. congolense infection. In this study, we have identified one T. congolense protein as a new candidate serodiagnostic antigen. The 46.4 kDa protein (TcP46, Gene ID: TcIL3000.0.25950) is expressed 5.36 times higher in metacyclic forms than epimastigote forms. The complete nucleotide sequences of TcP46 contained an open reading frame of 1,218 bp. Southern blot analysis indicated that at least two copies of the TcP46 gene were tandemly-arranged in the T. congolense genome. The recombinant TcP46 (rTcP46) was expressed in Escherichia coli as a glutathione S-transferase (GST) fusion protein. Western blot analysis and confocal laser scanning microscopy revealed that the native TcP46 protein is expressed in the cytoplasm during all life-cycle stages of the parasite. Moreover, an enzyme-linked immunosorbent assay (ELISA) based on rTcP46 detected the specific antibodies as early as 8 days post infection from mice experimentally infected with T. congolense. No cross reactivity was observed in the rTcP46-based ELISA against serum samples from cattle experimentally infected with Babesia bigemina, B. bovis and Anaplasma marginale. These results suggest that rTcP46 could be used as a serodiagnostic antigen for T. congolense infection. PMID- 24492331 TI - Unusual Forms of Adrenal and Extra-Adrenal Myelolipomas. AB - Myelolipomas are rare benign tumors of poorly understood tumorigenesis composed of mature hematopoietic tissue and fat. They mostly occur in the adrenal glands, but extra-adrenal myelolipomas have been reported in other locations such as the presacral region or retroperitoneum. It is not unusual that they are incidental findings revealed in the study of different diseases. We report 3 unusual examples of myelolipomas. The first is a multiple, unusually large, extra-adrenal myelolipoma, presented as an autopsy finding in an individual who had died suddenly from a central nervous system hemorrhage. The remaining 2 were incidental findings in patients studied for different reasons. Both were located within another neoplasm, namely an adrenal adenoma and a liver focal nodular hyperplasia. Moreover, the first showed infiltration by a non-Hodgkin lymphoma. PMID- 24492332 TI - Utility of Ki-67, CD10, CD34, p53, CD117, and mast cell content in the differential diagnosis of cellular fibroadenomas and in the classification of phyllodes tumors of the breast. AB - Adequate management of phyllodes tumors of the breast (PTB) remains a challenge because of the difficulty in correctly establishing preoperative diagnosis. The aim of this study was to evaluate the usefulness of Ki-67, CD10, CD34, p53, CD117, and of the number of mast cells in the differential diagnosis of benign PTB and cellular fibroadenomas (CFs) as well as in the grading of PTB. Fifty-one primary PTB and 14 CFs were examined by immunohistochemistry.When evaluating CD117 expression, higher epithelial expression was present in CF as well as an increased number of mast cells in benign PTB. Stromal expression of Ki-67, CD10, CD34, and p53 were relevant to PTB grading, of which the first 3 showed significance in the distinction of benign and borderline PTB, as well as between benign and malignant PTB. P53 was relevant only for the discrimination between benign and malign PTB. None of the markers showed significance in distinguishing between borderline and malign PTB. PMID- 24492333 TI - Revisiting the evolutionary history and roles of protein phosphatases with Kelch like domains in plants. AB - Protein phosphatases with Kelch-like domains (PPKL) are members of the phosphoprotein phosphatases family present only in plants and alveolates. PPKL have been described as positive effectors of brassinosteroid (BR) signaling in plants. Most of the evidence supporting this role has been gathered using one of the four homologs in Arabidopsis (Arabidopsis thaliana), brassinosteroid insensitive1 suppressor (BSU1). We reappraised the roles of the other three members of the family, BSL1, BSL2, and BSL3, through phylogenetic, functional, and genetic analyses. We show that BSL1 and BSL2/BSL3 belong to two ancient evolutionary clades that have been highly conserved in land plants. In contrast, BSU1-type genes are exclusively found in the Brassicaceae and display a remarkable sequence divergence, even among closely related species. Simultaneous loss of function of the close paralogs BSL2 and BSL3 brings about a peculiar array of phenotypic alterations, but with marginal effects on BR signaling; loss of function of BSL1 is, in turn, phenotypically silent. Still, the products of these three genes account for the bulk of PPKL-related activity in Arabidopsis and together have an essential role in the early stages of development that BSU1 is unable to supplement. Our results underline the functional relevance of BSL phosphatases in plants and suggest that BSL2/BSL3 and BSU1 may have contrasting effects on BR signaling. Given that BSU1-type genes have likely undergone a functional shift and are phylogenetically restricted, we caution that inferences based on these genes to the whole family or to other species may be misleading. PMID- 24492334 TI - Vegetative and sperm cell-specific aquaporins of Arabidopsis highlight the vacuolar equipment of pollen and contribute to plant reproduction. AB - The water and nutrient status of pollen is crucial to plant reproduction. Pollen grains of Arabidopsis (Arabidopsis thaliana) contain a large vegetative cell and two smaller sperm cells. Pollen grains express AtTIP1;3 and AtTIP5;1, two members of the Tonoplast Intrinsic Protein subfamily of aquaporins. To address the spatial and temporal expression pattern of the two homologs, C-terminal fusions of AtTIP1;3 and AtTIP5;1 with green fluorescent protein and mCherry, respectively, were expressed in transgenic Arabidopsis under the control of their native promoter. Confocal laser scanning microscopy revealed that AtTIP1;3 and AtTIP5;1 are specific for the vacuoles of the vegetative and sperm cells, respectively. The tonoplast localization of AtTIP5;1 was established by reference to fluorescent protein markers for the mitochondria and vacuoles of sperm and vegetative cells and is at variance with the claim that AtTIP5;1 is localized in vegetative cell mitochondria. AtTIP1;3-green fluorescent protein and AtTIP5;1 mCherry showed concomitant expression, from first pollen mitosis up to pollen tube penetration in the ovule, thereby revealing the dynamics of vacuole morphology in maturating and germinating pollen. Transfer DNA insertion mutants for either AtTIP1;3 or AtTIP5;1 showed no apparent growth phenotype and had no significant defect in male transmission of the mutated alleles. By contrast, a double knockout displayed an abnormal rate of barren siliques, this phenotype being more pronounced under limited water or nutrient supply. The overall data indicate that vacuoles of vegetative and sperm cells functionally interact and contribute to male fertility in adverse environmental conditions. PMID- 24492335 TI - Using a viral vector to reveal the role of microRNA159 in disease symptom induction by a severe strain of Cucumber mosaic virus. AB - In transgenic Arabidopsis (Arabidopsis thaliana), expression of the Cucumber mosaic virus (CMV) 2b silencing suppressor protein from the severe subgroup IA strain Fny disrupted microRNA (miRNA)-regulated development but orthologs from mild subgroup II strains (Q and LS) did not, explaining strain-specific differences in symptom severity. However, it is unknown which miRNAs affected by Fny2b critically affect viral symptoms. Observations that Fny2b-transgenic plants phenocopy microRNA159ab (mir159ab) mutant plants and that Fny2b altered miR159ab regulated transcript levels suggested a role for miR159ab in elicitation of severe symptoms by Fny-CMV. Using restoration of the normal phenotype in transgenic plants expressing an artificial miRNA as a proof of concept, we developed a LS-CMV-based vector to express sequences mimicking miRNA targets. Expressing a miR159 target mimic sequence using LS-CMV depleted miR159 and induced symptoms resembling those of Fny-CMV. Suppression of Fny-CMV-induced symptoms in plants harboring mutant alleles for the miR159ab targets MYB domain protein33 (MYB33) and MYB65 confirmed the importance of this miRNA in pathogenesis. This study demonstrates the utility of a viral vector to express miRNA target mimics to facilitate functional studies of miRNAs in plants. PMID- 24492336 TI - Phytochrome B promotes branching in Arabidopsis by suppressing auxin signaling. AB - Many plants respond to competition signals generated by neighbors by evoking the shade avoidance syndrome, including increased main stem elongation and reduced branching. Vegetation-induced reduction in the red light:far-red light ratio provides a competition signal sensed by phytochromes. Plants deficient in phytochrome B (phyB) exhibit a constitutive shade avoidance syndrome including reduced branching. Because auxin in the polar auxin transport stream (PATS) inhibits axillary bud outgrowth, its role in regulating the phyB branching phenotype was tested. Removing the main shoot PATS auxin source by decapitation or chemically inhibiting the PATS strongly stimulated branching in Arabidopsis (Arabidopsis thaliana) deficient in phyB, but had a modest effect in the wild type. Whereas indole-3-acetic acid (IAA) levels were elevated in young phyB seedlings, there was less IAA in mature stems compared with the wild type. A split plate assay of bud outgrowth kinetics indicated that low auxin levels inhibited phyB buds more than the wild type. Because the auxin response could be a result of either the auxin signaling status or the bud's ability to export auxin into the main shoot PATS, both parameters were assessed. Main shoots of phyB had less absolute auxin transport capacity compared with the wild type, but equal or greater capacity when based on the relative amounts of native IAA in the stems. Thus, auxin transport capacity was unlikely to restrict branching. Both shoots of young phyB seedlings and mature stem segments showed elevated expression of auxin-responsive genes and expression was further increased by auxin treatment, suggesting that phyB suppresses auxin signaling to promote branching. PMID- 24492337 TI - Central venous access by trainees: a systematic review and meta-analysis of the use of simulation to improve success rate on patients. AB - INTRODUCTION: Simulation training for invasive procedures may improve patient safety by enabling efficient training. This study is a meta-analysis with rigorous inclusion and exclusion criteria designed to assess the real patient procedural success of simulation training for central venous access. METHODS: Published randomized controlled trials and prospective 2-group cohort studies that used simulation for the training of procedures involving central venous access were identified. The quality of each study was assessed. The primary outcome was the proportion of trainees who demonstrated the ability to successfully complete the procedure. Secondary outcomes included the mean number of attempts to procedural success and periprocedural adverse events. Proportions were compared between groups using risk ratios (RRs), whereas continuous variables were compared using weighted mean differences. Random-effects analysis was used to determine pooled effect sizes. RESULTS: We identified 550 studies, of which 5 (3 randomized controlled trials, 2 prospective 2-group cohort studies) studies of central venous catheter (CVC) insertion were included in the meta analysis, composed of 407 medical trainees. The simulation group had a significantly larger proportion of trainees who successfully placed CVCs (RR, 1.09; 95% confidence interval [CI], 1.03-1.16, P<0.01). In addition, the simulation group had significantly fewer mean attempts to CVC insertion (weighted mean difference, -1.42; 95% CI, -2.34 to -0.49, P<0.01). There was no significant difference in the rate of adverse events between the groups (RR, 0.50; 95% CI, 0.19-1.29; P=0.15). CONCLUSIONS: Training programs should consider adopting simulation training for CVC insertion to improve the real patient procedural success of trainees. PMID- 24492338 TI - Standardized patient-based simulation training as a tool to improve the management of chronic disease. AB - INTRODUCTION: Patient education is a critical factor in the treatment of chronic disease because it reduces gaps in health care and disease management. We implemented different methods of physician training for patient education of asthma and compared the effects on patients' health. METHOD: Four interventions were administered to groups of primary care physicians in one health care maintenance organization. All physicians received a list of their patients who were classified with uncontrolled asthma. Additional educational methods were implemented as follows: no additional intervention (group 1); lectures on patient education (group 2); standardized patient-based simulation training (group 3); and lectures and standardized patient-based simulations (group 4). We compared among the intervention groups and to a control group changes in rates of patients with uncontrolled asthma at 1 and 2 years after the intervention. RESULTS: During 1 year of follow-up, rates of uncontrolled asthma decreased from 7.2% to 6.2% (by 15%), from 7.5% to 6.5% (by 13%), from 6.4% to 5.1% (by 19%), and from 6.3% to 4.6% (by 27%) in intervention groups 1 to 4, respectively (P<0.01). Rates decreased by approximately 7% more in all intervention groups at 2 years of follow-up. No decrease in rates was observed in the control group. CONCLUSIONS: An intervention for primary care physicians on educating patients with asthma to manage their disease resulted in improved patient health. The most effective intervention was the combination of lectures and standardized patient-based simulation. PMID- 24492339 TI - Augmenting health care failure modes and effects analysis with simulation. AB - This study explores whether simulation plays a role in health care failure mode and effects analysis (HFMEA); it does this by evaluating whether additional data are found when a traditional HFMEA is augmented with simulation. Two multidisciplinary teams identified vulnerabilities in a process by brainstorming, followed by simulation. Two means of adding simulation were investigated as follows: just simulating the process and interrupting the simulation between substeps of the process. By adding simulation to a traditional HFMEA, both multidisciplinary teams identified additional data that were relevant for deeper analysis. The study indicates that simulation has a role in HFMEA. Both ways of using simulation seemed feasible, and our results are not conclusive in selecting one over the other. PMID- 24492340 TI - In vitro assessment of the effects of vedolizumab binding on peripheral blood lymphocytes. AB - Vedolizumab (VDZ) is a humanized monoclonal antibody in development for the treatment of inflammatory bowel disease. VDZ binds to the alpha4beta7 integrin complex and inhibits its binding to mucosal addressin cell adhesion molecule-1 (MAdCAM-1), thus preventing lymphocyte extravasation to gut mucosal tissues. To understand whether VDZ has additional effects that may affect its overall safety as a therapeutic molecule, we examined other potential actions of VDZ. In vitro assays with human peripheral blood lymphocytes demonstrated that VDZ fails to elicit cytotoxicity, lymphocyte activation, and cytokine production from memory T lymphocytes and does not interfere with the suppressive ability of regulatory T cells. Furthermore, we demonstrated that VDZ induces internalization of alpha4beta7 and that the integrin is rapidly re-expressed and fully functional after VDZ withdrawal. These studies provide insight into the mechanisms underlying the observed safety profile of VDZ in clinical trials. PMID- 24492341 TI - The effect of pH dependence of antibody-antigen interactions on subcellular trafficking dynamics. AB - A drawback of targeting soluble antigens such as cytokines or toxins with long lived antibodies is that such antibodies can prolong the half-life of the target antigen by a "buffering" effect. This has motivated the design of antibodies that bind to target with higher affinity at near neutral pH relative to acidic endosomal pH (~pH 6.0). Such antibodies are expected to release antigen within endosomes following uptake into cells, whereas antibody will be recycled and exocytosed in FcRn-expressing cells. To understand how the pH dependence of antibody-antigen interactions affects intracellular trafficking, we generated three antibodies that bind IL-6 with different pH dependencies in the range pH 6.0-7.4. The behavior of antigen in the presence of these antibodies has been characterized using a combination of fixed and live cell fluorescence microscopy. As the affinity of the antibody:IL-6 interaction at pH 6.0 decreases, an increasing amount of antigen dissociates from FcRn-bound antibody in early and late endosomes, and then enters lysosomes. Segregation of antibody and FcRn from endosomes in tubulovesicular transport carriers (TCs) into the recycling pathway can also be observed in live cells, and the extent of IL-6 association with TCs correlates with increasing affinity of the antibody:IL-6 interaction at acidic pH. These analyses result in an understanding, in spatiotemporal terms, of the effect of pH dependence of antibody-antigen interactions on subcellular trafficking and inform the design of antibodies with optimized binding properties for antigen elimination. PMID- 24492343 TI - Effects of altered FcgammaR binding on antibody pharmacokinetics in cynomolgus monkeys. AB - Antibody interactions with Fcgamma receptors (FcgammaRs), like FcgammaRIIIA, play a critical role in mediating antibody effector functions and thereby contribute significantly to the biologic and therapeutic activity of antibodies. Over the past decade, considerable work has been directed towards production of antibodies with altered binding affinity to FcgammaRs and evaluation of how the alterations modulate their therapeutic activity. This has been achieved by altering glycosylation status at N297 or by engineering modifications in the crystallizable fragment (Fc) region. While the effects of these modifications on biologic activity and efficacy have been examined, few studies have been conducted to understand their effect on antibody pharmacokinetics (PK). We present here a retrospective analysis in which we characterize the PK of three antibody variants with decreased FcgammaR binding affinity caused by amino acid substitutions in the Fc region (N297A, N297G, and L234A/L235A) and three antibody variants with increased FcgammaRIIIA binding affinity caused by afucosylation at N297, and compare their PK to corresponding wild type antibody PK in cynomolgus monkeys. For all antibodies, PK was examined at a dose that was known to be in the linear range. Since production of the N297A and N297G variants in Chinese hamster ovary cells results in aglycosylated antibodies that do not bind to FcgammaRs, we also examined the effect of expression of an aglycosylated antibody, without sequence change(s), in E. coli. All the variants demonstrated similar PK compared with that of the wild type antibodies, suggesting that, for the six antibodies presented here, altered FcgammaR binding affinity does not affect PK. PMID- 24492342 TI - NFkappaB induces overexpression of bovine FcRn: a novel mechanism that further contributes to the enhanced immune response in genetically modified animals carrying extra copies of FcRn. AB - Among the many functions of the neonatal Fc receptor (FcRn) for IgG, it binds to IgG-opsonized antigen complexes and propagates their traffic into lysosomes where antigen processing occurs. We previously reported that transgenic (Tg) mice and rabbits that carry multiple copies and overexpress FcRn have augmented humoral immune responses. Nuclear factor-kappa B (NFkappaB) is a critical molecule in the signaling cascade in the immune response. NFkappaB induces human FcRn expression and our previous in silico analysis suggested NFkappaB binding sites in the promoter region of the bovine (b) FcRn alpha-chain gene (FCGRT). Here, we report the identification of three NFkappaB transcription binding sites in the promoter region of this gene using luciferase reporter gene technology, electromobility shift assay and supershift analysis. Stimulation of primary bovine endothelial cells with the Toll-like receptor-4 ligand lipopolysaccharide (LPS), which mediates its effect via NFkappaB, resulted in rapid upregulation of the bFcRn expression and a control gene, bovine E-selectin. This rapid bFcRn gene induction was also observed in the spleen of bFcRn Tg mice treated with intraperitoneally injected LPS, analyzed by northern blot analysis. Finally, NFkappaB-mediated bFcRn upregulation was confirmed at the protein level in macrophages isolated from the bFcRn Tg mice using flow cytometry with a newly developed FcRn specific monoclonal antibody that does not cross-react with the mouse FcRn. We conclude that NFkappaB regulates bFcRn expression and thus optimizes its functions, e.g., in the professional antigen presenting cells, and contributes to the much augmented humoral immune response in the bFcRn Tg mice. PMID- 24492344 TI - Consequences of glycan truncation on Fc structural integrity. AB - Effective characterization of protein-based therapeutic candidates such as monoclonal antibodies (mAbs) is important to facilitate their successful progression from early discovery and development stages to marketing approval. One challenge relevant to biopharmaceutical development is, understanding how the stability of a protein is affected by the presence of an attached oligosaccharide, termed a glycan. To explore the utility of molecular dynamics simulations as a complementary technique to currently available experimental methods, the Fc fragment was employed as a model system to improve our understanding of protein stabilization by glycan attachment. Long molecular dynamics simulations were performed on three Fc glycoform variants modeled using the crystal structure of a human IgG1 mAb. Two of these three glycoform variants have their glycan carbohydrates partially or completely removed. Structural differences among the glycoform variants during simulations suggest that glycan truncation and/or removal can cause quaternary structural deformation of the Fc as a result of the loss or disruption of a significant number of inter-glycan contacts that are not formed in the human IgG1 crystal structure, but do form during simulations described here. Glycan truncation/removal can also increase the tertiary structural deformation of CH2 domains, demonstrating the importance of specific carbohydrates toward stabilizing individual CH2 domains. At elevated temperatures, glycan truncation can also differentially affect structural deformation in locations (Helix-1 and Helix-2) that are far from the oligosaccharide attachment point. Deformation of these helices, which form part of the FcRn, could affect binding if these regions are unable to refold after temperature normalization. During elevated temperature simulations of the deglycosylated variant, CH2 domains collapsed onto CH3 domains. Observations from these glycan truncation/removal simulations have improved our understanding on how glycan composition can affect mAb stability. PMID- 24492347 TI - Aqueous photochemical reactions of chloride, bromide, and iodide ions in a diode array spectrophotometer. Autoinhibition in the photolysis of iodide ions. AB - The aqueous photoreactions of three halide ions (chloride, bromide and iodide) were studied using a diode array spectrophotometer to drive and detect the process at the same time. The concentration and pH dependences of the halogen formation rates were studied in detail. The experimental data were interpreted by improving earlier models where the cage complex of a halogen atom and an electron has a central role. The triiodide ion was shown to exert a strong inhibiting effect on the reaction sequence leading to its own formation. An assumed chemical reaction between the triiodide ion and the cage complex interpreted the strong autoinhibition effect. It is shown that there is a real danger of unwanted interference from the photoreactions of halide ions when halide salts are used as supporting electrolytes in spectrophotometric experiments using a relatively high intensity UV light source. PMID- 24492345 TI - Effect of a tail piece cysteine deletion on biochemical and functional properties of an epidermal growth factor receptor-directed IgA2m(1) antibody. AB - Antibodies of human IgA isotype are critical components of the mucosal immune system, but little is known about their immunotherapeutic potential. Compared with IgG antibodies, IgA molecules carry a C-terminal tail piece extension of 18 amino acids with a free cysteine at position 471. This cysteine is required for the formation of dimeric IgA antibodies, but may impair molecular characteristics of monomeric IgA antibodies as therapeutic reagents. Thus, we generated and characterized a d471-mutated antibody against the epidermal growth factor receptor (EGFR) and compared it to its respective IgA2m(1) wild type antibody. Both wild type and mutated IgA antibodies demonstrated similar EGFR binding and were similarly efficient in inhibiting EGF binding and in blocking EGF-mediated cell proliferation. Recruitment of Fc-mediated effector functions like antibody dependent cell-mediated cytotoxicity by monocytes, macrophages or PMN was similar, but the d471-mutated IgA exhibited different biochemical properties compared with wild type antibody. As expected, mutated IgA did not form stable dimers in the presence of human joining (J)-chain, but we also observed reduced levels of dimeric aggregates in the absence of J-chain. Furthermore, glycoprofiling revealed different glycosylation patterns for both antibodies, including considerably less mannosylation of d471-mutated antibodies. Overall, our results demonstrate that the deletion of the C-terminal cysteine of IgA2 did not affect the investigated effector functions compared with wild type antibody, but it improved biochemical properties of an IgA2m(1) antibody against EGFR, and may thereby assist in exploring the immunotherapeutic potential of recombinant IgA antibodies. PMID- 24492346 TI - A bispecific antibody against two different epitopes on hepatitis B surface antigen has potent hepatitis B virus neutralizing activity. AB - Treatment of chronic hepatitis B virus (HBV) infection with interferon and viral reverse transcriptase inhibitor regimens results in poor viral clearance, loss of response, and emergence of drug-resistant mutant virus strains. These problems continue to drive the development of new therapeutic approaches to combat HBV. Here, we engineered a bispecific antibody using two monoclonal antibodies cloned from hepatitis B surface antigen (HBsAg)-specific memory B cells from recombinant HBsAg-vaccinated healthy volunteers. Next, we evaluated its efficacy in neutralizing HBV in HepaRG cells. This bispecific antibody, denoted as C4D2-BsAb, had superior HBV-neutralizing activity compared with the combination of both parental monoclonal antibodies, possibly through steric hindrance or induction of HBsAg conformational changes. Moreover, C4D2-BsAb has superior endocytotic characteristics into hepatocytes, which inhibits the secretion of HBsAg. These results suggest that the anti-HBsAg bispecific antibody may be an effective treatment method against HBV infection. PMID- 24492348 TI - Developing a sustainable nutrition research agenda in sub-Saharan Africa- findings from the SUNRAY project. PMID- 24492350 TI - The effect of FTO rs9939609 on major depression differs across MDD subtypes. PMID- 24492349 TI - APOE2 enhances neuroprotection against Alzheimer's disease through multiple molecular mechanisms. AB - The common APOE2 gene variant is neuroprotective against Alzheimer's disease (AD) and reduces risk by nearly 50%. However, the mechanisms by which APOE2 confers neuroprotection are largely unknown. Here we showed that ApoE protein abundance in human postmortem cortex follows an isoform-dependent pattern (E2>E3>E4). We also identified a unique downstream transcriptional profile determined by microarray and characterized by downregulation of long-term potentiation (LTP) related transcripts and upregulation of extracellular matrix (ECM)/integrin related transcripts in E2 cases and corroborated this finding at the protein level by demonstrating increases in ECM collagens and laminins. In vivo studies of healthy older individuals demonstrated a unique and advantageous biomarker signature in E2 carriers. APOE2 also reduced the risk of mild cognitive impairment to AD conversion by half. Our findings suggest that ApoE2 protein abundance, coupled with its inability to bind to LDLRs, may act to increase amyloid-beta (Ab) clearance. In addition, increased ECM and reduced LTP-related expression results in diminished activity-dependent Ab secretion and/or excitotoxicity, and thus also promotes neuroprotection. PMID- 24492351 TI - Neurodegenerative disease: Synaptic scaffolding protein neuroligin 1 links amyloid deposition, neuroinflammation and impaired memory. PMID- 24492352 TI - Sensory systems: Promising results in a gene therapy trial for retinal disease. PMID- 24492353 TI - Increased risk of myocardial infarction with dabigatran: fact or fiction? AB - Dabigatran is a direct, competitive inhibitor of thrombin recently approved for the prophylaxis of stroke and systemic embolism in patients with nonvalvular atrial fibrillation. In some of the clinical trials evaluating the efficacy and safety of dabigatran in different clinical settings [i.e., prevention of venous thromboembolism (VTE) after orthopedic surgery, secondary prevention of VTE, and acute coronary syndromes (ACS)], a trend toward an increase in acute coronary events among patients receiving dabigatran has been reported, thus raising concerns of a possible relationship between dabigatran and myocardial infarction, especially in high-risk patients. However, as shown in our article, current evidence is inconclusive on this topic; more data are needed to detail this hypothetical association, and other considerations, such as the well-known protective effect of warfarin against ACS, should be taken into account as a possible explanation. PMID- 24492354 TI - Time course changes of cystatin C and inflammatory and biochemical markers in non ST-elevation acute coronary syndromes. AB - BACKGROUND: Serum cystatin C (Cys-C), a good marker of renal function, predicts prognosis in non-ST-elevation acute coronary syndromes (NSTE-ACS). However, no data are available on the time course of Cys-C values after discharge. In this study, Cys-C was measured during admission (ACS sample) and 6 weeks after discharge, and was correlated with troponin (c-TNT), high-sensitivity C-reactive protein (hsCRP), interleukin 6 (IL-6) and the N-terminal portion of the pro-brain natriuretic peptide (proBNP) peptide (NT-proBNP) in a highly selected homogeneous group of NSTE-ACS patients. METHODS: In this prospective, multicentre study, patients with a first NSTE-ACS, single-vessel disease and successful percutaneous coronary interventions (PCIs) had their sera collected, aliquoted and stored at the enrolling site and then shipped for analysis to the clinical chemistry core laboratory. RESULTS: Cys-C values slightly, but significantly, increased from the ACS samples to the 6-week samples. In contrast, hsCRP, NT-proBNP and IL-6 values significantly decreased from the ACS to the 6-week sample. Patients with elevated c-TNT levels had higher hsCRP, NT-proBNP and IL-6 values than patients with normal c-TNT levels in the ACS sample, whereas Cys-C levels were similar in patients with and without elevated c-TNT. Cys-C was highly correlated with estimated glomerular filtration rate in both the ACS and 6-week samples. CONCLUSIONS: In contrast to inflammatory and biochemical stress markers, Cys-C is not affected by the occurrence of myocardial necrosis or by acute left ventricular impairment, being a reliable marker of renal function during NSTE ACS. PMID- 24492355 TI - Pericarditis with troponin elevation: is it true pericarditis and a reason for concern? PMID- 24492356 TI - Blunted inflammatory response in STEMI patients timely reperfused. AB - BACKGROUND: Acute coronary syndrome is characterized by an acute inflammatory systemic response. We investigated whether timely reperfusion could reduce the inflammatory response in patients with ST-elevation acute myocardial infarction (STEMI). METHODS: Forty-seven consecutive patients with STEMI eligible for fibrinolysis and admitted to a coronary care unit were enrolled in the study and reperfused with tenecteplase; 33 patients admitted 6 h after the onset of chest pain (late comers), who therefore underwent delayed coronary angioplasty, acted as controls. All patients underwent serial blood sampling in order to evaluate plasma concentrations of C-reactive protein (CRP), fibrinogen and erythrocyte sedimentation rate (ESR) for 4 days. Patients treated with primary (<6 h from symptom onset) or rescue angioplasty were excluded from the study. RESULTS: CRP, ESR and fibrinogen in patients who were timely reperfused showed significantly lower values compared to late comer controls (P < 0.05). In a multivariable analysis considering age, sex, diabetes, presence of anterior wall infarction, presence of Q-waves, left-ventricular ejection fraction and peak troponin levels, timely reperfusion was inversely related to CRP peak values (hazard ratio 0.74, 95% confidence interval 0.55-0.98, P < 0.05). CONCLUSION: Timely reperfusion can blunt inflammatory activation in patients with STEMI. PMID- 24492357 TI - Mutations within the rplD Gene of Linezolid-Nonsusceptible Streptococcus pneumoniae Strains Isolated in the United States. AB - Three invasive Streptococcus pneumoniae strains nonsusceptible to linezolid were isolated in the United States between 2001 and 2012 from the CDC's Active Bacterial Core surveillance. Linezolid binds ribosomal proteins where structural changes within its target site may confer resistance. Our study identified mutations and deletions near the linezolid binding pocket of two of these strains within the rplD gene, which encodes ribosomal protein L4. Mutations in the 23S rRNA alleles or the rplV gene were not detected. PMID- 24492358 TI - Bactericidal activity of N-chlorotaurine against biofilm-forming bacteria grown on metal disks. AB - Many orthopedic surgeons consider surgical irrigation and debridement with prosthesis retention as a treatment option for postoperative infections. Usually, saline solution with no added antimicrobial agent is used for irrigation. We investigated the activity of N-chlorotaurine (NCT) against various biofilm forming bacteria in vitro and thereby gained significant information on its usability as a soluble and well-tolerated active chlorine compound in orthopedic surgery. Biofilms of Staphylococcus aureus were grown on metal alloy disks and in polystyrene dishes for 48 h. Subsequently, they were incubated for 15 min to 7 h in buffered solutions containing therapeutically applicable concentrations of NCT (1%, 0.5%, and 0.1%; 5.5 to 55 mM) at 37 degrees C. NCT inactivated the biofilm in a time- and dose-dependent manner. Scanning electron microscopy revealed disturbance of the biofilm architecture by rupture of the extracellular matrix. Assays with reduction of carboxanilide (XTT) showed inhibition of the metabolism of the bacteria in biofilms. Quantitative cultures confirmed killing of S. aureus, Staphylococcus epidermidis, and Pseudomonas aeruginosa biofilms on metal alloy disks by NCT. Clinical isolates were slightly more resistant than ATCC type strains, but counts of CFU were reduced at least 10-fold by 1% NCT within 15 min in all cases. NCT showed microbicidal activity against various bacterial strains in biofilms. Whether this can be transferred to the clinical situation should be the aim of future studies. PMID- 24492359 TI - Fungicidal mechanisms of cathelicidins LL-37 and CATH-2 revealed by live-cell imaging. AB - Antifungal mechanisms of action of two cathelicidins, chicken CATH-2 and human LL 37, were studied and compared with the mode of action of the salivary peptide histatin 5 (Hst5). Candida albicans was used as a model organism for fungal pathogens. Analysis by live-cell imaging showed that the peptides kill C. albicans rapidly. CATH-2 is the most active peptide and kills C. albicans within 5 min. Both cathelicidins induce cell membrane permeabilization and simultaneous vacuolar expansion. Minimal fungicidal concentrations (MFC) are in the same order of magnitude for all three peptides, but the mechanisms of antifungal activity are very different. The activity of cathelicidins is independent of the energy status of the fungal cell, unlike Hst5 activity. Live-cell imaging using fluorescently labeled peptides showed that both CATH-2 and LL-37 quickly localize to the C. albicans cell membrane, while Hst5 was mainly directed to the fungal vacuole. Small amounts of cathelicidins internalize at sub-MFCs, suggesting that intracellular activities of the peptide could contribute to the antifungal activity. Analysis by flow cytometry indicated that CATH-2 significantly decreases C. albicans cell size. Finally, electron microscopy showed that CATH-2 affects the integrity of the cell membrane and nuclear envelope. It is concluded that the general mechanisms of action of both cathelicidins are partially similar (but very different from that of Hst5). CATH-2 has unique features and possesses antifungal potential superior to that of LL-37. PMID- 24492360 TI - Sustained delivery of commensal bacteria from pod-intravaginal rings. AB - Topical administration of live commensal bacteria to the vaginal tract holds significant potential as a cost-effective strategy for the treatment of sexually transmitted infections and the delivery of mucosal vaccines. Probiotic-releasing intravaginal rings (IVRs) embody significant theoretical advantages over traditional daily-dosage forms, such as sustained and controlled delivery leading to improved adherence to therapy compared to that of frequent dosing. The conventional IVR designs, however, are not amenable to the delivery of live bacteria. We have developed a novel pod-IVR technology where polymer-coated tablets ("pods") of Lactobacillus gasseri strain ATCC 33323, a commensal microorganism of human origin, are embedded in silicone IVRs. The release rate of bacterial cells is controlled by the diameter of a delivery channel that exposes a portion of the pod to external fluids. In vitro studies demonstrated that the prototype devices released between 1.1*10(7) and 14*10(7) cells per day for up to 21 days in a controlled sustained fashion with stable burst-free release kinetics. The daily release rates were correlated with the cross-sectional area of the delivery channel. Bacteria in the IVR pods remained viable throughout the in vitro studies and formed biofilms on the surfaces of the devices. This proof of-principle study represents the first demonstration of a prolonged, sustained release of bacteria from an intravaginal device and warrants further investigation of this device as a nonchemotherapeutic agent for the restoration and maintenance of normal urogenital flora. PMID- 24492361 TI - Variation in potency and spectrum of tigecycline activity against bacterial strains from U.S. medical centers since its approval for clinical use (2006 to 2012). AB - Tigecycline was initially approved by the U.S. Food and Drug Administration (FDA) in June 2005. We assessed the evolution of tigecycline in vitro activities since the initial approval of tigecycline for clinical use by analyzing the results of 7 years (2006 to 2012) of data from the SENTRY Antimicrobial Surveillance Program in the United States. We also analyzed trends over time for key resistance phenotypes. The analyses included 68,608 unique clinical isolates collected from 29 medical centers and tested for susceptibility using reference broth microdilution methods. Tigecycline was highly active against Gram-positive organisms, with MIC50 and MIC90 values of 0.12 and 0.25 MUg/ml for Staphylococcus aureus (28,278 strains; >99.9% susceptible), 0.06 to 0.12 and 0.12 to 0.25 MUg/ml for enterococci (99.3 to 99.6% susceptible), and <=0.03 and <=0.03 to 0.06 MUg/ml for streptococci (99.9 to 100.0% susceptible), respectively. When tested against 20,457 Enterobacteriaceae strains, tigecycline MIC50 and MIC90 values were 0.25 and 1 MUg/ml, respectively (98.3% susceptible using U.S. FDA breakpoints). No trend toward increasing tigecycline resistance (nonsusceptibility) was observed for any species or group during the study period. The prevalence of multidrug resistant (MDR) and extensively drug-resistant (XDR) Enterobacteriaceae increased from 4.4 and 0.5%, in 2006 to 8.5 and 1.5% in 2012, respectively. During the same period, the prevalence of Escherichia coli and Klebsiella spp. with an extended spectrum beta-lactamase (ESBL) phenotype increased from 5.8 and 9.1% to 11.1 and 20.4%, respectively, whereas rates of meropenem-nonsusceptible Klebsiella pneumoniae escalated from 2.2% in 2006 to 10.8% in 2012. The results of this investigation show that tigecycline generally retained potent activities against clinically important organisms isolated in U.S. institutions, including MDR organism subsets of Gram-positive and Gram-negative pathogens. PMID- 24492362 TI - In vitro activities of dermaseptins K4S4 and K4K20S4 against Escherichia coli, Staphylococcus aureus, and Pseudomonas aeruginosa planktonic growth and biofilm formation. AB - The rising number of infections caused by biofilm formation and the difficulties associated with their treatment by conventional antimicrobial therapies have led to an intensive search for novel antibiofilm agents. Dermaseptins are antimicrobial peptides with a number of attractive properties that might offer alternative therapies against resistant microorganisms. In this study, we synthesized a set of dermaseptin-derived peptides and evaluated their activities against Gram-positive and Gram-negative bacterial biofilm formation. All dermaseptin-derived peptides demonstrated concentration-dependent antibiofilm activities at microgram concentrations, and their activities were dependent on the nature of the peptides, with the highest levels of activity being exhibited by highly charged molecules. Fluorescent binding and confocal microscopy demonstrated that dermaseptin K4S4, a substituted derivative of the native molecule S4, significantly decreased the viability of planktonic and surface attached bacteria and stopped biofilm formation under dynamic flow conditions. Cytotoxicity assays with HeLa cells showed that some of the tested peptides were less cytotoxic than current antibiotics. Overall, these findings indicate that dermaseptin derivatives might constitute new lead structures for the development of potent antibiofilm agents. PMID- 24492363 TI - Isavuconazole therapy protects immunosuppressed mice from mucormycosis. AB - We studied the in vitro and in vivo efficacies of the investigational drug isavuconazole against mucormycosis due to Rhizopus delemar. Isavuconazole was effective, with MIC and minimal fungicidal concentration (MFC) values ranging between 0.125 and 1.00 MUg/ml. A high dose of isavuconazole prolonged the survival time and lowered the tissue fungal burden of cyclophosphamide/cortisone acetate-treated mice infected with R. delemar and was as effective as a high-dose liposomal amphotericin B treatment. These results support the further development of this azole against mucormycosis. PMID- 24492365 TI - Pharmacokinetics of isoniazid in low-birth-weight and premature infants. AB - Isoniazid (INH) is recommended for use as posttuberculosis exposure preventive therapy in children. However, no pharmacokinetic data are available for INH treatment in low-birth-weight (LBW) infants, who undergo substantial developmental and physiological changes. Our objectives in this study were to determine the pharmacokinetic parameters of INH at a dose of 10 mg/kg of body weight/day and to define its pharmacokinetics relative to the arylamine N acetyltransferase-2 (NAT2) genotype. An intensive prospective pharmacokinetic sampling study was conducted at Tygerberg Children's Hospital, South Africa, in which we measured INH blood plasma concentrations at 2, 3, 4 and 5 h postdose. Twenty LBW infants (14 male, 16 exposed to HIV) were studied. The median birth weight was 1,575 g (interquartile range, 1,190 to 2,035 g) and the median gestational age was 35 weeks (interquartile range, 34 to 38 weeks). The NAT2 acetylation statuses of the infants were homozygous slow (SS) (5 infants), heterozygous intermediate (FS) (11 infants), and homozygous fast (FF) (4 infants). Using a noncompartmental analysis approach, the median maximum drug concentration in blood serum (Cmax) was 5.63 MUg/ml, the time after drug administration to reach CmaxTmax) was 2 h, the area under the concentration-time curve from 2 to 5 h (AUC2-5) was 13.56 MUg . h/ml, the half-life (t1/2) was 4.69 h, and the elimination constant rate (kel) was 0.15 h(-1). The alanine aminotransferase levels were normal, apart from 2 isolated values at two and three times above the normal levels. Only the three-times-elevated value was repeated at 6 months and normalized. All LBW infants achieved target INH blood plasma concentrations comparable to the adult values. Reduced elimination was observed in smaller and younger infants and in slow acetylators, cautioning against higher doses. The safety data, although limited, were reassuring. More data, however, are required for newborn infants. PMID- 24492364 TI - CYP2B6 18492T->C polymorphism compromises efavirenz concentration in coinfected HIV and tuberculosis patients carrying CYP2B6 haplotype *1/*1. AB - Data regarding the effect of the CYP2B6 18492T->C polymorphism on plasma efavirenz concentrations and 96-week virologic responses in patients coinfected with HIV and tuberculosis (TB) are still unavailable. A total of 139 antiretroviral-naive HIV-infected adults with active TB were prospectively enrolled to receive efavirenz 600 mg-tenofovir 300 mg-lamivudine 300 mg. Eight single nucleotide polymorphisms (SNPs) within CYP2B6 were genotyped. Seven SNPs, including 64C->T, 499C->G, 516G->T, 785A->G, 1375A->G, 1459C->T, and 21563C->T, were included for CYP2B6 haplotype determination. The CYP2B6 18492T->C polymorphism was studied in 48 patients who carried haplotype *1/*1. At 12 and 24 weeks after antiretroviral therapy, plasma efavirenz concentrations at 12 h after dosing were measured. Plasma HIV RNA was monitored every 12 weeks for 96 weeks. Of 48 patients {body weight [mean+/-standard deviation (SD)], 56+/-10 kg}, 77% received a rifampin-containing anti-TB regimen. No drug resistance-associated mutation was detected at baseline. The frequencies of the wild type (18492TT) and the heterozygous (18492TC) and homozygous (18492CC) mutants of the CYP2B6 18492T >C polymorphism were 39%, 42%, and 19%, respectively. At 12 weeks, mean (+/-SD) efavirenz concentrations of patients who carried the 18492TT, 18492TC, and 18492CC mutants were 2.8+/-1.6, 1.7+/-0.9, and 1.4+/-0.5 mg/liter, respectively (P=0.005). At 24 weeks, the efavirenz concentrations of the corresponding groups were 2.4+/-0.8, 1.7+/-0.8, and 1.2+/-0.4 mg/liter, respectively (P=0.003). A low efavirenz concentration was independently associated with 18492T->C (beta=-0.937, P=0.004) and high body weight (beta=-0.032, P=0.046). At 96 weeks, 19%, 17%, and 28% of patients carrying the 18492TT, 18492TC, and 18492CC mutants, respectively, had plasma HIV RNA levels of >40 copies/ml and developed efavirenz-associated mutations (P=0.254). In summary, the CYP2B6 18492T->C polymorphism compromises efavirenz concentrations in patients who carry CYP2B6 haplotype *1/*1 and are coinfected with HIV and tuberculosis. PMID- 24492366 TI - Population pharmacokinetics of emtricitabine in HIV-1-infected adult patients. AB - The aims of this study were to describe emtricitabine concentration-time courses in a large population of HIV-1-infected adults, to evaluate the influence of renal function on emtricitabine disposition, and to assess current dosing adjustment recommendations. Emtricitabine blood plasma concentrations were determined from samples collected from 161 adult patients during therapeutic drug monitoring and measured by liquid chromatography coupled to tandem mass spectrometry. The data were analyzed by a population approach. Emtricitabine pharmacokinetics was best described by a two-compartment model in which the absorption and distribution rate constants were assumed to be equal. Typical population parameter estimates (interindividual variability) were apparent elimination and intercompartmental clearances of 15.1 liters/h (17.4%) and 5.75 liters/h, respectively, and apparent central and peripheral volumes of distribution of 42.3 liters and 55.4 liters, respectively. The apparent elimination clearance was significantly related to creatinine clearance (CLCR), reflecting renal function. For 200 mg once a day (QD), the median area under the concentration-time curve over 24 h (AUC0-24) was 12.5 mg.h/liter for patients with normal renal function (CLCR, >80 ml/min), 14.7 mg.h/liter for patients with mild renal impairment (CLCR, 79 to 50 ml/min), and 17.9 mg.h/liter for patients with moderate renal impairment (CLCR, 49 to 30 ml/min). Simulations of the recommended dosing schemes for the oral solid form of emtricitabine (i.e., 200 mg per 48 h according to renal function) led to lower emtricitabine exposures for patients with moderate renal impairment (median AUC0-48, 17.2 mg.h/liter) than for patients with normal renal function (median AUC0-48, 25.6 mg.h/liter). Administering 18 ml of emtricitabine oral solution (10 mg/ml) QD to patients with moderate renal impairment should yield emtricitabine exposures similar to those in patients with normal renal function. PMID- 24492367 TI - Factors that cause trimethoprim resistance in Streptococcus pyogenes. AB - The use of trimethoprim in treatment of Streptococcus pyogenes infections has long been discouraged because it has been widely believed that this pathogen is resistant to this antibiotic. To gain more insight into the extent and molecular basis of trimethoprim resistance in S. pyogenes, we tested isolates from India and Germany and sought the factors that conferred the resistance. Resistant isolates were identified in tests for trimethoprim or trimethoprim sulfamethoxazole (SXT) susceptibility. Resistant isolates were screened for the known horizontally transferable trimethoprim-insensitive dihydrofolate reductase (dfr) genes dfrG, dfrF, dfrA, dfrD, and dfrK. The nucleotide sequence of the intrinsic dfr gene was determined for resistant isolates lacking the horizontally transferable genes. Based on tentative criteria, 69 out of 268 isolates (25.7%) from India were resistant to trimethoprim. Occurring in 42 of the 69 resistant isolates (60.9%), dfrF appeared more frequently than dfrG (23 isolates; 33.3%) in India. The dfrF gene was also present in a collection of SXT-resistant isolates from Germany, in which it was the only detected trimethoprim resistance factor. The dfrF gene caused resistance in 4 out of 5 trimethoprim-resistant isolates from the German collection. An amino acid substitution in the intrinsic dihydrofolate reductase known from trimethoprim-resistant Streptococcus pneumoniae conferred resistance to S. pyogenes isolates of emm type 102.2, which lacked other aforementioned dfr genes. Trimethoprim may be more useful in treatment of S. pyogenes infections than previously thought. However, the factors described herein may lead to the rapid development and spread of resistance of S. pyogenes to this antibiotic agent. PMID- 24492368 TI - Comparison of local features from two Spanish hospitals reveals common and specific traits at multiple levels of the molecular epidemiology of metallo-beta lactamase-producing Pseudomonas spp. AB - Twenty-seven well-characterized metallo-beta-lactamase (MBL)-producing Pseudomonas strains from two distantly located hospitals were analyzed. The results revealed specific features defining the multilevel epidemiology of strains from each hospital in terms of species, clonality, predominance of high risk clones, composition/diversity of integrons, and linkages of Tn402-related structures. Therefore, despite the global trends driving the epidemiology of MBL producing Pseudomonas spp., the presence of local features has to be considered in order to understand this threat and implement proper control strategies. PMID- 24492369 TI - Impact of renal function on the pharmacokinetics and safety of ceftolozane tazobactam. AB - Ceftolozane-tazobactam is a novel antipseudomonal cephalosporin with a beta lactamase inhibitor. We investigated the pharmacokinetics (PK) and safety of ceftolozane-tazobactam in subjects with various degrees of renal function. In two phase I, open-label studies, a single dose of ceftolozane-tazobactam was administered as a 1-h intravenous infusion to 24 subjects with normal, mild, or moderate renal impairment (1,000/500 mg) and six subjects with severe renal impairment (500/250 mg). Six subjects with end-stage renal disease (ESRD) received two doses of ceftolozane-tazobactam (500/250 mg each), pre- and posthemodialysis (post-HD). PK parameters were determined by noncompartmental methods. Plasma exposure to ceftolozane-tazobactam increased as renal function declined with only slightly increased exposures in subjects with mild renal impairment; the median area under the concentration-time curve from time zero to infinity (AUC0-infinity) for ceftolozane and tazobactam increased 1.4- and 1.2 fold, respectively. In subjects with moderate renal impairment, the AUC0-infinity increased 2.5- and 2.2-fold for ceftolozane and tazobactam, respectively. In subjects with severe renal impairment, the dose-normalized median AUC0-infinity for ceftolozane and tazobactam increased 4.4- and 3.8-fold, respectively. In ESRD subjects, ceftolozane and tazobactam concentrations declined rapidly following the start of HD, with approximately 66 and 56% reductions in overall exposure based on the AUC0-infinity before and after dialysis. Slight increases in exposure with mild renal impairment do not warrant a dose adjustment; however, subjects with moderate or severe renal impairment and those on HD require a decrease in the dose, a change in the frequency of administration, or both to achieve exposures within the established safety and efficacy margins of ceftolozane-tazobactam. Ceftolozane-tazobactam was well tolerated by all renal impairment groups. PMID- 24492370 TI - Molecular survey of the dissemination of two blaKPC-harboring IncFIA plasmids in New Jersey and New York hospitals. AB - Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains have spread worldwide and become a major threat in health care facilities. Transmission of blaKPC, the plasmid-borne KPC gene, can be mediated by clonal spread and horizontal transfer. Here, we report the complete nucleotide sequences of two novel blaKPC-3-harboring IncFIA plasmids, pBK30661 and pBK30683. pBK30661 is 74 kb in length, with a mosaic plasmid structure; it exhibits homologies to several other plasmids but lacks the plasmid transfer operon (tra) and the origin of transfer (oriT) that are required for plasmid transfer. pBK30683 is a conjugative plasmid with a cointegrated plasmid structure, comprising a 72-kb element that highly resembles pBK30661 (>99.9% nucleotide identities) and an extra 68-kb element that harbors tra and oriT. A PCR scheme was designed to detect the distribution of blaKPC-harboring IncFIA (pBK30661-like and pBK30683 like) plasmids in a collection of clinical Enterobacteriaceae isolates from 10 hospitals in New Jersey and New York. KPC-harboring IncFIA plasmids were found in 20% of 491 K. pneumoniae isolates, and all carried blaKPC-3. pBK30661-like plasmids were identified mainly in the epidemic sequence type 258 (ST258) K. pneumoniae clone, while pBK30683-like plasmids were widely distributed in ST258 and other K. pneumoniae sequence types and among non-K. pneumoniae Enterobacteriaceae species. This suggests that both clonal spread and horizontal plasmid transfer contributed to the dissemination of blaKPC-harboring IncFIA plasmids in our area. Further studies are needed to understand the distribution of this plasmid group in other health care regions and to decipher the origins of pBK30661-like and pBK30683-like plasmids. PMID- 24492371 TI - Phenethyl isothiocyanate inhibits shiga toxin production in enterohemorrhagic Escherichia coli by stringent response induction. AB - The pathogenicity of enterohemorrhagic Escherichia coli (EHEC) depends on production of Shiga toxins, which are encoded by stx genes located in the genomes of lambdoid prophages. Efficient expression of these genes requires prophage induction and lytic development of phages. Treatment of EHEC infections is problematic due to not only the resistance of various strains to antibiotics but also the fact that many antibiotics cause prophage induction, thus resulting in high-level expression of stx genes. Here we report that E. coli growth, Shiga toxin-converting phage development, and production of the toxin by EHEC are strongly inhibited by phenethyl isothiocyanate (PEITC). We demonstrate that PEITC induces the stringent response in E. coli that is mediated by massive production of a global regulator, guanosine tetraphosphate (ppGpp). The stringent response induction arises most probably from interactions of PEITC with amino acids and from amino acid deprivation-mediated activation of ppGpp synthesis. In mutants unable to synthesize ppGpp, development of Shiga toxin-converting phages and production of Shiga toxin are significantly enhanced. Therefore, ppGpp, which appears at high levels in bacterial cells after stimulation of its production by PEITC, is a negative regulator of EHEC virulence and at the same time efficiently inhibits bacterial growth. This is in contrast to stimulation of virulence of different bacteria by this nucleotide reported previously by others. PMID- 24492372 TI - Novel regimens identified in mice for treatment of latent tuberculosis infection in contacts of patients with multidrug-resistant tuberculosis. AB - Preventing the development of tuberculosis (TB) in contacts of patients with multidrug-resistant TB (MDR-TB) by the treatment of latent TB infection (LTBI) is highly desirable. However, few safe, well tolerated, and effective drugs are available to treat MDR-LTBI and the published guidance is limited. Fortunately, six new chemical entities from four classes developed to treat TB have entered clinical trials in the past decade. We tested three of these drugs alone and in combination in an experimental paucibacillary LTBI chemotherapy model using BALB/c and C3HeB/FeJ mice immunized with a recombinant strain of Mycobacterium bovis bacillus Calmette-Guerin (rBCG30) and then challenged with a low-dose aerosol of M. tuberculosis H37Rv. The regimens tested contained bedaquiline (TMC), PA-824 (Pa), sutezolid (PNU), and/or one of two fluoroquinolones. Control mice received rifampin (RIF) or isoniazid (INH). In BALB/c mice, TMC-containing regimens and the Pa-PNU combination were the most active test regimens and were at least as effective as RIF. Pa, PNU, and levofloxacin had activity comparable to that of INH. Virtually identical results were observed in C3HeB/FeJ mice. This study confirms the potent activity of TMC observed previously in BALB/c mice and highlights Pa alone or in combination with either PNU or a fluoroquinolone as a regimen worthy of evaluation in future clinical trials of MDR-LTBI. Given their closer pathological representation of human TB lesions, C3HeB/FeJ mice may become a preferred model for the experimental chemotherapy of LTBI. Future studies should evaluate additional clinically relevant LTBI regimens in this strain including relapse as an endpoint. PMID- 24492373 TI - Dronedarone, an amiodarone analog with improved anti-Leishmania mexicana efficacy. AB - Dronedarone and amiodarone are cationic lipophilic benzofurans used to treat cardiac arrhythmias. They also have activity against the parasitic protozoan Trypanosoma cruzi, the causative agent of Chagas' disease. They function by disrupting intracellular Ca2+ homeostasis of the parasite and by inhibiting membrane sterol (ergosterol) biosynthesis. Amiodarone also has activity against Leishmania mexicana, suggesting that dronedarone might likewise be active against this organism. This might be of therapeutic interest, since dronedarone is thought to have fewer side effects in humans than does amiodarone. We show here that dronedarone effectively inhibits the growth of L. mexicana promastigotes in culture and, more importantly, has excellent activity against amastigotes inside infected macrophages (the clinically relevant form) without affecting the host cell, with the 50% inhibitory concentrations against amastigotes being 3 orders of magnitude lower than those obtained previously with T. cruzi amastigotes (0.65 nM versus 0.75 MUM). As with amiodarone, dronedarone affects intracellular Ca2+ homeostasis in the parasite, inducing an elevation of intracellular Ca2+ levels. This is achieved by rapidly collapsing the mitochondrial membrane potential and inducing an alkalinization of acidocalcisomes at a rate that is faster than that observed with amiodarone. We also show that dronedarone inhibits parasite oxidosqualene cyclase, a key enzyme in ergosterol biosynthesis known to be vital for survival. Overall, our results suggest the possibility of repurposing dronedarone as a treatment for cutaneous, and perhaps other, leishmaniases. PMID- 24492374 TI - Highly transparent and conducting graphene-embedded ZnO films with enhanced photoluminescence fabricated by aerosol synthesis. AB - Graphene/inorganic hybrid structures have attracted increasing attention in research aimed at producing advanced optoelectronic devices and sensors. Herein, we report on aerosol synthesis of new graphene-embedded zinc oxide (ZnO) films with higher optical transparency (>80% at visible wavelengths), improved electrical conductivity (>2 orders of magnitude, ~ 20 kOmega/?), and enhanced photoluminescence (~ 3 times), as compared to bare ZnO film. The ZnO/graphene composite films, in which reduced graphene oxide nanoplatelets (~ 4 nm thick) are embedded in nanograined ZnO (~ 50 nm in grain size), were fabricated from colloidal suspensions of graphene oxide with an aqueous zinc precursor. These new luminescent ZnO/graphene composites, with high optical transparency and improved electrical conductivity, are promising materials for use in optoelectronic devices. PMID- 24492375 TI - Blocking CD40-TRAF6 signaling is a therapeutic target in obesity-associated insulin resistance. AB - The immune system plays an instrumental role in obesity and insulin resistance. Here, we unravel the role of the costimulatory molecule CD40 and its signaling intermediates, TNF receptor-associated factors (TRAFs), in diet-induced obesity (DIO). Although not exhibiting increased weight gain, male CD40(-/-) mice in DIO displayed worsened insulin resistance, compared with wild-type mice. This worsening was associated with excessive inflammation of adipose tissue (AT), characterized by increased accumulation of CD8(+) T cells and M1 macrophages, and enhanced hepatosteatosis. Mice with deficient CD40-TRAF2/3/5 signaling in MHCII(+) cells exhibited a similar phenotype in DIO as CD40(-/-) mice. In contrast, mice with deficient CD40-TRAF6 signaling in MHCII(+) cells displayed no insulin resistance and showed a reduction in both AT inflammation and hepatosteatosis in DIO. To prove the therapeutic potential of inhibition of CD40 TRAF6 in obesity, DIO mice were treated with a small-molecule inhibitor that we designed to specifically block CD40-TRAF6 interactions; this compound improved insulin sensitivity, reduced AT inflammation, and decreased hepatosteatosis. Our study reveals that the CD40-TRAF2/3/5 signaling pathway in MHCII(+) cells protects against AT inflammation and metabolic complications associated with obesity whereas CD40-TRAF6 interactions in MHCII(+) cells aggravate these complications. Inhibition of CD40-TRAF6 signaling by our compound may provide a therapeutic option in obesity-associated insulin resistance. PMID- 24492377 TI - Structural elucidation of the neutral glycosphingolipids, mono-, di-, tri- and tetraglycosylceramides from the marine crab Erimacrus isenbeckii. AB - The neutral glycosphingolipids, mono-, di-, tri- and tetraglycosylceramides (GL 1, GL-2, GL-3, GL-4a and GL-4b), were identified from whole tissues of the marine crab Erimacrus isenbeckii by successive column chromatography with ion exchange Sephadex (QAE-Sephadex), magnesium silicate (Florisil) and silicic acid (Iatrobeads) resins. Through component analysis, sugar analysis, methylation studies, exoglycosidase cleavage, and various chromatographic and spectrometric techniques, their structures were proposed to be as follows: GL-1, Glcbeta1-1Cer; GL-2, Manbeta1-4Glcbeta1-1Cer; GL-3, Galbeta1-3Manbeta1-4Glcbeta1-1Cer; and GL-4a and GL-4b, Gal3Mealpha1-4Galbeta1-3Manbeta1-4Glcbeta1-1Cer. The main molecular species of the aliphatic moiety in each purified glycolipid were 18:0, 22:0, 22:1 d14:1 (fatty acid-sphingoid) and 18:0-d16:1 for GL-1; 18:0-d16:1 and 22:1-d14:1, d16:1 for GL-2; 22:1, 24:1-d16:1 for GL-3; 22:1, 24:1-d16:1 for GL-4a; and h22:1, h24:1-d16:1 for GL-4b, respectively. By immunological detection, an arthro-series glycosphingolipid (At3Cer; GlcNAcbeta1-3Manbeta1-4Glcbeta1-1Cer) was also detected as a minor component. The characteristic arthro-series glycosphingolipid has been observed in most animals belonging to the phylum Arthropoda. PMID- 24492376 TI - Identification of germline transcriptional regulatory elements in Aedes aegypti. AB - The mosquito Aedes aegypti is the principal vector for the yellow fever and dengue viruses, and is also responsible for recent outbreaks of the alphavirus chikungunya. Vector control strategies utilizing engineered gene drive systems are being developed as a means of replacing wild, pathogen transmitting mosquitoes with individuals refractory to disease transmission, or bringing about population suppression. Several of these systems, including Medea, UD(MEL), and site-specific nucleases, which can be used to drive genes into populations or bring about population suppression, utilize transcriptional regulatory elements that drive germline-specific expression. Here we report the identification of multiple regulatory elements able to drive gene expression specifically in the female germline, or in the male and female germline, in the mosquito Aedes aegypti. These elements can also be used as tools with which to probe the roles of specific genes in germline function and in the early embryo, through overexpression or RNA interference. PMID- 24492378 TI - Control of dual stimuli-responsive vesicle formation in aqueous solutions of single-tailed ferrocenyl surfactant by varying pH and redox conditions. AB - This paper reports a method to control the formation and disruption of vesicles from a novel single-tailed surfactant (11-ferrocenylundecylammonium bromide, 11 FAB), which contains two stimuli-responsive groups corresponding to pH variation and redox reaction conditions, by external stimuli. Although 11-FAB is a single tailed surfactant, pure 11-FAB spontaneously forms vesicles in water. Microscopic observations of 2.5 mM aqueous solutions of pure 11-FAB (pH = 5.2) show that a number of 11-FAB vesicles are giant, with diameters of 10-30 MUm. The disruption of vesicles is observed in aqueous 11-FAB solutions under basic conditions. The vesicles are then reformed under acidic conditions. Reduced 11-FAB also forms large vesicles in electrolyte solutions. These vesicles are disrupted by electrochemical oxidation and reformed by subsequent chemical reduction. This reversible disruption and reformation of vesicles is attributed to the drastic change in the molecular structure of 11-FAB. To our knowledge, this is the first report of control over the formation and disruption of vesicles using two stimuli responses. PMID- 24492379 TI - Extraction and characterization of glucosinolates and isothiocyanates from rape seed meal. AB - While some isothiocyanate (ITCs) are attractive targets for the agricultural and pharmaceutical industries, the presence of goitrin and ITCs has hampered the widespread utilization of rapeseed meal. ITCs are the products of the myrosinase mediated hydrolysis of glucosinolate (GSLs). As such, a study was conducted in order to gain a better understanding into the identity of the GSLs contained in rapeseed meal. Extraction of the GSLs was carried out with 20% ethanol, affording 3.0% GSL content. The resulting GSL extracts were purified via silica gel column chromatography resulting in the isolation of main three pure GLSs (GSL A, B, and C) and a final GSL content of 39.8%. The indirect-identification of the GSLs in rapeseed meal was also carried out via GC/MS analysis of ITCs. The GSLs, progoitrin and gluconapin, were present in the highest concentration in these extracts. Interestingly, only goitrin was produced when GSL A was the substrate for the defatted rapeseed meal mediated hydrolysis reaction. This indicates GSL A is a progoitrin. Conversely, 3-butenyl ITC was produced only when GSL B was used as substrate, indicating GSL B is gluconapin. These results will be helpful for opening the doors for the use of rapeseed meal in the agricultural or pharmaceutical sectors. PMID- 24492380 TI - Suppressive effects of carotenoids on the antigen-induced degranulation in RBL 2H3 rat basophilic leukemia cells. AB - In this study, the anti-degranulation effects of fifteen carotenoids were evaluated using RBL-2H3 rat basophilic leukemia cell line as a mast cell model. Nine carotenoids, fucoxanthin, zeaxanthin, beta-carotene, astaxanthin, 3 hydroxyechinenone, fucoxanthinol, lycopene, beta-cryptoxanthin, and siphonaxanthin significantly suppressed antigen-induced mast cell degranulation. Under the same conditions, the cellular carotenoid contents were quantified using high performance liquid chromatography-photodiode array (HPLC-PDA). There was no correlation between the cellular carotenoid contents and their anti-degranulation activities. These results indicate that the differences in the anti-degranulation activities of carotenoids were not related to their uptake by the cells. PMID- 24492381 TI - Effectiveness of immobilized lipase Thermomyces lanuginosa in catalyzing interesterification of palm olein in batch reaction. AB - Lipase Thermomyces lanuginosa has shown potential in modifying oils and fats through interesterification. Analyzing the physicochemical properties of the modified oils is important to determine the effectiveness of lipase in catalyzing interesterification. In this study, the effectiveness of the immobilized lipase (Lipozyme((r)) TL IM) in catalyzing interesterification of palm olein in pilot scale batch reactor was determined. The evaluation was done by analyzing the changes of triacylglycerol (TAGs) composition, sn-2 position fatty acids composition and the physical properties of the palm olein after the interesterifications. The pilot-scale batch reaction was conducted for 8 hours with 5 %w/w enzyme dosage based on the results of TAGs composition of the laboratory-scale interesterified products. The pilot-scale results showed that Lipozyme((r)) TL IM act as an effective enzyme in converting TAGs, in which 4.5% of trisaturated TAGs (PPP and PPS) were produced in the batch reaction. The formation of these new TAGs had also altered the thermal and physical properties of the palm olein. These interesterified products showed a broad peak and shoulder at high temperature, ranging from 10 degrees C to 40 degrees C, indicating the formation of some new TAGs with high melting points. However, the enzyme did not perform perfectly as a 1,3-specific enzyme in the reaction as a significant reduction of oleic acid and an increment of palmitic acid at the sn-2 position was observed. PMID- 24492382 TI - A copper complex supported by an N2S-tridentate ligand inducing efficient heterolytic O-O bond cleavage of alkylhydroperoxide. AB - We have recently reported a copper(II)-superoxide complex supported by an N3 tridentate ligand (L(N3)), which exhibits a similar structure and reactivity to those of a putative reactive intermediate involved in the catalytic reactions of copper monooxygenases such as peptidylglycine alpha-hydroxylating monooxygenase (PHM) and dopamine beta-monooxygenase (DbetaM). In this study, we have synthesised and characterised copper complexes supported by a related sulphur containing ligand (L(N2S)) to get insight into the notable electronic effect of the sulphur donor atom in the reaction with cumene hydroperoxide, inducing efficient heterolytic O-O bond cleavage. PMID- 24492383 TI - A two-compartment population pharmacokinetic-pharmacodynamic model of digoxin in adults, with implications for dosage. AB - A population pharmacokinetic/pharmacodynamic model of digoxin in adult subjects was originally developed by Reuning et al in 1973. They clearly described the 2 compartment behavior of digoxin, the lack of correlation of effect with serum concentrations, and the close correlation of the observed inotropic effect of digoxin with the calculated amount of drug present in the peripheral nonserum compartment. Their model seemed most attractive for clinical use. However, to make it more applicable for maximally precise dosage, its model parameter values (means and SD's) were converted into discrete model parameter distributions using a computer program developed especially for this purpose using the method of maximum entropy. In this way, the parameter distributions became discrete rather than continuous, suitable for use in developing maximally precise digoxin dosage regimens, individualized to an adult patient's age, gender, body weight, and renal function, to achieve desired specific target goals either in the central (serum) compartment or in the peripheral (effect) compartment using the method of multiple model dosage design. Some illustrative clinical applications of this model are presented and discussed. This model with a peripheral compartment reflecting clinical effect has contributed significantly to an improved understanding of the clinical behavior of digoxin in patients than is possible with models having only a single compartment, and to the improved management of digoxin therapy for more than 20 years. PMID- 24492385 TI - Rheumatoid arthritis: Are FcRL4+ B cells the next target for RA biologic therapy? PMID- 24492390 TI - Rheumatoid arthritis: Clue to role of cannabinoid receptors in RA. PMID- 24492386 TI - Neural mechanisms underlying the pain of juvenile idiopathic arthritis. AB - Pain is the most common symptom of juvenile idiopathic arthritis (JIA) and is arguably a more important factor in disability than the progression of the disease itself. Studies have highlighted the extent of this pain and its persistence in some young patients despite effective disease control. Understanding and effective management of pain in JIA is limited, and improved diagnosis and treatment would benefit from increased knowledge of the mechanisms underlying pain in childhood. This Review focuses upon the developmental neurobiology of pain, reviewing studies in animal models that increase clinical understanding and inform treatment of the painful manifestations of JIA. Pain processing in the juvenile nervous system differs from that in adults: nociceptive thresholds are lower and endogenous pain control systems are slow to mature. Furthermore, increasing evidence points to tissue injury in childhood having prolonged effects upon the developing pain system. Injury, inflammation and stress in early life can 'prime' peripheral nociceptors and central pain circuits, such that the pain associated with tissue inflammation is exacerbated in later life. A developmental, mechanism-based approach towards developing novel targets for the treatment of pain in JIA might therefore benefit the patient both as a child and as an adult if the disease recurs or persists. PMID- 24492391 TI - Pyramiding resistances based on translation initiation factors in Arabidopsis is impaired by male gametophyte lethality. AB - In eukaryotes, eIF4E translation initiation factors are essential proteins encoded by a small multigene family. In plants, they are a major source of host plant resistance to potyviruses that require specific 4E factors to infect cells. Combining mutations in different eIF4E genes could be a way of broadening the spectrum of plant resistance to viruses. We attempted to combine null mutations affecting the two main Arabidopsis thaliana 4E factors eIF4E1 and eIFiso4E but discovered that this combination is lethal. Transmission through the male gametophyte is completely abolished in the eif4e1 eifiso4e double mutant. This shows that eIF4E1 and eIFiso4E are essential for male gametophyte development and act redundantly. These results may have implications for eIF4E-based pyramiding strategies to improve crop resistance. PMID- 24492392 TI - Biodistribution and radiation dosimetry of deuterium-substituted 18F-fluoromethyl [1, 2-2H4]choline in healthy volunteers. AB - (11)C-choline and (18)F-fluoromethylcholine ((18)F-FCH) have been used in patients to study tumor metabolic activity in vivo; however, both radiotracers are readily oxidized to respective betaine analogs, with metabolites detectable in plasma soon after injection of the radiotracer. A more metabolically stable FCH analog, (18)F-fluoromethyl-[1,2-(2)H4]choline ((18)F-D4-FCH), based on the deuterium isotope effect, has been developed. We report the safety, biodistribution, and internal radiation dosimetry profiles of (18)F-D4-FCH in 8 healthy human volunteers. METHODS: (18)F-D4-FCH was intravenously administered as a bolus injection (mean +/- SD, 161 +/- 2.17 MBq; range, 156-163 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at 6 time points, up to 4 h after tracer injection. Serial whole-blood, plasma, and urine samples were collected for radioactivity measurement and plasma radiotracer metabolites. Tissue (18)F radioactivities were determined from quantitative analysis of the images, and time-activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time-activity curve normalized to injected activities and standard organ volumes. Dosimetry calculations were performed using OLINDA/EXM 1.1. RESULTS: The injection of (18)F-D4-FCH was well tolerated in all subjects, with no radiotracer related serious adverse event reported. The mean effective dose averaged over both men and women (+/- SD) was estimated to be 0.025 +/- 0.004 (men, 0.022 +/- 0.002; women, 0.027 +/- 0.002) mSv/MBq. The 5 organs receiving the highest absorbed dose (mGy/MBq) were the kidneys (0.106 +/- 0.03), liver (0.094 +/- 0.03), pancreas (0.066 +/- 0.01), urinary bladder wall (0.047 +/- 0.02), and adrenals (0.046 +/- 0.01). Elimination was through the renal and hepatic systems. CONCLUSION: (18)F-D4-FCH is a safe PET radiotracer with a dosimetry profile comparable to other common (18)F PET tracers. These data support the further development of (18)F-D4-FCH for clinical imaging of choline metabolism. PMID- 24492401 TI - Chronic immune thrombocytopenia in childhood. AB - Chronic thrombocytopenias are pathological conditions defined as a persistent platelet count below the normal range for more than 6-12 months, clinically characterized by mucocutaneous bleeding. Recently, an International Working Group of expert clinicians has redefined standard terminology and definitions of primary and secondary chronic immune thrombocytopenia (ITP). A document issued on acute childhood idiopathic thrombocytopenic purpura (AIEOP) provides parents and physicians with guidelines for the management of chronic ITP and gives prominence to the periodic re-evaluation of differential diagnosis. The majority of chronic ITP children do not require pharmacological treatments, especially if symptoms are absent or minimal and the treatment decision depends on several factors, in particular clinical conditions rather than platelets count. The recommendations distinguish three therapeutic strategies: emergency or symptomatic treatment, maintenance therapy and treatment aiming at definitive remission. Experimental/off-label treatment of chronic ITP are reported in the literature, such as the use of rituximab. Currently, other drugs (thrombopoiesis stimulating factors, mycophenolate, dapsone, danazol, azathioprine, rFVIIa, cyclophosphamide, vinca alkaloids and cyclosporine) are recommended in special cases or trials. PMID- 24492402 TI - Recurrent Bell's palsy in a patient with Crohn's disease on methotrexate. PMID- 24492403 TI - Chronic hepatitis E virus infection: challenges in diagnosis and recognition in the United States. PMID- 24492404 TI - Pseudomelanosis of stomach, duodenum, and jejunum. AB - Pseudomelanosis is a rare finding during upper gastrointestinal endoscopy, and is most commonly seen in the duodenum. Involvement of other organs in the upper gastrointestinal tract is extremely rare, with only 1 reported case involving the stomach, duodenum, and jejunum. We present a case of a 60-year-old woman with mild anemia and hematemesis, who was found to have characteristic speckled pattern of gray-black pigmentation on endoscopic examination. To the best of our knowledge, this is the second reported case of pseudomelanosis involving the stomach, duodenum, and jejunum. PMID- 24492405 TI - Characteristics of inflammatory bowel disease serology in patients with indeterminate colitis. AB - GOALS AND BACKGROUND: Inflammatory bowel disease (IBD) serology testing is often used in patients with indeterminate colitis (IC) to help distinguish between ulcerative colitis (UC) and Crohn's disease (CD). We investigated the performance of serology testing in predicting future diagnosis in this setting. STUDY: This was an observational study of individuals with IC at a single center who underwent IBD serology testing [anti-Saccharomyces cerevisiae antibody (ASCA), perinuclear anti-neutrophil cytoplasmic antibody (pANCA), and anti-outer membrane porin C antibody (anti-OmpC)] and had at least 12 months follow-up from the time of serology test results. RESULTS: A total of 117 individuals with IC and with 1 year follow-up data were enrolled. All IC patients had endoscopic and histologic evidence of colitis at enrollment. One year after serology testing, 58 (50%) individuals with IC were diagnosed with UC, 49 (42%) with CD, and 10 (9%) remained labeled with IC. The sensitivity/specificity of an initial positive pANCA for a subsequent diagnosis of UC was 78%/44%. For ASCA and anti-OmpC, the results were 18%/84% and 27%/75%, respectively, for a subsequent diagnosis of CD. A positive pANCA test was associated with a likelihood ratio (LR) of 1.4 [95% confidence interval (CI), 1.1-1.8] for a subsequent diagnosis of UC at 1 year. Neither positive ASCA (LR 1.1; 95% CI, 0.5-2.5) nor anti-OmpC (LR 1.1; 95% CI, 0.6-2.0) was associated with a subsequent diagnosis of CD in patients with IC. CONCLUSIONS: The disease phenotype in the majority of individuals initially labeled with IC evolved to be more consistent with either UC or CD on follow-up. pANCA, ASCA, and anti-OmpC, individually, were of limited utility in predicting a patient's subsequent disease phenotype. PMID- 24492406 TI - Musculoskeletal manifestations in inflammatory bowel disease: a revisit in search of immunopathophysiological mechanisms. AB - Inflammatory bowel diseases are chronic inflammatory disorders of multiple organ systems, primarily involving the gut, with chronic relapsing and remitting course. Musculoskeletal involvement is the most common extraintestinal manifestation. Distinct cell-mediated and humoral immunopathophysiological mechanisms have been identified underlying gut and joint inflammation in patients with inflammatory bowel disease and arthritis. Genetic polymorphisms in genes coding for NOD2 and IL12/IL23 complex lead to impaired antigenic handling in the gut and local immune dysregulation. The gut-synovial axis hypothesis implicates both environmental and host factors acting as triggers to initiate inflammation in genetically predisposed individuals, leading to priming of Th1 and Th17 lymphocytes in the gut and subsequent homing to the synovial tissue. Similar to gut, antibody-dependent cell-mediated cytotoxicity and complement-mediated cell lysis may also contribute to the joint damage. Involvement of peripheral joints occurs in 2 distinct manners, one being oligoarticular asymmetric arthritis associated with active disease and the other being polyarticular symmetric involvement of small joints. The axial involvement may include asymptomatic sacroiliitis, inflammatory back pain, and ankylosing spondylitis, running an independent clinical course. Noninflammatory involvement of the musculoskeletal system may present as osteopenia, osteonecrosis, fibromyalgia, or myopathies, leading to significant impact on quality of life. PMID- 24492407 TI - Assessment of upper esophageal sphincter function on high-resolution manometry: identification of predictors of globus symptoms. AB - BACKGROUND: Globus is commonly encountered in clinical practice, but high resolution manometry (HRM) characteristics are incompletely characterized. We evaluated HRM metrics in globus subjects, compared with age-matched and sex matched dysphagia subjects and healthy controls. STUDY: Twenty-four subjects with globus (53.3 +/- 2.3 y, 58% female) were compared with 24 age-matched and sex matched subjects with nonobstructive dysphagia (52.5 +/- 2.5 y, 58% female), and 21 healthy controls (27.6 +/- 0.6 y, 52% female). Sphincter and segment anatomy, and pressure volume metrics assessed skeletal (proximal contractile integral) and smooth muscle contraction (distal contractile integral). Parameters significantly different across groups on univariate analysis were subjected to multivariate logistic regression and receiver-operating characteristic analysis to identify HRM predictors of globus. RESULTS: Upper esophageal sphincter (UES) postswallow residual pressures were highest in globus (2.6 +/- 0.5 vs. 2.3 +/- 0.5 mm Hg in dysphagia and 0.6 +/- 0.6 mm Hg in controls, P = 0.03); 66.7% had recordable UES residual pressure, in contrast to 9.5% of controls, and 37.5% of dysphagia patients (P = 0.0002). Although different from controls, UES length and basal pressure, and segment 1 parameters did not differ from dysphagia controls. In a multivariate model, measurable UES residual pressure (odds ratio, 6.33; 95% confidence interval, 1.79-25.96) independently predicted globus. Receiver operating characteristic analysis identified a threshold of 0.4 mm Hg UES residual pressure in segregating globus (sensitivity 66.7%, specificity 71.5%, positive predictive value 55.2%, and negative predictive value 80.0%). CONCLUSION: HRM with measurement of UES residual pressure allows objective assessment of patients with globus sensation, and has potential to complement current diagnostic strategies. PMID- 24492408 TI - Hepatitis C and work impairment: a review of current literature. AB - Approximately 2.7 to 4.1 million people have chronic hepatitis C (HCV) in the United States. Although often thought of as an asymptomatic disease, several studies have revealed that those with chronic HCV experience increased work impairment manifested as decreased work productivity and increased absenteeism and presenteeism (attending work while being impaired). This review article summarizes the current literature examining the link between chronic HCV and work impairment for those with and without treatment and liver transplant recipients. We searched PubMed for epidemiological studies of HCV and its effect on worker productivity. We used a combination of the keywords "Hepatitis C," "disability," "work," "occupation," "labor," "productivity," and "absenteeism." Multiple studies were identified in our search and all confirmed the hypothesis that chronic HCV infection, with and without active treatment, lead to decreased work productivity and increased absenteeism. This was also found to be true for those who had undergone liver transplantation. Those living with chronic HCV infection experience increased work impairment manifested as decreased work productivity and increased absenteeism. This was found to be true whether or not patients were undergoing active treatment and for liver transplant recipients. Identifying a trend toward increased disability in patients with chronic HCV can help promote appropriate health care, government, and work allocation of resources to help minimize economic, social, and health burdens. PMID- 24492410 TI - Hollow superparamagnetic PLGA/Fe3O4 composite microspheres for lysozyme adsorption. AB - Uniform hollow superparamagnetic poly(lactic-co-glycolic acid) (PLGA)/Fe(3)O(4) composite microspheres composed of an inner cavity, PLGA inner shell and Fe(3)O(4) outer shell have been synthesized by a modified oil-in-water (O/W) emulsion-solvent evaporation method using Fe(3)O(4) nanoparticles as a particulate emulsifier. The obtained composite microspheres with an average diameter of 2.5 MUm showed excellent monodispersity and stability in aqueous medium, strong magnetic responsiveness, high magnetite content (>68%), high saturation magnetization (58 emu g(-1)) and high efficiency in lysozyme adsorption. PMID- 24492411 TI - Negative electrospray ionization on porous supporting tips for mass spectrometric analysis: electrostatic charging effect on detection sensitivity and its application to explosive detection. AB - The simplicity and easy manipulation of a porous substrate-based ESI-MS technique have been widely applied to the direct analysis of different types of samples in positive ion mode. However, the study and application of this technique in negative ion mode are sparse. A key challenge could be due to the ease of electrical discharge on supporting tips upon the application of negative voltage. The aim of this study is to investigate the effect of supporting materials, including polyester, polyethylene and wood, on the detection sensitivity of a porous substrate-based negative ESI-MS technique. By using nitrobenzene derivatives and nitrophenol derivatives as the target analytes, it was found that the hydrophobic materials (i.e., polyethylene and polyester) with a higher tendency to accumulate negative charge could enhance the detection sensitivity towards nitrobenzene derivatives via electron-capture ionization; whereas, compounds with electron affinities lower than the cut-off value (1.13 eV) were not detected. Nitrophenol derivatives with pKa smaller than 9.0 could be detected in the form of deprotonated ions; whereas polar materials (i.e., wood), which might undergo competitive deprotonation with the analytes, could suppress the detection sensitivity. With the investigation of the material effects on the detection sensitivity, the porous substrate-based negative ESI-MS method was developed and applied to the direct detection of two commonly encountered explosives in complex samples. PMID- 24492409 TI - Preterm birth and childhood wheezing disorders: a systematic review and meta analysis. AB - BACKGROUND: Accumulating evidence implicates early life factors in the aetiology of non-communicable diseases, including asthma/wheezing disorders. We undertook a systematic review investigating risks of asthma/wheezing disorders in children born preterm, including the increasing numbers who, as a result of advances in neonatal care, now survive very preterm birth. METHODS AND FINDINGS: Two reviewers independently searched seven online databases for contemporaneous (1 January 1995-23 September 2013) epidemiological studies investigating the association between preterm birth and asthma/wheezing disorders. Additional studies were identified through reference and citation searches, and contacting international experts. Quality appraisal was undertaken using the Effective Public Health Practice Project instrument. We pooled unadjusted and adjusted effect estimates using random-effects meta-analysis, investigated "dose-response" associations, and undertook subgroup, sensitivity, and meta-regression analyses to assess the robustness of associations. We identified 42 eligible studies from six continents. Twelve were excluded for population overlap, leaving 30 unique studies involving 1,543,639 children. Preterm birth was associated with an increased risk of wheezing disorders in unadjusted (13.7% versus 8.3%; odds ratio [OR] 1.71, 95% CI 1.57-1.87; 26 studies including 1,500,916 children) and adjusted analyses (OR 1.46, 95% CI 1.29-1.65; 17 studies including 874,710 children). The risk was particularly high among children born very preterm (<32 wk gestation; unadjusted: OR 3.00, 95% CI 2.61-3.44; adjusted: OR 2.81, 95% CI 2.55-3.12). Findings were most pronounced for studies with low risk of bias and were consistent across sensitivity analyses. The estimated population attributable risk of preterm birth for childhood wheezing disorders was >=3.1%. Key limitations related to the paucity of data from low- and middle-income countries, and risk of residual confounding. CONCLUSIONS: There is compelling evidence that preterm birth-particularly very preterm birth-increases the risk of asthma. Given the projected global increases in children surviving preterm births, research now needs to focus on understanding underlying mechanisms, and then to translate these insights into the development of preventive interventions. REVIEW REGISTRATION: PROSPERO CRD42013004965. PMID- 24492412 TI - Downregulation of CYP3A and P-glycoprotein in the secondary inflammatory response of mice with dextran sulfate sodium-induced colitis and its contribution to cyclosporine A blood concentrations. AB - CYP3A and P-glycoprotein (P-gp) play important roles in drug metabolism and excretion; however, their functions in pathological conditions remain unclear. Hepatobiliary abnormalities have been described in patients with ulcerative colitis, which may affect drug metabolism and excretion in the liver and small intestine. We examined the functions of CYP3A and P-gp in the liver and small intestine of mice with dextran sodium sulfate (DSS)-induced colitis. Up to day 7, inflammatory markers were significantly increased in the livers of DSS-treated mice, accompanied by decreased CYP3A. Additionally hepatobiliary transporters and Pregnane X receptor, which regulates the transcriptional activation of CYP3A, were reduced. Both CYP3A and P-gp were significantly decreased in the upper small intestine of DSS-treated mice on day 7. This was associated with the increased expression of inducible nitric oxide synthase, but not changes in nuclear receptor expression. On day 7 of DSS treatment, the concentrations of cyclosporine A (CsA), a substrate of both CYP3A and P-gp, were significantly higher than controls. These results indicated the existence of a second inflammatory response in the liver and upper small intestine of mice with DSS induced colitis, and bioavailability of CsA was increased by the dysfunction of CYP3A and P-gp in these organs. PMID- 24492413 TI - Proteolytic and non-proteolytic activation of keratinocyte-derived latent TGF beta1 induces fibroblast differentiation in a wound-healing model using rat skin. AB - Transforming growth factor-beta1 (TGF-beta1) reportedly causes the differentiation of fibroblasts to myofibroblasts during wound healing. We investigated the mechanism underlying the activation of latent TGF-beta1 released by keratinocytes in efforts to identify promising pharmacological approaches for the prevention of hypertrophic scar formation. A three-dimensional collagen gel matrix culture was prepared using rat keratinocytes and dermal fibroblasts. Stratified keratinocytes promoted the TGF receptor-dependent increase in alpha smooth muscle actin (alpha-SMA) immunostaining and mRNA levels in fibroblasts. Latent TGF-beta1 was found to be localized suprabasally and secreted. alpha-SMA expression was inhibited by an anti-alphav-integrin antibody and a matrix metalloproteinase (MMP) inhibitor, GM6001. In a two-dimensional fibroblast culture, alpha-SMA expression depended on the production of endogenous TGF-beta1 and required alphav-integrin or MMP for the response to recombinant latent TGF beta1. In keratinocyte-conditioned medium, MMP-dependent latent TGF-beta1 secretion was detected. Applying this medium to the fibroblast culture enhanced alpha-SMA production. This effect was decreased by GM6001, the anti-alphav integrin antibody, or the preabsorption of latent TGF-beta1. These results indicate that keratinocytes secrete latent TGF-beta1, which is liberated to fibroblasts over distance and is activated to produce alpha-SMA with the aid of a positive-feedback loop. MMP inhibition was effective for targeting both keratinocytes and fibroblasts in this model. PMID- 24492414 TI - New insights into the pharmacological potential of plant flavonoids in the catecholamine system. AB - Flavonoids are biologically active polyphenolic compounds widely distributed in plants. Recent research has focused on high dietary intake of flavonoids because of their potential to reduce the risks of diseases such as cardiovascular diseases, diabetes, and cancers. We report here the effects of plant flavonoids on catecholamine signaling in cultured bovine adrenal medullary cells used as a model of central and peripheral sympathetic neurons. Daidzein (0.01 - 1.0 MUM), a soy isoflavone, stimulated (14)C-catecholamine synthesis through plasma membrane estrogen receptors. Nobiletin (1.0 - 100 MUM), a citrus polymethoxy flavone, enhanced (14)C-catecholamine synthesis through the phosphorylation of Ser19 and Ser40 of tyrosine hydroxylase, which was associated with (45)Ca(2+) influx and catecholamine secretion. Treatment with genistein (0.01 - 10 MUM), another isoflavone, but not daidzein, enhanced [(3)H]noradrenaline uptake by SK-N-SH cells, a human noradrenergic neuroblastoma cell line. Daidzein as well as nobiletin (>= 1.0 MUM) inhibited catecholamine synthesis and secretion induced by acetylcholine, a physiological secretagogue. The present review shows that plant flavonoids have various pharmacological potentials on the catecholamine system in adrenal medullary cells, and probably also in sympathetic neurons. PMID- 24492415 TI - Broadband polarization-independent perfect absorber using a phase-change metamaterial at visible frequencies. AB - We report a broadband polarization-independent perfect absorber with wide-angle near unity absorbance in the visible regime. Our structure is composed of an array of thin Au squares separated from a continuous Au film by a phase change material (Ge2Sb2Te5) layer. It shows that the near perfect absorbance is flat and broad over a wide-angle incidence up to 80 degrees for either transverse electric or magnetic polarization due to a high imaginary part of the dielectric permittivity of Ge2Sb2Te5. The electric field, magnetic field and current distributions in the absorber are investigated to explain the physical origin of the absorbance. Moreover, we carried out numerical simulations to investigate the temporal variation of temperature in the Ge2Sb2Te5 layer and to show that the temperature of amorphous Ge2Sb2Te5 can be raised from room temperature to > 433 K (amorphous-to-crystalline phase transition temperature) in just 0.37 ns with a low light intensity of 95 nW/MUm(2), owing to the enhanced broadband light absorbance through strong plasmonic resonances in the absorber. The proposed phase-change metamaterial provides a simple way to realize a broadband perfect absorber in the visible and near-infrared (NIR) regions and is important for a number of applications including thermally controlled photonic devices, solar energy conversion and optical data storage. PMID- 24492416 TI - Distinct Orai-coupling domains in STIM1 and STIM2 define the Orai-activating site. AB - STIM1 and STIM2 are widely expressed endoplasmic reticulum (ER) Ca(2+) sensor proteins able to translocate within the ER membrane to physically couple with and gate plasma membrane Orai Ca(2+) channels. Although they are structurally similar, we reveal critical differences in the function of the short STIM-Orai activating regions (SOAR) of STIM1 and STIM2. We narrow these differences in Orai1 gating to a strategically exposed phenylalanine residue (Phe-394) in SOAR1, which in SOAR2 is substituted by a leucine residue. Remarkably, in full-length STIM1, replacement of Phe-394 with the dimensionally similar but polar histidine head group prevents both Orai1 binding and gating, creating an Orai1 non-agonist. Thus, this residue is critical in tuning the efficacy of Orai activation. While STIM1 is a full Orai1-agonist, leucine-replacement of this crucial residue in STIM2 endows it with partial agonist properties, which may be critical for limiting Orai1 activation stemming from its enhanced sensitivity to store depletion. PMID- 24492420 TI - Donation after circulatory death: current practices, ongoing challenges, and potential improvements. AB - Organ donation after circulatory death (DCD) has been endorsed by the World Health Organization and is practiced worldwide. This overview examines current DCD practices, identifies problems and challenges, and suggests clinical strategies for possible improvement. Although there is uniform agreement on DCD donor candidacy (ventilator-dependent individuals with nonrecoverable or irreversible neurologic injury not meeting brain death criteria), there are variations in all aspects of DCD practice. Utilization of DCD organs is limited by hypoxia, hypotension, reduced--then absent--organ perfusion, and ischemia/reperfusion syndrome. Nevertheless, DCD kidneys exhibit comparable function and survival to donors with brain death kidneys, although they have higher rates of primary graft nonfunction, delayed graft function, discard, and retrieval associated injury. Concern over ischemic organ injury underscores the reluctance to recover extrarenal DCD organs since lack of medical therapy to support inadequate allograft function limits their acceptability. Nevertheless, limited results with DCD pancreas, liver, and lung allografts (but not heart) are now approaching that of donors with brain death organs. Pretransplant machine perfusion of DCD kidneys (vs. static storage) may reduce delayed graft function but has no effect on long-term organ function and survival. Normothermic regional perfusion used during DCD abdominal organ retrieval may reduce ischemic organ injury and increase the number of usable organs, although critical confirmative studies have yet to be done. Minor increases in usable DCD kidneys could accrue from increased use of pediatric DCD kidneys and from selective use of DCD/ECD kidneys, whereas a modest increase could result through utilization of donors declared dead beyond 1 hr from withdrawal of life support therapy. A significant increase in transplantable kidneys could be achieved by extension of the concept of living kidney donation in relation to imminent death of potential DCD donors. Progress in research to identify, prevent, and repair DCD-associated organ retrieval injury should improve utilization of DCD organs. Recent results using ex situ pretransplant organ perfusion of DCD organs has been encouraging in this regard. PMID- 24492417 TI - Stabilization of neuronal connections and the axonal cytoskeleton. AB - Stabilization of axonal connections is an underappreciated, but critical, element in development and maintenance of neuronal functions. The ability to maintain the overall architecture of the brain for decades is essential for our ability to process sensory information efficiently, coordinate motor activity, and retain memories for a lifetime. While the importance of the neuronal cytoskeleton in this process is acknowledged, little has been known about specializations of the axonal cytoskeleton needed to stabilize neuronal architectures. A novel post translational modification of tubulin that stabilizes normally dynamic microtubules in axons has now been identified. Polyamination appears to be enriched in axons and is developmentally regulated with a time course that correlates with increased microtubule stabilization. Identifying one of the molecular mechanisms for maintaining neuronal connections creates new research avenues for understanding the role of stabilizing neuronal architecture in neuronal function and in neuropathology. PMID- 24492421 TI - Cardiovascular death in kidney recipients treated with renin-angiotensin system blockers. AB - BACKGROUND: Angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) are widely prescribed after kidney transplantation, but evidence for an improvement in outcomes is mixed. A recent trial demonstrated a significantly lower incidence of major cardiovascular events in ACEI-treated recipients. METHODS: Collaborative Transplant Study data on cardiovascular death during years 2 to 10 after kidney transplantation in patients with a functioning graft were analyzed according to whether ACEI/ARB or other antihypertensive therapy (excluding diuretics) was administered at year 1. RESULTS: Of 39,251 transplants analyzed, 15,250 (38.9%) received ACEI/ARB and 24,001 (61.1%) received other antihypertensive therapy at year 1 after transplantation. The mean duration of follow-up was 5.8 years. During years 2 to 10 after transplantation, cardiovascular death occurred in 918 patients (cumulative incidence=4.7%) with a functioning graft. The rate of cardiovascular death was similar in patients who received ACEI/ARB therapy or other antihypertensive treatment overall and in subpopulations of patients who were considered by the transplant center to be at an increased cardiovascular risk, had no pretransplant risk factors, were aged 60 years and older, were treated for diabetes at year 1, or had serum creatinine of 130 MUmol/L or higher at year 1. Multivariable Cox regression analysis confirmed that treatment with ACEI/ARB did not confer a beneficial effect beyond that conferred by other antihypertensive treatments on the cumulative incidence of cardiovascular death during years 2 to 10 (hazard ratio=1.1, P=0.24). CONCLUSIONS: This large-scale retrospective analysis of prospectively collected data shows that the rate of cardiovascular death in kidney transplant recipients receiving ACEI/ARB or other antihypertensive medications is virtually identical. PMID- 24492423 TI - Pharmacokinetic study of conversion from tacrolimus twice-daily to tacrolimus once-daily in stable lung transplantation. AB - BACKGROUND: Tacrolimus twice-daily (TAC BID) is widely used in lung transplantation (LT), but there are little data on the use of tacrolimus once daily (TAC QD) in this population. The objective of this study was to compare the pharmacokinetics (PK) of TAC BID and TAC QD in stable, adult LT patients. METHODS: Phase II, open-label, single-center, single-arm, prospective pilot PK study. Nineteen LT recipients with more than 6 months of postoperative follow-up and on TAC BID-based therapy were converted to TAC QD on a 1:1 (mg/mg) basis. Patients had been stable during the previous 3 months, and cystic fibrosis patients were excluded. One 24-hr PK profile was obtained on day -14 while patients were under TAC BID. A second PK profile was obtained 14 to 28 days after switching (day 0) to the same dose of TAC QD. Pre- and post-switch 24-hr PK profiles were compared. RESULTS: Mean AUC0-24 hr was 279.8 ng mL/hr for TAC BID and 278.7 ng mL/hr for TAC QD (P=0.92). AUC0-12 hr of TAC BID was higher than the AUC12-24 hr. There was a good correlation between AUC0-24 hr and C24 for both QD (r=0.96) and BID (r=0.94) formulations. There were no differences in the adverse events occurring with the two formulations. CONCLUSIONS: Tacrolimus bioavailability in steady state is similar in BID and QD formulations after conversion in stable LT recipients, excluding those with cystic fibrosis. Thus, our results indicate TAC BID can be safely switched to the more convenient QD formulation in this population. PMID- 24492422 TI - Telomere length of recipients and living kidney donors and chronic graft dysfunction in kidney transplants. AB - BACKGROUND: A biological marker that would allow clinicians to determine the length of time an allograft will remain functional after transplantation would greatly aid the ability to stratify donors by risk and to use biologically "young" allografts in young recipients, maximizing the use of this rare resource. Telomere length (TL) has been proposed to be such a marker to determine the biological age of a tissue. METHODS: We genotyped DNA from 1805 recipients and 1038 living kidney donors for TL to determine the association of TL with acute rejection (AR), chronic graft dysfunction (CGD), and graft failure of kidney allografts. DNA was isolated from peripheral blood white blood cells and TL was measured in DNA using the multiplexed monochrome quantitative polymerase chain reaction assay. RESULTS: As has been previously shown, we found a significant association between log-transformed TL and donor age (P=3.8*10) and recipient age (P=5.6*10). Univariate and multivariate analysis did not show any significant associations between log-transformed TL in donor or recipient DNA with AR, CGD, or graft failure, although we did observe an association between donor chronological age and CGD (P=0.018). CONCLUSION: Although older allografts have been shown to be at greater risk for AR and CGD, this does not appear to be associated with shorter TL. Different markers will need to be identified to determine how biological age impacts transplant outcome, such as age-related fibrosis or tubular atrophy and tubular loss. PMID- 24492424 TI - Home blood pressure monitoring in heart transplant recipients: comparison with ambulatory blood pressure monitoring. AB - BACKGROUND: How reliable is home blood pressure monitoring (HBPM) in heart transplant recipients is not known. Possibly, it may underestimate hypertensive burden, because blood pressure (BP) nondipper profile is frequent among these patients. This prospective study has been designed to determine whether HBPM adequately identifies hypertension in heart transplant recipients. METHOD: We compared HBPM with ambulatory blood pressure monitoring (ABPM) for the diagnosis of uncontrolled hypertension in 74 patients 13.5+/-6.7 years after heart transplantation. HBPM was measured with a validated semiautomatic device twice every morning and twice every evening on 7 consecutive days, within 15 days of ABPM. We also measured the relationship between HBPM, ABPM, and organ damage as measured by albuminuria and left ventricular mass. RESULTS: A nondipper profile was found in 53 (72%) patients. HBPM and ABPM were close according to Pearson bivariate correlations. There was no significant correlation between left ventricular mass and BP either at HBPM or ABPM. Proteinuria significantly correlated with systolic BP either at HBPM (R=0.42; P=0.0002) or ABPM (R=0.25; P=0.03). HBPM adequately classified 61 of 74 (82%) patients as hypertensives or as nonhypertensives or controlled hypertensives. CONCLUSION: Despite a high prevalence of nondipper profile, HBPM gives a reliable estimate of BP burden in most heart transplant recipients. Thus, our results strongly suggest that HBPM is useful for the long-term follow-up of heart transplant recipients. PMID- 24492425 TI - A "smarter" way to recruit organ donors? PMID- 24492426 TI - Sequential split liver followed by isolated intestinal transplant: the "liver first" approach: report of a case. PMID- 24492427 TI - No progress in ABO titer measurement: time to aim for a reference? PMID- 24492428 TI - New findings in anatomy of blood supply to rat femur isolated vascularized bone marrow transplantation model. PMID- 24492429 TI - Lithium use for bipolar disorder post renal transplant: is mood stabilization without toxicity possible? PMID- 24492430 TI - Successful excision of a suspected mycotic transplant renal artery patch aneurysm with renal allograft autotransplantation. PMID- 24492431 TI - Prostate cancer: What is the real IMPACT of BRCA1/BRCA2 mutation? PMID- 24492432 TI - Incontinence: Using a virtual reality dance game to improve mixed incontinence. PMID- 24492434 TI - Kidney cancer: Sunitinib has similar efficacy irrespective of age in mRCC. PMID- 24492433 TI - The mechanism of action of BCG therapy for bladder cancer--a current perspective. AB - Bacillus Calmette-Guerin (BCG) has been used to treat non-muscle-invasive bladder cancer for more than 30 years. It is one of the most successful biotherapies for cancer in use. Despite long clinical experience with BCG, the mechanism of its therapeutic effect is still under investigation. Available evidence suggests that urothelial cells (including bladder cancer cells themselves) and cells of the immune system both have crucial roles in the therapeutic antitumour effect of BCG. The possible involvement of bladder cancer cells includes attachment and internalization of BCG, secretion of cytokines and chemokines, and presentation of BCG and/or cancer cell antigens to cells of the immune system. Immune system cell subsets that have potential roles in BCG therapy include CD4(+) and CD8(+) lymphocytes, natural killer cells, granulocytes, macrophages, and dendritic cells. Bladder cancer cells are killed through direct cytotoxicity by these cells, by secretion of soluble factors such as TRAIL (tumour necrosis factor related apoptosis-inducing ligand), and, to some degree, by the direct action of BCG. Several gaps still exist in our knowledge that should be addressed in future efforts to understand this biotherapy of cancer. PMID- 24492435 TI - Prostate cancer: Superior outcomes after a long learning curve with RARP. PMID- 24492436 TI - Prostate cancer: Post-treatment complications of radiotherapy and prostatectomy. PMID- 24492437 TI - A cationic-cationic co-surfactant templating route for synthesizing well-defined multilamellar vesicular silica with an adjustable number of layers. AB - Vesicular mesoporous silica with well-defined multilamellar structures was prepared using didodecyldimethylammonium bromide (DDAB)/cetyltrimethylammonium bromide (CTAB) as a structure-directing agent. The number of vesicular silica layers can be tuned from 7 to 2 by changing the molar ratio of DDAB to CTAB. PMID- 24492438 TI - Neurology is psychiatry--and vice versa. AB - This paper explores the relationship between neurology and psychiatry. It marshals evidence that disorders of the brain typically have neurological and psychological-cognitive, affective, behavioural-manifestations, while disorders of the psyche are based in the brain. Given the inseparability of neurological and psychiatric disorders, their disease classifications should eventually fuse, and joint initiatives in training, service and research should be strongly encouraged. PMID- 24492439 TI - Clinical experiences in fungal keratitis caused by Acremonium. AB - PURPOSE: To report the predisposing risk factors, clinical presentation, management, and therapeutic outcomes of fungal keratitis caused by Acremonium. METHODS: This is a retrospective study of cases with Acremonium fungal keratitis that presented to our tertiary referral center between January 2006 and August 2012. Patient demographic and clinical details were determined and reported. RESULTS: Five cases of fungal keratitis from Acremonium species were identified in five patients (three males, two females). The mean age of the patients was of 73.4+/-5.46 years, with a mean follow-up time of 124+/-72 days. All patients had a history of corneal trauma with vegetable matter. Four cases were unresponsive to initial treatment (0.2% fluconazole, 0.15% amphotericin B) and required topical 5% natamycin, and, in two out of five cases, topical 1% voriconazole. CONCLUSION: The most common risk factors for Acremonium fungal keratitis was ocular trauma. When a corneal lesion is found to be unresponsive to the initial treatment, we should consider adding or substituting topical natamycin or voriconazole for treatment. PMID- 24492440 TI - Beyond the double banana: improved recognition of temporal lobe seizures in long term EEG. AB - PURPOSE: To investigate whether extending the 10-20 array with 6 electrodes in the inferior temporal chain and constructing computed montages increases the diagnostic value of ictal EEG activity originating in the temporal lobe. In addition, the accuracy of computer-assisted spectral source analysis was investigated. METHODS: Forty EEG samples were reviewed by 7 EEG experts in various montages (longitudinal and transversal bipolar, common average, source derivation, source montage, current source density, and reference-free montages) using 2 electrode arrays (10-20 and the extended one). Spectral source analysis used source montage to calculate density spectral array, defining the earliest oscillatory onset. From this, phase maps were calculated for localization. The reference standard was the decision of the multidisciplinary epilepsy surgery team on the seizure onset zone. Clinical performance was compared with the double banana (longitudinal bipolar montage, 10-20 array). RESULTS: Adding the inferior temporal electrode chain, computed montages (reference free, common average, and source derivation), and voltage maps significantly increased the sensitivity. Phase maps had the highest sensitivity and identified ictal activity at earlier time-point than visual inspection. There was no significant difference concerning specificity. CONCLUSIONS: The findings advocate for the use of these digital EEG technology-derived analysis methods in clinical practice. PMID- 24492441 TI - Ictal EEG source imaging in frontal lobe epilepsy leads to improved lateralization compared with visual analysis. AB - PURPOSE: To investigate the utility of EEG source imaging to lateralize ictal patterns in frontal lobe epilepsy, which were nonlateralized by standard EEG analysis. METHODS: Prospective analysis of 17 seizures in 8 patients with unilateral frontal lobe epilepsy MRI lesions and nonlateralizing ictal scalp EEG. We applied four EEG source imaging techniques (phase maps, symmetric dipoles, low resolution brain electromagnetic tomography analysis, and classical low resolution brain electromagnetic tomography analysis recursively applied) to the averaged seizure pattern. We tested (1) the ability of these techniques to lateralize seizure patterns, (2) the agreement of the lateralization result with MRI lesion side and subdural EEG recordings, individually for each method and for concordance of all. RESULTS: We found lateralizing results in 5 of 17 seizures when analyzing phase maps, 8 of 17 when analyzing dipoles, and 5 of 17 in both classical low-resolution brain electromagnetic tomography analysis recursively applied and low-resolution brain electromagnetic tomography analysis. No discordance with the MRI lesion side was seen when analyzing phase maps, whereas dipole analysis was discordant to the MRI lesion in two seizures, classical low resolution brain electromagnetic tomography analysis recursively applied in one, and low-resolution brain electromagnetic tomography analysis in two. Agreement between all imaging methods was found in three seizures (three patients), all in line with the side of the MRI lesion. CONCLUSIONS: Advanced EEG review methods and source localization provide useful lateralizing information in difficult frontal lobe epilepsy seizure patterns. PMID- 24492442 TI - Predictive value of isolated epileptiform discharges for a favorable therapeutic response to antiepileptic drugs in nonepileptic psychiatric patients. AB - The efficacy of antiepileptic drugs (AEDs) in treating behavioral symptoms in nonepileptic psychiatric patients with abnormal EEGs is currently unknown. Although isolated epileptiform discharges have been reported in many psychiatric conditions, they are most commonly observed in patients with aggression, panic, or autistic spectrum disorders. The literature search was guided by 3 criteria: (1) studies had patients who did not experience seizures, (2) patients had EEGs, and (3) an AED was administered. Most important finding is that the number of "controlled" studies was extremely small. Overall, most reports suggest that the use of an AED can be associated with clinical and, at times, improved EEG abnormalities. Additionally, six controlled studies were found for other psychiatric disorders, such as learning disabilities with similar results. Overall, the use of anticonvulsants to treat nonepileptic psychiatric patients needs further controlled studies to better define indications, adequate EEG work up, best AED to be used, and optimal durations of treatment attempts. PMID- 24492443 TI - Underrecognized anomaly: proximal martin-gruber anastomosis at the elbow. AB - PURPOSE: A proximal Martin-Gruber anastomosis (MGA) is an underrecognized anomaly and can mimic ulnar neuropathy at the elbow on electrodiagnostic testing. Martin Gruber anastomosis is mainly recognized as a crossover from median nerve or its branches to ulnar nerve at the forearm, but may occur at the elbow (proximal MGA). The authors report their experience with MGA at the elbow. METHODS: Using standard nerve conduction techniques, the authors prospectively detected electrodiagnostic evidence of a proximal MGA at the elbow over the course of 4 years. An accompanying ulnar neuropathy was diagnosed based on clinical findings, focal conduction slowing, and needle electromyography. RESULTS: A proximal MGA involving branch of ulnar nerve was detected in 16 cases. The detection of proximal MGA to the first dorsal interosseous muscles was more sensitive than to the adductor digiti minimi muscles in their series. CONCLUSIONS: A proximal MGA is an underrecognized anomaly. This study is the largest series for proximal MGA in the literature. The authors recommend considering proximal MGA in any cases of ulnar neuropathy at the elbow, especially if the apparent conduction block is not associated with slowing of conduction velocity, and a discrepancy between clinical and electrodiagnostic findings is present. PMID- 24492444 TI - A clinically applicable approach for detecting spontaneous action potential spikes in amyotrophic lateral sclerosis with a linear electrode array. AB - Examination of spontaneous muscle activity is an important part of the routine electromyogram (EMG) in assessing neuromuscular diseases. The EMG is specifically valuable as a diagnostic test in supporting the diagnosis of amyotrophic lateral sclerosis. High-density surface EMG is a relatively new technique that has until now been used in research but has the potential for clinical application. This study presents a simple high-density surface EMG method for automatic detection of spontaneous action potentials from surface electrode array recordings of patients with amyotrophic lateral sclerosis. To reduce computational complexity while maintaining useful information from the electrode array recording, the multichannel high-density surface EMG was transferred to single-dimensional data by calculating the maximum difference across all channels of the electrode array. A spike detection threshold was then set in the single-dimensional domain to identify the firing times of each spontaneous action potential spike, whereas a spike extraction threshold was used to define the onset and offset of the spontaneous spikes. These data were used to extract the spontaneous spike waveforms from the electrode array EMG. A database of detected spontaneous spikes was thus obtained, including their waveforms, on all channels along with their corresponding firing times. This newly developed method makes use of the information from different channels of the electrode array EMG recording. It also has the primary feature of being simple and fast in implementation, with convenient parameter adjustment and user-computer interaction. Hence, it has good possibilities for clinical application. PMID- 24492445 TI - Potential advantages of the H-reflex of the biceps femoris-long head in documenting S1 radiculopathy. AB - PURPOSE: A novel H-reflex method using the biceps femoris-long head (BF-LH) was investigated to collect the normative data for this reflex arc and assess its clinical utility for S1 radiculopathy evaluation. Comparability with conventional tibial and Sol H-reflex findings was also determined. METHODS: BF-LH H-reflexes were recorded using surface electrodes to S1-root stimulation in 43 unilateral S1 radiculopathy patients (radiculopathy group) and 34 normal subjects (control group) from March 2009 to December 2011. H-M interval and peak-to-peak amplitudes were measured. The BF-LH H-reflex and the H-reflex from the soleus muscle (Sol H reflex) to both tibial nerve stimulation (tibial H-reflex) and S1-root stimulation were used and compared for application in S1 radiculopathy evaluation. RESULTS: BF-LH H-reflexes were reliably recorded for all control group subjects. Abnormal BF-LH H-reflexes were recorded for 40 (93.0%) radiculopathy group patients in the involved extremity, and abnormal involved side tibial H-reflexes and Sol H-reflexes were recorded in 31 (72.1%) and 41 (95.3%) radiculopathy group patients, respectively. The BF-LH H-reflex exhibited significantly higher sensitivity for evaluation of S1 radiculopathy, accurate in 40 (93.0%) radiculopathy group patients, than that provided by the conventional tibial H-reflex of only 31 (72.1%) (P < 0.05). CONCLUSIONS: The BF-LH H-reflex is a highly sensitive and reliable clinical tool for evaluation of the S1 spinal reflex pathway in radiculopathy that is distinct from the Sol H-reflex and conventional tibial H-reflex arcs. PMID- 24492446 TI - Quantitative electromyography of the frontalis muscle. AB - PURPOSE: Identification of abnormal motor unit potentials (MUP), in particular those caused by myopathic processes, is generally difficult in facial muscles because the MUPs are already low in amplitude and short in duration. Therefore, quantitative measures for the limits of abnormality are needed more frequently for these muscles, especially for the pathological processes predominantly affecting the craniofacial area. In this study, we aimed to determine some quantitative values that may help us to differentiate "myogenic" and "neurogenic" processes in periocular muscles. METHODS: The frontalis muscle was examined unilaterally with multi-MUP and interference pattern analyses in 32 normal subjects, 31 patients with different types of myopathy, and 13 patients with facial palsy. Abnormality limits were calculated by using five previously suggested methods, two of which were based on group means and the other three on determining the outlier values. The sensitivity and specificity of multi-MUP and interference pattern parameters in discriminating abnormal findings by using these different methods were analyzed. RESULTS: Statistically significant differences for all MUP parameters, except for the frequency, was found between the groups (P < 0.001). Motor unit potential duration, size index, and amplitude were the most valuable parameters for distinguishing the individual abnormalities. However, their discriminating power was higher for neuropathies than for myopathies. Interference pattern analysis was found not to have any superior sensitivity to MUP analysis. In this study, the outlier analysis that depends on the 5th to 95th percentile limits of the pooled data provided the best power for the discrimination of both neuropathies and myopathies from normal subjects. CONCLUSION: Multi-MUP analysis seems to be helpful in differentiating the patients with neurogenic and-to a lesser extent-myogenic facial muscle involvement. PMID- 24492447 TI - Median nerve somatosensory evoked potential monitoring during carotid endarterectomy: does reference choice matter? AB - Median nerve somatosensory evoked potential monitoring is commonly used during carotid endarterectomy to permit selective shunting in only those patients who are determined to have inadequate collateral flow after carotid cross-clamping. The N20 component is recorded from the CPc (contralateral centroparietal) electrode; either CPi (ipsilateral centroparietal) or Fpz (forehead) can be used as the reference. Because of the distribution of the subcortically generated N18 component, the CPc-Fpz derivation might record both the N20 and the N18 components and might therefore inadequately detect hemispheric ischemia after carotid cross-clamping. Somatosensory evoked potentials recorded were compared using these 2 derivations during 38 carotid endarterectomies to assess their ability to detect neurophysiologic changes after carotid cross-clamping. Although, as expected, the baseline N20 component was significantly larger when recorded with the CPc-Fpz derivation than with the CPc-CPi derivation (3.1 vs. 2.4 MUV in the hemisphere ipsilateral to the clamped carotid, P < 0.001), there was no significant difference in the postclamp amplitude decline between the 2 derivations (8.7% vs. 8.6%, P = 0.82). It is concluded that CPc-Fpz is an acceptable derivation for recording postclamp hemispheric somatosensory evoked potential changes during carotid endarterectomy and may be advantageous because it provides a larger amplitude somatosensory evoked potential than the CPc-CPi derivation. PMID- 24492448 TI - N400 effect when a semantic anomaly is detected in action representation. A source localization analysis. AB - The strength relationship between action and language was largely discussed. In the present research, we explored this link by considering the cortical response (N400 event-related potential effect) to the semantic incongruence induced by a final anomalous object-related action within an actions' sequence. Seventeen participants performed an explicit task to distinguish congruous from incongruous final target action. Event-related potentials analysis showed a significant N400 like effect more frontally (dorsolateral prefrontal cortex) and temporoparietal (mainly left supramarginal gyrus) distribution in response to incongruous condition. It can be argued that the N400-like effect is similar in nature to the N400, which is generally evoked by linguistic stimuli. Nevertheless, the cortical source analysis (low-resolution electromagnetic tomography) showed significant differences for the cortical generators induced by an action processing. This fact may be explained by assuming that object-related action representation activates a specific cortical network, more directly related to congruous/incongruous object use comprehension in relationship with a specific context. PMID- 24492449 TI - Repeated measurements of the auditory oddball paradigm is related to recovery from the vegetative state. AB - The auditory oddball response has been found to be of predictive value for neurologic outcome at the early stages of coma. In the present study, the auditory oddball response was examined longitudinally during the recovery from the vegetative state to consciousness. This response was repeatedly examined every 2 weeks for an average period of 3.5 months in severely brain-injured patients. Results showed that amplitude of the auditory oddball response was unrelated to the behavioral changes during the patients' recovery from the vegetative state to consciousness. However, the presence and size of a negative potential at about 350 milliseconds predicted behavioral outcome, both for the short and long term (2 to 3 years after injury). Practical and theoretical implications of these findings are discussed. PMID- 24492450 TI - Parallel improvement of cognitive functions and P300 latency following donepezil treatment in patients with Alzheimer's disease: a case-control study. AB - PURPOSE: To evaluate the effect of donepezil, one of the cholinesterase inhibitors, on P300 measurements in patients with Alzheimer's disease (AD) and investigate the relationship between the subfactors of cognitive performance and P300 components. METHODS: One hundred outpatients with AD were evaluated for cognitive function (cognitive ability screening instrument) and event-related potentials before and after 22 to 23 weeks of treatment with donepezil (5 mg/day). Twenty age-matched normal control subjects were recruited. RESULTS: The patients with AD showed prolonged P300 and N200 latency, no significant differences in N100 and P200 components, and poor performance in neuropsychological assessments compared with control subjects at baseline. After donepezil treatment, the patients with AD had reduction in P300 latency at Pz lead, which was associated with a parallel improvement in cognitive function in terms of remote memory, recent memory, visual instruction, and orientation. The pre-post treatment difference of P300 latency significantly correlated with the cognitive ability screening instrument score difference and recent memory score difference, respectively. CONCLUSIONS: The patients with AD still had intact early sensory processing but impaired higher-level cognitive processes that could influence behavior deviation. The donepezil treatment, which enhances higher level cognitive processing time, revealed that P300 latency decreases as cognitive capability increases, especially improved in recent memory. PMID- 24492451 TI - Rapid eye movement sleep behavior disorder as an outlier detection problem. AB - OBJECTIVE: Idiopathic rapid eye movement (REM) sleep behavior disorder is a strong early marker of Parkinson's disease and is characterized by REM sleep without atonia and/or dream enactment. Because these measures are subject to individual interpretation, there is consequently need for quantitative methods to establish objective criteria. This study proposes a semiautomatic algorithm for the early detection of Parkinson's disease. This is achieved by distinguishing between normal REM sleep and REM sleep without atonia by considering muscle activity as an outlier detection problem. METHODS: Sixteen healthy control subjects, 16 subjects with idiopathic REM sleep behavior disorder, and 16 subjects with periodic limb movement disorder were enrolled. Different combinations of five surface electromyographic channels, including the EOG, were tested. A muscle activity score was automatically computed from manual scored REM sleep. This was accomplished by the use of subject-specific features combined with an outlier detector (one-class support vector machine classifier). RESULTS: It was possible to correctly separate idiopathic REM sleep behavior disorder subjects from healthy control subjects and periodic limb movement subjects with an average validation area under the receiver operating characteristic curve of 0.993 when combining the anterior tibialis with submentalis. Additionally, it was possible to separate all subjects correctly when the final algorithm was tested on 12 unseen subjects. CONCLUSIONS: Detection of idiopathic REM sleep behavior disorder can be regarded as an outlier problem. Additionally, the EOG channels can be used to detect REM sleep without atonia and is discriminative better than the traditional submentalis. Furthermore, based on data and methodology, arousals and periodic limb movements did only have a minor influence on the quantification of the muscle activity. Analysis of muscle activity during nonrapid eye movement sleep may improve the separation even further. PMID- 24492452 TI - Corticomotor excitability during a noxious stimulus before and after exercise in women with fibromyalgia. AB - The purposes of this study were to assess corticomotor excitability in people with fibromyalgia during a noxious stimulus before and after fatiguing exercise and examine associations with pain perception. Fifteen women with fibromyalgia completed three sessions: one familiarization and two experimental. The experimental sessions were randomized and involved measurement of pain perception and motor evoked potentials before and after (1) quiet rest and (2) isometric contraction of the elbow flexor muscles. Motor evoked potential amplitude of brachioradialis muscle was measured following transcranial magnetic stimulation delivered before, during, and after a noxious mechanical stimulus. After quiet rest, there was no change in pain perception. After the submaximal contraction, there was considerable variability in the pain response. Based on the changes in the experimental pain, subjects were divided into three groups (increase, decrease, and no change in pain). There was an interaction between pain response and the pain-induced change in motor evoked potentials. Those individuals who had an increase in motor evoked potentials during the pain test had an increase in pain after exercise. Thus, women with fibromyalgia were classified based on their pain response to exercise, and this response was associated with the change in corticomotor excitability during the application of a noxious stimulus. PMID- 24492453 TI - Breath-holding spells may be associated with maturational delay in myelination of brain stem. AB - PURPOSE: To evaluate possible contribution of maturational delay of brain stem in the etiology of breath-holding spells in children using brain stem auditory evoked potentials. METHODS: The study group included children who experienced breath-holding spells. The control group consisted of healthy age- and sex matched children. Age, gender, type and frequency of spell, hemoglobin, and ferritin levels in study group and brain stem auditory evoked potentials results in both groups were recorded. Study group was statistically compared with control group for brain stem auditory evoked potentials. RESULTS: The mean age of study and control groups was 26.3 +/- 14.6 and 28.9 +/- 13.9 months, respectively. The III-V and I-V interpeak latencies were significantly prolonged in the study group compared with the control group (2.07 +/- 0.2 milliseconds; 1.92 +/- 0.13 milliseconds and 4.00 +/- 0.27 milliseconds; 3.83 +/- 0.19 milliseconds; P = 0.009 and P = 0.03, respectively). At the same time, III-V and I-V interpeak latencies of patients without anemia in the study group compared with those of control group were significantly prolonged (2.09 +/- 0.24 milliseconds; 1.92 +/- 0.13 milliseconds and 4.04 +/- 0.28 milliseconds; 3.83 +/- 0.19 milliseconds; P = 0.007 and P = 0.01, respectively). CONCLUSIONS: Our results consider that maturational delay in myelination of brain stem may have a role in the etiology of breath-holding spells in children. PMID- 24492454 TI - Role of intraoperative monitoring in pedicle screw placement-useful or not? PMID- 24492455 TI - Role of intraoperative monitoring in pedicle screw placement. PMID- 24492456 TI - Glagov's phenomenon: has our understanding of vascular remodeling changed? PMID- 24492457 TI - Antioxidant therapy with N-acetylcysteine for contrast-induced acute kidney injury: a final nail in the coffin? PMID- 24492459 TI - Magnetic properties of granular CoCrPt:SiO 2 thin films deposited on GaSb nanocones. AB - We report on the effect of microstructure and geometrically induced modifications of the magnetic properties of granular CoCrPt:SiO2 films with weakly interacting magnetic grains deposited on pre-structured GaSb nanocone templates fabricated by an ion erosion technique. By tuning the irradiation conditions, nanocone patterns of different cone sizes were prepared (from 28 to 120 nm in diameter and 32 to 330 nm high, respectively). The influence of the intergranular exchange coupling was also investigated by varying the SiO2 content from 8 to 12 at.%. Deposition of CoCrPt:SiO2 on samples with small nanocones leads to a close magnetic grain packing, which results in the formation of extended magnetic domains larger than the average distance between the GaSb cones. In contrast, on larger nanocones, the magnetic coating grows on the side-walls, with a large separation between neighboring cones, leading to magnetic single-domain regions, which are correlated to the underlying structure. Magnetometry indicates that both remanence and coercivity decrease with increasing cone size and/or SiO2 content due to a combined effect of the angular distribution of the magnetic easy axis of the grains and the intergranular exchange coupling strength. PMID- 24492461 TI - JPH203, an L-type amino acid transporter 1-selective compound, induces apoptosis of YD-38 human oral cancer cells. AB - Compared to most normal cells that express L-type amino acid transporter 2, L type amino acid transporter 1 is highly expressed in cancer cells and presumed to support their elevated growth and proliferation. This study examined JPH203, a potent and selective L-type amino acid transporter 1 inhibitor, and its ability to suppress YD-38 human oral cancer cell growth. The YD-38 cells express L-type amino acid transporter 1 with its associating protein 4F2 heavy chain, but not L type amino acid transporter 2. JPH203 and BCH, a non-selective L-type amino acid transporter inhibitor, completely inhibited l-leucine uptake in YD-38 cells. As expected, the intrinsic affinity of JPH203 to inhibit l-leucine uptake was far more efficient than BCH. Likewise, JPH203 and BCH inhibited YD-38 cell growth, with JPH203 being superior to BCH. JPH203 up-regulated the population of apoptotic YD-38 cells through the activation of apoptotic factors, including caspases and PARP. These results suggest that the inhibition of L-type amino acid transporter 1 activity via JPH203, which may act as a potential novel anti-oral cancer agent, leads to apoptosis by inducing the intracellular depletion of the neutral amino acids essential for cancer cell growth in YD-38 human oral cancer cells. PMID- 24492460 TI - TNF-alpha blockade induces IL-10 expression in human CD4+ T cells. AB - IL-17+ CD4+ T (Th17) cells contribute to the pathogenesis of several human inflammatory diseases. Here we demonstrate that TNF inhibitor (TNFi) drugs induce the anti-inflammatory cytokine IL-10 in CD4+ T cells including IL-17+ CD4+ T cells. TNFi-mediated induction of IL-10 in IL-17+ CD4+ T cells is Treg-/Foxp3 independent, requires IL-10 and is overcome by IL-1beta. TNFi-exposed IL-17+ CD4+ T cells are molecularly and functionally distinct, with a unique gene signature characterized by expression of IL10 and IKZF3 (encoding Aiolos). We show that Aiolos binds conserved regions in the IL10 locus in IL-17+ CD4+ T cells. Furthermore, IKZF3 and IL10 expression levels correlate in primary CD4+ T cells and Aiolos overexpression is sufficient to drive IL10 in these cells. Our data demonstrate that TNF-alpha blockade induces IL-10 in CD4+ T cells including Th17 cells and suggest a role for the transcription factor Aiolos in the regulation of IL-10 in CD4+ T cells. PMID- 24492462 TI - Evaluation of three-dimensional cultured HepG2 cells in a nano culture plate system: an in vitro human model of acetaminophen hepatotoxicity. AB - Overdoses of acetaminophen (paracetamol, N-acetyl-p-aminophenol; APAP) cause severe liver injury, yet there is no common or high throughput in vitro human APAP model. This study examined the characteristics and usefulness of HepG2 cells grown in a nano culture plate (NCP) system, a three-dimensional culture method, as an in vitro human model for APAP-induced hepatotoxicity. The NCP-cultured HepG2 cells showed higher expression of mRNA and protein levels of cytochrome P450 2E1, which metabolizes APAP to a toxic metabolite, APAP-cysteine adduct formation, and higher sensitivity against APAP-induced cell injury compared with conventionally cultured cells. We demonstrated that treatment of APAP in NCP cultured HepG2 cells shows key mechanistic features of APAP-induced hepatotoxicity, such as decreases in intracellular glutathione and mitochondrial membrane potential, activation of JNK, and cellular injury; and pharmacological agents, such as Cyclosporine A (a mitochondrial permeability transition inhibitor) and SP600125 (a JNK inhibitor), prevented cell injury induced by APAP exposure. In addition, the antidote of APAP-induced hepatotoxicity, N acetylcysteine, could attenuate cellular injury induced by APAP in NCP-cultured HepG2 cells. We suggest that cellular injury induced by APAP treatment using an NCP-HepG2 system is a useful human model to study mechanisms and screen drug candidates of APAP-induced hepatotoxicity. PMID- 24492463 TI - Preventive and alleviative effect of tramadol on neuropathic pain in rats: roles of alpha2-adrenoceptors and spinal astrocytes. AB - The acute analgesic effect of tramadol has been extensively investigated; however, its long-term effect on neuropathic pain has not been well clarified. In this study, we examined the effects of repeated administration of tramadol on partial sciatic nerve ligation-induced neuropathic pain in rats. Each drug was administered once daily from 0 - 6 days (preventive effect) or 7 - 14 days (alleviative effect) after the surgery. Mechanical allodynia was evaluated just before (preventive or alleviative effect) and 1 h after (analgesic effect) drug administration. Like morphine, first administration of tramadol (20 mg/kg) showed an acute analgesic effect on the developed mechanical allodynia, which was diminished by naloxone. Like amitriptyline, repeated administration of tramadol showed preventive and alleviative effects on the mechanical allodynia that was diminished by yohimbine, but not naloxone. The alleviative effects of tramadol lasted even after drug cessation or in the presence of yohimbine. Repeated administration of tramadol increased the dopamine beta-hydroxylase immunoreactivity in the spinal cord. Furthermore, tramadol inhibited the nerve ligation-induced activation of spinal astrocytes, which was reduced by yohimbine. These results suggest that tramadol has both MU-opioid receptor-mediated acute analgesic and alpha2-adrenoceptor-mediated preventive and alleviative effects on neuropathic pain, and the latter is due to alpha2-adrenoceptor-mediated inhibition of astrocytic activation. PMID- 24492464 TI - Involvement of 5-HT3 and 5-HT4 receptors in the regulation of circadian clock gene expression in mouse small intestine. AB - Several lines of evidence suggest that 5-HT receptors play a critical role in the expression of clock genes in the suprachiasmatic nucleus, the main circadian oscillator in hamsters. The contributions of 5-HT-receptor subtypes in the intestine, where they are expressed at high concentrations, are however not yet clarified. The 5-HT synthesis inhibitor, p-chlorophenylalanine, attenuated the daily rhythm of Per1 and Per2 gene expression in the intestine. Injection of 5-HT and agonists of the 5-HT3 and 5-HT4 receptors increased Per1/Per2 expression and decreased Bmal1 expression in a dose-dependent manner. Although treatment with antagonists of 5-HT3 and 5-HT4 alone did not affect clock gene expression, co injection of these antagonists with 5-HT blocked the 5-HT-induced changes in clock gene expression. Increased tissue levels of 5-HT due to treatment with the antidepressants clomipramine and fluvoxamine did not affect clock gene expression. The present results suggest that the 5-HT system in the small intestine may play a critical role in regulating circadian rhythms through 5 HT3/5-HT4-receptor activation. PMID- 24492458 TI - Insights into the distribution and abundance of the ubiquitous candidatus Saccharibacteria phylum following tag pyrosequencing. AB - The phylum candidatus Saccharibacteria formerly known as Candidate Division TM7 is a highly ubiquitous phylum with 16S rRNA gene sequences reported in soils, sediments, wastewater and animals, as well as a host of clinical environments. Here, the application of two taxon-specific primers on environmental and human associated samples using bar-coded tag pyrosequencing revealed two new clades for this phylum to exist and we propose that the division consists of 2 monophyletic and 2 polyphyletic clades. Investigation into TM7 ecology revealed that a high proportion (58%) of phylotypes were sample specific, few were widely distributed and of those most widely distributed all belonged to subdivision 3. Additionally, 50% of the most relatively abundant phylotypes observed were also subdivision 3 members. Community analysis showed that despite the presence of a high proportion of unique phylotypes, specific groups of samples still harbor similar TM7 communities with samples clustering together. The lack of relatively abundant phylotypes from subdivisions 1, 2 and 4 and the presence of very few cosmopolitan members' highlights not only the site specific nature of this phylum but provides insight into why the majority of studies into TM7 have been biased towards subdivision 3. PMID- 24492466 TI - Insulin regulates the novel adipokine adipolin/CTRP12: in vivo and ex vivo effects. AB - There has been intense interest in the adipokines of the C1q complement/TNF related protein (CTRP) superfamily. Adipolin (CTRP12) has been described as a novel adipokine, abundantly expressed in adipose tissue with insulin-sensitising and anti-inflammatory effects. We wanted to investigate the effects of acute and chronic hyperinsulinaemia on circulating adipolin concentrations (ELISA) via a prolonged insulin-glucose infusion in humans. We also examined the effects of insulin and the insulin sensitiser, rosiglitazone, on adipolin concentrations (western blotting) in human adipose tissue explants. We found that hyperinsulinaemic induction in healthy lean human subjects significantly increased circulating levels of adipolin (P<0.05 and P<0.01). Furthermore, in subcutaneous adipose tissue explants, insulin significantly increased adipolin protein expression and secretion (P<0.05 and P<0.01). This effect was attenuated by the phosphatidylinositol 3-kinase inhibitor, LY294002 (P<0.05). Moreover, the insulin-sensitising peroxisome proliferator-activated receptor gamma (PPARgamma) agonist, rosiglitazone, significantly increased adipolin protein expression and secretion in subcutaneous adipose tissue explants (P<0.05 and P<0.01). This effect was inhibited by the PPARgamma antagonist, GW9662 (P<0.05). Our data provide novel insights into adipolin physiology in human subjects. PMID- 24492467 TI - VIP contribution to the decidualization program: regulatory T cell recruitment. AB - During early pregnancy, the human uterus undergoes profound tissue remodeling characterized by leukocyte invasion and production of proinflammatory cytokines, followed by tissue repair and tolerance maintenance induction. Vasoactive intestinal peptide (VIP) is produced by trophoblast cells and modulates the maternal immune response toward a tolerogenic profile. Here, we evaluated the contribution of the VIP/VPAC to endometrial renewal, inducing decidualization and the recruitment of induced regulatory T cells (iTregs) that accompany the implantation period. For that purpose, we used an in vitro model of decidualization with a human endometrial stromal cell line (HESC) stimulated with progesterone (P4) and lipopolysaccharide (LPS) simulating the inflammatory response during implantation and human iTregs (CD4(+)CD25(+)FOXP3(+)) differentiated from naive T cells obtained from peripheral blood mononuclear cells of fertile women. We observed that VIP and its receptor VPAC1 are constitutively expressed in HESCs and that P4 increased VIP expression. Moreover, in HESC VIP induced expression of RANTES (CCL5), one of the main chemokines involved in T cell recruitment, and this effect is enhanced by the presence of P4 and LPS. Finally, assays of the migration of iTregs toward conditioned media from HESCs revealed that endogenous VIP production induced by P4 and LPS and RANTES production were involved, as anti-RANTES neutralizing Ab or VIP antagonist prevented their migration. We conclude that VIP may have an active role in the decidualization process, thus contributing to recruitment of iTregs toward endometrial stromal cells by increasing RANTES expression in a P4-dependent manner. PMID- 24492468 TI - IGF1R blockade with ganitumab results in systemic effects on the GH-IGF axis in mice. AB - Ganitumab is a fully human MAB to the human type 1 IGF receptor (IGF1R). Binding assays showed that ganitumab recognized murine IGF1R with sub-nanomolar affinity (KD=0.22 nM) and inhibited the interaction of murine IGF1R with IGF1 and IGF2. Ganitumab inhibited IGF1-induced activation of IGF1R in murine lungs and CT26 murine colon carcinoma cells and tumors. Addition of ganitumab to 5-fluorouracil resulted in enhanced inhibition of tumor growth in the CT26 model. Pharmacological intervention with ganitumab in naive nude mice resulted in a number of physiological changes described previously in animals with targeted deletions of Igf1 and Igf1r, including inhibition of weight gain, reduced glucose tolerance and significant increase in serum levels of GH, IGF1 and IGFBP3. Flow cytometric analysis identified GR1/CD11b-positive cells as the highest IGF1R expressing cells in murine peripheral blood. Administration of ganitumab led to a dose-dependent, reversible decrease in the number of peripheral neutrophils with no effect on erythrocytes or platelets. These findings indicate that acute IGF availability for its receptor plays a critical role in physiological growth, glucose metabolism and neutrophil physiology and support the presence of a pituitary IGF1R-driven negative feedback loop that tightly regulates serum IGF1 levels through Gh signaling. PMID- 24492470 TI - High saturated-fat and low-fibre intake: a comparative analysis of nutrient intake in individuals with and without type 2 diabetes. AB - OBJECTIVE: The aim of dietary modification, as a cornerstone of type 2 diabetes (T2DM) management, is to optimise metabolic control and overall health. This study describes food and nutrient intake in a sample of adults with T2DM, and compares this to recommendations, and to intake in age, sex, body mass index (BMI) and social-class matched adults without T2DM. DESIGN: A cross-sectional analysis of food and nutrient intake in 124 T2DM individuals (64% male; age 57.4+/-5.6 years, BMI 32.5+/-5.8 kg m(-2)) and 124 adults (age 57.4+/-7.0 years, BMI 31.2+/-5.0 kg m(-2)) with no diabetes (ND) was undertaken using a 4-day semiweighed food diary. Biochemical and anthropometric variables were also measured. RESULTS: While reported energy intake was similar in T2DM vs ND (1954 vs 2004 kcal per day, P=0.99), T2DM subjects consumed more total-fat (38.8% vs 35%, P?0.001), monounsaturated-fat (13.3% vs 12.2%; P=0.004), polyunsaturated-fat (6.7% vs 5.9%; P<0.001) and protein (18.6% vs 17.5%, P?0.01). Both groups exceeded saturated-fat recommendations (14.0% vs 13.8%). T2DM intakes of carbohydrate (39.5% vs 42.9%), non-milk sugar (10.4% vs 15.0%) and fibre (14.4 vs 18.9 g) were significantly lower (P<0.001). Dietary glycaemic load (GL) was also lower in T2DM (120.8 vs 129.2; P=0.02), despite a similar glycaemic index (59.7 vs 60.1; P=0.48). T2DM individuals reported consuming significantly more wholemeal/brown/wholegrain breads, eggs, oils, vegetables, meat/meat products, savoury snacks and soups/sauces and less white breads, breakfast cereals, cakes/buns, full-fat dairy, chocolate, fruit juices, oily fish and alcohol than ND controls. CONCLUSION: Adults with T2DM made different food choices to ND adults. This resulted in a high saturated-fat diet, with a higher total-fat, monounsaturated-fat, polyunsaturated-fat and protein content and a lower GL, carbohydrate, fibre and non-milk sugar content. Dietary education should emphasise and reinforce the importance of higher fibre, fruit, vegetable and wholegrain intake and the substitution of monounsaturated for saturated-fat sources, in energy balanced conditions. PMID- 24492469 TI - WRKY transcription factors: Jack of many trades in plants. AB - WRKY transcription factors are one of the largest families of transcriptional regulators found exclusively in plants. They have diverse biological functions in plant disease resistance, abiotic stress responses, nutrient deprivation, senescence, seed and trichome development, embryogenesis, as well as additional developmental and hormone-controlled processes. WRKYs can act as transcriptional activators or repressors, in various homo- and heterodimer combinations. Here we review recent progress on the function of WRKY transcription factors in Arabidopsis and other plant species such as rice, potato, and parsley, with a special focus on abiotic, developmental, and hormone-regulated processes. PMID- 24492471 TI - Development of a fluorescent sensor for illicit date rape drug GHB. AB - The first fluorescent sensor (GHB Orange) for date rape drug GHB was developed. It exhibits the fluorescence quenching property for GHB and allows its detection in various drinks. The interaction mechanism was elucidated as intramolecular charge transfer induced by a hydrogen bond. This discovery will help in solving the drug facilitated sexual assault problems. PMID- 24492473 TI - Proposed formation and dynamical signature of a chiral Bose liquid in an optical lattice. AB - Recent experiments on p-orbital atomic bosons have suggested the emergence of a spectacular ultracold superfluid with staggered orbital currents in optical lattices. This raises fundamental questions concerning the effects of thermal fluctuations as well as possible ways of directly observing such chiral order. Here we show via Monte Carlo simulations that thermal fluctuations destroy this superfluid in an unexpected two-step process, unveiling an intermediate normal phase with spontaneously broken time-reversal symmetry, dubbed a 'chiral Bose liquid'. For integer fillings (n>=2) in the chiral Mott regime, thermal fluctuations are captured by an effective orbital Ising model, and Onsager's powerful exact solution is adopted to determine the transition from this intermediate liquid to the para-orbital normal phase at high temperature. A lattice quench is designed to convert the staggered angular momentum, previously thought by experts difficult to directly probe, into coherent orbital oscillations, providing a time-resolved dynamical signature of chiral order. PMID- 24492472 TI - Acidic extracellular pH neutralizes the autophagy-inhibiting activity of chloroquine: implications for cancer therapies. AB - Acidic pH is an important feature of tumor microenvironment and a major determinant of tumor progression. We reported that cancer cells upregulate autophagy as a survival mechanism to acidic stress. Inhibition of autophagy by administration of chloroquine (CQ) in combination anticancer therapies is currently evaluated in clinical trials. We observed in 3 different human cancer cell lines cultured at acidic pH that autophagic flux is not blocked by CQ. This was consistent with a complete resistance to CQ toxicity in cells cultured in acidic conditions. Conversely, the autophagy-inhibiting activity of Lys-01, a novel CQ derivative, was still detectable at low pH. The lack of CQ activity was likely dependent on a dramatically reduced cellular uptake at acidic pH. Using cell lines stably adapted to chronic acidosis we could confirm that CQ lack of activity was merely caused by acidic pH. Moreover, unlike CQ, Lys-01 was able to kill low pH-adapted cell lines, although higher concentrations were required as compared with cells cultured at normal pH conditions. Notably, buffering medium pH in low pH-adapted cell lines reverted CQ resistance. In vivo analysis of tumors treated with CQ showed that accumulation of strong LC3 signals was observed only in normoxic areas but not in hypoxic/acidic regions. Our observations suggest that targeting autophagy in the tumor environment by CQ may be limited to well-perfused regions but not achieved in acidic regions, predicting possible limitations in efficacy of CQ in antitumor therapies. PMID- 24492474 TI - Inhibition of NOX/VPO1 pathway and inflammatory reaction by trimethoxystilbene in prevention of cardiovascular remodeling in hypoxia-induced pulmonary hypertensive rats. AB - Recent studies show that resveratrol exerts beneficial effects on prevention of pulmonary hypertension. This study is performed to explore the effects of trimethoxystilbene, a novel resveratrol analog, on rat pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-induced pulmonary arterial hypertension (PAH) and the underlying mechanisms. Sprague-Dawley rats were placed in a chamber and exposed to 10% O(2) continuously for 4 weeks to induce PAH. The effects of trimethoxystilbene (5 or 10 mg/kg per day, intragastric [i.g.]) and resveratrol (as a positive control, 25 mg/kg per day, i.g.) on hypoxia-induced PAH vascular remodeling and right ventricle hypertrophy were evaluated. At the end of experiments, the index for pulmonary vascular remodeling and right ventricle hypertrophy, inflammatory cell infiltration in lung tissue, the plasma levels and lung tissue contents of hydrogen peroxide (H(2)O(2)), the mRNA and protein levels for NADPH oxidases (NOX2, NOX4) and vascular peroxidase 1 (VPO1) in pulmonary artery or right ventricle were measured. The results showed that trimethoxystilbene treatment significantly attenuated hypoxia-induced pulmonary vascular remodeling (such as decrease in the ratio of wall thickness to vessel external diameter) and right ventricle hypertrophy (such as decrease in the ratio of right ventricle weight to the length of the tibia), accompanied by downregulation of NOX2, NOX4, and VPO1 expression in pulmonary artery or right ventricle, decrease in H(2)O(2) production and inflammatory cell infiltration in lung tissue. Trimethoxystilbene is able to prevent pulmonary vascular remodeling and right ventricle hypertrophy in hypoxia-induced rat model of PAH, which is related to inhibition of the NOX/VPO1 pathway-mediated oxidative stress and the inflammatory reaction. PMID- 24492475 TI - Ethyl pyruvate ameliorates monocrotaline-induced pulmonary arterial hypertension in rats. AB - BACKGROUND: Ethyl pyruvate (EP) is an anti-inflammatory and anti-oxidant agent associated with many diseases. In this study, we evaluated whether EP could attenuate monocrotaline-induced pulmonary arterial hypertension (PAH). METHODS: A PAH model was established by subcutaneously injecting a single dose of monocrotaline (60 mg/kg). And then a daily intraperitoneal injection of EP (50 mg/kg) was administered on day 1 to day 28 (preventive EP treatment) or day 15 to day 28 (therapeutic EP treatment). Hemodynamic changes were measured by catheterization, and the right ventricle hypertrophy index, the medial wall thickness, and the medial wall areas were also calculated. Enzyme-linked immunosorbent assay and immunohistochemical analysis were used to determine the serum levels and expression of tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and endothelin-1 (ET-1) in the lung tissue. RESULTS: Both preventive and therapeutic EP treatment significantly ameliorated hemodynamic changes and vascular remodeling indicators (all P < 0.05). The serum levels and expression of TNF-alpha, IL-6, and ET-1 in the lung tissue were also significantly decreased (all P < 0.05). CONCLUSIONS: EP ameliorates monocrotaline induced PAH and reverses pulmonary vascular remolding in rats by inhibiting the release of TNF-alpha and IL-6 and reducing the expression of ET-1. PMID- 24492476 TI - The use of oxidized regenerated cellulose in oncoplastic breast surgery: "warning" for postoperative follow-up! PMID- 24492477 TI - Critical analysis of the classification of glaucomas issued by the European Glaucoma Society in 2008. AB - PURPOSE: To critically analyze the 2008 European Glaucoma Society classification of glaucomas, in order to reveal its advantages and shortcomings. METHODS: The paper tries to determine the extent to which this classification is clear (being based on a coherent and consistently followed set of criteria), is comprehensive (framing all forms of glaucoma), helps to understand the sickness (using a logical framing system), and facilitates therapeutic decision making (offering direct therapeutic suggestions). RESULTS AND CONCLUSION: The paper shows that, compared with all the previous classifications, the 2008 European Glaucoma Society classification is one step ahead (in the way of classifying the group of secondary angle-closure glaucomas), two steps behind (in rejecting two useful categories of congenital glaucoma), and similar in several respects: that it is based on criticizable fundamental and secondary criteria that cannot cover all forms of sickness gathered at a particular crossing; that it uses several equally weighted criteria for one single crossing (division); that it frames one clinical entity in several clinical categories; that it does not reflect reality in some aspects; and that it does not offer direct therapeutic suggestions: after framing a case in a scheme built on the basis of gonioscopic observation, it requires a second stage of pathogenic analysis, so that the ophthalmologist is able to decide the correct treatment only in the third stage. All these considerations justify the efforts to find a new classification that will be able to correct the abovementioned shortcomings. PMID- 24492478 TI - Structure and hydrogen bonding of the hydrated selenite and selenate ions in aqueous solution. AB - The structure and hydrogen bonding of the hydrated selenite, SeO3(2-), and selenate, SeO4(2-), ions have been studied in aqueous solution by large angle X ray scattering (LAXS), EXAFS and double difference infrared (DDIR) spectroscopy. The mean Se-O bond distances are 1.709(2) and 1.657(2) A, respectively, as determined by LAXS, and 1.701(3) and 1.643(3) A by EXAFS. These bond distances are slightly longer than the mean distances found in the solid state, 1.691 and 1.634 A, respectively. The structures of HSeO3(-), H2SeO3 and HSeO4(-) in aqueous solution have been determined by EXAFS giving the same Se-O bond distances as for the selenite and selenate ions, respectively. The mean Se...O(w) distance to the water molecules hydrogen binding to selenite oxygens is 3.87(2) A, and it is 4.36(8) A to those clustered outside the lone electron-pair. The selenate ion has a symmetric hydration shell with only one Se...O(w) distance, 3.94(2) A. The mean Se-O...O(w) angle in the hydrated selenite ion is 114.5 degrees , and the large temperature factor of the Se...O(w) distance strongly indicates equilibrium between two and three water molecules hydrogen bound to the selenite oxygens. The mean Se-O...O(w) angle in the hydrated selenate ion is 120 degrees which strongly indicates that two water molecules hydrogen bind to the selenate oxygens. The DDIR spectra show peaks for the affected water bound to the selenite and selenate ions at 2491 +/- 2 and 2480 +/- 39 cm(-1), respectively, compared to 2509 cm(-1) in pure water. This shows that the selenite and selenate ions shall be regarded as weak structure makers. PMID- 24492479 TI - DNA-PKcs activates the Chk2-Brca1 pathway during mitosis to ensure chromosomal stability. AB - The catalytic subunit of DNA-dependent protein kinase (DNA-PKcs) is known to have a critical role in DNA double-strand break repair. We have previously reported that DNA-PKcs is activated when cells enter mitosis and functions in mitotic spindle assembly and chromosome segregation. Here we report that DNA-PKcs is the upstream regulator of the Chk2-Brca1 pathway, which impacts microtubule dynamics, kinetochore attachment and chromosomal segregation in mitosis. Downstream from Chk2, Brca1 promotes monoubiquitination of gamma-tubulin to inhibit microtubule nucleation and growth. We found that DNA-PKcs is essential for mitotic Chk2 phosphorylation at Thr68. As in Chk2- and Brca1-deficient cells, loss of DNA-PKcs resulted in chromosome misalignment and lagging during anaphase owing to elevation in microtubule dynamics. Importantly, these mitotic aberrations in DNA PKcs-defective cells were alleviated by the overexpression of phosphomimetic Chk2 or Brca1 mutant proteins but not their wild-type counterparts. Taken together, these results demonstrate that DNA-PKcs regulates mitotic spindle organization and chromosomal instability via the Chk2-Brca1 signaling pathway. PMID- 24492480 TI - Tumor suppressor NDRG2 tips the balance of oncogenic TGF-beta via EMT inhibition in colorectal cancer. AB - Transforming growth factor-beta (TGF-beta), a pluripotent cytokine expressed in the colon, has a crucial but paradoxical role in colorectal cancer (CRC). TGF beta is a potent proliferation inhibitor of normal colon epithelial cells and acts as a tumor suppressor. However, TGF-beta also promotes invasion and metastasis during late-stage CRC, thereby acting as an oncogene. Thus, understanding the factors behind the paradoxical roles of TGF-beta and elucidating the mechanisms by which TGF-beta-induced proliferation inhibition is impaired in CRC are necessary. Here, we found that the N-Myc tumor suppressor gene downstream-regulated gene NDRG2 (N-Myc downstream-regulated gene 2), which is a TGF-beta-responsive gene, abrogated TGF-beta-induced epithelial-mesenchymal transition (EMT) and further inhibited the invasion and migration of CRC cells. TGF-beta positively induced NDRG2 expression through direct transactivation mediated by Sp1 and by abrogation of the repressive c-Myc/Miz-1 complex on NDRG2 promoter in normal epithelial cells. Aberrant hypermethylation of NDRG2, which could respond to TGF-beta growth inhibition signaling, abrogated the inhibitory effect of NDRG2 in TGF-beta-induced EMT in CRCs. Reduced NDRG2 expression was highly correlated with the invasion stage and metastasis of CRC. Our study establishes that NDRG2 is a new tumor suppressor gene that responds to TGF-beta anti-proliferative signaling and tips the balance of oncogenic TGF-beta during late-stage CRC. PMID- 24492481 TI - Structural data on the periplasmic aldehyde oxidoreductase PaoABC from Escherichia coli: SAXS and preliminary X-ray crystallography analysis. AB - The periplasmic aldehyde oxidoreductase PaoABC from Escherichia coli is a molybdenum enzyme involved in detoxification of aldehydes in the cell. It is an example of an alphabetagamma heterotrimeric enzyme of the xanthine oxidase family of enzymes which does not dimerize via its molybdenum cofactor binding domain. In order to structurally characterize PaoABC, X-ray crystallography and small angle X-ray scattering (SAXS) have been carried out. The protein crystallizes in the presence of 20% (w/v) polyethylene glycol 3350 using the hanging-drop vapour diffusion method. Although crystals were initially twinned, several experiments were done to overcome twinning and lowering the crystallization temperature (293 K to 277 K) was the solution to the problem. The non-twinned crystals used to solve the structure diffract X-rays to beyond 1.80 A and belong to the C2 space group, with cell parameters a = 109.42 A, b = 78.08 A, c = 151.77 A, beta = 99.77 degrees , and one molecule in the asymmetric unit. A molecular replacement solution was found for each subunit separately, using several proteins as search models. SAXS data of PaoABC were also collected showing that, in solution, the protein is also an alphabetagamma heterotrimer. PMID- 24492482 TI - Silicon enhances the growth of Phaeodactylum tricornutum Bohlin under green light and low temperature. AB - Phaeodactylum tricornutum Bohlin is an ideal model diatom; its complete genome is known, and it is an important economic microalgae. Although silicon is not required in laboratory and factory culture of this species, previous studies have shown that silicon starvation can lead to differential expression of miRNAs. The role that silicon plays in P. tricornutum growth in nature is poorly understood. In this study, we compared the growth rate of silicon starved P. tricornutum with that of normal cultured cells under different culture conditions. Pigment analysis, photosynthesis measurement, lipid analysis, and proteomic analysis showed that silicon plays an important role in P. tricornutum growth and that its presence allows the organism to grow well under green light and low temperature. PMID- 24492483 TI - Synergistic chromatin repression of the tumor suppressor gene RARB in human prostate cancers. AB - DNA methylation and polycomb proteins are well-known mediators of epigenetic silencing in mammalian cells. Usually described as mutually exclusive, this statement is today controversial and recent in vitro studies suggest the co existence of both repressor systems. We addressed this issue in the study of Retinoic Acid Receptor beta (RARbeta), a tumor suppressor gene frequently silenced in prostate cancer. We found that the RARbeta promoter is hypermethylated in all studied prostate tumors and methylation levels are positively correlated with H3K27me3 enrichments. Thus, by using bisulfite conversion and pyrosequencing of immunoprecipitated H3K27me3 chromatin, we demonstrated that DNA methylation and polycomb repression co-exist in vivo at this locus. We found this repressive association in 6/6 patient tumor samples of different Gleason score, suggesting a strong interplay of DNA methylation and EZH2 to silence RARbeta during prostate tumorigenesis. PMID- 24492484 TI - Alcohol-induced autophagy contributes to loss in skeletal muscle mass. AB - Patients with alcoholic cirrhosis and hepatitis have severe muscle loss. Since ethanol impairs skeletal muscle protein synthesis but does not increase ubiquitin proteasome-mediated proteolysis, we investigated whether alcohol-induced autophagy contributes to muscle loss. Autophagy induction was studied in: A) Human skeletal muscle biopsies from alcoholic cirrhotics and controls, B) Gastrocnemius muscle from ethanol and pair-fed mice, and C) Ethanol-exposed murine C2C12 myotubes, by examining the expression of autophagy markers assessed by immunoblotting and real-time PCR. Expression of autophagy genes and markers were increased in skeletal muscle from humans and ethanol-fed mice, and in myotubes following ethanol exposure. Importantly, pulse-chase experiments showed suppression of myotube proteolysis upon ethanol-treatment with the autophagy inhibitor, 3-methyladenine (3MA) and not by MG132, a proteasome inhibitor. Correspondingly, ethanol-treated C2C12 myotubes stably expressing GFP-LC3B showed increased autophagy flux as measured by accumulation of GFP-LC3B vesicles with confocal microscopy. The ethanol-induced increase in LC3B lipidation was reversed upon knockdown of Atg7, a critical autophagy gene and was associated with reversal of the ethanol-induced decrease in myotube diameter. Consistently, CT image analysis of muscle area in alcoholic cirrhotics was significantly reduced compared with control subjects. In order to determine whether ethanol per se or its metabolic product, acetaldehyde, stimulates autophagy, C2C12 myotubes were treated with ethanol in the presence of the alcohol dehydrogenase inhibitor (4 methylpyrazole) or the acetaldehyde dehydrogenase inhibitor (cyanamide). LC3B lipidation increased with acetaldehyde treatment and increased further with the addition of cyanamide. We conclude that muscle autophagy is increased by ethanol exposure and contributes to sarcopenia. PMID- 24492486 TI - Ag2S/g-C3N4 composite photocatalysts for efficient Pt-free hydrogen production. The co-catalyst function of Ag/Ag2S formed by simultaneous photodeposition. AB - Without Pt as cocatalyst, the photocatalytic hydrogen evolution activity of graphitic carbon nitride (g-C3N4) or even its composite is normally rather low (<1 MUmol h(-1)). Exploring Pt-free cocatalysts to substitute precious Pt is of great importance in the photocatalytic field. In the present work, Ag2S-modified g-C3N4 (Ag2S/g-C3N4) composite photocatalysts were prepared via a simple precipitation method. The results demonstrated that the photocatalytic H2 production activity of g-C3N4 can be remarkably increased by the combination of Ag2S. The optimal Ag2S loading was found to be 5 wt%, giving a H2 production of 10 MUmol h(-1), around 100 times that of pure g-C3N4. The enhanced photocatalytic activity can be mainly attributed to the effective charge transfer between g-C3N4 and Ag/Ag2S, of which the latter is formed by simultaneous photodeposition in the photocatalytic H2 evolution reaction and acts as an efficient co-catalyst for the g-C3N4. This work showed the possibility for utilization of Ag2S or Ag/Ag2S as a substitute for Pt in the photocatalytic production of H2 using g-C3N4. PMID- 24492485 TI - CGI-58, a key regulator of lipid homeostasis and signaling in plants, also regulates polyamine metabolism. AB - Comparative Gene Identification-58 (CGI-58) is an alpha/beta hydrolase-type protein that regulates lipid homeostasis and signaling in eukaryotes by interacting with and stimulating the activity of several different types of proteins, including a lipase in mammalian cells and a peroxisomal ABC transporter (PXA1) in plant cells. Here we show that plant CGI-58 also interacts with spermidine synthase 1 (SPDS1), an enzyme that plays a central role in polyamine metabolism by converting putrescine into spermidine. Analysis of polyamine contents in Arabidopsis thaliana plants revealed that spermidine levels were significantly reduced, and putrescine increased, in both cgi-58 and cgi-58/pxa1 mutant plants, relative to pxa1 mutant or wild-type plants. Evaluation of polyamine-related gene expression levels, however, revealed similar increases in transcript abundance in all mutants, including cgi-58, pxa1, and cgi-58/pxa1, in comparison to wild type. Taken together, the data support a model whereby CGI-58 and PXA1 contribute to the regulation of polyamine metabolism at the transcriptional level, perhaps through a shared lipid-signaling pathway, and that CGI-58 also acts independently of PXA1 to increase spermidine content at a post transcriptional level, possibly through protein-protein interaction with SPDS1. PMID- 24492487 TI - Hormonal changes during menopause and the impact on fluid regulation. AB - Reproductive surgeries leave women more susceptible to postoperative hypervolemic hyponatremia because during this period women can retain water at an accelerated pace and much faster than they do sodium. This review proposes that estrogen and progestogen exposure play an important role in the increased risk of hyponatremia in menopausal women. Estrogen and progesterone exposure have important effects on both body fluid regulation and cardiovascular function and both of these reproductive hormones impact blood pressure responses to sodium loads. This article provides information on the effects of female reproductive hormones and hormone therapy (HT) on fluid regulation and cardiovascular function during menopause. Thirst- and fluid-regulating hormones respond to both osmotic and volume stimuli. Aging women maintain thirst sensitivity to osmotic stimuli but lose some thirst sensitivity to changes in central body fluid volume. Thus, older adults are more at risk of dehydration because they may replenish fluids at a slower rate. Estrogen therapy increases osmotic sensitivity for mechanisms to retain body water so may help menopausal women control body fluids and avoid dehydration. Some progestogens can mitigate estradiol effects on water and sodium retention through competition with aldosterone for the mineralocorticoid receptor and attenuating aldosterone-mediated sodium retention in the distal tubule. However, some progestogens can increase cardiovascular risks. Appropriate balance of these hormones within HT is important to avoid the negative consequences of body fluid and sodium retention, including edema and hypertension. PMID- 24492488 TI - Possible Loss of GABAergic Inhibition in Mice With Induced Adenomyosis and Treatment With Epigallocatechin-3-Gallate Attenuates the Loss With Improved Hyperalgesia. AB - We have previously reported that induction of adenomyosis in mice results in progressive hyperalgesia, uterine hyperactivity, and elevated plasma corticosterone levels and that epigallocatechin-3-gallate (EGCG) treatment dose dependently suppressed myometrial infiltration and improved generalized hyperalgesia. In this study, we examined whether adenomyosis induced in mice results in the loss of GABAergic inhibition as manifested by the diminished glutamate decarboxylase (GAD) 65-expressing neurons in the brainstem nucleus raphe magnus (NRM) that could correlate with heightened hyperalgesia. We also evaluated whether EGCG treatment would reverse these changes and also improve the expression of some proteins known to be involved in adenomyosis. Adenomyosis was induced in 28 female ICR mice and additional 12 were used as blank controls, as reported previously. At the 16th week, all mice with induced adenomyosis received low- or high-dose EGCG treatment or untreated. Mice without adenomyosis received no treatment. After 3 weeks of treatment, their uterine horns and brains were harvested. The right uterine horn was used for immunohistochemistry analysis and for counting the number of macrophages infiltrating into the ectopic endometrium. The brainstem NRM sections were subjected to immunofluorescence staining for GAD65. We found that mice with induced adenomyosis had significantly diminished GAD65-expressing neurons, concomitant with heightened hyperalgesia. Treatment with EGCG increased these neurons in conjunction with improved hyperalgesia, reduced the expression of p-p65, cycloxygenase 2, oxytocin receptor, collagen I and IV, and transient receptor potential vanilloid type 1 in ectopic endometrium or myometrium, reduced the number of macrophages infiltrating into the ectopic endometrium while elevated the expression of progesterone receptor isoform B. Thus, adenomyosis-induced pain resembles neuropathic pain in that there is a remarkable central plasticity. PMID- 24492489 TI - Genetic variants in the CYP24A1 gene are associated with prostate cancer risk and aggressiveness in a Korean study population. AB - BACKGROUND: Vitamin D-deactivating enzyme CYP24A1 had controversial effects on prostate cancer risk; the genetic study also showed the controversial results. Therefore, we identified the relationships between polymorphisms in CYP24A1 and prostate cancer in a Korean cohort. METHODS: We evaluated the association between 21 single-nucleotide polymorphisms (SNPs) in the CYP24A1 and prostate cancer in Korean men (272 prostate cancers and 173 controls). BPH patients with high PSA or abnormal digital rectal examination who underwent negative prostate biopsy were enrolled in the control group. Twenty-one SNPs in the CYP24A1 were selected from the International HapMap database and the NCBI database with calculation of minor allele frequency and linkage disequilibrium, preferably including the SNPs that were nonsynonymous and located within exons. We also investigated the association between 21 SNPs in the CYP24A1 gene and known clinical characteristics, such as the PSA level, clinical stage, pathological stage and Gleason score. RESULTS: The statistical analysis suggested that five CYP24A1 sequence variants (rs2248461 odds ratio (OR): 0.63, rs2248359-OR: 0.65, rs6022999-OR: 0.65, rs2585428-OR: 0.46, rs4809959-OR: 0.52) had a significant association with prostate cancer risk after multiple comparisons by a method of false discovery rate. Logistic analyses of the CYP24A1 polymorphisms with several prostate cancer-related factors showed that several SNPs were significant: four SNPs to PSA level, three to clinical stage, two to pathological stage and two SNPs to the Gleason score. CONCLUSIONS: The results of this study suggest that some CYP24A1 gene polymorphisms might be associated with the risk of prostate cancer in Korean men. Five CYP24A1 sequence variants showed the significance to predict prostate cancer, and several SNPs of CYP24A1 gene had an important finding to predict prostate cancer-related factors. However, these results should be validated in future large-scale studies. PMID- 24492490 TI - Time-dependent expression of cytochrome p450 epoxygenases during human prenatal development. AB - There is growing evidence that some members of cytochrome P450 enzymes contribute to regulation of normal prenatal development. CYP epoxygenases (CYP2C and CYP2J subfamilies) convert arachidonic acid into four regioisomeric epoxyeicosatrienoic acids (EETs), biologically active molecules involved in mitogenesis and cell signaling. Almost nothing is known about localization of their expression in tissues during human prenatal development. The spatio-temporal expression pattern of CYP2C8, CYP2C9, CYP2C19 and CYP2J2 in human embryonic/fetal intestines, liver, and kidney was investigated by immunohistochemical method. CYP epoxygenases are expressed already in early stages of development in these embryonic/fetal tissues (as early as 7th week of IUD in the intestines, 5th week of IUD in the liver, and 6th week of IUD in the kidney). In kidney, CYP epoxygenases are expressed in the metanephrogenic blastema (but not in the uninduced mesenchyme) and in the tubular system. In the intestines, diverse CYP epoxygenases distribution along crypt villus axis could suggest role in cell differentiation. Moreover, we detected higher CYP2J2 level in these organs than in adult tissue samples. PMID- 24492491 TI - Label free detection of pseudorabies virus infection in Vero cells using laser force analysis. AB - The rapid and robust identification of viral infections has broad implications for a number of fields, including medicine, biotechnology and biodefense. Most detection systems rely on specific molecules, such as nucleic acids or proteins, to identify the target(s) of interest. These molecules afford great specificity, but are often expensive, labor-intensive, labile and limited in scope. Label free detection methods seek to overcome these limitations by instead using detection methods that rely on intrinsic properties as a basis for identifying and separating species of interest and thus do not rely on specific prior knowledge of the target. Optical chromatography, one such technique, uses the balance between optical and fluidic drag forces within a microfluidic channel to determine the optical force on cells or particles. Here we present the application of individual optical force measurements as a means of investigating pseudorabies virus infection in Vero cells. Optical force differences are seen between cells from uninfected and infected populations at a multiplicity of infection as low as 0.001 and as soon as 2 hours post infection, demonstrating the potential of this technique as a means of detecting viral infection. Through the application of a pattern recognition neural network, individual cell size data are combined with optical force as a means of classifying cell populations. Potential applications include the early detection of bloodborne pathogens for the prevention of sepsis and other diseases as well as the detection of biological threat agents. PMID- 24492492 TI - NOX4 regulates autophagy during energy deprivation. AB - NADPH oxidase is a cellular enzyme devoted to the production of reactive oxygen species (ROS). NOX4 and NOX2 are the main isoforms of NADPH oxidase in the cardiovascular system. In our recent study, we demonstrated that NOX4, but not NOX2, is a critical mediator of the cardiomyocyte adaptive response to energy stress. NOX4 activity and protein levels are increased in the endoplasmic reticulum (ER) but not in mitochondria of cardiomyocytes during the early phase of energy deprivation. NOX4-derived production of ROS in the ER is a critical event that activates autophagy through stimulation of the EIF2AK3/PERK-EIF2S1/eIF 2alpha-ATF4 pathway. NOX4-dependent autophagy is an important mechanism to preserve cellular energy and limit cell death in energy-deprived cardiomyocytes. Aside from elucidating a crucial physiological function of NOX4 during cellular energy stress, our study dissects a novel signaling mechanism that regulates autophagy under this condition. PMID- 24492493 TI - Plant cell remodeling by autophagy: switching peroxisomes for green life. AB - Plant seedlings are not photoautotrophs until they are equipped with photosynthetic machinery. Some plant cells are remodeled after being exposed to light, and a group of peroxisomal proteins are degraded during the remodeling. Autophagy was proposed as one of the mechanisms for the degradation of peroxisomal proteins. We recently showed that ATG7-dependent autophagy is partially responsible for the degradation of obsolete peroxisomal proteins during Arabidopsis seedling growth. PMID- 24492494 TI - Translating research into practice. PMID- 24492495 TI - Corneoplastique: art of vision surgery. AB - Corneoplastique incorporates the entire spectrum of Vision corrective surgery including Lasik, premium cataract surgery, corneal surgery, ocular surface surgery and the full range of anterior segment surgery itself in manipulating the optics of every eye towards unaided emmetropia to define each and every eye surgeon as a "Vision Corrective Surgeon". This concept of approaching each case individually and designing vision therewith enables surgeons to correct not only virgin eyes but also approach complex cases and complications with the goal of 20/20 vision. Armed with this holistic approach, eye surgeons can use minimally invasive, aesthetically pleasing and visually focused surgery in single or staged process aiming for each patient's Best Vision Potential (BVP) raising eye surgery itself then to an Art! PMID- 24492496 TI - Effects of melatonin on Wi-Fi-induced oxidative stress in lens of rats. AB - INTRODUCTION: Melatonin has been considered a potent antioxidant that detoxifies a variety of reactive oxygen species in many pathophysiological states of eye. The present study was designed to determine the effects of Wi-Fi exposure on the lens oxidant, antioxidant redox systems, as well as the possible protective effects of melatonin on the lens injury induced by electromagnetic radiation (EMR). MATERIALS AND METHODS: Thirty-two rats were used in the current study and they were randomly divided into four equal groups as follows: First and second groups were cage-control and sham-control rats. Rats in third group were exposed to Wi-Fi (2.45 GHz) for duration of 60 min/day for 30 days. As in the third group, the fourth group was treated with melatonin. The one-hour exposure to irradiation in second, third and fourth took place at noon each day. RESULTS: Lipid peroxidation levels in the lens were slightly higher in third (Wi-Fi) group than in cage and sham control groups although their concentrations were significantly (P < 0.05) decreased by melatonin supplementation. Glutathione peroxidase (GSH-Px) activity was significantly (P < 0.05) lower in Wi-Fi group than in cage and sham control groups although GSH-Px (P < 0.01) and reduced glutathione (P < 0.05) values were significantly higher in Wi-Fi + melatonin group than in Wi-Fi group. CONCLUSIONS: There are poor oxidative toxic effects of one hour of Wi-Fi exposure on the lens in the animals. However, melatonin supplementation in the lens seems to have protective effects on the oxidant system by modulation of GSH-Px activity. PMID- 24492497 TI - 2-ethylpyridine, a cigarette smoke component, causes mitochondrial damage in human retinal pigment epithelial cells in vitro. AB - PURPOSE: Our goal was to identify the cellular and molecular effects of 2 ethylpyridine (2-EP, a component of cigarette smoke) on human retinal pigment epithelial cells (ARPE-19) in vitro. MATERIALS AND METHODS: ARPE-19 cells were exposed to varying concentrations of 2-EP. Cell viability (CV) was measured by a trypan blue dye exclusion assay. Caspase-3/7 and caspase-9 activities were measured by fluorochrome assays. The production of reactive oxygen/nitrogen species (ROS/RNS) was detected with a 2',7'-dichlorodihydrofluorescein diacetate dye assay. The JC-1 assay was used to measure mitochondrial membrane potential (DeltaPsim). Mitochondrial redox potential was measured using a RedoxSensor Red kit and mitochondria were evaluated with Mitotracker dye. RESULTS: After 2-EP exposure, ARPE-19 cells showed significantly decreased CV, increased caspase-3/7 and caspase-9 activities, elevated ROS/RNS levels, decreased DeltaPsim value and decreased redox fluorescence when compared with control samples. CONCLUSIONS: These results show that 2-EP treatment induced cell death by caspase-dependent apoptosis associated with an oxidative stress and mitochondrial dysfunction. These data represent a possible mechanism by which smoking contributes to age related macular degeneration and other retinal diseases and identify mitochondria as a target for future therapeutic interventions. PMID- 24492498 TI - Decision making nomogram for intrastromal corneal ring segments in keratoconus. AB - PURPOSE: To create a nomogram for the insertion of intrastromal corneal ring segments (ICRS) (Intacs) in eyes with keratoconus. SETTING: Tertiary eye care center in South India. MATERIALS AND METHODS: This prospective, non-randomized, interventional case series used a self-designed decision-making nomogram for the selection of ICRS in keratoconus patients based on the centration of the cone, mean refractive spherical equivalent (MRSE), and mean keratometry (Km) values. The 3, 6, and 12 months clinical outcomes were compared to historical controls. Primary endpoints were improvement in uncorrected and best-corrected vision and change in the keratometric values. RESULTS: Group A comprised of 52 eyes of 50 patients that followed the nomogram, while Group B comprised of 25 eyes of 23 non nomogram historical controls matched for baseline parameters.In Group A, the uncorrected distance visual acuity (UDVA) improved from 0.16 +/- 0.15 to 0.25 +/- 0.16 (P < 0.001), corrected distance visual acuity (CDVA) from 0.58 +/- 0.2 to 0.69 +/- 0.21 (P = 0.022), MRSE from -5.41 +/- 4.94 to -1.71 +/- 2.88 (P < 0.001), Km from 51.77 +/- 5.45 to 48.63 +/- 4.37 (P < 0.001), and astigmatism reduced from 5.86 +/- 2.61 to 4.91 +/- 2.72 diopters (P < 0.001).In Group B, improvement in the average MRSE was from -6.44 +/- 5.32 to -3.26 +/- 2.82 (P < 0.013) and in the average Km from 53.64 +/- 5.32 to 50.31 +/- 5.02 (P < 0.001). Other parameters did not improve significantly.A statistically significant difference was present in the percentage of patients achieving a good clinical outcome between the two groups (P < 0.001; Chi-square). CONCLUSION: The nomogram provides a means to choose the appropriate ICRS, hence improving the outcome in patients with keratoconus. PMID- 24492499 TI - Transforming ocular surface stem cell research into successful clinical practice. AB - It has only been a quarter of a century since the discovery of adult stem cells at the human corneo-scleral limbus. These limbal stem cells are responsible for generating a constant and unending supply of corneal epithelial cells throughout life, thus maintaining a stable and uniformly refractive corneal surface. Establishing this hitherto unknown association between ocular surface disease and limbal dysfunction helped usher in therapeutic approaches that successfully addressed blinding conditions such as ocular burns, which were previously considered incurable. Subsequent advances in ocular surface biology through basic science research have translated into innovations that have made the surgical technique of limbal stem cell transplantation simpler and more predictable. This review recapitulates the basic biology of the limbus and the rationale and principles of limbal stem cell transplantation in ocular surface disease. An evidence-based algorithm is presented, which is tailored to clinical considerations such as laterality of affliction, severity of limbal damage and concurrent need for other procedures. Additionally, novel findings in the form of factors influencing the survival and function of limbal stem cells after transplantation and the possibility of substituting limbal cells with epithelial stem cells of other lineages is also discussed. Finally this review focuses on the future directions in which both basic science and clinical research in this field is headed. PMID- 24492500 TI - The KIDROP model of combining strategies for providing retinopathy of prematurity screening in underserved areas in India using wide-field imaging, tele-medicine, non-physician graders and smart phone reporting. AB - AIM: To report the Karnataka Internet Assisted Diagnosis of Retinopathy of Prematurity (KIDROP) program for retinopathy of prematurity (ROP) screening in underserved rural areas using an indigenously developed tele-ROP model. MATERIALS AND METHODS: KIDROP currently provides ROP screening and treatment services in three zones and 81 neonatal units in Karnataka, India. Technicians were trained to use a portable Retcam Shuttle (Clarity, USA) and validated against ROP experts performing indirect ophthalmoscopy. An indigenously developed 20-point score (STAT score) graded their ability (Level I to III) to image and decide follow-up based on a three-way algorithm. Images were also uploaded on a secure tele-ROP platform and accessed and reported by remote experts on their smart phones (iPhone, Apple). RESULTS: 6339 imaging sessions of 1601 infants were analyzed. A level III technician agreed with 94.3% of all expert decisions. The sensitivity, specificity, positive predictive value and negative predictive value for treatment grade disease were 95.7, 93.2, 81.5 and 98.6 respectively. The kappa for technicians to decide discharge of babies was 0.94 (P < 0.001). Only 0.4% of infants needing treatment were missed.The kappa agreement of experts reporting on the iPhone vs. Retcam for treatment requiring and mild ROP were 0.96 and 0.94 (P < 0.001) respectively. CONCLUSIONS: This is the first and largest real-world program to employ accredited non-physicians to grade and report ROP. The KIDROP tele-ROP model demonstrates that ROP services can be delivered to the outreach despite lack of specialists and may be useful in other middle-income countries with similar demographics. PMID- 24492501 TI - Recent developments in retinal lasers and delivery systems. AB - Photocoagulation is the standard of care for several ocular disorders and in particular retinal conditions. Technology has offered us newer lasing mediums, wavelengths and delivery systems. Pattern scan laser in proliferative diabetic retinopathy and diabetic macular edema allows laser treatment that is less time consuming and less painful. Now, it is possible to deliver a subthreshold micropulse laser that is above the threshold of biochemical effect but below the threshold of a visible, destructive lesion thereby preventing collateral damage. The advent of solid-state diode yellow laser allows us to treat closer to the fovea, is more effective for vascular structures and offers a more uniform effect in patients with light or irregular fundus pigmentation. Newer retinal photocoagulation options along with their advantages is discussed in this review. PMID- 24492502 TI - Comparison of saccadic reaction time between normal and glaucoma using an eye movement perimeter. AB - AIM: To compare the saccadic reaction time (SRT) in both the central and peripheral visual field in normal and glaucomatous eyes using eye movement perimetery (EMP). MATERIALS AND METHODS: Fifty-four normal and 25 glaucoma subjects underwent EMP and visual field testing on the Humphrey Field Analyser (HFA) 24-2 program. The EMP is based on infrared tracking of the corneal reflex. Fifty-four test locations corresponding to the locations on the 24-2 HFA program were tested. SRTs at different eccentricities and for different severities of glaucoma were compared between normal and glaucoma subjects. RESULTS: Mean SRT was calculated for both normal and glaucoma subjects. Mann-Whitney U test showed statistically significant (P < 0.001) differences in SRT's between normal and glaucoma subjects in all zones. CONCLUSION: SRT was prolonged in eyes with glaucoma across different eccentricities. PMID- 24492503 TI - Adaptive optics imaging of the retina. AB - Adaptive optics is a relatively new tool that is available to ophthalmologists for study of cellular level details. In addition to the axial resolution provided by the spectral-domain optical coherence tomography, adaptive optics provides an excellent lateral resolution, enabling visualization of the photoreceptors, blood vessels and details of the optic nerve head. We attempt a mini review of the current role of adaptive optics in retinal imaging. PubMed search was performed with key words Adaptive optics OR Retina OR Retinal imaging. Conference abstracts were searched from the Association for Research in Vision and Ophthalmology (ARVO) and American Academy of Ophthalmology (AAO) meetings. In total, 261 relevant publications and 389 conference abstracts were identified. PMID- 24492504 TI - Differential systemic gene expression profile in patients with diabetic macular edema: responders versus nonresponders to standard treatment. AB - INTRODUCTION: Diabetic macular edema (DME) is a vision-threatening complication of diabetic retinopathy. The current practice of management is a" trial and error "method of using intravitreal antivascular endothelial growth factor (VEGF)'' or steroids to treat the patient and watch the response. However, if the patient's genetic profile helps us choose appropriate medicine, it would help customize treatment option for each patient. This forms the basis of our study. MATERIALS AND METHODS: A case-control, prospective, observational series, where DME patients were treated with bevacizumab and subclassified as treatment naomicronve, treatment responders, and treatment nonresponders. Blood samples of 20 subjects were studied, with five patients in each of the groups (nondiabetic- group 1, treatment naomicronve- group 2, treatment responder- group 3, and treatment nonresponder-group 4). Whole blood RNA extraction followed by labeling, amplification and hybridization was done, and microarray data analyzed. Genes were classified based on functional category and pathways. RESULTS: The total number of genes upregulated among all three experimental groups was 5, whereas 105 genes were downregulated. There were no common genes upregulated between the responders and nonresponders. There was only one gene upregulated between the diabetic and diabetic responders posttreatment. There were 19 genes upregulated and 8 genes downregulated in the inflammatory pathway in group 2 versus group 1. There were no downregulated genes detected in vascular angiogenesis and transcription group. There were identical numbers of genes up- and downregulated in the inflammatory pathway. Seventeen genes were upreguated and 11 genes downregulated in receptor activity, which remained the predominant group in the group classification. DISCUSSION: In summary, this study would provide an insight into the probable signaling mechanisms for disease pathogenesis as well as progression. This type of study eventually would aid in developing or improvising existing treatment modules with a rational approach towards personalized medicine, in future addressing the differential responses to treatment. PMID- 24492505 TI - Cytokines and Biologics in non-infectious autoimmune uveitis: bench to bedside. AB - Intraocular inflammatory eye disease is one of the important causes of ocular morbidity. Even though the prevalence of uveitis is less common in relation to diabetic retinopathy, glaucoma or age related macular degeneration, the complexity and heterogeneity of the disease makes it more unique. Putative uveitogenic retinal antigens incite innate immunity by the process of antigen mimicry and have been shown to be associated in patients with intraocular inflammatory disease by numerous experimental studies. Laboratory diagnostic tools to aid the etiologic association in intraocular inflammatory disease have evolved over the last two decades and we are entering into an era of molecular diagnostic tests. Sophisticated novel technologies such as multiplex bead assays to assess biological signatures have revolutionized the management of complex refractory uveitis. Nevertheless, there is still a long way to go to establish the causal relationship between these biomarkers and specific uveitic entities. Experimental studies have shown the supreme role of infliximab in the management of Behcet's disease. Despite significant experimental and case control studies, the deficiency of randomized clinical trials using these biologic agents has handicapped us in exploring them as a front line therapy in severe refractory uveitis. Studies still need to answer the safety of these potentially life threatening drugs in a selected group of patients and determine when to commence and for how long the treatment has to be given. This review article covers some basic concepts of cytokines in uveitis and their potential application for therapy in refractory uveitis. PMID- 24492506 TI - Scanning the macula for detecting glaucoma. AB - BACKGROUND: With the advent of spectral domain optical coherence tomography (SDOCT), there has been a renewed interest in macular region for detection of glaucoma. However, most macular SDOCT parameters currently are thickness parameters which evaluate thinning of the macular layers but do not quantify the extent of area over which the thinning has occurred. We therefore calculated a new macular parameter, "ganglion cell complex surface abnormality ratio (GCC SAR)" that represented the surface area over which the macular thickness was decreased. PURPOSE: To evaluate the ability of SAR in detecting perimetric and preperimetric glaucoma. DESIGN: Retrospective image analysis. MATERIALS AND METHODS: 68 eyes with perimetric glaucoma, 62 eyes with preperimetric glaucoma and 165 control eyes underwent GCC imaging with SDOCT. SAR was calculated as the ratio of the abnormal to total area on the GCC significance map. STATISTICAL ANALYSIS: Diagnostic ability of SAR in glaucoma was compared against that of the standard parameters generated by the SDOCT software using area under receiver operating characteristic curves (AUC) and sensitivities at fixed specificities. RESULTS: AUC of SAR (0.91) was statistically significantly better than that of GCC average thickness (0.86, P = 0.001) and GCC global loss volume (GLV; 0.88, P = 0.01) in differentiating perimetric glaucoma from control eyes. In differentiating preperimetric glaucoma from control eyes, AUC of SAR (0.72) was comparable to that of GCC average thickness (0.70, P > 0.05) and GLV (0.72, P > 0.05). Sensitivities at specificities of 80% and 95% of SAR were comparable (P > 0.05 for all comparisons) to that of GCC average thickness and GLV in diagnosing perimetric and preperimetric glaucoma. CONCLUSION: GCC SAR had a better ability to diagnose perimetric glaucoma compared to the SDOCT software provided global GCC parameters. However, in diagnosing preperimetric glaucoma, the ability of SAR was similar to that of software provided global GCC parameters. PMID- 24492507 TI - Changing paradigms of anti-VEGF in the Indian scenario. AB - Anti-vascular endothelial growth factors (VEGF) agents have revolutionized the treatment of retinal diseases. Use of anti-VEGF agents in the Indian Scenario present some unique challenges considering the absence of compounding pharmacies, poor penetrance of health insurance and limited affordability of the citizens of a developing economy. To study the changing paradigms of anti-VEGF use in the Indian scenario, all articles published by Indian authors, data from web-based surveys amongst Indian vitreo-retinal specialists were reviewed. In the paucity of compounding pharmacies in India, fractionation and injection techniques differ from those of developed countries. Frequent anti-VEGF monotherapy offers the best anatomical and visual results, but economics of scale do not allow the same in the Indian scenario, resulting in PRN dosing and combination of anti-VEGF with laser photocoagulation, being the commonly employed treatment protocols. PMID- 24492508 TI - Varied phenotypic presentations of homocystinuria in two siblings. PMID- 24492509 TI - Periorbital dirofilariasis. PMID- 24492510 TI - Management of macular epiretinal membrane secondary to accidental globe perforation during retrobulbar anesthesia. PMID- 24492511 TI - Post-perforation epimacular membrane: do's and don'ts. PMID- 24492512 TI - Intravitreal bevacizumab monotherapy for treatment-naive polypoidal choroidal vasculopathy. PMID- 24492514 TI - Effect of mild hypothermic cardiopulmonary bypass on the amplitude of somatosensory-evoked potentials. AB - BACKGROUND: Several neurophysiological techniques are used to intraoperatively assess cerebral functioning during surgery and intensive care, but the introduction of hypothermia as a means of intraoperative neuroprotection has brought their reliability into question. The present study aimed to evaluate the effect of mild hypothermia on somatosensory-evoked potentials' (SSEPs) amplitude and latency in a cohort of cardiopulmonary bypass (CPB) patients as the temperature reached the steady-state. MATERIALS AND METHODS: The amplitude and latency of 4 different SSEP signals--N9, N13, P14/N18 interpeak, and N20/P25- were evaluated retrospectively in 84 patients undergoing CPB during normothermic (36 degrees C+/-0.43 degrees C) and mild hypothermic (32 degrees C+/-1.38 degrees C) conditions. SSEPs were recorded in normothermia immediately after the induction of anesthesia and in hypothermia as the temperature reached its steady state, specifically, when the nasopharyngeal temperature was equivalent to the rectal temperature (+/-0.5 degrees C). A paired-samples t test was performed for each SSEP to test the differences in latencies and amplitudes between normothermic and hypothermic conditions. RESULTS: Compared with normothermia, hypothermia not only significantly increased the latency of all SSEPs, N9 (P<0.001), N13 (P<0.001), P14/N18 (P<0.001), and N20/P25 (P<0.001), but also the amplitude of N9 (P<0.001) and N20/P25 (P<0.001). CONCLUSIONS: The increased amplitude in particularly of cortical SSEPs (N20/P25), detected specifically during steady-state hypothermia, seems to support the clinical utility of this methodology in monitoring the brain function not only during cardiac surgery with CPB, but also in other settings like therapeutic hypothermia procedures in an intensive care unit. PMID- 24492515 TI - A modified technique for auriculotemporal nerve blockade when performing selective scalp nerve block for craniotomy. PMID- 24492513 TI - ERBB2 overexpression suppresses stress-induced autophagy and renders ERBB2 induced mammary tumorigenesis independent of monoallelic Becn1 loss. AB - Defective autophagy has been implicated in mammary tumorigenesis, as the gene encoding the essential autophagy regulator BECN1 is deleted in human breast cancers and Becn1(+/-) mice develop mammary hyperplasias. In agreement with a recent study, which reports concurrent allelic BECN1 loss and ERBB2 amplification in a small number of human breast tumors, we found that low BECN1 mRNA correlates with ERBB2-overexpression in breast cancers, suggesting that BECN1 loss and ERBB2 overexpression may functionally interact in mammary tumorigenesis. We now report that ERBB2 overexpression suppressed autophagic response to stress in mouse mammary and human breast cancer cells. ERBB2-overexpressing Becn1(+/+) and Becn1(+/-) immortalized mouse mammary epithelial cells (iMMECs) formed mammary tumors in nude mice with similar kinetics, and monoallelic Becn1 loss did not alter ERBB2- and PyMT-driven mammary tumorigenesis. In human breast cancer databases, ERBB2-expressing tumors exhibit a low autophagy gene signature, independent of BECN1 mRNA expression, and have similar gene expression profiles with non-ERBB2-expressing breast tumors with low BECN1 levels. We also found that ERBB2-expressing BT474 breast cancer cells, despite being partially autophagy deficient under stress, can be sensitized to the anti-ERBB2 antibody trastuzumab (tzb) by further pharmacological or genetic autophagy inhibition. Our results indicate that ERBB2-driven mammary tumorigenesis is associated with functional autophagy suppression and ERBB2-positive breast cancers are partially autophagy deficient even in a wild-type BECN1 background. Furthermore and extending earlier findings using tzb-resistant cells, exogenously imposed autophagy inhibition increases the anticancer effect of trastuzumab on tzb-sensitive ERBB2-expressing breast tumor cells, indicating that pharmacological autophagy suppression has a wider role in the treatment of ERBB2-positive breast cancer. PMID- 24492516 TI - Intraoperative monitoring of brain tissue oxygenation during arteriovenous malformation resection. AB - BACKGROUND: In normal perfusion pressure breakthrough (NPPB) it is assumed that following arteriovenous malformation (AVM) resection, vasoparalysis persists in the margins of the lesion and that a sudden increase in cerebral blood flow (CBF) after AVM exclusion leads to brain swelling and postsurgical complications. However, the pathophysiology NPPB remains controversial.The aim of our study was to investigate the oxygenation status in tissue surrounding AVMs and in the distant brain using intraoperative monitoring of cerebral partial pressure of oxygen (PtiO(2)) to achieve a better understanding of NPPB pathophysiology. METHODS: Patients with supratentorial AVMs were monitored intraoperatively using 2 polarographic Clark-type electrodes. To establish reference values, we also studied PtiO(2) in a group of patients who underwent surgery to treat incidental aneurysms. RESULTS: Twenty-two patients with supratentorial AVMs and 16 patients with incidentally found aneurysms were included. Hypoxic pattern was defined as PtiO(2)<=15 mm Hg and/or PtiO(2)/PaO(2) ratio <=0.10. Tissue hypoxia was detected in 63.6% of the catheters placed in the perinidal area and in 43.8% of catheters placed in a distant area. AVM excision significantly improved oxygenation both around the AVM and in the distant area. CONCLUSIONS: The PtiO(2)/PaO(2) ratio is a better indicator than absolute PtiO(2) in detecting tissue hypoxia in mechanically ventilated patients. Intraoperative monitoring showed tissue hypoxia in the margins of AVMs and in the distant ipsilateral brain as the most common finding. Surgical removal of AVMs induces a significant improvement in the oxygenation status in both areas. PMID- 24492517 TI - Monitored anesthesia care with dexmedetomidine for chronic subdural hematoma surgery. PMID- 24492518 TI - Yeast and mammalian autophagosomes exhibit distinct phosphatidylinositol 3 phosphate asymmetries. AB - Phosphatidylinositol 3-kinase is indispensable for autophagy but it is not well understood how its product, phosphatidylinositol 3-phosphate (PtdIns(3)P), participates in the biogenesis of autophagic membranes. Here, by using quick freezing and freeze-fracture replica labelling, which enables determination of the nanoscale distributions of membrane lipids, we show that PtdIns(3)P in yeast autophagosomes is more abundant in the luminal leaflet (the leaflet facing the closed space between the outer and inner autophagosomal membranes) than in the cytoplasmic leaflet. This distribution is drastically different from that of the mammalian autophagosome in which PtdIns(3)P is confined to the cytoplasmic leaflet. In mutant yeast lacking two cytoplasmic phosphatases, ymr1Delta and sjl3Delta, PtdIns(3)P in the autophagosome is equally abundant in the two membrane leaflets, suggesting that the PtdIns(3)P asymmetry in wild-type yeast is generated by unilateral hydrolysis. The observed differences in PtdIns(3)P distribution suggest that autophagy in yeast and mammals may involve substantially different processes. PMID- 24492519 TI - Experimental observation of optical differentiation and optical Hilbert transformation using a single SOI microdisk chip. AB - Optical differentiation and optical Hilbert transformation play important roles in communications, computing, information processing and signal analysis in optical domain offering huge bandwidth. Meanwhile, silicon-based photonic integrated circuit is one of the most promising candidates for all-optical signal processing due to its intrinsic advantages of low power consumption, compact footprint, ultra-high speed and compatibility with electronic integrated circuits. In this study, we analyze the interrelation between first-order optical differentiation and optical Hilbert transformation and then experimentally demonstrate a feasible integrated scheme which can simultaneously function as first-order optical differentiation and optical Hilbert transformation based on a single microdisk resonator. This finding may motivate the development of integrated optical signal processors. PMID- 24492521 TI - Fucoidan extracted from Fucus evanescens prevents endotoxin-induced damage in a mouse model of endotoxemia. AB - An important problem of treating patients with endotoxemia is to find drugs to reduce the negative effects of endotoxin on the organism. We tested fucoidan (sulfated polysaccharide) from the brown alga Fucus evanescens as a potential drug in a mouse model of endotoxemia inducted by lipopolysaccharide (LPS). The survival time of mice injected with LPS increased under fucoidan treatment compared with the group of mice injected with LPS only. The preventive administration of fucoidan to mice with endotoxemia resulted in inhibition of increased levels of proinflammatory cytokines (TNFalpha and IL-6), as well as decreasing of the processes of hypercoagulability. The parenteral or per os administration of fucoidan resulted in decreasing the degree of microcirculatory disorders and secondary dystrophic-destructive changes in parenchymal organs of mice with endotoxemia. Taken together, these results demonstrate that fucoidan prevents endotoxin-induced damage in a mouse model of endotoxemia and increases the mice's resistance to LPS. PMID- 24492520 TI - Gageostatins A-C, antimicrobial linear lipopeptides from a marine Bacillus subtilis. AB - Concerning the requirements of effective drug candidates to combat against high rising multidrug resistant pathogens, we isolated three new linear lipopeptides, gageostatins A-C (1-3), consisting of hepta-peptides and new 3-beta-hydroxy fatty acids from the fermentation broth of a marine-derived bacterium Bacillus subtilis. Their structures were elucidated by analyzing a combination of extensive 1D, 2D NMR spectroscopic data and high resolution ESIMS data. Fatty acids, namely 3-beta-hydroxy-11-methyltridecanoic and 3-beta-hydroxy-9,11 dimethyltridecanoic acids were characterized in lipopeptides 1 and 2, respectively, whereas an unsaturated fatty acid (E)-7,9-dimethylundec-2-enoic acid was assigned in 3. The 3R configuration of the stereocenter of 3-beta hydroxy fatty acids in 1 and 2 was established by Mosher's MTPA method. The absolute stereochemistry of amino acid residues in 1-3 was ascertained by acid hydrolysis followed by Marfey's derivatization studies. Gageostatins 1-3 exhibited good antifungal activities with MICs values of 4-32 ug/mL when tested against pathogenic fungi (R. solani, B. cinerea and C. acutatum) and moderate antibacterial activity against bacteria (B. subtilis, S. aeureus, S. typhi and P. aeruginosa) with MICs values of 8-64 ug/mL. Futhermore, gageostatins 1-3 displayed cytotoxicity against six human cancer cell lines with GI50 values of 4.6-19.6 ug/mL. It is also noteworthy that mixed compounds 1+2 displayed better antifungal and cytotoxic activities than individuals. PMID- 24492522 TI - Association between the lipoprotein-associated phospholipase A2 activity and the progression of subclinical atherosclerosis. AB - AIM: The lipoprotein-associated phospholipase A2(Lp-PLA2) level has been shown to be associated with the risk of clinical cardiovascular events. We aimed to investigate whether Lp-PLA2 is associated with the progression of subclinical atherosclerosis in the general population. METHODS: The degree of carotid plaque and the maximal intima-media thickness(IMT) were measured twice over a 5-year interval in 913 participants 45 to 74 years of age at baseline in a cohort study. The associations between the plasma Lp-PLA2 activity and the progression of carotid plaque and changes in the IMT level were assessed according to sex after adjusting for traditional risk factors and the high-sensitivity C-reactive protein(hsCRP) level. RESULTS: During the 5-year follow-up period, the progression of plaque was observed in 58.5% of men and 48.3% of women. The median maximal IMT level increased by 0.12 mm in men and 0.09 mm in women per year. The progression of plaque and changes in the IMT level increased according to the quartile of the Lp-PLA2 activity in men(p<0.05 for trend), but not women. Following adjustment for traditional risk factors and the hsCRP level, the odds ratio for plaque progression associated with an increase in the Lp-PLA2 activity of one standard deviation was 1.28(95% CI=1.09-1.49, p=0.043) in men and 0.92(95% CI=0.78-1.08, p=0.273) in women. The regression coefficient for IMT progression was 0.003(p=0.004) in men and -0.001(p=0.166) in women after adjusting for the other factors. CONCLUSIONS: The Lp-PLA2 level is associated with the progression of subclinical atherosclerosis in men. Lp-PLA2 may play an important role in the pathogenesis of atherosclerosis and be a potential target for the early prevention of cardiovascular disease. PMID- 24492523 TI - Relationship between a low ankle brachial index and all-cause death and cardiovascular events in subjects with and without diabetes. AB - AIMS: The association between a low ankle brachial index(ABI) and mortality and vascular morbidity in Japanese individuals with diabetes and the independence of this association from other risk factors have not yet been examined in the primary care setting among a large number of patients. METHODS: An observational prospective cohort study was performed among 3,004 Japanese individuals(2,598 patients with diabetes) to examine all-cause death and cardiovascular disease(CVD) in relation to low ABI(<0.9) values and other risk factors. RESULTS: Low ABI values were found in 127 subjects(4.2%) and was associated with smoking, diabetes, hypertension, pulse pressure, glycosylated hemoglobin A1C, lipid profiles, glomerular filtration rate, uric acid and prevalent CVD at baseline. Over 13,242 person-years, 93 deaths and 117 cases of CVD occurred. In a multivariate Cox regression analysis, the hazard ratio for low-normal ABI values was 3.97(95% CI, 2.29 to 6.88) for all-cause death and 2.86(95% CI, 1.83-4.49) for fatal and non-fatal CVD and all-cause death. Similar hazard ratios were found when the subjects were confined to those with diabetes. All risk analyses indicated that age, a low ABI, diabetes, a history of CVD and smoking remained significantly and independently predictive of CVD and all-cause death. CONCLUSIONS: A low ABI exhibits significant cross-sectional associations with conventional risk factors and further more with the glomerular filtration rate, uric acid level and presence of prevalent CVD at baseline, and a low ABI independently predicts subsequent death and cardiovascular events. These findings support the concept that a low ABI is an integrated marker of an excess risk of death and cardiovascular events, independent of conventional risk factors. PMID- 24492524 TI - Small molecule BODIPY dyes as non-fullerene acceptors in bulk heterojunction organic photovoltaics. AB - A series of acceptor-donor-acceptor molecules containing terminal BODIPY moieties conjugated through the meso position were synthesized. Deep LUMO energy levels and good visible absorption led to their use as acceptors in bulk heterojunction solar cells. Inverted devices were fabricated, reaching efficiencies as high as 1.51%. PMID- 24492525 TI - Canadian Society of Nephrology 2014 clinical practice guideline for timing the initiation of chronic dialysis. PMID- 24492526 TI - Peripartum outcomes: non-adjuvanted v. adjuvanted H1N1 vaccination. PMID- 24492527 TI - Regulating e-cigarettes as drugs is not the best solution. PMID- 24492528 TI - Expanding scope of pharmacists. PMID- 24492529 TI - Patient advocacy. PMID- 24492531 TI - A novel technique for inferior rectus recession. AB - PURPOSE: To introduce a novel technique of inferior rectus recession operation to allow larger amounts of recession without causing lower lid retraction and to compare this method with the results obtained in standard inferior rectus recession. MATERIAL AND METHODS: This study included 20 patients operated on in the authors' clinic. The median age of the patients was 24.5+/-18.6 (4-73) years and the median follow-up was 9.3+/-11.8 (3-43) months. Ten patients operated on with the standard method were labeled Group 1 and ten patients operated on with the new method were labeled Group 2. Without exceeding 4 mm, inferior rectus recession to the whole muscle was performed in Group 1 patients. Inferior rectus recession was also performed on patients in Group 2 following the new method. Using a spatula, approximately 10% of the muscle surface fibers were detached intact as a thin layer, and the remaining 90% of deeper fibers were recessed 4-8 mm as planned. Patients' preoperative deviations and lower lid positions were recorded. The same parameters were checked in the first and third month postoperatively. Both groups were evaluated retrospectively by screening their files, and the Mann-Whitney U test was used for statistical evaluation. RESULTS: Lower lid retraction was seen in four patients of Group 1. There was no retraction in Group 2. While there was a need to perform additional vertical muscle procedures for vertical deviations and lower lid retractions in Group 1, it was observed that there was no need for additional procedures in Group 2 patients. There was a statistically meaningful difference between the two procedures (P<0.05). CONCLUSION: This novel technique was found to be an effective surgical method for permitting more recession without the risk of lower lid retraction. PMID- 24492533 TI - Does a higher metal oxidation state necessarily imply higher reactivity toward H atom transfer? A computational study of C-H bond oxidation by high-valent iron oxo and -nitrido complexes. AB - In this work, the reactions of C-H bond activation by two series of iron-oxo ( (Fe(IV)), (Fe(V)), (Fe(VI))) and -nitrido model complexes ( (Fe(IV)), (Fe(V)), (Fe(VI))) with a nearly identical coordination geometry but varying iron oxidation states ranging from iv to vi were comprehensively investigated using density functional theory. We found that in a distorted octahedral coordination environment, the iron-oxo species and their isoelectronic nitrido analogues feature totally different intrinsic reactivities toward C-H bond cleavage. In the case of the iron-oxo complexes, the reaction barrier monotonically decreases as the iron oxidation state increases, consistent with the gradually enhanced electrophilicity across the series. The iron-nitrido complex is less reactive than its isoelectronic iron-oxo species, and more interestingly, a counterintuitive reactivity pattern was observed, i.e. the activation barriers essentially remain constant independent of the iron oxidation states. The detailed analysis using the Polanyi principle demonstrates that the different reactivities between these two series originate from the distinct thermodynamic driving forces, more specifically, the bond dissociation energies (BDEE-Hs, E = O, N) of the nascent E-H bonds in the FeE-H products. Further decomposition of the BDEE-Hs into the electron and proton affinity components shed light on how the oxidation states modulate the BDEE-Hs of the two series. PMID- 24492532 TI - Activation of the NLRP1b inflammasome independently of ASC-mediated caspase-1 autoproteolysis and speck formation. AB - Despite its clinical importance in infection and autoimmunity, the activation mechanisms of the NLRP1b inflammasome remain enigmatic. Here we show that deletion of the inflammasome adaptor ASC in BALB/c mice and in C57BL/6 macrophages expressing a functional NLRP1b prevents anthrax lethal toxin (LeTx) induced caspase-1 autoproteolysis and speck formation. However, ASC(-/-) macrophages undergo normal LeTx-induced pyroptosis and secrete significant amounts of interleukin (IL)-1beta. In contrast, ASC is critical for caspase-1 autoproteolysis and IL-1beta secretion by the NLRC4, NLRP3 and AIM2 inflammasomes. Notably, LeTx-induced inflammasome activation is associated with caspase-1 ubiquitination, which is unaffected in ASC-deficient cells. In vivo, ASC-deficient mice challenged with LeTx produce significant levels of IL-1beta, IL-18 and HMGB1 in circulation, although caspase-1 autoproteolysis is abolished. As a result, ASC(-/-) mice are sensitive to rapid LeTx-induced lethality. Together, these results demonstrate that ASC-driven caspase-1 autoprocessing and speck formation are dispensable for the activation of caspase-1 and the NLRP1b inflammasome. PMID- 24492530 TI - Current and potential immune therapies and vaccines in the management of psoriasis. AB - Psoriasis is a chronic, immune skin disease associated with significant morbidity. Development of psoriasis is influenced by numerous genes, one allele is HLA-CW*0602. Other genes and single nucleotide polymorphisms affect immunologic pathways and antimicrobial peptide synthesis. Dendritic cells initiate psoriasis by activating T-cells toward a Th1 and Th17 response, with increased cytokines including TNF-alpha, IL-6, -12, -17, -22, and -23. IL-22 appears to promote keratinocyte dedifferentiation and increased antimicrobial peptide synthesis while TNF-alpha and IL-17 induce leukocyte localization within the psoriatic plaque. These recent insights identifying key cytokine pathways have led to the development of inhibitors with significant efficacy in the treatment of psoriasis. While a strategy for vaccine modulation of the immune response in psoriasis is in progress, with new technology they may provide a cost effective long-term treatment that may induce tolerance or targeted self inhibition for patients with autoimmune disorders, such as psoriasis. PMID- 24492534 TI - CEACAM6 promotes tumor migration, invasion, and metastasis in gastric cancer. AB - Carcinoembryonic antigen-related cell adhesion molecule 6 (CEACAM6) shows increased expression in a wide variety of human cancers, and its over-expression is associated with enhanced migration, invasion, and in vivo metastasis. Here, we reported that CEACAM6 was up-regulated in gastric cancer (GC) cell lines and tumor tissues. Over-expression of CEACAM6 in MKN-45 and SGC-7901 GC cells promoted migration and invasion in vitro and metastasis in athymic mice, whereas migration and invasion of MKN-28 and SNU-16 GC cells were suppressed by knockdown of CEACAM6. We also observed that steroid receptor coactivator (C-SRC) phosphorylation was increased when CEACAM6 was over-expressed in SGC-7901 cells. Taken together, these results suggested that CEACAM6 functions as an oncoprotein in GC and may be an important metastatic biomarker and therapeutic target. PMID- 24492535 TI - Notch signaling in the differentiation of MEE cells from the developing mouse palate. PMID- 24492536 TI - MicroRNAs and anticancer drugs. AB - MicroRNAs (miRNAs) are a class of small, non-coding, and endogenous RNA molecules, which are evolutionarily conserved but play a significant role in regulation of protein-coding gene expression at posttranscriptional and translational levels. Strikingly, a single miRNA is able to trigger hundreds of putative target genes by incomplete or complete complementary binding to their 3' untranslated regions. Given their appearance in almost all types of tissues, miRNAs have been demonstrated to be intensively involved in normal and pathological processes of human cells. Aside from the role as invaluable biomarkers in indication of tumorigenesis and tumor progression, numerous studies have revealed the potential of miRNAs as novel targets of anticancer drugs in cancer therapy. In this review article, we focus on the summary of the latest publications on the topic of miRNA and anticancer drugs, and expect to shed light on understanding the molecular mechanisms of chemoresistance involving miRNA regulation. These pieces of evidence will eventually provide insight into the development of novel and more efficacious anticancer drugs in the future. PMID- 24492537 TI - Defining reference genes for quantitative real-time PCR analysis of anther development in rice. AB - Quantitative real-time polymerase chain reaction (qPCR) is one of the most accurate and widely used methods for gene expression analysis. However, the choice of reference genes for normalization is critical for accurate quantification of gene expression. As development of genomics, mining large-scale datasets such as microarray and RNA-sequencing data becomes a new approach for exploitation of new reference genes. In this study, we analyzed an RNA-sequencing dataset of rice anther and 167 microarray datasets involving different tissues and developing stages of rice anthers and pollens. We selected 12 candidate genes and other 5 reference genes, including ACT1, eEF-1alpha, GAPDH, Exp2, and CCDC72 used in previous studies, and evaluated their expression in eight tissues and different developmental stages of anthers in rice variety 9311 and Yuetai. UPF3, eIF4A-3, GAPDH, and PPP6 were identified as the most suitable reference genes for qPCR analysis of anther development in rice. The new candidate reference genes showed more stable expression than the traditionally used reference genes. These results provide a set of reliable reference genes for studies in rice anther developmental process. PMID- 24492538 TI - Workplace-based influenza vaccination promotion practices among large employers in the United States. AB - OBJECTIVE: Influenza vaccination levels in the working-age population are low. Workplace promotion practices can increase employee vaccination levels, but the extent of employers' use of these practices is unknown. We aimed to estimate the prevalence of employers' use of evidence-based practices for promoting influenza vaccination in the workplace. METHODS: We conducted a telephone survey of large employers across the United States regarding their use of evidence-based practices to promote vaccination. RESULTS: Eighty-four percent of 583 employers surveyed offered on-site vaccination. Use of four promotion practices was high (75% or more), but the remaining four practices were used by only a minority of employers. There is particular room for improvement in the use of practices that increase physical access to vaccination. CONCLUSIONS: Employers are highly engaged in basic influenza vaccination promotion practices, but there is potential to increase levels of use. PMID- 24492540 TI - Nonruminant Nutrition Symposium: Controlling feed cost by including alternative ingredients into pig diets: a review. AB - Sustained price increases for traditional cereal grain and protein meal feed commodities have forced the pork industry to consider the dietary inclusion of alternative feedstuffs. Crop seed may serve as feedstuffs but their demand as feedstock for human food, biofuel, and bioindustrial products has increased. Together with these products, coproducts such as distillers dried grains with solubles, wheat millrun, and canola meal are produced. As omnivores, pigs are ideally suited to convert these non-human-edible coproducts into high-quality food animal protein. Therefore, coproducts and other low-cost alternative feedstuffs such as pulses and oilseeds can be included in pig diets to reduce feed cost per metric ton of feed. However, inclusion of alternative feedstuffs in pig diets does not necessarily reduce feed cost per kilogram of gain. Therefore, the use of novel and existing feedstuffs in pig diets must be optimized following their characterization for energy and AA profile. Alternative feedstuffs generally have a high content of at least 1 of the following antinutritional factors (ANF): fiber, tannins, glucosinolates, and heat-labile trypsin inhibitors. Several methods can optimize nutrient use of pigs fed alternative feedstuffs by reducing effects of their ANF. These methods include 1) particle size reduction to increase nutrient digestibility, 2) dehulling or scarification to reduce tannin and fiber content of pulses and oilseeds, 3) air classification to create fractions that have a greater content of nutrients and lower content of ANF than the feedstock, 4) heat treatments such as extrusion, toasting, roasting, and micronization to reduce heat-labile ANF, 5) dietary supplementation with fiber-degrading enzymes or predigestion of fibrous feedstuffs or diets with fiber degrading enzymes to increase dietary nutrient availability, and 6) formulation of diets based on bioavailable AA coefficients. In conclusion, the feeding of alternative ingredients may reduce feed cost per unit of pork produced provided that their price per unit NE or digestible lysine is less than that of the traditional feedstuffs and that negative effects of their ANF are controlled. PMID- 24492539 TI - Near field enhanced photocurrent generation in p-type dye-sensitized solar cells. AB - Over the past few decades, the field of p-type dye-sensitized solar cell (p-DSSC) devices has undergone tremendous advances, in which Cu-based delafossite nanocrystal is of prime interest. This paper presents an augment of about 87% improvement in photocurrent observed in a particular configuration of organic dye P1 sensitized CuCrO2 delafossite nanocrystal electrode coupled with organic redox shuttle, 1-methy-1H- tetrazole-5-thiolate and its disulfide dimer when Au nanoparticles (NPs, with diameter of about 20 nm) is added into the photocathode, achieving a power convert efficiency of 0.31% (measured under standard AM 1.5 G test conditions). Detailed investigation shows that the local electrical-magnetic field effect, induced by Au NPs among the mesoporous CuCrO2 film, can improve the charge injection efficiency at dye/semiconductor interface, which is responsible for the bulk of the gain in photocurrent. PMID- 24492541 TI - Bovine lateral saphenous veins exposed to ergopeptine alkaloids do not relax. AB - The ergot alkaloid ergovaline has demonstrated a persistent and sustained contractile response in several different vascular models. It was hypothesized that different alkaloids isolated from tall fescue (Lolium arundinaceum) will contribute to this contractile response differently. The objective was to compare contractile-response patterns of single additions of the ergoline alkaloids lysergic acid, lysergol, and ergonovine and the ergopeptine alkaloids ergotamine, ergocristine, ergocryptine, ergocornine, and ergovaline (provided as tall fescue seed extract). Lateral saphenous veins were collected from 6 Holstein steers (BW = 397 +/- 28 kg) immediately after slaughter, sliced into cross-sections, and suspended in myograph chambers containing oxygenated Krebs-Henseleit buffer (95% O2/5% CO2; pH = 7.4; 37 degrees C). Treatments were added at 0 min and buffer was replaced in 15-min intervals for a 120-min incubation. In addition to maximum tension and time to reach maximum tension, percent relaxation and rate of relaxation were determined following maximum tension for each treatment. All compounds tested produced significant contractile responses (P < 0.05). All ergoline alkaloids reached maximum response in less time (P < 0.05) than the remaining compounds and began to relax immediately after first buffer change. Lysergic acid had the greatest (P < 0.05) percent relaxation and ergonovine had the greatest (P < 0.05) rate of relaxation. The ergopeptine alkaloids ergovaline, ergotamine, ergocristine, ergocryptine, and ergocornine had slower developing contractile responses with a longer (P < 0.05) interval until maximum tension was achieved compared to the ergoline alkaloids. Maximal responses to all the ergopeptine alkaloids, however, all persisted for the 120-min duration with negligible relaxation occurring. The different classes of alkaloids differed greatly in the type of contractile response generated in the lateral saphenous vein. Persistence of contractile response is thought to be the primary contributing factor to the vasoconstriction observed in animals demonstrating signs of fescue toxicosis, where different ergot alkaloids can contribute differently. PMID- 24492542 TI - Meat Science and Muscle Biology Symposium: Escherichia coli O157:H7, diet, and fecal microbiome in beef cattle. AB - Shiga-toxigenic Escherichia coli, such as E. coli O157:H7, are foodborne zoonotic pathogens that can cause severe illness and death in humans. The gastrointestinal tract of ruminant animals has been identified as a primary habitat for E. coli O157:H7 and, in cattle, the hindgut tract appears to be a primary site for colonization. This pathogen has been found in cattle feces, on cattle hides, and in the production environment, and transmission to humans has occurred as a result of consumption of contaminated ground beef, water, and produce. Interventions to reduce the pathogen at beef harvest have significantly reduced the occurrence of the pathogen, but outbreaks and recalls due to the pathogen still occur for beef products. Interventions in the feedyard before harvest have had little success, but critical control points for implementing interventions are limited compared with the beef abattoir. The percentage of animals shedding E. coli O157:H7 in the feces can be highly variable from pen to pen, and the levels in the feces can vary from animal to animal. Animals colonized and shedding E. coli O157:H7 at high levels are a small fraction of animals in a pen but are important source for transferring the pathogen amongst the penmates. Recent research has indicated that diet may greatly influence the shedding of E. coli O157:H7. In addition, diet can influence the microbiota composition of the feces. However, little is known about the interaction between the indigenous microbiota and fecal shedding of E. coli O157:H7. Understanding the influence of indigenous microbiota on the colonization and shedding of E. coli O157:H7 will provide a potential avenue for intervention in the preharvest production environment not yet exploited. PMID- 24492543 TI - Effects of using ground redberry juniper and dried distillers grains with solubles in lamb feedlot diets: growth, blood serum, fecal, and wool characteristics. AB - Effects of using ground redberry juniper and dried distillers grains with solubles (DDGS) in Rambouillet lamb (n = 45) feedlot diets on growth, blood serum, fecal, and wool characteristics were evaluated. In a randomized design study with 2 feeding periods (Period 1 = 64% concentrate diet, 35 d; Period 2 = 85% concentrate diet, 56 d), lambs were individually fed 5 isonitrogenous diets: a control diet (CNTL) that contained oat hay but not DDGS or juniper or DDGS based diets in which 0 (0JUN), 33 (33JUN), 66 (66JUN), or 100% (100JUN) of the oat hay was replaced by juniper. During Period 1, lambs fed CNTL had greater (P < 0.05) DMI and ADG and tended to have greater (P < 0.10) G:F than lambs fed 0JUN or lambs fed DDGS-based diets. Lamb DMI, ADG, and G:F quadratically increased (P < 0.008) as juniper increased in the DDGS-based diets. During Period 2, lambs fed CNTL had greater (P < 0.05) DMI than lambs fed 0JUN or lambs fed DDGS-based diets, but ADG was similar (P > 0.41). Compared to 0JUN, lambs fed CNTL had similar (P = 0.12) G:F and tended to have less G:F (P = 0.07) than lambs fed DDGS based diets. Among lambs fed DDGS-based diets, DMI was similar (P > 0.19), ADG increased linearly (P = 0.03), and G:F tended to decrease quadratically (P = 0.06) as juniper increased in the diet. Serum IGF-1, serum urea N (SUN), and fecal N were greater (P < 0.05) and serum Ca and P and fecal P were similar (P > 0.13) for lambs fed CNTL vs. lambs fed DDGS-based diets (CNTL). Within lambs fed DDGS-based diets, SUN increased quadratically (P = 0.01) and fecal N increased linearly (P = 0.004), which can partially be attributed to increased dietary urea and condensed tannin intake. Most wool characteristics were not affected, but wool growth per kilogram of BW decreased quadratically (P = 0.04) as percentage of juniper increased in the DDGS-based diets. When evaluating the entire 91-d feeding trial, results indicated that replacing all of the ground oat hay with ground juniper leaves and stems in lamb growing and finishing diets is not detrimental to animal performance and that DDGS-based diets can reduce total feedlot costs, as compared to sorghum grain and cottonseed meal-based diets. However, compared to using juniper or oat hay as the sole roughage source, using both during the growing period (Period 1) enhanced growth performance and further reduced total feedlot costs. PMID- 24492544 TI - Milk production traits of beef cows as affected by horn fly count and sire breed type. AB - Horn fly infestations negatively impact economic traits of beef cattle. Our objective was to determine the impact of horn flies on beef cattle milk yield and quality. Cows (n = 53) were derived from Brangus dams and sired by Bonsmara (n = 7), Brangus (n = 13), Charolais (n = 8), Gelbvieh (n = 5), Hereford (n = 12), and Romosinuano (n = 8) bulls. Horn fly counts and estimates of milk yield and quality were recorded monthly from May through October on individual cows. Data for milk yield and quality and horn fly count were analyzed by mixed model least squares using a linear model including sire breed, cow in sire breed, month, and month * sire breed. Effects of horn fly count on milk yield and quality were estimated by analysis of covariance using log horn fly count and log horn fly count * sire breed. Horn fly counts varied by month (P < 0.0001), with lowest population recorded in May (99 flies) and peaked in August (520 flies). Bonsmara and Gelbvieh sired cows had greater (P < 0.05) milk yield compared to Hereford sired cows (8.75 and 8.62 vs. 6.02 kg/d, respectively). Milk yield from Charolais, Romosinuano, and Brangus sired cows was intermediate (7.28, 7.00, and 7.06 kg/d, respectively). Regression of milk yield on fly count differed (P < 0.05) among sire breeds. Milk yield was reduced (P < 0.05) by 0.99 and 0.64 kg/d per unit increase in log horn fly count in Gelbvieh and Bonsmara sired cows. Regression coefficient for milk yield on log horn fly count was reduced (P < 0.01) in Gelbvieh sired cows when compared with Brangus, Charolais, Hereford, and Romosinuano sired cows, and coefficients for Bonsmara sired cows were reduced (P < 0.05) in comparison to Brangus sired cows. Increases in log fly count were associated with decreases (P < 0.05) in milk fat, solids-not-fat, and milk urea nitrogen. Milk yield was reduced (P < 0.05) by increased fly numbers depending on month of lactation and interaction with log horn fly count. In May, June, and July milk yield was reduced 0.72, 0.68, and 0.71 kg/d per unit increase in log horn fly count. Our results indicate that horn fly infestations reduce milk yield and quality of spring-calving beef cows depending on sire breed and month of lactation. Development of sustainable beef production systems may include selecting breed types whose milk yield and quality is less influenced by horn flies, allowing for better expression of genetic potential for milk yield in nutritionally challenging environments. PMID- 24492545 TI - Effects of feeding frequency and dietary water content on voluntary physical activity in healthy adult cats. AB - Low physical activity has been identified as a major risk factor for the development of feline obesity and diabetes. This study aimed to evaluate the effects of increased meal frequency and dietary water content on voluntary physical activity in cats fed to maintain BW. Ten adult lean neutered male cats were used in 2 tests, both crossover studies composed of a 14-d adaptation period, followed by a 7-d measurement of physical activity from d 15 to d 22 using Actical activity collars. Cats were group housed for most of the day, except for times when they were individually housed in cages to access their diet under a 16:8 h light:dark cycle. In Exp. 1, the difference in voluntary physical activity among cats fed 1, 2, 4, or a random number of meals per day were tested in a 4 * 4 Latin square design in 4 individual rooms. In Exp. 2, the effect of increasing dietary water content on voluntary physical activity was tested in a crossover design including a 5-d phase for fecal and urine collection from d 22 to 27. Cats were randomly assigned to 2 rooms and fed a dry commercial diet with or without added water (70% hydrated) twice daily. Activity levels were expressed as "activity counts" per epoch (15 s). In Exp. 1, average daily activity level for 1-meal-fed cats was lower than 4-meal-fed (P = 0.004) and random-meal-fed (P = 0.02) cats, especially during the light period. The activity level of cats during the dark period was greater in 1-meal-fed cats compared with cats fed 2 meals (P = 0.008) or 4 meals (P = 0.007) daily. Two-hour food anticipatory activity (FAA) before scheduled meal times for 1-meal-fed cats was lower (P < 0.001) than for the multiple-meal-fed cats. In Exp. 2, average daily activity level of cats fed the 70% hydrated diet tended to be higher (P = 0.06) than cats fed the dry diet, especially during the dark period (P = 0.007). Two-hour FAA before the afternoon meal for cats fed the 70% hydrated diet was lower (P < 0.05) than for cats fed the dry diet. Cats fed the 70% hydrated diet had greater daily fecal (P = 0.008) and urinary (P = 0.001) outputs and lower (P < 0.001) urinary specific gravity compared to cats fed the dry diet. In conclusion, increased feeding frequency and dietary water content, without changing energy intake or dietary macronutrient composition, appear to promote physical activity, which may aid in weight management in cats. PMID- 24492546 TI - Impact of nursery feeding program on subsequent growth performance, carcass quality, meat quality, and physical and chemical body composition of growing finishing pigs. AB - An experiment was conducted to examine the effect of the nursery feeding program on subsequent growth performance, carcass quality, meat quality, and physical and chemical body composition of growing-finishing pigs. Four dietary treatments were used in a 2 * 2 factorial arrangement of treatments based on diet complexity (Complex vs. Simple) and in-feed antibiotics (2,730 [+AB] vs. 0 [-AB] mg of chlortetracycline /kg].A total of 552 pigs, in 5 blocks, were weaned at 21 +/- 2 d of age with an initial BW of 7.03 +/- 0.07 kg. Each experimental block had 3 pens per treatment, with 8 pigs per pen in blocks 1 and 2, and 10 pigs per pen in the remaining 3 blocks. Nursery diets were fed in a 3-phase feeding program (Phase I, II, and III diets fed for 1, 2, and 3 wk, respectively). All pigs were fed common grower-finisher diets thereafter. Six pigs per treatment were slaughtered for chemical body composition analysis at wk 2, 8, 12, and 17 postweaning. An additional 11 pigs per treatment were slaughtered at wk 17 postweaning (approximately 115 kg BW or market weight) for analysis of carcass characteristics, chemical and physical body composition, and meat quality. During the nursery phase, ADG was lower (P < 0.05) for pigs fed the Simple diet than those fed the Complex diet (491 vs. 528 g/d). Antibiotic usage improved (P < 0.05) ADG in Phases II (408 vs. 438 g/d) and III (689 vs. 720 g/d). In Phase I and II, G:F was lower (P < 0.05) for pigs fed the Simple diet than those fed the Complex diet (0.46 vs. 0.58 and 0.75 vs. 0.78 in Phases I and II, respectively). During the grower phase, pigs previously fed -AB diets grew faster than pigs fed +AB diets (P < 0.05; 1,009 vs. 971 g/d). There were no treatment effects on overall ADG or G:F from weaning to finishing. Nursery feeding program did not affect carcass quality characteristics. However, pigs previously fed +AB diets tended (P = 0.07) to have increased LM depth. Nursery feeding program had no effect on objective or subjective meat quality measures, chemical body composition, or the weight of primal and retail carcass cuts at wk 17 postweaning, with the exception of primal belly weight. These results indicate that feeding simple nursery diets, or nursery diets without antibiotics, compromises growth performance during the nursery period but does not affect overall growth performance between weaning and market BW, carcass characteristics, and meat quality. Thus, feed costs for nursery pigs can be reduced by feeding simple diets without compromising market BW and carcass and meat quality. PMID- 24492547 TI - Effects of increasing levels of corn dried distillers grains with solubles and monensin on ruminal biohydrogenation and duodenal flows of fatty acids in beef heifers fed high-grain diets. AB - Corn dried distillers grains with solubles (DDGS) contains high crude fat and is reported to confer to PUFA some degree of protection from ruminal biohydrogenation (BH). There is also indication that inclusion in diets of high energy feed such as DDGS results in a reduced response to monensin in feedlot cattle. This study was conducted to determine the effects of increasing corn DDGS inclusion and monensin on ruminal BH and duodenal flows of fatty acid (FA). Five ruminally and duodenally cannulated Angus heifers (initial BW, 556 +/- 36 kg) were assigned to a 5 * 5 Latin square with 2 * 2 + 1 factorial arrangement. Treatments were control (CON; 10% barley silage, 87.8% barley grain, 2.2% mineral and vitamin supplement, and 28 mg monensin/kg DM) and diets substituting 20% (LDG) or 40% (HDG) corn DDGS for barley grain combined with 28 (ML) or 48 mg (MH) monensin/kg diet DM: 1) CONML, 2) LDGML, 3) LDGMH, 4) HDGML, and 5) HDGMH. Intakes of total and individual FA increased (P < 0.01) with inclusion of DDGS in the diet and tended (P = 0.10) to be less for heifers fed MH than ML diets. Overall, there was no interaction between levels of DDGS and monensin on ruminal BH, flows of FA to duodenum, and intestinal digestibility. Flows (g/d) of CLA c9,t11, alpha-linolenic acid (C18:3n-3), MUFA, and PUFA to the duodenum were linearly increased (P < 0.01) with increasing DDGS inclusion. However, increased monensin trended to decrease the flows of linoleic acid (C18:2 c9 c12; P = 0.07), alpha-linolenic acid (P = 0.07), and MUFA (P = 0.08) and decreased that of PUFA (P = 0.05). Ruminal BH of unsaturated FA (USFA), PUFA, and C18:2 c9,c12 did not differ among treatments. The FA profiles in the duodenal digesta were not different except for the percentage of CLA c9,t11, which tended (P = 0.06) to linearly increase with increasing DDGS such that it was greater (P = 0.04) for HDG than for the LDG diet. Additionally, the percentage of CLA t10,c12 linearly (P < 0.01) increased with increasing DDGS inclusion. Intestinal digestibility of SFA (P < 0.01), USFA (P = 0.05), and total FA (P = 0.01) was greater for heifers fed HDG than heifers fed LDG diets. These results indicate that increasing corn DDGS in finishing diet increases the provision of PUFA to feedlot cattle due to increased intake and flows of PUFA to the duodenum. Increasing supplementation of monensin from 28 to 48 mg/kg DM had no effect on ruminal BH and intestinal digestibility of FA but decreased intake and duodenal flows of FA. PMID- 24492548 TI - Methionine improves breast muscle growth and alters myogenic gene expression in broilers. AB - To investigate the mechanism underlying the regulatory effect of Met on broiler growth, the growth performance, organ development, serum profile, myogenic gene expression, and methylation of myostatin gene exon 1 region in response to dietary Met status were evaluated. A total of 192 one-day-old Arbor Acres broiler chicks were housed in 3-layer cages in a temperature-controlled room with continuous lighting. The temperature of the room was maintained at 32 to 34 degrees C for the first 3 d and then reduced by 2 to 3 degrees C per week to a final temperature of 20 degrees C. Cages were randomly allocated to 2 dietary treatments with 6 replicate cages (8 males and 8 females/cage) per treatment. Control starter and finisher diets contained 0.50 and 0.43% Met, respectively. Corresponding values for a +Met treatment were 0.60 and 0.53% Met, respectively. The birds receiving the +Met diets had a greater (P < 0.05) G:F throughout the experiment. The +Met diets increased (P < 0.05) the relative weight of breast muscle and the concentrations of uric acid and triglyceride in serum at 42 d of age, whereas other serum measurements were not affected by treatments. Increased myogenic factor 5 (Myf5) and myocyte enhancer factor 2B (MEF2B) and decreased myostatin mRNA expression were observed in broilers fed the +Met diets (P < 0.05). However, methylation of myostatin gene exon 1 region was not different between groups. In conclusion, broilers fed the +Met diets increased breast muscle growth that was reflected in the expected expression of myostatin, Myf5, and MEF2B genes. PMID- 24492549 TI - 2013 Early Career Achievement Award--Recognizing achievement of young scholars working to foster the discovery, sharing, and application of knowledge concerning the responsible use of animals to enhance human life and well-being. PMID- 24492550 TI - Effect of Lactobacillus plantarum on diarrhea and intestinal barrier function of young piglets challenged with enterotoxigenic Escherichia coli K88. AB - The present study was performed to investigate the preventative effect of Lactobacillus plantarum on diarrhea in relation to intestinal barrier function in young piglets challenged with enterotoxigenic Escherichia coli (ETEC) K88. Seventy-two male piglets (4 d old) were assigned to 2 diets (antibiotic-free basal diet with or without L. plantarum, 5 * 10(10) cfu/kg diet) and subsequently challenged or not with ETEC K88 (1 * 10(8) cfu per pig) on d 15 in a 2 * 2 factorial arrangement of treatments. Feed intake and BW were measured on d 15 and 18 (3 d after challenge) for determination of growth performance. On d 18, 1 piglet from each pen was slaughtered to evaluate small intestinal morphology and expression of tight junction proteins at the mRNA and protein levels while another piglet was used for the intestinal permeability test. Before and after ETEC K88 challenge, piglets fed L. plantarum had greater BW, ADG, and ADFI (P < 0.05) and marginally greater G:F (P < 0.10) compared to piglets fed the unsupplemented diet. After ETEC K88 challenge, the challenged piglets did not show an impaired growth performance but had greater incidence of diarrhea compared to the nonchallenged piglets. There was an interaction between dietary L. plantarum and ETEC K88 challenge (P < 0.05) as L. plantarum prevented the ETEC K88-induced diarrhea. Piglets challenged with ETEC K88 also had greater urinary lactulose:mannitol and plasma concentration of endotoxin, shorter villi, deeper crypt depth, and reduced villous height:crypt depth in the duodenum and jejunum and decreased zonula occludens-1 mRNA and occludin mRNA and protein expression in the jejunum (P < 0.05). These deleterious effects caused by ETEC K88 were inhibited by feeding L. plantarum (P < 0.05). There were no effects of either treatment on the morphology and expression of tight junction proteins in ileum. In conclusion, L. plantarum, given to piglets in early life, improved performance and effectively prevented the diarrhea in young piglets induced by ETEC K88 challenge by improving function of the intestinal barrier by protecting intestinal morphology and intestinal permeability and the expression of genes for tight junction proteins (zonula occludens-1 and occludin). PMID- 24492551 TI - Beef Species Symposium: potential limitations of NRC in predicting energetic requirements of beef females within western U.S. grazing systems. AB - Assessment of beef cow energy balance and efficiency in grazing-extensive rangelands has occurred on a nominal basis over short time intervals and has not accounted for the complexity of metabolic and digestive responses; behavioral adaptations to climatic, terrain, and vegetation variables; and documentation of the effects of nutrient form and supply to grazing cattle. Previous research using pen-fed cows demonstrated differences (P < 0.01) in efficiency of weight change ranging from 135 to 58 g/Mcal ME intake. Furthermore, variation in efficiency of ME use for tissue energy gain or loss ranged from 36% to 80%. In general, energy costs for maintenance, tissue accretion, and mobilization were greatest in Angus-based cows, intermediate in Brahman- and Hereford-based cows, and least in dairy-based cows. The most efficient cattle may reflect the types that are successful in semiarid grazing environments with low input management. Successful range cattle systems are likely the result of retention of animals that best adapted to the grazing environment and thus were potentially more efficient. Animals exposed to a variety of stressors may continually adapt, so energy expenditure is reduced and may tend to depart from the modeled beef cow in the 1996 NRC Beef Cattle Requirements. Critical factors comprising cow lifetime achievement, including reproductive success, disease resistance, and calf weaning weight, may be driven by cow total energy utilization in energy-limiting environments. Therefore, energy adjustments for adapted cattle within these landscapes and seasonal BW changes can alter seasonal NEm requirements. Evaluated studies indicate that in static grazing environments, NRC prediction fitness was improved compared with predictions from dynamic systems where cattle were influenced less by management and more by environmental conditions. Preliminary herd analyses cast doubt on the accuracy of NRC BCS descriptions representing NEm requirements of adapted females utilizing semiarid rangelands. Possible gaps are proposed that could be the basis for prediction inaccuracies. A more complete understanding of mechanisms contributing to productivity in the field than the current model predicts will improve future models to better simulate energetic accountability and subsequent female performance. PMID- 24492552 TI - Additive effects of growth promoting technologies on performance of grazing steers and economics of the wheat pasture enterprise. AB - This research was designed to evaluate the effect of monensin (Elanco Animal Health, Greenfield, IN) supplementation via mineral or pressed protein block with or without a growth-promoting implant on performance of steers grazing wheat pasture in Arkansas over 2 yr. Preconditioned steers (n = 360, BW = 238 +/- 5.1 kg) grazed 15 1.6-ha wheat pastures in the fall (n = 60 steers each fall, stocking rate of 2.5 steers/ha) or 30 0.8-ha wheat pastures in the spring (n = 120 steers each spring, stocking rate of 5 steers/ha). Steers in each pasture were given free-choice access to nonmedicated mineral (CNTRL; MoorMan's WeatherMaster Range Minerals A 646AAA; ADM Alliance Nutrition, Inc., Quincy, IL), or were supplemented with monensin (Elanco Animal Health, Greenfield, IN) via mineral containing 1.78 g monensin/kg (RMIN; MoorMan's Grower Mineral RU-1620 590AR; ADM Alliance Nutrition, Inc.), or pressed protein block containing 0.33 g monensin/kg (RBLCK; MoorMan's Mintrate Blonde Block RU; ADM Alliance Nutrition, Inc.). Additionally, one-half of the steers in each pasture were implanted (IMPL) with 40 mg trenbolone acetate and 8 mg estradiol (Component TE-G with Tylan; Elanco Animal Health). There was no interaction (P >= 0.71) between supplement treatment and growth-promoting implants, and ADG for RMIN and RBLCK were increased (P < 0.01) over CNTRL by 0.07 to 0.09 kg/d, respectively. Implanting steers with Component TE-G increased (P < 0.01) ADG by 0.14 kg/d. The combination of these growth-promoting technologies are a cost-effective means of increasing beef production by 22% without increasing level of supplementation or pasture acreage. Utilizing ionophores and implants together for wheat pasture stocker cattle decreased cost of gain by 26%. Utilizing both IMPL and monensin increased net return by $30 to $54/steer for RMIN or $18 to $43/steer for RBLCK compared with UNIMPL CNTRL at Low and High values of BW gain, respectively. PMID- 24492553 TI - Impact of ractopamine hydrochloride on growth, efficiency, and carcass traits of finishing pigs in a three-phase marketing strategy. AB - The objectives were to determine the effects of ractopamine hydrochloride (RAC) in a 3-phase marketing strategy. One thousand seven hundred forty pigs were used in 80 single-sex pens in 2 blocks. Each pen housed approximately 22 pigs. Sixteen percent of the total population of pigs was sold during the first marketing period, 18% was sold during the second marketing period, and the remaining 66% was sold during the third marketing period. Data were analyzed as a randomized complete block design of 2 treatments. Pigs in the second marketing group had greater growth performance indicators than pigs in the first marketing group. Over the entire feeding period, pigs fed RAC were 2.73 kg heavier (P < 0.0001), had 0.11 kg/d greater (P < 0.0001) ADG, and had 0.04 greater (P < 0.0001) G:F than pigs not fed RAC. Hot carcass weights were 3.3% greater (P < 0.0001), carcass yields were 0.68 (% units) greater (P < 0.0001), fat depth was 7.2% less (P < 0.0001), loin depth was 5.6% greater (P < 0.0001), and estimated carcass lean was 0.97% units greater (P < 0.0001) in RAC-fed pigs when compared with pigs not fed RAC. By the end of the first marketing period carcasses from pigs fed RAC (89.73 kg) were 2.1% heavier (P = 0.04) and gained 0.19 kg/d more (P = 0.03) carcass weight than carcasses from pigs not fed RAC (87.89 kg). By the end of the second marketing period carcasses from pigs fed RAC (99.00 kg) were 3.1% heavier (P < 0.001) and gained 0.14 kg/d more (P < 0.001) carcass weight than carcasses from pigs not fed RAC (96.02 kg). By the end of the third marketing period carcasses from pigs fed RAC (102.75 kg) were 3.7% heavier (P < 0.0001) and gained 0.10 kg/d more (P < 0.0001) carcass weight than carcasses from pigs not fed RAC (99.06 kg). Although carcass gain per day decreased with extended RAC feeding duration, HCW advantages continued to increase as feeding duration was increased from 7 d to 35 d. Growth benefits were evident during the initial marketing period, but as duration increased differences diminished. Therefore, RAC can provide the expected growth performance benefits when included in the diet for up to 21 d, but HCW advantages continue to increase throughout the entire 35 d feeding period. Even though carcass benefits were not as evident in pigs sold during the first marketing period, advantages (particularly HCW) continued to increase with each marketing period. PMID- 24492554 TI - Risk factors associated with multiple ovulation and twin birth rate in Irish dairy and beef cattle. AB - The objective of this study was to quantify the phenotypic and genetic risk factors associated with multiple ovulations and twin births in cattle. Prevalence and cow- and herd-level risk factors associated with ovulation rate were determined using 40,617 ultrasonographic records of the reproductive tract from 27,907 dairy and beef cows from 738 commercial herds. Prevalence of twin births was estimated from the Irish national database containing 23,658,351 calving events from 8,546,695 cows from 125,251 dairy and beef herds; factors associated with twin births were determined using a random subsample of 505,200 calving events from 280,638 cows in 81,329 herds. The mean prevalence of multiple ovulations was 6.83% while the prevalence of twin births was 1.74%. Occurrence of both multiple ovulations and twin births was associated with the month of scan (P < 0.0001) and month of calving (P < 0.0001), respectively, and peaked in November for multiple ovulations and October for twin births. The likelihood of multiple ovulations increased with interval postpartum and peaked between 45 to 185 d postcalving, after which the likelihood declined. The likelihood of both multiple ovulations (P < 0.0001) and twin births (P < 0.0001) increased with increasing cow parity. A greater proportion of Holstein, Friesian, Simmental, Hereford, and Charolais breed fractions were associated with a greater likelihood of multiple ovulations. There was no difference between breed proportion of the cow and incidence of twin births, where all breed proportions examined, litter difference existed among breeds in their association with risk of twin births. Although multiple ovulations were lowly heritable (0.028 +/- 0.003), their occurrence was repeatable (0.326 +/- 0.342) while twin birth rate in cattle was lowly heritable (0.017 +/- 0.004) and repeatable (0.018 +/- 0.011). The genetic SD of the presence of multiple ovulations and twin births was 0.04 and 0.02, respectively, indicating considerable genetic variation, especially for multiple ovulations. A moderate genetic correlation (0.66 +/- 0.16) existed between multiple ovulations and twin births. PMID- 24492555 TI - Postnatal piglet husbandry practices and well-being: the effects of alternative techniques delivered in combination. AB - After birth, piglets undergo procedures likely to cause stress. The aim of this study was to evaluate stress responses evoked by 2 combinations (More Stressful [all a] or Less Stressful [all a] or More Stressful [all b]) of alternative methods for performing the following processing procedures: 1) teeth resection (TR) - [a] clip vs. [b] grind; 2) identification (ID) - [a] ear tag vs. [b] ear notch; 3)iron administration (FE) - [a] inject vs. [b] oral; 4) castration (CA) - [a] cords cut vs. [b] cords torn; 5) taildocking (TD) - [a] cold clip vs. [b] hot clip [corrected]. Ten litters of eight 2- and 3-d-old piglets were assigned to each procedure. Within each litter 1 male and 1 female piglet was assigned to 1 of 4 possible procedures: the 2 combinations, sham procedures, and sham procedures plus blood sampling. Blood was collected before processing and at 45 min, 4 h, 48 h, 1 wk, and 2 wk afterward and assayed for cortisol and beta endorphin concentrations. Procedures were videotaped and analyzed to evaluate the time taken to perform the procedure and the number of squeals, grunts, and escape attempts. Vocalizations were analyzed to determine mean and peak frequencies and duration. Piglets were weighed before the procedure and at 24 h, 48 h, 1 wk, and 2 wk afterward. Identification, tail docking, and castration lesions were scored on a 0 to 5 scale at 24 h, 1 wk, and 2 wk postprocedure. Both combinations of methods took longer to carry out than sham procedures and resulted in more squeals, grunts, and escape attempts during the procedures and higher peak frequencies of vocalizations compared with the control treatments (P < 0.05). Cortisol concentrations 45 min after processing were also higher in the 2 combination treatments than in the sham treatments (P < 0.05). Comparing between procedure treatments, the More Stressful combination of methods took longer to carry out, resulted in higher beta-endorphin concentrations at 1 wk, had higher peak frequency of vocalizations, and increased ear (P < 0.05) and tail wound (P < 0.1) lesion scores at 1 wk than the Less Stressful combination. Growth during d 2 to 7 postprocedure was lower in More Stressful piglets than control piglets (P < 0.05) but by 2 wk, growth was unaffected. Using measures of behavior, physiology, and productivity, the More Stressful combination of procedures decreased welfare relative to the Less Stressful combination; however, both combinations decreased welfare relative to controls. The time taken to carry out the procedure would appear to be an important factor in the strength of the stress response. PMID- 24492556 TI - The effect of follicle age on pregnancy rate in beef cows. AB - The effect of the age of the ovulatory follicle on fertility in beef cows was investigated. Multiparous (n = 171) and primiparous (n = 129) postpartum beef cows in 2 groups (G1 and G2) received estradiol benzoate (EB; 1 mg/500 kg BW, intramuscular [i.m.]) 5.5 d (G1; n = 162) and 6.5 d (G2; n = 138) after the final GnRH of a synchronization program (5d CO-Synch + CIDR) to induce emergence of a new follicular wave (NFW), followed by prostaglandin F2alpha (PGF(2alpha); 25 mg, i.m.) administration either 5.5 d ("young" follicle, YF; n = 155) or 9.5 d ("mature" follicle, MF; n = 145) after EB. Estrous detection coupled with AI 12 h later (estrus-AI) was performed for 60 h (MF) and 84 h (YF) after PGF(2alpha); cows not detected in estrus within this period received timed AI (TAI) coupled with GnRH at 72 and 96 h, respectively. Within the first 72 h after PGF(2alpha), more (P < 0.01) cows in the MF (76.3%) than YF treatment (47.7%) exhibited estrus, but through 96 h, the proportion detected in estrus (P < 0.05) and interval from PGF(2alpha) to estrus (P < 0.01) were greater in the YF than MF treatment (88.6% vs. 76.3%, 78.9 +/- 0.8 vs. 57.5 +/- 1.6 h, respectively). Age of the ovulatory follicle at AI was greater (P < 0.01) in the MF (9.32 +/- 0.04 d) than YF (6.26 +/- 0.02 d) treatment, but follicle diameter at AI and pregnancy rates did not differ between MF (13.1 +/- 0.2 mm; 72.0%) and YF (12.9 +/- 0.1 mm; 67.1%) treatments. Regardless of treatment, the diameter of the ovulatory follicle at AI and pregnancy rate were greater (P < 0.01) with estrus-AI (13.1 +/ 0.1 mm; 75.0%) than TAI (12.6 +/- 0.2 mm; 55.4%). Cows in the MF treatment that initiated a second NFW after EB but before PGF(2alpha) (MF2; n = 47) were induced to ovulate with GnRH and TAI at 72h, when ovulatory follicles were 4 d old and 10.2 +/- 0.2 mm in diameter. Pregnancy rate for TAI (51.1%) in MF2 did not differ from TAI pregnancy rate (55.4%) across the MF and YF treatments. In summary, the age of the ovulatory follicle affected interval to estrus and AI but did not influence pregnancy rate in suckled beef cows. PMID- 24492557 TI - Sire evaluation for total number born in pigs using a genomic reaction norms approach. AB - In the era of genome-wide selection (GWS), genotype-by-environment (G*E) interactions can be studied using genomic information, thus enabling the estimation of SNP marker effects and the prediction of genomic estimated breeding values (GEBV) for young candidates for selection in different environments. Although G*E studies in pigs are scarce, the use of artificial insemination has enabled the distribution of genetic material from sires across multiple environments. Given the relevance of reproductive traits, such as the total number born (TNB) and the variation in environmental conditions encountered by commercial dams, understanding G*E interactions can be essential for choosing the best sires for different environments. The present work proposes a two-step reaction norm approach for G*E analysis using genomic information. The first step provided estimates of environmental effects (herd-year-season, HYS), and the second step provided estimates of the intercept and slope for the TNB across different HYS levels, obtained from the first step, using a random regression model. In both steps, pedigree ( A: ) and genomic ( G: ) relationship matrices were considered. The genetic parameters (variance components, h(2) and genetic correlations) were very similar when estimated using the A: and G: relationship matrices. The reaction norm graphs showed considerable differences in environmental sensitivity between sires, indicating a reranking of sires in terms of genetic merit across the HYS levels. Based on the G: matrix analysis, SNP by environment interactions were observed. For some SNP, the effects increased at increasing HYS levels, while for others, the effects decreased at increasing HYS levels or showed no changes between HYS levels. Cross-validation analysis demonstrated better performance of the genomic approach with respect to traditional pedigrees for both the G*E and standard models. The genomic reaction norm model resulted in an accuracy of GEBV for "juvenile" boars varying from 0.14 to 0.44 across different HYS levels, while the accuracy of the standard genomic prediction model, without reaction norms, varied from 0.09 to 0.28. These results show that it is important and feasible to consider G*E interactions in evaluations of sires using genomic prediction models and that genomic information can increase the accuracy of selection across environments. PMID- 24492558 TI - Influence of the para-aminohippuric acid analysis method on the net hepatic flux of nutrients in lactating cows. AB - Para-aminohippuric acid (pAH) is a marker frequently used to measure plasma or blood flow. In sheep studies, it is recognized that its determination must include a deacetylation step to counteract the hepatic acetylation of pAH. Such a procedure is not of common usage in cattle studies although a recent suggestion of hepatic pAH acetylation in dairy cows may have important consequences for hepatic nutrient fluxes. The aims of this study were to evaluate pAH analytical methods according to international procedures of metrology and confirm hepatic acetylation of pAH in dairy cows. The effect of the matrix used to prepare the standard curve was tested, and the influence of the pAH analytical method on blood flows and subsequent net hepatic fluxes of nutrients was determined. For the first objective, accuracy profiles were established and bias, indicators of precision, and limits of quantification were reported for 2 analytical methods (without and with a pAH deacetylation step) using 2 different standard matrices (water and plasma). Second, the net hepatic flux of different nutrients was determined including or not the deacetylation step and preparing the standard curves in plasma using samples collected from 5 multicatheterized lactating Jersey cows. The choice of the matrix had a significant impact on plasma pAH concentrations as illustrated by accuracy profiles. Water matrix decreased (P < 0.01) the slope, y-intercept, and the absorbance at concentration 0 mg pAH/L of the standard curve in both methods (without and with the deacetylation), supporting that standards prepared in water should not be used to analyze plasma samples. Samples collected on cows confirmed hepatic acetylation of pAH across the liver. Deacetylation, performed using plasma as the standard matrix, increased (P < 0.05) plasma pAH concentrations from 18.4, 26, and 23.5 to 21.4, 28.9, and 27.3 mg/L in the artery, portal vein, and hepatic vein, respectively. Deacetylation decreased the hepatic venous and arterial plasma and blood flows (P < 0.05) by 9 and 55%, respectively, modifying the net hepatic flux of acetate, total amino acid, and oxygen by more than 19% (P < 0.05). In conclusion, our results highlight the importance of including a deacetylation step in the pAH analysis method in cattle studies and of using plasma as standard matrix. PMID- 24492559 TI - Triennial Growth Symposium--Effects of dietary 25-hydroxycholecalciferol and cholecalciferol on blood vitamin D and mineral status, bone turnover, milk composition, and reproductive performance of sows. AB - To evaluate the role of vitamin D3 during gestation and lactation of sows, 2 independent experiments were performed with the aim of investigating sow reproductive performance, milk composition (study 1 only), and changes in blood status of 25-hydroxycholecalciferol (25-OH-D3), 1,25-dihydroxycholecalciferol (1,25-(OH)2-D3; study 2 only), minerals, and bone markers of sows during gestation and lactation. Study 1 comprised 39 primi- and multiparous crossbred sows fed 1 of 3 barley meal-based diets fortified with 200 IU/kg vitamin D3 (NRC, 1998; treatment DL), 2,000 IU/kg vitamin D3 (cholecalciferol; treatment DN), or 50 MUg 25-OH-D3 (calcidiol; treatment HD)/kg feed. This study was conducted over a 4-parity period under controlled conditions. Study 2, running over 1 parity only, was performed in a commercial farm with 227 primi- and multiparous sows allocated to 2 dietary treatments: control (CON), receiving 2,000 IU vitamin D3/kg (equivalent to 50 MUg/kg) feed (114 sows), and test (HYD), supplemented with 50 MUg 25-OH-D3/kg feed (113 sows). Blood samples of sows were collected at 84 and 110d postcoitum and 1, 5, and 33 d postpartum (study 1) and at insemination and 28 and 80 d postinsemination as well as d 5 and 28 postpartum (study 2). Colostrum and milk samples in study 1 were obtained at 1, 9, and 33 d of lactation after oxytocin administration. Plasma 25-OH-D3 concentrations were increased (P < 0.05) in sows receiving 25-OH-D3 (HD and HYD) at any time of sampling whereas circulating plasma concentrations of 1,25-(OH)2-D3, Ca, and P were not affected by treatment. Milk concentrations of Ca and P were similar, but 25-OH-D3 content (except in colostrum) was clearly increased (P< 0.05) when 25-OH D3 was fed. Most characteristics of sow reproductive performance responded similarly to the 2 sources and levels of vitamin D3, but weight gain of piglets between birth and weaning was decreased (P< 0.05) in offspring of DL and HD sows compared with animals of treatment DN (study 1). In study 2 total litter weight and birth weight per piglet were increased (P< 0.05) with 25-OH-D3 supplementation in comparison with the control (CON). Overall, feeding sows with 25-OH-D3 was considered to improve maternal supply with vitamin D3 and thereby maintain Ca homeostasis during gestation and lactation. PMID- 24492560 TI - Effects of the Programmed Nutrition Beef Program on meat quality characteristics. AB - The objective of this study was to examine the effects of alternative finishing strategies on beef steak color and cooked meat characteristics. Beef steers (n = 64 pens; 8 steers/pen) were allocated to a randomized complete block design with a 2 * 2 factorial treatment arrangement and initial body weight serving as the blocking factor. Factor 1 consisted of dietary treatment with cattle either being fed a conventional feedlot diet (CON) or a diet that included Programmed Nutrition Beef Program supplements. Cattle in the Programmed Nutrition (PN) treatments were fed in two-stages: 1) the basal diet with Programmed Nutrition Beef Receiver from d 1 to 20 and the basal diet with Programmed Nutrition Beef Finisher from d 21 to harvest. Factor 2 consisted of the inclusion (EGP+) or absence (EGP-) of an exogenous growth promoting program. Steers in the EGP+ treatments were implanted initially with Component E-S, reimplanted with Component TE-IS, and fed 400 mg . d(-1) . steer(-1) of ractopamine hydrochloride for the final 28 d before harvest. Steers were harvested on d 175 of feeding and 1 strip loin was removed from 2 carcasses selected at random from each pen for transport to Kansas State University. After 14 d of aging, loins were fabricated into 2.54-cm thick steaks for objective and trained sensory panel measurement of cooked meat characteristics and objective color measurements during 7 d retail display. There were no interactions (P > 0.10) between feeding strategy and exogenous growth promotants for all objective measures of color and cooked meat characteristics. Throughout the display period, PN steaks were darker (P = 0.02) than CON steaks, but surface percentages of oxymyoglobin and metmyoglobin and metmyoglobin reducing ability were unaffected by feeding strategy (P > 0.10). Loins and steaks from PN cattle possessed decreased moisture loss during aging and cooking (P < 0.01). Trained sensory panel evaluation of cooked meat revealed a dietary program * growth promotant interaction for myofibrillar tenderness, connective tissue amount, and overall tenderness (P = 0.01). Compared to the CON/EGP- and PN/EGP- treatments, steaks from the CON/EGP+ and PN/EGP+ treatments were evaluated by panelists as being less myofibrillar and overall tender (P < 0.05). The alternative feeding strategies presented in this study can favorably impact water-holding capacity without negatively compromising retail display discoloration. PMID- 24492561 TI - Phenotypic and genetic relationships of feeding behavior with feed intake, growth performance, feed efficiency, and carcass merit traits in Angus and Charolais steers. AB - Feeding behavior traits including daily feeding duration (FD), daily feeding head down time (HD), average feeding duration per feeding event (FD_AVE), average feeding head down time per feeding event (HD_AVE), feeding frequency (FF), and meal eating rate (ER) were analyzed to estimate their phenotypic and genetic correlations with feed intake, growth performance, residual feed intake (RFI), ultrasound, and carcass merit traits in Angus and Charolais finishing steers. Heritability estimates for FD, HD, FD_AVE, HD_AVE, FF, and ER were 0.27 +/- 0.09 (SE), 0.25 +/- 0.09, 0.19 +/- 0.06, 0.11 +/- 0.05, 0.24 +/- 0.08, and 0.38 +/- 0.10, respectively, in the Angus population and 0.49 +/- 0.12, 0.38 +/- 0.11, 0.31 +/- 0.09, 0.29 +/- 0.10, 0.43 +/- 0.11, and 0.56 +/- 0.13, respectively, in the Charolais population. In both the Angus and Charolais steer populations, FD and HD had relatively stronger phenotypic (0.17 +/- 0.06 to 0.32 +/- 0.04) and genetic (0.29 +/- 0.17 to 0.54 +/- 0.18) correlations with RFI in comparison to other feeding behavior traits investigated, suggesting the potential of FD and HD as indicators in assessing variation of RFI. In general, feeding behavior traits had weak phenotypic correlations with most of the ultrasound and carcass merit traits; however, estimated genetic correlations of the feeding behavior traits with some fat deposition related traits were moderate to moderately strong but differed in magnitude or sign between the Angus and Charolais steer populations, likely reflecting their different biological types. Genetic parameter estimation studies involving feeding behavior traits in beef cattle are lacking and more research is needed to better characterize the relationships between feeding behavior and feed intake, growth, feed utilization, and carcass merit traits, in particular with respect to different biological types of cattle. PMID- 24492562 TI - Effects of corn processing and dietary wet corn gluten feed inclusion on performance and digestion of newly received growing cattle. AB - Effects of corn processing and of dietary inclusion of wet corn gluten feed (WCGF) on growth performance and digestibility were analyzed in 2 experiments. Dietary treatments were arranged as a 2 * 2 factorial. Diets contained corn as either whole-shelled corn (WSC) or as dry-rolled corn (DRC), and they contained either 47% corn with no WCGF or 29% corn with 30% WCGF. In Exp. 1, 279 crossbred calves (230 kg) were allocated to treatments in a complete block design and were used to measure performance and digestion during a 60-d receiving period. Corn processing did not affect (P >= 0.31) growth performance. Inclusion of WCGF in the diet increased final BW and ADG (P = 0.03) but did not affect gain efficiency (P = 0.45). Digestibility of DM was increased (P < 0.01) by dietary inclusion of WCGF, and this response was greater in diets containing DRC than in those containing WSC (interaction P = 0.02). For Exp. 2, a digestibility trial used 5 ruminally cannulated Holstein heifers (248 +/- 13 kg BW) in a 4 * 4 Latin square with the additional animal administered the same treatment sequence as another heifer. A tendency (P = 0.09) was observed for heifers fed DRC to have greater DMI than those fed WSC. Dietary WCGF inclusion increased (P <= 0.01) DMI. Similar to observations in Exp. 1, DM digestibility was improved by addition of 30% WCGF to diets containing DRC but not diets containing WSC (interaction P = 0.02). Ruminal pH was not affected by corn processing (P = 0.90), but it tended (P = 0.09) to be increased by dietary WCGF additions. Ruminal VFA concentrations were not different between WSC and DRC, but dietary inclusion of 30% WCGF decreased (P < 0.01) acetate concentrations and increased (P = 0.05) butyrate concentrations. Liquid passage rate from the rumen and ruminal liquid volume were not affected by corn processing or dietary WCGF inclusion (P >= 0.66). In summary, processing corn had no effect on steer performance, but including WCGF in the diet at 30% of DM increased gains of steers over the 60-d receiving period. Diet digestibility did not follow the same pattern observed for gains and efficiencies. PMID- 24492563 TI - Calpain-1 activity in bovine muscle is primarily influenced by temperature, not pH decline. AB - The objectives of this study were to 1) determine the conditions (temperature and pH) that exist in early postmortem muscle of normally chilled and delay chilled beef carcasses to provide a model for in vitro work and 2) determine the mechanism by which early postmortem temperature/pH conditions found in beef muscle influence the enzymes that regulate the aging process in vitro. For objective 1, 7 finished beef animals (HCW 385 +/- 8 kg) were harvested with the right sides subjected to normal chilling (2.3 degrees C) approximately 1.25 h postmortem and the left sides subjected to ambient temperature (delay chilling; 22.6 degrees C) for an additional 4.75 h postmortem and then allowed to chill at 2.3 degrees C. Delay chilled carcasses had a more rapid pH decline (P < 0.05) and a slower rate of carcass cooling (P < 0.05). No differences were observed between normally chilled and delay chilled samples for sarcomere length or postmortem proteolysis of troponin T (TnT; P > 0.10). Warner-Bratzler shear force (WBSF) was reduced in steaks from normally chilled carcasses at 14 d (P < 0.05), while results indicated a strong, positive correlation between 14-d WBSF and 3-h longissimus dorsi muscle (LM) temperature (r = 0.67, P < 0.01) as well as a strong, negative correlation between 14-d WBSF and 6-h LM pH (r = -0.65, P < 0.02). These results were used to design the methodology for objective 2, where isolated myofibrils were subjected to MU-calpain digestion at 4 or 22 degrees C with either a fast or slow initial pH decline. As expected, digestions with a fast initial pH decline had lower pH values in the early time points of the incubation (P < 0.05). No differences were detected in MU-calpain activity or in the degradation of intact TnT between the fast and slow pH decline treatments (P > 0.10); however, warmer digestions resulted in a tendency for increased activation of MU-calpain (P < 0.10) and a significant reduction in intact TnT (P < 0.05). Additionally, a temperature * time interaction was revealed in MU calpain activity and in the degradation of intact TnT (P < 0.05). Specifically, assayed calpain activity was lower at 0.17, 0.33, 1, and 3 h and greater at 72 h in warmer digestions, while intact TnT disappearance was greater as both time and digestion temperature increased. Meat aging and MU-calpain activity are influenced by both temperature and pH, but more research is necessary to fully realize their relationships. PMID- 24492564 TI - Technical note: Comparison of automated ribosomal intergenic spacer analysis and denaturing gradient gel electrophoresis to assess bacterial diversity in the rumen of sheep. AB - The aim of this study was to compare automated ribosomal intergenic spacer analysis (ARISA) and denaturing gradient gel electrophoresis (DGGE) techniques to assess bacterial diversity in the rumen of sheep. Sheep were fed 2 diets with 70% of either alfalfa hay or grass hay, and the solid (SOL) and liquid (LIQ) phases of the rumen were sampled immediately before feeding (0 h) and at 4 and 8 h postfeeding. Both techniques detected similar differences between forages, with alfalfa hay promoting greater (P < 0.05) bacterial diversity than grass hay. In contrast, whereas ARISA analysis showed a decrease (P < 0.05) of bacterial diversity in SOL at 4 h postfeeding compared with 0 and 8 h samplings, no variations (P > 0.05) over the postfeeding period were detected by DGGE. The ARISA technique showed lower (P < 0.05) bacterial diversity in SOL than in LIQ samples at 4 h postfeeding, but no differences (P > 0.05) in bacterial diversity between both rumen phases were detected by DGGE. Under the conditions of this study, the DGGE was not sensitive enough to detect some changes in ruminal bacterial communities, and therefore ARISA was considered more accurate for assessing bacterial diversity of ruminal samples. The results highlight the influence of the fingerprinting technique used to draw conclusions on factors affecting ruminal bacterial diversity. PMID- 24492565 TI - Effect of follicle age on conception rate in beef heifers. AB - The objective of this study was to determine the effect of age of the ovulatory follicle on fertility in beef heifers. Ovulation was synchronized with the 5 d CO Synch + controlled intravaginal drug release (CIDR) program in heifers in Montana (MT; n = 162, Hereford and Angus Crossbred) and Ohio (OH; n = 170, Angus Crossbred). All heifers received estradiol benzoate (EB; 1 mg/500 kg BW, [i.m.]) 6 d after the final GnRH of the synchronization program to induce follicular atresia and emergence of a new follicular wave (NFW) followed by prostaglandin F2alpha (PGF(2alpha); 25 mg, i.m.) administration either 5 d ("young" follicle [YF]; n = 158) or 9 d ("mature" follicle [MF]; n = 174) after EB. Estrous detection was performed for 5 d after PGF(2alpha) with AI approximately 12 h after onset of estrus. Ovarian ultrasonography (MT location only) was performed in YF and MF at EB, 5 d after EB, PGF(2alpha), and AI. Heifers in MT (n = 20) and OH (n = 18) that were not presynchronized or did not initiate a NFW were excluded from further analyses, resulting in 142 and 152 heifers in MT and OH, respectively. Heifers from the MF treatment in MT that initiated a second NFW after EB but before PGF(2alpha) (MF2; n = 14) were excluded from the primary analysis. In the secondary analysis, the MF2 group was compared to MF and YF treatments in MT. Estrous response was similar (90%; 252/280) between treatments and locations. Proestrus interval (from PGF(2alpha) to estrus) and age of the ovulatory follicle at AI were similar for MF heifers between locations (54.6 +/- 1.7 h and 8.3 +/- 0.07 h) but were greater (P < 0.01) for YF heifers in OH (78.5 +/- 1.4 h and 5.3 +/- 0.06 h) than MT (67.4 +/- 1.6 h and 4.8 +/- 0.06 h; treatment * location, P < 0.01). However, conception rate did not differ for MF (63.8%; 74/116) and YF (67.0%; 91/136) treatments. In the MT heifers, follicle size and follicle age at AI in the YF treatment (10.4 +/- 0.15 mm and 4.8 +/- 0.06 d, respectively) was less (P < 0.01) than in the MF treatment (11.0 +/- 0.18 mm and 8.3 +/- 0.11 d, respectively), but conception rate to AI did not differ between treatments in MT. In the MF2 group proestrus interval was greater (P < 0.01); hence, diameter of the ovulatory follicle and age were similar to that for the YF treatment. Conception rate to AI did not differ between MF2, MF, and YF (61.5, 63.3, and 64.7%, respectively) in MT. In conclusion, manipulation of age of the nonpersistent ovulatory follicle at spontaneous ovulation did not influence conception rate. PMID- 24492566 TI - The effect of cyclical and mild heat stress on productivity and metabolism in Afshari lambs. AB - To investigate the effect of heat stress (HS) on production and metabolism of Afshari sheep, 32 intact male lambs (33.2 +/- 4.5 kg) were used in a completely randomized design using 2 experimental periods. In period 1 all 32 lambs were housed in thermal neutral (TN) conditions (25.6 +/- 2.6 degrees C and a temperature-humidity index [THI] of 72.0 +/- 2.6) and fed ad libitum for 8 d. In period 2 (P2; 9 d), 16 lambs were subjected to cyclical HS (29.0 to 43.0 degrees C and a THI >=80 for 24 h/d) and the other 16 lambs were maintained in TN conditions but pair fed (pair-fed thermal neutral [PFTN]) to the HS lambs. During each period DMI and water intake were measured daily. Respiration rate, rectal temperature, and skin temperature at the shoulder, rump, and front and rear leg were recorded at 0700 and 1400 h daily. Water intake increased (P < 0.05) during P2 in both HS and TN lambs (88 and 35%, respectively). Heat stress increased the 0700 and 1400 h surface temperature at the shoulder (3.0 and 10.6%), rump (2.7 and 12.7%), rear leg (3.1 and 13%), and front leg (3.0 and 13%) and respiratory rates (72 and 124%; P < 0.01, respectively, for 0700 and 1400 h) but only the 1400 h rectal temperature was increased (P < 0.01; 0.54 degrees C) in HS lambs. Plasma glucose concentration decreased in P2 (P < 0.01) in both the HS and PFTN lambs. Basal insulin concentrations decreased in PFTN controls but increased in HS lambs (environment * period interaction; P < 0.05). Blood urea nitrogen concentration was not affected by environment or period, but NEFA levels were slightly elevated (P < 0.01) in both PFTN and HS lambs during P2. Interestingly, HS did not affect DMI, but ADG was reduced (36%; P < 0.01) compared to the PFTN lambs. These results indicate that the direct effects of heat (not mediated by reduced DMI) are partially responsible for reduced growth in heat-stressed lambs. PMID- 24492567 TI - Ammonia and hydrogen sulfide emissions from swine production facilities in North America: a meta-analysis. AB - Literature on NH3 and H2S emissions from swine production facilities in North America was reviewed, and a meta-analysis was conducted on measured emissions data from swine houses and manure storage facilities as well as concentration data in the vicinity of swine production facilities. Results from more than 80 studies were compiled with results from the 11 swine sites in the National Air Emissions Monitoring Study (NAEMS). Data across studies were analyzed statistically using the MIXED procedures of SAS. The median emission rates from swine houses across various production stages and manure handling systems were 2.78 and 0.09 kg/yr per pig for NH3 and H2S, respectively. The median emission rates from swine storage facilities were 2.08 and 0.20 kg/yr per pig for NH3 and H2S, respectively. The size of swine farm that may trigger the need to report NH3 emissions under the Emergency Planning and Community Right-to-Know Act (EPCRA) is 3,410 pigs on the basis of the median NH3 emission rate (4.86 kg/yr per pig), but the threshold can be as low as 992 pigs on the basis of the 90th-percentile emission rates (16.71 kg/yr per pig). Swine hoop houses had significantly higher NH3 emission rate (14.80 kg/yr per pig) than other manure-handling systems (P < 0.01), whereas deep-pit houses had the highest H2S emission rate (16.03 kg/yr per pig, P = 0.03). Farrowing houses had the highest H2S emission rate (2.50 kg/yr per pig), followed by gestation houses, and finishing houses had the lowest H2S emission rate (P < 0.01). Regression models for NH3 and H2S emission rates were developed for finishing houses with deep pits, recharge pits, and lagoons. The NH3 emission rates increased with increasing air temperature, but effects of air temperature on H2S emission rates were not significant. The recharge interval of manure pits significantly affected H2S but not NH3 emission rates. The H2S emission rates were also influenced by the size of the operation. Although NH3 and H2S concentrations at the edge of swine houses or lagoons were often higher than corresponding acute or intermediate minimum risk levels (MRL), they decreased quickly to less than corresponding chronic or intermediate MRL as distances from emission sources increased. At the distances 30 to 1,185 m from emission sources, the average ambient concentrations for NH3 and H2S were 46 +/- 46 ug/m(3) and 4.3 +/- 8.6 ug/m(3) respectively. PMID- 24492568 TI - Deletion on chromosome 5 associated with decreased reproductive efficiency in female cattle. AB - Reproductive efficiency is arguably the most economically important trait in commercial beef cattle production, as failure to achieve pregnancy reduces the number of calves marketed per cow exposed to breeding. Identification of variation in the genome with predictive merit for reproductive success would facilitate accurate prediction of daughter pregnancy rate in sires enabling effective selection of bulls producing daughters with improved fertility. Copy number variation (CNV) is one form of structural variation that results in abnormal copies of DNA in the genome. Our lab previously reported a region between 25 and 70 Mb on chromosome 5 associated with reproductive efficiency. To further evaluate this region for genomic variations such as CNV, we initially applied a genomewide association approach based on the >700,000 SNP marker assay and PennCNV analysis to 68 Bos indicus cross females from a large commercial ranch in central Florida. A genomic segment located on chromosome 5, spanning the region of approximately 58.37 to 58.44 Mb (Bovine UMD3.1 assembly) was identified as containing a deletion associated with decreased reproductive efficiency. To verify this deletion, a quantitative real-time PCR test was developed to evaluate additional females in the central Florida and U.S. Meat Animal Research Center (USMARC) populations. The frequency of the homozygous deletion was 7% (23/319) in the central Florida population (Bos indicus cross) for females with 2 consecutive failed breeding seasons and 0% in the USMARC population (predominantly Bos taurus) of low reproductive females. To date, we have not identified the deletion in Bos taurus cattle, suggesting that the deletion is specific to Bos indicus cattle. From these data, we have identified a deletion on chromosome 5 associated with reproductive efficiency in Bos indicus-influenced cattle. PMID- 24492569 TI - Supplying dextrose before insemination and L-arginine during the last third of pregnancy in sow diets: effects on within-litter variation of piglet birth weight. AB - Preweaning piglet mortality is largely attributed to the incidence of low birth weight and birth weight variation within the litter. Therefore, developing strategies to increase within-litter uniformity of piglet birth weight is important. This study investigated the effects of different feeding strategies based on specific nutrient supplies in sow diet on the within-litter variation of piglet birth weight (BW0). Four batches of highly prolific crossbred Landrace * Large White sows were used. Three dietary treatments were compared: supplies of dextrose during the week before insemination (190 g/d) and of L-arginine (25.5 g/d) from d 77 of pregnancy until term (DEXA, n = 26); a dietary supplementation of L-arginine only (25.5 g/d), from d 77 of pregnancy until term (ARGI, n = 24); and no supplementation to a standard gestation diet (CTL; n = 23). Total born piglets (TB), i.e., piglets born alive (BA) and stillborn piglets, were numbered and weighed at birth and at weaning. Data were analyzed by ANOVA using the MIXED procedure in a model that included dietary treatment (ARGI, DEXA, and CTL), initial parity (1, 2 and 3, 4, and more), and backfat thickness (below or above the average value at the onset of the experiment: 15.7 mm) as the main effects and batch as random effect. The treatment did not influence (P > 0.10) the number of piglets at birth (on average 15.6 +/- 3.8 and 14.2 +/- 3.6 for TB and BA, respectively) or piglet BW0 (on average 1.48 +/- 0.26 and 1.50 +/- 0.26 kg for TB and BA, respectively). The coefficient of variation of piglet BW0 (CV(BW0)) was less in litters from ARGI sows than in litters from CTL sows and intermediate in litters from DEXA sows (for TB: 21.4, 23.4, and 25.7%, P = 0.08; for BA: 20.6, 22.5, and 25.4%, P = 0.03, in the ARGI, DEXA, and CTL groups, respectively). Irrespective of diet, CV(BW0) was less (P < 0.01) in litters with 16 TB piglets or less than in the largest litters (20.9 vs. 26.5%). Litter growth rate during lactation and litter size at weaning were not influenced (P > 0.10) by dietary treatments. In conclusion, supplementing gestation diet with L-arginine during the last third of pregnancy reduced within-litter variation of piglet birth weight. Combining L-arginine dietary supply with a supplementation of dextrose before insemination provided no additional benefit. PMID- 24492570 TI - Influence of trough versus pasture feeding on average daily gain and carcass characteristics in ruminants: a meta-analysis. AB - Quantitative meta-analysis was run on 108 publications featuring 116 experiments and 399 treatments dealing with the effect of trough or pasture feeding environment (FE) on ruminant performances. The objective was to compare the effect of trough or pasture FE on ADG, diet OM digestibility (OMD), various carcass characteristics, and the interaction between FE and complementation modalities. Live weight was adjusted to compare results between species. Results showed that trough-fed animals had higher ADG (+17.89%; P < 0.001), hot carcass yield (HYield; + 2.47%; P < 0.001) and carcass fat content (+ 24.87%; P < 0.001) than pasture-fed animals but lower carcass muscle and bone percentages (-1.60% [P = 0.010] and -7.63% [P = 0.003], respectively). Feeding environment had no effect on diet OMD (P = 0.818), but the number of observations was low. After considering the addition or not of concentrate in the diet (addiCO), FE effect persisted on ADG (P = 0.024) and carcass fat content (P = 0.027) but not on HYield (P = 0.078) or muscle and bone percentages (P = 0.119 and P = 0.581, respectively). After considering the nature of the concentrate (natCO), FE effect persisted on ADG (P < 0.001) and HYield (P = 0.004). Considering the percentage of concentrate in the diet (PCO) erased FE effect on ADG (P = 0.891) and HYield (P = 0.128). In contrast, considering the quantity of concentrate(QCO) erased FE effect on ADG (P = 0.084) but not on HYield (P = 0.006) or on carcass fat and muscle contents (P = 0.040 and P = 0.040, respectively) although the FE effect on carcass bone content persisted (P = 0.550). Animal species and physiological stage had no effect on any of the variables studied (P > 0.05) but experiment did (P <= 0.001). The increase in ADG was positively correlated to HYield in cattle (P = 0.002) and small ruminants (P = 0.003) and positively linked to carcass fat content (P = 0.007) but not carcass muscle content, which actually decreased (P = 0.001). Overall, this meta-analysis confirmed previous reports of FE effects and revealed how the differences generally reported result from a confounding effect of FE and nature of the diet. Indeed, in most of the studies used, trough-fed animals were supplemented with concentrate whereas pasture-fed animals were not. This research also highlighted the fact that pasture-fed animals have the potential to achieve the same performances as trough-fed animals when fed a similar diet. PMID- 24492571 TI - Recording rumination time by a rumination monitoring system in Jersey heifers fed grass/clover silage and hay at three feeding levels. AB - This study was conducted with the objective to validate a rumination monitoring system (RMS). The RMS was developed by SCR Engineers Ltd. (Netanya, Israel) to record individual rumination times in commercial dairy herds. Four heifers were fed 4 forage types at 3 feeding levels in 4 periods in a Latin square design. The forage types were spring growth of grass/clover harvested early (May 9) and late (May 25) conserved as silage and hay, creating 4 forage types: early harvest silage (ES), early harvest hay (EH), late harvest silage (LS), and late harvest hay (LH). Feeding levels were ad libitum, 90% of ad libitum, and 60% of ad libitum. Data were collected for 24 h at ad libitum feeding level, for 96 h at 90% of ad libitum, and for 24 h at 60% of ad libitum. Rumination time was recorded by the RMS in minutes per 2-h interval (RT(RMS2_i)) and per 24-h interval (RT(RMS24)). As a reference method, rumination time was recorded by chewing halters identifying rumination time by jaw movements (JM) and was accumulated into minutes per 2-h interval (RT(JM2_i)) and per 24-h interval (RT(JM24)) over the same time intervals as RT(RMS2_i) and RT(RMS24). Differences between RT(RMS2_i) and RT(JM2_i) were observed for EH, LS, and LH, with differences of 3.4 (P < 0.001), 1.1 (P = 0.03), and 3.3 (P < 0.001) min per 2-h interval. In addition, feeding restrictively at 90% and 60% of ad libitum resulted in greater rumination time recorded by the RMS compared to JM, with differences of 2.6 min per 2-h interval (P < 0.001) for 90% of ad libitum and 1.6 min per 2-h interval (P = 0.01) for 60% of ad libitum. Further, the differences between rumination times recorded by the RMS compared to JM were different among the 4 heifers. Despite these effects, rumination time recorded by the RMS correlated well with rumination time recorded by JM with correlation between RT(RMS2_i) and RT(JM2_i) of r = 0.91 (P < 0.001) and between RT(RMS24) and RT(JM24) of r = 0.79 (P < 0.001). PMID- 24492572 TI - Dietary exposure to ergot alkaloids decreases contractility of bovine mesenteric vasculature. AB - Ergot alkaloids are hypothesized to cause vasoconstriction in the midgut, and prior exposure may affect the vasoactivity of these compounds. The objectives of this study were to profile vasoactivity of ergot alkaloids in bovine mesenteric artery (MA) and vein (MV) and determine if previous exposure to endophyte infected tall fescue seed affected vasoactivity of ergocryptine (ERP), ergotamine (ERT), ergocristine (ERS), ergocornine (ERO), ergonovine (ERN), lysergic acid (LSA), ergovaline-containing tall fescue seed extract (EXT), and 5 hydroxytryptamine (5HT; serotonin). Ruminally cannulated Angus steers (n = 12; BW = 547 +/- 31 kg) were paired by weight and randomly assigned to 6 blocks. Steers were ruminally dosed daily with 1 kg of either endophyte-infected (E+; 4.45 mg ergovaline/kg DM) or endophyte-free (E-; 0 mg ergovaline/kg DM) tall fescue seed for 21 d before slaughter. Branches of MA and MV supporting the cranial portion of the ileum were collected after slaughter on d 22, placed in a modified Krebs Henseleit buffer on ice, cleaned, sectioned, and mounted in a multimyograph chamber. Contractile response was normalized to a maximum KCl response. Inner diameter (P = 0.04) and outer diameter (P = 0.02) of MA were smaller for E+ steers than E- steers. Maximum contractile responses to 120 mM KCl were not different between seed treatments in MA (P = 0.33; E-: 2.67 +/- 0.43 g; E+: 3.33 +/- 0.43 g) or MV (P = 0.26; E-: 2.01 +/- 0.18 g; E+: 1.81 +/- 0.18 g). Steers receiving E+ had a smaller (P < 0.01) MA contractile response than E- steers to ERP, ERT, ERS, ERO, ERN, EXT, and 5HT. Steers receiving E+ had a smaller (P < 0.05) MV contractile response than E- steers to ERP, ERT, ERS, ERN, EXT, and 5HT. Lysergic acid failed to induce a contractile response in MA and MV. The contractile response in MA and MV of E- steers produced by 5HT was very large. The EXT was the most potent (P < 0.05) agonist in MV and MA of E+ steers. These data showed that ergot alkaloids were vasoactive in the bovine midgut, and steers exposed to E+ had diminished contractility to some ergot alkaloids in small intestinal vasculature. The findings of this study suggest that dietary exposure to ergot alkaloids has the potential to alter nutrient absorption from the midgut by decreasing blood flow to and from the midgut due to vasoconstriction. PMID- 24492573 TI - Dietary energy source largely affects tissue fatty acid composition but has minor influence on gene transcription in Iberian pigs. AB - A trial was performed to compare the effects of different dietary sources of MUFA on the fatty acid (FA) composition, lipid metabolism, and gene transcription in different tissues of Iberian pigs. Twenty-seven Iberian male pigs of 28 kg live weight (LW) were divided in 2 groups and fed with 1 of 2 isocaloric diets: a standard diet with carbohydrates as energy source (CH) and a diet enriched with high-oleic sunflower oil (HO). Ham adipose tissue was sampled by biopsy at 44 and 70 kg LW. At 110 kg LW pigs were slaughtered and backfat, loin, and liver tissues were sampled. Animals of the HO group showed higher MUFA content and lower SFA in all the analyzed tissues (P < 0.001). These main effects were established early during the treatment and increased only slightly along time. Small diet effects were also detected on PUFA, which showed differences according to sampling time, tissue, and lipid fraction. Effects of diet on gene expression were explored with a combined approach analyzing adipose tissue transcriptome and quantifying the expression of a panel of key genes implicated in lipogenesis and lipid metabolism processes in backfat, muscle, and liver. Backfat transcriptome showed small effects of diet on gene expression, in number and magnitude. According to the posterior probabilities (PP) of the probe-specific expression differences between dietary groups (PP < 0.01), 37 genes were considered differentially expressed (DE). Gene ontology allowed relating them with several biological functions including lipid metabolic processes. Quantitative PCR confirmed several DE genes in adipose tissue (RXRG, LEP, and ME1; P < 0.0001, P < 0.05, and P < 0.0001, respectively), but no DE gene was found in loin or liver tissues. Joint results agree with a metabolic adjustment of adipose tissue FA levels by the subtle effect of the diet on the regulation of several lipid metabolism pathways, mainly FA oxidation and prostanoid synthesis, with LEP, RXRG, and PTGS2 genes playing mayor roles. PMID- 24492574 TI - Meat Science and Muscle Biology Symposium: Development of bacteriophage treatments to reduce Escherichia coli O157:H7 contamination of beef products and produce. AB - Escherichia coli O157:H7 remains a foodborne pathogen of concern with infections associated with products ranging from ground beef to produce to processed foods. We previously demonstrated that phage-based technologies could reduce foodborne pathogen colonization in live animals. Here, we examined if a 3-phage cocktail could reduce E. coli O157:H7 in experimentally contaminated ground beef, spinach, and cheese. The 3 phages were chosen from our E. coli O157:H7 phage library based on their distinct origins of isolation, lytic ranges, and rapid growth (40- to 50 min life cycle). Two phages belonged to the Myoviridae family and the other phage belonged to the Siphoviridae family. The phage cocktail was added to ground beef, spinach leaves, and cheese slices contaminated with E. coli O157:H7 (10(7) cfu) at a multiplicity of infection of 1. Phage treatment reduced (P < 0.05) the concentrations of E. coli O157:H7 by 1.97 log10 cfu/mL in ground beef when stored at room temperature (24 degrees C) for 24 h, 0.48 log10 cfu/mL at refrigeration (4 degrees C), and 0.56 log10 cfu/mL in undercooked condition (internal temperature of 46 degrees C). Likewise, phage treatment reduced (P < 0.05) E. coli O157:H7 by 3.28, 2.88, and 2.77 log10 cfu/mL in spinach when stored at room temperature for 24, 48, and 72 h, respectively. Phage treatment, however, did not reduce E. coli O157:H7 concentrations in contaminated cheese. Additionally, 3 phage-resistant E. coli O157:H7 strains (309-PR [phage resistant] 1, 309-PR4, and 502-PR5) were isolated and characterized to test if phage resistance could limit long-term use of phages as biocontrol agents. Growth kinetics and adsorption assays indicated that phage resistance in strains 309-PR4 and 502-PR5 was mediated, at least in part, by prevention of phage adsorption. Phage resistance in strain 309-PR1 was the result of limited phage proliferation. Phage resistance was stably maintained in vitro throughout a 4-d subculture period in the absence of phage. No significant reductions in bacterial growth or cell adhesion were observed in resistant strains. Taken together, our results provide additional support for the use of phage to control E. coli O157:H7 in food products; however, the emergence of phage-resistant bacteria could limit the efficacy of phage products. Therefore, further studies are needed to develop resistance mitigation strategies to optimize phage-based technologies. PMID- 24492575 TI - Effect of cross-fostering and oral supplementation with colostrums on performance of newborn piglets. AB - The aim of the experiment was to study the effect on litter performance of two oral supplementation strategies on piglets born weighing 1.35 kg or less (SP; CON: no oral supplementation; COL: supplementation with 15 mL of sow colostrum orally administered to piglets within 4 h after the farrowing was completed). Two levels of cross-fostering strategies, performed 24 h after farrowing, were also studied (HL: litters fixed at 12 piglets, ensuring that less than 50% of the piglets of the litter were SP; LL: litters fixed at 12 piglets, with most of the piglets of the litter being SP; in both cases the aim was to minimize moving piglets from one sow to another as much as possible). The combination of the 2 management strategies described above resulted in a 2 * 2 factorial model. Forty six litters were used. Litters were allocated to 1 of the 4 treatments: CON-HL, CON-LL, COL-HL, and COL-LL. Piglets were weighed on d 1 and 19 postpartum. Mortality was recorded. On d 4 postpartum, a 2-mL blood sample was obtained from 79 SP piglets born from multiparous sows included in the experiment. To obtain a negative control group, blood samples were obtained on d 4 postpartum from 8 additional SP piglets that were separated from their mothers at birth and bottle fed with milk replacement for 12 h. LL sows had lower within-litter CV of BW at d 1 than HL sows (16.2% vs. 21.9% +/- 0.91%; P = 0.003), but they did not differ for litter CV of BW at d 19 (23.2% vs. 23.4% +/- 1.72%). At d 19, HL sows had fewer dead piglets per litter than LL sows (0.80 vs. 1.69 +/- 0.307; P = 0.022), and COL-HL sows had fewer dead piglets per litter than CON-HL (0.47 vs. 1.14 +/- 0.160; P = 0.062). Cross-fostering SP in the same litter did not prevent a litter's CV of BW from increasing at weaning. Piglets from the COL group had higher IgG concentration than piglets from the CON group (P = 0.001). However, piglets from the negative control group had lower IgG concentration than those from the COL and CON groups (5.41 +/- 2.320 vs. 30.60 +/- 1.582 and 21.53 +/- 0.951 mg/mL, respectively; P < 0.001 in both cases). Allocating small piglets to the same litter through cross-fostering had a negative effect on mortality and did not improve litter CV of BW at weaning. Colostrum supplementation of SP piglets improved IgG blood level on d 4. In addition, in nonhomogenized litters, colostrum supplementation of SP piglets might be a good management strategy to improve litter performance. PMID- 24492576 TI - Evaluation of feeding distiller's grains, containing virginiamycin, on antimicrobial susceptibilities in fecal isolates of Enterococcus and Escherichia coli and prevalence of resistance genes in cattle. AB - Dried distiller's grains (DG) produced from ethanol fermentations dosed with 0 (control), 2, or 20 mg/kg virginiamycin-based product or spiked with virginiamycin (VM) postfermentation were fed to cattle and effects on antimicrobial susceptibility, and prevalence of antimicrobial resistance genes in commensal bacteria was examined. Biological activity assays of DG (from each fermentation) indicated a concentration of 0, 0.7, and 8.9 mg/kg VM, respectively. Twenty-four crossbred beef steers were fed 1 of 4 diets (containing 8% of each of the different batches of DG) and a fourth using 8% of the control DG (0 mg/kg VM) + 0.025 g/kg V-Max50 (positive control) for 7 wk. Fecal samples were collected weekly throughout the experimental period and cultured for Escherichia coli and Enterococcus, and isolates were examined for antimicrobial susceptibility, antimicrobial resistance genes (vatE, ermB, and msrC in Enterococcus), and integrons (E. coli). No treatment differences (P > 0.05) were observed in antimicrobial susceptibility of the E. coli isolates. Enterococcus isolates were resistant to more antimicrobials; however, this was influenced by the species of Enterococcus and not treatment (P > 0.10). The prevalence of ermB was greater (P < 0.05) in the control isolates after 4 and 6 wk while at wk 7, prevalence was greater (P < 0.01) in the 0.7 and 8.9 mg/kg VM treatments. Taken together, the minor treatment differences observed for the presence of ermB coupled with the lack of effect on antimicrobial susceptibility patterns suggest that feeding DG containing VM residues should have minimal if any impact on prevalence of antimicrobial resistance. PMID- 24492577 TI - The effect of birth weight and age at tail docking and ear notching on the behavioral and physiological responses of piglets. AB - Selection for high prolificacy has resulted in litters comprising a large number of low-birth-weight (LBW) piglets. Given their presence in over 75% of litters and increased mortality rate, it is clear that a greater understanding of LBW piglet management is required for both animal welfare and productivity. In this study, we compared the effects of tail docking and ear notching LBW and average birth-weight (ABW) piglets at 1 or 3 d of age on suckling, behavior, passive transfer of immunoglobulins, and growth. Six piglets per litter from 20 litters (n = 120 piglets) were used in a 2 * 2 complete block design. Piglets were weighed at birth and designated as LBW (0.6 to 1.0 kg) or ABW (>= 1.2 kg) and "processed" (tail docked and ear notched) at either 1 or 3 d of age. Vocalizations were recorded during the procedures. The acute behavioral responses were observed for 10 min after the procedure. Piglets were observed for 6 h after birth and after the procedure to determine their presence at nursing bouts. On d 5, blood samples were collected to determine concentrations of serum immunoglobulins (IgA and IgG) and IGF-I. Piglet weights were recorded at birth and on d 5, 14, and 21. During the procedures, LBW piglets produced fewer (P = 0.03) calls than ABW piglets. Piglets from either birth weight category produced a similar number (calls/s; P = 0.29) of high-frequency calls (>= 1,000 Hz), which are indicative of pain and distress, although the average frequency (Hz) of these calls was greatest (P = 0.05) for ABW piglets processed on d 3. Immediately following the procedures, LBW piglets spent more (P = 0.005) time dog-sitting and less (P = 0.005) time lying than ABW piglets. When observed with the sow, LBW males spent more (P = 0.001) time alone and had the lowest (P = 0.007) attendance at nursing bouts compared with LBW females and all ABW piglets. Concentrations of serum IgA (P = 0.06) and IgG (P = 0.04) and plasma IGF-I (P = 0.003) were lower for LBW than ABW piglets regardless of age of processing although the magnitude of these differences was likely not of biological significance. Average-birth weight piglets may be less reactive to the acute effects of the procedures on d 1 than on d 3. Given the decreased likelihood of a LBW piglet surviving to weaning (P = 0.001), delaying processing until 3 d of age for LBW piglets may eliminate unnecessary procedures. PMID- 24492578 TI - Preference of domestic horses for shade in a hot, sunny environment. AB - Provision of shade is recommended by best practice guidelines for horses living in hot, sunny environments despite a lack of research focused on potential benefits. We found in a previous study that horses without access to shade showed greater rectal temperature (RT), respiration rate (RR), and skin temperature (SK) and exhibited more sweat than horses that were completely shaded. Yet not known is whether horses will choose to stand in the shade when given a choice of areas with and without this resource. Our objective was to assess horse preference for shaded and unshaded areas in the hot and arid, sunny summer weather in Davis, California. For this preference test, 12 healthy, adult horses (6 mares, 6 geldings) were randomized into 3 sequential trials using 4 horses in each trial. The trials consisted of 2 d of acclimation and either 5 d (Trial 1) or 7 d (Trials 2 and 3) of observation. Horses were housed individually in dry lot pens. Half of each pen was covered by an open-sided shade structure. The amount of the pen shaded varied slightly throughout the day with a mean of 50.1% of the pen shaded. Physiological measurements (RT, RR, SK, sweat score) were recorded at 0900, 1230, and 1800 h. Behavioral observations (horses' location relative to shade, time spent walking, foraging, and standing) were recorded at 5-min intervals from 1300 to 1800 h daily and at 10-min intervals from 1800 to 1300 h on alternate days. Insect avoidance behavior was recorded for 1 min/h for each horse. Weather factors were recorded every 5 min, 24 h/d throughout the study; mean daytime ambient temperature was 29 degrees C +/- 5 degrees C. Data were analyzed using PROC MIXED in SAS. Horses were located in the shade in 7.1% more observations than by chance (SE = 1.3, P < 0.001), with greatest use before and during peak solar radiation and then again following peak black globe temperature. Horses performed more walking and foraging behavior in the shaded areas (P < 0.01). Our research indicates that individually housed horses prefer shade when it is available in hot, sunny environments. These results support recommendations for access to shade when developing best practice guidelines for the care of domestic horses. PMID- 24492579 TI - Selection for feed efficiency traits and correlated genetic responses in feed intake and weight gain of Nellore cattle. AB - The objectives of this study were to estimate genetic parameters for indicator traits of feed efficiency and to recommend traits that would result in better responses to selection for increased weaning weight (weaning weight adjusted to 210 d of age [W210]), ADG, and metabolic BW (BW(0.75)) and lower DMI. Records of W210 from 8,004 Nellore animals born between 1978 and 2011 and postweaning performance test records from 678 males and females born between 2004 and 2011 were used. The following feed efficiency traits were evaluated: G:F, partial efficiency of growth (PEG), relative growth rate (RGR), Kleiber's ratio (KR), residual feed intake (RFI), residual weight gain (RWG), and residual intake and gain (RIG). Covariance and variance components were estimated by the restricted maximum likelihood method using multitrait analysis under an animal model. Estimates of genetic gain and correlated responses were obtained considering single-stage and 2-stage selection. Heritability estimates were 0.22 +/- 0.03 (W210), 0.60 +/- 0.08 (DMI), 0.42 +/- 0.08 (ADG), 0.56 +/- 0.06 (BW(0.75)), 0.19 +/- 0.07 (G:F), 0.25 +/- 0.09 (PEG), 0.19 +/- 0.07 (RGR), 0.22 +/- 0.07 (KR), 0.33 +/- 0.10 (RFI), 0.13 +/- 0.07 (RWG), and 0.19 +/- 0.08 (RIG). The genetic correlations of DMI with W210 (0.64 +/- 0.10), ADG (0.87 +/- 0.06), and BW(0.75) (0.84 +/- 0.05) were high. The only efficiency traits showing favorable responses to selection for lower DMI were G:F, PEG, RFI, and RIG. However, the use of G:F, PEG, or RFI as a selection criterion results in unfavorable correlated responses in some growth traits. The linear combination of RFI and RWG through RIG is the best selection criterion to obtain favorable responses in postweaning growth and feed intake of Nellore cattle in single-stage selection. Genetic gains in feed efficiency are expected even after preselection for W210 and subsequent feed efficiency testing of the preselected animals. PMID- 24492580 TI - Effect of lipid sources with different fatty acid profiles on the intake, performance, and methane emissions of feedlot Nellore steers. AB - The present study was conducted to evaluate the effect of lipids with different fatty acid profiles on the intake, performance, and enteric CH4 emission of Nellore steers. A total of 45 Nellore animals with an average initial BW of 419 +/- 11 kg (at 15 +/- 2 mo) were distributed in a completely randomized design consisting of 5 treatments and 9 replicates. The roughage feed was maize silage (600 g/kg on a DM basis) plus concentrate (400 g/kg on a DM basis). The dietary treatments were as follows: without additional fat (WF), palm oil (PO), linseed oil (LO), protected fat (PF; Lactoplus), and whole soybeans (WS). The lipid source significantly affected (P < 0.05) nutrient intake. The greatest intakes of DM, OM, and CP were observed in the animals that were fed the WF or PF diets, and the lowest intakes were observed in the animals that were fed the PO diet. Intake of NDF decreased (P < 0.05) with the addition of PO. Enteric methane emission (g/kg DMI) was reduced by an average of 30% when the animals were fed diets containing WS, LO, and PO (P < 0.05), and these diets caused a larger reduction in the energy loss in the form of methane compared to those without added fat and with added PF (3.3 vs. 4.7%). The different fatty acid profiles did not affect the backfat thickness or the loin eye area of the animals (P > 0.05). However, animals fed PO displayed lower daily weight gain (0.36 kg/d), feed efficiency (0.08 kg ADG/kg DM), HCW (245 kg), and hot yield percentage (52.6%) compared to animals that were fed the other diets. Therefore, PO compared to the other lipid sources used in this study reduces intake, performance, feed efficiency, and carcass yield. Therefore, PO is not suggested for feedlot-finished animals. PMID- 24492581 TI - Standardized ileal digestibility of amino acids in alfalfa meal, sugar beet pulp, and wheat bran compared to wheat and protein ingredients for growing pigs. AB - A total of 11 (8 + 3 for replacement) barrows with an initial BW of 23 kg and fitted with a simple T-cannula at the distal ileum were used in 2 consecutive experiments (Exp. 1 and Exp. 2) to determine the standardized ileal digestibility (SID) of AA in 7 assay feed ingredients according to 2 consecutive duplicated 4 * 4 Latin square designs. In Exp. 1, 3 corn starch-based assay diets were formulated to contain 170 g CP/kg (as-fed basis) from either soybean meal (SBM), canola meal (CM), or meat-and-bone meal (MBM) and 1 assay diet that contained 136 g CP/kg (as-fed basis) from wheat as commonly used feed ingredients for pigs. In Exp. 2, the pigs were fed 4 assay diets formulated to contain 170 g CP/kg (as-fed basis) from either the same SBM as in Exp. 1 or a combination of this SBM and alfalfa meal (AM), sugar beet pulp (SB), or wheat bran (WB) to compare the SID of AA in these feed ingredients with those used in Exp. 1. The SID of AA in CM was lower compared to SBM (P < 0.05) with intermediate values for MBM and wheat. Among fiber rich feed ingredients, SID values were lower in SB compared to WB (P < 0.05) with intermediate values for AM. In AM, SID values ranged between 29 and 45% for Lys, Cys, Thr, and Phe and between 51 and 71% for Arg, His, Ile, Leu, Met, and Val. In SB, SID values ranged between -21 and 46% for Cys, Thr, Phe, and Val and between 51 and 61% for Arg, His, Ile, Leu, Lys, and Met. In WB, SID values were between 55 and 64% for Lys, Cys, Phe, Thr, and Val and between 68 and 80% for Arg, His, Ile, Leu, and Met. The SID values in WB, SB, and AM provided in the present study may improve diet formulation when these feed ingredients are used in diet formulation for pigs. PMID- 24492582 TI - Interactive effects of bulk density of steam-flaked corn and concentration of Sweet Bran on feedlot cattle performance, carcass characteristics, and apparent total tract nutrient digestibility. AB - Two hundred twenty-four steers (initial BW = 363 +/- 1.57 kg) were used in a 2 * 3 + 1 factorial arrangement of treatments to evaluate the interactive effects of concentration of wet corn gluten feed (WCGF) and bulk density (BD) of steam flaked corn (SFC) on feedlot performance, carcass characteristics, and apparent total tract digestibility. Diets consisted of 0, 15, or 30% WCGF (DM basis) with a BD of SFC at 283 or 360 g/L. The additional treatment consisted of 15% WCGF, SFC at 283 g/L, and a 6% inclusion of alfalfa hay vs. 9% for all other treatments. Steers were fed once daily for an average of 163 d. During a 5-d digestion period, DMI was measured, and fecal samples were collected for measurement of nutrient digestibility using dietary acid insoluble ash as a marker. There were few WCGF * BD interactions for feedlot performance, carcass characteristics, and digestibility. Similarly, contrasts between the treatment containing 15% WCGF/360 g/L SFC and 15% WCGF/360 g/L with 6% hay yielded few differences for performance and carcass data. Final BW responded quadratically (P <= 0.02) to WCGF inclusion and showed increased (P <= 0.007) BW for greater BD. As WCGF inclusion increased, G:F and calculated NE values (P <= 0.03) decreased quadratically. Steers consuming 360 g/L SFC had greater (P < 0.05) G:F than those fed 283 g/L SFC. Marbling score, HCW, 12th-rib fat thickness, and calculated yield grade increased quadratically (P <= 0.04) with increased inclusion of WCGF. Percentage of cattle grading premium Choice or greater responded quadratically (P = 0.04) to WCGF concentration. Increasing BD increased (P <= 0.01) HCW, dressing percent, marbling score, and 12th-rib fat thickness and decreased calculated yield grade and percentage of cattle grading Select; however, lower BD tended (P = 0.09) to increase LM area. Intake of DM, OM, CP, and NDF and fecal output during the digestibility period increased linearly (P <= 0.01) with increasing WCGF, and greater BD increased (P <= 0.04) intake of DM, OM, starch, and CP. Starch digestibility decreased quadratically (P = 0.008) as WCGF increased; however, digestibility of CP and NDF increased (P <= 0.02) linearly as WCGF increased. The 283 g/L BD increased (P <= 0.02) starch and CP digestibility compared with 360 g/L. These data suggest that increasing WCGF in feedlot diets with a greater BD of SFC can increase performance and carcass characteristic, but it might not be ideal for starch digestibility. PMID- 24492583 TI - Preparation and evaluation of microemulsion formulations of naproxen for dermal delivery. AB - Naproxen (Np) is an example of a non-steroidal anti-inflammatory drug (NSAID) commonly used for the reduction of pain and inflammation. In order to develop an alternative formulation for the topical administration of Np, microemulsions were evaluated as delivery vehicles. Four formulations were prepared using isopropyl myristate (IPM) as oil phase, Span 80, Labrafil M, Labrasol, Cremophor EL as surfactants, ethanol as co-surfactant and distilled water or 0.5 N NaOH solution as aqueous phase. The final concentration of Np in the microemulsion system was 100 mg/g (w/w). The physicochemical properties such as electrical conductivity, droplet size, viscosity, pH and phase inversion temperature of microemulsions were measured. Stability tests of the formulations were also performed at 5+/-2, 25+/-2 and 40+/-2 degrees C. The abilities of various microemulsions and selected commercial (C) formulation to deliver Np through the skin were evaluated in vitro using diffusion cells fitted with rat skins. The in vitro permeation data showed that microemulsions increased the permeation rate of Np between 4.335-9.040 times over the C formulation. Furthermore Np successfully permeated across the skin from the microemulsion with the highest flux rate (1.347+/-0.005 mg.cm(-2).h(-1)) from a formulation (M4Np) consisting of IPM (2.36 g), Labrosol (0.13 g), Span 80 (0.62 g), ethanol (5.23 g), 0.5 N NaOH solution (0.66 g) and Np (1 g). According to the histological investigations, no obvious skin irritation was observed for the studied microemulsions. These results indicate that the microemulsion formulation may be appropriate vehicles for the topical delivery of Np. PMID- 24492584 TI - Design and evaluation of polysaccharide-based transdermal films for the controlled delivery of nifedipine. AB - It was aimed to develop the matrix type polysaccharide-based transdermal films of nifedipine (NFD) to provide its long term plasma concentration. The mechanical tests were carried out on gel formulations which were utilised in the fabrication of transdermal films to determine the type of polymer (pectin, sodium alginate) and plasticizer (propylene glycol, glycerine) as well as their concentrations. The mechanical strength, elasticity, bioadhesiveness and the drug release characteristics of optimised films containing NFD were evaluated. Permeation of NFD from the films with/without adding an enhancer (nerolidol) was followed through excised rat skin using Franz diffusion cells. Results showed that the gels composed of either pectin or sodium alginate were appropriate for the fabrication of transdermal films of NFD, and the addition of propylene glycol improved mechanical strength, flexibility, and bioadhesiveness of the films. Permeation data showed that nerolidol was an effective permeation enhancer for the polysaccharide-based transdermal films of NFD. PMID- 24492585 TI - Optimization of primary drying condition for pharmaceutical lyophilization using a novel simulation program with a predictive model for dry layer resistance. AB - The purpose of this study was to develop a novel simulation program to accurately predict the maximum product temperature and the primary drying time in lyophilization using the predictive model for dry layer resistance, which is the resistance of dried cake against water vapor flow. Ten percent sucrose aqueous solution was selected as a model formulation. It was demonstrated that the deviations between the predicted and measured maximum product temperature were attributed to the error of dry layer resistance at a given drying condition, which was different from the measured dry layer resistance in a preliminary lyophilization run for the simulation program. However, when the predictive model of dry layer resistance was used for the simulation program, the model remarkably enhanced the accuracy of the simulation program to predict the maximum product temperature and primary drying time under various operating conditions. Furthermore, the primary drying condition required for minimized drying at a close collapse temperature was successfully discovered through one preliminary run. Therefore, it is expected that the developed simulation program is useful for designing the lyophilization cycle without a trial and error approach. PMID- 24492586 TI - Vaginal chitosan tablets with clotrimazole-design and evaluation of mucoadhesive properties using porcine vaginal mucosa, mucin and gelatine. AB - Topical administration of clotrimazole represents the common use therapy in the antimycotic genitourinary tract treatment. Due to the fast self-cleaning action of the vagina, commercially available vaginal dosage forms with clotrimazole cannot assure prolonged contact time with mucosa, therefore the main objective of this study was to develop a dosage form for vaginal administration of clotrimazole using chitosan-a biodegradable and biocompatible derivative of chitin. Tablets mucoadhesive properties were examined using texture analyser under the presence of porcine vaginal mucosa and two different models of adhesive layers- mucin gel and gelatine discs. In addition, friability, hardness, swelling behaviour, residence time, surface morphology of the performed tablets, the in vitro release profile of clotrimazole and clotrimazole release kinetics were determined. The release of clotrimazole from formulations with 25 or 40% of chitosan (F2 and F3) followed non Fickian diffusion through chitosan-gel layer and was retarded up to 6 h. Additionally, tablets F2 showed the best results in terms of mucoadhesive properties and appeared to be a good alternative to commercially available antimycotic vaginal dosage forms. PMID- 24492587 TI - Effect of cytochrome P450 2C19 and 2C9 amino acid residues 72 and 241 on metabolism of tricyclic antidepressant drugs. AB - Although cytochromes P450 2C9 (CYP2C9) and 2C19 (CYP2C19) have 91% amino acid identity, they have different substrate specificities. Previous studies have suggested that several amino acid residues may be involved in substrate specificity. In this study, we focused on the roles of two amino acids, residues 72 and 241. The amino acids in these positions have opposite charges in CYP2C9 and 2C19; the former has lysines in both positions (Lys72 and Lys241), and the latter has glutamic acids (Glu72 and Glu241). Reciprocal mutants for both CYP2C19 and 2C9 were produced, and their metabolic activities and spectroscopic properties were examined using three tricyclic antidepressant (TCA) drugs: amitriptyline, imipramine, and dothiepin. Although CYP2C19 wild-type (WT) had a high metabolic activity for all three drugs, the E72K mutation decreased enzymatic activity by 29-37%, while binding affinities were diminished 2.5- to 20 fold. On the other hand, low activity and low affinity of CYP2C9 WT were recovered notably by K72E mutation. The metabolic activities and binding affinities were minimally affected by CYP2C19 E241K and CYP2C9 K241E mutations. We could also show linear correlations between metabolic activities and binding affinities, and hence we conclude that amino acid residue 72 plays a key role in TCA drug metabolism by limiting the binding affinities of CYP2C19 and CYP2C9. PMID- 24492588 TI - Synthesis and biological activity of 1alpha,2alpha,25-trihydroxyvitamin D3: active metabolite of 2alpha-(3-hydroxypropoxy)-1alpha,25-dihydroxyvitamin D3 by human CYP3A4. AB - Our previous studies revealed that recombinant human CYP3A4 converted 2alpha-(3 hydroxypropoxy)-1alpha,25-dihydroxyvitamin D3 (O2C3), which was a more potent binder to vitamin D receptor (VDR) than the natural hormone, 1alpha,25 dihydroxyvitamin D3 (1alpha,25(OH)2D3, 1), to 1alpha,2alpha,25-trihydroxyvitamin D3 (2). Here, we synthesized 2 using the Trost Pd-mediated coupling reaction between an A-ring precursor and a CD-ring bromoolefin and evaluated its preliminary biological activity. We found that metabolite 2 from O2C3 was still active as a VDR ligand while maintaining human VDR binding affinity (27.3% of 1alpha,25(OH)2D3) and HL-60 cell differentiation activity (62% of 1alpha,25(OH)2D3). PMID- 24492589 TI - Anti-inflammatory compounds from the aerial parts of Aceriphyllum rossii. AB - A new megastigmane glycoside, galloyl linarionoside A (1), together with 13 known compounds (2-14) were isolated from the aerial parts of Aceriphyllum rossii ENGLER. (Saxifragaceae). The chemical structures of the isolated compounds were established mainly by using nuclear magnetic resonance spectra, mass spectrometry, and modified Mosher's method. Among the isolates, compounds 4, 5, 6 and 7 showed potent inhibitory activity against the lipopolysaccharide-induced nitric oxide production in RAW264.7 macrophage cells with IC50 values of 12.5, 9.5, 10.5 and 9.3 uM, respectively. The anti-inflammatory effect of compound 7 was accompanied by dose-dependent decreases in the production of inducible nitric oxide synthase and cyclooxygenase-2 proteins not in the inhibitor kappa B (IkappaB)-dependent nuclear factor-kappa B activation. PMID- 24492590 TI - NF-kappaB inhibitory activities of glycosides and alkaloids from Zanthoxylum schinifolium stems. AB - Zanthoxylum schinifolium is an aromatic shrub, the pericarp and leaves of which are widely used in culinary applications in East Asian countries. In the present study, one new neolignan glycoside, zanthoxyloside A (1) together with 16 known glycosides (2-12) and alkaloids (13-17), were isolated from methanol extract of the stems of Z. schinifolium. The absolute configuration of one known monoterpenoid glycoside (2) was determined. The structures of the isolated compounds were established by one dimensional (1D), 2D NMR and mass spectrometry. The nuclear factor-kappaB (NF-kappaB) inhibitory activities of the isolated compounds stimulated with tumor necrosis factor alpha (TNFalpha) were measured using a luciferase reporter system. Compounds 1, 5, 16, and 17 exhibited significant inhibition of NF-kappaB activation in a dose-dependent manner. Furthermore, compounds 1, 5, 16, and 17 inhibited TNFalpha-induced expression of inducible nitric oxide synthase (iNOS) and intercellular adhesion molecule-1 (ICAM-1) mRNA and dose-dependent inhibition of iNOS promoter activity. PMID- 24492591 TI - Cembranoid diterpenes from the soft coral Lobophytum crassum and their anti inflammatory activities. AB - Nine cembranoid diterpenes 1-9, including four new compounds, crassumols D-G (1 4), were isolated from the methanol extract of the Vietnamese soft coral Lobophytum crassum. Spectroscopic methods were used to elucidate the structures of these compounds. Compound 5 exhibited a potent inhibitory effect on tumor necrosis factor-alpha (TNFalpha)-induced nuclear factor-kappa B (NF-kappaB) transcriptional activation in HepG2 cells and significantly inhibited the mRNA expression of cyclooxygenase-2 (COX-2) and inducible nitric oxide synthase (iNOS) in a dose-dependent manner. PMID- 24492592 TI - Nakijiquinone S and nakijinol C, new meroterpenoids from a marine sponge of the family spongiidae. AB - New meroterpenoids, nakijiquinone S (1) and nakijinol C (2), have been isolated from an Okinawan marine sponge of the family Spongiidae. The gross structures and relative stereochemistries of 1 and 2 were elucidated on the basis of their spectral data. Nakijiquinone S (1) and nakijinol C (2) were new meroterpenoids consisting of a clerodane-type decalin ring connected to a 2-butoxy-5-hydroxy benzoquinone unit or methyl 2,3,4-trihydroxybenzoate unit through a methylene, respectively. Nakijiquinone S (1) and nakijinol C (2) showed antimicrobial activities against several bacteria and fungi. PMID- 24492593 TI - Nagelamide I and 2,2'-didebromonagelamide B, new dimeric bromopyrrole-imidazole alkaloids from a marine sponge Agelas sp. AB - New dimeric bromopyrrole-imidazole alkaloids, nagelamide I (1) and 2,2' didebromonagelamide B (2), have been isolated from an Okinawan marine sponge Agelas species. The structures of 1 and 2 were elucidated based on analyses of the spectral data. Nagelamide I (1) was the first symmetric dimeric bromopyrrole imidazole alkaloid consisting of two subunits connected with a single bond. PMID- 24492594 TI - Tritium labeling of detonation nanodiamonds. AB - For the first time, the radioactive labeling of detonation nanodiamonds was efficiently achieved using a tritium microwave plasma. According to our measurements, the total radioactivity reaches 9120 +/- 120 MUCi mg(-1), with 93% of (3)H atoms tightly bonded to the surface and up to 7% embedded into the diamond core. Such (3)H doping will ensure highly stable radiolabeled nanodiamonds, on which surface functionalization is still allowed. This breakthrough opens the way to biodistribution and pharmacokinetics studies of nanodiamonds, while this approach can be scalable to easily treat bulk quantities of nanodiamonds at low cost. PMID- 24492595 TI - Kingianic acids A-G, Endiandric acid analogues from Endiandra kingiana. AB - A phytochemical investigation of the methanolic extract of the bark of Endiandra kingiana led to the isolation of seven new tetracyclic endiandric acid analogues, kingianic acids A-G (1-7), together with endiandric acid M (8), tsangibeilin B (9) and endiandric acid (10). Their structures were determined by 1D- and 2D-NMR analysis in combination with HRMS experiments. The structure of compounds 9 and 10 were confirmed by single-crystal X-ray diffraction analysis. These compounds were screened for Bcl-xL and Mcl-1 binding affinities and cytotoxic activity on various cancer cell lines. Compound 5 showed moderate cytotoxic activity against human colorectal adeno-carcinoma (HT-29) and lung adenocarcinoma epithelial (A549) cell lines, with IC50 values in the range 15-17 uM, and compounds 3, 6 and 9 exhibited weak binding affinity for the anti-apoptotic protein Mcl-1. PMID- 24492596 TI - Optimal disparity estimation in natural stereo images. AB - A great challenge of systems neuroscience is to understand the computations that underlie perceptual constancies, the ability to represent behaviorally relevant stimulus properties as constant even when irrelevant stimulus properties vary. As signals proceed through the visual system, neural states become more selective for properties of the environment, and more invariant to irrelevant features of the retinal images. Here, we describe a method for determining the computations that perform these transformations optimally, and apply it to the specific computational task of estimating a powerful depth cue: binocular disparity. We simultaneously determine the optimal receptive field population for encoding natural stereo images of locally planar surfaces and the optimal nonlinear units for decoding the population responses into estimates of disparity. The optimal processing predicts well-established properties of neurons in cortex. Estimation performance parallels important aspects of human performance. Thus, by analyzing the photoreceptor responses to natural images, we provide a normative account of the neurophysiology and psychophysics of absolute disparity processing. Critically, the optimal processing rules are not arbitrarily chosen to match the properties of neurophysiological processing, nor are they fit to match behavioral performance. Rather, they are dictated by the task-relevant statistical properties of complex natural stimuli. Our approach reveals how selective invariant tuning-especially for properties not trivially available in the retinal images-could be implemented in neural systems to maximize performance in particular tasks. PMID- 24492598 TI - Biodegradation of cyanide by acetonitrile-induced cells of Rhodococcus sp. UKMP 5M. AB - A Rhodococcus sp. UKMP-5M isolate was shown to detoxify cyanide successfully, suggesting the presence of an intrinsic property in the bacterium which required no prior cyanide exposure for induction of this property. However, in order to promote growth, Rhodococcus sp. UKMP-5M was fully acclimatized to cyanide after 7 successive subcultures in 0.1 mM KCN for 30 days. To further shorten the lag phase and simultaneously increase the tolerance towards higher cyanide concentrations, the bacterium was induced with various nitrile compounds sharing a similar degradatory pathway to cyanide. Acetonitrile emerged as the most favored inducer and the induced cells were able to degrade 0.1 mM KCN almost completely within 18 h. With the addition of subsequent aliquots of 0.1 mM KCN a shorter period for complete removal of cyanide was required, which proved to be advantageous economically. Both resting cells and crude enzyme of Rhodococcus sp. UKMP-5M were able to biodegrade cyanide to ammonia and formate without the formation of formamide, implying the identification of a simple hydrolytic cyanide degradation pathway involving the enzyme cyanidase. Further verification with SDS-PAGE revealed that the molecular weight of the active enzyme was estimated to be 38 kDa, which is consistent with previously reported cyanidases. Since the recent advancement in the application of biological methods in treating cyanide-bearing wastewater has been promising, the discovery of this new bacterium will add value by diversifying the existing microbial populations capable of cyanide detoxification. PMID- 24492599 TI - Cloning and expression of a family 10 xylanase gene (Aoxyn10) from Aspergillus oryzae in Pichia pastoris. AB - A full-length cDNA sequence of Aoxyn10, a gene encoding a glycoside hydrolase (GH) family 10 xylanase from Aspergillus oryzae, was amplified from the total RNA by 3' and 5' rapid amplification of cDNA ends. The cDNA sequence is 1,689 bp, containing 5', 3' untranslated regions and a 1,422 bp open reading frame (ORF) that encodes a 21-aa signal peptide and a 452-aa mature peptide (designated AoXyn10). Multi-alignment revealed that AoXyn10 contains two regions: a catalytic domain (CD) and a family 1 carbohydrate-binding module (CBM1). The three dimensional (3-D) structure of the CD was predicted by multiple template-based homology modeling. A 2,308-bp complete DNA sequence of Aoxyn10 was obtained from the genomic DNA by both pUCm-T vector-mediated and conventional PCRs, harboring 5', 3' flanking regulatory regions, five exons and four introns. Moreover, Aoxyn10 was extracellularly expressed in Pichia pastoris. One transformant labeled as P. pastoris GS/Xyn4-11 was selected, expressing the highest recombinant AoXyn10 (named reAoXyn10) activity of 45.0 U/ml. SDS-PAGE analysis revealed that reAoXyn10, a glycoprotein with an apparent molecular weight (M.W.) of about 56.0 kDa, was secreted into the cultured medium. The purified reAoXyn10 displayed the maximum activity at pH 5.5 and 60 degrees C. It was stable at a pH range of 4.0-7.0, and at 50 degrees C or below. Its activity was not affected by an array of metal ions or EDTA, but was inhibited by Mn(2+) and Ba(2+). The Km and Vmax of reAoXyn10 were 1.7 mg/ml and 817 MUmol/min/mg, respectively. PMID- 24492597 TI - Working memory retrieval as a decision process. AB - Working memory (WM) is a core cognitive process fundamental to human behavior, yet the mechanisms underlying it remain highly controversial. Here we provide a new framework for understanding retrieval of information from WM, conceptualizing it as a decision based on the quality of internal evidence. Recent findings have demonstrated that precision of WM decreases with memory load. If WM retrieval uses a decision process that depends on memory quality, systematic changes in response time distribution should occur as a function of WM precision. We asked participants to view sample arrays and, after a delay, report the direction of change in location or orientation of a probe. As WM precision deteriorated with increasing memory load, retrieval time increased systematically. Crucially, the shape of reaction time distributions was consistent with a linear accumulator decision process. Varying either task relevance of items or maintenance duration influenced memory precision, with corresponding shifts in retrieval time. These results provide strong support for a decision-making account of WM retrieval based on noisy storage of items. Furthermore, they show that encoding, maintenance, and retrieval in WM need not be considered as separate processes, but may instead be conceptually unified as operations on the same noise-limited, neural representation. PMID- 24492600 TI - Molecular characterization of Flavobacterium columnare isolated from a natural outbreak of columnaris disease in farmed fish, Catla catla from India. AB - Flavobacterium columnare is currently one of the important bacterial pathogens causing columnaris disease in several farmed fish species across diverse geographies. A presumptive columnaris disease outbreak in farmed catla, Catla catla (Hamilton), was investigated with the aim of isolating and identifying the causative pathogen. F. columnare (strain RDC-1) was isolated from gills of infected fish and identified by conventional biochemical methods, and through species specific polymerase chain reaction and sequencing of the 16S rDNA for molecular identification. Strain RDC-1 belonged to genomovar II with 99% similarity to available 16S rDNA sequences of F. columnare, and also shared 70% DNA-DNA relatedness with known strains of F. columnare. Bath immersion studies of RDC-1 showed development of columnaris disease in catla fingerlings within 7 days, with a cumulative mortality of 83.3%. This is the first molecular confirmation of Flavobacterium columnare as a fish pathogen of farmed Catla catla in India. PMID- 24492601 TI - Antimicrobial and anti-adhesive properties of biosurfactant produced by lactobacilli isolates, biofilm formation and aggregation ability. AB - This study aimed to investigate the antimicrobial and anti-adhesive properties of biosurfactant extracted from ten lactobacilli species isolated from Egyptian dairy products. The produced biosurfactants showed distinct antimicrobial and anti-adhesive activities against several pathogenic microorganisms. Furthermore, lactobacilli isolates were studied for biofilm formation and lactic acid production in different growth media. All lactobacilli isolates produced biofilm on polystyrene surface in all media tested to different degrees. L. acidophilus showed the highest biofilm formation in Rogosa medium. However, the highest lactic acid production was recorded by L. brevis (39.63 g/L), followed by L. reuteri (33.32 g/L) in MRS medium. Evaluation based on in vitro studies including auto-aggregation and co-aggregation with three pathogenic bacterial strains was further analyzed. All lactobacilli isolates tested were able to auto-aggregate (ranging from 51.12% to 78.17% assessed at 5 h of incubation). The lactobacilli isolates co-aggregate with the tested bacterial strains to different degrees; among them L. delbrueckii showed the highest scores of co-aggregation with Candida albicans ATC70014, reaching 59.37%. The aggregation ability exhibited by the isolated lactobacilli, together with the antimicrobial and anti-adhesive properties observed for their biosurfactants, opens future prospects for their use against microorganisms responsible for diseases and infections and as effective probiotic strains. PMID- 24492602 TI - Immunoprotection of glyceraldehyde-3-phosphate dehydrogenase (GAPDH) from Lactococcus garvieae against Lactococcosis in tilapia. AB - In this study, the gene encoding 40 kDa GAPDH of L. garvieae was determined and overexpressed by using the Escherichia coli expression system. Analysis results indicated that the sequences of GAPDH of L. garvieae nucleotide and its amino acid are highly homologous (80.4-100%) to several products of GAPDH from L. garvieae and other Streptococcus-related bacteria. According to Western blotting results, rabbit antiserum and tilapia infection serum reacted strongly to the recombinant GAPDH protein. In another experiment, tilapia were immunized intraperitoneally with formalin-killed L. garvieae whole cells, recombinant GAPDH (50 MUg fish(-1)) from L. garvieae or both. ISA 763A was used as an adjuvant for vaccine and saline was used as a negative control. The fish challenged at 4 weeks after immunization with GAPDH+WC+ISA had the highest survival rate at 100%, followed by fish immunized with WC+ISA or GAPDH+ISA, which had RPS values of 87.5% and 50%, respectively. Additionally, specific antibody responses against L. garvieae whole cells and GAPDH were based on enzyme-linked immunosorbent assay. Following 4 weeks of immunization, the specific antibody level of all vaccine groups significantly increased, except for antibody responses against L. garvieae GAPDH of those immunized with formalin-killed L. garvieae whole cells. Our results further demonstrated that GAPDH from L. garvieae protected tilapia from experimental L. garvieae infection, implying the potential use of L. garvieae GAPDH as a vaccine against L. garvieae. PMID- 24492603 TI - Microbial community structure and diversity in the soil spatial profile of 5-year old Robinia pseudoacacia 'Idaho,' determined by 454 sequencing of the 16S RNA gene. AB - Relatively little information is available regarding the variability of microbial communities inhabiting deeper soil layers. We investigated the distribution of soil microbial communities down to 1.2 m in 5-year-old Robinia pseudoacacia 'Idaho' soil by 454 sequencing of the 16S RNA gene. The average number of sequences per sample was 12,802. The Shannon and Chao 1 indices revealed various relative microbial abundances and even distribution of microbial diversity for all evaluated sample depths. The predicted diversity in the topsoil exceeded that of the corresponding subsoil. The changes in the relative abundance of the major soil bacterial phyla showed decreasing, increasing, or no consistent trends with respect to sampling depth. Despite their novelty, members of the new candidate phyla OD1 and TM7 were widespread. Environmental variables affecting the bacterial community within the environment appeared to differ from those reported previously, especially the lack of detectable effect from pH. Overall, we found that the overall relative abundance fluctuated with the physical and chemical properties of the soil, root system, and sampling depth. Such information may facilitate forest soil management. PMID- 24492604 TI - Sediminicoccus rosea gen. nov. sp. nov., isolated from the sediment of a eutrophic lake. AB - A polyphasic study was carried out to clarify the taxonomic position of a novel strain R-30(T) isolated from the surficial layer of sediment from Taihu Lake of China. The strain formed pink colored colonies comprising coccodial cells on R2A agar. Phylogenetic analysis based on the 16S rRNA gene sequences showed that strain R-30(T) clustered with the strains of genus Roseococcus and strain Rubritepida flocculans, with Roseococcus suduntuyensis SHET(T) as the closest relative, sharing 95.6% similarity. The major fatty acids (>5%) were 18:1omega7c (66.7%), 16: 1omega7c/16:1omega6c (10.2%) and 16:0 (8.0%). The major polar lipids were diphosphatidyl glycerol (DPG), phosphatidyl methylethanolamine (PME), phosphatidyl ethanolamine (PE) and phosphatidyl choline (PC). The genomic DNA G+C content was 73.9 mol%. On the basis of the phylogenetic analysis and physiological and biochemical characteristics, we conclude that strain R-30(T) represents a novel genus and species of the family Acetobacteraceae, for which we propose the name Sediminicoccus rosea gen nov. sp. nov. with R-30(T) (= CGMCC 1.12302(T) = NBRC 109675(T)) as the type species and type strain. PMID- 24492606 TI - 3-Deazaneplanocin A (DZNep), an inhibitor of S-adenosylmethionine-dependent methyltransferase, promotes erythroid differentiation. AB - EZH2, a core component of polycomb repressive complex 2 (PRC2), plays a role in transcriptional repression through histone H3 Lys-27 trimethylation and is involved in various biological processes, including hematopoiesis. It is well known that 3-deazaneplanocin A (DZNep), an inhibitor of S-adenosylmethionine dependent methyltransferase that targets the degradation of EZH2, preferentially induces apoptosis in various hematological malignancies, suggesting that EZH2 may be a new target for epigenetic treatment. Because PRC2 participates in epigenetic silencing of a subset of GATA-1 target genes during erythroid differentiation, inhibition of EZH2 may influence erythropoiesis. To explore this possibility, we evaluated the impact of DZNep on erythropoiesis. DZNep treatment significantly induced erythroid differentiation of K562 cells, as assessed by benzidine staining and quantitative RT-PCR analysis for representative erythroid-related genes, including globins. When we evaluated the effects of DZNep in human primary erythroblasts derived from cord blood CD34-positive cells, the treatment significantly induced erythroid-related genes, as observed in K562 cells, suggesting that DZNep induces erythroid differentiation. Unexpectedly, siRNA mediated EZH2 knockdown had no significant effect on the expression of erythroid related genes. Transcriptional profiling of DZNep-treated K562 cells revealed marked up-regulation of SLC4A1 and EPB42, previously reported as representative targets of the transcriptional corepressor ETO2. In addition, DZNep treatment reduced the protein level of ETO2. These data suggest that erythroid differentiation by DZNep may not be directly related to EZH2 inhibition but may be partly associated with reduced protein level of hematopoietic corepressor ETO2. These data provide a better understanding of the mechanism of action of DZNep, which may be exploited for therapeutic applications for hematological diseases, including anemia. PMID- 24492607 TI - Evolutionarily conserved heterogeneous nuclear ribonucleoprotein (hnRNP) A/B proteins functionally interact with human and Drosophila TAR DNA-binding protein 43 (TDP-43). AB - Human TDP-43 represents the main component of neuronal inclusions found in patients with neurodegenerative diseases, especially frontotemporal lobar degeneration and amyotrophic lateral sclerosis. In vitro and in vivo studies have shown that the TAR DNA-binding protein 43 (TDP-43) Drosophila ortholog (TBPH) can biochemically and functionally overlap the properties of the human factor. The recent direct implication of the human heterogeneous nuclear ribonucleoproteins (hnRNPs) A2B1 and A1, known TDP-43 partners, in the pathogenesis of multisystem proteinopathy and amyotrophic lateral sclerosis supports the hypothesis that the physical and functional interplay between TDP-43 and hnRNP A/B orthologs might play a crucial role in the pathogenesis of neurodegenerative diseases. To test this hypothesis and further validate the fly system as a useful model to study this type of diseases, we have now characterized human TDP-43 and Drosophila TBPH similarity in terms of protein-protein interaction pathways. In this work we show that TDP-43 and TBPH share the ability to associate in vitro with Hrp38/Hrb98DE/CG9983, the fruit fly ortholog of the human hnRNP A1/A2 factors. Interestingly, the protein regions of TDP-43 and Hrp38 responsible for reciprocal interactions are conserved through evolution. Functionally, experiments in HeLa cells demonstrate that TDP-43 is necessary for the inhibitory activity of Hrp38 on splicing. Finally, Drosophila in vivo studies show that Hrp38 deficiency produces locomotive defects and life span shortening in TDP-43 with and without animals. These results suggest that hnRNP protein levels can play a modulatory role on TDP-43 functions. PMID- 24492608 TI - Antifibrotic effects of noscapine through activation of prostaglandin E2 receptors and protein kinase A. AB - Myofibroblast differentiation is a key process in the pathogenesis of fibrotic disease. We have shown previously that differentiation of myofibroblasts is regulated by microtubule polymerization state. In this work, we examined the potential antifibrotic effects of the antitussive drug, noscapine, recently found to bind microtubules and affect microtubule dynamics. Noscapine inhibited TGF beta-induced differentiation of cultured human lung fibroblasts (HLFs). Therapeutic noscapine treatment resulted in a significant attenuation of pulmonary fibrosis in the bleomycin model of the disease. Noscapine did not affect gross microtubule content in HLFs, but inhibited TGF-beta-induced stress fiber formation and activation of serum response factor without affecting Smad signaling. Furthermore, noscapine stimulated a rapid and profound activation of protein kinase A (PKA), which mediated the antifibrotic effect of noscapine in HLFs, as assessed with the PKA inhibitor, PKI. In contrast, noscapine did not activate PKA in human bronchial or alveolar epithelial cells. Finally, activation of PKA and the antifibrotic effect of noscapine in HLFs were blocked by the EP2 prostaglandin E2 receptor antagonist, PF-04418948, but not by the antagonists of EP4, prostaglandin D2, or prostacyclin receptors. Together, we demonstrate for the first time the antifibrotic effect of noscapine in vitro and in vivo, and we describe a novel mechanism of noscapine action through EP2 prostaglandin E2 receptor-mediated activation of PKA in pulmonary fibroblasts. PMID- 24492609 TI - Lipopolysaccharide engineering in Neisseria meningitidis: structural analysis of different pentaacyl lipid A mutants and comparison of their modified agonist properties. AB - Engineering the lipopolysaccharide (LPS) biosynthetic pathway offers the potential to obtain modified derivatives with optimized adjuvant properties. Neisseria meningitidis strain H44/76 was modified by expression of the pagL gene encoding lipid A 3-O-deacylase from Bordetella bronchiseptica and by inactivation of the lgtB gene encoding the terminal oligosaccharide galactosyltransferase. Mass spectrometry analysis of purified mutant LPS was used for detailed compositional analysis of all present molecular species. This determined that the modified LPS was mainly pentaacylated, demonstrating high efficiency of conversion from the hexaacyl to the 3-O-deacylated form by heterologous lipid A 3 O-deacylase (PagL) expression. MS analyses also provided evidence for expression of only one major oligosaccharide glycoform, which lacked the terminal galactose residue as expected from inactivation of the lgtB gene. The immunomodulatory properties of PagL-deacylated LPS were compared with another pentaacyl form obtained from an lpxL1(-) mutant, which lacks the 2' secondary acyl chain. Although both LPS mutants displayed impaired capacity to induce production of the pro-inflammatory cytokine IL-6 in the monocytic cell line Mono Mac 6, induction of the Toll-interleukin-1 receptor domain-containing adaptor-inducing interferon beta-dependent chemokine interferon-gamma-induced protein 10 was largely retained only for the lgtB(-)/pagL(+) mutant. Removal of remaining hexaacyl species exclusively present in lgtB(-)/pagL(+) LPS demonstrated that these minor species potentiate but do not determine the activity of this LPS. These results are the first to indicate a qualitatively different response of human innate cells to pentaacyl lpxL1(-) and pagL(+) LPS and show the importance of detailed structure function analysis when working with modified lipid A structures. The pagL(+) LPS has significant potential as immune modulator in humans. PMID- 24492611 TI - Persephone/Spatzle pathogen sensors mediate the activation of Toll receptor signaling in response to endogenous danger signals in apoptosis-deficient Drosophila. AB - Apoptosis is an evolutionarily conserved mechanism that removes damaged or unwanted cells, effectively maintaining cellular homeostasis. It has long been suggested that a deficiency in this type of naturally occurring cell death could potentially lead to necrosis, resulting in the release of endogenous immunogenic molecules such as damage-associated molecular patterns (DAMPs) and a noninfectious inflammatory response. However, the details about how danger signals from apoptosis-deficient cells are detected and translated to an immune response are largely unknown. In this study, we found that Drosophila mutants deficient for Dronc, the key initiator caspase required for apoptosis, produced the active form of the endogenous Toll ligand Spatzle (Spz). We speculated that, as a system for sensing potential DAMPs in the hemolymph, the dronc mutants constitutively activate a proteolytic cascade that leads to Spz proteolytic processing. We demonstrated that Toll signaling activation required the action of Persephone, a CLIP domain serine protease that usually reacts to microbial proteolytic activities. Our findings show that the Persephone proteolytic cascade plays a crucial role in mediating DAMP-induced systemic responses in apoptosis deficient Drosophila mutants. PMID- 24492610 TI - TRPM2 channels protect against cardiac ischemia-reperfusion injury: role of mitochondria. AB - Cardiac TRPM2 channels were activated by intracellular adenosine diphosphate ribose and blocked by flufenamic acid. In adult cardiac myocytes the ratio of GCa to GNa of TRPM2 channels was 0.56 +/- 0.02. To explore the cellular mechanisms by which TRPM2 channels protect against cardiac ischemia/reperfusion (I/R) injury, we analyzed proteomes from WT and TRPM2 KO hearts subjected to I/R. The canonical pathways that exhibited the largest difference between WT-I/R and KO-I/R hearts were mitochondrial dysfunction and the tricarboxylic acid cycle. Complexes I, III, and IV were down-regulated, whereas complexes II and V were up-regulated in KO-I/R compared with WT-I/R hearts. Western blots confirmed reduced expression of the Complex I subunit and other mitochondria-associated proteins in KO-I/R hearts. Bioenergetic analyses revealed that KO myocytes had a lower mitochondrial membrane potential, mitochondrial Ca(2+) uptake, ATP levels, and O2 consumption but higher mitochondrial superoxide levels. Additionally, mitochondrial Ca(2+) uniporter (MCU) currents were lower in KO myocytes, indicating reduced mitochondrial Ca(2+) uptake was likely due to both lower psim and MCU activity. Similar to isolated myocytes, O2 consumption and ATP levels were also reduced in KO hearts. Under a simulated I/R model, aberrant mitochondrial bioenergetics was exacerbated in KO myocytes. Reactive oxygen species levels were also significantly higher in KO-I/R compared with WT-I/R heart slices, consistent with mitochondrial dysfunction in KO-I/R hearts. We conclude that TRPM2 channels protect the heart from I/R injury by ameliorating mitochondrial dysfunction and reducing reactive oxygen species levels. PMID- 24492612 TI - Methyllysine reader plant homeodomain (PHD) finger protein 20-like 1 (PHF20L1) antagonizes DNA (cytosine-5) methyltransferase 1 (DNMT1) proteasomal degradation. AB - Inheritance of DNA cytosine methylation pattern during successive cell division is mediated by maintenance DNA (cytosine-5) methyltransferase 1 (DNMT1). Lysine 142 of DNMT1 is methylated by the SET domain containing lysine methyltransferase 7 (SET7), leading to its degradation by proteasome. Here we show that PHD finger protein 20-like 1 (PHF20L1) regulates DNMT1 turnover in mammalian cells. Malignant brain tumor (MBT) domain of PHF20L1 binds to monomethylated lysine 142 on DNMT1 (DNMT1K142me1) and colocalizes at the perinucleolar space in a SET7 dependent manner. PHF20L1 knockdown by siRNA resulted in decreased amounts of DNMT1 on chromatin. Ubiquitination of DNMT1K142me1 was abolished by overexpression of PHF20L1, suggesting that its binding may block proteasomal degradation of DNMT1K142me1. Conversely, siRNA-mediated knockdown of PHF20L1 or incubation of a small molecule MBT domain binding inhibitor in cultured cells accelerated the proteasomal degradation of DNMT1. These results demonstrate that the MBT domain of PHF20L1 reads and controls enzyme levels of methylated DNMT1 in cells, thus representing a novel antagonist of DNMT1 degradation. PMID- 24492613 TI - CvfA protein and polynucleotide phosphorylase act in an opposing manner to regulate Staphylococcus aureus virulence. AB - We previously identified CvfA (SA1129) as a Staphylococcus aureus virulence factor using a silkworm infection model. S. aureus cvfA-deleted mutants exhibit decreased expression of the agr locus encoding a positive regulator of hemolysin genes and decreased hemolysin production. CvfA protein hydrolyzes a 2',3'-cyclic phosphodiester bond at the RNA 3' terminus, producing RNA with a 3'-phosphate (3' phosphorylated RNA, RNA with a 3'-phosphate). Here, we report that the cvfA deleted mutant phenotype (decreased agr expression and hemolysin production) was suppressed by disrupting pnpA-encoding polynucleotide phosphorylase (PNPase) with 3'- to 5'-exonuclease activity. The suppression was blocked by introducing a pnpA encoding PNPase with exonuclease activity but not by a pnpA-encoding mutant PNPase without exonuclease activity. Therefore, loss of PNPase exonuclease activity suppressed the cvfA-deleted mutant phenotype. Purified PNPase efficiently degraded RNA with 2',3'-cyclic phosphate at the 3' terminus (2',3' cyclic RNA), but it inefficiently degraded 3'-phosphorylated RNA. These findings indicate that 3'-phosphorylated RNA production from 2',3'-cyclic RNA by CvfA prevents RNA degradation by PNPase and contributes to the expression of agr and hemolysin genes. We speculate that in the cvfA-deleted mutant, 2',3'-cyclic RNA is not converted to the 3'-phosphorylated form and is efficiently degraded by PNPase, resulting in the loss of RNA essential for expressing agr and hemolysin genes, whereas in the cvfA/pnpA double-disrupted mutant, 2',3'-cyclic RNA is not degraded by PNPase, leading to hemolysin production. These findings suggest that CvfA and PNPase competitively regulate RNA degradation essential for S. aureus virulence. PMID- 24492614 TI - Missense mutations in pyruvate kinase M2 promote cancer metabolism, oxidative endurance, anchorage independence, and tumor growth in a dominant negative manner. AB - The present study was designed to examine the functional relevance of two heterozygous mutations (H391Y and K422R), observed earlier by us in the Bloom syndrome condition. Cells stably expressing exogenous wild-type or mutant PKM2 (K422R or H391Y) or co-expressing both wild type and mutant (PKM2-K422R or PKM2 H391Y) were assessed for cancer metabolism and tumorigenic potential. Interestingly, cells co-expressing PKM2 and mutant (K422R or H391Y) showed significantly aggressive cancer metabolism as compared with cells expressing either wild-type or mutant PKM2 independently. A similar trend was observed for oxidative endurance, tumorigenic potential, cellular proliferation, and tumor growth. These observations signify the dominant negative nature of mutations. Remarkably, PKM2-H391Y co-expressed cells showed a maximal effect on all the studied parameters. Such a dominant negative impaired function of PKM2 in tumor development is not known; this study demonstrates for the first time the possible predisposition of Bloom syndrome patients with impaired PKM2 activity to cancer and the importance of studying genetic variations in PKM2 in the future to understand their relevance in cancer in general. PMID- 24492616 TI - The ClpXP protease is responsible for the degradation of the Epsilon antidote to the Zeta toxin of the streptococcal pSM19035 plasmid. AB - Most bacterial genomes contain different types of toxin-antitoxin (TA) systems. The omega-epsilon-zeta proteinaceous type II TA cassette from the streptococcal pSM19035 plasmid is a member of the epsilon/zeta family, which is commonly found in multiresistance plasmids and chromosomes of various human pathogens. Regulation of type II TA systems relies on the proteolysis of antitoxin proteins. Under normal conditions, the Epsilon antidote neutralizes the Zeta toxin through the formation of a tight complex. In this study, we show, using both in vivo and in vitro analyses, that the ClpXP protease is responsible for Epsilon antitoxin degradation. Using in vivo studies, we examined the stability of the plasmids with active or inactive omega-epsilon-zeta TA cassettes in B. subtilis mutants that were defective for different proteases. Using in vitro assays, the degradation of purified His6-Epsilon by the His6-LonBs, ClpPBs, and ClpXBs proteases from B. subtilis was analyzed. Additionally, we showed that purified Zeta toxin protects the Epsilon protein from rapid ClpXP-catalyzed degradation. PMID- 24492615 TI - Metabolic reprogramming of macrophages: glucose transporter 1 (GLUT1)-mediated glucose metabolism drives a proinflammatory phenotype. AB - Glucose is a critical component in the proinflammatory response of macrophages (MPhis). However, the contribution of glucose transporters (GLUTs) and the mechanisms regulating subsequent glucose metabolism in the inflammatory response are not well understood. Because MPhis contribute to obesity-induced inflammation, it is important to understand how substrate metabolism may alter inflammatory function. We report that GLUT1 (SLC2A1) is the primary rate-limiting glucose transporter on proinflammatory-polarized MPhis. Furthermore, in high fat diet-fed rodents, MPhis in crown-like structures and inflammatory loci in adipose and liver, respectively, stain positively for GLUT1. We hypothesized that metabolic reprogramming via increased glucose availability could modulate the MPhi inflammatory response. To increase glucose uptake, we stably overexpressed the GLUT1 transporter in RAW264.7 MPhis (GLUT1-OE MPhis). Cellular bioenergetics analysis, metabolomics, and radiotracer studies demonstrated that GLUT1 overexpression resulted in elevated glucose uptake and metabolism, increased pentose phosphate pathway intermediates, with a complimentary reduction in cellular oxygen consumption rates. Gene expression and proteome profiling analysis revealed that GLUT1-OE MPhis demonstrated a hyperinflammatory state characterized by elevated secretion of inflammatory mediators and that this effect could be blunted by pharmacologic inhibition of glycolysis. Finally, reactive oxygen species production and evidence of oxidative stress were significantly enhanced in GLUT1-OE MPhis; antioxidant treatment blunted the expression of inflammatory mediators such as PAI-1 (plasminogen activator inhibitor 1), suggesting that glucose-mediated oxidative stress was driving the proinflammatory response. Our results indicate that increased utilization of glucose induced a ROS-driven proinflammatory phenotype in MPhis, which may play an integral role in the promotion of obesity-associated insulin resistance. PMID- 24492618 TI - Development and Validation of the Juvenile Sexual Offense Recidivism Risk Assessment Tool-II. AB - This article describes the development and initial validation of the Juvenile Sexual Offense Recidivism Risk Assessment Tool-II (JSORRAT-II). Potential predictor variables were extracted from case file information for an exhaustive sample of 636 juveniles in Utah who sexually offended between 1990 and 1992. Simultaneous and hierarchical logistic regression analyses were used to identify the group of variables that was most predictive of subsequent juvenile sexual recidivism. A simple categorical scoring system was applied to these variables without meaningful loss of accuracy in the development sample for any sexual (area under the curve [AUC] = .89) and sexually violent (AUC = .89) juvenile recidivism. The JSORRAT-II was cross-validated on an exhaustive sample of 566 juveniles who had sexually offended in Utah in 1996 and 1997. Reliability of scoring the tool across five coders was quite high (intraclass correlation coefficient [ICC] = .96). Relative to the development sample, however, there was considerable shrinkage in the indices of predictive accuracy for any sexual (AUC = .65) and sexually violent (AUC = .65) juvenile recidivism. The reduced level of accuracy was not explained by severity of the index sexual offense, time at risk, or missing data. Capitalization on chance and other explanations for the possible reduction in predictive accuracy are explored, and potential uses and limitations of the tool are discussed. PMID- 24492617 TI - Noncanonical activation of Notch1 protein by membrane type 1 matrix metalloproteinase (MT1-MMP) controls melanoma cell proliferation. AB - Notch1 is an evolutionarily conserved signaling molecule required for stem cell maintenance that is inappropriately reactivated in several cancers. We have previously shown that melanomas reactivate Notch1 and require its function for growth and survival. However, no Notch1-activating mutations have been observed in melanoma, suggesting the involvement of other activating mechanisms. Notch1 activation requires two cleavage steps: first by a protease and then by gamma secretase, which releases the active intracellular domain (Notch1(NIC)). Interestingly, although ADAM10 and -17 are generally accepted as the proteases responsible of Notch1 cleavage, here we show that MT1-MMP, a membrane-tethered matrix metalloproteinase involved in the pathogenesis of a number of tumors, is a novel protease required for the cleavage of Notch1 in melanoma cells. We find that active Notch1 and MT1-MMP expression correlate significantly in over 70% of melanoma tumors and 80% of melanoma cell lines, whereas such correlation does not exist between Notch1(NIC) and ADAM10 or -17. Modulation of MT1-MMP expression in melanoma cells affects Notch1 cleavage, whereas MT1-MMP expression in ADAM10/17 double knock-out fibroblasts restores the processing of Notch1, indicating that MT1-MMP is sufficient to promote Notch1 activation independently of the canonical proteases. Importantly, we find that MT1-MMP interacts with Notch1 at the cell membrane, supporting a potential direct cleavage mechanism of MT1-MMP on Notch1, and that MT1-MMP-dependent activation of Notch1 sustains melanoma cell growth. Together, the data highlight a novel mechanism of activation of Notch1 in melanoma cells and identify Notch1 as a new MT1-MMP substrate that plays important biological roles in melanoma. PMID- 24492619 TI - Prioritizing Child Pornography Notifications: Predicting Direct Victimization. AB - The growing number of notifications for child pornography (CP) possession constitutes a capacity problem for police forces entrusted with the investigation of these offenses. Notifications of CP offenses in which the investigation reveals concurrent direct victimization, in the form of contact offenses, grooming, online offending, or the production of CP material, form a potential target group for prioritization. The first of the twofold aims of this study was to validate the occurring distinction between mixed suspects (i.e., CP possession suspects who were also ever associated with direct victimization) and CP-only suspects (i.e., CP possession suspects who were never associated with direct victimization) to predict an outcome of the investigation including direct victimization. The second aim was to explore variables related to direct victimization among CP-only suspects. A total of 150 files of police investigations into notifications for CP offenses were studied. Findings confirmed significantly greater prevalence of direct victimization as an outcome of the investigation among mixed suspects than CP-only suspects (90% vs. 10%). Among CP-only suspects, direct victimization was predicted by (a) prior police contacts, charges, or convictions concerning noncontact sexual offending, (b) the confiscation of more than two computers during the house search, and (c) a more serious nature of the CP material that formed the basis for the notification in terms of younger victims and more extreme content. These variables may point to a small subgroup of heavily invested CP offenders who are at a higher risk to cross the line to direct victimization. Cross-validation of these preliminary findings is indicated. PMID- 24492620 TI - Dynamic urea bond for the design of reversible and self-healing polymers. AB - Polymers bearing dynamic covalent bonds may exhibit dynamic properties, such as self-healing, shape memory and environmental adaptation. However, most dynamic covalent chemistries developed so far require either catalyst or change of environmental conditions to facilitate bond reversion and dynamic property change in bulk materials. Here we report the rational design of hindered urea bonds (urea with bulky substituent attached to its nitrogen) and the use of them to make polyureas and poly(urethane-urea)s capable of catalyst-free dynamic property change and autonomous repairing at low temperature. Given the simplicity of the hindered urea bond chemistry (reaction of a bulky amine with an isocyanate), incorporation of the catalyst-free dynamic covalent urea bonds to conventional polyurea or urea-containing polymers that typically have stable bulk properties may further broaden the scope of applications of these widely used materials. PMID- 24492621 TI - Long-term single-dose efficacy of a vesicular stomatitis virus-based Andes virus vaccine in Syrian hamsters. AB - Andes virus (ANDV) is highly pathogenic in humans and is the primary etiologic agent of hantavirus cardiopulmonary syndrome (HCPS) in South America. Case fatality rates are as high as 50% and there are no approved vaccines or specific therapies for infection. Our laboratory has recently developed a replication competent recombinant vesicular stomatitis virus (VSV)-based vaccine that expressed the glycoproteins of Andes virus in place of the native VSV glycoprotein (G). This vaccine is highly efficacious in the Syrian hamster model of HCPS when given 28 days before challenge with ANDV, or when given around the time of challenge (peri-exposure), and even protects when administered post exposure. Herein, we sought to test the durability of the immune response to a single dose of this vaccine in Syrian hamsters. This vaccine was efficacious in hamsters challenged intranasally with ANDV 6 months after vaccination (p = 0.025), but animals were not significantly protected following 1 year of vaccination (p = 0.090). The decrease in protection correlated with a reduction of measurable neutralizing antibody responses, and suggests that a more robust vaccination schedule might be required to provide long-term immunity. PMID- 24492622 TI - Using the Bayley-III to assess neurodevelopmental delay: which cut-off should be used? AB - BACKGROUND: As the latest edition of the Bayley Scales (Bayley-III) produces higher scores than its predecessor (BSID-II), there is uncertainty about how to classify moderate-severe neurodevelopmental delay. We have investigated agreement between classifications of delay made using the BSID-II and Bayley-III. METHODS: BSID-II Mental Development Index (MDI) and Bayley-III cognitive and language scales were administered in 185 extremely preterm (<27 wk) children. A combined Bayley-III score (CB-III) was computed. Agreement between delay classified using MDI scores <70 and various Bayley-III cut-offs was assessed. RESULTS: Bayley-III cognitive and language scores were close to the normative mean and were higher than BSID-II MDI scores. Nineteen (10.2%) children had MDI <70. Bayley-III scores <70 significantly underestimated the proportion with MDI <70. Bayley-III cognitive and language scores <85 had 99% agreement with MDI <70 and underestimated delay by 1.1%. CB-III scores <80 had 98% agreement and produced the same proportion with delay. CONCLUSION: Bayley-III cognitive and language scores <85 or CB-III scores <80 provide the best definition of moderate-severe neurodevelopmental delay for equivalence with MDI <70. CB-III scores have the advantage of producing a single continuous outcome measure but require further validation. The relative accuracy of both tests for predicting long-term outcomes requires investigation. PMID- 24492624 TI - Carbon multi-shell cages. AB - Complex chemical compounds found as minerals or synthesized in labs evidenced a multi-shell structure. Also, fullerenes aggregate, randomly or following a well defined geometry, in multi-shells. The way of space filling differs as a function of the dimensions and shape of the composing small cages. In this paper an attempt to build and evaluate the stability of several fullerene aggregates is made. The results show multi-shell covalently bonded structures with stability comparable to that of C60, the reference fullerene in nanoscience. The calculations were made at the DFTB and DFT levels of theory. PMID- 24492623 TI - Reconstitution of coronary vasculature by an active fraction of Geum japonicum in ischemic hearts. AB - Chronic coronary heart disease (cCHD) is characterized by atherosclerosis, which progressively narrows the coronary artery lumen and impairs myocardial blood flow. Restoration of occluded coronary vessels with newly formed collaterals remains an ideal therapeutic approach due to the need for redirecting blood flow into the ischemic heart. In this study, we investigated the effect of an active fraction isolated from Geum joponicum (AFGJ) on angiogenesis in cCHD hearts. Our results demonstrated that AFGJ not only enhanced capillary tube formation of endothelial cells, but also promoted the growth of new coronary collaterals (at the diameter 0.021-0.21 mm) in the ischemic region of hearts in rat cCHD model. Our study also indicated that the growth of new collaterals in ischemic hearts resulted in improved functional recovery of the cCHD hearts as demonstrated by ECG and echocardiography analyses. These data suggest that AFGJ may provide a novel therapeutic method for effective treatment of cCHD. PMID- 24492627 TI - Improving the one-year mortality of stroke patients: an 18-year observation in a teaching hospital. AB - Long-term follow-up and comparison of serial changes in the one-year mortality after stroke are important in assessing the quality of stroke management. This study determined the one-year survival rate and prognostic factors of hospitalized hemorrhagic and ischemic stroke patients from 1991 to 2008 in a teaching hospital in Taiwan. We also evaluated the improvements in the one-year mortality after stroke during an 18-year study period. Patients admitted for cerebral hemorrhage (n = 3,678) and cerebral infarction (n = 16,010), identified from an in-patient electronic database, were linked to the National Death Registry of Taiwan. Actuarial analysis was used to determine the one-year survival rates, and Cox proportional hazard regression model was used to investigate the predictors for the one-year mortality of stroke patients. For patients with cerebral hemorrhage and infarction and who were admitted from 1991 to 2008, the one-year survival rates were 71% and 84%, respectively. In addition, stroke patients who also suffered from myocardial infarction, chronic renal illness, and pneumonia and had high Charlson comorbidity index scores showed increased risks of mortality due to cerebral hemorrhage and infarction. Compared with the patients admitted from 1991 to 1996, those admitted from 1997 to 2002 and from 2003 to 2008 showed 15%-20% and 20%-25% reduction in one-year mortality risk in cerebral hemorrhage and infarction, respectively. This result demonstrates the continuous quality improvement of stroke management in the hospital from 1991 to 2008. Further reduction in one-year mortality can be achieved by early recognition and prompt treatment of certain comorbidities. PMID- 24492625 TI - The role of PKD in cell polarity, biosynthetic pathways, and organelle/F-actin distribution. AB - Protein Kinase D (PKD) 1, 2, and 3 are members of the PKD family. PKDs influence many cellular processes, including cell polarity, structure of the Golgi, polarized transport from the Golgi to the basolateral plasma membrane, and actin polymerization. However, the role of the PKD family in cell polarity has not yet been elucidated in vivo. Here, we show that KO mice displayed similar localization of the apical and basolateral proteins, transport of VSV-G and a GPI anchored protein, and similar localization of actin filaments. As DKO mice were embryonic lethal, we generated MEFs that lacked all PKD isoforms from the PKD1 and PKD2 double floxed mice using Cre recombinase and PKD3 siRNA. We observed a similar localization of various organelles, a similar time course in the transport of VSV-G and a GPI-anchored protein, and a similar distribution of F actin in the PKD-null MEFs. Collectively, our results demonstrate that the complete deletion of PKDs does not affect the transport of VSV-G or a GPI anchored protein, and the distribution of F-actin. However, simultaneous deletion of PKD1 and PKD2 affect embryonic development, demonstrating their functional redundancy during development. PMID- 24492628 TI - Postoperative drainage with one chest tube is appropriate for pulmonary lobectomy: a randomized trial. AB - To expand postoperative residual lungs after pulmonary lobectomy, thoracic drainage with two chest tubes has been recommended. Several studies recently demonstrated that postoperative drainage with one chest tube (PD1) was as safe as that with two chest tubes (PD2). However, most of the patients in those studies underwent lobectomy by standard thoracotomy. Although the number of pulmonary lobectomies by video-assisted thoracic surgery (VATS) has been increasing in recent years, there have been no reports that compared PD1 with PD2 after pulmonary lobectomy, including that by VATS. To elucidate whether postoperative management with PD1 is as safe as that with PD2, we conducted a randomized controlled trial. Lung cancer patients who underwent lobectomies with mediastinal nodal dissection in our hospital were assigned to one of two groups: one chest tube placed in PD1 group and two chest tubes placed in PD2 group. A total of 108 patients were registered in the study. There were no significant differences in the age, gender, pathological stage or histological type between two groups. Since the residual lung expansion was good in both groups, there were no patients who needed thoracentesis. There were no significant differences in the number of cases with pleurodesis, the amount/duration of drainage or the pain of the patients between two groups. In conclusion, since PD1 has advantages in saving cost and time and in low risk of transcutaneous infection, PD1 is appropriate after pulmonary lobectomy by VATS and by open thoracotomy. PMID- 24492629 TI - Osteoma of the internal auditory canal mimicking vestibular schwannoma: case report and review of 17 recent cases. AB - Osteoma of the internal auditory canal (IAC) is an uncommon benign bone tumor. Its imaging features may be similar to other IAC lesions, such as vestibular schwannomas that are benign and usually slow-growing but sometimes life threatening tumors. Thus, detecting IAC lesions and differentiating osteoma from other IAC lesions are both important clinically. We report a case of misdiagnosis of an IAC osteoma as an IAC schwannoma based on magnetic resonance (MR) imaging using the three-dimensional constructive interference in steady state (CISS) sequence instead of T1-weighted MR imaging with gadolinium. We also review 17 cases of IAC osteomas reported in the past 22 years. A 61-year-old female was admitted to our department with IAC lesion incidentally discovered by the CISS sequence. The lesion was diagnosed as an IAC schwannoma, and was followed up annually under "wait and scan" management. Follow-up T1-weighted MR imaging with gadolinium showed no enhancement of the tumor, and additional computed tomography (CT) of the temporal bone showed a solitary pedunculated bony lesion, resulting in the diagnosis of IAC osteoma. The CISS sequence is useful for detecting small IAC lesions, such as vestibular schwannomas. However, the CISS sequence has limitations for qualitative diagnosis and can misdiagnose osteomas as schwannomas. Use of the CISS sequence without T1-weighted MR imaging with gadolinium for the screening of a lesion of the IAC and cerebellopontine angle should consider the possibility of IAC osteomas, and temporal bone CT or T1 weighted MR imaging with gadolinium should be performed when an IAC lesion is detected. PMID- 24492631 TI - Screen-printed graphite macroelectrodes for the direct electron transfer of cytochrome c: a deeper study of the effect of pH on the conformational states, immobilization and peroxidase activity. AB - The direct electron transfer of cytochrome c has been studied at screen-printed graphite macroelectrodes without recourse to mediators or the need for any electrode pre-treatment as is commonly employed within the literature. A wide range of pH values from 2.0 to 11.0 have been explored upon the electrochemical response of cytochrome c and different voltammetric signatures have been observed. The direct electron transfer of the alkaline transition of cytochrome c was found impeded within alkaline media leading to either an irreversible redox process or even no voltammetric responses. In acidic aqueous media the electrochemical process is observed to undergo a mixed diffusion and adsorption controlled process rather than a purely diffusional process of the native conformation as observed at pH 7.0. Interestingly, at pH 3.5 a new conformational state is revealed in cooperation with the native conformation. The immobilization of the protein was satisfactorily obtained using a simple method by cycling the protein at specific solution pH values allowing amperometric responses to be obtained and gives rise to useful pseudo-peroxidase activity for sensing H2O2. Apparent Michaelis-Menten constant values (Km) were calculated via the Lineweaver Burk method with deduced values of 25 +/- 4, 98 +/- 12 and 230 +/- 30 mM, respectively for pH values of 2.0, 3.0 and 7.0. Such work is important for those utilising cytochrome c in bio-electrochemical and related applications. PMID- 24492630 TI - Critical roles of nardilysin in the maintenance of body temperature homoeostasis. AB - Body temperature homoeostasis in mammals is governed centrally through the regulation of shivering and non-shivering thermogenesis and cutaneous vasomotion. Non-shivering thermogenesis in brown adipose tissue (BAT) is mediated by sympathetic activation, followed by PGC-1alpha induction, which drives UCP1. Here we identify nardilysin (Nrd1 and NRDc) as a critical regulator of body temperature homoeostasis. Nrd1(-/-) mice show increased energy expenditure owing to enhanced BAT thermogenesis and hyperactivity. Despite these findings, Nrd1(-/ ) mice show hypothermia and cold intolerance that are attributed to the lowered set point of body temperature, poor insulation and impaired cold-induced thermogenesis. Induction of beta3-adrenergic receptor, PGC-1alpha and UCP1 in response to cold is severely impaired in the absence of NRDc. At the molecular level, NRDc and PGC-1alpha interact and co-localize at the UCP1 enhancer, where NRDc represses PGC-1alpha activity. These findings reveal a novel nuclear function of NRDc and provide important insights into the mechanism of thermoregulation. PMID- 24492632 TI - Compensation of physical activity and sedentary time in primary school children. AB - PURPOSE: There is considerable debate about the possibility of physical activity compensation. This study examined whether increased levels in physical activity and/or sedentary behavior on 1 d were predictive of lower levels in these behaviors on the following day (compensatory mechanisms) among children. METHODS: Two hundred and forty-eight children (121 boys and 127 girls) age 8-11 yr from nine primary schools in Melbourne, Australia, wore a GT3X+ ActiGraph for seven consecutive days. Time spent in light physical activity (LPA) and moderate- to vigorous-intensity physical activity (MVPA) was derived using age-specific cut points. Sedentary time was defined as 100 counts per minute. Meteorological data (temperature, precipitation, relative humidity, and daylight hours) were obtained daily and matched to accelerometer wear days. Multilevel analyses (day, child, and school) were conducted using generalized linear latent and mixed models. RESULTS: On any given day, every additional 10 min spent in MVPA was associated with approximately 25 min less LPA and 5 min less MVPA the following day. Similarly, additional time spent in LPA on any given day was associated with less time in LPA and MVPA the next day. Time spent sedentary was associated with less sedentary time the following day. Adjusting for meteorological variables did not change observed compensation effects. No significant moderating effect of sex was observed. CONCLUSION: The results are consistent with the compensation hypothesis, whereby children appear to compensate their physical activity or sedentary time between days. Additional adjustment for meteorological variables did not change the observed associations. Further research is needed to examine what factors may explain apparent compensatory changes in children's physical activity and sedentary time. PMID- 24492633 TI - Reliability and validity of a domain-specific last 7-d sedentary time questionnaire. AB - PURPOSE: The objective of this study is to examine test-retest reliability, criterion validity, and absolute agreement of a self-report, last 7-d sedentary behavior questionnaire (SIT-Q-7d), which assesses total daily sedentary time as an aggregate of sitting/lying down in five domains (meals, transportation, occupation, nonoccupational screen time, and other sedentary time). Dutch (DQ) and English (EQ) versions of the questionnaire were examined. METHODS: Fifty-one Flemish adults (ages 39.4 +/- 11.1 yr) wore a thigh accelerometer (activPAL3TM) and simultaneously kept a domain log for 7 d. The DQ was subsequently completed twice (median test-retest interval: 3.3 wk). Thigh-acceleration sedentary time was log annotated to create comparable domain-specific and total sedentary time variables. Four hundred two English adults (ages 49.6 +/- 7.3 yr) wore a combined accelerometer and HR monitor (Actiheart) for 6 d to objectively measure total sedentary time. The EQ was subsequently completed twice (median test-retest interval: 3.4 wk). In both samples, the questionnaire reference frame overlapped with the criterion measure administration period. All participants had five or more valid days of criterion data, including one or more weekend day. RESULTS: Test-retest reliability (intraclass correlation coefficient (95% CI)) was fair to good for total sedentary time (DQ: 0.68 (0.50-0.81); EQ: 0.53 (0.44-0.62)) and poor to excellent for domain-specific sedentary time (DQ: from 0.36 (0.10-0.57) (meals) to 0.66 (0.46-0.79) (occupation); EQ: from 0.45 (0.35-0.54) (other sedentary time) to 0.76 (0.71-0.81) (meals)). For criterion validity (Spearman rho), significant correlations were found for total sedentary time (DQ: 0.52; EQ: 0.22; all P <0.001). Compared with domain-specific criterion variables (DQ), modest-to-strong correlations were found for domain-specific sedentary time (from 0.21 (meals) to 0.76 (P < 0.001) (screen time)). The questionnaire generally overestimated sedentary time compared with criterion measures. CONCLUSION: The SIT-Q-7d appears to be a useful tool for ranking individuals in large-scale observational studies examining total and domain-specific sitting. PMID- 24492634 TI - Effect of work and recovery durations on W' reconstitution during intermittent exercise. AB - PURPOSE: We recently presented an integrating model of the curvature constant of the hyperbolic power-time relationship (W') that permits the calculation of the W' balance (W'BAL) remaining at any time during intermittent exercise. Although a relationship between recovery power and the rate of W' recovery was demonstrated, the effect of the length of work or recovery intervals remains unclear. METHODS: After determining VO2max, critical power, and W', 11 subjects completed six separate exercise tests on a cycle ergometer on different days, and in random order. Tests consisted of a period of intermittent severe-intensity exercise until the subject depleted approximately 50% of their predicted W'BAL, followed by a constant work rate (CWR) exercise bout until exhaustion. Work rates were kept constant between trials; however, either work or recovery durations during intermittent exercise were varied. The actual W' measured during the CWR (W'ACT) was compared with the amount of W' predicted to be available by the W'BAL model. RESULTS: Although some differences between W'BAL and W'ACT were noted, these amounted to only -1.6 +/- 1.1 kJ when averaged across all conditions. The W'ACT was linearly correlated with the difference between VO2 at the start of CWR and VO2max (r = 0.79, P < 0.01). CONCLUSIONS: The W'BAL model provided a generally robust prediction of CWR W'. There may exist a physiological optimum formulation of work and recovery intervals such that baseline VO2 can be minimized, leading to an enhancement of subsequent exercise tolerance. These results may have important implications for athletic training and racing. PMID- 24492636 TI - Modelling the behaviour of switchable-hydrophilicity solvents. AB - A switchable-hydrophilicity solvent (SHS) is a solvent that in one state forms a biphasic mixture with water but can be reversibly switched to another state that is miscible with water. We describe a mathematical model of the behaviour of CO2 triggered SHS that narrows the search field for these solvents in terms of their basicity and hydrophilicity. By its predictive power, the mathematical model can assist in the optimization of processes using SHSs in terms of extrinsic parameters such as pressure and the relative volumes of solvent and water used. Models are presented for both a two-liquid system (consisting of the amine solvent and water) and a three-liquid system (consisting of the amine solvent, water, and 1-octanol). Partitioning data with toluene as the third component is also shown for comparison with 1-octanol. PMID- 24492635 TI - Hes1 is involved in the self-renewal and tumourigenicity of stem-like cancer cells in colon cancer. AB - A small subpopulation of cancer cells with stem cell-like features might be responsible for tumour generation, progression, and chemoresistance. Hes1 influences the maintenance of certain stem cells and progenitor cells and the digestive systems. We found upregulated Hes1 in poorly differentiated cancer samples compared with well-differentiated tumour samples, and most of the adenocarcinomas exhibited significantly higher levels of Hes1 mRNA compared with that observed in matched normal colon samples. Moreover, Hes1 expression was found to be correlated with the expression of stem cell markers in colon cancer samples, and Hes1 upregulates the expression of stemness-related genes in colon cancer cells. In addition, Hes1 enhances the self-renewal properties of the stem like cells by increasing the sizes of CD133+ cells and SP cells and the ability of tumour sphere formation. Additionally, the Hes1-overexpressing cells formed significantly larger and higher number of colonies, as determined through the colony and the soft agar assays. More importantly, Hes1 enhances the tumourigenicity of colon cancer cell lines in nude mice and exhibits a strong tumour-formation ability at a cell density of 1 * 10(3). Taken together, our data indicate that Hes1 induces stem-like cell self-renewal and increases the number of tumour-initiating cells in colon cancer. PMID- 24492638 TI - Traumatic spinal cord injuries: evidence from 30 years in a single centre. AB - STUDY DESIGN: Retrospective data analysis. OBJECTIVES: Traumatic spinal cord injury (TSCI) is a devastating injury that causes a lifelong disability, involving mostly young men. The aim of the study was to analyse some clinical and epidemiological features of TSCI patients admitted to the Spinal Unit of Florence, Italy, during 30 years, from 1981 to 2010. SETTING: Spinal Unit, Careggi University Hospital, Florence, Italy. METHODS: The medical files from the computerised database of the patients who sustained TSCI from 1 January 1981 to 31 December 2010 and received comprehensive care in the same centre were analysed. Information was collected with regard to demographic data, causes of injury, time of injury, associated injuries, treatment of the vertebral lesion and neurological condition at discharge. RESULTS: A total of 1479 patients were included. The number of two-wheeler road traffic accidents (RTAs) has increased over the years, whereas the percentage of falls and sports accidents has been quite constant. The lesions due to 4-wheeler RTAs tend to decrease. Lesions due to falls mainly affected older persons than those due to sports accidents, with a mean age at the time of injury of 52 and 25 years, respectively. Diving was the most common cause among sports and leisure accidents. Associated injuries were present in 56% of all the cases included. CONCLUSION: The cases of spinal cord injury due to two-wheeler RTAs have increased over the years probably because of the increasing diffusion of the use of such a vehicle, and such an eventuality has to be taken into consideration in future prevention strategies. PMID- 24492637 TI - Unidirectional hybridization and reproductive barriers between two heterostylous primrose species in north-west Yunnan, China. AB - BACKGROUND AND AIMS: Heteromorphy in flowers has a profound effect on breeding patterns within a species, but little is known about how it affects reproductive barriers between species. The heterostylous genus Primula is very diverse in the Himalaya region, but hybrids there have been little researched. This study examines in detail a natural hybrid zone between P. beesiana and P. bulleyana. METHODS: Chloroplast sequencing, AFLP (amplified fragment length polymorphism) markers and morphological comparisons were employed to characterize putative hybrids in the field, using synthetic F1s from hand pollination as controls. Pollinator visits to parent species and hybrids were observed in the field. Hand pollinations were conducted to compare pollen tube growth, seed production and seed viability for crosses involving different morphs, species and directions of crossing. KEY RESULTS: Molecular data revealed all hybrid derivatives examined to be backcrosses of first or later generations towards P. bulleyana: all had the chloroplast DNA (cpDNA) of this species. Some individuals had morphological traits suggesting they were hybrids, but they were genetically similar to P. bulleyana; they might have been advanced generation backcrosses. Viable F1s could not be produced with P. bulleyana pollen on P. beesiana females, irrespective of the flower morphs used. Within-morph crosses for each species had very low (<10 %) seed viability, whereas crosses between pin P. bulleyana (female) and pin P. beesiana had a higher seed viability of 30 %. Thus genetic incompatibility mechanisms back up mechanical barriers to within-morph crosses in each species, but are not the same between the two species. The two species share their main pollinators, and pollinators were observed to fly between P. bulleyana and hybrids, suggesting that pollinator behaviour may not be an important isolating factor. CONCLUSIONS: Hybridization is strongly asymmetric, with P. bulleyana the only possible mother and all detected hybrids being backcrosses in this direction. Partial ecological isolation and inhibition of heterospecific pollen, and possibly complete barriers to F1 formation on P. beesiana, may be enough to make F1 formation very rare in these species. Therefore, with no F1 detected, this hybrid zone may have a finite life span as successive generations become more similar to P. bulleyana. PMID- 24492639 TI - The experience of using the scale of functional independence measure in individuals undergoing spinal cord injury rehabilitation in Brazil. AB - STUDY DESIGN: Retrospective cohort. OBJECTIVES: The aim of this study was to evaluate the correlation between the level and completeness of the injury with Functional Independence Measure (FIM) score and the validity and responsiveness of the FIM in Brazilian individuals with spinal cord injury admitted to rehabilitation. SETTING: SARAH Network of Rehabilitation Hospitals, Brasilia, Brazil. METHODS: A total of 218 patients with spinal cord injury admitted for rehabilitation in 2006 was included in this study. The validity was assessed as the ability of the FIM to discriminate different levels of disability (cervical, thoracic and lumbar) at admission and the responsiveness was obtained by analyzing admission and discharge data for each of the three injury groups. RESULTS: Total FIM score, motor FIM score and each of the 13 items were valid when comparing three groups and comparing groups two by two, except the items 'eating' and 'grooming' among paraplegics, and 'stairs' at cervical and thoracic levels. The scale was not responsive to the five cognitive items, 'stairs' and 'eating', among paraplegics, or 'grooming', 'bathing' and 'dressing upper body' in lumbar level patients. The patient difficulty in performing tasks can vary among populations. Therefore, the continuous evaluation process of psychometric characteristics is important to validate the use of the instrument in different contexts. PMID- 24492641 TI - Growth, reproductive performance, carcass characteristics and meat quality in F1 and F2 progenies of somatic cell-cloned pigs. AB - The objective of this study was to examine the health and meat production of cloned sows and their progenies in order to demonstrate the application of somatic cell cloning to the pig industry. This study compared the growth, reproductive performance, carcass characteristics and meat quality of Landrace cloned sows, F1 progenies and F2 progenies. We measured their body weight, growth rate and feed conversion and performed a pathological analysis of their anatomy to detect abnormalities. Three of the five cloned pigs were used for a growth test. Cloned pigs grew normally and had characteristics similar to those of the control purebred Landrace pigs. Two cloned gilts were bred with a Landrace boar and used for a progeny test. F1 progenies had characteristics similar to those of the controls. Two of the F1 progeny gilts were bred with a Duroc or Large White boar and used for the progeny test. F2 progenies grew normally. There were no biological differences in growth, carcass characteristics and amino acid composition among cloned sows, F1 progenies, F2 progenies and conventional pigs. The cloned sows and F1 progenies showed normal reproductive performance. No specific abnormalities were observed by pathological analysis, with the exception of periarteritis in the F1 progenies. All pigs had a normal karyotype. These results demonstrate that cloned female pigs and their progenies have similar growth, reproductive performance and carcass quality characteristics and that somatic cell cloning could be a useful technique for conserving superior pig breeds in conventional meat production. PMID- 24492640 TI - Resveratrol reverses cadmium chloride-induced testicular damage and subfertility by downregulating p53 and Bax and upregulating gonadotropins and Bcl-2 gene expression. AB - This study was performed to investigate the protective and therapeutic effects of resveratrol (RES) against CdCl2-induced toxicity in rat testes. Seven experimental groups of adult male rats were formulated as follows: A) controls+NS, B) control+vehicle (saline solution of hydroxypropyl cyclodextrin), C) RES treated, D) CdCl2+NS, E) CdCl2+vehicle, F) RES followed by CdCl2 and M) CdCl2 followed by RES. At the end of the protocol, serum levels of FSH, LH and testosterone were measured in all groups, and testicular levels of TBARS and superoxide dismutase (SOD) activity were measured. Epididymal semen analysis was performed, and testicular expression of Bcl-2, p53 and Bax was assessed by RT PCR. Also, histopathological changes of the testes were examined microscopically. Administration of RES before or after cadmium chloride in rats improved semen parameters including count, motility, daily sperm production and morphology, increased serum concentrations of gonadotropins and testosterone, decreased testicular lipid peroxidation and increased SOD activity. RES not only attenuated cadmium chloride-induced testicular histopathology but was also able to protect against the onset of cadmium chloride testicular toxicity. Cadmium chloride downregulated the anti-apoptotic gene Bcl2 and upregulated the expression of pro apoptotic genes p53 and Bax. Resveratrol protected against and partially reversed cadmium chloride testicular toxicity via upregulation of Bcl2 and downregulation of p53 and Bax gene expression. The antioxidant activity of RES protects against cadmium chloride testicular toxicity and partially reverses its effect via upregulation of BCl2 and downregulation of p53 and Bax expression. PMID- 24492642 TI - Relationships between the appearances and changes of estrous signs and the estradiol-17beta peak, luteinizing hormone surge and ovulation during the periovulatory period in lactating dairy cows kept in tie-stalls. AB - Lactating Holstein-Friesian cows kept in tie-stall barn were used as subjects in this study. Rectal examination, ultrasonography and blood sampling were conducted every other day and then daily after the day on which diameter of the corpus luteum decreased. After the luteal diameter decreased for 2 consecutive days, rectal and ultrasound examinations, blood sampling, and observation of estrous signs were conducted at 6-h intervals. Most of the estrous signs became obvious with the increase in estradiol-17beta (E2) and became most remarkable 24 to 30 hours before ovulation, at which point the E2 peak and luteinizing hormone (LH) surge were achieved, and then weakened which progression to ovulation. The correlation between the intensity of four estrous signs (hyperemia and swelling of the intravaginal part of the uterus, opening of the external uterine orifice and viscosity of the cervical mucus) and the plasma E2 concentration was higher than that of three estrous signs (swelling of the vulva, contraction of the uterus, diameter of uterine horn) and the plasma E2 concentration. The relaxation of the intravaginal part of the uterus showed a unique change compared with the other estrous signs, and it became most obvious 6, 12 and 18 h before ovulation; this obviously relaxed period was consistent with the generally accepted theoretical optimal time for artificial insemination (AI), i.e., 6 to 24 h after initiation of estrus. These results suggest that observation of estrous signs by vaginoscopic examination gave useful information for detection of the optimal timing of AI in the periovulatory period in lactating dairy cows kept in a tie stall barn. PMID- 24492643 TI - Prevalence and determinants of anxiety and depression symptoms in patients with type 2 diabetes in Lithuania. AB - BACKGROUND: Depression is associated with a variety of diabetes complications, including diabetic retinopathy, nephropathy, neuropathy, and macrovascular complications. The prevalence of the symptoms of anxiety (32%) and depression (22.4%) in patients with diabetes is considerably higher than in general population samples (10%). The aim of this study was to evaluate the prevalence and determinants of anxiety and depression symptoms in patients with type 2 diabetes (T2DM). MATERIAL AND METHODS: This survey was conducted during 2007 2010. In total, 1500 patients were invited to participate in the study. The Hospital Anxiety and Depression Scale (HADS) was used to measure depression and anxiety for the evaluation of the depressive state and anxiety. Statistical analysis was carried out using SPSS 17.0. RESULTS: More than 70% of all respondents who participated in the study had diabetes mellitus complications (72.2%). The prevalence of mild to severe depression score was 28.5% (95% CI 25.7 31.4). The prevalence of anxiety was 42.4% (95% CI 39.3-45.5). Anxiety was more frequent among females (46.8%) than among males (34.7%) (p<0.001). A significant negative trend was observed between prevalence of anxiety and depression, and age and education (p for trend <0.001). CONCLUSIONS: A significant association between depression and diabetic complications was identified (p<0.05). Duration of diabetes was a risk factor significantly associated with higher scores of anxiety among the patients with T2DM. PMID- 24492645 TI - Characteristics of atmospheric gravity waves observed using the MU (Middle and Upper atmosphere) radar and GPS (Global Positioning System) radio occultation. AB - The wind velocity and temperature profiles observed in the middle atmosphere (altitude: 10-100 km) show perturbations resulting from superposition of various atmospheric waves, including atmospheric gravity waves. Atmospheric gravity waves are known to play an important role in determining the general circulation in the middle atmosphere by dynamical stresses caused by gravity wave breaking. In this paper, we summarize the characteristics of atmospheric gravity waves observed using the middle and upper atmosphere (MU) radar in Japan, as well as novel satellite data obtained from global positioning system radio occultation (GPS RO) measurements. In particular, we focus on the behavior of gravity waves in the mesosphere (50-90 km), where considerable gravity wave attenuation occurs. We also report on the global distribution of gravity wave activity in the stratosphere (10-50 km), highlighting various excitation mechanisms such as orographic effects, convection in the tropics, meteorological disturbances, the subtropical jet and the polar night jet. PMID- 24492646 TI - Efficacy of Evolving Early-Extubation Strategy on Early Postoperative Functional Recovery in Pediatric Open-Heart Surgery: A Matched Case-Control Study. AB - There has been a paradigm shift toward "fast-track" management with early extubation (EE) in cardiac surgery. Our retrospective, matched case-control study wishes to define the benefits of EE in pediatric congenital heart surgery. We examined 50 consecutive pediatric cardiac surgery patients extubated in the operating room (February 2009 to July 2009) against a control group of delayed extubation patients. No significant differences were found in preoperative variables except heart failure medication. Significant intraoperative variables included the following: blood products (363 vs 487 mL, P = .023), morphine (62% vs 6%, P < .0001), and inotropes (16% vs 60%, P < .0001) given. Postoperatively significant differences included hospital stay and lower inotrope scores in the early-extubation group (14.89 vs 31.68, P < .0001). The reintubation rate was not significant. EE patients have equivalent hemodynamic profiles shown by a decreased necessity for inotropic support. We conclude that EE is feasible in low /medium-risk pediatric congenital heart surgery patients. PMID- 24492647 TI - Noteworthy cardiac surgical literature in 2013. AB - The year of 2013 has continued to expand our understanding of the treatment of cardiac surgical patients. The noteworthy articles chosen for this review address new opinions on common surgical issues such as the appropriateness of coronary bypass compared with percutaneous intervention as well as more novel approaches to repair of insufficient aortic valves. The review continues by discussing the implications of the Centers for Medicare and Medicaid Services National Coverage Decisions for both transcatheter aortic valve replacement and ventricular assist device in addition to notable articles on each. PMID- 24492644 TI - Transition metal catalyzed borylation of functional pi-systems. AB - Borylated functional pi-systems are useful building blocks to enable efficient synthesis of novel molecular architectures with beautiful structures, intriguing properties and unique functions. Introduction of boronic ester substituents to a variety of extended pi-systems can be achieved through either iridium-catalyzed direct C-H borylation or the two-step procedure via electrophilic halogenation followed by palladium-catalyzed borylation. This review article focuses on our recent progress on borylation of large pi-conjugated systems such as porphyrins, perylene bisimides, hexabenzocoronenes and dipyrrins. PMID- 24492648 TI - Endpoints of resuscitation: what are they anyway? AB - Hemodynamic optimization of surgical patients during and after surgery in the Surgical Intensive Care Unit is meant to improve outcomes. These outcomes have been measured by Length Of Stay (LOS), rate of infection, days on ventilator, etc. Unfortunately, the adaptation of modern technology to accomplish this has been slow in coming. Ever since Shoemaker described in 1988 using a pulmonary artery catheter (PAC) to guide fluid and inotropic administration to deliver supranormal tissue oxygenation, many authors have written about different techniques to achieve this "hemodynamic optimization". Since the PAC and CVC have both gone out of favor for utilization to monitor and improve hemodynamics, many clinicians have resorted using the easy to use static measurements of blood pressure (BP), heart rate (HR), and urine output. In this paper, the authors will review why these static measurements are no longer adequate and review some of the newer technology that have been studied and proven useful. This review of newer technologies combined with laboratory measurements that have also proven to help guide the clinician, may provide the impetus to adopt new strategies in the operating rooms (OR) and SICU. PMID- 24492649 TI - Correlated spin currents generated by resonant-crossed Andreev reflections in topological superconductors. AB - Topological superconductors, which support Majorana fermion excitations, have been the subject of intense studies due to their novel transport properties and their potential applications in fault-tolerant quantum computations. Here we propose a new type of topological superconductors that can be used as a novel source of correlated spin currents. We show that inducing superconductivity on a AIII class topological insulator wire, which respects a chiral symmetry and supports protected fermionic end states, will result in a topological superconductor. This topological superconductor supports two topological phases with one or two Majorana fermion end states, respectively. In the phase with two Majorana fermions, the superconductor can split Cooper pairs efficiently into electrons in two spatially separated leads due to Majorana-induced resonant crossed Andreev reflections. The resulting currents in the leads are correlated and spin-polarized. Importantly, the proposed topological superconductors can be realized using quantum anomalous Hall insulators in proximity to superconductors. PMID- 24492650 TI - Loss of protein kinase Cdelta/HuR interaction is necessary to doxorubicin resistance in breast cancer cell lines. AB - The protein kinase Cdelta (PKCdelta) interacts with and phosphorylates HuR, dictating its functionality. We show here that the genotoxic stimulus induced by doxorubicin triggers PKCdelta interaction with HuR and leads to HuR phosphorylation on serines 221 and 318 and cytoplasmic translocation. This series of events is crucial to elicit the death pathway triggered by doxorubicin and is necessary to promote HuR function in post-transcriptional regulation of gene expression, because genetic ablation of PKCdelta caused the inability of HuR to bind its target mRNAs, topoisomerase IIalpha (TOP2A) included. In in vitro select doxorubicin-resistant human breast cancer cell lines upregulating the multidrug resistance marker ABCG2, PKCdelta, and HuR proteins were coordinately downregulated together with the doxorubicin target TOP2A protein whose mRNA was HuR-regulated. Therefore, we show here that PKCdelta, HuR, and TOP2A constitute a network mediating doxorubicin efficacy in breast cancer cells. The importance of these molecular events in cancer therapy is suggested by their being profoundly suppressed in cells selected for doxorubicin resistance. PMID- 24492651 TI - Pharmacological evaluation of selective alpha2c-adrenergic agonists in experimental animal models of nasal congestion. AB - Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective alpha2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of alpha2c adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 ul). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike d-pseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC(80)) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that alpha2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion. PMID- 24492652 TI - All-trans-retinoic acid improves cholestasis in alpha-naphthylisothiocyanate treated rats and Mdr2-/- mice. AB - Chronic cholestasis results in liver injury and eventually liver failure. Although ursodeoxycholic acid (UDCA) showed limited benefits in primary biliary cirrhosis, there is an urgent need to develop alternative therapy for chronic cholestatic disorders. Previous studies from our laboratory demonstrated that all trans-retinoic acid (atRA) is a potent suppressor of CYP7A1, the rate-limiting enzyme in bile acid synthesis. atRA also repressed the expression of tumor growth factor-beta and collagen 1A1 in activated primary human stellate cells and LX2 cells. When administered together with UDCA to bile duct-ligated rats, this combined therapy significantly reduced the bile acid pool size and improved liver conditions. To further examine whether atRA alone or in combination with UDCA has greater beneficial effects than UDCA treatment alone, we assessed this treatment in two additional chronic cholestatic rodent models: alpha-naphthylisothiocyanate (ANIT)-treated rats and the Mdr2(-/-) (Abcb4(-/-)) knockout mouse. atRA alone significantly reduced bile duct proliferation, inflammation, and hydroxyproline levels in ANIT-treated rats, whereas the combination of atRA and UDCA significantly reduced plasma bile salt level compared with UDCA treatment. atRA alone or in combination with UDCA significantly reduced plasma levels of alkaline phosphatase and bile salts in 12-week-old Mdr2(-/-) mice. Reduced bile duct proliferation and inflammation were also observed in the livers of these mice. Together, atRA alone or in combination with UDCA significantly reduced the severity of liver injury in these two animal models, further supporting the combination treatment of atRA and UDCA as a potential new therapy for patients with chronic cholestatic liver disease who have not responded fully to UDCA. PMID- 24492653 TI - SII and the fronto-parietal areas are involved in visually cued tactile top-down spatial attention: a functional MRI study. AB - Visual cue-oriented, tactile top-down attention (vTA) has been well investigated behaviorally. However, vTA-related brain activation remains unclear, and whether SI (primary somatosensory cortex) or SII (secondary somatosensory cortex) is modulated by the top-down process of tactile cognition remains particularly controversial. We used the Posner paradigm in which a visual spatial cue directed attention to a tactile target [tactile spatial attention (TS) task]. The TS is compared with a visual nonspatially cued, tactile attention task [tactile neutral attention (TN) task]. The behavioral results showed no significant differences between the TS and TN tasks. However, we considered the possibility that the visual spatial hint affected the TS neural network. Brain-imaging data showed that the inferior parietal lobe was activated more during the TS task than during the TN task. Furthermore, we present evidence to support SII modulation by top down processing during the TS task. PMID- 24492654 TI - Expression of OsMATE1 and OsMATE2 alters development, stress responses and pathogen susceptibility in Arabidopsis. AB - Multidrug and Toxic compound Extrusion proteins (MATE) are a group of secondary active transporters with ubiquitous occurrences in all domains of life. This is a newly characterized transporter family with limited functional knowledge in plants. In this study, we functionally characterised two members of rice MATE gene family, OsMATE1 and OsMATE2 through expression in heterologous system, Arabidopsis. Expression of OsMATEs in Arabidopsis altered growth and morphology of transgenic plants. Genome-wide expression analysis revealed modulation of genes involved in plant growth, development and biotic stress in transgenic lines. Transgenic plants displayed sensitivity for biotic and abiotic stresses. Elevated pathogen susceptibility of transgenic lines was correlated with reduced expressions of defence related genes. Promoter and cellular localization studies suggest that both MATEs express in developing and reproductive organs and are plasma-membrane localised. Our results reveal that OsMATE1 and OsMATE2 regulate plant growth and development as well as negatively affect disease resistance. PMID- 24492655 TI - Egg yolk and glycerol requirements for freezing boar spermatozoa treated with methyl beta-cyclodextrin or cholesterol-loaded cyclodextrin. AB - Egg yolk (EY) and glycerol are common constituents of extenders used for sperm cryopreservation. It has been demonstrated that using cholesterol-loaded cyclodextrins (CLC) improves sperm cryosurvival in several species. However, standard freezing extenders might not be the most appropriate for CLC-treated sperm. This study evaluated the EY and glycerol requirements for freezing CLC treated boar spermatozoa. Semen samples from 34 ejaculates coming from 4 boars were used. Each ejaculate was split into three aliquots: one was used untreated (control), and the other two were treated with 1 mg of CLC or methyl-beta cyclodextrin/120 * 10(6) sperm for 15 min at 22 C prior to cryopreservation. Our results indicated that reducing the concentration of EY was detrimental for sperm viability after thawing (31.57 +/- 2 vs. 19.89% +/- 2 for 20 and 10% EY, respectively; P <0.05), even in semen treated with CLC. On the other hand, it was observed that the traditional concentration of glycerol (3%) was not the appropriate for freezing CLC-treated sperm (61.10 +/- 3 vs. 47.87% +/- 3 viable sperm for control and CLC-treated sperm, respectively; P <0.05). Thus, CLC treated sperm showed a higher tolerance to high glycerol concentrations (5%) in terms of sperm viability (59.19% +/- 3) than non-treated sperm (45.58% +/- 3; P<0.05). Therefore, it could be necessary to modify the freezing extenders for CLC-treated sperm. Nevertheless, additional studies will be needed to evaluate alternative cryoprotectants and to determine the effect of high glycerol concentrations on sperm functionality. PMID- 24492656 TI - Expression of aldo-keto reductase 1C23 in the equine corpus luteum in different luteal phases. AB - Regression of the corpus luteum (CL) is characterized by a decay in progesterone (P4) production (functional luteolysis) and disappearance of luteal tissues (structural luteolysis). In mares, structural luteolysis is thought to be caused by apoptosis of luteal cells, but functional luteolysis is poorly understood. 20alpha-hydroxysteroid dehydrogenase (20alpha-HSD) catabolizes P4 into its biologically inactive form, 20alpha-hydroxyprogesterone (20alpha-OHP). In mares, aldo-keto reductase (AKR) 1C23, which is a member of the AKR superfamily, has 20alpha-HSD activity. To clarify whether AKR1C23 is associated with functional luteolysis in mares, we investigated the expression of AKR1C23 in the CL in different luteal phases. The luteal P4 concentration and levels of 3beta hydroxysteroid dehydrogenase (3beta-HSD) mRNA were higher in the mid luteal phase than in the late and regressed luteal phases (P<0.05), but the level of 3beta-HSD protein was higher in the late luteal phase than in the regressed luteal phase (P<0.05). The luteal 20alpha-OHP concentration and the level of AKR1C23 mRNA were higher in the late luteal phase than in the early and mid luteal phases (P<0.05), and the level of AKR1C23 protein was also highest in the late luteal phase. Taken together, these findings suggest that metabolism of P4 by AKR1C23 is one of the processes contributing to functional luteolysis in mares. PMID- 24492657 TI - The association of mitochondrial potential and copy number with pig oocyte maturation and developmental potential. AB - ATP is critical for oocyte maturation, fertilization, and subsequent embryo development. Both mitochondrial membrane potential and copy number expand during oocyte maturation. In order to differentiate the roles of mitochondrial metabolic activity and mtDNA copy number during oocyte maturation, we used two inhibitors, FCCP (carbonyl cyanide p-(tri-fluromethoxy)phenyl-hydrazone) and ddC (2'3 dideoxycytidine), to deplete the mitochondrial membrane potential (Deltaphim) and mitochondrial copy number, respectively. FCCP (2000 nM) reduced ATP production by affecting mitochondrial Deltaphim, decreased the mRNA expression of Bmp15 (bone morphogenetic protein 15), and shortened the poly(A) tails of Bmp15, Gdf9 (growth differentiation factor 9), and Cyclin B1 transcripts. FCCP (200 and 2000 nM) also affected p34(cdc2) kinase activity. By contrast, ddC did not alter ATP production. Instead, ddC significantly decreased mtDNA copy number (P < 0.05). FCCP (200 and 2000 nM) also decreased extrusion of the first polar body, whereas ddC at all concentrations did not affect the ability of immature oocytes to reach metaphase II. Both FCCP (200 and 2000 nM) and ddC (200 and 2000 uM) reduced parthenogenetic blastocyst formation compared with untreated oocytes. However, these inhibitors did not affect total cell number and apoptosis. These findings suggest that mitochondrial metabolic activity is critical for oocyte maturation and that both mitochondrial metabolic activity and replication contribute to the developmental competence of porcine oocytes. PMID- 24492658 TI - Aging-related changes in in vitro-matured bovine oocytes: oxidative stress, mitochondrial activity and ATP content after nuclear maturation. AB - The objective of this research was to clarify the aging-related changes in in vitro-matured bovine oocytes. Firstly, we examined the fertilization and embryonic development of bovine oocytes after 22 and 30-34 h of in vitro maturation (IVM). The oocytes after 30-34 h of IVM (penetrated by sperm at around 40 h after starting IVM) showed a lower developmental rate to blastocysts (P<0.01), although normal fertilization rates were similar regardless of IVM duration. In the next experiment, reactive oxygen species (ROS), mitochondrial activity and ATP content in oocytes after 20, 30 and 40 h of IVM were examined. The lowest level of ROS was found in the group subjected to 30 h of IVM. The mitochondrial activity and ATP content in the group subjected to 40 h of IVM were higher than in the group subjected to 20 h of IVM (P<0.01), and those in the group subjected to 30 h of IVM showed intermediate values. Thereafter, the mitochondrial activities at 3 days after in vitro fertilization in embryos derived from the oocytes subjected to 22 and 34 h of IVM were evaluated. In the group subjected to 34 h of IVM, high-polarized mitochondria were frequently observed at the periphery of blastomeres. The present results suggest that high mitochondrial activity observed in oocytes after prolonged IVM culture and localization of high-polarized mitochondria at the periphery of blastomeres during early embryonic development may be associated with the low developmental competence in aged bovine oocytes. PMID- 24492659 TI - Rescue in vitro fertilization method for legacy stock of frozen mouse sperm. AB - Sperm cryopreservation has been widely adopted for maintenance of the genetically engineered mouse (GEM). The cryopreserved sperm are being exchanged among many institutes worldwide. However, the recipients are not always able to obtain high fertilization rates with the frozen sperm shipped from senders. In this study, we cryopreserved mouse sperm via various methods and performed in vitro fertilization (IVF) in which the combination of methyl-beta-cyclodextrin for sperm preincubation and reduced glutathione for insemination was used (the MBCD GSH IVF). In addition, frozen sperm sent from the Jackson Laboratory (USA) were thawed and used for IVF in the same manner. The fertilization rates of both the sperm cryopreserved via the methods applied in some countries and the cryopreserved GEM sperm improved when used with the MBCD-GSH IVF method. Therefore, we strongly believe that the MBCD-GSH IVF method brings about relatively high fertilization rates with any strain of frozen mouse sperm. PMID- 24492660 TI - Defining the membrane disruption mechanism of kalata B1 via coarse-grained molecular dynamics simulations. AB - Kalata B1 has been demonstrated to have bioactivity relating to membrane disruption. In this study, we conducted coarse-grained molecular dynamics simulations to gain further insight into kB1 bioactivity. The simulations were performed at various concentrations of kB1 to capture the overall progression of its activity. Two configurations of kB1 oligomers, termed tower-like and wall like clusters, were detected. The conjugation between the wall-like oligomers resulted in the formation of a ring-like hollow in the kB1 cluster on the membrane surface. Our results indicated that the molecules of kB1 were trapped at the membrane-water interface. The interfacial membrane binding of kB1 induced a positive membrane curvature, and the lipids were eventually extracted from the membrane through the kB1 ring-like hollow into the space inside the kB1 cluster. These findings provide an alternative view of the mechanism of kB1 bioactivity that corresponds with the concept of an interfacial bioactivity model. PMID- 24492661 TI - Resting-state functional magnetic resonance imaging: review of neurosurgical applications. AB - Recent research in brain imaging has highlighted the role of different neural networks in the resting state (ie, no task) in which the brain displays spontaneous low-frequency neuronal oscillations. These can be indirectly measured with resting-state functional magnetic resonance imaging, and functional connectivity can be inferred as the spatiotemporal correlations of this signal. This technique has proliferated in recent years and has allowed the noninvasive investigation of large-scale, distributed functional networks. In this review, we give a brief overview of resting-state networks and examine the use of resting state functional magnetic resonance imaging in neurosurgical contexts, specifically with respect to neurooncology, epilepsy surgery, and deep brain stimulation. We discuss the advantages and disadvantages compared with task-based functional magnetic resonance imaging, the limitations of resting-state functional magnetic resonance imaging, and the emerging directions of this relatively new technology. PMID- 24492662 TI - Treatment of a basilar trunk perforator aneurysm with the pipeline embolization device: case report. AB - BACKGROUND AND IMPORTANCE: Basilar trunk perforator (BTP) aneurysms are rare lesions that pose significant challenges to microsurgical clipping and endovascular coiling. We present the intriguing case of a ruptured BTP aneurysm that was successfully treated with the Pipeline Embolization Device (PED). CLINICAL PRESENTATION: An elderly woman presenting with subarachnoid hemorrhage was found to have a 1.5-mm aneurysm arising from the proximal portion of a thin midbasilar perforator. The decision was made to treat this aneurysm with flow diversion in an attempt to preserve the patency of the perforator and to avoid the hazards associated with parent vessel trapping. A 3 * 12-mm PED was successfully deployed in the basilar trunk across the neck of the aneurysm, causing stasis in the aneurysm, with continuous flow through the parent vessel. The procedure and postoperative course were uneventful. A follow-up angiogram 2 weeks later showed complete disappearance of the aneurysm with preservation of the patency of the perforator. At the 6-month follow-up, the patient was asymptomatic and remained neurologically intact. CONCLUSION: We present the first case of a BTP aneurysm treated with the PED. The aneurysm was successfully occluded, and the patency of the feeding vessel was preserved. In light of the limitations of coiling and the hazards associated with microsurgery and parent vessel trapping, the PED may be a valuable option for BTP aneurysms. PMID- 24492663 TI - Parameters from preoperative overnight oximetry predict postoperative adverse events. AB - BACKGROUND: Continuous home monitoring of oxygen saturation has become a reliable and feasible practice. The objective of this study was to investigate the role of preoperative overnight oximetry in predicting postoperative adverse events. METHODS: Following research ethics board approval, consented patients underwent a preoperative overnight monitoring of oxygen saturation with a portable oximeter. Parameters from the oximetry data were extracted and their predictive performance for postoperative adverse events was evaluated. RESULTS: A total of 573 patients were studied with age: 60+/-12 years and 45% male. Oxygen desaturation index (ODI), cumulative time percentage with SpO2 <90% (CT90) and mean SpO2 were identified as significant predictors for postoperative adverse events. The privilege sensitivity, optimal predictive and privilege specificity cut-offs were: ODI: >3.0 events/h, >9.2 events/h and > 28.5 events/h; CT90: >0.1%, >1.1% and >7.2%; mean SpO2: <96.2%, <94.6% and <92.7%. The odds ratio for corresponding optimal cut-offs was: ODI 1.9 (95% CI: 1.4,2.7); CT90: 1.7 (95% CI: 1.2,2.4) and mean SpO2: 2.7 (95% CI: 1.9,3.8). The patients classified as high risk by ODI or CT90 or mean SpO2 had a significantly higher rate of postoperative adverse events. For ODI >28.5 vs. ODI ?28.5 events/h, the odds ratio adjusted with age, gender, body mass index and American Society of Anesthesiologists physical status was 2.2 (95% CI: 1.3-3.9). CONCLUSION: Patients with mean preoperative overnight SpO2 <92.7% or ODI >28.5 events/h or CT90 >7.2% are at higher risk for postoperative adverse events. Overnight oximetry could be a useful tool to stratify patients for the risk of postoperative adverse events. PMID- 24492664 TI - Brain ischemia with normal cerebral perfusion pressure after TBI: when to increase arterial carbon dioxide pressure? PMID- 24492665 TI - Mesenchymal stromal cell therapies: potential and pitfalls for ARDS. AB - Mesenchymal stem/stromal cells (MSCs) offer considerable promise as a novel therapeutic strategy for acute respiratory distress syndrome (ARDS). MSCs may be able to "reprogramme" the immune response to reduce destructive inflammatory elements while preserving the host response to pathogens. In addition, MSCs may be able to enhance the repair and resolution of lung injury. Resolution of ARDS is impeded by destruction of the integrity of the epithelial barrier, which inhibits alveolar fluid clearance and depletes surfactant. MSCs appear to restore epithelial and endothelial function, via both paracrine and cell contact dependent effects. ARDS is frequently a component of a generalized process resulting in dysfunction and failure of multiple organs. MSCs have been demonstrated to decrease injury and/or restore function in other organs, including the kidney, liver and heart. MSCs may directly attenuate bacterial sepsis, the commonest and most severe cause of ALI/ARDS. The fact that MSCs are in clinical studies for a wide range of disease processes is a clear advantage for translating MSCs to clinical testing in patients with ARDS. However, some important knowledge gaps exist that may impede clinical translation. The ultimate success of MSCs as a therapy for patients with ARDS will likely be dependent on a greater knowledge of their mechanisms of action and the determination of the optimal strategies for their use in the clinical setting. PMID- 24492666 TI - Regional anesthesia and enhanced recovery after surgery. AB - Regional anesthesia is associated with recognized physiological advantages; however trials evaluating its impact on postoperative outcomes have shown contrasting results, probably because these effects have not been utilized in a multimodal perioperative care program. Enhanced recovery has attracted clinical interest because of its standardized, coordinated, multidisciplinary perioperative care plan that incorporates several evidenced-based interventions with positive influence on postoperative patient recovery. A critical analysis of the published evidence is here presented in order to understand the role of regional anesthesia and analgesia as part of the multidisciplinary components of the enhanced recovery program. Clearly, there are synergistic benefits derived from integrating specific regional anesthetic and analgesic techniques with other perioperative elements characteristic of a particular surgical procedure. This challenge requires a team approach in delivering such integrated care, ultimately providing the best cure for patient. PMID- 24492667 TI - Severe phenotype of rapid-onset obesity, hypoventilation, hypothalamic dysfunction, and autonomic dysfunction syndrome. PMID- 24492668 TI - Photoautotrophic hydrogen production by eukaryotic microalgae under aerobic conditions. AB - Eukaryotic algae and cyanobacteria produce hydrogen under anaerobic and limited aerobic conditions. Here we show that novel microalgal strains (Chlorella vulgaris YSL01 and YSL16) upregulate the expression of the hydrogenase gene (HYDA) and simultaneously produce hydrogen through photosynthesis, using CO2 as the sole source of carbon under aerobic conditions with continuous illumination. We employ dissolved oxygen regimes that represent natural aquatic conditions for microalgae. The experimental expression of HYDA and the specific activity of hydrogenase demonstrate that C. vulgaris YSL01 and YSL16 enzymatically produce hydrogen, even under atmospheric conditions, which was previously considered infeasible. Photoautotrophic H2 production has important implications for assessing ecological and algae-based photolysis. PMID- 24492669 TI - New type of complex alkali and alkaline earth metal borates with isolated (B12O24)12) anionic group. AB - Compounds with isolated anionic groups often exhibit special linear and nonlinear optical properties and possess potential applications such as birefringence, second harmonic generation and stimulated Raman scattering crystals. In this paper, two new alkali and alkaline earth mixed-metal borates, Li3KB4O8 and LiNa2Sr8B12O24F6Cl, with isolated (B12O24)(12-) anionic groups have been successfully synthesized by spontaneous crystallization. Their structures were determined by single crystal X-ray diffraction and they both crystallize in the same space group, R3[combining macron]. More interestingly, further structure comparison shows that the discovered anhydrous borates with the (B12O24)(12-) groups also crystallize in the same space group R3[combining macron], which is related with the local symmetry of the (B12O24)(12-) groups. These structural features suggest that the crystal structures of the family of compounds depend more on their anionic groups. In addition, the property characterizations of the two new borates were investigated by TG-DSC, IR and UV-vis-NIR diffuse reflectance. PMID- 24492670 TI - Nutritional-risk scoring systems in the intensive care unit. AB - PURPOSE OF REVIEW: There is a need to develop a screening tool to assist clinical staff in deciding whether or not a patient in the ICU should be given nutrition support. The purpose of this review is to analyze the recent randomized trials in this context. RECENT FINDINGS: Five trials describe the effect of early supplemental parenteral nutrition. Four of these trials suggested a positive effect on clinical outcome. The results, including lengths of stay in the ICU (range on average: 3-17 days) and lengths of mechanical ventilation (range on average: 2-11 days), are discussed within the nutritional and metabolic framework of patients in intensive care. The limitations of existing screening tools, Nutritional Risk Screening 2002 (NRS 2002) and Nutrition risk in the critically ill (NUTRIC score) are described, and it also appears that the APACHE II score is not useful for predicting a possible benefit of nutrition support. SUMMARY: As a tentative conclusion, it is recommended to provide adequate nutrition support to severely ill patients who are likely to stay in the ICU with mechanical ventilation for a week or more. PMID- 24492671 TI - Noncompetitive inhibition of proton-coupled folate transporter by myricetin. AB - Myricetin is a flavonoid that has recently been suggested to interfere with the intestinal folate transport system. The present study was conducted to examine that possibility, focusing on its inhibitory effect on proton-coupled folate transporter (PCFT) as the molecular entity of the transport system. The uptake transport of folate was first examined in the Caco-2 cell as an intestinal epithelial cell model, and its carrier-mediated component, of which the Michaelis constant (Km) was 0.407 uM, was found to be noncompetitively inhibited by myricetin with an inhibition constant (Ki) of 61 uM. Consistent with that, folate transport by human PCFT stably expressed in Madin-Darby canine kidney II (MDCKII) cells, of which the Km was 1.246 uM, was also noncompetitively inhibited by myricetin with a Ki of 130 uM. Thus, myricetin was suggested to inhibit intestinal folate transport by acting noncompetitively on PCFT, although the Km and Ki were similarly shifted to some extent to be smaller in Caco-2 cells. Finally, epigallocatechin-3-gallate was also suggested to act in a noncompetitive manner as an inhibitory flavonoid. Care may need to be taken, therefore, in the ingestion of myricetin and some flavonoids to maintain the absorption of folate and antifolate drugs. PMID- 24492672 TI - Development of mice exhibiting hepatic microsomal activity of human CYP3A4 comparable to that in human liver microsomes by intravenous administration of an adenovirus vector expressing human CYP3A4. AB - Cytochrome P450 3A4 (CYP3A4) plays a crucial role in the pharmacokinetic and safety profiles of drugs. However, it is difficult to properly predict the pharmacokinetics and hepatotoxicity of drugs in humans using data from experimental animals, because the catalytic activities of CYP3A4 and other drug metabolizing enzymes differ between human and animal organs. In order to easily generate an animal model for proper evaluation of human CYP3A4-mediated drug metabolism, we developed a human CYP3A4-expressing adenovirus (Ad) vector based on our novel Ad vector exhibiting significantly lower hepatotoxicity (Ad-E4-122aT hCYP3A4). Intravenous administration of Ad-E4-122aT-hCYP3A4 at a dose of 2 * 10(11) virus particles/mouse produced a mouse exhibiting human CYP3A4 activity at a level similar to that in the human liver, as shown in the dexamethasone metabolic experiment using liver microsomes. The area under the curve (AUC) of 6betaOHD was 2.7-fold higher in the Ad-E4-122aT-hCYP3A4-administered mice, compared with the mice receiving a control Ad vector. This Ad vector-expressing human CYP3A4 would thus be a powerful tool for evaluating human CYP3A4-mediated drug metabolism in the livers of experimental animals. PMID- 24492673 TI - Competitive inhibition of AQP7-mediated glycerol transport by glycerol derivatives. AB - Aquaporin 7 (AQP7) is an aquaglyceroporin that has recently been found to operate as a facilitative carrier rather than a channel for glycerol, although its primary function is as a water channel. To probe into its substrate specificity, we examined the inhibitory effect of a series of acyl glycerol derivatives on glycerol transport mediated by human AQP7 stably expressed in Madin-Darby canine kidney II cells. According to kinetic analyses, AQP7-mediated glycerol transport was found to be competitively inhibited by monoacetin, monobutyrin and diacetin. Therefore, it may be possible that they all could be recognized as substrates by AQP7. The inhibition constant (Ki) of monoacetin (134 uM) was smaller than that of diacetin (420 uM), but greater than the Michaelis constant for glycerol (11.8 uM). Considering another finding that inhibition by triacetin was insignificant, it is likely that a decrease in the number of hydroxyl groups in the glycerol molecule by acetyl derivatization leads to a decrease in affinity for AQP7. The Ki of monobutyrin (80 uM) was, on the other hand, comparable with that of monoacetin, suggesting that the extension of the acyl chain by two hydrocarbon units does not have an impact on affinity for AQP7. PMID- 24492675 TI - Are equity aspects communicated in Nordic public health documents? AB - AIMS: To explore if the term equity was applied and how measures for addressing social inequalities in health and reducing inequity were communicated in selected Nordic documents concerning public health. METHODS: Documents from Denmark, Finland, Norway, and Sweden were collected and analysed by Nordic authors. Data included material from websites of ministries and authorities responsible for public health issues, with primary focus on steering documents, action programmes, and reports from 2001 until spring 2013. RESULTS: Most strategies applied in Danish, Finnish, and Swedish documents focused on the population in general but paid special attention to vulnerable groups. The latest Danish and Finnish documents communicate a clearer commitment to address social inequalities in health. They emphasise the social gradient and the need to address the social determinants in order to improve the position of disadvantaged groups. Norwegian authorities have paid increasing attention to inequity/social inequalities in health and initiated a new law in 2012 which aims to address the social gradient in a more clear way than seen elsewhere in the Nordic countries. CONCLUSIONS: In the Nordic countries, redistribution by means of universal welfare policies is historically viewed as a vital mechanism to improve the situation of vulnerable groups and level the social gradient. To establish the concept of equity as a strong concern and a core value within health promotion, it is important to be aware how policies can contribute to enable reduction of social health differences. PMID- 24492674 TI - A comparison of carboplatin and paclitaxel with cisplatinum and 5-fluorouracil in definitive chemoradiation in esophageal cancer patients. AB - BACKGROUND: In esophageal cancer (EC) patients who are not eligible for surgery, definitive chemoradiation (dCRT) with curative intent using cisplatinum with 5 fluorouracil (5-FU) is the standard chemotherapy regimen. Nowadays carboplatin/paclitaxel is also often used. In this study, we compared survival and toxicity rates between both regimens. PATIENTS AND METHODS: This multicenter study included 102 patients treated in five centers in the Northeast Netherlands from 1996 till 2008. Forty-seven patients received cisplatinum/5-FU (75 mg/m(2) and 1 g/m(2)) and 55 patients carboplatin/paclitaxel (AUC2 and 50 mg/m(2)). RESULTS: Overall survival (OS) was not different between the cisplatinum/5-FU and carboplatin/paclitaxel group {[P = 0.879, hazard ratio (HR) 0.97 [confidence interval (CI) 0.62-1.51]}, with a median survival of 16.1 (CI 11.8-20.5) and 13.8 months (CI 10.8-16.9). Median disease-free survival (DFS) was comparable [P = 0.760, HR 0.93 (CI 0.60-1.45)] between the cisplatinum/5-FU group [11.1 months (CI 6.9-15.3)] and the carboplatin/paclitaxel group [9.7 months (CI 5.1-14.4)]. Groups were comparable except clinical T stage was higher in the carboplatin/paclitaxel group (P = 0.008). High clinical T stage (cT4) was not related to OS and DFS in a univariate analysis (P = 0.250 and P = 0.201). A higher percentage of patients completed the carboplatin/paclitaxel regimen (82% versus 57%, P = 0.010). Hematological and nonhematological toxicity (>=grade 3) in the carboplatin/paclitaxel group (4% and 18%) was significantly lower than in the cisplatinum/5-FU (19% and 38%, P = 0.001). CONCLUSIONS: In this study, we showed comparable outcome, in terms of DFS and OS for carboplatin/paclitaxel compared with cisplatinum/5-FU as dCRT treatment in EC patients. Toxicity rates were lower in the carboplatin/paclitaxel group together with higher treatment compliance. Carboplatin/paclitaxel as an alternative treatment of cisplatinum/5 FU is a good candidate regimen for further evaluation. PMID- 24492676 TI - Photosynthetic competence of the marine aerobic anoxygenic phototrophic bacterium Roseobacter sp. under organic substrate limitation. AB - This paper describes the photosynthetic response of a Roseobacter strain of marine aerobic anoxygenic phototrophic bacteria to an organic substrate limitation. In batch cultures, higher values of the spheroidenone/bacteriochlorophyll a ratio were observed under substrate-deficient conditions. Interestingly, the maximum photochemical quantum efficiencies of the photosystem under substrate-deficient conditions using blue or green excitation were significantly higher than those under substrate-replete conditions. These results indicate that spheroidenone, which can absorb green light, may play an important role in their photosynthesis as a light-harvesting antenna pigment, and the photosynthetic competence of the Roseobacter strain can increase in an organic substrate-deficient environment. PMID- 24492677 TI - Ultra-pure single wall carbon nanotube fibres continuously spun without promoter. AB - We report a new strategy towards the control of carbon nanotube (CNT) structure and continuous fibre formation using a floating catalyst direct spinning CVD process. In the procedures used to date, a sulphur promoter precursor is added to significantly enhance the rate of CNT formation in the floating catalyst synthesis. Within the reaction zone, the rapidly grown nanotubes self-assemble into bundles, followed by their continuous spinning into fibres, yarns, films or tapes. In this paper we demonstrate a catalyst control strategy in the floating catalyst system, where the CNT formation process is independent of the presence of a promoter but leads to successful spinning of the macroscopic carbon nanotube assemblies with specific morphology, high purity (Raman D/G 0.03) and very narrow diameter range (0.8-2.5 nm). This can be achieved by the control of catalyst precursor decomposition and subsequent formation of homogeneous nano-sized catalyst particles. PMID- 24492680 TI - Chemical designs of functional photoactive molecular assemblies. AB - Molecular assemblies with well-defined structures capable of photo-induced electron transfer and charge transport or photochemical reactions are reviewed. Hierarchical supramolecular architectures, which assemble the modular units into specific spatial arrangements and facilitate them to work cooperatively, are vital for the achievement of photo-functions in these systems. The chemical design of molecular building blocks and noncovalent interactions exploited to realize supramolecular organizations are particularly discussed. Reviewing and recapitulating the chemical evolution traces of these accomplished systems will hopefully delineate certain fundamental design principles and guidelines useful for developing more advanced functions in the future. PMID- 24492678 TI - Rho GTPases in erythroid maturation. AB - PURPOSE OF REVIEW: This review summarizes our current understanding of the roles of Rho GTPases in early erythropoiesis, downstream of cytokine signaling, and in terminal erythroblast maturation and enucleation, as master regulators of the cytoskeleton and cytokinesis. RECENT FINDINGS: Similarities of structural and signaling requirements of erythroblast enucleation with the cytokinesis process have been confirmed and expanded in the last year, suggesting that enucleation is a form of asymmetric cell division. Myosin, the classic actin partner in cytokinesis, was shown to play an essential role in enucleation. Studies with multispectral high-speed cell imaging in flow demonstrated a sequential process requiring establishment of polarity through a unipolar microtubule spindle in orthochromatic erythroblasts, followed by Rac-directed formation of a contractile actomyosin ring and coalescence of lipid rafts between reticulocyte and pyrenocyte, steps which reiterate the choreography of cytokinesis. mDia2, a Rho effector known to play a role in enucleation, was also found essential for erythroblast cytokinesis as its deficiency in mice caused failure of primitive erythropoiesis and embryonic death. SUMMARY: Further elucidation of the role of Rho GTPases in the erythroid lineage development may reveal potential targets for improving red blood cell production in vivo and in vitro. PMID- 24492679 TI - Comparative survival analysis of adjuvant therapy with iodine-131-labeled lipiodol to hepatic resection of primary hepatocellular carcinoma: a meta analysis. AB - OBJECTIVE: Adjuvant therapies play an important role in delaying the recurrence of hepatocellular carcinoma (HCC) in patients with resectable tumor. Among the available options, use of radionuclides is an effective strategy. This meta analysis aims to examine the evidence pertaining to the effectiveness of adjuvant therapy with intra-arterial iodine-131-labeled lipiodol ((131)I-lipiodol) to hepatic resection of HCC. METHODS: A literature survey was conducted of multiple electronic databases including PubMed/Medline, Embase, CINAHL, Cochrane library, and Google Scholar using various combinations of the most relevant key terms. The odds ratio-based meta-analysis of recurrence and survival rates was performed with RevMan software (version 5.2) using a random-effect model. Heterogeneity was assessed by chi(2) and I(2) statistics. RESULTS: When compared with the resection only group, recurrence rates at 2 and 5 years were significantly lower in patients who received adjuvant therapy with intra-arterial I-lipiodol, with a corresponding odds ratio (95% confidence interval) of 0.45 (0.29-0.70) and 0.52 (0.32-0.85), respectively. The 3- and 5-year overall survival rates were found to be significantly higher in patients who received adjuvant therapy with (131)I lipiodol than in patients who were not given any adjuvant therapy. Between-study statistical heterogeneity was moderate. CONCLUSION: Postoperative adjuvant therapy with intra-arterial (131)I-lipiodol to hepatic resection of HCC significantly improves overall and disease-free survival rates and reduces recurrence rates. However, well-designed randomized trials are needed to arrive at conclusive evidence. PMID- 24492681 TI - Defect-induced supersolidity with soft-core bosons. AB - More than 40 years ago, Andreev, Lifshitz and Chester suggested the possible existence of a peculiar solid phase of matter, the microscopic constituents of which can flow superfluidly without resistance due to the formation of zero-point defects in the ground state of self-assembled crystals. Yet, a physical system where this mechanism is unambiguously established remains to be found, both experimentally and theoretically. Here we investigate the zero-temperature phase diagram of two-dimensional bosons with finite-range soft-core interactions. For low particle densities, the system is shown to feature a solid phase in which zero-point vacancies emerge spontaneously and give rise to superfluid flow of particles through the crystal. This provides the first example of defect-induced, continuous-space supersolidity consistent with the Andreev-Lifshitz-Chester scenario. PMID- 24492682 TI - Clinicians sometimes miss cases of latent primary adrenal insufficiency involving stress-related health changes. PMID- 24492683 TI - Incidence of malignancies in patients with IgG4-related disease. AB - OBJECTIVE: It has been discussed whether IgG4-related disease (IgG4-RD), including autoimmune pancreatitis (AIP), is associated with malignancy; however, the issue has not been clarified. METHODS: We analyzed 113 patients with IgG4-RD in whom malignancy was not diagnosed at the time of IgG4-RD onset and the follow up period was longer than six months. A total of 95 patients had AIP. The mean follow-up period was 73 months. The incidence of the observed malignancies was compared with the expected incidence in an age- and sex-matched general Japanese population based on the Vital Statistics of Japan. RESULTS: There were 15 malignancies (lung cancer in five patients, pancreatic cancer in two patients, gastric cancer in two patients, bile duct cancer in one patient, renal cancer in one patient, breast cancer in one patient, tongue cancer in one patient, malignant melanoma in one patient and acute myeloid leukemia in one patient) in 14 patients during the follow-up period. The calculated standardized incidence rate of the total malignancies was not significant, that is, 1.04 (95% CI 0.57 1.75). CONCLUSION: The incidence of total malignancies in IgG4-RD patients is similar to that observed in the general population. At present, it is reasonable to conclude that IgG4-RD is not associated with an increased incidence of total malignancies. PMID- 24492684 TI - Gender differences in the ratio of eicosapentaenoic acid to arachidonic acid in an inland prefecture, Tochigi: Tochigi Ryomo EPA/AA Trial in Coronary Artery Disease (TREAT-CAD). AB - OBJECTIVE: The plasma eicosapentaenoic acid to arachidonic acid ratio (EPA/AA), which is determined only by dietary intake, has been attracting attention as a new risk marker for coronary artery disease (CAD). A Japanese inland prefecture, Tochigi, ranks higher mortality rate from CAD and lower seafood consumption, compared to other prefectures. The aim of this study was to investigate the EPA/AA ratio in residents of Tochigi prefecture. METHODS: We measured the EPA/AA ratio in patients undergoing diagnostic coronary angiography, because of suspicion for having CAD, all of whom were residents of Tochigi prefecture or its bordering area. Patients A total of 428 patients were enrolled in 5 centers. RESULTS: The median value of the EPA/AA ratio in the study patients was 0.37, which seems to be lower than the value of the whole Japan. The EPA/AA ratio was similar in patients with and without CAD. Female patients had lower EPA/AA ratios than male patients. When subjects were divided into 10-year age groups, 30- to 39 year-old male and female patients displayed similar EPA/AA ratios. However, the ratios of 50- to 59-year old female patients (p=0.001) and 60- to 69-year old female patients (p=0.034) were significantly lower than those of age-matched male patients. CONCLUSION: In female residents of Tochigi prefecture, and particularly in menopausal female patients suspected of CAD, the EPA/AA ratio might be lower than male patients. EPA intake can help prevent cardiovascular events, especially in menopausal female residents of an area where the fish intake is low. PMID- 24492685 TI - History of stress-related health changes: a cue to pursue a diagnosis of latent primary adrenal insufficiency. AB - OBJECTIVE: Routine delays in the diagnosis of primary adrenal insufficiency (PAI) are well known and conceivably attributable to the absence of cues, other than anti-adrenal autoantibodies, to pursue subclinical PAI. Subclinical PAI is latent unless the afflicted patient encounters stress such as an acute illness, surgery, psychosocial burden, etc. It remains to be demonstrated whether a history of stress-related health changes is a useful cue to pursue a diagnosis of latent PAI. METHODS: The patients were selected for a history of recurrent symptoms, i.e., gastrointestinal symptoms, fatigue, or lassitude, aggravated by stress and alleviated by the removal of stress, and signs, i.e., weight loss, hypotension, and hyperpigmentation. As the early morning cortisol levels were low or low normal and the adrenocorticotropic hormone (ACTH) levels were within the reference ranges, provocation tests, i.e., insulin-induced hypoglycemia tests and low-dose (1 MUg) corticotropin tests (LDTs), were used to estimate the hypothalamus-pituitary-adrenal (HPA) axis status. Patients with the HPA axis dysfunction on two provocation tests were supplemented with physiologic doses of glucocorticoids (GCs). The effects of GC supplementation on stress-related health changes were observed. RESULTS: The ACTH levels after insulin-induced hypoglycemia were higher and the cortisol levels were lower in the patients than in the control subjects. The cortisol levels in the patients were increased less significantly by LDT than those observed in the control subjects. Stress-related health changes ceased to recur and signs, i.e., a low body weight, hypotension, and hyperpigmentation, were ameliorated following GC supplementation. CONCLUSION: A history of stress-related health changes is useful as a cue to pursue latent PAI in patients with low or low-normal early morning cortisol levels. PMID- 24492686 TI - Insulin resistance correlates with the arterial stiffness before glucose intolerance. AB - OBJECTIVE: The elevated plasma glucose level and/or insulin resistance in diabetes or impaired glucose tolerance play important roles in the pathogenesis of arterial stiffness. The present study investigated whether insulin resistance correlated with arterial stiffness before the development of glucose intolerance. METHODS: We conducted a cross-sectional analysis in 872 young to middle-age individuals with normal glucose tolerance (aged 36.2+/-8.5 years, BMI 24.6+/-3.1 kg/m2 [mean+/-SD]). The homeostasis model assessment (HOMA) index was used as a quantitative assessment of the fasting insulin resistance (FIR), and the plasma insulin level after glucose loading was adopted as an index of the post-challenge insulin resistance (PIR). The Matsuda index [ISI (composite)] was used as a measurement of the insulin sensitivity. The arterial stiffness assessed by the brachial-ankle pulse wave velocity (baPWV) was adopted to quantify its independent associations with insulin resistance. RESULTS: The univariate linear regression analysis indicated that the fasting plasma glucose level (FPG, beta = 68.2; 95% CI 40.9, 95.6; p<0.001), post-challenge plasma glucose level (PPG, beta = 25.3; 95% CI 15.6, 35.0; p<0.001), FIR (beta = 24.5; 95% CI 14.1, 35.0; p<0.001), PIR (beta=1.30; 95% CI 0.87, 1.73; p<0.001) and ISI (composite) (beta = -3.55; 95% CI -5.02, -2.07; p<0.001) were all significantly correlated with the baPWV. After adjustment for sex, age, BMI, heart rate, smoking, systolic blood pressure, total cholesterol, LDL-cholesterol and family history of diabetes, the multivariate linear regression analysis demonstrated that the PIR (model 1, beta = 0.39, p=0.038; model 2, beta = 0.39, p=0.035; model 3, beta = 0.39, p=0.035) was an independent contributor to the baPWV, while the FIR, FPG, PPG and ISI (composite) failed to show any significant contribution. CONCLUSION: The insulin resistance correlated with the arterial stiffness before glucose intolerance. PMID- 24492687 TI - Effects of alogliptin in chronic kidney disease patients with type 2 diabetes. AB - OBJECTIVE: Diabetes is a major risk factor for chronic kidney disease (CKD). In this study, we examined the effects of alogliptin on blood glucose control and the renal function in type 2 diabetes CKD patients. METHODS: We recruited 36 CKD patients with type 2 diabetes. The patients were followed up for six months after adding alogliptin. Blood biochemical, urine test and office BP values were obtained six months before and after the start of treatment. RESULTS: The mean HbA1c value was not decreased; however, the 1,5-AG values tended to improve (p=0.1023). The mean eGFR was unchanged. There were no significant changes in the patients with an eGFR of 60 mL/min/1.73 m2 or more (25 patients) or in the patients with an eGFR less than 60 mL/min/1.73 m2 (11 patients). A total of 15 patients were identified to have rapidly declining diabetic nephropathy, with an annual reduction in eGFR of 5 mL/min/1.73 m2 or more. The slope of the regression line for eGFR (-1.296 before starting treatment with alogliptin) was positive, increasing up to 0.08786. The eGFR values appeared to stop decreasing and positively reversed. The urinary albumin-to-creatinine ratio exhibited a downward trend. The effect on the renal function was independent of the levels of blood sugar, blood pressure and lipids. CONCLUSION: We examined the ability of alogliptin to maintain the renal function in patients with CKD complicated by type 2 diabetes. Our study suggests that alogliptin can be safely administered in patients with CKD. However, although we expected alogliptin to demonstrate renal protective effects, were unable to detect statistically significant differences. One reason for this finding is that there are few registered cases. PMID- 24492688 TI - Effects of recombinant human soluble thrombomodulin treatment for disseminated intravascular coagulation at a single institution--an analysis of 62 cases caused by infectious diseases and 30 cases caused by hematological diseases. AB - OBJECTIVE: Disseminated intravascular coagulation (DIC) is a clinical condition with high mortality that is characterized by the systemic activation of coagulation pathways resulting in multiple organ failure. Although no standard treatment for DIC has been established, recent reports have indicated that recombinant human soluble thrombomodulin (rTM) is effective against DIC. METHODS: To elucidate the clinical characteristics and outcomes of DIC, we retrospectively analyzed 92 DIC patients who were treated with rTM at Miyazaki Prefectural Hospital over a 4-year period (62 patients had infectious diseases and 30 patients had hematological diseases). A diagnosis of DIC was made based on the diagnostic criteria of the Japanese Association for Acute Medicine (JAAM) and Japanese Ministry of Health and Welfare (JMHW) for infectious diseases and hematological diseases, respectively. In addition to treating the underlying disease, rTM was administered for six consecutive days. RESULTS: In this study, 49 of the 92 DIC patients (53.3%) experienced resolution of DIC seven days after administration (46.8% patients with infectious disease and 66.7% with hematological disease). A higher survival rate was observed after a 28-day observation period in 69 of the 92 patients (75.0%) (72.6% of the patients with infectious disease and 80.0% of the patients with hematological disease). A lower DIC score at the initiation of rTM treatment was closely related to a higher rate of resolution of DIC. CONCLUSION: Our findings indicate that rTM therapy is an effective, safe and feasible treatment for DIC patients. Furthermore, making an accurate and early diagnosis of DIC and providing subsequent immediate treatment with rTM may improve the resolution of DIC. PMID- 24492690 TI - Three cases of vasospastic angina that developed following the initiation of corticosteroid therapy. AB - Three patients diagnosed as having remitting seronegative symmetrical synovitis with pitting edema syndrome, pemphigus erythematosus and idiopathic interstitial pneumonia were treated with oral prednisolone. Several weeks after starting the treatment, they experienced repeated chest pain attacks between midnight and early morning, although none of the patients had a past history of ischemic heart disease. One of the patients exhibited aggravation of symptoms soon after increasing the dose of prednisolone. A definitive diagnosis of vasospastic angina was made using electrocardiograms, coronary angiography and vasospasm provocation tests. These cases emphasize that clinicians should be aware of the possible occurrence of vasospastic angina following the initiation of corticosteroid therapy. PMID- 24492689 TI - Response to clopidogrel and its association with chronic kidney disease in noncardiogenic ischemic stroke patients. AB - OBJECTIVE: Noncardiogenic ischemic stroke patients with chronic kidney disease (CKD) are known to have a greater rate of ischemic stroke recurrence than those without. Although clopidogrel is often used to prevent the recurrence of noncardiogenic ischemic stroke, the relationship between the response to clopidogrel and CKD is unclear. In the present study, the relationship between the response to clopidogrel and the presence of CKD was investigated in noncardiogenic ischemic stroke patients. METHODS: A total of 129 noncardiogenic ischemic stroke patients receiving 75 mg/day of clopidogrel for >=1 week were evaluated. The VerifyNow P2Y12 Assay was used to measure the level of platelet aggregation induced by 20 MUM of adenosine diphosphate, and the degree of platelet aggregation and frequency of clopidogrel resistance were compared between 34 patients with CKD and 95 patients without CKD. Clopidogrel resistance was defined as a P2Y12 Reaction Units (PRU) value of >230 and/or % inhibition <20%. RESULTS: The PRU value was 201.9+/-91.3 in the patients with CKD and 163.3+/-86.4 in the patients without CKD (p=0.035). The frequency of a PRU value of >230 was 44.1% (15 patients) among the patients with CKD and 17.9% (17 patients) among those without CKD (p=0.002). The percent inhibition was 29.9%+/ 28.1% among the patients with CKD and 41.1%+/-28.0% among the patients without CKD (p=0.030). The frequency of % inhibition <20% was 47.1% (16 patients) among the patients with CKD and 26.3% (25 patients) among those without CKD (p=0.026). CONCLUSION: The present study showed that noncardiogenic ischemic stroke patients with CKD have a greater frequency of clopidogrel resistance, thus suggesting that the response to clopidogrel is diminished in these patients. PMID- 24492691 TI - Heart failure in which coronary spasms played an important role. AB - A 69-year-old woman was admitted for further examinations and treatment of chest pain. Emergency cardiac catheterization showed no significant stenosis on coronary angiograms; however, diffuse wall hypokinesis was observed on a left ventriculogram. After treating the patient's heart failure, cardiac catheterization was performed again. A spasm provocation test showed coronary spasms of the right and left coronary arteries. A right ventricular endomyocardial biopsy revealed denaturation and fibrosis of the myocardium under the endocardium, thus suggesting the presence of myocardial ischemia. This case highlights coronary spasms as a cause of heart failure. PMID- 24492692 TI - Hypophosphatemic osteomalacia due to drug-induced Fanconi's syndrome associated with adefovir dipivoxil treatment for hepatitis B. AB - We herein present the case of a 58-year-old Japanese man with Fanconi's syndrome with a 13-month history of bone pain in his ribs, hips, knees and ankles. He had been receiving low-dose adefovir dipivoxil (ADV) for the treatment of lamivudine resistant chronic hepatitis B virus infection for eight years and subsequently developed severe hypophosphatemia and proximal renal tubule dysfunction. Magnetic resonance imaging showed multiple insufficiency fractures in the ribs, ileum, tibia and calcaneus. Whole-body bone scintigraphy demonstrated increased uptake in those areas. Following dose reduction of ADV and the administration of treatment with calcitriol and phosphates, the patient's serum phosphate level increased and his clinical symptoms improved. Physicians prescribing ADV should carefully monitor the renal function and serum phosphate level. PMID- 24492693 TI - Convulsive seizures with a therapeutic dose of isoniazid. AB - An 86-year-old woman who had been treated for tuberculous peritonitis and pulmonary tuberculosis, exhibited a disturbance of consciousness and tonic-clonic convulsions seven days after the administration of the antituberculous drug isoniazid. As her serum vitamin B6 level was remarkably low, she was diagnosed with convulsive seizures due to vitamin B6 deficiency associated with isoniazid treatment. Seizures refractory to standard anticonvulsant therapy were controlled with the administration of pyridoxine. Most reported cases of isoniazid-induced convulsive seizures occurred as a result of an overdose due to attempted suicide. This report presents a case of convulsive seizures that occurred in association with the short-term administration of a therapeutic dose of isoniazid. PMID- 24492694 TI - An autopsy case of malignant pleural mesothelioma associated with nephrotic syndrome. AB - A 64-year-old man who had been exposed to asbestos was referred to our hospital for a detailed examination of left pleural effusion. A laboratory examination of the urine and blood revealed nephrotic syndrome. A thoracoscopic examination did not yield a definitive diagnosis. Twenty months later, a left pleural tumor became apparent, and the patient died of respiratory failure and cachexia. An autopsy revealed epithelioid malignant pleural mesothelioma. The glomeruli appeared normal under light microscopy. A review of the English literature revealed only three reports of malignant mesothelioma associated with minimal change nephrotic syndrome. The natural course of malignant mesothelioma with nephrotic syndrome has not been previously reported. PMID- 24492695 TI - Relapse of acute myeloid leukemia mimicking autoimmune pancreatitis after bone marrow transplantation. AB - We herein present the case of a 30-year-old man who developed recurrent pancreatitis and chronic graft-versus-host disease following unrelated bone marrow transplantation for acute myeloid leukemia (AML) with t(16;21)(p11;q22). Autoimmune pancreatitis was initially suspected due to the radiological findings and lack of response to gabexate mesilate and antibiotics. An examination of specimens successfully obtained via endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) demonstrated invasion of AML cells in the pancreatic tissue. EUS-FNA is a less invasive method and a particularly useful diagnostic tool in severely ill patients. PMID- 24492696 TI - A novel frameshift mutation in exon 4 causing a deficiency of high-molecular weight kininogen in a patient with splenic infarction. AB - High-molecular-weight kininogen (HMWK) deficiency is a very rare hereditary disorder. We herein report a case of HMWK deficiency with splenic infarction. The HMWK activity of the proband was markedly decreased (0.9%). Direct sequencing of his HMWK gene showed a homozygous "TC" insertion at c523-524 in exon 4. This insertion led to an amino acid substitution, Ser175Ser, resulting in a frameshift mutation and a premature stop codon in amino acid 183. Furthermore, the HMWK activity was also reduced in the patient's three children, who exhibited the heterozygous "TC" insertion at c523-524 in exon 4. This is the first report of this gene alteration in a patient with HMWK deficiency. PMID- 24492697 TI - Glossopharyngeal nerve and vagus nerve palsies associated with influenza vaccination. AB - We herein report the first case of glossopharyngeal nerve and vagus nerve palsies that appeared after an influenza vaccination. A 15-year-old boy developed dysphagia and dysarthria seven days after receiving an inoculation of the inactivated influenza vaccine. Massive intravenous immunoglobulin (IVIg) treatment was applied, as the patient's symptoms were considered to be immunological adverse effects of the influenza vaccine. He responded well to IVIg, and the symptoms immediately diminished. The mechanisms underlying the development of neurologic symptoms following vaccination are difficult to determine; however, providing immediate immunological treatment, such as IVIg, is effective and beneficial in countering these symptoms. PMID- 24492698 TI - Acute kidney injury in a patient with polyarteritis nodosa and multiple myeloma. AB - We herein report the case of a Japanese man with polyarteritis nodosa (PAN) accompanied by multiple myeloma (MM). The patient was diagnosed with PAN. Concurrently, IgG kappa paraprotein was detected, and bone marrow changes indicative of MM were observed. Prednisolone (PSL) administered at a dose of 30 mg/day was initiated; however, the serum creatinine level increased. In spite of increasing the dose of PSL to 45 mg/day and initiating treatment with double filtration plasmapheresis, the patient's renal dysfunction continued to progress and haemodialysis was introduced. He died from pneumonia 12 months after admission. We conclude that renal failure is an important risk factor in the prognosis of PAN accompanied by MM. PMID- 24492699 TI - Kartagener's syndrome and rheumatoid arthritis. AB - We herein present the case of a 47-year-old woman with rheumatoid arthritis (RA) complicated by Kartagener's syndrome (KS). Although her RA disease activity score (DAS28-CRP) decreased following the administration of periodontitis treatment and etanercept, she did not achieve symptom relief or DAS28-CRP remission. After undergoing surgery for chronic sinusitis, her articular symptoms improved and the DAS28-CRP declined to the level of remission. Patients with KS may develop respiratory infections due to an impaired defense mechanism against microbes in the airway. Therefore, in patients with RA complicated by KS, comprehensive management of infection, including surgical therapy for sinusitis, is needed to reduce the RA disease activity. PMID- 24492700 TI - Mediastinal fibrosis and positive antineutrophil cytoplasmic antibodies: coincidence or common etiology? AB - Retroperitoneal fibrosis (RPF) with positive antineutrophil cytoplasmic antibodies (ANCA) has been reported in several cases. We herein present the case of a 52-year-old woman who was diagnosed with mediastinal fibrosis (MF) on a thoracoscopic surgical biopsy. The patient had positive myeloperoxidase ANCA and thereafter developed crescentic glomerulonephritis, which was considered to be a form of ANCA-related nephritis. Both the MF and crescentic glomerulonephritis favorably responded to immunosuppressive therapy. These findings suggest a common pathogenesis of these disorders involving ANCA positivity, as reported in patients with RPF. PMID- 24492701 TI - Spontaneous meningitis due to Streptococcus salivarius subsp. salivarius: cross reaction in an assay with a rapid diagnostic kit that detected Streptococcus pneumoniae antigens. AB - Streptococcus salivarius subsp. salivarius occasionally causes meningitis associated with iatrogenic or traumatic events. We herein describe a case of meningitis caused by this organism in a patient without any apparent risk factors. In an assay of the patient's cerebrospinal fluid, cross-reaction occurred with Streptococcus pneumoniae antigen-coated latex particles in the Pastorex Meningitis Kit. In the in vitro assays, three of the five clinically isolated S. salivarius strains showed cross-reactions with the kit, indicating that these strains expressed pneumococcal antigen-like antigens. This case shows that meningitis caused by S. salivarius can occur spontaneously and it may sometimes be misdiagnosed as S. pneumoniae infection. PMID- 24492702 TI - A brilliant sandwich type fluorescent nanostructure incorporating a compact quantum dot layer and versatile silica substrates. AB - A "hydrophobic layer in silica" structure was designed to integrate a compact quantum dot (QD) layer with high quantum yield into scalable silica hosts containing desired functionality. This was based on metal affinity driven assembly of hydrophobic QDs with versatile silica substrates and homogeneous encapsulation of organosilica/silica layers. PMID- 24492705 TI - Retraction: Mechanistic analysis of the role of BLCA-4 in bladder cancer pathobiology. PMID- 24492704 TI - A transgenic mouse model for early prostate metastasis to lymph nodes. AB - The emergence of recurrent, metastatic prostate cancer following the failure of androgen-deprivation therapy represents the lethal phenotype of this disease. However, little is known regarding the genes and pathways that regulate this metastatic process, and moreover, it is unclear whether metastasis is an early or late event. The individual genetic loss of the metastasis suppressor, SSeCKS/Gravin/AKAP12 or Rb, genes that are downregulated or deleted in human prostate cancer, results in prostatic hyperplasia. Here, we show that the combined loss of Akap12 and Rb results in prostatic intraepithelial neoplasia (PIN) that fails to progress to malignancy after 18 months. Strikingly, 83% of mice with PIN lesions exhibited metastases to draining lymph nodes, marked by relatively differentiated tumor cells expressing markers of basal (p63, cytokeratin 14) and luminal (cytokeratin 8 and androgen receptor) epithelial cells, although none expressed the basal marker, cytokeratin 5. The finding that PIN lesions contain increased numbers of p63/AR-positive, cytokeratin 5-negative basal cells compared with WT or Akap12-/- prostate lobes suggests that these transitional cells may be the source of the lymph node metastases. Taken together, these data suggest that in the context of Rb loss, Akap12 suppresses the oncogenic proliferation and early metastatic spread of basal-luminal prostate tumor cells. PMID- 24492706 TI - Role of different platinum precursors on the formation and reaction mechanism of FePt nanoparticles and their electrocatalytic performance towards methanol oxidation. AB - We report the formation mechanism of FePt nanoparticles (NPs) by a high temperature polyol method using an equimolar ratio of Fe and Pt-precursor with different Pt-precursors. Pt(acac)2, PtCl2, PtCl4 and H2PtCl6.H2O were used as Pt precursors and Fe(acac)3 as the only Fe-precursor. Different stoichiometric compositions along with variation in size were obtained by using different precursors of Pt. Nearly, equiatomic FePt having a size ~2 nm was formed with Pt(acac)2. However, Pt rich phases were formed using all other precursors with a size ranging between 3.6 to 6.4 nm. It was found that the atomic percentage (at%) of Fe in the FePt NPs depends on the reaction parameters. The decomposition behaviour of Fe and Pt-precursors were examined by vibrating sample magnetometer and thermogravimetric measurements. A possible reaction mechanism for Fe depleted FePt formation is proposed which suggests that the reduction potential and decomposition behaviour of the organic and inorganic salts of Pt significantly modify the nucleation behaviour. The electrocatalytic properties of all the four nanomaterials towards methanol oxidation have been investigated by cyclic voltammetry. It is found that Fe19Pt81 with an average size of 6.2 nm shows the highest catalytic response. PMID- 24492707 TI - Symbiosis as a general principle in eukaryotic evolution. AB - Eukaryotes have evolved and diversified in the context of persistent colonization by non-pathogenic microorganisms. Various resident microorganisms provide a metabolic capability absent from the host, resulting in increased ecological amplitude and often evolutionary diversification of the host. Some microorganisms confer primary metabolic pathways, such as photosynthesis and cellulose degradation, and others expand the repertoire of secondary metabolism, including the synthesis of toxins that confer protection against natural enemies. A further route by which microorganisms affect host fitness arises from their modulation of the eukaryotic-signaling networks that regulate growth, development, behavior, and other functions. These effects are not necessarily based on interactions beneficial to the host, but can be a consequence of either eukaryotic utilization of microbial products as cues or host-microbial conflict. By these routes, eukaryote-microbial interactions play an integral role in the function and evolutionary diversification of eukaryotes. PMID- 24492708 TI - The impact of history on our perception of evolutionary events: endosymbiosis and the origin of eukaryotic complexity. AB - Evolutionary hypotheses are correctly interpreted as products of the data they set out to explain, but they are less often recognized as being heavily influenced by other factors. One of these is the history of preceding thought, and here I look back on historically important changes in our thinking about the role of endosymbiosis in the origin of eukaryotic cells. Specifically, the modern emphasis on endosymbiotic explanations for numerous eukaryotic features, including the cell itself (the so-called chimeric hypotheses), can be seen not only as resulting from the advent of molecular and genomic data, but also from the intellectual acceptance of the endosymbiotic origin of mitochondria and plastids. This transformative idea may have unduly affected how other aspects of the eukaryotic cell are explained, in effect priming us to accept endosymbiotic explanations for endogenous processes. Molecular and genomic data, which were originally harnessed to answer questions about cell evolution, now so dominate our thinking that they largely define the question, and the original questions about how eukaryotic cellular architecture evolved have been neglected. This is unfortunate because, as Roger Stanier pointed out, these cellular changes represent life's "greatest single evolutionary discontinuity," and on this basis I advocate a return to emphasizing evolutionary cell biology when thinking about the origin of eukaryotes, and suggest that endogenous explanations will prevail when we refocus on the evolution of the cell. PMID- 24492711 TI - Cellular reprogramming. AB - Nuclear reprogramming technology was first established more than 50 years ago. It can rejuvenate somatic cells by erasing the epigenetic memories and reconstructing a new pluripotent order. The recent discovery reviewed here that induced pluripotency can be achieved by a small set of transcription factors has opened up unprecedented opportunities in the pharmaceutical industry, the clinic, and laboratories. This technology allows us to access pathological studies by using patient-specific induced pluripotent stem (iPS) cells. In addition, iPS cells are also expected to be a rising star for regenerative medicine, as sources of transplantation therapy. PMID- 24492709 TI - Retromer: a master conductor of endosome sorting. AB - The endosomal network comprises an interconnected network of membranous compartments whose primary function is to receive, dissociate, and sort cargo that originates from the plasma membrane and the biosynthetic pathway. A major challenge in cell biology is to achieve a thorough molecular description of how this network operates, and in so doing, how defects contribute to the etiology and pathology of human disease. We discuss the increasing body of evidence that implicates an ancient evolutionary conserved complex, termed "retromer," as a master conductor in the complex orchestration of multiple cargo-sorting events within the endosomal network. PMID- 24492710 TI - Genomic imprinting in mammals. AB - Genomic imprinting affects a subset of genes in mammals and results in a monoallelic, parental-specific expression pattern. Most of these genes are located in clusters that are regulated through the use of insulators or long noncoding RNAs (lncRNAs). To distinguish the parental alleles, imprinted genes are epigenetically marked in gametes at imprinting control elements through the use of DNA methylation at the very least. Imprinted gene expression is subsequently conferred through lncRNAs, histone modifications, insulators, and higher-order chromatin structure. Such imprints are maintained after fertilization through these mechanisms despite extensive reprogramming of the mammalian genome. Genomic imprinting is an excellent model for understanding mammalian epigenetic regulation. PMID- 24492712 TI - Neuronal signaling through endocytosis. AB - The distinctive morphology of neurons, with complex dendritic arbors and extensive axons, presents spatial challenges for intracellular signal transduction. The endosomal system provides mechanisms that enable signaling molecules initiated by extracellular cues to be trafficked throughout the expanse of the neuron, allowing intracellular signals to be sustained over long distances. Therefore endosomes are critical for many aspects of neuronal signaling that regulate cell survival, axonal growth and guidance, dendritic branching, and cell migration. An intriguing characteristic of neuronal signal transduction is that endosomal trafficking enables physiological responses that vary based on the subcellular location of signal initiation. In this review, we will discuss the specialized mechanisms and the functional significance of endosomal signaling in neurons, both during normal development and in disease. PMID- 24492713 TI - Adaptor protein STAP-2 modulates cellular signaling in immune systems. AB - Signal-transducing adaptor protein-2 (STAP-2) is a recently identified adaptor protein that contains a pleckstrin homology (PH), Src homology 2 (SH2)-like domains, and proline-rich regions in its C-terminal. STAP-2 belongs to a family of STAP adaptor proteins and plays a crucial role in a variety of cellular signal transduction pathways by interacting with signaling or transcriptional molecules. STAP-2, in particular, regulates both the innate and adaptive immune systems. STAP-2 functionally interacts with signal transducers and activators of transcription 3 (STAT3) and STAT5 in cytokine signaling pathways. In addition, STAP-2 also binds to myeloid differentiation factor 88 (MyD88) and inhibitor (I)kappaB kinase alpha/beta (IKK-alpha/beta) in Toll-like receptor4 (TLR4) signaling, and enhances the production of inflammatory cytokines in macrophages. More importantly, experiments using STAP-2 deficient mice show that STAP-2 modulates several T-cell functions such as cell motility, survival and death. It is also reported that STAP-2 controls the immunoglobulin E (IgE)-mediated allergy response. This accumulated evidence indicates that adaptor protein STAP-2 is an important modulator of both the innate and adaptive immune systems. PMID- 24492714 TI - Nanoparticles for cancer therapy. Foreword. PMID- 24492715 TI - Nanoparticles consisting of tocopheryl succinate are a novel drug-delivery system with multifaceted antitumor activity. AB - Tumor heterogeneity hampers the clinical efficacy of cancer chemotherapy. Therefore, it is necessary to develop a multifaceted, rational treatment strategy with the potential to modulate overall tumor heterogeneity. Since combination therapy using several drugs has been shown to have enhanced therapeutic effects compared with monotherapy, combining agents with different antitumor effects would be a multifaceted form of therapy to overcome tumor heterogeneity. Therefore, the development of effective drug-delivery system (DDS) carriers for combination therapy is required. The ideal DDS carrier for combination therapy should itself have antitumor activity in addition to the ability to deliver drugs to tumors. alpha-Tocopheryl succinate (TS), a succinic acid ester of alpha tocopherol, has attracted attention as a unique antitumor agent, and TS itself can form nanoparticles. In this review, we introduce nanoparticles consisting of TS as a novel DDS carrier with multifaceted antitumor effects for combination therapy. PMID- 24492716 TI - Systemic delivery of small RNA using lipid nanoparticles. AB - Gene silencing mediated by RNA interference (RNAi) is expected to have a beneficial impact on the treatment of many diseases because of its potency, selectivity and versatility. To maximize the potential of RNAi effectors such as small interfering RNA and microRNA in clinical therapy, the development of a practical delivery system is required, especially for systemic administration. Recent studies demonstrated that chemical modification of these small RNAs and/or encapsulation of them into lipid nanoparticles is a promising strategy to achieve targeted delivery via systemic administration. In this review article, we introduce recent progress of the research on systemic delivery systems for RNAi therapeutics and consider crucial elements for the design of lipid nanoparticles as a small RNA vector. PMID- 24492717 TI - Selective delivery of oxaliplatin to tumor tissue by nanocarrier system enhances overall therapeutic efficacy of the encapsulated oxaliplatin. AB - Oxaliplatin (trans-l-diaminocyclohexane oxalatoplatinum; l-OHP), a third generation platinum antitumor drug, is currently approved in combination with 5 flurouracil (5-FU)/leucovorin (FOLFOX) for standard first- and second-line treatment of metastatic or advanced-stage colorectal cancer. Despite l-OHP's better tolerability in comparison with other platinum compounds such as cisplatin and carboplatin, its clinical efficiency is limited by the dose-limiting side effects including cumulative neurotoxicity and acute dysesthesias. In addition, like other platinum chemotherapeutic agents, l-OHP therapy is limited by reduced accumulation levels in tumor tissues, nonselective accumulation in healthy organs and/or tissues, inactivation by conjugation with glutathione, and the development of drug resistance. Accordingly, successful outcome of cancer treatment using l OHP requires selective delivery of a relatively high concentration of the drug to tumor tissues. In this review we focus on utilization of different drug-delivery vehicles such as liposomes, polymeric nanocarriers, and carbon nanotubes in enhancing selective delivery of l-OHP to tumor tissues and consequently improving overall efficacy of l-OHP-containing drug-delivery systems. PMID- 24492718 TI - Combination of nanoparticles with physical stimuli toward cancer therapy. AB - Drug delivery systems represent an important strategy for cancer treatment. The targeted delivery of drugs is required for effective and safe cancer therapy. In cancer therapy, the target cells include cancer cells and immunocompetent cells such as antigen presenting cells. Anticancer drugs utilized include small molecular drugs, proteins and nucleic acid medicines. In order to deliver these drugs into the target cells, various nanoparticles have been developed. However, the efficacy of the nanoparticulate system itself is generally insufficient for the safe and effective treatment of cancer. For example, polyethylene glycol (PEG)-modified (PEGylated) nanoparticles accumulate in cancerous tissues; however, the PEG moiety on the surface of the nanoparticles disturbs cellular uptake, which is known as the 'PEG dilemma.' Thus, additional strategies such as receptor-mediated targeting are necessary to improve the delivery and cellular uptake of nanoparticles. Among additional strategies, in this review we have focused on the combination of nanoparticles with various physical stimuli, such as electric pulse and ultrasound, to improve the targeted delivery of the nanoparticles. PMID- 24492719 TI - Effects on serum uric acid by difference of the renal protective effects with atorvastatin and rosuvastatin in chronic kidney disease patients. AB - Hyperuricemia and hyperlipidemia have attracted attention as progression factors for chronic kidney disease (CKD). In the drug treatment of hyperuricemia and hyperlipidemia complications, Atorvastatin (ATV), which inhibits urinary protein, increases glomerular filtration rate (GFR) and has renal protective effects, and Rosuvastatin (ROS) were found be suitable because they promote serum uric acid (SUA) excretion. However, these drugs were administered at very high doses in previous studies. In this study, we have investigated the effects of ATV or ROS on renal protective effects and their SUA levels before and three months after each drug administration in CKD patients. We retrospectively investigated outpatients presenting with CKD (stages 3) on the basis of their electronic medical records as subjects. Estimated GFR (eGFR) was significantly increased after ATV administration, whereas no change in eGFR was observed following ROS administration. Furthermore, SUA levels significantly decreased after ATV administration, whereas no changes were observed following ROS administration. Therefore, it may be not necessary to administer drugs that lower the SUA levels to patients presenting with hyperuricemia and hyperlipidemia complications associated with moderate renal failure, such as patients with at least stage 3 CKD. We consider that, by selecting ATV, the renal protective effects and SUA lowering effect would be sufficient. PMID- 24492720 TI - Antiemetic effect of a potent and selective neurokinin-1 receptor antagonist, FK886, on cisplatin-induced acute and delayed emesis in ferrets. AB - The antiemetic effect of a potent and selective neurokinin-1 (NK1) receptor antagonist, FK886 ([3,5-bis(trifluoromethyl)phenyl][(2R)-2-(3-hydroxy-4 methylbenzyl)-4-{2-[(2S)-2-(methoxymethyl)morpholin-4-yl]ethyl}piperazin-1 yl]methanone dihydrochloride), on cisplatin-induced acute and delayed emesis in ferrets was studied. Intravenous administration of FK886 dose-dependently inhibited cisplatin (10 mg/kg)-induced acute emesis with a minimum effective dose (MED) of 0.32 mg/kg. In the same study, oral FK886 administered 8 h prior to cisplatin also dose-dependently inhibited the acute emesis during the 4-h observation period with an MED of 3.2 mg/kg. Further, when given by repeated oral administration of >=1.6 mg/kg at 12-h intervals, the first dose being administered 1 min before cisplatin, FK886 significantly decreased the number of emetic responses in cisplatin (5 mg/kg)-induced delayed emesis. In the same study, oral FK886 (3.2 mg/kg) repeatedly administrated at 12-h intervals, the first dose being administered 36 h post cisplatin, also significantly attenuated the delayed emesis. Pharmacokinetic data in ferrets showed that plasma FK886 reached a maximum concentration within 0.5 h of administration, suggesting rapid oral absorption. In addition, rapid brain penetration of FK886 was suggested by complete and near complete inhibition of GR73632- and copper sulfate-induced emesis, respectively, by low-dose intravenous FK886 administered shortly before the emetogens. These results suggest that FK886 is an orally available NK1 receptor antagonist which is effective against both the acute and delayed emesis induced by cisplatin. Because of its therapeutic efficacy on the delayed emesis and rapid brain distribution after oral administration, FK886 may have potential as an antiemetic agent that can be used for interventional treatment of chemotherapy-induced delayed emesis. PMID- 24492721 TI - 20S-Ginsenoside Rh2 induces apoptosis in human Leukaemia Reh cells through mitochondrial signaling pathways. AB - 20(S)-Ginsenoside Rh2 (GRh2) and ginsenoside Rg3 (GRg3) are members of the protopanaxadiol family and have been investigated for possible chemopreventive activity. This study explored the biological and apoptotic mechanisms induced by 20(S)-GRh2 in human acute leukaemia line-Reh cells. Reh cells were treated with different concentration of 20(S)-GRh2 in vitro. Cell viability was determined by Cell Counting Kit-8 and Annexin V/7-AAD assays. Mitochondrial membrane potential (MMP) was examined through JC-1 staining. Activation of caspases associated with the mitochondria-mediated apoptosis pathway was determined by Western blot. We observed that survival of Reh cells decreased after exposure to 20(S)-GRh2 in a concentration-dependent manner. Moreover, 20(S)-GRh2 can induce mitochondria depolarization of Reh cells as evident in the shift in JC-1 fluorescence from red to green. In addition, 20(S)-GRh2 induced the release of mitochondrial cytochrome c and activation of caspase-9 and caspase-3 in Reh cells. These results indicate that 20(S)-GRh2 could induce apoptosis through the mitochondrial pathway, demonstrating its potential as a chemotherapeutic agent for leukaemia therapy. PMID- 24492722 TI - (2S)-2'-Methoxykurarinone inhibits osteoclastogenesis and bone resorption through down-regulation of RANKL signaling. AB - (2S)-2'-Methoxykurarinone (MK), a compound isolated from the roots of Sophora flavescens, has various physiological properties, such as anti-inflammatory, antipyretic, antidiabetic, and antineoplastic effects. However, the effect of S. flavescens-derived MK on osteoclastogenesis remains unknown. Therefore, we examined the effect and mechanism of action of MK on receptor activator of nuclear factor-kappaB ligand (RANKL)-induced osteoclast differentiation and bone resorption. MK inhibited osteoclast differentiation in bone marrow cell osteoblast cocultures but did not affect the RANKL-to-osteoprotegerin ratio induced by osteoclastogenic factors in osteoblasts. MK also inhibited RANKL induced osteoclast differentiation from bone marrow macrophages in a dose dependent manner, without cytotoxicity. Pretreatment with MK significantly suppressed the Akt, p38, c-Jun N terminal kinase (JNK), c-Fos, and nuclear factor of activated T cells c1 (NFATc1) pathways and inhibited the bone-resorbing activity of mature osteoclasts. These results collectively suggest that MK inhibits osteoclast differentiation and bone resorption through RANKL-induced mitogen-activated protein kinases (MAPKs) and c-Fos-NFATc1 signaling pathways. PMID- 24492723 TI - Novel diagnostic method of peritoneal injury using dual macromolecular markers. AB - Long-term peritoneal dialysis (PD) frequently produces morphological and functional changes of the peritoneum, which makes continuation of PD difficult. Moreover, the progression of peritoneal injury causes complications and poor prognosis. Since therapeutic treatments for peritoneal injury during PD have yet to be established, it is important to diagnose peritoneal injury as early as possible. The aim of this study was to develop a method of monitoring peritoneal function to diagnose peritoneal injury. Model rats of peritoneal injury were prepared by intraperitoneal injection of methylglyoxal (MGO) for five consecutive days. Then, marker substances of various molecular weights (phenolsulfonphthalein, fluorescein isothiocyanate-dextran (FD)-10, FD-40, FD-70, FD-2000 or tetramethylrhodamine-dextran (RD)-10) were injected into the peritoneal cavity. At 120 min after injection, the remaining amounts of all marker substances were significantly decreased in the MGO-treated rats compared with those in the vehicle-treated rats. Molecular weight dependence of the peritoneal permeability was observed. A substance with a molecular weight of approximately 10000 was found to be suitable to diagnose peritoneal injury. Moreover, coadministration of RD-10 with FD-2000 enabled us to monitor enhanced peritoneal permeability and the transfer of water simultaneously, without the recovery of whole PD fluid, even in the case of different ultrafiltration volumes. We demonstrated the usefulness of administering substances to evaluate peritoneal permeability and the transfer of water simultaneously to diagnose peritoneal injury. This study should be valuable for safe and effective PD. PMID- 24492724 TI - Berberine inhibits fluphenazine-induced up-regulation of CDR1 in Candida albicans. AB - Over-expression of the Candida drug resistance gene CDR1 is a common mechanism generating azole-resistant Candida albicans in clinical isolates. CDR1 is transcriptionally activated through the binding of the transcription factor Tac1p to the cis-acting drug-responsive element (DRE) in its promoter. We previously demonstrated that the combination of fluconazole (FLC) and berberine (BBR) produced significant synergy when used against FLC-resistant C. albicans in vitro. In this study, we found that BBR inhibited both the up-regulation of CDR1 mRNA and the transport function of Cdr1p induced by fluphenazine (FNZ). Further, electrophoretic mobility shift assays suggested that the transcription activation complex of protein-DRE was disrupted by BBR, and electrospray ionization mass spectrometry analysis showed that BBR bound to the DRE of CDR1. Thus we propose that BBR inhibits the FNZ-induced transcriptional activation of CDR1 in C. albicans by blocking transcription factor binding to the DRE of CDR1. These results contribute to our understanding of the mechanism of synergistic effect of BBR and FLC. PMID- 24492725 TI - Components of foods inhibit a drug exporter, human multidrug and toxin extrusion transporter 1. AB - Human multidrug and toxic compounds extrusion transporter 1 (hMATE1/SLC47A1) is a H(+)-coupled organic cation exporter responsible for the final step of excretion of various xenobiotics at the kidney and liver. In this study, effects of dietary constituents on hMATE1 mediated drug transport were examined to evaluate possible food-drug interactions. Bergamottin inhibited hMATE1 mediated tetraethyl ammonium transport activity, with a Ki of 98.7 uM. Coumarins, flavonols, and catechin inhibited hMATE1 activity. Among 23 compounds tested, isorhamnetin was the strongest inhibitor of hMATE1 with the Ki of 0.32 uM in a competitive manner. Since isorhamnetin is abundant in Ginkgo biloba that is widely used for herbal supplements, the findings suggest the potential hMATE1 related food-drug interactions. PMID- 24492726 TI - Histological protection by nilvadipine against neurotoxicity induced by NOC12, a nitric oxide donor, in the rat retina. AB - In the present study, we histologically examined the effects of nilvadipine on neuronal injury induced by intravitreal (i.v.) N-methyl-D-aspartate (NMDA) (200 nmol/eye) and intravitreal NOC12 (400 nmol/eye), a nitric oxide donor, in the rat retina. Morphometric evaluation at 7 d after injection of NMDA or NOC12 showed that treatment with nilvadipine (1 mg/kg, i.v.) 15 min prior to injection of NMDA or NOC12 dramatically reduced the retinal damage. These results suggest that nilvadipine protects neurons against excitotoxic injury in the rat retina in vivo at least in part via an antioxidative effect. PMID- 24492727 TI - Detection of antibodies to human T-cell leukemia virus types 1 and 2 in breast milk from East Asian women. AB - We investigated the incidence of human T-cell leukemia virus type I (HTLV-1) infection in a total of 17 regions in four countries, including 13 regions in Japan, as well as Korea (Seoul and Busan), China, and Vietnam, by testing breast milk using a particle agglutination assay (PA) and line immunoassay (LIA). Among 266 samples from Japan, 24 (9.0%) were positive on PA and 3 (1.1%) were positive on LIA. Among 50 samples from Seoul, 2 were positive on PA and 1 was positive on LIA. In contrast, all 50 samples from Busan were negative on both tests, suggesting the maldistribution of HTLV-1 infectants in South Korea. The numbers of positive samples were 2/91 on PA and 1/91 on LIA for China and 1/88 on both PA and LIA for Vietnam. In China, one sample with a high probability of HTLV-2 infection was identified by LIA and synthetic peptide enzyme-linked immunosorbent assay (ELISA). We examined HTLV-1 antibody in breast milk samples using commercially available test kits, suggesting the existence of HTLV-1 carriers in endemic areas in Southeast Asia and an HTLV-2 infectant in China. As a part of human ethno-epidemiological research, these results constitute valuable epidemiological data. Further studies on the sensitivity, specificity, and reliability of assays using antibodies to HTLV-1 and 2 in breast milk will be necessary for large-scale epidemiological surveys of HTLV infection. PMID- 24492728 TI - Asterosaponins from the Starfish Astropecten monacanthus suppress growth and induce apoptosis in HL-60, PC-3, and SNU-C5 human cancer cell lines. AB - Using various chromatographic experiments, six asterosaponins (1-6) were isolated from the MeOH extract of the Vietnamese starfish Astropecten monacanthus. The cytotoxic activities of the MeOH extract and six asterosaponins were evaluated on three human cancer cell lines, HL-60 (promyelocytic leukemia), PC-3 (prostate cancer), and SNU-C5 (colorectal cancer). Relative to the effects of the postitive control mitoxantrone, the MeOH extract (with IC50 values ranging from 0.84+/-0.03 to 3.96+/-0.14 ug/mL) and astrosterioside D (5) (with IC50 values ranging from 4.31+/-0.07 to 5.21+/-0.15 uM) exhibited potent cytotoxic effects against all three tested human cancer cell lines. In addition, the MeOH extract and astrosterioside D (5) have an effect on leading to apoptosis. Interestingly, the apoptosis of induction was accompanied by down-regulation of phosphatidyl inositol 3-kinase (PI3K)/AKT signaling and extracellular signal-regulated kinase (ERK) 1/2 mitogen-activated protein kinase (MAPK) signaling, and decrease of c myc expression. Further studies are required to establish use of the asterosaponins from A. monacanthus as remedial and/or nutraceutical purposes. PMID- 24492729 TI - Comparison of the effects of single doses of elcatonin and pregabalin on oxaliplatin-induced cold and mechanical allodynia in rats. AB - Oxaliplatin frequently causes peripheral neuropathy. Clinical studies have indicated that pregabalin ameliorates oxaliplatin-induced peripheral neuropathy. However, pregabalin frequently causes dizziness and somnolence. We previously reported that elcatonin, a synthetic analog of eel calcitonin, attenuated oxaliplatin-induced cold and mechanical allodynia in rats. The aim of the present study was to compare the anti-allodynic effects of elcatonin and pregabalin in the rats developing the oxaliplatin-induced neuropathy. Male Sprague-Dawley rats were treated with a single dose of oxaliplatin (6 mg/kg, intraperitoneally (i.p.)) to induce cold and mechanical allodynia. We assessed the effects of subcutaneous elcatonin (20 U/kg) and oral pregabalin (30 mg/kg) on cold and mechanical allodynia by cold stimulation (8 degrees C) to the hind paw of the rats and the von Frey test, respectively. Elcatonin reversed the effects of oxaliplatin-induced cold and mechanical allodynia in rats for a longer time period than pregabalin does. These results suggested that elcatonin might be useful for the clinical treatment of oxaliplatin-induced neuropathy. PMID- 24492730 TI - Effects of bupropion and pramipexole on cell proliferation in the hippocampus of adrenocorticotropic hormone-treated rats. AB - The dopamine reuptake inhibitor bupropion and dopamine D2/3 receptor agonist pramipexole have been clinically proven to improve both depression and treatment resistant depression. We examined its influence on the duration of immobility during the forced swim test in adrenocorticotropic hormone (ACTH)-treated rats and further analyzed the possible role of the dopamine nerve system in this effect. Bupropion and pramipexole significantly decreased the duration of immobility in normal and ACTH-treated rats. We previously demonstrated that the chronic administration of ACTH caused a significant decrease in hippocampal cell proliferation and neurogenesis. In this study, we used the mitotic marker 5-bromo 2'-deoxyridine to investigate the effects of bupropion and pramipexole on cell proliferation in the subgranular zone of the hippocampal dentate gyrus following chronic treatment with ACTH. The ACTH treatment for 14 d decreased adult hippocampal cell proliferation. The chronic administration of bupropion for 14 d blocked the loss of cell proliferation resulting from the chronic treatment with ACTH, whereas pramipexole did not. The administration of bupropion may have treatment-resistant antidepressive properties, which may be partly attributed to the normalization of hippocampal cell proliferation. PMID- 24492731 TI - Xanthocidin derivatives as topoisomerase IIalpha enzymatic inhibitors. AB - Few studies have examined xanthocidin, a biotic isolated from Streptomyces xanthocidicus in 1966, because its supply is limited. Based on its chemical structure, xanthocidin has the potential to become a lead compound in the production of agrochemicals and anti-cancer drugs; however, it is unstable under both basic and acidic conditions. We recently established the total synthesis of xanthocidin using the FeCl3-mediated Nazarov reaction, and obtained two stable derivatives (#1 and #2). The results of the present study demonstrated that these derivatives exhibited the inhibitory activity of topoisomerase IIalpha, known as a molecular target for cancer chemotherapy, and this was attributed to the respective exo-methylene ketone group without DNA intercalation. The results obtained also suggest that these derivatives may have value as lead compounds in the synthesis of topoisomerase IIalpha inhibitors. PMID- 24492732 TI - What is the aim of immunosuppressive treatment in patients with graves' orbitopathy? AB - PURPOSE: The EUGOGO criteria and the clinical activity score (CAS) have been used as outcome measures to report response rates for patients after pulsed intravenous methylprednisolone (PIM) therapy. This study compares the results after PIM for both criteria and evaluates the number of rehabilitative surgeries performed in relation to treatment outcome. METHODS: This was a retrospective review of patients with active moderate-to-severe Graves' orbitopathy (GO) treated with PIM (cumulative dose of 4.5 to 5 g). The EUGOGO criteria or improvement in CAS (>=2 points) was used as the primary outcome measure. Baseline characteristics were examined to evaluate any determinants of treatment response. Additional immunosuppressive therapy after PIM and rehabilitative surgical procedures for all patients within a 2-year period were also recorded. RESULTS: Thirty-two patients were identified. Using the EUGOGO criteria, an improvement was seen in 38%, no change (stabilization) in 47%, and worsening of the disease in 15%. The response rate using the CAS was 63%. According to the EUGOGO criteria and the CAS, 20% (4/20) and 33% (4/12) of nonresponders required additional immunosuppressive treatment after PIM. None of the responders required additional immunosuppressive therapy. There was a reduction of 0.5 surgeries per patient for responders using either outcome measures. CONCLUSIONS: In this study, PIM alone stabilizes active GO in 85% and reduces the severity of GO in 38% of the patients. Despite incongruent response rates obtained using the EUGOGO criteria and the CAS, both outcome measures were good predictors for additional immunosuppressive treatment and additional rehabilitative surgeries in nonresponders. PMID- 24492733 TI - Intramuscular ectopic lacrimal gland cyst masquerading as myocysticercosis. AB - Ectopic lacrimal gland within the orbit is an extremely rare choristoma occurring due to sequestration of a portion of normal lacrimal gland at an abnormal site during embryogenesis. Most cases of orbital ectopic lacrimal gland present with progressive unilateral proptosis and often become symptomatic in the first 3 decades of life. Although diagnosis is aided by a high clinical suspicion and radiologic features, histopathologic examination is confirmatory. To the best of the knowledge, the authors report the first case of an intramuscular ectopic lacrimal gland in the inferior rectus muscle simulating myocysticercosis. PMID- 24492734 TI - Glial heterotopia or ectopic brain masquerading as a dacyrocystocele. AB - Glial heterotopia is an extremely rare clinical entity mostly presenting in head and neck region secondary to an abnormal development of an isolated mature central nervous system (CNS) tissue at an abnormal location without any continuity with the brain, spinal cord, or meninges. Its origin is either due to mechanical isolation of glial tissues by the developing cranial bones or secondary to misdirected or sequestered embryonic neuroectodermal stem cells outside the CNS. The authors present an exceptionally rare case of a heterotopic glial nodule masquerading as a dacryocystocele, its radiological features along with a brief clinicopathological correlation. PMID- 24492735 TI - Incidence and severity of acute adverse reactions to four different gadolinium based MR contrast agents. AB - PURPOSE: Differences in acute adverse reactions to different gadolinium (Gd) based contrast agents have not been thoroughly evaluated. We investigated the relationships among the incidence and severity of acute adverse reactions, backgrounds of patients, and 4 types of different Gd-based contrast agents (gadopentetate dimeglumine, gadoteridol, gadoterate meglumine, and gadoxetate disodium). MATERIALS AND METHODS: We retrospectively reviewed the radiological records of 10,595 consecutive patients (4,343 female; 6,252 male; mean age, 63.8 +/- 14.0 years) who underwent contrast-enhanced magnetic resonance imaging between August 2006 and March 2011. Adverse reactions were classified as mild, moderate, and severe according to the definition of the American College of Radiology. The incidence of adverse reactions were compared on the basis of clinical characteristics and type, dose, and delivery methods of contrast agents by univariate and multivariate logistic regression analyses. RESULTS: The incidence of overall reactions was 0.45% (48/10,595); 45 reactions were mild and three were moderate. No severe reactions were observed. Although the incidence of adverse reactions did not differ significantly between male and female patients, younger individuals were at higher risk for acute adverse reactions. The contrast injection rate and contrast dose were not significantly related to the incidence of adverse reactions. The incidence of adverse reactions was significantly higher for gadoxetate disodium (0.82%) than gadopentetate dimeglumine (0.43%). CONCLUSION: The incidence of acute adverse reactions elicited by Gd-based contrast agents injection was only 0.45%. Younger age was a risk factor for acute reactions. All 4 agents were found to be safe, although gadoxetate disodium showed a relatively higher incidence of adverse reactions. PMID- 24492736 TI - A rare case of focal multiple medullary venous malformations with ipsilateral cerebral surface varix. AB - We report here a rare case of focal multiple venous malformations (VMs) in the white matter, via a draining vein arising from each VM, connecting with an ipsilateral cerebral surface venous varix. The male teen was asymptomatic neurologically. A diagnostic process using of MRI/MRDSA in this extremely rare entity is important as the more incidental discovery is expected with increasing opportunities of performing brain CT/MRI for various indications. PMID- 24492737 TI - Feasibility of 4D flow MR imaging of the brain with either Cartesian y-z radial sampling or k-t SENSE: comparison with 4D Flow MR imaging using SENSE. AB - PURPOSE: A drawback of time-resolved 3-dimensional phase contrast magnetic resonance (4D Flow MR) imaging is its lengthy scan time for clinical application in the brain. We assessed the feasibility for flow measurement and visualization of 4D Flow MR imaging using Cartesian y-z radial sampling and that using k-t sensitivity encoding (k-t SENSE) by comparison with the standard scan using SENSE. MATERIALS AND METHODS: Sixteen volunteers underwent 3 types of 4D Flow MR imaging of the brain using a 3.0-tesla scanner. As the standard scan, 4D Flow MR imaging with SENSE was performed first and then followed by 2 types of acceleration scan-with Cartesian y-z radial sampling and with k-t SENSE. We measured peak systolic velocity (PSV) and blood flow volume (BFV) in 9 arteries, and the percentage of particles arriving from the emitter plane at the target plane in 3 arteries, visually graded image quality in 9 arteries, and compared these quantitative and visual data between the standard scan and each acceleration scan. RESULTS: 4D Flow MR imaging examinations were completed in all but one volunteer, who did not undergo the last examination because of headache. Each acceleration scan reduced scan time by 50% compared with the standard scan. The k-t SENSE imaging underestimated PSV and BFV (P < 0.05). There were significant correlations for PSV and BFV between the standard scan and each acceleration scan (P < 0.01). The percentage of particles reaching the target plane did not differ between the standard scan and each acceleration scan. For visual assessment, y-z radial sampling deteriorated the image quality of the 3 arteries. CONCLUSION: Cartesian y-z radial sampling is feasible for measuring flow, and k-t SENSE offers sufficient flow visualization; both allow acquisition of 4D Flow MR imaging with shorter scan time. PMID- 24492738 TI - Longitudinal monitoring with multiple MR techniques in a case of progressive multifocal leukoencephalopathy associated with multiple myeloma. AB - Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain caused by the JC virus in immunocompromised patients. We report characteristic features of proton MR spectroscopy, 3-dimensional pseudo continuous arterial spin labeling imaging, and diffusion tensor imaging in a 53 year-old patient with PML. The utility of multi-modal magnetic resonance techniques for longitudinal monitoring was indicated by their reevaluation over time and consideration of their relation to prognosis. PMID- 24492739 TI - Improvement of T1 contrast in whole-brain black-blood imaging using motion sensitized driven-equilibrium prepared 3D turbo spin echo (3D MSDE-TSE). AB - We demonstrated a new scheme for performing the T1-enhanced whole-brain black blood imaging pulse sequence using motion-sensitized driven-equilibrium prepared 3-dimensional (3D) turbo spin echo (MSDE-TSE) with anti-driven-equilibrium post pulse. The use of an anti-driven-equilibrium pulse considerably improved the T1 contrast of MSDE-TSE black-blood images. This sequence can be used for whole brain 3D volumetric T1-weighted black-blood imaging and may improve the accuracy of anatomical localization for certain brain lesions. PMID- 24492740 TI - Absolute quantitation of glutamate, GABA and glutamine using localized 2D constant-time COSY spectroscopy in vivo. AB - PURPOSE: We propose an absolute quantitation method for metabolites with strongly coupled spin systems using localized 2-dimensional (2D) constant-time correlation spectroscopy (CT-COSY). We also develop two methods for improving the quality of in vivo CT-COSY spectra. METHODS: We substituted an image selected in vivo spectroscopy (ISIS) pulse for a 180 degrees slice pulse in the CT-COSY module to decrease the slice displacement error caused by the chemical shift difference. We measured the slice displacement error due to the differences in the carrier frequency of slice pulse in a phantom experiment to demonstrate this feature. We also developed an asymmetric sampling scheme along the t1 direction to resolve diagonal peaks even in the magnitude mode of 2D spectra. We collected CT-COSY signals of a human brain for a 14% asymmetric sampling scheme. After reconstruction, we obtained a 2D CT-COSY spectrum in magnitude mode and compared a peak of glutamate (Glu) C4H on that spectrum to a peak displayed in absorption mode. In our proposed absolute quantitation method, we developed T2 correction, curve-fitting for computing peak volume and calibration by an internal water reference. We used the method to measure the Glu concentration in 10-mM glutamate phantom experiments. We also attempted to measure concentrations of Glu, gamma aminobutyric acid (GABA) and glutamine (Gln) in a human brain. RESULTS: Slice displacement error was decreased by a factor of 2.5 using the proposed sequence. Spectra with narrow linewidths could be obtained using the asymmetric sampling scheme in the magnitude mode. Measured Glu concentration in the solution phantom was 9.4 mM. Concentrations of Glu (9.5 mM), GABA (0.61 mM) and Gln (3.6 mM) in a human brain measured by our method agreed well with previously reported values. CONCLUSION: Concentrations of metabolites with strongly coupled spin systems can be measured using our proposed absolute quantitation method on 2D CT-COSY spectra. PMID- 24492741 TI - Flour pads: devices to improve CHESS fat suppression. AB - PURPOSE: We compared the suppression of lingering fat signals in chemical shift selective (CHESS) images by pads filled with flour and pads filled with rice in a phantom and human subjects. MATERIALS AND METHODS: First, we prepared a phantom by creating an empty space in a mass of lard and filling the space with air, rice, or flour. Then, we obtained MR images of the phantoms in the center of the magnetic field and at a position 8 cm to the left (off-center) to compare lingering fat signals. MR images of the knee were obtained in 10 healthy volunteers using CHESS after placing a polyurethane sponge pillow, rice pad, or flour pad in the popliteal space under the flexed knee. We visually assessed the number of areas with lingering fat signals and the statistical differences among the groups were assessed using Tukey's test. RESULTS: Similarly to rice, flour clearly decreased lingering fat signals in the phantom study. A similar effect was obtained in the off-center images. In the volunteer study, the mean number of areas with lingering fat signals was 2.5 with a sponge pillow, 0.5 with the rice pad, and 0.3 with the flour pad. Those numbers were significantly different using flour pad and rice pad compared with sponge pillow (P < 0.001). No significant differences were seen between flour pads and rice pads (P = 0.662). CONCLUSION: Flour pads can suppress lingering fat signals in CHESS images. PMID- 24492742 TI - Diffusion-weighted imaging of ovarian torsion: usefulness of apparent diffusion coefficient (ADC) values for the detection of hemorrhagic infarction. AB - PURPOSE: We undertook this study to evaluate the need for diffusion-weighted (DW) magnetic resonance (MR) imaging in detecting hemorrhagic infarction following ovarian torsion. METHODS: The study included 14 consecutive patients aged 12 to 74 years (average age, 36 years) with surgical confirmation of ovarian torsion who underwent 1.5-tesla MR imaging. Pathologically, hemorrhagic infarction was found in 7 patients. We retrospectively reviewed signal intensity on T1-, T2-, and diffusion-weighted images and apparent diffusion coefficients (ADCs) in swollen ovarian stroma. RESULTS: Fallopian tube thickening was seen in all patients. In patients with ovarian cystic lesion, maximum cyst wall thickness was significantly higher in patients with hemorrhagic infarction (mean, 13.5 +/- 4.1 mm) than those without (mean, 5.0 +/- 1.0 mm) (P < .05). Signal intensity did not differ significantly on T1-weighted, T2-weighted, and DW images between patients with and without hemorrhagic infarction. ADCs were significantly lower in patients with hemorrhagic infarction (1.20 +/- 0.50 [* 10(-3) mm(2)/s]) than those without (2.04 +/- 0.26 [* 10(-3) mm(2)/s]) (P < .01). With an ADC threshold of 1.80 [* 10(-3) mm(2)/s], sensitivity for hemorrhagic infarction was 0.88 (7 of 8), and specificity was 1.00 (6 of 6). CONCLUSION: ADC measurements were useful for detecting hemorrhagic infarction in patients with ovarian torsion. PMID- 24492743 TI - Serial scans in healthy volunteers following intravenous administration of gadoteridol: time course of contrast enhancement in various cranial fluid spaces. AB - PURPOSE: Heavily T2-weighted, 3-dimensional, fluid-attenuated inversion recovery (hT2W-3D-FLAIR) imaging has been reported to detect low concentrations of gadolinium-based contrast media (GBCM) in the anterior eye segment (AES), subarachnoid space (SAS), and labyrinthine perilymph as well as in the cerebrospinal fluid (CSF) of the internal auditory canal (IAC) 4 hours after intravenous administration of a single dose (IV-SD-GBCM) in patients with inner ear disorders. To elucidate the time course of contrast enhancement in healthy volunteers, we obtained hT2W-3D-FLAIR serially after IV-SD-GBCM. MATERIALS AND METHODS: We obtained hT2W-3D-FLAIR before and 0.5, 1.5, 3, 4.5 and 6 hours after IV-SD-GBCM in 6 healthy volunteers and measured signal intensity of the AES, SAS surrounding the optic nerve (SAS-ON), SAS in Meckel's cave (SAS-MC), pontine parenchyma, CSF in the IAC (CSF-IAC), CSF in the ambient cistern (CSF-AC), CSF in the lateral ventricles (CSF-LV), perilymph (PL), and endolymph (EL) in the labyrinth. We then compared averaged values among all time points using analysis of variance (ANOVA). RESULTS: After IV-SD-GBCM, we observed no change in signal intensity in the pontine parenchyma, CSF-LV, or EL and significant enhancement in all other structures. Maximum enhancement was most frequent at 4.5 hours after IV SD-GBCM in the SAS-ON and PL, at 1.5 hours in the AES and SAS-MC, and at 3 hours in the CSF-IAC and CSF-AC. CONCLUSIONS: Contrast enhancement can be detected by hT2W-3D-FLAIR in the AES, SAS-ON, SAS-MC, PL, CSF-IAC, and CSF-AC in healthy volunteers after IV-SD-GBCM. Timing of maximum enhancement differed among locations. These data might serve as basic knowledge for future clinical research. PMID- 24492744 TI - Bayesian analysis of perfusion-weighted imaging to predict infarct volume: comparison with singular value decomposition. AB - PURPOSE: We compared the performances of a Bayesian estimation method and oscillation index singular value decomposition (oSVD) deconvolution for predicting final infarction using data previously obtained from 10 cynomolgus monkeys with permanent unilateral middle cerebral artery (MCA) occlusion. METHODS: We conducted baseline perfusion-weighted imaging 3 hours after MCA occlusion and generated time to peak, first moment of transit, cerebral blood flow, cerebral blood volume, and mean transit time maps using Bayesian and oSVD methods. Final infarct volume was determined by follow-up diffusion-weighted imaging (DWI) scanned 47 hours after MCA occlusion and from histological specimens. We used a region growing technique with various thresholds to determine perfusion abnormality volume. The best threshold was defined when the mean perfusion volume matched the mean final infarct volume, and Pearson's correlation coefficients (r) and intraclass correlations (ICC) were calculated between perfusion abnormality and final infarct volume at that threshold. These coefficients were compared between Bayesian and oSVD using Wilcoxon's signed rank test. P-value < 0.05 was considered a statistically significant difference. RESULTS: The Pearson's correlation coefficients were larger but not significantly different for the Bayesian technique than oSVD in 4 of 5 perfusion maps when final infarct was determined by specimen volume (P = 0.104). When final infarct volume was defined by DWI volume, all perfusion maps had a significantly higher correlation coefficient by Bayesian technique than oSVD (P = 0.043). For ICC, all perfusion maps had higher value in Bayesian than oSVD calculation, and significant differences were observed both on specimen- and DWI-defined volumes (P = 0.043 for both). CONCLUSION: The Bayesian method is more reliable than oSVD deconvolution in estimating final infarct volume. PMID- 24492745 TI - Beyond click chemistry - supramolecular interactions of 1,2,3-triazoles. AB - The research on 1,2,3-triazoles has been lively and ever-growing since its stimulation by the advent of click chemistry. The attractiveness of 1H-1,2,3 triazoles and their derivatives originates from their unique combination of facile accessibility via click chemistry and truly diverse supramolecular interactions, which enabled myriads of applications in supramolecular and coordination chemistry. The nitrogen-rich triazole features a highly polarized carbon atom allowing the complexation of anions by hydrogen and halogen bonding or, in the case of the triazolium salts, via charge-assisted hydrogen and halogen bonds. On the other hand, the triazole offers several N-coordination modes including coordination via anionic and cationic nitrogen donors of triazolate and triazolium ions, respectively. After CH-deprotonation of the triazole and the triazolium, powerful carbanionic and mesoionic carbene donors, respectively, are available. The latter coordination mode even features non-innocent ligand behavior. Moreover, these supramolecular interactions can be combined, e.g., in ion-pair recognition, preorganization by intramolecular hydrogen bond donation and acceptance, and in bimetallic complexes. Ultimately, by clicking two building blocks into place, the triazole emerges as a most versatile functional unit allowing very successful applications, e.g., in anion recognition, catalysis, and photochemistry, thus going far beyond the original purpose of click chemistry. It is the intention of this review to provide a detailed analysis of the various supramolecular interactions of triazoles in comparison to established functional units, which may serve as guidelines for further applications. PMID- 24492746 TI - Negative Poisson's ratios in metal nanoplates. AB - The Poisson's ratio is a fundamental measure of the elastic-deformation behaviour of materials. Although negative Poisson's ratios are theoretically possible, they were believed to be rare in nature. In particular, while some studies have focused on finding or producing materials with a negative Poisson's ratio in bulk form, there has been no such study for nanoscale materials. Here we provide numerical and theoretical evidence that negative Poisson's ratios are found in several nanoscale metal plates under finite strains. Furthermore, under the same conditions of crystal orientation and loading direction, materials with a positive Poisson's ratio in bulk form can display a negative Poisson's ratio when the material's thickness approaches the nanometer scale. We show that this behaviour originates from a unique surface effect that induces a finite compressive stress inside the nanoplates, and from a phase transformation that causes the Poisson's ratio to depend strongly on the amount of stretch. PMID- 24492747 TI - Atomic-scale chemical imaging and quantification of metallic alloy structures by energy-dispersive X-ray spectroscopy. AB - Determination of atomic-scale crystal structure for nanostructured intermetallic alloys, such as magnetic alloys containing Al, Ni, Co (alnico) and Fe, is crucial for understanding physical properties such as magnetism, but technically challenging due to the small interatomic distances and the similar atomic numbers. By applying energy-dispersive X-ray spectroscopy (EDS) mapping to the study of two intermetallic phases of an alnico alloy resulting from spinodal decomposition, we have determined atomic-scale chemical composition at individual lattice sites for the two phases: one is the B2 phase with Fe0.76Co0.24 Fe0.40Co0.60 ordering and the other is the L2(1) phase with Ni0.48Co0.52 at A sites, Al at B(Iota)-sites and Fe0.20Ti0.80 at B(IotaIota)-sites, respectively. The technique developed through this study represents a powerful real-space approach to investigate structure chemically at the atomic scale for a wide range of materials systems. PMID- 24492749 TI - Cryptic resistance in Staphylococcus aureus: a risk for the treatment of skin infection? AB - PURPOSE OF REVIEW: The purpose of this review is to explore major challenges that face routine diagnostic laboratories in detecting cryptic (hidden) antibiotic resistances in Staphylococcus aureus and the impact of these covert resistances in the management of skin and soft tissue infections. RECENT FINDINGS: The review covers recent literature and works regarding a number of evolving mechanisms and forms of antibiotic resistances in S. aureus, including novel oxacillin susceptible-mecA-positive meticillin-resistant S. aureus (OS-MRSA) strains and MRSA isolates that harbour a divergent mecA homologue termed mecC within the novel staphylococcal cassette chromosome mec XI element. SUMMARY: S. aureus strains causing skin and soft tissue infections are evolving with regard to virulence as well as antimicrobial resistance. Cryptic resistances continue to escape routine diagnostic tests. This means that there are still many unknowns regarding their global dissemination, virulence, threats in clinical practice and optimal treatment strategies. Larger studies are needed to further understand the pathogenic consequences of cryptic resistances in S. aureus in skin and soft tissue infections, which may ultimately provide novel preventive or treatment approaches for this significant human pathogen. PMID- 24492748 TI - Comparative analysis of proteomes and functionomes provides insights into origins of cellular diversification. AB - Reconstructing the evolutionary history of modern species is a difficult problem complicated by the conceptual and technical limitations of phylogenetic tree building methods. Here, we propose a comparative proteomic and functionomic inferential framework for genome evolution that allows resolving the tripartite division of cells and sketching their history. Evolutionary inferences were derived from the spread of conserved molecular features, such as molecular structures and functions, in the proteomes and functionomes of contemporary organisms. Patterns of use and reuse of these traits yielded significant insights into the origins of cellular diversification. Results uncovered an unprecedented strong evolutionary association between Bacteria and Eukarya while revealing marked evolutionary reductive tendencies in the archaeal genomic repertoires. The effects of nonvertical evolutionary processes (e.g., HGT, convergent evolution) were found to be limited while reductive evolution and molecular innovation appeared to be prevalent during the evolution of cells. Our study revealed a strong vertical trace in the history of proteins and associated molecular functions, which was reliably recovered using the comparative genomics approach. The trace supported the existence of a stem line of descent and the very early appearance of Archaea as a diversified superkingdom, but failed to uncover a hidden canonical pattern in which Bacteria was the first superkingdom to deploy superkingdom-specific structures and functions. PMID- 24492750 TI - What role do viruses play in nosocomial pneumonia? AB - PURPOSE OF THE REVIEW: Viruses are an increasingly recognized cause of community acquired pneumonia (CAP), but their exact role in nosocomial pneumonia is still debated. This review focuses on the role of viruses as a cause of nosocomial pneumonia. RECENT FINDINGS: Respiratory viruses may be responsible for healthcare associated pneumonia, because affected patients and those with CAP have the same risk factors for viral disease. In mechanically ventilated patients, viruses belonging to the Herpesviridae family, namely herpes simplex virus (HSV) and cytomegalovirus, can be reactivated and cause bronchopneumonitis or ventilator associated pneumonia, respectively. Recent results confirmed the high rate of HSV reactivation in the distal airways of mechanically ventilated patients, and that patients with high virus loads (>10(5) copies/ml of bronchoalveolar lavage fluid) have poorer outcomes than those with low or no virus load. However, the responsibility of mimivirus, initially described as a possible cause of pneumonia, was not confirmed for nosocomial pneumonia. SUMMARY: Respiratory viruses are mainly responsible for CAP, but they may also cause healthcare associated pneumonia. HSV bronchopneumonitis and cytomegalovirus pneumonia are not rare diseases, and patients with Herpesviridae lung infections have worse prognoses than those without. Whether or not those Herpesviridae infections are responsible for true morbidity or morbidity remains to be determined. PMID- 24492751 TI - Developments in skin and soft tissue infection. PMID- 24492752 TI - Response to: 'Are autoantibodies to RNA-polymerase III to be incorporated in routine diagnostic laboratory algorithms for systemic autoimmune rheumatic diseases?' by Jan Damoiseaux. PMID- 24492753 TI - Fatty pancreas, insulin resistance, and beta-cell function: a population study using fat-water magnetic resonance imaging. AB - OBJECTIVES: Nonalcoholic fatty liver disease is the most common chronic liver disease. Fatty pancreas has also been described but is difficult to assess. It is now possible to measure pancreatic and liver fat accurately with magnetic resonance imaging (MRI). We aimed to define the normal range of pancreatic fat and identify factors associated with fatty pancreas. In addition, the effect of fatty liver and fatty pancreas on insulin resistance (IR) and pancreatic beta cell function was studied. METHODS: Fat-water MRI and proton-magnetic resonance spectroscopy were performed on 685 healthy volunteers from the general population to measure pancreatic and liver fat, respectively. On the basis of fasting plasma glucose and insulin levels, the IR and beta-cell function were assessed using the homeostasis model assessment (HOMA). RESULTS: Among subjects without significant alcohol consumption or any component of metabolic syndrome, 90% had pancreatic fat between 1.8 and 10.4%. Using the upper limit of normal of 10.4%, 110 (16.1%; 95% confidence interval 13.3-18.8%) subjects had fatty pancreas. On multivariable analysis, high serum ferritin, central obesity, and hypertriglyceridemia were independent factors associated with fatty pancreas. Subjects with both fatty pancreas and fatty liver had higher HOMA-IR than did those with either condition alone. Fatty pancreas was not associated with HOMA-beta after adjusting for liver fat and body mass index. CONCLUSIONS: In all, 16.1% of this community cohort of adult Hong Kong Chinese volunteers had a fatty pancreas by our definition. Central obesity, hypertriglyceridemia, and hyperferritinemia are associated with fatty pancreas. Individuals with fatty pancreas have increased IR. PMID- 24492754 TI - Colorectal cancer incidence in Asian populations in California: effect of nativity and neighborhood-level factors. AB - OBJECTIVES: Heritable and environmental factors may contribute to differences in colorectal cancer (CRC) incidence across populations. We capitalized on the resources of the California Cancer Registry (CCR) and California's diverse Asian population to perform a cohort study exploring the relationships between CRC incidence, nativity, and neighborhood-level factors across Asian subgroups. METHODS: We identified CRC cases in the CCR from 1990 to 2004 and calculated age adjusted CRC incidence rates for non-Hispanic Whites and US-born vs. foreign-born Asian ethnic subgroups, stratified by neighborhood socioeconomic status (SES) and "ethnic enclave." Trends were studied with joinpoint analysis. RESULTS: CRC incidence was lowest among foreign-born South Asians (22.0/100,000; 95% confidence interval (CI): 19.7-24.5/100,000) and highest among foreign-born Japanese (74.6/100,000; 95% CI: 70.1-79.2/100,000). Women in all Asian subgroups except Japanese, and men in all Asian subgroups except Japanese and US-born Chinese, had lower CRC incidence than non-Hispanic Whites. Among Chinese men and Filipino women and men, CRC incidence was lower among foreign-born than US-born persons; the opposite was observed for Japanese women and men. Among non-Hispanic Whites, but not most Asian subgroups, CRC incidence decreased over time. CRC incidence was inversely associated with neighborhood SES among non-Hispanic Whites, and level of ethnic enclave among Asians. CONCLUSIONS: CRC incidence rates differ substantially across Asian subgroups in California. The significant associations between CRC incidence and nativity and residence in an ethnic enclave suggest a substantial effect of acquired environmental factors. The absence of declines in CRC incidence rates among most Asians during our study period may point to disparities in screening compared with Whites. PMID- 24492757 TI - Interocular amplitude and latency differences of pattern ERG and pattern VEP parameters. AB - PURPOSE: To determine the normal interocular differences in amplitudes and peak times of the pattern electroretinograms (PERGs) and pattern visual evoked potentials (PVEPs) and to investigate whether the PERG and PVEP parameters correspond in lateral dominance or whether the eye-side distributions of the functional parameters are similar. METHODS: The PERGs and PVEPs were recorded in healthy subjects (N = 77) according to the standards of the International Society for Clinical Electrophysiology of Vision, with the modification of the check size of the PERG to 0.5 degrees. This allows stimulation of the macular ganglion cells and their corresponding visual pathways in healthy subjects. RESULTS: Comparison of the averaged higher and lower response amplitudes and the shorter and longer response peak times showed significant differences (p < 0.001) in both the PERG and the PVEP parameters (median [5 to 95%]): the P50 (1.92% [0 to 5.48%]) and N95 (2.06% [0 to 13.95%]) peak times and the P50 (11.82% [1.32 to 29.93%) and N95 (9.45% [1.17 to 30.38%]) amplitudes of the PERGs and the P100 (1.04% [0 to 4.15%]) and N135 (1.96% [0 to 12.36%]) peak times and the P100 (9.86% [1.26 to 29.76%]) and N135 (11.19% [1.18 to 29.99%]) amplitudes of the PVEPs. No significant correlation was found concerning the eye dominance of the PERG and PVEP parameters. CONCLUSIONS: Our results reveal a significant interocular difference on PERG and PVEP recording, but this could not be ascribed to the anatomy of the retina and related visual pathways. If the difference between the eyes is not taken into account, misinterpretation may occur in a pathological process. PMID- 24492756 TI - Patient acceptability of tear collection in the primary healthcare setting. AB - PURPOSE: The primary healthcare setting is well placed for health screening. Tear fluid composition gives valuable information about the eye and systemic health, and there is now significant interest in the potential application of tears as a tool for health screening; however, the acceptability of tear collection in the primary healthcare setting as compared with other methods of human sample collection has not been previously addressed. The objective of this study was to evaluate the patient acceptability of tear collection in a primary healthcare setting. METHODS: This was a cross-sectional study on 383 adult patients seeking primary healthcare, who were not diabetic and were not attending for an eye related complaint. Tear collection was done using Schirmer strips, and an interviewer-administered questionnaire was conducted to collate information on the pain score (0-10) of the Schirmer tear collection, as well as to score the pain associated with their previous experience of antecubital venous puncture and finger prick test. RESULTS: The pain score for Schirmer tear collection was significantly lower (p < 0.001) than antecubital venous puncture but higher (p < 0.001) than finger prick. The pain scores for all three procedures were significantly higher in participants of younger age, female gender, and higher education level. Among the participants, 70% did not mind their tears being collected to screen for eye problems, whereas only 38% did not mind this procedure being performed for general health screening. Nevertheless, 69% of the participants preferred tear to urine collection, and 74% of participants preferred tear to blood collection. CONCLUSIONS: Tear collection using Schirmer strips is a highly acceptable form of investigation that has the potential for use in health screening in the primary healthcare setting. This study has implications on using tear collection as a method of ocular and systemic health screening in the primary healthcare setting. PMID- 24492758 TI - Corneal power change is predictive of myopia progression in orthokeratology. AB - PURPOSE: This study aims to investigate the relationship between corneal refractive power change along three axes (nasal, temporal, and inferior) after orthokeratology (OK) treatment and 2-year axial growth in children. METHODS: Thirty-two Chinese children aged from 9 to 14 were fitted with OK. When corneal reshaping process following OK treatment was completed and stabilized, the 3 month topographic outputs were taken as the post-OK data. Corneal refractive powers along the nasal, temporal, and inferior axes were collected over an 8-mm diameter ring in 1-mm steps using the sagittal power map. The maximum power change along each axis was selected and divided into two subcategories, level 1 and level 2, depending on whether the value was below or above the average. Axial length (AL) was measured every 6 months during a 24-month period. The relationship between the maximum power changes and 2-year axial elongation were analyzed. RESULTS: Twenty-seven subjects completed the 24-month study. After OK treatment, statistically significant steepening (p < 0.05) was observed at the nasal 2 mm and 3 mm; temporal 3 mm; and inferior 2 mm, 3 mm, and 4 mm locations compared with the apical center. AL increased significantly throughout the 24 month observation period (p < 0.001). Changes in corneal refractive power significantly affected axial elongation (nasal, p = 0.001; temporal, p = 0.011; inferior, p = 0.001). Two-year axial elongation in patients with larger corneal power changes (level 2) was reduced by 54% to 69% compared with those with smaller corneal power changes (level 1). Maximum power changes along the three axes were negatively correlated (p < 0.05) with 2-year axial growth. CONCLUSIONS: Subjects with larger magnitude of corneal relative peripheral power change along specific axes after OK treatment experienced slower axial elongation by the end of 24 months. This effect might be mediated by the induction of greater amount of relative myopic defocus on the peripheral retina. Our study lends weight to potential OK lens designs for myopia control in children. PMID- 24492755 TI - The Royal Free Hospital score: a calibrated prognostic model for patients with cirrhosis admitted to intensive care unit. Comparison with current models and CLIF-SOFA score. AB - OBJECTIVES: Prognosis for patients with cirrhosis admitted to intensive care unit (ICU) is poor. ICU prognostic models are more accurate than liver-specific models. We identified predictors of mortality, developed a novel prognostic score (Royal Free Hospital (RFH) score), and tested it against established prognostic models and the yet unvalidated Chronic Liver Failure-Sequential Organ Failure Assessment (CLIF-SOFA) model. METHODS: Predictors of mortality were defined by logistic regression in a cohort of 635 consecutive patients with cirrhosis admitted to ICU (1989-2012). The RFH score was derived using a 75% training and 25% validation set. Predictive accuracy and calibration were evaluated using area under the receiver operating characteristic (AUROC) and goodness-of-fit chi(2) for the RFH score, as well as for SOFA, Model for End-Stage Liver Disease (MELD), Acute Physiology and Chronic Health Evaluation (APACHE II), and Child-Pugh. CLIF SOFA was applied to a recent subset (2005-2012) of patients. RESULTS: In-hospital mortality was 52.3%. Mortality improved over time but with a corresponding reduction in acuity of illness on admission. Predictors of mortality in training set, which constituted the RFH score, were the following: bilirubin, international normalized ratio, lactate, alveolar arterial partial pressure oxygen gradient, urea, while variceal bleeding as indication for admission conferred lesser risk. Classification accuracy was 73.4% in training and 76.7% in validation sample and did not change significantly across different eras of admission. The AUROC for the derived model was 0.83 and the goodness-of-fit chi(2) was 3.74 (P=0.88). AUROC for SOFA was 0.81, MELD was 0.79, APACHE II was 0.78, and Child-Pugh was 0.67. In 2005-2012 cohort, AUROC was: SOFA: 0.74, CLIF SOFA: 0.75, and RFH: 0.78. Goodness-of-fit chi(2) was: SOFA: 6.21 (P=0.63), CLIF SOFA: 9.18 (P=0.33), and RFH: 2.91 (P=0.94). CONCLUSIONS: RFH score demonstrated good discriminative ability and calibration. Internal validation supports its generalizability. CLIF-SOFA did not perform better than RFH and the original SOFA. External validation of our model should be undertaken to confirm its clinical utility. PMID- 24492759 TI - Double-pass system assessing the optical quality of pseudophakic eyes. AB - PURPOSE: To compare the optical quality measurements obtained from the double pass system and ocular aberrations, subjective visual acuity, and contrast sensitivity score in pseudophakic eyes. METHODS: Three months after cataract surgery, modulation transfer function (MTF) cutoff frequency, Strehl ratio, objective scatter index, and objective pseudoaccommodation obtained from the double-pass system were compared with total aberration, higher-order aberration, and spherical aberration obtained from ray-tracing aberrometer. In addition, parameters of the double-pass system were compared with subjective visual acuity and the contrast sensitivity score. RESULTS: Forty eyes of 40 patients were included. The MTF cutoff frequency and Strehl ratio were negatively correlated with total aberration (r = -0.503, p = 0.003; r = -0.509, p = 0.003, respectively) and subjective visual acuity (r = -0.453, p = 0.007; r = -0.354, p = 0.040, respectively). The objective scatter index was positively correlated with total aberration (r = 0.451, p = 0.024) and subjective visual acuity (r = 0.516, p = 0.008). The MTF cutoff frequency showed a correlation with contrast sensitivity score under photopic and mesopic conditions. CONCLUSIONS: Optical quality parameters obtained from the double-pass system were correlated with ocular aberrations, subjective visual acuity, and contrast sensitivity score in pseudophakic eyes. PMID- 24492760 TI - An ocular surface prosthesis for keratoglobus and Terrien's marginal degeneration. AB - PURPOSE: This case report describes the challenges in fitting corneas using the prosthetic replacement of ocular surface ecosystem (PROSE) device in a unique case of bilateral keratoglobus (KG) with Terrien's marginal degeneration (TMD). CASE REPORT: KG and TMD are uncommon corneal ectatic conditions, characterized by protrusion and thinning of the cornea. Optical correction with spectacles is limited, as this may not provide the best-corrected visual acuity because of irregular corneal astigmatism. Corneal gas-permeable lenses can provide optimal vision, but they have poor fitting characteristics in advanced stages. The PROSE device has the advantage of masking the irregularity of the cornea with a tear lens and a contact lens power that provides a smooth refractive surface. This case report describes the fitting aspects of the PROSE device in a case diagnosed with KG and TMD. A generous vault allows the PROSE device to sink into the conjunctiva more, causing impingement, but a PROSE with higher vault is required as corneal clearance decreases with wear time. Corneal thickness measurements during the trial can give a better idea of corneal edema expected after prescribing the PROSE device. Optical coherence tomography is a useful tool for measuring diurnal changes in the corneal thickness and vault over a period in such challenging cases. CONCLUSIONS: Modification of not only the vault but also the haptic and total diameter of the device is required to achieve an optimal fit. Though challenging, successful fitting of the scleral lens in ectatic corneas is attainable, with the aid of anterior imaging and spline technologies. PMID- 24492761 TI - Psychological detachment from work during off-job time: predictive role of work and non-work factors in Japanese employees. AB - Psychological detachment from work, an off-job experience of "switching off" mentally, seems to be crucial for promoting employee's well-being. Previous studies on predictors of psychological detachment mainly focused on job-related factors, and only a few studies focused on family-related and personal factors. This study focuses not only on job-related factors (job demands, job control, workplace support) but also on family-related (family/friend support) and personal factors (workaholism), and examines the relation of these three factors with psychological detachment. Data of 2,520 Japanese employees was randomly split into two groups and then analyzed using cross-validation. Hierarchical multiple regression analyses revealed that family/friend support had a positive association with psychological detachment, whereas a subscale of workaholism (i.e. working compulsively) had negative associations with it across the two groups. Results suggest that family/friend support would facilitate psychological detachment whereas workaholism would inhibit it. PMID- 24492762 TI - Sneezing and allergic dermatitis were increased in engineered nanomaterial handling workers. AB - The aim of this study was to survey the work-relatedness of symptoms and diseases among engineered nanomaterials handling workers by questionnaire. A total of 258 exposed workers and 200 comparison workers were recruited from 14 nanomaterials handling factories in Taiwan. In addition to current disease status (prevalence), we classified the diseases worsened by employment (worsened by work). The control banding nanotool risk level matrix was adopted to categorize the severity and probability of nanomaterial exposure. The work-relatedness of symptoms was also self-reported in the questionnaire. The only symptom identified as significantly work-related was sneezing (5.88% in risk level 2 and 7.91% in risk level 1 vs. 2.00% in controls, p=0.04). The prevalences of work-related dry cough (p=0.06) and productive cough (p=0.09) in nanomaterials handling workers were also higher than those in controls. The only disease significantly worsened by work was allergic dermatitis (4.20% in risk level 2, 0% in risk level 1 vs. 0.50% in control, p=0.01). The incidence of angina in nanoworkers was also higher than in controls (p=0.06). In addition to allergic diseases, cardiopulmonary symptoms such as cough and angina may be used as screening tools for medical surveillance of people handling engineered nanomaterials. PMID- 24492763 TI - Development of a short questionnaire to measure an extended set of job demands, job resources, and positive health outcomes: the new brief job stress questionnaire. AB - This study aimed to investigate the reliability and construct validity of a new version of the Brief Job Stress Questionnaire (New BJSQ), which measures an extended set of psychosocial factors at work by adding new scales/items to the current version of the BJSQ. Additional scales/items were extensively collected from theoretical job stress models and similar questionnaires in several countries. Scales/items were field-tested and refined through a pilot internet survey. Finally, an 84-item questionnaire (141 items in total when combined with the current BJSQ) was developed. A nationally representative survey was administered to employees in Japan (n=1,633) to examine the reliability and construct validity. Most scales showed acceptable levels of internal consistency and test-retest reliability. Principal component analyses showed that the first factor explained 50% or greater proportion of the variance in most scales. A scale factor analysis and a correlation analysis showed that these scales fit the theoretical expectations. These findings provided a piece of evidence that the New BJSQ scales are reliable and valid. Although more detailed content and construct validity should be examined in future study, the New BJSQ is a useful instrument to evaluate psychosocial work environment and positive mental health outcomes in the current workplace. PMID- 24492764 TI - Controllability of vortex domain structure in ferroelectric nanodot: fruitful domain patterns and transformation paths. AB - Ferroelectric vortex domain structure which exists in low-dimensional ferroelectrics is being intensively researched for future applications in functional nanodevices. Here we demonstrate that adjusting surface charge screening in combination with temperature can provide an efficient way to gain control of vortex domain structure in ferroelectric nanodot. Systematical simulating experiments have been conducted to reveal the stability and evolution mechanisms of domain structure in ferroelectric nanodot under various conditions, including processes of cooling-down/heating-up under different surface charge screening conditions, and increasing/decreasing surface charge screening at different temperatures. Fruitful phase diagrams as functions of surface screening and temperature are presented, together with evolution paths of various domain patterns. Calculations discover up to 25 different kinds of domain patterns and 22 typical evolution paths of phase transitions. The fruitful controllability of vortex domain structure by surface charge screening in combination with temperature should shed light on prospective nanodevice applications of low dimensional ferroelectric nanostructures. PMID- 24492767 TI - New horizons for cancer gene therapy. PMID- 24492765 TI - Subanesthetic ketamine treatment promotes abnormal interactions between neural subsystems and alters the properties of functional brain networks. AB - Acute treatment with subanesthetic ketamine, a non-competitive N-methyl-D aspartic acid (NMDA) receptor antagonist, is widely utilized as a translational model for schizophrenia. However, how acute NMDA receptor blockade impacts on brain functioning at a systems level, to elicit translationally relevant symptomatology and behavioral deficits, has not yet been determined. Here, for the first time, we apply established and recently validated topological measures from network science to brain imaging data gained from ketamine-treated mice to elucidate how acute NMDA receptor blockade impacts on the properties of functional brain networks. We show that the effects of acute ketamine treatment on the global properties of these networks are divergent from those widely reported in schizophrenia. Where acute NMDA receptor blockade promotes hyperconnectivity in functional brain networks, pronounced dysconnectivity is found in schizophrenia. We also show that acute ketamine treatment increases the connectivity and importance of prefrontal and thalamic brain regions in brain networks, a finding also divergent to alterations seen in schizophrenia. In addition, we characterize how ketamine impacts on bipartite functional interactions between neural subsystems. A key feature includes the enhancement of prefrontal cortex (PFC)-neuromodulatory subsystem connectivity in ketamine treated animals, a finding consistent with the known effects of ketamine on PFC neurotransmitter levels. Overall, our data suggest that, at a systems level, acute ketamine-induced alterations in brain network connectivity do not parallel those seen in chronic schizophrenia. Hence, the mechanisms through which acute ketamine treatment induces translationally relevant symptomatology may differ from those in chronic schizophrenia. Future effort should therefore be dedicated to resolve the conflicting observations between this putative translational model and schizophrenia. PMID- 24492768 TI - Soon PLOS Medicine will be ten: a call for papers on the health of pre-adolescent children. PMID- 24492769 TI - Measurement of mitochondrial Ca2+ transport mediated by three transport proteins: VDAC1, the Na+/Ca2+ exchanger, and the Ca2+ uniporter. AB - Ca(2+) is a ubiquitous cellular signal, with changes in intracellular Ca(2+) concentration not only stimulating a number of intercellular events but also triggering cell death pathways, including apoptosis. Mitochondrial Ca(2+) uptake and release play pivotal roles in cellular physiology by regulating intracellular Ca(2+) signaling, energy metabolism and cell death. Ca(2+) transport across the inner and outer mitochondrial membranes is mediated by several proteins, including channels, antiporters, and a uniporter. In this article, we present the background to several methods now established for assaying mitochondrial Ca(2+) transport activity across both mitochondrial membranes. The first of these is Ca(2+) transport mediated by the outer mitochondrial protein, the voltage dependent anion-selective channel protein 1 (VDAC1, also known as porin 1), both as a purified protein reconstituted into a planar lipid bilayer (PLB) or into liposomes and as a mitochondrial membrane-embedded protein. The second method involves isolated mitochondria for assaying the activity of an inner mitochondrial membrane transport protein, the mitochondrial Ca(2+) uniporter (MCU) that transports Ca(2+) and is powered by the steep mitochondrial membrane potential. In the event of Ca(2+) overload, this leads to opening of the mitochondrial permeability transition pore (MPTP) and cell death. The third method describes how Na(+)-dependent mitochondrial Ca(2+) efflux mediated by mitochondrial NCLX, a member of the Na(+)/Ca(2+) exchanger superfamily, can be assayed in digitonin-permeabilized HEK-293 cells. The Ca(2+)-transport assays can be performed under various conditions and in combination with inhibitors, allowing detailed characterization of the transport activity of interest. PMID- 24492770 TI - Translational therapeutics in genetically engineered mouse models of cancer. AB - Advances in knowledge of the molecular alterations of human cancers, refinements in technologies for the generation of genetically engineered mouse models (GEMMs), and the development of cancer therapies have accelerated in recent years. Progress in these fields provides the foundation for clinically relevant studies to be performed in GEMMs, through which it is possible to glean information on drug efficacy and to identify determinants of sensitivity and resistance to drugs and drug combinations. GEMMs used in pre-, co-, and postclinical studies must closely recapitulate the genetics, histopathology, and response to therapy of the human disease. Prevention and intervention trials can be designed in GEMMs to test the effects of drugs on tumor initiation, regression, and progression. Given their complexity, careful consideration of the infrastructure requirements and practical aspects of each individual experiment, including enrollment, tumor monitoring, and dose and schedule, must be considered in the design of therapeutic studies in GEMMs. Advantages of GEMMs include the ability to rapidly perform drug efficacy studies in a defined genetic background, the ease of pharmacodynamic and pharmacokinetic assessments, and the possibility of experimentally manipulating model systems to address questions that cannot be addressed in patients. In light of these features, GEMMs are useful tools for translational studies to inform clinical trials in cancer patients. PMID- 24492771 TI - Assay of Ca2+ transport by VDAC1 reconstituted into liposomes. AB - Ca(2+) permeability mediated by voltage-dependent anion-selective channel protein 1 (VDAC1) can be tested by reconstitution of purified VDAC1 into liposomes. Here, we describe a setup for this membranal system, which has been used to study the transport activity of various transporters, including VDAC1, and allows detection of the passage of molecules across the lipid bilayer. Despite the disadvantage of needing radiolabeled molecules, this system is highly desirable when the transport properties of noncharged molecules and/or active transporters are studied. PMID- 24492772 TI - Assays of mitochondrial Ca2+ transport and Ca2+ efflux via the MPTP. AB - Studying Ca(2+) transport in mitochondria in connection with energy production, as well as cell death, is of great importance. Ca(2+) activates several key enzymes in the mitochondrial matrix to enhance ATP production. This provides an important mechanism for synchronizing energy production with the energy demands of Ca(2+)-activated processes, such as contraction, allowing important feedback effects to help shape cytosolic Ca(2+) signals. A rise in mitochondrial Ca(2+) can convey both apoptotic and necrotic death signals by inducing opening of the mitochondrial permeability transition pore (MPTP). Here, we present a protocol for measuring Ca(2+) transport and release in isolated mitochondria. PMID- 24492773 TI - Mitochondrial Na+/Ca2+ exchange assays. AB - Here, we describe two complementary assays designed to analyze mitochondrial Na(+)/Ca(2+) exchange activity. In both procedures, the counter ion transport of sodium and calcium ions across the inner membrane of mitochondria is assayed in permeabilized cells preloaded with a mitochondria-selective Na(+) probe, CoroNa Red, or with a mitochondria-targeted calcium sensor, ratiometric-pericam, respectively. These methods, therefore, do not require a mitochondrial preisolation step, with the native cellular mitochondrial architecture being maintained. Importantly, these methods equilibrate the cytosol with the extracellular milieu to allow control over the extra-mitochondrial ionic environment, while eliminating any possible interference by plasma membrane transporters. PMID- 24492774 TI - Generation of drug-resistant tumors using intermittent dosing of tyrosine kinase inhibitors in mouse. AB - Resistance to targeted therapies has emerged as a major hurdle for the successful use of drugs in the clinic. Therefore, understanding the underlying molecular mechanisms of drug resistance is crucial for the identification of strategies to prevent and overcome it. Given the defined nature of the oncogenic lesions present in genetically engineered mouse models (GEMMs) and the relative ease of sample collection and analysis, they are ideal systems in which to recapitulate the response and subsequent emergence of resistance to targeted therapies. When agents that are very effective at eradicating tumors are used in GEMMs, obtaining drug-resistant tumors can be a challenge. One approach to generating such tumors is the use of a suboptimal intermittent dosing strategy to treat the animals, which allows for periods of tumor growth and progression in the absence of drug. This intermittent dosing strategy has been used successfully to study resistance to the tyrosine kinase erlotinib in lung cancer models and is described here. Although this protocol is specific for this experimental system, the concepts and general design can be adapted for use with GEMMs of other cancers. PMID- 24492775 TI - Mosaic analysis with double markers (MADM) in mice. AB - The human brain comprises more than 100 billion neurons, each of which has an elaborate shape and a complex pattern of connections. To untangle this complexity, it is often useful to visualize one neuron at a time. Mosaic analysis with double markers (MADM) is a genetic method for labeling and manipulating individual neurons. This method was developed in mice and it allows simultaneous labeling and gene knockout in clones of somatic cells or isolated single cells in vivo. In MADM, labeling is achieved by using site-specific recombinases to induce the reconstitution of chimeric fluorescent proteins. Here we provide the standard procedure for utilizing MADM to examine lineage analysis, neural circuit tracing, and gene function. ROSA26-MADM is used as an example because the reagents are published and available. As MADM cassettes are introduced onto more chromosomes, genes located on these other chromosomes can be subjected to mosaic analysis in an analogous manner to that described below. We present detailed protocols with troubleshooting guides, as well as applications of the technique in tracing neural circuits, live imaging of developing neurons, and studying mechanisms of neuronal morphogenesis. PMID- 24492776 TI - Genetic labeling of neurons in mouse brain. AB - Mammalian central nervous systems consist of highly diverse types of neurons, which are the functional units of neural circuits. To understand the organization, assembly, and function of neural circuits, it is necessary to develop and to improve technologies that allow efficient and robust visualization of neurons in their native environment in vivo. Here we discuss various genetic strategies for achieving specific and robust neuron labeling in mice. PMID- 24492777 TI - Cre-dependent adeno-associated virus preparation and delivery for labeling neurons in the mouse brain. AB - Virus-mediated gene delivery is a powerful strategy for labeling and manipulating neurons in mammalian brains. A major drawback of this gene delivery method has been the lack of cell-type specificity. However, methods that combine Cre-knockin mice and Cre-activated adeno-associated virus (AAV) have now been developed to achieve high-level, stable, and cell-type-specific gene expression. Here, we describe a protocol for the design, production, and delivery of Cre-dependent AAVs. This method is simple and highly efficient, and allows chronic live imaging of defined classes of synapses in the mouse brain. PMID- 24492778 TI - Tracking receptors using individual fluorescent and nonfluorescent nanolabels. AB - The plasma membrane is a fluid-mosaic structure in which some molecules seem to be randomly distributed and others show a precise compartmentalization that is related to their functional properties. These membrane domains are submicrometer in size and therefore are close to or below the optical diffraction limit. This makes their study difficult by conventional microscopy. Moreover, these compartments are usually dynamic in size and composition as their component molecules can continuously enter and exit by diffusion. Real-time, high resolution, live-imaging methods rather than static imaging are thus required to reflect the real behavior of membrane molecules. Single-molecule techniques fulfill these requirements, as they provide information about the dynamics of molecules, together with nanometer resolution to study their distribution. Here we describe imaging and tracking techniques using nanometer-sized optical labels for the study of the movement of individual or small assemblies of membrane proteins. These labels include fluorescent dyes, luminescent nanocrystals, and absorbing metallic nanoparticles. Single-molecule tracking (SMT), with the use of organic dyes and semiconductor quantum dots (QDs), and single-particle tracking (SPT), with the use of gold nanoparticles, allow one to study the diffusion of individual molecules, their compartmentalization, and their interactions with other molecules. This protocol describes three methods for imaging and tracking membrane proteins: SMT using an organic dye, quantum dot tracking (QDT), and single-nanoparticle photothermal tracking (SNaPT) using gold nanoparticles. Organic dyes and QDs are tracked by single-molecule epifluorescence microscopy. Gold nanoparticles are detected by photothermal heterodyne imaging (PHI) and tracked using a triangulation scheme. PMID- 24492779 TI - Imaging biological samples with atomic force microscopy. AB - Atomic force microscopy (AFM) is an invaluable tool both for obtaining high resolution topographical images and for determining the values of mechanical and structural properties of specimens adsorbed onto a surface. AFM is useful in an array of fields and applications, from materials science to biology. It is an extremely versatile technique that can be applied to almost any surface-mounted sample and can be operated in ambient air, ultrahigh vacuum, and, most importantly for biology, liquids. AFM can be used to explore samples ranging in size from atoms to molecules, molecular aggregates, and cells. Individual biomolecules can be viewed and manipulated at the nanoscale, providing fundamental biological information. In particular, the study of the mechanical properties of biomolecular aggregates at the nanoscale constitutes an important source of data to elaborate mechanochemical structure/function models of single particle biomachines, expanding and complementing the information obtained from bulk experiments. PMID- 24492780 TI - Scanning microarray slides. AB - Here we describe some practical concerns surrounding the scanning of microarray slides that have been hybridized with fluorescent dyes. We use a laser scanner that has two lasers, each set to excite a different fluor, and separate detectors to capture emission from each fluor. The laser passes over an address (position on the scanned surface) and the detectors capture photons emitted from each address. Two superimposed image files are written that carry intensities for each channel for each pixel of the image scan. These are the raw data. Image analysis software is used to identify and summarize the intensities of the pixels that make up each spot. After comparison to background pixels, the processed intensity levels representing the gene expression measurements are associated with the identity of each spot. PMID- 24492781 TI - Tips on hybridizing, washing, and scanning affymetrix microarrays. AB - Starting in the late 1990s, Affymetrix, Inc. produced a commercial system for hybridizing, washing, and scanning microarrays that was designed to be easy to operate and reproducible. The system used arrays packaged in a plastic cassette or chamber in which the prefabricated array was mounted and could be filled with fluid through resealable membrane ports either by hand or by an automated "fluidics station" specially designed to handle the arrays. A special rotating hybridization oven and a specially designed scanner were also required. Primarily because of automation and standardization the Affymetrix system was and still remains popular. Here, we provide a skeleton protocol with the potential pitfalls identified. It is designed to augment the protocols provided by Affymetrix. PMID- 24492782 TI - Methods for processing microarray data. AB - Quality control must be maintained at every step of a microarray experiment, from RNA isolation through statistical evaluation. Here we provide suggestions for analyzing microarray data. Because the utility of the results depends directly on the design of the experiment, the first critical step is to ensure that the experiment can be properly analyzed and interpreted. What is the biological question? What is the best way to perform the experiment? How many replicates will be required to obtain the desired statistical resolution? Next, the samples must be prepared, pass quality controls for integrity and representation, and be hybridized and scanned. Also, slides with defects, missing data, high background, or weak signal must be rejected. Data from individual slides must be normalized and combined so that the data are as free of systematic bias as possible. The third phase is to apply statistical filters and tests to the data to determine genes (1) expressed above background, (2) whose expression level changes in different samples, and (3) whose RNA-processing patterns or protein associations change. Next, a subset of the data should be validated by an alternative method, such as reverse transcription-polymerase chain reaction (RT-PCR). Provided that this endorses the general conclusions of the array analysis, gene sets whose expression, splicing, polyadenylation, protein binding, etc. change in different samples can be classified with respect to function, sequence motif properties, as well as other categories to extract hypotheses for their biological roles and regulatory logic. PMID- 24492783 TI - A hybrid method for prediction and repositioning of drug Anatomical Therapeutic Chemical classes. AB - In the Anatomical Therapeutic Chemical (ATC) classification system, therapeutic drugs are divided into 14 main classes according to the organ or system on which they act and their chemical, pharmacological and therapeutic properties. This system, recommended by the World Health Organization (WHO), provides a global standard for classifying medical substances and serves as a tool for international drug utilization research to improve quality of drug use. In view of this, it is necessary to develop effective computational prediction methods to identify the ATC-class of a given drug, which thereby could facilitate further analysis of this system. In this study, we initiated an attempt to develop a prediction method and to gain insights from it by utilizing ontology information of drug compounds. Since only about one-fourth of drugs in the ATC classification system have ontology information, a hybrid prediction method combining the ontology information, chemical interaction information and chemical structure information of drug compounds was proposed for the prediction of drug ATC classes. As a result, by using the Jackknife test, the 1st prediction accuracies for identifying the 14 main ATC-classes in the training dataset, the internal validation dataset and the external validation dataset were 75.90%, 75.70% and 66.36%, respectively. Analysis of some samples with false-positive predictions in the internal and external validation datasets indicated that some of them may even have a relationship with the false-positive predicted ATC-class, suggesting novel uses of these drugs. It was conceivable that the proposed method could be used as an efficient tool to identify ATC-classes of novel drugs or to discover novel uses of known drugs. PMID- 24492784 TI - The effect of starvation on blood stream cancer cell metastasis to the liver in rat after laparotomy. AB - BACKGROUND: Preoperative malnutrition worsens the prognosis of cancer patients. However, it is not certain how preoperative malnutrition affects postoperative hematogenous metastasis. We examined the influence of preoperative starvation on liver metastasis in rats using intra-vascular injection of AH109A hepatoma cells. METHODS: Male donryu rats were divided into Fasting and Control groups. Rats received laparotomy and (125)I-iodo-deoxyuridine labeled AH109A hepatoma cells were inoculated via superior mesenteric vein. Radioactivity in the organs, macroscopic liver metastasis, white blood cell count, leukocyte count, NK cell activity, endogenous serum corticosterone and ACTH concentration and mRNA expression of cytokine in the liver and brain were evaluated at certain time points. RESULTS: 48hours preoperative starvation reduced body weight and induced a state of malnutrition. Accumulation of radioactivity in the liver was more than 4 times higher, and the number of liver metastases was 3.5 times higher in the Fasting than in the Control group. Preoperative starvation caused an almost 2 fold increase in plasma endogenous corticosterone levels and a 66% reduction in white blood cell and lymphocyte counts. Postoperative hypothalamus pituitary adrenal axis response was preserved. In addition, inflammatory cytokine expression in the liver was suppressed in the starved animals, suggesting that preoperative starvation led to a state of cellular immunosuppression, which would be an important factor for liver metastasis. CONCLUSION: Preoperative malnutrition by 48 hours starvation reduced inflammatory cytokine response and cellular immunity, resulting in an increase in hematogenous liver metastasis. PMID- 24492785 TI - Fully solution-processed flexible organic thin film transistor arrays with high mobility and exceptional uniformity. AB - Printing fully solution-processed organic electronic devices may potentially revolutionize production of flexible electronics for various applications. However, difficulties in forming thin, flat, uniform films through printing techniques have been responsible for poor device performance and low yields. Here, we report on fully solution-processed organic thin-film transistor (TFT) arrays with greatly improved performance and yields, achieved by layering solution-processable materials such as silver nanoparticle inks, organic semiconductors, and insulating polymers on thin plastic films. A treatment layer improves carrier injection between the source/drain electrodes and the semiconducting layer and dramatically reduces contact resistance. Furthermore, an organic semiconductor with large-crystal grains results in TFT devices with shorter channel lengths and higher field-effect mobilities. We obtained mobilities of over 1.2 cm(2) V(-1) s(-1) in TFT devices with channel lengths shorter than 20 MUm. By combining these fabrication techniques, we built highly uniform organic TFT arrays with average mobility levels as high as 0.80 cm(2) V( 1) s(-1) and ideal threshold voltages of 0 V. These results represent major progress in the fabrication of fully solution-processed organic TFT device arrays. PMID- 24492786 TI - Cardiomyopathies: paediatric screening criterion for HCM. PMID- 24492787 TI - Coronary artery disease: appropriate testing for stable ischaemic heart disease. AB - Currently, numerous tests are available for the assessment and triage of patients with stable ischaemic heart disease. National societies in the USA have collaborated to develop appropriate use criteria to give guidance to clinicians about the evidence-based use of these tests. PMID- 24492788 TI - Valvular disease: implications of new-onset conduction abnormalities after TAVI. PMID- 24492790 TI - Arrhythmias: AF recurrence after cryoablation. PMID- 24492791 TI - (Pb,Cd)-O covalency in PbTiO3-CdTiO3 with enhanced negative thermal expansion. AB - Recently experiments have found that negative thermal expansion is a common phenomenon in PbTiO3-based materials, and their negative thermal expansion is affected by various substitutions. Interestingly, Cd substitution in PbTiO3 has a unique effect in enhancing negative thermal expansion compared with any other A site substitutions. Therefore, studying Cd substitution in PbTiO3, the role of which still remains unclear, would bring us deeper understanding on the nature of the negative thermal expansion of PbTiO3-based materials. Structure calculations, density of states, Bader analysis and the minimum electron density of Pb1 xCdxTiO3 supercells have been reported on the chemical bond through first principles calculations here. We found that the hybridization between (Pb,Cd)-O orbitals exists in tetragonal phase. Furthermore, the hybridization between Cd-O orbitals is stronger than that between Pb-O orbitals, and Cd-O covalency promotes the average A-site hybridization. Simultaneously, the average bulk coefficient of thermal expansion is negative and inversely proportional to the Cd substitution amount. So, (Pb,Cd)-O covalency in the tetragonal Pb1-xCdxTiO3 is responsible for the nature of enhanced negative thermal expansion in accordance with our previous experimental investigations. PMID- 24492792 TI - Robust small area prediction for counts. AB - A new semiparametric approach to model-based small area prediction for counts is proposed and used for estimating the average number of visits to physicians for Health Districts in Central Italy. The proposed small area predictor can be viewed as an outlier robust alternative to the more commonly used empirical plug in predictor that is based on a Poisson generalized linear mixed model with Gaussian random effects. Results from the real data application and from a simulation experiment confirm that the proposed small area predictor has good robustness properties and in some cases can be more efficient than alternative small area approaches. PMID- 24492793 TI - Sample size considerations in active-control non-inferiority trials with binary data based on the odds ratio. AB - This paper presents an approximate closed form sample size formula for determining non-inferiority in active-control trials with binary data. We use the odds-ratio as the measure of the relative treatment effect, derive the sample size formula based on the score test and compare it with a second, well-known formula based on the Wald test. Both closed form formulae are compared with simulations based on the likelihood ratio test. Within the range of parameter values investigated, the score test closed form formula is reasonably accurate when non-inferiority margins are based on odds-ratios of about 0.5 or above and when the magnitude of the odds ratio under the alternative hypothesis lies between about 1 and 2.5. The accuracy generally decreases as the odds ratio under the alternative hypothesis moves upwards from 1. As the non-inferiority margin odds ratio decreases from 0.5, the score test closed form formula increasingly overestimates the sample size irrespective of the magnitude of the odds ratio under the alternative hypothesis. The Wald test closed form formula is also reasonably accurate in the cases where the score test closed form formula works well. Outside these scenarios, the Wald test closed form formula can either underestimate or overestimate the sample size, depending on the magnitude of the non-inferiority margin odds ratio and the odds ratio under the alternative hypothesis. Although neither approximation is accurate for all cases, both approaches lead to satisfactory sample size calculation for non-inferiority trials with binary data where the odds ratio is the parameter of interest. PMID- 24492794 TI - Various varying variances: The challenge of nuisance parameters to the practising biostatistician. AB - The 1997 Biometrics paper by Mike Kenward and James Roger has become a citation classic (more than 1260 citations by End June 2013 according to Google Scholar) and the solution that they proposed to deal with the problem of significance tests of fixed effects in REML models is now incorporated in many software packages and accepted by all biostatisticians as the method of choice. Nevertheless, it does not solve all problems, since there is more to analysis than just significance and since the problems that models with more than one variance pose arise in many contexts. In this paper, I discuss some problems and applications and make some tentative suggestions as to how they may be tackled. My excuse for raising problems I do not solve is that it may inspire James and Mike to complete what they started. PMID- 24492795 TI - A Bayesian network for modelling blood glucose concentration and exercise in type 1 diabetes. AB - This article presents a new statistical approach to analysing the effects of everyday physical activity on blood glucose concentration in people with type 1 diabetes. A physiologically based model of blood glucose dynamics is developed to cope with frequently sampled data on food, insulin and habitual physical activity; the model is then converted to a Bayesian network to account for measurement error and variability in the physiological processes. A simulation study is conducted to determine the feasibility of using Markov chain Monte Carlo methods for simultaneous estimation of all model parameters and prediction of blood glucose concentration. Although there are problems with parameter identification in a minority of cases, most parameters can be estimated without bias. Predictive performance is unaffected by parameter misspecification and is insensitive to misleading prior distributions. This article highlights important practical and theoretical issues not previously addressed in the quest for an artificial pancreas as treatment for type 1 diabetes. The proposed methods represent a new paradigm for analysis of deterministic mathematical models of blood glucose concentration. PMID- 24492796 TI - Patterns of burns and scalds in children. AB - OBJECTIVE: To describe the characteristics of childhood burns and scalds, mechanisms and agents to inform prevention. METHODS: Prospective multicentred cross-sectional study of children (<16 years) with unintentional burns/scalds from five Emergency Departments (ED), a burns assessment unit and three regional children's Burns Units. DATA COLLECTED: site, severity, distribution of the burn/scald, age, motor development of the child, agent and mechanism of the injury. Comparative analysis for children <5 and 5-16 years. RESULTS: Of 1215 children, 58% (709) had scalds, 32% (390) contact burns and 116 burns from other causes, 17.6% (214/1215) were admitted to hospital and the remaining treated in ED or burns assessment centre. 72% (878) were <5 years, peak prevalence in 1-year olds. Commonest scald agent (<5 years) was a cup/mug of hot beverage 55% (305/554), and commonest mechanism was a pull-down injury 48% (66/554). In 5-16 year-olds, scalds were from hot water 50% (78/155) and spill injuries 76% (118/155). Scalds affected the front of the body in 96% (680/709): predominantly to the face, arms and upper trunk in <5-year-olds, older children had scalds to the lower trunk, legs and hands. Contact burns (<5 years) were from touching 81% (224/277) hot items in the home, predominant agents: hair straighteners or irons 42% (117/277), oven hobs 27% (76/277), 5-16-year-olds sustained more outdoor injuries 46% (52/113). 67% (262/390) of all contact burns affected the hands. CONCLUSIONS: Scalds to infants and toddlers who pull hot beverages over themselves or sustain burns from touching irons, hair straighteners or oven hobs are a high priority for targeted prevention. PMID- 24492797 TI - Treatment of chronic viral hepatitis C in children and adolescents: UK experience. AB - AIM: To review the efficacy and tolerability of pegylated interferon-alpha and ribavirin for treatment of chronic hepatitis C (CHC) in children in the UK. METHODS: Retrospective review of children treated for CHC in 3 UK paediatric specialist liver centres between 2005 and 2010. Data on viral response to treatment, demographic and clinical details were collected. Treatment outcome was assessed by the absence of detectable viral RNA in blood 24 weeks after treatment sustained viral response (SVR). RESULTS: 75 children were included; 34 genotype 1; 39 genotypes 2 and 3; 2 genotype 4. Overall SVR was achieved in 54/71 (76%); 65% genotype 1; 89% genotypes 2 and 3; 100% genotype 4. Early response at 12 weeks was achieved in 53 and sustained in 47 (89%). Data on rapid response after 4 weeks of treatment were available in 25; 17/25 (68%) responded and 16 of these (94%) achieved SVR. IL28 T/T genotype was associated with higher SVR. There were no significant changes in weight and height z scores from baseline compared with 24 weeks post-treatment follow-up. No child discontinued treatment due to side effects, although 43 required dose modification. Treatment affected quality of life (QoL) in the initial 12 weeks of treatment, which improved by the end of treatment. CONCLUSIONS: Children respond well to therapy for CHC. Treatment was tolerated with minimal impact on QoL and no significant effect on growth. Knowledge of viral and IL28 genotypes and early viral response is useful to plan treatment in children and provide appropriate counselling. PMID- 24492798 TI - Ratios of effector to central memory antigen-specific CD4(+) T cells vary with antigen exposure in HIV+ patients. AB - The OX40/CD25 assay is a novel technique that assesses antigen-specific CD4(+) T cell responses. To unequivocally demonstrate that responding cells are memory cells that become activated after secondary stimulation, naive CD45RA(+) and memory CD45RO(+) populations were stimulated with cytomegalovirus (CMV) lysate and the combined expression of CD25 and OX40 measured. As expected, the naive population showed very little response, whereas there was a higher response from the memory counterpart. To further elucidate CD4(+) memory T-cell subsets involved in recall responses, CD4(+) T cells were separated into central memory (Tcm) and effector memory (Tem) subsets and stimulated with antigen-pulsed antigen-presenting cells (APCs). CMV responses in healthy donors showed a Tem dominant response with a Tem/Tcm ratio of 1.2, whereas the tetanus toxoid responses were dominated by a Tcm response with a Tem/Tcm ratio of 0.35. To determine memory response in the chronic of HIV infection, patient samples were used. A similar pattern to healthy donors was observed in seven chronic HIV+ patients at week 4 after anti-retroviral therapy who responded to CMV with a larger response coming from Tem. The pattern was similar after 48 weeks of therapy but the responses were lower in magnitude. In chronic HIV+ patients who respond to Gag peptides, following institution of therapy there was an inversion of the ratio of the responding memory subsets compared with week 4, with a greater response from Tcm at week 48. This result was concordant with reduction in antigen load. As immune activation decreased there was also a decrease in the percentage of responding effector memory cells and maintenance of long-term central memory. PMID- 24492799 TI - Toll-like receptors and NLRP3 as central regulators of pancreatic islet inflammation in type 2 diabetes. AB - The global health and economic burden of type 2 diabetes (T2D) has reached staggering proportions. Current projections estimate that 592 million people will have diabetes by 2035. T2D-which comprises 90% of cases-is a complex disease, in most cases resulting from a combination of predisposing genes and an unhealthy environment. Clinical onset of the disease occurs when pancreatic beta cells fail in the face of insulin resistance. It has long been appreciated that chronic activation of the innate immune system is associated with T2D, and many organs critical to the regulation of glucose homeostasis show signs of a chronic inflammatory process, including the pancreatic islets of Langerhans. Recent clinical trials using IL-1-targeting agents have confirmed that inflammation contributes to beta-cell failure in humans with T2D. However, little is known about the nature of the pro-inflammatory response within the islet, and there is considerable debate about the triggers for islet inflammation, which may be systemically derived and/or tissue-specific. In this review, we present evidence that Toll-like receptors 2 and 4 and the NLRP3 (Nucleotide-binding oligomerization domain, Leucine-rich Repeat and Pyrin domain containing 3) inflammasome are triggers for islet inflammation in T2D and propose that the activation of macrophages by these triggers mediates islet endocrine cell dysfunction. Therapeutically targeting these receptors may improve hyperglycemia and protect the beta cell in T2D. PMID- 24492800 TI - The unconventional expression of IL-15 and its role in NK cell homeostasis. AB - Natural killer (NK) cells are the founding members of the innate lymphoid cell family and contribute to the rapid production of inflammatory mediators upon pathogen detection. The evolution of receptors for self major histocompatibility complex-I and stress-induced ligands also bestows upon NK cells an important effector role in the clearance of virus-infected and transformed cells. NK cells are dependent on the pleiotropic cytokine interleukin (IL)-15 for their development, differentiation and optimal function. Here I review the regulation of IL-15 in vivo, its role in driving NK cell differentiation and discuss the function of NK cell diversification with regard to innate immunity. PMID- 24492802 TI - Photo- and thermo-induced spin crossover in a cyanide-bridged {Mo(V)2Fe(II)2} rhombus molecule. AB - The self-assembly of [Mo(V)(CN)8](3-) and [Fe(II)(bik)2(S)2](2+) affords a cyanide-bridged {Mo(V)2Fe(II)2} rhombus molecule that shows photomagnetic effect under laser light irradiation at low temperature and exhibits thermo-induced spin crossover near ambient temperature. PMID- 24492808 TI - The neurology of pregnancy: a tribute to dr autumn klein. Preface. PMID- 24492809 TI - Neuroradiology in women of childbearing age. AB - PURPOSE OF REVIEW: This review summarizes safety concerns associated with diagnostic neuroimaging in patients who are of childbearing age, focusing on diagnostic modalities and radiologic features of neurologic conditions encountered by pregnant women. RECENT FINDINGS: During pregnancy, women experience a range of physiologic changes that can affect neurologic function. These include endocrine, hemodynamic, endothelial, immunologic, and coagulopathic changes that can alter susceptibility to stroke, subarachnoid hemorrhage, demyelination, venous thrombosis, and other neurologic conditions. Unique safety concerns are associated with imaging procedures performed to diagnose neurologic conditions that occur during pregnancy. SUMMARY: This review discusses the use of diagnostic neuroimaging, including administration of IV contrast, in pregnant women and in nonpregnant women of childbearing age. PMID- 24492810 TI - Multiple sclerosis in pregnancy. AB - PURPOSE OF REVIEW: This article reviews the current understanding of the interactions between multiple sclerosis (MS) and pregnancy, and implications for reproductive counseling. This is a key topic in MS because the typical patient is a young woman of childbearing age. RECENT FINDINGS: It has been known for some time that MS disease activity markedly reduces during the last trimester of pregnancy, then markedly increases in the 3 months postpartum before returning to the prepregnancy baseline. High relapse rate or disability before pregnancy, as well as relapse during pregnancy, have been associated with increased risk for postpartum attacks. Recent data continue to support the conclusion that long-term disease progression is not worsened (and may actually be lessened) with pregnancy in patients with relapsing MS; the data are not so clear for those with progressive MS. Among the MS disease-modifying therapies, the only one that requires contraception use by men is the new oral agent teriflunomide, because the drug is present in semen. It is reassuring that, to date, no human teratogenic effects have been documented for any of the MS disease-modifying therapies. SUMMARY: Pregnancy has a profound effect on MS disease activity. Identification of the responsible mechanisms for this effect should lead to new disease insights and therapeutic strategies. PMID- 24492801 TI - Innate and adaptive type 2 immune cell responses in genetically controlled resistance to intestinal helminth infection. AB - The nematode Heligmosomoides polygyrus is an excellent model for intestinal helminth parasitism. Infection in mice persists for varying lengths of time in different inbred strains, with CBA and C57BL/6 mice being fully susceptible, BALB/c partially so and SJL able to expel worms within 2-3 weeks of infection. We find that resistance correlates not only with the adaptive Th2 response, including IL-10 but with activation of innate lymphoid cell and macrophage populations. In addition, the titer and specificity range of the serum antibody response is maximal in resistant mice. In susceptible strains, Th2 responses were found to be counterbalanced by IFN-gamma-producing CD4(+) and CD8(+) cells, but these are not solely responsible for susceptibility as mice deficient in either CD8(+) T cells or IFN-gamma remain unable to expel the parasites. Foxp3(+) Treg numbers were comparable in all strains, but in the most resistant SJL strain, this population does not upregulate CD103 in infection, and in the lamina propria the frequency of Foxp3(+)CD103(+) T cells is significantly lower than in susceptible mice. The more resistant SJL and BALB/c mice develop macrophage-rich IL-4Ralpha-dependent Type 2 granulomas around intestinal sites of larval invasion, and expression of alternative activation markers Arginase-1, Ch3L3 (Ym1) and RELM-alpha within the intestine and the peritoneal lavage was also strongly correlated with helminth elimination in these strains. Clodronate depletion of phagocytic cells compromises resistance of BALB/c mice and slows expulsion in the SJL strain. Thus, Type 2 immunity involves IL-4Ralpha-dependent innate cells including but not limited to a phagocyte population, the latter likely involving the action of specific antibodies. PMID- 24492811 TI - Pregnancy and epilepsy. AB - PURPOSE OF REVIEW: This review encompasses issues regarding the management of women with epilepsy and pregnancy, including preconception planning, antiepileptic drug (AED) effects on the exposed offspring, and consequences of seizures during pregnancy, with an emphasis on counseling points and risk management. RECENT FINDINGS: In utero valproate exposure continues to show the highest risk of congenital malformations and of adverse cognitive outcomes, including autism, compared to other AEDs. In utero topiramate exposure is associated with facial clefts. In utero exposure to lamotrigine, carbamazepine, phenytoin, and levetiracetam has been evaluated in large numbers of offspring, and all of these AEDs have a low risk of major congenital malformations, near 2.5%. The risk of major congenital malformations due to in utero AED exposure is dose associated. Folic acid taken at the time of conception decreases the risk of adverse cognitive outcomes. AED polytherapy may adversely affect fertility, and in utero exposure of AED polytherapy is associated with infants who are small for their gestational age. Seizure freedom before pregnancy is a good predictor of remaining seizure free during pregnancy. SUMMARY: Counseling points are complex for managing women with epilepsy contemplating pregnancy, including evaluation of AED choice and dose. The physician must have knowledge of the issues to enable an honest discussion and appropriate decision making in partnership with the patient. PMID- 24492812 TI - Cerebrovascular disorders complicating pregnancy. AB - PURPOSE OF REVIEW: This article discusses the physiologic changes of pregnancy and how they affect risk of ischemic and hemorrhagic stroke and then reviews epidemiology, diagnosis, and treatment of ischemic and hemorrhagic stroke in pregnancy and the puerperium. RECENT FINDINGS: This article updates our understanding of the relationship of preeclampsia/eclampsia to the posterior reversible encephalopathy syndrome and the reversible cerebral vasoconstriction syndrome, emphasizing their shared pathogenesis. It reviews the most recent data and offers recommendations concerning the use of thrombolytic and other revascularization therapies for pregnancy-related strokes. SUMMARY: Although cerebrovascular complications are uncommon occurrences during pregnancy and the puerperium, stroke is still the most common seriously disabling complication of pregnancy. Therefore, stroke and other vascular issues raise questions about the best evaluation and management that is safe for mother and child. PMID- 24492813 TI - Peripheral neuropathies in pregnancy. AB - PURPOSE OF REVIEW: This article provides an overview of the most common peripheral neuropathic disorders in pregnancy with a focus on clinical recognition, diagnosis, and treatment. RECENT FINDINGS: The literature on this topic consists primarily of case reports, case series, and retrospective reviews. Recent work, particularly in carpal tunnel syndrome, brachial neuritis, and inherited neuropathies in pregnancy, has added to our knowledge of this field. Awareness of diabetic polyneuropathy with associated autonomic dysfunction in pregnancy has grown as the incidence of diabetes mellitus increases in women of childbearing age. SUMMARY: Women may develop mononeuropathy, plexopathy, radiculopathy, or polyneuropathy during pregnancy or postpartum. Pregnancy often influences consideration of etiology, treatment, and prognosis. In women of childbearing age with known acquired or genetic neuromuscular disorders, pregnancy should be anticipated and appropriate counseling provided. An interdisciplinary approach with other medical specialties is often necessary. PMID- 24492815 TI - Headache in pregnancy. AB - PURPOSE OF REVIEW: This article provides an overview of the diagnosis and management of primary and secondary headaches that may occur during pregnancy and postpartum. Headache presenting in pregnancy is of significant concern to the affected woman. Quick and correct diagnosis leads to the optimal management, minimizing risks to the pregnancy. RECENT FINDINGS: Several strategies have been developed to distinguish secondary headaches that need urgent assessment and management from benign primary and secondary headaches and to minimize the risk of misdiagnosis. Recent guidelines for the drug treatment of headaches are considered in the context of updated information on the safety of drugs in pregnancy and lactation. SUMMARY: Primary headaches are common and typically improve during pregnancy. Management during pregnancy and lactation is similar to management in the nonpregnant state, with a few exceptions. Secondary causes of headache that are more likely to occur during pregnancy include cerebral venous thrombosis, posterior reversible encephalopathy syndrome resulting from eclampsia, post-dural puncture headache, stroke, and pituitary apoplexy. PMID- 24492814 TI - Pregnancy and myasthenia gravis. AB - PURPOSE OF REVIEW: Myasthenia gravis (MG) is an acquired autoimmune disorder characterized by fluctuating ocular, limb, or oropharyngeal muscle weakness due to an antibody-mediated attack at the neuromuscular junction. The female incidence of MG peaks in the third decade during the childbearing years. A number of exacerbating factors may worsen MG, including pregnancy. When treatment is needed, it must be carefully chosen with consideration of possible effects on the mother with MG, the pregnancy, and the fetus. RECENT FINDINGS: Decisions are complex in the treatment of women with MG contemplating pregnancy or with presentation during pregnancy. While data is largely observational, a number of characteristic patterns and issues related to risk to the patient, integrity of the pregnancy, and risks to the fetus are recognized. Familiarity with these special considerations when contemplating pregnancy is essential to avoid potential hazards in both the patient and the fetus. Use of immunosuppressive agents incurs risk to the fetus. Deteriorating MG with respiratory insufficiency poses risk to both the mother and the fetus. SUMMARY: This article reviews available information regarding expectations and management for patients with MG in the childbearing age. Treatment decisions must be individualized based on MG severity, distribution of weakness, coexisting diseases, and welfare of the fetus. Patient participation in these decisions is essential for successful management. PMID- 24492816 TI - Movement disorders in pregnancy. AB - PURPOSE OF REVIEW: This review discusses movement disorders that occur during pregnancy, the treatment of preexisting movement disorders, and the influence the pregnant state has on movement disorders symptoms, in order to guide clinicians in providing better counseling for female patients who are pregnant or considering pregnancy. RECENT FINDINGS: Unique considerations for movement disorders during pregnancy include investigations and their safety during pregnancy and the impact of treatment on both the pregnant patient and her fetus. SUMMARY: The most common movement disorders arising in pregnancy are restless leg syndrome and chorea gravidarum. Preexisting movement disorders in women who become pregnant may also be seen. PMID- 24492817 TI - Neuro-ophthalmic disorders in pregnancy. AB - PURPOSE OF REVIEW: This review discusses evaluation and treatment of neuro ophthalmic disorders in the pregnant patient. RECENT FINDINGS: Any neuro ophthalmic abnormality seen in nonpregnant women can be seen in pregnant women. Pregnancy-specific complications (preeclampsia and eclampsia) cause visual symptoms and can affect the entire visual axis. SUMMARY: Appropriate evaluation and examination is important to preserve the health and vision of the mother and prevent complications in the fetus. Evaluation should proceed in the same way for a pregnant patient as it would for a nonpregnant patient, with few exceptions. Treatment decisions may be influenced by stage of pregnancy. PMID- 24492818 TI - Reproductive issues in women with multiple sclerosis: ethical considerations. AB - Addressing the reproductive concerns of women with multiple sclerosis (MS) is vital for comprehensive care. Contraception, conception, pregnancy, and breast feeding present many vexing questions to the woman with MS. The risks and benefits of using disease-modifying therapy during the various stages of a woman's reproductive life are topics that need to be discussed. The physician's primary duty is to the patient; however, the physician must also consider the fetus and later the child. In helping guide the patient in making medical decisions, the physician must take into account the patient's motivation for those decisions, including family obligations, cultural norms, and patient values. The physician is instrumental in providing the patient with sound, nonjudgmental information and advice so that she may make a well-informed, autonomous decision about her health and her disease. PMID- 24492819 TI - Epilepsy and pregnancy: a practical approach to mitigating legal risk. AB - Women with epilepsy are at increased risk of obstetric complications and poorer cognitive outcomes for their offspring. This article aims to provide neurologists with a practical framework for understanding, identifying, and managing legal risk when treating pregnant women with epilepsy. PMID- 24492820 TI - Coding in pregnancy with a focus on epilepsy. PMID- 24492825 TI - Patient management problem. PMID- 24492828 TI - A novel network pharmacology approach to analyse traditional herbal formulae: the Liu-Wei-Di-Huang pill as a case study. AB - Understanding the mechanisms of the pharmacological effects of herbal formulae from traditional Chinese medicine (TCM) is important for their appropriate application. However, this understanding has been impeded by the complex nature of herbal formulae. A herbal formula is a mixture of hundreds of chemical ingredients with multiple potential targets. The effects produced by an entire herbal formula cannot be adequately explained by considering separately each ingredient in it. This is a recognised problem that remains in need of methods to solve it. Here we introduce a holistic analysis method to decipher the molecular mechanisms of herbal formulae. This method combines chemical and therapeutic properties with network pharmacology, using a novel approach to evaluate the importance of the targets and ingredients of herbal formulae. We used the Liu-Wei Di-Huang (LWDH) pill, a classic herbal formula, as an example to illustrate our method and validated some results by a following experiment. We revealed the core molecular targets and bioprocess network of the pharmacological effects of LWDH and inferred its therapeutic indications. This method provides a novel strategy to understand the mechanisms of herbal formulae in a holistic way and implies new applications of classic herbal formulae. PMID- 24492829 TI - Influence of sourdough on in vitro starch digestibility and predicted glycemic indices of gluten-free breads. AB - Gluten-free flours (buckwheat, quinoa, sorghum and teff) were fermented using obligate heterofermentative strain Weissella cibaria MG1 (Wc) and facultative heterofermentative Lactobacillus plantarum FST1.7 (Lp). Starch hydrolysis of breads with and without sourdough (controls) was analyzed in vitro using enzymatic digestion followed by dialysis (10-11 kDa). Hydrolysis indices as well as predicted glycemic indices (pGI) were calculated from reducing sugars released into the dialysate. Amounts of resistant starch (RS; % of total starch) were determined by enzymatic digestion. Upon sourdough addition, RS significantly decreased in buckwheat (Wc 1.28%, Lp 1.44%) and teff sourdough breads (Wc 0.87%, Lp 0.98%) in comparison to their controls (2.01% and 1.92%, respectively). However, no correlation was found with starch hydrolysis. Predicted GIs were reduced upon sourdough addition in wheat (ctrl 100; Wc 85; Lp 76) in comparison to control breads. This was not the case in most gluten-free breads with the exception of sorghum (ctrl 72; Lp 69) and teff sourdough breads (ctrl 74; Lp 68). In contrast, increased pGIs were found in quinoa (ctrl 95; Wc 106; Lp 103) and buckwheat sourdough breads (ctrl 80; Wc 89; Lp 86). PMID- 24492830 TI - Efficacy and safety of muscarinic antagonists as add-on therapy for male lower urinary tract symptoms. AB - Alpha-adrenoceptor antagonists (alpha-blockers) are widely prescribed to treat lower urinary tract symptoms (LUTS) in men but fail to ameliorate LUTS sufficiently, especially the storage symptoms related to frequency, urgency and nocturia. We performed a meta-analysis of randomised controlled trials (RCTs) comparing an alpha-blocker plus muscarinic antagonist with an alpha-blocker alone in male LUTS patients who were treated with alpha-blocker prior to randomisation. The review contained six randomised controlled trials (RCTs) that included a total of 2,208 male patients who were randomised to receive alpha-blocker plus muscarinic antagonist or alpha-blocker alone. The add-on group experienced significantly greater improvement in both total IPSS (International Prostate Symptom Score) and storage IPSS. Adverse events (AEs) were commonly experienced by both groups (41.6 vs. 33.3%) though they were not severe. Our meta-analysis indicated that muscarinic antagonists as add-on therapy alleviate LUTS, especially storage symptoms. The add-on therapy demonstrated safety and tolerability comparable with alpha-blocker monotherapy in male with LUTS. PMID- 24492831 TI - Breast cancer: CALOR favours adjuvant therapy for ILRR of breast cancer. PMID- 24492832 TI - Lung cancer: whack a GLI Hedgehog. PMID- 24492833 TI - Breast cancer: progress from NOAH study comes in twos. PMID- 24492834 TI - Bilateral breast cancers. AB - An increasingly large proportion of women with unilateral breast cancer are treated with bilateral mastectomy. The rationale behind bilateral surgery is to prevent a second primary breast cancer and thereby to avoid the resultant therapy and eliminate the risk of death from contralateral breast cancer. Bilateral mastectomy has been proposed to benefit women at high risk of contralateral cancer, such as carriers of BRCA1 and BRCA2 mutations, but for women without such mutations, the decision to remove the contralateral breast is controversial. It is important to evaluate the risk of contralateral breast cancer on an individual basis, and to tailor surgical treatment accordingly. On average, the annual risk of contralateral breast cancer is approximately 0.5%, but increases to 3% in carriers of a BRCA1 or BRCA2 mutation. Risk factors for contralateral breast cancer include a young age at first diagnosis of breast cancer and a family history of breast cancer. Contralateral mastectomy has not been proven to reduce mortality from breast cancer, but the benefit of such surgery is not expected to become apparent until the second decade after treatment. An alternative to contralateral mastectomy is adjuvant hormonal therapy (such as tamoxifen), but the extent of risk reduction is smaller (approximately 50%) compared to 95% or more for contralateral mastectomy. This Review focuses on the risk factors for contralateral breast cancer, and discusses the evidence that bilateral mastectomy might reduce mortality in patients with unilateral breast cancer. PMID- 24492835 TI - Kidney cancer: sunitinib has similar efficacy irrespective of age in mRCC. PMID- 24492836 TI - Clinical relevance of circulating cell-free microRNAs in cancer. AB - Efficient patient management relies on early diagnosis of disease and monitoring of treatment. In this regard, much effort has been made to find informative, blood-based biomarkers for patients with cancer. Owing to their attributes-which are specifically modulated by the tumour-circulating cell-free microRNAs found in the peripheral blood of patients with cancer may provide insights into the biology of the tumour and the effects of therapeutic interventions. Moreover, the role of microRNAs in the regulation of different cellular processes points to their clinical utility as blood-based biomarkers and future therapeutic targets. MicroRNAs are optimal biomarkers owing to high stability under storage and handling conditions and their presence in blood, urine and other body fluids. In particular, detection of levels of microRNAs in blood plasma and serum has the potential for an earlier cancer diagnosis and to predict prognosis and response to therapy. This Review article considers the latest developments in the use of circulating microRNAs as prognostic and predictive biomarkers and discusses their utility in personalized medicine. PMID- 24492837 TI - Cancer Systems Biology: a peek into the future of patient care? AB - Traditionally, scientific research has focused on studying individual events, such as single mutations, gene function, or the effect that mutating one protein has on a biological phenotype. A range of technologies is beginning to provide information that will enable a holistic view of how genomic and epigenetic aberrations in cancer cells can alter the homeostasis of signalling networks within these cells, between cancer cells and the local microenvironment, and at the organ and organism level. This process, termed Systems Biology, needs to be integrated with an iterative approach wherein hypotheses and predictions that arise from modelling are refined and constrained by experimental evaluation. Systems biology approaches will be vital for developing and implementing effective strategies to deliver personalized cancer therapy. Specifically, these approaches will be important to select those patients who are most likely to benefit from targeted therapies and for the development and implementation of rational combinatorial therapies. Systems biology can help to increase therapy efficacy or bypass the emergence of resistance, thus converting the current-often short term-effects of targeted therapies into durable responses, ultimately to improve patient quality of life and provide a cure. PMID- 24492838 TI - Extracellular signal-regulated kinase phosphorylation in forebrain neurones contributes to osmoregulatory mechanisms. AB - Vasopressin secretion from the magnocellular neurosecretory cells (MNCs) is crucial for body fluid homeostasis. Osmotic regulation of MNC activity involves the concerted modulation of intrinsic mechanosensitive ion channels, taurine release from local astrocytes as well as excitatory inputs derived from osmosensitive forebrain regions. Extracellular signal-regulated protein kinases (ERK) are mitogen-activated protein kinases that transduce extracellular stimuli into intracellular post-translational and transcriptional responses, leading to changes in intrinsic neuronal properties and synaptic function. Here, we investigated whether ERK activation (i.e. phosphorylation) plays a role in the functioning of forebrain osmoregulatory networks. We found that within 10 min after intraperitoneal injections of hypertonic saline (3 m, 6 m) in rats, many phosphoERK-immunopositive neurones were observed in osmosensitive forebrain regions, including the MNC containing supraoptic nuclei. The intensity of ERK labelling was dose-dependent. Reciprocally, slow intragastric infusions of water that lower osmolality reduced basal ERK phosphorylation. In the supraoptic nucleus, ERK phosphorylation predominated in vasopressin neurones vs. oxytocin neurones and was absent from astrocytes. Western blot experiments confirmed that phosphoERK expression in the supraoptic nucleus was dose dependent. Intracerebroventricular administration of the ERK phosphorylation inhibitor U 0126 before a hyperosmotic challenge reduced the number of both phosphoERK immunopositive neurones and Fos expressing neurones in osmosensitive forebrain regions. Blockade of ERK phosphorylation also reduced hypertonically induced depolarization and an increase in firing of the supraoptic MNCs recorded in vitro. It finally reduced hypertonically induced vasopressin release in the bloodstream. Altogether, these findings identify ERK phosphorylation as a new element contributing to the osmoregulatory mechanisms of vasopressin release. PMID- 24492839 TI - Vitamin C and E supplementation hampers cellular adaptation to endurance training in humans: a double-blind, randomised, controlled trial. AB - In this double-blind, randomised, controlled trial, we investigated the effects of vitamin C and E supplementation on endurance training adaptations in humans. Fifty-four young men and women were randomly allocated to receive either 1000 mg of vitamin C and 235 mg of vitamin E or a placebo daily for 11 weeks. During supplementation, the participants completed an endurance training programme consisting of three to four sessions per week (primarily of running), divided into high-intensity interval sessions [4-6 * 4-6 min; >90% of maximal heart rate (HRmax)] and steady state continuous sessions (30-60 min; 70-90% of HRmax). Maximal oxygen uptake (VO2 max ), submaximal running and a 20 m shuttle run test were assessed and blood samples and muscle biopsies were collected, before and after the intervention. Participants in the vitamin C and E group increased their VO2 max (mean +/- s.d.: 8 +/- 5%) and performance in the 20 m shuttle test (10 +/ 11%) to the same degree as those in the placebo group (mean +/- s.d.: 8 +/- 5% and 14 +/- 17%, respectively). However, the mitochondrial marker cytochrome c oxidase subunit IV (COX4) and cytosolic peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC-1alpha) increased in the m. vastus lateralis in the placebo group by 59 +/- 97% and 19 +/- 51%, respectively, but not in the vitamin C and E group (COX4: -13 +/- 54%; PGC-1alpha: -13 +/- 29%; P <= 0.03, between groups). Furthermore, mRNA levels of CDC42 and mitogen-activated protein kinase 1 (MAPK1) in the trained muscle were lower in the vitamin C and E group than in the placebo group (P <= 0.05). Daily vitamin C and E supplementation attenuated increases in markers of mitochondrial biogenesis following endurance training. However, no clear interactions were detected for improvements in VO2 max and running performance. Consequently, vitamin C and E supplementation hampered cellular adaptations in the exercised muscles, and although this did not translate to the performance tests applied in this study, we advocate caution when considering antioxidant supplementation combined with endurance exercise. PMID- 24492840 TI - GABAergic and glycinergic inputs modulate rhythmogenic mechanisms in the lamprey respiratory network. AB - We have previously shown that GABA and glycine modulate respiratory activity in the in vitro brainstem preparations of the lamprey and that blockade of GABAA and glycine receptors restores the respiratory rhythm during apnoea caused by blockade of ionotropic glutamate receptors. However, the neural substrates involved in these effects are unknown. To address this issue, the role of GABAA, GABAB and glycine receptors within the paratrigeminal respiratory group (pTRG), the proposed respiratory central pattern generator, and the vagal motoneuron region was investigated both during apnoea induced by blockade of glutamatergic transmission and under basal conditions through microinjections of specific antagonists. The removal of GABAergic, but not glycinergic transmission within the pTRG, causes the resumption of rhythmic respiratory activity during apnoea, and reveals the presence of a modulatory control of the pTRG under basal conditions. A blockade of GABAA and glycine receptors within the vagal region strongly increases the respiratory frequency through disinhibition of neurons projecting to the pTRG from the vagal region. These neurons were retrogradely labelled (neurobiotin) from the pTRG. Intense GABA immunoreactivity is observed both within the pTRG and the vagal area, which corroborates present findings. The results confirm the pTRG as a primary site of respiratory rhythm generation, and suggest that inhibition modulates the activity of rhythm-generating neurons, without any direct role in burst formation and termination mechanisms. PMID- 24492841 TI - Glutamate receptors in the nucleus tractus solitarius contribute to ventilatory acclimatization to hypoxia in rat. AB - When exposed to a hypoxic environment the body's first response is a reflex increase in ventilation, termed the hypoxic ventilatory response (HVR). With chronic sustained hypoxia (CSH), such as during acclimatization to high altitude, an additional time-dependent increase in ventilation occurs, which increases the HVR. This secondary increase persists after exposure to CSH and involves plasticity within the circuits in the central nervous system that control breathing. Currently these mechanisms of HVR plasticity are unknown and we hypothesized that they involve glutamatergic synapses in the nucleus tractus solitarius (NTS), where afferent endings from arterial chemoreceptors terminate. To test this, we treated rats held in normoxia (CON) or 10% O2 (CSH) for 7 days and measured ventilation in conscious, unrestrained animals before and after microinjecting glutamate receptor agonists and antagonists into the NTS. In normoxia, AMPA increased ventilation 25% and 50% in CON and CSH, respectively, while NMDA doubled ventilation in both groups (P < 0.05). Specific AMPA and NMDA receptor antagonists (NBQX and MK801, respectively) abolished these effects. MK801 significantly decreased the HVR in CON rats, and completely blocked the acute HVR in CSH rats but had no effect on ventilation in normoxia. NBQX decreased ventilation whenever it was increased relative to normoxic controls; i.e. acute hypoxia in CON and CSH, and normoxia in CSH. These results support our hypothesis that glutamate receptors in the NTS contribute to plasticity in the HVR with CSH. The mechanism underlying this synaptic plasticity is probably glutamate receptor modification, as in CSH rats the expression of phosphorylated NR1 and GluR1 proteins in the NTS increased 35% and 70%, respectively, relative to that in CON rats. PMID- 24492842 TI - Blunted sympathoinhibitory responses in obesity-related hypertension are due to aberrant central but not peripheral signalling mechanisms. AB - The gut hormone cholecystokinin (CCK) acts at subdiaphragmatic vagal afferents to induce renal and splanchnic sympathoinhibition and vasodilatation, via reflex inhibition of a subclass of cardiovascular-controlling neurons in the rostroventrolateral medulla (RVLM). These sympathoinhibitory and vasodilator responses are blunted in obese, hypertensive rats and our aim in the present study was to determine whether this is attributable to (i) altered sensitivity of presympathetic vasomotor RVLM neurons, and (ii) aberrant peripheral or central signalling mechanisms. Using a diet-induced obesity model, male Sprague-Dawley rats exhibited either an obesity-prone (OP) or obesity-resistant (OR) phenotype when placed on a medium high fat diet for 13-15 weeks; control animals were placed on a low fat diet. OP animals had elevated resting arterial pressure compared to OR/control animals (P < 0.05). Barosensitivity of RVLM neurons was significantly attenuated in OP animals (P < 0.05), suggesting altered baroreflex gain. CCK induced inhibitory responses in RVLM neurons of OR/control animals but not OP animals. Subdiaphragmatic vagal nerve responsiveness to CCK and CCK1 receptor mRNA expression in nodose ganglia did not differ between the groups, but CCK induced significantly less Fos-like immunoreactivity in both the nucleus of the solitary tract and the caudal ventrolateral medulla of OP animals compared to controls (P < 0.05). These results suggest that blunted sympathoinhibitory and vasodilator responses in obesity-related hypertension are due to alterations in RVLM neuronal responses, resulting from aberrant central but not peripheral signalling mechanisms. In obesity, blunted sympathoinhibitory mechanisms may lead to increased regional vascular resistance and contribute to the development of hypertension. PMID- 24492844 TI - B-RAF and its novel negative regulator reticulocalbin 1 (RCN1) modulates cardiomyocyte hypertrophy. AB - AIM: Activation of the kinase RAF and its downstream targets leads to cardiomyocyte hypertrophy. It has been hypothesized that B-RAF might be the main activator of MEK in various cell types. Therefore, the aim of this study was to investigate the role of B-RAF and its modulating factors in cardiomyocyte hypertrophy. METHODS AND RESULTS: Neonatal rat cardiomyocytes were pre-treated with and without the specific B-RAF inhibitor SB590885 and then stimulated with phenylephrine to induce hypertrophy. Inhibition of B-RAF completely impeded the hypertrophic response and led to a significant reduction of MEK1/2 phosphorylation. By applying a eukaryotic cDNA expression screen, based on a dual luciferase reporter assay for B-RAF activity measurement, we identified RCN1 as a new negative modulator of B-RAF activity. Adenovirus-mediated overexpression of reticulocalbin 1 (RCN1) completely impeded phenylephrine-induced hypertrophy and led to significantly reduced MEK1/2 phosphorylation. Conversely, adenoviral knockdown of RCN1 with a specific synthetic miRNA induced cardiomyocyte hypertrophy and significantly increased MEK1/2 phosphorylation. CONCLUSIONS: In summary, our results show that the inhibition of B-RAF abolishes cardiomyocyte hypertrophy and we identified RCN1 as novel negative modulator of cardiomyocyte hypertrophy by inhibition of the mitogen-activated protein kinase signalling cascade. Our results show that B-RAF kinase activity is essential for cardiac hypertrophy and RCN1, its newly identified negative regulator, abolishes hypertrophic response of cardiomyocytes in vitro. PMID- 24492843 TI - Drosophila Tempura, a novel protein prenyltransferase alpha subunit, regulates notch signaling via Rab1 and Rab11. AB - Vesicular trafficking plays a key role in tuning the activity of Notch signaling. Here, we describe a novel and conserved Rab geranylgeranyltransferase (RabGGT) alpha-like subunit that is required for Notch signaling-mediated lateral inhibition and cell fate determination of external sensory organs. This protein is encoded by tempura, and its loss affects the secretion of Scabrous and Delta, two proteins required for proper Notch signaling. We show that Tempura forms a heretofore uncharacterized RabGGT complex that geranylgeranylates Rab1 and Rab11. This geranylgeranylation is required for their proper subcellular localization. A partial dysfunction of Rab1 affects Scabrous and Delta in the secretory pathway. In addition, a partial loss Rab11 affects trafficking of Delta. In summary, Tempura functions as a new geranylgeranyltransferase that regulates the subcellular localization of Rab1 and Rab11, which in turn regulate trafficking of Scabrous and Delta, thereby affecting Notch signaling. PMID- 24492845 TI - Mechanisms and biological roles of contact-dependent growth inhibition systems. AB - Bacterial contact-dependent growth inhibition (CDI) is mediated by the CdiA/CdiB family of two-partner secretion proteins. CDI(+) cells bind to susceptible target bacteria and deliver a toxic effector domain derived from the carboxyl terminus of CdiA (CdiA-CT). More than 60 distinct CdiA-CT sequence types have been identified, and all CDI toxins characterized thus far display RNase, DNase, or pore-forming activities. CDI systems also encode CdiI immunity proteins, which specifically bind and inactivate cognate CdiA-CT toxins to prevent autoinhibition. CDI activity appears to be limited to target cells of the same species, suggesting that these systems play a role in competition between closely related bacteria. Recent work on the CDI system from uropathogenic Escherichia coli (UPEC 536) has revealed that its CdiA-CT toxin binds tightly to a cysteine biosynthetic enzyme (CysK) in the cytoplasm of target cells. The unanticipated complexity in the UPEC CDI pathway raises the possibility that these systems perform other functions in addition to growth inhibition. Finally, we propose that the phenomenon of CDI is more widespread than previously appreciated. Rhs (rearrangement hotspot) systems encode toxin-immunity pairs, some of which share significant sequence identity with CdiA-CT/CdiI proteins. A number of recent observations suggest that Rhs proteins mediate a distinct form of CDI. PMID- 24492846 TI - Genome recognition by MYC. AB - MYC dimerizes with MAX to bind DNA, with a preference for the E-box consensus CACGTG and several variant motifs. In cells, MYC binds DNA preferentially within transcriptionally active promoter regions. Although several thousand promoters are bound under physiological (low MYC) conditions, these represent only a fraction of all accessible, active promoters. MYC overexpression-as commonly observed in cancer cells-leads to invasion of virtually all active promoters, as well as of distal enhancer elements. We summarize here what is currently known about the mechanisms that may guide this process. We propose that binding site recognition is determined by low-affinity protein-protein interactions between MYC/MAX dimers and components of the basal transcriptional machinery, other chromatin-associated protein complexes, and/or DNA-bound transcription factors. DNA binding occurs subsequently, without an obligate requirement for sequence recognition. Local DNA scanning then leads to preferential stabilization of the MYC/MAX dimer on high-affinity DNA elements. This model is consistent with the invasion of all active promoters that occurs at elevated MYC levels, but posits that important differences in affinity persist between physiological target sites and the newly invaded elements, which may not all be bound in a productive regulatory mode. The implications of this model for transcriptional control by MYC in normal and cancer cells are discussed in the light of the latest literature. PMID- 24492847 TI - Oncogenic mechanisms in Burkitt lymphoma. AB - Burkitt lymphoma is a germinal center B-cell-derived cancer that was instrumental in the identification of MYC as an important human oncogene more than three decades ago. Recently, new genomics technologies have uncovered several additional oncogenic mechanisms that cooperate with MYC to create this highly aggressive cancer. The transcription factor TCF-3 is central to Burkitt lymphoma pathogenesis. TCF-3 is rendered constitutively active in Burkitt lymphoma by two related mechanisms: (1) somatic mutations that inactivate its negative regulator ID3, and (2) somatic mutations in TCF-3 that block the ability of ID3 to bind and interfere with its activity as a transcription factor. TCF-3 is also a master regulator of normal germinal center B-cell differentiation. Within the germinal center, TCF-3 up-regulates genes that are characteristically expressed in the rapidly dividing centroblasts, the putative cell of origin for Burkitt lymphoma, while repressing genes expressed in the less proliferative centrocytes. TCF-3 promotes antigen-independent (tonic) B-cell-receptor signaling in Burkitt lymphoma by transactivating immunoglobulin heavy- and light-chain genes while repressing PTPN6, which encodes the phosphatase SHP-1, a negative regulator of B cell-receptor signaling. Tonic B-cell-receptor signaling sustains Burkitt lymphoma survival by engaging the PI3 kinase pathway. In addition, TCF-3 promotes cell-cycle progression by transactivating CCND3, encoding a D-type cyclin that regulates the G1-S phase transition. Additionally, CCND3 accumulates oncogenic mutations that stabilize cyclin D3 protein expression and drive proliferation. These new insights into Burkitt lymphoma pathogenesis suggest new therapeutic strategies, which are sorely needed in developing regions of the world where this cancer is endemic. PMID- 24492850 TI - Experimental and computational studies on the formation of cyanate from early metal terminal nitrido ligands and carbon monoxide. AB - An important challenge in the artificial fixation of N2 is to find atom efficient transformations that yield value-added products. Here we explore the coordination complex mediated conversion of ubiquitous species, CO and N2, into isocyanate. We have conceptually split the process into three steps: (1) the six-electron splitting of dinitrogen into terminal metal nitrido ligands, (2) the reduction of the complex by two electrons with CO to form an isocyanate linkage, and (3) the one electron reduction of the metal isocyanate complex to regenerate the starting metal complex and release the product. These steps are explored separately in an attempt to understand the limitations of each step and what is required of a coordination complex in order to facilitate a catalytic cycle. The possibility of this cyanate cycle was explored with both Mo and V complexes which have previously been shown to perform select steps in the sequence. Experimental results demonstrate the feasibility of some of the steps and DFT calculations suggest that, although the reduction of the terminal metal nitride complex by carbon monoxide should be thermodynamically favorable, there is a large kinetic barrier associated with the change in spin state which can be avoided in the case of the V complexes by an initial binding of the CO to the metal center followed by rearrangement. This mandates certain minimal design principles for the metal complex: the metal center should be sterically accessible for CO binding and the ligands should not readily succumb to CO insertion reactions. PMID- 24492848 TI - Sweat gland progenitors in development, homeostasis, and wound repair. AB - The human body is covered with several million sweat glands. These tiny coiled tubular skin appendages produce the sweat that is our primary source of cooling and hydration of the skin. Numerous studies have been published on their morphology and physiology. Until recently, however, little was known about how glandular skin maintains homeostasis and repairs itself after tissue injury. Here, we provide a brief overview of sweat gland biology, including newly identified reservoirs of stem cells in glandular skin and their activation in response to different types of injuries. Finally, we discuss how the genetics and biology of glandular skin has advanced our knowledge of human disorders associated with altered sweat gland activity. PMID- 24492851 TI - Isolated penile Kaposi's sarcoma in a HIV-positive patient stable on treatment for three years. AB - Kaposi's sarcoma (KS) is an AIDS-defining condition. Typically, KS affects the skin with or without visceral involvement. The extensive use of antiretroviral therapy (ART) has decreased the incidence of KS amongst the HIV-positive population. We report a case of a 40-year-old man with HIV-1 infection with CD4 count of 551 cells/mm(3)and an undetectable viral load who presented with two skin-coloured KS lesions on the prepuce of the penis. Diagnosis was confirmed by histopathology. He had been commenced on ART three years earlier with a nadir CD4 count of 255 cells/mm(3) He had achieved and maintained viral suppression since commencing ART. The patient was initially treated with cryotherapy and 5% imiquimod as the lesions were presumed to be warts. The lack of response to treatment prompted further investigation. We carried out a literature search of published cases of penile KS over the past 10 years. The majority of articles regarding penile KS were published in the pre-ART era and involved patients with AIDS. Over the past 10 years, published cases of penile KS have almost exclusively been in HIV-negative men. We found 10 published cases of penile KS in HIV-negative men and only one other published case of penile KS in a HIV-positive man, who had severe immune suppression with CD4 count below 200 cells/mm(3) This is the first case report to describe a HIV-positive patient stable on ART with a CD4 count above 200 cells/mm(3)and suppressed HIV-1 viral load, to develop two KS lesions on the penis. Clinicians have to remain suspicious of penile lesions and appreciate the crucial role a biopsy with histopathological analysis plays in confirming a diagnosis. In addition, this case illustrates that unusual presentations of KS can still occur in treated HIV-positive patients with sustained immune recovery. PMID- 24492852 TI - Hepatitis C prevalence in HIV-infected individuals: a comparison of inpatient and outpatient care. AB - Summary Due to the shared risk factors for viral transmission, coinfection of human immunodeficiency virus (HIV) and hepatitis C virus (HCV) is common. This study examined the seroprevalence of HCV among HIV-infected patients in inpatient and outpatient settings. A retrospective chart review of 256 HIV-infected patients was conducted in Prince George's Hospital Center (inpatients from 1 September 2011 to 1 March 2012) and Glenridge Medical Center (outpatients from 1 January 2011 to 31 December 2012). The mean age of the population was 46 +/- 12 and 44 +/- 11 for inpatients and outpatients, respectively. HIV-infected men comprised 61.9% inpatients and 64.8% outpatients. The overall prevalence of HCV infection in HIV/AIDS patients was 12.5% (32/256), with a higher prevalence in the inpatient group than that in the outpatient group (24.6% vs 11.2%, p < 0.01). The percentages of drug abuse (43.8% vs 16.5%, p < 0.01) and alcoholism (25.0% and 14.3%, p < 0.05) in HCV/HIV-coinfected patients were higher than those in HIV monoinfected patients. In addition, only 64.9% of HIV-infected and 50.0% of HCV/HIV-coinfected inpatients were followed up with outside care after discharge. To our knowledge, this study, for the first time, revealed that HCV/HIV coinfection was significantly higher in inpatients compared to outpatients. Considering the high prevalence and comorbidities associated with HCV/HIV coinfection, it is recommended that evaluation of hepatic damage, especially fibrosis, should be initiated during hospitalization as well as outpatient care. PMID- 24492849 TI - Epigenetic regulation of epidermal differentiation. AB - In a cell, the chromatin state is controlled by the highly regulated interplay of epigenetic mechanisms ranging from DNA methylation and incorporation of different histone variants to posttranslational modification of histones and ATP-dependent chromatin remodeling. These changes alter the structure of the chromatin to either facilitate or restrict the access of transcription machinery to DNA. These epigenetic modifications function to exquisitely orchestrate the expression of different genes, and together constitute the epigenome of a cell. In the skin, different epigenetic regulators form a regulatory network that operates to guarantee skin stem cell maintenance while controlling differentiation to multiple skin structures. In this review, we will discuss recent findings on epigenetic mechanisms of skin control and their relationship to skin pathologies. PMID- 24492853 TI - Poorly differentiated thyroid cancer. AB - PURPOSE OF REVIEW: Poorly differentiated thyroid carcinomas (PDTCs) comprise a small subset of heterogeneous thyroid tumors, occupying an intermediate area between well differentiated follicular or papillary carcinoma and anaplastic carcinomas, from both a histopathogenetic and a clinical point of view. PDTCs are more aggressive than the well differentiated, but less aggressive than the anaplastic thyroid cancers. They have a distinct biological behavior, and the classification of these tumors into a separate group appears justified. RECENT FINDINGS: The criteria used to diagnose PDTC have been an area of controversy. The multiple definitions of PDTC make the literature difficult to interpret. No clinical features can accurately diagnose PDTCs. Thus, the results of histocytology, immunohistochemistry, and molecular genetics tests aid in diagnosis. Given the aggressiveness of PDTCs, with increased recurrence and decreased survival rates, a multimodality treatment approach is required. SUMMARY: We conducted a comprehensive review of the current diagnostic and therapeutic tools in the management of patients with PDTCs. The present article aims to review the various aspects of this tumor type, from morphology to immunohistochemistry, and molecular abnormalities from a practical and daily practice-oriented point of view. PMID- 24492854 TI - What are the implications of human papillomavirus status in oropharyngeal tumors for clinical practice? AB - PURPOSE OF REVIEW: Human papillomavirus (HPV) status itself is an important and very probably the strongest prognostic factor in head and neck cancer. Because of the prognostic advantage of patients with HPV-positive cancers, the issue of the quality of life of survivors has become increasingly important. The possibility of treatment de-escalation in patients with virally induced tumors is being considered. Many challenges have to be addressed in order to integrate HPV status in the routine decision-making in patients with oropharyngeal cancer. The present review discusses the standardization of detection methods suitable for clinical use and the differences in predictive parameters between patients with HPV positive and HPV-negative tumors. RECENT FINDINGS: The gold standard for the identification of patients with oropharyngeal tumors etiologically linked to HPV infection is undoubtedly the detection of HPV 16 E6/E7 mRNA. The detection of a surrogate marker of active viral infection, p16ink4a, has a low sensitivity when used alone and must therefore be combined with the detection of HPV DNA or HPV specific antibodies. The detailed knowledge of the importance of specific prognostic parameters is crucial in the choice of treatment. Nodal staging is probably much less important in HPV-positive cancers. SUMMARY: It is of great importance to implement standardized testing for the identification of patients with HPV-induced oropharyngeal tumors. The treatment decision models in HPV positive tumors have to take into account the probably different prognostic value of nodal parameters. Before introducing treatment de-escalation in patients with virally induced tumors into clinical practice, more research and clinical studies are needed. PMID- 24492855 TI - A novel cyclometallated Pt(II)-ferrocene complex induces nuclear FOXO3a localization and apoptosis and synergizes with cisplatin to inhibit lung cancer cell proliferation. AB - Cisplatin is a platinum-based compound that acts as an alkylating agent and is used to treat a variety of malignant tumors including lung cancer. As cisplatin has significant limitations in the clinic, alternative platinum compounds such as cycloplatinated complexes have been considered as attractive anti-tumor agents. Here, we report the antiproliferative activity of a novel diastereomerically pure cycloplatinated complex (Sp,1S,2R)-[Pt{(kappa(2)-C,N)[(eta(5)-C5H3)-CH[double bond, length as m-dash]N-CH(Me)-CH(OH)-C6H5]Fe(eta(5)-C5H5)}Cl(DMSO)] 6a, against A549 non-small cell lung cancer. Mechanistic studies revealed that compound 6a induces nuclear translocation of a FOXO3a reporter protein as well as endogenous FOXO3a in U2OS and A549 cells, respectively. Accordingly, treatment of A549 cells with compound 6a activates the intrinsic caspase pathway and dramatically increases the percentage of apoptotic cells. Furthermore, 6a displays a synergistic antiproliferative effect when applied together with cisplatin. Compound 6a is also active in other cancer cell lines including NCI-H460 large cell lung cancer cells. Importantly, antiproliferative activity of the platinacycle 6a on the non-tumor and non-proliferating 3T3-L1 cell line is weaker than in all cancer cell lines tested. PMID- 24492856 TI - Presymptomatic and preimplantation genetic diagnosis: neurology, NextGenetics, and the next generation. PMID- 24492857 TI - Effects of erythropoietin on ischemia, follicular survival, and ovarian function in ovarian grafts. AB - Ovarian tissue transplantation is performed to preserve fertility in patients undergoing chemotherapy and radiotherapy. However, ischemia/reperfusion (IR) injury and free radical production occurring during the revascularization of the transplanted tissue are the major limitations of this procedure. The aim of this study was to investigate the effect of erythropoietin (EPO) as an antioxidant on oxidative stress and ovary survival following transplantation. The Naval Medical Research Institute (NMRI) mice (4-5 weeks old) were divided into three groups (six mice per group): control; autograft+saline, and autograft+EPO (500 IU/kg i.p.). After 28 days, ovary compartments were estimated stereologically. DNA fragmentation and plasma malondialdehyde (MDA), progesterone, and estradiol (E2) concentrations were also evaluated. The results were analyzed using one-way ANOVA and Tukey's test, and the means were significantly different at P<0.05. The mean total volume of ovary, cortex, and medulla and the number of follicles increased significantly in the autograft+EPO group (P<0.01). Apoptosis rate in the autograft+EPO group was lower than that in the autograft+saline group. The concentration of MDA decreased significantly in the autografted EPO-treated group than in the autografted saline-treated group (P<0.01). The concentration of E2 increased significantly in the autograft+EPO group than in the autograft+saline group (P<0.01). EPO reduced IR injury, increasing follicle survival and function in grafted ovaries. Free Persian abstract A Persian (Farsi) translation of the abstract is freely available online at http://www.reproduction online.org/content/147/5/733/suppl/DC1. PMID- 24492858 TI - Food restriction during lactation suppresses Kiss1 mRNA expression and kisspeptin stimulated LH release in rats. AB - Among the numerous physiological changes that accompany lactation is the suppression of the reproductive axis. The aim of this study was to investigate a possible role for the kisspeptin system in the restoration of the hypothalamic pituitary-gonadal axis during late lactation in rats using a food restriction model that allows manipulation of the duration of lactational anovulation. Kiss1 mRNA expression and kisspeptin-immunoreactive cell counts were examined in both food-restricted dams and ad libitum (AL)-fed dams across late lactation when LH concentrations begin to increase. In the arcuate nucleus, Kiss1 mRNA expression and kisspeptin-positive cell counts were suppressed during late lactation. In the anteroventral periventricular (AVPV), day 15 food-restricted dams had significantly lower AVPV Kiss1 mRNA expression and a decreased LH response to exogenous kisspeptin compared with the AL-fed dams. Following 5 days of ad libitum food intake, these values were restored to levels similar to those in dams that had been fed ad libitum throughout lactation. In conclusion, this study shows that delayed restoration of the reproductive axis due to food restriction is associated with a decrease in kisspeptin sensitivity and low AVPV Kiss1 mRNA in late lactation. PMID- 24492860 TI - Quantum-enhanced absorption refrigerators. AB - Thermodynamics is a branch of science blessed by an unparalleled combination of generality of scope and formal simplicity. Based on few natural assumptions together with the four laws, it sets the boundaries between possible and impossible in macroscopic aggregates of matter. This triggered groundbreaking achievements in physics, chemistry and engineering over the last two centuries. Close analogues of those fundamental laws are now being established at the level of individual quantum systems, thus placing limits on the operation of quantum mechanical devices. Here we study quantum absorption refrigerators, which are driven by heat rather than external work. We establish thermodynamic performance bounds for these machines and investigate their quantum origin. We also show how those bounds may be pushed beyond what is classically achievable, by suitably tailoring the environmental fluctuations via quantum reservoir engineering techniques. Such superefficient quantum-enhanced cooling realises a promising step towards the technological exploitation of autonomous quantum refrigerators. PMID- 24492861 TI - A green and facile approach for the synthesis of water-dispersible reduced graphene oxide based on ionic liquids. AB - A green and facile route for producing reduced graphene oxide based on ionic liquids has been proposed, in which the as-prepared graphene can be redispersed stably in water (up to 0.6 mg mL(-1)) after being made into a flow-directed solid film. PMID- 24492859 TI - Impact of intermittent screening and treatment for malaria among school children in Kenya: a cluster randomised trial. AB - BACKGROUND: Improving the health of school-aged children can yield substantial benefits for cognitive development and educational achievement. However, there is limited experimental evidence of the benefits of alternative school-based malaria interventions or how the impacts of interventions vary according to intensity of malaria transmission. We investigated the effect of intermittent screening and treatment (IST) for malaria on the health and education of school children in an area of low to moderate malaria transmission. METHODS AND FINDINGS: A cluster randomised trial was implemented with 5,233 children in 101 government primary schools on the south coast of Kenya in 2010-2012. The intervention was delivered to children randomly selected from classes 1 and 5 who were followed up for 24 months. Once a school term, children were screened by public health workers using malaria rapid diagnostic tests (RDTs), and children (with or without malaria symptoms) found to be RDT-positive were treated with a six dose regimen of artemether-lumefantrine (AL). Given the nature of the intervention, the trial was not blinded. The primary outcomes were anaemia and sustained attention. Secondary outcomes were malaria parasitaemia and educational achievement. Data were analysed on an intention-to-treat basis. During the intervention period, an average of 88.3% children in intervention schools were screened at each round, of whom 17.5% were RDT-positive. 80.3% of children in the control and 80.2% in the intervention group were followed-up at 24 months. No impact of the malaria IST intervention was observed for prevalence of anaemia at either 12 or 24 months (adjusted risk ratio [Adj.RR]: 1.03, 95% CI 0.93-1.13, p = 0.621 and Adj.RR: 1.00, 95% CI 0.90-1.11, p = 0.953) respectively, or on prevalence of P. falciparum infection or scores of classroom attention. No effect of IST was observed on educational achievement in the older class, but an apparent negative effect was seen on spelling scores in the younger class at 9 and 24 months and on arithmetic scores at 24 months. CONCLUSION: In this setting in Kenya, IST as implemented in this study is not effective in improving the health or education of school children. Possible reasons for the absence of an impact are the marked geographical heterogeneity in transmission, the rapid rate of reinfection following AL treatment, the variable reliability of RDTs, and the relative contribution of malaria to the aetiology of anaemia in this setting. TRIAL REGISTRATION: www.ClinicalTrials.gov NCT00878007. PMID- 24492863 TI - An appraisal of the 2012 American College of Rheumatology Guidelines for the Management of Gout. AB - PURPOSE OF REVIEW: Appraisal of the 2012 American College of Rheumatology (ACR) Guidelines for the Management of Gout. RECENT FINDINGS: The ACRs first clinical practice guidelines for the management of gout focus on recommendations for nonpharmacologic and pharmacologic approaches to hyperuricaemia and the treatment and prophylaxis of acute gouty arthritis. The RAND/UCLA appropriateness methodology employed assessed risks and benefits of alternative treatments for efficacy, safety and quality but not for cost-effectiveness. Novel recommendations include the use of either allopurinol or febuxostat for first line urate-lowering drug therapy (ULT), screening for HLA-B*5801 prior to initiation of allopurinol in Asians at relatively high risk for allopurinol hypersensitivity, and the use of pegloticase for patients with severe, symptomatic, tophaceous gout refractory to, or intolerant of, appropriately dosed ULTs. Appraisal and comparison with other guidelines using Guidelines International Network and Appraisal of Guidelines, Research and Evaluation (AGREE II) criteria showed good scores for scope and purpose, stakeholder involvement, rigour of development, clarity of presentation, editorial independence and, overall quality, but not for applicability. SUMMARY: The ACR guidelines provide comprehensive, up-to-date, good-quality, evidence-based, expert consensus recommendations for the management of gout in clinical practice but score poorly for applicability. To improve the management of gout in the community a summary of key recommendations, criteria for audit and standards of care are now required. PMID- 24492862 TI - Phosphorylated tau as a candidate biomarker for amyotrophic lateral sclerosis. AB - IMPORTANCE: An increasingly varied clinical spectrum of cases with amyotrophic lateral sclerosis (ALS) has been identified, and objective criteria for clinical trial eligibility are necessary. OBJECTIVE: To develop a cerebrospinal fluid (CSF) biomarker sensitive and specific for the diagnosis of ALS. DESIGN, SETTING, AND PARTICIPANTS: A case-control study including 51 individuals with ALS and 23 individuals with a disorder associated with a 4-repeat tauopathy was conducted at an academic medical center. MAIN OUTCOMES AND MEASURES: The CSF level of tau phosphorylated at threonine 181 (ptau) and ratio of ptau to total tau (ttau). RESULTS: Using a cross-validation prediction procedure, we found significantly reduced CSF levels of ptau and the ptau:ttau ratio in ALS relative to 4-repeat tauopathy and to controls. In the validation cohort, the receiver operating characteristic area under the curve for the ptau:ttau ratio was 0.916, and the comparison of ALS with 4-repeat tauopathy showed 92.0% sensitivity and 91.7% specificity. Correct classification based on a low CSF ptau:ttau ratio was confirmed in 18 of 21 cases (86%) with autopsy-proved or genetically determined disease. In patients with available measures, ptau:ttau in ALS correlated with clinical measures of disease severity, such as the Mini-Mental State Examination (n = 51) and ALS Functional Rating Scale-Revised (n = 42), and regression analyses related the ptau:ttau ratio to magnetic resonance imaging (n = 10) evidence of disease in the corticospinal tract and white matter projections involving the prefrontal cortex. CONCLUSIONS AND RELEVANCE: The CSF ptau:ttau ratio may be a candidate biomarker to provide objective support for the diagnosis of ALS. PMID- 24492867 TI - An unusual inflammatory rash. PMID- 24492868 TI - Causal diagrams to better understand missingness. PMID- 24492869 TI - Measure radiation exposure and sensitivity. PMID- 24492870 TI - Does nissen fundoplication decrease reflux-related problems including respiratory illness in children with neurological impairment? PMID- 24492871 TI - Does Nissen fundoplication decrease reflux-related problems including respiratory illness in children with neurological impairment?--reply. PMID- 24492872 TI - Induction or augmentation of labor and autism. PMID- 24492873 TI - Induction or augmentation of labor and autism. PMID- 24492874 TI - Induction or augmentation of labor and autism. PMID- 24492875 TI - Induction or augmentation of labor and autism--reply. PMID- 24492876 TI - Online privacy and your teen. PMID- 24492878 TI - Enhanced phase resetting in the synchronized suprachiasmatic nucleus network. AB - The suprachiasmatic nucleus (SCN) adapts to both the external light-dark (LD) cycle and seasonal changes in day length. In short photoperiods, single-cell activity patterns are tightly synchronized (i.e., in phase); in long photoperiods, these patterns are relatively dispersed, causing lower amplitude rhythms. The limit cycle oscillator has been used to describe the SCN's circadian rhythmicity and predicts that following a given perturbation, high-amplitude SCN rhythms will shift less than low-amplitude rhythms. Some studies reported, however, that phase delays are larger when animals are entrained to a short photoperiod. Because phase advances and delays are mediated by partially distinct (i.e., nonoverlapping) biochemical pathways, we investigated the effect of a 4-h phase advance of the LD cycle in mice housed in either short (LD 8:16) or long (LD 16:8) photoperiods. In vitro recordings revealed a significantly larger phase advance in the SCN of mice entrained to short as compared to long photoperiods (4.2 +/- 0.3 h v. 1.4 +/- 0.9 h, respectively). Surprisingly, in mice with long photoperiods, the behavioral phase shift was larger than the phase shift of the SCN (3.7 +/- 0.4 h v. 1.4 +/- 0.9 h, respectively). To exclude a confounding influence of running-wheel activity on the magnitude of the shifts of the SCN, we repeated the experiments in the absence of running wheels and found similar shifts in the SCN in vitro in short and long days (3.0 +/- 0.5 h v. 0.4 +/- 0.9 h, respectively). Interestingly, removal of the running wheel reduced the phase shifting capacity of mice in long days, leading to similar behavioral shifts in short and long photoperiods (1.0 +/- 0.1 h v. 1.0 +/- 0.4 h). As the behavioral shifts in the presence of wheels were larger than the shift of the SCN, it is suggested that additional, non-SCN neuronal networks in the brain are involved in regulating the timing of behavioral activity. On the basis of the phase shifts observed in vitro, we conclude that highly synchronized SCN networks with high amplitude rhythms show a larger phase-shifting capacity than desynchronized networks of low amplitude. PMID- 24492879 TI - The proportion of light-responsive neurons determines the limit cycle properties of the suprachiasmatic nucleus. AB - In mammals, the central clock in the suprachiasmatic nucleus (SCN) controls physiological and behavioral circadian rhythms and is entrained to the external light-dark cycle. The ability of the SCN to entrain can be measured by exposing the animal to a light-dark cycle with a duration that deviates from 24 h (T cycles); a wider entrainment range reflects a higher ability to entrain. The neurons of the SCN are either light responsive or light unresponsive and are mutually synchronized. The coupling and synchronization between individual SCN neurons and between groups of neurons within the SCN influence the SCN's ability to entrain. Some studies suggest that enhanced coupling decreases the entrainment range, whereas others suggest that enhanced coupling increases the entrainment range. The latter results are surprising, as they are not consistent with the prevalent assumption that the SCN is a limit cycle oscillator that has larger phase shifts when the amplitude is smaller. Here, we used the Poincare and Goodwin models to test entrainment properties using various proportions of neurons that are responsive to an external stimulus. If all neurons receive external input, the SCN shows limit cycle behavior in all conditions. If all neurons do not receive light input, we found that the entrainment range of the SCN was positively related to coupling strength when coupling was weak. When coupling strength was stronger and above a critical value, the entrainment range was negatively correlated with coupling strength. The results obtained from our simulations were confirmed by analytical studies. Thus, the limit cycle behavior of the SCN appears to be critically dependent on the coupling strength among the neurons and the proportion of neurons that respond to the entraining stimulus. PMID- 24492880 TI - The circatidal rhythm persists without the optic lobe in the mangrove cricket Apteronemobius asahinai. AB - Whether the circatidal rhythm is generated by a machinery common to the circadian clock is one of the important and interesting questions in chronobiology. The mangrove cricket Apteronemobius asahinai shows a circatidal rhythm generating active and inactive phases and a circadian rhythm modifying the circatidal rhythm by inhibiting activity during the subjective day simultaneously. In the previous study, RNA interference of the circadian clock gene period disrupted the circadian rhythm but not the circatidal rhythm, suggesting a difference in molecular mechanisms between the circatidal and circadian rhythms. In the present study, to compare the neural mechanisms of these 2 rhythms, we observed locomotor activity in the mangrove cricket after surgical removal of the optic lobe, which has been shown to be the locus of the circadian clock in other crickets. We also noted the pigment-dispersing factor immunoreactive neurons (PDF-IRNs) in the optic lobe, because PDF is a key output molecule in the circadian clock system in some insects. The results showed that the circadian modulation was disrupted after the removal of the optic lobes but that the circatidal rhythm was maintained with no remarkable changes in its free-running period. Even in crickets in which some PDF-immunoreactive somata remained after removal of the optic lobe, the circadian rhythm was completely disrupted. The remnants of PDF IRNs were not correlated to the occurrence and free-running period of the circatidal rhythm. These results indicate that the principal circatidal clock is located in a region(s) different from the optic lobe, whereas the circadian clock is located in the optic lobe, as in other crickets, and PDF-IRNs are not important for circatidal rhythm. Therefore, it is suggested that the circatidal rhythm of A. asahinai is driven by a neural basis different from that driving the circadian rhythm. PMID- 24492881 TI - A kinetic study of the effects of light on circadian rhythmicity of the frq promoter of Neurospora crassa. AB - The role of the frq gene in the Neurospora crassa circadian rhythm has been widely studied, but technical limitations have hindered a thorough analysis of frq circadian expression waveform. Through our experiments, we have shown an improved precision in defining Neurospora's circadian rhythm kinetics using a codon optimized firefly luciferase gene reporter linked to a frq promoter. In vivo examination of this real-time reporter has allowed for a better understanding of the relationship of the light responsive elements of the frq promoter to its circadian feedback components. We provide a detailed phase response curve showing the phase shifts induced by a light pulse applied at different points of the circadian cycle. Using the frq-luc reporter, we have found that a 12-h light:12-h dark cycle (12L:12D) results in a luciferase expression waveform that is more complex and higher in amplitude than that seen in free-running conditions of constant darkness (DD). When using a lighting regime more consistent with solar timing, rather than a square wave pattern, one observes a circadian waveform that is smoother, lower in amplitude, and different in phasing. Using dim light in place of darkness in these experiments also affects the resulting waveform and phasing. Our experiments illustrate Neurospora's circadian kinetics in greater detail than previous methods, providing further insight into the complex underlying biochemical, genetic, and physiological mechanisms underpinning the circadian oscillator. PMID- 24492882 TI - Bright to dim oscillatory response of the Neurospora circadian oscillator. AB - The fungus Neurospora crassa constitutes an important model system extensively used in chronobiology. Several studies have addressed how environmental cues, such as light, can reset or synchronize a circadian system. By means of an optimized firefly luciferase reporter gene and a controllable lighting system, we show that Neurospora can display molecular circadian rhythms in dim light when cultures receive bright light prior to entering dim light conditions. We refer to this behavior as the "bright to dim oscillatory response" (BDOR). The bright light treatment can be applied up to 76 h prior to dim exposure, and it can be as short as 15 min in duration. We have characterized this response in respect to the duration of the light pulse, the time of the light pulse before dim, the intensity of dim light, and the oscillation dynamics in dim light. Although the molecular mechanism that drives the BDOR remains obscure, these findings suggest that a long-term memory of bright light exists as part of the circadian molecular components. It is important to consider the ecological significance of such dim light responses in respect to how organisms naturally maintain their timing mechanism in moonlight. PMID- 24492883 TI - Effects of rotation interval on sleepiness and circadian dynamics on forward rotating 3-shift systems. AB - A physiologically based mathematical model of sleep-wake cycles is used to examine the effects of shift rotation interval (RI) (i.e., the number of days spent on each shift) on sleepiness and circadian dynamics on forward rotating 3 shift schedules. The effects of the schedule start time on the mean shift sleepiness are also demonstrated but are weak compared to the effects of RI. The dynamics are studied for a parameter set adjusted to match a most common natural sleep pattern (i.e., sleep between 0000 and 0800) and for common light conditions (i.e., 350 lux of shift lighting, 200 lux of daylight, 100 lux of artificial lighting during nighttime, and 0 lux during sleep). Mean shift sleepiness on a rotating schedule is found to increase with RI, reach maximum at intermediate RI=6 d, and then decrease. Complete entrainment to shifts within the schedules is not achieved at RI<=10 d. However, circadian oscillations synchronize to the rotation cycles, with RI=1,2 d and RI>=6 d demonstrating regular periodic changes of the circadian rhythm. At rapid rotation, circadian phase stays within a small 4-h interval, whereas slow rotation leads to around-the-clock transitions of the circadian phase with constantly delayed sleep times. Schedules with RI=3-5 d are not able to entrain the circadian rhythms, even in the absence of external circadian disturbances like social commitments and days off. To understand the circadian dynamics on the rotating shift schedules, a shift response map is developed, showing the direction of circadian change (i.e., delay or advance) depending on the relation between the shift start time and actual circadian phase. The map predicts that the un-entrained dynamics come from multiple transitions between advance and delay behavior on the shifts in the schedules. These are primarily caused by the imbalance between the amount of delay and advance on the different shift types within the schedule. Finally, it is argued that shift response maps can aid in the development of shift schedules with desired circadian characteristics. PMID- 24492884 TI - Deep-fried signaling: tempura gets notch cooking. PMID- 24492885 TI - Synthesis of Cu, Zn and Cu/Zn brass alloy nanoparticles from metal amidinate precursors in ionic liquids or propylene carbonate with relevance to methanol synthesis. AB - Microwave-induced decomposition of the transition metal amidinates {[Me(C(N(i)Pr)2)]Cu}2 (1) and [Me(C(N(i)Pr)2)]2Zn (2) in the ionic liquid 1-butyl 3-methylimidazolium tetrafluoroborate ([BMIm][BF4]) or in propylene carbonate (PC) gives copper and zinc nanoparticles which are stable in the absence of capping ligands (surfactants) for more than six weeks. Co-decomposition of 1 and 2 yields the intermetallic nano-brass phases beta-CuZn and gamma-Cu3Zn depending on the chosen molar ratios of the precursors. Nanoparticles were characterized by high-angle annular dark field-scanning transmission electron microscopy (HAADF STEM), dynamic light scattering and powder X-ray diffractometry. Microstructure characterizations were complemented by STEM with spatially resolved energy dispersive X-ray spectrometry and X-ray photoelectron spectroscopy. Synthesis in ILs yields significantly smaller nanoparticles than in PC. beta-CuZn alloy nanoparticles are precursors to catalysts for methanol synthesis from the synthesis gas H2/CO/CO2 with a productivity of 10.7 mol(MeOH) (kg(Cu) h)(-1). PMID- 24492886 TI - Production of green biodegradable plastics of poly(3-hydroxybutyrate) from renewable resources of agricultural residues. AB - This work describes potential opportunities for utilization of agro-industrial residues to produce green biodegradable plastics of poly(3-hydroxybutyrate) (PHB). Wheat straws were examined with good efficacy of carbon substrates using Cupriavidus necator. Production was examined in separate hydrolysis and fermentation (SHF) in the presence and absence of WS hydrolysis enzymes, and in simultaneous saccharification and fermentation (SSF) with enzymes. Results showed that production of PHB in SSF was more efficient in terms of viable cell count, cell dry weight, and PHB production and yield compared to those of SHF and glucose-control cultures. While glucose control experiment produced 4.6 g/L PHB; SSF produced 10.0 g/L compared to 7.1 g/L in SHF when utilizing enzymes during WS hydrolysis. Results showed that most of sugars produced during the hydrolysis were consumed in SHF (~98 %) compared to 89.2 % in SSF. Results also demonstrated that a combination of glucose and xylose can compensate for the excess carbon required for enhancing PHB production by C. necator. However, higher concentration of sugars at the beginning of fermentation in SHF can lead to cell inhibition and consequently catabolite repressions. Accordingly, results demonstrated that the gradual release of sugars in SSF enhanced PHB production. Moreover, the presence of sugars other than glucose and xylose can eliminate PHB degradation in medium of low carbon substrate concentrations in SSF. PMID- 24492887 TI - From stem cell niche environments to engineering of corneal epithelium tissue. AB - Studies on stem cells (SC) show that SC functions are determined by the extracellular microenvironment, known as the "niche", and by intrinsic genetic programs in the SCs; both are involved in regulating the delicate balance of self renewal and differentiation. We have identified an animal model of limbal SC (LSC) deficiency and transplantation of SC-containing limbal tissue to treat the LSC deficiency, which could not only replace LSCs by providing new healthy corneal epithelial cells but also restore the lost niche of the limbal stromal layer, causing the regression of vessels and rearrangement of the corneal stromal lamellae. The purpose of the ex-vivo expansion technique is to develop a method that will enable culture of a small number of SCs which could than be expanded in a defined cultured system while preserving the original characteristics and properties of the SCs. In addition, SC characteristics will continue to be maintained when the cultured cells are transplanted back into the host. Bromodeoxyuridine-retaining, DeltaNp63, ABCG2, p120, and N-cadherin immunoreactive studies of LSC cultured on an amniotic membrane have been performed. Pathological studies have been conducted for cases with preexisting central corneal stromal opacity treated by transplantation of LSCs followed by penetrating keratoplasty. The results indicate that the amniotic membrane can provide the niche environment for cultured LSCs and maintain the limbal-like environment for the transplanted area of cornea. PMID- 24492890 TI - How do radiologists evaluate osteonecrosis? AB - OBJECTIVES: Management of patients with osteonecrosis of the hip remains controversial and challenging. Because the prognosis and treatment are determined in large part by the stage and extent of the disease, it is important to use a reliable and efficient method for evaluation and staging. The objective of this study was to determine how musculoskeletal (MSK) radiologists evaluate osteonecrosis and whether this evaluation is adequate. MATERIALS AND METHODS: A 12-part questionnaire was designed to determine how MSK radiologists evaluate patients with osteonecrosis of the femoral head (ONFH). This was sent to 888 members of the Society of Skeletal Radiology. RESULTS: One hundred and twenty-one members responded to essentially all questions. Patients were evaluated using plain radiographs and MRI. All agreed that it is clinically important to determine the extent of necrosis and joint involvement, and 115 (95 %) stated that this should be part of the radiologists' evaluation. However, only 55 (46 %) said that in practice they used a specific system of classification, and most of these used the Ficat and Arlet classification, which does not indicate the extent of involvement. One hundred and seven (88 %) respondents included a simple visual estimate of the extent of involvement, and a small number added a specific measurement of lesion size. The majority indicated that they were infrequently consulted about which imaging studies should be obtained. CONCLUSIONS: Although radiologists recognize the clinical importance of determining the extent of necrosis and joint involvement in patients with ONFH, in practice the methods used to evaluate these patients often do not accomplish this satisfactorily. The use of an effective classification, which includes both stage and extent of involvement, should be stressed, as it will lead to improved treatment of patients with ON. Physicians who order imaging studies for patients with ON should be encouraged to consult routinely with their radiology colleagues regarding which studies to request, as well as on the interpretation of these studies. PMID- 24492888 TI - FDG-PET in pathologically confirmed spontaneous 4R-tauopathy variants. AB - The 4-repeat (4R)-tauopathies can be clinically heterogeneous and difficult to diagnose. An FDG-PET pattern of hypometabolism has been previously reported in clinically suspected 4R-tauopathies. Considering that pathological confirmation has not been used as inclusion criteria in these studies, however, the possibility exists that atypical cases were excluded. We studied pathologically confirmed cases of 4R-tauopathies to determine if FDG-PET patterns of hypometabolism different than those previously described exist. We identified all autopsy confirmed 4R-tauopathies with FDG-PET imaging performed between 2010 and 2013 within the Mayo Clinic database. Clinical features and FDG-PET imaging were compared to a group of normal controls. Ten patients, seven of which had autopsy confirmed progressive supranuclear palsy (PSP), were identified. We also identified two cases with globular glial tauopathy (GGT) and one case of corticobasal degeneration (CBD). The overall predominant imaging findings included bilateral caudate hypometabolism in nine cases, mild asymmetric thalamic hypometabolism in eight, midbrain hypometabolism in seven, and bilateral hypometabolism in the supplementary motor area in seven. No differences were observed between PSP and GGT. The one CBD case had asymmetric parietal hypometabolism that was not seen in the PSP and GGT cases. As previously described, 4R-tauopathies are associated with frontal, caudate, midbrain and thalamic hypometabolism on FDG-PET. This is the first report of FDG-PET in GGT, and although our series was limited, no features distinguish GGT from PSP. There was some evidence that parietal hypometabolism may be suggestive of CBD. PMID- 24492891 TI - Spontaneous hip dislocation secondary to intraarticular neurofibroma: a case report. AB - Spontaneous hip dislocation due to intraarticular neurofibroma in patients with neurofibromatosis type 1 is extremely rare. We describe the imaging features of spontaneous dislocation of hip due to histologically proven intraarticular neurofibroma in young woman with neurofibromatosis type 1, and review the literature. PMID- 24492892 TI - Coverage with evidence development: what to consider. PMID- 24492895 TI - Why don't we use clozapine more often? PMID- 24492894 TI - 17beta-Estradiol induces sulfotransferase 2A1 expression through estrogen receptor alpha. AB - Sulfotransferase (SULT) 2A1 catalyzes sulfonation of drugs and endogenous compounds and plays an important role in xenobiotic metabolism as well as in the maintenance of steroid and lipid homeostasis. A recent study showed that 17beta estradiol (E2) increases the mRNA levels of SULT2A1 in human hepatocytes. Here we report the underlying molecular mechanisms. E2 enhanced SULT2A1 expression in human hepatocytes and HepG2-ER cells (HepG2 stably expressing ERalpha). SULT2A1 induction by E2 was abrogated by antiestrogen ICI 182,780, indicating a key role of ERalpha in the induction. Results from deletion and mutation assays of SULT2A1 promoter revealed three cis-elements located within -257/+140 region of SULT2A1 that are potentially responsible for the induction. Chromatin immunoprecipitation assay verified the recruitment of ERalpha to the promoter region. Electrophoretic mobility shift assays revealed that AP-1 proteins bind to one of the cis elements. Interestingly, SULT2A1 promoter assays using ERalpha mutants revealed that the DNA-binding domain of ERalpha is indispensable for SULT2A1 induction by E2, suggesting that direct ERalpha binding to the SULT2A1 promoter is also necessary for the induction. Taken together, our results indicate that E2 enhances SULT2A1 expression by both the classical and nonclassical mechanisms of ERalpha action. PMID- 24492897 TI - Global mental health reforms: Challenges in developing a community-based program for maltreated children and adolescents in Brazil. AB - This column describes the planning and development of The Equilibrium Program (TEP) for multiply traumatized and neglected children and adolescents with mental and general medical problems in Sao Paulo, Brazil. The program is a partnership between university faculty, various service providers, the courts, and the city government. In the first step, child psychiatry faculty from the University of Sao Paulo visited central-city areas and group shelters to talk to street youths to better understand their needs. A nearby community sports center building was chosen to be a center where youths could access services and engage in recreational activities and where the work of family integration could be facilitated. A multidisciplinary team conducts an in-depth assessment and creates an intervention plan, overseen by a case manager. Challenges to implementing such programs are discussed. PMID- 24492898 TI - Research and services partnerships: Responding to needs of clinical operations partners: transferring implementation facilitation knowledge and skills. AB - This column describes a facilitation strategy that incorporates evidence-based implementation knowledge and practice-based wisdom. The authors also describe a partnership between research and clinical operations leaders in the U.S. Department of Veterans Affairs to bridge the gap between implementation knowledge and its use. The initial product of the partnership, the Implementation Facilitation Training Manual: Using External and Internal Facilitation to Improve Care in the Veterans Health Administration, is a resource that can be used by others to guide implementation efforts. PMID- 24492893 TI - Inhibition of the multidrug resistance P-glycoprotein: time for a change of strategy? AB - P-glycoprotein (P-gp) is a key player in the multidrug-resistant phenotype in cancer. The protein confers resistance by mediating the ATP-dependent efflux of an astonishing array of anticancer drugs. Its broad specificity has been the subject of numerous attempts to inhibit the protein and restore the efficacy of anticancer drugs. The general strategy has been to develop compounds that either compete with anticancer drugs for transport or act as direct inhibitors of P-gp. Despite considerable in vitro success, there are no compounds currently available to "block" P-gp-mediated resistance in the clinic. The failure may be attributed to toxicity, adverse drug interaction, and numerous pharmacokinetic issues. This review provides a description of several alternative approaches to overcome the activity of P-gp in drug-resistant cells. These include 1) drugs that specifically target resistant cells, 2) novel nanotechnologies to provide high dose, targeted delivery of anticancer drugs, 3) compounds that interfere with nongenomic transfer of resistance, and 4) approaches to reduce the expression of P-gp within tumors. Such approaches have been developed through the pursuit of greater understanding of resistance mediators such as P-gp, and they show considerable potential for further application. PMID- 24492899 TI - Personal accounts: United I stand: how improved perception transformed my mental health. PMID- 24492900 TI - Improving capacity to monitor and support sustainability of mental health peer run organizations. AB - Peer-run mental health organizations are managed and staffed by people with lived experience of the mental health system. These understudied organizations are increasingly recognized as an important component of the behavioral health care and social support systems. This Open Forum describes the National Survey of Peer Run Organizations, which was conducted in 2012 to gather information about peer run organizations and programs, organizational operations, policy perspectives, and service systems. A total of 895 entities were identified and contacted as potential peer-run organizations. Information was obtained for 715 (80%) entities, and 380 of the 715 responding entities met the criteria for a peer-run organization. Implementation of the Affordable Care Act may entail benefits and unintended consequences for peer-run organizations. It is essential that we understand this population of organizations and continue to monitor changes associated with policies intended to provide better access to care that promotes wellness and recovery. PMID- 24492901 TI - Differences between parents of young versus adult children seeking to participate in family-to-family psychoeducation. AB - OBJECTIVE: Parents of individuals with mental illness often play a central role in initiating and supporting their children's treatment. This study compared psychological symptoms and experiences of parents of younger versus older consumers. Parents were seeking to participate in a family education program for relatives of individuals with mental illness. METHODS: Domains of caregiving and distress were assessed among parents of youths (N=56), of young adults (N=137), and of adults >=30 (N=72) who were seeking to participate in the National Alliance on Mental Illness Family-to-Family program. RESULTS: Parents of youths endorsed greater burden, difficulties, and emotional distress than parents of young adults, who in turn endorsed greater burden, difficulties, and emotional distress than parents of older adults. CONCLUSIONS: Findings suggest that burden, difficulties, and emotional distress among parents seeking participation in this program may be highest when children with mental health concerns are younger and that the burdens recede as children age. PMID- 24492902 TI - Association of empathy of nursing staff with reduction of seclusion and restraint in psychiatric inpatient care. AB - OBJECTIVE: Disruptive behavior leading to seclusion or restraint increases with patients in a high-acuity stage of mental illness who have histories of aggressive behavior. The study examined whether greater nursing staff empathy skills and motivation reduced use of seclusion and restraint and whether empathy training can further this effect. METHODS: In 1,098 nursing shifts in 2 six-month periods one year apart, hierarchical analyses examined the effects of nursing shift and patient characteristics, the effect for each shift of nurses' skill and motivation to use empathy, and whether empathy training reduced use of seclusion and restraint. RESULTS: With controls for shift, patient, and other staffing variables, analyses showed that the presence of more nursing staff with above average empathy ratings was strongly associated with reduced use of seclusion and restraint but empathy training showed no further benefit. CONCLUSIONS: Recruiting and retaining empathic nursing staff may be the best way to reduce the use of seclusion and restraint. PMID- 24492903 TI - Inadequate treatment of black Americans with bipolar disorder. AB - OBJECTIVE: This study examined disparity in bipolar disorder treatment for black and white Americans. METHODS: The sample included 167 respondents to the National Comorbidity Survey Replication who had lifetime type I or II bipolar disorder. Treatment adequacy and potential correlates were assessed. RESULTS: No black respondent received minimally adequate mood-stabilizing treatment, and blacks were less likely than whites to have taken a mood stabilizer in the prior year. Service use, sociodemographic characteristics, and symptom expression did not explain this disparity. CONCLUSIONS: There was substantial racial inequality in bipolar disorder treatment. Issues guiding this disparity may be unique to this disorder, and clarification of the source of disparity is needed. PMID- 24492904 TI - Effectiveness RCT of a CBT intervention for youths who lost parents in the Sichuan, China, earthquake. AB - OBJECTIVE: Many children who lost parents in the 2008 earthquake in Sichuan Province, China, experienced symptoms of posttraumatic stress disorder (PTSD) and depression. This randomized controlled study compared the treatment effectiveness of short-term cognitive-behavioral therapy (CBT) with a general supportive intervention and with a control group of nontreatment. METHODS; Thirty-two Chinese adolescents were randomly assigned to three treatment groups. Participants were compared for psychological resilience (Connor-Davidson Resilience Scale), symptoms of PTSD (Children's Revised Impact of Events Scale), and depression (Center for Epidemiologic Studies Depression Scale) at baseline, after treatment, and three-month follow-up. RESULTS: CBT was effective in reducing PTSD and depressive symptoms and improved psychological resilience. General support was more effective than no intervention in improving psychological resilience. CONCLUSIONS: Short-term CBT group intervention seems to be a robust intervention for natural disaster victims. Short-term CBT group intervention was more effective than the general supportive intervention and the no-treatment group in enhancing psychological resilience and reducing PTSD and depression among adolescents who had lost parents in the earthquake. The general supportive intervention was effective only in improving psychological resilience. PMID- 24492905 TI - Use of mental health services by children and adolescents six months after the World Trade Center attack. AB - OBJECTIVE: The authors describe use of mental health services among children and adolescents after the September 11, 2001, attack on the World Trade Center. METHODS: Six months after the attack, sixth- through 12th-graders (N=6,986) who were representative of the student population were asked about their use of mental health services to talk about the attack as well as their exposure to the attack, symptoms of posttraumatic stress and major depressive disorders, and any conversations about the attack with a parent, teacher, or religious leader. RESULTS: Eighteen percent had used mental health services. Using in-school services was associated with conversation with a teacher about the attack. Using services outside school was associated with direct exposure to the attack, previous trauma exposure, probable psychiatric diagnosis, and conversation with a teacher or religious leader about the attack. CONCLUSIONS: Teachers and religious leaders can function as gatekeepers to identify children in need following a disaster. PMID- 24492906 TI - Perceived trauma during hospitalization and treatment participation among individuals with psychotic disorders. AB - OBJECTIVE; This study assessed the association of perceptions of traumatic experiences during psychiatric hospitalizations and treatment participation. METHODS: Participants (N=395) in the Suffolk County Mental Health Project, who had been admitted for the first time for a psychotic disorder ten years earlier, were interviewed. The authors examined associations of perceived trauma and distressing or coercive experiences during hospitalizations in the past ten years with patient characteristics and treatment participation. RESULTS: Sixty-nine percent of participants reported perceived trauma. Perceived trauma was more common among females versus males and homemakers versus full-time workers. It was not associated with treatment seeking or time in treatment. However, reporting forced medication was associated with reduced time in treatment, especially for persons with schizophrenia spectrum disorders. CONCLUSIONS: Although perceptions of trauma during psychiatric hospitalization were common, they may be unrelated to treatment participation. However, there was modest evidence of a link between coercive experiences and reduced treatment time. PMID- 24492907 TI - Prevalence of psychotic symptoms. PMID- 24492908 TI - Prevalence of psychotic symptoms: in reply. PMID- 24492909 TI - GPs and new compulsory admission procedures in France. PMID- 24492910 TI - Google searches for suicide and risk of suicide. PMID- 24492911 TI - Administration announces $100 million in new funds for mental health services. PMID- 24492913 TI - Illness perception differences between Russian- and Hebrew-speaking Israeli oncology patients. AB - Illness perception influences health and illness behaviors. This study was designed to estimate illness perception differences between Russian-speaking and Hebrew-speaking Israeli oncology patients. Changes in illness perception associated with time spent in Israel among Russian-speaking patients were also evaluated. Additionally, we evaluated differences in illness perception of patients exposed to Chernobyl's consequences. A total of 144 oncology patients (77 Hebrew-speaking, 67 Russian-speaking) completed personal data questionnaires and The illness perception questionnaire revised, translated into Russian for this study. Significantly more Russian-speaking oncology patients perceived their illness as chronic and having negative consequences on life (p < .01). Russian speaking oncology patients tend to have a more negative perception of cancer compared to Hebrew-speaking patients. Time spent in Israel may create more positive perceptions of cancer among these patients. No illness perception differences were found concerning Chernobyl consequences. PMID- 24492915 TI - Twenty years of the Journal of Clinical Psychology in Medical Settings: we hope you will enjoy the show. AB - The 20th anniversary of the Journal of Clinical Psychology in Medical Settings is celebrated by highlighting the scientist-practitioner philosophy on which it was founded. The goal of the Journal-to provide an outlet for evidence-based approaches to healthcare that underscore the important scientific and clinical contributions of psychology in medical settings-is discussed. The contemporary relevance of this approach is related to the current implementation of the Patient Protection and Affordable Care and its focus on accountability and the development of an interprofessional healthcare workforce; both of which have been foci of the Journal throughout its history and will continue to be so into the future. Several recommendations of future topic areas for the Journal to highlight regarding scientific, practice, policy, and education and training in professional health service psychology are offered. Successfully addressing these topics will support the growth of the field of psychology in the ever evolving healthcare system of the future and continue ensure that the Journal is a key source of professional information in health service psychology. PMID- 24492914 TI - Psychologists' evaluation of bariatric surgery candidates influenced by patients' attachment representations and symptoms of depression and anxiety. AB - This study examines whether patients self-reported attachment representations and levels of depression and anxiety influenced psychologists' evaluations of morbidly obese patients applying for bariatric surgery. A sample of 250 patients (mean age 44, 84 % female) who were referred for bariatric surgery completed questionnaires to measure adult attachment and levels of depression and anxiety. Psychologists rated patients' suitability for bariatric surgery using the Cleveland Clinic Behavioural Rating System (CCBRS), unaware of the results of the completed questionnaires. Attachment anxiety (OR = 2.50, p = .01) and attachment avoidance (OR = 3.13, p = .001) were found to be associated with less positive evaluations on the CCBRS by the psychologists, and symptoms of depression and anxiety mediated this association. This study strongly supports the notion that patients' attachment representations influence a psychologist's evaluation in an indirect way by influencing the symptoms of depression and anxiety patients report during an assessment interview. The clinical implications of these findings are discussed. PMID- 24492920 TI - Troubleshooting public data archiving: suggestions to increase participation. AB - An increasing number of publishers and funding agencies require public data archiving (PDA) in open-access databases. PDA has obvious group benefits for the scientific community, but many researchers are reluctant to share their data publicly because of real or perceived individual costs. Improving participation in PDA will require lowering costs and/or increasing benefits for primary data collectors. Small, simple changes can enhance existing measures to ensure that more scientific data are properly archived and made publicly available: (1) facilitate more flexible embargoes on archived data, (2) encourage communication between data generators and re-users, (3) disclose data re-use ethics, and (4) encourage increased recognition of publicly archived data. PMID- 24492919 TI - The latest neuroimaging findings in borderline personality disorder. AB - Borderline personality disorder (BPD) is a severe mental disorder, characterized by pronounced deficits in emotion regulation, cognitive disturbances including dissociation, impulsivity, and interpersonal disturbances. Over the last decades, neuroimaging has become one of the most important methods to investigate neurobiological alterations possibly underlying core features of BPD. The aim of our article is to provide an overview of the latest neuroimaging research in BPD focusing on functional and structural MRI studies published since 2010. Findings of these studies are depicted and discussed referring to central domains of BPD psychopathology. On a neurochemical level, altered function in neurotransmitter systems including the serotonin, glutamate, and GABA systems was observed in patients with BPD. On a neural level, individuals with BPD showed structural and functional abnormalities in a fronto-limbic network including regions involved in emotion processing (e.g., amygdala, insula) and frontal brain regions implicated in regulatory control processes (e.g., anterior cingulate cortex, medial frontal cortex, orbitofrontal cortex, and dorsolateral prefrontal cortex). Limbic hyperreactivity and diminished recruitment of frontal brain regions may yield a link between disturbed emotion processing and other core features of BPD such as impulsivity and interpersonal disturbances. To clarify whether findings are specific to BPD, comparisons with other clinical groups are needed. PMID- 24492922 TI - Treatment strategies for myocardial recovery in heart failure. AB - OPINION STATEMENT: Heart failure is a progressive disorder characterized by adverse left ventricular remodeling. Until recently, this has been thought to be an irreversible process. Mechanical unloading with a left ventricular assist device (LVAD), particularly if combined with neurohormonal blockade with heart failure medications, can lead to a reversal of the heart failure phenotype, a process called "reverse remodeling." Reverse remodeling refers to the regression of pathologic myocardial hypertrophy and improvement in LV chamber size that can occur in response to treatment. Myocardial recovery is the sustained normalization of structural, molecular, and hemodynamic changes sufficient to allow explant of the LVAD. Despite the fact that reverse remodeling is commonly seen in LVAD patients in clinical practice, myocardial recovery sufficient to allow device explantation is still rare. Previous experience suggests that young patients with short duration of heart failure and less myocardial fibrosis may be more likely to recover. Alternatively, it may just be that clinicians make a greater effort to recover these subgroups. A combined approach of mechanical unloading with LVADs and pharmacological management, together with regular testing of underlying myocardial function with the pump reduced to a speed at which it is not contributing, can increase the frequency of sustained recovery from heart failure. The goal is to achieve optimal unloading of the myocardium, combined with pharmacologic therapy aimed at promoting reverse remodeling. Myocardial recovery must be considered as a therapeutic target. Clinical variables such as pump speed and blood pressure must be optimized to promote maximal unloading, leading to reverse remodeling and myocardial recovery. Frequent echocardiographic and hemodynamic evaluation of underlying myocardial function must be performed. The combination of LVAD therapy with optimal neurohormonal blockade appears promising as an approach to myocardial recovery. In addition, there is a growing body of translational research which, when combined with LVADs, may further promote more durable recovery. Strategies to thicken the myocardium to enhance the durability of recovery prior to explantation, such as clenbuterol (which induces "physiological hypertrophy"), or intermittently reducing the pump speed to increase myocardial load may be beneficial. Emergence of cardiac stem cells and alternative biologic agents, when added to current therapies, may have a complementary role in promoting and maintaining myocardial recovery. This review will summarize both current strategies and emerging therapies. PMID- 24492921 TI - A New Bliss Independence Model to Analyze Drug Combination Data. AB - The Bliss independence model is widely used to analyze drug combination data when screening for candidate drug combinations. The method compares the observed combination response (Y(O)) with the predicted combination response (Y(P)), which was obtained based on the assumption that there is no effect from drug-drug interactions. Typically, the combination effect is declared synergistic if Y(O) is greater than Y(P). However, this method lacks statistical rigor because it does not take into account the variability of the response measures and can frequently cause false-positive claims. In this article, we introduce a two-stage response surface model to describe the drug interaction across all dose combinations tested. This new method enables robust statistical testing for synergism at any dose combination, thus reducing the risk of false positives. The use of the method is illustrated through an application describing statistically significant "synergy regions" for candidate drug combinations targeting epidermal growth factor receptor and the insulin-like growth factor 1 receptor. PMID- 24492923 TI - Prognostic significance of CD204-positive macrophages in upper urinary tract cancer. AB - BACKGROUND: Evidence suggests that CD204-positive (CD204(+)) tumor-infiltrating macrophages are associated with aggressive behavior of various cancers; however, the clinical, pathological, and prognostic associations of tumor-infiltrating CD204(+) macrophages in urothelial cancer have not been reported. METHODS: A tissue microarray was constructed from the centers and peripheries of 171 upper urinary tract cancers treated with nephroureterectomy. CD204 immunohistochemistry was performed. The density of CD204(+) cells was calculated using image analysis software, and survival analyses were performed using the Kaplan-Meier method and multivariate Cox proportional hazards regression models. RESULTS: High CD204(+) cell density at the centers and peripheries of tumors was significantly associated with several adverse prognostic factors, including sessile architecture, histological high-grade, presence of lymphovascular invasion, concomitant carcinoma in situ, higher tumor stage, and lymph node metastasis. High CD204(+) cell density was significantly associated with shorter metastasis free and cancer-specific survival (log-rank p < 0.001) and shorter metastasis free survival in multivariate analysis. CONCLUSIONS: A high density of tumor infiltrating CD204(+) macrophages was associated with aggressive behavior of upper urinary tract cancer. Our results suggest that a specific immune microenvironment may be associated with the biological behavior of urothelial cancer and that CD204 may serve as a novel prognostic biomarker for these tumors. PMID- 24492925 TI - Targeting abasic site-containing DNA with annelated quinolizinium derivatives: the influence of size, shape and substituents. AB - The interactions of regular DNA and abasic site-containing DNA (AP-DNA) with quinolizinium (1a), the linearly fused benzo[b]quinolizinium (2a), the angularly fused benzo[a]quinolizinium (3a), benzo[c]quinolizinium (4a), and dibenzo[a,f]quinolizinium (5a) as well as derivatives thereof were studied with photometric and viscosimetric titrations (regular DNA), fluorimetric titrations and thermal DNA denaturation experiments (regular DNA and AP-DNA). Whereas the parent quinolizinium ion (1a) and the benzo-annelated derivatives 2a, 3a and 4a exhibit no significant affinity to AP-DNA, additional benzo-annelation in 5a leads to an increased selective stabilization of AP-DNA by this ligand. Hence, the latter compound represents the first example of a ligand that does not require ancillary substituents for efficient AP-DNA stabilization. In addition, studies of derivatives with varied substitution patterns revealed an impact of substituents on the stabilization of the AP-DNA. We discovered that a chloro substituent affects the propensity of a ligand to bind to AP-DNA in a similar way as the methyl substituent and may be employed complementary to the known methyl effect to increase the binding affinity of a ligand. PMID- 24492924 TI - Direct reprogramming of porcine fibroblasts to neural progenitor cells. PMID- 24492926 TI - Distribution of AMPA receptor subunit glur1 in the bed nucleus of the stria terminalis and effect of stress. AB - The brain circuitry thought to be involved in stress responses includes several nuclei of the extended amygdala. The bed nucleus of the stria terminalis (BNST) is thought to be involved in the generation of sustained, nonspecific anxiety. Previous behavioral and electrophysiological experiments demonstrate that glutamate systems are involved in anxiety-like behaviors in the BNST. Antagonists for AMPA receptors injected into the BNST decrease anxiety-like behaviors. However, little is known about the role of AMPA receptors and the mechanism by which they act in the establishment of anxiety-like behavior in response to a stressor. We hypothesized that the distribution of AMPA receptors is changed following a paradigm of unpredictable footshock as has been seen in the basolateral amygdala (BLA). We examined the subcellular localization of the GluR1 subunits of the AMPA receptor. We found that the neuropil of the BNST had a lower density of dendritic spines compared to dendritic shafts in the BLA. The majority of elements immunolabeled for GluR1 were dendritic shafts and spines with axonal and glial elements rarely labeled. Compared with controls, no significant effect was observed on days 1, 6, or 14 poststress. However, there was a trend for an increase at 6 and 14 days poststress. These data demonstrate that GluR1 subunits are primarily located on postsynaptic elements in the BNST. Moreover, it was shown that the response of the AMPA GluR1 subunit does not undergo a significant migration into spines from dendrites in response to a stressor as has been demonstrated in the BLA. PMID- 24492927 TI - The continuing challenge of turning promising observational evidence about risk for dementia to evidence supporting prevention. PMID- 24492928 TI - Granulocyte colony-stimulating factor (G-CSF) patterns of use in cancer patients receiving myelosuppressive chemotherapy. AB - PURPOSE: Febrile neutropenia (FN) is a common and serious complication of myelosuppressive chemotherapy. Guidelines recommend primary granulocyte colony stimulating factors (G-CSF) prophylaxis (PPG) in patients with a high risk (HR, >20 %) of developing FN. We performed a retrospective analysis using a subset of the Medicare 5 % database to assess patterns of G-CSF use and FN occurrence among elderly cancer patients receiving myelosuppressive chemotherapy. METHODS: Chemotherapy courses for patients aged 65+ years were identified; only the first course was used for this analysis. Using clinical guidelines, chemotherapy regimens were classified as HR or intermediate risk (IR) for FN. The first administration of G-CSF was classified as either PPG (within the first 5 days of the first cycle), secondary prophylaxis, or reactive. RESULTS: Twelve thousand seven hundred seven courses across five tumor types were classified as having a HR or IR regimen. G-CSF was used in 24.5-73.8 % of patients receiving a HR FN regimen, with the highest use in breast cancer or NHL. Except for breast cancer (where PPG was used in 52.1 %), PPG was given in less than half of patients receiving a HR regimen. Depending on the tumor type, 4.8-22.6 % of patients with a HR regimen had a neutropenia-related hospitalization. CONCLUSIONS: Guidelines recommend PPG with HR FN regimens and older age (>65 years), an important risk factor for developing severe neutropenic complications. However, our results show that in this elderly population, PPG was not routinely used (range 4.8-52.1 %) in patients receiving HR FN regimens. Careful attention to FN risk factors, including chemotherapy regimen and patient age, is needed when planning treatment strategies. PMID- 24492929 TI - Incidence, predictive factors, and prognosis for winged scapula in breast cancer patients after axillary dissection. AB - PURPOSE: Axillary lymph node dissection is part of breast cancer surgery, and winged scapula is a possible sequela. Data regarding its incidence, predictive factors, and patient prognosis remains inconsistent. Ignorance of its diagnosis may lead to undertreatment with physical morbidity. METHODS: Breast cancer patients with axillary lymph node dissection were prospectively recruited. Postoperative examinations by the physiotherapy staff were performed. RESULTS: One hundred eighty-seven patients were recruited during July-October 2012; 51 patients had a positive diagnosis (27.2 %), with 38 patients (86 %) who recovered completely from the winged scapula, while 6 patients (13 %) still had winged scapula at 6 months after surgery. One hundred thirty patients underwent mastectomy and 100 cases had immediate reconstruction. Age, BMI, previous shoulder joint morbidity, and breast surgery were not associated with winged scapula. Neoadjuvant treatment, mastectomy or conservative surgery, immediate reconstruction, tumor size, and nodal involvement also did not show any correlation. Breast reconstruction with prosthesis, even with serratus muscle dissection, does not increase the incidence of winged scapula. CONCLUSION: Winged scapula is not an uncommon incidence after breast cancer surgery. Physiotherapy is related to the complete recovery. The severity or grading of the winged scapula and the recovery time after physiotherapy should be investigated in the future studies. PMID- 24492931 TI - Menopausal hormone therapy has risks and benefits during the intervention and poststopping phase. PMID- 24492930 TI - Exhaled IL-8 in systemic lupus erythematosus with and without pulmonary fibrosis. AB - The purpose of this study is to evaluate the relationship between the concentration of interleukin-8 (IL-8) in exhaled breath condensate (EBC) and bronchoalveolar lavage fluid (BALF) with the disease activity score and pulmonary function of systemic lupus erythematosus (SLE) patients with and without pulmonary fibrosis. Thirty-four SLE patients and 31 healthy controls were enrolled and evaluated using high-resolution computed tomography (HRCT), pulmonary function tests, systemic lupus activity measure (SLAM), assessing BALF and EBC. IL-8 levels in BALF and EBC samples were measured with an enzyme immunosorbent assay kit. The mean (+/-SEM) IL-8 concentrations in BALF and EBC were higher in SLE patients compared to healthy controls (34.84 +/- 95.0 vs. 7.65 +/- 21.22 pg/ml, p < 0.001; 3.82 +/- 0.52 pg/m vs. 1.7 +/- 1.7 pg/ml, p < 0.001, respectively). SLE patients had increased percentage of neutrophils in BALF when compared with control group (1.00 +/- 5.99 vs. 0.00 +/- 0.56 %, p = 0.0003). Pulmonary fibrosis in HRCT was found in 50 % of SLE patients. The disease activity scored by SLAM was significantly higher and total lung capacity was significantly lower in SLE patients with pulmonary fibrosis (8.00 +/- 3.17 vs. 6.00 +/- 2.31, p = 0.01; 88.00 +/- 28.29 vs. 112.00 +/- 21.08 % predicted, p = 0.01, respectively). In SLE patients with pulmonary fibrosis, correlations were found between SLAM and IL-8 concentration in BALF, forced expiratory volume in 1 s and forced vital capacity (r = 0.65, p = 0.006; r = -0.53, p = 0.035; r = 0.67, p = 0.006, respectively). Our results indicate that IL-8 plays an important role in the pathogenesis of SLE. An increased concentration of IL-8 according to BALF could be considered as a useful biomarker of SLE activity and pulmonary fibrosis in SLE. PMID- 24492932 TI - IL-6 alters osteocyte signaling toward osteoblasts but not osteoclasts. AB - Mechanosensitive osteocytes regulate bone mass in adults. Interleukin 6 (IL-6), such as present during orthodontic tooth movement, also strongly affects bone mass, but little is known about the effect of IL-6 on osteocyte function. Therefore we aimed to determine in vitro whether IL-6 affects osteocyte mechanosensitivity, and osteocyte regulation of osteoclastogenesis and osteoblast differentiation. MLO-Y4 osteocytes were incubated with/without IL-6 (1 or 10 pg/mL) for 24 hr. Subsequently, osteocytes were subjected to mechanical loading by pulsating fluid flow (PFF) for 1 hr. Mouse osteoclast precursors were cultured for 7 days on top of IL-6-treated osteocytes. Conditioned medium from osteocytes treated with/without IL-6 was added to MC3T3-E1 pre-osteoblasts for 14 days. Exogenous IL-6 (10 pg/mL) did not alter the osteocyte response to PFF. PFF significantly enhanced IL-6 production by osteocytes. IL-6 enhanced Rankl expression but reduced caspase 3/7 activity by osteocytes, and therefore did not affect osteocyte-stimulated osteoclastogenesis. Conditioned medium from IL-6 treated osteocytes reduced alkaline phosphatase (ALP) activity and Runx2 expression in osteoblasts, but increased expression of the proliferation marker Ki67 and osteocalcin. Our results suggest that IL-6 is produced by shear-loaded osteocytes and that IL-6 may affect bone mass by modulating osteocyte communication toward osteoblasts. PMID- 24492933 TI - Early postoperative changes of the foveal surface in epiretinal membranes: comparison of 23-gauge macular surgery with air vs. balanced salt solution. AB - OBJECTIVE: To analyze the foveal surface using binary image analysis after spectral-domain optical coherence tomography (SD-OCT) following 23-gauge macular surgery in epiretinal membranes (ERM) using either air tamponade (AIR) or balanced salt solution (BSS). METHODS: One hundred twenty-four eyes (124 patients) with ERM that had undergone membrane peeling with installation of air or BSS were analyzed retrospectively. Ophthalmic examination was performed at baseline and 3 months. OUTCOME MEASURES: The foveal area and surface symmetry, area matched thickness, area matched contour, and best-corrected visual acuity (BCVA). The OCT images were analyzed after binary conversion with ImageJ software. RESULTS: Eighty eyes (80 patients) of 124 screened patients were included (AIR group: 39 patients, BSS group: 41 patients). Median follow-up time was 14 weeks (range, 9-19 weeks). Three months after surgery, the median horizontal area decreased significantly in both groups (p < 0.0001). At follow up, the foveal surface symmetry values for the BSS group (median, 22.73 MUm, range, 0-153) were significantly lower than for the AIR group (median, 23.95 MUm, range, 0-160.43) (p < 0.0001). The area-matched thickness increased significantly in both groups (p < 0.001). The AIR group showed a significant increase of the area matched contour for the nasal located measurement-areas N1 (p < 0.0003), N2 (p < 0.0079), N3 (p < 0.007). The BSS group showed a significant increase of the area-matched contour for the measurement areas N1 (p < 0.019), N2 (p < 0.0014), and N4 (p < 0.022). After surgery, median BCVA for both groups increased significantly to 0.3 logMAR. CONCLUSIONS: The analysis of early contour changes after ERM surgery was technically possible. Long-term data have to be looked at before the clinical impact of this methodology can be estimated. Although there were no big differences between both groups (AIR vs. BSS), this could change within a longer and more representative follow-up. PMID- 24492934 TI - Generation of induced pluripotent stem cells from conjunctiva. AB - PURPOSE: The objective of this study was to determine whether cells from the conjunctiva could be reprogrammed into induced pluripotent stem (iPS) cells, providing an alternative source of stem cells. METHODS: We employed a doxycycline induced reprogrammable mouse strain to generate iPS cells from conjunctiva. The identity of the stem cells was confirmed by reverse transcription polymerase chain reaction (RT-PCR) and immunofluorescence assays. Immunocytochemistry and teratoma assays are established means for scoring stem cell pluripotency. The reprogramming efficiencies of conjunctival cells and ear fibroblasts were compared. RESULTS: We confirmed the identity of the stem cells and demonstrated expression of pluripotency markers (OCT4, SOX2, NANOG, and SSEA1), as tested by RT-PCR and immunofluorescence assays. In addition, derived iPS cells differentiated successfully into embryoid bodies, and showed teratoma formation when injected into immunodeficient mice. Reprogramming conjunctival tissue is as efficient as reprogramming ear fibroblasts. Conjunctiva-iPS exhibited classic features of embryonic stem (ES) cells with respect to morphology, expression of surface antigens, and pluripotency-associated transcription factors, capacity to differentiate in vitro, and the ability to form all three germ layers in vivo. CONCLUSION: The present study demonstrated that conjunctival cells, which are readily obtained during the course of many routine conjunctival biopsies and ophthalmic procedures, can be another reliable source of iPS cells. PMID- 24492935 TI - Intravitreal vascular endothelial growth factor. AB - PURPOSE: To evaluate whether a specific pre-analytical stabilization regimen is needed for naive vitreous taps to detect true values of intrinsic VEGF levels. METHODS: Fourteen consecutive patients with different vitreomacular pathologies without blood-retina-barrier breakdown were scheduled for standard 23-gauge three port pars plana vitrectomy, and naive vitreous taps were sampled at the beginning of each procedure. The extracted vitreous specimen was split; one half was immediately stored in a -20 degrees C freezer (unstabilized samples) and the other half was instantly stabilized with albumin (2.5 % final conc.), followed by arginine stabilization (1.25 M final conc.) and consecutively stored in a -20 degrees C freezer (stabilized samples). RESULTS: Intravitreal VEGF was detected in all 14 analyzed samples (100 %). VEGF levels were shown to be 46.5 pg/ml +/- 62.3 pg/ml (MV +/- SD; range: 5.99-232.3 pg/ml) in unstabilized, and 120.4 pg/ml +/- 94.4 pg/ml (range: 42.9 pg/ml-289.6 pg/ml) in stabilized vitreous samples. Intravitreal VEGF levels in stabilized vitreous samples were on average 2.6-fold, and thus significantly higher than in unstabilized taps of same eyes (p = 0.001, Wilcoxon test). VEGF levels in stabilized vitreous samples can be up to 8.5 times higher than in corresponding unstabilized vitreous taps of same eyes (bootstrap analysis). Intravitreal VEGF levels in unstabilized samples correlate with those in stabilized vitreous taps (r = 0.594; p = 0.025; Pearson). CONCLUSIONS: An adequate pre-analytic stabilization regimen is needed to evaluate the most accurate intravitreal VEGF levels. This in turn will result in a better understanding of the physiological as well as pathological role of VEGF within the eye. Furthermore, knowing the true value of intravitreal VEGF levels will help to calculate the dosage of intravitrealy applied anti-VEGF drugs. PMID- 24492936 TI - Volumetric evaluation of hepatic tumors: multi-vendor, multi-reader liver phantom study. AB - PURPOSE: To compare liver lesion volume measurement on multiple 3D software platforms using a liver phantom. METHODS: An anthropomorphic phantom constructed with ten liver lesions of varying size, attenuation, and shape with known volume and long axis measurement was scanned (120 kVp, 80-440 smart mA, NI 12). DICOM data were uploaded to five commercially available 3D visualization systems and manual tumor volume was obtained by three-independent readers. Accuracy and reproducibility of linear and volume measurements were compared. The two most promising systems were then compared with an additional prototype system by two readers using both manual and semi-automated measurement with similar comparison between linear and volume measures. Measurements were performed on 5- and 1.25-mm data sets. Inter- and intra-observer variability was also assessed. RESULTS: Overall mean % volume error on the five commercially available software systems (averaging all ten liver lesions among all three readers) was 8.0% +/- 7.5%, 13.7% +/- 11.2%, 14.2% +/- 15.2%, 16.4% +/- 14.8 %, and 16.9% +/- 13.8%, varying almost twofold across vendor. Moderate inter-observer variability was present. Volume measurement was slightly more accurate than linear measurement, but linear measurement was more reproducible across readers and systems. On the two "best" systems, the manual measurement method was more accurate than the automated method (p = 0.001). The prototype system demonstrated superior semi-automated assessment, with a mean % volume error of 5.3% +/- 4.1% (vs. 17.8% +/- 11.1% and 31.5% +/- 19.7%, p < 0.001), with improved inter- and intra-observer variability. CONCLUSIONS: Accuracy and reproducibility of volume assessment of liver lesions varies significantly by vendor, which has important implications for clinical use. PMID- 24492938 TI - Association between X-ray repair cross-complementing group 1 Arg194Trp polymorphism and prostate cancer risk. AB - X-ray repair cross-complementing group 1 (XRCC1) plays an important role in the maintenance of the genomic integrity. Previous studies on the association between XRCC1 Arg194Trp polymorphism and prostate cancer risk reported conflicting results. To get a more precise assessment of the association between XRCC1 Arg194Trp polymorphism and prostate cancer risk, we performed a meta-analysis of previously published studies. Eligible studies were searched in PubMed, Embase, and China National Knowledge Infrastructure (CNKI) databases. Nine studies with a total of 5,407 subjects were finally included into the meta-analysis. Odds ratio (OR) with 95% confidence interval (95%CI) was used to assess the association. Overall, there was no obvious association between XRCC1 Arg194Trp polymorphism and prostate cancer risk (Trp vs. Arg: OR = 1.02, 95%CI 0.84-1.25, P = 0.824; TrpTrp vs. ArgArg: OR = 1.17, 95%CI 0.83-1.66, P = 0.374; TrpTrp/ArgTrp vs. ArgArg: OR = 1.00, 95%CI 0.79-1.28, P = 0.990; TrpTrp vs. ArgArg/ArgTrp: OR = 1.20, 95%CI 0.85-1.68, P = 0.301). Subgroup analysis according to ethnicity also detected no significant association in both Asians and Caucasians. In conclusion, the meta-analysis suggests that there is no obvious association between XRCC1 Arg194Trp polymorphism and prostate cancer risk. PMID- 24492939 TI - Efficacy of acetylsalicylic acid (aspirin) in skin B16-F0 melanoma tumor-bearing C57BL/6 mice. AB - Several epidemiological studies show that aspirin can act as a chemopreventive agent and decrease the incidences of various cancers including melanoma. In this work, we investigated the in vitro and in vivo efficacy of acetylsalicylic acid (ASA) as an antimelanoma agent in B16-F0 cells and skin B16-F0 melanoma tumor mouse model. Our findings indicate that the IC50 (48 h) for ASA in B16-F0 melanoma cells was 100 MUM and that ASA caused a dose- and time-dependent GSH depletion and increase in reactive oxygen species (ROS) formation in B16-F0 melanoma cells. Male C57BL/6 mice were inoculated s.c. with 1 * 10(6) B16-F0 melanoma cells. ASA (80, 100, and 150 mg/kg) was initiated on day 1 or day 7, or day 9 after cell inoculation and continued daily for 13, 7, and 5 days, respectively. Animals were weighed daily and sacrificed on day 13. The tumors were excised and weighed. The animals receiving 13 days of ASA therapy at 80, 100, and 150 mg/kg demonstrated tumor growth inhibition by 1 +/- 12%, 19 +/- 22%, and 50 +/- 29%, respectively. Animals receiving 7 days of therapy at 80, 100, and 150 mg/kg demonstrated tumor growth inhibition by 12 +/- 14%, 27 +/- 14%, and 40 +/- 14%, respectively. No significant tumor growth inhibition was observed with 5 days of therapy. ASA at 100 and 150 mg/kg caused significant tumor growth inhibition in C57BL/6 mice when administered for 13 and 7 days, respectively. The results obtained in this study are consistent with the recent epidemiologically based report that aspirin is associated with lower melanoma risk in humans. PMID- 24492940 TI - Lack of association between -174G>C and -634C>G polymorphisms in interleukin-6 promoter region and lung cancer risk: a meta-analysis. AB - Evidence suggested that the -174G>C and -634C>G polymorphisms in interleukin-6 (IL6) promoter region may modulate risk of lung cancer; however, the conclusion was still inconclusive. Therefore, we performed this meta-analysis to determine the association between IL6 -174G>C and -634C>G polymorphisms and lung cancer risk. The association strength was measured by odds ratios (ORs) and 95% confidence intervals (CI). Egger's test and Begg's test were performed to detect potential publication bias. By searching PubMed, EMBASE and China National Knowledge Infrastructure, we included 16 eligible studies in this meta-analysis, involving 6,202 lung cancer cases and 7,067 controls. Five studies about -174G>C polymorphism and 11 studies about -634C>G polymorphism were analyzed. By pooling eligible studies, we found no significant association of -174G>C with lung cancer risk (C vs. G: OR = 1.029; 95% CI, 0.957-1.106; heterogeneity, P = 0.478) and no statistic association of -634C > G with lung cancer susceptibility (G vs. C: OR = 1.050; 95% CI, 0.893-1.235; Heterogeneity, P < 0.001). No significant publication bias was observed. In conclusion, we found that -634C>G and -174G>C polymorphisms in IL6 promoter region were not associated with lung cancer risk. PMID- 24492941 TI - Association of four polymorphisms in the death receptor 4 gene with cancer risk: an updated meta-analysis. AB - To date, no scientific consensus about the associations of DR4 C626G, A683C, A1322G, and G422A polymorphisms with cancer risk has been reached. Therefore, we conducted a meta-analysis to assess the associations. This meta-analysis involved 16 studies, of which 15 (4,261 cases and 4,598 controls) described C626G genotypes, 8 (2,898 cases and 3,135 controls) described A683C genotypes, 6 (1,564 cases and 1,673 controls) described A1322G genotypes, and 5 (584 cases and 607 controls) described A683C genotypes. We associated all the four polymorphisms with cancer risk. The C626G polymorphism was associated with slightly elevated cancer risk in recession model comparison [odds ratio (OR)=1.12, 95 % confidence interval (CI)=1.00-1.26, P heterogeneity=0.425]. In the subgroup analysis by cancer type, significantly elevated cancer risks were found among groups with lung cancer for heterozygote comparison (OR=1.76, 95 % CI=1.00-3.09, P heterogeneity=0.863). The A1322G polymorphism was associated with significantly elevated cancer risk in the different models (heterozygote comparison: OR=1.21, 95 % CI=1.00-1.46, P heterogeneity=0.347; dominant model: OR=1.21, 95 % CI=1.01 1.46, P heterogeneity=0.189; allele model comparison for G allele vs. A allele: OR=1.17, 95 % CI=1.02-1.35, P heterogeneity=0.173). The A683C and G422A polymorphisms were not associated with cancer risk in all genetic models. The C626G and A1322G polymorphisms are associated with increased cancer risk, but the A683C polymorphism is rarely associated with cancer risk. PMID- 24492942 TI - Increased FAT10 expression is related to poor prognosis in pancreatic ductal adenocarcinoma. AB - It has been reported that FAT10 plays an important role in cell proliferation. Their activity is increased in malignant cells compared to benign cells. However, the clinical and functional significance of FAT10 expression has not been characterized previously in pancreatic ductal adenocarcinoma (PDAC). The purpose of this study was to assess FAT10 expression and to explore its contribution to PDAC. Real-time quantitative PCR was performed to examine FAT10 expression in 38 pairs of fresh frozen PDAC tissues and corresponding noncancerous tissues. Using immunohistochemistry, we performed a retrospective study of the FAT10 expression levels on 134 archival PDAC paraffin-embedded samples. The relationship between FAT10 mRNA expression and clinicopathological features was analyzed by appropriate statistics. Kaplan-Meier analysis and Cox proportional hazards regression models were used to investigate the correlation between FAT10 expression and prognosis of PDAC patients. The relative mRNA expression of FAT10 was significantly higher in PDAC tissues than in adjacent noncancerous tissues (P<0.001). By immunohistochemistry, the data revealed that high FAT10 expression was significantly correlated with clinical stage (P<0.001), histological differentiation (P=0.004), and lymph node metastasis (P=0.013). Consistent with these results, we found that high expression of FAT10 was significantly correlated with poor survival in PDAC patients (P<0.001). Furthermore, Cox regression analyses showed that FAT10 expression was an independent predictor of overall survival. In conclusion, this study confirmed the overexpression of FAT10 and its association with tumor progression in PDAC. It also provided the first evidence that FAT10 expression in PDAC was an independent prognostic factor of patients, which might be a potential diagnostic and therapeutic target of PDAC. PMID- 24492944 TI - Unexpected regio- and chemoselectivity of cationic gold-catalyzed cycloisomerizations of propargylureas: access to tetrasubstituted 3,4 dihydropyrimidin-2(1H)-ones. AB - Cationic gold-catalyzed cycloisomerizations of propargylureas, derived in situ from secondary propargylamines and aryl or alkyl isocyanates, have been studied. The reaction outcome was found to be different from what was previously observed for the tosyl isocyanate-derived ureas in terms of both regio- and chemoselectivity. As a result, the current protocol offers efficient access to the 3,4-dihydropyrimidin-2(1H)-one core through the 6-endo-dig N-cyclization. PMID- 24492943 TI - Inactivation of Wnt signaling by a human antibody that recognizes the heparan sulfate chains of glypican-3 for liver cancer therapy. AB - Wnt signaling is important for cancer pathogenesis and is often up-regulated in hepatocellular carcinoma (HCC). Heparan sulfate proteoglycans (HSPGs) function as coreceptors or modulators of Wnt activation. Glypican-3 (GPC3) is an HSPG that is highly expressed in HCC, where it can attract Wnt proteins to the cell surface and promote cell proliferation. Thus, GPC3 has emerged as a candidate therapeutic target in liver cancer. While monoclonal antibodies to GPC3 are currently being evaluated in preclinical and clinical studies, none have shown an effect on Wnt signaling. Here, we first document the expression of Wnt3a, multiple Wnt receptors, and GPC3 in several HCC cell lines, and demonstrate that GPC3 enhanced the activity of Wnt3a/beta-catenin signaling in these cells. Then we report the identification of HS20, a human monoclonal antibody against GPC3, which preferentially recognized the heparan sulfate chains of GPC3, both the sulfated and nonsulfated portions. HS20 disrupted the interaction of Wnt3a and GPC3 and blocked Wnt3a/beta-catenin signaling. Moreover, HS20 inhibited Wnt3a-dependent cell proliferation in vitro and HCC xenograft growth in nude mice. In addition, HS20 had no detectable undesired toxicity in mice. Taken together, our results show that a monoclonal antibody primarily targeting the heparin sulfate chains of GPC3 inhibited Wnt/beta-catenin signaling in HCC cells and had potent antitumor activity in vivo. CONCLUSION: An antibody directed against the heparan sulfate of a proteoglycan shows efficacy in blocking Wnt signaling and HCC growth, suggesting a novel strategy for liver cancer therapy. PMID- 24492945 TI - The impact of concurrent granulocyte-macrophage colony-stimulating factor on quality of life in head and neck cancer patients: results of the randomized, placebo-controlled Radiation Therapy Oncology Group 9901 trial. AB - PURPOSE: The Radiation Therapy Oncology Group (RTOG) conducted a randomized, placebo-controlled trial evaluating the efficacy of GM-CSF in reducing mucosal injury and symptom burden from curative radiotherapy for head and neck (H&N) cancer. METHODS: Eligible patients with H&N cancer receiving radiation encompassing >=50 % of the oral cavity or oropharynx received subcutaneous GM-CSF or placebo. Quality of life (QoL) was assessed using the RTOG-modified University of Washington H&N Symptom Questionnaire at baseline 4, 13, 26, and 48 weeks from radiation initiation. RESULTS: Of 125 eligible patients, 114 were evaluable for QoL (58 GM-CSF, 56 placebo). Patient demographics, clinical characteristics, and baseline symptom scores were well balanced between the treatment arms. At the end of the acute period (13 weeks), patients in both arms reported negative change in total symptom score indicating increase in symptom burden relative to baseline (mean -18.4 GM-CSF, -20.8 placebo). There was no difference in change in total symptom score (p > 0.05) or change in mucous, pain, eating, or activity domain scores (p > 0.01) between patients in the GM-CSF and placebo arms. Analysis limited to patients treated per protocol or with an acceptable protocol deviation also found no difference in change in total symptom score (p > 0.05) or change in domain scores (p > 0.01) between treatment arms. Provider assessment of acute mucositis during treatment did not correlate with patient-reported mucous domain and total symptom scores (p > 0.05). CONCLUSION: GM-CSF administered concurrently during head and neck radiation does not appear to significantly improve patient reported QoL symptom burden. PMID- 24492947 TI - Echocardiographic assessment of pulmonary artery systolic pressure and outcomes in ambulatory heart failure patients. AB - BACKGROUND: Pulmonary hypertension (PH) in patients with heart failure (HF) is associated with worse outcomes and is rapidly being recognized as a therapeutic target. To facilitate pragmatic research efforts, data regarding the prognostic importance of noninvasively assessed pulmonary artery systolic pressure (PASP) in stable ambulatory patients with HF are needed. METHODS AND RESULTS: We examined the association between echocardiographic PASP and outcomes in 417 outpatients with HF (age, 54 +/- 13 years; 60.7% men; 50.4% whites; 24.9% with preserved ejection fraction). Median PASP was 36 mm Hg (interquartile range [IQR]: 29, 46). After a median follow-up of 2.6 years (IQR: 1.7, 3.9) there were 72 major events (57 deaths; 9 urgent heart transplants; and 6 ventricular assist device implantations) and 431 hospitalizations for HF. In models adjusting for clinical risk factors and therapy, a 10-mm Hg higher PASP was associated with 37% higher risk (95% CI: 18, 59; P<0.001) for major events, and 11% higher risk (95% CI: 1, 23; P=0.039) for major events or HF hospitalization. The threshold that maximized the likelihood ratio for both endpoints was 48 mm Hg; those with PASP >= 48 mm Hg (N=84; 20.1%) had an adjusted hazard ratio of 3.33 (95% CI: 1.96, 5.65; P<0.001) for major events and 1.47 (95% CI: 1.02, 2.11; P=0.037) for major events or HF hospitalization. Reduced right ventricular systolic function had independent prognostic utility over PASP for adverse outcomes. Right atrial pressure and transtricuspid gradient both contributed to risk. CONCLUSIONS: Elevated PASP, determined by echocardiography, identifies ambulatory patients with HF at increased risk for adverse events. PMID- 24492948 TI - The association of regional intensity of neurosurgical care with spinal fusion surgery in the USA. AB - PURPOSE: There is wide regional variability in the volume of procedures performed for similar surgical patients throughout the USA. The purpose of this study was to investigate the association of spinal fusion operations with several socioeconomic factors. METHODS: We performed a retrospective cohort study involving patients who underwent any neurosurgical procedure from 2005 to 2010 and were registered in National Inpatient Sample (NIS). A sub-cohort of patients undergoing spinal operations was also created. Regression techniques were used to investigate the association of the average intensity of neurosurgical care (defined as the average number of neurosurgical procedures per capita) with the average rate of fusions. RESULTS: In the study period, there were 707,951 patients undergoing spinal procedures, who were registered in NIS. There were significant disparities in the fusion rate among different states (ANOVA, P < 0.0001), which ranged from 0.41 in Maine, where non-fusion surgeries were very predominant, to 0.62 in Virginia, where fusion was the main treatment modality used. In a multivariate analysis, the intensity of neurosurgical care was associated with an increased fusion rate. A similar effect was observed for coverage by private insurance, higher income, urban hospitals, large hospital size, African American patients, and patients with less comorbidities. Hospital location in the northeast was associated with a lower rate in comparison to the midwest, and south. Coverage by Medicaid was associated with lower fusion rate. CONCLUSIONS: We observed significant disparities in the integration of fusion operations in spine surgery practices in the USA. Increased intensity of neurosurgical care was associated with a higher fusion rate. PMID- 24492949 TI - A prospective, cluster-randomized controlled trial of exercise program to prevent low back pain in office workers. AB - PURPOSE: The objective of this study was to evaluate the effects of an exercise program focusing on muscle stretching and endurance training on the 12-month incidence of low back pain (LBP) in office workers. METHODS: A 12-month prospective cluster-randomized controlled trial was conducted in healthy office workers with lower-than-normal trunk extension flexibility or trunk muscle endurance. Healthy office workers (n = 563) were randomly assigned at the cluster level into either intervention (n = 282) or control (n = 281) groups. Participants in the intervention group received an exercise program that included daily stretching exercise and twice-a-week muscle endurance training. Those in the control group received no intervention. The 12-month incidence of LBP was the primary outcome. Secondary outcome were pain intensity, disability level, and quality of life and health status. Analyses were performed using the Cox proportional hazard models. RESULTS: Over the 12-month follow-up, 8.8% of participants in the intervention group and 19.7% in the control group developed incidence of LBP. Hazard rate ratios showed a protective effect of the exercise program for LBP (HR = 0.37, 95% CI 0.22-0.64) after adjusting for biopsychosocial factors. There was no significant difference in pain intensity, disability, and quality of life and health status between those who reported incidence of LBP in the intervention and control groups. CONCLUSION: An exercise program consisting of muscle stretching and endurance training is an effective intervention to reduce incident LBP for office workers with lower-than-normal trunk extension flexibility or trunk muscle endurance. PMID- 24492950 TI - Micro-computed tomography based computational fluid dynamics for the determination of shear stresses in scaffolds within a perfusion bioreactor. AB - Perfusion bioreactors are known to exert shear stresses on cultured cells, leading to cell differentiation and enhanced extracellular matrix deposition on scaffolds. The influence of the scaffold's porous microstructure is investigated for a polycaprolactone (PCL) scaffold with a regular microarchitecture and a silk fibroin (SF) scaffold with an irregular network of interconnected pores. Their complex 3D geometries are imaged by micro-computed tomography and used in direct pore-level simulations of the entire scaffold-bioreactor system to numerically solve the governing mass and momentum conservation equations for fluid flow through porous media. The velocity field and wall shear stress distribution are determined for both scaffolds. The PCL scaffold exhibited an asymmetric distribution with peak and plateau, while the SF scaffold exhibited a homogenous distribution and conditioned the flow more efficiently than the PCL scaffold. The methodology guides the design and optimization of the scaffold geometry. PMID- 24492952 TI - Enhanced organic solvent tolerance of Escherichia coli by 3-hydroxyacid dehydrogenase family genes. AB - A 3-hydroxyisobutyrate dehydrogenase-encoding gene mmsB has been identified as one of the key genes responsible for the enhanced organic solvent tolerance (OST) of Pseudomonas putida JUCT1. In this study, the OST-related effect of two 3 hydroxyacid dehydrogenase family genes (mmsB and zwf) was investigated in Escherichia coli JM109. It was noted that the growth of E. coli JM109 was severely hampered in 4% decalin after zwf knockout. Additionally, its complementation resulted in significantly enhanced solvent tolerance compared with its parent strain. Furthermore, E. coli JM109 carrying mmsB showed better OST capacity than that harboring zwf. To construct E. coli strains with an inheritable OST phenotype, mmsB was integrated into the genome of E. coli JM109 by red-mediated recombination. Using E. coli JM109(DE3) (DeltaendA::mmsB) as host strain, whole-cell biocatalysis was successfully carried out in an aqueous/butyl acetate biphasic system with a remarkably improved product yield. PMID- 24492951 TI - Swertiamarin ameliorates inflammation and osteoclastogenesis intermediates in IL 1beta induced rat fibroblast-like synoviocytes. AB - OBJECTIVE AND DESIGN: Rheumatoid arthritis is a chronic inflammatory and autoimmune disease that leads to aggressive joint cartilage and bone destruction. Swertiamarin is a secoiridoid glycoside found in Enicostema axillare (Lam) A. Raynal, a medicinal plant used in the Indian system of traditional medicine. In the present study, the potential of swertiamarin was evaluated in IL-1beta induced fibroblast-like synoviocytes (FLS). METHODS: The FLS were isolated from Freund's Complete Adjuvant induced arthritic (AA) rats and cultured with IL 1beta. The normal FLS and AA-FLS were cultured and used for subsequent experiment in fibroblastic morphology form. The efficacy of swertiamarin (10-50 MUg/ml) was evaluated on mRNA and protein expression levels of inflammatory and osteoclastogenesis mediators. The efficacy was also evaluated on p38 MAPKalpha levels with time course studies (2, 4, 6, 8 and 12 h). RESULTS: IL-1beta induced cell proliferation (149.46 +/- 13.73 %) and NO production (162.03 +/- 11.03%) in AA-FLS; treatment with swertiamarin controlled proliferation (82.77 +/- 4.22%) and NO production (82.06 +/- 3.91% at 50 MUg/ml) in a dose-dependent manner. It also significantly (P < 0.05) modulated the expression of apoptotic marker (caspase 3), proinflammation mediators (TNFalpha, IL-6, PGE2, COX-2, iNOS, MMPs) and osteoclastogenic mediator (RANKL) at both the mRNA and protein levels. Treatment with swertiamarin inhibited the levels of p38 MAPKalpha in a dose dependent manner and also significantly (P < 0.05) attenuated the release of the same in time dependent mode. CONCLUSION: These findings suggest that treatment with swertiamarin attenuated IL-1beta induced FLS, and it revealed anti inflammatory potential by attenuating aggressive FLS. PMID- 24492953 TI - Magnetic nanoparticles supported ionic liquids improve firefly luciferase properties. AB - Ionic liquids as neoteric solvents, microwave irradiation, and alternative energy source are becoming as a solvent for many enzymatic reactions. We recently showed that the incubation of firefly luciferase from Photinus pyralis with various ionic liquids increased the activity and stability of luciferase. Magnetic nanoparticles supported ionic liquids have been obtained by covalent bonding of ionic liquids-silane on magnetic silica nanoparticles. In the present study, the effects of [gamma-Fe2O3@SiO2][BMImCl] and [gamma-Fe2O3@SiO2][BMImI] were investigated on the structural properties and function of luciferase using circular dichroism, fluorescence spectroscopy, and bioluminescence assay. Enzyme activity and structural stability increased in the presence of magnetic nanoparticles supported ionic liquids. Furthermore, the effect of ingredients which were used was not considerable on K(m) value of luciferase for adenosine-5' triphosphate and also K(m) value for luciferin. PMID- 24492954 TI - A mathematical model of oxidative deamination of amino acid catalyzed by two D amino acid oxidases and influence of aeration on enzyme stability. AB - Two D-amino acid oxidases (DAAO) from different sources (Arthrobacter protophormiae and porcine kidney) were used to oxidatively deaminate D-methionine in the batch reactor. A mathematical model of the process was developed and validated by the experiments carried out without and with oxygen supply by aeration. Kinetic parameters of the model were estimated from the initial reaction rate experiments. Aeration increased the reaction rate in the initial part of the reaction and reduced the time necessary to achieve the final substrate conversion. However, it had a negative influence on the operational stability of enzymes. Operational stability decay rate constants estimated from the experimental data increased with the airflow rate, which indicated lower operational stability of enzymes. It was found that oxygen concentration significantly influenced the stability of DAAO from porcine kidney. Enzyme from microbial source had better operational stability and one order of magnitude lower values of decay rate constants. PMID- 24492955 TI - Functional mutations in and characterization of VHH against Helicobacter pylori urease. AB - Manipulation of clinically significant antibodies can effectively improve the processes of diagnosis and treatment. Affinity maturation process has a significant role in improvement of antibodies efficiency. Error-prone PCR technique is one of the proposed methods for improvement of the affinity of antibodies. In the present research, a method was applied to camel heavy-chain antibody (VHH, nanobody) raised against UreC subunit of urease enzyme from Helicobacter pylori. This VHH was used as a starting molecule to construct a highly diversified phage displayed VHH library. The constructed library of nanobody mutants was subjected to several rounds of panning against UreC antigen. High-affinity mutant was selected. Our VHH (HMR23) showed 1.5-fold higher binding activity than the parental VHH. In addition, the mutant VHH presented a better performance in inhibition of urease activity at low concentrations retaining its specificity and thermal stability. PMID- 24492956 TI - Synthesis, spectroscopic properties, and biological applications of eight novel chlorinated fluorescent proteins-labeling probes. AB - Eight novel chlorinated fluorescent proteins-labeling probes with a linker and reactive group were prepared in 7 steps by the reaction of chlorinated resorcinols with 3, 6-dichloro-4-carboxyphthalic anhydride in the presence of methanesulfonic acid. Structures of target compounds and intermediates were determined via IR, MS, (1)H NMR and element analysis. The spectral properties of the chlorinated fluoresceins were studied. These fluorescent probes showed absorbance peaks at 508-536 nm and fluorescence peaks at 524-550 nm. It was found that they have absorption and emission maxima at long wavelengths and high fluorescence quantum yields. Emission spectra of chlorinated fluoresceins shifted towards long wavelength with increase in chlorine. The probes were used for fluorescence imaging of cells in order to investigate whether they can conjugate to cells. The fluorescence imaging of living cells showed that they were localized in cell nucleus. However, they were localized in cytosol of chemically fixed cells. These probes will be useful reagents for the preparation of stable fluorescent conjugates. PMID- 24492957 TI - Novel method for determination of anthracene by coupling dispersive liquid-liquid extraction to first-derivative synchronous spectrofluorimetry. AB - A novel method could be adopted successfully for determination of anthracene in environmental samples, utilizing dispersive liquid-liquid extraction followed by first-derivative synchronous fluorimetry at a constant wavelength difference Deltalambda = 165 nm, where a linear calibration curve was obtained in a concentration range of 0.5-100 ng mL(-1) at 244 nm. The detection limit was 0.1 ng mL(-1). The method can be easily adopted for determination of anthracene in aqueous media including tap water and river water. The recoveries obtained were 85.40-108.02%. The proposed method was validated according to International Conference of Harmonization (ICH) guide lines and successfully applied to determine anthracene in pure form and in water samples including real life water samples from different sources. All the results obtained were compared with those of published method, where no a significant difference was observed. PMID- 24492958 TI - Risks of compounded drugs. PMID- 24492960 TI - Investigation of ionic liquids for efficient removal and reliable storage of radioactive iodine: a halogen-bonding case. AB - A series of ionic liquids (ILs) were investigated for removal and storage of radioactive iodine (I2) waste released by nuclear power plants. The I2 removal efficiency of ILs was dependent upon the anion species while cation species seemed to have little influence. Particularly, the I2 removal efficiency of [Bmim][Br] was higher than 96% in 5 hours. The nitrogen gas sweeping tests showed that [Bmim][Br] holds I2 tightly, and the leak of I2 from it was negligible under daily life conditions. Spectroscopy studies indicated that high removal efficiencies and storage reliability of ILs were attributed to halogen bonding (XB). PMID- 24492959 TI - Continuous interscalene brachial plexus block versus parenteral analgesia for postoperative pain relief after major shoulder surgery. AB - BACKGROUND: Postoperative pain may lead to adverse effects on the body, which might result in an increase in morbidity. Its management therefore poses a unique challenge for the clinician. Major shoulder surgery is associated with severe postoperative pain, and different modalities are available to manage such pain, including opioid and non-opioid analgesics, local anaesthetics infiltrated into and around the shoulder joint and regional anaesthesia. All of these techniques, alone or in combination, have been used to treat the postoperative pain of major shoulder surgery but with varying success. OBJECTIVES: The objective of this review was to compare the analgesic efficacy of continuous interscalene brachial plexus block (ISBPB) with parenteral opioid analgesia for pain relief after major shoulder surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (2012, Issue 12), MEDLINE (1950 to December 2012), EMBASE (1980 to December 2012), Web of Science (1954 to December 2012), CINAHL (1982 to December 2012) and bibliographies of published studies. SELECTION CRITERIA: We included randomized controlled trials assessing the effectiveness of continuous ISBPB compared with different forms of parenteral opioid analgesia in relieving pain in adult participants undergoing elective major shoulder surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted outcome data. MAIN RESULTS: We included two randomized controlled trials (147 participants). A total of 17 participants were excluded from one trial because of complications related to continuous ISBPB (16) or parenteral opioid analgesia (one). Thus we have information on 130 participants (66 in the continuous ISBPB group and 64 in the parenteral opioid group). The studies were clinically heterogeneous. No meta-analysis was undertaken. However, results of the two included studies showed better pain relief with continuous ISBPB following major shoulder surgery and a lower incidence of complications when interscalene block is performed under ultrasound guidance rather than without it. AUTHORS' CONCLUSIONS: Because of the small number of studies (two) relevant to the subject and the high risk of bias of the selected studies, no reasonable conclusion can be drawn. PMID- 24492961 TI - Water electrolysis with a conducting carbon cloth: subthreshold hydrogen generation and superthreshold carbon quantum dot formation. AB - A conducting carbon cloth, which has an interesting turbostratic microstructure and functional groups that are distinctly different from other ordered forms of carbon, such as graphite, graphene, and carbon nanotubes, was synthesized by a simple one-step pyrolysis of cellulose fabric. This turbostratic disorder and surface chemical functionalities had interesting consequences for water splitting and hydrogen generation when such a cloth was used as an electrode in the alkaline electrolysis process. Importantly, this work also gives a new twist to carbon-assisted electrolysis. During electrolysis, the active sites in the carbon cloth allow slow oxidation of its surface to transform the surface groups from C?OH to COOH and so forth at a voltage as low as 0.2 V in a two-electrode system, along with platinum as the cathode, instead of 1.23 V (plus overpotential), which is required for platinum, steel, or even graphite anodes. The quantity of subthreshold hydrogen evolved was 24 mL cm(-2) h(-1) at 1 V. Interestingly, at a superthreshold potential (>1.23 V+overpotential), another remarkable phenomenon was found. At such voltages, along with the high rate and quantity of hydrogen evolution, rapid exfoliation of the tiny nanoscale (5-7 nm) units of carbon quantum dots (CQDs) are found in copious amounts due to an enhanced oxidation rate. These CQDs show bright-blue fluorescence under UV light. PMID- 24492962 TI - The intramembrane proteases signal Peptide peptidase-like 2a and 2b have distinct functions in vivo. AB - We reported recently that the presenilin homologue signal peptide peptidase-like 2a (SPPL2a) is essential for B cell development by cleaving the N-terminal fragment (NTF) of the invariant chain (li, CD74). Based on this, we suggested that pharmacological modulation of SPPL2a may represent a novel approach to deplete B cells in autoimmune disorders. With regard to reported overlapping substrate spectra of SPPL2a and its close homologue, SPPL2b, we investigated the role of SPPL2b in CD74 NTF proteolysis and its impact on B and dendritic cell homeostasis. In heterologous expression experiments, SPPL2b was found to cleave CD74 NTF with an efficiency similar to that of SPPL2a. For in vivo analysis, SPPL2b single-deficient and SPPL2a/SPPL2b double-deficient mice were generated and examined for CD74 NTF turnover/accumulation, B cell maturation and functionality, and dendritic cell homeostasis. We demonstrate that in vivo SPPL2b does not exhibit a physiologically relevant contribution to CD74 proteolysis in B and dendritic cells. Furthermore, we reveal that both proteases exhibit divergent subcellular localizations in B cells and different expression profiles in murine tissues. These findings suggest distinct functions of SPPL2a and SPPL2b and, based on a high abundance of SPPL2b in brain, a physiological role of this protease in the central nervous system. PMID- 24492963 TI - Miro-1 links mitochondria and microtubule Dynein motors to control lymphocyte migration and polarity. AB - The recruitment of leukocytes to sites of inflammation is crucial for a functional immune response. In the present work, we explored the role of mitochondria in lymphocyte adhesion, polarity, and migration. We show that during adhesion to the activated endothelium under physiological flow conditions, lymphocyte mitochondria redistribute to the adhesion zone together with the microtubule-organizing center (MTOC) in an integrin-dependent manner. Mitochondrial redistribution and efficient lymphocyte adhesion to the endothelium require the function of Miro-1, an adaptor molecule that couples mitochondria to microtubules. Our data demonstrate that Miro-1 associates with the dynein complex. Moreover, mitochondria accumulate around the MTOC in response to the chemokine CXCL12/SDF-1alpha; this redistribution is regulated by Miro-1. CXCL12 dependent cell polarization and migration are reduced in Miro-1-silenced cells, due to impaired myosin II activation at the cell uropod and diminished actin polymerization. These data point to a key role of Miro-1 in the control of lymphocyte adhesion and migration through the regulation of mitochondrial redistribution. PMID- 24492964 TI - Essential role of TID1 in maintaining mitochondrial membrane potential homogeneity and mitochondrial DNA integrity. AB - The tumorous imaginal disc 1 (TID1) protein localizes mainly to the mitochondrial compartment, wherein its function remains largely unknown. Here we report that TID1 regulates the steady-state homogeneity of the mitochondrial membrane potential (Deltapsi) and maintains the integrity of mitochondrial DNA (mtDNA). Silencing of TID1 with RNA interference leads to changes in the distribution of Deltapsi along the mitochondrial network, characterized by an increase in Deltapsi in focal regions. This effect can be rescued by ectopic expression of a TID1 construct with an intact J domain. Chronic treatment with a low dose of oligomycin, an inhibitor of F1Fo ATP synthase, decreases the cellular ATP content and phenocopies TID1 loss of function, indicating a connection between the disruption of mitochondrial bioenergetics and hyperpolarization. Prolonged silencing of TID1 or low-dose oligomycin treatment leads to the loss of mtDNA and the consequent inhibition of oxygen consumption. Biochemical and colocalization data indicate that complex I aggregation underlies the focal accumulation of Deltapsi in TID1-silenced cells. Given that TID1 is proposed to function as a cochaperone, these data show that TID1 prevents complex I aggregation and support the existence of a TID1-mediated stress response to ATP synthase inhibition. PMID- 24492969 TI - N-heterocyclic carbene catalyzed activation of esters: a new option for asymmetric domino reactions. AB - Esters-what else! A new strategy in NHC organocatalysis allows the alpha-, beta- and gamma-activation of saturated and unsaturated esters. The resulting acyl azolium intermediates efficiently participate in domino reactions with suitable substrates to generate synthetically valuable carbo- and heterocycles with very good diastereo- and excellent enantioselectivities. PMID- 24492970 TI - Induction of electromotive force by an autonomously moving magnetic bot. AB - We report the observation of the induction of electromotive force (emf) into a Faraday coil by an autonomously moving composite magnetic particle in aqueous medium. The particle consisted of a micron-sized polymer sphere, which was decorated with catalytic Pd nanoparticles (NPs) and attached to a micron-scale (N 42 grade) rare-earth magnet. The Pd NPs catalytically decomposed H2 O2 to generate O2 , resulting in buoyancy-driven vertical motion of the particle, while the micromagnet induced emf during the flight. Because a small volume of ethanol was layered on top of the liquid, the bubble burst when the particle ascended to the top and thus nearly continuous vertical motion was achieved. Spikes of alternating electrical signal could be observed up to 20 times per minute. The signal was sufficiently strong to illuminate light-emitting diodes following appropriate amplification. This distinctive approach is expected to pave the way to developing synthetic bots which are autonomously propelled, generating their own signal for running complex circuitry. PMID- 24492965 TI - Yeast Edc3 targets RPS28B mRNA for decapping by binding to a 3' untranslated region decay-inducing regulatory element. AB - mRNA decapping commits a transcript to complete turnover in eukaryotic cells. In yeast, general mRNA decapping requires the Dcp1/Dcp2 decapping enzyme and a set of decapping activators, including Pat1, Dhh1, Edc3, and the Lsm1-7 complex. The exact function and mode of action of each of these decapping activators in mRNA decapping largely remain elusive. Here, we analyzed the role of Edc3 in the decay of yeast RPS28B mRNA, a pathway triggered by a negative-feedback autoregulatory mechanism. We show that Edc3-mediated RPS28B mRNA decay requires either of two orthologous proteins, Rps28a and Rps28b, expressed from the RPS28A and RPS28B genes, respectively. Contrary to a generally accepted model, we found that Rps28b does not bind to the 3'-untranslated region (UTR) regulatory element in RPS28B mRNA. Instead, Edc3 is directly involved in binding the element, and Rps28b binds Edc3 and regulates its activity. Decay of RPS28B mRNA requires the Lsm and YjeF-N domains of Edc3, but surprisingly, decay of YRA1 pre-mRNA, the only other known substrate of Edc3, requires only the Lsm domain. Collectively, our experiments reveal a new role for Edc3 in mRNA substrate recognition and suggest that this activity is subject to intricate regulation by additional factors, including the Rps28 ribosomal protein. PMID- 24492971 TI - Octafunctionalized biphenylenes: molecular precursors for isomeric graphene nanostructures. AB - A straightforward method for the octafunctionalization of biphenylene based on the [2+2]-cycloaddition of an aryne intermediate has been developed. This enabled a "North-South" extension of biphenylene towards isomeric graphene nanoribbons composed of four-, six-, and eight-membered rings. This procedure furthermore allowed an "East-West" expansion to [n]phenylenes with different lengths. For the fabrication of isomeric nanongraphenes, octaarylbiphenylenes decorated with phenyl, pyrenyl, and thieno substituents were prepared. The subsequent oxidative cyclodehydrogenation provided an expanded helicene as a model compound. PMID- 24492972 TI - Metal-free deoxygenation of carbohydrates. AB - The conversion of readily available cellulosic biomass to valuable feedstocks and fuels is an attrative goal but a challenging transformation that requires the cleavage of multiple nonactivated C?O bonds. Herein, the Lewis acid trispentafluorophenylborane (B(C6 F5 )3 ) is shown to catalyze the metal-free hydrosilylative reduction of monosaccharides and polysaccharides to give hydrocarbons with reduced oxygen content. The choice of the silane reductant influences the degree of deoxygenation, with diethylsilane effecting the complete reduction to produce hexanes while tertiary silanes give partially deoxygenated tetraol and triol products. PMID- 24492973 TI - Divergent syntheses of fused beta-naphthol and indene scaffolds by rhodium catalyzed direct and decarbonylative alkyne-benzocyclobutenone couplings. AB - A tunable rhodium-catalyzed intramolecular alkyne insertion reaction proceeding through the C?C cleavage of benzocyclobutenones is described. Selective formation of either the direct or decarbonylative insertion product can be controlled by using different catalytic systems. A variety of fused beta-naphthol and indene scaffolds were obtained in good yields with high functional group tolerance. This work illustrates a divergent approach to synthesize fused-ring systems by C?C activation/functionalization. PMID- 24492974 TI - Children's cancer camps: a sense of community, a sense of family. AB - Childhood cancer is a family affair, and each year in Canada, approximately 1,400 children and adolescents under the age of 20 are diagnosed with cancer. Innumerable challenges accompany this diagnosis, and in recognition of the stress of childhood cancer, children's cancer camps arose in the 1970s to help children and their families escape the rigidity and severity of cancer treatment. Very little is known about these cancer camps, and to that end, a philosophical hermeneutic study was conducted to understand the meaning of children's cancer camps for the child with cancer and the family. Six families were interviewed to bring understanding to this topic. While the research included findings related to the concept of play, fit and acceptance, storytelling, and grief, this paper will detail the finding related to the solidarity of the community--the "camp family"--as one that creates intense, healing bonds. PMID- 24492976 TI - Synthesis of substituted 3-furanoates from MBH-acetates of acetylenic aldehydes via tandem isomerization-deacetylation-cycloisomerization: access to Elliott's alcohol. AB - A new method for the synthesis of 5-substituted furan-3-carboxylates from Morita Baylis-Hillman acetates of acetylenic aldehydes is reported. The process involves palladium-catalyzed isomerization followed by base-promoted deacetylation and cycloisomerization reactions. The utility of this chemistry is further demonstrated by the synthesis of Elliott's alcohol, a key intermediate of the pyrethroid resmethrins. PMID- 24492975 TI - Past and present definitions of epileptogenesis and its biomarkers. AB - Descriptions of epileptic seizures and epilepsy date back to antiquity, and research into fundamental mechanisms of epilepsy in animal models, as well as patients, has been carried out for over a century. Studies of epileptogenesis, however, as distinct from ictogenesis, have been pursued for only a few decades, and antiepileptogenesis, the prevention of epilepsy or its progression, and the reversal of the epileptogenic process or cure, are relatively recent interests of the basic research community. The goal to develop antiepileptogenic interventions would be greatly facilitated by the identification of reliable biomarkers of epileptogenesis that could be used to create cost-effective, high-throughput screening models for potential antiepileptogenic compounds, as well as enrich patient populations and serve as surrogate endpoints for clinical trials. Without such biomarkers, the cost for clinical validation of antiepileptogenic interventions would be prohibitive. Epileptogenic mechanisms, antiepileptogenic interventions, and biomarkers are likely to be specific for the many different causes of epilepsy, which include genetic influences, cell loss and synaptic plasticity, malformations of cortical development, and autoimmune disorders, to name but a few. A high priority is currently being placed on investigations to elucidate fundamental mechanisms of epileptogenesis and identify biomarkers for specific models of human epilepsy, such as mesial temporal lobe epilepsy with hippocampal sclerosis, traumatic brain injury, and a variety of pediatric diseases, including tuberous sclerosis and West syndrome. PMID- 24492978 TI - Carcass and non-carcass component yields of crossbred Boer and Brazilian semiarid indigenous goats subjected to different feeding levels. AB - The effect of different feeding levels (ad libitum, 25 and 50 % restriction) and genotypes (1/2 Boer * 1/2 nondescript breed goats, Caninde, and Moxoto) on carcass quantitative characteristics and non-carcass components (NCC) were evaluated. Forty-five intact male goats were distributed in a 3 * 3 factorial design with five replicates. There was no effect of genotype on carcass weights and yields and retail cuts weights and yields (P > 0.05). Compared to Moxoto, 1/2 Boer presented better carcass conformation and higher weights (P < 0.01) and yields of viscera from gastrointestinal tract (P < 0.05), and compared to the other genotypes (P < 0.01), 1/2 Boer presented larger carcass compactness. Carcass weights and yields, retail cuts weights and NCC, and soft tissues yields were higher (P < 0.01) in goats fed ad libitum. The two restriction levels did not differ (P > 0.05) for these variables. There were interactions of genotype and feeding level. At ad libitum feeding, 1/2 Boer had higher weights of breast and shank, leg, soft tissues, and gastrointestinal viscera compared to the Moxoto (P < 0.05). The crossing of nondescript breed goats with Boer may be a strategy for increasing the efficiency of goat meat production in the Brazilian semiarid. Moreover, in times of feed scarcity, farmers may use higher feed restriction levels to keep animals, since for most of the parameters evaluated, there were no differences between the restriction levels. PMID- 24492977 TI - Health impact evaluation of alternative management systems in vicuna (Vicugna vicugna mensalis) populations in Peru. AB - To determine the impact of farming over vicuna population in Peru, serum samples were collected from 207 vicunas (126 captive vicunas and 81 free-ranging vicunas) and 614 domestic South American camelids (571 alpacas and 43 llamas), in ten Andean communities at the Salinas y Aguada Blanca reserve, province of Arequipa, southern Peru. Samples were tested for the presence of leptospirosis, foot and mouth disease (FMD), bovine viral diarrhea (BVD), bovine herpesvirus type 1 (BHV 1), brucellosis, bluetongue disease (BT), paratuberculosis, and neosporosis. Serological results showed that 1.9% (4/207) of vicunas, 18.6% (106/571) of alpacas, and 23.3% (10/43) of llamas were positive to one or more Leptospira serovars. One percent of vicunas (2/207) and 2.4% of domestic camelids (15/614) had Neospora caninum antibodies tested by ELISA, but only two vicunas and two alpacas were confirmed by Western blot. Epidemiological evaluation found an association of leptospirosis to sex and age (p < 0.001), with female subjects older than 2.5 years at higher risk of infection. Interestingly, antibodies against Leptospira serovars were only found in captive vicunas. This is the first study where health status of free-ranging and captive vicunas has been compared. Results indicate minimal to nil presence of FMD, BVD, BHV-1, brucellosis, BT, paratuberculosis, and neosporosis allied to health disorders in our sample. The detection of seropositive animals against Leptospira, however, unveils the likely significance of leptospirosis in wild and domestic South American camelids, the impact of mixed husbandry over vicuna population and the risk to human health. PMID- 24492979 TI - Hydrolyzed whey peptide-based diet ameliorates hepatic ischemia-reperfusion injury in the rat nonalcoholic fatty liver. AB - PURPOSES: The number of patients with nonalcoholic fatty liver disease (NAFLD) is increasing. Hepatic steatosis is a major risk factor for hepatic failure after ischemia-reperfusion (I/R) injury. Hydrolyzed whey peptide (HWP) is a functional liquid-type nutritional diet containing whey peptide, which has previously been shown to exert anti-inflammatory effects. In the present study, we examined the effects of HWP on the hepatic I/R injury in a rat NAFLD model. METHODS: Rats fed a methionine/choline-deficient diet for 4 weeks were divided into two groups after 30 min of whole liver ischemia. In Group-M, HWP was given immediately after reperfusion and every 6 h thereafter. In Group-C, the vehicle was given in the same manner. The liver function tests and microscopic findings of the liver after reperfusion were compared between the two groups. RESULTS: The serum transaminase levels in Group-M were significantly lower than those in Group-C after reperfusion. The gene expression levels of IL-6 and inducible nitric oxide synthase (iNOS) were significantly lower in Group-M compared to Group-C. The TNF alpha and uncoupling protein-2 (UCP-2) expression levels were also markedly lower in Group-M. The hepatic necrotic areas in Group-M were significantly smaller than those in Group-C. CONCLUSION: The administration of a HWP diet ameliorated the hepatic I/R injury in rats with NAFLD. PMID- 24492982 TI - A local public campaign reduces outpatient antibiotic prescribing in Italy. PMID- 24492980 TI - Natural course of Fabry disease and the effectiveness of enzyme replacement therapy: a systematic review and meta-analysis: effectiveness of ERT in different disease stages. AB - OBJECTIVE: Current available evidence on long-term effectiveness of enzyme replacement therapy (ERT) for Fabry disease is limited. More insight is needed whether ERT effectiveness differs in patients with and without baseline end-organ damage. DESIGN: Through a systematic review, untreated and ERT treated males and females with Fabry disease were compared for main clinical outcomes: renal function, left ventricular mass (LVmass), cerebral white matter lesions (WMLs) and end-organ complications. Through a meta-analysis ERT effectiveness was estimated in different disease stages. DATA EXTRACTION: Two reviewers assessed quality of the included studies according to guidelines for prognosis research. Data were synthesized using a random effects meta-analysis. RESULTS: Thirty-one studies were systematically reviewed while six studies were included in the meta analysis. In patients with a GFR > 60 ml/min/1.73 m(2), decline of renal function was similar for treated and untreated patients. Only ERT treated males with a GFR < 60 ml/min/1.73 m(2) had a slower rate of decline in renal function, possibly attributable to anti-proteinuric therapy. Regardless of left ventricular hypertrophy (LVH) at baseline, LVmass remained stable or increased in males despite ERT, however at a slower rate compared to untreated male patients. In ERT treated females with LVH LVmass decreased, and remained stable in females without LVH. WMLs can not be prevented by ERT. Stroke, cardiac and end-stage renal complications develop, though the incidence of new complications seems to be reduced during ERT. CONCLUSION: ERT is effective in reducing LVH, but has a limited effect on renal function. Improved treatment options are needed for Fabry disease. PMID- 24492983 TI - The science and art of theoretical location. PMID- 24492981 TI - Aldehyde dehydrogenase 2 deficiency ameliorates alcoholic fatty liver but worsens liver inflammation and fibrosis in mice. AB - Aldehyde dehydrogenase 2 (ALDH2) is the major enzyme that metabolizes acetaldehyde produced from alcohol metabolism. Approximately 40-50% of East Asians carry an inactive ALDH2 gene and exhibit acetaldehyde accumulation after alcohol consumption. However, the role of ALDH2 deficiency in the pathogenesis of alcoholic liver injury remains obscure. In the present study, wild-type and ALDH2(-/-) mice were subjected to ethanol feeding and/or carbon tetrachloride (CCl4 ) treatment, and liver injury was assessed. Compared with wild-type mice, ethanol-fed ALDH2(-/-) mice had higher levels of malondialdehyde-acetaldehyde (MAA) adduct and greater hepatic inflammation, with higher hepatic interleukin (IL)-6 expression but surprisingly lower levels of steatosis and serum alanine aminotransferase (ALT). Higher IL-6 levels were also detected in ethanol-treated precision-cut liver slices from ALDH2(-/-) mice and in Kupffer cells isolated from ethanol-fed ALDH2(-/-) mice than those levels in wild-type mice. In vitro incubation with MAA enhanced the lipopolysaccharide (LPS)-mediated stimulation of IL-6 production in Kupffer cells. In agreement with these findings, hepatic activation of the major IL-6 downstream signaling molecule signal transducer and activator of transcription 3 (STAT3) was higher in ethanol-fed ALDH2(-/-) mice than in wild-type mice. An additional deletion of hepatic STAT3 increased steatosis and hepatocellular damage in ALDH2(-/-) mice. Finally, ethanol-fed ALDH2(-/-) mice were more prone to CCl4 -induced liver inflammation and fibrosis than ethanol-fed wild-type mice. CONCLUSION: ALDH2(-/-) mice are resistant to ethanol-induced steatosis but prone to inflammation and fibrosis by way of MAA mediated paracrine activation of IL-6 in Kupffer cells. These findings suggest that alcohol, by way of acetaldehyde and its associated adducts, stimulates hepatic inflammation and fibrosis independent from causing hepatocyte death, and that ALDH2-deficient individuals may be resistant to steatosis and blood ALT elevation, but are prone to liver inflammation and fibrosis following alcohol consumption. PMID- 24492984 TI - Drosophila Nesprin-1 controls glutamate receptor density at neuromuscular junctions. AB - Nesprin-1 is a core component of a protein complex connecting nuclei to cytoskeleton termed LINC (linker of nucleoskeleton and cytoskeleton). Nesprin-1 is anchored to the nuclear envelope by its C-terminal KASH domain, the disruption of which has been associated with neuronal and neuromuscular pathologies, including autosomal recessive cerebellar ataxia and Emery-Dreifuss muscular dystrophy. Here, we describe a new and unexpected role of Drosophila Nesprin-1, Msp-300, in neuromuscular junction. We show that larvae carrying a deletion of Msp-300 KASH domain (Msp-300 (?KASH) ) present a locomotion defect suggestive of a myasthenia, and demonstrate the importance of muscle Msp-300 for this phenotype, using tissue-specific RNAi knock-down. We show that Msp-300 (?KASH) mutants display abnormal neurotransmission at the larval neuromuscular junction, as well as an imbalance in postsynaptic glutamate receptor composition with a decreased percentage of GluRIIA-containing receptors. We could rescue Msp-300 (?KASH) locomotion phenotypes by GluRIIA overexpression, suggesting that the locomotion impairment associated with the KASH domain deletion is due to a reduction in junctional GluRIIA. In summary, we found that Msp-300 controls GluRIIA density at the neuromuscular junction. Our results suggest that Drosophila is a valuable model for further deciphering how Nesprin-1 and LINC disruption may lead to neuronal and neuromuscular pathologies. PMID- 24492985 TI - Efficacy and safety of olmesartan/amlodipine/hydrochlorothiazide in patients with hypertension not at goal with mono, dual or triple drug therapy: results of the CHAMPiOn study. AB - OBJECTIVE: To assess the efficacy and safety of once daily olmesartan medoxomil (OM)/amlodipine besylate (AM)/hydrochlorothiazide (HCTZ) 40/10/25 mg in patients with hypertension not at goal with mono, dual or triple drug therapy. METHODS: This was a single-center, prospective, open-label, blinded-endpoint study. After a 1-week screening visit, 40 patients were enrolled into the study and given once daily treatment with OM/AM/HCTZ after the patients underwent baseline ambulatory blood pressure monitoring (ABPM) on their original therapy. The primary endpoint was changes from baseline in mean 24 h ABPM [systolic blood pressure (SBP)] after the first day of therapy with OM/AM/HCTZ 40/10/25 mg. Secondary endpoints were changes from baseline in mean 24 h ABPM [diastolic blood pressure (DBP)] after the first day of therapy with OM/AM/HCTZ 40/10/25 mg; mean changes from baseline in trough seated SBP (SeSBP) at day 1 and SeSBP at weeks 1, 2, 3 and 4; mean changes from baseline in trough seated DBP (SeDBP) at day 1 and SeDBP at weeks 1, 2, 3 and 4; and the percentage of subjects achieving mean 24 h, daytime and night time ABPM BP goals. RESULTS: The baseline paired t-test systolic ABPM was 134.0 +/- 2.77 mmHg and day 1 was 128.6 +/- 2.47 mmHg with a treatment difference of 5.55 +/- 1.3 mmHg (p<0.0001). At week 1, paired t-test ABPM SBP reduction was 117.7 +/- 2.0 mmHg with a treatment difference of -16.5 +/- 1.8 mmHg (p < 0.0001). At week 2, paired t-test ABPM SBP reduction was 115.8 +/- 1.8 mmHg with a treatment difference of -18.4 +/- 2.0 mmHg (p < 0.0001). At week 3, paired t test ABPM SBP reduction was 115.5 +/- 1.9 mmHg with a treatment difference of 18.6 +/- 2.0 mmHg (p < 0.0001). At week 4, paired t-test ABPM SBP reduction was 115.5 +/- 1.8 mmHg with a treatment difference of -18.6 +/- 2.2 mmHg (p < 0.0001). The baseline paired t-test SeSBP was 142 +/- 2.43 mmHg and day 1 was 132 +/- 2.59 mmHg with a treatment difference of -9.78 +/- 1.51 mmHg (p < 0.0001). At week 1, paired t-test SeSBP reduction was 124.0 +/- 1.6 mmHg with a treatment difference of -17.9 +/- 1.8 mmHg (p < 0.0001). At week 2, paired t-test SeSBP reduction was 120.3 +/- 1.7 mmHg with a treatment difference of -21.5 +/- 2.1 mmHg (p < 0.0001). At week 3, paired t-test SeSBP reduction was 118.5 +/- 1.8 mmHg with a treatment difference of -23.3 +/- 1.7 mmHg (p < 0.0001). At week 4, paired t-test SeSBP reduction was 119.6 +/- 1.7 mmHg with a treatment difference of -22.2 +/- 1.9 mmHg (p < 0.0001). CONCLUSION: Treatment with OM/AM/HCTZ achieved superior (SBP) ABPM reductions compared with mono, dual or triple drug therapy, resulting in all patients achieving systolic ABPM goal without ABPM documented hypotension. PMID- 24492986 TI - Early 'in-lab' use of levosimendan in patients with cardiogenic shock unsuitable for intra-aortic balloon pump counterpulsation. AB - Intra-aortic balloon pump counterpulsation is currently the most used mechanical assistance device for patients with cardiogenic shock due to acute myocardial infarction. However, a recently published meta-analysis and trial failed to confirm previous knowledge. We report the results of four patients with ST elevation myocardial infarction, complicated by cardiogenic shock unsuitable for intra-aortic balloon pump counterpulsation treated with early levosimendan infusion during primary percutaneous coronary intervention. PMID- 24492987 TI - Acute myocardial infarction due to liquid nicotine in a young man. PMID- 24492988 TI - Holmium laser enucleation of the prostate versus transurethral resection of the prostate: a randomized clinical trial. AB - OBJECTIVE: To evaluate the efficacy and safety of holmium laser enucleation of the prostate (HoLEP) and transurethral resection of the prostate (TURP), for treatment of benign prostatic hyperplasia (BPH). METHODS: A total of 164 cases of BPH were selected from patients who were hospitalized between January 2010 and December 2011. Patients had received either HoLEP or TURP treatment. Clinical data were collected from the perioperative period, 1 month after surgery, and 12 months after surgery. RESULTS: There was no significant difference between the two groups in the maximum urinary flow rate (Q max), postvoid residual volume (PVR), international prostate symptom score (IPSS), or quality-of-life score (QOL score) at 1 month after surgery (p = 0.56, p = 0.346, p = 0.536 and p = 0.145, respectively). However, after 12 months, patients from the HoLEP group demonstrated better scores in Qmax, PVR, IPSS, and QOL than those from the TURP group (p = 0.037, p = 0.003, p < 0.001 and p = 0.019, respectively). The two groups had comparable operation time (p = 0.105), catheterization time (p = 0.173), and length of hospital stay (p = 0.395), but were statistically different in the weight of resected prostate tissue (p < 0.001), bladder irrigation time (p < 0.001), hemoglobin levels (p = 0.011), and blood sodium levels (p = 0.002) after surgery. CONCLUSIONS: Compared to TURP, HoLEP was safer and had better long term efficacy as assessed by multiple quantitative measures. Therefore, HoLEP may present a better option in the treatment of BPH. PMID- 24492989 TI - Blue dye is sufficient for sentinel lymph node biopsy in breast cancer. AB - BACKGROUND: Most previous studies have reported superior results when blue dye and radiocolloids were used together for sentinel lymph node (SLN) biopsy in early breast cancer. Blue dye was reported to perform poorly when used alone, although more recent studies have found otherwise. This study reviewed the authors' practice of performing SLN biopsy with blue dye alone. METHODS: This was a retrospective review of patients who underwent SLN biopsy using blue dye alone from 2001 to 2005, when SLN biopsy was performed selectively and always followed by axillary lymph node dissection (ALND), and from 2006 to 2010, when SLN biopsy was offered to all suitable patients and ALND done only when the SLN was not identified or positive for metastasis. RESULTS: Between 2001 and 2005, 170 patients underwent SLN biopsy with blue dye alone. The overall SLN non identification rate was 8.4 per cent. The overall false-negative rate was 34 per cent, but decreased with each subsequent year to 13 per cent in 2005. From 2006 to 2010, 610 patients underwent SLN biopsy with blue dye alone. The SLN was not identified in 12 patients (2.0 per cent) and no significant contributing factor was identified. A median of 2 (range 1-11) SLNs were identified. A non-SLN was found to be positive for metastasis in two patients with negative SLNs. Axillary nodal recurrence developed in one patient; none developed internal mammary nodal recurrence. Anaphylaxis occurred in one patient. CONCLUSION: Blue dye performed well as a single modality for SLN biopsy. Non-identification, axillary nodal recurrence and serious allergic reactions were uncommon. PMID- 24492991 TI - Health and morbidity among Bedouin women in southern Israel: a descriptive literature review of the past two decades. AB - In this paper we describe health and morbidity characteristics of Bedouin women in southern Israel, based on papers published over the past 20 years. This is a unique population whose customs, tradition, singular circumstances as a population "in transit", and underprivileged socio-economic status are reflected in mental illness, pregnancy course, perinatal morbidity and mortality rates, and acute and chronic disease. Recognition of these characteristics can help the medical team treat various health problems in this population as well as other populations with similar characteristics. PMID- 24492992 TI - Cardiovascular responses to counterweighted single-leg cycling: implications for rehabilitation. AB - PURPOSE: Although difficult to coordinate, single-leg cycling allows for greater muscle-specific exercise capacity and subsequently greater stimulus for metabolic and vascular adaptations compared to typical double-leg cycling. The purpose of this investigation was to compare metabolic, cardiovascular and perceptual responses of double-leg cycling to single-leg cycling with and without the use of a counterweight. METHODS: Ten healthy individuals (age 22 +/- 2 years; body mass 78.0 +/- 11.2 kg; height 1.8 +/- 0.1 m) performed three cycling conditions consisting of double-leg cycling (DL), non-counterweighted single-leg cycling (SLNCW) and single-leg cycling with a 97 N counterweight attached to the unoccupied crank arm (SLCW). For each condition, participants performed cycling trials (80 rpm) at three different work rates (40, 80 and 120 W). Oxygen consumption (VO2), respiratory exchange ratio (RER), heart rate (HR), femoral blood flow, rating of perceived exertion (RPE) and liking score were measured. RESULTS: VO2 and HR were similar for DL and SLCW conditions. However, during SLNCW, VO2 was at least 23 +/- 13 % greater and HR was at least 15 +/- 11 % greater compared to SLCW across all three intensities. Femoral blood flow was at least 65.5 +/- 43.8 % greater during SLCW compared to DL cycling across all three intensities. RPE was lower and liking scores were greater for SLCW compared to SLNCW condition. CONCLUSION: Counterweighted single-leg cycling provides an exercise modality that is more tolerable than typical single-leg cycling while inducing greater peripheral stress for the same cardiovascular demand as double leg cycling. PMID- 24492993 TI - Environmental enrichment eliminates the anxiety phenotypes in a triple transgenic mouse model of Alzheimer's disease. AB - Although the impacts of environmental enrichment (EE) in several genetic models of Alzheimer's disease (AD) have been documented, the focus has remained predominantly on cognition. Few have investigated the expression of emotional phenotypes that mimic the notable affective features in AD. Here, we studied the interaction between EE and the coexpression of three genetic risk factors (mutations) for AD. In a longitudinal design, 3*Tg-AD mutants and wild type controls were compared at 6-7 months and subsequently at 12-13 months of age. Under standard housing, phenotypes of heightened anxiety levels were identified in the 3*Tg-AD mice in the elevated plus maze and open-field tests. Such trait differences between genotypes were substantially diminished under EE housing, which was attributable to the anxiolytic impact of EE on the mutant mice as much as the anxiogenic impact of EE on the wild type mice. In contrast, the phenotypes in learned fear were not significantly modified by EE in the tests of Pavlovian freezing and conditioned active avoidance conducted at either age. Rearing under EE thus has uncovered a novel distinction between innate and acquired expressions of fear response in the 3*Tg-AD mouse model that might be relevant to the mental health management of AD. PMID- 24492994 TI - Timing matters: temporal dynamics of stress effects on memory retrieval. AB - Stress may impair memory retrieval. This retrieval impairment has been attributed to the action of the stress hormone cortisol, which is released with a delay of several minutes after a stressful encounter. Hence, most studies tested memory retrieval 20-30 min after stress, when the stress-induced cortisol increase peaks. In the present experiment, we investigated whether retrieval impairments can also be found at later intervals after stress. To this end, participants learned a list of words on day 1. Twenty-four hours later, they were first exposed to a stressor or a nonstressful control manipulation and completed a recognition test for the words either immediately thereafter, 25 min later, or 90 min later. Our findings showed that stress did not impair memory retrieval when memory was tested immediately after the stressor, before cortisol levels were elevated. However, retrieval performance was impaired 25 min after stress, when cortisol levels peaked, as well as 90 min after the stressor, when cortisol levels had already returned to baseline. The retrieval impairment 90 min after stress appeared to be even stronger than the one after 25 min. These findings suggest that the detrimental effects of stress on retrieval performance may last longer than is usually assumed. PMID- 24492995 TI - Influences of motor contexts on the semantic processing of action-related language. AB - The contribution of the sensory-motor system to the semantic processing of language stimuli is still controversial. To address the issue, the present article focuses on the impact of motor contexts (i.e., comprehenders' motor behaviors, motor-training experiences, and motor expertise) on the semantic processing of action-related language and reviews the relevant behavioral and neuroimaging findings. The existing evidence shows that although motor contexts can influence the semantic processing of action-related concepts, the mechanism of the contextual influences is still far from clear. Future investigations will be needed to clarify (1) whether motor contexts only modulate activity in motor regions, (2) whether the contextual influences are specific to the semantic features of language stimuli, and (3) what factors can determine the facilitatory or inhibitory contextual influences on the semantic processing of action-related language. PMID- 24492996 TI - Neuromyelitis optica IgG stimulates an immunological response in rat astrocyte cultures. AB - Neuromyelitis optica (NMO) is a primary astrocyte disease associated with central nervous system inflammation, demyelination, and tissue injury. Brain lesions are frequently observed in regions enriched in expression of the aquaporin-4 (AQP4) water channel, an antigenic target of the NMO IgG serologic marker. Based on observations of disease reversibility and careful characterization of NMO lesion development, we propose that the NMO IgG may induce a dynamic immunological response in astrocytes. Using primary rat astrocyte-enriched cultures and treatment with NMO patient-derived serum or purified IgG, we observed a robust pattern of gene expression changes consistent with the induction of a reactive and inflammatory phenotype in astrocytes. The reactive astrocyte factor lipocalin 2 and a broad spectrum of chemokines, cytokines, and stress response factors were induced by either NMO patient serum or purified IgG. Treatment with IgG from healthy controls had no effect. The effect is disease-specific, as serum from patients with relapsing-remitting multiple sclerosis, Sjogren's, or systemic lupus erythematosus did not induce a response in the cultures. We hypothesize that binding of the NMO IgG to AQP4 induces a cellular response that results in transcriptional and translational events within the astrocyte that are consistent with a reactive and inflammatory phenotype. Strategies aimed at reducing the inflammatory response of astrocytes may short circuit an amplification loop associated with NMO lesion development. PMID- 24492997 TI - Biomechanical analysis of two fixation methods for proximal chevron osteotomy of the first metatarsal. AB - PURPOSE: The proximal chevron osteotomy provides high correctional power. However, relatively high rates of dorsiflexion malunion of up to 17 % are reported for this procedure. This leads to insufficient weight bearing of the first ray and therefore to metatarsalgia. Recent biomechanical and clinical studies pointed out the importance of rigid fixation of proximal metatarsal osteotomies. Therefore, the aim of the present study was to compare biomechanical properties of fixation of proximal chevron osteotomies with variable locking plate and cancellous screw respectively. METHODS: Ten matched pairs of human fresh frozen cadaveric first metatarsals underwent proximal chevron osteotomy with either variable locking plate or cancellous screw fixation after obtaining bone mineral density. Biomechanical testing included repetitive plantar to dorsal loading from 0 to 31 N with the 858 Mini Bionix((r)) (MTS((r)) Systems Corporation, Eden Prairie, MN, USA). Dorsal angulation of the distal fragment was recorded. RESULTS: The variable locking plate construct reveals statistically superior results in terms of bending stiffness and dorsal angulation compared to the cancellous screw construct. There was a statistically significant correlation between bone mineral density and maximum tolerated load until construct failure occurred for the screw construct (r = 0.640, p = 0.406). CONCLUSION: The results of the present study indicate that variable locking plate fixation shows superior biomechanical results to cancellous screw fixation for proximal chevron osteotomy. Additionally, screw construct failure was related to levels of low bone mineral density. Based on the results of the present study we recommend variable locking plate fixation for proximal chevron osteotomy, especially in osteoporotic bone. PMID- 24492998 TI - Comment on Korsten et al.: Operative or conservative treatment in patients with Rockwood type III acromioclavicular dislocation: a systematic review and update of current literature. PMID- 24492999 TI - MiR-21 is an Ngf-modulated microRNA that supports Ngf signaling and regulates neuronal degeneration in PC12 cells. AB - The neurotrophins Ngf, Bdnf, NT-3, NT4-5 have key roles in development, survival, and plasticity of neuronal cells. Their action involves broad gene expression changes at the level of transcription and translation. MicroRNAs (miRs)-small RNA molecules that control gene expression post-transcriptionally-are increasingly implicated in regulating development and plasticity of neural cells. Using PC12 cells as a model system, we show that Ngf modulates changes in expression of a variety of microRNAs, including miRs known to be modulated by neurotrophins-such as the miR-212/132 cluster-and several others, such as miR-21, miR-29c, miR-30c, miR-93, miR-103, miR-207, miR-691, and miR-709. Pathway analysis indicates that Ngf-modulated miRs may regulate many protein components of signaling pathways involved in neuronal development and disease. In particular, we show that miR-21 enhances neurotrophin signaling and controls neuronal differentiation induced by Ngf. Notably, in a situation mimicking neurodegeneration-differentiated neurons deprived of Ngf-this microRNA is able to preserve the neurite network and to support viability of the neurons. These findings uncover a broad role of microRNAs in regulating neurotrophin signaling and suggest that aberrant expression of one or more Ngf-modulated miRs may be involved in neurodegenerative diseases. PMID- 24493000 TI - Clinical and radiological findings in long-term intracranial pressure monitoring. AB - BACKGROUND: Advantages of telemetric devices for long-term intracranial pressure (ICP) measurement have been mentioned several times in the literature. However, descriptions of associated complications are lacking. Therefore, the presented observational study focused on clinical and radiological findings after insertion of an intraparenchymal telemetric ICP monitor. METHODS: Between April 2010 and February 2013, 185 telemetric ICP catheters were implanted for diagnostic purposes. All patients were clinically followed. Radiological, microbiological and clinical data were analysed. RESULTS: One brain abscess (0.5 %) and two cutaneous infections (1.1 %) occurred in 185 patients. Staphylococcus spp. could be detected in all cases. Six patients (3.2 %) suffered from single new-onset seizures and one patient (0.5 %) from a temporary hemiparesis. Intracerebral haemorrhages occurred in 15.6 %, most of the time as small punctate bleedings. Perifocal oedematous reactions surrounding inserted telemetric catheters could be observed in 46.9 %. Multiple imaging studies revealed a tendency of complete oedema resolution over time. CONCLUSIONS: Infectious as well as haemorrhagic complication rates are well comparable with the common literature. The long-term implantation of an ICP probe does not seem to increase the risk of wound infections or brain abscess formation. Surprisingly, very high numbers of oedematous reactions after insertion of the intraparenchymal ICP monitor were seen. Reasons therefore could only be speculated upon. PMID- 24493002 TI - Letter to the editor: validity of the results of a perioperative protocol to reduce shunt infections. PMID- 24493001 TI - Cranioplasty with autologous cryopreserved bone after decompressive craniectomy: complications and risk factors for developing surgical site infection. AB - BACKGROUND: Renewed interest has developed in decompressive craniectomy, and improved survival is shown when this treatment is used after malignant middle cerebral artery infarction. The aim of this study was to investigate the frequency and possible risk factors for developing surgical site infection (SSI) after delayed cranioplasty using autologous, cryopreserved bone. METHODS: This retrospective study included 74 consecutive patients treated with decompressive craniectomy during the time period May 1998 to October 2010 for various non traumatic conditions causing increased intracranial pressure due to brain swelling. Complications were registered and patient data was analyzed in a search for predictive factors. RESULTS: Fifty out of the 74 patients (67.6 %) survived and underwent delayed cranioplasty. Of these, 47 were eligible for analysis. Six patients (12.8 %) developed SSI following the replacement of autologous cryopreserved bone, whereas bone resorption occurred in two patients (4.3 %). No factors predicted a statistically significant rate of SSI, however, prolonged procedural time and cardiovascular comorbidity tended to increase the risk of SSI. CONCLUSIONS: SSI and bone flap resorption are the most frequent complications associated with the reimplantation of autologous cryopreserved bone after decompressive craniectomy. Prolonged procedural time and cardiovascular comorbidity tend to increase the risk of SSI. PMID- 24493003 TI - Low-temperature activation of hematite nanowires for photoelectrochemical water oxidation. AB - Hematite (alpha-Fe2 O3 ) nanostructures have been extensively studied as photoanode materials for photoelectrochemical (PEC) water oxidation. However, the photoactivity of pristine hematite nanostructures is fairly low and typically requires thermal activation at temperature of 650 degrees C or above. Here, we report a new method for enhancing the photocurrent of hematite nanowires at a substantially lower temperature of 350 degrees C by means of a two-step annealing process (activation process). Hydrothermally grown beta-FeOOH nanowires were first annealed in a pure N2 environment at 350 degrees C to form magnetite, followed by partial oxidation in air to convert magnetite to hematite. During this process, Fe(2+) sites (oxygen vacancies) were intentionally created to increase the donor density and therefore the electrical conductivity of hematite. The oxygen-deficient hematite nanowire photoanode created at low temperature (350 degrees C) show considerably enhanced photoactivity compared to pristine hematite sample that prepared by thermal annealing of beta-FeOOH nanowires at 550 degrees C in air. Moreover, this low-temperature annealing method can be coupled with an element doping method to further increase the photoactivity of hematite nanowire. Sn-doped hematite nanowires prepared by the same low-temperature annealing method show at least three fold enhanced photocurrent compared to the undoped sample. Significantly, the highest temperature in the entire annealing process was 350 degrees C, which is the lowest activation temperature ever reported for hematite nanowire photoanodes. PMID- 24493004 TI - Microfluidic fabrication of cell-derived nanovesicles as endogenous RNA carriers. AB - Exosomes/microvesicles are known to shuttle biological signals between cells, possibly by transferring biological signal components such as encapsulated RNAs and proteins, plasma membrane proteins, or both. Therefore exosomes are being considered for use as RNA and protein delivery vehicles for various therapeutic applications. However, living cells in nature secrete only a small number of exosomes, and procedures to collect them are complex; these complications impede their use in mass delivery of components to targeted cells. We propose a novel and efficient method that forces cells through hydrophilic microchannels to generate artificial nanovesicles. These mimetic nanovesicles contain mRNAs, intracellular proteins and plasma membrane proteins, and are shaped like cell secreted exosomes. When recipient cells are exposed to nanovesicles from embryonic stem cells, mRNAs of Oct 3/4 and Nanog are transferred from embryonic stem cells to the target cells. This result suggests that mimetic nanovesicles can be used as vehicles to deliver RNA. This nanovesicle formation method is expected to be used in exosome research and to have applications in drug and RNA delivery systems. PMID- 24493005 TI - Water promoted C-C bond cleavage: facile synthesis of 3,3-bipyrrole derivatives from dienones and tosylmethyl isocyanide (TosMIC). AB - A simple and highly efficient synthetic strategy to access 3,3-bipyrrole derivatives by the reaction of dienone derivatives with TosMIC is reported. The reaction involves a van Leusen's pyrrole synthesis followed by an unusual C-C bond cleavage in the presence of water under mild conditions. PMID- 24493006 TI - New unsweetened truths about sugar. PMID- 24493007 TI - Editor's note February 2014. PMID- 24493008 TI - Impact of right ventricular dyssynchrony on left ventricular performance in patients with pulmonary hypertension. AB - Pulmonary hypertension has been associated with right ventricular (RV) dyssynchrony which may induce left ventricular (LV) dysfunction and dyssynchrony through ventricular interdependence. The present study evaluated the influence of RV dyssynchrony on LV performance in patients with pulmonary hypertension. One hundred and seven patients with pulmonary hypertension (age 63 +/- 14 years, systolic pulmonary arterial pressure 60 +/- 19 mmHg) and LV ejection fraction (EF) >35% were evaluated. Ventricular dyssynchrony was assessed with speckle tracking echocardiography and defined as the standard deviation of the time to peak longitudinal strain of six segments of the RV (RV-SD) and the LV (LV-SD) in the apical 4-chamber view. Mean RV-SD and LV-SD assessed with longitudinal strain speckle tracking echocardiography were 51 +/- 28 and 47 +/- 21 ms, respectively. The patient population was divided according to the median RV-SD value of 49 ms. Patients with RV-SD >=49 ms had significantly worse NYHA functional class (2.7 +/ 0.7 vs. 2.3 +/- 0.7, p = 0.004), RV function (tricuspid annular plane systolic excursion: 16 +/- 4 vs. 19 +/- 4 mm, p < 0.001), LVEF (50 +/- 10 vs. 55 +/- 8%, p = 0.001), and larger LV-SD (57 +/- 18 vs. 36 +/- 18 ms, p < 0.001). RV-SD significantly correlated with LV-SD (r = 0.55, p < 0.001) and LVEF (r = -0.23, p = 0.02). Multiple linear regression analysis showed an independent association between RV-SD and LV-SD (beta = 0.35, 95%CI 0.21-0.49, p < 0.001). RV dyssynchrony is significantly associated with LV dyssynchrony and reduced LVEF in patients with pulmonary hypertension. PMID- 24493010 TI - Plasmacytoid dendritic cell-derived IFN-alpha promotes murine liver ischemia/reperfusion injury by induction of hepatocyte IRF-1. AB - Plasmacytoid dendritic cells (pDC) constitute the body's principal source of type I interferon (IFN) and are comparatively abundant in the liver. Among various cytokines implicated in liver ischemia and reperfusion (I/R) injury, type I IFNs have been described recently as playing an essential role in its pathogenesis. Moreover, type I IFNs have been shown to up-regulate hepatocyte expression of IFN regulatory factor 1 (IRF-1), a key transcription factor that regulates apoptosis and induces liver damage after I/R. Our aim was to ascertain the capacity of IFN alpha released by liver pDC to induce liver damage through hepatic IRF-1 up regulation after I/R injury. Our findings show that liver pDC mature and produce IFN-alpha in response to liver I/R. Liver pDC isolated after I/R induced elevated levels of IRF-1 production by hepatocytes compared with liver pDC isolated from sham-operated mice. Notably, hepatic IRF-1 expression was reduced significantly by neutralizing IFN-alpha. In vivo, IFN-alpha neutralization protected the liver from I/R injury by reducing hepatocyte apoptosis. This was associated with impaired expression of IRF-1 and proapoptotic molecules such as Fas ligand, its receptor (Fas) and death receptor 5, which are regulated by IRF-1. Furthermore, pDC-depleted mice failed to up-regulate hepatic IFN-alpha and displayed less liver injury associated with reduced levels of hepatic interleukin (IL)-6, tumor necrosis factor-alpha, and hepatocyte apoptosis after I/R compared with controls. CONCLUSION: these data support the hypothesis that IFN-alpha derived from liver pDC plays a key role in the pathogenesis of liver I/R injury by enhancing apoptosis as a consequence of induction of hepatocyte IRF-1 expression. PMID- 24493011 TI - [Quality management in intensive care medicine]. AB - Treatment of critical ill patients in the intensive care unit is tantamount to well-designed risk or quality management. Several tools of quality management and quality assurance have been developed in intensive care medicine. In addition to external quality assurance by benchmarking with regard to the intensive care medicine, peer review procedures have been established for external quality assurance in recent years. In the process of peer review of an intensive care unit (ICU), external physicians and nurses visit the ICU, evaluate on-site proceedings, and discuss with the managing team of the ICU possibilities for optimization. Furthermore, internal quality management in the ICU is possible based on the 10 quality indicators of the German Interdisciplinary Society for Intensive Care Medicine (DIVI, "Deutschen Interdisziplinaren Vereinigung fur Intensiv- und Notfallmedizin"). Thereby every ICU has numerous possibilities to improve their quality management system. PMID- 24493009 TI - Retention in care within 1 year of initial HIV care visit in a multisite US cohort: who's in and who's out? AB - Biannual attendance at medical visits is an established measure of retention in HIV care. We examined factors associated with attending at least 2 clinic visits at least 90 days apart among HIV-infected, antiretroviral therapy (ART)-naive HIV Outpatient Study participants entering care during 2000 to 2011. Of 1441 patients, 85% were retained in care during the first year of observation. Starting ART during the year was the strongest correlate of retention (adjusted odds ratio [aOR] 6.4, 95% confidence interval [CI] 4.4-9.4). After adjusting for starting ART, publicly insured patients (aOR 0.6, 95% CI 0.4-1.0), and patients with baseline CD4 counts <200 cells/mm(3) (aOR 0.5, 95% CI 0.3-0.9) or missing CD4 counts (aOR 0.3, 95% CI 0.2-0.6) were less likely to be retained in care. Although most patients had recommended biannual care visits, some ART-naive individuals may require additional interventions to remain in care. Promptly initiating ART may facilitate engagement in care. PMID- 24493012 TI - Combinatorial approach for large-scale identification of linked peptides from tandem mass spectrometry spectra. AB - The combination of chemical cross-linking and mass spectrometry has recently been shown to constitute a powerful tool for studying protein-protein interactions and elucidating the structure of large protein complexes. However, computational methods for interpreting the complex MS/MS spectra from linked peptides are still in their infancy, making the high-throughput application of this approach largely impractical. Because of the lack of large annotated datasets, most current approaches do not capture the specific fragmentation patterns of linked peptides and therefore are not optimal for the identification of cross-linked peptides. Here we propose a generic approach to address this problem and demonstrate it using disulfide-bridged peptide libraries to (i) efficiently generate large mass spectral reference data for linked peptides at a low cost and (ii) automatically train an algorithm that can efficiently and accurately identify linked peptides from MS/MS spectra. We show that using this approach we were able to identify thousands of MS/MS spectra from disulfide-bridged peptides through comparison with proteome-scale sequence databases and significantly improve the sensitivity of cross-linked peptide identification. This allowed us to identify 60% more direct pairwise interactions between the protein subunits in the 20S proteasome complex than existing tools on cross-linking studies of the proteasome complexes. The basic framework of this approach and the MS/MS reference dataset generated should be valuable resources for the future development of new tools for the identification of linked peptides. PMID- 24493014 TI - Effect of supervised exercise on physical function and balance in patients with intermittent claudication. AB - BACKGROUND: The aim of the study was to identify whether a standard supervised exercise programme (SEP) for patients with intermittent claudication improved specific measures of functional performance including balance. METHODS: A prospective observational study was performed at a single tertiary vascular centre. Patients with symptomatic intermittent claudication (Rutherford grades 1 3) were recruited to the study. Participants were assessed at baseline (before SEP) and 3, 6 and 12 months afterwards for markers of lower-limb ischaemia (treadmill walking distance and ankle : brachial pressure index), physical function (6-min walk, Timed Up and Go test, and Short Physical Performance Battery (SPPB) score), balance impairment using computerized dynamic posturography with the Sensory Organization Test (SOT), and quality of life (VascuQoL and Short Form 36). RESULTS: Fifty-one participants underwent SEP, which significantly improved initial treadmill walking distance (P = 0.001). Enrolment in a SEP also resulted in improvements in physical function as determined by 6-min maximum walking distance (P = 0.006), SPPB score (P < 0.001), and some domains of both generic (bodily pain, P = 0.025) and disease-specific (social domain, P = 0.039) quality of life. Significant improvements were also noted in balance, as determined by the SOT (P < 0.001). CONCLUSION: Supervised exercise improves both physical function and balance impairment. PMID- 24493013 TI - Quantitation of human metallothionein isoforms: a family of small, highly conserved, cysteine-rich proteins. AB - Human metallothioneins (MTs) are important regulators of metal homeostasis and protectors against oxidative damage. Their altered mRNA expression has been correlated with metal toxicity and a variety of cancers. Current immunodetection methods lack the specificity to distinguish all 12 human isoforms. Each, however, can be distinguished by the mass of its acetylated, cysteine-rich, hydrophilic N terminal tryptic peptides. These properties were exploited to develop a bottom-up MALDI-TOF/TOF-MS-based method for their simultaneous quantitation. Key features included enrichment of N-terminal acetylated peptides by strong cation exchange chromatography, optimization of C18 reversed-phase chromatography, and control of methionine oxidation. Combinations of nine isoforms were identified in seven cell lines and two tissues. Relative quantitation was accomplished by comparing peak intensities of peptides generated from pooled cytosolic proteins alkylated with 14N- or 15N-iodoacetamide. Absolute quantitation was achieved using 15N iodoacetamide-labeled synthetic peptides as internal standards. The method was applied to the cadmium induction of MTs in human kidney HK-2 epithelial cells expressing recombinant MT-3. Seven isoforms were detected with abundances spanning almost 2 orders of magnitude and inductions up to 12-fold. The protein to-mRNA ratio for MT-1E was one-tenth that of other MTs, suggesting isoform specific differences in protein expression efficiency. Differential expression of MT-1G1 and MT-1G2 suggested tissue- and cell-specific alternative splicing for the MT-1G isoform. Protein expression of MT isoforms was also evaluated in human breast epithelial cancer cell lines. Estrogen-receptor-positive cell lines expressed only MT-2 and MT-1X, whereas estrogen-receptor-negative cell lines additionally expressed MT-1E. The combined expression of MT isoforms was 38-fold greater in estrogen-receptor-negative cell lines than in estrogen-receptor positive cells. These findings demonstrate that individual human MT isoforms can be accurately quantified in cells and tissues at the protein level, complementing and expanding mRNA measurement as a means for evaluating MTs as potential biomarkers for cancers or heavy metal toxicity. PMID- 24493015 TI - Differentiation of non-pylori Helicobacter species based on PCR-restriction fragment length polymorphism of the 23S rRNA gene. AB - Phenotypic identification of non-pylori Helicobacter species has always been problematic and time-consuming in comparison with many other bacteria. We developed a rapid two-step identification assay based on PCR-restriction fragment length polymorphism (PCR-RFLP) analysis of the 23S rRNA gene for differentiating between non-pylori Helicobacter species. A new genus-specific primer pair based on all available complete and partial 23S rRNA sequences of Helicobacter species was designed. In silico restriction analysis of variable regions of the 23S rRNA gene suggested SmaI and HindIII endonucleases would provide a good level of differentiation. Analysis of the obtained 23S rRNA RFLP patterns divided all Helicobacter study strains into three species groups (groups A-C) and 12 unique restriction patterns. Wolinella succinogenes also gave a unique pattern. Our proposed PCR-RFLP method was found to be as a valuable tool for routine identification of non-pylori Helicobacter species from human or animal samples. PMID- 24493016 TI - Joint electrical, photophysical, and photovoltaic studies on truxene dye sensitized solar cells: impact of arylamine electron donors. AB - The judicious design of electron donors is one of the viable tactics to improve the efficiency of organic dyes for dye-sensitized solar cells (DSCs) employing outer-sphere redox couples. Herein, a hexahexyltruxene-substituted 4-(hexyloxy)-N phenylaniline (HT-HPA) segment is constructed and employed as the electron donor in two organic push-pull dyes (M28 and M29) with high molar absorption coefficient values. Relative to its congener (C241) possessing the dihexyloxy substituted triphenylamine electron donor, M29 exhibits red-shifted absorption as well as enhanced maximum molar absorption coefficient values. A thorough comparison with M29 and C241 demonstrates that the HT-HPA segment adequately insulates the TiO2 surface from the electrolyte, which prevents back recombination and prolongs electron lifetime in the semiconductor. The diminishment of charge recombination not only enables attainment of strikingly high photovoltages (approaching 1 V), but also overcompensates the disadvantageous impact of lower dye-load amounts. As a result, the dye transformation from C241 to M29 brings forth an efficiency improvement from 7.3 % to 8.5 % at the 100 mW cm(-2) simulated AM1.5 conditions. Our work should shed light on the future design of more powerful push-pull organic photosensitizers for iodine-free DSCs. PMID- 24493019 TI - "Other" Troubles: Deconstructing Perceptions and Changing Responses to Refugees in Canada. AB - Canadian national identity is based on a self-image of humanitarianism and liberality governed by ethical and moral principles of social justice, universal health care and equity for all. However, recent changes to the Interim Federal Health Program (IFHP) demonstrate that the current discourse on refugee policy in Canada is built on a socially constructed image of "the refugee." Drawing on contemporary refugee literature we look at how refugees are constructed as the 'Other,' both nationally and internationally. Using the recent changes to the IFHP as a case example, we demonstrate that the construction of "the refugee" as an Other has informed the cuts to refugee care in Canada. Exposing Othering in Canadian refugee policy is necessary for providing helpful and equitable treatment to refugees in Canada. PMID- 24493018 TI - Glutamatergic candidate genes in autism spectrum disorder: an overview. AB - Autism spectrum disorders (ASD) are neurodevelopmental disorders with early onset in childhood. Most of the risk for ASD can be explained by genetic variants that act in interaction with biological environmental risk factors. However, the architecture of the genetic components is still unclear. Genetic studies and subsequent systems biological approaches described converging functional effects of identified genes towards pathways relevant for neuronal signalling. Mouse models suggest an aberrant synaptic plasticity at the neuropathological level, which is believed to be conferred by dysregulation of long-term potentiation or depression of neuronal connections. A central pathway regulating these mechanisms is glutamatergic signalling. Here, we hypothesized that susceptibility genes for ASD are enriched for components of this pathway. To further understand the impact of ASD risk genes on the glutamatergic pathway, we performed a systematic review using the literature database "pubmed" and the "AutismKB" knowledgebase. We provide an overview of the glutamatergic system in typical brain function and development, and summarize findings from linkage, association, copy number variants, and sequencing studies in ASD to provide a comprehensive picture of the glutamatergic landscape of ASD genetics. Genetic variants associated with ASD were enriched in glutamatergic pathways, affecting receptor signalling, metabolism and transport. Furthermore, in genetically modified mouse models for ASD, pharmacological compounds acting on ionotropic or metabotropic receptor activity are able to rescue ASD reminscent phenotypes. We conclude that glutamatergic genetic risk factors for ASD show a complex pattern and further studies are needed to fully understand its mechanisms, before translation of findings into clinical applications and individualized treatment approaches will be possible. PMID- 24493021 TI - Inferring correlations: from exemplars to categories. AB - Research and theorizing suggest a processing advantage of category-level correlations over exemplar-level correlations. That research has also shown that category-level correlations serve as a proxy for inferring exemplar-level correlations. For example, an individual may learn that the demand for a product category, like cheese, in one store predicts the demand for this category in another. The individual could then draw the unwarranted conclusion that the demand for an exemplar, like cheddar, would also predict the demand for this exemplar in the other store. This notion is supported by previous experiments demonstrating that the subjective exemplar-level correlation follows the implication of the category-level correlation. However, in virtually all previous experiments suggesting a processing advantage for category-level over exemplar level correlations, the stimulus correlation at the category level was substantial, whereas the correlation at the exemplar level was weak. Here, we tested the hypothesis that individuals process the level that is most informative, either the exemplar or the category level. We presented participants with a zero correlation at the category level, but varied the correlation at the exemplar level. Participants presented with a zero correlation across exemplar products correctly reproduced a zero correlation across product categories. When presented with a substantial correlation at the exemplar level, however, they erroneously reproduced a similar correlation at the category level. These findings therefore imply that there is no general processing advantage for correlations at higher aggregation levels. Instead, individuals seemingly attend to the level that holds the most regular information. Findings are discussed regarding the role of covariation strength in correlation detection and use. PMID- 24493020 TI - The telomeric sync model of speciation: species-wide telomere erosion triggers cycles of transposon-mediated genomic rearrangements, which underlie the saltatory appearance of nonadaptive characters. AB - Charles Darwin knew that the fossil record is not overwhelmingly supportive of genetic and phenotypic gradualism; therefore, he developed the core of his theory on the basis of breeding experiments. Here, I present evidence for the existence of a cell biological mechanism that strongly points to the almost forgotten European concept of saltatory evolution of nonadaptive characters, which is in perfect agreement with the gaps in the fossil record. The standard model of chromosomal evolution has always been handicapped by a paradox, namely, how speciation can occur by spontaneous chromosomal rearrangements that are known to decrease the fertility of heterozygotes in a population. However, the hallmark of almost all closely related species is a differing chromosome complement and therefore chromosomal rearrangements seem to be crucial for speciation. Telomeres, the caps of eukaryotic chromosomes, erode in somatic tissues during life, but have been thought to remain stable in the germline of a species. Recently, a large human study spanning three healthy generations clearly found a cumulative telomere effect, which is indicative of transgenerational telomere erosion in the human species. The telomeric sync model of speciation presented here is based on telomere erosion between generations, which leads to identical fusions of chromosomes and triggers a transposon-mediated genomic repatterning in the germline of many individuals of a species. The phenotypic outcome of the telomere-triggered transposon activity is the saltatory appearance of nonadaptive characters simultaneously in many individuals. Transgenerational telomere erosion is therefore the material basis of aging at the species level. PMID- 24493022 TI - Reply: To PMID 23913408. PMID- 24493023 TI - Interaction of the chemokines I-TAC (CXCL11) and SDF-1 (CXCL12) in the regulation of tumor angiogenesis of colorectal cancer. AB - The chemokine CXCL12 has a decisive role in tumor progression by mediating pro angiogenic and pro-metastatic effects through its receptor CXCR4. The CXCL12 pathway is connected with another chemokine, CXCL11, through its second receptor CXCR7. CXCL11 also binds to the CXCR3 receptor. CXCL11 function in tumor angiogenesis is likely receptor dependent because CXCR3 predominantly mediates angiostatic signals whereas CXCR7 mediated signaling is rather angiogenic. We therefore studied the interaction of CXCL12 and CXCL11 in an in vivo model of colorectal cancer metastasis. GFP-transfected CT26.WT colorectal cancer cells were implanted into the dorsal skinfold chamber of syngeneic BALB/c mice. The animals received either peritumoral application of CXCL11 or intraperitoneal injections with neutralizing antibodies against CXCL11, CXCL12 or both. Tumor growth characteristics, angiogenesis, cell migration, invasive tumor growth, tumor cell proliferation and apoptosis were studied by intravital fluorescence microscopy and immunohistochemistry during an observation period of 14 days. Local exposure to CXCL11 significantly stimulated tumor growth compared to controls and enhanced invasive growth characteristics without affecting tumor angiogenesis and tumor cell migration. Neither CXCL11 nor CXCL12-blockade had a significant impact on tumor growth and angiogenesis, whereas the combined neutralization of CXCL11 and CXCL12 almost completely abrogated tumor vessel formation. As a consequence, tumor growth and invasive growth characteristics were reduced compared to the other groups. The results of the present study underline the interaction of CXCL12 and CXCL11 during tumor angiogenesis. The combined blockade of both signaling pathways may provide an interesting anti angiogenic approach for anti-tumor therapy. PMID- 24493025 TI - Healthy lifestyle for metabolic health: no more excuse! PMID- 24493026 TI - McArdle's disease in the seventh decade: challenges in diagnosis and management. PMID- 24493027 TI - Maternal diabetes affects rat placental morphology and pregnancy. PMID- 24493028 TI - Therapeutic effectiveness of potassium iodine in drug-naive patients with Graves' disease: a single-center experience. AB - Iodine is beneficial against Graves' thyrotoxicosis, though its effects are short lived. However, its long-term effectiveness as an initial therapy has not been fully elucidated. Here, we compared the effects of potassium iodine (KI) and methimazole (MMI) in Graves' thyrotoxicosis and on thyrotropin receptor antibody (TRAb) levels. Between 2008 and 2011, 293 patients with untreated Graves' disease visited the outpatient clinic of Juntendo University. Of these, 227 patients were treated with MMI and 30 treated with KI as the initial therapy. To compare the effects of KI and MMI, we identified patients with similar probabilities of receiving MMI or KI using propensity score (PS) analysis based on the observed clinical features. PS matching created 20 matched pairs of patients with Graves' disease treated with MMI and KI. The baseline characteristics of post-matched patients treated with MMI were comparable to those treated with KI (FT3; 7.16 +/- 2.30, 6.56 +/- 1.85 pg/ml, FT4; 2.57 +/- 0.79, 2.49 +/- 0.70 ng/dl, respectively). The initial dose of MMI was 14.0 +/- 8.2 mg/day and that of KI was 53.6 +/- 11.7 mg/day. Three patients of the KI group did not respond to the monotherapy, requiring the inclusion of antithyroid drugs. One patient on MMI developed moderate skin eruption, but continued the treatment. Patients who continued the initial treatment showed significant and comparable reductions in FT4, FT3 and TRAb by MMI as well as by KI at the end of 12-month treatment. Although patients were limited to mild untreated Graves' disease thyrotoxicosis, KI offers a possible alternative initial treatment for this condition. PMID- 24493029 TI - Papillary carcinoma in thyroglossal duct cyst: role of fine needle aspiration and frozen section biopsy to guide surgical approach. PMID- 24493024 TI - Genetics of breast cancer bone metastasis: a sequential multistep pattern. AB - Bone metastasis accounts for the vast majority of breast cancer (BC) metastases, and is related to a high rate of morbidity and mortality. A number of seminal studies have uncovered gene expression signatures involved in BC development and bone metastasis; each of them points at a distinct step of the 'invasion metastasis cascade'. In this review, we provide most recently discovered functions of sets of genes that are selected from widely accepted gene signatures that are implicate in BC progression and bone metastasis. We propose a possible sequential pattern of gene expression that may lead a benign primary breast tumor to get aggressiveness and progress toward bone metastasis. A panel of genes which primarily deal with features like DNA replication, survival, proliferation, then, angiogenesis, migration, and invasion has been identified. TGF-beta, FGF, NFkappaB, WNT, PI3K, and JAK-STAT signaling pathways, as the key pathways involved in breast cancer development and metastasis, are evidently regulated by several genes in all three signatures. Epithelial to mesenchymal transition that is also an important mechanism in cancer stem cell generation and metastasis is evidently regulated by these genes. This review provides a comprehensive insight regarding breast cancer bone metastasis that may lead to a better understanding of the disease and take step toward better treatments. PMID- 24493030 TI - Effects of incretin-based therapy in patients with heart failure and myocardial infarction. AB - Studies designed to evaluate the short-term effects of incretin-related drugs in subjects with cardiac disease are still preliminary. In patients with heart failure, two of five studies showed that glucagon-like peptide-1 (GLP-1) infusion was associated with an absolute increase in left ventricular ejection fraction (LVEF) by 6-10 %, whereas no significant benefit was observed in the remaining three studies. In patients with coronary artery disease, single infusion of the GLP-1 receptor analog, exenatide, did not increase LVEF, but this drug may decrease infarct size in patients with myocardial infarction presenting with short duration of ischemic symptoms. Single dose of GLP-1 and the dipeptidyl peptidase-IV (DPP-IV) inhibitor, sitagliptin, may improve left ventricular function, predominantly in ischemic segments, and attenuate post-ischemic stunning. Nausea, vomiting and hypoglycemia were the most common adverse effects associated with GLP-1 and exenatide administration. Increased heart rate was also observed with exenatide in patients with heart failure. Large randomized trials including diabetic patients with preexisting heart failure and myocardial infarction showed that chronic therapy with the DPP-IV inhibitors saxagliptin and alogliptin did not reduce cardiovascular events or mortality. Moreover, saxagliptin use was associated with significant increase in frequency of heart failure requiring hospitalization, hypoglycemia and angioedema. Overall, short term preliminary data suggest potential cardioprotective effects of exenatide and sitagliptin in patients with heart failure and myocardial infarction. Meanwhile, long-term randomized trials suggest no benefit of alogliptin, and increased harm associated with the use of saxagliptin. PMID- 24493031 TI - Association of the genetic variants of insulin receptor substrate 1 (IRS-1) with type 2 diabetes mellitus in a Saudi population. AB - Type 2 diabetes mellitus (T2DM) is a chronic degenerative disease, phenotypically and genetically heterogeneous, characterized by high levels of glucose and metabolic complications. Insulin receptor substrate 1 (IRS-1) plays a key role in the insulin-stimulated signal transduction pathway. A glycine-to-arginine substitution at codon 972 (G972R) (rs1801278) in the IRS-1 gene has been associated with impaired insulin action. Another SNP rs2943641 in the IRS-1 gene has been found to be associated with T2DM and insulin resistance in genome-wide association studies. The aim of the present study was to evaluate whether rs1801278 and rs2943641 are associated with increased risk of T2DM in the Saudi population. The study included 376 T2DM cases and 380 healthy controls. Genomic DNA was isolated using a commercially available kit supplied by Norgen Biotech Corp. Genotyping was performed by PCR and RFLP analysis. There was a significant difference in the genotypic distribution as well as allelic frequency between the T2DM cases and controls in case of both the polymorphisms for rs1801278 (1.752, 95 % CI 1.002-3.121; p = 0.04), and for rs2943641 (OR = 1.482, 95 % CI 1.176 1.867; p = 0.001). In conclusion, both the (rs1801278 and rs2943641) polymorphisms are associated with T2DM in the Saudi population. PMID- 24493034 TI - SegAnnDB: interactive Web-based genomic segmentation. AB - MOTIVATION: DNA copy number profiles characterize regions of chromosome gains, losses and breakpoints in tumor genomes. Although many models have been proposed to detect these alterations, it is not clear which model is appropriate before visual inspection the signal, noise and models for a particular profile. RESULTS: We propose SegAnnDB, a Web-based computer vision system for genomic segmentation: first, visually inspect the profiles and manually annotate altered regions, then SegAnnDB determines the precise alteration locations using a mathematical model of the data and annotations. SegAnnDB facilitates collaboration between biologists and bioinformaticians, and uses the University of California, Santa Cruz genome browser to visualize copy number alterations alongside known genes. AVAILABILITY AND IMPLEMENTATION: The breakpoints project on INRIA GForge hosts the source code, an Amazon Machine Image can be launched and a demonstration Web site is http://bioviz.rocq.inria.fr. PMID- 24493035 TI - ARTS: automated randomization of multiple traits for study design. AB - Collecting data from large studies on high-throughput platforms, such as microarray or next-generation sequencing, typically requires processing samples in batches. There are often systematic but unpredictable biases from batch-to batch, so proper randomization of biologically relevant traits across batches is crucial for distinguishing true biological differences from experimental artifacts. When a large number of traits are biologically relevant, as is common for clinical studies of patients with varying sex, age, genotype and medical background, proper randomization can be extremely difficult to prepare by hand, especially because traits may affect biological inferences, such as differential expression, in a combinatorial manner. Here we present ARTS (automated randomization of multiple traits for study design), which aids researchers in study design by automatically optimizing batch assignment for any number of samples, any number of traits and any batch size. AVAILABILITY AND IMPLEMENTATION: ARTS is implemented in Perl and is available at github.com/mmaiensc/ARTS. ARTS is also available in the Galaxy Tool Shed, and can be used at the Galaxy installation hosted by the UIC Center for Research Informatics (CRI) at galaxy.cri.uic.edu. PMID- 24493033 TI - The cleverSuite approach for protein characterization: predictions of structural properties, solubility, chaperone requirements and RNA-binding abilities. AB - MOTIVATION: The recent shift towards high-throughput screening is posing new challenges for the interpretation of experimental results. Here we propose the cleverSuite approach for large-scale characterization of protein groups. DESCRIPTION: The central part of the cleverSuite is the cleverMachine (CM), an algorithm that performs statistics on protein sequences by comparing their physico-chemical propensities. The second element is called cleverClassifier and builds on top of the models generated by the CM to allow classification of new datasets. RESULTS: We applied the cleverSuite to predict secondary structure properties, solubility, chaperone requirements and RNA-binding abilities. Using cross-validation and independent datasets, the cleverSuite reproduces experimental findings with great accuracy and provides models that can be used for future investigations. AVAILABILITY: The intuitive interface for dataset exploration, analysis and prediction is available at http://s.tartaglialab.com/clever_suite. PMID- 24493036 TI - Response to mold contamination of intravenous magnesium sulfate produced by a compounding pharmacy. PMID- 24493037 TI - Variation in levels of some leaf enzymes. AB - Several procedures were compared for efficiency in the extraction of certain leaf enzymes (phosphoenolpyruvate carboxylase, ribulose 1,5-diphosphate carboxylase and malate dehydrogenase) in Atriplex hastata (a "C3" species exhibiting conventional photosynthetic metabolism), and in A. spongiosa (a "C4" species in which the initial photosynthetic products are C4 dicarboxylic acids). Glycolate oxidase was also assayed in some cases, and Atriplex nummularia and Sorghum bicolor were also used as test material. A simple procedure, involving a mortar and pestle grind with carborundum added to the grinding mixture, was found to be as effective as glass bead grind procedures. In addition, it was more rapid and showed less variability with different operations.Using the carborundum grind procedure, sources of variability in enzyme activity in apparently uniform leaves were compared, as were effects of time of day, leaf age and storage procedure. In general, if apparently uniform leaves could be selected, variability in levels of enzyme activity appeared to be relatively small, not exceeding about 12%. Time of day also appeared to be relatively unimportant for the enzymes examined. However, the ontogentic status of the plant was found to be an important source of variability. Leaf age was also a major source of variability where the activity was expressed on a fresh weight basis, but specific activity (i.e. activity expressed on a protein basis) was relatively constant, at least with the range of species and leaf ages examined here.Storage of fresh samples in liquid nitrogen for 24 h, prior to extraction and assay, led to only a small reduction in activity, but substantial changes occurred if storage was in dry ice or in ice and also where extracts were stored in a deep freeze. PMID- 24493038 TI - Ultrastructure of barley aleurone cells as shown by freeze-etching. AB - Aleurone tissue from non-germinated or germinating barley seeds, as well as from isolated aleurone layers imbibed with water or gibberellic acid, was frozen directly in Freon and investigated by the freeze-etching technique. Aleurone grains remained spherical under all conditions, although the volume increased on hydration. They contained both protein crystalloids and globoids (phytin or lipid) embedded in the matrix. Globoids appeared to be membrane-enclosed. Spherosomes were evidently enclosed within a normal membrane, and they were in close contact with the membrane of aleurone grains, covering the surfaces of the latter. A highly-ordered particle structure was seen on some preparations of the plasmalemma. During germination no alterations were observed in membrane structure. PMID- 24493039 TI - Effect of relative hormone concentration on auxin-gibberellin interaction in correlative inhibition of axillary buds. AB - Indole-3-acetic acid (IAA) applied to the fully elongated second internode of decapitated Phaseolus multiflorus plants always inhibited axillary bud elongation at concentrations down to 100 MUg/g lanolin, whereas gibberellic acid (GA3) enhanced bud elongation at concentrations down to 1000 MUg/g lanolin. Lower concentrations than these of either IAA or GA3 were without significant effect. All possible combinations of IAA and GA3 within the concentration range 10(1) to 10(5) MUg/g lanolin were antagonistic; IAA tending to inhibit, and GA3 promote, axillary bud elongation growth. Treatment of an elongating internode with the hormones resulted in an increase in inhibition of bud growth by IAA in the presence of GA3. PMID- 24493040 TI - [Inhibition of Elongation of Hypocotyls of Sinapis alba with FUDR]. AB - Seedlings of Sinapis alba which were grown in light for 24, 48 and 72 h after 36 h of dark treatment renew elongation when transferred to dark again. The rate of elongation decreases with increased light treatment. The per cent as well as absolute inhibition of elongation by FUDR decreases with the duration of light treatment. The shortening of the hypocotyl is due mainly to the inhibition of cell elongation. The inhibition is not directly proportional to DNA synthesis at any particular time.Plants without cotyledons are less inhibited than those with cotyledons. Cytosine arabinoside is inhibitory only at high concentrations. According to these results elongation inhibition by FUDR does not involve the entire DNA-synthesis. PMID- 24493041 TI - A lysosomal aminopeptidase isozyme in differentiating yeast cells and protoplasts. AB - Cells of Saccharomyces cerevisiae that have been growing exponentially for many generations contain low activities of lysosomal enzymes. In contrast to such fully adapted cells, differentiating or resting cells contain comparatively high activities of these enzymes. Thus, the digestive enzymes seem to be involved in the process of biochemical differentiation.One of the four aminopeptidase isozymes present in extracts from yeast cells is localized in the vacuoles. This lysosomal enzyme can be separated from the other aminopeptidases by Sephadex G 150 gel filtration. Its specific activity is about 4 times higher in stationary cells than in exponentially growing cells.Upon incubating protoplasts in a buffered sorbitol medium the activities of proteases and RNase increase significantly. A corresponding increase of lysosomal aminopeptidase activity occurs in the absence of glutamic acid or casein hydrolysate. Cycloheximide and actinomycin D inhibit the increase of lysosomal hydrolase activities in differentiating protoplasts. The observed changes of enzyme activities are probably due to induced synthesis of the respective proteins. PMID- 24493042 TI - Metabolic changes in washed, isolated steles. AB - Steles isolated from maize roots grown under non-sterile conditions showed an increase in ion absorption capacity and in the rate of oxygen uptake when washed for 24 h, although the levels of protein and of several hydrolytic and respiratory tnzymes fell over the same period. Fresh isolated cortex showed higher activity than fresh steles in relation to both ion absorption and respiration. The large increase with washing in the ion absorption capacity of the steles was not observed when the tissue was isolated from roots grown under sterile conditions. These results are discussed in relation to proposed mechanisms for the radial transport of ions across the root and to the effect of micro-organisms on ion absorption studies in higher plant cells. PMID- 24493043 TI - Patterns of translocation and metabolism of (14)C-labelled IAA in the phloem of Willow. AB - When 2-(14)-C-labelled IAA was applied to an isolated segment of Willow via a bark abrasion the pathway of transport of this compound was found to be located in the sieve elements as evidenced by the pattern of activity found in honeydew excreted by individuals of Tuberolachnus salignus (Gmelin) feeding on the segment.Further experiments have established that polarity of transport of (14)C IAA occurs in a basipetal direction when isolated segments of willow are orientated in a vertical position, with the morphological apex uppermost. No polarity was found when segments were orientated in a vertical position with the morphological base uppermost, or when the segments were orientated in a horizontal position. The metabolism of (14)C-IAA was also studied with respect to orientation. It was shown that the conversion rate of IAA to IAA aspartate was influenced by the orientation of the segment. It is considered that this is not a direct effect of orientation on the rate of metabolism of IAA. PMID- 24493044 TI - [Electronmicroscopic detection of a special kind of cytoplasmic vesicle in Micrasterias denticulata]. AB - Electronmicroscopic studies of growing and non-growing cells of Micrasterias denticulata Breb., fixed with glutaraldehyde-OsO4, showed a special kind of cytoplasmic vesicle which has so far not been found in other cells. These particles (1000-1200 A in diameter) are characterized, by an unusual, multilayered membrane and a rod-like content of high electronoptic density. The vesicles are found to be accumulated in the vicinity of the nucleus and in a positional relationship to the nuclear pores. Although no evidence could be found either for a direct passage of the vesicles through the pores or for a "blebbing" process from the nuclear membrane, the rod-containing vesicles could be functional in the process of nuclearcytoplasmic exchange. PMID- 24493045 TI - Hydrogen production by photosystem I of Scenedesmus: Effect of heat and salicylaldoxime on electron transport and photophosphorylation. AB - Photosynthesis, photoreduction, the p-benzoquinone Hill reaction, and glucose uptake by whole cells, as well as cyclic photophosphorylation (with PMS) by chloroplast particles were strongly inhibited by 10(-2) M salicylaldoxime or by heating whole cells for 1-2 min at 55 degrees . In contrast, H2 photoproduction by whole cells of mutant No. 11 and wild type Scenedesmus and PS I-mediated MR reduction by chloroplast particles were either stimulated or not significantly inhibited by these agents. H2 production by mutant No. 8 was slightly depressed by salicylaldoxime. DCMU inhibited H2 photoproduction with 10(-2) M salicylaldoxime approximately 20%, indicating some contribution of electrons by endogenous organic compounds to photosystem II between the O2-evolving mechanism and the DCMU-sensitive site. We conclude that photohydrogen production by PS I of Scenedesmus does not require cyclic photophosphorylation but is due to non-cyclic electron flow from organic substrate(s) through PS I to hydrogenase where molecular H2 is released. PMID- 24493046 TI - [Identification of abscisic acid in roots]. AB - Twenty-day-old pea roots were extracted with methanol. Abscisic acid could be detected in the root extract by use of UV- and ORD-spectra. PMID- 24493047 TI - Plastids in sieve elements and companion cells of Tilia americana. AB - Contrary to an earlier report, the sieve elements and companion cells of Tilia americana contain plastids. In young sieve elements and companion cells the plastids contain a moderately electronopaque matrix and internal membranes; the latter are very numerous in the plastids of the sieve elements. Plastids of mature sieve elements contain an electron-transparent matrix, apparently fewer internal membranes than the plastids of young elements, and a single starch grain each. The plastids of companion cells undergo little or no structural modification during cellular differentiation, and apparently contain no starch. PMID- 24493052 TI - Interfacial assembly of mussel-inspired au@ag@ polydopamine core-shell nanoparticles for recyclable nanocatalysts. AB - Recyclable nanocatalysts of core-shell bimetallic nanocrystals are developed through polydopamine coating-directed one-step seeded growth, interfacial assembly, and substrate-immobilization of Au@Ag core-shell nanocrystals. This strategy provides new opportunities to design and optimize heterogeneous nanocatalysts with tailored size, morphology, chemical configuration, and supporting substrates for metal-catalyzed reactions. PMID- 24493053 TI - Increased mobility induced by addition of a Lewis acid to a Lewis basic conjugated polymer. AB - Through simple addition of a Lewis acid to a conjugated polymer bearing a Lewis basic heteroatom, the hole transport of the polymer can be effectively p-doped resulting in a two-orders increase in hole mobility. The temperature dependent hole transport of a variety of Lewis acid concentrations are explored. PMID- 24493054 TI - A flexible bimodal sensor array for simultaneous sensing of pressure and temperature. AB - Diverse signals generated from the sensing elements embedded in flexible electronic skins (e-skins) are typically interfered by strain energy generated through processes such as touching, bending, stretching or twisting. Herein, we demonstrate a flexible bimodal sensor that can separate a target signal from the signal by mechanical strain through the integration of a multi-stimuli responsive gate dielectric and semiconductor channel into the single field-effect transistor (FET) platform. PMID- 24493058 TI - Incidence of and risk factors for sentinel lymph node metastasis in patients with a postoperative diagnosis of ductal carcinoma in situ. AB - BACKGROUND: Positive sentinel lymph nodes (SLNs) are found in up to 13 per cent of women with a preoperative diagnosis of ductal carcinoma in situ (DCIS) of the breast and in up to 4 per cent of those with a postoperative diagnosis. This retrospective national register study investigated the incidence of positive SLNs in women with a postoperative diagnosis of DCIS, and the value of additional tumour sectioning to identify occult tumour invasion. METHODS: All surgical patients with a final histopathological diagnosis of pure DCIS registered in the Swedish national breast cancer register in 2008 and 2009 were eligible. Additional sectioning was performed on archived primary tumour tissue from women with SLN metastasis (including cases of isolated tumour cells) and matched SLN negative control patients with the aim of detecting occult invasion. RESULTS: SLN tumour deposits were reported in 11 of 753 women who had SLN biopsy (macrometastases, 2; micrometastases, 3; isolated tumour cells, 6), resulting in a SLN positivity rate of 0.7 per cent (5 of 753). Occult invasion was found in one (9 per cent) of these 11 patients and in two (10 per cent) of 21 control patients. No risk factors for SLN metastasis were identified. CONCLUSION: SLN positivity is rare in women with a histopathological diagnosis of pure DCIS. Additional primary tumour assessment may reveal occult invasion in both SLN metastasis-positive and -negative patients. The value of performing SLN biopsy in the setting of a preoperative diagnosis of DCIS was limited, and current Swedish practice should therefore be questioned. PMID- 24493059 TI - Hybrid endovascular treatment of an aberrant right subclavian artery with Kommerell aneurysm. AB - Aberrant right subclavian artery is a rare anatomical finding of abnormal embryologic development of the dorsal aorta and right subclavian artery. An associated aortic outpouching, or Kommerell diverticulum, may develop at the origin of the aberrant right subclavian artery. Given historically high rates of aneurysm rupture and mortality, early repair is indicated. Successful aneurysm exclusion can be accomplished with thoracic endovascular stent grafting following open carotid-subclavian bypass, maintaining upper extremities perfusion. Such hybrid techniques offer a decrease in mortality and complication rates. Herein, we describe a successful repair of a symptomatic (dysphagia, weight loss) aberrant right subclavian artery with Kommerell diverticulum using this hybrid open-endovascular approach. PMID- 24493060 TI - Visceral organ protection in aortic arch surgery: safety of moderate hypothermia. AB - OBJECTIVES: Although antegrade selective cerebral perfusion (ASCP) provides good brain protection during aortic arch surgery, the issue of distal organ protection during circulatory arrest remains to be clarified. The aim of the study was to retrospectively evaluate the outcome of aortic arch surgery using ASCP at different temperatures, focusing on visceral functions (VFs). METHODS: Three hundred and thirty-four patients underwent elective aortic arch surgery using ASCP from November 1996 to March 2011. Those patients without early postoperative low cardiac output syndrome were included. VFs were evaluated by comparing preoperative and postoperative creatinine, aspartate amino transferase, alanine amino transferase and bilirubin. Univariate and multivariate analysis were performed. RESULTS: Three hundred and four patients represent the cohort of the study. Deeper systemic hypothermia (<=25 degrees C) (Group A) was used in 194 patients (63.8%) and moderate hypothermia (>25 degrees C) (Group B) in 110 patients (36.2%). The 30-day mortality rate was 3.6% in Group B and 5.2% in Group A (P = NS). Permanent neurological deficits occurred in 4 (3.6%) and in 14 patients (7.2%) of Group A and Group B, respectively (P = NS). Postoperative renal insufficiency requiring dialysis occurred in 6 patients (5.4%) in Group A and in 15 patients (7.7%) in Group B, the differences were not statistically significant. Biochemical markers of VFs increased in the postoperative period without differences between groups. At the multivariate analysis, cardiopulmonary bypass time >180 min (odds ratio (OR) = 2.16) was the only significant risk factor for renal dysfunction with or without liver dysfunction, while cardiopulmonary bypass time longer than 180 min (OR = 2.28) and hypothermia higher than 25 degrees C (OR = 0.54) were found to be independently related to liver dysfunction. CONCLUSIONS: Our results confirmed that ASCP with moderate hypothermia at 26 degrees C is a safe method for brain protection. Moreover, during circulatory arrest, moderate hypothermia also offers good protection of visceral organs and it should be preferred for limited periods (<60 min) of visceral ischaemia because it may reduce the systemic inflammatory response and the reperfusion organ injury. PMID- 24493061 TI - Giant true inferoposterior left ventricular aneurysm presenting with heart failure: insights from multimodality imaging. PMID- 24493062 TI - [Therapeutic options in malignant cerebral venous and sinus thrombosis]. AB - BACKGROUND: Cerebral venous and sinus thrombosis (CVST) constitutes less than 0.5 1 % of all strokes and occurs predominantly in young female adults. In general the clinical outcome is favorable but 3-15 % of patients die in the acute phase and in the majority of cases due to cerebral herniation. Intensive care treatment analogous to that of severe ischemic infarct leads to an aggressive interdisciplinary therapy concept that can achieve good clinical outcome. Based on five cases of severe CVST treatment options will be presented. RESULTS: All five patients were affected by impending or incipient cerebral herniation and severe focal neurological deficits which resulted in the decision to implement thrombectomy, thrombolysis or hemicraniectomy. Despite the severe course and many intensive care complications which suggested a poor prognosis, all five patients could be transferred to rehabilitation after having survived the acute phase and achieved an amazingly good overall clinical outcome. CONCLUSION: Considering the life-threatening course of severe CVST, aggressive interdisciplinary management by endovascular thrombectomy and hemicraniectomy can lead to a scarcely expected clinical outcome without disability or severe dependency. This treatment should be performed early and in an escalatory manner in patients with severe CVST who have an increased risk of an unfavorable outcome due to edema, infarction and hemorrhage. PMID- 24493064 TI - Saving babies: the impact of public education programs on infant mortality. AB - We take advantage of unique data on specific activities conducted under the Sheppard-Towner Act from 1924 through 1929 to focus on how public health interventions affected infant mortality. Interventions that provided one-on-one contact and opportunities for follow-up care, such as home visits by nurses and the establishment of health clinics, reduced infant deaths more than did classes and conferences. These interventions were particularly effective for nonwhites, a population with limited access to physicians and medical care. Although limited data on costs prevent us from making systematic cost-benefit calculations, we estimate that one infant death could be avoided for every $1,600 (about $20,400 in 2010 dollars) spent on home nurse visits. PMID- 24493065 TI - Marriage duration and divorce: the seven-year itch or a lifelong itch? AB - Previous studies have shown that the risk of divorce is low during the first months of marriage; it then increases, reaches a maximum, and thereafter begins to decline. Some researchers consider this pattern consistent with the notion of a "seven-year itch," while others argue that the rising-falling pattern of divorce risk is a consequence of misspecification of longitudinal models because of omitted covariates or unobserved heterogeneity. The aim of this study is to investigate the causes of the rising-falling pattern of divorce risk. Using register data from Finland and applying multilevel hazard models, the analysis supports the rising-falling pattern of divorce by marriage duration: the risk of marital dissolution increases, reaches its peak, and then gradually declines. This pattern persists when I control for the sociodemographic characteristics of women and their partners. The inclusion of unobserved heterogeneity in the model leads to some changes in the shape of the baseline risk; however, the rising falling pattern of the divorce risk persists. PMID- 24493063 TI - Reporting errors in siblings' survival histories and their impact on adult mortality estimates: results from a record linkage study in Senegal. AB - Estimates of adult mortality in countries with limited vital registration (e.g., sub-Saharan Africa) are often derived from information about the survival of a respondent's siblings. We evaluated the completeness and accuracy of such data through a record linkage study conducted in Bandafassi, located in southeastern Senegal. We linked at the individual level retrospective siblings' survival histories (SSH) reported by female respondents (n = 268) to prospective mortality data and genealogies collected through a health and demographic surveillance system (HDSS). Respondents often reported inaccurate lists of siblings. Additions to these lists were uncommon, but omissions were frequent: respondents omitted 3.8 % of their live sisters, 9.1 % of their deceased sisters, and 16.6 % of their sisters who had migrated out of the DSS area. Respondents underestimated the age at death of the siblings they reported during the interview, particularly among siblings who had died at older ages (>=45 years). Restricting SSH data to person years and events having occurred during a recent reference period reduced list errors but not age and date errors. Overall, SSH data led to a 20 % underestimate of 45 q 15 relative to HDSS data. Our study suggests new quality improvement strategies for SSH data and demonstrates the potential use of HDSS data for the validation of "unconventional" demographic techniques. PMID- 24493066 TI - Synthetic aminomethylnaphthoquinones inhibit the in vitro replication of bovine herpesvirus 5. AB - Bovine herpesvirus type 5 (BoHV-5) is an etiologic agent of meningoencephalitis in cattle. The aim of this study was to evaluate the antiviral potential of a series of synthetic Mannich bases derived from lawsone and to investigate at which stage of the BoHV-5 replicative cycle the compounds might be acting. The most potent and selective inhibitor exhibited CC50 and EC50 values of 1867 MUM +/ 8.3 and 3.8 MUM +/- 1.2, respectively (ACV: 989 MUM +/- 2 and 166 MUM +/- 2, respectively). PMID- 24493067 TI - Sensitivity of biochemical test in comparison with other methods for the detection of mycoplasma contamination in human and animal cell lines stored in the National Cell Bank of Iran. AB - Mycoplasma contamination in cell culture is considered as serious problem in the manufacturing of biological products. Our goal in this research is to find the best standard and rapid method with high sensitivity, specificity, accuracy and predictive values of positive and negative results for detection of mycoplasma contamination in cell cultures of the National Cell Bank of Iran. In this study, 40 cell lines suspected to mycoplasma contamination were evaluated by three different methods: microbial culture, enzymatic mycoalert((r)) and molecular. Enzymatic evaluation was performed using the mycoalert((r)) kit while in the molecular technique, a universal primer pair was designed based on the common and fixed 16SrRNA ribosomal sequences used. Mycoplasma contaminations in cell cultures with molecular, enzymatic and microbial culture methods were determined as 57.5, 52.5 and 40 %, respectively. These results confirmed the higher rate of sensitivity, specificity and accuracy for the molecular method in comparison with enzymatic and microbial methods. Polymerase chain reaction (PCR) assay based on fixed and common sequences in the 16SrRNA, is a useful valuable and reliable technique with high sensitivity, specificity and accuracy for detection of mycoplasma contamination in cell cultures and other biological products. The enzymatic mycoalert((r)) method can be considered as a substitution for conventional microbial culture and DNA staining fluorochrome methods due to its higher sensitivity, specificity and speed of detection (<20 min). PMID- 24493068 TI - Protective effects of cyclosativene on H2O 2-induced injury in cultured rat primary cerebral cortex cells. AB - Sesquiterpenes have attracted much interest with respect to their protective effect against oxidative damage that may be the cause of many diseases including several neurodegenerative disorders and cancer. Our previous unpublished work suggested that cyclosativene (CSV), a tetracyclic sesquiterpene, has antioxidant and anticarcinogenic features. However, little is known about the effects of CSV on oxidative stress induced neurotoxicity. We used hydrogen peroxide (H2O2) exposure for 6 h to model oxidative stress. Therefore, this experimental design allowed us to explore the neuroprotective potential of CSV in H2O2-induced toxicity in new-born rat cerebral cortex cell cultures for the first time. For this aim, MTT and lactate dehydrogenase release assays were carried out to evaluate cytotoxicity. Total antioxidant capacity (TAC) and total oxidative stress (TOS) parameters were used to evaluate oxidative changes. In addition to determining of 8-hydroxy-2-deoxyguanosine (8-OH-dG) levels, the single cell gel electrophoresis (or Comet assay) was also performed for measuring the resistance of neuronal DNA to H2O2-induced challenge. Our results showed that survival and TAC levels of the cells decreased, while TOS, 8-OH-dG levels and the mean values of the total scores of cells showing DNA damage (Comet assay) increased in the H2O2 alone treated cultures. But pre-treatment of CSV suppressed the cytotoxicity, genotoxicity and oxidative stress which were increased by H2O2. On the basis of these observations, it is suggested that CSV as a natural product with an antioxidant capacity in mitigating oxidative injuries in the field of neurodegenerative disorders. PMID- 24493069 TI - Sticker shock and the price of new therapies for hepatitis C: is it worth it? PMID- 24493070 TI - Role of Ki-67 proliferation index in the assessment of patients with neuroendocrine neoplasias regarding the stage of disease. AB - BACKGROUND: Neuroendocrine neoplasias (NEN) of the gastroenteropancreatic (GEP) system frequently present with metastatic deposits. The proliferation marker Ki 67 is used for diagnosis and to assess the prognosis of disease. The aim of our study was to evaluate the usefulness of Ki-67 % in the assessment of NEN patients with regard to their disease stage in clinical practice. Additionally, a comparative analysis of Ki-67 levels among different sites of disease was performed. METHODS: This retrospective study included patients with GEP NEN referred to our center from 2010 to 2012. The NEN diagnosis was confirmed by standard histopathology. Ki-67 immunohistochemistry was done on paraffin-embedded sections using an automated Leica immunohistochemistry machine. NEN grading was carried out according to European Neuroendocrine Tumor Society recommendations (low grade [G1] to intermediate grade [G2], well to moderately differentiated neuroendocrine neoplasms; high-grade [G3], moderately to poorly differentiated neuroendocrine neoplasms). Results of tumor staging and grading were correlated. In a subgroup of cases, comparative analysis of Ki-67 levels in different sites of disease was carried out. RESULTS: One hundred sixty-one GEP NEN patients were included in the study. Metastatic disease was seen in 46.1 % (53/115) of G1 tumors, 77.8 % (28/36) of G2 tumors, and 100 % of (10/10) G3 tumors (p = 0.0002). When stratified according to primary tumor site, metastatic disease was documented in 42.9 % (36/84) of patients with pancreatic NEN and in 91.9 % (34/37) of those with small intestinal primary. Stage IV metastatic disease was present in 27.8 % (32/115) and 72.2 % (26/36) of the G1 and G2 tumors, respectively, and in 90 % (9/10) of the G3 tumors. Assessment of the Ki-67 index for a subset of cases at metastatic sites as well as the primary tumor site showed discrepancies in 35.3 % cases. In 7/9 (77.8 %) patients with liver metastases, Ki-67 % was higher in the liver lesions than in the primary tumor. CONCLUSIONS: Patients with GEP NEN exhibiting a high Ki-67 proliferation index present with metastatic disease in the vast majority of cases. Depending upon the primary tumor site, metastases are to be expected also in tumors with low Ki-67 %, although they are considered less aggressive. Different disease sites may express heterogeneous Ki-67 levels. PMID- 24493071 TI - Fluorescence detection of malignant liver tumors using 5-aminolevulinic acid mediated photodynamic diagnosis: principles, technique, and clinical experience. AB - BACKGROUND: Photoactive drugs selectively accumulate in malignant tissue specimens and cause drug-induced fluorescence. Photodynamic diagnosis (PDD) and fluorescence can distinguish normal from malignant tissue. OBJECTIVE METHODS: From May 2012 to September 2013, a total of 70 patients underwent hepatic resections using 5-ALA-mediated PDD for liver tumors at our hospital. RESULTS: 5 ALA fluorescence was detected in all hepatocellular carcinoma cases with serosa invasion. In liver metastasis from colorectal cancer cases with serosa invasion, 18 patients (85.7 %) were detected, and three patients (14.2 %) whose tumors showed complete response to neoadjuvant chemotherapy showed no fluorescence. Both superficial and deep malignant liver tumors were detected with 92.5 % sensitivity. Using 5-ALA-mediated PDD, tumors remaining at the cut surface and postoperative bile leakage were less frequent than in our previous hepatic resections using conventional white-light observation. Moreover, all malignant liver tumors were completely removed with a clear microscopic margin using 5-ALA, with a significant difference in resection margin width between 5-ALA-mediated PDD (6.7 +/- 6.9 mm) and white-light observation (9.2 +/- 7.0 mm; p = 0.0083). CONCLUSIONS: With the detection of malignant liver tumors, residual tumor and bile leakage at the cut surface of the remnant liver were improved by PDD with 5 ALA. This procedure may provide greater sensitivity than the conventional procedure. Furthermore, 5-ALA-mediated PDD can ensure histological clearance regardless of the resection margin and preserve as much liver parenchyma as possible in patients with impaired liver function. PMID- 24493073 TI - Robust chaotic map-based authentication and key agreement scheme with strong anonymity for telecare medicine information systems. AB - To ensure only authorized access to medical services, several authentication schemes for telecare medicine information systems (TMIS) have been proposed in the literature. Due to its better performance than traditional cryptography, Hao et al. proposed an authentication scheme for TMIS using chaotic map based cryptography. They claimed that their scheme could resist various attacks, including the smart card stolen attack. However, we identify that their scheme is vulnerable to the stolen smart card attack. The reason causing the stolen smart card attack is that the scheme is designed based on the assumption that the scheme itself achieves user untraceability. Then, we propose a robust authentication and key agreement scheme. Compared with the previous schemes, our scheme not only enjoys more security features, but also has better efficiency. Our analysis indicates that designing a two-factor authentication scheme based on the assumption that privacy protection is achieved in the scheme itself may pose potential security risks. The lesson learned is that, we should avoid this situation in the future design of two-factor authentication schemes. PMID- 24493072 TI - A new method based on Adaptive Discrete Wavelet Entropy Energy and Neural Network Classifier (ADWEENN) for recognition of urine cells from microscopic images independent of rotation and scaling. AB - So far, analysis and classification of urine cells number has become an important topic for medical diagnosis of some diseases. Therefore, in this study, we suggest a new technique based on Adaptive Discrete Wavelet Entropy Energy and Neural Network Classifier (ADWEENN) for Recognition of Urine Cells from Microscopic Images Independent of Rotation and Scaling. Some digital image processing methods such as noise reduction, contrast enhancement, segmentation, and morphological process are used for feature extraction stage of this ADWEENN in this study. Nowadays, the image processing and pattern recognition topics have come into prominence. The image processing concludes operation and design of systems that recognize patterns in data sets. In the past years, very difficulty in classification of microscopic images was the deficiency of enough methods to characterize. Lately, it is seen that, multi-resolution image analysis methods such as Gabor filters, discrete wavelet decompositions are superior to other classic methods for analysis of these microscopic images. In this study, the structure of the ADWEENN method composes of four stages. These are preprocessing stage, feature extraction stage, classification stage and testing stage. The Discrete Wavelet Transform (DWT) and adaptive wavelet entropy and energy is used for adaptive feature extraction in feature extraction stage to strengthen the premium features of the Artificial Neural Network (ANN) classifier in this study. Efficiency of the developed ADWEENN method was tested showing that an avarage of 97.58% recognition succes was obtained. PMID- 24493074 TI - The feasibility of computer-aided monitoring of the workflow in surgical pathology: a five-year experience. AB - To explore the feasibility of computer-aided monitoring of the workflow in surgical pathology. We collected 5-year data about computer-aided monitoring of the workflow in surgical pathology and analyzed the four subprocesses in the surgical pathologic process: 1) from arranging surgical pathology examination to receipt of the examination sheet and sample by the laboratory; 2) from receipt of the sample to issuance of the pathology report; 3) from issuance of the pathology report to automatic computer forwarding of positive pathology reports by e-mail to the physician who ordered the examination; 4) from receipt of the positive report by the physician to his/her response of acknowledging receipt. A total 115,648 surgical pathological cases were reviewed in this study. The overdue rate of delivery of samples was 0.82%. The most common cause (62.92%) of overdue delivery was clinicians in the outpatient department arranging for the examination more than 1 day in advance of specimen collection. The cumulative rates of report completion within 1, 2, 3, 4 and 5 work days were 12.82%, 53.56%, 86.42%, 95.90% and 98.85%, respectively. The rate of overdue reporting was 1.15% over the 5-year study. The most common cause (56.30%) of overdue reporting was case complexity. The learning time for adapting this subprocess of report issuance was 7 months. There were 12,151 positive reports (10.51% of all cases) that required automatic computer forwarding to the physicians' e-mail boxes. A total of 113 cases (0.93%) failed in automatic computer forwarding during the 5 year period. The learning time for constructing a stable automatic computer forwarding system was 2.5 years. Of the 12,038 reports successfully forwarded, 10,107 (83.96%) were received by physicians and acknowledged by automated receipt within 120 h, and the other 1,931 (16.04%) showed no response within 120 h. The major reason for an overdue reply was that the physicians did not check their e mail boxes (94.89%). We used a preliminary computer-aided system to monitor the workflow in surgical pathology. This system might be used as one of the methods of quality assurance in surgical pathology. PMID- 24493075 TI - Peyronie's Disease: A Historical Perspective. AB - Peyronie's disease (PD), more commonly known as penile curvature, is caused by plaque formation in the connective tissue of the penis. PD affects 0.3% to 8.9% of men, most commonly between ages 40 and 60 years and can cause significant psychological distress, regardless of severity. There is a rich history behind the initial reports of PD, initial beliefs about pathogenesis, and initial treatment. This article aims to discuss the history of PD as well as the evolution of causes and treatments throughout time up to present-day theories of pathogenesis and treatment. PMID- 24493076 TI - Baseline Comorbidities Enhance the Risk of Treatment-Induced Depression in HCV Infected Men: A Pilot Study. AB - BACKGROUND: Hepatitis C virus (HCV) infection is associated with clinical depression,a condition that is aggravated on interferon-based therapy. In HCV infection, men often appear more resilient to depression than women. However, men are subject to depression in diseases that tend to be comorbid in HCV-infected. AIM: This study examined whether HCV-infected men with baseline comorbidities were more or less susceptible to depression prior to and on treatment. METHODS: Patients with chronic HCV infection preparing to begin treatment participated (n = 37). The presence of baseline comorbidities was determined by pretreatment medication regimes. Depression was measured by the Beck Depression Inventory prior to and following 2, 4, 8, and 12 weeks of interferon therapy. RESULTS: At baseline, cohorts with (n = 16) and without (n = 21) comorbidities had equivocal demographics and infection characteristics. Comorbidities did not associate with baseline depression. However, on treatment, men with baseline comorbidities demonstrated an elevated risk for the onset of de novo depression (odds ratio = 19.25; confidence interval = 1.41, 582.14; p = .008). This was not observed for women. Baseline comorbidities did not alter the need for treatment discontinuations or the ability to achieve a sustained viral response. CONCLUSION: The results of this study suggest that baseline comorbidities render men more susceptible to interferon treatment-induced depression. PMID- 24493077 TI - A comparison between the AASM 2012 and 2007 definitions for detecting hypopnea. AB - PURPOSE: To compare the apnea-hypopnea indices (AHIs) derived using three hypopnea definitions published by the American Academy of Sleep Medicine (AASM) and to determine the impact of the new modifications of the definition on AHIs and the diagnosis of obstructive sleep apnea (OSA). METHODS: The study comprised 100 consecutive patients who were investigated for OSA using overnight diagnostic polysomnography (PSG). The hypopneas were scored in three passes by two certified sleep technologists; in the first pass, the hypopneas were scored using the 2007 AASM "Alternative" (H Alt) criteria. In the second pass, the hypopneas were scored using the 2007 AASM "Recommended" (H Rec) criteria. In the third pass, the hypopneas were scored according to the new AASM "2012" (H 2012) criteria. Agreement analysis of the results obtained using the three scoring criteria was performed using the Bland-Altman plot methodology. RESULTS: The studied group had a mean age of 45.5+/-12.6 years and a body mass index of 30.2+/-5.8 kg/m2. Using the H 2012, H Rec and H Alt criteria, the AHIs were 37.9+/-27.6, 14.8+/-22.4 and 29.6+/-27.0/h, respectively (p<0.05). The Bland-Altman analysis of the AHI demonstrated that more events were nearly always detected using the H 2012 definition. CONCLUSION: A significant difference in detecting hypopnea events exists among the H 2012, H Rec and H Alt definitions. The 2007 AASM "Recommended" definition tended to result in lower AHI than the other two definitions. PMID- 24493079 TI - Conflict of interest in online point-of-care clinical support websites. AB - Point-of-care evidence-based medicine websites allow physicians to answer clinical queries using recent evidence at the bedside. Despite significant research into the function, usability and effectiveness of these programmes, little attention has been paid to their ethical issues. As many of these sites summarise the literature and provide recommendations, we sought to assess the role of conflicts of interest in two widely used websites: UpToDate and Dynamed. We recorded all conflicts of interest for six articles detailing treatment for the following conditions: erectile dysfunction, fibromyalgia, hypogonadism, psoriasis, rheumatoid arthritis and Crohn's disease. These diseases were chosen as their medical management is either controversial, or they are treated using biological drugs which are mostly available by brand name only. Thus, we hypothesised that the role of conflict of interest would be more significant in these conditions than in an illness treated with generic medications or by strict guidelines. All articles from the UpToDate articles demonstrated a conflict of interest. At times, the editor and author would have a financial relationship with a company whose drug was mentioned within the article. This is in contrast with articles on the Dynamed website, in which no author or editor had a documented conflict. We offer recommendations regarding the role of conflict of interest disclosure in these point-of-care evidence-based medicine websites. PMID- 24493080 TI - Blood pressure regulation to prevent progression of blunt traumatic intracranial hemorrhage in stable patients. AB - BACKGROUND: Target blood pressure (BP) in stable (non-hypotensive) patients with acute isolated blunt traumatic intracranial hemorrhage (TICH) is unknown. To address this issue, our study correlated BP with radiological volumetric progression (RP) and neurological deterioration (ND) in these patients. METHODS: A retrospective review of hemodynamically stable adults (n = 184) with isolated TICH not requiring emergent surgery consecutively admitted to a Level I trauma center. BPs before admission computed tomography (CT) scan (CT1) and between CT1 and a follow-up CT (CT2) were correlated with TICH volume and Glasgow Coma Scale (GCS) during these time periods. Predictors for deterioration were studied. Primary outcomes were increased measured TICH and decreased GCS at the CT1-CT2 interval. RESULTS: Age (57 years), % male (73), ISS (17), % falls (77), comorbidities (1.2/pt), and % anticoagulation (20) were similar in patients with or without RP (n = 107, 58%) or ND (n = 34, 18%). By univariate analysis, RP patients had an average systolic (SBP), diastolic (DBP), and mean BP (MAP) similar to non-RP patients; whereas ND patients compared to non-ND patients had a higher mean admission DBP (p < 0.02) and MAP (p < 0.04), a higher mean admission peak MAP (p < 0.01) and DBP (p < 0.01), a higher CT1-CT2 interval peak DBP (p < 0.01) and peak MAP (p < 0.01), and a lower CT1-CT2 nadir SBP (p < 0.04). Spearman rank correlation test did not show association among average SBP, MAP, DBP, absolute or % change in BPs, and absolute or % change in TICH volumes in any phase. Multivariate analysis identified higher nadir admission SBP [adjusted odds ratio (AOR) 1.29 per 10 mmHg increase] and lower peak MAP during the CT1-CT2 period (AOR 0.71 per 10 mmHg decrease) as independent predictors of RP, and a peak DBP in the CT1-CT2 interval (AOR 1.48) as an independent predictor of ND. Other predictors of ND included bilateral admission TICH (AOR 3.31) and increased injury volume (AOR 1.36), while the number of comorbidities/patient (AOR 4.34), bilateral injury (AOR 3.12), and midline shift (AOR 4.34) predicted RD. CONCLUSIONS: A comprehensive dynamic analysis correlating repeated BP determinations with quantifiable repeated parameters of TICH deterioration (injury volume and GCS) did not demonstrate a clinically relevant protective target BP value. Current practices of BP control in this specific group of patients should be further investigated. LEVEL OF EVIDENCE III: Prognostic, Level II study. PMID- 24493081 TI - Added sugar intake and cardiovascular diseases mortality among US adults. AB - IMPORTANCE Epidemiologic studies have suggested that higher intake of added sugar is associated with cardiovascular disease (CVD) risk factors. Few prospective studies have examined the association of added sugar intake with CVD mortality. OBJECTIVE To examine time trends of added sugar consumption as percentage of daily calories in the United States and investigate the association of this consumption with CVD mortality. DESIGN, SETTING, AND PARTICIPANTS National Health and Nutrition Examination Survey (NHANES, 1988-1994 [III], 1999-2004, and 2005 2010 [n = 31,147]) for the time trend analysis and NHANES III Linked Mortality cohort (1988-2006 [n = 11 733]), a prospective cohort of a nationally representative sample of US adults for the association study. MAIN OUTCOMES AND MEASURES Cardiovascular disease mortality. RESULTS Among US adults, the adjusted mean percentage of daily calories from added sugar increased from 15.7% (95% CI, 15.0%-16.4%) in 1988-1994 to 16.8% (16.0%-17.7%; P = .02) in 1999-2004 and decreased to 14.9% (14.2%-15.5%; P < .001) in 2005-2010. Most adults consumed 10% or more of calories from added sugar (71.4%) and approximately 10% consumed 25% or more in 2005-2010. During a median follow-up period of 14.6 years, we documented 831 CVD deaths during 163,039 person-years. Age-, sex-, and race/ethnicity-adjusted hazard ratios (HRs) of CVD mortality across quintiles of the percentage of daily calories consumed from added sugar were 1.00 (reference), 1.09 (95% CI, 1.05-1.13), 1.23 (1.12-1.34), 1.49 (1.24-1.78), and 2.43 (1.63 3.62; P < .001), respectively. After additional adjustment for sociodemographic, behavioral, and clinical characteristics, HRs were 1.00 (reference), 1.07 (1.02 1.12), 1.18 (1.06-1.31), 1.38 (1.11-1.70), and 2.03 (1.26-3.27; P = .004), respectively. Adjusted HRs were 1.30 (95% CI, 1.09-1.55) and 2.75 (1.40-5.42; P = .004), respectively, comparing participants who consumed 10.0% to 24.9% or 25.0% or more calories from added sugar with those who consumed less than 10.0% of calories from added sugar. These findings were largely consistent across age group, sex, race/ethnicity (except among non-Hispanic blacks), educational attainment, physical activity, health eating index, and body mass index. CONCLUSIONS AND RELEVANCE Most US adults consume more added sugar than is recommended for a healthy diet. We observed a significant relationship between added sugar consumption and increased risk for CVD mortality. PMID- 24493082 TI - Quantitative measurement of starch in very small amounts of leaf tissue. AB - A specific enzyme method is described for the routine estimation of starch in small quantities (10-30 mg) of dried leaf tissue. A beta-glucanase-free preparation of amyloglucosidase is employed to hydrolyse starch to glucose; this is subsequently estimated by the glucose oxidase technique. The method gives result which agree closely with those obtained by a specific iodine-precipitation method. PMID- 24493083 TI - [Differences in the light-activation of NADP-dependent glyceraldehyde-3-phosphate dehydrogenase and of ribulose-5-phosphate kinase between plants containing the Calvin and those containing the C4-dicarboxylic acid pathway of photosynthetic carbon reduction]. AB - 1. Preceding experiments had shown that irradiance of intact leaves or of isolated chloroplasts causes a reversible increase in the activity of NADP-GPD (Ziegler and Ziegler, 1965) as well as of ribulose-5-phosphate kinase (Latzko and Gibbs, 1969). Examination of several species which carry out the Calvin type of photosynthetic CO2 fixation (Vicia faba, Spinacia oleracea, Nicotiana tabacum, Avena sativa) now revealed that the dark level of NADP-GPD activity ranges between 300-400 MUmol NADPH/mg chlorophyll.h; irradiance causes an activation to an turnover rate of 900-1600 MUmol NADPH/mg chlorophyll.h. 2. The dark-level of ribulose-5-phosphate kinase in these Calvin type plants corresponds to about 400 ?gmmol PO4---/mg chlorophyll?sdh. It rises to 900?2-1300 ?gmmol PO4---/mg chlorophyll?sdh after irradiance. 3. In all species examined which carry out the C4-dicarboxylic acid type of CO2 fixation (Zea mays, Cyperus rotundus, Portulacca oleracea, Saccharum officinarum) the dark-level of NADP-GPD as well as of ribulose-5-phosphate kinase is already as high as the light-level of Calvin type plants. In these species irradiance either activates both enzymes only to a small extent (Saccharum officinarum, Portulacea oleracea) or it activates only one of the two enzymes to an exceptional high activity (NADP-GPD in Zea mays, ribulose-5 phosphate kinase in Cyperus rotundus), while the activity of the other one remains nearly constant. 4. The dark-level of NADP-GPD in young Zea mays (2 leaves expanded) is as high as in adult plants; moreover its further activation by light corresponds to that in adult plants. In contrast, the dark-activity of ribulose-5-phosphate kinase in young Zea mays corresponds to the lower level found in Calvin type plants and is activated by irradiance in the same manner as it is in the latter plants. 5. The activity of ribose-5-phosphate isomerase is not influenced by light. PMID- 24493084 TI - [The wettability of leaf surfaces and the submicroscopic structure of their wax]. AB - The wettability of a leaf surface is defined by the contact angle between a water droplet and the surface of the leaf.Contact angles of 60-80 degrees were measured on easily wettable leaves. These leaves have no wax on the outer cuticular layer.Contact angles of 130-160 degrees were measured on leaves with a low wettability. These leaves have wax on the outer cuticular layer, which shows submicroscopic structures characteristic of the particular plants.A comparison of the wettability and the different structures of the wax showed no true distinctions.The wax does not adhere strongly to the outer cuticular layer and is cast off in the case of old leaves. Therefore the wetability alters with the age of the leaves. If the wax on young leaves is destroyed or removed by outer influences it can be produced again within a few hours.The rebuilt structure of the wax is not always similar to the original one. When the wax was dissolved by organic solvents no new wax formation was observed.Cigarette smoke greatly increases the wettability of leaves of Tropaeolum majus, parochetus communis and Chelidonium majus without causing a visible alteration of the submicroscopic structure. In this case the leaves recover their water-repellency within a few hours, but not if they were treated with Diesel smoke.When the wax structure was destroyed by fungus or Aleurodina no new wax formation was observed. PMID- 24493085 TI - [Presence of nuclear invaginations in the cells of some floral nectaries and hydathodes]. AB - Although nectaries and hydathodes differ in many anatomical and physiological aspects, they have some identical features. The purpose of this paper is to expose such features in the nuclear morphology. Special attention is devoted to invaginations containing cytoplasm. Many organelles are found in the cytoplasmic pockets; among them, mitochondria and plasts appear frequently deeply enclosed by the nuclear membrane.It is postulated that the form of these nuclei is related to the process of secretion and guttation. PMID- 24493086 TI - [Gibberellic acid stimulated gene activity in the endosperm of Phaseolus]. AB - Gibberellic acid, injected into maturing ovules of Phaseolus vulgaris, induces 3.2-fold enhancement of the number of additional nucleoli within the endopolyploid endosperm nuclei. The additional nucleoli originate at different sites of polytene chromosome-like chromosome bundles. They contain RNA and are sensitive to actinomycin D. Similar nucleolar bodies are extruded by the main nucleolus. It is assumed that gibberellic acid stimulates the chromosomal and nucleolar RNA synthesis, i.e., the gene activity, in the endosperm nuclei.RNA synthesis was tested by (3)H-thymidine it could be seen that gibberellin-treated and gibberellin-treated endosperms were labeled, but those of actinomycin-treated endosperms were not. Using (3)H-thymidine it could be seen that gibberellin treated endosperm nuclei continue to replicate their DNA for a longer period than untreated nuclei. Hence it follows that the treated nuclei become more highly endopolyploid and are capable of functioning longer than the untreated ones. PMID- 24493087 TI - Ultrastructure and distribution of microbodies in leaves of grasses with and without CO2-photorespiration. AB - A comparative study was made of the ultrastructure, distribution and abundance of leaf microbodies in four species of "temperate" grasses with high and four "tropical" grasses with low CO2-photorespiration. The temperate grasses were all festucoid; the tropical grasses included two panicoid species and two chloridoid. Comparisons of relative abundance were made by computing the average numbers of microbody profiles per cell section.Although microbodies were present in the green parenchymatous leaf cells in all grasses examined, their average number per cell was in general severalfold greater in the grasses with high CO2 photorespiration than in those with low. Furthermore, whereas in the grasses with high CO2-photorespiration the microbodies were distributed through the mesophyll, in those with low CO2-photorespiration they were concentrated in the vascular bundle-sheath cells and were smaller and relatively scarce in the mesophyll cells. The leaf microbodies of the eight grass species resembled one another in general morphology, but differed to some extent in regard to size and type of inclusion. Microbodies of all four festucoid species contained numerous fibrils with a discernible substructure. Those of the two panicoid species contained clusters of round bodies with transparent cores. The equivalence of the microbodies to peroxisomes as biochemically defined was shown cytochemically by employing 3,3'-diaminobenzidine for the localization of catalase, a marker enzyme for the peroxisome. This reaction was blocked by the catalase inhibitor, aminotriazole.The observations on the relative abundance and distribution of peroxisomes in leaves of grasses with high CO2-photorespiration versus those with low are consistent with the published biochemical data on the levels and distribution of peroxisomal enzymes in representatives of plants with high and low CO2-photorespiration, and may help explain the differences in apparent photorespiratory levels between these two groups of plants. PMID- 24493088 TI - [Comparative action of (+/-)-abscisic acid, coumarin, p-coumaric acid and some of their derivatives on the growth of the first wheat leaf]. AB - The activities of (+/-)-abscisic acid and a number of compounds derived from p coumaric acid and coumarin and their interaction with gibberellic acid in the control of the elongation of the first wheat leaf are examined. (+/-)-Abscisic acid strongly inhibits leaf growth in the presence as well as in the absence of gibberellic acid, but the inhibition is greater in the presence of gibberellic acid (3 MUg/l already have an observable effect). Among other compounds, only ferulic acid and coumarin significantly reduce leaf elongation, and they are effective only at high concentrations (1.44 . 10(-4) M/l). PMID- 24493089 TI - Risk of desmoid tumours after open and laparoscopic colectomy in patients with familial adenomatous polyposis. AB - BACKGROUND: Desmoid tumour (DT) is a main cause of death after prophylactic colectomy in patients with familial adenomatous polyposis (FAP). The purpose of this study was to evaluate the impact of prophylactic laparoscopic colectomy on the risk of developing DT in patients with FAP. METHODS: The database of a single institution was reviewed. Patients with classical FAP with defined genotype who underwent either open or laparoscopic colectomy between 1947 and 2011 were included in the study. The impact of various demographic and clinical features on the risk of developing DT was assessed. RESULTS: A total of 672 patients underwent prophylactic colectomy: 602 by an open and 70 by a laparoscopic approach. With a median (range) follow-up of 132 (0-516) months in the open group and 60 (12-108) months in the laparoscopic group, 98 patients (16.3 per cent) developed DT after an open procedure compared with three (4 per cent) following laparoscopic surgery. The estimated cumulative risk of developing DT at 5 years after surgery was 13.0 per cent in the open group and 4 per cent in the laparoscopic group (P = 0.042). In multivariable analysis, female sex (hazard ratio (HR) 2.18, 95 per cent confidence interval 1.40 to 3.39), adenomatous polyposis coli mutation distal to codon 1400 (HR 3.85, 1.90 to 7.80), proctocolectomy (HR 1.67, 1.06 to 2.61), open colectomy (HR 6.84, 1.96 to 23.98) and year of surgery (HR 1.04, 1.01 to 1.07) were independent risk factors for the diagnosis of DT after prophylactic surgery. CONCLUSION: Laparoscopic surgery decreased the risk of DT after prophylactic colectomy in patients with FAP. PMID- 24493091 TI - Concordance for prognostic models with competing risks. AB - The concordance probability is a widely used measure to assess discrimination of prognostic models with binary and survival endpoints. We formally define the concordance probability for a prognostic model of the absolute risk of an event of interest in the presence of competing risks and relate it to recently proposed time-dependent area under the receiver operating characteristic curve measures. For right-censored data, we investigate inverse probability of censoring weighted (IPCW) estimates of a truncated concordance index based on a working model for the censoring distribution. We demonstrate consistency and asymptotic normality of the IPCW estimate if the working model is correctly specified and derive an explicit formula for the asymptotic variance under independent censoring. The small sample properties of the estimator are assessed in a simulation study also against misspecification of the working model. We further illustrate the methods by computing the concordance probability for a prognostic model of coronary heart disease (CHD) events in the presence of the competing risk of non-CHD death. PMID- 24493092 TI - A cross-sectional study to evaluate the awareness and attitudes of physicians towards reducing the cost of prescription drugs, Mumbai. AB - BACKGROUND: In India, about half of the total health expenditure is spent on medicines. The projected increase in various diseases coupled with the skyrocketing drug prices have further compounded the drug cost burden. We conducted a study to assess the awareness, attitudes, and practices of physicians with regard to various cost containment measures and the factors affecting them. METHODS: A cross-sectional, questionnaire-based, observational study was conducted over a period of 3 months among 200 physicians, after permission from the Institutional Ethics Committee, at the Grant Medical College and Sir J J Group of Hospitals, Mumbai. The STROBE (Strengthening The Reporting of OBservational studies in Epidemiology) guidelines were followed. RESULTS: Cost considerations were important to 97 % of government doctors (GDs) and 72 % of private doctors (PDs). Eighty percent of both GDs and PDs said that safety and efficacy were more important than cost. Seventy-one percent of GDs and 65 % of PDs knew about the various cost reduction methods. Twenty-four percent of GDs and 65 % of PDs said that they graded drugs according to cost. Ninety-four percent of GDs and 73 % of PDs said that patent protection should not be extended to life saving drugs. Sixty-four percent of GDs and 10 % of PDs, and 20 % of GDs and 10 % of PDs were in favor of the stepwise introduction of drugs and the use of generics, respectively. Factors precluding the use of cheaper alternatives were narrow therapeutic index drugs (43.5 %) and fear of substandard quality (38.5 %). CONCLUSION: Doctors are indeed concerned about the high cost of drugs. More awareness needs to be created about the use of cheaper generics. The government has a very important role to play in reducing the cost of prescription drugs and making healthcare affordable. PMID- 24493093 TI - Portal hypertensive enteropathy diagnosed by capsule endoscopy in cirrhotic patients: a nationwide multicenter study. AB - BACKGROUND AND AIM: Due to the limited data on portal hypertensive enteropathy (PHE), the prevalence of and clinical factors related to PHE remain unclear. This study determined the prevalence of PHE using capsule endoscopy (CE) and PHE related clinical factors. METHODS: This was a retrospective multicenter study using the Capsule Endoscopy Nationwide Database Registry. From 2,879 cases that underwent CE, 45 cirrhosis patients with portal hypertension (PH) were enrolled and divided into PHE (n = 18) and non-PHE (n = 27) groups. From computed tomography (CT) images, six secondary changes due to PH were scored to give a total CT score of 0-6. The main outcome variable was the prevalence of PHE and PHE-related clinical factors. RESULTS: The prevalence of PHE was 40 %. Comparing the PHE and non-PHE groups, the most common findings were angiodysplasias in 55.7 % (vs. 7.4 %, p = 0.001) and varices in 38.9 % (vs. 0 %, p = 0.001). Active bleeding was observed in 16.6 and 3.7 %, respectively, but this difference was not significant. In the univariate analysis, Child-Turcotte-Pugh class C (p = 0.002) and a high CT score (>=3 vs. <3, p = 0.004) were significantly associated with PHE. However, only a high CT score was significant in the multivariate analysis (odds ratio 11.19; 95 % confidence interval, 1.59-infinity; p = 0.040). CONCLUSIONS: The prevalence of PHE was 40 %, and it might be more prevalent in cirrhosis patients with PH who have a high CT score. CE is a useful diagnostic tool for evaluating PHE in cirrhosis patients with PH. PMID- 24493094 TI - Proton magnetic resonance spectroscopy of brain metabolic shifts induced by acute administration of 2-deoxy-d-glucose and lipopolysaccharides. AB - In vivo proton magnetic resonance spectroscopy ((1) H MRS) of outbred stock ICR male mice (originating from the Institute of Cancer Research) was used to study the brain (hippocampus) metabolic response to the pro-inflammatory stimulus and to the acute deficiency of the available energy, which was confirmed by measuring the maximum oxygen consumption. Inhibition of glycolysis by means of an injection with 2-deoxy-d-glucose (2DG) reduced the levels of gamma-aminobutyric acid (GABA, p < 0.05, in comparison with control, least significant difference (LSD) test), N acetylaspartate (NAA, p < 0.05, LSD test) and choline compounds, and at the same time increased the levels of glutamate and glutamine. An opposite effect was found after injection with bacterial lipopolysaccharide (LPS) - a very common pro inflammatory inducer. An increase in the amounts of GABA, NAA and choline compounds in the brain occurred in mice treated with LPS. Different metabolic responses to the energy deficiency and the pro-inflammatory stimuli can explain the contradictory results of the brain (1) H MRS studies under neurodegenerative pathology, which is accompanied by both mitochondrial dysfunction and inflammation. The prevalence of the excitatory metabolites such as glutamate and glutamine in 2DG treated mice is in good agreement with excitation observed during temporary reduction of the available energy under acute hypoxia or starvation. In turn, LPS, as an inducer of the sickness behavior, which was manifested as depression, sleepiness, loss of appetite etc., shifts the brain metabolic pattern toward the prevalence of the inhibitory neurotransmitter GABA. PMID- 24493095 TI - Cysteine co-oxidation process driven by native peptide folding: an example on HER2 receptor model system. AB - Synthetic models of receptors that have relevant biological roles are valuable tools for studying receptors itself and the corresponding ligands. Their properties can be validated at first by their capacity to fold in solution under native-like conditions and to assume conformations structurally and functionally equivalent to those in the native receptor. In this context, a new strategy to prepare the two-fragments synthetic receptor model HER2-DIVMP, an independent structural and functional motif of HER2, has been developed and the folding properties have been investigated. The strategy is based on a one-step cysteine co-oxidation procedure in slightly alkaline aqueous buffers, whereby the two separate peptide chains are allowed to self-assemble in solution. Under these conditions, the two chains spontaneously form the expected heterodimer with the correct pattern of disulfide bridges. To gain insights on the folding mechanism, we investigated the folding of two scrambled variants of the constituent peptide chains. PMID- 24493096 TI - Severe obesity, heart disease, and death among white, African American, and Hispanic postmenopausal women. AB - OBJECTIVE: To compare mortality, nonfatal coronary heart disease (CHD), and congestive heart failure (CHF) risk across BMI categories in white, African American, and Hispanic women, with a focus on severe obesity (BMI >= 40), and examine heterogeneity in weight-related CHD risk. METHODS: Among 156,775 Women's Health Initiative observational study and clinical trial participants (September 1993-12 September 2005), multivariable Cox models estimated relative risk for mortality, CHD, and CHF. CHD incidence was calculated by anthropometry, race, and cardiovascular risk factors (CVRF). RESULTS: Mortality, nonfatal CHD, and CHF incidence generally rose with BMI category. For severe obesity versus normal BMI, hazard ratios (HRs, 95% confidence interval) for mortality were 1.97 (1.77-2.20) in white, 1.55 (1.20-2.00) in African American, and 2.59 (1.55-4.31) in Hispanic women; for CHD, HRs were 2.05 (1.80-2.35), 2.24 (1.57-3.19), and 2.95 (1.60-5.41) respectively; for CHF, HRs were 5.01 (4.33-5.80), 3.60 (2.30-5.62), and 6.05 (2.49-14.69). CVRF variation resulted in substantial variation in CHD rates across BMI categories, even in severe obesity. CHD incidence was similar by race/ethnicity when differences in BMI or CVRF were accounted for. CONCLUSIONS: Severe obesity increases mortality, nonfatal CHD, and CHF risk in women of diverse race/ethnicity. CVRF heterogeneity contributes to variation in CHD incidence even in severe obesity. PMID- 24493097 TI - Morphometric analysis of the proximal ulna using three-dimensional computed tomography and computer-aided design: varus, dorsal, and torsion angulation. AB - PURPOSE: The proximal ulna, particularly the course of the posterior border, has a complex three-dimensional (3D) morphology which has been highlighted recently due to its clinical relevance in relation to surgical treatments. 3D computed tomography (CT) reconstruction and computer-aided design (CAD) based software can help to visualize the complex anatomy and thus aid the investigation of the more detailed morphology of the proximal ulna. METHODS: In our current study, 3D CT reconstruction images of 20 cadavers were imported into the 3D CAD program. Three morphologic angle parameters of the proximal ulna were measured including the dorsal, varus and torsion angulation. The torsion angulation was measured using the flat spot of olecranon dorsal aspect. We measured the total length of the ulna and the distance between the olecranon tip and the apex of dorsal and varus angulation. Furthermore, the thickness of olecranon was also measured for all the specimens. RESULTS: The results showed that the mean dorsal, varus, and torsion angulation was 4.3 degrees (range 2.6 degrees -5.9 degrees ), 12.1 degrees (range 7.9 degrees -17.6 degrees ), and 22.5 degrees (range 16.6 degrees -30.5 degrees ), respectively. The average length ratio of the dorsal and varus angulation apex to the total ulnar length was 26.4 % (range 19.8-30.7 %) and 32.7 % (range 27.5-37.5 %), respectively. The average of olecranon thickness at the proximal tip, mid-olecranon fossa, and at coronoid tip level was 17.8 mm (range 14.1-22.8 mm), 19.7 mm (range 15.8-23.1 mm), and 35.1 mm (range 27.9-41.8 mm), respectively. CONCLUSION: In conclusion, variations in the proximal ulna have to be considered when anatomically contoured dorsal plates are applied. Knowledge of the 3D morphologic anatomy of the proximal ulna would provide important information on fracture reductions, and the design of a precontoured dorsal plate or a prosthetic ulnar stem. PMID- 24493098 TI - Gallbladder agenesis: laparoscopic views of a significant diagnostic challenge. PMID- 24493099 TI - Reply: To PMID 23564560. PMID- 24493101 TI - [The big mystery]. PMID- 24493102 TI - Monoclonal antibody disposition: a simplified PBPK model and its implications for the derivation and interpretation of classical compartment models. AB - The structure, interpretation and parameterization of classical compartment models as well as physiologically-based pharmacokinetic (PBPK) models for monoclonal antibody (mAb) disposition are very diverse, with no apparent consensus. In addition, there is a remarkable discrepancy between the simplicity of experimental plasma and tissue profiles and the complexity of published PBPK models. We present a simplified PBPK model based on an extravasation rate-limited tissue model with elimination potentially occurring from various tissues and plasma. Based on model reduction (lumping), we derive several classical compartment model structures that are consistent with the simplified PBPK model and experimental data. We show that a common interpretation of classical two compartment models for mAb disposition-identifying the central compartment with the total plasma volume and the peripheral compartment with the interstitial space (or part of it)-is not consistent with current knowledge. Results are illustrated for the monoclonal antibodies 7E3 and T84.66 in mice. PMID- 24493103 TI - Photophysical properties and photochemistry of substituted cinnamates and cinnamic acids for UVB blocking: effect of hydroxy, nitro, and fluoro substitutions at ortho, meta, and para positions. AB - Photophysical properties and photochemistry of various substituted cinnamates and cinnamic acids for ultraviolet B blocking were investigated experimentally and theoretically. This series includes monohydroxy, -nitro, and -fluoro derivatives. The absorption spectra were satisfactorily reproduced by the direct SAC-CI method with respect to the peak position and intensity. The transition character of the low-lying two pipi* and sigmapi* states for these 18 derivatives was analyzed. The para derivatives have a different transition character of the pipi* transitions compared with those of the ortho and meta derivatives. To elucidate the relaxation mechanism, the emission spectra were observed with oxygen quenching and the photostability was examined experimentally. The calculated radiative lifetimes indicate that the ortho- and meta-substituted derivatives have longer lifetimes for emission than the para derivatives. The potential energy curves of the first and second singlet excited states of the hydroxy derivatives as well as the vertical singlet and triplet transitions were examined to investigate the relaxation qualitatively. The ortho and meta derivatives have an energy barrier or flat surface in S1 resulting in fluorescence, whereas the para derivatives show nonradiative decay without an energy barrier. The para hydroxy derivative was found to be an excellent UV absorber based on its broad absorption in the UVB/UVA regions, less emission, and higher photostability. PMID- 24493104 TI - Analytic standard errors for exploratory process factor analysis. AB - Exploratory process factor analysis (EPFA) is a data-driven latent variable model for multivariate time series. This article presents analytic standard errors for EPFA. Unlike standard errors for exploratory factor analysis with independent data, the analytic standard errors for EPFA take into account the time dependency in time series data. In addition, factor rotation is treated as the imposition of equality constraints on model parameters. Properties of the analytic standard errors are demonstrated using empirical and simulated data. PMID- 24493105 TI - Fatal Bipolaris spicifera infection in an immunosuppressed child. PMID- 24493106 TI - Rectal schwannoma on endoscopic polypectomy. AB - Conventional gastrointestinal schwannomas are rare, most frequently occurring in the stomach while colorectal locations are uncommon and only a small number of cases have been reported. We are reporting this case as it is a very rare tumour at a very rare location. Though schwannomas are considered benign neoplasms, rare cases of malignant schwannoma have been reported. Owing to the uncertainty of the prognosis, our patient is under long-term endoscopic surveillance. PMID- 24493107 TI - Asymptomatic primary rectal neuroendocrine carcinoma presented as a large pelvic mass. AB - A 55-year-old healthy Thai man presented with incidental finding of a well circumscribed, 5.8*5.4 cm mass in the right side of the pelvic cavity with heterogeneous density by a CT scan performed for trauma. No other distant lesion was detected. The pathology from pelvic mass showed poorly differentiated neuroendocrine carcinoma (NEC). A submucosal mass of 10 cm from the anal verge was found at colonoscopy, and a biopsy showed the same histopathology as in the pelvic mass. Final diagnosis was poorly differentiated primary rectal NEC with metastasis to the right iliac node (by CT scan). Carboplatin and etoposide were given for six cycles and tumour size was decreased. PMID- 24493108 TI - Infected and ruptured retroperitoneal teratoma. PMID- 24493109 TI - An unusual case of ectodermal dysplasia: combating senile features at an early age. AB - Ectodermal dysplasia (ED) refers to a group of inherited diseases that have developmental defects in at least two major structures derived from the ectoderm, that is, hair, teeth, nails and sweat glands. Although more than 192 distinct disorders have been described, the most common is X-linked recessive hypohidrotic ED (Christ-Siemens-Touraine syndrome). Since such patients usually presents with missing teeth, dentists are usually the first person to diagnose such cases. Diagnosis of such cases is important because absence of sweat glands can lead to hyperthermia which can be life-threatening if proper care is not taken. Through this manuscript, we report a case of anhidrotic ED affecting deciduous and permanent dentition, which is rare. PMID- 24493110 TI - The elephant man syndrome. PMID- 24493111 TI - A moth-eaten radius. PMID- 24493112 TI - Squamous cell carcinoma of the renal pelvis presenting as sacral bone metastasis. AB - We present a rare presentation of squamous cell carcinoma of the kidney with chronic low backache. The diagnosis of this uncommon tumour of the renal pelvis was achieved after incidentally detecting a large staghorn calculus, which on further imaging with contrast-enhanced CT of the abdomen and pelvis was suggestive of the features of renal tumour with sacral bone lesion. The rarity of this metastatic tumour, with its unusual presentation, is discussed. PMID- 24493113 TI - Extremely atypical thrombus coating the left atrium and left atrial appendage. PMID- 24493100 TI - Cognitive function and brain structure in persons with type 2 diabetes mellitus after intensive lowering of blood pressure and lipid levels: a randomized clinical trial. AB - IMPORTANCE: Persons with type 2 diabetes mellitus (T2DM) are at increased risk for decline in cognitive function, reduced brain volume, and increased white matter lesions in the brain. Poor control of blood pressure (BP) and lipid levels are risk factors for T2DM-related cognitive decline, but the effect of intensive treatment on brain function and structure is unknown. OBJECTIVE: To examine whether intensive therapy for hypertension and combination therapy with a statin plus a fibrate reduces the risk of decline in cognitive function and total brain volume (TBV) in patients with T2DM. DESIGN, SETTING, AND PARTICIPANTS: A North American multicenter clinical trial including 2977 participants without baseline clinical evidence of cognitive impairment or dementia and with hemoglobin A1c (HbA1c) levels less than 7.5% randomized to a systolic BP goal of less than 120 vs less than 140 mm Hg (n = 1439) or to a fibrate vs placebo in patients with low density lipoprotein cholesterol levels less than 100 mg/dL (n = 1538). Participants were recruited from August 1, 2003, through October 31, 2005, with the final follow-up visit by June 30, 2009. MAIN OUTCOME MEASURES: Cognition was assessed at baseline and 20 and 40 months. A subset of 503 participants underwent baseline and 40-month brain magnetic resonance imaging to assess for change in TBV and other structural measures of brain health. RESULTS: Baseline mean HbA1c level was 8.3%; mean age, 62 years; and mean duration of T2DM, 10 years. At 40 months, no differences in cognitive function were found in the intensive BP lowering trial or in the fibrate trial. At 40 months, TBV had declined more in the intensive vs standard BP-lowering group (difference, -4.4 [95% CI, -7.8 to 1.1] cm(3); P = .01). Fibrate therapy had no effect on TBV compared with placebo. CONCLUSIONS AND RELEVANCE: In participants with long-standing T2DM and at high risk for cardiovascular events, intensive BP control and fibrate therapy in the presence of controlled low-density lipoprotein cholesterol levels did not produce a measurable effect on cognitive decline at 40 months of follow-up. Intensive BP control was associated with greater decline in TBV at 40 months relative to standard therapy. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00000620. PMID- 24493114 TI - Ventricular fibrillation due to coronary vasospasm. AB - A 43-year-old woman developed a sudden-onset severe chest pain and breathlessness at home. She collapsed within minutes and received bystander cardiopulmonary resuscitation from her husband. On arrival, the paramedics identified ventricular fibrillation requiring defibrillation. She was admitted to the intensive care unit for observation. A coronary angiogram performed at our hospital demonstrated non-obstructive disease of the right coronary artery. Her antidepressant medications were discontinued and she was discharged. No specific cause was found for the arrhythmia and collapse. One week later, she developed similar chest pain. An ECG showed transient ST-elevation in the inferior leads. Symptoms and ECG changes resolved with sublingual nitroglycerin. During the course of a repeat coronary angiogram the patient developed severe spasm of the right coronary artery associated with typical chest pain and ST-elevation in the inferior leads. She was treated with insertion of a drug-eluting stent and a cardiac defibrillator. PMID- 24493116 TI - Quality of life improves after strabismus surgery in patients with Graves' orbitopathy. AB - OBJECTIVE: To evaluate the influence of strabismus surgery on quality of life (QoL) in Graves' orbitopathy (GO) patients. DESIGN: Prospective study of case series. METHODS: Consecutive GO-patients who were scheduled for their first strabismus surgery were included in the study. The patients completed the GO-QoL questionnaire within 3 months before the surgery and 2-4 months after the surgery. A complete orthoptic examination, including the field of binocular single vision (BSV), was performed. Clinically relevant response (CRR) in the QoL was also evaluated. RESULTS: In this study, 28 patients were included. The GO-QoL score for visual functioning was 46.3+/-24.2 before surgery and 65.7+/-30.5 after surgery (P=0.009). The GO-QoL score for appearance changed from 60.6+/-25.9 to 69.5+/-24.2 (P=0.005). After surgery, the field of BSV increased from 24.3+/-34.8 to 68.5+/-36.0 points (P=0.000). A weak correlation was found between the field of BSV and the visual functioning score after surgery (r=0.417; P=0.034). CRR was found in 20 (71%) patients. Those with a CRR showed a larger field of BSV (P=0.002) and better GO-QoL scores (P=0.008). CONCLUSIONS: GO-QoL score increases significantly for both visual functioning and appearance after the first strabismus surgery in GO-patients, showing the highest improvement for the visual functioning questions. Both the GO-QoL and field of BSV outcomes correlate well with the CRR. PMID- 24493115 TI - Time to adjuvant therapy and other variables in localized gastric and gastroesophageal junction (GEJ) cancer (IJGC-D-13-00162). AB - BACKGROUND: Adjuvant chemotherapy with or without radiation in patients with completely resected gastric and gastroesophageal (GE) junction cancer has been associated with better outcomes. In practice, however, there are often delays in commencing adjuvant therapy. The study aims to determine the prognostic importance of timing of adjuvant therapy in such patients. METHODS: A cohort of patients with early stage (IB-IVM0) gastric and GE junction cancer diagnosed between 2002 and 2007 in the province of Saskatchewan was assessed. Cox proportional hazard analysis was used to identify various clinic-pathological factors that correlate with disease-free survival (DFS). RESULTS: One hundred seventy-four eligible patients with a median age of 71 years (range 36-93) and M/F ratio of 113:61 were identified. Of 174 patients, 60 (35%) received adjuvant therapy. Median follow-up was 18 months (interquartile range 9-37). Twenty-eight percent received adjuvant therapy within 56 days. Median DFS of patients who received adjuvant therapy within 56 days was 37 months (95% CI 6.6-67.3) versus 33 months (95% CI 18.3-47.7) if adjuvant therapy was administered beyond 56 days (p = 0.67). On multivariate analysis, state III-IVM0 disease, hazard ratio (HR) 2.4 (95% CI 1.6-3.5), and age >=65 years, HR 2.2 (95% CI 1.4-3.5), were significantly correlated with inferior disease-free survival. CONCLUSIONS: Only about one third of patients who received adjuvant therapy were treated within 56 days of surgery. Although stages III and IVM0 and older age were associated with inferior outcome, delay in adjuvant therapy was not associated with inferior survival. PMID- 24493117 TI - Meta-analysis of postoperative morbidity and perioperative mortality in patients receiving neoadjuvant chemotherapy or chemoradiotherapy for resectable oesophageal and gastro-oesophageal junctional cancers. AB - BACKGROUND: The long-term survival benefits of neoadjuvant chemotherapy (NAC) and chemoradiotherapy (NACR) for oesophageal carcinoma are well established. Both are burdened, however, by toxicity that could contribute to perioperative morbidity and mortality. METHODS: MEDLINE, the Cochrane Library and Embase were searched to capture the incidence of any postoperative complications, cardiac complications, respiratory complications, anastomotic leakage, postoperative 30-day mortality, total postoperative mortality and treatment-related mortality in randomized clinical trials comparing NAC or NACR with surgery alone, or NAC versus NACR. Meta-analyses comparing NAC and NACR were conducted by using adjusted indirect comparison. RESULTS: Twenty-three relevant studies were identified. Comparing NAC or NACR with surgery alone, there was no increase in morbidity or mortality attributable to neoadjuvant therapy. Subgroup analysis of NACR for squamous cell carcinoma (SCC) suggested an increased risk of total postoperative mortality and treatment-related mortality compared with surgery alone: risk ratio 1.95 (95 per cent confidence interval 1.06 to 3.60; P = 0.032) and 1.97 (1.07 to 3.64; P = 0.030) respectively. A combination of direct comparison and adjusted indirect comparison showed no difference between NACR and NAC regarding morbidity or mortality. CONCLUSION: Neither NAC nor NACR for oesophageal carcinoma increases the risk of postoperative morbidity or perioperative mortality compared with surgery alone. There was no clear difference between NAC and NACR. Care should be taken with NACR in oesophageal SCC, where an increased risk of postoperative mortality and treatment-related mortality was apparent. PMID- 24493118 TI - A cytochemical study of the leaf-gland enzymes of insectivorous plants of the genus Pinguicula. AB - Cytochemical methods have been used to study the distribution of acid phosphatase, esterase, ribonuclease, amylase and protease activity in the stimulated and unstimulated leaf glands of Pinguicula grandiflora, P. vulgaris, P. lusitanica, and P. caudata. Two gland types are present, stalked and sessile. The stalked glands bear a muco-polysaccharide secretion droplet, and are concerned with capture of the prey; the sessile glands are specialised for digestion. In unstimulated glands of both classes, acid phosphatase, esterase and ribonuclease activity is associated with the anticlinal walls of the head cells, which have a characteristic spongy inner surface, comparable with that of transfer cells. Acid phosphatase and esterase activity was also detected in the vacuoles of the head cells of the sessile glands. Substrate film tests showed that amylase is readily released from the stalked glands but not from the sessile ones, while in contrast proteolytic activity is mainly associated with the sessile glands.On stimulation by suitable nitrogenous materials, the glands begin to sectete fluid onto the leaf surface within 1 hr. During the process the enzymes held in the spongy walls are discharged, and activity is also lost from the intracellular sites in the sessile glands.Digestion on the leaf surface and resorption of the products has been followed autoradiographically after feeding of (14)C-labelled protein. Within 2 hr, digestion products enter the leaf, and move towards the margin in the vascular system. Movement out of the leaf begins within 12 hr. Microautoradiographs showed a concentration of products around the bases of the sessile glands and in the cells of the gland head, showing that these glands are involved in resorption as well as secretion.A possible mechanism of gland function is discussed. PMID- 24493119 TI - [Anion influx, ATP level and CO2 fixation in Limnophila gratioloides and Chara foetida]. AB - Influx of anions (5x10(-4) M Cl(-) or SO4 (2-)) across the plasmalemma, ATP levels and CO2 fixation in Limnophila and Chara have been measured in a comparative study.In Limnophila, influx, ATP level and CO2 fixation were progressively reduced by increasing concentrations of carbonyl cyanide m chlorophenylhydrazone (CCCP) in the light (4000 lux) as well as in the dark. In Chara, not only influx but also ATP levels were much less reduced in the light than in the dark.At 5x10(-4) M external salt concentration the action of light or dark is to change active influx of anions. Thus this study provides strong evidence to support the view that active anion uptake is directly dependent on ATP rather than on electron flow or NADPH. The possible significance of differences in the photophosphorylation systems of various plants is stressed. PMID- 24493120 TI - [On the oxidation of glycolate by unicellular green algae]. AB - O2-uptake and CO2-release by a chlorophyll-free, carotenoid-containing mutant of Chlorella vulgaris increase on addition of Na-glycolate by factors of 4-5 and 5 6, respectively (Fig. 1). In an enzyme preparation of that alga (sonification, centrifugation, precipitation with 0-30% (NH4)2SO4, dialysis) activity of glycolate oxidase can be demonstrated by O2-uptake (Fig. 2a) as well as by reduction of the artificial electron acceptor DCPIP (Fig. 2b). The same holds true for whole cells as well as equally prepared enzyme preparations of heterotrophically or autotrophically grown wildtype Chlorella vulgaris, provided the cells are cracked by a "French press" instead of a sonicator (Figs. 3a-c and 4a-c). Glyoxylate is the main reaction product (Table). Oxidation of exogenous glycolate is rapidly performed by whole cells of Scenedesmus quadricauda and of Ankistrodesmus convolutus, too, but hardly or not at all by Chlorella pyrenoidosa and Ankistrodesmus braunii. No definite influence of the level of CO2 applied during growth is found: Chlorella vulgaris and Ankistrodesmus convolutus show a rapid oxidation of glycolate after growth under 0,03 and 1,5% CO2 in air, whereas Chlorella pyrenoidosa and Ankistrodesmus braunii do not show an enhanced O2 uptake on addition of glycolate after either condition (Fig. 5). Various developmental stages of Chlorella pyrenoidosa respond differently to addition of glycolate, the extra O2-consumption varying between about 25% (mature cells) and 50-60% (young cells) of the endogenous rate (Fig. 6). It thus appears that species of unicellular green algae within the same genus have strong or weak glycolate oxidase activity and that several external factors have only a modifying effect on that enzyme. PMID- 24493121 TI - The structure and mitotic behaviour of a nuclear inclusion in a fern. AB - A study has been made of the structure and behaviour during mitosis of a crystalline inclusion within cell nuclei of roots of Dryopteris filix-max. The inclusion within the interphase nucleus is an aggregate of randomly oriented crystals. All the crystals are similar, and consist of a cubic array of particles of unit spacing approximately 100 A. During mitosis, the inclusions are eliminated from the nucleoplasm at prometaphase. The crystals reappear within the nucleus at early interphase by a process of random crystallisation from a preformed mass of amorphous material. The results are discussed in the light of previous work on nuclear inclusions in plants and of current theories of the mode of action of microtubules. PMID- 24493122 TI - [Demonstration of Phytochrome-mediated de novo-Synthesis of phenylalanine ammonia lyase (PAL, E.C. 4.3.1.5) in seedlings of Sinapis alba L. by Density Labeling with Deuterium]. AB - Using the in vivo density labeling technique with deuterium oxide it is confirmed that during phytochrome mediated photomorphogenesis in mustard seedlings a true de novo synthesis of phenylalanine ammonia-lyase is induced by active phytochrome (P fr). PMID- 24493123 TI - Plastid development in primary leaves of Phaseolus vulgaris : The effects of D threo and L-threo chloramphenicol on the light-induced formation of enzymes of the photosynthetic carbon pathway. AB - The development of increased activities of ribulosediphosphate carboxylase (EC 4.1.1.39) and of phosphoribulokinase (EC 2.7.1.19) in greening bean leaves was completely inhibited by D-threo chloramphenicol but unaffected by L-threo chloramphenicol. This indicates that these enzymes are synthesized by the ribosomes of the developing plastids. A different mechanism appears to be responsible for the development of activity of NADP-dependent triosephosphate dehydrogenase (EC 1.2.1.13) where the D-threo isomer gave 45% inhibition and the L-threo isomer gave 18% inhibition. Thus both specific (D-threo isomer) and unspecific (both isomers) inhibition occurred. It is suggested that the development of NADP-dependent triosephosphate dehydrogenase activity may result from the allosteric activation, in the plastids, of the NAD-dependent enzyme (Muller et al., 1969) which has been synthesized by cytoplasmic ribosomes. Neither isomer inhibited the development of five other enzymes of the photosynthetic carbon cycle namely ribosephosphate isomerase (EC 5.3.1.6), phosphoglycerate kinase (EC 2.7.2.3), triosephosphate isomerase (EC 5.3.1.1), tructosediphosphate aldolase (EC 4.1.2.13) and transketolase (EC 2.2.1.1), but there was a significant stimulation of the activity of transketolase by D-threo chloramphenicol. PMID- 24493125 TI - Abscisie acid in the leaf of Vernonia anthelmintiea. PMID- 24493124 TI - Kinetics of iron absorption by excised rice roots. AB - Studies on the rate of iron absorption by excised rice roots from solutions of different concentrations of FeSO4 showed the presence of two patterns, one in the low (0.005-0.5 mM) and the other in the high (1-30 mM) concentration range. The presence of CaSO4 or MnSO4 at 0.5 mM enhanced Fe(++) absorption in the low concentration range, while CaSO4 at 10 mM inhibited Fe absorption in the high concentration range in a competitive manner. Fe(++) absorption at both low and high concentrations was sensitive to metabolic inhibitors. The isotherm for Fe(++) absorption at O degrees exhibited an initial absorption shoulder in both low and high concentrations and was suggestive of a latent ion-transport capacity for Fe(++) in rice roots. PMID- 24493126 TI - An integrated study of the affinities of the Abeta16 peptide for Cu(I) and Cu(II): implications for the catalytic production of reactive oxygen species. AB - A new fluorescent probe Abeta16wwa based upon the Abeta16 peptide has been developed with two orders of magnitude greater fluorescence intensity for sensitive detection of interactions with Cu(II). In combination with the Cu(I) probe Ferene S, it is confirmed that the Abeta16 peptide binds either Cu(I) or Cu(II) with comparable affinities at pH 7.4 (log K = -10.4; log K = -10.0). It follows from this property that the Cu-Abeta16 complex is a robust if slow catalyst for the aerial oxidation of ascorbate with H2O2 as primary product (initial rate, ~0.63 min(-1) for Cu-Abeta16 versus >2.5 min(-1) for Cuaq(2+)). An integrated study of variants of this peptide identifies the major ligands and binding modes involved in its copper complexes in solution. The dependence of K upon pH is consistent with a two-coordinate Cu(I) site in which dynamic processes exchange Cu(I) between the three available pairs of imidazole sidechains provided by His6, His13 and His14. The N-terminal amine is not involved in Cu(I) binding but is a key ligand for Cu(II). Acetylation of the N-terminus alters the redox thermodynamic gradient for the Cu centre and suppresses its catalytic activity considerably. The data indicate the presence of dynamic processes that exchange Cu(II) between the three His ligands and backbone amide at physiological pH. His6 is identified as a key ligand for catalysis as its presence minimises the pre organisation energy required for interchange of the two copper redox sites. These new thermodynamic data strengthen structural interpretations for the Cu-Abeta complexes and provide valuable insights into the molecular mechanism by which copper chemistry may induce oxidative stress in Alzheimer's disease. PMID- 24493127 TI - Influence of the betas haplotype and alpha-thalassemia on stroke development in a Brazilian population with sickle cell anaemia. AB - Stroke is a catastrophic complication of sickle cell anaemia (SCA) and is one of the leading causes of death in both adults and children with SCA. Evidence suggests that some genetic polymorphisms could be related to stroke development, but their association remains controversial. Here, we performed genotyping of five published single nucleotide polymorphisms, the alpha-thalassemia genotype, the G6PD A (-) variant deficiency, and the beta(S) haplotype in a large series of SCA patients with well-defined stroke phenotypes. Of 261 unrelated SCA patients included in the study, 67 (9.5 %) presented a documented, primary stroke event. Markers of haemolysis (red blood cell (RBC) counts, p = 0.023; reticulocyte counts, p = 0.003; haemoglobin (Hb) levels, p < 0.001; indirect bilirubin levels, p = 0.006; lactate dehydrogenase (LDH) levels, p = 0.001) were associated with stroke susceptibility. Genetically, only the beta(S) haplotype (odds ratio (OR) 2.9, 95 % confidence interval (CI) 1.56 to 4.31; p = 0.003) and the alpha(3.7kb) thalassemia genotype (OR 0.31, 95 % CI 0.11 to 0. 83; p = 0.02) were associated with increased and decreased stroke risk, respectively. In multivariate analysis, the beta(S) haplotype was independently associated with stroke development (OR 2.26, 95 % CI 1.16 to 4.4; p = 0.016). Our findings suggest that only the beta(S) haplotypes and the alpha(3.7kb)-thalassemia genotype modulate the prevalence of stroke in our SCA population. Genetic heterogeneity among different populations may account for the irreproducibility amongst different studies. PMID- 24493128 TI - Absence of TERT promoter mutations in esophageal adenocarcinoma. PMID- 24493129 TI - Different quantification algorithms may lead to different results: a comparison using proton MRS lipid signals. AB - Proton magnetic resonance spectroscopy (MRS) is a sensitive method for investigating the biochemical compounds in a tissue. The interpretation of the data relies on the quantification algorithms applied to MR spectra. Each of these algorithms has certain underlying assumptions and may allow one to incorporate prior knowledge, which could influence the quality of the fit. The most commonly considered types of prior knowledge include the line-shape model (Lorentzian, Gaussian, Voigt), knowledge of the resonating frequencies, modeling of the baseline, constraints on the damping factors and phase, etc. In this article, we study whether the statistical outcome of a biological investigation can be influenced by the quantification method used. We chose to study lipid signals because of their emerging role in the investigation of metabolic disorders. Lipid spectra, in particular, are characterized by peaks that are in most cases not Lorentzian, because measurements are often performed in difficult body locations, e.g. in visceral fats close to peristaltic movements in humans or very small areas close to different tissues in animals. This leads to spectra with several peak distortions. Linear combination of Model spectra (LCModel), Advanced Method for Accurate Robust and Efficient Spectral fitting (AMARES), quantitation based on QUantum ESTimation (QUEST), Automated Quantification of Short Echo-time MRS (AQSES)-Lineshape and Integration were applied to simulated spectra, and area under the curve (AUC) values, which are proportional to the quantity of the resonating molecules in the tissue, were compared with true values. A comparison between techniques was also carried out on lipid signals from obese and lean Zucker rats, for which the polyunsaturation value expressed in white adipose tissue should be statistically different, as confirmed by high-resolution NMR measurements (considered the gold standard) on the same animals. LCModel, AQSES Lineshape, QUEST and Integration gave the best results in at least one of the considered groups of simulated or in vivo lipid signals. These outcomes highlight the fact that quantification methods can influence the final result and its statistical significance. PMID- 24493130 TI - Intrahepatic cholestasis of pregnancy and the risk of subsequent hepatobiliary disorders. PMID- 24493131 TI - ER stress, autophagy and immunogenic cell death in photodynamic therapy-induced anti-cancer immune responses. AB - Tumours are a form of pseudo-organs with their own microenvironment where the cancer cells nurture a dysfunctional immune environment incapable of inciting anti-tumour immunity. It had been proposed that the only way to counteract such an immune system dysfunction in tumours is by eliciting, therapeutically, a cancer cell death pathway that is accompanied by high immunogenicity and possibly inhibits or reduces the influence of the pro-tumourigenic cytokine signalling. Subsequently, a small and a large-scale screening study as well as several targeted studies found that few, selected anticancer therapeutic regimens are able to induce a promising kind of cancer cell demise called immunogenic cell death (ICD), which can activate the immune system owing to the spatiotemporally defined emission of danger signals. Recently, photodynamic therapy (PDT) utilizing the photosensitiser, hypericin (Hyp), became the first PDT paradigm characterized to be capable of inducing bona fide ICD. In the present perspective, we discuss the various technical, conceptual, and molecular advancements and unprecedented results revealed by Hyp-PDT that have influenced the fields of ICD, ER stress biology, cancer cell death, anti-cancer immune responses, photoimmunology and PDT. PMID- 24493132 TI - Real-time feedback control of pH within microfluidics using integrated sensing and actuation. AB - We demonstrate a microfluidic system which applies engineering feedback principles to control the pH of a solution with a high degree of precision. The system utilizes an extended-gate ion-sensitive field-effect transistor (ISFET) along with an integrated pseudo-reference electrode to monitor pH values within a microfluidic reaction chamber. The monitored reaction chamber has an approximate volume of 90 nL. The pH value is controlled by adjusting the flow through two input channels using a pulse-width modulated signal applied to on-chip integrated valves. We demonstrate real-time control of pH through the feedback-controlled stepping of 0.14 pH increments in both the increasing and decreasing direction. The system converges to the pH setpoint within approximately 20 seconds of a step change. The integration of feedback theory into a microfluidic environment is a necessary step for achieving complete control over the microenvironment. PMID- 24493133 TI - Electrochemical treatment of domestic wastewater using boron-doped diamond and nanostructured amorphous carbon electrodes. AB - The performance of the electrochemical oxidation process for efficient treatment of domestic wastewater loaded with organic matter was studied. The process was firstly evaluated in terms of its capability of producing an oxidant agent (H2O2) using amorphous carbon (or carbon felt) as cathode, whereas Ti/BDD electrode was used as anode. Relatively high concentrations of H2O2 (0.064 mM) was produced after 90 min of electrolysis time, at 4.0 A of current intensity and using amorphous carbon at the cathode. Factorial design and central composite design methodologies were successively used to define the optimal operating conditions to reach maximum removal of chemical oxygen demand (COD) and color. Current intensity and electrolysis time were found to influence the removal of COD and color. The contribution of current intensity on the removal of COD and color was around 59.1 and 58.8%, respectively, whereas the contribution of treatment time on the removal of COD and color was around 23.2 and 22.9%, respectively. The electrochemical treatment applied under 3.0 A of current intensity, during 120 min of electrolysis time and using Ti/BDD as anode, was found to be the optimal operating condition in terms of cost/effectiveness. Under these optimal conditions, the average removal rates of COD and color were 78.9 +/- 2 and 85.5 +/- 2 %, whereas 70% of total organic carbon removal was achieved. PMID- 24493134 TI - The identification and quantitative analysis of abscisic acid in plant extracts by gas-liquid chromatography. AB - New techniques are described which permit the quantitative analysis of microgram quantities of abscisic acid in plant extracts by gas chromatography. Presumptive methyl abscisate peaks on gas chromatograms are positively identified by photosensitised isomerisation to methyl 2-trans-abscisate. Losses of abscisic acid during pre-purification are corrected by using 2-trans-abscisic acid as an internal standard. PMID- 24493135 TI - Occurrence of proteolytic inhibitors in various tissues of barley. AB - The three groups of proteolytic inhibitors present in resting barley grains, namely, trypsin inhibitors, Aspergillus-proteinase inhibitors, and inhibitors of endogenous proteinases, occur in both the embryo and the two endosperm tissues. There are pronounced quantitative differences, however. The three inhibitor activities in the embryo are, respectively, 6-, 0.1-, and 6-fold of those in the endosperm.During germination at 20 degrees all inhibitor activities disappear from the endosperms in 4-5 days. Young rootlets and coleoptiles contain inhibitors of trypsin and Aspergillus proteinase, but these disappear after 4-5 days' germination. However, the trypsin inhibitor content per seedlings remains roughly constant through the whole period. The Aspergillus-proteinase inhibitors, in contrast, exhibit a pronounced increase of activity per seedling.No inhibitor activities were detected in leaves and roots at later stages of growth.The trypsin inhibitor which we have earlier purified from resting grains occurs exclusively in the two endospermal tissues and is immunologically entirely different from the trypsin inhibitors present in embryos and young seedlings. PMID- 24493136 TI - The tertiary endodermis in barley roots: Fine structure in relation to radial transport of ions and water. AB - The presence of numerous pits containing plasmodesmata in the inner tangential wall of the tertiary endodermis in barley roots is demonstrated by electron microscopy. The pit floor is covered by a thin layer of material which is continuous with and resembles the tertiary wall. The plasmodesmatal pore is constricted at its ends so that the plasmalemma lining the pore is appressed to the desmotubule. The frequency of plasmodesmata and their cross-sectional area is estimated, and phosphate and water fluxes through them are calculated on the assumption that they represent the only communication between the cortex and the vascular tissue. The pressure gradient across the ends of the plasmodesmata necessary to support the observed water flux is calculated for limiting cases of the pore radius and the viscosity of the fluid passing through the pore. PMID- 24493137 TI - The effect of hormones on anthocyanin accumulation in cell cultures of Haplopappus gracilis. AB - Suspension cultures of Haplopappus gracilis accumulated anthocyanin when grown in defined media with 4.5*10(-6)M 2,4-D. Transfer of cells to media with 10(-5)M kinetin or benzyladenine and no auxin or 10(-7)M NAA for 6 days resulted in increased anthocyanin concentration of the cells but the total amount of pigment was unaffected due to differences in growth rates. The cultures yielded up to 35 mg pigment per gram dry weight.Cells grown in batch culture in media with 10(-5)M kinetin and with 10(-7) M NAA or 5*10(-5)M NAA sampled and analyzed daily grew at the same rate. The concentration of anthocyanin differed, being lower in cells at 5*10(-5)M NAA. After 6 days there was a rapid increase in pigment formation, and by 14 days the concentration of anthocyanin in cells in the two media were the same.When the cells were cultured in 3.5-1 phytostats and 600 ml culture was replaced daily with 600 ml medium, anthocyanins accumulated when the NAA concentration was 10(-7)M but not at 10(-6)M. At 10(-7)M NAA the cultures remained pigmented and anthocyanin accumulation could be restored after a temporary loss of pigmentation due to an earlier, higher auxin concentration. The changes in concentration of phenylalanine ammonia-lyase did not correspond to changes in the rate of anthocyanin accumulation. The enzyme showed a maximum 4-8 h after inoculation of cells to fresh media. Cells grown on agar plates and rich in anthocyanin were observed to divide without loss of pigmentation, demonstrating that cells differentiated with respect to anthocyanin production undergo mitosis. PMID- 24493138 TI - Changes in proteolytic enzyme activities and transformation of nitrogenous compounds in the germinating seeds of kidney bean (Phaseolus vulgaris). AB - Hydrolytic activity towards synthetic substrates and denatured proteins was measured in the extracts of the seeds of kidney bean at various stages of germination up to 16 days.Of the peptide hydrolases, chymotrypsin-type activity was stable for the first 7 days, then rapidly increased towards the end; leucine aminopeptidase activity decreased to a minimum (8th day) then slowly increased again; trypsin-type activity remained constant throughout.Proteolytic and autodigesting activities showed an optimum between pH 5.0 and 5.5. Both activities decreased slowly first, then rose to a sharp maximum at the 8th day. The haemoglobin-digesting activity after a minimum increased again at the 14th day. The autodigesting activity had an additional maximum.Concomitant with these changes, non-protein nitrogen increased twofold by the 5th day, remained constant up to the 12th day and then increased again. Protein content on the other hand decreased first, had a maximum at the 9th day after which it steadily decreased again. The amounts of albumins and globulins changed independently of each other: albumins decreased continuously with the exception of a steady period (5-9th days), while globulins were more stable except for a sharp minimum (6-7th days) and a steady decrease after the 13th day. PMID- 24493139 TI - [Studies on microbodies in spadix appendices of Arum maculatum L. and Sauromatum guttatum schott]. AB - When the sections of the spadix appendix of Arum are incubated in a medium containing diaminobenzidine and H2O2, only the membrane of microbodies is stained. On the other hand, microbodies of Sauromatum show a stained matrix as usual. Catalase-containing cell organelles isolated from spadix appendices of Arum show the same typical membrane staining as the microbodies in situ do. Thus the identity of these organelles with microbodies seems to be proved. After anthesis the microbodies in situ usually do not give a positive reaction for catalase with diaminobenzidine and H2O2. However, cytochemical and biochemical tests for catalase on microbodies isolated during this stage of development clearly demonstrate the presence of this enzyme. Uricase is localized in the microbodies of Arum as well as catalase. No malate dehydrogenase, peroxidase, and allantoinase could be found in the microbodies. Before anthesis the microbodies of spadix appendices of Arum have an equilibrium density in aqueous sucrose of 1.22 gcm(-3). After anthesis the density changes into 1.23 to 1.24 gcm(-3). PMID- 24493140 TI - [An attempt at a causal analysis of the geotropical reaction chain in the Chara rhizoid]. AB - In the initial phase of the geotropical reaction of the Chara rhizoid the growth difference postulated by Sievers (1967c) between the physically upper, slightly subapical flank and the lower one is demonstrated. In horizontal exposure the growth of the extreme cell apex is continued, while the growth of the lower flank is inhibited and that of the upper one is promoted. In the end phase the cell apex shows a damped oscillation until it finally reaches the vertical growth direction. The statoliths follow the oscillating growth of the cell tip from one flank to the opposite one until they are statistically equally redistributed in their normal position.-In vertical exposure under reduced turgor pressure the statoliths fall down into the extreme cell apex, where they inhibit the growth of this part of the cell wall, while the subapical wall grows transversally.-It is concluded that the statoliths inhibit the growth of the cell wall area which they cover.-The physical phase of the reaction chain, the susception, is the gravity induced downward displacement of the statoliths. The physiological phase starts with the diversion of the acropetal transport of the Golgi vesicles to the upper part of the cell, which is caused by the block of statoliths (perception). The greater rate of vesicle incorporation into the upper flank in comparison to the lower one causes the subapical growth difference which results in the curvature (reaction).-In the case of the Chara rhizoid Golgi- and statolith-apparatus function as a self-regulating cellular system. PMID- 24493141 TI - A microtubular crystal associated with the Golgi field of Pleurochrysis scherffelii. AB - In young vegetative cells of the Chrysophycean alga Pleurochrysis scherffelii, a characteristic array of microtubules is associated with the Golgi apparatus. This novel structure is described from frozen-etched preparations. The microtubular crystals flank the Golgi stack at either side at an oblique angle and lie in between the Golgi and the periplastidal ER and a parietal vacuole. The microtubules have an outer diameter of 195-230 A and are spaced in a hexagonal pattern with center-to-center distances of 300-330 A. The crystals lie free in the cytoplasm and are not surrounded by a membrane although they frequently associate with membraneous elements of the parietal vacuole or periplastidal ER. The microtubules are interconnected by bridge-like links. Possible functions of these crystals, especially in relation to secretion and protoplast rotation, are discussed. PMID- 24493143 TI - Reply: To PMID 23960026. PMID- 24493142 TI - Risk of hypertension in cancer patients treated with aflibercept: a systematic review and meta-analysis. AB - BACKGROUND: Aflibercept is currently approved as second-line treatment for patients with metastatic colorectal cancer, and its application in other types of tumors is undergoing clinical evaluation. Hypertension is one of its major adverse effects with a substantial variation in the reported incidences and has not been systematically investigated. METHODS: We searched PubMed, EMBASE, and Cochrane Library databases from January 2000 to August 2013 and abstracts presented at annual meetings from 2004 to 2013 to identify relevant studies. Eligible studies were phase II and III prospective clinical trials of aflibercept in patients with any type of cancer describing events of hypertension. Summary incidence rates, odds ratios (OR), and 95 % confidence intervals (CIs) were calculated employing fixed- or random-effects models depending on the heterogeneity of the included trials. RESULTS: A total of 15 trials with 4,451 patients were included for the meta-analysis. The summary incidences of all-grade and high-grade hypertension were 42.4 % (95 % CI 35.0-50.3) and 17.4 % (95 % CI 13.7-21.9), respectively. The use of aflibercept in cancer patients was associated with a significantly increased risk of all-grade (OR 4.47, 95 % CI 3.84-5.22, p < 0.001) and high-grade (OR 4.97, 95 % CI 3.95-6.27, p < 0.001) hypertension. The risk of developing hypertension with aflibercept was significantly higher than that of bevacizumab (all-grade: OR 1.93, 95 % CI 1.61 2.32, p < 0.001; high-grade: OR 2.06, 95 % CI 1.79-2.37, p < 0.001). CONCLUSIONS: The use of aflibercept is associated with a significantly increased risk of developing all-grade and high-grade hypertension compared with control. Close monitoring and adequate managements are highly recommended to decrease cardiovascular complication. PMID- 24493144 TI - Low serum levels of vitamin D in metastatic cancer patients: a case-control study. AB - Accompanying comorbidities observed during the cancer treatment usually affect the course and outcome of the therapy. Hypovitaminosis D, which is one of these conditions, is a resolvable problem, if recognized. In this study, we investigated whether the serum 25(OH)D levels of the patients who were presented to our outpatient clinic were different from the serum levels of the healthy population living in the same area. Our study included 90 patients who were presented to the Medical Oncology outpatient clinic and 90 age, gender, body mass index and ethnic origin matched controls without a known disease, who were presented to the outpatient clinics of the Departments of Internal Diseases and Family Medicine for routine controls. Blood count tests, detailed biochemistry tests (including serum levels of Cr, Ca and P), measurement of serum 25(OH)D levels and C-reactive protein were performed in serum samples of all of the patients and controls. Mean serum levels of 25(OH)D were 13.5 ng/ml (SD 5.1) in all cancer patients, 13.1 ng/ml (SD 4.2) in the patients who were presented for adjuvant therapy, 13.8 ng/ml (SD 5.5) in the patients who were presented at metastatic stage and 18.4 ng/ml (SD 12.5) in the controls. Mean serum CRP levels were 5.4 mg/dl (SD 1.2) in the control group, 8.4 mg/dl (SD 4.3) in the adjuvant therapy group and 20.3 (SD 16.8) in the patients with metastatic disease. Generally, all cancer patients (p 0.003) and the patients with metastatic cancer (p 0.004) had lower serum 25(OH)D levels compared to controls, and there was an inverse correlation between serum 25(OH)D and CRP levels in patients with metastatic cancer (p 0.036). In metastatic cancer patients, hypovitaminosis D may be a comorbidity and it is recommended to consider during initial evaluation and follow-up. Because it might improve these patients quality of life and chemotherapy adherence. PMID- 24493145 TI - Importance of tumor size in soft tissue sarcomas: a proposal for a nomogram based on a score system to staging soft tissue sarcomas in the postoperative setting. AB - In order to adequately stage patients with extremity soft tissue sarcomas (ESTS), it is mandatory to include all adverse prognostic factors and create an integral staging system. We were able to evaluate a nomogram based on a score (STSSS), to improve ESTS staging. We retrospectively evaluated 596 patients with ESTS in stages I-III, of the American Joint Committee on Cancer (AJCC), who had a complete resection. We analyzed the influence of clinicopathological factors on metastasis, recurrence, and disease-specific survival. The STSSS was based on histologic grade (HG), profundity, tumor size (TS), and surgical margins; we also compared STSSS versus AJCC systems in their ability to stage ESTS. The mean TS was 11.8 cm, with 50%>10 cm. Large TS and high HG were independent but adverse prognostic factors for metastasis. In addition, large TS, high grade, and R1 resection were independent adverse prognostic factors for decreased survival. There was a progressive decline in survival as TS increased, although AJCC staging did not correlate well between stages (IA vs. IB p=0.233, IA vs. IIA p=0.123, IA vs. IIB p=0.075, IB vs. IIA p=0.472, IB vs. IIB p=0.211). STSSS showed differences between these categories for 5-year survival (I vs. II p=0.003, II vs. III p=0.002, III vs. IV p<0.001). Surgical margins, HG, and TS are important determinants for metastases and survival. We also found a strong correlation between survival and prognosis with the use of STSSS in the immediate postoperative setting. PMID- 24493146 TI - [Testicular adrenal rest tumors in adolescents]. AB - BACKGROUND: Testicular adrenal rest tumors (TART) frequently occur in patients with congenital adrenal hyperplasia (CAH) and can be detected and treated in childhood as well as in adolescence. Due to the intricate dilimitation to other testicular masses the correct diagnosis of TART can be problematic. An extensive endocrinologic evaluation and ultrasound examination are mandatory. Even though TART are benign lesions a high-dose therapy with glucocorticoid and/or mineralocorticoid suppletion is necessary for protecion or regain of fertility. METHODS: A surgical approach can be considered, depending on stage of disease and response on drug therapy. Consequent treatment and constant therapy monitoring might significantly improve long-term outcome. RESULTS: Currently there is no validated standard therapy concept, which can be explained by the heterogenity of disease patterns progression and the limited data available, respectively. Therefore treatment should be subject to specialized centres. PMID- 24493147 TI - Outbreak of bacteremia due to Burkholderia contaminans linked to intravenous fentanyl from an institutional compounding pharmacy. AB - IMPORTANCE Many health care facilities compound medications on site to fulfill local demands when customized formulations are needed, national supply is critically low, or costs for manufactured pharmaceuticals are excessive. Small, institutional compounding facilities may perform the same high-risk procedures as large distributors of compounded medications. OBJECTIVES To investigate an outbreak related to contamination of compounded sterile preparations and to determine processes to prevent future outbreaks. DESIGN, SETTING, AND PARTICIPANTS We performed an outbreak investigation of inpatients at Duke University Hospital from August 31 through September 6, 2012. The investigation included a case-control study, compounding facility inspection and environmental sampling, observation of a mock compounding demonstration, and microbiologic and molecular testing of sequestered medication. EXPOSURES Intravenous fentanyl prepared by an institutional compounding pharmacy. MAIN OUTCOMES AND MEASURES Microbiologic and molecular evidence of contamination of a compounded sterile preparation and failure of routine sterility testing. RESULTS Blood cultures of 7 patients during a 7-day period at Duke University Hospital yielded pan susceptible Burkholderia cepacia complex bacteria. The risk factor common to all patients was receipt of continuous fentanyl infusion prepared by our institutional compounding pharmacy (odds ratio, 11.22; 95% CI, 2.09-infinity; P = .01). The outbreak was terminated after sequestration of compounded fentanyl. An intensive evaluation of the compounding facility, its practice, and its procedures was completed. Investigators evaluated the clean room, collected targeted microbiologic samples within the compounding pharmacy environment, and observed a mock demonstration of compounding practice. The B cepacia complex was found in the anteroom sink drain and pH probe calibration fluid from the compounding clean room. Multiple microbiologic analyses of sequestered fentanyl initially failed. Ultimately, a batched, vacuum-assisted filtration method produced B cepacia complex from a single lot. Molecular analyses using repetitive element polymerase chain reaction and pulsed-field gel electrophoresis confirmed a clonal Burkholderia contaminans strain from patients, fentanyl, and environmental samples. CONCLUSIONS AND RELEVANCE An outbreak of B contaminans bacteremia was linked to contamination of locally compounded intravenous fentanyl. Health care facilities that house institutional compounding facilities must be vigilant in efforts to prevent, recognize, and terminate medication related outbreaks. PMID- 24493148 TI - Antenatal fear of childbirth and sense of coherence among healthy pregnant women in Japan: a cross-sectional study. AB - While antenatal fear of childbirth (FOC) has been associated with many psychosocial variables, few studies have focused on individual stress resiliency. Sense of coherence (SOC) is one of the essential components of individual stress resiliency. This study investigates the relationship between antenatal FOC and SOC in Japanese healthy pregnant women. Self-reported questionnaires were distributed to 240 women at 37 gestational weeks at an obstetric clinic in Tokyo, Japan. Structural regression modeling was conducted to identify the causal relationships between FOC and SOC. The non-recursive model showed significant acceptance of fit (chi-square value/degree of freedom = 1.72, comparative fit index = 0.97, and root mean square error of approximation = 0.05). The model identified SOC as a direct cause of FOC (beta = -0.89, p < 0.001), not a reflection of FOC. We found that SOC was negatively linked with antenatal fear of childbirth. High SOC works as a resiliency factor that helps pregnant women cope with the stress of their upcoming childbirth and reduces FOC. PMID- 24493149 TI - Guanidine hydrochloride mediated denaturation of E. coli Alanyl-tRNA synthetase: identification of an inactive dimeric intermediate. AB - E. coli Alanyl-tRNA synthetase (AlaRS) not only catalyzes tRNA charging but also can bind to its own promoter DNA sequence and repress its own transcription. It exists as a dimer in its native form and so far this is the only aminoacyl-tRNA synthetase whose full length structure is unresolved. Guanidine hydrochloride mediated unfolding of AlaRS has been studied under equilibrium conditions using various spectroscopic techniques such as intrinsic tryptophan fluorescence, 1 anilino-8-naphthalene-sulfonic acid binding, near and far-UV circular dichroism and analytical ultracentrifugation. These studies revealed that in presence of gdnHCl AlaRS unfolded in a multistep pathway. At 0.8 M gdnHCl, AlaRS formed a molten globule like intermediate, which was enzymatically inactive. Further characterization of this intermediate proved that there was no oligomer breakdown at this denaturant concentration. This study clearly indicates that unlike many other oligomeric proteins AlaRS unfolding does not follow the hierarchical model as in this enzyme tertiary structure gets disrupted well before the disruption of quaternary interaction. PMID- 24493150 TI - Relationship of anthropometric indices to abdominal and total body fat in youth: sex and race differences. AB - OBJECTIVE: To determine the influence of sex and race on relationships between anthropometry (body mass index [BMI], waist circumference [WC], waist-to-height ratio [W/Ht]) and adiposity (fat mass [FM], abdominal subcutaneous [SAT] and visceral adipose tissue [VAT]) in African American and white youth. METHODS: The sample included 382 youth 5-18 years of age. FM and abdominal adiposity were assessed using dual energy X-ray absorptiometry and magnetic resonance imaging. Regression was used to examine sex and race effects in the relationship between independent (BMI, WC, and W/Ht) and dependent (FM, SAT and VAT) variables. RESULTS: BMI and WC were highly related to adiposity while W/Ht was moderately related. The association of BMI with FM and SAT was independent of sex and race, while the relationships of WC and W/Ht with FM and SAT were influenced by both sex and race. In contrast, the association between BMI and VAT was influenced by sex and race, while the relationships of WC and W/Ht with VAT were not. CONCLUSIONS: WC and W/Ht have similar relationships with adiposity; however, WC presented stronger relationships. BMI is a predictor of overall adiposity but sex and race play a role in its relationship with VAT. PMID- 24493151 TI - Effects of cytokine-suppressive anti-inflammatory drugs on inflammatory activation in ex vivo human and ovine fetal membranes. AB - Intrauterine infection and inflammation are responsible for the majority of early (<32 weeks) spontaneous preterm births (PTBs). Anti-inflammatory agents, delivered intra-amniotically together with antibiotics, may be an effective strategy for preventing PTB. In this study, the effects of four cytokine suppressive anti-inflammatory drugs (CSAIDs: N-acetyl cysteine (NAC), SB239063, TPCA-1 and NEMO binding domain inhibitor (NBDI)) were assessed on human and ovine gestational membrane inflammation. Full-thickness membranes were collected from healthy, term, human placentas delivered by Caesarean section (n=5). Using a Transwell model, they were stimulated ex vivo with gamma-irradiation-killed Escherichia coli applied to the amniotic face. Membranes from near-term, ovine placentas were stimulated in utero with lipopolysaccharide, Ureaplasma parvum or saline control and subjected to explant culture. The effects of treatment with CSAIDs or vehicle (1% DMSO) on accumulation of PGE2 and cytokines (human interleukin 6 (IL6), IL10 and TNFalpha; ovine IL8 (oIL8)) were assessed in conditioned media at various time points (3-20 h). In human membranes, the IKKbeta inhibitor TPCA-1 (7 MUM) and p38 MAPK inhibitor SB239063 (20 MUM) administered to the amniotic compartment were the most effective in inhibiting accumulation of cytokines and PGE2 in the fetal compartment. NAC (10 mM) inhibited accumulation of PGE2 and IL10 only; NBDI (10 MUM) had no significant effect. In addition to the fetal compartment, SB239063 also exerted consistent and significant inhibitory effects in the maternal compartment. TPCA-1 and SB239063 suppressed oIL8 production, while all CSAIDs tested suppressed ovine PGE2 production. These results support the further investigation of intra amniotically delivered CSAIDs for the prevention of inflammation-mediated PTB. PMID- 24493152 TI - Woman abuse in Canada: sociological reflections on the past, suggestions for the future. AB - Woman abuse in Canada started receiving much sociological attention in the mid 1980s. This article describes past scholarly achievements, assesses current contributions, and suggests progressive ways of responding to future challenges. Special attention is given to how broader political economic forces help shape and constrain research on a variety of highly injurious male-to-female assaults that occur in private settings. PMID- 24493153 TI - Marriage migration, patriarchal bargains, and wife abuse: a study of South Asian women. AB - This article contributes to the literature on wife abuse by using the patriarchal bargaining framework, which highlights the issue of agency as women strive to achieve their goals within the constraints of family and culture. Study participants were recent South Asian immigrants to the United States. Narrative analysis revealed that patriarchal constraints in natal families, culture, and expectations of benefits gained through marriage influenced many of the women to migrate for marriage. When husbands enforced extreme patriarchy with abuse, women's personal efforts to contain abuse were largely ineffective. However, advocacy agency interventions did help some women break out of extreme patriarchy. PMID- 24493154 TI - Cranial tibial plating in the management of failed tibial tuberosity advancement in four large breed dogs. AB - The management of failed surgical procedures involving osteotomy for tibial tuberosity advancement can be demanding due to the limited available bone stock, which must be large enough to counteract the powerful proximal and cranial distractive forces exerted by the quadriceps mechanism. Initial mode of failure may be related to implant failure, fracture of the tibial tuberosity, or a combination of both. The complications and management of the cases reported here were all associated with avulsion fracture of the tibial tuberosity following tibial tuberosity advancement. In all cases, a cranial tibial dynamic compression plate was applied to reduce the fractures and stabilize the osteotomy. No further major complications associated with the implants or fracture occurred. Radiographic evidence of progression of fracture healing was documented in all four cases at the six to eight-week postoperative follow-up. Long-term follow-up information was available for three out of four cases at nine to 23 months after surgery by telephone interview and validated owner questionnaires. Owners reported return to normal exercise with intermittent lameness occurring in two of the three cases. The authors concluded that this technique offers an alternative technique for the management of such fractures, in particular in large breed dogs where sufficient tibial tuberosity bone stock remains. PMID- 24493155 TI - Diagnosis and treatment of gout. PMID- 24493156 TI - Assessment of ischaemic burden in angiographic three-vessel coronary artery disease with high-resolution myocardial perfusion cardiovascular magnetic resonance imaging. AB - AIMS: This study compared the myocardial ischaemic burden (MIB) in patients with angiographic three-vessel coronary artery disease (3VD) using high-resolution and standard-resolution myocardial perfusion cardiovascular magnetic resonance (perfusion CMR) imaging. METHODS AND RESULTS: One hundred and five patients undergoing coronary angiography had two separate stress/rest perfusion CMR studies, one with standard-resolution (2.5 mm in-plane) and another with high resolution (1.6 mm in-plane). Quantitative coronary angiography was used to define patients with angiographic 3VD. Perfusion CMR images were anonymized, randomly ordered and visually reported by two observers acting in consensus and blinded to all clinical and angiographic data. Perfusion was graded in each segment on a four-point scale and summed to produce a perfusion score and estimate of MIB for each patient. In patients with angiographic 3VD (n = 35), high-resolution acquisition identified more abnormal segments (7.2 +/- 3.8 vs. 5.3 +/- 4.0; P = 0.004) and territories (2.4 +/- 0.9 vs. 1.6 +/- 1.1; P = 0.002) and a higher overall perfusion score (20.1 +/- 7.7 vs. 11.9 +/- 9.4; P < 0.0001) per patient compared with standard-resolution. The number of segments with subendocardial ischaemia was greater with high-resolution acquisition (195 vs. 101; P < 0.0001). Hypoperfusion in all three territories was identified in 57% of 3VD patients by high-resolution compared with only 29% by standard-resolution (P = 0.04). The area-under-the-curve (AUC) for detecting angiographic 3VD using the estimated MIB was significantly greater with high-resolution than standard resolution acquisition (AUC = 0.90 vs. 0.69; P < 0.0001). CONCLUSION: In patients with angiographic 3VD, the ischaemic burden detected by perfusion CMR is greater with high-resolution acquisition due to better detection of subendocardial ischaemia. High-resolution perfusion CMR may therefore be preferred for risk stratification and management of this high-risk patient group. PMID- 24493157 TI - Elimination of EGFR-expressing circulating tumor cells in patients with metastatic breast cancer treated with gefitinib. AB - PURPOSE: The purpose of the study is to evaluate the effect of gefitinib, an anti EGFR TKI on circulating tumor cells (CTCs) in patients with metastatic breast cancer (MBC). METHODS: Seventeen patients with MBC with detectable CTCs after the completion of prior treatment received gefitinib 250 mg/day p.o. CTCs were monitored by immunofluorescence microscopy after double staining with anti cytokeratin (A45-B/B3) and either anti-CD45 or anti-EGFR antibodies. RESULTS: A median reduction of 96.4 and 94.1 % in CTC count was observed in 11 (64.7 %) and 12 (70.6 %) of patients after the first and the second treatment cycles, respectively. Total CTC numbers declined by 73 and 44 % after the first and second treatment cycles, respectively. In nine patients with EGFR(+)/CK(+) CTCs, gefitinib resulted in a reduction of both EGFR(+) and EGFR(-) CTCs, and after the third course, most detected CTCs were EGFR(-). In two patients, with a sustained decrease in CTC numbers, a PFS of 16.0 and 19.0 months was observed and in one of them, it was associated with clinical objective response. CONCLUSION: Treatment resistant CTCs could be eliminated by gefitinib in MBC, and EGFR expression on CTCs merits further validation as a potential biomarker for specific and effective targeting of CTCs. PMID- 24493158 TI - In memoriam--Professor J Gerald (Gerry) Collee CBE, FRSE, MD, FRCPath, FRCPE (1929-2013). PMID- 24493159 TI - Nosocomial spread of meticillin-resistant Staphylococcus aureus with beta-lactam inducible arbekacin resistance. AB - A meticillin-resistant Staphylococcus aureus (MRSA) strain with additional beta lactam-inducible aminoglycoside resistance was previously reported by a group at the Kitasato University in Japan. In addition to gentamicin, the 'Kitasato strain' was resistant to arbekacin (ABK), which is primarily used as an anti-MRSA aminoglycoside. No further studies regarding the spread of MRSA strains with the newly identified resistance mechanism have been reported to date. To obtain epidemiological data on MRSA strains with the antagonistic resistance and to analyse their genetic features, we examined the emergence of beta-lactam inducible ABK-resistant MRSA strains at our university hospital using longitudinal analysis. Among the 396 isolates, 35 (8.8 %) were found to be ABK resistant MRSA strains (the resistance being induced by beta-lactams). Moreover, based on the pulsed-field gel electrophoresis profiles, the clonality of those MRSA strains changed at different time periods. In the Kitasato strain, the antagonistic mechanism was clearly demonstrated by the integration of transposable elements; a Tn4001-IS257 hybrid structure that contained an aminoglycoside resistance gene cointegrated into a region downstream of the beta lactamase gene. In most of the MRSA strains detected in our study, the antagonistic interaction was explained by the same mechanism as that found in the Kitasato strain. Interestingly, sequence analysis showed that all of our strains carried IS257 insertion sites which were different from those of the Kitasato strain. This study shows that MRSA strains with the additional antagonistic resistance are not uncommon and have been increasingly disseminating in clinical settings. PMID- 24493160 TI - Primary amoebic meningoencephalitis: amoebicidal effects of clinically approved drugs against Naegleria fowleri. PMID- 24493162 TI - Normalization of a NAFLD gene expression signature. PMID- 24493161 TI - Dietary patterns during high school and risk of colorectal adenoma in a cohort of middle-aged women. AB - Adolescent diet may be etiologically relevant for later risk of colorectal adenoma, a precursor of colorectal cancer. We aimed to examine associations between adolescent dietary patterns (derived using factor analysis) and risk of colorectal adenoma in middle adulthood. We analyzed data from 17,221 women participating in the Nurses' Health Study II, who had completed a validated high school (HS) food frequency questionnaire in 1998 when they were 34-51 years old, and had subsequently undergone at least one lower bowel endoscopy. Between 1998 and 2007, 1,299 women were diagnosed with at least one colorectal adenoma. In multivariable models adjusted for adult dietary patterns, a higher "prudent" pattern during HS, characterized by high consumption of vegetables, fruit and fish was associated with a statistically significantly lower risk of rectal (odds ratio [OR] highest vs. lowest quintile, 0.45, 95% CI 0.27-0.75, p-trend = 0.005), but not colon adenomas. A higher "Western" pattern during HS, characterized by high consumption of desserts and sweets, snack foods and red and processed meat, was significantly associated with rectal (OR 1.78, 95% CI 1.12-2.85, p-trend = 0.005) and advanced (OR 1.58, 95% CI 1.07-2.33, p-trend = 0.08), but not associated with colon or non-advanced adenomas. This study suggests that overall eating patterns during high school may influence later risk of rectal and advanced adenoma, independent of adult diet. Our results support the hypothesis that diet during early life may influence colorectal carcinogenesis. PMID- 24493163 TI - Diclofenac versus fluorometholone after strabismus surgery in children. AB - AIMS: To compare the effects of topical diclofenac sodium with those of fluorometholone on intraocular pressure (IOP) and conjunctival inflammation after strabismus surgery. METHODS: We retrospectively analysed 60 Korean children who underwent strabismus surgery for intermittent exotropia in an institutional referral centre. Patients received topical diclofenac 0.1% or fluorometholone 0.1% after surgery for up to 4 weeks. IOP, patient discomfort, conjunctival inflammation and conjunctival injection were evaluated at 1, 2, 3 and 4 weeks after surgery. RESULTS: In the fluorometholone group, 23% showed an increase of >=10 mm Hg compared to the baseline IOP within 4 weeks of surgery. The fluorometholone group showed a significant change in IOP compared to baseline (p<0.001) at all follow-up time points, whereas the diclofenac group showed no significant increase in IOP. An increased risk of IOP elevation of >=10 mm Hg was observed after fluorometholone use in patients under 7 years of age. There was no significant difference in patient discomfort, conjunctival inflammation or conjunctival injection between the two groups. Conjunctival injection was more pronounced with muscle resection than with recession at 1 month after surgery. CONCLUSIONS: Postoperative topical diclofenac is an excellent substitute for steroids, particularly in young children under 7 years of age. PMID- 24493164 TI - Techniques for safe organ recovery after endovascular aortic and bariatric operations. PMID- 24493165 TI - Interpretations on chloroplast reproduction derived from correlations between cells and chloroplasts. AB - The size ranges of chloroplasts in living mesophyll cells of Spinacia oleracea, Allium cepa, Beta vulgaris (Swiss chard and red beet) and Nicotiana glutinosa are extremely wide, e.g., ranging from about 6 u(2) to 103 u(2) in face area for spinach. Moreover, the size distributions are positively skewed. We interpret the size range and skewed size distributions primarily to reflect an enormous growth of the bulk of the chloroplasts from small, equal-sized chloroplasts produced by fission of a small sub-population of constricted mature chloroplasts. While actual fission has never been observed, a slow division rate of the constricted chloroplasts in N. glutinosa can account for the increase in chloroplast numbers per cell during leaf development and for the presence of small, non-constricted chloroplasts after the small chloroplasts which developed during the initial meristem activity have enlarged. Chloroplast numbers and total amount of chloroplast material per cell face were positively correlated with mesophyll-cell face size. However, the fraction of the cell face occupied with chloroplasts was essentially constant and independent of cell size and cell age while being markedly different for different species of plants. There appear to be some family characteristics in that closely related species have similar size distributions and ranges of chloroplast sizes. The observations are discussed with respect to the ontogeny of chloroplasts in higher plants. PMID- 24493166 TI - [Studies of nucleic acids and protein metabolism during initiation of adventitious roots]. AB - Changes in the metabolism of nucleic acids and proteins were followed during the initiation of adventitious roots of Cicer arietinum. During the first 24 h, several phases of activation of the metabolism were found. The use of inhibitors of RNA synthesis showed that an early phase of incorporation of precursors into RNA is essential for the initiation phenomena. This phase is more sensitive to inhibitors and activators (hormones) than all other phases. The rapid turn-over of RNA synthesized during the first 6 h and the inefficience of inhibitors after this time suggested that a stable (non-RNA) factor maintains the activation. This factor must be synthesized soon after the stimulus of cutting. PMID- 24493167 TI - Ouabain-insensitive K influx in Hydrodictyon africanum. AB - The occurrence is reported of cells of Hydrodictyon africanum which have, contrary to previous reports by the author, a K influx which is almost insensitive to ouabain. The conditions which govern the ouabain-sensitivity of the K influx have not yet been defined. The low ouabain sensitivity of the total K influx seems to be related to a smaller than usual activity of the component of K influx which is linked to Na efflux, and also to a smaller sensitivity of this component to inhibition by ouabain. The major components of K influx in ouabain insensitive cells correspond to those components previously described as the passive and Cl-linked components.The occurrence is also reported of an increased sensitivity of active Cl influx (and the coupled cation influxes) in the light to uncouplers when the medium is aerated or otherwise stirred. PMID- 24493168 TI - RNA synthesis and the germination of light-sensitive lettuce seeds. AB - The germination of lettuce seeds is inhibited by the nucleotide base analogue 6 methylpurine. RNA synthesis has been measured during imbibition and germination as (32)P-phosphate incorporation into RNA species as fractionated by polyacrylamide gel electrophoresis. Seeds were surface sterilized and imbibed in the presence of various antibiotics. RNA preparations from lettuce seeds were coelectrophoresed with (3)H-RNA prepared from bacteria to check for bacterial contamination of the seeds. There is a much higher rate of RNA synthesis in illuminated, germinating seeds as compared to dark, non-germinating seeds. This difference does not develop until after 12 hours of imbibition at 27 degrees , which is the time of onset of germination and radicle growth. PMID- 24493169 TI - Influence of IAA upon the longitudinal and tangential movement of labelled sugars in the phloem of Willow. AB - Using a bark abrasion technique, the influence of IAA upon patterns of sugar translocation in isolated stem segments of Willow (Salix viminalis L.) has been studied. IAA was found to exert a considerable influence over translocation in both a longidutinal and tangential direction. Studies on longitudinal movement have led to the postulation of two possible effects of IAA on this system. Firstly a stimulation of sugar loading from the storage parenchyma into the sieve elements as described by Lepp and Peel (1970), and secondly a direct effect upon, the longitudinal transport process. The situation with regard to the tangential transport system is not as clear in all its aspects, though once again it is postulated that IAA may have a direct effect upon the movement of sugars in the tangential transport system. PMID- 24493170 TI - [Fine structure of sieve-tube plastids of Aristolochia and Asarum (Aristolochiaceae)]. AB - Sieve-tube plastids of Aristolochia (5 species investigated) contain several starch grains and always one large crystalloid. In Asarum (3 species investigated) starch has not been found in the sieve-tubes. Their plastids contain several cuneate crystalloids that are sometimes arranged around an invisible centre. Asarum sieve-tube plastids look almost like typical plastids of monocotyledon sieve-tubes.-Crystalloids of Aristolochia and of Asarum sieve-tube plastids are composed of 50-60 A subunits in straight and parallel order as crystalloids in monocotyledon sieve-tube plastids are.The results of the investigations of the fine structure are discussed in relation to the position of the Aristolochiaceae in the system of angiosperms. PMID- 24493171 TI - Sequential changes in amylase isozymes during grain maturation in barley. AB - Changes in amylase isozyme patterns on polyacrylamide gels were followed during maturation in grains of Deba Abed barley. Early stage seeds contained a single, high-mobility enzyme (Band A) which had an estimated molecular weight of 4.2*10(4) and a high activity with beta-limit dextrin as a substrate. It was shown, by dissection, that Band A was confined to the aleurone layer and probably represented the initial product of amylase synthesis.This form was succeeded, in mid-course, by a less mobile form (Band B), a beta-amylase with a molecular weight of approximately 1.3*10(5). Late-dough stage grains contained a complex of low-mobility beta-amylase bands which were shown, by papain digestion, to be protein-bound forms of Band B.The changes are discussed on the basis of a unified series consisting of elaborated forms of the initial Band A type of activity. PMID- 24493172 TI - Rapid action of abscisic acid on photosynthesis and stomatal resistance. AB - (RS)-Abscisic acid, a natural plant hormone, has been found to inhibit photosynthesis in both detached and attached primary wheat leaves. The action occurs rapidly and is accompanied by large increases in stomatal diffusive resistance. PMID- 24493174 TI - Corrigendum. PMID- 24493173 TI - Abscission: Control of cellulase secretion by ethylene. AB - Ethylene was found to be required for the release or secretion of cellulase from the cytoplasm to the cell wall in bean-petiole abscission-zone explants. This is an addition to its previously known action in accelerating senescence and cellulase synthesis in abscission. PMID- 24493175 TI - Cord transection in monoamniotic twins: use of a 1000-micron fiber with conical tip. PMID- 24493176 TI - The breadth of orthopaedics: in print and on the web. PMID- 24493177 TI - The current state of bearing surfaces in total hip replacement. AB - We reviewed the literature on the currently available choices of bearing surface in total hip replacement (THR). We present a detailed description of the properties of articulating surfaces review the understanding of the advantages and disadvantages of existing bearing couples. Recent technological developments in the field of polyethylene and ceramics have altered the risk of fracture and the rate of wear, although the use of metal-on-metal bearings has largely fallen out of favour, owing to concerns about reactions to metal debris. As expected, all bearing surface combinations have advantages and disadvantages. A patient based approach is recommended, balancing the risks of different options against an individual's functional demands. PMID- 24493178 TI - Acetabular fractures in patients aged > 55 years: a systematic review of the literature. AB - The increasing prevalence of osteoporosis in an ageing population has contributed to older patients becoming the fastest-growing group presenting with acetabular fractures. We performed a systematic review of the literature involving a number of databases to identify studies that included the treatment outcome of acetabular fractures in patients aged > 55 years. An initial search identified 61 studies; after exclusion by two independent reviewers, 15 studies were considered to meet the inclusion criteria. All were case series. The mean Coleman score for methodological quality assessment was 37 (25 to 49). There were 415 fractures in 414 patients. Pooled analysis revealed a mean age of 71.8 years (55 to 96) and a mean follow-up of 47.3 months (1 to 210). In seven studies the results of open reduction and internal fixation (ORIF) were presented: this was combined with simultaneous hip replacement (THR) in four, and one study had a mixture of these strategies. The results of percutaneous fixation were presented in two studies, and a single study revealed the results of non-operative treatment. With fixation of the fracture, the overall mean rate of conversion to THR was 23.1% (0% to 45.5%). The mean rate of non-fatal complications was 39.8% (0% to 64%), and the mean mortality rate was 19.1% (5% to 50%) at a mean of 64 months (95% confidence interval 59.4 to 68.6; range 12 to 143). Further data dealing with the classification of the fracture, the surgical approach used, operative time, blood loss, functional and radiological outcomes were also analysed. This study highlights that, of the many forms of treatment available for this group of patients, there is a trend to higher complication rates and the need for further surgery compared with the results of the treatment of acetabular fractures in younger patients. PMID- 24493179 TI - Osteochondral lesions of the talus: aspects of current management. AB - Osteochondral lesions (OCLs) occur in up to 70% of sprains and fractures involving the ankle. Atraumatic aetiologies have also been described. Techniques such as microfracture, and replacement strategies such as autologous osteochondral transplantation, or autologous chondrocyte implantation are the major forms of surgical treatment. Current literature suggests that microfracture is indicated for lesions up to 15 mm in diameter, with replacement strategies indicated for larger or cystic lesions. Short- and medium-term results have been reported, where concerns over potential deterioration of fibrocartilage leads to a need for long-term evaluation. Biological augmentation may also be used in the treatment of OCLs, as they potentially enhance the biological environment for a natural healing response. Further research is required to establish the critical size of defect, beyond which replacement strategies should be used, as well as the most appropriate use of biological augmentation. This paper reviews the current evidence for surgical management and use of biological adjuncts for treatment of osteochondral lesions of the talus. PMID- 24493180 TI - Are cam and pincer deformities as common as dysplasia in Japanese patients with hip pain? AB - In Japan, osteoarthritis (OA) of the hip secondary to acetabular dysplasia is very common, and there are few data concerning the pathogeneses and incidence of femoroacetabular impingement (FAI). We have attempted to clarify the radiological prevalence of painful FAI in a cohort of Japanese patients and to investigate the radiological findings. We identified 176 symptomatic patients (202 hips) with Tonnis grade 0 or 1 osteoarthritis, whom we prospectively studied between August 2011 and July 2012. There were 61 men (65 hips) and 115 women (137 hips) with a mean age of 51.8 years (11 to 83). Radiological analyses included the alpha angle, centre-edge angle, cross-over sign, pistol grip deformity and femoral head neck ratio. Of the 202 hips, 79 (39.1%) had acetabular dysplasia, while 80 hips (39.6%) had no known aetiology. We found evidence of FAI in 60 hips (29.7%). Radiological FAI findings associated with cam deformity were the most common. There was a significant relationship between the pistol grip deformity and both the alpha-angle (p < 0.001) and femoral head-neck ratio (p = 0.024). Radiological evidence of symptomatic FAI was not uncommon in these Japanese patients. PMID- 24493181 TI - Establishment of a hip replacement project in a district hospital in Burkina Faso: analysis of technical problems and peri-operative complications. AB - Total hip replacement (THR) still is a rare intervention in many African countries. In Burkina Faso it is not performed on a regular basis. A visiting programme for THR was started in a district hospital with no previous relevant experience. In this paper we present an analysis of the surgical technical problems and peri-operative complications of 152 THRs in 136 patients and three bipolar hemiarthroplasties in three patients undertaken in this new programme with limited orthopaedic equipment. There were 86 male and 53 female patients with a mean age of 49 years (21 to 78). We identified 77 intra-operative technical problems in 51 operations. There were 24 peri-operative complications in 21 patients, 17 of which were bony in nature. So far, ten revision THRs have been performed in nine patients. Regular analysis of the technical problems and complications was used to improve quality, and we identified patient selection adapted to the local circumstances as important to avoid complications. Our reflections on the problems encountered in initiating such a programme may be of help to other teams planning similar projects. PMID- 24493182 TI - An estimation of the incidence of squeaking and revision surgery for squeaking in ceramic-on-ceramic total hip replacement: a meta-analysis and report from the Australian Orthopaedic Association National Joint Registry. AB - Squeaking arising from a ceramic-on-ceramic (CoC) total hip replacement (THR) may cause patient concern and in some cases causes patients to seek revision surgery. We performed a meta-analysis to determine the incidence of squeaking and the incidence of revision surgery for squeaking. A total of 43 studies including 16,828 CoC THR that reported squeaking, or revision for squeaking, were entered into the analysis. The incidence of squeaking was 4.2% and the incidence of revision for squeaking was 0.2%. The incidence of squeaking in patients receiving the Accolade femoral stem was 8.3%, and the incidence of revision for squeaking in these patients was 1.3%. PMID- 24493183 TI - Clinical and radiographic outcomes of acetabular impaction grafting without cage reinforcement for revision hip replacement: a minimum ten-year follow-up study. AB - Impaction bone grafting for the reconstitution of bone stock in revision hip surgery has been used for nearly 30 years. Between 1995 and 2001 we used this technique in acetabular reconstruction, in combination with a cemented component, in 304 hips in 292 patients revised for aseptic loosening. The only additional supports used were stainless steel meshes placed against the medial wall or laterally around the acetabular rim to contain the graft. All Paprosky grades of defect were included. Clinical and radiographic outcomes were collected in surviving patients at a minimum of ten years after the index operation. Mean follow-up was 12.4 years (sd 1.5) (10.0 to 16.0). Kaplan-Meier survival with revision for aseptic loosening as the endpoint was 85.9% (95% CI 81.0 to 90.8) at 13.5 years. Clinical scores for pain relief remained satisfactory, and there was no difference in clinical scores between cups that appeared stable and those that appeared radiologically loose. PMID- 24493184 TI - The challenge of pelvic discontinuity: cup-cage reconstruction does better than conventional cages in mid-term. AB - The use of ilioischial cage reconstruction for pelvic discontinuity has been replaced by the Trabecular Metal (Zimmer, Warsaw, Indiana) cup-cage technique in our institution, due to the unsatisfactory outcome of using a cage alone in this situation. We report the outcome of 26 pelvic discontinuities in 24 patients (20 women and four men, mean age 65 years (44 to 84)) treated by the cup-cage technique at a mean follow-up of 82 months (12 to 113) and compared them with a series of 19 pelvic discontinuities in 19 patients (18 women and one man, mean age 70 years (42 to 86)) treated with a cage at a mean follow-up of 69 months (1 to 170). The clinical and radiological outcomes as well as the survivorship of the groups were compared. In all, four of the cup-cage group (15%) and 13 (68%) of the cage group failed due to septic or aseptic loosening. The seven-year survivorship was 87.2% (95% confidence interval (CI) 71 to 103) for the cup-cage group and 49.9% (95% CI 15 to 84) for the cage-alone group (p = 0.009). There were four major complications in the cup-cage group and nine in the cage group. Radiological union of the discontinuity was found in all successful cases in the cup-cage group and three of the successful cage cases. Three hips in the cup-cage group developed early radiological migration of the components, which stabilised with a successful outcome. Cup-cage reconstruction is a reliable technique for treating pelvic discontinuity in mid-term follow-up and is preferred to ilioischial cage reconstruction. If the continuity of the bone graft at the discontinuity site is not disrupted, early migration of the components does not necessarily result in failure. PMID- 24493185 TI - The influence of immediate knee flexion on blood loss and other parameters following total knee replacement. AB - In an initial randomised controlled trial (RCT) we segregated 180 patients to one of two knee positions following total knee replacement (TKR): six hours of knee flexion using either a jig or knee extension. Outcome measures included post operative blood loss, fall in haemoglobin, blood transfusion requirements, knee range of movement, limb swelling and functional scores. A second RCT consisted of 420 TKR patients randomised to one of three post-operative knee positions: flexion for three or six hours post-operatively, or knee extension. Positioning of the knee in flexion for six hours immediately after surgery significantly reduced blood loss (p = 0.002). There were no significant differences in post operative range of movement, swelling, pain or outcome scores between the various knee positions in either study. Post-operative knee flexion may offer a simple and cost-effective way to reduce blood loss and transfusion requirements following TKR. We also report a cautionary note regarding the potential risks of prolonged knee flexion for more than six hours observed during clinical practice in the intervening period between the two trials, with 14 of 289 patients (4.7%) reporting lower limb sensory neuropathy at their three-month review. PMID- 24493186 TI - Effects of psychological distress and perceptions of illness on recovery from total knee replacement. AB - This cohort study investigated the influence of psychological factors, including perception of illness, anxiety and depression on recovery and functional outcome after total knee replacement surgery. A total of 100 patients (55 male; 45 female) with a mean age of 71 (42 to 92) who underwent a primary total knee replacement for osteoarthritis were recruited into this study. In all 97 participants completed the six week and 87 the one year follow-up questionnaires. Pre-operatively patients completed the revised Illness Perception Questionnaire, Hospital Anxiety and Depression Scale and Recovery Locus of Control Scale. Function was assessed pre-operatively, at six weeks and one year using Oxford Knee Score (OKS) and the goniometer-measured range of movement (ROM). The results showed that pre-operative function had the biggest impact on post-operative outcome for ROM and OKS. In addition questionnaire variables and depression had an impact on the OKS at six weeks. Depression and anxiety were also associated with a higher (worse) knee score at one year but did not influence the ROM at either six weeks or one year. Recovery from total knee replacement can be difficult to predict. This study has identified psychological factors that play an important role in recovery from surgery and functional outcome. These should be taken into account when considering patients for total knee replacement. PMID- 24493187 TI - Increased risk of revision for high flexion total knee replacement with thicker tibial liners. AB - The outcome of total knee replacement (TKR) using components designed to increase the range of flexion is not fully understood. The short- to mid-term risk of aseptic revision in high flexion TKR was evaluated. The endpoint of the study was aseptic revision and the following variables were investigated: implant design (high flexion vs non-high flexion), the thickness of the tibial insert (<= 14 mm vs > 14 mm), cruciate ligament (posterior stabilised (PS) vs cruciate retaining), mobility (fixed vs rotating), and the manufacturer (Zimmer, Smith & Nephew and DePuy). Covariates included patient, implant, surgeon and hospital factors. Marginal Cox proportional hazard models were used. In a cohort of 64 000 TKRs, high flexion components were used in 8035 (12.5%). The high flexion knees with tibial liners of thickness > 14 mm had a density of revision of 1.45/100 years of observation, compared with 0.37/100 in non-high flexion TKR with liners <= 14 mm thick. Relative to a standard fixed PS TKR, the NexGen (Zimmer, Warsaw, Indiana) Gender Specific Female high flexion fixed PS TKR had an increased risk of revision (hazard ratio (HR) 2.27 (95% confidence interval (CI) 1.48 to 3.50)), an effect that was magnified when a thicker tibial insert was used (HR 8.10 (95% CI 4.41 to 14.89)). Surgeons should be cautious when choosing high flexion TKRs, particularly when thicker tibial liners might be required. PMID- 24493188 TI - Anatomical total shoulder replacement with rotator cuff repair for osteoarthritis of the shoulder. AB - We assessed the clinical results, radiographic outcomes and complications of patients undergoing total shoulder replacement (TSR) for osteoarthritis with concurrent repair of a full-thickness rotator cuff tear. Between 1996 and 2010, 45 of 932 patients (4.8%) undergoing TSR for osteoarthritis underwent rotator cuff repair. The final study group comprised 33 patients with a mean follow-up of 4.7 years (3 months to 13 years). Tears were classified into small (10), medium (14), large (9) or massive (0). On a scale of 1 to 5, pain decreased from a mean of 4.7 to 1.7 (p = < 0.0001), the mean forward elevation improved from 99 degrees to 139 degrees (p = < 0.0001), and the mean external rotation improved from 20 degrees (0 degrees to 75 degrees ) to 49 degrees (20 degrees to 80 degrees ) (p = < 0.0001). The improvement in elevation was greater in those with a small tear (p = 0.03). Radiographic evidence of instability developed in six patients with medium or large tears, indicating lack of rotator cuff healing. In all, six glenoid components, including one with instability, were radiologically at risk of loosening. Complications were noted in five patients, all with medium or large tears; four of these had symptomatic instability and one sustained a late peri prosthetic fracture. Four patients (12%) required further surgery, three with instability and one with a peri-prosthetic humeral fracture. Consideration should be given to performing rotator cuff repair for stable shoulders during anatomical TSR, but reverse replacement should be considered for older, less active patients with larger tears. PMID- 24493189 TI - Stable fixation of the IBP humeral component implanted without cement in total elbow replacement: a radiostereometric analysis study of 16 elbows at two-year follow-up. AB - We determined the short-term clinical outcome and migration within the bone of the humeral cementless component of the Instrumented Bone Preserving (IBP) total elbow replacement in a series of 16 patients. There were four men and 12 women with a mean age at operation of 63 years (40 to 81). Migration was calculated using radiostereometric analysis. There were no intra-operative complications and no revisions. At two-year follow-up, all patients showed a significant reduction in pain and functional improvement of the elbow (both p < 0.001). Although ten components (63%) showed movement or micromovement during the first six weeks, 14 (88%) were stable at one year post-operatively. Translation was primarily found in the proximal direction (median 0.3 mm (interquartile range (IQR) -0.09 to 0.8); the major rotational movement was an anterior tilt (median 0.7 degrees (IQR 0.4 degrees to 1.6 degrees )). One malaligned component continued to migrate during the second year, and one component could not be followed beyond three months because migration had caused the markers to break off the prosthesis. This study shows promising early results for the cementless humeral component of the IBP total elbow replacement. All patients had a good clinical outcome, and most components stabilised within six months of the operation. PMID- 24493190 TI - Arthroscopic debridement in the treatment of patients with osteoarthritis of the elbow, based on computer simulation. AB - We retrospectively assessed the value of identifying impinging osteophytes using dynamic computer simulation of CT scans of the elbow in assisting their arthroscopic removal in patients with osteoarthritis of the elbow. A total of 20 patients were treated (19 men and one woman, mean age 38 years (19 to 55)) and followed for a mean of 25 months (24 to 29). We located the impinging osteophytes dynamically using computerised three-dimensional models of the elbow based on CT data in three positions of flexion of the elbow. These were then removed arthroscopically and a capsular release was performed. The mean loss of extension improved from 23 degrees (10 degrees to 45 degrees ) pre-operatively to 9 degrees (0 degrees to 25 degrees ) post-operatively, and the mean flexion improved from 121 degrees (80 degrees to 140 degrees ) pre-operatively to 130 degrees (110 degrees to 145 degrees ) post-operatively. The mean Mayo Elbow Performance Score improved from 62 (30 to 85) to 95 (70 to 100) post-operatively. All patients had pain in the elbow pre-operatively which disappeared or decreased post-operatively. According to their Mayo scores, 14 patients had an excellent clinical outcome and six a good outcome; 15 were very satisfied and five were satisfied with their post-operative outcome. We recommend this technique in the surgical management of patients with osteoarthritis of the elbow. PMID- 24493191 TI - Sleep apnoea adversely affects the outcome in patients who undergo posterior lumbar fusion: a population-based study. AB - Despite the increasing prevalence of sleep apnoea, little information is available regarding its impact on the peri-operative outcome of patients undergoing posterior lumbar fusion. Using a national database, patients who underwent lumbar fusion between 2006 and 2010 were identified, sub-grouped by diagnosis of sleep apnoea and compared. The impact of sleep apnoea on various outcome measures was assessed by regression analysis. The records of 84,655 patients undergoing posterior lumbar fusion were identified and 7.28% (n = 6163) also had a diagnostic code for sleep apnoea. Compared with patients without sleep apnoea, these patients were older, more frequently female, had a higher comorbidity burden and higher rates of peri-operative complications, post operative mechanical ventilation, blood product transfusion and intensive care. Patients with sleep apnoea also had longer and more costly periods of hospitalisation. In the regression analysis, sleep apnoea emerged as an independent risk factor for the development of peri-operative complications (odds ratio (OR) 1.50, confidence interval (CI) 1.38;1.62), blood product transfusions (OR 1.12, CI 1.03;1.23), mechanical ventilation (OR 6.97, CI 5.90;8.23), critical care services (OR 1.86, CI 1.71;2.03), prolonged hospitalisation and increased cost (OR 1.28, CI 1.19;1.37; OR 1.10, CI 1.03;1.18). Patients with sleep apnoea who undergo posterior lumbar fusion pose significant challenges to clinicians. PMID- 24493192 TI - Lack of fifth anchoring point and violation of the insertion of the rotator cuff during antegrade humeral nailing: pitfalls in straight antegrade humeral nailing. AB - Antegrade nailing of proximal humeral fractures using a straight nail can damage the bony insertion of the supraspinatus tendon and may lead to varus failure of the construct. In order to establish the ideal anatomical landmarks for insertion of the nail and their clinical relevance we analysed CT scans of bilateral proximal humeri in 200 patients (mean age 45.1 years (sd 19.6; 18 to 97) without humeral fractures. The entry point of the nail was defined by the point of intersection of the anteroposterior and lateral vertical axes with the cortex of the humeral head. The critical point was defined as the intersection of the sagittal axis with the medial limit of the insertion of the supraspinatus tendon on the greater tuberosity. The region of interest, i.e. the biggest entry hole that would not encroach on the insertion of the supraspinatus tendon, was calculated setting a 3 mm minimal distance from the critical point. This identified that 38.5% of the humeral heads were categorised as 'critical types', due to morphology in which the predicted offset of the entry point would encroach on the insertion of the supraspinatus tendon that may damage the tendon and reduce the stability of fixation. We therefore emphasise the need for 'fastidious' pre-operative planning to minimise this risk. PMID- 24493193 TI - Disability following combat-sustained nerve injury of the upper limb. AB - Injuries to the limb are the most frequent cause of permanent disability following combat wounds. We reviewed the medical records of 450 soldiers to determine the type of upper limb nerve injuries sustained, the rate of remaining motor and sensory deficits at final follow-up, and the type of Army disability ratings granted. Of 189 soldiers with an injury of the upper limb, 70 had nerve related trauma. There were 62 men and eight women with a mean age of 25 years (18 to 49). Disabilities due to nerve injuries were associated with loss of function, neuropathic pain or both. The mean nerve-related disability was 26% (0% to 70%), accounting for over one-half of this cohort's cumulative disability. Patients injured in an explosion had higher disability ratings than those injured by gunshot. The ulnar nerve was most commonly injured, but most disability was associated with radial nerve trauma. In terms of the final outcome, at military discharge 59 subjects (84%) experienced persistent weakness, 48 (69%) had a persistent sensory deficit and 17 (24%) experienced chronic pain from scar related or neuropathic pain. Nerve injury was the cause of frequent and substantial disability in our cohort of wounded soldiers. PMID- 24493194 TI - The influence of age, gender and treatment with steroids on the incidence of osteonecrosis of the femoral head during the management of severe acute respiratory syndrome: a retrospective study. AB - Corticosteroid use has been implicated in the development of osteonecrosis of the femoral head (ONFH). The exact mechanism and predisposing factors such as age, gender, dosage, type and combination of steroid treatment remain controversial. Between March and July 2003, a total of 539 patients with severe acute respiratory syndrome (SARS) were treated with five different types of steroid. There were 129 men (24%) and 410 women (76%) with a mean age of 33.7 years (21 to 59). Routine screening was undertaken with radiographs, MRI and/or CT to determine the incidence of ONFH. Of the 129 male patients with SARS, 51 (39.5%) were diagnosed as suffering from ONFH, compared with only 79 of 410 female patients (19.3%). The incidence of ONFH in the patients aged between 20 and 49 years was much higher than that of the group aged between 50 and 59 years (25.9% (127 of 491) versus 6.3% (3 of 48); p = 0.018). The incidence of ONFH in patients receiving one type of steroid was 12.5% (21 of 168), which was much lower than patients receiving two different types (28.6%; 96 of 336) or three different types of steroid (37.1%; 13 of 35). PMID- 24493196 TI - Immediate soft-tissue reconstruction using a rectus abdominis myocutaneous flap following wide resection of malignant bone tumours of the pelvis. AB - Resection of malignant bony tumours of the pelvis creates large bone and soft tissue defects, and is frequently associated with complications such as wound dehiscence and deep infection. We present the results of six patients in whom a rectus abdominis myocutaneous (RAM) flap was used following resection of a malignant tumour of the pelvis. Bony reconstruction was performed using a constrained hip tumour prosthesis in three patients, vascularised fibular graft in two and frozen autograft in one. At a mean follow-up of 63 months (16 to 115), no patients had a problem with the wound. Immediate reconstruction using a RAM flap may be used after resection of a malignant tumour of the pelvis to provide an adequate volume of tissue to eliminate the dead space, cover the exposed bone or implants with well-vascularised soft tissue and to reduce the risk of complications. PMID- 24493195 TI - Uncemented, custom-made, hydroxyapatite-coated collared distal femoral endoprostheses: up to 18 years' follow-up. AB - We reviewed the outcome of 69 uncemented, custom-made, distal femoral endoprosthetic replacements performed in 69 patients between 1994 and 2006. There were 31 women and 38 men with a mean age at implantation of 16.5 years (5 to 37). All procedures were performed for primary malignant bone tumours of the distal femur. At a mean follow-up of 124.2 months (4 to 212), 53 patients were alive, with one patient lost to follow-up. All nine implants (13.0%) were revised due to aseptic loosening at a mean of 52 months (8 to 91); three implants (4.3%) were revised due to fracture of the shaft of the prosthesis and three patients (4.3%) had a peri-prosthetic fracture. Bone remodelling associated with periosteal cortical thinning adjacent to the uncemented intramedullary stem was seen in 24 patients but this did not predispose to failure. All aseptically loose implants in this series were diagnosed to be loose within the first five years. The results from this study suggest that custom-made uncemented distal femur replacements have a higher rate of aseptic loosening compared to published results for this design when used with cemented fixation. Loosening of uncemented replacements occurs early indicating that initial fixation of the implant is crucial. PMID- 24493197 TI - Reverse Ponseti-type treatment for children with congenital vertical talus: comparison between idiopathic and teratological patients. AB - Children with congenital vertical talus (CVT) have been treated with extensive soft-tissue releases, with a high rate of complications. Recently, reverse Ponseti-type casting followed by percutaneous reduction and fixation has been described, with excellent results in separate cohorts of children with CVT, of either idiopathic or teratological aetiology. There are currently no studies that compare the outcome in these two types. We present a prospective cohort of 13 children (21 feet) with CVT of both idiopathic and teratological aetiology, in which this technique has been used. Clinical, radiological and parent-reported outcomes were obtained at a mean follow-up of 36 months (8 to 57). Six children (nine feet) had associated neuromuscular conditions or syndromes; the condition was idiopathic in seven children (12 feet). Initial correction was achieved in all children, with significant improvement in all radiological parameters. Recurrence was seen in ten feet. Modification of the technique to include limited capsulotomy at the initial operation may reduce the risk of recurrence. The reverse Ponseti-type technique is effective in the initial correction of CVT of both idiopathic and teratological aetiology. Recurrence is a problem in both these groups, with higher rates than first reported in the original paper. However, these rates are less than those reported after open surgical release. PMID- 24493198 TI - The incidence of avascular necrosis and the radiographic outcome following medial open reduction in children with developmental dysplasia of the hip: a systematic review. AB - The incidence of clinically significant avascular necrosis (AVN) following medial open reduction of the dislocated hip in children with developmental dysplasia of the hip (DDH) remains unknown. We performed a systematic review of the literature to identify all clinical studies reporting the results of medial open reduction surgery. A total of 14 papers reporting 734 hips met the inclusion criteria. The mean follow-up was 10.9 years (2 to 28). The rate of clinically significant AVN (types 2 to 4) was 20% (149/734). From these papers 221 hips in 174 children had sufficient information to permit more detailed analysis. The rate of AVN increased with the length of follow-up to 24% at skeletal maturity, with type 2 AVN predominating in hips after five years' follow-up. The presence of AVN resulted in a higher incidence of an unsatisfactory outcome at skeletal maturity (55% vs 20% in hips with no AVN; p < 0.001). A higher rate of AVN was identified when surgery was performed in children aged < 12 months, and when hips were immobilised in >= 60 degrees of abduction post-operatively. Multivariate analysis showed that younger age at operation, need for further surgery and post operative hip abduction of >= 60 degrees increased the risk of the development of clinically significant AVN. PMID- 24493200 TI - Assessment of age-related changes in heritability and IGF-1 gene effect on circulating IGF-1 levels. AB - It is well established that insulin-like growth factor 1 (IGF-1) circulating levels correlate with age and that heritability and influence of IGF-1 gene variation on IGF-1 levels also well-known. However, the influence of age on the genetic factors determining IGF-1 levels is not clear. In this study, we compared heritability estimates between younger (<52 years) and older (>52 years) twins and tested: (a) whether single nucleotide polymorphisms (SNPs) lying within 100 kbp of the IGF-1 gene are also associated with IGF-1 variation and (b) whether associated SNPs show interaction with age on IGF-1 levels. To achieve these aims, we measured plasma levels of IGF-1 and genotyped 18 SNPs with minor allele frequency >0.1 in a large sample, 4,471 UK female twins. Heritability explained 42 % of IGF-1 variation adjusted for age and in unadjusted sample was independent of age. Ten SNPs in four haploblocks showed significant association with IGF-1 levels, with p = 0.01-0.0005. The most distal SNP was located up to 90 kbp from the IGF-1 gene. When their age-dependent effects were examined, one SNP, rs855203, showed significant (p = 0.0009) age-dependent interaction effect on IGF 1 levels variation. This is the first study to test the age * genotype interaction in IGF-1 levels. The genomic region marked by rs855203 may consequently be of significance for further molecular and pharmacogenetic research, in particular in advanced age. PMID- 24493201 TI - In vivo activation of the PI3K-Akt pathway in mouse beta cells by the EGFR mutation L858R protects against diabetes. AB - AIMS/HYPOTHESIS: EGF receptor (EGFR) signalling is required for normal beta cell development and postnatal beta cell proliferation. We tested whether beta cell proliferation can be triggered by EGFR activation at any age and whether this can protect beta cells against apoptosis induced by diabetogenic insults in a mouse model. METHODS: We generated transgenic mice with doxycycline-inducible expression of constitutively active EGFR (L858R) (CA-EGFR) under the insulin promoter. Mice were given doxycycline at various ages for different time periods, and beta cell proliferation and mass were analysed. Mice were also challenged with streptozotocin and isolated islets exposed to cytokines. RESULTS: Expression of EGFR (L858R) led to increased phosphorylation of EGFR and Akt in pancreatic islets. CA-EGFR expression during pancreatic development (embryonic day [E]12.5 to postnatal day [P]1) increased beta cell proliferation and mass in newborn mice. However, CA-EGFR expression in adult mice did not affect beta cell mass. Expression of the transgene improved glycaemia and markedly inhibited beta cell apoptosis after a single high dose, as well as after multiple low doses of streptozotocin. In vitro mechanistic studies showed that CA-EGFR protected isolated islets from cytokine-mediated beta cell death, possibly by repressing the proapoptotic protein BCL2-like 11 (BIM). CONCLUSIONS/INTERPRETATION: Our findings show that the expression of CA-EGFR in the developing, but not in the adult pancreas stimulates beta cell replication and leads to increased beta cell mass. Importantly, CA-EGFR protects beta cells against streptozotocin- and cytokine-induced death. PMID- 24493202 TI - Fetuin-A influences vascular cell growth and production of proinflammatory and angiogenic proteins by human perivascular fat cells. AB - AIMS/HYPOTHESIS: Fetuin-A (alpha2-Heremans-Schmid glycoprotein), a liver-derived circulating glycoprotein, contributes to lipid disorders, diabetes and cardiovascular diseases. In a previous study we found that perivascular fat cells (PVFCs) have a higher angiogenic potential than other fat cell types. The aim was to examine whether fetuin-A influences PVFC and vascular cell growth and the expression and secretion of proinflammatory and angiogenic proteins, and whether TLR4-independent pathways are involved. METHODS: Mono- and co-cultures of human PVFCs and endothelial cells were treated with fetuin-A and/or palmitate for 6-72 h. Proteins were quantified by ELISA and Luminex, mRNA expression by real-time PCR, and cell growth by BrDU-ELISA. Some PVFCs were preincubated with a nuclear factor kappaB NFkappaBp65 inhibitor, or the toll-like receptor 4 (TLR4) inhibitor CLI-095, or phosphoinositide 3-kinase (PI3K)/Akt inhibitors and/or stimulated with insulin. Intracellular forkhead box protein O1 (FoxO1), NFkappaBp65 and inhibitor of kappaB kinase beta (IKKbeta) localisation was visualised by immunostaining. RESULTS: PVFCs expressed and secreted IL-6, IL-8, plasminogen activator inhibitor 1 (PAI-1), basic fibroblast growth factor (bFGF), platelet derived growth factor (PDGF)-BB, monocyte chemotactic protein-1 (MCP-1), vascular endothelial growth factor (VEGF), placental growth factor (PLGF) and hepatocyte growth factor (HGF). Fetuin-A upregulated IL-6 and IL-8, and this was potentiated by palmitate and blocked by CLI-095. Immunostaining and electrophoretic mobility shift assay (EMSA) showed partial NFkappaBp65 activation. MCP-1 was upregulated and blocked by CLI-095, but not by palmitate. However, HGF was downregulated, which was slightly potentiated by palmitate. This effect persisted after TLR4 pathway blockade. Stimulation of insulin-PI3K-Akt signalling by insulin resulted in nuclear FoxO1 extrusion and HGF upregulation. Fetuin-A counteracted these insulin effects. CONCLUSIONS/INTERPRETATION: Fetuin-A and/or palmitate influence the expression of proinflammatory and angiogenic proteins only partially via TLR4 signalling. HGF downregulation seems to be mediated by interference with the insulin-dependent receptor tyrosine kinase pathway. Fetuin-A may also influence angiogenic and proinflammatory proteins involved in atherosclerosis. PMID- 24493203 TI - Strategic targeting of advance care planning interventions: the Goldilocks phenomenon. AB - Strategically selecting patients for discussions and documentation about limiting life-sustaining treatments-choosing the right time along the end-of-life trajectory for such an intervention and identifying patients at high risk of facing end-of-life decisions-can have a profound impact on the value of advance care planning (ACP) efforts. Timing is important because the completion of an advance directive (AD) too far from or too close to the time of death can lead to end-of-life decisions that do not optimally reflect the patient's values, goals, and preferences: a poorly chosen target patient population that is unlikely to need an AD in the near future may lead to patients making unrealistic, hypothetical choices, while assessing preferences in the emergency department or hospital in the face of a calamity is notoriously inadequate. Because much of the currently studied ACP efforts have led to a disappointingly small proportion of patients eventually benefitting from an AD, careful targeting of the intervention should also improve the efficacy of such projects. A key to optimal timing and strategic selection of target patients for an ACP program is prognostication, and we briefly highlight prognostication tools and studies that may point us toward high-value AD interventions. PMID- 24493204 TI - Superficial blood flow of the superior labrum associated with rotator cuff tear using laser Doppler flowmeter. AB - INTRODUCTION: Superior labrum anterior and posterior (SLAP) lesions due to overuse by repeated pitching motion and trauma are often noted and usually. However, shoulder disorders with a chronic course are often accompanied by SLAP lesions. SLAP lesions are frequently observed during arthroscopic surgery of the shoulder joint for rotator cuff tear in middle-aged and elderly individuals, suggesting the involvement of factors other than pitching motion and traumatic events in the pathogenesis. We considered that blood flow in the labrum is altered. The purpose of this study was to clarify the superficial blood flow in the superior labrum during arthroscopic surgery of the rotator cuff tear and investigate whether it is altered with labrum injury. MATERIALS AND METHODS: We evaluated 33 subjects with a mean age of 55.1 years who underwent arthroscopic surgery for partial or complete rotator cuff tears. The blood flow measurement site for the superior labrum was set at the supraglenoid tubercle attachment site, and blood flow was measured twice using laser Doppler flowmeter. The mean was calculated and compared among the normal labrum and type 1 SLAP lesions. RESULTS: The morphology of the labrum was normal in 16 subjects, and 17 subjects had type 1 SLAP lesions. The mean blood flow was 1.75 ml/min/100 g in subjects with a normal labrum; however, in subjects with type 1 SLAP lesions, blood flow was 1.32 ml/min/100 g, showing significant differences (P < 0.01). CONCLUSION: Superficial blood flow in the superior labrum of the shoulder with rotator cuff tear was measured using laser Doppler flowmetry. The blood flow in type 1 SLAP lesions was lower than that in the normal labrum. PMID- 24493205 TI - Pharmacokinetics of indomethacin in pregnancy. AB - BACKGROUND AND OBJECTIVES: Although indomethacin has been widely used for the treatment of preterm labor over the past 40 years, there are few reports regarding its pharmacokinetics in pregnant women. METHODS: This opportunistic study assessed the steady-state pharmacokinetics of indomethacin in pregnant subjects to whom an oral dose of 25 mg every 6 h was prescribed. Indomethacin concentrations in plasma and urine were analyzed by a validated high-performance liquid chromatography method with mass spectrometric detection. RESULTS: The mean area under the plasma concentration versus time curve at steady state (AUCss) was 1.91 +/- 0.53 MUg.h/mL, mean peak plasma concentration (C max) was 1.02 +/- 0.49 MUg/mL, and mean time to reach C max (t max) was 1.3 +/- 0.7 h. The mean apparent clearance at steady state was 14.5 +/- 5.5 L/h, which is higher than the apparent clearance reported in the literature for non-pregnant subjects. Indomethacin crosses the placenta; the mean fetal/maternal ratio from five sets of cord blood samples collected at delivery was 4.0 +/- 1.1. CONCLUSIONS: Further studies are needed to determine whether any dose adjustments are necessary as a result of the increased clearance of indomethacin during pregnancy. PMID- 24493206 TI - Ophthalmic findings in an infant with phosphomannomutase deficiency. AB - INTRODUCTION: We present the ocular features including full-field electroretinography (ff-ERG) and spectral domain optical coherence tomography (SD OCT) in a 14-month-old infant with congenital disorder of glycosylation type 1a (PMM2-CDG). METHODS AND RESULTS: An infant with failure to thrive, bilateral neurosensory hearing loss, cerebellar hypoplasia, and pericardial effusions was referred to ophthalmic genetics for evaluation. The patient had fix and follow vision, an intermittent esotropia, moderate myopia, a hypo pigmented macula, and mild attenuation of the retinal vasculature. Electroretinography showed severe reduction in both rod and cone-dependent responses with a negative waveform pattern. Handheld SD-OCT revealed severe attenuation of the outer retina throughout the macula, but with preservation of outer retinal structures in the fovea. CONCLUSION: PMM2-CDG is a rare congenital disorder for which both ff-ERG and SD-OCT were useful in demonstrating early changes in retinal architecture and function. PMID- 24493207 TI - The number of chews and meal duration affect diet-induced thermogenesis and splanchnic circulation. AB - OBJECTIVE: To determine the effects of the number of chews and meal duration on diet-induced thermogenesis (DIT) and splanchnic blood flow (BF). METHODS: Healthy normal-weight subjects (11 subjects in the 100-kcal test and 10 subjects in the 300-kcal test) participated in two trials: a rapid-eating trial and a slow-eating trial. The meal duration and the number of chews were recorded. DIT was calculated from oxygen uptake and body mass, and splanchnic BF was calculated from the diameters of and blood velocities in the celiac artery and superior mesenteric artery, which were recorded until 90 min after consuming the food samples. RESULTS: For the 100-kcal and 300-kcal food samples, DIT and postprandial splanchnic BF in both the celiac artery and superior mesenteric artery were significantly larger in the slow-eating trial than in the rapid eating trial. There were significant correlations among meal duration, the number of chews, DIT, and postprandial splanchnic BF, with the exception of the relationship between DIT and splanchnic BF in the 300-kcal trial. CONCLUSIONS: These results suggest that fewer chews and/or shorter meal duration decreases DIT and the postprandial splanchnic BF, and that the increased DIT is at least partially due to the postprandial splanchnic circulation. PMID- 24493208 TI - Influence of syllable structure on L2 auditory word learning. AB - This study investigated the role of syllable structure in L2 auditory word learning. Based on research on cross-linguistic variation of speech perception and lexical memory, it was hypothesized that Japanese L1 learners of English would learn English words with an open-syllable structure without consonant clusters better than words with a closed-syllable structure and consonant clusters. Two groups of college students (Japanese group, N = 22; and native speakers of English, N = 21) learned paired English pseudowords and pictures. The pseudoword types differed in terms of the syllable structure and consonant clusters (congruent vs. incongruent) and the position of consonant clusters (coda vs. onset). Recall accuracy was higher for the pseudowords in the congruent type and the pseudowords with the coda-consonant clusters. The syllable structure effect was obtained from both participant groups, disconfirming the hypothesized cross-linguistic influence on L2 auditory word learning. PMID- 24493210 TI - Total knee replacement in a dog with a non-union type B3 tibial plateau fracture. AB - A six-year-old German Shorthaired Pointer was presented with a 12 month history of left pelvic limb lameness following trauma. Clinical examination revealed marked thickening and reduced range-of-motion of the left stifle and radiographs were suggestive of a non-union type B3 tibial plateau fracture with severe secondary osteoarthritis. Total knee replacement was performed with adjunctive stabilization of the proximal tibial fracture fragment. Clinical follow-up at six and 12 months with quantitative gait analysis revealed significant improvement in limb function. PMID- 24493211 TI - Evaluating the performance of clinical criteria for predicting mismatch repair gene mutations in Lynch syndrome: a comprehensive analysis of 3,671 families. AB - Carriers of mismatch repair (MMR) gene mutations have a high lifetime risk for colorectal and endometrial cancers, as well as other malignancies. As mutation analysis to detect these patients is expensive and time-consuming, clinical criteria and tumor-tissue analysis are widely used as pre-screening methods. The aim of our study was to evaluate the performance of commonly applied clinical criteria (the Amsterdam I and II Criteria, and the original and revised Bethesda Guidelines) and the results of tumor-tissue analysis in predicting MMR gene mutations. We analyzed 3,671 families from the German HNPCC Registry and divided them into nine mutually exclusive groups with different clinical criteria. A total of 680 families (18.5%) were found to have a pathogenic MMR gene mutation. Among all 1,284 families with microsatellite instability-high (MSI-H) colorectal cancer, the overall mutation detection rate was 53.0%. Mutation frequencies and their distribution between the four MMR genes differed significantly between clinical groups (p < 0.001). The highest frequencies were found in families fulfilling the Amsterdam Criteria (46.4%). Families with loss of MSH2 expression had higher mutation detection rates (69.5%) than families with loss of MLH1 expression (43.1%). MMR mutations were found significantly more often in families with at least one MSI-H small-bowel cancer (p < 0.001). No MMR mutations were found among patients under 40-years-old with only colorectal adenoma. Familial clustering of Lynch syndrome-related tumors, early age of onset, and familial occurrence of small-bowel cancer were clinically relevant predictors for Lynch syndrome. PMID- 24493213 TI - Long noncoding RNA in liver diseases. AB - The identification of the presence of large RNA transcripts that do not code for proteins but that may have biological functions has provided an important new perspective in gene regulation. These long noncoding RNAs (lncRNAs) are being increasingly recognized to contribute to many biological processes through diverse mechanisms. The roles of these emerging genes are being recognized across kingdoms. These findings are profoundly altering our understanding of disease pathobiology and leading to the emergence of new biological concepts underlying human diseases. Strategies for the discovery and characterization of lncRNAs are highlighted. Several lncRNAs have been described in liver disease, and in liver cancers in particular. Their molecular mechanisms of action, function, and contributions to disease pathophysiology are reviewed. LncRNA genes associated with liver diseases have potential roles as biomarkers of disease diagnosis, prognosis, or therapeutic response as well as direct targets for therapeutic intervention. CONCLUSION: The emerging knowledge in this rapidly advancing field offers promise for new fundamental knowledge and clinical applications that will be relevant for human liver diseases. PMID- 24493214 TI - ATP-driven Rad50 conformations regulate DNA tethering, end resection, and ATM checkpoint signaling. AB - The Mre11-Rad50 complex is highly conserved, yet the mechanisms by which Rad50 ATP-driven states regulate the sensing, processing and signaling of DNA double strand breaks are largely unknown. Here we design structure-based mutations in Pyrococcus furiosus Rad50 to alter protein core plasticity and residues undergoing ATP-driven movements within the catalytic domains. With this strategy we identify Rad50 separation-of-function mutants that either promote or destabilize the ATP-bound state. Crystal structures, X-ray scattering, biochemical assays, and functional analyses of mutant PfRad50 complexes show that the ATP-induced 'closed' conformation promotes DNA end binding and end tethering, while hydrolysis-induced opening is essential for DNA resection. Reducing the stability of the ATP-bound state impairs DNA repair and Tel1 (ATM) checkpoint signaling in Schizosaccharomyces pombe, double-strand break resection in Saccharomyces cerevisiae, and ATM activation by human Mre11-Rad50-Nbs1 in vitro, supporting the generality of the P. furiosus Rad50 structure-based mutational analyses. These collective results suggest that ATP-dependent Rad50 conformations switch the Mre11-Rad50 complex between DNA tethering, ATM signaling, and 5' strand resection, revealing molecular mechanisms regulating responses to DNA double-strand breaks. PMID- 24493219 TI - Leaf microbodies (peroxisomes) and catalase localization in plants differing in their photosynthetic carbon pathways. AB - The tropical grasses sugarcane (Saccharum officinarum) and pangolagrass (Digitaria decumbens) contained fewer leaf microbodies than temperate orchardgrass (Dactylis glomerata). Leaf microbodies were seen in both the mesophyll and bundle sheath cells of tropical grasses. The fibrous elements in the microbodies of tropical grasses differed from those of the temperate grass. Catalase was predominantly localized in the microbodies of leaf cells (3,3' diaminobenzidine method). The site of greatest catalase activity appeared to be the fibrous and/or crystalline inclusions within the microbodies. The low rates of photorespiration noted in tropical grasses do not appear to be due to the complete absence of the necessary organelles. PMID- 24493215 TI - Conversion from twice daily tacrolimus capsules to once daily extended-release tacrolimus (LCP-Tacro): phase 2 trial of stable liver transplant recipients. AB - LCP-Tacro is an extended-release formulation of tacrolimus designed for once daily dosing. Studies in renal transplantation demonstrate greater bioavailability with similar safety and efficacy vs. twice-daily tacrolimus capsules. In this phase 2 study, adult stable liver transplant patients on tacrolimus capsules (Prograf) twice-daily were converted to tacrolimus tablets (LCP-Tacro) once-daily; patients continued on LCP-Tacro once-daily for days 8-21; target trough levels were 5-15 ng/mL; 24-hour pharmacokinetic (PK) assessments were done on days 7 (baseline pre-switch), 14, and 21. A 6 month extension study phase evaluated PK and safety following a total of 52 weeks of LCP-Tacro. Fifty seven patients completed LCP-Tacro dosing in the core study; 43 completed the extension phase. The mean conversion ratio was 0.71 (Prograf:LCP-Tacro). PK data demonstrated consistent exposure (AUC) at the lower conversion dose. Cmax , Cmax /Cmin ratio, percent fluctuation and swing were significantly (P<0.001) lower and Tmax significantly (P<0.001) longer for LCP-Tacro vs. Prograf. AUC24 and Cmin correlation coefficients after 7 and 14 days of therapy were >=0.93. There were no significant differences in PK parameters at week 26 vs. 14. One patient experienced an unrelated serious adverse event (SAE) during the core study and discontinued. There were six unrelated SAEs in the extension and 1 possibly related (rejection) that resolved; there were 3 discontinuations due to AEs during the extension. In this study, patients were safely converted from Prograf twice-daily to LCP-Tacro. The greater bioavailability of LCP-Tacro allowed for once-daily dosing and similar (AUC) exposure at a dose approximately 30% less than the total daily dose of Prograf. LCP-Tacro displayed significantly lower peak and peak-trough fluctuations. LCP-Tacro administered over one year was well tolerated with no new safety concerns. PMID- 24493220 TI - Action potentials resulting from mechanical stimulation of pea epicotyls. AB - Non-propagating, asynchronous action potentials may be detected with an extracellular electrode placed on the hook of the pea epicotyl following mechanical stimulation. These may well mediate the release of ethylene which has previously been shown to control the diameter of mechanically stressed shoots. PMID- 24493221 TI - Indole-3-methanol-a metabolite of indole-3-acetic acid in pea seedlings. AB - Degradation of indole-3-acetic acid was investigated in etiolated pea shoots; the study was limited to indolic metabolites. The products formed were fractionated by column chromatography and identified by thin-layer chromatography and chemical methods. The pathway of indole-3-acetic acid degradation involving indole-3 aldehyde was found to be more significant than stated in literature, and indole-3 methanol was established as the major indolic metabolite. PMID- 24493222 TI - Photoreduction of acetylene by heterocysts. AB - Heterocysts of aerobically grown Anabaena cylindrica can reduce acetylene in the light, without added cofactors, up to 30% as rapidly as can the intact filaments from which they are derived. PMID- 24493223 TI - Tryptophan-dependent indoleacetic-acid biosynthesis from indole, demonstrated by double-labelling experiments. AB - (3)H-serine+(14)C-indole were administered to tips of sterily-grown pea seedlings and of non-sterile oat coleoptiles. The Try and IAA produced were extracted and purified by paper chromatography, and their (3)H/(14)C ratios were determined. The (3)H/(14)C ratio of IAA was lower than the (3)H/(14)C ratio of Try. However, the same decrease of the IAA (3)H/(14)C ratio was found when (3)H, (14)C-Try was supplied instead of (3)H-serine+(14)C-indole. This result supports the view that Try is the native IAA precursor and that no significant bypass from indole to IAA exists in the plant material used. PMID- 24493224 TI - Characterization of gibberellins from dark-grown Phaseolus coccineus seedlings by gas-liquid chromatography and combined gas chromatography-mass spectrometry. AB - An extract from 6000 dark-grown Phaseolus coccineus seedlings was purified by countercurrent distribution and G-10 Sephadex followed by gradient elution from a silicic acid partition column with increasing amounts of ethyl actetate in n hexane. 25 fractions were collected and tested with the barley-aleurone, 'Tan ginbozu' dwarf-rice, lettuce, cucumber, dwarf-pea, d-1, d-2, d-3 and d-5 maize, oat first-internode, and sugarcane-spindle bioassays. Major gibberellin (GA)-like activity was detected in fractions 4 (500MUg GA3-equivalents) and 12-13 (270 MUg GA3-equivalents) with smaller amounts in fractions 6, 8-9, 15-16, 18, 20, 23 and 25. The extracts were also applied to AMO-1618=dwarfed Ph.-coccineus seedlings. Fractions 4, 8 and 12 promoted the growth of both light- and dark-grown seedlings. GA1, GA3, GA4 and GA8 were active in the Phaseolus bioassay but GA8 glucoside was inactive.The biological and chromatographic properties of fractions 4, 8-9 and 12-13 correspond with those of GA4, GA19 and GA1. The identity of GA4 in fraction 4 was conclusively established by combined gas chromatography-mass spectrometry (GC-MS) of the methyl ester and the trimethylsilyl ether of the methyl ester. Gasliquid-chromatography peaks corresponding to these derivatives of GA19 and GA1 were detected on QF-1 and SE-33 columns but their intensities were too weak to permit conclusive identification by GC-MS. PMID- 24493225 TI - [An attempt to interpret the kinetics of isotope exchange between C(18)O 2 and the water of a leaf: Experiments in the dark]. AB - The interpretation of photosynthesis experiments using (18)O as a tracer becomes very difficult on account of the exchange rate between oxygen atoms of carbon dioxide and water. The mathematical analysis of the kinetics of isotope exchange between CO2 highly enriched with (18)O and the water of an aerial leaf kept in darkness allows the determination of two velocity coefficients, k e and k. k e, related to the gaseous CO2 diffusion, makes it possible to evaluate the CO2 flow between the gaseous phase and the leaf, as well as the diffusion resistance of the boundary layer and the leaf stomata. k, related to the CO2 hydration, gives the in situ enzymic activity of carbonic anhydrase. Measurements carried out on a great number of leaves show that k e and k vary in the same direction.In addition, a simple relation exists between the isotopic composition of the gaseous phase and the corresponding values of the C(18)O2 inside the leaf. Thus it is possible to determine the conditions for a leaf that may be favourable for light experiments designed to ascertain the origin of photosynthetic oxygen by use of (18)O. PMID- 24493226 TI - Evaluation of evidence for the presence of indole-3-acetic acid in marine algae. AB - Using a two-dimensional thin layer chromatography system (TLC) we have been unable to detect endogenous indole-3-acetic acid (IAA) (as an Ehrlichpositive spot on TLC plates) in the acidic, ether-soluble fraction of alkaline hydrolysates of 10 species of marine algae. Exogenously added IAA, admixed with algal extracts, was completely separated on chromatograms from other Ehrlich positive compounds which were present in the extracts. Several regions of auxin like activity were located on chromatograms of Fucus extracts. From experiments on the recovery of exogenously added IAA from algal extracts, we calculate that if IAA is present in algae, the levels are below 0.1 MUg IAA/g fresh weight. The claim by previous workers that IAA is present in marine algae is critically discussed. PMID- 24493227 TI - The effect of a prolonged 2,4-dichlorophenoxyacetic-acid treatment on transpiration and stomatal distribution in tomato leaves. AB - The effect of 2,4-dichlorophenoxyacetic acid applied during plant development on transpiration rate and distribution of stomata was studied in the wilty tomato mutant, flacca, and the normal cultivar, Rheinlands Ruhm. The rate of transpiration per unit leaf area was higher in treated than untreated leaves. Stomatal density in treated leaves did not increase; the stomates were able to open and close, and their aperture width under light was not greater than in untreated leaves. The ratio between stomata on the upper and lower leaf surfaces was higher in treated plants. PMID- 24493228 TI - Clinical testing of an alternate method of inserting bone-implanted fiducial markers. AB - BACKGROUND: Deep brain stimulation (DBS) surgery utilizes image guidance via bone implanted fiducial markers to achieve the desired submillimetric accuracy and to provide means for attaching microstereotactic frames. For maximal benefit, the markers must be inserted to the correct depth since over-insertion leads to stripping and under-insertion leads to instability. PURPOSE: The purpose of the study was to test clinically a depth-release drive system, the PosiSeatTM, versus manual insertion (pilot hole followed by manual screwing until tactile determined correct seating) for implanting fiducial markers into the bone. METHODS: With institutional review board approval, the PosiSeatTM was used to implant markers in 15 DBS patients (57 fiducials). On post-insertion CT scans, the depth of the gap between the shoulder of the fiducial markers and the closest bone surface was measured. Similar depth measurements were performed on the CT scans of 64 DBS patients (250 fiducials), who underwent manual fiducial insertion. RESULTS: Median of shoulder-to-bone distance for PosiSeatTM and manual insertion group were 0.03 and 1.06 mm, respectively. Fifty percent of the fiducials had the shoulder-to-bone distances within 0.01-0.09 mm range for the PosiSeat group and 0.04-1.45 mm range for the manual insertion group. These differences were statistically significant. CONCLUSIONS: A depth-release drive system achieves more consistent placement of bone-implanted fiducial markers than manual insertion. PMID- 24493229 TI - Prevalence of feeding disorders in children with cleft palateonly: a retrospective study. AB - OBJECTIVES: The purpose of this study in children with cleft palate only (CPO) is to (1) explore the prevalence of feeding problems on a retrospective basis, (2) investigate rates of nasogastric (NG) feeding, (3) examine the prevalence of associated disorders and/or syndromes (AssD/S), (4) investigate if there are certain risk factors associated with feeding difficulties, NG feeding, and failure of breastfeeding, and (5)investigate the effect of palatoplasty on feeding difficulties. MATERIALS AND METHODS: In total, 90 questionnaires were included in this study. The medical records were reviewed. RESULTS: Feeding difficulties were reported in 67 % (n =60) of all cases. NG feeding was given in 32% (n =28) of all children. Forty-nine children (54 %) have associated malformations. There is no significant relation for gender, gestational age,and birth weight as risk factors for feeding difficulties, NG feeding, and failure of breastfeeding. The severity of the cleft is significantly related to the prevalence of AssD/S. After palatoplasty, feeding difficulties improved in 79 % of the CPO children. CONCLUSIONS AND CLINICAL RELEVANCE: First, our results clearly indicate that children with CPO are at high risk of developing feeding difficulties (67 %); NG feeding is often necessary (32 %). Second, our results also indicate that the more severe the cleft, the more likely the chance for AssD/S. Third, these verity of the cleft is significantly related to the prevalence of AssD/S. Fourth, there is no significant relation for gender, gestational age, and birth weight as risk factors for feeding difficulties, NG feeding, and failure of breastfeeding. Fifth, improvement of feeding difficulties after surgery supports the importance of the soft palate closure in relation to sucking patterns and feeding skills. PMID- 24493230 TI - Three-unit CAD/CAM-generated lithium disilicate FDPs after a mean observation time of 46 months. AB - OBJECTIVES: Lithium disilicate can easily be machined by CAM techniques in its metasilicate status. Due to slightly inferior material properties, the material is not yet recommended for three-unit fixed dental prosthesis (FDP) as it is the case for the press material up to the second bicuspid. Therefore, the aim of this clinical study was to evaluate the performance of CAD/CAM-fabricated lithium disilicate FDPs. MATERIALS AND METHODS: A total of 32 anterior and posterior FDPs were provided for 32 patients. Twelve FDPs were fabricated chair-side. The first recall took place 6 months after insertion and then annually. The FDPs were rated according to biological and technical complications. As failure, those events were defined, which led to the removal of a FDP. The failure-free (survival) rate and the complication-free rate were calculated according to Kaplan-Meier. RESULTS: After a mean observation time of 46 months (SD +/- 8.4 months), three endodontic complications in two FDPs, two minor chippings, and one catastrophic fracture occurred. One FDP had to be removed due to persisting undefined complaints. Thus, the failure-free rate and the complication-free rate were revealed as 93 and 83 %, respectively. CONCLUSIONS: Despite the limited observation period, the results are promising, especially due to the fact that the fractured FDP did not fulfill the recommended connector dimensions. CLINICAL RELEVANCE: Inserted as a full-contour three-unit FDP within its indications, the CAD/CAM lithium disilicate ceramic offers an appropriate alternative to layered restorations. PMID- 24493232 TI - Potential--and potential pitfalls--of screening newborns for critical congenital heart disease. PMID- 24493231 TI - Six-month results following treatment of aggressive periodontitis with antimicrobial photodynamic therapy or amoxicillin and metronidazole. AB - OBJECTIVE: The use of antibacterial photodynamic therapy (aPDT) additionally to scaling and root planing (SRP) has been shown to positively influence the clinical outcomes. However, at present, it is unknown to what extent aPDT may represent a potential alternative to the use of systemic antibiotics in nonsurgical periodontal therapy in patients with aggressive periodontitis (AP). The aim of this study was to evaluate the outcomes following nonsurgical periodontal therapy and additional use of either aPDT or amoxicillin and metronidazole (AB) in patients with AP. MATERIAL AND METHODS: Thirty-six patients with AP displaying at least three sites with pocket depth (PD) >=6 mm were treated with SRP and either systemic administration of AB for 7 days or with two episodes of aPDT. The following clinical parameters were evaluated at baseline and at 6 months: plaque index (PI), bleeding on probing (BOP), PD, gingival recession (GR) and clinical attachment level (CAL). RESULTS: Thirty-five patients have completed the 6-month evaluation. At 6 months, mean PD was statistically significantly reduced in both groups (from 5.0 +/- 0.8 to 3.0 +/- 0.6 mm with AB and from 5.1 +/- 0.5 to 3.9 +/- 0.8 mm with aPDT (p < 0.001)). AB yielded statistically significantly higher improvements in the primary outcome parameter PD (p < 0.001) when compared to aPDT. The number of pockets >=7 mm was reduced from 141 to 3 after AB (p < 0.001) and from 137 to 45 after aPDT (p = 0.03). Both therapies resulted in statistically significant reductions in all parameters compared to baseline. CONCLUSION: While both treatments resulted in statistically significant clinical improvements, AB showed statistically significantly higher PD reduction and lower number of pockets >=7 mm compared to aPDT. CLINICAL RELEVANCE: In patients with AP, the two times application of aPDT in conjunction with nonsurgical periodontal therapy cannot be considered an alternative to the systemic use of amoxicillin and metronidazole. PMID- 24493233 TI - The role of religious leaders in health promotion for older Mexicans with diabetes. AB - Clergy in the Mexico play a major role in addressing the health care needs of their congregants. With qualitative semi-structured key-informant interviews, this study explored the views of ten male Mexican religious leaders (mostly Catholic) about their understanding of their role in diabetes health promotion. The major themes from the qualitative interviews emphasized the importance of open communication between church leaders and their parishioners, the role of the church in diabetes programs, and the unique position of religious institutions as a link between physical and spiritual aspects of health. Implications for diabetes interventions are discussed. PMID- 24493236 TI - High-salt intake induced visceral adipose tissue hypoxia and its association with circulating monocyte subsets in humans. AB - OBJECTIVE: To investigate the feasibility of blood oxygen level dependent magnetic resonance imaging (BOLD-MRI) in evaluating human visceral adipose tissue (AT) oxygenation induced by salt loading/depletion and its association with changes in circulating monocyte subsets. METHODS: A dietary intervention study was performed in 23 healthy volunteers beginning with a 3-day usual diet followed by a 7-day high-salt diet (>=15 g NaCl/day) and a 7-day low-salt diet (<=5 g NaCl/day). BOLD-MRI was used to evaluate oxygenation in perirenal AT. RESULTS: Salt loading led to a consistent AT hypoxia (increase in the R2* signal, 25.2 +/- 0.90 s(-1) vs. baseline 21.5 +/- 0.71 s(-1) , P < 0.001) and suppression of circulating renin-angiotensin-aldosterone system (RAAS), as well as an expansion of the CD14++CD16+ monocytes and monocyte pro-inflammatory activation. In salt depletion phase, the hypoxic state of AT and the expanded CD14++CD16+ monocyte pool were regressed to baseline levels, accompanied by a rebound activation of RAAS. Moreover, AT oxygenation level was positively correlated with the CD14++CD16+ monocytes (r = 0.419, P < 0.001). CONCLUSIONS: This work provides proof-of-principle evidence supporting the feasibility of BOLD-MRI in monitoring visceral AT oxygenation in humans induced by dietary salt loading/depletion. In addition, the CD14++CD16+ monocytes may participate in the pathogenesis of high salt intake induced AT hypoxia. PMID- 24493237 TI - Efficacy of REACH Forgiveness across cultures. AB - OBJECTIVE: This study investigates the efficacy of the 6-hour REACH Forgiveness intervention among culturally diverse undergraduates. METHOD: Female undergraduates (N = 102) and foreign extraction (46.2%) and domestic (43.8%) students in the United States were randomly assigned to immediate treatment or waitlist conditions. Treatment efficacy and the effect of culture on treatment response were assessed using measures of emotional and decisional forgiveness across 3 time periods. RESULTS: Students in the treatment condition reported greater improvement in emotional forgiveness, but not decisional forgiveness, relative to those in the waitlist condition. Gains were maintained at a 1-week follow-up. Although culture did not moderate the effect of treatment, a main effect of culture on emotional forgiveness and marginally significant interaction effect of culture on decisional forgiveness were found. CONCLUSION: The REACH Forgiveness intervention was efficacious for college students from different cultural backgrounds when conducted in the United States. However, some evidence may warrant development of culturally adapted forgiveness interventions. PMID- 24493235 TI - Impacts of a neonicotinoid, neonicotinoid-pyrethroid premix, and anthranilic diamide insecticide on four species of turf-inhabiting beneficial insects. AB - Many turf managers prefer to control foliage- and root-feeding pests with the same application, so-called multiple-targeting, using a single broad-spectrum insecticide or a premix product containing two or more active ingredients. We compared the impact of a neonicotinoid (clothianidin), a premix (clothianidin + bifenthrin), and an anthranilic diamide (chlorantraniliprole), the main insecticide classes used for multiple targeting, on four species of beneficial insects: Harpalus pennsylvanicus, an omnivorous ground beetle, Tiphia vernalis, an ectoparasitoid of scarab grubs, Copidosoma bakeri, a polyembryonic endoparasitoid of black cutworms, and Bombus impatiens, a native bumble bee. Ground beetles that ingested food treated with clothianidin or the premix suffered high mortality, as did C. bakeri wasps exposed to dry residues of those insecticides. Exposure to those insecticides on potted turf cores reduced parasitism by T. vernalis. Bumble bee colonies confined to forage on white clover (Trifolium repens L.) in weedy turf that had been treated with clothianidin or the premix had reduced numbers of workers, honey pots, and immature bees. Premix residues incapacitated H. pennsylvanicus and C. bakeri slightly faster than clothianidin alone, but otherwise we detected no synergistic or additive effects. Chlorantraniliprole had no apparent adverse effects on any of the beneficial species. Implications for controlling turf pests with least disruption of non target invertebrates are discussed. PMID- 24493238 TI - Impact of pretransplant rifaximin therapy on early post-liver transplant infections. AB - Bacterial and fungal infections are major causes of morbidity and mortality after liver transplantation (LT). The role of intestinal decontamination in the prevention of post-LT infections is controversial. Rifaximin is widely used for the treatment of hepatic encephalopathy. The effect of rifaximin on post-LT infections is unknown. The aim of our study was to determine the effect of rifaximin therapy in the pretransplant period on early bacterial infections (EBIs) and fungal infections within the first 30 days after LT. All adult patients who underwent LT at our institution (January 2009 to July 2011) were included in this retrospective cohort study. Patients receiving antibiotics other than pretransplant protocol antibiotics were excluded. Patients were stratified into 2 groups based on the presence or absence of rifaximin therapy for at least 2 days before LT. Infections were defined by the isolation of any bacterial or fungal organisms within 30 days of LT. Multivariate regression analysis, Student t tests, and Pearson's chi-square tests were used to compare the 2 groups. Two hundred sixty-eight patients were included, and 71 of these patients (26.5%) were on rifaximin at the time of LT. The 2 groups were comparable with respect to age, sex, race, and Model for End-Stage Liver Disease score. There were no significant differences in the rates of EBIs (30% for the non-rifaximin group and 25% for the rifaximin group, P = 0.48) or fungal infections between the 2 groups. There was no increase in antimicrobial resistance among the infecting organisms. There was no difference in survival between the rifaximin and non-rifaximin groups (98% versus 97%, P = 0.36). In conclusion, the use of rifaximin in the pre-LT period was not associated with an increased risk of bacterial or fungal infections in the early post-LT period. PMID- 24493239 TI - The ultrastructure of the salt gland of Spartina foliosa. AB - The salt gland in Spartina foliosa is composed of two cells, a large basal cell and a smaller, dome-shaped cap cell which is located on a neck-like protrusion of the basal cell. There is no cuticular layer separating the salt gland from the mesophyll tissue. The basal cell has dense cytoplasm which contains numerous mitochondria, rod-like wall protuberances, and infoldings of the plasmalemma which extend into the basal cell and partition the basal cell cytoplasm. The protuberances originate on the wall between the basal and the cap cells and are isolated from the basal-cell cytoplasm by the infoldings of the plasmalemma. While the cap cell has no partitioning membrane system or wall protuberances, it resembles the basal cell by having dense cytoplasm and numerous mitochondria.The basal cell seems to be designed for efficient movement of ions toward the cap cell. The long, dead-end extracellular channels in the basal cell of Spartina appear comparable to surface specializations seen in the secreting epithelium of animal cells which carry out solute-linked water transport. The number of mitochondria and their close association with the plasmalemma extensions suggest that they have an important role in the transfer of ions through the basal cell.The accumulated ions would move into the extracellular spaces along an osomotic gradient where the accompanying passive flow of water would move the ions into the cap-cell wall and from there the solution would pass out through the pores in the cuticle. PMID- 24493240 TI - Root cell ultrastructure of Zea mays embryo during early stages of germination. AB - The ultrastructure of root cells of the germinating corn embryo has been studied during the first 72 hours of soaking. The most spectacular ultrastructural modifications occur in the nucleus. In the dry seed, the chromatin is heavily condensed and complete dispersion occurs during the first 8 hr of germination. The nucleolus appears as a compact structure in the dormant embryo, and as a uniform granular structure after 3 hr. At the 8th hour, large nucleolar vacuoles appear filled with material structurally similar to chromatin. Later on, the nucleolus is composed of a central, fibrillo-granular region surrounded by a thin, peripheral, granular region and fewer nucleolar vacuoles are found.In a previous autoradiographic study (Deltour, 1970), it was shown that the onset of RNA synthesis in these cells occurs 4 hr after soaking. From that time to the 8th hour, uridine-(3)H is incorporated exclusively into the chromatin. Incorporation of radioactive uridine into the nucleolus begins only after the 8th hour.It is interesting that the onset of RNA synthesis in the chromatin occurs simultaneously with the dispersion of this cell component, and that the appearance of vacuoles in the nucleolus is correlated with the beginning if uridine incorporation into this organelle.The following ultrastructural changes take place in the cytoplasm; (a) the lamellae system of proplastids increases slightly; (b) phytoferritin granules present in the proplastids of the dry seed disappear very rapidly; (c) polysomes appear 72 hr after soaking; (d) the spherosomes which are essentially localized in the vicinity of the wall in the dormant embryo become uniformly distributed throughout the cytoplasm at the 72nd hr. PMID- 24493241 TI - [Further studies on the variability of the photosynthetic unit]. AB - The light saturation curves of photosynthesis of a yellow Chlorella mutant and the normal green strain have been investigated with monochromatic light at 15 different wavelengths in the range from 400 to 700 nm.The concentration of lipophilic quinones in relation to the chlorophyll content at different stages of regreening has also been studied. 1. On the basis of the amount of chlorophyll the photosynthetic efficiency of the yellow-green Chlorella mutant in red light of 672 and 681 nm wavelength is five times as great as that of the normal green type. On the basis of dry weight the two strains fix about the same amount of CO2. 2. In the mutant light saturation always occurs at higher intensities than in the normal strain. 3. Under conditions of light saturation maximal photosynthetic activity of the mutant is less in white light than in red light. 4. The ratio molecules quinone/molecules chlorophyll of the mutant is much higher than that of the normal control. 5. The results 1-4 are explained by the variability of the size of the photosynthetic unit. In the normal form 460 chlorophyll molecules are available for one electron transport system, that is system I and system II together, or 230 molecules per quantum absorbed. In the mutant there are only 80-100 molecules present, or 40-50 molecules per quantum absorbed.For maximum photosynthetic efficiency 30-50 molecules of chlorophyll per unit are needed. 6. Blue light, especially of 452 nm wavelength, strongly inhibits CO2 fixation in the mutant, which then increases slowly in a following red light period. PMID- 24493242 TI - [Selective inhibition of the synthesis of AMP-rich RNA by alpha-amanitin in higher plant cells]. AB - The effect of alpha-amanitin on the synthesis of AMP-rich RNA has been investigated. After incubation of freely suspended callus cells of parsley with the toxin and pulse labelling (30 min) with (32)P-orthophosphate, the high AMP content of the RNA component eluted from MAK columns behind the 25 S-RNA disappears. The base ratio of this RNA becomes ribosomal (CMP 20.1, AMP 26.5, GMP 28.4, UMP 25.0). Polyacrylamide gel electrophoresis of the high molecular RNA shows that radioactivity is incorporated only into the 32 S-RNA. At higher alpha amanitin concentrations the total nucleic acid synthesis is reduced. In this case only the high molecular RNA (32 S-RNA) is produced. PMID- 24493243 TI - [Influence of very short photoperiods on the growth, pigment composition and chloroplast ultrastructure of Lolium multiflorum]. AB - We have described some characteristics of Lolium multiflorum cultivated under very short photoperiods (2 hours and 1 hour). The estimations of leaf growth were based on dry weight, surface measurements, and chlorophyll content. The pigment analyses were carried out by column chromatography; chloroplast ultrastructure was observed after chemical fixation.These measurements have permitted us to note a sharp drop in the growth curve of plants grown under different day-lengths: the limiting photoperiod lies between 1 hour and 2 hours of daily illumination.Pigment analyses and chloroplast ultrastructure observations show that there is a greater difference between plants cultivated under 1 hour and 2 hours of daily illumination than between plants cultivated under 2 hours and 12 hours.A decrease in day-length causes a deficit in the chlorophyll b content as well as a poor development of the grana.We have attempted to correlate these structural anomalies with the abnormal chlorophyll a/chlorophyll b ratio. PMID- 24493244 TI - Gramicidin-D-stimulated influx of monovalent cations into plant roots. AB - Gramicidin D and nigericin were found to stimulate K(+) influx into oat roots. Valinomycin and nonactin had little effect on K(+) influx. The region of the root most sensitive to gramicidin was the elongation zone. Monocot roots were more sensitive to gramicidin than dicot roots. At 0.2 mM KCl, gramicidin stimulated K(+) influx by 4- to 8fold over a 30-min absorption period. Although a gramicidin response is detectable within one minute, maximum stimulation occurred after a slight (approximately 2-min) lag period. The gramicidin effect was much greater at 0.2 mM KCl than at 20 mM KCl. Respiratory inhibitors reduced the gramicidin stimulated K(+) influx by 50-80%. The results are discussed in terms of possible mechanisms of action of the various ionophores on ion transport in roots. PMID- 24493245 TI - Control of bud inhibition in Cyperus. AB - The axillary buds in the leaf crown of Cyperus alternifolius seedlings remain completely inhibited although the shoot is determinate and has no active apex. Buds can be released by detachment of the crown from the plant or by direct application of aqueous enzyladenine (BA), and grow out as inflorescences or vegetative shoots. These arise from activated growth centers of the primordial reproductive branch system which is enclosed within the prophyll of the inhibited bud. Buds are also released by the growth retardant, (2-chloroethyl) trimethylammonium chloride (CCC). Gibberellic acid maintains bud inhibition in detached crowns and inhibits bud release caused by CCC or BA. Naphthaleneacetic acid somewhat reduces BA-induced bud release and causes abnormal root proliferation in CCC-treated crowns. It is suggested that a high level of gibberellin within the crown, possibly in relation to a low level of cytokinin, maintains bud inhibition. PMID- 24493246 TI - [Action of 5-bromouracil and its nucleosides on the morphogenesis of the cuttings of etiolated tomato seedlings]. AB - 1. 5-Bromouracil inhibits the growth of the hypocotyl and the rhizogenesis in the cuttings of etiolated tomato seedlings only at high concentrations. 5 Bromouridine is inactive, but 5-bromodeoxyuridine strongly inhibits both phenomena. 2. The inhibition induced by 5-bromouracil cannot be reversed by thymine, deoxythymidine, uracil, uidine or beta-alanine, a catabolic product of uracil. 3. Deoxythymidine is the one pyrimidine nucleoside which reverses the inhibition of growth and rhizogenesis brought about by 5-bromodeoxyuridine. 4. Deoxycytidine enhances the inhibition of rhizogenesis caused by 5 bromodeoxyuridine. Such an effect on the growth of the hypocotyl is not observed. 5. Taking into consideration the data in the literature, it is concluded: a)5 bromouracil can act in several ways which possibly differ according to the plant species: in some instances (as in the case described here), it seems to act by a mechanism unconnected with the metabolism of pyrimidine nucleic bases: b) 5 bromodeoxyuridine is a specific antimetabolite of deoxythymidine, but other metabolic interactions exist between 5-bromodeoxyuridine and deoxycytidine, each of the latter substances probably acting as a modifier of the metabolism of the other. PMID- 24493248 TI - Cyanobacterial heat-shock response: role and regulation of molecular chaperones. AB - Cyanobacteria constitute a morphologically diverse group of oxygenic photoautotrophic microbes which range from unicellular to multicellular, and non nitrogen-fixing to nitrogen-fixing types. Sustained long-term exposure to changing environmental conditions, during their three billion years of evolution, has presumably led to their adaptation to diverse ecological niches. The ability to maintain protein conformational homeostasis (folding-misfolding-refolding or aggregation-degradation) by molecular chaperones holds the key to the stress adaptability of cyanobacteria. Although cyanobacteria possess several genes encoding DnaK and DnaJ family proteins, these are not the most abundant heat shock proteins (Hsps), as is the case in other bacteria. Instead, the Hsp60 family of proteins, comprising two phylogenetically conserved proteins, and small Hsps are more abundant during heat stress. The contribution of the Hsp100 (ClpB) family of proteins and of small Hsps in the unicellular cyanobacteria (Synechocystis and Synechococcus) as well as that of Hsp60 proteins in the filamentous cyanobacteria (Anabaena) to thermotolerance has been elucidated. The regulation of chaperone genes by several cis-elements and trans-acting factors has also been well documented. Recent studies have demonstrated novel transcriptional and translational (mRNA secondary structure) regulatory mechanisms in unicellular cyanobacteria. This article provides an insight into the heat-shock response: its organization, and ecophysiological regulation and role of molecular chaperones, in unicellular and filamentous nitrogen-fixing cyanobacterial strains. PMID- 24493247 TI - The protein tyrosine kinases EpsB and PtkA differentially affect biofilm formation in Bacillus subtilis. AB - The Gram-positive soil bacterium Bacillus subtilis is able to choose between motile and sessile lifestyles. The sessile way of life, also referred to as biofilm, depends on the formation of an extracellular polysaccharide matrix and some extracellular proteins. Moreover, a significant proportion of cells in a biofilm form spores. The first two genes of the 15-gene operon for extracellular polysaccharide synthesis, epsA and epsB, encode a putative transmembrane modulator protein and a putative protein tyrosine kinase, respectively, with similarity to the TkmA/PtkA modulator/kinase couple. Here we show that the putative kinase EpsB is required for the formation of structured biofilms. However, an epsB mutant is still able to form biofilms. As shown previously, a ptkA mutant is also partially defective in biofilm formation, but this defect is related to spore formation in the biofilm. The absence of both kinases resulted in a complete loss of biofilm formation. Thus, EpsB and PtkA fulfil complementary functions in biofilm formation. The activity of bacterial protein tyrosine kinases depends on their interaction with modulator proteins. Our results demonstrate the specific interaction between the putative kinase EpsB and its modulator protein EpsA and suggest that EpsB activity is stimulated by its modulator EpsA. PMID- 24493249 TI - FgIlv5 is required for branched-chain amino acid biosynthesis and full virulence in Fusarium graminearum. AB - In this study, we characterized FgIlv5, a homologue of the Saccharomyces cerevisiae keto-acid reductoisomerase (KARI) from the important wheat head scab fungus Fusarium graminearum. KARI is a key enzyme in the branched-chain amino acid (BCAA, including leucine, isoleucine and valine) biosynthetic pathway that exists in a variety of organisms from bacteria to fungi and higher plants, but not in mammals. The FgILV5 deletion mutant DeltaFgIlv5-4 failed to grow when the culture medium was nutritionally limited for BCAAs. When grown on potato-dextrose agar plates, DeltaFgIlv5-4 exhibited a significant decrease in aerial hyphae formation and red pigmentation. Conidia formation was also blocked in DeltaFgIlv5 4. Exogenous addition of 1 mM isoleucine and valine was able to rescue the defects of mycelial growth and conidial morphogenesis. Cellular stress assays showed that DeltaFgIlv5-4 was more sensitive to osmotic and oxidative stresses than the wild-type strain. In addition, virulence of DeltaFgIlv5-4 was dramatically reduced on wheat heads, and a low level of deoxynivalenol production was detected in DeltaFgIlv5-4 in wheat kernels. The results of this study indicate that FgIlv5 is involved in valine and isoleucine biosynthesis and is required for full virulence in F. graminearum. PMID- 24493250 TI - Sorafenib use in hepatocellular carcinoma: more questions than answers. PMID- 24493252 TI - Agrobacterium-mediated genetic transformation and plant regeneration of the hardwood tree species Fraxinus profunda. AB - This transformation and regeneration protocol provides an integral framework for the genetic improvement of Fraxinus profunda (pumpkin ash) for future development of plants resistant to the emerald ash borer. Using mature hypocotyls as the initial explants, an Agrobacterium tumefaciens-mediated genetic transformation system was successfully developed for pumpkin ash (Fraxinus profunda). This transformation protocol is an invaluable tool to combat the highly aggressive, non-native emerald ash borer (EAB), which has the potential to eliminate native Fraxinus spp. from the natural landscape. Hypocotyls were successfully transformed with Agrobacterium strain EHA105 harboring the pq35GR vector, containing an enhanced green fluorescent protein (EGFP) as well as a fusion gene between neomycin phosphotransferase (nptII) and gusA. Hypocotyls were cultured for 7 days on Murashige and Skoog (MS) medium with 22.2 MUM 6-benzyladenine (BA), 4.5 MUM thidiazuron (TDZ), 50 mg L(-1) adenine hemisulfate (AS), and 10 % coconut water (CW) prior to transformation. Hypocotyls were transformed using 90 s sonication plus 10 min vacuum infiltration after Agrobacterium was exposed to 100 MUM acetosyringone for 1 h. Adventitious shoots were regenerated on MS medium with 22.2 MUM BA, 4.5 MUM TDZ, 50 mg L(-1) AS, 10 % CW, 400 mg L(-1) timentin, and 20 mg L(-1) kanamycin. Timentin at 400 and 20 mg L(-1) kanamycin were most effective at controlling Agrobacterium growth and selecting for transformed cells, respectively. The presence of nptII, GUS (beta-glucuronidase), and EGFP in transformed plants was confirmed using polymerase chain reaction (PCR), while the expression of EGFP was also confirmed through fluorescent microscopy and reverse transcription-PCR. This transformation protocol provides an integral foundation for future genetic modifications of F. profunda to provide resistance to EAB. PMID- 24493253 TI - Biosafety management and commercial use of genetically modified crops in China. AB - As a developing country with relatively limited arable land, China is making great efforts for development and use of genetically modified (GM) crops to boost agricultural productivity. Many GM crop varieties have been developed in China in recent years; in particular, China is playing a leading role in development of insect-resistant GM rice lines. To ensure the safe use of GM crops, biosafety risk assessments are required as an important part of the regulatory oversight of such products. With over 20 years of nationwide promotion of agricultural biotechnology, a relatively well-developed regulatory system for risk assessment and management of GM plants has been developed that establishes a firm basis for safe use of GM crops. So far, a total of seven GM crops involving ten events have been approved for commercial planting, and 5 GM crops with a total of 37 events have been approved for import as processing material in China. However, currently only insect-resistant Bt cotton and disease-resistant papaya have been commercially planted on a large scale. The planting of Bt cotton and disease resistant papaya have provided efficient protection against cotton bollworms and Papaya ringspot virus (PRSV), respectively. As a consequence, chemical application to these crops has been significantly reduced, enhancing farm income while reducing human and non-target organism exposure to toxic chemicals. This article provides useful information for the colleagues, in particular for them whose mother tongue is not Chinese, to clearly understand the biosafety regulation and commercial use of genetically modified crops in China. PMID- 24493254 TI - Root carboxylate exudation capacity under phosphorus stress does not improve grain yield in green gram. AB - Genetic variability in carboxylate exudation capacity along with improved root traits was a key mechanism for P-efficient green gram genotype to cope with P stress but it did not increase grain yield. This study evaluates genotypic variability in green gram for total root carbon exudation under low phosphorus (P) using (14)C and its relationship with root exuded carboxylates, growth and yield potential in contrasting genotypes. Forty-four genotypes grown hydroponically with low (2 MUM) and sufficient (100 MUM) P concentrations were exposed to (14)CO2 to screen for total root carbon exudation. Contrasting genotypes were employed to study carboxylate exudation and their performance in soil at two P levels. Based on relative (14)C exudation and biomass, genotypes were categorized. Carboxylic acids were measured in exudates and root apices of contrasting genotypes belonging to efficient and inefficient categories. Oxalic and citric acids were released into the medium under low-P. PDM-139 (efficient) was highly efficient in carboxylate exudation as compared to ML-818 (inefficient). In low soil P, the reduction in biomass was higher in ML-818 as compared to PDM-139. Total leaf area and photosynthetic rate averaged for genotypes increased by 71 and 41 %, respectively, with P fertilization. Significantly, higher root surface area and volume were observed in PDM-139 under low soil P. Though the grain yield was higher in ML-818, the total plant biomass was significantly higher in PDM-139 indicating improved P uptake and its efficient translation into biomass. The higher carboxylate exudation capacity and improved root traits in the later genotype might be the possible adaptive mechanisms to cope with P-stress. However, it is not necessary that higher root exudation would result in higher grain yield. PMID- 24493255 TI - Atlantoaxial epidural abscess secondary to grass awn migration in a dog. AB - A two-year-old female Lucerne Hound was presented with a one-week history of signs of progressive neck pain, inappetence, apathy, and an elevated rectal temperature. Findings of magnetic resonance imaging (MRI) were consistent with a foreign body abscess in the epidural space at the level of the first and second cervical vertebrae. A left-sided dorso-lateral atlantoaxial approach was performed, revealing an epidural abscess containing a grass awn. The clinical signs resolved within three days of surgery and the dog made a full recovery. This case report shows that grass awns can migrate to the atlantoaxial region in dogs and MRI findings lead to a suspicion of caudo-cranial migration within the spinal canal. PMID- 24493256 TI - Modest mid-term outcomes after isolated arthroscopic debridement of acetabular labral tears. AB - PURPOSE: Currently, there is a paucity of literature regarding outcomes after isolated labral debridement. The purpose of this study was to (1) report the reoperation rate following isolated labral debridement, (2) report clinical and functional outcomes after labral debridement with a minimum 2-year follow-up and (3) identify risk factors for worse clinical and functional outcomes. It was hypothesized that inferior outcomes are associated with an increasing Tonnis grade and those with untreated femoral acetabular impingement (FAI). METHODS: The records of patients undergoing hip arthroscopy between 1998 and 2005 were reviewed. Patients with labral tears who underwent isolated arthroscopic labral debridement were identified. Kaplan-Meier estimate of failure (defined as subsequent surgery) was performed for all patients. Patients with minimum 2-year follow-up were assessed with Modified Harris Hip Score (MHHS) and Hip Outcome Score (HOS). Univariate analysis was then performed to assess which factors were associated with worse clinical and functional outcomes. RESULTS: Fifty-nine hips in 57 patients met our inclusion criteria (39 females, 18 males) with a mean age of 46 +/- 14 years and mean follow-up of 5 (range 2-14) years. Overall, 45 % of the hips failed for repeat surgery (20 %) or rating for hip function as abnormal or severely abnormal (25 %). Twelve hips (20 %) required subsequent surgical intervention at a mean 23 (range 6-60) months (7 total hip arthroplasties, 2 open revisions, 3 arthroscopic revisions). Of the remaining hips, mean MHHS was 83.4 +/- 19.7, mean HOS ADL score was 83.8 +/- 21.3 and mean HOS sport score was 70.6 +/- 32.9, with 33 of 41 (75 %) reporting normal or nearly normal current level of function. Univariate analysis revealed that hips with untreated bony impingement (p = 0.01) or requiring concomitant chondroplasty (p = 0.03) had inferior clinical outcome scores. CONCLUSIONS: Isolated arthroscopic labral debridement for hip labral tears had 45 % combined poor results when strictly defining failure as repeat surgery or abnormal hip rating. Untreated FAI and concomitant chondroplasty were risk factors for inferior outcome. We recommend concomitant treatment for bony impingement lesions and preservation of the labrum whenever possible. PMID- 24493257 TI - Differences in ACL biomechanical risk factors between field hockey and lacrosse female athletes. AB - PURPOSE: Previous investigations have revealed a greater incidence of anterior cruciate ligament (ACL) injuries in female lacrosse versus field hockey players. Lacrosse is played in an upright posture with overhead throwing and catching, while field hockey is almost exclusively played in a crouched, forward-flexed position. Biomechanical factors, including decreased knee, hip, and trunk flexion angles, have been identified as risk factors for ACL injury. The purpose of this study was to assess ACL biomechanical risk factors in female field hockey and lacrosse players to determine whether sport-specific posture might contribute to the increased incidence of ACL injury observed in lacrosse athletes. METHODS: Thirty-one Division I NCAA females from field hockey and lacrosse completed four tasks, three times per leg: bilateral drop jump, single-leg drop jump (SDJ), single-leg jump onto a Bosu ball (SDB), and a 45 degrees anticipated cut. Kinematic and force plate data were used to evaluate knee flexion angle, knee adduction moment, hip flexion angle, and trunk flexion and sway angles. Muscle activity of the lateral hamstrings and vastus lateralis was used to estimate peak hamstring activity and the quadriceps/hamstring ratio at the time of peak quadriceps activity (co-contraction ratio). RESULTS: During the SDJ and SDB, peak knee flexion angles were greater in field hockey compared with lacrosse. During cutting, field hockey players were more flexed at the trunk and had greater trunk sway, compared with the lacrosse players. No significant difference was observed for the co-contraction ratio for any of the tasks. CONCLUSIONS: Decreased knee flexion angle during landing, consistent with sport-specific playing postures, may contribute to the higher incidence of ACL injury in lacrosse players relative to field hockey. Sport-specific training injury prevention programmes may benefit from considering these differences between specialized athletes. LEVEL OF EVIDENCE: II. PMID- 24493258 TI - A method for selecting a protocol for routine body CT scan using Gemstone Spectral Imaging with or without adaptive statistical iterative reconstruction: phantom experiments. AB - PURPOSE: To investigate a method for selecting a protocol for body CT scan to acquire monochromatic images (MIs) by gemstone spectral imaging (GSI) with or without adaptive statistical iterative reconstruction (ASiR). MATERIALS AND METHODS: We subjected a phantom to conventional scanning at 120 kVp and 50-700 mAs and GSI at 165-600 mAs; reconstructed MIs at 65 keV with ASiR 0-100 % for GSI; placed 5 regions of interest on each of 3 consecutive reconstructed slices to obtain the averaged standard deviation (SD) as image noise for conventional scan and GSI. Linear regression analysis yielded the mAs by conventional scan that could be used to achieve similar image noise by GSI. RESULTS: To achieve similar noise, we found excellent linear correlation of mAs between GSI with ASiR 0-100 % and conventional scan (r = 1.00, P < 0.0001), and obtained a table of equivalent mAs between MIs at 65 keV and conventional CT at 120 kVp. CONCLUSIONS: We can select a protocol for body CT scan for MIs at 65 keV with or without ASiR with results comparable to those of conventional CT at 120 kVp. PMID- 24493259 TI - Prevention of postoperative recurrence in Crohn's disease. PMID- 24493260 TI - SNARE and regulatory proteins induce local membrane protrusions to prime docked vesicles for fast calcium-triggered fusion. AB - Synaptic vesicles fuse with the plasma membrane in response to Ca(2+) influx, thereby releasing neurotransmitters into the synaptic cleft. The protein machinery that mediates this process, consisting of soluble N-ethylmaleimide sensitive factor attachment protein receptors (SNAREs) and regulatory proteins, is well known, but the mechanisms by which these proteins prime synaptic membranes for fusion are debated. In this study, we applied large-scale, automated cryo-electron tomography to image an in vitro system that reconstitutes synaptic fusion. Our findings suggest that upon docking and priming of vesicles for fast Ca(2)(+)-triggered fusion, SNARE proteins act in concert with regulatory proteins to induce a local protrusion in the plasma membrane, directed towards the primed vesicle. The SNAREs and regulatory proteins thereby stabilize the membrane in a high-energy state from which the activation energy for fusion is profoundly reduced, allowing synchronous and instantaneous fusion upon release of the complexin clamp. PMID- 24493261 TI - CD4 counts of nonperinatally HIV-infected youth and young adults presenting for HIV care between 2002 and 2010. PMID- 24493262 TI - Muscle dysfunction in hypertrophic cardiomyopathy: what is needed to move to translation? AB - Hypertrophic cardiomyopathy (HCM) is caused by mutations in sarcomere genes. As such, HCM provides remarkable opportunities to study how changes to the heart's molecular motor apparatus may influence cardiac structure and function. Although the genetic basis of HCM is well-described, there is much more limited understanding of the precise consequences of sarcomere mutations--how they remodel the heart, and how these changes lead to the dramatic clinical consequences associated with HCM. More precise characterization of the mechanisms leading from sarcomere mutation to altered cardiac muscle function is critical to gain insight into fundamental disease biology and phenotypic evolution. Such knowledge will help foster development of novel treatment strategies aimed at correcting and preventing disease development in HCM. PMID- 24493263 TI - Spatial and temporal variability of water quality in the coral reefs of Tayrona National Natural Park, Colombian Caribbean. AB - Tayrona National Natural Park (TNNP) is a hotspot of coral reef biodiversity in the Colombian Caribbean, located between the city of Santa Marta (>455,000 inhabitants) and several smaller river mouths (Rio Piedras, Mendihuaca, Guachaca). The region also experiences a strong seasonal variation in physical parameters (temperature, salinity, wind, and water currents) due to alternating dry seasons with coastal upwelling and rainy seasons. However, the spatial and temporal effects on water quality parameters relevant for coral reef functioning have not been investigated. Therefore, inorganic nutrient, chlorophyll a, and particulate organic carbon (POC) concentrations along with biological O2 demand (BOD), pH, and water clarity directly above local coral reefs (~10 m water depth) were monitored for 25 months in four bays along a distance gradient (12-20 km) to Santa Marta in the southwest and to the first river mouth (17-27 km) in the east. This is by far the most comprehensive coral reefs water quality dataset for the region. Findings revealed that particularly during non-upwelling, chlorophyll a and POC concentrations along with BOD significantly increased with decreasing distance to the rivers in the east, suggesting that the observed spatial water quality decline was triggered by riverine runoff and not by the countercurrent located Santa Marta. Nitrate, nitrite, and chlorophyll a concentrations significantly increased during upwelling, while pH and water clarity decreased. Generally, water quality in TNNP was close to oligotrophic conditions adequate for coral reef growth during non-upwelling, but exceeded critical threshold values during upwelling and in relation to riverine discharge. PMID- 24493264 TI - Spatial variability and temporal changes in the trace metal content of soils: implications for mine restoration plan. AB - Trace metals in soils may be inherited from the parent materials or added to the system due to anthropogenic activities. In proposed mining areas, trace metals become an integral part of the soil system. Usually, researchers undertake experiments on plant species selection (for the restoration plan) only after the termination of mining activities, i.e. without any pre-mining information about the soil-plant interactions. Though not shown in studies, it is clear that several recovery plans remain unsuccessful while carrying out restoration experiments. Therefore, we hypothesize that to restore the area effectively, it is imperative to consider the pre-mining scenario of metal levels in parent material as well as the vegetation ecology of the region. With these specifics, we examined the concentrations of trace metals in parent soils at three proposed bauxite locations in the Eastern Ghats, India, and compared them at a spatio temporal scale. Vegetation quantification and other basic soil parameters accounted for establishing the connection between soil and plants. The study recorded significant spatial heterogeneity in trace metal concentrations and the role of vegetation on metal availability. Oxidation reduction potential (ORP), pH and cation exchange capacity (CEC) directly influenced metal content, and Cu and Ni were lithogenic in origin. It implies that for effective restoration plant species varies for each geological location. PMID- 24493265 TI - Developing a fuzzy neural network-based support vector regression (FNN-SVR) for regionalizing nitrate concentration in groundwater. AB - The aim of this study is to develop a fuzzy neural network-based support vector regression model (FNN-SVR) for mapping crisp-input and fuzzy-output variables. In this model, an artificial neural network (ANN) estimator based on multilayer perceptron (MLP) is considered as the kernel function of the SVR, whereas asymmetric triangular fuzzy H-level sets are assumed for model parameters including weight and biases of the ANN model. A genetic algorithm (GA) with real coding is implemented to optimize the model parameters during the training phase. To evaluate the efficiency and applicability of the proposed model, it is applied for simulating and regionalizing nitrate concentration in Karaj Aquifer in Iran. The goodness-of-fit criteria indicate a better performance of the FNN-SVR compared to some benchmark models such as geostatistic techniques as well as traditional SVR models with linear, quadratic, polynomial, and Gaussian kernel functions for modeling nitrate concentrations in groundwater. PMID- 24493268 TI - Use of SSRIs among Danish children: a nationwide study. AB - Our objective was to describe the use of selective serotonin reuptake inhibitors (SSRIs) in the entire Danish population of children and adolescents from 1995 to 2011. Data on filled SSRIs were obtained for all children in Denmark aged 5-17 during 1995-2011. The amount and type of SSRIs filled were calculated as well as incidence rates and prevalence proportions. Furthermore, we looked at concurrent use of other psychotropic drug treatment duration. A total of 23,547 children aged 5-17 used SSRIs during the study period, most commonly sertraline followed by citalopram. Overall, the incidence rate increased from 0.57 per 1,000 person years in 1997 to 3.30 in 2010 and fell to 2.55 in 2011, while the prevalence proportion rose from 0.1 per 1,000 children at the end of 1995 to 3.3 at the end of 2011. However, these findings were driven entirely by an increase among adolescents (12-17 years), where the prevalence proportion rose from 0.11 and 0.36 to 4.64 and 8.52 per 1,000 boys and girls, respectively. A significant proportion of SSRI users used other psychotropic drugs concurrently, most notably antipsychotics (12-28 %) and psychostimulants (10-33 %). About 50 % of adolescents and 40 % of children discontinued treatment within 12 months of initiation. We found a marked increase in the use of SSRI drugs among adolescents in Denmark between 1995 and 2011. Whether this increase reflects a true increase in disorder occurrence, an increase in diagnostic intensity or more aggressive treatment remains uncertain. PMID- 24493269 TI - Culture of preantral follicles in poly(ethylene) glycol-based, three-dimensional hydrogel: a relationship between swelling ratio and follicular developments. AB - This study was undertaken to examine how the softness of poly(ethylene) glycol (PEG)-based hydrogels, creating a three-dimensional (3D) microenvironment, influences the in vitro growth of mouse ovarian follicles. Early secondary, preantral follicles of 2 week-old mice were cultured in a crosslinked four-arm PEG hydrogel. The hydrogel swelling ratio, which relates to softness, was modified within the range 25.7-15.5 by increasing the reactive PEG concentration in the precursor solution from 5% to 15% w/v, but it did not influence follicular growth to form the pseudoantrum (60-80%; p = 0.76). Significant (p < 0.04) model effects, however, were detected in the maturation and developmental competence of the follicle-derived oocytes. A swelling ratio of > 21.4 yielded better oocyte maturation than other levels, while the highest competence to develop pronuclear and blastocyst formation was detected at 20.6. In conclusion, gel softness, as reflected in swelling ratio, was one of the essential factors for supporting folliculogenesis in vivo within a hydrogel-based, 3D microenvironment. PMID- 24493267 TI - Nutrition, immunological mechanisms and dietary immunomodulation in ADHD. AB - Attention-deficit hyperactivity disorder (ADHD) etiology is not completely understood, but common comorbid dysfunction of the gastrointestinal and immune system suggests that these systems may be affected by a common genetic background and molecular mechanisms. For example, increased levels of specific cytokines were observed in ADHD. Moreover, ADHD has a high comorbidity with both Th1- and Th2-mediated disorders like ear infections, eczema and asthma. A common pathophysiological mechanism was suggested to underlie both asthma and ADHD, while several genes that are linked to ADHD have immune functions. Furthermore, immunological recognition of food provoking ADHD-like behavior was suggested. An immune imbalance, probably requiring a predisposing genetic background, is therefore suggested to contribute to ADHD etiology, with immune dysregulation being more likely than a single subcellular defect. However, next to allergic mechanisms, also pharmacological mechanisms (especially in case of food additives) might be involved. In addition, though cellular (cytokine-related) rather than antibody-mediated immune mechanisms seem involved, specific immune inflammatory markers other than antibodies have not been systematically studied in ADHD. Substantial alterations implicated in ADHD apparently occur in the immune system and epigenetic regulation of gene expression. As a result, chronic inflammation and oxidative stress could develop, which can lead to ADHD symptoms, for example by chronic T-cell-mediated neuroinflammation. If immune pathways contribute to ADHD, both its diagnosis and treatment should be reconsidered. Modulation of immune system activity might have potential in ADHD treatment, for example by nutritional approaches providing safe and low-cost ADHD therapy, but further research in these fields is implicated. PMID- 24493270 TI - Gender, race, and electrophysiologic characteristics of the branched recurrent laryngeal nerve. AB - OBJECTIVES/HYPOTHESIS: The extralaryngeal branching of recurrent laryngeal nerves (RLN) conveys an increased risk of nerve injury during thyroid surgery. We hypothesized that racial and gender variations in prevalence of branched RLN exist. STUDY DESIGN: A retrospective review of all patients who underwent thyroid surgery in a 4-year period in a single surgeon practice. METHODS: The RLN was routinely identified during thyroid surgery. Presence of RLN branching, its distance from the laryngeal nerve entry point (NEP), and functionality of the branches were ascertained. Patient demographics, rates of neural branching, and distance of bifurcation from the NEP were evaluated using statistical analysis. RESULTS: We identified 719 RLNs at risk in 491 patients who underwent central neck surgery. Four hundred and five (82.5%) patients were female and 86 (17.5%) patients were male. There were 218 (44.4%) African American patients and 251 (51.1 %) Caucasian patients. In African American patients, 42.1% RLNs bifurcated compared to 33.2% RLNs in Caucasian (P = 0.017) patients. The RLNs of African American and Caucasian patients bifurcated at comparable distances (P = 0.30). In male patients, 39.1% RLNs bifurcated; whereas in female patients 36.2% RLNs bifurcated (P = 0.53). On average, RLN bifurcation in female patients was at a longer distance from NEP compared to that of male patients (P = 0.012). Electrophysiologic testing found motor fibers in all anterior branches and three posterior extralaryngeal RLN branches. CONCLUSION: African American patients have a higher rate of RLN bifurcation compared to Caucasian patients but no statistically significant difference in distance from NEP. Female patients tend to have longer branching variants of bifid RLNs. RLN motor fibers reside primarily in the anterior branch but may occur in the posterior branch. PMID- 24493272 TI - Effects of moisture stress on the multiplication and expansion of cells in leaves of sugar beet. AB - Sugar beets were subjected to moisture stress by decreasing the water potential of the culture solution osmotically with polyethylene glycol by a known amount, DeltaPsi pi , and, alternatively by applying matric potential, Psi tau , at the plant roots. Lowering the water potential at the root surface less than 200 millibars by either method resulted in significant decreases in the rate of cell multiplication. The final number of cells per leaf at Psi pi = -372 mb the final was 165% of that at Psi pi = -473 mb (DeltaPsi tau = -101 mb); similarly at Psi tau = -15 mb the final cell number was 198% of that at Psi tau = -196 mb (DeltaPsi tau = -181 mb). The mean cell volume of leaves was not significantly affected by these levels of moisture stress. PMID- 24493273 TI - RNA synthesis during pollen germination. AB - Regulation of pollen germination of Petunia was investigated by determining RNA content and composition in an in vitro system in the presence and absence of the transcription inhibitor actinomycin D and by labelling with C14-orotic acid.At the beginning of the progamic phase 2 stages can be distinguished: First (up to 15 minutes) no essential RNA synthesis occurs, but merely a release takes place of the protein-bound RNA carried by the pollen grains. The second stage (up to 60 minutes) shows only little RNA synthesis which has not the main regulatory function.At the RNA translation level germination is controlled mainly by activation and inactivation of long living RNA. PMID- 24493271 TI - Bland embolization versus chemoembolization of hepatocellular carcinoma before transplantation. AB - There is conflicting literature regarding the superiority of transarterial chemoembolization (TACE) versus bland transarterial embolization (TAE), and this has not been well studied before transplantation. Twenty-five TAE patients were matched in a 1:2 ratio with TACE patients by the initial radiographic tumor size and number in a retrospective, case-controlled study. The patients were otherwise treated according to the same protocols. The method of embolization was chosen on the basis of interventionalist practices at 2 sites within the program. Kaplan Meier survival analyses at 1 and 3 years were the primary endpoints. There were no significant demographic differences between the groups. The mean adjusted Model for End-Stage Liver Disease scores at transplantation and waiting times were not significantly different between the TAE and TACE patients (MELD scores: 26 +/- 3 versus 24 +/- 3 points, P = 0.12; waiting times: 13 +/- 8 versus 11 +/- 10 months, P = 0.43). TAE patients (16%) were less likely than TACE patients (40%) to require 2 procedures (P = 0.04). Explant tumors were completely necrotic for 36% of the TAE patients and for 26% of the TACE patients. The 3-year overall survival rates were 78% for the TAE patients and 74% for the TACE patients (P = 0.66), and the 3-year recurrence-free survival rates were 72% for the TAE patients and 68% for the TACE patients (P = 0.67). On an intention-to-treat basis, there was no significant risk of wait-list dropout associated with TAE or TACE (P = 0.83). In conclusion, there were no significant differences in wait list dropout or in overall or recurrence-free survival between HCC patients undergoing TAE and HCC patients undergoing TACE before transplantation. PMID- 24493274 TI - The incorporation of amino acids into the protein of isolated soya bean mitochondria. AB - A system involving the incorporation of amino acids into the protein of mitochondria isolated aseptically from soya bean hypocotyls has been partially characterized. Incorporation is optimal at pH 7.4, is dependent on magnesium, phosphate and succinate, is resistant to pancreatic RNAase and cycloheximide, but is sensitive to D-threo-chloramphenicol, oligomycin, DNP, and changes in osmotic concentration. PMID- 24493275 TI - Progressive release of carboxylating enzymes during mechanical grinding of sugar cane leaves. AB - The progressive release of protein, chlorophyll, phenol oxidase activity and phenolic compounds during the mechanical disruption of sugar cane leaves has been correlated with the release of carboxylating enzymes. Enzymes of the photosynthetic carbon reduction cycle were released in parallel with chlorophyll, the bulk of which was recovered in grana-containing chloroplasts. PEP carboxylase activity followed the release of total protein. Increased activities of the carboxylating enzymes were obtained in the presence of thioglycollate. There is evidence that PEP carboxylase resides in the cytoplasm rather than in either type of chloroplast. These results are discussed in relation to the possible localisation of carboxylation reactions in the sugar cane leaf. PMID- 24493276 TI - [Nuclear basic proteins and growth in hypocotyls of Lupinus albus L. seedlings]. AB - Characteristic changes in the basic nuclear proteins/DNA ratio may be observed during the residual growth of lupine seedling hypocotyls.This ratio decreases at the very beginning of hypocotyl growth (growth initiation) but increases during its active growth. A second decline coincides with gemmule development. No further increase in the relative amount of basic proteins can be observed during the diminishing elongation before growth ceases.These results may be related to the known regulating action of the gemmule on hypocotyl growth. PMID- 24493277 TI - The relative role of stomata in transpiration and assimilation. AB - The ways in which transpiration and assimilation depend on stomatal aperture are compared. It is shown that transpiration and assimilation are equally sensitive to change of stomatal aperture when the internal resistance to assimilation is equal to an effective resistance to evaporation which exists because of the coupling of heat and vapour exchanges between leaf and atmosphere. Generally the ratio of transpiration to assimilation changes with stomatal aperture in a manner which is determined by the relative magnitude of these resistances and on temperature. Some possible implications in relation to the optimal behaviour of stomata are discussed. PMID- 24493278 TI - [The influence of the geotropic induction on the content and the distribution of auxin in the hypocotyls of Helianthus and on their sensitivity to the growth substance]. AB - 1. Comparative measurements of the geotropic curvature and of the auxin distribution in the same gravitational field were performed to test the relation between the transversal growth substance gradient and the observed tropic reaction. In order to examine whether the extent of the curvature is fully explaned by the asymmetry of the auxin distribution in the opposite halves of the stimulated organ, comparable growth substance gradients were produced in vertical hypocotyls by supplying them asymmetrically with synthetic auxin from external sources. After identical times the auxin content in both halves of the organ was measured and compared with the curvatures produced. The general result of all these experiments, repeated under various conditions, is the finding that a given transversal auxin concentration gradient produces much stronger curvatures in organs exposed to the transversal gravitational field than in those left in the vertical position. This observation confirms our assumption that the geotropic stimulus, in addition to changing the auxin distribution in the stimulated organ, also strongly influences its sensitivity to the growth substance. 2. Further comparative measurements revealed still another drastic effect of the geotropic stimulus. Hypocotyls put in the horizontal position absorb considerably more auxin supplied to them laterally than comparable organs do in the vertical position. This effect concerns chiefly the upper half of the stimulated stem. 3. The last experiments of this research deal with the problem of the de novo production of growth substance under the influence of the geotropic stimulus. In the growing zone of intact seedlings the content of endogenous auxin is considerably increased under the influence of the transversally acting gravitation. This effect, however, is completely missing in plants whose natural auxin sources (cotyledons, plumula) have been removed by decapitation. Therefore the possibility has to be considered that the rise of the auxin-level observed in the geotropicaly stimulated zone may be due not to a de novo formation of growth substance but to the increased absorption capacity of the tissue for auxin already present in its natural sources. PMID- 24493279 TI - Lunularic acid, a common endogenous growth inhibitor of liverworts. AB - By gas-liquid chromotography and thin layer chromatography, an endogenous growth inhibitor of Lunularia cruciata has been detected in seven other representatives of the class of liverworts. All liverworts so far examined have been found to contain lunularic acid. Evidence for the identity of the previously isolated, but unidentified, endogenous growth inhibitor of Marchantia polymorpha and lunularic acid is presented. PMID- 24493280 TI - Scanning electron-microscopy of abscission-zone surfaces of Valencia-orange fruit. AB - The scanning electron-microscope was used to obtain a more adequate view of the separation surfaces exposed when the stem was pulled from the fruit of Valencia orange. Separations were made at 0, 24 and 48 h after ethylene treatment of the fruit. The most noticeable differences are the lessened amount of tearing in proximal vascular bundles at 48 h and decreased rupture of distal parenchyma cells first observed at 24 h. PMID- 24493281 TI - Auxin deficiency at the onset on root growth in Allium cepa. AB - 3-Indolylacetic acid (IAA) increased the length of the epidermis cells of onion roots during the initial stage of root growth, when cell length has not yet reached its maximum value, by up to 50% (10(-11) M), while in the later, steady state or dynamic equilibrium stage no promotive effects were present. It is suggested that the lesser elongation capacity of the cells at the onset of root growth is related to a deficiency in auxin while the steady-state phase is characterized by hormonal balance. PMID- 24493282 TI - Association between anti-U1 ribonucleoprotein antibodies and inflammatory mediators in cerebrospinal fluid of patients with neuropsychiatric systemic lupus erythematosus. AB - OBJECTIVE: We investigated possible associations between neurotoxic inflammatory mediators (IMs) and anti-U1RNP antibodies (Abs) in cerebrospinal fluid (CSF) of neuropsychiatric systemic lupus erythematosus (NPSLE). METHODS: Serum and CSF anti-U1RNP Abs were detected using an RNA-immunoprecipitation assay and CSF anti U1RNP Ab levels were measured by ELISA. IFN-alpha, MCP-1 and IL-8 levels in CSF were determined by quantitative multiplex cytokine analysis. IM levels were compared among anti-U1RNP-positive and anti-U1RNP-negative NPSLE as well as other rheumatic disease controls (controls). RESULTS: Anti-U1RNP Abs were detected in serum (58%) and in CSF (18%) of 82 NPSLE patients. CSF MCP-1 levels were higher in NPSLE than in controls. CSF IFN-alpha level was higher in CSF anti-U1RNP Ab positive than in -negative patients or controls. When limited to serum anti-U1RNP Ab-positive patients, however, levels of all three IMs in CSF were higher in CSF anti-U1RNP Ab-positive than in -negative patients. Anti-U1RNP Ab levels in CSF correlated with CSF MCP-1, but not IFN-alpha and IL-8 levels. CONCLUSIONS: CSF anti-U1RNP Ab positivity is associated with increased level of CSF IFN-alpha. MCP 1 levels correlated with CSF anti-U1RNP Ab levels, whereas the increased CSF MCP 1 was not specific to CSF anti-U1RNP Ab-positive NPSLE. PMID- 24493283 TI - Acceleration of SLE-like syndrome development in NZBxNZW F1 mice by beta-glucan. AB - Beta-glucans are naturally occurring polysaccharides that exert important immunostimulatory activities. In the present study, we evaluated whether beta glucans could modulate the development and the course of systemic lupus erythematosus (SLE). To this aim, we employed the classical model of SLE represented by the F1 hybrid between the NZB and NZW mouse strains which develop severe lupus-like phenotypes comparable to that of SLE patients. The administration of beta-glucan was associated to a more aggressive development of the disease and a worse prognosis, as observed from the clinical, biochemical and histopathological data. This finding implies that restraint should be practised in the possible use of beta-glucans as immunomodulators in human therapy in the context of SLE. PMID- 24493284 TI - Dynamically reconfigurable fibre optical spanner. AB - In this paper we describe a pneumatically actuated fibre-optic spanner integrated into a microfluidic Lab-on-a-Chip device for the controlled trapping and rotation of living cells. The dynamic nature of the system allows interactive control over the rotation speed with the same optical power. The use of a multi-layer device makes it possible to rotate a cell both in the imaging plane and also in a perpendicular plane allowing tomographic imaging of the trapped living cell. The integrated device allows easy operation and by combining it with high-resolution confocal microscopy we show for the first time that the pattern of rotation can give information regarding the sub-cellular composition of a rotated cell. PMID- 24493285 TI - Nin one binding protein expression as a prognostic marker in prostate carcinoma. AB - BACKGROUND: To investigate the prognostic value of expression levels of nin one binding protein (Nob1) in prostate carcinoma. METHODS: Nob1 protein levels were evaluated by Western blot in samples from 40 prostate carcinomas and matched adjacent non-neoplastic prostate tissues. Nob1 expression was also assessed by immunohistochemistry in samples from 300 prostate carcinoma and matched adjacent non-neoplastic prostate tissues, as well as 20 benign prostatic hyperplasia samples. The findings were compared with clinical and pathologic parameters and patient outcome. RESULTS: Nob1 protein analysis showed significant differences between the prostate carcinomas and control groups tested. Immunohistochemical analysis showed that Nob1 positivity was higher in prostate carcinoma than that in paired adjacent non-cancerous tissues (58 vs 7 %, P < 0.001). Nob1 positivity was significantly associated with high Gleason scores and metastasis in patients. Nob1 expression was significantly associated with shorter biochemical recurrence free survival (BCRFS). Multivariate analysis revealed that Nob1 is an independent marker for BCRFS. CONCLUSIONS: These findings provide evidence that Nob1 is an indicator of poor prognosis in prostate carcinoma. PMID- 24493286 TI - Meta-analysis of the cytotoxic T-lymphocyte antigen 4 gene +6230G/A polymorphism and cancer risk. AB - OBJECTIVES: Cytotoxic T-lymphocyte antigen-4 (CTLA4, CD152) is one of the most fundamental immunosuppressive cytokines that inhibits T-cell activation and terminates the T-cell response by blocking signals stimulated via CD28. A number of studies have assessed the association between CTLA-4 +6230G/A polymorphism and cancer risk. However, the results remain controversial. METHODS: In the present study, we performed a meta-analysis to derive a more precise estimation of the relationship. A comprehensive literature search was performed using the PubMed database for relevant articles published (updated to November 21, 2013). Odds ratios (ORs) and 95 % confidence intervals (CIs) were used to assess the strength of the association. RESULTS: A total of 13 articles with 14 studies were selected for this meta-analysis, including 4,489 cases and 4,715 controls. Combined analysis revealed no associations between CTLA-4 +6230G/A polymorphism and cancer risk. However, in stratified analysis by cancer type, we found that CTLA-4 +6230G/A polymorphism was associated with the risk of breast cancer (AA vs. AG + GG: OR = 0.77, 95 % CI 0.60-0.97, P = 0.03; AA vs. GG: OR = 0.66, 95 % CI 0.46 0.95, P = 0.02) and cervical cancer (AA vs. AG + GG: OR = 0.56, 95 % CI 0.42 0.75, P < 0.01). Additionally, in subgroup analysis based on ethnicity, significant association was also found between the CTLA-4 +6230G/A polymorphism and cancer risk in the Asian population (AA vs. AG + GG: OR = 0.71, 95 % CI 0.59 0.84, P < 0.01). CONCLUSION: This meta-analysis indicates that CTLA-4 +6230G/A polymorphism may be associated with a decreased risk of breast cancer and cervical cancer in Chinese population. PMID- 24493287 TI - Gene expression signature for biliary atresia and a role for interleukin-8 in pathogenesis of experimental disease. AB - Biliary atresia (BA) is a progressive fibroinflammatory obstruction of extrahepatic bile ducts that presents as neonatal cholestasis. Due to the overlap in clinical, biochemical, and histological features with other causes of cholestasis, the diagnosis requires an intraoperative cholangiogram. Thus, we determined whether diseased livers express a gene expression signature unique to BA. Applying stringent statistical analysis to a genome-wide liver expression platform of 64 infants with BA at the time of diagnosis, 14 age-appropriate subjects with intrahepatic cholestasis as diseased controls and seven normal controls, we identified 15 genes uniquely expressed in BA with an accuracy of 92.3%. Among these genes, IL8 and LAMC2 were sufficient to classify subjects with BA distinctly from diseased controls with an area under the curve of 0.934 (95% confidence interval [CI]: 0.84-1.03), sensitivity of 96.9%, and specificity of 85.7% using their combined first principal component. Direct measurement of interleukin (IL)8 protein in the serum, however, was not different between the two groups. To investigate whether the liver-restricted increase in IL8 was relevant to disease pathogenesis, we inactivated the signaling of IL8 homologs by genetic targeting of the Cxcr2 receptor in a murine model of experimental BA. Disruption of Cxcr2 shortened the duration of cholestasis, decreased the incidence of bile duct obstruction, and improved survival above wild-type neonatal mice. CONCLUSION: The hepatic expression of IL8 and LAMC2 has high sensitivity for BA at diagnosis and may serve as a biomarker of disease, with an important role for the IL8 signaling in experimental BA. PMID- 24493290 TI - Characterization of a reversible lameness model in the horse. AB - OBJECTIVE: Characterization of a model of reversible foot lameness in the horse. METHODS: Both forelimb hooves were fitted with a circumferential clamp. After three baseline measurements utilizing a force platform, one clamp was tightened to induce a grade 2.5/5 lameness and left in place for 120 hours. Serial heart rate and force platform measurements were obtained and the asymmetry index was calculated. After 120 hours, the clamp was released and force platform data recorded until the horse returned to soundness. The procedure was repeated for the opposite forelimb. The responses of treatment compared with the control for each outcome were analysed using linear mixed models. Time, limb (left or right), order of treatment, and interaction between time and order were used as fixed effects, whereas horse and limb were used as random effects. RESULTS: There was a significant increase in lameness associated with time and treatment order, where the second limb treated was more lame, based on the force platform data. The heart rate increased significantly with time and was significantly greater while the first limb was being treated. There was a significant effect of time on the increased subjective lameness score. CLINICAL SIGNIFICANCE: The lameness was present throughout the measurement period, though the level of lameness lessened with time. The model may be applicable for evaluation of mechanisms to treat pain in the horse. The reason for the difference in treatment order needs to be identified. PMID- 24493289 TI - One-day treatment of small molecule 8-bromo-cyclic AMP analogue induces cell based VEGF production for in vitro angiogenesis and osteoblastic differentiation. AB - Small molecule-based regenerative engineering is emerging as a promising strategy for regenerating bone tissue. Small molecule cAMP analogues have been proposed as novel biofactors for bone repair and regeneration and, while promising, the effect that these small molecules have on angiogenesis, a critical requirement for successful bone regeneration, is still unclear. Our previous research demonstrated that the small molecule cAMP analogue 8-bromoadenosine-3',5'-cyclic monophosphate (8-Br-cAMP) was able to promote initial osteoblast adhesion on a polymeric scaffold via cAMP signalling cascades. Here, we report that 8-Br-cAMP is capable of inducing in vitro cell-based VEGF production for angiogenesis promotion. We first demonstrated that treating osteoblast-like MC3T3-E1 cells with 8-Br-cAMP for 1 day significantly increased VEGF production and secretion. We then demonstrated that 8-Br-cAMP-induced cell-secreted VEGF is biologically active and may promote angiogenesis, as evidenced by increased human umbilical vein endothelial cells (HUVECs) migration and tubule formation. In addition, treatment of MC3T3-E1 cells with 8-Br-cAMP for as short as a single day resulted in enhanced ALP activity as well as matrix mineralization, demonstrating in vitro osteoblastic differentiation. A short-term 8-Br-cAMP treatment also addresses the concern of non-specific cytotoxicity, as our data indicate that a 1-day 8-Br-cAMP treatment scheme supports cellular proliferation of MC3T3-E1 cells as well as HUVECs. While the major concern associated with small molecule drugs is the risk of non-specific cytotoxicity, the short exposure treatment outlined in this paper provides a very promising strategy to mitigate the risk associated with small molecules. Copyright (c) 2013 John Wiley & Sons, Ltd. PMID- 24493291 TI - Acute pancreatitis following brentuximab vedotin therapy for refractory Hodgkin lymphoma: a case report. PMID- 24493292 TI - Genetic analysis of a type IV pili-like locus in the archaeon Methanococcus maripaludis. AB - Methanococcus maripaludis is a stringently anaerobic archaeon with two studied surface structures, archaella and type IV pili. Previously, it was shown that three pilin genes (mmp0233 [epdA], mmp0236 [epdB] and mmp0237 [epdC]) located within an 11 gene cluster in the genome were necessary for normal piliation. This study focused on analysis of the remaining genes to determine their potential involvement in piliation. Reverse transcriptase PCR experiments demonstrated the 11 genes formed a single transcriptional unit. Deletions were made in all the non pilin genes except mmp0231. Electron microscopy revealed that all the genes in the locus except mmp0235 and mmp0238 were essential for piliation. Complementation with a plasmid-borne wild-type copy of the deleted gene restored at least some piliation. We identified genes for an assembly ATPase and two versions of the conserved pilin platform forming protein necessary for pili assembly at a separate genetic locus. PMID- 24493293 TI - Purification and characterization of plantaricin Y, a novel bacteriocin produced by Lactobacillus plantarum 510. AB - Lactobacillus plantarum 510, previously isolated from a koshu vineyard in Japan, was found to produce a bacteriocin-like inhibitory substance which was purified and characterized. Mass spectrometry analysis showed that the mass of this bacteriocin is 4,296.65 Da. A partial sequence, NH2- SSSLLNTAWRKFG, was obtained by N-terminal amino acid sequence analysis. A BLAST search revealed that this is a unique sequence; this peptide is thus a novel bacteriocin produced by Lactobacillus plantarum 510 and was termed plantaricin Y. Plantaricin Y shows strong inhibitory activity against Listeria monocytogenes BCRC 14845, but no activity against other pathogens tested. Bacteriocin activity decreased slightly after autoclaving (121 degrees C for 15 min), but was completely inactivated by protease K. Furthermore, trypsin-digested bacteriocin product fragments retained activity against L. monocytogenes BCRC 14845 and exhibited a different inhibitory spectrum. PMID- 24493294 TI - Development of urologic laparoscopy in Germany, Austria, and Switzerland: a survey among urologists. AB - PURPOSE: Laparoscopy introduction has dramatically changed urology. Novel techniques, such as laparoendoscopic single-site surgery (LESS) and natural orifice translumenal endoscopic surgery (NOTES), might also have substantial influence. This 2012 survey evaluated present laparoscopy use, its appraisal among urologic surgeons, laparoscopy training, and use of new techniques. Results were compared to the previous surveys, demonstrating the 10-year development of laparoscopy. METHODS: A detailed questionnaire regarding demographic data, laparoscopy use, attitudes concerning laparoscopy, and novel techniques was send to 424 departments in Germany, Austria, and Switzerland. Procedures performed in 25 indications were quantitatively evaluated. RESULTS: The response rate was 63 % (269). Eighty-six percent of the respondents reported performing laparoscopy, compared to 54 % in 2002. Only 16 % expected economic advantages with laparoscopy, whereas 67 % expected shorter hospitalization. Seventy percent of responders anticipated comparable functional and oncological results between laparoscopic procedures and open surgery. Slow learning curves (81 %) and insufficient training facilities (32 %) were reported to impair laparoscopic surgery. On average, laparoscopic and non-laparoscopic surgical teams consisted of 2.5 and 3.5 members, respectively. LESS procedures were performed at 15 % of institutions. Twenty-two percent of respondents considered NOTES techniques valuable for future urology. Few indications (laparoscopic prostatectomies or nephrectomies) were performed frequently in specialized centers, and the rapidly increasing procedure numbers observed between 2002 and 2007 had dropped to a mild accretion. The results demonstrate broad acceptance of laparoscopy in German urologic surgery, depict the need for structured training facilities, and indicate limited impact of novel techniques (LESS and NOTES). CONCLUSIONS: The survey demonstrates the 10-year development of urologic laparoscopy and the broad acceptance of laparoscopic techniques. PMID- 24493295 TI - How to treat an appendiceal inflammatory mass: operatively or nonoperatively? AB - INTRODUCTION: While there is consensus on how to treat acute appendicitis, the most suitable treatment for an appendiceal inflammatory mass is still debated. This study compares the outcomes of operative and nonoperative management. MATERIAL AND METHODS: We retrospectively evaluated 119 patients (2007-2011) with an appendiceal inflammatory mass, 85 of whom were treated nonoperatively and 34 operatively. Of the nonoperative patients, 69 did not receive interventional treatment and 16 underwent percutaneous drainage of an accompanying abscess; the data for these patients were analyzed separately. RESULTS: Of the noninterventional managed patients, 49 (71.0%) experienced at least one recurrence and 37 (53.6%) ultimately needed an acute surgical or radiological intervention. Of the 16 patients who underwent percutaneous drainage, 7 (43.8%) experienced at least one recurrence and 6 (37.5%) underwent an acute surgical or (second) percutaneous intervention. None of the operated patients had a recurrence and the incidence of complications was 17.6%. The incidence of underlying malignant tumor in our study population was 5.9%. In 35 patients, the definitive diagnosis remained unclear because the patients did not undergo surgery or follow-up colonoscopy after nonoperative treatment. The rate of extensive (ileocecal + hemicolonic) resection in all operated patients was 30.8%. CONCLUSION: We conclude that the high rate of recurrence and intervention in the nonoperative group and the high proportion of these patients who did not receive adequate follow-up despite the relatively high rate (5.9%) of bowel malignancy support the operative management of an appendiceal inflammatory mass. Noninterventional management or a percutaneous intervention should be reserved as a bridge to surgery for patients with a large accompanying abscess or as treatment for patients with significant comorbidity. If nonoperative treatment is chosen, follow-up colonoscopy is mandatory to exclude malignancy. PMID- 24493296 TI - Single-stage vs. two-stage management for concomitant gallstones and common bile duct stones: a prospective randomized trial with long-term follow-up. AB - AIM: The preferred approach to the management of common bile duct (CBD) stones is uncertain, with single-stage laparoscopic cholecystectomy and CBD exploration vs. two-stage preoperative endoscopic CBD clearance followed by laparoscopic cholecystectomy being debated. To address this, a prospective randomized study which compared these two management strategies was undertaken. METHODS: Between Jan 2002 and Dec 2005, patients with gallstones and common bile duct stones diagnosed by preoperative ultrasonography and magnetic resonance cholangiopancreatography were randomized to single-stage vs. two-stage treatment. In a single-stage group, laparoscopic cholecystectomy and CBD exploration were undertaken at the same operation, whereas in a two-stage group, endoscopic stone clearance was followed by laparoscopic cholecystectomy 2-5 days later. Early treatment success and complications and longer-term follow-up for the two groups were compared. RESULTS: Two hundred twenty-one patients were enrolled in the trial, 110 in the single-stage group and 111 in the two-stage group. There was no significant difference in the success rate of CBD clearance (93.6 vs. 94.6%, p = 0.76) or the complication rates (3.6 vs. 5.1%, p = 0.527) between the groups. However, at longer-term follow-up, recurrent CBD stones were seen more often in the two-stage group (9.5 vs. 2.1%, p = 0.037). CONCLUSION: The single-stage and two-stage approaches were equally effective in achieving initial clearance of CBD stones. However, recurrent CBD stones occurred more commonly in patients who had undergone two-stage treatment with initial endoscopic stone clearance, followed by laparoscopic cholecystectomy. PMID- 24493299 TI - Association of the type of 5q loss with complex karyotype, clonal evolution, TP53 mutation status, and prognosis in acute myeloid leukemia and myelodysplastic syndrome. AB - We analyzed 1,200 patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) harboring a 5q deletion in order to clarify whether the type of 5q loss is associated with other biological markers and prognosis. We investigated all patients by chromosome banding analysis, FISH with a probe for EGR1 (5q31) and, if necessary, to resolve complex karyotypes with 24-color-FISH. Moreover, 420 patients were analyzed for mutations in the TP53 gene. The patient cohort was subdivided based on type of 5q loss: Patients with interstitial deletions and patients with 5q loss due to unbalanced rearrangements or monosomy 5. Loss of the long arm of chromosome 5 due to an unbalanced rearrangement occurred more often in AML (286/627; 45.6%) than MDS (188/573; 32.8%; P < 0.001). In both entities, patients with 5q loss due to unbalanced translocations showed complex karyotypes more frequently (MDS: 179/188; 95.2% vs. 124/385; 32.2%; P < 0.001; AML: 274/286; 95.8% vs. 256/341; 75.1%; P < 0.001). Moreover, in MDS unbalanced 5q translocations were associated with clonal evolution (109/188; 58.0% vs. 124/385; 32.2%; P < 0.001), mutation of TP53 (64/67; 95.5% vs. 40/120; 40.0%; P < 0.001), and shorter survival (15.3 months vs. not reached; P < 0.001). In MDS, complex karyotype was an independent adverse prognostic factor (HR = 5.34; P = 0.032), whereas in AML presence of TP53 mutations was the strongest adverse prognostic factor (HR = 2.21; P = 0.026). In conclusion, in AML and MDS, loss of the long arm of chromosome 5 due to unbalanced translocations is associated with complex karyotype and in MDS, moreover, with clonal evolution, mutations in the TP53 gene and adverse prognosis. PMID- 24493298 TI - Effects of Pro-Tex on zebrafish (Danio rerio) larvae, adult common carp (Cyprinus carpio) and adult yellowtail kingfish (Seriola lalandi). AB - Aquaculture practices bring several stressful events to fish. Stressors not only activate the hypothalamus-pituitary-interrenal-axis, but also evoke cellular stress responses. Up-regulation of heat shock proteins (HSPs) is among the best studied mechanisms of the cellular stress response. An extract of the prickly pear cactus (Opuntia ficus indica), Pro-Tex, a soluble variant of TEX-OE((r)), may induce expression of HSPs and reduce negative effects of cellular stress. Pro Tex therefore is used to ameliorate conditions during stressful aquaculture related practices. We tested Pro-Tex in zebrafish (Danio rerio), common carp (Cyprinus carpio L.) and yellowtail kingfish (Seriola lalandi) exposed to aquaculture-relevant stressors (thermal stress, net confinement, transport) and assessed its effects on stress physiology. Heat shock produced a mild increase in hsp70 mRNA expression in 5-day-old zebrafish larvae. Pro-Tex increased basal hsp70 mRNA expression, but decreased heat-shock-induced expression of hsp70 mRNA. In carp, Pro-Tex increased plasma cortisol and glucose levels, while it did not affect the mild stress response (increased plasma cortisol and glucose) to net confinement. In gills, and proximal and distal intestine, stress increased hsp70 mRNA expression; in the distal intestine, an additive enhancement of hsp70 mRNA expression by Pro-Tex was seen under stress. In yellowtail kingfish, Pro-Tex reduced the negative physiological effects of transport more efficiently than when fish were sedated with AQUI-S((r)). Overall, our data indicate that Pro-Tex has protective effects under high levels of stress only. As Pro-Tex has potential for use in aquaculture, its functioning and impact on health and welfare of fish should be further studied. PMID- 24493300 TI - Disease mechanisms and clonidine treatment in adolescent chronic fatigue syndrome: a combined cross-sectional and randomized clinical trial. AB - IMPORTANCE: Chronic fatigue syndrome (CFS) is a disabling condition with unknown disease mechanisms and few treatment options. OBJECTIVE: To explore the pathophysiology of CFS and assess clonidine hydrochloride pharmacotherapy in adolescents with CFS by using a hypothesis that patients with CFS have enhanced sympathetic activity and that sympatho-inhibition by clonidine would improve symptoms and function. DESIGN, SETTING, AND PARTICIPANTS: Participants were enrolled from a single referral center recruiting nationwide in Norway. A referred sample of 176 adolescents with CFS was assessed for eligibility; 120 were included (34 males and 86 females; mean age, 15.4 years). A volunteer sample of 68 healthy adolescents serving as controls was included (22 males and 46 females; mean age, 15.1 years). The CSF patients and healthy controls were assessed cross-sectionally at baseline. Thereafter, patients with CFS were randomized 1:1 to treatment with low-dose clonidine or placebo for 9 weeks and monitored for 30 weeks; double-blinding was provided. Data were collected from March 2010 until October 2012 as part of the Norwegian Study of Chronic Fatigue Syndrome in Adolescents: Pathophysiology and Intervention Trial. INTERVENTIONS: Clonidine hydrochloride capsules (25 ug or 50 ug twice daily for body weight <35 kg or >35 kg, respectively) vs placebo capsules for 9 weeks. MAIN OUTCOMES AND MEASURES: Number of steps per day. RESULTS: At baseline, patients with CFS had a lower number of steps per day (P < .001), digit span backward score (P = .002), and urinary cortisol to creatinine ratio (P = .001), and a higher fatigue score (P < .001), heart rate responsiveness (P = .02), plasma norepinephrine level (P < .001), and serum C-reactive protein concentration (P = .04) compared with healthy controls. There were no significant differences regarding blood microbiology evaluation. During intervention, the clonidine group had a lower number of steps per day (mean difference, -637 steps; P = .07), lower plasma norepinephrine level (mean difference, -42 pg/mL; P = .01), and lower serum C-reactive protein concentration (mean ratio, 0.69; P = .02) compared with the CFS placebo group. CONCLUSIONS AND RELEVANCE: Adolescent CFS is associated with enhanced sympathetic nervous activity, low-grade systemic inflammation, attenuated hypothalamus pituitary-adrenal axis function, cognitive impairment, and large activity reduction, but not with common microorganisms. Low-dose clonidine attenuates sympathetic outflow and systemic inflammation in CFS but has a concomitant negative effect on physical activity; thus, sympathetic and inflammatory enhancement may be compensatory mechanisms. Low-dose clonidine is not clinically useful in CFS. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01040429. PMID- 24493301 TI - Conformational and coalescence behavior of trialkylphosphates in vacuum, water and dodecane. AB - The conformations of trialkylphosphates (alkyl = propyl, butyl, pentyl and hexyl) in various diluents were studied by molecular dynamics simulations. The population density of various conformers of trialkylphosphate in different diluents such as water and n-dodecane was determined. The Helmholtz energy change accompanied by the transition between various conformations was computed. The aggregation behavior of tributylphosphate in water and water-dodecane medium was studied. PMID- 24493303 TI - Epicuticular wax in the stomatal antechamber of sitka spruce and its effects on the diffusion of water vapour and carbon dioxide. AB - The distribution of wax tubes on the leaf surfaces is described, especially the presence of wax tubes in the antechambers of the stomata. The extra resistances which the wax-filled antechambers add to the other resistances in the pathway for diffusion of water vapour and of carbon dioxide are calculated. We conclude that the wax-filled stomatal antechambers reduce the rate of transpiration by about two thirds but reduce the rate of photosynthesis by only about one third. Thus wax-filled stomatal antechambers are excellent antitranspirants. PMID- 24493304 TI - Chlorophyll formation and the development of photosynthesis in illuminated etiolated pea leaves. AB - The protein synthesis inhibitors chloramphenicol and terramycin, and light of low intensity were used to retard the rate of chlorophyll formation in illuminated dark grown pea leaves. In the control leaves the onset of photosynthesis, as measured by carbon dioxide exchange of the whole leaves, and reduction of ferricyanide and metmyoglobin and photo-oxidation of ascorbate in isolated chloroplasts, was observed after 2-4 hours illumination. The photosynthetic activity of the treated leaves did not commence until 10-12 hours illumination had elapsed. In both the control and treated leaves the onset of photosynthesis occurred when the total chlorophyll content was 0.04 mg/g fresh weight. The precise point of photosynthetic inception was apparently more related to the attainment of a specific total chlorophyl content than to the ratio of chlorophyll a to chlorophyll b. A marked increase in the evolution of carbon dioxide in the light was observed in the treated leaves during the first 10 hours of greening. This observation could not be ascribed to photorespiration since the leaves did not possess an active photosystem. It is suggested that the enhanced respiration may have been due to the light-induced activation of synthetic pathways responsible for the formation of chloroplast constituents. PMID- 24493305 TI - [Changes in labelling patterns after feeding Bryophyllum tubiflorum with (14)CO 2 at different moments during the light/dark period : II. Relations between malate content of the tissue and the labelling patterns after (14)CO 2 light fixation]. AB - The distribution of radioactivity between the products of (14)CO2 light fixation in phyllodia of Bryophyllum tubiflorum could be influenced experimentally by manipulating the malic acid content of the cells. Accelerating the deacidification of the tissue during the light period by application of higher light intensities accelerated the increase of malate labelling and the decrease of the sucrose labelling after (14)CO2 light fixation under our standard conditions (10 min preillumination, 15 min (14)CO2 light fixation, 8000 lux).In other experiments different malate contents of the tissues were induced by treating the phyllodia with different temperatures during the night period. In the morning, phyllodia with low malate content transferred most of the label into malate, and phyllodia with high malate content incorporated most of the (14)C radioactivity into sugars. However, this was true only after preillumination of 1 hour. When the phyllodia fixed (14)CO2 without preillumination, no differences in the labelling patterns between acidified and non-acidified phyllodia could be observed.In experiments using leaf tissue slices of Bryophyllum daigremontianum we could again observe that malate was labelled more heavily in the deacidified tissue than in the acidified controls, with less radioactivity being transferred into phosphate esters and sugars. The rates of (14)CO2 light fixation were identical in tissue slices with high and low malate content. However, the rates of CO2 dark fixation in the acidified samples were clearly lower than those in the deacidified ones. The low rate of CO2 dark fixation in acidified samples could not be inhibited by an inhibitor of PEP-carboxylase as the high CO2 dark fixation rate of the deacidified tissue could be inhibited.The results are discussed in relation to the feed back inhibition of PEP-carboxylase in vivo by malate. Compartmentation also seemed to be involved in controlling the flow of carbon during CO2 light fixation in succulent tissue. PMID- 24493306 TI - [Fine structure in the extrafloral nectary of Vicia faba L]. AB - In the extrafloral nectary of the broad bean there is evidence of two fundamental types of cells: one with dense hyaloplasm, well developed ergastoplasm and golgi apparatus, all features of glandular cells, and another with opposite features. The cells of the head of the secretory hairs and those of the subjacent epidermis which are not prolonged with such a hair are of the first type. The epidermal cells prolonged with a hair and the pedicellar cell of this hair are of the second type. Moreover, the companion cells of the subjacent conducting bundle look like cells of the first type, especially those of the head of the secretory hairs owing to their numerous wall protuberances. Cells of the second type are presumably involved in transit processes between phloem and trichome, and cells of the first type in excretory processes. PMID- 24493307 TI - [Influence of rifampicin, chloramphenicl and cycloheximide on uridine incorporation into chloroplast ribosome precursors of Chlorella]. AB - The unicellular green alga Chlorella incorporates labeled uridine mainly into the precursors of chloroplast ribosomes. After treatment with rifampicin for 60 min, the uridine incorporation into the particles is completely inhibited. Chloramphenicol treatment results in the same complete inhibition. In constrast, cycloheximide (actidione) slightly stimulates the incorporation of uridine into the chloroplast ribosome precursors.Short-time incorporation of inorganic phosphate into the ribosome fractions is nearly unaffected by rifampicin and chloramphenicol, but it is strongly inhibited by cycloheximide.Isolation and chromatographic separation of nucleic acids after treatment of cells with rifampicin shows that uridine incorporation into RNA is completely inhibited. Chloramphenicol causes only partial inhibition of uridine labeling in the high molecular weight RNA. Here again, cycloheximide stimulates the uridine incorporation.The results indicate that uridine is preferentially incorporated by Chlorella cells into the chloroplast ribosome precursors. Inorganic phosphate is introduced both into cytoplasmic and into chloroplasmic RNA, but because of the quantitative distribution, the cytoplasmic ribosomes are more extensively labeled. Since only inhibitors of bacterial and chloroplasmic RNA-and protein synthesis affect the formation of uridine-labeled ribosomes, this synthesis must take place in the chloroplast itself. PMID- 24493308 TI - "Apical dominance" in the sporangiophore of the fungus Phycomyces. AB - Control, by the spores, over the elongation and the branching of the sporangiophore is described. If the sporangium is removed from a sporangiophore, the sporangiophore stops growing within a few hours. 6-16h later a branch grows from the defunct growing zone. This branch forms a new sporangium and spores, and then starts to elongate again. The original growing zone can be "rescued" by replacing the sporangium with another sporangium or a sporangium-sized drop of spores. If the original growing zone is rescued, then it continues growing and the sporangiophore does not form a branch. It can only be rescued, however, within the first 60 min after the original sporangium is removed. PMID- 24493309 TI - Oxygen consumption of Phycomyces sporangiophores. AB - The respiration of stage-I,-III, and-IV sporangiophores of Phycomyces was measured. The [Formula: see text] of stages-I and-IV is low compared to that of actively growing mycelium. The [Formula: see text] of stage-III sporangiophores is somewhat higher than that of stages-I and-IV. As stage-I sporangiophores elongate their respiration rate increases proportionately. The respiration rate of stage-IV sporangiophores does not change as they elongate. In stage-IV sporangiophores the growing zone and the columella together consume as much oxygen as the rest of the sporangiophore does. Changes in the sporangiophore's growth rate have no effect on its oxygen consumption. PMID- 24493310 TI - Physiological aspects of conjugation in fission yeast. AB - Conjugation was studied in Schizosaccharomyces pombe using liquid media. Nitrogen, which was growth-limiting in a synthetic medium, had to be consumed completely before conjugation could start. Conjugation was preceded by sexual agglutination. Agglutinability was not constitutive in heterothallic strains. It only developed when cells of h (+) and h (-) mating type were grown in mixed culture for at least 2.5 hr before the start of conjugation. PMID- 24493311 TI - Outcomes after liver transplantation for patients with hepatocellular carcinoma and a low risk of dropout from the transplant waiting list. PMID- 24493312 TI - The combined expression of VPREB3 and ID3 represents a new helpful tool for the routine diagnosis of mature aggressive B-cell lymphomas. AB - Genomic studies, such as gene expression profiling and next-generation sequencing studies, have provided new insights into the phenotypic characteristics and pathogenesis of mature aggressive B-cell lymphomas. In particular, mutations in the transcription factors ID3 and TCF3, leading to overexpression of B-cell receptor components such as VPREB3, have been shown to be specific for Burkitt lymphoma (BL) and play an important tumourigenic role by mediating the activation of the pro-survival phosphatidylinositol-3-OH kinase pathway. We performed immunohistochemical analysis by applying commercially available anti-VPREB3 antibody to a large cohort of 185 genetically and immunophenotypically characterized mature aggressive B-cell lymphomas and analyzed these results together with recent data on ID3 expression. The combined expression of both VPREB3 and ID3 was associated with a diagnosis of BL with high sensitivity (0.77), high specificity (0.75) and high negative predictive values (0.96), however, with lower positive predictive value (0.30). Double negative cases were absent in the group of BLs but could be found in approximately one third of the remaining cases of mature aggressive B-cell lymphomas. Further, we could not identify a correlation with MYC, BCL2 or BCL6 aberrations with neither VPREB3 nor ID3 expression in each of the diagnostic groups analyzed. Our results, which are in line with recently discovered mutations in next-generation sequencing studies, suggest that the combined immunohistochemical detection of VPREB3 and ID3 is applicable to the routine diagnostic in case of mature aggressive B-cell lymphomas. In particular, it represents a useful and routinely applicable diagnostic tool to exclude BL diagnosis in case of single positive or double negative cases. PMID- 24493313 TI - Role of P2X7 purinoceptors in neuroprotective mechanism of ischemic postconditioning in mice. AB - Cerebral ischemia-reperfusion (I-R) injury is one of the primary causes of ischemic stroke. Ischemic postconditioning (iPoCo) is evolving as an important adaptive technique to contain I-R injury. Some recent studies have shown neuroprotective effect of iPoCo. However, neuroprotective mechanism of iPoCo is not clear. So, the present study has been undertaken to investigate the possible role of P2X7 purinoceptors in neuroprotective mechanism of iPoCo in mice. Bilateral carotid artery occlusion for 12 min followed by R for 24 h produced a significant rise in cerebral infarct size and neurological severity score (NSS) along with impairment of memory and motor coordination. iPoCo, involving three episodes of 10-s carotid artery occlusion with intermittent R of 10 s applied just after ischemic insult of 12 min, produced a significant decrease in cerebral infarct size and NSS along with reversal of I-R-induced impairment of memory and motor coordination. iPoCo induced neuroprotective effects were significantly abolished by pretreatment with selective purinergic P2X7 receptor blocker Brilliant Blue G (40 mg/kg intraperitoneal). It may be concluded that neuroprotective effect of iPoCo probably involves in activation of purinergic P2X7 receptors. PMID- 24493314 TI - FoxO3a-mediated activation of stress responsive genes during early torpor in a mammalian hibernator. AB - The torpor-arousal cycle of mammalian hibernation is characterized by drastic changes in physiological state that are supported by reprogramming of metabolic functions. The entrance and arousal phases of the cycle function as transitional stages, where major changes in oxygen metabolism take place. Acute changes in oxygen delivery can lead to either ischemia-related injuries during torpor induction or reperfusion damage during arousal. This study examines the regulation of the forkhead box O3 (FoxO3) transcription factor, which functions to increase cellular cytoprotection in response to oxidative stress stimuli. Immunoblots show that total expression of FoxO3a was elevated during early torpor (ET) and late torpor by 3.6- and 4.5-fold, respectively, compared to euthermic control. However, enhanced phosphorylation of FoxO3a at Thr-32 was only evident during ET by 1.5-fold, accompanied by increased phosphorylation of c-Jun N terminal kinases by 1.2-fold. During ET, increased nuclear inclusion of FoxO3a was evident along with its transcriptional co-activator beta-catenin by 1.9- and 2.7-fold, respectively. As well, FoxO3a DNA binding was elevated by 1.8-fold during ET, along with increased expression of FoxO3a downstream genes catalase, p27, and cyclin G 2 , by 1.4-, 1.6-, and 1.3-fold, respectively. Overall, the results indicate activation of FoxO3a during ET, suggesting a role of FoxO3a in response to cellular stress during hibernation. PMID- 24493315 TI - Advances in tissue engineering through stem cell-based co-culture. AB - Stem cells are the future in tissue engineering and regeneration. In a co culture, stem cells not only provide a target cell source with multipotent differentiation capacity, but can also act as assisting cells that promote tissue homeostasis, metabolism, growth and repair. Their incorporation into co-culture systems seems to be important in the creation of complex tissues or organs. In this review, critical aspects of stem cell use in co-culture systems are discussed. Direct and indirect co-culture methodologies used in tissue engineering are described, along with various characteristics of cellular interactions in these systems. Direct cell-cell contact, cell-extracellular matrix interaction and signalling via soluble factors are presented. The advantages of stem cell co-culture strategies and their applications in tissue engineering and regenerative medicine are portrayed through specific examples for several tissues, including orthopaedic soft tissues, bone, heart, vasculature, lung, kidney, liver and nerve. A concise review of the progress and the lessons learned are provided, with a focus on recent developments and their implications. It is hoped that knowledge developed from one tissue can be translated to other tissues. Finally, we address challenges in tissue engineering and regenerative medicine that can potentially be overcome via employing strategies for stem cell co-culture use. PMID- 24493316 TI - Hypertrophic cardiomyopathy with familial chylomicronemia syndrome: is it an incidental finding or a new association? PMID- 24493317 TI - Lissencephaly with subcortical band heterotopia in an Indian family. PMID- 24493318 TI - Spirometric evaluation in juvenile idiopathic arthritis: data from eastern India. AB - OBJECTIVE: To evaluate lung function in juvenile idiopathic arthritis (JIA) patients. METHODS: This was a case control study carried out at Institute of Post Graduate Medical Education & Research, Kolkata, involving JIA patients between 5 and 12 y. They were diagnosed and classified on the basis of International League of Associations for Rheumatology (ILAR) criteria and compared with same number of age, sex, height and weight matched controls. Forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1), FEV1/FVC ratio, forced expiratory flow between 25 and 75% of vital capacity (FEF25-75%) and peak expiratory flow rate (PEFR) of cases were compared to those of matched controls. RESULTS: Among 36 JIA patients initially recruited, 9 were excluded. Of the remaining 27 patients, male: female ratio was 17:10. Mean age, height and weight of JIA patients were 9.15 y, 124.67 cm and 23.78 kg respectively. Six patients had oligoarthritis, 3 had rheumatoid factor positive (RF+) polyarthritis, 10 had rheumatoid factor negative (RF-) polyarthritis and 8 had systemic JIA. Eleven patients had active disease and 15 patients required methotrexate. None had respiratory symptoms. Mean duration of the disease was 2.96 y. Mean FVC and FEV1 were significantly less in JIA patients compared to controls (p value=0.0003 and 0.0007, respectively). FEV1/FVC in both the groups was similar (p value=0.96). Mean Z scores for FVC and FEV1 were significantly higher in JIA patients (p value=0.0064 and 0.0030, respectively). CONCLUSION: Spirometry in JIA patients demonstrated statistically significant restrictive pattern of alteration in pulmonary function. PMID- 24493319 TI - Late symptomatic myocarditis in Kawasaki disease: an unusual manifestation. PMID- 24493320 TI - The microvasculature in the equine distal phalanx: implications for fracture healing. AB - OBJECTIVES: To describe the intra-osseous microvasculature of the distal phalanx of the equine forelimb with regard to its potential clinical relevance. METHODS: Eleven clinically normal equine forelimbs were used from six adult horses (range: 4 to 18 years old) euthanatized for reasons unrelated to lameness. In each limb the median artery was catheterized at the level of the carpus and India ink was injected under constant manual pressure. The limbs were frozen and 5 mm thick sections of the foot were cut in the sagittal, coronal, or transverse planes on a band saw. The sections were fixed in 10% formalin and cleared using a modified Spalteholz technique. Once cleared, the sections were photographed and the microvascular anatomy identified. RESULTS: The vascular injections revealed a rich intra-osseous microvascular supply of the distal phalanx originating from the medial and lateral palmar digital arteries. In addition, numerous smaller vessels from the terminal arch, formed by anastomosis of the medial and lateral palmar digital arteries, could be seen branching into the distal aspects of the distal phalanx. This distal portion of the distal phalanx appeared more densely vascularized than the proximal part in all specimens examined. CLINICAL SIGNIFICANCE: The increased vascularity demonstrated in the distal portion of the distal phalanx appears to correlate with improved fracture healing reported in this area. This may also explain why healing fractures which involve both the distal and proximal portions of the distal phalanx have been described as progressing from distal-to-proximal. PMID- 24493321 TI - Specialty use among patients with treated hypertension in a patient-centered medical home. AB - BACKGROUND: Little is known about how delivery of primary care in the patient centered medical home (PCMH) influences outpatient specialty care use. OBJECTIVE: To describe changes in outpatient specialty use among patients with treated hypertension during and after PCMH practice transformation. DESIGN: One-group, 48 month interrupted time series across baseline, PCMH implementation and post implementation periods. PATIENTS: Adults aged 18-85 years with treated hypertension. INTERVENTION: System-wide PCMH redesign implemented across 26 clinics in an integrated health care delivery system, beginning in January 2009. MAIN MEASURES: Resource Utilization Band variables from the Adjusted Clinical Groups case mix software characterized overall morbidity burden (low, medium, high). Negative binomial regression models described adjusted annual differences in total specialty care visits. Poisson regression models described adjusted annual differences in any use (yes/no) of selected medical and surgical specialties. KEY RESULTS: Compared to baseline, the study population averaged 7% fewer adjusted specialty visits during implementation (P < 0.001) and 4% fewer adjusted specialty visits in the first post-implementation year (P = 0.02). Patients were 12% less likely to have any cardiology visits during implementation and 13% less likely during the first post-implementation year (P < 0.001). In interaction analysis, patients with low morbidity had at least 27% fewer specialty visits during each of 3 years following baseline (P < 0.001); medium morbidity patients had 9% fewer specialty visits during implementation (P < 0.001) and 5% fewer specialty visits during the first post-implementation year (P = 0.007); high morbidity patients had 3% (P = 0.05) and 5% (P = 0.009) higher specialty use during the first and second post-implementation years, respectively. CONCLUSIONS: Results suggest that more comprehensive primary care in this PCMH redesign enabled primary care teams to deliver more hypertension care, and that many needs of low morbidity patients were within the scope of primary care practice. New approaches to care coordination between primary care teams and specialists should prioritize high morbidity, clinically complex patients. PMID- 24493322 TI - Antihypertensive medication initiation among young adults with regular primary care use. AB - BACKGROUND: Young adults with hypertension have the lowest prevalence of controlled blood pressure compared to middle-aged and older adults. Uncontrolled hypertension, even among young adults, increases future cardiovascular event risk. However, antihypertensive medication initiation is poorly understood among young adults and may be an important intervention point for this group. OBJECTIVE: The purpose of this study was to compare rates and predictors of antihypertensive medication initiation between young adults and middle-aged and older adults with incident hypertension and regular primary care contact. DESIGN: A retrospective analysis PARTICIPANTS: Adults >= 18 years old (n = 10,022) with incident hypertension and no prior antihypertensive prescription, who received primary care at a large, Midwestern, academic practice from 2008-2011. MAIN MEASURES: The primary outcome was time from date of meeting hypertension criteria to antihypertensive medication initiation, or blood pressure normalization without medication. Kaplan-Meier analysis was used to estimate the probability of antihypertensive medication initiation over time. Cox proportional-hazard models (HR; 95% CI) were fit to identify predictors of delays in medication initiation, with a subsequent subpopulation analysis for young adults (18-39 years old). KEY RESULTS: After a mean follow-up of 20 (+/-13) months, 34% of 18-39 year-olds with hypertension met the endpoint, compared to 44% of 40-59 year-olds and 56% of >= 60 year-olds. Adjusting for patient and provider factors, 18-39 year-olds had a 44% slower rate of medication initiation (HR 0.56; 0.47-0.67) than >= 60 year olds. Among young adults, males, patients with mild hypertension, and White patients had a slower rate of medication initiation. Young adults with Medicaid and more clinic visits had faster rates. CONCLUSIONS: Even with regular primary care contact and continued elevated blood pressure, young adults had slower rates of antihypertensive medication initiation than middle-aged and older adults. Interventions are needed to address multifactorial barriers contributing to poor hypertension control among young adults. PMID- 24493323 TI - Effects of simvastatin, ezetimibe, and their combination on histopathologic alterations caused by adjuvant-induced arthritis. AB - The objective of the present study was to investigate the effects of monotherapy with simvastatin or ezetimibe compared with those of an ezetimibe + simvastatin combination on the histopathologic aspects of arthritis induced by Complete Freund's Adjuvant in rats. The characteristics of diarthrosis were analyzed 7 and 28 days after arthritis induction with regard to the regularity and integrity of articular cartilage, the presence of leukocytes in blood vessels at the inflammation site, and the cytokine levels in articular tissue. Monotherapy with simvastatin or ezetimibe and the ezetimibe + simvastatin combination effectively reduced the cytokine levels (interleukin-6 and tumor necrosis factor) and articular lesions that are characteristic of this experimental disease. Although the results did not reveal significant differences between the monotherapy and the combined therapy, they suggest that these drugs have considerable antiinflammatory properties, as reflected by an attenuation of articular cartilage lesions mediated by a reduction in the levels of proinflammatory cytokines. PMID- 24493324 TI - Cordycepin (3'-deoxyadenosine) down-regulates the proinflammatory cytokines in inflammation-induced osteoporosis model. AB - The effect of cordycepin (3'-deoxyadenosine) on inflammation-induced osteoporosis (IMO) was studied in this paper. After the rats were treated orally with cordycepin (20 mg/kg), serum osteocalcin (OC), homocysteine (HCY), C-terminal cross-linked telopeptides of collagen type I (CTX), maleic dialdehyde (MDA), polymorphonuclear cells (PMN), interleukin-1beta (IL-1beta), and tumor necrosis factor-alpha (TNF-alpha), they were examined by ELISA or immunohistochemistry. The specimens from the liver were also processed for light microscopic examination. The IMO rats showed a significant increase in plasma CTX, MDA, PMN, IL-1beta, TNF-alpha, and nitrate levels as well as a significant decrease in plasma OC. These changes were attenuated by cordycepin (20 mg/kg) supplementation in the IMO rats. Examination of the liver specimens revealed mononuclear cell infiltration in the portal areas in the IMO rats which was not detected in the cordycepin (20 mg/kg) rats. These results suggest that cordycepin may act as an anti-inflammatory agent in magnesium silicate-induced inflammation in osteoporosis. PMID- 24493325 TI - Gapdh gene expression is modulated by inflammatory arthritis and is not suitable for qPCR normalization. AB - Gene expression studies are fundamental for the understanding of complex diseases, providing new insights into the pathogenic process and new tools for diagnostic and patient stratification. Gene profiling studies by real-time PCR require the use of reference genes for normalization and an appropriate validation is essential for accurate results. We performed a comprehensive assessment of six common housekeeping genes in the K/BxN serum-induced arthritis model in mice. Classical statistics and NormFinder analyses pointed out Gapdh as the less stable and therefore unsuitable as a reference control. Gapdh was considerably down-regulated in arthritic joints and therefore produced an overestimation of transcriptional changes. Hptr, B2m, and Rpl13a showed the most constant expression. Collectively our data advise against the use of Gapdh in gene expression studies in the acute phase of the K/BxN model and adds a cautionary note on the need to validate the reference genes for reliable, comparable, and reproducible results. PMID- 24493326 TI - Coblation total tonsillectomy and adenoidectomy versus coblation partial intracapsular tonsillectomy and adenoidectomy in children. AB - OBJECTIVES/HYPOTHESIS: To evaluate the postoperative course of children who underwent coblation T&A versus those who underwent coblation partial intracapsular tonsillectomy and adenoidectomy (PITA). STUDY DESIGN: Retrospective cohort study. METHODS: Records of children undergoing consecutive tonsillectomies from July 2009 to October 2012 were analyzed. All surgeries used a coblation device. Outcomes including intraoperative and postoperative bleeding, pain, and return to preoperative diet were analyzed comparing the coblation T&A and coblation PITA patients. RESULTS: Of 415 patients evaluated, 258 (62.2%) underwent coblation T&A and 157 (37.8%) underwent coblation PITA. Seventeen (4.1%) patients experienced postoperative hemorrhage, 15 (88.2%) of whom underwent T&A and two (11.8%) of whom underwent PITA (P = 0.024). Multivariate analysis demonstrated that coblation T&A was a significant contributor to postoperative hemorrhage, with an odds ratio of 4.8 (95% confidence interval [CI]: 1.08-21.21) compared to coblation PITA. Patients who underwent T&A resumed normal diets significantly later (8 days, SD 4.6) than those who underwent PITA (5.4 days, standard deviation [SD]: 3.4) (P = 0.022). In terms of pain severity, more T&A patients reported "severe" pain and more PITA patients reported "moderate" pain (P = 0.047). More T&A patients experienced a "post-op dip," defined as increased pain during postoperative days 5-9, than did PITA patients (P < 0.001). CONCLUSIONS: Coblation PITA is a safe procedure that has a lower incidence of intraoperative and postoperative bleeding in children compared to coblation T&A. Patients may have less pain and return to preoperative diets sooner than those undergoing coblation T&A. PMID- 24493327 TI - Prognostic implications of optimal medical therapy in patients undergoing percutaneous coronary intervention for acute coronary syndrome in octogenarians. AB - The proportion of elderly acute coronary syndrome (ACS) patients who receive optimal medical therapy (OMT) after percutaneous coronary intervention (PCI) and whether OMT affects their long-term outcomes remain unclear. We retrospectively investigated 405 ACS patients who underwent stent implantation between 2005 and 2009, and compared the outcomes between patients <80 years of age vs. >=80 years of age. The prescription rate of the recommended medical agents for ACS in both groups during hospitalization and 2 years after admission was also retrieved. Among the enrolled study population, 75 patients (19%) were aged >=80 years. These elderly patients had a higher 2-year mortality compared with patients aged <80 years group. The prescription rate of beta-blockers, angiotensin-blocking drugs, and statins tended to be lower in patients aged >=80 years than in those aged <80 years. Furthermore, among patients >=80 years of age, those who received OMT had better clinical outcome of 2-year mortality compared to those without OMT. Elderly patients with ACS treated by PCI are at substantially higher risk of adverse events than younger patients. However, they are less likely to receive OMT. PCI with OMT might improve the clinical outcomes of elderly ACS patients. PMID- 24493329 TI - Conundrum of treatment for early-stage hepatocellular carcinoma: radiofrequency ablation instead of liver transplantation as the first-line treatment? PMID- 24493328 TI - Nucleotide differences of coxsackievirus B3 and chronic myocarditis. AB - The in vivo mechanisms in chronic myocarditis remain unclear. The aim of the current study was to clarify the genomic difference of amyocarditic (CB3O) and myocarditic (CB3M) coxsackievirus B3 (CB3) and the pathogenesis of in vivo mechanisms in chronic myocarditis. We examined the histopathology of CB3 inoculated wild-type (WT) and severe combined immunodeficient (SCID) mice with and without adoptive transfer of lymphocytes. There were no differences in viral growth between CB3O and CB3M. There were four to six nucleotide differences in the sequence of CB3O in comparison with the known CB3M. The difference in virus sequence between CB3O and CB3M was very minimal. The changes were located in 1A, 1C, and 1D regions, which encode the structural capsid proteins. Definite myocarditis developed in WT C3H (H-2(k)) inoculated with CB3M. On the contrary, trivial or mild myocarditis occurred in WT C3H mice inoculated with CB3O. In SCID C3H and SCID C57BL/6 (H-2(b)) mice, definite myocarditis developed by inoculation with both CB3O and CB3M. Myocardial lesion was less severe in the mice infected with CB3O than in those with CB3M. After anti-CD8 antibody treatment, myocarditis was easily induced in mice originally showing resistance to infection. In addition, chronic myocarditis developed in CB3O-infected SCID C3H mice reconstituted with CB3M-sensitized splenocytes of WT C3H mice. The development of chronic myocarditis primarily depends on the presence or absence of the virus genome, and secondarily on the complex interaction between virus virulence and immunological background of the host. CB3 infection may cause chronic myocarditis with ongoing inflammation with or without viral persistence. PMID- 24493330 TI - Single-pill combination of telmisartan and hydrochlorothiazide: studies and pooled analyses of earlier hypertension treatment. AB - Lowering blood pressure (BP) in patients with high blood pressure reduces cardiovascular risk. Studies support health benefits when BP goals are achieved earlier in the course of treatment. Many patients require combination therapy to achieve BP goals; initial use of combination therapy may improve earlier BP goal attainment. This analysis reports the results of a search of the Boehringer Ingelheim clinical trial database for randomized, double-blind studies of telmisartan/hydrochlorothiazide (T/H) combination therapy compared with blood pressure monotherapies. Nine studies were identified. This report examined six separate analyses of these nine studies (three analyses of individual trials; three analyses for which two trials each were pooled). The focus of this report is the BP effects of combination T/H therapy compared with respective monotherapies at the earliest available time points (Weeks 1, 2, 3 and/or 4). These analyses included a total of 5,358 patients. During these earlier time periods, combination T/H reduced systolic BP (SBP) and diastolic BP (DBP) significantly more than placebo or respective monotherapies in most treatment comparisons for patients initiated on monotherapy. Combination T/H also allowed significantly more patients to achieve BP (<140/90 mmHg), SBP (<140 mmHg), and DBP (<90 mmHg) goal attainment rates compared with placebo (p < 0.0002), and numerically higher compared with T or H monotherapy. In patients uncontrolled by monotherapy, combination T/H significantly reduced SBP/DBP more than monotherapy (p < 0.0001). Similarly, BP, SBP and DBP goal attainment rates were significantly higher with combination T/H therapy (p < 0.0022). Reported adverse events with T/H therapy were generally similar to monotherapy, and placebo. In summary, the six separate analyses of nine different trials demonstrated that T/H significantly lowered BP as early as 1-4 weeks after initiation of therapy, with greater BP lowering, and greater BP goal attainment than with monotherapies or placebo. PMID- 24493332 TI - Evaluation of droplet digital PCR for characterizing plasmid reference material used for quantifying ammonia oxidizers and denitrifiers. AB - DNA reference materials of certified value have a critical function in many analytical processes of DNA measurement. Quantification of amoA genes in ammonia oxidizing bacteria (AOB) and archaea (AOA), and of nirS and nosZ genes in the denitrifiers is very important for determining their distribution and abundance in the natural environment. A plasmid reference material containing nirS, nosZ, amoA-AOB, and amoA-AOA is developed to provide a DNA standard with copy number concentration for ensuring comparability and reliability of quantification of these genes. Droplet digital PCR (ddPCR) was evaluated for characterization of the plasmid reference material. The result revealed that restriction endonuclease digestion of plasmids can improve amplification efficiency and minimize the measurement bias of ddPCR. Compared with the conformation of the plasmid, the size of the DNA fragment containing the target sequence and the location of the restriction site relative to the target sequence are not significant factors affecting plasmid quantification by ddPCR. Liquid chromatography-isotope dilution mass spectrometry (LC-IDMS) was used to provide independent data for quantifying the plasmid reference material. The copy number concentration of the digested plasmid determined by ddPCR agreed well with that determined by LC-IDMS, improving both the accuracy and reliability of the plasmid reference material. The reference value, with its expanded uncertainty (k = 2), of the plasmid reference material was determined to be (5.19 +/- 0.41) * 10(9) copies MUL(-1) by averaging the results of two independent measurements. Consideration of the factors revealed in this study can improve the reliability and accuracy of ddPCR; thus, this method has the potential to accurately quantify DNA reference materials. PMID- 24493331 TI - Abatacept as a successful therapy for myositis-a case-based review. AB - Only limited evidence exists on the therapeutic potential of biologic agents in the treatment of myositis. We present a brief review of the literature on off label experiences of biologic agents in myositis, with a special interest in abatacept. Rituximab has been indicated to be beneficial and well tolerated in one large randomized controlled trial and many smaller studies. Initial data on tumour necrosis factor (TNF) inhibitors are conflicting. There are only a few case reports and mechanistic studies on the treatment of myositis with other biologics, including alemtuzumab, anakinra, tocilizumab and abatacept. We report a patient with severe myositis overlap syndrome, manifesting also as rheumatoid arthritis, peripheral vasculitis and interstitial lung disease. Her myositis was refractory to many conventional and biologic therapies but was well controlled with abatacept. This suggests that abatacept might be a beneficial option for the treatment of refractory myositis and that clinical trials are needed to further investigate its efficacy. PMID- 24493333 TI - Determination of venlafaxine and O-desmethylvenlafaxine in dried blood spots for TDM purposes, using LC-MS/MS. AB - Dried blood spot (DBS) sampling and quantitative analyses of many current therapeutic drug monitoring (TDM)-guided drugs are advantageous because of the minimal invasive sampling strategy. Here, a fast and robust LC-MS/MS method was developed and analytically validated for simultaneous determination of venlafaxine (VEN) and O-desmethylvenlafaxine (ODV) in DBS. Six-millimeter circles were punched out from DBS collected on Whatman DMPK-C paper, and the DBS was extracted with acetonitrile/methanol at 1:3. The total run time was 4.8 min. The assay was linear in the range of 20-1,000 MUg/L for both VEN and ODV. Assay accuracy and precision was well within limits of acceptance (LLOQ = 20 MUg/L). Normal hematocrit concentrations (0.30-0.50) did not influence the results neither did a normal spot volume (40-80 MUL). Punch position at the perimeter instead of the center of the blood spot gave a bias ranging from 2.4 to 10.4%. Correlation between plasma and spiked DBS samples was high. The concentrations found in spiked DBS samples were higher than those in plasma, indicating that a conversion factor for translation of DBS to plasma values is needed. This analytically validated method is suitable for determination of VEN and ODV in DBS and applicable for TDM. The method will be used for TDM of VEN in the Dutch CYSCE multicenter trial (NCT01778907). PMID- 24493334 TI - Combined application of comprehensive analysis for DNA modification and reporter gene mutation assay to evaluate kidneys of gpt delta rats given madder color or its constituents. AB - DNA adductome analysis using liquid chromatography-tandem mass spectrometry is a promising tool to exhaustively search DNA modifications. Given that the molecular weight of chemical-specific adducts is determined by the total molecular weights of the active form and nucleotide bases, we developed a new method of comprehensive analysis for chemical-specific DNA adducts based on the principle of adductome analysis. The actual analytical mass range was 50 mass units up or down from the average molecular weight of the four DNA bases plus the molecular weight of the expected active form of the chemical. Using lucidin-3-O primeveroside (LuP), lucidin-modified bases formed by its active form were exhaustively searched using this new method. Various DNA adducts, including Luc-N (2)-dG and Luc-N (6)-dA, were identified in the kidneys of rats given LuP. Together with measurement of 8-hydroxydeoxyguanosine (8-OHdG) levels, the combined application of this new method with a reporter gene mutation assay was performed to clarify renal carcinogenesis induced by madder color (MC) that includes LuP and alizarin (Alz) as constituent agents. A DNA adductome map derived from MC-treated rats was almost identical to that of LuP-treated rats, but not Alz-treated rats. Although 8-OHdG levels were elevated in MC- and Alz treated rats, significant increases in gpt and Spi(-) mutant frequencies were observed only in MC- and LuP-treated rats. In addition, the spectrum of gpt mutants in MC-treated rats showed almost the same pattern as those in LuP-treated rats. The overall data suggest that LuP may be responsible for MC-induced carcinogenicity and that the proposed methodology is appropriate for exploring and understanding mechanisms of chemical carcinogenesis. PMID- 24493335 TI - Surface-enhanced Raman spectroscopy of blood plasma and serum using Ag and Au nanoparticles: a systematic study. AB - Surface-enhanced Raman spectroscopy (SERS) is a good candidate for the development of fast and easy-to-use diagnostic tools, possibly used on biofluids in point-of-care or screening tests. In particular, label-free SERS spectra of blood serum and plasma, two biofluids widely used in diagnostics, could be used as a metabolic fingerprinting approach for biomarker discovery. This study aims at a systematic evaluation of SERS spectra of blood serum and plasma, using various Ag and Au aqueous colloids, as SERS substrates, in combination with three excitation lasers of different wavelengths, ranging from the visible to the near infrared. The analysis of the SERS spectra collected from 20 healthy subjects under a variety of experimental conditions revealed that intense and repeatable spectra are quickly obtained only if proteins are filtered out from samples, and an excitation in the near-infrared is used in combination with Ag colloids. Moreover, common plasma anticoagulants such as EDTA and citrate are found to interfere with SERS spectra; accordingly, filtered serum or heparin plasma are the samples of choice, having identical SERS spectra. Most bands observed in SERS spectra of these biofluids are assigned to uric acid, a metabolite whose blood concentration depends on factors such as sex, age, therapeutic treatments, and various pathological conditions, suggesting that, even when the right experimental conditions are chosen, great care must be taken in designing studies with the purpose of developing diagnostic tests. PMID- 24493336 TI - Direct probe atmospheric pressure photoionization/atmospheric pressure chemical ionization high-resolution mass spectrometry for fast screening of flame retardants and plasticizers in products and waste. AB - In this study, we develop fast screening methods for flame retardants and plasticizers in products and waste based on direct probe (DP) atmospheric pressure photoionization (APPI) and atmospheric pressure chemical ionization (APCI) coupled to a high-resolution (HR) time-of-flight mass spectrometer. DP APPI is reported for the first time in this study, and DP-APCI that has been scarcely exploited is optimized for comparison. DP-APPI was more selective than DP-APCI and also more sensitive for the most hydrophobic compounds. No sample treatment was necessary, and only a minimal amount of sample (few milligrams) was used for analysis that was performed within a few minutes. Both methods were applied to the analysis of plastic products, electronic waste, and car interiors. Polybrominated diphenylethers, new brominated flame retardants, and organophosphorus flame retardants were present in most of the samples. The combination of DP with HR mass spectra and data processing based on mass accuracy and isotopic patterns allowed the unambiguous identification of chemicals at low levels of about 0.025 % (w/w). Under untargeted screening, resorcinol bis(biphenylphosphate) and bisphenol A bis(bisphenylphosphate) were identified in many of the consumer products of which literature data are still very limited. PMID- 24493337 TI - Use of experimental designs for the optimization of stir bar sorptive extraction coupled to GC-MS/MS and comprehensive validation for the quantification of pesticides in freshwaters. AB - Although experimental design is a powerful tool, it is rarely used for the development of analytical methods for the determination of organic contaminants in the environment. When investigated factors are interdependent, this methodology allows studying efficiently not only their effects on the response but also the effects of their interactions. A complete and didactic chemometric study is described herein for the optimization of an analytical method involving stir bar sorptive extraction followed by thermal desorption coupled with gas chromatography and tandem mass spectrometry for the rapid quantification of several pesticides in freshwaters. We studied, under controlled conditions, the effects of thermal desorption parameters and the effects of their interactions on the desorption efficiency. The desorption time, temperature, flow, and the injector temperature were optimized through a screening design and a Box-Behnken design. The two sequential designs allowed establishing an optimum set of conditions for maximum response. Then, we present the comprehensive validation and the determination of measurement uncertainty of the optimized method. Limits of quantification determined in different natural waters were in the range of 2.5 to 50 ng L(-1), and recoveries were between 90 and 104 %, depending on the pesticide. The whole method uncertainty, assessed at three concentration levels under intra-laboratory reproducibility conditions, was below 25 % for all tested pesticides. Hence, we optimized and validated a robust analytical method to quantify the target pesticides at low concentration levels in freshwater samples, with a simple, fast, and solventless desorption step. PMID- 24493340 TI - Backbone and side-chain (1)H, (13)C, and (15)N NMR assignments of the N-terminal domain of Escherichia coli LpoA. AB - The peptidoglycan is a major component of the bacterial cell wall and is essential to maintain cellular integrity and cell shape. Penicillin-Binding Proteins (PBPs) catalyze the final biosynthetic steps of peptidoglycan synthesis from lipid II precursor and are the main targets of beta-lactam antibiotics. The molecular details of peptidoglycan growth and its regulation are poorly understood. Presumably, PBPs are active in peptidoglycan synthesizing multi enzyme complexes that are controlled from inside the cell by cytoskeletal elements. Recently, two outer-membrane lipoproteins, LpoA and LpoB, were shown to be required in Escherichia coli for the function of the main peptidoglycan synthases, PBP1A and PBP1B, by stimulating their transpeptidase activity. However, the mechanism of PBP-activation by Lpo proteins is not known, and the Lpo proteins await structural characterization at atomic resolution. Here we present the backbone and side-chain (1)H, (13)C, (15)N NMR assignments of the N terminal domain of LpoA from E. coli for structural and functional studies. PMID- 24493339 TI - In vivo left-ventricular contact force analysis: comparison of antegrade transseptal with retrograde transaortic mapping strategies and correlation of impedance and electrical amplitude with contact force. AB - AIMS: Clinical outcomes following radiofrequency ablation of ventricular tachycardias (VTs) depend on catheter tip-to-tissue contact force (CF). Left ventricular (LV) mapping is performed via antegrade-transseptal or retrograde transaortic approaches, and the applied CF may depend on the approach used. This study evaluated (i) the impact of antegrade-transseptal vs. retrograde transaortic LV-mapping approaches on CF and catheter stability and (ii) the clinical value of the commonly used surrogate markers of catheter-myocardial contact-impedance, unipolar, and bipolar electrogram amplitudes. METHODS AND RESULTS: An antegrade-transseptal and a retrograde-transaortic LV-mapping approach was performed in 10 patients undergoing VT ablation by using CF-sensing catheters. Operators were blinded to CF data and data were analysed according to 11 predefined LV segments. Three thousand three hundred and twenty-four mapping points (1577 antegrade, 1747 retrograde) were analysed, including 80 (2.4%) points with maximum CF > 100 g. Median antegrade and retrograde CF were 16.0 g (q1-q3; 8.4-26.2) and 15.3 g (9.8-23.4), respectively. Contact force was significantly higher antegradely in mid-anteroseptum, mid-lateral, and apical segments, and significantly higher retrogradely in basal-anteroseptum, basal inferoseptum, basal-inferior, and basal-lateral segments. Contact force did correlate with impedance, unipolar, and bipolar electrogram amplitudes; however, there were large overlaps. CONCLUSIONS: Antegrade vs. retrograde LV-mapping approaches result in different CF. A combined approach to the LV mapping may improve the overall LV mapping, potentially resulting in better clinical outcomes for the left VT catheter ablation. The previous surrogate markers used to assess CF do correlate with in vivo CF; however, due to a larger overlap, their clinical value is limited. PMID- 24493341 TI - (1)H, (15)N and (13)C resonance assignments of the yeast Pih1 and Tah1 C-terminal domains complex. AB - We report the nearly complete (1)H, (15)N and (13)C resonance assignment of the complex formed by the C-terminal domains of Pih1 and Tah1 from S. cerevisiae and evidence the folding ability of Tah1 under complex formation. PMID- 24493343 TI - Secretion of photosynthetic products by carrot tissue cultures. AB - Green carrot callus cultures when exposed to (14)CO2 in a liquid medium showed ligh-dependent (14)C-incorporation into sucrose, glutamine and malic acid. About 5% of total (14)C fixed in a 3 h period appeared in these products in the bathing medium; this was not due to tissue damage. Kinetic studies showed that the release occurred from a metabolic and not a storage compartment. The effects of DCMU, temperature and fluoroacetate demonstrated that release from this compartment was under respiratory and not photosynthetic control. PMID- 24493342 TI - Late detection of critical congenital heart disease among US infants: estimation of the potential impact of proposed universal screening using pulse oximetry. AB - IMPORTANCE: Critical congenital heart disease (CCHD) was added to the Recommended Uniform Screening Panel for Newborns in the United States in 2011. Many states have recently adopted or are considering requirements for universal CCHD screening through pulse oximetry in birth hospitals. Limited previous research is directly applicable to the question of how many US infants with CCHD might be identified through screening. OBJECTIVES: To estimate the proportion of US infants with late detection of CCHD (>3 days after birth) based on existing clinical practice and to investigate factors associated with late detection. DESIGN, SETTING, AND PARTICIPANTS: Descriptive and multivariable analysis. Data were obtained from a multisite population-based study of birth defects in the United States, the National Birth Defects Prevention Study (NBDPS). We included all live-born infants with estimated dates of delivery from January 1, 1998, through December 31, 2007, and nonsyndromic, clinically verified CCHD conditions potentially detectable through screening via pulse oximetry. MAIN OUTCOMES AND MEASURES: The main outcome measure was the proportion of infants with late detection of CCHD through echocardiography or at autopsy under the assumption that universal screening at birth hospitals might reduce the number of such late diagnoses. Secondary outcome measures included prevalence ratios for associations between selected demographic and clinical factors and late detection of CCHD. RESULTS: Of 3746 live-born infants with nonsyndromic CCHD, late detection occurred in 1106 (29.5% [95% CI, 28.1%-31.0%]), including 6 (0.2%) (0.1%-0.4%) first receiving a diagnosis at autopsy more than 3 days after birth. Late detection varied by CCHD type from 9 of 120 infants (7.5% [95% CI, 3.5%-13.8%]) with pulmonary atresia to 497 of 801 (62.0% [58.7%-65.4%]) with coarctation of the aorta. In multivariable analysis, late detection varied significantly by CCHD type and study site, and infants with extracardiac defects were significantly less likely to have late detection of CCHD (adjusted prevalence ratio, 0.58 [95% CI, 0.49-0.69]). CONCLUSIONS AND RELEVANCE: We estimate that 29.5% of live-born infants with nonsyndromic CCHD in the NBDPS received a diagnosis more than 3 days after birth and therefore might have benefited from routine CCHD screening at birth hospitals. The number of infants in whom CCHD was detected through screening likely varies by several factors, including CCHD type. Additional population-based studies of screening in practice are needed. PMID- 24493344 TI - The red light controlled production of gibberellin in etiolated wheat leaves. AB - Most of the gibberellin activity detectable in extracts of etiolated wheat leaf tissue occurs in a bound form. There is a rapid increase in extractable gibberellin-like substances following exposure of the tissue to red light with a concomitant fall in the amount of bound gibberellin. Actinomycin-D and AMo 1618 do not inhibit this initial phase of red light stimulated gibberellin production.It is concluded that red light stimulated gibberellin production in etiolated wheat leaf tissue is due to release from a bound form and to synthesis. PMID- 24493345 TI - The hormonal control of wheat leaf unrolling. AB - The unrolling of etiolated wheat leaf sections in the dark is stimulated by the application of gibberellic acid (GA3). GA3 is most effective if applied for a short time at the beginning of incubation. Kinetin also stimulated leaf unrolling in the dark. AMO1618 and CCC inhibit red light and kinetin-stimulated unrolling. Gibberellin-like substances extracted from red light-treated leaf tissue are effective in stimulating leaf unrolling.Ethylene production in leaf sections is stimulated by IAA, GA3 and kinetin and inhibited by ABA. A brief exposure to red light decreases the ability of the tissue to produce ethylene. It is concluded that ethylene plays no important role in the control of leaf unrolling by red light or by the application of hormones. PMID- 24493346 TI - Auxins and cytokinins exuded during formation of roots by detached primary leaves and stems of dwarf French bean (Phaseolus vulgaris L.). AB - Hypocotyls of detached stems standing in culture solution produced adventitious roots sooner than did petioles of detached primary leaves. An auxin, probably indol-3-ylacetic acid, appeared in the solutions before the hypocotyls or petioles produced roots. After attaining a maximum, the amounts of auxin in the solutions decreased as fewer roots were formed. Two cytokinins were found in the culture solutions; one had a similar Rf to zeatin, the other ran more slowly on chromatograms. The amounts of cytokinin in the solutions were associated with root formation. Stems soon died unless their hypocotyls formed roots, but the primary leaves survived without roots forming provided a callus formed on the petiole. Hence adventitious roots, or callus tissues, may have produced cytokinins that replaced those produced by the original roots, found in sap exuded from the stem stumps, and were essential for survival of the stems and leaves. PMID- 24493347 TI - The behaviour of (14)C profiles in Helianthus seedlings. AB - The log. (14)C activity/distance profile in the stems of Helianthus seedlings consists of two main parts: region 1, the linear advancing front and region 2, which is also linear but with a less steep slope. As the front passes down the stem, the slope of region 1 remains constant but the amplitude of the front becomes attenuated. The attenuation increases with temperature. The apparent velocity of the profile, which can be derived from the position of the front, is also temperature dependent. Small amounts of (14)C occur in the stem ahead of the profile; these amounts increase with a rise of temperature. Region 2 behaves differently: its slope decreases steadily with time but it is insensitive to temperature. The behaviour of this region is dependent on the movement of tracer into an immobile fraction as well as on the longitudinal movement of tracer in the translocation stream. PMID- 24493348 TI - Sucrose suppression of chlorophyll synthesis in carrot callus cultures. AB - Substrate levels of sucrose were shown to reduce chlorophyll synthesis in carrot tissue culture strain CRT1 but not in strain CRT2. In CRT1 the effect was shown to be a suppression of greening specifically by sucrose rather than a reducing sugar requirement for chlorophyll synthesis. In CRT1 sucrose caused both a reduction in chloroplast numbers per cell and a suppression of lamellar development in plastids. This effect on chloroplast structure was consistent with the observed reduced photosynthetic efficiency (micromoles CO2 per hour per mg chlorophyll) of CRT1 calluses grown on sucrose. PMID- 24493349 TI - A simple bioassay for detecting "antitranspirant" activity of naturally occurring compounds such as abscisic acid. AB - Isolated epidermal strips of Commelina communis L. showed progressively smaller stomatal openings when incubated in abscisic acid solutions ranging in concentration from 10(-8) to 10(-4) M. The effects were reproducible and did not appear to be affected by the presence of auxin, gibberellic acid or kinetin. This specificity suggests that this method may prove valuable as a quick, sensitive bioassay for abscisic acid and other related compounds which might be used as antitranspirants on field crops. The fungal toxin fusicoccin, previously reported to cause increased stomatal opening on intact leaves, partially reversed the closure induced by abscisic acid. PMID- 24493350 TI - Influence of daylength on gibberellin metabolism and stem growth in Silene armeria. AB - When radioactive gibberellin A5 ((3)H-GA5) was applied to the apices and surrounding young leaves of the long-day plant Silene armeria, it was partially converted to at least two other acidic substances. One of them was similar to GA3 in chromatographic, but not in biological properties. The other metabolite was more polar than GA3 and inactive in the dwarf d-5 corn assay.The rate of (3)H-GA5 conversion was influenced by the photoperiod under which Silene plants were grown. Exposure to 2 long days significantly increased (3)H-GA5 metabolism over that in control plants kept under short days. The increased conversion of (3)H GA5 persisted for at least a few days after transferring Silene plants back from long to short days. Likewise, stem growth induced by long photoperiods continued for a considerable period of time under subsequent short days.Application of the growth retardant AMO-1618 to Silene reduced the levels of two endogenous GA-like substances, one of them with GA5-like properties, more under long than under short days. These results indicate that long photoperiods, which induce flower formation and stem elongation in Silene, increase the turnover of endogenous gibberellins. PMID- 24493351 TI - Photocontrol of the orientation of cell division in Adiantum : II. Effects of the direction of white light on the apical cell of gametophytes. AB - Two-dimensional prothallia of Adiantum capillus-veneris always expanded in a plane which was at a right angle to any given direction of irradiation with continuous white light. The expansion began with a longitudinal division of the apical cell, in the filamentous protonema, and the orientation of the mitotic cell plate of this first longitudinal division as well as the subsequent divisions was always parallel to the direction of the incident light. When three irradiations with white light, interrupted by periods of darkness, were given, two transverse and one subsequent longitudinal division were induced. When the last two irradiations were given from the same direction, the cell plate of the first longitudinal division in most protonemata was oriented parallel to the direction of light. However, when the direction of light during the third irradiation was at right angle to that during the second, the frequency of the longitudinal division greatly decreased but that of the third transverse division increased. Thus, the orientation of the first longitudinal division appeared to be controlled in some way not only by the irradiation which actually induced the third division but also by that inducing the preceding transverse division, while the direction of light for the first transverse division had little effect on the orientation of the third division. PMID- 24493352 TI - [Different CO2-sensitivities of the gas exchange of the two leaf surfaces of Zea mays]. AB - CO2 exchange and transpiration of the two leaf surfaces of Zea mays were measured at various external CO2 concentrations between 50 and 10000 ppm (V/V). The CO2 exchange of the upper surface followed an "optimum curve" with a maximum near 300 ppm, whereas the CO2 exchange of the lower epidermis approximated a "saturation curve" from 100 to 3000 ppm. The transpiration data of both leaf surfaces at three CO2 concentrations indicated that these results were due to stomatal interference with the saturation curve of photosynthesis. The results show, again that the guard cells of the two leaf surfaces can react differently. Data obtained with viscous flow porometers or with diffusion porometers employing an unidirectional diffusion of a gas, through an amphistomatic leaf should therefore be interpreted with great caution. PMID- 24493353 TI - Lack of evidence for distinguishing florigen and flower hormone in Perilla. AB - The minimal duration of short-day (SD) treatment necessary to cause flower formation in the SD plant Perilla is 9 days, whereas leaves exposed to at least 12 SD can function as donors in grafting experiments. Zhdanova's report that SD given consecutively to different individual leaves for 2 or 3 days resulted in flowering, could not be confirmed. PMID- 24493354 TI - Characterization and evaluation of the efficacy of cationic complex mediated plasmid DNA delivery in human embryonic palatal mesenchyme cells. AB - The purpose of this study was to develop and test a non-viral gene delivery system that can be employed to deliver genes of interest into a pre-osteoblastic cell line. Human embryonic palatal mesenchymal (HEPM 1486) cells were transfected with vector-plasmid DNA (pDNA) complexes. We explored calcium phosphate and polyethylenimine (PEI) as non-viral vectors and compared their respective in vitro transfection efficacies. Plasmid DNA encoding luciferase protein (LUC) was complexed with PEI (with differing N:P ratios) and calcium phosphate (with differing Ca:P ratios), using established protocols. The complexes prepared were then characterized for size and surface charge, using a Malvern Zetasizer Nano ZS. The transfection efficiency and cytotoxicity of the prepared complexes were evaluated in HEPM cells. The PEI-pDNA complexes over the whole range of N:P ratios were found to be < 160 nm in size, while the calcium phosphate-pDNA complexes were relatively bigger. The PEI-pDNA complexes prepared at a N:P ratio of 10 were found to have maximum transfection efficiency at 4 h of treatment, with minimal cytotoxicity. The highest transfection efficiency obtained with calcium phosphate-pDNA complexes (Ca:P 200) was nearly 12-fold lower than that obtained with PEI-pDNA complexes (N:P 10). Following this, transgene expression in the HEPM cells treated with complexes prepared at a N:P ratio of 10 was further examined, using pDNA coding for enhanced green fluorescent protein (EGFP N1) or therapeutically relevant platelet-derived growth factor B (PDGF-B). In conclusion, PEI was a more effective vector for delivering genes of interest to pre-osteoblasts than calcium phosphate. Copyright (c) 2014 John Wiley & Sons, Ltd. PMID- 24493355 TI - Complementary molecular approaches reveal heterogeneous CDH1 germline defects in Italian patients with hereditary diffuse gastric cancer (HDGC) syndrome. AB - Germline inactivation of the E-cadherin gene (CDH1) is associated with hereditary diffuse gastric cancer (HDGC), a rare autosomal dominant syndrome predisposing to both diffuse gastric cancer (DGC) and lobular breast cancer (LBC). We searched for CDH1 germline defects in 32 HDGC Italian probands selected according to international consensus criteria and in 5 selected relatives. We used a series of molecular methods, including: DNA sequencing, multiplex ligation-dependent probe amplification, single-nucleotide primer extension, bisulfite sequencing, reverse transcription PCR, and bioinformatics tools. We identified pathogenic mutations in 6 out of 32 probands (19%): one truncating and two missense mutations, one large deletion, one allelic expression imbalance and one splicing defect. Three out of six CDH1 constitutive alterations were novel. Our data support the need for a multimethod approach for CDH1 genetic testing, demonstrating that both DNA and RNA analyses are required to increase the detection rate of pathogenic mutations, thus reducing the number of patients without a clear molecular diagnosis. On the whole, our results indicate that not only DGC patients, but also subjects with personal or family history of LBC might benefit from CDH1 genetic testing. Moreover, our findings support the notion that prophylactic gastrectomy should be offered to asymptomatic CDH1 mutation carriers; indeed, while endoscopic analysis with histological examination of random gastric biopsies can miss cancer foci, gastrectomy performed in these subjects always revealed foci of cancer cells. PMID- 24493356 TI - A rare case of peripheral ulcerative keratitis associated with Behcet's disease. AB - We report a rare case of peripheral ulcerative keratitis (PUK) associated with Behcet's disease. A 34-year-old female presented with right ocular pain persisting for 8 months. The patient had been treated for previously diagnosed Behcet's disease. The corrected visual acuity was 20/32 in the right eye. Ocular examination revealed mild conjunctival hyperemia and a deep ulcerative lesion with perilesional haziness in the peripheral cornea. Autoimmune screening and corneal culture were negative. One month following treatment with topical and systemic immunosuppressants, the symptom had resolved. Slit-lamp examination showed a healed corneal lesion, and visual acuity improved to 20/20. Despite its rare occurrence, PUK can develop in patients with Behcet's disease. Therefore, patients presenting PUK require examination for Behcet's disease using a systemic evaluation. PMID- 24493357 TI - Morphometrical analysis of the thoracolumbar dural sac in sheep using computed assisted myelography. AB - OBJECTIVES: Sheep are frequently used as animal models in experimental spinal injury studies. Therefore, extensive knowledge of ovine spinal dimensions is essential for experimental design and interpretation of results obtained in these trials. This study aimed to obtain quantitative morphometrical data of the thoracolumbar dural sac in sheep and determine the anatomical relationship between the dural sac and the vertebral canal. METHODS: Computed assisted myelography imaging was carried out in five adult German Black-Headed Mutton sheep under general anaesthesia. Transverse images were acquired with 2 mm slice thickness from the first thoracic to the sixth lumbar vertebrae. Sagittal and transverse diameters and the cross-sectional area of the dural sac and vertebral canal were measured. To determine the anatomical relationship between the dural sac and vertebral canal, the pedicle-dural sac distance (PPSD) and the epidural space as well as the SAC (available space for the dural sac) were calculated. RESULTS: Sagittal diameters of the dural sac ranged from 5.1 to 12.0 mm. Transverse diameters ranged from 5.6 to 12.2 mm. The dural sac area covered 45.9% and 49.0% of the thoracic and lumbar vertebral canal area. The PDSD in the lumbar vertebrae was up to 15.8% larger than in the thoracic ones. The dural sac area was significantly positively correlated with the transverse diameter and area of the vertebral canal. CLINICAL SIGNIFICANCE: The lumbar vertebral canal contained more space for the dural sac, which seems to be safer for testing spinal implants. PMID- 24493358 TI - Beyond the DSM: development of a transdiagnostic psychiatric neuroscience course. AB - OBJECTIVE: Clinical and neurobiological data suggest that psychiatric disorders, as traditionally defined in the Diagnostic and Statistical Manual of Mental Disorders (DSM), are (1) more comorbid than expected by chance, (2) often share neurobiological signatures, and (3) reflect alterations across multiple brain systems that mediate particular mental processes. As such, emerging conceptualizations such at the National Institute of Mental Health's Research Domain Criteria Project (RDoC) have suggested that a different way to understand psychopathology may be with respect to the degree of dysfunction in each of these brain systems, seen dimensionally, which both cross traditional diagnostic boundaries and extend to a healthy range of functioning. At present, however, this scientific perspective has not been incorporated into neuroscience education in psychiatry, nor has its relationship to clinical care been made clear. METHODS: We describe the rationale and implementation of a reformulated neuroscience course given to psychiatric residents at Stanford University centered on the conceptual framework of RDoC. Data are presented on resident feedback before and after revision of the course. RESULTS: A clear motivation and rationale exists for teaching neuroscience in a transdiagnostic framework. This course was taken up well by the residents, with overall feedback significantly more positive than that prior to the course revision. CONCLUSION: This "proof of concept" neuroscience course illustrates a potential route for bridging between rapid advances in psychiatric neuroscience and the clinical education for trainees not otherwise versed in neuroscience but who are needed for scientific advances to translate to the clinic. The promise of this approach may be in part related to the similarity between this framework and problem-based approaches common in routine clinical care. In such approaches, clinicians focus on the expressed complaints of their individual patient and identify specific symptoms as the target of treatment--symptoms which are presumably the expression of dysfunction in specific brain systems. PMID- 24493359 TI - Attitudes toward neuroscience education among psychiatry residents and fellows. AB - OBJECTIVE: The purpose of this study is to assess the attitudes of psychiatry trainees toward neuroscience education in psychiatry residency and subsequent training in order to inform neuroscience education approaches in the future. METHODS: This online survey was designed to capture demographic information, self assessed neuroscience knowledge, attitudes toward neuroscience education, preferences in learning modalities, and interest in specific neuroscience topics. Volunteers were identified through the American Psychiatric Association, which invited 2,563 psychiatry trainees among their members. RESULTS: Four hundred thirty-six trainees completed the survey. Nearly all agreed that there is a need for more neuroscience education in psychiatry residency training (94%) and that neuroscience education could help destigmatize mental illness (91%). Nearly all (94%) expressed interest in attending a 3-day course on neuroscience. Many neuroscience topics and modes of learning were viewed favorably by participants. Residents in their first 2 years of training expressed attitudes similar to those of more advanced residents and fellows. Some differences were found based on the level of interest in a future academic role. CONCLUSIONS: This web-based study demonstrates that psychiatry residents see neuroscience education as important in their training and worthy of greater attention. Our results suggest potential opportunities for advancing neuroscience education. PMID- 24493360 TI - Teaching clinical neuroscience to psychiatry residents: model curricula. PMID- 24493361 TI - Who's your expert? Use of an expert opinion survey to inform development of American Psychiatric Association practice guidelines. AB - OBJECTIVE: For many clinical questions in psychiatry, high-quality evidence is lacking. Credible practice guidelines for such questions depend on transparent, reproducible, and valid methods for assessing expert opinion. The objective of this study was to develop and demonstrate the feasibility of a method for assessing expert opinion to aid in the development of practice guidelines by the American Psychiatric Association (APA). METHODS: A "snowball" process initially soliciting nominees from three sets of professional leaders was used to identify experts on a guideline topic (psychiatric evaluation). In a Web-based survey, the experts were asked to rate their level of agreement that specific assessments improve specific outcomes when they are included in an initial psychiatric evaluation. The experts were also asked about their own practice patterns with respect to the doing of the assessments. The main outcome measures are the following: number of nominated experts, number of experts who participated in the survey, and number and nature of quantitative and qualitative responses. RESULTS: The snowball process identified 1,738 experts, 784 (45 %) of whom participated in the opinion survey. Participants generally, but not always, agreed or strongly agreed that the assessments asked about would improve specified outcomes. Participants wrote 716 comments explaining why they might not typically include some assessments in an initial evaluation and 1,590 comments concerning other aspects of the topics under consideration. CONCLUSIONS: The snowball process based on initial solicitation of Psychiatry's leaders produced a large expert panel. The Web-based survey systematically assessed the opinions of these experts on the utility of specific psychiatric assessments, providing useful information to substantiate opinion-based practice guidelines on how to conduct a psychiatric evaluation. The considerable engagement of respondents shows promise for using this methodology in developing future APA practice guidelines. PMID- 24493363 TI - Cytometry Part B March 2014. PMID- 24493362 TI - Teaching residents about emotional intelligence and its impact on leadership. AB - OBJECTIVE: Although leadership is a core component of the work life of physicians, most physicians are ill-prepared to assume leadership roles upon completion of residency training. The authors sought to determine if medical residents could learn the components of emotional intelligence and thereby facilitate improved leadership styles. METHODS: The authors created an educational workshop that included readings (provided to attendees in preparation for the workshop), a formalized presentation on emotional intelligence, and role playing of scenarios (with debriefing and discussion) involving leadership opportunities. RESULTS: The majority of participants reported that they left the workshop more informed about leadership and with more skills that could enhance their roles as leaders. CONCLUSIONS: While enhancing knowledge and skills, which were demonstrated after attendance at a seminar, additional measures of effective leadership are still needed. PMID- 24493364 TI - N-Formyl-7-amino-11-cycloamphilectene, a marine sponge metabolite, binds to tubulin and modulates microtubule depolymerization. AB - The importance of protein-small molecule interaction in drug discovery, medicinal chemistry and biology has driven the development of new analytical methods to disclose the whole interactome of bioactive compounds. To accelerate targets discovery of N-formyl-7-amino-11-cycloamphilectene (CALe), a marine bioactive diterpene isolated from the Vanuatu sponge Axinella sp., a chemoproteomic-based approach has been successfully developed. CALe is a potent anti-inflammatory agent, modulating NO and prostaglandin E2 overproduction by dual inhibition of the enhanced inducible NO synthase expression and cyclo-oxygenase-2 activity, without any evidence of cytotoxic effects. In this paper, several isoforms of tubulin have been identified as CALe off-targets by chemical proteomics combined with bio-physical orthogonal approaches. In the following biological analysis of its cellular effect, CALe was found to protect microtubules against the colcemid depolymerizing effect. PMID- 24493365 TI - Prevalence of potentially inappropriate prescribing and prescribing omissions in older Irish adults: findings from The Irish LongituDinal Study on Ageing study (TILDA). AB - PURPOSE: We sought to estimate the prevalence of potentially inappropriate prescriptions (PIP) and potential prescribing omissions (PPOs) using a subset of the STOPP/START criteria in a population based sample of Irish adults aged >= 65 years using data from The Irish LongituDinal Study on Ageing (TILDA). METHODS: A subset of 26 PIP indicators and 10 PPO indicators from the STOPP/START criteria were applied to the TILDA dataset. PIP/PPO prevalence according to individual STOPP/START criteria and the overall prevalence of PIP/PPO were estimated. The relationship between PIP and PPOs and polypharmacy, age, gender and multimorbidity was examined using logistic regression. RESULTS: The overall prevalence of PIP in the study population (n=3,454) was 14.6 %. The most common examples of PIP identified were NSAID with moderate-severe hypertension (200 participants; 5.8 %) and aspirin with no history of coronary, cerebral, or peripheral vascular symptoms or occlusive event (112 participants; 3.2 %). The overall prevalence of PPOs was 30 % (n=1,035). The most frequent PPO was antihypertensive therapy where systolic blood pressure consistently >160 mmHg (n=341, 9.9 %), There was a significant association between PIP and PPO and polypharmacy when adjusting for age, sex and multimorbidity (adjusted OR 2.62, 95 % CI 2.05-3.33 for PIP and adjusted OR 1.46, 95 % CI 1.23-1.75 for prescribing omissions). CONCLUSION: Our findings indicate prescribing omissions are twice as prevalent as PIP in the elderly using a subset of the STOPP/START criteria as an explicit process measure of potentially inappropriate prescribing and prescribing omissions. Polypharmacy was independently associated with both PPO and PIP. Application of such screening tools to prescribing decisions may reduce unnecessary medication, related adverse events, healthcare utilisation and cost. PMID- 24493366 TI - Elevated serum levels of interleukin-6 in endemic Burkitt lymphoma in Ghana. PMID- 24493367 TI - Transorbital penetrating cerebral injury caused by a wooden stick: surgical nuances for removal of a foreign body lodged in cavernous sinus. AB - PURPOSE: Penetrating head injury (PHI) is rare in civilian population and is mostly caused by low-velocity modes. A transorbital penetrating intracranial injury is very rare and more severe than traumatic brain injury. METHODS: We report a rare case of transorbital penetrating cranial injury caused by a wooden stick. The surgical strategy was planned as the wooden stick was lodged in the right cavernous sinus. RESULTS: The wooden stick was successfully removed. Patient made an uneventful recovery. CONCLUSIONS: Transorbital penetrating injuries are uncommon form of injury and require a multidisciplinary approach. No attempt should be made to remove the foreign body without the backup of an operating room because of the possibility that the object may be tamponading an injured vessel. A careful planning and a strict adherence to basic perioperative principles can lead to a satisfactory outcome. PMID- 24493368 TI - A randomized study of ventriculoperitoneal shunt versus endoscopic third ventriculostomy for the management of tubercular meningitis with hydrocephalus. AB - OBJECTIVE: This study aims at generating knowledge to understand the conditions in which either of the two procedures (endoscopic third ventriculostomy (ETV) and shunt) are better options and to develop good practice guidelines for the treatment of tubercular meningitis (TBM) hydrocephalus. METHODS: This study was conducted on 48 patients in pediatric age group (less than or equal to 18 years) of TBM hydrocephalus. The patients were randomized to one of the cerebrospinal fluid diversion procedures (ETV or shunt). The two procedures were compared for their outcome, both radiologically and clinically. RESULTS: Twenty-four cases underwent shunt, out of which 13 (68%) cases were successful. Twelve (70.3%) cases belonged to grade 3, while one case was of grade 1. In ETV group, 10 (42%) cases had a successful outcome, out of which 7 (38.8%) cases were in grade 3, while 1 case each belonged to grades 1, 2, and 4. Incidence of ETV failure was more in younger age group, i.e., <2 years (n = 7), while no such correlation with age was found in shunt cases. CONCLUSION: Though with the present study it looks like that the relative risk of ETV failure is higher than that for shunt, but the risk becomes progressively lower with time. Therefore, if patients survive the early high-risk period, they could experience a long-term survival advantage devoid of life-long shunt-related complications. Though for definitive comparison, a long-term study is needed. PMID- 24493371 TI - Drowning. PMID- 24493370 TI - Gray & white matter tissue contrast differentiates Mild Cognitive Impairment converters from non-converters. AB - The clinical relevance of gray/white matter contrast ratio (GWR) in mild cognitive impairment (MCI) remains unknown. This study examined baseline GWR and 3-year follow-up diagnostic status in MCI. Alzheimer's Disease Neuroimaging Initiative MCI participants with baseline 1.5 T MRI and 3-year follow-up clinical data were included. Participants were categorized into two groups based on 3-year follow-up diagnoses: 1) non-converters (n = 69, 75 +/- 7, 26 % female), and 2) converters (i.e., dementia at follow-up; n = 69, 75 +/- 7, 30 % female) who were matched on baseline age and Mini-Mental State Examination scores. Groups were compared on FreeSurfer generated baseline GWR from structural images in which higher values represent greater tissue contrast. A general linear model, adjusting for APOE-status, scanner type, hippocampal volume, and cortical thickness, revealed that converters evidenced lower GWR values than non converters (i.e., more degradation in tissue contrast; p = 0.03). Individuals with MCI who convert to dementia have lower baseline GWR values than individuals who remain diagnostically stable over a 3-year period, statistically independent of cortical thickness or hippocampal volume. PMID- 24493372 TI - Comparative study of the relative signal intensity on DWI, FLAIR, and T2 images in identifying the onset time of stroke in an embolic canine model. AB - In acute stroke magnetic resonance imaging, many attempts have been made to identify the onset time of ischemic events using the simply quantitative judgment of relative signal intensity (rSI) from various MR images. However, no uniform opinion has been achieved broadly till now. The controversy might derive from the potential patients' selection bias of clinical retrospective study, the discrepant MR parameters, and the various sample sizes among different studies. Thus, we evaluated the temporal change of the relative DWI signal intensity (rDWI), relative ADC value (rADC), relative FLAIR signal intensity (rFLAIR), and relative T2 signal intensity (rT2), and further compare their diagnostic value in identifying the hyperacute lesions based on our embolic canine model with clear onset time. Twenty ischemic models were successfully established. All rSI values were linearly correlated to time with significance until 24 h after model establishment (P < 0.05). Paired comparison of ROC curves showed that significant difference was found between rADC and other three rSIs (P < 0.0001). However, no significant difference was found among rDWI, rT2 and rFLAIR. Our results indicated that rDWI, rFLAIR and rT2 may be helpful to predict the onset time of ischemic events with the similar diagnostic value. However, the rADC does not have comparable predictive value in our embolic canine model. PMID- 24493373 TI - Association analysis of four candidate genetic variants with sporadic amyotrophic lateral sclerosis in a Chinese population. AB - Recently, four single nucleotide polymorphisms (SNPs), including rs2814707 in the 9p21, rs12608932 in the UNC13A gene, rs13048019 in the TIMA1 gene, and rs2228576 in the SCNN1A gene have been reported to be associated with the risk for developing amyotrophic lateral sclerosis (ALS) in Caucasian population. However, this association is not consistent among different studies and yet to be tested in ALS patients in Mainland China. This study included 397 sporadic ALS (SALS) patients and 287 unrelated Chinese healthy controls from Southwest China. Four SNPs listed above were genotyped by using Sequenom's iPLEX assay. No significant differences in the genotype distributions or minor allele frequencies in all SNPs were found between ALS group and control group, between the spinal-onset group and bulbar-onset group, and between the early-onset group and the late-onset group. Our results suggest that these SNPs are unlikely to be common cause of SALS in Chinese population. PMID- 24493374 TI - Similarities and differences of international guidelines for bioequivalence: an update of the Brazilian requirements. PMID- 24493375 TI - Postnatal development of the skull of Dinilysia patagonica (Squamata-stem Serpentes). AB - The snake skull represents a profound transformation of the ancestral squamate cranium in which dermal skull roof bones were integrated with the braincase, in a manner convergent with that which occurred during the origin of mammals. However, the ontogeny of snake characters at the origin of the clade has until now been inaccessible. Here we describe a postnatal ontogenetic series of the Late Cretaceous stem snake Dinilysia patagonica and compare it to that of extant lizards and snakes. Comparative analysis indicates notable ontogenetic changes, including advanced state of ossification, isometric growth of the otic capsule, fusion of the stylohyal to the quadrate, and great posterior elongation of the supratemporal. Of these transformations, the unfused condition of braincase bones and the retention of a large otic capsule in adults are examples of paedomorphic and peramorphic processes, respectively. Some ontogenetic transformations detected, in particular those present in middle ear, skull roof and suspensorium, are strikingly similar to those present in extant snakes. Nevertheless, Dinilysia retains a lizard-like paroccipital process without an epiphyseal extremity, and a calcified epiphysis that caps the sphenoccipital tubercle. Finally, the integration of the dermal skull roof with the braincase is similar to that seen in mammals with regard to the overall closure of the braincase, but the two evolutionary and developmental modules appear less integrated in snakes in that the parietal bone of the dermal skull roof progressively overlaps the supraoccipital of the chondrocranial braincase. PMID- 24493376 TI - An electronic order set for acute myocardial infarction is associated with improved patient outcomes through better adherence to clinical practice guidelines. AB - BACKGROUND: Adherence to evidence-based recommendations for acute myocardial infarction (AMI) remains unsatisfactory. OBJECTIVE: Quantifying association between using an electronic AMI order set (AMI-OS) and hospital processes and outcomes. DESIGN: Retrospective cohort study. SETTING: Twenty-one community hospitals. PATIENTS: A total of 5879 AMI patients were hospitalized between September 28, 2008 and December 31, 2010. MEASUREMENTS: We ascertained whether patients were treated using the AMI-OS or individual orders (a la carte). Dependent process variables were use of evidence-based care; outcome variables were mortality and rehospitalization. RESULTS: Use of individual and combined therapies improved outcomes (eg, 50% lower odds of 30-day mortality for patients with >=3 therapies). The 3531 patients treated using the AMI-OS were more likely to receive evidence-based therapies (eg, 50% received 5 different therapies vs 36% a la carte). These patients had lower 30-day mortality (5.7% vs 8.5%) than the 2348 treated using a la carte orders. Although AMI-OS patients' predicted mortality risk was lower (3.2%) than that of a la carte patients (4.8%), the association of improved processes and outcomes with the use of the AMI-OS persisted after risk adjustment. For example, after inverse probability weighting, the relative risk for inpatient mortality in the AMI-OS group was 0.67 (95% confidence interval: 0.52-0.86). Inclusion of use of recommended therapies in risk adjustment eliminated the benefit of the AMI-OS, highlighting its mediating effect on adherence to evidence-based treatment. CONCLUSIONS: Use of an electronic order set is associated with increased adherence to evidence-based care and better AMI outcomes. PMID- 24493377 TI - Application of variable threshold intensity to segmentation for white matter hyperintensities in fluid attenuated inversion recovery magnetic resonance images. AB - INTRODUCTION: White matter hyperintensities (WMHs) are regions of abnormally high intensity on T2-weighted or fluid-attenuated inversion recovery (FLAIR) magnetic resonance imaging (MRI). Accurate and reproducible automatic segmentation of WMHs is important since WMHs are often seen in the elderly and are associated with various geriatric and psychiatric disorders. METHODS: We developed a fully automated monospectral segmentation method for WMHs using FLAIR MRIs. Through this method, we introduce an optimal threshold intensity (I O ) for segmenting WMHs, which varies with WMHs volume (V WMH), and we establish the I O -V WMH relationship. RESULTS: Our method showed accurate validations in volumetric and spatial agreements of automatically segmented WMHs compared with manually segmented WMHs for 32 confirmatory images. Bland-Altman values of volumetric agreement were 0.96 +/- 8.311 ml (bias and 95 % confidence interval), and the similarity index of spatial agreement was 0.762 +/- 0.127 (mean +/- standard deviation). Furthermore, similar validation accuracies were obtained in the images acquired from different scanners. CONCLUSIONS: The proposed segmentation method uses only FLAIR MRIs, has the potential to be accurate with images obtained from different scanners, and can be implemented with a fully automated procedure. In our study, validation results were obtained with FLAIR MRIs from only two scanner types. The design of the method may allow its use in large multicenter studies with correct efficiency. PMID- 24493378 TI - Cerebral amyloid angiopathy-related inflammation: imaging findings and clinical outcome. AB - INTRODUCTION: We aim to investigate the clinical onset, computed tomography (CT) and magnetic resonance (MR) imaging findings, and follow-up of patients with cerebral amyloid angiopathy (CAA)-related inflammation, an uncommon but clinically striking presentation of CAA. METHODS: We retrospectively reviewed the clinical manifestations, CT/MR imaging findings, and outcome of ten consecutive patients with CAA-related inflammation. In each patient, a brain CT study was performed at hospital admission, and brain MR imaging was carried out 2 to 4 days later. Clinical and radiologic follow-up findings were evaluated in all patients. RESULTS: The most common clinical onset was rapidly progressive cognitive decline, followed by focal neurological signs. Brain CT/MR showed unenhanced expansive subcortical lesions, corresponding to areas of vasogenic edema, associated with chronic lobar, cortical, or cortical-subcortical micro/macrohemorrhages. Clinical symptoms recovered in a few weeks under treatment in eight patients and spontaneously in the remaining two. MRI follow-up at 2 to 12 months after treatment showed resolution of the lesions. Three patients experienced symptomatic disease recurrence, with new lesions on CT/MR. CONCLUSION: In the absence of histological data, early recognition of the clinical symptoms and typical radiologic features of CAA-related inflammation is essential to enable timely establishment of proper treatment. PMID- 24493379 TI - Grid cell spatial tuning reduced following systemic muscarinic receptor blockade. AB - Grid cells of the medial entorhinal cortex exhibit a periodic and stable pattern of spatial tuning that may reflect the output of a path integration system. This grid pattern has been hypothesized to serve as a spatial coordinate system for navigation and memory function. The mechanisms underlying the generation of this characteristic tuning pattern remain poorly understood. Systemic administration of the muscarinic antagonist scopolamine flattens the typically positive correlation between running speed and entorhinal theta frequency in rats. The loss of this neural correlate of velocity, an important signal for the calculation of path integration, raises the question of what influence scopolamine has on the grid cell tuning as a read out of the path integration system. To test this, the spatial tuning properties of grid cells were compared before and after systemic administration of scopolamine as rats completed laps on a circle track for food rewards. The results show that the spatial tuning of the grid cells was reduced following scopolamine administration. The tuning of head direction cells, in contrast, was not reduced by scopolamine. This is the first report to demonstrate a link between cholinergic function and grid cell tuning. This work suggests that the loss of tuning in the grid cell network may underlie the navigational disorientation observed in Alzheimer's patients and elderly individuals with reduced cholinergic tone. PMID- 24493380 TI - Robust diamond meshes with unique wettability properties. AB - Robust diamond meshes with excellent superhydrophobic and superoleophilic properties have been fabricated. Superhydrophobicity is observed for water with varying pH from 1 to 14 with good recyclability. Reversible superhydrophobicity and hydrophilicity can be easily controlled. The diamond meshes show highly efficient water-oil separation and water pH droplet transference. PMID- 24493381 TI - [Translational medicine on the road to tailored therapies. 58. Annual Meeting of the Society of Thrombosis and Haemostasis e.V]. PMID- 24493382 TI - Biogenic polyamines capture CO2 and accelerate extracellular bacterial CaCO3 formation. AB - Bacteria, including cyanobacteria, as well as some fungi, are known to deposit calcium carbonate (CaCO(3)) extracellularly in calcium-containing artificial medium. Despite extensive investigation, the mechanisms involved in extracellular formation of CaCO(3) by bacteria have remained unclear. The ability of synthetic amines to remove carbon dioxide (CO(2)) from natural gas led us to examine the role of biogenic polyamines in CaCO(3) deposition by bacteria. Here, we demonstrated that biogenic polyamines such as putrescine, spermidine, and spermine were able to react with atmospheric CO(2) and the resultant carbamate anion was characterized by using nuclear magnetic resonance (NMR) analysis. Biogenic polyamines accelerated the formation of CaCO(3), and we artificially synthesized the dumbbell-shaped calcites, which had the same form as observed with bacterial CaCO3 precipitates, under nonbacterial conditions by using polyamines. The reaction rate of calcification increased with temperature with an optimum of around 40 degrees C. Our observation suggests a novel scheme for CO(2) dissipation that could be a potential tool in reducing atmospheric CO(2) levels and, therefore, global warming. PMID- 24493384 TI - Retraction note: Meloxicam taste-masked oral disintegrating tablet with dissolution enhanced by ion exchange resins and cyclodextrin. PMID- 24493383 TI - Evolution of the relaxin/insulin-like gene family in anthropoid primates. AB - The relaxin/insulin-like gene family includes signaling molecules that perform a variety of physiological roles mostly related to reproduction and neuroendocrine regulation. Several previous studies have focused on the evolutionary history of relaxin genes in anthropoid primates, with particular attention on resolving the duplication history of RLN1 and RLN2 genes, which are found as duplicates only in apes. These studies have revealed that the RLN1 and RLN2 paralogs in apes have a more complex history than their phyletic distribution would suggest. In this regard, alternative scenarios have been proposed to explain the timing of duplication, and the history of gene gain and loss along the organismal tree. In this article, we revisit the question and specifically reconstruct phylogenies based on coding and noncoding sequence in anthropoid primates to readdress the timing of the duplication event giving rise to RLN1 and RLN2 in apes. Results from our phylogenetic analyses based on noncoding sequence revealed that the duplication event that gave rise to the RLN1 and RLN2 occurred in the last common ancestor of catarrhine primates, between ~ 44.2 and 29.6 Ma, and not in the last common ancestor of apes or anthropoids, as previously suggested. Comparative analyses based on coding and noncoding sequence suggests an event of convergent evolution at the sequence level between co-ortholog genes, the single-copy RLN gene found in New World monkeys and the RLN1 gene of apes, where changes in a fraction of the convergent sites appear to be driven by positive selection. PMID- 24493385 TI - Laboratory tests during direct oral anticoagulant treatment. PMID- 24493386 TI - Efficacy, safety, and trends in assisted reproductive technology in Japan analysis of four-year data from the national registry system. AB - PURPOSE: This study aimed to evaluate the efficacy, safety, and trends in assisted reproductive technology (ART) in Japan. METHODS: Data pertaining to treatment cycles, pregnancy rate, live birth rate, age distribution, single embryo transfer rate, and multiple pregnancy rate were analyzed for patients registered in the national ART registry system of Japan from 2007 to 2010. RESULTS: The total number of treatment cycles was 161,164, 190,613, 213,800, and 242,161 in 2007, 2008, 2009, and 2010, respectively. The number of ART treatments administered to patients aged >=40 years was 31.2 %, 32.1 %, 33.4 %, and 35.7 %, respectively, showing an increasing trend from 2007 to 2010. In each of these years, the total pregnancy rate per embryo transfer was 24.4 %, 21.9 %, 22.3 %, and 21.9 % for fresh cycles, respectively, and 32.0 %, 32.1 %, 32.5 %, and 33.7 % for frozen cycles, respectively. The single embryo transfer rate was 49.9 %, 63.6 %, 70.6 %, and 73.0 %, respectively, showing an increasing trend, while the multiple pregnancy rate was 11.5 %, 6.8 %, 5.3 %, and 4.8 %, respectively, showing a decreasing trend. CONCLUSIONS: From 2007 to 2010 in Japan, the number of ART treatment cycles, number of elderly patients treated, and the single embryo transfer rate increased, while the multiple pregnancy rate decreased. However, the overall pregnancy rate remained stable during the study period. PMID- 24493388 TI - A learning health care system for pediatrics. PMID- 24493387 TI - Ovarian response to controlled ovarian hyperstimulation in women with cancer is as expected according to an age-specific nomogram. AB - PURPOSE: To evaluate the ovarian response to controlled ovarian hyperstimulation (COH) in cancer patients according to an age-specific nomogram for the number of retrieved oocytes. METHODS: Retrospective observational study carried out in a University affiliated fertility clinic. Forty-eight patients with cancer underwent ovarian stimulation for oocyte cryopreservation. An age - specific nomogram for the number of retrieved oocytes was built with 1536 IVF cycles due to male factor exclusively, oocyte donation and age related fertility preservation. The number of oocytes retrieved in cancer patients was compared to the expected response according to the nomogram using the Z-score. RESULTS: The mean number of total retrieved oocytes in patients with cancer was 14.04 +/- 8.83. After applying the Z-score to compare the number of retrieved oocytes between women with cancer and the expected response according to the age-specific nomogram, we did not observe a statistically significant difference (Z-score 0.23; 95 % CI [-0.13-0.60]). CONCLUSION(S): According to our results, patients with cancer exhibit an ovarian response as expected by age. Despite the limitation of the sample size, the obtained results should encourage oncologists for early referral of women with cancer to fertility specialists. PMID- 24493389 TI - Role of routine imaging in detecting recurrent lymphoma: A review of 258 patients with relapsed aggressive non-Hodgkin and Hodgkin lymphoma. AB - After first-line therapy, patients with Hodgkin lymphoma (HL) and aggressive non HL are followed up closely for early signs of relapse. The current follow-up practice with frequent use of surveillance imaging is highly controversial and warrants a critical evaluation. Therefore, a retrospective multicenter study of relapsed HL and aggressive non-HL (nodal T-cell and diffuse large B-cell lymphomas) was conducted. All included patients had been diagnosed during the period 2002-2011 and relapsed after achieving complete remission on first-line therapy. Characteristics and outcome of imaging-detected relapses were compared with other relapses. A total of 258 patients with recurrent lymphoma were included in the study. Relapse investigations were initiated outside preplanned visits in 52% of the patients. Relapse detection could be attributed to patient reported symptoms alone or in combination with abnormal blood tests or physical examination in 64% of the patients. Routine imaging prompted relapse investigations in 27% of the patients. The estimated number of routine scans per relapse was 91-255 depending on the lymphoma subtype. Patients with imaging detected relapse had lower disease burden (P = 0.045) and reduced risk of death following relapse (hazard ratio = 0.62, P = 0.02 in multivariate analysis). Patient-reported symptoms are still the most common factor for detecting lymphoma relapse and the high number of scans per relapse calls for improved criteria for use of surveillance imaging. However, imaging-detected relapse was associated with lower disease burden and a possible survival advantage. The future role of routine surveillance imaging should be defined in a randomized trial. PMID- 24493390 TI - Inadvertent sodium loading with renal replacement therapy in critically ill patients. AB - BACKGROUND: Inadvertent sodium (Na(+)) flux may occur during renal replacement therapy (RRT) in ICU. The objective of this study was to estimate sodium flux during RRT. METHODS: Between September 2011 to December 2012 we studied 60 ICU patients receiving extended daily dialysis (EDD, Fresenius 4008S) or continuous renal replacement technique (CRRT, Aquarius 6.01). CRRT was categorized as dialysis with continuous veno-venous haemofiltration (CVVH) or haemodiafiltration (CVVHDF). Sodium balance was calculated as the difference between affluent and effluent fluid sodium concentration corrected for volume. The duration of study was either the duration of a single EDD session or 24 h of CRRT. RESULTS: Both EDD and CRRT contributed to a positive Na(+) flux. Despite similar demographics, CRRT patients had a greater positive sodium flux (p < 0.001). At multivariate analysis, factors [exp(b) (SE), p] which significantly affected sodium flux in each mode of RRT were: (1) EDD (R(2) = 0.42): gradient between RRT Na(+) and serum Na(+) [20.9 (5.8), p < 0.02], and total litres of exchange [1.5 (0.68), p < 0.04]; (2) CVVH (R(2) = 0.77): gradient between RRT Na(+) and serum Na(+) [21.8 (4.7), p < 0.001], dialysis day [-20.9 (9.8), p < 0.05], and total litres of exchange [5.2 (0.96), p < 0.001]; (3) CVVHDF (R(2) = 0.73): gradient between RRT Na(+) and serum Na(+) [23.8 (3.7), p < 0.001], and total fluid removal [-18.5 (3.26), p < 0.001]. CONCLUSION: RRT may inadvertently contribute to sodium load in critically ill patients and is affected by multiple factors including gradient between RRT Na(+) and serum Na(+). PMID- 24493391 TI - Reinitiation of peritoneal dialysis after catheter removal for refractory peritonitis. AB - AIM: A high proportion of patients whose catheters are removed are unable to successfully reinitiate peritoneal dialysis (PD) due to irreversible peritoneal injury or to decisions made by the patient or the nephrologist for different and often empiric reasons. The present study examined the outcomes of patients reinitiated on PD after peritonitis. METHODS: We reviewed all patients with end stage renal disease who were initiated on continuous ambulatory peritoneal dialysis at our Institute in south India between 1998 and 2012, identifying those in whom the catheter was removed and the cases where PD was reinitiated, analysing the reasons and outcome. We compared data of patients who could be reinitiated on PD with those who could not be reinitiated and also data of patients who successfully continued PD after reinitiation with those who suffered technique failure. RESULTS: Peritoneal dialysis was reinitiated in 31 (19.4%) of 159 patients whose catheter was removed owing to refractory peritonitis, including after an episode of Pseudomonas aeruginosa and fungal peritonitis. Some patients had the catheter placed for a third time. No significant difference was found between patients who reinitiated PD vs. did not, or between those who were successful in reinitiating PD vs. unsuccessful. CONCLUSION: Notwithstanding the small cohort size, the present study demonstrates that reinitiating PD is feasible in a developing country, and also that reinitiation of PD is possible after an episode of P. aeruginosa and fungal peritonitis. However, future studies in a larger patient cohort and assessing dialysis adequacy are required to confirm and extend our findings. PMID- 24493392 TI - A model describing photosynthesis in terms of gas diffusion and enzyme kinetics. AB - A model predicting net photosynthesis of individual plant leaves for a variety of environmental conditions has been developed. It is based on an electrical analogue describing gas diffusion from the free atmosphere to the sites of CO2 fixation and a Michaelis-Menten equation describing CO2 fixation. The model is presented in two versions, a simplified form without respiration and a more complex form including respiration. Both versions include terms for light and temperature dependence of CO2 fixation and light control of stomatal resistance. The second version also includes terms for temperature, light, and oxygen dependence of respiration and O2 dependence of CO2 fixation.The model is illustrated with curves based on representative values of the various environmental and biological parameters. These curves relate net photosynthesis to light intensity, [CO2], [O2], temperature, and resistances to CO2 uptake. The shape of the [CO2]-net photosynthesis curves depends on the total diffusion resistance to CO2 uptake and the Michaelis constant for CO2 uptake. The curves range from typical Michaelis-Menten to Blackman types.The model is combined with a model of leaf energy exchange permitting simultaneous estimation of net photosynthesis and transpiration. The combined model is illustrated with curves relating transpiration to photosynthesis under a wide variety of environmental conditions. Environmental regimes yielding maximum efficiency of water use are identified for the given assumptions and biological parameters. PMID- 24493393 TI - Comparative photorespiration in Amaranthus, soybean and corn. AB - A tracer technique was used to measure photorespiration in Amaranthus lividus, soybean and corn. Under a light intensity of 40 Wm(-2) (400-700 nm) efflux of tracer carbon dioxide from Amaranthus into air was comparable to that from soybean over a 30-min period and 10 times that from corn. Initial rates of efflux of tracer into air from Amaranthus were higher than from soybean and 9 times that from corn. Efflux of CO2 from Amaranthus over 30 min in 120 Wm(-2) was only 5 times that of corn and the initial rate was only one third that of soybean. Though total efflux from soybean was similar at the two light intensities, the initial rate was slightly higher under 120 Wm(-2). For Amaranthus and soybean, pure oxygen doubled total efflux of CO2 and substantially increased the initial rate compared with CO2-free air whereas there was no effect on corn. A comparison of the light and dark curves suggests that light and dark respiration had different substrates. The results are interpreted in terms of the recycling of photorespiratory CO2. PMID- 24493394 TI - Floral initiation in Lolium temulentum L.: the role of phytochrome in the responses to red and far-red light. AB - The possibility that phytochrome is involved in the promotion of flowering by far red light was investigated. The addition of far-red (FR) to a day extension with red (R) light promotes inflorescence initiation in Lolium. A 2-hour interruption with darkness also promoted flowering compared with the uninterrupted red light control; apex length was further increased by a 10-minute FR irradiation given before the 2-hour dark interruption and was decreased by 10-minutes of R light given in the middle: both FR promotion and R inhibition were reversed by R and FR respectively. Apex length increased approximately linearly with increasing duration of dark interruption up to at least 2 1/2 hours. When varying ratios of R:FR light were substituted for a 2-hour dark period, apex length was increasingly depressed as the % R was increased above 25%; no difference between 25% R/75% FR and 100% FR could be detected. Apex length was inversely linearly related to the calculated [Pfr]/[P] ratios above about 40% Pfr.FR promoted flowering when given during a 5-hour interruption of a day extension with R light but, between 0.25 and 0.90 J m(2) s(-1), there was no effect of intensity of FR; at 0.11 J m(-2) s(-1) apex length was shorter than at 0.25 J m(-2) s(-1) but longer than in darkness. When the duration of FR (from the beginning of a dark interruption of a day extension with R) was varied, apex length increased with increasing duration of FR up to 1 1/4 to 2 hours but further increasing the duration of FR did not promote flowering more.The results implicate phytochrome in the promotion of flowering by FR light. It has been demonstrated that a low [Pfr]/[P] ratio (less than present in 25% R/75% FR) is needed over a relatively long period of time: this explains why a relatively high proportion of FR light must be added to R for several hours in order to give maximum promotion of flowering. It is concluded that, in Lolium, the increased flowering response to FR light is brought about by a reduction of [Pfr]/[P] ratio at the appropriate time, although the possibility that another effect of far-red is also involved has not been rigorously excluded. PMID- 24493395 TI - Wall structure of a bitunicate ascus. AB - The bitunicate ascus develops in two stages prior to ascospore formation: 1) initial growth and expansion of the ascus mother-cell, and 2) deposition of a secondary wall layer, the endotunica, within the outer primary wall layer, the ectotunica. The layers of the bitunicate ascus are composed of microfibrils embedded in an amorphous matrix. The ectotunica and the endotunica differonly in the arrangement of the microfibrils. The primary wall layer is deposited during growth and expansion of the ascus mother-cell; the microfibrils are parallel to the ascus-protoplast surface. The secondary wall layer is deposited after the ascus mother-cell has fully expanded and before ascospore formation; the microfibrils are arranged in a banded pattern. Expansion of the ascus wall during ascospore expulsion is accomplished by a rapid reorientation of the microfibrils of the secondary layer. PMID- 24493396 TI - [Action spectra of anthocyanin synthesis in tissue cultures and seedlings of Haplopappus gracilis]. AB - The biosynthesis of anthocyanin in tissue cultures and intact seedlings of Haplopappus gracilis is a light-dependent reaction which can be induced by blue light only. Anthocyanin appeared in all organs of the seedling.Wounding of the plant led to an increase in the content of anthocyanin due to increased anthocyanin synthesis in the cotyledons.The action spectra of anthocyanin formation in tissue cultures and intact seedlings have two peaks, one at 438 nm and the other at 372 nm. The limit of activity in the direction of longer wavelengths lies between 474 and 493 nm. Red light of short and long wavelength is ineffective in the induction of pigment synthesis. The photoreceptor of the light reaction is supposed to be a yellow pigment (flavoprotein or carotinoid). In contrast to the intact plants, isolated cotyledons and wounded seedlings are able to form anthocyanin not only in the blue region but also during irradiation with red light of high intensity. The action spectrum of anthocyanin synthesis in the isolated cotyledons has a marked maximum at about 440 nm and a second one at about 660 nm. A little activity can be observed throughout the visible spectrum. The pigment synthesis induced by red light can be completely suppressed by DCMU, an inhibitor of photosynthesis. This indicates that in the case of the activity in the red light caused by wounding chlorophyll serves as photoreceptor.The anthocyanin synthesis in tissue cultures and seedlings could not be influenced by low energy radiation in the red or in the far red region, even after induction of anthocyanin synthesis by blue light of high intensity. Therefore it seems that the phytochrome system is not involved in anthocyanin synthesis in Haplopappus gracilis. PMID- 24493397 TI - [High resistance to X-rays of the activity and light-induced activation of NADP dependent glyceraldehyde phosphate dehydrogenase in Ankistrodesmus braunii]. AB - In Ankistrodesmus braunii, a unicellular alga, the activity of NADP-dependent glyceraldehyde phosphate dehydrogenase (GPD) in darkness is very resistant to X rays. The light-induced increase in the activity of this enzyme within one minute is also not affected by irradiation. Doses up to 1060 Krad had no inhibitory effect. The increase of GPD activity during the life cycle, however, is very sensitive to X-rays. PMID- 24493398 TI - The greening of chromoplasts in Daucus carota L. AB - Evidence was obtained for the transformation of chromoplasts to chloroplasts in the cortex parenchyma of carrot during exposure to light. Typical chromoplasts containing carotene crystals but no lamellar system were observed at the onset of illumination. The ensuing synthesis of chlorophyll and a lamellar system was accompanied by disappearance of the carotene crystals. Only chloroplasts were present after 48 hr in the light. The different stages of plastid development were observed using the electron microscope. PMID- 24493399 TI - Specialties performing paracentesis procedures at university hospitals: implications for training and certification. AB - BACKGROUND: Paracentesis procedure competency is not required for internal medicine or family medicine board certification, and national data show these procedures are increasingly referred to interventional radiology (IR). However, practice patterns at university hospitals are less clear. OBJECTIVE: To evaluate which specialties perform paracentesis procedures at university hospitals, compare characteristics of patients within each specialty, and evaluate length of stay (LOS) and hospital costs. DESIGN, SETTING, PATIENTS: Observational administrative database review of patients with liver disease who underwent paracentesis procedures in hospitals participating in the University HealthSystem Consortium (UHC) Database from January 2010 through December 2012. UHC is an alliance of 120 academic medical centers and their 290 affiliated hospitals. EXPOSURE: Patients with liver disease who underwent inpatient paracentesis procedures. MEASUREMENTS: We compared characteristics of patients who underwent paracentesis procedures by physician specialty, modeling the effects of patient characteristics on the likelihood of IR referral. We also analyzed LOS and hospital costs among patients with a >20% predicted probability of IR referral. RESULTS: There were 97,577 paracentesis procedures performed during 70,862 hospital stays in 204 hospitals. IR performed 29% of paracenteses versus 49% by medicine and medicine subspecialties including gastroenterology/hepatology. Patients who were female, obese, and those with lower severity of illness were more likely to be referred to IR. Patients with a medicine or gastroenterology/hepatology paracentesis had a similar LOS compared to IR. Hospital costs were an estimated as $1308 less for medicine and $803 less for gastroenterology/hepatology compared to admissions with IR procedures (both P = 0.0001). CONCLUSIONS: Internal medicine- and family medicine-trained clinicians frequently perform paracentesis procedures on complex inpatients but are not currently required to be competent in the procedure. Increasing bedside paracentesis procedures may reduce healthcare costs. PMID- 24493402 TI - Numerical simulation of the fluid structure interactions in a compliant patient specific arteriovenous fistula. AB - The objective of the study is to investigate numerically the fluid-structure interactions (FSI) in a patient-specific arteriovenous fistula (AVF) and analyze the degree of complexity that such a numerical simulation requires to provide clinically relevant information. The reference FSI simulation takes into account the non-Newtonian behavior of blood, as well as the variation in mechanical properties of the vascular walls along the AVF. We have explored whether less comprehensive versions of the simulation could still provide relevant results. The non-Newtonian blood model is necessary to predict the hemodynamics in the AVF because of the predominance of low shear rates in the vein. An uncoupled fluid simulation provides informative qualitative maps of the hemodynamic conditions in the AVF; quantitatively, the hemodynamic parameters are accurate within 20% maximum. Conversely, an uncoupled structural simulation with non-uniform wall properties along the vasculature provides the accurate distribution of internal wall stresses, but only at one instant of time within the cardiac cycle. The FSI simulation advantageously provides the time-evolution of both the hemodynamic and structural stresses. However, the higher computational cost renders a clinical use still difficult in routine. PMID- 24493403 TI - Segmentation of biomedical images using active contour model with robust image feature and shape prior. AB - In this article, a new level set model is proposed for the segmentation of biomedical images. The image energy of the proposed model is derived from a robust image gradient feature which gives the active contour a global representation of the geometric configuration, making it more robust in dealing with image noise, weak edges, and initial configurations. Statistical shape information is incorporated using nonparametric shape density distribution, which allows the shape model to handle relatively large shape variations. The segmentation of various shapes from both synthetic and real images depict the robustness and efficiency of the proposed method. PMID- 24493404 TI - Effect of exercise on patient specific abdominal aortic aneurysm flow topology and mixing. AB - Computational fluid dynamics modeling was used to investigate changes in blood transport topology between rest and exercise conditions in five patient-specific abdominal aortic aneurysm models. MRI was used to provide the vascular anatomy and necessary boundary conditions for simulating blood velocity and pressure fields inside each model. Finite-time Lyapunov exponent fields and associated Lagrangian coherent structures were computed from blood velocity data and were used to compare features of the transport topology between rest and exercise both mechanistically and qualitatively. A mix-norm and mix-variance measure based on fresh blood distribution throughout the aneurysm over time were implemented to quantitatively compare mixing between rest and exercise. Exercise conditions resulted in higher and more uniform mixing and reduced the overall residence time in all aneurysms. Separated regions of recirculating flow were commonly observed in rest, and these regions were either reduced or removed by attached and unidirectional flow during exercise, or replaced with regional chaotic and transiently turbulent mixing, or persisted and even extended during exercise. The main factor that dictated the change in flow topology from rest to exercise was the behavior of the jet of blood penetrating into the aneurysm during systole. PMID- 24493405 TI - Reward-based incentives for smoking cessation: how a carrot became a stick. PMID- 24493406 TI - Blockade of corticotropin-releasing hormone receptor 1 attenuates early-life stress-induced synaptic abnormalities in the neonatal hippocampus. AB - Adult individuals with early stressful experience exhibit impaired hippocampal neuronal morphology, synaptic plasticity and cognitive performance. While our knowledge on the persistent effects of early-life stress on hippocampal structure and function and the underlying mechanisms has advanced over the recent years, the molecular basis of the immediate postnatal stress effects on hippocampal development remains to be investigated. Here, we reported that repeated blockade of corticotropin-releasing hormone receptor 1 (CRHR1) ameliorated postnatal stress-induced hippocampal synaptic abnormalities in neonatal mice. Following the stress exposure, pups with fragmented maternal care showed retarded dendritic outgrowth and spine formation in CA3 pyramidal neurons and reduced hippocampal levels of synapse-related proteins. During the stress exposure, repeated blockade of glucocorticoid receptors (GRs) by daily administration of RU486 (100 ug g(-1) ) failed to attenuate postnatal stress-evoked synaptic impairments. Conversely, daily administration of the CRHR1 antagonist antalarmin hydrochloride (20 ug g( 1) ) in stressed pups normalized hippocampal protein levels of synaptophysin, postsynaptic density-95, nectin-1, and nectin-3, but not the N-methyl-d-aspartate receptor subunits NR1 and NR2A. Additionally, GR or CRHR1 antagonism attenuated postnatal stress-induced endocrine alterations but not body growth retardation. Our data indicate that the CRH-CRHR1 system modulates the deleterious effects of early-life stress on dendritic development, spinogenesis, and synapse formation, and that early interventions of this system may prevent stress-induced hippocampal maldevelopment. PMID- 24493407 TI - Urinary retention in an infant caused by a posterior urethral diverticulum lithiasis following surgery for anorectal malformation. PMID- 24493409 TI - C9ORF72: grabbing a tiger by the tail. PMID- 24493408 TI - The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype. AB - The GGGGCC (G4C2) repeat expansion in C9ORF72 is the most common cause of familial amyotrophic lateral sclerosis (ALS), frontotemporal lobar dementia (FTLD) and ALS-FTLD, as well as contributing to sporadic forms of these diseases. Screening of large cohorts of ALS and FTLD cohorts has identified that C9ORF72 ALS is represented throughout the clinical spectrum of ALS phenotypes, though in comparison with other genetic subtypes, C9ORF72 carriers have a higher incidence of bulbar onset disease. In contrast, C9ORF72-FTLD is predominantly associated with behavioural variant FTD, which often presents with psychosis, most commonly in the form of hallucinations and delusions. However, C9ORF72 expansions are not restricted to these clinical phenotypes. There is a higher than expected incidence of parkinsonism in ALS patients with C9ORF72 expansions, and the G4C2 repeat has also been reported in other motor phenotypes, such as primary lateral sclerosis, progressive muscular atrophy, corticobasal syndrome and Huntington like disorders. In addition, the expansion has been identified in non-motor phenotypes including Alzheimer's disease and Lewy body dementia. It is not currently understood what is the basis of the clinical variation seen with the G4C2 repeat expansion. One potential explanation is repeat length. Sizing of the expansion by Southern blotting has established that there is somatic heterogeneity, with different expansion lengths in different tissues, even within the brain. To date, no correlation with expansion size and clinical phenotype has been established in ALS, whilst in FTLD only repeat size in the cerebellum was found to correlate with disease duration. Somatic heterogeneity suggests there is a degree of instability within the repeat and evidence of anticipation has been reported with reducing age of onset in subsequent generations. This variability/instability in expansion length, along with its interactions with environmental and genetic modifiers, such as TMEM106B, may be the basis of the differing clinical phenotypes arising from the mutation. PMID- 24493410 TI - Virtual screening with AutoDock Vina and the common pharmacophore engine of a low diversity library of fragments and hits against the three allosteric sites of HIV integrase: participation in the SAMPL4 protein-ligand binding challenge. AB - To rigorously assess the tools and protocols that can be used to understand and predict macromolecular recognition, and to gain more structural insight into three newly discovered allosteric binding sites on a critical drug target involved in the treatment of HIV infections, the Olson and Levy labs collaborated on the SAMPL4 challenge. This computational blind challenge involved predicting protein-ligand binding against the three allosteric sites of HIV integrase (IN), a viral enzyme for which two drugs (that target the active site) have been approved by the FDA. Positive control cross-docking experiments were utilized to select 13 receptor models out of an initial ensemble of 41 different crystal structures of HIV IN. These 13 models of the targets were selected using our new "Rank Difference Ratio" metric. The first stage of SAMPL4 involved using virtual screens to identify 62 active, allosteric IN inhibitors out of a set of 321 compounds. The second stage involved predicting the binding site(s) and crystallographic binding mode(s) for 57 of these inhibitors. Our team submitted four entries for the first stage that utilized: (1) AutoDock Vina (AD Vina) plus visual inspection; (2) a new common pharmacophore engine; (3) BEDAM replica exchange free energy simulations, and a Consensus approach that combined the predictions of all three strategies. Even with the SAMPL4's very challenging compound library that displayed a significantly lower amount of structural diversity than most libraries that are conventionally employed in prospective virtual screens, these approaches produced hit rates of 24, 25, 34, and 27 %, respectively, on a set with 19 % declared binders. Our only entry for the second stage challenge was based on the results of AD Vina plus visual inspection, and it ranked third place overall according to several different metrics provided by the SAMPL4 organizers. The successful results displayed by these approaches highlight the utility of the computational structure-based drug discovery tools and strategies that are being developed to advance the goals of the newly created, multi-institution, NIH-funded center called the "HIV Interaction and Viral Evolution Center". PMID- 24493411 TI - Impact of distance-based metric learning on classification and visualization model performance and structure-activity landscapes. AB - This study concerns large margin nearest neighbors classifier and its multi metric extension as the efficient approaches for metric learning which aimed to learn an appropriate distance/similarity function for considered case studies. In recent years, many studies in data mining and pattern recognition have demonstrated that a learned metric can significantly improve the performance in classification, clustering and retrieval tasks. The paper describes application of the metric learning approach to in silico assessment of chemical liabilities. Chemical liabilities, such as adverse effects and toxicity, play a significant role in drug discovery process, in silico assessment of chemical liabilities is an important step aimed to reduce costs and animal testing by complementing or replacing in vitro and in vivo experiments. Here, to our knowledge for the first time, a distance-based metric learning procedures have been applied for in silico assessment of chemical liabilities, the impact of metric learning on structure activity landscapes and predictive performance of developed models has been analyzed, the learned metric was used in support vector machines. The metric learning results have been illustrated using linear and non-linear data visualization techniques in order to indicate how the change of metrics affected nearest neighbors relations and descriptor space. PMID- 24493412 TI - Impact of a predefined mediastinal ROI on inter-observer variability of planar 123I-MIBG heart-to-mediastinum ratio. AB - AIM: Purpose of this study was to assess the impact of mediastinal region of interest (ROI) definition on intra- and inter-observer variability in relation to collimator type. METHODS: Thirty-five subjects with CHF (80% men, mean age 66 +/- 9 years, NYHA 2.4 +/- 0.5, LVEF 29 +/- 8.4%) were enrolled. 15 minutes and 4 hours post-injection (p.i.) of (123)I-MIBG, planar images were sequentially acquired with low energy high energy (LEHR) and medium energy (ME) collimators. In the first analysis, observer-defined mediastinal ROI was used. In the second analysis, a predefined mediastinal ROI was used. Intra- and inter-observer variability of late H/M was assessed using Lin's concordance coefficient (LCC). RESULTS: There was substantial agreement between all three observers using predefined mediastinum ROI. LCCs for LEHR were 0.98, 0.96, and 0.95, for ME 0.98, 0.97, and 0.97. However, observer-defined mediastinal ROI resulted in poor moderate agreement. LCCs for LEHR were 0.82, 0.94, and 0.70, for ME 0.77, 0.91, and 0.80. Intra-observer analysis using predefined mediastinal ROI showed substantial agreement. LCC was 0.97 for LEHR and 0.96 for ME. CONCLUSION: Predefined mediastinal ROI results in low intra- and inter-observer variability of late H/M and is, therefore, to be preferred over observer-defined mediastinal ROI. Intra- and inter-observer variability of late H/M is not influenced by collimator choice. PMID- 24493414 TI - Role of multimodality imaging including Thallium-201 myocardial perfusion imaging in the diagnosis and monitoring of treatment response in cardiac sarcoidosis. PMID- 24493413 TI - Combination of 123I-metaiodobenzylguanidine scintigraphy and flow-mediated dilation for the detection of patients with coronary spastic angina. AB - BACKGROUND: This study evaluated the usefulness of cardiac sympathetic nerve activity, estimated by (123)I-MIBG scintigraphy, and endothelial function, estimated by flow-mediated dilation (FMD), in the detection of coronary spastic angina (CSA). METHODS AND RESULTS: We compared 78 consecutive patients suspected of CSA with ten age-matched controls. On the basis of a spasm provocation test with acetylcholine, 53 patients were diagnosed as CSA and 25 patients were considered to have chest-pain syndrome (CPS). The total defect score (TDS) by delayed (123)I-MIBG scintigraphy was significantly higher in both patient groups than in controls (P < 0.05), and was significantly higher in CSA than in CPS patients (P = 0.02). The heart/mediastinum activity (H/M) ratio by delayed (123)I MIBG scintigraphy and FMD were significantly lower in both patient groups than in controls (P < 0.05), and were lower in CSA than in CPS patients (P = 0.04). In receiver-operating curve analysis, the areas under the curve for TDS, H/M, and FMD were 0.78, 0.72, and 0.70, respectively. The combination of delayed (123)I MIBG scintigraphy and FMD showed a higher diagnostic value than either method alone. CONCLUSIONS: (123)I-MIBG scintigraphy and FMD can distinguish CSA patients among patients complaining of chest pain at rest, with good sensitivity and specificity. PMID- 24493415 TI - Methods for Gene Transfer Using DNA-Adenovirus Conjugates. AB - Strategies have been developed to accomplish gene delivery via the receptor mediated pathway employing molecular conjugate vectors (1-13). As cells possess endogenous pathways for internalization of macromolecules, the utilization of these pathways for the purpose of DNA delivery represents a strategy that potentially allows certain practical advantages. In this regard, these cellular internalization pathways can be highly efficient. For example, internalization of the iron transport protein transferrin can be on the order of thousands of molecules per minute per cell (14,15). These pathways thus represent a potentially efficient physiologic method to transport DNA across the cell membrane of eukaryotic cells. To accomplish gene transfer via receptor-mediated endocytosis, a vehicle must be derived that allows DNA entry into these cellular pathways. For this purpose, molecular conjugate vectors have been derived. These vector agents consist of two linked functional domains: a DNA-binding domain to transport the DNA as part of the vector complex, and a ligand domain to target a cellular receptor that allows entry of the conjugate-DNA complex into a receptor mediated endocytosis pathway. For incorporating DNA into the complex for gene delivery, binding must be achieved in a nondamaging, reversible manner. For this linkage, an electrostatic association between the binding domain and the nucleic acid is accomplished. To achieve this, the DNA binding domain is comprised of a polycationic amine, such as poly(L)lysine. This can associate with the negatively charged DNA in an electrostatic, noncovalent manner. To achieve entry of the complex through a receptor-mediated pathway, a ligand for the target cell is utilized. The ligand domain is covalently linked to the polylysine to create the molecular conjugate vector. The ligand domain may be a native or synthetic cell surface receptor ligand, an antireceptor antibody, or other agent that allows specific association with target cell membranes. PMID- 24493416 TI - Methods for the construction and propagation of recombinant adeno-associated virus vectors. AB - The development of gene transfer vectors from the human parvovirus, adeno associated virus (AAV), has provided scientists with an efficient and effective way of delivering genes into mammalian cells. This chapter aims to explore the various practical aspects of the AAV vector system, and in consequence, to highlight particular difficulties that may be encountered by workers new to the field. However, before describing the methodology involved in the generation of recombinant AAV vectors, it is of value to briefly discuss the structure and life cycle of this unique virus. Detailed and more extensive reviews that describe the biology of adeno-associated virus are also available (1-3). PMID- 24493417 TI - Generation of high-titer, helper-free retroviruses by transient transfection. AB - Retroviral gene transfer is presently one of the most powerful techniques for introducing stably heritable genetic material into mammalian cells (reviewed in ref. 1). One serious drawback of this technique, however, has been the difficulty in readily producing high-titer recombinant retroviruses. For many applications, such as infecting rare target cells or the majority of cells in tissue culture, the recombinant virus titer must be at least 10(6) infectious units/mL. Although one can usually obtain high-titer mixtures of recombinant and replication competent retroviruses in a relatively short time, many applications such as cell marking studies or studying genes in vivo demand freedom from replication competent virus. PMID- 24493418 TI - Methods for the construction of retroviral vectors and the generation of high titer producers. AB - Retroviral vectors are powerful tools for gene transfer that are useful in the context of experimental as well as clinical applications. Defective recombinant retroviruses allow for efficient gene transfer into a broad range of mammalian cells derived from different species and different tissues. Safe gene transfer can be achieved using helper-free viral stocks, owing to the development of vectors and packaging cell lines that minimize the probability of hazardous recombination events. Retrovirus-mediated gene transfer leads to stable proviral integration in the target-cell genome, a key feature when the foreign genetic material must be faithfully transmitted to the progeny of the transduced parental cell, murine leukemia virus (MLV)-based vectors accommodate numerous modifications, thus providing a plastic tool that can be tailored for very diverse applications. PMID- 24493419 TI - Development of replication-defective herpes simplex virus vectors. AB - Numerous diseases of the nervous system result from single gene or multifactorial gene defects such as cancer, immune pathological disorders, metabolic diseases, and common neurodegenerative syndromes (Parkinson's and Alzheimer's diseases). A greater understanding of the molecular, biochemical, and genetic factors involved in the progression of a specific disease state has led to the development of genetic therapies using direct gene transfer to ameliorate the disease condition or correct a genetic defect in situ. Standard gene therapeutic approaches employing retroviruses have not proven feasible for treating disorders of the central nervous system (CNS) since these vectors require dividing cells for integration and expression of the transgene, whereas CNS neurons are postmitotic, terminally differentiated cells. Thus, methods for delivery and expression of therapeutic gene products to treat CNS disease will require new delivery strategies and vehicles including the development of novel vectors for direct gene transfer. These vectors should: efficiently deliver the therapeutic gene(s) to a sufficient number of nondividing neurons; persist long-term in a nonintegrated state within the nerve cell nucleus without disturbing host cell functions; and be able to regulate therapeutic gene expression for diseases that may either require high-level transient transgene expression or continuous low level synthesis of the therapeutic product. PMID- 24493420 TI - Methods for the use of poliovirus vectors for gene delivery. AB - Poliovirus is a member of the Picornaviridae family of viruses. Characteristic of all members of this family, the poliovirus genome consrsis of approx 7500 bp of RNA of the plus sense polarity (1,2). Poliovirus is undoubtedly one of the most thoroughly characterized animal viruses. The three-dimensional structure of the entire virion is known (3), an infectious cDNA clone of the poliovirus genome has been generated (4,5), the entire nucleic acid sequence of poliovirus has been determined (1), and the cellular receptor that pohovirus uses to enter cells has been cloned and sequenced (6). The availability of a transgenic mouse expressing the poliovirus receptor has facilitated further description of the pathogenesis of poliovirus (7,8). PMID- 24493421 TI - Methods for the construction of human papillomavirus vectors. AB - A number of vector systems have been developed for the delivery of therapeutic genes into cells (1). Many viral vectors suffer from the disadvantage of random integration into the chromosome, making the expression of the cloned genes dependent on the chromosomal context of the inserted DNA. Papillomaviruses (PVs) are potentially important vector systems because of their extrachromosomal replication in target cells. The PVs are small DNA viruses that infect humans and a wide range of animals. Human papillomaviruses (HPVs) induce benign proliferative squamous eplthelial and fibro-epithelial lesions (warts and papillomas) in their natural hosts (2). Some HPVs are also involved in the pathogenesis of anogenital cancer and, in particular, cancer of the cervix (2). Papillomaviruses contain circular, double-stranded DNA of approx 8 kb, and usually replicate extrachromosomally at a copy number estimated to be between 10 and 100 (3). The potential advantages of PV vectors include expression of cloned genes from an extrachromosomal state that may be more amenable to uniform expression and possible elimination of problems associated with integration of DNA into transcriptionally inactive regions of the cellular chromosomes. Since PV DNA is not encapsidated, it may be possible to insert larger DNA sequences into such vectors, provided the DNA can still replicate in a stable manner. Bovine papillomavirus type 1 (BPV-1) vectors have been used to produce stable cell lines expressing foreign proteins (for reviews, see refs. 4-7). The BPV-1 vectors used in these studies contained both replication and transforming genes, and in most cases, extrachromosomal replication of these vectors was accompanied by transformation of the target cells (8-12). Recent advances in our understanding of the replication and transforming genes of PVs have resulted in renewed efforts to develop vectors that can be established as stable extrachromosomal plasmids and express foreign proteins without oncogenic transformation of the host cell. The current article deals mostly with the potential of HPVs as vectors for gene therapy. PMID- 24493422 TI - Methods for liposome-mediated gene transfer to the arterial wall. AB - Cationic liposomes are preparations of positively charged lipids used for transfection of mammalian cells in vitro and in vivo. Although viruses efficiently infect mammalian cells, the potential risks of viral gene delivery spurred research in the development of synthetic chemical vectors that would duplicate viral delivery but have no risk of infectious complications. These nonviral vectors were first developed in the late 1980s. Cationic lipids are attractive vectors for vascular gene transfer studies owing to ease of preparation, reproducibility, and safety (1-3). In this chapter, we describe our experience with vascular gene transfer using four liposome reagents: DOTMA/DOPE, DC-cholesterol, DOSPA/DOPE, and DMRIE/DOPE. PMID- 24493423 TI - Methods for Targeted Gene Transfer to Liver Using DNA-Protein Complexes. AB - The potential of therapeutic gene transfer to treat human disease has prompted a diverse and growing range of basic and applied research efforts to explore and develop gene therapy strategies (1-5). Reported approaches to gene therapy mclude the uses of retroviruses (6,7), adenovirus (8,9), receptor-mediated endocytosis (10,11), direct injection (12), and liposomes (13,14), among others. Targeted delivery of DNA via receptors has been successfully applied using protein ligands to the hepatic asialoglycoprotein receptor (ASGr) (10,15-18), and, subsequently, the transferrin receptor (11). The ASGr is a cell-surface receptor that is highly represented on hepatocytes. Thus, genes targeted to this receptor can be delivered in a highly selective manner to the liver. PMID- 24493424 TI - Methods for the Use of Retroviral Vectors for Transfer of the CFTR Gene to Airway Epithelium. AB - Cystic fibrosis (CF) is a recessive genetic disease that affects the regulation of ion transport in the epithelia of various organs in the body including the lungs, pancreas, intestine, salivary glands, and urogenital tract. The protein encoded by the CF gene is an integral plasma membrane protein called the cystic fibrosis transmembrane conductance regulator (CFTR) and has been shown to function as a chloride channel (1). In the lungs, CFTR dysfunction affects electrolyte and fluid transport across the apical membrane of airway epithelial cells. There, sodium hyperabsorption and defective chloride secretion lead to dehydration of the fluids on the airway surface and, in turn, this leads to chronic infections and severe damage. The severity of CF lung disease and the potential accessibility of the airways to gene transfer vectors has led to proposals that gene therapy be applied for the treatment of CF lung disease (2). PMID- 24493425 TI - Methods for adenovirus-mediated gene transfer to airway epithelium. AB - Recombinant adenoviral vectors have proven to be extremely efficient tools for transferring genes into multiple organ systems including the lung (1-5), liver (6 10), muscle (11,12), joint (13), vasculature (14,15), and central nervous system (16-18). The lung presents unique advantages as a target organ for the evaluation of these vectors as tools for in vivo gene therapy owing to the accessibility of target cells by direct instillation or inhalation of recombinant virus in the airway. Multiple therapeutic applications of gene therapy to the lung include both inherited disorders such as cystic fibrosis (CF) and alpha-antitrypsin deficiency, as well as acquired disorders such as bronchitis, asthma, emphysema, and respiratory malignancies. The most widely studied application to date has involved the analysis of recombinant adenoviruses for gene therapy of CF lung disease (1-5). To this end, multiple phase I clinical trails are now underway evaluating the safety of recombinant adenoviral vectors for gene therapy of cystic fibrosis lung disease (19). This clinical application of these vectors in CF lung disease presents the largest comprehensive effort of in vivo gene therapy to date. Such a substantial effort has offered the advantage of multiple preclinical studies evaluating delivery of adenoviral vectors to the lung in numerous animal models such as the cotton rat (4,5,20), human bronchial xenografts (1), mouse (21), and nonhuman primates (2,3,22,23). PMID- 24493426 TI - Methods for retrovirus-mediated gene transfer to fetal lung. AB - With the advent of improved vectors for DNA delivery, somatic gene therapeutic approaches have expanded rapidly in the last few years. The vast majority of applications include ex vivo and in vivo protocols in patients postnatally. Nonetheless there is increasing interest and compelling reasons to consider prenatal application of somatic gene therapy (1,2. In the current chapter, we will review theoretical, ethical, and experimental support for in utero gene therapy and then outline the methodology and large animal model we are currently using to consider retrovirus-mediated gene transfer to fetal lung. In this latter regard, the candidate inherited disorder is cystic fibrosis and the reader is referred to Chapters 1 and 12 in this volume. PMID- 24493427 TI - In situ retrovirus-mediated gene transfer into the liver. AB - Gene transfer into hepatocytes is a promising approach for the treatment of genetic liver diseases. Candidate diseases for human trials are life-threatening disorders resulting from a single genetic defect that do not compromise other liver functions and the organization of the hepatic tissue. Orthotopic liver transplantation has been successfully performed in patients with genetic liver disease, but then use is limited by the high mortality risk, the need for chronic immunosuppression, and the availability of organs. Gene therapy would pro vide an alternative to transplantation by restoring the expression of the defective gene in an organ that is otherwise structurally and functionally normal. PMID- 24493428 TI - Methods for delivery of genes to hepatocytes in vivo using recombinant adenovirus vectors. AB - In many ways, the liver represents an ideal target organ for gene delivery. Anatomically, the sheer bulk cof its tissue mass and its dual blood supply are advantageous for intravascular injection of virus into either portal or systemic circulation. The portal vein provides a direct iv route into the liver. It also theoretically provides an indirect route by oral administration since the portal system drains the gut. PMID- 24493429 TI - Methods for producing high titer, pantropic retroviral vectors for gene transfer into leukemic T-cells. AB - Current limitations to the use of Moloney murine leukemia virus (MoMLV)-derived retroviral vectors as a tool for gene transfer include the inability to obtain high-titer vector stocks and the narrow host cell range of these vectors. To overcome these disadvantages, we developed a new class of pantropic retroviral vector that has a broadened host cell range and can be concentrated to very high titers (>10(9) colony forming units [CFU]/mL) (1). PMID- 24493430 TI - Methods for efficient retrovirus-mediated gene transfer to mouse hematopoietic stem cells. AB - A variety of genetic and acquired diseases could conceivably be treated by gene therapy targeted to hematopoietic stem cells (HSC). Inevitably, the effort to develop reliable methods of gene transfer into stem cells has raised many questions about their biology and role in the development and maintenance of hematopoiesis. As a result, we currently have a convergence of research goals in the areas of stem cell biology and gene therapy. Murine models for stem cell transduction have played a useful role in establishing two basic principles: retroviral vectors can transduce pluripotent self-renewing hematopoietic stem cells and retroviral vectors can express foreign gene products in the differentiated progeny of stem cells. Murine models also have allowed the identification of several key factors that allow efficient transduction of stem cells and each of these is dealt with here. However, methods for stem cell transduction that are effective with mouse cells have only been partially successful in dog, nonhuman primate, and human models. Whereas scale-up of stem cell transduction procedures for human applications will present unique technical problems, mouse models may yet provide further insight into the mechanisms of efficient stem cell gene transfer that can then be used to design enhanced and reproducible protocols. PMID- 24493431 TI - Methods for retrovirus-mediated gene transfer into primary T-lymphocytes. AB - Recombinant retroviruses are efficient vectors for introducing genes into many mammalian cell types. They are useful in the context of clinical as well as experimental applications, owing to their ability to generate high-titer and helper-free viral stocks. Retroviral vectors are especially appropriate for the transduction of primary lymphocytes, because gene transfer is mediated by nonimmunogenic vectors and stable vector integration in the target genome is achieved. Stable integration in cells undergoing clonal expansion ensures that the foreign genetic material will be faithfully transmitted to the cells' progeny. PMID- 24493432 TI - Methods for Retrovirus-Mediated Gene Transfer to CD34(+) Enriched Cells. AB - Hematopoietic stem cells (HSC) provide for contmuous replenishment of the entire immune and hematopoietic systems, and also replenish themselves in a process termed self-renewal (1).The HSCs can be enriched from hematopoietic tissues using MAbs that bind to the CD34 antigen, a universally recognized marker for hematopoietic progenitors (2-4).Enriched HSC populations are being widely investigated for use in transplantation and gene therapy because they appear to provide rapid hematopoietic reconstitution in myeloablated patients (5-11), and they offer good targets for gene transfer (12-17). PMID- 24493433 TI - Methods for the use of genetically modified keratinocytes in gene therapy. AB - Recent advances in molecular genetics have resulted in the development of new technologies for the introduction and expression of genes in human somatic cells. Recombinant retroviral vectors have become a popular method for introducing such genes, primarily because the frequency of gene transfer is usually high and the introduced genes are stably integrated into the host genome. Gene therapy and gene transfer technology, although typically thought of as a means to correct genetic disease, have other potential clinical applications in the areas of protein delivery and tissue engineering. Numerous types of cells/tissues have been successfully genetically modified and are potential targets for retroviral mediated gene therapy (1).The successful use of these tissues in gene therapy relies on methods to cultivate and transplant the cells after genetic modification. PMID- 24493434 TI - Methods for particle-mediated gene transfer into skin. AB - During the past 5 yr, particle-mediated delivery techniques have been developed as a physical means for gene transfer into various eukaryotic systems, including plants, insects, fish, and mammals (1-7). For mammalian somatic tissues, this technology, popularly known as the gene gun method, has been shown effective in transfection of skin, liver, pancreas, muscle, spleen, and other organs in vivo (3,4); brain, mammary, and leukocyte pnmary cultures or explants ex vivo (2,5-7); and a wide range of different mammalian cell lines in vitro (3,6,7). PMID- 24493435 TI - Methods for liposome-mediated gene transfer to tumor cells in vivo. AB - Despite considerable progress in the understanding of the molecular basis of cancer, many malignancies remain resistant to traditional forms of treatment. Certain cancers, such as melanoma or renal cell carcinoma, respond to modulation of immune function, presumably because the immune system is induced to recognize mutant proteins in tumor cells. The advent of cationic liposomes as safe and increasingly efficient vectors for gene transfer in vivo has allowed the development of new approaches to immunotherapy that offer alternative therapies for cancer in the future. PMID- 24493436 TI - Methods for retrovirus-mediated gene transfer to tumor cells. AB - The past several years have seen a renewed interest in active immunotherapy approaches for the treatment of human tumors because of the exciting findings learned from preclinical studies employing genetically altered tumor vaccines. Many clinical protocols are currently being conducted using several different genetic approaches for augmenting antitumor immune responses. These include: 1. Ex vivo gene transfer of cytokine genes into tumor cells. 2. Ex vivo gene transfer of suicide genes into tumor cells with subsequent activation of the suicide mechanism in vivo 3. Ex vivo cytohne gene transfer to cultured tumor intiltrating lymphocytes (TIL) to generate more potent T-cells for adoptive transfer 4. In viva gene transfer of major histocompatibility complex (MHC) class I molecules by direct injection of the gene into an accessible tumor mass. PMID- 24493437 TI - Cationic liposome-mediated gene transfer to tumor cells in vitro and in vivo. AB - Development of safe and effective technology for delivering functional DNA into cells in an intact organism is crucial to broad applications of gene therapy to human disease. Both viral and nonviral vectors have been developed. Of the technologies currently being studied, liposomal delivery system is particularly attractive. Cationic liposome-mediated gene transfection (lipofection), a relatively new technique pioneered by Felgner and coworkers (1), was highly efficient for transfecting cells in culture. The liposomes were composed of an equimolar mixture of a synthetic cationic lipid N-[1-(2,3,-dioleyloxy)propyl] N,N,N,-trimethylammonium chloride (DOTMA) and a helper lipid dioleoyl phosphatidylethanolamine (DOPE) Fig. 1). The DOTMA/DOPE mixture (Lipofectin) forms complexes with DNA by charge interaction upon mixing at room temperature. Other catronic lipids are DOTAP, LipofectAMINE, Lipofectam, and DC-chol. The DOTAP is a diester analog of DOTMA and commercially available. LipofectAMINE and Lipofectam are polycationic lipids with a spermine head group that show increased frequency and activity of eukaryotic cell transfection (2,3). 3beta-[N-(N',N' dimethyaminoaminoethane) carbamoyl] cholesterol (DC-chol) (Fig. 1), a cationic cholesterol derivative, was introduced by Gao and Huang (4) and is routinely used in our laboratory. The DC-chol is now commercially available but can be easily synthesized with a single-step reaction from N,N-dimethylethylenediamine and cholesterol chloroformate (4), and improves the efficiency of transfection with minimal toxicity.Liposomes prepared with DC-chol and DOPE (3?2 molar ratio) are stable at 4 degrees C for at least 1 yr (unpublished data). PMID- 24493438 TI - Methods for the use of cytokine gene-modified tumor cells in immunotherapy of cancer. AB - The development over the past few years has shown that gene therapy has become a true perspective. By January 1994, 63 clinical gene therapy protocols (gene therapy or marker studies) have been reviewed and most approved by U.S. control committees. Of these, 13 aim at inserting and expressing cytokine genes in tumor cells in order to use such gene-modified cells as vaccines in cancer patients, This idea is based on mouse experimental models that showed that tumor cells transfected with a variety of cytokine genes were rejected in immunocompetent animals. Tumor rejection induced by the locally produced cytokine results from an inflammatory response at the tumor site. Several observations are remarkable: the high efficacy of local cytokines to induce an antitumor response in the absence of systemic toxicity; a surprisingly large number of cytokines possess antitumor activity in this assay (IL-1, IL-2, IL-4, IL-6, IL-7, TNF, LT, IFN-gamma, MCAF, G CSF, GM-CSF, IP-10); and in several models, cytokine-producing tumors were heavily infiltrated by T-lymphocytes that contributed to tumor destruction (for review see ref. 1). The latter observation is interesting because T-cells can most specifically recognize and destroy tumor cells and are critically involved in tumor immunity Consistently, in several tumor models, mice that were immunized by cytokine-gene transfected tumors also rejected the nontransduced parental tumor and occasionally were able to eliminate small preexisting tumor loads. Tumor immunity was dependent on T-cells. Thus, cytokine gene-modified tumor cell vaccines are thought to trigger a local immune response in cancer patients, which is directed against putative, so far unknown tumor antigens and which are effective against residual (presumably small) tumor loads (e.g., micrometastasis). It is important to note that these genetic approaches to cancer immunotherapy are the beginning of a developing field and still have to address some unresolved problems such as inappropriate presentation of tumor antigens by the tumor cells, tumor-induced immune suppression, tumor heterogeneity, or the question as to whether they are more effective than the previous attempts of immunotherapy. Currently, three cytokine gene therapy variations with IL-2, IL-4, TNF, IFN-gamma, or GM-CSF genes are tested: transfected autologous tumor cells; transfected allogeneic tumor cells; and transfected autologous fibroblasts mixed with tumor cells as vaccine. In most cases, the cells are irradiated before injection. Results from these initial clinical trials do not exist yet. PMID- 24493439 TI - Methods for generation of genetically modified fibroblasts for immunotherapy of cancer. AB - Considerable evidence has accumulated indicating that cultured human or rodent tumor cells can be successfully transduced with cytokine genes and selected in the appropriate antibiotic-containing culture media. The selected transductants are generally able to secrete the cytokine coded for by the transduced gene, and in many cases, substantial levels (e.g., ng quantities) of the cytokine are produced. Using retroviral vectors, it has been possible to obtain stably transduced tumor cells with a variety of cytokine genes (1-4). These tumor cells have been used for immunotherapy of cancer in numerous animal models of tumor growth or metastasis, and more recently, in vaccination protocols in patients with cancer. One possible criticism that can be leveled at this type of vaccination approach is that cultured, genetically modified, and selected tumor cells might have phenotypic characteristics that are substantially different from those of unmodified tumor cells. Since retroviral vectors are often used for transduction, it is also possible that viral antigens expressed on transduced tumor cells contribute to the immune response generated as a result of vaccination. Also, primary cultures of human tumor cells are often difficult to establish and maintain. PMID- 24493440 TI - Methods for gene transfer to synovium. AB - Development of methods for gene transfer to synoviocytes was borne from the idea that gene therapy could be used to more effectively treat rheumatoid arthritis (EU) and other joint disorders (1). Current pharmaceutical modalities in use against RA have limited effectiveness because of problems related to inefficient targeting of drugs to the joint, as well as inefficacies of the drugs themselves. Drug delivery to the joint by traditional oral, iv, and intramuscular routes, depends on passive diffusion of the drug from the synovial vasculature into the joint space (2). Thus, high systemic concentrations of the drug are necessary to achieve therapeutic intra-articular drug levels; in chronic RA, perfusion of the synovium may be compromised (3), driving required systemic drug levels even higher. This is of major concern, as the pharmaceuticals used to treat this disease are associated with serious side effects. Further compounding these problems is the chronic nature of RA, which requires lifelong treatment with high dosages of these drugs. PMID- 24493441 TI - Methods for adenovirus-mediated gene transfer to synovium in vivo. AB - The synovial membrane that lines diarthrodial joints is composed of a loose layer of cells (1-4 cells in depth) that overlie the surface of articular and periarticular subsynovial tissues including connective tissue, adipose tissue, tendon, bone, and articular cartilage. Using light microscopy, the synovial lining tissue appears discontinuous and lacks a clearly defined basement membrane, although the cells appear to be retained by a reticulum. Cells present below this membrane include mast cells and endothelial cells (up to 10% of the total cell population; refs. 1,2). Ultrastructural studies of the synovium have indicated that at least two major types of cells are present within the synovial membrane. Type A cells are monocytoid in appearance and contain abundant endoplasmic reticulum with fewer vesicles, vacuoles, and mitochondria. Type B cells are fibroblastoid in appearance and contain large granules, numerous filopodia, mitochondria, and intracellular vesicles. The percentage of Type A and B cells present within adult synovium varies between species (3-5). In addition, cells with an intermediate ultrastructural appearance and morphology may exist within adult synovium (6). PMID- 24493442 TI - Methods for the use of stromal cells for therapeutic gene therapy. AB - The logic behind the use of bone marrow stromal cells in gene therapy relies heavily on data that indicate the uniqueness of the bone marrow stromal cell as a differentiated cell phenotype distinct from the embryo fibroblast, adult connective tissue fibroblast, and cells derived from other sites such as the skin, or connective tissue in muscle (Table 1) (1-15). Bone marrow stromal cells comprise the slowly proliferating supportive tissue of the hematopoietic microenvironment. The anatomic localization, biology, physiology, and growth of these cells in tissue culture have been the subject of intense investigation by experimental and clinical hematologists for several years (16-28). A major controversy in basic hematology has been the question of whether bone marrow stromal cells of the hematopoietic microenvironment are transplantable. Classic bone marrow transplantation biology (30-38) has provided significant data to indicate that the hematopoietic stem cell and committed progeny are transplantable in vivo (for review, see refs. 29,39). Techniques to transplant bone marrow stem cells have gained common acceptance in both experimental and clinical hematology. In contrast, transplantation of slowly proliferating stromal cells of the hematopoietic microenvironment has only recently been demonstrated (29,33,40-51), and confirmed by others (52). The use of bone marrow stromal cells in somatic cell gene therapy has recently become a realistic option. for clinical therapeutic management. PMID- 24493443 TI - Suppression of the human carcinoma phenotype by an antioncogene ribozyme. AB - A spectrum of oncogenes have been identified and are thought to be associated with the progression of neoplasia. These oncogenes include the following: growth factors/receptors, kinases, nuclear proteins (i.e., Fos/Jun), and tumor suppressor genes. Perturbation of one or more of these genes can transform normal cells into invasive/metastatic cancer cells. Understanding the role of these oncogenes for specific types of cancer may lead to a more rational basis for tissue-specific targets in cancer gene therapy. PMID- 24493444 TI - Methods for cancer gene therapy using tumor suppressor genes. AB - Under experimental conditions, fusion of normal and malignant cells in many different combinations most often results in the suppression of the tumorigenic phenotype of tumor cells (1). This phenomenon led to a hypothesis that the normal genome might contain "recessive cancer genes" that, when expressed, would suppress the growth of tumors (2). Since the rdentification and cloning of the retinoblastoma (Rb) and p53 genes, the study of what are now called tumor suppressor genes has progressed rapidly. Although tumors generally develop through multiple changes in several genes, the malignant phenotype can be reversed by the introduction of a single chromosome derived from a normal cell, suggesting that single suppressor genes may be able to overcome the effects of multiple changes related to tumor progression (3). PMID- 24493445 TI - Reply: To PMID 24006277. PMID- 24493447 TI - Screening for lung cancer with low-dose computed tomography. PMID- 24493448 TI - Screening for lung cancer with low-dose computed tomography. PMID- 24493449 TI - Characterizing RNA-protein interaction using cross-linking and metabolite supplemented nuclear RNA-immunoprecipitation. AB - RNA-immunoprecipitation (RNA-IP) is a method used to isolate and identify RNA molecules specifically associated with an RNA-binding protein. Non-coding RNAs are emerging as key regulators of many biological and developmental pathways and RNA-IP has become an important tool in studying their function(s). While RNA-IP is successfully used to determine protein-RNA interaction, specific details regarding the level of this association and the metabolic requirement of this interaction which can influence the success of RNA-IP remain unclear. Here, we investigate the conditions required for efficient nuclear RNA-IP using Arabidopsis AGO4 (Argonaute 4) and siRNA binding as the study model. We showed that formaldehyde cross-linking, but not UV cross-linking, allowed for efficient pull-down of 24-nt siRNAs, suggesting that AGO4-siRNA interaction involves other protein(s). We also showed that, while formaldehyde cross-linking could also be performed on purified nuclei, ATP supplementation to the nuclei isolation buffer was needed to efficiently pull down 24-nt siRNAs. This result indicates that ATP is required for efficient siRNA loading onto AGO4. As most of the known RNA mediated regulatory processes occur in the nucleus, our findings on cross-linking conditions and metabolite requirement for successful AGO4 nuclear RNA-IP provide a valuable insight and future consideration when studying the function of protein RNA interactions in plants. PMID- 24493450 TI - Sequence variation in promoter regions of genes for CC chemokine ligands (CCL)19 and 21 in Czech patients with myocardial infarction. AB - Recruitment of inflammatory cells to the arterial wall is an important pathogenic mechanism of atherosclerosis and coronary artery disease (CAD). Functional variability in the genes encoding for chemokines that promote infiltration of atherosclerotic plaques by macrophages and lymphocytes may therefore contribute to the genetic susceptibility to CAD. We, therefore, investigated the association between myocardial infarction (MI) and polymorphisms in the promoter regions of the chemokine genes CCL19 and CCL21. Based on re-sequencing screening we selected and, using PCR-SSP, determined three polymorphisms of CCL19 gene (GenBank ID rs2233872) and CCL21 gene (GenBank ID rs11574914 and rs11574915) in 211 Czech patients with MI and 150 healthy control subjects. There was no difference in allelic frequencies of the investigated SNPs between patients and controls (p>0.05). However, the proportion of homozygotes for the minor G allele of the CCL21 promoter variant (rs11574915 GG) was lower among the MI patients (1%) in comparison with the control subjects (5%, nominal p=0.03). Though rare in the Czech population, CCL21 (rs11574915) GG genotype may confer protection from myocardial infarction. Our preliminary data have to be independently replicated. PMID- 24493451 TI - Recombinant expression and characterization of a novel endoglucanase from Bacillus subtilis in Escherichia coli. AB - The goal of this work was to produce high levels of endoglucanase in Escherichia coli for its potential usage in different industrial applications. Endoglucanase gene was amplified from genomic DNA of Bacillus subtilis JS2004 by PCR. The isolated putative endoglucanase gene consisted of an open reading frame of 1,701 nucleotides and encoded a protein of 567 amino acids with a molecular mass of 63 kDa. The gene was cloned into pET-28a(+) and expressed in E. coli BL21 (DE3). Optimum temperature and pH of the recombinant endoglucanase were 50 degrees C and 9, respectively which makes it very attractive for using in bio-bleaching and pulp industry. It had a K M of 1.76 MUmol and V max 0.20 MUmol/min with carboxymethylcellulose as substrate. The activity of recombinant endoglucanse was enhanced by Mg2+, Ca2+, isopropanol and Tween 20 and inhibited by Hg2+, Zn2+, Cu2+, Ni2+ and SDS. The activity of this recombinant endoglucanase was significantly higher than wild type. Therefore, this recombinant enzyme has potential for many industrial applications involving biomass conversions, due to characteristic of broad pH and higher temperature stability. PMID- 24493452 TI - The degradation of canavanine by jack bean cotyledons. AB - Germinating jack bean cotyledons liberated (14)CO2 when fed (14)C-guanidoxy canavanine but did not accumulate any (14)C-compounds other than the applied canavanine. This suggested that the canavanine was being degraded by the action of canavanase to canaline and urea, the urea then being converted to ammonia and carbon dioxide by the action of urease. Hydroxyurea and acetohydroxamic acid (both inhibitors of urease activity) strongly inhibited the liberation of (14)CO2 from (14)C-guanidoxy-canavanine by the cotyledons but neither compound induced the accumulation of (14)C-urea within the tissues. This inhibitory action of hydroxyurea on (14)CO2 output was thought to be due at least in part, to this inhibition of canavanase activity. PMID- 24493453 TI - Barriers to the radial diffusion of ions in maize roots. AB - The water-extractable and ion-exchangeable fractions of the free space of maize roots for sodium ions has been determined. The free space of whole roots, excised roots and isolated stelar and cortical tissues, has been compared and the results examined for any evidence of a barrier between the cortex and the stele. Similarly the free space of whole roots and excised roots, from which the epidermal and outer cortical cells have been removed by shaving, has been compared and the results examined for any evidence of an epidermal barrier.Whole roots gave a free space value some 20% lower than excised roots. It was calculated that this difference could be accounted for if the cortical tissues only were considered in estimating the whole root value, that is if the stele was considered as participating in the excised root but not in the whole root. Samples in which isolated cortical and stelar material were measured together, or separately and the value calculated, gave similar values to those obtained for excised roots. These results are interpreted as evidence that a barrier to free diffusion exists between the cortical and the stelar tissues at or near the endodermis. Shaving both whole and excised roots increased the free space by about 35%. However, as this value was similar for both, it was concluded that the increase was due to the contribution of damaged cortical cells and does not indicate that the epidermis is an effective barrier to the diffusive entry of sodium ions into the root. PMID- 24493454 TI - [Modifications of DNA content in sugar beet cells]. AB - In epidermal cells of the cytoledons of sugar beets, Beta vulgaris L., the DNA content per cell can be increased 2-4 fold by means of compensatory growth and other measures of better nutrition, by application of stronger light, or by addition of more moisture to the soil. It decreases with deviations from the optimal growth temperature (22 degrees C) and after lack of nitrogen in the nutritive solution. Differences in DNA content, representing mainly differences in the level of endopolyploidy, result in corresponding differences in the number of plastids in the cells. PMID- 24493455 TI - [Metabolism of isoflavones and coumestanes in cell and callus suspension cultures of Phaseolus aureus Roxb]. AB - The isoflavone daidzein, the coumestanes coumestrol and soyagol as well as 2',4,4'-trihydroxychalcone were isolated from callus and cell suspensions of root tip tissue from Phaseolus aureus Roxb. Upon prolonged culturing callus suspensions gradually became cell suspensions, a process which was accompanied by a decrease in the accumulation of phenolics. Upon transfer of the cells into 3 different media containing beta-indolyl acetic acid, kinetin or alpha-naphthalene acetic acid, a drastic increase in the amount of coumestrol was measured.The data are discussed in relation to the observed differentiation of the cultures after application of the various hormones. The cultures were shown to metabolize daidzein and other phenylpropanoid compounds. A pronounced binding of daidzein to polymeric, ethanol-insoluble material is discussed in relation to our earlier findings in isoflavone metabolism. PMID- 24493456 TI - [Fluxes, accumulation and transport of Cl(-) in excised corn roots]. AB - Fluxes, accumulation and transport rates of Cl(-) in excised corn roots were investigated.Flux equilibrium in 5*10(-4)M KCl was not reached within an experimental period of 28 hr.Transport of Cl(-) (5*10(-4)M KCl) through the xylem of 4-6 cm long excised corn roots had a lag of 1-2 hr. From 6 to 28 hr rates of accumulation and transport were nearly constant (5*10(-4)M KCl). The velocity of volume-flow within the xylem was 1.5-2 cm hr(-1) (5*10(-4)M KCl). (36)Cl(-) efflux through the cut end of roots preloaded in K(36)Cl of low concentration exhibits a discontinuity which is explained by addition of two fluxes: efflux of ions concentrated in the xylem (and symplasm) plus efflux from the vacuoles through the xylem.Accumulation of Cl(-) by excised roots approaches a maximum level (Jackson and Edwards, 1966). Influx rates remain constant while efflux rates increase with time. It is shown in this paper that the flux of Cl(-) through the xylem becomes a large proportion of the influx across the plasmalemma. Flux rates suggest that more than 50% of the Cl(-) ions transported to the xylem passed through a vacuole (5*10(-4)M KCl; 20-28 hr). PMID- 24493457 TI - Evidence for a sodium influx pump in sunflower roots. AB - Transmembrane electrical potential differences in the cortical cells of the root of the sunflower (Helianthus annuus) have been measured using microelectrodes. The plants were grown in culture solution with a range of sodium concentrations. It was found that increasing the external sodium concentration had virtually no effect on the transmembrane potential. The vacuolar content of sodium did not change significantly with the age of the tissue indicating that sodium was in flux equilibrium in our experiments. This allowed the Nernst equation to be used to calculate the electrochemical potential gradient for sodium between the vacuole and the external solution. It was concluded that sodium was being transported into the vacuole against the electrochemical potential gradient. The location and role of the inwardly directed sodium pump implied by these results is discussed in relation to the efflux pumps for sodium reported for roots of other species. Potassium was also accumulated against the electrochemical potential gradient by these cells.Sodium was found to stimulate the growth of H. annuus when present in the culture solution at very low concentrations. PMID- 24493458 TI - [Enzyme activities in the sieve tube sap of Robinia pseudoacacia L. and of other tree species]. AB - 1. Electron microscopic studies of the sieve tube sap obtained from the secondary phloem of Robinia pseudoacacia by the method of Hartig (1860) showed the presence of well developed mitochondria in addition to membrane fragments. 2. In this sieve tube sap the following enzymes could be detected qualitatively: UTP-glucose 1-phosphate-uridyl transferase, UDPG-fructose glucosyl transferase, glucose-6 phosphate dehydrogenase, hexokinase (for glucose and fructose), phosphohexose isomerase, phosphofructokinase, and UDPG-pyrophosphatase. 3. The following enzymes were determined quantitatively: phosphorylase, amylase, aldolase, triosephosphate isomerase, NAD(+)-dependent glyceraldehyde-3-phosphate dehydrogenase, phosphoglyceromutase, enolase, pyruvate kinase, pyruvate decarboxylase, alcohol dehydrogenase, isocitrate dehydrogenase, fumarase, malate dehydrogenase, glutamate-pyruvate transaminase, glutamate dehydrogenase, glutamate-oxalacetate transaminase, and anorganic pyrophosphatase. 4. The following enzymes could not be detected: UDGP dehydrogenase, UDPG-fructose-6 phosphate-glucosyltransferase, invertase, phosphoglucomutase, lactate dehydrogenase, and citrate synthase. 5. The enzyme pattern in the sieve tube saps of Tilia platyphyllos, Carpinus betulus, Fraxinus americana, Quercus borealis maxima, and Salix viminalis is qualitatively similar to that of Robinia, but shows quantitative differences (as far as analyzed). 6. The meaning of the results for the metabolism and function of the sieve tubes in situ is discussed. PMID- 24493459 TI - [Investigation of the relation between extracellular excretion of glycollate and the photosynthetic CO2-uptake in the blue-green alga Anacystis nidulans]. AB - The formations of transients in CO2 exchange in the blue-green alga Anacystic nidulans is dependent on the temperature used during the measurements. The algae were grown in a low light intensity (4000 lux) under normal air conditions and measured in the same low CO2 concentration (0.03 vol. %) but under a higher light intensity (10 000 lux). At a temperature of +20 degrees C the stationary rate of CO2 uptake was reached directly. At a temperature of +35 degrees C, on the other hand, a maximum of CO2 uptake could be observed at the beginning of the light period followed by a steady rate of photosynthesis, which was higher than at +20 degrees C. In the beginning of the dark period a CO2 outburst appeared at 35 degrees C.Only at a low temperature (+20 degrees C) did we find a light induced glycollate excretion; after a maximum at 7 1/2 minutes illumination the release of glycollate ceases and the level decreases to a lower value. A similar time course exists during illumination in red light (621 nm, 1.5.10(-8) einsteins) and a temperature of +20 degrees C. In blue light (432 nm, 1,5.10(-8) einsteins, +20 degrees C) and in white light at a high temperature (+35 degrees C) we could not find any light induced glycollate excretion. Our results are discussed in reference to the photorespiration. We explain the formation of transients in CO2 uptake of Anacystis at a high temperature (+35 degrees C) and in blue light (+20 degrees C) on the basis of the influence of photorespiration. PMID- 24493460 TI - Memory-related eye movements challenge behavioral measures of pattern completion and pattern separation. AB - The hippocampus creates distinct episodes from highly similar events through a process called pattern separation and can retrieve memories from partial or degraded cues through a process called pattern completion. These processes have been studied in humans using tasks where participants must distinguish studied items from perceptually similar lure items. False alarms to lures (incorrectly reporting a perceptually similar item as previously studied) are thought to reflect pattern completion, a retrieval-based process. However, false alarms to lures could also result from insufficient encoding of studied items, leading to impoverished memory of item details and a failure to correctly reject lures. The current study investigated the source of lure false alarms by comparing eye movements during the initial presentation of items to eye movements made during the later presentation of item repetitions and similar lures in order to assess mnemonic processing at encoding and retrieval, respectively. Relative to other response types, lure false alarms were associated with fewer fixations to the initially studied items, suggesting that false alarms result from impoverished encoding. Additionally, lure correct rejections and lure false alarms garnered more fixations than hits, denoting additional retrieval-related processing. The results suggest that measures of pattern separation and completion in behavioral paradigms are not process-pure. PMID- 24493461 TI - Shallow water marine sediment bacterial community shifts along a natural CO2 gradient in the Mediterranean Sea off Vulcano, Italy. AB - The effects of increasing atmospheric CO(2) on ocean ecosystems are a major environmental concern, as rapid shoaling of the carbonate saturation horizon is exposing vast areas of marine sediments to corrosive waters worldwide. Natural CO(2) gradients off Vulcano, Italy, have revealed profound ecosystem changes along rocky shore habitats as carbonate saturation levels decrease, but no investigations have yet been made of the sedimentary habitat. Here, we sampled the upper 2 cm of volcanic sand in three zones, ambient (median pCO(2) 419 MUatm, minimum Omega(arag) 3.77), moderately CO(2)-enriched (median pCO(2) 592 MUatm, minimum Omega(arag) 2.96), and highly CO(2)-enriched (median pCO(2) 1611 MUatm, minimum Omega(arag) 0.35). We tested the hypothesis that increasing levels of seawater pCO(2) would cause significant shifts in sediment bacterial community composition, as shown recently in epilithic biofilms at the study site. In this study, 454 pyrosequencing of the V1 to V3 region of the 16S rRNA gene revealed a shift in community composition with increasing pCO(2). The relative abundances of most of the dominant genera were unaffected by the pCO(2) gradient, although there were significant differences for some 5 % of the genera present (viz. Georgenia, Lutibacter, Photobacterium, Acinetobacter, and Paenibacillus), and Shannon Diversity was greatest in sediments subject to long-term acidification (>100 years). Overall, this supports the view that globally increased ocean pCO(2) will be associated with changes in sediment bacterial community composition but that most of these organisms are resilient. However, further work is required to assess whether these results apply to other types of coastal sediments and whether the changes in relative abundance of bacterial taxa that we observed can significantly alter the biogeochemical functions of marine sediments. PMID- 24493462 TI - Influence of shrub encroachment on the soil microbial community composition of remnant hill prairies. AB - Hill prairies are remnant grasslands perched on the bluffs of major river valleys, and because their steep slopes make them unsuitable for traditional row crop agriculture, they have some of the lowest levels of anthropogenic disturbance of any prairie ecosystems in the Midwestern USA. However, many decades of fire suppression have allowed for shrub encroachment from the surrounding forests. While shrub encroachment of grasslands can modify soil respiration rates and nutrient storage, it is not known whether shrubs also alter the community composition of soil microorganisms. We conducted transect sampling of nine different hill prairie remnants showing varying degrees of shrub encroachment, and we used DNA-based community profiling (automated ribosomal intergenic spacer analysis) to characterize the composition of bacterial and fungal communities in the open prairie habitat, the shrub-encroached border, and the surrounding forest. While both bacterial and fungal communities showed statistically significant variation across these habitats, their predominant patterns were different. Bacterial communities of forest soils were distinct from those of the open prairie and the shrub-encroached areas, while fungal communities of the open prairie were distinct from those of the forest and the shrub-encroached border. Shrub encroachment significantly altered the community composition of soil fungal communities. Furthermore, fungal communities of heavily encroached prairie remnants more closely resembled those of the surrounding forest than those of lightly encroached prairies. Thus, shrub encroachment can cause soil fungi to shift from a "grassland" community to a "woody" community, with potential consequences for soil processes and plant microbe interactions. PMID- 24493463 TI - Amyloid-beta and tau: the trigger and bullet in Alzheimer disease pathogenesis. AB - The defining features of Alzheimer disease (AD) include conspicuous changes in both brain histology and behavior. The AD brain is characterized microscopically by the combined presence of 2 classes of abnormal structures, extracellular amyloid plaques and intraneuronal neurofibrillary tangles, both of which comprise highly insoluble, densely packed filaments. The soluble building blocks of these structures are amyloid-beta (Abeta) peptides for plaques and tau for tangles. Amyloid-beta peptides are proteolytic fragments of the transmembrane amyloid precursor protein, whereas tau is a brain-specific, axon-enriched microtubule associated protein. The behavioral symptoms of AD correlate with the accumulation of plaques and tangles, and they are a direct consequence of the damage and destruction of synapses that mediate memory and cognition. Synapse loss can be caused by the failure of live neurons to maintain functional axons and dendrites or by neuron death. During the past dozen years, a steadily accumulating body of evidence has indicated that soluble forms of Abeta and tau work together, independently of their accumulation into plaques and tangles, to drive healthy neurons into the diseased state and that hallmark toxic properties of Abeta require tau. For instance, acute neuron death, delayed neuron death following ectopic cell cycle reentry, and synaptic dysfunction are triggered by soluble, extracellular Abeta species and depend on soluble, cytoplasmic tau. Therefore, Abeta is upstream of tau in AD pathogenesis and triggers the conversion of tau from a normal to a toxic state, but there is also evidence that toxic tau enhances Abeta toxicity via a feedback loop. Because soluble toxic aggregates of both Abeta and tau can self-propagate and spread throughout the brain by prionlike mechanisms, successful therapeutic intervention for AD would benefit from detecting these species before plaques, tangles, and cognitive impairment become evident and from interfering with the destructive biochemical pathways that they initiate. PMID- 24493466 TI - Patella cubiti: a case report and literature review. AB - Patella cubiti is a rare elbow anomaly in which either the entire olecranon or a part of it remains separate from the proximal ulna. Pain and stiffness are the usual presenting symptoms while some patients are diagnosed incidentally following a minor trauma. Our case report is of a 24-year-old male wrestler with bilateral patella cubiti which was painful on right side and asymptomatic on the left. We also mention an additional cause of pain in patella cubiti-intra articular loose bodies. These loose bodies were removed surgically and the patient remained asymptomatic at 6-months follow-up. Presence of growth disturbance in the secondary epiphyseal centre of first lumbar vertebra supports the 'developmental theory' of origin of patella cubiti. A compilation of data available in the literature on patella cubiti has been included. PMID- 24493464 TI - Effect of a combined treatment with erythropoietin and melatonin on renal ischemia reperfusion injury in male rats. AB - BACKGROUND: Renal ischemia reperfusion (IR) is an important cause of renal dysfunction. It contributes to the development of acute renal failure. Oxidative damage from reactive oxygen species is considered to be the principal component involved in the pathophysiological tissue alterations observed during IR. The purpose of this study was to evaluate the effect of a combined treatment with erythropoietin (EPO) plus melatonin (MEL), which are known anti-inflammatory and antioxidant agents, in IR-induced renal injury in rats. METHODS: Wistar Albino rats were unilaterally nephrectomized and subjected to 45 min of renal pedicle occlusion followed by 24 h of reperfusion. MEL (10 mg/kg, i.p) and EPO (5000 U/kg, i.p) were administered prior to ischemia. After 24 h of reperfusion, blood samples were collected for the determination of superoxide dismutase (SOD), glutathione peroxidase (GPx), plasma levels of total antioxidant capacity (TAC), and malondialdehyde (MDA) and serum urea level. Also, renal samples were taken for histological evaluation. RESULTS: Ischemia reperfusion significantly increased urea, blood SOD, and GPx levels. Histological findings of the IR group indicated that there was increase in tubular and glomerular hyaline cast, thickening of Bowman capsule basement membrane, and renal impairment in the glomerular epithelium. Treatment with EPO and MEL significantly decreased blood SOD, GPx, and urea levels and increased TAC level. In the EPO + MEL group, while the histopathological changes were lower than those in EPO group, they were the same as MEL group. CONCLUSION: EPO and MEL combination treatment exerted more nephroprotective effects than EPO treatment and nearly had protective effects similar to MEL treatment. PMID- 24493467 TI - The contribution of environmental pollution in the development of allergic rhinitis (AR) and asthma has been previously studied and documented. Introduction. PMID- 24493468 TI - The role of secondhand smoke in allergic rhinitis: a systematic review. AB - BACKGROUND: The objective of this work was to systematically review existing literature on the association between allergic rhinitis (AR) and secondhand smoking (SHS) in children and adults. METHODS: We performed a literature search encompassing the last 25 years in PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), Cochrane CENTRAL, Web of Science, Scopus, and EMBASE. Inclusion criteria included English language papers containing original human data with greater than 6 subjects. Data was systematically collected on study design, patient demographics, clinical characteristics/outcomes, and level-of evidence (Oxford Center of Evidence-Based Medicine). Quality assessment of the studies was performed using the Newcastle-Ottawa scale. Two investigators independently reviewed all manuscripts. RESULTS: The initial search yielded 590 abstracts, of which 40 articles were included. 12 (37.5%) of the 32 articles studying children and 5 (62.5%) of the 8 articles studying adults showed a statistically significant association between AR and SHS. One article was a prospective cohort study (Level 2b) and all other articles were case-control studies (Level 3b). For characterizing AR, 10 (25%) studies included skin-prick testing and 5 (12.5%) used in vitro testing. For determining presence of SHS, 39 (97.5%) of the studies used questionnaires and 1 article used a cotinine/creatinine ratio. CONCLUSION: This review demonstrated a majority of adult studies vs a minority of children studies found a significant association between AR and SHS. However, the percent difference between age groups was not statistically significant. Further higher-quality studies with validated methods for diagnosing AR and quantifying SHS exposure should be performed to better evaluate the relationship between AR and SHS in adults and children. PMID- 24493465 TI - An association between serum gamma-glutamyltransferase and proteinuria in drinkers and non-drinkers: a Japanese nationwide cross-sectional survey. AB - BACKGROUND: The association between alcohol consumption and chronic kidney disease (CKD), characterized by reduced glomerular filtration rate and proteinuria, is controversial. Recent studies suggest that serum gamma glutamyltransferase (GGT) level, a conventional marker of excessive alcohol consumption, predicts the CKD incidence. Little information is available on the difference in the clinical impact of alcohol consumption and GGT on proteinuria. METHODS: The present cross-sectional survey included 332,296 Japanese people aged >=40 years in 2008. To examine the associations of GGT and alcohol consumption with proteinuria, 134,600 men and 197,696 women were classified into 20 categories based on GGT quartiles and alcohol consumption categories, and their prevalence rate ratios (PRR) of proteinuria defined as >=1+ of dipstick urinary protein were calculated after adjusting for clinically relevant factors. RESULTS: Prevalence of proteinuria was 7.5 and 3.7 % in men and women, respectively. In both gender an association between alcohol consumption and proteinuria was in a J shaped fashion with the lowest PRR of mild drinkers with <=19 g/day of ethanol consumption, whereas an association between serum GGT level and proteinuria was linear. Compared with rare drinkers in the lowest GGT quartile, the subjects in higher GGT quartiles had a higher probability of proteinuria, irrespective of alcohol consumption. An optimal cutoff level of serum GGT was 43.6 and 23.2 IU/L in men and women, respectively. CONCLUSIONS: The subjects with higher serum GGT level had a higher probability of proteinuria, regardless of alcohol consumption, suggesting that GGT has a clinically greater impact on CKD than alcohol consumption. PMID- 24493469 TI - Comparison of L-strut preservation in endonasal and endoscopic septoplasty: a cadaveric study. AB - BACKGROUND: Preservation of an adequate cartilaginous L-strut to prevent complications of septoplasty has been long recognized as critical. However, no previous study has examined the dimensions of the L-strut that remain after septoplasty. We hypothesized that differences in exposure and visualization between endoscopic and endonasal techniques would result in differences in preserved L-strut dimensions. We designed this study to determine L-strut dimensions after performance of septoplasty with endonasal and endoscopic technique. METHODS: We performed a cadaveric study with 24 heads randomly assigned to undergo endonasal vs endoscopic septoplasty by senior resident surgeons (postgraduate year 4 [PGY-4] and PGY-5). Removal of the skin-soft tissue envelope and mucoperichondrium was performed after septoplasty to permit direct measurement of the L-strut. Minimum and maximum widths were recorded for the caudal and dorsal segments; a single measurement was recorded for the width at the anterior septal angle. Statistical analysis was carried out using the 2 tailed distribution Student t test. RESULTS: There was no significant difference in caudal or anterior septal width between endonasal and endoscopic techniques. There was a statistically significant difference in dorsal segment width for both minimum and maximum values, with endoscopic technique resulting in a narrower dorsal segment than endonasal technique (mean minimum value of 10.8 mm vs 13.2 mm, respectively, p = 0.03; and mean maximum value of 12.6 mm vs 16 mm, respectively, p = 0.01). There was significant variation in resident surgeon performance, with the performance of 1 resident surgeon accounting for the difference in minimum dorsal width. CONCLUSION: Differences in exposure and visualization between endoscopic and endonasal septoplasty techniques may result in differences in preserved L-strut dimensions. Care should be taken with endoscopic technique to prevent overly aggressive resection of septal cartilage, particularly with learners of this technique. PMID- 24493471 TI - Prevalence and patterns of demyelinating central nervous system disorders in urban Mangalore, South India. AB - There is a dearth of epidemiological data about multiple sclerosis (MS) and related demyelinating disorders in India. In this study, a registry method was used for collecting data from secure sources and the index cases were verified Seventy nine patients were identified . A crude prevalence of 8.3/100,000 was obtained for MS and 6.2/100,000 for clinically-isolated syndrome (CIS). Age standardized prevalence of MS relative to the world population was 7.8/100,000. Neuromyelitis optica (NMO) and spectrum disorders (NMOS) constituted 13.9% of all demyelinating disorders, with a prevalence of 2.6/100,000. Larger studies with more refined survey methodologies are required to understand the true prevalence of demyelinating disorders in India. PMID- 24493470 TI - Neuropathic pain in neuromyelitis optica affects activities of daily living and quality of life. AB - Though pain in neuromyelitis optica (NMO) has been described in two recent reports, the proportion with true neuropathic pain (NP), its features, impact on activities of daily living (ADL) and quality of life has not been well characterised. A cross-sectional study of 50 NMO patients with transverse myelitis was performed using Douleur Neuropathique 4, Brief Pain Inventory, Extended Disability Status Scale and Short Form 36. NP was identified in 62% of patients. Pain was constant in 68% affecting most ADL. Pain was associated with significant reduction of the SF36 Mental Composite Score. The high prevalence of NP and associated disability necessitates an in-depth enquiry in patients with NMO. PMID- 24493472 TI - The anti-VLA-4 antibody natalizumab induces erythroblastaemia in the majority of the treated patients with multiple sclerosis. AB - The presence of erythroblasts in the peripheral blood is generally associated with severe underlying disorders. The anti-very late antigen-4 (anti-VLA-4) antibody natalizumab, which is approved for treatment of multiple sclerosis, mediates an increase in circulating haematopoietic stem cells and may also trigger erythroblastaemia. We investigated the prevalence of erythroblastaemia in sequential blood smears of 14 natalizumab-treated and 14 interferon-treated patients with multiple sclerosis. Erythroblastaemia was found in 13 natalizumab treated subjects (93%), whereas all controls were negative (p<0.0001). Knowledge of this frequent side effect is crucial for the correct interpretation of blood smears in natalizumab-treated patients and to avoid unnecessary diagnostic procedures. PMID- 24493474 TI - Epstein-Barr virus-specific adoptive immunotherapy for progressive multiple sclerosis. AB - Defective control of Epstein-Barr virus (EBV) infection by cytotoxic CD8(+) T cells might predispose to multiple sclerosis (MS) by allowing EBV-infected autoreactive B cells to accumulate in the central nervous system. We have treated a patient with secondary progressive MS with in vitro-expanded autologous EBV specific CD8(+) T cells directed against viral latent proteins. This adoptive immunotherapy had no adverse effects and the patient showed clinical improvement with reduced disease activity on magnetic resonance imaging and decreased intrathecal immunoglobulin production. This is the first report of the use of EBV specific adoptive immunotherapy to treat MS or any other autoimmune disease. PMID- 24493475 TI - Diagnostic uncertainty during the transition to secondary progressive multiple sclerosis. AB - Secondary progressive multiple sclerosis (MS) is typically defined as deterioration independent of relapses for >= 6 months following an initial relapsing-remitting course; however, this definition is not always easily applied in clinical practice and the declaration of the change in clinical phenotype is often delayed. To identify the length of time required to re-classify relapsing remitting MS (RRMS) patients whom have clinically transitioned to secondary progressive MS (SPMS) in clinical practice. We reviewed 123 patients with long term follow-up and identified a sub-group whom transitioned from RRMS to SPMS, then characterized this transition period. There were 14/20 patients who transitioned during the follow-up period that had visits with uncertainty related to the clinical phenotype characterized by possible, but not definitive progression. The mean duration of this period of uncertainty was 2.9 +/- 0.8 years. A period of diagnostic uncertainty regarding the transition from RRMS to SPMS existed in many of our patients. Potential reasons included the subtle nature of early progressive disease and caution in applying a progressive label, in light of the lack of evidence-based treatments as well as third-party payer concerns. Delay in definitive identification of an SPMS phenotype has a variety of implications related to patient care and research. PMID- 24493476 TI - Development of a surface to increase retinal pigment epithelial cell (ARPE-19) proliferation under reduced serum conditions. AB - Age related macular degeneration of the eye is brought about by damage to the retinal pigment epithelium (RPE) and is a major cause of adult blindness. One potential treatment method is transplantation of RPE cells grown in vitro. Maintaining RPE cell viability and physiological function in vitro is a challenge, and this must also be achieved using materials that can be subsequently used to deliver an intact cell sheet into the eye. In this paper, plasma polymerisation has been used to develop a chemically modified surface for maintaining RPE cells in vitro. Multiwell plates modified with a plasma copolymer of allylamine and octadiene maintained RPE cell growth at a level similar to that of TCPS. However, the addition of bound glycosaminoglycans (GAGs) to the plasma polymerised surface significantly enhanced RPE proliferation. Simply adding GAG to the culture media had no positive effect. It is shown that a combination of plasma polymer and GAG is a promising method for developing suitable surfaces for cell growth and delivery, that can be applied to any substrate material. PMID- 24493477 TI - Patient, hospital, and geographic disparities associated with comanagement during hospitalization for colorectal cancer surgery. AB - BACKGROUND: Comanagement of surgical patients has increased, but information regarding detailed characteristics of patients receiving comanagement during hospitalization for colorectal cancer (CRC) surgery is lacking. OBJECTIVE: To examine the use of and characteristics associated with comanagement of patients hospitalized for CRC surgery. DESIGN: This study used a population-based cross sectional design. SETTING: We used the linked 2000 to 2005 Surveillance, Epidemiology, and End Results and Medicare claims data. PATIENTS: We included 37,065 patients aged 66 years or older, hospitalized for definitive CRC surgery following stage I to III diagnosis. MEASUREMENTS: The outcome of interest was comanagement during hospitalization for CRC surgery, and we examined the association between several patient and hospital characteristics. Comanagement was defined as having a relevant physician (ie, internal medicine hospitalist/generalist) submit a claim for evaluation and management services on 70% or more of the days of hospitalization of the patient. RESULTS: During hospitalization for CRC surgery, 27.6% of patients were comanaged, but this percentage varied widely across hospitals (from 1.9% to 83.2%). Several patient and hospital characteristics were associated with the use of comanaged care, of which important characteristics included older age at diagnosis, presence of comorbidity, emergency surgery, and hospital volume. CONCLUSIONS: Extensive variability existed in comanagement use across patients and hospitals, likely reflecting the lack of evidence for its clinical effectiveness. PMID- 24493478 TI - A randomized controlled trial evaluating the efficacy of a theory-based intervention promoting condom use among Chinese monogamous female sexually transmitted infection patients. AB - BACKGROUND: Chinese monogamous women may contract sexually transmitted diseases (STD) from their sole male sex partner, but these women do not have high self efficacy in negotiating about condom use with their regular sex partners. PURPOSE: We aim to investigate the relative efficacy of a theory-based and clinic based cognitive behavioral intervention versus a control intervention in increasing prevalence of condom use with their male sex partner among Chinese monogamous female sexually transmitted disease patients. METHODS: A randomized controlled trial (RCT) was conducted. Participants were randomly allocated into the intervention group (n = 88) or the control group (n = 88). All participants were phone interviewed at baseline and at 2 and 3 months after completion of the baseline survey. The three-session group intervention was based on the information-motivation-behavioral skills (IMB) model. Participants of the control group were provided with educational pamphlets. The primary outcome was consistent condom use in the last month. Relative risks were calculated, and multiple logistic regression models were fit. RESULTS: As compared to the control group, the intervention group reported higher prevalence of consistent condom use with the sole male sex partner in the last month at month 2 (75.3 versus 59.8%, RR = 1.26, 95% CI = 1.01, 1.57) and month 3 (77.8 versus 54.6%, RR = 1.42, 95% CI = 1.13, 1.80), whilst the baseline between-group difference was statistically non significant. Some other secondary outcomes such as "intention to request condom use in the next month even if the sexual partner dislikes using condoms" were also statistically significant. Furthermore, the majority (94%) of the intervention group members were satisfied with the intervention. CONCLUSIONS: The theory-based intervention is potentially efficacious, but the follow-up period was relatively short. Large-scale randomized clinical trials and subsequent translational research are greatly warranted in the future. PMID- 24493479 TI - Vascular imaging in diabetes. AB - Diabetes is a global epidemic affecting individuals of all socioeconomic backgrounds. Despite intensive efforts, morbidity and mortality secondary to the micro- and macrovascular complications remain unacceptably high. As a result, the use of imaging modalities to determine the underlying pathophysiology, early onset of complications, and disease progression has become an integral component of the management of such individuals. Echocardiography, stress echocardiography, and nuclear imaging have been the mainstay of noninvasive cardiovascular imaging tools to detect myocardial ischemia, but newer modalities such as cardiac MRI, cardiac CT, and PET imaging provide incremental information not available with standard imaging. While vascular imaging to detect cerebrovascular and peripheral arterial disease non-invasively has traditionally used ultrasound, CT- and MRI based techniques are increasingly being employed. In this review, we will provide an outline of recent studies utilizing non-invasive imaging techniques to assist in disease diagnosis as well as monitoring disease progression. In addition, we will review the evidence for newer modalities such as MR spectroscopy, 3D intravascular ultrasound, and optical coherence tomography that provide exquisite detail of metabolic function and coronary anatomy not available with standard imaging, but that have not yet become mainstream. PMID- 24493480 TI - A Latin American perspective on the new ACC/AHA clinical guidelines for managing atherosclerotic cardiovascular disease. AB - Atherosclerotic heart disease and stroke are leading causes of disability and death worldwide, affecting not only developed countries, but also low- and middle income regions. Different strategies for handling dyslipidemia as a critical pathogenic risk factor for atherosclerosis have been proposed. However, these recommendations are not applied at all in many countries or even in whole regions of the world. Recently, new US guidelines on risk assessment, lifestyle changes, and high blood cholesterol level treatment to manage atherosclerotic disease were released. In this article, we analyze these new guidelines and discuss their potential applications in preventive cardiovascular medicine in Latin America. PMID- 24493481 TI - Behavioral pharmacology of pain. AB - Behavioral methods are extensively used in pain research. Rodent modeling tends to rely on evoked responses but there is a growing interest in behavioral readouts that may capture elements of ongoing pain and disability, reflecting the major clinical signs and symptoms. Clinically, analgesics show greater efficacy in acute pain after standard surgery than in chronic conditions but are never completely effective on a population basis. In contrast, experimental pharmacological studies in rodents often demonstrate full efficacy, but there is variability in sensitivity between models and readouts. Full efficacy is rarely seen when more complex or multiple readouts are used to quantify behavior, especially after acute surgery or in studies of clinical pain in animals. Models with excellent sensitivity for a particular drug class exist and are suitable for screening mechanistically similar drugs. However, if used to compare drugs with different modes of action or to predict magnitude of clinical efficacy, these models will be misleading. Effective use of behavioral pharmacology in pain research is thus dependent on selection and validation of the best models for the purpose. PMID- 24493482 TI - The impact of anti-TNF therapy on the nonspecialist. PMID- 24493484 TI - Wide QRS complex rhythm with pulseless electrical activity. PMID- 24493483 TI - Slow-growing angiomatous lesions on the limbs. PMID- 24493485 TI - Q: should patients with gout avoid thiazides for hypertension? PMID- 24493486 TI - Stiff, numb hands (JUNE 2013). PMID- 24493487 TI - In reply. PMID- 24493488 TI - Canagliflozin. PMID- 24493489 TI - Canagliflozin. PMID- 24493490 TI - In reply. PMID- 24493491 TI - Clinical update in sexually transmitted diseases-2014. AB - Sexually transmitted diseases (STDs) and their associated syndromes are extremely common in clinical practice. Early diagnosis, appropriate treatment, and partner management are important to ensure sexual, physical, and reproductive health in our patients. PMID- 24493493 TI - Anticoagulation and antiplatelet therapy in acute coronary syndromes. AB - Antiplatelet and anticoagulant drugs are the mainstay of treatment of acute coronary syndrome (ACS). The last 30 years have seen the development of various agents, a deeper understanding of the pathobiology of this disease, and an evolution in its treatment. We review the role of contemporary agents in ACS and highlight key clinical trials of these agents. PMID- 24493494 TI - Managing risks of TNF inhibitors: an update for the internist. AB - Tumor necrosis factor (TNF) inhibitors have many beneficial effects, but they also pose infrequent but significant risks, including serious infection and malignancy. These risks can be minimized by judicious patient selection, appropriate screening, careful monitoring during treatment, and close communication between primary care physicians and subspecialists. PMID- 24493495 TI - Pulmonary capillary hemangiomatosis: the puzzle takes shape. PMID- 24493496 TI - Lung-gut cross talk: a potential mechanism for intestinal dysfunction in patients with COPD. PMID- 24493497 TI - Disability in patients with COPD. PMID- 24493498 TI - Legionnaires' disease: importance of high index of suspicion in patients in the ICU with community-acquired pneumonia. PMID- 24493499 TI - Evolution of ICU design: smarter is better. PMID- 24493500 TI - Whether a bill becomes a law. PMID- 24493502 TI - Point: Should Medicare allow respiratory therapists to independently practice and bill for educational activities related to COPD? Yes. PMID- 24493503 TI - Counterpoint: Should Medicare allow respiratory therapists to independently practice and bill for educational activities related to COPD? No. PMID- 24493504 TI - Rebuttal from Drs Fuhrman and Aranson. PMID- 24493505 TI - Rebuttal from Drs Courtright and Manaker. PMID- 24493506 TI - Trends in the prevalence of asthma. AB - The asthma epidemic of the last few decades may have peaked; studies suggest that the incidence and prevalence of asthma has decreased in some countries in the last few years, although other studies suggest continuing small increases in prevalence. Increasing awareness and changing diagnostic habits make precise evaluation of epidemiologic trends difficult in the absence of a gold-standard test for asthma, and on a global basis uncertainty persists. Trends in prevalence in some populations (eg, immigrants, farming communities) suggest both adverse and beneficial effects of specific environmental factors. Although the effects of indoor allergens, dampness, and mold and of outdoor air pollutants, especially traffic related, have traditionally dominated risk-factor research, more recent epidemiologic and clinical studies have focused on metabolic and nutritional factors, including maternal obesity and vitamin D levels, mode of delivery and its effect on the infant microbiome, fetal and infant growth, the psychosocial environment, and medication use by mother and infant. It is likely that changes in incidence and prevalence are due to multiple factors, each contributing a relatively small effect. Longitudinal studies from pregnancy through childhood to adulthood will yield greater insights into the complex pathways leading to asthma. PMID- 24493507 TI - Grappling with genomic incidental findings in the clinical realm. AB - We have learned a remarkable amount in recent decades about genomics and its potential contributions to human health and medical practice. However, genomic sequencing technology, which is starting to become incorporated into clinical care, also raises ethical challenges. In particular, there has been significant debate about the appropriate management of genomic incidental findings (GIFs), which we define as pathogenic or likely pathogenic test results that are not apparently relevant to the diagnostic indications for which the tests were ordered. Although there is an emerging consensus that clinicians will have at least some obligation to disclose GIFs to patients, the scope of that obligation is unclear. This commentary identifies nuanced issues that clinicians will likely face in the foreseeable future regarding their emerging obligations to disclose clinically actionable GIFs. Will clinicians be expected to look actively for GIFs? Should GIFs for adult-onset disorders be disclosed to children? What obligations will clinicians have to disclose GIFs to family members of deceased patients? What role should informed consent play? There is value to exploring the range of views on these questions at this time, before genomic sequencing has fully matured as a technology, so that clinicians can anticipate how they will respond to the discovery of GIFs once sequencing becomes a more routine part of clinical care. Genomics is ultimately going to play an important role in the practice of pulmonary medicine, and it is important for pulmonologists and other subspecialists to be well informed about what to expect. PMID- 24493508 TI - Defective respiratory tract immune surveillance in asthma: a primary causal factor in disease onset and progression. AB - The relative importance of respiratory viral infections vs inhalant allergy in asthma pathogenesis is the subject of ongoing debate. Emerging data from long term prospective birth cohorts are bringing increasing clarity to this issue, in particular through the demonstration that while both of these factors can contribute independently to asthma initiation and progression, their effects are strongest when they act in synergy to drive cycles of episodic airways inflammation. An important question is whether susceptibility to infection and allergic sensitization in children with asthma arises from common or shared defect(s). We argue here that susceptibility to recurrent respiratory viral infections, failure to generate protective immunologic tolerance to aeroallergens, and ultimately the synergistic interactions between inflammatory pathways triggered by concomitant responses to these agents all result primarily from functional deficiencies within the cells responsible for local surveillance for antigens impinging on airway surfaces: the respiratory mucosal dendritic cell (DC) network. The effects of these defects in DCs from children wtih asthma are accentuated by parallel attenuation of innate immune functions in adjacent airway epithelial cells that reduce their resistance to the upper respiratory viral infections, which are the harbingers of subsequent inflammatory events at asthma lesion site(s) in the lower airways. An important common factor underpinning the innate immune functions of these unrelated cell types is use of an overlapping series of pattern recognition receptors (exemplified by the Toll-like receptor family), and variations in the highly polymorphic genes encoding these receptors and related molecules in downstream signaling pathways appear likely contributors to these shared defects. Findings implicating recurrent respiratory infections in adult-onset asthma, much of which is nonatopic, suggest a similar role for deficient immune surveillance in this phenotype of the disease. PMID- 24493509 TI - Shadows amid sunshine: regulating financial conflicts in medical research. AB - Under brand new rules implementing the Physician Payments Sunshine Act (Sunshine Act), a wide range of financial relationships, including many research-related payments, between industry, physicians, and teaching hospitals will be publicly disclosed through comprehensive, standardized payment reporting. The Sunshine Act represents the latest in a series of regulatory attempts to address financial conflicts of interest that may bias research conduct and threaten subject safety. This article summarizes the major aspects of the Sunshine Act affecting medical research, how it interacts with existing laws and policies, and identifies important unresolved issues and implementation challenges that still lie ahead with the rollout of the legislation underway. The Sunshine Act primarily depends on disclosure as a regulatory tool. As such, its long-term impact remains open to question. Disclosure in this context may have limited utility given, among other reasons, uncertainty about who the intended recipients are and their ability to use the information effectively. Apart from the insufficiency of transparency, this article further explores how proportionality, fairness, and accountability considerations make optimal regulation of financial conflicts in medical research quite challenging. PMID- 24493511 TI - Restrictive lung disease in pregnancy. AB - Restrictive lung disease is uncommon in pregnancy. We reviewed 15 pregnancies in 12 women with restrictive disease due to kyphoscoliosis, neuromuscular disease, or parenchymal lung disease. Median FVC was 40% predicted, and six women (50%) had an FVC < 1.0 L. In the 14 pregnancies in which at least two spirometry readings were available, FVC increased in three pregnancies, decreased in three, and remained stable in eight, with maximal changes of 0.4 L. Three women required supplemental oxygen, and one woman with neuromuscular disease required noninvasive ventilation. Premature delivery occurred in nine pregnancies (60%), and 10 deliveries (67%) were by cesarean section. Neuraxial anesthesia was used in 10 of 15 deliveries but was limited in the others by difficult spinal anatomy. There was no maternal or neonatal mortality. Women with restrictive lung disease tolerate pregnancy reasonably well, but many have premature delivery. A multidisciplinary approach is essential, with monitoring of spirometry and oxygenation and planning for labor and delivery. PMID- 24493510 TI - Clinical applications of targeted temperature management. AB - Targeted temperature management (TTM) has been investigated experimentally and used clinically for over 100 years. The initial rationale for the clinical application of TTM, historically referred to as therapeutic hypothermia, was to decrease the metabolic rate, allowing the injured brain time to heal. Subsequent research demonstrated the temperature dependence of diverse cellular mechanisms including endothelial dysfunction, production of reactive oxygen species, and apoptosis. Consequently, modern use of TTM centers on neuroprotection following focal or global neurologic injury. Despite a solid basic science rationale for applying TTM in a variety of disease processes, including cardiac arrest, traumatic brain injury, ischemic stroke, neonatal ischemic encephalopathy, sepsis induced encephalopathy, and hepatic encephalopathy, human efficacy data are limited and vary greatly from disease to disease. Ten years ago, two landmark investigations yielded high-quality data supporting the application of TTM in comatose survivors of out-of-hospital cardiac arrest. Additionally, TTM has been demonstrated to improve outcomes for neonatal patients with anoxic brain injury secondary to hypoxic ischemic encephalopathy. Trials are currently under way, or have yielded conflicting results in, examining the utility of TTM for the treatment of ischemic stroke, traumatic brain injury, and acute myocardial infarction. In this review, we place TTM in historic context, discuss the pathophysiologic rationale for its use, review the general concept of a TTM protocol for the management of brain injury, address some of the common side effects encountered when lowering human body temperature, and examine the data for its use in diverse disease conditions with in-depth examination of TTM for postarrest care and pediatric applications. PMID- 24493512 TI - Innovative designs for the smart ICU: part 1: from initial thoughts to occupancy. AB - Designing a smart ICU is a time-consuming, complex, multiphased, political, and costly exercise. This process begins with two notions: First, all hospital parties agree that a new or renovated ICU is required, and second, the hospital has agreed to allocate space, personnel, and fiscal resources for the project. In this first of a three-part series on innovative designs for the smart ICU, we will explore the roles of the ICU design team in managing the design process. The team must be administratively empowered, knowledgeable, and forward thinking. The first charge of the design team is to develop a clear vision for the goals, look and feel, and functionality of the new ICU. This vision must be guided by the imperative to positively impact patients, staff, and visitors. The team must concentrate on innovative but practical ideas that are in compliance with building codes and design guidelines and address issues related to renovation vs new construction. Mock-ups, both physical and computer generated, and a simulation laboratory for advanced technologies should be used to test design assumptions and reveal problems well in advance of actual ICU construction and technology implementation. Technology platforms need to be standardized within the ICU and equipment purchases protected against early obsolescence. The ramifications and expectations of the new ICU must be thoughtfully considered and dealt with during the design process. Last, it is essential that the design group continue its involvement in the new ICU during construction, occupancy, and post occupancy. PMID- 24493513 TI - A man in his 50s develops 3-min central apneas during a titration study: complex sleep apnea syndrome. PMID- 24493514 TI - A middle-aged man with cough, chest pain, and pulmonary artery filling defect: primary pulmonary artery sarcoma. PMID- 24493517 TI - Passive pulmonary hypertension: more than hydrostatics. PMID- 24493518 TI - Response. PMID- 24493519 TI - Systolic BP and heart rate in pulmonary hypertension. PMID- 24493520 TI - Response. PMID- 24493521 TI - Elevation of troponins in rhabdomyolysis. PMID- 24493522 TI - Rhabdomyolysis: some extra clues to diagnosis. PMID- 24493523 TI - Response. PMID- 24493524 TI - Interobserver variability in grading acute rejection after lung transplantation. PMID- 24493525 TI - Response. PMID- 24493526 TI - The SAMe-TT2R2 score: far from clinical application. PMID- 24493527 TI - Response. PMID- 24493528 TI - Pulmonary hypertension drugs were never properly tested in heart failure. PMID- 24493529 TI - Response. PMID- 24493530 TI - Just because we can does not mean we should: a perspective on combined tracheostomy and percutaneous endoscopic gastrostomy tube insertion. PMID- 24493531 TI - Response. PMID- 24493532 TI - Increased oxidative stress at altitude. PMID- 24493533 TI - Response. PMID- 24493534 TI - The competence debate. PMID- 24493535 TI - Response. PMID- 24493536 TI - CNS complications in pulmonary arteriovenous malformations. PMID- 24493537 TI - Response. PMID- 24493538 TI - Evidence roflumilast reduces severe exacerbations? PMID- 24493539 TI - Response. PMID- 24493540 TI - New bifurcated silicone stent for the treatment of posttransplant bronchus intermedius stenosis: new silicone stent in posttransplant stenosis. PMID- 24493541 TI - Response. PMID- 24493542 TI - Sensitivity of blood culture vs polymerase chain reaction for skin contaminants in specimen retrieved via the distal lumen of Seldinger-guided central venous catheters. PMID- 24493543 TI - Response. PMID- 24493544 TI - Physiotherapy in patients in the ICU treated with IV tissue plasminogen activator for stroke. PMID- 24493545 TI - Response. PMID- 24493546 TI - Pulmonary hypertension. PMID- 24493547 TI - Response. PMID- 24493548 TI - Chickenpox in unexplained pulmonary necrotizing granulomas. PMID- 24493549 TI - Response. PMID- 24493550 TI - Post hoc subgroup analysis. PMID- 24493551 TI - Response. PMID- 24493554 TI - A man in his 40s with a history of hypertension and alcohol dependency presenting to the ED with respiratory distress: septic shock in the setting of ARDS. PMID- 24493555 TI - Treatment effect on brain atrophy correlates with treatment effect on disability in multiple sclerosis. PMID- 24493556 TI - Assessing the availability of the teratogenic drug isotretinoin outside the pregnancy prevention programme: a survey of e-pharmacies. AB - PURPOSE: The increase in online purchasing of medications raises safety concerns regarding teratogenic drugs. The use of the teratogenic drug 'isotretinoin' for women of childbearing age requires strict adherence to the Pregnancy Prevention Programme (PPP), a risk minimisation measure imposed on prescribers and users. We sought to determine how readily consumers can purchase isotretinoin online and the associated safety procedures and information. METHODS: A descriptive cross sectional survey was conducted of 50 e-pharmacies identified from commonly used search engines. E-pharmacy characteristics and isotretinoin PPP specific criteria were evaluated. Purchases of isotretinoin from seven e-pharmacies not bearing authentication logos and not requiring a prescription were assessed for PPP policy adherence, purchasing procedures and compound quality. RESULTS: Forty three (86%) of the e-pharmacies did not have an authentication seal/logo. Isotretinoin could be purchased from 42 sites without a valid prescription. Information on isotretinoin causing birth defects was lacking in 25 of the 50 sites, on not taking isotretinoin in pregnancy in 24 sites and not taking isotretinoin if planning or at risk of a pregnancy in 33 sites. Of the eight attempted purchases, seven arrived, all without any patient information leaflet. All were verified as isotretinoin. CONCLUSION: The Internet provides a loophole for purchasing of medications known to cause congenital abnormalities, which needs to be addressed by medicines regulatory agencies worldwide. The current PPP for isotretinoin may be failing to protect mothers and babies from preventable harm-clinicians need to be aware of this, and the public needs to be educated about the potential risks. PMID- 24493557 TI - Respiratory outcome of prematurely born infants following human rhinovirus A and C infections. AB - Human rhinoviruses (HRVs) are a common cause of lower respiratory tract infections (LRTIs) and are associated with chronic respiratory morbidity. Our aim was to determine whether HRV species A or C were associated with chronic respiratory morbidity and increased health care utilisation in prematurely born infants. A number of 153 infants with a median gestational age of 34 (range 23 35) weeks were prospectively followed. Nasopharyngeal aspirates were collected whenever the infants had LRTIs regardless of hospitalisation status. Parents completed a respiratory diary card and health questionnaire about their infant when they were 11 and 12 months corrected age, respectively. The health-related cost of care during infancy was calculated from the medical records using the National Health Service (NHS) reference costing scheme and the British National Formulary for children. There were 32 infants that developed 40 HRV LRTIs; samples were available from 23 of the 32 infants for subtyping. Nine infants had HRV-A LRTIs, 13 HRV-C LRTIs, and one infant had a HRV-B LRTI. Exclusion of infants who also had RSV LRTIs revealed that the infants who had a HRV-C LRTI were more likely to wheeze (p < 0.0005) and use respiratory medications (p < 0.0005) and had more days of wheeze (p = 0.01) and used an inhaler (p = 0.02) than the no LRTI group. In addition, the respiratory cost of care was greater for the HRV-C LRTI than the no LRTI group (p < 0.0005). CONCLUSION: Our results suggest HRV-C is associated with chronic respiratory morbidity during infancy in prematurely born infants. PMID- 24493558 TI - Preimplantation genetic diagnosis (PGD) for genetic prion disorder due to F198S mutation in the PRNP gene. AB - IMPORTANCE: To describe the first case of preimplantation genetic diagnosis (PGD) and in vitro fertilization (IVF) performed for the prevention of genetic prion disease in the children of a 27-year-old asymptomatic woman with a family history of Gerstmann-Straussler-Sheinker syndrome (GSS). OBSERVATIONS: PGD and fertilization cycles resulted in detection of 6 F198S mutation-free embryos. Of these, 2 were selected for embryo transfer to the patient's uterus, yielding a clinical twin pregnancy and birth of healthy but slightly premature offspring with normal development at age 27 months. CONCLUSION AND RELEVANCE: IVF with PGD is a viable option for couples who wish to avoid passing the disease to their offspring. Neurologists should be aware of PGD to be able to better consult at risk families on their reproductive choices. PMID- 24493559 TI - Effects of temperature and glycerol and methanol-feeding profiles on the production of recombinant galactose oxidase in Pichia pastoris. AB - Optimization of protein production from methanol-induced Pichia pastoris cultures is necessary to ensure high productivity rates and high yields of recombinant proteins. We investigated the effects of temperature and different linear or exponential methanol-feeding rates on the production of recombinant Fusarium graminearum galactose oxidase (EC 1.1.3.9) in a P. pastoris Mut(+) strain, under regulation of the AOX1 promoter. We found that low exponential methanol feeding led to 1.5-fold higher volumetric productivity compared to high exponential feeding rates. The duration of glycerol feeding did not affect the subsequent product yield, but longer glycerol feeding led to higher initial biomass concentration, which would reduce the oxygen demand and generate less heat during induction. A linear and a low exponential feeding profile led to productivities in the same range, but the latter was characterized by intense fluctuations in the titers of galactose oxidase and total protein. An exponential feeding profile that has been adapted to the apparent biomass concentration results in more stable cultures, but the concentration of recombinant protein is in the same range as when constant methanol feeding is employed. PMID- 24493560 TI - The effect of total facial nerve decompression in preventing further recurrence of idiopathic recurrent facial palsy. AB - The objective is to study the role of total facial nerve decompression in preventing further episodes and promoting facial nerve recovery of idiopathic recurrent facial palsy. 24 cases with idiopathic recurrent facial palsy were involved in the study, among which 16 undergoing total facial nerve decompression were classified into the surgery group, and 8 who refused surgery and received prednisolone were included in the control group. The recurrence rate and facial nerve function recovery of the two groups were compared. The mean follow-up of surgery and control group was 4.9 years (range 3-7 years) and 5.0 years (range 3 8 years), respectively. Further attacks of facial palsy affected 1 of 16 cases (6.2 %) among surgery group in comparison to 4 of 8 cases (50 %) among control group, with statistical difference (p < 0.05). 15 of 16 cases (93.8 %) recovered to Grade I or Grade II in surgery group in contrast to 6 of 8 cases (75.0 %) in control group, without statistical difference (p > 0.05). In conclusion, total facial nerve decompression is effective to prevent further episodes of facial palsy in idiopathic recurrent facial palsy, but ineffective to promote facial nerve recovery. PMID- 24493561 TI - When is surgical therapy for head and neck malignant epithelial tumors not indicated? PMID- 24493562 TI - Objective and subjective outcome in 42 patients after treatment of sialolithiasis by transoral incision of Warthon's duct: a retrospective middle-term follow-up study. AB - In this retrospective follow-up study, we present the middle-term results of transoral removal of submandibular calculi by incision in the floor of the mouth together with a patient satisfaction survey. These results will be compared with those of international studies. This is an individual retrospective cohort follow up study. Forty-two patients had salivary calculi removed by incision in the mouth in the period from August 2009 to July 2012 at the Ear-nose-throat department of the North Zealand Hospital, Hillerod, Denmark. A retrospective study was carried out, focusing on the effects of the surgery and on patient satisfaction. The patients completed a questionnaire and underwent an objective physical exam. We found a high success rate (93 %), high patient satisfaction (94 %) and a high number of patients with no symptoms (92 %). In 94 % of the patients the gland was preserved, and there were no infections. One patient (3 %) suffered from damage to the lingual nerve, and 6 % (n = 2) claimed to suffer from continuous tingling of the tongue. Based on the present study and previous studies on transoral removal of calculi by incision in the floor of the mouth, we find this procedure effective, brief and safe for removal of large, immobile calculi from the hilum of the submandibular gland to the papilla. PMID- 24493563 TI - Clinical characteristics and surrogate markers of eosinophilic chronic rhinosinusitis in Southern China. AB - The surrogate markers for subclassifying eosinophilic chronic rhinosinusitis (ECRS) and non-ECRS remain elusive. We herein performed a cross-sectional study to assess the clinical implication of clinical symptoms, CT findings, blood eosinophil (EOS) examination based on histological examination of tissue eosinophilia in 105 adult CRS patients (including 72 with nasal polyps and 33 without nasal polyps) in southern China. We found the mean score of smell loss was significantly higher in ECRS subgroup than those in non-ECRS subgroup (p < 0.05), whereas the average ethmoid osteitis index in non-ECRS subgroup was significantly higher than that in ECRS subgroup (p < 0.05). Moreover, we found both the mean blood EOS number and ratio were significantly higher in ECRS subgroup than those in non-ECRS subgroup (p < 0.05). By applying receiver operating characteristic (ROC) curve analysis, we found blood EOS number had a sensitivity of 84.9 % and specificity of 84.4 % [area under the curve (AUC): 0.873] at the cutoff level of 0.16 * 10(9)/L, and blood EOS ratio had a sensitivity of 89.0 % and specificity of 84.4 % (AUC: 0.863) at the cutoff level of 2.05 % in this cohort. Our findings indicated that smell loss score, ethmoid osteitis index and blood EOS number and ratio may be used for the differential diagnosis of ECRS as the surrogate markers. PMID- 24493565 TI - Directed modification of the Aspergillus usamii beta-mannanase to improve its substrate affinity by in silico design and site-directed mutagenesis. AB - beta-Mannanases (EC 3.2.1.78) can catalyze the cleavage of internal beta-1,4-D mannosidic linkages of mannan backbones, and they have found applications in food, feed, pulp and paper, oil, pharmaceutical and textile industries. Suitable amino acid substitution can promote access to the substrate-binding groove and maintain the substrate therein, which probably improves the substrate affinity and, thus, increases catalytic efficiency of the enzyme. In this study, to improve the substrate affinity of AuMan5A, a glycoside hydrolase (GH) family 5 beta-mannanase from Aspergillus usamii, had its directed modification conducted by in silico design, and followed by site-directed mutagenesis. The mutant genes, Auman5A (Y111F) and Auman5A (Y115F), were constructed by megaprimer PCR, respectively. Then, Auman5A and its mutant genes were expressed in Pichia pastoris GS115 successfully. The specific activities of purified recombinant beta mannanases (reAuMan5A, reAuMan5A(Y111F) and reAuMan5A(Y115F)) towards locust bean gum were 152.5, 199.6 and 218.9 U mg(-1), respectively. The two mutants were found to be similar to reAuMan5A regarding temperature and pH characteristics. Nevertheless, the K m values of reAuMan5A(Y111F) and reAuMan5A(Y115F), towards guar gum, decreased to 2.95 +/- 0.22 and 2.39 +/- 0.33 mg ml(-1) from 4.49 +/- 0.07 mg ml(-1) of reAuMan5A, which would make reAuMan5A(Y111F) and reAuMan5A(Y115F) promising candidates for industrial processes. Structural analysis showed that the two mutants increased their affinity by decreasing the steric conflicts with those more complicated substrates. The results suggested that subtle conformational modification in the substrate-binding groove could substantially alter the substrate affinity of AuMan5A. This study laid a solid foundation for the directed modification of substrate affinities of beta mannanases and other enzymes. PMID- 24493566 TI - Internal medicine rounding practices and the Accreditation Council for Graduate Medical Education core competencies. AB - BACKGROUND: The Accreditation Council for Graduate Medical Education (ACGME) has established the requirement for residency programs to assess trainees' competencies in 6 core domains (patient care, medical knowledge, practice-based learning, interpersonal skills, professionalism, and systems-based practice). As attending rounds serve as a primary means for educating trainees at academic medical centers, our study aimed to identify current rounding practices and attending physician perceived capacity of different rounding models to promote teaching within the ACGME core competencies. METHODS: We disseminated a 24 question survey electronically using educational and hospital medicine leadership mailing lists. We assessed attending physician demographics and the frequency with which they used various rounding models, as defined by the location of the discussion of the patient and care plan: bedside rounds (BR), hallway rounds (HR), and card-flipping rounds (CFR). Using the ACGME framework, we assessed the perceived educational value of each model. RESULTS: We received 153 completed surveys from attending physicians representing 34 institutions. HR was used most frequently for both new and established patients (61% and 43%), followed by CFR for established patients (36%) and BR for new patients (22%). Most attending physicians indicated that BR and HR were superior to CFR in promoting the following ACGME competencies: patient care, systems-based practice, professionalism, and interpersonal skills. CONCLUSIONS: HR is the most commonly employed rounding model. BR and HR are perceived to be valuable for teaching patient care, systems-based practice, professionalism, and interpersonal skills. CFR remains prevalent despite its perceived inferiority in promoting teaching across most of the ACGME core competencies. PMID- 24493567 TI - Towards habitat-oriented systems biology of "Aromatoleum aromaticum" EbN1: chemical sensing, catabolic network modulation and growth control in anaerobic aromatic compound degradation. AB - The denitrifying betaproteobacterium "Aromatoleum aromaticum" EbN1 is a well studied model organism for anaerobic degradation of aromatic compounds. Following publication of its genome in 2005, comprehensive physiological-proteomic studies were conducted to deduce functional understanding from the genomic blueprint. A catabolic network (85 predicted, 65 identified proteins) for anaerobic degradation of 24 aromatic growth substrates (including 11 newly recognized) was established. Newly elucidated pathways include those for 4-ethylphenol and plant derived 3-phenylpropanoids, involving functional assignment of several paralogous genes. The substrate-specific regulation of individual peripheral degradation pathways is probably initiated by highly specific chemical sensing via dedicated sensory/regulatory proteins, e.g. three different sigma54-dependent one-component sensory/regulatory proteins are predicted to discriminate between three phenolic substrates (phenol, p-cresol and 4-ethylphenol) and two different two-component systems are assumed to differentiate between two alkylbenzenes (toluene, ethylbenzene). Investigations under in situ relevant growth conditions revealed (a) preferred utilization of benzoate from a mixture with succinate results from repressed synthesis of a C4-dicarboxylate TRAP transporter; (b) response to alkylbenzene-induced solvent stress comprises metabolic re-routing of acetyl-CoA and reducing equivalents to poly(3-hydroxybutyrate) synthesis, alteration of cellular membrane composition and formation of putative solvent efflux systems; and (c) multifaceted adaptation to slow growth includes adjustment of energy demand for maintenance and preparedness for future nutritional opportunities, i.e. provision of uptake systems and catabolic enzymes for multiple aromatic substrates despite their absence. This broad knowledge base taken together with the recent development of a genetic system will facilitate future functional, biotechnological (stereospecific dehydrogenases) and habitat re-enacting ("eco "systems biology) studies with "A. aromaticum" EbN1. PMID- 24493568 TI - An alginate-like exopolysaccharide biosynthesis gene cluster involved in biofilm aerial structure formation by Pseudomonas alkylphenolia. AB - Pseudomonas alkylphenolia is known to form different types of multicellular structures depending on the environmental stimuli. Aerial structures formed during vapor p-cresol utilization are unique. Transposon mutants that showed a smooth colony phenotype failed to form a differentiated biofilm, including aerial structures and pellicles, and showed deficient surface spreading motility. The transposon insertion sites were located to a gene cluster designated epm (extracellular polymer matrix), which comprises 11 ORFs in the same transcriptional orientation. The putative proteins encoded by the genes in the epm cluster showed amino acid sequence homology to those found in the alginate biosynthesis gene clusters, e.g., in Pseudomonas aeruginosa at similarity levels of 32.3-86.4 %. This overall resemblance indicated that the epm gene cluster encodes proteins that mediate the synthesis of an exopolysaccharide composed of uronic acid(s) similar to alginate. Our preliminary results suggested that the epm-derived polymer is a substituted polymannuronic acid. Gene clusters homologous to the epm gene cluster are found in the genomes of a few species of the genera Pseudomonas, Alcanivorax, and Marinobacter. A mutational analysis showed that the epmJ and epmG genes encoding putative exopolysaccharide-modifying enzymes are required to form multicellular structures. An analysis of the activity of the promoter P epmD using a transcriptional fusion to the green fluorescence protein gene showed that the epm genes are strongly expressed at the tips of the specialized aerial structures. Our results suggested that the epm gene cluster is involved in the formation of a scaffold polysaccharide that is required to form multicellular structures in P. alkylphenolia. PMID- 24493569 TI - Microbial shifts of the silkworm larval gut in response to lettuce leaf feeding. AB - Silkworm (Bombyx mori L.) larvae were used as an ideal animal protein source for astronauts in the bioregenerative life support system (BLSS). Here, we compared the difference in bacterial communities of the silkworm larval gut between the BLSS rearing way (BRW) and the traditional rearing way (TRW) through culture dependent approach, 16S rRNA gene analysis, and denaturing gradient gel electrophoresis (DGGE). The culture-dependent approach revealed that the numbers of gut bacteria of silkworm in the BRW significantly decreased compared with that of the TRW. The analysis of clone libraries showed that the gut microbiota in the BRW was significantly less diverse than that in the TRW. Acinetobacter and Bacteroides were dominant populations in the BRW, and Bacillus and Arcobacter dominated in the TRW. DGGE profiles confirmed the difference of silkworm gut bacterial community between two rearing ways. These results demonstrate that gut bacteria change from the BRW contributes to the decrease of silkworm physiological activity. This study increases our understanding of the change of silkworm gut microbiota in response to lettuce leaf feeding in the BRW. We could use the dominant populations to make probiotic products for nutrient absorption and disease prevention in the BLSS to improve gut microecology, as well as the yield and quality of animal protein. PMID- 24493570 TI - Analysis and succession of nitrifying bacteria community structure in sequencing biofilm batch reactor. AB - To reveal the succession procedure of ammonia-oxidizing bacteria (AOB) and nitrite-oxidizing bacteria (NOB) community structure in sequencing biofilm batch reactor (SBBR), the molecular biological techniques of denaturing gradient gel electrophoresis (DGGE), cloning, and real-time PCR were applied. DGGE showed that the structural diversity of the bacterial community increased during the biofilm formation period, and some kinds of populations had been highly preponderant consistently. The results of cloning and sequencing revealed that Nitrosomonas was the dominant species. The real-time PCR analysis indicated that the amount of the AOB increased significantly after the cultivation period, and the NOB gradually decreased. The AOB content on the 25th day was 17 times that of the 6th day. It also showed the biofilm formed successfully with accumulating nitrite and prepared to achieve the achievement of simultaneous nitrification and denitrification in SBBR. Furthermore, the ammonia-oxidizing rate was in correspondence with the NH4 (+)-N removal efficiency. PMID- 24493571 TI - The contribution of Pir protein family to yeast cell surface display. AB - Proteins with internal repeats (Pir) in the Baker's yeast are located on the cell wall and include four highly homologous members. Recently, Pir proteins have become increasingly used as anchor proteins in yeast cell surface display systems. These display systems are classified into three types: N-terminal fusion, C-terminal fusion, and inserted fusion. In addition to the GPI (glycosylphosphatidyl inositol) and the FL/FS anchor proteins, these three Pir based systems significantly increase the choices for target proteins to be displayed. Furthermore, Pir proteins can also be used as a fusion partner for target proteins to be effectively secreted into culture medium. Here, we summarize the development and application of Pir proteins as anchor proteins. PMID- 24493572 TI - High-level expression in Corynebacterium glutamicum of nitrile hydratase from Rhodococcus rhodochrous for acrylamide production. AB - The nhhBAG gene of Rhodococcus rhodochrous M33 that encodes nitrile hydratase (NHase), converting acrylonitrile into acrylamide, was cloned and expressed in Corynebacterium glutamicum under the control of an ilvC promoter. The specific enzyme activity in recombinant C. glutamicum cells was about 13.6 MUmol/min/mg dry cell weight (DCW). To overexpress the NHase, five types of plasmid variants were constructed by introducing mutations into 80 nucleotides near the translational initiation region (TIR) of nhhB. Of them, pNBM4 with seven mutations showed the highest NHase activity, exhibiting higher expression levels of NhhB and NhhA than wild-type pNBW33, mainly owing to decreased secondary structure stability and an introduction of a conserved Shine-Dalgarno sequence in the translational initiation region. In a fed-batch culture of recombinant Corynebacterium cells harboring pNBM4, the cell density reached 53.4 g DCW/L within 18 h, and the specific and total enzyme activities were estimated to be 37.3 MUmol/min/mg DCW and 1,992 MUmol/min/mL, respectively. The use of recombinant Corynebacterium cells for the production of acrylamide from acrylonitrile resulted in a conversion yield of 93 % and a final acrylamide concentration of 42.5 % within 6 h when the total amount of fed acrylonitrile was 456 g. PMID- 24493573 TI - Autoantibodies to IL-17A may be correlated with the severity of mucocutaneous candidiasis in APECED patients. AB - The relative roles of various autoantibodies against IL-17-type cytokines in susceptibility to chronic mucocutaneous candidiasis (CMC) in patients with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) remain poorly defined. The purpose of this longitudinal study was to analyze the relationship between the occurrence of mucocutaneous candidiasis and levels of anti-IL-17A, anti-IL-17F and anti-IL-22 autoantibodies. We studied six APECED patients from four families with various disease manifestations. Clinical data were collected during regular follow-up. Anti-endocrine organ antibody levels and clinical chemistry and immunology parameters were determined in routine laboratory assays on freshly isolated serum. Levels of autoantibodies against IL 17A, IL-17F, IL-22, IFN-alpha, IFN-omega and TNF-alpha, and cytokine release by Candida-exposed blood cells were determined by ELISA. Mutations were analyzed by sequencing genomic DNA. Four patients carried the germline c.769C > T homozygous nonsense mutation, which results in R257X truncation of the AIRE protein, and two patients from the same family were compound heterozygous for the c.769C > T/c.1344delC mutation. We found persistently high levels of antibodies against IL 17A in the serum samples of one patient presenting CMC since infancy and low or undetectable anti-IL-17A antibody levels in the sera of five patients with no candidiasis or without severe candidiasis. By contrast, levels of autoantibodies against IL-17F and IL-22 were higher in all patients than in healthy controls. Release of IL-17-type cytokines by Candida-exposed blood mononuclear cells was low or negligible in all patients tested. We suggest that anti-IL-17A antibodies may play an important role in the predisposition to candidiasis of APECED patients. However, the lack of severe CMC in APECED patients with high levels of IL-17F and anti-IL-22 autoantibodies clearly calls into question the role of these antibodies as the principal cause of cutaneous and mucosal candidiasis in at least some APECED patients. These data also suggest that the impaired release of IL-17-type cytokines by blood cells may be an element of the immunopathology of CMC in APECED patients. PMID- 24493574 TI - Polypharmacy in heart failure patients. AB - In heart failure (HF), the progressive use of multiple drugs and a complex therapeutic regimen is common and is recommended by international guidelines. With HF being a common disease in the elderly, patients often have numerous comorbidities that require additional specific treatment, thus producing a heavy pill burden. Polypharmacy, defined as the chronic use of five or more medications, is an underestimated problem in the management of HF patients. However, polypharmacy has an important impact on HF treatment, as it often leads to inappropriate drug prescription, poor adherence to pharmacological therapies, drug-drug interactions, and adverse effects. The growing complexity of HF patients, whose mean age increases progressively and who present multiple comorbidities, suggests the need for newer models of primary care to improve the management of HF patients. Self-care, telemonitoring, and natriuretic peptide guided therapy represent promising new HF care models to face the complexity of the disease and its therapeutic regimen. PMID- 24493575 TI - Pathophysiology and potential clinical applications for testing of peripheral chemosensitivity in heart failure. AB - Enhanced peripheral chemosensitivity (PChS) is a common finding in congestive heart failure (CHF). Although initially it may be regarded as a compensatory mechanism to maintain adequate oxygenation and tissue perfusion, importantly it also contributes to disease progression. The magnitude of PChS is related to the severity of CHF but does not depend on its etiology. Numerous methodologies have been developed to assess PChS reliably; however, only two methods based on acute hypoxia have proven to be clinically and prognostically useful. The pathophysiology behind increased PChS is complex and involves disturbances in regional blood flow, gaseous neurotransmission, redox processes, and angiotensin signaling. Augmented PChS is believed to translate into sympathetic overactivity, decreased barosensitivity, reduced exercise tolerance, more arrhythmic events, and poor outcomes. In this review, we present current knowledge regarding the pathophysiology of peripheral chemoreflex, available methods for assessment, and clinical significance of increased PChS. PMID- 24493576 TI - Characterization of fenofibrate-mediated anti-proliferative pro-apoptotic effects on high-grade gliomas and anti-invasive effects on glioma stem cells. AB - Glioblastoma is the most common, and at the same time, most aggressive type of high-grade glioma (HGG). The prognosis of glioblastoma patients treated with standard therapy including surgery, temozolomide and radiation therapy remains poor. Peroxisome proliferator-activated receptor-alpha (PPARalpha) agonists are in widespread clinical use for the treatment of hyperlipidemia. Recent evidence has suggested a potential role in various cancers including glioblastoma. In this study, we characterized the effects of PPARalpha agonist, fenofibrate, directly on HGG cells and glioma stem cells (GSC). Fenofibrate exhibited dose-dependent p53-independent anti-proliferative effects on HGG starting at 25 MUM and pro apoptotic effects starting at 50 MUM, suggesting that the anti-proliferative actions are present only at 25 MUM. PPARalpha was expressed in all HGG cell lines. Inhibition of PPARalpha with specific inhibitor GW6471 did not affect either proliferation or apoptosis suggesting that these are PPARalpha-independent effects. Fenofibrate treatment of HGG cells robustly diminished the expression of key signaling pathways, including NF-kappaB and cyclin D1. Phosphorylation of Akt was also diminished, with no change in total Akt. Effects on apoptotic signaling molecules, Bax and Bcl-xL, had a trend towards pro-apoptotic effects. With respect to GSC, fenofibrate treatment at 25 MUM significantly decreased invasion in association with a decrease in CD133 and Oct4 expression. Overall, results support consideration of fenofibrate as an anti-glioma agent and establish its potential as an adjunct treatment strategy for HGG. Translation to the clinical setting could be rapid given its current use as a clinical agent and its low toxicity profile. PMID- 24493578 TI - Erythropoietin-induced treatment costs in patients suffering from renal anemia - a comparison between biosimilar and originator drugs. AB - OBJECTIVES: Renal anemia is a serious concern for morbidity and lower quality-of life of patients suffering from chronic kidney disease resulting in a high economic burden when administering erythropoiesis-stimulating agents (ESAs). The aim of this study was to estimate erythropoietin-induced treatment costs in patients suffering from renal anemia undergoing dialysis treated with originator or biosimilar drugs. METHODS: A retrospective analysis was undertaken of ESA related pharmacotherapy between January 1, 2008 and December 31, 2010 based on treatment and pharmacy claims data of 16,895 dialysis patients contained in the database of the Association of Statutory Health Insurance Physicians, Bavaria. All patients received an ESA treatment (ATC code B03XA) and chronic maintenance hemodialysis due to chronic kidney disease stage 5. RESULTS: Total drug expenditures for ESA-originators and biosimilars amounted to ? 78.447 million for the 3-year study period. In hemodialysis patients cumulative defined daily doses (DDDs) were 7,727,782.14. Mean costs per DDD were ? 10.79 (originators) and ? 8.56 (biosimilars). A biosimilar substitution quota of 50% provides a savings potential of ? 6.14 million [range ? 3.07-9.22 million (25-75% quota)]. CONCLUSION: A more common biosimilar prescription in renal anemia patients suffering from chronic kidney disease provides a noteworthy economic savings potential. PMID- 24493577 TI - Expression and localization of serine protease Htra1 in neuroblastoma: correlation with cellular differentiation grade. AB - Neuroblastoma (NB) is a paediatric tumor that arises from neural crest and shows heterogeneous clinical and biological features. The serine-protease high temperature requirement A1 (HtrA1) has a pivotal role in both cell proliferation and differentiation. Here we report the expression and localization of HtrA1 in NB tumor samples to assess HtrA1 role as a possible new biomarker of cellular differentiation in NB patients. HtrA1 protein expression by Western Blot assay was performed in 60 tissue samples of 50 children with NB and 10 children with ganglioneuroblastoma (GNB). HtrA1 was expressed in 56/60 (93.3 %) samples with different expression levels: low levels in 36/56 samples (64.3 %) and high levels in 20/56 (35.7 %). Higher levels were found in 1, 2 and 4s stages (80 %), whereas 3 and 4 stages (20 %) showed a low expression, with a statistically significant difference (p = 0.003). Among not amplified N-MYC group, 28 (60 %) had low/absent expression of HtrA1: seven with recurrent disease and negative outcome and 21 in continuous complete remission (CCR), whereas all samples with high expression of HtrA1 (17/44) were in CCR (p = 0.03). The immunohistochemical analysis showed localization of HtrA1 in differentiated areas higher than in undifferentiated areas where the protein was absent. Moreover, HtrA1 was highly expressed in all GNB samples. In conclusion, the over-expression of HtrA1 is correlated to cellular differentiation grade and stage of NB at diagnosis. Moreover, HtrA1 could represent a new marker of undifferentiation and biological aggressiveness of NB. PMID- 24493580 TI - [Service productivity in hospital nursing--conceptual framework of a productivity analysis]. AB - BACKGROUND AND OBJECTIVES: Decreasing staff numbers compounded by an increasing number of cases is regarded as main challenge in German hospital nursing. These input reductions accompanied by output extensions imply that hospital nursing services have had to achieve a continuous productivity growth in the recent years. Appropriately targeted productivity enhancements require approved and effective methods for productivity acquisition and measurement. However, there is a lack of suitable productivity measurement instruments for hospital nursing services. This deficit is addressed in the present study by the development of an integrated productivity model for hospital nursing services. Conceptually, qualitative as well as quantitative aspects of nursing services productivity are equally taken into consideration. METHODS: Based on systematic literature reviews different conceptual frameworks of service productivity and the current state of research in hospital nursing services productivity were analysed. On this basis nursing sensitive inputs, processes and outputs were identified and integrated into a productivity model. RESULTS: As an adequate framework for a hospital nursing services productivity model the conceptual approach by Gronroos/Ojasalo was identified. The basic structure of this model was adapted stepwise to our study purpose by integrating theoretical and empirical findings from the research fields of service productivity, nursing productivity as well as national and international nursing research. Special challenges existed concerning the identification of relevant influencing factors as well as the representation of nursing sensitive outputs. The final result is an integrated productivity model, which can be used as an adequate framework for further research in hospital nursing productivity. CONCLUSIONS: Research on hospital nursing services productivity is rare, especially in Germany. The conceptual framework developed in this study builds on established knowledge in service productivity research. The theoretical findings have been advanced and adapted to the context of German hospital nursing services. The presented productivity model represents a unique combination of services and nursing services research, which did not exist so far. By operationalisation of the model's components it can be used as the basis for further empirical -research. PMID- 24493579 TI - [Management documentation of therapeutic units on inpatient treatment for people with dementia--does it allow conclusion to be drawn them about inpatient services? An exploratory analysis]. AB - BACKGROUND: Against the background of the continuously growing incidence rates of gerontopsychiatric disorders, their economic dimen-sions, and the effects on persons affected as well as their social environments, the present study focuses on an analysis of the services provided in acute psychiatric care settings for patients with dementia. RESULTS are based on secondary data. AIM OF THE STUDY: We aim to compare therapeutic service units of different clusters of occupational groups (physicians/psychologists, nurses/special therapists) for the ICD-10 diagnostic groups F00-F03 and G30 in the years 2010 (starting with July) and 2011. Main research question is how many patients are mappable with 'therapeutic units' (Therapieeinheiten, TE) of the operation and procedures catalogue (OPS). METHODS: The present study is based on an analysis of the S21 KHEntgG data record of 35 acute psychiatric facilities. Data collection took place within the project "Versorgungsindikatoren fur die Psychiatrie und Psychosomatik (VIPP)", "Supply indicators for psychiatric and psychosomatic settings". The data record implies statewide data of specialised hospitals, university hospitals and departments of psychiatry of the Federal Republic of Germany. RESULTS: In total, 5 111 cases were included in the analysis. Nurses and special therapists carried out significantly more therapeutic units in the main diagnoses groups (F01, F03 and G30) and the care groups (regular vs. intensive) than physicians and psychologists (p<0.05). It was not possible to map all patients with the use of therapeutic units (G30 78.8%, F01 83.4%, F03 81.2%). Mapping of patients was significantly higher in the intensive care compared to regular care in both occupational clusters (p<0.05). CONCLUSIONS: We demonstrated that the "therapeutic units" of the OPS codes are now used in the routine data (S21 KHEntgG), and that they are able to portray relevant aspects of non-medication therapeutic service. The present study provides a preliminary/exploratory overview on the services provided, mapped by therapeutic units. Future research should focus on the overlap between the category "therapeutic" units and the services actually provided. PMID- 24493581 TI - Dyadic effects of coping strategies on emotional state and quality of life in prostate cancer patients and their spouses. AB - BACKGROUND: During cancer, coping strategies adopted by patients with prostate cancer and their spouses have an effect on their own emotional state and quality of life (QoL). However, the effects of coping strategies used by a member of a couple on the well-being of the other member are unknown. The aim of this study is to examine the dyadic effects of coping strategies on the emotional state and QoL of couples dealing with cancer. METHODS: Ninety-nine couples completed various self-questionnaires to assess psychological and physical QoL, anxiety, depressive symptoms, and coping strategies at the beginning, middle, and end of primary treatment. RESULTS: Results obtained with the actor-partner interdependence model showed that coping strategies used by patients or spouses play a key role not only in their own well-being but also in their partners'. Indeed, when patients use problem-focused coping or social support-seeking, they, as well as their spouses, experience fewer anxiety and depressive symptoms. Conversely, patients or spouses who use emotion-focused coping experience higher levels of anxiety and depressive symptoms. Finally, and it is a surprising result, when spouses seek social support, patients feel greater anxiety. CONCLUSIONS: These findings suggest that both patients and spouses should be included in psychosocial programs, which develop and reinforce their ability to cope with cancer. Couples may benefit from membership in support groups allowing them to share their experiences. PMID- 24493582 TI - The use of a supraglottic airway device as an extubation bridge for the difficult airway. PMID- 24493583 TI - And the winner is... PMID- 24493584 TI - Ottoline Leyser: the beauty of plant genetics. Interviewed by Caitlin Sedwick. PMID- 24493585 TI - Hop-on hop-off: polysomes take a tour of the cell on endosomes. AB - After export from the nucleus, ribosomes need to be distributed throughout the entire cell so that protein synthesis can occur even at distant sites. In the elongated hyphal cell of the fungus Ustilago maydis, Higuchi et al. (2014. J. Cell Biol. http://dx.doi.org/10.1083/jcb.201307164) now demonstrate that polysomes associate with early endosomes that undergo kinesin 3- and dynein dependent long-range motility. The bidirectional movement of early endosomes randomly distributes polysomes, which may ensure the even distribution of the translation machinery across the entire cell. PMID- 24493586 TI - Traversing the basement membrane in vivo: a diversity of strategies. AB - The basement membrane is a dense, highly cross-linked, sheet-like extracellular matrix that underlies all epithelia and endothelia in multicellular animals. During development, leukocyte trafficking, and metastatic disease, cells cross the basement membrane to disperse and enter new tissues. Based largely on in vitro studies, cells have been thought to use proteases to dissolve and traverse this formidable obstacle. Surprisingly, recent in vivo studies have uncovered a remarkably diverse range of cellular- and tissue-level strategies beyond proteolysis that cells use to navigate through the basement membrane. These fascinating and unexpected mechanisms have increased our understanding of how cells cross this matrix barrier in physiological and disease settings. PMID- 24493587 TI - Early endosome motility spatially organizes polysome distribution. AB - Early endosomes (EEs) mediate protein sorting, and their cytoskeleton-dependent motility supports long-distance signaling in neurons. Here, we report an unexpected role of EE motility in distributing the translation machinery in a fungal model system. We visualize ribosomal subunit proteins and show that the large subunits diffused slowly throughout the cytoplasm (Dc,60S = 0.311 um(2)/s), whereas entire polysomes underwent long-range motility along microtubules. This movement was mediated by "hitchhiking" on kinesin-3 and dynein-driven EEs, where the polysomes appeared to translate EE-associated mRNA into proteins. Modeling indicates that this motor-driven transport is required for even cellular distribution of newly formed ribosomes. Indeed, impaired EE motility in motor mutants, or their inability to bind EEs in mutants lacking the RNA-binding protein Rrm4, reduced ribosome transport and induced ribosome aggregation near the nucleus. As a consequence, cell growth was severely restricted. Collectively, our results indicate that polysomes associate with moving EEs and that "off- and reloading" distributes the protein translation machinery. PMID- 24493588 TI - PP2ARts1 is a master regulator of pathways that control cell size. AB - Cell size checkpoints ensure that passage through G1 and mitosis occurs only when sufficient growth has occurred. The mechanisms by which these checkpoints work are largely unknown. PP2A associated with the Rts1 regulatory subunit (PP2A(Rts1)) is required for cell size control in budding yeast, but the relevant targets are unknown. In this paper, we used quantitative proteome-wide mass spectrometry to identify proteins controlled by PP2A(Rts1). This revealed that PP2A(Rts1) controls the two key checkpoint pathways thought to regulate the cell cycle in response to cell growth. To investigate the role of PP2A(Rts1) in these pathways, we focused on the Ace2 transcription factor, which is thought to delay cell cycle entry by repressing transcription of the G1 cyclin CLN3. Diverse experiments suggest that PP2A(Rts1) promotes cell cycle entry by inhibiting the repressor functions of Ace2. We hypothesize that control of Ace2 by PP2A(Rts1) plays a role in mechanisms that link G1 cyclin accumulation to cell growth. PMID- 24493589 TI - A G protein-coupled receptor and the intracellular synthase of its agonist functionally cooperate. AB - Export of newly synthesized G protein-coupled receptors (GPCRs) remains poorly characterized. We show in this paper that lipocalin-type prostaglandin D2 (PGD2) synthase (L-PGDS) interacts intracellularly with the GPCR DP1 in an agonist independent manner. L-PGDS promotes cell surface expression of DP1, but not of other GPCRs, in HEK293 and HeLa cells, independent of L-PGDS enzyme activity. In addition, formation of a DP1-Hsp90 complex necessary for DP1 export to the cell surface is dependent on the interaction between L-PGDS and the C-terminal MEEVD residues of Hsp90. Surprisingly, PGD2 synthesis by L-PGDS is promoted by coexpression of DP1, suggesting a possible intracrine/autocrine signaling mechanism. In this regard, L-PGDS increases the formation of a DP1-ERK1/2 complex and increases DP1-mediated ERK1/2 signaling. Our findings define a novel cooperative mechanism in which a GPCR (DP1) promotes the activity of the enzyme (L-PGDS) that produces its agonist (PGD2) and in which this enzyme in turn acts as a cofactor (of Hsp90) to promote export and agonist-dependent activity of the receptor. PMID- 24493591 TI - CellGeo: a computational platform for the analysis of shape changes in cells with complex geometries. AB - Cell biologists increasingly rely on computer-aided image analysis, allowing them to collect precise, unbiased quantitative results. However, despite great progress in image processing and computer vision, current computational approaches fail to address many key aspects of cell behavior, including the cell protrusions that guide cell migration and drive morphogenesis. We developed the open source MATLAB application CellGeo, a user-friendly computational platform to allow simultaneous, automated tracking and analysis of dynamic changes in cell shape, including protrusions ranging from filopodia to lamellipodia. Our method maps an arbitrary cell shape onto a tree graph that, unlike traditional skeletonization algorithms, preserves complex boundary features. CellGeo allows rigorous but flexible definition and accurate automated detection and tracking of geometric features of interest. We demonstrate CellGeo's utility by deriving new insights into (a) the roles of Diaphanous, Enabled, and Capping protein in regulating filopodia and lamellipodia dynamics in Drosophila melanogaster cells and (b) the dynamic properties of growth cones in catecholaminergic a differentiated neuroblastoma cells. PMID- 24493592 TI - Synthesis and functional characterization of imbutamine analogs as histamine H3 and H4 receptor ligands. AB - Imbutamine (4-(1H-imidazol-4-yl)butanamine) is a potent histamine H3 (H3R) and H4 receptor (H4R) agonist (EC50 values: 3 and 66 nM, respectively). Aiming at improved selectivity for the H4R, the imidazole ring in imbutamine was methyl substituted or replaced by various differently substituted heterocycles (1,2,3 triazoles, 1,2,4-triazoles, pyridines, pyrimidines) as potential bioisosteres. Investigations in [(35)S]GTPgammaS binding assays using membranes of Sf9 insect cells expressing the respective human histamine receptor subtype revealed only very weak activity of most of the synthesized hetarylalkylamines at both receptors. By contrast, the introduction of substituents at the 4-imidazolyl ring was most effective regarding H4R selectivity. This holds for methyl substitution in position 2 and, especially, in position 5. 5-Methylimbutamine (H4R: EC50 = 59 nM, alpha = 0.8) was equipotent with imbutamine at the hH4R, but revealed about 16-fold selectivity for the hH4R compared to the hH3R (EC50 980 nM, alpha = 0.36), whereas imbutamine preferred the hH3R. The functional activities were in agreement with radioligand binding data. The results support the hypothesis that, by analogy with histamine, methyl substitution in histamine homologs offers a way to shift the selectivity in favor of the H4R. PMID- 24493590 TI - Live imaging of prions reveals nascent PrPSc in cell-surface, raft-associated amyloid strings and webs. AB - Mammalian prions refold host glycosylphosphatidylinositol-anchored PrP(C) into beta-sheet-rich PrP(Sc). PrP(Sc) is rapidly truncated into a C-terminal PrP27-30 core that is stable for days in endolysosomes. The nature of cell-associated prions, their attachment to membranes and rafts, and their subcellular locations are poorly understood; live prion visualization has not previously been achieved. A key obstacle has been the inaccessibility of PrP27-30 epitopes. We overcame this hurdle by focusing on nascent full-length PrP(Sc) rather than on its truncated PrP27-30 product. We show that N-terminal PrP(Sc) epitopes are exposed in their physiological context and visualize, for the first time, PrP(Sc) in living cells. PrP(Sc) resides for hours in unexpected cell-surface, slow moving strings and webs, sheltered from endocytosis. Prion strings observed by light and scanning electron microscopy were thin, micrometer-long structures. They were firmly cell associated, resisted phosphatidylinositol-specific phospholipase C, aligned with raft markers, fluoresced with thioflavin, and were rapidly abolished by anti-prion glycans. Prion strings and webs are the first demonstration of membrane-anchored PrP(Sc) amyloids. PMID- 24493593 TI - Steroidomimetic aminomethyl spiroacetals as novel inhibitors of the enzyme Delta8,7-sterol isomerase in cholesterol biosynthesis. AB - Grundmann's ketone is converted to a spiroacetal containing a 5-hydroxymethyl-5 nitro-1,3-dioxane moiety whose hydroxymethyl group can be esterified or directly substituted with primary and secondary amines. Among the resulting aminomethyl spiroacetals, several ones bearing diamino residues were found to be inhibitors of the enzyme Delta8,7-isomerase in cholesterol biosynthesis. The complex bicyclic building block derived from Grundmann's ketone could be replaced by a properly substituted tetraline scaffold, without noteworthy loss in activity. This opens the opportunity to perform further structural modifications for the design of new steroidomimetic inhibitors of human Delta8,7-isomerase. PMID- 24493598 TI - What is discomfort in persons with dementia who are agitated?--reply. PMID- 24493599 TI - What is discomfort in persons with dementia who are agitated? PMID- 24493600 TI - Arsenic in rice and other foods. PMID- 24493601 TI - Arsenic in rice and other foods--reply. PMID- 24493602 TI - Conflicts of interest in approvals of food additives. PMID- 24493603 TI - Conflicts of interest in approvals of food additives. PMID- 24493604 TI - Conflicts of interest in approvals of food additives--reply. PMID- 24493605 TI - Dedicated observation unit for patients with "observation status". PMID- 24493606 TI - Dedicated observation unit for patients with "observation status"--reply. PMID- 24493607 TI - Statins and musculoskeletal adverse events. PMID- 24493608 TI - Statins and musculoskeletal adverse events. PMID- 24493609 TI - Statins and musculoskeletal adverse events--reply. PMID- 24493610 TI - Statins and musculoskeletal adverse events--reply. PMID- 24493611 TI - Technical difficulties and evaluating e-health interventions. PMID- 24493612 TI - Technical difficulties and evaluating e-health interventions. PMID- 24493613 TI - Promotion of "low t" and the role of testosterone clinical trials. PMID- 24493614 TI - Technical difficulties and evaluating e-health interventions--reply. PMID- 24493615 TI - Promotion of "low T" and the role of testosterone clinical trials--reply. PMID- 24493616 TI - Vertebral augmentation for symptomatic compression fractures is supported by randomized clinical trials. PMID- 24493617 TI - Vertebral augmentation for symptomatic compression fractures is supported by randomized clinical trials--reply. PMID- 24493619 TI - Vertebroplasty: changing levels of evidence and conflict of interest. PMID- 24493623 TI - Temsirolimus enhances the efficacy of cetuximab in colon cancer through a CIP2A dependent mechanism. AB - PURPOSE: A dozen clinical trials examining a combination of temsirolimus and cetuximab in treating metastatic colon cancer are currently underway. We investigated the role of cancerous inhibitor of protein phosphatase 2A (CIP2A) in the synergism between temsirolimus and cetuximab in colon cancer. METHODS: Five colon cancer cell lines were used for in vitro studies. Signal transduction pathways were assessed by immunoblotting. The synergism between studied drugs was analyzed with combination indexes. Gene silencing was performed using small interfering RNAs. The efficacies of temsirolimus and cetuximab were tested in nude mice with colon cancer xenografts. Transcriptional activity was assessed using a reporter assay. The inhibitors leupeptin, chloroquine, and MG132 were used to assess protein degradation. The association between CIP2A, clinicopathological parameters, and survival was examined by immunohistochemical staining using a tumor tissue microarray. RESULTS: Temsirolimus decreased the resistance of cells to cetuximab by both inhibiting transcription of CIP2A and increasing degradation of CIP2A through the lysosomal-autophagy pathway. The mammalian target of rapamycin (mTOR) protein immunoprecipitated along with CIP2A. Temsirolimus decreased expression of phosphorylated extracellular regulated protein kinase (pErk) and phosphorylated v-akt murine thymoma viral oncogene (pAKT) and decreased the interaction of CIP2A and mTOR in cell lines without the K-ras codon 12 mutation. CIP2A was a prognostic marker only in colon cancer patients with weak expression of pErk or pAKT. CONCLUSIONS: Temsirolimus decreases cellular resistance to cetuximab by regulating CIP2A expression in colon cancer cells. Potential biomarkers for CIP2A inhibitors include pErk and pAKT. PMID- 24493624 TI - Helping cancer patients to quit smoking by understanding their risk perception, behavior, and attitudes related to smoking. AB - BACKGROUND: Evidence shows that smoking is a major cause of cancer, and cancer patients who continue smoking are at greater risk for all causes of mortality, cancer recurrence, and second primary cancers. Nevertheless, many cancer patients still smoke and are not willing to quit. This study aimed at understanding the needs and concerns of current and ex-smoking cancer patients, including their risk perceptions, and the behavior and attitudes related to smoking. METHODS: A qualitative research was conducted in an oncology outpatient clinic. A one-to-one semi-structured interview was conducted with current Chinese smokers and ex smokers after they had been diagnosed with cancer. Data saturation was achieved after interviewing a total of 20 current smokers and 20 ex-smokers. RESULTS: A total of 241 patients who were smokers prior to their diagnosis of cancer were identified. Of 241 patients, 208 (86.31%) quitted and 33 (13.69%) continued smoking after receiving a cancer diagnosis. In general, patients who refused to quit smoking subsequent to a cancer diagnosis thought that the perceived barriers to quitting outweighed the perceived benefits of quitting. In contrast, most cancer patients who quit after their cancer diagnoses thought that the perceived benefits of quitting greatly outweighed the perceived barriers to quitting. CONCLUSIONS: It is vital that healthcare professionals should help cancer patients to quit smoking. Understanding how current smokers and ex-smokers perceive the risks of smoking, and their behavior, attitudes, and experiences related to smoking is an essential prerequisite for the design of an effective smoking cessation intervention. PMID- 24493625 TI - mGluR5: exploration of orthosteric and allosteric ligand binding pockets and their applications to drug discovery. AB - Since its discovery in 1992, mGluR5 has attracted significant attention and been linked to several neurological and psychiatric diseases. Ligand development was initially focused on the orthosteric binding pocket, but lack of subtype selective ligands changed the focus to the transmembrane allosteric binding pocket. This strategy has resulted in several drug candidates in clinical testing. In the present article we explore the orthosteric and allosteric binding pockets in terms of structure and ligand recognition across the mGluR subtypes and groups, and discuss the clinical potential of ligands targeting these pockets. We have performed binding mode analyses of non- and group-selective orthosteric ligands based on molecular docking in mGluR crystal structures and models. For the analysis of the allosteric binding pocket we have combined data from all mGluR5-mutagenesis studies, collectively reporting five negative allosteric modulators and 47 unique mutations, and compared it to the closest related homolog, mGluR1. PMID- 24493626 TI - Mangiferin antagonizes rotenone: induced apoptosis through attenuating mitochondrial dysfunction and oxidative stress in SK-N-SH neuroblastoma cells. AB - In the present study, using a human neuroblastoma SK-N-SH cells, we explored antioxidant, mitochondrial protective and antiapoptotic properties of mangiferin against rotenone-mediated cytotoxicity. SK-N-SH cells are divided into four experimental groups based on 3-(4,5-dimethyl2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay-untreated cells, cells incubated with rotenone (100 nM), cells treated with mangiferin (20 MUg) (pretreatment 4 h before) + rotenone (100 nM) and mangiferin alone treated. 24 h after treatment with rotenone and 28 h after treatment with mangiferin, levels of ATP thiobarbituricacid reactive substances and reduced glutathione and activities of enzymatic antioxidants including superoxide dismutase, catalase and glutathione peroxidise were measured. Finally mitochondrial transmembrane potential and expressions of apoptotic protein were also analysed. Pre-treatment with mangiferin significantly enhanced cell viability, ameliorated decrease in mitochondrial membrane potential and decreased rotenone-induced apoptosis in the cellular model of Parkinson's disease. Moreover oxidative imbalance induced by rotenone was partially rectified by mangiferin. Our results indicated that anti-apoptotic properties of this natural compound due to its antioxidant and mitochondrial protective function protect rotenone induced cytotoxicity. PMID- 24493627 TI - Multi-target design strategies in the context of Alzheimer's disease: acetylcholinesterase inhibition and NMDA receptor antagonism as the driving forces. AB - In recent years, the multi-target-directed ligand concept has been used to design a variety of molecules hitting different biological targets for Alzheimer's disease. We have sought to combine, in the same molecule, the neuroprotective action of N-methyl-D-aspartate receptor antagonism with the symptomatic relief offered by cholinergic activity through acetylcholinesterase inhibition. This strategy could potentially maintain the positive outcomes of memantine acetylcholinesterase inhibitor combinations, but with the benefits of a single molecule therapy. Herein, we discuss selected examples of multifunctional compounds, which we rationally designed to simultaneously modulate these targets. We also examine the intertwined relationship between acetylcholinesterase, N methyl-D-aspartate receptors, and other active players in the neurotoxic cascade. PMID- 24493628 TI - Treatment of giardiasis: current status and future directions. AB - Giardiasis is a common yet neglected cause of diarrheal illness worldwide. Antimicrobial therapy is usually but not always effective and drug resistance has become an increasing concern. Several promising drug candidates have been recently identified that can overcome antibiotic resistance in Giardia. These include derivatives of 5-nitroimidazoles and benzimidazoles, as well as hybrid compounds created from combinations of different antigiardial drugs. High throughput screening of large compound libraries has been a productive strategy for identifying antigiardial activity in drugs already approved for other indications, e.g. auranofin. This article reviews the current treatment of giardiasis, mechanisms of resistance, advances in drug and vaccine development, and directions for further research on this significant human pathogen. PMID- 24493629 TI - Better postdiagnosis diet quality is associated with reduced risk of death among postmenopausal women with invasive breast cancer in the women's health initiative. AB - BACKGROUND: Few studies have evaluated whether adherence to dietary recommendations is associated with mortality among cancer survivors. In breast cancer survivors, we examined how postdiagnosis Healthy Eating Index (HEI)-2005 scores were associated with all-cause and cause-specific mortality. METHODS: Our prospective cohort study included 2,317 postmenopausal women, ages 50 to 79 years, in the Women's Health Initiative's Dietary Modification Trial (n = 1,205) and Observational Study (n = 1,112), who were diagnosed with invasive breast cancer and completed a food frequency questionnaire after being diagnosed. We followed women from this assessment forward. We used Cox proportional hazards models to estimate multivariate-adjusted HRs and 95% confidence intervals (CI) for death from any cause, breast cancer, and causes other than breast cancer, according to HEI-2005 quintiles. RESULTS: Over 9.6 years, 415 deaths occurred. After adjustment for key covariates, women consuming better quality diets had a 26% lower risk of death from any cause (HRQ4:Q1, 0.74; 95% CI, 0.55-0.99; Ptrend = 0.043) and a 42% lower risk of death from non-breast cancer causes (HRQ4:Q1, 0.58; 95% CI, 0.38-0.87; Ptrend = 0.011). HEI-2005 score was not associated with breast cancer death (HRQ4:Q1, 0.91; 95% CI, 0.60-1.40; Ptrend = 0.627). In analyses stratified by tumor estrogen receptor (ER) status, better diet quality was associated with a reduced risk of all-cause mortality among women with ER(+) tumors (n = 1,758; HRQ4:Q1, 0.55; 95% CI, 0.38-0.79; Ptrend = 0.0009). CONCLUSION: Better postdiagnosis diet quality was associated with reduced risk of death, particularly from non-breast cancer causes. IMPACT: Breast cancer survivors may experience improved survival by adhering to U.S. dietary guidelines. PMID- 24493631 TI - Ginsenoside metabolites inhibit P-glycoprotein in vitro and in situ using three absorption models. AB - P-glycoprotein, an ATP-dependent transporter expressed in the gastrointestinal tract and tumor cells, mediates the efflux transport of multiple drugs. Inhibition or induction of P-glycoprotein by herbal ingredients can lead to herb drug interactions and thus influence the activities of P-glycoprotein substrate drugs. The present study aimed to explore the effect of nine naturally occurring ginsenosides and their intestinal bacterial metabolites on P-glycoprotein mediated transport. The results showed that three ginsenoside metabolites (CK, Ppd, and Ppt) formed by intestinal bacteria significantly enhanced rhodamine 123 retention in Caco-2 cells, increased the absorptive permeability of rhodamine 123, and decreased the efflux ratio of digoxin in two absorption models, which were comparable to the effects of the known P-glycoprotein inhibitor verapamil. However, the prototype ginsenosides such as Rb1, Rb2, and Re showed no inhibitory effect on P-glycoprotein activity. In situ intestinal perfusion experiments also showed that CK, Ppd, and Ppt increased the absorption rate constant and permeability coefficient of rhodamine 123. Long-term treatment with CK, Ppd, and Ppt had no effect on P-glycoprotein mRNA expression in Caco-2 cells. In conclusion, CK, Ppd, and Ppt are potent P-glycoprotein inhibitors, indicating an unpredictable herb-drug interaction when ginsenosides are coadministered orally with P-glycoprotein substrate drugs. PMID- 24493630 TI - A genome-wide association study of early-onset breast cancer identifies PFKM as a novel breast cancer gene and supports a common genetic spectrum for breast cancer at any age. AB - Early-onset breast cancer (EOBC) causes substantial loss of life and productivity, creating a major burden among women worldwide. We analyzed 1,265,548 Hapmap3 single-nucleotide polymorphisms (SNP) among a discovery set of 3,523 EOBC incident cases and 2,702 population control women ages <= 51 years. The SNPs with smallest P values were examined in a replication set of 3,470 EOBC cases and 5,475 control women. We also tested EOBC association with 19,684 genes by annotating each gene with putative functional SNPs, and then combining their P values to obtain a gene-based P value. We examined the gene with smallest P value for replication in 1,145 breast cancer cases and 1,142 control women. The combined discovery and replication sets identified 72 new SNPs associated with EOBC (P < 4 * 10(-8)) located in six genomic regions previously reported to contain SNPs associated largely with later-onset breast cancer (LOBC). SNP rs2229882 and 10 other SNPs on chromosome 5q11.2 remained associated (P < 6 * 10( 4)) after adjustment for the strongest published SNPs in the region. Thirty-two of the 82 currently known LOBC SNPs were associated with EOBC (P < 0.05). Low power is likely responsible for the remaining 50 unassociated known LOBC SNPs. The gene-based analysis identified an association between breast cancer and the phosphofructokinase-muscle (PFKM) gene on chromosome 12q13.11 that met the genome wide gene-based threshold of 2.5 * 10(-6). In conclusion, EOBC and LOBC seem to have similar genetic etiologies; the 5q11.2 region may contain multiple distinct breast cancer loci; and the PFKM gene region is worthy of further investigation. These findings should enhance our understanding of the etiology of breast cancer. PMID- 24493633 TI - Daily crosswords improve verbal fluency: a brief intervention study. AB - OBJECTIVE: Phonemic verbal fluency (PVF) is a cognitive function that involves serial processes termed clustering and switching and which is impacted in both normal aging and dementia. The cognitive reserve hypothesis suggests that appropriate cognitive stimulation could maintain or improve cognitive performance. This study examines the effect on PVF performance of a brief crossword-based intervention in a cognitively normal, community-based sample. METHODS: Thirty-seven members of active retirement groups volunteered to participate and were randomly assigned to a crossword group and a control group. The former attempted a crossword daily for 4 weeks while the latter kept a daily gratitude diary for the same period. RESULTS: 2 * 2 mixed analyses of variance revealed that the crossword group performed significantly better over time than the control group in both total PVF score and in the cluster size component. CONCLUSION: Daily crosswords may be a simple and effective means of bolstering PVF performance in older people. PMID- 24493634 TI - Barriers to mental health service use and preferences for addressing emotional concerns among lung cancer patients. AB - OBJECTIVE: This study examined barriers to mental health service use and preferences for addressing emotional concerns among lung cancer patients (N=165) at two medical centers in the Midwestern United States. METHODS: Lung cancer patients completed an assessment of anxiety and depressive symptoms, mental health service use, barriers to using these services, and preferences for addressing emotional concerns. RESULTS: Only 45% of distressed patients received mental health care since their lung cancer diagnosis. The most prevalent patient reported barriers to mental health service use among non-users of these services (n=110) included the desire to independently manage emotional concerns (58%) and inadequate knowledge of services (19%). In addition, 57% of distressed patients who did not access mental health services did not perceive the need for help. Seventy-five percent of respondents (123/164) preferred to talk to a primary care physician if they were to have an emotional concern. Preferences for counseling, psychiatric medication, peer support, spiritual care, or independently managing emotional concerns also were endorsed by many patients (range=40-50%). Older age was associated with a lower likelihood of preferring to see a counselor. CONCLUSIONS: Findings suggest that many distressed lung cancer patients underuse mental health services and do not perceive the need for such services. Efforts to increase appropriate use of services should address patients' desire for autonomy and lack of awareness of services. PMID- 24493635 TI - A virtual reality endoscopic simulator augments general surgery resident cancer education as measured by performance improvement. AB - Colorectal cancer is the second most common cause of death in the USA. The need for screening colonoscopies, and thus adequately trained endoscopists, particularly in rural areas, is on the rise. Recent increases in required endoscopic cases for surgical resident graduation by the Surgery Residency Review Committee (RRC) further emphasize the need for more effective endoscopic training during residency to determine if a virtual reality colonoscopy simulator enhances surgical resident endoscopic education by detecting improvement in colonoscopy skills before and after 6 weeks of formal clinical endoscopic training. We conducted a retrospective review of prospectively collected surgery resident data on an endoscopy simulator. Residents performed four different clinical scenarios on the endoscopic simulator before and after a 6-week endoscopic training course. Data were collected over a 5-year period from 94 different residents performing a total of 795 colonoscopic simulation scenarios. Main outcome measures included time to cecal intubation, "red out" time, and severity of simulated patient discomfort (mild, moderate, severe, extreme) during colonoscopy scenarios. Average time to intubation of the cecum was 6.8 min for those residents who had not undergone endoscopic training versus 4.4 min for those who had undergone endoscopic training (p < 0.001). Residents who could be compared against themselves (pre vs. post-training), cecal intubation times decreased from 7.1 to 4.3 min (p < 0.001). Post-endoscopy rotation residents caused less severe discomfort during simulated colonoscopy than pre-endoscopy rotation residents (4 vs. 10%; p = 0.004). Virtual reality endoscopic simulation is an effective tool for both augmenting surgical resident endoscopy cancer education and measuring improvement in resident performance after formal clinical endoscopic training. PMID- 24493632 TI - Traumatic brain injury using mouse models. AB - The use of mouse models in traumatic brain injury (TBI) has several advantages compared to other animal models including low cost of breeding, easy maintenance, and innovative technology to create genetically modified strains. Studies using knockout and transgenic mice demonstrating functional gain or loss of molecules provide insight into basic mechanisms of TBI. Mouse models provide powerful tools to screen for putative therapeutic targets in TBI. This article reviews currently available mouse models that replicate several clinical features of TBI such as closed head injuries (CHI), penetrating head injuries, and a combination of both. CHI may be caused by direct trauma creating cerebral concussion or contusion. Sudden acceleration-deceleration injuries of the head without direct trauma may also cause intracranial injury by the transmission of shock waves to the brain. Recapitulation of temporary cavities that are induced by high-velocity penetrating objects in the mouse brain are difficult to produce, but slow brain penetration injuries in mice are reviewed. Synergistic damaging effects on the brain following systemic complications are also described. Advantages and disadvantages of CHI mouse models induced by weight drop, fluid percussion, and controlled cortical impact injuries are compared. Differences in the anatomy, biomechanics, and behavioral evaluations between mice and humans are discussed. Although the use of mouse models for TBI research is promising, further development of these techniques is warranted. PMID- 24493636 TI - Patient navigators' reflections on the navigator-patient relationship. AB - Patient navigation emerged as a strategy to reduce cancer disparities among low income and minority patients and has demonstrated efficacy in improving clinical outcomes. Observational studies have contributed valuable evaluations of navigation processes and tasks; however, few have offered in-depth reflections about the relationship between patient and navigator from the navigators' perspective. These approaches have addressed the emotional and relational components of patient navigation through the lens of process factors, relegating the navigator-patient relationship to a siloed, compartmentalized functionality. To expand upon existing task-oriented definitions of navigation, we conducted qualitative interviews among community-based patient navigators who coordinated care for uninsured, predominantly Hispanic, women receiving cancer screening and follow-up care in a county outside Chicago. Interviews were recorded, transcribed, and analyzed for themes within the navigator-patient relationship domain. The main themes that emerged centered on relational roles, relational boundaries, and ideal navigator relational qualities. While patient navigators described engaging with patients in a manner similar to a friend, they stressed the importance of maintaining professional boundaries. Navigators' support assisted patients in bridging their hospital and community lives, a result of navigators' investment in both hemispheres. We conclude that the navigator patient relationship is not a self-contained utility, but rather the medium through which all other navigator functions are enabled. These insights further characterize the navigator-patient relationship, which will help shape the development of future navigation programs and support the need for further research on the impact of relationship factors on clinical and psychosocial outcome measures. PMID- 24493637 TI - Activation of intra-epithelial lymphocytes; their morphology, marker expression and ultimate fate. AB - Intraepithelial lymphocytes (IELs) have been considered to play a key role in the defense system of the small intestine. Its mechanism has not been made sufficiently clear. Studies on IELs have been extremely limited to functions of alphabeta T-cell receptor (alphabetaTCR) IELs (alphabeta-IELs). Since, in the mouse duodenum and jejunum, gammadelta-IELs consist 75 % of IELs, it thus would be inappropriate to argue the mechanism without extensive discussions over the functions of gammadelta-IELs. In previous studies, we found that the anti-CD3 monoclonal antibody (mAb) injection induced DNA fragmentation in intestinal epithelial cells (IECs) and DNA repair immediately after, that these responses were reproduced by anti-gammadeltaTCR mAb not by anti-alphabetaTCR mAb and that the DNA fragmentation was induced by Granzyme B secreted by IELs, totally independent of Perforin. To further explore the functions of IELs in situ, we undertook experiments exclusively focused on IELs, on their changes and ultimate fate after the stimulation in mouse in vivo system. The current study demonstrated that the injected anti-CD3 mAb bound to CD3 on IELs, that the mAb activated gammadelta-IELs, leading to their degranulation, that changes occurred irreversibly in IELs and finally that activated IELs died in situ. gammadelta IELs could be considered to respond to various stimulations most likely without the need of accessory cells ("always ready for rapid response"), to die in situ ("disposable") and thus to respond to the stimulation only once ("a one-shot responder"). These characteristics of gammadelta-IELs are important to further elucidate the functions of gammadelta-IELs in the intestinal defense system. PMID- 24493638 TI - MicroRNAs and human diseases: diagnostic and therapeutic potential. AB - MicroRNAs (miRNAs) are endogenous, non-coding small RNAs that regulate gene expression at the post-transcriptional level. Recent studies have shown that miRNAs are aberrantly expressed in various human diseases, ranging from cancer to cardiovascular hypertrophy. The expression profiles of the miRNAs clearly differentiate the normal from the pathological state and thus their potential as novel biomarkers in the diagnosis and prognosis of several human diseases is immense. Emerging data on the role of miRNAs in the pathogenesis of various human diseases have paved the way to test their ability to act as novel therapeutic tools. In the present review, we will explore the current knowledge about the role of miRNAs in various human diseases. In addition, we will focus on the emerging evidences demonstrating the potential of miRNAs as novel biomarkers and the strategies to use them as therapeutic tools. PMID- 24493641 TI - Histone modifications related to chromosome silencing and elimination during male meiosis in Bengalese finch. AB - We report here that a germline-restricted chromosome (GRC) is regularly present in males and females of the Bengalese finch (Lonchura domestica). While the GRC is euchromatic in oocytes, in spermatocytes this chromosome is cytologically seen as entirely heterochromatic and presumably inactive. The GRC is observed in the cytoplasm of secondary spermatocytes, indicating that its elimination from the nucleus occurs during the first meiotic division. By immunofluorescence on microspreads, we investigated the presence of histone H3 modifications throughout male meiosis, as well as in postmeiotic stages. We found that the GRC is highly enriched in di- and trimethylated histone H3 at lysine 9 during prophase I, in agreement with the presumed inactive state of this chromosome. At metaphase I, dimethylated histone H3 is no longer detectable on the GRC and its chromatin is more faintly stained with DAPI. The condensed GRC is underphosphorylated at serine 10 compared to the regular chromosomes during metaphase I, being phosphorylated later at this site after the first meiotic division. From these results, we proposed that trimethylation of histone H3 at lysine 9 on the GRC chromatin increases during metaphase I. This hypermethylated state at lysine 9 may preclude the phosphorylation of the adjacent serine 10 residue, providing an example of cross-talk of histone H3 modifications as described in experimental systems. The differential underphosphorylation of the GRC chromatin before elimination is interpreted as a cytologically detectable byproduct of deficient activity of Aurora B kinase, which is responsible for the phosphorylation of H3 at serine 10 during mitosis and meiosis. PMID- 24493642 TI - The effect of polymerization method in stereo-active block copolymers on the stability of polymeric micelles and their drug release profile. AB - PURPOSE: To investigate the effect of polymerization method on the stability and drug release properties of polymeric micelles formed using stereo-active block copolymers. METHODS: Diblock copolymers consisting of methoxy poly ethylene oxide (MePEO) and poly(lactide)s (PLA)s of different stereochemistry were synthesized by bulk or solution polymerization. Polymers and micelles were characterized for their chemical structure by (1)H NMR, optical rotation by polarimetry, critical micellar concentration by fluorescence spectroscopy, thermal properties by differential scanning calorimetry, morphology by transmission electron microscopy and size as well as kinetic stability by dynamic light scattering. Release of encapsulated nimodipine from polymeric micelles at different levels of loading was also investigated. RESULTS: Solution polymerization yielded a higher degree of crystallinity for stereo-regular PLA blocks. Consequently, the related polymeric micelles were kinetically more stable than those prepared by bulk polymerization. At high drug loading levels, the release of nimodipine was more rapid from polymeric micelles with crystalline cores. At lower levels of drug loading, drug release was slower and independent of the stereochemistry of the core. CONCLUSIONS: The results underline the effect of polymerization method in defining core crystallinity in stereoregular block copolymer micelles. It also shows the impact of core crystallinity on enhancing micellar stability and drug release. PMID- 24493643 TI - Driving nucleolar assembly. AB - In this issue of Genes & Development, Grob and colleagues (pp. 220-230) identify the minimal molecular requirements to assemble a fully functional nucleolus in human cells and demonstrate the importance of the nucleolar transcription factor upstream binding factor (UBF) as a mitotic bookmark at the ribosomal DNA (rDNA). PMID- 24493644 TI - lncRNA recruits RNAi and the exosome to dynamically regulate pho1 expression in response to phosphate levels in fission yeast. AB - Numerous noncoding transcripts of unknown function have recently been identified. In this study, we report a novel mechanism that relies on transcription of noncoding RNA prt (pho1-repressing transcript) regulating expression of the pho1 gene. A product of this gene, Pho1, is a major secreted phosphatase needed for uptake of extracellular phosphate in fission yeast. prt is produced from the promoter located upstream of the pho1 gene in response to phosphate, and its transcription leads to deposition of RNAi-dependent H3K9me2 across the pho1 locus. In contrast, phosphate starvation leads to loss of H3K9me2 and pho1 induction. Strikingly, deletion of Clr4, a H3K9 methyltransferase, results in faster pho1 induction in response to phosphate starvation. We propose a new role for noncoding transcription in establishing transient heterochromatin to mediate an effective transcriptional response to environmental stimuli. RNAi recruitment to prt depends on the RNA-binding protein Mmi1. Importantly, we found that the exosome complex and Mmi1 are required for transcription termination and the subsequent degradation of prt but not pho1 mRNA. Moreover, in mitotic cells, transcription termination of meiotic RNAs also relies on this mechanism. We propose that exosome-dependent termination constitutes a specialized system that primes transcripts for degradation to ensure their efficient elimination. PMID- 24493645 TI - The molecular topography of silenced chromatin in Saccharomyces cerevisiae. AB - Heterochromatin imparts regional, promoter-independent repression of genes and is epigenetically heritable. Understanding how silencing achieves this regional repression is a fundamental problem in genetics and development. Current models of yeast silencing posit that Sir proteins, recruited by transcription factors bound to the silencers, spread throughout the silenced region. To test this model directly at high resolution, we probed the silenced chromatin architecture by chromatin immunoprecipitation (ChIP) followed by next-generation sequencing (ChIP seq) of Sir proteins, histones, and a key histone modification, H4K16-acetyl. These analyses revealed that Sir proteins are strikingly concentrated at and immediately adjacent to the silencers, with lower levels of enrichment over the promoters at HML and HMR, the critical targets for transcriptional repression. The telomeres also showed discrete peaks of Sir enrichment yet a continuous domain of hypoacetylated histone H4K16. Surprisingly, ChIP-seq of cross-linked chromatin revealed a distribution of nucleosomes at silenced loci that was similar to Sir proteins, whereas native nucleosome maps showed a regular distribution throughout silenced loci, indicating that cross-linking captured a specialized chromatin organization imposed by Sir proteins. This specialized chromatin architecture observed in yeast informs the importance of a steric contribution to regional repression in other organisms. PMID- 24493646 TI - Loss of Drosophila Ataxin-7, a SAGA subunit, reduces H2B ubiquitination and leads to neural and retinal degeneration. AB - The Spt-Ada-Gcn5-acetyltransferase (SAGA) chromatin-modifying complex possesses acetyltransferase and deubiquitinase activities. Within this modular complex, Ataxin-7 anchors the deubiquitinase activity to the larger complex. Here we identified and characterized Drosophila Ataxin-7 and found that reduction of Ataxin-7 protein results in loss of components from the SAGA complex. In contrast to yeast, where loss of Ataxin-7 inactivates the deubiquitinase and results in increased H2B ubiquitination, loss of Ataxin-7 results in decreased H2B ubiquitination and H3K9 acetylation without affecting other histone marks. Interestingly, the effect on ubiquitination was conserved in human cells, suggesting a novel mechanism regulating histone deubiquitination in higher organisms. Consistent with this mechanism in vivo, we found that a recombinant deubiquitinase module is active in the absence of Ataxin-7 in vitro. When we examined the consequences of reduced Ataxin-7 in vivo, we found that flies exhibited pronounced neural and retinal degeneration, impaired movement, and early lethality. PMID- 24493647 TI - Pharmacological rescue of Ras signaling, GluA1-dependent synaptic plasticity, and learning deficits in a fragile X model. AB - Fragile X syndrome, caused by the loss of Fmr1 gene function, is the most common form of inherited mental retardation, with no effective treatment. Using a tractable animal model, we investigated mechanisms of action of a few FDA approved psychoactive drugs that modestly benefit the cognitive performance in fragile X patients. Here we report that compounds activating serotonin (5HT) subtype 2B receptors (5HT2B-Rs) or dopamine (DA) subtype 1-like receptors (D1-Rs) and/or those inhibiting 5HT2A-Rs or D2-Rs moderately enhance Ras-PI3K/PKB signaling input, GluA1-dependent synaptic plasticity, and learning in Fmr1 knockout mice. Unexpectedly, combinations of these 5HT and DA compounds at low doses synergistically stimulate Ras-PI3K/PKB signal transduction and GluA1 dependent synaptic plasticity and remarkably restore normal learning in Fmr1 knockout mice without causing anxiety-related side effects. These findings suggest that properly dosed and combined FDA-approved psychoactive drugs may effectively treat the cognitive impairment associated with fragile X syndrome. PMID- 24493649 TI - Integrating molecular diagnostics into histopathology training: the Belfast model. AB - Molecular medicine is transforming modern clinical practice, from diagnostics to therapeutics. Discoveries in research are being incorporated into the clinical setting with increasing rapidity. This transformation is also deeply changing the way we practise pathology. The great advances in cell and molecular biology which have accelerated our understanding of the pathogenesis of solid tumours have been embraced with variable degrees of enthusiasm by diverse medical professional specialties. While histopathologists have not been prompt to adopt molecular diagnostics to date, the need to incorporate molecular pathology into the training of future histopathologists is imperative. Our goal is to create, within an existing 5-year histopathology training curriculum, the structure for formal substantial teaching of molecular diagnostics. This specialist training has two main goals: (1) to equip future practising histopathologists with basic knowledge of molecular diagnostics and (2) to create the option for those interested in a subspecialty experience in tissue molecular diagnostics to pursue this training. It is our belief that this training will help to maintain in future the role of the pathologist at the centre of patient care as the integrator of clinical, morphological and molecular information. PMID- 24493648 TI - Activation of MAPK overrides the termination of myelin growth and replaces Nrg1/ErbB3 signals during Schwann cell development and myelination. AB - Myelination depends on the synthesis of large amounts of myelin transcripts and proteins and is controlled by Nrg1/ErbB/Shp2 signaling. We developed a novel pulse labeling strategy based on stable isotope labeling with amino acids in cell culture (SILAC) to measure the dynamics of myelin protein production in mice. We found that protein synthesis is dampened in the maturing postnatal peripheral nervous system, and myelination then slows down. Remarkably, sustained activation of MAPK signaling by expression of the Mek1DD allele in mice overcomes the signals that end myelination, resulting in continuous myelin growth. MAPK activation leads to minor changes in transcript levels but massively up-regulates protein production. Pharmacological interference in vivo demonstrates that the effects of activated MAPK signaling on translation are mediated by mTOR independent mechanisms but in part also by mTOR-dependent mechanisms. Previous work demonstrated that loss of ErbB3/Shp2 signaling impairs Schwann cell development and disrupts the myelination program. We found that activated MAPK signaling strikingly compensates for the absence of ErbB3 or Shp2 during Schwann cell development and myelination. PMID- 24493650 TI - Lymph node revealing solutions in colorectal cancer: should they be used routinely? AB - The Royal College of Pathologists (RCPath) and College of American Pathologists recommend that at least 12 lymph nodes should be harvested for adequate staging of colorectal carcinoma. Just one nodal tumour deposit upstages the malignancy from pN0 to pN1. This is critically important as node-positive patients (pN1) are considered for adjuvant chemotherapy whereas node-negative patients (pN0) may not be. It is not always easy to harvest the required number, especially in patients with rectal carcinoma who may have received neoadjuvant therapy-an increasingly common treatment. The use of neoadjuvant therapy is known to further decrease the number and size of identifiable lymph nodes within specimens, meaning that the lymph node harvest often fails to reach RCPath guidelines. Lymph node revealing solutions consisting of either single chemicals such as alcohol or acetone or compounds have been investigated to help improve the lymph node harvest in difficult specimens, for example, those received following neoadjuvant therapy. Published research evidence reviewed here suggests that lymph node revealing solutions significantly improve lymph node harvesting, and that glacial acetic acid, ethanol, water and formalin is advantageous in comparison with other revealing solutions in that it is safe, cheap, easy to use and relatively quick. However, the quantity of good evidence is limited and the clinical implications of improving lymph node harvesting require further research. PMID- 24493651 TI - Psychological medicine and the future of psychiatry. AB - Psychological medicine (liaison psychiatry) aims to integrate psychiatry into other areas of medicine. It is currently enjoying considerable expansion. The degree to which it can take advantage of this opportunity will be important not only for its own future, but also for the survival of psychiatry as a medical discipline. PMID- 24493652 TI - Psychiatric diagnosis: impersonal, imperfect and important. AB - Psychiatric diagnosis is in the spotlight following the recent publication of DSM 5. In this article we consider both the benefits and limitations of diagnosis in psychiatry. The use of internationally recognised diagnoses, although insufficient alone, is part of a psychiatrist's professional responsibility to provide high-quality, evidence-based care for patients. PMID- 24493653 TI - Disorders of gender identity: what to do and who should do it? AB - Transsexualism is not usually indicative of psychopathology. In carefully selected individuals, with multidisciplinary support, a change of social gender role and cross-sex hormone treatment greatly improves the psychological and social state. Sustained improvement merits gender reassignment surgery. The key is early referral with subsequent primary care cooperation in the treatment plan. PMID- 24493654 TI - Interventions for reducing benzodiazepine use in older people: meta-analysis of randomised controlled trials. AB - BACKGROUND: The use of benzodiazepines has been advised against in older people, but prevalence rates remain high. AIMS: To review the evidence for interventions aimed at reducing benzodiazepine use in older people. METHOD: We conducted a systematic review, assessment of risk of bias and meta-analyses of randomised controlled trials of benzodiazepine withdrawal and prescribing interventions. RESULTS: Ten withdrawal and eight prescribing studies met the inclusion criteria. At post-intervention, significantly higher odds of not using benzodiazepines were found with supervised withdrawal with psychotherapy (odds ratio (OR) = 5.06, 95% CI 2.68-9.57, P<0.00001) and withdrawal with prescribing interventions (OR = 1.43, 95% CI 1.02-2.02, P = 0.04) in comparison with the control interventions treatment as usual (TAU), education placebo, withdrawal with or without drug placebo, or psychotherapy alone. Significantly higher odds of not using benzodiazepines were also found for multifaceted prescribing interventions (OR = 1.37, 95% CI 1.10-1.72, P = 0.006) in comparison with control interventions (TAU and prescribing placebo). CONCLUSIONS: Supervised benzodiazepine withdrawal augmented with psychotherapy should be considered in older people, although pragmatic reasons may necessitate consideration of other strategies such as medication review. PMID- 24493655 TI - Might hyperoxia during surgical anaesthesia contribute to older patients' higher dementia risk? PMID- 24493656 TI - Authors' reply. PMID- 24493657 TI - Physiotherapists can help implement physical activity programmes in clinical practice. PMID- 24493659 TI - A novel TctA citrate transporter from an activated sludge metagenome: structural and mechanistic predictions for the TTT family. AB - We isolated a putative citrate transporter of the tripartite tricarboxylate transporter (TTT) class from a metagenomic library of activated sludge from a sewage treatment plant. The transporter, dubbed TctA_ar, shares ~50% sequence identity with TctA of Comamonas testosteroni (TctA_ct) and other beta Proteobacteria, and contains two 20-amino acid repeat signature sequences, considered a hallmark of this particular transporter class. The structures for both TctA_ar and TctA_ct were modeled with I-TASSER and two possible structures for this transporter family were proposed. Docking assays with citrate resulted in the corresponding sets of proposed critical residues for function. These models suggest functions for the 20-amino acid repeats in the context of the two different architectures. This constitutes the first attempt at structure modeling of the TTT family, to the best of our knowledge, and could aid functional understanding of this little-studied family. PMID- 24493660 TI - Context-dependent resistance against butterfly herbivory in a polyploid herb. AB - Spatial variation in biotic interactions and natural selection are fundamental parts of natural systems, and can be driven by differences in both trait distributions and the local environmental context of the interaction. Most studies of plant-animal interactions have been performed only in natural settings, making it difficult to disentangle the effects of traits and context. To assess the relative importance of trait differences and environmental context for among-population variation in plant resistance to herbivory, we compared oviposition by the butterfly Anthocharis cardamines on two ploidy types of the herb Cardamine pratensis under experimentally controlled conditions with oviposition in natural populations. Under controlled conditions, plants from octoploid populations were significantly more preferred than plants from tetraploid populations. This difference was largely mediated by differences in flower size. Among natural populations, there was no difference in oviposition rates between the two ploidy types. Our results suggest that differences in oviposition rates among populations of the two cytotypes in the field are caused mainly by differences in environmental context, and that the higher attractiveness of octoploids to herbivores observed under common environmental conditions is balanced by the fact that they occur in habitats which harbor lower densities of butterflies. This illustrates that spatial variation in biotic interactions is the net result of differences in trait distributions of the interacting organisms and differences in environmental context, and that variation in both traits and context are important in understanding species interactions. PMID- 24493662 TI - Characteristic alatoid 'cineole cassette' monoterpene synthase present in Nicotiana noctiflora. AB - Nicotiana species of the section Alatae emit a characteristic floral scent comprising the' cineole cassette' monoterpenes 1,8-cineole, limonene, myrcene, beta-pinene, alpha-pinene, sabinene and alpha-terpineol. All previously isolated 'cineole cassette'-monoterpene synthase genes are multi product enzymes that synthesize the seven compounds of the 'cineole cassette'. Interestingly, so far this 'alatoid' trait was only shared with the eponymous species Nicotiana suaveolens of the sister section Suaveolentes. To determine the origin of the 'cineole cassette' monoterpene phenotype other potential parent species of section Noctiflorae or Petunoides as well as of the distantly related section Trigonophyllae were analysed. A monoterpene synthase producing the set of 'cineole cassette' compounds was isolated from N. noctiflorae. N. obtusifolia emitted solely 1,8-cineole and no monoterpenes were found in floral scents of N. petunoides and N. palmeri. Interestingly, the phylogenetic analysis clustered the new gene of N. noctiflora closely to the terpineol synthase genes of e.g. N. alata rather than to cineole synthase genes of e.g. N. forgetiana. PMID- 24493663 TI - Mental health effects of intimate terrorism and situational couple violence among Black and Hispanic women. AB - An important aspect of Johnson's intimate terrorism (IT) and situational couple violence (SCV) typology is his assertion that victims experience different negative outcomes depending on which category of violence they endure. Anderson calls for reexamining this typology to highlight the importance of coercive control with or without physical violence present. Similar to most studies, Anderson's research uses a sample that includes mostly White women. The current study employs Anderson's methods and ordinary least squares (OLS) regression analyses, but uses a sample of predominantly Black women and Latinas from the 1998 Chicago Women's Health Risk Study. PMID- 24493661 TI - Critical review of outcome research on interpersonal psychotherapy for anxiety disorders. AB - BACKGROUND: Interpersonal psychotherapy (IPT) has demonstrated efficacy in treating mood and eating disorders. This article critically reviews outcome research testing IPT for anxiety disorders, a diagnostic area where cognitive behavioral therapy (CBT) has dominated research and treatment. METHODS: A literature search identified six open and five controlled trials of IPT for social anxiety disorder (SAD), panic disorder, and posttraumatic stress disorder. RESULTS: Studies were generally small, underpowered, and sometimes methodologically compromised. Nonetheless, minimally adapted from its standard depression strategies, IPT for anxiety disorders yielded positive results in open trials for the three diagnoses. In controlled trials, IPT fared better than waiting list (N = 2), was equipotent to supportive psychodynamic psychotherapy (N = 1), but less efficacious than CBT for SAD (N = 1), and CBT for panic disorder (N = 1) in a methodologically complicated study. IPT equaled CBT in a group residential format (N = 1). CONCLUSIONS: IPT shows some promise for anxiety disorders but has thus far shown no advantages in controlled trials relative to other therapies. Methodological and ecological issues have complicated testing of IPT for anxiety disorders, clouding some findings. The authors discuss difficulties of conducting non-CBT research in a CBT-dominated area, investigator bias, and the probable need to further modify IPT for anxiety disorders. Untested therapies deserve the fairest possible testing. PMID- 24493664 TI - Experiences of Muslim and non-Muslim battered immigrant women with the police in the United States: a closer understanding of commonalities and differences. AB - Little research has been conducted to distinguish the unique experiences of specific groups of interpersonal violence victims. This is especially true in the case of battered Muslim immigrant women in the United States. This article examines battered Muslim immigrant women's experiences with intimate partner violence and their experiences with the police. Furthermore, to provide a more refined view related to battered Muslim immigrant women's situation, the article compares the latter group's experiences to battered non-Muslim immigrant women's experiences. Finally, we seek to clarify the similarities and differences between battered immigrant women aiming to inform responsive police service delivery. PMID- 24493665 TI - Mechanisms of phenytoin-induced toxicity in freshly isolated rat hepatocytes and the protective effects of taurine and/or melatonin. AB - Phenytoin is a widely used antiepileptic drug. However, hepatotoxicity is one of its adverse effects reported in some patients. The mechanism(s) by which phenytoin causes hepatotoxicity is not clear yet. This study was designed to evaluate the cytotoxic mechanism(s) of phenytoin toward rat hepatocytes (whose cytochrome P450 enzymes had been induced by Phenobarbital). Furthermore, the effect of taurine and/or melatonin on this toxicity was investigated. Cell death, reactive oxygen species (ROS) formation, lipid peroxidation (LPO), and mitochondrial depolarization were monitored as toxicity markers. Results showed that phenytoin caused an elevation in ROS formation, depletion of intracellular reduced glutathione, increase in cellular oxidized glutathione, enhancement of LPO, and mitochondrial damage. Taurine (1 mM) and/or melatonin (1 mM) administration decreased the intensity of cellular injury caused by phenytoin. This study suggests the protective role of taurine and/or melatonin against phenytoin-induced cellular damage probably through their reactive radical scavenging properties and their effects on mitochondria. PMID- 24493666 TI - At return to play following hamstring injury the majority of professional football players have residual isokinetic deficits. AB - BACKGROUND: There is an ongoing debate regarding the optimal criteria for return to sport after an acute hamstring injury. Less than 10% isokinetic strength deficit is generally recommended but this has never been documented in professional football players after rehabilitation. Our aim was to evaluate isokinetic measurements in MRI-positive hamstring injuries. METHODS: Isokinetic measurements of professional football players were obtained after completing a standardised rehabilitation programme. An isokinetic strength deficit of more than 10% compared with the contralateral site was considered abnormal. Reinjuries within 2 months were recorded. RESULTS: 52 players had a complete set of isokinetic testing before clinical discharge. There were 27 (52%) grade 1 and 25 (48%) grade 2 injuries. 35 of 52 players (67%) had at least one of the three hamstring-related isokinetic parameters that display a deficit of more than 10%. The percentage of players with 10% deficit for hamstring concentric 60 degrees /s, 300 degrees /s and hamstring eccentric was respectively 39%, 29% and 28%. There was no significant difference of mean isokinetic peak torques and 10% isokinetic deficits in players without reinjury (N=46) compared with players with reinjury (N=6). CONCLUSIONS: When compared with the uninjured leg, 67% of the clinically recovered hamstring injuries showed at least one hamstring isokinetic testing deficit of more than 10%. Normalisation of isokinetic strength seems not to be a necessary result of the successful completion of a football-specific rehabilitation programme. The possible association between isokinetic strength deficit and increased reinjury risk remains unknown. PMID- 24493667 TI - A catalyst for change: the European cancer Patient's Bill of Rights. PMID- 24493669 TI - Loss of imprinting at the 14q32 domain is associated with microRNA overexpression in acute promyelocytic leukemia. AB - Distinct patterns of DNA methylation characterize the epigenetic landscape of promyelocytic leukemia/retinoic acid receptor-alpha (PML-RARalpha)-associated acute promyelocytic leukemia (APL). We previously reported that the microRNAs (miRNAs) clustered on chromosome 14q32 are overexpressed only in APL. Here, using high-throughput bisulfite sequencing, we identified an APL-associated hypermethylation at the upstream differentially methylated region (DMR), which also included the site motifs for the enhancer blocking protein CCCTC-binding factor (CTCF). Comparing the profiles of diagnostic/remission paired patient samples, we show that hypermethylation was acquired in APL in a monoallelic manner. The cytosine guanine dinucleotide status of the DMR correlated with expression of the miRNAs following a characteristic position-dependent pattern. Moreover, a signature of hypermethylation was also detected in leukemic cells from an established transgenic PML-RARA APL mouse model at the orthologous region on chromosome 12, including the CTCF binding site located upstream from the mouse miRNA cluster. These results, together with the demonstration that the region does not show DNA methylation changes during myeloid differentiation, provide evidence that 14q32 hypermethylation is implicated in the pathogenesis of APL. We propose a model in which loss of imprinting at the 14q32 domain leads to overexpression of the miRNAs in APL. PMID- 24493668 TI - STIM1 calcium sensor is required for activation of the phagocyte oxidase during inflammation and host defense. AB - The stromal-interacting molecule 1 (STIM1) is a potent sensor of intracellular calcium, which in turn regulates entry of external calcium through plasma membrane channels to affect immune cell activation. Although the contribution of STIM1 to calcium signaling in lymphocytes has been well studied, the role of this protein in neutrophil-mediated inflammation and host defense is unknown. We report that STIM1-deficient murine neutrophils show loss of store-operated calcium entry (SOCE) in response to both soluble ligands that activate G-proteins as well as Fcgamma-receptor or integrin ligation that activates tyrosine kinase signaling. This results in modest defects in phagocytosis and degranulation responses but a profound block in superoxide production by the phagocyte oxidase. We trace the primary intracellular target of calcium to be protein kinase C isoforms alpha and beta (PKCalpha and PKCbeta), which in turn phosphorylate subunits of the oxidase leading to superoxide production. In vivo the loss of SOCE in stim1(-/-) chimeric mice results in marked susceptibility to bacterial infections but also protection from tissue injury in hepatic ischemia/reperfusion injury. These results demonstrate the critical role of STIM1-mediated SOCE and define major protein targets of calcium signaling in neutrophil activation during inflammatory disease. PMID- 24493670 TI - Tracing the development of acute myeloid leukemia in CBL syndrome. AB - We describe the development of acute myeloid leukemia (AML) in an adult with CBL syndrome caused by a heterozygous de novo germline mutation in CBL codon D390. In the AML bone marrow, the mutated CBL allele was homozygous after copy number neutral loss-of-heterozygosity and amplified through a chromosomal gain; moreover, an inv(16)(p13q22) and, as assessed by whole-exome sequencing, 12 gene mutations (eg, in CAND1, NID2, PTPRT, DOCK6) were additionally acquired. During complete remission of the AML, in the presence of normal blood counts, the hematopoiesis stably maintained the homozygous CBL mutation, which is reminiscent of the situation in children with CBL syndrome and transient juvenile myelomonocytic leukemia. No additional mutations were identified by whole-exome sequencing in granulocytes during complete remission. The study highlights the development of AML in an adult with CBL syndrome and, more generally, in genetically aberrant but clinically inconspicuous hematopoiesis. PMID- 24493671 TI - A man with acute venous thromboembolism and thrombocytopenia. Heparin induced thrombocytopenia. PMID- 24493672 TI - Integrated school-based surveillance for soil-transmitted helminth infections and lymphatic filariasis in Gampaha district, Sri Lanka. AB - We explored the practicality of integrating surveillance for soil-transmitted helminthiasis (STH, assessed by Kato-Katz) with transmission assessment surveys for lymphatic filariasis (LF) in two evaluation units (EUs) in Gampaha district, Sri Lanka (population 2.3 million). The surveys were performed 6 years after five annual rounds of mass drug administration with diethylcarbamazine and albendazole. Each transmission assessment survey tested children (N = 1,462 inland EU; 1,642 coastal EU) sampled from 30 primary schools. Low filarial antigenemia rates (0% and 0.1% for the inland and coastal EUs) suggest that LF transmission is very low in this district. The STH rates and stool sample participation rates were 0.8% and 61% (inland) and 2.8% and 58% (coastal). Most STH detected were low or moderate intensity Trichuris trichiura infections. The added cost of including STH testing was ~$5,000 per EU. These results suggest that it is feasible to integrate school-based surveillance for STH and LF. PMID- 24493673 TI - Nasal carriage of multi-drug resistant Panton-Valentine leucocidin-positive methicillin-resistant Staphylococcus aureus in children in Tripoli-Libya. AB - Methicillin-resistant Staphylococcus aureus (MRSA) colonized children are at an increased risk of developing infections than methicillin-sensitive S. aureus colonized children. Nasal specimens from inpatient children, mothers of inpatient children, healthcare workers, and outpatient children at Tripoli Children Hospital (TCH) were examined for MRSA by chromogenic MRSA ID medium. Susceptibility of MRSA isolates to antibiotics was determined by the disc diffusion method. The nasal carriage rate of MRSA among inpatient children (8.3%, 24 of 289), their mothers (11%, 22 of 200), and healthcare workers (12.4%, 22 of 178) was significantly higher than among outpatient children (2.2%, 2 of 91) (P < 0.05, P < 0.02, and P < 0.006, respectively). Of the examined MRSA isolates (N = 35) 10 (28.6%) were positive for Panton-Valentine leucocidin genes by polymerase chain reaction. Multidrug resistance was found in 24.3% (17 of 70) of MRSA isolates. Nasal carriage of multidrug-resistant Panton-Valentine leucocidin positive MRSA is not uncommon among inpatient children and their mothers in Tripoli. PMID- 24493674 TI - Kinetics of chikungunya infections during an outbreak in Southern Thailand, 2008 2009. AB - The Indian Ocean chikungunya epidemic re-emerged in Thailand in August 2008. Forty-five adults with laboratory-confirmed chikungunya in Songkhla province, Thailand were clinically assessed and serially bled throughout the acute and convalescent phase of the disease. Patient symptoms, antibody responses, and viral kinetics were evaluated using observational assessments, polymerase chain reaction (PCR), and serological assays. All subjects experienced joint pain with 42 (93%) involving multiple joints; the interphalangeal most commonly affected in 91% of the subjects. The mean duration of joint pain was 5.8 days, 11 (25%) experiencing discomfort through the duration of the study. Rash was observed in 37 (82%) subjects a mean 3.5 days post onset of symptoms. Patents were positive by PCR for a mean of 5.9 days with sustained peak viral load through Day 5. The IgM antibodies appeared on Day 4 and peaked at Day 7 and IgG antibodies first appeared at Day 5 and rose steadily through Day 24. PMID- 24493675 TI - Oxidative stress markers correlate with renal dysfunction and thrombocytopenia in severe leptospirosis. AB - Leptospirosis is a zoonotic disease that causes severe manifestations such as Weil's disease and pulmonary hemorrhage syndrome. The aim of this study was to evaluate whether reactive oxygen species (ROS) production and antioxidant reduced glutathione (GSH) levels are related to complications in patients hospitalized with leptospirosis. The ROS production and GSH levels were measured in blood samples of 12 patients and nine healthy controls using chemiluminescence and absorbance assays. We found that ROS production was higher and GSH levels were lower in leptospirosis patients compared with healthy individuals. Among patients, GSH depletion was correlated with thrombocytopenia and elevated serum creatinine, whereas a strong positive correlation was observed between ROS production and elevated serum potassium. Additional investigation of the biological significance of ROS production and GSH levels is warranted as they may guide the development of novel adjuvant therapies for leptospirosis targeting oxidative stress. PMID- 24493676 TI - Autochthonous blastomycosis of the adrenal: first case report from Asia. AB - Systemic endemic mycoses, such as blastomycosis, are rare in Asia and have been reported as health risks among travelers who visit or reside in an endemic area. Adrenal involvement is rarely seen in blastomycosis and has never been reported from Asia. We report the first case of blastomycosis with bilateral involvement of the adrenals in a diabetic patient residing in the state of Arunachal Pradesh, India. PMID- 24493679 TI - High-frequency oscillatory ventilation: the devil may be in the details. PMID- 24493677 TI - Application of RLEP real-time PCR for detection of M. leprae DNA in paraffin embedded skin biopsy specimens for diagnosis of paucibacillary leprosy. AB - The TaqMan real-time polymerase chain reaction (PCR) assay was evaluated systematically with respect to the standard curve, linear range, and used for detecting Mycobacterium leprae DNA in paraffin-embedded skin biopsy specimens from 60 confirmed leprosy patients and three healthy individuals and 29 other dermatoses and bacterial DNA from 21 different species. The test was further evaluated with 51 paucibacillary (PB) patients. The results showed that the test had good sensitivity (8 fg) and good specificity with no cross-reactivity with 21 other bacterial species and the control specimens, except one with Xanthomatosis. The real-time PCR detection rate for the 51 PB specimens was 74.5% (38 of 51). We conclude that the real-time PCR test is a useful adjunct test for diagnosing early stage or PB leprosy cases. PMID- 24493680 TI - Helping to clarify mechanical ventilation protocols. PMID- 24493681 TI - Extubation failure after successful spontaneous breathing trial: prediction is still a challenge! PMID- 24493682 TI - Tailoring noninvasive ventilation management in non-ICU settings and the cardiac surgery context. PMID- 24493683 TI - Pulmonary function and flow-volume loop patterns in patients with tracheobronchomalacia: is there an independent effect? PMID- 24493684 TI - Pulmonary function and flow-volume loop patterns in patients with tracheobronchomalacia: is there an independent effect? Reply. PMID- 24493685 TI - Sustainable health services are crucial to reducing NHS's carbon footprint, conference hears. PMID- 24493686 TI - Type 2 diabetes management in Hong Kong ethnic minorities: what primary care physicians need to know. AB - OBJECTIVES: To identify the demographics and compare diabetes control in ethnic minority group diabetes patients with Chinese diabetes patients who are managed in primary care settings and to explore strategies to improve their care. DESIGN: Retrospective case series. SETTING: General Outpatient Clinic of a Hong Kong Hospital Authority hospital. PATIENTS: Chinese type 2 diabetes patients and ethnic minority groups who had been regularly followed up with annual assessments carried out between 1 March 2012 to 28 February 2013 were recruited. Their serum levels of fasting glucose, creatinine, estimated glomerular filtration rate, haemoglobin A1c levels, lipid profile, blood pressure, and co-morbidities were retrieved from the Clinical Management System. Student's t test and analysis of variance were used to evaluate continuous variables and the Chi squared test for categorical data. All statistical tests were two-sided, and a P value of <0.05 was considered significant. RESULTS: Among 4346 type 2 diabetes patients fulfilling the inclusion criteria, 3966 (91.3%) patients were Chinese and 380 (8.7%) were from the ethnic minority groups. Compared with Chinese diabetes patients, the latter were much younger and more obese (both P<0.001). Their glycaemic control was poorer than age- and sex-matched Chinese diabetes patients (P=0.006). Control of systolic blood pressure was similar in the two groups, but the mean diastolic blood pressure was higher in the ethnic minority groups than in the controls (78 +/- 11 mm Hg vs 73 +/- 11 mm Hg; P<0.001). With regard to lipid control, their total cholesterol, low-density lipoprotein, and triglyceride levels were similar, but high-density lipoprotein levels were much lower in the ethnic minority groups than their Chinese counterparts (1.19 +/- 0.33 mmol/L vs 1.28 +/- 0.36 mmol/L; P=0.001). Among the five major ethnic minority groups with diabetes, Pakistani patients had particularly poor glycaemic control and the Nepalese had the poorest diastolic blood pressure control. CONCLUSIONS: Ethnic minority groups are an integral part of the Hong Kong population. Compared with Chinese diabetes patients, those from the ethnic minorities were much younger and more obese. Deficiencies exist in the comprehensive management of diabetes in these ethnic minorities, particularly with respect to glycaemic control. Culturally tailored health care interventions are therefore warranted to promote patient education and clinical effectiveness and to improve their long-term health status. PMID- 24493687 TI - Ibuprofen versus indomethacin treatment of patent ductus arteriosus: comparative effectiveness and complications. AB - OBJECTIVES: To compare the effectiveness and complications of intravenous ibuprofen versus indomethacin treatment of patent ductus arteriosus in preterm infants. DESIGN: Retrospective case series. SETTING: A tertiary referral centre in Hong Kong. PATIENTS: A total of 95 infants who had received at least one course of indomethacin or ibuprofen for closure of patent ductus arteriosus from January 2008 to December 2011 were studied. MAIN OUTCOME MEASURES: Following the total switch from indomethacin to ibuprofen in clinical use in April 2010, outcomes of infants receiving indomethacin and ibuprofen were compared. The primary outcomes including rates of failed medical closure and recourse to surgical ligation were compared. The secondary outcomes including rates of all cause mortality, bronchopulmonary dysplasia, intestinal complications (necrotising enterocolitis, spontaneous intestinal perforation), change in urine output and serum creatinine, and progression of any intraventricular haemorrhage were also evaluated. RESULTS: The failure rate of medical treatment was similar in the indomethacin and ibuprofen groups, with 16 (31%) such infants in the indomethacin group and 14 (33%) in the ibuprofen group; for ibuprofen this yielded a relative risk of 1.06 (95% confidence interval, 0.66-1.67; P=0.852). The proportion of infants having surgical ligation was also similar. A higher rate of intestinal complications (necrotising enterocolitis or spontaneous intestinal perforation) was encountered in our ibuprofen group (P=0.043). No significant difference was observed in other secondary outcomes determined. CONCLUSION: In our clinical practice, ibuprofen and indomethacin were shown to be equally effective for medical closure of patent ductus arteriosus in premature infants. With the higher rates of intestinal complications and similar effects on renal function in the ibuprofen group, we conclude that ibuprofen may not have fewer adverse effects than indomethacin. PMID- 24493688 TI - [Radiation hygiene in interventional radiology suite]. AB - Exposure of both patients and medical staff to relatively high doses of radiation is one of the features characteristic of interventional radiology (IR). Regulations regarding this kind of therapeutic management can be found in many legal references and recommendations of European Union Law. The purpose of the paper is collection and systematic analysis of activities and procedures associated with the question of radiation hygiene which should be observed in IR suites. Requirements regarding equipment of the IR suite, as well as radiation protection of patients and medical staff, constitute main questions included in the paper, worked out on the basis of valid regulations and occupational experience of the authors. Particular attention is paid to borderline requirements regarding modern IR suite equipment and its organization. Part of the paper is devoted to the understanding of physical laws of ionizing radiation in biological space and its surroundings. Understanding of physical laws, proper utilization of IR suite equipment, and strict compliance with recommendations of radiation protection by both patients and medical staff are critical for limitation of the harmful influence of radiation during interventional therapeutic procedures. An additional role of the paper is to make it easier to take decisions when creating new IR suites, in accordance with valid regulations and the rule of functionality. PMID- 24493689 TI - [Systemic and local mechanisms leading to cachexia in cancer]. AB - Cachexia is a multifactorial syndrome of atrophy of skeletal muscle and adipose tissue, resulting in progressive loss of body weight associated with low quality of life and poor prognosis in cancer. Studies on experimental animal models and observations on patients have shown that the soluble factors secreted by tumor cells and tissues of the patient can participate in regulation of the wasting process. Cachexia is often accompanied by anorexia, which is caused by predominance of signals inhibiting appetite in the hypothalamus, such as release of proopiomelanocortin and anorexigenic action of proinflammatory cytokines (IL 1alpha, IL-1beta, IL-6, TNF-alpha). Cachexia is also accompanied by extensive metabolic changes consisting of increase of resting energy expenditure and disturbance of carbohydrate, protein and lipid metabolism. Increased expression of protein uncoupling phosphorylation leads to increased thermogenesis in skeletal muscle. Tumor tissue hypoxia caused by its growth beyond blood vessels activates the transcription factor HIF-1, which results in increase in glycolysis, and leads to lactic acid accumulation and activation of the energy inefficient Cori cycle. Loss of fat tissue is caused by increase of lipolysis induced by lipid-mobilizing factor (LMF) and proinflammatory cytokines. Skeletal muscle wasting in cachexia is caused by a reduction of protein synthesis at the stage of initiation and elongation of translation and the simultaneous increase of protein degradation via ubiquitin-dependent and lysosomal pathways. The main mediators of skeletal muscle wasting in cancer are proteolysis-inducing factor (PIF), proinflammatory cytokines, and angiotensin II acting through increased levels of reactive oxygen species (ROS) and nuclear factor NF-kappaB activation, as well as glucocorticoid activated FOXO transcription factors and myostatin. Understanding of the complexity of the interaction of factors produced by the tumor and the patient's body may form the basis for the development of effective treatments for cachexia in cancer and other pathological conditions. PMID- 24493690 TI - We are all businesspeople now. PMID- 24493696 TI - Fatostatin displays high antitumor activity in prostate cancer by blocking SREBP regulated metabolic pathways and androgen receptor signaling. AB - Current research links aberrant lipogenesis and cholesterogenesis with prostate cancer development and progression. Sterol regulatory element-binding proteins (SREBP; SREBP-1 and SREBP-2) are key transcription factors controlling lipogenesis and cholesterogenesis via the regulation of genes related to fatty acid and cholesterol biosynthesis. Overexpression of SREBPs has been reported to be significantly associated with aggressive pathologic features in human prostate cancer. Our previous results showed that SREBP-1 promoted prostate cancer growth and castration resistance through induction of lipogenesis and androgen receptor (AR) activity. In the present study, we evaluated the anti-prostate tumor activity of a novel SREBP inhibitor, fatostatin. We found that fatostatin suppressed cell proliferation and anchorage-independent colony formation in both androgen-responsive LNCaP and androgen-insensitive C4-2B prostate cancer cells. Fatostatin also reduced in vitro invasion and migration in both the cell lines. Further, fatostatin caused G2-M cell-cycle arrest and induced apoptosis by increasing caspase-3/7 activity and the cleavages of caspase-3 and PARP. The in vivo animal results demonstrated that fatostatin significantly inhibited subcutaneous C4-2B tumor growth and markedly decreased serum prostate-specific antigen (PSA) level compared with the control group. The in vitro and in vivo effects of fatostatin treatment were due to blockade of SREBP-regulated metabolic pathways and the AR signaling network. Our findings identify SREBP inhibition as a potential new therapeutic approach for the treatment of prostate cancer. PMID- 24493697 TI - Gramicidin A blocks tumor growth and angiogenesis through inhibition of hypoxia inducible factor in renal cell carcinoma. AB - Ionophores are hydrophobic organic molecules that disrupt cellular transmembrane potential by permeabilizing membranes to specific ions. Gramicidin A is a channel forming ionophore that forms a hydrophilic membrane pore that permits the rapid passage of monovalent cations. Previously, we found that gramicidin A induces cellular energy stress and cell death in renal cell carcinoma (RCC) cell lines. RCC is a therapy-resistant cancer that is characterized by constitutive activation of the transcription factor hypoxia-inducible factor (HIF). Here, we demonstrate that gramicidin A inhibits HIF in RCC cells. We found that gramicidin A destabilized HIF-1alpha and HIF-2alpha proteins in both normoxic and hypoxic conditions, which in turn diminished HIF transcriptional activity and the expression of various hypoxia-response genes. Mechanistic examination revealed that gramicidin A accelerates O(2)-dependent downregulation of HIF by upregulating the expression of the von Hippel-Lindau (VHL) tumor suppressor protein, which targets hydroxylated HIF for proteasomal degradation. Furthermore, gramicidin A reduced the growth of human RCC xenograft tumors without causing significant toxicity in mice. Gramicidin A-treated tumors also displayed physiologic and molecular features consistent with the inhibition of HIF dependent angiogenesis. Taken together, these results demonstrate a new role for gramicidin A as a potent inhibitor of HIF that reduces tumor growth and angiogenesis in VHL-expressing RCC. PMID- 24493698 TI - Novel target for peptide-based imaging and treatment of brain tumors. AB - Malignant gliomas are associated with high mortality due to infiltrative growth, recurrence, and malignant progression. Even with the most efficient therapy combinations, median survival of the glioblastoma multiforme (grade 4) patients is less than 15 months. Therefore, new treatment approaches are urgently needed. We describe here identification of a novel homing peptide that recognizes tumor vessels and invasive tumor satellites in glioblastomas. We demonstrate successful brain tumor imaging using radiolabeled peptide in whole-body SPECT/CT imaging. Peptide-targeted delivery of chemotherapeutics prolonged the lifespan of mice bearing invasive brain tumors and significantly reduced the number of tumor satellites compared with the free drug. Moreover, we identified mammary-derived growth inhibitor (MDGI/H-FABP/FABP3) as the interacting partner for our peptide on brain tumor tissue. MDGI was expressed in human brain tumor specimens in a grade-dependent manner and its expression positively correlated with the histologic grade of the tumor, suggesting MDGI as a novel marker for malignant gliomas. PMID- 24493700 TI - Does the patient know best? Quality of life assessment in multiple sclerosis trials. PMID- 24493699 TI - Suppression of spontaneous ca elevations prevents atrial fibrillation in calsequestrin 2-null hearts. AB - BACKGROUND: Atrial fibrillation (AF) risk has been associated with leaky ryanodine receptor 2 (RyR2) Ca release channels. Patients with mutations in RyR2 or in the sarcoplasmic reticulum Ca-binding protein calsequestrin 2 (Casq2) display an increased risk for AF. Here, we examine the underlying mechanisms of AF associated with loss of Casq2 and test mechanism-based drug therapy. METHODS AND RESULTS: Compared with wild-type Casq2+/+ mice, atrial burst pacing consistently induced atrial flutter or AF in Casq2-/- mice and in isolated Casq2 /- hearts. Atrial optical voltage maps obtained from isolated hearts revealed multiple independent activation sites arising predominantly from the pulmonary vein region. Ca and voltage mapping demonstrated diastolic subthreshold spontaneous Ca elevations (SCaEs) and delayed afterdepolarizations whenever the pacing train failed to induce AF. The dual RyR2 and Na channel inhibitor R propafenone (3 MUmol/L) significantly reduced frequency and amplitude of SCaEs and delayed afterdepolarizations in atrial myocytes and intact atria and prevented induction of AF. In contrast, the S-enantiomer of propafenone, an equipotent Na channel blocker but much weaker RyR2 inhibitor, did not reduce SCaEs and delayed afterdepolarizations and failed to prevent AF. CONCLUSIONS: Loss of Casq2 increases risk of AF by promoting regional SCaEs and delayed afterdepolarizations in atrial tissue, which can be prevented by RyR2 inhibition with R-propafenone. Targeting AF caused by leaky RyR2 Ca channels with R propafenone may be a more mechanism-based approach to treating this common arrhythmia. PMID- 24493701 TI - The potential role of epigenetic modifications in the heritability of multiple sclerosis. AB - It is now well established that both genetic and environmental factors contribute to and interact in the development of multiple sclerosis (MS). However, the currently described causal genetic variants do not explain the majority of the heritability of MS, resulting in 'missing heritability'. Epigenetic mechanisms, which principally include DNA methylation, histone modifications and microRNA mediated post-transcriptional gene silencing, may contribute a significant component of this missing heritability. As the development of MS is a dynamic process potentially starting with inflammation, then demyelination, remyelination and neurodegeneration, we have reviewed the dynamic epigenetic changes in these aspects of MS pathogenesis and describe how environmental risk factors may interact with epigenetic changes to manifest in disease. PMID- 24493702 TI - Progressive resistance therapy is not the best way to rehabilitate deficits due to multiple sclerosis: no. PMID- 24493703 TI - Progressive resistance therapy is not the best way to rehabilitate deficits due to multiple sclerosis: yes. PMID- 24493704 TI - Progressive resistance therapy is not the best way to rehabilitate deficits due to multiple sclerosis: commentary. PMID- 24493705 TI - Overseas visitors and free NHS care. PMID- 24493706 TI - Aspirin use in heart failure: is low-dose therapy associated with mortality and morbidity benefits in a large community population? AB - Background- Aspirin use in heart failure (HF) is controversial. The drug has proven benefit in comorbidities associated with HF; however, retrospective analysis of angiotensin-converting enzyme inhibitor trials and prospective comparisons with warfarin have shown increased risk of morbidity with aspirin use. This study aims to evaluate the association of low-dose aspirin with mortality and morbidity risk in a large community-based cohort. Methods and Results- This was a retrospective cohort study of patients attending an HF disease management program. Aspirin use at baseline and its association with mortality and HF hospitalization in the population was examined. Of 1476 patients (mean age, 70.4+/-12.4 years; 63% men), 892 (60.4%) were prescribed aspirin. Low dose aspirin (75 mg/d) was prescribed to 828 (92.8%) patients. Median follow-up time was 2.6 (0.8-4.5) years. During the follow-up period, 464 (31.4%) patients died. In adjusted analysis, low-dose aspirin use was associated with reduced mortality risk compared with nonaspirin use (hazard ratio=0.58; 95% confidence interval, 0.46-0.74), and this was confirmed by a propensity-matched subgroup analysis. Low-dose aspirin use was associated with reduced risk of HF hospitalization compared with nonaspirin use in the total population (adjusted hazard ratio=0.70; 95% confidence interval, 0.54-0.90). In adjusted analysis, there was no difference in mortality or HF hospitalization between high-dose aspirin users (>75 mg/d) and nonaspirin users. Conclusions- In this study, low dose aspirin therapy was associated with a significant reduction in mortality and morbidity risk during long-term follow-up. These results suggest that low-dose aspirin may have a continuing role in secondary prevention in HF and underline the need for more trials of low-dose aspirin use in HF. PMID- 24493708 TI - Large cohort study is launched to find causes of stroke and dementia in India. PMID- 24493709 TI - Informed consent, vulnerability and the risks of group-specific attribution. AB - People in extraordinary situations are vulnerable. As research participants, they are additionally threatened by abuse or exploitation and the possibility of harm through research. To protect people against these threats, informed consent as an instrument of self-determination has been introduced. Self-determination requires autonomous persons, who voluntarily make decisions based on their values and morals. However, in nursing research, this requirement cannot always be met. Advanced age, chronic illness, co-morbidity and frailty are reasons for dependencies. These in turn lead to limited abilities or opportunities for decision-making and self-determination. Exclusion of vulnerable people from research projects would disadvantage them by not covering their needs, which would violate the ethical principles of justice and beneficence. Commonly, vulnerability is attributed to social groups. The consequence for individuals, attributed as belonging to such a vulnerable group, is that the principles of respect for autonomy, justice and beneficence are subordinated to the principle of non-maleficence, understood as avoiding the risk to cause more harm than good. In addition, group-specific attribution could lead to stigmatizing because labelling a person as deviation from a norm violates integrity. For clinical nursing research, the question arises how the protection of vulnerable people could be granted without compromising ethical principles. The concept of relational ethics provides a possible approach. It defines vulnerability as the relation between a person's health status and the extent to which this person is dependent on the researcher and the research context. Vulnerability is not attributed solely to a person but to a situation, meaning the person is viewed in context. By combining vulnerability as a context-related and situational concept with existing approaches of informed consent, the different ethical principles can be balanced and preserved at every step of the research process. PMID- 24493710 TI - Ethical considerations of doll therapy for people with dementia. AB - The use of doll therapy for people with dementia has been emerging in recent years. Providing a doll to someone with dementia has been associated with a number of benefits which include a reduction in episodes of distress, an increase in general well-being, improved dietary intake and higher levels of engagement with others. It could be argued that doll therapy fulfils the concepts of beneficence (facilitates the promotion of well-being) and respect for autonomy (the person with dementia can exercise their right to engage with dolls if they wish). However, some may believe that doll therapy is inappropriate when applied to the concepts of dignity (people with dementia are encouraged to interact with dolls) and non-maleficence (potential distress this therapy could cause for family members). The absence of rigorous empirical evidence and legislative guidelines render this a therapy that must be approached cautiously owing to the varied subjective interpretations of Kitwood's 'malignant social psychology' and bioethics. This article suggests that by applying a 'rights-based approach', healthcare professionals might be better empowered to resolve any ethical tensions they may have when using doll therapy for people with dementia. In this perspective, the internationally agreed upon principles of the United Nations Convention on the Rights of Persons with Disabilities provide a legal framework that considers the person with dementia as a 'rights holder' and places them at the centre of any ethical dilemma. In addition, those with responsibility towards caring for people with dementia have their capacity built to respect, protect and fulfil dementia patient's rights and needs. PMID- 24493711 TI - Nurses' perceptions of the use of restraint in pediatric somatic care. AB - BACKGROUND: The interest in the children's role in pediatric care is connected to children's health-related autonomy and informed consent in care. Despite the strong history of children's rights, nurses' role in the everyday nursing phenomenon, that is, restraint in somatic pediatric care, is still relatively seldom reported. AIM: The aim of this study is to describe nurses' perceptions of the use of restraint in somatic pediatric care. The ultimate aim is to deepen the understanding of the phenomenon of restraint, whose previous study has been fragmented. METHODS: Qualitative approach was selected because of the lack of previous information. Due to the sensitivity of the research question, individual interviewees were selected among voluntary nurses (n = 8). All participants were registered nurses with general work experience as nurses of 5-16 years on average and specifically 1.5-10 years in pediatric nursing. Inductive content analysis was used for aiming to produce a synthesis of the research phenomenon. ETHICAL CONSIDERATIONS: The research received organizational approval by the university hospital, and informed consent and confidentiality were ensured. RESULTS: Restraint in pediatric nursing was process-like, but occurred without advanced planning. The restraint-related process included five categories: (a) identification of the situations where restraint may occur, (b) finding preventive methods, (c) identification of different forms of restraint, (d) rationing the use of restraint, and (e) post-restraint acts. Restraint was seen as a part of pediatric nursing which occurred daily and involved several professionals. According to the nurses' illustrations, restraint means doing things even when a child is not agreeable. CONCLUSION: Restraint is part of somatic pediatric nursing, described as the last, but in some cases, the only resort for carrying out care or treatment. Restraint is not a goal in itself, but an instrumental tool and procedure in carrying out care. In the future, more information about nurses' role and the use of restraint in pediatric nursing is still needed. PMID- 24493712 TI - Patient-reported quality of supportive care among patients with colorectal cancer in the Veterans Affairs Health Care System. AB - PURPOSE: High-quality supportive care is an essential component of comprehensive cancer care. We implemented a patient-centered quality of cancer care survey to examine and identify predictors of quality of supportive care for bowel problems, pain, fatigue, depression, and other symptoms among 1,109 patients with colorectal cancer. PATIENTS AND METHODS: Patients with new diagnosis of colorectal cancer at any Veterans Health Administration medical center nationwide in 2008 were ascertained through the Veterans Affairs Central Cancer Registry and sent questionnaires assessing a variety of aspects of patient-centered cancer care. We received questionnaires from 63% of eligible patients (N = 1,109). Descriptive analyses characterizing patient experiences with supportive care and binary logistic regression models were used to examine predictors of receipt of help wanted for each of the five symptom categories. RESULTS: There were significant gaps in patient-centered quality of supportive care, beginning with symptom assessment. In multivariable modeling, the impact of clinical factors and patient race on odds of receiving wanted help varied by symptom. Coordination of care quality predicted receipt of wanted help for all symptoms, independent of patient demographic or clinical characteristics. CONCLUSION: This study revealed substantial gaps in patient-centered quality of care, difficult to characterize through quality measurement relying on medical record review alone. It established the feasibility of collecting patient-reported quality measures. Improving quality measurement of supportive care and implementing patient reported outcomes in quality-measurement systems are high priorities for improving the processes and outcomes of care for patients with cancer. PMID- 24493714 TI - Should dose-intense immunochemotherapy be the new standard of care for primary CNS lymphoma? PMID- 24493715 TI - Some practical considerations for phase III studies with biomarker evaluations. PMID- 24493716 TI - Role of radiotherapy to bulky disease in elderly patients with aggressive B-cell lymphoma. AB - PURPOSE: R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) is standard care for aggressive B-cell lymphoma. A prospective trial was conducted to investigate the role of additive radiotherapy (RT) to bulky and extralymphatic disease. PATIENTS AND METHODS: The best arm of the RICOVER-60 trial (6*R-CHOP-14+2R [R-CHOP administered once every 2 weeks plus two additional applications of rituximab] plus involved-field RT [36 Gy] to sites of initial bulky [>= 7.5 cm] disease and extralymphatic involvement) was compared with a cohort receiving the same immunochemotherapy but without RT in an amendment to the RICOVER-60 trial (RICOVER-noRTh) in a prospective fashion. RESULTS: After a median observation time of 39 months, 164 of 166 RICOVER-noRTh patients were evaluable. In a multivariable analysis of the intention-to-treat population adjusting for International Prognostic Index risk factors and age (> 70 years), event-free survival (EFS) of patients with bulky disease was inferior without additive RT (hazard ratio [HR], 2.1; 95% CI, 1.3 to 3.5; P = .005), with trends for inferior progression-free (PFS; HR, 1.8; 95% CI, 1.0 to 3.3; P = .058) and overall survival (OS; HR, 1.6; 95% CI, 0.9 to 3.1; P = .127). In a per-protocol analysis with 11 patients in RICOVER-noRTh excluded for receiving unplanned RT, multivariable analysis revealed HRs of 2.7 (95% CI, 1.3 to 5.9; P = .011) for EFS, 4.4 (95% CI, 1.8 to 10.6; P = .001) for PFS, and 4.3 (95% CI, 1.7 to 11.1; P = .002) for OS for patients not receiving RT to bulky disease. CONCLUSION: Additive RT to bulky sites abrogates bulky disease as a risk factor and improves outcome of elderly patients with aggressive B-cell lymphoma. Whether RT can be spared in patients with (metabolic) complete remission after immunochemotherapy must be addressed in appropriately designed prospective trials. PMID- 24493713 TI - Cytogenetic prognostication within medulloblastoma subgroups. AB - PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials. PMID- 24493717 TI - Open-label, exploratory phase II trial of oral itraconazole for the treatment of basal cell carcinoma. AB - PURPOSE: Itraconazole, a US Food and Drug Administration-approved antifungal drug, inhibits the Hedgehog (HH) signaling pathway, a crucial driver of basal cell carcinoma (BCC) tumorigenesis, and reduces BCC growth in mice. We assessed the effect of itraconazole on the HH pathway and on tumor size in human BCC tumors. PATIENTS AND METHODS: Patients with >= one BCC tumor > 4 mm in diameter were enrolled onto two cohorts to receive oral itraconazole 200 mg twice per day for 1 month (cohort A) or 100 mg twice per day for an average of 2.3 months (cohort B). The primary end point was change in biomarkers: Ki67 tumor proliferation and HH activity (GLI1 mRNA). Secondary end points included change in tumor size in a subset of patients with multiple tumors. RESULTS: A total of 29 patients were enrolled, of whom 19 were treated with itraconazole. Itraconazole treatment was associated with two adverse events (grade 2 fatigue and grade 4 congestive heart failure). Itraconazole reduced cell proliferation by 45% (P = .04), HH pathway activity by 65% (P = .03), and reduced tumor area by 24% (95% CI, 18.2% to 30.0%). Of eight patients with multiple nonbiopsied tumors, four achieved partial response, and four had stable disease. Tumors from untreated control patients and from those previously treated with vismodegib showed no significant changes in proliferation or tumor size. CONCLUSION: Itraconazole has anti-BCC activity in humans. These results provide the basis for larger trials of longer duration to measure the clinical efficacy of itraconazole, especially relative to other HH pathway inhibitors. PMID- 24493718 TI - Reply to M.C. Chamberlain. PMID- 24493719 TI - Next-generation histopathologic diagnosis: a lesson from a hepatic carcinosarcoma. PMID- 24493720 TI - Do we really need another epidermal growth factor receptor tyrosine kinase inhibitor in first-line treatment for patients with non-small-cell lung cancer and EGFR mutations? PMID- 24493721 TI - American Society of Clinical Oncology Expert Statement: collection and use of a cancer family history for oncology providers. PMID- 24493722 TI - Quality of cancer family history and referral for genetic counseling and testing among oncology practices: a pilot test of quality measures as part of the American Society of Clinical Oncology Quality Oncology Practice Initiative. AB - PURPOSE: Family history of cancer (CFH) is important for identifying individuals to receive genetic counseling/testing (GC/GT). Prior studies have demonstrated low rates of family history documentation and referral for GC/GT. METHODS: CFH quality and GC/GT practices for patients with breast (BC) or colon cancer (CRC) were assessed in 271 practices participating in the American Society of Clinical Oncology Quality Oncology Practice Initiative in fall 2011. RESULTS: A total of 212 practices completed measures regarding CFH and GC/GT practices for 10,466 patients; 77.4% of all medical records reviewed documented presence or absence of CFH in first-degree relatives, and 61.5% of medical records documented presence or absence of CFH in second-degree relatives, with significantly higher documentation for patients with BC compared with CRC. Age at diagnosis was documented for all relatives with cancer in 30.7% of medical records (BC, 45.2%; CRC, 35.4%; P <= .001). Referall for GC/GT occurred in 22.1% of all patients with BC or CRC. Of patients with increased risk for hereditary cancer, 52.2% of patients with BC and 26.4% of those with CRC were referred for GC/GT. When genetic testing was performed, consent was documented 77.7% of the time, and discussion of results was documented 78.8% of the time. CONCLUSION: We identified low rates of complete CFH documentation and low rates of referral for those with BC or CRC meeting guidelines for referral among US oncologists. Documentation and referral were greater for patients with BC compared with CRC. Education and support regarding the importance of accurate CFH and the benefits of proactive high-risk patient management are clearly needed. PMID- 24493723 TI - Needs assessments in reducing distress among patients with cancer. PMID- 24493724 TI - Discovery and exploitation of novel targets by approved drugs. PMID- 24493725 TI - Reply to W. Hollingworth et al. PMID- 24493726 TI - Successful administration of ipilimumab to two kidney transplantation patients with metastatic melanoma. PMID- 24493727 TI - Myeloma relapse involving the heart and presenting as acute cardiac failure. PMID- 24493728 TI - Reply to S. Goteti et al. PMID- 24493729 TI - Targeting Epstein-Barr virus-associated lymphomas. PMID- 24493730 TI - Sector resection with or without postoperative radiotherapy for stage I breast cancer: 20-year results of a randomized trial. AB - PURPOSE: To investigate how radiotherapy (XRT) adds to tumor control using a standardized surgical technique with meticulous control of surgical margins in a randomized trial with 20 years of follow-up. PATIENTS AND METHODS: Three hundred eighty-one women with pT1N0 breast cancer were randomly assigned to sector resection with (XRT group) or without (non-XRT group) postoperative radiotherapy to the breast. With follow-up through 2010, we estimated cumulative proportion of recurrence, breast cancer death, and all-cause mortality. RESULTS: The cumulative probability of a first breast cancer event of any type after 20 years was 30.9% in the XRT group and 45.1% in the non-XRT group (hazard ratio [HR], 0.58; 95% CI, 0.41 to 0.82). The benefit of radiotherapy was achieved within the first 5 years. After 20 years, 50.4% of the women in the XRT group died compared with 54.0% in the non-XRT group (HR, 0.92; 95% CI, 0.71 to 1.19). The cumulative probability of contralateral cancer or death as a result of cancer other than breast cancer was 27.1% in the XRT group and 24.9% in the non-XRT group (HR, 1.17; 95% CI, 0.77 to 1.77). In an anticipated low-risk group, the cumulative incidence of first breast cancer of any type was 24.8% in the XRT group and 36.1% in the non-XRT group (HR, 0.61; 95% CI, 0.35 to 1.07). CONCLUSION: Radiotherapy protects against recurrences during the first 5 years of follow-up, indicating that XRT mainly eradicates undetected cancer foci present at primary treatment. The similar rate of recurrences beyond 5 years in the two groups indicates that late recurrences are new tumors. There are subgroups with clinically relevant differences in risk. PMID- 24493731 TI - BRAF V600E mutation in two distinct meningeal melanocytomas associated with a nevus of Ota. PMID- 24493732 TI - Afatinib-related nonhematologic adverse events: is common evaluation enough for now? PMID- 24493733 TI - Reply to F. De Marinis et al. PMID- 24493734 TI - Reply to E.R. Haspinger et al. PMID- 24493736 TI - Design and application of cotranscriptional non-enzymatic RNA circuits and signal transducers. AB - Nucleic acid circuits are finding increasing real-life applications in diagnostics and synthetic biology. Although DNA has been the main operator in most nucleic acid circuits, transcriptionally produced RNA circuits could provide powerful alternatives for reagent production and their use in cells. Towards these goals, we have implemented a particular nucleic acid circuit, catalytic hairpin assembly, using RNA for both information storage and processing. Our results demonstrated that the design principles developed for DNA circuits could be readily translated to engineering RNA circuits that operated with similar kinetics and sensitivities of detection. Not only could purified RNA hairpins perform amplification reactions but RNA hairpins transcribed in vitro also mediated amplification, even without purification. Moreover, we could read the results of the non-enzymatic amplification reactions using a fluorescent RNA aptamer 'Spinach' that was engineered to undergo sequence-specific conformational changes. These advances were applied to the end-point and real-time detection of the isothermal strand displacement amplification reaction that produces single stranded DNAs as part of its amplification cycle. We were also able to readily engineer gate structures with RNA similar to those that have previously formed the basis of DNA circuit computations. Taken together, these results validate an entirely new chemistry for the implementation of nucleic acid circuits. PMID- 24493735 TI - PARP1-TDP1 coupling for the repair of topoisomerase I-induced DNA damage. AB - Poly(ADP-ribose) polymerases (PARP) attach poly(ADP-ribose) (PAR) chains to various proteins including themselves and chromatin. Topoisomerase I (Top1) regulates DNA supercoiling and is the target of camptothecin and indenoisoquinoline anticancer drugs, as it forms Top1 cleavage complexes (Top1cc) that are trapped by the drugs. Endogenous and carcinogenic DNA lesions can also trap Top1cc. Tyrosyl-DNA phosphodiesterase 1 (TDP1), a key repair enzyme for trapped Top1cc, hydrolyzes the phosphodiester bond between the DNA 3'-end and the Top1 tyrosyl moiety. Alternative repair pathways for Top1cc involve endonuclease cleavage. However, it is unknown what determines the choice between TDP1 and the endonuclease repair pathways. Here we show that PARP1 plays a critical role in this process. By generating TDP1 and PARP1 double-knockout lymphoma chicken DT40 cells, we demonstrate that TDP1 and PARP1 are epistatic for the repair of Top1cc. The N-terminal domain of TDP1 directly binds the C-terminal domain of PARP1, and TDP1 is PARylated by PARP1. PARylation stabilizes TDP1 together with SUMOylation of TDP1. TDP1 PARylation enhances its recruitment to DNA damage sites without interfering with TDP1 catalytic activity. TDP1-PARP1 complexes, in turn recruit X ray repair cross-complementing protein 1 (XRCC1). This work identifies PARP1 as a key component driving the repair of trapped Top1cc by TDP1. PMID- 24493737 TI - Improved search heuristics find 20,000 new alignments between human and mouse genomes. AB - Sequence similarity search is a fundamental way of analyzing nucleotide sequences. Despite decades of research, this is not a solved problem because there exist many similarities that are not found by current methods. Search methods are typically based on a seed-and-extend approach, which has many variants (e.g. spaced seeds, transition seeds), and it remains unclear how to optimize this approach. This study designs and tests seeding methods for inter mammal and inter-insect genome comparison. By considering substitution patterns of real genomes, we design sets of multiple complementary transition seeds, which have better performance (sensitivity per run time) than previous seeding strategies. Often the best seed patterns have more transition positions than those used previously. We also point out that recent computer memory sizes (e.g. 60 GB) make it feasible to use multiple (e.g. eight) seeds for whole mammal genomes. Interestingly, the most sensitive settings achieve diminishing returns for human-dog and melanogaster-pseudoobscura comparisons, but not for human mouse, which suggests that we still miss many human-mouse alignments. Our optimized heuristics find ~20,000 new human-mouse alignments that are missing from the standard UCSC alignments. We tabulate seed patterns and parameters that work well so they can be used in future research. PMID- 24493739 TI - DAXX co-folds with H3.3/H4 using high local stability conferred by the H3.3 variant recognition residues. AB - Histone chaperones are a diverse class of proteins that facilitate chromatin assembly. Their ability to stabilize highly abundant histone proteins in the cellular environment prevents non-specific interactions and promotes nucleosome formation, but the various mechanisms for doing so are not well understood. We now focus on the dynamic features of the DAXX histone chaperone that have been elusive from previous structural studies. Using hydrogen/deuterium exchange coupled to mass spectrometry (H/DX-MS), we elucidate the concerted binding folding of DAXX with histone variants H3.3/H4 and H3.2/H4 and find that high local stability at the variant-specific recognition residues rationalizes its known selectivity for H3.3. We show that the DAXX histone binding domain is largely disordered in solution and that formation of the H3.3/H4/DAXX complex induces folding and dramatic global stabilization of both histone and chaperone. Thus, DAXX uses a novel strategy as a molecular chaperone that paradoxically couples its own folding to substrate recognition and binding. Further, we propose a model for the chromatin assembly reaction it mediates, including a stepwise folding pathway that helps explain the fidelity of DAXX in associating with the H3.3 variant, despite an extensive and nearly identical binding surface on its counterparts, H3.1 and H3.2. PMID- 24493738 TI - An antisense promoter in mouse L1 retrotransposon open reading frame-1 initiates expression of diverse fusion transcripts and limits retrotransposition. AB - Between 6 and 30% of human and mouse transcripts are initiated from transposable elements. However, the promoters driving such transcriptional activity are mostly unknown. We experimentally characterized an antisense (AS) promoter in mouse L1 retrotransposons for the first time, oriented antiparallel to the coding strand of L1 open reading frame-1. We found that AS transcription is mediated by RNA polymerase II. Rapid amplification of cDNA ends cloning mapped transcription start sites adjacent to the AS promoter. We identified >100 novel fusion transcripts, of which many were conserved across divergent mouse lineages, suggesting conservation of potential functions. To evaluate whether AS L1 transcription could regulate L1 retrotransposition, we replaced portions of native open reading frame-1 in donor elements by synonymously recoded sequences. The resulting L1 elements lacked AS promoter activity and retrotransposed more frequently than endogenous L1s. Overexpression of AS L1 transcripts also reduced L1 retrotransposition. This suppression of retrotransposition was largely independent of Dicer. Our experiments shed new light on how AS fusion transcripts are initiated from endogenous L1 elements across the mouse genome. Such AS transcription can contribute substantially both to natural transcriptional variation and to endogenous regulation of L1 retrotransposition. PMID- 24493740 TI - Climate change effects on human health: projections of temperature-related mortality for the UK during the 2020s, 2050s and 2080s. AB - BACKGROUND: The most direct way in which climate change is expected to affect public health relates to changes in mortality rates associated with exposure to ambient temperature. Many countries worldwide experience annual heat-related and cold-related deaths associated with current weather patterns. Future changes in climate may alter such risks. Estimates of the likely future health impacts of such changes are needed to inform public health policy on climate change in the UK and elsewhere. METHODS: Time-series regression analysis was used to characterise current temperature-mortality relationships by region and age group. These were then applied to the local climate and population projections to estimate temperature-related deaths for the UK by the 2020s, 2050s and 2080s. Greater variability in future temperatures as well as changes in mean levels was modelled. RESULTS: A significantly raised risk of heat-related and cold-related mortality was observed in all regions. The elderly were most at risk. In the absence of any adaptation of the population, heat-related deaths would be expected to rise by around 257% by the 2050s from a current annual baseline of around 2000 deaths, and cold-related mortality would decline by 2% from a baseline of around 41 000 deaths. The cold burden remained higher than the heat burden in all periods. The increased number of future temperature-related deaths was partly driven by projected population growth and ageing. CONCLUSIONS: Health protection from hot weather will become increasingly necessary, and measures to reduce cold impacts will also remain important in the UK. The demographic changes expected this century mean that the health protection of the elderly will be vital. PMID- 24493741 TI - Ion transport and cancer: from initiation to metastasis. PMID- 24493742 TI - Potassium channels in cell cycle and cell proliferation. AB - Normal cell-cycle progression is a crucial task for every multicellular organism, as it determines body size and shape, tissue renewal and senescence, and is also crucial for reproduction. On the other hand, dysregulation of the cell-cycle progression leading to uncontrolled cell proliferation is the hallmark of cancer. Therefore, it is not surprising that it is a tightly regulated process, with multifaceted and very complex control mechanisms. It is now well established that one of those mechanisms relies on ion channels, and in many cases specifically on potassium channels. Here, we summarize the possible mechanisms underlying the importance of potassium channels in cell-cycle control and briefly review some of the identified channels that illustrate the multiple ways in which this group of proteins can influence cell proliferation and modulate cell-cycle progression. PMID- 24493743 TI - Cl- and K+ channels and their role in primary brain tumour biology. AB - Profound cell volume changes occur in primary brain tumours as they proliferate, invade surrounding tissue or undergo apoptosis. These volume changes are regulated by the flux of Cl(-) and K(+) ions and concomitant movement of water across the membrane, making ion channels pivotal to tumour biology. We discuss which specific Cl(-) and K(+) channels are involved in defined aspects of glioma biology and how these channels are regulated. Cl(-) is accumulated to unusually high concentrations in gliomas by the activity of the NKCC1 transporter and serves as an osmolyte and energetic driving force for volume changes. Cell volume condensation is required as cells enter M phase of the cell cycle and this pre mitotic condensation is caused by channel-mediated ion efflux. Similarly, Cl(-) and K(+) channels dynamically regulate volume in invading glioma cells allowing them to adjust to small extracellular brain spaces. Finally, cell condensation is a hallmark of apoptosis and requires the concerted activation of Cl(-) and Ca(2+) activated K(+) channels. Given the frequency of mutation and high importance of ion channels in tumour biology, the opportunity exists to target them for treatment. PMID- 24493744 TI - Role of anoctamins in cancer and apoptosis. AB - Anoctamin 1 (TMEM16A, Ano1) is a recently identified Ca(2+)-activated chloride channel and a member of a large protein family comprising 10 paralogues. Before Ano1 was identified as a chloride channel protein, it was known as the cancer marker DOG1. DOG1/Ano1 is expressed in gastrointestinal stromal tumours (GIST) and particularly in head and neck squamous cell carcinoma, at very high levels never detected in other tissues. It is now emerging that Ano1 is part of the 11q13 locus, amplified in several types of tumour, where it is thought to augment cell proliferation, cell migration and metastasis. Notably, Ano1 is upregulated through histone deacetylase (HDAC), corresponding to the known role of HDAC in HNSCC. As Ano1 does not enhance proliferation in every cell type, its function is perhaps modulated by cell-specific factors, or by the abundance of other anoctamins. Thus Ano6, by regulating Ca(2+)-induced membrane phospholipid scrambling and annexin V binding, supports cellular apoptosis rather than proliferation. Current findings implicate other cellular functions of anoctamins, apart from their role as Ca(2+)-activated Cl(-) channels. PMID- 24493745 TI - Remodelling of Ca2+ transport in cancer: how it contributes to cancer hallmarks? AB - Cancer involves defects in the mechanisms underlying cell proliferation, death and migration. Calcium ions are central to these phenomena, serving as major signalling agents with spatial localization, magnitude and temporal characteristics of calcium signals ultimately determining cell's fate. Cellular Ca(2+) signalling is determined by the concerted action of a molecular Ca(2+) handling toolkit which includes: active energy-dependent Ca(2+) transporters, Ca(2+)-permeable ion channels, Ca(2+)-binding and storage proteins, Ca(2+) dependent effectors. In cancer, because of mutations, aberrant expression, regulation and/or subcellular targeting of Ca(2+)-handling/transport protein(s) normal relationships among extracellular, cytosolic, endoplasmic reticulum and mitochondrial Ca(2+) concentrations or spatio-temporal patterns of Ca(2+) signalling become distorted. This causes deregulation of Ca(2+)-dependent effectors that control signalling pathways determining cell's behaviour in a way to promote pathophysiological cancer hallmarks such as enhanced proliferation, survival and invasion. Despite the progress in our understanding of Ca(2+) homeostasis remodelling in cancer cells as well as in identification of the key Ca(2+)-transport molecules promoting certain malignant phenotypes, there is still a lot of work to be done to transform fundamental findings and concepts into new Ca(2+) transport-targeting tools for cancer diagnosis and treatment. PMID- 24493746 TI - Interactions of ion transporters and channels with cancer cell metabolism and the tumour microenvironment. AB - Major changes in intra- and extracellular pH homoeostasis are shared features of most solid tumours. These changes stem in large part from the metabolic shift of most cancer cells towards glycolytic metabolism and other processes associated with net acid production. In combination with oncogenic signalling and impact from factors in the tumour microenvironment, this upregulates acid-extruding plasma membrane transport proteins which maintain intracellular pH normal or even more alkaline compared with that of normal cells, while in turn acidifying the external microenvironment. Mounting evidence strongly indicates that this contributes significantly to cancer development by favouring e.g. cancer cell migration, invasion and chemotherapy resistance. Finally, while still under explored, it seems likely that non-cancer cells in the tumour microenvironment also exhibit altered pH regulation and that this may contribute to their malignant properties. Thus, the physical tumour microenvironment and the cancer and stromal cells within it undergo important reciprocal interactions which modulate the tumour pH profile, in turn severely impacting on the course of cancer progression. Here, we summarize recent knowledge of tumour metabolism and the tumour microenvironment, placing it in the context of tumour pH regulation, and discuss how interfering with these properties may be exploited clinically. PMID- 24493747 TI - The chemistry, physiology and pathology of pH in cancer. AB - Cell survival is conditional on the maintenance of a favourable acid-base balance (pH). Owing to intensive respiratory CO2 and lactic acid production, cancer cells are exposed continuously to large acid-base fluxes, which would disturb pH if uncorrected. The large cellular reservoir of H(+)-binding sites can buffer pH changes but, on its own, is inadequate to regulate intracellular pH. To stabilize intracellular pH at a favourable level, cells control trans-membrane traffic of H(+)-ions (or their chemical equivalents, e.g. ) using specialized transporter proteins sensitive to pH. In poorly perfused tumours, additional diffusion reaction mechanisms, involving carbonic anhydrase (CA) enzymes, fine-tune control extracellular pH. The ability of H(+)-ions to change the ionization state of proteins underlies the exquisite pH sensitivity of cellular behaviour, including key processes in cancer formation and metastasis (proliferation, cell cycle, transformation, migration). Elevated metabolism, weakened cell-to-capillary diffusive coupling, and adaptations involving H(+)/H(+)-equivalent transporters and extracellular-facing CAs give cancer cells the means to manipulate micro environmental acidity, a cancer hallmark. Through genetic instability, the cellular apparatus for regulating and sensing pH is able to adapt to extracellular acidity, driving disease progression. The therapeutic potential of disturbing this sequence by targeting H(+)/H(+)-equivalent transporters, buffering or CAs is being investigated, using monoclonal antibodies and small molecule inhibitors. PMID- 24493748 TI - Role of pHi, and proton transporters in oncogene-driven neoplastic transformation. AB - The change of a normal, healthy cell to a transformed cell is the first step in the evolutionary arc of a cancer. While the role of oncogenes in this 'passage' is well known, the role of ion transporters in this critical step is less known and is fundamental to our understanding the early physiological processes of carcinogenesis. Cancer cells and tissues have an aberrant regulation of hydrogen ion dynamics leading to a reversal of the normal tissue intracellular to extracellular pH gradient (DeltapHi to DeltapHe). When this perturbation in pH dynamics occurs during carcinogenesis is less clear. Very early studies using the introduction of different oncogene proteins into cells observed a concordance between neoplastic transformation and a cytoplasmic alkalinization occurring concomitantly with a shift towards glycolysis in the presence of oxygen, i.e. 'Warburg metabolism'. These processes may instigate a vicious cycle that drives later progression towards fully developed cancer where the reversed pH gradient becomes ever more pronounced. This review presents our understanding of the role of pH and the NHE1 in driving transformation, in determining the first appearance of the cancer 'hallmark' characteristics and how the use of pharmacological approaches targeting pH/NHE1 may open up new avenues for efficient treatments even during the first steps of cancer development. PMID- 24493749 TI - Interaction of tumour cells with their microenvironment: ion channels and cell adhesion molecules. A focus on pancreatic cancer. AB - Cancer must be viewed as a 'tissue', constituted of both transformed cells and a heterogeneous microenvironment, the 'tumour microenvironment' (TME). The TME undergoes a complex remodelling during the course of multistep tumourigenesis, hence strongly contributing to tumour progression. Ion channels and transporters (ICTs), being expressed on both tumour cells and in the different cellular components of the TME, are in a strategic position to sense and mediate signals arising from the TME. Often, this transmission is mediated by integrin adhesion receptors, which are the main cellular receptors capable of mediating cell-to cell and cell-to-matrix bidirectional signalling. Integrins can often operate in conjunction with ICT because they can behave as functional partners of ICT proteins. The role of integrin receptors in the crosstalk between tumour cells and the TME is particularly relevant in the context of pancreatic cancer (PC), characterized by an overwhelming TME which actively contributes to therapy resistance. We discuss the possibility that this occurs through integrins and ICTs, which could be exploited as targets to overcome chemoresistance in PC. PMID- 24493751 TI - Functional properties of ion channels and transporters in tumour vascularization. AB - Vascularization is crucial for solid tumour growth and invasion, providing metabolic support and sustaining metastatic dissemination. It is now accepted that ion channels and transporters play a significant role in driving the cancer growth at all stages. They may represent novel therapeutic, diagnostic and prognostic targets for anti-cancer therapies. On the other hand, although the expression and role of ion channels and transporters in the vascular endothelium is well recognized and subject of recent reviews, only recently has their involvement in tumour vascularization been recognized. Here, we review the current literature on ion channels and transporters directly involved in the angiogenic process. Particular interest will be focused on tumour angiogenesis in vivo as well as in the different steps that drive this process in vitro, such as endothelial cell proliferation, migration, adhesion and tubulogenesis. Moreover, we compare the 'transportome' system of tumour vascular network with the physiological one. PMID- 24493750 TI - Ion channels and transporters in tumour cell migration and invasion. AB - Cell migration is a central component of the metastatic cascade requiring a concerted action of ion channels and transporters (migration-associated transportome), cytoskeletal elements and signalling cascades. Ion transport proteins and aquaporins contribute to tumour cell migration and invasion among other things by inducing local volume changes and/or by modulating Ca(2+) and H(+) signalling. Targeting cell migration therapeutically bears great clinical potential, because it is a prerequisite for metastasis. Ion transport proteins appear to be attractive candidate target proteins for this purpose because they are easily accessible as membrane proteins and often overexpressed or activated in cancer. Importantly, a number of clinically widely used drugs are available whose anticipated efficacy as anti-tumour drugs, however, has now only begun to be evaluated. PMID- 24493752 TI - Ion channels and apoptosis in cancer. AB - Humans maintain a constant cell number throughout their lifespan. This equilibrium of cell number is accomplished when cell proliferation and cell death are kept balanced, achieving a steady-state cell number. Abnormalities in cell growth or cell death can lead to an overabundance of cells known as neoplasm or tumours. While the perception of cancer is often that of an uncontrollable rate of cell growth or increased proliferation, a decrease in cell death can also lead to tumour formation. Most cells when detached from their normal tissue die. However, cancer cells evade cell death, tipping the balance to an overabundance of cell number. Therefore, overcoming this resistance to cell death is a decisive factor in the treatment of cancer. Ion channels play a critical role in cancer in regards to cell proliferation, malignant angiogenesis, migration and metastasis. Additionally, ion channels are also known to be critical components of apoptosis. In this review, we discuss the modes of cell death focusing on the ability of cancer cells to evade apoptosis. Specifically, we focus on the role ion channels play in controlling and regulating life/death decisions and how they can be used to overcome resistance to apoptosis in the treatment of cancer. PMID- 24493753 TI - Regulation of voltage-gated sodium channel expression in cancer: hormones, growth factors and auto-regulation. AB - Although ion channels are increasingly being discovered in cancer cells in vitro and in vivo, and shown to contribute to different aspects and stages of the cancer process, much less is known about the mechanisms controlling their expression. Here, we focus on voltage-gated Na(+) channels (VGSCs) which are upregulated in many types of carcinomas where their activity potentiates cell behaviours integral to the metastatic cascade. Regulation of VGSCs occurs at a hierarchy of levels from transcription to post-translation. Importantly, mainstream cancer mechanisms, especially hormones and growth factors, play a significant role in the regulation. On the whole, in major hormone-sensitive cancers, such as breast and prostate cancer, there is a negative association between genomic steroid hormone sensitivity and functional VGSC expression. Activity-dependent regulation by positive feedback has been demonstrated in strongly metastatic cells whereby the VGSC is self-sustaining, with its activity promoting further functional channel expression. Such auto-regulation is unlike normal cells in which activity-dependent regulation occurs mostly via negative feedback. Throughout, we highlight the possible clinical implications of functional VGSC expression and regulation in cancer. PMID- 24493754 TI - Ion channels and anti-cancer immunity. AB - The outcome of a malignant disease depends on the efficacy of the immune system to destroy cancer cells. Key steps in this process, for example the generation of a proper Ca(2+) signal induced by recognition of a specific antigen, are regulated by various ion channel including voltage-gated Kv1.3 and Ca(2+) activated KCa3.1 K(+) channels, and the interplay between Orai and STIM to produce the Ca(2+)-release-activated Ca(2+) (CRAC) current required for T-cell proliferation and function. Understanding the immune cell subset-specific expression of ion channels along with their particular function in a given cell type, and the role of cancer tissue-dependent factors in the regulation of operation of these ion channels are emerging questions to be addressed in the fight against cancer disease. Answering these questions might lead to a better understanding of the immunosuppression phenomenon in cancer tissue and the development of drugs aimed at skewing the distribution of immune cell types towards killing of the tumour cells. PMID- 24493758 TI - Connected health: emerging disruptive technologies. PMID- 24493757 TI - Ion channels and transporters in the development of drug resistance in cancer cells. AB - Multi-drug resistance (MDR) to chemotherapy is the major challenge in the treatment of cancer. MDR can develop by numerous mechanisms including decreased drug uptake, increased drug efflux and the failure to undergo drug-induced apoptosis. Evasion of drug-induced apoptosis through modulation of ion transporters is the main focus of this paper and we demonstrate how pro-apoptotic ion channels are downregulated, while anti-apoptotic ion transporters are upregulated in MDR. We also discuss whether upregulation of ion transport proteins that are important for proliferation contribute to MDR. Finally, we discuss the possibility that the development of MDR involves sequential and localized upregulation of ion channels involved in proliferation and migration and a concomitant global and persistent downregulation of ion channels involved in apoptosis. PMID- 24493759 TI - Connected health and the rise of the patient-consumer. PMID- 24493755 TI - Targeting ion transport in cancer. AB - The metabolism of cancer cells differs substantially from normal cells, including ion transport. Although this phenomenon has been long recognized, ion transporters have not been viewed as suitable therapeutic targets. However, the acidic pH values present in tumours which are well outside of normal limits are now becoming recognized as an important therapeutic target. Carbonic anhydrase IX (CAIX) is fundamental to tumour pH regulation. CAIX is commonly expressed in cancer, but lowly expressed in normal tissues and that presents an attractive target. Here, we discuss the possibilities of exploiting the acidic, hypoxic tumour environment as possible target for therapy. Additionally, clinical experience with CAIX targeting in cancer patients is discussed. PMID- 24493756 TI - Ion channels in cancer: future perspectives and clinical potential. AB - Ion transport across the cell membrane mediated by channels and carriers participate in the regulation of tumour cell survival, death and motility. Moreover, the altered regulation of channels and carriers is part of neoplastic transformation. Experimental modification of channel and transporter activity impacts tumour cell survival, proliferation, malignant progression, invasive behaviour or therapy resistance of tumour cells. A wide variety of distinct Ca(2+) permeable channels, K(+) channels, Na(+) channels and anion channels have been implicated in tumour growth and metastasis. Further experimental information is, however, needed to define the specific role of individual channel isoforms critically important for malignancy. Compelling experimental evidence supports the assumption that the pharmacological inhibition of ion channels or their regulators may be attractive targets to counteract tumour growth, prevent metastasis and overcome therapy resistance of tumour cells. This short review discusses the role of Ca(2+) permeable channels, K(+) channels, Na(+) channels and anion channels in tumour growth and metastasis and the therapeutic potential of respective inhibitors. PMID- 24493760 TI - Connected health: a review of technologies and strategies to improve patient care with telemedicine and telehealth. AB - With the advent of national health reform, millions more Americans are gaining access to a health care system that is struggling to provide high-quality care at reduced costs. The increasing adoption of electronic technologies is widely recognized as a key strategy for making health care more cost-effective. This article examines the concept of connected health as an overarching structure for telemedicine and telehealth, and it provides examples of its value to professionals as well as patients. Policy makers, academe, patient advocacy groups, and private-sector organizations need to create partnerships to rapidly test, evaluate, deploy, and pay for new care models that use telemedicine. PMID- 24493761 TI - Telehealth: seven strategies to successfully implement disruptive technology and transform health care. AB - "Telehealth" refers to the use of electronic services to support a broad range of remote services, such as patient care, education, and monitoring. Telehealth must be integrated into traditional ambulatory and hospital-based practices if it is to achieve its full potential, including addressing the six domains of care quality defined by the Institute of Medicine: safe, effective, patient-centered, timely, efficient, and equitable. Telehealth is a disruptive technology that appears to threaten traditional health care delivery but has the potential to reform and transform the industry by reducing costs and increasing quality and patient satisfaction. This article outlines seven strategies critical to successful telehealth implementation: understanding patients' and providers' expectations, untethering telehealth from traditional revenue expectations, deconstructing the traditional health care encounter, being open to discovery, being mindful of the importance of space, redesigning care to improve value in health care, and being bold and visionary. PMID- 24493762 TI - Telehealth among US hospitals: several factors, including state reimbursement and licensure policies, influence adoption. AB - Telehealth is widely believed to hold great potential to improve access to, and increase the value of, health care. Gaining a better understanding of why some hospitals adopt telehealth technologies while others do not is critically important. We examined factors associated with telehealth adoption among US hospitals. Data from the Information Technology Supplement to the American Hospital Association's 2012 annual survey of acute care hospitals show that 42 percent of US hospitals have telehealth capabilities. Hospitals more likely to have telehealth capabilities are teaching hospitals, those equipped with additional advanced medical technology, those that are members of a larger system, and those that are nonprofit institutions. Rates of hospital telehealth adoption by state vary substantially and are associated with differences in state policy. Policies that promote private payer reimbursement for telehealth are associated with greater likelihood of telehealth adoption, while policies that require out-of-state providers to have a special license to provide telehealth services reduce the likelihood of adoption. Our findings suggest steps that policy makers can take to achieve greater adoption of telehealth by hospitals. PMID- 24493763 TI - For telehealth to succeed, privacy and security risks must be identified and addressed. AB - The success of telehealth could be undermined if serious privacy and security risks are not addressed. For example, sensors that are located in a patient's home or that interface with the patient's body to detect safety issues or medical emergencies may inadvertently transmit sensitive information about household activities. Similarly, routine data transmissions from an app or medical device, such as an insulin pump, may be shared with third-party advertisers. Without adequate security and privacy protections for underlying telehealth data and systems, providers and patients will lack trust in the use of telehealth solutions. Although some federal and state guidelines for telehealth security and privacy have been established, many gaps remain. No federal agency currently has authority to enact privacy and security requirements to cover the telehealth ecosystem. This article examines privacy risks and security threats to telehealth applications and summarizes the extent to which technical controls and federal law adequately address these risks. We argue for a comprehensive federal regulatory framework for telehealth, developed and enforced by a single federal entity, the Federal Trade Commission, to bolster trust and fully realize the benefits of telehealth. PMID- 24493764 TI - Mobile health applications: the patchwork of legal and liability issues suggests strategies to improve oversight. AB - Mobile health (mHealth) technology has facilitated the transition of care beyond the traditional hospital setting to the homes of patients. Yet few studies have evaluated the legal implications of the expansion of mHealth applications, or "apps." Such apps are affected by a patchwork of policies related to medical licensure, privacy and security protection, and malpractice liability. For example, the privacy protections of the Health Insurance Portability and Accountability Act (HIPAA) of 1996 may apply to only some uses of the apps. Similarly, it is not clear what a doctor's malpractice liability would be if he or she injured a patient as the result of inaccurate information supplied by the patient's self-monitoring health app. This article examines the legal issues related to the oversight of health apps, discusses current federal regulations, and suggests strategies to improve the oversight of these apps. PMID- 24493765 TI - Lessons from tele-emergency: improving care quality and health outcomes by expanding support for rural care systems. AB - Tele-emergency services provide immediate and synchronous audio/video connections, most commonly between rural low-volume hospitals and an urban "hub" emergency department. We performed a systematic literature review to identify tele-emergency models and outcomes. We then studied a large tele-emergency service in the upper Midwest. We sent a user survey to all seventy-one hospitals that used the service and received 292 replies. We also conducted telephone interviews and site visits with ninety clinicians and administrators at twenty nine of these hospitals. Participants reported that tele-emergency improves clinical quality, expands the care team, increases resources during critical events, shortens time to care, improves care coordination, promotes patient centered care, improves the recruitment of family physicians, and stabilizes the rural hospital patient base. However, inconsistent reimbursement policy, cross state licensing barriers, and other regulations hinder tele-emergency implementation. New value-based payment systems have the potential to reduce these barriers and accelerate tele-emergency expansion. PMID- 24493766 TI - Distributing medical expertise: the evolution and impact of telemedicine in arkansas. AB - Arkansas's telemedicine system has evolved since 2003 from a support mechanism for high-risk pregnancy consultations to an initiative that spans medical specialties, including asthma care, pediatric cardiology, gynecology, and mental health. The system has also expanded care to diverse populations, including incarcerated women and people with HIV/AIDS. This article describes the system's evolution, organization, and diverse activities. It also shows how telemedicine can have a positive impact on a rural state and how such a state can become an engine for change regionally. The Arkansas telemedicine system faced classic challenges to uptake and function, in building and sustaining funding, in obtaining insurance reimbursement for services, and in educating patients and providers. The system's impacts on health outcomes and medical practice culture have also reached beyond patient care and provider support. The existing yet continually evolving telemedicine infrastructure and partnerships in Arkansas will respond to the state's inevitable health care reform adaptations from the Affordable Care Act and could provide direction for other states seeking to adopt or expand their telemedicine efforts. PMID- 24493767 TI - Use of telemedicine can reduce hospitalizations of nursing home residents and generate savings for medicare. AB - Hospitalizations of nursing home residents are frequent and result in complications, morbidity, and Medicare expenditures of more than a billion dollars annually. The lack of a physician presence at many nursing homes during off hours might contribute to inappropriate hospitalizations. Findings from our controlled study of eleven nursing homes provide the first indications that switching from on-call to telemedicine physician coverage during off hours could reduce hospitalizations and therefore generate cost savings to Medicare in excess of the facility's investment in the service. But those savings were evident only at the study nursing homes that used the telemedicine service to a greater extent, compared to the other study facilities. Telemedicine service providers and nursing home leaders might need to take additional steps to encourage buy-in to the use of telemedicine at facilities with such services. At the same time, closer alignment of the stakeholders that bear the costs of telemedicine and those that might realize savings because of its use could offer further incentives for the adoption of telemedicine. PMID- 24493768 TI - Kaiser Permanente Northern California: current experiences with internet, mobile, and video technologies. AB - The US health care system has been slow to adopt Internet, mobile, and video technologies, which have the capability to engage patients in their own care, increase patients' access to providers, and possibly improve the quality of care while reducing costs. Nevertheless, there are some pockets of progress, including Kaiser Permanente Northern California (KPNC). In 2008 KPNC implemented an inpatient and ambulatory care electronic health record system for its 3.4 million members and developed a suite of patient-friendly Internet, mobile, and video tools. KPNC has achieved many successes. For example, the number of virtual "visits" grew from 4.1 million in 2008 to an estimated 10.5 million in 2013. This article describes KPNC's experience with Internet, mobile, and video technologies and the obstacles faced by other health care providers interested in embracing them. The obstacles include the predominant fee-for-service payment model, which does not reimburse for virtual visits; the considerable investment needed to deploy these technologies; and physician buy-in. PMID- 24493769 TI - Analysis of Teladoc use seems to indicate expanded access to care for patients without prior connection to a provider. AB - Despite the potential benefits of telehealth applications, little is known about their overall impact on care. This is critical because rising health care costs and a shortage of primary care providers make it likely that telehealth services will play an increasingly important role in health care delivery. To help fill this gap in knowledge, we describe early experiences with Teladoc, one of the largest telemedicine providers in the United States, which provides care directly to patients over the telephone or via the Internet. We analyzed claims data for a large California agency serving public employees that recently offered Teladoc as a covered service. The 3,701 Teladoc "visits" we studied were for a broad range of diagnostic categories, the most common of which were acute respiratory conditions, urinary tract infections, and skin problems. Compared to patients who visited a physician's office for a similar condition, adult Teladoc users were younger and less likely to have used health care before the introduction of Teladoc. Patients who used Teladoc were less likely to have a follow-up visit to any setting, compared to those patients who visited a physician's office or emergency department. Teladoc appears to be expanding access to patients who are not connected to other providers. Future research should assess the impact of Teladoc and other telehealth interventions on the quality and cost of care. PMID- 24493770 TI - Mobile phone diabetes project led to improved glycemic control and net savings for Chicago plan participants. AB - Even with the best health care available, patients with chronic illnesses typically spend no more than a few hours a year in a health care setting, while their outcomes are largely determined by their activities during the remaining 5,000 waking hours of the year. As a widely available, low-cost technology, mobile phones are a promising tool to use in engaging patients in behavior change and facilitating self-care between visits. We examined the impact of a six-month mobile health (mHealth) demonstration project among adults with diabetes who belonged to an academic medical center's employee health plan. In addition to pre post improvements in glycemic control (p=0.01) and patients' satisfaction with overall care (p=0.04), we observed a net cost savings of 8.8 percent. Those early results suggest that mHealth programs can support health care organizations' pursuit of the triple aim of improving patients' experiences with care, improving population health, and reducing the per capita cost of health care PMID- 24493771 TI - Despite increased use and sales of statins in India, per capita prescription rates remain far below high-income countries. AB - Statin use has increased substantially in North America and Europe, with resultant reductions in cardiovascular mortality. However, little is known about statin use in lower-income countries. India is of interest because of its burden of cardiovascular disease, the unique nature of its prescription drug market, and the growing globalization of drug sales. We conducted an observational study using IMS Health data for the period February 2006-January 2010. During the period, monthly statin prescriptions increased from 45.8 to 84.1 per 1,000 patients with coronary heart disease-an increase of 0.80 prescriptions per month. The proportion of the Indian population receiving a defined daily statin dose increased from 3.35 percent to 7.78 percent. Nevertheless, only a fraction of those eligible for a statin appeared to receive the therapy, even though there were 259 distinct statin products available to Indian consumers in January 2010. Low rates of statin use in India may reflect problems with access to health care, affordability, underdiagnosis, and cultural beliefs. Because of the growing burden of cardiovascular disease in lower-income countries such as India, there is an urgent need to increase statin use and ensure access to safe products whose use is based on evidence. Policies are needed to expand insurance, increase medications' affordability, educate physicians and patients, and improve regulatory oversight. PMID- 24493772 TI - New neighborhood grocery store increased awareness of food access but did not alter dietary habits or obesity. AB - National and local policies to improve diet in low-income US populations include increasing physical access to grocery stores and supermarkets in underserved neighborhoods. In a pilot study that evaluated the impacts of opening a new supermarket in a Philadelphia community considered a "food desert"-part of the Pennsylvania Fresh Food Financing Initiative-we found that the intervention moderately improved residents' perceptions of food accessibility. However, it did not lead to changes in reported fruit and vegetable intake or body mass index. The effectiveness of interventions to improve physical access to food and reduce obesity by encouraging supermarkets to locate in underserved areas therefore remains unclear. Nevertheless, the present findings suggest that simply improving a community's retail food infrastructure may not produce desired changes in food purchasing and consumption patterns. Complementary policy changes and interventions may be needed to help consumers bridge the gap between perception and action. The replication of our findings in other settings and research into the factors that influence community residents' receptivity to improved food access are urgently required. PMID- 24493773 TI - New medicaid enrollees in Oregon report health care successes and challenges. AB - Medicaid expansions will soon cover millions of new enrollees, but insurance alone may not ensure that they receive high-quality care. This study examines health care interactions and the health perceptions of an Oregon cohort three years after they gained Medicaid coverage. During in-depth qualitative interviews, 120 enrollees reported a wide range of interactions with the health care system. Forty percent of the new enrollees sought care infrequently because they were confused about coverage, faced access barriers, had bad interactions with providers, or felt that care was unnecessary. For the 60 percent who had multiple health care interactions, continuity and ease of the provider-patient relationship were critical to improved health. Some newly insured Medicaid enrollees recounted rapid improvements in health. However, most reported that gains came after months or years of working closely and systematically with a provider. Our findings suggest that improving communication with beneficiaries and increasing the availability of coordinated care across settings could reduce the barriers that new enrollees are likely to face. PMID- 24493774 TI - Value-based insurance design program in north Carolina increased medication adherence but was not cost neutral. AB - Value-based insurance design (VBID) has shown promise for improving medication adherence by lowering or eliminating patients' payments for some medications. Yet the business case for VBID remains unclear. VBID is based on the premise that higher medication and administrative expenses incurred by insurers will be offset by lower nonmedication expenditures that result from better disease control. This article examines Blue Cross Blue Shield of North Carolina's VBID program, which began in 2008. The program eliminated copayments for generic medications and reduced copays for brand-name medications. Patient adherence improved 2.7-3.4 percent during the two-year study period. Hospital admissions decreased modestly, but there were no significant changes in emergency department use or total health expenditures. The insurer incurred $6.4 million in higher medication expenditures; total nonmedication expenditures for the study population decreased $5.7 million. Our results provide limited support for the idea that VBID can be cost-neutral in specific subpopulations. The business case for VBID may be more compelling over the long term and in high risk subgroups for whose members cost is an important barrier to improved medication adherence. PMID- 24493775 TI - Quantifying The Food And Drug Administration's rulemaking delays highlights the need for transparency. AB - The Food and Drug Administration (FDA) frequently uses its rulemaking process to establish or modify the way it regulates drugs, medical devices, and other medical products. The federal agency's rulemaking is controversial because of its perceived complexity, lack of transparency, and lengthy duration. To shed light on the FDA's rulemaking process, we examined the evolution of significant rules that the agency published during 2000-12 for drugs, devices, and other medical products. We found that the rules' median time to finalization was 7.3 years, with the pre-rule phase and postreview deliberation within the FDA accounting for the majority of that time. Rules that involved mandatory cost-benefit analyses were associated with an additional delay of approximately two years. We also found that longer review times were significantly associated with a reduction in the stringency of final rules, compared to the originally proposed versions. We recommend improving FDA's rulemaking by allocating additional resources to increase efficiency and by embarking on initiatives to promote transparency by the FDA and other parts of the executive branch. PMID- 24493776 TI - Undocumented immigrants and kidney transplant: costs and controversy. PMID- 24493777 TI - Helmsley trust support for telehealth improves access to care in rural and frontier areas. AB - Rural residents in need of health care face many challenges. In 2009 the Leona M. and Harry B. Helmsley Charitable Trust created the Rural Healthcare Program to improve access to and quality of care in areas of the upper Midwest challenged by health care workforce shortages and low population density. The program has focused its efforts on telehealth in seven upper Midwestern states. Since 2009 the Rural Healthcare Program has approved $22 million in grants to eighty-five rural hospitals to implement eEmergency services. The service's videoconferencing technology connects rural emergency department staff with emergency physicians and nurses located at the service's "hub." Initial analyses indicate that eEmergency has helped participating rural hospitals increase patients' access to specialists, increase the use of evidence-based treatment, decrease time to transfer a patient to a facility able to provide a higher level of care, and reduce unnecessary patient transfers. This article describes the health care challenges rural communities face and the telehealth projects supported by the Helmsley Trust's Rural Healthcare Program. PMID- 24493779 TI - Health care providers in rural America. PMID- 24493780 TI - An urban legend about emergency departments. PMID- 24493781 TI - Emergency department use: the authors reply. PMID- 24493783 TI - TEPC gas gain measurements in propane. AB - Knowledge of the gas gain is important to optimise the design and the operating characteristics of tissue-equivalent proportional counters (TEPCs), especially for simulated sites smaller than 1 um. TEPC area monitors of the order of centimetres must operate at very low gas pressure to simulate micrometric volumes, consequently the Townsend theory cannot be applied: effects related to the presence of an electric-field gradient become important and must be considered. A detailed description of the electron avalanche formation is complex, but in most practical cases an analytical formula can be used. The so called gradient-field model includes three characteristic constants of the counting gas, which were already experimentally determined for propane-tissue equivalent (TE) and dimethyl ether (DME) gases. The aim of this work is to measure the gas-dependent parameters for propane gas. Preliminary results obtained with a spherical TEPC are presented. PMID- 24493782 TI - Coalition formation to address structural determinants of methamphetamine use in Thailand. AB - Despite two recent government-sponsored 'wars on drugs', methamphetamine use continues to be a pervasive problem in Thailand. Out of concern for reported human rights abuses, there has been a call from the international community to take a different approach from the government's 'zero tolerance'. This paper describes the adaptation of the Connect to Protect(r) coalition formation process from urban U.S. cities to three districts in northern Thailand's Chiang Mai province, aimed to reduce methamphetamine use by altering the risk environment. Project materials, including manuals and materials (e.g. key actor maps and research staff memos), were reviewed to describe partnering procedures and selection criteria. Potential community partners were identified from various government and community sectors with a focus on including representatives from health, police, district and sub-district government officials. Of the 64 potential partners approached, 59 agreed to join one of three district-level coalitions. Partner makeup included 25% from the health sector, 22% who were sub district government officials and 10% were representatives from the police sector. Key partners necessary for endorsement of and commitment to the coalition work included district-level governors, police chiefs and hospital directors for each district. Initial coalition strategic planning has resulted in policies and programs to address school retention, youth development initiatives and establishment of a new drug treatment and rehabilitation clinic in addition to other developing interventions. Similarities in building coalitions, such as the need to strategically develop buy-in with key constituencies, as well as differences of whom and how partners were identified are explored. PMID- 24493784 TI - Dosimetric performance evaluation regarding proton beam incident angles of a lithium-based AB-BNCT design. AB - The (7)Li(p,xn)(7)Be nuclear reaction, based on the low-energy protons, could produce soft neutrons for accelerator-based boron neutron capture therapy (AB BNCT). Based on the fact that the induced neutron field is relatively divergent, the relationship between the incident angle of proton beam and the neutron beam quality was evaluated in this study. To provide an intense epithermal neutron beam, a beam-shaping assembly (BSA) was designed. And a modified Snyder head phantom was used in the calculations for evaluating the dosimetric performance. From the calculated results, the intensity of epithermal neutrons increased with the increase in proton incident angle. Hence, either the irradiation time or the required proton current can be reduced. When the incident angle of 2.5-MeV proton beam is 120 degrees , the required proton current is ~13.3 mA for an irradiation time of half an hour. PMID- 24493785 TI - Prevalence and risk factors for central sleep apnea in infants with laryngomalacia. AB - OBJECTIVE: To identify the prevalence of and risk factors for central sleep apnea (CSA) in infants who are diagnosed with laryngomalacia. STUDY DESIGN: Case series with chart review. SETTING: Quaternary care pediatric hospital. SUBJECTS AND METHODS: We performed a chart review in infants with laryngomalacia. All infants had diagnostic polysomnography (PSG) performed from 2003 to 2012. Infants who underwent supraglottoplasty or other upper airway surgery prior to PSG were excluded. CSA was defined as central apnea index >= 5. Demographic data, underlying diseases, and PSG data were reviewed and analyzed. RESULTS: Fifty-four patients met the inclusion criteria. The mean age at the date PSG was performed was 3.4 +/- 2.7 months. The prevalence of CSA in infants with laryngomalacia was 46.3%. Odds ratio (OR) of CSA was above 2.0 in patients with the following risk factors: underlying neurologic disease, hypotonia, or syndrome (OR = 2.5, P = .13), history of apparent life-threatening events (OR = 2.7, P = .19), premature infants (OR = 2.2, P = .33), and age less than 3 months (OR = 2.3, P = .15). However, none of the risk factors were statistically significant. Analysis of sleep architecture revealed a decrease in total sleep time (345.4 +/- 70.6 minutes vs 393.5 +/- 68.3 minutes, P = .02) and sleep efficiency (67.7 +/- 8.9% vs 75.2 +/- 9.3%, P = .004) in the CSA group. CONCLUSION: CSA is relatively common in infants with laryngomalacia. There seems to be a higher prevalence of CSA in infants with certain risk factors, but none of the risk factors are statistically significant. The presence of CSA can lead to alteration in sleep architecture. In addition to clinical evaluation, polysomnography may be warranted for the evaluation of infants with laryngomalacia and associated complex medical conditions. PMID- 24493786 TI - Dexamethasone and risk of bleeding in children undergoing tonsillectomy. AB - OBJECTIVE: To determine whether dexamethasone use in children undergoing tonsillectomy is associated with increased risk of postoperative bleeding. STUDY DESIGN: Retrospective cohort study using a multihospital administrative database. SETTING: Thirty-six US children's hospitals. SUBJECTS: Children undergoing same day tonsillectomy between the years 2004 and 2010. METHODS: We used discrete time failure models to estimate the daily hazards of revisits for bleeding (emergency department or hospital admission) up to 30 days after surgery as a function of dexamethasone use. Revisits were standardized for patient characteristics, antibiotic use, year of surgery, and hospital. RESULTS: Of 139,715 children who underwent same-day tonsillectomy, 97,242 (69.6%) received dexamethasone and 4182 (3.0%) had a 30-day revisit for bleeding. The 30-day cumulative standardized risk of revisits for bleeding was greater with dexamethasone use (3.11% vs 2.71%; standardized difference 0.40% [95% confidence interval, 0.13%-0.67%]; P = .003), and the increased risk was observed across all age strata. Dexamethasone use was associated with a higher standardized rate of revisits for bleeding in the postdischarge time periods of days 1 through 5 but not during the peak period for secondary bleeding, days 6 and 7. CONCLUSIONS: In a real-world practice setting, dexamethasone use was associated with a small absolute increased risk of revisits for bleeding. However, the upper bound of this risk increase does not cross published thresholds for a minimal clinically important difference. Given the benefits of dexamethasone in reducing postoperative nausea and vomiting and the larger body of evidence from trials, these results support guideline recommendations for the routine use of dexamethasone. PMID- 24493787 TI - Laryngeal muscle activity in unilateral vocal fold paralysis patients using electromyography and coronal reconstructed images. AB - OBJECTIVE: To assess laryngeal muscle activity in unilateral vocal fold paralysis (UVFP) patients using laryngeal electromyography (LEMG) and coronal images. STUDY DESIGN: Case series with chart review. SETTING: University hospital. SUBJECTS AND METHODS: Twenty-one patients diagnosed with UVFP of at least 6 months in duration with paralytic dysphonia, underwent LEMG, phonatory function tests, and coronal imaging. A 4-point scale was used to grade motor unit (MU) recruitment: absent = 4+, greatly decreased = 3+, moderately decreased = 2+, and mildly decreased = 1+. Maximum phonation time (MPT) and mean flow rate (MFR) were employed. Coronal images were assessed for differences in thickness and vertical position of the vocal folds during phonation and inhalation. RESULTS: MU recruitment in thyroarytenoid/lateral cricoarytenoid (TA/LCA) muscle complex results were 1+ for 4 patients, 2+ for 5, 3+ for 6, and 4+ for 6. MPT was positively correlated with MU recruitment. Thinning of the affected fold was evident during phonation in 19 of the 21 subjects. The affected fold was at an equal level with the healthy fold in all 9 subjects with MU recruitment of 1+ and 2+. Eleven of 12 subjects with MU recruitments of 3+ and 4+ showed the affected fold at a higher level than the healthy fold. There was a significant difference between MU recruitment and the vertical position of the affected fold. CONCLUSIONS: Synkinetic reinnervation may occur in some cases with UVFP. MU recruitments of TA/LCA muscle complex in UVFP patients may be related to phonatory function and the vertical position of the affected fold. PMID- 24493788 TI - Secondary tracheoesophageal puncture in-office using Seldinger technique. AB - OBJECTIVE: Evaluate the safety and efficacy of in-office secondary tracheoesophageal puncture (TEP) technique using transnasal esophagoscopy (TNE) and the Seldinger technique in conjunction with a cricothyroidotomy kit for placement. STUDY DESIGN: Case series with chart review. SETTING: Academic medical center. SUBJECT AND METHODS: A retrospective chart review was performed on 83 subjects who underwent in-office secondary TEP. Variables that were examined included disease site, staging, histologic diagnosis, extent of resection and reconstruction, chemoradiation, functional voice status (as assessed by speech pathologist in most recent note), and complications directly related to the procedure. RESULTS: Eighty-three individuals from our institution met our criteria for in-office secondary TEP from 2005 to August 2012. Of these, 97.6% (81/83) had no complications of TEP. The overall complication rate was 2.4% (2/83). Complications included bleeding from puncture site and closure of puncture site after dislodgement of prosthesis at the time of puncture. Fluent conversational speech was achieved in 69.9% of all patients (58/83), and an additional 19.3% (16/83) achieved functional/intelligible speech; of those, 3.6% (3/83) were unable to achieve fluent conversational speech due to anatomic defects from previous surgery. CONCLUSION: An in-office TEP can be safely performed using the Seldinger technique with direct visualization using TNE, despite the extent of resection or reconstruction, with functional speech outcomes comparable to other studies available in the literature. PMID- 24493789 TI - Barriers to same-day discharge of patients undergoing total and completion thyroidectomy. AB - OBJECTIVE: Describe barriers to same-day surgery for patients undergoing total and completion thyroidectomy. STUDY DESIGN: Case series with chart review. SETTING: Academic health sciences center. SUBJECTS AND METHODS: The subjects were patients who underwent total thyroidectomy or completion thyroidectomy and remained in hospital overnight or longer. A review was performed on patients who were operated on by a single surgeon from July 2005 through June 2013. RESULTS: Two hundred and sixty-eight cases were planned for same-day surgery. One hundred patients were not discharged on the same day (37%). Patients observed overnight or admitted to hospital had significantly lower postoperative calcium levels, 8.4 mg/dL (P < .0001), and lower intraoperative parathyroid hormone (PTH), mean 6.0 pg/mL (P < .0001). Those significantly more likely to require overnight observation were male patients (P = .0117), black patients (P = .0045), those with completion thyroidectomy (P = .0039), and those with a complication of surgery (P = .003). CONCLUSION: Intraoperative PTH less than 10 pg/mL was the most frequent factor (25.7%) precluding same-day discharge, followed by admission for social/financial/transportation reasons (22.6%), large dead space from goiter (15.5%), multiple comorbidities (13.4%), multiple surgical reasons (5.2%), airway observation (5.2%), pain management (3.1%), and intractable nausea due to general anesthetic (2.1%). Hypocalcemia and postoperative bleeding still remain obstacles to outpatient thyroid surgery; however, the use of rapid PTH testing, modern hemostatic techniques, appropriate calcium prophylaxis, and experienced clinical decision making can effectively stratify which patients require overnight observation. PMID- 24493790 TI - Is cardiology evaluation necessary in children with electrocardiogram abnormalities noted on polysomnogram? AB - OBJECTIVES: (1) To determine the prevalence of cardiac disease in children with electrocardiogram (ECG) abnormalities on polysomnogram (PSG). (2) To assess whether factors such as family history of heart disease and severity of sleep apnea are associated with cardiac disease. STUDY DESIGN: Case series with chart review from 2002 to 2012. SETTING: Tertiary children's hospital. SUBJECTS AND METHODS: Children between 1 and 16 years of age with ECG abnormalities on PSG who were referred to cardiology for evaluation were included. Children with a known history of cardiac disease were excluded. RESULTS: Sixty-one children had ECG abnormalities on PSG and were subsequently referred to cardiology. The mean age was 6.5 years (SD, 4.5), and 64% (n = 39) of subjects were African American. The mean obstructive apnea hypopnea index (AHI) was 8.8 (SD, 13.3), and 26% of the children had severe obstructive sleep apnea (AHI >10). The most common ECG abnormality (n = 52) recorded on PSG was premature ventricular contractions. Thirty percent (n = 18) of children had marked arrhythmias noted on their PSG ECG. Most children referred to cardiology underwent echocardiogram (45/61) and 24 hour arrhythmia monitoring (42/61). Five children (8%) had cardiac pathology, including atrial and ventricular ectopy, tuberous sclerosis, mitral regurgitation, and aortic insufficiency. Factors such as family history of heart disease (P = .40) and severe OSA (P = .74) were not associated with cardiac pathology. CONCLUSION: Cardiac pathology in children with abnormal ECGs on PSG is common. Cardiology referral in such patients should be considered. Further research is needed to determine the appropriate cardiac workup. PMID- 24493791 TI - Endoscopic reconstruction of surgically created skull base defects: a systematic review. AB - OBJECTIVES: To systematically review the literature concerning techniques of closure of endoscopically created skull base defects based on site of skull base defect and flow rate of cerebrospinal fluid (CSF). DATA SOURCES: PubMed, SCOPUS, and Cochrane databases. REVIEW METHODS: A comprehensive systematic literature review. RESULTS: The literature search produced a total of 1708 studies. Of these, 1585 studies were excluded based on title and/or abstract review. A total of 123 articles remained for full-text review, 101 of which were subsequently excluded primarily because of lack of detailed information as to the reconstructive techniques used or clinical outcomes. Of the 22 studies remaining for final analysis, all were case series. A total of 673 patients were included in the analysis, with an overall postoperative CSF leak rate of 8.5%. Subgroup analysis was performed based on location of the skull base defect and presence and quality of intraoperative CSF leak. CONCLUSIONS: Based on level 4 evidence, in cases of low-flow intraoperative CSF leaks, skull base reconstruction with multilayered free grafts and synthetic materials offers similar outcomes to vascularized flaps. In cases of high-flow intraoperative CSF leaks, pedicled vascularized flaps appear to be superior. Location of the defect does not seem to be a significant factor in determining successful closure, with the exception of clival defects. In all other sites, good closure may be achieved by multiple reconstructive approaches. More consistency in data reporting and higher levels of evidence will ultimately be necessary to make definitive recommendations. PMID- 24493793 TI - The interrater and intrarater reliability of the Philpott-Javer staging system based on level of training. AB - OBJECTIVE: The Philpott-Javer postoperative endoscopic mucosal staging system for allergic fungal rhinosinusitis has previously demonstrated acceptable interrater reliability among rhinologists. There are, however, numerous learners involved in patient care at tertiary centers. This study aims to analyze the interrater and intrarater reliability of this system among learners in otolaryngology at different stages in training. STUDY DESIGN: A prospective analysis of retrospectively collected endoscopic photographs. SETTING: A tertiary care teaching hospital (January 2013). SUBJECTS: Fifty patients undergoing routine follow-up. METHOD: Three photographs from each of 50 patients undergoing routine postsurgical nasoendoscopy were reviewed. Images were played twice, 1 week apart, in 2 differently randomized cycles and scored according to Philpott-Javer criteria by a rhinologist, a rhinology fellow, a senior otolaryngology resident, a junior otolaryngology resident, and a medical student. Interobserver reliability was assessed using the intraclass correlation coefficient, while intrarater reliability was assessed by Shrout-Fleiss kappa values. Agreement between each learner and the rhinologist was also assessed using kappa values. RESULTS: The interclass correlation among the 5 raters was 0.7600 (95% confidence interval, 0.6917-0.8161) for the Philpott-Javer scoring system, suggesting substantial reliability. Intrarater data showed substantial to almost-perfect reliability (kappa values between 0.668 and 0.815) among all raters using this system. There was also moderate to substantial agreement between the learners and the rhinologist (kappa values between 0.534 and 0.710). CONCLUSION: Results suggest that the Philpott-Javer staging system has acceptable intrarater and interrater reliability among learners of differing levels of clinical experience and is suitable for evaluating progress following surgery. PMID- 24493792 TI - Aquaporin-1 promoter hypermethylation is associated with improved prognosis in salivary gland adenoid cystic carcinoma. AB - OBJECTIVES: Aquaporin-1 (AQP1) is a candidate oncogene that is epigenetically modified in adenoid cystic carcinoma (ACC). We sought to (1) assess AQP1 promoter methylation and expression in an ACC cohort, (2) identify correlations between AQP1 and clinical outcomes, and (3) explore the role of AQP1 in tumor progression in vitro. STUDY DESIGN: Laboratory study, retrospective chart review. SETTING: Academic medical center. METHODS: DNA and RNA were isolated from ACC tumors and control salivary gland tissues. Quantitative methylation-specific polymerase chain reaction (PCR) was performed on bisulfite-treated DNA. Quantitative reverse transcription PCR was performed after cDNA synthesis. Cell lines stably overexpressing an AQP1 plasmid or empty vector were generated. Cell scratch and Matrigel invasion assays were performed. Retrospective chart review was performed for collection of clinical information. RESULTS: Methylation results from 77 tumors and 30 controls demonstrated that AQP1 was hypomethylated in tumors (P < .0001). Fifty-eight tumors (75.3%) displayed AQP1 hypomethylation compared with controls. AQP1 expression levels assessed in 58 tumors and 23 controls demonstrated a trend toward increased expression in tumors (P = .08). Univariate analysis revealed that AQP1 hypermethylation was associated with increased overall survival. No associations between AQP1 expression level and survival were found. AQP1 overexpression did not affect cell migratory or invasive capacities in vitro. CONCLUSION: AQP1 promoter hypomethylation is common in ACC, and AQP1 tends to be overexpressed in these tumors. Increased AQP1 methylation is associated with improved prognosis on univariate analysis, but expression is not associated with outcomes. Further in vitro studies are necessary to clarify the role of AQP1 in ACC. PMID- 24493795 TI - Targeted ablation of Crb2 in photoreceptor cells induces retinitis pigmentosa. AB - In humans, the Crumbs homolog-1 (CRB1) gene is mutated in autosomal recessive Leber congenital amaurosis and early-onset retinitis pigmentosa. In mammals, the Crumbs family is composed of: CRB1, CRB2, CRB3A and CRB3B. Recently, we showed that removal of mouse Crb2 from retinal progenitor cells, and consequent removal from Muller glial and photoreceptor cells, results in severe and progressive retinal degeneration with concomitant loss of retinal function that mimics retinitis pigmentosa due to mutations in the CRB1 gene. Here, we studied the effects of cell-type-specific loss of CRB2 from the developing mouse retina using targeted conditional deletion of Crb2 in photoreceptors or Muller cells. We analyzed the consequences of targeted loss of CRB2 in the adult mouse retina using adeno-associated viral vectors encoding Cre recombinase and short hairpin RNA against Crb2. In vivo retinal imaging by means of optical coherence tomography on retinas lacking CRB2 in photoreceptors showed progressive thinning of the photoreceptor layer and cellular mislocalization. Electroretinogram recordings under scotopic conditions showed severe attenuation of the a-wave, confirming the degeneration of photoreceptors. Retinas lacking CRB2 in developing photoreceptors showed early onset of abnormal lamination, whereas retinas lacking CRB2 in developing Muller cells showed late onset retinal disorganization. Our data suggest that in the developing retina, CRB2 has redundant functions in Muller glial cells, while CRB2 has essential functions in photoreceptors. Our data suggest that short-term loss of CRB2 in adult mouse photoreceptors, but not in Muller glial cells, causes sporadic loss of adhesion between photoreceptors and Muller cells. PMID- 24493796 TI - The TCR ligand-inducible expression of CD73 marks gammadelta lineage commitment and a metastable intermediate in effector specification. AB - Numerous studies indicate that gammadelta T cell receptor (gammadeltaTCR) expression alone does not reliably mark commitment of early thymic progenitors to the gammadelta fate. This raises the possibility that the gammadeltaTCR is unable to intrinsically specify fate and instead requires additional environmental factors, including TCR-ligand engagement. We use single cell progenitor assays to reveal that ligand acts instructionally to direct adoption of the gammadelta fate. Moreover, we identify CD73 as a TCR ligand-induced cell surface protein that distinguishes gammadeltaTCR-expressing CD4(-)CD8(-) progenitors that have committed to the gammadelta fate from those that have not yet done so. Indeed, unlike CD73(-) gammadeltaTCR(+) progenitors, which largely adopt the alphabeta fate upon separation from the intrathymic selecting environment, those that express CD73 remain CD4(-)CD8(-) and committed to the gammadelta fate. CD73 is expressed by >90% of peripheral gammadelta cells, suggesting this is a common occurrence during development. Moreover, CD73 induction appears to mark a metastable intermediate stage before acquisition of effector function, suggesting that gammadelta lineage and effector fate are specified sequentially. These findings have important implications for the role of ligand in gammadelta lineage commitment and its relationship to the specification of effector fate. PMID- 24493794 TI - Meta-analysis of loci associated with age at natural menopause in African American women. AB - Age at menopause marks the end of a woman's reproductive life and its timing associates with risks for cancer, cardiovascular and bone disorders. GWAS and candidate gene studies conducted in women of European ancestry have identified 27 loci associated with age at menopause. The relevance of these loci to women of African ancestry has not been previously studied. We therefore sought to uncover additional menopause loci and investigate the relevance of European menopause loci by performing a GWAS meta-analysis in 6510 women with African ancestry derived from 11 studies across the USA. We did not identify any additional loci significantly associated with age at menopause in African Americans. We replicated the associations between six loci and age at menopause (P-value < 0.05): AMHR2, RHBLD2, PRIM1, HK3/UMC1, BRSK1/TMEM150B and MCM8. In addition, associations of 14 loci are directionally consistent with previous reports. We provide evidence that genetic variants influencing reproductive traits identified in European populations are also important in women of African ancestry residing in USA. PMID- 24493797 TI - USP21 negatively regulates antiviral response by acting as a RIG-I deubiquitinase. AB - Lys63-linked polyubiquitination of RIG-I is essential in antiviral immune defense, yet the molecular mechanism that negatively regulates this critical step is poorly understood. Here, we report that USP21 acts as a novel negative regulator in antiviral responses through its ability to bind to and deubiquitinate RIG-I. Overexpression of USP21 inhibited RNA virus-induced RIG-I polyubiquitination and RIG-I-mediated interferon (IFN) signaling, whereas deletion of USP21 resulted in elevated RIG-I polyubiquitination, IRF3 phosphorylation, IFN-alpha/beta production, and antiviral responses in MEFs in response to RNA virus infection. USP21 also restricted antiviral responses in peritoneal macrophages (PMs) and bone marrow-derived dendritic cells (BMDCs). USP21-deficient mice spontaneously developed splenomegaly and were more resistant to VSV infection with elevated production of IFNs. Chimeric mice with USP21 deficient hematopoietic cells developed virus-induced splenomegaly and were more resistant to VSV infection. Functional comparison of three deubiquitinases (USP21, A20, and CYLD) demonstrated that USP21 acts as a bona fide RIG-I deubiquitinase to down-regulate antiviral response independent of the A20 ubiquitin-editing complex. Our studies identify a previously unrecognized role for USP21 in the negative regulation of antiviral response through deubiquitinating RIG-I. PMID- 24493798 TI - Antiviral drug ganciclovir is a potent inhibitor of microglial proliferation and neuroinflammation. AB - Aberrant microglial responses contribute to neuroinflammation in many neurodegenerative diseases, but no current therapies target pathogenic microglia. We discovered unexpectedly that the antiviral drug ganciclovir (GCV) inhibits the proliferation of microglia in experimental autoimmune encephalomyelitis (EAE), a mouse model for multiple sclerosis (MS), as well as in kainic acid-induced excitotoxicity. In EAE, GCV largely prevented infiltration of T lymphocytes into the central nervous system (CNS) and drastically reduced disease incidence and severity when delivered before the onset of disease. In contrast, GCV treatment had minimal effects on peripheral leukocyte distribution in EAE and did not inhibit generation of antibodies after immunization with ovalbumin. Additionally, a radiolabeled analogue of penciclovir, [(18)F]FHBG, which is similar in structure to GCV, was retained in areas of CNS inflammation in EAE, but not in naive control mice, consistent with the observed therapeutic effects. Our experiments suggest GCV may have beneficial effects in the CNS beyond its antiviral properties. PMID- 24493801 TI - Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation. AB - A hallmark of immunological memory is the ability of previously primed T cells to undergo rapid recall responses upon antigen reencounter. Classic work has suggested that memory T cells proliferate in response to lower doses of antigen than naive T cells and with reduced requirements for co-stimulation. In contrast to this premise, we observed that naive but not memory T cells proliferate in vivo in response to limited antigen presentation. To reconcile these observations, we tested the antigen threshold requirement for cell cycle entry in naive and central memory CD8(+) T cells. Although both naive and memory T cells detect low dose antigen, only naive T cells activate cell cycle effectors. Direct comparison of TCR signaling on a single cell basis indicated that central memory T cells do not activate Zap70, induce cMyc expression, or degrade p27 in response to antigen levels that activate these functions in naive T cells. The reduced sensitivity of memory T cells may result from both decreased surface TCR expression and increased expression of protein tyrosine phosphatases as compared with naive T cells. Our data describe a novel aspect of memory T cell antigen threshold sensitivity that may critically regulate recall expansion. PMID- 24493799 TI - Monovalent engagement of the BCR activates ovalbumin-specific transnuclear B cells. AB - Valency requirements for B cell activation upon antigen encounter are poorly understood. OB1 transnuclear B cells express an IgG1 B cell receptor (BCR) specific for ovalbumin (OVA), the epitope of which can be mimicked using short synthetic peptides to allow antigen-specific engagement of the BCR. By altering length and valency of epitope-bearing synthetic peptides, we examined the properties of ligands required for optimal OB1 B cell activation. Monovalent engagement of the BCR with an epitope-bearing 17-mer synthetic peptide readily activated OB1 B cells. Dimers of the minimal peptide epitope oriented in an N to N configuration were more stimulatory than their C to C counterparts. Although shorter length correlated with less activation, a monomeric 8-mer peptide epitope behaved as a weak agonist that blocked responses to cell-bound peptide antigen, a blockade which could not be reversed by CD40 ligation. The 8-mer not only delivered a suboptimal signal, which blocked subsequent responses to OVA, anti IgG, and anti-kappa, but also competed for binding with OVA. Our results show that fine-tuning of BCR-ligand recognition can lead to B cell nonresponsiveness, activation, or inhibition. PMID- 24493802 TI - Re-entry into quiescence protects hematopoietic stem cells from the killing effect of chronic exposure to type I interferons. AB - Type I interferons (IFN-1s) are antiviral cytokines that suppress blood production while paradoxically inducing hematopoietic stem cell (HSC) proliferation. Here, we clarify the relationship between the proliferative and suppressive effects of IFN-1s on HSC function during acute and chronic IFN-1 exposure. We show that IFN-1-driven HSC proliferation is a transient event resulting from a brief relaxation of quiescence-enforcing mechanisms in response to acute IFN-1 exposure, which occurs exclusively in vivo. We find that this proliferative burst fails to exhaust the HSC pool, which rapidly returns to quiescence in response to chronic IFN-1 exposure. Moreover, we demonstrate that IFN-1-exposed HSCs with reestablished quiescence are largely protected from the killing effects of IFNs unless forced back into the cell cycle due to culture, transplantation, or myeloablative treatment, at which point they activate a p53 dependent proapoptotic gene program. Collectively, our results demonstrate that quiescence acts as a safeguard mechanism to ensure survival of the HSC pool during chronic IFN-1 exposure. We show that IFN-1s can poise HSCs for apoptosis but induce direct cell killing only upon active proliferation, thereby establishing a mechanism for the suppressive effects of IFN-1s on HSC function. PMID- 24493804 TI - Erythropoietin guides multipotent hematopoietic progenitor cells toward an erythroid fate. AB - The erythroid stress cytokine erythropoietin (Epo) supports the development of committed erythroid progenitors, but its ability to act on upstream, multipotent cells remains to be established. We observe that high systemic levels of Epo reprogram the transcriptomes of multi- and bipotent hematopoietic stem/progenitor cells in vivo. This induces erythroid lineage bias at all lineage bifurcations known to exist between hematopoietic stem cells (HSCs) and committed erythroid progenitors, leading to increased erythroid and decreased myeloid HSC output. Epo, therefore, has a lineage instructive role in vivo, through suppression of non-erythroid fate options, demonstrating the ability of a cytokine to systematically bias successive lineage choices in favor of the generation of a specific cell type. PMID- 24493803 TI - 2B4 (CD244) induced by selective CD28 blockade functionally regulates allograft specific CD8+ T cell responses. AB - Mounting evidence in models of both autoimmunity and chronic viral infection suggests that the outcome of T cell activation is critically impacted by the constellation of co-stimulatory and co-inhibitory receptors expressed on the cell surface. Here, we identified a critical role for the co-inhibitory SLAM family member 2B4 (CD244) in attenuating primary antigen-specific CD8(+) T cell responses in the presence of immune modulation with selective CD28 blockade. Our results reveal a specific up-regulation of 2B4 on antigen-specific CD8(+) T cells in animals in which CD28 signaling was blocked. However, 2B4 up-regulation was not observed in animals treated with CTLA-4 Ig (abatacept) or CD28 blockade in the presence of anti-CTLA-4 mAb. 2B4 up-regulation after CD28 blockade was functionally significant, as the inhibitory impact of CD28 blockade was diminished when antigen-specific CD8(+) T cells were deficient in 2B4. In contrast, 2B4 deficiency had no effect on CD8(+) T cell responses during unmodified rejection or in the presence of CTLA-4 Ig. We conclude that blockade of CD28 signals in the presence of preserved CTLA-4 signals results in the unique up-regulation of 2B4 on primary CD8(+) effectors, and that this 2B4 expression plays a critical functional role in controlling antigen-specific CD8(+) T cell responses. PMID- 24493805 TI - Cell cycling with the SEB: a personal view. AB - This review, written from a personal perspective, traces firstly the development of plant cell cycle research from the 1970s onwards, with some focus on the work of the author and of Dr Dennis Francis. Secondly there is a discussion of the support for and discussion of plant cell cycle research in the SEB, especially through the activities of the Cell Cycle Group within the Society's Cell Biology Section. In the main part of the review, selected aspects of DNA replication that have of been of special interest to the author are discussed. These are DNA polymerases and associated proteins, pre-replication events, regulation of enzymes and other proteins, nature and activation of DNA replication origins, and DNA endoreduplication. For all these topics, there is mention of the author's own work, followed by a brief synthesis of current understanding and a look to possible future developments. PMID- 24493806 TI - Update on pharmacological heart failure therapies in children: do adult medications work in children and if not, why not? PMID- 24493808 TI - Combined aortic and pulmonic stenosis in an octogenarian: findings from echocardiography, catheterization, and pathology. PMID- 24493809 TI - Multimodality imaging of an unusual case of an obstructive intracaval mass by an aberrant liver. PMID- 24493810 TI - Sexual health concerns in patients with cardiovascular disease. PMID- 24493812 TI - Letter by Xue et al regarding article, "myocardial injury after noncardiac surgery and its association with short-term mortality". PMID- 24493813 TI - Response to letter regarding article, "myocardial injury after noncardiac surgery and its association with short-term mortality". PMID- 24493817 TI - National assessment of warfarin anticoagulation therapy for stroke prevention in atrial fibrillation. AB - BACKGROUND: Anticoagulation control with warfarin, as assessed by the international normalized ratio (INR), is challenging. Time in the therapeutic range has been inversely correlated with major hemorrhage, thrombosis, and mortality. Quest Diagnostics offers standardized INR laboratory testing services to approximately half of US physician practices. To inform national stroke prevention strategies, we evaluated anticoagulation control in office-based community practices. METHODS AND RESULTS: We selected individuals with >=2 months of INR data, INR results of >1.2, and an ICD-9 diagnosis code of atrial fibrillation. Frequency of INR testing and time in the therapeutic range were analyzed by age, sex, length of testing period, number of referred patients per provider, and median household income (based on home ZIP code). We identified 138 319 individuals referred by 37 939 physicians, yielding a total of 2 683 674 INR results. Patients had a mean age of 74 years; 81% were >=65 years of age, and 55% were >=75 years of age. The mean time in the therapeutic range was 53.7% overall and improved with time on treatment, increasing from 47.6% for patients with <6 months of testing to 57.5% for those with >=6 months of testing (P<0.0001). The number of patients tested per physician practice was positively associated with time in the therapeutic range. Younger age, female sex, and lower income were also independently associated with poorer anticoagulant control. CONCLUSION: This study demonstrates widespread suboptimal anticoagulation control, suggesting an urgent need to improve oral anticoagulation care for most patient segments in the United States. PMID- 24493818 TI - Lymphatic specific disruption in the fine structure of heparan sulfate inhibits dendritic cell traffic and functional T cell responses in the lymph node. AB - Dendritic cells (DCs) are potent APCs essential for initiating adaptive immunity. Following pathogen exposure, trafficking of DCs to lymph nodes (LNs) through afferent lymphatic vessels constitutes a crucial step in the execution of their functions. The mechanisms regulating this process are poorly understood, although the involvement of certain chemokines in this process has recently been reported. In this study, we demonstrate that genetically altering the fine structure (N sulfation) of heparan sulfate (HS) specifically in mouse lymphatic endothelium significantly reduces DC trafficking to regional LNs in vivo. Moreover, this alteration had the unique functional consequence of reducing CD8(+) T cell proliferative responses in draining LNs in an ovalbumin immunization model. Mechanistic studies suggested that lymphatic endothelial HS regulates multiple steps during DC trafficking, including optimal presentation of chemokines on the surface of DCs, thus acting as a co-receptor that may function "in trans" to mediate chemokine receptor binding. This study not only identifies novel glycan mediated mechanisms that regulate lymphatic DC trafficking, but it also validates the fine structure of lymphatic vascular-specific HS as a novel molecular target for strategies aiming to modulate DC behavior and/or alter pathologic T cell responses in lymph nodes. PMID- 24493819 TI - Coexpression of TLR2 or TLR4 with HLA-DR potentiates the superantigenic activities of Mycoplasma arthritidis-derived mitogen. AB - Mycoplasma arthritidis-derived mitogen (MAM) is a member of the superantigen family that structurally differs from other members while still capable of initiating cognate APC/T cell interaction. In addition to the critical role of MHC class II molecules, it has been suggested that TLR2 and TLR4 may cooperate with MHC class II during MAM-induced responses. In this study, we investigated the direct involvement of TLR2 and TLR4 in MAM binding and presentation to T cells. Our results showed that MAM fails to bind to TLR2- and TLR4-transfected cells. However, coexpression of TLR2 or TLR4 with HLA-DR significantly increases MAM binding and the subsequent T cell activation compared with cells expressing HLA-DR alone. The upregulated MAM binding and activity in HLA-DR/TLR-transfected cells is abrogated by an anti-HLA-DR Ab. Interestingly, we also found that MAM complexed with soluble HLA-DR is capable of binding to both TLR2 and TLR4. The enhancing effect of TLR2 or TLR4 on MAM-induced T cell proliferation was not due to TLR ligand contamination in the MAM preparation. Taken together, these results strongly suggest that binding of MAM to HLA-DR leads to a conformational change in MAM structure allowing its interaction with TLR2 and TLR4 and a better recognition by T cells. PMID- 24493820 TI - Candida-elicited murine Th17 cells express high Ctla-4 compared with Th1 cells and are resistant to costimulation blockade. AB - Effector and memory T cells may cross-react with allogeneic Ags to mediate graft rejection. Whereas the costimulation properties of Th1 cells are well studied, relatively little is known about the costimulation requirements of microbe elicited Th17 cells. The costimulation blocker CTLA-4 Ig has been ineffective in the treatment of several Th17-driven autoimmune diseases and is associated with severe acute rejection following renal transplantation, leading us to investigate whether Th17 cells play a role in CD28/CTLA-4 blockade-resistant alloreactivity. We established an Ag-specific model in which Th1 and Th17 cells were elicited via Mycobacterium tuberculosis and Candida albicans immunization, respectively. C. albicans immunization elicited a higher frequency of Th17 cells and conferred resistance to costimulation blockade following transplantation. Compared with the M. tuberculosis group, C. albicans-elicited Th17 cells contained a higher frequency of IL-17(+)IFN-gamma(+) producers and a lower frequency of IL-10(+) and IL-10(+)IL-17(+) cells. Importantly, Th17 cells differentially regulated the CD28/CTLA-4 pathway, expressing similarly high CD28 but significantly greater amounts of CTLA-4 compared with Th1 cells. Ex vivo blockade experiments demonstrated that Th17 cells are more sensitive to CTLA-4 coinhibition and therefore less susceptible to CTLA-4 Ig. These novel insights into the differential regulation of CTLA-4 coinhibition on CD4(+) T cells have implications for the immunomodulation of pathologic T cell responses during transplantation and autoimmunity. PMID- 24493821 TI - IgA enhances NETosis and release of neutrophil extracellular traps by polymorphonuclear cells via Fcalpha receptor I. AB - Polymorphonuclear cells (neutrophils) are the first cells that arrive at sites of infections. According to the current dogma, they are involved in eliminating bacteria, after which they die through apoptosis. We now demonstrate that enhanced IgA-induced phagocytosis of bacteria or beads by neutrophils led to increased cell death. Nuclear changes and positivity for the general cell death marker 7-aminoactinomycin D were observed, but the absence of annexin V membrane staining supported that neutrophils did not die via apoptosis, in contrast to neutrophils that had not phagocytosed bacteria. Moreover, increased release of neutrophil extracellular traps (NETs) was observed, which was most likely due to augmented production of reactive oxygen species after uptake of IgA-opsonized particles. Blocking the IgA Fc receptor FcalphaRI abrogated phagocytosis and NET formation. Thus, FcalphaRI triggering on neutrophils resulted in a rapid form of cell death that is referred to as NETosis, as it is accompanied by the release of NETs. As such, IgA may play a prominent role in mucosal inflammatory responses, where it is the most prominent Ab, because it enhanced both phagocytosis of bacteria and formation of NETs, which are effective mechanisms that neutrophils employ to eliminate pathogens. PMID- 24493822 TI - Multiparametric bioinformatics distinguish the CD4/CD8 ratio as a suitable laboratory predictor of combined T cell pathogenesis in HIV infection. AB - HIV disease progression is characterized by numerous pathological changes of the cellular immune system. Still, the CD4 cell count and viral load represent the laboratory parameters that are most commonly used in the clinic to determine the disease progression. In this study, we conducted an interdisciplinary investigation to determine which laboratory parameters (viral load, CD4 count, CD8 count, CD4 %, CD8 %, CD4/CD8) are most strongly associated with pathological changes of the immune system. Multiparametric flow cytometry was used to assess markers of CD4(+) and CD8(+) T cell activation (CD38, HLA-DR), exhaustion (PD-1, Tim-3), senescence (CD28, CD57), and memory differentiation (CD45RO, CD27) in a cohort of 47 untreated HIV-infected individuals. Using bioinformatical methods, we identified 139 unique populations, representing the "combined T cell pathogenesis," which significantly differed between the HIV-infected individuals and healthy control subjects. CD38, HLA-DR, and PD-1 were particularly expressed within these unique T cell populations. The CD4/CD8 ratio was correlated with more pathological T cell populations (n = 10) and had a significantly higher average correlation coefficient than any other laboratory parameters. We also reduced the dimensionalities of the 139-unique populations by Z-transformations and principal component analysis, which still identified the CD4/CD8 ratio as the preeminent surrogate of combined T cell pathogenesis. Importantly, the CD4/CD8 ratio at baseline was shown to be significantly associated with CD4 recovery 2 y after therapy initiation. These results indicate that the CD4/CD8 ratio would be a suitable laboratory predictor in future clinical and therapeutic settings to monitor pathological T cell events in HIV infection. PMID- 24493823 TI - Protective role of LGP2 in influenza virus pathogenesis. AB - Influenza A virus triggers a contagious respiratory disease that can cause considerable morbidity and mortality. Using an in vitro approach, we previously demonstrated that the pattern recognition receptor retinoic acid-inducible gene I (RIG-I) plays a key role in influenza A virus-mediated immune response. However, the importance of RIG-I signaling in vivo has not been thoroughly examined, because of the lack of an appropriate mouse models. To circumvent this issue, we generated a new transgenic mouse overexpressing LGP2 (hereafter, "LGP2 TG mice"), a major regulator of the RIG-I signaling pathway. The time course of several parameters was compared in infected wild-type and LGP2 TG mice. We found that LGP2 TG mice displayed significantly reduced inflammatory mediators and a lower leukocyte infiltration into the bronchoalveolar airspace. More importantly, LGP2 TG mice had a significant survival advantage. Hence, our in vivo study reveals that LGP2 is a major downregulator of the influenza A virus-triggered detrimental inflammatory response. PMID- 24493825 TI - Molecular and stimulus-response profiles illustrate heterogeneity between peripheral and cord blood-derived human mast cells. AB - Different protocols exist for in vitro development of HuMCs from hematopoietic stem cells, which results in distinct mast cells regarding molecular markers and activation patterns. Here, we introduce a SR profile using immunological, neurogenic, and pharmacological stimuli to characterize cellular functionality. Mast cells were obtained from three culture protocols using two types of PBdMCs (CD34+ PBdMC or CD133+ PBdMC) and one type of CBdMC (CD133+ CBdMC). We analyzed resting cells for specific mast cell markers at protein and mRNA levels, thereby creating a molecular profile. To characterize the SR profile, we stimulated cells with anti-IgE, C3a, C5a, Substance P, or Compound 48/80 and measured the release of histamine and cytokines (IL-10, IL-13, GM-CSF, TNF-alpha). Molecular profiling revealed that CD133+ CBdMC expressed less chymase, FcepsilonRIalpha, and CD203c but more CD117 compared with CD34+ and CD133+ PBdMC. The SR profile for histamine release illustrated a functional heterogeneity between PBdMC and CBdMC. PBdMC released >10% histamine upon stimulation with anti-IgE, C3a, Substance P, and Compound 48/80, whereas CBdMC only reacted to C3a. Cytokine secretion was only detected after anti-IgE stimulation. Here, the SR profile identified the CD133+ PBdMC as the most active cells regarding secretion of IL-10, IL-13, GM-CSF, and TNF-alpha. Cells from all three culture protocols, however, produced IL-10 spontaneously at comparable levels. We recommend validating mast cell cultures by means of molecular and SR profiles to characterize the mast cells and enhance consensus among studies. PMID- 24493826 TI - Implications of chemokines, chemokine receptors, and inflammatory lipids in atherosclerosis. AB - Chemokines are a diverse group of molecules with important implications for the development of solid tissues and normal function of the immune system. However, change of the conditions for such a complex system can have important and dangerous consequences leading to diseases. The specific implications of the various chemokines in diseases have been elucidated in the last few years, prompting hope of manipulating this system for therapy or prevention of diseases. On the other hand, inflammatory lipids are biologically active molecules with crucial impacts on the function of various cell types, including immune cells in health and disease. Here, we describe how these lipids affect the chemokine system and how they interact with chemokines to shape chronic inflammation in the case of atherosclerosis. PMID- 24493824 TI - Prognostic value of vitamin D level for all-cause mortality, and association with inflammatory markers, in HIV-infected persons. AB - BACKGROUND: Low 25-hydroxyvitamin D (25(OH)D) has been associated with inflammation, human immunodeficiency virus (HIV) disease progression, and death. We aimed to identify the prognostic value of 25(OH)D for AIDS, non-AIDS-defining events and death, and its association with immunological/inflammatory markers. METHODS: Prospective 1-1 case-control study nested within the EuroSIDA cohort. Matched cases and controls for AIDS (n = 50 matched pairs), non-AIDS-defining (n = 63) events and death (n = 41), with plasma samples during follow-up were selected. Conditional logistic regression models investigated associations between 25(OH)D levels and annual 25(OH)D change and the probability of events. Mixed models investigated relationships between 25(OH)D levels and immunological/inflammatory markers. RESULTS: In sum, 250 patients were included. Median time between first and last sample and last sample and event was 44.6(interquartile range [IQR]: 22.7-72.3) and 3.1(IQR: 1.4-6.4) months. Odds of death decreased by 46.0%(95% confidence interval [CI], 2.0-70.0, P = .04) for a 2 fold increase in latest 25(OH)D level. There was no association between 25(OH)D and the occurrence of AIDS or non-AIDS-defining events (P > .05). In patients with current 25(OH)D <10 ng/mL, hsIL-6 concentration increased by 4.7%(95% CI, .2,9.4, P = .04) annually after adjustment for immunological/inflammatory markers, and no change in hsCRP rate was observed (P = .76). CONCLUSIONS: Low Vitamin D predicts short term mortality in HIV-positive persons. Effectiveness of vitamin D supplementation on inflammation and patient outcomes should be investigated. PMID- 24493827 TI - Phase I study of oral rigosertib (ON 01910.Na), a dual inhibitor of the PI3K and Plk1 pathways, in adult patients with advanced solid malignancies. AB - PURPOSE: To determine the pharmacokinetics (PK), maximum tolerated dose (MTD), safety, and antitumor activity of an oral formulation of rigosertib, a dual phosphoinositide 3-kinase (PI3K) and polo-like kinase 1 (Plk1) pathway inhibitor, in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies received rigosertib twice daily continuously in 21 day cycles. Doses were escalated until intolerable grade >=2 toxicities, at which point the previous dose level was expanded to define the MTD. All patients were assessed for safety, PK, and response. Urinary PK were performed at the MTD. Archival tumors were assessed for potential molecular biomarkers with multiplex mutation testing. A subset of squamous cell carcinomas (SCC) underwent exome sequencing. RESULTS: Forty-eight patients received a median of 2 cycles of therapy at 5 dose levels. Rigosertib exposure increased with escalating doses. Dose-limiting toxicities were hematuria and dysuria. The most common grade >=2 drug-related toxicities involved urothelial irritation. The MTD is 560 mg twice daily. Activity was seen in head and neck SCCs (1 complete response, 1 partial response) and stable disease for >=12 weeks was observed in 8 additional patients. Tumors experiencing >=partial response had PI3K pathway activation, inactivated p53, and unique variants in ROBO3 and FAT1, two genes interacting with the Wnt/beta-catenin pathway. CONCLUSIONS: The recommended phase II dose of oral rigosertib is 560 mg twice daily given continuously. Urinary toxicity is the dose-limiting and most common toxicity. Alterations in PI3K, p53, and Wnt/beta catenin pathway signaling should be investigated as potential biomarkers of response in future trials. PMID- 24493828 TI - High-resolution array CGH and gene expression profiling of alveolar soft part sarcoma. AB - PURPOSE: Alveolar soft part sarcoma (ASPS) is a soft tissue sarcoma with poor prognosis, and little molecular evidence exists for its origin, initiation, and progression. The aim of this study was to elucidate candidate molecular pathways involved in tumor pathogenesis. EXPERIMENTAL DESIGN: We employed high-throughput array comparative genomic hybridization (aCGH) and cDNA-Mediated Annealing, Selection, Ligation, and Extension Assay to profile the genomic and expression signatures of primary and metastatic ASPS from 17 tumors derived from 11 patients. We used an integrative bioinformatics approach to elucidate the molecular pathways associated with ASPS progression. FISH was performed to validate the presence of the t(X;17)(p11.2;q25) ASPL-TFE3 fusion and, hence, confirm the aCGH observations. RESULTS: FISH analysis identified the ASPL-TFE3 fusion in all cases. aCGH revealed a higher number of numerical aberrations in metastatic tumors relative to primaries, but failed to identify consistent alterations in either group. Gene expression analysis highlighted 1,063 genes that were differentially expressed between the two groups. Gene set enrichment analysis identified 16 enriched gene sets (P < 0.1) associated with differentially expressed genes. Notable among these were several stem cell gene expression signatures and pathways related to differentiation. In particular, the paired box transcription factor PAX6 was upregulated in the primary tumors, along with several genes whose mouse orthologs have previously been implicated in Pax6 DNA binding during neural stem cell differentiation. CONCLUSION: In addition to suggesting a tentative neural line of differentiation for ASPS, these results implicate transcriptional deregulation from fusion genes in the pathogenesis of ASPS. PMID- 24493829 TI - The impact of EGFR T790M mutations and BIM mRNA expression on outcome in patients with EGFR-mutant NSCLC treated with erlotinib or chemotherapy in the randomized phase III EURTAC trial. AB - PURPOSE: Concomitant genetic alterations could account for transient clinical responses to tyrosine kinase inhibitors of the EGF receptor (EGFR) in patients harboring activating EGFR mutations. EXPERIMENTAL DESIGN: We have evaluated the impact of pretreatment somatic EGFR T790M mutations, TP53 mutations, and Bcl-2 interacting mediator of cell death (BCL2L11, also known as BIM) mRNA expression in 95 patients with EGFR-mutant non-small-cell lung cancer (NSCLC) included in the EURTAC trial (trial registration: NCT00446225). RESULTS: T790M mutations were detected in 65.26% of patients using our highly sensitive method based on laser microdissection and peptide-nucleic acid-clamping PCR, which can detect the mutation at an allelic dilution of 1 in 5,000. Progression-free survival (PFS) to erlotinib was 9.7 months for those with T790M mutations and 15.8 months for those without, whereas among patients receiving chemotherapy, it was 6 and 5.1 months, respectively (P < 0.0001). PFS to erlotinib was 12.9 months for those with high and 7.2 months for those with low/intermediate BCL2L11 expression levels, whereas among chemotherapy-treated patients, it was 5.8 and 5.5 months, respectively (P = 0.0003). Overall survival was 28.6 months for patients with high BCL2L11 expression and 22.1 months for those with low/intermediate BCL2L11 expression (P = 0.0364). Multivariate analyses showed that erlotinib was a marker of longer PFS (HR = 0.35; P = 0.0003), whereas high BCL2L11 expression was a marker of longer PFS (HR = 0.49; P = 0.0122) and overall survival (HR = 0.53; P = 0.0323). CONCLUSIONS: Low-level pretreatment T790M mutations can frequently be detected and can be used for customizing treatment with T790M-specific inhibitors. BCL2L11 mRNA expression is a biomarker of survival in EGFR-mutant NSCLC and can potentially be used for synthetic lethality therapies. PMID- 24493830 TI - Positron emission tomography imaging with 18F-labeled ZHER2:2891 affibody for detection of HER2 expression and pharmacodynamic response to HER2-modulating therapies. AB - PURPOSE: Expression of HER2 has profound implications on treatment strategies in various types of cancer. We investigated the specificity of radiolabeled HER2 targeting ZHER2:2891 Affibody, [(18)F]GE-226, for positron emission tomography (PET) imaging. EXPERIMENTAL DESIGN: Intrinsic cellular [(18)F]GE-226 uptake and tumor-specific tracer binding were assessed in cells and xenografts with and without drug treatment. Specificity was further determined by comparing tumor localization of a fluorescently labeled analogue with DAKO HercepTest. RESULTS: [(18)F]GE-226 uptake was 11- to 67-fold higher in 10 HER2-positive versus HER2 negative cell lines in vitro independent of lineage. Uptake in HER2-positive xenografts was rapid with net irreversible binding kinetics making possible the distinction of HER2-negative [MCF7 and MCF7-p95HER2: NUV60 (%ID/mL) 6.1 +/- 0.7; Ki (mL/cm(3)/min) 0.0069 +/- 0.0014] from HER2-positive tumors (NUV60 and Ki: MCF7-HER2, 10.9 +/- 1.5 and 0.015 +/- 0.0035; MDA-MB-361, 18.2 +/- 3.4 and 0.025 +/- 0.0052; SKOV-3, 18.7 +/- 2.4 and 0.036 +/- 0.0065) within 1 hour. Tumor uptake correlated with HER2 expression determined by ELISA (r(2) = 0.78), and a fluorophore-labeled tracer analogue colocalized with HER2 expression. Tracer uptake was not influenced by short-term or continuous treatment with trastuzumab in keeping with differential epitope binding, but reflected HER2 degradation by short-term NVP-AUY922 treatment in SKOV-3 xenografts (NUV60: 13.5 +/- 2.1 %ID/mL vs. 9.0 +/- 0.9 %ID/mL for vehicle or drug, respectively). CONCLUSIONS: [(18)F]GE 226 binds with high specificity to HER2 independent of cell lineage. The tracer has potential utility for HER2 detection, irrespective of prior trastuzumab treatment, and to discern HSP90 inhibitor-mediated HER2 degradation. PMID- 24493831 TI - Phase I dose-escalation study of onartuzumab as a single agent and in combination with bevacizumab in patients with advanced solid malignancies. AB - PURPOSE: This first-in-human study evaluated the safety, immunogenicity, pharmacokinetics, and antitumor activity of onartuzumab, a monovalent antibody against the receptor tyrosine kinase MET. EXPERIMENTAL DESIGN: This 3+3 dose escalation study comprised three stages: (i) phase Ia dose escalation of onartuzumab at doses of 1, 4, 10, 20, and 30 mg/kg intravenously every 3 weeks; (ii) phase Ia cohort expansion at the recommended phase II dose (RP2D) of 15 mg/kg; and (iii) phase Ib dose escalation of onartuzumab at 10 and 15 mg/kg in combination with bevacizumab (15 mg/kg intravenously every 3 weeks). Serum samples were collected for evaluation of pharmacokinetics, potential pharmacodynamic markers, and antitherapeutic antibodies. RESULTS: Thirty-four patients with solid tumors were treated in phase Ia and 9 in phase Ib. Onartuzumab was generally well tolerated at all dose levels evaluated; the maximum tolerated dose was not reached. The most frequent drug-related adverse events included fatigue, peripheral edema, nausea, and hypoalbuminemia. In the phase Ib cohort, onartuzumab at the RP2D was combined with bevacizumab and no dose-limiting toxicities were seen. Onartuzumab showed linear pharmacokinetics in the dose range from 4 to 30 mg/kg. The half-life was approximately 8 to 12 days. There were no apparent pharmacokinetic interactions between onartuzumab and bevacizumab, and antitherapeutic antibodies did not seem to affect the safety or pharmacokinetics of onartuzumab. A patient with gastric carcinoma in the 20-mg/kg dose cohort achieved a durable complete response for nearly 2 years. CONCLUSIONS: Onartuzumab was generally well tolerated as a single agent and in combination with bevacizumab in patients with solid tumors. PMID- 24493832 TI - EASL- and mRECIST-evaluated responses to combination therapy of sorafenib with transarterial chemoembolization predict survival in patients with hepatocellular carcinoma. AB - PURPOSE: Published studies have not investigated the suitability of Response Evaluation Criteria in Solid Tumors (RECIST), European Association for the Study of the Liver (EASL) criteria, and modified RECIST (mRECIST) for assessing the response of patients with hepatocellular carcinoma to treatment with sorafenib combined with transarterial chemoembolization. Here, we aimed to define the earliest time at which the response to combination therapy could be accurately assessed and validate the prognostic value of these criteria at this early posttherapy time point. EXPERIMENTAL DESIGN: A total of 114 consecutive patients with hepatocellular carcinoma receiving combination therapy were retrospectively enrolled. The therapy response at different time points was assessed using RECIST, EASL, and mRECIST. Cox regression analysis and Kaplan-Meier curves were used to assess overall survival (OS) in the responders and nonresponders. RESULTS: At the third follow-up (median, 94 days; range, 89-102 days) after therapy, the response rates obtained using EASL (50.6%) and mRECIST (51.6%) were greater than that obtained using RECIST (16.5%). The agreement was strong between the mRECIST and EASL results (k = 0.9) but weak between mRECIST and RECIST (k = 0.3). The EASL and mRECIST responses significantly correlated with survival. Risk reductions of 52% and 50% were observed for EASL and mRECIST responders, respectively, compared with nonresponders. However, no significant association between the treatment response and survival was observed using RECIST. CONCLUSIONS: The earliest time to evaluate the response to combination therapy is 3 months (median, 94 days) after therapy. EASL and mRECIST responses are independent predictors for OS at this early time point. PMID- 24493833 TI - A lincRNA-DYNLRB2-2/GPR119/GLP-1R/ABCA1-dependent signal transduction pathway is essential for the regulation of cholesterol homeostasis. AB - Accumulated evidence shows that G protein-coupled receptor 119 (GPR119) plays a key role in glucose and lipid metabolism. Here, we explored the effect of GPR119 on cholesterol metabolism and inflammation in THP-1 macrophages and atherosclerotic plaque progression in apoE(-/-) mice. We found that oxidized LDL (Ox-LDL) significantly induced long intervening noncoding RNA (lincRNA)-DYNLRB2-2 expression, resulting in the upregulation of GPR119 and ABCA1 expression through the glucagon-like peptide 1 receptor signaling pathway. GPR119 significantly decreased cellular cholesterol content and increased apoA-I-mediated cholesterol efflux in THP-1 macrophage-derived foam cells. In vivo, apoE(-/-) mice were randomly divided into two groups and infected with lentivirus (LV)-Mock or LV GPR119 for 8 weeks. GPR119-treated mice showed decreased liver lipid content and plasma TG, interleukin (IL)-1beta, IL-6, and TNF-alpha levels, whereas plasma levels of apoA-I were significantly increased. Consistent with this, atherosclerotic lesion development was significantly inhibited by infection of apoE(-/-) mice with LV-GPR119. Our findings clearly indicate that, Ox-LDL significantly induced lincRNA-DYNLRB2-2 expression, which promoted ABCA1-mediated cholesterol efflux and inhibited inflammation through GPR119 in THP-1 macrophage derived foam cells. Moreover, GPR119 decreased lipid and serum inflammatory cytokine levels, decreasing atherosclerosis in apoE(-/-) mice. These suggest that GPR119 may be a promising candidate as a therapeutic agent. PMID- 24493834 TI - Lipoprotein lipase activity is required for cardiac lipid droplet production. AB - The rodent heart accumulates TGs and lipid droplets during fasting. The sources of heart lipids could be either FFAs liberated from adipose tissue or FAs from lipoprotein-associated TGs via the action of lipoprotein lipase (LpL). Because circulating levels of FFAs increase during fasting, it has been assumed that albumin transported FFAs are the source of lipids within heart lipid droplets. We studied mice with three genetic mutations: peroxisomal proliferator-activated receptor alpha deficiency, cluster of differentiation 36 (CD36) deficiency, and heart-specific LpL deletion. All three genetically altered groups of mice had defective accumulation of lipid droplet TGs. Moreover, hearts from mice treated with poloxamer 407, an inhibitor of lipoprotein TG lipolysis, also failed to accumulate TGs, despite increased uptake of FFAs. TG storage did not impair maximal cardiac function as measured by stress echocardiography. Thus, LpL hydrolysis of circulating lipoproteins is required for the accumulation of lipids in the heart of fasting mice. PMID- 24493835 TI - The role of the medial frontal cortex in the maintenance of emotional states. AB - Evidence is accruing that people can maintain their emotional states, but how they do it and which brain regions are responsible still remains unclear. We examined whether people maintain emotional states 'actively', with explicit elaboration of the emotion, or 'passively', without elaboration. Twenty-four participants completed an emotion maintenance task in which they either maintained the emotional intensity from the first picture of a pair to compare to that of the second picture ('maintain' condition), or only rated their emotional response to the second picture ('non-maintain' condition). Supporting the 'active' maintenance hypothesis, when maintaining vs not maintaining emotion, participants exhibited increased height and width of activation in the dorsal medial frontal cortex (MFC) and lateral prefrontal cortex, regions associated with explicit emotion generation and manipulation of contents in working memory, respectively. Supporting the 'passive' maintenance hypothesis, however, when viewing negative emotional pictures (vs neutral pictures) that were not explicitly maintained, participants exhibited greater duration of activity in the rostral MFC, a region associated with implicit emotion generation. Supported by behavioral findings, this evidence that people maintain emotional states both naturally in the rMFC and strategically in the dMFC may be critical for understanding normal as well as disordered emotion regulation. PMID- 24493836 TI - Functional connectivity with ventromedial prefrontal cortex reflects subjective value for social rewards. AB - According to many studies, the ventromedial prefrontal cortex (VMPFC) encodes the subjective value of disparate rewards on a common scale. Yet, a host of other reward factors-likely represented outside of VMPFC-must be integrated to construct such signals for valuation. Using functional magnetic resonance imaging (fMRI), we tested whether the interactions between posterior VMPFC and functionally connected brain regions predict subjective value. During fMRI scanning, participants rated the attractiveness of unfamiliar faces. We found that activation in dorsal anterior cingulate cortex, anterior VMPFC and caudate increased with higher attractiveness ratings. Using data from a post-scan task in which participants spent money to view attractive faces, we quantified each individual's subjective value for attractiveness. We found that connectivity between posterior VMPFC and regions frequently modulated by social information including the temporal-parietal junction (TPJ) and middle temporal gyrus-was correlated with individual differences in subjective value. Crucially, these additional regions explained unique variation in subjective value beyond that extracted from value regions alone. These findings indicate not only that posterior VMPFC interacts with additional brain regions during valuation, but also that these additional regions carry information employed to construct the subjective value for social reward. PMID- 24493837 TI - Effects of valence and divided attention on cognitive reappraisal processes. AB - Numerous studies have investigated the neural substrates supporting cognitive reappraisal, identifying the importance of cognitive control processes implemented by prefrontal cortex (PFC). This study examined how valence and attention affect the processes used for cognitive reappraisal by asking participants to passively view or to cognitively reappraise positive and negative images with full or divided attention. When participants simply viewed these images, results revealed few effects of valence or attention. However, when participants engaged in reappraisal, there was a robust effect of valence, with the reappraisal of negative relative to positive images associated with more widespread activation, including within regions of medial and lateral PFC. There also was an effect of attention, with more lateral PFC recruitment when regulating with full attention and more medial PFC recruitment when regulating with divided attention. Within two regions of medial PFC and one region of ventrolateral PFC, there was an interaction between valence and attention: in these regions, divided attention reduced activity during reappraisal of positive but not negative images. Critically, participants continued to report reappraisal success even during the Divided Attention condition. These results suggest multiple routes to successful cognitive reappraisal, depending upon image valence and the availability of attentional resources. PMID- 24493839 TI - Neural response during explicit and implicit face processing varies developmentally in bipolar disorder. AB - Both children and adults with bipolar disorder (BD) exhibit face emotion labeling deficits and neural circuitry dysfunction in response to emotional faces. However, few studies have compared these groups directly to distinguish effects of age and diagnosis. Such studies are important to begin to elucidate the developmental trajectory of BD and facilitate its diagnosis, prevention and treatment. This functional magnetic resonance imaging study compares 41 individuals with BD (19 children; 22 adults) and 44 age-matched healthy individuals (25 children; 19 adults) when making explicit or implicit judgments about angry or happy face morphs across a range of emotion intensity. Linear trend analyses revealed that BD patients, irrespective of age, failed to recruit the amygdala in response to increasing angry face. This finding was no longer significant when the group was restricted to euthymic youth or those without comorbid attention deficit hyperactivity disorder although this may reflect low statistical power. Deficits in subgenual anterior cingulate modulation were observed in both patient groups but were related to implicit processing for child patients and explicit processing for adult patients. Abnormalities in face emotion labeling and the circuitry mediating it may be biomarkers of BD that are present across development. PMID- 24493838 TI - Autistic traits modulate frontostriatal connectivity during processing of rewarding faces. AB - Deficits in facial mimicry have been widely reported in autism. Some studies have suggested that these deficits are restricted to spontaneous mimicry and do not extend to volitional mimicry. We bridge these apparently inconsistent observations by testing the impact of reward value on neural indices of mimicry and how autistic traits modulate this impact. Neutral faces were conditioned with high and low reward. Subsequently, functional connectivity between the ventral striatum (VS) and inferior frontal gyrus (IFG) was measured while neurotypical adults (n = 30) watched happy expressions made by these conditioned faces. We found greater VS-IFG connectivity in response to high reward vs low reward happy faces. This difference was negatively proportional to autistic traits, suggesting that reduced spontaneous mimicry of social stimuli seen in autism, may be related to a failure in the modulation of the mirror system by the reward system rather than a circumscribed deficit in the mirror system. PMID- 24493840 TI - Hypoactive medial prefrontal cortex functioning in adults reporting childhood emotional maltreatment. AB - Childhood emotional maltreatment (CEM) has adverse effects on medial prefrontal cortex (mPFC) morphology, a structure that is crucial for cognitive functioning and (emotional) memory and which modulates the limbic system. In addition, CEM has been linked to amygdala hyperactivity during emotional face processing. However, no study has yet investigated the functional neural correlates of neutral and emotional memory in adults reporting CEM. Using functional magnetic resonance imaging, we investigated CEM-related differential activations in mPFC during the encoding and recognition of positive, negative and neutral words. The sample (N = 194) consisted of patients with depression and/or anxiety disorders and healthy controls (HC) reporting CEM (n = 96) and patients and HC reporting no abuse (n = 98). We found a consistent pattern of mPFC hypoactivation during encoding and recognition of positive, negative and neutral words in individuals reporting CEM. These results were not explained by psychopathology or severity of depression or anxiety symptoms, or by gender, level of neuroticism, parental psychopathology, negative life events, antidepressant use or decreased mPFC volume in the CEM group. These findings indicate mPFC hypoactivity in individuals reporting CEM during emotional and neutral memory encoding and recognition. Our findings suggest that CEM may increase individuals' risk to the development of psychopathology on differential levels of processing in the brain; blunted mPFC activation during higher order processing and enhanced amygdala activation during automatic/lower order emotion processing. These findings are vital in understanding the long-term consequences of CEM. PMID- 24493841 TI - Someone has to give in: theta oscillations correlate with adaptive behavior in social bargaining. AB - During social bargain, one has to both figure out the others' intentions and behave strategically in such a way that the others' behaviors will be consistent with one's expectations. To understand the neurobiological mechanisms underlying these behaviors, we used electroencephalography while subjects played as proposers in a repeated ultimatum game. We found that subjects adapted their offers to obtain more acceptances in the last round and that this adaptation correlated negatively with prefrontal theta oscillations. People with higher prefrontal theta activity related to a rejection did not adapt their offers along the game to maximize their earning. Moreover, between-subject variation in posterior theta oscillations correlated positively with how individual theta activity influenced the change of offer after a rejection, reflecting a process of behavioral adaptation to the others' demands. Interestingly, people adapted better their offers when they knew that they where playing against a computer, although the behavioral adaptation did not correlate with prefrontal theta oscillation. Behavioral changes between human and computer games correlated with prefrontal theta activity, suggesting that low adaptation in human games could be a strategy. Taken together, these results provide evidence for specific roles of prefrontal and posterior theta oscillations in social bargaining. PMID- 24493842 TI - Increased involvement of the parahippocampal gyri in a sad mood predicts future depressive symptoms. AB - Behavioral studies suggest a relationship between autobiographical memory, rumination and depression. The objective of this study was to determine whether remitted depressed patients show alterations in connectivity of the posterior cingulate cortex (PCC, a node in the default mode network) with the parahippocampal gyri (PHG, a region associated with autobiographical memory) while intensively recalling negative memories and whether this is related to daily life symptoms and to the further course of depression. Sad mood was induced with keywords of personal negative life events in participants with remitted depression (n = 29) and matched healthy controls (n = 29) during functional magnetic resonance imaging. Additionally, daily life assessments of mood and rumination and a 6-month follow-up were conducted. Remitted depressed participants showed greater connectivity than healthy controls of the PCC with the PHG, which was even stronger in patients with more previous episodes. Furthermore, patients with increased PCC-PHG connectivity showed a sadder mood and more rumination in daily life and a worsening of rumination and depression scores during follow-up. A relationship of negative autobiographical memory processing, rumination, sad mood and depression on a neural level seems likely. The identified increased connectivity probably indicates a 'scar' of recurrent depression and may represent a prognostic factor for future depression. PMID- 24493843 TI - Individual differences in anxiety predict neural measures of visual working memory for untrustworthy faces. AB - When facing strangers, one of the first evaluations people perform is to implicitly assess their trustworthiness. However, the underlying processes supporting trustworthiness appraisal are poorly understood. We hypothesized that visual working memory (VWM) maintains online face representations that are sensitive to physical cues of trustworthiness, and that differences among individuals in representing untrustworthy faces are associated with individual differences in anxiety. Participants performed a change detection task that required encoding and maintaining for a short interval the identity of one face parametrically manipulated to be either trustworthy or untrustworthy. The sustained posterior contralateral negativity (SPCN), an event-related component (ERP) time-locked to the onset of the face, was used to index the resolution of face representations in VWM. Results revealed greater SPCN amplitudes for trustworthy faces when compared with untrustworthy faces, indicating that VWM is sensitive to physical cues of trustworthiness, even in the absence of explicit trustworthiness appraisal. In addition, differences in SPCN amplitude between trustworthy and untrustworthy faces correlated with participants' anxiety, indicating that healthy college students with sub-clinical high anxiety levels represented untrustworthy faces in greater detail compared with students with sub clinical low anxiety levels. This pattern of findings is discussed in terms of the high flexibility of aversive/avoidance and appetitive/approach motivational systems. PMID- 24493845 TI - Neural correlates of social decision-making in severely antisocial adolescents. AB - Neurobiological and behavioral findings suggest that the development of delinquent behavior is associated with atypical social-affective processing. However, to date, no study has examined neural processes associated with social interactions in severely antisocial adolescents. In this study we investigated the behavioral and neural processes underlying social interactions of juvenile delinquents and a matched control group. Participants played the mini-Ultimatum Game as a responder while in the MRI scanner. Participants rejected unfair offers significantly less when the other player had 'no alternative' compared with a 'fair' alternative, suggesting that they took the intentions of the other player into account. However, this effect was reduced in the juvenile delinquents. The neuroimaging results revealed that juvenile delinquents showed less activation in the temporal parietal junction (TPJ) and inferior frontal gyrus (IFG). However, the groups showed similar activation levels in the dorsal anterior cingulate cortex (dACC) and the right anterior insula (AI) when norms were violated. These results indicate that juvenile delinquents with severe antisocial behavior process norm violations adequately, but may have difficulties with attending spontaneously to relevant features of the social context during interactions. PMID- 24493844 TI - Future planning: default network activity couples with frontoparietal control network and reward-processing regions during process and outcome simulations. AB - We spend much of our daily lives imagining how we can reach future goals and what will happen when we attain them. Despite the prevalence of such goal-directed simulations, neuroimaging studies on planning have mainly focused on executive processes in the frontal lobe. This experiment examined the neural basis of process simulations, during which participants imagined themselves going through steps toward attaining a goal, and outcome simulations, during which participants imagined events they associated with achieving a goal. In the scanner, participants engaged in these simulation tasks and an odd/even control task. We hypothesized that process simulations would recruit default and frontoparietal control network regions, and that outcome simulations, which allow us to anticipate the affective consequences of achieving goals, would recruit default and reward-processing regions. Our analysis of brain activity that covaried with process and outcome simulations confirmed these hypotheses. A functional connectivity analysis with posterior cingulate, dorsolateral prefrontal cortex and anterior inferior parietal lobule seeds showed that their activity was correlated during process simulations and associated with a distributed network of default and frontoparietal control network regions. During outcome simulations, medial prefrontal cortex and amygdala seeds covaried together and formed a functional network with default and reward-processing regions. PMID- 24493846 TI - The social network-network: size is predicted by brain structure and function in the amygdala and paralimbic regions. AB - The social brain hypothesis proposes that the large size of the primate neocortex evolved to support complex and demanding social interactions. Accordingly, recent studies have reported correlations between the size of an individual's social network and the density of gray matter (GM) in regions of the brain implicated in social cognition. However, the reported relationships between GM density and social group size are somewhat inconsistent with studies reporting correlations in different brain regions. One factor that might account for these discrepancies is the use of different measures of social network size (SNS). This study used several measures of SNS to assess the relationships SNS and GM density. The second goal of this study was to test the relationship between social network measures and functional brain activity. Participants performed a social closeness task using photos of their friends and unknown people. Across the VBM and functional magnetic resonance imaging analyses, individual differences in SNS were consistently related to structural and functional differences in three regions: the left amygdala, right amygdala and the right entorhinal/ventral anterior temporal cortex. PMID- 24493847 TI - The neural bases of uninstructed negative emotion modulation. AB - Although numerous neuroimaging studies have examined what happens when individuals are instructed to regulate their emotions, we rarely receive such instruction in everyday life. This study sought to examine what underlies uninstructed modulation of negative affect by examining neural responses when 'responding naturally' to negative stimuli-and for comparison-during instructed reappraisal of negative stimuli as well. Two analyses were conducted to identify how variability in negative affect related to neural responses when responding naturally. First, in a within-participant analysis, lower levels of self-reported negative affect on a given trial were associated with recruitment of dorsolateral and dorsomedial prefrontal cortex (PFC)-brain regions also active during instructed reappraisal-whereas higher levels of negative affect were associated with recruitment of the amygdala-a region that responded more strongly overall to negative than neutral stimuli. Second, in a between-participant analysis, lower levels of average self-reported negative affect were associated with recruitment of ventromedial PFC. These results suggest that uninstructed modulation of emotion involves a combination of two types of regulatory processes, with moment to-moment modulation depending on prefrontal regions that support reappraisal and individual differences in modulation depending on ventromedial PFC, a region involved in fear extinction. PMID- 24493848 TI - Long-term expression of human contextual fear and extinction memories involves amygdala, hippocampus and ventromedial prefrontal cortex: a reinstatement study in two independent samples. AB - Human context conditioning studies have focused on acquisition and extinction. Subsequent long-term changes in fear behaviors not only depend on associative learning processes during those phases but also on memory consolidation processes and the later ability to retrieve and express fear and extinction memories. Clinical theories explain relapse after successful exposure-based treatment with return of fear memories and remission with stable extinction memory expression. We probed contextual fear and extinction memories 1 week (Day8) after conditioning (Day1) and subsequent extinction (Day2) by presenting conditioned contexts before (Test1) and after (Test2) a reinstatement manipulation. We find consistent activation patterns in two independent samples: activation of a subgenual part of the ventromedial prefrontal cortex before reinstatement (Test1) and (albeit with different temporal profiles between samples) of the amygdala after reinstatement (Test2) as well as up-regulation of anterior hippocampus activity after reinstatement (Test2 > Test1). These areas have earlier been implicated in the expression of cued extinction and fear memories. The present results suggest a general role for these structures in defining the balance between fear and extinction memories, independent of the conditioning mode. The results are discussed in the light of hypotheses implicating the anterior hippocampus in the processing of situational ambiguity. PMID- 24493849 TI - Escape from harm: linking affective vision and motor responses during active avoidance. AB - When organisms confront unpleasant objects in their natural environments, they engage in behaviors that allow them to avoid aversive outcomes. Here, we linked visual processing of threat to its behavioral consequences by including a motor response that terminated exposure to an aversive event. Dense-array steady-state visual evoked potentials were recorded in response to conditioned threat and safety signals viewed in active or passive behavioral contexts. The amplitude of neuronal responses in visual cortex increased additively, as a function of emotional value and action relevance. The gain in local cortical population activity for threat relative to safety cues persisted when aversive reinforcement was behaviorally terminated, suggesting a lingering emotionally based response amplification within the visual system. Distinct patterns of long-range neural synchrony emerged between the visual cortex and extravisual regions. Increased coupling between visual and higher-order structures was observed specifically during active perception of threat, consistent with a reorganization of neuronal populations involved in linking sensory processing to action preparation. PMID- 24493850 TI - Structural and functional bases of inhibited temperament. AB - Children born with an inhibited temperament are at heightened risk for developing anxiety, depression and substance use. Inhibited temperament is believed to have a biological basis; however, little is known about the structural brain basis of this vulnerability trait. Structural MRI scans were obtained from 84 (44 inhibited, 40 uninhibited) young adults. Given previous findings of amygdala hyperactivity in inhibited individuals, groups were compared on three measures of amygdala structure. To identify novel substrates of inhibited temperament, a whole brain analysis was performed. Functional activation and connectivity were examined across both groups. Inhibited adults had larger amygdala and caudate volume and larger volume predicted greater activation to neutral faces. In addition, larger amygdala volume predicted greater connectivity with subcortical and higher order visual structures. Larger caudate volume predicted greater connectivity with the basal ganglia, and less connectivity with primary visual and auditory cortex. We propose that larger volume in these salience detection regions may result in increased activation and enhanced connectivity in response to social stimuli. Given the strong link between inhibited temperament and risk for psychiatric illness, novel therapeutics that target these brain regions and related neural circuits have the potential to reduce rates of illness in vulnerable individuals. PMID- 24493851 TI - If it bleeds, it leads: separating threat from mere negativity. AB - Most theories of emotion hold that negative stimuli are threatening and aversive. Yet in everyday experiences some negative sights (e.g. car wrecks) attract curiosity, whereas others repel (e.g. a weapon pointed in our face). To examine the diversity in negative stimuli, we employed four classes of visual images (Direct Threat, Indirect Threat, Merely Negative and Neutral) in a set of behavioral and functional magnetic resonance imaging studies. Participants reliably discriminated between the images, evaluating Direct Threat stimuli most quickly, and Merely Negative images most slowly. Threat images evoked greater and earlier blood oxygen level-dependent (BOLD) activations in the amygdala and periaqueductal gray, structures implicated in representing and responding to the motivational salience of stimuli. Conversely, the Merely Negative images evoked larger BOLD signal in the parahippocampal, retrosplenial, and medial prefrontal cortices, regions which have been implicated in contextual association processing. Ventrolateral as well as medial and lateral orbitofrontal cortices were activated by both threatening and Merely Negative images. In conclusion, negative visual stimuli can repel or attract scrutiny depending on their current threat potential, which is assessed by dynamic shifts in large-scale brain network activity. PMID- 24493852 TI - Dose equivalents for second-generation antipsychotics: the minimum effective dose method. AB - BACKGROUND: Clinicians need to know the right antipsychotic dose for optimized treatment, and the concept of dose equivalence is important for many clinical and scientific purposes. METHODS: We refined a method presented in 2003, which was based on the minimum effective doses found in fixed-dose studies. We operationalized the selection process, updated the original findings, and expanded them by systematically searching more recent literature and by including 13 second-generation antipsychotics. To qualify for the minimum effective dose, a dose had to be significantly more efficacious than placebo in the primary outcome of at least one randomized, double-blind, fixed-dose trial. In a sensitivity analysis, 2 positive trials were required. The minimum effective doses identified were subsequently used to derive olanzapine, risperidone, haloperidol, and chlorpromazine equivalents. RESULTS: We reviewed 73 included studies. The minimum effective daily doses/olanzapine equivalents based on our primary approach were: aripiprazole 10 mg/1.33, asenapine 10 mg/1.33, clozapine 300 mg/40, haloperidol 4 mg/0.53, iloperidone 8 mg/1.07, lurasidone 40 mg/5.33, olanzapine 7.5 mg/1, paliperidone 3 mg/0.4, quetiapine 150 mg/20, risperidone 2 mg/0.27, sertindole 12 mg/1.60, and ziprasidone 40 mg/5.33. For amisulpride and zotepine, reliable estimates could not be derived. CONCLUSIONS: This method for determining antipsychotic dose equivalence entails an operationalized and evidence-based approach that can be applied to the various antipsychotic drugs. As a limitation, the results are not applicable to specific populations such as first-episode or refractory patients. We recommend that alternative methods also be updated in order to minimize further differences between the methods and risk of subsequent bias. PMID- 24493853 TI - Preliminary study of autologous bone marrow nucleated cells transplantation in children with spinal cord injury. AB - The objective of this study was to assess the safety and efficacy of transplanting bone marrow nucleated cells (BMNCs) to treat children with complete interruption of spinal cord (SC) continuity. The present study was conducted from 2005 to 2011. The inclusion criteria were a magnetic resonance imaging-confirmed complete interruption of SC continuity and no improvement in neurological status within 6 months after standard therapy. Bone marrow was isolated from the iliac ala and submitted to BMNC isolation. Subsequently, the cell suspension was administered into the SC cavity and intravenously. In total, 18 of 19 intraspinal and intravenous BMNC transplantation procedures performed caused no adverse events. One case was connected with transient bradycardia. The experimental therapy showed no late complications in the 1- to 6-year follow-up evaluation period. Neurological improvement was observed in two patients who received multiple implantations. One patient demonstrated improved superficial sensation from Th3 to Th12/L1 and a restored bladder-filling sensation. In the other case, superficial sensation was improved from C2 to C5, and the respiratory drive, the swallowing reflex, and tongue movements were restored. Spasticity and quality of life were improved in three of five patients. In addition, skin pressure ulcers healed and did not recur. Our preliminary results demonstrate the safety and feasibility of BMNC transplantation in children with complete SC injury. The results indicate that a certain degree of neurological and quality-of-life improvement can be attained by children with chronic complete SC injury who receive multiple BMNC implantations. PMID- 24493855 TI - A niche-like culture system allowing the maintenance of primary human acute myeloid leukemia-initiating cells: a new tool to decipher their chemoresistance and self-renewal mechanisms. AB - Acute myeloid leukemia-initiating cells (LICs) are responsible for the emergence of leukemia and relapse after chemotherapy. Despite their identification more than 15 years ago, our understanding of the mechanisms responsible for their self renewal activity and their chemoresistance remains poor. The slow progress in this area is partly due to the difficulty of studying these cells ex vivo. Indeed, current studies are reliant on xenotransplantation assays in immunodeficient mice. In this paper, we report that by modeling key elements of the bone marrow niche using different stromal feeder layers and hypoxic culture conditions, we can maintain LICs over at least 3 weeks and support their self renewal properties demonstrated through primary and secondary successful xenograft. We provide a proof of principle that this niche-like culture system can be used to study LIC chemoresistance following in vitro cytarabine treatment similarly to the xenograft chemotherapy model. We found that although LICs are believed to be more chemoresistant than non-LICs, functionally defined LICs are not enriched after cytarabine treatment, and heterogeneity in their resistance to treatment can be seen between patients and even within the same patient. We present a culture system that can be used as an in vitro surrogate for xenotransplantation and that has the potential to dramatically increase the throughput of the investigation of LICs. This would further provide the means by which to identify and target the functionality of the different signaling pathways involved in the maintenance and resistance of LICs to improve acute myeloid leukemia treatments. PMID- 24493854 TI - Prospectively isolated NGN3-expressing progenitors from human embryonic stem cells give rise to pancreatic endocrine cells. AB - Pancreatic endocrine progenitors obtained from human embryonic stem cells (hESCs) represent a promising source to develop cell-based therapies for diabetes. Although endocrine pancreas progenitor cells have been isolated from mouse pancreata on the basis of Ngn3 expression, human endocrine progenitors have not been isolated yet. As substantial differences exist between human and murine pancreas biology, we investigated whether it is possible to isolate pancreatic endocrine progenitors from differentiating hESC cultures by lineage tracing of NGN3. We targeted the 3' end of NGN3 using zinc finger nuclease-mediated homologous recombination to allow selection of NGN3eGFP(+) cells without disrupting the coding sequence of the gene. Isolated NGN3eGFP(+) cells express PDX1, NKX6.1, and chromogranin A and differentiate in vivo toward insulin, glucagon, and somatostatin single hormone-expressing cells but not to ductal or exocrine pancreatic cells or other endodermal, mesodermal, or ectodermal lineages. This confirms that NGN3(+) cells represent pancreatic endocrine progenitors in humans. In addition, this hESC reporter line constitutes a unique tool that may aid in gaining insight into the developmental mechanisms underlying fate choices in human pancreas and in developing cell-based therapies. PMID- 24493857 TI - Chemically induced specification of retinal ganglion cells from human embryonic and induced pluripotent stem cells. AB - The loss of retinal ganglion cells (RGCs) is the primary pathological change for many retinal degenerative diseases. Although there is currently no effective treatment for this group of diseases, cell transplantation to replace lost RGCs holds great potential. However, for the development of cell replacement therapy, better understanding of the molecular details involved in differentiating stem cells into RGCs is essential. In this study, a novel, stepwise chemical protocol is described for the differentiation of human embryonic stem cells and induced pluripotent stem cells into functional RGCs. Briefly, stem cells were differentiated into neural rosettes, which were then cultured with the Notch inhibitor N-[N-(3,5-difluorophenacetyl)-l-alanyl]-S-phenylglycine t-butyl ester (DAPT). The expression of neural and RGC markers (BRN3A, BRN3B, ATOH7/Math5, gamma-synuclein, Islet-1, and THY-1) was examined. Approximately 30% of the cell population obtained expressed the neuronal marker TUJ1 as well the RGC markers. Moreover, the differentiated RGCs generated action potentials and exhibited both spontaneous and evoked excitatory postsynaptic currents, indicating that functional and mature RGCs were generated. In combination, these data demonstrate that a single chemical (DAPT) can induce PAX6/RX-positive stem cells to undergo differentiation into functional RGCs. PMID- 24493856 TI - Concise review: drug discovery in the age of the induced pluripotent stem cell. AB - For decades, the paradigm of drug discovery and development has relied on immortalized cell lines, animal models of human disease, and clinical trials. With the discovery of induced pluripotent stem cell (iPSC) technology in 2007, a new human in vitro drug testing platform has potentially augmented this set of tools by providing additional ways to screen compounds for safety and efficacy. The growing number of human disease models made with patient-specific iPSCs has made it possible to conduct research on a wide range of disorders, including rare diseases and those with multifactorial origin, as well as to simulate drug effects on difficult-to-obtain tissues such as brain and cardiac muscle. Toxicity and teratogenicity assays developed with iPSC-derived cells can also provide an additional layer of safety before advancing drugs to clinical trials. The incorporation of iPSC technology into drug therapy development holds promise as a more powerful and nuanced approach to personalized medicine. PMID- 24493858 TI - The sexual health of female sex workers compared with other women in England: analysis of cross-sectional data from genitourinary medicine clinics. AB - BACKGROUND: While female sex workers (FSWs) are assumed to be at increased risk of sexually transmitted infections (STIs), there are limited comparative data with other population groups available. Using routine STI surveillance data, we investigated differences in sexual health between FSWs and other female attendees at genitourinary medicine (GUM) clinics in England. METHODS: Demographic characteristics, STI prevalence and service usage among FSWs and other attendees in 2011 were compared using logistic regression. RESULTS: In 2011, 2704 FSWs made 8411 recorded visits to 131/208 GUM clinics, (primarily large, FSW-specialist centres in London). FSWs used a variety of services, however, 10% did not have an STI/HIV test at presentation. By comparison with other female attendees, FSWs travelled further for their care and had increased risk of certain STIs (e.g., gonorrhoea ORadj: 2.76, 95% CI 2.16 to 3.54, p<0.001). Migrant FSWs had better sexual health outcomes than UK-born FSWs (e.g., period prevalence of chlamydia among those tested: 8.5% vs 13.5%, p<0.001) but were more likely to experience non-STI outcomes (eg, pelvic inflammatory disease ORadj: 2.92, 95% CI 1.57 to 5.41, p<0.001). CONCLUSIONS: FSWs in England have access to high-quality care through the GUM clinic network, but there is evidence of geographical inequality in access to these services. A minority do not appear to access STI/HIV testing through clinics, and some STIs are more prevalent among FSWs than other female attendees. Targeted interventions aimed at improving uptake of testing in FSWs should be developed, and need to be culturally sensitive to the needs of this predominantly migrant population. PMID- 24493860 TI - Chronic kidney disease and the aging population. PMID- 24493864 TI - Acute mitral regurgitation in Takotsubo cardiomyopathy. AB - Takotsubo cardiomyopathy (TTC) is a well-recognised entity that commonly manifests with chest pain, ST segment abnormalities and transient left ventricular apical ballooning without coronary artery obstructive disease. This syndrome usually portends a favourable outcome. In the rare haemodynamically unstable TTC patients, acute mitral regurgitation (MR) related to systolic anterior motion (SAM) of the mitral valve and left ventricular outflow tract obstruction (LVOTO) is to be considered. Bedside echocardiography is key in recognition of this latter condition as vasodilators, inotropic agents or intra aortic balloon counter-pulsation worsen the patient's clinical status. We discuss here a case of TTC where nitrate-induced subaortic obstruction and mitral regurgitation led to haemodynamic instability. PMID- 24493859 TI - Risk factors for rectal lymphogranuloma venereum in gay men: results of a multicentre case-control study in the U.K. AB - OBJECTIVE: To identify risk factors for rectal lymphogranuloma venereum (rLGV) in men who have sex with men (MSM). DESIGN: A case-control study at 6 U.K. hospitals compared MSM with rLGV (cases) with rLGV-negative controls: MSM without potential rLGV symptoms (CGa) and separately, MSM with such symptoms (CGs). METHODS: Between 2008 and 2010, there were 90 rLGV cases, 74 CGa and 69 CGs recruited. Lifestyles and sexual behaviours in the previous 3 months were reported using internet-based computer-assisted self-interviews. Logistic regression was used to investigate factors associated with rLGV. RESULTS: Cases were significantly more likely to be HIV-positive (89%) compared with CGa (46%) and CGs (64%). Independent behavioural risks for rLGV were: unprotected receptive anal intercourse (adjusted OR (AOR)10.7, 95% CI 3.5 to 32.8), fisting another (AOR=6.7, CI 1.8 to 25.3), sex under the influence of gamma-hydroxybutyrate (AOR=3.1, CI 1.3 to 7.4) and anonymous sexual contacts (AOR=2.7, CI 1.2 to 6.3), compared with CGa; unprotected insertive anal intercourse (AOR=4.7, CI 2.0 to 10.9) and rectal douching (AOR=2.9 CI 1.3 to 6.6), compared with CGs. An incubation period from exposure to symptoms of 30 days was indicated. CONCLUSIONS: Unprotected receptive anal intercourse is a key risk factor for rectal LGV with the likelihood that rectal-to-rectal transmission is facilitated where insertive anal sex also occurs. The association between HIV and rLGV appears linked to HIV-positive men seeking unprotected sex with others with the same HIV status, sexual and drug interests. Such men should be targeted for frequent STI screening and interventions to minimise associated risks. PMID- 24493865 TI - Left anterior descending coronary artery flow after primary angioplasty in acute anterior ST-elevation myocardial infarction: how much flow is needed for left ventricular functional recovery? AB - The treatment of choice in acute ST-elevation myocardial infarction (STEMI) is primary percutaneous coronary intervention (PPCI). Although, thrombolysis in myocardial infarction (TIMI) and myocardial blush grade (MBG) measures provide semi-quantitative flow evaluation after PPCI, serial and quantitative volumetric flow evaluation is still lacking. AIM: Serial assessment of left anterior descending (LAD) coronary artery flow in patients with anterior myocardial infarction (MI), immediately after PPCI, 48 h later and pre-discharge and compare findings in patients with optimal and suboptimal PPCI result and their relation to left ventricular ejection fraction (LVEF). METHODS: Velocities in the LAD were recorded within 6 h after PPCI and one week later in 36 patients presenting with acute anterior STEMI. Sixteen patients had TIMI and MBG less than 3 after PPCI were considered to have suboptimal result. Sampling of LAD coronary artery velocity was obtained from trans-thoracic Doppler. Flow in the LAD coronary artery was estimated using heart rates, Doppler time velocity integrals and LAD color Doppler diameters. RESULTS: Diastolic LAD coronary artery flow immediately after PPCI in subjects with suboptimal PPCI, 29 +/- 21 ml/min was lower than in those with optimal result, 39.8 +/- 21 ml/min, p<0.05. Diastolic flow in the LAD coronary artery increased to 50.3 +/- 28.5 ml/min two days after PPCI in patients with suboptimal PPCI, p=0.04, and to 49.6 +/- 13.8 ml/min in those optimal result, p=0.04. LVEF increased by 9% in patients with optimal PPCI, p=0.004, and did not change in the other group. CONCLUSIONS: (a) After PPCI, flow in the LAD coronary artery was dynamic; (b) in the presence of suboptimal PPCI, early LAD coronary artery flow was reduced; (c) pre-discharge, LAD coronary artery flow increased; and (d) LVEF increased only in optimal PPCI group associated with higher early LAD coronary artery flow. PMID- 24493866 TI - Diagnostic accuracy of 3D color volume-rendered CT images for peroneal tendon dislocation in patients with acute calcaneal fractures. AB - BACKGROUND: Use of three-dimensional (3D) color volume-rendered (VR) images has been reported to be more time-efficient compared to that of cross-sectional computed tomography (CT) images for the diagnosis of peroneal tendon dislocation. However, the diagnostic performance of this technique has not been studied. PURPOSE: To test diagnostic accuracy of 3D color VR CT images of ankle for peroneal tendon dislocation in patients with acute calcaneal fractures. MATERIAL AND METHODS: The study consisted of 121 ankle CT studies from 105 consecutive patients (85 men, 20 women; mean age, 42 years; age range, 16-75 years) with acute calcaneal fractures. Peroneal tendon dislocation was diagnosed on multiplanar CT images by consensus of two experienced musculoskeletal radiologists, which served as the reference standard. Three other musculoskeletal radiologists independently reviewed 3D images alone on a workstation. The readers determined whether or not there was peroneal tendon dislocation using three degrees of certainty (definite, probable, and possible). Diagnostic performance of 3D images for peroneal tendon dislocation was evaluated by calculating the sensitivities, specificities, and area under the receiver-operating characteristic (ROC) curves. RESULTS: Forty-eight (40%) out of 121 studies showed peroneal tendon dislocation based on the expert readings using multiplanar reformatted images. Sensitivities/specificities of 3D images measured 0.92/0.81, 0.88/0.90, and 0.81/0.92 for three readers, respectively. The area under the proper binormal ROC curve based on all three readers (0.93, 0.94, and 0.92) measured 0.93 with a 95% confidence interval of 0.89-0.98. CONCLUSION: Diagnostic accuracy of 3D images is comparable to, but not as good as that of MPR images for the diagnosis of peroneal tendon dislocation in patients with acute calcaneal fractures. PMID- 24493867 TI - Proteasome inhibitors in progressive renal diseases. AB - Proteasome (PS) is a sophisticated protein degradation machinery comprising a 20S proteolytic core particle provided with caspase-like, trypsin-like and chymotrypsin-like activities on ubiquitinilated proteins. The products of this selective, complex, controlled and strictly coordinated system play a crucial role in cell cycle progression and apoptosis; activation of transcription factors, cytokines and chemokines; degradation and generation of MHC class I presented peptides. PS has recently emerged as a promising drug target in cancer therapy, and bortezomib has been approved for refractory multiple myeloma. PS proteolysis is crucial for the degradation of the inhibitory protein IkB of nuclear factor kB (NF-kB), and hence, an interesting field of research has been developed on possible benefits of drugs with anti-PS activity in disease conditions with hyper-expression of NF-kB. PS inhibitors are being adopted in pilot studies in antibody-mediated renal rejection and in AL amyloidosis, with increasing scientific interest in possible applications in lupus, IgA nephropathy, idiopathic nephrotic syndrome and renal fibrosis. The most often used PS inhibitor, bortezomib, has a severe peripheral neurotoxicity, and the search for effective and less toxic PS-targeted drugs is a challenging area also in nephrology. PMID- 24493868 TI - A perspective on anti-CCN2 therapy for chronic kidney disease. AB - Kidney fibrosis is the common end point of chronic kidney disease independent of aetiology. Currently, no effective therapy exists to reduce kidney fibrosis. CCN2 appears to be an interesting candidate for anti-fibrotic drug targeting, because it holds a central position in the development of kidney fibrosis and interacts with a variety of factors that are involved in the fibrotic response, including transforming growth factor (TGF) beta and Bone morphogenetic proteins. Although CCN2 modifies many pathways, it does not appear to have a membrane receptor of its own. Numerous experimental and clinical studies lowering CCN2 bioavailability have shown promising results with minimal adverse side effects. This review aims to provide an overview of the current state of CCN2 research with a focus on anti fibrotic therapy. PMID- 24493869 TI - PDGF and the progression of renal disease. AB - Progressive renal diseases represent a global medical problem, in part because we currently lack effective treatment strategies. Inhibition of platelet-derived growth factors (PDGFs) might represent one such novel strategy. PDGFs are required for normal kidney development by the recruitment of mesenchymal cells to both glomeruli and the interstitium. PDGFs are expressed in renal mesenchymal cells and, upon injury, in epithelial and infiltrating cells. They exert autocrine and paracrine effects on PDGF receptor-bearing mesenchymal cells, i.e. mesangial cells, fibroblasts and vascular smooth-muscle cells, which are crucially involved in progressive renal diseases. Proliferation but also migration and activation of these mesenchymal cells are the major effects mediated by PDGFs. These actions predefine the major roles of PDGFs in renal pathology, particularly in mesangioproliferative glomerulonephritis and interstitial fibrosis. Whereas for the former, the role of PDGFs is very well described and established, the latter is increasingly better documented as well. An involvement of PDGFs in other renal diseases, e.g. acute kidney injury, vascular injury and hypertensive as well as diabetic nephropathy, is less well established or presently unknown. Nevertheless, PDGFs represent a promising therapeutic option for progressive renal diseases, especially those characterized by mesangial cell proliferation and interstitial fibrosis. Clinical studies are eagerly awaited, in particular, since several drugs inhibiting PDGF signalling are available for clinical testing. PMID- 24493871 TI - Aldosterone synthase inhibitors in cardiovascular and renal diseases. AB - Aldosterone is involved in various cardiovascular pathologies, including hypertension, heart failure, atherosclerosis and fibrosis. Mineralocorticoid receptor (MR)-dependent and -independent, genomic and non-genomic processes mediate its complex effects. Spironolactone and eplerenone, both MR antagonists, are the only commercially available compounds targeting directly the actions of aldosterone. However, due to the poor selectivity (spironolactone), low potency (eplerenone) and the fact that only MR-dependent effects of aldosterone can be inhibited, these drugs have limited clinical use. An attractive approach to abolish potentially all of aldosterone-mediated pathologies is the inhibition of aldosterone synthase. This review summarizes current knowledge on the complex effects mediated by aldosterone, potential advantages and disadvantages of aldosterone inhibition and novel directions in the development of aldosterone synthase inhibitors. PMID- 24493870 TI - TWEAK and the progression of renal disease: clinical translation. AB - Tumour necrosis factor-like weak inducer of apoptosis (TWEAK) activates the fibroblast growth factor-inducible-14 (Fn14) receptor. TWEAK has actions on intrinsic kidney cells and on inflammatory cells of potential pathophysiological relevance. The effects of TWEAK in tubular cells have been explored in most detail. In cultured murine tubular cells TWEAK induces the expression of inflammatory cytokines, downregulates the expression of Klotho, is mitogenic, and in the presence of sensitizing agents promotes apoptosis. Similar actions were observed on glomerular mesangial cells. In vivo TWEAK actions on healthy kidneys mimic cell culture observations. Increased expression of TWEAK and Fn14 was reported in human and experimental acute and chronic kidney injury. The role of TWEAK/Fn14 in kidney injury has been demonstrated in non-inflammatory compensatory renal growth, acute kidney injury and chronic kidney disease of immune and non-immune origin, including hyperlipidaemic nephropathy, lupus nephritis (LN) and anti-GBM nephritis. The nephroprotective effect of TWEAK or Fn14 targeting in immune-mediated kidney injury is the result of protection from TWEAK-induced injury of renal intrinsic cells, not from interference with the immune response. A phase I dose-ranging clinical trial demonstrated the safety of anti-TWEAK antibodies in humans. A phase II randomized placebo-controlled clinical trial exploring the efficacy, safety and tolerability of neutralizing anti-TWEAK antibodies as a tissue protection strategy in LN is ongoing. The eventual success of this trial may expand the range of kidney diseases in which TWEAK targeting should be explored. PMID- 24493872 TI - Endothelin antagonism for patients with chronic kidney disease: still a hope for the future. AB - Endothelin is tightly involved in the regulation of vascular and renal function in health and in disease. In a variety of animal models of kidney disease, endothelin promotes renal injury through effects on inflammation and fibrosis. Furthermore, experimental data strongly suggest that blocking the actions of endothelin should be beneficial in patients with chronic kidney disease. However, despite encouraging pre-clinical and clinical evidence, endothelin antagonists are not yet an established treatment option in patients with chronic kidney disease. This article reviews key physiological and pathophysiological aspects of the endothelin system in the vasculature and the kidney, as well as results of pre-clinical and clinical studies on the use of endothelin antagonists in chronic kidney disease. We will also provide an outlook on the future of endothelin antagonism in this area, and issues to be resolved before endothelin antagonists are to become a reality for patients with chronic kidney disease. PMID- 24493873 TI - Sulodexide and glycosaminoglycans in the progression of renal disease. AB - Experimental data in cell cultures and animal models suggest that sulodexide and glycosaminoglycans are potentially effective drugs to treat chronic kidney diseases and prevent progression to renal failure. However, no conclusive evidence support the use of them in human renal disease. In acute and chronic glomerulonephritis, only few studies have been performed. Sulodexide has been more intensely investigated in diabetic nephropathy (DN) where the body of data supports its effectiveness as an antialbuminuric agent in early stages. Unfortunately, there is no study in DN patients on the effect of sulodexide on clinical end points. PMID- 24493874 TI - mTOR controls kidney epithelia in health and disease. AB - Renal epithelial function is the cornerstone of key excretory processes performed by our kidneys. Most of these tasks need to be tightly controlled to keep our internal environment in balance. Recently, the mTOR signalling network emerged as a key pathway controlling renal epithelial cells from the glomerular tuft along the entire nephron. Both mTOR complexes, mTORC1 and mTORC2, regulate such diverse processes as glomerular filtration and the fine tuning of tubular electrolyte balance. Most importantly, dysregulation of mTOR signalling contributes to prevalent kidney diseases like diabetic nephropathy and cystic kidney disease. The following review shall summarize our current knowledge of the renal epithelial mTOR signalling system under physiological and pathophysiological conditions. PMID- 24493876 TI - A quarter of a century of job transitions in Germany. AB - By examining trends in intra-organizational and inter-organizational job transition probabilities among professional and managerial employees in Germany, we test the applicability of mainstream career theory to a specific context and challenge its implied change assumption. Drawing on data from the German Socio Economic Panel (GSOEP), we apply linear probability models to show the influence of time, economic cycle and age on the probability of job transitions between 1984 and 2010. Results indicate a slight negative trend in the frequency of job transitions during the analyzed time span, owing to a pronounced decrease in intra-organizational transitions, which is only partly offset by a comparatively weaker positive trend towards increased inter-organizational transitions. The latter is strongly influenced by fluctuations in the economic cycle. Finally, the probability of job transitions keeps declining steadily through the course of one's working life. In contrast to inter-organizational transitions, however, this age effect for intra-organizational transitions has decreased over time. PMID- 24493877 TI - Tunable dielectric liquid lens on flexible substrate. AB - We demonstrate the fabrication of a tunable-focus dielectric liquid lens (DLL) on a flexible substrate made of polydimethylsiloxane, which was wrapped onto a goggle surface to show its functionality. As a positive meniscus converging lens, the DLL has the focal length variable from 14.2 to 6.3 mm in 1.3 s when the driving voltage increases to 125 Vrms. The resolving power of the DLL is 17.95 line pairs per mm. The DLL on a flexible, curvilinear surface is promising for expanded field of view covered as well as in reconfigurable optical systems. PMID- 24493878 TI - Effect of handling and processing on pesticide residues in food- a review. AB - Pesticides are one of the major inputs used for increasing agricultural productivity of crops. The pesticide residues, left to variable extent in the food materials after harvesting, are beyond the control of consumer and have deleterious effect on human health. The presence of pesticide residues is a major bottleneck in the international trade of food commodities. The localization of pesticides in foods varies with the nature of pesticide molecule, type and portion of food material and environmental factors. The food crops treated with pesticides invariably contain unpredictable amount of these chemicals, therefore, it becomes imperative to find out some alternatives for decontamination of foods. The washing with water or soaking in solutions of salt and some chemicals e.g. chlorine, chlorine dioxide, hydrogen peroxide, ozone, acetic acid, hydroxy peracetic acid, iprodione and detergents are reported to be highly effective in reducing the level of pesticides. Preparatory steps like peeling, trimming etc. remove the residues from outer portions. Various thermal processing treatments like pasteurization, blanching, boiling, cooking, steaming, canning, scrambling etc. have been found valuable in degradation of various pesticides depending upon the type of pesticide and length of treatment. Preservation techniques like drying or dehydration and concentration increase the pesticide content many folds due to concentration effect. Many other techniques like refining, fermentation and curing have been reported to affect the pesticide level in foods to varied extent. Milling, baking, wine making, malting and brewing resulted in lowering of pesticide residue level in the end products. Post harvest treatments and cold storage have also been found effective. Many of the decontamination techniques bring down the concentration of pesticides below MRL. However, the diminution effect depends upon the initial concentration at the time of harvest, substrate/food and type of pesticide. There is diversified information available in literature on the effect of preparation, processing and subsequent handling and storage of foods on pesticide residues which has been compiled in this article. PMID- 24493879 TI - Optimization of microwave-assisted hot air drying conditions of okra using response surface methodology. AB - Okra (Abelmoschus esculentus) was dried to a moisture level of 0.1 g water/g dry matter using a microwave-assisted hot air dryer. Response surface methodology was used to optimize the drying conditions based on specific energy consumption and quality of dried okra. The drying experiments were performed using a central composite rotatable design for three variables: air temperature (40-70 degrees C), air velocity (1-2 m/s) and microwave power level (0.5-2.5 W/g). The quality of dried okra was determined in terms of color change, rehydration ratio and hardness of texture. A second-order polynomial model was well fitted to all responses and high R(2) values (>0.8) were observed in all cases. The color change of dried okra was found higher at high microwave power and air temperatures. Rehydration properties were better for okra samples dried at higher microwave power levels. Specific energy consumption decreased with increase in microwave power due to decrease in drying time. The drying conditions of 1.51 m/s air velocity, 52.09 degrees C air temperature and 2.41 W/g microwave power were found optimum for product quality and minimum energy consumption for microwave convective drying of okra. PMID- 24493880 TI - Antibacterial efficacy of nisin, pediocin 34 and enterocin FH99 against L. monocytogenes, E. faecium and E. faecalis and bacteriocin cross resistance and antibiotic susceptibility of their bacteriocin resistant variants. AB - The bacteriocin susceptibility of Listeria monocytogenes MTCC 657, Enterococcus faecium DSMZ 20477, E. faecium VRE, and E. faecalis ATCC 29212 and their corresponding bacteriocin resistant variants was assessed. The single and combined effect of nisin and pediocin 34 and enterocin FH99 bacteriocins produced by Pediococcus pentosaceus 34, and E. faecium FH99, respectively, was determined. Pediocin34 proved to be more effective in inhibiting L. monocytogenes MTCC 657. A greater antibacterial effect was observed against E. faecium DSMZ 20477 and E. faecium (VRE) when the a combination of nisin, pediocin 34 and enterocin FH99 were used whereas in case of L. monocytogenes MTCC 657 a combination of pediocin 34 and enterocin FH99 was more effective in reducing the survival of pathogen. Bacteriocin cross-resistance and the antibiotic susceptibility of wild type and their corresponding resistant variants were assessed and results showed that resistance to a bacteriocin may extend to other bacteriocins within the same class and also the acquired resistance to bacteriocins can modify the antibiotic susceptibility/resistance profile of the bacterial species used in the study. According to the hydrophobicity nisin resistant variant of L. monocytogenes was more hydrophobic (p < 0.001), whereas the pediocin 34 and enterocin FH99 resistant variants were less hydrophobic than the wild type strain. Nisin, pediocin 34 and enterocin FH99 resistant variants of E. faecium DSMZ 20477 and E. faecium VRE were less hydrophobic than their wild type counterparts. Nisin resistant E. faecalis ATCC 29212 was less hydrophobic than its wild type counterpart. PMID- 24493881 TI - Structure-function activity of dehydrozingerone and its derivatives as antioxidant and antimicrobial compounds. AB - Dehydrozingerone, structural half analogue of curcumin, is a phenolic compound isolated from ginger (Zingiber officinale) rhizomes. Dehydrozingerone and several of its derivatives such as glucopyranosides and its tetra acetate derivative and 4-O-acetyl and methyl derivatives of dehydrozingerone were synthesized in the present study. Dehydrozingerone, synthesised with improved yield was used for the synthesis of Dehydrozingerone 4-O-beta-D-glucopyranoside (first time report) by modified Koenigs-Knorr-Zemplen method. Structures of all the compounds have been established using spectroscopic methods. These compounds were tested for radical scavenging activity by DPPH and FRAP method as well as for antibacterial and antifungal activities. The parent molecule exhibited better scavenging activity as compared to its derivatives indicating the significance of free phenolic hydroxyl group. Also, Dehydrozingerone and its derivatives exhibited antibacterial as well as antifungal activity due to the conjugation system present, which includes alpha,beta-unsaturated carbonyl (C = O) group. This study gave an insight into structural requirements for dehydrozingerone activity. PMID- 24493882 TI - Effect of number and washing solutions on functional properties of surimi-like material from duck meat. AB - Duck meat is less utilized than other meats in processed products because of limitations of its functional properties, including lower water holding capacity, emulsion stability, and higher cooking loss compared with chicken meat. These limitations could be improved using surimi technology, which consists of washing and concentrating myofibrillar protein. In this study, surimi-like materials were made from duck meat using two or three washings with different solutions (tap water, sodium chloride, sodium bicarbonate, and sodium phosphate buffer). Better improvement of the meat's functional properties was obtained with three washings versus two washings. Washing with tap water achieved the highest gel strength; moderate elevation of water holding capacity, pH, lightness, and whiteness; and left a small amount of fat. Washing with sodium bicarbonate solution generated the highest water holding capacity and pH and high lightness and whiteness values, but it resulted in the lowest gel strength. Processing duck meat into surimi-like material improves its functional properties, thereby making it possible to use duck meat in processed products. PMID- 24493883 TI - Experimental design of medium optimization for invertase production by Pichia sp. AB - The culture medium requirement for invertase production by Pichia sp. was optimized and identified by initial screening method of Plackett-Burman. Furthermore, optimum concentrations of medium components, which were selected by in initial screening by Plackett-Burman, were determined by the Box-Behnken and its representative three-factor response-surface method. The regression models showed significantly high R (2) values of 97% for invertase activities, indicating that they are appropriate for predicting relationships between yeast extract, peptone and sucrose concentration with invertase production. According to the model the optimal concentrations of sucrose, yeast extract and peptone were 40, 5 and 4 g/ml, respectively. These predicted conditions were verified by validation experiments. In the optimized medium Pichia sp. produced invertase with activity of 38.71 U/ml, which is 4 times higher than that produced in original medium. Thus, this statistical approach enabled rapid identification and integration of key medium parameters for Pichia sp. BCCS M1, resulted the high invertase production. PMID- 24493884 TI - Optimization of some conditions of Neutrase-catalyzed plastein reaction to mediate ACE-inhibitory activity in vitro of casein hydrolysate prepared by Neutrase. AB - Casein hydrolysate was prepared by hydrolyzing casein with Neutrase and then modified by a Neutrase-catalyzed plastein reaction. The prepared hydrolysate had a degree of hydrolysis of 13.0% and exhibited ACE inhibition in vitro with an IC50 value of 40.4 MUg?mL(-1). With the decreased amount of free amino groups of the modified hydrolysate as the response, some conditions of the plastein reaction including substrate concentration, enzyme to substrate ratio, reaction temperature and time were studied by single factor experiments and response surface methodology, and optimized finally as 62% (w/w), 3.0 kU?g(-1) peptides, 30 degrees C and 6.3 h, respectively. The maximum decreased amount of free amino groups of the modified hydrolysate prepared under these optimized conditions was 210.0 MUmol?g(-1) peptides, while corresponding IC50 value was lowered to 14.7 MUg?mL(-1). The present result indicates that Neutrase-catalyzed plastein reaction was capable of enhancing ACE-inhibitory activity in vitro of casein hydrolysate, and also highlights the importance of a forthcoming study to investigate the peptide compositions of the modified hydrolysate and the role of protease used in the plastein reaction. PMID- 24493885 TI - Quality changes of anchovy (Stolephorus heterolobus) under refrigerated storage of different practical industrial methods in Thailand. AB - Quality changes of anchovy (Stolephorus heterolobus) muscle during 7 days of refrigerated storage with ice and without ice were studied using several indicators: changes of ATP degradation products, K-value, TVB-N, TMA-N, Lactic acid, biogenic amines, sensory and microbiological analysis. During 7-day of refrigerated storage with ice and without ice, K-value, TVB-N, TMA-N and D, L lactic acids contents increased with longer storage time (p <= 0.05). Major biogenic amines found in anchovy muscle during refrigerated storage were cadaverine, agmatine and tyramine, followed by putrescine and histamine. Skin and external odour by sensory evaluation, progressive decreases were observed as refrigeration time progressed. Storage of anchovy with ice resulted in a better maintenance of sensory quality, better control microbial activity, and the slowing down of biochemical degradation mechanisms. This result introduces the use of refrigerated storage with ice as a practical preliminary chilling for anchovy during industrial processing. PMID- 24493886 TI - Characterization of modified pearl millet (Pennisetum typhoides) starch. AB - Pearl millet starch (Pennisetum typhoides) was isolated and subjected to hydrothermal, acidic and enzymatic modifications. Native and various modified starches were characterized in terms of yield, moisture, protein, ash, bulk density, swelling power, solubility, colour, sediment volume, gel consistency, water binding capacity, pasting properties, freeze thaw stability and paste clarity. Hydrothermal modification (HTMS) caused an increase in swelling power and solubility. L value was higher for acid and enzymatically modified starches (EMS). A significant reduction (p <= 0.05) in sediment volume and water binding capacity was observed for acid modified starch (AMS) and EMS. Peak viscosity values declined for all modifications. However, EMS and AMS showed an improved freeze-thaw stability and paste clarity. PMID- 24493887 TI - Moisture sorption characteristics of wadi, a legume-based traditional condiment. AB - Moisture sorption characteristics of wadi, a condiment in the Indian Subcontinent, were investigated at temperature of 15-45 degrees C and water activities (aw) of 0.11-0.97. The sorption isotherms were sigmoidal. Nine different mathematical models were found to effectively describe the moisture sorption data on the basis of regression analyses and goodness of fit. Each model was statistically evaluated by means of percent root mean square and coefficient of determination. The GAB model gave the best fit in the entire range of aw. Temperature dependence of the GAB constants and good fit were determined. Using the Caurie's model, the properties of sorbed water, such as monolayer moisture content, number of adsorbed monolayers, density of sorbed water, bound water content and surface area of adsorption, which decreased with an increase in temperature, were calculated. The monolayer moisture content ranged from 102.7 to 128.7 g/kg solids in wadi. The optimum storage temperature and aw for wadi were 15-25 degrees C and <0.7, respectively. PMID- 24493888 TI - In vitro hypoglycemic effects of Butea monosperma Lam. leaves and bark. AB - The present study evaluated the antidiabetic potential of Butea monosperma Lam. Kuntze (Fabaceae) leaves and the stem bark using various in vitro techniques. The samples were studied for their effects on glucose adsorption, diffusion, amylolysis kinetics, enteric enzymes and glucose transport across yeast cells. Both the samples adsorbed glucose and the adsorption of glucose increased with increase in glucose concentration. The samples also inhibited movement of glucose across the dialysis membrane to varying degree in both glucose diffusion and amylolysis kinetic experiment models. B. monosperma leaves inhibited alpha amylase, alpha-glucosidase and sucrase enzymes in succession to varying degrees, whereas the bark inhibited only alpha-amylase to a significant extent and slightly activated alpha-glucosidase and sucrase enzymes. The extracts of both leaves and bark promoted glucose uptake by yeast cells compared to control. Enhancement of glucose uptake was dependent on both the sample and glucose concentration. It was directly proportional to the sample concentration and inversely proportional to the molar concentration of the glucose. From the results of the study, it is inferred that, B. monosperma leaves and bark possesses antidiabetic activity. However, these effects need to be confirmed using in vivo models and clinical trials for its effective utilization as therapeutic agents. PMID- 24493889 TI - Plastic fats from sal, mango and palm oil by lipase catalyzed interesterification. AB - Speciality plastic fats with no trans fatty acids suitable for use in bakery and as vanaspati substitute were prepared by interesterification of blends of palm stearin (PSt) with sal and mango fats using Lipozyme TLIM lipase as catalyst. The blends containing PSt/sal or PSt/mango showed short melting range and hence are not suitable as bakery shortenings. Lipase catalysed interesterification extended the plasticity or melting range of all the blends. The blends containing higher proportion of PSt with sal fat (50/50) were harder having high solids at and above body temperature and hence cannot be used as bakery shortenings. The blends with PSt/sal (30-40/60-70) after interesterification showed melting profiles similar to those of commercial hydrogenated bakery fats. Similarly, the blends containing PSt/mango (30-40/60-70) after interesterification also showed melting profiles similar to those of commercial hydrogenated shortenings. The slip melting point and solidification characteristics also confirm the plastic nature of these samples. The improvement in plasticity after interesterification is due to formation of higher melting as well as lower melting triglycerides during lipase catalysed interesterification. PMID- 24493890 TI - Enzymatic and non-enzymatic antioxidant potentials of Chlorella vulgaris grown in effluent of a confectionery industry. AB - Enzymatic and non-enzymatic antioxidant potentials of Chlorella vulgaris have gained considerable importance in recent decades. C. vulgaris strain highly tolerant to extreme pH variations was isolated and mass-cultivated in the wastewater from a confectionery industry. C.vulgaris showed better growth in wastewater than in improvised CFTRI medium. The microalgal biomass was then screened for the following antioxidants: peroxidase, superoxide dismutase, polyphenol oxidase, glutathione peroxidase, chlorophyll a, ascorbic acid, alpha tocopherol and reduced glutathione. The total polyphenol content of the strain was also studied. The strain showed a high degree of enzymatic antioxidant activity (0.195 * 10(-5) +/- 0.0072 units/cell peroxidase, 0.04125 * 10(-5) +/- 0.001 units/cell superoxide dismutase, 0.2625 * 10(-5) +/- 0.003 units/cell polyphenol oxidase and 0.025 * 10(-5) +/- 0.003 glutathione peroxidase). The microalgal biomass also showed, per milligram weight, 0.2182 +/- 0.005 MUg of ascorbic acid, 0.00264 +/- 0.001 MUg of alpha-tocopherol and 0.07916 +/- 0.004 MUg of reduced glutathione. These results represent the possibility of using C. vulgaris grown in confectionery industry wastewater as a source of nutritious supplement, which is highly promising in terms of both economic and nutritional point of view. PMID- 24493892 TI - Physico-chemical changes in rice bran oil during heating at frying temperature. AB - Rice bran oil was subjected to static heating at 180 + 2 degrees C in a domestic fryer for 8 h in this process 150 ml of the heated oil samples were drawn, at intervals of every 2 h, to study the changes in the physico-chemical characteristics. Results indicated that the peroxide value and free fatty acid content increased gradually from 0.2 to 2.9 Meq.O2/kg of oil and 0.25 to 0.63% respectively. The oil became darker as given by the colour value (5R + Y) 63 Lovibond units. Tocopherol content was found to decrease from 48 mg/100gram to 5 mg/100gram at the end of 8 h of heating whereas, oryzanol was fairly stable (1.59 to 1.40%). The p-anisidine value and Total polar compound (TPC) increased from 5.04 to 18.30 and 1.0 to1.8% respectively, showing the formation of secondary oxidation products. Rice bran oil is a non-Newtonian fluids having shear thinning behavior. Heating was found to cause an increase in the flow behavior index. Fatty acid composition did not show significant changes except for the linoleic acid content which decreased from 29.4 to 27.1%. PMID- 24493891 TI - Isozymes of antioxidative enzymes during ripening and storage of ber ( Ziziphus mauritiana Lamk.). AB - Isozyme profile of antioxidative enzymes viz. superoxide dismutase (SOD), peroxidase (POX), catalase (CAT) and ascorbate peroxidase (APX) was studied during ripening and storage of two cultivars of ber fruit (Ziziphus mauritiana Lamk.) differing in their shelf-lives viz. Umran (shelf-life, 8-9 d) and Kaithali (shelf-life, 4-5 d). The profile revealed that Umran variety exhibited three bands each of SOD and POX while in Kaithali, these enzymes had two isoenzymes throughout ripening. CAT and APX, however, showed two isozymes each during ripening of both the varieties and the pattern remained the same at all the stages of ripening except at the initial stage i.e immature green stage where single CAT isozyme was visible. During storage, one extra band each of SOD and POX present only in Umran got disappeared at later stages of storage, whereas in Kaithali, the pattern remained unchanged. Also, there was no change in the pattern of CAT and APX isozymes during storage of both the varieties. One isozyme of CAT could be considered as ripening related while one isozyme each of SOD and POX could be related to higher shelf life of fruits. PMID- 24493894 TI - Glycemic and insulinemic responses to carbohydrate rich whole foods. AB - Glycemic and insulinemic responses to food may depend on several intrinsic factors such as the type of sugar, molecular arrangement, size of starch granules, co-components in the whole food like moisture, fat, protein, fiber, as well as external factors like processing technique and total amount consumed. The postprandial glycemic response to equivalent quantities of test food and standard food is compared using Glycemic Index food (GI food). The incremental area under the curve for blood glucose and insulin at fasting, 30, 60, 90 and 120 min after consumption of different doses (50 and 100 g) of carbohydrate rich foods like rice and chapatti were compared with standard food, white bread. The GI food value for 50 g of chapatti and rice was 44 and 11 respectively. The Insulinemic Index food (II food) values, calculated similarly, for 50 g portion of chapatti and rice were 39 and 6 respectively. Glycemic and insulinemic response showed a dose dependent increase from 50 to 100 g. Both glycemic and insulinemic impact of chapatti were found to be significantly higher than that of rice (p < 0.05). The GI food and II food values will facilitate qualitative and quantitative judgment about the selection of specific foods for effective metabolic control. PMID- 24493893 TI - Biological activities of fructooligosaccharide (FOS)-containing Coix lachryma jobi Linn. extract. AB - Fructooligosaccharide (FOS), a prebiotic was extracted from the grain of Coix lachryma-jobi Linn. (Job's tears) by hot water extraction at 60 degrees C for 1 h. The resulting dried powder extract was assayed for FOS content of 1-kestose (GF2), nystose (GF3) and 1-beta-D-fructofuranosylnystose (GF4) using HPLC equipped with RI detector. Total FOS content of the extract was 24.98 +/- 7.48% (g/100 g crude extract). The biological activity including antioxidant and cytotoxicity of the FOS-containing extract was determined. The antioxidant activity by DPPH free radical scavenging of FOS-containing extract was comparable to vitamin C (0.97 fold of vitamin C) with a slight lipid peroxidation inhibition activity. The extract exhibited no cytotoxic effect on normal human skin fibroblast. These results have confirmed not only the source of FOS from Job's tears extract but also its potential application as antioxidant in food or cosmetic products. PMID- 24493895 TI - Quality of omega-3 fatty acid enriched low-fat chicken meat patties incorporated with selected levels of linseed flour/oil and canola flour/oil. AB - The aim of the present study was to compare the nutritional, processing and sensory characteristics of low-fat omega-3 enriched fatty acids chicken meat patties (CMP) prepared with the incorporation of 4% linseed flour (T1), 2% canola flour (T2), 3% linseed oil (T3), and 4% canola oil (T4) and to estimate their cost of production. The total fat and crude fiber content was increased (P < 0.05) with the incorporation of linseed flour. The emulsion stability and cooking yield was greater (P < 0.05) in T4 among all the treatments. The percent shrinkage was lower (P < 0.05) in linseed/canola oil incorporated CMP than their respective flours. The colour and appearance and flavour scores were lower (P < 0.05) in canola flour than canola oil incorporated CMP. The texture scores were not influenced (P < 0.05) in linseed-and canola-treated products. The overall acceptability was greatest (P < 0.05) in T4 whereas, lowest (P < 0.05) in T2 among all treated products. The cost of production was increased by 3-5% with the incorporation of linseed and canola oil whereas it was almost same for control and linseed flour. PMID- 24493896 TI - Functional effects of dried okra powder on reconstituted dried yam flake and sensory properties of ojojo-a fried yam (Dioscorea alata L.) snack. AB - Processing of raw yam (D. alata) tuber (RY) to more stable and instant form could ease the tedium in preparation, increase popularity and commercial potential of ojojo-a fried yam snack. In this study, the potential of dried okra powder (1% 5%) to reduce the sensory quality impairment in ojojo made from instant yam (D. alata) flake (YF) was tested. Inclusion of okra powder significantly increased the viscosity and increased dispersibility of reconstituted yam flour. Addition of okra powder significantly (p < 0.05) reduced the fat and increased the moisture content of ojojo. Furthermore, increasing addition of okra consistently improved the sensory acceptability of ojojo by increasing the product's moistness and fluffiness with reduced crispiness and roughness. In conclusion, addition of 0%-2% of okra powder to reconstituted YF produced ojojo samples which compared favourably with those made from RY in terms of colour, flavour and taste. PMID- 24493897 TI - Utilization of zero-trans non-interesterified and interesterified shortenings in cookie production. AB - The effects of zero-trans chemically interesterified (in-es) and non interesterified (non-in-es) cottonseed (CO), hazelnut (HO) and olive oil (OO) and their blends (25, 50 and 75%) with palm oil (PO) were studied in the production of cookies. All the experimental shortenings had zero-trans fatty acids (TFA) while the shortening contained 14.20% TFA. Incorporation of CO in PO considerably increased the linoleic acid content whereas the raising of HO and OO ratio in the blend increased the oleic acid content. Zero-TFA and lower saturated /unsaturated fatty acid ratio (SFA/UFA) of some of the experimental shortenings indicated an important in nutritional properties of cookies produced from these experimental shortenings. Cookies with in-es shortenings showed significantly higher (p < 0.05) spread ratios and L Hunter color than their non-in-es shortenings added counterparts. It can be concluded that chemical interesterification is a promising method to produce cookie shortenings with zero-TFA. PMID- 24493898 TI - Optimization of extraction conditions for phytic acid from rice bran using response surface methodology and its antioxidant effects. AB - Solid-liquid extraction of phytic acid (PA) from rice bran was optimized by the maximization of the yield using response surface methodology. A Box-Behnken design was used to monitor the effects of three processing parameters of extraction on the PA yield, including ratio of acid solution to raw material (mL/g), hydrochloric acid concentration (mol/L), and extraction time (h). The results showed that the optimal conditions were acid solution/raw material of 8.5:1 (mL/g), HCl concentration 0.62 mol/L and extraction time 5.5 h. Validation tests indicated that the actual yield of PA was (2.15 +/- 0.02)% with RSD = 1.92% (n = 5) under the optimized conditions, which was in good agreement with predicted yield. Antioxidant assays suggested that the extracted PA had weaker DPPH, hydroxyl and superoxide free-radical-scavenging capabilities than vitamin C at the same concentration of 0.5 mg/mL. PMID- 24493899 TI - Identification of anthocyanins in black soybean (Glycine max (L.) Merr.) varieties. AB - Anthocyanin pigments in black soybean (Glycine max (L.) Merr.) varieties as Tawonkong (TW) and Geomjeongkong-2 (G2) were identified to evaluate their potentials as nutritional function, natural colorant or functional foods. Anthocyanin extraction was conducted with acidified methanol with 0.1 M HCl (85:15, v/v). Identification of anthocyanin was conducted by comparison with purified standards by HPLC and mass spectrometry (MS). G2 showed six different types of pigments by HPLC, whereas TW showed seven pigments. Three major anthocyanins (peaks 1, 3, 4) were detected in both varieties and peak 1 was characterized as delphinidin-3-O-beta-D-glucoside, peak 3 as cyanidin-3-O-beta-D glucoside (C3G), and peak 4 as petunidin-3-O-beta-D-glucoside by comparison of chromatographic properties with authentic standards and MS. Minor peaks 5, 6 and 7 in TW were tentatively identified as pelargonidin-3-O-glucoside, pelargonidin-3 O-(6"-malonylglucoside) and cyanidin on the basis of MS. MS with major ions at 287 and 449 of peak 2 were exactly same as those of peak 3 meaning that peak 2 has cyanidin and other hexose different from glucose. After acid hydrolysis of fractioned peak 2, HPLC showed the hexose as galactose, and peak 2 was identified as C3Glactose. The most abundant anthocyanin in black soybean (Glycine max (L.) Merr.) was C3G and G2 showed the higher amount of total anthocyanins than TW (p < 0.001). PMID- 24493900 TI - Effect of frozen storage on the anthocyanins and phenolic components of pomegranate juice. AB - Pomegranate juice's valuable nutritional components may be reduced during its processing or storage. This work examined the effect of frozen storage at -25 degrees C on some chemical characteristics of pomegranate juice. Total anthocyanin content of pomegranate juice, which was measured using the pH differential method, decreased by 11% after 20 days of frozen storage. Phenolic components, measured using a Folin and Ciocalteu assay by means of a UV-vis spectrophotometer, decreased by 29% after 20 days of frozen storage. Antioxidant activity, measured based on the radical scavenging properties of the juice using the 2,2-diphenyl-1-picrylhydrazyl method, decreased by 50% after 20 days of frozen storage. Pomegranate juice has 5 major anthocyanins, including Cyanidin 3 glucoside, Cyanidin 3,5-diglucoside, Delphinidin 3-glucoside, Pelargonidin 3 glucoside and Pelargonidin 3,5-diglucoside are 5 major anthocyanins of pomegranate juice. They were measured using the LC-MS method and results showed that Pelargonidin 3,5- diglucoside had the greatest decrease. Also, the LC-MS method showed that ellagic acid decreased by 15%. PMID- 24493901 TI - Comparative antioxidant effect of BHT and water extracts of banana and sapodilla peels in raw poultry meat. AB - Antioxidant properties of banana (Musa paradisiaca) and Sapodilla/Chikoo (Manilkara zapota) peel extracts in chicken patties were evaluated. Four treatments viz., I. Control (meat + 2% salt), II.BHT (meat + 2% salt + 0.1% BHT), III. BPE (meat + 2% salt + 2% banana peel extract) and IV. SPE (meat + 2% salt + 2% sapodilla/chikoo peel extract) were compared for changes in colour and lipid oxidation during 8 days refrigerated storage (4 +/- degrees C). The average phenolic content was 550.2 and 550.8 mg gallic acid equivalent per 10 g peel in BPE and SPE respectively. Free radical scavenging activity was 66.9 and 67.8% in BPE and SPE respectively. Banana peel extract had significantly (P < 0.05) higher reducing activity (1.6) as compared to sapodilla peel extract (0.91). During refrigerated storage period, all color parameters decreased significantly in all treatments. Observation on lipid oxidation showed a significantly (P < 0.05) higher TBARS values in control than other three treatments. The increase in TBARS from initial day of storage to last day of storage was highest in control (514.3%) as compared to BHT (387.7%), BPE (370.6%) and SPE (383.7%). Both synthetic antioxidants and natural extracts significantly decreased the TBARS. The average decrease in TBARS values during 8 days of storage was 56.8%, 38.3% and 37.2% values in BHT, BPE and SPE treatments respectively. Therefore, it was concluded that water extracts obtained from banana and sapodilla peels could be explored as natural antioxidants in poultry meat and meat products. PMID- 24493902 TI - Glycemic index and significance of barnyard millet (Echinochloa frumentacae) in type II diabetics. AB - The study was undertaken to assess nutrient composition, glycemic index and health benefits of barnyard millet in type II diabetics. The millet had 10.5% protein 3.6% fat, 68.8% carbohydrate and 398 kcal/100 g energy. The total dietary fibre content was high (12.6%) including soluble (4.2%) and insoluble (8.4%) fractions. Low glycemic index of the grains both dehulled (50.0) and dehulled and heat treated (41.7) was recorded. The feeding intervention of 28 days revealed a significant reduction in glucose (139.2 to 131.1 mg/dl), LDL-C (from 167.7 to 162.9 mg/dl), VLDL-C (from 24.0 to 23.2 mg/dl), ratio of TC: HDL (from 4.7 to 4.6) and LDL: HDL (from 3.2 to 3.1) in the experimental diabetic groups. Similar, but marginal changes were observed in experimental non diabetics. Marginal decrease of triglycerides and increase of HDL were registered in diabetic groups due to barnyard millet intervention. The study indicated that the dehulled and heat treated barnyard millet is beneficial for type-II diabetics. PMID- 24493903 TI - Manufacture of low lactose concentrated ultrafiltered-diafiltered retentate from buffalo milk and skim milk. AB - Lactose concentration was reduced by 68.64 and 74.64 % in buffalo milk and skim milk by their respective 3.05 fold and 4.4 fold UF-DF concentration. The maximum UF-DF concentration of buffalo milk to 66.65 % volume reduction was observed as compared to 74.35 % volume reduction in buffalo skim milk. Average initial permeate flux rate of buffalo milk (42.86 l/h/m(2)) was much lower than skim milk (71.43 l/h/m(2)), which dropped to 2.86 and 5.95 l/h/m(2) during UF-DF concentration. The initial permeate flux rate of homogenized buffalo milk (26.79 l/h/m(2)) was comparatively lower than that of buffalo milk which dropped to 2.38 l/h/m(2) after 66.33 % volume reduction and 3.02 fold UF-DF concentration. PMID- 24493904 TI - Detection of hemolytic strains of Aeromonas hydrophila and A . sobria along with other Aeromonas spp. from fish and fishery products by multiplex PCR. AB - Hemolytic strains of Aeromonas spp. from fish and fishery products were detected by multiplex PCR. The selected primers for the amplification of segments of ahh1, asa1 and 16S rRNA gene yielded products with the size of 130 bp, 249 bp and 356 bp, respectively. This assay was found to be highly sensitive, as it could detect 7 and 9 cells of Aeromonas hydrophila and A. sobria with a detection limit of 1 pg of pure genomic DNA. The assay, when screened for 73 commercial fish and fishery product samples consisting of freshwater, marine fish and shellfish, showed 56 % positive for Aeromonas spp., 16 % for Aeromonas hydrophila and 13 % for A. sobria. This assay provides specific and reliable results and can be a powerful tool for the simultaneous detection of hemolytic strains of A. hydrophila A. sobria and other Aeromonas spp. from fish and fishery products. PMID- 24493905 TI - A Convergent Synthesis of Homogeneous Reducible Polypeptides. AB - The convergent syntheses of homogeneous disulfide cross-linked polypeptides are reported. Reducible polypeptides were synthesized containing four and eight dodecapeptides in two and three linear conjugation steps. Critical for the convergent methodology was the use of orthogonally protected cysteines as either acetamidomethyl (Acm) or Fmoc-thiazolidine (Thz). Both groups could be selectively deprotected with silver trifluoromethanesulfonate in the presence of internal disulfide bonds using TFA and aqueous conditions, respectively. This approach allows for large, reducible polypeptides to be synthesized in efficient yields and minimizes the number of conjugation steps, allowing the development and optimization of gene delivery polypeptides containing multiple peptide components necessary to overcome the numerous in vivo barriers for efficacious gene delivery. PMID- 24493906 TI - Dimensions of Temperament and Depressive Symptoms: Replicating a Three-Way Interaction. AB - High negative emotionality (NE), low positive emotionality (PE), and low self regulatory capacity (i.e., effortful control or EC) are related to depressive symptoms and furthermore, may moderate one another's relations to such symptoms. Indeed, preliminary evidence suggests they may operate in a three-way interaction (Dinovo & Vasey, 2011), but the replicability of that finding remains unknown. Therefore, we tested this NExPExEC interaction in association with depressive symptoms in 5 independent samples. This interaction was significant in 4 of the 5 samples and a combined sample and approached significance in the fifth sample. In contrast, the NExPExEC interaction was unrelated to general anxious symptoms and thus may be specific to symptoms of depression. Implications, directions for future research, and limitations are discussed. PMID- 24493907 TI - Infant word recognition: Insights from TRACE simulations. AB - The TRACE model of speech perception (McClelland & Elman, 1986) is used to simulate results from the infant word recognition literature, to provide a unified, theoretical framework for interpreting these findings. In a first set of simulations, we demonstrate how TRACE can reconcile apparently conflicting findings suggesting, on the one hand, that consonants play a pre-eminent role in lexical acquisition (Nespor, Pena & Mehler, 2003; Nazzi, 2005), and on the other, that there is a symmetry in infant sensitivity to vowel and consonant mispronunciations of familiar words (Mani & Plunkett, 2007). In a second series of simulations, we use TRACE to simulate infants' graded sensitivity to mispronunciations of familiar words as reported by White and Morgan (2008). An unexpected outcome is that TRACE fails to demonstrate graded sensitivity for White and Morgan's stimuli unless the inhibitory parameters in TRACE are substantially reduced. We explore the ramifications of this finding for theories of lexical development. Finally, TRACE mimics the impact of phonological neighbourhoods on early word learning reported by Swingley and Aslin (2007). TRACE offers an alternative explanation of these findings in terms of mispronunciations of lexical items rather than imputing word learning to infants. Together these simulations provide an evaluation of Developmental (Jusczyk, 1993) and Familiarity (Metsala, 1999) accounts of word recognition by infants and young children. The findings point to a role for both theoretical approaches whereby vocabulary structure and content constrain infant word recognition in an experience-dependent fashion, and highlight the continuity in the processes and representations involved in lexical development during the second year of life. PMID- 24493908 TI - Inaugurating the Study of Animal Metacognition. AB - Metacognition-the ability to monitor and control one's own cognition-is a sophisticated ability that reveals humans' reflective mind and consciousness. Researchers have begun to explore whether animals share humans' metacognitive capacity. This article reprises the original study that explored metacognition across species. A captive dolphin performed an auditory pitch-discrimination task using High/Low discrimination responses and an Uncertainty response with which he could decline to complete any trials he chose. He selectively declined the difficult trials near his discriminative threshold-just as humans do. This comparative exploration of metacognition required a trial-intensive titration of perceptual threshold and the training of a distinctive behavioral response. It could not have been conducted in the wild, though the naturalistic observation of dolphin uncertainty behaviors and risk-management strategies would no doubt yield complementary insights. The dolphin study inaugurated a new area of cross-species research. This research area opens a new window on reflective mind in animals, illuminates the phylogenetic emergence of metacognition, and may reveal the antecedents of human consciousness. PMID- 24493909 TI - Contact CMOS imaging of gaseous oxygen sensor array. AB - We describe a compact luminescent gaseous oxygen (O2) sensor microsystem based on the direct integration of sensor elements with a polymeric optical filter and placed on a low power complementary metal-oxide semiconductor (CMOS) imager integrated circuit (IC). The sensor operates on the measurement of excited-state emission intensity of O2-sensitive luminophore molecules tris(4,7-diphenyl-1,10 phenanthroline) ruthenium(II) ([Ru(dpp)3]2+) encapsulated within sol-gel derived xerogel thin films. The polymeric optical filter is made with polydimethylsiloxane (PDMS) that is mixed with a dye (Sudan-II). The PDMS membrane surface is molded to incorporate arrays of trapezoidal microstructures that serve to focus the optical sensor signals on to the imager pixels. The molded PDMS membrane is then attached with the PDMS color filter. The xerogel sensor arrays are contact printed on top of the PDMS trapezoidal lens-like microstructures. The CMOS imager uses a 32 * 32 (1024 elements) array of active pixel sensors and each pixel includes a high-gain phototransistor to convert the detected optical signals into electrical currents. Correlated double sampling circuit, pixel address, digital control and signal integration circuits are also implemented on-chip. The CMOS imager data is read out as a serial coded signal. The CMOS imager consumes a static power of 320 uW and an average dynamic power of 625 uW when operating at 100 Hz sampling frequency and 1.8 V DC. This CMOS sensor system provides a useful platform for the development of miniaturized optical chemical gas sensors. PMID- 24493910 TI - QRS as a Risk Stratification Tool: Putting the Fragments Together. PMID- 24493911 TI - Fragmented QRS as a Predictor of Appropriate Implantable Cardioverter defibrillator Therapy. AB - BACKGROUND: Fragmented QRS (fQRS) has been shown to be a marker of local myocardial conduction abnormalities and a predictor of cardiac events in selected populations. We hypothesized that the presence of a fQRS might predict arrhythmic events in patients who received an implantable cardioverter-defibrillator (ICD), regardless of the indications for implantation. METHODS AND RESULTS: A cohort of 107 consecutive patients (mean age, 53 years; 82% male) who underwent an ICD implantation was studied. We defined fQRS, on a routine 12-lead ECG, as the presence of an additional R wave or notching in the nadir of the S wave in 2 consecutive leads corresponding to a major coronary artery territory. In the presence of bundle branch block, more than 2 notches in the R or S waves in 2 consecutive leads were required to characterize fQRS. Patients were followed for 21.3+/-23 months for appropriate ICD therapy (antitachycardia pacing and/or shock). ICDs were implanted predominantly in patients with ischemic cardiomyopathy (N=45, 42.1%), followed by Brugada syndrome (N=26, 24.3%). fQRS presented in 42 patients (39.3%). During follow-up, patients with fQRS received more appropriate ICD therapy than those without fQRS (45.2% vs. 10.8%, P<0.0001). After adjustment for covariates, fQRS remained an independent predictor for appropriate ICD therapy (hazard ratio=5.32, 95% confidence interval=2.11-13.37, P<0.0001). CONCLUSION: The presence of fQRS appeared to be directly associated with appropriate ICD therapy. PMID- 24493912 TI - Dual atrioventricular nodal pathways physiology: a review of relevant anatomy, electrophysiology, and electrocardiographic manifestations. AB - More than half a century has passed since the concept of dual atrioventricular (AV) nodal pathways physiology was conceived. Dual AV nodal pathways have been shown to be responsible for many clinical arrhythmia syndromes, most notably AV nodal reentrant tachycardia. Although there has been a considerable amount of research on this topic, the subject of dual AV nodal pathways physiology remains heavily debated and discussed. Despite advances in understanding arrhythmia mechanisms and the widespread use of invasive electrophysiologic studies, there is still disagreement on the anatomy and physiology of the AV node that is the basis of discontinuous antegrade AV conduction. The purpose of this paper is to review the concept of dual AV nodal pathways physiology and its varied electrocardiographic manifestations. PMID- 24493913 TI - Successful Non-fluoroscopic Radiofrequency Ablation of Incessant Atrial Tachycardia in a High Risk Twin Pregnancy. AB - We describe a patient presenting with incessant ectopic atrial tachycardia during a high risk twin pregnancy. Tachycardia was resistant to escalating doses of beta blockade with digoxin. Because of increasing left ventricular dysfunction early in the third trimester, catheter ablation was performed successfully at 30 weeks gestation. Electro-anatomic mapping permitted the entire procedure to be conducted without the use of ionizing radiation. The pregnancy proceeded to successful delivery near term and after three years the patient remains recurrence free with normal left ventricular function, off all medication. PMID- 24493914 TI - Evaluation of Left Ventricular Endocardial Cardiac Resynchronization Therapy in a Non-responder with Ventricular Arrhythmias. AB - Approximately one third of patients treated with cardiac resynchronization therapy do not derive any detectable benefit. In these patients, acute invasive hemodynamic evaluation can be used for therapy optimization. This report describes the use of systematic invasive hemodynamic measurements for clinical decision making in a patient who experienced severe ventricular arrhythmias and clinical deterioration following a biventricular upgrade. PMID- 24493915 TI - Complex biventricular pacing - a case series. AB - It is established that cardiac resynchronisation therapy (CRT) reduces mortality and hospitalisation and improves functional class in patients with NYHA class 3-4 heart failure, an ejection fraction of <= 35% and a QRS duration of >= 120ms. Recent updates in the American guidelines have expanded the demographic of patients in whom CRT may be appropriate. Here we present two cases of complex CRT; one with a conventional indication but occluded central veins and the second with a novel indication for CRT post cardiac transplant. PMID- 24493916 TI - Dual AV Nodal Nonreentrant Tachycardia Resulting in Inappropriate ICD Therapy in a Patient with Cardiac Sarcoidosis. AB - Dual atrioventricular nodal nonreentrant tachycardia (DAVNNT) occurs due to concurrent antegrade conduction over fast and slow atrioventricular nodal pathways and is treated by slow pathway modification. We describe a unique case of a patient with cardiac sarcoidosis who received inappropriate ICD shocks for DAVNNT. Atrial and ventricular device electrograms satisfied both rate and V>A criteria for ventricular tachycardia. We postulate that alterations in refractoriness and conduction as is seen in cardiac sarcoidosis (CS) may have contributed to occurrence of DAVNNT. PMID- 24493917 TI - Parahisian atrial tachycardia: cryoablation from the aortic cusp. PMID- 24493918 TI - The ABC of a Simple Method for Pulmonary Vein Angiography. AB - Catheter-directed intervention to treat atrial fibrillation (AF) is becoming widely accepted procedure in current clinical practice. For assessment of pulmonary vein (PV) anatomy, angiography of left atrium (LA) and/or PV is often performed. We present a new, simple angiographic method for PVs and LA opacification using SL1 sheath. Total of 100 patients in our clinic underwent this procedure. In all of the cases good angiographic results were achieved. No immediate or late complications related to this procedure were observed. PMID- 24493919 TI - Idiopathic right atrial scar. PMID- 24493920 TI - Reducing dropout of contact lens wear with Biotrue multipurpose solution. AB - PURPOSE: To evaluate whether the use of Biotrue multipurpose solution (MPS) could significantly reduce the likelihood with which patients drop out of using daily wear contact lenses (CLs) amongst 18-44-year-old frequent replacement CL wearers. METHODS: Daily wear CL subjects habitually using MPSs (other than Biotrue MPS) who reported an intent to imminently drop out of CL wear because of comfort and dryness complaints were recruited to participate in this investigation. Subjects were switched to Biotrue MPS and continued to use habitual CL types with the new MPS for 2 weeks. Subjects completed an online satisfaction questionnaire at baseline and after 2 weeks to assess the change in symptoms and the intent to drop out of CL wear. Six months after completion of the initial study, a follow up survey was administered to a subset of the initial participants. RESULTS: A total of 153 daily wear (silicone hydrogel and hydrogel) subjects completed this 2-week study with Biotrue MPS. When measuring those with the highest propensity to drop out of lens wear (n=93) after switching to Biotrue MPS, 90% of subjects significantly reduced their likelihood of dropping out of CL wear (P<0.0001). Online interviews were conducted with 73 of the study participants 6 months after completion of the initial study. A total of 93% of participants responded that they were still wearing CLs at least once per week. Of the 7% of respondents who were not currently wearing lenses 6 months after the initial study, two had dropped out of lens wear completely, and three still wore lenses less than once per week. CONCLUSION: Patients intending to drop out of CL wear due to discomfort and dryness significantly reduced their propensity of discontinuing lens wear following use of Biotrue MPS. Six months after completion of the study, 93% of patients were still wearing CLs at least once per week. PMID- 24493921 TI - Listeria monocytogenes endophthalmitis following keratoconjunctivitis. AB - Endophthalmitis due to endogenous or exogenous bacteria is a rare infection of the eye. We report a case of endophthalmitis following Listeria monocytogenes keratoconjunctivitis in a 27-year-old healthy white male presenting with hand motion visual acuity, right eye mucopurulent conjunctivitis, elevated intraocular pressure, and pigmented hypopyon 6 months post-keratectomy. The conjunctivitis was unresponsive to a 5-day course of topical tobramycin eye drops, and the patient developed keratitis with pain that progressed to endophthalmitis after 21 days. Diagnostic B-scan revealed vitreous exudates. Intraocular fluid specimen showed Gram-positive organisms and the aqueous culture grew penicillin /aminoglycoside-sensitive L. monocytogenes. The patient was given intravitreal and systemic vancomycin and ceftazidime. The eye was unresponsive to intravenous penicillin and gentamicin; the anterior chamber progressively flattened and developed phthisis bulbi. L. monocytogenes keratoconjunctivitis may lead to bacterial endophthalmitis. Prompt culture and early antibiotic therapy are recommended. PMID- 24493922 TI - Advance care planning in stroke: influence of time on engagement in the process. AB - PURPOSE: Individuals who experience stroke have a higher likelihood of subsequent stroke events, making it imperative to plan for future medical care. In the event of a further serious health event, engaging in the process of advanced care planning (ACP) can help family members and health care professionals (HCPs) make medical decisions for individuals who have lost the capacity to do so. Few studies have explored the views and experiences of patients with stroke about discussing their wishes and preferences for future medical events, and the extent to which stroke HCPs engage in conversations around planning for such events. In this study, we sought to understand how the process of ACP unfolded between HCPs and patients post-stroke. PATIENTS AND METHODS: Using grounded theory (GT) methodology, we engaged in direct observation of HCP and patient interactions on an acute stroke unit and two stroke rehabilitation units. Using semi-structured interviews, 14 patients and four HCPs were interviewed directly about the ACP process. RESULTS: We found that open and continual ACP conversations were not taking place, patients experienced an apparent lack of urgency to engage in ACP, and HCPs were uncomfortable initiating ACP conversations due to the sensitive nature of the topic. CONCLUSION: In this study, we identified lack of engagement in ACP post-stroke, attributable to patient and HCP factors. This encourages us to look further into the process of ACP in order to develop open communication between the patient with stroke, their families, and stroke HCPs. PMID- 24493923 TI - Clinical issues of mucus accumulation in COPD. AB - Airway mucus is part of the lung's native immune function that traps particulates and microorganisms, enabling their clearance from the lung by ciliary transport and cough. Mucus hypersecretion and chronic productive cough are the features of the chronic bronchitis and chronic obstructive pulmonary disease (COPD). Overproduction and hypersecretion by goblet cells and the decreased elimination of mucus are the primary mechanisms responsible for excessive mucus in chronic bronchitis. Mucus accumulation in COPD patients affects several important outcomes such as lung function, health-related quality of life, COPD exacerbations, hospitalizations, and mortality. Nonpharmacologic options for the treatment of mucus accumulation in COPD are smoking cessation and physical measures used to promote mucus clearance. Pharmacologic therapies include expectorants, mucolytics, methylxanthines, beta-adrenergic receptor agonists, anticholinergics, glucocorticoids, phosphodiesterase-4 inhibitors, antioxidants, and antibiotics. PMID- 24493925 TI - Adjuvanted poly(lactic-co-glycolic) acid nanoparticle-entrapped inactivated porcine reproductive and respiratory syndrome virus vaccine elicits cross protective immune response in pigs. AB - Porcine reproductive and respiratory syndrome (PRRS), caused by the PRRS virus (PRRSV), is an economically devastating disease, causing daily losses of approximately $3 million to the US pork industry. Current vaccines have failed to completely prevent PRRS outbreaks. Recently, we have shown that poly(lactic-co glycolic) acid (PLGA) nanoparticle-entrapped inactivated PRRSV vaccine (NP-KAg) induces a cross-protective immune response in pigs. To further improve its cross protective efficacy, the NP-KAg vaccine formulation was slightly modified, and pigs were coadministered the vaccine twice intranasally with a potent adjuvant: Mycobacterium tuberculosis whole-cell lysate. In vaccinated virulent heterologous PRRSV-challenged pigs, the immune correlates in the blood were as follows: 1) enhanced PRRSV-specific antibody response with enhanced avidity of both immunoglobulin (Ig)-G and IgA isotypes, associated with augmented virus neutralizing antibody titers; 2) comparable and increased levels of virus specific IgG1 and IgG2 antibody subtypes and production of high levels of both T helper (Th)-1 and Th2 cytokines, indicative of a balanced Th1-Th2 response; 3) suppressed immunosuppressive cytokine response; 4) increased frequency of interferon-gamma(+) lymphocyte subsets and expanded population of antigen presenting cells; and most importantly 5) complete clearance of detectable replicating challenged heterologous PRRSV and close to threefold reduction in viral ribonucleic acid load detected in the blood. In conclusion, intranasal delivery of adjuvanted NP-KAg vaccine formulation to growing pigs elicited a broadly cross-protective immune response, showing the potential of this innovative vaccination strategy to prevent PRRS outbreaks in pigs. A similar approach to control other respiratory diseases in food animals and humans appears to be feasible. PMID- 24493927 TI - Tipepidine in children with attention deficit/hyperactivity disorder: a 4-week, open-label, preliminary study. AB - BACKGROUND: Tipepidine (3-[di-2-thienylmethylene]-1-methylpiperidine) has been used solely as a nonnarcotic antitussive in Japan since 1959. The safety of tipepidine in children and adults has already been established. It is reported that tipepidine inhibits G-protein-coupled inwardly rectifying potassium (GIRK) channel currents. The inhibition of GIRK channels by tipepidine is expected to modulate the level of monoamines in the brain. We put forward the hypothesis that tipepidine can improve attention deficit/hyperactivity disorder (ADHD) symptoms by modulating monoaminergic neurotransmission through the inhibition of GIRK channels. The purpose of this open-label trial was to confirm whether treatment with tipepidine can improve symptoms in pediatric patients with ADHD. SUBJECTS AND METHODS: This was a 4-week, open-label, proof-of-efficacy pilot study for pediatric subjects with ADHD. Ten pediatric ADHD subjects (70% male; mean age, 9.9 years; combined [inattentive and hyperactive/impulsive] subtype, n=7; inattentive subtype, n=3; hyperimpulsive subtype, n=0) received tipepidine hibenzate taken orally at 30 mg/day for 4 weeks. All subjects were assessed using the ADHD Rating Scale IV (ADHD-RS), Japanese version, and the Das-Naglieri Cognitive Assessment System (DN-CAS), Japanese version. RESULTS: A comparison of baseline scores and 4-week end-point scores showed that all the ADHD-RS scores (total scores, hyperimpulsive subscores, and inattentive subscores) improved significantly (P<0.001). Furthermore, a comparison of baseline DN-CAS total scores and 4-week end-point scores showed a mild trend of improvement (P=0.093). Tipepidine was well tolerated, with no patients discontinuing medication because of side effects. CONCLUSION: Our pilot study suggests that tipepidine therapy may prove to be an effective alternative treatment for pediatric patients with ADHD. Nonetheless, more detailed randomized, double-blind trials are needed to confirm tipepidine's efficacy. PMID- 24493924 TI - Ammonium glycyrrhizinate-loaded niosomes as a potential nanotherapeutic system for anti-inflammatory activity in murine models. AB - BACKGROUND: Liquorice extracts demonstrate therapeutic efficacy in treating dermatitis, eczema, and psoriasis when compared with corticosteroids. In this work, nonionic surfactant vesicles (niosomes, NSVs) containing polysorbate 20 (Tween 20), cholesterol, and cholesteryl hemisuccinate at different molar concentrations were used to prepare monoammonium glycyrrhizinate (AG)-loaded NSVs. The anti-inflammatory properties of AG-loaded NSVs were investigated in murine models. METHODS: The physicochemical properties of the NSVs were characterized using dynamic light scattering. The fluidity of the lipid bilayer was evaluated by measuring the fluorescence intensity of diphenylhexatriene. The drug entrapment efficiency of AG was assessed using high-performance liquid chromatography. The physicochemical stability of the NSVs was evaluated as a function of time using dynamic light scattering combined with Turbiscan Lab Expert analysis. Serum stability was determined by incubating the NSVs with 10% v/v fetal bovine serum. The cytotoxic effects of the NSVs were investigated in human dermal fibroblasts using the Trypan blue dye exclusion assay (for cell mortality) and an MTT assay (for cell viability). Release profiles for the AG loaded NSVs were studied in vitro using cellulose membranes. NSVs showing the most desirable physicochemical properties were selected to test for in vivo anti inflammatory activity in murine models. The anti-inflammatory activity of the NSVs was investigated by measuring edema and nociception in mice stimulated with chemical agents. RESULTS: NSVs showed favorable physicochemical properties for in vitro and in vivo administration. In addition, they demonstrated long-term stability based on Turbiscan Lab Expert analysis. The membrane fluidity of the NSVs was not affected by self-assembling of the surfactants into colloidal structures. Fluorescence anisotropy was found to be independent of the molar ratios of cholesteryl hemisuccinate and/or cholesterol during preparation of the NSVs. The anti-inflammatory AG drug showed no effect on the stability of the NSVs. In vivo experiments demonstrated that AG-loaded NSVs decreased edema and nociceptive responses when compared with AG alone and empty NSVs. In vitro and in vivo results demonstrated that pH sensitive and neutral NSVs show no statistical significant difference. CONCLUSION: NSVs were nontoxic and showed features favorable for potential administration in vivo. In addition, neutral NSVs showed signs of increased anti-inflammatory and antinociceptive responses when compared with AG. PMID- 24493926 TI - Optimized synthesis of glycyrrhetinic acid-modified chitosan 5-fluorouracil nanoparticles and their characteristics. AB - The nanoparticle drug delivery system, which uses natural or synthetic polymeric material as a carrier to deliver drugs to targeted tissues, has a broad prospect for clinical application for its targeting, slow-release, and biodegradable properties. Here, we used chitosan (CTS) and hepatoma cell-specific binding molecule glycyrrhetinic acid to synthesize glycyrrhetinic acid-modified chitosan (GA-CTS). The synthetic product was confirmed by infrared (IR) spectra and hydrogen-1 nuclear magnetic resonance. The GA-CTS/5-fluorouracil (5-FU) nanoparticles were synthesized by combining GA-CTS and 5-FU and conjugating 5-FU onto the GA-CTS nanomaterial. The central composite design was performed to optimize the preparation process as CTS:tripolyphosphate sodium (TPP) weight ratio =5:1, 5-FU:CTS weight ratio =1:1, TPP concentration =0.05% (w/v), and cross link time =50 minutes. GA-CTS/5-FU nanoparticles had a mean particle size of 193.7 nm, a polydispersity index of 0.003, a zeta potential of +27.4 mV, and a drug loading of 1.56%. The GA-CTS/5-FU nanoparticle had a protective effect on the drug against plasma degrading enzyme, and provided a sustained release system comprising three distinct phases of quick, steady, and slow release. Our study showed that the peak time, half-life time, mean residence time and area under the curve of GA-CTS/5-FU were longer or more than those of the 5-FU group, but the maximum concentration (C(max)) was lower. We demonstrated that the nanoparticles accumulated in the liver and have significantly inhibited tumor growth in an orthotropic liver cancer mouse model. PMID- 24493929 TI - Combined overexpression of HIVEP3 and SOX9 predicts unfavorable biochemical recurrence-free survival in patients with prostate cancer. AB - BACKGROUND: To clarify the involvement of HIVEP3 and SOX9 coexpression in prostate cancer (PCa). METHODS: A small interfering RNA was used to knockdown SOX9 expression in a PCa cell line and to analyze the effects of SOX9 inhibition on the expression of HIVEP3 in vitro. Then, HIVEP3 and SOX9 expression patterns in the human PCa tissues were detected using quantitative reverse transcription polymerase chain reaction (qRT-PCR) analysis and immunohistochemistry. RESULTS: We found that the downregulation of SOX9 could inhibit the expression of HIVEP3 in the PCa cells in vitro. In addition, both HIVEP3 and SOX9 messenger RNA expression levels in the PCa tissues were significantly higher than those in the noncancerous prostate tissues (P=0.006 and P<0.001, respectively). Moreover, the immunohistochemical staining scores of HIVEP3 in the PCa tissues with PSA failure were significantly higher than those without (P=0.042); the increased SOX9 protein expression was more frequently found in the PCa tissues with a high Gleason score (P=0.045) and a high clinical stage (P=0.012). The tumors showing the HIVEP3-high/SOX9-high expression more frequently had PSA failure (P=0.024). When the patients with an HIVEP3 overexpression combined with the SOX9 overexpression, this group had a worse biochemical recurrence-free survival (P<0.001). Furthermore, the multivariate analysis showed that the HIVEP3/SOX9 coexpression was an independent predictor of an unfavorable biochemical recurrence-free survival. CONCLUSION: Our data offer the convincing evidence for the first time that a combined analysis of HIVEP3 and SOX9 may help to predict the tumor progression and prognosis of PCa patients. In particular, the overexpression of HIVEP3 in PCa might partly explain the poor prognosis of patients with an upregulation of SOX9. PMID- 24493930 TI - Cost-effectiveness of ticagrelor versus clopidogrel in patients with acute coronary syndromes in Canada. AB - BACKGROUND: Ticagrelor demonstrated a significant reduction in major cardiac events in patients with acute coronary syndrome (ACS) compared with clopidogrel in the Platelet Inhibition and Patient Outcomes (PLATO) trial. The objective of this study was to assess the cost-effectiveness of ticagrelor compared with clopidogrel in ACS patients from the perspective of the Canadian publicly funded health care system. METHODS: A two-part model was developed consisting of a 1 year decision tree and a lifetime Markov model. Within the decision tree, patients remained event-free, experienced a nonfatal myocardial infarction, a nonfatal stroke, or death due to vascular or nonvascular related causes based on data from the PLATO trial. The lifetime Markov model followed these patients and allowed for subsequent myocardial infarction, stroke, and death. Patient utility and resource use were derived from the PLATO trial. Transition probabilities and specific Canadian unit costs were derived from published sources. Univariate and probabilistic sensitivity analyses were conducted. RESULTS: In the base case lifetime analysis, treatment with ticagrelor resulted in more years of life per person (0.097), more quality-adjusted life years per person (QALYs, 0.084), and an incremental cost per QALY gained of $9,745 (Canadian$), assuming a generic cost for clopidogrel. A probabilistic sensitivity analysis demonstrated the robustness of the base case analysis, with a 93% probability of being below $20,000 per QALY gained and a 99% probability of being below $30,000 per QALY gained. CONCLUSION: Ticagrelor is a clinically superior and cost-effective option for the prevention of thrombotic events among ACS patients in Canada. PMID- 24493931 TI - Therapeutic treatment with a novel hypoxia-inducible factor hydroxylase inhibitor (TRC160334) ameliorates murine colitis. AB - BACKGROUND AND AIM: Mucosal healing in inflammatory bowel disease (IBD) can be achieved by improvement of intestinal barrier protection. Activation of hypoxia inducible factor (HIF) has been identified as a critical factor for barrier protection during mucosal insult and is linked with improvement in symptoms of colitis. Although prophylactic efficacy of HIF hydroxylase inhibitors in murine colitis have been established, its therapeutic efficacy in clinically relevant therapeutic settings have not been established. In the present study we aim to establish therapeutic efficacy of TRC160334, a novel HIF hydroxylase inhibitor, in animal models of colitis. METHODS: The efficacy of TRC160334 was evaluated in two different mouse models of colitis by oral route. A prophylactic efficacy study was performed in a 2,4,6-trinitrobenzene sulfonic acid-induced mouse model of colitis representing human Crohn's disease pathology. Additionally, a therapeutic efficacy study was performed in a dextran sulfate sodium-induced mouse model of colitis, a model simulating human ulcerative colitis. RESULTS: TRC160334 treatment resulted in significant improvement in disease end points in both models of colitis. TRC160334 treatment resulted into cytoprotective heatshock protein 70 induction in inflamed colon. TRC160334 successfully attenuated the rate of fall in body weight, disease activity index, and macroscopic and microscopic scores of colonic damage leading to overall improvement in study outcome. CONCLUSION: Our findings are the first to demonstrate that therapeutic intervention with a HIF hydroxylase inhibitor ameliorates IBD in disease models. These findings highlight the potential of TRC160334 for its clinical application in the treatment of IBD. PMID- 24493933 TI - Challenges associated with the management of gynecological cancers in a tertiary hospital in South East Nigeria. AB - BACKGROUND: There are reports of increasing incidence of gynecological cancers in developing countries and this trend increases the need for more attention to gynecological cancer care in these countries. OBJECTIVE: The purpose of this study was to describe the presentation and treatment of gynecological cancers and identify barriers to successful gynecological cancer treatment in a tertiary hospital in South East Nigeria. METHODS: This study was a retrospective longitudinal analysis of the presentation and treatment of histologically diagnosed primary gynecological cancers from 2000 to 2010. Analysis was by descriptive and inferential statistics at the 95% level of confidence using Statistical Package for the Social Sciences version 17 software. RESULTS: Records of 200 gynecological cancers managed during the study period were analyzed. Over 94% of cervical cancers presented in advanced stages of the disease and received palliative/symptomatic treatment. Only 1.9% of cervical cancer patients had radical surgical intervention, and postoperative mortality from these radical surgeries was 100%. Approximately 76% of patients with ovarian cancer had debulking surgery as the mainstay of treatment followed by adjuvant chemotherapy. Postoperative mortality from ovarian cancer surgery was 63%. Cutting edge cytotoxic drugs were not used as chemotherapy for ovarian and chorionic cancers. Compliance with chemotherapy was poor, with over 70% of ovarian cancer patients failing to complete the prescribed courses of chemotherapy. Most patients with endometrial and vulval cancers had only surgical treatment, as compliance with follow-up for adjuvant chemotherapy or radiotherapy was poor. Functional radiotherapy facilities were not available at the center during the study period, thereby necessitating external referrals to centers hundreds of kilometers away. CONCLUSION: Late presentation of cases, noncompliance with treatment regimens, lack of use of cutting edge cytotoxic drugs, the poor outcome of radical surgeries, and lack of a functional radiotherapy facility combined to create a very difficult gynecological cancer care environment at the study center. PMID- 24493932 TI - US perspective on gluten-related diseases. AB - The incidence of allergy and autoimmune disease in the US and other industrialized nations is increasing, and gluten-related disorders are no exception. The US has documented a profound rise in celiac disease that cannot be fully explained by improved serological techniques or better recognition by physicians. Non-celiac gluten sensitivity, a condition only recently recognized by the medical community, has become a commonly diagnosed entity. Proteins, including gluten are increasingly being identified as a source of wheat allergy. Although the gluten free diet represents a safe and effective treatment for these conditions, there is still much to be learned about the development of gluten related disorders and the apparent increase in incidence within the US. In this article, we present a review of current knowledge on the epidemiology of gluten related disorders within a global context, with a focus on diagnostic trends and the evaluation of potential risk factors. PMID- 24493935 TI - Spontaneous bilateral peripapillary, subhyaloid and vitreous hemorrhage with only minor platelet deficit in idiopathic thrombocytopenic purpura. AB - A 45-year-old female with underlying idiopathic thrombocytopenic purpura (ITP) complained of acute onset of reduced vision and floaters, in both eyes, for 3 weeks. Visual acuity was 6/36 and 6/60 in the right eye and left eye, respectively. Ophthalmoscopy showed bilateral peripapillary, subhyaloid and vitreous hemorrhage. Hematological evaluation revealed moderate anemia (hemoglobin: 93 g/L) and mild thrombocytopenia (platelets: 120*10(9)/L). She was co-managed by a hematologist and ophthalmologists; she was treated medically. Follow-up care during the next 6 weeks revealed spontaneous, partially resolving hemorrhage, with improvement of visual acuity. The purpose of this case report is to highlight ophthalmic involvement of ITP in this patient, despite her only-mild thrombocytopenia, and her spontaneous recovery, despite her receiving only medical treatment. PMID- 24493934 TI - Impact of ovarian function on cardiovascular health in women: focus on hypertension. AB - Arterial blood pressure levels and the prevalence of hypertension are generally lower in premenopausal women compared with age-matched men. The lower blood pressure levels in premenopausal women are associated with a lower risk of the development and progression of cardiovascular disease. In contrast, menopause, a state characterized by a physiologic reduction in ovarian hormone levels, is associated with progressive increases in blood pressure and an overall increase in the risk of cardiovascular disease. These observations suggest an association between blood pressure regulation and changes in ovarian hormone levels, estrogens in particular. In addition to menopause, the risk of hypertension and cardiovascular disease is also dramatically increased in premenopausal women with chronic diseases such as diabetes and systemic lupus erythematosus. Studies suggest that these chronic diseases may be associated with an imbalance in ovarian hormones, which may explain the increased risk of hypertension and cardiovascular disease in these women. However, the use of hormone therapy to manage the risk and prevent the development of hypertension and cardiovascular diseases in women remains controversial. The precise mechanisms by which estrogens contribute to the regulation of blood pressure are still not completely understood. However, accumulating evidence suggests that modulating the activity of locally active hormone systems is one of the major mechanisms by which estrogens exert their effects on target organs, including the vasculature, kidneys, and immune system. In particular, the interaction between estrogens and the renin-angiotensin system has been implicated in the regulation of blood pressure and cardiovascular function in both humans and experimental models. This review summarizes our current understanding of the mechanisms by which estrogens regulate blood pressure and the potential use of hormone therapy in prevention of hypertension and consequent cardiovascular risk. PMID- 24493928 TI - Effect of eprosartan-based antihypertensive therapy on coronary heart disease risk assessed by Framingham methodology in Canadian patients: results of the POWER survey. AB - PURPOSE/INTRODUCTION: The Canadian Hypertension Education Program (CHEP) has identified blood pressure (BP) control as a key target for an overall reduction in cardiovascular disease risk. The POWER survey (Physicians' Observational Work on Patient Education According to their Vascular Risk) used Framingham methodology to investigate the impact of an angiotensin-receptor-blocker-based regimen on arterial BP and total coronary heart disease (CHD) risk in a subset of patients recruited in Canada. METHODS: 309 Canadian practices screened for patients with either newly diagnosed or uncontrolled mild/moderate hypertension (sitting systolic blood pressure [SBP] >140 mmHg with diastolic blood pressure [DBP] <110 mmHg). Treatment comprised eprosartan 600 mg/day with add-on antihypertensive therapy after 1 month if required. The primary efficacy variable was change in SBP at 6 months; the secondary variable was the absolute change in the Framingham 10-year CHD risk score. RESULTS: 1,385 patients were identified, of whom 1,114 were included in the intention-to-treat (ITT) cohort. Thirty-eight point four percent of ITT patients were managed with monotherapy at 6 months, versus 35.2% and 13.7% with two-drug or multiple-drug therapy, respectively. SBP in the ITT cohort declined 22.4 (standard deviation [SD] 14.8) mmHg and DBP declined 10.5 (SD 10.3) mmHg during that time. The absolute mean Framingham score declined 2.1 (SD 3.1) points with significant age and sex variation (P<0.001) and differences between the various Framingham methods used. DISCUSSION/CONCLUSION: Primary care physicians were able to use a strategy of BP lowering and CHD risk assessment to achieve significant reductions in BP and Framingham-assessed CHD risk. The effect size estimate of the different Framingham methods varied noticeably; reasons for those differences warrant further investigation. PMID- 24493936 TI - New bioactive compounds from korean native mushrooms. AB - Mushrooms are ubiquitous in nature and have high nutritional attributes. They have demonstrated diverse biological effects and therefore have been used in treatments of various diseases, including cancer, diabetes, bacterial and viral infections, and ulcer. In particular, polysaccharides, including beta-glucan, are considered as the major constituents responsible for the biological activity of mushrooms. Although an overwhelming number of reports have been published on the importance of polysaccharides as immunomodulating agents, not all of the healing properties found in these mushrooms could be fully accounted for. Recently, many research groups have begun investigations on biologically active small-molecular weight compounds in wild mushrooms. In this mini-review, both structural diversity and biological activities of novel bioactive substances from Korean native mushrooms are described. PMID- 24493937 TI - New additions to lichen mycota of the republic of Korea. AB - The current study describes seven species that are new to the lichen mycota of South Korea. A taxonomic description of Arthonia excipienda, A. radiata, Arthothelium ruanum, Enterographa leucolyta, Fissurina elaiocarpa, Rinodina oleae, and Thelotrema porinaceum was given and supported by distribution, ecology, and illustrations. Each species was compared with a species showing close resemblance. PMID- 24493938 TI - Taxonomic study of amanita subgenus lepidella and three unrecorded amanita species in Korea. AB - Amanita Pers. is a well-known monophyletic mushroom genus with a broad distribution. However, the diversity of Korean Amanita species has been underestimated, and most taxonomic studies conducted in Korea have only investigated their morphological characteristics. This approach is frequently insufficient for correct identification in fungal classification; therefore, we constructed a phylogeny of Amanita subgen. Lepidella in order to understand the phylogenetic placements of 16 Amanita specimens collected in Korea in 2012. The phylogeny constructed using the sequence data of the internal transcribed spacers and the partial large subunit of ribosomal RNA identified nine Amanita species (A. citrina, A. excelsa var. spissa, A. flavipes, A. fritillaria, A. oberwinklerana, A. pallidorosea, A. rubescens, A. subjunquillea, and A. volvata); of these, A. fritillaria, A. oberwinklerana, and A. pallidorosea are new to Korea. PMID- 24493939 TI - Delimitation of russula subgenus amoenula in Korea using three molecular markers. AB - Distinguishing individual Russula species has been difficult due to extensive phenotypic plasticity and obscure morphological and anatomical discontinuities. Due to highly similar macroscopic features, such as the presence of a red-cap, species identification within the Russula subgenus Amoenula is particularly difficult. Three species of the subgenus Amoneula have been reported in Korea. We used a combination of morphology and three molecular markers, the internal transcribed spacer (ITS), 28S nuclear ribosomal large subunit (LSU), and RNA polymerase II gene (RPB2), for identification and study of the genetic diversity of Russula subgenus Amoenula in Korea. We identified only two species in Korea (R. mariae and R. violeipes); these two species were indistinguishable according to morphology and LSU, but were found to be reciprocally monophyletic species using ITS and RPB2. The markers, ITS, LSU, and RPB2, have been tested in the past for use as DNA barcoding markers, and findings of our study suggest that ITS and RPB2 had the best performance for the Russula subgenus Amoneula. PMID- 24493940 TI - Contributions to the foliicolous lichens flora of South Korea. AB - South Korea is covered primarily by temperate vegetation; therefore, foliicolous lichens may not be expected to play an important role in its lichen flora. However, this study describes four foliicolous lichen species, Strigula concreta, S. macrocarpa, S. melanobapha, and S. subelegans, which are new to South Korea. These findings will lead to further research on foliicolous lichens and provide a better understanding of their distribution within the East Asian region. This is the first detailed report on foliicolous lichens and their distribution in South Korea. PMID- 24493941 TI - Influence of Food Waste Compost on the Yield and Mineral Content of Ganoderma lucidum, Lentinula edodes, and Pholiota adipose Fruiting Bodies. AB - The objectives of this study were to evaluate applicability of food waste compost (FWC) as a substrate for cultivation of Ganoderma lucidum, Lentinula edodes, and Pholiota adipose, and to determine contents of Ca, Mg, Na, and K in fruiting bodies (FB). FB yield per substrate in FWC-free controls was 53 +/- 4 g/kg for G. lucidum, 270 +/- 90 g/kg for L. edodes, and 1,430 +/- 355 g/kg for P. adipose. Substrates supplemented with FWC showed the highest FB production at FWC content of 10% for G. lucidum (64 +/- 6 g/kg), and 13% for L. edodes (665 +/- 110 g/kg) and P. adipose (2,345 +/- 395 g/kg), which were 1.2~2.5 times higher than the values for the controls. P. adipose contained higher amounts of mineral elements than the other species. Ca, Mg, Na, and K content in FB did not show a significant relation to FWC content. PMID- 24493942 TI - Efficient Recovery of Lignocellulolytic Enzymes of Spent Mushroom Compost from Oyster Mushrooms, Pleurotus spp., and Potential Use in Dye Decolorization. AB - This study was conducted in order to perform efficient extraction of lignocellulolytic enzymes amylase (EC 3.2.1.1), cellulase (EC 3.2.1.4), laccase (EC 1.10.3.2), and xylanase (EC 3.2.1.8) from spent mushroom compost (SMC) of Pleurotus ostreatus, P. eryngii, and P. cornucopiae. Optimal enzyme recovery was achieved when SMCs were extracted with 50 mM sodium citrate (pH 4.5) buffer at 4C for 2 hr. Amylase, cellulase, and xylanase activities showed high values in extracts from P. ostreatus SMC, with 2.97 U/g, 1.67 U/g, and 91.56 U/g, respectively, whereas laccase activity and filter paper degradation ability were highest in extracts from P. eryngii SMC, with values of 9.01 U/g and 0.21 U/g, respectively. Enzymatic activities varied according to the SMCs released from different mushroom farms. The synthetic dyes remazol brilliant blue R and Congo red were decolorized completely by the SMC extract of P. eryngii within 120 min, and the decolorization ability of the extract was comparable to that of 0.3 U of commercial laccase. In addition, laccase activity of the SMC extract from P. eryngii was compared to that of commercial enzymes or its industrial application in decolorization. PMID- 24493943 TI - Biological Control of Aphid Using Fungal Culture and Culture Filtrates of Beauveria bassiana. AB - Aphids are one of the most destructive pests in crop production such as pepper, cucumber, and eggplants. The importance of entomopathogenic fungi as alternative pest control agents is increasing. Conidia of entomopathogenic fungi are influenced by environmental conditions, such as temperature and relative humidity, and cause slow and fluctuating mortality. These factors have prevented wider application and use of biocontrol agents. For investigation of means of mitigation of such problems, we conducted bioassays with 47 fungal culture filtrates in order to evaluate the potential of secondary metabolites produced by entomopathogenic fungi for use in aphid control. Among 47 culture filtrates cultured potato dextrose broth, filtrate of Beauveria bassiana Bb08 showed the highest mortality (78%) against green peach aphid three days after treatments. Filtrate of Bb08 cultured in Adamek's medium showed higher toxicity as 100% to third instar nymphs of the aphid compared with seven other filtrates cultured in different broths amended with colloidal chitin or oil. The culture filtrates and fungal cultures from media amended with colloidal chitin or oil had lower control efficacies than filtrates without these additives in three different media. These results indicate that the fungal culture fluid or culture filtrate of B. bassiana Bb08 cultured in Adamek's medium has potential for development as a mycopesticide for aphid control. PMID- 24493944 TI - Incidence, Molecular Characteristics and Pathogenicity of Gibberella fujikuroi Species Complex Associated with Rice Seeds from Asian Countries. AB - Gibberella fujikuroi species complex (GFSC) was isolated from rice (Oryza sativa L.) seed samples from ten Asian countries and investigated for incidence of GFSC, molecular characteristics, and pathogenicity. Regardless of geographic origin, GFSC was detected with incidences ranging from 3% to 80%. Four species, Fusarium fujikuroi, F. concentricum, F. proliferatum, and F. verticillioides, were found to show an association with rice seeds, with F. fujikuroi being the predominant species. In phylogenetic analyses of DNA sequences, no relationship was found between species, isolates, and geographic sources of samples. Unidentified fragments of the beta-tubulin gene were observed in ten isolates of F. fujikuroi and F. verticillioides. With the exception of three isolates of F. fujikuroi, F. fujikuroi, F. proliferatum, and F. verticillioides were found to have FUM1 (the fumonisin biosynthetic gene); however, FUM1 was not found in isolates of F. concentricum. Results of pathogenicity testing showed that all isolates caused reduced germination of rice seed. In addition, F. fujikuroi and F. concentricum caused typical symptoms of bakanae, leaf elongation and chlorosis, whereas F. proliferatum and F. verticillioides only caused stunting of seedlings. These findings provide insight into the characteristics of GFSC associated with rice seeds and might be helpful in development of strategies for management of bakanae. PMID- 24493945 TI - Biocontrol Activity of Bacillus amyloliquefaciens CNU114001 against Fungal Plant Diseases. AB - A total of 62 bacterial isolates were obtained from Gomsohang mud flat, Mohang mud flat, and Jeju Island, Republic of Korea. Among them, the isolate CNU114001 showed significant antagonistic activity against pathogenic fungi by dual culture method. The isolate CNU114001 was identified as Bacillus amyloliquefaciens by morphological observation and molecular data analysis, including 16SrDNA and gyraseA (gyrA) gene sequences. Antifungal substances of the isolate were extracted and purified by silica gel column chromatography, thin layer chromatography, and high performance liquid chromatography. The heat and UV ray stable compound was identified as iturin, a lipopeptide (LP). The isolate CNU114001 showed broad spectrum activity against 12 phytopathogenic fungi by dual culture method. The semi purified compound significantly inhibits the mycelial growth of pathogenic fungi (Alternaria panax, Botrytis cinera, Colletotrichum orbiculare, Penicillium digitatum, Pyricularia grisea and Sclerotinia sclerotiorum) at 200 ppm concentration. Spore germ tube elongation of Botrytis cinerea was inhibited by culture filtrate of the isolate. Crude antifungal substance showed antagonistic activity against cucumber scleotiorum rot in laboratory, and showed antagonistic activity against tomato gray mold, cucumber, and pumpkin powdery mildew in greenhouse condition. PMID- 24493946 TI - Endocarpon subramulosum (Verrucariaceae) a New Species of Lichenized Fungi from South Korea. AB - In this paper, we describe Endocarpon subramulosum as a new species from temperate regions of South Korea, which grows over soil on rocks. The proposed new species is morphologically similar to E. ramulosum Harada, which has so far been reported from Japan. PMID- 24493947 TI - A New Record of Candida kashinagacola (Synonym Ambrosiozyma kashinagacola) from Galleries of Platypus koryoensis, the Oak Wilt Disease Vector, in Korea. AB - The ambrosia beetle, Platypus koryoensis, is an economically important pest affecting oak trees in Korea. Candida kashinagacola was isolated from galleries of the beetle in oak wood and identified by analyses of morphology, physiological properties, and nucleotide sequence of the large subunit ribosomal DNA. This is the first report on Candida species associated with oak wilt disease vectored by the ambrosia beetle, Platypus koryoensis, in Korea. PMID- 24493948 TI - Molecular Taxonomy of Ganoderma cupreum from Southern India Inferred from ITS rDNA Sequences Analysis. AB - Ganoderma is a cosmopolitan wood-rot basidiomycete that has been extensively studied for its pathogencity and medicinal properties. Identification of Ganoderma based on macro-microscopic features led to large number of synonyms which resulted in 250 taxonomic names. A Ganoderma species collected from Courtallam, Tamil Nadu was identified as G. cupreum. Phylogenetic analysis inferred from internal transcribed spacer rDNA region resolved the Indian isolate MYC1 as Ganoderma cupreum which clustered with Australian and Asian "cupreum" clade with 85% bootstrap support BS and shared 99% and 98% nucleotide similarity with Malaysian and Australian 'cupreum' respectively. This study represents the first molecular evidence of G. cupreum from Asian origin. PMID- 24493949 TI - Isolation of Fungal Pathogens to an Edible Mushroom, Pleurotus eryngii, and Development of Specific ITS Primers. AB - Fungal pathogens have caused severe damage to the commercial production of Pleurotus eryngii, the king oyster mushroom, by reducing production yield, causing deterioration of commercial value, and shortening shelf-life. Four strains of pathogenic fungi, including Trichoderma koningiopsis DC3, Phomopsis sp. MP4, Mucor circinelloides MP5, and Cladosporium bruhnei MP6, were isolated from the bottle culture of diseased P. eryngii. A species-specific primer set was designed for each fungus from the ITS1-5.8S rDNA-ITS2 sequences. PCR using the ITS primer set yielded a unique DNA band for each fungus without any cross reaction, proving the validity of our method in detection of mushroom fungal pathogens. PMID- 24493950 TI - A New Record of Penicillium pimiteouiense from Beach Soil in Malaysia. AB - Three isolates of Penicillium pimiteouiense were recovered from sandy beach soil samples in Penang Island, Peninsular Malaysia. All the isolates were identified based on morphological characteristics and phylogenetic analysis of internal transcribed spacer regions and beta-tubulin gene. This is a first record of P. pimiteouiense in Malaysia. PMID- 24493951 TI - First record of the polychaete Ficopomatus uschakovi (Pillai, 1960) (Annelida, Serpulidae) in the Colombian Caribbean, South America. AB - The genus Ficopomatus (Serpulidae) consists of sessile, tubicolous polychaete annelid worms that may colonize a diversity of substrata, and tolerate considerable variations in salinity. Thus, members of this genus, including Ficopomatus uschakovi, in some cases are exotic and maybe invasive. The purpose of our research was to collect and identify marine organisms associated with the submerged roots of mangrove trees in the Gulf of Uraba, Colombian Caribbean, South America. Within the Gulf, there is a well-developed forest of the Red Mangrove, Rhizophora mangle, along the margins of El Uno Bay. We sampled the roots of R. mangle from five stations of the bay, and we identified specimens of F. uschakovi from each of those stations. Ficopomatus uschakovi was found to be more abundant in regions of the bay that exhibit the lowest salinity. Based on a morphological comparison of the present specimens with the original species description, revised descriptions, and other records from the Indo-West Pacific, Mexican Pacific, and Venezuelan and Brazilian Caribbean, we suggest that F. uschakovi has a broader geographical distribution. Furthermore, because of this broad distribution, and the observed tolerance for low salinity in our study, we also suggest that F. uschakovi is a euryhaline species. It is also likely that F. uschakovi will be found in other localities in the Gulf of Uraba, and in other regions of the Colombian Caribbean. Thus, this record extends the distribution of the species to the Colombian Caribbean, giving the species a continuous distribution across the northern coast of South America. PMID- 24493952 TI - Brachymyrmex species with tumuliform metathoracic spiracles: description of three new species and discussion of dimorphism in the genus (Hymenoptera, Formicidae). AB - Brachymyrmex is a taxonomically challenging ant genus that is badly in need of review. Most species are very small and soft bodied and current descriptions regularly lack clarity making species identification a daunting task. Furthermore, the monophyly of Brachymyrmex has not been established and the relationships among its species and with closely related genera are poorly understood. Most species of Brachymyrmex are monomorphic, but two dimorphic species have been assigned to the genus before. Here, we redescribe these dimorphic taxa, B. pilipes and B. micromegas, and describe three new monomorphic species, B. brasiliensis sp. n., B. delabiei sp. n. and B. feitosai sp. n. All five species occur in Brazil and have tumuliform metathoracic spiracles, which are lacking in other Brachymyrmex species. We discuss dimorphism and its evolution in the genus and provide a distribution map, illustrations and a species identification key based on workers. PMID- 24493953 TI - A new species of the Rhinella margaritifera species group (Anura, Bufonidae) from the montane forest of the Selva Central, Peru. AB - We describe a new species of the bufonid toad genus Rhinella from transition montane forest of the buffer zones of the Yanachaga-Chemillen National Park and the Pui Pui Protected Forest (eastern slopes of Andes, Selva Central, Peru). The new species belongs to the Rhinella margaritifera species group (confirmed by mtDNA data) and differs from all its members by the absence of tympanic membrane and tympanic annulus. It is characterized by medium size (SVL 57.5-65.5 mm, n = 5), moderately developed cranial crests, absence of neural crest of vertebrae, absence of bone protrusion at angle of jaw, presence of lateral rows of enlarged tubercles, and absence of subgular vocal sac and vocal slits in males. In addition, based on the molecular phylogenetic analyses of selected Rhinella species we propose the monophylum containing R. chavin, R. festae, R. macrorhina, R. manu, R. nesiotes, R. rostrata, and R. yanachaga as a new species group under the name Rhinella festae species group. PMID- 24493954 TI - The "Fungia patella group" (Scleractinia, Fungiidae) revisited with a description of the mini mushroom coral Cycloseris boschmai sp. n. AB - The recent taxonomic history of extant free-living Cycloseris species is briefly reviewed, resulting in the description of Cycloseris boschmai sp. n. (Scleractinia, Fungiidae) and a discussion on the validity of two other recently described species. Some Cycloseris species were previously considered to belong to the Fungia patella group, which also concerned misidentified museum specimens that actually belong to the new species. Other specimens of C. boschmai sp. n. were photographed and collected in the course of 30 years of fieldwork. The new mushroom coral is compared with other free-living Cycloseris species by means of an identification key. With a maximum diameter of 50 mm, it is the smallest free living mushroom coral discovered so far. It can also be distinguished by its large primary order costae and variable colouration. Its distribution range is limited to the Coral Triangle, where it can be observed as an uncommon species on lower reef slopes. PMID- 24493956 TI - The second confirmed record of the scorpion genus Chactas Gervais, 1844 (Scorpiones, Chactidae) from Ecuador with description of a new species from the Amazonian Province of Sucumbios. AB - A new species, Chactas moreti sp. n., is described from Ecuadorian Amazonia. It can be distinguished from Chactas mahnerti Lourenco, 1995, the other known species of this genus from Ecuador by its smaller body size, distinct morphometric values, overall darker blackish-brown coloration, totally smooth vesicle, and a concave anterior margin of carapace. This is the second confirmed record of the genus Chactas Gervais from Ecuador. The geographical pattern of distribution of the genus is also discussed. PMID- 24493955 TI - Revision of three camaenid and one bradybaenid species (Gastropoda, Stylommatophora) from China based on morphological and molecular data, with description of a new bradybaenid subspecies from Inner Mongolia, China. AB - We have revised the taxonomy of three camaenid and one bradybaenid species from China and described one new subspecies of the genus Bradybaena (Family Bradybaenidae) from Inner Mongolia, China. The genitalia of three Satsuma (Family Camaenidae) species S. mellea stenozona (Moellendorff, 1884), S. meridionalis (Moellendorff, 1884), comb. n. and S. uncopila (Heude, 1882), comb. n. assigned to the genus Bradybaena previously,lack a dart sac and mucous glands. Moreover, the molecular phylogeny has revealed close relationships between the three species and the genus Satsuma. Two species, S. stenozona (Moellendorff, 1884) from Fuzhou and Ganesella citrina Zilch, 1940 from Wuyi Mountain, are considered as synonymous and should be a subspecies of S. mellea mellea (Pfeiffer, 1866) because of the morphological and molecular similarities. Meanwhile, the other two are placed in the genus Satsuma: S. meridionalis (Moellendorff, 1884), comb. n. and S. uncopila (Heude, 1882), comb. n. G. virgo Pilsbry, 1927 differs from species of the genera Ganesella and Satsuma not only in its shell, but also in anatomical characters, such as having a dart sac and mucous gland, and lacking a flagellum. Additionally, phylogenetic analyses highly support the sister relationship with other Bradybaena species. Thus, placement of G. virgo Pilsbry, 1927 in the genus Bradybaena issuggested. PMID- 24493957 TI - Studies on California ants: a review of the genus Temnothorax (Hymenoptera, Formicidae). AB - The following ten new species of the ant genus Temnothorax are described and illustrated: T. anaphalantus (California, Baja California), T. arboreus (California), T. caguatan (Oregon, California, Baja California), T. morongo (California, Baja California), T. myrmiciformis (California, Baja California), T. nuwuvi (Nevada), T. paiute (California, Nevada), T. pseudandrei (Arizona, California), T. quasimodo (California) and T. wardi (California). A key to workers of the twenty-two Temnothorax species known or expected to occur in California is provided. PMID- 24493958 TI - A revision of the octocoral genus Ovabunda Alderslade, 2001 (Anthozoa, Octocorallia, Xeniidae). AB - The family Xeniidae (Octocorallia) constitutes an abundant benthic component on many Indo-West Pacific coral reefs and is ecologically important in the Red Sea. The genus Ovabunda Alderslade, 2001 was recently established to accommodate previous Xenia species with sclerites comprised of a mass of minute corpuscle shaped microscleres. The aim of the present study was to examine type material of Xenia species in order to verify their generic affiliation. We present here a comprehensive account of the genus Ovabunda, using scanning electron microscopy to depict sclerite microstructure. We assign three Xenia species to the genus: O. ainex comb. n., O. gohari comb. n., and O. crenata comb. n.; and synonymize several other species of Ovabunda. We provide a key to Ovabunda species and conclude that they are mainly confined to the Red Sea, with some occurrence in the West Indian Ocean. PMID- 24493959 TI - Contributions to the knowledge of the Chinese Primeuchroeus Linsenmaier, 1968 (Hymenoptera, Chrysididae), with a key to species. AB - The genus Primeuchroeus Linsenmaier, 1968 from China is revised and an illustrated identification key is produced for the first time. Three species are recorded from China, with one species, Primeuchroeus yongdaerianus Kim, new to China. PMID- 24493960 TI - Morphogenia: a new genus of the Neotropical tribe Jubini (Coleoptera, Staphylinidae, Pselaphinae) from the Brazilian Amazon. AB - A new genus and species of the large Neotropical pselaphine tribe Jubini is described from Manaus, Brazil, based on material preserved in the Natural History Museum, London. Morphogenia struhli gen. et sp. n. represents the possible sister taxon of the abundant and speciose genus Barrojuba Park, sharing with it the putatively derived condition of anterolaterally shifted vertexal foveae, producing a smoothly convex vertex devoid of fovea or sulci. However, unlike Barrojuba, Morphogenia retains a plesiomorphic antebasal sulcus on the pronotum in both sexes, and additionally lacks elaborate abdominal fovea-like pockets and teeth on the lateral margins of the pronotum that are typical of Barrojuba. The genus is also unusual among jubine genera in lacking the characteristic V- or Y shaped gular carina. In contrast to the commonly-collected Barrojuba, specimens of Morphogenia are absent in extensive jubine collections housed in museums in the United States, indicating that the new taxon may be relatively scarce or localised. PMID- 24493961 TI - A preliminary report on the distribution of lizards in Qatar. AB - We have updated the list of the lizard species present in Qatar and produced the first distribution maps based on two field surveys in 2012 and 2013. We used the QND95/Qatar National Grid with a grid of 10 * 10 km squares for mapping. Our results show the occurrence of 21 lizard species in Qatar, from the 15 species indicated in the last biodiversity report conducted in 2004. The most abundant family found in Qatar is Gekkonidae with nine species (Bunopus tuberculatus, Cyrtopodion scabrum, Hemidactylus robustus, H. flaviviridis, H. persicus, Stenodactylus arabicus, S. slevini, S. doriae, Pseudoceramodactylus khobarensis), followed by Lacertidae with four species (Acanthodactylus schmidti, A. opheodurus, Mesalina brevirostris, M. adramitana), Agamidae with three species (Trapelus flavimaculatus, Uromastyx aegyptia, Phrynocephalus arabicus), Scincidae with two species (Scincus mitranus, Trachylepis septemtaeniata), and Varanidae (Varanus griseus), Sphaerodactylidae (Pristurus rupestris) and Trogonophiidae (Diplometopon zarudnyi) with one species each. The species richness fluctuated largely across Qatar between one and eleven species per grid square. We believe that the lizard fauna records in Qatar are still incomplete and that additional studies are required. However, our study here fills a gap concerning lizard biodiversity knowledge in the Gulf Region. PMID- 24493962 TI - The millipede genus Orthomorpha Bollman, 1893 in Laos (Diplopoda, Polydesmida, Paradoxosomatidae), with descriptions of new species. AB - The genus Orthomorpha is currently represented in Laos by nine species, including three, O. paviei Brolemann, 1896, O. communis Likhitrakarn, Golovatch & Panha, 2011 and O. cambodjana (Attems, 1953), which are new to the fauna of the country, and further three new to science: O. suberectoides sp. n., O. gladiata sp. n. and O. sutchariti sp. n. PMID- 24493963 TI - Lectotype designations and nomenclatural changes in Xylographus Mellie (Coleoptera, Ciidae). AB - We designate lectotypes and propose nomenclatural changes in Xylographus Mellie (Coleoptera, Ciidae) based on type specimens deposited in the Museum of Comparative Zoology (USA), Museum fur Naturkunde Berlin (Germany), the Natural History Museum (UK), Museum d'Histoire Naturelle de la Ville de Geneve (Switzerland), Museum National d'Histoire Naturelle (France), Naturhistoriska Riksmuseet (Sweden) and Naturhistorisches Museum Wien (Austria). We designate lectotypes for the following species: Cis fultoni Broun, 1886, Xylographus anthracinus Mellie, 1849, X. bicolor Pic, 1916, X. brasiliensis Pic, 1916, X. ceylonicus Ancey, 1876, X. contractus Mellie, 1849, X. corpulentus Mellie, 1849, X. dentatus Pic, 1922, X. gibbus Mellie, 1849, X. hypocritus Mellie, 1849, X. javanus Pic, 1937, X. lemoulti Pic, 1916, X. longicollis Pic, 1922, X. madagascariensis Mellie, 1849, X. nitidissimus Pic, 1916, X. perforatus Gerstaecker, 1871, X. porcus Gorham, 1886, X. punctatus Mellie, 1849, X. ritsemai Pic, 1921, X. rufescens Pic, 1921, X. rufipennis Pic, 1934, X. rufipes Pic, 1930, X. seychellensis Scott, 1926, X. subopacus Pic, 1929, X. subsinuatus Pic, 1916, X. suillus Gorham, 1886, X. testaceitarsis Pic, 1916 and X. tomicoides Reitter, 1902. We propose the following syn. n. (senior synonym listed first): X. anthracinus = X. testaceitarsis, X. brasiliensis = X. lucasi Lopes-Andrade & Zacaro, X. corpulentus = X. lemoulti and X. richardi Mellie, X. madagascariensis = X. eichelbaumi Reitter, X. rufipennis, X. seychellensis Scott and X. tarsalis Fahraeus, X. nitidissimus = X. longicollis, X. subsinuatus = X. rufescens. We exclude three species from Xylographus: Cis renominatus, nom. n. (for X. dentatus Pic, 1922, not C. dentatus Mellie, 1849), Paratrichapus fultoni (Broun, 1886), comb. n. and P. javanus (Pic, 1937), comb. n. PMID- 24493964 TI - Redescription of Japanagromyza inferna Spencer, first recorded from Brazil, and a key to the Neotropical species of Japanagromyza Sasakawa (Diptera, Agromyzidae). AB - Japanagromyza inferna Spencer is recorded for the first time from Brazil, in the North coast of the State of Rio de Janeiro, inducing galls in Centrosema virginianum L. (Fabaceae). The species is redescribed, with illustrations of male and female terminalia. A key to the identification of the Neotropical species of Japanagromyza Sasakawa is presented. PMID- 24493965 TI - Description and DNA barcoding of Crematogaster fraxatrix Forel, 1911 and two new closely related species from Cambodia and Indonesia (Hymenoptera, Formicidae). AB - Crematogaster fraxatrix Forel, 1911 and two new species, C. chhangi sp. n. and C. simboloni sp. n., are described from Cambodia and Indonesia, respectively. DNA sequences were generated for C. fraxarix and the two newly described species using 3 amplications of two regions of the mitochondrial gene COI with a total of 1129 bp. The mean interspecific divergences are 9.4% and 23.5% for C. fraxatrix vs. C. chhangi, C. simboloni, respectively. DNA sequences reveal that C. simboloni is found to be genetically distinct from the other two species, but C. chhangi is not distinct from C. fraxatrix. PMID- 24493966 TI - Reassessment of the taxonomic position of Iranocypris typhlops Bruun & Kaiser, 1944 (Actinopterygii, Cyprinidae). AB - The Iranian cave barb (Iranocypris typhlops Bruun & Kaiser, 1944) is a rare and endemic species of the family Cyprinidae known from a single locality in the Zagros Mountains, western Iran. This species is "Vulnerable" according to the IUCN Red List and is one of the top four threatened freshwater fish species in Iran. Yet, the taxonomic position of I. typhlops is uncertain. We examined phylogenetic relationships of this species with other species of the family Cyprinidae based on the mitochondrial cytochrome b gene. Our results show that I. typhlops is monophyletic and is sister taxon of a cluster formed by Garra rufa (Heckel, 1843) and Garra barreimiae (Fowler & Steinitz, 1956) within a clade that includes other species of the genus Garra. Based on previous molecular and morphological studies, as well as our new results, we recommend that I. typhlops should be transferred to the genus Garra Hamilton, 1822. PMID- 24493967 TI - Biological properties and perspective applications of "Bio-neuter" chemicals? PMID- 24493968 TI - Targeting cancer using cholesterol conjugates. AB - Conjugation of cholesterol moiety to active compounds for either cancer treatment or diagnosis is an attractive approach. Cholesterol derivatives are widely studied as cancer diagnostic agents and as anticancer derivatives either in vitro or in vivo using animal models. In largely growing studies, anticancer agents have been chemically conjugated to cholesterol molecules, to enhance their pharmacokinetic behavior, cellular uptake, target specificity, and safety. To efficiently deliver anticancer agents to the target cells and tissues, many different cholesterol-anticancer conjugates were synthesized and characterized, and their anticancer efficiencies were tested in vitro and in vivo. PMID- 24493969 TI - Emergency department visits and admissions due to drug related problems at Riyadh military hospital (RMH), Saudi Arabia. AB - OBJECTIVES: Aim of this study was to prospectively determine the incidence and types of emergency department (ED) visits and admissions due to drug related problems (DRPs) at Riyadh Military Hospital (RMH), to assess the severity and preventability of these drug related admissions or visits, and to identify the drugs and patient groups that are most commonly involved. METHOD: Patients (n = 300) were selected randomly from patients presented to the ED during the study period (one month). Computerized randomization program was used to select ten beds daily on different areas and times. Patient was eligible to be included if either visited ED or admitted through it due to DRPs. RESULTS: During the study period, 300 patients presented to ED were randomly selected with a mean age of 47.8 +/- 27.7 years. One hundred and forty of them were females (46.67%) and 160 were male patients (53.33%). Of these 300 patients, 56 (18.7%) were presented to ED due to DRPs, and 244 (81.3%) patients were presented to ED due to non-drug related problems (NDRPs). About ninety-three percent (n = 52) of the DRP group were exposed to hospital admission while only 7.1% (n = 4) were ED visits (Fig. 2). Male to female ratio in ED visits was 3:1 while it was 9.7:8.9 in the ED admission group. CONCLUSION: The prospective design of this study, sample size, and randomization increases the likelihood that our estimates are accurate and increase the generalizability of our findings. Most DRPs attributed to hospital admissions or visits were avoidable. Direct patient contact with pharmacist and family physician was beneficial in providing a safe and effective therapy. Corrective, preventive and educational strategies should concentrate on the most frequently reported populations, diseases and medications. The study addresses the proper use of medications to ensure the best outcomes of pharmacological interventions. Finally, more studies with longer duration focusing on DRPs in Saudi Arabia are needed. PMID- 24493970 TI - Medications prescribing pattern toward insured patients. AB - BACKGROUND AND OBJECTIVE: The rising costs of health care continue to make health insurance important for many countries. Health insurance may cover different aspects of health care in Saudi Arabia including the prescribed drugs. Physicians usually have different personal attitudes toward insured and uninsured patients. This study is to investigate the prescribing behavior of physicians to those groups of patients in the private setting. DESIGN AND SETTING: A prospective study was conducted during the period between October 2011 and January 2012, in three Saudi private hospitals. METHOD: Prescriptions for insured and uninsured patients were randomly selected and analyzed. Data regarding diagnosis, age, gender, co-morbidity, number of items and the total cost of the medication in Saudi Riyals (SR) were collected through a chart review form. RESULTS: Three thousand sixty six patients' prescriptions were included in this study, 34.7% of them were females. 273 patients (75.2%) were insured while 90 were not. 24.8% were patients who paid cash. Majority (57.6%) of the patients were with diabetes plus hypertension and other co-morbidity. 20.7% of patients were taking three medications or less, while 67.8% were taking 4-10 and 11.6% were taking more than 10 medications. Analysis of differences showed that, patients who were insured have a higher number of prescribed medications (p ? 0.001), and a higher total price of prescription than those who were paying cash only (p ? 0.001). In a more confirmatory step, all uninsured patients (n = 90) were closely matched in the age, gender, diagnosis and hospital with similar 90 insured patients. Results of this matching process confirmed the above findings. CONCLUSION: Physicians in private setting are more likely to prescribe more drugs and/or brand drugs to insured patients than for uninsured patients. Further studies to view the reasons behind this behavior and strategies to prevent such actions are needed. PMID- 24493971 TI - Saudi young patient understanding of information about side effects: Verbal versus numerical expression. AB - OBJECTIVE: To determine the effect of providing different formats about side effect information (verbal versus numerical) to acne patients in Saudi Arabia that are newly prescribed Roaccutane. DESIGN: A prospective study assessing patients' degree of estimation about side effect information. PARTICIPANTS: One hundred and forty-one acne patients newly prescribed Roaccutane. SETTINGS: Four dermatology clinics in Riyadh. Two in tertiary hospitals and the other two in private clinics. INTERVENTION: Each patient received information about two different side effects for Roaccutane. The side effect provided was supplemented with the probability of occurrence, which was written either in words or in numbers. (Dry eye "very common" or "30%"; Loss of hair "rare" or "0.01%"). MAIN OUTCOME MEASURES: Patient's estimation of side effect occurrence. Other outcomes were the likelihood of experiencing the side effect, the severity of the side effect, their perception of risk of the side effects to their general health, their satisfaction with the information provided and, whether the information provided will influence their decision to take the medicine. RESULT: The mean estimate for side effect occurrence for the dry eyes was 46% in the verbal group and 41% in the numerical group (p = 0.5); for loss of hair it was 50% in the verbal group and 39% in the numerical group (p = 0.03). There are no significant differences between verbal and numerical groups regarding the remaining measures. CONCLUSION: Patients overestimate the probability of occurrence of side effect. Verbal format of probability of occurrence is associated with higher estimation than the numerical format. PMID- 24493972 TI - Effect of long acting local anesthetic on postoperative pain in teeth with irreversible pulpitis: Randomized clinical trial. AB - OBJECTIVE: The objective of this study was to compare the effect of long acting anesthetics on postoperative pain in teeth with irreversible pulpitis. METHODOLOGY: Forty patients were randomly assigned into two groups of twenty patients each. Each patient who fit the inclusion criteria was administered local anesthesia before undergoing root canal treatment. The anesthetic solution was either 2% lidocaine with 1:80,000 epinephrine or 0.5% bupivacaine with 1:200,000 epinephrine. Patients were instructed to complete a VAS pain score at 6, 12, 24 h after single visit root canal treatment. Data were analyzed by Mann-Whitney, Cochrane Q analysis and t test to compare qualitative and quantitative data between the groups. RESULTS: The results showed the levels of pain of the patients who received lidocaine as the anesthetic agent and had significantly more postoperative pain after root canal treatment (P < 0.05) but had significantly decreased pain by 24 h compared to the bupivacaine group patients who had significantly lower postoperative pain levels at 6 and 12 h. CONCLUSION: The use of long acting local anesthetic can significantly reduce the postoperative pain in teeth with irreversible pulpitis. PMID- 24493973 TI - Diisocyanate mediated polyether modified gelatin drug carrier for controlled release. AB - Gelatin is an extensively studied biopolymer hydrogel drug carrier due to its biocompatibility, biodegradability and non-toxicity of its biodegraded products formed in vivo. But with the pristine gelatin it is difficult to achieve a controlled and desirable drug release characteristics due to its structural and thermal lability and high solubility in aqueous biofluids. Hence it is necessary to modify its solubility and structural stability in biofluids to achieve controlled release features with improved drug efficacy and broader carrier applications. In the present explorations an effort is made in this direction by cross linking gelatin to different extents using hitherto not studied isocyanate terminated poly(ether) as a macrocrosslinker prepared from poly(ethylene glycol) and isophorone diisocyanate in dimethyl sulfoxide. The crosslinked samples were analyzed for structure by Fourier transform-infrared spectroscopy, thermal behavior through thermogravimetric analysis and differential scanning calorimetry. The cross linked gelatins were biodegradable, insoluble and swellable in biofluids. They were evaluated as a carrier for in vitro drug delivery taking theophylline as a model drug used in asthma therapy. The crosslinking of gelatin decreased the drug release rate by 10-20% depending upon the extent of crosslinking. The modeled drug release characteristics revealed an anomalous transport mechanism. The release rates for ampicillin sodium, 5 fluorouracil and theophylline drugs in a typical crosslinked gelatin carrier were found to depend on the solubility and hydrophobicity of the drugs, and the pH of the fluid. The observed results indicated that this material can prove its mettle as a viable carrier matrix in drug delivery applications. PMID- 24493974 TI - Formulation and optimization of orodispersible tablets of flutamide. AB - The present study aimed to formulate orodispersible tablets of flutamide (FTM) to increase its bioavailability. Orodispersible tablets were prepared by direct compression technique using three different approaches namely; super disintegration, effervescence and sublimation. Different combined approaches were proposed and evaluated to optimize tablet characteristics. Sodium starch glycolate (SSG) was used as the superdisintegrant. The prepared powder mixtures were subjected to both pre and post compression evaluation parameters including; IR spectroscopy, micromeritics properties, tablet hardness, friability, wetting time, disintegration time and in-vitro drug release. IR studies indicated that there was no interaction between the drug and the excipients used except Ludipress. The results of micromeritics studies revealed that all formulations were of acceptable to good flowability. Tablet hardness and friability indicated good mechanical strength. Wetting and dispersion times decreased from 46 to 38 s by increasing the SSG concentration from 3.33 to 6.66% w/w in tablets prepared by superdisintegration method. The F8 formulation which was prepared by combined approaches of effervescence and superdisintegrant addition gave promising results for tablet disintegration and wetting times but failed to give faster dissolution rate. The incorporation of 1:5 solid dispersion of FTM: PEG 6000 instead of the pure drug in the same formulation increased the drug release rate from 73.12 to 96.99% after 15 min. This increase in the dissolution rate may be due to the amorphization of the drug during the solid dispersion preparation. The presence of the amorphous form of the drug was shown in the IR spectra. PMID- 24493975 TI - Random sparse sampling strategy using stochastic simulation and estimation for a population pharmacokinetic study. AB - The purpose of this study was to use the stochastic simulation and estimation method to evaluate the effects of sample size and the number of samples per individual on the model development and evaluation. The pharmacokinetic parameters and inter- and intra-individual variation were obtained from a population pharmacokinetic model of clinical trials of amlodipine. Stochastic simulation and estimation were performed to evaluate the efficiencies of different sparse sampling scenarios to estimate the compartment model. Simulated data were generated a 1000 times and three candidate models were used to fit the 1000 data sets. Fifty-five kinds of sparse sampling scenarios were investigated and compared. The results showed that, 60 samples with three points and 20 samples with five points are recommended, and the quantitative methodology of stochastic simulation and estimation is valuable for efficiently estimating the compartment model and can be used for other similar model development and evaluation approaches. PMID- 24493977 TI - Interplay of biopharmaceutics, biopharmaceutics drug disposition and salivary excretion classification systems. AB - The aim of this commentary is to investigate the interplay of Biopharmaceutics Classification System (BCS), Biopharmaceutics Drug Disposition Classification System (BDDCS) and Salivary Excretion Classification System (SECS). BCS first classified drugs based on permeability and solubility for the purpose of predicting oral drug absorption. Then BDDCS linked permeability with hepatic metabolism and classified drugs based on metabolism and solubility for the purpose of predicting oral drug disposition. On the other hand, SECS classified drugs based on permeability and protein binding for the purpose of predicting the salivary excretion of drugs. The role of metabolism, rather than permeability, on salivary excretion is investigated and the results are not in agreement with BDDCS. CONCLUSION: The proposed Salivary Excretion Classification System (SECS) can be used as a guide for drug salivary excretion based on permeability (not metabolism) and protein binding. PMID- 24493976 TI - Phenol as a novel sclerosing agent: A safety and efficacy study on experimental animals. AB - BACKGROUND: Varicose and ectatic cutaneous vessels are common chronic conditions that might need surgical treatment. There are several treatment modalities, but all can cause complications and have significant recurrence rates. A new effective and safe treatment with low or no recurrence is needed. Phenol seems to be a potential therapeutic agent. OBJECTIVE: To assess the efficacy and safety of phenol as a sclerosing agent in the treatment of varicose veins and other vascular ectatic conditions. METHODS: The dorsal ear veins of white New Zealand rabbits were injected with 0.1 ml of a sclerosing agent. Four experimental groups were used to test the sclerosant efficacy of different concentrations of phenol (1%, 5%, 20% and 50%). Sodium tetradecyl sulphate (STS), a commonly used sclerosing agent, was used as a positive control, while normal saline was used as a negative control. The blood vessels of the treated ears were photographed before and 1 h, 2 days, 8 days and 45 days after treatment. Biopsies from the treated areas were obtained for histologic examinations. RESULTS: A concentration of 1% phenol was too low to cause significant vascular changes, whereas a concentration of 5% phenol caused 90% lumen narrowing. Interestingly, 1% STS only caused 25% lumen narrowing. Concentrations of 20 and 50% phenol caused 100% lumen narrowing but caused haemorrhage and necrosis. Toxicity monitoring showed no apparent haematologic, cardiac, pulmonary, hepatic or renal toxicity associated with the concentrations of phenol used in this study. CONCLUSION: A concentration of 5% phenol appears to be a potent and safe sclerosing agent for ectatic small vessels. This provides a significant new therapeutic option, which may eventually advance to the clinic and have an impact on the treatment of patients suffering from varicose veins and other vascular ectatic conditions. PMID- 24493978 TI - Editorial medicine and media. PMID- 24493979 TI - Medicine, media communication and ethical aspects. AB - On World Press Freedom Day (3rd of May 2009) details of the Frida Haus ranking list of press freedom in countries around the world were officially disclosed. Bosnia and Herzegovina is ranked at 98 place, and in the region better ranked is only Montenegro, which is located between 78 and 80 place along with Botswana and Eastern Timor. Top rated is Iceland with 9 points and on the last place is North Korea, with 98 points. Almost every profession has its deontology/ethical principles. However, medicine and the media are specifically targeted by public controversy with regard to the consequences of their responsibilities for the individual and the overall population. Until twenty years ago, the media were the main social system or a reflection of the social system and dominated the field of public communication, which implicitly reflected in the organization, operation and effects of companies, corporations, etc. as the overall social system, increasing the gross national product and its various categories enabled boom. Medicine and health represent to a wide range of people, perhaps, the most interesting source of information, and probably there isn't a person that once was not interested in quality professional and verified information regarding some of their medical condition or overall health status. It is estimated that today there are more than a million Web sites on health and diseases, which means that the availability of health information for users is better today than ever before. However, it is important to patients and users of web sites with health information to learn how to properly use them, and learn to assess whether the information published on this site are of reliable quality, which depends on the authors who put the information on the web site, their topicality, simplicity in use and especially the diversity of the medical content of these web pages. It is the Internet that allows the revolution in relation patient-health care- health services provider. First look is at the symptoms and other health information on the Internet before patients actually go to the doctor. In response to this there is change in the relation patient- doctor, there are attempts to allow the patient to make a test, for example, cholesterol in the blood prior to scheduling the examination by the doctor. The vision of the future is Web-based and secure health record (Medical Record) that can be maintained in some kind of health plan or supervised by a physician. Such a site can be used when the patient is traveling or when he or she goes to the pharmacy or doctor of any specialty. Access to appropriate information may strengthen patients to express their demands and medical professionalism in order to improve clinical decision making. Information on support of patients and their involvement in prevention, alternative treatments and their care should be a central part of quality improvement strategies. Improving the quality of information and helping people use the most of what is offered have to be realized by implementing the strategies. Governments should invest in public education programs to encourage people to critically evaluate health information. For their share, they will have to be aware of the scope and quality of information sources that can be used by patients, so that they can get advice from them in an appropriate manner. PMID- 24493980 TI - Controversy and concerns in the relationship of medicine and the media in bosnia and herzegovina. AB - Medicine and the media are two areas important in the life of every man, which are in almost daily contact with each other and in dependence. Their relations in BiH are currently elemental, focused on direct, immediate needs, without defined rules, with a lot of disorientation, incompetence and irresponsibility, often without respect for at least the minimum rules of conduct and respect, often with a lot of conflict and hostility. The goal of our work is based on the analysis of newspaper articles, TV programs and Web sites in the period of one year and was to assess the current situation and suggest solutions. In order to acquire objective insight into the current situation, in the preparation of the symposium "Medicine and Media" in Mostar, we analyzed all stories related to medicine in two daily newspapers, two weekly, three TV stations in the period from September 1st 2008 to August 31st 2009, and the web sites of hospital institutions, Department of Health Insurance in Bosnia and Herzegovina and the Ministries of Health which were available online on 1st and 2nd September 2009. In total we managed to process 402 contents as written content, TV shows or stories in TV shows and 28 web pages, and we believe that our sample is representative. We have found the following characteristics of the current situation in BiH that have to be changed: Topics in the press, web sites or programs on health services should have some kind of certification, i.e. licensing so that is clear that the contents of the announcement is made under control of health care professionals, i.e., licensed or of optional entertainment content; In cases of professional accusation of any specific person, usually a doctor, not to state full name of the before the existence of binding court decisions, or in case of possible litigation not to allow favoring of any party of the dispute; In addition to the interest in the work of health institutions it is necessary to direct media attention towards the work of the Institute and the ministries of health insurance, because very few reports deal with their work and activities; It is necessary to emphasize investigative reporting with good topics covered by professionals and annual prizes awarded to the authors of such content about medicine in BiH should be considered. PMID- 24493981 TI - Rate of bipolar affective disorder registered according to total pattern of morbidity at psychiatry clinic in sarajevo from 2006-2008. AB - INTRODUCTION: Affective disorders were known even in ancient times. Today is the official name of the ICD-10 bipolar affective disorder (F31) and represent sub category of mood disorders (affective disorders) with code F30-F39. GOAL: The aim of this study was to examine and display the frequency of bipolar disorders in the total number of patients at the Psychiatric Clinic in the period 2006-2008, in order to examine the demographic profile of patients and to determine the length of hospitalization. One of the goals is also to show the number of patients with bipolar disorder compared to all other patients in the group F30 39, with respect to the research period. PATIENTS AND METHODS: During the research is used a retrospective-prospective study of clinical-epidemiological character. The study included all 3713 patients with different diagnoses, which were hospitalized at the Psychiatric Clinic of the Clinical Center in Sarajevo in the period from January 1st 2006 to December 31st 2008. From the total number of 3713 respondents selected are those with bipolar affective disorder, 63 (1.7%). The diagnosis was set according to ICD-10 Classification (F30-39). RESULTS: Of the total number of patients 3713, there were 63 (1.7%) subjects with BD. From this number in 2006 was 21 (1.6%); in 2007-20 (1.7%), and in 2008-22 (1.7%) Patients with F31.1 was present in 2006 year as 5 (23.9%) cases and in 2007 the dominant group consists of respondents with F31.2-8 (40%), while in 2008 patients with F31.2 had 7 cases (31, 8%). The average duration of hospitalization in 2006 amounted to 43.7 days in 2007 to 40.9 and in 2008 to 37 days. CONCLUSION: Bipolar disorder is often incorrectly diagnosed as is also possible in this study given the small percentage of the disorder in relation to the total number of patients. Bipolar disorder has a direct impact on the quality of life of patients. Because of these facts, timely diagnosis and appropriate treatment are very important, and as a result, their suicide prevention. PMID- 24493982 TI - Medical law - challenges in bosnia and herzegovina. AB - THERE ARE FOUR TYPES OF RESPONSIBILITIES THAT ARISE ON THE BASIS OF MEDICAL ERRORS: a) Disciplinary (Punishment of the competent Association for restriction or revocation of the license); b) Civil liability (compensation); c) Criminal responsibility (protection of individual interests to protect the interests of the society); d) Violation (fine for minor damage) To increase the number of criminal proceedings mostly influenced the lack of compensation system for harm because the injured party considered that after the positive completion of criminal proceedings can easily make a claim. Therefore they do not address the local Association or Ministry of Health to investigate a case, but to the criminal proceedings to try to get compensation. It turned out that this is a dispute that is usually long lasting, with an uncertain outcome, which does not bring satisfaction to the plaintiff, and had a series of negative consequences in the general approach to the treatment of patients known as "defensive medicine". As a result of the increased number of lawsuits due to medical errors are caused the following negative consequences: a) Great vigilance of physicians in communicating with patients, who must sign a 2-3 statements when entering the hospital, and that sometimes are not really familiar with the nature of illness and required treatment; b) Significant increase in the number of unnecessary tests which are required by doctors to insure themselves from the potential liability, which at a given moment are not really necessary; c) Lack of medical error reporting system allows individuals to avoid their reporting, which affects the course of treatment and prognosis; d) Often avoidance by the doctors to perform some necessary procedures that are risky, with increasingly open refusal to cure a poor prognosis case which they left to the next level of treatment. Disappears so called "heroic approach" to the treatment in the B&H health system known from the war period and gives way to extreme caution, because the doctors expect that their every procedure will be under scrutiny; e) All of these factors create a mode known worldwide as "defensive medicine", which increases the cost of treatment and lower level of health care; f) Reduced volume of education, because older physicians are reluctant to let residents decide on specific work procedures and operations; g) There is already a critical shortage of some medical specialties, and inevitably follows increase in price from these service areas and increase of the waiting list. PMID- 24493983 TI - Physical health after trauma. AB - Family medicine physicians in their daily practice meet with a number of diseases and conditions that are the result of stress and physical trauma. One of the most frequent is post-traumatic stress disorder syndrome, which in our terms is a result of the aggression on Bosnia and Herzegovina and in total morbidity occupies more than 30% of all mental illnesses. This paper describes one such case in our practice. Timely diagnosis means the establishment of adequate therapy and relatively successful treatment. PMID- 24493984 TI - Nursing information systems. AB - Computer technology is a reality of our modern world. It gives us a tool which can be used to help us cope with the complexity and efficiency which is often required in many areas of work. It is an erroneous assumption that it robs a situation of its human qualities. No one would deny that the use of a word processor denies the possibility of highly creative writing being produced or that computerized checkouts make the interaction skills of the checkout person irrelevant to the process of struggling with the week's shopping once more. In many ways, the use of the computer frees the person from the drudgery of repetitive labour to allow more time and effort to be available for the more personal skills to find expression. Recording assessment data using a computer keyboard allows just as much caring communication between nurse and clients as writing it down on a form. The critical factor is not the method of recording but the interpersonal skills and motivation of the nurse. The nursing profession is at last beginning to appreciate the role which the new technology can have in improving the service provided to patients. Only by taking an active role now in the implementation of computers to clinical practice can nurses maintain control of their own professional contribution to the large complex systems at present being implemented in many health care settings. Knowledge based systems are set to become a major component in the nurse's ability to take on this role. PMID- 24493985 TI - Evaluation of usage of information diagnostic technology in family and general medicine. AB - INTRODUCTION: In recent decades, the development and improvement of technology is rapidly advancing. The development of science, new materials, information technology, new procedures and other modern achievements were his first confirmation sought to improve living conditions, particularly in achieving better health conditions. In an effort to improve living conditions, solve the problem of severe diseases and to facilitate treatment, new technologies, almost always find its first application in medicine. In such conditions of general pressure of new modern technologies, health professionals often succumb to uncritically use these technologies. METHODOLOGY: Analyzing data collected from 30,000 research papers that have done 30 doctors of family medicine and 30 doctors of general medicine, and from interviews conducted with all 60 doctors who participated in the research. RESULTS: a) Teams of family medicine have a significantly higher professional education, and it should be noted that there was no significant difference in length of service of employees; b) Teams of family medicine have significantly less committed population on which the care; c) Teams of family medicine in an average have fewer visits per day than the teams in general medicine; d) Information diagnostic technologies are more accessible to family medicine teams. CONCLUSION: It is necessary to introduce a technology assessment as a standard scientific methods in decision making and the creation of the health system. In fact, it is necessary to establish and enable institutions to assess health technologies and join the developed world in creating better health care. PMID- 24493986 TI - International public health. AB - Public health is a broad field that touches several different medical disciplines such as epidemiology, public health informatics, health statistics, environmental protection (ecology), sociology, health promotion, disease prevention and organization of health care for nosological groups of the population. In Europe and the world today is developed a fairly extensive network of scientific and professional institutions engaged in research projects, studies, organization of scientific conferences and publishing scientific and professional articles from the field of public health. Their goal is to promote scientific advances in the field of public health through the exchange of experiences of public-health professionals, training, demonstration of appropriate research models, simulation and application in medical practice. PMID- 24493987 TI - The development of infectology in bosnia and herzegovina, with special emphasis on the development and history of infectious clinic, clinical center of sarajevo university. AB - CONFLICT OF INTEREST: none declared There is a relatively low amount of historical data about development of infectology in Bosnia and Herzegovina, but that does not mean that these medical disciplines didn't have important events and actors that are important for the development of this medical discipline in B&H. In this review we intent to show your several characteristic events and important persons, which left a lasting impression in the development of infectology service in BIH and especially in Sarajevo. Development center for this discipline was in Sarajevo. Experts on infectious diseases were sent from Sarajevo to other health centers to organize new ministry there. Infectology as an organized health care dates back to the Austro-Hungarian period, when a part of the State Hospital in Sarajevo formed a separate Department of Infectious Diseases. Thanks to the competent professional and later teaching staff in this discipline and the importance of health care of patients with infectious diseases, in Sarajevo and other cities in Bosnia, infectious diseases care has experienced expansion and increasing importance and quality. Infectious disease specialists were very quick in organizing their professional association and with exchange of knowledge and experience have contributed substantially to the above assertion. The "Association of infectious diseases of Bosnia and Herzegovina" was founded during the aggression on BIH, in 1994 and in 1997 they organized the first scientific congress of the Association of the infectious disease specialist with international participation. Improving the health of the population in the area of infectious diseases was significantly helped by infectious diseases clinics at clinical centers in BIH and departments for infectious diseases within the hospitals in B&H. Association of the infectious disease is a significant coordinator for scientific and professional activities, but also the environment in which infectious disease specialists are able to share their knowledge and experiences. PMID- 24493988 TI - Brucella endocarditis in prosthetic valves. AB - CONFLICT OF INTEREST: none declared. INTRODUCTION: Brucella endocarditis (BE) is a rare but severe and potentially lethal manifestation of brucellosis. Pre existing valves lesions and prosthetic valves (PV) are favorable for BE. CASE REPORT: We represent the case of a 46-year-old man who was treated at the Clinic for Infectious Diseases, Clinical Center of Sarajevo University, as blood culture positive (Brucella melitensis) mitral and aortic PV endocarditis. He was treated with combined anti-brucella and cardiac therapy. Surgical intervention was postponed due to cardiac instability. Four months later he passed away. Surgery was not performed. PMID- 24493989 TI - Analysis of comorbidity of the patients affected by staphylococcal bacteremia/sepsis in the last ten years. AB - CONFLICT OF INTEREST: none declared. INTRODUCTION: Staphylococcal bacteremia/sepsis is one of the most serious bacterial infections around the world. In individuals with pre-existing diseases, there is always an increased risk of infections occurring due to impaired immune system, a variety of drug therapy, exposure to a diagnostic and therapeutic procedure and frequent hospitalizations. OBJECTIVES: To analyze the prevalence of comorbidity in a patient with the staphylococcal bacteremia/sepsis according to the diagnosis, the site of infection and according to the isolated agent. PATIENTS AND METHODS: We analyzed the patients affected by the staphylococcal bacteremia/sepsis and treated in the Clinic for Infectious Diseases during a ten-year period. RESULTS: 87 patients were included, out of whom 20 (23%) with clinical signs of the bacteremia and 67 (77%) of sepsis. In the analyzed sample, in 36 (41.4%) were not registered comorbidity. Hospital infections are represented by the previous antibiotic, corticosteroid and chemo therapy, pressure ulcers, and different implants. In all comorbidity, the most common isolated bacteria was S. aureus primarily strain MSSA followed by MRSA strain which is more frequent in patients who were surgically treated (comorbidity-various implants). CONCLUSION: The results suggest the importance of being mindful of the staphylococcal etiology of the bacteremia/sepsis in patients with comorbidities due to the selection of an adequate initial empirical therapy and reducing the risks of the septic shock. PMID- 24493990 TI - Varicella Pneumonia in a 39-year-old Female in Third Trimester Twin Pregnancy. AB - CONFLICT OF INTEREST: none declared. INTRODUCTION: Chickenpox is disease caused by varicella-zoster virus (VZV), with possibly devastated consequences during pregnancy, for mother and neonate. Pneumonia is most common complication in pregnancy with very high mortality. CASE REPORT: A 39-year-old female in third trimester twin pregnancy, referred to Clinic for infectious diseases in Sarajevo, with five days history of illness. Before the admission her condition get worse, with fatigue, exhaustion, and shortness of breath. In a first three days patient was febrile, tachydispnoic and ortopnoic. We started therapy with acyclovir and antibiotic. After four days we had detoriation in patient's condition. Chest X ray revealed infiltrative shadows in basal parts of lung. Antimicrobial therapy was changed and corticosteroids were associated. Significant improvement was noticed after five days of therapy. CONCLUSION: Varicella pneumonia during third trimester may have serious consequences for mother and child, with possible fatal outcome. PMID- 24493991 TI - Complicated Varicella Infection at 8-year-old Boy with Pulmonary Agenesis. AB - CONFLICT OF INTEREST: none declared. INTRODUCTION: Varicella or chickenpox is highly contagious, childhood infectious disease caused by primary infection with varicella - zoster virus from the herpes family of viruses. Usually it has a mild clinical course, rarely with described complication, mostly affecting respiratory tract and rarely the central nervous system. CASE REPORT: The case present 8 year old boy hospitalized eighth day of disease with clinical pictures of varicella complication. Upon receipt tachydyspnea, high fever, tachycardia, hypotensive with positive findings on lung auscultation in the sense of pneumonia. Extremely high values of non-specific inflammatory parameters are implied on bacterial infection which is treated using triple antimicrobial therapy and antiviral. A detailed clinical, laboratory and radiological evaluation is determined of clinical disease complication under a picture of MODS that required prolonged multidisciplinary treatment in ICU. CONCLUSION: The disease had a favorable clinical outcome in terms of training completely without consequences but, with the detected congenital absence lower lobe of right lung and transposition of the brachiocephalic trunk. PMID- 24493992 TI - On the occasion of the 4th congress of infectiologists of bosnia and herzegovina with international participation. AB - The 4th Congress of Infectiologists of Bosnia-Herzegovina with international participation was held in Konjic, on 30. May to 02. June 2012. In addition to the prominent infectious disease experts from almost all university centers in B&H, the teachers at medical schools in Bosnia-Herzegovina, infectious disease specialists who work in health institutions in B&H, this Congress was attended by infectious disease experts from Serbia (12 participants), Turkey (3 participants), Croatia (3 participants), Macedonia (3 participants), Germany (2 participants) and Montenegro (2 participants). Topics included: Infections of the skin, soft tissue and bones, Sepsis and endocarditis, Infectious diseases emergencies and pediatric infectology, Emerging and reemerging infectious diseases, Hospital infections, Sexualy transmitted diseases, Infectious diagnostic and therapeutic protocols. Participating invited speakers were following professors: Salih Hosoglu (Turkey), Hakan Leblebicioglu (Turkey), Resat Ozaras (Turkey), Karsten Plotz (Germany), Ilija Kuzman (Croatia), Bruno Barsic (Croatia), Goran Tesovic (Croatia). In addition to experts in infectious diseases at this Congress, their works were presented by experts from other medical disciplines, but with infectious character issues (Professors: Sead Ahmetagic, Ismet Gavrankapetanovic, Zora Vukobrat-Bijedic, Senija Rasic, Halima Resic, Adnan Kapidzic, Ivo Curic, Jelena Ravlija, Amela Begic, Izet Masic, Sadeta Hamzic, and others). Some of the papers that were presented at this Congress have been published in extenso, in the Medical Archives and Materia Socio Medica. One part as abstracts (both journals are indexed in over 10 databases), and will be electronically available to the general scientific community in Bosnia Herzegovina, Europe and worldwide. In this way, the Bosnian infectious disease experts, as a science and profession, will be worthily represented to the colleagues from other countries in the region and beyond. PMID- 24493993 TI - Detection of Caprine-specific Nucleic Acid Sequences in Goat Milk Using Polymerase Chain Reaction. AB - CONFLICT OF INTEREST: none declared. INTRODUCTION: This study was carried out to evaluate PCR-based method for detection of DNA in goat milk. It utilized primers targeting the mitochondrial cytochrome -b (mtcyt-b) gene, which was used as a target DNA for PCR amplification. METHODS: For the specific identification of goat mtcyt-b gene, pair of primers (GSL1, GSR2), were used, which produced a 428 base pair (bp) PCR product from milk samples as well as from peripheral blood. Amplification products were visualized on ethidium bromide-stained agarose gels. RESULTS AND DISCUSSION: Amplification products were not detected when the PCR was applied to DNA from animal species including cattle, sheep, swine, camel, deer, horse, donkey, and human, which indicates that the 2 pairs of primers are specific for goat. CONCLUSION: DNA can be extracted from goat milk and would be advantageous in the variety of application such as species identification in milk and milk. PMID- 24493994 TI - Ceftazidime-avibactam: an evidence-based review of its pharmacology and potential use in the treatment of Gram-negative bacterial infections. AB - Avibactam (NXL104, AVE1330A) is a semi-synthetic, non-beta-lactam, beta-lactamase inhibitor that is active against Ambler class A, class C, and some class D serine beta-lactamases. In this review, we summarize the in vitro data, pharmacology, mechanisms of action and resistance, and clinical trial data relating to the use of this agent combined with ceftazidime for the treatment of Gram-negative bacterial infections. The addition of avibactam to ceftazidime improves its in vitro activity against Enterobacteriaceae and Pseudomonas aeruginosa. Avibactam does not improve the activity of ceftazidime against Acinetobacter spp., Burkholderia spp., or most anaerobic Gram-negative rods. Pharmacodynamic data indicate that ceftazidime-avibactam is bactericidal at concentrations achievable in human serum. Animal studies demonstrate that ceftazidime-avibactam is effective in ceftazidime-resistant Gram-negative septicemia, meningitis, pyelonephritis, and pneumonia. Limited clinical trials published to date have reported that ceftazidime-avibactam is as effective as therapy with a carbapenem in complicated urinary tract infection and complicated intra-abdominal infection (combined with metronidazole) including infection caused by cephalosporin resistant Gram-negative isolates. Safety and tolerability of ceftazidime avibactam in clinical trials has been excellent, with few serious drug-related adverse events reported. Given the abundant clinical experience with ceftazidime and the significant improvement that avibactam provides in its activity against contemporary beta-lactamase-producing Gram-negative pathogens, it is likely this new combination agent will play a role in the empiric treatment of complicated urinary tract infections (monotherapy) and complicated intra-abdominal infections (in combination with metronidazole) caused or suspected to be caused by antimicrobial-resistant pathogens (eg, extended spectrum beta-lactamase-, AmpC-, or Klebsiella pneumoniae carbapenemase-producing Enterobacteriaceae and multidrug resistant P. aeruginosa). Potential future uses also include hospital-acquired pneumonia (in combination with antistaphylococcal and antipneumococcal agents) or treatment of skin and soft tissue infections caused by antimicrobial-resistant Gram-negative pathogens (eg, diabetic foot infections), but further clinical trials are required. PMID- 24493995 TI - Transforming growth factor-beta1 in plaque morphea. AB - INTRODUCTION: Morphea (localized scleroderma) is a rare cutaneous disease characterized by skin fibrosis of unknown pathogenesis. Transforming growth factor-beta (TGF-beta) is a potent profibrotic factor. The role of TGF-beta in morphea remains unclear. AIM: The goal of this study was to estimate the expression level of TGF-beta1 in skin and peripheral blood mononuclear cells as well as the plasma levels of TGF-beta1 in plaque morphea (MEP). MATERIAL AND METHODS: The study involved 20 MEP patients. Three control groups were involved: 1 - plasma: 36 healthy volunteers; 2 - PBMC: 47 healthy volunteers; 3 - skin biopsies: 13 samples collected during mastectomy (breast cancer was not skin involved). The analysis of TGF-beta1 plasma levels was performed with the use an adequate ELISA kit, while real-time polymerase chain reaction was employed for the expression of TGF-beta1 in peripheral blood mononuclear cells (PBMC) and skin. RESULTS: In our study we have not detected differences in TGF-beta 1 expression in PBMC, skin, nor in plasma levels of TGF-beta1 between MEP patients and healthy controls, regardless of disease activity and its duration. CONCLUSIONS: The results of our study contradict the claim of the substantial role of TGF-beta1 in the most common morphea subtype - MEP. PMID- 24493996 TI - Evaluation of biophysical skin parameters and assessment of hair growth in patients with acne treated with isotretinoin. AB - INTRODUCTION: Treatment of the severe forms of acne vulgaris remains a challenge. Isotretinoin is a drug often used in these cases. Retinoids affect the mechanisms that play a role in the pathogenesis of acne, reduce the production of sebum and sizes of the sebaceous glands. However, isotretinoin appears to have undesirable side effects in the skin, mucous membranes and hair. AIM: THE AIM OF THIS STUDY WAS TO ASSESS THE EFFECT OF ACNE VULGARIS TREATMENT WITH ISOTRETINOIN ON BIOPHYSICAL SKIN PARAMETERS: skin sebum and stratum corneum hydration levels, transepidermal water loss values, pH, erythema and hair growth parameters: total number, density and proportion of anagen hair. MATERIAL AND METHODS: THE STUDY INCLUDED THIRTY PATIENTS WITH ACNE TYPES: papulopustular, conglobata and phlegmonosa. Patients were treated with isotretinoin at a dose of 0.5-1.0 mg/kg/day for a period of 4-7 months. The measurements of skin biophysical parameters were performed before and after the treatment using Sebumeter SM815, Corneometer CM825, Tewameter TM300, MX Mexameter MX18 and Skin-pH-Meter PH908. Hair growth parameters were evaluated with FotoFinder Dermoscope using the TrichoScan Professional V3.0.8.76 software. RESULTS: The results of biophysical skin parameter measurements after the treatment showed a reduction in the severity of seborrhea. However, the skin was dry, which confirmed a lowered degree of stratum corneum hydration and an increase in transepidermal water loss values. Moreover, severity of erythema, an increase in pH value, and variations in selected hair growth parameters: decrease in total count, density and proportion of anagen hair were demonstrated. CONCLUSIONS: The reduction in the skin sebum levels was observed after the treatment. There was dryness of the skin, which was confirmed by biophysical skin parameter measurements. Changes in the hair growth parameters showed telogen effluvium hair loss. PMID- 24493997 TI - Patch test results in patients with allergic contact dermatitis in the Podlasie region. AB - INTRODUCTION: The aim of the study was to provide current data on the incidence of allergy to various contact allergens in patients with allergic contact eczema and the analysis of selected socio-demographic data of the patients. MATERIAL AND METHODS: The study included 1532 patients (1010 women and 522 men) treated for allergic contact dermatitis at the Department of Dermatology and Venereology and at the Dermatology Outpatient Clinic in Bialystok in 2007-2011. The assessment of selected demographic data and skin lesions was based on the MOAHFLA index, while the results of patch tests were analyzed with modified Baseline European Series consisting of 31 allergens. RESULTS: In the group of patients with eczema, 34.1% were men, and 55% of all respondents were people over 40 years of age. The occupational character of skin lesions was found in 22.5%. Most frequently (38.9%) skin lesions were localized on the hands, rarely involved legs (3.98%). Atopic dermatitis was diagnosed in 4.5% of patients. The ten most frequent allergens were: nickel sulfate (24%), cobalt chloride (15.3%), fragrance mix (8.25%), potassium dichromate (6.8%), balsam of Peru (5.5%), neomycin (4.42%), paraphenylenediamine (3.85%), Quatermium-15 (2.1%), detreomycin (1.83%) and budesonide (1.44% of tested patients). CONCLUSIONS: Frequent allergy to detreomycin indicates the need of patch testing for this allergen of all examined patients with allergic contact dermatitis. The increased frequency of the nickel allergy is a worrying problem and indicates the need for education about the risk factors for nickel allergy development and the implementation of appropriate legal regulations. PMID- 24493998 TI - Grain dust originating from organic and conventional farming as a potential source of biological agents causing respiratory diseases in farmers. AB - INTRODUCTION: Agricultural producers are exposed to a number of different health risks associated with their work environment. AIM: The objective of the study was to assess the degree of colonization by fungi in terms of quantity and in terms of variety of species the samples taken from the settled dust from combine threshing of rye cultivation from organic and conventional farms in the Province of Lublin. MATERIAL AND METHODS: This paper is a preliminary quantitative assessment of the species of fungi colonizing the samples of settled dust collected during combine threshing from organic and conventional farms in the Province of Lublin. One of the stages of the project was the classification of biosafety BSL (biosafety level) of selected isolates and API ZYM tests to evaluate the potential ability of isolates to cause adverse health effects. To determine the concentration and composition of fungi in collected samples plate dilution method was used with two media: Malt Agar and Potato Dextrose Agar. RESULTS: MOST COMMONLY ISOLATED FUNGI IN SETTLED DUST SAMPLES COLLECTED DURING COMBINE THRESHING FROM ORGANIC FARMS, ON PDA MEDIUM WERE: Alternaria alternata and Aureobasidium pullulans. Cultures on MA medium were dominated by Alternaria alternata, Mycelia sterilia and Fusarium poae. In samples of dust from conventional crops, the predominant species was Alternaria alternata on PDA medium and on MA medium. CONCLUSIONS: The obtained results show a potential risk of people involved in agricultural work. PMID- 24493999 TI - Emotional intelligence as an indicator of satisfaction with life of patients with psoriasis. AB - INTRODUCTION: Research reports confirm the existence of a relation between emotional intelligence and various aspects of human functioning. It protects psychical and physical health of an individual, helps to adapt to new conditions and, consequently, contributes to the increase in life quality expressed in satisfaction with life. Psoriasis, a chronic skin disease, may negatively influence the psychical state of a patient and his or her social functioning, which leads to the decrease in satisfaction with life. AIM: This research aimed at determining the relation between emotional intelligence and satisfaction with life in a group of patients with psoriasis. MATERIAL AND METHODS: The research group consisted of 81 people with psoriasis (40 men and 41 women) with the average age of 41.22 (SD = 14.18). The research tools used included the Emotional Intelligence Questionnaire INTE, Satisfaction With Life Scale (SWLS), personal questionnaire and PASI scale. RESULTS: There is a positive correlation between emotional intelligence and satisfaction with life in the group of patients with psoriasis. Especially factor I - using emotions in thinking and operating - positively correlates with satisfaction with life. CONCLUSIONS: Emotional intelligence together with the percentage of body area taken by pathological changes are the indicators of satisfaction with life in patients with psoriasis. PMID- 24494000 TI - Rye grains and the soil derived from under the organic and conventional rye crops as a potential source of biological agents causing respiratory diseases in farmers. AB - INTRODUCTION: INTRODUCTION: Due to the specific work environment, farmers are exposed to various biological occupational hazard. Among these factors significant are fungi present in the grain and also in the soil. The fungi may be the cause of human diseases including skin infections, asthma, allergic rhinitis and many others. AIM: The aim of this study was to quantify and identify species of fungi colonizing rye grain samples and the soil under cultivation. MATERIAL AND METHODS: THE MATERIAL CONSISTED OF GRAIN AND SOIL SAMPLES FROM TWO AGRICULTURAL SYSTEMS: organic and conventional. To determine the concentration and composition of fungi in collected samples, two media: Malt Agar (MA, Becton, Dickinson and Company) and Potato Dextrose Agar (PDA, Becton, Dickinson and Company) were used. The composition of species in fungal flora was determined using macroscopic and microscopic methods. The isolates of fungi were ranked in the appropriate classes of biosafety BSL. RESULTS: THE MOST FREQUENTLY ISOLATED FUNGI FROM ORGANIC RYE GRAIN, REGARDLESS OF THE MEDIA USED, WERE SPECIES: Aureobasidium pullulans and Alternaria alternata. In conventional farms, most species isolated from rye grain were: Aureobasidium pullulans, Cladosporium oxysporum, Alternaria alternata and yeast-like fungi. Most often species isolated from the soil was Penicillium citreo-viride. CONCLUSIONS: All the results of the research demonstrate the potential hazard to the health of people working in agriculture. Significant exposure of this professional group is associated with the presence of harmful biological agents present in the grain and soil from its cultivation. PMID- 24494001 TI - The relation between type D personality and the clinical condition of patients suffering from psoriasis. AB - INTRODUCTION: TYPE D PERSONALITY IS THE LAST DISTINGUISHED SPECIFIC TYPE OF PERSONALITY THAT IS CHARACTERISED BY TWO DIMENSIONS: a tendency for feeling negative emotions - depression, anxiety, anger or hostility, and a tendency for withdrawal from the society. The latest research shows the significant role played by type D personality in the aetiology and course of a variety of diseases. AIM: The article discusses the problem of the occurrence of type D personality in the group of patients suffering from psoriasis. Diversities in the clinical condition of psoriasis patients due to increasing type D personality traits are specified. MATERIAL AND METHODS: Ninety psoriasis patients and 86 healthy subjects participated in the research. In the research questionnaires, the scale for assessing increasing psoriasis complaints and the DS-14 scale to assess type D personality were applied. RESULTS: Research results made it possible to corroborate more frequent occurrence of type D personality among psoriasis patients. Moreover, it was found that with increasing negative affectivity - one of type D personality components - complaints increase as far as the clinical condition of psoriasis patients is concerned. CONCLUSIONS: Monitoring of psychological well-being of psoriasis patients, especially within type D personality, seems to be a vital element, irrespective of purely medical treatment. PMID- 24494002 TI - Skin care during the menopause period: noninvasive procedures of beauty studies. AB - Ageing is a resultant of two processes, including genetically encoded changes in an organism and modifications caused by a negative external environment impact. In the histological aspect, the skin ageing, due to endogenous factors and hormonal changes shows: excessive dryness, Malpighian layer thinning, microcirculation disorders, collagenic or elastin fiber degradation and simultaneous glycation, decreased speed of sebum and perspiration secretion. It is said that skin is a functional picture of the organism and endocrinological system. Any hormone concentration ups and downs may improve its appearance or significantly worsen its condition as well as it may lead to occurrence of dermatological changes. In adult women, the ageing process changes its significance step by step. Despite the passage of time, women want to feel good inside their skins. The adult skin is more requiring and it needs special care, often using a cosmetic apparatus. For better effect and permanent revitalization of the ageing skin, it is recommended to apply properly selected home-use cosmetic preparations. A holistic approach makes it possible to reach the skin density and thickness increase, wrinkles shallowing, humidity and resilience improvement and also recovery of the proper face oval. PMID- 24494003 TI - Case report of African tick-bite fever from Poland. AB - A confirmed case of rickettsiosis acquired in South Africa and recognized in Poland was described. The patient fulfilled clinical criteria highly suggestive of African tick bite fever, such as eschars, regional lymphadenitis, cutaneous rash within 10 days after his return from sub-Saharan Africa. Infection with Rickettsia africae was confirmed by polymerase chain reaction and sequencing. PMID- 24494004 TI - Eruptive xanthomas. AB - Xanthomas are localized lipid deposits in the skin, tendons and subcutaneous tissue associated with lipid abnormality. The hyperlipidemia responsible for this disorder can be caused by a primary genetic defect, a secondary disorder, or both. That kind of skin exanthema may be the first signal of cardiovascular risk. We present a 24-year-old woman with a skin eruption that had appeared a few months earlier. PMID- 24494005 TI - A 6-year-old boy with Sulzberger and Garbe dermatosis: a case report and literature review. AB - Sulzberger-Garbe disease was described in 1937. Not more than a hundred of cases of the disease have been reported in the literature. Despite a quite specific picture, there are no features that could undeniably be attributed to this particular disease entity. Discoid exudative and lichenoid lesions are main lesions in this dermatosis. The disease is associated with severe pruritus. The lesions are located on the trunk and extremities as well as the genitals. Eosinophilia is frequently found in the course of the disease. Sulzberger-Garbe dermatosis has been diagnosed mainly in middle-aged males of Jewish origin but it can occur in both sexes at any age. Good therapeutic response to systemic corticosteroids has been observed. It is still controversial whether the disease should be classified as an independent clinical entity. PMID- 24494006 TI - Coexistence of Parry-Romberg syndrome with homolateral segmental vitiligo. AB - Parry-Romberg syndrome or progressive facial hemiatrophy was first described by Caleb Parry in 1825 and Moritz Romberg in 1846. This disorder is characterized by slowly progressing acquired unilateral hemifacial atrophy, which affects subcutaneous tissue together with the muscles and underlying bones. The pathogenesis and precise incidence of the syndrome remain unclear. Immune mediated processes and disturbed central regulation, leading to the hyperactivity of the sympathetic nervous system, are primarily considered in the pathogenesis of this disorder. Parry-Romberg syndrome and localized scleroderma are considered to be interrelated as both of them have a similar clinicopathological appearance. We report the case of a 46-year-old man affected by both progressive atrophy of the left side of the face and homolateral, segmental vitiligo in the left side of the trunk and face. PMID- 24494007 TI - Why pharmacists should care about the marketing of unhealthy foods: Increasing our role in public health policy / Pourquoi les pharmaciens devraient-ils s'interesser a la promotion des aliments nefastes pour la sante? Contribuons davantage aux politiques en matiere de sante publique. PMID- 24494008 TI - Unprofessional behavior. PMID- 24494010 TI - Moving on and adapting after 4 months. PMID- 24494009 TI - Practical guidelines are necessary for successful pharmacist integration into primary care. PMID- 24494011 TI - Why pharmacists should not think of marketing as a dirty word. PMID- 24494012 TI - Eligibility requirements for community pharmacy medication review services in Canada. PMID- 24494013 TI - A practice tool for the new oral anticoagulants. PMID- 24494014 TI - Pharmacy-based Immunization in Rural Communities Strategy (PhICS): A community cluster-randomized trial. AB - BACKGROUND: Influenza is a major cause of morbidity and mortality in Canada, with up to 7000 influenza-related deaths occurring every year. The elderly and individuals with chronic diseases are at increased risk for influenza-related morbidity and mortality. METHODS: We conducted a 2-year, community cluster randomized trial targeting elderly people and at-risk groups to assess the effectiveness of pharmacy-based influenza vaccination clinics on influenza vaccination rates. Small rural communities in interior and northern British Columbia were randomly allocated to the intervention or control. In the intervention communities, pharmacy-based influenza vaccination clinics were held and were promoted to eligible patients using personalized invitations from the pharmacists, invitations distributed opportunistically by a pharmacist to eligible patients presenting to pharmacies during the flu season and community wide promotion using posters and the local media. The main outcome measure was a difference in the mean influenza vaccination rates. The immunization rates were calculated using the number of immunizations given in each community divided by the population size estimated from the census data. RESULTS: Baseline influenza immunization rates in the population >=65 years of age were the same in the control (n = 10, mean 85.6% [SD 16.6]) and intervention (n = 14, mean 83.8% [SD 16.3]) communities in 2009 (p = 0.79). In 2010, the mean influenza immunization rate was 56.9% (SD 28.0) in the control communities (n = 15) and 80.1% (SD 18.4) in the intervention communities (n = 14) (p = 0.01) for those >=65 years of age. However, in 2010, for those 2 to 64 years with chronic medical conditions, the immunization rates were lower in the intervention communities (mean 16.3% [SD 7.1]) compared with the control communities (mean 21.2% [SD 5.8]) (p = 0.04). CONCLUSION: Clinics were feasible and well attended and they resulted in increased vaccination rates for elderly residents. In contrast, vaccination rates in the younger population with comorbidities remained low and unchanged. PMID- 24494015 TI - Perspectives and experiences of health care professionals and patients regarding treatments for type 2 diabetes. AB - BACKGROUND: Several treatment options exist for type 2 diabetes, but little is known about the factors considered by health care providers (HCPs) and patients in Canada in making therapeutic decisions. This study explores perceptions and practices of HCPs and patients related to add-on (i.e., second-line) therapy for type 2 diabetes when initial therapy no longer provides adequate glycemic control. METHODS: HCPs (pharmacists, family physicians, diabetes educators, endocrinologists and nurse practitioners) and patients with type 2 diabetes in Ottawa and Halifax were randomly selected to participate in the study. Phone interviews were conducted with endocrinologists and nurse practitioners and focus groups with the other HCPs and patients. RESULTS AND INTERPRETATION: Sixty HCPs and 14 patients participated in the study. Metformin was consistently reported by prescribers (physicians and nurse practitioners) as the preferred initial therapy. Important factors in choosing second-line therapy (once glycemic control was inadequate with metformin) were antihyperglycemic efficacy, risk of hypoglycemia and weight gain, and long-term safety. Other considerations were cost, insurance coverage and patient preference. There were differences within and between HCP groups in how these other factors were considered and in the perceived advantages and disadvantages of each drug class. Some patients expressed anxiety when second-line agents were prescribed, and others felt poorly informed about treatment options. CONCLUSION: In choosing a second-line therapy for type 2 diabetes, most HCPs placed a high priority on antihyperglycemic efficacy, although there was considerable variability in the relative weight placed on other factors. These findings point to an opportunity for pharmacists to collaborate more actively with other HCPs to ensure that treatment decisions are based on the best available evidence and to educate and involve patients in these decisions. PMID- 24494017 TI - Diabetes updates and patient tools. PMID- 24494016 TI - Pharmacy students' experiences in provision of community pharmacy mental health services. AB - BACKGROUND: Little information is available describing the pharmacy student's experience working in community practice with people with lived experience of mental illness. Students' perspectives as observers, learners, technical staff and future pharmacists are important. OBJECTIVE: To gain a better understanding of the pharmacy student experience in community pharmacy-based service provision to people with lived experience of mental illness. METHODS: We conducted a qualitative study using interpretive description and application of the Theoretical Domains Framework. Focus groups were held with third- and fourth-year undergraduate pharmacy students from one Canadian university. RESULTS: Two student focus groups were held in the fall of 2012 with 11 students (7 third year and 4 fourth year), 6 women and 5 men, mean age 24.5 (range, 21 to 30) years, averaging 3.2 years (range, 2 weeks to 7 years) of cumulative, mostly part-time, community pharmacy experience. Three broad themes emerged from the pharmacy student experience: (1) business tension; (2) roles, responsibilities and relationships; and (3) stigma. Students discussed their own roles, responsibilities and relationships in a pluralistic identity experience (i.e., pharmacy student, technician, future pharmacist). Application of the Theoretical Domains Framework demonstrated numerous influences on behaviour. CONCLUSIONS: From the students' description of community pharmacy-based care of people with lived experience of mental illness, significant issues exist with current practices and behaviours. Advancing the role of pharmacists and pharmacy students to meet the needs of people with mental illness will require strategies to address multifactorial influences on behaviour. PMID- 24494018 TI - Energize your pharmacy practice. PMID- 24494019 TI - Clinical evaluation of forceps eruption: reestablishing biologic width and restoring no restorable teeth. AB - INTRODUCTION: Complicated crown- root fractures, extended caries and iatrogenic destruction often result in insufficient sound tooth structures and compromise the biologic width. Two common options for re-establishing flap with osseous surgery. Although some advantages are related to these two options, but coronal movement of gingival and alveolar bone in orthodontic extrusion, esthetic problem and inconsistent topography between the involved tooth and the adjacent teeth following osseous surgery are the involved tooth and the adjacent teeth following osseous surgery are the major disadvantages of these two approaches. The purpose of this investigation was to evaluate clinically as well as radiographically the effect of surgical extrusion upon the surrounding root structures. MATERIALS AND METHODS: The material consisted of 21 developed single roots (1 upper and 3 lower) surgically extruded in 17 patients (15 male and 2 female mean age 26 years, ranging 10-40). The indication for surgical extrusion was in 15 cases complicated crown root fracture and in 6 cases early loss of the crown due to an extensive decay. The roots were used where there were completed root developments and the apical fragments were long enough to accommodate a post retained crown. Preoperative radiograph as well as photograph was taken and the clinical and radiographic findings were monitored. The roots were transplanted in their socket in order to reestablish the biologic width. Fixation was carried out with a suture splint and/ or periodontal dressing for 7 days. Recall radiographs were taken at 1 and 4 weeks and at 3 month internals over a 12- month period. RESULTS: Clinically none of the material of 21 teeth demonstrated ankylosis, abnormal mobility and sensibility to percussion or palpation radiographically, PDL healing at 12- month follow up was found in 20 teeth (95.2%). CONCLUSION: successful results up to the time of evaluation encouraged further use of surgical extrusion. Long term evaluation is recommended. PMID- 24494020 TI - Clinical and Radiographic Evaluation of Success Rate with MTA Plug in Open Apices. AB - INTRODUCTION: The ideal endodontic treatment for the teeth with in complete root ends and necrotic pulps may involve the use of material which forms an immediate apical barrier instead of long term calcium hydroxide therapy. Such procedure may lead us to a single appointment endodontic treatment. The purpose of the present study was to evaluate clinical and radiographic success rate in necrotic teeth with open apices treated with MTA as an apical plug. MATERIALS AND METHODS: Thirty five patients between the ages of 8-16 with total number of 41 necrotic anterior teeth containing open apices were selected. In the first visit, root canals were debrided and filled with calcium hydroxide. After one week, calcium hydroxide was removed and MTA with the thickness of 3 to 4 mm was put in the apical region of the canals. After 24 hours, the remaining part of the canals was filled with guttapercha and sealer and the teeth were restored with composite. All the cases were evaluated clinically and radiographically after 3 and 6 months and data were analyzed by McNemar test. RESULTS: No clinical symptoms were observed in 97.6% of the teeth after 3 months and in none after 6 months. The study showed a significant difference from pretreatment status. After 3 months radiographic evaluation showed that in 17 cases (41.5%), lesions were reduced and in 14 cases (34.1 %), lesions remained the same, and in 10 cases (24.4%) lesions disappeared. After 6 months in 21 cases (51.2%), lesions were reduced, in 3 cases (7.3%) lesions remained the same and in 17 cases (41.5%) lesions disappeared. These finding were statistically different from pretreatment data. CONCLUSION: The results indicate that MTA can be used as an apical plug in the teeth with open apices following root canal debridement and disinfection with calcium hydroxide. Further investigations with longer follow-ups are recommended in order to evaluate the effect of this material. PMID- 24494021 TI - A comparative study of lidocaine and lidocaine- mannitol in anesthetizing human teeth with inflamed pulps. AB - INTRODUCTION: Failure to achieve adequate and profound anesthesia in teeth with acute pulp inflammation is a common condition during emergency visits in root canal therapy. Many different anesthetic solutions such as morphine and capsaicin have accordingly been examined. Mannitol- an alcoholic sugar with high osmotic pressure level- is applicated for reducing intracranial and post retinal pressure in medicine. It has also been used for its diuretic effect. In combination with local anesthetic solution, it increases permeability of the nerve fiber sheath and leads to influx of the local anesthetic through cytoplasmic membrane .The purpose of the present study was to compare the efficacy of routine local anesthesia with or without using mannitol in teeth with inflamed pulps. MATERIALS AND METHODS: one hundred patients with acute dental pain in posterior teeth were selected. Vials with 3 ml anesthetic solution containing 2.5% lidocaine with 1/80000 epinephrine or 2.5% lidocaine with 1/80000 epinephrine and 0.5 mol mannitol were used for anesthesia. For each patient, the routine injection technique was applied, during the removal of decay and dentine. Depth of anesthesia was evaluated and the supplementary injection was done in case of pain feeling and then pulpotomy was done. The analysis of data was done using chi square statistical test. RESULTS: The results showed that complete anesthesia after the first injection was obtained with lidocaine mannitol in 46% and with lidocaine alone in 38% of cases. However, the difference was not significant. CONCLUSION: These finding suggest that the addition of mannitol to the standard anesthetic solution could insignificantly increase the level of anesthesia in teeth with inflamed pulps. PMID- 24494023 TI - Prognosis of traumatic injuries to the anterior teeth (treated in shahid beheshti and tehran dental schools during 1996-2001). AB - INTRODUCTION: Traumatic injuries to the teeth are among the most serious dental accidents, with the anterior teeth being mostly affected. Some consequences of dental trauma include misshaping, speech defects, psychological and social effects. The knowledge of the field can reduce the suffering, cost, and the time for patients, parents, and health care providers. The aim of this study was to investigate the treatment prognosis of anterior traumatized teeth in patients referred to Endodontics and pediatrics Departments of Shahid Behesthi and Tehran Dental Schools during 1996-2001. MATERIALS AND METHODS: Fifty patients participated in this descriptive study. All affected by trauma to the teeth and completing the proposed treatment. Retrospective data, based on trauma forms as well as the clinical notes a questionnaire prepared for the study and analyzed in terms of age, gender, the type of trauma and etiology. RESULTS: Eighty four percent of the studied traumatized teeth were maxillary centrals. Falling-outs are most frequent cause of the traumas (56.5%), followed by sport and play events (30.4%). Enamel- dentin fractures with and without pulpal involvement were the most prevalent trauma types. Most of the selected treatment procedures were involved with pulp and periapical areas. CONCLUSION: Based on the finding of the study, the prognosis of traumatized anterior teeth in patients referred to the studied centers was estimated to be good. PMID- 24494022 TI - Interface between newly formed dentine and mineral trioxide aggregate: a preliminary scanning electron microscopy study. AB - INTRODUCTION: This study was carried out to investigate calcific tissue formation against mineral trioxide aggregate (MTA) after pulp capping. MATERIALS AND METHODS: The pulps of six teeth from four dogs were exposed and capped with MTA. After extraction each tooth was sectioned into halves. Each half was then further sectioned in the mesiodistal or buccolingual direction. Calcified tissue of the capped area was examined from either the pulpal side or in profile view using scanning electron microscopy and focused ion beam imaging. RESULTS: The results from all views showed that MTA crystals were in direct contact with calcified tissue. Calcified bridges after focused ion beam preparation showed the same pattern that were seen by scanning electron microscopy in profile view. Newly deposited dentine and early phase of calcosphirit structures could clearly be distinguished from older tubular dentine. CONCLUSION: MTA when used as a pulp capping agent could produce calcific tissue in underlying pulp. PMID- 24494024 TI - Endodontic therapy in a three canal mandibular second premolar. AB - This article describes a clinical case of mandibular second premolar with three separated canals in apical third of the root that are diagnosed and endodontically treated. Sound knowledge of root canal anatomy and morphology, tactile examination of canal walls, critical interpretation of radiographs and high magnification examination are essential elements of success in complicated root canal therapy. PMID- 24494025 TI - History of dental infections associates with cancer in periodontally healthy subjects: a 24-year follow-up study from sweden. AB - BACKGROUND: Infections of teeth are highly prevalent, often leading to tooth extractions. Missing teeth can thus be considered as proxy for chronic dental infections, caries or periodontitis. We followed-up a cohort for 24 years investigating the association between missing teeth and the incidence of cancer with the hypothesis that dental chronic inflammation links to cancer. METHODS: WHO ICD-7-9-10 malignant diagnoses were recorded from the Swedish Cancer Registry from 1985 to 2009 in 1 390 individuals who had underwent clinical oral examination in 1985. The subjects appeared periodontally healthy and thus the probable reason for tooth extractions was deep caries. Using Fisher's exact t test and multiple logistic regression analysis the results were analysed for the association between cancer incidence and baseline oral health parameters and a number of other explanatory factors. RESULTS: Of the 1 390 subjects 71 had got cancer by year 2009. The results of the multiple regression analysis showed that between any type of cancer as a dependent variable, and several independent explanatory variables, missing second molar in the right mandible and age appeared as the principle independent predictors significantly associating with cancer, with an odds ratio (95% confidence interval) of 2.62 (1.18-5.78) and 1.91 (1.06-3.43), respectively. CONCLUSIONS: In periodontally healthy subjects extracted molars, proxy for past dental infections, seemed to predict cancer risk in the studied age group - hence supporting a role of chronic dental infection/inflammation in carcinogenesis. PMID- 24494027 TI - Does the measles virus contribute to carcinogenesis? - a review. AB - An association between the measles virus and classical Hodgkin lymphoma has previously been suggested by us. This has been refuted by two European groups. A reevaluation of the arguments held against our thesis was carried out and further evidence for a relationship between the measles virus and additional solid tumors has been presented. We have suggested a molecular mechanism to support a possible contribution of the virus to carcinogenesis in classical Hodgkin lymphoma. PMID- 24494026 TI - Emerging biological treatments for uterine cervical carcinoma. AB - Cervical cancer is the third most common cancer worldwide, and the development of new diagnosis, prognostic, and treatment strategies is a major interest for public health. Cisplatin, in combination with external beam irradiation for locally advanced disease, or as monotherapy for recurrent/metastatic disease, has been the cornerstone of treatment for more than two decades. Other investigated cytotoxic therapies include paclitaxel, ifosfamide and topotecan, as single agents or in combination, revealing unsatisfactory results. In recent years, much effort has been made towards evaluating new drugs and developing innovative therapies to treat cervical cancer. Among the most investigated molecular targets are epidermal growth factor receptor and vascular endothelial growth factor (VEGF) signaling pathways, both playing a critical role in cervical cancer development. Studies with bevacizumab or VEGF receptor tyrosine kinase have given encouraging results in terms of clinical efficacy, without adding significant toxicity. A great number of other molecular agents targeting critical pathways in cervical malignant transformation are being evaluated in preclinical and clinical trials, reporting preliminary promising data. In the current review, we discuss novel therapeutic strategies which are being investigated for the treatment of advanced cervical cancer. PMID- 24494028 TI - Potential Urinary Protein Biomarker Candidates for the Accurate Detection of Prostate Cancer among Benign Prostatic Hyperplasia Patients. AB - Globally, Prostate cancer (PCa) is the most frequently occurring non-cutaneous cancer, and is the second highest cause of cancer mortality in men. Serum prostate specific antigen (PSA) has been the standard in PCa screening since its approval by the American Food & Drug Administration (FDA) in 1994. Currently, PSA is used as an indicator for PCa - patients with a serum PSA level above 4ng/mL will often undergo prostate biopsy to confirm cancer. Unfortunately fewer than ~30% of these men will biopsy positive for cancer, meaning that the majority of men undergo invasive biopsy with little benefit. Despite PSA's notoriously poor specificity (33%), there is still a significant lack of credible alternatives. Therefore an ideal biomarker that can specifically detect PCa at an early stage is urgently required. The aim of this study was to investigate the potential of using deregulation of urinary proteins in order to detect Prostate Cancer (PCa) among Benign Prostatic Hyperplasia (BPH). To identify the protein signatures specific for PCa, protein expression profiling of 8 PCa patients, 12 BPH patients and 10 healthy males was carried out using LC-MS/MS. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This was followed by validating relative expression levels of proteins present in urine among all the patients using quantitative real time-PCR. This approach revealed that significant the down-regulation of Fibronectin and TP53INP2 was a characteristic event among PCa patients. Fibronectin mRNA down-regulation, was identified as offering improved specificity (50%) over PSA, albeit with a slightly lower although still acceptable sensitivity (75%) for detecting PCa. As for TP53INP2 on the other hand, its down-regulation was moderately sensitive (75%), identifying many patients with PCa, but was entirely non-specific (7%), designating many of the benign samples as malignant and being unable to accurately identify more than one negative. PMID- 24494029 TI - An ultra-sensitive immunoassay for quantifying biomarkers in breast tumor tissue. AB - Urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor type-1 (PAI-1) have been validated at the highest level of evidence as clinical biomarkers of prognosis in breast cancer. The American Society of Clinical Oncology recommends using uPA and PAI-1 levels in breast tumors for deciding whether patients with newly diagnosed node-negative breast cancer can forgo adjuvant chemotherapy. The sole validated method for quantifying uPA and PAI-1 levels in breast tumor tissue is a colorimetric ELISA assay that takes 3 days to complete and requires 100-300 mg of fresh or frozen tissue. In this study we describe a new assay method for quantifying PAI-1 levels in human breast tumor tissue. This assay combines pressure-cycling technology to extract PAI-1 from breast tumor tissue with a highly sensitive liposome polymerase chain reaction immunoassay for quantification of PAI-1 in the tissue extract. The new PAI-1 assay method reduced the total assay time to one day and improved assay sensitivity and dynamic range by >100, compared to ELISA. PMID- 24494031 TI - Preclinical Development of ONC1-13B, Novel Antiandrogen for Prostate Cancer Treatment. AB - Recently new drugs targeting androgen-dependent axis have been approved for the treatment of castration-resistant prostate cancer (CRPC) - Zytiga and Xtandi (formerly MDV3100), several other candidates (for example, ARN-509) are in early phases of clinical trials. However despite significant improvement in overall survival with new treatments it is evident that resistance to these drugs develops. One of the approaches to overcome it is combination therapy and from this point of view some potential for drug-drug interactions can limit the application of the drug. We describe here the preclinical development of ONC1 13B, antagonist of androgen receptor, with similar to MDV3100 and ARN-509 mechanism of action. It efficiently inhibits DHT-stimulated PSA expression and proliferation of prostate cancer cells, prevents binding of androgens to the AR ligand-binding domain, androgen-stimulated AR nuclear translocation and coactivator complex formation. In the LnCaP-Z2 xenograft model of prostate cancer ONC1-13B inhibits tumor growth and suppresses PSA expression. The in vivo activity of ONC1-13B is comparable to that of MDV3100 at similar doses, and even higher, calculated per unit of concentration in plasma. Distribution of ONC1-13B to the brain is less than that shown for MDV3100 and ARN-509, decreasing the risk of GABA-related seizure development. Additionally ONC1-13B induces significantly lower in vitro CYP3A activity than for example MDV3100 (known strong CYP3A inducer) or ARN-509 and could be well suited for co-therapy with drugs that are known CYP3A substrates. Thus ONC1-13B is a new promising antiandrogen demonstrating high efficacy in a preclinical model of prostate cancer, with lower potential for seizures and drug-drug interaction. PMID- 24494032 TI - Dynamics and activation in response regulators: the beta4-alpha4 loop. AB - Two-component signal transduction systems of microbes are a primary means to respond to signals emanating from environmental and metabolic fluctuations as well as to signals coordinating the cell cycle with macromolecular syntheses, among a large variety of other essential roles. Signals are recognized by a sensor domain of a histidine kinase which serves to convert signal binding to an active transmissible phosphoryl group through a signal-induced ATP-dependent autophosphorylation reaction directed to histidine residue. The sensor kinase is specifically mated to a response regulator, to which it transfers the phosphoryl group that activates the response regulator's function, most commonly gene repression or activation but also interaction with other regulatory proteins. Two component systems have been genetically amplified to control a wide variety of cellular processes; for example, both Escherichia coli and Pseudomonas aeruginosa have 60 plus confirmed and putative two-component systems. Bacillus subtilis has 30 plus and Nostoc punctiformis over 100. As genetic amplification does not result in changes in the basic structural folds of the catalytic domains of the sensor kinase or response regulators, each sensor kinase must recognize its partner through subtle changes in residues at the interaction surface between the two proteins. Additionally, the response regulator must prepare itself for efficient activation by the phosphorylation event. In this short review, we discuss the contributions of the critical beta4-alpha4 recognition loop in response regulators to their function. In particular, we focus on this region's microsecond-millisecond timescale dynamics propensities and discuss how these motions play a major role in response regulator recognition and activation. PMID- 24494033 TI - Decreased pulmonary function measured in children exposed to high environmental relative moldiness index homes. AB - BACKGROUND: Exposures to water-damaged homes/buildings has been linked to deficits in respiratory health. However, accurately quantifying this linkage has been difficult because of the methods used to assess water damage and respiratory health. PURPOSE: The goal of this analysis was to determine the correlation between the water-damage, as defined by the Environmental Relative Moldiness Index (ERMI) value in an asthmatic child's home, and the child's pulmonary function measured by spirometry, "forced expiratory volume in one second, percent predicted" or FEV1%. METHODS: This analysis utilized data obtained from the "Heads-off Environmental Asthma in Louisiana" (HEAL) study. The children (n= 109), 6 to 12 years of age, who had completed at least one spirometry evaluation and a dust sample collected for ERMI analysis from the home at approximately the same time as the spirometry testing, were included in the analysis. Statistical evaluation of the correlation between ERMI values and FEV1% was performed using the Spearman's Rank Correlation analysis. The relationship between ERMI values and FEV1% was performed using B-spline regression. RESULTS: The average ERMI value in the HEAL study homes was 7.3. For homes with ERMI values between 2.5 and 15, there was a significant inverse correlation with the child's lung function or FEV1% measurement (Spearman's rho -0.23; p= 0.03), i.e. as the ERMI value increased, the FEV1% value decreased. CONCLUSIONS: Measures of water-damage (the ERMI) and clinical assessments of lung function (FEV1%) provided a quantitative assessment of the impact of water-damaged home exposures on children's respiratory health. PMID- 24494030 TI - Should EMT of Cancer Cells Be Understood as Epithelial-Myeloid Transition? AB - Cancer cells express epithelial markers, and when progressing in malignancy they may express markers of the mesenchymal cell type. Therefore an epithelial mesenchymal transition of the cancer cells is assumed. However the mesenchymal markers can equally well be interpreted as myeloid markers since they are common in both types of cell lineages. Moreover, cancer cells express multiple specific markers of the myeloid lineages thus giving rise to the hypothesis that the transition of cancer cells may be from epithelial to myeloid cells and not to mesenchymal cells. This interpretation would better explain why cancer cells, often already in their primary cancer site, frequently show properties common to those of macrophages, platelets and pre-/osteoclasts. PMID- 24494034 TI - Effect of Aqueous Extract of Giant Horsetail (Equisetum giganteum L.) in Antigen Induced Arthritis. AB - Equisetum giganteum is a plant used in traditional medicine as diuretic. From our knowledge this is the first time this plant is tested in an in vivo model of acute inflammation. To evaluate the effect of aqueous extract of giant horsetail (AEGH) as immunomodulatory therapy, antigen-induced arthritis (AIA) was generated in mice with methylated bovine serum albumin (mBSA). Inflammation was evaluated by articular nociception, leukocytes migration and lymphocyte proliferation. AEGH reduced nociception at 3, 6 and 24 h (P < 0.01), decreased leukocyte migration (P < 0.015), and inhibited lymphocyte proliferation stimulated with Concanavalin A and Lipopolysaccharide (P < 0.05). In conclusion, AEGH has an anti-inflammatory potential in acute model of inflammation, as well as immunomodulatory effect on both B and T lymphocytes, with an action independent of cytotoxicity. PMID- 24494035 TI - Characterization of spontaneous, transient adenosine release in the caudate putamen and prefrontal cortex. AB - Adenosine is a neuroprotective agent that inhibits neuronal activity and modulates neurotransmission. Previous research has shown adenosine gradually accumulates during pathologies such as stroke and regulates neurotransmission on the minute-to-hour time scale. Our lab developed a method using carbon-fiber microelectrodes to directly measure adenosine changes on a sub-second time scale with fast-scan cyclic voltammetry (FSCV). Recently, adenosine release lasting a couple of seconds has been found in murine spinal cord slices. In this study, we characterized spontaneous, transient adenosine release in vivo, in the caudate putamen and prefrontal cortex of anesthetized rats. The average concentration of adenosine release was 0.17+/-0.01 uM in the caudate and 0.19+/-0.01 uM in the prefrontal cortex, although the range was large, from 0.04 to 3.2 uM. The average duration of spontaneous adenosine release was 2.9+/-0.1 seconds and 2.8+/-0.1 seconds in the caudate and prefrontal cortex, respectively. The concentration and number of transients detected do not change over a four hour period, suggesting spontaneous events are not caused by electrode implantation. The frequency of adenosine transients was higher in the prefrontal cortex than the caudate-putamen and was modulated by A1 receptors. The A1 antagonist DPCPX (8-cyclopentyl-1,3 dipropylxanthine, 6 mg/kg i.p.) increased the frequency of spontaneous adenosine release, while the A1 agonist CPA (N(6)-cyclopentyladenosine, 1 mg/kg i.p.) decreased the frequency. These findings are a paradigm shift for understanding the time course of adenosine signaling, demonstrating that there is a rapid mode of adenosine signaling that could cause transient, local neuromodulation. PMID- 24494036 TI - Influence of protein-micelle ratios and cysteine residues on the kinetic stability and unfolding rates of human mitochondrial VDAC-2. AB - Delineating the kinetic and thermodynamic factors which contribute to the stability of transmembrane beta-barrels is critical to gain an in-depth understanding of membrane protein behavior. Human mitochondrial voltage-dependent anion channel isoform 2 (hVDAC-2), one of the key anti-apoptotic eukaryotic beta barrel proteins, is of paramount importance, owing to its indispensable role in cell survival. We demonstrate here that the stability of hVDAC-2 bears a strong kinetic contribution that is dependent on the absolute micellar concentration used for barrel folding. The refolding efficiency and ensuing stability is sensitive to the lipid-to-protein (LPR) ratio, and displays a non-linear relationship, with both low and high micellar amounts being detrimental to hVDAC 2 structure. Unfolding and aggregation process are sequential events and show strong temperature dependence. We demonstrate that an optimal lipid-to-protein ratio of 2600?1 - 13,000?1 offers the highest protection against thermal denaturation. Activation energies derived only for lower LPRs are ~17 kcal mol( 1) for full-length hVDAC-2 and ~23 kcal mol(-1) for the Cys-less mutant, suggesting that the nine cysteine residues of hVDAC-2 impart additional malleability to the barrel scaffold. Our studies reveal that cysteine residues play a key role in the kinetic stability of the protein, determine barrel rigidity and thereby give rise to strong micellar association of hVDAC-2. Non linearity of the Arrhenius plot at high LPRs coupled with observation of protein aggregation upon thermal denaturation indicates that contributions from both kinetic and thermodynamic components stabilize the 19-stranded beta-barrel. Lipid protein interaction and the linked kinetic contribution to free energy of the folded protein are together expected to play a key role in hVDAC-2 recycling and the functional switch at the onset of apoptosis. PMID- 24494037 TI - Effect of vitamin D status on pharmacological treatment efficiency: Impact on cost-effective management in medicine. AB - At least 80% of the whole Polish population, including prepubertal children and adolescents, adults and seniors, are vitamin D deficient, defined as 25(OH)D < 50 nmol/L. 83% of Polish newborns start their lives at the state of vitamin D deficiency because 78% of their mothers are also deficient. It was observed that treating patient vitamin D deficiency to vitamin D status serum 25(OH)D) 75-100 nmol/L increased effectiveness of therapies in infectious diseases (chronic hepatitis C, tuberculosis), osteoporosis, multiple sclerosis, epilepsy, Chronic Kidney Diseases and atopic dermatitis. . For these reasons doctors should take special attension to vitamin D status in patients suffering for these diseases properly implementing recent vitamin D recommendation. PMID- 24494038 TI - Novel vitamin D photoproducts and their precursors in the skin. AB - Novel metabolic pathways initiated by the enzymatic action of CYP11A1 on 7DHC (7 dehydrocholesterol), ergosterol, vitamins D3 and D2 were characterized with help of chemical synthesis, UV and mass spectrometry and NMR analyses. The first pathway follows the sequence 7DHC->22(OH)7DHC -> 20,22(OH)27DHC -> 7DHP (7 dehydropregnenolone), which can further be metabolized by steroidogenic enzymes. The resulting 5,7-dienes can be transformed by UVB to corresponding, biologically active, secosteroids. Action of CYP11A1 on vitamin D3 and D2 produces novel hydroxyderivatives with OH added at positions C17, C20, C22, C23 and C24, some of which can be hydroxylated by CYP27B1 and/or by CYP27A1 and/ or by CYP24A1.The main products of these pathways are biologically active with a potency related to their chemical structure and the target cell type. Main products of CYP11A1 mediated metabolism on vitamin D are non-calcemic and non-toxic at relatively high doses and serve as partial agonists on the vitamin D receptor. New secosteroids are excellent candidates for therapy of fibrosing, inflammatory or hyperproliferative disorders including cancers and psoriasis. PMID- 24494040 TI - Vitamin D status and sun exposure in southeast Asia. AB - Vitamin D deficiency is more common in South Asia and Southeast Asia than is appreciated. Most studies defined 25-hydroxyvitamin D levels [25(OH)D] levels of less than 50 nmol/L (20 ng/mL) as vitamin D deficiency. With this cut-off level, the prevalence of vitamin D deficiency was about 70% or higher in South Asia and varied from 6-70% in Southeast Asia. The determinants for the variation of vitamin D status are skin pigmentation, aging, the sun protection behaviors such as application of a sunscreen, religious, lifestyle and nutritional differences. Advanced age is a known risk factor for vitamin D deficiency. Interestingly, elderly in countries such as Korea and Thailand, had higher 25(OH)D levels when compared with young people. This widespread vitamin D deficiency problem especially in the young generation is an urgent health issue that needs to be remedied. PMID- 24494039 TI - Novel vitamin D compounds and skin cancer prevention. AB - As skin cancer is one of the most costly health issues in many countries, particularly in Australia, the possibility that vitamin D compounds might contribute to prevention of this disease is becoming increasingly more attractive to researchers and health communities. In this article, important epidemiologic, mechanistic and experimental data supporting the chemopreventive potential of several vitamin D-related compounds are explored. Evidence of photoprotection by the active hormone, 1alpha,25dihydroxyvitamin D3, as well as a derivative of an over-irradiation product, lumisterol, a fluorinated analog and bufalin, a potential vitamin D-like compound, are provided. The aim of this article is to understand how vitamin D compounds contribute to UV adaptation and potentially, skin cancer prevention. PMID- 24494041 TI - The relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of non-melanoma skin cancer (NMSC): Present concepts and future perspectives. AB - Solar UV (UV)-B-radiation exerts both beneficial and adverse effects on human health. On the one hand, it is the most important environmental risk factor for the development of non-melanoma skin cancer [NMSC; most importantly basal (BCC) and squamous (SCC) cell carcinomas], that represent the most common malignancies in Caucasian populations. On the other hand, the human body's requirements of vitamin D are mainly achieved by UV-B-induced cutaneous photosynthesis. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer has been convincingly demonstrated. In line with these findings, epidemiologic and laboratory investigations now indicate that vitamin D and its metabolites have a risk reducing effect for NMSC. Potential mechanisms of action include inhibition of the hedgehog signaling pathway (BCC) and modulation of p53 mediated DNA damage response (SCC). As a consequence of these new findings it can be concluded that UV-B-radiation exerts both beneficial and adverse effects on risk and prognosis of NMSC. It can be assumed that many independent factors, including frequency and dose of UV-B exposure, skin area exposed, and individual factors (such as skin type and genetic determinants of the skin's vitamin D status and of signaling pathways that are involved in the tumorigenesis of NMSC) determine whether UV-B exposure promotes or inhibits tumorigenesis of NMSC. Moreover, these findings may help to explain many of the differential effects of UV-B radiation on risk of NMSC, including variation in the dose-dependent risk for development of SCC in situ (actinic keratosis, AK), invasive SCC, and BCC. In this review, we analyze the relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of NMSC and give an overview of present concepts and future perspectives. PMID- 24494043 TI - Vitamin D and UV exposure in chronic kidney disease. AB - With loss of renal function and decreasing glomerula filtration rate the serum levels of 25-hydroxyvitamin D [25(OH)D] as well as 1,25-dihydroxyvitamin D [1,25 (OH)2 D] often decrease simultaneously. In representative groups of German patients on renal replacement therapy (hemodialysis, peritoneal dialysis, kidney transplantation) our group retrospectively analyzed the vitamin D status over a period of 12 y (1995-2006). Only 11% of patients had a serum level of 25(OH)D that was > 30 ng/ml, more than 70% had a level of 25(OH)D < 20 ng/ml. In clinical trials we used sun-simulating artificial lamps to produce vitamin D3 in the skin. Partial-body irradiation (15% of body surface) was used during the routine hemodialysis treatment. Whole-body UV exposure was done in a standing position three times a week before the hemodialysis treatment. With both procedures we observed an increase of the serum level of 25(OH)2D3 by approx. 35-50% over a period of 2-3 mo, maintenance of trabecular bone mineral density and a normalization of systolic and diastolic blood pressure. Heart rate variability improved during the whole-body radiation intervention period by 20-25%. Patients who continued the whole-body irradiation regularly two or three times before starting the routine hemodialysis session had maintained normal levels of circulating 25(OH)D3 and of 1,25(OH)2D3. Therefore, from our data it can be recommended that intermittent suberythemal UVB exposure with a sun-simulation spectrum is effective to treat and/or protect against vitamin D deficiency in chronic and end-stage kidney disease patients. PMID- 24494044 TI - Vitamin D status among healthy postmenopausal women in South America. AB - Vitamin D status has been extensively studied throughout the world. However, most of the studies are from North America, Europe and Oceania. This review describes published evidence on vitamin D status among healthy postmenopausal women in South America, where food is not fortified with vitamin D. A literature search identified ten studies from only three countries in the region: Argentina, Brazil and Chile. These studies reported a high prevalence of vitamin D deficiency, in spite of their location at latitudes with abundant sunlight throughout the year. In studies with proper design, a clear North-South gradient was revealed with higher 25(OH)D levels toward the equator. Seasonal changes in 25(OH)D were more likely to be detected in younger subjects. These results are very similar to what has been reported in the Northern Hemisphere and they emphasize the importance of recommendations for a higher vitamin D intake in this population from South America. PMID- 24494045 TI - Vitamin D and melanoma. AB - Recreational sun exposure and sunburn are causal for melanoma but the risk is strongly genetically determined. Health promotion advice about sun protection should be aimed at susceptible individuals (pale skin, freckles, large numbers of melanocytic nevi and a family history). We discuss here the evidence that sun sensitive people have lower vitamin D levels and that, in practice, it is very difficult for such individuals to achieve sufficient levels without supplementation in the UK at least. We conclude that melanoma susceptible sun avoidant individuals should be advised to avoid insufficiency by supplementation. Vitamin D is anti-proliferative in vitro for some melanoma cell lines. In a large melanoma cohort we have observed that lower serum 25-hydroxyvitamin D2/D3 levels at diagnosis were associated with thicker tumors and poorer prognosis (study as yet not validated). In the UK, melanoma patients commonly have sub-optimal 25 hydroxyvitamin D2/D3 levels at and post diagnosis; we discuss approaches to management of such patients based on some new data from our group. PMID- 24494042 TI - Sunlight and Vitamin D: A global perspective for health. AB - Vitamin D is the sunshine vitamin that has been produced on this earth for more than 500 million years. During exposure to sunlight 7-dehydrocholesterol in the skin absorbs UV B radiation and is converted to previtamin D3 which in turn isomerizes into vitamin D3. Previtamin D3 and vitamin D3 also absorb UV B radiation and are converted into a variety of photoproducts some of which have unique biologic properties. Sun induced vitamin D synthesis is greatly influenced by season, time of day, latitude, altitude, air pollution, skin pigmentation, sunscreen use, passing through glass and plastic, and aging. Vitamin D is metabolized sequentially in the liver and kidneys into 25-hydroxyvitamin D which is a major circulating form and 1,25-dihydroxyvitamin D which is the biologically active form respectively. 1,25-dihydroxyvitamin D plays an important role in regulating calcium and phosphate metabolism for maintenance of metabolic functions and for skeletal health. Most cells and organs in the body have a vitamin D receptor and many cells and organs are able to produce 1,25 dihydroxyvitamin D. As a result 1,25-dihydroxyvitamin D influences a large number of biologic pathways which may help explain association studies relating vitamin D deficiency and living at higher latitudes with increased risk for many chronic diseases including autoimmune diseases, some cancers, cardiovascular disease, infectious disease, schizophrenia and type 2 diabetes. A three-part strategy of increasing food fortification programs with vitamin D, sensible sun exposure recommendations and encouraging ingestion of a vitamin D supplement when needed should be implemented to prevent global vitamin D deficiency and its negative health consequences. PMID- 24494046 TI - Vitamin D status and sun exposure in India. AB - BACKGROUND: Little if any cutaneous production of vitamin D3 occurs at latitudes above and below 35 degrees N and 35 degrees S during the winter months. It was postulated that those residing in tropics synthesize enough vitamin D3 year round. Several studies have documented the effect of latitude, season and time of the day on the cutaneous production of vitamin D3 in an ampoule model. Studies from India have shown high prevalence of vitamin D deficiency despite abundant sunshine. METHODS: We studied the influence of season and time of the day on synthesis of previtamin D3 in an ampoule model in Tirupati, (latitude 13.40 degrees N and longitude 77.2 degrees E) south India, between May 2007 to August 2008. Sealed borosilicate glass ampoules containing 50 MUg of 7-DHC in 1 ml of methanol were exposed to sunlight hourly from 8 a.m. until 4 p.m. The percent conversion of 7-DHC to previtamin D3 and its photoproducts and the percent of previtamin D3 and vitamin D3 formed was estimated and related to solar zenith angle. RESULTS: The percent conversion of 7-DHC to previtamin D3 and its photoproducts and formation of previtamin D3 and vitamin D3 was maximal between 11 a.m. to 2 p.m. of the day during the entire year (median 11.5% and 10.2% respectively at 12.30 p.m.). CONCLUSIONS: Therefore at this latitude exposure to sunlight between the hours of 11 a.m. and 2 p.m. will promote vitamin D production in the skin year round. PMID- 24494047 TI - Effects of sidechain length and composition on the kinetic conversion and product distribution of vitamin D analogs determined by real-time NMR. AB - Novel pregna-5, 7-dienes were synthesized and subjected to UVB irradiation to generate the corresponding pre-D intermediates, tachysterol and lumisterol analogs. The kinetics of the conversion from each of the pre-D intermediates to the corresponding novel D analogs was investigated by using real time 1H NMR measurements inside the NMR magnet. Both the length and composition of the side chains were found to affect the rate of the kinetic conversion from pre-D intermediates to the thermodynamically more stable D analogs. Compound 7cc which has both a long side chain and a tertiary alcohol moiety showed the highest conversion rate, while compound 4a-S which has a very short side chain without the tertiary alcohol had the lowest conversion rate among the 13 tested compounds. We also determined product distributions for these 5,7-dienes upon UVB irradiation followed by thermodynamic equilibration. No clear correlations between product distribution and side chain length or composition were identifiable under the current experimental conditions, suggesting there are other factors affecting the kinetics during the photochemical reactions for these 5,7-dienes. To the best of our knowledge, this is the first time the influences of side chain length and composition on the real time conversion kinetics from pre-D to D are studied. This study could serve as step-stones in future kinetic studies of novel biologically active 5,7-dienes and their corresponding D analogs under more physiologically relevant ex vivo or in vivo conditions, as well as providing important insights into optimizing yields of the desired active products during their organic syntheses. PMID- 24494048 TI - Biologically efficient solar radiation: Vitamin D production and induction of cutaneous malignant melanoma. AB - Solar ultraviolet (UV) radiation is the main source of vitamin D production and is also the most important environmental risk factor for cutaneous malignant melanoma (CMM) development. In the present study the relationships between daily or seasonal UV radiation doses and vitamin D status, dietary vitamin D intake and CMM incidence rates at different geographical latitudes were investigated. North South gradients of 25-hydroxyvitamin D (25(OH)D) generation and CMM induction were calculated, based on known action spectra, and compared with measured vitamin D levels and incidence rates of CMM. The relative roles of UVA and UVB in CMM induction are discussed. Latitudinal dependencies of serum 25(OH)D levels and CMM incidence rates can only partly be explained by ambient UV doses. The UV sensitivity is different among populations with different skin color. This is well known for CMM, but seems also to be true for vitamin D status. The fact that UV-induced vitamin D may reduce the risk of CMM complicates the discussion. To some extent high dietary vitamin D intake seems to compensate low UV doses. PMID- 24494049 TI - Autism prevalence in the United States with respect to solar UV-B doses: An ecological study. AB - Evidence is mounting that vitamin D deficiency is intimately involved in autism. We report on autism prevalence by US state for those aged 6-17 y in 2010 with respect to indices of solar UV-B (UVB) doses. We calculated autism prevalence rates for white, black and Asian Americans by using total prevalence and relative populations of minors for each ethnic group by state. Analyses omit AK and HI (considered extreme cases), WY (no data), along with AZ and ND for black Americans (low numbers) and DC, ME, MT, ND and SD for Asian Americans (low numbers). For white Americans, the regression coefficient for solar UVB doses and autism prevalence ranged from -0.52 in January to -0.57 in October. For black Americans, the regression coefficient for latitude was 0.61, whereas those for solar UVB ranged from -0.55 to -0.61. For Asian Americans, the values for solar UVB ranged from -0.28 to -0.38. The inverse correlation between solar UVB and autism prevalence is similar to that for many types of cancer in the US. The journal literature indicates that adverse effects on fetal brain development during pregnancy due to vitamin D deficiency can explain these findings. However, we cannot rule out a role of vitamin D deficiency in early life. These results add to the evidence that vitamin D deficiency may be an important risk factor for autism and suggest that pregnant women and autistic individuals raise their serum 25-hydroxyvitamin D concentrations above 30 ng/ml. PMID- 24494050 TI - Photobiology of vitamin D in mushrooms and its bioavailability in humans. AB - Mushrooms exposed to sunlight or UV radiation are an excellent source of dietary vitamin D2 because they contain high concentrations of the vitamin D precursor, provitamin D2. When mushrooms are exposed to UV radiation, provitamin D2 is converted to previtamin D2. Once formed, previtamin D2 rapidly isomerizes to vitamin D2 in a similar manner that previtamin D3 isomerizes to vitamin D3 in human skin. Continued exposure of mushrooms to UV radiation results in the production of lumisterol2 and tachysterol2. It was observed that the concentration of lumisterol2 remained constant in white button mushrooms for up to 24 h after being produced. However, in the same mushroom tachysterol2 concentrations rapidly declined and were undetectable after 24 h. Shiitake mushrooms not only produce vitamin D2 but also produce vitamin D3 and vitamin D4. A study of the bioavailability of vitamin D2 in mushrooms compared with the bioavailability of vitamin D2 or vitamin D3 in a supplement revealed that ingestion of 2000 IUs of vitamin D2 in mushrooms is as effective as ingesting 2000 IUs of vitamin D2 or vitamin D3 in a supplement in raising and maintaining blood levels of 25-hydroxyvitamin D which is a marker for a person's vitamin D status. Therefore, mushrooms are a rich source of vitamin D2 that when consumed can increase and maintain blood levels of 25-hydroxyvitamin D in a healthy range. Ingestion of mushrooms may also provide the consumer with a source of vitamin D3 and vitamin D4. PMID- 24494051 TI - Vitamin D: Light side and best time of sunshine in Riyadh, Saudi Arabia. AB - Low levels of 25-hydroxyvitamin D have been documented among inhabitants of the wider Middle East and North African countries. Sunlight has long been recognized as a major provider of vitamin D. In this study we aimed to determine the optimum time for sun exposure in the Central region of Riyadh, Saudi Arabia. Ampoules containing 7-dehydrocholesterol in ethanol were exposed to sunlight every hour starting from sunrise until sunset in July and December. Our results demonstrated that the time of the day has a major influence in vitamin D production. In this study, summer production of previtamin D3 was observed to occur between 8:00 PM to 4:00 PM with peak hours between 10:00 AM to 12:00 PM. During wintertime however, the conversion began later at around 9:30 AM and ended sooner at 2:00 PM, with peak hours at 10:00 AM to 12 noon. In conclusion, the optimum time to get sun exposure for vitamin D3 production in Riyadh, during summer is from 9:00 AM and before 10:30 AM, as well as after 2:00 PM until 3:00 PM, while during winter it's from 10:00 AM until 2:00 PM. These times are important on a public health perspective, as it's free, relatively safe and the most enjoyable. This strategy is a highly efficacious way for improving the vitamin D status for children and adults and preventing vitamin D deficiency. PMID- 24494052 TI - What is the relationship between ultraviolet B and global incidence rates of colorectal cancer? AB - The purpose of this study is to examine the relationship between ultraviolet B and global incidence of colorectal cancer, while controlling for relevant covariates. Linear regression was used to assess the relationship between latitude and incidence rates of colon cancer in 173 countries. Multiple linear regression was employed to investigate the relationship between ultraviolet B dose and colorectal cancer rates while controlling for per capita intake of energy from animal sources, per capita health expenditure, pigmentation, and life expectancy. Data on all variables were available for 139 countries. Incidence of colon cancer was highest in countries distant from the equator (R(2) = 0.50, p < 0.0001). UV B dose (p < 0.0001) was independently, inversely associated with incidence rates of colorectal cancer after controlling for intake of energy from animal sources, per capita health expenditure, pigmentation, and life expectancy (R(2) for overall model = 0.76, p < 0.0001). Consistent with previous research, UVB was inversely associated with incidence of colon cancer. Further research on vitamin D and prevention of colon cancer in individuals should be conducted, including studies of higher serum 25-hydroxyvitamin D concentrations than have been studied to date. PMID- 24494053 TI - North-South gradients of melanomas and non-melanomas: A role of vitamin D? AB - Incidence rates of skin cancer increase with decreasing latitude in Norway, as in many other countries with white populations. The latitudinal trends of the incidence rates of skin cancer were studied and compared with data for vitamin D induced by UV and for vitamin D intake. The north-south gradient for CMM incidence rates on sun exposed skin is much smaller than those for BCC and SCC, and that for BCC is smaller than that for SCC. This indicates that SCC and BCC are mainly due to solar UVB, while UVA may play a significant role for CMM and a smaller role for BCC, since the north-south gradient of annual UVB fluences is larger than that of UVA fluences. However, there is an inverse latitudinal gradient of skin cancer in central Europe. This is probably due to a gradient of skin color, since white skin is an important determinant of increased risk of skin cancer. The role of vitamin D for skin cancer risk is difficult to evaluate, since serum levels of 25-hydroxyvitamin D, as well as vitamin D intakes, are widely different from country to country. Still, epidemiological evidence indicates a role: for melanomas arising on non-sun exposed body localizations (uveal melanomas, melanomas arising in the vulva and perianal/anorectal regions) there appears to be no latitudinal gradient, or, a negative gradient, i.e., increasing rates with decreasing latitude as would be expected if UV-generated vitamin D plays a protective role. Both skin cancer risk and vitamin D photosynthesis decrease with increasing skin darkness. PMID- 24494054 TI - Effects of sunlight on behavior and 25-hydroxyvitamin D levels in two species of Old World fruit bats. AB - It has long been accepted that most vertebrate animals meet their vitamin D requirements from exposure of skin to UV-B (UV-B) radiation. Many factors affect this endogenous synthesis of vitamin D, including season, latitude, time of day, age, presence of hair, and degree of skin pigmentation. Most bats roost in dark places by day and forage at night, and thus have little or no potential for sunlight exposure. Notwithstanding, some tropical species are diurnal and are known to roost in the canopy of trees where they may be exposed to sunlight for up to 12 h each day. In this study, two species of captive tropical bats (both species are active at night but one, Rousettus aegyptiacus, roosts in caves, tombs, and buildings, whereas the other, Pteropus hypomelanus, roosts in trees) were evaluated for their ability to endogenously synthesize vitamin D. Following timed periods of sunlight exposure, blood plasma was analyzed using a competitive protein binding assay (CPBA) to determine concentrations of 25-hydroxyvitamin D [25(OH)D], the major circulating vitamin D metabolite. The ability to photoconvert provitamin D (7-dehydrocholesterol, 7-DHC) in the sub-tropical winter was determined using sunlight exposed borosilicate samples of 7-DHC in hourly increments. Finally, both species were evaluated in their preference for a roost site by the release of individuals into sunlight or shade in timed trials. OUR RESULTS SUPPORT THE HYPOTHESES: (1) when exposed to natural sunlight, both species exhibited an ability to endogenously synthesize vitamin D, although significant differences were found between the two, (2) photoconversion of 7-DHC to previtamin D3 is possible during the mid-day hours of a sub-tropical winter day and (3) captive, cave roosting R. aegyptiacus will choose shaded roost sites while captive P. hypomelanus will show no preference for either shade or sun. PMID- 24494056 TI - The effectiveness of a short food frequency questionnaire in determining vitamin D intake in children. AB - Previous studies have found a high prevalence of vitamin D deficiency in children, yet few validated dietary vitamin D assessment tools are available for use in children. Our objective was to determine whether a short food frequency questionnaire (SFFQ) can effectively assess vitamin D intake in children. Vitamin D intake ascertained by a SFFQ was compared with assessments by a previously validated long food frequency questionnaire (LFFQ) in a population of 296 healthy 6- to 14-y-old children (54% male, 60% African American) from Pittsburgh, PA. The questionnaires were completed at two points 6 mo apart. Median reported daily vitamin D intake from the SFFQ (baseline: 380 IU, follow-up: 363 IU) was higher than the LFFQ (255 IU and 254 IU, respectively). Reported median dairy intake, including milk, cheese, and yogurt, was 3.7 cups/day, which meets the USDA recommendation for children. Vitamin D intake reported by the 2 questionnaires was modestly correlated at baseline and follow-up (r = 0.35 and r = 0.37, respectively; p < 0.001). These associations were stronger in Caucasians (r = 0.48 and r = 0.49, p < 0.001) than in African Americans (r = 0.27 and r = 0.31; p = 0.001). The sensitivity of the SFFQ for predicting daily vitamin D intake, defined as intake of >= 400 IU on both the SFFQ and LFFQ, was 65%. Specificity, defined as intake of < 400 IU on both questionnaires, was 42%. Vitamin D requirements may not be met despite adequate consumption of dairy products. The SFFQ was found to be a modestly valid and sensitive tool for dietary assessment of vitamin D intake in children. PMID- 24494057 TI - Seasonal variation in the serum 25-hydroxyvitamin D levels of young and elderly active and inactive adults in Sao Paulo, Brazil: The Sao PAulo Vitamin D Evaluation Study (SPADES). AB - OBJECTIVE: To evaluate the 25-hydroxyvitamin D [25(OH)D] concentrations in individuals in the city of Sao Paulo belonging to different age groups and exhibiting specific behavioral characteristics and to correlate the 25(OH)D concentration with the level of UV radiation (UVR). PATIENTS AND METHODS: A total of 591 individuals were included, distributed as follows: 177 were living in institutions (NURSING, 76.2 +/- 9.0 y old), 243 were part of the community elderly (COMMUNITY, 79.6 +/- 5.3 y old), 99 were enrolled in a physical activity program targeting the elderly (ACTIVE, 67.6 +/- 5.4 y old) and 72 were young (YOUNG, 23.9 +/- 2.8 y old). Blood samples from all individuals were collected throughout the year. UVR measurements were taken by an official meteorology institution. RESULTS: The UVR values varied throughout the year, following a sinusoidal-like pattern. Because of the Earth's orbit, we hypothesized that there would be cyclic patterns for the 25(OH)D and UVR values that repeat every 12 mo. The general formula is represented by the equation P1+P2?sin(-2?pi12?(t-P3)) The mean 25(OH)D concentration and the amplitude of the variation were significantly higher for the YOUNG and ACTIVE groups than for the COMMUNITY and NURSING groups. The nadir for UVR was in June, whereas the nadir for the 25(OH)D concentration was in the spring, corresponding to a delay of one season. CONCLUSIONS: There was seasonal variation in the 25(OH)D concentration for all the groups studied; however, the amplitude of the variation was higher for the groups of young and physically active people, possibly due to the higher level of sunlight exposure for these groups. The lowest 25(OH)D concentration was detected in the spring. PMID- 24494055 TI - What is the role of vitamin D in autism? AB - A growing body of literature suggests that higher serum 25-hydroxyvitamin D [25(OH)D] concentrations, either in utero or in early life, may reduce the risk of autism. For example, an ecological study in the companion paper inversely correlated solar UV-B doses in the United States with prevalence of autism among those aged 6-17 y. That study proposed that vitamin D deficiency during pregnancy could account for this finding, although the findings are also consistent with childhood vitamin D deficiency contributing to the condition. Also, in a recent study, children with autism had lower serum 25(OH)D concentrations than did control subjects (19 vs. 33 ng/ml), despite parents of each group reporting the same amount of sun exposure. The same study found highly significant inverse correlations between 25(OH)D and autism rating scales and between 25(OH)D and levels of an antineuronal antibody. This finding indicates that higher serum 25(OH)D concentrations may reduce the symptoms of established autism. Because activated vitamin D, a secosteroid, upregulates DNA-repair genes, vitamin D deficiency during development may inhibit the repair of de novo DNA mutations in fetuses and infants and thus contribute to risk of autism. Vitamin D might also reduce the risk or severity of autism through its anti-inflammatory actions, antiautoimmune effects, increasing seizure threshold, increasing T-regulatory cells, protecting the mitochondria, and upregulating glutathione, which scavenges oxidative by-products and chelates (captures and excretes) heavy metals. Vitamin D deficiency during pregnancy and childhood is a widespread and growing epidemic. PMID- 24494058 TI - Association between vitamin D levels and central adiposity in an eastern Africa outpatient clinical population. AB - Background Eastern Africa is a vast area straddling the Equator at roughly between latitude 18 degrees North and 25 degrees South of the Equator. This region enjoys overhead or near overhead sunshine throughout the year receiving an estimated 200-275 W/M2 of UVB annually. It is a region undergoing rapid socio economic changes and thus impacting change in work habits and environment from the outdoors to the indoors. There however exists a dearth of vitamin D3 data on people in this region despite the recognition of vitamin D3 deficiency being a global epidemic. The purpose of this study was to examine the status of vitamin D3 and central obesity in this clinical population and their relationship if any. Methods Serum 25(OH)D, Waist circumference (WC) and Waist to Hip ratio (WHR) data on 182 outpatients attending a Therapeutic Lifestyle Changes was retrospectively analyzed by gender, age category and ethnicity. Results Vitamin D deficiency and insufficiency in this clinical population in Eastern Africa, females had lower serum concentration, with the younger population having lower serum concentrations than the elderly. There was also a significant difference in serum levels when data was analyzed by ethnicity. Similarly central obesity was also highly prevalent in this population. The odds of being Vitamin D deficient was 3.3 times (p = 0.022) higher among individuals with elevated waist circumference than those with normal waist circumferences. Among the males, the odds of being Vitamin D deficient and having an elevated waist circumference was 6.8 times (p = 0.011) higher than for males with normal waist circumferences. This was however not observed among the females. Conclusion Living on or close to the equator and having overhead or near overhead sunshine throughout the year in and of itself is not a guarantee of adequate serum 25(OH)D concentrations. It may therefore be prudent for clinicians in this region to risk stratify their patients based on work location, age category and ethnicity. PMID- 24494060 TI - Acute warfarin toxicity: An unanticipated consequence of amoxicillin/clavulanate administration. AB - PATIENT: Male, 53 FINAL DIAGNOSIS: Acute Warfarin toxicity Symptoms: - MEDICATION: Warfarin Clinical Procedure: - Specialty: Hematology. OBJECTIVE: Unusual clinical course. BACKGROUND: Warfarin remains the most common anticoagulant in the management of thromboembolic diseases. However, its extensive drug interaction requires frequent monitoring and dose adjustments. Almost all antibiotics, including penicillins, have the potential to interact with warfarin causing either under or over anticoagulation which increases the risk for thrombus formation and significant bleeding respectively. CASE REPORT: A 53-year-old Caucasian male with a history of protein C deficiency and recurrent intravascular thrombosis developed a dental abscess. He was treated with amoxicillin/clavulanate 500/125 mg twice daily and referred to a dentist. He developed significant bleeding after tooth extraction. INR was 20.4. He received fresh frozen plasma and vitamin K with resolution of bleeding. CONCLUSIONS: While rare, clinically significant prolonged prothrombin time and potentially life threatening bleeding can occur when amoxicillin/clavulanate is concomitantly administered with warfarin. Prompt recognition and intervention is necessary to avoid life threatening complications from warfarin-amoxicillin/clavulanate interaction. PMID- 24494059 TI - A pilot study assessing the effect of prolonged administration of high daily doses of vitamin D on the clinical course of vitiligo and psoriasis. AB - Autoimmunity has been associated with vitamin D deficiency and resistance, with gene polymorphisms related to vitamin D metabolism frequently described in affected patients. High doses of vitamin D3 may conceivably compensate for inherited resistance to its biological effects. This study aimed to assess the efficacy and safety of prolonged high-dose vitamin D3 treatment of patients with psoriasis and vitiligo. Nine patients with psoriasis and 16 patients with vitiligo received vitamin D3 35,000 IU once daily for six months in association with a low-calcium diet (avoiding dairy products and calcium-enriched foods like oat, rice or soya "milk") and hydration (minimum 2.5 L daily). All psoriasis patients were scored according to "Psoriasis Area and Severity Index" (PASI) at baseline and after treatment. Evaluation of clinical response of vitiligo patients required a quartile grading scale. All patients presented low vitamin D status (serum 25(OH)D3 <= 30 ng/mL) at baseline. After treatment 25(OH)D3 levels significantly increased (from 14.9 +/- 7.4 to 106.3 +/- 31.9 ng/mL and from 18.4 +/- 8.9 to 132.5 +/- 37.0 ng/mL) and PTH levels significantly decreased (from 57.8 +/- 16.7 to 28.9 +/- 8.2 pg/mL and from 55.3 +/- 25.0 to 25.4 +/- 10.7 pg/mL) in patients with psoriasis and vitiligo respectively. PTH and 25(OH)D3 serum concentrations correlated inversely. The PASI score significantly improved in all nine patients with psoriasis. Fourteen of 16 patients with vitiligo had 25 75% repigmentation. Serum urea, creatinine and calcium (total and ionized) did not change and urinary calcium excretion increased within the normal range. High dose vitamin D3 therapy may be effective and safe for vitiligo and psoriasis patients. PMID- 24494061 TI - Potent and selective inhibitors of CDPK1 from T. gondii and C. parvum based on a 5-aminopyrazole-4-carboxamide scaffold. AB - 5-Aminopyrazole-4-carboxamide was used as an alternative scaffold to substitute for the pyrazolopyrimidine of a known "bumped kinase inhibitor" to create selective inhibitors of calcium-dependent protein kinase-1 from both Toxoplasma gondii and Cryptosporidium parvum. Compounds with low nanomolar inhibitory potencies against the target enzymes were obtained. The most selective inhibitors also exhibited submicromolar activities in T. gondii cell proliferation assays and were shown to be non-toxic to mammalian cells. PMID- 24494062 TI - Gender and offender status predicting treatment success in refugees and asylum seekers with PTSD. AB - BACKGROUND: Current knowledge is limited regarding patient characteristics related to treatment outcome of posttraumatic stress disorders (PTSD) in refugees and asylum seekers. OBJECTIVE: Gender, torture status, offender status, level of anger, and level of depression were investigated for possible effects on the treatment outcome. METHOD: Patient characteristics were explored in 54 refugees and asylum seekers who had completed a treatment program for PTSD. Non-responders (10), those who had the same or higher levels of symptom severity after treatment, were compared with responders, those who had lower symptom severity after treatment (44). Symptom severity was measured by Clinician-Administered PTSD Scale. The non-responders and responders constituted the dichotomous, dependent variable. The independent variables were gender, torture status, offender status, level of anger, and level of depression. T-tests and Exact Unconditional Homogeneity/Independence Tests for 2*2 Tables were used to study the relationship to treatment outcome. RESULTS: Being male and reporting to have been a violent offender were significantly more frequent characteristics among the non-responders compared to the responders. The levels of pretreatment anger, depression and torture status did not affect the treatment outcome. CONCLUSIONS: The study adds support to findings that females benefit more from treatment of PTSD than males and that violent offenders are difficult to treat within the standard treatment programs. PMID- 24494064 TI - Synthesis and evaluation of the cytotoxicity of a series of 1,3,4-thiadiazole based compounds as anticancer agents. AB - OBJECTIVE(S): Nowadays, cancer is an important public health problem in all countries. Limitations of current chemotherapy for neoplastic diseases such as severe adverse reactions and tumor resistance to the chemotherapeutic drugs have been led to a temptation for focusing on the discovery and development of new compounds with potential anticancer activity. MATERIALS AND METHODS: A new series of 1,3,4-thiadiazole-derived compounds (3a-3l) were synthesized. N-(5-Mercapto 1,3,4-thiadiazol-2-yl)-2-(4-methoxyphenyl) acetamide (2) was prepared through direct amidation of 4-methoxyphenylacetic acid (2) with 5-amino-1,3,4-thiadiazole 2-thiol using EDC (N-Ethyl-N-dimethylaminopropyl carbodiimide) and HOBt (Hydroxybenzotriazole). Then, various derivatives of benzyl chloride containing electron withdrawing and electron donating moieties were reacted with compound 2 to prepare compounds 3a-3l. In vitro cytotoxicity assessment using MTT method was applied and results are presented as IC50. RESULTS: All the synthesized compounds were characterized by (1)H-NMR and IR spectroscopy. Some of the synthesized compounds were also characterized using MS spectroscopy. Related melting points were also recorded. According to the obtained data from MTT assay, all compounds (3a-3l) demonstrated a higher cytotoxic activity against MDA-MB-231 breast cancer cell line in comparison with other cell lines. CONCLUSION: It is notable that four synthesized compounds 3h (IC50= 11 +/- 0.18 uM), 3j (IC50= 10 +/- 0.39 uM), 3k (IC50= 11 +/- 0.77 uM) and 3l (IC50= 8 +/- 0.69 uM) exhibited higher cytotoxic activity against MDA-MB-231 cell line compared to imatinib (IC50= 20 +/- 0.69 uM) as the reference drug. PMID- 24494065 TI - Partial purification and characterization of anticoagulant factor from the snake (echis carinatus) venom. AB - OBJECTIVE(S): Snake venoms contain complex mixture of proteins with biological activities. Some of these proteins affect blood coagulation and platelet function in different ways. Snake venom toxin may serve as a starting material for drug design to combat several pathophysiological problems such as cardiovascular disorders. In the present study, purification of anticoagulation factor from venom of snake (Echis carinatus) was studied. MATERIALS AND METHODS: Anticoagulation activity of crude venom, fractions and purified peptide were determined by using prothrombin time (PT) and thrombin time (TT). Three fractions were partially purified from the venom of E. Carinatus by gel filtration on sephadex G-75 and final purification was performed by high-performance liquid chromatography (HPLC) with C18 column. A purified anticoagulant factor was derived which showed a single protein band in SDS-PAGE electrophoresis under reducing condition. RESULTS: RESULTS of PT and TT tests for purified peptide (EC217) were found to be 102+/-4.242 and < 5 min. respectively. Determination of molecular weight revealed that the active purified peptide (EC217) was about 30 KD. CONCLUSION: The present study showed that the venom of E. carinatus contains at least one anticoagulant factor. PMID- 24494063 TI - Pathogenesis of epilepsy: challenges in animal models. AB - Epilepsy is one of the most common chronic disorders affecting individuals of all ages. A greater understanding of pathogenesis in epilepsy will likely provide the basis fundamental for development of new antiepileptic therapies that aim to prevent the epileptogenesis process or modify the progression of epilepsy in addition to treatment of epilepsy symptomatically. Therefore, several investigations have embarked on advancing knowledge of the mechanism underlying epileptogenesis, understanding in mechanism of pharmacoresistance and discovering antiepileptogenic or disease-modifying therapy. Animal models play a crucial and significant role in providing additional insight into mechanism of epileptogenesis. With the help of these models, epileptogenesis process has been demonstrated to be involved in various molecular and biological pathways or processes. Hence, this article will discuss the known and postulated mechanisms of epileptogenesis and challenges in using the animal models. PMID- 24494066 TI - Blood coagulation induced by Iranian saw-scaled viper (echis carinatus) venom: identification, purification and characterization of a prothrombin activator. AB - OBJECTIVE(S): Echis carinatus is one of the venomous snakes in Iran. The venom of Iranian Echis carinatus is a rich source of protein with various factors affecting the plasma protein and blood coagulation factor. Some of these proteins exhibit types of enzymatic activities. However, other items are proteins with no enzymatic activity. MATERIALS AND METHODS: In order to study the mechanism and effect of the venom on human plasma proteins, the present study has evaluated the effect of crude venom and all fractions. A procoagulant factor (prothrombin activator) was isolated from the venom of the Iranian snake Echis carinatus with a combination of gel filtration (Sephadex G-75), ion-exchange chromatography (DEAE- Sepharose) and reverse phase HPLC. Furthermore, proteolytic activity of the crude venom and all fractions on blood coagulation factors such as prothrombin time (PT) was studied. RESULTS: In the present study, the PT test was reduced from 13.4 s to 8.6 s when human plasma was treated with crude venom (concentraion of venom was 1 mg/ml). The purified procoagulant factor revealed a single protein band in SDS polyacrylamide electrophoresis under reducing conditions and its molecular weight was estimated at about 65 kDa. A single-band protein showed fragment patterns similar to those generated by the group A prothrombin activators, which convert prothrombin into meizothrombin independent of the prothrombinase complex. CONCLUSION: This study showed that the fraction which separated from Iranian snake Echis carinatus venom can be a prothrombin activators. It can be concluded that this fraction is a procoagulant factor. PMID- 24494067 TI - Expression and clinical significance of activating transcription factor 3 in human breast cancer. AB - OBJECTIVE(S): Breast cancer is the most common type of cancer among women worldwide. This study investigated the expression and clinical significance of activating transcription factor 3 (ATF3) in human breast cancer and its relationship with the clinical outcome of breast cancer. Materials and Methods : ATF3 expressions were detected in 114 primary breast cancer tissues and 114 adjacent normal tissues using immunohistochemistry (IHC) assay. Categorical variables were statistically compared by chi-square or Fisher's exact test. Survival curves were evaluated using the Kaplan-Meier method and comparisons of survival rates were tested using a Log-rank test. Results : IHC analysis showed that the positive expression of ATF3 protein was detected in breast cancer tissue with a positive ratio of 76.3%, and the positive ATF3 expression in adjacent normal breast tissue was 13.2%, which is lower than that in breast cancer tissue samples (P<0.01). Furthermore, ATF3 expression showed significant correlation with TNM stage, invasion, lymph node metastasis and number of metastatic lymph nodes (P=0.038, P=0.029, P=0.026, and P=0.039 respectively), and did not correlate with patients' age and tumor size (P>0.05). A significant difference in overall survival rate was found between the patients with positive expression of ATF3 protein and those with negative expression (P=0.041). Conclusion : Increased ATF3 expression participate in the tumorigenesis, invasion and metastasis of breast cancer, and ATF3 may be useful as a new prognostic indicator for breast cancer patients. PMID- 24494068 TI - Synthesis and in vitro cytotoxic activity of novel chalcone-like agents. AB - OBJECTIVE(S): Chalcones and their rigid analogues represent an important class of small molecules having anticancer activities. Therefore, in this study the synthesis and cytotoxic activity of new 3-benzylidenchroman-4-ones were described as rigid chalcone analogues. MATERIALS AND METHODS: The reaction of resorcinol with 3-chloropropionic acid in the presence of CF3SO3H was afforded corresponding propiophenone. It was cyclized using 2M NaOH to give 7-hydroxy-4-chromanone. O Alkylation of 7-hydroxy-4-chromanone with alkyl iodide in the presence of K2CO3 gave 7-alkoxychroman-4-one. Finally, condensation of chroman-4-one derivatives with different aldehydes afforded target compounds in good yields. The newly synthesized compounds were tested in vitro against different human cancer cell lines including K562 (human erythroleukemia), MDA-MB-231 (human breast cancer), and SK-N-MC (human neuroblastoma) cells. The cell viability was evaluated using MTT colorimetric assay. RESULTS: Most of the compounds showed good inhibitory activity against cancer cells. Among them, compound 4a containing 7-hydroxy group on chromanone ring and 3-bromo-4-hydroxy-5-methoxy substitution pattern on benzylidene moiety was the most potent compound with IC50 values <= 3.86 ug/ml. It was 6-17 times more potent than etoposide against tested cell lines. CONCLUSION: We described synthesis and cytotoxic activity of poly-functionalized 3-benzylidenechroman-4-ones as new chalcone-like agents. These compounds can be considered as conformationally constrained congeners of chalcones to tolerate the poly-functionalization on the core structures for further optimization. PMID- 24494069 TI - The effect of platelet rich plasma on chondrogenic differentiation of human adipose derived stem cells in transwell culture. AB - OBJECTIVE(S): Platelet-rich plasma (PRP) has recently emerged as a promising strategy in regenerative medicine due to its multiple endogenous growth factors. Little is known about the role of PRP as a promoter in chondrogenesis of human adipose derived stem cells (hADSCs). The aim of this study was to determine whether PRP may be considered as a natural and easy achievable source of growth factors to promote the chondrogenic differentiation of hADSCs in Transwell culture. Materials and Methods : Biochemical, immunohistological and molecular assays were used to evaluate the effect of different concentrations (5%, 10%, and 15%) of PRP on chondrogenic differentiation of hADSCs in Transwell culture. Results : The cells in the presence of 10% PRP produced markedly higher amounts of GAG and DNA, in comparison to the control group. PRP also increased chondrogenic markers in these cells, such as sox-9, aggrecan and collagen type II. A high expression level of collagen type X as a hypertrophic marker was observed in cartilage produced by using either PRP or TGF-beta1. Conclusion : Our findings indicate that autologous PRP at an optimum concentration had beneficial effects on differentiation of hADSCs in Transwell culture. Further, in vivo studies are necessary to fully define the clinical implications of PRP. PMID- 24494070 TI - Anti-aging effects of some selected Iranian folk medicinal herbs-biochemical evidences. AB - OBJECTIVE(S): In the current study, the effects of selected folk medicinal herbs were evaluated in D-galactose-induced aging in male mice. MATERIALS AND METHODS: Male BALB/c mice were randomly divided into 12 groups composing sham, control, and treated groups. Aging was induced by administration of D-galactose (500 mg/kg/day for 6 weeks). A positive control group was assigned that received vitamin E (200 mg/kg/day). The extract of herbs was prepared, lyophilized, and used in this study. The herbs were administered by gavage for 4 weeks to D galactose-aged animals at the selected doses (mg/kg/day) as follows: Zingiber officinale (250), Glycyrrhiza glabra (150), Rosmarinus officinalis (300), Peganum harmala (50), Aloe vera (150), Satureja hortensis (200), Teucrium scordium (200), Hypericum perforatum (135) and Silybum marianum (150). One group of animals was assigned as sham and not given D-galactose. RESULTS: At the end of treatment, pro inflammatory markers including tumor necrosis factor-alpha (TNF-alpha), interlukine-1beta (IL-beta), interlukine-6 (IL-6), NF-kappaB (NF-kappab), total antioxidant power (TAP), thiobarbituric acid reactive substances (TBARS) as lipid peroxidation (LPO) marker and male sex hormones i.e. testosterone and dehydroepiandrosterone-sulfate (DHEA-S) were measured in the blood. CONCLUSION: These data for the first time indicate significant anti-aging potential of examined herbs. RESULTS showed that D-galactose induces a significant oxidative stress and promotes proinflammatory cascade of aging while all herbs more or less recovered these changes. Among 9 herbal extracts, Silybum marianum showed the best effect in restoring aging changes. PMID- 24494071 TI - A New Approach for Scatter Removal and Attenuation Compensation from SPECT/CT Images. AB - OBJECTIVE(S): In SPECT, the sinogram contains scatter and lack of attenuated counts that degrade the reconstructed image quality and quantity. Many techniques for attenuation and scatter correction have been proposed. An acceptable method of correction is to incorporate effects into an iterative statistical reconstruction. Here, we propose new Maximum Likelihood Expectation Maximization (MLEM) formula to correct scattering and attenuating photons during reconstruction. MATERIALS AND METHODS: In this work, scatters are estimated through Klein-Nishina formula in all iterations and CT images are used for accurate attenuation correction. Reconstructed images resulted from different MLEM reconstruction formula have been compared considering profile agreement, contrast, mean square error, signal-to-noise ratio, contrast-to-noise ratio and computational time. RESULTS: The proposed formula has a good profile agreement, increased contrast, signal-to-noise (SNR) & contrast-to-noise ratio (CNR), computational time and decreased mean square error (MSE) compared with uncorrected images and/or images from conventional formula. CONCLUSION: In conclusion, by applying the proposed formula we were able to correct attenuation and scatter via MLEM and improve the image quality, which is a necessary step for both qualitative and quantitative SPECT images. PMID- 24494072 TI - Does propylthiouracil increase the gentamicin-induced nephrotoxicity in rat? AB - OBJECTIVE(S): The aim of this study was to evaluate the effect of subacute administration of propylthiouracil (PTU) on gentamicin (GM)-induced nephrotoxicity in male rats. MATERIALS AND METHODS: Male Wistar rats were divided into 4 experimental groups as follow: (1) CONTROL GROUP: isotonic saline (1 ml/kg, IP. for 18 d), (2) GM group: 100 mg/kg, IP for 8 d, (3) PTU group: PTU (10 mg/kg, IP for 18 d.) and (4) PTU + GM group: GM (100 mg/kg, IP. for 8d) and PTU (10 mg/kg, IP. for 18 d). Blood sample was taken from all animals and then the animals were sacrificed under light ether anesthesia on the day after the last injection. Sera were separated and were used to measure the urea and creatinine. Microscopic evaluation of renal injury was performed using a semiquantitative scale to evaluate the degree of tubular necrosis. RESULTS: GM markedly increased serum urea and creatinine, as well as acute tubular necrosis (ATN), glomerular atrophy, hyaline casts formation in tubular lumen, interstitial nephritis and infiltration of inflammatory cells. PTU administration alone caused hyperemia and interstitial nephritis and infiltration of lymphocytic inflammatory cells in cortex but it had no marked effect on glomerular and tubular morphology and function. Co-administration of PTU and GM potentiates the GM-induced nephrotoxicity characterized by diffuse ATN; diffuse hyaline cast formation in lumen and infiltration of inflammatory cell in kidney tissues. CONCLUSION: Our data indicate that PTU potentiates GM-induced nephrotoxicity. The underlying mechanism(s) via which PTU potentiates GM renal toxicity remains to be elucidated. PMID- 24494073 TI - Artificial Neural Networks Analysis Used to Evaluate the Molecular Interactions between Selected Drugs and Human Cyclooxygenase2 Receptor. AB - OBJECTIVE(S): A fast and reliable evaluation of the binding energy from a single conformation of a molecular complex is an important practical task. Artificial neural networks (ANNs) are strong tools for predicting nonlinear functions which are used in this paper to predict binding energy. We proposed a structure that obtains binding energy using physicochemical molecular descriptions of the selected drugs. MATERIAL AND METHODS: The set of 33 drugs with their binding energy to cyclooxygenase enzyme (COX2) in hand, from different structure groups, were considered. 27 physicochemical property descriptors were calculated by standard molecular modeling. Binding energy was calculated for each compound through docking and also ANN. A multi-layer perceptron neural network was used. RESULTS: The proposed ANN model based on selected molecular descriptors showed a high degree of correlation between binding energy observed and calculated. The final model possessed a 27-4-1 architecture and correlation coefficients for learning, validating and testing sets equaled 0.973, 0.956 and 0.950, respectively. CONCLUSION: RESULTS show that docking results and ANN data have a high correlation. It was shown that ANN is a strong tool for prediction of the binding energy and thus inhibition constants for different drugs in very short periods of time. PMID- 24494074 TI - Antiproliferative activity and apoptosis induction of crude extract and fractions of avicennia marina. AB - OBJECTIVE(S): Regarding the presence of many active biological constituents in Avicennia marina, the present investigation was carried out to study cytotoxic activity of crude methanol leave extract and column chromatographic fractions of A. marina against MDA-MB 231 cell line (human breast cancer cell) and HEK (Human embryonic kidney cell) line. MATERIALS AND METHODS: The anticancer activity of crude methanol extract and sub-fractions were evaluated, using MTT assay. The induction of apoptosis was determined by analyzing DNA fragmentation in breast cancer cells treated with active fraction of crude methanol extract using agarose gel electrophoresis. To investigate molecular mechanism of apoptosis, gene expression levels of p53 and Bcl-2 were measured using quantitative real time PCR. RESULTS: Fraction 10 was the most active fraction and was detected with HPLC as luteolin. The 50% cell cytotoxic concentration (CC50) of crude methanol extract and luteolin was 250 and 28 ug/ml, respectively. This fraction was found to be an apoptotic agent against MDA-MB 231 cells, which leads to causing DNA fragmentation. The mRNA expression level of Bcl-2 and p53 was significantly decreased and increased respectively in cancer cells treated by luteolin. CONCLUSION: The results suggested that Luteolin isolated from Avicennia marina could probably induce apoptosis on breast cancer cell line by the regulation of p53 and Bcl-2 pathways. PMID- 24494075 TI - Effects of opium smoking cessation on the nasopharyngeal microbial flora. AB - BACKGROUND: To determine the effect of opium smoking cessation on the frequency and type of microorganisms in the nasopharynx of opium smokers. METHODS: This was a cross-sectional study performed in psychology and ENT department of Moradi Hospital of Rafsanjan University of Medical Sciences in 2008 (Kerman, Iran). Nasopharyngeal cultures were taken from 50 opium smokers before and 2 to 3 months after cessation of opium smoking. Potential pathogens were identified. FINDINGS: Eight potential pathogens were isolated from nasopharyngeal cultures obtained from 43 individuals before opium smoking cessation, and 4 were recovered from 33 individuals after cessation (P < 0.0001). Streptococcus pneumonia, staphylococcus saprofiticus, streptococos alpha hemolytic, and staphylococcus aureus in 2(nd) culture were not seen. The most sensitivity to antibiotics was related to ceftriaxone (84%), ciprofloxacin (74%) and cloxacillin (72%); the most resistance was to amoxicillin (26%) and the least resistance was to chloramphenicol. CONCLUSION: In our study, some potential pathogens decreased or even disapeared after opium cessation. Our patients have not been advised to change their number of cigarettes. We have used methadone pill for substitution of opium. It seems that opium smoking affects nasopharyngeal flora. PMID- 24494076 TI - Relationship of opium dependency and stroke. AB - BACKGROUND: Stroke is the third cause of mortality and not only leads to dependency, which is a great social, individual and cultural problem, but also can affect the physiology, immune system and coagulation system such as plasma fibrinogen, and it may potentially increase the risk of stroke. This study investigated the relationship of opium dependency and stroke. METHODS: This case- control study was carried out in 2003-2004 in Shefa Hospital in Kerman, Iran. The case group included 105 stroke patients and control group included the same number of patients from urology ward. There were 55 females and 50 males in each group. Patients' data were collected through their medical history, physical examinations, and diagnosis procedures recorded in specific questionnaires. Data were analyzed using Chi square test. FINDINGS: 31 patients (29.5%) in the case and 11 (10.5%) in the control group were opium dependent and the difference was significant (P = 0.001). The relationship of cigarette smoking and stroke was also significant (P = 0.0001). To find the independent effect of each of these two factors, a logistic regression analysis was done, which showed that the independent relationship of each of these two was significant (Odds ratio = 2.207, P = 0.012 and Odds ratio = 2.36, P = 0.040 for cigarette and opium dependency respectively). CONCLUSION: Opium dependency can be regarded as an independent risk factor for stroke. As this corresponds to previous findings as to opium dependency can increase plasma fibrinogen and development of atherosclerosis, it is important for prophylactic manages. PMID- 24494077 TI - Opiate dependents' experiences of the therapeutic relationship in methadone centers; a qualitative study. AB - BACKGROUND: Methadone maintenance therapy is a treatment of choice for opiate addiction. Understanding opiate dependents' experiences of patients' treatment is a key to continue the treatment and can provide help to revise the standards of methadone centers and improve the quality of treatment. This study aimed to describe the essence and structure of opiate dependents' experiences with methadone maintenance therapy. METHODS: It was a qualitative phenomenological study, in which participants were selected from opiate dependents referred to methadone centers in Kerman city in 2007. Sampling was purposive and continued until data saturation, which was achieved at 32 participants. Data were collected by in-depth interviews. Colaizzi's method was applied for data analysis. The rigor of the present study was assessed based on the criteria of confirmability and credibility. FINDINGS: A total of 26 themes were extracted and categorized into three main themes including positive therapeutic alliance, negative therapeutic alliance and therapeutic alliance requests. CONCLUSION: Client centered therapy in methadone clinics creates a positive therapeutic alliance, and persuades patients to continue their treatment. Establishing a good relationship with patients during their treatment procedure is an effective way to meet the goals. Individual and group counseling sessions and advices on family and career related issues during the treatment should be considered as well. PMID- 24494078 TI - Comparative Evaluation of Psychiatric Disorders in Opium and Heroin Dependent Patients?This article has been published in the Journal of Rafsanjan University of Medical Sciences in Persian language. AB - BACKGROUND: Opium dependency is an important health problem in Iran. Several studies show that most opium dependent patients have concomitant psychiatric disorders. The aim of this study was evaluation of psychiatric disorders in opium dependency in comparison with heroin dependency. METHODS: This is a descriptive study on 192 male opium dependent patients who were admitted in dual- diagnosis ward of Beheshti Hospital in Kerman for detoxification. After evaluation of their demographic data, they were assessed by means of SCL-90-R test. FINDINGS: The mean age of subjects was 33.92+/-7.67 years. All scales of SCL-90-R were evaluated as borderline or sick. The scores of obsession-compulsion, anxiety, phobia, psychosis, PST, and GSI were significantly higher in heroin dependents compared to opium dependent patients (P < 0.05). CONCLUSION: It is recommended that all patients with opium dependency should be evaluated for co-morbid psychiatric disorders. This may improve the outcome and management of their dependency. PMID- 24494079 TI - Frequency of Anabolic Steroids Abuse in Bodybuilder Athletes in Kerman City?This article has been published in the Journal of Rafsanjan University of Medical Sciences in Persian language. AB - BACKGROUND: Athletes, especially bodybuilders, abuse anabolic steroid drugs to improve their strength and enhance their muscle growth and appearance. This study was conducted to determine the type and frequency of anabolic steroids abuse in bodybuilder athletes in Kerman City. METHODS: A confidential questionnaire which included demographic data (age, education), name of abused anabolic drug and duration of drug abuse was completed by 202 bodybuilder athletes, and the collected data were analyzed using Chi Square test. A value of p < 0.05 was considered significant. FINDINGS: The frequency of anabolic steroid abuse was 18.8%. The mean period of bodybuilding activity was significantly higher in those used the anabolic drugs (38.8 months), comparing to those did not use any drugs (14.3 months). Oxymetholone was the most common drug used by athletes (42% merely used Oxymetholone). The frequency of anabolic steroids abuse was not related to education and age of the bodybuilder athletes. CONCLUSION: Bodybuilder athletes in Kerman city abuse anabolic steroids, and the health care system should plan to inform them about anabolic steroid adverse effects. PMID- 24494080 TI - Epidemiologic Study on Drug Abuse among First and Second Grade High School Students in Kerman. AB - BACKGROUND: This study investigated the epidemiology of drug abuse among high school students in Kerman. METHODS: This was a cross-sectional study on a randomly selected sample of 652 first and second grade high school students (256 boys, 396 girls) in Kerman. They were informed that their answers would be classified and nameless before they filled questionnaires. Schools and classes were selected using stratified sampling method. FINDINGS: From total 652 students participated in this study, 39.2% (256) were boys and 60.7% (396) were girls. Most of the students had information about opium (70.7% of boys and 79.8% of girls), and then alcohol (55.9% of boys and 53.9% of girls). Most offered substance to the students was alcohol (25% in boys and 12.4% in girls). The most effective encouragement for using drugs was through their friends (39% in boys, 16.9% in girls). The most used drug was alcohol among boys (11.4%) and sedative tablets among girls (12.2%). Boys preferred to use drugs in wedding ceremonies (11.3%) but girls proffered their houses (4.8%). The first reason for using drugs was socializing with unsavory friends (29.4%) and the second one was domestic problems (21.4%). CONCLUSION: The results of this study indicated dangerously increase of drug abuse among teenagers, who are the future of the society. If these results could be generalized, authorities must think of serious solutions for this rising problem. PMID- 24494081 TI - Prevalence of cigarette smoking in schizophrenic patients compared to other hospital admitted psychiatric patients. AB - BACKGROUND: This study aimed to estimate the prevalence of cigarette smoking and some of the related factors among schizophrenic and other hospitalized psychiatric patients. METHODS: This was a cross-sectional study on 120 patients hospitalized in Shahid Beheshti hospital in Kerman in 2005. Patients were equally devided in two groups of schizophrenia and other psychiatric disorders. Sampling was based on statistical census and data were collected using a questionnaire including 27 questions on demographic data, psychiatric disorder, smoking cigarettes and other substances, and Fagerstrom test. Data were analyzed by Chi square and ANOVA tests using SPSS software. FINDINGS: Prevalence and severity of cigarette smoking was 71.6% and 6.47% among schizophrenic and 51.6% and 6.40% among other psychiatric patients, respectively and the difference was not significant. History of withdrawal was 25.6% and 58.1% in the schizophrenia and other disorders respectively and the difference was significant (P < 0.05). Addiction to other substances was 51.6% in schizophrenic and 45% in the other patients and the most prevalent substances in both groups were opium and alcohol. The severity of smoking cigarettes was 6.9 along with other drug abuses and 5.1 in cases with just smoking based on Fagerstrom test and the difference was significant (P < 0.05). CONCLUSION: The prevalence of cigarette smoking in both schizophrenia and other psychiatric patients is higher than normal population, but there is no significant difference between these two groups. Schizophrenic patients need persistent supportive and supervising programs for cigarette smoking abuse treatment because of their cognitive, motivate and social problems. PMID- 24494082 TI - Exploit the developed countries experiences of primary school education to prevent drug addiction and implications for iran. AB - BACKGROUND: The purpose of this study was to evaluate various educations in primary schools to prevent drug addiction. METHODS: In this qualitative study, data included the experiences of those who been students in the developed countries for some years as well as their parents. The data were collected by semi-structured and unstructured interviews as well as documents. FINDINGS: The results showed that education for prevention of drug addiction begins in primary schools in the developed countries using various methods. These educations are not occasional but constant and infused in all curriculum subjects and grades. Students become familiar with various drugs and learn about their effects. CONCLUSION: Our findings showed that social problems are discussed openly in schools of the developed countries and students try to find solutions which are considered by authorities. PMID- 24494083 TI - Rare variant of lycanthropy and ecstasy. AB - BACKGROUND: Lycanthropy is an unusual belief or delusion in which the patient thinks that he/she has been transformed into an animal. In rare cases, the patient believes that another person has been transformed into an animal. CASE REPORT: We report a patient with an uncommon variant of lycanthropy is introduced. The symptoms appeared after consumption of ecstasy. This shows the occurrences of uncommon and rare psychosis after ecstasy drug use especially in patients susceptible to schizophrenia. Ecstasy drug can induce paranoid psychosis similar to schizophrenia. In the presented case, ecstasy seemed to have a role in patient's underlying susceptibility to schizophrenia. PMID- 24494084 TI - Psychosis following Tramadol Withdrawal. AB - BACKGROUND: Tramadol is a centrally acting opioid analgesic used to treat moderate to sever pain. It has more advantage and less opioid adverse effects than conventional opioid analgesia. CASE REPORT: This article reports a patient with tramadol dependency that had psychosis after tramadol withdrawal. CONCLUSION: By the increase of tramadol usage for relief of chronic pain, tramadol abuse and dependency is increased. Some of tramadol withdrawal symptoms are not related to opioid, for example when the effectiveness is not only on opioid receptors, but on catecholamine and serotonin receptors. So, together with typical symptoms of withdrawal, atypical symptomes had been reported. Psychosis is one of tramadol atypical withdrawal symptoms which subsided a few days after suppression of withdrawal symptoms. In such cases, the diagnosis is substance withdrawal instead of psychotic disorder due to substance withdrawal and treatment is based on this diagnosis. PMID- 24494085 TI - Comparing Symptoms of Withdrawal, Rapid Detoxi-fication and Detoxification with Clonidine in Drug Dependent Patients. AB - BACKGROUND: Considering the fear of drug addicts from hangover symptoms and the costs of withdrawal treatment and their importance in deciding to withdraw, it is helpful to identify various ways of withdrawal and their effects. This study investigated the withdrawal symptoms of two methods of detoxification with clonidine and rapid detoxification of clonidine with naltrexone. METHODS: This was a clinical trial study. Patients referred to Shahid Beheshti hospital for narcotic addiction treatment were randomly divided into two groups. Group matching was done based on entry and excluding criteria. Data were collected using a demographic questionnaire including questions on the drug abuse and the consumption method, and a questionnaire on the symptoms of opioid withdrawal. FINDINGS: Restlessness, vomiting, feeling sick and significant decrease of diastolic blood pressure was higher in rapid detoxification method group. However, considering background variables, Spearman correlation coefficient showed significant relationship just for lacrimation. Temptation for drug consumption was lower for heavy abusers in rapid detoxification method and in general, those who had higher amount of consumption and were treated by rapid detoxification, experienced less temptation for consumption. CONCLUSION: Rapid detoxification can be the first level treatment for heavy abusers, because it reduces the temptation for drug consumption and has shorter hospitalization and, as a result, has lower cost. PMID- 24494087 TI - Experiences of opium dependents from performance of methadone centers of kerman, iran. AB - BACKGROUND: To assess patients' satisfaction and to evaluate methadone therapy program, it is important to understand the experiences of opium dependents during the treatment period in methadone centers and determine the quality of this program and revise standards based on that. This study aimed to describe the nature and structure of patients' experiences during treatment in methadone centers. METHODS: This was a qualitative method using phenomenology. Sampling was purposive and the participants were selected from opium dependents referred to Kerman methadone centers during 2007. Sampling continued until data saturation and the sample size was 32. Colaizzi's method was applied for data analysis. FINDINGS: The findings of this study included 27 codes categorized in four main groups: experiences of structure, personnel, patients, and regulations. These four categories showed the main structure of experiences in methadone centers. CONCLUSION: Lack of treatment centers in near-by cities or the problems of those centers suggest that it is necessary to establish new centers or solve the problems of centers in near-by cities. The type of patients referring to the centers plays a role in treatment process. The regular presence of physicians and other personnel and their concerns and care for patients as well as longer working hours of the centers have roles in patients' satisfaction and increase of consistency with treatment. Discussing the rules and regulations of the center with patients including the obligatory of daily reference to the center to obtain medicine and injections sound necessary. Also, it is necessary to find ways for solving problems of urine tests. PMID- 24494086 TI - Relationship of opioid dependence and positive and negative symptoms in schizophrenic patients. AB - BACKGROUND: Many schizophrenic patients are engaged in self-medication drug abuse, including narcotics. It is assumed that many of these patients have a greater number of psychotic symptoms, and show noncompliance with treatment. In this study, we investigated relationship of positive and negative symptoms and opioid dependence in these patients. METHODS: This was a descriptive cross sectional study on 100 patients with schizophrenia. The diagnoses were made based on DSM-IV criteria. After evaluating demographic data, the patients were assessed with positive and negative symptom scale (PANSS) test. Data were analyzed using SPSS10 software. FINDINGS: Fifty percent of patients were identified to be opioid dependent based on DSM-IV criteria. Seventy five percent of patients were male and the rest were female. The mean (SD) scores of positive symptoms were 39.58 (23.374) and 54.34 (21.025) in non-dependent and dependent patients, respectively (P = 0.01). Other statistical measurements were unremarkable. CONCLUSION: High prevalence of opioid dependence in our sample can be due to availability of these substances in the community. Opioid may be used as self medication, can reduce the severity of positive symptoms, and may also make positive symptoms more tolerable for patients. PMID- 24494088 TI - Disruptive Behavior Disorders in 8 to 14 Years Old Offspring's of Opium and Heroin Dependent Parents: a Case-Control Study. AB - BACKGROUND: Drug abuse is usually associated with behavioral disorders in children especially conduct disorder. This study investigated the behavioral disorders of children whose parents were opium or heroin dependent in compare with children whose parents were non-addicts to find the effects of drug abuse on offspring's behavior disorders by adjusting intervening factors. METHODS: This case-control study, compared the behavioral disorders of 128 students (aged 8 to 14 years) in two groups of opium or heroin dependent parents and non-dependent parents (n = 64 in both groups) using Child Behavior Checklist (CBCL) questionnaire. Parents of both groups were checked not to have any significant psychiatric disorder (such as personality disorder or mood disorder), major health problem, and history of divorce. To compare percentages of the two groups, chi square and if required exact test were used. FINDINGS: There was no statistically significant difference between the two groups in subscales of oppositional behavior problems and problems disorders. CONCLUSION: According to the results, in case there is no psychiatric co-morbidity associated with opium and heroin abuse, drug dependency does not seem to have any effect on disruptive bahavior disorder of children. Due to study limitations, the results cannot be generalized without conducting the study on a bigger population. PMID- 24494089 TI - Reliability and Validity of A Persian Version of Substance Dependence Severity Scale (SDSS). AB - BACKGROUND: Iran (I.R.) is suffering the growing problem of opiate abuse. In evaluation of the treatment plan for opium dependent patients, a valid and reliable instrument is needed to measure patients' severity of dependence. This study aimed to assess the reliability and validity of the Persian version of the "Substance Dependence Severity Scale" (SDSS). METHODS: After translating the English version of SDSS to Persian and then back translating it to English, a structured interview with 200 opium dependent patients was conducted to collect data. Then, reliability (internal consistency and test-retest procedure) and construct validity were tested. FINDINGS: The alpha coefficient was 0.77 and the correlation between test and retest results showed a high correlation coefficient (0.97) which confirmed the reliability. Construct validity was assessed by a cross-check against General Health Questionnaire (GHQ) and the results were in favor of its validity. But the correlation between the amount of substance usage and scores of the 1(st) and 2(nd) questions were not within the acceptable range. CONCLUSION: The results support the reliability of the Persian version of SDSS, but to confirm its validity further studies are needed. PMID- 24494090 TI - Knowledge of Dentistry, Medicine, and Pharmacy Students about Psychedelic Drugs in Kerman University of Medical Sciences. AB - BACKGROUND: Psychedelic drugs can cause one to get out of normal status and permanent cerebral defects, via affecting central nervous system. Consumption of theses drugs seems to be increasing nowadays especially among the youth and university educated population. We conducted a study to evaluate the awareness of medical science students of Kerman University of medical science who are going to be the future medical population. METHODS: This cross-sectional study was carried out on 471 of students of medicine, dentistry and pharmacy which were in the first to forth year of their education about psychedelic drugs (Ecstasy, LSD, Ice, crack and Yaba). To evaluate the students' awareness of drugs we used questionnaire with reliability and validity proven via pilot study. Statistics analysis was performed using SPSS13 software. FINDINGS: Average of their age was 3.2 +/- 20.4. Overall among the students, 56.7% were in the low level of insight, 34.3% in medium and 6.9% in good level and 2.2% had best insight of the drugs. Also only 32.2% of students had the full information about the name of drug, 25.7 % had information about the form of them, 24% about the addiction with them, 7% about their complication and only 5% about the origin of drugs. The information about all psychedelic drugs was higher among pharmacy students, students of the third year and males. CONCLUSION: Our study showed a low insight about psychedelic drugs like Ecstasy, LSD, Ice, Crack, and Yaba among the students. According to this lack of information of these groups, it is suggested that educational courses about the complication, signs and symptoms of these drugs be held. PMID- 24494091 TI - Effect of addiction to computer games on physical and mental health of female and male students of guidance school in city of isfahan. AB - BACKGROUND: This study aimed to investigate the effects of addiction to computer games on physical and mental health of students. METHODS: The study population includes all students in the second year of public guidance schools in the city of Isfahan in the educational year of 2009-2010. The sample size includes 564 students selected by multiple steps stratified sampling. Dependent variables include general health in dimensions of physical health, anxiety and sleeplessness and impaired social functioning. Data were collected using General Health Questionnaire (GHQ-28) scale and a questionnaire on addiction to computer games. Pearson's correlation coefficient and structural model were used for data analysis. FINDINGS: There was a significant positive correlation between students' computer games addiction and their physical and mental health in dimensions of physical health, anxiety and sleeplessness There was a significant negative relationship between addictions to computer games and impaired social functioning. CONCLUSION: The results of this study are in agreement with the findings of other studies around the world. As the results show, addiction to computer games affects various dimensions of health and increases physical problems, anxiety and depression, while decreases social functioning disorder. PMID- 24494092 TI - Lead serum levels in opium-dependent individuals. AB - BACKGROUND: Drug abuse, especially opium abuse, is a major public health problem in Iran. Recent reports suggest that opium sellers cheat their customers by adding lead to the opium. Contaminated opium can threaten the health of consumers. The present study aimed to compare the serum level of lead between opium dependents and a control group. METHODS: This was a cross-sectional study in which 50 opium dependents aged 20 to 60 years old were compared with a control group of 43 non-dependents who were matched with the case group in terms of sex and age. The serum level of lead and liver function tests including serum total bilirubin, AST, ALT, Alkaline-phosphatase and hemoglobin were measured for all subjects. FINDINGS: The mean level of serum lead concentration in opium dependents and controls was 3929.358 +/- 147.67 and 3532.721 +/- 1141.53, respectively and the difference was not statistically significant. There was no significant correlation between serum level of lead and age, duration of opium dependency, serum total bilirubin, hemoglobin, AST, ALT, and Alkaline-phosphate. CONCLUSION: Although there was no significant relationship between opium consumption and serum level of lead, the concentration of lead in dependents' serum was higher than controls. Further studies are needed to approve this relationship to be used for screening and on time diagnosis of opium dependents. PMID- 24494093 TI - Reporting a Case of Injecting Methylphenidate (Ritalin) Tablets, Intensified Symptoms of Schizoph-renia or Induce Separate Mental Disorder? AB - BACKGROUND: Methylphenidate is one of the classic amphetamines which can cause or exacerbate psychotic symptoms in schizophrenia patients. CASE REPORT: In this paper, a young man is presented with injection of methylphenidate tablets with acute cellulitis due to this injection and the related symptoms. In the first hospitalization and after recovery from psychotic disorder due to tablet injections, he was under treatment with anti-psychotics because of other symptoms related to schizophrenia. Although the patient was regularly under schizophrenic medication after discharge, he was hospitalized twice more due to psychotic symptoms that appeared after injecting methylphenidate. CONCLUSION: This report shows psychotic symptoms in schizophrenic patients after injecting methylphenidate. These symptoms cannot be prevented even by anti-psychotic medication of background disease. This case shows the existence of two kinds of psychoses, functional (due to schizophrenia) and organic psychoses (due to methylphenidate use) in the same patient. PMID- 24494094 TI - Religious attitude associated with general health and smoking in Iranian students. AB - BACKGROUND: Given the university students' model role in the society and the importance of period of university education in selecting behavioral methods and lifestyles in the future have made it necessary to study the smoking pattern and its associated factors and complications among students. The aim of this study was to compare religious attitude and mental health between smoking and non smoking students. METHODS: In this research, religious attitude and mental health was studied in 1065 smoking and non-smoking students of Kerman University of Medical Sciences. In this study, three questionnaires were used (Demographic Questionnaire, General Health Questionnaire and Religious Attitude Scale Questionnaire) which were completed by the students voluntarily. The data were analyzed by descriptive statistic methods, multivariate analysis of variance (MANOVA), t-test, Pearson correlation, and regression coefficient. FINDINGS: The mean age of smokers was 20 years and most of the smokers were male (78.9%), single (86.5%) and in BS or BA degree (52.5%). Most of them smoked a cigarette or more in the past month. The average age of start of smoking was 18 years. There was no significant difference between religious attitude and mental health in smoking students in terms of gender but in non-smoking students there was a significant difference in this regard. Smoking students had lower mental health status and religious attitude in comparison with non-smoking students. Between religious attitude and general health in smoking and non-smoking students was also a direct association. CONCLUSION: Due to psychological and physiological consequences of cigarette smoking, promoting smoking prevention by religious missionaries and university professors, and helping the students to quit smoking by counselors, psychologists and psychiatrics are necessary. PMID- 24494095 TI - A review on hematological factors in opioid-dependent people (opium and heroin) after the withdrawal period. AB - BACKGROUND: Long-term use of opioids has acute effects on homeostasis of the body. Discovering the impacts of opioids on hematological parameters of narcotics withdrawal and dependents blood may be helpful in recognizing the homeostasis condition of their body for the useful treatment. METHODS: In this study a cross sectional method was applied. The abusers of opium and heroin for more than two consecutive years were considered as opium and heroin dependent groups, respectively. The dependent people, who passed the 1-month withdrawal period, entered the study as opium and heroin withdrawal groups. In this study, hematological factors of heroin and opium dependent and withdrawal groups were investigated. FINDINGS: The RBC count remained unchanged in all groups. The WBC count had a significant increase in opium dependent group but in heroin dependent group and withdrawal group there was no significant difference. HGB level had a significant increase only in opium and heroin withdrawal groups. The percentage of HCT had a significant increase in all groups. The MCV increased in heroin and opium dependent groups. MCH level increased significantly in heroin and opium withdrawal groups. MCHC level had a significant increase in all groups. Neutrophil and lymphocyte counts in heroin and opium addicted groups significantly decreased. Platelet, neutrophil and monocyte counts significantly increased in opium dependent group. Monocyte countshowed a significant reduction in heroin withdrawal group. Eosinophil count showed no difference in any of the groups. CONCLUSION: The current study indicated that not only the chronic and long-term use of opium and heroin, also withdrawal of addicted people could change hematological parameters related to human serum. PMID- 24494096 TI - A comparison of the efficacy of buprenorphine and clonidine in detoxification of heroin-dependents and the following maintenance treatment. AB - BACKGROUND: This study compared the success rates of buprenorphine and clonidine in detoxification of heroin-dependents and evaluated the recurrence of drug abuse in patients taking naltrexone in a 6 month follow up. METHODS: A double-blind study was carried out in Kerman's psychiatric hospital on heroin-dependents seeking detoxification during the years 2007-2009.These patients were randomized into 2 groups receiving clonidine and buprenorphine. The success rate of detoxification was evaluated at the end of the trial and each patient was discharged with a daily consumption of 25 mg naltrexone. They were monitored for 6 months with respect to naltrexone consumption and withdrawal from drug abuse. FINDINGS: Overall 49 patients participated in the study. The success rate of detoxification with naltrexone was confirmed in all subjects. In the group receiving clonidine, 2 subjects (9.5%) had a clinical opiate withdrawal scale (COWS) above 12 in day 5 (P=0.186) and none of the subjects in the group taking buprenorphine had a COWS above 12 in day 5. The signs and symptoms of withdrawal and the desire for substance abuse was declined significantly in both groups over time; 19% of subjects detoxified with clonidine and 39% detoxified with buprenorphine continued taking naltrexone for one month and 52% detoxified with clonidine and 53.5% detoxified with buprenorphine entered the maintenance treatment. The average days remaining in treatment and being free of recurrence of drug abuse was not significantly different between the two groups in a 6 month follow-up. CONCLUSION: Administration of buprenorphine within a few days was more efficient in reducing the signs and symptoms of withdrawal when compared to clonidine. However, recurrence of drug abuse was not significantly different between the two groups. PMID- 24494097 TI - The effect of methadone maintenance therapy on harm reduction in opiate dependents in kerman socio-behavioral consulting centers. AB - BACKGROUND: Socio-behavioral consulting centers offer methadone maintenance therapy which is a very useful method for drug dependents. These centers offer a wide range of services like education, consulting, prevention, care taking of patients and treatment for high risk groups such as AIDS-infected patients. Methadone maintenance therapy (MMT) is helpful in harm minimization and increasing the quality of the drug dependent's life; therefore, reducing infection in HIV patients. This study intends to investigate the importance of MMT on harm reduction in opioid dependents in Kerman. METHODS: This descriptive, cross sectional study was performed on 110 patients referred to No. 1 and No. 2 socio-behavioral consulting centers in Kerman city in 2005 and 2006. Data was gathered by questionnaires once at the beginning of treatment and once 6 months after. Then the data was analyzed by SPSS13 and chi square test. FINDINGS: Methadone maintenance therapy resulted in a 97.3% reduction in common injections, 96.4% decrease in arrest and imprisonment, 80% decrease in family problems and 68.2% decrease in drug abuse and negative morphine tests in these centers. After 6 months of treatment, drug consumption expenses were also diminished. CONCLUSION: This study showed that treatment with MMT in these centers reduced dangerous behaviors, increased the quality of life and controlled transmission of dangerous diseases such as AIDS and hepatitis in the community. PMID- 24494099 TI - Identity disturbance and substance-dependence in patients with borderline personality disorder. AB - BACKGROUND: Identity disturbance is one of the DSM-IV criteria for borderline personality disorder, but there has been little attention to its nature. Four subsets of identity disturbance (role absorption, painful incoherence, inconsistency and lack of commitment) have been assessed. This study aimed to assess the role of these subsets in patients with borderline personality disorder and to examine the relationship between identity disturbances and substance dependence. METHODS: This case-control study was conducted on 40 patients with borderline personality disorder who were referred to Shahid Beheshti Hospital in Kerman from 2004 to 2005 and 40 healthy people who were matched with the case group in term of gender and educational level. Data gathering was carried out with three questionnaires including a demographic-related questionnaire, disturbance questionnaire (including 35 items) and a questionnaire related to substance-dependence and its related factors. Statistical analysis was performed using SPSS 11 for Windows, t test and ANOVA. FINDINGS: The mean score of 33 items of the identity disturbance questionnaire were greater with significant difference in the case group (P<0.05). The means differences in the two groups in all subsets were statistically significant, except for role absorption (P<0.05). The means differences in all subsets in substance-dependent and substance independent subjects in both groups were not significant statistically. The most common substance-dependence in both groups was related to cigarette smoking and cannabis. Opium and cannabis dependence was significantly greater in patients with borderline personality disorder. CONCLUSION: Identity disturbance is one of the major criteria for borderline personality disorder, but in different societies the role of its subsets are different. On the other hand, assessing subsets of identity disturbance has no value in assessing substance-dependence in patients with borderline personality disorder. PMID- 24494098 TI - Assessing the Effect of Opium Dependence on Visual Evoked Potential (VEP) in Men. AB - BACKGROUND: Opium-dependence having different effects on the nervous system is a common problem, especially in the Middle East and Iran. The aim of this study is evaluating the effects of opium-dependence on visual evoked potential (VEP) in men. METHODS: Thirty subjects with both chronic cigarette smoking and opium dependence (group 1) and 30 subjects with only chronic cigarette smoking (group 2) were included in this cross-sectional case-control study and after urinary tests of opium, the pattern reversal visual evoked potentials (PRVEP) were recorded in the standard condition and variables such as N75, P100, N135 and amplitude were obtained and then analyzed with SPSS16. P value < 0.05 was assumed significant statistically. FINDINGS: The mean of N75 (70.426 +/- 22.028), P100 (115.457 +/- 29.176) and N135 (165.402 +/- 66.712) was not significantly different between the two groups. The mean of the amplitude of VEP in group 1 (6.856 +/- 3.248) was significantly higher than group 2 (4.933 +/- 2.50) (P < 0.05). CONCLUSION: Our study showed that chronic cigarette smoking and opium dependence have no significant effect on the late components of the VEP (N75, P100 and N135), but chronic cigarette smoking and opium-dependence together significantly increase the amplitude of VEP compared with chronic cigarette smoking alone, probably due to the chronic stimulatory effects of concomitant use of these two substances on the eyes and the visual nervous system. PMID- 24494100 TI - Comparison of internalizing disorders in 8-14-year-old offspring of opium and heroin dependent parents: a case-control study. AB - BACKGROUND: In general, parental substance abuse is associated with children's emotional and behavioral problems. This study only investigated the internalizing problems (depression, anxiety and physical complains) in children of opioid or heroin-dependent parents in comparison with non-opioid dependent parents in order to determine the effects of drug dependency after excluding the confounding factors. METHODS: This case-control study compared the internalizing problems of one hundred twenty eight 8 to 14-year-old students in two offspring groups of opioid or heroin-dependent parents (n=64) and non opioid dependent parents (n=64). Then we used the Child Behavior Checklist (CBCL). Parents in both groups had no major psychiatric disorders (e.g., personality disorders, mood and anxiety disorders or psychosis), no history of major medical diseases, and no history of divorce. Analysis was performed using chi square or Fisher's exact test. FINDINGS: The anxiety/depression subscales in children of non opioid dependent parents were significantly higher in comparison with children of opioid or heroin dependent parents. CONCLUSION: Substance dependence in addition to reducing parental supervision on children may cause lack of knowledge and unawareness of their children's anxiety and mood problems. Considering study limitations, study repetition in larger statistical population is necessary for generalizing the study findings. In order to assess internalizing problems in further studies, usage of behavioral checklists for self-report of children and youth is recommended. PMID- 24494102 TI - Comparing the social skills of students addicted to computer games with normal students. AB - BACKGROUND: This study aimed to investigate and compare the social skills of studentsaddicted to computer games with normal students. The dependentvariable in the present study is the social skills. METHODS: The study population included all the students in the second grade ofpublic secondary school in the city of Isfahan at the educational year of2009-2010. The sample size included 564 students selected using thecluster random sampling method. Data collection was conducted usingQuestionnaire of Addiction to Computer Games and Social SkillsQuestionnaire (The Teenage Inventory of Social Skill or TISS). FINDINGS: The results of the study showed that generally, there was a significantdifference between the social skills of students addicted to computer gamesand normal students. In addition, the results indicated that normal studentshad a higher level of social skills in comparison with students addicted tocomputer games. CONCLUSION: As the study results showed, addiction to computer games may affectthe quality and quantity of social skills. In other words, the higher theaddiction to computer games, the less the social skills. The individualsaddicted to computer games have less social skills.). PMID- 24494101 TI - Predictors of transition in different stages of smoking: a longitudinal study. AB - BACKGROUND: We investigated longitudinally the prevalence of smoking according to three stages of smoking (never smoking, experimenting the smoking, and regular smoking), the rates of transition from one stage to another one, and determinant predictors of transition through these stages of smoking. METHODS: Of all 10(th) grade students in Tabriz, 1785 students were randomly selected and assessed twice, with a 12-month interval, with respect to the changes of stage. The predictor variables were measured when the students were in the 10(th) grade. Logistic regression and principal component analysis were used to analysis data at grade 11. FINDINGS: Of 1785 students, 14.3% (CI 95%: 12.3-16.4) and 2.8% (CI 95%: 2.0-4.0) of the never smokers became experimenters and regular smokers, respectively and 16.5% (CI 95%: 12.4-21.7) of the experimenters became regular smokers. Among never smokers, participating in smoker groups (OR=1.24), having smoker friends (OR=1.85) and a positive attitude towards smoking (OR=1.22) predicted experimentation; and participating in smokers groups (OR=1.35) and a lower socioeconomic class (OR=0.36) predicted regular smoking. Among experimenters, students having general high risk behaviors (OR=2.56) and participating in smoker groups (OR=2.58) were distinguished as those who progressed to regular smoking in follow-up. CONCLUSION: Programs aimed at smoking prevention and intervention should incorporate plans which focus on predictors of transition through smoking stages, and targeting participation in smoker groups. PMID- 24494103 TI - Physical effects of methadone maintenance treatment from the standpoint of clients. AB - BACKGROUND: Studies have shown that methadone maintenance treatment (MMT) iseffective in improving the client's quality of life and physical health.This study aimed to describe the nature and structure of drugdependents' experiences and the physical effects of MMT. METHODS: The present study is a qualitative and a phenomenology study on 32clients referred to methadone clinics in the city of Kerman in 2008.Colaizzi's method was used for data analysis and to evaluate the data,validity and reliability criteria were used. FINDINGS: Encoded concepts were categorized in general groups of effectiveness ongeneral health, sleep, appetite and weight, sexual desire, appearance andother effects. These six categories showed the main structure of experienceand physical effects of MMT. CONCLUSION: The clients' viewpoints towards this treatment had a role in theirexperience expression and feelings, but MMT had an overall positivephysical effect on the clients. PMID- 24494104 TI - Does exercise deprivation increase the tendency towards morphine dependence in rats? AB - BACKGROUND: Exercise deprivation has been concluded to have some negative effectson psychological well-being. This study was conducted to find outwhether exercise deprivation may lead to morphine dependence in rats. METHODS: Forty male Wistar rats weighing 162 +/- 9 g were housed in clear plasticcages in groups of two under standard laboratory conditions. The studyhad two phases. In phase I, the animals were randomly divided intoexercised (E) and unexercised (UE) groups (n = 20 each) and treadmillrunning was performed based on a standard protocol for three weeks. Atthe end of the training period, plasma beta-endorphin levels weredetermined in four rats from each group. In phase II, the animals wereprovided with two bottles, one containing tap water and the other 25mg/l morphine sulfate in tap water for a total of 12 weeks. At the end ofthis phase naloxone was injected intraperitoneally to precipitatemorphine withdrawal. FINDINGS: THERE WAS NO SIGNIFICANT DIFFERENCE BETWEEN UE AND E GROUPS INMORPHINE CONSUMPTION (MG/KG/WK) [ GROUP: F(1,14) = 0.2, P = 0.690; time:F(11,154) =18.72, P < 0.001; interaction: F(11,154) = 1.27 , P = 0.245]. Nostatistically significant difference between the two groups of animals wasseen regarding withdrawal signs. CONCLUSION: The study showed that discontinuation of exercise does not increasethe tendency of morphine dependence in rats. PMID- 24494105 TI - Estimation of the active network size of kermanian males. AB - BACKGROUND: Estimation of the size of hidden and hard-to-reach sub-populations, suchas drug-abusers, is a very important but difficult task. Network scale up(NSU) is one of the indirect size estimation techniques, which relies onthe frequency of people belonging to a sub-population of interest amongthe social network of a random sample of the general population. In thisstudy, we estimated the social network size of Kermanian males (C) asone of the main prerequisites for using NSU. METHODS: A 500 random sample of Kermanian males between 18 and 45 years oldwere interviewed. We asked the size of their active networks using directquestions. In addition, we received the frequency of six names from thevital registry office among Kermanian males, and we estimated Cindirectly using the received frequencies and the frequency of thesenames among the networks of our sample. FINDINGS: Although different methods showed quite different Cs between 100 and350, the best estimation for C was 303, which means that on average eachKermanian male knows around 303 males between the age range of 18 and45 years. The estimated C did not have any strong association with thedemographic variables of our subjects. CONCLUSION: Using the estimated C we may use the NSU technique to assess thefrequency of many important hidden sub populations such as drugabusersand those who have sexual contact with men and women. PMID- 24494106 TI - Attention deficit hyperactivity disorder (ADHD) and conduct disorder in children of drug dependent parents. AB - BACKGROUND: Attention deficit hyperactivity disorder and conduct disorder are amongrelatively prevalent disorders during childhood and adolescence.Considering the negative impact of the parents' drug dependency andbipolar disorder, the present study aimed to determine the prevalence ofADHD and conduct disorder in children of drug-dependent and bipolar parents. METHODS: In this case-control study, the case group included two groups ofpatients with drug dependency and bipolar disorder hospitalized inShahid Beheshti hospital in Kerman who had 7 to 11-year-old children.The control group included healthy individuals without any drugdependency or other psychiatric disorders. Data were collected usingRutter scale Form A (parents' form) and a demographic questionnaire.Data were analyzed with ANOVA, Chi-square and Tamhane's post-hoc test. FINDINGS: Rutter's abnormal scores were generally 7.11% in children of drugdependent parents, 14% in children of bipolar parents and 1.6% in childrenof healthy parents demonstrating no significant difference. The frequencyof conduct disorder in the bipolar and drug dependent group was higherthan the healthy group, but the difference was not significant. Thefrequency of ADHD was 8.9% in the drug dependency group and 1% inthe control group which shows a significant difference. CONCLUSION: Drug dependency in parents may be a leading factor to mentaldisorders such as ADHD and conduct disorder in children. PMID- 24494107 TI - Substance misuse patterns and blood types of self-introduced addicts to substance rehabilitation centers of bam city. AB - BACKGROUND: With regard to the perceptible population, cultural, social andenvironmental changes in the aftermath of the earthquake in Bam City,this study was conducted to pinpoint substance misuse patterns and tofigure out the probable relationship between substance misuse andblood types of the addicts referred to Substance rehabilitation Clinicsfrom 2006 to 2007 in Bam City. METHODS: In this case-control study, the sample size includes volunteering andself-introduced addicts and also a random selection of 360 healthyclients referred to the Blood Transfusion Organization as the controlgroup. Both groups' data were analyzed using descriptive statistics andChi square and the odds ratio was estimated too. FINDINGS: Three-hundred ninety nine individuals from nearly 3000 clients referred tothe rehabilitation clinic from 2005 to 2008 participated with completeconsent in the study. The highest frequency belonged to opium addicts(85.6%) and the most prevalent addiction type pertains to opiumconsumption via smoke inhalation (58.2%). The probability rate of ABnegative blood type compared to other blood types among the addicts was6.07 fold the control group. CONCLUSION: There has been an increasing rate of addiction in bam after earthquakeand The substance consumption pattern has moved towards moredangerous methods. The high prevalence of AB blood type bringsabout a lot of presuppositions for geneticists, epidemiologists,hematologists and all majors in basic sciences. PMID- 24494109 TI - Tobacco Quit Rates among Youth in an Urban Health Centre of Mumbai: A Cross Sectional Study. AB - BACKGROUND: Tobacco use is a major cause of preventable death and disease in India.A nationally representative case-control study of smoking in India(2008) revealed that only 2% of smokers had spontaneously quit. Thisstudy was undertaken to assess tobacco quit rates among the youth in anurban health center and to determine barriers in quitting tobacco use. METHODS: This cross sectional study was conducted among the youth attendingMalwani Urban Health Centre. Hundred thirty-three subjects wereselected by a universal sampling method. Data was collected using asemi structured questionnaire. FINDINGS: The majority of the youth were in the 18 to 21-year-old age group (43%),Male (82.4%), Muslim (65.4%) and unmarried (57.1%). The tobacco quitrate among these cases was 8.3%. Quitting tobacco use was significantlyassociated with the person's religion, marital status and living with the family. CONCLUSION: Fear of cancer was the most common reason for quitting tobacco. Themajor reason for initiation of tobacco consumption was peer pressureand betel quid was the most common form. Not experiencing anyharmful effects of tobacco was the most common reason for notquitting tobacco. PMID- 24494108 TI - The Prevalence of at Least One-Time Substance Abuse among Kerman Pre-university Male Students. AB - BACKGROUND: Substance abuse is one of the main health problems in Iran andawareness about its spread and procedure of spread in the society,particularly the susceptible society of students, is very important withregard to the population pyramid of Iran. METHODS: This study was performed by cross-sectional method. The sampling sizewas 610 male students in pre-university grade by a probabilistic clustersampling. Our research instrument was the WHO questionnaire. FINDINGS: The experience of smoking cigarettes was seen in 34.6% of thestudents, 51.5% used hookah, 37.7% drank alcohol, 40.7% used nonprescribedtranquilizers, 10.2% used high-dosage painkillers, 6.6% usedecstasy, 6.7% hashish, 4.9% heroin, 8.7% opium and 9.7% used Pam orchewable tobacco. The first age of experiencing smoking cigarette was 14.0, hookah 13.9,alcohol 14.6, tranquilizers 13.1, high dosage painkillers 15.3, ecstasy17.0, hashish 16.7, heroin 16.7, opium 16.7 and using chewable tobacco15.3 years. The improper use of ecstasy pills, opium, heroin andchewable tobacco was more in governmental schools compared withnon profit school centers. There was a relationship between the low educational level of the fatherand consuming alcohol, strong intoxicants, heroin, opium, pam andexcessive use of cigarettes. On the other hand, there was a relationship between the low educationallevel of the mother with using cigarettes, hookah, alcohol, tranquilizers,strong painkillers, ecstasy, heroin, opium, pam and excessive usage of cigarettes. CONCLUSION: According to this study, in spite of the fact that drug abuse is at awarning rate, the tendency toward hookah, tranquilizers and alcohol is noticeable. PMID- 24494110 TI - The study of substructures of addiction phenomena in high school students using problem finding workshops. AB - BACKGROUND: Addiction is one of the complicated problems in Iranian young population. The social and cultural dimensions of this social disease are less considered. So considering socio-cultural and environmental resources, this study investigated the substructures of addiction according to the viewpoints of high school students of Kerman, Iran in 2007-2008. METHODS: This qualitative study accomplished in ten high schools through a one-day problem finding workshop and continued until data saturation. The resulted terms and phrases were analyzed by content analysis. To assure about the validity and reliability, the outputs reviewed by workshops participants, and classification and codification of the data were executed separately by two experts. FINDINGS: A total of 212 students, 45.3% girls and 54.7% boys, participated in the study. The students introduced the followings as the addiction substantial fundaments: lack of knowledge, positive attitude and interpretation of addiction as a value, family or friends' habit, economy status, psycho-personality problems and availability. Rules infirmity or non-implementation of the current rules enforcement, geographical status and addiction as a conspiracy were also observed in students' statements. CONCLUSION: The positive attitudes and historical roots of addiction along with the process of changing the values caused the growth of drug addiction in young population which could neutralize the security measures, legislations policy and even the knowledge. Therefore, intensification of personal protective factors and culturalization addressed for improving inner layers of values are recommended. PMID- 24494111 TI - Attitude of University Students towards Waterpipe Smoking: Study in Iran. AB - BACKGROUND: Tobacco is consumed in various forms, and there has been an increasing trend worldwide in the use of waterpipe. This study aimed to assess the university students' attitudes towards waterpipe. METHODS: This was a cross sectional study; 1130 students randomly were selected from universities of Kerman, Iran. They were provided with a researcher-made questionnaire after obtaining the informed consent. The anonymous questionnaires were completed with ensuring about information confidentiality. In addition to the underlying questions, the questionnaires consisted of 10 attitude survey questions. Higher scores indicated more positive attitudes. FINDINGS: The obtained results indicated a significant difference of attitude of the students who were current or occasional smokers of waterpipe in comparison with the students who never smoked it towards addictiveness, social acceptance or rejection and its harmfulness; so that their attitudes were more positive (P < 0.05). Mean +/- SD of attitude score of the students who never consumed waterpipe before, those who had the history of consuming it at least once and those who were current smokers were 1.40 +/- 0.40, 1.50 +/- 0.41 and 1.70 +/- 0.43, respectively (P < 0.001). CONCLUSION: Waterpipe smoking was associated with false beliefs and positive attitudes among the students; therefore, the necessity of education and attitude changing is required in this regard. PMID- 24494112 TI - Comparison of Physical Fitness among Smoker and Non-Smoker Men. AB - BACKGROUND: It is well documented that cigarette smoking has negative impacts on body health, as well as social health, economy, culture, etc. Nowadays, there is a large body of evidence that smoking is the cause of numerous life-threatening diseases like cardiovascular and pulmonary diseases along with different kinds of cancer. The aim of this study was to compare the physical fitness of smokers and non smokers. METHODS: This cross-sectional study was conducted on 64 non sportsmen (34 non-smokers and 30 smokers) aging 19-27 years. Both groups were matched for age, weight, height and body mass index (BMI). The smokers used cigarettes at least 5 cigarettes a day for 2 years. None of them had a musculoskeletal disease. We used a questionnaire and physical fitness tests for data gathering. The tests were used to measure muscle strength, endurance, speed, agility and flexibility in both groups. FINDINGS: The muscle strength was significantly different in smokers and non-smokers (P = 0.012). Moreover, smokers had less agility (P = 0.004) and speed (P = 0.008) than non-smokers. However, although smokers were weaker than non- smokers, the differences in muscle endurance (P = 0.066) and flexibility (P = 0.095) were not the statistically significant. CONCLUSION: According to these results, the smokers were less powerful than nonsmokers. In addition, physical activity skills in young smokers were decreased. Therefore, smoking will cause a gradual loss of physical strength and active personal and social power. PMID- 24494113 TI - Determination and prioritizing of addiction prevention factors in delfan city, iran. AB - BACKGROUND: In recent decades, drug abuse has been one of the most important problems of human societies and has been imposing enormous charges to them. Exposing addicts to infectious diseases, social and economic harmful impacts, expensive and reversibility of treatment methods have caused that drug abuse prevention programs be more inexpensive and more effective than treatment. One of the most important methods of drug abuse prevention is identification and prioritization of them according to scientific methods. The purpose of this study was to investigate addiction prevention methods among adolescents and teenagers from the viewpoints of addicts, their parents, authorities and prioritizing the prevention methods based on analytical hierarchy process (AHP) model in Delfan city, Iran. METHODS: Statistical samples included 17 authorities, 42 addicts, and 23 parents that have been selected through purposive sampling. Data collection instruments involved structured and semi-structured interviews. Data were analyzed based on quantitative and qualitative methods, encoding and categorization. In this study, AHP model was used for prioritizing the prevention methods. This model is one of the most efficient and comprehensive designed techniques for multi-criteria decision making; it formulates the possibility of natural complex problems as hierarchy. FINDINGS: The results indicated that the most important methods of drug abuse prevention were using media, case studies, planning for leisure times, educating social skills, integrating drug prevention methods in religious customs and respect to teenagers. Among these factors, the media and respect to adolescents with weights 0.3321 and 0.2389 had the highest preferences for the prevention of drug addiction, respectively. Planning for leisure time with weight of 0.1349 had the lowest importance than media and teenager respectful factor and higher priority than religion customs, dating and learning lessons factors. On the contrary, integrating in religion customs, using case studies with weights 0.1145, 0.1114 and 0.0680 had the lowest preferences, respectively, and can be considered in later settings. CONCLUSION: The interviewees mentioned the most important addiction prevention methods in respect to teenagers, religious customs, media, dating skills, learning lessons from examples and attention to the leisure times among which the media has been the most efficient method. Because, publicity of the media as a national media is available to the public and it is not dedicated for a special group or class of people and everyone can use it regardless of his literacy and knowledge level. PMID- 24494114 TI - Experiences of drug dependent fathers in relation with their children: a qualitative study. AB - BACKGROUND: The effects of substance abusing on children of all ages has been considered. The major problem of these children is the inability of their parents to implement their parental tasks and duties. In Iran, addressing the issue of substance abuse has a history of several decades. Identifying the experiences of these individuals about relating to their children is important in effective therapeutic planning to help drug dependent people continue their treatment. METHODS: This qualitative study was conducted using phenomenological approach. Subjects were selected from among the referrals to the substance abuse treatment centers in Kerman. This study lasted for 11 months from October 2008 to August 2009 and tried to use purposive sampling to select the subjects with as much diversity as possible from the drug-dependent males who had at least one child. All those who had history of addiction less than two years were excluded. Thematic analysis was used to analyze the findings. FINDINGS: Participants were 35 opiate-dependent males. The mean age of subjects was 43.18 +/- 8.25. Five themes were extracted from analyzing the interviews including emotional relations, economical problems, experiences of communicating with children, the effects of substance abuse on children, and the role of children on the quitting process. CONCLUSION: To promote the quality of services offered to drug dependents who have decided to quit, family therapy and psychotherapy are recommended to help addicted individuals reduce the problems they have with their children. PMID- 24494115 TI - The Risk of Suicide according to Drug Abuse and Nicotine Dependence in Patients with War Injuries and Chronic Traumatic Stress Disorder. AB - BACKGROUND: The incidence of suicide is higher in individuals with post-traumatic stress disorder (PTSD) than the general population. This prevalence rate is related to many factors including drug dependence. This study was conducted in people wounded during the Iran-Iraq war with PTSD, in order to compare the risk of suicide in those with and without drug and nicotine dependence. METHODS: This cross-sectional study, conducted in 2007-2008, comprised 104 male individuals who had participated in the Iran-Iraq war and had a current diagnosis of PTSD. They had been referred to a psychiatry hospital and the psychiatrists' offices in Kerman, Iran. Three questionnaires were used including Davidson Trauma Scale, California Risk Estimator for Suicide and the Fagerstrom Test for Nicotine Dependence to assess the severity of PTSD, the risk of suicide, and nicotine dependence, respectively. Data were analyzed by descriptive and analytical statistics using chi-square, regression, analysis of variance (ANOVA), student-t and correlation tests. FINDINGS: The severity of PTSD was significantly different in individuals with low to moderate dependence on cigarette smoking than in those with heavy dependence on smoking (P = 0.002). However, the corresponding figures were not significantly different in individuals with and without substance abuse. Although the risk of suicide had no significant difference among individuals with low to moderate dependence on cigarettes compared to those with high nicotine dependence, it was higher in subjects with substance abuse than in those without it (P = 0.0001). CONCLUSION: Our findings suggest that dependence on cigarettes may not play a role in increasing the risk of suicide, whereas the dependence on opium and its derivatives may increase this risk. Therefore, prevention and treatment of drug abuse may be effective on the incidence of suicide in patients with war injuries and PTSD. PMID- 24494116 TI - The Relationship of Early Maladaptive Schemas, Attributional Styles and Learned Helplessness among Addicted and Non-Addicted Men. AB - BACKGROUND: Addiction is considered as one of the major problems in family and community in the world. According to cognitive view, organizing the experiences determines how to behave. Due to their importance in interpretation of special situations, cognitive schemas and attributional styles have a significant role in cognitive theories. The aim of this study was to compare early maladaptive schemas and attributional styles in addicts and non-addicts to recognize their role in addiction. METHODS: In this causal-comparative study, 200 addicted and non-addicted men were randomly selected. Young early maladaptive schema and attributional styles questionnaires were used. Data analysis was performed by independent t-test, Pearson correlation and regression. FINDINGS: The study population included 81 addicted and 90 non-addicted men. There were significant differences between early maladaptive schemas and attributional styles in the two groups of addicted and non-addicted men (P < 0.001). In addition, addicts had higher levels of learned helplessness. A direct relationship was found between learned helplessness and frequency of addiction treatments (r ? 0.234, P < 0.05). CONCLUSION: Our study showed that addicts suffer from high levels of early maladaptive schemas. They had a more pessimistic attributional style. Moreover, addicts who developed higher levels of learned helplessness were less successful in addiction treatment and more likely to use drugs again after treatment. These issues show that addiction institutions and therapists have to pay attention to cognitive factors for addiction prevention. PMID- 24494117 TI - Methadone treatment in Iranian opiate addicts: a preliminary report. AB - BACKGROUND: This study aimed to investigate the initial dosage of methadone and factors affecting it in maintenance therapy. METHODS: This cross-sectional, descriptive-analytic study was conducted on 157 individuals referring to a methadone maintenance therapy (MMT) clinic. The initial dosage of methadone was 20-45 mg which was adjusted during the treatment based on each patient's evaluation. Three groups were formed according to methadone dosage (less than 30 mg, between 30-50 mg, and more than 50 mg). FINDINGS: Significant relations were observed between increased methadone dosage in the initial phase and marital status (P = 0.03), injection (P = 0.03), medical comorbidity (P = 0.009), and borderline personality disorder (P < 0.001). CONCLUSION: Further studies with larger sample size and including the history of previous detoxification, substance abuse, omission of self-recording, evaluation of women's addiction and MMT program performance with counseling support should be performed. PMID- 24494118 TI - A Comparison between APGAR Scores and Birth Weight in Infants of Addicted and Non Addicted Mothers. AB - BACKGROUND: Addiction in pregnant women causes complications such as abortion, asphyxia and cerebral and physical problems. APGAR score assesses vital signs and birth weight and represents the physical and brain growth of newborns. In this study, the effects of opium addiction in mothers on birth weight and APGAR scores of neonates were discussed. METHODS: This study analytic, descriptive study was conducted on 49 pregnant women addicted to oral consumption of opium (0.5-0.8 grams daily) and 49 non-addicted women who referred to Afzalipour Hospital associated with Kerman University of Medical Sciences. Information including various personal characteristics, history of addiction and drug consumption, and the possibility of taking other drugs was collected by a researcher and recorded confidentially in a checklist. Birth weight and APGAR score t first, fifth and tenth minutes were also recorded. Statistical analysis was performed using Pearson correlation test, independent t-test, and repeated measure to evaluate the APGAR scores and other characteristics of the two groups of infants. FINDINGS: Average birth weight of infants with addicted mothers was 2255 grams which had a significant difference with infants born by non-addicted mothers (P < 0.0001). Average APGAR scores at the first minute were 7.6 +/- 1.1 and 8.6 +/- 1.1 among infants from addicted and non-addicted mothers, respectively. Average APGAR scores over time (at minutes 1, 5 and 10) had a significant difference (P < 0.0001) where an ascending trend was seen. This difference was significant in both groups (P = 0.003). CONCLUSION: Drug addiction in mothers decreases the APGAR score and birth weight of infants. PMID- 24494119 TI - Comparing the Effectiveness of Behavioral Recognition and Group Stress Surmounting Techniques Instructions on Changing University Students' Positive Attitudes towards Opiate Abuse. AB - BACKGROUND: One of the most important strategies in preventing addiction is changing positive attitudes and stabilizing negative attitudes towards opiate abuse. Current research has been comparing the effectiveness of behavioral recognition and stress surmounting techniques instructions on changing students' positive attitudes towards opiate abuse. METHODS: To determine the effectiveness of behavioral-recognition and group stress surmounting instructions on changing student's positive attitudes towards opiate abuse, 90 students (45 boys and 45 girls) who had got good grades in attitude measuring questionnaire were chosen and were randomly assigned in 3 groups (two test groups and the control group) and then, were randomly replaced in 15 person groups with sex distinction. The research data were analyzed using multivariate statistical analysis method. FINDINGS: The results of pot-test analyses showed significant improvement compared with pretest analysis in both training methods and in both genders (P < 0.05). Then, the surmounting methods group training and recognition-behavioral group training both significantly improved positive attitudes towards opiate abuse in male and female students. CONCLUSION: Behavioral-recognition and stress surmounting techniques instructions brought about changes in students attitudes towards opiate abuse and these changes were more prominent in female students than in males. PMID- 24494120 TI - Economic appraisal of urine opiates screening test: a study in kerman, iran. AB - BACKGROUND: Cost effectiveness, the ratio of relative costs of a program to its desired outcomes, is one of the basic issues in various screening programs performed to detect opium abuse. This study aimed to find the cost-effectiveness of opiates abuse screening through urine analysis. METHODS: A total number of 64698 individuals were selected and divided into to five distinct groups based on the reason for which they were tested. Cost-effectiveness of opiates abuse screening in each group was calculated by dividing the total cost, including personnel and overhead costs, to the number of detected cases. Finally, the results were compared. FINDINGS: The total number of positive cases based on rapid screening assay (RSA) and thin layer chromatography (TLC) was 3460 (5.3%). According to incremental cost-effectiveness analysis, screening program of the group referred by the police was the most cost-effective program with the breakeven point at 2%. CONCLUSION: According to the obtained results, continuation of drug abuse screening programs is recommended. PMID- 24494121 TI - Internet addiction based on personality characteristics of high school students in kerman, iran. AB - BACKGROUND: The new phenomenon of Internet addiction among teenagers and young adults is one of the modern addictions in industrial and post-industrial societies. The purpose of this research was to predict the Internet addiction based on the personality characteristics of high school students in Kerman. METHODS: This research was a descriptive correlational study. The statistical population included 538 male and female students in the second grade of high school in Kerman during 2010. The subjects were randomly selected by multistage clustering. Data was collected by two questionnaires including the five-factor Revised NEO Personality Inventory and the Internet dependency questionnaire. The data was analyzed using ANOVA test and multivariable regression analysis. FINDINGS: The findings showed a significant relationship between the personality trait of emotional stability and academic fields, i.e. students with higher emotional stability experience less negative emotions when confronting with problems. Therefore, it is less likely for them to alleviate the negative emotions by the extreme and obsessed usage of the Internet. In addition, it appears that the students with high extroversion scores prefer social, face to face interactions with other people to interaction with the virtual world. Conversely, more introvert students avoid interactions with other people due to their shyness. Thus, they communicate with the virtual world more. CONCLUSION: Three personality traits of loyalty, emotional stability, and extroversion are the most significant predictors of Internet addiction in high school students. PMID- 24494123 TI - The Relationship of Decision-Making Styles and Attributional Styles in Addicted and Non-addicted Men. AB - BACKGROUND: One of social problems which has affected our society and resulted in problems for different groups of people is drug abuse. This issue indicates a serious psychological, physical and social problem in community. Social skills have positive and successful influences in prevention of substance abuse. This includes the ability to explain events correctly and then appropriate decision making. This study compares decision making styles and attributional styles between addicted and non addicted men to recognize their role in addiction. METHODS: In this study, 200 addicted and non addicted men were randomly selected. Decision-making style and attributional style questionnaires were used. Data analysis was performed by independent Student's t and Pearson correlation tests. FINDINGS: The study population included 81 addicted and 90 non-addicted men. Addicted and non addicted men were significantly different in rational decision making style (P < 0.05). Negative relationship was found between rational decision making and optimistic attribution style (r = -0.305, P < 0.01) and direct relationship was found between rational decision making and learned helplessness (r = 0.309, P < 0.01). CONCLUSION: Our study showed that addicts are less rational in decision making and addicts that developed learned helplessness were less rational and did not have optimistic attribution style. These issues show that addiction institutions and therapists have to pay attention to cognitive factors for addiction prevention. PMID- 24494122 TI - The Relationship between Childhood Maltreatment and Opiate Dependency in Adolescence and Middle Age. AB - BACKGROUND: Child maltreatment is a global phenomenon with possible serious long term consequences. The present study aimed to determine the relationship between childhood maltreatment and opiate dependency in older age. METHODS: In this study, 212 opiate dependent individuals and 216 control subjects were selected consecutively. The data collection instrument was a questionnaire which consisted of background variables, General Health Questionnaire-12 (GHQ-12), and Childhood Trauma Questionnaire (CTQ). The questionnaires were anonymously completed by both groups in a private environment after obtaining informed consents. FINDINGS: The mean age in the addicts and non-addicts were 31.4 +/- 6.7 and 30.8 +/- 7.5, respectively (P = 0.367). Moreover, 84.4% of the opiate abusers and 76.9% percent of the control group were male (P = 0.051). The mean score of CTQ in the study and control groups were 47.2 +/- 1.0 and 35.8 +/- 0.6, respectively (P < 0.001). The frequency of all types of abuse and neglect were higher in the addicted group. While 70.3% of the study group reported at least one type of childhood maltreatment, this figure was as low as 33.8% in the control group (P < 0.001). After adjusting the two groups for differing background characteristics and the GHQ-12 score, emotional abuse (OR = 5.06), physical neglect (OR = 1.96), and sexual abuse (OR = 1.89) were proved to have significant relationships with addiction to opiates. CONCLUSION: The frequency of all types of childhood maltreatment in the group addicted to opiates was higher than the control group. Emotional abuse, physical neglect, and sexual abuse had significant effects after adjusting other variables. PMID- 24494124 TI - Reviewing the prevalence of (cigarette) smoking and its related factors in students of tehran university, iran. AB - BACKGROUND: This study aimed to determine the prevalence of smoking behaviors among students in Tehran University, Iran. METHODS: This was a cross-sectional study on 400 participants of Tehran University. A self-administrated, anonymous questionnaire was used for data gathering. FINDINGS: The mean age of students was 21.70 +/- 2.73 years, and 92% of them were single. The prevalence of smoking was 27.3% including 35.4% of men and 12.6% of women (P < 0.001). The mean duration of smoking was 4.22 +/- 3.05 years. There was a significant association between smoking behaviors among students and their age, gender, type of accommodation, field of study, income status, duration of study, and existence of smoking habits among family members. CONCLUSION: The prevalence of cigarette smoking among university students is high. The lack of adequate information about smoking related diseases indicates the incapability and inefficiency of educational programs on this issue. PMID- 24494125 TI - The Relationship between Mental Health and General Self-Efficacy Beliefs, Coping Strategies and Locus of Control in Male Drug Abusers. AB - BACKGROUND: Various studies have been conducted to determine the causes of drug abuse from a psychological perspective. Mental health has also been among the studied factors. The present study aimed to investigate the relationship between mental health and general self-efficacy beliefs, coping strategies and locus of control in male drug abusers. METHODS: This was a correlational descriptive study involving all male drug abusers (4,493 cases) at self-introducing detoxification centers in Kerman, Iran, during 2010-11. A total number of 354 patients were selected randomly with cluster sampling. Measurement tools were included Goldberg's General Health Questionnaire (GHQ-28), Generalized Self-Efficacy Scale (GSE-10), Coping Responses Inventory (CSI), and Internal-External Locus of Control Scale (I-E). The survey data were analyzed by SPSS using Pearson correlation and stepwise regression. FINDINGS: There were significant correlations between mental health and self-efficacy beliefs (r = -0.626), problem-oriented coping strategy (r = -0.535), emotion-oriented coping strategy (r = 0.573), external locus of control (r = -0.298), and internal locus of control (r = -0.525) (P < 0.01 for all). The results of the regression analysis showed that 58.7 percent of total variance of mental health can be estimated by general self-efficacy beliefs, coping strategies and locus of control. CONCLUSION: In general, the results showed that increased levels of general self efficacy, problem-oriented coping strategy and internal locus of control will improve mental health. In contrast, decreased general self-efficacy, emotion oriented coping strategy and external locus of control would lead to decreased mental health. PMID- 24494126 TI - The Role of Self-esteem in Tendency towards Drugs, Theft and Prostitution. AB - BACKGROUND: Addiction, theft and Prostitution are of the most important problems of contemporary society. On the other hand, self-esteem is one of the most important variables and concepts that might have a meaningful influence on these problems. This study aims to investigate the role of self-esteem in the individuals' tendency to addiction, theft and prostitution in Kerman city, Iran. METHODS: The statistical population of this study is those individuals who had a record of addiction, theft and prostitution in Kerman prison, and the ordinary individuals. The research sample consisted of 300 individuals, 200 of whom were those with record of addiction, theft and prostitution in the central prison of Kerman city, and 100 ordinary people. Because some of the research questionnaires were not returned, only 283 questionnaires were analyzed. The instrument for determining the respondents' self-esteem was Eysenck Self-esteem Inventory. FINDINGS: Self-esteem had a meaningful role in the individual's tendency to addiction, theft and prostitution. CONCLUSION: On the basis of the research results, it can be concluded that those who are involved in addiction, theft and prostitution have a lower self-esteem compared with the ordinary person. Thus, it is necessary to increase an individual's self-esteem in order to decrease their tendency to addiction, theft and prostitution. PMID- 24494127 TI - The prevalence of musculoskeletal pain in male cigarette smoking students at shiraz university of medical sciences, iran. AB - BACKGROUND: The rising trend of smoking cigarettes, especially among the youth, has become a great concern in Iranian society. Not only does smoking cigarettes harm one financially, but also it will cause immense damage to the smoker as well as the society. This paper investigated the prevalence of musculoskeletal pain and the factors affecting it in young smokers. METHODS: The research has been conducted on 400 men smokers aged 18-30 studying at Shiraz University of Medical Sciences. Data was collected through a questionnaire containing information about age, history and amount of smoking, existence of pain and its severity according to the visual analog scale (VAS). The subjects were randomly selected while making sure the proportion of subjects from each department was appropriate. The subjects were smokers for more than two years and smoked more than five cigarettes a day. Data was analyzed by analysis of variance (ANOVA) and the least significant difference (LSD) test. FINDINGS: Among all studied subjects, 129 (32.25%) suffered from musculoskeletal pain. Most of the subjects (31.25%) had pain in their backs. The relationship between the duration of smoking and musculoskeletal pain, as well as that between the number of cigarettes smoked per day and the pain, was direct and significant. However, no significant relationship was found between age and pain. CONCLUSION: The occurrence of musculoskeletal pain in male students was relatively high. This fact can bring irrecoverable damages to the society and would put its health at risk. It also decreases the socioeconomic improvements. PMID- 24494128 TI - The Correlation between Emotional Intelligence and Instable Personality in Substance Abusers. AB - BACKGROUND: Substance dependence has recently turned into one of the most important social problems. Clinical findings have shown personality traits, social relations, attitudes and values, along with emotional intelligence factors such as emotions, feelings, emotions management, challenging with problems, problem solving, tolerating psychological pressure, impulse control, self esteem and interpersonal relations, to affect substance dependence. Consequently, understanding the meaning and developing tools for assessment of emotional intelligence are significantly vital in human psychological health. This study aimed to investigate the relation between emotional intelligence and instable personality in substance abusers. METHODS: The present correlational study selected 80 male addicts through available sampling. The subjects referred to the Therapeutic Community Center and Kimia, Yas, and Aban Clinics in Yazd, Iran. Their emotional intelligence and personality were evaluated by BarOn questionnaire and Eysenck personality questionnaire (EPQ) for adults, respectively. Pearson's correlation coefficient was used to assess the correlations between different factors. FINDINGS: There was a negative significant correlation (P = 0.050) between emotional intelligence and instable personality in substance abusers. Problem solving and optimism (P = 0.001), interpersonal relation (P = 0.010), self esteem (P = 0.013), and realities (P = 0.017) had significant effects on instable personality. CONCLUSION: Based on our findings, emotional intelligence was significantly correlated with instable personality in substance abusers. However, using more accurate tools in order to assess all aspects of personality can give better results. PMID- 24494130 TI - The Correlation between Methadone Dosage and Comorbid Psychiatric Disorders in Patients on Methadone Maintenance Treatment. AB - BACKGROUND: Methadone Maintenance Treatment is a useful method for opioid dependents, which results in harm reduction and increased quality of life in opioid dependents. The prevalence of psychiatric disorders in addicts is higher than in the general population which can interfere with the course and treatment of substance dependents and decrease the efficacy of treatment. METHODS: This descriptive, cross-sectional study was aimed to determine the correlation between psychiatric disorders and methadone dosage. It was performed on 154 patients of Kerman Shahid Beheshti Hospital's Methadone Clinic during a six month period from Dec 2010 to Jul 2011. The study population was chosen by convenience sampling. The searching tools were Socio-Demographic Questionnaire, psychiatric structured interview based on DSM-IV-TR, Beck Depression Inventory, Young Mania Rating Scales, and Anxiety and Depression Rating Scales. FINDINGS: Significant correlations were observed between increased methadone dosage and antisocial personality disorder. In addition, significant positive correlations were observed between increased methadone dosage and Hamilton anxiety scores, Hamilton depression scores and Young Mania scores. CONCLUSION: High methadone dosage may be a marker of coexisting psychiatric disorders in patients on methadone maintenance treatment which indicates the necessity of devoting further attention to this group. Psychiatric services should be open and accessible to the patients, especially those who seek treatment voluntarily. Early diagnosis and treatment of patients with coexisting psychiatric disorders may increase the efficacy of methadone maintenance treatment. PMID- 24494129 TI - Chemistry, pharmacology, and toxicology of khat (catha edulis forsk): a review. AB - Catha edulis (khat) is a plant grown commonly in the horn of Africa. The leaves of khat are chewed by the people for its stimulant action. Its young buds and tender leaves are chewed to attain a state of euphoria and stimulation. Khat is an evergreen shrub, which is cultivated as a bush or small tree. The leaves have an aromatic odor. The taste is astringent and slightly sweet. The plant is seedless and hardy, growing in a variety of climates and soils. Many different compounds are found in khat including alkaloids, terpenoids, flavonoids, sterols, glycosides, tannins, amino acids, vitamins and minerals. The phenylalkylamines and the cathedulins are the major alkaloids which are structurally related to amphetamine. The major effects of khat include those on the gastro-intestinal system and on the nervous system. Constipation, urine retention and acute cardiovascular effects may be regarded as autonomic (peripheral) nervous system effects; increased alertness, dependence, tolerance and psychiatric symptoms as effects on the central nervous system. The main toxic effects include increased blood pressure, tachycardia, insomnia, anorexia, constipation, general malaise, irritability, migraine and impaired sexual potency in men. Databases such as Pubmed, Medline, Hinary, Google search, Cochrane and Embase were systematically searched for literature on the different aspects of khat to summarize chemistry, pharmacology, toxicology of khat (Catha edulis Forsk). PMID- 24494131 TI - Destructive Effects of Prenatal WIN 55212-2 Exposure on Central Nervous System of Neonatal Rats. AB - BACKGROUND: Cannabinoid, particularly hashish and WIN 55212-2 (WIN), consumption during embryonic period may affect fetal growth, and the development of motor functioning, memory and cognitive functions. Therefore, the present study aimed to evaluate the effects of WIN 55212-2 during embryonic period on behavioral responses, as well as tissue and memory changes among neonatal rats. METHODS: WIN treated groups subcutaneously received daily doses of 0.5 or 1 mg/kg WIN suspended in 1% Tween-80-saline (1 ml/kg) from days 5 to 20 of pregnancy. The vehicle group received 1% Tween-80-saline from days 5 to 20 of pregnancy. Three, five and seven weeks after birth, the effects of maternal WIN consumption on infants' body weight, mortality, histological changes, motor functioning, and memory function were assessed. FINDINGS: Prenatal WIN consumption was associated with atrophy of cerebellum cortex in granular and Purkinje cells layers. WIN treatment of pregnant rats produced a significant decrease in the rearing frequency of the offspring, but significantly increased the grooming frequency at 22, 36 and 50 days of age. During the acquisition trials, approach latencies were not significantly different between all groups of rats (50 days old). When the trial was repeated 24 hours and seven days later (retention trial), the avoidance latencies of the WIN-exposed group were significantly shorter than those of the control and vehicle animals. The mortality percent was increased significantly and litter size was decreased significantly in WIN (1 mg/kg) treated rats compared to the control, vehicle and WIN (0.5 mg/kg) treatment groups. CONCLUSION: These findings suggested that prenatal exposure to WIN probably induces long-term alterations in histological, motor functioning, and learning and memory parameters. PMID- 24494132 TI - Evaluation of the effectiveness of chemical dependency counseling course based on patrick and partners. AB - BACKGROUND: The twelve step program is one of the programs that are administered for overcoming abuse of drugs. In this study, the effectiveness of chemical dependency counseling course was investigated using a hybrid model. METHODS: In a survey with sample size of 243, participants were selected using stratified random sampling method. A questionnaire was used for collecting data and one sample t-test employed for data analysis. FINDINGS: Chemical dependency counseling courses was effective from the point of view of graduates, chiefs of rehabilitation centers, rescuers and their families and ultimately managers of rebirth society, but it was not effective from the point of view of professors and lecturers. The last group evaluated the effectiveness of chemical dependency counseling courses only in performance level. CONCLUSION: It seems that the chemical dependency counseling courses had appropriate effectiveness and led to change in attitudes, increase awareness, knowledge and experience combination and ultimately increased the efficiency of counseling. PMID- 24494133 TI - Nicotine content of domestic cigarettes, imported cigarettes and pipe tobacco in iran. AB - BACKGROUND: There are many different kinds of cigarettes and tobacco available in the market. Since nicotine content of various brands of cigarettes are very variable, therefore evaluation and comparison of nicotine content of different brands of cigarettes is important. The goal of the present study was to determine and compare nicotine content of various domestic and imported cigarettes available in the area. METHODS: Fourteen popular imported brands and nine popular domestic brands of cigarettes and three available brands of tobaccos were investigated for the amounts of nicotine content. Nicotine was extracted from each cigarette and tobacco samples and was analyzed by high performance liquid chromatography (HPLC) method. FINDINGS: The amount of nicotine in each cigarette was from 6.17 to 12.65 mg (1.23 +/- 0.15 percent of tobacco weight in each cigarette) in domestic cigarettes. It was between 7.17-28.86 mg (1.80 +/- 0.25 percent of tobacco weight in each cigarette) for imported cigarette, and between 30.08- 50.89 mg (3.82 +/- 1.11 percent) for the pipe nicotine. There was significant difference in nicotine amount between imported and domestic brands of cigarettes. There was also no significant difference in nicotine content between light and normal cigarettes in imported brands. CONCLUSION: Nicotine content of all tested cigarettes, imported and domestic brands, were higher than the international standard. PMID- 24494134 TI - Comparison of Mental Health, Aggression and Hopefulness between Student Drug Users and Healthy Students (A Study in Iran). AB - BACKGROUND: Addiction is a social problem and a destructive phenomenon; like other social diversions, addiction destroys the country's most valuable assets, which are obviously the youth and the adolescents. In this regard, this study has been performed with the aim of comparing the mental health, aggression, and hopefulness of student drug-users and healthy students. METHODS: The study has been performed by descriptive-analytical method among students of Kerman's universities in Iran. The study sample contained 520 people who were selected using a stratified random sampling method. Three questionnaires including General Health Questionnaire (GHQ-28), Buss-Perry Aggression Questionnaire (BPAQ) and Miller Hopefulness questionnaire have been used for data gathering. In this study, the student drug-users are those who use a substance (cigarettes, hookah, alcohol, opium, etc.) at least once a week. FINDINGS: Findings showed that out of the 520 people under-study, 34.62% (180 people) are drug users, by whom the percentages of different substances used are as following: Hookah: 38.33%; Cigarettes: 28.35%; Alcohol: 20.55%; Opium: 5.55%; Cannabis: 2.23%; Heroin: 1.12%; Crack: 0.55%; Glass: 1.66 % and Psychotropic Pills and Ecstasy: 1.66%. A significant difference was observed in comparing the mental health, aggression, and hopefulness of student drug-users and healthy students (P < 0.05), so that the student drug-users had lower mental health and hopefulness and showed more aggression than the healthy group. CONCLUSION: Substance abuse endangers the mental health of people and drug-users show more aggression and are less hopeful. PMID- 24494135 TI - Suicide in narcotic drugs dependents. AB - BACKGROUND: The problem of addiction is one of the four global crises. These patients are more vulnerable to mental disorders. This study aimed to examine the risk of suicide in drug dependent patients. METHODS: In this cross-sectional study, patients who referred for addiction treatment were selected and the control group was chosen among their companions who did not have narcotic drugs dependence. Suicide risk was assessed through California Suicide Risk Assessment Questionnaire. Beck's Depression Inventory questionnaire was used to assess the depression level. FINDINGS: The comparison of average education (P < 0.01) and the unemployment rate (P = 0.03) and previous attempted suicide (P = 0.01) between the narcotic drug dependent group and control group showed a statistically significant difference. Suicide risk score (P < 0.01) and depression score (P < 0.01) differences were statistically significant. The average scores of depression score in addicts was significantly associated with their previous attempted suicide (P = 0.01). In the control group, there was a significant association in suicide score and depression score with their previous attempted suicide (P < 0.01). Suicide score were compared based on the depression degree in both groups and statistically significant differences were found (P < 0.01). CONCLUSION: The suicide risk and depression in drug addicts are more than general population and they are closely related to each other. PMID- 24494136 TI - The Mediating Role of Metacognition in the Relationship between Internet Addiction and General Health. AB - BACKGROUND: Internet addiction is one of the harmful effects of the Internet. The findings of several studies have indicated a relationship between general health and Internet addiction. Metacognition, which includes the knowledge, processes, and strategies to evaluate, and monitor or control the cognition, can play a significant role in this regard. The present research aimed to assess the mediating role of metacognitive variables in the relationship between Internet addiction and general health. METHODS: This correlational study included 94 male and female users with different nationalities at Internet cafes in Abu Dhabi (the United Arab Emirates). All subjects aged at least 18 years and were proficient in English. The research tools included the General Health Questionnaire (with a reliability of 0.89), Metacognition Questionnaire (with a reliability of 0.82), and Kimberly Young's Internet Addiction Test (with a reliability of 0.88). The hypothesis was tested applying SPSS18 and Amos18. FINDINGS: The results indicated a significant positive relationship between all aspects of metacognition and Internet addiction (r = 0.30; P < 0.01). A significant positive relationship was also observed between Internet addiction and general health (r = 0.47; P < 0.01). Path analysis revealed the mediating role of metacognition in the relationship between low general health and Internet addiction. Among the metacognitive variables, the mind control had the highest correlation coefficient (r = 0.80). CONCLUSION: The internet and digital technologies have caused unwanted and negative effects which are classified as emerging damages. The relationship between Internet addiction and general health has been confirmed in this research. In addition, metacognitive processes can have a positive and mediating role on this relationship. PMID- 24494137 TI - Studying prevalence and pattern of taking narcotic and ecstasy drugs by patients admitted to special care centers of shahid bahonar hospital, kerman, iran. AB - BACKGROUND: Addiction is the repeated use of a chemical substance which affects the biological function of the brain and endangers physical health of the addicted person. Prevalence and pattern of taking drugs were assessed in the current study in a Special Cares Trauma Center. So the specialized physician could manage the medical procedure more easily through identification of addicted patients and type of their narcotics. METHODS: This cross-sectional study was conducted on 545 patients admitted to the Special Cares Center of Shahid Bahonar Hospital, Kerman, Iran, during 2010-2012. The data were collected by special information collection forms and then analyzed using SPSS software. FINDINGS: Among the total studied samples, around 55% of admitted patients were addicts. Opium was the most frequently used narcotic among the addicted patients with a percentage of 62%. Smoking was the most common method of taking the narcotics. 90% of addicted persons were male and 95% of them held diploma and under-diploma educational degrees. Among the reasons for admission of addicted patients to the Special Cares Clinic of Trauma Center, head trauma was the dominant cause (51%). CONCLUSION: Addiction is considerably more prevalent among the population admitted to the Special Cares Center compared to the society, indicating greater vulnerability of addicted individuals in the society. Addiction to traditional and indigenous drugs are still the most prevalent, and fortunately, these drugs are easier to substitute and medicate compared to the new industrial narcotics. PMID- 24494138 TI - The relationship of metacognitive beliefs and tendency to addiction in sistan and baluchistan university, zahedan, iran. AB - BACKGROUND: The aim of this study was to examine the relationship between metacognitive beliefs and the tendency to addiction in the students of the University of Sistan and Baluchistan, located in the South-East of Iran, during the academic year of 2009-2010. METHODS: This was a descriptive, correlational study, and the statistical samples were 200 male BSc students selected with cluster random sampling procedures from the three schools of Literature, Science, and Engineering. The measuring tools were the metacognition Questionnaire-30 (MCQ 30), and Addiction Potential Scale. Data analysis was done by the SPSS software using the Pearson correlation coefficient, and multiple regressions. FINDINGS: The result of data analysis showed that metacognitive beliefs and their subscales had a significant negative relationship with the tendency toward addiction (P < 0.01). The results show that fewer metacognitive characteristics are associated with a high tendency to addiction. CONCLUSION: The findings of this study indicate that disturbed metacognitive beliefs is a good predictor of students tendency to addiction, therefore, teaching strategies metacognition is important in the prevention of young people's Tendency toward- addiction. PMID- 24494139 TI - Opium dependency in recurrent painful renal lithiasis colic. AB - BACKGROUND: The main goal of this study is to determine the relationship between opium dependency and frequency of urolithiasis renal colics. METHODS: In a cross sectional study we compared opium dependency in urolithiasis patients (case group) with non-urolithiasis patients (control group) and assessed urolithiasis related renal colics as risk factor to opium dependency prevalence. Dependency was defined as the diagnostic criteria specified in DSM-IV questionnaire and Urolithiasis was diagnosed by standard methods (imaging modalities as US, X-Ray). FINDINGS: From 450 urolithiasis adult patients (120 female and 370 male with the age range of 18-67 years) 157 (34.88%) were opium addicts, however from the 340 non-urolithiasis patients (matched age group and gender ratios) only16 (4.70%) were opium addicts (P < 0.001). 56.68% of urolithiasis patients (who had a history of more than 15 renal colics (related to stone forming frequencies) were addicts for more than 10 years (P < 0.05). A strong positive correlation between the duration of dependency and renal colic rate was detected in these patients (P < 0.001, r = 0.999). CONCLUSION: This study showed that the risk of opium dependency is higher among urolithiasis patients. Moreover, there was a relation between urolithiasis frequencies (renal colics) and the duration of dependency. Other factors such as severity of pain, perception and faith of patients in the therapeutic effects of opium or local availability of opium were also effective in opium dependency. PMID- 24494140 TI - Comparison of the efficacy of buprenorphine and clonidine in detoxification of opioid-dependents. AB - BACKGROUND: Since the number of drug users is increasing, applying a method of detoxification with fewer side effects during withdrawal from opioids and greater reliability seems to be necessary. In addition, without maintenance treatment, there will be limited success of treatment. This study aimed to compare success rates of detoxification with sublingual buprenorphine and clonidine and to evaluate addiction relapse in patients using naltrexone in a six-month follow-up. METHODS: This double-blind trial was carried out on opioid dependent patients in a psychiatric hospital in Kerman (Iran) during 2007-09. The subjects were randomly selected from individuals who had referred for detoxification. They were allocated to two groups to receive either clonidine (n = 21) or buprenorphine (n = 14). The success rates of the two methods were assessed at the end of the course and patients were discharged while prescribed with 25 mg daily use of naltrexone. They were followed up for six months and the continuous use of naltrexone and relapse of substance abuse were evaluated. FINDINGS: A total number of 35 patients entered the study. Success of detoxification with naltrexone was confirmed in all cases. One person (8.4%) in the clonidine group and no patient in the buprenorphine group had a clinical opiate withdrawal scale (COWS) score of more than 12 (P > 0.05). The mean levels of objective signs and subjective symptoms of withdrawal and the desire for drug abuse had significant reductions during detoxification period in both groups (P < 0.001). However, the difference in these variables between the two groups was not statistically significant (P > 0.05). Naltrexone was used for an average of one month in 43% and 64% of subjects in the clonidine and buprenorphine groups, respectively. In addition, 62% of patients in the clonidine group and 92.8% of subjects in the buprenorphine group received maintenance treatment. Nevertheless, the mean number of days staying in treatment was not significantly difference between the two groups (P > 0.05). CONCLUSION: Buprenorphine is as effective as clonidine in controlling withdrawal symptoms. A greater percentage of patients detoxified by buprenorphine received maintenance treatment, but there was not a significant difference in relapse rates between the two methods. PMID- 24494141 TI - The prevalence of problematic internet use and the related factors in medical students, kerman, iran. AB - BACKGROUND: Although problematic Internet use (PIU) is a growing problem among adolescents, few studies have examined its prevalence among university students in Iran. This study was designed to investigate the prevalence of PIU and its potential risk factors among students at Kerman University of Medical Sciences, Kerman, Iran. METHODS: In a cross-sectional study, data was collected from 976 university students. PIU was assessed by the 18-item Problematic Internet Use Questionnaire. In addition, information on demographics and Internet usage pattern was also collected. FINDINGS: A total of 920 students completed the survey (response rate = 94.8%). Of them, 98% were Internet users. Overall, 21% of the students were identified as problematic Internet users. Logistic regression analysis showed that spending more time online, having a history of psychiatric disorders, and using the Internet for chatting and playing games were risk factors for PIU. CONCLUSION: PIU is a common problem among university students. These results suggest the need for preventive and interventional strategies for this vulnerable group. PMID- 24494142 TI - Comparison of Duration of Spinal Anesthesia with Lidocaine or Lidocaine plus Epinephrine between Addicts and Non-addicts. AB - BACKGROUND: Duration of spinal anesthesia depends on the type of anesthetic agent, dosage and additive materials such as epinephrine, ephedrine and opioid. We compared the duration of spinal anesthesia with lidocaine 5% with or without epinephrine in addict and non-addict patients undergoing inferior limb fracture surgery. METHODS: This single blinded randomized clinical trial was performed on 201 males (height ranged 150-180 cm) who referred to the Shahid Bahonar Hospital of Kerman for the inferior limb fracture. Their physical class was matched to the American association standard class 1 and 2, and they were appropriate candidates for the spinal anesthesia. The addict or non-addict groups were each divided into two subgroups. 75 mg of 5% lidocaine was prescribed for one subgroup, and the other subgroup received 75 mg of 5% lidocaine plus 0.2 mg epinephrine. The level of primary anesthesia was elevated to T6. Duration of returning to the 4 primary sensory levels was measured since baseline. FINDINGS: A significant increase in the duration of anesthesia level in both addict and non-addict patients receiving lidocaine plus epinephrine was observed compared to the subgroups receiving lidocaine alone (P < 0.01). Duration of decrease in sensory level in addict subgroups receiving lidocaine or lidocaine plus epinephrine was lower compared to non-addict patients (P < 0.001). In addict subgroup receiving lidocaine alone, a significant decrease was observed in the time needed for decrease in sensory level (P < 0.01). CONCLUSION: According to the results of this study, regardless of the anesthetic agent being used, duration of spinal anesthesia was shorter in addict patients compared to non-addict ones. Addition of epinephrine to lidocaine 5% increased the duration of spinal anesthesia in both addict and non-addict patients. PMID- 24494143 TI - Impacts of mothers' occupation status and parenting styles on levels of self control, addiction to computer games, and educational progress of adolescents. AB - BACKGROUND: Addiction to computer (video) games in adolescents and its relationship with educational progress has recently attracted the attention of rearing and education experts as well as organizations and institutes involved in physical and mental health. The current research attempted to propose a structural model of the relationships between parenting styles, mothers' occupation status, and addiction to computer games, self-control, and educational progress of secondary school students. METHODS: Using multistage cluster random sampling, 500 female and male secondary school students in Kerman (Iran) were selected and studied. The research tools included self-control, parenting styles, and addiction to computer games questionnaires and a self-made questionnaire containing demographic details. The data was analyzed using exploratory factor analysis, Cronbach's alpha coefficient and route analysis (in LISREL). FINDINGS: We found self-control to have a linking role in the relationship between four parenting styles and educational progress. Mothers' occupation status was directly and significantly correlated with addiction to computer games. Although four parenting styles directly and significantly affected addiction to computer games, the findings did not support the linking role of addiction to computer games in the relationship between four parenting styles and educational progress. CONCLUSION: In agreement with previous studies, the current research reflected the impact of four parenting styles on self-control, addiction to computer games, and educational progress of students. Among the parenting styles, authoritative style can affect the severity of addiction to computer games through self-control development. It can thus indirectly influence the educational progress of students. Parents are recommended to use authoritative parenting style to help both self-management and psychological health of their children. The employed mothers are also recommended to have more supervision and control on the degree and type of computer games selected by their children. PMID- 24494144 TI - Effects of methadone on liver enzymes in patients undergoing methadone maintenance treatment. AB - BACKGROUND: Methadone is currently the most frequently used substance in the treatment of short-term and particularly long-term opiate dependence. Patients' beliefs about the adverse effects of methadone on function of organs, especially liver, have widely affected the use of this substance. This study aimed to determine the effects of methadone on liver enzyme levels in patients on methadone maintenance treatment. METHODS: In a retrospective study, a total of 94 patients undergoing methadone maintenance therapy were recruited from Shahid Beheshti Hospital (Kerman, Iran). Liver enzyme levels in all patients were tested every six months from the onset of treatment until 24 months. The relations between test results and age, gender, and methadone dose were then evaluated. Data was analyzed using logistic regression with random data plan. FINDINGS: At the 24th month, alanine aminotransferase (ALT) levels in 4 patients (4.3%) and aspartate aminotransferase (AST) levels in 3 patients (3.2%) were above normal. Among 46 patients (50%) who had normal alkaline phosphatase (ALP) levels after 24 months, 26 subjects were younger than 40 and 20 subjects were over 40 years of age. The mean age of subjects with abnormal ALP levels and the mean methadone dose were 39.9 years and 19.55 cc, respectively. CONCLUSION: The results of this study indicated the significant effect of methadone on ALP levels. These effects can account for cholestatic pattern liver injury (obstruction). Further prospective studies including greater samples of patients with heart and liver complications and encompassing other drugs are required to confirm our findings. PMID- 24494145 TI - Comparison of total hip arthroplasty and core decompression in avascular necrosis of the femoral head after taking temgesic and norgesic. AB - BACKGROUND: Osteonecrosis is common after taking Temgesic and Norgesic. This study intended to suggest the preferable surgical treatment in osteonecrosis patients who use these drugs. METHODS: Twenty tree patients with hip osteonecrosis who were hospitalized in the Kerman hospitals after using Temgesic and Norgesic were followed for about 14 months from 2008 to 2010 (from a minimum of 2 months to a maximum of 2 years). 65% of patients underwent total hip arthroplasty (THA) and core decompression was performed for 35% of them. Patients were compared based on functional scoring of hip before and after surgery. FINDINGS: Duration of drug use was 38 months on average and injection frequency of drug was averagely 3 months. The average functional scoring of hip was 9.1 before operation and 16 after it (P < 0.001). Recovery rate of patients in THA was very good and in core decompression was good. CONCLUSION: In treatment of osteonecrosis after taking Temgesic and Norgesic, the THA surgery in comparison with core decompression showed better results and caused significant clinical improvement. PMID- 24494146 TI - Smoking pattern in family members of smokers in slums of surat city, Western India. AB - BACKGROUND: The relationship between becoming a smoker and having smoker parents, siblings, and relatives is still uncovered in India. The influences of a smoking role model in a family on smoking habits of individuals are yet to be revealed. This study aimed to understand the relationship of smoking abuse of a person with smoking of their family members. METHODS: This community-based cross-sectional study was conducted in the slums of 20 urban health centers (UHCs) of Surat city (India). A pretested semi-structured questionnaire was used to collect data. The data was analyzed using Epi-Info software. FINDINGS: Among 281 smoker participants, 168 (59.8%), 55 (19.6%), 95 (33.8%), and 50 (17.8%) had smoking fathers, grandparents, siblings, and other relatives, respectively. While 131 participants (44.6%) had correct information about the law of banned smoking, 249 participants (88.6%) were in favor of this law. The association of smoking abuse in fathers with smoking abuse in siblings came out to be odds ratio (OR) = 3.75 (95% CI: 2.11-6.63) and grandparents to be odds ratio 16.43 (95% CI: 4.98-54.17), respectively. The association between education and following the law of banned smoking was statistically significant OR = 2.98 (95% CI: 1.43-6.00). CONCLUSION: Substance abuse in parents, siblings, and other relatives is likely to influence the behavior of the person towards it. Persons living in the same vicinity may also greatly influence the behavior of an individual. PMID- 24494147 TI - Efficacy of integrating stress coping skills training with detoxification on social adjustment of addicted women. AB - BACKGROUND: Addiction as a biopsychosocial problem has been dramatically increased in our country. Adverse consequences of the addiction in women have been shown to be more than men, which in turn can affect family members' health and wellbeing. The current study examined the efficacy of stress coping skills training in addicted women referring to an outpatient centre of addiction prevention located in Welfare Organization of Gorgan, Iran. METHODS: 30 women with low levels of social adjustment measured by Social Adjustment Scale were randomly assigned to coping skills training with detoxification treatments (experimental) or detoxification alone groups. Both groups (n = 15) completed pre post assessments of Bell's adjustment Inventory. Experimental group received coping skills training program in ten sessions, each session last 90 minutes. FINDINGS: Social adjustment was considerably improved more in addicted women who followed coping skills training program with detoxification treatment in comparison with the women who was undergone only detoxification treatment. CONCLUSION: Skills training program can help addicted women to better cope with their adjustment problem and these skills should be integrated into detoxification programs for this population. PMID- 24494148 TI - The relationship of emotional intelligence and mental disorders with internet addiction in internet users university students. AB - BACKGROUND: This study aimed to evaluate the relationship of emotional intelligence and mental disorders, with internet addiction in university students. METHODS: The method of study was descriptive-pilot one and correlation. Two hundred internet users (male and female) from Isfahan University and Isfahan University of Technology were randomly selected. For data collection Carson's emotional intelligence Questionnaire SCL-90 scale and Internet Addiction Test were used. Data analysis was implemented using multivariate regression statistical method. FINDINGS: Anxiety, obsessive-compulsive, aggression, phobia, hypochondria disorders, and emotional intelligence were the most significant predictors of Internet addiction. Moreover, there were significant correlations between these variables and Internet addiction disorder (P < 0.001). Moreover the findings showed that there were significant associations between depressive (R = 0.33), summarization (R = 0.24), and interpersonal sensitivity (R = 0.20) disorders. In this study no correlation was found between internet addiction disorder with psychosis and paranoid ideation. Moreover, among mental disorders, there was only a significant difference between the sexes in depression (P < 0.001); the men showed more depressive tendencies than women. CONCLUSION: The results showed a correlation between emotional intelligence and mental disorders with internet addiction, but these results can help therapists, psychologists and counselors in providing services to help internet addicts. PMID- 24494149 TI - Assessment of Knowledge, Attitude, Behaviour and Interpersonal Factors Related to the Use of Tobacco among Youth of Udaipur City, Rajasthan, India: A Cross Sectional Study. AB - BACKGROUND: Tobacco is the most important preventable cause of disease burden and death all over the world. Apart from being the single most important determinant of cancer and cardiovascular diseases, smoking is also a threat to oral health. The Global Youth Tobacco Survey (GYTS) as a part of Global Tobacco Surveillance System (GTSS) was developed to monitor tobacco use, elicit attitudes about tobacco, and obtain information on exposure to tobacco smoke among youth. This study aimed to assess the prevalence, knowledge, attitude, behaviour and interpersonal factors related to the use of tobacco among youth of Udaipur city, Rajasthan, India. METHODS: This study was conducted among 1031, 15 to 25 year old youths studying in the different colleges of Udaipur city, Rajasthan, India. The Global Youth Tobacco Survey (GYTS) core questionnaire was used. Simple descriptive statistics were used for the data. FINDINGS: Out of the total 1031 participants (mean age: 19.55 +/- 1.35), 632 (61.2%) were men (mean age: 19.66 +/ 1.36) and 399 (38.7%) were women (mean age: 19.35 +/- 1.35). 493 (47.8%) were current tobacco users, the majority of which were men 411 (39.8%). 122 (11.8%) had a previous history of tobacco use, while 416 (40.3%) reported that they had never used tobacco in any form. The majority of the men, 305 (29.5%), were consuming tobacco daily. Majority of current, 152 (30.8%), and ever tobacco users, 122 (41.8%), smoke and chew gutkha at places of entertainment followed by smoking or chewing at school/college premises. The majority of them bought gutkha themselves, 292 (47.4%). Moreover, the majority of current tobacco users, 298 (72.5%) men and 82 (100%) women, wanted to stop smoking /gutkha chewing. CONCLUSION: The present study indicates that there is a high prevalence of use of tobacco among youth of Udaipur city, Rajasthan, India. PMID- 24494150 TI - Prevalence of Human Immunodeficiency Virus Infection among Injection Drug Users Released from Jail. AB - BACKGROUND: Injecting drug users (IDUs) and prisoners are considered to be highly vulnerable to human immunodeficiency virus (HIV) infection in Iran. This study was carried out to determine the prevalence of HIV infection among IDUs released from jail in Bahar (Hamadan, Iran). METHODS: In a cross-sectional study, 118 IDUs who were prisoners during 2001-07 were evaluated. Their demographic and personal characteristics were assessed by a questionnaire. In order to determine HIV positive individuals, blood samples were obtained from the participants and tested by enzyme-linked immunosorbent assay and Western blot technique. FINDINGS: Overall, 20.3% of the subjects had used non-sterile injecting equipment during their imprisonment. The prevalence of HIV infection among the studied population was 4.2%. CONCLUSION: As the prevalence of HIV among IDUs released from jail is high, it is necessary for prison authorities to take measures against the increase in the prevalence of HIV among this group. PMID- 24494151 TI - The Effectiveness of Group Therapy on the Family Functioning of Individuals under Methadone Treatment: A Clinical Trial. AB - BACKGROUND: A significant number of opioid-dependent patients in Iran are now being treated by methadone maintenance therapy (MMT). One of the social complications of substance dependency is family disorganization and a decrease in marital satisfaction. This study aimed to determine the effect of group therapy based on the transtheoretical model of change on family functioning of the patients under MMT. METHODS: In this open clinical trial, 48 married people who were between the ages of 19 and 40, and under methadone maintenance therapy had been assigned to two random groups of test and control. In the intervention group, group therapy was held based on the transtheoretical model of behavior change, for 29 sessions (two times a week). To assess the overall health and pathology of the family, the two questionnaires Family Assessment Device (FAD) and Marital Conflict Questionnaire (MCQ), both with approved reliability and validity, were used. FINDINGS: A total of 24 patients in the control group and 23 patients in the intervention group (one person withdrew from the study in the early meetings) were evaluated. The mean +/- SD of age of the control and intervention groups, respectively, were 33.9 +/- 4.8 and 32.8 +/- 4.3 (P = 0.40). Before the intervention began the average score of FAD and MCQ questionnaires between the two groups was comparable. After the intervention was over the score of each of the two questionnaires, with the adjustment of the baseline score, was lower in the treatment group than the control group, the difference was marginally significant (P < 0.10). CONCLUSION: The family functioning of the MMT treated patients showed improvement. Therefore, with the use of stage-of-change and group therapy, steps can be taken for improving family functioning of these patients. Due to the relatively long duration and frequency of treatment sessions the feasibility of this intervention needs further research. PMID- 24494152 TI - Factors Influencing Drug Injection History among Prisoners: A Comparison between Classification and Regression Trees and Logistic Regression Analysis. AB - BACKGROUND: Due to the importance of medical studies, researchers of this field should be familiar with various types of statistical analyses to select the most appropriate method based on the characteristics of their data sets. Classification and regression trees (CARTs) can be as complementary to regression models. We compared the performance of a logistic regression model and a CART in predicting drug injection among prisoners. METHODS: Data of 2720 Iranian prisoners was studied to determine the factors influencing drug injection. The collected data was divided into two groups of training and testing. A logistic regression model and a CART were applied on training data. The performance of the two models was then evaluated on testing data. FINDINGS: The regression model and the CART had 8 and 4 significant variables, respectively. Overall, heroin use, history of imprisonment, age at first drug use, and marital status were important factors in determining the history of drug injection. Subjects without the history of heroin use or heroin users with short-term imprisonment were at lower risk of drug injection. Among heroin addicts with long-term imprisonment, individuals with higher age at first drug use and married subjects were at lower risk of drug injection. Although the logistic regression model was more sensitive than the CART, the two models had the same levels of specificity and classification accuracy. CONCLUSION: In this study, both sensitivity and specificity were important. While the logistic regression model had better performance, the graphical presentation of the CART simplifies the interpretation of the results. In general, a combination of different analytical methods is recommended to explore the effects of variables. PMID- 24494154 TI - Relationships of dissociative disorders and personality traits in opium addicts on methadone treatment. AB - BACKGROUND: Drug abuse is a major public health problem. Some believe that when dissociation fails to defend against emotional, physical, or sexual trauma, the person will find relief from unpleasant thoughts and emotions in opium use. On the other hand, personality disorders are considered as important predictors of treatment outcomes in drug abusers. Due to lack of adequate research in this regard, we evaluated dissociative disorders and personality traits of opium addicts on methadone treatment. METHODS: This cross-sectional analytic study included 111 non-psychotic subjects on methadone treatment (case group) and 69 non-addicts (control group). After recording demographic characteristics, Dissociative Experiences Scale (DES) and Millon Multiaxial Inventory III were applied to assess dissociative symptoms and clinical personality patterns of all participants. FINDINGS: Dissociative symptoms were significantly more common in the case group than in the control group (P = 0.044). While hysterionic personality disorder was more frequent in the control group (P = 0.008), sadistic, antisocial, and schizotypal personality disorders were significantly more common in the case group (P = 0.008, 0.002, and 0.023, respectively). CONCLUSION: We found relations between history of drug dependence, dissociative symptoms, and personality disorders. Therefore, the mentioned disorders need to be kept in mind while planning addiction treatment modalities and identifying high risk groups. PMID- 24494153 TI - Comparing the effects of methadone maintenance treatment, therapeutic community, and residential rehabilitation on quality of life and mental health of drug addicts. AB - BACKGROUND: This study compared the effects of three drug addiction treatment methods on quality of life and mental health of drug addicts. METHODS: In this study, 227 Iranian male drug addicts were selected from Mazandaran Province (northern Iran). They were randomized to be treated with methadone maintenance treatment, therapeutic community, or residential rehabilitation. The Short Form Health Survey (SF-36) and the General Health Questionnaire (GHQ) were completed by the subjects at the start and end of the study. The length of intervention and SF-36 and GHQ scores before and after treatment were compared between groups. All statistical analyses were performed in SPSS. FINDINGS: Significant differences in quality of life and mental health scores were found between the three groups. We found that if drug addicts stay in the therapeutic community center for more than 6 months, this method will be the most effective intervention to improve quality of life and mental health of drug abusers. CONCLUSION: Evaluation of different methods drug addiction treatment is very difficult. Therefore, further studies are required to better understand the effects of therapeutic community. PMID- 24494155 TI - Opium induces apoptosis in jurkat cells. AB - BACKGROUND: The direct effect of some opioids on immune cells has been demonstrated. The aim of this study was to assess the apoptotic effect of opium on Jurkat T lymphocyte cells. METHODS: Different concentrations of opium (2.86 * 10-3 to 2.86 * 10-11 g/ml) were added to 24-well plates containing 5 * 105 Jurkat cells. Apoptotic events were assessed after 6, 24, and 72 hours by flow cytometric detection of surface phosphatidylserine. FINDINGS: Significant differences in apoptosis of Jurkat cells were seen at 24 and 72 hours in different concentrations of opium (P < 0.05). After 72 hours, significant increase in necrosis of Jurkat cells was seen in opium concentration of 2.85 * 10 3 g/ml compared to cells without opium (control) (P < 0.05). CONCLUSION: These results showed that opium directly increases apoptosis and necrosis of T lymphocytes. This effect may play a role in immune dysfunction in opium addicts. PMID- 24494156 TI - Relation of opium addiction with the severity and extension of myocardial infarction and its related mortality. AB - BACKGROUND: Despite some evidences about protective or triggering role of opium use in patients with coronary artery disease, the exact role of opium is still under question. The current study aimed to address the relation of opium dependence on the severity and extension of myocardial infarction (MI) and its related mortality. METHODS: The study population consisted of 460 consecutive patients (239 opium addicts and 221 non-addicts) with first acute MI. Study information was extracted from hospital recorded files as well as face to face interview. FINDINGS: In-hospital mortality in opium addicted patients was numerically lower than another group (5.4% versus 8.2%), but this difference was not statistically significant. Regarding types of MI, anterior wall MI was higher in non-addicted patients than addicts (36.4% versus 26.4%). Among patients with anterior wall MI, early mortality was significantly higher in non-addicted compared to addicted subjects (20.0% versus 7.9% P = 0.043). The main associated factors of in-hospital mortality due to acute MI in addicts were advanced age and family history of coronary artery disease and in non-addicts were advanced age and hypertension. CONCLUSION: In current study total in-hospital mortality was not different between opium addicted and non-addicted groups but opium may reduce the occurrence of anterior wall MI and its related early mortality. PMID- 24494157 TI - A Study of the Correlation between Computer Games and Adolescent Behavioral Problems. AB - BACKGROUND: Today, due to developing communicative technologies, computer games and other audio-visual media as social phenomena, are very attractive and have a great effect on children and adolescents. The increasing popularity of these games among children and adolescents results in the public uncertainties about plausible harmful effects of these games. This study aimed to investigate the correlation between computer games and behavioral problems on male guidance school students. METHODS: This was a descriptive-correlative study on 384 randomly chosen male guidance school students. They were asked to answer the researcher's questionnaire about computer games and Achenbach's Youth Self-Report (YSR). FINDINGS: The Results of this study indicated that there was about 95% direct significant correlation between the amount of playing games among adolescents and anxiety/depression, withdrawn/depression, rule-breaking behaviors, aggression, and social problems. However, there was no statistically significant correlation between the amount of computer game usage and physical complaints, thinking problems, and attention problems. In addition, there was a significant correlation between the students' place of living and their parents' job, and using computer games. CONCLUSION: Computer games lead to anxiety, depression, withdrawal, rule-breaking behavior, aggression, and social problems in adolescents. PMID- 24494158 TI - Frequency of Smoking and Specialized Awareness among Doctors and Nurses of Hospitals in Kerman, Iran. AB - BACKGROUND: Nicotine is one of the strongest poisons. Every year about 75 thousand of Iranians die due to smoking. Since doctors and nurses have a major role in controlling smoking, this study tried to investigate the prevalence of cigarette smoking among doctors and nurses and their awareness about the effects of smoking. METHODS: This descriptive study was conducted on all doctors (n = 150) and nurses (n = 400) of hospitals affiliated with Kerman University of Medical Sciences (Kerman, Iran). Data was collected through a questionnaire with reliability of 0.8 and validity of 0.79. It consisted of two parts to assess demographic characteristics of the participants and their awareness about the side effects of smoking. Their awareness was ranked from poor to excellent based on the number of correct answers. Chi-square and Mann-Whitney tests were then used to analyze the collected data. FINDINGS: Of 550 questionnaires, 524 were completed (51.3% by the nurses and 48.7% by the doctors. While 21.2% of all participants smoked cigarettes, 71.8% of doctors and 95.3% of nurses did not smoke. The levels of awareness among nurses and doctors were determined as poor and moderate, respectively. CONCLUSION: The higher prevalence of smoking among nurses confirms the significance of education. The level of awareness among the studied doctors and nurses was not desirable. Enhancing the awareness and attitude of medical staff will improve not only their own performance but also the behavioral pattern of the society. PMID- 24494159 TI - Interrelationship of smoking, lip and gingival melanin pigmentation, and periodontal status. AB - BACKGROUND: Cigarette smoking is a significant risk factor for periodontal disease. It also causes pigmentation of oral mucosa. The present study was aimed to assess the effects of smoking on lip and gingival pigmentation and periodontal status and the relationship between pigmentation and periodontal parameters. METHODS: A total of 109 smokers and an equal number of non-smoker controls (mean age: 35.9 years, range: 35-44 years) comprised the study sample. All the participants were assessed for pigmentation on lip and gingiva and overall periodontal status (gingival bleeding, probing depth, and loss of attachment at six points in each tooth). FINDINGS: All the smokers in this study had lip and gingival pigmentation. Two-third of non-smokers had no pigmentation. The mean scores of lip and gingival pigmentation in smokers were seven and four times higher than those of non-smokers, respectively. Pigmentation and periodontal parameters (except gingival bleeding) were found to be positively related with exposure to smoking exposure. Probing depth and loss of attachment were the highest in subjects with pigmented lips and grade three pigmented gingiva. CONCLUSION: Smoking influenced lip and gingival pigmentation and periodontium. All individuals with lip pigmentation presented some form of gingival pigmentation. Probing depth and loss of attachment were more severe in subjects with lip and gingival pigmentation. PMID- 24494160 TI - Substance Abuse among Students of Zanjan's Universities (Iran): A Knot of Today's Society. AB - BACKGROUND: In order to assess the status of drug abuse and likely addiction among university students, a descriptive study was designed. METHODS: 1200 subjects among the students of three universities in Zanjan were selected by stratified random sampling and their demographic information and history of substance abuse including hookah, cigarette, codeine, ibuprofen, alcohol, diazepam, tramadol, cannabis, opium, grass, heroin, crack, X pill, morphine, marijuana, Librium, and LSD were assessed by a standard questionnaire and were analyzed in 2010. FINDINGS: The mean age of students was 21.3 +/- 2.3 years (ranged 18-38 years) and the mean age of drug abuse onset was 19.45 years old. 48.2% of male students and 23.4% of female had a history of drug abuse at least once. 6.3% of males and 1.2% of female subjects were addicted constantly which the difference was statically significant (P < 0.001). 32.7% were motivated by pain and 13.3% seeking for pleasure. Hookah with 18% and LSD with 1% had the lowest and highest percentage of drug use, respectively. CONCLUSION: Substance abuse was higher in males than females. Drug abuse was higher among older students with higher degree, and with psychological disorder history. It seems that we require goal directed programs to control and reduce the prevalence of substance abuse, raise students' awareness and increase students' information about substance disadvantages especially in their entrance. PMID- 24494161 TI - Fetishism due to methamphetamine (glass) abuse: a case report. AB - BACKGROUND: Fetishism is a type of paraphilia. The focus of sexual arousal in fetishism is oriented towards inanimate objects. Sexual arousal and craving are some of the reasons the youth resort to crystal (glass). Drug abuse may cause disorders in sexual function. CASE REPORT: The patient was a 41 years old man. He married in age 22 years and experienced frequent intercourses with his wife from which he gained pleasure and it was his preferable method. Her wife left ten years ago. The patient started crystal administration through insufflations since seven months ago. Simultaneous with crystal abuse, wearing women's underwear was the only medium through which the patient reached sexual orgasm. DISCUSSION: A lot of psychological symptoms related to new substances (for example glass) are new to psychiatrists treating dependency in medical clinics. Fetishism may coexist with addiction as comorbidity. Another point to be mentioned is that, symptoms of fetishism increased and decreased with more and less glass administration, indicating that symptoms of paraphilia emerge as a result of glass use. In addition, prior to glass use, the patient maintained normal sexual tendencies, had experienced sexual intercourse and did not suffer from any type of paraphilia. PMID- 24494162 TI - Prevalence of use of anabolic steroids by bodybuilders using three methods in a city of iran. AB - BACKGROUND: The prevalence of substance use among bodybuilding athletes has been poorly studied in Iran. This study was conducted to examine the prevalence of drug use, especially anabolic steroids, among bodybuilding athletes. METHODS: This cross-sectional study was conducted in the first half of 2013 among body building athletes referring to gyms located in Kerman, Iran. Five gyms were selected randomly and 380 athletes were invited to complete a self-administered anonymous questionnaire, consecutively. The questionnaire included two parts; baseline characteristics and substance related questions. The prevalence of anabolic steroids was estimated based on three methods; self-report, projective question, and crosswise model. FINDINGS: We enrolled 298 male athletes in the final analysis. Mean +/- SD age of subjects was 25.9 +/- 8.4. The most frequent recent (past 30 days) drug use was waterpipe smoking (45%). The second most frequently used drug was alcohol (26.5%, recent use). Based on self-reports, the prevalence of lifetime anabolic steroid use was calculated to be 24.5%. The corresponding figure based on crosswise method was obtained to be 56.8%. Participants believed that a median of 40% of athletes had used anabolic steroids in their lifetime. The prevalence of anabolic steroid was higher in single and less educated individuals (P < 0.05). The main reason for using anabolic steroids was to increase muscle size. CONCLUSION: The prevalence of drug use, especially tobacco, alcohol, and anabolic steroids, was high among bodybuilding athletes. We could not rely on self-reports to examine anabolic steroid use. PMID- 24494163 TI - The Effect of Concomitant Ethanol and Opium Consumption on Lipid Profiles and Atherosclerosis in Golden Syrian Hamster's Aorta. AB - BACKGROUND: Cardiovascular disease (CVD) is the main cause of mortality in the world and is normally argued as the third cause of all mortalities. Opium and alcohol every day consumption can cause people to have many health problems. The present study aimed to assess the effect of ethanol and opium consumption on lipid profiles and atherosclerosis in aorta. METHODS: Twenty four male golden Syrian hamsters were randomly divided into four treatment groups (n = 6): Control, addicted (40 mg/kg), alcohol (6.0 g/kg) and combination of opium and alcohol. All of the hamsters were scarified and their livers were removed immediately and fixed in formalin solution 10%. The plasma levels of the lipid profiles were measured enzymatically. Aorta sections were examined by a pathologist. FINDINGS: The amount of the total cholesterol significantly increased in ethanol (P < 0.05) and combination (P < 0.05) groups, while it had a non-significant decrease in opium group. Serum triglyceride significantly increased in ethanol (P < 0.05) and combination (P < 0.001) groups, as well as this parameter increased in opium group but it was not significant. Low-density lipoprotein cholesterol (LDL-C) markedly increased in the combination group (P < 0.05). No significant difference was observed in serum LDL-C among other treatment groups. Levels of high-density lipoprotein cholesterol had a significant rise only in ethanol group. Change in aorta histology was not significant. CONCLUSION: The results showed that consumption of opium plus alcohol has harmful effects on lipid profile; however, it had no effect on aorta histology that was maybe due to the short period of the treatment. PMID- 24494164 TI - Beneficial Effects of Rosmarinus Officinalis for Treatment of Opium Withdrawal Syndrome during Addiction Treatment Programs: A Clinical Trial. AB - BACKGROUND: Withdrawal syndrome may influence patient's motivation for participation in addiction treatment programs. Management of the symptoms can improve the success rate of addiction treatment programs. In the present study, we have evaluated the efficiency of an herbal product as adjunct therapy for alleviation of withdrawal syndrome in opium abuse. METHODS: In the present clinical trial, 81 patients were assigned into case and control groups. The control group was treated with methadone and placebo for 4 weeks. The case group was treated with methadone and powdered dried leaves of Rosmarinus officinalis for the same interval. Occurrence of withdrawal syndrome was compared between groups on days 3, 7, and 14 after beginning of the treatment, and the possible signs and symptoms of withdrawal syndrome were checked. The clinical opioid withdrawal scale (COWS) was used for evaluation of withdrawal syndrome in the patients. FINDINGS: Patients in the case group experienced less severe withdrawal syndrome compared to those in the control group; chiefly bone pain, perspiration, and insomnia. CONCLUSION: The present study showed that rosemary can be used as an optional extra drug for treatment of withdrawal syndrome during treatment programs for opium addiction and possibly addiction to other opioids. PMID- 24494165 TI - Frequency of Opium Addiction in Patients with Ischemic Stroke and Comparing their Cerebrovascular Doppler Ultrasound Changes to Non-Addicts. AB - BACKGROUND: Ischemic stroke is a major cause of mortality and morbidity worldwide. Various studies on the etiology of this disease are in progress. Some studies have suggested that opium abuse may is associated with increased risk of ischemic stroke. The present study aimed to analyze the frequency of opium addiction and to compare cerebrovascular ultrasound patients' changes to non addicts. METHODS: This cross-sectional study was performed on 97 patients with ischemic stroke. The diagnosis was confirmed by imaging and paraclinical studies. All the patients underwent cerebrovascular ultrasound in the first 4 days of symptoms onset. A questionnaire containing demographic data, opium use information [based on the 4th Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV) criteria], and vascular ultrasound findings were completed for each patient and the results were analyzed using descriptive statistics and chi-square test. FINDINGS: In this study, 38 patients (39.18%) were addicted to opium and the remaining were non-addicts. Among the addicted patients, 31 patients were male and 7 patients were female, while 26 and 33 patients of non-addicts were male and female, respectively (P < 0.01). Among the risk factors for stroke, smoking was higher in the addicts than in non-addicts (P = 0.04). Frequency of vascular stenosis and stenosis location did not show a statistical significant difference between the addicted and non-addicted patients. CONCLUSION: More than one-third of the patients with stroke were addicted to opium which was higher than general population; although the pattern of stenosis in these patients was similar to the non-addicts. PMID- 24494166 TI - Smoking intensity and its relation to general health of the students of kerman university of medical sciences, iran. AB - BACKGROUND: Considering the need for a better understanding of smoking among the student population and its impact on their mental health and their success, this study was conducted in Kerman Medical Sciences University. METHODS: This cross sectional study on 772 students, chosen by random sampling, was conducted in 2007. Subjects were assessed with 28-question questionnaires that included demographic questions, questions about smoking, fagerstrom nicotine dependence test, and a general health questionnaire (GHQ). FINDINGS: The prevalence of smoking was 15. 8%. Records of failing in high school and conditional failures of a university semester in smokers were significantly higher than non-smokers. The average scores of the mental health questionnaires showed a significant difference between smokers and non-smokers (P < 0.001). Based on the results, 35.2% of smokers and 5.9% of non-smokers had mental illnesses. CONCLUSION: Since cigarette dependence in teens and youth are significantly high and failures in education and mental health disorders are more common among them, it is necessary that the authorities pay more attention to the social skill training and timely diagnosis of mental disorders. PMID- 24494167 TI - Association between Parental Addiction and Types of Child Abuse in High-School Students of Kerman, Iran. AB - BACKGROUND: Child abuse is one of the vulnerabilities that threaten child's physical and mental health in childhood and is associated with serious short-term and long-term complications. The present study aimed to review the association of parental addiction with types of child abuse in high-school students of Kerman, Iran. METHODS: In this cross-sectional study, 360 students were recruited and studied through cluster sampling method. Abuse and the related factors were assessed using a standard self-report 48-item questionnaire. FINDINGS: Average child abuse among the study subjects was 27.6%. Physical behavior, negligence, and emotional abuse were seen in 9.7%, 23.6%, and 17.9% of the subjects, respectively. Parental addiction had a significant association (P = 0.001) with incidence of all the child abuse domains. CONCLUSION: Special consideration to families of addicted parents and early identification of child abuse cases may prevent the adverse side effects. PMID- 24494169 TI - Reviewing the Association between the History of Parental Substance Abuse and the Rate of Child Abuse. AB - BACKGROUND: Substance abuse is a social, and health problem in Middle Eastern countries such as Iran. One of its most devastating effects is domestic violence against children. This study examined the association between the history of parental substance abuse, and rate of child abuse in Ahvaz, Iran. METHODS: This was a case-control study. The study population included all parents with high school children in Ahwaz within the academic year 2012-2013. The sample size was 384 people in two groups; with a history of substance abuse (case group) and no history of substance abuse (control group). Multi-stage cluster random sampling method was used through the Cochran formula. The data collection tools included a Childhood Trauma Questionnaire (CTQ) (Bernstein, 1995), a demographic questionnaire, Duncan Socioeconomic Index (DSI), and a researcher-made questionnaire for the history of substance abuse. For data analysis, statistical indicators such as percentage, mean, standard deviation, t-test, and correlation and regression analysis were used. FINDINGS: Data analysis showed that there was a significant positive correlation among parents with a history of substance abuse and domestic violence toward children. Mean and standard deviation of the violence level in families with normal parents were 61.34 +/- 16.88, and in families with a history of substance abuse were 98.99 +/- 32.07. Therefore, the test results showed that there was a significant difference between normal families and families with history of substance abuse and violence toward children (P < 0.001, t = 8.60). CONCLUSION: Based on the findings, the history of domestic violence and parental substance abuse (physical and emotional abuse, emotional and physical neglect) had a significant positive correlation with their behavior toward their children. After matching the two groups we found that the most common types of violence against children by their parents were, respectively, emotional violence (r = 58%), physical neglect (r = 54%), emotional neglect (r = 46%), and then physical violence (r = 39%). PMID- 24494168 TI - Psychopathological Dimensions in Substance Abusers with and without HIV/AIDS and Healthy Matched Group. AB - BACKGROUND: Inattention to symptoms of mental disorders and substance abuse in patients with HIV/AIDS and other at-risk groups, may lead to irreversible damages. The purpose of this study was to compare the psychopathological dimensions in substance abusers with and without HIV/AIDS and healthy matched groups. METHODS: In a cross-sectional and analytical study, selected samples (by available, consecutive, and objective methods) were 43 HIV-positive substance abusers, 49 HIV negative substance abusers under methadone maintenance therapy (MMT) in the counseling clinic of Behavioral Diseases and Addiction Abandonment, and 45 ordinary individuals. All of them were evaluated by matched confounding variables via Symptom Checklist-90-Revised (SCL-90-R). FINDINGS: Results indicated a significant difference between these groups in the Global Severity Index (GSI), Positive Symptom Distress Index (PSDI), and Positive Symptom Total (PST) (P < 0.001). Two by two the comparison of the three groups from psychopathological dimensions revealed that substance abusers with HIV/AIDS persistently suffer more mental problems in all dimensions compared with healthy individuals (P < 0.05). In addition, in comparison with HIV negative substance abusers, they also suffer more mental problems in other dimensions, including somatization, interpersonal sensitivity, depression, anxiety, phobia, and psychoticism (P < 0.05). Yet, the difference in paranoid ideation, hostility, and obsessive-compulsive cases was insignificant. Two by two, the comparison between healthy individuals and substance abusers without HIV/AIDS showed higher levels of depression and psychoticism in substance abusers (P < 0.05), but no difference in other dimensions. CONCLUSION: Comorbidity of substance abuse and HIV diagnosis intensify mental disorder symptoms. Moreover, lack of prevention and implementation of appropriate psychological and psychiatric interventions after substance abuse and HIV lead to extended establishment of mental disorder symptoms. PMID- 24494170 TI - Responsible of Socio-economic Factors with Addiction in Yazd, Iran: An Opinion Survey. AB - BACKGROUND: Addiction has a long history in Iran and it is one of the social problems that create psychological and social conflicts for addicts and their families. Addiction just like other social deviations affects young who are the most valuable assets of a nation. Recognition of socio-economic factors responsible for addiction can help planning and management of programs to fight against addiction. METHODS: This cross-sectional study was conducted using a questionnaire on 261 spouses of addicts referring to the detoxification centers of Yazd, Iran who were selected randomly. Their perspectives regarding factors thought to be effective in addiction were examined. Statistical tests included chi-square and Kruskal-Wallis tests. FINDINGS: Economic problems, divorce, marital problems, lack of familial supervision, unemployment, psychological and physical problems had a statistically significant relationship with the income of the family (P < 0.05), such that with an increase in income of the family these factors played a lesser significant role in addiction. CONCLUSION: Control of surrounding factors and increase in self-esteem are two important factors that can help effectively control addiction in the young population. After addiction, though environmental and surrounding factors play a role in preventing return to addiction, their role is reduced. PMID- 24494171 TI - Meta-analysis of Smoking Prevalence in Iran. AB - BACKGROUND: There are numerous studies and documents regarding the prevalence of smoking in Iran. Thus, to provide suitable information for decision-making and policy-making in this regard, the prevalence of smoking in Iran was evaluated using the meta-analysis of the results of the existing researches. METHODS: Data were collected by searching the keywords cigarette, smoking, tobacco, and nicotine in English databases, searching their Persian equivalents in Persian Databases, and in non-electronic resources. After studying the titles and texts of collected articles, the repeated and irrelevant cases were excluded. Cases which had the inclusion criteria of this meta-analysis were entered into the Stata software. According to heterogeneity results, random effect model was used to estimate the prevalence of smoking. FINDINGS: In initial studies and non communicable surveillance system, 274992 Iranian adults were studied regarding daily smoking. Among initial studies, smoking prevalence varied from 12.3% to 38.5% in men, and from 0.6% to 9.8% in women. Based on the meta-analysis of initial studies and risk factors of non-communicable disease surveillance system, smoking prevalence was estimated 21.7% and 19.8% in men and 3.6% and 0.94% in women, respectively. Moreover, smoking prevalence in all subjects was estimated 13.9% according to the meta-analysis of the initial study. CONCLUSION: The findings of this meta-analysis revealed that a significant part of the general population over 15 years of age, and one fifth of Iranian male adults smoke. Thus, concerning causal relationship confirmed between smoking and most diseases, if suitable guidelines are not employed the diseases related to this factor will increase in Iran. PMID- 24494172 TI - A Potential 'Curative' Modality for Crohn's Disease---Modeled after Prophylaxis of Bovine Johne's Disease. AB - A naturally occurring, gastrointestinal disorder of ruminants (Johne's disease) is a chronic, debilitating, lethal disease. The causative agent is Mycobacterium avium subspecies paratuberculosis (MAP). Exposure that leads to disease occurs primarily in utero and/or during the neonatal period. Outside a dietzia probiotic treatment, there are no preventive/curative therapies. Interestingly, MAP is at the center of a controversy as to its role (cause of, perpetuate of, innocent bystander) in Crohn's disease, ulcerative colitis, irritable bowel syndrome, diabetes, sarcoidosis, Blau syndrome, and multiple sclerosis-diseases in which the incidence of systemic MAP is higher than that in the general population. Conventional therapeutic modalities, including biologic agents, for the majority of these diseases are, in general, directed at curtailing processes that are an intricate part of inflammation, with goals to induce and maintain remission. Most possess side effects of varying severity, lose therapeutic value, and more importantly, few are directed at prevention, attainment of long lasting remissions or cures, and essential none at reduction/elimination of MAP. This report presents a rationale for how/why Dietzia subsp. C79793-74 should be clinically evaluated for efficacy in patients with IBD. Arguments are based on previous studies that demonstrated (a) clinical similarities of Johne's disease and Crohn's disease, (b) inhibition of growth of MAP by Dietzia under specific culture conditions, (c) safe usage for extended daily treatments of adult cattle (up to 24 months), and (d) when used as a probiotic, curtailed diarrhea and cured 40% of adult cattle with early stage paratuberculosis. PMID- 24494173 TI - Homozygous Deletion of Glutathione Peroxidase 1 and Aldehyde Dehydrogenase 1a1 Genes Is Not Associated with Schizophrenia-Like Behavior in Mice. AB - Much evidence suggests that oxidative stress plays a role in schizophrenia pathogenesis. Major oxidative stress sources include hydrogen peroxide and biogenic aldehydes that are mainly cleared in vivo by glutathione peroxidase (GPX) and aldehyde dehydrogenase (ALDH), respectively. Both enzymes are richly expressed in brain. Schizophrenia patients have significantly increased plasma levels of malondialdehyde and glutathione, combined with decreased GPX activity and ALDH1 mRNA levels in the ventral tegmental area. Absence of Aldh1a1 (murine homolog of ALDH1) gene causes increased basal extracellular dopamine concentrations, a common characteristic of schizophrenia. Studies investigating association between gene polymorphisms of GPX1 (the most abundant form of GPX) or ALDH1A1 with schizophrenia also have not clearly demonstrated whether ALDH1A1 or GPX1 is involved in pathogenesis of schizophrenia. To investigate possible contributions of ALDH and GPX to pathological behaviors associated with schizophrenia, we generated mice with both Aldh1a1 and Gpx1 gene deletions (KO). Aldh1a1/Gpx1 KO and wild type (WT) mice had similar number of novel entry and alteration in Y-maze test, suggesting no cognition deficit in KO. Furthermore, KO and WT displayed similar social interaction and novelty preferences in three chambered tests. Overall, KO and WT had similar activity levels, as indicated by their entries in the Y-maze and sociability tests. Furthermore both genotypes buried a similar percentage of marbles in a 30 min marble-burying task. In summary, homozygous deletion of Gpx1 and Aldh1a1 genes was not associated with schizophrenia-like behavioral phenotypes including anxiety, hyperactivity, cognitive deficit or social disability. Our findings suggest that constitutive absence of these genes alone is unlikely to give rise to common behavioral schizophrenia symptoms. However, these mice may be highly sensitive to oxidative challenges during critical stages of prenatal or juvenile brain development. PMID- 24494174 TI - Effects of typified propolis on mutans streptococci and lactobacilli: a randomized clinical trial. AB - OBJECTIVE: The aim of this study was to determine in a randomized, double-blind, placebo-controlled clinical trial the effects of typified propolis and chlorhexidine rinses on salivary levels of mutans streptococci (MS) and lactobacilli (LACT). METHODS: One hundred patients were screened for salivary levels of MS >100,000 CFUs/mL of saliva. All patients presented with at least one cavitated decayed surface. Sixty patients met entry criteria. Subjects were adults 18-55 years old. After restoration of cavitated lesions patients were randomized to 3 experimental groups: 1) PROP-alcohol-free 2% typified propolis rinse (n = 20); 2) CHX- 0.12% chlorhexidine rinse; 3) PL-placebo mouthrinse. Patients rinsed unsupervised 15 mL of respective rinses twice a day for 1 min for 28 days. Patients were assessed for the salivary levels of MS (Dentocult SM) and LACT (Dentocult LB) at baseline, 7-day, 14-day, and at 28-day visits (experimental effects) and at 45-day visit (residual effects). General linear models were employed to analyze the data. RESULTS: PROP was superior to CHX at 14 day and 28-day visits in suppressing the salivary levels of MS (p < .05). PROP was superior to PL at all visits (p < .01). The residual effects of PROP in suppressing the salivary levels of MS could still be observed at the 45-day visit, where significant differences between PROP and CHX (p < .05), were demonstrated. PROP was significantly superior than CHX in suppressing the levels of salivary LACT at the 28-day visit (p < .05). CONCLUSION: Typified propolis rinse was effective in suppressing cariogenic infections in caries-active patients when compared to existing and placebo therapies. PMID- 24494175 TI - Differentiating c8-t1 radiculopathy from ulnar neuropathy: a survey of 24 spine surgeons. AB - Study Design Questionnaire. Objective To evaluate the ability of spine surgeons to distinguish C8-T1 radiculopathies from ulnar neuropathy. Methods Twenty-four self-rated "experienced" cervical spine surgeons completed a questionnaire with the following items. (1) If the ulnar nerve is cut at the elbow, which of the following would be numb: ulnar forearm, small and ring fingers; only the ulnar forearm; only the small and ring fingers; or none of the above? (2) Which of the following muscles are weak with C8-T1 radiculopathies but intact with ulnar neuropathy at the elbow: flexor digiti minimi brevis, flexor pollicis brevis, abductor digiti minimi, abductor pollicis brevis, adductor pollicis, opponens digiti minimi, opponens pollicis, medial lumbricals, lateral lumbricals, dorsal interossei, palmar interossei? Results Fifteen of 24 surgeons (63%) correctly answered the first question-that severing the ulnar nerve results in numbness of the fifth and fourth fingers. None correctly identified all four nonulnar, C8-T1 innervated options in the second question without naming additional muscles. Conclusion The ulnar nerve provides sensation to the fourth and fifth fingers and medial border of the hand. The medial antebrachial cutaneous nerve provides sensation to the medial forearm. The ulnar nerve innervates all intrinsic hand muscles, except the abductor and flexor pollicis brevis, opponens pollicis, and lateral two lumbricals, which are innervated by C8 and T1 via the median nerve. By examining these five muscles, one can clinically differentiate cubital tunnel syndrome from C8-T1 radiculopathies. Although all participants considered themselves to be experienced cervical spine surgeons, this study reveals inadequate knowledge regarding the clinical manifestations of C8-T1 radiculopathies and cubital tunnel syndrome. PMID- 24494176 TI - Fluoroscopically guided extraforaminal cervical nerve root blocks: analysis of epidural flow of the injectate with respect to needle tip position. AB - Study Design Retrospective evaluation of consecutively performed fluoroscopically guided cervical nerve root blocks. Objective To describe the incidence of injectate central epidural flow with respect to needle tip position during fluoroscopically guided extraforaminal cervical nerve root blocks (ECNRBs). Methods Between February 19, 2003 and June 11, 2003, 132 consecutive fluoroscopically guided ECNRBs performed with contrast media in the final injected material (injectate) were reviewed on 95 patients with average of 1.3 injections per patient. Fluoroscopic spot images documenting the procedure were obtained as part of standard quality assurance. An independent observer not directly involved in the procedures retrospectively reviewed the images, and the data were placed into a database. Image review was performed to determine optimal needle tip positioning for injectate epidural flow. Results Central epidural injectate flow was obtained in only 28.9% of injections with the needle tip lateral to midline of the lateral mass (zone 2). 83.8% of injectate went into epidural space when the needle tip was medial to midline of the lateral mass (zone 3). 100% of injectate flowed epidurally when the needle tip was medial to or at the medial cortex of the lateral mass (zone 4). There was no statistically significant difference with regards to central epidural flow and the needle tip position on lateral view. Conclusion To ensure central epidural flow with ECNRBs one must be prepared to pass the needle tip medial to midplane of the lateral mass or to medial cortex of the lateral mass. Approximately 16% of ECNRBs with needle tip medial to midline of the lateral mass did not flow into epidural space. One cannot claim a nerve block is an epidural block unless epidural flow of injectate is observed. PMID- 24494177 TI - Experiments with a novel content-based image retrieval software: can we eliminate classification systems in adolescent idiopathic scoliosis? AB - Study Design Preliminary evaluation of new tool. Objective To ascertain whether the newly developed content-based image retrieval (CBIR) software can be used successfully to retrieve images of similar cases of adolescent idiopathic scoliosis (AIS) from a database to help plan treatment without adhering to a classification scheme. Methods Sixty-two operated cases of AIS were entered into the newly developed CBIR database. Five new cases of different curve patterns were used as query images. The images were fed into the CBIR database that retrieved similar images from the existing cases. These were analyzed by a senior surgeon for conformity to the query image. Results Within the limits of variability set for the query system, all the resultant images conformed to the query image. One case had no similar match in the series. The other four retrieved several images that were matching with the query. No matching case was left out in the series. The postoperative images were then analyzed to check for surgical strategies. Broad guidelines for treatment could be derived from the results. More precise query settings, inclusion of bending films, and a larger database will enhance accurate retrieval and better decision making. Conclusion The CBIR system is an effective tool for accurate documentation and retrieval of scoliosis images. Broad guidelines for surgical strategies can be made from the postoperative images of the existing cases without adhering to any classification scheme. PMID- 24494178 TI - Early predictors of health-related quality of life outcomes in polytrauma patients with spine injuries: a level 1 trauma center study. AB - Study Design Retrospective review on clinical-quality trauma registry prospective data. Objective To identify early predictors of suboptimal health status in polytrauma patients with spine injuries. Methods A retrospective review on a prospective cohort was performed on spine-injured polytrauma patients with successful discharge from May 2009 to January 2011. The Short Form 12 Questionnaire Health Survey (SF-12) was used in the health status assessment of these patients. Univariate and multivariate logistic regression models were applied to investigate the effects of the Injury Severity Score, age, blood sugar level, vital signs, brain trauma severity, comorbidities, coagulation profile, spine trauma-related neurologic status, and spine injury characteristics of the patients. Results The SF-12 had a 52.3% completion rate from 915 patients. The patients who completed the SF-12 were younger, and there were fewer patients with severe spinal cord injuries (American Spinal Injury Association classifications A, B, and C). Other comparison parameters were satisfactorily matched. Multivariate logistic regression revealed five early predictive factors with statistical significance (p <= 0.05). They were (1) tachycardia (odds ratio [OR] = 1.88; confidence interval [CI] = 1.11 to 3.19), (2) hyperglycemia (OR = 2.65; CI = 1.51 to 4.65), (3) multiple chronic comorbidities (OR = 2.98; CI = 1.68 to 5.26), and (4) thoracic spine injuries (OR = 1.54; CI = 1.01 to 2.37). There were no independent early predictive factors identified for suboptimal mental health related qualify of life outcomes. Conclusion Early independent risk factors predictive of suboptimal physical health status identified in a level 1 trauma center in polytrauma patients with spine injuries were tachycardia, hyperglycemia, multiple chronic medical comorbidities, and thoracic spine injuries. Early spine trauma risk factors were shown not to predict suboptimal mental health status outcomes. PMID- 24494179 TI - The effect of a cyclooxygenase 2 inhibitor on early degenerated human nucleus pulposus explants. AB - Study Design Preclinical in vitro culture of human degenerated nucleus pulposus (NP) tissue. Objective Cyclooxygenase 2 inhibitors (e.g., celecoxib) inhibit prostaglandin E2 (PGE2) production, and they have been shown to upregulate regeneration of articular cartilage. In this study, we developed an explant culture system for use with human tissue and tested the potential of celecoxib. Methods NP explants were cultured with or without 1 MUM of celecoxib and were analyzed at days 0 and 7 for biochemical content (water, sulfated glycosaminoglycans, hydroxyproline, and DNA), gene expression (for disk matrix anabolic and catabolic markers), and PGE2 content. Results Water and biochemical contents as well as gene expression remained close to native values after 1 week of culture. PGE2 levels were not increased in freshly harvested human NP tissue and thus were not reduced in treated tissues. Although no anabolic effects were observed at the dosage and culture duration used, no detrimental effects were observed and some specimens did respond by lowering PGE2. Conclusions Human degenerated NP explants were successfully cultured in a close to in vivo environment for 1 week. Further research, especially dosage-response studies, is needed to understand the role of PGE2 in low back pain and the potential of celecoxib to treat painful disks. PMID- 24494180 TI - Neurologic recovery after anterior cervical discectomy and fusion. AB - Study Design Retrospective review. Objective The objective of this study is to describe the natural history of neurologic recovery after anterior cervical discectomy and fusion (ACDF). Methods Patients between 18 and 80 years of age, diagnosed with cervical radiculopathy, who underwent single-level ACDF and were followed for a minimum of 2 years were identified from a single-center database. Sensory and motor deficits were documented and graded based on physical examination findings at preoperative and postoperative visits, and used to calculate deficit rates. Results One hundred eighteen patients were included in the study. Mean age was 46 +/- 9.2 years and mean follow-up time was 3.8 +/- 2.1 years. At the time of surgery, 66% had a sensory deficit. Recovery of sensory function was seen in 85% of patients within 1 year. At final follow-up, new sensory deficits had developed in 30% of patients, 60% of whom had adjacent-level sensory deficits. Patients with preoperative sensory deficits tended to be more likely to develop a new deficit postoperatively (p = 0.05). At the time of surgery, 55% had a motor deficit. Recovery of motor function was seen in 95% of patients within 1 year, and 14% developed new postoperative motor deficits by final follow-up. Of those patients who developed a new motor deficit postoperatively, 76% did so at an adjacent level. Conclusions In our series, a high percentage of patients recovered neurologic function during the first year after ACDF. Adjacent-level and remote-level degeneration were large contributors to neurologic deficits that occurred in subsequent years. PMID- 24494181 TI - Surgical strategies to improve fixation in the osteoporotic spine: the effects of tapping, cement augmentation, and screw trajectory. AB - Study Design Biomechanical study of pedicle screw fixation in osteoporotic bone. Objective To investigate whether it is better to tap or not tap osteoporotic bone prior to placing a cement-augmented pedicle screw. Methods Initially, we evaluated load to failure of screws placed in cancellous bone blocks with or without prior tapping as well as after varying the depths of tapping prior to screw insertion. Then we evaluated load to failure of screws placed in bone block models with a straight-ahead screw trajectory as well as with screws having a 23 degree cephalad trajectory (toward the end plate). These techniques were tested with nonaugmented (NA) screws as well as with bioactive cement (BioC) augmentation prior to screw insertion. Results In the NA group, pretapping decreased fixation strength in a dose-dependent fashion. In the BioC group, the tapped screws had significantly greater loads to failure (p < 0.01). Comparing only the screw orientation, the screws oriented at 23 degrees cephalad had a significantly higher failure force than their respective counterparts at 0 degrees (p < 0.01). Conclusions Standard pedicle screw fixation is often inadequate in the osteoporotic spine, but this study suggests tapping prior to cement augmentation will substantially improve fixation when compared with not tapping. Angulating screws more cephalad also seems to enhance aging spine fixation. PMID- 24494183 TI - Traumatic lumbosacral spondyloptosis: a case report and review of the literature. AB - Study Design Case report and review of the literature. Objective To report a case of traumatic L5-S1 spondyloptosis and review the literature. Method A 28-year-old man presented with severe low back pain, numbness at the soles of feet, and bowel and bladder dysfunction. Two days before admission, a tree trunk fell on his back while he was seated. A two-stage posterior-anterior procedure was performed. At the first stage, posterior decompression, reduction, and fusion with instrumentation were performed. At the second stage, which was performed 6 days after the first stage, the patient underwent anterior lumbar interbody fusion. The patient received physical therapy 1 week after the second stage. Results The patient's numbness improved immediately after the first posterior surgery. His fecal and urinary incontinence improved 6 months after discharge. He has been pain-free for a year and has returned to work. Conclusion A PubMed search was performed using the following keywords: lumbosacral spondyloptosis, lumbosacral dislocation, and L5-S1 traumatic dislocation. The search returned only nine reported cases of traumatic spondyloptosis. Traumatic spondyloptosis at the lumbosacral junction is a rare ailment that should be suspected in cases of high, direct, and posterior impact on the low lumbar area, and surgical treatment should be the standard choice of care. PMID- 24494182 TI - Case study of a spinal epidural capillary hemangioma: a 4-year postoperative follow-up. AB - Study Design Case study. Objectives We report the case of a 58-year-old Caucasian man, who presented with a 4-month history of increasing low back pain and gait difficulty. Objective neurologic examination revealed a severe paraparetic symptomatology without any sphincter involvement. Methods Spinal magnetic resonance imaging (MRI) showed an extradural mass formation situated dorsally at the level of thoracic vertebrae T2 to T4. Results A laminectomy was performed with total removal of the mass; histology suggested a highly vascularized lesion with lobular architecture, which seems a very rare case, compatible with a capillary hemangioma. Conclusions A careful follow-up for the next 4 years, including control MRIs every postoperative year, showed a very good neurologic condition of the patient and no recurrence on imaging findings. PMID- 24494184 TI - Subaxial cervical spine trauma: evaluation and surgical decision-making. AB - Study Design Literature review. Objective To discuss the evaluation and management of subaxial cervical spine trauma (C3-7). Methods A literature review of the main imaging modalities, classification systems, and nonsurgical and surgical treatment performed. Results Computed tomography and reconstructions allow for accurate radiologic identification of subaxial cervical spine trauma in most cases. Magnetic resonance imaging can be utilized to evaluate the stabilizing discoligamentous complex, the nerves, and the spinal cord. The Subaxial Injury Classification (SLIC) is a new system that aids in injury classification and helps guide the decision-making process of conservative versus surgical treatment. Though promising, the SLIC system requires further validation. When the decision for surgical treatment is made, early decompression (less than 24 hours) has been associated with better neurologic recovery. Surgical treatment should be individualized based on the injury characteristics and surgeon's preferences. Conclusions The current state of subaxial cervical spine trauma is one of great progress. However, many questions remain unanswered. We need to continue to account for the individual patient, surgeon, and hospital circumstances that effect decision making and care. PMID- 24494185 TI - Effect of pumpkin on the quality characteristics and storage quality of aerobically packaged chicken sausages. AB - The present study was undertaken to evaluate the effect of different levels of pumpkin on the quality characteristics of chicken sausages. The pumpkin was incorporated at three different levels viz. 6, 12 and 18 percent replacing lean meat in the formulation. The products were analyzed for various physicochemical and sensory attributes. pH, emulsion stability, cooking yield, crude protein, ether extract and ash content of the products showed significantly (p < 0.05) decreasing trend with increasing levels of incorporation of pumpkin however, there was a significant (p < 0.05) increase in the moisture and crude fibre content. Based on various parameters, 12 percent level of incorporation was optimized as best. Chicken sausages with optimum level of pumpkin along with control were aerobically packaged in LDPE pouches and assessed for storage quality under refrigerated (4 +/- 1 degrees C) conditions. The mean values of pH and all the sensory parameters showed significantly (p < 0.05) decreasing trend for both control as well as treatment samples whereas TBARS (mg malonaldehyde/kg) value, total plate count (log cfu/g) and yeast and mould count (log cfu/g) showed significantly (p < 0.05) increasing trend with storage. Coliforms (log cfu/g) were not detected throughout the period of storage. Thus, fibre enriched chicken sausages could be successfully stored for a period of 14 days at refrigeration temperature (4 +/- 1 degrees C) without any significant loss in quality. PMID- 24494186 TI - Preventive and therapeutic effects of nitrite supplementation in experimental inflammatory bowel disease. AB - BACKGROUND: Inorganic nitrate and nitrite have emerged as alternative substrates for nitric oxide (NO) generation in the gastrointestinal tract, and have shown to be protective against drug-induced gastric injury. The aim of this study was to investigate the preventive and therapeutic effects of nitrate and nitrite in a model of experimental colitis. METHODS: Colitis was induced in mice by administrating dextran sulfate sodium (DSS) with concurrent administration of nitrite (1 mM) or nitrate (10 mM) in the drinking water for 7 days. A therapeutic approach was also investigated by initiating nitrite treatment 3 days after DSS induced colitis. Clinical and inflammatory markers were assessed and the colonic mucus thickness was measured in vivo. The effect of nitrite on wound healing was evaluated using colon epithelial cells. RESULTS: Concurrent administration of DSS and nitrite (1 mM) alleviated inflammation as determined by reduced disease activity index score (DAI) and increased colon length, while nitrate (10 mM) only reduced the DAI-score. Nitrite also displayed therapeutic effects by ameliorating established colonic inflammation with reduced colonic expression of iNOS and improving histopathology. DSS-induced decrease in colonic mucus thickness was completely prevented by nitrite administration. In addition, goblet cell abundance was lower by DSS treatment, but was increased by addition of nitrite. Further studies using colon epithelial cells revealed an NO-dependent improvement in wound healing with nitrite administration. CONCLUSION: Nitrite exerts both preventive and therapeutic effects in colonic inflammation. The protective effects involve preservation of an intact adherent mucus layer and regulation of epithelial cell restitution. PMID- 24494188 TI - Study designs to investigate Nox1 acceleration of neoplastic progression in immortalized human epithelial cells by selection of differentiation resistant cells. AB - To investigate the role of NADPH oxidase homolog Nox1 at an early step of cell transformation, we utilized human gingival mucosal keratinocytes immortalized by E6/E7 of human papillomavirus (HPV) type 16 (GM16) to generate progenitor cell lines either by chronic ethanol exposure or overexpression with Nox1. Among several cobblestone epithelial cell lines obtained, two distinctive spindle cell lines - FIB and NuB1 cells were more progressively transformed exhibiting tubulogenesis and anchorage-independent growth associated with increased invasiveness. These spindle cells acquired molecular markers of epithelial mesenchymal transition (EMT) including mesenchymal vimentin and simple cytokeratins (CK) 8 and 18 as well as myogenic alpha-smooth muscle actin and caldesmon. By overexpression and knockdown experiments, we showed that Nox1 on a post-translational level regulated the stability of CK18 in an ROS-, phosphorylation- and PKCepilon-dependent manner. PKCepilon may thus be used as a therapeutic target for EMT inhibition. Taken together, Nox1 accelerates neoplastic progression by regulating structural intermediate filaments leading to EMT of immortalized human gingival epithelial cells. PMID- 24494187 TI - Autophagy as an essential cellular antioxidant pathway in neurodegenerative disease. AB - Oxidative stress including DNA damage, increased lipid and protein oxidation, are important features of aging and neurodegeneration suggesting that endogenous antioxidant protective pathways are inadequate or overwhelmed. Importantly, oxidative protein damage contributes to age-dependent accumulation of dysfunctional mitochondria or protein aggregates. In addition, environmental toxins such as rotenone and paraquat, which are risk factors for the pathogenesis of neurodegenerative diseases, also promote protein oxidation. The obvious approach of supplementing the primary antioxidant systems designed to suppress the initiation of oxidative stress has been tested in animal models and positive results were obtained. However, these findings have not been effectively translated to treating human patients, and clinical trials for antioxidant therapies using radical scavenging molecules such as alpha-tocopherol, ascorbate and coenzyme Q have met with limited success, highlighting several limitations to this approach. These could include: (1) radical scavenging antioxidants cannot reverse established damage to proteins and organelles; (2) radical scavenging antioxidants are oxidant specific, and can only be effective if the specific mechanism for neurodegeneration involves the reactive species to which they are targeted and (3) since reactive species play an important role in physiological signaling, suppression of endogenous oxidants maybe deleterious. Therefore, alternative approaches that can circumvent these limitations are needed. While not previously considered an antioxidant system we propose that the autophagy lysosomal activities, may serve this essential function in neurodegenerative diseases by removing damaged or dysfunctional proteins and organelles. PMID- 24494189 TI - Circulating levels of linoleic acid and HDL-cholesterol are major determinants of 4-hydroxynonenal protein adducts in patients with heart failure. AB - OBJECTIVE: Measurements of oxidative stress biomarkers in patients with heart failure (HF) have yielded controversial results. This study aimed at testing the hypothesis that circulating levels of the lipid peroxidation product 4 hydroxynonenal bound to thiol proteins (4HNE-P) are strongly associated with those of its potential precursors, namely n-6 polyunsaturated fatty acids (PUFA). METHODS AND RESULTS: Circulating levels of 4HNE-P were evaluated by gas chromatography-mass spectrometry in 71 control subjects and 61 ambulatory symptomatic HF patients along with various other clinically- and biochemically relevant parameters, including other oxidative stress markers, and total levels of fatty acids from all classes, which reflect both free and bound to cholesterol, phospholipids and triglycerides. All HF patients had severe systolic functional impairment despite receiving optimal evidence-based therapies. Compared to controls, HF patients displayed markedly lower circulating levels of HDL- and LDL-cholesterol, which are major PUFA carriers, as well as of PUFA of the n-6 series, specifically linoleic acid (LA; P=0.001). Circulating 4HNE-P in HF patients was similar to controls, albeit multiple regression analysis revealed that LA was the only factor that was significantly associated with circulating 4HNE-P in the entire population (R (2)=0.086; P=0.02). In HF patients only, 4HNE P was even more strongly associated with LA (P=0.003) and HDL-cholesterol (p<0.0002). Our results demonstrate that 4HNE-P levels, expressed relative to HDL cholesterol, increase as HDL-cholesterol plasma levels decrease in the HF group only. CONCLUSION: Results from this study emphasize the importance of considering changes in lipids and lipoproteins in the interpretation of measurements of lipid peroxidation products. Further studies appear warranted to explore the possibility that HDL-cholesterol particles may be a carrier of 4HNE adducts. PMID- 24494190 TI - Mitochondria-targeted heme oxygenase-1 induces oxidative stress and mitochondrial dysfunction in macrophages, kidney fibroblasts and in chronic alcohol hepatotoxicity. AB - The inducible form of Heme Oxygenase-1 (HO-1), a major endoplasmic reticulum (ER) associated heme protein, is known to play important roles in protection against oxidative and chemical stress by degrading free heme released from degradation of heme proteins. In this study we show that induced expression of HO-1 by subjecting macrophage RAW-264.7 cells to chemical or physiological hypoxia resulted in significant translocation of HO-1 protein to mitochondria. Transient transfection of COS-7 cells with cloned cDNA also resulted in mitochondrial translocation of HO-1. Deletion of N-terminal ER targeting domain increased mitochondrial translocation under the transient transfection conditions. Mitochondrial localization of both intact HO-1 and N-terminal truncated HO-1 caused loss of heme aa-3 and cytochrome c oxidase (CcO) activity in COS-7 cells. The truncated protein, which localizes to mitochondria at higher levels, induced substantially steeper loss of CcO activity and reduced heme aa3 content. Furthermore, cells expressing mitochondria targeted HO-1 also induced higher ROS production. Consistent with dysfunctional state of mitochondria induced by HO-1, the mitochondrial recruitment of autophagy markers LC-3 and Drp-1 was also increased in these cells. Chronic ethanol feeding in rats also caused an increase in mitochondrial HO-1 and decrease in CcO activity. These results show that as opposed to the protective effect of the ER associated HO-1, mitochondria targeted HO-1 under normoxic conditions induces mitochondrial dysfunction. PMID- 24494191 TI - The role of Nox1 and Nox2 in GPVI-dependent platelet activation and thrombus formation. AB - BACKGROUND: Activation of the platelet-specific collagen receptor, glycoprotein (GP) VI, induces intracellular reactive oxygen species (ROS) production; however the relevance of ROS to GPVI-mediated platelet responses remains unclear. OBJECTIVE: The objective of this study was to explore the role of the ROS producing NADPH oxidase (Nox)1 and 2 complexes in GPVI-dependent platelet activation and collagen-induced thrombus formation. METHODS AND RESULTS: ROS production was measured by quantitating changes in the oxidation-sensitive dye, H2DCF-DA, following platelet activation with the GPVI-specific agonist, collagen related peptide (CRP). Using a pharmacological inhibitor specific for Nox1, 2 acetylphenothiazine (ML171), and Nox2 deficient mice, we show that Nox1 is the key Nox homolog regulating GPVI-dependent ROS production. Nox1, but not Nox2, was essential for CRP-dependent thromboxane (Tx)A2 production, which was mediated in part through p38 MAPK signaling; while neither Nox1 nor Nox2 was significantly involved in regulating CRP-induced platelet aggregation/integrin alphaIIbbeta3 activation, platelet spreading, or dense granule and alpha-granule release (ATP release and P-selectin surface expression, respectively). Ex-vivo perfusion analysis of mouse whole blood revealed that both Nox1 and Nox2 were involved in collagen-mediated thrombus formation at arterial shear. CONCLUSION: Together these results demonstrate a novel role for Nox1 in regulating GPVI-induced ROS production, which is essential for optimal p38 activation and subsequent TxA2 production, providing an explanation for reduced thrombus formation following Nox1 inhibition. PMID- 24494193 TI - Methylglyoxal in cells elicits a negative feedback loop entailing transglutaminase 2 and glyoxalase 1. AB - Glyoxalase 1 (GlxI) is the key enzyme that converts the highly reactive alpha-oxo aldehydes into the corresponding alpha-hydroxy acids using l-glutathione as a cofactor. In our preliminary data, GlxI was identified as a substrate of transglutaminase 2 (TG2), a ubiquitous enzyme with multiple functions. According to the catalytic properties of TG2, protein cross-linking, polyamine conjugation, and/or deamidation are potential post-translational modifications. In this article, we have demonstrated that TG2 catalyzes either polyamine conjugation or deamidation to GlxI depending on the presence of polyamines or not. Deamidation leads to activation of GlxI while polyamine conjugation results in activation of GlxI as well as stabilization of GlxI against denaturation treatment. In cultured HeLa cells, methylglyoxal challenge causes increase in intracellular levels of reactive oxygen species (ROS) and calcium leading to TG2 activation and subsequent transamidation and activation of GlxI. The inhibition of TG2 significantly weakens the cell resistance to the methylglyoxal challenge. Thus, GlxI is a novel substrate of TG2 and is activated by TG2 in vitro and in cellulo. Exposure to methylglyoxal elicits a negative feedback loop entailing ROS, calcium, TG2 and GlxI, thus leading to attenuation of the increase in the methylglyoxal level. The results imply that cancer cells highly express TG2 or GlxI can endure the oxidative stress derived from higher glycolytic flux and may gain extra growth advantage from the aerobic glycolysis. PMID- 24494192 TI - New insights into the mechanisms of polyphenols beyond antioxidant properties; lessons from the green tea polyphenol, epigallocatechin 3-gallate. AB - Green tea is rich in polyphenol flavonoids including catechins. Epigallocatechin 3-gallate (EGCG) is the most abundant and potent green tea catechin. EGCG has been extensively studied for its beneficial health effects as a nutriceutical agent. Based upon its chemical structure, EGCG is often classified as an antioxidant. However, treatment of cells with EGCG results in production of hydrogen peroxide and hydroxyl radicals in the presence of Fe (III). Thus, EGCG functions as a pro-oxidant in some cellular contexts. Recent investigations have revealed many other direct actions of EGCG that are independent from anti oxidative mechanisms. In this review, we discuss these novel molecular mechanisms of action for EGCG. In particular, EGCG directly interacts with proteins and phospholipids in the plasma membrane and regulates signal transduction pathways, transcription factors, DNA methylation, mitochondrial function, and autophagy to exert many of its beneficial biological actions. PMID- 24494194 TI - A review of the mitochondrial and glycolytic metabolism in human platelets and leukocytes: implications for their use as bioenergetic biomarkers. AB - The assessment of metabolic function in cells isolated from human blood for treatment and diagnosis of disease is a new and important area of translational research. It is now becoming clear that a broad range of pathologies which present clinically with symptoms predominantly in one organ, such as the brain or kidney, also modulate mitochondrial energetics in platelets and leukocytes allowing these cells to serve as "the canary in the coal mine" for bioenergetic dysfunction. This opens up the possibility that circulating platelets and leukocytes can sense metabolic stress in patients and serve as biomarkers of mitochondrial dysfunction in human pathologies such as diabetes, neurodegeneration and cardiovascular disease. In this overview we will describe how the utilization of glycolysis and oxidative phosphorylation differs in platelets and leukocytes and discuss how they can be used in patient populations. Since it is clear that the metabolic programs between leukocytes and platelets are fundamentally distinct the measurement of mitochondrial function in distinct cell populations is necessary for translational research. PMID- 24494195 TI - Mechanism of faster NO scavenging by older stored red blood cells. AB - The blood storage lesion involves morphological and biochemical changes of red blood cells (RBCs) that occur during storage. These include conversion of the biconcave disc morphology to a spherical one, decreased mean corpuscular hemoglobin concentration, varied mean corpuscular volume, reduced integrity of the erythrocyte membrane with formation of microparticles, and increased cell free hemoglobin. We studied the extent that older stored red blood cells scavenge nitric oxide (NO) faster than fresher stored red blood cells. Using electron paramagnetic resonance spectroscopy and stopped-flow absorption spectroscopy to measure the rate of NO uptake and reaction with hemoglobin in red cells, we found that older stored red blood cells scavenge NO about 1.8 times faster than fresher ones. Based on these experimental data, we simulated NO scavenging by fresher or older stored red blood cells with a biconcave or spherical geometry, respectively, in order to explore the mechanism of NO scavenging related to changes that occur during blood storage. We found that red blood cells with a spherical geometry scavenges NO about 2 times slower than ones with a biconcave geometry, and a smaller RBC hemoglobin concentration or volume increases NO scavenging by red blood cells. Our simulations demonstrate that even the most extreme possible changes in mean corpuscular hemoglobin concentration and mean corpuscular volume that favor increased NO scavenging are insufficient to account for what is observed experimentally. Therefore, RBC membrane permeability must increase during storage and we find that the permeability is likely to increase between 5 and 70 fold. Simulations using a two-dimensional blood vessel show that even a 5-fold increase in membrane permeability to NO can reduce NO bioavailability at the smooth muscle. BACKGROUND: Transfusion of older stored blood may be harmful. RESULTS: Older stored red blood cells scavenge nitric oxide more than fresher cells. CONCLUSION: As stored red blood cells age, structural and biochemical changes occur that lead to faster scavenging. SIGNIFICANCE: Increased nitric oxide scavenging by red blood cells as a function of storage age contributes to deleterious effects upon transfusion. PMID- 24494196 TI - Absence of manganese superoxide dismutase delays p53-induced tumor formation. AB - BACKGROUND: Manganese superoxide dismutase (MnSOD) is a mitochondrial antioxidant enzyme that is down-regulated in a majority of cancers. Due to this observation, as well as MnSOD's potent antioxidant enzymatic activity, MnSOD has been suggested as a tumor suppressor for over 30 years. However, testing this postulate has proven difficult due to the early post-natal lethality of the MnSOD constitutive knock-out mouse. We have previously used a conditional tissue specific MnSOD knock-out mouse to study the effects of MnSOD loss on the development of various cell types, but long-term cancer development studies have not been performed. We hypothesized the complete loss of MnSOD would significantly increase the rate of tumor formation in a tissue-specific manner. RESULTS: Utilizing a hematopoietic stem cell specific Cre-recombinase mouse model, we created pan-hematopoietic cell MnSOD knock-out mice. Additionally, we combined this MnSOD knock-out with two well established models of lymphoma development: B-lymphocyte specific Myc over-expression and conditional pan hematopoietic cell p53 knock-out. Mice were allowed to age unchallenged until illness or death had occurred. Contrary to our initial hypothesis, the loss of MnSOD alone was insufficient in causing an increase in tumor formation, but did cause significant life-shortening skin pathology in a strain-dependent manner. Moreover, the loss of MnSOD in conjunction with either Myc overexpression or p53 knock-out did not accelerate tumor formation, and in fact delayed lymphomagenesis in the p53 knock-out model. CONCLUSIONS: Our findings strongly suggest that MnSOD does not act as a classical tumor suppressor in hematological tissues. Additionally, the complete loss of MnSOD may actually protect from tumor development by the creation of an unfavorable redox environment for tumor progression. In summary, these results in combination with our previous work suggest that MnSOD needs to be tightly regulated for proper cellular homeostasis, and altering the activity in either direction may lead to cellular dysfunction, oncogenesis, or death. PMID- 24494197 TI - Modulation of mitochondrial bioenergetics in a skeletal muscle cell line model of mitochondrial toxicity. AB - Mitochondrial toxicity is increasingly being implicated as a contributing factor to many xenobiotic-induced organ toxicities, including skeletal muscle toxicity. This has necessitated the need for predictive in vitro models that are able to sensitively detect mitochondrial toxicity of chemical entities early in the research and development process. One such cell model involves substituting galactose for glucose in the culture media. Since cells cultured in galactose are unable to generate sufficient ATP from glycolysis they are forced to rely on mitochondrial oxidative phosphorylation for ATP generation and consequently are more sensitive to mitochondrial perturbation than cells grown in glucose. The aim of this study was to characterise cellular growth, bioenergetics and mitochondrial toxicity of the L6 rat skeletal muscle cell line cultured in either high glucose or galactose media. L6 myoblasts proliferated more slowly when cultured in galactose media, although they maintained similar levels of ATP. Galactose cultured L6 cells were significantly more sensitive to classical mitochondrial toxicants than glucose-cultured cells, confirming the cells had adapted to galactose media. Analysis of bioenergetic function with the XF Seahorse extracellular flux analyser demonstrated that oxygen consumption rate (OCR) was significantly increased whereas extracellular acidification rate (ECAR), a measure of glycolysis, was decreased in cells grown in galactose. Mitochondria operated closer to state 3 respiration and had a lower mitochondrial membrane potential and basal mitochondrial O2 (*-) level compared to cells in the glucose model. An antimycin A (AA) dose response revealed that there was no difference in the sensitivity of OCR to AA inhibition between glucose and galactose cells. Importantly, cells in glucose were able to up-regulate glycolysis, while galactose cells were not. These results confirm that L6 cells are able to adapt to growth in a galactose media model and are consequently more susceptible to mitochondrial toxicants. PMID- 24494198 TI - Nitrosopersulfide (SSNO(-)) accounts for sustained NO bioactivity of S nitrosothiols following reaction with sulfide. AB - Sulfide salts are known to promote the release of nitric oxide (NO) from S nitrosothiols and potentiate their vasorelaxant activity, but much of the cross talk between hydrogen sulfide and NO is believed to occur via functional interactions of cell regulatory elements such as phosphodiesterases. Using RFL-6 cells as an NO reporter system we sought to investigate whether sulfide can also modulate nitrosothiol-mediated soluble guanylyl cyclase (sGC) activation following direct chemical interaction. We find a U-shaped dose response relationship where low sulfide concentrations attenuate sGC stimulation by S nitrosopenicillamine (SNAP) and cyclic GMP levels are restored at equimolar ratios. Similar results are observed when intracellular sulfide levels are raised by pre-incubation with the sulfide donor, GYY4137. The outcome of direct sulfide/nitrosothiol interactions also critically depends on molar reactant ratios and is accompanied by oxygen consumption. With sulfide in excess, a 'yellow compound' accumulates that is indistinguishable from the product of solid phase transnitrosation of either hydrosulfide or hydrodisulfide and assigned to be nitrosopersulfide (perthionitrite, SSNO(-); lambda max 412 nm in aqueous buffers, pH 7.4; 448 nm in DMF). Time-resolved chemiluminescence and UV-visible spectroscopy analyses suggest that its generation is preceded by formation of the short-lived NO-donor, thionitrite (SNO(-)). In contrast to the latter, SSNO(-) is rather stable at physiological pH and generates both NO and polysulfides on decomposition, resulting in sustained potentiation of SNAP-induced sGC stimulation. Thus, sulfide reacts with nitrosothiols to form multiple bioactive products; SSNO(-) rather than SNO(-) may account for some of the longer-lived effects of nitrosothiols and contribute to sulfide and NO signaling. PMID- 24494199 TI - Intracellular redox status controls membrane localization of pro- and anti migratory signaling molecules. AB - Shifts in intracellular Reactive Oxygen Species (ROS) have been shown to contribute to carcinogenesis and to tumor progression. In addition to DNA and cell damage by surges in ROS, sub-lethal increases in ROS are implicated in regulating cellular signaling that enhances pro-metastatic behavior. We previously showed that subtle increases in endogenous H2O2 regulate migratory and invasive behavior of metastatic bladder cancer cells through phosphatase inhibition and consequential phosphorylation of p130cas, an adapter of the FAK signaling pathway. We further showed that enhanced redox status contributed to enhanced localization of p130cas to the membrane of metastatic cells. Here we show that this signaling complex can similarly be induced in a redox-engineered cell culture model that enables regulation of intracellular steady state H2O2 level by enforced expression of superoxide dismutase 2 (Sod2) and catalase. Expression of Sod2 leads to enhanced p130cas phosphorylation in HT-1080 fibrosarcoma and UM-UC-6 bladder cancer cells. These changes are mediated by H2O2, as co-expression of Catalase abrogates p130cas phosphorylation and its interaction with the adapter protein Crk. Importantly, we establish that the redox environment influence the localization of the tumor suppressor and phosphatase PTEN, in both redox-engineered and metastatic bladder cancer cells that display endogenous increases in H2O2. Importantly, PTEN oxidation leads to its dissociation from the plasma membrane. This indicates that oxidation of PTEN not only influences its activity, but also regulates its cellular localization, effectively removing it from its primary site of lipid phosphatase activity. These data introduce hitherto unappreciated paradigms whereby ROS can reciprocally regulate the cellular localization of pro- and anti-migratory signaling molecules, p130cas and PTEN, respectively. These data further confirm that altering antioxidant status and the intracellular ROS environment can have profound effects on pro-metastatic signaling pathways. PMID- 24494200 TI - Endothelial nitric oxide synthase in red blood cells: key to a new erythrocrine function? AB - Red blood cells (RBC) have been considered almost exclusively as a transporter of metabolic gases and nutrients for the tissues. It is an accepted dogma that RBCs take up and inactivate endothelium-derived NO via rapid reaction with oxyhemoglobin to form methemoglobin and nitrate, thereby limiting NO available for vasodilatation. Yet it has also been shown that RBCs not only act as "NO sinks", but exert an erythrocrine function - i.e an endocrine function of RBC - by synthesizing, transporting and releasing NO metabolic products and ATP, thereby potentially controlling systemic NO bioavailability and vascular tone. Recent work from our and others laboratory demonstrated that human RBCs carry an active type 3, endothelial NO synthase (eNOS), constitutively producing NO under normoxic conditions, the activity of which is compromised in patients with coronary artery disease. In this review we aim to discuss the potential role of red cell eNOS in RBC signaling and function, and to critically revise evidence to this date showing a role of non-endothelial circulating eNOS in cardiovascular pathophysiology. PMID- 24494201 TI - Ursolic acid protects monocytes against metabolic stress-induced priming and dysfunction by preventing the induction of Nox4. AB - AIMS: Dietary supplementation with ursolic acid (UA) prevents monocyte dysfunction in diabetic mice and protects mice against atherosclerosis and loss of renal function. The goal of this study was to determine the molecular mechanism by which UA prevents monocyte dysfunction induced by metabolic stress. METHODS AND RESULTS: Metabolic stress sensitizes or "primes" human THP-1 monocytes and murine peritoneal macrophages to the chemoattractant MCP-1, converting these cells into a hyper-chemotactic phenotype. UA protected THP-1 monocytes and peritoneal macrophages against metabolic priming and prevented their hyper-reactivity to MCP-1. UA blocked the metabolic stress-induced increase in global protein-S-glutathionylation, a measure of cellular thiol oxidative stress, and normalized actin-S-glutathionylation. UA also restored MAPK phosphatase-1 (MKP1) protein expression and phosphatase activity, decreased by metabolic priming, and normalized p38 MAPK activation. Neither metabolic stress nor UA supplementation altered mRNA or protein levels of glutaredoxin-1, the principal enzyme responsible for the reduction of mixed disulfides between glutathione and protein thiols in these cells. However, the induction of Nox4 by metabolic stress, required for metabolic priming, was inhibited by UA in both THP 1 monocytes and peritoneal macrophages. CONCLUSION: UA protects THP-1 monocytes against dysfunction by suppressing metabolic stress-induced Nox4 expression, thereby preventing the Nox4-dependent dysregulation of redox-sensitive processes, including actin turnover and MAPK-signaling, two key processes that control monocyte migration and adhesion. This study provides a novel mechanism for the anti-inflammatory and athero- and renoprotective properties of UA and suggests that dysfunctional blood monocytes may be primary targets of UA and related compounds. PMID- 24494202 TI - NADPH oxidase-dependent redox signaling in TGF-beta-mediated fibrotic responses. AB - Uncontrolled fibrosis in organs like heart, kidney, liver and lung is detrimental and may lead to end-stage organ failure. Currently there is no effective treatment for fibrotic disorders. Transforming growth factor (TGF)-beta has a fundamental role in orchestrating the process of fibrogenesis; however, interventions directly targeting TGF-beta would have undesired systemic side effects due to the multiple physiological functions of TGF-beta. Further characterization of the downstream signaling pathway(s) involved in TGF-beta mediated fibrosis may lead to discovery of novel treatment strategies for fibrotic disorders. Accumulating evidence suggests that Nox4 NADPH oxidase may be an important downstream effector in mediating TGF-beta-induced fibrosis, while NADPH oxidase-dependent redox signaling may in turn regulate TGF-beta/Smad signaling in a feed-forward manner. It is proposed that pharmacological inhibition of the Nox4 function may represent a novel approach in treatment of fibrotic disorders. PMID- 24494203 TI - Possible involvement of nuclear factor erythroid 2-related factor 2 in the gene expression of Cyp2b10 and Cyp2a5. AB - Cytochrome P450 gene expression is altered by various chemical compounds. In this study, we used nuclear factor erythroid 2-related factor 2 (Nrf2)-deficient (Nrf2(-?-)) mice to investigate the involvement of Nrf2 in Cyp2b10 and Cyp2a5 gene expression. Phorone, an Nrf2 activator, strongly increased Cyp2b10 and Cyp2a5 mRNA as well as Nrf2 target genes, including NAD(P)H-quinone oxidoreductase-1 and heme oxygenase-1, in wild-type mouse livers 8 h after treatment. The phorone-induced mRNA levels in Nrf2(-?-) mouse livers were lower than that in wild-type mouse livers. Nrf2(-?-) mice showed attenuated Cyp2b10 and Cyp2a5 induction by phenobarbital, a classical Cyp2b inducer. These findings suggest that the Nrf2 pathway is involved in Cyp2b10 and Cyp2a5 gene expression. PMID- 24494205 TI - The Hartford hearing: is United listening? PMID- 24494206 TI - Simplicity isn't always a virtue. PMID- 24494207 TI - Options: eradication, doom or oblivion. PMID- 24494208 TI - RI clinicians, researchers share advances in recognition and treatment of CVD. PMID- 24494204 TI - Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. AB - Peripheral neuropathy is a severe dose limiting toxicity associated with cancer chemotherapy. Ever since it was identified, the clear pathological mechanisms underlying chemotherapy induced peripheral neuropathy (CIPN) remain sparse and considerable involvement of oxidative stress and neuroinflammation has been realized recently. Despite the empirical use of antioxidants in the therapy of CIPN, the oxidative stress mediated neuronal damage in peripheral neuropathy is still debatable. The current review focuses on nerve damage due to oxidative stress and mitochondrial dysfunction as key pathogenic mechanisms involved in CIPN. Oxidative stress as a central mediator of apoptosis, neuroinflammation, metabolic disturbances and bioenergetic failure in neurons has been highlighted in this review along with a summary of research on dietary antioxidants and other nutraceuticals which have undergone prospective controlled clinical trials in patients undergoing chemotherapy. PMID- 24494209 TI - Gender-specific aspects of cardiovascular disease. AB - When William Heberden gave his classic description of angina pectoris in 1768, he inadvertently described a gender-specific difference in heart disease when he noted the predominance of men with this condition. It is only in the last few decades that the medical profession has recognized that women are equally afflicted with atherosclerotic cardiovascular disease, albeit with some differences in presentation, risk factors and outcomes. This article will detail the ways in which men and women differ when it comes to the number one killer in the developed, and increasingly the developing, world. PMID- 24494210 TI - Takotsubo cardiomyopathy: a clinical review. AB - Takotsubo cardiomyopathy is a reversible cardiomyopathy which has increasingly been recognized in the differential diagnosis of patients presenting with acute coronary syndrome. It is characterized by transient systolic ventricular dysfunction with regional wall motion abnormalities beyond a single vascular territory and in the absence of significant epicardial coronary artery obstruction. Often, there is an acute emotional or physical stressor immediately preceding the presentation. Classical apical ballooning is seen on ventriculography or echocardiography but variants with isolated basal or mid wall akinesis have been described. Catecholamine excess and cardiotoxicity is the most compelling putative mechanism. The long-term prognosis is excellent but serious complications including cardiogenic shock and arrhythmias may occur acutely. Supportive treatment is the mainstay of therapy. PMID- 24494211 TI - Cardiac magnetic resonance imaging and computed tomography: state of the art in clinical practice. AB - Recent technological innovations in CT and MR imaging of the heart have vastly expanded the clinical utility of these modalities allowing them to complement and in some ways surpass the capabilities of more traditional methods. Cardiac MR (CMR) has an unrivaled ability to assess contractile function, characterize tissue, and detect minute areas of scar. In turn, CMR can reliably risk stratify ischemic heart disease and has emerged as a non-invasive gold standard technique for imaging non-ischemic cardiomyopathies.1 Cardiac CT (CCT) by comparison reveals cardiac structure and, in particular, coronary anatomy with remarkable sub-millimeter detail. For the first time, coronary stenoses can be directly and reliably visualized non-invasively. Owing to its very high negative predictive value for the detection of significant coronary obstruction, CCT can accurately exclude coronary disease as a cause of chest pain in low- to intermediate-risk populations. This article describes these modalities and their recent clinical advances. PMID- 24494212 TI - New diagnostic and therapeutic possibilities for diastolic heart failure. AB - Despite the fact that up to half of all heart failure occurs in patients without evidence of systolic cardiac dysfunction, there are no universally accepted diagnostic markers and no approved therapies for heart failure with preserved ejection fraction (HFpEF). HFpEF, otherwise known as diastolic heart failure, has nearly the same grim prognosis as systolic heart failure, and diastolic heart failure is increasing in incidence and prevalence. Major trials have shown that many of the treatments that are salutary in systolic heart failure have no beneficial effects in diastolic heart failure, suggesting different underlying mechanisms for these two disorders. Even criteria for diagnosis of HFpEF are still debated, and there is still no gold standard marker to detect diastolic dysfunction. Here, we will review some promising new insights into the pathogenesis of diastolic dysfunction that may lead to new diagnostic and therapeutic tools. PMID- 24494213 TI - Transcatheter aortic valve replacement: a review of current indications and outcomes. AB - In patients with symptomatic severe aortic stenosis, surgical aortic valve replacement (SAVR) improves survival, quality of life, and functional status compared with medical therapy. Based on the results of the randomized PARTNER Trial, Transcatheter Aortic Valve Replacement (TAVR) using the Edwards Sapien balloon expandable valve is now available in the United States for patients who are either inoperable due to anatomic concerns or severe medical co-morbidities, or as an alternative in patients considered high risk for SAVR. Fifty-six patients have been treated with TAVR at Rhode Island Hospital from March 2012 through October 2013 with similar outcomes to The PARTNER Trial and several large European registries. Second- generation valves and lower profile delivery systems designed to reduce the incidence of vascular complications, stroke, and perivalvular leak; and extension of TAVR to intermediate risk surgical patients, are under investigation. PMID- 24494214 TI - Using the alcohol, smoking and Substance Involvement Screening Test (ASSIST) to determine substance abuse prevalence in the RI trauma population. AB - BACKGROUND: Level I trauma centers are required to provide screening and brief interventions for alcohol abuse. The World Health Organization (WHO) Alcohol, Smoking and Substance Involvement Screening Test (ASSIST) is a validated screening measure for all substances of abuse. This study is the first to use the ASSIST to screen a trauma population. METHODS: A cross-sectional screening study using the ASSIST was conducted which included all patients admitted to the trauma service at Rhode Island Hospital during July and August 2012 who met inclusion criteria. RESULTS: The ASSIST categorized 25% of participants as needing a brief intervention for alcohol and an additional 6.3% as needing more intensive treatment. At least a brief intervention was indicated for at least one other substance besides alcohol in 37% of participants. CONCLUSIONS: The ability of the ASSIST to identify misuse of multiple substances makes it a good candidate for the screening measure used by trauma centers. PMID- 24494215 TI - Cecal volvulus diagnosed on CT in two distinct clinical settings. PMID- 24494218 TI - [German Medizinische Wochenschrift. Dear readers and even mature doctors,...]. PMID- 24494216 TI - Sexual orientation and health risks among RI high school students. PMID- 24494219 TI - Author's reply: To PMID 23202390. PMID- 24494220 TI - Author's reply: To PMID 23275214. PMID- 24494221 TI - Reply to Dixson: Infanticide triggers primate monogamy. PMID- 24494222 TI - Reply to Struys: Role of biomarker of 2-hydroxyglutarate in acute myeloid leukemia. PMID- 24494223 TI - Loss of cationic peptides with agarose gel-immobilized tris[2 carboxyethyl]phosphine (TCEP). PMID- 24494224 TI - Health on the agenda in Scottish independence referendum. PMID- 24494225 TI - Uptake of PrEP for HIV slow among MSM. PMID- 24494226 TI - Quacks and hacks: Georgian medicine and the power of advertising. PMID- 24494227 TI - Caffeinated sugar-sweetened beverages and common physical complaints in Icelandic children aged 10-12 years. AB - OBJECTIVE: Consumption of caffeinated sugar-sweetened beverages (CSSBs) among children and adolescents has increased markedly in recent years but the consequence of their consumption is not well understood. The objective of this study was to assess the prevalence of CSSBs in children aged 10-12 years and examine the relationship between CSSBs and common physical complaints. METHODS: Data from the 2013 cross-sectional population school survey Youth in Iceland (N=11,267, response rate: 90.1%, girls 49.7%)was used to assess the prevalence of cola and energy drink consumption and associations to headaches, stomachaches, sleeping problems and low appetite. RESULTS: Around 19% of boys and 8% of girls reported consuming cola drinks on a daily basis and 7% of boys and 3% of girls reported consuming energy drinks. A general trend of a dose-response relationship was observed between CSSBs and physical complaints for both types of beverages. These relationships were generally stronger for energy drinks than cola drinks. CONCLUSION: Our findings call into question the acceptability, availability, and marketing of CSSBs to 10-12 year-old children and adolescents. For validation purposes replications of these analyses are needed in other parts of the world, including studies using prospective longitudinal designs. PMID- 24494228 TI - Epigenetic modifications of nuclei differ between root meristematic tissues of Hordeum vulgare. AB - Recent studies on the role of epigenetic modifications during plant development emphasize the fact that both positional information and tissue specificity are essential factors that establish epigenetic marks and thus determine cell fate and differentiation processes. The root apical meristem (RAM ), which contains stem cells and generates radial patterns of tissues, is an ideal model for studying the correlation between cell position and cell-type differentiation, with particular emphasis on the patterns, global levels, and landscapes of epigenetic modifications. To date, there has been no clear evidence for differential levels of histone and DNA modification across root meristematic tissues. Our study clearly indicates that levels of modifications with potential epigenetic effects vary between RAM tissues. Of particular interest is that histone H4 acetylation in the epidermis is not simply replication-dependent and probably plays a role in epidermal cell differentiation. PMID- 24494229 TI - miR393 and miR164 influence indeterminate but not determinate nodule development. AB - The roles of auxin in the regulation of symbiotic legume nodule formation are unclear. We recently showed that enhanced sensitivity to auxin resulting from overexpression of miR160 inhibits determinate nodule formation in soybean. We examined the roles of miR393 and miR164 in soybean (that forms determinate nodules) and Medicago truncatula (that forms indeterminate nodules). Our results together with previous studies suggest that indeterminate nodule formation requires a higher, but narrow window of auxin sensitivity and that miR164 regulation is not crucial for determinate nodule formation. PMID- 24494230 TI - Analysis of UV-B regulated miRNAs and their targets in maize leaves. AB - UV-B radiation elicits physiological and developmental changes in plants. In this work, to characterize the mechanisms of gene regulation by UV-B radiation, the global miRNA expression profiles in juvenile maize leaves were compared under control conditions in the absence of UV-B and after an 8 h-UV-B treatment similar to ambient UV-B levels using small RNA microarrays. Seventeen miRNA s were identified that were differentially expressed in response to UV-B. In parallel, the expression of putative mRNA targets was examined in mRNA microarrays using the same RNA samples used for the small RNA analysis. In general, there is a strong negative correlation to the miRNA expression. Thus, post-transcriptional regulation is an important step in gene expression by UV-B radiation in maize. PMID- 24494231 TI - The impact of cytokinin on jasmonate-salicylate antagonism in Arabidopsis immunity against infection with Pst DC3000. AB - Cytokinin has long been shown to be an essential modulator of growth and development in plants. However, its implications in plant immunity have only recently been realized. The interaction between jasmonate and salicylate pathways is regarded as a central backbone of plant immune defense. However, the effect of cytokinin on the jasmonate and salicylate mediated balance in plant immunity is still not known. Here, we analyze the impact of cytokinin on the jasmonate salicylate antagonism in Arabidopsis immunity regarding infection with hemibiotrophic pathogen Pseudomonas syringae pv tomato DC3000 (Pst DC3000). Systems biology analysis of a refined hormone immune pathway model provides insights into the impact of cytokinin on the balance between jasmonate and salicylic acid pathways in Arabidopsis. Targeted experiments validate model simulations monitoring bacterial growth in wild type plants as well as in jasmonate pathway mutants. An integrated analysis shows that CK promotes the SA pathway of plant immunity and does not promote JA-mediated Arabidopsis susceptibility against infection with Pst DC3000. Finally, we discuss these results in the context of an emerging model of auxin-cytokinin antagonism in plant immunity. PMID- 24494232 TI - Near-isogenic lines for measuring phenotypic effects of DIMBOA-Glc methyltransferase activity in maize. AB - Three O-methyltransferases (BX10a, b, c) catalyze the conversion of 2,4-dihydroxy 7-methoxy-1,4-benzoxazin-3-one glucoside (DIM BOA-Glc) to 2-hydroxy-4,7-dimethoxy 1,4-benzoxazin-3-one glucoside (HDMBOA -Glc) in maize (Zea mays). Variation in benzoxazinoid accumulation and resistance to Rhopalosiphum maidis (corn leaf aphid) was attributed to a natural CACTA family transposon insertion that inactivates Bx10c. Whereas maize inbred line B73 has this transposon insertion, line CM L277 does not. To characterize the phenotypic effects of DIM BOA-Glc methyltransferase activity, we created near-isogenic lines derived from B73 and CM L277 that do or do not contain the transposon insertion. Bx10c inactivation causes high DIM BOA -Glc, low HDMBOA-Glc, and decreased aphid reproduction relative to near-isogenic lines that have a functional Bx10c gene. These results confirm the importance of this locus in maize aphid resistance. The availability of Bx10c near-isogenic lines will facilitate further research on the function of different benzoxazinoids and DIM BOA-Glc methyltransferase activity in maize defense against herbivores and pathogens. PMID- 24494233 TI - The role of RAR1 in Agrobacterium-mediated plant transformation. AB - RAR 1 is identified as a critical protein involved in plant innate immunity. We investigated the role of RAR 1 in Agrobacterium-mediated plant transformation based on the previous findings that accessory proteins associated with the E3 ligase complex such as SGT1, which tightly interacts with RAR 1, play a role in the transformation process. RAR1 gene silencing in Nicotiana benthamiana and Arabidopsis rar1 mutant analyses suggested that RAR1 is required for early stages of Agrobacterium-mediated plant transformation. This finding further illustrates that RAR 1, along with SGT1, that serve as a HSP90 co-chaperone is important for Agrobacterium-mediated plant transformation. PMID- 24494234 TI - Cosuppression of NtmybA1 and NtmybA2 causes downregulation of G2/M phaseexpressed genes and negatively affects both cell division and expansion in tobacco. AB - During the plant cell cycle, genes preferentially expressed at the G2/M phase are regulated by R1R2R3-type Myb transcription factors. To address the function of 2 tobacco R1R2R3-Myb proteins, NtmybA1 and NtmybA2, we generated transgenic tobacco plants in which endogenous NtmybA2 transcripts were significantly decreased, presumably due to cosuppression triggered by the presence of the NtmybA2 transgene. These lines showed a concomitant downregulation of structurally related NtmybA1 and many G2/M-expressed genes. In the cosuppression plants, we found a dwarf phenotype due to both reduced cell size and decreased cell number. Our results provide evidence confirming our previous view that NtmybA1 and NtmybA2 may regulate cell expansion as well as cell division by transcriptionally activating many G2/M-expressed genes in tobacco. PMID- 24494235 TI - The Arabidopsis gene ATST4a in not a typical brassinosteroid catabolic gene. AB - Brassinosteroid (BR) homeostasis is maintained in part by this hormone's catabolism. The presence of multiple BR-catabolic pathways in Arabidopsis demonstrates the importance of this process in growth and development. Previous biochemical analyses suggest that AT ST4a has BR catalytic activity. We have used both overexpression and loss-of-function genetic approaches to further explore the role of ATST4a in Arabidopsis. Up to 1000-fold overexpression of the ATST4a gene did not result in any characteristic BR-deficient phenotypes. In addition, the T-DNA insertion null mutant atst4a1-1 did not display enhanced seedling hypocotyl growth in the presence or absence of the active BR brassinolide when grown in white light. This lack of hallmark characteristics for BR-inacitivion genes suggests that ATST4a encodes an atypical BR catabolic enzyme. PMID- 24494236 TI - Disproportionality in safety warnings. PMID- 24494237 TI - A cellular gene as a double surveillance agent for plant to combat pathogen. AB - The tomato extreme resistance R-gene encodes Tm2/ Tm22 protein that interacts with the tobamovirus movement protein (MP) to induce hypersensitive response (HR) resulting in local resistance. R-gene mediated local resistance requires a functional RbCS that interacts with MP, restricting virus local infection. RbCS MP interaction is also required for tobamovirus systemic infection. "Loss-of function" RbCS allows local but not systemic infection. Thus, RbCS, a cellular gene, acts as a double surveillance agent to protect plant from pathogenic attack, suggesting a previously un-recognized defense strategy in plants. PMID- 24494238 TI - Induction and establishment of somatic embryogenesis in elite Indian cotton cultivar (Gossypium hirsutum L. cv Khandwa-2). AB - Embryogenesis in cotton is a difficult task due its genome dependency. We used 3 cotton cultivars (Khandwa-2, G. Cot. 10, and BC-68-2) and Coker-312 as control for regeneration. Efficient somatic embryogenesis was induced in agronomically important Indian cotton cultivars, Khandwa-2 and G. Cot. 10. For callusing in all the cultivars, different media combinations were tried. Embryogenesis was initiated on a hormone-free MS medium (MSB). For embryo maturation and recovery excess of L-glutamine and l-asparagine were used. Khandwa-2 somatic embryos were successfully regenerated into plants. However, no plantlet was obtained in case of G. Cot. 10. Callus induction was also observed in BC-68-2 but there was no embryogenesis observed. The study indicated that the medium and genotype significantly effects embryogenesis. An efficient protocol is described here for regenerating plants via somatic embryogenesis in an elite Indian cotton cultivar Khandwa-2. PMID- 24494239 TI - Piriformospora indica rescues growth diminution of rice seedlings during high salt stress. AB - Piriformospora indica association has been reported to increase biotic as well as abiotic stress tolerance of its host plants. We analyzed the beneficial effect of P. indica association on rice seedlings during high salt stress conditions (200 and 300 mM NaCl). The growth parameters of rice seedlings such as root and shoot lengths or fresh and dry weights were found to be enhanced in P. indica inoculated rice seedlings as compared with non-inoculated control seedlings, irrespective of whether they are exposed to salt stress or not. However, salt stressed seedlings performed much better in the presence of the fungus compared with non-inoculated control seedlings. The photosynthetic pigment content [chlorophyll (Chl) a, Chl b, and carotenoids] was significantly higher in P. indica-inoculated rice seedlings under high salt stress conditions as compared with salt-treated non-inoculated rice seedlings, in which these pigments were found to be decreased. Proline accumulation was also observed during P. indica colonization, which may help the inoculated plants to become salt tolerant. Taken together, P. indica rescues growth diminution of rice seedlings under salt stress. PMID- 24494240 TI - Unraveling the iron deficiency responsive proteome in Arabidopsis shoot by iTRAQ OFFGEL approach. AB - Iron (Fe) is required by plants for basic redox reactions in photosynthesis and respiration, and for many other key enzymatic reactions in biological processes. Fe homeostatic mechanisms have evolved in plants to enable the uptake and sequestration of Fe in cells. To elucidate the network of proteins that regulate Fe homeostasis and transport, we optimized the iTRAQ-OFFGEL method to identify and quantify the number of proteins that respond to Fe deficiency in the model plant Arabidopsis. In this study, Fe deficiency was created using Fe-deficient growth conditions, excess zinc (Zn), and use of the irt1-1 mutant in which the IRT1 Fe transporter is disrupted. Using the iTRAQ-OFFGEL approach, we identified 1139 proteins, including novel Fe deficiency-responsive proteins, in microsomal fractions isolated from 3 different types of Fe-deficient shoots compared with just 233 proteins identified using conventional iTRAQ-CEX. Further analysis showed that greater numbers of low-abundance proteins could be identified using the iTRAQ-OFFGEL method and that proteins could be identified from numerous cellular compartments. The improved iTRAQ-OFFGEL method used in this study provided an efficient means for identifying greater numbers of proteins from microsomal fractions of Arabidopsis shoots. The proteome identified in this study provides new insight into the regulatory cross talk between Fe-deficient and excess Zn conditions. PMID- 24494241 TI - Salicylic acid induces vanillin synthesis through the phospholipid signaling pathway in Capsicum chinense cell cultures. AB - Signal transduction via phospholipids is mediated by phospholipases such as phospholipase C (PLC) and D (PLD), which catalyze hydrolysis of plasma membrane structural phospholipids. Phospholipid signaling is also involved in plant responses to phytohormones such as salicylic acid (SA). The relationships between phospholipid signaling, SA, and secondary metabolism are not fully understood. Using a Capsicum chinense cell suspension as a model, we evaluated whether phospholipid signaling modulates SA-induced vanillin production through the activation of phenylalanine ammonia lyase (PAL), a key enzyme in the biosynthetic pathway. Salicylic acid was found to elicit PAL activity and consequently vanillin production, which was diminished or reversed upon exposure to the phosphoinositide-phospholipase C (PI-PLC) signaling inhibitors neomycin and U73122. Exposure to the phosphatidic acid inhibitor 1-butanol altered PLD activity and prevented SA-induced vanillin production. Our results suggest that PLC and PLD-generated secondary messengers may be modulating SA-induced vanillin production through the activation of key biosynthetic pathway enzymes. PMID- 24494242 TI - The Arabidopsis exocyst subcomplex subunits involved in a golgi-independent transport into the vacuole possess consensus autophagy-associated atg8 interacting motifs. AB - The exocyst complex is a multi-subunits evolutionary conserved complex, which was originally shown to be primarily associated with vesicular transport to the plasma membrane. A recent report (Kulich et al., 2013 Traffic; In Press) revealed that AtEXO70B1, one of the multiple subunits of the exocyst complex of Arabidopsis thaliana plants, is co-transported with the autophagy-associated Atg8f protein to the vacuole. This pathway does not involve the Golgi apparatus. The co-localization of AtEXO70B1 and Atg8f suggests either that both of these proteins are co-transported together to the vacuole or, alternatively, that Atg8 binds to a putative Atg8 interacting motif (AIM) located within the AtEXO70B1 polypeptide, apparently forming a tethering complex for an autophagic complex that is transported to the vacuole. In the present addendum, by tooling a bioinformatics approach, we show that AtEXO70B1 as well as the additional 20 paralogs of Arabidopsis EXO70 exocyst subunits each possess one or more AIMs whose consensus sequence implies their high fidelity binding to Atg8. This indicates that the autophagy machinery is strongly involved in the assembly, transport, and apparently also the function of AtEXO70B1 as well as the exocyst sub complex. PMID- 24494243 TI - Novel proteins interacting with peroxisomal protein receptor PEX7 in Arabidopsis thaliana. AB - Peroxisomal matrix protein transport relies on 2 cytosolic receptors, PEX5 and PEX7, which import peroxisomal targeting signal type 1 (PTS1) and PTS2-containing proteins, respectively. To better understand the transport mechanism of PEX7, we isolated PEX7 complexes using proteomics. We identified PEX5 as well as PTS1- and PTS2-containing proteins within the complex, thereby confirming the interaction between PEX5 and PEX7 during cargo transport that had been previously characterized by biochemical approaches. In addition, a chaperone T-complex and 2 small Rab GTPases were identified. We recently reported that the RabE1c is involved in the degradation of the PEX7 when abnormal PEX7 is accumulated on the peroxisomal membrane. This study expands our knowledge on the transport machinery via PEX7 by identifying both known and novel PEX7-interacting proteins and thus is helpful for further investigation of the regulation of the peroxisomal protein receptor during its translocation. PMID- 24494244 TI - Structural diversity of signal recognition particle RNAs in plastids. AB - One of the pathways for protein targeting to the plasma membrane in bacteria utilizes the co-translationally acting signal recognition particle (SRP), a universally conserved ribonucleoprotein complex consisting of a 54 kDa protein and a functional RNA. An interesting exception is the higher plant chloroplast SRP, which lacks the otherwise essential RNA component. Furthermore, green plant chloroplasts have an additional post-translational SRP-dependent transport system in which the chloroplast-specific cpSRP43 protein binds to imported substrate proteins and to the conserved 54 kDa SRP subunit (cpSRP54). While homologs to the bacterial SRP protein and RNA component previously have been identified in genome sequences of red algae and diatoms, a recent study investigated the evolution of the green plant SRP system.1 Analysis of hundreds of plastid and nuclear genomes showed a surprising pattern of multiple losses of the plastid SRP RNA during evolution and a widespread presence in all non-spermatophyte plants and green algae. Contrary to expectations, all green organisms that have an identified cpSRP RNA also contain a cpSRP43. Notably, the structure of the plastid SRP RNAs is much more diverse than that of bacterial SRP RNAs. The apical GNRA tetraloop is only conserved in organisms of the red lineage and basal organisms of the green lineage, whereas further chloroplast SRP RNAs are characterized by atypical, mostly enlarged apical loops. PMID- 24494245 TI - The phosphoinositide dependent-phospholipase C pathway differentially controls the basal expression of DREB1 and DREB2 genes. AB - We recently showed that-in Arabidopsis thaliana suspension cells-phosphoinositide dependent-phospholipase C (PI-PLC) and diacylglycerol kinase (DGK) negatively regulated the basal expression of most DREB2 genes. DREB2 genes encode transcription factors that bind to Drought Responsive Elements (DRE). Those elements are also bound by DREB1 factors. While DREB2 factors are mostly involved in drought and heat responses, DREB1s are induced in the response to chilling. We here show that the pharmacological inhibition of PI-PLC or DGK leads to the basal induction of DREB1 genes. However, the induction is much less marked for the DREB1 genes than that of DREB2A, a member of the DREB2 family. This illustrates that DREB1 and DREB2 genes, while having the same targets, are not submitted to the same transcription regulation, and that lipid signaling might in part explain these differences in the regulation of the DREB genes. PMID- 24494246 TI - Looking back at a prediction gone awry, visioning the future of imaging. PMID- 24494247 TI - Peering into the future. Is a new world for radiologists, images, and care delivery on the horizon? PMID- 24494248 TI - In pursuit of the Holy Grail: scalable, interoperable clinical decision support. Consortia making progress on standards, tools, and strategies for implementation. PMID- 24494249 TI - Patient matching. Chime panel discusses potential approaches and 'dream' solution to a growing challenge for CIOs. PMID- 24494250 TI - Population health from the front lines. Orlando Health's Schooler speaks exclusively with HCI about population health. PMID- 24494251 TI - ACO development in New Jersey: first-stage. The CMO of Barnabas Health in New Jersey has much to say regarding lessons learned in ACO development thus far. PMID- 24494252 TI - Connectivity revolution: Internet2 and its bold transformation initiative. Robert Vietzke of Internet2 shares his perspectives on the transformation of computing capability. PMID- 24494253 TI - Author's reply: To PMID 23538376. PMID- 24494254 TI - Health indicators for renal replacement therapy in Saudi Arabia. PMID- 24494255 TI - Anaphylaxis to sugammadex. PMID- 24494256 TI - Time to get comfortable with a labour epidural. AB - Women frequently request regional analgesia during labour, yet little is known about how long it takes before they become comfortable. This prospective observational study aimed to determine various time-points following maternal request for regional analgesia in labour until comfort was achieved. It was conducted in two tertiary referral centres for maternity care in Australia between December 2009 and May 2010.Midwives and anaesthetists recorded times of maternal request for regional analgesia, anaesthetist contact,anaesthetist's arrival in the labour room, local anaesthetic infiltration on starting the procedure, injection of neuraxial local anaesthetic and first report of maternal comfort. Composite median times and interquartile range were recorded for maternal request to anaesthetist arrival, anaesthetist arrival to maternal comfort and total time from request to comfort. Statistical modelling and regression analyses assessed possible factors associated with these time intervals. A P value <0.05 was considered significant. Of the 324 maternal requests, 244 out of 324 (75.3%, 95% confidence interval 70.2% to 79.9%) were recorded as having achieved satisfactory labour analgesia. Median interquartile range times observed were: maternal request to anaesthetist arrival: 20 (10 to 35) minutes; anaesthetist arrival to maternal comfort: 40 (30 to 50) minutes; and total time from request to comfort: 65 (50 to 85) minutes. We have shown that approximately one hour is required for a mother to achieve comfort following her request for epidural analgesia during labour. Our findings are likely to provide useful information for antenatal education, enhance informed consent and improve the provision of anaesthetic services for labour analgesia. PMID- 24494257 TI - Bitter pill indeed. PMID- 24494258 TI - PGY-1 option for licensure. PMID- 24494260 TI - How to give wisely and well. PMID- 24494259 TI - Limited cone beam radiography. PMID- 24494261 TI - Wellness is a healthy investment. PMID- 24494262 TI - Apologies, unanticipated outcomes, and mistakes Massachusetts General Laws Chapter 233 Section 79l: has anything changed? PMID- 24494263 TI - Guided bone regeneration for mandibular implants. PMID- 24494264 TI - Boston University Henry M. Goldman School of Dental Medicine: 50th anniversary. PMID- 24494265 TI - Anxiety sensitivity levels: a predictor of treatment compliance or avoidance. AB - The goal of this article is to stress the importance of understanding the presence of varying levels of pretreatment anxiety sensitivity to certain anticipated dental events and the role it plays as a predictor of anxious behavior and patient responses when individuals are confronted with fear-causing events, such as dental treatment. The varying intensity of anxiety sensitivity levels (ASL) in individuals serves to lessen or heighten the anxious and fearful response to potentially anxiety-provoking stimuli, such as pain. This level of anxiety sensitivity can often be traced back to the degree of knowledge or lack of information possessed by the patient regarding anticipated treatment and the practitioner's degree of acumen and completeness in history gathering. It has been suggested clinically that the level of anxiety sensitivity is directly related to the ability to predict whether or not treatment compliance will be achieved in an individual. Knowing the factors-either physiological or psychological-that are in play and that produce negative and aversive responses within a patient before and during treatment is key to solving these barriers to dental care. PMID- 24494266 TI - Ten under 10. PMID- 24494267 TI - Antimicrobial activity of sodium hypochlorite in endodontics. AB - One of the major objectives in endodontic therapy is to disinfect the entire root canal system. This goal may be achieved using mechanical instrumenation and chemical irrigation in conjunrction with medication of the root canal between treatment sessions. Microorganisms and their by-products are considered to be the major cause of pulpal and periradicular patholic. In order to reduce or eliminate bacteria and popular tissue remnants, the use of various irrigation solution during treatment have been suggested. Sodium hypochlorite (NaOCI), the most common irrigant, is an excellent nonspecific proteolytic and antimicrobial agent. The purpose of this paper is to review the antimicrobial activity of sodium hypochlorite. PMID- 24494268 TI - A clinico-pathologic correlation. AB - A 66-year-old female was referred to our department for evaluation of exposed bone in the hard palate. She was asymptomatic at the time of her initial consultation; however, she was concerned about a non-healing lesion that had been present for five months. The patient reported having injured her hard palate while eating sometime in November 2011. Subsequently she was followed by her general dentist, who had noticed improvement of the area. Approximately three months later, she noticed worsening of the lesion along with discomfort. She was conservatively managed at that point with penicillin and chlorhexidine mouth rinse without any improvement of her condition. PMID- 24494269 TI - Recurrent aphthous stomatitis. PMID- 24494270 TI - Filling in the gap. PMID- 24494276 TI - Emergency department readiness for pediatric illness and injury. AB - There are approximately 25 million emergency department visits by children each year in the United States. It can be challenging for healthcare providers to maintain the readiness of emergency departments in terms of equipment availability, policies and procedures for the care of children, and quality improvement for pediatric patients. Nearly 90% of children are seen in general emergency departments, and 50% of emergency departments see fewer than 10 pediatric patients per day, resulting in somewhat limited experience with critically ill and injured children for most emergency care clinicians. In the framework of the current healthcare system that is wrought with overcrowding, underfunding, and highly variable pediatric capabilities, children are arguably at the greatest risk for medical error. This issue reviews the current state of pediatric readiness in emergency departments, the necessary steps to ensure day to-day readiness, the published guidelines for pediatric readiness, and systems based innovations in pediatric readiness. PMID- 24494277 TI - [Efficacy and safety evaluation of acupuncture combined with auricular point sticking therapy in the treatment of polycystic ovary syndrome]. AB - OBJECTIVE: To compare the efficacy differences between acupuncture combined with auricular point sticking therapy and clomiphene oral administration in the treatment of polycystic ovary syndrome (PCOS). METHODS: One hundred cases of PCOS were randomized into two groups, 50 cases in each one. Acupuncture com bined with auricular point sticking group (group A): acupuncture was applied at Guanyuan (CV 4), Zhongji (CV 3) and Zigong (EX-CA 1), once daily; auricular point sticking was applied at Spleen (pi, CO13), Endocrine (neifenmi, CO18), Unterus and Kidney (shen, CO10), t he plaster was changed once a week. Clomiphene grou p (group B): oral clomiphene was prescribed at the 5th day of the menstrual, for 5 consecutive days, totally 3 menstrual cycles was needed. The ovulation induction, pregnancy and menstruation resuming of patients in the two ' , The totally effective rate was 90.00% (45/50) in group A, which was group were observed and compared. RESULTS: The totally effective rate was 90.0% (45/50) in group A, which was superior to 86.0% (43/50) in group B (P<0.05); the ovulation rate and pregnancy rate were 68.0% (34/50)and 64. 0% (32/50) in group A, whiche were superior to that of group B (all P<0. 05); the menstruation resuming rate was 94.00 (47/50) in group A, which was superior to 88.00 (44/50) in group B (P<0.05). No adverse effect was observed in group A, while in group B, varying degrees of nausea, vomiting, headache and dermatitis were observed in 29 cases, ovarian hyperstimulation syndrome (OHSS) like polycystic ovary was observed in 14 cases under the B ultrasound. CONCLUSION: Acupuncture combined with auricular point sticking therapy has a better effect than clomiphene in the treatment of PCOS without any adverse effect. PMID- 24494278 TI - [A case of Behcet's disease]. PMID- 24494280 TI - [Post-stroke shoulder-hand syndrome treated with acupuncture and rehabilitation: a randomized controlled trial]. AB - OBJECTIVE: To assess the clinical efficacy on post-stroke shoulder-hand syndrome (SHS) treated with acupuncture and rehabilitation and the impacts on patients' nailfold microcirculation. METHODS: One hundred and twenty patients were randomized into an acupuncture rehabilitation group and a simple rehabilitation group, 60 cases in each one. In the simple rehabilitation group, OT (comprehensive rehabilitation therapy) training was adopted. In the acupuncture rehabilitation group, on the basis of the treatment as the simple rehabilitation, acu puncture was added at Taiyuan (LU 9), Zusanli (ST 36), Xuanzhong (GB 39), Waiguan (TE 5), Shousanli (LI 10), Quchi (LI 11) and Jianyu (LI 15). Acupuncture was given once a day, 7 days made one session. Totally, 4 sessions of treatment were required. Fugl-Meyer score, upper limb pain score, the score of nerve function defect and the items of nailfold microcirculation of patients were assessed in the the two groups before and after treatment. The efficacy was compared between the two groups. RESULTS: (1) The upper limb pain, the systematic motor function of the upper limbs, the nerve function defect, nailfold microcirculation and clinical symptoms were all improved after treatment in either the acupuncture rehabilitation group or the simple rehabilitation group as compared with those before treatment, indicating the significant difference (P<0. 05, P<0. 01). (2) The im provements in the upper limb pain (0. 90+/-0.71 vs 1. 80+/-0. 66), the systematic motor function of the upper limbs (42. 43 13. 57 vs 29. 98+/-15. 11), the nerve function defect (8. 60+/-11. 61 vs 13. 0+/-1. 74), nailfold microcirculation (total score 3. 18+/-1.32 vs 4.34+/-1.23) and clinical symptoms in the acupuncture rehabilitation group after treatment were different significantly as compared with those in the simple rehabilitation group (PO0. 05,P-O. 01), and the results in the acupuncture rehabilitation group were superior to the simple rehabilitation group. (3) In the acupuncture rehabilitation group, the markedly effective rate was 50. 0% (30/60) and the total effective rate was 93.3% (56/60), which was better than 16.7% (10/60) and 63. 3% (38/60) respectively in the simple rehabilitation group (all P<0. 05). CONCLUSION: Both the combined therapy of acupuncture and rehabilitation and the simple rehabilitation training are effective in the treatment of post-stroke SHS, and promote the status of nailfold microcirculation, the efficacy of the combined therapy is better than that of the latter. PMID- 24494279 TI - [Herbal acupoint sticking combined with electroacupuncture therapy in the treatment of Bell's palsy: a randomized controlled trial]. AB - OBJECTIVE: To observe the clinical efficacy and safety of electroacupuncture (EA) combined with herbal acupoint sticking in the treatment of Bell's palsy and provide optimizations for the clinic. METHODS: One hundred and two cases of Bell's palsy were randomized into an EA combined with herbal acupoint sticking group (group A, 50 cases) and an EA group (group B, 52 cases), EA at Cuanzhu (BL 2), Yangbai (GB 14), Taiyang (EX-HN 5), Quanliao (SI 18),Xiaguan (ST 7), Yingxiang (LI 20), etc. were applied in both groups and "facial paralys No.I " was applied at Yifeng (TE 17) in group A, once daily and 10 times totally were needed. The score of facial nerve function, clinical efficacy were compared before and after treatment. At 1 and 3 month follow up visit, the quality of life scale( WHOQOL-BREF) and the occurrence of complication were observed. RESULTS: The scores of facial nerve function in group A and group B were all significantly improved compared with those before treatment (48. 2+/- 2. 9 vs 25. 7 +/- 4. 9, 45. 9 +/- 6. 2 vs 25. 8 +/- 5. 5, both P0. 05). The occurrence of complication in group A (1 case) was significantly less than that in group B (8 cases, P 0. 05). CONCLUSION: Compared with EA, the combination of EA and acupoint sticking therapy for Bell's palsy cannot only improve the clinical efficacy and reduce the occurrence of complication but also reliable without any side effect. PMID- 24494281 TI - [Efficacy observation on electroacupuncture in the treatment of oculomotor impairment caused by ophthalmic nerve injury]. AB - OBJECTIVE: To observe the difference in the clinical efficacy on oculomotor impairment between electroacupuncture and acupuncture and explore the best therapeutic method in the treatment of this disease. METHODS: Sixty cases of oculomotor impairment were randomized into an electroacupuncture group and an acupuncture group, 30 cases in each one. In the electroacupuncture group, the points were selected on extraocular muscles, the internal needling technique in the eye was used in combination of electroacupuncture therapy. In the acupuncture group, the points and needling technique were same as the electroacupuncture group, but without electric stimulation applied. The treatment was given 5 times a week, 15 treatments made one session. After 3 sessions of treatment, the clinical efficacy, palpebral fissure size, pupil size, oculomotor range and the recovery in diplopia were compared before and after treatment in the two groups. RESULTS: In the electroacupuncture group, the palpebral fissure size was (9.79+/ 2.65)mm and the eyeball shifting distance was (18.12+/-1. 30)mm, which were hig her than (8.23+/-2.74)mm and (16.71+/-1. 44)mm respectively in the acupuncture group. In the electroacupuncture group, the pupil diameter was (0. 44 +/-0. 42)mm, which was less than (0. 72 +/- 0. 53)mm in the acupuncture group, indicating the significant difference (all P<0. 05). The cured rate was 63. 33% (19/30) and the total effective rate was 93.33% (28/30) in the electroacupuncture group, which was better than 36.67% (11/30) and 83. 333 (25/30) in the acupuncture group separately, indicating the significant difference (all P<0. 05). CONCLUSION: Electroacupuncture presents the obvious advantages in the treatment of oculomotor impairment, characterized as quick and high effect, short duration of treatment and remarkable improvements in clinical symptoms, there are important significance for the improvement of survival quality of patients. PMID- 24494282 TI - [Precautionary study on acupuncture pretreatment for stroke at the early stage]. AB - OBJECTIVE: To assess the clinical efficacy of acupuncture pretreatment for the prevention of stroke based on promoting the circulation of the Governor Vessel and regulating mentality, and explore its effect mechanism. METHODS: Seventy cases of transient ischemic attack (TIA) were randomized into an acupuncture group (35 cases) and a western medicine group (35 cases). In the acupuncture group, acupuncture therapy of promoting the circulation of the Governor Vessel and regulating mentality was applied at Yaoyangguan (GV 3), Mingmen (GV 4), Zhiyang (GV 9), Shenzhu (GV 12), Dazhui (GV 14), Yamen (GV 15), Fengfu (GV 16), Baihui (GV 20) and Neck-Jiaji (EX-B 2). Acupuncture was given 6 times a week, at the interval of one day between two weeks. Totally, 21 days of treatment were taken as a session. In the western medicine group, aspirin enteric coated tablets were prescribed, 25 mg/tablet, 100 mg/day, once a night for oral administration, and 21 days of medication were taken as 1 session. There were 3 days at the interval between two sessions in each group and totally 2 sessions were required. Transcranial Doppler (TCD) was adopted before treatment and in two sessions of treatment to observe, mean flow velocity (Vm) of middle cerebral artery (MCA), vertebral artery (VA), basilar arte ry (BA) and pulsatility index (PI). The standard of the efficacy assessment of stroke aura was taken as the main efficacy index in the assessment of theraputic effect, the adverse reaction was observed. RESULTS: 1In TIA, MCA blood flow was accelerated in internal carotid system, and BA blood flow was accelerated in vertebral-basilar artery system. The treatments in the two groups enabled the blood flow in the responsible blood vessels slow down and the results in the acupuncture group L(60. 54+/-11.76)cm/s, (36. 17+/-8. 65)cm/s] were better than those in the western medicine group [(72. 34+/-9. 15)cm/s,(65. 23 +/-8. 99)cm/s] (P0. 05). CONCLUSION: Acupuncture intervention based on promoting the circulation of the Governor Vessel and regulating mentality achieves the superior efficacy on TIA and less adverse reactions as compared with aspirin. The effect mechanism is related potentially to the improvement of cerebral vascular hemodynamic. PMID- 24494283 TI - [Observation on clinical efficacy of acute pain treated with the intervention of different time of needle retention]. AB - OBJECTIVE: To compare the efficacy on acute pain treated under the different time of needle retention so as to provide the scientific evidence for the optimization of needle retention time for acupuncture analgesia. METHODS: Eighty cases of acute pain (acute lumbar sprain, stiffness of neck) were randomized into 4 groups. Acupuncture was applied to all the patients. After the arrival of needling sensation, the needles were retained for 20 min, 30 min, 45 min and 60 min in different groups separately. For acute lumbar sprain, Ashi (Extra), Houxi (SI 3) and Weizhong (BL 40) were the main points. For stiffness of neck, Ashi (Extra), Fengchi (GB 20) and Lieque (LU 7) were the main points. McGill pain scale, the internationally recognized pain description and measurement was adopted to observe the indexes and record the score changes of each item of pain symptoms before and 3 months after treatment. The immediate analgesic efficacy under different time of needle retention and the longterm efficacy in follow-up visit 3 months after treatment were compared and assessed among the groups. RESULTS: The scores of visual analogue scale (VAS) and present pain intensity (PPI) after treatment were all improved significantly as compared with those before treatment in the 4 groups (all P<0. 01), and the result in the 45 min group was superior to the other 3 groups (VAS: 2.90+/-0.87 vs 5. 52 +/-1.01, 4.45+/-0.81, 5.95+/-1.07; PPI: 1.40+/-0.21 vs 2.26+/-0.54, 2. 21+/-0. 43, 2. 28+/ 0. 74, all P<0. 01). The total effective rate of the immediate analgesia was 95. 0% (19/20) in the 45 min group, which was better than that in each of the other 3 groups. CONCLUSION: The 45 min of needle retention achieves the best efficacy of acupuncture analgesia in treatment of acute pain. PMID- 24494284 TI - [Acupuncture with blood-letting puncture for 52 cases of bullous myringitis]. PMID- 24494285 TI - [Clinical observation on cervical headache treated with acupuncture and fire needling technique]. AB - OBJECTIVE: To observe the efficacy in cervical headache of acupuncture combined with fire needling and the simple acupuncture therapy. METHODS: One hundred and eighty cases were randomized into an acupuncture plus fire needling group (group A) and an acupuncture group (group B), 90 cases in each one. Baihui (GV 20), Wangu (GB 12), Fengchi (GB 20), Tianzhu (BL 10) and Neck-Jiaji (EX-B 2) were selected in the two groups. In group A, the fire needling technique was applied to all the above points before acupuncture with filiform needles. In group B, the acupuncture therapy was used only. The treatment was given once a day, the efficacy was compared between the two groups after 20 treatments. RESULTS: The total effective rate was 95.6% (86/90) in group A and was 84. 4% (76/90) in group B, indicating the significant difference in comparison (P<0.05). VAS were 7.44+/ 1.26 and 0.73+/-l. 44 before and after treatment in group A separately, those were 7.56+/-1.07 and 2. 56+/-2. 99 in group B, indicating the significant difference in comparison (P<0.01). The difference in VAS after treatment was significant between the two groups. In group A, the follow-up visit was conducted at 3 months and 6 months after treatment for the cured cases. The total recurrence rate in the patients without bony pathological changes was 14.8% (4/27) and that in the patients with bony pathological changes was 43. 5% (10/23), there was significant difference between them (P<0. 05). CONCLUSION: The combined therapy of fire needling technique and filiform needle acupuncture improves the efficacy and sustains the efficacy especially on cervical headache without bony pathological changing. PMID- 24494286 TI - [Efficacy observation on traumatic nerve injury treated with different acupuncture therapies]. AB - OBJECTIVE: To observe the difference in the efficacy on traumatic nerve injury among electroacupuncture, warm needling therapy and electroacupuncture plus warm needling therapy and explore the better therapeutic method. METHODS: The electromyography (EMG) and electroneurography (ENG) of 93 cases showed traumatic nerve injury of moderate damage. According to the single blind randomization principle, they were divided into an electroacupuncture (EA) group, a warm needling therapy (WN) group and an EA plus WN group, 31 cases in each one. The main acupoints were selected from Yangming Meridian and Shaoyang Meridian corresponding to the distribution of damaged nerves. EA, WN and EA plus WN were applied separately. The treatment was given once every day, 15 treatments made one session. After 3 sessions of treatment (45 treatments in total), EMG and ENG were re-checked and the results were analyzed statistically. RESULTS: Regarding the total effective rate and effective rate, it was 96. 8% (30/31) in the EA plus WN group, which was better than 74.2% (23/31) in the EA group and 77. 4% (24/31) in the WN group (P<0. 05). Concerning to the improvements of EMG, the result in the EA plus WN group was 96.8% (30/31), which was better than the other two groups [74. 2%(23/31),74. 2%(23/31)] (P<0. 05). In terms of the recovery of nerve conduction and amplitude, the results in EA plus WN group [(50.9+/-4. 6)m/s,(8. 8+/-2. 9),microVx1 000] were better than the other two groups [(43.7+/ 3.1)m/s,(4. 2+/-1. 9)microV X 1 000,(43. 8+/-3. 3)m/s,(4. 5+/-2. 2)microV X 1 000] (P<0. 05). CONCLUSION: EA combined with WN is a better therapy of acupuncture and moxibustion in the treatment of traumatic nerve injury. PMID- 24494287 TI - [Efficacy observation on wrist-ankle needle for primary dysmenorrhea in undergraduates]. AB - OBJECTIVE: To compare efficacy difference among wrist-ankle needle, body acupuncture and ibuprofen in the treatment of primary dysmenorrhea. METHODS: Ninety-five cases were randomly divided into a wrist-ankle needle group (32 cases), a body-acupuncture group (31 cases) and an ibuprofen group (32 cases). Acupunc- , ture at Lower 1 and Lower 2 area was applied in the wrist-ankle needle group. Acupuncture at Guanyuan (CV 4) and Sanyinjiao (SP 6) were applied in the body-acupuncture group. Ibuprofen sustained-release capsules were given for oral administration in the ibuprofen group. The treatment began 3 days before menses, once a day, until pain was relieved. One menstrual cycle was taken as a treatment course, continuously for 3 courses and efficacy were observed in three groups. The symptom score of dysmenorrhea and visual analogue scale (VAS) were used to assess pain severity before and after treatment. RESULTS: 1The efficacy differences in three groups were statistically significant (P<0.01), in which the total effective rate was 90. 0% (27/30) in the wrist-ankle needle group, 73.4% (22/30) in the body-acupuncture group and 46. 7% (14/30) in the ibuprofen group. 2 After the treatment, symptom score of dysmenorrhea and VAS were all obviously lower than that before the treatment in three groups (all P<0.01). Compared with ibuprofen group (7.12+/-2.70), after the treatment symptom score of dysmenorrhea in the wrist-ankle needle group (4.00+/-3.40) and body-acupuncture group (5. 53+/ 2. 80) was obviously decreased (P<0.01, P<0.05), and VAS in the wrist-ankle needle group was significantly reduced (P<0.05). Compared with body-acupuncture group (5. 53+/-2.80), symptom score of dysmenorrhea in the wrist-ankle needle group (4.00+/- 3. 40) was obviously decreased (P<0. 05). CONCLUSION: The wrist ankle needle has better effect than body acupuncture and ibuprofen on the treatment of primary dysmenorrhea, which could significantly improve dysmenorrhea symptoms. PMID- 24494289 TI - [Acupuncture at yan (LO 5, eye) for Catarrhal conjunctivitis]. PMID- 24494288 TI - [Academician SHI Xue-min's clinical experience on treatment of hypertension with acupuncture]. AB - Dr. SHI Xue-min, academician of Chinese Academy of Engineering, has an unique treatment of hy pertension with acupuncture. Aiming at preventing damages of the target organs, improving the living quality of patients, and avoiding cardio cerebral accidents, Dr. SHI set up his own methods to treat hypertension. Based on the theory of "sea of qi" and "mental regulation", he adopts Renying (ST 9) as the major acupoint, eliminating wind through activating blood circulation and regulating the function of liver and spleen are taken as the treating principles. Acupuncture manipulations are strictly regulated with clear criterions. Summarizations on pathological basis and clinical researches on hypertension treatment with acupuncture are carried out as well. PMID- 24494290 TI - [Forty-six cases of hiccup after stroke treated with acupuncture of strengthening spleen and control liver]. PMID- 24494291 TI - [Time-effect study on instant analgesic effect of the dragon-tiger fighting needling method on primary dysmenorrhea]. AB - OBJECTIVE: To observe the clinical analgesic efficacy and the relation between clinical analgesic effect and duration of effect of two acupuncture methods of Longhu Jiaozhan (fight of dragon and tiger, an acupuncture reinforcing and reducing manipulation characterized with nine counterclockwise and six clockwise rotations) and even manipulations. METHODS: Sixty-two patients with primary dysmenorrhea were randomly divided into an observation group (32 cases) and a control group (30 cases). The observation group was applied with Longhu Jiaozhan manipulation, while the control group was applied with even manipulation. Acupuncture treatment was given on both of the groups since onset of the pain. The score of the visual analogue scale (VAS) of the 2 groups was observed at different times. And 8 VAS values were recorded at the point right before acupuncture, needle remaining of 5 min, 10 min, 20 min and 30 min as well as and 30 min, 60 min, 120 min after needle withdrawal. Comparison was made on differences between the 2 groups. RESULTS: Comparison with the same group before acupuncture showed that the VAS difference of the time from needling remaining of 5 min to 120 min after acupuncture were all with statistic significance (all P<0. 01). The score of VAS of needle remaining for 20 min and 30 min of the observation group was without significant difference (P>0. 05). The score of VAS value of needle remaining for 20 min and 30 min of the control group was with significant difference (P<0. 01). Comparison of the VAS scores before the treatment and the scores of the 2nd menstrual cycle were found with significant difference (P<0. 01). The VAS score of 2nd menstrual cycle was (28. 73 +/- 16. 15) in the observation group, which was better than (46. 93+/-12. 18) in the control group (P<0. 001). Comparison of the VAS score of the two groups at 5 min r emaining of the needle was without statistic significance between two groups (P>0. 05). However, the VAS impairment magnitude difference at that moment was with statistic significance (P<0.01). From the time of needle remaining for 10 min, 20 min, 30 min until 120 min after needling, the differences of the VAS scores and impairment range were all with statistic significance (all P<0. 01). The effects of the two acupuncture techniques could both be maintained up to 2 hours after needling. CONCLUSION: Both methods of acupuncture have immediate and long-term analgesic effect in a certain degree on primary dysmenorrhea. However, compared with the control group, the advantage of analgesic effect in the observation group is significantly superior. 20 min needling remaining can reach the best analgesic effect. PMID- 24494292 TI - [Effect of nursing intervention on the prevention of burns in warm needling moxibustion]. AB - OBJECTIVE: To explore the effect of nursing intervention on the prevention of burns in warm needling moxibustion. METHODS: Two hundred patients received warm needling treatment were collected from January to December 2011 and were randomized into an observation group and a control group, 100 cases veceived ten hundreds of treatment in each group. In the control group, the routine nursing was applied in warm needling moxibustion. In the observation group, on the basic method as the control group, the nursing intervention was used. The burns incidence and the satisfaction of patients in warm needling moxibustion were recorded in the patients of the two groups. RESULTS: The burns incidence was 0.6% (6/1000) in the observation group, which was lower apparently than 1. 5% (15/1000) in the control group (P<0. 05). The satisfaction of patients in warm needling moxibustion was 99.0% (99/100) in the observation group, which was higher obviously than 88.0% (88/100) in the control group (P<0. 01). CONCLUSION: The nursing intervention prevents effectively from burns in warm needling moxibustion, reduces medical injuries, avoids the pains of patients and plays the active role in the patient satisfaction. PMID- 24494293 TI - [Influence of acupuncture and moxibustion pretreatment at "Neiguan" (PC 6) on Connexin 43 in myocardial cell in rabbits of myocardial ischemia reperfusion]. AB - OBJECTIVE: To observe change of expression level of Connexin 43 (Cx 43) in myocardial mitochondria of ischemia reperfusion injury after pretreatment of acupuncture and moxibustion at "Neiguan" (PC 6) in rabbits, Thirty-two New Zealand and compare the different effect between electroacupuncture and moxibustion. METHODS: big-eared white rabbits were randomly divided into a model group, an electroacupuncture group, a moxibustion group and a sham-operation group, 8 cases in each one. The model of myocardial ischemia reperfusion injury was established in the first three groups. Before and after animal model was successfully made, the electroacupuncture and moxibustion were applied at "Neiguan" (PC 6) for 20 min respectively in the electroacupuncture group and moxibustion group. After the experiment, distribution of Cx 43 was observed under optical microscope while mean value of integral optical density (IOD) of Cx 43 in myocardial cell was tested. RESULTS: The distribution of Cx 43 in the model group was obviously scattered and sparse, but more expression of Cx 43 could be seen in the other three groups that were shaped as strip, chain or irregular and was perpendicular to cell long axis or formed side-side connection that was parallel to long axis. Shape and distribution of Cx 43 expression in the moxibustion group were not obviously different from that in the electroacupuncture group. The mean value of IOD of Cx 43 expression in myocardial cell in the electroacupuncture group (735. 10 +/- 152. 01), moxibustion group (836. 15 +/- 247. 10) and sham operation group (950.56+/-223.37) was higher than that in the model group (312. 68+/-1105. 20), and difference of the mean value in the electroacupuncture group was not statistically significant from that in the moxibustion group. CONCLUSION: The pretreatment of acupuncture and moxibustion at "Neiguan" (PC 6) in rabbit could increase expression of Cx 43 in myocardial cell and participate in electrical coupling and metabolic coupling to protect myocardial cell from ischemia reperfusion. However, differences of mean value of Cx 43 expression in myocardial cell were not statistically significant during electroacupuncture and moxibustion at "Neiguan" (PC 6). PMID- 24494294 TI - [Regulation of moxibustion for expression of gastric mucosa cell-related marker protein in rats with acute gastric ulcer]. AB - OBJECTIVE: To explore relevant material basis of moxibustion for recovering gastric mucosal lesion. METHODL Forty-five SD rats were randomly divided into a normal goup, a model group, an acupoint group and a control group, 15 rats in the model group and 10 rats in the rest three groups. Except the normal group, binding and cold stress method were used to establish gastric mucosa injury model. The suspended moxibustion was applied in the acupoint group and control group at acupoints of the stomach meridian ("Liangmen" (ST 21) and "Zusanli" (ST36) and control acupoints (Laterally 1cm next to the "Liangmen" (ST 21) and Zusanli" (ST36), once a day, consectutively for 12 days. After 12 days, morphology of gastric mucosal was observed under optical microscope; protein fingerprints of gastric mucosa cell in rats were detected by protein fingerprint technology, weak cation chip and weak anion chip. Also mass to charge ratio of differential proteins in groups were compared and analyzed. RESULTS: Compared with the model group, index of gastric mucosal lesion in the acupoint group was reduced and its morphology was obviously improved (P<0.05). Campared with control group, index and morphology of gastric mucosal lesion were significantly improved in the acupoint group (P<0.05). According to test of weak cation chip, there was four marker proteins that had expression differences, indicating moxibustion at acupoints of stomach meridian could inrease expression of three marker protein whose molecular weight was 1354Da, 5692Da and 8432Da (all P<0.05) while reduce expression of marker protein with molecular weight of 3287Da (_<0.05). According to test of weak anion chip, moxibustion at acupoints of stomach meridian could increase expression of three marker proteins whose molecular weight was 2412 Da, 3026Da and 6475 Da (allP<0.05). CONCLUSION: Moxibustion at acupoints of the stomach meridian could regulate differential expression of gastric mucosa cell related marker protein in rats with acute gastric ulcer and recover gastric mucosal lesion, it's effect is better than that of the points of laterally 1 cm next to acupoint. PMID- 24494295 TI - [Effect of electric acupoint stimulation on shivering in cesarean section]. AB - OBJECTIVE: To explore the efficacy of electric acupoint stimulation on shivering in cesarean section. METHODS: Eighty cases of parturients, under the America Society of Anesthesiologists (ASA) physical status II , were randomized into a transcutaneous electrical acupoint stimulation (TEAS) assisted anesthesia group (group A) and an anesthesia group (group B). Spinal-epidural anesthesia(CSEA) puncture was applied to both groups and 8 mg of 0. 75% bubivacaine was given by spinal injection, the block level was T4 T8. In group A, TEAS was applied before CSEA at paired acupoints-ipsilateral Hegu (LI 4)-Laogong (PC 8) and Sanyinjiao (SP 6)-Zusanli (ST 36) till ending the surgery. The 4 pair of bilateral acupoints were fixed with self-adhesive electrodes and connected with Han's acupoint and nerve stimulator (HANS, LH402H), the frequency was 2 Hz/ 15 Hz, the intensity was 10- 30 mA and the form was densedisperse wave within the patients' tolarance. The heart rate (HR), mean arterial pressure (MAP), oxyhemoglobin saturation (SPO) and shivering degree were recorded before anesthesia (To), 1 min after anesthesia puncture (Ti), 1 min after the delivery (Tz), during abdomen closure (T3) and at the end of surgery (T4). RESULTS: The occurrence rate of shivering was 35. 0% (14/40) in group A, which was lower to 67. 5% (27/40, P<0. 05) in group B; the degree of shivering was lighter in group A than that in group B at T2, T3 and T4 (all P<0. 01). In group A, HR was faster at T1 and T2 compared to that at To (all P<0. 05), while at T3 and T4, the HR was the same with that before anesthesia (all P>0. 05). In group B, the HR was faster at T1, T2, T3 and T4 compared to that at T0 (P<0. 05, P<0. 01). In both groups, the MAP was lower at T1, T2 (P<0.05,P<0.01) and resumed to that before anesthesia at T3 and T4 (all P>0.05); there was no statistical significance of SPO2 in both groups (all P>0.05). CONCLUSION: TEAS can reduce the occurrence rate of shivering and steady the heart rate in cesarean section. PMID- 24494296 TI - [Design and application of hand-wrist caring moxibustion box]. AB - A hand-wrist moxibustion box is designed to effectively solve difficulty to have moxibustion at handwrist joint and problem of bad moxibustion effect as well as improve heat efficiency of moxibustion. The device is consisted of a box and protective screening. The box is hollow with opening on top and bottom. A reversible cover is fixed on the top of the box and support frames are put in the inner-middle. On the side wall there is a hole that is at the same horizontal level of support frames, and horizontal protective screening is put on the bottom. The design of this moxibustion box is novel and unique, simple and reasonable, which could give moxibustion on hand and wrist at the same time. Also it is easily made with low cost, easy to use and favorable effect. It is an innovation on moxibustion box. PMID- 24494297 TI - [Controlled study of ultrasound-guided acupotomy on spinal and articular diseases]. AB - OBJECTIVEL to study the visualization of acupotomy therapy and to summarize differences of interventional ultrasound combined with acupotomy on spinal and articular diseases. METHODS: With randomized block design, 20 cases of shoulder periarthritis, 20 cases of knee arthritis, 20 cases of lumbar disc herniation and 20 cases of cervical disc herniation were divided into an ultrasound-guided group and regular group, 10 cases of each diseas in each group. The ultrasound-guided acupotomy and regular acupotomy were given for one time, respectively. Efficacy was observed after one week. Visual analogue scale (VAS) and fuction score were applied for efficacy assessment, including Wang's funtion evaluation table for cervical disc herniation, modified lumbago assessment by Japanese Orthopaedic Association for lumbar disc herniation, modified lumbago assessment arthritis and CMC shoulder funtion scale for shoulder periarthritis. The changes of scores of patients in two groups were observed before and after the treatment. RESULTS: Each disease in each group achieved favorable efficacy; compared before and after treatment, differences of VAS and each function score all were statistically significant (allP<0.01). The efficacy of lumbar disc herniation and cerical disc herniation in two groups was not obviously different (both P>0.01). The efficacy of lumbar disc herniation and cervical disc herniation in two groups was not obviously different (bothP>0.05), while VAS and fuction scores improvements of shoulder periarthritis and knee +/-5.75 vs 75.72+/-8.56; knee arthritis: 90.40+/ 7.35 vs 75.54+/-9.21, both P<0.05). CONCLUSION: Whether ultrasound guidance is applied during acupotomy therapy made no obvious influence on efficacy of lumbar disc herniation and cervical disc herniation, but for shoulder periarthritis and knee arthritis better results could be acchieved with ultrasound guidance. PMID- 24494298 TI - [Explanation on bloodletting mechanism of scraping therapy]. AB - On the base of acupuncture techniques in Chinese medicine, locations, apparatus and manipulation of scraping are analyzed in this article. It is held that scraping, no matter with the location, tools and manipulations of application, meets the requirements of shallow stimulation on collaterals described in Huangdi Neijing (Huangdi's Internal Classic). And the methods of scraping to cause shazhen (subcutaneous hemorrhage showed in scattered red spots on the skin) to eliminate pathogens in collaterals is also approved to meet the mechanism of Chinese medicine which expels pathogens with bloodletting. Therefore, it is held that scraping is a complete treating technique of shallow stimulation on collaterals. PMID- 24494299 TI - [Medicine-waxing application method on facial acupoint area for 50 cases of peripheral facial paralysis]. PMID- 24494300 TI - [Application and selection of insomnia scales in acupuncture clinical research]. AB - The characteristics and application of Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), Insomnia Severity Index (ISI), Epworth Sleepiness Scale (ESS) and other commonly used international insomnia evaluation scales are introduced in this article. Analysis are also carried out on clinical literature about insomnia treatment with acupuncture. Problems of scale applications are classified mainly into three categories, namely (1) Too many self-made scales; (2) Lack of application standardization; (3) Lack of variety in application, limited application of Life Quality Scale. And relevant suggestions are also proposed in this article. PMID- 24494301 TI - [On the pronunciation and meaning of Jimen (LR 14) acupoint]. PMID- 24494302 TI - [Re-discussion on bias]. AB - The reasons of bias that is caused in the design of randomized controlled trial are analyzed in this article. It is emphasized that the design of randomized controlled trial in TCM acupuncture should follow its basic concepts and cores and make clear normative standards of placebo acupuncture. The concept of real time control is proposed and focusing on activating the nerve cells process in threshold field is advised, which will make profound influence on development of medical science of acupuncture and moxibustion. PMID- 24494303 TI - [Press at Baihui (GV 20) for carsickness]. PMID- 24494304 TI - [Penetration acupuncture at expression muscle for 12 cases of severe peripheral facial paralysis]. PMID- 24494305 TI - [Preliminary study on acupoint location, needle entry point and acupuncture manipulation of Zhongliao (BL 33) point]. PMID- 24494306 TI - [Studies on causes of gynecology postoperative urinary retention and its acupuncture treatment]. AB - Urinary retention is a frequent-encountered complication after gynaecological surgery. It affects the postoperative recovery and decreases the life quality of patients. In recent years, extensive researches on causes and treatments of postoperative urinary retention are carried out in clinic. And it is approved that acupuncture treatment, which includes body needling, moxibustion, combination of acupuncture and moxibustion, acupoint injection and medication plasters, has reliable effects and less side-effects. Acupuncture treatment on postoperative urinary retention keeps developing and innovating. And it is held to have better effect when compare with western medicine. PMID- 24494307 TI - [In the midst of society]. PMID- 24494308 TI - [Poverty in old age and health in wealthy Germany. Who wants to combat poverty effectively, must eliminate social inequalities]. PMID- 24494309 TI - [Pflegezeitschrift has encountered 2 members of MedMobil, which offers medical care to needy persons. "Not just homeless persons come to us"]. PMID- 24494310 TI - [New data on dying in the hospital and effects on nursing. Significant progress and inadequate conditions]. PMID- 24494311 TI - [Providing for the elderly with inpatient aid to homeless persons. We close the care gap]. PMID- 24494312 TI - [Report from the supportive ambulatory nursing care. When different is normal]. PMID- 24494313 TI - [Addiction in the elderly: how nurses can intervene effectively and take preventative action. Wine blessed old age]. PMID- 24494314 TI - [The concept of a medical ambulance for persons living under precarious conditions]. PMID- 24494316 TI - [The patient's rights law. Minor improvements - a partial need for correction]. PMID- 24494315 TI - [Undocumented illegal immigrants in the hospital. Escape from the treatment room]. PMID- 24494317 TI - [Nursing in Finland - looking back on a stay abroad in Helsinki. "Greetings from Vantaa"!]. PMID- 24494318 TI - [Patients living in impoverished areas have more severe ischemic strokes]. PMID- 24494319 TI - [The Kaiser Friedrich Hospital in Sanremo, Italy, circa 1900: multicultural aspects of nursing under Marie Cauer. 25 years nursing in Sanremo]. PMID- 24494320 TI - [The effects of cholera epidemics on the development of nursing in the 19th century. Looking death in the eye]. PMID- 24494321 TI - [Dealing with drug addicted residents. "Can I have a cigarette"?]. PMID- 24494322 TI - Oncothermia: a new paradigm and promising method in cancer therapies. AB - In "hypethermia", the procedure of raising the temperature of a part, or the whole body, up to 42 degrees C to kill cancer cells for a defined period of time is applied alone or as an adjunctive with various established cancer treatment modalities such as radiotherapy and chemotherapy. However, "hyperthermia" is not generally accepted as conventional therapy due to the complications of deep heating and lack of focusing of the heat effect only for malignant tissues. The idea of oncothermia solves the selective deep action on malignant tissue on nearly cellular level. Oncothermia is highly improved, safe and effective "hyperthermia" in clinical cancer therapy supported by in vivo, in vitro, and human research as shown in this article. Advantage of oncothermia: while the classical insufficiently, focused "hyperthermia" has to heat up in case of the multiple lesions overlapping all the volume, which contains both normal tissues and malignant tissues; while oncothermia automatically focuses on the malignant tissues in its multiple places, without treating the healthy tissue in between. The modulated radiofrequency current (RF) flows through the malignancies only. The radiofrequency modulated current with 13,56 MHz (fractal modulated) between 2 electrodes automatically focuses through malignant tissues with lower impedance and will flow mainly in the extracellular electrolyte because the normal cells are electronically isolated by their membrane by more than one-million V/m electrical field strength. Oncothermia today has the ability to be a candidate to a widely accepted modality of the standard cancer treatment. PMID- 24494323 TI - Treatment of nocturia symptoms with acupuncture. AB - Nocturia is a common symptom in the elderly. It causes sleeping disorders and is also associated with a higher risk of falling and increased mortality. The majority of nocturia patients prescribed desmopressin although it may cause significant hyponatremia which is a serious life threatening side effect. There is a need to use safer alternative treatment strategies specialy for older nocturia patients. We aim to examine the effect of acupuncture treatment on nocturia patients as a safe alternative treatment option. 35 nocturia patients have been joined to our study aged between 28 to 72. Among those patients in the study, 23 were female while 12 were male. Acupuncture treatment were applied in every 2 days totaling 10 sessions and each treatment session has lasted for 20 minutes. Nocturia frequency of the patients were recorded 1 to 6 before acupuncture treatment sessions. We have observed that nocturia symptoms recovered completely in 60% of the patients at the end of 10 sessions of the treatment while nocturia frequency were reduced to one per night in 37% of the patients. On the other hand nocturia sypmtoms in 2.8% of the patients were not changed at all. As a result 97% of the patients have responded to acupuncture treatment positively which applied bilaterally to Yintang point, Ki 3, Liv 3, Sp 9, L.I. 4, Ht 7, Sp 6, Lu 9, Sp 3, P 6 points. According to our results we conclude that acupuncture treatment should be widely used in nocturia patients of older ages as well as relatively younger adults. PMID- 24494324 TI - More than 97% of human papilloma virus type 16 (HPV-16) was found with chrysotile asbestos & relatively smooth round tumor outline, and less than 3% was found with HPV-18 and tremolite asbestos & irregular sawtooth-like zigzag outline in breast cancer tissues in over 500 mammograms of female patients: their implications in diagnosis, treatment, and prevention of breast cancer. AB - In the past, Human Papillomavirus Type 16 (HPV-16) was considered to be the main cause of cancer in the oropharynx and genital organs. Cervical cancer of the uterus is the most well-known cancer associated with HPV-16. Among the oncogenic HPVs, types 16 and 18 are most responsible for the majority of the HPV-caused cancers. Recently, using EMF Resonance Phenomenon between 2 identical substances, we non-invasively measured HPV-16 and HPV-18 among 25 physicians and 25 dentists and found that all 50 have HPV-16 in oral cavities and oropharynx but not HPV-18. However most dentists have a stronger infection than physicians. Among them were 2 female dentists with breast cancer containing HPV-16 and strong infections of HPV-16 in the oral cavities and oropharynx. When the author checked their breast cancer positive areas as well as the mammograms of cancer positive areas, Chrysotile Asbestos co-existed with an infection of HPV-16. We then examined over 500 published mammograms of women with malignant breast cancer published by other institutes, and we found HPV-16 in more than 97% and HPV-18 in less than 3% of the breast cancer mammograms examined. Less than 0.4% of cases were found as a variety of combination of HPV-16 & HPV-18. We also discovered that breast cancer with HPV-16 always co-exists with increased Chrysotile Asbestos deposits, and the outline of the breast cancer positive area is a relatively smooth and round or oval shape, and breast cancer with HPV-18 always co-exists with increased Tremolite Asbestos, where the tumor outline is an irregular saw-tooth like zigzag pattern. Based on these findings, better methods of diagnosis, treatment and prevention with a vaccine can be developed. PMID- 24494325 TI - [President's word]. PMID- 24494326 TI - [Acoustic analysis of the articulatory disorders of patients affected by peripheral facial paralysis]. AB - INTRODUCTION: The study of joint disorders in facial paralysis is an important element of support to guide rehabilitation. MATERIAL: The material used for the registration of the database is a digital recorder Zoom H4N (way format, sample rate 44,100 Hz, 16 bit quantization). The microphone used is a Shure Beta 58, super cardioid. All recordings are made in a specific room. METHODS: The annotation of the corpus is done using Praat software and its plug-in EasyAlign order to achieve alignment phonetics. RESULTS: High frequency power ratio (HPR) is a good indicator of the setting in motion of the articulators as the number of explosions of bilabial phoneme was significantly related to the motor of the face and lips, and the score at dynamometer. The VOT was significantly shorter in patients with grade IV and V-VI than in control subjects. The results highlight a significant difference between the values of F3for the vowels /i/ and /y/, depending on the severity of the damage. There is even, for the most severe grades, there are a hundred Hertz difference between F3 of /i/ and that of /y/, which means that these two vowels becomes impossible to discriminate. CONCLUSIONS: If these functional disorders are much discomfort for patients, however, these are not speaking of articulatory disorder in the strict sense, according to the definition of Borel Maisonny. We must therefore focus more specifically to the acoustic analysis of speech in order to check for spectral indices likely to identify these disorders. PMID- 24494327 TI - [Prosodic analysis of speech of patient affected by peripheral facial paralysis]. AB - INTRODUCTION: The aim of study of prosody in facial palsy is to assess the intensity of pathology in suprasegmental viewpoint in order to establish a proper rehabilitation. METHODS: Patients were recorded during a reading and spontaneous speech test and a prosodic observation of speech spectrogram provided by Praat software. RESULTS: The Accentual Groups lowering and significant dysprosodics elements (adverse effects and breaking balance) and a larger amount of disfluencies showed that the prosody of patients with facial palsy is altered because they need to swallow their saliva intentionally. Then, the decrease of Mean Length of Utterance (MLU) and the opinion of the jury highlight a decrease in desire to communicate and a loss of speech informativeness. CONCLUSIONS: In patients with severe facial palsy, there is an impact of swallowing disorder (caused by salivary stasis) on the prosody of speech, with variations in the position of intonations boundaries and the intensity of prosodic marking. This also creates impact on fluency and on the perception of the message by the listener. PMID- 24494328 TI - [Vocal and behavioral adaptations of program sellers in work situation]. AB - Are program sellers at the Parisian Operas at risk of developing vocal problems? What are the adaptations they use to be heard and understood in this loud environment? Six program sellers were recorded and observed at work. The methodology applied included a questionnaire, acoustic analysis of the records, a videolaryngostroboscopic examination, analysis of objective and subjective measures of vocal function. The results confirmed the existence of voice risk factors and symptoms of vocal fatigue that may justify a preventive intervention. The adaptations that program sellers carry out follow the characteristics of what is called "Lombard Speech". In addition, announces reveal common and individual specificities such as prosodic and acoustic types. PMID- 24494329 TI - [From intelligibility to comprehension, which measurement in practice?]. AB - The modelling of the tests assessing speech disorders in touch with the international classification of the functioning implies a reflection on measurement tools. The access to the sense of the message from decoding of the signal to the action infers at the interlocutor's justifies various methods. The objective of this work is to demonstrate the limit of the usual tests of intelligibility. MATERIAL AND METHOD: A population of 10 subjects presenting a speech disorder secondary to a Head and Neck cancer and 2 subjects controls recorded a corpus of 80 syllables developed with the most frequent 16 French consonants and 5 vowels. The test of intelligibility consisted of a task of identification of consonants by a jury of 11 listeners. RESULTS: About is the method used to estimate the informative value of the consonants tested, the uvular consonant /r/ and the nasal In/, /m/ are very well perceived. The weighting by the rate of confusion makes tipped over the position of labiodentales If/, /v/ and that of / p/. The just perception of the sound/p/ would be underestimated while sounds /v/ and /f/ would be overestimated. Sounds /g/, /k/, /j/ remain the least well received. This observation results probably from the profile of distortions produced by the selection of the population and probably from the frequency of the syllables containing these consonants in the french language for the sample of the corpus. CONCLUSION: The rate of confusion appears as a fundamental element, inciting to look for more relevant methods of analysis of the results of the tests of intelligibility. PMID- 24494330 TI - [Social consequence of a dysphonic voice, design and validation of a questionnaire and first results]. AB - In our society, based on communication, dysphonia becomes a handicap that could be responsible of work discrimination. Actually, several commercial services are provided by phone only, and voice quality is mandatory for the employees. This work aim was to determine the social picture relayed by dysphonia. Our hypothesis was that dysphonia sounds pejorative compared to normal voice. 40 voice samples (30 dysphonic and 10 normal) were presented randomly to a perceptual jury of 20 naive listener. The task was for each of them to fill a questionnaire, designed specifically to describe the speaker's look and personality. 20 items were evaluated, divided into 4 categories: health, temperament, appearance, and way of life. The results showed significant differences between normal subjects and dysphonic patients. For instance, the pathological voices were depicted as more tired, introverted, sloppy than normal voices, and less trustable. No significant differences were found according to the severity of voice disorders. This work is presently continued. It allowed to validate our questionnaire and has offers great perspectives on patient's management and voice therapy. PMID- 24494331 TI - [The sound intensity after cordectomy of type II-III]. AB - OBJECTIVES: The aim of this paper is to compare the intensity of the French oral vowels of 10 patients after cordectomies of types II or III with a group of 10 healthy subjects. This surgery removes the mucosa, the ligament and a part of the vocal muscle of the touched vocal fold, which causes a less efficient closure and a vibratory asymmetry. Consequently, glottal leaks associated with a difficult preservation of the subglottic pressure (PSG) can appear. The intensity is mainly bound to the strength of adduction of the vocal folds and to the management of the PSG. In these conditions, the quality of the control of this parameter by our patients may be altered. METHODS: The intensity (in dB) was measured on three vowels [a, i, u] produced in an isolated context (n= 60). This parameter was also measured on this same vowels surounded by stop consonants, which results in logatomes of type CV1.CV2.CVC3 (n= 360). RESULTS: We show particularly that the surgery does not alter the parameter of the intensity. The differences between patients and control subjects for isolated productions result from compensatory strategies. We also highlight an increase of the intensity in voiced context for both groups. CONCLUSIONS: The patients treated by cordectomies of types II-III keep a powerful sound. The intrinsic characteristics of the intensity of the vowels are maintained after this surgery. PMID- 24494332 TI - [Evaluation of quality of life and swallowing in patients with cancer of the oropharynx treated with assisted transoral robotic surgery]. AB - OBJECTIVES: To present the preliminary results of the qualiit of life and quality of swallowing in a series of 15 patien! treated with oropharyngectomy by transoral robotic-assisted (CTAR) (robot da Vinci, Intuitive Surgical ). MATERIALS AND METHODS: A prospective monocentric non-randomized study of 15 patients with cancer of the oropharynx. Were analyzed: demographics, quality of life questionnaires (QLQ-C30 and H&N 35 EORTC) and quality of swallowing questionnairex (MDADI, DHI and EAT 10) with an average of 1 year after the end of the treatment. RESULTS: Fifteen patients (10 males and 5 females), mean age of 65 years (47-73 years) were included. The tumours were classified as: cT1: 4; cT2: 10 cT3: 1. Five of the 15 patients received postoperative chemoradiotherapy as histo-pathological studies showed multiple metastatic cervical lymph nodes +/- capsular rupture. For the analysis of the quality of life and quality of swallowing, the patients were divided into two groups. Group A included patients who underwent CTARs and group B, patients operated by CTAR with adjuvant chemoradiotherapy. At 12 months of the procedure, all patients had a deglutition considered as normal without feeding tube nor tracheostomy. With the three scales used, the quality of swallowing was satisfactory for all patients. It was better for patients in group A than for patients in group B. In terms of quality of life, the EORTC QLQ-C30 scale showed our patients had a high rate of satisfaction scale in "health and overall quality of life". For the EORTC H&N35 questionnaire, mean scores for "specific symptoms" were also low except for the following three items "dry mouths", "sticky saliva" and "sexuality problem". The first two items were statistically more frequent (p = 0.02 and p = 0.001) in group B patients. CONCLUSION: After transoral robotic-assisted oropharyngectomy, patients have a good quality of life and swallowing. Postoperative chemoradio-therapy compromises the quality of swallowing. Multicentric studies are required to confirm these preliminary results. PMID- 24494333 TI - The benefit of phoniatricians and ENT surgeons working together? AB - These 3 clinical cases relate dysphonia and dystonia with female speaking and singing performers whose medical care was messy and involving several physicians. A close collaboration between phoniatricians and phonosurgeons brought effective solutions to these cases. PMID- 24494334 TI - [Evaluation of the use of hyaluronic acid in iatrogenic scars after phonosurgery (excluding surgical oncology) and ligamento-epithelial abnormalities of the vocal cords]. AB - Between January of 2007 and December of 2011, six patients underwent revision microphonosurgery because of scarring complicating the initial surgery. The technique consisted of detaching the scarred area, the insertion of fibrils of hyaluronic acid (Merogel), a microsuture and possibly intra-cordal fat injection. A pre-and post-operative phoniatric protocol assessed the results which appear encouraging. PMID- 24494335 TI - Our mission: implement the ACA, 'with great vigor'! PMID- 24494336 TI - Enrollment: can you lend a hand? PMID- 24494337 TI - How behavioral health professionals can shape the future of healthcare teams. PMID- 24494338 TI - Health reform drives an addiction mega-merger. PMID- 24494339 TI - Ohio moves on Medicaid expansion. PMID- 24494340 TI - Compliance programs stress 'effectiveness'. PMID- 24494341 TI - Verifying an audit's accuracy. PMID- 24494342 TI - Mental health/substance abuse treatment mergers continue, with mixed feelings on substance abuse side. PMID- 24494343 TI - Outcomes measurement essential for post-reform healthcare success. PMID- 24494344 TI - Major renovations abound for 50-year-old facility. PMID- 24494345 TI - Kiosk-based "office" extends reach of health services providers. PMID- 24494346 TI - Can happiness improve cancer survival? PMID- 24494347 TI - New peer review law provides due process to physicians. PMID- 24494348 TI - New cervical cancer screening guidelines: start older, test less often. PMID- 24494349 TI - Sadness, suicide, and sexual behavior in Arkansas: results from the youth risk behavior survey 2011. AB - We used the 2011 Arkansas Youth Risk Behavior Survey to estimate the prevalence of risky sexual behavior and sexual assault and to measure its association with teen suicidality. In Arkansas, 50.3% of students reported ever having sexual intercourse, 26% onset at 14 or younger, 36 % having had more than one partner, and 10.2% having been physically forced to have sex. "Being forced to have sex" was a risk factor for depression and all components of the suicide continuum. Additionally, early onset of sexual activity and having more than one partner increased the risk for depression, suicidal ideation, plan, and attempt. Suicide is a grievous and preventable tragedy, sadly standing among the leading causes of death for teens.' In this series, we examine risk factors for suicidality among Arkansas high school students; in this installment, we examine sexual behavior. A previous study utilizing the Rhode Island Youth Risk Behavior Survey (YRBS) found an association between having forced sexual intercourse and suicide. Furthermore, an association between psychiatric disorders and risky sexual behaviors, including both early onset and number of partners was found in a birth cohort study revealed. We hypothesize that Arkansas' teens reporting risky sexual behavior and sexual assault are at higher risk of depression and suicidality as well. PMID- 24494350 TI - The physician's role in infant and child death review in Arkansas. AB - Arkansas has higher infant and child death rates than the United States overall. Multidisciplinary Infant and Child Death Review Teams are tasked to provide detailed information about unexpected infant and child deaths from the perspective of the affected community. The goals of the review are to develop specific intervention and prevention measures to decrease pediatric deaths, and examine the processes utilized by agencies to influence changes in policies, procedures and law. PMID- 24494352 TI - A work in progress. PMID- 24494351 TI - Medicine in old Fort Smith: struggles with mud and quacks. AB - Dr. J. G. Eberle's efforts to pave the streets of Fort Smith are illustrative of the challenges facing Arkansas in the nineteenth century. Development of sewers, drains, and a safe water supply helped control epidemics of malaria, yellow fever, cholera, and other forms of dysentery. During this time the medical profession struggled to establish professional standards before the great reforms of medical education took hold in the twentieth century. The military hospital of the Civil War was a precursor of the role hospitals would play in bringing higher standards of care to their communities. PMID- 24494353 TI - Communication equals control. PMID- 24494354 TI - A simulator for fistula repair. PMID- 24494355 TI - Connecting the dots. PMID- 24494356 TI - Facebook friend. PMID- 24494357 TI - The appification of practice. PMID- 24494358 TI - Honorary M.D. PMID- 24494359 TI - Is there life after the House of Delegates? PMID- 24494360 TI - Big Data, big influence. PMID- 24494361 TI - Health care's digital divide. PMID- 24494362 TI - Minnesota clinics' adoption, use and exchange of electronic health information. AB - In 2007, Minnesota passed a law requiring all health care providers in the state to implement an interoperable electronic health record (EHR) system by January 1, 2015. Since then, the Minnesota Department of Health has been monitoring progress each year by surveying hospitals, clinics and other health and health care facilities about their EHR use. This article summarizes findings from the 2013 survey of ambulatory clinics. Those results show Minnesota clinics are well on the way to achieving the state's goals for using EHRs to exchange information: 87% of clinics have adopted EHRs, 80% routinely use medication guides and alerts, and 36% exchange health information with unaffiliated settings. PMID- 24494363 TI - 2009 H1N1 vaccination in Minnesota: an evaluation by ZIP code. AB - According to Minnesota Immunization Information Connection (MIIC) data, 23% of Minnesotans were vaccinated against 2009 pandemic H1N1 influenza. We analyzed 2009 H1N1 vaccination data at the ZIP code level to learn more about who received the vaccine between 2009 and 2010. We found significant differences in H1N1 vaccination rates by percentage of residents living below the family poverty line, percentage of non-Caucasian residents in a ZIP code and median family income. When stratified by urban or rural location, median family income was significantly associated with vaccination rate only in urban settings; the percentage of non-Caucasians living in an area was significant only in rural settings. In both urban and rural settings, most H1N1 vaccinations were given in a private facility, although the proportion was much higher in urban ZIP codes (81.5%) than rural ZIP codes (53.2%, P < 0.0001). Further research is needed to find out why vaccination rates were associated with increasing median family income in urban areas and why in rural areas, people living in ZIP codes with a higher percentage of non-Caucasian residents were more likely to be vaccinated after controlling for poverty and median income. PMID- 24494364 TI - Paging Steve Jobs ... can someone build a better EHR? PMID- 24494365 TI - Cracking the capsule. PMID- 24494366 TI - Stopping the stigma. PMID- 24494367 TI - Minnesota's suicide trend ticks upward. PMID- 24494368 TI - A bullying pulpit. PMID- 24494369 TI - Public health's mental health agenda. PMID- 24494370 TI - Help for the nonpsychiatrist: resources for those on the frontline. PMID- 24494371 TI - Hoarding: the subject of reality television now has a place in the DSM-5. PMID- 24494372 TI - Warriors' hidden wounds: the VA tries to stem the rising suicide rate among veterans. PMID- 24494373 TI - The doctor is in another town: telepsychiatry brings care to people in rural Minnesota. PMID- 24494374 TI - The 20-minute clinic visit: It's sometimes easier for physicians to bring up what families cannot. PMID- 24494375 TI - "Recovery": when we are talking about mental illness, we need to define what we mean. PMID- 24494376 TI - Making your practice more welcoming to patients with a mental illness. PMID- 24494377 TI - What clinicians need to know about DSM-5. PMID- 24494378 TI - A plan to align substance abuse, mental health and primary care efforts in Minnesota. PMID- 24494379 TI - A model for educating children and adolescents in a psychiatric care setting. PMID- 24494380 TI - Adeline's mother: a glimpse at the person in the patient. PMID- 24494381 TI - Seeing with new eyes. PMID- 24494382 TI - Promoting cultures of thinking: transforming nursing education to transform nursing practice. AB - Contemporary nursing education is highly invested in the development of the academic, critical, and empirical aspects of education that represent the science of nursing, and concomitantly less attentive to the development of the creative, interpersonal aspects of education typically associated with the art of nursing. This represents a reversal of historic patterns in nursing education, but the pendulum may have swung so far that there could be costs to nursing practice unless the creative, interpersonal aspects of education can be reclaimed and balanced. Ideas and suggestions regarding how nurse educators might foster the creation of cultures of thinking, which represent whole-brain, integrated teaching approaches that are based on emerging neurocognitive evidence, are discussed. PMID- 24494383 TI - Expressive remix therapy: using digital media art in therapeutic group sessions children and adolescents. AB - Stories play a significant role in how we feel about and interact with the world. Narrative therapy and expressive arts therapy are major influences on the creation of expressive remix therapy, a new form of engagement with clients. This article is an exposition of this particular mental health modality. The use of digital media art in therapy in group settings will be discussed, and examples of how to use digital media art and technology in group therapy sessions are provided. The intention of this article is to promote a renewed appreciation for stories as the backdrop for all narrative work; it also seeks to inspire people to look at the practice of mental health differently, particularly the tools used to positively impact clients. PMID- 24494384 TI - Care coordination and the essential role of the nurse. AB - Quality improvement and cost control rely on effective coordination of patient care. Registered nurses (RNs) across the continuum of care play an essential role in care coordination. Greater health care efficiencies can be realized through coordination of care centered on the needs and preferences of patients and their families. Professional nursing links these approaches, promoting quality, safety, and efficiency in care, resulting in improved health care outcomes that are consistent with nursing's holistic, patient-centered framework of care. This model for RN care coordination provides a guideline for nurses in direct care as well as those in highly specialized care coordination positions. PMID- 24494385 TI - Faith community nursing: health and healing within a spiritual congregation. AB - Originally named parish nursing because of its beginnings in the Christian faith, the term faith community nursing (FCN) has been adopted to encompass nurses from other faiths. The American Nurses Association recognized parish nursing as a nursing specialty and, in collaboration with the Health Ministries Association, published the Scope and Standards of Parish Nursing Practice in 1998 (revised in 2005). In this article, the authors explore the philosophy, objectives, growth, and practice of this specialty. PMID- 24494386 TI - Transformative advance care planning: the Honoring Choices Minnesota experience. AB - In the United States, discussing end-of-life wishes and preferences has been taboo ever since death and dying moved from a stage of life to a medical condition. This article describes the transformative nature of a Minnesota health care initiative, Honoring Choices Minnesota (HCM). As the world's largest nongovernmental, voluntary community-centered initiative, HCM is changing the culture around speaking of death and dying, one conversation at a time. PMID- 24494387 TI - Mindfulness practice with urban youth: a nursing experience. AB - Contemporary care models and new knowledge in neuroscience and brain development are the foundation for including mindfulness in the delivery of holistic health care. Youth who experience persistent poverty or other chronic environmental stressors face serious challenges to health development. This article shares a nursing challenge in piloting a mindfulness program with urban youth who have experienced homelessness. PMID- 24494388 TI - Not changing minds but softening hearts. AB - When a political decision threatened to divide communities, the Minnesota Council of Churches found a way not to change minds but to soften hearts. The Respectful Conversations Project built empathy and improved relationships, and is still helping to bring peace to communities and strengthening civic engagement in the state. PMID- 24494389 TI - Relationship-based care in the neonatal intensive care unit. AB - At St. Joseph's Regional Medical Center in Paterson, New Jersey, implementation of the Relationship-Based Care (RBC) model of care delivery and enculturation of the philosophy of care embodied in Jean Watson's Theory of Human Caring (Watson, 2007) improved patient outcomes and supported quality nursing care across the continuum of care in our organization. The ability of staff nurses to create an atmosphere of professional inquiry that places patients and families at the center of practice supported implementation of RBC in our neonatal intensive care unit (NICU). PMID- 24494390 TI - They told us we would change. PMID- 24494391 TI - You must be stronger than the challenges. PMID- 24494392 TI - [The law does not prevent health care professionals from reading patient data]. PMID- 24494393 TI - [Investigation of the benefits and risks of zolpidem is ongoing]. PMID- 24494394 TI - [Birth control pills and thrombosis--again. Benefits outweigh the risks--low risk with long-acting contraceptive methods]. PMID- 24494395 TI - [Birth control pills, surgery and casting leads to high risk of venous thrombosis in women. Better prophylaxis is needed for surgical procedures, as shown in case control study]. PMID- 24494396 TI - [Many medical symptom scales do not measure up. Review of the estimation methodology]. PMID- 24494397 TI - [Minimally invasive implantation of left ventricular assist devices. Good results in the first procedure in Sweden]. PMID- 24494398 TI - [HbA1c will complement other methods in the diagnosis of diabetes. Coordinated introduction in Sweden in January 2014]. PMID- 24494399 TI - [Patient rights and patient pacts]. PMID- 24494400 TI - [There are two kinds of wound edge protection devices in laparotomy, of which one is ineffective]. PMID- 24494401 TI - [Safe and proper care at universities]. PMID- 24494402 TI - [Research at child health service centers. Participation in national studies should be included in the agreements]. PMID- 24494404 TI - [Disgraceful with poorer health care for people with reduced autonomy]. PMID- 24494403 TI - [Increased prescription of azithromycin: New recommendations on the way for sexually transmitted infections caused by bacteria]. PMID- 24494405 TI - [Charlotte Yhlen--the first Swedish woman becoming a medical doctor. She had to move from Sweden to work as a physician]. AB - Charlotte Yhlen (1839-1919) was the first Swedish woman with medical education. New research has shed light on this forgotten pioneer. Charlotte was born in a Southern Sweden in a family without academical tradition. In her youth she got inspired by the woman emancipation movement. At an age of 28 she emigrated to the USA and studied at the Woman's Medical College of Pennsylvania. Her student thesis dealt with glaucoma. After graduation, Charlotte applied for work in Sweden but got rejected. Therefore, she moved back to the USA to work at Woman's Hospital of Philadelphia and later with a private practice as a general practitioner. In 1874, she married a Norwegian engineer and the couple got two children. Her husband's successful company Tinius Olsen Company was probably the reason why she gave up her medical career in her 50s. The article describes the conditions for love and work for the first Swedish women with academical education. PMID- 24494406 TI - [From warfarin to new oral anticoagulants in clinical practice. What is the future of anticoagulant therapy in atrial fibrillation?]. PMID- 24494407 TI - [Therapeutic adherence: between saying and doing]. PMID- 24494408 TI - [Thromboembolic and hemorrhagic risk stratification in patients with atrial fibrillation. Part I: the thromboembolic risk]. AB - Atrial fibrillation, whose prevalence is in constant increase, is associated to a noticeably greater thrombo-embolic risk. Various associated factors, such as older age, arterial hypertension, heart failure, previous cerebrovascular events (stroke and transient ischemic attacks), diabetes mellitus, female sex and vascular diseases determine a further increase of the risk of stroke in patients with atrial fibrillation. Robust evidence exists on the efficacy of traditional anticoagulant oral therapy in the prevention of thrombo-embolic risk in these patients, but fears and concerns of hemorrhagic events for the physicians and the logistic difficulties related to the periodic International Normalized Ratio evaluation for the patients are at the basis of a noticeable under-utilization of the therapy with vitamin K antagonists in the real world. Stratification of the thrombo-embolic risk has thus particular importance; for this scope we may use now score systems as CHA2DS2 and, above all, CHA2DS2-Vasc, that allows the identification of truly low risk patients, which do not require an antithrombotic treatment. Novel oral anticoagulants, lastly, will help physicians in order to obtain a better management of trombo-embolic risk in atrial fibrillation. PMID- 24494409 TI - [The portopulmonary hypertension: an overview from diagnosis to treatment]. AB - Portopulmonary hypertension (POPH) refers to the condition of pulmonary arterial hypertension (PAH) in association with portal hypertension. Among patients with portal hypertension, reported incidence rates of POPH range from 2 to 10% and long-term prognosis in cases of POPH is poor. Fundamental issues of management of POPH include identification of patients likely to benefit from liver transplantation (LTx) and treatment with specific pulmonary vasodilators before and after LTx. This review presents as an overview of the current knowledge on the epidemiology, diagnosis, treatment and prognosis of patients with portopulmonary hypertension. PMID- 24494410 TI - [Evaluating short term efficacy of educative support in a cardiovascular rehabilitation using the MICRO-Q test: a single centre experience]. AB - Object of this study was to evaluate the efficacy of multiprofessional meetings in order to improve patients' knowledge about cardiovascular diseases, risk factors and correct lifestyle in a Cardiovascular Rehabilitation Department. METHODS: from November 2011 to June 2012 two MICRO-Q questionnaires were given to the Fossano Cardiovascular Rehabilitation's patients before and after the educational meetings to test their improvement after having followed educational meetings. RESULTS: 73 patients have answered the questionnaires (57 males, mean age 68,5 +/-11.73ys). From these data emerged a significant improvement of knowledge about cardiovascular risk factors (75,34% vs 91,78%; p=0,01), smoke (79,45% vs 93,15%; p=0,03), stress (76,71% vs 91,78; p=0,023), diet (84,93% vs 97,26%; p=0,02), physical activity (63,01% vs 84,93%; p=0,005) and right things to do in case of chest pain (34,25% vs 52,05%; p=0,04). CONCLUSIONS: educational meetings had an important role in improve patients' knowledge about cardiovascular risk factors, correct lifestyle and diet. Moreover MICRO-Q questionnaires demonstrated to be useful tools in order to improve the educational meetings according to the real needs of our patients. PMID- 24494411 TI - [The usefulness of Moynihan questionnaire in the evaluation of knowledge on healthy diet of patients undergoing cardiology rehabilitation]. AB - BACKGROUND: The aim of study was to test the usefulness of Moynihan questionnaire in the evaluation of knowledge on healthy diet of patients undergoing cardiology rehabilitation. METHODS: We enrolled 51 patients (pts): 41 men and 10 women, mean age 67.97 +/-11.2 years. The case study included: 21 pts that underwent coronary bypass surgery, 16 pts replaced plastic tube, 14 pts had surgery for the other reasons. All pts underwent nutritional investigation by a dietitian. Anthropometric and biochemical parameters were detected and, by the end, the Moynihan questionnaire was administrated. Pts underwent nutritional coaching, and questionnaire and dietary assessment were rechecked after 3 months. RESULTS: At baseline, the mean Questionnaire score was 22.4 +/- 3.2 points, decreased to 20.6 +/-3.1 points after 3 months (p<0.05). A detailed analysis of the questions showed that the major informations gaps were related to consumption of fruits and vegetables, consumption of fat and salt. In addition pts have acquired more general knowledge about food composition. CONCLUSIONS: The Moynihan questionnaire is an useful instrument of evaluation of dietary knowledge even in selected patients population. In the present study involving patients after cardiac surgery the main difficulties were related to high age of pts, the low cultural level and, mainly, to the post-surgery stress. However, an increase of correct answers as well as an increased knowledge about food composition were detected after educational intervention performed by the dietitian. PMID- 24494412 TI - [Italian survey on physical activity of the members of GICR-iACPR 2012]. AB - BACKGROUND AND AIMS: The International Physical Activity Questionnaire (IPAQ) was issued in 2005 by the WHO as an international standard for the evaluation of physical activity (PA) [1-11]. The Italian Association for Cardiovascular Prevention and Rehabilitation (GICR-IACPR) is promoting nationwide calls for action aimed at the implementation of cardiovascular (CV) prevention guidelines. The awareness of cardiac rehabilitation professionals (CRP) with regards to healthy lifestyle is assumed. METHODS: The IPAQ was submitted to delegates of 2012 IACPR congress. Sex, age, position and geographic location were also asked. We received 136 questionnaires back. The data were analysed using the established scoring protocol by the IPAQ Research Committee and datasets were compared to WHO global recommendations on PA for health. RESULTS: 136 questionnaires were evaluated (years aged 50.5, 42% M), 13 were excluded after cleaning. Thus 123 tests were classified in 3 levels of PA, according to WHO rec. H:45 subjects with higher level of participation and greater health benefits. M:75 subjects who accumulate a moderate level of PA. L:3 subjects who did not meet criteria for category high or moderate. CONCLUSIONS: According to a preliminary analyses of currently available IPAQ, 61% GICR-CRP seems sufficiently active for a health benefit, 37% have additional health benefits, and only 2% is not active enough for health. Comparing these figures with those of the 2010 survey, we found an average age higher in males and an improvement in the time and intensity of PA. PMID- 24494413 TI - Achieving smarter health care. PMID- 24494414 TI - Phoenix in February: calling all rural health care leaders. AB - There are three big reasons to attend the Rural Health Care Leadership Conference. Weather is just one of them. PMID- 24494415 TI - Cost calculator. Medicare's new value proposition. PMID- 24494416 TI - Click here. Making strides withonline billing. PMID- 24494417 TI - Making a grade. A report card on report cards. PMID- 24494418 TI - Message in a bottle. PMID- 24494419 TI - Clearing the barriers to hospital-physician connectivity. PMID- 24494420 TI - Including the home as a care setting. PMID- 24494421 TI - Big savings. Aggressive pharmacy management yields big savings. PMID- 24494422 TI - Toward a healthier tomorrow. PMID- 24494423 TI - Mind+matter=health care's new math. AB - Thanks to the provisions in the Affordable Care Act and other federal mandates and a mission to improve outcomes, providers are integrating behavioral and medical health care. That can lead to fewer readmissions and, in the long run, lower costs. Some hospitals and partner providers already have taken significant strides in that direction. PMID- 24494424 TI - Diabetes: Moving toward a more individualized approach. AB - New and emerging treatment plans are abandoning long-held ideas and becoming much more targeted to diabetes patients' individual needs. But a personalized approach could make quality measurement and pay-for-performance more complicated, and they will need to change, too. PMID- 24494425 TI - High-value health care. Achieving success and demonstrating results. AB - A panel of hospital executives and industry experts came together in Chicago recently to discuss the transformational initiatives that can lead to the delivery of high-value health care. Here's what they had to say about the critical changes in infrastructure and care processes that will be necessary. PMID- 24494426 TI - Extending the food chain. AB - A Toledo, Ohio, hospital used to throw away the meals it didn't serve. Now it helps to feed its hungry neighbors. PMID- 24494427 TI - A holistic approach to cutting costs. PMID- 24494428 TI - Wishful thinking. CIOs and other health execs weigh in on their I.T. wish lists for 2014 and beyond. PMID- 24494429 TI - A new look at the supply chain. PMID- 24494430 TI - Kinder cuts. New approaches to data can bring real-time improvements to surgery. PMID- 24494431 TI - Efficiency expert. Interview by Elizabeth Gardner. PMID- 24494432 TI - ECVP logos. PMID- 24494433 TI - Face perception is whole or none: disentangling the role of spatial contiguity and interfeature distances in the composite face illusion. AB - Compelling evidence that faces are perceived holistically or configurally comes from the composite face illusion: identical top halves of a face are perceived as being different if they are aligned with different bottom halves. The visual illusion disappears when the top and bottom face halves are spatially misaligned. Whether this is because the two halves no longer form a whole face (ie they form two segmented parts), or because of an increase in interfeatures distance in the misaligned condition (eg eyes-mouth distance) remains unclear. Here, thirty-four participants performed a delayed matching composite task in which the amount of spatial misalignment between face halves varied parametrically (from 8.33% of face width to 100%). The difference in performance between aligned and misaligned faces (ie the composite face effect) was already of full magnitude at the smallest level of misalignment. These results imply that a small spatial misalignment is sufficient to measure the composite face effect. From a theoretical standpoint, they indicate that it is the breaking of a whole configuration rather than the increase in relative distance between the face parts that explains the presence or absence of the composite face effect, clarifying an outstanding issue concerning the nature of holistic face perception. PMID- 24494434 TI - Size-invariant facial expression categorization and associated gaze allocation within social interaction space. AB - As faces often appear under very different viewing conditions (eg brightness, viewing angle, or viewing distance), invariant facial information recognition is a key to our social interactions. Although we would clearly benefit from differentiating different facial expressions (eg angry vs happy) at a distance, there is surprisingly little research examining how expression categorization and associated gaze allocation are affected by viewing distance within the range of typical social space. In this study I systematically varied the size of faces displaying six basic facial expressions of emotion with varying intensities to mimic viewing distances ranging from arms length to 5 m, and employed a self paced expression categorization task to measure participants' categorization performance and associated gaze patterns. Irrespective of the displayed expression and its intensity, the participants showed indistinguishable categorization accuracy and reaction time across the tested face sizes. Reducing face size decreased the number of fixations directed at the faces but increased individual fixation durations, and shifted gaze distribution from scanning all key internal facial features to fixating at mainly the central face region. The results suggest size-invariant facial expression categorization behaviour within social interaction distance which could be linked to a holistic gaze strategy for extracting expressive facial cues. PMID- 24494435 TI - Visuospatial attention and motor skills in kung fu athletes. AB - The present study compared the performance of a group of sixteen kung fu athletes with that of a control group of fourteen nonathletes on a speeded visuospatial task and a hand-tapping motor task. In the visuospatial task the results showed that athletes were faster than the control participants when stimuli were presented at the periphery of the visual field at a middle and high presentation speed with short interstimulus intervals. Athletes were also significantly faster than nonathlete participants when performing motor actions such as hand-tapping with their dominant hand but groups did not differ with the nondominant hand. These results support the view that athletes perform some speeded visuospatial and motor tasks faster than nonathletes under certain conditions. The findings suggest that, after several years of practice, kung fu athletes develop certain skills that allow them to perform motor speed maneuvers under time pressure conditions. PMID- 24494436 TI - Not physically present contours can yield illusory motion. AB - We demonstrate a perceptual effect whereby contours not physically present in a visual scene can yield striking illusory motion. The not physically present contours are paths of invariant contrast polarity (CP). For example, when a square checkerboard composed of dark and light square checks with small black and white discs covering the vertices is put in lateral motion, there is the striking perception of vertical expansion/contraction. Such a checkerboard has (not physically present) diagonal paths of CP presentation with vertical components. However, when a square checkerboard made up of square black and very light checks with gray discs of luminance intermediate to the checks is put in lateral motion, no expansion/contraction is seen. For this checkerboard the vertical components of paths of CP preservation cancel each other out, predicting the lack of perception of vertical expansion/contraction. We also discuss how not physically present contours can explain previously described effects and suggest new effects to be explored. PMID- 24494437 TI - The effects of perceptual priming on 4-year-olds' haptic-to-visual cross-modal transfer. AB - Four-year-old children often have difficulty visually recognizing objects that were previously experienced only haptically. This experiment attempts to improve their performance in these haptic-to-visual transfer tasks. Sixty-two 4-year-old children participated in priming trials in which they explored eight unfamiliar objects visually, haptically, or visually and haptically together. Subsequently, all children participated in the same haptic-to-visual cross-modal transfer task. In this task, children haptically explored the objects that were presented in the priming phase and then visually identified a match from among three test objects, each matching the object on only one dimension (shape, texture, or color). Children in all priming conditions predominantly made shape-based matches; however, the most shape-based matches were made in the Visual and Haptic condition. All kinds of priming provided the necessary memory traces upon which subsequent haptic exploration could build a strong enough representation to enable subsequent visual recognition. Haptic exploration patterns during the cross-modal transfer task are discussed and the detailed analyses provide a unique contribution to our understanding of the development of haptic exploratory procedures. PMID- 24494438 TI - iMAP and iMAP2 produce erroneous statistical maps of eye-movement differences. AB - The programs iMAP and iMAP2, developed by Caldara and Miellet (2011 Behavior Research Methods 43 846-878), have attempted to implement a general approach to the analysis of eye-movement data, providing not only 'heat maps' of areas of greater and lesser activity but also, and potentially of great practical importance, significance tests which take into account spatial autocorrelation in fixation locations. The tests in particular allow different groups to be compared, as in one of Caldara and Miellet's example datasets where fixation patterns of Western Caucasian and East Asian participants are said to be significantly different. The present paper argues that the significance tests, as implemented, used an inappropriate algorithm and therefore gave erroneous results. In particular, if participants are randomly allocated to two groups, which is a conventional randomization test, then in every case the program claimed to find 'significant differences', which cannot be correct. A simple, modified statistical technique, based around a simple two-group t-test, with error functions and spatial autocorrelation taken into account, finds no differences between the example groups of participants. That conclusion is reinforced by analyzing simulated data with or without true differences, when iMAP/iMAP2 always finds significant differences, irrespective of sample size, whereas the modified method finds significant differences for only the largest sample sizes. Previous research using iMAP/iMAP2 may have come to erroneous conclusions about differences in fixation patterns between groups. PMID- 24494439 TI - Where have eye been? Observers can recognise their own fixations. AB - We are often not explicitly aware of the location of our spatial attention, despite its influence on our perception and cognition. During a picture memory task, we asked whether people could later recognise their eye fixations in a two alternative test. In three separate experiments, participants performed above chance when discriminating their own fixation patterns from random locations or locations fixated in a different image. Recognition was much poorer when the task was to spot your own versus someone else's fixations on the same stimulus, but performance remained better than chance. That we are sensitive to our own scan patterns has implications for perception, memory, and meta-cognition. PMID- 24494440 TI - Facial features influence the categorization of female sexual orientation. AB - Social categorization is a rapid and automatic process, and people rely on various facial cues to accurately categorize each other into social groups. Recently, studies have demonstrated that people integrate different cues to arrive at accurate impressions of others' sexual orientations. The amount of perceptual information available to perceivers could affect these categorizations, however. Here, we found that, as visual information decreased from full faces to internal facial features to just pairs of eyes, so did the accuracy of judging women's sexual orientation. Yet and still, accuracy remained significantly greater than chance across all conditions. More important, however, participants' response bias varied significantly depending on the facial feature judged. Perceivers were significantly more likely to consider that a target may be lesbian as they viewed less of the faces. Thus, although facial features may be continuously integrated in person construal, they can differentially affect how people see each other. PMID- 24494441 TI - Subsymmetries predict auditory and visual pattern complexity. AB - A mathematical measure of pattern complexity based on subsymmetries possessed by the pattern, previously shown to correlate highly with empirically derived measures of cognitive complexity in the visual domain, is found to also correlate significantly with empirically derived complexity measures of perception and production of auditory temporal and musical rhythmic patterns. Not only does the subsymmetry measure correlate highly with the difficulty of reproducing the rhythms by tapping after listening to them, but also the empirical measures exhibit similar behavior, for both the visual and auditory patterns, as a function of the relative number of subsymmetries present in the patterns. PMID- 24494442 TI - The use and misuse of biomedical data: is bigger really better? AB - Very large biomedical research databases, containing electronic health records (EHR) and genomic data from millions of patients, have been heralded recently for their potential to accelerate scientific discovery and produce dramatic improvements in medical treatments. Research enabled by these databases may also lead to profound changes in law, regulation, social policy, and even litigation strategies. Yet, is "big data" necessarily better data? This paper makes an original contribution to the legal literature by focusing on what can go wrong in the process of biomedical database research and what precautions are necessary to avoid critical mistakes. We address three main reasons for approaching such research with care and being cautious in relying on its outcomes for purposes of public policy or litigation. First, the data contained in biomedical databases is surprisingly likely to be incorrect or incomplete. Second, systematic biases, arising from both the nature of the data and the preconceptions of investigators, are serious threats to the validity of research results, especially in answering causal questions. Third, data mining of biomedical databases makes it easier for individuals with political, social, or economic agendas to generate ostensibly scientific but misleading research findings for the purpose of manipulating public opinion and swaying policymakers. In short, this paper sheds much-needed light on the problems of credulous and uninformed acceptance of research results derived from biomedical databases. An understanding of the pitfalls of big data analysis is of critical importance to anyone who will rely on or dispute its outcomes, including lawyers, policymakers, and the public at large. The Article also recommends technical, methodological, and educational interventions to combat the dangers of database errors and abuses. PMID- 24494443 TI - The individual mandate as healthcare regulation: what the Obama Administration should have said in NFIB v. Sebelius. AB - There was an argument that the Obama Administration's lawyers could have made- but didn't--in defending Obamacare's individual mandate against constitutional attack. That argument would have highlighted the role of comprehensive health insurance in steering individuals' healthcare savings and consumption decisions. Because consumer-directed healthcare, which reaches its apex when individuals self-insure, suffers from several known market failures and because comprehensive health insurance policies play an unusually aggressive regulatory role in attempting to correct those failures, the individual mandate could be seen as an attempt to eliminate inefficiencies in the healthcare market that arise from individual decisions to self-insure. This argument would done a better job than the Obama Administration's of aligning the individual mandate with existing Commerce Clause and Necessary and Proper Clause precedent, and it would have done a better job of addressing the conservative Justices' primary concerns with upholding the mandate. This Article lays out this forgone defense of the individual mandate. PMID- 24494444 TI - Beyond abortion: why the personhood movement implicates reproductive choice. AB - In 2008, an amendment was proposed to the Colorado Constitution that sought to attach the rights and protections associated with legal "personhood" to any human being from the moment of fertilization. Although the initiative was defeated, it sparked a nation-wide Personhood Movement that has spurred similar efforts at the federal level and in over a dozen states. Personhood advocates choose terms like "fertilization," or phrases such as "human being at any stage of development, " to identify the "person"-defining moment in the reproductive process, and these designations have profound implications for reproductive choice. Proponents are outspoken in their desire to outlaw abortion, but they are less transparent about their intent with respect to other aspects of reproductive choice, such as contraception and infertility treatments. This paper describes the background of the Personhood Movement and its attempt to achieve legal protection of the preborn from the earliest moments of biological development. Following the late 2011 failure of the personhood measure in Mississippi, the language used within the Movement was dramatically changed in an attempt to address some of the concerns raised regarding implications for reproductive choice. Putting abortion to one side, this paper identifies why the personhood framework that is contemplated by the proposed changes does not eliminate the potential for restrictions on contraception and in vitro fertilization (IVF) that put the lives of these newly recognized persons at risk; nor should it if proponents intend to remain consistent with their position. The paper goes on to suggest what those restrictions might look like based on recent efforts being proposed at the state level and frameworks that have already been adopted in other countries. PMID- 24494445 TI - A comprehensive strategy to overhaul FDA authority for misleading food labels. AB - The modern food environment is considered a primary driver of obesity and other nutrition-related chronic diseases. A significant contribution to this environment is the proliferation of claims on food packaging that provides a misleading picture of a product's healthfulness. The Food and Drug Administration (FDA) is the agency responsible for food labels but it lacks the regulatory authority and adequate resources to address the majority of questionable labeling practices. The FDA's current system of enforcement is thus essentially based on voluntary compliance and consumer- and manufacturer-initiated litigation has not successfully filled the regulatory gap. This manuscript reviews the current state of food labeling claims and the FDA's inadequate authority over misbranded food products. It analyzes competing views on regulatory compliance strategies and argues that a regulatory overhaul consistent with the best science and the First Amendment is necessary. With increased resources and authority, the FDA can meet current public health challenges and adequately ensure that labels are clear and consumers are properly informed and protected. PMID- 24494446 TI - Evaluating New Hampshire's first-in-the-nation early offer alternative to medical malpractice litigation. PMID- 24494448 TI - Continuing education for professional growth. PMID- 24494447 TI - Closing the gaps and loopholes: analyzing tax exemption of non-profit hospital joint ventures after the Affordable Care Act. PMID- 24494449 TI - The truth about depth of cure. PMID- 24494450 TI - Myofascial pain. PMID- 24494451 TI - Yet another oral health conundrun burning mouth syndrome. PMID- 24494452 TI - ADA delegates pass resolution urging state dental boards to register US dental labs. PMID- 24494453 TI - Simplified sinus lift surgery. PMID- 24494454 TI - Predictably solving a prosthetic dilemma: a partially edentulous mandible opposed by a worn maxillary denture. PMID- 24494455 TI - A new day in dentistry: technology supports collaboration with the laboratory team. PMID- 24494456 TI - Full-mouth restoration of a severely decayed dentition. PMID- 24494457 TI - Optimizing core buildiups and post and core restorations: improving clinical techniques with new resin materials. PMID- 24494459 TI - Isthmus gifts. PMID- 24494458 TI - Composite resins 2.0: entering a new age of posterior composites. PMID- 24494460 TI - Aesthetic zone challenges: severe anterior wear, part 3: restoratively driven interdisciplinary treatment planning. PMID- 24494462 TI - Intraoral video cameras. PMID- 24494461 TI - Craniofacial enhancement using a biomimetic oral appliance. PMID- 24494463 TI - Mucinous differentiation in colorectal cancer: molecular, histological and clinical aspects. AB - BACKGROUND: Mucinous colorectal carcinoma represents a subtype of colorectal carcinoma (CRC), which is characterized by abundant amount of extracellular mucin. We reviewed the molecular, histological and clinical aspects of mucinous CRC as compared to the non-mucinous type. METHODS: A systematic web-based research was performed using Web of Knowledge. The combination of the Boolean search terms "COLO" AND "MUC" was used. The literature was searched until July 2013. RESULTS: Patients with mucinous CRC have distinct clinical and pathological features. Mucinous CRC tends to occur in younger patients, are often seen in the proximal colon, are more diagnosed at an advanced stage and are more frequently associated with hereditary non-polyposis colorectal cancer (HNPCC) and young-age sporadic colorectal cancer. The prognostic significance of mucinous differentiation remains uncertain; some studies have shown a poor response to oxaliplatin and/or irinotecan based chemotherapy. Mucinous CRC is associated with a higher expression of MUC2 and MUC5AC, but a lower expression of MUC1. The differential expression of mucins has been related to altered risk of metastasis and death. Recently, mucins have been used as targets for molecular therapy and as a source of immune therapy. Mucinous differentiation is associated with other specific genetic and molecular features such as increased BRAF mutation rate and microsatellite instability. CONCLUSION: Mucinous CRC is a distinct clinical, pathological, and molecular entity. The implications of mucinous differentiation for treatment response and outcome are not fully elucidated, but the available data suggest an adverse effect. The use of mucins as immunotargets may show therapeutic promise for mucinous CRC. PMID- 24494464 TI - Comparison between single incision and conventional laparoscopic cholecystectomy for uncomplicated cholelithiasis. AB - AIM: To compare surgical outcomes of patients presenting with uncomplicated cholelithiasis and operated by single incision (SILC) or by conventional laparoscopic cholecystectomy (CLC). METHODS: The series concerned 58 consecutive patients operated between October 2008 and October 2009. There were 11 men and 47 women with a mean age of 47 years and a BMI of 29. Six patients had a past surgical history with a midline incision. The main parameters analysed were duration of operation, morbidity, postoperative pain, return to normal activities and aesthetic result. One month and one year after surgery, the cosmetic result was assessed on a visual analogue scale (VAS), a score between 9 and 10 was considered as an excellent cosmetic result. RESULTS: A SILC was performed in 26 and a CLC in 32 patients. Patients in the SILC group were characterised by a lower BMI : 25 versus 32 (p <0.001) and by the absence of previous midline incision: 0/26 (0%) versus 6/32 (19%) (p <0.028). Outcomes were similar between groups except the aesthetic result. Multivariate statistical analysis revealed that the percentage of excellent cosmetic result was higher in SILC than in CLC group : respectively 73% (19/26) vs. 28% (9/32) one month postoperatively (OR : 5.3, 95% CI: 1-23, p <0.03) and 92% (22/24) versus 55% (17/31) one year postoperatively (OR : 6.9, 95% CI : 1-46, p < 0.04). CONCLUSIONS: Our study demonstrates that SILC is a feasible and safe procedure in a selected population. Compared to CLC, the only obvious benefit is a better cosmetic result that is still observed one year after surgery. PMID- 24494465 TI - Obesity trends in the surgical population at a large academic center : a comparison between 1989-1991 to 2006-2008 epochs. AB - BACKGROUND: Changes in the prevalence of obesity of surgical patients overtime and in relation to the general population have not been well characterized. METHODS: Height, weight, age and gender data of adult patients who underwent general anesthesia at our institution were abstracted. Reliable data was available for the years 1989-1991 and 2006-2008, and comparisons were made between these epochs. Additional comparisons were made between our Minnesota surgical patients and the general Minnesota population. RESULTS: Substantial changes in patient weight occurred with a decline in normal weight patients (body mass index [BMI] < or =25.0) from 41.6% to 30.9% (P <0.001), while the prevalence of obesity (BMI 30-34.9) increased from 14.9% to 20.6% (P <0.001) and morbidly obesity (BMI > 35) from 7.1% to 14.8% (P <0.001). Minnesota surgical patients had a higher prevalence of obesity in every demographic category (P <0.001) compared to the general population. CONCLUSION: A substantial increase in the prevalence of obesity and morbid obesity among surgical patients at our institution occurred and the prevalence of obesity in our contemporary practice is higher than the general population. These observations most likely have profound implications on healthcare delivery resources, though its impact has yet to be determined. PMID- 24494466 TI - Protective effect of montelukast, a cysteinyl leukotriene receptor-1 antagonist, against intestinal ischemia-reperfusion injury in the rat. AB - OBJECTIVE: Ischemia-reperfusion (I-R) injury of the intestine is a significant problem because the initial damage caused by ischemia is exacerbated by reperfusion. In this study, we examined the protective effect of montelukast against I-R-induced intestinal tissue damage. MATERIALS AND METHODS: Eight-week old male Sprague-Dawley rats were randomly divided into three treatment groups : a sham-operated group, a group receiving I-R, and a group receiving I-R plus montelukast (I-R/M). Tissue samples were evaluated and scored histologically. The blood levels of malondialdehyde (MDA), myeloperoxidase (MPO), glutathione (GSH), and cardiotrophin-1 (CT-1) were measured. RESULTS: In the I-R group, the histological score and the levels of serum MDA and MPO were increased compared with those in the control group. In the I-R/M group, the histological score and serum MDA and MPO levels were significantly decreased compared with those in the I-R group. Additionally, compared with the IR group, the I-R/M group had increased serum GSH and CT-1 levels and a decreased intestinal injury score. Ileal sections from the I-R/M group showed minimal alterations, characterized by moderate lifting of the epithelial layer from the lamina propria, and few apoptotic enterocytes were observed compare with the number in the I-R group. CONCLUSION: The findings of the present study demonstrated that montelukast can protect I-R-induced intestinal damage in rats. PMID- 24494467 TI - Use of health-related quality-of-life measurements to estimate individuals' health on screening. AB - OBJECTIVES: to investigate the utility of assessing Health-Related Quality of Life (HRQoL) in a large group of subjects participating in a screening program for aneurysm and the relationship between HRQoL, diagnosis of aneurysm and related risk factors. METHODS: subjects involved in this screening program were submitted the EQ-5D questionnaire to report their own HRQoL. HRQoL was reported also a second time by the subjects who were diagnosed with aneurysm during screening and who returned for a monitoring follow up visit a few months later. We evaluated compliance with HRQoL data collection and performed multiple regression analyses in order to investigate the possible relationship between demographic and clinical data with HRQoL. RESULTS: 1,633 subjects screened (6.1% diagnosed with aneurysm) and 125 subjects diagnosed with aneurysm and attending a follow-up visit reported their HRQoL. Completion of the EQ-5D questionnaire was well accepted by both physicians and subjects undergoing screening. HRQoL was not significantly different between the screening and followup visits, on adjusting for age and sex. At the screening visit, HRQoL was associated with ASA class, heart condition, BMI and respiratory diseases. No associations were found at the follow-up visit. CONCLUSION: Assessing HRQoL in screening programs is feasible and well accepted and add useful information on health of large numbers of subjects from general population. This could be considered as a routine approach to optimizing the informative role of screening programs in guiding other investigations or interventions. PMID- 24494468 TI - Influence of postoperative fluid management on pulmonary function after esophagectomy. AB - PURPOSE: The aim of this study was to investigate the effects of a restrictive vs. a liberal postoperative fluid therapy guided by intrathoracic blood volume index (ITBVI) on hemodynamic and pulmonary function in patients undergoing elective esophagectomy. Perioperative fluid therapy may influence postoperative physiology and morbidity after esophageal surgery. Definitions of adequate infusion amounts and evident rules for a fluid therapy are missing. METHODS: After esophagectomy, 22 patients were randomized either to a restrictive group (RG) with low range of ITBVI (600-800 ml/m2) or a liberal group (LG) with normal ITBVI (800-1000 ml/m2). Infusion regimen was modified twice a day according to transpulmonary thermodilution measurements until the 5th postoperative day. Primary endpoint was paO2/FIO2-ratio. Secondary endpoints were pulmonary function, fluid balance and hemodynamic as well as morbidity. RESULTS: Demographic and surgical details did not differ between both groups. The calculated sample size was not reached. There were no postoperative differences in paO2/FIO2-ratio, ITBVI, hemodynamic parameters, or morbidity either. Cumulative fluid uptake was 4.1 liter less in the RG on the 5th postoperative day (p = 0.01), and pulmonary function was better in these patients (area under curve day 2-7 for forced vital capacity (FVC), forced expiratory volume in one second (FEV1), peak expiratory flow (PEF) each <0.05). CONCLUSION: ITBVI guided restrictive infusion therapy yields a lower fluid uptake, but may not result in a difference of clinical relevant parameters. A fluid restriction after esophagectomy should always be combined with hemodynamic monitoring because additional infusions may be required. PMID- 24494469 TI - Evaluation of surgical glove perforation after laparoscopic and open cholecystectomy. AB - BACKGROUND: Surgical gloves provide a protective barrier against blood-born pathogens. Studies reveal glove perforation rates of up to 45%, which are often unrecognized by the surgeon or nurse. The goal of this study was to evaluate how often glove perforation occurs after laparoscopic and open cholecystectomy. METHODS: Gloves from the operating surgeon and the first assistant were collected after operation and tested immediately using two methods : 1. Water leak test - the approved standardized method to detect holes after filling up the gloves with 1000ml of water. 2. Electrical resistance test - method to detect gloves conductivity immersed in saline bath. RESULTS: Altogether, 376 gloves were studied. The overall perforation rate was 8%. Perforations more frequently were observed after laparoscopic than open cholecystectomy. The gloves worn by the operator were more likely to be perforated than those worn by the assistant surgeon in both types of operations. The most common site of perforation was in the index finger of the non- dominant hand. Thirty percent of gloves conducted electrical current, while 22% of them had no macroscopic evidence of perforation. CONCLUSION: Many of gloves might have microperforations that can not be detected using water leak test. PMID- 24494470 TI - The role of surgical methods in the treatment of anorectal malignant melanoma (AMM). AB - PURPOSE: Anorectal malignant melanoma (AMM) is a rare tumor with a poor prognosis. The aim of this study was to investigate the clinicopathological characteristics and treatment outcomes in patients with AMM. METHODS: The study included 21 patients diagnosed with AMM between 2000 and 2010 that were evaluated with regard to age, sex, disease stage, treatment modality, and survival. Stage I, II, and III were defined as localized primary malignant melanoma, regional lymph node metastasis, and distant metastasis, respectively. RESULTS: In all, 12 (57%) patients were female and 9 (43%) were male ; median age was 61 years (range : 30-84 years). Among the 21 patients, 7 (47%) underwent abdominoperineal resection and 8 (53%) were treated using wide local excision. Four (19%) patients were classified as stage I, 10 (48%) as stage II, and 7 (33%) patients as stage III. In total, 10 patients received adjuvant therapy. Median overall and progression-free survival was 12 and 9 months, respectively. The 1-year and 5 year overall survival estimates were 59% and 42%, and progression free survival were 49% and 7%, respectively. Patients aged > 60 years (P = 0.145), female patients (P = 0.076), patients with localized disease (P = 0.045), patients that underwent wide local excision (P = 0.619), and patients that received adjuvant therapy (P = 0.962) had longer survival. CONCLUSIONS: The prognosis of AMM remains very poor and disease stage is the only predictor of survival. Abdominoperineal resection does not confer an advantage, in terms of survival, in patients with AMM. PMID- 24494471 TI - The effects of tramadol infiltration on wound healing in rats. AB - PURPOSE: Infiltration of a local anesthetic to provide postoperative analgesia is a frequently used method. However the infiltrated agents may have negative effects on wound healing. This study aimed to investigate the effects of tramadol, a weak opioid with a local anesthetic effect, on wound healing. METHODS: Wistar albino rats were used in the study. Tramadol and saline infiltration was randomly performed on the left and right backs of rats. Following a linear incision, the site was sutured. A follow-up was conducted after seven days, and the tissue samples from both locations were extracted for histopathological examinations (fibrotic index : no fibrosis 0, mild 1, moderate 2, severe 3) and hydroxyproline measurements. RESULTS: The hydroxyproline level found in the tramadol group was 0.060 +/- 0.04 ng/mg.protein. In the control group the hydroxyproline level was 0.012 +/-0.01 ng/mg.protein (p = 0.01). The fibrotic index levels in the tramadol group were higher than the control group (p < 0.001). CONCLUSION: It was concluded that tramadol infiltration in a surgical incision site has no adverse effect on wound healing. PMID- 24494472 TI - Totally laparoscopic right hemicolectomy with intracorporeal anastomosis is a technically and oncologically safe procedure. AB - BACKGROUND: During laparoscopic right hemicolectomy, most surgeons perform an extracorporeal anastomosis. A totally laparoscopic procedure with intracorporeal anastomosis may improve cosmesis because midline- or paraumbilical incisions can be avoided. Here, we investigate the safety of an intracorporeal anastomosis from a technical and oncological perspective. METHODS: All patients who underwent right hemicolectomy with intracorporeal anastomosis between 2003-2011 were retrospectively analyzed. Parameters were duration of surgery, intraoperative blood loss, mortality and morbidity. Adequacy of oncologic resections was scored by resectional margins and number of harvested lymph nodes. RESULTS: A total of 162 patients were included with a median age of 69 years (IQR60-76). The duration of surgery was 100 minutes (80-120) and intraoperative blood loss was 30 mL (10 100). Hundred-twenty patients (74%) underwent an oncologic resection. Number of harvested lymph nodes was 12 (9-18). RO-resection was achieved in 100%. Four patients died (2.5%). Postoperative complications were: anastomotic leakage (3.1%; n = 5), ileus (4.9%; n = 8), abscesses (2.5% ; n = 4), wound infection (3.1% ; n = 5) and cardiopulmonary complications (10.5% ; n = 17). Duration of oncological follow-up was 2.5 years (1.3-4.6). Local recurrence and overall survival rates at two years were 0.8% and 85.4%, respectively. CONCLUSION: Right hemicolectomy with intracorporeal anastomosis is a technically and oncologically safe procedure with acceptable operating time and low mortality. PMID- 24494473 TI - The effects of supplementation with a mixture of arginine, glutamine, and beta hydroxy beta-methylbutyrate on the healing of colon anastomoses. AB - BACKGROUND: Several researchers have investigated how wound healing is effected by supplementation with each of the following amino acids : arginine (Arg), glutamine (Glu), and beta-hydroxy beta-methylbutyrate (HMB). This research investigates how a combination of these amino acids improves the wound healing associated with anastomoses. METHODS: We tested the effects of a combination of Arg, Glu, and HMB on the healing of colon anastomoses in 50 male rats. We randomly divided the animals into two equal groups. In each animal, the cecum was transected from its midpoint to create an end-to end anastomosis. During the first postoperative week, Group 1 (G1) animals were fed standard chow, and Group 2 (G2) animals were fed standard chow plus a ready-to-use supplement that contained a mixture of Arg, Glu, and HMB. At the end of the week, all of the rats were sacrificed, and a cecum segment containing the anastomosis line was resected. Bursting pressure and tissue hydroxyproline were measured for all animals. RESULTS: The mean values for hydroxyproline were 0.0013 ng/mg protein/ml (SD +/-0.00075) and 0.034 ng/mg protein/ ml (SD +/- 0.022) for G1 and G2, respectively (p <0.0001). The mean values for bursting pressure measurements were 122.8 mmHg (SD +/- 9.4) and 192.8 mmHg (SD+/- 31) for G1 and G2, respectively (p <0.0001). Statistically significant differences between the groups in terms of both bursting pressure levels and tissue hydroxyproline levels were observed. CONCLUSION: In an animal model of colon surgery, supplementation with a combination of three amino acids seemingly benefits anastomosis healing. PMID- 24494474 TI - Pancreatic ectopia: a case report. AB - Pancreas ectopia / Ectopic pancreas (EP) is a rare congenital disease, most typically diagnosed in asymptomatic patients by incidental detection during surgery or at autopsy. It is defined by the presence of pancreatic tissue localized in various places drifting from the foregut or mesentery. It is subject to the same various inflammatory or neoplastic disorders that may affect the orthotopic pancreas, e.g. pancreatitis or pancreatic tumours. Upper GI endosonography is a key examination (tool) in detecting and defining gastroduodenal ectopic pancreas. However its diagnosis remains difficult. The final diagnosis relies on histopathologic analysis of the resected tumor required to confirm the diagnosis. Its treatment is based on patients' condition and symptoms as well as the kind of surgery depending on the location of the ectopic pancreatic tissue. PMID- 24494475 TI - Ectopic pancreatic tissue at the umbilicus in childhood: a case report and review of the literature. AB - Ectopic pancreatic tissue at the umbilicus is very rare. To our best knowledge, only fourteen cases of ectopic pancreatic tissue at the umbilicus are reported. In this paper we present the case of a two-year-old boy with an abrasion at the umbilicus. He had a poorly healing scar that started bleeding after recurrent injuries. Abdominal ultrasound revealed an unclear cystic structure with no communication to intra-abdominal structures. Surgical resection was performed without complications. Histology diagnosed an ectopic pancreatic tissue with reactive epidermal changes. We present a review of the literature and the clinical manifestations and treatment of the previously reported fourteen cases. PMID- 24494476 TI - Closure of thoracolumbar myelomeningocele with a four muscle flap technique in the newborn. AB - We present a new surgical technique where skin closure was obtained in the treatment of a thoracolumbar myelomeningocele by mobilization of four muscle flaps, two reverse latissimus dorsi muscle flaps combined with the caudal portions of two trapezius muscle flaps. PMID- 24494477 TI - A rare cause of bleeding after laparoscopic sleeve gastrectomy : pseudo-aneurysm of the gastro-omental artery. AB - A serious complication of laparoscopic sleeve gastrectomy (LSG) is bleeding that is primarily located along the staples lines. Bleeding may be due to several causes, including hematomas, trocar sites, or visceral pseudo-aneurysms. We reported here a case of bleeding related to a pseudo-aneurysm of the gastro omental artery. An LSG was performed on a 43-year-old woman (BMI = 46 kg/m2) without apparent surgical complications. Fifteen days later, she was admitted to the emergency department for hematemesis and symptoms of hemorrhagic shock. Abdominal computed tomography angiography revealed blood in the stomach, without a digestive leak, and active bleeding from a pseudo-aneurysm of the gastro omental artery. An arterial embolisation was performed with the sandwich technique and angiographic guide wires and the placement of several detachable coils. The patient was discharged two days later. We demonstrated for the first time that post-LSG bleeding may involve a pseudo-aneurysm of the gastro-omental artery. PMID- 24494478 TI - Acute pancreatitis as the initial manifestation of an adenocarcinoma of the major duodenal papilla in a patient with familial adenomatous polyposis syndrome: a case report and literature review. AB - We report a case of an ampullary carcinoma presenting as acute pancreatitis in a patient with familial adenomatous polyposis (FAP) syndrome and severe duodenal adenomatosis. A 48-year-old woman was hospitalised because of an episode of acute pancreatitis. She had a history of prophylactic total colectomy for FAP 2 years earlier. On admission, abdominal ultrasonography and computed tomography revealed dilatation of the main pancreatic and common bile duct. Spigelman's stage IV duodenal adenomatosis involving the major duodenal papilla was diagnosed on endoscopy and a classical Whipple procedure was proposed. Pathologic examination of the duodenopancreatectomy specimen revealed a tubular adenocarcinoma of the papilla that occluded the major pancreatic ducts. The patient had no evidence of disease and experienced no recurrent attacks of acute pancreatitis during a 36 month period of follow-up. PMID- 24494479 TI - Laparoscopic appendectomy combined with TEP for de Garengeot hernia: case report. AB - INTRODUCTION: A de Garengeot hernia is defined as a femoral hernia containing the vermiform appendix. De Garengeot hernia is a rare condition, reported to occur in only 0.8% of all femoral hernias. Acute appendicitis presenting within a femoral hernia is even rarer, occuring in 0.08-0.13% of all cases of acute appendicitis. CASE REPORT: We present the case of a 64-year-old woman with the diagnosis of incarcerated groin hernia. An urgent laparoscopy was performed showing the distal part of the appendix passing through a small right-sided femoral hernia. A laparoscopic appendectomy was performed, followed by TEP-procedure for femoral hernia repair. DISCUSSION: To our knowledge, this is the first report of this type of approach for a de Garengeot hernia. PMID- 24494480 TI - History of surgery: a global view. PMID- 24494481 TI - Adsorption of Cr(III) from acidic solutions by crop straw derived biochars. AB - Cr(III) adsorption by biochars generated from peanut, soybean, canola and rice straws is investigated with batch methods. Adsorption of Cr(III) increased as pH rose from 2.5 to 5.0. Adsorption of Cr(III) led to peak position shifts in the FTIR-PAS spectra of the biochars and made zeta potential values less negative, suggesting the formation of surface complexes between Cr3+ and functional groups on the biochars. The adsorption capacity of Cr(III) followed the order: peanut straw char > soybean straw char > canola straw char > rice straw char, which was consistent with the content of acidic functional groups on the biochars. The increase in Cr3+ hydrolysis as the pH rose was one of the main reasons for the increased adsorption of Cr(III) by the biochars at higher pH values. Cr(III) can be adsorbed by the biochars through electrostatic attraction between negative surfaces and Cr3+, but the relative contribution of electrostatic adsorption was less than 5%. Therefore, Cr(III) was mainly adsorbed by the biochars through specific adsorption. The Langumir and Freundlich equations fitted the adsorption isotherms well and can therefore be used to describe the adsorption behavior of Cr(III) by the crop straw biochars. The crop straw biochars have great adsorption capacities for Cr(III) under acidic conditions and can be used as adsorbents to remove Cr(III) from acidic wastewaters. PMID- 24494482 TI - Critical velocity in phosphorus exchange processes across the sediment-water interface. AB - Sediments are ultimate sinks of nutrients in lakes that record the pollution history evolutionary processes, and anthropogenic activities of a lake. However, sediments are considered as inner sources of environmental factor changes such as the variation in hydrodynamic conditions because of the nutrients they release. How does this process happen? This study investigates a typical nutrient phosphorus (P) exchange among sediment, suspended particle matter (SPM), and water. Compared with numerical and experimental studies, this study confirms that the critical velocity that occurs at a lower flow rate state exists in the range of 7 to 15 cm/sec. Critical velocity below the critical flow rate promotes the migration of particulate phosphorus (PP) to the SPM. On the other hand, critical velocity above the critical flow rate promotes the release of PP in water. PMID- 24494483 TI - Starch/polyvinyl alcohol blended materials used as solid carbon source for tertiary denitrification of secondary effluent. AB - Starch/polyvinyl alcohol (PVA) blended materials for using as a solid carbon source (SCS) were prepared by blending PVA and gelatinized starch in an aqueous solution system, in which PVA served as framework material and starch as carbon source. The optimization of starch content and temperature effects were investigated. It was indicated that higher denitrification efficiency could be achieved with more starch in the materials. The average specific denitrification rates were 0.93, 0.66, 0.37 and 0.36 mg/(g x day) corresponding to starch content of 70%, 60%, 40% and 30% respectively at 37 degrees C. The denitrification rates increased when operating temperature was raised from 23 degrees C to 30 degrees C and then 37 degrees C. The mechanism of carbon release was analyzed incorporating the experimental results of abiotic release in deionized water. The organic carbon was mainly hydrolyzed by microbes, and the biological release efficiencies were at the range of 89.2% to 96.0%. A long-term experiment with a continuous flow reactor with SCS material containing 70% starch was conducted to gain some experience for practical application. When the influent nitrate concentration was in the range of 35.2 to 39.1 mg/L, hydraulic retention time of 4 hr, and operating temperature of 30 degrees C, a nitrogen removal efficiency up to 94.6% and denitrification rate of 0.217 kg/(m3 x day) was achieved. The starch-based materials developed in this study can be used as a solid carbon source for tertiary nitrogen removal from secondary effluent. PMID- 24494484 TI - Influence of dissolved organic matter character on mercury incorporation by planktonic organisms: an experimental study using oligotrophic water from Patagonian lakes. AB - Ligands present in dissolved organic matter (DOM) form complexes with inorganic divalent mercury (Hg2+) affecting its bioavailability in pelagic food webs. This investigation addresses the influence of a natural gradient of DOM present in Patagonian lakes on the bioaccumulation of Hg2+ (the prevailing mercury species in the water column of these lakes) by the algae Cryptomonas erosa and the zooplankters Brachionus calyciflorus and Boeckella antiqua. Hg2+ accumulation was studied through laboratory experiments using natural water of four oligotrophic Patagonian lakes amended witht'97Hg2+. The bioavailability of Hg2+ was affected by the concentration and character of DOM. The entrance of Hg2+ into pelagic food webs occurs mostly through passive and active accumulation. The incorporation of Hg2+ by Cryptomonas, up to 27% of the Hg2+ amended, was found to be rapid and dominated by passive adsorption, and was greatest when low molecular weight compounds with protein-like or small phenolic signatures prevailed in the DOM. Conversely, high molecular weight compounds with a humic or fulvic signature kept Hg2+ in the dissolved phase, resulting in the lowest Hg2+ accumulation in this algae. In Brachionus and Boeckella the direct incorporation of Hg from the aqueous phase was up to 3% of the Hg2+ amended. The dietary incorporation of Hg2+ by Boeckella exceeded the direct absorption of this metal in natural water, and was remarkably similar to the Hg2+ adsorbed in their prey. Overall, DOM concentration and character affected the adsorption of Hg2+ by algae through competitive binding, while the incorporation of Hg2+ into the zooplankton was dominated by trophic or dietary transfer. PMID- 24494485 TI - Assessment and management of the performance risk of a pilot reclaimed water disinfection process. AB - Chlorination disinfection has been widely used in reclaimed water treatment plants to ensure water quality. In order to assess the downstream quality risk of a running reclaimed water disinfection process, a set of dynamic equations was developed to simulate reactions in the disinfection process concerning variables of bacteria, chemical oxygen demand (COD), ammonia and monochloramine. The model was calibrated by the observations obtained from a pilot disinfection process which was designed to simulate the actual process in a reclaimed water treatment plant. A Monte Carlo algorithm was applied to calculate the predictive effluent quality distributions that were used in the established hierarchical assessment system for the downstream quality risk, and the key factors affecting the downstream quality risk were defined using the Regional Sensitivity Analysis method. The results showed that the seasonal upstream quality variation caused considerable downstream quality risk; the effluent ammonia was significantly influenced by its upstream concentration; the upstream COD was a key factor determining the process effluent risk of bacterial, COD and residual disinfectant indexes; and lower COD and ammonia concentrations in the influent would mean better downstream quality. PMID- 24494486 TI - Health risks associated with heavy metals in the drinking water of Swat, northern Pakistan. AB - The concentrations of heavy metals such as Cd, Cr, Cu, Mn, Ni, Pb and Zn were investigated in drinking water sources (surface and groundwater) collected from Swat valley, Khyber Pakhtunkhwa, Pakistan. The potential health risks of heavy metals to the local population and their possible source apportionment were also studied. Heavy metal concentrations were analysed using atomic absorption spectrometer and compared with permissible limits set by Pakistan Environmental Protection Agency and World Health Organization. The concentrations of Cd, Cr, Ni and Pb were higher than their respective permissible limits, while Cu, Mn and Zn concentrations were observed within their respective limits. Health risk indicators such as chronic daily intake (CDI) and health risk index (HRI) were calculated for adults and children separately. CDIs and HRIs of heavy metals were found in the order of Cr > Mn > Ni > Zn > Cd > Cu > Pb and Cd > Ni > Mn > Cr > Cu > Pb > Zn, respectively. HRIs of selected heavy metals in the drinking water were less than 1, indicating no health risk to the local people. Multivariate and univariate statistical analyses showed that geologic and anthropogenic activities were the possible sources of water contamination with heavy metals in the study area. PMID- 24494487 TI - Establishing eutrophication assessment standards for four lake regions, China. AB - The trophic status assessment of lakes in different lake regions may provide important and fundamental information for lake trophic state classification and eutrophication control. In this study, a region-specific lake eutrophication assessment standard was established through a frequency distribution method based on chlorophyll-a concentration. The assessment standards under the oligotrophic state for lakes in the Eastern plain, Yungui Plateau, Northeast Plain and Mountain Mongolia-Xinjiang regions are total phosphorus of 0.068, 0.005, 0.011, 0.005 mg/L; total nitrogen of 1.00, 0.16, 0.37, 0.60 mg/L; Secchi depth of 0.60, 8.00, 1.55, 3.00 m; and COD(Mn) of 2.24, 1.00, 5.11, 4.00 mg/L, respectively. Moreover, a region-specific comprehensive trophic level index was developed to provide an understandable assessment method for the public. The results indicated that the frequency distribution analysis based on chlorophyll-a combined with trophic level index provided a useful metric for the assessment of the lake trophic status. In addition, the difference of eutrophication assessment standards in different lake regions was analyzed, which suggested that the sensitivities of algae to nutrients and the assessment standard of trophic status possessed significant regional differences for the four lake ecoregions. Lake eutrophication assessment standards would contribute to maximizing the effectiveness of future management strategies, to control and minimize lake eutrophication problems. PMID- 24494488 TI - Electrochemical oxidation of recalcitrant organic compounds in biologically treated municipal solid waste leachate in a flow reactor. AB - Biologically-treated municipal solid waste (MSW) leachate still contains many kinds of bio-recalcitrant organic matter. A new plate and frame electrochemical reactor was designed to treat these materials under flow conditions. In the electrochemical oxidation process, NH3 and color could be easily removed by means of electro-generated chlorine/hypochlorite within 20 min. The effects of major process parameters on the removal of organic pollutants were investigated systematically. Under experimental conditions, the optimum operation parameters were current density of 65 mA/cm2, flow velocity of 2.6 cm/sec in electrode gap, and initial chloride ion concentration of 5000 mg/L. The COD in the leachate could be reduced below 100 mg/L after 1 hr of treatment. The kinetics and mechanism of COD removal were investigated by simultaneously monitoring the COD change and chlorine/hypochlorite production. The kinetics of COD removal exhibited a two-stage kinetic model, and the decrease of electro-generated chlorine/hypochlorite production was the major mechanism for the slowing down of the COD removal rate in the second stage. The narrowing of the electrode gap is beneficial for COD removal and energy consumption. PMID- 24494489 TI - Identical full-scale biogas-lift reactors (Blrs) with anaerobic granular sludge and residual activated sludge for brewery wastewater treatment and kinetic modeling. AB - Two identical full-scale biogas-lift reactors treating brewery wastewater were inoculated with different types of sludge to compare their operational conditions, sludge characteristics, and kinetic models at a mesophilic temperature. One reactor (R1) started up with anaerobic granular sludge in 12 weeks and obtained a continuously average organic loading rate (OLR) of 7.4 kg chemical oxygen demand (COD)/(m3 x day), COD removal efficiency of 80%, and effluent COD of 450 mg/L. The other reactor (R2) started up with residual activated sludge in 30 weeks and granulation accomplished when the reactor reached an average OLR of 8.3 kg COD/(m3 x day), COD removal efficiency of 90%, and effluent COD of 240 mg/L. Differences in sludge characteristics, biogas compositions, and biogas-lift processes may be accounted for the superior efficiency of the treatment performance of R2 over R1. Grau second-order and modified StoverKincannon models based on influent and effluent concentrations as well as hydraulic retention time were successfully used to develop kinetic parameters of the experimental data with high correlation coefficients (R2 > 0.95), which further showed that R2 had higher treatment performance than R1. These results demonstrated that residual activated sludge could be used effectively instead of anaerobic granular sludge despite the need for a longer time. PMID- 24494490 TI - Water quality evaluation of Haihe River with fuzzy similarity measure methods. AB - Fuzzy similarity measures, which are used to judge the closeness of two fuzzy sets, are presented to evaluate the water quality of the Haihe River. Based on the membership functions and coefficient of variation as the weights, four fuzzy similarity measures (including Lattice similarity measure, Hamming similarity measure, Euclidean similarity measure and the max-min similarity measure) are used to classify the 299 samples into the proper water quality standard ranks. The results are compared with the traditional distance discriminant methods. The calculation of two traditional distance discriminant methods (both Euclidean distance and absolute value distance) is also based on the use of coefficients of variation as the weights. Without the Lattice similarity measure, for this method loses some information, the correct assignment of samples classified into the same water quality ranks is 75.92% with the other three similarity measures and two distance discriminant methods. This result shows the reliability of the five methods. Only considering the three similarity measures, there were only 1.01% of the samples that did not classify to the same ranks, while the corresponding ratio of the two distance discriminant methods was 5.69%. The results of leave one-out cross validation show that more than 88% of the samples are classified to the proper ranks, which demonstrates that the similarity measures are suitable to evaluate the water quality of the Haihe River. PMID- 24494491 TI - Waste oyster shell as a kind of active filler to treat the combined wastewater at an estuary. AB - Estuaries have been described as one of the most difficult environments on Earth. It is difficult to know how to treat the combined wastewater in tidal rivers at the estuary, where the situation is very different from ordinary fresh water rivers. Waste oyster shell was used as the active filler in this study in a bio contact oxidation tank to treat the combined wastewater at the Fengtang Tidal River. With a middle-experimental scale of 360 m3/day, the average removal efficiency of COD, BOD, NH3-N, TP and TSS was 80.05%, 85.02%, 86.59%, 50.58% and 85.32%, respectively, in this bio-contact oxidation process. The living microbes in the biofilms on the waste oyster shell in this bio-contact oxidation tank, which were mainly composed of zoogloea, protozoa and micro-metazoa species, revealed that waste oyster shell as the filler was suitable material for combined wastewater degradation. This treatment method using waste oyster shell as active filler was then applied in a mangrove demonstration area for water quality improvement near the experiment area, with a treatment volume of 5 x 10(3) m3/day. Another project was also successfully applied in a constructed wetland, with a wastewater treatment volume of 1 x 10(3) m3/day. This technology is therefore feasible and can easily be applied on a larger scale. PMID- 24494492 TI - Waste activated sludge treatment based on temperature staged and biologically phased anaerobic digestion system. AB - The concept of temperature staged and biological phased (TSBP) was proposed to enhance the performance of waste-activated sludge anaerobic digestion. Semi continuous experiments were used to investigate the effect of temperature (35 to 70 degrees C) as well as the hydraulic retention time (HRT) (2, 4 and 6 days) on the acidogenic phase. The results showed that the solubilization degree of waste activated sludge increased from 14.7% to 30.1% with temperature increasing from 35 to 70 degrees C, while the acidification degree was highest at 45 degrees C (17.6%), and this was quite different from the temperature impact on hydrolysis. Compared with HRT of 2 and 6 days, 4 days was chosen as the appropriate HRT because of its relatively high solubilization degree (24.6%) and acidification degree (20.1%) at 45 degrees C. The TSBP system combined the acidogenic reactor (45 degrees C, 4 days) with the methanogenic reactor (35 degrees C, 16 days) and the results showed 84.8% and 11.4% higher methane yield and volatile solid reduction, respectively, compared with that of the single-stage anaerobic digestion system with HRT of 20 days at 35 degrees C. Moreover, different microbial morphologies were observed in the acidogenic- and methanogenic-phase reactors, which resulted from the temperature control and HRT adjustment. All the above results indicated that 45 degrees C was the optimum temperature to inhibit the activity of methanogenic bacteria in the acidogenic phase, and temperature staging and phase separation was thus accomplished. The advantages of the TSBP process were also confirmed by a full-scale waste-activated sludge anaerobic digestion project which was an energy self-sufficient system. PMID- 24494493 TI - Diel and seasonal variation of methane and carbon dioxide fluxes at site Guojiaba, the Three Gorges Reservoir. AB - In order to investigate the CH4 and CO2 fluxes across the water-gas interface and identify their controlling factors, four diel field campaigns and one monthly sampling campaign during June 2010-May 2011 were carried out at a site near the Three Gorges Dam, China. The averaged CH4 and CO2 fluxes across the air-water interface from the site were much less than those reported from reservoirs in tropic and temperate regions, and from the natural river channels of the Yangtze River. CH4 Fluxes at the site were very low compared to most other reservoirs or natural lakes. One of the most important reasons may be due to the oxidation of CH4 in the water column owing to the great water depth and high DO in water in the Three Gorges Reservoir. The averaged monthly CH4 and CO2 fluxes at the site during the observation year were 0.05 mg/(m2 x hr) and 104.43 mg/(m2 x hr) respectively with the maximum occurred in July 2010. The monthly CO2 fluxes during the observation year were positively correlated to the surface water temperature, and negatively correlated to the air pressure and the surface water pH. The CO2 flux showed a positive correlation with DOC to some extent, although not significantly, which indicated that allochthonous organic C was a major source of CO2 and biogeochemical processes in this reservoir were C-limited. The significantly positive correlation between the reservoir outflow and the seasonal gas flux indicate the disturbance condition of the water body dominated the seasonal gas emission. PMID- 24494495 TI - Capture of carbon dioxide from flue gas on TEPA-grafted metal-organic framework Mg2(dobdc). AB - Carbon dioxide (CO2) adsorption on a standard metal-organic framework Mg2(dobdc) (Mg/DOBDC or Mg-MOF-74) and a tetraethylenepentamine (TEPA) modified Mg2(dobdc) (TEPA-Mg/DOBDC) were investigated and compared. The structural information, surface chemistry and thermal behavior of the adsorbent samples were characterized by X-ray powder diffraction (XRD), infrared spectroscopy (IR), thermogravimetric analysis (TGA) and nitrogen adsorption-desorption isotherm analysis. CO2 adsorption capacity was measured by dynamic adsorption experiments with N2-CO2 mixed gases at 60 degrees C. Results showed that the CO2 adsorption capacity of Mg/DOBDC was significantly improved after amine modification, with an increase from 2.67 to 6.06 mmol CO2/g adsorbent. Moreover, CO2 adsorption on the TEPA-Mg/DOBDC adsorbent was promoted by water vapor, and the adsorption capacity was enhanced to 8.31 mmol CO2/g absorbent. The adsorption capacity of the TEPA Mg/DOBDC adsorbent dropped only 3% after 5 consecutive adsorption/desorption cycles. Therefore, this kind of adsorbent can be considered as a promising material for the capture of CO2 from flue gas. PMID- 24494496 TI - Atmospheric emission characterization of a novel sludge drying and co-combustion system. AB - A novel system combining sludge drying and co-combustion with coal was applied in disposing sludge and its atmospheric emission characteristics were tested. The system was composed of a hollow blade paddle dryer, a thermal drying exhaust gas control system, a 75 tons/hr circulating fluidized bed and a flue gas cleaning system. The emissions of NH3, SO2, CH4 and some other pollutants released from thermal drying, and pollutants such as NOx, SO2 etc. discharged by the incinerator, were all tested. Polychlorinated dibenzo-p-dioxins and polychlorinated dibenzofurans (PCDD/Fs) in the flue gas from the incinerator were investigated as well. The results indicated that the concentrations of NOx and SO2 in the flue gas from the incinerator were 145 and 16 mg/m3, respectively. and the I-TEQ concentration of 2,3,7,8-substitued PCDD/Fs was 0.023 ng I-TEQ/Nm3. All these values were greatly lower than the emission standards of China. In addition, there was no obvious odor in the air around the sludge dryer. The results demonstrated that this drying and co-combustion system is efficient in controlling pollutants and is a feasible way for large-scale treatment of industrial sludge and sewage sludge. PMID- 24494494 TI - Emissions of parent, nitrated, and oxygenated polycyclic aromatic hydrocarbons from indoor corn straw burning in normal and controlled combustion conditions. AB - Emission factors (EFs) of parent polycyclic aromatic hydrocarbons (pPAHs), nitrated PAHs (nPAHs), and oxygenated PAHs (oPAHs) were measured for indoor corn straw burned in a brick cooking stove under different burning conditions. The EFs of total 28 pPAHs, 6 nPAHs and 4 oPAHs were (7.9 +/- 3.4), (6.5 +/- 1.6) x 10( 3), and (6.1 +/- 1.4) x 10(-1) mg/kg, respectively. Fuel charge size had insignificant influence on the pollutant emissions. Measured EFs increased significantly in a fast burning due to the oxygen deficient atmosphere formed in the stove chamber. In both restricted and enhanced air supply conditions, the EFs of pPAHs, nPAHs and oPAHs were significantly higher than those measured in normal burning conditions. Though EFs varied among different burning conditions, the composition profiles and calculated isomer ratios were similar, without significant differences. The results from the stepwise regression model showed that fuel burning rate, air supply amount, and modified combustion efficiency were the three most significant influencing factors, explaining 72%-85% of the total variations. PMID- 24494497 TI - Electrochemical and spectroscopic characteristics of dissolved organic matter in a forest soil profile. AB - Dissolved organic matter (DOM) represents one of the most mobile and reactive organic compounds in ecosystem and plays an important role in the fate and transport of soil organic pollutants, nutrient cycling and more importantly global climate change. Electrochemical methods were first employed to evaluate DOM redox properties, and spectroscopic approaches were utilized to obtain information concerning its composition and structure. DOM was extracted from a forest soil profile with five horizons. Differential pulse voltammetry indicated that there were more redox-active moieties in the DOM from upper horizons than in that from lower horizons. Cyclic voltammetry further showed that these moieties were reversible in electron transfer. Chronoamperometry was employed to quantify the electron transfer capacity of DOM, including electron acceptor capacity and electron donor capacity, both of which decreased sharply with increasing depth. FT-IR, UV-Vis and fluorescence spectra results suggested that DOM from the upper horizons was enriched with aromatic and humic structures while that from the lower horizons was rich in aliphatic carbon, which supported the findings obtained by electrochemical approaches. Electrochemical approaches combined with spectroscopic methods were applied to evaluate the characteristics of DOM extracted along a forest soil profile. The electrochemical properties of DOM, which can be rapidly and simply obtained, provide insight into the migration and transformation of DOM along a soil profile and will aid in better understanding of the biogeochemical role of DOM in natural environments. PMID- 24494498 TI - Soil microbial community structure and function responses to successive planting of Eucalyptus. AB - Many studies have shown soil degradation after the conversion of native forests to exotic Eucalyptus plantations. However, few studies have investigated the long term impacts of short-rotation forestry practices on soil microorganisms. The impacts of Eucalyptus successive rotations on soil microbial communities were evaluated by comparing phospholipid fatty acid (PLFA) abundances, compositions, and enzyme activities of native Pinus massoniana plantations and adjacent 1st, 2nd, 3rd, 4th generation Eucalyptus plantations. The conversion from P. massoniana to Eucalyptus plantations significantly decreased soil microbial community size and enzyme activities, and increased microbial physiological stress. However, the PLFA abundances formed "u" shaped quadratic functions with Eucalyptus plantation age. Alternatively, physiological stress biomarkers, the ratios of monounsaturated to saturated fatty acid and Gram+ to Gram- bacteria, formed "n"' shaped quadratic functions, and the ratio of cy17:0 to 16:1omega7c decreased with plantation age. The activities of phenol oxidase, peroxidase, and acid phosphatase increased with Eucalyptus plantation age, while the cellobiohydrolase activity formed "u" shaped quadratic functions. Soil N:P, alkaline hydrolytic nitrogen, soil organic carbon, and understory cover largely explained the variation in PLFA profiles while soil N:P, alkaline hydrolytic nitrogen, and understory cover explained most of the variability in enzyme activity. In conclusion, soil microbial structure and function under Eucalyptus plantations were strongly impacted by plantation age. Most of the changes could be explained by altered soil resource availability and understory cover associated with successive planting of Eucalyptus. Our results highlight the importance of plantation age for assessing the impacts of plantation conversion as well as the importance of reducing disturbance for plantation management. PMID- 24494499 TI - Anaerobic co-digestion of municipal biomass wastes and waste activated sludge: dynamic model and material balances. AB - The organic matter degradation process during anaerobic co-digestion of municipal biomass waste (MBW) and waste-activated sludge (WAS) under different organic loading rates (OLRs) was investigated in bench-scale and pilot-scale semi continuous stirred tank reactors. To better understand the degradation process of MBW and WAS co-digestion and provide theoretical guidance for engineering application, anaerobic digestion model No.1 was revised for the co-digestion of MBW and WAS. The results showed that the degradation of organic matter could be characterized into three different fractions, including readily hydrolyzable organics, easily degradable particulate organics, and recalcitrant particle organics. Hydrolysis was the rate-limiting step under lower OLRs, and methanogenesisis was the rate-limiting step for an OLR of 8.0 kg volatile solid (VS)/(m3 x day). The hydrolytic parameters of carbohydrate, protein, and lipids were 0.104, 0.083, and 0.084 kg chemical oxygen demand (COD)/(kg COD x hr), respectively, and the reaction rate parameters of lipid fermentation were 1 and 1.25 kg COD/(kg COD x hr) for OLRs of 4.0 and 6.0 kg VS/(m3 x day). A revised model was used to simulate methane yield, and the results fit well with the experimental data. Material balance data were acquired based on the revised model, which showed that 58.50% of total COD was converted to methane. PMID- 24494500 TI - Coking wastewater increases micronucleus frequency in mouse in vivo via oxidative stress. AB - Coking wastewater has caused serious health risk in coal-producing areas of China, however its toxic effects have not been well understood. The genotoxicity induced by coking wastewater on mice in vivo and its possible oxidative mechanisms were investigated via observing the induction of micronuclei in polychromatic erythrocytes of mouse bone marrow, and subsequently determining the antioxidative enzyme activities (superoxide dismutase Cu, Zn-SOD, Se-dependent glutathione peroxidase, and catalase), thiobarbituric acid reactive substance contents and protein carbonyl levels in brains and livers of mice. Results showed that the tested coking wastewater caused a significant increase of micronucleus frequencies in a concentration-dependent manner. Also, the sample increased lipid peroxidation and protein oxidation levels, which was accompanied by changes in antioxidative status. Interestingly, pre-treatment with an antioxidant (vitamin C) led to a statistical reduction in the micronucleus frequency caused by coking wastewater. This implies that coking wastewater induces evident genetic damage in mammalian cells, and exposure to polluted areas might pose a potential genotoxic risk to human beings; in the process, oxidative stress played a crucial role. PMID- 24494501 TI - Biological nutrient removal by internal circulation upflow sludge blanket reactor after landfill leachate pretreatment. AB - The removal of biological nutrient from mature landfill leachate with a high nitrogen load by an internal circulation upflow sludge blanket (ICUSB) reactor was studied. The reactor is a set of anaerobic-anoxic-aerobic (A2/O) bioreactors, developed on the basis of an expended granular sludge blanket (EGSB), granular sequencing batch reactor (GSBR) and intermittent cycle extended aeration system (ICEAS). Leachate was subjected to stripping by agitation process and poly ferric sulfate coagulation as a pretreatment process, in order to reduce both ammonia toxicity to microorganisms and the organic contents. The reactor was operated under three different operating systems, consisting of recycling sludge with air (A2/O), recycling sludge without air (low oxygen) and a combination of both (A2/O and low oxygen). The lowest effluent nutrient levels were realised by the combined system of A2/O and low oxygen, which resulted in effluent of chemical oxygen demand (COD), NH3-N and biological oxygen demand (BOD5) concentrations of 98.20, 13.50 and 22.50 mg/L. The optimal operating conditions for the efficient removal of biological nutrient using the ICUSB reactor were examined to evaluate the influence of the parameters on its performance. The results showed that average removal efficiencies of COD and NH3-N of 96.49% and 99.39%, respectively were achieved under the condition of a hydraulic retention time of 12 hr, including 4 hr of pumping air into the reactor, with dissolved oxygen at an rate of 4 mg/L and an upflow velocity 2 m/hr. These combined processes were successfully employed and effectively decreased pollutant loading. PMID- 24494503 TI - Synthesis and enhanced visible-light responsive of C,N,S-tridoped TiO2 hollow spheres. AB - C,N,S-tridoped TiO2 hollow spheres (labeled as C,N,S-THs) were synthesized using carbon spheres as template and C,N,S-tridoped TiO2 nanoparticles as building blocks. The structure and physicochemical properties of the catalysts were characterized by Xray diffraction (XRD), scanning electron microscopy (SEM), UV Vis diffuse reflectance spectrum (DRS), N2 adsorption-desorption isotherms, X-ray photoelectron spectroscopy (XPS) and Photoluminescence emission spectroscopy (PL). The results showed that the hollow spheres had average diameter of about 200 nm and the shell thickness was about 20 nm. The tridoped TiO2 hollow spheres exhibited strong absorption in the visible-light region. C,N,S-tridoped could narrow the band gap of the THs by mixing the orbit O 2p with C 2p, N 2p and S 3p orbits and shift its optical response from ultraviolet (UV) to the visible-light region. PL analysis indicated that the electron-hole recombination rate of TiO2 hollow spheres had been effectively inhibited when doped with C, N and S elements. The photocatalytic activities of the samples were evaluated for the degradation of X-3B (Reactive Brilliant Red dye, C.I. Reactive Red 2) aqueous solution under visible-light (lambda > 420 nm) irradiation. It was found that the C,N,S-tridoped TiO2 hollow spheres indicated higher photocatalytic activity than commercial P25 and the undoped counterpart photocatalyst. PMID- 24494502 TI - Porous FeOx/BiVO4-deltaS0.08: highly efficient photocatalysts for the degradation of methylene blue under visible-light illumination. AB - Porous S-doped bismuth vanadate with an olive-like morphology and its supported iron oxide (y wt.% FeOx/BiVO4-deltaS0.08, y = 0.06, 0.76, and 1.40) photocatalysts were fabricated using the dodecylamine-assisted alcohol hydrothermal and incipient wetness impregnation methods, respectively. It is shown that the y wt.% FeOx/BiVO4-deltaS0.08 photocatalysts contained a monoclinic scheetlite BiVO4 phase with a porous olive-like morphology, a surface area of 8.8 9.2 m2/g, and a bandgap energy of 2.38-2.42 eV. There was co-presence of surface Bi5+, Bi3+, V5+, V3+, Fe3+, and Fe2+ species in y wt.% FeOx/BiVO4-deltaS0.08. The 1.40 wt.% FeOx/BiVO4-deltaS0.08 sample performed the best for Methylene Blue degradation under visible-light illumination. The photocatalytic mechanism was also discussed. We believe that the sulfur and FeOx co-doping, higher oxygen adspecies concentration, and lower bandgap energy were responsible for the excellent visible-light-driven catalytic activity of 1.40 wt.% FeOx/BiVO4 deltaS0.08. PMID- 24494504 TI - Pure and Mg-doped self-assembled ZnO nano-particles for the enhanced photocatalytic degradation of 4-chlorophenol. AB - A novel self-assembled pure and Mg doped ZnO nano-particles (NPs) were successfully synthesized by a simple low temperature co-precipitation method. The prepared photocatalysts were characterized by X-ray diffraction, high resolution scanning electron microscopy, high resolution transmission electron microscopy, diffuse reflectance spectroscopy and photoluminescence (PL) spectroscopy. The results indicated that the prepared photocatalysts showed high crystallinity with a uniform size distribution of the NPs. The degradation of cholorphenols is highly mandatory in today's scenario as they are affecting the environment adversely. Thus, the photocatalytic degradation of 4-chlorophenol (4-CP), a potent endocrine disrupting chemical in aqueous medium was investigated by both pure and Mg-doped ZnO NPs under UV-light irradiation in the present study. The influence of the Mg content on the structure, morphology, PL character and photocatalytic activity of ZnO NPs were investigated systematically. Furthermore,the effect of different parameters such as 4-CP concentration, photocatalyst amount, pH and UV-light wavelength on the resulting photocatalytic activity was investigated. PMID- 24494505 TI - Achieving control of cervical cancer in Papua New Guinea: what are the research and program priorities? PMID- 24494506 TI - Male circumcision for HIV prevention in Papua New Guinea: a summary of research evidence and recommendations for public health following a national policy forum. AB - In 2005, a clinical trial in South Africa found that circumcision of young men could reduce their risk of acquiring HIV (human immunodeficiency virus) infection by over 60%. In the following year, two more trials in Africa confirmed this finding, leading the World Health Organization to recommend male circumcision as a public health strategy for HIV prevention in high-incidence countries. In order to inform public health policy in Papua New Guinea (PNG), two major research projects were initiated with the goals of investigating the status of penile cutting practices and assessing understandings, acceptability, feasibility and cost-effectiveness of male circumcision for HIV prevention. In addition, behavioural surveillance surveys systematically asked questions on penile cutting practices and an ethnographic literature review informed historical perspectives of penile cutting in PNG. Key findings from these research activities were presented at a National Policy Forum on Male Circumcision for HIV Prevention held in Port Moresby in November 2011. The Forum made three key recommendations: (1) the formation of a joint National Department of HealthlNational AIDS Council Secretariat Policy Committee on male circumcision; (2) the establishment of an integrated harm reduction program; and (3) that future policy on wide-scale roll out of male circumcision for HIV prevention in PNG be informed by a combination of data from (a) male circumcision intervention pilot programs and (b) research on the potential protective effect of other forms of penile cutting. PMID- 24494508 TI - 'Stret tokers'--taking sexual health promotion to the village level in East New Britain Province, Papua New Guinea. AB - The East New Britain Sexual Health Improvement Project (ENBSHIP) partners with the East New Britain Provincial Health Office. The project supports initiatives at the provincial, district and community levels to strengthen health services and expand the community response to sexually transmitted infections (STIs). Community mobilization is based on a lengthy engagement process with local leadership structures at district, local level government and village levels. At the village level, ENBSHIP works through community activators called 'stret tokers' [straight talkers]. These individuals are selected by their communities and trained to raise awareness of sexually transmitted infections and build a bridge between communities and health services. Training includes simple, gender sensitive community development principles and basic information about STI transmission and prevention. 'Stret tokers' are supported to understand the complex issues that underpin STI transmission and treatment-seeking behaviour, and to mobilize their communities to respond to these issues. ENBSHIP has highlighted the value of taking sexual health promotion to the village level while also strengthening health services. The initiative has been met with great enthusiasm and has received excellent support from host communities. At the same time there have been many challenges and lessons learned of potential value to other community-based initiatives in Papua New Guinea. PMID- 24494507 TI - Health workers, health facilities and penile cutting in papua new guinea: implications for male circumcision as an HIV prevention strategy. AB - There has been increasing interest in Papua New Guinea (PNG) in male circumcision (MC) for HIV (human immunodeficiency virus) prevention following compelling evidence from ecological studies and clinical trials in Africa, and the World Health Organization's recommendation in 2007 that MC be considered part of comprehensive HIV prevention programs in high-prevalence settings. Though no national policy has been established in PNG, East Sepik Province (ESP) commenced a formal program of MC in 2006, and there is evidence that PNG health workers are involved in other penile foreskin cutting activities in many areas. As part of a wider Male Circumcision Acceptability and Impact Study in PNG, we conducted an audit at a sample of PNG health facilities to assess their suitability for implementing a national MC program, and to identify issues that may arise in any future roll-out. The clinical audits demonstrated the difficulties with procurement and availability of equipment for general services around PNG, shortage of staff and capacity, and limitations of available clinical space. Results show that the ESP program has been successful; however, the success relies heavily on commitment from key workers to volunteer their time and services. A review of penile cutting activities by health care workers outside of the ESP program showed that the PNG health system is already involved in contemporary and traditional penile cutting practices via formal and informal arrangements: for example, by responding to complications from penile cuts performed by non-health workers, assisting community members to perform penile cutting through provision of equipment and advice, or providing regular penile foreskin cutting services for contemporary and traditional practices. PMID- 24494509 TI - Epidemiological surveillance of human papillomavirus prevalence and type distribution in Papua New Guinea: the selection of an appropriate laboratory tool. AB - Cervical cancer is one of the most common cancers among women worldwide and is a leading cause of cancer death in Papua New Guinea (PNG). It is well established that persistent infection with high-risk types of human papillomavirus (HPV) is necessary for the development of cervical cancer. The recent licensing of two vaccines for the prevention of the two most common high-risk HPV types has prompted renewed interest in the prevention of cervical cancer and HPV in PNG. This review aims to assess and compare available technologies suitable for the epidemiological surveillance of HPV in PNG. Data from the surveillance exercise will provide critical information to the National Department of Health to make an informed decision regarding the introduction of a preventive HPV vaccine. PMID- 24494510 TI - The contribution of church health services to maternal health care provision in Papua New Guinea. AB - Access to maternal health services is one key to the reduction of maternal mortality in Papua New Guinea. Church health services (CHS) are known to administer around 45% of rural health facilities. We undertook a descriptive analysis based on health facility service provision data for 2009 from the National Health Information System (NHIS), supported by document review and interviews. We recoded NHIS data on facilities by administration by CHS or government health service, judged their capacity for emergency obstetric care (EmOC) and analysed service provision for 2009. For rural services (i.e., outside of provincial capitals), CHS were recorded as providing 58% of health facility childbirth care and 38% of first antenatal visits. Obstetric referral patterns and facility capacity suggested many facilities were likely to have only basic EmOC and limited referral options. Nationally, CHS provided 21% of temporary methods of contraception (measured in couple-year protection) but 85% of referrals for permanent contraception. There was marked variation across provinces with clear implications for where health system strengthening could be beneficial to maternal survival. Our findings also disclosed gaps in the NHIS around monitoring of complicated childbirth and inclusion of community-based care. PMID- 24494511 TI - Formal and informal maternal health care: comparing the service provision of health facilities and village health volunteers in East Sepik Province. AB - Maternal health across Papua New Guinea (PNG) is of extreme public health concern. In response, the National Department of Health explicitly prioritized improving maternal, neonatal and child health services, envisaging increased collaboration between the formal health system and community-based initiatives as one method for achieving this. This study examined the patterns of formal and non formal service utilization during pregnancy and childbirth in one province. We analysed the activity database of the East Sepik Women and Children's Health Project's Village Health Volunteer (VHV) program, an informal health service in East Sepik Province of PNG, estimating VHV activity and coverage for two maternal health care services (first antenatal care visit and VHV-attended deliveries) and comparing these to the volume and estimated coverage of these services delivered by the formal health system in East Sepik over the years 2007 to 2010. We found a significant increase in women's utilization of VHVs for first antenatal care and for an attended delivery. Reported coverage of these services delivered by the formal health service declined or at best remained static over the same time period. Our data cannot illuminate the causes of an apparent and highly concerning decline in health facility usage for assisted delivery, nor the reasons for increased usage of VHVs. The factors contributing to these trends in service provision require urgent study, to improve our understanding of the drivers of utilization of critical maternal health services. Our study demonstrates that VHVs deliver a substantial proportion of maternal health services in East Sepik. This finding alone highlights the importance of considering this cadre when planning health service improvements and suggests that a national VHV policy that builds on the work of the National Health Plan in defining the most appropriate role for VHVs in maternal health care is long overdue. PMID- 24494512 TI - Sociodemographic factors associated with maternal health care utilization in Wosera, East Sepik Province, Papua New Guinea. AB - This retrospective study sought to describe the utilization of maternal health services in a rural community in Wosera, East Sepik Province, Papua New Guinea. Interviews were undertaken with a convenience sample of 391 women of reproductive age. We examined the relationship between socioeconomic and demographic characteristics and the use of antenatal clinic services and delivery at a health centre. Despite uptake of antenatal care services by 79% of women, two-thirds of women gave birth at home. Women's education was an independent predictor for maternal health care utilization, for both antenatal care and delivery at a health facility. At least one visit to an antenatal clinic was the strongest predictor of delivering at a health care facility. Women expressed barriers to assisted childbirth such as distance to health facilities, especially when labour came fast, and feelings of shame in presenting to a facility to give birth. This study provides important information relating to the uptake of maternal health care services. Despite the uptake of available antenatal care services, intrapartum services are not well accessed. PMID- 24494513 TI - Poor weight gain in late third trimester: a predictor of poor perinatal outcome for term deliveries? AB - In many parts of the world weighing women in antenatal clinics is no longer thought to be important. At Port Moresby General Hospital we noticed that failure to gain weight in the third trimester (or weight loss) was associated with poor perinatal outcomes. To investigate this issue we designed a prospective case control study to determine whether poor weight gain in the third trimester is a useful clinical indicator of poor placental function by being associated with intrauterine growth restriction (IUGR) or inadequate placental function in labour by being significantly associated with suspected intrapartum fetal compromise, birth asphyxia, meconium aspiration syndrome and neonatal intensive care unit admission. We found that a failure to gain weight for more than three weeks preceding the onset of labour was significantly associated with intrapartum fetal compromise (OR 2.24), IUGR (OR 2.88), meconium aspiration syndrome (OR 4.19), the presence of thick meconium or the passage of meconium during labour (OR 2.26) and the need for admission to the neonatal intensive care unit for more than 24 hours (OR 2.22). Weighing women in the antenatal clinic setting is a useful way of screening for deteriorating or inadequate placental function, and is particularly relevant in settings where more sophisticated modalities of screening and diagnosis of placental function are not available. PMID- 24494514 TI - Operative vaginal delivery at Port Moresby General Hospital from 1977 to 2010. AB - This paper presents 35 years of history of operative vaginal delivery at the Port Moresby General Hospital (PMGH). From the early 1970s when Dr. G.C. Bird was appointed as Head of Obstetrics at PMGH, vacuum extraction has been the preferred method of assisted vaginal delivery. In the early 1970s, Dr Bird began to experiment with more effective configurations of the then standard metal Malmstrom vacuum extraction cup: the Bird anterior cup was introduced in 1973 and the posterior cup in 1974. These modifications to the vacuum extractor cup allowed for more effective placement of the cup on the flexion point on the fetal head thereby facilitating more successful vacuum-assisted delivery. Between 1977 and 2010 there were a total of 11,458 vacuum extractions (average rate 3.9%) performed, with an average failure rate of 2.5%. During the same period there were 565 vaginal forceps deliveries (rate 0.2%), 11,550 caesarean sections (rate 3.9%) and 182 symphysiotomies (all for failed vacuum extraction procedures) performed. Over the period trends that are noted include a slowly rising caesarean section rate from 2% in the 1970s to nearly 5% in the current decade. Over the same period the assisted vaginal delivery rate has dropped from 10-15% in the 1970s to 3-4% since 2000. The combined fresh stillbirth and early neonatal mortality rate for infants > or = 1.5 kg and > or = 2.5 kg for the period was 11.3/1000 and 9.5/1000 respectively, and compares to a combined fresh stillbirth and early neonatal mortality rate of 8.7/1000 for assisted vaginal delivery. PMID- 24494515 TI - Outcome of infants born to unbooked mothers: a short report from Goroka General Hospital, Eastern Highlands Province, Papua New Guinea. AB - Despite the increasing availability of antenatal care in Papua New Guinea (PNG), women continue to present for confinement without having previously attended antenatal clinic. In this brief report we present the findings of a five-year retrospective study conducted at Goroka General Hospital, Eastern Highlands Province, PNG. Mothers who had not previously accessed antenatal care ('unbooked mothers') were more likely to experience stillbirth or early neonatal death of their infant than booked mothers. PMID- 24494516 TI - Effect of drought stress on superoxide dismutase activity in two species of Haloxylon aphyllum and Haloxylon persicum. AB - Superoxide dismutase activity changes were studied at different periodic tensions using of spectrophotometric measurement of decline in NitroBlue Tetrazolium reduction to Blue Formazan at 560 nm in Haloxylon aphyllum and Haloxylon persicum. The aim of this study was to investigate the changes of superoxide dismutase in applied drought stress in two species of Haloxylon. The results showed that the effect of drought stress on increase in superoxide dismutase activity was significant (p < 0.01) in two haloxylon species. Drought increased enzyme activity at severe tensions. When two haloxylon species were placed under 7 and 14 days no-watering treatments (mild tensions), the enzyme activity was more than its activity in control treatment and less than one in 21 and 28 days no-watering treatments (severe tensions). The enzyme activity in branchlets of Haloxylon aphyllum under 21 and 28 days no-watering treatments was 20.2 and 29.5% more than its activity under control treatment respectively. This activity in Haloxylon persicum was 21.6 and 31.4% more than its activity under control treatment, respectively. With the advent of drought, superoxide dismutase activity increased in two species of haloxylon. The increasing of superoxide dismutase activity in time of dryness advent in Haloxylon aphyllum was more than Haloxylon persicum, which can be raised as an acceptable factor and vindicator in being more resistant of Haloxylon aphyllum to environmental drought. PMID- 24494517 TI - Scale characteristics of two fish species, Acanthopagrus bifasciatus (Forsskal, 1775) and Rhabdosargus sarba (Forsskal, 1775) from the Red Sea at Jeddah, Saudi Arabia. AB - The present work aimed to screening and documenting the diversity of scale characteristics of two species belonging to two different genera of the family Sparidae: Acanthopagrus bifasciatus and Rhabdosargus sarba from the Red Sea. The valid useful scale characters for systematic purposes were determined in the term of morphometry and Scanning Electron Microscopic techniques. A wide spectrum of size-free intraspecific variations between different body regions was recorded in each species in terms of morphometric indices. The scale characters included the overall form of the scales and their morphometrics, radii counts, shape of interradial tongues, the first circuli, form of interradial circuli and their denticles, the outer lateral and inner lateral circuli and the form of their denticles, granulation of the caudal field and the shape of ctenii. Moreover, the form of the lateral line canal, the relative position of their anterior and posterior openings and the cantilevered anterior extension of the canal were valid in differentiation between species. PMID- 24494518 TI - Influence of Npk inorganic fertilizer treatment on the proximate composition of the leaves of Ocimum gratissimum (L.) and Gongronema latifolium (benth). AB - The influence of NPK inorganic fertilizer treatment on the proximate composition of the leaves of Ocimum gratissimum (L.) and Gongronema latifolium (Benth) was investigated. Cultivated O. gratissimum and G. latifolium were treated with NPK (15:15:15) fertilizer at 100, 200, 300, 400 and 500 kg h(-1) treatment levels in planting buckets derived using the furrow slice method two months after seedling emergence. No fertilizer treatment served as control. The leaves of the plants were harvested for analysis one month after treatment. The leaf was used for the analysis because it the most eaten part. Fertilizer treatment significantly (p < 0.05) increased the dry matter, moisture content, ash, crude protein, crude fibre, crude fat contents of the leaves of both plants. On the other hand, fertilizer treatment significantly, (p < 0.05) decreased the carbohydrate and the calorific value of the leaves of the plants. The increase in the concentrations of these substances as a result of fertilizer of fertilizer treatment might be due to the role of fertilizer in chlorophyll content of plant's leaves, which in turn enhanced the process of photosynthesis leading to increased synthesis of these substances. The decrease in the carbohydrate content might be due to its conversion to other materials in the plants. The results obtained were discussed in line with current literatures. PMID- 24494519 TI - Comparing the efficiency of Cyperus alternifolius and Phragmites australis in municipal wastewater treatment by subsurface constructed wetland. AB - Nowadays, application of natural wastewater treatment systems such as wetland not only reduces economic costs and energy consumption, but also decreases environmental pollution. This study aimed to compare efficiency of Cyperus alternifolius and Phragmites australis in Municipal wastewater treatment by Subsurface Constructed Wetland Method. This is an applied-interventionnal study in which three reactors (control pilot, Cyperus alternifolius (umbrella palm) plant pilot and Phragmites australis (reed) plant pilot were designed by subsurface constructed wetland method. Then 90 samples were taken from input and output of reactors with four-day retention time. These samples were tested and finally the data were analyzed by Paired Sample Test statistical analysis. The results showed that removal efficiency of the parameters such as COD, BOD5, TSS, NO3-N, NH3-N, PO4-P, total coliform and fecal coliform was 74, 73, 84, 40, 36, 70, 33 and 38% in Cyperus alternifolius plant wetland, 44, 34, 77, 15, 0.3, 1, 17 and 26% in control wetland and 59, 54, 73, 6, 3, 10, 93 and 50 in Phragmites australis plant wetland, respectively. This reduction rate in all parameters- except fecal coliform- was statistically significant (p = 0.05). The results of this study showed that Cyperus alternifolius plant had higher efficiency in the removal of chemical parameters, whereas Phragmites australis plant had appropriate efficiency in the removal of microbiological parameters. Therefore, it can be concluded that application of these two plants can be effective in wastewater treatment. PMID- 24494520 TI - Induction of resistance in tomato plants against tomato mosaic tobamovirus using beneficial microbial isolates. AB - The possibility of making use of the phenome non of Systemic Acquired Resistance (SAR) to control viruses achieved by the soaking treatment of tomato seeds cv. Castl Rock with three growth forms to Bacillus circulans, Pseudomonas fluorescens 2 and Trichoderma harzianum against Tomato mosaic tobamovirus (ToMV) infection. All the application forms of beneficial biotic inducers were reduced the mean number of ToMV local lesions on Datura metel. P. fluorescens 2 was found to be the best treatment in three forms on reduction of local lesion number 42.2, 32.7 and 38.1 of microbial liquid culture, microbial cells or spores and microbial culture filtrate forms, respectively, while the highest mean numbers of local lesions were 51.5, 61.7 and 73.5 of microbial liquid culture, microbial cells or spores and microbial culture filtrate, respectively for T. harzianum. The microbial culture filtrate form was more effective than other microbial forms to reduce mean number of ToMV local lesions to B. circulans, P. fluorescens 2 and T. harzianum isolates, 40.7, 32.1 and 51.5, respectively. The individual microbial isolates on all three microbial forms able to vary ToMV local lesions similarity (homologous or heterologous) and morphology (size center and surrounded with halo or without halo) compared with TMV mother strain. PMID- 24494521 TI - Comparison of titanium elastic nails with traction and spica cast in treatment of children's femoral shaft fractures. AB - Titanium Elastic Nails (TEN) are commonly used to stabilize femoral fractures in school-aged children, but there have been few studies assessing the risk of traditional traction and application of spica cast. The aim of this study was to compare of titanium elastic nails with traction and spica cast in treatment of children's femoral shaft fractures. A group of thirty children aged 6-12 years with one-sided femoral shaft fracture were randomly allocated either to traction with spica casting group or titanium elastic nails group and were followed up to 1 year. Factors such as age, sex, time needed for walking with aids, time needed for independent walking, time needed for callus formation, time absent from school, time spent in hospital, malunion, malalignment and wound complication were recorded and compared. Fifteen patients (10 boys, 5 girls) with a mean age of 8.33 +/- 1.63 years were treated by traction and spica casting. The other 15 (9 boys, 6 girls) with a mean age of 8.73 +/- 1.53 years underwent surgery using TEN. Mean absence time from school, length of hospital stay, time needed for walking with and without help and angular deviation (varus or valgus) were significantly lower in the group treated by TEN (p-value < 0.05). Time needed for callus formation was significantly lower in spica casting group (p-value < 0.001). No statistically significant difference was observed between the two groups regarding malunion wound complications and hospital charges. The results indicated that a child in whom a femoral fracture is treated with TEN achieves recovery milestones significantly faster than a child treated with traction and spica cast. PMID- 24494522 TI - Propagation of Vatica diospyroides symington: an endangered medicinal dipterocarp of peninsular Thailand by cultures of embryonic axes and leaf-derived calli. AB - Embryonic axes and young leaves of Vatica diospyroides Symington were excised sterilely and then cultured on MS medium supplemented with 0-20 mg L(-1) of a growth regulator and 0-0.3% Activated Charcoal (AC). The growth regulators tested were 2, 4-Dichlorophenoxyacetic acid (2,4-D), alpha-Naphthaleneacetic acid (NAA) and 3, 6-Dichloro-2-methoxybensoic acid (Dicamba). Vigorous shoot development was observed with 0-20 mg L(-1) of each plant growth regulator and 0.1-0.15% AC. Shoot-derived calli were obtained 6 months after culturing embryonic axes on MS medium, with 15 mg L(-1) dicamba and 0.1% AC. Interestingly, after culturing young leaves for 2 months, the highest weight of compact calli (0.40 g) was achieved with a medium containing 20 mg L(-1) dicamba and 0.1% AC, in darkness. These were successfully multiplied by renewing and culturing in the same medium and transfer to shooting induction in MS medium supplemented with 0-20 mg L(-1) 6 benzyladenine (BA). Unfortunately, shoot induction from calli was unsuccessful and despite initiated roots being induced. A successful in vitro propagation protocol of V. diospyroides should be thus investigated more extensively. PMID- 24494523 TI - Olive plants (Olea europaea L.) as a bioindicator for pollution. AB - In the present work, olive plant (Olea europaea L.) was used as a biological indicator for pollution in which, molecular and physiological parameters were studied. Olive plants were collected from polluted and non-polluted areas in Jeddah - Saudi Arabia, traffic area as an air polluted area, sewage treatment station as water polluted area, industrial area as solid waste polluted, costal area as marine polluted area and an area without a direct source of pollution far away from the city center, which was used as control. These changes conducted with nucleic acid content, minerals content, pigments and some growth parameters. Results showed significant reductions in DNA and RNA contents under all polluted sites. Mineral contents were varied widely depending on the different pollutants and locations of olive plant. Generally, micro-elements varied (increase/decrease) significantly within collected samples and the source of pollution. All growth parameters were decreased significantly within the studied samples of all pollutant areas except the relative water content was increased. The content of chlorophyll a has decreased highly significantly in all polluted leaves. While the content of chlorophyll b has increased significantly in all polluted leaves especially in air polluted leaves. The total content of carotenoid pigments has decreased highly significantly in all polluted leaves. It was concluded that olive plant can be used as a biological indicator to the environmental pollutants. PMID- 24494524 TI - Protected methionine prolonged provision improves summer production and reproduction of lactating dairy cows. AB - The objective was to establish prolonged effects of a rumen-protected Met (RPM) product (SmartamineM) on milk production and reproduction of high-producing early lactation cows under extended very high ambient temperatures. Twenty four fresh Holstein cows (27 +/- 9 days in milk, 617 kg b.wt., 2.8 body condition score) including 12 second lactation and 12 higher lactation cows were randomly assigned to either control or RPM-supplemented total mixed rations (TMR, 520:480 g kg(-1) forage:concentrate), and were fed continuously for 5 months. Cows were offered TMR 3 times daily post-milking plus a top-dress alfalfa hay. The study was conducted from May through November of 2009 in central Iranian province of Isfahan. The RPM group had consistently greater 5-month-long average DM intake (21.9 vs. 19.1 kg day(-1)), milk yield (42.4 vs. 37.4 kg day(-1)), milk fat content (33 vs. 27.5 g kg(-1)), fat yield (1.40 vs. 1.04 kg day(-1)), milk protein content (29.6 vs. 27.5 g kg(-1)) and protein yield (1.25 vs. 1.02 kg day( 1)). Mature cows tended to produce more milk (42.2 vs. 37.6 kg day(-1)) and milk fat (1.30 vs. 1.13 kg day(-1)) than second lactation cows. The RPM significantly improved ovary function, estrus expression visibility and body condition score (3 vs. 2.6), while shortening days open (106 vs. 143) and calving interval (387 vs. 421 d). Findings provide compelling evidence for beneficial effects of prolonged RPM provision on feed intake, milk production, and reproduction of Holstein cows under concurrent metabolic pressures of early lactation and stressful high ambient temperatures. PMID- 24494525 TI - Post-harvest loss of farm raised Indian and Chinese major carps in the distribution channel from Mymensingh to Rangpur of Bangladesh. AB - Post-harvest loss of catla (Catla catla), rohu (Labeo rohita), mrigal (Cirrhinus mrigala), silver carp (Hypophthalmichthys molitrix), grass carp (Ctenopharyngodon idella) and sarpunti (Puntius sarana) in a single distribution chain from harvest in Mymensingh to retail sale Rangpur town were determined, in order to obtain information on quality deterioration and existing handling and icing conditions so that suggestions for improving such practices can be made. Quality defect points of the fish at different steps of distribution channels were determined using a sensory based quality assessment tool. Percent quality loss of fish at each step of distribution was calculated from the number of cases that crossed sensory quality cut-off points. Neither of the fish lost their quality when they were in the farm gate, during transportation and in wholesale markets in Rangpur but most of the fishes lost their quality at the retail fish shops. The quality loss was 8, 12, 8, 6, 10 and 14% in case of C. catla, C. mrigala, L. rohita, H. molitrix, C. idella and P. sarana respectively in the retail markets. Fishes were not properly handled, bamboo baskets wrapped with polythene sheet were used as carrying container and inadequate ice was used during transportation. Retailers were found to be more proactive in the use of ice. However, most of the fishes were deteriorated during retail sale. The losses of farmed fishes could be minimized by adopting good handling practices like using insulated container and adequate icing. PMID- 24494526 TI - Frequency of autoimmune diseases in those suffering from vitiligo in comparison with normal population. AB - Vitiligo is more common in people with certain autoimmune diseases. Here we studied the association between vitiligo and autoimmune diseases. In this case control study, 86 patients with vitiligo were questioned about the location of vitiligo, family history, treatment and therapeutic response. All patients were examined both clinically and with laboratory tests to detect the presence of autoimmune disorders including autoimmune thyroid disease, pernicious anemia, insulin dependent diabetes, and Systemic Lupus Erythematic (SLE) and Addison disease. We compared the prevalence of autoimmune disorder in vitiligo patients with that in a group of age-and gender-matched normal population. Average age of disease onset was 21.8 +/- 11 years; 61% of patients were female and 39% were male. The most common locations of vitiligo were hands (33.7%) and face (32.1%). The most common pattern of onset was vulgaris type (40%). Nearly one-fourth of patients had a positive family history of vitiligo. Prevalence of thyroid disorders in vitiligo patients and control group was 21.1 and 7%, respectively. The difference was statistically significant (p = 0.008). The most common autoimmune disorder in patient with vitiligo was hypothyroidism. Family history had a poor prognostic effect on response to therapy. PMID- 24494527 TI - PCR applications in identification of saliva samples exposed to different conditions (streptococci detection based). AB - Oral streptococci represent about 20% of the total oral bacteria, so if it is possible to detect the presence of oral specific bacteria from a forensic specimen by Polymerase chain reaction, this could be used to verify the presence of saliva. Aim of this study is detection of Streptococcus salivarius which is one of the most common streptococci in oral bacteria and Streptococcus mutans which is common in cases of dental caries in various body fluids and skin swabs and assessment of which one of both organisms is more reliable in saliva identification, cross sectional study on Egypt population. Negative control samples (15 samples) were taken from various body fluids (urine, semen) and skin swabs. Mock forensic samples (85 samples) included fresh saliva, saliva, cotton fabrics contaminated with saliva, cigarette butts, bitten apple and semen mixed with saliva samples). DNA extraction was done using DNeasy blood and tissue kit (Qiagen, Tokyo, Japan). Polymerase chain reaction was done for DNA amplification using Polymerase chain reaction master mix then gel electrophoresis was done for samples qualification. Control bacteria were S. salivarius and Streptococcus mutans. Streptococcus salivarius was detected in 83.5% of all saliva contained samples and S. mutans was detected in 67% of saliva contained samples. Both bacteria were not detected in other body fluids and skin swabs, so S. salivarius is more reliable in saliva identification as well as differentiating it from other body fluids. Polymerase chain reaction is valuable in detection of saliva by detecting S. salivarius. PMID- 24494528 TI - Combined inoculation of Pseudomonas fluorescens and Trichoderma harzianum for enhancing plant growth of vanilla (Vanilla planifolia). AB - This study was conducted to evaluate the plant growth promoting efficiency of combined inoculation of rhizobacteria on Vanilla plants. Based on the in vitro performance of indigenous Trichoderma spp. and Pseudomonas spp., four effective antagonists were selected and screened under greenhouse experiment for their growth enhancement potential. The maximum percentage of growth enhancement were observed in the combination of Trichoderma harzianum with Pseudomonas fluorescens treatment followed by Pseudomonas fluorescens, Trichoderma harzianum, Pseudomonas putida and Trichoderma virens, respectively in decreasing order. Combined inoculation of Trichoderma harzianum and Pseudomonas fluorescens registered the maximum length of vine (82.88 cm), highest number of leaves (26.67/plant), recorded the highest fresh weight of shoots (61.54 g plant(-1)), fresh weight of roots (4.46 g plant(-1)) and dry weight of shoot (4.56 g plant(-1)) where as the highest dry weight of roots (2.0806 g plant(-1)) were achieved with treatments of Pseudomonas fluorescens. Among the inoculated strains, combined inoculation of Trichoderma harzianum and Pseudomonas fluorescens recorded the maximum nitrogen uptake (61.28 mg plant(-1)) followed by the combined inoculation of Trichoderma harzianum (std) and Pseudomonas fluorescens (std) (55.03 mg plant(-1)) and the highest phosphorus uptake (38.80 mg plant(-1)) was recorded in dual inoculation of Trichoderma harzianum and Pseudomonas fluorescens. PMID- 24494529 TI - Microbial quality of some vegetables sold in ED DueimTwon, Sudan. AB - This study was probably the first research carried out to investigate the microbiological quality of some vegetables sold in ED DueimTwon, Sudan. Four species of vegetables were used, Arugula (Eruca sativa), Mloukhia (Corchorus olitorius), Tomato (Lycopersicon esculentum) and Green pepper (Capsicum annuum). The samples were collected and examined according to standardized methods for total viable bacteria, coliforms and fecal coliform count. The average of total viable count ranged from 1.2 x 105-5.6 x 105 CFU mL(-1) for Arugula; 2.1 x 105 2.8 x 107 CFU mL(-1) for Mloukhia; 3.4 x 105-4.8 x 105 for Tomato and 2.3 x 105 8.0 x 106 CFU mL(-1) for Green pepper. However, the maximum level of total and fecal coliform were (93, 21); (28, 11); (75, 15) and (150, 20) MPN 100 mL(-1), respectively. Twelve bacteria belonging to five genera were isolated. Staphylococcus (33%) was the most predominant isolated followed by Enterobacteriaceae (25%), Bacillus (17%) and Streptococcus (17%). Micrococcus (8%) was the least dominant isolated. The results of microbial counts of these vegetable samples in this study indicate that, the agricultural practices, harvesting, hygiene, transporting and selling points are poor and therefore, the higher microbial load could be risked for public health. PMID- 24494530 TI - IgG antibodies in patients with pemphigus vulgaris before and after diagnosing with immunofluorescence. AB - Pemphigus is defined as a group of chronic self-immune vesicular diseases histologically recognized by inter-epidermic vesicles resulting from acantholysis. The aim of this study was to evaluate the precipitant and circulative IgG antibodies in patients with pemphigus vulgaris before and after treating with immunofluorescence. Sixty-two patients (34 females and 28 males) with clinically and pathologically confirmed P.V. were studied prospectively over a one year period of time during which direct and indirect immunofluorescent tests were performed before and after treatment. They had mild or moderate forms of disease. All patients received prednisolon 1-2 mg/kg/day and Azathioprine 2-3 mg/kg/day or methylpredisolon (1 g day(-1) for 4 days) and cyclophosphamide (500 mg/first day) pulse therapy due to general condition. Thirty- four females and 28 males enrolled, the mean age were 39.5 years (SD = 12.7). Before treatment, 10 and 52 cases were positive for skin depositing + or ++) and circulatory IgG (1/20 -1/60), respectively. Two to 3 month later, 37 were IgG positive with titers 1/20 to 1/160. The correlation between circulatory IgG before and after treatment was weakly positive (p = 0.05, r = 0.415). In the present study, treatment methods used for patients suffering from pemphigus vulgaris were not successful in significantly decreasing the circulative autoantibodies levels. PMID- 24494531 TI - Pest and disease tolerance in rice cv Pusa Basmati as related to different locally available organic manures grown in new alluvail region of West Bengal, India. AB - Field experiments were carried out to evaluate relative efficacy of organic manures in improving productivity, pest tolerance of rice in lateritic soil. Three commercial manures viz., Processed Municipality Waste (PMW), Vermicompost (VC) and Oil Cake Pellets (OCP) were assessed in relation to Farmyard Manure (FYM) and with Chemical Fertilizer (CF). Among the organic manures tested, FYM produced maximum grain yield. Maximum tolerance to pests and pathogens in terms of per cent affected hills/panicles was observed when manured with VC followed by FYM. Chemical fertilizer showed significantly higher per cent affected hills and plants compared to all other organic manures. Among the commercial manures, PMW emerged as a potential alternative to FYM and VC. PMID- 24494532 TI - Estimation of genetic parameters, inbreeding trend and its effects on production and reproduction traits of native fowls in Fars province. AB - In this study, the data and pedigree records of the native fowls collected by Fars Native Fowls Breeding Center during 1990-2004 were analyzed. A pedigree file collected on 30855 hens and roosters was used to calculate the inbreeding coefficients and its trend and its effect on production and reproduction traits. The average of inbreeding coefficient for all birds was 0.002% ranging from 0 to 14.8%. In this population, 14% of the birds were inbred with an average inbreeding coefficient of 0.019%. The Inbreeding coefficient was considered as covariate to estimate its effect on economic traits including body weight in 12 weeks (BW12), egg number during 12 weeks (EN), mean egg weight between 28 to 32 weeks (MEW) and Age of Sexual Maturity (ASM). Results showed that inbreeding does not have a significant effect on the traits under study (p > 0.05). Moreover, heritability, genetic and phenotypic correlations between traits was estimated through a multiple traits animal model procedure by restricted maximum likelihood using ASREML software. The estimated heritabilities were 0.53, 0.47, 0.57 and 0.22 for body weight in 12 weeks (BW12), Age of Sexual Maturity (ASM), mean Egg Weight (EW) and Egg Number (EN), respectively. Because of relatively high heritabilities of productive and reproductive traits, it is possible to achieve more genetic gains in these traits using appropriate genetic selection. PMID- 24494533 TI - Infection prevention: 2013 review and update for neurodiagnostic technologists. AB - Since 1995 ASET has published recommendations for infection prevention (Altman 1995, Altman 2000, Sullivan and Altman 2008). In keeping with the desire of providing current updates every five years, this article reviews the aforementioned past publications and incorporates new information from books and Occupational Safety and Health Administration (OSHA) regulations. Knowledge of current infection control practices and recommendations is essential for every neurodiagnostic technologist, no matter if employed in a hospital, an ambulatory setting, an intensive care unit, or the operating room. All technologists who have direct patient contact are responsible for ensuring best practices for infection prevention. PMID- 24494534 TI - The relationship between sleep-activated interictal epileptiform discharges and intelligence in children. AB - This study investigates the relationship between interictal epileptiform discharges (IEDs) during sleep in children with benign rolandic epilepsy (BRE) and cognitive test scores as measured by the Wechsler Intelligence Scale for Children-Fourth Edition (WISC-IV) with the hypothesis that, as IEDs increase, cognitive test scores decrease. Studies have shown that generalized seizures and status epilepticus can negatively impact cognition (Dodrill 2004), that children with epilepsy have lower cognitive function on average than children without epilepsy and that children with epilepsy and abnormal electroencephalograms (EEGs) have lower cognitive function than children with epilepsy and normal EEGs (Bailet et al. 2000). Studies have also indicated that as IEDs decrease, neurocognitive test scores increase (Baglietto et al. 2001). The current study evaluated sleep-activated IEDs in children with the specific syndrome of benign rolandic epilepsy based on the frequency of LEDs in sleep in relation to cognitive test scores. Neuropsychological test scores from the WISC-IV were gathered along with the number of spikes per minute detected in EEG recordings. Statistical analysis revealed a negative correlation between spike frequency and both processing speed and coding scores, though the relationship did not reach statistical significance. This study concludes that there may be correlations between increased spike density and cognitive test scores, or there might be other factors impacting cognition in BRE, but a larger sample is needed to further investigate. In addition, it is possible that a negative result in the present study represents good news, that the number of IEDs in BRE does not harm the brain by negatively impacting cognition. PMID- 24494535 TI - Intraoperative neurophysiological monitoring during sacrectomy procedures. AB - Previously intraoperative neurophysiological monitoring (IONM) has not been used along with a computer based navigation system for en bloc resection of a sacral Ewing sarcoma. In order to improve the post-operative neurological outcome of the patient we decided to include IONM in our procedure. A partial or complete resection of a sacral tumor may result in the loss of neurological functions due to close proximity of vascular, neural, and visceral structures. A prolonged two stage surgical procedure may be a high risk procedure for position related brachial plexus injury. An 18-year-old male presented with left lower extremity weakness, which worsened with gait. His MRI was consistent with a sacral mass causing compression on the left S1 and S2 roots. A surgical resection was planned with anterior and posterior approaches. IONM helped guide the surgical team to prevent damaging the sacral roots on the normal side (right) and position related upper extremity brachial plexus injuries. Our technique involving IONM can be used safely for accurate en bloc removal of a sacral tumor with a safe margin while protecting the neural function and minimizing recurrence. This case report demonstrates that intraoperative neurophysiological monitoring was useful in identifying and reversing impending nerve injury during sacrectomy surgery. Significant changes were seen in ulnar and posterior tibial somatosensory evoked potentials (SSEPs). We recommend that IONM should be considered for safe margin en bloc sacral tumor resection and prevention of injury to the sacral root and brachial plexus. PMID- 24494536 TI - Facets of leadership. AB - Leadership, leader are words that are often used to describe an individual who possesses exceptional values, communication skills, confidence, respect, and effectively uses their trust and influence to promote harmony and teamwork. These individuals are visionaries, excellent communicators, trustworthy with integrity, and have character that others want to emulate. Leaders are change agents and must have an openness to change and not fear the risk of failure. Often ignored is one of the most essential characteristics needed by these individuals; before one can lead others effectively, he or she must know him or herself. PMID- 24494537 TI - Re: Overview of using T1/T2 and 10-10 subtemporal electrode chains for localizing EEG abnormalities by Susan M. Feravich, R. EEG T., CLTM, BS and Crystal M. Keller, R. EEG T., CLTM, BA The Neurodiagnostic Journal 2013; 53(1):27-45. PMID- 24494538 TI - Author's reply: To PMID 23682538. PMID- 24494539 TI - [Innovation and practice of component structure theory on material basis of traditional Chinese medicine prescriptions]. AB - The component structure theory on material basis of traditional Chinese medicine prescriptions provides a new research thought and method for studies on traditional Chinese medicine prescriptions in line with integrated and systemic characteristics of traditional Chinese medicine. Through years of exploration and accumulation, studies on component structures have made achievements. On the basis of summarizing the component structure development of material basis of traditional Chinese medicine prescriptions, we systematically explained the background of component structures and their roles and progress in quality control of traditional Chinese medicine prescriptions and modern innovative traditional Chinese medicine preparations. Studies on component structures promote the changes in material basis of traditional Chinese medicine prescriptions, and point out the direction for the modernization development of traditional Chinese medicine prescriptions. PMID- 24494540 TI - [Research strategy and practice of "multi-dimensional structure and process dynamics quality control system" of traditional Chinese medicines]. AB - The quality control is one of the key problems in the modernization and internationalization of traditional Chinese medicines (TCM). As TCMs have the characteristics of integrity and systematicness, their effect in disease prevention and treatment is the result of multi-component synergistic effect. Currently, the quality control of TCMs is mostly measured with a single index, which can not reflect the integrity of TCMs. As TCM components could play the role in preventing and treating diseases through multiple targets and channels, only if we expound the specific composition and structural relations among inherent components, and determine the optimum composition and structure ratio of TCMs in preventing and treating diseases and revealing their optimal efficiency, safety and stability, can we get rid of the conventional quantitative model, and realize the scientific integral quality control in a real sense. On the basis of the component structure theory, we propose "multi-dimensional structure and process dynamics quality control system" in this article, and systematically expound the optimal efficiency of TCMs, in order to provide a theoretical basis for improving the efficacy of TCM preparation products. PMID- 24494541 TI - [Establishment and application of "multi-dimensional structure and process dynamic quality control technology system" in preparation products of traditional Chinese medicine (I)]. AB - Safety is an important component of the quality control of traditional Chinese medicine (TCM) preparation products, as well as an important guarantee for clinical application. Currently, the quality control of TCMs in Chinese Pharmacopoeia mostly focuses on indicative compounds for TCM efficacy. TCM preparations are associated with multiple links, from raw materials to products, and each procedure may have impacts on the safety of preparation. We make a summary and analysis on the factors impacting safety during the preparation of TCM products, and then expound the important role of the "multi-dimensional structure and process dynamic quality control technology system" in the quality safety of TCM preparations. Because the product quality of TCM preparation is closely related to the safety, the control over safety-related material basis is an important component of the product quality control of TCM preparations. The implementation of the quality control over the dynamic process of TCM preparations from raw materials to products, and the improvement of the TCM quality safety control at the microcosmic level help lay a firm foundation for the development of the modernization process of TCM preparations. PMID- 24494542 TI - [Establishment and application of "multi-dimensional structure and process dynamic quality control system" in preparation products of traditional Chinese medicine (II)]. AB - Appropriate dosage forms of traditional Chinese medicine (TCM) preparation products, improve effectively drug efficacy and reduce side effects, and also facilitate the use in clinic. In addition, it may also promote the development of the modernization of TCM. TCMs were developed to finish products which possessed suitable dosage form characteristics through multiple steps from raw herbs to preparation. In this paper, we discussed other two key technologies of "multi dimensional structure & process dynamic quality control system": (1) The dosage form is an important factor affecting the efficacy and safety for the prevention and treatment of diseases. Therefore, the control of the quality of the formulation characteristics is more important. (2) Process dynamic quality control: the dynamic quality control in the production process is particularly critical because drugs are produced rather than testing. In this paper, the paper demonstrates the important role of the system in the quality control of TCM for strengthening the quality control of the production process of TCM preparation, and then further providing a theoretical basis for improving the efficacy of TCM products. PMID- 24494544 TI - [Study thought of multi-dimensional structure quality control of Xiaoaiping injection based on material basis component structure]. AB - The quality control over traditional Chinese medicine (TCM) preparations has long been an important issue on the international development road of TCMs. Because of the complexity of TCM ingredients, preparation production and its quality control become a big difficulty. How to produce TCM preparations with preparation quality stability and controllability is the key problem in urgent need of solution in current TCM preparation field. The author thought that according to the characteristics of TCM preparation process, the multidimensional dynamic quality control model in the production process might become one of methods for solving quality controllability of TCM preparations. Therefore, we proposed the study through of the multi-dimensional structure quality control based on TCM material basis component structure. The study aims to control over the stability of TCM preparation quality during the whole process of dynamic changes (the component analysis monitoring on intermediates during the process of production, herbal source, intermediate production to preparation products). Xiaoaiping injection was taken as the example to expound the multidimensional quality control process of Xiaoaiping injection, in the hope of providing new ideas for the quality control over modern TCM preparations. PMID- 24494543 TI - [Study on "multi-dimensional structure and process dynamics quality control system" of Danshen infusion solution based on component structure theory]. AB - As traditional Chinese medicine (TCM) preparation products feature complex compounds and multiple preparation processes, the implementation of quality control in line with the characteristics of TCM preparation products provides a firm guarantee for the clinical efficacy and safety of TCM preparation products. Danshen infusion solution is a preparation commonly used in clinic, but its quality control is restricted to indexes of finished products, which can not guarantee its inherent quality. Our study group has proposed "multi-dimensional structure and process dynamics quality control system" on the basis of "component structure theory", for the purpose of controlling the quality of Danshen infusion solution at multiple levels and in multiple links from the efficacy-related material basis, the safety-related material basis, the characteristics of dosage form to the preparation process. This article, we bring forth new ideas and models to the quality control of TCM preparation products. PMID- 24494545 TI - [Multi-dimensional structure quality control technology system of Danmu injection based on component structural theory]. AB - Danmu is one of common medicines in folks of Li nationality, with such effects in clearing heat and removing toxicity, antisepsis and anti-inflammation. Danmu injection, which is developed with Danmu herbs, has been clinically applied for years and showed curative efficacy. Currently, though many studies have been conducted to analyze chemical constituents in Danmu in details, its pharmacodynamic material basis related to disease prevention and treatment has not been defined. Furthermore, as the quality control methods for Danmu and its preparations remain restricted to single index component and irrational to some extent, it fails to ensure their inherent quality. On the basis of the summary of previous study results, as well as the "component structural theory" of the material basis, we established a "multi-dimensional structure quality control technology system" that is capable of reflecting the integrity of effects of Danmu injection and component structure hierarchy, and performed a dynamic monitoring over the whole process from medicinal materials and preparation products, so as to ensure the inherent quality of Danmu injection. PMID- 24494546 TI - [Application of oral micro-carrier drug delivery system in studies on traditional Chinese medicine]. AB - Drug-loading micro-particles are a targeted, positioned and controlled-release drug delivery carrier with a wide application prospect. Various micro-carrier drug delivery systems have their own advantages in promoting absorption, improving stability, targeting and controlled release. Accordingly, it is of far reaching significance for the studies on micro carrier drug delivery systems to build oral traditional Chinese medicine (TCM) compound micro-carrier drug delivery systems with effective TCM components and effective fractions. This article introduces several features and advantages of oral micro-carrier drug delivery systems, and summarizes their application in the field of TCMs. PMID- 24494547 TI - [Advance in studies on antibacterial effect of flavonoids]. AB - As antibiotic drug resistance has become one of the most serious threats to global public health, there is a pressing need to look for new effective therapeutic drugs. Flavonoids are a large class of chemicals widely exist in plants, and have such effects as direct antibiotics, synergistic antibiotics and inhibition of bacterial activity. In this article, we made a summary for the advance in studies on the antibacterial effects of flavonoids and their mechanism. PMID- 24494548 TI - [Overview research of uremic ulearance granule treating chronic renal failure]. AB - The effective bioactivity compositions of uremic clearance granul (UCG) include isoflavonoids, emodin, astragaloside, paeoniflorin, salvianolic acid A, and so on. The effects of UCG treating chronic renal failure (CRF) in clinical pharmacodynamics mainly refer to improve renal function and the complications of CRF. The mechanisms involved in vivo basically include depressing transforming growth factor (TGF)-beta1 over-expression, lessening podocyte injury,inhibiting tubular epithelial myofibroblast transdifferentiation, ameliorating microinflammation status, retarding oxidative stress, and alleviating insulin resistance. PMID- 24494549 TI - [Research progress of alternative production approaches of salidroside]. AB - Salidroside, one of the active components of Rhodiola plants, is a phenolic glycoside with significant biological activities. The investigation and development of alternative production approaches of salidroside is of high academic and application values due to the limited resource of Rhodiola plants, and from which the low yield of salidroside. This review summarized the research progress and perspective of the alternative production approaches of salidroside including both chemosynthetic and biosynthetic methods and pathways. PMID- 24494550 TI - [Studies on high efficient plant regeneration system from anther callus of Bupleurum chinense]. AB - The callus of Bupleurum chinense with anthers at the stage of uninucleate was induced. After several subcultures, anther calli of B. chinense were cultured at 20 MS culture mediums with different plant hormones to differentiate into plantlets. Differentiation of callus was detected after 21 and 49 days to select the most effective medium. There were 19 culture mediums in which anther callus could differentiate into plantlets with differentiation rate range from 3% to 60% , and most less than 20%. MS + KT 0.5 mg x L(-1) + sucrose 30 g c L(-1) + phytagel 5 g x L(-1) was the best differentiation medium with the differentiation rate of 60%, followed by MS + ZT 1.0 mg x L(-1) + sucrose 30 g x L(-1) + phytagel 5 g x L(-1) with the differentiation rate of 58%. Then plantlets were transferred to rooting medium to obtain whole plant. All plantlets could root in the rooting medium of MS + sucrose 30 g x L(-1) + phytagel 5 g x L(-1) and 1/2 MS + NAA 0.5 mg x L(-1) + sucrose 30 g x L(-1) + phytagel of 5 g L(-1) with the rooting rate of 100%. As a result, the high efficient and stable plant regeneration system was established from anther callus of B. chinense. PMID- 24494551 TI - [Factor of Prunella vulgaris yield components and morphological characteristics of relationship in different populations]. AB - Prunella vulgaris is a perennial herb whose dry spike is used for medicine in China. It is also a very important traditional medicine. Current study was conducted to the biomass components factors of P. vulgaris in the different ecological environments for the development and protection. The results showed that the contribution factor of the production in different environments was significant differences. In favorable environment, the length of leaf, numbers of leaves, height, reproductive branch number of individuals gave the greatest contribution. In transitional habitats, the diameter of stem and spike, the length of leaf contributed the most. While in the undergrowth and dry hillside, the length of root, the width of leaf, the length of spike were the main factors for biomass. PMID- 24494552 TI - [Extraction, purification and identification of type II collagen from Agkistrodon acutus]. AB - The object of the research was to extract, purify and identify the type II collagen of Agkistrodon acutus. Type II collagen of A. acutus was extracted by enzyme decomposition method, and purified by ion exchange column chromatography. It was characterized by SDS-PAGE gel electrophoresis, ultraviolet spectrophotometry, infrared absorption spectroscopy and mass spectroscopy. The results showed that the size of C II was about 130 kDa. It absorbed at 223 nm. IR spectrum obtained showed that the triple helical domains of amino-acid sequences were characterized by the repetition of triplets Gly-X-Y. The MS spectrum graphically stated that C II extracted from cow and A. acutus have the similar peptides. The C II of A. acutus was obtained by extraction and purification. Appraisal analysis by SDS-PAGE, UV, IR and MS, C II of A. acutus was consistent with the standard C II of cow. It was proved that the extracted protein was C II. PMID- 24494553 TI - [Population dynamics and control techniques of aphids on honeysuckle]. AB - The objective of this study is to define the population dynamics of Semiaphis heraclei in the main-producing district of Lonicera japonica in Shandong, and screen for highly efficient, safety control technique. Through fixed field investigation, we tested the toxicity of eight kinds of insecticides by using dipping methods, and carried out the field experiment. The results showed that the aphids' emergence peak appeared in May. The aphids on the Sijihua variety of L. japonica was more susceptible and the peak was also seven days earlier than Damao variety of L. japonica. The aphid populations on Sijihua were 1 fold than those on the Daomao in happened peak. Comparing the eight kinds of insecticides, the LC50 of lambda-cyhaothrin, abamectin, imidacloprid and pyrethrin to wingless aphids were 1.494, 1.690, 2.840, 2.861 mg x L(-1), respectively, whose toxicity were higher, the toxicity of matrine, pymetrozine and azadirachtin were also high. The field efficacy trials indicated that during the period of aphids occurred, 25% imidacloprid wettable powder, 1.8% abamectin missible oil, 2.5% lambda-cyhaothrin missible oil, 25% pymetrozine wettable powder, 5% pyrethrin missible oil, 1% matrine water aqua were sprayed at concentrations of 20,000, 2,000, 2,500, 5,000, 500 and 50 times, respectively,the control effect achieved 91.69%, 98.90%, 96.18%, 95.06%, 99.24%, 90.10%, respectively, after 5 days. During the growing period of L. japonica in spring, application of thiamethoxam, thiacloprid, pymetrozine and imidacloprid, all of the control effect against aphids achieved above 98.88% after 50 days. The result indicated that May was the S. heraclei Takahashi's emergence peak in Pingyi, Shandong. The efficient safety and environmentally friendly insecticides by spraying and systemic insecticide of pymetrozine and imidacloprid by root application were all efficient controlled aphids. These insecticides were long for controlling S. heraclei Takahashi and worthy of being widely applied. PMID- 24494554 TI - [Measurement of sown area of safflower based on PCA and texture features classification and remote sensing imagery]. AB - To improve accuracy of estimation in planted safflower acreage,we selected agricultural area in Yumin County, Xinjiang as the study area. There safflower was concentrated planted. Supervised classification based on Principal Component Analysis (PCA) and texture feature were used to obtain the safflower acreage from image captured by ZY-3. The classification result was compared with only spectral feature and spectral feature with texture feature. The research result shows that this method can effectively solve the problem of low accuracy and fracture classification result in single data source classification. The overall accuracy is 87.519 1%, which increases by 7.117 2% compared with single data source classification. Therefore, the classification method based on PCA and texture features can be adapted to RS image classification and estimate the acreage of safflower. This study provides a feasible solution for estimation of planted safflower acreage by image captured by ZY-3 satellite. PMID- 24494555 TI - [Quantitive variation of polysaccharides and alcohol-soluble extracts in F1 generation of Dendrobium officinale]. AB - Using phenol-sulfuric acid method and hot-dip method of alcohol-soluble extracts, the contents of polysaccharides and alcohol-soluble extracts in 11 F1 generations of Dendrobium officinale were determined. The results showed that the polysaccharides contents in samples collected in May and February were 32.89% 43.07% and 25.77%-35.25%, respectively, while the extracts contents were 2.81% 4.85% and 7.90%-17.40%, respectively. They were significantly different among families. The content of polysaccharides in offspring could be significantly improved by hybridization between parents with low and high polysaccharides contents, and the hybrid vigor was obvious. Cross breeding was an effective way for breeding new varieties with higher polysaccharides contents. Harvest time would significantly affect the contents of polysaccharides and alcohol-soluble extracts. The contents of polysaccharides in families collected in May were higher than those of polysaccharides in families collected in February, but the extracts content had the opposite variation. The extents of quantitative variation of polysaccharides and alcohol-soluble extracts were different among families, and each family had its own rules. It would be significant in giving full play to their role as the excellent varieties and increasing effectiveness by studying on the quantitative accumulation regularity of polysaccharides and alcohol-soluble extracts in superior families (varieties) of D. officinale to determine the best harvesting time. PMID- 24494556 TI - [Study on distributed patterns of scoparone and ayapin in Dendrobium species from Yunnan]. AB - An HPLC method for determination of scoparone and ayapin was established for investigating the distributed patterns of scoparone and ayapin in 37 species of Dendrobium. The contents of scoparone and ayapin in varied collected samples were determined by the established HPLC method. The pseudo-bulbs sampled were collected according to different growth age of D. thyrsiflorum. The results showed that the contents of scoparone and ayapin were much differently distributed in species of Dendrobium. Only D. thyrsiflorum and D. densfilorum contained both scoparone and ayapin, the content decreased with the growth age. A fewer amount of ayapin was tested in D. loddigesii from Wenshan. The scoparone and ayapin were not determined in the rest species of Dendrobium. The method was concise, sensitive, accurate and reproducible. It could be applied to assay scoparone and ayapin in populations of herbal Dendrobium. PMID- 24494557 TI - [Chemical studies on roots of Ficus hirta]. AB - Seventeen compounds were isolated from the 95% ethanolic extract of the root of Ficus hirta. Their structures were identified on the basis of physicochemical properties and spectral data analysis. The structures were elucidated as cyclomorusin (1), 3-O-[(6-O-E-sinapoyl)-beta-D-glucopyranosyl]-(1 --> 2)-beta-D glucopyranoside (2), 3,5,4'-trihydroxy-6,7,3'-trimethoxyflavone (3), quercetin (4), tricin (5), acacetin (6), luteolin (7), apigenin (8), (E) -suberenol (9), meranzin hydrate (10), methyl eugenol (11), 3-methoxy-4-hydroxybenzoic acid (12), p-hydroxybenzoic acid (13), methyl chlorogenate (14), emodin (15), alpha-amyrin acetate (16), and beta-sitosterol emodin (17), respectively. Compounds 1-6, 9-15 were isolated from this plant for the first time. PMID- 24494559 TI - [Removal of heavy metals from extract of Angelica sinensis by EDTA-modified chitosan magnetic adsorbent]. AB - The concentrations of heavy metals in the extracting solutions of traditional Chinese medicine are usually very low. Furthermore, a vast number of organic components contained in the extracting solutions would be able to coordinate with heavy metals, which might lead to great difficulty in high efficient removal of them from the extracting solutions. This paper was focused on the removal of heavy metals of low concentrations from the extracting solution of Angelica sinensis by applying an EDTA-modified chitosan magnetic adsorbent (EDTA-modified chitosan/SiO2/Fe3O4, abbreviated as EDCMS). The results showed that EDCMS exhibited high efficiency for the removal of heavy metals, such as Cu, Cd and Pb, e.g. the removal percentage of Cd and Pb reached 90% and 94.7%, respectively. Besides, some amounts of other heavy metals like Zn and Mn were also removed by EDCMS. In addition, the total solid contents, the amount of ferulic acid and the HPLC fingerprints of the extracting solution were not changed significantly during the heavy metal removal process. These results indicate that EDCMS may act as an applicable and efficient candidate for the removal of heavy metals from the extracting solution of A. sinensis. PMID- 24494558 TI - [Analysis and identification of chemical constituents in Siwu decoction by UPLC-Q TOF-MS(E)]. AB - This research analyzed the chemical constituents of Siwu decoction by UPLC-Q-TOF MS(E). Base on the data of mass and related-literatures, 43 peaks were profiled and 25 compounds, which contain 8 monoterpene glycosides from Paeonia lactiflora and 13 phthalides from Rhizoma chuanxiong and Radix angelica sinensis mainly, were identified in both positive and negative mode respectively. Meanwhile, chemical constituents of water extract and 60% ethanol extract of Siwu decoction were compared by the principal constituent analysis with MarkerLynx software, which provides the basis for the active ingredients of Siwu decoction. PMID- 24494560 TI - [Study on HPLC digital fingerprint of Coptidis Rhizoma and content determination of seven alkaloids]. AB - To establish an HPLC digital fingerprint for Rhizoma Coptidis produced in E'mei, and apply it in the determination of Rhizoma Coptidis herbs produced in main producing areas nationwide, while determining the content of seven quaternary ammonium alkaloids contained in Coptidis Rhizoma, in order to provide basis for scientific evaluation and effective control over quality of Rhizoma Coptidis. Diamonsil C18 column (4.6 mm x 250 mm, 5 microm) was adopted and eluted with acetonitrile 0.025 mol x L(-1) KH2PO4 solution (adjust pH to 3.0 with H3PO4) (40:60) containing SDS 1.7 g x L(-1). The flow rate was 1.2 mL x min(-1), the detective wavelength was 345 nm, and the column temperature was 40 degrees C. The chromatographic fingerprint similarity evaluation system for traditional Chinese medicines (state pharmacopeia committee of China) was used for analysis. The chromatographic fingerprint similarity of ten batches of Coptidis Rhizoma samples produced in Emei was more than 0. 99. There were altogether 10 common peaks, and eight of them were identified. A comparative analysis showed a high similarity between samples from five main producing areas nationwide and Coptidis Rhizoma herbs in E'mei. Meanwhile, the content of seven major alkaloids contained in Coptidis Rhizoma herbs, namely groenlandicine, columbamine, jatrorrhizine, epiberberine, coptisine, palmatine and berberine were determined. As the method was highly sensitive and specific, the combination of HPLC digital fingerprint and alkaloid content determination could reflect its inherent quality in an all round way, which provided scientific basis for the quality control of Coptidis Rhizoma. PMID- 24494561 TI - [Effect of Siwu decoction and its combined administration on hepatic P450 enzymatic activity and mRNA expression in rats]. AB - To study the effect of Siwu decoction (SWD) compound and its combined administration on hepatic P450 enzymatic activity and mRNA expression in rats. Rats were orally administered with SWD and water decoction combined with other medicines for two weeks, and then sacrificed. Their livers were perfused with normal saline to prepare liver micrisomes. Mixed probe and liver microsome in vitro incubation method were adopted to detect the effect of SWD on hepatic cytochrome P450. The real-time quantitative polymerase chain reaction (Q-PCR) was used to detect the effect of SWD on the expression of hepatic cytochrome P450. Compared with the control group, the SWD compound group showed higher CYP1A2 enzymatic activity (P < 0.05); Rehmanniae-paeoniae, angelicae-paeoniae, angelicae rhizome, paeoniae-rhizome groups had lower CYP1A2 and CYP2C19 enzymatic activities (P < 0.05); And the compound group, the single component group and the combination group showed lower CYP2B6 enzymatic activities (P < 0.05). The compound could up-regulated the mRNA expression of CYP2B1 (P < 0.05); And the four single components could down-regulated the mRNA expression of CYP2B1 (P < 0.05). SWD compound had the effect in inducing CYP1A2 enzymatic activity. The rehmanniae-paeoniae group and the angelicae-paeoniae group had identical enzymatic activity with the control group, but significant down-regulation in CYP1A2 enzymatic activity after being combined with paeoniae. The compound and its combined administration showed the inhibitory effect on CYP2B6 enzymatic activity, particularly being combined with angelicae. The compound showed identical effect with the four single components in terms of CYP1A2 mRNA expression and enzymatic activity. PMID- 24494562 TI - [Protective effect of isoorientin on alcohol-induced hepatic fibrosis in rats]. AB - OBJECTIVE: To observe the effect and mechanism of isoorientin from Gypsophila elegans on alcohol-induced hepatic fibrosis in rats. METHOD: ninety healthy male Wistar rats were randomly divided into six groups: the normal control group, the model control group, the colchicines group (positive control, 1.0 mg x kg(-1) x d(-1)), the high, middle and low-dose isoorientin groups (20, 50, 100 mg x kg(-1) x d(-1)). The normal control group received normal saline, while other groups received alcohol to cause hepatic fibrosis. After 24-weeks treatment, the alanine aminotransferase (ALT), aspartate aminotransferase (AST), Interleukin 6 (IL-6), tumor necrosis factor-alpha (TNF-alpha), hyaluronic acid (HA), laminin (LN), type III precollagen (PCIII), hydroxyproline (Hyp), Myeloperoxidase (MPO), malondialdehyde (MDA), superoxide dismutase (SOD), glutathione peroxidase (GSH Px) were assayed according to the manufacturer's instructions, the alpha-SMA and TGF-beta1 were detected by western blotting, and the histopathological changes was observed by H&E staining. RESULT: Isoorientin could improve the liver function by decreasing the activity of ALT, AST, IL-6, TNF-alpha, MDA, MPO, HA, LN, PCIII and Hyp (P < 0.05), increasing the activity of SOD and GSH-Px (P < 0.05), and reducing the expression of alpha-SMA and TGF-beta1 (P < 0.05). In addition, the high and middle-dose isoorientin groups showed more remarkable effect CONCLUSION: Isoorientin from G. elegans can protect hepatic fibrosis induced by alcohol. PMID- 24494563 TI - [Effect of Taohong Siwu decoction on angiogenesis of medicine-induced incomplete abortion in early pregnancy rats and expressions of Ang-1, Ang-2 and Tie-2]. AB - OBJECTIVE: To observe the effect of Taohong Siwu decoction (THSWD) on micro vascular density (MVD) in rat uterus, the content of angiopoietin-1 (Ang-1) and angiopoietin-2 (Ang-2) in serum, and the expression of tyrosine kinasa receptor (Tie-2) in uterus. METHOD: Early pregnancy rats were intragastrically administrated with misoprostol (100 microg x kg(-1)) and mifepristong (8.3 mg x kg(-1)) to established the incomplete-abortion model. The incomplete-abortion rats were randomly divided into the model group (the same volume of distilled water), the positive control group (at the daily dose of 4.3 g x kg(-1) Motherwort Particles), and THSWD-treated groups (at the daily dose of 18.0, 9.0 and 4.5 g x kg(-1)). Pregnant rats were taken as the control group (the same volume of distilled water). After the successive oral administration for 7 days, blood was collected from aorta abdominalis, and rat uterine tissues were collected. The content of serum Ang-1 and Ang-2 were detected by ELISA; And the levels of Tie-2 and MVD in uterine tissues were detected by SP immunohistochemistry. RESULT: THSWD remarkably increased the levels of MVD in uterus of medicine-induced abortion rats, the content of Ang-1 and Ang-2 in serum, and the expression of Tie-2 in uterine tissues. CONCLUSION: THSWD has the effect in markedly promoting angiogenesis in incomplete-abortion rats. Its mechanism may be related to the regulation of concentrations of Ang-1 and Ang-2 in serum and Tie-2 in uterine tissues. PMID- 24494564 TI - [Analgesic effect of ferulic acid on CCI mice: behavior and neurobiological analysis]. AB - To study the analgesic effect of chronic administration with ferulic acid, and preliminarily discuss its mechanism. Thermal hyperalgesia and mechanical allodynia tests were conducted to observe the analgesic effect of chronic administration with ferulic acid on CCI mice. The neurochemical detection method was applied to observe the effect chronic administration with ferulic acid on monoamine neurotransmitter and monoamine oxidase activity. Compared with the normal group, CCI mice showed notable reduction in heat sensation and nociceptive threshold in and mechanical allodynia. Ferulic acid (10, 20, 40 and 80 mg x kg( 1), po) could significantly reverse the situations. In an in-depth study, we found that the reason for these results was that ferulic acid was dose-dependent in increasing 5-HT and NE levels in hippocampus, frontal cortex and amygdale and could inhibit MAO-A activity in mouse brains. These results showed that ferulic acid has the analgesic effect. Its mechanism may be related to the inhibition of monoamine oxidase activity and the increase in monoamine neurotransmitter in mouse brains. PMID- 24494566 TI - [Study on intervention effect of Jieduquyuziyin prescription systemic lupus erythematosus by HPLC-Q-TOF/MS]. AB - To establish a metabonomic method based on high performance liquid chromatography quadrupole-time of flight mass spectrometry (HPLC-Q-TOF/MS), in order to study the changes in serum metabolites of systemic lupus erythematosus (SLE) mice after treatment of Jieduquyuziyin prescription, the pathogenesis of SLE and mechanism of drug action. The orthogonal partial least squares (OPLS) was applied for the pattern recognition of experimental data, finding a significant difference in the control group, the SLE model group, the Jieduquyuziyin prescription-treated group and the prednisone acetate-treated group. According to the OPLS load diagram, 12 differential metabolites, including traumatic acid, PAF, 12 (S)-HEPE, 15(S)-HETrE and Hepoxilin B3 were identified by using accurate mass combined with MS/MS data After treatment with Jieduquyuziyin prescription, the relative contents of PAF, 12 (S)-HETE were close to the level of the control group. According to the analysis on metabolic pathway, SLE could cause significant changes in unsaturated fatty acid and amino acid metabolism pathway, while Jieduquyuziyin prescription has a effect in regulating disorder of unsaturated fatty acid metabolism pathway. PMID- 24494565 TI - [Protective effect of succinic acid on primary cardiomyocyte hypoxia/reoxygenation injury]. AB - To establish cardiomyocyte hypoxia/reoxygenation injury model by culturing primary cardiomyocytes from suckling SD rats, in order to study the effect of succinic acid on LDH leakage rate cardiomyocyte ischemia/reperfusion injury. Furthermore, flow cytometry and western blot were conducted to detect the effect of succinic acid on cardiomyocyte apoptosis, cleaved caspase-3 and p-Akt, and discuss the protective effect of succinic acid on primary cardiomyocyte hypoxia/reoxygenation injury of primary cardiomyocytes from neonatal SD rats. According to the findings of the study, succinic acid at the concentrations ranging between 31.25 mg x L(-1) and 500 mg x L(-1) had no significant effect on primary cardiomyocyte activity, and succinic acid at the concentrations of 400, 200, 100, 50 mg x L(-1) could notably reduce cardiomyocyte ischemia/reperfusion LDH leakage rate (P < 0.01 or P < 0.05, respectively). Succinic acid at the concentrations of 400 mg x L(-1) and 200 mg x L(-1) could significantly reduce the percentage of cardiomyocyte apoptosis (P < 0.05), and inhibit the protein expression of cleaved caspase-3 caused by cardiomyocyte ischemia/reperfusion (P < 0.05). Succinic acid at the concentration of 400 mg x L(-1) could remarkably increase the protein expression of cardiomyocyte Akt (P < 0.05), while succinic acid at the concentration of 200 mg x L(-1) had no obvious effect on the protein expression of cardiomyocyte Akt. Therefore, this study demonstrated that succinic acid could inhibit necrosis and apoptosis caused by cardiomyocyte hypoxia/reoxygenation by activating Akt phosphorylation. PMID- 24494567 TI - [Study on determination of caffeic acid, chlorogenic acid in rat plasma and their pharmacokinetics with LC-MS/MS]. AB - To establish a LC-MS/MS method to determine caffeic acid, chlorogenic acid in rat plasma and study their pharmacokinetics in rats. Six Sprague-Dawley rats were intravenously injected with 4 mL x kg(-1) of Dengzhanxixin injection, respectively. Their drug plasma concentration was determined by LC-MS/MS, with tinidazole as an internal standard. The pharmacokinetic parameters were calculated by DAS 1.0. The linear concentration ranges of caffeic acid, and chlorogenic acid were 2-128 microg x L(-1) (r = 0.998 1) and 3-384 microg x L(-1) (r = 0.998 7), respectively. The methodological test showed conformance to the requirements. The intraday and inter-day variable coefficients were both less than 10.0%, indicating that both of legitimate precise and accuracy were in conformity with the requirements of biological sample analysis. For caffeic acid, the pharmacokinetic parameter t1/2beta AUC0-t, and CL were (130.91 +/- 38.77) min, (4.89 +/- 0.96) mg x min x L(-1) and (0.12 +/- 0.02) L x min(-1) x kg(-1), respectively. For chlorogenic acid, the pharmacokinetic parameter t1/2beta , AUC0 t, and CL were (49.38 +/- 8.85) min, (9.54 +/- 0.95) mg x min x L(-1) and (0.09 +/- 0.003) L x min(-1) x kg(-1), respectively. The LC-MS/MS analysis method established in this study was proved to be so accurate and sensitive that it can be applied to the pharmacokinetic study of caffeic acid and chlorogenic acid. PMID- 24494568 TI - [Pharmacokinetics study on Danshensu in rats by brain microdialysis and automated blood technique]. AB - To research the pharmacokinetic of Danshensu in brain via microdialysis method and automated blood technique. A microdialysis probe was inserted into the left lateral ventricle, and then dialysate samples and blood samples were continuously collected after iv Danshensu. LC-MS/MS was used to determinate for Danshensu in the dialysate samples. The in vivo recovery was used for the calibration of probe. WinNonlin was used for analyzing all pharmacokinetic data. Pharmacokinetic parameters of DSS in blood and in brain showed that Ke, t1/2,, AUC0-t, MRT were 0.04, 0.018 min(-1), 16.64, 58.76 min, 812.59, 51.19 min x mg x L(-1), 15.28, 79.97 min, respectively. The results were indicated that the study was successfully established LC-MS/MS detection method for Danshensu. Microdialysis combined with automated blood technique could better reflect the dynamic characteristics of Danshensu in the rat brain, and it provides a new perspective for pharmacokinetic study. PMID- 24494569 TI - [Comparative pharmacokinetic studies of borneol in brain and plasma of stroke or sham-operated rats after administration of Xingnaojing]. AB - In order to research the pharmacokinetic characteristic of borneol in plasma and brain of stroke rats given XNJ and investigate the influence of stroke on the borneol passing through the blood-brain barrier, this study established the GC to determine the borneol in brain and blood, and made the stroke mode rats by middle carotid artery occlusion (MCAO) and set sham-operated group. After oral administration of Xingnaojing (XNJ) suspension, their blood and brain were collected at different time and detected by GC. The data was analysed by Kinetica. Results showed that in stroke group, the Cmax and AUC0-t of brain and plasma are (1.82 +/- 0.825), (1.35 +/- 0.43) mg x L(-1) and (123.39 +/- 55.82), (87.91 +/- 39.81) mg x L(-1) x min, Te (brain/blood drug ratio) was 70.93%; those pharmacokinetic values were larger than in sham-operated group. We can conclude that the pathological state of stroke can increase the amount of borneol permeating into brain. PMID- 24494570 TI - [Adverse reaction induced by licorice preparations: clinical analysis of 93 cases]. AB - Licorice is a traditional Chinese medicine commonly used in clinic. The products,what contain licorice or licorice extract, has early been involved in the field of cosmetics except for the field of pharmaceuticals and food. Consequently, the reporting on adverse reactions induced by licorice preparations are more frequent. Based on the clinical data of licorice preparations adverse reactions, we described the characteristics of the licorice-related adverse reactions, and proposed specific measures to reduce the incidence of adverse reactions, provided a reference for the rational use of licorice preparations. PMID- 24494571 TI - [Identification of medicinal plants used as Tibetan traditional medicine Chuan-Bu based on nrDNA markers]. AB - OBJECTIVE: To identify the common Tibetan herb Chuan-Bu. METHOD: Local herbalists were visited to observe which plants were being used as Chuan-Bu. Samples of the indigenous plants were collected at the same time. Leaf materials were collected from field surveys. Total genomic DNA was extracted from silica gel-dried leaf samples. The PCR products were purified and directly sequenced. RESULT: As the origin of Chuan-Bu in Tibet autonomous region was authenticated, two species were determined, i. e. Euphorbia stracheyiand E. wallichii. Also, based on our earlier research, the origin of Chuan-Bu in Gansu province, is from E. kansuensis. The sequences of ITS1 for E. stracheyi and E. wallichii were 261 bp in size, and 221 bp in ITS2, respectively. The size of the 5.8S coding region was 164 bp for all species examined in the genus. Especially, there was a heterozygous locus in ITS1 (C/G; position 72) for E. stracheyi. The nucleotide divergence between sequences of the 6 species in pairwise comparisons was calculated and the result showed that the variable site could be detected in each pairwise comparison of sequences. Also, there were 8 point mutations in the 5.8S coding region. CONCLUSION: nrDNA ITS sequences can be used as the molecular markers to identify the Tibetan herb Chuan-Bu and such Traditional Chinese Medicines from the same genus Euphorbia as E. lathyris, E. humifusa and E. pekinensis. PMID- 24494572 TI - [Research on effect of Baimai powder effective compounds group promotes neurogenesis and maintains of neural stem cells after cerebral infarction]. AB - The neural stem cells (NSCs), play a crucial role in stroke treatment, which can be regulated by a few of traditional Chinese medicines. In this study, the effect of the Mongolian medicine Baimai powder effective compounds group (BMECG) on the proliferation of NSCs has been investigated. The cultured NSCs which were isolated from newborn rat cerebral cortical in vitro were exposed to oxygen glucose deprivation/reoxgenation (OGD/R). The CFSE immunofluorescence staining was employed to identify the proliferation of NSCs by flow cytometry. Furthermore, the bilateral carotid artery occlusion (BCAO) was established on Kunming mice, and all groups were ig for 7 d respectively. The neurobehavioral changes was studied with rota-rod treadmill test, after that, the brain of mice were detected by immunohistochemistry with labeling of Nestin and pathological observation at 7 days after BCAO. It was found that, proliferation of NSCs was increased by BMECG in in vitro and in vivo. And BMECG significantly improved the time of staying in the rota-rod, it can promote the foundction of in cerebral cortex. It is concluded that these results further support the hypothesis that neuroprotective effect of BMECG may relate to the ability of stimulating self renew of NSCs, which can be provided a new insight and strategy of anti neuropathy of stroke. PMID- 24494573 TI - [Quality standard of uygur medicine Medicago sativa seeds]. AB - In this paper, microscopic identification method was adopted to observe the microscopic characters of ten batches of Medicago sativa seeds. And M. sativa seeds were identificated by TLC method in contrast to trigonelline and stachydrine hydrochloride. The impurities, moisture, ash, sour insoluble ash were detected based on Chinese Pharmacopoeia 2010 version (Vol I ). An HPLC method was also established for determination of trigonelline in the M. sativa seeds. The contents of impurities, moisture, ash, sour insoluble ash should not exceed 5%, 10%, 6%, and 2%, respectively. The content of trigonelline should be not less than 0.795 6 mg x g(-1). The experimental methods were accurate and reliable, and can be used as the quality control of the seeds of M. sativa. PMID- 24494574 TI - [Establishment of three-dimensional integrated "serum pharmacochemistry pharmacokinetics (pharmacodynamics)-systems biology" for research of traditional Chinese medicine prescription and its application in Yinchenhao Tang]. AB - Traditional Chinese medicine (TCM) prescription is a valuable asset for clinical medication, has multi-component and multi-target characteristics. However, due to the complex ingredients of prescription, the unclear mechanism, the lack of scientific data to support the dose-response relationship, it has become the bottleneck for the in-depth study for the process of modernization and internationalization of TCM. It requires the integration of Chinese medicine theory, modern analysis and data mining technology to build new research model for characteristic of TCM prescription. This paper provides an overview of TCM serum pharmacochemistry, pharmacokinetics (pharmacodynamics) and systems biology theory and practice, to establish the integrated three-dimensional "serum pharmacochemistry-pharmacokinetics (pharmacodynamics)-systems biology" for the research of TCM prescription to reveal the pharma-material basis and action mechanism and the compatibility scientific connotation, with a prescription Yinchenhao Tang as a case study. PMID- 24494575 TI - [Post-marketing clinical study of traditional Chinese medicine--lessons learned from comprehensive evaluation of Fufang Zaoren capsule]. AB - By comprehensive review and analysis of post-marketing clinical research on the efficacy and safety,we concluded that Fufang Zaoren capsule has certain therapeutic effects for insomnia, although current clinical research design needs improving. The post-marketing clinical studies also showed that it causes several adverse reactions at the recommended doses, such as chills, fever, dizziness, nausea, shortness of breath, chest tightness and palpitations, whereas high doses of Fufang Zaoren capsule can cause delayed extrapyramidal symptoms. Health Canada government website also prompted the L-tetrahydropalmatine in Fufang Zaoren capsule caused liver damage in pregnant women. The authors summarized the risk points, factors and risk control in the clinical use of Fufang Zaoren capsule and also present their perspective on the research status, existing problems and corresponding countermeasures in the post-marketing clinical re-evaluation of traditional Chinese medicine. PMID- 24494576 TI - [Endangered resources and origin changes of Pinellia ternate in Huanghuai plain]. AB - The wild Pinellia ternata resource was surveyed by field investigation, visiting surveys combine with literature study and changing factors of the wild P. ternata in the area of Huanghuai Plain were analyzed. The results indicated that Huanghuai Plain wild P. ternata resources were scarce and nearly extinct. The chemical farming methods in Huanghuai Plain have endangered the survival of the wild P. ternata. PMID- 24494577 TI - Inscribing the history of conflict--from Germany to Syria; Japan to Afghanistan. PMID- 24494578 TI - Dambusters: a personal view. PMID- 24494579 TI - Rethinking 'our common future': a physician's remarks 25 years after the release of 'Brundtland report'. PMID- 24494580 TI - Biosafety, biosecurity and internationally mandated regulatory regimes: compliance mechanisms for education and global health security. AB - This paper highlights the biosafety and biosecurity training obligations that three international regulatory regimes place upon states parties. The duty to report upon the existence of such provisions as evidence of compliance is discussed in relation to each regime. We argue that such mechanisms can be regarded as building blocks for the development and delivery of complementary biosafety and biosecurity teaching and training materials. We show that such building blocks represent foundations upon which life and associated scientists- through greater awareness of biosecurity concerns--can better fulfil their responsibilities to guard their work from misuse in the future. PMID- 24494582 TI - Simulated adhesion between realistic hydrocarbon materials: effects of composition, roughness, and contact point. AB - The work of adhesion is an interfacial materials property that is often extracted from atomic force microscope (AFM) measurements of the pull-off force for tips in contact with flat substrates. Such measurements rely on the use of continuum contact mechanics models, which ignore the atomic structure and contain other assumptions that can be challenging to justify from experiments alone. In this work, molecular dynamics is used to examine work of adhesion values obtained from simulations that mimic such AFM experiments and to examine variables that influence the calculated work of adhesion. Ultrastrong carbon-based materials, which are relevant to high-performance AFM and nano- and micromanufacturing applications, are considered. The three tips used in the simulations were composed of amorphous carbon terminated with hydrogen (a-C-H), and ultrananocrystalline diamond with and without hydrogen (UNCD-H and UNCD, respectively). The model substrate materials used were amorphous carbon with hydrogen termination (a-C-H) and without hydrogen (a-C); ultrananocrystalline diamond with (UNCD-H) and without hydrogen (UNCD); and the (111) face of single crystal diamond with (C(111)-H) and without a monolayer of hydrogen (C(111)). The a-C-H tip was found to have the lowest work of adhesion on all substrates examined, followed by the UNCD-H and then the UNCD tips. This trend is attributable to a combination of roughness on both the tip and sample, the degree of alignment of tip and substrate atoms, and the surface termination. Continuum estimates of the pull-off forces were approximately 2-5 times larger than the MD value for all but one tip-sample pair. PMID- 24494581 TI - Too good to be true? An assessment of health system progress in Afghanistan, 2002 2012. AB - The bold decision was taken in Afghanistan in 2002 to provide donor-funded public health services by means of contracting-out of predefined health care packages. This study seeks to identify the extent to which progress has been made in public health services provision in the context of broader state-building agendas. The article argues that the provision of public health services was also intended to generate a peace dividend and to legitimize the newly established government. The widely portrayed success of the contracting model is backed up by very high official figures for health service coverage. This contrasts with evidence at household level, which suggests limited utilization of public health services, and perceptions that these offer inferior quality, and a preference for private providers. The dissonance between these findings is striking and confirms that public health care cannot remain immune from powerful market forces, nor from contextual determinants outside the health field. PMID- 24494583 TI - Modeling metal stocks and flows: a review of dynamic material flow analysis methods. AB - Dynamic material flow analysis (MFA) is a frequently used method to assess past, present, and future stocks and flows of metals in the anthroposphere. Over the past fifteen years, dynamic MFA has contributed to increased knowledge about the quantities, qualities, and locations of metal-containing goods. This article presents a literature review of the methodologies applied in 60 dynamic MFAs of metals. The review is based on a standardized model description format, the ODD (overview, design concepts, details) protocol. We focus on giving a comprehensive overview of modeling approaches and structure them according to essential aspects, such as their treatment of material dissipation, spatial dimension of flows, or data uncertainty. The reviewed literature features similar basic modeling principles but very diverse extrapolation methods. Basic principles include the calculation of outflows of the in-use stock based on inflow or stock data and a lifetime distribution function. For extrapolating stocks and flows, authors apply constant, linear, exponential, and logistic models or approaches based on socioeconomic variables, such as regression models or the intensity-of use hypothesis. The consideration and treatment of further aspects, such as dissipation, spatial distribution, and data uncertainty, vary significantly and highly depends on the objectives of each study. PMID- 24494584 TI - The conformational stability of nonfibrillar amyloid-beta peptide oligomers critically depends on the C-terminal peptide length. AB - The amyloid-beta (Abeta) peptide is one key molecule in the pathogenesis of Alzheimer's disease. We investigated the conformational stability of a nonfibrillar tetrameric Abeta structure by molecular dynamics (MD) simulations revealing that the stability of the Abeta tetramer depends critically on the C terminal length. In contrast to the Abeta17-40 tetramer, which proved to be instable, the simulations demonstrate structural integrity of the Abeta17-42 and Abeta17-43 tetramers. These differences in stability can be attributed to an extension of the middle strand of a three-stranded antiparallel beta sheet through residues 41-43, only present in the longer Abeta species that aggregate faster and are more neurotoxic. Additional MD simulations demonstrate that this higher stability is also present in the monomers forming the tetramer. In conclusion, our findings suggest the existence of a nonfibrillar oligomer topology that is significantly more stable for the longer Abeta species, thus offering a structural explanation for their higher neurotoxicity. PMID- 24494585 TI - Kinetics of glycogen synthase kinase (GSK)3beta and phosphorylated GSK3beta (Ser 9) expression in experimentally induced periapical lesions. AB - AIM: To investigate the kinetics of GSK3beta and p-GSK3beta (Ser 9) expression in experimentally induced rat periapical lesions and to explore their possible functions in the pathogenesis of periapical lesions. METHODOLOGY: Periapical lesions were established in Wistar rats by occlusal pulp exposure in mandibular first molar teeth. The animals were killed on days 0, 7, 14, 21 and 28. Micro computed tomographic, histological and enzyme histochemical analyses were performed to detect the progression of periapical lesions. Immunohistochemistry, double-dye immunofluorescence and Western blot were performed to determine the expression of GSK3beta and p-GSK3beta (Ser 9) in periapical tissues. RESULTS: From day 0 to day 28, the lesion volume and area gradually expanded, and the GSK3beta-positive cells gradually ascended. A few p-GSK3beta (Ser 9)-positive cells and osteoclasts appeared on day 7 and then climaxed on day 14. The numbers then simultaneously decreased from day 21 to day 28. Western blot analysis revealed that p-GSK3beta (Ser 9) and GSK3beta proteins were expressed at all time points. The positive cells and protein expression ratio of p-GSK3beta (Ser 9) against GSK3beta increased from day 0 to day 14 and then decreased from day 14 to day 28. Finally, double-dye immunofluorescence assay revealed that p-GSK3beta (Ser 9)-positive and RANKL-positive cells were co-localized around periapical lesions on days 14 and 28. CONCLUSIONS: GSK3beta and p-GSK3beta (Ser 9) can be observed and may be involved in alveolar bone resorption and inflammatory response in periapical lesions, as well as associated with periapical lesion pathogenesis. PMID- 24494586 TI - Alternative splice forms of CTLA-4 induced by antisense mediated splice-switching influences autoimmune diabetes susceptibility in NOD mice. AB - Activated and regulatory T cells express the negative co-stimulatory molecule cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) that binds B7 on antigen presenting cells to mediate cellular responses. Single nucleotide polymorphisms in the CTLA-4 gene have been found to affect alternative splicing and are linked to autoimmune disease susceptibility or resistance. Increased expression of a soluble splice form (sCTLA-4), lacking the transmembrane domain encoded by exon 3, has been shown to accelerate autoimmune pathology. In contrast, an exon 2 deficient form lacking the B7 ligand binding domain (liCTLA-4), expressed by diabetes resistant mouse strains has been shown to be protective when expressed as a transgene in diabetes susceptible non-obese diabetic (NOD) mice. We sought to employ an antisense-targeted splice-switching approach to independently produce these CTLA-4 splice forms in NOD mouse T cells and observe their relative impact on spontaneous autoimmune diabetes susceptibility. In vitro antisense targeting of the splice acceptor site for exon 2 produced liCTLA-4 while targeting exon 3 produced the sCTLA-4 form in NOD T cells. The liCTLA-4 expressing T cells exhibited reduced activation, proliferation and increased adhesion to intercellular adhesion molecule-1 (ICAM-1) similar to treatment with agonist alpha-CTLA-4. Mice treated to produce liCTLA-4 at the time of elevated blood glucose levels exhibited a significant reduction in the incidence of insulitis and diabetes, whereas a marked increase in the incidence of both was observed in animals treated to produce sCTLA-4. These findings provide further support that alternative splice forms of CTLA-4 affects diabetes susceptibility in NOD mice and demonstrates the therapeutic utility of antisense mediated splice switching for modulating immune responses. PMID- 24494587 TI - Immune correlates of talactoferrin alfa in biopsied tumor of relapsed/refractory metastatic non-small cell lung cancer patients. AB - CONTEXT: Talactoferrin alfa (TLF) is a unique recombinant form of human lactoferrin. The hypothesized mechanism of action involves TLF binding to the intestinal endothelium inducing dendritic cell maturation and cytokine release leading to infiltration of tumor with monocytes and T-lymphocytes and inhibition of tumor growth. OBJECTIVE: Based on promising phase II trial results, this correlative study was undertaken to examine immune mechanism of action of TLF in metastatic non-small cell lung cancer (NSCLC) patients. METHODS: Talactoferrin was administered orally at 1.5 g bid weeks 1-12 with 2 weeks off on a 14-week cycle. Enrolled patients had a pathologic diagnosis of NSCLC previously treated with at least two lines of systemic treatment. Patients had core biopsy of tumor before initiation of talactoferrin and at week 7 on TLF. Flow cytometry and quantitative immunohistochemistry for immune correlates were performed on the biopsied specimens. RESULTS: Four patients with metastatic NSCLC were enrolled. The trial was halted pre-maturely in light of negative phase III trial results. For the two patients who had repeat on-treatment tumor biopsies, a consistent increase in monocytes as a percentage of total immune cells was observed. Otherwise, no clear trend of increase or decrease was observed in any other immune cell parameters compared to matched patient pre-treatment biopsies. CONCLUSION: Repeat biopsies for immune correlates by flow cytometry and quantitative immunohistochemistry in NSCLC patients are feasible. In the few patients sampled before trial closure, increased monocytes as a total percentage of the immune cell population within tumor was observed in response to TLF. PMID- 24494588 TI - Applying a palliative care approach in residential care: effects on nurse assistants' experiences of care provision and caring climate. AB - BACKGROUND: A palliative care approach aims to integrate psychosocial and existential as well as relationship aspects in the care and is an approach that can be used in residential care. Nurse assistants are the ones who are closest to the residents but have limited prerequisites for working in accordance with the palliative care approach. We aimed to investigate the effects on nurse assistants' experiences of care provision and the caring climate of an intervention applying a palliative care approach in residential care. METHODS: An intervention involving nurse assistants (n = 75) and their leaders (n = 9), in comparison with controls (n = 110), was evaluated using a questionnaire at three points in time. RESULTS: In the intervention group, positive effects were seen concerning the nurse assistants' reports of the care provision in that they focused more on the residents' stories about their lives and on communicating with the residents about what gave meaning to their lives. Also, negative effects were seen when the nurse assistants rated that the residents' needs for medical and nursing care had not been met at the facility directly after the intervention. No effects were seen concerning the caring climate or the prerequisites of providing more person-centred care. CONCLUSION: The intervention seemed to have encouraged the nurse assistants to focus on relationship aspects with the residents. So as not to jeopardise the NAs' well-being and to support NAs in keeping themselves involved in existential issues, their support most certainly needs to be continuous and ongoing. However, in spite of the leaders' involvement, the intervention was not sufficient for changing the organisational prerequisites for more person-centred care. PMID- 24494589 TI - Molecular rotors as conditionally fluorescent labels for rapid detection of biomolecular interactions. AB - We demonstrate the use of fluorescent molecular rotors as probes for detecting biomolecular interactions, specifically peptide-protein interactions. Molecular rotors undergo twisted intramolecular charge transfer upon irradiation, relax via the nonradiative torsional relaxation pathway, and have been typically used as viscosity probes. Their utility as a tool for detecting specific biomolecular interactions has not been explored. Using the well characterized p53-Mdm2 interaction as a model system, we designed a 9-(2-carboxy-2-cyanovinyl) julolidine-based p53 peptide reporter, JP1-R, which fluoresces conditionally only upon Mdm2 binding. The reporter was used in a rapid, homogeneous assay to screen a fragment library for antagonists of the p53-Mdm2 interaction, and several inhibitors were identified. Subsequent validation of these hits using established secondary assays suggests increased sensitivity afforded by JP1-R. The fluorescence of molecular rotors contingent upon target binding makes them a versatile tool for detecting specific biomolecular interactions. PMID- 24494590 TI - Management of patients with homozygous familial hypercholesterolemia. PMID- 24494591 TI - Longitudinal electrocardiographic evaluation of dogs with degenerative mitral valve disease. AB - BACKGROUND: Increased heart rate (HR) and decreased heart rate variability (HRV) are evident in some dogs with degenerative mitral valve disease (DMVD). OBJECTIVES: Evaluation of the factors influencing HR and HRV (assessed by the vasovagal tonus index; VVTI) and their change over time in dogs with DMVD. ANIMALS: Client-owned dogs (n = 257) with DMVD recruited from first opinion practice. METHODS: Prospective longitudinal follow-up at six-monthly intervals of dogs with DMVD. Dogs followed up for at least 18 months (n = 102) were grouped according to their outcome as dogs dying/euthanized because of cardiac disease (n = 28; Group 1), noncardiac disease (n = 40; Group 2) and dogs alive (n = 34; Group 3). HR and VVTI were measured on 1-minute ECG recordings. Repeated measures linear models were constructed to investigate the factors that influence HR and VVTI and their changes over time. RESULTS: Heart rate and VVTI were affected by disease severity and were different in Cavaliers compared to other breeds. Group 1 and Group 2 dogs underwent an increase in HR and decrease in VVTI, evident at least 18 months before death. Group 1 had a further decrease in VVTI followed by an increase in HR approximately 1 year and 6 months before death, respectively. CONCLUSIONS AND CLINICAL IMPORTANCE: Dogs with DMVD have an increase in HR and decrease in HRV over a year before death, with greater changes in those dogs dying/euthanized because of cardiac disease. Both HR and VVTI can potentially be regarded as biomarkers for all-cause mortality. PMID- 24494592 TI - Methods for the discovery of new anti-aging products--targeted approaches. AB - INTRODUCTION: Aging is considered to be one of the most complicated and heterogeneous phenomena and is the main risk factor for most chronic diseases, disabilities and declining health. Aging cells cease to divide and drive the progression of illness through various pathways. Over the years, a number of anti aging medicines of natural and synthetic origin have been introduced. Indeed, some studies have identified senescent cells as potential therapeutic targets in the treatment of aging and age-related diseases. AREAS COVERED: In this review, the authors highlight and critically review the possible mechanisms of the aging process and related illnesses. The authors give particular attention to illnesses, including Alzheimer's disease, Parkinson's disease, skin aging and cardiovascular diseases. EXPERT OPINION: Several reports have highlighted that mitochondria are a key factor in the progression of aging and neurodegenerative illnesses. This is due to their production of extra amounts of reactive oxygen species, which leads into progressive caspase-dependent apoptosis and cell death. Therefore, strategies to prevent/reduce oxidative stress-mediated aging, whether environmental, nutritional and pharmacological, need to be taken into account. Presently, Drosophila melanogaster and Caenorhabditis elegans, which focus on the evolutionary and genetic foundations of aging, have helped to establish the screening of several synthetic and natural compounds with large cohorts in a quick manner. However, there is yet to be any efficient experimental evidence to prove the exact role of senescent cells in age-related dysfunction and further studies are required to better understand these processes. PMID- 24494593 TI - Impact of baseline patient characteristics on interventions to reduce diabetes distress: the role of personal conscientiousness and diabetes self-efficacy. AB - AIMS: To improve patient-centred care by determining the impact of baseline levels of conscientiousness and diabetes self-efficacy on the outcomes of efficacious interventions to reduce diabetes distress and improve disease management. METHODS: Adults with Type 2 diabetes with diabetes distress and self care problems (N = 392) were randomized to one of three distress reduction interventions: computer-assisted self-management; computer-assisted self management plus problem-solving therapy; and health education. The baseline assessment included conscientiousness and self-efficacy, demographics, diabetes status, regimen distress, emotional burden, medication adherence, diet and physical activity. Changes in regimen distress, emotional burden and self-care between baseline and 12 months were recorded and ancova models assessed how conscientiousness and self-efficacy qualified the significant improvements in distress and management outcomes. RESULTS: Participants with high baseline conscientiousness displayed significantly larger improvements in medication adherence and emotional burden than participants with low baseline conscientiousness. Participants with high baseline self-efficacy showed greater improvements in diet, physical activity and regimen distress than participants with low baseline self-efficacy. The impact of conscientiousness and self efficacy were independent of each other and occurred across all three intervention groups. A significant interaction indicated that those with both high self-efficacy and high conscientiousness at baseline had the biggest improvement in physical activity by 12 months. CONCLUSIONS: Both broad personal traits and disease-specific expectations qualify the outcomes of efficacious interventions. These findings reinforce the need to change from a one-size-fits all approach to diabetes interventions to an approach that crafts clinical interventions in ways that fit the personal traits and skills of individual people. PMID- 24494594 TI - An alternative time for telling: when conceptual instruction prior to problem solving improves mathematical knowledge. AB - BACKGROUND: The sequencing of learning materials greatly influences the knowledge that learners construct. Recently, learning theorists have focused on the sequencing of instruction in relation to solving related problems. The general consensus suggests explicit instruction should be provided; however, when to provide instruction remains unclear. AIMS: We tested the impact of conceptual instruction preceding or following mathematics problem solving to determine when conceptual instruction should or should not be delayed. We also examined the learning processes supported to inform theories of learning more broadly. SAMPLE: We worked with 122 second- and third-grade children. METHOD: In a randomized experiment, children received instruction on the concept of math equivalence either before or after being asked to solve and explain challenging equivalence problems with feedback. RESULTS: Providing conceptual instruction first resulted in greater procedural knowledge and conceptual knowledge of equation structures than delaying instruction until after problem solving. Prior conceptual instruction enhanced problem solving by increasing the quality of explanations and attempted procedures. CONCLUSIONS: Providing conceptual instruction prior to problem solving was the more effective sequencing of activities than the reverse. We compare these results with previous, contrasting findings to outline a potential framework for understanding when instruction should or should not be delayed. PMID- 24494595 TI - The interaction of a histidine-rich protein hpn with the membrane mimics: implications for pathologic roles of Hpn in Helicobacter pylori. AB - BACKGROUND: Hpn is a small histidine-rich protein in Helicobacter pylori. This protein has been shown to play roles in nickel storage and detoxification and to exhibit cytotoxicity to gastric epithelial cells. Hpn can be secreted outside of the bacterium and forms amyloid-like structures. OBJECTIVE: To study the interactions between Hpn and membrane mimics, which may further our understanding of the pathologic roles of this bacterium. METHODS: Various biochemical and biophysical methods, such as secondary structure determination be CD, calcein release assay with fluorescence spectrometry, and Laurdan and Prodan generalized polarization determination have been used to characterize the interaction between Hpn and membrane mimics. RESULTS: Membrane mimics induced the formation of alpha helix in Hpn. The interaction disrupts the integrity of the membrane mimics and leads to the release of inner calcein probe. The experiments involving the Laurdan and Prodan fluorescence indicated that increasing the total protein/lipid ratio leads to a less ordered and more hydrated lipid membrane structure close to the water/lipid interface of lipid bilayers modeling the mitochondrial inner membrane. CONCLUSION: The present data indicated that Hpn may take part in the pathological roles of Helicobacter pylori through membrane interactions. PMID- 24494596 TI - Electrochemical study of astaxanthin and astaxanthin n-octanoic monoester and diester: tendency to form radicals. AB - The carotenoid astaxanthin known for its powerful antioxidant activity was electrochemically investigated along with the synthesized astaxanthin n-octanoic monoester and astaxanthin n-octanoic diester. Cyclic voltammograms (CVs) revealed a two-electron transfer oxidation for all three carotenoids with a difference in the two oxidation potentials (DeltaE = E2(0) - E1(0)) slightly increasing from astaxanthin to the monoester to diester. Minimal or no exposure to water prevented the formation of carotenoid neutral radicals from dications and radical cations, causing near absence of the fifth peak in the CVs. This makes the CVs almost reversible and enables a more precise simulation of the redox potentials and the equilibrium constants for the formation of radical cations. The first oxidation potential (E1(0)) of 0.7678, 0.7738, and 0.7753 V versus SCE and the second oxidation potential (E2(0)) of 0.9828, 0.9931, and 0.9966 V versus SCE for astaxanthin, monoester, and diester, respectively, have been standardized to the potential of ferrocene of 0.528 V vs SCE given in a previous study. Reduction potentials (E3(0)) for formation of carotenoid neutral radicals from dications after proton loss from the three studied carotenoids are presented and compared to those of other carotenoids. According to our DFT calculations, the most favorable sites for deprotonation of radical cations and dications are found on the cyclohexene rings. These measurements provide insight into important properties of these carotenoids like radical scavenging of (*)OH, (*)CH3, and (*)OOH by proton abstraction from the carotenoid or the formation of carotenoid neutral radicals from radical cations which can quench photoexcited states. There is no essential difference in first oxidation potentials for the three carotenoids, which suggests a similar scavenging rate of the esters of astaxanthin toward (*)OH, (*)CH3, and (*)OOH radicals when compared to astaxanthin itself. The large equilibrium constants K(com) (102.4, 409.6, and 204.8 for astaxanthin, monoester, and diester) derived from simulation indicate a preference for radical cation formation for both astaxanthin and its esters, while electron transfer to form dications will be unlikely. Proton transfer from the radical cations, which are weak acids, to the neighboring proton acceptors will form neutral radicals, which allows quenching of excited states. PMID- 24494597 TI - General approach to the synthesis of the chlorosulfolipids danicalipin A, mytilipin A, and malhamensilipin A in enantioenriched form. AB - A second-generation synthesis of three structurally related chlorosulfolipids has been developed. Key advances include highly stereocontrolled additions to alpha,beta-dichloroaldehydes, kinetic resolutions of complex chlorinated vinyl epoxide intermediates, and Z-selective alkene cross metatheses of cis-vinyl epoxides. This strategy facilitated the synthesis of enantioenriched danicalipin A, mytilipin A, and malhamensilipin A in nine, eight, and 11 steps, respectively. PMID- 24494599 TI - Male mealworm beetles increase resting metabolic rate under terminal investment. AB - Harmful parasite infestation can cause energetically costly behavioural and immunological responses, with the potential to reduce host fitness and survival. It has been hypothesized that the energetic costs of infection cause resting metabolic rate (RMR) to increase. Furthermore, under terminal investment theory, individuals exposed to pathogens should allocate resources to current reproduction when life expectancy is reduced, instead of concentrating resources on an immune defence. In this study, we activated the immune system of Tenebrio molitor males via insertion of nylon monofilament, conducted female preference tests to estimate attractiveness of male odours and assessed RMR and mortality. We found that attractiveness of males coincided with significant down-regulation of their encapsulation response against a parasite-like intruder. Activation of the immune system increased RMR only in males with heightened odour attractiveness and that later suffered higher mortality rates. The results suggest a link between high RMR and mortality and support terminal investment theory in T. molitor. PMID- 24494598 TI - Deletion of the Kv2.1 delayed rectifier potassium channel leads to neuronal and behavioral hyperexcitability. AB - The Kv2.1 delayed rectifier potassium channel exhibits high-level expression in both principal and inhibitory neurons throughout the central nervous system, including prominent expression in hippocampal neurons. Studies of in vitro preparations suggest that Kv2.1 is a key yet conditional regulator of intrinsic neuronal excitability, mediated by changes in Kv2.1 expression, localization and function via activity-dependent regulation of Kv2.1 phosphorylation. Here we identify neurological and behavioral deficits in mutant (Kv2.1(-/-) ) mice lacking this channel. Kv2.1(-/-) mice have grossly normal characteristics. No impairment in vision or motor coordination was apparent, although Kv2.1(-/-) mice exhibit reduced body weight. The anatomic structure and expression of related Kv channels in the brains of Kv2.1(-/-) mice appear unchanged. Delayed rectifier potassium current is diminished in hippocampal neurons cultured from Kv2.1(-/-) animals. Field recordings from hippocampal slices of Kv2.1(-/-) mice reveal hyperexcitability in response to the convulsant bicuculline, and epileptiform activity in response to stimulation. In Kv2.1(-/-) mice, long-term potentiation at the Schaffer collateral - CA1 synapse is decreased. Kv2.1(-/-) mice are strikingly hyperactive, and exhibit defects in spatial learning, failing to improve performance in a Morris Water Maze task. Kv2.1(-/-) mice are hypersensitive to the effects of the convulsants flurothyl and pilocarpine, consistent with a role for Kv2.1 as a conditional suppressor of neuronal activity. Although not prone to spontaneous seizures, Kv2.1(-/-) mice exhibit accelerated seizure progression. Together, these findings suggest homeostatic suppression of elevated neuronal activity by Kv2.1 plays a central role in regulating neuronal network function. PMID- 24494600 TI - Inhibition of glucosylceramide synthase stimulates autophagy flux in neurons. AB - Aggregate-prone mutant proteins, such as alpha-synuclein and huntingtin, play a prominent role in the pathogenesis of various neurodegenerative disorders; thus, it has been hypothesized that reducing the aggregate-prone proteins may be a beneficial therapeutic strategy for these neurodegenerative disorders. Here, we identified two previously described glucosylceramide (GlcCer) synthase inhibitors, DL-threo-1-Phenyl-2-palmitoylamino-3-morpholino-1-propanol and Genz 123346(Genz), as enhancers of autophagy flux. We also demonstrate that GlcCer synthase inhibitors exert their effects on autophagy by inhibiting AKT-mammalian target of rapamycin (mTOR) signaling. More importantly, siRNA knock down of GlcCer synthase had the similar effect as pharmacological inhibition, confirming the on-target effect. In addition, we discovered that inhibition of GlcCer synthase increased the number and size of lysosomal/late endosomal structures. Although inhibition of GlcCer synthase decreases levels of mutant alpha-synuclein in neurons, it does so, according to our data, through autophagy-independent mechanisms. Our findings demonstrate a direct link between glycosphingolipid biosynthesis and autophagy in primary neurons, which may represent a novel pathway with potential therapeutic value for the treatment of Parkinson's disease. Inhibition of GlcCer synthase enhances autophagy by inhibiting AKT-mTOR signaling, and increases the number and size of lysosomal/late endosomal structures. Furthermore, inhibition of GlcCer synthase decreased levels of mutant alpha-synuclein in neurons, which may represent a potential therapeutic target for Parkinson's disease. PMID- 24494601 TI - Electroejaculation increases low molecular weight proteins in seminal plasma modifying sperm quality in Corriedale rams. AB - This study was conducted to evaluate the effect of seminal collection method (artificial vagina or electroejaculation) on the protein composition of seminal plasma and sperm quality parameters in Corriedale rams. To address this question, we assessed the effect of seminal collection method on motility, plasma membrane integrity and functionality, mitochondrial functionality and the decondensation state of nuclear chromatin in sperm cells. Volume, pH, osmolarity, protein concentration, total protein content and protein profile using sodium dodecyl sulphate-polyacrylamide gel electrophoresis (SDS-PAGE) and 2-D polyacrylamide electrophoresis of seminal plasma collected with artificial vagina and electroejaculation were also analysed. The main findings from this study were that ejaculates obtained with electroejaculation had (i) a higher number of spermatozoa with intact plasma membrane and functional mitochondria and (ii) a higher proportion of seminal plasma, total protein content and relative abundance of low molecular weight proteins than ejaculates obtained with artificial vagina. Five of these proteins were identified by mass spectrometry: binder of sperm 5 precursor; RSVP14; RSVP22; epididymal secretory protein E1 and clusterin. One protein spot with molecular weight of approximately 31 kDa and isoelectric point of 4.8 was only found in the seminal plasma from electroejaculation. PMID- 24494602 TI - Effectiveness of artesunate-amodiaquine vs. artemether-lumefantrine for the treatment of uncomplicated falciparum malaria in Nanoro, Burkina Faso: a non inferiority randomised trial. AB - OBJECTIVES: Artemisinin-based combination therapies (ACTs) are essential for the effective control of falciparum malaria in endemic countries. However, in most countries, such choice has been carried out without knowing their effectiveness when deployed in real-life conditions, that is, when treatment is not directly observed. We report here the results of a study assessing the effectiveness of the two ACTs currently recommended in Burkina Faso for the treatment of uncomplicated malaria, that is, artemether-lumefantrine (AL) and artesunate amodiaquine (ASAQ). METHODS: Between September 2008 and January 2010, 340 children were randomised to one of the two study arms and followed up for 42 days. Treatment was administered according to routine practices, that is, the first dose was given by study nurses who explained to the parent/guardian how to administer the other doses at home during the following 2 days. RESULTS: The results showed a significantly higher unadjusted adequate clinical and parasitological response in the ASAQ (58.4%) than in the AL arm (46.1%) at day 28 but these trends were similar after correction with PCR data (ASAQ (89.7%) and AL (89.8%)). New infections started to appear after day 14, first in the AL and then in the ASAQ arm but at day 42 day of follow-up we observed no difference in the occurrence of recrudescent infection. CONCLUSION: Despite a lower cure rate than those reported in efficacy studies in which the treatment administration was directly observed, both AL and ASAQ can still be used for the treatment of uncomplicated malaria in Burkina Faso. PMID- 24494603 TI - Oral mucosal lesions: findings from the Australian National Survey of Adult Oral Health. AB - BACKGROUND: The prevalence of oral mucosal lesions (OMLs) and factors associated with these has not previously been reported in the Australian population. This study aimed to report on the prevalence of OMLs in Australian adults and to evaluate their association with socio-demographic factors. METHODS: This study utilized data from the Australian National Survey of Adult Oral Health 2004-06, which employs a multi-stage, stratified random sample selection procedure. Information on socio-demographics, smoking and presence of OMLs were collected using telephone interview, self-reported questionnaires and comprehensive oral examination. A multivariate regression model was generated to estimate effect of factors on the prevalence of non-ulcerated OMLs. RESULTS: A total of 3551 dentate adult Australians had complete data for this analysis. Over 20% of study participants presented with an OML on the day of examination. The prevalence of suspected malignancy was less than 1% and over 17% for non-ulcerated OMLs. Prevalence of non-ulcerated OMLs was associated with age, gender, residential location, household income and smoking. CONCLUSIONS: The study reported that epidemiological survey can provide useful information on OMLs. Certain population groups had a higher risk of having the condition. Preventing smoking uptake and smoking cessation can reduce the prevalence of OMLs in the population. PMID- 24494604 TI - Suicide risk among lesbian, gay, bisexual, and transgender military personnel and veterans: what does the literature tell us? AB - Research suggests that both the military and veteran and the lesbian, gay, bisexual, and transgender (LGBT) populations may be at increased risk for suicide. A literature review was conducted to identify research related to suicide risk in the LGBT military and veteran populations. Despite the paucity of research directly addressing this issue, themes are discussed evident in the literature on LGBT identity and suicide risk as well as LGBT military service members and veterans. Factors such as social support and victimization appear to be particularly relevant. Suggestions are made with respect to future research that is needed on this very important and timely topic. PMID- 24494605 TI - Fear of childbirth in nulliparous and multiparous women: a population-based analysis of all singleton births in Finland in 1997-2010. AB - OBJECTIVE: To identify risk factors for fear of childbirth (FOC) according to parity and socioeconomic status, and to evaluate associations between FOC and adverse perinatal outcomes. DESIGN: A cohort study. SETTING: The Finnish Medical Birth Register. POPULATION: All 788 317 singleton births during 1997-2010 in Finland. METHODS: Fear of childbirth was defined according to the International Classification of Diseases code O99.80, and its associations with several risk factors and perinatal outcomes were analysed by multivariable logistic regression. MAIN OUTCOME MEASURES: Prevalence of, risk factors for and outcomes of FOC. RESULTS: Fear of childbirth was experienced by 2.5% of nulliparous women and 4.5% of multiparous women. The strongest risk factors for FOC in nulliparous women were depression [adjusted odds ratio (aOR), 6.35; 95% confidence interval (CI), 5.25-7.68], advanced maternal age (aOR, 3.78; 95% CI, 3.23-4.42) and high or unspecified socioeconomic status. In multiparous women, the strongest risk factors for FOC were depression (aOR, 5.47; 95% CI, 4.67-6.41), previous caesarean section (CS) (aOR, 3.02; 95% CI, 2.93-3.11) and high or unspecified socioeconomic status. Among both nulliparous and multiparous women, FOC was associated with higher rates of CS (3.3-fold and 4.5-fold higher, respectively) and a lower incidence of low birthweight (<2500 g), small for gestational age babies, preterm birth and low Apgar scores at 1 minute. CONCLUSIONS: High and unspecified socioeconomic status, advanced maternal age and depression are predisposing factors for FOC regardless of parity. Among multiparous women, a previous CS increases vulnerability to FOC. FOC is associated with increased rates of CS, but does not adversely affect other pregnancy outcomes. PMID- 24494606 TI - The role of dose reduction with NSAID use. AB - Effective pain relief with use of nonsteroidal anti-inflammatory drugs (NSAIDs) may come at the cost of an increased risk for serious cardiovascular (CV), gastrointestinal (GI), and renal complications. Research has shown that these adverse events are more likely to occur with higher NSAID dosing and in individuals with a preexisting risk for CV and GI complications. To minimize the potential risk for an adverse event, numerous regulatory bodies and medical societies recommend using the lowest effective NSAID dose for the shortest time necessary. One potential strategy is to offer patients lower doses of standard NSAID formulations. However, efforts to modify physician prescribing behavior may be challenging because of concerns regarding the potential for suboptimal pain management. Another strategy has emerged through use of new technology that produces submicron NSAID formulations. This new technology is also an approach that could provide effective pain relief at low doses. This article reviews the role of dose and duration in the risk for NSAID-associated adverse events, and discusses the potential benefits associated with new low-dose submicron NSAID formulations. PMID- 24494608 TI - An overview of pain management: the clinical efficacy and value of treatment. AB - Appropriate treatment of pain requires an understanding of the characteristics of pain, including the severity and the nature of the pain-for example, acute versus chronic pain or nociceptive versus neuropathic pain. Appropriate treatment requires an understanding of the efficacies of the available agents in different pain models, and their adverse events, to best match them to the type of pain. While numerous classes of drugs are used to treat pain, 3 categories in particular-acetaminophen, nonsteroidal anti-inflammatory drugs (NSAIDs), and opioids-are most often used for the treatment of pain, along with adjuvants (eg, muscle relaxants, anticonvulsants). Each of these drugs is associated with different adverse events and with varying degrees of efficacy. In general, acetaminophen is the least potent, while NSAIDs and opioids offer stronger analgesic effects. At the same time, acetaminophen use can cause acute liver failure, and NSAIDs are associated with serious complications impacting the gastrointestinal, cardiovascular, and renal systems. Opioids can cause cognitive deficiency, motor impairment, and respiratory depression, among other problems; they also represent a significant addiction risk in certain groups of patients. This article reviews the safety and efficacy of NSAIDs relative to other therapeutic agents in the treatment of 4 common types of pain, summarizes clinical treatment guidelines in these types of pain, and compares the relative roles of NSAIDs, acetaminophen, and opioids in treating pain. PMID- 24494609 TI - Quantifying the impact of NSAID-associated adverse events. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely used among patients experiencing many different types of pain, including inflammatory, acute pain (eg, injury, low back pain, headache, postoperative pain), and chronic pain (eg, rheumatoid arthritis, osteoarthritis). However, both traditional NSAIDs and second-generation NSAIDs (cyclooxygenase-2 inhibitors) can lead to very expensive and serious adverse events. Gastrointestinal, cardiovascular, and renal complications associated with NSAIDs have been shown to be dose-dependent. In 2005, to help minimize these risks, the US Food and Drug Administration issued a public health advisory stating that "NSAIDs should be administered at the lowest effective dose for the shortest duration consistent with individual patient treatment goals." This article reviews the undue clinical and economic burden associated with NSAID-related serious adverse events. PMID- 24494610 TI - Translating clinical guidelines into practice: the effective and appropriate use of human growth hormone. AB - There are 9 recombinant human growth hormone (rhGH) products currently available for 10 US Food and Drug Administration-approved indications; each rhGH product is approved for 1 or more indications. Adult and pediatric patients with the various conditions for which rhGH is indicated, from idiopathic short stature (ISS) and growth hormone (GH) deficiency to short bowel syndrome and HIV/AIDS wasting, may benefit from rhGH treatment. In clinical practice, pediatric patients with GH deficiency or ISS make up the majority of the population receiving treatment with rhGH. Most rhGH products are provided through specialty pharmacies that often have to balance the needs of the patient, their own utilization objectives, and the availability of the rhGH on formulary from a particular payer. Often, a payer will prefer only 2 or 3 rhGH products to cover all 10 indications. As such, managed care professionals need to be more informed about the options available and should be familiar with the different indications to help educate patients about treatment. Additionally, healthcare providers should endeavor to identify and manage the care of appropriate patients who would potentially benefit from rhGH therapy, and should be aware of formulary options. Because many of the patients are children and young adults, adherence to treatment is a concern; patient education on the importance of treatment adherence should be ongoing. Various mechanisms are in place (eg, prior authorization requirements and case manager follow-up) to help ensure that rhGH products are used, and used appropriately. This publication includes highlights from a roundtable discussion by key opinion leaders (clinicians and managed care professionals) on how managed care policies and clinical guidelines on appropriate use of rhGH translate into real-world practice. Also discussed are the efficacy and safety of rhGH therapy for its pediatric indications, and the role of specialty pharmacies in managing patient access to therapy. PMID- 24494611 TI - Clinically relevant interactions between newer antidepressants and second generation antipsychotics. AB - INTRODUCTION: Combinations of newer antidepressants and second-generation antipsychotics (SGAs) are frequently used by clinicians. Pharmacokinetic drug interaction (PK DI) and poorly understood pharmacodynamic (PD) drug interaction (PD DI) can occur between them. AREAS COVERED: This paper comprehensively reviews PD DI and PK DI studies. EXPERT OPINION: More PK DI studies are needed to better establish dose correction factors after adding fluoxetine and paroxetine to aripiprazole, iloperidone and risperidone. Further PK DI studies and case reports are also needed to better establish the need for dose correction factors after adding i) fluoxetine to clozapine, lurasidone, quetiapine and olanzapine; ii) paroxetine to olanzapine; iii) fluvoxamine to asenapine, aripiprazole, iloperidone, lurasidone, olanzapine, quetiapine and risperidone; iv) high sertraline doses to aripiprazole, clozapine, iloperidone and risperidone: v) bupropion and duloxetine to aripiprazole, clozapine, iloperidone and risperidone; and vi) asenapine to paroxetine and venlafaxine. Possible beneficial PD DI effects occur after adding SGAs to newer antidepressants for treatment-resistant major depressive and obsessive-compulsive disorders. The lack of studies combining newer antidepressants and SGAs in psychotic depression is worrisome. PD DIs between newer antidepressants and SGAs may be more likely for mirtazapine and bupropion. Adding selective serotonin reuptake inhibitors and SGAs may increase QTc interval and may very rarely contribute to torsades de pointes. PMID- 24494612 TI - The cognitive domain of a glider in the game of life. AB - This article examines in some technical detail the application of Maturana and Varela's biology of cognition to a simple concrete model: a glider in the game of Life cellular automaton. By adopting an autopoietic perspective on a glider, the set of possible perturbations to it can be divided into destructive and nondestructive subsets. From a glider's reaction to each nondestructive perturbation, its cognitive domain is then mapped. In addition, the structure of a glider's possible knowledge of its immediate environment, and the way in which that knowledge is grounded in its constitution, are fully described. The notion of structural coupling is then explored by characterizing the paths of mutual perturbation that a glider and its environment can undergo. Finally, a simple example of a communicative interaction between two gliders is given. The article concludes with a discussion of the potential implications of this analysis for the enactive approach to cognition. PMID- 24494613 TI - Institutions and cooperation in an ecology of games. AB - Social dilemmas have long been studied formally as cooperation games that pit individual gains against those of the group. In the real world, individuals face an ecology of games where they play many such games simultaneously, often with overlapping co-players. Here, we study an agent-based model of an ecology of public goods games and compare the effectiveness of two institutional mechanisms for promoting cooperation: a simple institution of limited group size (capacity constraints) and a reputational institution based on observed behavior. Reputation is shown to allow much higher relative payoffs for cooperators than do capacity constraints, but only if (1) the rate of reputational information flow is fast enough relative to the rate of social mobility, and (2) cooperators are relatively common in the population. When these conditions are not met, capacity constraints are more effective at protecting the interests of cooperators. Because of the simplicity of the limited-group-size rule, capacity constraints can also generate social organization, which promotes cooperation much more quickly than can reputation. Our results are discussed in terms of both normative prescriptions and evolutionary theory regarding institutions that regulate cooperation. More broadly, the ecology-of-games approach developed here provides an adaptable modeling framework for studying a wide variety of problems in the social sciences. PMID- 24494614 TI - Statistical thermodynamics concepts and mathematical tools for a multi-agent ecosystem. AB - Finding the distribution of systems over their possible states is a mathematical problem. One possible solution is the method of the most probable distribution developed by Boltzmann. This method has been instrumental in developing statistical mechanics and explaining the origin of many thermodynamics concepts, like entropy or temperature, but is also applicable in many other fields like ecology or economics. Artificial ecosystems have many features in common with ecological or economic systems, but surprisingly the method does not appear to have been very successful in this field of application. The hypothesis of this article is that this failure is due to the incorrect interpretation of the method's concepts and mathematical tools. We propose to review and reinterpret the method so that it can be correctly applied and all its potential exploited in order to study and characterize the global behavior of an artificial multi-agent ecosystem. PMID- 24494615 TI - Results on the convergence of Braitenberg vehicle 3a. AB - Braitenberg vehicles are well-known models of animal behavior used as steering mechanisms in mobile robotics and artificial life. Because of their simplicity, they are mainly used for teaching robotics, while the lack of a quantitative theory has limited their use for research purposes. This article contributes to our formal understanding of Braitenberg vehicle 3a by presenting the convergence properties of its trajectories under parabolic-shaped stimuli. We show previously unreported features of the motion of the vehicle: the conditional stability, the oscillatory behavior, and the existence of periodic trajectories. The mathematical model used provides a theoretical relation between the environment, the internal control mechanism of the vehicle, and some morphological parameters, a link already found in experimental works. This work provides theoretical support for experimental research using Braitenberg vehicle 3a, and paves the way for further research in biology, robotics, and artificial life. PMID- 24494616 TI - The practice of agent-based model visualization. AB - We discuss approaches to agent-based model visualization. Agent-based modeling has its own requirements for visualization, some shared with other forms of simulation software, and some unique to this approach. In particular, agent-based models are typified by complexity, dynamism, nonequilibrium and transient behavior, heterogeneity, and a researcher's interest in both individual- and aggregate-level behavior. These are all traits requiring careful consideration in the design, experimentation, and communication of results. In the case of all but final communication for dissemination, researchers may not make their visualizations public. Hence, the knowledge of how to visualize during these earlier stages is unavailable to the research community in a readily accessible form. Here we explore means by which all phases of agent-based modeling can benefit from visualization, and we provide examples from the available literature and online sources to illustrate key stages and techniques. PMID- 24494617 TI - Multifunctional nucleic acids for tumor cell treatment. AB - We report on a multifunctional nucleic acid, termed AptamiR, composed of an aptamer domain and an antimiR domain. This composition mediates cell specific delivery of antimiR molecules for silencing of endogenous micro RNA. The introduced multifunctional molecule preserves cell targeting, anti-proliferative and antimiR function in one 37-nucleotide nucleic acid molecule. It inhibits cancer cell growth and induces gene expression that is pathologically damped by an oncomir. These findings will have a strong impact on future developments regarding aptamer- and antimiR-related applications for tumor targeting and treatment. PMID- 24494618 TI - Multiple sclerosis update. AB - Multiple sclerosis (MS) is a chronic but incurable disease of the central nervous system (CNS) that is often diagnosed in the second or third decade of life. It is more common among women than men, significantly impairs patient quality of life, and is associated with substantial costs to patients, healthcare systems, and society. Of the approximately 2.3 million individuals worldwide that have MS, more than 400,000 reside in the United States. Although the etiology of MS is not completely understood, a great deal of evidence suggests a complex relationship between environmental and genetic factors. The pathophysiology of MS involves an aberrant attack by the host immune system on oligodendrocytes, which synthesize and maintain myelin sheaths in the CNS. There are 4 identified disease courses in MS, and approximately 85% of people with MS present with relapsing-remitting MS, which is characterized by discrete acute attacks followed by periods of remission. Signs and symptoms of MS are dependent on the demyelinated area(s) of the CNS and often involve sensory disturbances, limb weakness, fatigue, and increased body temperature. The criteria for a diagnosis of MS include evidence of damage in at least 2 separate areas of the CNS, evidence that the damage occurred at different time points, and the ruling out of other possible diagnoses. Diseasemodifying drugs (DMDs) that reduce the frequency of relapses, development of brain lesions, and progression of disability are the standard of care for relapsing forms of MS, and the use of DMDs should be initiated as early as possible. PMID- 24494619 TI - Management of multiple sclerosis. AB - Patients with multiple sclerosis (MS), a disease of the central nervous system that disrupts signals within the brain and also the signals between the brain and body, will likely experience symptoms that may negatively impact their quality of life (QOL). Due to the complexity of MS and its disease burden, multidisciplinary management that combines pharmacologic and nonpharmacologic strategies with patient education is necessary. Diagnosing relapses of MS in clinical practice can be difficult due to the multiple subtypes of MS, variations of symptomatology, and pseudo-relapses. Managing relapses also presents its own set of challenges, for example, evaluating if treatment is appropriate and determining which agent would be most effective for a patient if treatment is recommended. Patient education is essential for achieving optimal outcomes for patients with MS and improving patient QOL, and should increase awareness of: (1) the disease itself and its progression; (2) the signs and symptoms of MS; (3) current treatment strategies and plan of care; (4) the recognition and management of relapses; (5) the value of treatment adherence and impact of nonadherence; and (6) hope for the future. The management of active MS may be further complicated by the complex variety of pharmacotherapeutic options, and in some instances, by having to switch between agents and drug classes. Newer agents in development (eg, alemtuzumab, ocrelizumab, laquinimod) offer the opportunity to expand the therapeutic armamentarium, although further long-term data are required to evaluate any safety concerns associated with newer agents. PMID- 24494620 TI - Managed care aspects of managing multiple sclerosis. AB - Multiple sclerosis (MS) is a chronic disease of the central nervous system usually diagnosed in the second or third decade of life; MS is more common among women than men by a ratio of 3 to 1. With its relatively early age of onset and symptoms that impair patients' quality of life, MS requires lifelong, dynamic treatment, and places a substantial economic burden on individuals, healthcare systems, and society. The costs associated with providing benefits for MS therapy are growing rapidly and the increasing complexity of the MS market is impacting disease management for payers. Employers are also increasingly aware of the costs associated with MS and are asking health plans to advise on the most appropriate and cost-effective ways to manage both pharmacologic and non-pharmacologic therapies for MS. Health plans, by necessity, must therefore balance appropriate access to treatments for MS with the need to manage rising treatment costs. To meet this goal, payers require population-based solutions, guidelines, and treatment algorithms for the management of MS that can be used in clinical and formulary management decision making in the context of an evolving therapeutic landscape. Further, comparative studies are necessary for payers to determine which agents may work best on a population basis. Due to the current lack of appropriate clinical guidance and insufficient head-to-head data on disease modifying drugs, strategies for health plans and clinical management have been designed using the best available evidence. Undoubtedly, management of this class will continue to evolve with the launch of newer agents. PMID- 24494621 TI - Size limit on the formation of periodic mesoporous organosilicas (PMOs). AB - The decrease of the lattice size of periodic mesoporous organosilicas (PMOs) is one important goal in obtaining a microporous material for storage or adsorption of small molecules. To determine the influence of different synthesis parameters in the lattice size, here we performed in situ small-angle X-ray diffraction studies and show that a variation of the surfactant's headgroup size is not directly followed by the lattice parameter of the resulting structure. We show that in the surfactant series of penta-, hexa-, hepta-, octa-, nona-, and decaethylene glycol monododecyl ether (C12(EO)n, n = 5, 6, 7, 8, 9, 10) the lattice size decreases between n = 5 and n = 8 and then increases, while the ordering of the materials is always cubic (space group Fd3m). This size effect is due to the ethylene oxide (EO) chain conformation that changes as the number of EO groups increases. Short ethylene oxide chains tend to have a so-called "zigzag" conformation while an increase of the chain length leads to a "Maander" (coiling) conformation. Although this phenomenon is most commonly observed for chains consisting of more than 10 ethylene oxide units, we found a minimum PMO lattice size for 8 EO units and intermediate values for 6 and 7 EO units. The increase of the lattice parameter for more than 9 EO units is attributed to the increasing number of "Maander" configurated EO units. PMID- 24494622 TI - Temporal and spatial trends in freshwater fish tissue mercury concentrations associated with mercury emissions reductions. AB - Mercury (Hg) concentrations were monitored from 1999 to 2011 in largemouth bass (LMB) and yellow perch (YP) in 23 lakes in Massachusetts USA during a period of significant local and regional Hg emissions reductions. Average LMB tissue Hg concentration decreases of 44% were seen in 13 of 16 lakes in a regional Hg "hotspot" area. YP in all lakes sampled in this area decreased 43% after the major emissions reductions. Comparative decreases throughout the remainder of the state were 13% and 19% for LMB and YP respectively. Annual tissue mercury concentration rate decreases were 0.029 (LMB) and 0.016 mg Hg/kg/yr (YP) in the hotspot. In lakes around the rest of the state, LMB showed no trend and YP Hg decreased 0.0068 mg Hg/kg/yr. Mercury emissions from major point sources in the hotspot area decreased 98%, and 93% in the rest of the state from the early 1990s to 2008. The significant declines in fish Hg concentrations in many lakes occurred over the second half of a two decade decrease in Hg emissions primarily from municipal solid waste combustors and, secondarily, from other combustion point sources. In addition to the substantial Hg emissions reductions achieved in Massachusetts, further regional, national and global emissions reductions are needed for fish Hg levels to decrease below fish consumption advisory levels. PMID- 24494623 TI - Predictors of smoking cessation medication use among nonobese and obese smokers. AB - The objective of this study was to identify and compare the predictors of smoking cessation medication use among obese and nonobese adult smokers. A retrospective cross-sectional study was conducted using the Medical Expenditure Panel Survey (MEPS) data (2008-2009). The study participants included smokers aged 18 years and older who self-reported their smoking status as smoker. The outcome variable was utilization of any Food and Drug Administration approved smoking cessation medication (varenicline, bupropion, and nicotine replacement therapy). Multivariable logistic regression analyses were conducted. A total of 82.20 million (weighted sample size for two years) adult smokers were included; of which nearly 30% were obese-smokers. The use of smoking cessation medication was 2.66% and 5.17% among nonobese and obese smokers, respectively. Multivariable logistic regression results showed that race/ethnicity, health insurance coverage, prescription insurance coverage, usual source of health care, urban residence, region, Charlson comorbidity index, and instrumental activities of daily living (IADL), were significant predictors of using smoking cessation medications. The overall smoking cessation medication use rate was low implying limited compliance to guideline. Predictors identified in this study should be taken into consideration in health promotion programs that are designed to optimize the utilization of these smoking cessation medications. PMID- 24494624 TI - Smoking crushed hyoscine/scopolamine tablets as drug abuse. AB - BACKGROUND: Hyoscine N-butyl bromide/scopolamine (H/S) is a type of anticholinergic agent that is commonly used as an antispasmodic drug. We have evaluated the effects of crushed H/S smoking in prisoners who illicitly abused this drug. METHODS: All imprisoned cases with at least a 3-month history of HS were evaluated from April 2012 to September 2012. Demographic information, history, and clinical findings were studied. RESULTS: In total, 36 male cases with a mean (SD, min-max) age of 33.3 (3.6, 27-42) years were included. All subjects were cigarette smokers with a history of substance abuse and were under Methadone Maintenance Therapy (MMT). The majority (75%) of participants smoked H/S tablet with pin, and others used aluminum foil. Hallucinations were the most common neurological features. Amnesia (88%), insomnia (83%), palpitation (86%), flushing (86%), irritability (94%), and inability to concentrate (91%) were the most common findings. Among them, auditory (61%), visual (72%), and tactile (72%) hallucinations were reported. CONCLUSIONS: This is the first case study of hyoscine smoking abuse. We found that H/S acts similar to other hallucinogens. Concurrent abuse of H/S in cases under MMT could be a future trend of abuse. Clinicians should be aware of abuse potential of H/S in treatment of some patients for drug overdose. PMID- 24494625 TI - Home-based respiratory rehabilitation in adult patients with moderate or severe persistent asthma. AB - OBJECTIVE: We assessed retrospectively the feasibility of a home-based respiratory rehabilitation (RR) program for asthmatics under optimal pharmacological treatment, as this type of care can reduce costs and offer a more patient-friendly approach for subjects with persistent asthma. METHODS: Fifty-two patients with persistent asthma were recruited to the RR program (20 males, 32 females, 54 +/- 11 (SD) years, forced expiratory volume in one second 71 +/- 33% of predicted mean value, BMI 29.9 +/- 7.9 kg/m(2)). This two-month protocol comprised education sessions, respiratory physiotherapy and an exercise training program at home and in groups supervised by an adapted physical activity instructor. RESULTS: Thirty-nine patients completed the whole RR program, i.e. 25% dropout. The dropout rate was significantly higher with respect to younger patients in employment. The number of exacerbations decreased significantly during the year following the program, regardless of whether the patients had dropped out (p < 0.02) or not (p < 0.001). The distance walked during a 6-min walking test increased by 33 m (p < 0.001). Several indices measured during a cycle ergometer test increased significantly after RR: peak oxygen uptake (10%), oxygen uptake at ventilatory threshold (12%) and maximum load (19%), all at a similar maximum heart rate. Concerning quality of life assessment, the Short-Form 36 Item Health Survey revealed a non-significant improvement in the "health change" item after RR (p < 0.07). CONCLUSIONS: This study demonstrates the potential of a home-based program in the treatment and rehabilitation of patients with asthma. Both functional and physiologic indices improved during the follow up period. PMID- 24494626 TI - Asthma medication adherence among urban teens: a qualitative analysis of barriers, facilitators and experiences with school-based care. AB - OBJECTIVE: Teens with persistent asthma do not always receive daily preventive medications or do not take them as prescribed, despite established clinical guidelines. The purpose of this study was to understand urban teens' experiences with asthma management, preventive medication adherence and participation in a school-based intervention. METHODS: Teens (12-15 years) with persistent asthma, and prescribed preventive medication, participated in a pilot study that included daily observed medication therapy at school and motivational interviewing. Semi structured interviews occurred at final survey. Qualitative content analysis enabled data coding to identify themes. RESULTS: Themes were classified as "general asthma management" or "program-specific." For general management, routines were important, while hurrying interfered with taking medications. Forgetfulness was most commonly linked to medication nonadherence. Competing demands related to school preparedness and social priorities were barriers to medication use. Independence with medications was associated with several benefits (e.g. avoiding parental nagging and feeling responsible/mature). Program specific experiences varied. Half of teens reported positive rapport with their school nurse, while a few felt that their nurse was dismissive. Unexpected benefits and barriers within the school structure included perceptions about leaving the classroom, the distance to the nurse's office, the necessity of hall passes and morning school routines. Importantly, many teens connected daily medication use with fewer asthma symptoms, incenting continued adherence. CONCLUSIONS: Teens with asthma benefit from adherence to preventive medications but encounter numerous barriers to proper use. Interventions to improve adherence must accommodate school demands and unique teen priorities. The school nurse's role as an ally may support teens' transition to medication independence. PMID- 24494627 TI - Fistula eligibility: a work in progress. AB - Effective hemodialysis requires a reliable vascular access. Clinical practice guidelines strongly recommend the fistula as the preferred option followed by arteriovenous (AV) grafts, with central venous catheters being least preferred. Recently, there has been a growing awareness of the limitations of the fistula, its high rate of primary failure and that a fistula may not be appropriate for all patients initiating or on hemodialysis. However, determinates for fistula eligibility have not been clearly defined. The creation and use of a fistula requires the complex integration of patient, biological, and surgical factors, none of which can be easily predicted or planned. There have been several successful initiatives over the last decade addressing patient suitability for AV access, but none have validated defined criteria for fistula eligibility. We discuss these initiatives by addressing: 1) process of care, 2) radiological and nonradiological tests and procedures, and 3) alternative surgical approaches. Careful clinical judgment, appropriate vascular access assessment and placement, and an individualized approach to the risks and benefits will optimize patient health outcomes while minimizing prolonged catheter dependence among hemodialysis patients. PMID- 24494629 TI - Synthesis of (Z)-1-thio- and (Z)-2-thio-1-alkenyl boronates via copper-catalyzed regiodivergent hydroboration of thioacetylenes: an experimental and theoretical study. AB - A Cu-catalyzed divergent hydroboration of thioacetylenes has been achieved, providing (Z)-1-thio- or (Z)-2-thio-1-alkenyl boronates in moderate to high yields with excellent regio- and stereoselectivity, by using pinacolborane or bis(pinacolato)diboron as the hydroborating reagents, respectively. DFT calculations indicate that the sulfur atom plays a key role in determining the regioselectivity through polarizing the C-C triple bonds and participating in the HOMO orbitals. Moreover, the SR group can serve as a good leaving group, resulting in the concise synthesis of six regio- and stereoisomers of trisubstituted alkenes 5 via the iterative cross-coupling of C-B and C-S bonds. Clearly, it will be valuable for assembling stereochemically diverse trisubstituted olefins in organic synthesis. PMID- 24494628 TI - Antibodies to islet cell autoantigens, rotaviruses and/or enteroviruses in cord blood and healthy mothers in relation to the 2010-2011 winter viral seasons in Israel: a pilot study. AB - AIMS: To determine whether antivirus and/or islet cell antibodies can be detected in healthy pregnant mothers without diabetes and/or their offspring at birth in two winter viral seasons. METHODS: Maternal and cord blood sera from 107 healthy pregnant women were tested for islet cell autoantibodies using radioligand binding assays and for anti-rotavirus and anti-CoxB3 antibody using an enzyme linked immunosorbent assay. RESULTS: Glutamic acid decarboxylase (GAD)65 autoantibodies and rotavirus antibodies, present in both maternal and cord blood sera, correlated with an odds ratio of 6.89 (95% CI: 1.01-46.78). For five, 22 and 17 pregnancies, antibodies to GAD65, rotavirus and CoxB3, respectively, were detected in cord blood only and not in the corresponding maternal serum. In 10 pregnancies, rotavirus antibody titres in the cord blood exceeded those in the corresponding maternal serum by 2.5-5-fold. Increased antibody titres after the 20(th) week of gestation suggested CoxB3 infection in one of the 20 pregnancies and rotavirus in another. CONCLUSION: The concurrent presence of GAD65 antibodies in cord blood and their mothers may indicate autoimmune damage to islet cells during gestation, possibly caused by cross-placental transmission of viral infections and/or antivirus antibodies. Cord blood antibody titres that exceed those of the corresponding maternal sample by >2.5-fold, or antibody-positive cord blood samples with antibody-negative maternal samples, may imply an active in utero immune response by the fetus. PMID- 24494630 TI - Competitive adsorption of dopamine and rhodamine 6G on the surface of graphene oxide. AB - Competitive adsorption-desorption behavior of popular fluorescent labeling and bioanalyte molecules, Rhodamine 6G (R6G) and dopamine (DA), on a chemically heterogeneous graphene oxide (GO) surface is discussed in this study. Individually, R6G and DA compounds were found to adsorb rapidly on the surface of graphene oxide as they followed the traditional Langmuir adsorption behavior. FTIR analysis suggested that both R6G and DA molecules predominantly adsorb on the hydrophilic oxidized regions of the GO surface. Thus, when R6G and DA compounds were adsorbed from mixed solution, competitive adsorption was observed around the oxygen-containing groups of GO sheets, which resulted in partial desorption of R6G molecules from the surface of GO into the solution. The desorbed R6G molecules can be monitored by fluorescence change in solution and was dependent on the DA concentration. We suggest that the efficient competitive adsorption of different strongly bound bioanalytes onto GO-dye complex can be used for the development of sensitive and selective colorimetric biosensors. PMID- 24494631 TI - Unexpected complex formation between coralyne and cyclic diadenosine monophosphate providing a simple fluorescent turn-on assay to detect this bacterial second messenger. AB - Cyclic diadenosine monophosphate (c-di-AMP) has emerged as an important dinucleotide that is involved in several processes in bacteria, including cell wall remodeling (and therefore resistance to antibiotics that target bacterial cell wall). Small molecules that target c-di-AMP metabolism enzymes have the potential to be used as antibiotics. Coralyne is known to form strong complexes with polyadenine containing eight or more adenine stretches but not with short polyadenine oligonucleotides. Using a panel of techniques (UV, both steady state fluorescence and fluorescence lifetime measurements, circular dichroism (CD), NMR, and Job plots), we demonstrate that c-di-AMP, which contains only two adenine bases is an exception to this rule and that it can form complexes with coralyne, even at low micromolar concentrations. Interestingly, pApA (the linear analog of c-di-AMP that also contains two adenines) or cyclic diguanylate (c-di GMP, another nucleotide second messenger in bacteria) did not form any complex with coralyne. Unlike polyadenine, which forms a 2:1 complex with coralyne, c-di AMP forms a higher order complex with coralyne (>=6:1). Additionally, whereas polyadenine reduces the fluorescence of coralyne when bound, c-di-AMP enhances the fluorescence of coralyne. We use the quenching property of halides to selectively quench the fluorescence of unbound coralyne but not that of coralyne bound to c-di-AMP. Using this simple selective quenching strategy, the assay could be used to monitor the synthesis of c-di-AMP by DisA or the degradation of c-di-AMP by YybT. Apart from the practical utility of this assay for c-di-AMP research, this work also demonstrates that, when administered to cells, intercalators might not only associate with polynucleotides, such as DNA or RNA, but also could associate with cyclic dinucleotides to disrupt or modulate signal transduction processes mediated by these nucleotides. PMID- 24494632 TI - Nanomolar pyrophosphate detection in water and in a self-assembled hydrogel of a simple terpyridine-Zn2+ complex. AB - A simple terpyridine-Zn(II) complex is shown to act as an efficient and highly selective fluorescent sensor for pyrophosphate in water at physiological pH. The sensor complex showed an unprecedented fluorescence response (~500 fold increase) and a record nanomolar sensitivity (detectable fluorescent response at 20 nM and LOD ~ 0.8 nM). It has successfully been used to stain and record confocal fluorescence microscopy images of HeLa cells. Moreover, the complex was found to self-assemble into a hydrogel which was subsequently used to coat disposable paper strips for easy, low-cost detection of pyrophosphate. PMID- 24494633 TI - Impact of diagnosis and early treatment on the course of multiple sclerosis. AB - Multiple sclerosis (MS) is a progressive inflammatory disease of the central nervous system that results in neurological dysfunction and disability. The initiation of disease-modifying therapy (DMT) early in the course of MS may improve the prognosis for patients with MS and reduce the occurrence of neurological damage. In patients with relapsing-remitting MS (RRMS), DMT reduces the rate of relapses, reduces the appearance of magnetic resonance imaging markers of disease activity, and slows the course of disability progression. DMT has been shown to be more effective when initiated early in the course of MS. In patients who have not yet developed clinically definite MS (CDMS), but have had 1 attack of neurological symptoms consistent with MS (ie, clinically isolated syndrome [CIS]), the initiation of DMT (specifically, interferon beta, glatiramer acetate, and teriflunomide) following this attack has been shown to delay the conversion to CDMS. Current guidelines have recognized the benefits of early treatment of MS with DMTs. However, there are a number of barriers to implementing early MS treatment. Early diagnosis and treatment of MS can be hindered because patients may delay consulting a physician about their neurological symptoms or may be reluctant to start DMT. Further, even after initiating DMT, continued adherence to treatment is often poor. These delays in treatment and a lack of adherence to treatment are associated with poor patient outcomes. The objectives of this review are to highlight the importance of early diagnosis and treatment of CIS or RRMS and discuss the favorable outcomes associated with early initiation of DMT. PMID- 24494634 TI - Choosing the best treatment for multiple sclerosis: comparative effectiveness, safety, and other factors involved in disease-modifying therapy choice. AB - Comparative effectiveness research (CER) has emerged as a priority for outlining the advantages and disadvantages of disease-modifying therapies (DMTs) for multiple sclerosis (MS). CER can provide physicians with valuable information to assist them in selecting the most appropriate therapeutics for their patients with MS. For payers, data from CER could inform decisions regarding the level of coverage for current and developing MS therapeutics, and drive the use of the most effective treatments for patients with MS. The base of CER data for DMTs has been expanding, and findings from a number of CER studies for currently available DMTs have been published, while further CER studies are planned to evaluate currently available and new DMTs or DMTs in development. While CER can be used to guide DMT selection for physicians and payers, the safety and tolerability of these treatments must be considered as well. Other emerging factors (eg, biomarkers and patient-specific factors) may also serve as important determinants of DMT choice in the future. PMID- 24494635 TI - An update on new and emerging therapies for relapsing-remitting multiple sclerosis. AB - Disease-modifying therapies (DMTs), known to actively reduce relapses and delay disability progression, have been used for the treatment of relapsing-remitting multiple sclerosis (RRMS) for over a decade. These well-known therapies include intramuscular (IM) interferon (IFN) beta-1a (Avonex), subcutaneous (SC) IFN beta 1a (Rebif), SC IFN beta- 1b (Betaseron; Extavia), and SC glatiramer acetate (Copaxone). These first-line therapies have shown only partial benefits for controlling multiple sclerosis (MS) disease activity and are often associated with inadequate patient adherence. Low patient adherence to therapy may be related to the mode of administration or to the side effects associated with treatment. The intravenous DMT natalizumab (Tysabri; dosed monthly) provides high therapeutic efficacy and good compliance but is considered a second-line intervention because of the associated increased risk for progressive multifocal leukoencephalopathy. In 2010, fingolimod (Gilenya), the first oral DMT, was approved by the US Food and Drug Administration (FDA) for the treatment of MS. Recently, 2 new oral DMTs received FDA approval for the treatment of RRMS: teriflunomide (Aubagio) and dimethyl fumarate (Tecfidera). In addition, oral laquinimod, several monoclonal antibodies (eg, alemtuzumab, daclizumab, and ocrelizumab), and other agents have shown preliminary beneficial results in relapsing MS in phase 3 clinical trials. These new and emerging DMTs may provide a more efficacious individualized therapeutic approach, more favorable methods of administration (eg, oral administration), and/or a lower frequency of infusions (eg, annually, 3-5 daily infusions over a year for alemtuzumab) that may improve patient adherence and clinical outcomes. PMID- 24494636 TI - Unraveling the core-shell structure of ligand-capped Sn/SnOx nanoparticles by surface-enhanced nuclear magnetic resonance, Mossbauer, and X-ray absorption spectroscopies. AB - A particularly difficult challenge in the chemistry of nanomaterials is the detailed structural and chemical analysis of multicomponent nano-objects. This is especially true for the determination of spatially resolved information. In this study, we demonstrate that dynamic nuclear polarization surface-enhanced solid state NMR spectroscopy (DNP-SENS), which provides selective and enhanced NMR signal collection from the (near) surface regions of a sample, can be used to resolve the core-shell structure of a nanoparticle. Li-ion anode materials, monodisperse 10-20 nm large tin nanoparticles covered with a ~3 nm thick layer of native oxides, were used in this case study. DNP-SENS selectively enhanced the weak 119Sn NMR signal of the amorphous surface SnO2 layer. Mossbauer and X-ray absorption spectroscopies identified a subsurface SnO phase and quantified the atomic fractions of both oxides. Finally, temperature-dependent X-ray diffraction measurements were used to probe the metallic beta-Sn core and indicated that even after 8 months of storage at 255 K there are no signs of conversion of the metallic beta-Sn core into a brittle semiconducting alpha-phase, a phase transition which normally occurs in bulk tin at 286 K (13 degrees C). Taken together, these results indicate that Sn/SnOx nanoparticles have core/shell1/shell2 structure of Sn/SnO/SnO2 phases. The study suggests that DNP SENS experiments can be carried on many types of uniform colloidal nanomaterials containing NMR-active nuclei, in the presence of either hydrophilic (ion-capped surfaces) or hydrophobic (capping ligands with long hydrocarbon chains) surface functionalities. PMID- 24494637 TI - Salt tolerance evolves more frequently in C4 grass lineages. AB - Salt tolerance has evolved many times in the grass family, and yet few cereal crops are salt tolerant. Why has it been so difficult to develop crops tolerant of saline soils when salt tolerance has evolved so frequently in nature? One possible explanation is that some grass lineages have traits that predispose them to developing salt tolerance and that without these background traits, salt tolerance is harder to achieve. One candidate background trait is photosynthetic pathway, which has also been remarkably labile in grasses. At least 22 independent origins of the C4 photosynthetic pathway have been suggested to occur within the grass family. It is possible that the evolution of C4 photosynthesis aids exploitation of saline environments, because it reduces transpiration, increases water-use efficiency and limits the uptake of toxic ions. But the observed link between the evolution of C4 photosynthesis and salt tolerance could simply be due to biases in phylogenetic distribution of halophytes or C4 species. Here, we use a phylogenetic analysis to investigate the association between photosynthetic pathway and salt tolerance in the grass family Poaceae. We find that salt tolerance is significantly more likely to occur in lineages with C4 photosynthesis than in C3 lineages. We discuss the possible links between C4 photosynthesis and salt tolerance and consider the limitations of inferring the direction of causality of this relationship. PMID- 24494638 TI - Standing waves as an explanation for generic stationary correlation patterns in noninvasive EEG of focal onset seizures. AB - Cerebral electrical activity is highly nonstationary because the brain reacts to ever changing external stimuli and continuously monitors internal control circuits. However, a large amount of energy is spent to maintain remarkably stationary activity patterns and functional inter-relations between different brain regions. Here we examine linear EEG correlations in the peri-ictal transition of focal onset seizures, which are typically understood to be manifestations of dramatically changing inter-relations. Contrary to expectations we find stable correlation patterns with a high similarity across different patients and different frequency bands. This skeleton of spatial correlations may be interpreted as a signature of standing waves of electrical brain activity constituting a dynamical ground state. Such a state could promote the formation of spatiotemporal neuronal assemblies and may be important for the integration of information stemming from different local circuits of the functional brain network. PMID- 24494639 TI - [Dealing with rare diseases in medicine and dermatology -- new developments]. PMID- 24494645 TI - Hydroxychloroquine-induced hyperpigmentation. PMID- 24494640 TI - Vasculitis in childhood - a dermatological approach. AB - Vasculitis, an inflammatory condition affecting the blood vessels, may be restricted to a single organ or involve several organ systems. The size of the involved vessels is an important criterion for categorization of vasculitides, which is a prerequisite for rapid diagnosis and initiation of treatment. In pediatric patients, this particularly applies to Kawasaki disease. However, making the diagnosis can be challenging for dermatologists as skin involvement may be variable and non-specific. In contrast, Henoch-Schonlein purpura (IgA vasculitis) presents with the classic picture of palpable purpura. It predominantly affects postcapillary venules frequently following upper respiratory tract infections. Severe organ involvement is relatively rare in children and the prognosis is good. As renal involvement may occur during the course of disease, continuous monitoring is required. Acute hemorrhagic edema of infancy is considered as a distinct type of immune complex vasculitis and is characterized by a triad of fever, edema and rosette-shaped purpura. The clinical course of this rare disease is usually benign and self-limited. Due to the variability of clinical symptoms and manifestations, management of childhood vasculitides represents a special challenge requiring interdisciplinary collaboration. Dermatologists should be aware of their important role especially for making an early diagnosis. PMID- 24494649 TI - Production of wild buffalo (Bubalus arnee) embryos by interspecies somatic cell nuclear transfer using domestic buffalo (Bubalus bubalis) oocytes. AB - The objective of this study was to explore the possibility of producing wild buffalo embryos by interspecies somatic cell nuclear transfer (iSCNT) through handmade cloning using wild buffalo somatic cells and domestic buffalo (Bubalus bubalis) oocytes. Somatic cells derived from the ear skin of wild buffalo were found to express vimentin but not keratin and cytokeratin-18, indicating that they were of fibroblast origin. The population doubling time of skin fibroblasts from wild buffalo was significantly (p < 0.05) higher, and the cell proliferation rate was significantly (p < 0.05) lower compared with that of skin fibroblasts from domestic buffalo. Neither the cleavage (92.6 +/- 2.0% vs 92.8 +/- 2.0%) nor the blastocyst rate (42.4 +/- 2.4% vs 38.7 +/- 2.8%) was significantly different between the intraspecies cloned embryos produced using skin fibroblasts from domestic buffalo and interspecies cloned embryos produced using skin fibroblasts from wild buffalo. However, the total cell number (TCN) was significantly (p < 0.05) lower (192.0 +/- 25.6 vs 345.7 +/- 42.2), and the apoptotic index was significantly (p < 0.05) higher (15.1 +/- 3.1 vs 8.0 +/- 1.4) for interspecies than that for intraspecies cloned embryos. Following vitrification in open-pulled straws (OPS) and warming, although the cryosurvival rate of both types of cloned embryos, as indicated by their re-expansion rate, was not significantly different (34.8 +/- 1.5% vs 47.8 +/- 7.8), the apoptotic index was significantly (p < 0.05) higher for vitrified-warmed interspecies than that for corresponding intraspecies cloned embryos (48.9 +/- 7.2 vs 23.9 +/- 2.8). The global level of H3K18ac was significantly (p < 0.05) lower in interspecies cloned embryos than that in intraspecies cloned embryos. The expression level of HDAC1, DNMT3a and CASPASE3 was significantly (p < 0.05) higher, that of P53 was significantly (p < 0.05) lower in interspecies than in intraspecies embryos, whereas that of DNMT1 was similar between the two types of embryos. In conclusion, these results demonstrate that wild buffalo embryos can be produced by iSCNT. PMID- 24494650 TI - Current status of prognostication in classical Hodgkin lymphoma. AB - Classical Hodgkin lymphoma (cHL) is characterized by a paucity of neoplastic Hodgkin/Reed Sternberg (HRS) cells within a complex cellular milieu that is rendered immunologically incapable of reacting against CD30(+) HRS cells due to a plethora of immune escape mechanisms initiated by the neoplastic cells. Accounting for 25% of all lymphomas and nearly 95% of all Hodgkin lymphomas, patients with cHL are typically young adults. Besides traditional prognostic factors, such as the International Prognostic Index (IPI), newer imaging and ancillary biomarkers (CD68, Galectin-1 and plasma microRNA) have shown promise. Furthermore, the evolution of gene expression profiling (GEP) in recent years has enabled the development of several practically feasible GEP-based predictors with prognostic relevance. This review discusses the current status of clinical prognostication in cHL, the critical role of histological evaluation in light of several mimicking entities, and the relevance of tissue as well as serum biomarkers pertaining to immune escape mechanisms and recent GEP studies. PMID- 24494651 TI - Inhibitory effects of sword bean extract on alveolar bone resorption induced in rats by Porphyromonas gingivalis infection. AB - BACKGROUND: The domesticated legume, Canavalia gladiata (commonly called the sword bean), is known to contain canavanine. The fruit is used in Chinese and Japanese herbal medicine for treating the discharge of pus, but its pharmacological mechanisms are still unclear. OBJECTIVES: This study examined the effect of sword bean extract (SBE) on (i) oral bacteria and human oral epithelial cells in vitro, and (ii) the initiation and progression of experimental Porphyromonas gingivalis-induced alveolar bone resorption in rats. MATERIAL AND METHODS: A high-performance liquid chromatography/ultraviolet method was applied to quantitate canavanine in SBE. By assessing oral bacterial growth, we estimated the minimum inhibitory concentration and minimum bactericidal concentration of SBE, canavanine, chlorhexidine gluconate (CHX) solution. The cytotoxicity of SBE, canavanine, CHX, leupeptin and cystatin for KB cells was determined using a trypan blue assay. The effects of SBE, canavanine, leupeptin and cystatin on Arg gingipain (Rgp) and Lys-gingipain (Kgp) were evaluated by colorimetric assay using synthetic substrates. To examine its effects on P. gingivalis-associated periodontal tissue breakdown, SBE was orally administered to P. gingivalis infected rats. RESULT: Sword bean extract contained 6.4% canavanine. SBE and canavanine inhibited the growth of P. gingivalis and Fusobacterium nucleatum. The cytotoxicity of SBE, canavanine and cystatin on KB cells was significantly lower than that of CHX. Inhibition of Rgp with SBE was comparable to that with leupeptin, a known Rgp inhibitor, and inhibition of Kgp with SBE was significantly higher than that with leupeptin at 500 MUg/mL ( p < 0.05). P. gingivalis-induced alveolar bone resorption was significantly suppressed by administration of SBE, with bone levels remaining comparable to non-infected animals ( p < 0.05). CONCLUSION: The present study suggests that SBE might be effective against P. gingivalis-associated alveolar bone resorption. PMID- 24494653 TI - GES polypharmacology fingerprints: a novel approach for drug repositioning. AB - Polypharmacology is now recognized as an increasingly important aspect of drug design. We previously introduced the Gaussian ensemble screening (GES) approach to predict relationships between drug classes rapidly without requiring thousands of bootstrap comparisons as in current promiscuity prediction approaches. Here we present the GES "computational polypharmacology fingerprint" (CPF), the first target fingerprint to encode drug promiscuity information. The similarity between the 3D shapes and chemical properties of ligands is calculated using PARAFIT and our HPCC programs to give a consensus shape-plus-chemistry ligand similarity score, and ligand promiscuity for a given set of targets is quantified using the GES fingerprints. To demonstrate our approach, we calculated the CPFs for a set of ligands from DrugBank that are related to some 800 targets. The performance of the approach was measured by comparing our CPF with an in-house "experimental polypharmacology fingerprint" (EPF) built using publicly available experimental data for the targets that comprise the fingerprint. Overall, the GES CPF gives very low fall-out while still giving high precision. We present examples of polypharmacology relationships predicted by our approach that have been experimentally validated. This demonstrates that our CPF approach can successfully describe drug-target relationships and can serve as a novel drug repurposing method for proposing new targets for preclinical compounds and clinical drug candidates. PMID- 24494652 TI - Basic psychological needs, suicidal ideation, and risk for suicidal behavior in young adults. AB - Associations between the satisfaction of basic psychological needs of autonomy, competence, and relatedness with current suicidal ideation and risk for suicidal behavior were examined. Two logistic regressions were conducted with a cross sectional database of 440 university students to examine the association of need satisfaction with suicidal ideation and risk for suicidal behavior, while controlling for demographics and depressive symptoms. Suicidal ideation was reported by 15% of participants and 18% were found to be at risk for suicidal behavior. A one standard deviation increase in need satisfaction reduced the odds of suicidal ideation by 53%, OR (95% CI) = 0.47 (0.33-0.67), and the odds of being at risk for suicidal behavior by 50%, OR (95% CI) = 0.50 (0.37-0.69). Young adults whose basic psychological needs are met may be less likely to consider suicide and engage in suicidal behavior. Prospective research is needed to confirm these associations. PMID- 24494654 TI - Ion release from calcium and fluoride containing dental varnishes. AB - BACKGROUND: A range of dental varnishes have been commercialized recently that contain calcium and inorganic phosphate in addition to fluoride. The aim of this study was to analyse the fluoride, calcium and inorganic phosphate ion release from: (1) MI Varnish containing casein phosphopeptide-amorphous calcium phosphate (CPP-ACP); (2) Clinpro White containing functionalized tricalcium phosphate (fTCP); (3) Enamel Pro containing amorphous calcium phosphate; (4) Bifluorid 5 containing calcium fluoride; and (5) Duraphat (no added calcium control). METHODS: The varnishes were applied to a standardized surface area of polyvinyl chloride (n = 7 per group) and immersed in 25 g of distilled deionized water which was changed at 1, 4, 24, 72 and 168 hours. The ion release was determined by ion chromatography and expressed as MUmol (cumulative) per gram of varnish. RESULTS: All varnishes released measurable fluoride and calcium, however only MI Varnish and Enamel Pro released significant levels of inorganic phosphate. At 24 hours the order of cumulative fluoride release was: 1>3>4>2=5 with 1 significantly higher (p < 0.05) than the rest. At 72 and 168 hours, the cumulative calcium release was: 1>4>3>2=5 with 1 significantly higher (p < 0.05) than the rest. CONCLUSIONS: MI Varnish containing CPP-ACP had the highest release of calcium and fluoride ions. PMID- 24494655 TI - Engineered peptides for nanohybrid assemblies. AB - Inspired by biological material synthesis, synthetic biomineralization peptides have been screened through a laboratory evolution using biocombinatorial techniques. In this study, using the fine examples in nature, silica binding peptides and gold binding peptides were fused together to form a hybrid peptide. We designed fusion peptides with different gold binding and silica binding parts. First, we have tested the binding capability of the fusion peptides using quartz crystal microbalance on gold surface and silica surface. Second, S1G1 hybrid peptide enabled assembly of gold nanoparticles on a silica surface was achieved. Finally, nanomaterial synthesis ability of the S1G1 peptide was presented by the formation of a silica film on a gold surface. In this study, we are presenting a hybrid peptide tool for nanohybrid assembly as a promising route for nanotechnology applications. PMID- 24494656 TI - Transferring learning to our consumers. PMID- 24494657 TI - A decade in retrospect. AB - Over the past decade, several events and publications have influenced and refocused continuing nursing education. Several of these are briefly reviewed in this column. PMID- 24494658 TI - Resilience-building strategies for nurses in transition. AB - Nursing is stressful, especially for the new graduate entering the work-force and for those transitioning into new roles. This article explores one large health system's approach to supporting those nurses through a 1-day program devoted to enhancing their resilience. A few resilience-building strategies are highlighted. PMID- 24494659 TI - Leading through meetings. AB - Whether formal or informal, meetings reflect relational opportunities that are critical to effective leadership. Professional development educators can influence the quality, cost, and impact of meetings by emphasizing their structure, conduct, and behavioral dynamics. PMID- 24494660 TI - Understanding massively open online courses. AB - Massively open online courses (MOOCs) are an innovative delivery system for educational offerings. MOOCs have been hailed with optimism for making education accessible to many, but at the same time, they have been criticized for poor participant completion rates. Nurse educators are considering whether and how to use MOOCs; this column explains MOOCs and their advantages and disadvantages for nurse educators. PMID- 24494661 TI - Increasing capacity for evidence-based practice through the evidence-based practice academy. AB - Although mentoring is an important aspect of implementing evidence-based practice (EBP), few models exist for EBP education. The EBP Academy is an innovative, 6 month educational program designed to develop clinical staff as EBP nurse mentors. Sessions provide protected time for participants to work on their EBP projects with assigned mentors who have EBP expertise and similar clinical or research interests. Participants develop EBP projects focused on improving care in their clinical areas. Evaluation of the EBP Academy is based on a four-level model, including participant feedback about the program, perception of meeting program objectives, ability to apply knowledge to practice through EBP projects, and outcome data measured as a result of implementing the EBP changes. By developing EBP mentors, capacity to move nursing practice to a stronger evidence based foundation can be enhanced. Positive, professional nursing and patient outcomes have been demonstrated when structured EBP education is provided. PMID- 24494662 TI - Grafting amphiphilic brushes onto halloysite nanotubes via a living RAFT polymerization and their Pickering emulsification behavior. AB - Amphiphilic brushes of poly(4-vinylpyridine)-block-polystyrene (P4VP-b-PS) and polystyrene-block-poly(4-vinylpyridine) (PS-b-P4VP) are grafted onto halloysite nanotubes (HNTs) via a surface reversible addition-fragmentation chain transfer (RAFT) living polymerization through anchoring R group in RAFT agent S-1-dodecyl S'-(R,R'-dimethyl-R"-acetic acid) trithiocarbonates (DDMAT). The characterization of TGA, TEM, and GPC show that amphiphilic brushes are successfully grafted onto HNTs in a living manner. To verify the amphiphilicity of HNTs grafted with block copolymers, their Pickering emulsification behavior in water/soybean oil diphase mixture is studied. The results show that modified HNTs can emulsify water/soybean oil diphase mixture and the emulsification performance is dependent on microstructure of amphiphilic brushes such as hydrophilic/hydrophobic segment size and sequence. PMID- 24494663 TI - The impact of human papillomavirus genotype on colposcopic appearance: a cross sectional analysis. AB - OBJECTIVE: To study colposcopic performance in diagnosing high-grade cervical intraepithelial neoplasia or cervical cancer (CIN2+ and CIN3+) using colposcopic characteristics and high-risk human papillomavirus (hrHPV) genotyping. DESIGN: Cross-sectional multicentre study. SETTING: Two colposcopy clinics in The Netherlands and Spain. POPULATION: Six hundred and ten women aged 17 years and older referred for colposcopy because of abnormal cytology. METHODS: A cervical smear was obtained. Colposcopists identified the worst lesion, graded their impression and scored the colposcopic characteristics of the lesions. Up to four biopsies were collected, including one biopsy from visually normal tissue. MAIN OUTCOME MEASURES: CIN2+ and CIN3+, positive for HPV16 or other high-risk HPV types (non-16 hrHPV-positive). RESULTS: The mean age in HPV16-positive CIN2+ women was 35.1 years compared with 39.1 years in women with other hrHPV types (P = 0.002). Sensitivity for colposcopy to detect CIN2+ was 87.9% (95%CI 83.2-91.5), using colposcopic cut-off of 'any abnormality'. The remaining CIN2+ were found by a biopsy from visually normal tissue or endocervical curettage (ECC). Detection of CIN2+ by lesion-targeted biopsies was not different between HPV16-positive women [119/135; 88.1% (95%CI 81.2-92.9)] and non-16 hrHPV-positive women [100/115; 87.0% (95%CI 79.1-92.3); P = 0.776]. In multivariate analysis, 'acetowhitening' [odds ratio (OR) 1.91, 95%CI 1.56-3.17], 'time of appearance' (OR 1.95, 95%CI 1.21-3.15) and 'lesion >25% of visible cervix' (OR 2.25, 95%CI 1.44-3.51) were associated with CIN2+. CONCLUSIONS: In this population following European screening practice, HPV16-related CIN2+ lesions were detected at younger age and showed similar colposcopic impression as non-16 hrHPV high-grade lesions. There was no relationship between any of the colposcopic characteristics and HPV16 status. PMID- 24494664 TI - Intra-axonal protein aggregation in the peripheral nervous system. AB - Intracellular protein aggregates are common pathological hallmarks of many neurodegenerative disorders, and a defect in axonal transport is also incriminated. Here, we studied intra-axonal abnormal protein aggregation and axonopathy by using immunohistochemistry and electron microscopy on peripheral nerve biopsies from 12 patients with chronic axonal peripheral neuropathy (PN) of unknown etiology. Among these patients, three had idiopathic Parkinson's disease (PD). Intra-axonal ubiquitin aggregates were more numerous in the patients with PD. Intra-axonal aggregates of tau AT8 were found in five patients without PD. Phosphorylated alpha-synuclein aggregation was absent in all cases, while intra axonal colocalization of 14-3-3 beta and ubiquitin was observed in two PD cases. Electron microscopy revealed enlarged axons crowded with organelles in six cases, including the three patients with PD, thus attesting a slowing of the axoplasmic flux. The number of ubiquitin aggregates was correlated with features of reduced axonal flux, while no such correlation was found for tau and 14-3-3 beta. Age did not correlate with the number of tau, ubiquitin, and 14-3-3 aggregates. Thus, both ubiquitin and/or abnormal tau intra-axonal aggregates may be found in chronic axonal PN. Ubiquitin aggregates might reduce the axonal flux or result from a disease producing slowing of axonal transport. PMID- 24494665 TI - Incidence of Type 2 diabetes among occupational classes in Sweden: a 35-year follow-up cohort study in middle-aged men. AB - AIMS: To assess if low occupational class was an independent predictor of Type 2 diabetes in men in Sweden over a 35-year follow-up, after adjustment for both conventional risk factors and psychological stress. METHODS: A random population based sample of 6874 men aged 47-56 years without a history of diabetes was divided into five occupational classes and the men were followed from 1970 to 2008. Diabetes cases were identified through the Swedish inpatient and death registers. Subdistribution hazard ratios (SHRs) and 95% CIs from competing risk regressions, cumulative incidence and conditional probabilities were calculated, after accounting for the risk of death attributed to other causes. RESULTS: A total of 907 (13%) men with diabetes were identified over 35 years with a median follow-up of 27.9 years. The cumulative incidence of diabetes, when taking into account death as a competing event, was 11% in high officials, 12% in intermediate non-manual employees, 14% in assistant non-manual employees, 14% in skilled workers, and 16% in unskilled and semi-skilled workers. Men with unskilled and semi-skilled manual occupations had a significantly higher risk of diabetes than high officials (reference) after adjustment for age, BMI, hypertension, smoking and physical activity (SHR 1.39, 95% CI 1.08-1.78). Additional adjustment for self-reported psychological stress did not attenuate the results. CONCLUSIONS: A low occupational class suggests a greater risk of Type 2 diabetes, independently of conventional risk factors and psychological stress. PMID- 24494666 TI - TRACK as a complementary tool to GINA and NAEPP guidelines for assessing asthma control in pre-school children. AB - BACKGROUND: In this study, our goal is to evaluate the consistency between TRACK and the asthma control levels assessed according to the GINA and NAEPP guidelines in children younger than 5 years of age. METHODS: Patients under 5 years old, who were followed up for recurrent wheezing for at least 1 year have been included. Parents were given the TRACK questionnaire and the control level of asthma according to GINA and NAEPP guidelines were determined by a pediatric allergist blinded to TRACK scores. Patients were classified into two groups regarding the compatibility of the control level between TRACK and both GINA and NAEPP guidelines. RESULTS: A total of 365 questionnaires were evaluated. The TRACK cut off point of 80 provided the most consistent balance between sensitivity and specificity for the compatibility with both GINA and NAEPP (for GINA 0.763 and 0.663, kappa = 0.487, p < 0.001 and for NAEPP 0.761 and 0.769, kappa = 0.524, p < 0.001, respectively). When 80 was taken as the cut-off value for TRACK, the compatibility rate of asthma control levels between TRACK and GINA and TRACK and NAEPP was 71.0 and 76.4%, respectively. About 70.1% of the patients who had TRACK scores over 80 and had mild asthma were grouped as controlled according to GINA and 50.0% of patients who had TRACK scores over 80 and had moderate to severe asthma was grouped as uncontrolled according to GINA (p = 0.019). CONCLUSION: TRACK is compatible with NAEPP and GINA in majority of asthmatic children under 5 years of age. Nevertheless, there is a discrepancy between guidelines and TRACK scores; therefore, it should be used in conjunction with a detailed clinical examination in order to make a better decision for assessing the control levels and management plan. PMID- 24494667 TI - The rise and fall of access blood flow surveillance in arteriovenous fistulas. AB - Vascular access blood flow (Qa) surveillance has been described as a typical false paradigm, an example of how new tests are sometimes adopted even without good-quality evidence of their benefits. This may be true for grafts, but not necessarily for arteriovenous fistulas. We reviewed the literature on Qa surveillance in fistulas to see whether it complies with the World Health Organization's criteria for screening tests. Measuring Qa has a fairly good reproducibility. Qa shows an excellent-to-good accuracy for stenosis being the only bedside screening test that achieves a very high sensitivity while retaining a fair-to-good positive predictive value for Qa thresholds of 600 ml/minute or higher associated with a >25% drop in Qa, or findings suggesting stenosis on physical examination. The accuracy of Qa in predicting thrombosis is hard to establish because of the heterogeneity of published studies, though a Qa of 300 ml/minute seems the most reliable cutoff. Qa surveillance affords a significant 2 to 3-fold reduction in the risk of thrombosis by comparison with clinical monitoring alone when Qa criteria highly sensitive to stenosis are considered, regardless of the study design (randomized controlled trials, cohort studies with concurrent or historic controls). Using highly sensitive Qa screening criteria also halves the risk of access loss, although this effect is not statistically significant. Our analysis strongly suggests that Qa surveillance is an effective method for screening mature fistulas, though further, appropriately designed studies are needed to fully elucidate its benefits and cost effectiveness. PMID- 24494668 TI - Nonwoven-based gelatin/polycaprolactone membrane proves suitability in a preclinical assessment for treatment of soft tissue defects. AB - Standard preclinical assessments in vitro often have limitations regarding their transferability to human beings, mainly evoked by their nonhuman and tissue different/nontissue-specific source. Here, we aimed at employing tissue-authentic simple and complex interactive fibroblast-epithelial cell systems and their in vivo-relevant biomarkers for preclinical in vitro assessment of nonwoven-based gelatin/polycaprolactone membranes (NBMs) for treatment of soft tissue defects. NBMs were composed of electrospun gelatin and polycaprolactone nanofiber nonwovens. Scanning electron microscopy in conjunction with actin/focal contact integrin fluorescence revealed successful adhesion and proper morphogenesis of keratinocytes and fibroblasts, along with cells' derived extracellular matrix deposits. The "feel-good factor" of cells under study on the NBM was substantiated by forming a confluent connective tissue entity, which was concomitant with a stratified epithelial equivalent. Immunohistochemistry proved tissue authenticity over time by abundance of the biomarker vimentin in the connective tissue entity, and chronological increase of keratins KRT1/10 and involucrin expression in epithelial equivalents. Suitability of the novel NBM as wound dressing was evidenced by an almost completion of epithelial wound closure in a pilot mini-pig study, after a surgical intervention-caused gingival dehiscence. In summary, preclinical assessment by tissue-authentic cell systems and the animal pilot study revealed the NBM as an encouraging therapeutic medical device for prospective clinical applications. PMID- 24494669 TI - Heterospecific female mimicry in Ficedula flycatchers. AB - Mimicry is a widespread phenomenon. Vertebrate visual mimicry often operates in an intraspecific sexual context, with some males resembling conspecific females. Pied flycatcher (Ficedula hypoleuca) dorsal plumage varies from the ancestral black to female-like brown. Experimental studies have shown that conspecific and heterospecific (collared flycatcher, F. albicollis) individuals of both sexes respond, at least initially, to brown individuals as if they were female. We quantified the perceptual and biochemical differences between brown feathers and found that brown pied flycatcher males are indistinguishable from heterospecific, but not from conspecific, females in both aspects. To our knowledge, this is the first evidence of a visual mimetic signalling system in a sexual context where the model is heterospecific to the mimic. By only mimicking heterospecific females, brown pied flycatcher males can establish territories next to the more dominant collared flycatcher in sympatry, suffer less aggression by darker conspecifics in allopatry and preserve within-species sexual recognition throughout the breeding range. A closer look at the evolutionary history and ecology of these two species illustrates how such a mimetic system can evolve. Although likely rare, this phenomenon might not be unique to Ficedula flycatchers. PMID- 24494670 TI - Protein and lipid interactions driving molecular mechanisms of in meso crystallization. AB - The recent advances in the in meso crystallization technique for the structural characterization of G-protein coupled receptor (GPCR) proteins have established the usefulness of the lipidic-cubic phases (LCPs) in the field of crystallography of membrane proteins. It is surprising that despite the success of the approach, the molecular mechanisms of the in meso method are still not well understood. Therefore, the approach must rely on extensive screening for a suitable protein construct, for host and additive lipids, and for the appropriate precipitants and temperature. To shed light on the in meso crystallization mechanisms, we used extensive coarse-grained molecular dynamics simulations to study, in molecular detail, LCPs under different conditions (compositions and temperatures relevant to crystallogenesis) and their interactions with different types of GPCR constructs. The results presented show how the modulation of the lattice constant of the LCP (triggered by the addition of precipitant during the in meso assay), or of the host lipid type, can destabilize monomeric proteins in the bilayer of the LCP and thus drive their aggregation into the stacked lamellae, where the residual hydrophobic mismatch between the protein and the membrane can drive the formation of lateral contacts leading to nucleation and crystal growth. Moreover, we demonstrate how particular protein designs (such as transmembrane proteins engineered to contain large polar regions) can promote protein stacking interactions in the third, out-of-plane, dimension. The insights provided by the new aspects of the specific molecular mechanisms responsible for protein-protein interactions inside the cubic phase presented here should be helpful in guiding the rational design of future in meso trials with successful outcomes. PMID- 24494672 TI - Expression of concern. PMID- 24494671 TI - QC metrics from CPTAC raw LC-MS/MS data interpreted through multivariate statistics. AB - Shotgun proteomics experiments integrate a complex sequence of processes, any of which can introduce variability. Quality metrics computed from LC-MS/MS data have relied upon identifying MS/MS scans, but a new mode for the QuaMeter software produces metrics that are independent of identifications. Rather than evaluating each metric independently, we have created a robust multivariate statistical toolkit that accommodates the correlation structure of these metrics and allows for hierarchical relationships among data sets. The framework enables visualization and structural assessment of variability. Study 1 for the Clinical Proteomics Technology Assessment for Cancer (CPTAC), which analyzed three replicates of two common samples at each of two time points among 23 mass spectrometers in nine laboratories, provided the data to demonstrate this framework, and CPTAC Study 5 provided data from complex lysates under Standard Operating Procedures (SOPs) to complement these findings. Identification independent quality metrics enabled the differentiation of sites and run-times through robust principal components analysis and subsequent factor analysis. Dissimilarity metrics revealed outliers in performance, and a nested ANOVA model revealed the extent to which all metrics or individual metrics were impacted by mass spectrometer and run time. Study 5 data revealed that even when SOPs have been applied, instrument-dependent variability remains prominent, although it may be reduced, while within-site variability is reduced significantly. Finally, identification-independent quality metrics were shown to be predictive of identification sensitivity in these data sets. QuaMeter and the associated multivariate framework are available from http://fenchurch.mc.vanderbilt.edu and http://homepages.uc.edu/~wang2x7/ , respectively. PMID- 24494673 TI - Neurotrophin and endocannabinoid interactions in the neurobiology of pain. PMID- 24494674 TI - The molecular interplay between endocannabinoid and neurotrophin signals in the nervous system and beyond. AB - Neurotrophins are traditionally known for their roles in neuronal development, function and survival. More recent data has highlighted the importance of neurotrophin signalling in adult signalling contexts, including the regulation of synaptic transmission. In addition, neurotrophin levels are increased in inflammatory and neuropathic pain leading to sensitization to painful stimuli. Endocannabinoid (eCB) signalling was initially studied in the context of synaptic transmission and pain alleviation whilst recently gaining attention due to its involvement in the development of the nervous system. Similar to neurotrophins, eCB levels also rise during pain perception but result in diminished pain sensations. The overlap of cellular functions between neurotrophins and eCB signalling leads to the hypothesis that these signalling systems are positioned to regulate each other and narrow the multitude of actions that both systems can promote to the specific need of the cell. Therefore, in this review, we examine to what extent the involvement of these two signalling systems is co-ordinated as opposed to being coincidental, and causal to neuronal circuit modifications in pain. Available data point to numerous direct molecular interactions between the neurotrophin and eCB signalling systems in developmental and adult contexts, including receptor-level interplay, transcriptional control and synergistic regulation of downstream signalling cascades. Although experimental observations specifically in pain circuits are limited, the universality of downstream signalling systems from both neurotrophin and endocannabinoid receptors suggest an interdependent relationship between these two diverse signalling systems. PMID- 24494675 TI - The consequences of pain in early life: injury-induced plasticity in developing pain pathways. AB - Pain in infancy influences pain reactivity in later life, but how and why this occurs is poorly understood. Here we review the evidence for developmental plasticity of nociceptive pathways in animal models and discuss the peripheral and central mechanisms that underlie this plasticity. Adults who have experienced neonatal injury display increased pain and injury-induced hyperalgesia in the affected region but mild injury can also induce widespread baseline hyposensitivity across the rest of the body surface, suggesting the involvement of several underlying mechanisms, depending upon the type of early life experience. Peripheral nerve sprouting and dorsal horn central sensitization, disinhibition and neuroimmune priming are discussed in relation to the increased pain and hyperalgesia, while altered descending pain control systems driven, in part, by changes in the stress/HPA axis are discussed in relation to the widespread hypoalgesia. Finally, it is proposed that the endocannabinoid system deserves further attention in the search for mechanisms underlying injury-induced changes in pain processing in infants and children. PMID- 24494676 TI - Neurotrophins, endocannabinoids and thermo-transient receptor potential: a threesome in pain signalling. AB - Because of the social and economic costs of chronic pain, there is a growing interest in unveiling the cellular and molecular mechanisms underlying it with the aim of developing more effective medications. Pain signalling is a multicomponent process that involves the peripheral and central nervous systems. At the periphery, nociceptor sensitisation by pro-inflammatory mediators is a primary step in pain transduction. Although pain is multifactorial at cellular and molecular levels, it is widely accepted that neurotrophin (TrkA, p75NTR, Ret and GFRs), cannabinoid (CB1 and CB2), and thermo-transient receptor potential (TRPs; TRPV1, TRPA1 and TRPM8) receptors play a pivotal role. They form a threesome for which endocannabinoids appear to be a first line of defence against pain, while neurotrophins and thermoTRPs are the major generators of painful signals. However, endocannabinoids may exhibit nociceptive activity while some neurotrophins may display anti-nociception. Accordingly, a clear-cut knowledge of the modulation and context-dependent function of these signalling cascades, along with the molecular and dynamic details of their crosstalk, is critical for understanding and controlling pain transduction. Here, the recent progress in this fascinating topic, as well as the tantalizing questions that remain unanswered, will be discussed. Furthermore, we will underline the need for using a systems biology approach (referred to as systems pain) to uncover the dynamics and interplay of these intricate signalling cascades, taking into consideration the molecular complexity and cellular heterogeneity of nociceptor populations. Nonetheless, the available information confirms that pharmacological modulation of this signalling triad is a highly valuable therapeutic strategy for effectively treating pain syndromes. PMID- 24494678 TI - Neurobiology of pain, interoception and emotional response: lessons from nerve growth factor-dependent neurons. AB - Although nerve growth factor (NGF) is a well-known neurotrophic factor, it also acts as a mediator of pain, itch and inflammation. Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder caused by loss-of-function mutations in NTRK1, the gene encoding a receptor tyrosine kinase for NGF, TrkA. Mutations in NTRK1 cause the selective loss of NGF-dependent neurons in otherwise intact systems. NGF-dependent primary afferents are thinly myelinated Adelta or unmyelinated C-fibers that are dependent on the NGF-TrkA system during development. In CIPA, the lack of pain and the presence of anhidrosis (inability to sweat) are due to the absence of both NGF-dependent primary afferents and sympathetic postganglionic neurons, respectively. These peripheral neurons form an interface between the nervous system and the 'body proper' and play essential roles in the interoception and sympathetic regulation of various tissues or organs. Patients with CIPA also show mental retardation and characteristic behaviors and are probably neuron-deficient within the brain. However, the functions of NGF-dependent neurons in the brain are controversial, both in animal and in human studies. This review focuses on various brain regions that express TrkA mRNA, based on data from the Allen Human Brain Atlas, and discusses putative neuronal networks related to these brain regions in humans. A better understanding the distribution of NGF-dependent neurons in the brain will provide a framework for further studies to investigate pain, interoception and emotional responses. Furthermore, strategies targeting the molecular mechanisms through which the NGF-TrkA system functions may provide hope for the development of novel analgesics. PMID- 24494679 TI - From genes to pain: nerve growth factor and hereditary sensory and autonomic neuropathy type V. AB - Hereditary sensory and autonomic neuropathy type V (HSAN V) is an autosomal recessive disorder characterized by the loss of deep pain perception. The anomalous pain and temperature sensations are due to the absence of nociceptive sensory innervation. The neurotrophin nerve growth factor (NGF), by binding to tropomyosin receptor A (TrkA) and p75NTR receptors, is essential for the development and survival of sensory neurons, and for pain perception during adulthood. Recently a homozygous missense mutation (R100W) in the NGF gene has been identified in HSAN V patients. Interestingly, alterations in NGF signalling, due to mutations in the NGF TRKA gene, have also been involved in another congenital insensitivity to pain, HSAN IV, characterized not only by absence of reaction to painful stimuli, but also anhidrosis and mental retardation. These symptoms are absent in HSAN V patients. Unravelling the mechanisms that underlie the differences between HSAN IV and V could assist in better understanding NGF biology. This review highlights the recent key findings in the understanding of HSAN V, including insights into the molecular mechanisms of the disease, derived from genetic studies of patients with this disorder. PMID- 24494680 TI - Endocannabinoids and neuropathic pain: focus on neuron-glia and endocannabinoid neurotrophin interactions. AB - Although originally described as a signalling system encompassing the cannabinoid CB1 and CB2 receptors, their endogenous agonists (the endocannabinoids), and metabolic enzymes regulating the levels of such agonists, the endocannabinoid system is now viewed as being more complex, and including metabolically related endocannabinoid-like mediators and their molecular targets as well. The function and dysfunction of this complex signalling system in the molecular and cellular mechanisms of pain transduction and control has been widely studied over the last two decades. In this review article, we describe some of the latest advances in our knowledge on the role of the endocannabinoid system, in its most recent and wider conception, in pain pathways, by focusing on: (1) neuron-glia interactions; and (2) emerging data on endocannabinoid cross-talk with neurotrophins, such as nerve growth factor and brain-derived neurotrophic factor. PMID- 24494677 TI - Pro-neurotrophins, sortilin, and nociception. AB - Nerve growth factor (NGF) signaling is important in the development and functional maintenance of nociceptors, but it also plays a central role in initiating and sustaining heat and mechanical hyperalgesia following inflammation. NGF signaling in pain has traditionally been thought of as primarily engaging the classic high-affinity receptor tyrosine kinase receptor TrkA to initiate sensitization events. However, the discovery that secreted proforms of nerve NGF have biological functions distinct from the processed mature factors raised the possibility that these proneurotrophins (proNTs) may have distinct function in painful conditions. ProNTs engage a novel receptor system that is distinct from that of mature neurotrophins, consisting of sortilin, a type I membrane protein belonging to the VPS10p family, and its co receptor, the classic low-affinity neurotrophin receptor p75NTR. Here, we review how this new receptor system may itself function with or independently of the classic TrkA system in regulating inflammatory or neuropathic pain. PMID- 24494681 TI - Anandamide in primary sensory neurons: too much of a good thing? AB - The quest for possible targets for the development of novel analgesics has identified the activation of the cannabinoid type 1 (CB1) receptor outside the CNS as a potential means of providing relief from persistent pain, which currently constitutes an unmet medical need. Increasing tissue levels of the CB1 receptor endogenous ligand N-arachidonoylethanolamine (anandamide), by inhibiting anandamide degradation through blocking the anandamide-hydrolysing enzyme fatty acid amide hydrolase, has been suggested to be used to activate the CB1 receptor. However, recent clinical trials revealed that this approach does not deliver the expected relief from pain. Here, we discuss one of the possible reasons, the activation of the transient receptor potential vanilloid type 1 ion channel (TRPV1) on nociceptive primary sensory neurons (PSNs) by anandamide, which may compromise the beneficial effects of increased tissue levels of anandamide. We conclude that better design such as concomitant blocking of anandamide hydrolysis and anandamide uptake into PSNs, to inhibit TRPV1 activation, could overcome these problems. PMID- 24494682 TI - Heterogeneous presynaptic distribution of monoacylglycerol lipase, a multipotent regulator of nociceptive circuits in the mouse spinal cord. AB - Monoacylglycerol lipase (MGL) is a multifunctional serine hydrolase, which terminates anti-nociceptive endocannabinoid signaling and promotes pro nociceptive prostaglandin signaling. Accordingly, both acute nociception and its sensitization in chronic pain models are prevented by systemic or focal spinal inhibition of MGL activity. Despite its analgesic potential, the neurobiological substrates of beneficial MGL blockade have remained unexplored. Therefore, we examined the regional, cellular and subcellular distribution of MGL in spinal circuits involved in nociceptive processing. All immunohistochemical findings obtained with light, confocal or electron microscopy were validated in MGL knockout mice. Immunoperoxidase staining revealed a highly concentrated accumulation of MGL in the dorsal horn, especially in superficial layers. Further electron microscopic analysis uncovered that the majority of MGL-immunolabeling is found in axon terminals forming either asymmetric glutamatergic or symmetric gamma-aminobutyric acid/glycinergic synapses in laminae I/IIo. In line with this presynaptic localization, analysis of double-immunofluorescence staining by confocal microscopy showed that MGL colocalizes with neurochemical markers of peptidergic and non-peptidergic nociceptive terminals, and also with markers of local excitatory or inhibitory interneurons. Interestingly, the ratio of MGL immunolabeling was highest in calcitonin gene-related peptide-positive peptidergic primary afferents, and the staining intensity of nociceptive terminals was significantly reduced in MGL-knockout mice. These observations highlight the spinal nociceptor synapse as a potential anatomical site for the analgesic effects of MGL blockade. Moreover, the presence of MGL in additional terminal types raises the possibility that MGL may play distinct regulatory roles in synaptic endocannabinoid or prostaglandin signaling according to its different cellular locations in the dorsal horn pain circuitry. PMID- 24494684 TI - Supraspinal metabotropic glutamate receptors: a target for pain relief and beyond. AB - Glutamate is the main excitatory neurotransmitter in the central nervous system, controlling the majority of synapses. Apart from neurodegenerative diseases, growing evidence suggests that glutamate is involved in psychiatric and neurological disorders, including pain. Glutamate signaling is mediated via ionotropic glutamate receptors (iGluRs) and metabotropic glutamate receptors (mGluRs). So far, drugs acting via modulation of glutamatergic system are few in number, and all are associated with iGluRs and important side effects. The glutamatergic system may be finely modulated by mGluRs. Signaling via these receptors is slower and longer-lasting, and permits fine-tuning of glutamate transmission. There have been eight mGluRs cloned to date (mGluR1-mGluR8), and these are further divided into three groups on the basis of sequence homology, pharmacological profile, and second messenger signaling. The pattern of expression of mGluRs along the pain neuraxis makes them suitable substrates for the design of novel analgesics. This review will focus on the supraspinal mGluRs, whose pharmacological manipulation generates a variety of effects, which depend on the synaptic location, the cell type on which they are located, and the expression in particular pain modulation areas, such as the periaqueductal gray, which plays a major role in the descending modulation of pain, and the central nucleus of the amygdala, which is an important center for the processing of emotional information associated with pain. A particular emphasis will also be given to the novel selective mGluR subtype ligands, as well as positive and negative allosteric modulators, which have permitted discrimination of the individual roles of the different mGluR subtypes, and subtle modulation of central nervous system functioning and related disorders. PMID- 24494683 TI - Microinjection of 2-arachidonoyl glycerol into the rat ventral hippocampus differentially modulates contextually induced fear, depending on a persistent pain state. AB - The endogenous cannabinoid (endocannabinoid) system plays a key role in the modulation of aversive and nociceptive behaviour. The components of the endocannabinoid system are expressed throughout the hippocampus, a brain region implicated in both conditioned fear and pain. In light of evidence that pain can impact on the expression of fear-related behaviour, and vice versa, we hypothesised that exogenous administration of the endocannabinoid 2-arachidonoyl glycerol (2-AG) into the ventral hippocampus (vHip) would differentially regulate fear responding in the absence vs. the presence of formalin-evoked nociceptive tone. Fear-conditioned rats showed significantly increased freezing and a reduction in formalin-evoked nociceptive behaviour upon re-exposure to a context previously paired with footshock. Bilateral microinjection of 2-AG into the vHip significantly reduced contextually induced freezing in non-formalin-treated rats, and reduced formalin-evoked nociceptive behaviour in non-fear-conditioned rats. In contrast, 2-AG microinjection had no effect on fear responding in formalin treated rats, and no effect on nociceptive behaviour in fear-conditioned rats. The inhibitory effect of 2-AG on fear-related behaviour, but not pain-related behaviour, was blocked by co-administration of the cannabinoid receptor 1 (CB1) antagonist/inverse agonist rimonabant. Tissue levels of the endocannabinoids N arachidonoylethanolamide (anandamide, AEA) and 2-AG were similar in the vHip of fear-conditioned rats receiving formalin injection and the vHip of fear conditioned rats receiving saline injection. However, the levels of AEA and 2-AG were significantly lower in the contralateral ventrolateral periaqueductal grey of formalin-treated fear-conditioned rats than in that of their saline-treated counterparts. These data suggest that 2-AG-CB1 receptor signalling in the vHip has an anti-aversive effect, and that this effect is abolished in the presence of a persistent pain state. PMID- 24494687 TI - Involvement of the endocannabinoid system in osteoarthritis pain. AB - Osteoarthritis is a degenerative joint disease associated with articular cartilage degradation. The major clinical outcome of osteoarthritis is a complex pain state that includes both nociceptive and neuropathic mechanisms. Currently, the therapeutic approaches for osteoarthritis are limited as no drugs are available to control the disease progression and the analgesic treatment has restricted efficacy. Increasing evidence from preclinical studies supports the interest of the endocannabinoid system as an emerging therapeutic target for osteoarthritis pain. Indeed, pharmacological studies have shown the anti nociceptive effects of cannabinoids in different rodent models of osteoarthritis, and compelling evidence suggests an active participation of the endocannabinoid system in the pathophysiology of this disease. The ubiquitous distribution of cannabinoid receptors, together with the physiological role of the endocannabinoid system in the regulation of pain, inflammation and even joint function further support the therapeutic interest of cannabinoids for osteoarthritis. However, limited clinical evidence has been provided to support this therapeutic use of cannabinoids, despite the promising preclinical data. This review summarizes the promising results that have been recently obtained in support of the therapeutic value of cannabinoids for osteoarthritis management. PMID- 24494686 TI - No more pain upon Gq-protein-coupled receptor activation: role of endocannabinoids. AB - Marijuana has been used to relieve pain for centuries. The analgesic mechanism of its constituents, the cannabinoids, was only revealed after the discovery of cannabinoid receptors (CB1 and CB2) two decades ago. The subsequent identification of the endocannabinoids, anandamide and 2-arachidonoylglycerol (2 AG), and their biosynthetic and degradation enzymes discloses the therapeutic potential of compounds targeting the endocannabinoid system for pain control. Inhibitors of the anandamide and 2-AG degradation enzymes, fatty acid amide hydrolase and monoacylglycerol lipase, respectively, may be superior to direct cannabinoid receptor ligands as endocannabinoids are synthesized on demand and rapidly degraded, focusing action at generating sites. Recently, a promising strategy for pain relief was revealed in the periaqueductal gray (PAG). It is initiated by Gq-protein-coupled receptor (Gq PCR) activation of the phospholipase C-diacylglycerol lipase enzymatic cascade, generating 2-AG that produces inhibition of GABAergic transmission (disinhibition) in the PAG, thereby leading to analgesia. Here, we introduce the antinociceptive properties of exogenous cannabinoids and endocannabinoids, involving their biosynthesis and degradation processes, particularly in the PAG. We also review recent studies disclosing the Gq PCR-phospholipase C-diacylglycerol lipase-2-AG retrograde disinhibition mechanism in the PAG, induced by activating several Gq PCRs, including metabotropic glutamatergic (type 5 metabotropic glutamate receptor), muscarinic acetylcholine (M1/M3), and orexin 1 receptors. Disinhibition mediated by type 5 metabotropic glutamate receptor can be initiated by glutamate transporter inhibitors or indirectly by substance P, neurotensin, cholecystokinin and capsaicin. Finally, the putative role of 2-AG generated after activating the above neurotransmitter receptors in stress-induced analgesia is discussed. PMID- 24494685 TI - CB1 augments mGluR5 function in medial prefrontal cortical neurons to inhibit amygdala hyperactivity in an arthritis pain model. AB - The medial prefrontal cortex (mPFC) serves executive control functions and forms direct connections with subcortical areas such as the amygdala. Our previous work showed abnormal inhibition of mPFC pyramidal cells and hyperactivity of amygdala output neurons in an arthritis pain model. To restore mPFC activity and hence control pain-related amygdala hyperactivity this study focused on CB1 and mGluR5 receptors, which are important modulators of cortical functions. Extracellular single-unit recordings of infralimbic mPFC pyramidal cells and of amygdala output neurons in the laterocapsular division of the central nucleus (CeLC) were made in anesthetised adult male rats. mPFC neurons were classified as 'excited' or 'inhibited' based on their response to brief innocuous and noxious test stimuli. After arthritis pain induction, background activity and evoked responses of excited neurons and background activity and inhibition of inhibited neurons decreased. Stereotaxic application of an mGluR5-positive allosteric modulator (N cyclobutyl-6-((3-fluorophenyl)ethynyl) nicotinamide hydrochloride, VU0360172) into the mPFC increased background and evoked activity of excited, but not inhibited, mPFC neurons under normal conditions but not in arthritis. A selective CB1 receptor agonist (arachidonyl-2-chloroethylamide) alone had no effect but restored the facilitatory effects of VU0360172 in the pain model. Coactivation of CB1 and mGluR5 in the mPFC inhibited the pain-related activity increase of CeLC neurons but had no effect under normal conditions. The data suggest that excited mPFC neurons are inversely linked to amygdala output (CeLC) and that CB1 can increase mGluR5 function in this subset of mPFC neurons to engage cortical control of abnormally enhanced amygdala output in pain. PMID- 24494688 TI - The upstream Variable Number Tandem Repeat polymorphism of the monoamine oxidase type A gene influences trigeminal pain-related evoked responses. AB - Monoamines have an important role in neural plasticity, a key factor in cortical pain processing that promotes changes in neuronal network connectivity. Monoamine oxidase type A (MAOA) is an enzyme that, due to its modulating role in monoaminergic activity, could play a role in cortical pain processing. The X linked MAOA gene is characterized by an allelic variant of length, the MAOA upstream Variable Number Tandem Repeat (MAOA-uVNTR) region polymorphism. Two allelic variants of this gene are known, the high-activity MAOA (HAM) and low activity MAOA (LAM). We investigated the role of MAOA-uVNTR in cortical pain processing in a group of healthy individuals measured by the trigeminal electric pain-related evoked potential (tPREP) elicited by repeated painful stimulation. A group of healthy volunteers was genotyped to detect MAOA-uVNTR polymorphism. Electrical tPREPs were recorded by stimulating the right supraorbital nerve with a concentric electrode. The N2 and P2 component amplitude and latency as well as the N2-P2 inter-peak amplitude were measured. The recording was divided into three blocks, each containing 10 consecutive stimuli and the N2-P2 amplitude was compared between blocks. Of the 67 volunteers, 37 were HAM and 30 were LAM. HAM subjects differed from LAM subjects in terms of amplitude of the grand-averaged and first-block N2-P2 responses (HAM>LAM). The N2-P2 amplitude decreased between the first and third block in HAM subjects but not LAM subjects. The MAOA-uVNTR polymorphism seemed to influence the brain response in a repeated tPREP paradigm and suggested a role of the MAOA as a modulator of neural plasticity related to cortical pain processing. PMID- 24494690 TI - Current state of castration-resistant prostate cancer. AB - Prostate cancer (PrCa) is the most common cancer found among men in the United States, and is the second-leading cause of death for these individuals. Although most patients with prostate cancer experience disease control after primary therapy, approximately 20% to 40% of these patients will eventually encounter recurrent disease. While androgen deprivation therapy may achieve temporary tumor control or regression in the majority of patients with advanced disease, virtually all patients with metastatic disease will experience progressive PrCa. Consequently, their disease may no longer respond to primary androgen blockade and may then spread to distant sites, most commonly to the bones and/or regional lymph nodes. This state of disease, termed castration-resistant prostate cancer (CRPC), is heterogeneous, has a variety of clinical symptoms which may include biochemical progression, progression in bone, or soft tissue, and may present with or without symptoms from cancer. While treatments were previously somewhat limited, there has been a substantial increase in the understanding of the biological and genetic basis for PrCa progression. The mechanisms of androgen independence in CRPC include, but are not limited to, autocrine production of androgen by the prostate cancer cell, as well as androgen receptor activity despite low testosterone levels, through a variety of different mechanisms. These findings have led to more targeted therapies for CRPC, improved clinical outcomes, and increased survival. Further understanding of the mechanisms that cause castration resistance potentially could improve therapeutic efficacy. PMID- 24494691 TI - Challenges in treating advanced disease. AB - Castration-resistant prostate cancer (CRPC) has historically presented significant challenges to both clinicians and patients in regard to disease progression and consequent management. The first advances in the treatment of this state of prostate cancer with docetaxel chemotherapy demonstrated a survival benefit over the palliative standard of care, mitoxantrone combined with prednisone. The recognition that these patients still maintained active androgen receptor access identified new therapeutic agents for CRPC that aimed to further deplete testosterone levels or directly interact with the androgen receptor (ie, enzalutamide). Other therapeutic targets that have established efficacy in randomized phase 3 trials include bone metastases (ie, radium 223 dichloride), the immune system (ie, sipuleucel-T), and tubulin (ie, cabazitaxel). These new and evolving agents are positioned to substantially alter the therapeutic environment for CRPC and to improve patient outcomes and quality of life. PMID- 24494692 TI - Managed care implications in castration-resistant prostate cancer. AB - The management of prostate cancer (PrCa) and especially castration-resistant disease can be complex, challenging, and costly. Significant developments in the field of oncology have led to the further development of safe and effective therapies that are better targeted to particular tumor types and to individual patients. This is evident in castration-resistant prostate cancer (CRPC), where 5 new therapies proved to increase overall survival have debuted in just the past few years. With new therapies, however, come new treatment paradigms and new potential costs. It is vital that managed care clinicians and providers analyze the burden and the costs of cancer in the United States, especially those relating to PrCa and especially CRPC. This will allow a better understanding of how costs and issues relating to healthcare utilization affect the treatment of patients with CRPC, and impact individualized therapy and management decisions. PMID- 24494689 TI - The neurobiology of skeletal pain. AB - Disorders of the skeleton are one of the most common causes of chronic pain and long-term physical disability in the world. Chronic skeletal pain is caused by a remarkably diverse group of conditions including trauma-induced fracture, osteoarthritis, osteoporosis, low back pain, orthopedic procedures, celiac disease, sickle cell disease and bone cancer. While these disorders are diverse, what they share in common is that when chronic skeletal pain occurs in these disorders, there are currently few therapies that can fully control the pain without significant unwanted side effects. In this review we focus on recent advances in our knowledge concerning the unique population of primary afferent sensory nerve fibers that innervate the skeleton, the nociceptive and neuropathic mechanisms that are involved in driving skeletal pain, and the neurochemical and structural changes that can occur in sensory and sympathetic nerve fibers and the CNS in chronic skeletal pain. We also discuss therapies targeting nerve growth factor or sclerostin for treating skeletal pain. These therapies have provided unique insight into the factors that drive skeletal pain and the structural decline that occurs in the aging skeleton. We conclude by discussing how these advances have changed our understanding and potentially the therapeutic options for treating and/or preventing chronic pain in the injured, diseased and aged skeleton. PMID- 24494693 TI - Caries experience, mutans streptococci and total protein concentrations in children with protein-energy undernutrition. AB - BACKGROUND: The highest prevalence of protein-energy undernutrition is observed during early childhood, being also a time in which the presence of dental caries can be unusually aggressive. The present study aimed to verify if different levels of undernutrition could influence the risk of early childhood caries (ECC), in the presence of other predisposing factors. METHODS: One hundred and twenty undernourished 12-70 month old children, with or without ECC, were selected. Undernourished children were classified as being mildly, moderately or severely undernourished. All children were examined for determination of decayed, missing and filled surfaces (dmfs). Total protein concentration in saliva was analysed by the Bradford method. For microbiological analysis, mitis salivarius bacitracin agar medium was used. A binary logistic regression model was applied to test the simultaneous influence of different variables over caries experience. RESULTS: The risk of ECC was significantly higher with an increase in age (p = 0.000) and mutans streptococci counts (p = 0.032). Comparisons with the normal weight group showed that mildly (p = 0.004) and severely undernourished children (p = 0.037) had a higher risk of experiencing ECC, but this risk was not significantly elevated among moderately undernourished children (p = 0.158). CONCLUSIONS: Our results suggest that mildly and severely undernourished children have an increased risk of experiencing dental caries. Age is highly associated with the disease in this population. PMID- 24494694 TI - How weeds emerge: a taxonomic and trait-based examination using United States data. AB - Weeds can cause great economic and ecological harm to ecosystems. Despite their importance, comparisons of the taxonomy and traits of successful weeds often focus on a few specific comparisons - for example, introduced versus native weeds. We used publicly available inventories of US plant species to make comprehensive comparisons of the factors that underlie weediness. We quantitatively examined taxonomy to determine if certain genera are overrepresented by introduced, weedy or herbicide-resistant species, and we compared phenotypic traits of weeds to those of nonweeds, whether introduced or native. We uncovered genera that have more weeds and introduced species than expected by chance and plant families that have more herbicide-resistant species than expected by chance. Certain traits, generally related to fast reproduction, were more likely to be associated with weedy plants regardless of species' origins. We also found stress tolerance traits associated with either native or introduced weeds compared with native or introduced nonweeds. Weeds and introduced species have significantly smaller genomes than nonweeds and native species. These results support trends for weedy plants reported from other floras, suggest that native and introduced weeds have different stress adaptations, and provide a comprehensive survey of trends across weeds within the USA. PMID- 24494695 TI - What factors determine disclosure of suicide ideation in adults 60 and older to a treatment provider? AB - Correlates of patient disclosure of suicide ideation to a primary care or mental health provider were identified. Secondary analyses of IMPACT trial data were conducted. Of the 107 patients 60 years of age or older who endorsed thoughts of ending their life at least "a little bit" during the past month, 53 indicated they had disclosed these thoughts to a mental health or primary care provider during this period. Multiple logistic regression was used to identify predictors of disclosure to a provider. Significant predictors included poorer quality of life and prior mental health specialty treatment. Among participants endorsing thoughts of suicide, the likelihood of disclosing these thoughts to a provider was 2.96 times higher if they had a prior history of mental health specialty treatment and 1.56 times higher for every one-unit decrease in quality of life. Variation in disclosure of thoughts of suicide to a mental health or primary care provider depends, in part, on patient characteristics. Although the provision of evidence-based suicide risk assessment and guidelines could minimize unwanted variation and enhance disclosure, efforts to routinize the process of suicide risk assessment should also consider effective ways to lessen potential unintended consequences. PMID- 24494696 TI - Merging applicability domains for in silico assessment of chemical mutagenicity. AB - Using a benchmark Ames mutagenicity data set, we evaluated the performance of molecular fingerprints as descriptors for developing quantitative structure activity relationship (QSAR) models and defining applicability domains with two machine-learning methods: random forest (RF) and variable nearest neighbor (v NN). The two methods focus on complementary aspects of chemical mutagenicity and use different characteristics of the molecular fingerprints to achieve high levels of prediction accuracies. Thus, while RF flags mutagenic compounds using the presence or absence of small molecular fragments akin to structural alerts, the v-NN method uses molecular structural similarity as measured by fingerprint based Tanimoto distances between molecules. We showed that the extended connectivity fingerprints could intuitively be used to define and quantify an applicability domain for either method. The importance of using applicability domains in QSAR modeling cannot be understated; compounds that are outside the applicability domain do not have any close representative in the training set, and therefore, we cannot make reliable predictions. Using either approach, we developed highly robust models that rival the performance of a state-of-the-art proprietary software package. Importantly, based on the complementary approach used by the methods, we showed that by combining the model predictions we raised the applicability domain from roughly 80% to 90%. These results indicated that the proposed QSAR protocol constituted a highly robust chemical mutagenicity prediction model. PMID- 24494697 TI - Symptom burden and its association with change in glucose metabolism status over a 7-year period: the Hoorn Study. AB - AIMS: To study symptom burden among older people and its associations with change in glucose metabolism status over a 7-year period. METHODS: We conducted a prospective population-based cohort study among 397 older people. We used the revised Diabetes Symptom Checklist to assess symptom burden. Glucose metabolism status was determined using an oral glucose tolerance test. Analyses were adjusted for multiple confounders, including cardiovascular risk and risk of depression (Center for Epidemiological Studies Depression Scale score >= 16). RESULTS: Revised Diabetes Symptom Checklist total scores (range 0-100) increased slightly over time among people with normal glucose metabolism (mean difference beta1.04; P = 0.04) and those with impaired glucose metabolism (beta1.96; P = 0.01), but not among people with Type 2 diabetes (beta0.46; P = 0.55). These associations between symptom burden and glucose status were attenuated after full adjustment for multiple confounders and remained statistically significant for those with impaired glucose status. Linear mixed models showed significant mean differences in revised Diabetes Symptom Checklist total scores over time when comparing people with Type 2 diabetes with those with normal or impaired glucose metabolism, but not when comparing subjects with impaired vs normal glucose metabolism; these results did not alter after full adjustment. CONCLUSIONS: Symptom burden increased gradually over time in the people with impaired glucose metabolism and those with normal glucose metabolism, but not in patients with Type 2 diabetes over a 7-year follow-up period. PMID- 24494698 TI - Amino acid anions in organic ionic compounds. An ab initio study of selected ion pairs. AB - The combination of amino acids in their deprotonated and thus anionic form with a choline cation gives origin to a new and potentially important class of organic ionic compounds. A series of such neutral ion pairs has been investigated by first principle methods. The results reveal intriguing structural motives as well as regular patterns in the charge distribution and predict a number of vibrational and optical properties that could guide the experimental investigation of these compounds. The replacement of choline with its phosphocholine analogue causes the spontaneous reciprocal neutralization of cations and anions, taking place through the transfer of a proton between the two ions. Systems of this kind, therefore, provide a wide and easily accessible playground to probe the ionic/polar transition in organic systems, while the easy transfer of H(+) among neutral and ionic species points to their potential application as proton conductors. The analysis of the ab initio data highlights similarities as well as discrepancies from the rigid-ions force-field picture and suggests directions for the improvement of empirical models. PMID- 24494699 TI - Challenges and opportunities of the bio-pesticides production by solid-state fermentation: filamentous fungi as a model. AB - In recent years, production and use of bio-pesticides have increasing and replacing some synthetic chemical pesticides applied to food commodities. In this review, biological control is focused as an alternative, to some synthetic chemical treatments that cause environmental, human health, and food quality risks. In addition, several phytopathogenic microorganisms have developed resistance to some of these synthetic chemicals and become more difficult to control. Worldwide, the bio-pesticides market is growing annually at a rate of 44% in North America, 20% in Europe and Oceania, 10% in Latin and South American countries and 6% in Asia. Use of agro-industrial wastes and solid-state fermentation (SSF) technology offers an alternative to bio-pesticide production with advantages versus conventional submerged fermentations, as reduced cost and energy consumption, low production of residual water and high stability products. In this review, recent data about state of art regarding bio-pesticides production under SSF on agroindustrial wastes will be discussed. SSF can be defined as a microbial process that generally occurs on solid material in the absence of free water. This material has the ability to absorb water with or without soluble nutrients, since the substrate must have water to support the microorganism's growth and metabolism. Changes in water content are analyzed in order to select the conditions for a future process, where water stress can be combined with the best spore production conditions, obtaining in this way an inexpensive biotechnological option for modern agriculture in developing countries. PMID- 24494700 TI - Recent trends in ionic liquid (IL) tolerant enzymes and microorganisms for biomass conversion. AB - Second generation biofuel production depends on lignocellulosic (LC) biomass transformation into simple sugars and their subsequent fermentation into alcohols. However, the main obstacle in this process is the efficient breakdown of the recalcitrant cellulose to sugar monomers. Hence, efficient feedstock pretreatment and hydrolysis are necessary to produce a cost effective biofuel. Recently, ionic liquids (ILs) have been recognized as a promising solvent able to dissolve different biomass feedstocks, providing higher sugar yields. However, most of the hydrolytic enzymes and microorganisms are inactivated, completely or partially, in the presence of even low concentrations of IL, making necessary the discovery of novel hydrolytic enzymes and fermentative microorganisms that are tolerant to ILs. In this review, the current state and the challenges of using ILs as a pretreatment of LC biomass was evaluated, underlining the advances in the discovery and identification of new IL-tolerant enzymes and microorganisms that could improve the bioprocessing of biomass to fuels and chemicals. PMID- 24494701 TI - Genetic and metabolic engineering of microorganisms for the development of new flavor compounds from terpenic substrates. AB - Throughout human history, natural products have been the basis for the discovery and development of therapeutics, cosmetic and food compounds used in industry. Many compounds found in natural organisms are rather difficult to chemically synthesize and to extract in large amounts, and in this respect, genetic and metabolic engineering are playing an increasingly important role in the production of these compounds, such as new terpenes and terpenoids, which may potentially be used to create aromas in industry. Terpenes belong to the largest class of natural compounds, are produced by all living organisms and play a fundamental role in human nutrition, cosmetics and medicine. Recent advances in systems biology and synthetic biology are allowing us to perform metabolic engineering at the whole-cell level, thus enabling the optimal design of microorganisms for the efficient production of drugs, cosmetic and food additives. This review describes the recent advances made in the genetic and metabolic engineering of the terpenes pathway with a particular focus on systems biotechnology. PMID- 24494702 TI - Production of conidia of Beauveria bassiana in solid-state culture: current status and future perspectives. AB - Beauveria bassiana is an important entomopathogenic fungus widely commercialized in the world. Recent progress and achievements on conidia production have focused on a yield goal of 10(9) to 10(10) conidia per gram of dry substrate. Due to cost competitive perspectives, these yields should be associated with better production rates or productivities. This study presents a review of relevant studies of B. bassiana conidia production on solid-state cultures and the parameters that should be taken into account to maintain constant quality in the product to be commercialized. Conditions for maximizing production and infectivity of B. bassiana conidia are also analysed. PMID- 24494703 TI - Subcritical and supercritical technology for the production of second generation bioethanol. AB - There is increased interest in reducing our reliance on fossil fuels and increasing the share of renewable raw materials in our energy supply chain due to environmental and economic concerns. Ethanol is emerging as a potential alternative to liquid fuels due to its eco-friendly characteristics and relatively low production costs. As ethanol is currently produced from commodities also used for human and animal consumption, there is an urgent need of identifying renewable raw materials that do not pose a competitive problem. Lignocellulosic agricultural residues are an ideal choice since they can be effectively hydrolyzed to fermentable sugars and integrated in the context of a biorefinery without competing with the food supply chain. However, the conventional hydrolysis methods still have major issues that need to be addressed. These issues are related to the processing rate and generation of fermentation inhibitors, which can compromise the quality of the product and the cost of the process. As the knowledge of the processes taking place during hydrolysis of agricultural residues is increasing, new techniques are being exploited to overcome these drawbacks. This review gives an overview of the state of-the-art of hydrolysis with subcritical and supercritical water in the context of reusing agricultural residues for the production of suitable substrates to be processed during the fermentative production of bioethanol. Presently, subcritical and/or supercritical water hydrolysis has been found to yield low sugar contents mainly due to concurrent competing degradation of sugars during the hydrothermal processes. In this line of thinking, the present review also revisits the recent applications and advances to provide an insight of future research trends to optimize on the subcritical and supercritical process kinetics. PMID- 24494706 TI - Micropercutaneous cystolithotomy in children: our experience with the transillumination technique. AB - AIM: We present our experience with micropercutaneous cystolithotripsy (mPCCL) using transillumination-guided access in children with bladder stones and evaluate the safety and efficacy of this procedure. METHODS: Twelve children who underwent mPCCL for bladder stone removal in our department between January 2011 and September 2013 were included in this study. Percutaneous access was performed using the transillumination technique. The chief complaint, age and sex of the patients, stone size, operative time, complications, stone-free rate, and stone composition as determined by radiography diffraction analysis were recorded. RESULTS: The mean age of the patients was 2.6 (1-7) years. One out of 12 patients was a girl. The mean stone size was 14 mm (7-32 mm). The mean mPCCL procedure time was 38.7 (15-65) minutes. The mean hospital stay was 1.4 (0.5-4) days. The stone-free rate after one mPCCL intervention was 91.6% and increased to 100% after two sessions of mPCCL. The notable complications were transient macroscopic hematuria in one patient, acute urinary retention in one patient, and the need for a second session of mPCCL in another patient. The stones were composed of calcium oxalate (3), ammonium acid urate (1), calcium phosphate (1), cystine (1), struvite (1), and unknown (5). CONCLUSION: Transillumination-guided mPCCL is a safe and effective technique, does not require the use of ionizing radiation, is technically easy, and is a minimally invasive alternative for the management of bladder stones. It has many advantages, especially in pediatric patients, such as decreased urethral injury, no need for postoperative catheter insertion in most cases, and shorter operative time. PMID- 24494704 TI - Smurf2 regulates hematopoietic stem cell self-renewal and aging. AB - The age-dependent decline in the self-renewal capacity of stem cells plays a critical role in aging, but the precise mechanisms underlying this decline are not well understood. By limiting proliferative capacity, senescence is thought to play an important role in age-dependent decline of stem cell self-renewal, although direct evidence supporting this hypothesis is largely lacking. We have previously identified the E3 ubiquitin ligase Smurf2 as a critical regulator of senescence. In this study, we found that mice deficient in Smurf2 had an expanded hematopoietic stem cell (HSC) compartment in bone marrow under normal homeostatic conditions, and this expansion was associated with enhanced proliferation and reduced quiescence of HSCs. Surprisingly, increased cycling and reduced quiescence of HSCs in Smurf2-deficient mice did not lead to premature exhaustion of stem cells. Instead, HSCs in aged Smurf2-deficient mice had a significantly better repopulating capacity than aged wild-type HSCs, suggesting that decline in HSC function with age is Smurf2 dependent. Furthermore, Smurf2-deficient HSCs exhibited elevated long-term self-renewal capacity and diminished exhaustion in serial transplantation. As we found that the expression of Smurf2 was increased with age and in response to regenerative stress during serial transplantation, our findings suggest that Smurf2 plays an important role in regulating HSC self renewal and aging. PMID- 24494707 TI - Healthcare costs associated with skeletal-related events in breast cancer patients with bone metastases. AB - BACKGROUND: Patients with bone metastases secondary to breast cancer are pre disposed to skeletal-related events (SREs), including spinal cord compression (SCC), pathologic fracture (PF), surgery to bone (SB), and radiotherapy to bone (RT). OBJECTIVE: To document current patterns of healthcare utilization and costs of SREs in patients with breast cancer and bone metastases. METHODS: This was a retrospective, observational study using the Thomson MedStat MarketScan Commercial Claims and Encounters database from 9/2002 to 6/2011. Study subjects included all persons with claims for breast cancer and for bone metastases, and >=1 claims for an SRE. Unique SRE episodes were identified based on a gap of at least 90 days without an SRE claim, and classified by treatment setting (inpatient or outpatient) and SRE type (SCC, PF, SB, or RT). RESULTS: Of 17,266 patients with breast cancer and bone metastases, 9142 (53%) had one or more SRE episodes. Among 5809 patients who met all other criteria, there were 7617 SRE episodes over mean (SD) follow-up of 17.2 (15.2) months. The percentage of episodes that required inpatient treatment ranged from 11% (RT) to 76% (SB). On average, inpatient SCC episodes (n=83 episodes) were most costly; while outpatient PF episodes (n=552 episodes) were least costly. Of the total SRE costs (mean [SE] $21,072 [$36,462]/episode), 36% were attributable to outpatient RT (n=5265 episodes) and 31% to inpatient PF (n=838 episodes). LIMITATIONS: The administrative claims data used in this study may lack sensitivity and specificity for identification of clinical events and may not be generalizable to other populations. Also, for some SRE episode categories, the number of events was small and cost estimates may lack precision. CONCLUSION: In patients with breast cancer and bone metastases, SREs are associated with high costs and hospitalizations. PMID- 24494709 TI - Improving the voltammetric quantification of ill-defined peaks using second derivative signal transformation: example of the determination of platinum in water and sediments. AB - The determination of trace elements using stripping voltammetry may be seriously affected by the presence of intensive matrix background or interfering peaks, leading to poorer detection limits and/or inaccurate quantitative results. In this work, we have tested the use of signal transformation (e.g., second derivative) in the analysis of platinum in seawater and sediment digests by means of catalytic adsorptive stripping voltammetry. In natural waters, the limit of detection of Pt is affected by a broad background wave due to the formazone complex used in the sample matrix for its determination, while in sediment digests, the Pt peak may be interfered with due to the presence of elevated concentrations of Zn, affecting the accuracy of the determination. Results applying second derivative signal transformation revealed a significant improvement (2-3-fold) of the detection limit in water due to the minimization of background effects, therefore allowing shorter accumulation times and faster determinations. In the presence of interfering peaks, the inaccuracy resulting from erroneous baseline selection in the original signal is eliminated when the second derivative is used. Signal processing should be considered as a useful tool for other voltammetric methodologies where more accurate or faster determinations are needed. PMID- 24494708 TI - Characterization of the enhanced bone regenerative capacity of human periodontal ligament stem cells engineered to express the gene encoding bone morphogenetic protein 2. AB - Human periodontal ligament stem cells (hPDLSCs) are considered an appropriate cell source for therapeutic strategies. The aims of this study were to investigate the sustainability of bone morphogenetic protein 2 (BMP2) secretion and the bone regenerative capacity of hPDLSCs that had been genetically modified to express the gene encoding BMP2 (BMP2). hPDLSCs isolated from healthy third molars were transduced using replication-deficient recombinant adenovirus (rAd) encoding BMP2 (hPDLSCs/rAd-BMP2), and the cellular characteristics and osteogenic potentials of hPDLSCs/rAd-BMP2 were analyzed both in vitro and in vivo. hPDLSCs/rAd-BMP2 successfully secreted BMP2, formed colonies, and expressed immunophenotypes similar to their nontransduced counterparts. As to their osteogenic potential, hPDLSCs/rAd-BMP2 formed greater mineralized nodules and exhibited significantly higher levels of expression of BMP2 and the gene encoding alkaline phosphatase, and formed more and better quality bone than other hPDLSC containing or recombinant human BMP2-treated groups, being localized at the initial site until 8 weeks. The findings of the present study demonstrate that hPDLSCs/rAd-BMP2 effectively promote osteogenesis not only in vitro but also in vivo. The findings also suggest that hPDLSCs can efficiently carry and deliver BMP2, and that hPDLSCs/rAd-BMP2 could be used in an attractive novel therapeutic approach for the regeneration of deteriorated bony defects. PMID- 24494710 TI - Assessing the approach to a thrombosed AV graft. AB - The patency of the vascular access (VA) is a fight for the attending nephrologist. A retrospective observational study was conducted to compare the success rate of surgical versus endovascular technique percutaneous transluminal angioplasty (PTA) for graft thrombosis treatment. Of 3008 patients, 22.1% patients were dialyzed through grafts. Forty-five percent of all prevalent patients referred due to VA malfunction had a graft. For 18 months, 336 thrombosed grafts were submitted to surgery in 228 cases and to PTA in 126. PTA for thrombolysis included the Pharmaco-Mechanical Technique and the Arrow Trerotola Device. Procedures were performed as outpatient, with an average delay of 1 day. Immediate success was 100% for surgery and 87.3% for PTA. The unassisted patency for thrombosed grafts for surgery/PTA was 265.12 +/- 15.30/230.59 +/- 19.83 days respectively, favoring surgery. The primary patency for thrombosed grafts treated by surgery/PTA at 30, 90, and 180 days was, respectively, 74.1%/81%, 63.2%/67.5%, and 53.9%/55.6% all in favor of PTA. AV grafts have a much higher rate of thrombosis than fistulas. Graft thrombosis can be dealt either by surgery or PTA, with identical success. PMID- 24494711 TI - Thermodynamic characterization of halide-pi interactions in solution using "two wall" aryl extended calix[4]pyrroles as model system. AB - Herein, we report our latest experimental investigations of halide-pi interactions in solution. We base this research on the thermodynamic characterization of a series of 1:1 complexes formed between halides (Cl(-), Br( ), and I(-)) and several alpha,alpha-isomers of "two-wall" calix[4]pyrrole receptors bearing two six-membered aromatic rings in opposed meso positions. The installed aromatic systems feature a broad range of electron density as indicated by the calculated values for their electrostatic surface potentials at the center of the rings. We show that a correlation exists between the electronic nature of the aromatic walls and the thermodynamic stability of the X(-)?receptor complexes. We give evidence for the existence of both repulsive and attractive interactions between pi systems and halide anions in solution (between 1 and -1 kcal/mol). We dissect the measured free energies of binding for chloride and bromide with the receptor series into their enthalpic and entropic thermodynamic quantities. In acetonitrile solution, the binding enthalpy values remain almost constant throughout the receptor series, and the differences in free energies are provoked exclusively by changes in the entropic term of the binding processes. Most likely, this unexpected behavior is owed to strong solvation effects that make up important components of the measured magnitudes for the enthalpies and entropies of binding. The use of chloroform, a much less polar solvent, limits the impact of solvation effects revealing the expected existence of a parallel trend between free energies and enthalpies of binding. This result indicates that halide-pi interactions in organic solvents are mainly driven by enthalpy. However, the typical paradigm of enthalpy-entropy compensation is still not observed in this less polar solvent. PMID- 24494712 TI - Bacterial population structure and dynamics during the development of almond drupes. AB - AIMS: To describe the bacterial populations and their dynamics during the development of almond drupes. METHODS AND RESULTS: We examined 16S rRNA gene libraries derived from the bacterial populations on almond drupes at three stages of development: (i) when the drupes were full sized, but before embryo development, (ii) when the drupe hulls first began to split and (iii) when the drupes were fully mature, but before harvesting. Our data revealed that the immature drupes were colonized by relatively few types of bacteria, belonging mostly to common phyllosphere-associated bacteria within the genera Pseudomonas, Pantoea, Methylobacterium and Sphingomonas. However, after the hulls first began to split, the level of bacterial diversity increased and continued to do so until the drupes were fully mature. At the last sampling period, we observed several sequences belonging to bacteria that are not usually associated with the phyllosphere, including some identical to Salmonella enterica. CONCLUSIONS: The bacterial populations on almond drupes before hull split were composed of relatively few types, most of which were commonly associated with the phyllosphere. However, after hull split, the level of microbial diversity increased, which was mostly due to increased levels of bacteria that are not normally associated with the phyllosphere, including Salm. enterica. SIGNIFICANCE AND IMPACT OF THE STUDY: This is the first report of the bacterial populations associated with almond drupes and their dynamics during development. Of specific significance is the observation that Salm. enterica was present on the drupes just prior to harvesting, which may represent a critical control point. PMID- 24494713 TI - Activation of alpha1-adrenoceptors enhances excitatory synaptic transmission via a pre- and postsynaptic protein kinase C-dependent mechanism in the medial prefrontal cortex of rats. AB - The physiological effects of alpha1-adrenoceptors (alpha1-ARs) have been examined in many brain regions. However, little is known about the mechanism of modulation on synaptic transmission by alpha1-ARs in the medial prefrontal cortex (mPFC). The present study investigated how alpha1-AR activation regulates glutamatergic synaptic transmission in layer V/VI pyramidal cells of the rat mPFC. We found that the alpha1-AR agonist phenylephrine (Phe) induced a significant enhancement of the amplitude and frequency of miniature excitatory postsynaptic currents (mEPSCs). The facilitation effect of Phe on the frequency of mEPSCs involved a presynaptic protein kinase C-dependent pathway. Phe produced a significant enhancement on the amplitude of alpha-amino-3-hydroxy-5-methyl-4 isoxazolepropionic acid receptor (AMPA-R)- and N-methyl-D-aspartic acid receptor (NMDA-R)-mediated evoked excitatory postsynaptic currents (eEPSCs). Phe enhanced inward currents evoked by puff application of glutamate or NMDA. The Phe-induced facilitation of AMPA-R- and NMDA-R-mediated eEPSCs required, in part, postsynaptic Gq , phospholipase C and PKC. These findings suggest that alpha1-AR activation facilitates excitatory synaptic transmission in mPFC pyramidal cells via both pre- and post-synaptic PKC-dependent mechanisms. PMID- 24494714 TI - Water-induced changes in the charge-transport dynamics of titanate nanowires. AB - The temperature dependence of dielectric processes in humid titanate nanowires was investigated via broadband dielectric spectroscopy under quasi-isosteric conditions in the temperature range of 150-350 K. It was found that the dynamic parameters obtained from low-temperature measurements cannot describe the dielectric behavior of the system above 273 K, implying changes in the dynamics of the corresponding dielectric processes. The calculated activation energies and pre-exponential factors counterintuitively increase linearly with the amount of adsorbed water, and a compensation effect was also found to apply to all contributions in the TiONW spectra. PMID- 24494715 TI - Fitness valleys constrain HIV-1's adaptation to its secondary chemokine coreceptor. AB - Fitness valleys, in which mutations at different loci are singly deleterious but jointly beneficial, arise because of reciprocal sign epistasis. Recent theoretical work provides analytical approximations of times to cross fitness valleys via three mechanisms: sequential fixation, stochastic tunnelling and recombination. These times depend critically on the effective population size (N(e)). Human immunodeficiency virus type 1 (HIV-1) encounters fitness valleys in adapting to its secondary cell-surface chemokine coreceptor, CXCR4. Adaptation to CXCR4 tends to occur late in infection and only in about 50% of patients and is associated with disease progression. It has been hypothesized that the need to cross fitness valleys may explain the delayed and inconsistent adaptation to CXCR4. We have identified four fitness valleys from a previous study of fitness epistasis in adaptation to CXCR4 and use estimates of the within-patient variance N(e) for different patient treatment statuses and infection stages (conditions) to estimate times to cross the valleys. These valleys may be crossed predominantly by stochastic tunnelling, although mean crossing times are consistently longer than the durations of the conditions for which they are calculated. These results were confirmed with stochastic simulation. Simulations show that crossing times for a given condition are highly variable and that for each condition there is a low probability of crossing each valley. These findings support the hypothesis that fitness valleys constrain the adaptation of HIV-1 to CXCR4. This study provides the first detailed analysis of the evolutionary dynamics associated with empirical fitness valleys. PMID- 24494716 TI - Hypertension in hemodialysis patients: an opinion-based update. AB - Hypertension is highly prevalent in hemodialysis patients but its management remains a matter of debate. In this review, we discuss the observational studies on the association of blood pressure with outcomes, measurement of blood pressure in hemodialysis patients and present an opinion-based approach to treating hypertension. PMID- 24494717 TI - Stable isotope cellular imaging reveals that both live and degenerating fungal pelotons transfer carbon and nitrogen to orchid protocorms. AB - The objective of this study was to elucidate the transfer of nutrient elements in orchid symbiotic protocorms at the cellular level by imaging of stable isotope tracers. We address the long-standing question of whether nutrients move by transport across the symbiotic interface or solely by lysis of fungal pelotons. [U-(13) C]glucose and (15) NH4 (15) NO3 were added to Ceratobasidium sp. hyphae extending from symbiotic protocorms of Spiranthes sinensis. Isotope images were taken from resin-embedded sections of protocorms using ultra-high spatial resolution secondary ion mass spectrometry (SIMS). Analyses of regions of interest were conducted on isotope ratio images for fungal and host structures. Amyloplasts adjacent to young pelotons showed elevated (13) C/(12) C, which indicated that fungal carbon (C) was transferred from live hyphae. Senescent pelotons and their surrounding host cytoplasm showed significantly higher isotope ratios than young pelotons and surrounding host cytoplasm. These results indicate an inflow of C to senescent hyphae, which was then transferred to the host. The findings of this study provide some support for each of the two contradictory hypotheses concerning nutrient exchange in the symbiotic protocorm: the interface between the symbionts is involved before fungal senescence, and peloton degradation also releases a significant amount of C and nitrogen to host cells. PMID- 24494718 TI - Hydrophobic organic linkers in the self-assembly of small molecule-DNA hybrid dimers: a computational-experimental study of the role of linkage direction in product distributions and stabilities. AB - Detailed computational and experimental studies reveal the crucial role that hydrophobic interactions play in the self-assembly of small molecule-DNA hybrids (SMDHs) into cyclic nanostructures. In aqueous environments, the distribution of the cyclic structures (dimers or higher-order structures) greatly depends on how well the hydrophobic surfaces of the organic cores in these nanostructures are minimized. Specifically, when the cores are attached to the 3'-ends of the DNA component strands, they can insert into the minor groove of the duplex that forms upon self-assembly, favoring the formation of cyclic dimers. However, when the cores are attached to the 5'-ends of the DNA component strands, such insertion is hindered, leading to the formation of higher-order cyclic structures. These computational insights are supported by experimental results that show clear differences in product distributions and stabilities for a broad range of organic core-linked DNA hybrids with different linkage directions and flexibilities. PMID- 24494719 TI - The use of bone marrow stromal cells (bone marrow-derived multipotent mesenchymal stromal cells) for alveolar bone tissue engineering: basic science to clinical translation. AB - Bone tissue engineering is a promising field of regenerative medicine in which cultured cells, scaffolds, and osteogenic inductive signals are used to regenerate bone. Human bone marrow stromal cells (BMSCs) are the most commonly used cell source for bone tissue engineering. Although it is known that cell culture and induction protocols significantly affect the in vivo bone forming ability of BMSCs, the responsible factors of clinical outcome are poorly understood. The results from recent studies using human BMSCs have shown that factors such as passage number and length of osteogenic induction significantly affect ectopic bone formation, although such differences hardly affected the alkaline phosphatase activity or gene expression of osteogenic markers. Application of basic fibroblast growth factor helped to maintain the in vivo osteogenic ability of BMSCs. Importantly, responsiveness of those factors should be tested under clinical circumstances to improve the bone tissue engineering further. In this review, clinical application of bone tissue engineering was reviewed with putative underlying mechanisms. PMID- 24494720 TI - Shifting paradigms in non-small cell lung cancer: an evolving therapeutic landscape. AB - Globally, lung cancer is the leading cause of cancer-related mortality among both men and women, and while mortality associated with the disease has demonstrated relative stability over the years, evidence has suggested an increasing incidence and prevalence of the disease. Unfortunately, the diagnosis of lung cancer is often made late in the course of the disease, with almost 70% of patients presenting with locally advanced or metastatic disease at initial diagnosis. Non small cell lung cancer (NSCLC) is the most common form of the malignancy, occurring in up to 85% of cases. There are 3 subtypes of NSCLC: squamous-cell carcinoma, adenocarcinoma, and large-cell carcinoma. Enhanced understanding of the pathophysiology of NSCLC has led to substantial improvements in diagnostic, prognostic, and therapeutic interventions for NSCLC. The discovery of targetable molecular alterations in genes, such as epidermal growth factor receptor (EGFR), has driven the evolution of targeted therapies for NSCLC and shifted treatment paradigms for the disease. This article will summarize the epidemiology and pathophysiology of NSCLC, its associated gene mutations and biomarkers, and the approach to treatment, with a focus on patients whose tumors harbor EGFRactivating mutations. PMID- 24494721 TI - Biomarkers and molecular profiling in non-small cell lung cancer: an expanding role and its managed care implications. AB - Lung cancer is the leading cause of cancerrelated mortality in the world. The American Cancer Society estimated that in 2013, the disease will account for almost 159,500 deaths in the United States, or approximately 27% of all cancer deaths in the country. Lung cancer accounts for about 14% and 12% of all new cancer diagnoses in males and females, respectively, and nearly 70% of patients with lung cancer will present with locally advanced or metastatic disease at initial diagnosis. Despite evidence-based recommendations and clinical guidelines that support the utility of epidermal growth factor receptor (EGFR) mutation testing in improving targeted therapy in non-small cell lung cancer (NSCLC), the most common form of lung cancer, EGFR testing continues to be underutilized, as the procedure may cost up to $1000 and require up to 2 weeks for results. Additional research and data collection will be needed to ascertain the costeffectiveness and role of molecular testing and targeted therapies in the management of NSCLC. This article reviews the current testing strategy and treatment guidelines, and provides a pharmacoeconomic evaluation of the use of EGFR testing to guide the management of NSCLC in today's cost-constrained healthcare environment. PMID- 24494722 TI - Mental health interventions for children exposed to disasters and terrorism. AB - OBJECTIVE: The purpose of this review is to describe interventions used with children who are exposed to disasters and terrorism and to present information about the potential benefits of these interventions. METHODS: A literature search conducted in January 2013 using relevant databases and literature known to the authors that was not generated by the search yielded a total of 85 studies appropriate for review. RESULTS: Intervention approaches used with children exposed to disasters and terrorism included preparedness interventions, psychological first aid, psychological debriefing, psychoeducation, cognitive behavioral techniques, exposure and narrative techniques, eye movement desensitization and reprocessing, and traumatic grief interventions. The investigation of these interventions is complex, and studies varied in methodological rigor (e.g., sample size, the use of control groups, outcomes measured). CONCLUSIONS: Given the limitations in the currently available empirical information, this review integrates the literature, draws tentative conclusions about the current state of knowledge, and suggests future directions for study. PMID- 24494723 TI - The relation of cognitive reappraisal and expressive suppression to suicidal ideation and suicidal desire. AB - The differential relations between the emotion regulation strategies "cognitive reappraisal" and "expressive suppression" and suicidality in a mixed inpatient sample (N = 232, 69.4% female) of a German psychotherapeutic hospital were examined. Patients filled in the Emotion Regulation Questionnaire and items on suicidal ideation and desire. A structural equation model fitted the data (RMSEA = .044; CFI = .96) and revealed that "expressive suppression" significantly predicted increased suicidal ideation. Moderation analysis showed that results were independent from a current depressive episode. Potential implications for psychotherapeutic treatment of suicidality are discussed. PMID- 24494724 TI - Cortical degeneration in frontotemporal lobar degeneration with TDP-43 proteinopathy caused by progranulin gene mutation. AB - Familial frontotemporal lobar degeneration with transactive response (TAR) DNA binding protein of 43 kDa (TDP-43) proteinopathy (FTLD-TDP) is most commonly caused by progranulin (GRN) gene mutation. To characterize cortical degeneration in these cases, changes in density of the pathology across the cortical laminae of the frontal and temporal lobe were studied in seven cases of FTLD-TDP with GRN mutation using quantitative analysis and polynomial curve fitting. In 50% of gyri studied, neuronal cytoplasmic inclusions (NCI) exhibited a peak of density in the upper cortical laminae. Most frequently, neuronal intranuclear inclusions (NII) and dystrophic neurites (DN) exhibited a density peak in lower and upper laminae, respectively, glial inclusions (GI) being distributed in low densities across all laminae. Abnormally enlarged neurons (EN) were distributed either in the lower laminae or were more uniformly distributed across the cortex. The distribution of all neurons present varied between cases and regions, but most commonly exhibited a bimodal distribution, density peaks occurring in upper and lower laminae. Vacuolation primarily affected the superficial laminae and density of glial cell nuclei increased with distance across the cortex from pia mater to white matter. The densities of the NCI, GI, NII, and DN were not spatially correlated. The laminar distribution of the pathology in GRN mutation cases was similar to previously reported sporadic cases of FTLD-TDP. Hence, pathological changes initiated by GRN mutation, and by other causes in sporadic cases, appear to follow a parallel course resulting in very similar patterns of cortical degeneration in FTLD-TDP. PMID- 24494725 TI - Blockade of N-acetylaspartylglutamate peptidases: a novel protective strategy for brain injuries and neurological disorders. AB - The peptide neurotransmitter N-acetylaspartylglutamate (NAAG) is reported to suppress glutamate release mainly through selective activation of presynaptic Group II metabotropic glutamate receptor subtype 3 (mGluR3). Therefore, strategies of inhibition of NAAG peptidases and subsequent NAAG hydrolysis to elevate levels of NAAG could reduce glutamate release under pathological conditions and be neuroprotective by attenuating excitotoxic cell injury. A series of potent inhibitors of NAAG peptidases has been synthesized and demonstrated efficacy in experimental models of ischemic-hypoxic brain injury, traumatic brain injury, inflammatory pain, diabetic neuropathy, amyotrophic lateral sclerosis and phencyclidine-induced schizophrenia-like behaviors. The excessive glutamatergic transmission has been implicated in all of these neurological disorders. Thus, blockade of NAAG peptidases may augment an endogenous protective mechanism and afford neuroprotection in the brain. This review aims to summarize and provide insight into the current understanding of the novel neuroprotective strategy based on limiting glutamate excitotoxicity for a wide variety of brain injuries and neurological disorders. PMID- 24494726 TI - Intracerebroventricular administration of streptozotocin as an experimental approach to Alzheimer's disease. AB - The in vivo experimental simulation of Alzheimer's disease (AD) has been a field of paramount importance for Experimental Medicine and Neuroscience for more than 20 years. We herein provide a short overview of an experimental approach to sporadic AD that is based on the insulin-resistant state induced in the brains of animals following the intracerebroventricular (icv) administration of streptozotocin (STZ) at low doses. The icv administration of STZ is considered as an established, standardized and reproducible approach to sporadic AD, central aspects of the pathology of which it can reliably simulate. PMID- 24494727 TI - Efficacy of air/water syringe tip sterilization. AB - BACKGROUND: Dental procedures involve contact between instruments and the patient's tissues, blood or saliva. This study evaluated the efficacy of the standardized sterilization of non-disposable air/water syringe tips and corrosion and contaminant build-up in these tips. METHODS: The bacterial contamination of single-use and multiple-use non-disposable air/water syringe tips after routine use and sterilization was compared to that of single-use disposable tips by microbial culturing on PCA and blood agar plates. The effect of flushing the syringe tips prior to sterilization was also measured. The amount of corrosion in single-use and multiple-use non-disposable syringes was measured by SEM and EDS analyses. RESULTS: Non-disposable syringe tips had significantly (p < 0.05) greater bacterial contamination than single-use disposable tips. There were no statistically different levels of contamination between flushed and non-flushed non-disposable syringes or between single-use and multiple-use non-disposable syringes. SEM and EDS analyses showed greater evidence of corrosion and contaminant build-up in multiple-use syringes compared to single-use non disposable syringes. CONCLUSIONS: Sterilization of non-disposable air/water syringes is not completely effective and rinsing, or the number of uses, does not affect the effectiveness of sterilization. There may be a lower risk of cross infection from the use of disposable air/water syringe tips, instead of non disposable ones. PMID- 24494728 TI - Cost-effectiveness of glatiramer acetate and interferon beta-1a for relapsing remitting multiple sclerosis, based on the CombiRx study. AB - BACKGROUND: To assess the cost-effectiveness of the Disease Modifying Treatments (DMT), Glatiramer Acetate (GA) and Interferon beta-1a (IFN) in monotherapy alone and in combination for the prevention of relapses among Spanish patients aged between 18-60 years old with established Relapsing-Remitting Multiple Sclerosis (RRMS). METHODS: A Markov model was developed to represent the transition of a cohort of patients over a 10 year period using the perspective of the Spanish National Health Service (NHS). The model considered five different health states with 1-year cycles including without relapse, patients with suspect, non-protocol defined and protocol defined exacerbations, as well as a category information lost. Efficacy data was obtained from the 3-year CombiRx Study. Costs were reported in 2013 Euros and a 3% discount rate was applied for health and benefits. Deterministic results were presented as the annual treatment cost for the number of relapses. A probabilistic sensitivity analysis was performed to test the robustness of the model. RESULTS: Deterministic results showed that the expected annual cost per patient was lower when treated with GA (?13,843) compared with IFN (?15,589) and the combined treatment with IFN+GA (?21,539). The annual number of relapses were lower in the GA cohort with 3.81 vs 4.18 in the IFN cohort and 4.08 in the cohort treated with IFN+GA. Results from probabilistic sensitivity analysis showed that GA has a higher probability of being cost effective than treatment with IFN or IFN+GA for threshold values from ?28,000 onwards, independent of the maximum that the Spanish NHS is willing to pay for avoiding relapses. CONCLUSION: GA was shown to be a cost-effective treatment option for the prevention of relapses in Spanish patients diagnosed with RRMS. When GA in monotherapy is compared with INF in monotherapy and IFN+GA combined, it may be concluded that the first is the dominant strategy. PMID- 24494729 TI - Microcalorimetric determination of the entropy change upon the electrochemically driven surface aggregation of dodecyl sulfate. AB - The aggregation of amphiphilic molecules (e.g., the formation of micelles or membranes) is usually entropy-driven. We use electrochemical microcalorimetry to directly determine the entropy change a dodecyl sulfate molecule experiences upon potential-induced adsorption from aqueous solution into a surface aggregate. From measurements of the heat, which is reversibly exchanged during the adsorption or desorption process, we determined a value of 37 +/- 9 J/(mol K) for the aggregation entropy. This value is in accordance with entropies of micellization of dodecyl sulfate in solution. A comparison with estimates of the entropy of aggregation of dodecane in aqueous solutions reveals that the aggregation is driven by the entropic contribution of the hydrophobic hydrocarbon tail, in accordance with general models for the aggregation of amphiphilic molecules. PMID- 24494732 TI - Isolation and characterization of halophilic lactic acid bacteria acting as a starter culture for sauce fermentation of the red alga Nori (Porphyra yezoensis). AB - AIMS: A screening test was conducted for environmental samples to isolate halophilic lactic acid bacteria (HLAB) that can act as a starter in a Nori (Porphyra yezoensis)-sauce culture. METHOD AND RESULTS: After 9 months of incubation of enrichment cultures added with 25 kinds of environmental samples, growth of HLAB-like microorganisms was observed in six cultures salted at a 15% w/w level, including culture samples originally from mesopelagic water taken from 321 m-depth and from mountain snow taken at 2450 m-height. Ten strains were isolated and characterized as Tetragenococcus halophilus based on sequence analysis of the 16S rRNA gene. The isolates were inoculated into a newly prepared Nori-sauce culture and were confirmed to be able to act as a starter culture while three reference strains of T. halophilus obtained from a culture collection could not grow in the same culture. CONCLUSIONS: Halophilic lactic acid bacteria strains that can make growth in a highly salted Nori-sauce culture were isolated from environmental samples for the first time. All the isolates were identified as T. halophilus. SIGNIFICANCE AND IMPACT OF THE STUDY: The isolated strains are expected to be utilized as a starter culture for manufacturing fermented seaweed sauce, which will be the first fermented food products obtained from algae. PMID- 24494730 TI - Anticoagulants for secondary prevention after acute myocardial infarction: lessons from the past decade. AB - The impact of an acute coronary syndrome (ACS) event, such as an acute myocardial infarction (MI), is not limited to the acute management phase; patients face an elevated risk of residual atherothrombotic events that commonly requires chronic management for months or even years. Significant advances have been made in both the acute and chronic management of patients with acute MI over the past decade, resulting in improved prognoses. One of the hallmarks of modern treatment strategies is more aggressive antiplatelet treatment regimens. However, the risks of further ACS events, stroke and premature death remain elevated in these patients, and addressing this residual risk is challenging owing to interpatient variability, differences in management strategies between centres and countries, incomplete understanding of the specific pathophysiology of post-ACS thrombosis and limitations of current therapeutic approaches. The recent approval in Europe of the direct oral anticoagulant rivaroxaban for use in this setting in combination with clopidogrel and acetylsalicylic acid offers another strategy to consider in the management of these patients, and clinical strategies in this area continue to evolve. In this review, we chart the progress made over the past decade in reducing the burden of secondary thromboembolic events after acute MI and discuss the current position of and future perspectives on the inclusion of oral anticoagulants into care pathways in this setting. PMID- 24494734 TI - The remarkable [ReH9]2- dianion: molecular structure and vibrational frequencies. AB - The equilibrium geometries and vibrational frequencies of the extraordinary [ReH9](2-) dianion (D3h symmetry) are investigated using Hartree-Fock (HF) theory, coupled cluster theory with single and double excitations (CCSD), and coupled cluster theory with single, double, and perturbative triple excitations [CCSD(T)]. The new generation of energy-consistent relativistic pseudopotentials and correlation consistent basis sets [cc-pVXZ-PP (Re) and cc-pVXZ (H) (X = D, T, Q)] are used. Anharmonicity was considered using second-order vibrational perturbation theory. The predicted geometries and vibrational frequencies generally agree with experimental findings. In order to stabilize the [ReH9](2-) dianion, the M2ReH9 (M = Na, K) sandwich complexes (D3h symmetry) are studied at the CCSD(T)/VTZ (VTZ = cc-pVTZ-PP (Re) and cc-pVTZ (H, Na, K)) level of theory. Compared to the [ReH9](2-) dianion, the predicted vibrational frequencies involving Re-H stretching modes are improved, indicating the importance of considering counterions in electronically dense systems. The natural bond orbital analysis shows that each H atom only bonds with the Re center, and the 5d orbitals of Re and 1s orbitals of H are major factors for the covalent Re-H bonding. PMID- 24494735 TI - Renal cell carcinoma in patients with end-stage renal disease has favorable overall prognosis. AB - Patients with end-stage renal disease (ESRD) demonstrate a greater risk for renal cell carcinoma (RCC) than the general population. This study compared pathological and clinical outcomes in patients with RCC with and without ESRD. Patients with ESRD who underwent nephrectomy and were found to have RCC at our institution since 1999 were identified. The control group was composed of patients from the general population with RCC. The primary outcome was risk of cancer recurrence. The study included 338 RCC patients: 84 with ESRD and 243 without ESRD. In the ESRD group, mean tumor size was smaller, there was decreased prevalence of advanced T category (>3) , and the average Karakiewicz nomogram score was lower. ESRD was associated with decreased tumor recurrence and clear cell pathology. No patients with ESRD had metastatic disease. There was no difference in overall or cancer-specific mortality between the ESRD and control groups. Patients with ESRD who develop RCC have a better prognosis compared to RCC in patients without ESRD, which is likely secondary to favorable histopathologic phenotype as well as the likelihood of early diagnosis. Thus, the delay between nephrectomy and renal transplantation may not be necessary, especially in patients with asymptomatic, low grade tumors. PMID- 24494736 TI - Novel LAMB3 mutations cause non-syndromic amelogenesis imperfecta with variable expressivity. PMID- 24494737 TI - Immediate effects of bilateral sacroiliac joint manipulation on plantar pressure distribution in asymptomatic participants. AB - OBJECTIVE: To investigate the immediate effects of manipulation of bilateral sacroiliac joints (SIJs) on the plantar pressure distribution in asymptomatic participants in the standing position. DESIGN: Randomized, controlled, double blind clinical trial. PARTICIPANTS: Sixty-two asymptomatic men and women (mean age, 20.66+/-2.56 years) randomly assigned to 2 groups. INTERVENTIONS: The experimental group underwent mobilization without tension of the hips in the supine position and high-velocity, low-amplitude manipulation in the SIJs bilaterally. The control group underwent only mobilization, without tension of the hips in supine position. OUTCOME MEASURES: Pre- and postintervention outcomes measured by an assessor blinded to the treatment allocation of the participants included a baropodometric analysis performed by using a force platform. Baseline between-group differences were examined with a Kolmogorov-Smirnov test. A chi square test was used for categorical data. Analysis of covariance (ANCOVA) was used to assess differences between groups, with the preintervention value as covariant (95% confidence level). RESULTS: At baseline, no variables significantly differed between groups. Baropodometric analysis showed statistically significant differences in the location of the maximum pressure point in the experimental group (p=0.028). Pre- and postintervention analysis with ANCOVA showed statistically significant differences between both groups in the left hindfoot load percentage (interaction p=0.0259; ANCOVA p=0.0277), right foot load percentage (ANCOVA p=0.0380), and surface of the right forefoot (interaction p=0.0038). There was also a significant effect in the variables that analyze the entire foot (left foot: surface [interaction p=0.0452], percentage of load [ANCOVA p=0.0295]) and between both groups (right foot: weight [interaction p=0.0070; ANCOVA p=0.0296]). CONCLUSIONS: Sacroiliac joint manipulation applied bilaterally in asymptomatic persons resulted in immediate changes in load distribution on plantar support in the standing position. Study limitations and suggestions for future studies are discussed. PMID- 24494738 TI - Azolla domestication towards a biobased economy? AB - Due to its phenomenal growth requiring neither nitrogen fertilizer nor arable land and its biomass composition, the mosquito fern Azolla is a candidate crop to yield food, fuels and chemicals sustainably. To advance Azolla domestication, we research its dissemination, storage and transcriptome. Methods for dissemination, cross-fertilization and cryopreservation of the symbiosis Azolla filiculoides Nostoc azollae are tested based on the fern spores. To study molecular processes in Azolla including spore induction, a database of 37 649 unigenes from RNAseq of microsporocarps, megasporocarps and sporophytes was assembled, then validated. Spores obtained year-round germinated in vitro within 26 d. In vitro fertilization rates reached 25%. Cryopreservation permitted storage for at least 7 months. The unigene database entirely covered central metabolism and to a large degree covered cellular processes and regulatory networks. Analysis of genes engaged in transition to sexual reproduction revealed a FLOWERING LOCUS T-like protein in ferns with special features induced in sporulating Azolla fronds. Although domestication of a fern-cyanobacteria symbiosis may seem a daunting task, we conclude that the time is ripe and that results generated will serve to more widely access biochemicals in fern biomass for a biobased economy. PMID- 24494740 TI - Perceived parenting change and child posttraumatic stress following a natural disaster. AB - OBJECTIVE: Recent research suggests that not only parental psychopathology, but also parenting practices, have a role to play in the development of child posttraumatic stress symptoms (PTSS) following a natural disaster. The current study aimed to investigate the relationship between parents' perceptions of their parenting in the aftermath of a natural disaster, and child PTSS. METHODS: A cross-sectional design was used to explore the associations among child PTSS, parents' perceptions of altered (more anxious) parenting, and parental disaster related distress (altered cognitions and behaviors) in 874 elementary school children (ages 8-12 years) and their parents following a severe storm of cyclonic proportions. With parental consent, school-based screening was conducted in impacted communities 3 months after the storm. Children completed a screening questionnaire consisting of the Child Trauma Screening Questionnaire (CTSQ; used for identifying children at risk for posttraumatic stress disorder [PTSD]), as well as a range of questions assessing disaster exposure and threat perception. Parents completed questions relating to their perceptions of changes in their parenting since the storm, as well as two items relating to their own disaster related distress. RESULTS: Independent of other significant associations with child PTSS (such as age, gender, and disaster exposure), a high level of parent perceived altered parenting appeared to put children at increased risk for PTSS 3 months after the disaster. However, when the sample was stratified for the presence or absence of altered parent cognitions and behaviors following the storm, altered parenting was found to have a unique relationship with child PTSS only when parents reported altered disaster-related cognitions and behaviors. CONCLUSIONS: When parents report disaster-related cognitions and behaviors, their perception of altered parenting practices (becoming more protective, less granting of autonomy, and communicating a sense of current danger) is associated with child PTSS. Although it is not possible to draw conclusions about the direction of these relationships, this study identifies parenting practices that may constitute important targets for intervention. PMID- 24494739 TI - Skin tissue engineering for the infected wound site: biodegradable PLA nanofibers and a novel approach for silver ion release evaluated in a 3D coculture system of keratinocytes and Staphylococcus aureus. AB - Wound infection presents a challenging and growing problem. With the increased prevalence and growth of multidrug-resistant bacteria, there is a mounting need to reduce and eliminate wound infections using methodologies that limit the ability of bacteria to evolve into further drug-resistant strains. A well-known strategy for combating bacterial infection and preventing wound sepsis is through the delivery of silver ions to the wound site. High surface area silver nanoparticles (AgNPs) allowing extensive silver ion release have therefore been explored in different wound dressings and/or skin substitutes. However, it has been recently shown that AgNPs can penetrate into the stratum corneum of skin or diffuse into the cellular plasma membrane, and may interfere with a variety of cellular mechanisms. The goal of this study was to introduce and evaluate a new type of high surface area metallic silver in the form of highly porous silver microparticles (AgMPs). Polylactic acid (PLA) nanofibers were successfully loaded with either highly porous AgMPs or AgNPs and the antimicrobial efficacy and cytotoxicity of the two silver-based wound dressings were assessed and compared. To better mimic the physiological environment in vivo where both human cells and bacteria are present, a novel coculture system combining human epidermal keratinocytes and Staphylococcus aureus bacteria was designed to simultaneously evaluate human skin cell cytotoxicity with antimicrobial efficacy in a three dimensional environment. We found that highly porous AgMPs could be successfully incorporated in nanofibrous wound dressings, and exhibited comparable antimicrobial efficacy and cytotoxicity to AgNPs. Further, PLA nanofibers containing highly porous AgMPs exhibited steady silver ion release, at a greater rate of release, than nanofibers containing AgNPs. The replacement of AgNPs with the newly introduced AgMPs overcomes concerns regarding the use of nanoparticles and holds great promise as skin substitutes or wound dressings for infected wound sites. PMID- 24494741 TI - Suicidal ideation and behavior in adolescents aged 12-16 years: a 17-year follow up. AB - The prevalence of suicidal ideation/behavior in 1983 or 1987 and its association with future mental health in 2001 were evaluated in a provincially representative sample of Canadian adolescents (n = 1,248) aged 12 to 16 years. Approximately 13.3% (95% CI = 11.5-15.3) of adolescents self-reported suicidal ideation/behavior. Adolescent agreement with parent (kappa = .07) and teacher (kappa = .05) reports at baseline was low because adults identified so few subjects. In adulthood, the associations between adolescent self-reports of suicidal behavior/ideation and major depression and other mental health indicators were explained by respondent sex and adolescent emotional problems reported in 1983/1987. Adolescents with suicidal behavior/ideation often are not recognized by their parents and teachers and may be at risk for persistent psychiatric problems attributable to coexisting mental health problems early-on. PMID- 24494743 TI - Biochemical and radiological relationships in patients with pheochromocytoma: lessons from a case control study. AB - BACKGROUND: An elevation of fractionated plasma or urinary metanephrine (MN) or nor-metanephrine (NMN), collectively called metanephrines (MN and NMN), >4-fold above the upper limit of normal (ULN) is usually considered to be diagnostic for pheochromocytoma (PHEO). There are a greater number of false positive results when the elevations are more modest. AIM: To identify biochemical and radiological features in PHEOs with modest elevations (<4-fold above ULN) of metanephrines. METHODOLOGY: We retrospectively reviewed the charts of 112 patients with PHEO (10% extra-adrenal) and 208 patients with a non-PHEO adrenal mass operated from 1997-2011, who had metanephrines measured pre-operatively. We divided PHEO into group 1 (n = 90) with metanephrines >=4-fold ULN and group 2 (n = 22) with metanephrines <4-fold ULN. The non-PHEO group was designated as group 3. RESULTS: The median (range) tumour size in group 1 and group 2 was 4.8 cm (1.7 22) and 3.0 cm (1.7-5) respectively (P < 0.001). All patients with PHEO in group 2 had a tumour <5 cm in size. The MN fraction was elevated in about 65% of groups 1 and 2; only 2 (1%) patients in group 3 had an elevated urinary MN fraction, and none were associated with an elevated plasma MN fraction. All PHEOs had a pre contrast attenuation >=17 Hounsfield Units (HU). CONCLUSIONS: Modest elevations (<4-fold ULN) of the NMN fraction in an adrenal mass >5 cm are almost always falsely positive. Elevations in plasma and urinary MN fraction are less likely to be false positive. The CT pre-contrast attenuation of PHEOs is >10 HU. PMID- 24494742 TI - Serum biomarkers predict acute symptom burden in children after concussion: a preliminary study. AB - Pediatric emergency department (ED) visits for concussion have nearly tripled in the past decade. Despite this, there are limited bedside tools available to objectively diagnose injury and prognosticate recovery. Here, we perform a preliminary evaluation of the utility of glial fibrillary acidic protein (GFAP) in predicting initial and follow-up symptom burden in children and young adults 11-21 years of age, presenting to the ED after concussion. We enrolled 13 children and young adults presenting to the ED within 24 h of concussion, and obtained initial serum samples at that time as well as follow-up samples within 24-72 h of injury. Initial GFAP levels were associated with initial and follow-up symptom burden up to 1 month after injury, whereas follow-up GFAP levels did not correlate with symptom burden. These preliminary data suggest that GFAP may offer an objective measure of injury and recovery after pediatric concussion, potentially offering clinicians a new tool in the management of this common injury. PMID- 24494744 TI - Subclinical concentrations of chlorhexidine inhibit gelatinase activity of carious dentine in vitro. AB - BACKGROUND: There is evidence that dentine matrix gelatinases are involved in the destruction of carious dentine after demineralization by bacterial acids. It has also been observed that chlorhexidine, in very low concentrations, inhibits the activity of these enzymes in mammalian cells. The goal of this study was to determine if the gelatinase activity of carious dentine may be inhibited by chlorhexidine in clinical use concentrations. METHODS: Gelatinolytic activity was evaluated through zymography and identified by Western blot. The inhibitory effects of chlorhexidine at concentrations of 0.01%, 0.04%, 0.08% and 1% on the enzymatic activity of softened carious dentine samples were determined. RESULTS: In carious dentine, five bands of gelatinolytic activity were detected, with molecular sizes of 86, 75, 38, 33 and 32 kDa. The two bands of the greatest molecular size corresponded to latent and active metalloproteinase-9, respectively. Concentrations of chlorhexidine that were greater than or equal to 0.04% were sufficient to inhibit gelatinolytic activity in the observed bands of carious dentine. CONCLUSIONS: These results support the use of chlorhexidine in clinical use concentrations for the treatment and control of dentine caries. Our study demonstrates for the first time the inhibitory effect of chlorhexidine on gelatinases from carious human dentine. PMID- 24494746 TI - Comparison of prednisolone acetate and loteprednol etabonate for the treatment of benzalkonium chloride-induced dry eye syndrome in rats. AB - PURPOSE: The aim of the current study is to compare the effects of two corticosteroids, prednisolone acetate 1% (PA) and loteprednol etabonate 0.5% (LE), for the treatment of benzalkonium chloride (BAC)-induced dry eye syndrome (DES) in rats. METHODS: DES was established by topical administration of 0.2% BAC, a commonly used preservative in ophthalmic drugs, for 1 week. Rats were divided into 3 groups just after establishment of DES: PA-treated (Group 1, n=10), LE-treated (Group 2, n=10), and vehicle-treated (Group 3, n=10). Rats were treated by topical administration of PA, LE, or vehicle twice daily for 1 week. The Schirmer test, break-up time score, Fluorescein staining, Rose Bengal staining, and inflammatory index scoring (IIS) tests were performed at all weeks. After the end of the study, eyes of the rats were enucleated and analyzed using light microscopy. RESULTS: The mean aqueous tear volume was significantly increased in both PA- and LE-treated rats (P<0.05), although decreased in vehicle treated rats (P>0.05). Histologically, diffuse inflammatory cell infiltration was observed in vehicle-treated rats, while inflammation induced by BAC was almost completely resolved in both PA- and LE-treated groups. CONCLUSIONS: In the current study, we showed that both PA and LE are effective treatments in a rat model of BAC-induced DES, which is commonly observed in clinics. No significant differences were observed between the 2 corticosteroids in the efficacy of BAC induced type of DES treatment. PMID- 24494745 TI - Elucidation of structural elements for selectivity across monoamine transporters: novel 2-[(diphenylmethyl)sulfinyl]acetamide (modafinil) analogues. AB - 2-[(Diphenylmethyl)sulfinyl]acetamide (modafinil, (+/-)-1) is a unique dopamine uptake inhibitor that binds the dopamine transporter (DAT) differently than cocaine and may have potential for the treatment of psychostimulant abuse. To further investigate structural requirements for this divergent binding mode, novel thio- and sulfinylacetamide and ethanamine analogues of (+/-)-1 were synthesized wherein (1) the diphenyl rings were substituted with methyl, trifluoromethyl, and halogen substituents and (2) substituents were added to the terminal amide/amine nitrogen. Halogen substitution of the diphenyl rings of (+/ )-1 gave several amide analogues with improved binding affinity for DAT and robust selectivity over the serotonin transporter (SERT), whereas affinity improved at SERT over DAT for the p-halo-substituted amine analogues. Molecular docking studies, using a subset of analogues with DAT and SERT homology models, and functional data obtained with DAT (A480T) and SERT (T497A) mutants defined a role for TM10 in the substrate/inhibitor S1 binding sites of DAT and SERT. PMID- 24494747 TI - Preparation of silica-coated ultrathin gold nanowires with high morphological stability. AB - We demonstrated a preparation method of silica-coated straight ultrathin Au nanowires (NWs). Water-dispersive ultrathin Au NWs capped with a long-chain amidoamine derivative (C18AA) were used for silica coating. The Au NWs were partially covered with 3-mercaptopropanoic acid by the ligand exchange method, and silica coating of the Au NWs was carried out by the hydrolysis of tetraethoxysilane (TEOS) at pH > 6.7 because the shape of the Au NWs was changed under acidic conditions. The thickness of the silica layer depended on the concentration of TEOS, and the layer was able to decrease to 6-10 nm thick. We also demonstrated that the silica-coated Au NWs had high morphological stabilities against external stimuli such as a TEM electron beam, heat, and pH compared with the bare Au NWs. PMID- 24494748 TI - Can a first-order exponential decay model fit heart rate recovery after resistance exercise? AB - The time-constant of postexercise heart rate recovery (HRRtau ) obtained by fitting heart rate decay curve by a first-order exponential fitting has being used to assess cardiac autonomic recovery after endurance exercise. The feasibility of this model was not tested after resistance exercise (RE). The aim of this study was to test the goodness of fit of the first-order exponential decay model to fit heart rate recovery (HRR) after RE. Ten healthy subjects participated in the study. The experimental sessions occurred in two separated days and consisted of performance of 1 set of 10 repetitions at 50% or 80% of the load achieved on the one-repetition maximum test [low-intensity (LI) and high intensity (HI) sessions, respectively]. Heart rate (HR) was continuously registered before and during exercise and also for 10 min of recovery. A monoexponential equation was used to fit the HRR curve during the postexercise period using different time windows (i.e. 30, 60, 90, ... 600 s). For each time window, (i) HRRtau was calculated and (ii) variation of HR explained by the model (R(2) goodness of fit index) was assessed. The HRRtau showed stabilization from 360 and 420 s on LI and HI, respectively. Acceptable R(2) values were observed from the 360 s on LI (R(2) > 0.65) and at all tested time windows on HI (R(2) > 0.75). In conclusion, this study showed that using a minimum length of monitoring (~420 s) HRR after RE can be adequately modelled by a first-order exponential fitting. PMID- 24494749 TI - Serum microRNA155 is increased in patients with acute graft-versus-host disease. AB - To explore the clinical relevance of three lymphocyte-related serum microRNAs (miR-155, miR-214, and miR-326) to the pathogenesis of graft-versus-host disease (GVHD), 64 subjects who received allogeneic peripheral blood stem cell transplantation (allo-PBSCT) were recruited in this study, of whom 19 subjects did not develop GVHD, 25 subjects were diagnosed with acute GVHD (aGVHD), and 20 subjects were diagnosed with chronic GVHD (cGVHD). Serum miRNAs were determined by real-time RT-PCR. Expression level of miRNAs and the expression signatures of miRNAs as a panel were analyzed among the three groups. The expression level of miR-214 and miR-326 showed no significant difference between GVHD and non-GVHD groups. However, miR-155 was significantly up-regulated in GVHD patients. There was a correlation between the level of miR-155 and the severity of aGVHD. Moreover, serum IFN-gamma, IL-17, and IL-9 levels were higher in aGVHD patients with high miR-155. In conclusion, the expression level of lymphocyte-related miR 155 in serum was significantly increased in aGVHD patients. The miR-155 may be considered as a potential targeted therapy for aGVHD patients. PMID- 24494750 TI - Evidence of success. PMID- 24494752 TI - Regulator investigates low staffing levels in Bradford infirmary. PMID- 24494753 TI - Hospitals will release figures on numbers of people who self-harm. PMID- 24494754 TI - Migrants and visitors may have to pay for their emergency care. PMID- 24494755 TI - No change to waiting times target, Keogh tells MPs. PMID- 24494756 TI - Union stages protest in Belfast as patient numbers soar. PMID- 24494758 TI - Health champions step in to relieve pressures on staff. PMID- 24494759 TI - Care standards set to reduce mortality rates at weekends. PMID- 24494760 TI - End of life care in emergency settings. PMID- 24494761 TI - Board's eye view - keeping people safe. PMID- 24494762 TI - The bigger picture. PMID- 24494763 TI - Paramedic practitioners. PMID- 24494767 TI - Identifying and treating a life-threatening disease. AB - Meningococcal septicaemia is a life-threatening condition that all nurses working in emergency and urgent care settings are likely to come across during their careers. This article presents, and reflects on, a case study involving a woman with the disease whose signs and symptoms were atypical, and who was not therefore diagnosed with the condition immediately. The author aims to raise awareness among emergency nurses and nurse practitioners of the atypical signs and symptoms of the infection, and its consequences. The article also discusses how referring to patient scenarios can improve practice. PMID- 24494768 TI - Comparison of splinting and casting in the management of torus fracture. AB - Torus, or buckle, fractures are unique to, and common in, children, but their treatment varies by hospital protocol and practitioners' preference. This article reviews the literature on managing torus fractures with a splint and with plaster of Paris, and concludes that splinting is more cost effective, more likely to ensure quick return to normal function, and is preferred by parents. There is no conclusive evidence, however, that it is less painful. PMID- 24494769 TI - Automated cardiopulmonary resuscitation: a case study. AB - Rates of survival after cardiac arrest are low and correlate with the quality of cardiopulmonary resuscitation (CPR). Devices that deliver automated CPR (A-CPR) can provide sustained and effective chest compressions, which are especially useful during patient transfer and while simultaneous invasive procedures are being performed. The use of such devices can also release members of resuscitation teams for other work. This article presents a case study involving a man with acute myocardial infarction complicated by cardiogenic shock and pulmonary oedema. It describes how ED nursing and medical teams worked together to deliver A-CPR, discusses the use of A-CPR devices in a tertiary cardiac centre, and highlights the advantages of using such devices. PMID- 24494770 TI - Recognising and managing acute hyponatraemia. AB - A significant amount of clinicians' time is spent managing patients with complications arising from the use of sympatheticomimetic drugs such as cocaine and ecstasy, or MDMA. This article examines one of these complications, namely acute hyponatraemia, which can have life-threatening neurological consequences. Although there are few signs or symptoms of this condition, emergency clinicians should be able to recognise when it may have occurred, and should have a basic understanding of the role of sodium in autoregulation of cellular function, the different fluid compartments in the human body and the pathology of cerebral oedema. The article describes the importance of early recognition and swift treatment of acute hyponatraemia, as well as the methods for calculating fluid replacement to optimise chances of full recovery. PMID- 24494771 TI - Island life. PMID- 24494772 TI - Effectiveness of training senior dental students on oral health care for disabled patients. AB - INTRODUCTION: Studies in several countries have shown that dental students need an improved educational programme concerning management of disabled patients. We aimed to study the effect of providing a course entitled 'Oral health care of disabled patients' on knowledge and attitudes of senior dental students at Tehran University. MATERIALS AND METHODS: A total number of 70 students (n=70) were asked to fill in a questionnaire regarding their background, knowledge and attitudes, before and after the programme. The intervention group of 36 students (n=36) received a four-session course consisting of lectures, group discussion, screening and fluoride varnish provision for disabled patients. Statistical analysis was performed using the Mann-Whitney U-test, the chi-square test and linear regression modelling. RESULTS: Amongst all the participants, 36% had previously treated a disabled patient and 58% believed that merely specialists should treat disabled patients. Twenty-seven percentage of participants believed that hospital is the only proper facility for treating disabled patients. A considerable improvement in both knowledge and attitudes of students was observed following the intervention (P<0.05). CONCLUSIONS: Our findings indicate that a short-term training programme on oral health care has an immense impact on students' adherence to treating disabled patients. These results provide evidence to support the necessity of enrichment of the dental curriculum regarding oral health care for disabled patients. PMID- 24494773 TI - Enhancement of superconducting Tc (33 K) by entrapment of FeSe in carbon coated Au-Pd17Se15 nanoparticles. AB - FeSe has been an interesting member of the Fe-based superconductor family ever since the discovery of superconductivity in this simple binary chalcogenide. Simplicity of composition and ease of synthesis has made FeSe, in particular, very lucrative as a test system to understand the unconventional nature of superconductivity, especially in low-dimensional models. In this article we report the synthesis of composite nanoparticles containing FeSe nanoislands entrapped within an ent-FeSe-Pd16Se15-Au nanoparticle and sharing an interface with Pd17Se15. This assembly exhibits a significant enhancement in the superconducting Tc (onset at 33 K) accompanied by a noticeable lattice compression of FeSe along the <001> and <101> directions. The Tc in FeSe is very sensitive to application of pressure and it has been shown that with increasing external pressure Tc can be increased almost 4-fold. In these composite nanoparticles reported here, immobilization of FeSe on the Pd17Se15 surface contributes to increasing the effect of interfacial pressure, thereby enhancing the Tc. The effect of interfacial pressure is also manifested in the contraction of the FeSe lattice (up to 3.8% in <001> direction) as observed through extensive high-resolution TEM imaging. The confined FeSe in these nanoparticles occupied a region of approximately 15-25 nm, where lattice compression was uniform over the entire FeSe region, thereby maximizing its effect in enhancing the Tc. The nanoparticles have been synthesized by a simple catalyst-aided vapor transport reaction at 800 degrees C where iron acetylacetonate and Se were used as precursors. Morphology and composition of these nanoparticles have been studied in details through extensive electron microscopy. PMID- 24494774 TI - A novel mutation in the Albumin gene (R218S) causing familial dysalbuminemic hyperthyroxinemia in a family of Bangladeshi extraction. AB - BACKGROUND: Familial dysalbuminemic hyperthyroxinemia (FDH) is a common cause of euthyroid hyperthyroxinemia. Clinical recognition of FDH is crucial for preventing unnecessary therapy in clinically euthyroid patients with abnormal thyroid function tests. Our goal was to identify the cause of abnormal serum tests of thyroid function in a Canadian family of Bangladeshi extraction. PATIENTS: The proposita was found to have elevated free thyroxine (fT4) and free triiodothyronine (fT3) with nonsuppressed thyrotropin (TSH) on screening blood work. After detailed studies excluding hyperthyroidism and resistance to thyroid hormone, blood was obtained from all members of her immediate family for further investigation. METHODS: We conducted laboratory analyses and sequencing of candidate genes. RESULTS: Two members of this family have FDH, caused by a not previously identified mutation in the albumin gene. This mutation, located in exon 7 of the gene (652A>C), produces a single amino acid substitution in the protein molecule (R218S). The mutant albumin is associated with a ninefold increase in serum total T4 and a twofold increase in serum total reverse T3 compared to patients with normal albumin. Modeling data for the R218S variant are compatible with the increased binding affinity of this variant albumin for T4. CONCLUSIONS: The R218S substitution reported here causes FDH that, in terms of the magnitude of serum iodothyronine elevation, is intermediate to the two previously reported mutations at codon 218 FDH: R218H being more mild and R218P more severe. PMID- 24494775 TI - High-risk lead extraction using a hybrid approach: the blade and the lightsaber. PMID- 24494776 TI - Analysis of the interplay between depression, anxiety, and psychological resources in adolescence using self-report measures. AB - OBJECTIVE: Following recent literature which stresses the importance of broadening the conceptualization of mental functioning in youth, this paper aims to investigate structural relations between indicators of anxiety, depressive symptoms, and psychological resources in non-referred Italian adolescents, as captured by the Strengths and Difficulties Questionnaire (SDQ; Goodman 2001 ), the Spence Children's Anxiety Scale (SCAS; Spence 1998 ) and the Children Depression Inventory (CDI; Kovacs 1992 ). METHODS: A hierarchical model which considers both the interplays and overlaps between these instruments is tested by means of Confirmatory Factor Analysis, in order to explore the possibility to use the three tools within a meaningful screening battery. First, validity and reliability of SDQ, SCAS, and CDI is successfully controlled thanks to three appropriate preliminary studies, an evidence not already acquired in the Italian context for the adolescent population. Then, the focal study devises and tests a model that merges indicators of the SDQ, SCAS, and CDI scales into four correlated factors, that is, Psychological Resources, Externalized behavior problems, Internalized Fear and Internalized Anxious Misery. CONCLUSIONS: Overall, findings corroborate the combined use of SDQ, SCAS, and CDI as a screening battery for the assessment of mental functioning in youth adopting a dimensional rather than a categorical approach. PMID- 24494777 TI - The consequences of DSM-5 for psychiatric diagnosis and psychopharmacotherapy. AB - OBJECTIVE: After 10 years of preparation, DSM-5 was published in 2013. This paper will examine the possible effects of DSM-5 on psychiatric diagnosis and psychopharmacotherapy. METHODS: DSM-5 was compared with DSM-IV to identify the important changes in psychiatric diagnosis and possible consequences for psychopharmacotherapy. RESULTS: Contrary to the original plans, DSM-5 did not make radical changes and move towards dimensional diagnosis but preserved the previous categorical system of disorders and a primarily symptom-based descriptive approach. The dimensional approach was only adopted through the introduction of several transnosological specifiers and the option to make symptom- or syndrome-related assessments. The criteria for some disorders were changed, including affective, dependence and schizophrenic disorders, and a few new disorders were added. CONCLUSION: The DSM-IV diagnostic system was largely preserved, although some changes were made, primarily in the field of affective disorder and in several criteria sets. The new transnosological specifiers, severity assessments and cross-cutting dimensional assessments may help to individualise treatment. PMID- 24494778 TI - Thyroglobulin antibody levels do not predict disease status in papillary thyroid cancer. AB - BACKGROUND: Thyroglobulin antibodies (TgAb) are present in approximately 20% of patients with papillary thyroid cancer (PTC) and invalidate the serum thyroglobulin (Tg) level as a tumour marker. We examined whether trends in the TgAb level could serve as a surrogate marker of disease status in the surveillance of patients with PTC. METHODS: All patients found to have a least one positive postoperative TgAb level (determined by the Beckman-Coulter Access Assay) after undergoing initial surgery for PTC from 2000 to 2010 at a single institution were included. Log-log transformation and linear regression were applied to longitudinal TgAb levels, yielding patient-specific regression coefficients that categorized as follows: highly negative, moderately negative and positive/no trend. The recurrence rate in each category was then assessed. RESULTS: Ninety-three of 967 patients with PTC were included. Recurrent disease was detected in 19 patients (20%) after a mean follow-up time of 51 months. Regression coefficients in the highly negative and moderately negative groups were not different, and hence these groups were pooled. The proportion of recurrent cases in the negative trend group was similar to that in the positive/no trend group (19.7% vs 21.9%, NS). The mean regression coefficients were similar for recurrent and nonrecurrent cases within both the negative trend group (-0.89 vs -0.80, NS) and the positive/no trend group (0.08 vs 0.33, NS). CONCLUSION: Trends in the TgAb level do not predict disease status in PTC in our experience. In the context of most commercially available TgAb assays, surveillance of TgAb-positive patients will hinge on high-quality imaging until a valid alternative serum marker to Tg is identified. PMID- 24494779 TI - Long-term use of protease inhibitors is associated with bone mineral density loss. AB - HIV-infected patients are at high risk for bone mineral density (BMD) loss. The present study was designed to provide information on characteristics of BMD abnormalities in Japanese HIV-1-infected patients and risk factors involved in worsening of BMD. A total of 184 Japanese HIV-1-infected men were studied with a dual-energy X-ray absorptiometry scan (DXA) at the lumbar spine and femoral neck. Multivariate logistic regression models were used for comparison of the impact of risk factors on BMD loss. Osteopenia and osteoporosis were diagnosed in 46% and 10% of the patients at lumbar spine, and 54% and 12% at femoral neck, respectively. In logistic analysis, factors associated with low BMD at both lumbar spine and femoral neck were long-term treatment with a protease inhibitor (PI) [odds ratio (OR) 1.100 and 1.187 per 1 year increase of PI use; 95% confidence interval (CI) 1.003-1.207 and 1.043-1.351; p=0.042 and 0.009, respectively] and a low body mass index [OR: 0.938 and 0.852, CI 0.892-0.992 and 0.783-0.927; p=0.024 and <0.001, respectively]. Patients who discontinued PI had a significantly higher BMD than those who currently use PI at lumbar spine (t score -0.8 vs. -1.3, p=0.04) but not at femoral neck (-1.3 vs. -1.5, p=0.38). In HIV-infected Japanese patients, the duration of treatment with PI correlated significantly with BMD loss. Discontinuation of PI is a promising option in the treatment of BMD loss since it allows recovery of BMD, especially in the lumbar spine. PMID- 24494782 TI - Prospective evaluation of parent distress following pediatric burns and identification of risk factors for young child and parent posttraumatic stress disorder. AB - OBJECTIVE: Early childhood is a high-risk time for exposure to potentially traumatic medical events. We have previously reported that 10% of young children continue to have posttraumatic stress disorder (PTSD) 6 months after burn injury. This study aimed to 1) document the prevalence and prospective change in parental psychological distress over 6 months following their child's burn injury and 2) identify risk factors for posttraumatic stress symptoms (PTSS) in young children and their parents. METHODS: Participants were 120 parents of 1-6-year-old children with unintentional burn injuries. Data were collected within 2 weeks, 1 month, and 6 months of burn injury using developmentally sensitive diagnostic interviews and questionnaires. RESULTS: Within the first month, ~ 25% of parents had a probable PTSD diagnosis, and moderate to extremely severe levels of depression, anxiety, and stress. Distress levels decreased significantly over time; however, 5% of parents still had probable PTSD at 6 months. Hierarchical multiple regression and path analyses indicated that parent posttraumatic stress reactions contributed significantly to the development and maintenance of child PTSS. Other risk factors for child PTSS included premorbid emotional and behavioral difficulties and larger burn size. Risk factors identified for parent PTSS included prior trauma history, acute distress, greater number of child invasive procedures, guilt, and child PTSS. CONCLUSIONS: The findings from this study suggest that parents' responses to a traumatic event may play a particularly important role in a young child's psychological recovery. However, further research is needed to confirm the direction of the relationship between child and parent distress. This study identified variables that could be incorporated into screening tools or targeted by early intervention protocols to prevent the development of persistent child and parent PTSS following medical trauma. PMID- 24494783 TI - Effect of screw access channel filling materials on uniaxial retentive force of cement-retained implant restorations. AB - BACKGROUND: This study aimed to investigate the effect of various abutment screw access channel filling materials on the uniaxial retention of castings cemented onto the abutment using temporary cement. METHODS: Ten straight, regular platform Esthetic Abutments were used. Fifty castings were divided into five groups and the abutment screw access channels were filled with composite resin (Filtek Z 250), light-cured temporary filling (Clip), temporary filling (Coltosol), polyvinyl siloxane impression material (Elite H-D), or polytetrafluoroethylene (PTFE) tape. Castings were cemented and thermal cycled. A uniaxial tensile force with a cross-head speed of 5 mm/min, was applied to the castings until cement failure occurred. One-way analysis of variance was used to perform intergroup comparisons of the mean uniaxial retentive force (URF) values and Tukey's HSD test was used to determine the group causing the difference. RESULTS: There were statistically significant differences between the mean URF values for the groups (p < 0.01). The mean URF value for the composite resin group was statistically higher than those for the other filling material groups respectively (p < 0.05). CONCLUSIONS: The retention of castings cemented to straight implant abutments using non-eugenol temporary cement may be influenced by the screw access channel filling material. PMID- 24494784 TI - Varicella vaccination: a laboured take-off. AB - Varicella vaccines are highly immunogenic, efficacious and safe in preventing varicella disease. The USA has been the first country recommending universal vaccination. In the European Union/European Economic Area countries, the use of varicella vaccine is heterogeneous, with some countries recommending universal vaccination in children at national or regional level, others only in high-risk groups and others having no recommendation at all. Uncertainties on the potential impact of varicella vaccination on the epidemiology of varicella and herpes zoster still exist. These uncertainties are the main reason behind the diverse vaccine recommendations. Surveillance systems and mathematical models could be useful to address these uncertainties. However, the lack of surveillance of varicella and herpes zoster in some countries, as well as the high variability of surveillance systems in the countries that have one, makes it difficult to assess the effect of the vaccine. On the other hand, mathematical models are based on assumptions and should be interpreted carefully. Continuous surveillance of varicella and herpes zoster is needed to identify any changes in the epidemiological presentation of the diseases. In any case, continuous surveillance will be needed to fully describe the impact of the programmes currently running and clarify some of the actual uncertainties in the near future. Additionally, increasing our understanding of the risk factors for development of herpes zoster is required. PMID- 24494786 TI - Wetting transition from the Cassie-Baxter state to the Wenzel state on textured polymer surfaces. AB - The wetting transition from the Cassie-Baxter state to the Wenzel state on textured surfaces was investigated. Nano- to microscale hexagonal pillared lattices were prepared by nanoimprint lithography on fluorinated cycloolefin polymer substrates. The transition was clearly observed for water and some ionic liquids through contact angle measurements and optical microscopy. A simple model clearly demonstrated that the energy barrier in the wetting transition from the Cassie-Baxter state to the Wenzel state was dominated by the competition between the energy barrier and external forces, particularly the Laplace pressure in the present case. PMID- 24494785 TI - Temperament, hopelessness, and attempted suicide: direct and indirect effects. AB - This study evaluated whether hopelessness mediated the relations between temperament and recent suicide attempter status in a psychiatric sample. Negative temperament and positive temperament (particularly the positive emotionality subscale) uniquely predicted levels of hopelessness. Although these temperament constructs also demonstrated significant indirect effects on recent suicide attempter status, the effects were partially (for the broad temperament scales) or fully (for the positive emotionality subscale) mediated by the levels of hopelessness. These findings indicate that a tendency to experience excessive negative emotions as well as a paucity of positive emotions may lead individuals to experience hopelessness. Although temperament may also indirectly influence suicide attempter status, hopelessness mediates these relations. PMID- 24494787 TI - Incidence and trends in the diagnosis of traumatic extracranial cerebrovascular injury in the nationwide inpatient sample database, 2003-2010. AB - Patients with traumatic extracranial cerebrovascular injury (TCVI) comprise about 1% of all blunt trauma admissions according to numerous single-center studies. However, previous studies have used aggressive screening protocols; these studies may not reflect common practice and the overall incidence of TCVI. The annual incidence of the diagnosis of TCVI from 2003 to 2010 was estimated using the Nationwide Inpatient Sample (NIS). For comparison, a systematic review of previous studies of the incidence of the diagnosis of TCVI was conducted. The estimated total number of admissions with TCVI ranged from 1283 to 2652; these admissions represented 0.46-0.95% of all blunt trauma admissions. There was a significant increase in the incidence of TCVI during the study period. A total of 49 studies of TCVI reported incidences of diagnosis ranging from 0.03% to 4.8%. In conclusion, the annual nationwide incidence of the diagnosis of TCVI is increasing. Although NIS incidences of the diagnosis of TCVI are at the low end of the range of previous reports, the increasing incidence in the NIS data likely reflects increasing use of aggressive screening protocols. PMID- 24494788 TI - OMICS studies: How about metadata checklist and data publications? AB - Data fully utilized by the community resources promote progress rather than repetition. Effective data sharing can accelerate the transition from data to actionable knowledge, yet barriers to data sharing remain, both technological and procedural. The DELSA community has tackled the sharing barrier by creating a multi-omics metadata checklist for the life sciences. The checklist and associated data publication examples are now jointly published in Big Data and OMICS: A Journal of Integrative Biology. The checklist will enable diverse datasets to be easily harmonized and reused for richer analyses. It will facilitate data deposits, stand alone as a data publication, and grant appropriate credit to researchers. We invite the broader life sciences community to test the checklist for feedback and improvements. PMID- 24494789 TI - Best treatment option for infantile chronic myeloid leukemia patients: imatinib or hematopoietic stem cell transplantation? PMID- 24494790 TI - Effects of different periods of hypoxic training on glucose metabolism and insulin sensitivity. AB - This study examined the effects of different periods of hypoxic training on glucose metabolism. Sedentary subjects underwent hypoxic training (FiO2 = 15.0%) for either 2 weeks (2-week group; n = 11) or 4 weeks (4-week group; n = 10). The 2-week group conducted training sessions on 6 days week(-1) for 2 weeks, whereas the 4-week group conducted training sessions on 3 days week(-1) for 4 weeks. Body fat mass or abdominal fat area did not change after training period in either group. VO2max increased in both groups after training period (42 +/- 2 versus 43 +/- 2 ml min(-1) kg(-1) in 2-week group, 41 +/- 1 versus 42 +/- 2 ml min(-1) kg( 1) in 4-week group). Both groups showed a reduction in mean blood pressure after training period (92 +/- 3 versus 90 +/- 3 mmHg in 2-week group, 91 +/- 2 versus 87 +/- 2 mmHg in 4-week group, P <= 0.05). No change was observed in blood glucose response after glucose ingestion after training period. However, area under the curve for serum insulin concentrations after glucose ingestion significantly decreased in only 4-week group (6910 +/- 763 versus 5812 +/- 872 MUIU ml(-1) 120 min, P <= 0.05). In conclusion, hypoxic training reduced blood pressure with independent on training duration. However, a longer period of hypoxic training led to greater improvements in insulin sensitivity compared with equivalent training over a shorter period, suggesting that hypoxic training programmes for more than 4 weeks might be more beneficial for improving insulin sensitivity. PMID- 24494791 TI - Neonatal seizures: magnetic resonance imaging adds value in the diagnosis and prediction of neurodisability. AB - AIM: To determine the aetiological associations, neurological sequelae and role of magnetic resonance imaging (MRI) in term newborn infants with seizures. METHODS: Cohort study of infants >=37 weeks' gestation delivered in a tertiary level centre, prospectively identified and followed longitudinally for 18-24 months. RESULTS: An underlying aetiology was found in 95% of the 77 infants identified with seizures (3.0/1000 live births). The most common diagnosis was hypoxic-ischaemic encephalopathy (HIE) (65%), followed by neonatal stroke (12%). Nine infants died, 28 of the 68 survivors developed neurodevelopmental impairment (NDI), and 15 had recurrent seizures in the first 2 years, with both outcomes more likely in those with a diagnosis other than HIE. Abnormal MRI findings were found in 45 of the 70 infants imaged. The absence of major cerebral lesions was highly predictive of a normal neurological outcome. CONCLUSION: We report the first cohort of term infants with seizures fully investigated by MRI. The universal use of MRI enabled a cause to be identified in 95% of cases. The probability of having NDI or recurrence of seizures was extremely low with absence of major cerebral lesions on MRI. This study demonstrates the added value of MRI for diagnosis of aetiology and the prediction of neurological outcome. PMID- 24494792 TI - Efficacy and mechanism of anticonvulsant drugs in migraine. AB - Anticonvulsants represent one of the main substance classes used for the preventive treatment of migraine. Efficacy has been demonstrated in randomized placebo-controlled trials for topiramate and valproic acid including divalproex sodium. In the case of topiramate, efficacy has recently been proven for chronic migraine and even medication overuse headache, questioning the established concept of medication withdrawal. However, preventive treatment with anticonvulsants is frequently hampered by side effects that occasionally require treatment discontinuation. In addition, these data indicate that some anticonvulsant drugs are effective in migraine, while a number are clearly not useful. Effective anticonvulsants, such as topiramate and valproate, target nociceptive trigeminovascular and trigeminothalamic dural pathways or mechanisms involved in cortical spreading depression. Dissecting out how the anticonvulsants that do not work differ mechanistically from those that do will almost certainly provide avenues through which one can develop new treatments to bring to patients with migraine. PMID- 24494793 TI - Ceftaroline fosamil for the treatment of acute bacterial skin and skin structure infections. AB - Skin infections have traditionally been classified by the US FDA as uncomplicated and complicated. In August 2010, the FDA released a new guidance document for the development of drugs to treat acute bacterial skin and skin structure infections (ABSSSI) and this was updated in 2013. Several new issues were addressed and henceforth skin infections in clinical trials were termed ABSSSI. In the USA, the annual prevalence of methicillin-resistant Staphylococcus aureus-related skin infections have continuously increased from 32.7% in 1998 to 53.8% in 2007. Ceftaroline fosamil is the only cephalosporin approved in the USA for monotherapy treatment of ABSSSI including infections caused by methicillin-resistant S. aureus. The efficacy of ceftaroline fosamil was shown in the CANVAS clinical trials. The CANVAS Day-3 analyses met an earlier, primary efficacy time point requested by the FDA. Ceftaroline has minimal drug-drug interactions, is well tolerated and possesses the safety profile associated with the cephalosporin class. PMID- 24494794 TI - Ustekinumab for the treatment of psoriatic arthritis. AB - Psoriatic arthritis occurs commonly in those with psoriasis and is associated with progressive joint destruction, physical disability, reduced quality of life and increased mortality. For many patients the currently available treatment options including the anti-TNF treatments are inadequate. Recent data suggest that ustekinumab can provide an effective treatment option in these patients. We discuss the role of ustekinumab in the treatment of psoriatic arthritis and highlight areas requiring further work. PMID- 24494795 TI - "Please describe from your point of view a typical case of an error in palliative care": Qualitative data from an exploratory cross-sectional survey study among palliative care professionals. AB - CONTEXT: Patient safety is a concern in medicine, and the prevention of medical errors remains a challenge. The definition and understanding of an error is particularly difficult in palliative care, with scarce empirical evidence about the nature and causes of medical errors in that discipline. OBJECTIVES: This study explored incidents palliative care professionals perceive as typical errors in their practice, and descriptions of such events. METHODS: In the context of an exploratory, cross-sectional survey on errors in palliative care among professionals of palliative care institutions in Bavaria, Germany (n=168), participants described a typical case in which an error occurred. Data from free text answers was qualitatively analyzed, and categories for areas and causes of errors were extracted. RESULTS: The questionnaire was returned by 42% (n=70) of the sample. Two-thirds of respondents (n=46, 66%) gave a free-text answer describing a typical error in palliative care. Seven potential areas for errors were identified in the qualitative analysis: drug treatment, palliative sedation, communication, care organization, treatment plan, end-of-life care, and history taking. Six categories emerged as causes of errors: miscommunication, system failure, dysfunctional attitudes, lack of knowledge, wrong use of technology, and misjudgement. CONCLUSION: Data showed that medical errors in palliative care, as seen by professionals in the field, primarily affect medication and communication, and miscommunication and system failures are perceived as the leading causes of errors. A better understanding of the characteristics of errors within palliative care and further qualitative research are warranted to prevent errors and enhance patient safety. PMID- 24494796 TI - Histone deacetylase inhibitor sodium butyrate promotes the osteogenic differentiation of rat adipose-derived stem cells. AB - Adult stem cells hold great promise for use in tissue repair and regeneration. Recently, adipose tissue-derived stem cells (ADSCs) were found to be an appealing alternative to bone marrow stem cells (BMSCs) for bone tissue engineering. The main benefit of ADSCs is that they can be easily and abundantly available from adipose tissue. However, our prior study discovered an important phenomenon that BMSCs have greater osteogenic potential than ADSCs in vitro and epigenetic regulation plays a critical role in runt-related transcription factor 2 (Runx2) expression and thus osteogenesis. In this study, we aimed to improve the osteogenic potential of ADSCs by histone deacetylase inhibitor sodium butyrate (NaBu). We found that NaBu promoted rat ADSC osteogenic differentiation by altering the epigenetic modifications on the Runx2 promoter. PMID- 24494797 TI - Incremental value of larger interventricular conduction time in improving cardiac resynchronization therapy outcome in patients with different QRS duration. AB - INTRODUCTION: The left ventricular (LV) pacing site and the magnitude of the electrical delay within the LV, as expressed by prolonged QRS duration, are major determinants of cardiac resynchronization therapy (CRT) efficacy. We investigated the incremental value of positioning the LV lead in areas of late activation in order to enhance the response to CRT in patients with different degrees of QRS complex lengthening. METHODS AND RESULTS: This analysis was performed on 301 heart failure patients who received a CRT defibrillator. On implantation, the right ventricular (RV)-to-LV interval was measured as the delay between local activations recorded through the RV and LV leads in the final position. After 1 year, 171 (57%) patients displayed reverse LV remodeling, as measured by a >=15% reduction in the LV end-systolic volume. Both the RV-to-LV interval and its percentage value corrected for the QRS duration were significantly associated with a positive response to CRT. An RV-to-LV interval >80 milliseconds and an RV to-LV interval/QRS >58% yielded the best prediction of reverse remodeling. Although the response to CRT decreased with shorter QRS duration in the overall population, patients with an RV-to-LV interval >80 milliseconds showed a response rate >65% in all QRS subgroups. CONCLUSION: A longer RV-to-LV interval is associated with reverse LV remodeling after CRT. On implantation attempts could be made to maximize it when selecting the LV lead position, especially in patients with shorter QRS duration, and thus less likely to respond positively to CRT. PMID- 24494798 TI - Excessive activation of the alternative complement pathway in autosomal dominant polycystic kidney disease. AB - OBJECTIVES: The complement system is involved in many immune complex-mediated kidney diseases, yet its role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD) has not been examined in detail. METHODS AND RESULTS: Screening of the glycoproteome of urine samples from ADPKD patients revealed that levels of complement factor B (CFB), serpin peptidase inhibitor, complement component 1 inhibitor (SERPING1) and complement component 9 (C9) increased, whereas complement component 1, r subcomponent-like (C1RL), CD55 and CD59 levels decreased with disease progression. Immunostaining and Western blot analysis confirmed the enhanced expression of CFB and C9 in cystic kidneys from ADPKD patients. Immunostaining also showed that the expressions of CFB and C9 in renal biopsy tissues from patients with other types of chronic kidney disease were lower than in tissues from ADPKD patients. The effect of the complement inhibitor rosmarinic acid (RMA) was evaluated in Pkd1(-/-) mice and Han:SPRD Cy/+ rats. Compared with vehicle-treated Pkd1(-/-) animals, RMA-treated mice had significantly lower serum creatinine (-50%) and blood urea nitrogen (-78%) levels, two kidneys/body weight ratio (-60%) and renal cystic index (-60%). Similar results were found in Cy/+ rats. Lower numbers of Ki67-positive nuclei and inflammatory cells and reduced fibrosis were observed in both animal models upon treatment with RMA. CONCLUSIONS: These results suggest that excessive activation of the alternative complement pathway is associated with ADPKD progression, probably mediated by cyst-lining epithelial cell proliferation, tubulointerstitial inflammatory cell infiltration and fibrosis. Targeting the complement system might represent a new therapeutic strategy for ADPKD. PMID- 24494799 TI - Control of the grafting of hybrid polyoxometalates on metal and carbon surfaces: toward submonolayers. AB - A Keggin-type POM is attached to gold or glassy carbon surfaces by electro(chemical) or peptidic coupling. In addition to demonstrating the robust attachment of the POMs (by electrochemistry, XPS, and IRRAS), the surface concentration, layer thickness, and rate constant for electron transfer from the surface to the POMs have been measured. The use of such complementary techniques is mandatory to characterize the modified electrodes properly. Whatever the grafting method, experimental conditions are found to allow monolayer or submonolayer coverage. Besides covalently grafted species, additional electrostatically bonded POMs are present in the film. Cathodic polarization allows removing them to get a grafted film that is stable with time and potential, which is a requirement in the design of molecular memories. PMID- 24494800 TI - Biocatalysis with Escherichia coli-overexpressing cyclopentanone monooxygenase immobilized in polyvinyl alcohol gel. AB - This is the first reported study on the immobilization of living recombinant Escherichia coli cells that overexpress cyclopentanone monooxygenase in polyvinyl alcohol gel particles LentiKats(r). Immobilized cells overexpressing cyclopentanone monooxygenase have been used as a model of biocatalyst for enantioselective Baeyer-Villiger biooxidation of rac-bicyclo[3.2.0]hept-2-en-6 one into regioisomeric lactones. This process is useful for the syntheses of cytostatic sarkomycin, several prostaglandins and other biologically active compounds. The original technique for qualitative analysis of enzyme expression within free cells and cells entrapped in LentiKats(r) using SDS-PAGE was developed and used for verification of optimal conditions for the induction of cyclopentanone monooxygenase. Here, we successfully performed six repeated batch Baeyer-Villiger biooxidations utilizing entrapped cells using 40% (w/v) polyvinyl alcohol gel particles in flasks with baffles. The latter conditions have been found to be the most appropriate achieving optimal oxygen transfer within LentiKats(r). Moreover, immobilized cells retained their catalytic efficiency over six reaction cycles, while the catalytic efficiency of free cells decreased after three reaction cycles. SIGNIFICANCE AND IMPACT OF THE STUDY: Immobilization in polyvinylalcohol gel particles is desirable technique with presumptive impact on industrial applications of recombinant whole-cell Baeyer-Villiger monooxygenases as biocatalysts for production of bioactive compounds and precursors of potentially new drugs. An original immobilization of cells E. coli with overproduced Baeyer-Villiger monooxygenase improved their stability in repetitive batch biooxidations as compared to free cells. Detected autoinduction of recombinant enzyme in pET22b+ plays significant role in application of immobilized cells as it may increase specific activity of cells in repetitive use under growing reaction conditions. Original technique for qualitative analysis of enzyme expression within immobilized cells was developed. PMID- 24494801 TI - Kinetic Monte Carlo simulation of CO adsorption on sulfur-covered Pd(100). AB - The use of atomistic Kinetic Monte Carlo method was explored to examine the influence of sulfur poisoning on CO adsorption on Pd(100) surface. The model explicitly incorporates key elementary processes such as CO adsorption and CO desorption including diffusion of surface CO and S species. Relevant energetic and kinetic parameters were derived using information calculated from density functional theory as a starting point. Kinetic Monte Carlo simulation was performed to determine relevant observables such as CO saturation coverage as a function of amount of preadsorbed sulfur and to predict temperature programmed desorption spectra. PMID- 24494802 TI - Unconventional terahertz carrier relaxation in graphene oxide: observation of enhanced auger recombination due to defect saturation. AB - Photoexcited carrier relaxation is a recurring topic in understanding the transient conductivity dynamics of graphene-based devices. For atomically thin graphene oxide (GO), a simple free-carrier Drude response is expected to govern the terahertz (THz) conductivity dynamics--same dynamics observed in conventional CVD-grown graphene. However, to date, no experimental testimony has been provided on the origin of photoinduced conductivity increase in GO. Here, using ultrafast THz spectroscopy, we show that the photoexcited carrier relaxation in GO exhibits a peculiar non-Drude behavior. Unlike graphene, the THz dynamics of GO show percolation behaviors: as the annealing temperature increases, transient THz conductivity rapidly increases and the associated carrier relaxation changes from mono- to biexponential decay. After saturating the recombination decay through defect trapping, a new ultrafast decay channel characterized by multiparticle Auger scattering is observed whose threshold pump fluence is found to be 50 MUJ/cm2. The increased conductivity is rapidly suppressed within 1 ps due to the Auger recombination, and non-Drude THz absorptions are subsequently emerged as a result of the defect-trapped high-frequency oscillators. PMID- 24494804 TI - Graft stabilization with cyanoacrylate decreases shrinkage of free gingival grafts. AB - BACKGROUND: The aim of this study was to comparatively evaluate three different stabilization methods with regards to the amount of shrinkage in free gingival graft. METHODS: Forty-five patients were included in three study groups: where stabilization was achieved with conventional technique, cyanoacrylate or microsurgery. In the conventional group standardized 5-0 sutures were used. In the microsurgery group grafts were stabilized with 7-0 sutures and loupe. In the third group, graft was stabilized with cyanoacrylate. Keratinized tissue width, graft area, gingival recession were calculated by a specific software on standard photographs at baseline, 1-, 3-, 6-month follow-ups. Duration of surgery was also recorded. Pain in recipient and donor sites was assessed using visual analogue scale within the first postoperative week. RESULTS: Change in keratinized tissue width was similar in the study groups at all times. Graft shrinkage was significantly less (p < 0.05) in the cyanoacrylate group than the other groups, whereas those in the conventional and microsurgery groups were similar. Significantly less pain in the recipient site was reported by the patients in the cyanoacrylate group (p < 0.05). Duration of surgery was significantly less in the cyanoacrylate group than the other groups (p < 0.05). CONCLUSIONS: Less graft shrinkage in the free gingival graft, together with shorter surgery time and less pain in the recipient site obtained in the cyanoacrylate group, suggest that cyanoacrylate may be considered as an alternative for stabilization of free gingival grafts. PMID- 24494803 TI - Assessment of in situ adipose tissue inflammation by microdialysis. AB - BACKGROUND: Inflammation, and specifically adipose tissue (AT) inflammation, is part of the pathophysiology of obesity and HIV-associated lipodystrophy. Local AT protein assessment methods are limited, and AT inflammation studies have therefore primarily examined inflammatory gene expression. We therefore investigated the utility of microdialysis to study in situ AT interstitial inflammatory protein levels. MATERIAL AND METHODS: Abdominal subcutaneous AT microdialysis was performed in six healthy men, six HIV-infected men with lipodystrophy and six without lipodystrophy using the internal references (51) Cr EDTA and (125) I-human serum albumin. We measured 41 inflammatory proteins in microdialysis samples by Luminex technology, as well as systemic levels in 14 subjects. Furthermore, in vitro studies of the internal reference technique for microdialysis recovery of inflammatory proteins were made. RESULTS: We detected in situ AT interstitial levels of 14 inflammatory proteins by microdialysis, while the 27 other inflammatory proteins assessed were only detected sporadically. Initial levels of IL-6 and IL-8 were undetectable. Insertion trauma affected IL-1alpha, IL-6, IL-8, monocyte chemotactic factor (MCP)-1, IP-10, G CSF, growth-related oncogene (GRO), macrophage-derived chemokine (MDC) and macrophage inflammatory protein (MIP)-1beta levels, while fibroblast growth factor (FGF)-2 was not affected. Systemic and AT interstitial levels were poorly correlated. The microdialysis recovery of smaller proteins was higher than for larger, and the internal references improved microdialysis by accounting for variation in perfusion across the membrane. CONCLUSION: Interstitial inflammatory proteins can be sampled in situ using microdialysis. Use of internal references improves the microdialysis technique. However, insertion trauma hampers the use of microdialysis to study AT inflammatory levels, except for FGF-2. Still, microdialysis gives unique insight to in situ AT interstitial concentrations. PMID- 24494805 TI - Is diabetes patients' knowledge of laboratory tests for monitoring blood glucose levels associated with better glycaemic control? AB - AIM: To determine if there is any difference in indices of glycaemic control between type-2 diabetes patients who knew the laboratory tests for monitoring blood glucose and their peers who did not know. METHODS: Eighty-nine type-2 diabetes patients were studied after an overnight fast. The patients' bio-data, blood pressure, anthropometric indices and baseline biochemical parameters and glycated haemoglobin A1c (HbA1c) were measured. After a breakfast of stewed boiled rice, a 2-hour postprandial blood glucose was measured and a questionnaire administered. RESULTS: The patients' mean +/- SD HbA1c level was 8.6 +/- 2.4% and none of the patients knew about HbA1c test for monitoring glycaemic control. Interestingly, patients who knew about fasting blood glucose test had significantly lower HbA1c values than their counterparts who did not know (8.1 +/ 2.2 vs. 9.1 +/- 2.5%, p < 0.05). CONCLUSION: Diabetes self-management education incorporating laboratory-based information may assist to prevent poor glycaemic control in developing countries with increasing reports of hyperglycaemic emergencies. PMID- 24494806 TI - Prevalence of enterococcus species and their virulence genes in fresh water prior to and after storm events. AB - Enterococcus spp. isolates (n = 286) collected from six surface water bodies in subtropical Brisbane, Australia, prior to and after storm events, were identified to species level and tested for the presence of seven clinically important virulence genes (VGs). Enterococcus faecalis (48%), Enterococcus faecium (14%), Enterococcus mundtii (13%), and Enterococcus casseliflavus (13%) were frequently detected at all sites. The frequency of E. faecium occurrence increased from 6% in the dry period to 18% after the wet period. The endocarditis antigen (efaA), gelatinase (gelE), collagen-binding protein (ace), and aggregation substance (asa1) were detected in 61%, 43%, 43%, and 23% of Enterococcus isolates, respectively. The chances of occurrence of ace, gelE, efaA, and asa1 genes in E. faecalis were found to be much higher compared to the other Enterococcus spp. The observed odds ratio of occurrence of ace and gelE genes in E. faecalis was much higher at 7.96 and 6.40 times, respectively. The hyl gene was 3.84 times more likely to be detected in E. casseliflavus. The presence of multiple VGs in most of the E. faecalis isolates underscores the importance of E. faecalis as a reservoir of VGs in the fresh water aquatic environment. Consequently, if contaminated surface water is to be used for production of potable and nonpotable water some degree of treatment depending upon intended use such as detention in basins prior to use or chlorination is required. PMID- 24494807 TI - Is familial nonmedullary thyroid carcinoma more aggressive than sporadic nonmedullary thyroid carcinoma? PMID- 24494808 TI - Atomoxetine-induced hypomania-like symptoms in a preadolescent patient. PMID- 24494810 TI - Pharmacokinetics, tumor accumulation and antitumor activity of nanoliposomal irinotecan following systemic treatment of intracranial tumors. AB - AIM: We sought to evaluate nanoliposomal irinotecan as an intravenous treatment in an orthotopic brain tumor model. MATERIALS & METHODS: Nanoliposomal irinotecan was administered intravenously in the intracranial U87MG brain tumor model in mice, and irinotecan and SN-38 levels were analyzed in malignant and normal tissues. Therapy studies were performed in comparison to free irinotecan and control treatments. RESULTS: Tissue analysis demonstrated favorable properties for nanoliposomal irinotecan, including a 10.9-fold increase in tumor AUC for drug compared with free irinotecan and 35-fold selectivity for tumor versus normal tissue exposure. As a therapy for orthotopic brain tumors, nanoliposomal irinotecan showed a mean survival time of 54.2 versus 29.5 days for free irinotecan. A total of 33% of the animals receiving nanoliposomal irinotecan showed no residual tumor by study end compared with no survivors in the other groups. CONCLUSION: Nanoliposomal irinotecan administered systemically provides significant pharmacologic advantages and may be an efficacious therapy for brain tumors. PMID- 24494811 TI - Nephrotoxicity of concomitant use of tacrolimus and teicoplanin in allogeneic hematopoietic stem cell transplant recipients. AB - Both tacrolimus and glycopeptide antibiotics are known to be nephrotoxic, and are often concomitantly given after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. The aim of this study is to evaluate the nephrotoxicity of concomitant use of tacrolimus and glycopeptide antibiotics in HSCT recipients. We retrospectively evaluated 67 patients who received intravenous tacrolimus and teicoplanin concomitantly for >4 days after allogeneic HSCT for hematologic diseases. Therapeutic drug monitoring (TDM) was performed in all patients for both tacrolimus and teicoplanin. The median age of the patients was 48 years (range: 16-62), and the median duration of the co-administration of tacrolimus and teicoplanin was 11 days (range: 4-40). The mean serum creatinine (sCr) level tended to be elevated after the co-administration (from 0.69 +/- 0.26 to 0.75 +/- 0.30 mg/dL; P = 0.08); however, a 2-fold or greater increase in sCr was observed only in 2 (3.0%) patients. Increased sCr was reversible, and no patient required hemodialysis. These results suggest that the incidence of clinically significant nephrotoxicity can be minimized if the TDM of each drug is properly applied. PMID- 24494809 TI - What do infectious diseases physicians do? A 2-week snapshot of inpatient consultative activities across Australia, New Zealand and Singapore. AB - The practice of an infectious diseases (ID) physician is evolving. A contemporary understanding of the frequency and variety of patients and syndromes seen by ID services has implications for training, service development and setting research priorities. We performed a 2-week prospective survey of formal ID physician activities related to direct inpatient care, encompassing 53 hospitals throughout Australia, New Zealand and Singapore, and documented 1722 inpatient interactions. Infections involving the skin and soft tissue, respiratory tract and bone/joints together accounted for 49% of all consultations. Suspected/confirmed pathogens were primarily bacterial (60%), rather than viral (6%), fungal (4%), mycobacterial (2%) or parasitic (1%). Staphylococcus aureus was implicated in 409 (24%) episodes, approximately four times more frequently than the next most common pathogen. The frequency of healthcare-related infections (35%), immunosuppression (21%), diabetes mellitus (19%), prosthesis-related infections (13%), multiresistant pathogens (13%) and non-infectious diagnoses (9%) was high, although consultation characteristics varied between geographical settings and hospital types. Our study highlights the diversity of inpatient-related ID activities and should direct future teaching and research. ID physicians' ability to offer beneficial consultative advice requires broad understanding of, and ability to interact with, a wide range of referring specialities. PMID- 24494812 TI - Advances in enteric disease vaccines: from innovation to implementation. AB - The Seventh International Conference on Vaccines for Enteric Diseases Bangkok, Thailand, 6-8 November 2013 Hosting 222 participants from more than 25 countries, the Seventh International Conference on Vaccines for Enteric Diseases (VED 2013) displayed the considerable progress that has been made in recent years towards unraveling the burden and etiology of enteric infections, alongside advances in the development, testing and implementation of vaccines that target them. The pervasive nature of enteric diseases, and the significant morbidity and mortality they account for, underscore the substantial public health benefits achievable through the use of enteric vaccines. A number of key talking points raised during the conference are discussed here, including early experiences with the use of double-mutant heat-labile enterotoxin as an antigen and adjuvant, progress and challenges associated with the implementation of oral cholera vaccines, and the issue of impaired rotavirus vaccine immunogenicity in lower-income countries. PMID- 24494813 TI - The Swedish polio vaccine in memoriam. PMID- 24494814 TI - Scaffold for growing dense polymer brushes from a versatile substrate. AB - We have demonstrated a universal approach to growing polymer brushes from various substrates. Urushiol was mixed with initiator-containing catechol, and it was spin-coated or cast on various substrates. Because urushiol is strongly adhered to various substrates, the thin film can serve as a general scaffold for grafting polymer brushes from various substrates. Note that the film was formed even onto the surface of polyolefins and thermosetting resins that are known as chemically inert materials to functionalize the surface. Moreover, the initiator-immobilized scaffold showed mechanical robustness and chemical inertness because of the flexible long unsaturated hydrocarbon side chain of urushiol. After the grafting of polyelectrolyte PMTAC polymer brushes, the material obtained exhibited hydrophilicity, typical of PMTAC. The concept shown here could provide a general approach for grafting practical polymer brushes from various substrates. PMID- 24494815 TI - Reply: Morphology of far-field electrograms and antitachycardia pacing effectiveness among fast ventricular tachycardias occurring in ICD patients: the role of other discriminators. PMID- 24494816 TI - PPARgamma gene polymorphism, C-reactive protein level, BMI and periodontitis in post-menopausal Japanese women. AB - BACKGROUND: Several studies have reported inconsistent results regarding the association between the PPARgammaPro12Ala polymorphism and obesity. Obese individuals had higher C-reactive protein (CRP) levels compared with those of normal weight, and PPARgamma activation could significantly reduce serum high sensitive CRP level. We have previously suggested that the Pro12Ala polymorphism represents a susceptibility factor for periodontitis, which is a known risk factor for increased CRP level. OBJECTIVES: The aim was to investigate associations between PPARgamma gene polymorphism, serum CRP level, BMI and/or periodontitis among post-menopausal Japanese women. MATERIALS AND METHODS: The final sample in this study comprised 359 post-menopausal Japanese women. Periodontal parameters, including PD, CAL and BOP, were measured per tooth. PPARgammaPro12Ala genotype was determined by PCR-RFLP. Hs-CRP value was measured by a latex nephelometry assay. RESULTS: No significant differences in age, BMI or periodontal parameters were found between the genotypes. The percentages of sites with PD >= 4 mm were significantly higher among the hsCRP >= 1 mg/l group than the hsCRP < 1 mg/l group (p = 0.003). Positive correlations were found between serum hsCRP levels and the percentages of sites with PD >= 4 mm (p = 0.043) in PPARgamma Ala allele carriers, and BMI (p = 0.033) in non-carriers. After adjustment for model covariates, BMI was significantly associated with serum hsCRP level. CONCLUSION: The PPARgammaPro12Ala polymorphism was not independently associated with periodontitis, serum CRP level or BMI in post-menopausal Japanese women. However, serum hsCRP level correlated with periodontitis in Ala allele carriers, and with BMI in non-carriers. PMID- 24494817 TI - Genome-wide detection of signatures of selection in Korean Hanwoo cattle. AB - The Korean Hanwoo cattle have been intensively selected for production traits, especially high intramuscular fat content. It is believed that ancient crossings between different breeds contributed to forming the Hanwoo, but little is known about the genomic differences and similarities between other cattle breeds and the Hanwoo. In this work, cattle breeds were grouped by origin into four types and used for comparisons: the Europeans (represented by six breeds), zebu (Nelore), African taurine (N'Dama) and Hanwoo. All animals had genotypes for around 680 000 SNPs after quality control of genotypes. Average heterozygosity was lower in Nelore and N'Dama (0.22 and 0.21 respectively) than in Europeans (0.26-0.31, with Shorthorn as outlier at 0.24) and Hanwoo (0.29). Pairwise FST analyses demonstrated that Hanwoo are more related to European cattle than to Nelore, with N'Dama in an intermediate position. This finding was corroborated by principal components and unsupervised hierarchical clustering. Using genome-wide smoothed FST , 55 genomic regions potentially under positive selection in Hanwoo were identified. Among these, 29 were regions also detected in previous studies. Twenty-four regions were exclusive to Hanwoo, and a number of other regions were shared with one or two of the other groups. These regions overlap a number of genes that are related to immune, reproduction and fatty acid metabolism pathways. Further analyses are needed to better characterize the ancestry of the Hanwoo cattle and to define the genes responsible to the identified selection peaks. PMID- 24494820 TI - Understanding the role of H-bonding in aqueous self-assembly of two naphthalene diimide (NDI)-conjugated amphiphiles. AB - Supramolecular architectures with the synchronized combination of various directional noncovalent forces are ubiquitous in biological systems. However, reports of such abiotic synthetic systems involving H-bonding in aqueous medium are rare due to the challenge faced in the formation of such structures by overcoming the competition from the water molecules. In this paper we have studied self-assembly of two structurally related naphthalene-diimide (NDI) conjugated bola-amphiphiles (NDI-1 and NDI-2) in water with an aim to realize the specific role of H-bonding among the hydrazide units present in one of the two building blocks (NDI-2) on the self-assembly. Both chromophores showed vesicular assembly in aqueous solution driven primarily by pi-stacking among the NDI chromophores, which could be probed by UV-vis absorption spectra. Contrary to common belief, the lack of an H-bonding group in NDI-1 was found to be a boon in disguise in terms of the stability of the aggregates. Whereas NDI-2 aggregates showed LCST around 65-70 degrees C owing to the breaking of the H-bonds with increased temperature, the NDI-1 aggregates were found to be structurally intact until 90 degrees C, which may be attributed to the increased hydrophobicity introduced by the absence of the polar hydrazide group. Further concentration- and solvent-dependent UV-vis studies showed that NDI-1 formed assembled structure at greatly dilute solution and also in a solvent such as THF, confirming greater propensity for its self-assembly. As both bola-amphiphiles contain an electron deficient NDI chromophore, interaction of their vesicles was studied with an externally added electron-rich pyrene derivative. Surprisingly, NDI-1 did not show any charge-transfer interaction with the donor, whereas NDI-2 could effectively intercalate, leading to a functional membrane with tunable surface functionalities. This was attributed to the additional stability of the intercalated state by H-bonding among the hydrazide units. PMID- 24494818 TI - A secretory multifunctional serine protease, DegP of Plasmodium falciparum, plays an important role in thermo-oxidative stress, parasite growth and development. AB - Plasmodium falciparum heat shock proteins and proteases are known for their indispensable roles in parasite virulence and survival in the host cell. They neutralize various host-derived stress responses that are deleterious for parasite growth and invasion. We report identification and functional characterization of the first DegP from an apicomplexan (P. falciparum). To determine the molecular identity and functions of the parasite-encoded DegP, we complemented the Escherichia coli degP null mutant with a putative PfdegP gene, and the results showed that PfDegP complements the growth defect of the temperature sensitive DegP-deficient mutant and imparts resistance to non permissive temperatures and oxidative stress. Molecular interaction studies showed that PfDegP exists as a complex with parasite-encoded heat shock protein 70, iron superoxide dismutase and enolase. DegP expression is significantly induced in parasite culture upon heat shock/oxidative stress. Our data suggest that the PfDegP protein may play a role in the growth and development of P. falciparum through its ability to confer protection against thermal/oxidative stress. Antibody against DegP showed anti-plasmodial activity against blood-stage parasites in vitro, suggesting that PfDegP and its associated complex may be a potential focus for new anti-malarial therapies. STRUCTURED DIGITAL ABSTRACT: ?PfDegP physically interacts with PfHsp70 and PfEno by anti-bait co immunoprecipitation (View interaction) ?PfDegP physically interacts with PfEno, PfSod, PfOat, PfHsp70, PfLDH and PfGpi by anti-bait co-immunoprecipitation (View interaction) ?PfHsp-70 and PfDegP co-localize by fluorescence microscopy (View interaction) ?PfDegP physically interacts with PfOat, PfHsp70, PfEno, PfSod, PfGpi and PfLDH by surface plasmon resonance (View interaction) ?PfEno and PfDegP co-localize by fluorescence microscopy (View interaction) ?PfDegP and PfHsp70 co localize by co-sedimentation through density gradient (View interaction). PMID- 24494819 TI - Hemimegalencephaly: what happens when children get older? AB - AIMS: Hemimegalencephaly (HME) is a rare congenital malformation of cortical development, usually associated with developmental delay and severe epilepsy. This condition has rarely been reported in adults. The aim of this study was to examine and compare neurological findings in adult patients with HME. METHOD: We retrospectively examined adult patients with HME by evaluating the presence of neurocutaneous disorders, current cognitive development, seizure control, and documentation of therapies for seizure management and outcomes. RESULTS: Five patients were included in the study (three males, two females; mean age 23 y 9 mo [SD 6 y 1 mo], range 18-34 y). Four patients had HME that was associated with neurocutaneous syndromes and the remaining patient had isolated HME. Two patients required surgical treatment for seizures in childhood. One patient had no intellectual disability, while one had mild, and three severe intellectual disability. All patients presented motor deficits ranging from mild hemiparesis in two patients to non-ambulation in one patient. Patients in whom seizure onset occurred after the 7 years of age had better seizure control and psychomotor development in adulthood than patients in whom seizure onset occurred in the first year of life. INTERPRETATION: In our small sample of adults with HME, age at seizure onset, cognitive disability, and seizure control were found to be associated. PMID- 24494821 TI - Structural, energetic, and UV-Vis spectral analysis of UVA filter 4-tert-butyl-4' methoxydibenzoylmethane. AB - The growing awareness of the harmful effects of ultraviolet (UV) solar radiation has increased the production and consumption of sunscreen products, which contain organic and inorganic molecules named UV filters that absorb, reflect, or scatter UV radiation, thus minimizing negative human health effects. 4-tert-Butyl-4' methoxydibenzoylmethane (BMDBM) is one of the few organic UVA filters and the most commonly used. BMDBM exists in sunscreens in the enol form which absorbs strongly in the UVA range. However, under sunlight irradiation tautomerization occurs to the keto form, resulting in the loss of UV protection. In this study we have performed quantum chemical calculations to study the excited-state molecular structure and excitation spectra of the enol and keto tautomers of BMDBM. This knowledge is of the utmost importance as the starting point for studies aiming at the understanding of its activity when applied on human skin and also its fate once released into the aquatic environment. The efficiency of excitation transitions was rationalized based on the concept of molecular orbital superposition. The loss of UV protection was attributed to the enol -> keto phototautomerism and subsequent photodegradation. Although this process is not energetically favorable in the singlet bright state, photodegradation is possible because of intersystem crossing to the first two triplet states. PMID- 24494822 TI - Chiral propargylic cations as intermediates in SN1-type reactions: substitution pattern, nuclear magnetic resonance studies, and origin of the diastereoselectivity. AB - Nine propargylic acetates, bearing a stereogenic center (-C*HXR(2)) adjacent to the electrophilic carbon atom, were prepared and subjected to SN1-type substitution reactions with various silyl nucleophiles employing bismuth trifluoromethanesulfonate [Bi(OTf)3] as the Lewis acid. The diastereoselectivity of the reactions was high when the alkyl group R(2) was tertiary (tert-butyl), irrespective of the substituent X. Products were formed consistently with a diastereomeric ratio larger than 95:5 in favor of the anti-diastereoisomer. If the alkyl substitutent R(2) was secondary, the diastereoselectivity decreased to 80:20. The reaction was shown to proceed stereoconvergently, and the relative product configuration was elucidated. The reaction outcome is explained by invoking a chiral propargylic cation as an intermediate, which is preferentially attacked by the nucleophile from one of its two diastereotopic faces. Density functional theory (DFT) calculations suggest a preferred conformation in which the group R(2) is almost perpendicular to the plane defined by the three substituents at the cationic center, with the nucleophile approaching the electrophilic center opposite to R(2). Transition states calculated for the reaction of allyltrimethylsilane with two representative cations support this hypothesis. Tertiary propargylic cations with a stereogenic center (-C*HXR(2)) in the alpha position were generated by ionization of the respective alcohol precursors with FSO3H in SO2ClF at -80 degrees C. Nuclear magnetic resonance (NMR) spectra were obtained for five cations, and the chemical shifts could be unambiguously assigned. The preferred conformation of the cations as extracted from nuclear Overhauser experiments is in line with the preferred conformation responsible for the reaction of the secondary propargylic cations. PMID- 24494823 TI - Inverse Modeling of Water-Rock-CO2 Batch Experiments: Potential Impacts on Groundwater Resources at Carbon Sequestration Sites. AB - This study developed a multicomponent geochemical model to interpret responses of water chemistry to introduction of CO2 into six water-rock batches with sedimentary samples collected from representative potable aquifers in the Gulf Coast area. The model simulated CO2 dissolution in groundwater, aqueous complexation, mineral reactions (dissolution/precipitation), and surface complexation on clay mineral surfaces. An inverse method was used to estimate mineral surface area, the key parameter for describing kinetic mineral reactions. Modeling results suggested that reductions in groundwater pH were more significant in the carbonate-poor aquifers than in the carbonate-rich aquifers, resulting in potential groundwater acidification. Modeled concentrations of major ions showed overall increasing trends, depending on mineralogy of the sediments, especially carbonate content. The geochemical model confirmed that mobilization of trace metals was caused likely by mineral dissolution and surface complexation on clay mineral surfaces. Although dissolved inorganic carbon and pH may be used as indicative parameters in potable aquifers, selection of geochemical parameters for CO2 leakage detection is site-specific and a stepwise procedure may be followed. A combined study of the geochemical models with the laboratory batch experiments improves our understanding of the mechanisms that dominate responses of water chemistry to CO2 leakage and also provides a frame of reference for designing monitoring strategy in potable aquifers. PMID- 24494824 TI - The role of oral flora in the development of chemotherapy-induced oral mucositis. AB - Chemotherapy-induced mucositis is considered to be a major oncological problem, caused by the cytotoxic effects of cancer chemotherapy. In the last 10 years, there have been significant advances in the understanding of mucositis pathobiology. At the basic level, it is now well-understood that it is not just an epithelial process, but rather a complex interaction between epithelial and connective tissue compartments. There is also potential interaction between the oral microenvironment and the development of mucositis. Changes occur in the resident oral flora (commensal) throughout cancer treatment, and it is conceivable that these organisms and changes that occur may have an influence on the development of mucosal toxicity associated with cancer treatment. The aim of this review was to examine the potential contributions of oral microflora in the pathobiology of mucositis and identify pathways and interactions that could be targeted for therapeutic management of mucositis. PMID- 24494825 TI - An organizational approach for the assessment of DNA adduct data in risk assessment: case studies for aflatoxin B1, tamoxifen and vinyl chloride. AB - The framework analysis previously presented for using DNA adduct information in the risk assessment of chemical carcinogens was applied in a series of case studies which place the adduct information into context with the key events in carcinogenesis to determine whether they could be used to support a mutagenic mode of action (MOA) for the examined chemicals. Three data-rich chemicals, aflatoxin B1 (AFB1), tamoxifen (Tam) and vinyl chloride (VCl) were selected for this exercise. These chemicals were selected because they are known human carcinogens and have different characteristics: AFB1 forms a unique adduct and human exposure is through contaminated foods; Tam is a pharmaceutical given to women so that the dose and duration of exposure are known, forms unique adducts in rodents, and has both estrogenic and genotoxic properties; and VCl, to which there is industrial exposure, forms a number of adducts that are identical to endogenous adducts found in unexposed people. All three chemicals produce liver tumors in rats. AFB1 and VCl also produce liver tumors in humans, but Tam induces human uterine tumors, only. To support a mutagenic MOA, the chemical-induced adducts must be characterized, shown to be pro-mutagenic, be present in the tumor target tissue, and produce mutations of the class found in the tumor. The adducts formed by AFB1 and VCl support a mutagenic MOA for their carcinogenicity. However, the data available for Tam shows a mutagenic MOA for liver tumors in rats, but its carcinogenicity in humans is most likely via a different MOA. PMID- 24494826 TI - Toxicological and epidemiological studies of cardiovascular effects of ambient air fine particulate matter (PM2.5) and its chemical components: coherence and public health implications. AB - Recent investigations on PM2.5 constituents' effects in community residents have substantially enhanced our knowledge on the impacts of specific components, especially the HEI-sponsored National Particle Toxicity Component (NPACT) studies at NYU and UW-LRRI that addressed the impact of long-term PM2.5 exposure on cardiovascular disease (CVD) effects. NYU's mouse inhalation studies at five sites showed substantial variations in aortic plaque progression by geographic region that was coherent with the regional variation in annual IHD mortality in the ACS-II cohort, with both the human and mouse responses being primarily attributable to the coal combustion source category. The UW regressions of associations of CVD events and mortality in the WHI cohort, and of CIMT and CAC progression in the MESA cohort, indicated that [Formula: see text] had stronger associations with CVD-related human responses than OC, EC, or Si. The LRRI's mice had CVD-related biomarker responses to [Formula: see text]. NYU also identified components most closely associated with daily hospital admissions (OC, EC, Cu from traffic and Ni and V from residual oil). For daily mortality, they were from coal combustion ([Formula: see text], Se, and As). While the recent NPACT research on PM2.5 components that affect CVD has clearly filled some major knowledge gaps, and helped to define remaining uncertainties, much more knowledge is needed on the effects in other organ systems if we are to identify and characterize the most effective and efficient means for reducing the still considerable adverse health impacts of ambient air PM. More comprehensive speciation data are needed for better definition of human responses. PMID- 24494827 TI - Mechanisms for adsorption of methyl viologen on CdS quantum dots. AB - This paper describes the surface composition-dependent binding of the dichloride salt of methyl viologen (MV2+) to CdS quantum dots (QDs) enriched, to various degrees, with either Cd or S at the surface. The degree of enrichment is controlled synthetically and by postsynthetic dilution of the QDs in their solvent, THF. NMR shows the Cd-enriched QDs to contain a relatively dense (2.8 ligands/nm2) surface layer of oleic acid, in the form of Cd-oleate, and S enriched QDs to contain relatively sparse (1.0 ligands/nm2) surface density of native ligands containing both oleic acid and octadecene. Electron transfer mediated photoluminescence quenching of the QDs by MV2+ serves as a probe for the binding affinity of MV2+ for the surfaces of the QDs. Diluting Cd-enriched QDs removes Cd-oleate from the surface, exposing the stoichiometric CdS surface beneath and increasing the quenching efficiency of MV2+, whereas diluting S enriched QD does not change their surface chemistry or the efficiency with which they are quenched by MV2+. The photoluminescence quenching data for all of the surface chemistries we studied fit well to a Langmuir model that accounts for binding of MV2+ through two reaction mechanisms: (i) direct adsorption of MV2+ to exposed stoichiometric CdS surfaces (with an equilibrium adsorption constant of 1.5*10(5) M(-1)), and (ii) adsorption of MV2+ to stoichiometric CdS surfaces upon displacement of weakly bound Cd-oleate complexes (with an equilibrium displacement constant of 3.5*10(3) M(-1)). Ab initio calculations of the binding energy for adsorption of the dichloride salt of MV2+ on Cd- and S-terminated surfaces reveal a substantial preference of MV2+ for S-terminated lattices due to alignment of the positively charged nitrogens on MV2+ with the negatively charged sulfur. These findings suggest a strategy to maximize the adsorption of redox active molecules in electron transfer-active geometries through synthetic and postsynthetic manipulation of the inorganic surface. PMID- 24494828 TI - Global policy and local actions for vulnerable populations affected by disaster and displacement. PMID- 24494829 TI - Working with populations from a refugee background: an opportunity to enhance the occupational therapy educational experience. AB - BACKGROUND/AIM: The purpose of this study was to determine the educational value of an occupational therapy fieldwork placement where students work with people from a refugee background. Research was designed to contribute to the limited evidence regarding the benefits and challenges of traditional vs. non-traditional fieldwork settings and to explore the application of occupational therapy related to working with refugee populations. METHOD: Fourteen participants were interviewed using semi-structured, open-ended questions to explore perspectives on how their experience influenced their education and professional development. Face-to-face interviews were audio-recorded and transcribed verbatim. Transcriptions and hard-copy data were analysed to identify emergent themes and subthemes. Triangulation and member-checking increased trustworthiness. RESULTS: Three major themes emerged in this study: Operational therapy at its Core; Cultural Awareness and Competence; and Basic Skills for Any Setting. Subthemes emerged but for the purposes of this article only the major themes are discussed. CONCLUSION: A fieldwork experience working with people of a refugee background can facilitate the development of cultural awareness and competence, as well as foundational professional skills. In this setting, the importance of occupation based, client-centred practice can be fully realised. Results indicate that this fieldwork setting is a suitable environment for experiencing occupational therapy principles and that labelling fieldwork experiences working with people from a refugee background as 'non-traditional' may be inappropriate. Learning experiences reported by students also reveal the benefits of working independently at times without direct supervision of an occupational therapist. PMID- 24494830 TI - The role of occupational therapy in the recovery stage of disaster relief: a report from earthquake stricken areas in China. AB - Earthquakes and their destructive forces are unpredictable and difficult to prepare for. Unfortunately, another powerful earthquake of magnitude 7.2 had struck when this report was being prepared. The disabling events have long-term negative impacts on occupational performance of the individuals and communities being affected. Occupational therapy practitioners can use their professional expertise and power of engagement to restore life when individuals and communities are disrupted by natural disaster. The events of the Wenchuan Earthquake have raised awareness of the importance of rehabilitation services in remote areas of China and highlight the need to incorporate rehabilitation in response to the planning of future humanitarian catastrophes. With health agendas advancing rapidly in China, disaster rehabilitation cannot be left behind. Occupational therapists with their holistic, humanistic approach and scientific training can play an important role in restoring physical functions and enhancing occupation participation for survivors of the natural disasters. Active participation in and contribution to research and holistic management of disaster survivors should ensure the occupational therapy profession a seat at the table in future health policy and practice decisions on disaster management. PMID- 24494831 TI - Gender, disaster, and occupational health. PMID- 24494832 TI - People detained for prolonged periods in immigration detention experienced significant psychological and interpersonal difficulties that make it difficult to rebuild their lives following release from detention. PMID- 24494833 TI - Resettled young Sudanese and Somali refugees have high vocational and educational ambitions despite experiences of school disruption and language difficulties. PMID- 24494834 TI - Occupational UV exposure of environmental agents in Valencia, Spain. AB - Excessive exposure to ultraviolet radiation (UVR) is considered the most important environmental risk factor in the development of melanoma and skin cancer. Outdoor workers are among those with the highest risk from exposure to solar UVR, as their daily activities constantly expose them to this radiation source. A study was carried out in Valencia, Spain, in summer 2012 and involved a group of 11 workers for a period of six 2-day recordings. Sensitive spore-film filter-type personal dosimeters (VioSpor) were used to measure erythemal UVR received by environmental agents in the course of their daily work. Median 2-day UV exposure was 6.2 standard erythema dose (SED), with 1 SED defined as effective 100 J m(-2) when weighted with the Commission Internationale de L'Eclairage's (CIE) erythemal response function. These workers were found to receive a median of 8.3% total daily ambient ultraviolet erythemal radiation. Comparison with the occupational UV exposure limit showed that the subjects had received an erythemal UV dose in excess of occupational guidelines, indicating that protective measures against this risk are highly advisable. PMID- 24494836 TI - Optimizing micronutrients in pregnancies following bariatric surgery. PMID- 24494838 TI - Children born extremely preterm show significant lower cognitive, language and motor function levels compared with children born at term, as measured by the Bayley-III at 2.5 years. AB - AIM: To assess developmental outcomes of children aged 2.5 years born extremely preterm. METHODS: As a part of the population-based Extremely Preterm Infants in Sweden Study (EXPRESS), 399 children born before 27 weeks of gestation and 366 control children born at term were assessed with the Bayley Scales of Infant and Toddler Development, third edition (Bayley-III), assigning scores for cognition, receptive and expressive communication, fine and gross motor functions. Based on control group means, prevalences of developmental delay in the preterm group were calculated. Mean score differences between subtests constituting the overall Bayley-III indices were analysed within both groups. RESULTS: After controlling for socio-demographic, child and assessment variables, analyses showed significantly lower performances of the preterm group compared with the control group on the Bayley-III subtests. Prevalence of moderate-severe delay was 10.8% in cognitive, 14.9% in receptive communication, 14.5% in expressive communication, 12.4% in fine motor and 7.0% in gross motor functions. Significant differences between performances on subtests included in the same indices were detected. CONCLUSION: Extremely preterm children show significant lower cognitive, communicative and motor function levels at 2.5 years compared with children born at term. Bayley-III assessments permit the acquisition of nuanced information about development following extreme prematurity. PMID- 24494839 TI - Commentary: how long does one need to fast before a Fibroscan examination? PMID- 24494840 TI - Commentary: how long does one need to fast before a Fibroscan examination? Authors' reply. PMID- 24494842 TI - Commentary: detection of low level viraemia in telaprevir-based triple therapy for hepatitis C virus. PMID- 24494841 TI - Commentary: real-world triple therapy experience treating hepatitis C virus. PMID- 24494843 TI - Commentary: real-world triple therapy experience treating hepatitis C virus - authors' reply. PMID- 24494844 TI - Commentary: detection of low level viraemia in telaprevir-based triple therapy for hepatitis C virus - authors' reply. PMID- 24494845 TI - Commentary: what factors are important in diagnosing hepatic fibrosis? PMID- 24494846 TI - Commentary: what factors are important in diagnosing hepatic fibrosis? Authors' reply. PMID- 24494847 TI - Letter: a hidden cause of anaemia in inflammatory bowel disease patients - coeliac disease. PMID- 24494848 TI - Letter: sleep and psychological disorders in patients with inflammatory bowel diseases; another potential role of vitamin D deficiency. PMID- 24494849 TI - Letter: does the IFNL4 gene discovery really provide a causal role for the IL28B haplotype blocks? PMID- 24494850 TI - Letter: does the IFNL4 gene discovery really provide a causal role for the IL28B haplotype blocks? Authors' reply. PMID- 24494851 TI - Letter: the irony of oral iron - not an underdog for post-gastrointestinal bleeding anaemia. PMID- 24494852 TI - Letter: effects of gastric microenvironment on the management of iron deficiency anaemia. PMID- 24494853 TI - Letter: the irony of oral iron - not an underdog for post-gastrointestinal bleeding anaemia; authors' reply. PMID- 24494854 TI - Letter: effects of gastric microenvironment on the management of iron deficiency anaemia - authors' reply. PMID- 24494855 TI - Electron transfer reduction of nitriles using SmI2-Et3N-H2O: synthetic utility and mechanism. AB - The first general reduction of nitriles to primary amines under single electron transfer conditions is demonstrated using SmI2 (Kagan's reagent) activated with Lewis bases. The reaction features excellent functional group tolerance and represents an attractive alternative to the use of pyrophoric alkali metal hydrides. Notably, the electron transfer from Sm(II) to CN functional groups generates imidoyl-type radicals from bench stable nitrile precursors. PMID- 24494856 TI - Influence of the treatment of Listeria monocytogenes and Salmonella enterica serovar Typhimurium with citral on the efficacy of various antibiotics. AB - The main goal of this work was to study the bacterial adaptive responses to antibiotics induced by sublethal concentration of citral on first-and second generation cells of Listeria monocytogenes serovar 4b (CECT 4032) and Salmonella enterica serovar Typhimurium (CECT 443). The first-generation cells were not pretreated with citral, while the second-generation cells were obtained from cells previously exposed to citral during 5 h. The trials were conducted at 37 degrees C. The presence of citral in the culture medium and the antibiotic strips resulted in a reduced minimum inhibitory concentration (MIC) for the first generation cells of Listeria monocytogenes serovar 4b and Salmonella Typhimurium. This result was observed for almost all the antibiotics, compared with the same microorganisms of the control group (without citral), which could represent an additive effect. For Listeria serovar 4b, the second-generation cells of the test group maintained the same susceptibility to antibiotics compared with cells in the control group and in the test group of the first generation. The second generation cells of the control group indicated that the Salmonella Typhimurium maintained the same sensitivity to the antibiotics tested compared with the first generation of this group, except in the case of erythromycin, which exhibited an increased MIC value. With respect to the second-generation cells of Salmonella Typhimurium, the presence of citral determined a decrease in the antibiotic susceptibility for almost all of the antibiotics, except colistin, compared with the first-generation of the test group, which can be seen by increase of MIC values. In conclusion, the presence of citral in the culture medium of Listeria 4b and Salmonella Typhimurium increased the antibiotic susceptibility of the first generations, while we observed an increase in antibiotic resistance in the second generation of Salmonella Typhimurium. PMID- 24494857 TI - N-methylmesoporphyrin IX fluorescence as a reporter of strand orientation in guanine quadruplexes. AB - Guanine quadruplexes (GQ) are four-stranded DNA structures formed by guanine-rich DNA sequences. The formation of GQs inhibits cancer cell growth, although the detection of GQs in vivo has proven difficult, in part because of their structural diversity. The development of GQ-selective fluorescent reporters would enhance our ability to quantify the number and location of GQs, ultimately advancing biological studies of quadruplex relevance and function. N methylmesoporphyrin IX (NMM) interacts selectively with parallel-stranded GQs; in addition, its fluorescence is sensitive to the presence of DNA, making this ligand a possible candidate for a quadruplex probe. In the present study, we investigated the effect of DNA secondary structure on NMM fluorescence. We found that NMM fluorescence increases by about 60-fold in the presence of parallel stranded GQs and by about 40-fold in the presence of hybrid GQs. Antiparallel GQs lead to lower than 10-fold increases in NMM fluorescence. Single-stranded DNA, duplex, or i-motif, induce no change in NMM fluorescence. We conclude that NMM shows promise as a 'turn-on' fluorescent probe for detecting quadruplex structures, as well as for differentiating them on the basis of strand orientation. PMID- 24494858 TI - At the dawn of hair research - testing the limits of hair follicle regeneration. AB - In the late 1960s, tissue recombination studies by Roy Oliver on the model of rat vibrissae provided invaluable information about the morphogenetic properties of hair follicles. Now more than ever, the field is hopeful that a clinically reproducible procedure for cell-based hair regeneration is achievable. Highly inductive mesenchymal cells are thought to be the key ingredient necessary to achieve robust hair regeneration, and efforts are underway to develop protocols to improve the naturally low inductive properties of human dermal papilla cells. In this respect, the original studies by Oliver provide essential rodent research benchmarks, which current-day human studies should aim to reach. PMID- 24494859 TI - Dynamics of methicillin-resistant Staphylococcus aureus and methicillin susceptible Staphylococcus aureus carriage in pig farmers: a prospective cohort study. AB - Our purpose was to determine the dynamics of livestock-associated methicillin resistant Staphylococcus aureus (LA-MRSA) carriage and its determinants in persons working at pig farms, in order to identify targets for interventions. This prospective cohort study surveyed 49 pig farms in the Netherlands on six sampling dates in 1 year (2010-11). Nasal and oropharyngeal swabs were collected, as well as environmental surface samples from stables and house. Of 110 pig farmers, 38% were persistent MRSA nasal carriers. The average cross-sectional MRSA prevalence was 63%. Methicillin-susceptible S. aureus (MSSA) nasal carriage was associated with fewer MRSA acquisitions (prevalence rate (PR) = 0.47, p 0.02). In multivariate analysis, an age of 40-49 years (PR = 2.13, p 0.01), a working week of >=40 h (PR=1.89, p 0.01), giving birth assistance to sows (PR=2.26, p 0.03), removing manure of finisher pigs (PR=0.48, p 0.02), and wearing a facemask (PR = 0.13, p 0.02) were significantly related with persistent MRSA nasal carriage. A higher MRSA exposure in stables was associated with MRSA in pig farmers (p <0.0001). This study describes a very high prevalence of LA MRSA carriage in pig farmers, reflecting extensive exposure during work. We identified the possible protective effects of MSSA carriage and of continuously wearing a facemask during work. PMID- 24494860 TI - Biodegradation of veterinary ionophore antibiotics in broiler litter and soil microcosms. AB - Ionophore antibiotics (IPAs) are polyether compounds used in broiler feed to promote growth and control coccidiosis. Most of the ingested IPAs are excreted into broiler litter (BL), a mixture of excreta and bedding material. BL is considered a major source of IPAs released into the environment as BL is commonly used to fertilize agricultural fields. This study investigated IPA biodegradation in BL and soil microcosms, as a process affecting the fate of IPAs in the environment. The study focused on the most widely used IPAs, monensin (MON), salinomycin (SAL), and narasin (NAR). MON was stable in BL microcosms at 24-72% water content (water/wet litter, w/w) and 35-60 degrees C, whereas SAL and NAR degraded under certain conditions. Factor analysis was conducted to delineate the interaction of water and temperature on SAL and NAR degradation in the BL. A major transformation product of SAL and NAR was identified. Abiotic reaction(s) were primarily responsible for the degradation of MON and SAL in nonfertilized soil microcosms, whereas biodegradation contributed significantly in BL fertilized soil microcosms. SAL biotransformation in soil microcosms yielded the same product as in the BL microcosms. A new primary biotransformation product of MON was identified in soil microcosms. A field study showed that MON and SAL were stable during BL stacking, whereas MON degraded after BL was applied to grassland. The biotransformation product of MON was also detected in the top soil layer where BL was applied. PMID- 24494861 TI - Congenital absence of left atrial appendage. PMID- 24494862 TI - Modulation of drug resistance in ovarian adenocarcinoma using chemotherapy entrapped in hyaluronan-grafted nanoparticle clusters. AB - Resistance to anticancer drugs is considered a major cause of chemotherapy failure. One of the major mediators of resistance is the multidrug extrusion pump protein, P-glycoprotein (P-gp), an ATP-binding cassette (ABC) transporter with broad substrate specificity. In order to bypass this drug resistance mechanism, we have devised phospholipid-based nanoparticle clusters coated with the glycosaminoglycan hyaluronan, the major ligand of CD44, which is upregulated and undergoes different splice variations in many types of cancer cells. These particles, termed glycosaminoglycan particle nanoclusters or gagomers (GAGs), were self-assembled into ~500 nm diameter clusters, with zeta-potential values of ~-70 mV. Flow cytometry analysis provided evidence that, unlike free doxorubicin (DOX), a model chemotherapy, DOX entrapped in the GAGs (DOX-GAGs) accumulated in P-gp-overexpressing human ovarian adenocarcinoma cell line and dramatically decreased cell viability, while drug-free GAGs and the commercially available drug DOXIL (PEGylated liposomal DOX) did not produce therapeutic benefit. Furthermore, by using RNA interference strategy, we showed that DOX-GAGs were able to overcome the P-gp-mediated resistant mechanism of these cells. Most importantly, DOX-GAGs showed a superior therapeutic effect over free DOX in a resistant human ovarian adenocarcinoma mouse xenograft model. Taken together, these results demonstrated that GAGs might serve as an efficient platform for delivery of therapeutic payloads by bypassing P-gp-mediated multidrug resistance. PMID- 24494863 TI - Biofunctionalization of ulvan scaffolds for bone tissue engineering. AB - Photo-cross-linked ulvan scaffolds were designed with the aim to induce and support enzyme mediated formation of apatite minerals, in the absence of osteogenic growth factors. Scaffold formation with a desired geometry was investigated using chemically modified ulvan bearing radically polymerizable groups. Further bioactivity was incorporated by the use of alkaline phosphatase (ALP) induced minerals. Successful modification of UV cross-linked ulvan scaffolds was revealed by (1)H NMR. The presence of the mineral formation was evidenced by Raman spectroscopy and XRD techniques. Investigations of the morphology confirmed the homogeneous mineralization using ALP. The MC3T3 cell activity clearly showed that the mineralization of the biofunctionalized ulvan scaffolds was effective in improving the cellular activity. PMID- 24494864 TI - Who pays the price to finance the regulator? PMID- 24494865 TI - A 20% rise in NMC registration fee needed to cover FtP cases. AB - Nurses' registration fees could rise to L120 next year under budgetary plans drawn up by the nursing regulator. PMID- 24494867 TI - Competence test for non-EU nurses given go-ahead. AB - Overseas nurses will face tougher testing procedures before being allowed to practise in the UK. PMID- 24494871 TI - NMC defends disciplinary record as ex-mid staffs director leaves register. AB - The Nursing and Midwifery Council has defended its disciplinary process after moving to have Stafford Hospital's former chief nurse struck from the nursing register, just two months after she was given a caution. PMID- 24494875 TI - New sexual health commissioning framework will integrate services. AB - Public health nurses have welcomed the news that a national commissioning framework for HIV, sexual and reproductive health services will be developed to prevent fragmentation. PMID- 24494877 TI - Nurse support in police stations could help reduce reoffending. AB - Specialist nurses could hold the key to helping offenders whose learning disabilities often go ignored by police and criminal courts, the RCN says. PMID- 24494878 TI - World in brief. PMID- 24494880 TI - Half of NHS trusts fail to support mental wellbeing of employees. AB - Stressed nurses are not getting the support they deserve from employers, the RCN has warned. PMID- 24494882 TI - Nurses face fees hike and a rise in the number of conduct cases. AB - Not only could nurses' re-registration fees soar by 20 per cent next year, but by the end of 2015 registrants will face tighter rules on proving they are fit to practise. No wonder the leaders of the Nursing and Midwifery Council (NMC) are bracing themselves. PMID- 24494888 TI - IV fluid therapy. AB - Essential facts Many adult hospital inpatients need intravenous (IV) fluid therapy to prevent or correct problems with their fluid and electrolyte status, and infusion therapy is now an integral part of professional practice for nurses. Research suggests that as many as one in five patients receiving IV therapy could experience complications or die as a result of inappropriate use of fluids. PMID- 24494889 TI - More approachable care. AB - Lesbian, gay, bisexual and trans (LGBT) people often have greater health needs than the general population, but can find mainstream services difficult to access. Some NHS trusts are tailoring services to meet their needs and encouraging staff to be open and inclusive. PMID- 24494890 TI - A particular challenge. AB - Lesbian and bisexual women have an increased risk of breast cancer, yet can be reluctant to access healthcare services because of lack of awareness and discriminatory attitudes among professionals. Nurses and other healthcare professionals need to use inclusive language and avoid assuring that all patients are heteroexual. PMID- 24494891 TI - The new HIV threat. PMID- 24494914 TI - Applying the recovery model to physical rehabilitation. AB - Although rehabilitation literature frequently refers to recovery as the ultimate goal of therapeutic interventions, what recovery actually means is not clearly explained. However, the recovery model has been widely discussed in the context of mental health services, and it has been suggested that this model may also be applied to services for people with other long-term health conditions. This article explores this suggestion further by examining the recovery model and its relationship to physical rehabilitation. PMID- 24494915 TI - Pharmacological treatment of patients with advanced prostate cancer. AB - Prostate cancer is linked to the male sex hormone testosterone. In advanced disease, blocking the production of testosterone using androgen deprivation therapy causes regression of prostate cancer and minimises or prevents symptoms associated with the disease. Luteinising hormone-releasing hormone agonists are commonly used in the management of prostate cancer, however less is known about the role of the newer gonadotrophin-releasing hormone (GnRH) antagonists. This article focuses on the differences between the two treatments and provides nurses with the knowledge to explain the use of GnRH antagonists to patients and administer this therapy effectively. PMID- 24494916 TI - Managing ascites in patients with chronic liver disease. AB - This article discusses the pathophysiology of ascites, a complication associated with chronic liver disease. The diagnosis and grading of ascites and assessment of patients with the condition are explored. In addition, the nursing and medical management of ascites is discussed, and recommendations for interdisciplinary working and education are suggested. Nursing knowledge of this complication is essential to ensure that patients with ascites are cared for effectively and that their comfort is maximised. PMID- 24494917 TI - Pyelonephritis. AB - Acute pyelonephritis refers to a lower urinary tract infection that has spread to the pelvis of the kidney. An estimated one in 830 people in the UK experience kidney infection every year, and females are six times more likely to experience the infection than males. PMID- 24494918 TI - Helping those in crisis. AB - As clinical team leader on an acute inpatient mental health ward at Cygnet Health Care's Kewstoke Hospital, my role is to supervise and support my team and to work with the ward's 15 patients. PMID- 24494919 TI - Top marks for care equality. AB - For some years, employers who do excellent work in promoting equality for lesbian, gay and bisexual (LGB) people have been recognised by the Stonewall Workplace Equality Index. PMID- 24494922 TI - Student life - the fun way to safe practice. AB - When a newly appointed clinical education team was asked to set up a BSc (Hons) nursing programme, the team agreed that first-year students should receive early exposure to simulation exercises. PMID- 24494923 TI - An unusual presentation of nickel-associated "school chair sign". AB - Symmetric sources of exposure generally result in symmetric contact dermatitis, but patient habits may distort or modify exposures in ways that may obscure clinical relevance. We present a variant of "school chair sign" consistent with the child's usual habit of sitting obliquely with her right leg crossed over her left leg. PMID- 24494925 TI - Rasch analysis of The Melbourne Assessment of Unilateral Upper Limb Function. AB - AIM: This study investigated the internal construct validity and dimensionality of the Melbourne Assessment of Unilateral Upper Limb Function (Melbourne Assessment), a widely-used measure of quality of upper limb movement, valid for children aged 2 years 6 months to 15 years with cerebral palsy. METHOD: Rasch analysis was used to assess of Melbourne Assessment raw scores for 163 children (94 males, 69 females; mean age 8y, SD 3y 5mo). Analysis was undertaken on the full scale comprising 37 scores and on groups of scores separated into four distinct movement subscales: range of movement, accuracy, dexterity, and fluency. Tests were conducted to evaluate overall model fit, item fit, suitability of the response options, unidimensionality, and differential item functioning (DIF) for sex, child age, and different raters. RESULTS: The results did not support the unidimensionality of the 37-score scale. The four subscales showed adequate model fit after removal of some score items, and rescaling of others. The resulting subscales showed good internal consistency and no DIF for sex or child age. INTERPRETATION: This study provides empirical support for a revised version of the Melbourne Assessment which comprises 14 tasks and 30 movement scores grouped across four separate subscales. Further testing is required to assess the responsiveness of subscales to clinically important change. PMID- 24494926 TI - Trypanosoma brucei gambiense infection in vervet monkeys: a potential model for early-stage disease. AB - BACKGROUND: Non-human primates are important experimental models for human African trypanosomiasis. METHODS: Six monkeys were intravenously inoculated with 10(5) trypanosomes of Trypanosoma brucei gambiense IL 3253. They were monitored for 180 days for parasitemia, hematology, clinical and biochemical profiles. RESULTS: The pre-patent period was 2-3 days. From 33 to 123 dpi, the parasitemia was low and only detectable by the hematocrit centrifugation technique. Thereafter, to the end of the experimental period, the parasitemia was undetectable by parasitological methods. Clinical signs observed were lymphadenopathy and splenomegaly. Hematological changes included a decline in hemoglobin occurring between 14 and 56 dpi and a significant decline in platelet counts after infection. The levels of total protein, albumin and globulins increased from 26 dpi for the rest of the experimental period. No parasites were detected in cerebrospinal spinal fluid, and no brain pathology was observed. CONCLUSION: This vervet monkey model can only be used for early-stage disease Gambian sleeping sickness. PMID- 24494924 TI - Escherichia coli exposure inhibits exocytic SNARE-mediated membrane fusion in mast cells. AB - Mast cells orchestrate the allergic response through the release of proinflammatory mediators, which is driven by the fusion of cytoplasmic secretory granules with the plasma membrane. During this process, SNARE proteins including Syntaxin4, SNAP23 and VAMP8 play a key role. Following stimulation, the kinase IKKbeta interacts with and phosphorylates the t-SNARE SNAP23. Phosphorylated SNAP23 then associates with Syntaxin4 and the v-SNARE VAMP8 to form a ternary SNARE complex, which drives membrane fusion and mediator release. Interestingly, mast cell degranulation is impaired following exposure to bacteria such as Escherichia coli. However, the molecular mechanism(s) by which this occurs is unknown. Here, we show that E. coli exposure rapidly and additively inhibits degranulation in the RBL-2H3 rat mast cell line. Following co-culture with E. coli, the interaction between IKKbeta and SNAP23 is disrupted, resulting in the hypophosphorylation of SNAP23. Subsequent formation of the ternary SNARE complex between SNAP23, Syntaxin4 and VAMP8 is strongly reduced. Collectively, these results demonstrate that E. coli exposure inhibits the formation of VAMP8 containing exocytic SNARE complexes and thus the release of VAMP8-dependent granules by interfering with SNAP23 phosphorylation. PMID- 24494927 TI - A Bayesian sampler for optimization of protein domain hierarchies. AB - The process of identifying and modeling functionally divergent subgroups for a specific protein domain class and arranging these subgroups hierarchically has, thus far, largely been done via manual curation. How to accomplish this automatically and optimally is an unsolved statistical and algorithmic problem that is addressed here via Markov chain Monte Carlo sampling. Taking as input a (typically very large) multiple-sequence alignment, the sampler creates and optimizes a hierarchy by adding and deleting leaf nodes, by moving nodes and subtrees up and down the hierarchy, by inserting or deleting internal nodes, and by redefining the sequences and conserved patterns associated with each node. All such operations are based on a probability distribution that models the conserved and divergent patterns defining each subgroup. When we view these patterns as sequence determinants of protein function, each node or subtree in such a hierarchy corresponds to a subgroup of sequences with similar biological properties. The sampler can be applied either de novo or to an existing hierarchy. When applied to 60 protein domains from multiple starting points in this way, it converged on similar solutions with nearly identical log-likelihood ratio scores, suggesting that it typically finds the optimal peak in the posterior probability distribution. Similarities and differences between independently generated, nearly optimal hierarchies for a given domain help distinguish robust from statistically uncertain features. Thus, a future application of the sampler is to provide confidence measures for various features of a domain hierarchy. PMID- 24494928 TI - Cold acclimation-induced freezing tolerance of Medicago truncatula seedlings is negatively regulated by ethylene. AB - To evaluate the role of ethylene in cold acclimation and cold stress, freezing tolerance and characteristics associated with cold acclimation were investigated using legume model plant Medicago truncatula Gaertn Jemalong A17. There was a rapid suppression of ethylene production during cold acclimation in A17 plants. Ethylene level was negatively correlated with freezing tolerance as inhibition of ethylene biosynthesis by inhibitors of ethylene biosynthesis enhanced freezing tolerance, while exogenous application of ethylene reduced cold acclimation induced freezing tolerance. The involvement of ethylene signaling in modulation of freezing tolerance and cold acclimation was further studied using ethylene insensitive mutant sickle skl. Although skl mutant was more tolerant to freezing than its wild-type counterpart A17 plants, cold acclimation enhanced freezing tolerance in 17 plants, but not in skl mutant. Expression of several ethylene response genes including EIN3, EIN3/EIL and ERFs was suppressed in skl mutant compared to A17 plants under non-cold-acclimated conditions. Cold acclimation downregulated expression of EIN3, EIN3/EIL and ERFs in A17 plants, while expression patterns of these genes were relatively constant in skl mutant during cold acclimation. Cold acclimation-induced increases in transcription of MtCBFs and MtCAS15 were suppressed in skl mutant compared with A17 plants. These results suggest that MtSKL1 is required for perception of the change of ethylene level in M. truncatula plants for the full development of the cold acclimation response by suppressing expression of MtEIN3 and MtEIN3/EIL1, which in turn downregulates expression of MtERFs, leading to the enhanced tolerance of M. truncatula to freezing by upregulating MtCBFs and MtCAS15. PMID- 24494929 TI - Second-order photochemical upconversion in organic systems. AB - In order to extend the photon energy shift of sensitized upconversion processes based on triplet-triplet annihilation in multicomponent organic systems, we have demonstrated that it is possible to exploit a sequence of consecutive upconversion steps. We have therefore realized an all-optical device for double upconversion: a light blue-shift of more than 0.9 eV was obtained at an excitation irradiance of a few tens of milliwatts per square centimeter. PMID- 24494930 TI - Compartment proteomics analysis of white perch (Morone americana) ovary using support vector machines. AB - Compartment proteomics enable broad characterization of target tissues. We employed a simple fractionation method and filter-aided sample preparation (FASP) to characterize the cytosolic and membrane fractions of white perch ovary tissues by semiquantitative tandem mass spectrometry using label-free quantitation based on normalized spectral counts. FASP depletes both low-molecular-weight and high molecular-weight substances that could interfere with protein digestion and subsequent peptide separation and detection. Membrane proteins are notoriously difficult to characterize due to their amphipathic nature and association with lipids. The simple fractionation we employed effectively revealed an abundance of proteins from mitochondria and other membrane-bounded organelles. We further demonstrate that support vector machines (SVMs) offer categorical classification of proteomics data superior to that of parametric statistical methods such as analysis of variance (ANOVA). Specifically, SVMs were able to perfectly (100% correct) classify samples as either membrane or cytosolic fraction during cross validation based on the expression of 242 proteins with the highest ANOVA p values (i.e., those that were not significant for enrichment in either fraction). The white perch ovary cytosolic and membrane proteomes and transcriptome presented in this study can support future investigations into oogenesis and early embryogenesis of white perch and other members of the genus Morone. PMID- 24494931 TI - Prior myocardial infarction and presence of upper gastrointestinal conditions among patients with venous thromboembolism: prevalence, associated comorbidities and burden. AB - WHAT IS KNOWN AND OBJECTIVES: Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary embolism (PE), is a serious, life-threatening condition that often complicates treatment of individuals who are already ill and increases in risk with age. The comorbidity burden of VTE can complicate treatment; therefore, treatment should be influenced by the presence of comorbidities (Kearon 2012). The prevalence of common conditions in the VTE population is, therefore, an important subject of research. Prevalence of two common comorbid burdens, prior myocardial infarction (MI) and upper gastrointestinal (GI) conditions, was studied among survey respondents who reported DVT or PE. METHODS: Responses to the 2010 wave of the National Health and Wellness Survey (NHWS), a self-administered, internet-based questionnaire from a nationwide, demographically representative sample of adults, were evaluated. RESULTS AND DISCUSSION: Among the 814 participants reporting a history of VTE, 9.7% (n = 60) of the DVT subpopulation and 13.2% (n = 39) of the PE subpopulation also reported prior MI. In respondents with prior MI, cardiovascular, urological, and pain comorbidities were each reported as additional comorbidities by at least two thirds of respondents in both the PE and DVT subpopulations, with cardiovascular and urological conditions reported significantly (P < 0.05) more often than among respondents with no prior MI. Among the respondents reporting VTE, 48.9% (n = 302) of the subpopulation reporting DVT and 52.2% (n = 154) of those reporting PE also reported upper GI comorbidities. Cardiovascular and pain conditions in the respondents reporting upper GI comorbidities were each reported by more than three quarters of VTE patients in both the DVT and PE subpopulations and were significantly more common (P < 0.05) than among their counterparts without upper GI comorbidities. WHAT IS NEW AND CONCLUSION: The results of the NHWS indicate that VTE patients who have either of two common comorbid burdens, prior MI and concomitant upper GI conditions, also showed high levels of additional, concurrent comorbidities and generally poor health status. Clinicians must be aware of the total comorbidity profile of their patients who have experienced VTE in order to best manage them and prescribe appropriate therapy. PMID- 24494932 TI - A novel approach for the in situ synthesis of Pt-Pd nanoalloys supported on Fe3O4@C core-shell nanoparticles with enhanced catalytic activity for reduction reactions. AB - A facile two-step synthesis method has been developed for the synthesis of highly active and well-defined Pt-Pd nanoalloys supported on the surface of Fe3O4@C colloidal nanoparticles. The nanoalloys were characterized by X-ray diffraction (XRD), high-resolution transmission electron microscopy (HRTEM), scanning transmission electron microscopy (STEM) with line scanning of energy-dispersive X ray spectroscopy (EDS) and X-ray photoelectron spectroscopy. The nanoalloys exhibit remarkable catalytic activity toward reduction of 4-nitrophenol to 4 aminophenol by NaBH4. Furthermore, the catalytic activity of the supported nanoalloys could be further optimized by tuning the composition of the supported nanoalloys, and the optimized catalytic activity is obtained with a normalized rate constant of about 12.03 nmol(-1) s(-1) when the atomic ratio of Pd to Pt is tuned to 2.07:1, which is advancing among the Pd-based nanocatalysts reported in the recent years. PMID- 24494933 TI - Morphology of far-field electrograms and antitachycardia pacing effectiveness among fast ventricular tachycardias occurring in ICD patients: the role of other discriminators. PMID- 24494934 TI - Systems biology approaches to understand the role of auxin in root growth and development. AB - The past decade has seen major advances in our understanding of auxin regulated root growth and developmental processes. Key genes have been identified that regulate and/or mediate auxin homeostasis, transport, perception and response. The molecular and biochemical reactions that underpin auxin signalling are non linear, with feed-forward and feedback loops contributing to the robustness of the system. As our knowledge of auxin biology becomes increasingly complex and their outputs less intuitive, modelling is set to become much more important. For the last several decades modelling efforts have focused on auxin transport and, latterly, on auxin response. Recently researchers have employed multi-scale modelling approaches to predict emergent properties at the tissue and organ scales. Such innovative modelling approaches are proving very promising, revealing new mechanistic insights about how auxin functions within a multicellular context to control plant growth and development. In this review we initially describe examples of models capturing auxin transport and response pathways, and then discuss increasingly complex models that integrate multiple hormone response pathways, tissues and/or scales. PMID- 24494936 TI - The art and science of self-citations. PMID- 24494935 TI - Assessment of pain and activity using an electronic pain diary and actigraphy device in a randomized, placebo-controlled crossover trial of celecoxib in osteoarthritis of the knee. AB - OBJECTIVE: The primary goal was to determine whether a composite measure of pain and activity is a more responsive assessment of analgesic effect than pain alone or activity alone in patients with osteoarthritis (OA) of the knee. DESIGN: We conducted a randomized, double-blind, placebo-controlled, 2-period, crossover study of celecoxib vs. placebo in subjects with chronic pain due to knee OA. Patients with knee OA and baseline pain intensity score >=4 on a 0-10 numerical rating scale (NRS) before each period were randomized. Pain endpoints included in clinic pain score (24-hour and 1-week recall), daily paper diary pain score, current pain on an electronic pain diary (each on NRS), and WOMAC pain subscale. Activity measures included WOMAC function subscale and actigraphy using a device. Three composite pain-activity measures were prespecified. RESULTS: Sixty-three patients were randomized and 47 completed the study. The WOMAC pain subscale was the most responsive of all five pain measures. Pain-activity composites resulted in a statistically significant difference between celecoxib and placebo but were not more responsive than pain measures alone. However, a composite responder defined as having 20% improvement in pain or 10% improvement in activity yielded much larger differences between celecoxib and placebo than with pain scores alone. Actigraphy was more responsive than the WOMAC function scale, possibly due to lower placebo responsiveness. CONCLUSION: We have identified composite pain activity measures that are similarly or more responsive than pain-alone measures in patients with OA. Further research is warranted to determine the optimal method for computing these composites. PMID- 24494937 TI - A critical decade for public health: responsibility for energy transitions. PMID- 24494938 TI - The cost of a healthy and sustainable diet--who can afford it? AB - OBJECTIVE: Climate change is affecting the ability of food systems to provide sufficient nutritious and affordable foods at all times. Healthy and sustainable (H&S) food choices are important contributions to health and climate change policy efforts. This paper presents empirical data on the affordability of a food basket that incorporates principles of health and sustainability across different food sub-systems, socioeconomic neighbourhoods and household income levels in Greater Western Sydney, Australia. METHODS: A basket survey was used to investigate the cost of both a typical basket of food and a hypothetical H&S basket. The price of foods in the two baskets was recorded in five neighbourhoods, and the affordability of the baskets was determined across household income quintiles. RESULTS: The cost of the H&S basket was more than the typical basket in all five socioeconomic neighbourhoods, with most disadvantaged neighbourhood spending proportionately more (30%) to buy the H&S basket. Within household income levels, the greatest inequity was found in the middle income neighbourhood, showing that households in the lowest income quintile would have to spend up to 48% of their weekly income to buy the H&S basket, while households in the highest income quintile would have to spend significantly less of their weekly income (9%). CONCLUSION: The most disadvantaged groups in the region, both at the neighbourhood and household level, experience the greatest inequality in affordability of the H&S diet. IMPLICATIONS: The results highlight the current inequity in food choice in the region and the underlying social issues of cost and affordability of H&S foods. PMID- 24494939 TI - Associations between obesity and overweight and fall risk, health status and quality of life in older people. AB - OBJECTIVES: To determine whether overweight and obese individuals have higher reported fall and fall injury risk than individuals of healthy weight, and to examine the influence of BMI on health, quality of life and lifestyle characteristics of fallers. METHODS: A representative sample of community-based individuals aged 65 years and older in New South Wales was surveyed regarding their history of falls, height, weight, lifestyle and general health within a 12 month period. RESULTS: Obese individuals had a 31% higher risk of having fallen, but no higher risk of a fall-related injury compared to healthy-weight individuals. Obese fallers also had a 57% higher risk of believing nothing could be done to prevent falls; a 41% higher risk of using four or more medications; a 30% higher risk of experiencing moderate or extreme pain or discomfort; were 26% less likely have walked for two or more hours in the last week; and were less likely to think they were doing enough physical activity. CONCLUSIONS: Older obese individuals have an increased risk of falls and obese fallers have a higher prevalence of pain and inactivity than fallers of a healthy weight. IMPLICATIONS: A decrease in sedentary lifestyle and regular weight-bearing exercise may reduce fall risk in older obese individuals. PMID- 24494940 TI - Obesity and climate change mitigation in Australia: overview and analysis of policies with co-benefits. AB - OBJECTIVE: To provide an overview of the shared structural causes of obesity and climate change, and analyse policies that could be implemented in Australia to both equitably reduce obesity rates and contribute to mitigating climate change. METHODS: Informed by the political economy of health theoretical framework, a review was conducted of the literature on the shared causes of, and solutions to, obesity and climate change. Policies with potential co-benefits for climate change and obesity were then analysed based upon their feasibility and capacity to reduce greenhouse gas emissions and equitably reduce obesity rates in Australia. RESULTS: Policies with potential co-benefits fit within three broad categories: those to replace car use with low-emissions, active modes of transport; those to improve diets and reduce emissions from the food system; and macro-level economic policies to reduce the over-consumption of food and fossil fuel energy. CONCLUSION: Given the complex causes of both problems, it is argued that a full spectrum of complementary strategies across different sectors should be utilised. IMPLICATIONS: Such an approach would have significant public health, social and environmental benefits. PMID- 24494941 TI - Active travel to work in New South Wales 2005-2010, individual characteristics and association with body mass index. AB - OBJECTIVE: This study describes the prevalence of walking and cycling to work in New South Wales (NSW) from 2005-2010. It examines the demographic characteristics of those people walking and cycling to work and the association of walking and cycling with body mass index (BMI). METHODS: Data from the NSW Continuous Health Survey, a telephone survey of health indicators among a representative sample of residents aged 16 years or over, were used. RESULTS: There were no changes in the proportions of employed respondents walking or cycling to work in NSW from 2005 to 2010, with estimates ranging from 5.1-7.3% usually walking, and 1.4-1.8% usually cycling. People who walked (adjusted odds ratio [AOR]=1.07, 95%CI 1.00 1.14) or cycled (AOR=1.22, 95%CI 1.14-1.32) to work had higher levels of education, after adjusting for age, sex, income and residence. CONCLUSIONS: There has been no overall increase in active commuting in NSW (2005-2010). Better efforts to communicate the benefits of active travel and less sedentary travel are warranted, in particular among those with lower levels of education. IMPLICATIONS: More interventions are needed to encourage walking and cycling to work, in order to gain significant benefits in terms of maintaining a healthy weight. PMID- 24494942 TI - Minimal excess risk of cancer and reduced risk of death from cancer in Australian Department of Veterans' Affairs clients: a record linkage study. AB - OBJECTIVE: To quantify the risk of incident cancer and cancer-related mortality in Australian Government Department of Veterans' Affairs (DVA) clients. METHODS: A population-based record linkage study of 75,482 adult clients residing in New South Wales (NSW) from 2000 to 2007; median age 75 years (interquartile range, 68 79); 57% male. Standardised incidence ratios (SIRs) and mortality ratios (SMRs) for any cancer and by cancer type were calculated, relative to the NSW population. RESULTS: The risk of any cancer was slightly increased for males (SIR 1.07, 95%CI 1.04-1.10) but not females (SIR 1.00, 95%CI 0.96-1.04). Males exhibited a significantly elevated risk of prostate cancer (SIR 1.08), cutaneous melanoma (SIR 1.19), head and neck cancer (SIR 1.27) and connective tissue cancer (SIR 1.52). Females did not exhibit excess risk for any cancer type. Risk of cancer death was significantly reduced for any cancer (male SMR 0.78, 95%CI 0.75 0.81; female SMR 0.80, 95%CI 0.76-0.85) and for a range of haematopoietic and solid neoplasms including prostate (SMR 0.57), breast (SMR 0.62) and colon cancer (male SMR 0.67; female SMR 0.71). CONCLUSION: Cancer incidence rates are largely similar, and mortality rates moderately lower, for DVA clients compared to the NSW general population. IMPLICATIONS: These risk patterns may reflect service related history, a healthy-survivor effect, competing risk of death, and/or comprehensive health care entitlements with minimal to no co-payments. Our findings suggest DVA clients are probably accessing cancer screening services. Outcomes after cancer diagnosis are good, most probably due to comprehensive health care entitlements. PMID- 24494943 TI - The validity of self-reported cancer in an Australian population study. AB - OBJECTIVE: The aim of this study is to determine the validity of self-reported cancer data by comparing it to the Australian Cancer Database (ACD). METHODS: Self-reported data were obtained from the Australian Diabetes, Obesity and Lifestyle (AusDiab) study, which were then linked to the ACD up until 31 December 2010. Positive predictive value, negative predictive value, sensitivity and specificity were calculated. Cohen's kappa coefficient (K) was also calculated to assess the agreement between self-reported cancer and the ACD. Logistic regression was used to examine the determinants associated with false negative and false positive reporting. RESULTS: The overall sensitivity of self-report cancer was 71.1%, and sensitivities showed great variation by cancer site. Higher sensitivities were observed for breast (90.7%), bowel (77.8%) and prostate (77.1%) cancers, whereas the lowest sensitivity was observed for melanoma of the skin (36.9%). Similarly, the kappa coefficient analysis showed substantial agreement for self-reported breast cancer (K=0.79) and moderate agreement for melanoma (K=0.45) against the ACD. Years since cancer diagnosis and older age were associated with false negative reporting and older age was associated with false positive reporting. CONCLUSIONS AND IMPLICATIONS: The use of self-reported cancer to collect cancer outcomes has varying reliability, depending on cancer type and population. The findings presented here may assist medical researchers in making informed decisions when conducting research using self-reported cancer data in Australia where the acquisition of registry data is not feasible. PMID- 24494944 TI - Adherence to recommended health checks by women in mid-life: data from a prospective study of women across Australia. AB - OBJECTIVE: To examine the factors related to Papanicolaou (Pap) tests, mammography and cholesterol testing in mid-aged Australian women as they age. METHODS: Data were obtained from the 1946-51 cohort of the Australian Longitudinal Study on Women's Health, a prospective study of the health and lifestyle of Australian women. Data were collected via self-report mailed surveys on a three-yearly basis since 1996, when participants were aged 45-50. Demographic factors, health service use and health-related factors were examined in relation to screening practices in a lagged analysis. RESULTS: As women aged, they were less likely to have a Pap test and more likely to report having a mammogram and a cholesterol test. Smokers were less likely to have all screening tests, and HRT use and more general practitioner (GP) visits were associated with increased odds of having health checks. Compared to healthy weight, higher BMI was associated with increased odds of cholesterol testing but decreased odds for Pap testing; obese women had lower odds for mammography. Underweight women had lower odds for mammography and Pap testing. Worse self-rated health and self report of a chronic condition were significantly related to increased likelihood of cholesterol testing. While some demographic and area of residence factors were also significantly associated with screening, large inequities based on socioeconomic status were not evident. CONCLUSIONS: Health and healthcare use are important determinants of screening. IMPLICATIONS: Greater advantage needs to be taken of opportunities to encourage women with more health risk behaviours and health problems to engage in screening. PMID- 24494945 TI - Is Step Down Assessment of screen-detected lesions as safe as workup at a metropolitan assessment centre? AB - OBJECTIVE: BreastScreen WA offers population mammographic screening via fixed clinics in the metropolitan area and mobile clinics that visit country areas every two years. If an abnormality is suspected following mobile clinic screening, women undergo Step Down Assessment; diagnostic further views are performed at the mobile clinic and if a possibly significant abnormality persists, country women are referred to a Perth Metropolitan Breast Assessment Centre. The purpose of this retrospective cohort study was to determine if Step Down Assessment in country Western Australia offered the same diagnostic effectiveness as screening and assessment in the metropolitan area. METHODS: The study included all screening episodes at BreastScreen WA between 1999 and 2008. Screening episodes from metropolitan and mobile clinics were compared according to the primary outcomes of cancer detection rates, recall and further investigations, cancer size, return to screen rates and interval cancers. RESULTS: Cancer detection rate per 1,000 screening episodes was lower for the country program than the metropolitan program (3.07 (2.84-3.31) versus 7.04 (6.82 7.27)). The false negative (interval cancer) rate was lower for Step Down Assessment than for the metropolitan program. The size of cancers detected was similar for both screening services. Return to screen rates were comparable between both groups. CONCLUSION: The results indicate that the current service model is providing appropriate diagnostic effectiveness, as well as comparable client satisfaction, for country and metropolitan women. PMID- 24494946 TI - Shade in urban playgrounds in Sydney and inequities in availability for those living in lower socioeconomic areas. AB - OBJECTIVE: This study investigated the differences between the amount of shade covering typical activity areas in playgrounds of higher and lower socioeconomic status (SES) areas within metropolitan Sydney, Australia. METHODS: Using an established audit tool, surveyors visited 139 urban playgrounds and made 1,033 shade observations recording the estimated percentage of an activity area that was covered by shade and the type of shade available. RESULTS: Shade coverage was significantly associated with SES of an area and with type of activity area (p<0.001 for both), but not with time since last upgrade of playground (p=0.116). Activity areas in playgrounds in the lowest SES areas had 34% lower mean shade coverage (95%CI 18-50) than activity areas in playgrounds in the highest SES regions. The mean shade coverage for eating areas was found to be 35% higher (95%CI 27-43) than the main play areas for children. CONCLUSIONS: This study highlights inequities in available shade for those living in lower SES urban areas. Furthermore, the results of this study are concerning from a skin cancer prevention perspective as the playground areas where children spend the majority of their time (the main play equipment and stand-alone equipment) were considerably less shaded than the eating areas. IMPLICATIONS: Local government should ensure that the issue of playground shade is comprehensively addressed in all relevant planning and policy documents so that it becomes an increased priority when developing and upgrading parks and playgrounds. PMID- 24494947 TI - Occupational exposure to solar radiation in Australia: who is exposed and what protection do they use? AB - OBJECTIVE: Solar ultraviolet radiation (UVR) exposure is widely recognised as a leading cause of skin cancer, with outdoor workers being particularly at risk. Little is known on a national level about how many workers are exposed to solar radiation, the circumstances in which they are exposed, or their use of protective measures. METHODS: The Australian Work Exposures Study (AWES) was a cross-sectional telephone survey of 5,023 Australian workers aged 18 to 65. A subset of 1,113 respondents who indicated they worked outdoors was asked about their exposure to solar radiation in terms of the amount of time they spent working outdoors, their working location and their use of sun protective measures. RESULTS: A total of 1,100 respondents (22% overall) were assessed as being exposed to solar radiation at work. Exposure was more likely among males and those residing in lower socioeconomic and regional areas. Sun protection was used by 95% of the respondents, although the level of protection varied among workers, with only 8.7% classified as fully protected. CONCLUSIONS: This study provides valuable information regarding solar exposure that has not previously been available. IMPLICATIONS: The results of this study will inform strategies for risk reduction. PMID- 24494948 TI - Identifying individual- and population-level characteristics that influence rates of risky alcohol consumption in regional communities. AB - OBJECTIVE: To examine the extent to which individual- and community- level characteristics account for differences in risky alcohol consumption. METHOD: A cross-sectional postal survey of 2,977 randomly selected individuals from 20 regional communities in NSW, Australia. Individuals drinking at harmful levels on the AUDIT and for risk of harm in the short term and long-term were identified. Multi-level modelling of the correlates of risky alcohol consumption at the individual and community level was conducted. RESULTS: There were differences between communities in alcohol consumption patterns. Being male, unmarried and reporting worse health were significant individual-level correlates for drinking at levels for risk of harm in the long term. The number of GPs (+) and police (-) were significant community characteristics. Being younger (<=25), unmarried, Australian born and with a larger income was associated with drinking at levels for risk of harm in the short term and harmful drinking on the AUDIT. The number of hotels and clubs was positively associated with drinking at levels for risk of harm in the short term. CONCLUSIONS: Rates of risky drinking vary significantly between communities and both individual and community characteristics are significantly associated with risky alcohol consumption. IMPLICATIONS: A combination of individual- and population-level interventions, tailored to the risk profile of individual communities, is most likely to be optimally effective. PMID- 24494949 TI - Alcohol consumption and NHMRC guidelines: has the message got out, are people conforming and are they aware that alcohol causes cancer? AB - OBJECTIVE: To examine self-reported alcohol consumption and relationships between consumption, awareness of the 2009 NHMRC guidelines of no more than two standard drinks per day, drinking in excess of the guideline threshold and perceptions of alcohol as a risk factor for cancer. METHODS: Questions were included in annual, cross-sectional surveys of approximately 2,700 South Australians aged 18 years and over from 2004 to 2012. Consumption data for 2011 and 2012 were merged for the majority of analyses. RESULTS: In 2011 and 2012, 21.6% of adults drank in excess of the guideline threshold (33.0% males; 10.7% females). While 53.5% correctly identified the NHMRC consumption threshold for women, only 20.3% did so for men (39.0% nominated a higher amount). A large minority said they did not know the consumption threshold for women (39.2%) or men (40.4%). In 2012, only 36.6% saw alcohol as an important risk factor for cancer. Important predictors of excess consumption for men were: higher household income; and not perceiving alcohol as an important risk factor for cancer. Predictors for women were similar but the role of household income was even more prominent. CONCLUSIONS: Men were nearly three times as likely to drink in excess of the guidelines as women. The majority of the population did not see an important link between alcohol and cancer. Awareness of the latest NHMRC guidelines consumption threshold is still low, particularly for men. IMPLICATIONS: A strategy to raise awareness of the NHMRC guidelines and the link between alcohol and cancer is warranted. PMID- 24494950 TI - Trends in health status and chronic disease risk factors over 10-14 years in a remote Australian community: a matched pair study. AB - OBJECTIVE: To determine trends in health status over a 10-year interval in a high risk remote Australian Aboriginal community. METHODS: Two health surveys were performed, one between 1992 and 1997 and the other between 2004 and 2006, on people aged five years or older. Outcomes were compared across age-matched and sex-matched pairs. RESULTS: There were 1,209 matched pairs. In the second survey, birthweights tended to be higher, and there were significant increases in heights of adolescents and young adults, and high density lipoprotein cholesterol (HDL-C) levels generally. Young adult males were lighter, had lower measurements for waist circumference and blood pressure and less frequently had overt-albuminuria, while elevated blood pressure was less common in older males. However, females>=15 years had higher measurements for waist circumference, waist to hip ratio (WHR), body mass index (BMI) and diastolic blood pressure and a higher proportion of diabetes, notably in those aged older than 45 years. Males aged 15 24 years were less likely to be smokers while women aged less than 45 years were more often current drinkers. CONCLUSIONS: Results indicative of better nutrition among youth, better health of young adult males, stable or lower levels of albuminuria and improved HDL levels are all encouraging. The waist circumference increase in females might reflect better food access. An increase in diabetes in older subjects probably reflects recent enhanced survival of middle-aged and older people with--and at risk for--diabetes. PMID- 24494951 TI - Can Australia eliminate TB? Modelling immigration strategies for reaching MDG targets in a low-transmission setting. AB - BACKGROUND: The 2050 Millennium Development Goals (MDG) for tuberculosis (TB) aim for elimination of TB as a public health issue. We used a mathematical modelling approach to evaluate the feasibility of this target in a low-prevalence setting with immigration-related strategies directed at latent tuberculosis. METHODS: We used a stochastic individual-based model to simulate tuberculosis disease among immigrants to Victoria, Australia; a representative low-transmission setting. A variety of screening and treatment approaches aimed at preventing reactivation of latent infection were applied to evaluate overall tuberculosis incidence reduction and rates of multidrug resistant disease. RESULTS: Without additional intervention, tuberculosis incidence was predicted to reach 34.5 cases/million by 2050. Strategies involving the introduction of an available screening/treatment combination reduced TB incidence to between 16.9-23.8 cases/million, and required screening of 136-427 new arrivals for each case of TB prevented. Limiting screening to higher incidence regions of origin was less effective but more efficient. CONCLUSIONS: Public health strategies targeting latent tuberculosis infection in immigrants may substantially reduce tuberculosis incidence in a low prevalence region. However, immigration-focused strategies cannot achieve the 2050 MDG and alternative or complementary approaches are required. PMID- 24494952 TI - Are they protected? Immunity to vaccine-preventable diseases in healthcare workers at an Australian hospital. AB - OBJECTIVE: Australian guidelines for healthcare worker (HCW) vaccination were updated in 2010, and pre-employment assessment of new employees has previously been identified as a priority. We determined the vaccination status of a cohort of existing HCWs at a tertiary hospital in Melbourne, Victoria. METHODS: Random sampling of HCWs employed prior to 2006 with unknown/incomplete immunisation status was conducted between April and August 2011. Immunity to vaccine preventable diseases (VPDs) was determined serologically (hepatitis B, varicella, measles, mumps, rubella) and by questionnaire (diphtheria, tetanus and pertussis), with vaccination by a nurse immuniser. RESULTS: Overall, 95 HCWs were evaluated. Mean age and duration of employment were 47.2 and 12.6 years, respectively. Forty-seven staff (49%) required vaccination to comply with Australian immunisation guidelines: 18% were non-immune to hepatitis B, 2% to varicella, 8% to measles, 19% to mumps and 13% to rubella. HCWs without serological hepatitis B immunity were all staff with clinical roles. Total costs were $7,527.34 (mean $222.79/HCW). CONCLUSIONS: Immunity to VPDs among existing HCWs was inadequate. About half assessed HCWs were non-immune to at least one VPD, and non-immunity to hepatitis B was high. A comprehensive assessment strategy for existing employees is required to enhance vaccination coverage and compliance with national guidelines. IMPLICATIONS: Adequately resourced 'look back' immunisation assessment programs are required to reduce the risks of VPDs among existing staff and patients. Review of current approaches and national consensus regarding the need for mandatory strategies would assist this process. PMID- 24494953 TI - Hand hygiene and bacteraemia rates in Australian hospitals. PMID- 24494954 TI - Triumphs and challenges in recruiting same-sex parent families. PMID- 24494955 TI - Cannabis use among young people in Pacific Island Countries and Territories. PMID- 24494956 TI - Managing health risks of extreme weather events: need for a systematic approach. PMID- 24494957 TI - Barriers to better three-dose coverage with HPV vaccination in school-based programs. PMID- 24494958 TI - Issues for central ethics review of aged care service evaluations. PMID- 24494959 TI - A profile of sales audits of a remote Aboriginal community's general store: 1992 and 2011. PMID- 24494965 TI - Dual sgRNAs facilitate CRISPR/Cas9-mediated mouse genome targeting. AB - The bacterial clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated 9 (Cas9) system is a versatile RNA-guided mammalian genome modification system. One-step generation of mouse genome targeting has been achieved by co-microinjection of one-cell stage embryos with Cas9 mRNA and small/single guide (sg)RNA. Many studies have focused on enhancing the efficiency of this system. In the present study, we report that simultaneous use of dual sgRNAs to target an individual gene significantly improved the Cas9-mediated genome targeting with a bi-allelic modification efficiency of up to 78%. We further observed that the target gene modifications were characterized by efficient germline transmission and site-dependent off-target effects, and also that the apolipoprotein E gene knockout-mediated defects in blood biochemical parameters were recapitulated by CRISPR/Cas9-mediated heritable gene modification. Our results provide a dual sgRNAs strategy to facilitate CRISPR/Cas9-mediated mouse genome targeting. PMID- 24494966 TI - GENE-dosage effects on fitness in recent adaptive duplications: ace-1 in the mosquito Culex pipiens. AB - Gene duplications have long been advocated to contribute to the evolution of new functions. The role of selection in their early spread is more controversial. Unless duplications are favored for a direct benefit of increased expression, they are likely detrimental. In this article, we investigated the case of duplications favored because they combine already functionally divergent alleles. Their gene-dosage/fitness relations are poorly known because selection may operate on both overall expression and duplicates relative dosage. Using the well documented case of Culex pipiens resistance to insecticides, we compared strains with various ace-1 allele combinations, including two duplicated alleles carrying both susceptible and resistant copies. The overall protein activity was nearly additive, but, surprisingly, fitness correlated better with the relative proportion of susceptible and resistant copies rather than any absolute measure of activity. Gene dosage is thus crucial, duplications stabilizing a "heterozygote" phenotype. It corroborates the view that these were favored because they fix a permanent heterosis, thereby solving the irreducible trade-off between resistance and synaptic transmission. Moreover, we showed that the contrasted successes of the two duplicated alleles in natural populations depend on genetic changes unrelated to ace-1, confirming the probable implication of recessive sublethal mutations linked to structural rearrangements in some duplications. PMID- 24494967 TI - Chronic viral infections. PMID- 24494968 TI - How to interpret borderline HCV antibody test results: a comparative study investigating four different anti-HCV assays. AB - Anti-HCV testing is the first step to diagnose hepatitis C. Although anti-HCV assay performance improved during the last 2 decades, very high sensitivity required for screening may lead to limitations in specificity. Thus, there remains an uncertainty how to interpret anti-HCV test results with a borderline signal-to-cut-off ratio. Comparison was made of concordance and performance of four licensed anti-HCV assays in samples with borderline signal-to-cut-off ratios. Out of 12,090 consecutive samples tested for anti-HCV with the Abbott Architect Anti-HCV assay over a period of 29 months, 95 plasma samples with a signal-to-cut-off ratio between 0.5 and 2 were selected for this study. All samples were re-tested with the Enzygnost Anti-HCV version 4.0, the Ortho anti HCV version 3.0, and the Monolisa anti-HCV-Plus version 2 assays. Discordant samples were classified by additional immunoblot testing. Overall, only 52% of the Architect borderline samples gave similar results in all four assays. Inter assay concordance ranged between 58% and 80%. The highest discordance was observed between the Architect and the Monolisa assay (42%). In contrast, a high level of concordance was found between the Enzygnost and Ortho assays (80%). The Monolisa was best to identify negative samples (100%), while the Enzygnost correctly classified most of the positive samples (96%). Anti-HCV antibody assays show significant variation in classifying samples with low signal-to-cut-off ratios. Different performances may have cost and management implications, as false-positive results are not infrequent. However, sensitivities were good for all assays if indeterminate results are not considered as negative. PMID- 24494969 TI - The relation of plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) with HPV persistence in HIV-infected and HIV-uninfected women. AB - Other than CD4+ count, the immunologic factors that underlie the relationship of HIV/AIDS with persistent oncogenic HPV (oncHPV) and cervical cancer are not well understood. Plasmacytoid dendritic cells (pDCs) and regulatory T-cells (Tregs) are of particular interest. pDCs have both effector and antigen presenting activity and, in HIV-positive patients, low pDC levels are associated with opportunistic infections. Tregs downregulate immune responses, and are present at high levels in HIV-positives. The current pilot study shows for the first time that low pDC and high Treg levels may be significantly associated with oncHPV persistence in both HIV-positive and HIV-negative women. Larger studies are now warranted. PMID- 24494971 TI - Successful fluorescence-guided surgery on human colon cancer patient-derived orthotopic xenograft mouse models using a fluorophore-conjugated anti-CEA antibody and a portable imaging system. AB - BACKGROUND: Fluorescence-guided surgery (FGS) can enable successful cancer surgery where bright-light surgery often cannot. There are three important issues for FGS going forward toward the clinic: (a) proper tumor labeling, (b) a simple portable imaging system for the operating room, and (c) patient-like mouse models in which to develop the technology. The present report addresses all three. MATERIALS AND METHODS: Patient colon tumors were initially established subcutaneously in nonobese diabetic (NOD)/severe combined immune deficiency (SCID) mice immediately after surgery. The tumors were then harvested from NOD/SCID mice and passed orthotopically in nude mice to make patient-derived orthotopic xenograft (PDOX) models. Eight weeks after orthotopic implantation, a monoclonal anti-carcinoembryonic antigen (CEA) antibody conjugated with AlexaFluor 488 (Molecular Probes Inc., Eugene, OR) was delivered to the PDOX models as a single intravenous dose 24 hours before laparotomy. A hand-held portable fluorescence imaging device was used. RESULTS: The primary tumor was clearly visible at laparotomy with the portable fluorescence imaging system. Frozen section microscopy of the resected specimen demonstrated that the anti-CEA antibody selectively labeled cancer cells in the colon cancer PDOX. The tumor was completely resected under fluorescence navigation. Histologic evaluation of the resected specimen demonstrated that cancer cells were not present in the margins, indicating successful tumor resection. The FGS animals remained tumor free for over 6 months. CONCLUSIONS: The results of the present report indicate that FGS using a fluorophore-conjugated anti-CEA antibody and portable imaging system improves efficacy of resection for CEA-positive colorectal cancer. These data provide the basis for clinical trials. PMID- 24494973 TI - Quantification of the proteins of the bacterial ribosome using QconCAT technology. AB - The bacterial ribosome is a complex of three strands of RNA and approximately 55 proteins. During protein synthesis, the ribosome interacts with other proteins, numbered in the hundreds, forming some stable and some transient complexes. The stoichiometries of these complexes and of partially assembled ribosomes are often unknown. We describe the development of a flexible standard for the determination of stoichiometries of ribosomal particles and complexes. A core QconCAT, an artificial protein consisting of concatenated signature peptides derived from the ribosomal proteins L2, L4, L13, S4, S7, and S8, was developed. The core QconCAT DNA construct incorporates restriction sites for the insertion of cassettes encoding signature peptides from additional proteins under study. Two cassettes encoding signature peptides from the remaining 30S and 50S ribosomal proteins were prepared, and the resulting QconCATs were expressed, digested, and analyzed by mass spectrometry. The majority of Escherichia coli ribosomal proteins are small and basic; therefore, tryptic digestion alone yields insufficient signature peptides for quantification of all of the proteins. The ribosomal QconCATs therefore rely on a dual-enzyme strategy: endoproteinase Lys-C digestion and analysis followed by trypsin digestion and further analysis. The utility of technology was demonstrated by a determination of the effect of gentamicin on the protein composition of the E. coli ribosome. PMID- 24494974 TI - Utilization and efficacy of internet-based eHealth technology in gastroenterology: a systematic review. AB - OBJECTIVE: While there have been several reviews exploring the outcomes of various eHealth studies, none have been gastroenterology-specific. This paper aims to evaluate the research conducted within gastroenterology which utilizes internet-based eHealth technology to promote physical and psychological well being. MATERIAL AND METHODS: A systematic literature review of internet-based eHealth interventions involving gastroenterological cohorts was conducted. Searched databases included: EbSCOhost Medline, CINAHL, and PsycINFO. Inclusion criteria were studies reporting on eHealth interventions (both to manage mental health problems and somatic symptoms) in gastroenterology, with no time restrictions. Exclusion criteria were non-experimental studies, or studies using only email as primary eHealth method, and studies in language other than English. RESULTS: A total of 17 papers were identified; seven studies evaluated the efficacy of a psychologically oriented intervention (additional two provided follow-up analyses exploring the original published data) and eight studies evaluated disease management programs for patients with either irritable bowel syndrome, inflammatory bowel disease (IBD) or celiac disease. Overall, psychological eHealth interventions were associated with significant reductions in bowel symptoms and improvement in quality of life (QoL) that tended to continue up to 12 months follow up. The eHealth disease management was shown to generally improve QoL, adherence, knowledge about the disease, and reduce healthcare costs in IBD, although the studies were associated with various methodological problems, and thus, this observation should be confirmed in well designed interventional studies. CONCLUSIONS: Based on the evidence to date, eHealth internet-based technology is a promising tool that can be utilized to both promote and enhance gastrointestinal disease management and mental health. PMID- 24494975 TI - Fortification of corn masa flour with folic acid in the United States: an overview of the evidence. AB - Corn masa flour, used to make products such as corn tortillas, is a staple food for Hispanic populations residing in the United States, particularly among Mexican Americans and Central Americans. Research has indicated that Hispanic women in the United States continue to be at a higher risk of having a neural tube defect-affected pregnancy than women of other races/ethnicities, even after the introduction of folic acid fortification of cereal grain products labeled as "enriched." Corn masa flour has, therefore, been suggested as a potential food vehicle for folic acid in the United States. This paper explores the potential impact that folic acid fortification of corn masa flour could have on the Hispanic population in the United States. PMID- 24494976 TI - Indium chloride catalyzed alkylative rearrangement of propargylic acetates using alkyl chlorides, alcohols, and acetates: facile synthesis of alpha-alkyl alpha,beta-unsaturated carbonyl compounds. AB - Indium chloride catalyzed alkylative rearrangement of propargylic acetates into alpha-alkyl-alpha,beta-unsaturated carbonyl compounds has been achieved. Propargylic acetates functioned as alpha-acylvinyl anion equivalents to react with carbocations generated from alkyl chlorides. Other alkyl electrophiles such as alcohols and acetates were also applicable. PMID- 24494977 TI - Time-domain study of the S(3) state of 9-fluorenone. AB - We report a combined gas phase and solution phase study of 9-fluorenone. The structure and dynamics of isolated fluorenone in the S3-state were studied by resonant enhanced multiphoton ionization with picosecond pulses in a free jet of molecules excited between 285 and 312 nm. Ionization was performed with a second ps-pulse at 351 nm. The electronic spectrum is structured, and the origin of the C (1)B2 <- X (1)A1 transition was observed at 32,122 cm(-1). Several vibrational fundamentals appear in the spectrum. In the gas phase we observe a biexponential decay, which suggests an internal conversion to the coupled S1/S2-state within 10 40 ps. A further decay that is assigned to intersystem crossing was found to be longer than 500 ps. In addition to the gas phase measurements, we studied the photophysics of 9-fluorenone in cyclohexane by femtosecond-time-resolved transient absorption spectroscopy and observed very similar dynamics upon excitation to the S3 state: It deactivates within 8-11 ps by internal conversion, followed by intersystem crossing within 120-150 ps, forming a long-lived triplet state. Experiments in acetonitrile, however, showed marked differences. Intersystem crossing is ineffective in polar solvents because the lowest excited singlest state is of pipi* character and does not interact with the (3)pipi*. PMID- 24494978 TI - Leptin controls hair follicle cycling. AB - Leptin is a cytokine well known for its ability to control body weight and energy metabolism. Several lines of evidence have recently revealed that leptin also plays an important role in wound healing and immune modulation in skin. Sumikawa et al. Exp Dermatol 2014 evaluated the effect of leptin on hair follicle cycling using mutant and wild-type mice. They report that leptin is produced in dermal papilla cells in hair follicles and that leptin receptor-deficient db/db mice show an abnormality in hair follicle cycling. Moreover, leptin injection induced the transition into the growth stage of the hair cycle (anagen). On this basis, it now deserves exploration whether leptin-mediated signalling is a key stimulus for anagen induction and whether this may be targeted to manage human hair disorders with defect in the control of hair follicle cycling. PMID- 24494981 TI - Direct and quinone-mediated palladium reduction by Geobacter sulfurreducens: mechanisms and modeling. AB - Palladium(II) reduction to Pd(0) nanoparticles by Geobacter sulfurreducens was explored under conditions of neutral pH, 30 degrees C and concentrations of 25, 50, and 100 mg of Pd(II)/L aiming to investigate the effect of solid species of palladium on their microbial reduction. The influence of anthraquinone-2,6 disulfonate was reported to enhance the palladium reaction rate in an average of 1.7-fold and its addition is determining to achieve the reduction of solid species of palladium. Based on the obtained results two mechanisms are proposed: (1) direct, which is fully described considering interactions of amide, sulfur, and phosphoryl groups associated to proteins from bacteria on palladium reduction reaction, and (2) quinone-mediated, which implies multiheme c-type cytochromes participation. Speciation analysis and kinetic results were considered and integrated into a model to fit the experimental data that explain both mechanisms. This work provides elements for a better understanding of direct and quinone-mediated palladium reduction by G. sulfurreducens, which could facilitate metal recovery with concomitant formation of valuable palladium nanoparticles in industrial processes. PMID- 24494980 TI - Insulin pump use in young children in the T1D Exchange clinic registry is associated with lower hemoglobin A1c levels than injection therapy. AB - Insulin delivery via injection and continuous subcutaneous insulin infusion (CSII) via insulin pump were compared in a cross-sectional study (n = 669) and retrospective longitudinal study (n = 1904) of young children (<6 yr) with type 1 diabetes (T1D) participating in the T1D Exchange clinic registry. Use of CSII correlated with longer T1D duration (p < 0.001), higher parental education (p < 0.001), and annual household income (p < 0.006) but not with race/ethnicity. Wide variation in pump use was observed among T1D Exchange centers even after adjusting for these factors, suggesting that prescriber preference is a substantial determinant of CSII use. Hemoglobin A1c (HbA1c) was lower in pump vs. injection users (7.9 vs. 8.5%, adjusted p < 0.001) in the cross-sectional study. In the longitudinal study, HbA1c decreased after initiation of CSII by 0.2%, on average (p < 0.001). Frequency of a severe hypoglycemia (SH) event did not differ in pump vs. injection users (p = 0.2). Frequency of >=1 parent-reported diabetic ketoacidosis (DKA) event in the prior year was greater in pump users than injection users (10 vs. 8%, p = 0.04). No differences between pump and injection users were observed for clinic-reported DKA events. Children below 6 yr have many unique metabolic characteristics, feeding behaviors, and care needs compared with older children and adolescents. These data support the use of insulin pumps in this youngest age group, and suggest that metabolic control may be improved without increasing the frequency of SH, but care should be taken as to the possibly increased risk of DKA. PMID- 24494982 TI - Underwire brassieres are a source of nickel exposure. AB - Underwire brassieres with metal rim supports are a potential source of nickel exposure to consider. Awareness and avoidance of such may also help prevent nickel sensitization. PMID- 24494979 TI - The absence of CpG in plasmid DNA-chitosan polyplexes enhances transfection efficiencies and reduces inflammatory responses in murine lungs. AB - Chitosan polyplexes containing plasmid DNA (pDNA) have significant potential for pulmonary gene delivery applications. However, prior to using chitosan/pDNA polyplexes (CSpp) in clinical applications, their potential cytotoxicity needs to be investigated. In this study, we formulated 200-400 nm CSpp with amine to phosphate (N/P) ratios that ranged from 1 to 100. We compared two types of plasmids within CSpp: pDNA that was free of CpG sequences (CpG(-)) and pDNA that contained CpG sequences (CpG(+)). Both forms of CSpp showed low cytotoxicity when cultured with A549 and HEK293 cell lines in vitro. CSpp(CpG(-)) generated higher luciferase expression both in vitro, for A549 cells, and in vivo, compared with CSpp(CpG(+)). In addition, CSpp(CpG(-)) elicited milder inflammatory responses in mice one day subsequent to nasal instillation, as determined by proinflammatory cytokine levels within the bronchoalveolar lavage fluid. Our findings suggest that to achieve optimal gene expression with minimal cytotoxicity, inflammation, and oxidative stress, the N/P ratios and CpG sequences in the pDNA of CSpp need to be considered. These findings will inform the preclinical safety assessments of CSpp in pulmonary gene delivery systems. PMID- 24494983 TI - Arginine-terminated generation 4 PAMAM dendrimer as an effective nanovector for functional siRNA delivery in vitro and in vivo. AB - Successful therapeutic implementation of RNA interference critically depends on systems able to safely and efficiently deliver small interfering RNA (siRNA). Dendrimers are emerging as appealing nanovectors for siRNA delivery by virtue of their unique well-defined dendritic nanostructure within which is confined an intriguing cooperativity and multivalency. We have previously demonstrated that structurally flexible triethanolamine (TEA) core poly(amidoamine) (PAMAM) dendrimers of high generations are effective nanovectors for siRNA delivery in vitro and in vivo. In the present study, we have developed arginine-terminated dendrimers with the aim of combining and harnessing the unique siRNA delivery properties of the TEA-core PAMAM dendrimer and the cell-penetrating advantages of the arginine-rich motif. A generation 4 dendrimer of this family (G4Arg) formed stable dendriplexes with siRNA, leading to improved cell uptake of siRNA by comparison with its nonarginine bearing dendrimer counterpart. Moreover, G4Arg was demonstrated to be an excellent nanocarrier for siRNA delivery, yielding potent gene silencing and anticancer effects in prostate cancer models both in vitro and in vivo with no discernible toxicity. Consequently, importing an arginine residue on the surface of a dendrimer is an appealing option to improve delivery efficiency, and at the same time, the dendrimer G4Arg constitutes a highly promising nanovector for efficacious siRNA delivery and holds great potential for further therapeutic applications. PMID- 24494984 TI - Risk assessment for autism spectrum disorders by representative database. PMID- 24494985 TI - Reply to T. Kawada. PMID- 24494986 TI - Peroxidation radical formation and regiospecificity of recombinated Anabaena sp. lipoxygenase and its effect on modifying wheat proteins. AB - Peroxidation radical formation and the regiospecificity of recombinated lipoxygenase from Anabaena sp. PCC7120 (ana-rLOX) were characterized by using ESR and HPLC-MS. It was found that ana-rLOX oxygenated at the C-13 position of the substrate linoleic acid (LA); at C-13 and C-16 of alpha-linolenic acid (ALA); at C-9, C-12, and C-15 of arachidonic acid (AA); at C-12, C-15, and C-18 of eicosapentaenoic acid (EPA); and at C-14 and C-16 of docosahexaenoic acid (DHA), respectively. A total of 7, 14, 30, 28, and 18 radical adducts for LA, ALA, AA, EPA, and DHA were respectively identified by HPLC-MS. The functional characteristics of wheat protein, such as foaming capacity (FC), foam stability (FS), emulsifying activity index (EAI), emulsifying stability index (ESI), increased with enzymatic reactions. However, the average particle size of wheat proteins decreased with addition of ana-rLOX/LA. The ana-rLOX was also positivele effective in improving dough properties. These results provided clear evidence that ana-rLOX from Anabaena sp. could effectively improve the quality of wheat flour, which suggested that the enzyme could be applied as flour improver. PMID- 24494987 TI - Folate, folic acid and 5-methyltetrahydrofolate are not the same thing. AB - 1. Folate, an essential micronutrient, is a critical cofactor in one-carbon metabolism. Mammals cannot synthesize folate and depend on supplementation to maintain normal levels. Low folate status may be caused by low dietary intake, poor absorption of ingested folate and alteration of folate metabolism due to genetic defects or drug interactions. 2. Folate deficiency has been linked with an increased risk of neural tube defects, cardiovascular disease, cancer and cognitive dysfunction. Most countries have established recommended intakes of folate through folic acid supplements or fortified foods. External supplementation of folate may occur as folic acid, folinic acid or 5 methyltetrahydrofolate (5-MTHF). 3. Naturally occurring 5-MTHF has important advantages over synthetic folic acid - it is well absorbed even when gastrointestinal pH is altered and its bioavailability is not affected by metabolic defects. Using 5-MTHF instead of folic acid reduces the potential for masking haematological symptoms of vitamin B12 deficiency, reduces interactions with drugs that inhibit dihydrofolate reductase and overcomes metabolic defects caused by methylenetetrahydrofolate reductase polymorphism. Use of 5-MTHF also prevents the potential negative effects of unconverted folic acid in the peripheral circulation. 4. We review the evidence for the use of 5-MTHF in preventing folate deficiency. PMID- 24494988 TI - Macromolecular prodrug that provides the irinotecan (CPT-11) active-metabolite SN 38 with ultralong half-life, low C(max), and low glucuronide formation. AB - We have recently reported a chemical approach for half-life extension that utilizes beta-eliminative linkers to attach amine-containing drugs or prodrugs to macromolecules. The linkers release free drug or prodrug over periods ranging from a few hours to over 1 year. We adapted these linkers for use with phenol containing drugs. Here, we prepared PEG conjugates of the irinotecan (CPT-11) active metabolite SN-38 via a phenyl ether that release the drug with predictable long half-lives. Pharmacokinetic studies in the rat indicate that, in contrast to other SN-38 prodrugs, the slowly released SN-38 shows a very low C(max), is kept above target concentrations for extended periods, and forms very little SN-38 glucuronide (the precursor of enterotoxic SN-38). The low SN-38 glucuronide is attributed to low hepatic uptake of SN-38. These macromolecular prodrugs have unique pharmacokinetic profiles that may translate to less intestinal toxicity and interpatient variability than the SN-38 prodrugs thus far studied. PMID- 24494989 TI - Rechargeable room-temperature CF(x)-sodium battery. AB - Here we demonstrate for the first time that CFx cathodes show rechargeable capability in sodium ion batteries with an initial discharge capacity of 1061 mAh g(-1) and a reversible discharge capacity of 786 mAh g(-1). The highly reversible electrochemical reactivity of CFx with Na at room temperature indicates that the decomposition of NaF could be driven by carbon formed during the first discharge. The high reversible capacity made it become a promising cathode material for future rechargeable sodium batteries. PMID- 24494990 TI - Insights into aging. PMID- 24494991 TI - Study finds method to predict Alzheimer's within 2 years of screening. PMID- 24494993 TI - Bathing persons with Alzheimer's disease and related dementias. PMID- 24494995 TI - Abortion incidence and service availability in the United States, 2011. AB - CONTEXT: Following a long-term decline, abortion incidence stabilized between 2005 and 2008. Given the proliferation of state-level abortion restrictions, it is critical to assess abortion incidence and access to services since that time. METHODS: In 2012-2013, all facilities known or expected to have provided abortion services in 2010 and 2011 were surveyed. Data on the number of abortions were combined with population data to estimate national and state-level abortion rates. Incidence of abortions was assessed by provider type and caseload. Information on state abortion regulations implemented between 2008 and 2011 was collected, and possible relationships with abortion rates and provider numbers were considered. RESULTS: In 2011, an estimated 1.1 million abortions were performed in the United States; the abortion rate was 16.9 per 1,000 women aged 15-44, representing a drop of 13% since 2008. The number of abortion providers declined 4%; the number of clinics dropped 1%. In 2011, 89% of counties had no clinics, and 38% of women of reproductive age lived in those counties. Early medication abortions accounted for a greater proportion of nonhospital abortions in 2011 (23%) than in 2008 (17%). Of the 106 new abortion restrictions implemented during the study period, few or none appeared to be related to state level patterns in abortion rates or number of providers. CONCLUSIONS: The national abortion rate has resumed its decline, and no evidence was found that the overall drop in abortion incidence was related to the decrease in providers or to restrictions implemented between 2008 and 2011. PMID- 24494996 TI - Comparative analysis of gene expression under cold acclimation, deacclimation and reacclimation in Arabidopsis. AB - Cold acclimated plants show an elevated tolerance against subsequent cold stress. Such adaptation requires alterations in gene expression as well as physiological changes. We were interested in gene expression changes at the transcriptional level during adaptation processes. The patterns of transcriptional changes associated with cold acclimation, deacclimation and reacclimation in Arabidopsis leaves were characterized using the Coldstresschip. Gene expression profiles were further analyzed by 'coexpressed gene sets' using gene set enrichment analysis (GSEA). Genes involved in signal transduction through calcium, and cascades of kinases and transcription factor genes, were distinctively induced in the early response of cold acclimation. On the other hand, genes involved in antioxidation, cell wall biogenesis and sterol synthesis were upregulated in the late response of cold acclimation. After the removal of cold, the expression patterns of most genes rapidly returned to the original states. However, photosynthetic light harvesting complex genes and lipid metabolism-related genes stayed upregulated in cold deacclimated plants compared to non-treated plants. It is also notable that many well-known cold-inducible genes are slightly induced in reacclimation and their expression remains at relatively low levels in cold reacclimation compared to the expression during the first cold acclimation. The results in this study show the dynamic nature of gene expression occurring during cold acclimation, deacclimation and reacclimation. Our results suggest that there is a memory of cold stress and that the 'memory of cold stress' is possibly due to elevated photosynthetic efficiency, modified lipid metabolism, increased calcium signaling, pre-existing defense protein made during first cold acclimation and/or modified signal transduction from pre-existing defense protein. PMID- 24494998 TI - Molecular data and ecological niche modelling reveal the phylogeographic pattern of Cotinus coggygria (Anacardiaceae) in China's warm-temperate zone. AB - The phylogeography of common and widespread species helps to elucidate the history of local flora and vegetation. In this study, we selected Cotinus coggygria, a species widely distributed in China's warm-temperate zone. One chloroplast DNA (cpDNA) region and ecological niche modelling were used to examine the phylogeographic pattern of C. coggygria. The cpDNA data revealed two phylogeographic groups (Southern and Northern) corresponding to the geographic regions. Divergence time analyses revealed that divergence of the two groups occurred at approximately 147,000 years before the present (BP), which coincided with the formation of the downstream area of the Yellow River, indicating that the Yellow River was a weak phylogeographic divide for C. coggygria. The molecular data and ecological niche modelling also indicated that C. coggyria did not experience population expansion after glaciations. This study thus supports the fact that Pleistocene glacial cycles only slightly affected C. coggygria, which survived in situ and occupied multiple localised glacial refugia during glaciations. This finding is contrary to the hypothesis of large-scale range habitat contraction and retreat into a few main refugia. PMID- 24494997 TI - Humoral immune responses to HIV in the mucosal secretions and sera of HIV infected women. AB - Although sera and all external secretions contain antibodies to human immunodeficiency virus (HIV), their levels, specificity, isotypes, and relevant effector functions display a great degree of variability. Antibodies that bind HIV antigens and neutralize the virus are predominantly associated with the IgG isotype in sera and in all external secretions, even where total levels of IgG are much lower than those of IgA. Rectal fluid that contains high IgA, but low IgG levels, displayed low neutralizing activity independent of antibodies. Therefore, external secretions should be evaluated before and after selective depletion of Ig. At the systemic level, HIV-specific IgA may interfere with the effector functions of IgG, as suggested by recent studies of individuals systemically immunized with an experimental HIV vaccine. Although HIV-specific IgG and IgA antibodies may exhibit their protective activities at mucosal surfaces through interference with viral entry and local neutralization at the systemic level, such antibodies may display discordant effector functions. PMID- 24494999 TI - 2-Trifluoromethylated indoles via radical trifluoromethylation of isonitriles. AB - Either two or three C-C bonds are formed in the synthesis of 2 trifluoromethylindoles starting with readily prepared isonitriles and the Togni reagent as CF3 radical precursor. These transformations occur in the absence of transition metal, and products are obtained in moderate to good yields with excellent diastereoselectivity. PMID- 24495000 TI - Increased gene dosage plays a predominant role in the initial stages of evolution of duplicate TEM-1 beta lactamase genes. AB - Gene duplication is important in evolution, because it provides new raw material for evolutionary adaptations. Several existing hypotheses about the causes of duplicate retention and diversification differ in their emphasis on gene dosage, subfunctionalization, and neofunctionalization. Little experimental data exist on the relative importance of gene expression changes and changes in coding regions for the evolution of duplicate genes. Furthermore, we do not know how strongly the environment could affect this importance. To address these questions, we performed evolution experiments with the TEM-1 beta lactamase gene in Escherichia coli to study the initial stages of duplicate gene evolution in the laboratory. We mimicked tandem duplication by inserting two copies of the TEM-1 gene on the same plasmid. We then subjected these copies to repeated cycles of mutagenesis and selection in various environments that contained antibiotics in different combinations and concentrations. Our experiments showed that gene dosage is the most important factor in the initial stages of duplicate gene evolution, and overshadows the importance of point mutations in the coding region. PMID- 24495001 TI - Recurrent dermatitis and dermal hypersensitivity following a jellyfish sting: a case report and review of literature. AB - Jellyfish envenomation often causes an immediate painful vesiculopapular eruption. Less commonly it can cause a type IV allergic hypersensitivity that manifests with delayed or recurrent cutaneous lesions at the primary site or distant from the primary site. These secondary reactivations may be related to high antijellyfish immunoglobulin levels, intracutaneously sequestered antigen, or cross-reacting venom. Immunomodulators such as pimecrolimus and tacrolimus and topical and intralesional corticosteroid therapy decrease this recurrent dermatitis. We report a case of a 9-year-old girl with a recurrent jellyfish dermatitis lasting more than 1 year after the initial envenomation. The dermatitis finally resolved after treatment with tacrolimus and intralesional triamcinolone acetonide therapy. PMID- 24495002 TI - Effect of mutual position of electron donor and acceptor on photoinduced electron transfer in supramolecular chlorophyll-fullerene dyads. AB - In this study we have explored the influence of mutual position of chlorin electron donor and fullerene C60 electron acceptor on photoinduced electron transfer. Two zinc-chlorin-aza-[18]crown-6 compounds and three pyrrolidino[60]fullerenes with alkyl aminium and varying coordinative moieties were synthesized and used for self-assembling of a set of complexes via two-point binding. The aza[18]crown6 moieties were connected to chlorins via amide linker either at 13(4) or 17(4) position, hence, being attached on different sides of the chlorin plane. Furthermore, in the former case, the linker holds the crown closely spaced, whereas, in the latter, the linker gives more space and conformational freedom for the crown with respect to the chlorin macrocycle. The coordinative moieties at fullerene site, 3-pyridine, 4-pyridine, and 3-furan, were built by utilizing the Prato reaction. The two-point binding drove the molecules into specific complex formation by self-assembling; aminium ion was chelated by crown ether, while zinc moiety of chlorin was coordinated by pyridine and furan. Such pairing resulted in distinct supramolecular chlorin-fullerene dyads with defined distance and orientation. The performed computational studies at DFT level in solution, with TPSS-D3/def2-TZVP//def2-SVP, indicated different geometries and binding energies for the self-assembling complexes. Notably, the computations pointed out that for all the studied complexes, the donor-acceptor distances and binding energies were dictated by chirality of pyrrolidino ring at C60. The selective excitation of chlorin chromophore revealed efficient emission quenching in all dyads. The ultrafast spectroscopy studies suggested a fast and efficient photoinduced charge transfer in the dyads. The lifetimes of the charge separated states range from 55 to 187 ps in o-dichlorobenzene and from 14 to 60 ps in benzonitrile. Expectedly, the electron transfer rate was found to be critically dependent on the donor-acceptor distance; additionally, the mutual orientation of these entities was found to have significant contribution on the rate. PMID- 24495003 TI - The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. AB - Detection, treatment, and prevention of bone marrow diseases have long been the aims of experimental and clinical hematologists and mechanistically oriented toxicologists. Among these diseases is aplastic anemia, which manifests as the cessation of normal blood cell production; the leukemias, in contrast, feature the production of excessive hematologic cancer cells. Both diseases are associated with exposure to either industrial chemicals or cancer chemotherapeutic agents. Studies of hematopoietic bone marrow cells in culture have shown that the generation of circulating blood cells requires the interaction of hematopoietic stem cells (HSCs) with supporting marrow stromal cells; yet, isolation of HSCs from bone destroys the unique morphology of the marrow stroma in which the HSCs reside. Imaging techniques and related studies have made it possible to examine specific niches where HSCs may either initiate differentiation toward mature blood cells or reside in a dormant state awaiting a signal to begin differentiation. HSCs and related cells may be highly vulnerable to the mutagenic or toxic effects of drugs or other chemicals early in these processes. Additional studies are required to determine the mechanisms by which drug or chemical exposure may affect these cells and lead to either depression of bone marrow function or to leukemia. PMID- 24495004 TI - Endothelial markers are associated with thrombolysis resistance in acute stroke patients. AB - BACKGROUND AND PURPOSE: The endothelium is crucial in maintaining the haemostatic balance between pro- and anti-thrombotic factors. In this pilot study, the association of endothelial biomarkers with arterial recanalization and clinical outcome in the setting of acute ischaemic stroke (AIS) was evaluated amongst patients treated with recombinant tissue plasminogen activator (rt-PA). METHODS: Sixty-four AIS patients treated with rt-PA were prospectively recruited. Blood was collected before thrombolysis and analysed for von Willebrand factor (vWF), soluble thrombomodulin (sTM) and soluble endothelial protein C receptor (sEPCR). Complete recanalization was defined by a Thrombolysis in Myocardial Infarction Score of 3. Favourable clinical outcome was defined by a modified Rankin Score of 0-2 at 90 days. RESULTS: Amongst the 64 patients, 31 had no documented occlusion, 19 had persistent occlusion and 14 had complete recanalization. After adjustment for confounding factors, these patients presented lower sTM and sEPCR levels than patients with persistent occlusion (median sTM, 21 vs. 48 ng/ml, P = 0.008; median sEPCR, 78 vs. 114 ng/ml, P = 0.018), but similar levels compared with patients without occlusion. vWF levels did not differ between groups. None of these biomarkers was significantly associated with favourable outcome. CONCLUSIONS: Recanalization after thrombolytic therapy is associated with low sTM and sEPCR levels but not with vWF levels. If corroborated in further larger studies, these findings could be helpful in the identification of patients resistant to rt-PA thrombolysis who could benefit from a modified recanalization therapy. PMID- 24495005 TI - Simple synthetic method toward solid supported c60 visible light-activated photocatalysts. AB - Solid supported fullerene materials are prepared in aims of creating a fullerene based photocatalyst that is capable of producing (1)O2 in the aqueous phase. Past studies of using fullerene as a photocatalyst in water have exclusively focused on using water soluble fullerene derivatives and employed sophisticated chemistry to create immobilized fullerene materials. The method presented herein is much less synthetically complex and utilizes pristine fullerene, providing a drastically simpler route to supported fullerene materials and furthering their potential for use in environmental applications. Covalent immobilization was achieved through the nucleophilic addition of a terminal amine (located on a solid support) across a [6,6] fullerene double bond, resulting in attachment directly to C60's cage. Immobilization allowed supported fullerene moieties to produce (1)O2 in water under various illumination conditions and inactivate MS2 bacteriophages. In a water with natural organic matter, supported fullerene materials produced (1)O2 under visible light irradiation without exhibiting significant loss of photocatalytic activity after successive cycling. PMID- 24495010 TI - Mortality in high-risk patients with bleeding Mallory-Weiss syndrome is similar to that of peptic ulcer bleeding. Results of a prospective database study. AB - OBJECTIVE: The aim of this study was to identify the predictive factors influencing mortality in patients with bleeding Mallory-Weiss syndrome in comparison with peptic ulcer bleeding. MATERIAL AND METHODS: Between January 2005 and December 2009, 281 patients with endoscopically confirmed Mallory-Weiss syndrome and 1530 patients with peptic ulcer bleeding were consecutively evaluated. The 30-day mortality and clinical outcome were related to the patients' demographic data, endoscopic, and clinical characteristics. RESULTS: The one-year cumulative incidence for bleeding Mallory-Weiss syndrome was 7.3 cases/100,000 people and for peptic ulcer bleeding 40.4 cases/100,000 people. The age-standardized incidence for both bleeding Mallory-Weiss syndrome and peptic ulcer bleeding remained unchanged during the observational five-year period. The majority of patients with bleeding Mallory-Weiss syndrome were male patients with significant overall comorbidities (ASA class 3-4). Overall 30-day mortality rate was 5.3% for patients with bleeding Mallory-Weiss syndrome and 4.6% for patients with peptic ulcer bleeding (p = 0.578). In both patients with bleeding Mallory Weiss syndrome and peptic ulcer bleeding, mortality was significantly higher in patients over 65 years of age and those with significant overall comorbidities (ASA class 3-4). CONCLUSION: The incidence of bleeding Mallory-Weiss syndrome and peptic ulcer bleeding has not changed over a five-year observational period. The overall 30-day mortality was almost equal for both bleeding Mallory-Weiss syndrome and peptic ulcer bleeding and was positively correlated to older age and underlying comorbid illnesses. PMID- 24495006 TI - Deep proteome mapping of mouse kidney based on OFFGel prefractionation reveals remarkable protein post- translational modifications. AB - Performing a comprehensive nonbiased proteome analysis is an extraordinary challenge due to sample complexity and wide dynamic range, especially in eukaryotic tissues. Thus, prefractionation steps conducted prior to mass spectrometric analysis are critically important to reduce complex biological matrices and allow in-depth analysis. Here we demonstrated the use of OFFGel prefractionation to identify more low abundant and hydrophobic proteins than in a nonfractionated sample. Moreover, OFFGel prefractionation of a kidney protein sample was able to unveil protein functional relevance by detecting PTMs, especially when prefractionation was augmented with a targeted enrichment strategy such as TiO2 phospho-enrichment. The OFFGel-TiO2 combination used in this study was comparable to other global phosphoproteomics approaches (SCX-TiO2, ERLIC-TiO2, or HILIC-TiO2). The detailed mouse kidney proteome with the phosphopeptide enrichment presented here serves as a useful platform for a better understanding of how the renal protein modification machinery works and, ultimately, will contribute to our understanding of pathological processes as well as normal physiological renal functions. PMID- 24495011 TI - Determination of canal orifice co-ordinates and MB2 incidence of maxillary first molars in a Turkish sub-population. AB - OBJECTIVES: To measure the co-ordinates of the root canal orifices and to determine the incidence of mesiobuccal-2 (MB2) in maxillary first molars in a Turkish sub-population. MATERIALS AND METHODS: Standard digital photographs were taken under a stereomicroscope from the occlusal aspect of each tooth (n = 176) before and after crown removal. Canal orifices were negotiated under moderate magnification using dental loupes. The coordinates of the orifices and the distances of each from the central fossa were measured by using geographic software. Intensity maps of the orifice locations were created by using the co ordinates of all canal orifices. A representative map was drawn using the mean values of orifice locations and access projection area. RESULTS: In the right maxillary first molars, the mean values for the (X, Y) co-ordinates were (0.67, 2.68) for mesiobuccal-1 (MB1), (0.81, 0.84) for MB2, (-1.12, 1.26) for distobuccal-1 (D1), (-0.89, 0.23) for distobuccal-2 (D2) and (0, -2.50) for palatinal (P); the corresponding mean values in the left maxillary first molars were (-0.78, 2.56), (-0.98, 0.90), (0.99, 1.18), (0.69, 0.78) and (0.00, -2.53), respectively. The average MB1-MB2 distance was 1.97 mm. Distobuccalcanal orifices were localized at the distal side of the center in 98.3% of teeth. The incidence of MB2 was 46.02%. CONCLUSIONS: The distobuccal canal orifice is mostly located on the distal side of the central fossa. Thus, it should be considered that the access cavity of the maxillary molars may not be always limited mesially. The incidence of MB2 in this sub-population was 46.02%, which is of great importance clinically. PMID- 24495012 TI - Pulse granuloma of the lip: morphologic clues in its differential diagnosis. AB - Pulse granuloma is not a common condition in cutaneous pathology. In diagnosing this condition, it is essential to determine if the foreign fragmented bodies are really vegetable parts. Certain vegetable structures, such as hyaline rings, have been clearly emphasized in the literature. However, other vegetable parts can show certain morphologic similarities with animal structures, especially if observed in a fragmented biopsy, as is the case with the pericarp (which can mimic the cuticle of a maggot) or the endosperm (which can mimic the fat cells of the larva). Herein, we present a case of pulse granuloma involving the lip, an uncommon location for this condition. We also describe the histopathologic appearance of experimentally obtained maggots and pupae, as well as that of several vegetable seeds. We compare some of the vegetable and animal structures and emphasize the differential diagnosis between them. PMID- 24495013 TI - Increased frequencies of CD11b(+) CD33(+) CD14(+) HLA-DR(low) myeloid-derived suppressor cells are an early event in melanoma patients. AB - Myeloid-derived suppressor cells (MDSC) are a heterogeneous cell population characterized by immunosuppressive activity. Elevated levels of MDSC in peripheral blood are found in inflammatory diseases as well as in malignant tumors where they are supposed to be major contributors to mechanisms of tumor associated tolerance. We investigated the frequency and function of MDSC in peripheral blood of melanoma patients and observed an accumulation of CD11b(+) CD33(+) CD14(+) HLA-DR(low) MDSC in all stages of disease (I-IV), including early stage I patients. Disease progression and enhanced tumor burden did not result in a further increase in frequencies or change in phenotype of MDSC. By investigation of specific MDSC-associated cytokines in patients' sera, we found an accumulation of IL-8 in all stages of disease. T-cell proliferation assays revealed that MDSC critically contribute to suppressed antigen-specific T-cell reactivity and thus might explain the frequently observed transient effects of immunotherapeutic strategies in melanoma patients. PMID- 24495015 TI - Minimally invasive mitral valve surgery utilizing heart port technology. AB - OBJECTIVE: To determine operative outcomes of right mini-thoracotomy mitral valve surgery utilizing port access technology in first-time and reoperative cardiac surgery patients. METHODS: From 2002 to 2011, 881 patients underwent minimally invasive mitral valve surgery. Of these, 154 patients had previous cardiac operations via sternotomy (Group 1), of which 18 (12%) had two previous operations. Seven hundred and twenty-seven patients had no previous cardiac operations (Group 2). RESULTS: Patient demographics were similar in both groups. In Group 1, 76 (49%) patients had previous coronary artery bypass grafting, 13 (8%) had previous aortic valve surgery, and 57 (37%) had previous mitral valve surgery. Preoperative echo findings for Groups 1 and 2 included severe mitral regurgitation (MR) (88%, n = 135; 94%, n = 687), mitral stenosis (MS) (4%, n = 6; 2%, n = 12), MS + MR (8%, n = 13; 4%, n = 28), and ejection fraction (48%, 56%). Operative procedures in Groups 1 and 2 were MV repair (54%, n = 84; 89%, n = 645) and MV replacement (46%, n = 70; 11%, n = 82). Circulatory management techniques for Groups 1 and 2 included endoballoon (75%, n = 116; 79%, n = 576), Chitwood clamp (8%, n = 12; 20%, n = 147), and fibrillatory arrest (17%, n = 30; 0.5%, n = 4). Perioperative outcomes were: stroke: 2.5%, 1.6%; reoperation for bleeding: 5%, 6%; valvular reoperation rate: 0.6%, 2%; aortic dissection: 2.5%, 1%; and wound infection: 0%, 0%. Transfusion requirement was 49% (n = 76) and 31% (n = 232), respectively. Median hospital stay was seven and seven days, respectively. On postoperative echocardiography, 98% (n = 151) and 99% (n = 718) of patients had zero or trace MR (1+) with 100% freedom from MR > 2+. In-hospital mortality was 3% (n = 5) and 1% (n = 8). CONCLUSIONS: Operative outcomes with minimally invasive mitral valve surgery utilizing port access technology can be performed safely. Stroke rate was higher in the reoperative cases (p = NS) although similar to reports evaluating redo sternotomy in mitral valve cases. PMID- 24495014 TI - Long non-coding RNA UCA1 increases chemoresistance of bladder cancer cells by regulating Wnt signaling. AB - Chemotherapy is a reasonable alternative to cystectomy in patients with invasive and advanced bladder cancer. However, bladder cancer cells often develop drug resistance to these therapies, and ~ 50% of patients with advanced bladder cancer do not respond to chemotherapy. Recent studies have shown that long non-coding RNA (lncRNA) is involved in the development of chemoresistance. Here we investigated the role of the urothelial cancer-associated 1 (UCA1) lncRNA in cisplatin resistance during chemotherapy for bladder cancer. We showed that cisplatin-based chemotherapy results in up-regulation of UCA1 expression in patients with bladder cancer. Similarly, UCA1 levels are increased in cisplatin resistant bladder cancer cells. Over-expression of UCA1 significantly increases the cell viability during cisplatin treatment, whereas UCA1 knockdown reduces the cell viability during cisplatin treatment. UCA1 inhibition also partially overcomes drug resistance in cisplatin-resistant T24 cells. Furthermore, we showed that UCA1 positively regulates expression of wingless-type MMTV integration site family member 6 (Wnt6) in human bladder cancer cell lines. UCA1 and Wnt6 expression is also positively correlated in vivo. Up-regulation of UCA1 activates Wnt signaling in a Wnt6-dependent manner. We finally demonstrate that UCA1 increases the cisplatin resistance of bladder cancer cells by enhancing the expression of Wnt6, and thus represents a potential target to overcome chemoresistance in bladder cancer. PMID- 24495016 TI - Relationship types and contraceptive use within young adult dating relationships. AB - CONTEXT: Although expanding research has found that relationship characteristics can shape contraceptive use among young adults, limited research has examined how relationship characteristics intersect to form distinct types of relationships and how relationship types are linked to contraceptive use. METHODS: Data from the 2002-2005 rounds of the National Longitudinal Survey of Youth 1997 cohort were used to examine contraceptive use in 3,485 young adult dating relationships. Latent class analysis was employed to develop a typology of relationships using measures of relationship structure (duration) and quality (intimacy, commitment and conflict). Multinomial logistic regression analyses were used to estimate associations between relationship type and contraceptive use and method choice at last sex. RESULTS: Four types of relationships were identified, two shorter term and two longer term, differentiated by levels of intimacy, commitment and conflict. Young adults in longer term relationships with greater conflict and lower intimacy and commitment were less likely than those in other long-term relationships to use hormonal and dual methods versus no method (relative risk ratios, 0.6-0.7). Hormonal method use, versus no method use or condom use, was more prevalent in short-term relationships with greater intimacy and commitment and lower conflict than in other short-term relationships (1.7 and 1.9, respectively). CONCLUSIONS: Classifying short-term relationships as "casual" or long-term ones as "serious" may ignore heterogeneity within these categories that may have implications for contraceptive use. Future qualitative research could provide a better understanding of relationship types and couples' fertility intentions and access to and use of contraceptives. PMID- 24495017 TI - Studies on the regulation of the human E1 subunit of the 2-oxoglutarate dehydrogenase complex, including the identification of a novel calcium-binding site. AB - The regulation of the 2-oxoglutarate dehydrogenase complex is central to intramitochondrial energy metabolism. In the present study, the active full length E1 subunit of the human complex has been expressed and shown to be regulated by Ca2+, adenine nucleotides and NADH, with NADH exerting a major influence on the K0.5 value for Ca2+. We investigated two potential Ca2+-binding sites on E1, which we term site 1 (D114ADLD) and site 2 (E139SDLD). Comparison of sequences from vertebrates with those from Ca2+-insensitive non-vertebrate complexes suggest that site 1 may be the more important. Consistent with this view, a mutated form of E1, D114A, shows a 6-fold decrease in sensitivity for Ca2+, whereas variant ?site1 (in which the sequence of site 1 is replaced by A114AALA) exhibits an almost complete loss of Ca2+ activation. Variant ?site2 (in which the sequence is replaced with A139SALA) shows no measurable change in Ca2+ sensitivity. We conclude that site 1, but not site 2, forms part of a regulatory Ca2+-binding site, which is distinct from other previously described Ca2+-binding sites. PMID- 24495018 TI - Discovery and SAR of 6-alkyl-2,4-diaminopyrimidines as histamine H4 receptor antagonists. AB - This report discloses the discovery and SAR of a series of 6-alkyl-2 aminopyrimidine derived histamine H4 antagonists that led to the development of JNJ 39758979, which has been studied in phase II clinical trials in asthma and atopic dermatitis. Building on our SAR studies of saturated derivatives from the indole carboxamide series, typified by JNJ 7777120, and incorporating knowledge from the tricyclic pyrimidines led us to the 6-alkyl-2,4-diaminopyrimidine series. A focused medicinal chemistry effort delivered several 6-alkyl-2,4 diaminopyrimidines that behaved as antagonists at both the human and rodent H4 receptor. Further optimization led to a panel of antagonists that were profiled in animal models of inflammatory disease. On the basis of the preclinical profile and efficacy in several animal models, JNJ 39758979 was selected as a clinical candidate; however, further development was halted during phase II because of the observation of drug-induced agranulocytosis (DIAG) in two subjects. PMID- 24495019 TI - A simple gas-solid route to functionalize ordered carbon. AB - The reaction of nitric oxide (NO) and carbonaceous materials generates nitrogen functionalities on and in graphitic carbons and oxidizes some of the carbon. Here, we have exploited these phenomena to provide a novel route to surface functionalized multiwalled carbon nanotubes (MWCNTs). We investigated the impacts of NO on the physical and chemical properties of industrially synthesized multiwalled carbon nanotubes to find a facile treatment that increased the specific surface area (SBET) of the MWCNTs by ~20%, with only a minimal effect on their degree of graphitization. The technique caused less material loss (~12 wt %) than traditional gas-based activation techniques and grafted some nitrogen functional groups (1.1 at. %) on the MWCNTs. Moreover, we found that Ni nanoparticles deposited on NO-treated MWCNTs had a crystallite size of dNi = 13.1 nm, similar to those deposited on acid-treated MWCNTs (dNi = 14.2 nm), and clearly much smaller than those deposited under the same conditions on untreated MWCNTs (dNi = 18.3 nm). PMID- 24495020 TI - Down-regulation of TIMP3 leads to increase in TACE expression and TNFalpha production by placental trophoblast cells. AB - PROBLEM: To determine whether down-regulation of TIMP3 expression promotes TACE expression and increases in TNFalpha production by placental trophoblast cells. METHOD OF STUDY: Placental expression of TIMP3 and TACE was examined by immunostaining and Western blot. Effects of TIMP3 on TACE expression and TNFalpha production were assessed by transfection of TIMP3 siRNA into trophoblasts isolated from normal placentas. Effects of oxidative stress on trophoblast TIMP3 expression and TNFalpha production were also determined. Trophoblast production of TIMP3, TACE and TNFalpha were measured by ELISA. RESULTS: TIMP3 expression was markedly reduced in preeclamptic placentas compared with normal placentas; oxidative stress down-regulated trophoblast TIMP3 expression and production, P < 0.01. Down-regulation of TIMP3 expression by TIMP3 siRNA resulted in significant increases in TACE expression and TNFalpha production, P < 0.01. CONCLUSION: As TIMP3 is an endogenous TACE inhibitor, down-regulation of trophoblast TIMP3 expression/activity could result in increased TACE expression and subsequently lead to increased TNFalpha production in preeclamptic placentas. PMID- 24495021 TI - A new tool to asses risk of wandering in hospitalized patients. AB - This article describes the development and implementation of a wandering screening and intervention program based on identifying hospitalized patients with impaired cognition and mobility. A wandering screening tool developed by a multidisciplinary team was linked to appropriate levels of interventions available in the electronic health record. Advanced practice nurses (APNs) confirmed the accuracy of screening and interventions by bedside nurses for all patients who screened positive. Of 1,528 patients hospitalized during a 3-week period, 48 (3.1%) screened positive for wandering. At-risk patients were older (age >= 65) (66.7%), those admitted to surgical units (41.7%), Caucasian (89.6%), and men (58.3%). Thirteen (27.1%) had dementia and 45 (93.8%) had impaired cognition. Of those patients who screened positive for wandering, the APNs agreed with the bedside nurses' assessment in 79.2% of cases (38/48) about wandering risk and 89.5% (34/38 true positives) for the interventions. A two-item wandering screening tool and intervention was feasible for use by bedside nurses. Further studies are needed to determine whether this tool is effective in preventing wandering. PMID- 24495022 TI - Dermal versus total uptake of benzene from mineral spirits solvent during parts washing. AB - Quantitative approaches to assessing exposure to, and associated risk from, benzene in mineral spirits solvent (MSS), used widely in parts washing and degreasing operations, have focused primarily on the respiratory pathway. The dermal contribution to total benzene uptake from such operations remains uncertain because measuring in vivo experimental dermal uptake of this volatile human carcinogen is difficult. Unprotected dermal uptake involves simultaneous sustained immersion events and transient splash/wipe events, each yielding residues subject to evaporation as well as dermal uptake. A two-process dermal exposure framework to assess dermal uptake to normal and damaged skin was applied to estimate potential daily dermal benzene dose (Dskin ) to workers who used historical or current formulations of recycled MSS in manual parts washers. Measures of evaporation and absorption of MSS dermally applied to human subjects were modeled to estimate in vivo dermal uptake of benzene in MSS. Uncertainty and interindividual variability in Dskin was characterized by Monte Carlo simulation, conditioned on uncertainty and/or variability estimated for each model input. Dermal exposures are estimated to average 33% of total (inhalation + dermal) benzene parts washing dose, with approximately equal predicted portions of dermal dose due to splash/wipe and to continuous contact with MSS. The estimated median (95th percentile) dermal and total daily benzene doses from parts washing are: 0.0069 (0.024) and 0.025 (0.18) mg/day using current, and 0.027 (0.085) and 0.098 (0.69) mg/day using historical, MSS solvents, respectively. PMID- 24495024 TI - Some pain for surgeons? PMID- 24495025 TI - Centralizing and reporting of complex endovascular interventions. PMID- 24495023 TI - Three-dimensional analysis of the early development of the dentition. AB - Tooth development has attracted the attention of researchers since the 19th century. It became obvious even then that morphogenesis could not fully be appreciated from two-dimensional histological sections. Therefore, methods of three-dimensional (3D) reconstructions were employed to visualize the surface morphology of developing structures and to help appreciate the complexity of early tooth morphogenesis. The present review surveys the data provided by computer-aided 3D analyses to update classical knowledge of early odontogenesis in the laboratory mouse and in humans. 3D reconstructions have demonstrated that odontogenesis in the early stages is a complex process which also includes the development of rudimentary odontogenic structures with different fates. Their developmental, evolutionary, and pathological aspects are discussed. The combination of in situ hybridization and 3D reconstruction have demonstrated the temporo-spatial dynamics of the signalling centres that reflect transient existence of rudimentary tooth primordia at loci where teeth were present in ancestors. The rudiments can rescue their suppressed development and revitalize, and then their subsequent autonomous development can give rise to oral pathologies. This shows that tooth-forming potential in mammals can be greater than that observed from their functional dentitions. From this perspective, the mouse rudimentary tooth primordia represent a natural model to test possibilities of tooth regeneration. PMID- 24495027 TI - Early Australasian experience with branched endovascular thoracoabdominal aortic aneurysm repair. AB - INTRODUCTION: Endovascular technology can now support total endovascular thoracoabdominal aortic aneurysm repair with branches maintaining visceral and renal perfusion thus avoiding the need for massive open surgery. High-volume centres have reported encouraging results. We report our Australasian experience of 10 cases including the first-in-man 'off-the-shelf' graft. METHODS: Ten consecutive endovascular repairs performed with prospective data collection have been retrospectively analysed. RESULTS: Six men and four women with an average age of 72.4 years (range 55-85) were treated between 2009 and 2012. The mean aneurysm diameter was 7 cm (range 4.8-10.0) with aneurysms across all five Crawford classifications. One hundred per cent procedural technical success was achieved and all branches and fenestrations were patent at a median follow up of 12 months. In total, 30 branches were utilized together with seven fenestrations. One death from respiratory failure occurred on day 30 without endograft problems and there were two late aneurysm related deaths. Three patients experienced spinal cord ischaemia and one patient experienced two separate late endoleaks. Six patients had successful endografts and remain alive and well. DISCUSSION: For experienced endovascular surgeons working with a proctor 100% technical success in graft deployment is achievable. Endovascular skills alone do not guarantee long-term success; our results demonstrate the need for careful patient selection, the danger of spinal cord ischaemia and the potential for endoleaks. PMID- 24495028 TI - Three-point suture anchor repair of traumatic sternoclavicular joint dislocation. AB - BACKGROUND: Traumatic dislocation of the sternoclavicular joint (SCJ) is a rare injury. Previous techniques are associated with hardware migration, loss of reduction and infectious complications. We aim to describe our preferred surgical technique and summarize our experience with three-point suture technique of acute SCJ dislocation (SCJD). The objective of this study was to describe and assess the safety of three-point suture anchor repair technique in acute traumatic dislocation in the SCJ. METHODS: A 7-year retrospective study in a university affiliated level 1 trauma centre. Operative cases and the trauma registry was reviewed to identify all potential cases of SCJD between 2005 and 2011. Inclusion criteria for this study were computed tomography (CT) identification of Allman III SCJD, intra-operative confirmation of the CT findings, acute fixation defined as <7 days and surgical management with three-point suture anchor technique. Chronic cases, suspected SCJDs without CT confirmation, physeal injuries and other surgical techniques were excluded. RESULTS: Eight patients met inclusion criteria. The patients were aged 16-46 years (mean age 24 years). Two primary surgeons were involved and time to surgery ranging from day of presentation to day 6 post injury. No loss to follow-up with clinical examinations and imaging being attended at 2 and 6 weeks, and 3 months. Average follow-up was 10.75 +/- 5.30 months (3-18 months). All patients had uncomplicated post-operative course, with no evidence of respiratory compromise, swallowing difficulties during admission. In outpatient documentation there was no failure of hardware and no issues documented with regards to chronic pain or range of movement limitations secondary to pain. There have been no representations because of complications out to 6 years. CONCLUSIONS: This series supports the safety of the three-point suture anchor technique in the acute stabilization of SCJD. The technique is demonstrated as a safe, effective and reproducible method of SCJ fixation. PMID- 24495029 TI - Duodenojejunal intussusception: a rare occurrence. PMID- 24495030 TI - Dramatic complications of prostatis: a prostatic abscess and scrotal abscess. PMID- 24495031 TI - Re: The future of surgical education. PMID- 24495032 TI - Response to Re: The future of surgical education. PMID- 24495033 TI - Orientation of junior surgical staff to a surgical service. PMID- 24495034 TI - Host switching promotes diversity in host-specialized mycoparasitic fungi: uncoupled evolution in the Biatoropsis-usnea system. AB - Fungal mycoparasitism-fungi parasitizing other fungi-is a common lifestyle in some basal lineages of the basidiomycetes, particularly within the Tremellales. Relatively nonaggressive mycoparasitic fungi of this group are in general highly host specific, suggesting cospeciation as a plausible speciation mode in these associations. Species delimitation in the Tremellales is often challenging because morphological characters are scant. Host specificity is therefore a great aid to discriminate between species but appropriate species delimitation methods that account for actual diversity are needed to identify both specialist and generalist taxa and avoid inflating or underestimating diversity. We use the Biatoropsis-Usnea system to study factors inducing parasite diversification. We employ morphological, ecological, and molecular data-methods including genealogical concordance phylogenetic species recognition (GCPSR) and the general mixed Yule-coalescent (GMYC) model-to assess the diversity of fungi currently assigned to Biatoropsis usnearum. The degree of cospeciation in this association is assessed with two cophylogeny analysis tools (ParaFit and Jane 4.0). Biatoropsis constitutes a species complex formed by at least seven different independent lineages and host switching is a prominent force driving speciation, particularly in host specialists. Combining ITS and nLSU is recommended as barcode system in tremellalean fungi. PMID- 24495035 TI - Isostere-based design of 8-azacoumarin-type photolabile protecting groups: a hydrophilicity-increasing strategy for coumarin-4-ylmethyls. AB - Described is the development of 8-azacoumarin-4-ylmethyl groups as aqueous photolabile protecting groups. A key feature of the strategy is the isosteric replacement of the C7-C8 enol double bond of the Bhc derivative with an amide bond, resulting in conversion of the chromophore from coumarin to 8-azacoumarin. This strategy makes dramatically enhanced water solubility and facile photocleavage possible. PMID- 24495036 TI - Morphological and functional imaging in neurological and non-neurological Wilson's patients. AB - Wilson's disease causes disturbances of the central nervous system, affecting it both directly through copper toxicity and indirectly subject to a copper-induced hepatopathy, resulting in morphological and physiological changes in brain structures that can be captured by means of magnetic resonance imaging (MRI), (123)I-beta-CIT (2beta-carbomethoxy-3beta (4-iodophenyl)tropane)-SPECT (single photon emission computed tomography), (123)I-IBZM (benzamide)-SPECT and [(18)F]FDG -PET (fluorodeoxyglucose-positron emission tomography). MRI can reveal even slight morphological changes in non-neurological Wilson's patients. More marked findings in neurological Wilson's patients become evident in T1- and T2 weighted MRI. T1-weighted MRI predominantly detects atrophic changes, whereas T2 weighted MRI regularly records signal changes in the putamen. With the aid of these three nuclear-medicine examinations, nigrostriatal and metabolic disturbances are identified in neurological Wilson's patients only. Sufficient decoppering therapy prevents progression and even tends to improve symptoms. A correlation between any of the imaging findings in patients with the genetic phenotype and the incidence of the most common mutation H1069Q (homozygote or compound heterozygote) or other mutations could not be substantiated. PMID- 24495037 TI - Visceral fat accumulation is associated with cerebral small vessel disease. AB - BACKGROUND AND PURPOSE: Obesity is associated with the risk of coronary artery disease and stroke. Visceral fat plays a significant role in the atherogenic effects of obesity. Whether visceral fat accumulation, as measured by computed tomography (CT), is an independent risk factor for the presence of cerebral small vessel disease (SVD) was investigated. METHODS: This study comprised 506 Japanese subjects 35-74 years of age (mean 55.3 years) without a history of symptomatic cerebrovascular disease who underwent health screening tests, including brain magnetic resonance imaging, carotid echography and measurements of the visceral fat area (VFA) and subcutaneous fat area (SFA) on abdominal CT. Visceral fat accumulation was defined as VFA >= 100 cm(2) . Logistic regression analysis was performed to examine the associations between visceral fat accumulation and cerebral SVD such as white matter lesions (WMLs) and silent lacunar infarction (SLI). RESULTS: The prevalence of WMLs and SLI but not carotid plaque were significantly higher in subjects with VFA >= 100 cm(2) than those with VFA < 100 cm(2) . A VFA >= 100 cm(2) was associated with WMLs and SLI independent of age, cardiovascular risk factors and other measurements of obesity, such as waist circumference and body mass index. A large waist circumference was independently associated with SLI. SFA, the combination of VFA and SFA, and body mass index were not associated with WMLs or SLI. CONCLUSIONS: Visceral fat accumulation was independently associated with the presence of cerebral SVD in subjects without a history of symptomatic cerebrovascular disease. PMID- 24495039 TI - The unusual monomer recognition of guanine-containing mixed sequence DNA by a dithiophene heterocyclic diamidine. AB - DB1255 is a symmetrical diamidinophenyl-dithiophene that exhibits cellular activity by binding to DNA and inhibiting binding of ERG, an ETS family transcription factor that is commonly overexpressed or translocated in leukemia and prostate cancer [Nhili, R., Peixoto, P., Depauw, S., Flajollet, S., Dezitter, X., Munde, M. M., Ismail, M. A., Kumar, A., Farahat, A. A., Stephens, C. E., Duterque-Coquillaud, M., Wilson, W. D., Boykin, D. W., and David-Cordonnier, M. H. (2013) Nucleic Acids Res. 41, 125-138]. Because transcription factor inhibition is complex but is an attractive area for anticancer and antiparasitic drug development, we have evaluated the DNA interactions of additional derivatives of DB1255 to gain an improved understanding of the biophysical chemistry of complex function and inhibition. DNase I footprinting, biosensor surface plasmon resonance, and circular dichroism experiments show that DB1255 has an unusual and strong monomer binding mode in minor groove sites that contain a single GC base pair flanked by AT base pairs, for example, 5'-ATGAT-3'. Closely related derivatives, such as compounds with the thiophene replaced with furan or selenophane, bind very weakly to GC-containing sequences and do not have biological activity. DB1255 is selective for the ATGAT site; however, a similar sequence, 5'-ATGAC-3', binds DB1255 more weakly and does not produce a footprint. Molecular docking studies show that the two thiophene sulfur atoms form strong, bifurcated hydrogen bond-type interactions with the G-N-H sequence that extends into the minor groove while the amidines form hydrogen bonds to the flanking AT base pairs. The central dithiophene unit of DB1255 thus forms an excellent, but unexpected, single-GC base pair recognition module in a monomer minor groove complex. PMID- 24495040 TI - Complete atrioventricular septal defect: comparison of modified single-patch technique with two-patch technique in infants. AB - BACKGROUND: The purpose of this study was to compare the modified single-patch technique with the two-patch technique for infants with complete atrioventricular septal defects (AVSDs). METHODS: Between December 2001 and October 2011, 98 infants underwent complete AVSD primary repair. Forty-six patients had a modified single-patch technique; 59 patients had a two-patch technique. Eighty-seven patients had follow-up by echocardiography to measure the degree of valve regurgitation. RESULTS: There were two deaths (one in modified single-patch group and one in two-patch group). Cross-clamp times and cardiopulmonary bypass times were shorter in the modified single-patch group (70.56 +/- 21.05 vs. 83.76 +/- 22.74 minutes, p=0.004; 95.02 +/- 19.73 vs. 109.9 +/- 34.07, p=0.011). There was no patient with third-degree atrioventricular (AV) block in the modified single patch group, while two patients in the two-patch group required a pacemaker (3.85%, p=NS). During follow-up, one death occurred in the single-patch group and three deaths in the two-patch group. At last follow-up, ten patients had more than moderate left AV valve regurgitation (four in single-patch group vs. six in two-patch group, p=0.886) and eight patients required reoperation (three in single-patch group vs. five in two-patch group, p=0.841). One patient in the single-patch group required reoperation for a residual ventricular septal defect and none in the two-patch group. CONCLUSIONS: Modified single-patch repair in infants with complete AVSD is a safe and reproducible technique. The results are as good as the two-patch technique. Among long-term survivors, most have very good clinical and functional results and minimal or no regurgitation of either AV valve. PMID- 24495038 TI - Construction and validation of nano gold tripods for molecular imaging of living subjects. AB - Anisotropic colloidal hybrid nanoparticles exhibit superior optical and physical properties compared to their counterparts with regular architectures. We herein developed a controlled, stepwise strategy to build novel, anisotropic, branched, gold nanoarchitectures (Au-tripods) with predetermined composition and morphology for bioimaging. The resultant Au-tripods with size less than 20 nm showed great promise as contrast agents for in vivo photoacoustic imaging (PAI). We further identified Au-tripods with two possible configurations as high-absorbance nanomaterials from various gold multipods using a numerical simulation analysis. The PAI signals were linearly correlated with their concentrations after subcutaneous injection. The in vivo biodistribution of Au-tripods favorable for molecular imaging was confirmed using small animal positron emission tomography (PET). Intravenous administration of cyclic Arg-Gly-Asp-d-Phe-Cys (RGDfC) peptide conjugated Au-tripods (RGD-Au-tripods) to U87MG tumor-bearing mice showed PAI contrasts in tumors almost 3-fold higher than for the blocking group. PAI results correlated well with the corresponding PET images. Quantitative biodistribution data revealed that 7.9% ID/g of RGD-Au-tripods had accumulated in the U87MG tumor after 24 h post-injection. A pilot mouse toxicology study confirmed that no evidence of significant acute or systemic toxicity was observed in histopathological examination. Our study suggests that Au-tripods can be reliably synthesized through stringently controlled chemical synthesis and could serve as a new generation of platform with high selectivity and sensitivity for multimodality molecular imaging. PMID- 24495042 TI - The relationship between rash, tumour KRAS mutation status and clinical and quality of life outcomes in patients with advanced colorectal cancer treated with cetuximab in the NCIC CTG/AGITG CO.17. AB - BACKGROUND: The NCIC CTG/AGITG CO.17 trial demonstrated that cetuximab monotherapy improved overall and progression-free survival (OS and PFS) in patients previously treated for advanced colorectal cancer. A strong relationship was observed between benefit from cetuximab and development of rash. In this analysis, the association of rash and benefit from cetuximab is explored and presented by KRAS mutation status. MATERIAL AND METHODS: Rash was graded by NCI CTC 2.0 criteria. Landmark analysis was performed by excluding patients who died or dropped out within 28 days and then grouping by worst grade of rash experienced by day 28. Multivariate Cox models were conducted separately for patients with KRAS wild-type (WT) tumours and KRAS mutated (MUT) tumours. CO.17 primary outcome was OS. RESULTS: Development of grade 2 + rash on cetuximab was associated with a trend towards increased OS (HR 0.61 with 95% CI 0.36-1.02 and p = 0.06) and PFS (HR 0.68 with 95% CI 0.45-1.03 and p = 0.07) as compared to grade 0/1 rash in patients with WT tumours. In patients with WT tumours on cetuximab both grade 0/1 and grade 2 + rash were associated with increased PFS (HR 0.57 95% CI 0.38-0.86; p = 0.008; and HR 0.32 95% CI 0.21-0.49; p < 0.0001) respectively, in comparison with best supportive care (BSC). Only development of grade 2 + rash on cetuximab was associated with increased OS (HR 0.52 with 95% CI 0.34-0.80 and p = 0.003) in comparison with BSC. No significant difference was found in OS or PFS among patients on cetuximab with MUT tumours with either rash grade as compared to BSC. No consistent trend was observed for the association of severity of rash and quality of life (QoL). CONCLUSION: As all patients with WT tumours benefitted to some extent from cetuximab regardless of the grade of rash, grade of rash was not a useful predictive marker. PMID- 24495043 TI - Position paper: breast cancer screening, diagnosis, and treatment in Denmark. AB - BACKGROUND: During the last decades the diagnosis, treatment, and prognosis of breast cancer have changed and improved in Denmark. The first mammography screening programme started in 1991. However, for many years only about 20% of Danish women aged 50-69 were offered screening. The national roll-out of screening took place in 2008-2010. MATERIAL AND METHODS: Based on published Danish data, this overview describes the status of diagnosis and treatment, and the screening programme. For further evaluating the potential overdiagnosis and overtreatment, additional Danish Breast Cancer Cooperative Group (DBCG) data are included. RESULTS AND CONCLUSION: Using incidence-based mortality method, reduction in breast cancer mortality was estimated to be 25% in the target group of women after 10 years of screening in Copenhagen; an outcome comparable to that of randomised controlled trials. A recent Danish study has indicated overdiagnosis to be around 4%. Others have estimated overdiagnosis to be 33%. National DBCG data showed that the rude breast cancer incidence increased during the period 1990-2011 from 126 to 206 per 100 000. The incidence was almost constant for women younger than 50 years. In regions not offering screening, the incidence increased with 3% per year for women aged 50-69 years with similar trends for small and large tumours. After introduction of screening the increase in the age group 50-69 years was confined to small tumours <= 20 mm, and most pronounced for node negative patients. From the 1990s, the use of breast conserving surgery has increased from around 25% to 69% in 2010. Screening has not increased the number of mastectomies. Breast cancer treatment in Denmark is evidence based and in agreement with international recommendations. After the introduction of mammography screening the absolute number of patients with a more advanced stage at diagnosis and the absolute number of patients undergoing mastectomy have decreased. PMID- 24495044 TI - Arm and shoulder morbidity following surgery and radiotherapy for breast cancer. AB - PURPOSE: To explore the relationship between radiotherapy (RT) dose levels in the arm/shoulder region and arm/shoulder morbidity in breast cancer patients. MATERIAL AND METHODS: This study included 183 breast cancer patients who had received locoregional RT with or without chemotherapy and/or hormone treatment during the period 1998-2002. Individual RT dose level, reflected by dose-volume histograms (DVHs), for the shoulder joint and joining structures were obtained from archived CT-based RT plans. Individual median, mean and maximum arm/shoulder RT dose levels were extracted. Arm/shoulder morbidity was assessed 29-58 months after breast cancer treatment using the following clinical endpoints: arm pain, arm stiffness, swollen arm, use of arm, numbness, shoulder flexion and shoulder abduction difference, fibrosis and breast cancer-related lymphedema. The relationship between arm/shoulder RT dose level and these clinical endpoints was assessed by Spearman's correlation and multivariate logistic regression. RESULTS: Ninety-one percent of the included patients had some degree of arm/shoulder morbidity. Neither mean nor maximum RT dose level was associated with clinical endpoints. However, significant correlations (p < 0.05) were found between DVHs and arm stiffness, arm pain, use of arm and shoulder abduction difference, when arm/shoulder RT dose levels were approximately 15 Gy. CONCLUSIONS: Three dimensional conformal locoregional RT for breast cancer results in long-term arm/shoulder morbidity. To minimize this risk, large shoulder volumes receiving RT doses of approximately 15 Gy should be reduced. PMID- 24495045 TI - Binding and molecular dynamics studies of 7-hydroxycoumarin derivatives with human serum albumin and its pharmacological importance. AB - Human serum albumin (HSA) is one of the most widely studied proteins and is an important plasma protein responsible for binding and transport of many exogenous and endogenous drugs. Coumarin derivatives play a critical role as anticancer, antidiabetic, anticoagulant, and analgesic agents. Here we have studied the cytotoxic activity of 7-hydroxycoumarin derivatives (7HC-1, 7HC-2, and 7HC-3) on mouse macrophage (RAW 264.7) cell lines. These studies revealed that 7 hydroxycoumarin derivatives caused an increased inhibition in growth of inflamed macrophages in a concentration-dependent manner with an IC50 of 78, 63, and 50 MUM. Further studies, using fluorescence, circular dichroism spectroscopy, molecular docking, and molecular dynamics methods, show binding of 7HC (umbelliferone) derivatives with HSA at physiological pH 7.2. The binding constant of 7HC derivatives with HSA obtained from fluorescence emission was found to be K7HC-1 = 4.6 +/- 0.01 * 10(4) M(-1), K7HC-2 = 1.3 +/- 0.01 * 10(4) M( 1), and K7HC-3 = 7.9 +/- 0.01 * 10(4) M(-1) which corresponds to -6.34 kcal/mol, 5.58 kcal/mol, and -6.65 kcal/mol of free energy. In contrast, the binding of these coumarin derivatives (7HC-1, 7HC-2, and 7HC-3) was almost negligible with alpha-1-glycoprotein (AGP). Circular dichroism (CD) studies revealed a decreased alpha-helix content with an increase in the beta-sheets and random coils in HSA upon interaction with coumarin derivatives, suggesting a partial unfolding of the HSA secondary structure. Site probe studies with phenylbutazone (Site I) and ibuprofen (Site II) indicated that 7HC derivatives specifically bind to sub domains IIIA and IIIB of HSA which is further corroborated by molecular dynamics and docking studies suggesting that binding is specific in nature. The values of free energies and binding constants coincide for both experimental and in silico analysis and suggest that there are hydrophobic interactions when coumarin derivatives bind to HSA. Molecular dynamics studies showed that the HSA-coumarin complex reaches an equilibration state at around 3.5 ns which indicates that the HSA-coumarin complexes were stable. Thus these interactions play a central role in development of coumarin derivative-inspired drugs. PMID- 24495046 TI - Can nutritional supplements and rectal enema be used as bowel cleansing for colonoscopy?--Results of a randomized controlled pilot study. AB - OBJECTIVE: Currently available preparations for colonoscopy have low tolerability and may cause fluid and electrolyte shifts. An alternative method of bowel cleansing is required. MATERIAL AND METHODS: Preparation of the gut using oral nutritional supplements (ONS) and rectal enema was tested as an alternative method of bowel cleansing. During 2008-2012, patients were randomized to oral nutritional supplements (n = 27) for 5 days and rectal enema or polyethylene glycol (PEG) (n = 23) prior to colonoscopy. Blinded endoscopists rated the degree of bowel cleansing according to the Ottawa bowel preparation scale (OBS) (primary outcome). Tolerability of either preparation was also assessed RESULTS: Due to a high rate of bowel cleansing failure among patients receiving ONS, the study was interrupted prematurely. Colonoscopies were incomplete due to stools in 6 of 27 patients in the ONS group compared to 1 of 23 in the PEG group (ns). The mean total OBS were 8.3 +/- 3.3 and 5.3 +/- 2.8, respectively (p = 0.002). Four patients (15%) in the ONS group and eight patients (35%) receiving PEG had an OBS score <=4 (good preparation) (ns). ONS was better tolerated than PEG with more patients reporting acceptable taste (27 of 27 [100%] vs. 15 of 23 [65%], p = 0.001), and fewer reporting difficulties with the intake (0 of 27 [0%] vs. 10 of 23 [43%], p < 0.001) and nausea (5 of 27 [19%] vs. 13 of 23 [57%], p < 0.008). CONCLUSIONS: For routine use, ONS with enema instead of traditional preparation for colonoscopy with PEG cannot be generally recommended. PMID- 24495047 TI - Dynamic selenium assimilation, distribution, efflux, and maternal transfer in japanese medaka fed a diet of se-enriched mayflies. AB - Selenium (Se) trafficking in oviparous species remains understudied and a major source of uncertainty in developing sound Se regulations. Here, we utilized (75)Se to follow Se through a simulated natural food chain (water, periphyton, mayflies (Centroptilum triangulifer), fish (Japanese medaka)). We specifically examined Se assimilation efficiency, tissue distribution, efflux rate, and maternal transfer in medaka. Selenium assimilation efficiency (AE) averaged 63.2 +/- 8.8% from mayfly diets and was not affected by mayfly [Se] across a dietary range of 5.6-38.7 MUg g(-1) (dry wt). However, AE decreased significantly as mayfly larva size increased. Efflux rate constants (ke) were consistent between reproductively inactive (0.066 d(-1)) and spawning females (0.069 d(-1)). Total Se loss rate constant (ke+egg; efflux and egg deposition) was 0.17 d(-1) in spawning females. Interestingly, medaka appeared to rapidly shuttle Se to their eggs directly from their diet via the ovary, as opposed to mobilization from surrounding tissues, resulting in dynamic egg [Se] that was more attributable to recent dietary Se ingestion than female whole body [Se] in this asynchronous spawning fish. Spawning strategy likely plays a large role in the process of fish egg Se deposition and requires further attention to understand risk and toxicity of Se to fish. PMID- 24495048 TI - Comprehensive mapping of protein N-glycosylation in human liver by combining hydrophilic interaction chromatography and hydrazide chemistry. AB - Although glycoproteomics is greatly developed in recent years, our knowledge about N-glycoproteome of human tissues is still very limited. In this study, we comprehensively mapped the N-glycosylation sites of human liver by combining click maltose-hydrophilic interaction chromatography (HILIC) and the improved hydrazide chemistry. The specificity could be as high as 90% for hydrazide chemistry and 80% for HILIC. Altogether, we identified 14,480 N-glycopeptides matched with N-!P-[S|T|C] sequence motif from human liver, corresponding to 2210 N-glycoproteins and 4783 N-glycosylation sites. These N-glycoproteins are widely involved into different types of biological processes, such as hepatic stellate cell activation and acute phase response of human liver, which all highly associate with the progression of liver diseases. Moreover, the exact N glycosylation sites of some key-regulating proteins within different human liver physiological processes were also obtained, such as E-cadherin, transforming growth factor beta receptor and 29 members of G protein coupled receptors family. PMID- 24495049 TI - Expression of natural cytotoxicity receptors on peritoneal fluid natural killer cell and cytokine production by peritoneal fluid natural killer cell in women with endometriosis. AB - PROBLEM: To investigate the relationship between the expression of natural cytotoxicity receptors (NCRs) on peritoneal fluid (PF) natural killer (NK) (pfNK) cells and cytokine production by pfNK cells in women with endometriosis. METHOD OF STUDY: Peritoneal fluid was collected from women with endometriosis undergoing laparoscopic surgery (n = 21) and controls without endometriosis (n = 28). The expression of NK cell surface antigens such as CD16 and NCRs (NKp46, NKp44 and NKp30) on pfNK cells, and cytokines production by pfNK cells [tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-4, IL-10, GM-CSF and transforming growth factor (TGF)-beta1] were measured using multicolor flow cytometry. RESULTS: The percentages of CD56(+)/NKp46(+) cells and CD56(dim) /NKp46(+) cells in severe endometriosis group were significantly lower than that in controls. TNF-alpha and IFN-gamma production by pfNK cells in severe endometriosis group was significantly higher than those in controls. CONCLUSION: The differential expression of NKp46, TNF-alpha, and IFN-gamma on pfNK cells in women with severe endometriosis may allow the proliferation and angiogenesis of endometriotic cells. PMID- 24495050 TI - Xenotransplantation literature update, March-April 2013. PMID- 24495051 TI - Accuracy of nurse-performed compression ultrasonography in the diagnosis of proximal symptomatic deep vein thrombosis: a prospective cohort study. AB - BACKGROUND: Compression ultrasonography (CUS) has been recognized as the diagnostic procedure of choice for the investigation of patients with suspected deep vein thrombosis (DVT); the aim of this study was to assess the diagnostic accuracy of nurse-performed CUS for symptomatic proximal DVT of the lower limb. MATERIAL AND METHODS: We prospectively evaluated all consecutive outpatients referred for suspected DVT from January 2011 to December 2012. All patients underwent bilateral proximal lower limb CUS, first by trained nurses and then by physicians expert in vascular ultrasonography, with every group blinded with respect to each other. This test was repeated after 5-7 days in all negative or unclear examinations. Interobserver agreement and accuracy of nurse-performed CUS were calculated, considering the physician's final diagnosis as the reference test. RESULTS: Six hundred ninety-seven patients were included in the study. DVT was diagnosed in 122 patients by expert ultrasound physicians with an overall prevalence of 17.5% (95% confidence interval [CI] 15.8%-20.6%). Nurse agreement with the physician in DVT diagnosis was excellent (Cohen's kappa 0.82, 95% CI 0.79-0.85). Nurse-performed CUS had a sensitivity of 84.4% (95% CI 81.7%-87.1%) and a specificity of 97.0% (95% CI 95.8%-98.3%) with a diagnostic accuracy of 94.8% (95% CI 93.2%-96.5%). CONCLUSION: Our results suggest that nurse-performed CUS may be a potential useful alternative to physician performed CUS with a good accuracy. However, sensibility of nurse-performed CUS appeared suboptimal and future studies should incorporate in the evaluation of this technique other pretest tools that may increase its accuracy. PMID- 24495052 TI - Trait compensation and sex-specific aging of performance in male and female professional basketball players. AB - Phenotypic traits are often influenced by dynamic resource allocation trade-offs which, when occurring over the course of individual lifespan, may manifest as trait aging. Although aging is studied for a variety of traits that are closely tied to reproduction or reproductive effort, the aging of multiple traits related to fitness in other ways are less well understood. We took advantage of almost 30 years of data on human whole-organism performance in the National Basketball Association (USA) to examine trends of aging in performance traits associated with scoring. Given that patterns of aging differ between sexes in other animal species, we also analyzed a smaller dataset on players in the Women's National Basketball Association to test for potential sex differences in the aging of comparable traits. We tested the hypothesis that age-related changes in a specific aspect of overall performance can be compensated for by elevated expression of another, related aspect. Our analyses suggest that the aging of performance traits used in basketball is generally characterized by senescence in males, whereas age-related changes in basketball performance are less evident in females. Our data also indicate a different rate of senescence of different performance traits associated with scoring over a male's lifetime. PMID- 24495053 TI - The road less traveled: an Editor's journey. PMID- 24495054 TI - Reflections on 25 years at the Journal. PMID- 24495055 TI - Congratulations and happy 25th birthday, Emergency Medicine Australasia. PMID- 24495056 TI - Past, present and future of emergency care research. PMID- 24495057 TI - Clinical research is a priority for emergency medicine but how do we make it happen, and do it well? PMID- 24495058 TI - Clinical research priorities in emergency medicine: results of a consensus meeting and development of a weighting method for assessment of clinical research priorities. AB - INTRODUCTION: There is limited evidence regarding clinical research priorities in emergency medicine outside of some special interest groups. The ACEM Clinical Trials Group undertook a consensus meeting with the aim of developing a reproducible weighting matrix for assessing clinical research priorities. METHODS: A session at the ACEM annual scientific meeting was dedicated to this meeting. Results from a survey of the ACEM researcher database were presented, along with a proposed weighting matrix. After discussion and adjustment, consensus was achieved on the matrix. RESULTS: It was agreed that the following criteria be used in the matrix: research category and sub-category priority ranking from the ACEM researcher database survey, frequency of presentation of potentially eligible participants, the level of pre-existing evidence regarding the proposed research question and the likely clinical impact of the research. Each criterion was given a weighting, with clinical impact given the heaviest weighting. The weighting matrix was subsequently applied to the list of research questions that resulted from the researcher database survey and a list of research priorities determined. CONCLUSION: The weighting matrix allows reproducible comparison of research questions. The resultant list of research priorities will act as a guide for the ACEM Clinical Trials Group in determining future projects. PMID- 24495059 TI - Emergency Medicine in the fourth decade: angry young man or mid-life crisis? PMID- 24495060 TI - International emergency medicine: past and future. PMID- 24495061 TI - From little things: how it all started. PMID- 24495062 TI - Past and future of journal publishing. PMID- 24495063 TI - Future evolution of traditional journals and social media medical education. PMID- 24495064 TI - Future of publishing: perils, pitfalls and opportunities. PMID- 24495065 TI - Past and future of emergency medicine education and training. PMID- 24495066 TI - Real textbooks or e-books: what is happening right now?: E-books cause remarkable decrease in ED visits for paper cuts ... but are responsible for more trigger finger injuries from 'pinching' e-pages. PMID- 24495067 TI - Free Open Access Medical education (FOAM) for the emergency physician. PMID- 24495068 TI - Brave new world of emergency medicine education. PMID- 24495069 TI - Fit for the future? The relevance of Emergency Medicine Australasia to current and prospective emergency medicine trainees. PMID- 24495071 TI - The genesis of craniofacial biology as a health science discipline. AB - The craniofacial complex encapsulates the brain and contains the organs for key functions of the body, including sight, hearing and balance, smell, taste, respiration and mastication. All these systems are intimately integrated within the head. The combination of these diverse systems into a new field was dictated by the dental profession's desire for a research branch of basic science devoted and attuned to its specific needs. The traditional subjects of genetics, embryology, anatomy, physiology, biochemistry, dental materials, odontology, molecular biology and palaeoanthropology pertaining to dentistry have been drawn together by many newly emerging technologies. These new technologies include gene sequencing, CAT scanning, MRI imaging, laser scanning, image analysis, ultrasonography, spectroscopy and visualosonics. A vibrant unitary discipline of investigation, craniofacial biology, has emerged that builds on the original concept of 'oral biology' that began in the 1960s. This paper reviews some of the developments that have led to the genesis of craniofacial biology as a fully fledged health science discipline of significance in the advancement of clinical dental practice. Some of the key figures and milestones in craniofacial biology are identified. PMID- 24495072 TI - Improved mechanical and electronic properties of co-assembled folic acid gel with aniline and polyaniline. AB - Co-assembled folic acid (F) gel with aniline (ANI) (ANI:F = 1:2, w/w) is produced at 2% (w/v) concentration in water/DMSO (1:1, v/v) mixture. The gel is rigid and on polymerization of the gel pieces in aqueous ammonium persulfate solution co assembled folic acid - polyaniline (F-PANI) gel is formed. Both the co-assembled F-ANI and F-PANI gels have fibrillar network morphology, the fiber diameter and its degree of branching increase significantly from those of F gel. WAXS pattern indicates co-assembled structure with the F fiber at the core and ANI/PANI at its outer surface and the co-assembly is occurring in both F-ANI and F-PANI systems through noncovalent interaction of H-bonding and pi stacking processes between the components. FTIR and UV-vis spectra characterize the doped PANI formation and the MALDI mass spectrometry indicates the degree of polymerization of polyaniline in the range 24-653. The rheological experiments support the signature of gel formation in the co-assembled state and the storage (G') and loss (G") modulii increase in the order F gel< F-ANI gel < F-PANI gel, showing the highest increase in G' ~ 1100% for the F-PANI gel. The stress at break, elasticity, and stiffness also increase in the same order. The dc-conductivity of F-ANI and F-PANI xerogels is 2 and 7 orders higher than that of F xerogel. Besides, the current (I)-voltage (V) curves indicate that the F-xerogel is insulator, but F-ANI xerogel is semiconductor showing both electronic memory and rectification; on the other hand, the F-PANI xerogel exhibits a negative differential resistance (NDR) property with a NDR ratio of 3.0. PMID- 24495073 TI - Kinase activity and calmodulin binding are essential for growth signaling by the phytosulfokine receptor PSKR1. AB - The cell growth-promoting peptide phytosulfokine (PSK) is perceived by leucine rich repeat (LRR) receptor kinases. To elucidate PSK receptor function we analyzed PSKR1 kinase activity and binding to Ca(2+) sensors and evaluated the contribution of these activities to growth control in planta. Ectopically expressed PSKR1 was capable of auto- and transphosphorylation. Replacement of a conserved lysine within the ATP-binding region by a glutamate resulted in the inhibition of auto- and transphosphorylation kinase activities. Expression of the kinase-inactive PSKR1(K762E) receptor in the pskr null background did not restore root or shoot growth. Instead, the mutant phenotype was enhanced suggesting that the inactive receptor protein exerts growth-inhibitory activity. Bioinformatic analysis predicted a putative calmodulin (CaM)-binding site within PSKR1 kinase subdomain VIa. Bimolecular fluorescence complementation analysis demonstrated that PSKR1 binds to all isoforms of CaM, more weakly to the CaM-like protein CML8 but apparently not to CML9. Mutation of a conserved tryptophan (W831S) within the predicted CaM-binding site strongly reduced CaM binding. Expression of PSKR1(W831S) in the pskr null background resulted in growth inhibition that was similar to that of the kinase-inactive receptor. We conclude that PSK signaling requires Ca(2+) /CaM binding and kinase activity of PSKR1 in planta. We further propose that the inactivated kinase interferes with other growth-promoting signaling pathway(s). PMID- 24495074 TI - Heterogeneous nucleation of ice on carbon surfaces. AB - Atmospheric aerosols can promote the heterogeneous nucleation of ice, impacting the radiative properties of clouds and Earth's climate. The experimental investigation of heterogeneous freezing of water droplets by carbonaceous particles reveals widespread ice freezing temperatures. It is not known which structural and chemical characteristics of soot account for the variability in ice nucleation efficiency. Here we use molecular dynamics simulations to investigate the nucleation of ice from liquid water in contact with graphitic surfaces. We find that atomically flat carbon surfaces promote heterogeneous nucleation of ice, while molecularly rough surfaces with the same hydrophobicity do not. Graphitic surfaces and other surfaces that promote ice nucleation induce layering in the interfacial water, suggesting that the order imposed by the surface on liquid water may play an important role in the heterogeneous nucleation mechanism. We investigate a large set of graphitic surfaces of various dimensions and radii of curvature and find that variations in nanostructures alone could account for the spread in the freezing temperatures of ice on soot in experiments. We conclude that a characterization of the nanostructure of soot is needed to predict its ice nucleation efficiency. PMID- 24495075 TI - Synthesis of proline-based N-heterocyclic carbene ligands. AB - The synthesis of proline-based N-heterocyclic carbene ligands is reported. An approach to a variety of proline-containing imidazolium NHC precursors is presented. The proline amino acids are shown to be compatible with peptide synthetic methods by incorporation into tripeptides. Following peptide synthesis, the carbene is generated and bound to rhodium. PMID- 24495076 TI - Does EPA underestimate cancer risks by ignoring susceptibility differences? AB - A 2009 report of the National Research Council (NRC) recommended that the U.S. Environmental Protection Agency (EPA) increase its estimates of increased cancer risk from exposure to environmental agents by ~7-fold, due to an approximate ~25 fold typical ratio between the median and upper 95th percentile persons' cancer sensitivity assuming approximately lognormally distributed sensitivities. EPA inaction on this issue has raised concerns that cancer risks to environmentally exposed populations remain systematically underestimated. This concern is unwarranted, however, because EPA point estimates of cancer risk have always pertained to the average, not the median, person in each modeled exposure group. Nevertheless, EPA has yet to explain clearly how its risk characterization and risk management policies concerning individual risks from environmental chemical carcinogens do appropriately address broad variability in human cancer susceptibility that has been a focus of two major NRC reports to EPA concerning its risk assessment methods. PMID- 24495077 TI - Do-or-die life cycles and diverse post-infection resistance mechanisms limit the evolution of parasite host ranges. AB - In light of the dynamic nature of parasite host ranges and documented potential for rapid host shifts, the observed high host specificity of most parasites remains an ecological paradox. Different variants of host-use trade-offs have become a mainstay of theoretical explanations of the prevalence of host specialism, but empirical evidence for such trade-offs is rare. We propose an alternative theory based on basic features of the parasite life cycle: host selection and subsequent intrahost replication. We introduce a new concept of effective burst size that accounts for the fact that successful host selection does not guarantee intrahost replication. Our theory makes a general prediction that a parasite will expand its host range if its effective burst size is positive. An in silico model of bacteria-phage coevolution verifies our predictions and demonstrates that the tendency for relatively narrow host ranges in parasites can be explained even in the absence of trade-offs. PMID- 24495078 TI - Sorbicatechols A and B, antiviral sorbicillinoids from the marine-derived fungus Penicillium chrysogenum PJX-17. AB - Two novel sorbicillinoids combining a bicyclo[2.2.2]octane with a 2-methoxyphenol moiety, named sorbicatechols A (1) and B (2), were isolated from the culture of the marine sediment-derived fungus Penicillium chrysogenum PJX-17, together with the known protocatechuic acid methyl ester and caffeic acid methyl ester (3). Their structures, including absolute configurations, were assigned by analysis of NMR, MS data, and TDDFT ECD calculations. Compounds 1 and 2 exhibited activities against influenza virus A (H1N1), with IC50 values of 85 and 113 MU M, respectively. PMID- 24495079 TI - Epilepsy in the elderly: comparing clinical characteristics with younger patients. AB - The prevalence and incidence of epilepsies in elderly is high. Due to demographic development, the portion of elderly patients with epilepsy will continue to rise over the next decades. In this study, we aimed to investigate seizure semiology, etiology, comorbidity, and therapy in elderly patients dependent on onset of epilepsy and in comparison with younger patients. In a prospective multicentre study, 202 epilepsy patients were included in a consecutive manner and subdivided into three groups (group A1: >65 years, onset of epilepsy after the age of 65 years; group A2: >65 years with early onset epilepsy, seizure onset before the age of 50 years; and group B: <50 years with epilepsy). Clinical data with respect to epilepsy, seizures, comorbidity, etiology, and anti-epileptic drug (AED) therapy were assessed using a questionnaire developed especially for these patient groups and filled out by the physicians. The clinical profile with regard to etiology, postictal conditions, and comorbidities clearly depends on the age of the patients and age of onset of epilepsy. Patients with an epilepsy onset after 65 years need lower doses of AEDs, gain better seizure control and have more concomitant diseases than younger patients or elderly epilepsy patients with early-onset epilepsy. PMID- 24495081 TI - Solution structure of calmodulin bound to the target peptide of endothelial nitric oxide synthase phosphorylated at Thr495. AB - Nitric oxide synthase (NOS) plays a major role in a number of key physiological and pathological processes, and it is important to understand how this enzyme is regulated. The small acidic calcium binding protein, calmodulin (CaM), is required to fully activate the enzyme. The exact mechanism of how CaM activates NOS is not fully understood at this time. Studies have shown CaM to act like a switch that causes a conformational change in NOS to allow for the transfer of an electron between the reductase and oxygenase domains through a process that is thought to be highly dynamic and at least in part controlled by several possible phosphorylation sites. We have determined the solution structure of CaM bound to a peptide that contains a phosphorylated threonine corresponding to Thr495 in full size endothelial NOS (eNOS) to investigate the structural and functional effects that the phosphorylation of this residue may have on nitric oxide production. Our biophysical studies show that phosphorylation of Thr495 introduces electrostatic repulsions between the target sequence and CaM as well as a diminished propensity for the peptide to form an alpha-helix. The calcium affinity of the CaM-target peptide complex is reduced because of phosphorylation, and this leads to weaker binding at low physiological calcium concentrations. This study provides an explanation for the reduced level of NO production by eNOS carrying a phosphorylated Thr495 residue. PMID- 24495083 TI - Echocardiographic examination of the posterior atrioventricular groove. AB - Abnormalities of the posterior atrioventricular (AV) groove may be mischaracterized or overlooked in the course of routine echocardiographic imaging. Vascular abnormalities in this location include plethora of the coronary sinus and ectasia of the circumflex coronary artery. Excess accumulation of calcium (mitral annular calcification) and of fat (lipomatosis of the posterior AV groove) may also occur in this region. Masses (tumors or thrombus) arising from the floor of the left atrium or extrinsic to it (hiatal hernia, lymph nodes) may occupy the posterior AV groove. Abnormalities of the left ventricle, including aneurysms and pseudoaneurysms may present as masses in the posterior AV groove. This article discusses the echocardiographic features, differential diagnosis, and clinical significance of these abnormalities. PMID- 24495084 TI - The effect of different circadian blood pressure rhythms on left ventricular systolic dyssynchrony in patients with newly diagnosed essential hypertension. PMID- 24495080 TI - Topoisomerase II and leukemia. AB - Type II topoisomerases are essential enzymes that modulate DNA under- and overwinding, knotting, and tangling. Beyond their critical physiological functions, these enzymes are the targets for some of the most widely prescribed anticancer drugs (topoisomerase II poisons) in clinical use. Topoisomerase II poisons kill cells by increasing levels of covalent enzyme-cleaved DNA complexes that are normal reaction intermediates. Drugs such as etoposide, doxorubicin, and mitoxantrone are frontline therapies for a variety of solid tumors and hematological malignancies. Unfortunately, their use also is associated with the development of specific leukemias. Regimens that include etoposide or doxorubicin are linked to the occurrence of acute myeloid leukemias that feature rearrangements at chromosomal band 11q23. Similar rearrangements are seen in infant leukemias and are associated with gestational diets that are high in naturally occurring topoisomerase II-active compounds. Finally, regimens that include mitoxantrone and epirubicin are linked to acute promyelocytic leukemias that feature t(15;17) rearrangements. The first part of this article will focus on type II topoisomerases and describe the mechanism of enzyme and drug action. The second part will discuss how topoisomerase II poisons trigger chromosomal breaks that lead to leukemia and potential approaches for dissociating the actions of drugs from their leukemogenic potential. PMID- 24495085 TI - Reply: To PMID 23889460. PMID- 24495088 TI - Pyrolysis temperature-dependent changes in dissolved phosphorus speciation of plant and manure biochars. AB - Pyrolysis of plant and animal wastes produces a complex mixture of phosphorus species in amorphous, semicrystalline, and crystalline inorganic phases, organic (char) components, and within organo-mineral complexes. To understand the solubility of different phosphorus species, plant (cottonseed hull) and manure (broiler litter) wastes were pyrolyzed at 350, 500, 650, and 800 degrees C and exposed to increasingly more rigorous extraction procedures: water (16 h), Mehlich 3 (1 mM EDTA at pH 2.5 for 5 min), oxalate (200 mM oxalate at pH 3.5 for 4 h), NaOH-EDTA (250 mM NaOH + 5 mM EDTA for 16 h), and total by microwave digestion (concentrated HNO3/HCl + 30% H2O2). Relative to the total (microwave digestible) P, the percentage of extractable P increased in the following order: M3 < oxalate ~ water < NaOH-EDTA for plant biochars and water < M3 < NaOH-EDTA < oxalate for manure biochars. Solution phase (31)P NMR analysis of NaOH-EDTA extracts showed the conversion of phytate to inorganic P by pyrolysis of manure and plant wastes at 350 degrees C. Inorganic orthophosphate (PO4(3-)) became the sole species of >= 500 degrees C manure biochars, whereas pyrophosphate (P2O7(4 )) persisted in plant biochars up to 650 degrees C. These observations suggested the predominance of (i) amorphous (rather than crystalline) calcium phosphate in manure biochars, especially at >= 650 degrees C, and (ii) strongly complexed pyrophosphate in plant biochars (especially at 350-500 degrees C). Correlation (Pearson's) was observed (i) between electric conductivity and ash content of biochars with the amount of inorganic P species and (ii) between total organic carbon and volatile matter contents with the organic P species. PMID- 24495090 TI - Retraction notice: Eosinophilia in routine blood samples as a biomarker for solid tumor development - a study based on The Copenhagen Primary Care Differential Count (CopDiff ) Database. PMID- 24495089 TI - Cortical thickness and hippocampal shape in pure vascular mild cognitive impairment and dementia of subcortical type. AB - BACKGROUND AND PURPOSE: The progression pattern of brain structural changes in patients with isolated cerebrovascular disease (CVD) remains unclear. To investigate the role of isolated CVD in cognitive impairment patients, patterns of cortical thinning and hippocampal atrophy in pure subcortical vascular mild cognitive impairment (svMCI) and pure subcortical vascular dementia (SVaD) patients were characterized. METHODS: Forty-five patients with svMCI and 46 patients with SVaD who were negative on Pittsburgh compound B (PiB) positron emission tomography imaging and 75 individuals with normal cognition (NC) were recruited. RESULTS: Compared with NC, patients with PiB(-) svMCI exhibited frontal, language and retrieval type memory dysfunctions, which in patients with PiB(-) SVaD were further impaired and accompanied by visuospatial and recognition memory dysfunctions. Compared with NC, patients with PiB(-) svMCI exhibited cortical thinning in the frontal, perisylvian, basal temporal and posterior cingulate regions. This atrophy was more prominent and extended further toward the lateral parietal and medial temporal regions in patients with PiB(-) SVaD. Compared with NC subjects, patients with PiB(-) svMCI exhibited hippocampal shape deformities in the lateral body, whilst patients with PiB(-) SVaD exhibited additional deformities within the lateral head and inferior body. CONCLUSIONS: Our findings suggest that patients with CVD in the absence of Alzheimer's disease pathology can be demented, showing cognitive impairment in multiple domains, which is consistent with the topography of cortical thinning and hippocampal shape deformity. PMID- 24495091 TI - Modulation of blood-brain barrier permeability in mice using synthetic E-cadherin peptide. AB - The present work characterizes the effects of synthetic E-cadherin peptide (HAV) on blood-brain barrier (BBB) integrity using various techniques including magnetic resonance imaging (MRI) and near-infrared fluorescent imaging (NIRF). The permeability of small molecular weight permeability marker gadolinium diethylenetriaminepentaacetate (Gd-DTPA) contrast agent, the large molecular weight permeability marker, IRDye 800CW PEG, and the P-glycoprotein (P-gp) efflux transporter contrast agent, rhodamine 800 (R800), were examined in the presence and absence of HAV peptide. The results consistently demonstrated that systemic iv administration of HAV peptide resulted in a reversible disruption of BBB integrity and enhanced the accumulation of all the dyes examined. The magnitude of increase ranged from 2-fold to 5-fold depending on the size and the properties of the permeability markers. The time frame for BBB disruption with HAV peptide was rapid, occurring within 3-6 min following injection of the peptide. Furthermore, modulation of BBB permeability was reversible with the barrier integrity being restored within 60 min of the injection. The increased BBB permeability observed following HAV peptide administration was not attributable to changes in cerebral blood flow. These studies support the potential use of cadherin peptides to rapidly and reversibly modulate BBB permeability of a variety of therapeutic agents. PMID- 24495092 TI - Long-range movement of humpback whales and their overlap with anthropogenic activity in the South Atlantic Ocean. AB - Humpback whales (Megaptera novaeangliae) are managed by the International Whaling Commission as 7 primary populations that breed in the tropics and migrate to 6 feeding areas around the Antarctic. There is little information on individual movements within breeding areas or migratory connections to feeding grounds. We sought to better understand humpback whale habitat use and movements at breeding areas off West Africa, and during the annual migration to Antarctic feeding areas. We also assessed potential overlap between whale habitat and anthropogenic activities. We used Argos satellite-monitored radio tags to collect data on 13 animals off Gabon, a primary humpback whale breeding area. We quantified habitat use for 3 cohorts of whales and used a state-space model to determine transitions in the movement behavior of individuals. We developed a spatial metric of overlap between whale habitat and models of cumulative human activities, including oil platforms, toxicants, and shipping. We detected strong heterogeneity in movement behavior over time that is consistent with previous genetic evidence of multiple populations in the region. Breeding areas for humpback whales in the eastern Atlantic were extensive and extended north of Gabon late in the breeding season. We also observed, for the first time, direct migration between West Africa and sub-Antarctic feeding areas. Potential overlap of whale habitat with human activities was the highest in exclusive economic zones close to shore, particularly in areas used by both individual whales and the hydrocarbon industry. Whales potentially overlapped with different activities during each stage of their migration, which makes it difficult to implement mitigation measures over their entire range. Our results and existing population-level data may inform delimitation of populations and actions to mitigate potential threats to whales as part of local, regional, and international management of highly migratory marine species. PMID- 24495093 TI - Tinea pedis: the etiology and global epidemiology of a common fungal infection. AB - Tinea pedis, which is a dermatophytic infection of the feet, can involve the interdigital web spaces or the sides of the feet and may be a chronic or recurring condition. The most common etiological agents are anthropophiles, including Trichophyton rubrum sensu stricto, which is the most common, followed by Trichophyton interdigitale and Epidermophyton floccosum. There has been a change in this research arena, necessitating a re-evaluation of our knowledge on the topic from a multidisciplinary perspective. Thus, this review aimed to provide a solid overview of the current status and changing patterns of tinea pedis. The second half of the twentieth century witnessed a global increase in tinea pedis and a clonal spread of one major etiologic agent, T. rubrum. This phenomenon is likely due to increases in urbanization and the use of sports and fitness facilities, the growing prevalence of obesity and the aging population. For optimal patient care and management, the diagnosis of tinea pedis should be verified by microbiological analysis. In this review, we discuss the epidemiology, clinical forms, complications and mycological characteristics of tinea pedis and we highlight the pathogenesis, prevention and control parameters of this infection. PMID- 24495094 TI - Antibiotrophs: The complexity of antibiotic-subsisting and antibiotic-resistant microorganisms. AB - Widespread overuse of antibiotics has led to the emergence of numerous antibiotic resistant bacteria; among these are antibiotic-subsisting strains capable of surviving in environments with antibiotics as the sole carbon source. This unparalleled expansion of antibiotic resistance reveals the potent and diversified resistance abilities of certain bacterial strains. Moreover, these strains often possess hypermutator phenotypes and virulence transmissibility competent for genomic and proteomic propagation and pathogenicity. Pragmatic and prospicient approaches will be necessary to develop efficient therapeutic methods against such bacteria and to understand the extent of their genomic adaptability. This review aims to reveal the niches of these antibiotic-catabolizing microbes and assesses the underlying factors linking natural microbial antibiotic production, multidrug resistance, and antibiotic-subsistence. PMID- 24495095 TI - Actinobacterial enzyme inhibitors--a review. AB - Actinobacteria have potential as important new sources of enzyme inhibitors. Enzyme inhibitors have great demand in medicine, agriculture and biotechnology. In medicine, enzyme inhibitors can be used as therapeutic agents for bacterial, fungal, viral and parasitic diseases as well as treating cancer, neurodegenerative, immunological and cardiovascular diseases. Enzyme inhibitors are also valuable for the control of carbohydrate-dependent diseases such as diabetes, obesity and hyperlipidemia and melanogenesis in skin. They can be also involved in crop protection against plant pathogens, herbivorous pests and abiotic stresses such as drought. In this review, we discuss about several actinobacterial enzyme inhibitors with various industrial uses and biotechnological applications. PMID- 24495096 TI - Challenges and solutions for a rational vaccine design for TB-endemic regions. AB - Vaccines have been successful for global eradication or control of dreaded diseases such as smallpox, diphtheria, tetanus, yellow fever, whooping cough, polio, and measles. Unfortunately, this success has not been achieved for controlling tuberculosis (TB) worldwide. Bacillus Calmette Guerin (BCG) is the only available vaccine against TB. Paradoxically, BCG has deciphered success in the Western world but has failed in TB-endemic areas. In this article, we highlight and discuss the aspects of immunity responsible for controlling Mycobacterium tuberculosis infection and factors responsible for the failure of BCG in TB-endemic countries. In addition, we also suggest strategies that contribute toward the development of successful vaccine in protecting populations where BCG has failed. PMID- 24495097 TI - Colonization and infection with extended spectrum beta-lactamase producing Enterobacteriaceae in high-risk patients - Review of the literature from a clinical perspective. AB - BACKGROUND: The prevalence of extended-spectrum beta-lactamase producing Enterobacteriaceae (ESBL-E) is increasing worldwide. ESBL-E are known to colonize different body sites and cause bloodstream infections (BSI), pneumonia, intra abdominal infections and urinary tract infections. Even though ESBL-E-related morbidity and mortality in high-risk patients - patients receiving immunosuppressants or chemotherapy, as well as those treated in an ICU - is considerable, the management of ESBL-E in these populations has not been systematically reviewed. METHODS: For the purpose of this review, ICU patients, patients in hematology and oncology wards and transplant recipients were considered high-risk. An English-language Medline search was conducted to identify literature on epidemiology, risk factors, clinical impact and measures of infection control regarding ESBL-E in high-risk patients published between June 2002 and May 2013. RESULTS: Using the above described methodology, 43 relevant articles regarding high-risk patients and - for areas where literature on exclusively high-risk patients is scarce - 17 articles in standard risk settings were identified. The evidence on epidemiology, associated risk factors, treatment and hygiene measures were summarized. DISCUSSION: This review gives a complete overview on the management of ESBL-E in the high-risk setting. PMID- 24495098 TI - Current challenges in the treatment of osteoporosis: an opportunity for bazedoxifene. AB - BACKGROUND: Osteoporosis affects millions of postmenopausal women worldwide. Osteoporosis-related fractures can lead to chronic pain, disability, systemic complications, and increased risk of recurrent fractures, resulting in increased healthcare costs and mortality. Because currently available therapies have unique benefit/risk profiles, challenges remain in selecting the most appropriate treatment for each osteoporotic woman. RESEARCH AND RESULTS: Bazedoxifene (BZA), a new selective estrogen receptor modulator, is being developed for postmenopausal osteoporosis. In a 3 year, global, phase 3 study, BZA significantly reduced the risk of new vertebral fractures and nonvertebral fractures in women with higher baseline fracture risk compared with placebo. In two extensions of this study, the efficacy of BZA in reducing vertebral fracture risk was sustained over 7 years. BZA improved lumbar spine and total hip bone mineral density compared with placebo at 3 and 5 years, and demonstrated a favorable safety/tolerability profile, with no endometrial or breast stimulation. BZA was cost-effective compared with raloxifene in a 3 year, head-to-head comparative trial. Indirect comparisons further suggest that BZA may be as effective as bisphosphonates in reducing risk of nonvertebral fractures in women at high risk of fracture. BZA demonstrated efficacy and safety for treating postmenopausal osteoporosis over 7 years, particularly in women at a higher fracture risk. CONCLUSION: Because of its specific pharmacologic profile, BZA may be appropriate for postmenopausal women seeking a tolerable, safe, effective, and cost-effective long-term osteoporosis treatment. PMID- 24495099 TI - Fiber-post bond strength in canals obturated with a cross-linked gutta-percha core obturator. AB - The aim of this in-vitro study was to evaluate the bond strength of fiber posts cemented in a root canal filled using various root-canal obturation techniques. A total of 33 monoradicular samples, treated endodontically, were randomly assigned to three groups according to the root-canal obturation technique: group 1, continuous-wave technique; group 2, plastic-obturator-core technique; and group 3, cross-linked gutta-percha obturator-core technique. Fiber posts were luted in each sample and each was sectioned perpendicular to the post axis. The push-out test was performed using a universal machine and the maximum failure load was recorded in MPa mm(-2) . Several samples were randomly chosen for scanning electron microscopy evaluation. The mean debris and dentinal tubule-opening scores were calculated separately in the coronal and apical portions. Bond strength was significantly higher in group 1 than in groups 2 and 3. Debris scores were significantly higher in the apical portion of groups 2 and 3 than in group 1. Within the limitations of this study it can be affirmed that thermoplasticized alpha gutta-percha seemed to worsen the cleaning of post-space walls and hence reduced fiber-post bond strength. PMID- 24495100 TI - Highly transparent and UV-resistant superhydrophobic SiO(2)-coated ZnO nanorod arrays. AB - Highly transparent and UV-resistant superhydrophobic arrays of SiO2-coated ZnO nanorods are prepared in a sequence of low-temperature (<150 degrees C) steps on both glass and thin sheets of PET (2 * 2 in.(2)), and the superhydrophobic nanocomposite is shown to have minimal impact on solar cell device performance under AM1.5G illumination. Flexible plastics can serve as front cell and backing materials in the manufacture of flexible displays and solar cells. PMID- 24495101 TI - Anion (fluoride)-doped ceria nanocrystals: synthesis, characterization, and its catalytic application to oxidative coupling of benzylamines. AB - Fluoride doping in the CeO2 lattice has been achieved by a simple, reliable, reproducible, and safe solution-based method. F-containing CeO2 has retained the fluorite structure, and its effect has been confirmed from various analytical techniques such as powder X-ray diffraction, Fourier transform IR, Raman, UV visible diffuse reflectance, photoluminescence (PL), and X-ray photoelectron spectroscopy (XPS), scanning electron microscopy-energy-dispersive X-ray (EDX) and transmission electron microscopy-EDX analysis. The concentration of fluoride in the CeO2 lattice has been determined from chemical analysis and core-level XPS analysis. The concentration of Ce(3+) in the F-doped and undoped CeO2 samples have been determined both from XPS analysis as well as from variable-temperature magnetic susceptibility measurements. The characteristic Ce(3+) emission in the PL spectrum indicated the increase of Ce(3+) ion concentration in the F-doped sample, conforming to the results from XPS and magnetic measurements. F-doped CeO2 nanocrystals showed moderate monodispersity as determined from particle-size measurements using dynamic light scattering experiments and high surface area of 106.1 m(2)/g. Optical band gap of CeO2 has narrowed upon doping with fluoride ions from 3.05 to 2.95 eV. The formation of extrinsic oxygen vacancy complexes upon F-doping has been observed in the Raman spectrum (at 1097 cm(-1)) in addition to fingerprint bands of CeO2. The UV-shielding property and photocatalytic inactivity toward aqueous dye degradation process of F-doped CeO2 has suggested its potential use in cosmetic applications. Both F-doped CeO2 and CeO2 have been used as catalysts for oxidative coupling of benzylamines to imines in the presence of molecular oxygen under solvent-free conditions. F-doped CeO2 exhibited better catalytic efficiency than CeO2. The oxidation procedure using these catalysts is simple, environmentally benign, and solvent-free, and the catalysts are reusable. PMID- 24495102 TI - Nanoporous thermochromic VO2 (M) thin films: controlled porosity, largely enhanced luminous transmittance and solar modulating ability. AB - Vanadium dioxide is the most widely researched thermochromic material with a phase transition temperature (tau(c)) of around 68 degrees C, and its thermochromic performance can be enhanced by adding nanoporosity. Freeze-drying has been employed to fabricate nanostructures with different porosities from 16 to 45% by varying the prefreezing temperature and precursor concentration. The luminous transmittance (Tlum) and solar modulating ability (DeltaTsol) are greatly enhanced as a result of increasing pore size and pore density. The freeze dried sample with 7.5 mL of H2O2 precursor dip-coated at 300 mm/min gives the best combination of thermochromic properties (Tlum ~ 50%, DeltaTsol = 14.7%), which surpasses the best combined thermochromic performance reported to date that we are aware of (Tlum ~ 41%, DeltaTsol = 14.1%). PMID- 24495103 TI - The correlation between fecal calprotectin, simple clinical colitis activity index and biochemical markers in ulcerative colitis during high-dose steroid treatment. AB - OBJECTIVE: Monitoring active ulcerative colitis (UC) is essential for making correct and timely treatment decisions. The current monitoring is based on symptom scores and biochemical markers, among which the role of fecal calprotectin (FC) is debated. The aims were to assess the development in FC during steroid treatment and to compare FC with symptom scores and biochemical markers. MATERIAL AND METHODS: A prospective observational study, including 16 patients with active UC requiring high-dose steroid treatment. FC, C-reactive protein (CRP), leukocytes, hemoglobin, albumin, and simple clinical colitis activity index (SCCAI) were assessed before the initiation of treatment, as well as on days 2, 6, 13, and 27. The one-year follow-up data were retrospectively obtained. RESULTS: All patients had significant decreasing levels of FC (-1014 mg/kg, p = 0.0061), CRP (-10 mmol/l, p = 0.0313), and SCCAI (-3, p = 0.0002) during the first 4 days. After 27 days, the FC had decreased to 216 mg/kg (p = 0.002). A significant correlation between the changes in CRP and SCCAI was found (r(s) = 0.65, p = 0.03) but not between FC and CRP or SCCAI. Overall, significant correlations between absolute levels of FC, CRP, and SCCAI were found. Levels of FC on day 0 and day 4 were not predictive of sustained clinical remission at 1 year follow up. CONCLUSIONS: FC, CRP, and SCCAI seem to be reliable markers of treatment response during steroid treatment. High initial levels of FC and a subsequent rapid reduction during steroid treatment were identified. FC levels were not found to be predictive of disease prognosis after one year. PMID- 24495104 TI - A flail anterior tricuspid leaflet secondary to anteroposterior papillary muscle rupture in a neonate. AB - This article is a summary of a case of a neonate who presented with tricuspid valve insufficiency associated with papillary muscle rupture but, however, showed no signs of cardiac failure. The transthoracic three-dimensional echocardiographic findings in this case are described in detail herein. PMID- 24495105 TI - Study of marine natural products including resorcyclic acid lactones from Humicola fuscoatra that reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. AB - An extract of Humicola fuscoatra (UCSC strain no. 108111A) was shown to reactivate latent HIV-1 expression in an in vitro model of central memory CD4+ T cells. We report the bioassay-guided isolation and structure determination of several resorcyclic acid lactones, including four known compounds, radicicol (1, aka. monorden) and pochonins B (2), C (3), and N (4), and three new analogues, radicicols B-D (5-7). Compounds 1-3 and 5 showed moderate activities in the memory T cell model of HIV-1 latency. Radicicol (1) displayed lower potency in reactivating latent HIV-1 (EC50 = 9.1 MUM) relative to the HDAC inhibitors apicidin (EC50 = 0.3 MUM), romidepsin (EC50 = 0.003 MUM), and SAHA (EC50 = 0.6 MUM); however, it achieved equivalent maximum efficacy relative to the positive control compounds (98% of SAHA and romidepsin). PMID- 24495106 TI - Stereophotogrammetric evaluation of tooth-induced labial protrusion. AB - PURPOSE: To better manage dental treatment outcome, a previsualization of desired appearances can be used to understand patients' wishes. A deeper comprehension of labial modifications related to hard-tissue movements is advantageous. The purpose of the study was to evaluate tooth restoration-induced labial displacements in three dimensions. MATERIALS AND METHODS: In a group of 20 healthy Caucasian individuals, simulations of vestibular translations of maxillary anterior crowns were obtained by placing an acrylic resin veneer on the labial surfaces of maxillary incisors and canines. Three-dimensional stereophotogrammetric acquisitions were made to evaluate soft-tissue changes induced by the simulations. Linear dislocation of selected landmarks and labial surfaces were quantified using dedicated software. RESULTS: All paired and two midline labial landmarks had significant displacements, ranging from 13% (Subnasale landmark) to 103% (left Cheilion landmark) of veneer thickness (2 mm thick). A significant positive correlation was obtained between the lower lip displacement and overjet values. CONCLUSIONS: The vestibular shift of maxillary incisors and canines affect both upper and lower vermilion areas, without involving cutaneous perilabial landmarks. PMID- 24495107 TI - Progression and survival in Parkinson's disease with subthalamic nucleus stimulation. AB - BACKGROUND: Treatment for Parkinson's disease (PD) is symptomatic. Surgical treatment with continuous high-frequency stimulation of the subthalamic nucleus (STN-DBS) is established as a safe symptomatic treatment with long-term beneficial effects. It has been postulated that STN-DBS could halt the progression of PD through a disease modifying or neuroprotective effect. OBJECTIVE: To investigate the postulated disease modifying or neuroprotective effect of STN-DBS by comparing the rate of deterioration of parkinsonism and mortality over time in two selected and matched groups of patients with PD with and without surgery. METHODS: Group A was derived from all patients who received STN-DSB surgery at Oslo University Hospital, from January 2001 to December 2007. Group B was derived from a prevalence study of PD in the Stavanger area of Western Norway in 1993. The two groups were individually matched and the disease progression measured by Unified Parkinson's Disease Rating Scale-motor scores, and the mortality was compared. RESULTS: The mean annual change based on baseline and last observation scores in individually matched groups was 0.97 (SD = 3.57) for the surgery group and 1.04 (SD = 3.33) for the controls and thus not significantly different, F(1, 104) = .21, P = 0.89. The long-term mortality was also similar in the two groups during long-term follow-up, hazard ratio = 1.76, CL 0.91-3.40, P = 0.091. CONCLUSION: This study gives no support to a postulated disease modifying or neuroprotective effect of STN-DBS in patients with PD. PMID- 24495108 TI - Antisense gene inhibition by phosphorothioate antisense oligonucleotide in Arabidopsis pollen tubes. AB - Sexual reproduction is an essential biological event for proliferation of plants. The pollen tube (PT) that contained male gametes elongates and penetrates into the pistils for successful fertilization. However, the molecular mechanisms of plant fertilization remain largely unknown. Here, we report a transient inhibition of gene function using phosphorothioate antisense oligodeoxynucleotides (AS-ODNs) without cytofectin, which is a simple way to study gene function in Arabidopsis thaliana PTs. The PTs treated with AS-ODNs against both ANX1 and ANX2 showed short, knotted, and ruptured morphology in vitro/semi-in vitro, whereas normal PT growth was shown in its sense control in vitro/semi-in vitro. PT growth was impaired in a manner dependent on the dose of AS-ODNs against both ANX1 and ANX2 above 10 MUm. The treatment with AS-ODNs against ROP1 and CalS5 resulted in waving PTs and in short PTs with a few callose plugs, respectively. The expression levels of the target genes in PTs treated with their AS-ODNs were lower than or similar to those in the sense control, indicating that the inhibition was directly or indirectly related to the expression of each mRNA. The AS-ODN against fluorescent protein (sGFP) led to reduced sGFP expression, suggesting that the AS-ODN suppressed protein expression. This method will enable the identification of reproductively important genes in Arabidopsis PTs. PMID- 24495109 TI - Decomposition of condensed phase energetic materials: interplay between uni- and bimolecular mechanisms. AB - Activation energy for the decomposition of explosives is a crucial parameter of performance. The dramatic suppression of activation energy in condensed phase decomposition of nitroaromatic explosives has been an unresolved issue for over a decade. We rationalize the reduction in activation energy as a result of a mechanistic change from unimolecular decomposition in the gas phase to a series of radical bimolecular reactions in the condensed phase. This is in contrast to other classes of explosives, such as nitramines and nitrate esters, whose decomposition proceeds via unimolecular reactions both in the gas and in the condensed phase. The thermal decomposition of a model nitroaromatic explosive, 2,4,6-trinitrotoluene (TNT), is presented as a prime example. Electronic structure and reactive molecular dynamics (ReaxFF-lg) calculations enable to directly probe the condensed phase chemistry under extreme conditions of temperature and pressure, identifying the key bimolecular radical reactions responsible for the low activation route. This study elucidates the origin of the difference between the activation energies in the gas phase (~62 kcal/mol) and the condensed phase (~35 kcal/mol) of TNT and identifies the corresponding universal principle. On the basis of these findings, the different reactivities of nitro-based organic explosives are rationalized as an interplay between uni- and bimolecular processes. PMID- 24495110 TI - Mild and selective heterogeneous catalytic hydration of nitriles to amides by flowing through manganese dioxide. AB - A sustainable flow chemistry process for the hydration of nitriles, whereby an aqueous solution of the nitrile is passed through a column containing commercially available amorphous manganese dioxide, has been developed. The product is obtained simply by concentration of the output stream without any other workup steps. The protocol described is rapid, robust, reliable, and scalable, and it has been applied to a broad range of substrates, showing a high level of chemical tolerance. PMID- 24495111 TI - Three-dimensional analysis of molar development in the mouse from the cap to bell stage. AB - During four days of prenatal development in the mouse, the morphology of the first lower molar moves from the early cap to the bell stage. Five phenomena characterize this period: growth of the tooth germ; development of the cervical loop; histogenesis of the enamel organ; folding of the epithelial-mesenchymal junction associated with cusp formation; and change in cellular heterogeneity in the mesenchyme. All these processes are controlled by epithelial-mesenchymal interactions. These complex histo-morphogenetic events have been documented using histological sections and 3D reconstructions. When combined with functional tests in vitro, this approach allowed searching for possible relationships between simultaneous changes occurring in both the epithelial and ecto-mesenchymal compartments. Parallel changes that occur in the two tissues could result from different mechanisms, as illustrated by the increasing number of pre-odontoblasts and pre-ameloblasts during crown growth. Cell division was involved mainly in the ecto-mesenchyme, while proliferation and cell re-organization occurred in the inner dental epithelium. 3D reconstructions also raised still unsolved questions, such as the possible relationship between cusp size and spatial specification of cell kinetic parameters, changes in cell position within the inner dental epithelium, and tracing cell migration in the mesenchyme during development. PMID- 24495112 TI - T helper subsets & regulatory T cells: rethinking the paradigm in the clinical context of solid organ transplantation. AB - Recent years have witnessed remarkable expansion in the knowledge of how various immune/inflammatory cells and T helper (Th) cell subsets, including Th1, Th2, Th9, Th17, Th22, follicular T helper (Tfh) and Treg subpopulations, reciprocally regulate each other. This review highlights current understanding of the Th subsets paradigm, who are the old school players, who are the new kids on the block and how does each come to play in different clinical contexts in solid organ transplantation. The article commences with a brief overview of the development and characteristic cytokine profiles of individual members of the paradigm. However, the main focus of this review is on the current understanding of the Th subset paradigm, and how these unique subpopulations impact host responses towards solid organ allografts. More specifically, it will highlight the recent findings that implicate the paradigm in transplantation. The interplay among different subsets is discussed collectively in the clinical context of pretransplant immunological risk factors such as alloimmunization as well as post transplant immunological consequences such as rejection. Accumulating evidence suggests that Th17 cells play a role in the development of chronic allograft injury in transplantation of various organs. In vitro, tacrolimus suppressed Th1 and Th2 cells but not Th17 cells. Animal studies suggest that regulatory T cells (Treg)-based therapies could be effective as mechanisms of long-term drug-free transplant tolerance in humans. Indeed, a dual role for TGF-beta and Foxp3 in induced tolerance has been proposed, in which TGF-beta stimulates Foxp3 expression and is associated with the induction of Treg-facilitating acquisition of tolerance. Exploiting Th subsets' regulatory functions could potentially offer opportunities for immunological interventions in solid organ transplantation. PMID- 24495114 TI - Sexual conflict and interacting phenotypes: a quantitative genetic analysis of fecundity and copula duration in Drosophila melanogaster. AB - Many reproductive traits that have evolved under sexual conflict may be influenced by both sexes. Investigation of the genetic architecture of such traits can yield important insight into their evolution, but this entails that the heritable component of variation is estimated for males and females-as an interacting phenotype. We address the lack of research in this area through an investigation of egg production and copula duration in the fruit fly, Drosophila melanogaster. Despite egg production rate being determined by both sexes, which may cause sexual conflict, an assessment of this trait as an interacting phenotype is lacking. It is currently unclear whether copula duration is determined by males and/or females. We found significant female, but not male, genetic variance for egg production rate that may indicate reduced potential for ongoing sexually antagonistic coevolution. In contrast, copula duration was determined by significant genetic variance in both sexes. We also identified genetic variation in egg retention among virgin females. Although previously identified in wild populations, it is unclear why this should be present in a laboratory stock. This study provides a novel insight into the shared genetic architecture of reproductive traits that are the subject of sexual conflict. PMID- 24495113 TI - The structure and competitive substrate inhibition of dihydrofolate reductase from Enterococcus faecalis reveal restrictions to cofactor docking. AB - We are addressing bacterial resistance to antibiotics by repurposing a well established classic antimicrobial target, the dihydrofolate reductase (DHFR) enzyme. In this work, we have focused on Enterococcus faecalis, a nosocomial pathogen that frequently harbors antibiotic resistance determinants leading to complicated and difficult-to-treat infections. An inhibitor series with a hydrophobic dihydrophthalazine heterocycle was designed from the anti-folate trimethoprim. We have examined the potency of this inhibitor series based on inhibition of DHFR enzyme activity and bacterial growth, including in the presence of the exogenous product analogue folinic acid. The resulting preferences were rationalized using a cocrystal structure of the DHFR from this organism with a propyl-bearing series member (RAB-propyl). In a companion apo structure, we identify four buried waters that act as placeholders for a conserved hydrogen-bonding network to the substrate and indicate an important role in protein stability during catalytic cycling. In these structures, the nicotinamide of the nicotinamide adenine dinucleotide phosphate cofactor is visualized outside of its binding pocket, which is exacerbated by RAB-propyl binding. Finally, homology models of the TMP(R) sequences dfrK and dfrF were constructed. While the dfrK-encoded protein shows clear sequence changes that would be detrimental to inhibitor binding, the dfrF-encoded protein model suggests the protein would be relatively unstable. These data suggest a utility for anti-DHFR compounds for treating infections arising from E. faecalis. They also highlight a role for water in stabilizing the DHFR substrate pocket and for competitive substrate inhibitors that may gain advantages in potency by the perturbation of cofactor dynamics. PMID- 24495115 TI - Reduction of the off-flavor volatile generated by the yogurt starter culture including Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus in soymilk. AB - Streptococcus thermophilus and Lactobacillus delbrueckii subsp. bulgaricus establish a symbiotic relationship in milk; however, S. thermophilus predominantly grows in soymilk. This study determined that excess diacetyl was notably generated mainly by S. thermophilus in soymilk, and this flavor compound created an unpleasant odor in fermented soymilk. The addition of l-valine to soymilk reduced the amount of diacetyl and increased the levels of acetoin during fermentation by S. thermophilus . In addition, it was found that the expression of the ilvC gene was repressed and that of the als and aldB genes was stimulated in S. thermophilus by l-valine. Sensory evaluations with the triangle difference test and a preference test showed that the soymilk fermented with l-valine was significantly preferred compared with that without l-valine. In this study, we successfully controlled the metabolic flux of S. thermophilus in soymilk and produced more favorable fermented soymilk without the use of genetically modified lactic acid bacteria strains. PMID- 24495116 TI - Glucagon-like peptide-1 receptor agonists vs. insulin in inadequately controlled patients with type 2 diabetes. Is this meta-analysis miscalculated? PMID- 24495121 TI - Challenging current views on apolipoprotein E's role as stroke predictor. PMID- 24495120 TI - The Ah receptor in stem cell cycling, regulation, and quiescence. AB - Processes that regulate quiescence, self-renewal, and differentiation of hematopoietic stem cells (HSCs) are not well understood. Owing, in part, to the ability of xenobiotic ligands to have persistent effects on the immune system in experimental animals, there has been much work to define a physiological role of the aryl hydrocarbon receptor (AhR) and its relationship to human disease. Persistent AhR activation by dioxin, a potent agonist, results in altered numbers and function of HSCs in mice. HSCs from AhR(-/-) knockout (KO) mice are hyperproliferative and have an altered cell cycle. Aging KO mice show characteristics consistent with premature bone marrow exhaustion. We propose that the increased proliferation of HSCs lacking AhR expression or activity is a result of loss of quiescence, and as such, AhR normally acts as a negative regulator to curb excessive or unnecessary proliferation. Similarly, prolonged and/or inappropriate stimulation of AhR activity may compromise the ability of HSCs to sense environmental signals that allow these cells to balance quiescence, proliferation, migration, and differentiation. These data and others support a hypothesis that deregulation of AhR function has an important role in HSC regulation and in the etiology and/or progression of certain hematopoietic diseases, many of which are associated with aging. PMID- 24495122 TI - Exploring risk judgments in a trade dispute using Bayesian networks. AB - Bayesian networks (BNs) are graphical modeling tools that are generally recommended for exploring what-if scenarios, visualizing systems and problems, and for communication between stakeholders during decision making. In this article, we investigate their potential for exploring different perspectives in trade disputes. To do so, we draw on a specific case study that was arbitrated by the World Trade Organization (WTO): the Australia-New Zealand apples dispute. The dispute centered on disagreement about judgments contained within Australia's 2006 import risk analysis (IRA). We built a range of BNs of increasing complexity that modeled various approaches to undertaking IRAs, from the basic qualitative and semi-quantitative risk analyses routinely performed in government agencies, to the more complex quantitative simulation undertaken by Australia in the apples dispute. We found the BNs useful for exploring disagreements under uncertainty because they are probabilistic and transparently represent steps in the analysis. Different scenarios and evidence can easily be entered. Specifically, we explore the sensitivity of the risk output to different judgments (particularly volume of trade). Thus, we explore how BNs could usefully aid WTO dispute settlement. We conclude that BNs are preferable to basic qualitative and semi-quantitative risk analyses because they offer an accessible interface and are mathematically sound. However, most current BN modeling tools are limited compared with complex simulations, as was used in the 2006 apples IRA. Although complex simulations may be more accurate, they are a black box for stakeholders. BNs have the potential to be a transparent aid to complex decision making, but they are currently computationally limited. Recent technological software developments are promising. PMID- 24495123 TI - Negative magnetoresistance in a vertical single-layer graphene spin valve at room temperature. AB - Single-layer graphene (SLG) is an ideal material for spintronics because of its high charge-carrier mobility, long spin lifetime resulting from the small spin orbit coupling, and hyperfine interactions of carbon atoms. Here, we report a vertical spin valve with SLG with device configuration Co/SLG/Al2O3/Ni. We observed negative magnetoresistance (-0.4%) for the Co/SLG/Al2O3/Ni junction at room temperature. However, the Co/Al2O3/Ni junction, which is without graphene, shows positive magnetoresistance. The current-voltage (I-V) characteristics of both Co/SLG/Al2O3/Ni and Co/Al2O3/Ni junctions are nonlinear, and this reveals that charge transport occurs by a tunneling mechanism. We have also explained the reason for negative magnetoresistance for the Co/SLG/Al2O3/Ni junction. PMID- 24495124 TI - Cell-specific expression of uptake transporters--a potential approach for cardiovascular drug delivery devices. AB - Enhanced proliferation of human coronary artery smooth muscle cells (HCASMCs) and thereby formation of neointima is one of the factors contributing to failure of coronary stents. Even if the use of drug eluting stents (DES) and thereby the local delivery of cytotoxic compounds has significantly improved the clinical outcome, unselective cytotoxic effects are assumed to hamper clinical success. Novel pharmacological approaches are required to enhance cellular selectivity of locally delivered drugs. Cell specific overexpression of a drug transporter could be used to enhance cellular accumulation and therefore cell specificity. In the herein reported study we tested the possibility of cell specific transporter expression to enhance drug effects in HCASMCs. We generated adenoviral constructs to overexpress the organic cation transporter 1 (OCT1) under control of the promoter of SM22alpha, which had been previously reported as muscle cell specific gene. First the activity of the SM22alpha-promoter was assessed in various cell types supporting the notion of muscle cell specificity. Subsequently, the activity of the transporter was compared in infected HCAECs and HCASMCs revealing enhanced accumulation of substrate drugs in HCASMCs in presence of the SM22alpha promoter. Testing the hypothesis that this kind of targeting might serve as a mechanism for cell-specific drug effects, we investigated the impact on paclitaxel treatment in HCASMC and HCAECs, showing significantly increased antiproliferative activity of this substrate drug on muscle cells. Taken together, our findings suggest that cell-specific expression of transport proteins serves as mechanism governing the uptake of cytotoxic compounds for a selective impact on targeted cells. PMID- 24495125 TI - Long-term survival of dogs with adrenal-dependent hyperadrenocorticism: a comparison between mitotane and twice daily trilostane treatment. AB - BACKGROUND: Treatment of adrenal-dependent hyperadrenocorticism (ADH) involves either surgical resection of the adrenal tumor or medical therapy. For many years, mitotane has been considered the medical treatment of choice for dogs with ADH. OBJECTIVES: The aim of this study was to determine survival and prognostic factors for dogs with ADH treated with mitotane and trilostane. ANIMALS: Twenty six dogs with ADH were included in the study. METHODS: Fourteen dogs were treated with mitotane and 12 dogs were treated with trilostane. Medical records were reviewed. Epidemiologic factors, signalment, clinicopathologic abnormalities, endocrine test results, and treatment protocols were evaluated to identify potential predictive factors of overall survival time. RESULTS: Survival times of dogs treated with mitotane (median, 15.6 months) or trilostane (median, 14.0 months) were not significantly different. Using univariate analysis, age and postadrenocorticotropic hormone cortisol concentrations were inversely correlated with survival time. The multivariate model also identified weakness at presentation as a negative prognostic indicator. CONCLUSION AND CLINICAL IMPORTANCE: The type of medical treatment (mitotane versus trilostane) does not influence survival time in dogs with ADH; therefore, trilostane, a drug with less frequent and milder adverse effects, might be used as the primary medical treatment when adrenalectomy cannot be performed. PMID- 24495126 TI - Total and low-density lipoprotein cholesterol in high-risk patients treated with atorvastatin monotherapy in the United Kingdom: analysis of a primary-care database. AB - OBJECTIVE: British clinical guidelines recommend statins as first-line lipid modifying treatment (LMT) for patients at high risk of cardiovascular disease (CVD). We undertook an observational study to assess total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels in high-risk patients who were treated with atorvastatin monotherapy by UK general practitioners. METHODS: This retrospective database study included patients with a prescription for atorvastatin monotherapy between November 30, 2008, and November 30, 2011, with the index date defined as the first atorvastatin prescription during this period. Eligible high-risk patients with evidence of coronary heart disease (CHD), atherosclerotic vascular disease (AVD), diabetes mellitus (DM), or familial hypercholesterolemia (FH) were required to have >=1 TC and LDL-C measurement between 3 and 12 months after the index date, and continuous enrollment 1 year before and 1 year after the index date. Cholesterol levels were assessed using the National Institute for Health and Care Excellence (NICE) guidelines: TC <4.0 mmol/L or LDL-C <2.0 mmol/L. RESULTS: Of 2999 high-risk patients (60.2% men; mean [SD] age = 67.9 [10.6] years) meeting selection criteria, 23.9% 28.2%, 36.2%, and 11.6% received prescriptions for atorvastatin 10, 20, 40, and 80 mg, respectively (percentages do not sum to 100 because of rounding). Across all doses, the mean (SD) follow-up TC was 4.08 (0.80) mmol/L and LDL-C 2.08 (0.65) mmol/L. A large proportion of patients (88.8%) had TC < 5.0 mmol/L. However, only 45.8% had TC < 4.0 mmol/L, and 46.5% had LDL-C < 2.0 mmol/L. Although a larger proportion of patients with CHD/AVD + DM reached guideline-recommended lipid levels, only 63.7% of such patients had TC < 4.0 or LDL-C < 2.0 mmol/L, which are the current targets for this subgroup as recommended by NICE. CONCLUSIONS: Less than half of UK high-CVD-risk patients receiving atorvastatin monotherapy achieved guideline recommended treatment targets for TC, and less than two-thirds of patients with CHD/AVD + DM had values below TC (4.0 mmol/L) or LDL-C (2.0 mmol/L) targets. More effective lipid-lowering strategies may be warranted to optimize cholesterol lowering and target attainment in high-risk patients. Limitations of this study include its retrospective, observational nature. PMID- 24495127 TI - Dental management of patients irradiated for head and neck cancer. AB - Patients undergoing radiation therapy as either primary, adjuvant, combination therapy or palliative management of head and neck malignancies are prone to a range of dental complications. Strategies for prevention and management of such complications may be controversial. This article aims to highlight the current understanding and management of the dental needs for patients before, during and after radiation therapy. PMID- 24495128 TI - Transforming growth factor-beta1 regulates expression of the matrix metalloproteinase 20 (Mmp20) gene through a mechanism involving the transcription factor, myocyte enhancer factor-2C, in ameloblast lineage cells. AB - Matrix metalloproteinase-20 (Mmp20) plays an essential role in amelogenesis during tooth development and is regulated by transforming growth factor-beta1 (TGF-beta1) in mouse ameloblast lineage cells (ALCs). The objective of this study was to explore the role of myocyte enhancer factor-2C (MEF2C), a key transcription factor in craniofacial development, in TGF-beta1-induced Mmp20 gene expression. We investigated Mmp20 expression in ALCs over-expressing MEF2C and in ALCs with MEF2C knocked down. We also analyzed activity of the Mmp20 promoter using a transient reporter gene-expression assay in cultured ALCs. Putative transcription factor-binding sites for MEF2C and TGF-beta1 on the Mmp20 promoter were analyzed with bioinformatics tools and examined using an electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP). The expression of Mmp20 was induced, in a dose-dependent manner, by MEF2C over expression, and TGF-beta1-induced Mmp20 expression was blocked by MEF2C knockdown in ALCs. There was a TGF-beta1/MEF2C-responsive region, including a putative MEF2 binding site, between base pairs -356 and -73 of the Mmp20 promoter. Mutation of the putative MEF2-binding site significantly reduced Mmp20 promoter activity upon activation with MEF2C or TGF-beta1. In conclusion, TGF-beta1-induced Mmp20 expression in ALCs was regulated through the MEF2-binding site on the Mmp20 promoter and thus mediated by the MEF2C signaling pathway. PMID- 24495129 TI - Individual lithium disilicate crowns in a full-arch, implant-supported rehabilitation: a clinical report. AB - This clinical report presents the clinical outcome of a maxillary full-arch implant-supported fixed rehabilitation with lithium disilicate reinforced glass ceramic monolithic crowns opposing a mandibular metal-acrylic implant-supported fixed rehabilitation in a 62-year-old woman. Eight implants were successfully placed (four maxillary, four mandibular), and no complications occurred in the postoperative or maintenance periods. Six months after delivery, the maxillary and mandibular prostheses were found to be clinically, biologically, and mechanically stable, and the patient was satisfied with the esthetics and her ability to function. Although the present indications for the use of lithium disilicate are still restricted to tooth-borne restorations, it is possible to successfully rehabilitate edentulous patients through implant-supported fixed prostheses using lithium disilicate reinforced glass ceramic monolithic crowns. PMID- 24495130 TI - First inverse electron-demand Diels-Alder methodology of 3-chloroindoles and methyl coumalate to carbazoles. AB - The first successful inverse electron-demand Diels-Alder has been demonstrated with the 2-pyrone methyl coumalate in conjunction with substituted indoles. Utilizing 1-alkyl-3-chloroindoles as the electron-rich dienophile efficiently generates carbazoles without the need for additional metal catalysts. Through a thermal, one-pot Diels-Alder/decarboxylation/elimination domino sequence, access to a class of 3-methylcarbazoles is rapidly generated with exclusive regiocontrol in up to 90% yield. PMID- 24495131 TI - Telomere shortening: a biological marker of sporadic colorectal cancer with normal expression of p53 and mismatch repair proteins. AB - Uncontrolled growth of cells, a main criterion of cancer, is merged with pathologic telomere length alteration. Thereby, measurement of telomere length could provide important information on cell proliferation and senescence in cancer tissues. Telomere shortening and its potential correlation with clinicopathological predictive markers in sporadic colorectal cancer (CRC) with normal expression of mismatch repair (MMR) proteins (including Mlh1, Msh2, Pms2, and Msh6) and normal p53 expression was completely explored. Relative telomere length (RTL) was quantitatively measured in a cohort of 164 samples (68 patients with sporadic CRC and 96 healthy unrelated controls). Our results demonstrated a significant shortening of RTL in the tumor-derived tissue of patients compared with the control group (p<0.001). Interestingly, significant telomere shortening was observed in tumors from an ascending and sigmoid colon in comparison with tumors located in a descending colon. Additionally, the telomere length was significantly shorter in those with lymph node metastasis (p<0.05). The results suggest that pathological telomere shortening, leading to genome instability and lymphatic transformation, could serve as a potential sensitive detection and also as a classification marker for facilitating diagnosis and management of CRC. PMID- 24495132 TI - Echinococcus cysts affecting oromaxillofacial structures--a systematic review. AB - OBJECTIVES: Cystic echinococcosis is a worldwide spread zoonosis and humans become accidental intermediate hosts. Any tissue can be affected. However, oromaxillofacial cystic echinococcosis is very uncommon and has never been studied systematically and no evidence-based treatment recommendations are available. Aim of this paper is to summarize the current knowledge and clinical experience with oromaxillofacial manifestations of cystic echinococcosis. MATERIALS AND METHODS: PubMed database was accessed with a comprehensive, complex search strategy. Medical Subject Headings terms, wildcard search, truncated search terms and Boolean operators were used. No filters to restrict the results were set. Two evaluators jointly assessed the results in terms of defined criteria. RESULTS: The search strategy retrieved 538 results in total. After evaluation 83 publications presenting 108 cases on oromaxillofacial cystic echinococcosis were included. Parotid gland, mandibular region and maxillary region were most commonly affected. Median patient age was 22 years (range 2.5 months to 81 years). Surgical treatment was performed in 97 cases. CONCLUSIONS: In cases of oromaxillofacial cystic echinococcosis a thorough evaluation of the patients for further cysts is essential. Therapeutic treatment options are surgical or minimally invasive intervention and drug treatment with benzimidazoles. The diagnosis can be difficult and often require a multidisciplinary approach. PMID- 24495133 TI - Silicon monoxide at 1 atm and elevated pressures: crystalline or amorphous? AB - The absence of a crystalline SiO phase under ordinary conditions is an anomaly in the sequence of group 14 monoxides. We explore theoretically ordered ground-state and amorphous structures for SiO at P = 1 atm, and crystalline phases also at pressures up to 200 GPa. Several competitive ground-state P = 1 atm structures are found, perforce with Si-Si bonds, and possessing Si-O-Si bridges similar to those in silica (SiO2) polymorphs. The most stable of these static structures is enthalpically just a little more stable than a calculated random bond model of amorphous SiO. In that model we find no segregation into regions of amorphous Si and amorphous SiO2. The P = 1 atm structures are all semiconducting. As the pressure is increased, intriguing new crystalline structures evolve, incorporating Si triangular nets or strips and stishovite-like regions. A heat of formation of crystalline SiO is computed; it is found to be the most negative of all the group 14 monoxides. Yet, given the stability of SiO2, the disproportionation 2SiO(s) -> Si(s)+SiO2(s) is exothermic, falling right into the series of group 14 monoxides, and ranging from a highly negative DeltaH of disproportionation for CO to highly positive for PbO. There is no major change in the heat of disproportionation with pressure, i.e., no range of stability of SiO with respect to SiO2. The high-pressure SiO phases are metallic. PMID- 24495134 TI - Complete mitochondrial genome of the guppy (Poecilia reticulata). AB - The guppy (Poecilia reticulata), a member of the Poeciliidae family, is one of the most popular aquarium fish. Here, we reported the complete mitochondrial genome of P. reticulata. The genome is 16,570 bp in length, including 13 protein coding genes, 22 transfer RNA genes and 2 ribosomal RNA genes. The structure of non-coding control region was also analyzed. Comparing the mitochondrial genome of P. reticulata with its congener Xiphophorus maculatus revealed the high sequence similarity and the identical gene structure. The complete mitochondrial genome of the guppy would help study the evolution of Poeciliidae family. PMID- 24495135 TI - The complete mitochondrial genome of Celastrina hersilia (Lepidoptera: Lycaenidae). AB - The complete mitochondrial genome of Celastrina hersilia (Lepidoptera: Lycaenidae) is determined in this work. The mitochondrial genome is 15,304 bp in length, which contains typical 13 protein-coding genes (PCGs), 22 transfer RNA genes (tRNAs), 2 ribosomal RNA genes and 1 non-coding A + T-rich region. All PCGs are initiated by ATA or ATT codons, except for COI, which uses CGA as a start codon. Four PCGs (COI, COII, ND5, and ND4) terminate with incomplete termination codons TA or T, while the others use TAA as stop codons. Most of the tRNA genes can be folded into a typical cloverleaf structure. The A + T-rich region is 370 bp in length, which contains several features common to the other lepidopteran species. PMID- 24495136 TI - The complete mitochondrial genome of Paracheirodon axelrodi (Characiformes:Characidae:Paracheirodon). AB - The complete mitochondrial genome of Paracheirodon axelrodi was obtained by the traditional polymerase chain reaction method. The mitogenome was determined to be a 17,100 bp long circular molecule. It contains the typical complement of 13 protein-coding genes, 2 rRNAs and 22 tRNAs. This is first report on the complete mitogenome sequence of P. axelrodi. PMID- 24495137 TI - Complete mitochondrial genome sequence of the plant bug Adelphocoris fasciaticollis (Hemiptera: Heteroptera: Miridae). AB - The mitochondrial genome of Adelphocoris fasciaticollis Reuter, an important pest plant bug, is a typical circular DNA molecule of 15,434 bp with 37 genes and 77.4% A + T content. Twenty-three genes are located on the J-strand, the remaining being oriented on the N-strand. Gene order is identical to that of the typical arrangement of insects and other plant bugs. This genome is highly economized with 54 overlapped nucleotides between neighboring genes in 12 locations. All protein-coding genes initiate with ATN codons. All of the 22 tRNAs, ranging from 62 to 71 bp, have the clover-leaf structure. Two tRNAs, trnK and trnS1, use the non-standard anticodons TTT and TCT. The sizes of the large and small ribosomal RNA genes are 1229 and 793 bp, respectively. The control region is 922 bp in length with 78.2% A + T content and includes two 30-bp repeat units and two 35-bp repeat units. PMID- 24495138 TI - The complete mitochondrial genome of Sus cebifrons (Sus, Suidae). AB - In this work, we report the complete mitochondrial genome sequence of Sus cebifrons (Visayan warty pig). The total length of the mitogenome was 16,475 bp, and its overall base composition was estimated to be 35.0% for A, 25.8% for T, 26.2% for C and 13.0% for G, indicating an A-T (60.8%)-rich feature in Sus cebifrons mitogenome. It contained the typical structure of 13 protein-coding genes, 2 ribosomal RNA genes, 22 transfer RNA genes and a noncoding control region (D-loop region). The arrangement of these genes was the same as that found in other pigs. The complete mitochondrial genome sequence of the Sus cebifrons would provide new genetic resources for pig domestication study. PMID- 24495139 TI - The complete mitochondrial genome of Assamese Macaques (Macaca assamensis). AB - The complete mitochondrial genome of Assamese macaques (Macaca assamensis) was sequenced in this study. The genome is 16,542 bp long, consisting of 13 protein coding genes (PCGs), 2 ribosomal RNA genes, 22 transfer RNA genes and 2 non coding areas. Eight PCGs (COI, COII, ATP6, COIII, ND4L, ND4, ND6, CYTB) initiate with the start codon ATG and another two genes (ND1, ATP8) use GTG, while ND2, ND3 and ND5 start with ATT, ATC and ATA, respectively. Five genes (COII, ATP8, ATP6, ND4L and ND5) use the complete stop codon TAA, whereas four genes have incomplete stop codons, TA- (COIII) and T- - (ND3, ND4, CYTB), while others use standard canonical TAA as their termination codons. The largest non-coding control region with the length of 1091 bp is located between the tRNA-Pro and tRNA-Phe genes. PMID- 24495140 TI - The complete mitochondrial genome of Yunnan black goat (Capra hircus). AB - Yunnan black goat (Capra hircus) is one of the famous native goat breed in China. In this study, the complete nucleotide sequence of Yunnan black goat mitochondrial genome was determined for the first time. Sequence analysis showed that the genome structure was in typical with other vertebra animals. It contained 22 tRNA genes, 2 ribosomal RNA genes, 13 protein-coding genes and 1 control region (D-loop region). The base composition was A (33.6%), G (13.1%), C (26.0%) and T (27.3%), so the percentage of A and T (60.9%) was higher than that of G and C. PMID- 24495141 TI - Amyloid fibril formation by the chain B subunit of monellin occurs by a nucleation-dependent polymerization mechanism. AB - Proteins possessing very different structures, or even no structure, form amyloid fibrils that are very similar in internal structure. This suggests that the mechanisms by which amyloid fibrils form might be very similar, irrespective of whether the fibrils are associated with disease or with normal cellular function, or even if they have no physiological importance. In this context, it is important to have a model protein system whose amyloid fibril formation is robust in its reproducibility, which can reveal the fundamentals of the amyloid fibril reaction that may be applicable to all proteins. In this study, the aggregation mechanism of amyloid fibril formation by chain B of the heterodimeric protein monellin has been elucidated in detail. It is shown that the aggregation reaction meets all the stringent kinetic criteria of a homogeneous nucleation-dependent polymerization mechanism, which is valid over a wide range of protein concentrations. Quantitative analyses of the kinetic data using one approach based on features of the entire kinetic curve, and another based on only the initial rate of aggregation, indicate that the thermodynamic nucleus is a dimer. Spherical oligomers are observed by atomic force microscopy to form transiently early during fibril formation but are off-pathway to the direct fibril formation pathway. It is shown that amyloid fibril formation can be prevented by the addition of chain A of monellin at early stages of chain B aggregation: the two free chains combine to form native monellin, which leads to the dissociation of early aggregates. PMID- 24495142 TI - Which technique is better for detection of right-to-left shunt in patients with patent foramen ovale: comparing contrast transthoracic echocardiography with contrast transesophageal echocardiography. AB - BACKGROUND: At present there is no consensus on which technique is more suitable for the detection of right-to-left shunt (RLS) in patients with patent foramen ovale (PFO). The aim of study was to compare the efficacy of contrast transthoracic echocardiography (cTTE) and contrast transesophageal echocardiography (cTEE) in the detection of RLS. METHODS: A prospective study was undertaken in 29 patients with PFO. Both cTTE with harmonic imaging modality and cTEE with fundamental imaging modality were performed for all the patients. The severity of RLS were semiquantitatively assessed with a four-level grade system by scaling the numbers of microbubbles (MBs) in the left atrium after complete opacification of the right atrium within the first 3 cardiac cycles. Level 1 represents no MBs, indicating no RLS. Level 2, <=10 MBs, indicating mild RLS. Level 3, 11-30 MBs, indicating moderate RLS and Level 4, >30 MBs, indicating severe RLS. RESULTS: Contrast TTE demonstrated significantly higher sensitivity for detection of RLS than cTEE (86% vs. 56%, P < 0.05). For cTTE, there were 4, 1, 5, and 19 cases determined at levels 1, 2, 3, and 4, respectively, whereas for the same group of patients 13, 2, 6, and 7 cases were identified by cTEE at levels 1, 2, 3, and 4, respectively. The severity of RLS detected by cTTE was significantly greater than that by cTEE (P < 0.01). CONCLUSIONS: Contrast TTE is more efficacious in the detection of RLS than cTEE. The former can be used as an alternative to the latter in clinical practice. PMID- 24495143 TI - A novel HLA-B*18:80 allele identified by SBT typing in an Italian bone marrow volunteer donor. AB - A novel allele, officially named B*18:80, was detected in a Caucasoid individual by polymerase chain reaction-sequence-specific primers and SBT. The new allele differs from B*18:01:01 at two nucleotidic positions in codon 24 at exon 2. PMID- 24495144 TI - Covalent functionalized self-assembled lipo-polymerosome bearing amphotericin B for better management of leishmaniasis and its toxicity evaluation. AB - Amphotericin B remains the preferred choice for leishmanial infection, but it has limited clinical applications due to substantial dose limiting toxicities. In the present work, AmB has been formulated in lipo-polymerosome (L-Psome) by spontaneous self-assembly of synthesized glycol chitosan-stearic acid copolymer. The optimized L-Psome formulation with vesicle size of 243.5 +/- 17.9 nm, PDI of 0.168 +/- 0.08 and zeta potential of (+) 27.15 +/- 0.46 mV with 25.59 +/- 0.87% AmB loading was obtained. The field emission scanning electron microscopy (FESEM) and high resolution transmission electron microscopy (HRTEM) images suggest nearly spherical morphology of L-Psome. An in vitro study showed comparatively sustained AmB release (66.082 +/- 1.73% within 24 h) and high plasma stability compared to commercial Ambisome and Fungizone, where glycol chitosan content was found to be efficient in preventing L-Psome destabilization in the presence of plasma protein. In vitro and in vivo toxicity studies revealed less toxicity of AmB-L-Psome compared to commercialized Fungizone and Ambisome favored by monomeric form of AmB within L-Psome, observed by UV-visible spectroscopy. Experimental results of in vitro (macrophage amastigote system) and in vivo (Leishmania donovani infected hamsters) illustrated the efficacy of AmB-L-Psome to augment effective antileishmanial properties supported by upregulation of Th-1 cytokines (TNF-alpha, IL-12 and IFN-gamma) and inducible nitric oxide synthase, and downregulation of Th-2 cytokines (TGF-beta, IL-10 and IL-4), measured by quantitative mRNA analysis by real time PCR (RT-PCR). Conclusively, developed L Psome system could be a viable alternative to the current less stable, toxic commercial formulations and developed as a highly efficacious drug delivery system. PMID- 24495145 TI - Strengthening safety compliance in nuclear power operations: a role-based approach. AB - Safety compliance is of paramount importance in guaranteeing the safe running of nuclear power plants. However, it depends mostly on procedures that do not always involve the safest outcomes. This article introduces an empirical model based on the organizational role theory to analyze the influence of legitimate sources of expectations (procedures formalization and leadership) on workers' compliance behaviors. The sample was composed of 495 employees from two Spanish nuclear power plants. Structural equation analysis showed that, in spite of some problematic effects of proceduralization (such as role conflict and role ambiguity), procedure formalization along with an empowering leadership style lead to safety compliance by clarifying a worker's role in safety. Implications of these findings for safety research are outlined, as well as their practical implications. PMID- 24495147 TI - Superior antibacterial activity of zinc oxide/graphene oxide composites originating from high zinc concentration localized around bacteria. AB - New materials with good antibacterial activity and less toxicity to other species attract numerous research interest. Taking advantage of zinc oxide (ZnO) and graphene oxide (GO), the ZnO/GO composites were prepared by a facile one-pot reaction to achieve superior antibacterial properties without damaging other species. In the composites, ZnO nanoparticles (NPs), with a size of about 4 nm, homogeneously anchored onto GO sheets. The typical bacterium Escherichia coli and HeLa cell were used to evaluate the antibacterial activity and cytotoxicity of the ZnO/GO composites, respectively. The synergistic effects of GO and ZnO NPs led to the superior antibacterial activity of the composites. GO helped the dispersion of ZnO NPs, slowed the dissolution of ZnO, acted as the storage site for the dissolved zinc ions, and enabled the intimate contact of E. coli with ZnO NPs and zinc ions as well. The close contact enhanced the local zinc concentration pitting on the bacterial membrane and the permeability of the bacterial membrane and thus induced bacterial death. In addition, the ZnO/GO composites were found to be much less toxic to HeLa cells, compared to the equivalent concentration of ZnO NPs in the composites. The results indicate that the ZnO/GO composites are promising disinfection materials to be used in surface coatings on various substrates to effectively inhibit bacterial growth, propagation, and survival in medical devices. PMID- 24495146 TI - Periodontal disease and dental caries among Indigenous Australians living in the Northern Territory, Australia. AB - BACKGROUND: The aim of this study was to describe the caries experience and severity of periodontal disease in a convenience sample of Indigenous Australians living in the Northern Territory. METHODS: Data were gathered via self-reported questionnaire and dental examination by calibrated examiners. Socio-demographic characteristics were compared with data from the 2011 Australian census while prevalence of periodontal disease and dental caries was compared against weighted estimates from the National Survey of Adult Oral Health 2004-2006. In each comparison, non-overlapping 95% confidence intervals inferred a significant difference. Within-study comparisons were assessed via chi-square, t-tests and analysis of variance for differences among study participants. RESULTS: A total of 312 Indigenous Australian participants provided completed data (average age 39.5 +/- 10.5 years, 174 males). Of these, 87.5% were confirmed periodontitis cases; 3.5 times that of national-level estimates. The experience of untreated caries was five times that of national estimates (mean decayed 3.0 versus 0.6). Periodontitis case status was positively associated with older age, male gender and presence of diabetes. CONCLUSIONS: Periodontal disease and untreated caries were significantly more prevalent in this sample of Indigenous Australians compared to the general Australian population. The prevalence of periodontal disease was markedly higher than that previously described for Indigenous Australians. PMID- 24495148 TI - Experimental evolution of parasitoid infectivity on symbiont-protected hosts leads to the emergence of genotype specificity. AB - Host-parasitoid interactions may lead to strong reciprocal selection for traits involved in host defense and parasitoid counterdefense. In aphids, individuals harboring the facultative bacterial endosymbiont, Hamiltonella defensa, exhibit enhanced resistance to parasitoid wasps. We used an experimental evolution approach to investigate the ability of the parasitoid wasp, Lysiphlebus fabarum, to adapt to the presence of H. defensa in its aphid host Aphis fabae. Sexual populations of the parasitoid were exposed for 11 generations to a single clone of A. fabae, either free of H. defensa or harboring artificial infections with three different isolates of H. defensa. Parasitoids adapted rapidly to the presence of H. defensa in their hosts, but this adaptation was in part specific to the symbiont isolate they were evolving against and did not result in an improved infectivity on all symbiont-protected hosts. Comparisons of life-history traits among the evolved lines of parasitoids did not reveal any evidence for costs of adaptation to H. defensa in terms of correlated responses that could constrain such adaptation. These results show that parasitoids readily evolve counter-adaptations to heritable defensive symbionts of their hosts, but that different symbiont strains impose different evolutionary challenges. The symbionts thus mediate the host-parasite interaction by inducing line-by-line genetic specificity. PMID- 24495149 TI - Pharmacokinetics and safety of resveratrol derivatives in humans after oral administration of melinjo (Gnetum gnemon L.) seed extract powder. AB - Fruits and seeds of melinjo (Gnetum gnemon L.) are resveratrol derivative-rich materials. Pharmacokinetics of resveratrol derivatives in healthy volunteers after oral administration of 1000 mg of melinjo seed extract (MSE) powder were assessed and compared with those after oral dosing of trans-resveratrol (tRV) powder containing 4.8 mg of tRV only, equivalent to the content in 1000 mg MSE powder. Plasma tRV concentrations with enzymatic hydrolysis were maintained over 24 h, with a tmax of 12 h and a mean residence time (MRT) of 14 h, 5 and 2 times higher than those for tRV powder intake, respectively. Gnetin C, a resveratrol dimer, with hydrolysis was maintained in plasma for >96 h with a 36 h MRT. With repeated doses once daily for 28 days, plasma tRV and gnetin C concentrations with hydrolysis were in good agreement with the theoretical curves. MSE powder was well tolerated up to the oral dosing of 5000 mg with no serious adverse events. PMID- 24495150 TI - Formation of a covalent bond between a polyoxometalate and silica covered by SiH moieties. AB - Dehydroxylated silica was modified by grafting reaction of SiHMe2 groups. The resulting material was fully characterized by various methods including infrared and one- and two-dimensional solid-state NMR. This material can further react with dehydrated polyoxometalates (POMs), leading to the formation of a covalent POM-silica bond. In the case of H4PVMo11O40, hydrogen released during the grafting reaction reduces the POM. This leads to the formation of two surface species, which can be reoxidized in presence of oxygen. In the case of H3PW12O40, no reduction is observed. In both cases, (29)Si solid-state NMR shows that the POM-silica bond is covalent, contrary to what was observed in homogeneous conditions. PMID- 24495152 TI - Emerging tools for synthetic biology in plants. PMID- 24495151 TI - Hybridization chain reaction amplification of microRNA detection with a tetrahedral DNA nanostructure-based electrochemical biosensor. AB - There remains a great challenge in the sensitive detection of microRNA because of the short length and low abundance of microRNAs in cells. Here, we have demonstrated an ultrasensitive detection platform for microRNA by combining the tetrahedral DNA nanostructure probes and hybridization chain reaction (HCR) amplification. The detection limits for DNA and microRNA are 100 aM and 10 aM (corresponding to 600 microRNAs in a 100 MUL sample), respectively. Compared to the widely used supersandwich amplification, the detection limits are improved by 3 orders of magnitude. The uncontrolled surface immobilization and consumption of target molecules that limit the amplification efficiency of supersandwich are eliminated in our platform. Taking advantage of DNA nanotechnology, we employed three-dimensional tetrahedral DNA nanostructure as the scaffold to immobilize DNA recognition probes to increase the reactivity and accessibility, while DNA nanowire tentacles are used for efficient signal amplification by capturing multiple catalytic enzymes in a highly ordered way. The synergetic effect of DNA tetrahedron and nanowire tentacles have proven to greatly improve sensitivity for both DNA and microRNA detection. PMID- 24495153 TI - Functional integration of multiple genes into the genome of the oleaginous yeast Rhodosporidium toruloides. AB - The basidiomycetous yeast Rhodosporidium toruloides represents an excellent producer for microbial lipids and carotenoids. However, further rational engineering of this unconventional yeast remains challenging partially because of the absence of efficient and reliable transformation method. In this study, we developed an Agrobacterium-mediated transformation (ATMT) protocol for effective gene integration into the R. toruloides genome. Both haploid and diploid strains were successfully modified, and the integration was confirmed by colony PCR, Western blot analysis and genome walking. We further demonstrated that multiple genes could be integrated by consecutive ATMT, leading to engineered strains simultaneously resistant to multiple antibiotics. Our results provided a practical method for functional integration and expression of exogenous genes in R. toruloides, which should facilitate the development of genetic tools and the construction of superior strains to produce biofuel molecules and biochemicals. PMID- 24495154 TI - Subtotal resection of facial nerve schwannoma is not safe in the long run. AB - CONCLUSIONS: Subtotal resection of facial nerve schwannoma (FNS) could obtain favorable facial nerve function recovery, but has a high recurrence rate in the long run. Subtotal resection with about 95% tumor resected could be considered in the elderly with good facial nerve function, but is not recommended for younger patients. Subtotal resection with about 70-80% tumor resected should be replaced by complete tumor removal and nerve grafting. OBJECTIVES: To present long-term follow-up results of subtotal resection of FNS and discuss the indications for subtotal resection. METHODS: We performed subtotal resection of FNS in 15 cases and they were followed up for 7 years on average. RESULTS: In all, 93.3% of cases finally gained normal or near-normal facial nerve function (House-Brackmann (HB) grade I or II) and one case maintained grade III. Tumor recurrence or regrowth was noted in four cases (26.7%) during follow-up. Recurrence was observed in 10% of cases who had about 95% tumor resected and in 60% of cases who had 70-80% tumor resected. PMID- 24495155 TI - Quantum dot thermometry evaluation of geometry dependent heating efficiency in gold nanoparticles. AB - Quantum dot based thermometry, in combination with double beam confocal microscopy, was used to investigate the absorption/heating efficiency of gold nanoparticles with different morphologies (nanorods, nanocages, nanoshells, and nanostars), all of them with an intense localized surface plasmon resonance within the first biological window, at around 808 nm. The heating efficiency was found to be strongly dependent on the geometry of the nanostructure, with the largest values found for gold nanorods and long-edge gold nanostars, both of them with heating efficiencies close to 100%. Gold nanorods and nanocages were found to have the largest absorption cross section per unit mass among all the studied geometries, emerging as optimum photothermal agents with minimum metal loading for biosystems. PMID- 24495156 TI - The benefits for children's nurses of overseas placements: where is the evidence? AB - Overseas placements are presumed to provide students with experiences to enhance their cultural competence and to give them insights into other healthcare systems. However, the literature has not focused on what students of children's nursing might gain from an overseas placement. This paper is a report of a literature review (2003-2011) and our own student evaluation, both aimed at shedding new light on this important opportunity for learning for children's nurses. The literature review indicates that current research does not address the learning from overseas placements for children's nurses. Our student evaluation suggests children's nursing students are able to explore the position of children in the host culture and to place this in a healthcare context. Students also reported that they adhered to UK scope of student practice when delivering care to children on overseas placement. These placements provide a valuable learning experience for children's nurses. However, consideration in the shorter term is required to address issues of equity. Looking forward, further large scale studies are required to determine the long term effects of such experience on the health outcomes for children, and development of children's nurses and children's nursing globally. PMID- 24495157 TI - Fracture strength and nanoleakage of weakened roots reconstructed using relined glass fiber-reinforced dowels combined with a novel prefabricated core system. AB - PURPOSE: The aim of this study was to evaluate fracture strength and nanoleakage of endodontically treated weakened teeth after being restored with relined glass fiber-reinforced dowels and two types of cores. MATERIALS AND METHODS: Sixty sound human decoronated and endodontically treated teeth were embedded in epoxy resin blocks, then divided into three groups (n = 20) according to the method of root reconstruction. Group 1 (control): nonweakened roots were restored with glass fiber-reinforced dowels (UNIC); group 2: weakened roots restored with glass fiber-reinforced dowels relined with composite resin; group 3: weakened roots restored with glass fiber-reinforced dowels and a thick layer of luting cement. Dowels were cemented using Corposit, a dual-cured adhesive resin cement, then each group was assigned into two subgroups (n = 10) according to the type of core used; subgroup a: custom-made core using the same luting cement, subgroup b: prefabricated glass fiber-reinforced core (UNIC). Half the specimens of each subgroup were individually mounted at 45 degrees angles and statically compressed until fracture at a 0.5 mm/min crosshead speed with a 5 kN load cell. The type of failure was assessed using a magnification lens. The other half of the specimens were removed from the block, placed in silver nitrate solution for 24 hours followed by photo developer for 8 hours, then examined using environmental scanning electron microscope/energy dispersive analytical X-ray for nanoleakage evaluation. Data were statistically analyzed. RESULTS: The nonweakened group recorded the highest fracture strength values. The composite relined group showed significantly higher fracture strength values than the cement group. The prefabricated core yielded higher fracture strength values than the custom-made core. All groups showed a degree of nanoleakage, with higher scores recorded for the composite group. CONCLUSIONS: The fracture resistance of wide root canals can be improved by using glass fiber-reinforced dowels relined with composite resin as an alternative to increasing the thickness of luting cement; however, the percentage nanoleakage would increase. On the other hand, the recently introduced prefabricated glass fiber-reinforced core can be considered a promising technique, but further investigations are necessary. PMID- 24495158 TI - Health status and hypoglycaemia with insulin degludec versus insulin glargine: a 2-year trial in insulin-naive patients with type 2 diabetes. AB - Insulin degludec (IDeg) is a new basal insulin with an ultra-long and stable glucose-lowering effect. We compared once-daily IDeg and insulin glargine (IGlar), both in combination with metformin +/- dipeptidyl peptidase-4 inhibitors, in a 52-week, open-label, treat-to-target trial in patients with type 2 diabetes followed by a 52-week extension trial in which subjects [n = 725/1030 (70.4%)] maintained their initial randomised treatment. Health status was assessed at baseline and 105 weeks using the Short Form-36 (SF-36 v2) questionnaire. SF-36 scores were analysed (ITT population) using anova, with adjustments for covariates. At 105 weeks, the overall physical component score was significantly better with IDeg versus IGlar [treatment contrast (TC): 1.1 (0.1; 2.1)95% CI , p < 0.05]. This was largely because of significantly better physical functioning [TC: 1.1 (0.0; 2.3)95% CI , p < 0.05] and bodily pain sub domain scores [TC: 1.5 (0.2; 2.9)95% CI , p < 0.05]. Improvements in health status with IDeg compared to IGlar were maintained after 2 years. PMID- 24495160 TI - Catalytic cycloaddition of 2-methyleneaziridines with 1,1-dicyanoalkenes. AB - 2-Methyleneaziridine are a good substrate for the catalytic synthesis of cyclopentylidenamines via a [3 + 2] cycloaddition of 1,1-dicyanoalkenes using Bu2SnI2 as an effective catalyst. A C-attack from 2-methyleneaziridine yielded the desired products. PMID- 24495159 TI - The bone marrow niche, stem cells, and leukemia: impact of drugs, chemicals, and the environment. AB - Hematopoietic stem cells (HSCs) are a unique population of somatic stem cells that can both self-renew for long-term reconstitution of HSCs and differentiate into hematopoietic progenitor cells (HPCs), which in turn give rise, in a hierarchical manner, to the entire myeloid and lymphoid lineages. The differentiation and maturation of these lineages occurs in the bone marrow (BM) niche, a microenvironment that regulates self-renewal, survival, differentiation, and proliferation, with interactions among signaling pathways in the HSCs and the niche required to establish and maintain homeostasis. The accumulation of genetic mutations and cytogenetic abnormalities within cells of the partially differentiated myeloid lineage, particularly as a result of exposure to benzene or cytotoxic anticancer drugs, can give rise to malignancies like acute myeloid leukemia and myelodysplastic syndrome. Better understanding of the mechanisms driving these malignancies and susceptibility factors, both within HPCs and cells within the BM niche, may lead to the development of strategies for prevention of occupational and cancer therapy-induced disease. PMID- 24495161 TI - Flow cytometric characterization and clinical outcome of CD4+ T-cell lymphoma in dogs: 67 cases. AB - BACKGROUND: Canine T-cell lymphoma (TCL) is conventionally considered an aggressive disease, but some forms are histologically and clinically indolent. CD4 TCL is reported to be the most common subtype of TCL. We assessed flow cytometric characteristics, histologic features when available, and clinical outcomes of CD4+ TCL to determine if flow cytometry can be used to subclassify this group of lymphomas. OBJECTIVE: To test the hypothesis that canine CD4+ T cell lymphoma (TCL) is a homogeneous group of lymphomas with an aggressive clinical course. ANIMALS: Sixty-seven dogs diagnosed with CD4+ TCL by flow cytometry and treated at 1 of 3 oncology referral clinics. METHODS: Retrospective multivariable analysis of outcome in canine CD4+ TCL including patient characteristics, treatment, and flow cytometric features. RESULTS: The majority of CD4+ TCL were CD45+, expressed low class II MHC, and exhibited an aggressive clinical course independent of treatment regimen (median survival, 159 days). Histologically, CD4+ TCL were classified as lymphoblastic or peripheral T cell. Size of the neoplastic lymphocytes had a modest effect on both PFI and survival in this group. A small number of CD4+ TCL were CD45- and class II MHC high, and exhibited an apparently more indolent clinical course (median survival not yet reached). CONCLUSIONS AND CLINICAL IMPORTANCE: Although the majority of CD4+ TCL in dogs had uniform clinical and flow cytometric features and an aggressive clinical course, a subset had a unique immunophenotype that predicts significantly longer survival. This finding strengthens the utility of flow cytometry to aid in the stratification of canine lymphoma. PMID- 24495162 TI - Clinical factors and self-perceived oral health. AB - Self-perceived oral health is affected not only by awareness of the clinical status but also by comparisons with people of a similar age. This study explored the relative contributions of clinical variables assessing caries, periodontal status, and prosthetic status to self-perceived oral health within two age groups. Data of 891 adults (35-44 yr of age) and 760 older people (65-74 yr of age) from the Fourth German Oral Health Study (DMS IV, 2005) were evaluated. Self perceived oral health was obtained from questionnaires. Numbers of decayed, filled, and unreplaced teeth, mean attachment loss, bleeding on probing (BOP), the presence of a fixed denture, and the presence of a removable denture were assessed. Multinomial logistic regression models were developed for both age groups, separately, using stepwise methods. For adults, unreplaced teeth, filled teeth, decayed teeth, the presence of a removable denture, and mean attachment loss were added to the final model. For older people, the presence of a removable denture, unreplaced teeth, decayed teeth, mean attachment loss, filled teeth, and BOP were included in the final model. Awareness of the relative contributions of clinical variables to self-perceived oral health is important for obtaining a clearer understanding of patients' subjective and objective self-perceptions of oral health. PMID- 24495163 TI - Genomics education for the public: perspectives of genomic researchers and ELSI advisors. AB - AIMS: For more than two decades genomic education of the public has been a significant challenge. As genomic information becomes integrated into daily life and routine clinical care, the need for public education is even more critical. We conducted a pilot study to learn how genomic researchers and ethical, legal, and social implications advisors who were affiliated with large-scale genomic variation studies have approached the issue of educating the public about genomics. METHODS/RESULTS: Semi-structured telephone interviews were conducted with researchers and advisors associated with the SNP/HAPMAP studies and the Cancer Genome Atlas Study. Respondents described approach(es) associated with educating the public about their study. Interviews were audio-recorded, transcribed, coded, and analyzed by team review. Although few respondents described formal educational efforts, most provided recommendations for what should/could be done, emphasizing the need for an overarching entity(s) to take responsibility to lead the effort to educate the public. Opposing views were described related to: who this should be; the overall goal of the educational effort; and the educational approach. Four thematic areas emerged: What is the rationale for educating the public about genomics?; Who is the audience?; Who should be responsible for this effort?; and What should the content be? Policy issues associated with these themes included the need to agree on philosophical framework(s) to guide the rationale, content, and target audiences for education programs; coordinate previous/ongoing educational efforts; and develop a centralized knowledge base. Suggestions for next steps are presented. CONCLUSION: A complex interplay of philosophical, professional, and cultural issues can create impediments to genomic education of the public. Many challenges, however, can be addressed by agreement on a guiding philosophical framework(s) and identification of a responsible entity(s) to provide leadership for developing/overseeing an appropriate infrastructure to support the coordination/integration/sharing and evaluation of educational efforts, benefiting consumers and professionals. PMID- 24495164 TI - Optimized reverse micelle surfactant system for high-resolution NMR spectroscopy of encapsulated proteins and nucleic acids dissolved in low viscosity fluids. AB - An optimized reverse micelle surfactant system has been developed for solution nuclear magnetic resonance studies of encapsulated proteins and nucleic acids dissolved in low viscosity fluids. Comprising the nonionic 1-decanoyl-rac glycerol and the zwitterionic lauryldimethylamine-N-oxide (10MAG/LDAO), this mixture is shown to efficiently encapsulate a diverse set of proteins and nucleic acids. Chemical shift analyses of these systems show that high structural fidelity is achieved upon encapsulation. The 10MAG/LDAO surfactant system reduces the molecular reorientation time for encapsulated macromolecules larger than ~20 kDa leading to improved overall NMR performance. The 10MAG/LDAO system can also be used for solution NMR studies of lipid-modified proteins. New and efficient strategies for optimization of encapsulation conditions are described. 10MAG/LDAO performs well in both the low viscosity pentane and ultralow viscosity liquid ethane and therefore will serve as a general surfactant system for initiating solution NMR studies of proteins and nucleic acids. PMID- 24495165 TI - Transient improvements in fixational stability in strabismic amblyopes following bifoveal fixation and reduced interocular suppression. AB - PURPOSE: To test the hypothesis that fixational stability of the amblyopic eye in strabismics will improve when viewing provides both bifoveal fixation and reduced inter-ocular suppression by reducing the contrast to the fellow eye. METHODS: Seven strabismic amblyopes (Age: 29.2 +/- 9 years; five esotropes and two exotropes) showing clinical characteristics of central suppression were recruited. Interocular suppression was measured by a global motion task. For each participant, a balance point was determined which defined contrast levels for each eye where binocular combination was optimal (interocular suppression minimal). When the balance point could not be determined, this participant was excluded. Bifoveal fixation was established by ocular alignment using a haploscope. Participants dichoptically viewed similar targets (a cross of 2.3 degrees surrounded by a square of 11.3 degrees ) at 40 cm. Target contrasts presented to each eye were either high contrast (100% to both eyes) or balanced contrast (attenuated contrast in the fellow fixing eye). Fixation stability was measured over a 5 min period and quantified using bivariate contour ellipse areas in four different binocular conditions; unaligned/high contrast, unaligned/balance point, aligned/high contrast and aligned/balance point. Fixation stability was also measured in six control subjects (Age: 25.3 +/- 4 years). RESULTS: Bifoveal fixation in the strabismics was transient (58.15 +/- 15.7 s). Accordingly, fixational stability was analysed over the first 30 s using repeated measures anova. Post hoc analysis revealed that for the amblyopic subjects, the fixational stability of the amblyopic eye was significantly improved in aligned/high contrast (p = 0.01) and aligned/balance point (p < 0.01) conditions. Fixational stability of the fellow fixing eye was not different statistically across conditions. Bivariate contour ellipse areas of the amblyopic and fellow fixing eyes were therefore averaged for each amblyope in the four conditions and compared with normals. This averaged bivariate contour ellipse area was significantly greater (reduced fixational stability, p = 0.04) in amblyopes compared to controls except in the case of aligned and balanced contrast (aligned/balance point, p = 0.19). CONCLUSION: Fixation stability in the amblyopic eye appears to improve with bifoveal fixation and reduced interocular suppression. However, once initiated, bifoveal fixation is transient with the strabismic eye drifting away from foveal alignment, thereby increasing the angle of strabismus. PMID- 24495166 TI - Vitamin D intake and cardiometabolic risk factors in adolescents. AB - BACKGROUND: A growing body of research suggests that vitamin D might play an important role in overall health. No data exist on vitamin D intake for the Azorean adolescent population. The purpose of this study was to assess vitamin D intake and investigate a possible association between vitamin D intake and cardiometabolic risk factors in Azorean adolescents. METHODS: A cross-sectional school-based study was conducted on 496 adolescents (288 girls) aged 15-18 years from the Azorean Islands, Portugal. Anthropometric measurements (waist circumference and height), blood pressure (systolic), and plasma biomarkers [fasting glucose, insulin, total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TGs)] were measured to assess metabolic risk. Homeostasis model assessment (HOMA), TC-to-HDL-C ratio, and waist-to-height ratio were calculated. For each of these variables, a Z-score was computed by age and sex. A metabolic risk score was constructed by summing the Z-scores of all individual risk factors. High risk was considered when the individual had >=1 standard deviation (SD) of this score. Vitamin D intake was assessed with a semiquantitative food frequency questionnaire. Participants were classified into quartiles of vitamin D intake. Logistic regression was used to determine odds ratios for high cardiometabolic risk scores after adjusting for total energy intake, pubertal stage, fat mass percentage, and cardiorespiratory fitness. RESULTS: Mean (SD) vitamin D intake was 5.8 (6.5) MUg/day, and 9.1% of Azorean adolescents achieved the estimated average requirement of vitamin D (10 MUg/day or 400 IU). Logistic regression showed that the odds ratio for a high cardiometabolic risk score was 3.35 [95% confidence interval (CI) 1.28-8.75] for adolescents in the lowest vitamin D intake quartile in comparison with those in the highest vitamin D intake quartile, even after adjustment for confounders. CONCLUSION: A lower level of vitamin D intake was associated with worse metabolic profile among Azorean adolescents. PMID- 24495167 TI - Calibration using constrained smoothing with applications to mass spectrometry data. AB - Linear regressions are commonly used to calibrate the signal measurements in proteomic analysis by mass spectrometry. However, with or without a monotone (e.g., log) transformation, data from such functional proteomic experiments are not necessarily linear or even monotone functions of protein (or peptide) concentration except over a very restricted range. A computationally efficient spline procedure improves upon linear regression. However, mass spectrometry data are not necessarily homoscedastic; more often the variation of measured concentrations increases disproportionately near the boundaries of the instruments measurement capability (dynamic range), that is, the upper and lower limits of quantitation. These calibration difficulties exist with other applications of mass spectrometry as well as with other broad-scale calibrations. Therefore the method proposed here uses a functional data approach to define the calibration curve and also the limits of quantitation under the two assumptions: (i) that the variance is a bounded, convex function of concentration; and (ii) that the calibration curve itself is monotone at least between the limits of quantitation, but not necessarily outside these limits. Within this paradigm, the limit of detection, where the signal is definitely present but not measurable with any accuracy, is also defined. An iterative approach draws on existing smoothing methods to account simultaneously for both restrictions and is shown to achieve the global optimal convergence rate under weak conditions. This approach can also be implemented when convexity is replaced by other (bounded) restrictions. Examples from Addona et al. (2009, Nature Biotechnology 27, 663 641) both motivate and illustrate the effectiveness of this functional data methodology when compared with the simpler linear regressions and spline techniques. PMID- 24495168 TI - Echo diagnosis of rheumatic tricuspid valve disease. PMID- 24495170 TI - Hyposalivation in a 16-year-old girl: a case of salivary gland aplasia. AB - Salivary gland aplasia is a rare condition with only a small number of cases reported worldwide. It is more commonly seen in males and can occur either in isolation or association with other defects or syndromes. It may or may not occur with a hereditary background. Scant literature exists detailing the status of sublingual salivary glands in patients with any form of major salivary gland aplasia. This case report describes the clinical and magnetic resonance imaging presentation of a 16-year-old girl with major salivary gland aplasia detailing the status of all six major salivary glands. PMID- 24495169 TI - Engineering anisotropic biomimetic fibrocartilage microenvironment by bioprinting mesenchymal stem cells in nanoliter gel droplets. AB - Over the past decade, bioprinting has emerged as a promising patterning strategy to organize cells and extracellular components both in two and three dimensions (2D and 3D) to engineer functional tissue mimicking constructs. So far, tissue printing has neither been used for 3D patterning of mesenchymal stem cells (MSCs) in multiphase growth factor embedded 3D hydrogels nor been investigated phenotypically in terms of simultaneous differentiation into different cell types within the same micropatterned 3D tissue constructs. Accordingly, we demonstrated a biochemical gradient by bioprinting nanoliter droplets encapsulating human MSCs, bone morphogenetic protein 2 (BMP-2), and transforming growth factor beta1 (TGF- beta1), engineering an anisotropic biomimetic fibrocartilage microenvironment. Assessment of the model tissue construct displayed multiphasic anisotropy of the incorporated biochemical factors after patterning. Quantitative real time polymerase chain reaction (qRT-PCR) results suggested genomic expression patterns leading to simultaneous differentiation of MSC populations into osteogenic and chondrogenic phenotype within the multiphasic construct, evidenced by upregulation of osteogenesis and condrogenesis related genes during in vitro culture. Comprehensive phenotypic network and pathway analysis results, which were based on genomic expression data, indicated activation of differentiation related mechanisms, via signaling pathways, including TGF, BMP, and vascular endothelial growth factor. PMID- 24495171 TI - Self-healing encapsulation strategy for preparing highly stable, functionalized quantum-dot barcodes. AB - Quantum dot (QD) barcodes are becoming an urgent requirement for researchers and clinicians to obtain high-density information in multiplexed suspension (bead based) assay. However, how to improve the stability of quantum dot barcodes is a longstanding issue. Here, we present a new self-healing encapsulation strategy to generate functionalized uniform quantum dots barcodes with high physical and chemical stability. This efficient and facile strategy could make porous polymer microspheres self-heal to encapsulate QDs via the thermal motion and interaction of the molecular chains. Consequently, the new strategy solved especially the QDs leakage problem and improved the chemical stability under different pH physiological conditions as well as the longtime storage stability. In the meantime, the encoding capacity and the spatial distribution uniformity of quantum dots could be also improved. Furthermore, immunofluorescence assays for alpha fetoprotein (AFP) detections indicated that carboxyl groups on the surface of QD-encoded microspheres could facilitate efficient attachment of biomacromolecules. PMID- 24495172 TI - Carbide clusterfullerene Gd2C2@C92 vs dimetallofullerene Gd2@C94: a quantum chemical survey. AB - The geometric, electronic structure, and thermodynamic stability of Gd2C94 species, including dimetallofullerenes Gd2@C94 and carbide clusterfullerenes Gd2C2@C92, have been systematically investigated by a density functional theory approach combined with statistical mechanics calculations. Although the Gd2@C2(153480)-C94 is determined to possess the lowest energy, its molar fraction at the temperature region of fullerene formation is extremely low if the temperature effect is taken into consideration. Meanwhile, three C92-based carbide clusterfullerene species, Gd2C2@D3(126408)-C92, Gd2C2@C1(126390)-C92, and Gd2C2@C2(126387)-C92, with some higher energy are exposed to possess considerable thermodynamic stabilities within a related temperature interval, suggesting that carbide clusterfullerenes rather than dimetallofullerenes could be isolated experimentally. Although one isomer, Gd2C2@D3(126408)-C92, has been indeed obtained experimentally, a novel structure, Gd2C2@C1(126390)-C92, behaving as the most abundant isomer at more elevated temperatures with the largest SOMO-LUMO gap, is predicted for the first time to be another proper isomer isolated in the experiment. Moreover, in order to further analyze the interaction between gadolinium atoms and carbon atoms in either a carbide cluster or a fullerene cage, frontier molecular orbital, natural bond orbital, and Mayer bond order analyses have been employed, and the results show that the covalent interaction cannot be neglected. The IR spectra of Gd2C2@C92 have been simulated to provide some valuable guidance for future experiments. PMID- 24495173 TI - Assembly of debranched xylan from solution and on nanocellulosic surfaces. AB - This study focused on the assembly characteristics of debranched xylan onto cellulose surfaces. A rye arabinoxylan polymer with an initial arabinose/xylose ratio of 0.53 was debranched with an oxalic acid treatment as a function of time. The resulting samples contained reduced arabinose/xylose ratios significantly affecting the molecular architecture and solution behavior of the biopolymer. With this treatment, an almost linear xylan with arabinose DS of only 0.04 was obtained. The removal of arabinose units resulted in the self-assembly of the debranched polymer in water into stable nanoparticle aggregates with a size around 300 nm with a gradual increase in crystallinity of the isolated xylan. Using quartz crystal microbalance with dissipation monitoring, the adsorption of xylan onto model cellulose surfaces was quantified. Compared to the nonmodified xylan, the adsorption of debranched xylan increased from 0.6 to 5.5 mg m(-2). Additionally, adsorption kinetics suggest that the nanoparticles rapidly adsorbed to the cellulose surfaces compared to the arabinoxylan. In summary, a control of the molecular structure of xylan influences its ability to form a new class of polysaccharide nanoparticles in aqueous suspensions and its interaction with nanocellulose surfaces. PMID- 24495174 TI - Optimal investment in social signals. AB - This study is an attempt to determine how much individuals should invest in social communication, depending on the type of relationships they may form. Two simple models of social relationships are considered. In both models, individuals emit costly signals to advertise their "quality" as potential friends. Relationships are asymmetrical or symmetrical. In the asymmetrical condition (first model), we observe that low-quality individuals are discouraged from signaling. In the symmetrical condition (second model), all individuals invest in communication. In both models, high-quality individuals (elite) do not compete and signal uniformly. The level of this uniform signal and the size of the "elite" turn out to be controlled by the accuracy of signals. The two models may be relevant to several aspects of animal and human social communication. PMID- 24495175 TI - Itraconazole inhibits TNF-alpha-induced CXCL10 expression in oral fibroblasts. AB - OBJECTIVE: Itraconazole (ICZ) has a broad spectrum of antifungal activity including a wide range of Candida spp. TNF-alpha, an inflammatory cytokine associated with Th1-mediated oral inflammatory disease, enhances inflammatory mediators, such as CXCR3-agonistic chemokines including CXCL10. We examined the anti-inflammatory potential of ICZ against TNF-alpha-induced chemokines in oral fibroblasts. MATERIALS AND METHODS: We investigated the effects of ICZ on mRNA expressions of various TNF-alpha-induced chemokines in immortalized oral keratinocytes (RT7) and oral fibroblasts (GT1) using quantitative PCR analysis. Subsequently, the effects of ICZ and fluconazole (FLZ) on TNF-alpha-induced CXCL10 proteins in GT1 and primary fibroblasts were examined using enzyme-linked immunosorbent assays (ELISA). The effect of ICZ on signal transduction protein phosphorylation involved in CXCL10 production from TNF-alpha-stimulated GT1 was examined by western blotting. RESULTS: ICZ inhibited TNF-alpha-induced CXCL10 mRNA in GT1, but not RT7. Although ICZ did not affect TNF-alpha-induced IL-8 mRNA, the mRNAs of TNF-alpha-induced CXCR3-agonistic chemokines such as CXCL9 and CXCL11 were inhibited by ICZ in GT1. TNF-alpha-induced CXCL10 protein production in GT1 and primary fibroblasts was inhibited by ICZ, but not FLZ. Finally, ICZ inhibited TNF-alpha-induced phosphorylation of c-JUN, which is related to CXCL10 production by TNF-alpha-stimulated GT1. CONCLUSION: ICZ may be useful as therapy for Th1-mediated oral inflammatory disease. PMID- 24495176 TI - Oclacitinib (APOQUEL((r))) is a novel Janus kinase inhibitor with activity against cytokines involved in allergy. AB - Janus kinase (JAK) enzymes are involved in cell signaling pathways activated by various cytokines dysregulated in allergy. The objective of this study was to determine whether the novel JAK inhibitor oclacitinib could reduce the activity of cytokines implicated in canine allergic skin disease. Using isolated enzyme systems and in vitro human or canine cell models, potency and selectivity of oclacitinib was determined against JAK family members and cytokines that trigger JAK activation in cells. Oclacitinib inhibited JAK family members by 50% at concentrations (IC50 's) ranging from 10 to 99 nm and did not inhibit a panel of 38 non-JAK kinases (IC50 's > 1000 nM). Oclacitinib was most potent at inhibiting JAK1 (IC50 = 10 nM). Oclacitinib also inhibited the function of JAK1-dependent cytokines involved in allergy and inflammation (IL-2, IL-4, IL-6, and IL-13) as well as pruritus (IL-31) at IC50 's ranging from 36 to 249 nM. Oclacitinib had minimal effects on cytokines that did not activate the JAK1 enzyme in cells (erythropoietin, granulocyte/macrophage colony-stimulating factor, IL-12, IL-23; IC50 's > 1000 nM). These results demonstrate that oclacitinib is a targeted therapy that selectively inhibits JAK1-dependent cytokines involved in allergy, inflammation, and pruritus and suggests these are the mechanisms by which oclacitinib effectively controls clinical signs associated with allergic skin disease in dogs. PMID- 24495177 TI - Glial modulation of vibrissal sensory processing in rats. AB - Interactions between neurons and glial cells in the brain have important roles in brain functions such as development and plasticity of neural circuits or functions. Glial cells are much more actively involved in brain functions than previously thought. Here, we used vibrissal stimuli to induce sensoryevoked responses and multiunit spikes in the contralateral barrel cortex in a rat model. Local application of the gliotoxin DL-alpha-aminoadipate (AA) revealed that glial cells were involved in the sensoryevoked responses. The increases in the amplitude of somatosensory-evoked potential (SEP) and multiunit sensory-evoked spike rates in barrel cortex after AA injection were dramatic. Immunohistochemical staining of brain lipid binding protein (BLBP) and NeuN showed AA decreased cell number of astrocytes but not neurons in the barrel cortex. In conclusion, our results suggested an important role for astrocyte metabolism in normal synaptic activities. PMID- 24495178 TI - Effect of BayK 8644 on [Ca2+]i and viability in PC3 human prostate cancer cells. AB - The effect of BayK 8644 on cytosolic Ca2+ concentrations ([Ca2+]i) and viability in PC3 human prostate cancer cells was explored. Fura-2 was applied to measure [Ca2+]i. BayK 8644 at 1-50 MUM induced a [Ca22+]i rise concentration-dependently. The response was reduced by removing extracellular Ca2+. BayK 8644-evoked Ca2+ entry was inhibited by nifedipine, econazole, SK&F96365, and protein kinase C modulators. In Ca2+-free medium, incubation with the endoplasmic reticulum Ca2+ pump inhibitor 2,5-di-tert-butylhydroquinone (BHQ) abolished BayK 8644-induced [Ca2+]i rise. Inhibition of phospholipase C did not alter BayK 8644-induced [Ca2+]i rise. BayK 8644 killed cells in a concentrationdependent manner, which was not reversed by chelating cytosolic Ca2+ with 1,2-bis(2-aminophenoxy)ethane N,N,N',N'-tetraacetic acid/acetoxy methyl (BAPTA/AM). Collectively, in PC3 human prostate cancer cells, BayK 8644 induced a [Ca2+]i rise by evoking phospholipase C-independent Ca2+ release from the endoplasmic reticulum and Ca2+ entry via protein kinase C-sensitive store-operated Ca2+ channels (and/or T-type Ca2+ channels). At high concentrations, BayK 8644 caused cell death. PMID- 24495179 TI - Activation of snail and EMT-like signaling via the IKKalphabeta/NF-kappaB pathway in Apicidin-resistant HA22T hepatocellular carcinoma cells. AB - The molecular and phenotypic associations between chemo- or radio-resistance and the acquisition of epithelial-mesenchymal transition (EMT)-like phenotype are tightly related in cancer cells. Wnt/beta- catenin and NF-kappaB signaling pathways play crucial roles in EMT induction. Apicidin-resistant (Apicidin- R) HA22T cells are known to activate the Wnt/beta-catenin signaling pathway and MMP 2 expression via the IGF-IR/PI3K/Akt signaling pathway to enhance metastatic effects of cancer cells. In this study, we further investigated if Apicidin-R HA22T cells actually underwent EMT. In Apicidin-R HA22T cells, E-cadherin protein level was reduced but Vimentin, Snail and Twist were significantly activated. Activation of p-IKKalphabeta and p-IkappaBalpha was also observed in Apicidin-R HA22T cells. Apicidin-R HA22T cells displayed even higher NF-kappaB nuclear accumulation. Snail was enhanced but GSK3-beta was reduced. However, unphosphorylated GSK3-beta protein level was totally reversed when the Snail specific siRNA was applied in a knockdown experiment. Taken together, Apicidin-R HA22T cells could potentiate aggressive metastasis behavior due to up-regulation of Snail expression and promoted EMT effects via the IKKalphabeta/NF-kappaB pathway. In addition, Snail might decrease the GSK3-beta level resulting in extraordinarily activation of Wnt/beta-catenin signaling pathway. PMID- 24495181 TI - Role of the late sodium current in rate-dependent repolarization of the canine ventricle. AB - Late sodium current I(NaL) is an inward current participating in maintaining the plateau of the action potential. So far its role in the repolarization of canine hearts is not well known. In this paper, by taking advantage of a computer simulation method, we developed a one-dimensional transmural tissue to study the impacts of I(NaL) on rate-dependent repolarization and its ionic basis in the canine ventricle. An OpenMP parallel algorithm was performed on a four-core personal computer to accelerate the simulation. The results demonstrated that action potential durations of midmyocytes showed greater rate dependence than the endo- and epi-myocytes. When the pacing rate was reduced, repolarization of the tissue was prolonged while the transmural dispersion of repolarization (TDR) was enlarged. The enhancement of I(NaL) further amplified this rate-dependent repolarization and TDR meanwhile increased the risk of arrhythmogenesis. I(NaL) was found highly sensitive to the pacing rate by calculating its kinetics. The study suggested that I(NaL) played an important role in the rate-dependent repolarization of the canine ventricle. Selective blockade of I(NaL) could have clinical benefits, especially for such pathological conditions with enhanced I(NaL) as long QT 3 syndrome and heart failure. PMID- 24495180 TI - Physiological effects of bioceramic material: harvard step, resting metabolic rate and treadmill running assessments. AB - Previous biomolecular and animal studies have shown that a room-temperature far infrared-rayemitting ceramic material (bioceramic) demonstrates physical biological effects, including the normalization of psychologically induced stress conditioned elevated heart rate in animals. In this clinical study, the Harvard step test, the resting metabolic rate (RMR) assessment and the treadmill running test were conducted to evaluate possible physiological effects of the bioceramic material in human patients. The analysis of heart rate variability (HRV) during the Harvard step test indicated that the bioceramic material significantly increased the high-frequency (HF) power spectrum. In addition, the results of RMR analysis suggest that the bioceramic material reduced oxygen consumption (VO2). Our results demonstrate that the bioceramic material has the tendency to stimulate parasympathetic responses, which may reduce resting energy expenditure and improve cardiorespiratory recovery following exercise. PMID- 24495182 TI - The role of tyrosine kinase in Ca2+-independent contraction of the ropivacaine on rat aortic smooth muscle. AB - The tyrosine kinase signaling pathway plays an important role in the mediation of Ca2+ independent mechanisms of smooth muscle contraction. Several components of this pathway, including protein kinase C (PKC), p44/42 mitogen-activated protein kinase (p44/42 MAPK) and Rho-kinase are involved in Ca2+ independent mechanisms. Whether the tyrosine kinase pathway mediates vasoconstriction induced by the anesthetic ropivacaine remains unclear. The present study was designed to examine the role of tyrosine kinase in ropivacaine-induced, Ca2+-independent contraction of rat aortic smooth muscle. The effects of tyrosine kinase inhibitor on ropivacaine-induced contractile response were observed by isometric force measurement. The protein tyrosine phosphorylation, PKC, p44/42 MAPK, and membrane translocation of Rho-kinase were examined by Western blotting. Ropivacaine induced a concentration-dependent contractile response, and showed a number of effects on protein tyrosine phosphorylation. In this study, phosphorylation levels were shown to increase at lower concentrations of ropivacaine, but the levels decline at higher concentrations in rat aortic rings attenuated by the tyrosine kinase inhibitor genistein in a concentration-dependent fashion. Ropivacaine-induced phosphorylation of PKC and p44/42 MAPK and Rho-kinase membrane translocation were also significantly attenuated by genistein in similar decreasing manner as the PKC inhibitor bisindolylmaleimide I (Bis I) and the Rho kinase inhibitor, Y27632, but to a lesser degree than that by the p44/42 MAPK inhibitor, PD 098059. Our results showed that the ropivacaine-induced, Ca2+ independent-mediated contraction of rat aortic smooth muscle is, in part, regulated by tyrosine kinase-catalyzed protein tyrosine phosphorylation. PMID- 24495183 TI - Innovative progresses of the Chinese journal of Physiology in 2012. PMID- 24495184 TI - Roles of Coagulation and fibrinolysis in angiotensin II-enhanced microvascular thrombosis. AB - OBJECTIVE: AngII-induced HTN is associated with accelerated thrombus development in arterioles. This study assessed the contributions of different components of the coagulation cascade and fibrinolysis to AngII-mediated microvascular thrombosis. METHODS: Light/dye-induced thrombus formation (the time of onset and flow cessation) was quantified in cremaster muscle arterioles of AngII infused (two weeks) WT/AngII mice, EPCR-TgN, and mice deficient in PAI-1. WT/AngII mice were also treated with either tissue factor antibody, antithrombin III, heparin, hirudin, or murine APC. RESULTS: TF immunoblockade or hirudin treatment did not prevent the AngII-induced acceleration of thrombosis. While antithrombin III treatment prevented the acceleration in both thrombus onset and flow cessation, heparin only improved the time for blood flow cessation. Neither WT mice treated with murine APC nor EPCR-TgN were protected against AngII-induced thrombus development. A similar lack of protection was noted in PAI-1deficient mice. CONCLUSION: These findings implicate a role for thrombin generation pathway in the accelerated thrombosis induced by AngII and suggest that an impaired protein C pathway and increased PAI-1 do not make a significant contribution to this model of microvascular thrombosis. PMID- 24495185 TI - A population-level analysis of abdominal wall reconstruction by component separation in the morbidly obese patient: can it be performed safely? AB - Morbid obesity is increasing at an alarming rate and a significant portion of patients presenting for complex abdominal wall reconstruction (AWR) and component separation fall into this category, creating added medical and surgical challenges to an already difficult operation. The goal of this study was to utilise the Nationwide 2005-2010 American College of Surgeons National Surgical Quality Improvement database (ACS-NSQIP) to perform a population level analysis of the role of morbid obesity on 30-day perioperative morbidity with the hope of improving patient care, counselling and risk stratification. Morbidly obese patients (BMI > 40 kg/m(2)) were compared to non-obese patients (BMI < 30 kg/m(2)). Outcome variables assessed included major surgical complications, major medical complications, major renal complications, major wound complications, return to OR (ROR), and venous thromboembolism (VTE). Significant variables in a univariate analysis were included in a multivariate logistic regression controlling for patient characteristics (p < 0.05). In total, 1695 patients undergoing AWR were identified in the ACS-NSQIP database. Of these, 614 patients were non-obese (average BMI = 25.7 +/- 3.0 kg/m(2)) and 314 were morbidly obese (average BMI = 45.9 +/- 5.8 kg/m(2)). Multivariate analyses determined that morbid obesity did not significantly contribute to major surgical, medical, renal or wound complications. However, it was significantly associated with ROR (OR = 2.8, p < 0.001) and VTE (OR = 5.2, p = 0.04). Morbid obesity is an independent risk factor for ROR and VTE related complications, in the 30 day post-operative period. Additional perioperative care is warranted to decrease such early re operations and for preventable complications. PMID- 24495186 TI - Risk factors for mastectomy flap necrosis following immediate tissue expander breast reconstruction. AB - Tissue expander placement is a mainstay of reconstructive surgery in the post mastectomy patient. Necrosis of the native breast tissue is one of the most significant concerns in their post-operative care. The goal of this study is to elucidate factors that confer risk of this outcome. Chart review was conducted for a consecutive series of immediate tissue expander reconstructions by the two senior authors. Data was collected for several preoperative and intraoperative variables, as well as the outcome of mastectomy flap necrosis. Of the 1566 breasts that were examined, 135 (8.6%) experienced flap necrosis. The cohorts with and without flap necrosis were well matched. Those with the outcome of interest had significantly higher rates of switching to an autologous method of reconstruction (31.9% vs 6.2%, p < 0.001). Regression analysis revealed smoking status, increased age, tumescent mastectomy technique, and high (>66.67%) intraoperative tissue expander fill to confer increased risk of mastectomy flap necrosis. While smoking and older age are well-supported by the literature, tumescent technique and tissue expander fill are more novel points of discussion, which may serve as proxies for other issues. Awareness of these risk factors and their interplay will aid in clinical judgement and postoperative care of these patients. PMID- 24495187 TI - Late presentation to HIV/AIDS testing, treatment or continued care: clarifying the use of CD4 evaluation in the consensus definition. PMID- 24495188 TI - Antiretroviral treatment-based cost saving interventions may offset expenses for new patients and earlier treatment start. AB - OBJECTIVES: Combination antiretroviral therapy (cART) has become the main driver of total costs of caring for persons living with HIV (PLHIV). The present study estimated the short/medium-term cost trends in response to the recent evolution of national guidelines and regional therapeutic protocols for cART in Italy. METHODS: We developed a deterministic mathematical model that was calibrated using epidemic data for Lazio, a region located in central Italy with about six million inhabitants. RESULTS: In the Base Case Scenario, the estimated number of PLHIV in the Lazio region increased over the period 2012-2016 from 14 414 to 17 179. Over the same period, the average projected annual cost for treating the HIV infected population was ?147.0 million. An earlier cART initiation resulted in a rise of 2.3% in the average estimated annual cost, whereas an increase from 27% to 50% in the proportion of naive subjects starting cART with a nonnucleoside reverse transcriptase inhibitor (NNRTI)-based regimen resulted in a reduction of 0.3%. Simplification strategies based on NNRTIs co-formulated in a single tablet regimen and protease inhibitor/ritonavir-boosted monotherapy produced an overall reduction in average annual costs of 1.5%. A further average saving of 3.3% resulted from the introduction of generic antiretroviral drugs. CONCLUSIONS: In the medium term, cost saving interventions could finance the increase in costs resulting from the inertial growth in the number of patients requiring treatment and from the earlier treatment initiation recommended in recent guidelines. PMID- 24495189 TI - Foetal and postnatal exposure to high temperatures alter growth pattern but do not modify reproductive function in male rabbits. AB - PURPOSE: The 'foetal origin hypothesis' postulates that a number of organ structures and associated functions undergo programming during embryonic and foetal life and the neonatal period, which determines the set point of physiological and metabolic responses that carry into adulthood. We evaluate the relationship between high environmental temperatures and the reproductive function of male offspring to determine whether pregnant mammals and their infants are potentially vulnerable to the effects of climate change. METHODS: Rabbit pups were exposed to high temperatures during gestation and lactation. RESULTS: Foetal and postnatal exposure to high temperatures did not alter semen characteristics and was associated with a similar fertility rate and number of pups born. Moreover, males showed reduced rate of maturing and carcass traits at adulthood. CONCLUSION: Our findings suggest that male exposure during the foetal period to high temperatures did not affect sperm quality but permitted an adaptive phenotypic plasticity of growth in adulthood. PMID- 24495190 TI - Analysis of polymorphic sites in the promoter of the nitric oxide synthase 2 gene in Brazilian patients with leprosy. AB - Leprosy is one of the most neglected infectious tropical diseases of the skin and the nerves caused by the intracellular pathogen Mycobacterium leprae. The inducible NOS isoform encoded by NOS2A plays a vital role in host defence against bacterial infections. The functional promoter polymorphisms in NOS2A are associated with various autoimmune and infectious diseases. We investigated the association of NOS2A variants with progression of leprosy in a Brazilian cohort including 221 clinically classified patients and 103 unrelated healthy controls. We observed a novel variant ss528838018A/G in the promoter region at position 6558. The other functional variants were observed with low frequency of minor allele (<0.005). NOS2A promoter variant (-954G/C) was not observed in Brazilian populations, and the new observed promoter variant (ss528838018A/G) as well as other promoter variants were not associated with any clinical forms of leprosy in the Brazilian populations. PMID- 24495192 TI - pH-induced stability switching of the bacteriophage HK97 maturation pathway. AB - Many viruses undergo large-scale conformational changes during their life cycles. Blocking the transition from one stage of the life cycle to the next is an attractive strategy for the development of antiviral compounds. In this work, we have constructed an icosahedrally symmetric, low-energy pathway for the maturation transition of bacteriophage HK97. By conducting constant-pH molecular dynamics simulations on this pathway, we identify which residues are contributing most significantly to shifting the stability between the states along the pathway under differing pH conditions. We further analyze these data to establish the connection between critical residues and important structural motifs which undergo reorganization during maturation. We go on to show how DNA packaging can induce spontaneous reorganization of the capsid during maturation. PMID- 24495193 TI - Serum and urine Blastomyces antigen concentrations as markers of clinical remission in dogs treated for systemic blastomycosis. AB - BACKGROUND: Serum and urine Blastomyces antigen concentrations can be used to diagnose blastomycosis in dogs. OBJECTIVES: Blastomyces antigen concentrations correlate with clinical remission in dogs during antifungal treatment, and detect disease relapse after treatment discontinuation. ANIMALS: 21 dogs with newly diagnosed blastomycosis monitored until clinical remission (Treatment Phase), and 27 dogs monitored over 1 year from the time of antifungal discontinuation or until clinical relapse (After Treatment Phase). METHODS: Prospective study. Dogs were monitored monthly during treatment and every 3 months after treatment discontinuation, with a complete history, physical exam, chest radiographs, and ocular exam. Urine and serum Blastomyces antigen concentrations were measured at each visit using a quantitative enzyme immunoassay. RESULTS: At enrollment in the Treatment Phase, Blastomyces antigen was positive in all 21 urine samples (100% sensitivity; 95% CI 85-100%), and in 18 of 20 serum samples (90% sensitivity; 95% CI 70-97%). At 2-4 months of treatment, urine antigen was more sensitive for clinically detectable disease (82%; CI 60-94%) than serum antigen (18%; CI 6 41%). The sensitivity of the urine test for clinical relapse was 71% (CI 36-92%), with close to 100% specificity (CI 84-100%) during after treatment surveillance in this population. CONCLUSIONS: Urine Blastomyces antigen testing has high sensitivity for active disease at the time of diagnosis and during treatment, and moderate sensitivity but high specificity for clinical relapse. Urine testing should be useful at the time of diagnosis, when treatment discontinuation is being considered, and anytime there is poor clinical response or suspicion of relapse. PMID- 24495194 TI - Simultaneous inhibition of tumor growth and angiogenesis for resistant hepatocellular carcinoma by co-delivery of sorafenib and survivin small hairpin RNA. AB - The development of multidrug resistance (MDR) in human hepatocellular carcinoma (HCC) is one of the major obstacles for successful chemotherapy of HCC. Co delivery of sorafenib (SF) and survivin shRNA (shSur) was postulated to achieve synergistic effects in reversing MDR, suppressing tumor growth and angiogenesis. For this purpose, in this work, SF and shSur co-loaded pluronic P85 polyethyleneimine/d-alpha-tocopheryl polyethylene glycol 1000 succinate nanocomplexes (SSNs) were first designed and developed for the treatment of drug resistant HCC. The experimental results showed that SSNs could achieve effective cellular internalization and shSur transfection efficiency, induce significant downregulation of the survivin protein, and cause remarkable cell arrest and cell apoptosis. The tube formulation assay demonstrated that SSNs completely disrupted the enclosed capillary networks formed by human microvascular endothelial cells. The in vivo antitumor efficacy showed that SSNs were superior to that of other treatments on drug resistant hepatocellular tumor models. Therefore, it could be an efficient strategy to co-deliver SF and shSur for therapy of drug resistant HCC. PMID- 24495195 TI - Chitosan microencapsulation of various essential oils to enhance the functional properties of cotton fabric. AB - The present study dealt with emulsive fabrication of chitosan microcapsules encapsulating essential oils in the present of bio/surfactant. The size distribution, morphology and stability of microcapsules were examined by using advanced surface characterisation techniques. At cetyl trimethyl ammonium bromide (CTAB) concentration of 330 mg/L, the smallest average size of microcapsules was observed as12.8 MUm; whereas with biosurfactant at 50 mg/L, the microcapsules of smallest average size of 7.5 MUm were observed. The fabricated microcapsules were applied on a desized, bleached and mercerised cotton fabric by using pad-dry-cure method by using a modified dihydroxy ethylene urea as a cross-linking agent. The cross-linking was confirmed by using scanning electron microscopy and Fourier transform infrared spectroscopy techniques. The antibacterial activity of finished fabric was evaluated using the turbidity estimation method. The stiffness and wrinkle recovery properties of the treated fabric were also investigated by using the standard methods. In general, antibacterial activity of treated fabric increased with the increase in chitosan and essential oil concentrations, whereas stiffness increased with increase in concentration of chitosan but decreased with increase in essential oil concentration. PMID- 24495196 TI - Microencapsulation of gallium-indium (Ga-In) liquid metal for self-healing applications. AB - Microcapsules containing a liquid metal alloy core of gallium-indium (Ga-In) are prepared via in situ urea-formaldehyde (UF) microencapsulation. The capsule size, shape, thermal properties, and shell wall thickness are investigated. We prepare ellipsoidal capsules with major and minor diameter aspect ratios ranging from 1.64 to 1.08 and with major diameters ranging from 245 um to 3 um. We observe that as the capsule major diameter decreases, the aspect ratio approaches 1. The thermal properties of the prepared microcapsules are investigated by thermogravimetric (TGA) and differential scanning calorimetry (DSC). Microcapsules are shown to survive incorporation into an epoxy matrix and to trigger via mechanical damage to the cured matrix. Microcapsules containing liquid metal cores may have diverse applications ranging from self-healing to contrast enhancement or the demonstration of mechano-adaptive circuitry. PMID- 24495198 TI - Microbubbles in the left ventricle associated with mechanical aortic valve regurgitation signifies valvular (not peri-valvular) regurgitation. PMID- 24495199 TI - Recent novel approaches for population genomics data analysis. AB - Next-generation sequencing (NGS) technology is revolutionizing the fields of population genetics, molecular ecology and conservation biology. But it can be challenging for researchers to learn the new and rapidly evolving techniques required to use NGS data. A recent workshop entitled 'Population Genomic Data Analysis' was held to provide training in conceptual and practical aspects of data production and analysis for population genomics, with an emphasis on NGS data analysis. This workshop brought together 16 instructors who were experts in the field of population genomics and 31 student participants. Instructors provided helpful and often entertaining advice regarding how to choose and use a NGS method for a given research question, and regarding critical aspects of NGS data production and analysis such as library preparation, filtering to remove sequencing errors and outlier loci, and genotype calling. In addition, instructors provided general advice about how to approach population genomics data analysis and how to build a career in science. The overarching messages of the workshop were that NGS data analysis should be approached with a keen understanding of the theoretical models underlying the analyses, and with analyses tailored to each research question and project. When analysed carefully, NGS data provide extremely powerful tools for answering crucial questions in disciplines ranging from evolution and ecology to conservation and agriculture, including questions that could not be answered prior to the development of NGS technology. PMID- 24495200 TI - Alcohol drinking and cutaneous melanoma risk: a systematic review and dose-risk meta-analysis. AB - It has been suggested that alcohol intake increases sunburn severity, a major risk factor for cutaneous melanoma (CM). Several epidemiological studies have investigated the relationship between alcohol consumption and CM, but the evidence is inconsistent. Therefore, we aimed to quantify this relationship better, using a meta-analytical approach. The dose-risk relationship was also modelled through a class of flexible nonlinear meta-regression random effects models. The present meta-analysis included 16 studies (14 case-control and two cohort investigations) with a total of 6251 cases of CM. The pooled relative risk (RR) for any alcohol drinking compared with no/occasional drinking was 1.20 [95% confidence interval (CI) 1.06-1.37]. The risk estimate was similar in case control (RR 1.20, 95% CI 1.01-1.44) and cohort studies (RR 1.26, 95% CI 1.19 1.35). The pooled RR was 1.10 (95% CI 0.96-1.26) for light alcohol drinking (<= 1 drink per day) and 1.18 (95% CI 1.01-1.40) for moderate-to-heavy drinking. The pooled RR from 10 studies adjusting for sun exposure was 1.15 (95% CI 0.94-1.41), while the RR from six unadjusted studies was 1.27 (95% CI 1.20-1.35). No evidence of publication bias was detected. This meta-analysis of published data reveals that alcohol consumption is positively associated with the risk of CM. However, caution in interpreting these results is required, as residual confounding by sun exposure cannot be ruled out. PMID- 24495201 TI - Potential of M. oleifera for the treatment of water and wastewater. PMID- 24495202 TI - Biomarkers of cardiovascular disease are increased in untreated chronic periodontitis: a case control study. AB - BACKGROUND: The aim of this study was to evaluate the endothelial function, systemic inflammatory biomarkers and subgingival microbial profile associations in patients with and without periodontal disease. METHODS: Forty-four patients, half with chronic moderate to severe periodontitis (cases) and half gingivitis and incipient periodontitis (controls) were recruited. Anthropometric, clinical, biochemical parameters, endothelial function, subgingival microbiota, and eight plasma biomarkers of cardiovascular disease were assessed in both groups. RESULTS: Both groups were comparable in anthropometric parameters, blood pressure, and number of positive metabolic syndrome components. Univariate analyses demonstrated significantly higher plasma levels of E-selectin (64.5 +/- 30.9 vs 43.8 +/- 22.2; P = 0.026) and myeloperoxidase (MPO) (103 +/- 114.5 vs 49.1 +/- 35.6; P = 0.032) in cases than controls. In addition, significantly higher levels of E-selectin, MPO and ICAM-1 were found in periodontitis patients after adjustment by age and waist circumference. Red complex microorganisms were more frequently detected by culture and polymerase chain reaction in patients with severe to moderate periodontitis. CONCLUSIONS: Subgingival red complex bacteria and important cardiovascular risk markers were increased in untreated chronic moderate to severe periodontitis cases. Periodontitis seems to be associated with systemic inflammation that could increase the risk of cardiovascular events. The causal relation between periodontal infections and cardiovascular disease requires further research. PMID- 24495203 TI - Enhanced supercapacitive performance of chemically grown cobalt-nickel hydroxides on three-dimensional graphene foam electrodes. AB - Chemical growth of mixed cobalt-nickel hydroxides (CoxNi1-x(OH)2), decorated on graphene foam (GF) with desirable three-dimensional (3D) interconnected porous structure as electrode and its potential energy storage application is discussed. The nanostructured CoxNi1-x(OH)2 films with different Ni:Co (x) compositions on GF are prepared by using the chemical bath deposition (CBD) method. The structural studies (X-ray diffraction and X-ray photoelectron spectroscopy) of electrodes confirm crystalline nature of CoxNi1-x(OH)2/GF and crystal structure consists of Ni(OH)2 and Co(OH)2. The morphological properties reveal that nanorods of Co(OH)2 reduce in size with increases in nickel content and are converted into Ni(OH)2 nanoparticles. The electrochemical performance reveals that the Co0.66Ni0.33(OH)2/GF electrode has maximum specific capacitance of ~1847 F g(-1) in 1 M KOH within a potential window 0 to 0.5 V vs Ag/AgCl at a discharge current density of 5 A g(-1). The superior pseudoelectrochemical properties of cobalt and nickel are combined and synergistically reinforced with high surface area offered by a conducting, porous 3D graphene framework, which stimulates effective utilization of redox characteristics and communally improves electrochemical performance with charge transport and storage. PMID- 24495204 TI - The partners for life program: a couples approach to cardiac risk reduction. AB - Morbidity and mortality are reliably lower for the married compared with the unmarried across a variety of illnesses. What is less well understood is how a couple uses their relationship for recommended lifestyle changes associated with decreased risk for illness. Partners for Life compared a patient and partner approach to behavior change with a patient only approach on such factors as exercise, nutrition, and medication adherence. Ninety-three patients and their spouses/partners consented to participate (26% of those eligible) and were randomized into either the individual or couples condition. However, only 80 couples, distributed across conditions, contributed data to the analyses, due to missing data and missing data points. For exercise, there was a significant effect of couples treatment on the increase in activity and a significant effect of couples treatment on the acceleration of treatment over time. In addition, there was an interaction between marital satisfaction and treatment condition such that patients who reported higher levels of marital distress in the individuals condition did not maintain their physical activity gains by the end of treatment, while both distressed and nondistressed patients in the couples treatment exhibited accelerating gains throughout treatment. In terms of medication adherence, patients in the couples treatment exhibited virtually no change in medication adherence over time, while patients in the individuals treatment showed a 9% relative decrease across time. There were no condition or time effects for nutritional outcomes. Finally, there was an interaction between baseline marital satisfaction and treatment condition such that patients in the individuals condition who reported lower levels of initial marital satisfaction showed deterioration in marital satisfaction, while non satisfied patients in the couples treatment showed improvement over time. PMID- 24495205 TI - Investigation into the occurrence in food of veterinary medicines, pharmaceuticals, and chemicals used in personal care products. AB - Human exposure to emerging contaminants by indirect routes is of increasing interest. This study assessed the contamination of food by chemicals used in human pharmaceuticals (HPs), veterinary medicines (VMs), and personal care products (PCPs). A prioritization study was undertaken to identify the chemicals and food-producing scenarios most likely to result in contamination of food. Around 400 samples of mushrooms, vegetables, aquaculture products, and animal tissues were collected from sites in the United Kingdom, along with aquaculture products imported from Southeast Asia. A number of multianalyte methods were developed and validated for the analysis of the prioritized compounds in these samples. The analysis of all sample-method combinations required approximately 18000 determinations. Around 325 individual residues, including parabens, musk compounds, and antibiotics, were detected in 118 individual samples, but mostly at low nanograms per gram concentrations. Results suggest that the limited contamination of target chemicals occurred in the realistic food-producing scenarios investigated. PMID- 24495206 TI - Role of water in the dynamic disproportionation of Zn-based TCNQ(F4) coordination polymers (TCNQ = tetracyanoquinodimethane). AB - Intriguingly, coordination polymers containing TCNQ(2-) and TCNQF4(2-) (TCNQ = 7,7,8,8-tetracyanoquinodimethane, TCNQF4 = 2,3,5,6-tetrafluoro-7,7,8,8 tetracyanoquinodimethane, both designated as TCNQ(F4)(2-)) may be generated from reaction of metal ions with TCNQ(F4)*-. An explanation is now provided in terms of a solvent-dependent dynamic disproportionation reaction. A systematic study of reactions associated with TCNQ(F4) and electrochemically generated TCNQ(F4)MeCN*- and TCNQ(F4)MeCN(2-) revealed that disproportionation of TCNQ(F4)MeCN*- radical anions in acetonitrile containing a low concentration of water is facilitated by the presence of ZnMeCN(2+). Thus, while the disproportionation reaction 2TCNQ(F4)MeCN*- TCNQ(F4)MeCN + TCNQ(F4)MeCN(2-) is thermodynamically very unfavorable in this medium (Keq ~ 9 * 10(-10); TCNQF4), the preferential precipitation of ZnTCNQ(F4)(s) drives the reaction: ZnMeCN(2+) + 2 TCNQ(F4)MeCN*- ZnTCNQ(F4)(s) + TCNQ(F4)MeCN. The concomitant formation of soluble TCNQ(F4)MeCN and insoluble ZnTCNQ(F4)(s) and the loss of TCNQ(F4)MeCN*- were verified by UV visible and infrared spectroscopy and steady-state voltammetry. Importantly, the reverse reaction of comproportionation rather than disproportionation becomes the favored process in the presence of >=3% (v/v) water, due to the increased solubility of solid ZnTCNQ(F4)(s). Thus, in this "wet" environment, ZnMeCN(2+) and TCNQ(F4)MeCN*- are produced from a mixture of ZnTCNQ(F4)(s) and TCNQ(F4)MeCN and with the addition of water provides a medium for synthesis of [Zn(TCNQ(F4))2(H2O)2]. An important conclusion from this work is that the redox level of TCNQ(F4)-based materials, synthesized from a mixture of metal cations and TCNQ(F4)*-, is controlled by a solvent-dependent disproportionation/comproportionation reaction that may be tuned to favor formation of solids containing the monoanion radical, the dianion, or even a mixture of both. PMID- 24495207 TI - Informal and formal care of older people in Iceland. AB - BACKGROUND: Even if older people in the Nordic countries living in their homes usually have good access to formal help, the family plays an important role. Few studies have looked at the distribution of informal and formal care and the interplay between these spheres. The aim of this study is to shed light on the distribution of care and to analyse the patterns of care depending on the degree of limitations, the gender of the recipient and whether she/he is cohabitating or not. METHOD AND SAMPLE: The Icelandic survey 'Icelandic Older People' (ICEOLD) is a random nationally representative survey among persons 65+ living in their homes. Of those who participated (n = 782), 341 were men and 441 were women, giving a response rate of 66%. FINDINGS: About 60% of the people investigated in the survey had limitations with instrumental activities of daily living (IADL), and 10% of people had limitations with personal activities of daily living (PADL). The majority of the respondents with IADL or PADL limitations received either informal or formal help, but not both. When the IADL limitations increase, the informal care increases for men, but not for women, and the formal care increases for women, but decreases for men. Cohabiting men are much likelier to receive informal IADL help and less likely to receive formal help than men not cohabiting. Among women, corresponding differences are much smaller and not significant. When there is no spouse, the daughters help more than the sons and they help their mothers more than they help their fathers. CONCLUSION: More persons receive informal care than formal care, which shows the importance of the family. There is a gender difference in receiving care. Cohabitation is important for receiving informal care, especially for men. PMID- 24495208 TI - Signatures of malaria vaccine efficacy in ageing murine immune memory. AB - Malaria transmission occurs by mosquito bite. Thereafter, Plasmodium sporozoites specifically invade the liver, where they develop into thousands of merozoites that initiate blood-stage infection and clinical malaria. The pre-erythrocytic phase of a Plasmodium infection is the target of experimental whole-parasite vaccines against malaria. Repeated immunizations with high doses of live, metabolically active sporozoites can induce protracted protection against Plasmodium reinfection. Parasites lacking a Plasmodium-specific apicoplast protein, termed PALM, arrest very late during intrahepatic development just prior to liver merozoite release and can elicit sterile protection with two immunization doses only. In this report, we show in the robust Plasmodium berghei C57BL/6 model that partial protection extends beyond 1 year after the last immunization. In ageing mice, intracellular cytokine staining of Plasmodium peptide-stimulated intrahepatic CD8+ T cells revealed elevated levels of interferon gamma in vaccinated mice. We conclude that antigen-specific T cells persist in the target organ and are critical signatures of lasting protection. Our data also support the notions that memory T-cell responses generated early in life remain largely intact well into old age and that murine Plasmodium vaccination and infection models are suitable to study the mechanisms of maintenance and efficiency of adaptive immunity during immunosenescence. PMID- 24495209 TI - Gene and cell therapy funding opportunities in horizon 2020: an overview for 2014 2015. PMID- 24495210 TI - Isolation, purification, and cultivation of primary retinal microvascular pericytes: a novel model using rats. AB - OBJECTIVE: To isolate, purify, and cultivate primary retinal microvascular pericytes (RMPs) from rats to facilitate the study of their properties in vitro. METHODS: Primary RMPs were isolated from weanling rats by mechanical morcel and collagenase digestion, and purified by a step-wise combination of selective medium with different glucose concentrations, medium exchange, and partial enzymatic digestion. Morphology of RMPs was assessed by phase contrast microscopy. Further characterization was analyzed by immunofluorescence. Functional assay was evaluated by the pericytes- endothelial cells (ECs) coculture system. RESULTS: Retinal microvascular pericytes migrated out of microvascular fragments after 24-48 hours of plating and reached subconfluence on days 14-16. The cells showed typical pericyte morphology with large irregular triangular cell bodies and multiple long processes, and uniformly expressed the cellular markers alpha-SMA, PDGFR-beta, NG2 and desmin, but were negative for vWF, GS, GFAP and SMMHC. Ninety-nine percent of the cell population had double positive staining for alpha-SMA and PDGFR-beta. In the coculture system, RMPs can directly contact ECs and move together to form the capillary-like cords. CONCLUSIONS: Retinal microvascular pericytes can be readily obtained by our method. We report the first cultivation of primary RMPs from rats and establish a simple method for their isolation and purification. PMID- 24495211 TI - Similar in vitro effects and pulp regeneration in ectopic tooth transplantation by basic fibroblast growth factor and granulocyte-colony stimulating factor. AB - OBJECTIVES: Granulocyte-colony stimulating factor (G-CSF) has been shown to have combinatorial trophic effects with dental pulp stem cells for pulp regeneration. The aim of this investigation is to examine the effects of basic fibroblast growth factor (bFGF) in vitro and in vivo compared with those of G-CSF and to assess the potential utility of bFGF as an alternative to G-CSF for pulp regeneration. MATERIALS AND METHODS: Five different types of cells were examined in the in vitro effects of bFGF on cell migration, proliferation, anti-apoptosis, neurite outgrowth, angiogenesis, and odontogenesis compared with those of G-CSF. The in vivo regenerative potential of pulp tissue including vasculogenesis and odontoblastic differentiation was also compared using an ectopic tooth transplantation model. RESULTS: Basic fibroblast growth factor was similar to G CSF in high migration, proliferation and anti-apoptotic effects and angiogenic and neurite outgrowth stimulatory activities in vitro. There was no significant difference between bFGF and G-CSF in the regenerative potential in vivo. CONCLUSIONS: The potential utility of bFGF for pulp regeneration is demonstrated as a homing/migration factor similar to the influence of G-CSF. PMID- 24495212 TI - Impact of symptom remission on outpatient visits in depressed primary care patients treated with collaborative care management and usual care. AB - Depression symptoms contribute to significant morbidity and health care utilization. The aim of this study was to determine the impact of symptom improvement (to remission) on outpatient clinical visits by depressed primary care patients. This study was a retrospective chart review analysis of 1733 primary care patients enrolled into collaborative care management (CCM) or usual care (UC) with 6-month follow-up data. Baseline data (including demographic information, clinical diagnosis, and depression severity) and 6-month follow-up data (Patient Health Questionnaire scores and the number of outpatient visits utilized) were included in the data set. To control for individual patient complexity and pattern of usage, the number of outpatient visits for 6 months prior to enrollment also was measured as was the presence of medical comorbidities. Multiple logistic regression analysis demonstrated that clinical remission at 6 months was an independent predictor of outpatient visit outlier status (>8 visits) (odds ratio [OR] 0.609, confidence interval (CI) 0.460-0.805, P<0.01) when controlling for all other independent variables including enrollment into CCM or UC. The OR of those patients not in remission at 6 months having outpatient visit outlier status was the inverse of this at 1.643 (CI 1.243 2.173). The most predictive variable for determining increased outpatient visit counts after diagnosis of depression was increased outpatient visits prior to diagnosis (OR 4.892, CI 3.655-6.548, P<0.01). In primary care patients treated for depression, successful treatment to remission at 6 months decreased the likelihood of the patient having more than 8 visits during the 6 months after diagnosis. PMID- 24495214 TI - CO2 and O2 distribution in Rubisco suggests the small subunit functions as a CO2 reservoir. AB - Protein-gas interactions are important in biology. The enzyme ribulose-1,5 bisphosphate carboxylase/oxygenase (Rubisco) catalyzes two competing reactions involving CO2 and O2 as substrates. Carboxylation of the common substrate ribulose-1,5-bisphosphate leads to photosynthetic carbon assimilation, while the oxygenation reaction competes with carboxylation and reduces photosynthetic productivity. The migration of the two gases in and around Rubisco was investigated using molecular dynamics simulations. The results indicate that at equal concentrations of the gases, Rubisco binds CO2 stronger than it does O2. Amino acids with small hydrophobic side chains are the most proficient in attracting CO2, indicating a significant contribution of the hydrophobic effect in the interaction. On average, residues in the small subunit bind approximately twice as much CO2 as do residues in the large subunit. We did not detect any cavities that would provide a route to the active site for the gases. Instead, CO2 appears to be guided toward the active site through a CO2 binding region around the active site opening that extends to the closest neighboring small subunits. Taken together, these results suggest the small subunit may function as a "reservoir" for CO2 storage. PMID- 24495213 TI - Transarterial coil embolization of an abdominal aortocaval fistula in a dog. PMID- 24495215 TI - Identification of nephrotoxic compounds with embryonic stem-cell-derived human renal proximal tubular-like cells. AB - The kidney is a major target for drug-induced toxicity, and the renal proximal tubule is frequently affected. Nephrotoxicity is typically detected only late during drug development, and the nephrotoxic potential of newly approved drugs is often underestimated. A central problem is the lack of preclinical models with high predictivity. Validated in vitro models for the prediction of nephrotoxicity are not available. Major problems are related to the identification of appropriate cell models and end points. As drug-induced kidney injury is associated with inflammatory reactions, we explored the expression of inflammatory markers as end point for renal in vitro models. In parallel, we developed a new cell model. Here, we combined these approaches and developed an in vitro model with embryonic stem-cell-derived human renal proximal tubular-like cells that uses the expression of interleukin (IL)-6 and IL-8 as end points. The predictivity of the model was evaluated with 41 well-characterized compounds. The results revealed that the model predicts proximal tubular toxicity in humans with high accuracy. In contrast, the predictivity was low when well-established standard in vitro assays were used. Together, the results show that high predictivity can be obtained with in vitro models employing pluripotent stem cell derived human renal proximal tubular-like cells. PMID- 24495216 TI - Health-science students' self-efficacy, social support, and intention to work in rural areas of the Lao People's Democratic Republic. AB - INTRODUCTION: The Lao People's Democratic Republic (PDR), like almost all countries, is faced with a shortage of qualified health workers in rural and remote areas. The situation has worsened due to the unbalanced distribution of the health workforce, resulting from a tendency to gravitate to more central areas. METHODS: This cross-sectional study aimed to assess the proportion and associated factors affecting intention to work in a rural area among health science students in Vientiane, Lao PDR. All 403 final-year undergraduate and postgraduate students at the University of Health Sciences (UHS) in Vientiane - the only tertiary education facility that produces medical, family medicine, dentistry, pharmacy, medical technology, and nursing students - were asked to fill out self-administered questionnaires. In total, 356 respondents returned the completed questionnaires, yielding a response rate of 88.3%. RESULTS: Of the respondents, 40.7% (145/356) reported an intention to work in a rural area; 90.0% (131/145) preferred to work at district level; 21.3% reported high self-efficacy, whereas 79.8% reported low perceived social support for working in a rural area. Multiple logistic regression analysis revealed four variables were associated with intention to work in a rural area: hometown in a rural area; moderate/high self-efficacy; father having a secondary/high school education; and being a medical, family medicine/dentistry/pharmacy student. CONCLUSIONS: To increase the proportion of UHS graduates intending to work in a rural area, improved recruitment of students from rural areas, and enhanced self-efficacy and social support, are required. PMID- 24495217 TI - Description of five novel HLA-B alleles, B*07:184, B*41:27, B*42:19, B*50:32 and B*57:63, identified in Brazilian individuals. AB - Five novel HLA-B alleles were identified by HLA-SBT typing in seven unrelated Brazilian individuals. The new alleles discovered include HLA-B*07:184, B*41:27, B*42:19, B*50:32 and B*57:63 and were officially named by the World Health Organization (WHO) Nomenclature Committee. All new HLA-B alleles had nonsynonymous nucleotide substitution polymorphisms when compared to their most closely related HLA-B allele. PMID- 24495218 TI - How we implemented team-based learning for postgraduate doctors. AB - BACKGROUND: Team-based learning (TBL) has been shown to improve knowledge, teamwork and interactivity in medical school settings. There are fewer reports of its use with postgraduate doctors. We report on our experience of using TBL with residents. WHAT WE DID: We converted a didactic module of lectures into a TBL module for 44 psychiatry residents. This involved training faculty, orientating residents, writing TBL materials, delivering and evaluating the module. On the basis of the positive evaluations we aim to introduce more TBL. CONCLUSIONS: TBL can be successfully introduced into a residency training programme. Tips for implementation include: involve a TBL expert and provide experiential training for faculty; hold an orientation session for residents; and provide individual and team incentives to reinforce pre-class preparation and promote engagement with TBL. Avoid underestimating the effort involved in converting lecture-based teaching into TBL and do not assign excessive pre-session assignments. PMID- 24495219 TI - Phylogeography and biogeography of the lower Central American Neotropics: diversification between two continents and between two seas. AB - Lower Central America (LCA) provides a geologically complex and dynamic, richly biodiverse model for studying the recent assembly and diversification of a Neotropical biota. Here, we review the growing literature of LCA phylogeography studies and their contribution to understanding the origins, assembly, and diversification of the LCA biota against the backdrop of regional geologic and climatic history, and previous biogeographical inquiry. Studies to date reveal that phylogeographical signal within taxa of differing distributions reflects a diversity of patterns and processes rivalling the complexities of LCA landscapes themselves. Even so, phylogeography is providing novel insights into regional diversification (e.g. cryptic lineage divergences), and general evolutionary patterns are emerging. Congruent multi-taxon phylogeographic breaks are found across the Nicaraguan depression, Chorotega volcanic front, western and central Panama, and the Darien isthmus, indicating that a potentially shared history of responses to regional-scale (e.g. geological) processes has shaped the genetic diversity of LCA communities. By contrast, other species show unique demographic histories in response to overriding historical events, including no phylogeographic structure at all. These low-structure or incongruent patterns provide some evidence for a role of local, ecological factors (e.g. long-distance dispersal and gene flow in plants and bats) in shaping LCA communities. Temporally, comparative phylogeographical structuring reflects Pliocene Pleistocene dispersal and vicariance events consistent with the timeline of emergence of the LCA isthmus and its major physiographic features, e.g. cordilleras. We emphasise the need to improve biogeographic inferences in LCA through in-depth comparative phylogeography projects capitalising on the latest statistical phylogeographical methods. While meeting the challenges of reconstructing the biogeographical history of this complex region, phylogeographers should also take up the critical service to society of applying their work to the conservation of its fascinating biodiversity. PMID- 24495221 TI - Pulmonary arteriovenous malformations presenting as platypnea-orthodeoxia in graft-versus-host disease. AB - This case highlights the utility of agitated saline studies during transesophageal echocardiography (TEE) for detection of pulmonary arteriovenous malformations (PAVM) as a viable alternative to contrast-enhanced imaging studies. By carefully studying each pulmonary vein individually during saline contrast studies, TEE is able to demonstrate and localize PAVM. In addition, this report represents the first documentation of PAVM arising as a complication of graft-versus-host disease after allogeneic hematopoietic stem cell transplant. PMID- 24495220 TI - Heparinoids activate a protease, secreted by mucosa and tumors, via tethering supplemented by allostery. AB - Activation by glycosaminoglycans (GAGs) is an emerging trend among extracellular proteases important in disease. ProMMP-7, the zymogen of a matrix metalloproteinase secreted by mucosal epithelial and tumor cells, is activated at their surfaces by sulfated GAGs, but how? ProMMP-7 is activated in trans by representative heparin oligosaccharides in a length-dependent manner, with a large jump in activation at lengths of 16 monosaccharides. Imaging by atomic force microscopy visualized small complexes of proMMP-7 molecules linked by 8-mer lengths of heparinoids and extended assembles formed with 16-mer lengths of heparin. Complexes of proMMP-7 with polydisperse heparin or heparan sulfate were more diverse. Heparinoids evidently accelerate activation by tethering multiple proMMP-7 molecules together for proteolytic attack among neighbors. Removal of either the prodomain or C-terminal peptide sequence of KRSNSRKK from MMP-7 prevents formation of the long arrays induced by heparin 16-mers or heparan sulfate. The role of the C-terminus in activation assays suggests it contributes to remote, allosteric binding of GAGs. Enhancement of proteolytic velocity of MMP by GAGs indicates them to be effectors of V-type allostery. GAGs from proteoglycans appear to assemble proMMP-7 molecules for activation, an event preceding its tumorigenic or antibacterial proteolytic activities at cell surfaces. PMID- 24495222 TI - Comparison of a novel non-contact biomotion sensor with wrist actigraphy in estimating sleep quality in patients with obstructive sleep apnoea. AB - Ambulatory monitoring is of major clinical interest in the diagnosis of obstructive sleep apnoea syndrome. We compared a novel non-contact biomotion sensor, which provides an estimate of both sleep time and sleep-disordered breathing, with wrist actigraphy in the assessment of total sleep time in adult humans suspected of obstructive sleep apnoea syndrome. Both systems were simultaneously evaluated against polysomnography in 103 patients undergoing assessment for obstructive sleep apnoea syndrome in a hospital-based sleep laboratory (84 male, aged 55 +/- 14 years and apnoea-hypopnoea index 21 +/- 23). The biomotion sensor demonstrated similar accuracy to wrist actigraphy for sleep/wake determination (77.3%: biomotion; 76.5%: actigraphy), and the biomotion sensor demonstrated higher specificity (52%: biomotion; 34%: actigraphy) and lower sensitivity (86%: biomotion; 94%: actigraphy). Notably, total sleep time estimation by the biomotion sensor was superior to actigraphy (average overestimate of 10 versus 57 min), especially at a higher apnoea-hypopnoea index. In post hoc analyses, we assessed the improved apnoea-hypopnoea index accuracy gained by combining respiratory measurements from polysomnography for total recording time (equivalent to respiratory polygraphy) with total sleep time derived from actigraphy or the biomotion sensor. Here, the number of misclassifications of obstructive sleep apnoea severity compared with full polysomnography was reduced from 10/103 (for total respiratory recording time alone) to 7/103 and 4/103 (for actigraphy and biomotion sensor total sleep time estimate, respectively). We conclude that the biomotion sensor provides a viable alternative to actigraphy for sleep estimation in the assessment of obstructive sleep apnoea syndrome. As a non-contact device, it is suited to longitudinal assessment of sleep, which could also be combined with polygraphy in ambulatory studies. PMID- 24495223 TI - Fluorometric determination of alkaline phosphatase activity in food using magnetoliposomes as on-flow microcontainer devices. AB - Liposomes containing magnetic gold nanoparticles (AuNPs) and an enzymatic substrate (4-methylumbelliferyl-phosphate) have been used as on-flow microcontainers for reagent preconcentration in a flow injection method for the determination of alkaline phosphatase (ALP) activity. The dynamic range of the calibration graph was 6.4 * 10(-3)-0.25 U L(-1) ALP, and the detection limit was 1.9 * 10(-3) U L(-1). The precision, expressed as relative standard deviation (RSD%), was in the range of 0.7-2.4%. The overall method showed a sampling frequency of 10 h(-1). The method was applied to the determination of ALP in milk samples with recovery values ranging between 87.5 and 104.6%. The residual ALP activity in milk samples subjected to temperature treatments was also determined. The results obtained in the analysis of all milk samples were compared with those obtained by applying a previously described flow injection method. PMID- 24495224 TI - The roles of alphaV integrins in lens EMT and posterior capsular opacification. AB - Posterior capsular opacification (PCO) is the major complication arising after cataract treatment. PCO occurs when the lens epithelial cells remaining following surgery (LCs) undergo a wound healing response producing a mixture of alpha smooth muscle actin (alpha-SMA)-expressing myofibroblasts and lens fibre cells, which impair vision. Prior investigations have proposed that integrins play a central role in PCO and we found that, in a mouse fibre cell removal model of cataract surgery, expression of alphaV integrin and its interacting beta-subunits beta1, beta5, beta6, beta8 are up-regulated concomitant with alpha-SMA in LCs following surgery. To test the hypothesis that alphaV integrins are functionally important in PCO pathogenesis, we created mice lacking the alphaV integrin subunit in all lens cells. Adult lenses lacking alphaV integrins are transparent and show no apparent morphological abnormalities when compared with control lenses. However, following surgical fibre cell removal, the LCs in control eyes increased cell proliferation, and up-regulated the expression of alpha-SMA, beta1 integrin, fibronectin, tenascin-C and transforming growth factor beta (TGF-beta) induced protein within 48 hrs, while LCs lacking alphaV integrins exhibited much less cell proliferation and little to no up-regulation of any of the fibrotic markers tested. This effect appears to result from the known roles of alphaV integrins in latent TGF-beta activation as alphaV integrin null lenses do not exhibit detectable SMAD-3 phosphorylation after surgery, while this occurs robustly in control lenses, consistent with the known roles for TGF-beta in fibrotic PCO. These data suggest that therapeutics antagonizing alphaV integrin function could be used to prevent fibrotic PCO following cataract surgery. PMID- 24495225 TI - Identification of ligand-target pairs from combined libraries of small molecules and unpurified protein targets in cell lysates. AB - We describe the development and validation of interaction determination using unpurified proteins (IDUP), a method that selectively amplifies DNA sequences identifying ligand+target pairs from a mixture of DNA-linked small molecules and unpurified protein targets in cell lysates. By operating in cell lysates, IDUP preserves native post-translational modifications and interactions with endogenous binding partners, thereby enabling the study of difficult-to-purify targets and increasing the potential biological relevance of detected interactions compared with methods that require purified proteins. In IDUP, target proteins are associated with DNA oligonucleotide tags either non covalently using a DNA-linked antibody or covalently using a SNAP-tag. Ligand target binding promotes hybridization of a self-priming hairpin that is extended by a DNA polymerase to create a DNA strand that contains sequences identifying both the target and its ligand. These sequences encoding ligand+target pairs are selectively amplified by PCR and revealed by high-throughput DNA sequencing. IDUP can respond to the effect of affinity-modulating adaptor proteins in cell lysates that would be absent in ligand screening or selection methods using a purified protein target. This capability was exemplified by the 100-fold amplification of DNA sequences encoding FRB+rapamycin or FKBP+rapamycin in samples overexpressing both FRB and FKBP (FRB.rapamycin+FKBP, Kd ~ 100 fM; FKBP.rapamycin+FRB, Kd = 12 nM). In contrast, these sequences were amplified 10-fold less efficiently in samples overexpressing either FRB or FKBP alone (rapamycin+FKBP, Kd ~ 0.2 nM; rapamcyin+FRB, Kd = 26 MUM). Finally, IDUP was used to process a model library of DNA-linked small molecules and a model library of cell lysates expressing SNAP target fusions combined in a single sample. In this library*library experiment, IDUP resulted in enrichment of sequences corresponding to five known ligand+target pairs ranging in binding affinity from Kd = 0.2 nM to 3.2 MUM out of 67,858 possible combinations, with no false positive signals enriched to the same extent as that of any of the bona fide ligand+target pairs. PMID- 24495226 TI - The use of bisphosphonates in children: review of the literature and guidelines for dental management. AB - Bisphosphonates are inhibitors of osteoclastic bone resorption with therapeutic benefit in a variety of bone disorders in both adults and children. While these agents have been routinely used in adults for the past three decades, their more recent introduction into paediatric medicine means there is a paucity of data on long-term safety and effects on dental development. There is uncertainty regarding the dental management of children treated with bisphosphonates, particularly when invasive dental procedures, such as extractions and oral surgical procedures, are required. There are limited data with which to make recommendations about the dental management of patients treated with bisphosphonates, and there are no published recommendations that specifically address paediatric patients. This paper aims to outline paediatric uses and adverse effects of bisphosphonates and present recommendations on the dental management of children receiving bisphosphonates. PMID- 24495227 TI - Human cell growth regulator Ly-1 antibody reactive homologue accelerates processing of preribosomal RNA. AB - Ribosome biogenesis is an essential process for cell growth and proliferation and is enhanced in cancer and embryonic stem cells. Mouse Ly-1 antibody reactive clone product (Lyar) is expressed at very high levels in many tumor, leukemia or embryonic stem cells; is a novel nucleolar protein with zinc-finger DNA-binding motifs and is involved in cell growth regulation. However, cellular function of Lyar remains unexplored. Here, we show that human homologue of Lyar (LYAR) accelerates ribosome biogenesis at the level of processing of preribosomal RNA (pre-rRNA). We show that LYAR is excluded from the nucleolus after actinomycin D treatment and is present in preribosomal fraction of the nuclear extract as well as in the fractions with 40S, 60S and 90S sedimentation coefficients. LYAR is required for processing of 47S/45S, 32S, 30S and 21S pre-rRNAs. In addition, we show that over-expression of LYAR increases cell proliferation without affecting the expression of c-Myc or p53. Combined, these results suggest that some rapidly growing cells enhance ribosome biogenesis by increasing the expression of LYAR. PMID- 24495228 TI - Bancroftian filariasis: circulating B-1 cells decreased in microfilaria carriers and correlate with immunoglobulin M levels. AB - B-1 cells play an important role in the outcome of infection in schistosomiasis, pneumonia and experimental filariasis. However, no information exists regarding status of B-1 cells in clinical manifestations of human filariasis. We investigated the levels of B-1 cells from the total B cells by flow cytometry. Significantly low levels of B-1 cells and IgM antibodies were detected against a wide variety of autoantigens in microfilariae carriers as compared to endemic controls and patients with chronic pathology. A positive correlation was found between IgM antibodies to actin and ss-DNA. Absorption of plasma with soluble actin, myosin and lipopolysaccharides (LPS) resulted in significant removal of antifilarial antibodies. Affinity-purified anti-ss-DNA antibodies were found to be reactive to filarial antigens and various autoantigens. Further, a positive correlation was found between polyreactive antibodies and B-1 cells in filarial infected human subjects. After antifilarial treatment, levels of IgM antibodies to ss-DNA, actin, LPS and filarial antigen increased significantly indicating a role of polyreactive naturally occurring antibodies in filarial infection. Our findings add to the existing evidence that the B-cell defect in BALB.Xid mice account for susceptibility to murine filarial infection and indicate an important role for these antibodies in providing host protection against filarial infection. PMID- 24495229 TI - Neoglycoenzymes. PMID- 24495230 TI - Cytotoxic effects of etephon and maleic hydrazide in Vero, Hep2, HepG2 cells. AB - The toxicity of etephon and maleic hydrazide, used as plant growth regulators in agriculture, were reported as low in mammals in previous studies. However, in vitro cytotoxicity studies in mammalian cells are currently missing to understand their toxicity at molecular level. In the current study, the cytotoxicity of these compounds, were studied in Vero (African green monkey kidney epithelium), HepG2 (human hepatocellular carcinoma), Hep2 (human epidermoid cancer) cells by MTT ((3-(4,5-dimetiltiazol-2-il)-2,5-difeniltetrazolium bromure) and LDH (lactate dehydrogenase) assays. Maleic hydrazide had lower IC50 values for all cell lines compared to ethephon. Least cytotoxic effect treated by ethephon were observed in Vero, followed by HepG2 and Hep2. Similarly maleic hydrazide also showed least cytotoxicity on Vero cells, followed by Hep2 and HepG2 cells (p < 0.05). IC50 values in general were found to be highest in Vero cells, followed by HepG2 and Hep2 cells (p < 0.05). LDH and MTT assays showed correllation and had close relation except HepG2-maleic hydrazide application with the correlation coefficient for all >0.868 (p < 0.05). This study is expected to be a basis to understand the cytotoxic effects of ethephon and maleic hydrazide in mammal cells to be supplemented by further studies. PMID- 24495231 TI - Aspergillus fumigatus infection on a home-made tattoo. PMID- 24495232 TI - Influence of animal age on body concentrations of minerals in Japanese quail (Coturnix japonica). AB - Mathematical modelling of the relationships between mineral inputs and outputs would enable the prediction of mineral requirements of poultry under a wide range of conditions. To establish the feasibility of possible modelling of mineral requirements, the current study aimed to describe the individual mineral concentrations of whole bodies of quail over the life cycle from hatching to 70 days of age. Quail were reared indoors without any restrictions that could limit growth. Sampling of birds (n = 6-18) was carried out at 0, 3, 7, 14, 21, 35, 49 and 70 days after hatching. Freeze-dried samples of whole bodies (digestive contents removed) were analysed for ash, and macrominerals (calcium, magnesium, phosphorus, potassium, sodium) and microminerals (copper, iron, manganese, nickel, selenium, zinc). Ash concentration followed a curvilinear trend, with a maximum of 101.7 g/kg dry matter at 32.77 days. Individual mineral concentrations, expressed as a proportion of ash, were fluctuating over time, with the most prominent changes at 3 days and again at either 14 or 21 days. Dissimilar patterns in individual mineral concentrations resulted that ratios between minerals followed inconsistent patterns over time. Although mineral contents in absolute quantities can be described through modelling over the entire life cycle of the bird, it can be concluded that variable concentrations of individual minerals could complicate further model development. PMID- 24495233 TI - High-pressure open-channel on-chip electroosmotic pump for nanoflow high performance liquid chromatography. AB - Here, we construct an open-channel on-chip electroosmotic pump capable of generating pressures up to ~170 bar and flow rates up to ~500 nL/min, adequate for high performance liquid chromatographic (HPLC) separations. A great feature of this pump is that a number of its basic pump units can be connected in series to enhance its pumping power; the output pressure is directly proportional to the number of pump units connected. This additive nature is excellent and useful, and no other pumps can work in this fashion. We demonstrate the feasibility of using this pump to perform nanoflow HPLC separations; tryptic digests of bovine serum albumin (BSA), transferrin factor (TF), and human immunoglobulins (IgG) are utilized as exemplary samples. We also compare the performance of our electroosmotic (EO)-driven HPLC with Agilent 1200 HPLC; comparable efficiencies, resolutions, and peak capacities are obtained. Since the pump is based on electroosmosis, it has no moving parts. The common material and process also allow this pump to be integrated with other microfabricated functional components. Development of this high-pressure on-chip pump will have a profound impact on the advancement of lab-on-a-chip devices. PMID- 24495234 TI - Digital mammography screening with photon-counting technique: can a high diagnostic performance be realized at low mean glandular dose? AB - PURPOSE: To assess screening performance of a direct radiography (DR) photon counting system versus statewide screening units with different digital technologies. MATERIALS AND METHODS: The local ethics board approved retrospective study of prospectively acquired data from the North Rhine Westphalian mammography screening program (2009-2010). Informed consent was waived. Examinations in 13 312 women with a DR photon-counting system and statewide digital screening examinations in 993 822 women were included (37 computed radiography mammography systems and 55 DR systems). Diagnostic performance was assessed with cancer detection rate, recall rate, and proportion of small invasive cancers and ductal carcinoma in situ (DCIS). Mean glandular dose was calculated for DR photon counting and for a conventional DR subgroup. Differences were tested with chi(2) and t tests (P < .05). RESULTS: The cancer detection rate for subsequent screenings was higher for DR photon counting than statewide rates (0.76% [67 of 8842] vs 0.59% [3108 of 527 194], P = .05) at a higher recall rate (5.4% [475 of 8842] vs 3.3% [17 656 of 527 194], P = .001). Detection of invasive cancers up to 10 mm for DR photon counting was high for initial (40% [14 of 35]) and subsequent (42% [19 of 45]) screenings but not significantly different from statewide rates (initial, 31.6% [942 of 2979], P = .50; subsequent, 32.5% [765 of 2353], P = .25). The DCIS subsequent screening rate was higher for DR photon counting than statewide screening (0.23% [20 of 8842] vs 0.12% [616 of 527 194], P = .01) and the conventional DR subgroup (0.23% [20 of 8842] vs 0.12% [65 of 52 813], P = .025). Mean glandular dose for DR photon counting was significantly lower than that for conventional DR (0.60 mGy +/- 0.20 vs 1.67 mGy +/- 0.47 [craniocaudal views], 0.64 mGy +/- 0.23 vs 1.79 mGy +/- 0.53 [mediolateral oblique views], both P = .0001). CONCLUSION: Digital mammography screening with dose-efficient photon counting enables desirable detection rates of small invasive cancers and DCIS. Higher detection rates compared with statewide performance occurred with subsequent screening but had higher recall rates. PMID- 24495235 TI - Investigation of a commercial ELISA for the detection of canine procalcitonin. AB - BACKGROUND: Rapid identification of sepsis enables prompt administration of antibiotics and is essential to improve patient survival. Procalcitonin (PCT) is a biomarker used to diagnose sepsis in people. Commercial assays to measure canine PCT peptide have not been validated. OBJECTIVE: To investigate the validity of a commercially available enzyme-linked immunosorbent assay (ELISA) marketed for the measurement of canine PCT. ANIMALS: Three dogs with sepsis, 1 healthy dog, 1 dog with thyroid carcinoma. METHODS: Experimental study. The ELISA's ability to detect recombinant and native canine PCT was investigated and intra-assay and interassay coefficients of variability were calculated. Assay validation including mass spectrometry of the kit standard solution was performed. RESULTS: The ELISA did not consistently detect recombinant canine PCT. Thyroid lysate yielded a positive ELISA signal. Intra-assay variability ranged from 18.9 to 77.4%, while interassay variability ranged from 56.1 to 79.5%. Mass spectrometry of the standard solution provided with the evaluated ELISA kit did not indicate presence of PCT. CONCLUSIONS AND CLINICAL IMPORTANCE: The results of this investigation do not support the use of this ELISA for the detection of PCT in dogs. PMID- 24495236 TI - Use of clinical targets in diabetes patient education: qualitative analysis of the expectations and impact of a structured self-management programme in Type 1 diabetes. AB - AIMS: To explore the impact of education and target-setting on the life stories of patients with diabetes up to 10 years after they had participated in the Dose Adjustment for Normal Eating programme (DAFNE). METHODS: Qualitative, semi structured interviews were conducted before and after DAFNE courses to elicit narrative accounts from participants at three UK education centres. Observations of courses also took place. Data were gathered from 21 participants over 32 interviews and 146 h of observations, and analysed using a narrative approach. RESULTS: Findings suggest that patient education can create positive transformations in the lives of people with diabetes in ways that are not fully captured by simple quality-of-life scores. However, a review of evidence from other studies shows that DAFNE-recommended blood glucose results are in fact out of reach of even these most motivated and well-informed patients. This information was not shared with DAFNE attendees, who were expected to aim for near-normal HbA1c levels. After the course, participants sometimes perceived themselves as failing in their efforts, even when they had better than average blood glucose results. CONCLUSIONS: Specific and measurable low HbA1c targets may be desirable for reducing the risk of complications in diabetes, but they are not attainable or realistic even for most DAFNE graduates. It is suggested that setting goals without information about how achievable they really are could be counterproductive in terms of supporting and maintaining patient self-efficacy long-term. PMID- 24495237 TI - Nanoscale imaging and mechanical analysis of Fc receptor-mediated macrophage phagocytosis against cancer cells. AB - Fc receptor-mediated macrophage phagocytosis against cancer cells is an important mechanism in the immune therapy of cancers. Traditional research about macrophage phagocytosis was based on optical microscopy, which cannot reveal detailed information because of the 200-nm-resolution limit. Quantitatively investigating the macrophage phagocytosis at micro- and nanoscale levels is still scarce. The advent of atomic force microscopy (AFM) offers an excellent analytical instrument for quantitatively investigating the biological processes at single-cell and single-molecule levels under native conditions. In this work, we combined AFM and fluorescence microscopy to visualize and quantify the detailed changes in cell morphology and mechanical properties during the process of Fc receptor-mediated macrophage phagocytosis against cancer cells. Lymphoma cells were discernible by fluorescence staining. Then, the dynamic process of phagocytosis was observed by time-lapse optical microscopy. Next, AFM was applied to investigate the detailed cellular behaviors during macrophage phagocytosis under the guidance of fluorescence recognition. AFM imaging revealed the distinct features in cellular ultramicrostructures for the different steps of macrophage phagocytosis. AFM cell mechanical property measurements indicated that the binding of cancer cells to macrophages could make macrophages become stiffer. The experimental results provide novel insights in understanding the Fc-receptor-mediated macrophage phagocytosis. PMID- 24495238 TI - Investigation of the presence of beta-hydroxy-beta-methylbutyric acid and alpha hydroxyisocaproic acid in bovine whole milk and fermented dairy products by a validated liquid chromatography-mass spectrometry method. AB - A simple, rugged, quantitative, and confirmatory method based on liquid chromatography-mass spectrometry was developed and comprehensively validated for the analysis of the leucine metabolites beta-hydroxy-beta-methylbutyric acid (HMB) and alpha-hydroxyisocaproic acid (HICA) in bovine whole milk and yogurt. Mean accuracy (90-110% for HMB and 85-115% for HICA) and total precision (<10% RSD in most cases, except for <20% RSD for HMB at the limit of quantitation) at four concentration levels across three validation runs have been determined. Limits of quantitation for HMB and HICA in whole milk were 20 and 5 MUg/L, respectively. Measured concentrations of HMB and HICA were <20-29 and 32-37 MUg/L, respectively, in bovine whole milk and <5 and 3.0-15.2 mg/L, respectively, in yogurt. These concentrations are insufficient by large margins to deliver any musculoskeletal benefits, and fortification of milk and dairy products with HMB and/or HICA appears to be justified. PMID- 24495239 TI - Extensive changes in the transcriptional profile of human adipose tissue including genes involved in oxidative phosphorylation after a 6-month exercise intervention. AB - AIM: Adipose tissue has an important function in total energy homeostasis, and its dysregulation may contribute to lifestyle-related diseases such as type 2 diabetes, cancer and cardiovascular diseases. The aim of this study was to investigate genome-wide mRNA expression in adipose tissue in healthy men before and after an exercise intervention to identify genes or pathways that mediate the beneficial effect of regular exercise. We also investigated the difference in adipose tissue mRNA expression between individuals with or without a family history of type 2 diabetes. METHODS: The 6-month supervised exercise intervention was conducted in 47 healthy men (age 37.8 +/- 4.3 years, BMI 28.5 +/- 3.6 kg m( 2) ) with a previous low level of physical activity. RNA was analysed using GeneChip Human Gene 1.0 ST arrays (Affymetrix) before and after the exercise. RESULTS: We identified 2,560 significant transcripts differentially expressed before vs. after exercise with a false discovery rate (FDR) < 0.1%, including genes encoding the respiratory chain, histone subunits, small nucleolar RNAs and ribosomal proteins. Additionally, pathways enriched in response to exercise include the ribosome, oxidative phosphorylation, proteasome and many metabolic pathways, whereas the WNT and MAPK signalling pathways were down-regulated (FDR < 5%) after exercise. There were no significant differences in mRNA expression between individuals with or without a family history of type 2 diabetes. CONCLUSION: Exercise increased the expression of genes involved in oxidative phosphorylation, which is the opposite of what has been seen in adipose tissue from elderly or obese individuals with low physical fitness, and our study thereby demonstrates a mechanism for the beneficial effect of exercise. PMID- 24495240 TI - The epidemiology and pathophysiology of neurogenic bladder. AB - Neurogenic bladder is a disorder of the lower urinary tract created by damage to or diseases of the nervous system. Found in many patients with neurologic disorders, including multiple sclerosis, Parkinson's disease, spinal cord injury, and spina bifida among others, neurogenic bladder can lead to problematic symptoms and complications including urinary incontinence, frequency, and urgency, along with risk for infection and involvement of the upper urinary tract and kidney disease. The disorder can also create substantial embarrassment resulting in social isolation for affected patients. Healthcare utilization may be excessive in patients with neurogenic bladder, including office and emergency department visits and subsequent hospitalizations. Because of its significant effects on quality of life, it is important to reassess the epidemiology and physiology of neurogenic bladder, its diagnosis and assessment, and the impact of the symptoms and complications associated with it to better manage patients with this disorder and improve outcomes. PMID- 24495241 TI - Optimizing therapy and management of neurogenic bladder. AB - Clinicians managing patients with neurogenic bladder (NGB) and neurogenic detrusor overactivity (NDO) are faced with a myriad of complex choices when deciding on appropriate medical and/or surgical interventions to relieve bothersome symptoms associated with NGB and NDO, especially urinary incontinence. Therapies must provide maximum benefits while minimizing patients' risk for adverse events. A thorough knowledge and understanding of available and emerging medical and surgical treatment options for NGB/NDO is vital to assist clinicians in choosing appropriate treatment pathways and optimize response to therapy and individual outcomes. PMID- 24495242 TI - Managed care aspects of managing neurogenic bladder/neurogenic detrusor overactivity. AB - Neurogenic bladder (NGB) and neurogenic detrusor overactivity (NDO) manifesting in urinary incontinence (UI) can present substantial treatment challenges to clinicians managing patients with underlying neurologic disorders such as multiple sclerosis, Parkinson's disease, spinal cord injury, spina bifida, and stroke. Although the clinical disease burden alone is difficult for patients and those managing their disorders, the significant negative impact that NGB/NDO and UI can have on health-related quality of life and the economic costs surrounding these disorders can be devastating for patients already burdened with neurologic disorders. Careful clinician assessment of these quality-of-life issues and the economic impact of NGB/NDO with UI is needed to appropriately assess the burden these disorders place on patients and their management and to assist clinicians to design the most clinically, socially, and economically effective individualized management plans to optimize patient outcomes. PMID- 24495243 TI - Immunostimulatory lipid nanoparticles from herbal medicine. AB - Reproducibility is an important issue in biological characterization of drug candidates and natural products. It is not uncommon to encounter cases in which supposedly the same sample exhibits very different biological activities. During our characterization of macrophage-stimulatory lipids from herbal medicine, it was found that the potency of these lipids could vary substantially from experiment to experiment. Further analysis of this reproducibility issue led to the discovery of solvent-dependent nanoparticle formation by these lipids. While larger nanoparticles (approximately 100 nm) of these lipids showed modest macrophage-stimulatory activity, smaller nanoparticles (<10 nm) of the same lipids exhibited substantially higher potency. Thus, the study revealed an unexpected link between nanoparticle formation and macrophage-stimulatory activity of plant lipids. Although nanoparticles have been extensively studied in the context of vehicles for drug delivery, our finding indicates that drugs themselves can form nanoassemblies, and their biological properties may be altered by the way they assemble. PMID- 24495244 TI - Ethanol toxicokinetics resulting from inhalation exposure in human volunteers and toxicokinetic modeling. AB - Uncertainty exists regarding the validity of a previously developed physiologically-based pharmacokinetic model (PBPK) for inhaled ethanol in humans to predict the blood levels of ethanol (BLE) at low level exposures (<1000 ppm). Thus, the objective of this study is to document the BLE resulting from low levels exposures in order to refine/validate this PBPK model. Human volunteers were exposed to ethanol vapors during 4 h at 5 different concentrations (125-1000 ppm), at rest, in an inhalation chamber. Blood and exhaled air were sampled. Also, the impact of light exercise (50 W) on the BLE was investigated. There is a linear relationship between the ethanol concentrations in inhaled air and (i) BLE (women: r2= 0.98/men: r2= 0.99), as well as (ii) ethanol concentrations in the exhaled air at end of exposure period (men: r2= 0.99/women: r2= 0.99). Furthermore, the exercise resulted in a net and significant increase of BLE (2-3 fold). Overall, the original model predictions overestimated the BLE for all low exposures performed in this study. To properly simulate the toxicokinetic data, the model was refined by adding a description of an extra-hepatic biotransformation of high affinity and low capacity in the richly perfused tissues compartment. This is based on the observation that total clearance observed at low exposure levels was much greater than liver blood flow. The results of this study will facilitate the refinement of the risk assessment associated with chronic inhalation of low levels of ethanol in the general population and especially among workers. PMID- 24495245 TI - Urban air pollution and effects on biomarkers of systemic inflammation and coagulation: a panel study in healthy adults. AB - CONTEXT: Urban particulate air pollution is associated with cardiovascular diseases and mortality, possibly mediated through systemic inflammation and increased blood viscosity. OBJECTIVES: To examine short-term effects of exposure to urban air pollution on blood biomarkers for systemic inflammation and coagulation in a panel of healthy adults living in Gothenburg, Sweden. MATERIALS AND METHODS: The 16 volunteers, all non-smokers, median age 35 years, were called for blood sampling the morning after a day with high levels of urban particulate matter (PM10 > 30 ug/m3) or a day with low levels (PM10 < 15 ug/m3 and NO2 < 35 ug/m3). Associations between exposure to air pollution and each biomarker (C reactive protein, fibrinogen, serum amyloid A, coagulation factor VIII, plasminogen activator inhibitor-1, p-selectin, soluble intercellular adhesion molecule-1, soluble vascular adhesion molecule-1, Clara cell protein 16 and surfactant protein D) were examined using a linear mixed-effects model. RESULTS: In total, 12 sampling sessions were performed, six after high-pollution and six after low-pollution days, over 21 months. The ratio of air pollution levels between high- and low-pollution days was five for PM10 (median: 49 and 10 ug/m3) and two for NO2 (median: 47 and 24 ug/m3). No significant increase in blood levels of any of the biomarkers were seen after days with high air pollution levels compared with low levels. CONCLUSION: Biomarkers of inflammation and coagulation were not found to be significantly increased in the mornings after days with elevated levels of urban air pollution compared with low levels when performing repeated blood samplings in healthy volunteers. PMID- 24495246 TI - Wollastonite toxicity: an update. AB - This review updates earlier work addressing the epidemiology and toxicity of wollastonite. Earlier chronic animal bioassay and human mortality data were inadequate (IARC term) or negative and no new studies of these types have been published. Wollastonite has been determined to have low biopersistence in both in vivo and in vitro studies, which probably accounts for its relative lack of toxicity. Earlier morbidity studies of mining/mineral processing facilities in Finland and New York State indicated that exposure to wollastonite might result in pleural plaques (Finland) or decrements in certain measures of lung function (New York). More recent analysis of data from an ongoing health surveillance program at one facility (New York) indicates that there are no pleural plaques or interstitial lung disease or decrements in lung function among never smokers or former smokers occupationally exposed to wollastonite. This result probably reflects continued reduction in exposures as part of an ongoing product stewardship program at this facility and suggests that wollastonite has relatively low toxicity as currently managed. PMID- 24495247 TI - Lack of marked cyto- and genotoxicity of cristobalite in devitrified (heated) alkaline earth silicate wools in short-term assays with cultured primary rat alveolar macrophages. AB - Alkaline earth silicate (AES) wools are low-biopersistence high-temperature insulation wools. Following prolonged periods at high temperatures they may devitrify, producing crystalline silica (CS) polymorphs, including cristobalite, classified as carcinogenic to humans. Here we investigated the cytotoxic and genotoxic significance of cristobalite present in heated AES wools. Primary rat alveolar macrophages were incubated in vitro for 2 h with 200 ug/cm2 unheated/heated calcium magnesium silicate wools (CMS1, CMS2, CMS3; heat-treated for 1 week at, or 4 weeks 150 degrees C below, their respective classification temperatures) or magnesium silicate wool (MS; heated for 24 h at 1260 degrees C). Types and quantities of CS formed, and fiber size distribution and shape were determined by X-ray diffraction and electron microscopy. Lactate dehydrogenase release and alkaline and hOGG1-modified comet assays were used, +/- aluminum lactate (known to quench CS effects), for cytotoxicity/genotoxicity screening. Cristobalite content of wools increased with heating temperature and duration, paralleled by decreases in fiber length and changes in fiber shape. No marked cytotoxicity, and nearly no (CMS) or only slight (MS) DNA-strand break induction was observed, compared to the CS-negative control Al2O3, whereas DQ12 as CS positive control was highly active. Some samples induced slight oxidative DNA damage, but no biological endpoint significantly correlated with free CS, quartz, or cristobalite. In conclusion, heating of AES wools mediates changes in CS content and fiber length/shape. While changes in fiber morphology can impact biological activity, cristobalite content appears minor or of no relevance to the intrinsic toxicity of heated AES wools in short-term assays with rat alveolar macrophages. PMID- 24495248 TI - Toxicity of quantum dots on respiratory system. AB - Quantum dots (QDs), as advanced nanotechnology products, are widely used in the bio-medical field for diagnostic and therapeutic purposes due to their unique properties. Therefore, it becomes important for researchers to elucidate the adverse effects of QDs on human beings. This essay provides an overview of the toxic effects of QDs on respiratory system, which are summarized into two main parts: in vitro toxicity, including reduction of cell viability, genetic material damage and disordered immune cell reactions; as well as in vivo toxicity, involving accumulation of QDs, lung injury and inflammation, and potential long term adverse effects. As the toxic severity of a QD type depends on its composition, dose, size, surface chemistry and structure, it is a big challenge to determine a benchmark of QDs. Thus, we have to remember that each QD type is a unique nanocrystal, which needs to be assessed individually. However, there are still some feasible recommendations for minimizing the toxicity provided in this review. Overall, more and more large-scale well-organized toxicity studies of different QD types on different species need to be conducted in order to provide guidelines of QDs' safety application. PMID- 24495249 TI - Thin layer-based spectral and electrophoretic study of electro-oxidation of solid ellagic acid. AB - Acquisition of data from both in situ spectroscopy detection and online chromatography-like separation is important for studying complex electrochemical reactions. The present work provides an example of combination of thin-layer spectral and electrophoretic electrochemistry, both based on thin-layer electrolysis. Two thin-layer electrochemical cells were used to investigate the electro-oxidation of solid ellagic acid at different potentials, in acidic, physiological, and alkaline buffer media. UV-vis spectra and cyclic voltabsorptograms of the oxidation products were recorded in situ without interference from the solid reactant. Four oxidation products, depending upon the buffer pH and the applied potential, were separated and detected by electrophoretic electrochemistry. The major products possess redox stability, possibly with a diquinonemethide structure. The minor product is considered as an o-quinone derivative with a lactone-ring-opening, which can be reduced or further oxidized at appropriate potentials. A consecutive-parallel reaction mechanism is proposed for the formation of four products of ellagic acid in different pH media, which enriches the knowledge about the oxidation pathway and antioxidant property of this biologically active polyphenol compound. PMID- 24495250 TI - Satisfaction with care and rehabilitation among people with stroke, from hospital to community care. AB - BACKGROUND: Despite recent improvements in Swedish stroke care some patients still experience a lack of support and follow-up after discharge from hospital. In order to provide good care according to the National Board of Health and Welfare, systematic evaluations of stroke care must be performed. Quality indicators in the national guidelines could be useful when measuring quality of care in all parts of the stroke care chain. AIM: To investigate how people with stroke experienced their care, rehabilitation, support, and participation from hospital to community care. METHOD: Qualitative interviews were performed with 11 people in 2009-2010 covering their experiences of care, rehabilitation, support, and participation. The interviews were analysed with qualitative content analysis. RESULT: The interviewees were satisfied with their hospital care, but reported both positive and negative experiences of the continuing care. Most of them appreciated intense, specific, and professional rehabilitation, and had experienced these qualities in the rehabilitation they received in most parts of the stroke care chain. Those who received support from the community services expressed satisfaction with the staff, but also felt that autonomy was lost. Several did not feel involved in the health care planning, but instead relied on the judgement of the staff. CONCLUSION: To ensure high quality throughout the whole stroke care chain, people with stroke must be invited to participate in the care and the planning of care. To offer evidence-based stroke rehabilitation, it is important that the rehabilitation is specific, intense, and performed by professionals, regardless of where the rehabilitation is performed. A changed view of the patient's autonomy in residential community services should be developed, and this process must start from the staff and residents. PMID- 24495251 TI - How we implemented a resident-led medical simulation curriculum in a large internal medicine residency program. AB - Mannequin-based simulation in graduate medical education has gained widespread acceptance. Its use in non-procedural training within internal medicine (IM) remains scant, possibly due to the logistical barriers to implementation of simulation curricula in large residency programs. We report the Massachusetts General Hospital Department of Medicine's scale-up of a voluntary pilot program to a mandatory longitudinal simulation curriculum in a large IM residency program (n = 54). We utilized an eight-case curriculum implemented over the first four months of the academic year. An intensive care unit curriculum was piloted in the spring. In order to administer a comprehensive curriculum in a large residency program where faculty resources are limited, thirty second-year and third-year residents served as session facilitators and two senior residents served as chairpersons of the program. Post-session anonymous survey revealed high learner satisfaction scores for the mandatory program, similar to those of the voluntary pilot program. Most interns believed the sessions should continue to be mandatory. Utilizing residents as volunteer facilitators and program leaders allowed the implementation of a well-received mandatory simulation program in a large IM residency program and facilitated program sustainability. PMID- 24495252 TI - Application of intense pulsed light in the treatment of dermatologic disease: a systematic review. AB - BACKGROUND: The Food and Drug Administration (FDA) has approved intense pulsed light (IPL) devices for the treatment of a variety of benign pigmentary and vascular lesions, but the range of disease amenable to IPL treatment continues to expand, and there are no evidence-based clinical guidelines for its use in FDA approved and off-label indications. OBJECTIVE: To provide evidence-based recommendations to guide physicians in the application of IPL for the treatment of dermatologic disease. EVIDENCE REVIEW: A literature search of the CENTRAL (1991 to May 6, 2013), EMBASE (1974 to May 6, 2013), and MEDLINE in-process and nonindexed citations and MEDLINE (1964 to present) databases was conducted. Studies that examined the role of IPL in primary dermatologic disease were identified, and multiple independent investigators extracted and synthesized data. Recommendations were based on the highest level of evidence available. FINDINGS: Level 1 evidence was found for the use of IPL for the treatment of melasma, acne vulgaris, and telangiectasia. Level 2 evidence was found for the treatment of lentiginous disease, rosacea, capillary malformations, actinic keratoses, and sebaceous gland hyperplasia. Level 3 or lower evidence was found for the treatment of poikiloderma of Civatte, venous malformations, infantile hemangioma, hypertrophic scars, superficial basal cell carcinoma, and Bowen's disease. CONCLUSIONS: IPL is an effective treatment modality for a growing range of dermatologic disease and in some cases may represent a treatment of choice. It is typically well tolerated. Further high-quality studies are required. PMID- 24495253 TI - Oestrogen receptor-mediated expression of Olfactomedin 4 regulates the progression of endometrial adenocarcinoma. AB - Endometrial adenocarcinoma is the most common tumour of the female genital tract in developed countries, and oestrogen receptor (ER) signalling plays a pivotal role in its pathogenesis. When we used bioinformatics tools to search for the genes contributing to gynecological cancers, the expression of Olfactomedin 4 (OLFM4) was found by digital differential display to be associated with differentiation of endometrial adenocarcinoma. Aberrant expression of OLFM4 has been primarily reported in tumours of the digestive system. The mechanism of OLFM4 in tumuorigenesis is elusive. We investigated OLFM4 expression in endometrium, analysed the association of OLFM4 with ER signalling in endometrial adenocarcinoma, and examined the roles of OLFM4 in endometrial adenocarcinoma. Expression of OLFM4 was increased during endometrial carcinogenesis, linked to the differentiation of endometrioid adenocarcinoma, and positively related to the expression of oestrogen receptor-alpha (ERalpha) and progesterone receptor. Moreover, ERalpha-mediated signalling regulated expression of OLFM4, and knockdown of OLFM4 enhanced proliferation, migration and invasion of endometrial carcinoma cells. Down-regulation of OLFM4 was associated with decreased cumulative survival rate of patients with endometrioid adenocarcinoma. Our data suggested that impairment of ERalpha signal-mediated OLFM4 expression promoted the malignant progression of endometrioid adenocarcinoma, which may have significance for the therapy of this carcinoma. PMID- 24495254 TI - Multimetallic complexes and functionalized gold nanoparticles based on a combination of d- and f-elements. AB - The new DO3A-derived dithiocarbamate ligand, DO3A-(t)Bu-CS2K, is formed by treatment of the ammonium salt [DO3A-(t)Bu]HBr with K2CO3 and carbon disulfide. DO3A-(t)Bu-CS2K reacts with the ruthenium complexes cis-[RuCl2(dppm)2] and [Ru(CH?CHC6H4Me-4)Cl(CO)(BTD)(PPh3)2] (BTD = 2,1,3-benzothiadiazole) to yield [Ru(S2C-DO3A-(t)Bu)(dppm)2](+) and [Ru(CH?CHC6H4Me-4)(S2C-DO3A (t)Bu)(CO)(PPh3)2], respectively. Similarly, the group 10 metal complexes [Pd(C,N C6H4CH2NMe2)Cl]2 and [PtCl2(PPh3)2] form the dithiocarbamate compounds, [Pd(C,N C6H4CH2NMe2)(S2C-DO3A-(t)Bu)] and [Pt(S2C-DO3A-(t)Bu)(PPh3)2](+), under the same conditions. The linear gold complexes [Au(S2C-DO3A-(t)Bu)(PR3)] are formed by reaction of [AuCl(PR3)] (R = Ph, Cy) with DO3A-(t)Bu-CS2K. However, on reaction with [AuCl(tht)] (tht = tetrahydrothiophene), the homoleptic digold complex [Au(S2C-DO3A-(t)Bu)]2 is formed. Further homoleptic examples, [M(S2C-DO3A (t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3], are formed from treatment of NiCl2.6H2O, Cu(OAc)2, or Co(OAc)2, respectively, with DO3A-(t)Bu-CS2K. The molecular structure of [Ni(S2C-DO3A-(t)Bu)2] was determined crystallographically. The tert-butyl ester protecting groups of [M(S2C-DO3A-(t)Bu)2] (M = Ni, Cu) and [Co(S2C-DO3A-(t)Bu)3] are cleaved by trifluoroacetic acid to afford the carboxylic acid products, [M(S2C-DO3A)2] (M = Ni, Cu) and [Co(S2C-DO3A)3]. Complexation with Gd(III) salts yields trimetallic [M(S2C-DO3A-Gd)2] (M = Ni, Cu) and tetrametallic [Co(S2C-DO3A-Gd)3], with r(1) values of 11.5 (Co) and 11.0 (Cu) mM(-1) s(-1) per Gd center. DO3A-(t)Bu-CS2K can also be used to prepare gold nanoparticles, Au@S2C-DO3A-(t)Bu, by displacement of the surface units from citrate-stabilized nanoparticles. This material can be transformed into the carboxylic acid derivative Au@S2C-DO3A by treatment with trifluoroacetic acid. Complexation with Gd(OTf)3 or GdCl3 affords Au@S2C-DO3A-Gd with an r(1) value of 4.7 mM(-1) s(-1) per chelate and 1500 mM(-1) s(-1) per object. PMID- 24495255 TI - Air- and moisture-stable amphoteric molecules: enabling reagents in synthesis. AB - Researchers continue to develop chemoselective synthesis strategies with the goal of rapidly assembling complex molecules. As one appealing approach, chemists are searching for new building blocks that include multiple functional groups with orthogonal chemical reactivity. Amphoteric molecules that possess nucleophilic and electrophilic sites offer a versatile platform for the development of chemoselective transformations. As part of a program focused on new methods of synthesis, we have been developing this type of reagents. This Account highlights examples of amphoteric molecules developed by our lab since 2006. We have prepared and evaluated aziridine aldehydes, a class of stable unprotected alpha amino aldehydes. Structurally, aziridine aldehydes include both a nucleophilic amine nitrogen and an electrophilic aldehyde carbon over the span of three atoms. Under ambient conditions, these compounds exist as homochiral dimers with an aziridine-fused five-membered cyclic hemiaminal structure. We have investigated chemoselective reactions of aziridine aldehydes that involve both the aziridine and aldehyde functionalities. These transformations have produced a variety of densely functionalized nitrogen-containing compounds, including amino aldehydes, 1,2-diamines, reduced hydantoins, C-vinyl or alkynyl aziridines, and macrocyclic peptides. We have also developed air- and moisture-stable alpha-boryl aldehydes, another class of molecules that are kinetically amphoteric. The alpha-boryl aldehydes contain a tetracoordinated N-methyliminodiacetyl (MIDA) boryl substituent, which stabilizes the alpha-metalloid carbonyl system and prevents isomerization to its O-bond enolate form. Primarily taking advantage of chemoselective transformations at the aldehyde functionality, these alpha-boryl aldehydes have allowed us to synthesize a series of new functionalized boron containing compounds that are difficult or impossible to prepare using established protocols, such as alpha-borylcarboxylic acids, boryl alcohols, enol ethers, and enamides. Using alpha-borylcarboxylic acids as starting materials, we have also prepared several new amphoteric borylated reagents, such as alpha-boryl isocyanates, isocyanides, and acylboronates. These compounds are versatile building blocks in their own right, enabling the rapid synthesis of other boron containing molecules. PMID- 24495257 TI - Site-directed spin labeling-electron spin resonance mapping of the residues of cyanobacterial clock protein KaiA that are affected by KaiA-KaiC interaction. AB - The cyanobacterial clock proteins KaiA, KaiB and KaiC interact with each other to generate circadian oscillations. We have identified the residues of the KaiA homodimer affected through association with hexameric KaiC (KaiC6mer) using a spin-label-tagged KaiA C-terminal domain protein (KaiAc) and performing electron spin resonance (ESR) analysis. Cys substitution and/or the attachment of a spin label to residues located at the bottom area of the KaiAc concave surface, a KaiC binding groove, hindered the association of KaiAc with KaiC6mer, suggesting that the groove likely mediates the interaction with KaiC6mer. The residues affected by KaiC6mer association were concentrated in the three areas: the concave surface, a lobe-like structure (a mobile lobe near the concave surface) and a region adjacent to both the concave surface and the mobile lobe. The distance between the two E254, D255, L258 and R252 residues located on the mobile lobe decreased after KaiC association, suggesting that the two mobile lobes approach each other during the interaction. Analyzing the molecular dynamics of KaiAc showed that these structural changes suggested by ESR analysis were possible. Furthermore, the analyses identified three asymmetries in KaiAc dynamic structures, which gave us a possible explanation of an asymmetric association of KaiAc with KaiC6mer. PMID- 24495256 TI - Breed differences in natriuretic peptides in healthy dogs. AB - BACKGROUND: Measurement of plasma concentration of natriuretic peptides (NPs) is suggested to be of value in diagnosis of cardiac disease in dogs, but many factors other than cardiac status may influence their concentrations. Dog breed potentially is 1 such factor. OBJECTIVE: To investigate breed variation in plasma concentrations of pro-atrial natriuretic peptide 31-67 (proANP 31-67) and N terminal B-type natriuretic peptide (NT-proBNP) in healthy dogs. ANIMALS: 535 healthy, privately owned dogs of 9 breeds were examined at 5 centers as part of the European Union (EU) LUPA project. METHODS: Absence of cardiovascular disease or other clinically relevant organ-related or systemic disease was ensured by thorough clinical investigation. Plasma concentrations of proANP 31-67 and NT proBNP were measured by commercially available ELISA assays. RESULTS: Overall significant breed differences were found in proANP 31-67 (P < .0001) and NT proBNP (P < .0001) concentrations. Pair-wise comparisons between breeds differed in approximately 50% of comparisons for proANP 31-67 as well as NT-proBNP concentrations, both when including all centers and within each center. Interquartile range was large for many breeds, especially for NT-proBNP. Among included breeds, Labrador Retrievers and Newfoundlands had highest median NT proBNP concentrations with concentrations 3 times as high as those of Dachshunds. German Shepherds and Cavalier King Charles Spaniels had the highest median proANP 31-67 concentrations, twice the median concentration in Doberman Pinschers. CONCLUSIONS AND CLINICAL IMPORTANCE: Considerable interbreed variation in plasma NP concentrations was found in healthy dogs. Intrabreed variation was large in several breeds, especially for NT-proBNP. Additional studies are needed to establish breed-specific reference ranges. PMID- 24495258 TI - The burden of inappropriate emergency department pediatric visits: why Italy needs an urgent reform. AB - OBJECTIVE: To better understand the issue of inappropriate pediatric Emergency Department (ED) visits in Italy, including the impact of the last National Health System reform. STUDY DESIGN: A retrospective cohort study was conducted with five health care providers in the Veneto region (Italy) in a 2-year period (2010 2011). ED visits were considered "inappropriate" by evaluating both nursing triage and resource utilization, as addressed by the Italian Ministry of Health in 2007. Factors associated with inappropriate ED visits were identified. The cost of each visit was calculated. PRINCIPAL FINDINGS: In total, 134,358 ED visits with 455,650 performed procedures were recorded in the 2-year period; of these, 76,680 (57.1 percent) were considered inappropriate ED visits. Patients likely to make inappropriate ED visits were younger, female, visiting the ED during night or holiday, when the primary care provider (PCP) is not available. CONCLUSION: The National Health System reform aims to improve efficiency, effectiveness, and costs by opening PCP offices 24 hours a day and 7 days a week. This study highlights the need for a deep reorganization of the Italian Primary Care System not only providing a larger time availability but also treating the parents' lack of education on children's health. PMID- 24495259 TI - Review of findings in prophylactic gynaecological specimens in Lynch syndrome with literature review and recommendations for grossing. AB - AIMS: Prophylactic hysterectomy with bilateral salpingo-oophorectomy is being increasingly undertaken in patients with Lynch syndrome (LS). The pathological features in such specimens are not well described and, unlike the SEE-FIM protocol for salpingo-oophorectomy specimens in BRCA1/2 mutation carriers and the gastrectomy grossing protocols for patients with CDH1 (E-cadherin) mutations, guidelines have not been devised for the grossing of prophylactic gynaecological specimens from LS patients. We aimed to review the pathological findings in a series of prophylactic gynaecological specimens from LS patients and develop guidelines for the grossing of these specimens. METHODS AND RESULTS: We reviewed the pathological findings in 25 prophylactic gynaecological specimens from LS patients and audited the grossing protocols in different centres across Ontario, Canada. We found a 32% incidence of endometrial carcinoma or a precursor lesion; the two endometrial cancers identified were low-grade, low-stage endometrioid adenocarcinomas. To address the absence of guidelines for pathological examination, we undertook a literature review of gynaecological malignancies and incidental findings in prophylactic specimens in LS patients. CONCLUSION: We provide recommendations regarding the grossing of such specimens which includes in-toto examination of the lower uterine segment, endometrium, ovaries and fallopian tubes with representative sampling of the cervix. PMID- 24495260 TI - Plateau of adiposity in Australian children diagnosed with Type 1 diabetes: a 20 year study. AB - AIMS: To examine temporal trends in anthropometry in children with Type 1 diabetes from Sydney, Australia. METHODS: We conducted a retrospective study in a total of 1975 children with Type 1 diabetes, aged <16 years, between 1990 and 2009. Trends in height, weight and BMI standard deviation score after initial stabilization were examined by age group (<5 years, 5 to <10 years, 10 to 16 years) and time period of diagnosis (T1: 1990-1994, T2: 1995-1999; T3: 2000-2004 and T4: 2005-2009). Factors associated with BMI standard deviation score (time period, age group, gender and socio-economic status) were examined using multivariable linear regression. RESULTS: The mean BMI standard deviation score (+/-sd) increased between T1 and T2 (0.54 +/- 1.14 vs 0.81 +/- 1.14, P = 0.002), but remained steady thereafter (T3: 0.85 +/- 1.11, T4: 0.87 +/- 1.09; T2 to T4: P = 0.40). Similarly, the prevalence of overweight and obesity increased from T1 to T2 (26 to 35%, P = 0.01), but was unchanged thereafter (T3: 34%, T4: 34%; T2 to T4: P = 0.90). On multivariable regression analysis, a higher BMI standard deviation score was associated with younger age (>=5 years vs <5 years, beta= 0.40, 95% CI -0.51 to -0.28, P < 0.001), later time period (T2 to T4 vs T1, beta=0.30, 95% CI 0.16-0.45, P < 0.001) and male gender (beta=0.25, 95% CI 0.15 0.34, P < 0.001). CONCLUSION: The prevalence of overweight and obesity has remained unchanged in children at diagnosis of Type 1 diabetes over 15 years. These findings suggest that higher adiposity alone cannot account for the continued rising incidence of Type 1 diabetes in recent years. PMID- 24495261 TI - The clinical and economic consequences of obesity. AB - Obesity and its many serious comorbidities exert a heavy toll in both human and economic terms. More than one-third of adults in the United States are obese and, therefore, subject to elevated rates of diabetes, hypertension, dyslipidemia, and other cardiovascular disease risk factors. The negative effect on the quality of life (QoL) of these individuals is enormous. Among the severely obese, QoL scores are comparable to QoL scores associated with diabetes and laryngeal cancer. The medical costs of obesity-related illnesses in the United States have been estimated at $209.7 billion annually (in 2008 dollars). For example, with regard to impact on pharmaceutical costs, obesity is associated with a more than 13-fold increase in the cost of antidiabetic medications. The cost of absenteeism to employers has been estimated to exceed $4.3 billion annually. Successful and cost effective short-term treatments for obesity are available, and have been shown to reduce cardiovascular risk factors. Intensive lifestyle intervention with the goal of losing 7% of baseline body weight, for example, resulted in a 58% reduction in the risk of diabetes in patients with prediabetes. In clinical trials, improvements in other cardiovascular risk factors, such as elevated triglycerides and high blood pressure, have also been seen with a modest weight loss of 5% to 10% of baseline body weight. As obesity becomes an ever greater public health problem, additional interventions with long-term efficacy are needed to reduce body weight and maintain weight loss. PMID- 24495263 TI - Accurate diagnosis of small cerebral aneurysms <=5 mm in diameter with 3.0-T MR angiography. AB - PURPOSE: To evaluate the diagnostic accuracy of three-dimensional (3D) time-of flight (TOF) magnetic resonance (MR) angiography at 3.0 T in the detection of small cerebral aneurysms. MATERIALS AND METHODS: The institutional review board approved the study protocol, and patients or qualifying family members provided informed consent. A total of 403 consecutive patients undergoing 3D TOF MR angiography and digital subtraction angiography (DSA) were prospectively enrolled. Small aneurysms were those 5 mm in diameter or smaller. DSA served as the reference standard. Three observers were blinded to clinical and DSA results, and they independently analyzed all 3D TOF MR angiographic data sets. Interobserver agreement was expressed in terms of Cohen kappa value for categorical variables. Accuracy, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 3D TOF MR angiography in the detection of cerebral aneurysms were determined by using patient-, aneurysm-, and location-based evaluations. RESULTS: Of 403 patients, 273 aneurysms were detected with DSA in 230 patients. Patient-based evaluation with 3D TOF MR angiography at 3.0 T yielded an accuracy of 96%-97%, a sensitivity of 98.2%-98.7%, a specificity of 93.2% -94.8%, a PPV of 94.9%-96.2%, and an NPV of 97.6%-98.2% in the detection of cerebral aneurysms. Aneurysm-based evaluation yielded an accuracy of 96.4% 97.3%, a sensitivity of 98.5%-98.9%, a specificity of 93.2%-94.9%, a PPV of 95.7% 96.8%, and an NPV of 97.6%-98.2%. Aneurysm-location evaluations yielded similar results. CONCLUSION: Three-dimensional TOF MR angiography is a noninvasive method that shows promising diagnostic accuracy in the detection of small cerebral aneurysms. PMID- 24495264 TI - Detection of soft-tissue sarcoma recurrence: added value of functional MR imaging techniques at 3.0 T. AB - PURPOSE: To determine the added value of functional magnetic resonance (MR) sequences (dynamic contrast material-enhanced [DCE] and quantitative diffusion weighted [DW] imaging with apparent diffusion coefficient [ADC] mapping) for the detection of recurrent soft-tissue sarcomas following surgical resection. MATERIALS AND METHODS: This retrospective study was approved by the institutional review board. The requirement to obtain informed consent was waived. Thirty-seven patients referred for postoperative surveillance after resection of soft-tissue sarcoma (35 with high-grade sarcoma) were studied. Imaging at 3.0 T included conventional (T1-weighted, fluid-sensitive, and contrast-enhanced T1-weighted imaging) and functional (DCE MR imaging, DW imaging with ADC mapping) sequences. Recurrences were confirmed with biopsy or resection. A disease-free state was determined with at least 6 months of follow-up. Two readers independently recorded the signal and morphologic characteristics with conventional sequences, the presence or absence of arterial enhancement at DCE MR imaging, and ADCs of the surgical bed. The accuracy of conventional MR imaging in the detection of recurrence was compared with that with the addition of functional sequences. The Fisher exact and Wilcoxon rank sum tests were used to define the accuracy of imaging features, the Cohen kappa and Lin interclass correlation were used to define interobserver variability, and receiver operating characteristic analysis was used to define a threshold to detect recurrence and assess reader confidence after the addition of functional imaging to conventional sequences. RESULTS: There were six histologically proved recurrences in 37 patients. Sensitivity and specificity of MR imaging in the detection of tumor recurrence were 100% (six of six patients) and 52% (16 of 31 patients), respectively, with conventional sequences, 100% (six of six patients) and 97% (30 of 31 patients) with the addition of DCE MR imaging, and 60% (three of five patients) and 97% (30 of 31 patients) with the addition of DW imaging and ADC mapping. The average ADC of recurrence (1.08 mm(2)/sec +/- 0.19) was significantly different from those of postoperative scarring (0.9 mm(2)/sec +/- 0.00) and hematomas (2.34 mm(2)/sec +/- 0.72) (P = .03 for both). CONCLUSION: The addition of functional MR sequences to a routine MR protocol, in particular DCE MR imaging, offers a specificity of more than 95% for distinguishing recurrent sarcoma from postsurgical scarring. PMID- 24495265 TI - MR imaging of the prostate and adjacent anatomic structures before, during, and after ejaculation: qualitative and quantitative evaluation. AB - PURPOSE: To determine the possibility of obtaining high-quality magnetic resonance (MR) images before, during, and immediately after ejaculation and detecting measurable changes in quantitative MR imaging parameters after ejaculation. MATERIALS AND METHODS: In this prospective, institutional review board-approved, HIPAA-compliant study, eight young healthy volunteers (median age, 22.5 years), after providing informed consent, underwent MR imaging while masturbating to the point of ejaculation. A 1.5-T MR imaging unit was used, with an eight-channel surface coil and a dynamic single-shot fast spin-echo sequence. In addition, a quantitative MR imaging protocol that allowed calculation of T1, T2, and apparent diffusion coefficient (ADC) values was applied before and after ejaculation. Volumes of the prostate and seminal vesicles (SV) were calculated by using whole-volume segmentation on T2-weighted images, both before and after ejaculation. Pre- and postejaculation changes in quantitative MR parameters and measured volumes were evaluated by using the Wilcoxon signed rank test with Bonferroni adjustment. RESULTS: There was no significant change in prostate volumes on pre- and postejaculation images, while the SV contracted by 41% on average (median, 44.5%; P = .004). No changes before and after ejaculation were observed in T1 values or in T2 and ADC values in the central gland, while T2 and ADC values were significantly reduced in the peripheral zone by 12% and 14%, respectively (median, 13% and 14.5%, respectively; P = .004). CONCLUSION: Successful dynamic MR imaging of ejaculation events and the ability to visualize internal sphincter closure, passage of ejaculate, and significant changes in SV volumes were demonstrated. Significant changes in peripheral zone T2 and ADC values were observed. PMID- 24495266 TI - Is pain duration associated with morphologic changes of osteoid osteomas at CT? AB - PURPOSE: To assess the morphologic changes of osteoid osteomas on computed tomographic (CT) scans in association with pain duration. MATERIALS AND METHODS: Institutional review board approval was obtained. Informed consent was waived. From January 2008 to December 2012, 235 patients were treated with interstitial laser ablation at the Hopital Lariboisiere. Ninety-six patients with histopathologically proven osteoid osteomas, complete clinical files, and CT data were studied retrospectively. The following variables were assessed: age, sex, bone location, bone segment, location of the osteoid osteoma in relation to the native cortex, nidus area, nidus calcification area and attenuation at CT, and nidus mineralization ratio (percentage of the calcification area over the total nidus area). Analysis of variance, Kaplan-Meier method, and Cox multivariate regression model were used for statistical analyses. RESULTS: The study sample consisted of 96 patients, 68 of whom were male (71%) and 28 of whom were female (29%) (ratio of male to female patients, 2.4:1). Mean age +/- standard deviation was 22.2 years +/- 10.4 (range, 4-54 years; median, 18.5 years). The patients' age and nidus mineralization ratio increased significantly with pain duration (hazard ratio, 0.975 [P = .031] and 0.193 [P = .007], respectively). No significant association was found between pain duration and other variables, including the nidus area. In long bones, diaphyseal osteoid osteomas were significantly less mineralized than those in other locations (P = .009). CONCLUSION: The nidus mineralization ratio of osteoid osteomas increases significantly with pain duration and may be a marker of tumor age. Diaphyseal osteoid osteomas demonstrate a lower ratio of nidus mineralization. At the onset of symptoms, older patients experience pain for a longer period before treatment. PMID- 24495267 TI - In vivo 35Cl MR imaging in humans: a feasibility study. AB - PURPOSE: To implement chlorine 35 ((35)Cl) magnetic resonance (MR) at a 7-T whole body MR system and evaluate its feasibility for imaging humans. MATERIALS AND METHODS: All examinations were performed with ethical review board approval; written informed consent was obtained from all volunteers. Seven examinations each of brain and muscle in healthy volunteers and four examinations of patients were performed. Two patients with histologically confirmed glioblastoma multiforme underwent brain imaging. (35)Cl MR and (35)Cl inversion-recovery (IR) MR were performed. Two patients with genetically confirmed hypokalemic periodic paralysis underwent calf muscle imaging. Seven multiecho sequences (acquisition time, 5 minutes; voxel dimension, 11 mm(3)) were applied to determine transverse relaxation time as affected by magnetic field heterogeneity (T2*) and chlorine concentration. (35)Cl and sodium 23 ((23)Na) MR were conducted with a 7-T whole body MR system. (35)Cl longitudinal relaxation time (T1) and T2* of healthy human brain and muscle were determined with a three-dimensional density-adapted projection reconstruction technique to achieve short echo times and high signal to-noise ratio (SNR) efficiency. A nonlinear least squares routine and mono- (T1) and biexponential (T2*) models were used for curve fitting. RESULTS: Phantom imaging revealed 15-fold lower SNR and much shorter relaxation times for (35)Cl than (23)Na. In vivo T2* was biexponential and extremely short. Monoexponential fits of T1 revealed 9.2 and 4.0 milliseconds +/- 0.7 (standard deviation) for brain and muscle, respectively. In glioblastoma tissue, increased Cl(-) concentrations and increased Cl(-) IR signal intensities were detected. Voxel dimension and acquisition time, respectively, were 6 mm(3) and 9 minutes 45 seconds ((35)Cl MR) and 10 mm(3) and 10 minutes ((35)Cl IR MR). In patients with hypokalemic periodic paralysis versus healthy volunteers, Cl(-) and Na(+) concentrations were increased. Cl(-) concentration of muscle could be determined (voxel size, 11 mm(3); total acquisition time, 35 minutes). CONCLUSION: MR at 7 T enables in vivo imaging of (35)Cl in human brain and muscle in clinically feasible acquisition times (10-35 minutes) and voxel volumes (0.2-1.3 cm(3)). Pathophysiological changes of Cl(-) homeostasis due to cancer or muscular ion channel disease can be visualized. PMID- 24495268 TI - Statistical analysis of differential gene expression relative to a fold change threshold on NanoString data of mouse odorant receptor genes. AB - BACKGROUND: A challenge in gene expression studies is the reliable identification of differentially expressed genes. In many high-throughput studies, genes are accepted as differentially expressed only if they satisfy simultaneously a p value criterion and a fold change criterion. A statistical method, TREAT, has been developed for microarray data to assess formally if fold changes are significantly higher than a predefined threshold. We have recently applied the NanoString digital platform to study expression of mouse odorant receptor genes, which form with 1,200 members the largest gene family in the mouse genome. Our objectives are, on these data, to decrease false discoveries when formally assessing the genes relative to a fold change threshold, and to provide a guided selection in the choice of this threshold. RESULTS: Statistical tests have been developed for microarray data to identify genes that are differentially expressed relative to a fold change threshold. Here we report that another approach, which we refer to as tTREAT, is more appropriate for our NanoString data, where false discoveries lead to costly and time-consuming follow-up experiments. Methods that we refer to as tTREAT2 and the running fold change model improve the performance of the statistical tests by protecting or selecting the fold change threshold more objectively. We show the benefits on simulated and real data. CONCLUSIONS: Gene-wise statistical analyses of gene expression data, for which the significance relative to a fold change threshold is important, give reproducible and reliable results on NanoString data of mouse odorant receptor genes. Because it can be difficult to set in advance a fold change threshold that is meaningful for the available data, we developed methods that enable a better choice (thus reducing false discoveries and/or missed genes) or avoid this choice altogether. This set of tools may be useful for the analysis of other types of gene expression data. PMID- 24495269 TI - The effect of a change in selection procedures on students' motivation to study dentistry. AB - BACKGROUND: The aim of this study was to determine whether changes in student selection criteria at The University of Adelaide effected a change in motivation and influencing factors to study dentistry by comparing cohorts. METHODS: Online questionnaire completed by first-year dentistry students at The University of Adelaide between 1993-1996 and 1997-2005. RESULTS: All 666 students completed the questionnaire with 647 suitable for analysis. The likelihood of students being motivated for a career in dentistry because it 'fits with family' was greater for the 1997-2005 cohort (OR = 1.68, 95% CI = 1.14-2.49, p < 0.01) than it was for 1993-1996 enrollees, whereas 'status' became less important (OR = 0.47, 95% CI = 0.30-0.73, p < 0.01). Being influenced by a dentist (OR = 2.41, 95% CI = 1.63 3.55, p < 0.001) or a dental employee (OR = 3.19, 95% CI = 0.90-4.85, p < 0.001) was much greater for the 1997-2005 group than it was for the 1993-1996 cohort. Where students came from, parents' level of education and gender were not significant in the multivariate analysis of factors associated with motivation and influences of students' career choice. CONCLUSIONS: Changes to the selection procedure were associated with increased emphasis on lifestyle factors and the dental profession, but not with the desire to help people or the importance of the work itself in students' decision to study dentistry. PMID- 24495270 TI - Facilitating advance care planning with ethnically diverse groups of frail, low income elders in the USA: perspectives of care managers on challenges and recommendations. AB - This study examined care managers' perspectives on facilitating advance care planning (ACP) with ethnically diverse elders enrolled in a managed long-term care programme that coordinates medical and long-term care for frail, poor elders in the USA. Seven in-depth interviews and two focus groups were conducted with 24 lead supervisors and care managers of care management teams between July and August 2008; data were analysed with qualitative thematic analysis method. Participants identified four main sources of challenges: death and dying are taboo discussion topics; the dying process is beyond human control; family and others hold decision-making responsibility; and planning for death and dying is a foreign concept. Participants' recommendations to address these challenges were to develop trust with elders over time; cultivate cultural knowledge and sensitivity to respect value orientations; promote designating a healthcare proxy; recognise and educate families and community leaders as critical partners in ACP and provide practical support as needed throughout the illness experience. These findings suggest important practice implications for care managers working with increasingly diverse cultural groups of elders at the end of life. PMID- 24495271 TI - An intrauterine catch-up growth regimen increases food intake and post-natal growth in rats. AB - Nutritional conditions during the intrauterine stage are an important developmental programming factor that can affect the growth and metabolic status during foetal development and permanently alter the phenotypes of newborn offspring and adults. This study was performed to examine the effects of intrauterine catch-up growth (IUCG) on food intake, post-natal body growth and the metabolic status of offspring and growing rats. Control pregnant rats were fed ad libitum during the entire gestation period. For the IUCG regimen, pregnant rats were fed 50% of the food of the controls from pregnancy days 4 through 11 (8 days), followed by ad libitum feeding from pregnancy days 12 through parturition. The birth weight of offspring was not affected by the IUCG regimen. At weaning, offspring from each treatment group were assigned to two groups and given either a normal diet or high-fat diet (HFD) for 12 weeks until 103 days of age. In the normal diet group, the IUCG offspring showed a 9.0% increase (P < 0.05) in total food intake, were 11.2% heavier (p < 0.05) at 103 days of age and had an 11.0% greater (p < 0.05) daily weight gain compared with control offspring. The IUCG regimen did not affect body glucose and lipid metabolism. After exposure to the HFD, the IUCG regimen has not exacerbated metabolic disorders. In conclusion, our findings suggest that the IUCG nutritional regimen during pregnancy can increase the food intake and post-natal body growth of offspring without inducing metabolic disorders such as obesity and insulin resistance. The IUCG nutritional regimen might be used to improve the food intake and post-natal body growth of domestic animals. PMID- 24495272 TI - In vivo absorption comparison of nanotechnology-based silybin tablets with its water-soluble derivative. AB - In this study, the in vivo oral absorption of a nanocrystal tablet formulation of a BCS II poorly water-soluble drug was compared with that of its water-soluble salt form. Silybin is used as the model drug, and its nanosuspension was prepared by high-pressure homogenization. Effect of process and formulation parameters on properties of the nansuspensions was investigated. Dried powder of the nanosuspension was prepared by spray drying and used for preparing tablets. A pharmacokinetic study was performed in Beagle dogs to compare the absorption for tablets of silybin nanocrystals and silybin meglumine. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was determined. X-ray powder diffraction results indicated that silybin existed in a crystalline state after homogenization. In vivo absorption study in rats showed that the peroral absorption of silybin was enhanced remarkably by decreasing particle size. In vivo absorption of nanocrystal silybin tablet in Beagle dogs was comparable with that of the commercially available tablet of the water-soluble salt form of silybin. In conclusion, it is possible to increase the bioavailability of poorly soluble drugs by preparing its water-soluble derivative. PMID- 24495273 TI - Taste-masked and affordable donepezil hydrochloride orally disintegrating tablet as promising solution for non-compliance in Alzheimer's disease patients. AB - CONTEXT: Manufacturing process and superdisintegrants used in orally disintegrating tablet (ODT) formulation are often time discussed. However, the effect of suitable filler for ODT formulation is not explored thoroughly. OBJECTIVE: The aim of this study was to develop a novel taste masked and affordable donepezil hydrochloride ODT with fast disintegration time and stable to improve medication compliance of Alzheimer's disease patient. METHODS AND MATERIALS: The ODT was manufactured using simple wet-granulation method. Crospovidone XL-10 was used as superdisintegrant and optimization was done by comparing the effect of three grades of lactose monohydrate compound as filler: Starlac(r), Flowlac(r) and Tablettose(r). RESULTS AND DISCUSSION: Formulations containing higher amount of colloidal silicon dioxide showed increase in hardness, weight, disintegration time and wetting time after stability study. Formulation E which containing 50% of Starlac(r) was found with shortest in vitro disintegration time (21.7 +/- 1.67 s), in vivo disintegration time (24.0 +/- 1.05 s) and in vitro disintegration time in artificial salvia (22.5 +/- 1.67 s). Physical stability studies at 40 degrees C/75% RH for 6 months, Fourier transform infrared spectroscopy analysis and X-ray diffraction results showed that the formulation was stable. The drug-released profile showed that 80% of donepezil hydrochloride was released within 1 min. A single-dose, fasting, four period, seven-treatment, double-blinded study involving 16 healthy human volunteers was performed to evaluate the palatability of ODT. Formulation VII containing 10 mg of ammonium glycyrrhizinate was able to mask the bitter taste of the drug. CONCLUSION: The product has the potential to be commercialized and it might serve as solution for non-compliance among the Alzheimer's disease patients. PMID- 24495274 TI - Design, development and in-vitro evaluation of diclofenac taste-masked orodispersible tablet formulations. AB - CONTEXT: Fast onset of action is prerequisite for acute pain medication. A palatable orodispersible medicine of diclofenac providing rapid analgesic effect should improve patient compliance and treatment. OBJECTIVE: In the present study, diclofenac taste-masked orodispersible tablets (ODTs) with fast release characteristics were developed. Different taste-masking approaches and formulation concepts were screened in vitro for candidate selection. MATERIALS AND METHODS: Diclofenac was used as free acid. Five taste-masked microgranule formulations were prepared by wet granulation and/or coating processes, and compressed to ODTs. Citric acid (pH-modifying agent) and Eudragit(r) E PO (amino methacrylate copolymer) were used as taste-masking agents. Evaluation criteria were (i) disintegration time, (ii) processability and (iii) in-vitro dissolution profiles in simulated saliva (pH 7.4, 5 mL, 3 min) and compendial pH-change media (paddle, 50 rpm). The prototypes were compared to reference ODTs (without taste masking). Most suitable ODT prototypes were selected and further evaluated for taste-masking efficiency using an electronic tongue. RESULTS AND DISCUSSION: In simulated saliva, the drug was slower released from the prototypes (between 1.1% and 15.5%) than from reference ODTs (23.7%). Less dissolved particles are thus expected in vivo for taste perception. Two ODT prototypes showed fast and complete drug release in phosphate buffer. The formulation providing the most efficient taste-masking was selected guided by electronic tongue data. CONCLUSION: A novel palatable and fast acting diclofenac ODT formulation was successfully developed. Formulation design, development and in-vitro evaluation used in this study may serve as rational approach for manufacturing taste-masked orodispersible dosage forms. PMID- 24495275 TI - The characteristics of Audioscan and DPOAE measures in tinnitus patients with normal hearing thresholds. AB - OBJECTIVES: To investigate auditory dysfunction in patients with tinnitus and normal hearing thresholds using two sensitive audiological measures. DESIGN: The study was designed to investigate the characteristics of Audioscan and DPOAE tests in tinnitus patients with normal hearing thresholds. Audioscan and DPOAE notches were analysed and compared. All tests were performed in a sound-treated chamber or in a sound-treated room. STUDY SAMPLE: Forty-five tinnitus patients with normal hearing thresholds were examined following a written clinical protocol. RESULTS: The averaged hearing levels obtained from tinnitus participants were significantly worse at high frequencies than those derived from the normative data. There was a significantly higher prevalence of Audioscan and DPOAE notches, whose central frequencies matched tinnitus frequencies in the mid frequency regions, but not in the low- and high-frequency regions. A significant correlation was found between the centre frequencies of the Audioscan notches and the DPOAE notches from 500 to 4000 Hz. CONCLUSION: Tinnitus in different frequency regions may be associated with different underlying mechanisms of tinnitus generation. Some negative results on the Audioscan and DPOAE notches matching tinnitus pitches may be due to a limited set of discrete frequencies used for the tinnitus pitch matching test. PMID- 24495276 TI - Sounds perceived as annoying by hearing-aid users in their daily soundscape. AB - BACKGROUND: The noises in modern soundscapes continue to increase and are a major origin for annoyance. For a hearing-impaired person, a hearing aid is often beneficial, but noise and annoying sounds can result in non-use of the hearing aid, temporary or permanently. OBJECTIVE: The purpose of this study was to identify annoying sounds in a daily soundscape for hearing-aid users. DESIGN: A diary was used to collect data where the participants answered four questions per day about annoying sounds in the daily soundscape over a two-week period. STUDY SAMPLE: Sixty adult hearing-aid users. RESULTS: Of the 60 participants 91% experienced annoying sounds daily when using hearing aids. The annoying sound mentioned by most users, was verbal human sounds, followed by other daily sound sources categorized into 17 groups such as TV/radio, vehicles, and machine tools. When the hearing-aid users were grouped in relation to age, hearing loss, gender, hearing-aid experience, and type of signal processing used in their hearing aids, small and only few significant differences were found when comparing their experience of annoying sounds. CONCLUSIONS: The results indicate that hearing-aid users often experience annoying sounds and improved clinical fitting routines may reduce the problem. PMID- 24495277 TI - Comparison of oral and intravenous alfacalcidol in chronic hemodialysis patients. AB - BACKGROUND: Activated vitamin D is the mainstay of treatment for secondary hyperparathyroidism (SHPT) in chronic hemodialysis patients. However, the optimal route of administration is still debated. The aim of our study was to compare efficacy of oral vs intravenous (IV) administration of alfacalcidol in hemodialysis. A secondary objective was to determine the cost-effectiveness advantage of oral administration. METHODS: Eighty-eight chronic hemodialysis patients receiving IV alfacalcidol three times a week were included in the study. All were switched to the same dose of alfacalcidol given orally three times a week during the hemodialysis session. A budget impact analysis was performed. RESULTS: Mean patient age was 64 years old and 43% were males. The mean alfacalcidol dose administered was 2.1 MUg three times a week. After three months, serum parathormone (PTH) levels decreased from 80 to 59 pmol/L (p = 0.001) and total serum calcium levels increased from 2.34 to 2.40 mmol/L (p = 0.002). After six months, total serum calcium levels were still significantly higher. Alfacalcidol dosage was significantly decreased during study period; the mean reduction was 0.44 MUg per dose. Finally, oral administration was associated with an annual cost reduction of 197 678$CAN and an annual nursing time reduction of 25 days. CONCLUSION: Our findings support that switching IV to oral administration of alfacalcidol during hemodialysis sessions may lead to a similar control of SHPT with lower doses of activated vitamin D. This is a good strategy for optimizing compliance and may allow a dose reduction because of a greater efficacy to suppress PTH. Oral administration also has significant cost effectiveness advantages. PMID- 24495278 TI - In vitro suppression of dendritic cells by Helicobacter pylori OipA. AB - BACKGROUND: Outer inflammatory protein A (OipA) has an important role in Helicobacter pylori pathogenesis. In this study, we purified the outer membrane protein and evaluated the effects of this protein on maturation and cytokine production by dendritic cells (DCs). MATERIALS AND METHODS: The oipA gene was inserted into pET28a, and this construct was transformed into Escherichia coli BL21 (DE3). Purification of the recombinant protein was performed by Ni-NTA affinity chromatography. Immature DCs were purified from spleen of C57BL/6 mice with more than 90% purity and were treated with several concentrations of OipA (1 20 MUg/mL) overnight. Expression of maturation markers (CD86, CD40, and MHC-II) on the surface of DCs and production of IL-10 and IL-12 were assessed by flow cytometry and ELISA, respectively. RESULTS: The expression of DC maturation markers CD40, CD86, and MHC-II was downregulated on the surface of OipA-treated DCs at concentrations of 10 and 20 MUg/mL compared with negative control. Production of IL-10 decreases with increasing OipA concentration at a concentration of 5 MUg/mL, but we detected no change in IL-12 production. CONCLUSION: Inability to eliminate H. pylori from stomach is partly due to the evasion of the bacteria from the immune response. DCs are central mediators between innate and adaptive immunity, and DC cytokines direct the types of adaptive immune response. This study indicated that OipA of H. pylori is a DC maturation suppression factor. Previous studies have shown that H. pylori manage tolerogenic programming in DCs leading to long-time gastric colonization. In conclusion, H. pylori OipA helps the establishment of chronic infection with reduction in IL-10 and suppression of DC maturation. PMID- 24495279 TI - Reversible colour change in Arthropoda. AB - The mechanisms and functions of reversible colour change in arthropods are highly diverse despite, or perhaps due to, the presence of an exoskeleton. Physiological colour changes, which have been recorded in 90 arthropod species, are rapid and are the result of changes in the positioning of microstructures or pigments, or in the refractive index of layers in the integument. By contrast, morphological colour changes, documented in 31 species, involve the anabolism or catabolism of components (e.g. pigments) directly related to the observable colour. In this review we highlight the diversity of mechanisms by which reversible colour change occurs and the evolutionary context and diversity of arthropod taxa in which it has been observed. Further, we discuss the functions of reversible colour change so far proposed, review the limited behavioural and ecological data, and argue that the field requires phylogenetically controlled approaches to understanding the evolution of reversible colour change. Finally, we encourage biologists to explore new model systems for colour change and to engage scientists from other disciplines; continued cross-disciplinary collaboration is the most promising approach to this nexus of biology, physics, and chemistry. PMID- 24495280 TI - Levosimendan improves contractility in vivo and in vitro in a rodent model of post-myocardial infarction heart failure. AB - AIM: As few studies have presented a thorough analysis of the effect of levosimendan (LEV) on contractility, our purpose was to investigate in vivo cardiac function as well as in vitro cardiomyocyte function and calcium (Ca(2+) ) handling following LEV treatment. METHODS: Rats with post-myocardial infarction heart failure (HF) induced by ligation of the left anterior descending coronary artery and sham-operated animals were randomized to the infusion of LEV (2.4 MUg kg(-1) min(-1) ) or vehicle for 40 min. Echocardiographic examination was coupled to pressure-volume sampling in the left ventricle before (B) and after (40 min) infusion. Isolated left ventricular cardiomyocytes were studied in an epifluorescence microscope. RESULTS: HF LEV (n = 6), HF vehicle (n = 7), sham LEV (n = 5) and sham vehicle (n = 6) animals were included. LEV infusion compared to vehicle in HF animals reduced left ventricular end-diastolic pressure and mean arterial pressure (both P < 0.001) and improved the slope of the preload recruitable stroke work (P < 0.05). Administrating LEV to HF cardiomyocytes in vitro improved fractional shortening and Ca(2+) sensitivity index ratio, and increased the diastolic Ca(2+) (all P < 0.01). CONCLUSION: In HF animals, LEV improved the contractility by increasing the Ca(2+) sensitivity. Furthermore loading conditions were changed, and LEV could consequently change organ perfusion. An observed increase in diastolic Ca(2+) following LEV treatment and clinical implications of this should be further addressed. PMID- 24495281 TI - A facile one-pot synthesis of 2-arylamino-5-aryloxylalkyl-1,3,4-oxadiazoles and their urease inhibition studies. AB - A one-pot method for the synthesis of structural type urease inhibitors, 2-amino 1,3,4-oxadiazoles, was developed. The structures of the compounds were established using spectroanalytical techniques and unambiguously confirmed by single-crystal X-ray analysis of compound 3o. The synthesized compounds were tested against jack beans urease, and most of the compounds (3c, 3g, 3j, 3k, 3n, 3r-3v) were found more active than the standard. The most potent compound (3u) had an IC50 value of 6.03 +/- 0.02 MUm as compared to the IC50 value of the standard (thiourea; 22.0 +/- 1.2 MUm). The prominent urease inhibition activity of these compounds may serve as an important finding in the development of less toxic and more potent antiulcer drugs. The compounds were also investigated against four bacterial strains, and some of the compounds (3g and 3r) were found more potent than the standard drug (ciprofloxacin) against all the tested strains. The MIC value for compound 3g was 0.156 MUmol/mL against the tested bacterial strains. PMID- 24495282 TI - Cation and anion transport in a dicationic imidazolium-based plastic crystal ion conductor. AB - Here we investigate the organic ionic plastic crystal 1,2-bis[N-(N' hexylimidazolium-d2(4,5))]ethane 2PF6(-) in one of its solid plastic crystal phases by means of multinuclear solid-state (SS) NMR and pulsed-field-gradient NMR diffusometry. We quantify distinct cation and anion diffusion coefficients as well as the Arrhenius diffusion activation energies (Ea) in this dicationic imidazolium-based plastic crystal. Our studies suggest a change in transport mechanism for the cation upon varying thermal and magnetic treatment (9.4 T), evidenced by differences in cation and anion Ea. Moreover, variable temperature (2)H SSNMR line shapes support a change in local molecular environment upon slow cooling in B0. We quantify the percentage of mobile anions as a function of temperature with (19)F SSNMR, wherein two distinct spectral features are present. We also comment on the Arrhenius pre-exponential factor for diffusion (D0), giving insight into the number of degrees of freedom for transport for both cation and anion as a function of thermal treatment. Given the breadth and depth of our measurements, we propose that bulk ion transport is dominated by anion diffusion in ionic-liquid-like domain boundaries separating crystallites. This study elucidates fundamental properties of this plastic crystal, and allows for a more general and deeper understanding of ion transport within such materials. PMID- 24495283 TI - Toxic metal levels in children residing in a smelting craft village in Vietnam: a pilot biomonitoring study. AB - BACKGROUND: In Vietnam, environmental pollution caused by small-scale domestic smelting of automobile batteries into lead ingot is a growing concern. The village of Nghia Lo is a smelting craft village located roughly 25 km southeast of Hanoi in the Red River Delta. Despite the concern of toxic metal exposure in the village, biomonitoring among susceptible populations, such as children, has not been previously conducted. The aim of this study was to determine the body burden of toxic metals in children residing in a smelting craft village. METHODS: Twenty children from Nghia Lo, Vietnam, ages 18 months to four years were selected for capillary whole blood and toenail biomonitoring. Whole blood lead levels (BLLs) were measured using a portable lead analyzer, and toenail levels of arsenic, cadmium, chromium, lead, manganese, and mercury were analyzed with inductively coupled plasma-mass spectrometry. RESULTS: The findings show that all of the 20 children had detectable BLLs, and every child had levels that exceeded the Centers for Disease Control and Prevention guideline level of 5 MUg/dL. Eighty percent of tested subjects had BLLs higher than 10 MUg/dL. Five children (25%) had BLLs greater than 45 MUg/dL, the level of recommended medical intervention. In addition to blood lead, all of the children had detectable levels of arsenic, cadmium, chromium, lead, manganese, and mercury in toenail samples. Notably, average toenail lead, manganese, and mercury levels were 157 MUg/g, 7.41 MUg/g, and 2.63 MUg/g respectively, well above levels previously reported in children. Significant Spearman's rank correlations showed that there were relationships between blood and toenail lead levels (r = 0.65, p < 0.05), toenail levels of lead and cadmium (r = 0.66, p < 0.05), and toenail levels of manganese and chromium (r = 0.72, p < 0.001). Linear regression showed that reducing the distance to the nearest active smelter by half was associated with a 116% increase in BLL (p < 0.05). CONCLUSIONS: The results suggest that children in battery recycling and smelting craft villages in Vietnam are co-exposed to toxic metals. There is an urgent need for mitigation to control metal exposure related to domestic smelting. PMID- 24495284 TI - Evidence-based training and mentorship combined with enhanced outcomes surveillance to address the leading causes of neonatal mortality at the district hospital level in Ghana. AB - OBJECTIVE: To evaluate the impact of a district hospital intervention focused on enhancing healthcare provider capacity to address leading causes of neonatal death: birth asphyxia, infection and prematurity. METHODS: The neonatal quality improvement initiative was launched at two intervention referral district hospitals in Ghana. Local Health and Demographic Surveillance Systems were enlisted to enhance recording of neonatal and infant deaths in the community and at the facility. After baseline site assessments, a team of local paediatric experts conducted three clinical trainings on-site at each intervention hospital. Assessments were conducted to evaluate participant knowledge before and after participation in training modules. Monthly mentorship visits provided additional training to support the adoption of essential early neonatal care practices. RESULTS: In the first year of implementation, the initiative provided focused clinical training to 278 participants. A comparison of pre- and post-training test results demonstrates significant improvement in provider knowledge (73% vs. 89% correct, P < 0.001), with even greater improvement among trainees receiving recurrent refresher training (86% vs. 94% correct, P < 0.001). Participant feedback following training revealed enthusiasm about the programme and improved confidence. CONCLUSIONS: Locally led initiatives that invest directly in healthcare provider education and health systems strengthening represent a promising avenue for reducing neonatal morbidity and mortality. The NQI initiative demonstrates the positive impact of a district hospital intervention that combines on-site training, mentorship and enhanced demographic surveillance. PMID- 24495285 TI - Engineering the assembly of heme cofactors in man-made proteins. AB - Timely ligation of one or more chemical cofactors at preselected locations in proteins is a critical preamble for catalysis in many natural enzymes, including the oxidoreductases and allied transport and signaling proteins. Likewise, ligation strategies must be directly addressed when designing oxidoreductase and molecular transport functions in man-made, first-principle protein constructs intended to operate in vitro or in vivo. As one of the most common catalytic cofactors in biology, we have chosen heme B, along with its chemical analogues, to determine the kinetics and barriers to cofactor incorporation and bishistidine ligation in a range of 4-alpha-helix proteins. We compare five elementary synthetic designs (maquettes) and the natural cytochrome b562 that differ in oligomeric forms, apo- and holo-tertiary structural stability; qualities that we show can either assist or hinder assembly. The cofactor itself also imposes an assembly barrier if amphiphilicity ranges toward too hydrophobic or hydrophilic. With progressive removal of identified barriers, we achieve maquette assembly rates as fast as native cytochrome b562, paving the way to in vivo assembly of man-made hemoprotein maquettes and integration of artificial proteins into enzymatic pathways. PMID- 24495286 TI - Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis. AB - BACKGROUND: Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5 fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis. METHODS: Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student's t-test (paired two tailed) and chi2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05. RESULTS: BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR. CONCLUSIONS: BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis. PMID- 24495287 TI - Performance criteria for verbal autopsy-based systems to estimate national causes of death: development and application to the Indian Million Death Study. AB - BACKGROUND: Verbal autopsy (VA) has been proposed to determine the cause of death (COD) distributions in settings where most deaths occur without medical attention or certification. We develop performance criteria for VA-based COD systems and apply these to the Registrar General of India's ongoing, nationally representative Indian Million Death Study (MDS). METHODS: Performance criteria include a low ill-defined proportion of deaths before old age; reproducibility, including consistency of COD distributions with independent resampling; differences in COD distribution of hospital, home, urban or rural deaths; age-, sex- and time-specific plausibility of specific diseases; stability and repeatability of dual physician coding; and the ability of the mortality classification system to capture a wide range of conditions. RESULTS: The introduction of the MDS in India reduced the proportion of ill-defined deaths before age 70 years from 13% to 4%. The cause-specific mortality fractions (CSMFs) at ages 5 to 69 years for independently resampled deaths and the MDS were very similar across 19 disease categories. By contrast, CSMFs at these ages differed between hospital and home deaths and between urban and rural deaths. Thus, reliance mostly on urban or hospital data can distort national estimates of CODs. Age-, sex- and time-specific patterns for various diseases were plausible. Initial physician agreement on COD occurred about two-thirds of the time. The MDS COD classification system was able to capture more eligible records than alternative classification systems. By these metrics, the Indian MDS performs well for deaths prior to age 70 years. The key implication for low- and middle income countries where medical certification of death remains uncommon is to implement COD surveys that randomly sample all deaths, use simple but high quality field work with built-in resampling, and use electronic rather than paper systems to expedite field work and coding. CONCLUSIONS: Simple criteria can evaluate the performance of VA-based COD systems. Despite the misclassification of VA, the MDS demonstrates that national surveys of CODs using VA are an order of magnitude better than the limited COD data previously available. PMID- 24495288 TI - Age is not a contraindication to home-based dialysis - Quality-of-Life outcomes favour older patients on peritoneal dialysis regimes relative to younger patients. AB - AIM: To compare Quality of Life, anxiety and depression between older (>=65 years) and younger (<65 years) patients across automated peritoneal dialysis and continuous ambulatory peritoneal dialysis. BACKGROUND: There is a lack of studies as to whether the different peritoneal dialysis modalities confer similar outcomes in older and younger patients. DESIGN: Cross-sectional. METHODS: A total of 201 patients completed the Kidney Disease Quality of Life Short-Form, World Health Organization Quality of Life Instrument, Short Form and Hospital Anxiety and Depression Scale. Comorbidity and biochemical values were abstracted from medical records. RESULTS: Older patients reported significantly better quality of life than younger patients in the Kidney Disease Quality of Life Short-Form effects of kidney disease and patient satisfaction and the World Health Organization Quality of Life Instrument overall Quality-of-Life/health despite worse clinical profile. Quality of life outcomes were comparable between automated peritoneal dialysis and continuous ambulatory peritoneal dialysis with the exception of the Kidney Disease Quality of Life Short-Form symptoms in favour of automated peritoneal dialysis. Levels of anxiety and depression were equivalent for older and younger patients across peritoneal dialysis modalities. The observed quality-of-life advantages for older patients persisted after case mix adjustments and extended to more quality-of-life domains and depression and anxiety. CONCLUSION: Our findings of superior quality of life in patients aged >= 65 support the expansion of peritoneal dialysis use in older patients. Patients across different age groups should be given non-biased information about both peritoneal dialysis modalities and individual preferences should be elicited and carefully considered by healthcare providers. PMID- 24495289 TI - Association of epidermal growth factor receptor (EGFR) gene polymorphism with lung cancer risk: a systematic review. AB - Epidermal growth factor receptor (EGFR) is a member of the tyrosine kinase receptor family, which is thought to be involved in the development of cancer, as the EGFR gene is often amplified, and/or mutated in cancer cells. Lung cancer remains one of the most major causes of morbidity and mortality worldwide, accounting for more deaths than any other cancer cause. Gene polymorphism factor has been reported to be an important factor which increases the susceptibility of lung cancer. There lacks a well-documented diagnostic approach for the lung cancer risk, and the etiology of lung cancer is not clear. The current systematic review was performed to explore the association of EGFR gene polymorphism with lung cancer risk. In this review, association of EGFR 181946C > T, 8227G > A gene polymorphism with lung cancer was found, and EGFR Short genotype of cytosine adenine repeat number polymorphism was significantly associated with an increased risk of lung cancer. PMID- 24495290 TI - Investigation of the influence of external factors on the conformational dynamics of rhodopsin-like receptors by means of molecular dynamics simulation. AB - The study reports about the influence of binding of orthosteric ligands on the conformational dynamics of beta-2-adrenoreceptor. Using molecular dynamics (MD) simulation, we found that there was a little fraction of active states of the receptor in its apo (ligand-free) ensemble. Analysis of MD trajectories indicated that such spontaneous activation of the receptor is accompanied by the motion in intracellular part of its alpha-helices. Thus, receptor's constitutive activity directly results from its conformational dynamics. On the other hand, the binding of a full agonist resulted in a significant shift of the initial equilibrium towards its active state. Finally, the binding of the inverse agonist stabilized the receptor in its inactive state. It is likely that the binding of inverse agonists might be a universal way of constitutive activity inhibition in vivo. Our results indicate that ligand binding redistribute pre-existing conformational degrees of freedom (in accordance to the Monod-Wyman-Changeux Model) of the receptor rather than cause induced fit in it. Therefore, the ensemble of biologically relevant receptor conformations is encoded in its spatial structure, and individual conformations from that ensemble might be used by the cell in conformity with the physiological behavior. PMID- 24495293 TI - The importance of treatment adherence in HIV. AB - Treatment adherence is generally regarded as an important factor in achieving optimal outcomes across many disease states; in the treatment of HIV, poor adherence to treatment has the potential to impact outcomes on multiple levels. Poor adherence to antiretroviral therapy (ART) is associated with less effective viral suppression, which risks the immediate health of the patient, but also risks creating permanent treatment resistance to that particular agent or group of agents within a given combination therapy regimen. This may have downstream effects on treatment costs as well as therapeutic options. The causes of poor adherence to ART are extremely diverse, and include complexity of therapeutic regimens (eg, pill burden and dosing frequency), treatment side effects, poor health literacy, poor patient-physician relationship, and limited access to ART as a result of formulary restrictions or copayment costs. Treatment approaches, such as the use of fixed-dose combinations of ART agents to reduce dosing complexity, as well as educational interventions, such as medication therapy management initiatives, have been shown to improve adherence to therapy in HIV. It is important that all members of the healthcare team address potential barriers to adherence in order to achieve viral suppression and optimize outcomes in patients with HIV. PMID- 24495291 TI - Investigating the expression of metabotropic glutamate receptors in trigeminal ganglion neurons and satellite glial cells: implications for craniofacial pain. AB - CONTEXT/OBJECTIVE: Previous studies have demonstrated that various subtypes of the metabotropic glutamate receptors (mGluRs) are expressed in the dorsal root ganglion (DRG) of the peripheral nervous system (PNS), implicating that glutamate potentially contributes to sensory transmission through these receptors. While mGluR expression has been investigated largely in the DRG, the present study focused on mGluR expression on neurons and satellite glial cells (SGCs) of the trigeminal ganglion (TG). MATERIALS AND METHODS: To address the presence of mGluRs in rat TG neurons and their corresponding SGCs, the trigeminal ganglia from six adult male Wistar rats were isolated and immunohistochemistry and immunocytochemistry were performed. The expression of mGluR1alpha-, mGluR2/3- and mGluR8 on TG neurons and SGCs was investigated in tissue slices and isolated cells. RESULTS: 35.1 +/- 6.0% of the TG neurons were positive for mGluR1alpha, whereas 39.9 +/- 7.7% and 55.5 +/- 6.3% were positive for mGluR2/3 and mGluR8, respectively. Immunoreactive neurons expressing mGluRs were mainly medium- to large sized, with a smaller population of small-sized neurons showing immunoreactivity. The SGCs showed immunoreactivity toward mGluR1alpha and mGluR8, but not mGluR2/3, both in the tissue and in isolated cells. CONCLUSIONS: Findings from the present study showed that trigeminal neurons express mGluR1alpha, mGluR2/3 and mGluR8, while SGCs only express mGluR1alpha and mGluR8. This novel evidence may advance investigations on a possible role of mGluRs in relation to trigeminal pain transmission within the craniofacial region. PMID- 24495294 TI - Management of noninfectious diarrhea associated with HIV and highly active antiretroviral therapy. AB - In geographic locations where highly active antiretroviral therapy (HAART) is widely available, the nature of HIV-related diarrhea has shifted from being predominantly a consequence of opportunistic infection to being largely a side effect of HAART agents. With this shift has come a smaller risk for the life threatening wasting and weight loss, although serious instances of noninfectious diarrhea remain a concern. While estimates vary, in part due to the lack of a standard diarrhea definition, over a quarter of patients receiving HAART experience diarrhea. The negative effect on quality-of-life in patients with HAART-related diarrhea is profound; diarrhea may also increase the risk of poor adherence to treatment, with potentially serious effects on viral suppression and increased risk of drug resistance. Diagnosis of HAART-related diarrhea largely involves ruling out pathogen involvement, which, in addition to laboratory testing, may require endoscopic examination. Treatment was, until recently, mainly supportive in nature. The recent US Food and Drug Administration approval of crofelemer offers the first reliably effective treatment for HAART-related diarrhea. PMID- 24495295 TI - Dendritic and axonal targeting patterns of a genetically-specified class of retinal ganglion cells that participate in image-forming circuits. AB - BACKGROUND: There are numerous functional types of retinal ganglion cells (RGCs), each participating in circuits that encode a specific aspect of the visual scene. This functional specificity is derived from distinct RGC morphologies and selective synapse formation with other retinal cell types; yet, how these properties are established during development remains unclear. Islet2 (Isl2) is a LIM-homeodomain transcription factor expressed in the developing retina, including approximately 40% of all RGCs, and has previously been implicated in the subtype specification of spinal motor neurons. Based on this, we hypothesized that Isl2+ RGCs represent a related subset that share a common function. RESULTS: We morphologically and molecularly characterized Isl2+ RGCs using a transgenic mouse line that expresses GFP in the cell bodies, dendrites and axons of Isl2+ cells (Isl2-GFP). Isl2-GFP RGCs have distinct morphologies and dendritic stratification patterns within the inner plexiform layer and project to selective visual nuclei. Targeted filling of individual cells reveals that the majority of Isl2-GFP RGCs have dendrites that are monostratified in layer S3 of the IPL, suggesting they are not ON-OFF direction-selective ganglion cells. Molecular analysis shows that most alpha-RGCs, indicated by expression of SMI-32, are also Isl2-GFP RGCs. Isl2-GFP RGCs project to most retino-recipient nuclei during early development, but specifically innervate the dorsal lateral geniculate nucleus and superior colliculus (SC) at eye opening. Finally, we show that the segregation of Isl2+ and Isl2- RGC axons in the SC leads to the segregation of functional RGC types. CONCLUSIONS: Taken together, these data suggest that Isl2+ RGCs comprise a distinct class and support a role for Isl2 as an important component of a transcription factor code specifying functional visual circuits. Furthermore, this study describes a novel genetically-labeled mouse line that will be a valuable resource in future investigations of the molecular mechanisms of visual circuit formation. PMID- 24495296 TI - SInC: an accurate and fast error-model based simulator for SNPs, Indels and CNVs coupled with a read generator for short-read sequence data. AB - BACKGROUND: The rapid advancements in the field of genome sequencing are aiding our understanding on many biological systems. In the last five years, computational biologists and bioinformatics specialists have come up with newer, better and more efficient tools towards the discovery, analysis and interpretation of different genomic variants from high-throughput sequencing data. Availability of reliable simulated dataset is essential and is the first step towards testing any newly developed analytical tools for variant discovery. Although there are tools currently available that can simulate variants, none present the possibility of simulating all the three major types of variations (Single Nucleotide Polymorphisms, Insertions and Deletions and Copy Number Variations) and can generate reads taking a realistic error-model into consideration. Therefore, an efficient simulator and read generator is needed that can simulate variants taking the error rates of true biological samples into consideration. RESULTS: We report SInC (Snp, Indel and Cnv) an open-source variant simulator and read generator capable of simulating all the three common types of biological variants taking into account a distribution of base quality score from a most commonly used next-generation sequencing instrument from Illumina. SInC is capable of generating single- and paired-end reads with user defined insert size and with high efficiency compared to the other existing tools. SInC, due to its multi-threaded capability during read generation, has a low time footprint. SInC is currently optimised to work in limited infrastructure setup and can efficiently exploit the commonly used quad-core desktop architecture to simulate short sequence reads with deep coverage for large genomes. CONCLUSIONS: We have come up with a user-friendly multi-variant simulator and read-generator tools called SInC. SInC can be downloaded from http://sourceforge.net/projects/sincsimulator. PMID- 24495297 TI - A case of granulomatosis with polyangiitis complicated by cyclophosphamide toxicity and opportunistic infections: choosing between Scylla and Charybdis. AB - BACKGROUND: We report a case of progressive Granulomatosis with Polyangiitis (Wegener's Granulomatosis) with life-threatening complications of both the underlying disease and induction immunosuppressive therapy. Here, for the first time, cyclophosphamide toxicity and severe opportunistic infections including pneumocystis jirovecii- pneumonia were found in one case in a close temporal relationship. CASE PRESENTATION: A 34-year-old male patient of Caucasian ethnicity presented with acute renal failure necessitating hemodialysis treatment due to Granulomatosis with Polyangiitis (Wegener's Granulomatosis). Kidney disease progressed to end-stage renal disease shortly after first diagnosis. After the 2nd bolus of cyclophosphamide shortly, induction immunosuppression (glucocorticoid/cyclophosphamide) was interrupted for repeat infections and resumed 5 years later. By that time, the lungs developed large pulmonary cavernae most likely due to smoldering granuloma indicative for the failed goal of disease remission. Therefore, induction immunosuppression was resumed. Following two monthly boli of cyclophosphamide, the patient developed pericardial effusion and, consecutively, atrioventricular blockade most likely due to cyclophosphamide. After recovery, the patient was discharged without cotrimoxacole. 10 weeks after the last cyclophosphamide bolus and 6 weeks after cessation of cotrimoxacole, the patient was readmitted to the intensive-care unit with Pneumocystis jirovecii pneumonia, and died 6 months later or 74 months after first diagnosis of Granulomatosis with Polyangiitis. CONCLUSIONS: This case illustrates both the need for adequate immunosuppressive therapy to reach disease remission and the limitations thereof in terms of complications including cardiotoxicity of cyclophosphamide and Pneumocystis jirovecii pneumonia. In line with current recommendations, the present case strongly encourages pneumocystis jirovecii- pneumonia chemoprophylaxis for at least 6 months following induction therapy in Granulomatosis with Polyangiitis. PMID- 24495298 TI - Atomic force microscopy to study molecular mechanisms of amyloid fibril formation and toxicity in Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disease characterized by dementia and memory loss for which no cure or effective prevention is currently available. Neurodegeneration in AD is linked to formation of amyloid plaques found in brain tissues of Alzheimer's patients during post-mortem examination. Amyloid plaques are composed of amyloid fibrils and small oligomers insoluble protein aggregates. Although amyloid plaques are found on the neuronal cell surfaces, the mechanism of amyloid toxicity is still not well understood. Currently, it is believed that the cytotoxicity is a result of the nonspecific interaction of small soluble amyloid oligomers (rather than longer fibrils) with the plasma membrane. In recent years, nanotechnology has contributed significantly to understanding the structure and function of lipid membranes and to the study of the molecular mechanisms of membrane-associated diseases. We review the current state of research, including applications of the latest nanotechnology approaches, on the interaction of lipid membranes with the amyloid beta (Abeta) peptide in relation to amyloid toxicity. We discuss the interactions of Abeta with model lipid membranes with a focus to demonstrate that composition, charge and phase of the lipid membrane, as well as lipid domains and rafts, affect the binding of Abeta to the membrane and contribute to toxicity. Understanding the role of the lipid membrane in AD at the nanoscale and molecular level will contribute to the understanding of the molecular mechanism of amyloid toxicity and may aid into the development of novel preventive strategies to combat AD. PMID- 24495299 TI - The use of liveweight change as an indicator of oestrus in a seasonally calving, pasture-fed dairy herd. AB - This was an observational study of 828 lactations in 542 mixed-age dairy cows that calved seasonally in a single, pasture-fed herd in New Zealand in 2008 and 2009. The study objectives were to: (i) document daily liveweight change (?LW) before and after observed oestrus for cows subsequently diagnosed pregnant or non pregnant and (ii) quantify the sensitivity and specificity of ?LW as a test for oestrus. The sensitivity and specificity of ?LW when combined with other commonly used oestrous detection methods was also evaluated. In cows that conceived as a result of service at detected oestrus, liveweight loss began 1 day before the day of detection and was greatest on the day of detection (-9.6 kg, 95% CI -11.3 kg to -7.8 kg; p < 0.01) compared with LW recorded 2 days before the day of detection. In cows that did not conceive to a service at a detected oestrus, the lowest liveweights were recorded 1 day before the day oestrus was detected (-4.3 kg, 95% CI -7.7 to -0.8 kg; p = 0.02) compared with LW recorded 4 days before the day of detection. The sensitivity and specificity of ?LW as a means of oestrous detection were 0.42 (95% CI 0.40-0.45) and 0.96 (95% CI 0.95-0.97), respectively. When ?LW was combined with tail paint and visual observation, the oestrous detection sensitivity and specificity were 0.86 and 0.94, respectively. Monitoring LW change holds promise to enhance the sensitivity and specificity of oestrous detection in combination with other oestrous detection methods. PMID- 24495300 TI - Oestrogen up-regulates interleukin-21 production by CD4(+) T lymphocytes in patients with systemic lupus erythematosus. AB - Systemic lupus erythematosus (SLE) is an autoimmune disease in which abnormal immune responses are mediated by tissue-binding autoantibodies and immune complex deposition. Because most SLE patients are women of child-bearing age, oestrogen has been suggested to play an important role in SLE pathogenesis. One proposed role is to induce B-cell activation, culminating in increased autoantibody production. Interleukin-21 (IL-21) has been shown to be crucial in the differentiation of activated B cells into plasma cells. We therefore hypothesized that oestrogen up-regulates IL-21 production and induces subsequent B-cell activation in SLE patients. Peripheral blood was obtained from 22 SLE patients and 16 healthy controls. Expression levels of IL-21 and its receptor in serum, peripheral blood mononuclear cells, and CD4(+) T cells were higher in SLE patients than in healthy controls. Exposure of CD4(+) T cells from SLE patients to 17beta-oestradiol led to a dose- and time-dependent increase in IL-21 expression, which was abolished in the presence of mitogen-activated protein kinase (MAPK) (MAPK kinase, p38, Jun N-terminal kinase) inhibitors. B cells from healthy controls showed increased antibody production when they were co-cultured with oestrogen-treated CD4(+) T cells from SLE patients. Treatment with IL-21 antibody abrogated the increased antibody production of the co-culture systems. This study revealed the association between oestrogen and IL-21 in SLE patients. Oestrogen up-regulates IL-21 expression of CD4(+) T cells via MAPK-dependent pathways in SLE patients, which in turn induces increased antibody production by B cells. PMID- 24495302 TI - Executive functions and information processing in patients with type 2 diabetes in comparison to pre-diabetic patients. AB - BACKGROUND: Diabetes is associated with cognitive decline or dementia. The purpose of this study was to assess the executive functions and information processing in patients with type 2diabetes in comparison to pre-diabetic patients and normal subjects in Endocrine and Metabolism Research Center of Isfahan City from April to July 2011. METHODS: The sample consisted of 32 patients with type 2 diabetes, 28 pre-diabetic patients and 30 healthy individuals. Executive functions were assessed by Wisconsin Card Sorting Test (WCST). Information processing was assessed by Paced Auditory Serial Addition Test (PASAT) and sub tests of Wechsler Adult Intelligence Scale-Revised (WAIS-R). RESULTS: There was a significant difference among 3 groups, after the variables of age, sex and academic status were controlled (p <= 0.001). The pairwise comparisons of executive functions among three groups suggest a significant difference between diabetic and normal groups in WCST (perseveration) p = 0.018, and significant difference between diabetic and pre-diabetic patient in WCST (perseveration) p = 0.019. But there was no difference between three groups in WCST (category) and WCST (conceptual responses). The pairwise comparisons of information processing among three groups, suggest a significant difference between diabetic and normal groups in PASAT3". PASAT2", and Symbol coding (P = 0.003, P = 0.009, and P = 0.001, respectively). There was a significant correlation between demographic variable (FBS, HbA1c) and Symbol coding p = 0.05, p = 0.01 respectively) and significant correlation between (cholesterol) and WCST (conceptual responses) p = 0.05. The other variables were not correlated. CONCLUSION: There were significant differences in executive function and information processing in patients with type 2 diabetic and normal individuals. Thus, monitoring neuropsychological status besides controlling levels of blood sugar in these patients is important. PMID- 24495303 TI - Inaccuracy in factor VIII measurement due to administration of recombinant activated factor VII in vivo. PMID- 24495301 TI - Quality appraisal of generic self-reported instruments measuring health-related productivity changes: a systematic review. AB - BACKGROUND: Health impairments can result in disability and changed work productivity imposing considerable costs for the employee, employer and society as a whole. A large number of instruments exist to measure health-related productivity changes; however their methodological quality remains unclear. This systematic review critically appraised the measurement properties in generic self reported instruments that measure health-related productivity changes to recommend appropriate instruments for use in occupational and economic health practice. METHODS: PubMed, PsycINFO, Econlit and Embase were systematically searched for studies whereof: (i) instruments measured health-related productivity changes; (ii) the aim was to evaluate instrument measurement properties; (iii) instruments were generic; (iv) ratings were self-reported; (v) full-texts were available. Next, methodological quality appraisal was based on COSMIN elements: (i) internal consistency; (ii) reliability; (iii) measurement error; (iv) content validity; (v) structural validity; (vi) hypotheses testing; (vii) cross-cultural validity; (viii) criterion validity; and (ix) responsiveness. Recommendations are based on evidence syntheses. RESULTS: This review included 25 articles assessing the reliability, validity and responsiveness of 15 different generic self-reported instruments measuring health related productivity changes. Most studies evaluated criterion validity, none evaluated cross-cultural validity and information on measurement error is lacking. The Work Limitation Questionnaire (WLQ) was most frequently evaluated with moderate respectively strong positive evidence for content and structural validity and negative evidence for reliability, hypothesis testing and responsiveness. Less frequently evaluated, the Stanford Presenteeism Scale (SPS) showed strong positive evidence for internal consistency and structural validity, and moderate positive evidence for hypotheses testing and criterion validity. The Productivity and Disease Questionnaire (PRODISQ) yielded strong positive evidence for content validity, evidence for other properties is lacking. The other instruments resulted in mostly fair-to-poor quality ratings with limited evidence. CONCLUSIONS: Decisions based on the content of the instrument, usage purpose, target country and population, and available evidence are recommended. Until high-quality studies are in place to accurately assess the measurement properties of the currently available instruments, the WLQ and, in a Dutch context, the PRODISQ are cautiously preferred based on its strong positive evidence for content validity. Based on its strong positive evidence for internal consistency and structural validity, the SPS is cautiously recommended. PMID- 24495304 TI - The evolutionary ecology of testicular function: size isn't everything. AB - Larger testes are considered the quintessential adaptation to sperm competition. However, the strong focus on testis size in evolutionary research risks ignoring other potentially adaptive features of testicular function, many of which will also be shaped by post-mating sexual selection. Here we advocate a more integrated research programme that simultaneously takes into account the developmental machinery of spermatogenesis and the various selection pressures that act on this machinery and its products. The testis is a complex organ, and so we begin by outlining how we can think about the evolution of testicular function both in terms of the composition and spatial organisation of the testis ('testicular histology'), as well as in terms of the logical organisation of cell division during spermatogenesis ('testicular architecture'). We then apply these concepts to ask which aspects of testicular function we can expect to be shaped by post-mating sexual selection. We first assess the impact of selection on those traits most strongly associated with sperm competition, namely the number and kind of sperm produced. A broad range of studies now support our contention that post-mating sexual selection affects many aspects of testicular function besides gross testis size, for example, to maximise spermatogenic efficiency or to enable the production of particular sperm morphologies. We then broaden our focus to ask how testicular function is affected by fluctuation in sperm demand. Such fluctuation can occur over an individual's lifetime (for example due to seasonality in reproduction) and may select for particular types of testicular histology and architecture depending on the particular reproductive ecology of the species in question. Fluctuation in sperm demand also occurs over evolutionary time, due to shifts in the mating system, and this may have various consequences for testicular function, for example on rates of proliferation induced mutation and for dealing with intragenomic conflict. We end by suggesting additional approaches that could be applied to study testicular function, and conclude that simultaneously considering the machinery, products and scheduling of spermatogenesis will be crucial as we seek to understand more fully the evolution of this most fundamental of male reproductive traits. PMID- 24495305 TI - Calcitonin gene-related powerpeptide and its puzzling receptor. PMID- 24495306 TI - ADAM17 mediates OSCC development in an orthotopic murine model. AB - BACKGROUND: ADAM17 is one of the main sheddases of the cells and it is responsible for the cleavage and the release of ectodomains of important signaling molecules, such as EGFR ligands. Despite the known crosstalk between ADAM17 and EGFR, which has been considered a promising targeted therapy in oral squamous cell carcinoma (OSCC), the role of ADAM17 in OSCC development is not clear. METHOD: In this study the effect of overexpressing ADAM17 in cell migration, viability, adhesion and proliferation was comprehensively appraised in vitro. In addition, the tumor size, tumor proliferative activity, tumor collagenase activity and MS-based proteomics of tumor tissues have been evaluated by injecting tumorigenic squamous carcinoma cells (SCC-9) overexpressing ADAM17 in immunodeficient mice. RESULTS: The proteomic analysis has effectively identified a total of 2,194 proteins in control and tumor tissues. Among these, 110 proteins have been down-regulated and 90 have been up-regulated in tumor tissues. Biological network analysis has uncovered that overexpression of ADAM17 regulates Erk pathway in OSCC and further indicates proteins regulated by the overexpression of ADAM17 in the respective pathway. These results are also supported by the evidences of higher viability, migration, adhesion and proliferation in SCC-9 or A431 cells in vitro along with the increase of tumor size and proliferative activity and higher tissue collagenase activity as an outcome of ADAM17 overexpression. CONCLUSION: These findings contribute to understand the role of ADAM17 in oral cancer development and as a potential therapeutic target in oral cancer. In addition, our study also provides the basis for the development of novel and refined OSCC-targeting approaches. PMID- 24495307 TI - Evaluating linkage to care for hypertension after community-based screening in rural Uganda. AB - OBJECTIVES: To determine the frequency and predictors of hypertension linkage to care after implementation of a linkage intervention in rural Uganda. METHODS: During a multidisease screening campaign for HIV, diabetes and hypertension in rural Uganda, hypertensive adults received education, appointment to a local health facility and travel voucher. We measured frequency and predictors of linkage to care, defined as visiting any health facility for hypertension management within 6 months. Predictors of linkage to care were calculated using collaborative-targeted maximum likelihood estimation (C-TMLE). Participants not linking were interviewed using a standardised instrument to determine barriers to care. RESULTS: Over 5 days, 2252 adults were screened for hypertension and 214 hypertensive adults received a linkage intervention for further management. Of these, 178 (83%) linked to care within 6 months (median = 22 days). Independent predictors of successful linkage included older age, female gender, higher education, manual employment, tobacco use, alcohol consumption, hypertension family history and referral to local vs. regional health centre. Barriers for patients who did not see care included expensive transport (59%) and feeling well (59%). CONCLUSIONS: A community health campaign that offered hypertension screening, education, referral appointment and travel voucher achieved excellent linkage to care (83%). Young adults, men and persons with low levels of formal education were among those least likely to seek care. PMID- 24495309 TI - Breaking immunotolerance of tumors: a new perspective for dendritic cell therapy. AB - The use of dendritic cells (DC) in cancer immunotherapy is based on their potent abilities to present antigens, so they can act as 'natural adjuvants' to enhance immunogenicity of tumor antigens and stimulate specific cytotoxic T-cells. Large amounts of DC can be generated from bone marrow, neonatal cord blood, and peripheral blood CD34(+) hematopoietic stem cells, or from peripheral blood monocytes. The DC can then be pulsed with tumor antigens and re-infused. In vitro, antigen-pulsed DC can stimulate allogeneic T-cell proliferation and induction of autologous specific cytotoxic T-cells; in vivo, the cells inhibit the growth of tumors or protect hosts (i.e. mice) from development of inoculated tumors. The results of preliminary clinical trials have shown that DC vaccines are safe and elicit immune responses; however, the rates of clinical responses are low. It has become quite clear that one key reason for unsatisfactory clinical results is tumor-induced immunosuppression. Among the factors contributing to this type of immunosuppression are populations of regulatory cells including: T-regulatory (T(reg)) cells, myeloid-derived suppressor cells (MDSC), tumor-associated macrophages (TAM), and DC expressing 2,3-dioxygenase indoleamine (IDO-DC). This review presents an overview of the current understanding about populations of regulatory cells and the most current research efforts directed to overcome immunosuppressive activity due to the tumor microenvironment. PMID- 24495308 TI - Metabolomic insights into system-wide coordination of vertebrate metamorphosis. AB - BACKGROUND: After completion of embryogenesis, many organisms experience an additional obligatory developmental transition to attain a substantially different juvenile or adult form. During anuran metamorphosis, the aquatic tadpole undergoes drastic morphological changes and remodelling of tissues and organs to become a froglet. Thyroid hormones are required to initiate the process, but the mechanism whereby the many requisite changes are coordinated between organs and tissues is poorly understood. Metabolites are often highly conserved biomolecules between species and are the closest reflection of phenotype. Due to the extensive distribution of blood throughout the organism, examination of the metabolites contained therein provides a system-wide overview of the coordinated changes experienced during metamorphosis. We performed an untargeted metabolomic analysis on serum samples from naturally-metamorphosing Rana catesbeiana from tadpoles to froglets using ultraperformance liquid chromatography coupled to a mass spectrometer. Total and aqueous metabolite extracts were obtained from each serum sample to select for nonpolar and polar metabolites, respectively, and selected metabolites were validated by running authentic compounds. RESULTS: The majority of the detected metabolites (74%) showed statistically significant abundance changes (padj < 0.001) between metamorphic stages. We observed extensive remodelling of five core metabolic pathways: arginine and purine/pyrimidine, cysteine/methionine, sphingolipid, and eicosanoid metabolism and the urea cycle, and found evidence for a major role for lipids during this postembryonic process. Metabolites traditionally linked to human disease states were found to have biological linkages to the system-wide changes occuring during the events leading up to overt morphological change. CONCLUSIONS: To our knowledge, this is the first wide-scale metabolomic study of vertebrate metamorphosis identifying fundamental pathways involved in the coordination of this important developmental process and paves the way for metabolomic studies on other metamorphic systems including fish and insects. PMID- 24495310 TI - Intra-operative arrhythmia predicts post-operative arrhythmia and the need for temporary pacing wires. AB - OBJECTIVE: Protocols for the placement of temporary pacing wires vary among institutions. Our current protocol is to selectively place temporary pacing wires in those patients who develop haemodynamically significant intra-operative arrhythmia. We wished to identify how effective our current protocol is at identifying who will develop post-operative arrhythmia and need temporary pacing wires. METHODS: The charts of 880 patients over 8 years who underwent cardiopulmonary bypass were reviewed to find patients who developed intra operative arrhythmia, had temporary pacing wires placed, and whether or not they developed post-operative arrhythmia and required utilisation of the pacing wires. RESULTS: A total of 87 (9.9%) out of 880 patients who required cardiopulmonary bypass over 8 years had intra-operative arrhythmia and had temporary pacing wires placed. Of these, 59 (67.8%) had post-operative arrhythmia and utilised the pacing wires, whereas 28 (32.2%) did not have post-operative arrhythmia or utilise the pacing wires. In all, seven patients who did not have intra-operative arrhythmia or temporary pacing wires placed developed post-operative arrhythmia. CONCLUSION: Intra-operative arrhythmia is predictive of post-operative arrhythmia (70.2%) and our protocol is a sensitive means of identifying those who will develop post-operative arrhythmia (89.3%). PMID- 24495311 TI - Metal atom dynamics in superbulky metallocenes: a comparison of (Cp(BIG))2Sn and (Cp(BIG))2Eu. AB - Cp(BIG)2Sn (Cp(BIG) = (4-n-Bu-C6H4)5cyclopentadienyl), prepared by reaction of 2 equiv of Cp(BIG)Na with SnCl2, crystallized isomorphous to other known metallocenes with this ligand (Ca, Sr, Ba, Sm, Eu, Yb). Similarly, it shows perfect linearity, C-H...C(pi) bonding between the Cp(BIG) rings and out-of-plane bending of the aryl substituents toward the metal. Whereas all other Cp(BIG)2M complexes show large disorder in the metal position, the Sn atom in Cp(BIG)2Sn is perfectly ordered. In contrast, (119)Sn and (151)Eu Mobetabauer investigations on the corresponding Cp(BIG)2M metallocenes show that Sn(II) is more dynamic and loosely bound than Eu(II). The large displacement factors in the group 2 and especially in the lanthanide(II) metallocenes Cp(BIG)2M can be explained by static metal disorder in a plane parallel to the Cp(BIG) rings. Despite parallel Cp(BIG) rings, these metallocenes have a nonlinear Cpcenter-M-Cpcenter geometry. This is explained by an ionic model in which metal atoms are polarized by the negatively charged Cp rings. The extent of nonlinearity is in line with trends found in M(2+) ion polarizabilities. The range of known calculated dipole polarizabilities at the Douglas-Kroll CCSD(T) level was extended with values (atomic units) for Sn(2+) 15.35, Sm(2+)(4f(6) (7)F) 9.82, Eu(2+)(4f(7) (8)S) 8.99, and Yb(2+)(4f(14) (1)S) 6.55. This polarizability model cannot be applied to predominantly covalently bound Cp(BIG)2Sn, which shows a perfectly ordered structure. The bent geometry of Cp*2Sn should therefore not be explained by metal polarizability but is due to van der Waals Cp*...Cp* attraction and (to some extent) to a small p-character component in the Sn lone pair. PMID- 24495313 TI - Using climate-FVS to project landscape-level forest carbon stores for 100 years from field and LiDAR measures of initial conditions. AB - BACKGROUND: Forest resources supply a wide range of environmental services like mitigation of increasing levels of atmospheric carbon dioxide (CO2). As climate is changing, forest managers have added pressure to obtain forest resources by following stand management alternatives that are biologically sustainable and economically profitable. The goal of this study is to project the effect of typical forest management actions on forest C levels, given a changing climate, in the Moscow Mountain area of north-central Idaho, USA. Harvest and prescribed fire management treatments followed by plantings of one of four regionally important commercial tree species were simulated, using the climate-sensitive version of the Forest Vegetation Simulator, to estimate the biomass of four different planted species and their C sequestration response to three climate change scenarios. RESULTS: Results show that anticipated climate change induces a substantial decrease in C sequestration potential regardless of which of the four tree species tested are planted. It was also found that Pinus monticola has the highest capacity to sequester C by 2110, followed by Pinus ponderosa, then Pseudotsuga menziesii, and lastly Larix occidentalis. CONCLUSIONS: Variability in the growth responses to climate change exhibited by the four planted species considered in this study points to the importance to forest managers of considering how well adapted seedlings may be to predicted climate change, before the seedlings are planted, and particularly if maximizing C sequestration is the management goal. PMID- 24495312 TI - Comparison of physician-certified verbal autopsy with computer-coded verbal autopsy for cause of death assignment in hospitalized patients in low- and middle income countries: systematic review. AB - BACKGROUND: Computer-coded verbal autopsy (CCVA) methods to assign causes of death (CODs) for medically unattended deaths have been proposed as an alternative to physician-certified verbal autopsy (PCVA). We conducted a systematic review of 19 published comparison studies (from 684 evaluated), most of which used hospital based deaths as the reference standard. We assessed the performance of PCVA and five CCVA methods: Random Forest, Tariff, InterVA, King-Lu, and Simplified Symptom Pattern. METHODS: The reviewed studies assessed methods' performance through various metrics: sensitivity, specificity, and chance-corrected concordance for coding individual deaths, and cause-specific mortality fraction (CSMF) error and CSMF accuracy at the population level. These results were summarized into means, medians, and ranges. RESULTS: The 19 studies ranged from 200 to 50,000 deaths per study (total over 116,000 deaths). Sensitivity of PCVA versus hospital-assigned COD varied widely by cause, but showed consistently high specificity. PCVA and CCVA methods had an overall chance-corrected concordance of about 50% or lower, across all ages and CODs. At the population level, the relative CSMF error between PCVA and hospital-based deaths indicated good performance for most CODs. Random Forest had the best CSMF accuracy performance, followed closely by PCVA and the other CCVA methods, but with lower values for InterVA-3. CONCLUSIONS: There is no single best-performing coding method for verbal autopsies across various studies and metrics. There is little current justification for CCVA to replace PCVA, particularly as physician diagnosis remains the worldwide standard for clinical diagnosis on live patients. Further assessments and large accessible datasets on which to train and test combinations of methods are required, particularly for rural deaths without medical attention. PMID- 24495314 TI - Effects of food on the pharmacokinetics of gemigliptin/metformin sustained release 50/1,000 mg (25/500 mg x 2 tablets) fixeddose combination tablet in healthy male volunteers. AB - OBJECTIVES: For patient convenience, a gemigliptin/metformin sustainedrelease fixed-dose combination (FDC) tablet was developed. This study was conducted to investigate the effects of food on the pharmacokinetic (PK) profile of the FDC tablets. MATERIALS AND METHODS: This was an open-label, randomized, single dose, 2-period, 2-sequence crossover study in 24 healthy male volunteers. The FDC tablets (25/500 mg * 2 tablets) were administered in high-fat fed and fasted states on separate occasions, and each subject was randomly allocated to each sequence with a 7-day washout period. PK blood samplings were conducted from predose to 48 hours after dosing. Tolerability assessments were performed throughout the study. RESULTS: Nine adverse events (AEs) of mild intensity were reported from 8 subjects after study drug administration, and the AE frequency was similar between treatments. No serious AEs were reported. The PK parameters of gemigliptin and metformin were compared between fasting and fed states. For gemigliptin, the geometric mean ratios (GMRs) (fed : fasted state) of the Cmax and AUClast were 0.886 (90% confidence interval (CI) 0.781 - 1.006) and 1.021 (90% CI 0.949 - 1.099), respectively. For metformin, the GMRs of the Cmax and AUClast were 0.811 (90% CI 0.712 - 0.923) and 1.144 (90% CI 1.013 - 1.291), respectively. A prolonged tmax for metformin was observed. These results are similar to the effects of food on each component. CONCLUSION: The FDC tablet may have a similar PK profile as that of individual drugs and is generally tolerable when administered with food. These results indicate that the FDC tablet can be administered in the same dosing regimen as each component, especially that of metformin sustained-release. PMID- 24495316 TI - Caring nurse practice in the intrapartum setting: nurses' perspectives on complexity, relationships and safety. AB - AIM: This article reports on a qualitative study of nurse perceptions of caring nurse practice in the complex adaptive system of health care. BACKGROUND: Caring nurse practice encompasses technical skills and caring behaviours. Maternity care in the USA has seen worsening maternal and neonatal outcomes and safety has become a priority. As a result, hospital systems have begun efforts to improve outcomes, initiating safety and quality programmes that standardize care and implementing nursing frameworks that enhance relationships. DESIGN: Qualitative hermeneutic phenomenology. METHODS: A qualitative design analysed 13 nurses' perspectives on caring practice during the second stage of labour. In June and July of 2012, interviews were conducted with 13 labour and delivery nurses located in a hospital that had adopted a perinatal safety initiative and relationship-focused nursing model. The nurses described caring nurse practice and the factors that affected its provision. Transcripts of audio recordings and notes taken during interviews were analysed for themes and fundamental meanings. FINDINGS: Nurses' perspectives about the provision of caring nurse practice was affected by the complexity of the healthcare system, interactions with team members, challenges related to documentation; and respect for natural birth. CONCLUSION: Nurses at all levels of practice can use these perspectives to identify patterns in the complex adaptive healthcare system to improve quality and safety. Best practices include enhancing teamwork, implementing safety initiatives and promoting a Relationship-Based framework. Continued study of caring nurse practice could lead to establishment of additional safety and quality protocols vital to improving patient outcomes. PMID- 24495315 TI - Waist circumference and insulin resistance in elderly men: an analysis of Kahrizak elderly study. AB - BACKGROUND: Diagnosis of the metabolic syndrome (MS) is crucial for health care practitioners to identify at risk people for early treatment. Visceral obesity may make unnecessary other laborious measures of insulin resistance. The aim of this study was to see whether waist circumference (WC) can predict insulin resistance as well as MS in a group of Iranian elderly. METHODS: Out of 94 nondiabetic elderly, thirty three subjects were recognized with MS. MS diagnosis was based on NCEP ATP III (National Cholesterol Education Program Adult Treatment Panel III) and IDF (International Diabetes Federation) definitions. HOMA (Homeostasis Model Assessment) index was used to measure insulin sensitivity. Insulin resistance (IR) was defined as top quartile of HOMA. RESULTS: In both sexes, WC and HOMA index were significantly positively correlated. The optimal waist circumference (OWC) cutoff point was 94.5 cm for men and 90.5 cm for women. The high sensitivity (0.80) and specificity (0.84) of WC in males indicates the proportion of IR which is correctly identified and recognizes all non-IR males as such. In regression model only the TG level was associated with WC. But the WC is strongly associated with HOMA-IR. CONCLUSIONS: While OWC is very likely a good measure to exclude non-IR subjects in our study, determination of optimal WC to identify elderly IR subjects warrants further study in a larger sample of the general population. PMID- 24495317 TI - Adipose tissue and its role in organ crosstalk. AB - The discovery of adipokines has revealed adipose tissue as a central node in the interorgan crosstalk network, which mediates the regulation of multiple organs and tissues. Adipose tissue is a true endocrine organ that produces and secretes a wide range of mediators regulating adipose tissue function in an auto /paracrine manner and important distant targets, such as the liver, skeletal muscle, the pancreas and the cardiovascular system. In metabolic disorders such as obesity, enlargement of adipocytes leads to adipose tissue dysfunction and a shift in the secretory profile with an increased release of pro-inflammatory adipokines. Adipose tissue dysfunction has a central role in the development of insulin resistance, type 2 diabetes, and cardiovascular diseases. Besides the well-acknowledged role of adipokines in metabolic diseases, and the increasing number of adipokines being discovered in the last years, the mechanisms underlying the release of many adipokines from adipose tissue remain largely unknown. To combat metabolic diseases, it is crucial to better understand how adipokines can modulate adipose tissue growth and function. Therefore, we will focus on adipokines with a prominent role in auto-/paracrine crosstalk within the adipose tissue such as RBP4, HO-1, WISP2, SFRPs and chemerin. To depict the endocrine crosstalk between adipose tissue with skeletal muscle, the cardiovascular system and the pancreas, we will report the main findings regarding the direct effects of adiponectin, leptin, DPP4 and visfatin on skeletal muscle insulin resistance, cardiovascular function and beta-cell growth and function. PMID- 24495318 TI - Unmixing of fluorescence spectra to resolve quantitative time-series measurements of gene expression in plate readers. AB - BACKGROUND: To connect gene expression with cellular physiology, we need to follow levels of proteins over time. Experiments typically use variants of Green Fluorescent Protein (GFP), and time-series measurements require specialist expertise if single cells are to be followed. Fluorescence plate readers, however, a standard in many laboratories, can in principle provide similar data, albeit at a mean, population level. Nevertheless, extracting the average fluorescence per cell is challenging because autofluorescence can be substantial. RESULTS: Here we propose a general method for correcting plate reader measurements of fluorescent proteins that uses spectral unmixing and determines both the fluorescence per cell and the errors on that fluorescence. Combined with strain collections, such as the GFP fusion collection for budding yeast, our methodology allows quantitative measurements of protein levels of up to hundreds of genes and therefore provides complementary data to high throughput studies of transcription. We illustrate the method by following the induction of the GAL genes in Saccharomyces cerevisiae for over 20 hours in different sugars and argue that the order of appearance of the Leloir enzymes may be to reduce build-up of the toxic intermediate galactose-1-phosphate. Further, we quantify protein levels of over 40 genes, again over 20 hours, after cells experience a change in carbon source (from glycerol to glucose). CONCLUSIONS: Our methodology is sensitive, scalable, and should be applicable to other organisms. By allowing quantitative measurements on a per cell basis over tens of hours and over hundreds of genes, it should increase our understanding of the dynamic changes that drive cellular behaviour. PMID- 24495319 TI - Evaluation of chest tube administration of tissue plasminogen activator to treat retained hemothorax. AB - BACKGROUND: When retained hemothorax occurs, video-assisted thoracoscopy or thoracotomy is performed, but recently, tissue plasminogen activator (tPA) has been used. This study evaluated intrapleural tPA use for retained traumatic hemothoraces. METHODS: A retrospective review was conducted of trauma patients treated with intrapleural tPA for retained hemothorax. Data included demographics, past medical and surgical histories, injury details, treatment details, and outcomes. RESULTS: Seven patients (median age = 47 years, male = 6, blunt trauma = 6) met study criteria. All patients received a chest tube. Six patients later received computed tomography-guided drains for tPA infusion. Number of tPA treatments per patient varied from 1 to 5. Median total tPA dosage was 24 mg. Median time from injury to chest tube placement was 11 days and from chest tube placement to first tPA treatment was 4 days. No patients required a video-assisted thoracoscopy; however, 1 patient required thoracotomy. There were no deaths or bleeding complications attributed to intrapleural tPA. CONCLUSION: Although future studies are needed to identify optimum treatment guidelines, intrapleural tPA appears to be a safe and efficacious treatment option. PMID- 24495320 TI - Techniques of parathyroid exploration at North American endocrine surgery fellowship programs: what the next generation is being taught. AB - BACKGROUND: Minimally invasive techniques are now often used to treat primary hyperparathyroidism but with uncertain conformity and some controversy. Endocrine surgery fellowships (ESFPs) have recently proliferated. METHODS: The directors of the 19 ESFPs recognized by the American Association of Endocrine Surgeons were polled to identify the approaches currently taught to trainees. RESULTS: With 100% participation, all ESFPs obtain >=1 imaging study, and 95% use ultrasound to assess for concurrent thyroid nodules that require care. For an apparent single adenoma, all ESFPs minimize dissection, use intraoperative parathyroid hormone monitoring, and, if multiglandular disease is identified, perform 4-gland exploration. Outpatient surgery (89%) and postoperative oral calcium use (68%) are common. All programs define cure as durable normocalcemia (median, 6 months). CONCLUSIONS: American Association of Endocrine Surgeons fellowship programs teach congruent management strategies that include focused dissection, intraoperative parathyroid hormone use, and intent to cure. These consistencies define a future standard for assessment of parathyroidectomy outcomes. PMID- 24495321 TI - Self-gripping mesh versus sutured mesh in open inguinal hernia repair: system review and meta-analysis. AB - BACKGROUND: The objective of this article was to compare the outcomes of self gripping mesh (GM) with sutured mesh (SM) in open inguinal hernia repair. METHODS: A systematic review and meta-analysis were taken to compare the outcomes of GM and SM in open inguinal hernia repair. RESULTS: A total of 1,353 patients in 6 randomized controlled trials and 2 observational studies were reviewed (666 patients in GM group; 687 patients in SM group). The 2 groups did not significantly differ in chronic groin pain (P = .23) or recurrence (P = .59). The operating time was significantly shorter in GM group (P < .00001). There was no significant difference in infection (P = .18), seromas (P = .35), hematomas (P = .87), or discomfort (P = .58) between the 2 groups. CONCLUSIONS: The data showed that GM was equivalent to SM in open inguinal hernia repair. However, this new mesh still needs to be confirmed in large, multi-center, well-designed randomized controlled trials. PMID- 24495322 TI - Characterization of colony-forming cells in adult human articular cartilage. AB - Recent studies have shown that adult human articular cartilage contains stem-like cells within the native structure. In this study, we aimed to determine the localization of putative stem cell markers such as CD90, STRO-1, OCT-3/4, CD105 and CD166 in adult human articular cartilage tissue sections and demonstrate the expression of these markers within the expanded surface zone colony-forming (CF) cells and evaluate their differentiation potential. Biopsy samples were either fixed immediately for immunohistochemical analyses or processed for in vitro cell culture. Immunohistochemical and flow cytometry analyses were performed by using CD90, STRO-1, OCT-3/4, CD105 and CD166 antibodies. Isolated colony-forming (CF) cells were further stimulated, by using the appropriate growth factors in their pellet culture, to obtain cartilage, bone and adipose lineages. We observed that the expression of the stem cell markers were in various zones of the human adult cartilage. Flow cytometry results showed that in CF cells the expression of CD90 and CD166 was high, while OCT-3/4 was low. We also determined that CF cells could be stimulated towards cartilage, bone and adipose lineages. The results of this research support the idea that the resident stem-like cells in adult human articular cartilage express these putative stem cell markers, but further experimental investigations are needed to determine the precise localization of these cells. PMID- 24495323 TI - Recurrent stroke risk is high after a single cerebrovascular event in patients with symptomatic 50-99% carotid stenosis: a cohort study. AB - BACKGROUND: Recurrent TIAs are thought to signal a high stroke risk. The aim of this study is to examine if repeated ischemic events increase the risk of recurrent ipsilateral stroke among patients with symptomatic 50-99% carotid stenosis. METHODS: This is a secondary analysis of the ANSYSCAP study, where we analyzed recurrent ipsilateral ischemic stroke before carotid endarterectomy in 230 consecutive patients with symptomatic 50-99% carotid stenosis. Here, we further analyzed the patients according to if they were clinically stable, unstable or highly unstable - respectively defined as having 0, 1 or >=2 additional ipsilateral events within 7 days before and/or after the ischemic cerebrovascular event for which the patient sought health care (the presenting event). RESULTS: Of the 230 included patients, 155 (67%) were clinically stable, 47 (20%) were clinically unstable and 28 (12%) were clinically highly unstable. Eighteen patients suffered a stroke within 7 days; of these patients, 12 (67%) were clinically stable. The risk of recurrent ipsilateral ischemic stroke within 7 days was equally high for clinically stable (8%), unstable (9%) and highly unstable (7%) patients. Fourteen patients had 3-11 additional ipsilateral events; of these patients, only one suffered a recurrent ipsilateral ischemic stroke. CONCLUSIONS: The seemingly clinical stable symptomatic 50-99% carotid stenosis patients without additional ipsilateral events have a high risk of recurrent stroke. Patients without additional events should undergo preoperative evaluation and carotid endarterectomy in the same expedient manner as patients with additional events. PMID- 24495324 TI - Investigating the mechanisms of ribonucleotide excision repair in Escherichia coli. AB - Low fidelity Escherichia coli DNA polymerase V (pol V/UmuD'2C) is best characterized for its ability to perform translesion synthesis (TLS). However, in recA730 lexA(Def) strains, the enzyme is expressed under optimal conditions allowing it to compete with the cell's replicase for access to undamaged chromosomal DNA and leads to a substantial increase in spontaneous mutagenesis. We have recently shown that a Y11A substitution in the "steric gate" residue of UmuC reduces both base and sugar selectivity of pol V, but instead of generating an increased number of spontaneous mutations, strains expressing umuC_Y11A are poorly mutable in vivo. This phenotype is attributed to efficient RNase HII initiated repair of the misincorporated ribonucleotides that concomitantly removes adjacent misincorporated deoxyribonucleotides. We have utilized the ability of the pol V steric gate mutant to promote incorporation of large numbers of errant ribonucleotides into the E. coli genome to investigate the fundamental mechanisms underlying ribonucleotide excision repair (RER). Here, we demonstrate that RER is normally facilitated by DNA polymerase I (pol I) via classical "nick translation". In vitro, pol I displaces 1-3 nucleotides of the RNA/DNA hybrid and through its 5'->3' (exo/endo) nuclease activity releases ribo- and deoxyribonucleotides from DNA. In vivo, umuC_Y11A-dependent mutagenesis changes significantly in polymerase-deficient, or proofreading-deficient polA strains, indicating a pivotal role for pol I in ribonucleotide excision repair (RER). However, there is also considerable redundancy in the RER pathway in E. coli. Pol I's strand displacement and FLAP-exo/endonuclease activities can be facilitated by alternate enzymes, while the DNA polymerization step can be assumed by high fidelity pol III. We conclude that RNase HII and pol I normally act to minimize the genomic instability that is generated through errant ribonucleotide incorporation, but that the "nick-translation" activities encoded by the single pol I polypeptide can be undertaken by a variety of back-up enzymes. PMID- 24495325 TI - A systematic review of functional and quality of life assessment after major lower extremity amputation. AB - BACKGROUND: When judging the success or failure of major lower extremity (MLE) amputation, the assessment of appropriate functional and quality of life (QOL) outcomes is paramount. The heterogeneity of the scales and tests in the current literature is confusing and makes it difficult to compare results. We provide a primer for outcome assessment after amputation and assess the need for the additional development of novel instruments. METHODS: MEDLINE, EMBASE, and Google Scholar were searched for all studies using functional and QOL instruments after MLE amputation. Assessment instruments were divided into functional and QOL categories. Within each category, they were subdivided into global and amputation specific instruments. An overall assessment of instrument quality was obtained. RESULTS: The initial search revealed 746 potential studies. After a review of abstracts, 102 were selected for full review, and 40 studies were then included in this review. From the studies, 21 different assessment instruments were used 63 times. There were 14 (67%) functional measures and 7 (33%) QOL measures identified. Five (36%) of the functional instruments and 3 (43%) of the QOL measures were specific for MLE amputees. Sixteen instruments were used >1 time, but only 5 instruments were used >3 times. An additional 5 instruments were included that were deemed important by expert opinion. The 26 assessment instruments were rated. Fourteen of the best-rated instruments were then described. CONCLUSIONS: The heterogeneity of instruments used to measure both functional and QOL outcomes make it difficult to compare MLE amputation outcome studies. Future researchers should seek to use high-quality instruments. Clinical and research societies should endorse the best validated instruments for future use in order to strengthen overall research in the field. PMID- 24495326 TI - Double eversion carotid endarterectomy of tandem carotid lesions. AB - BACKGROUND: We describe an original method to treat tandem lesions of the internal carotid artery (ICA) and the common carotid artery (CCA). In this manuscript, we describe a "double eversion carotid endarterectomy" technique (DECE) and report our results. METHODS: A retrospective review in the medical records of patients that underwent DECE over a 15-year period was performed. Patient characteristics, operative details, preoperative imaging and lesion characteristics, perioperative outcomes, and follow-up data were documented and analyzed. Patients with ostial and mediastinal lesions were excluded from our study. Operations were divided into 2 categories: "planned," when the lesions were identified during preoperative imaging, and "necessary" when performed for secondary defects of the CCA detected intraoperatively. RESULTS: Between 1996 and 2011, a total of 15 patients with 17 tandem lesions underwent DECE. The mean age was 74.3 years. The mean degree of stenosis was 76.3% for the ICA and 61.5% for the CCA, with the majority of the lesions being asymptomatic (12/17). All procedures were performed under general anesthesia, and in 1 case an intraluminal shunt was used. The mean operative time was 83.4 min, with a mean primary clamping time of 29.2 min. In cases of secondary lesions, the mean reclamping time was 16.2 min. There was no mortality or major neurologic event within 30 days postoperatively. Postoperative complications included 2 major cardiac events and 1 case of cranial nerve XII injury that resolved during follow-up. There were no deaths or neurologic events during a mean follow-up of 27.5 months (range: 1 188 months). One patient required a reintervention after 5 years because of restenosis of the ICA. CONCLUSION: DECE is an alternative surgical technique for select tandem, nonostial carotid lesions. In addition, DECE can be performed as a "bailout" procedure for secondary CCA defects during conventional eversion carotid endarterectomy. PMID- 24495327 TI - Outcomes of combined somatosensory evoked potential, motor evoked potential, and electroencephalography monitoring during carotid endarterectomy. AB - BACKGROUND: While much has been written about multiple methods of neuromonitoring during carotid endarterectomy (CEA), there has been relatively little discussion of the use of triple monitoring via somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs) in conjunction with electroencephalography (EEG). Our objective was to evaluate the rate of detection and prevention of neurologic events by multinerve SEP, MEP, and EEG in patients undergoing CEA while under general anesthesia. METHODS: A prospective study of 181 consecutive patients undergoing CEA between June 2005 and September 2010 was reviewed. Intraoperative changes, including a 50% reduction in the amplitude of SEP waveforms, loss of MEP, and/or a 50% change in EEG frequency were noted as indications for shunting. This was correlated with the actual use of intraoperative shunting and postoperative neurologic sequelae at both 24 hours and 30 days. Median and tibial nerve SEPs and MEPs were also correlated. RESULTS: Eleven patients (6%) experienced intraoperative monitoring changes (SEP: 11/11; MEP: 6/11). Five of 11 patients with MEP/SEP changes underwent shunting, while the other 6 had normalization with the elevation of their blood pressure. Of the 11 patients that had neurophysiologic changes, 54% (6/11) were patients with symptomatic disease. No patients had significant EEG changes. The total shunt rate was 2.7% (5/181). No postoperative neurologic sequelae were noted. CONCLUSION: The ratio of shunting at 2.7% is equal to the lowest rates reported in the awake patient literature. Interestingly, the predicted synergy of multimodality monitoring cannot be directly attributed to an increased specificity resulting from the addition of SEP and MEP to EEG, because no patients had EEG changes. In addition, in today's cost-conscious world of health care, our results do not justify implementing this particular technique of neuromonitoring across the board-but it is apparent that the combination of these 3 modalities is both safe and effective with potential applications in symptomatic patients. PMID- 24495328 TI - Infected pseudoaneurysm after carotid endarterectomy: mismatch between clinical presentation and origin. AB - Pseudoaneurysm after carotid endarterectomy (CEA) is a rare complication, with an incidence lower than 1%. Infection as a cause of carotid pseudoaneurysm is uncommon, and is mostly caused by staphylococci. An 81-year-old woman, treated with right carotid endarterectomy 7 years earlier, presented with a diagnosis of right carotid pseudoaneurysm. The patient was neurologically asymptomatic; clinical status, laboratory, and imaging findings were negative for infection. She was referred to surgical treatment consisting of patch excision and a carotid polytetrafluoroethylene bypass grafting. During intervention a purulent fluid collection was discovered, and therefore an inverted great saphenous vein carotid bypass was performed. The postoperative course was normal. Microbiological examination on the purulent fluid collection and excised patch showed the presence of Staphylococcus epidermidis. Carotid pseudoaneurysms after CEA often arise in asymptomatic patients. Despite this common clinical presentation, an infective origin must always be taken into account before any intervention is planned. PMID- 24495329 TI - Spontaneous intrahepatic portosystemic shunt in Budd-Chiari syndrome. AB - Budd-Chiari syndrome (BCS) caused by hepatic venous outflow obstruction may result in portal hypertension and the development of intrahepatic collaterals that bypass the obstruction. Spontaneous intrahepatic portosystemic venous shunt (SIPSVS) is uncommon and may be associated with portal hypertension. SIPSVS is extremely rare in patients with BCS and has not been well documented. We report a case of SIPSVS in a 42-year-old woman with BCS caused by membranous obstruction and chronic thrombosis in the inferior vena cava (IVC). A direct vascular communication between the left portal vein and IVC was confirmed by sonography and a computed tomography angiography scan. The patient underwent successful percutaneous balloon angioplasty of the IVC. Surgical or endovascular treatment for SIPSVS was not carried out because the patient was asymptomatic and remained asymptomatic in terms of encephalopathy at a 1-year follow-up. PMID- 24495330 TI - Pancreaticoduodenal artery aneurysm associated with median arcuate ligament syndrome. AB - Aneurysm of the pancreaticoduodenal artery arcade has a well-documented association with occlusion of the celiac axis. The etiology of celiac occlusion is most commonly atherosclerotic disease. Occlusion or severe stenosis of the celiac artery secondary to a median arcuate ligament is less frequently encountered, and symptoms can be vague or completely lacking. We present a case of an asymptomatic 25-year-old woman who, in the course of being evaluated as a potential donor for living-related kidney transplantation, underwent a computed tomography angiography (CTA) scan that revealed an aneurysm of the pancreaticoduodenal artery. The aneurysm, as well as severe compression of the celiac axis by the median arcuate ligament, was confirmed by catheter angiography. The patient underwent successful endovascular coil embolization of the aneurysm. In our review of the existing medical literature, our patient is the youngest reported case of pancreaticoduodenal aneurysm caused by median arcuate ligament syndrome. PMID- 24495331 TI - Bilateral pulmonary artery aneurysms, coronary artery aneurysm, and ventricular pseudoaneurysm in Behcet disease. AB - Massive hemoptysis in Behcet disease (BD) is rare but often fatal. This report presents a 28-year-old man with recurrent massive hemoptysis. He was diagnosed with bilateral multiple pulmonary artery aneurysms (PAAs), coronary artery aneurysm, and ventricular pseudoaneurysm from BD. The patient underwent emergency right lower lobectomy with no obvious complications. No hemoptysis recurred during an 18-month follow-up. This report also reviews the occurrence of PAAs in BD, with an emphasis on the treatment approaches. PMID- 24495332 TI - Multiple mycotic aneurysms infected with Haemophilus influenzae. AB - Mycotic aneurysms are a relatively uncommon phenomenon that can pose a distinct treatment dilemma for the treating surgeon. It is rare to find Haemophilus influenzae as the causative organism, and it is even more rare to find multiple aneurysms in the same patient. We present the first case to our knowledge to be described in the literature of multiple mycotic aneurysms caused by H. influenzae. The treatment presented-using high-dose antibiotics and cryopreserved homografts-has worked well in this instance. This approach is supported in the literature. PMID- 24495333 TI - Splenic artery embolization for the treatment of bleeding gastric varices secondary to splenic vein thrombosis. AB - Splenic vein thrombosis can lead to gastric varices. Subsequent upper gastrointestinal bleeding may ensue related to the change in venous outflow to the portal system. Vascular surgeons are infrequently asked to assist in the management of this entity. However, with many vascular surgeons providing diverse endovascular-based interventions, understanding catheter-based solutions is imperative. This report presents a case in which arterial embolization was used to treat gastric variceal bleeding. PMID- 24495334 TI - Fibromyxoid excrescence of the aortic valve that manifested after catheterisation and required resection. AB - A 2-year-old boy developed fibromyxoid excrescence of the aortic valve 2 years after balloon dilatation for simple coarctation. Transthoracic echocardiography showed a mobile mass on the non-coronary cusp of the aortic valve. Definitive diagnosis was achieved after operative resection. This pathology was attributed to injury during catheter manipulation. Catheterised patients should be followed up carefully to avoid missing morphological changes. PMID- 24495335 TI - Prevalence and risk of Down syndrome in monozygotic and dizygotic multiple pregnancies in Europe: implications for prenatal screening. AB - OBJECTIVE: To determine risk of Down syndrome (DS) in multiple relative to singleton pregnancies, and compare prenatal diagnosis rates and pregnancy outcome. DESIGN: Population-based prevalence study based on EUROCAT congenital anomaly registries. SETTING: Eight European countries. POPULATION: 14.8 million births 1990-2009; 2.89% multiple births. METHODS: DS cases included livebirths, fetal deaths from 20 weeks, and terminations of pregnancy for fetal anomaly (TOPFA). Zygosity is inferred from like/unlike sex for birth denominators, and from concordance for DS cases. MAIN OUTCOME MEASURES: Relative risk (RR) of DS per fetus/baby from multiple versus singleton pregnancies and per pregnancy in monozygotic/dizygotic versus singleton pregnancies. Proportion of prenatally diagnosed and pregnancy outcome. STATISTICAL ANALYSIS: Poisson and logistic regression stratified for maternal age, country and time. RESULTS: Overall, the adjusted (adj) RR of DS for fetus/babies from multiple versus singleton pregnancies was 0.58 (95% CI 0.53-0.62), similar for all maternal ages except for mothers over 44, for whom it was considerably lower. In 8.7% of twin pairs affected by DS, both co-twins were diagnosed with the condition. The adjRR of DS for monozygotic versus singleton pregnancies was 0.34 (95% CI 0.25-0.44) and for dizygotic versus singleton pregnancies 1.34 (95% CI 1.23-1.46). DS fetuses from multiple births were less likely to be prenatally diagnosed than singletons (adjOR 0.62 [95% CI 0.50-0.78]) and following diagnosis less likely to be TOPFA (adjOR 0.40 [95% CI 0.27-0.59]). CONCLUSIONS: The risk of DS per fetus/baby is lower in multiple than singleton pregnancies. These estimates can be used for genetic counselling and prenatal screening. PMID- 24495337 TI - Unliganded estrogen receptor alpha stimulates bone sialoprotein gene expression. AB - Estrogen is one of the steroid hormones essential for skeletal development. The estrogen receptor (ER) is a transcription factor and a member of the steroid receptor superfamily. There are two different forms of the ER, usually referred to as alpha and beta, each encoded by a separate gene. Hormone-activated ERs form dimers, since the two forms are coexpressed in many cell types. Bone sialoprotein (BSP) is a tissue-specific acidic glycoprotein that is expressed by differentiated osteoblasts, odontoblasts and cementoblasts during the initial formation of mineralized tissue. To determine the molecular basis of the tissue specific expression of BSP and its regulation by estrogen and the ER, we have analyzed the effects of beta-estradiol and ERalpha on BSP gene transcription. ERalpha protein levels were increased after ERalpha overexpression in ROS17/2.8 cells. While BSP mRNA levels were increased by ERalpha overexpression, the endogenous and overexpressed BSP mRNA levels were not changed by beta-estradiol (10(-8)M, 24 h). Luciferase activities of different sized BSP promoter constructs (pLUC3~6) were increased by ERalpha overexpression, whereas basal and induced luciferase activities by ERalpha overexpression were not influenced by beta estradiol. Effects of ERalpha overexpression were abrogated by 2 bp mutations in either the cAMP response element (CRE) or activator protein 1 (AP1)/glucocorticoid response element (GRE). Gel shift analyses showed that ERalpha overexpression increased binding to the CRE and AP1/GRE elements. Notably, the CRE-protein complexes were disrupted by ERalpha, CREB and phospho CREB antibodies. The AP1/GRE-protein complexes were supershifted by the c-Fos antibody. These studies demonstrate that ERalpha stimulates BSP gene transcription in a ligand-independent manner by targeting the CRE and AP1/GRE elements in the rat BSP gene promoter. PMID- 24495336 TI - Acerola (Malpighia emarginata DC.) juice intake protects against alterations to proteins involved in inflammatory and lipolysis pathways in the adipose tissue of obese mice fed a cafeteria diet. AB - BACKGROUND: Obesity has been studied as a metabolic and an inflammatory disease and is characterized by increases in the production of pro-inflammatory adipokines in the adipose tissue.To elucidate the effects of natural dietary components on the inflammatory and metabolic consequences of obesity, we examined the effects of unripe, ripe and industrial acerola juice (Malpighia emarginata DC.) on the relevant inflammatory and lipolysis proteins in the adipose tissue of mice with cafeteria diet-induced obesity. MATERIALS/METHODS: Two groups of male Swiss mice were fed on a standard diet (STA) or a cafeteria diet (CAF) for 13 weeks. Afterwards, the CAF-fed animals were divided into five subgroups, each of which received a different supplement for one further month (water, unripe acerola juice, ripe acerola juice, industrial acerola juice, or vitamin C) by gavage. Enzyme-linked immunosorbent assays, Western blotting, a colorimetric method and histology were utilized to assess the observed data. RESULTS: The CAF water (control obese) group showed a significant increase in their adiposity indices and triacylglycerol levels, in addition to a reduced IL-10/TNF-alpha ratio in the adipose tissue, compared with the control lean group. In contrast, acerola juice and Vitamin C intake ameliorated the weight gain, reducing the TAG levels and increasing the IL-10/TNF-alpha ratio in adipose tissue. In addition, acerola juice intake led to reductions both in the level of phosphorylated JNK and to increases in the phosphorylation of IkappaBalpha and HSLser660 in adipose tissue. CONCLUSIONS: Taken together, these results suggest that acerola juice reduces low-grade inflammation and ameliorates obesity-associated defects in the lipolytic processes. PMID- 24495338 TI - Cannibalism in invasive, native and biocontrol populations of the harlequin ladybird. AB - BACKGROUND: Cannibalism is widespread in both vertebrates and invertebrates but its extent is variable between and within species. Cannibalism depends on population density and nutritional conditions, and could be beneficial during colonisation of new environments. Empirical studies are needed to determine whether this trait might facilitate invasion of a new area in natural systems. We investigated whether the propensity for cannibalism in H. axyridis differs both between native and invasive populations and between invasive populations from the core and from the front of the invasive area in Western Europe. We also compared the propensity for cannibalism of these natural populations with that of laboratory-reared biocontrol populations. We measured the cannibalism rates of eggs by first instar larvae and adult females at two different individual densities of ladybirds from three types of population (invasive, native and biocontrol), in laboratory-controlled conditions. RESULTS: Cannibalism was significantly greater in larvae from invasive populations compared to native or biocontrol populations, but there was no difference in cannibalism rates between populations from the core or front of the invaded range. Cannibalism was significantly lower in larvae from biocontrol populations compared to wild (invasive and native) populations. No differences in cannibalism rates of adult females were found between any populations. While high population density significantly increased cannibalism in both larvae and adults, the norm of reaction of cannibalism to individual density did not change significantly during the invasion and/or laboratory rearing processes. CONCLUSION: This study is the first to provide evidence for a higher propensity for cannibalism in invasive populations compared to native ones. Our experiments also shed light on the difference in cannibalism evolution with respect to life stages. However, we are still at an early stage in understanding the underlying mechanisms and several different research perspectives are needed to determine whether the higher propensity for cannibalism is a general feature of the invasion process. PMID- 24495339 TI - A point-based tool to predict conversion from mild cognitive impairment to probable Alzheimer's disease. AB - BACKGROUND: Our objective in this study was to develop a point-based tool to predict conversion from amnestic mild cognitive impairment (MCI) to probable Alzheimer's disease (AD). METHODS: Subjects were participants in the first part of the Alzheimer's Disease Neuroimaging Initiative. Cox proportional hazards models were used to identify factors associated with development of AD, and a point score was created from predictors in the final model. RESULTS: The final point score could range from 0 to 9 (mean 4.8) and included: the Functional Assessment Questionnaire (2-3 points); magnetic resonance imaging (MRI) middle temporal cortical thinning (1 point); MRI hippocampal subcortical volume (1 point); Alzheimer's Disease Cognitive Scale-cognitive subscale (2-3 points); and the Clock Test (1 point). Prognostic accuracy was good (Harrell's c = 0.78; 95% CI 0.75, 0.81); 3-year conversion rates were 6% (0-3 points), 53% (4-6 points), and 91% (7-9 points). CONCLUSIONS: A point-based risk score combining functional dependence, cerebral MRI measures, and neuropsychological test scores provided good accuracy for prediction of conversion from amnestic MCI to AD. PMID- 24495340 TI - Glycogenosome accumulation in the arrector pili muscle in Pompe disease. AB - BACKGROUND: Glycogenosis type II or Pompe disease is an autosomal-recessive lysosomal storage disease due to mutations in the gene encoding acid alpha glucosidase (GAA), an enzyme required for lysosomal glycogen degradation. The disease predominantly affects the skeletal and respiratory muscles but there is growing evidence of the involvement of smooth muscle cells in blood vessel walls, suggesting a multi-system disorder. Moreover, the failure of autophagy in Pompe disease could contribute to muscular atrophy and disease progression and is thought to compromise the efficacy of enzyme replacement therapy (ERT). METHODS: We investigated the light microscopical and ultrastructural pathology of the arrector pili muscle from punch skin biopsies from the calf of 6 adult Pompe disease patients and 6 age and gender matched healthy controls. Two patients had a follow-up biopsy after 19 and 20 month of ERT. RESULTS: The electron microscopic investigation of patient biopsies revealed the widespread occurrence of glycogenosomes, membrane bound accumulations of granular glycogen, associated with autophagic vacuoles. In the controls we detected only muscle cells with non membrane bound forms of glycogen. These morphological changes in smooth muscle cells are similar to those seen in skeletal muscle and smooth muscle cells of arterioles of Pompe patients. Furthermore, two patients with pre- and post-ERT skin biopsies showed a decrease in the number of cells with extensive autophagy after treatment. CONCLUSIONS: Electron microscopic examination of the arrector pili muscles appears to be a surrogate marker for the involvement of smooth muscles reflecting disease severity. These findings suggest that the standardized and widely used skin biopsy could offer a minimally invasive way to screen for smooth muscle involvement and warrant further studies in larger cohorts of patients. PMID- 24495341 TI - Usefulness of the Population Health Metrics Research Consortium gold standard verbal autopsy data for general verbal autopsy methods. AB - BACKGROUND: Verbal Autopsy (VA) is widely viewed as the only immediate strategy for registering cause of death in much of Africa and Asia, where routine physician certification of deaths is not widely practiced. VA involves a lay interview with family or friends after a death, to record essential details of the circumstances. These data can then be processed automatically to arrive at standardized cause of death information. METHODS: The Population Health Metrics Research Consortium (PHMRC) undertook a study at six tertiary hospitals in low- and middle-income countries which documented over 12,000 deaths clinically and subsequently undertook VA interviews. This dataset, now in the public domain, was compared with the WHO 2012 VA standard and the InterVA-4 interpretative model. RESULTS: The PHMRC data covered 70% of the WHO 2012 VA input indicators, and categorized cause of death according to PHMRC definitions. After eliminating some problematic or incomplete records, 11,984 VAs were compared. Some of the PHMRC cause definitions, such as 'preterm delivery', differed substantially from the International Classification of Diseases, version 10 equivalent. There were some appreciable inconsistencies between the hospital and VA data, including 20% of the hospital maternal deaths being described as non-pregnant in the VA data. A high proportion of VA cases (66%) reported respiratory symptoms, but only 18% of assigned hospital causes were respiratory-related. Despite these issues, the concordance correlation coefficient between hospital and InterVA-4 cause of death categories was 0.61. CONCLUSIONS: The PHMRC dataset is a valuable reference source for VA methods, but has to be interpreted with care. Inherently inconsistent cases should not be included when using these data to build other VA models. Conversely, models built from these data should be independently evaluated. It is important to distinguish between the internal and external validity of VA models. The effects of using tertiary hospital data, rather than the more usual application of VA to all-community deaths, are hard to evaluate. However, it would still be of value for VA method development to have further studies of population-based post-mortem examinations. PMID- 24495342 TI - Endometrial tuberculosis in a unicornuate uterus with a rudimentary horn. PMID- 24495343 TI - Isn't it time to separate the O from the G? PMID- 24495344 TI - Effect of Boswellia serrata supplementation on blood lipid, hepatic enzymes and fructosamine levels in type2 diabetic patients. AB - BACKGROUND: Type 2 diabetes is an endocrine disorder that affects a large percentage of patients. High blood glucose causes fatty deposits in the liver which is likely to increase in SGOT and SGPT activities. Significant increase in SGOT/SGPT and low HDL levels is observed in patients with diabetes. Serum fructosamine concentration reflects the degree of blood glucose control in diabetic patients. This study was aimed to investigate the antidiabetic, hypolipidemic and hepatoprotective effects of supplementation of Boswellia serrata in type2 diabetic patients. METHODS: 60 type 2 diabetic patients from both sexes (30 males and 30 females) were dedicated to the control and intervention groups (30 subjects per group). Boswellia serrata gum resin in amount of 900 mg daily for 6 weeks were orally administered (as three 300 mg doses) in intervention group and the control group did not receive anything. Blood samples were taken at the beginning of the study and after 6 weeks. Blood levels of fructosamine, lipid profiles as well as hepatic enzyme in type 2 diabetic patients were measured. RESULTS: Treatment of diabetic patient with Boswellia serrata was caused to significant increase in blood HDL levels as well as a remarkable decrease in cholesterol, LDL, fructosamine (p < 0.05) SGPT and SGOT levels after 6 weeks (p < 0.01). In spite of reduction of serum triglyceride, VLDL levels in intervention group, we did not detect a significant difference after 6 weeks. CONCLUSION: This study showed that Boswellia serrata supplementation can be beneficial in controlling blood parameters in patients with type 2 diabetes. Therefore, its use can be useful in patients with medicines. PMID- 24495345 TI - A meta-analysis of the factors influencing development rate variation in Aedes aegypti (Diptera: Culicidae). AB - BACKGROUND: Development rates of Aedes aegypti are known to vary with respect to many abiotic and biotic factors including temperature, resource availability, and intraspecific competition. The relative importance of these factors and their interactions are not well established across populations. We performed meta analysis on a dataset of development rate estimates from 49 studies. RESULTS: Meta-analytic results indicated that the environmental factor of temperature is sufficient to explain development rate variability in Ae. aegypti. While diet and density may greatly impact other developmental phenotypes, these results suggest that for development rate these factors should never be considered to the exclusion of temperature. The effect of temperature on development rate is not homogenous or constant. The sources of heterogeneity of the effect of temperature are difficult to analyze due to lack of consistent reporting of larval rearing methods. CONCLUSIONS: Temperature is the most important ecological determinant of development rate in Ae. aegypti, but its effect is heterogeneous. Ignoring this heterogeneity is problematic for models of vector population and vector-borne disease transmission. PMID- 24495347 TI - Early diagnosis and treatment of a posttraumatic pseudoaneurysm/dissection of the innominate artery. AB - A 25-year-old male developed a traumatic intimo-medial dissection and saccular pseudoaneurysm at the origin of the innominate artery following a motorcycle accident. On physical examination there was no perceivable trauma to the chest. In addition, there were no clinical symptoms that suggested this serious injury. The patient was managed with successful stent-graft placement on an elective basis. PMID- 24495346 TI - Different locations but common associations in subcortical hypodensities of presumed vascular origin: cross-sectional study on clinical and neurosonologic correlates. AB - BACKGROUND: Subcortical hypodensities of presumed vascular etiology (SHPVO) are a clinical, radiological and neuropathological syndrome with a still largely unexplained pathophysiology. Parallel to the clinical heterogeneity, there is also recognised cerebral topographical diversity with undetermined etiological implications. Our aim is to assess clinical and neurosonological predictors of SHPVO according to their location. METHODS: Cross sectional analysis of consecutive patients that underwent neurosonologic evaluation and head CT within one month, during a one year period. We excluded patients with absent temporal sonographic window, any pathology with a possible confounding effect on cerebral arterial pulsatility, atrial fibrillation and other etiologies of white matter diseases. The mean pulsatility index (PI) of both middle cerebral arteries was measured in the middle third of the M1 segment; intima media thickness was evaluated in the far wall of both common carotid arteries. SHPVO were rated by analysis of head CT in deep white matter (DWMH), periventricular white matter (PVWMH) and basal ganglia (BGH). We conducted a multivariate ordinal logistic regression model including all clinical, demographic and ultrasonographic characteristics to determine independent associations with SHPVO. RESULTS: We included 439 patients, mean age 63.47 (SD: 14.94) years, 294 (67.0%) male. The independent predictors of SHPVO were age (OR = 1.067, 95% CI: 1.047-1.088, p < 0.001 for DWMH; OR = 1.068, 95% CI: 1.049-1.088, p < 0.001 for PVWMH; OR = 1.05, 95% CI: 1.03-1.071, p < 0.001 for BGH), hypertension (OR = 1.909, 95% CI: 1.222 2.981, p = 0.004 for DWMH; OR = 1.907, 95% CI: 1.238-2.938, p = 0.003 for PVWMH; OR = 1.775, 95% CI: 1.109-2.843, p = 0.017 for BGH) and PI (OR = 17.994, 95% CI: 6.875-47.1, p < 0.001 for DWMH; OR = 5.739, 95%CI: 2.288-14.397, p < 0.001 for PVWMH; OR = 11.844, 95% CI: 4.486-31.268, p < 0.001 for BGH) for all locations of SHPVO. CONCLUSIONS: Age, hypertension and intracranial pulsatility are the main independent predictors of SHPVO across different topographic involvement and irrespective of extracranial atherosclerotic involvement. PMID- 24495348 TI - Pleomorphic xanthoastrocytoma of the spinal cord: case report and literature review. AB - Pleomorphic xanthoastrocytoma (PXA) is a rare slow-growing neoplasm that has predilection for the supratentorial compartment and the temporal lobe. Children and young adults are most frequently affected and they usually present with medically refractory seizures. PXAs involving the spinal cord have been rarely documented. We describe a 15-year-old boy who presented with shoulder/neck pain and upper extremity numbness/weakness. Neuroimaging revealed a solid, contrast enhancing, and intramedullary C5 - C6 mass. Microscopy demonstrated a typical WHO grade II PXA. Molecular testing did not reveal a BRAF V600E, IDH1 R132H, or IDH2 R172H mutation. Two years after a near total resection, significant tumor progression was noted via neuroimaging. To the authors' knowledge, this is the first description of the molecular characteristics of a spinal cord PXA. PMID- 24495349 TI - Spinal tanycytic ependymoma associated with neurofibromatosis type 2. PMID- 24495350 TI - Leptin gene promoter DNA methylation in WNIN obese mutant rats. AB - BACKGROUND: Obesity has become an epidemic in worldwide population. Leptin gene defect could be one of the causes for obesity. Two mutant obese rats WNIN/Ob and WNIN/GROb, isolated at National Centre for Laboratory Animal Sciences (NCLAS), Hyderabad, India, were found to be leptin resistant. The present study aims to understand the regulatory mechanisms underlying the resistance by promoter DNA methylation of leptin gene in these mutant obese rats. METHODS: Male obese mutant homozygous, carrier and heterozygous rats of WNIN/Ob and WNIN/GROb strain of 6 months old were studied to check the leptin gene expression (RT-PCR) and promoter DNA methylation (MassARRAY Compact system, SEQUENOM) of leptin gene by invivo and insilico approach. RESULTS: Homozygous WNIN/Ob and WNIN/GROb showed significantly higher leptin gene expression compared to carrier and lean counterparts. Leptin gene promoter DNA sequence region was analyzed ranging from transcription start site (TSS) to-550 bp length and found four CpGs in this sequence among them only three CpG loci (-309, -481, -502) were methylated in these WNIN mutant rat phenotypes. CONCLUSION: The increased percentage of methylation in WNIN mutant lean and carrier phenotypes is positively correlated with transcription levels. Thus genetic variation may have effect on methylation percentages and subsequently on the regulation of leptin gene expression which may lead to obesity in these obese mutant rat strains. PMID- 24495351 TI - Multiple hybridization events, polyploidy and low postmating isolation entangle the evolution of neotropical species of Epidendrum (Orchidaceae). AB - BACKGROUND: Hybridization and polyploidy are central processes in evolution and speciation. These mechanisms often lead to complex patterns of genetic variation and the creation of novel genotypes, which may establish if they become isolated from gene flow. However, in the absence of reproductive isolation, species boundaries might easily be disrupted. Here, we used a combination of AFLPs, chloroplast DNA markers and flow cytometry to investigate the evolutionary outcomes of hybridization between two endemic Ecuadorian species of Epidendrum (E. madsenii and E. rhopalostele) in three hybrid zones. Postmating isolation was also quantified to determine the role of this barrier in restraining gene flow between hybrids and the parental species. In addition, future ecological niche models were constructed to predict the outcomes of hybridization between these species. RESULTS: Our results confirmed the presence of hybrids in all hybrid zones, but revealed that a third parental species (E. falcisepalum) has contributed to one of the hybrid zones studied. Backcross genotypes were frequent in all hybrid zones, which was in accordance with the absence of strong reproductive barriers. The process of hybridization was highly asymmetric and followed in some cases by polyploidy. The projection of future niche models predicted a severe reduction in the area suitable for the occurrence of these species, although favorable conditions will still occur for the existence of the current hybrid zones. CONCLUSIONS: The recurrent process of hybridization has compromised the genetic integrity of the parental species. Most individuals of the parental species can no longer be considered as pure-bred individuals because most were classified as backcrossed hybrids. Novel genetic lineages occur in all hybrid zones implying that hybrids are fertile and can compete with the parental species. These results, together with the prediction of suitable conditions for the future occurrence of these hybrid zones, highlight the importance of conserving these geographic areas as sources of novel taxonomic entities. PMID- 24495353 TI - Influence networks based on coexpression improve drug target discovery for the development of novel cancer therapeutics. AB - BACKGROUND: The demand for novel molecularly targeted drugs will continue to rise as we move forward toward the goal of personalizing cancer treatment to the molecular signature of individual tumors. However, the identification of targets and combinations of targets that can be safely and effectively modulated is one of the greatest challenges facing the drug discovery process. A promising approach is to use biological networks to prioritize targets based on their relative positions to one another, a property that affects their ability to maintain network integrity and propagate information-flow. Here, we introduce influence networks and demonstrate how they can be used to generate influence scores as a network-based metric to rank genes as potential drug targets. RESULTS: We use this approach to prioritize genes as drug target candidates in a set of ER+ breast tumor samples collected during the course of neoadjuvant treatment with the aromatase inhibitor letrozole. We show that influential genes, those with high influence scores, tend to be essential and include a higher proportion of essential genes than those prioritized based on their position (i.e. hubs or bottlenecks) within the same network. Additionally, we show that influential genes represent novel biologically relevant drug targets for the treatment of ER+ breast cancers. Moreover, we demonstrate that gene influence differs between untreated tumors and residual tumors that have adapted to drug treatment. In this way, influence scores capture the context-dependent functions of genes and present the opportunity to design combination treatment strategies that take advantage of the tumor adaptation process. CONCLUSIONS: Influence networks efficiently find essential genes as promising drug targets and combinations of targets to inform the development of molecularly targeted drugs and their use. PMID- 24495354 TI - Beneficial effects of cocoa on lipid peroxidation and inflammatory markers in type 2 diabetic patients and investigation of probable interactions of cocoa active ingredients with prostaglandin synthase-2 (PTGS-2/COX-2) using virtual analysis. AB - BACKGROUND AND AIM: Altered glucose metabolism, oxidative stress, lipid levels and inflammatory markers are important risk factors in diabetes, cardiovascular, and many other diseases. Cocoa has been shown to exert antioxidant and anti inflammatory effects. The aim of this study is twofold: to assess the effect of Cocoa on the lipid profile and peroxidation in addition to the inflammatory markers in type 2 diabetic patients, and to represent a virtual model of probable action mechanism of observed clinical effects of Cocoa consumption using in silico analysis and bioinformatics data. METHODS: One hundred subjects with type 2 diabetes were included in a randomized clinical control trial. Fifty treatment subjects received 10 grams cocoa powder and 10 grams milk powder dissolved in 250 ml of boiling water, and the other fifty control subjects received only 10 grams milk powder dissolved in 250 ml boiling water. Both groups were on the mentioned regimen twice daily for 6 weeks. Blood samples were obtained prior to Cocoa consumption and 6 weeks after intervention. Serum lipids and lipoproteins profile, malondialdehyde and inflammatory markers including tumor necrosis factor alpha (TNF-alpha), interleukin-6 (IL-6) and high sensitive C-reactive protein (hs CRP) were measured. For statistical analysis two independent and paired samples t test and linear regression were used. Bioinformatics and virtual analysis were performed using string data base and Molegro virtual software. RESULTS: Cocoa consumption lowered blood cholesterol,triglyceride, LDL-cholesterol, and TNF alpha, hs-CRP, IL-6 significantly (P < 0.01). The results showed that the levels of HDL-cholesterol decreased significantly (P < 0.05) but Cocoa inhibited lipid peroxidation in treatment group than control group (P < 0.0001). Virtual analysis showed that the most frequent Cocoa ingredients, (+)-Catechin and (-) Epicatechin, can dock to the enzyme COX-2. CONCLUSION: These data support the beneficial effect of Cocoa on the lipid peroxidation prevention and inflammatory markers in type 2 diabetic patients. Cocoa ingredients block the Cox-2 activation and reduce inflammatory prostanoids synthesis according to virtual analysis. PMID- 24495352 TI - Suppression of neuroinflammation in forebrain-specific Cdk5 conditional knockout mice by PPARgamma agonist improves neuronal loss and early lethality. AB - BACKGROUND: Cyclin-dependent kinase 5 (Cdk5) is essential for brain development and function, and its deregulated expression is implicated in some of neurodegenerative diseases. We reported earlier that the forebrain-specific Cdk5 conditional knockout (cKO) mice displayed an early lethality associated with neuroinflammation, increased expression of the neuronal tissue-type plasminogen activator (tPA), and neuronal migration defects. METHODS: In order to suppress neuroinflammation in the cKO mice, we first treated these mice with pioglitazone, a PPARgamma agonist, and analyzed its effects on neuronal loss and longevity. In a second approach, to delineate the precise role of tPA in neuroinflammation in these mice, we generated Cdk5 cKO; tPA double knockout (dKO) mice. RESULTS: We found that pioglitazone treatment significantly reduced astrogliosis, microgliosis, neuronal loss and behavioral deficit in Cdk5 cKO mice. Interestingly, the dKO mice displayed a partial reversal in astrogliosis, but they still died at early age, suggesting that the increased expression of tPA in the cKO mice does not contribute significantly to the pathological process leading to neuroinflammation, neuronal loss and early lethality. CONCLUSION: The suppression of neuroinflammation in Cdk5 cKO mice ameliorates gliosis and neuronal loss, thus suggesting the potential beneficial effects of the PPARgamma agonist pioglitazone for the treatment for neurodegenerative diseases. PMID- 24495355 TI - A double-blind, randomized clinical trial of dietary supplementation on cognitive and immune functioning in healthy older adults. AB - BACKGROUND: Declining cognitive function is relatively common and increasingly prevalent. Studies have shown that different nutrients (e.g., Ginkgo biloba and vitamin E) appear to be effective at improving memory and concentration, while less is known about their effect on immunity. METHODS: This study investigated the effect of Ginkgo Synergy((r)) plus Choline (n = 33) and OPC Synergy((r)) plus Catalyn((r)) (n = 31) versus placebo (n = 33) in a 6-month, randomized, double blind trial on cognitive and immune functioning among English-speaking, non smoking, healthy older adults. The Stroop Color and Word Test, Trail Making Test A and B, Controlled Oral Word Association, Hopkins Verbal Learning, Mini-Mental State Exam, and Digit Symbol were administered at baseline and 3 and 6 months follow-up to assess cognitive functioning. Cytokines and growth factors were measured at baseline and 6 months to assess inflammation and immune functioning. Data were analyzed with linear mixed modeling. RESULTS: No serious adverse events were noted in this study. According to time on the Trail Making Test-B, the Ginkgo Synergy((r)) plus Choline arm showed improvement from baseline to 3 months follow-up (mean difference = 24.2; SE = 6.4; 95% CI: 8.6, 39.7; p = 0.01). On the Controlled Oral Word Association Trial-S, the scores significantly increased for the Ginkgo Synergy((r)) plus Choline arm from baseline to 6 months follow-up (mean difference = 2.1; SE = 0.8; 95% CI: 0.2, 3.9; p < 0.05) and for the OPC Synergy((r)) plus Catalyn((r)) arm from baseline to 3 months follow-up (mean difference = 2.1; SE = 0.8; 95% CI: 0.2, 4.0; p < 0.05). Epidermal growth factor significantly decreased from baseline to 6 months follow-up for the Ginkgo Synergy((r)) plus Choline arm (mean difference = 120.7; SE = 28.4; 95% CI: 62.6, 178.8; p < 0.001). CONCLUSIONS: Our study showed isolated and modest effects of a Ginkgo biloba plus choline-based formula on cognitive and immune functioning among healthy older adults with no history of significant cognitive deficits. Our trial was registered with clinicaltrials.gov (ID: NCT01672359). This study was supported by a grant from Standard Process, Inc. PMID- 24495357 TI - The Cognitive Behaviour Therapy Scale for Children and Young People (CBTS-CYP): development and psychometric properties. AB - BACKGROUND: There is increased interest in developing training in cognitive behaviour therapy (CBT) with children and young people. However, the assessment of clinical competence has relied upon the use of measures such as the Cognitive Therapy Scale-Revised (CTS-R: Blackburn et al., 2001) which has been validated to assess competence with adults. The appropriateness of this measure to assess competence when working with children and young people has been questioned. AIM: This paper describes the development and initial evaluation of the Cognitive Behaviour Therapy Scale for Children and Young People (CBTS-CYP) developed specifically to assess competence in CBT with children and young people. METHOD: A cross section of child CBT practitioners (n = 61) were consulted to establish face validity. Internal reliability, convergent validity and discriminative ability were assessed in two studies. In the first, 12 assessors independently rated a single video using both the Cognitive Behaviour Therapy Scale for Children and Young People (CBTS-CYP) and Cognitive Therapy Scale-Revised (CTS Revised: Blackburn et al., 2001). In the second, 48 different recordings of CBT undertaken with children and young people were rated on both the CBTS-CYP and CTS R. RESULTS: Face validity and internal reliability of the CBTS-CYP were high, and convergent validity with the CTS-R was good. The CBTS-CYP compared well with the CTS-R in discriminative ability. CONCLUSION: The CBTS-CYP provides an appropriate way of assessing competence in using CBT with children and young people. Further work is required to assess robustness with younger children and the impact of group training in reducing inter-rater variations. PMID- 24495356 TI - ESR1 gene promoter region methylation in free circulating DNA and its correlation with estrogen receptor protein expression in tumor tissue in breast cancer patients. AB - BACKGROUND: Tumor expression of estrogen receptor (ER) is an important marker of prognosis, and is predictive of response to endocrine therapy in breast cancer. Several studies have observed that epigenetic events, such methylation of cytosines and deacetylation of histones, are involved in the complex mechanisms that regulate promoter transcription. However, the exact interplay of these factors in transcription activity is not well understood. In this study, we explored the relationship between ER expression status in tumor tissue samples and the methylation of the 5' CpG promoter region of the estrogen receptor gene (ESR1) isolated from free circulating DNA (fcDNA) in plasma samples from breast cancer patients. METHODS: Patients (n = 110) with non-metastatic breast cancer had analyses performed of ER expression (luminal phenotype in tumor tissue, by immunohistochemistry method), and the ESR1-DNA methylation status (fcDNA in plasma, by quantitative methylation specific PCR technique). RESULTS: Our results showed a significant association between presence of methylated ESR1 in patients with breast cancer and ER negative status in the tumor tissue (p = 0.0179). There was a trend towards a higher probability of ESR1-methylation in those phenotypes with poor prognosis i.e. 80% of triple negative patients, 60% of HER2 patients, compared to 28% and 5.9% of patients with better prognosis such as luminal A and luminal B, respectively. CONCLUSION: Silencing, by methylation, of the promoter region of the ESR1 affects the expression of the estrogen receptor protein in tumors of breast cancer patients; high methylation of ESR1-DNA is associated with estrogen receptor negative status which, in turn, may be implicated in the patient's resistance to hormonal treatment in breast cancer. As such, epigenetic markers in plasma may be of interest as new targets for anticancer therapy, especially with respect to endocrine treatment. PMID- 24495358 TI - Scientific names of organisms: attribution, rights, and licensing. AB - BACKGROUND: As biological disciplines extend into the 'big data' world, they will need a names-based infrastructure to index and interconnect distributed data. The infrastructure must have access to all names of all organisms if it is to manage all information. Those who compile lists of species hold different views as to the intellectual property rights that apply to the lists. This creates uncertainty that impedes the development of a much-needed infrastructure for sharing biological data in the digital world. FINDINGS: The laws in the United States of America and European Union are consistent with the position that scientific names of organisms and their compilation in checklists, classifications or taxonomic revisions are not subject to copyright. Compilations of names, such as classifications or checklists, are not creative in the sense of copyright law. Many content providers desire credit for their efforts. CONCLUSIONS: A 'blue list' identifies elements of checklists, classifications and monographs to which intellectual property rights do not apply. To promote sharing, authors of taxonomic content, compilers, intermediaries, and aggregators should receive citable recognition for their contributions, with the greatest recognition being given to the originating authors. Mechanisms for achieving this are discussed. PMID- 24495359 TI - Protein quality affects bone status during moderate protein restriction in growing mice. AB - Adequate protein intake during development is critical to ensure optimal bone gain and to attain a higher peak bone mass later on. We hypothesized that the quality of the dietary protein is of prime importance for bone physiology during moderate protein restriction. The target population was growing Balb/C mice. We compared two protein restricted diets (6% of total energy as protein), one based on soy (LP-SOY) and one based on casein (LP-CAS). For comparison, a normal protein soy-based control group (NP-SOY) and a low protein group receiving an anabolic daily parathyroid hormone (PTH) 1-34 injection (LP-SOY+PTH) were included in the protocol. After 8weeks, LP-SOY mice had reduced body weights related to a lower lean mass whereas LP-CAS mice were not different from the NP SOY group. LP-SOY mice were characterized by lower femoral cortical thickness, bone volume, trabecular number and thickness and increased medullar adiposity when compared to both the LP-CAS and NP-SOY groups. However, the dietary intervention had no effect on the vertebral parameters. The negative effect of the LP-SOY diet was correlated to an impaired bone formation as shown by the reduced P1NP serum level as well as the reduced osteoid surfaces and bone formation rate in the femur. PTH injection in LP-SOY mice had no effect on total weight or lean mass, but improved all bone parameters at both femoral and vertebral sites, suggesting that amino acid deficiency was not the primary reason for degraded bone status in mice consuming soy protein. In conclusion, our study showed that under the same protein restriction (6% of energy), a soy diet leads to impaired bone health whereas a casein diet has little effect when compared to a normal protein control. PMID- 24495360 TI - Salivary histatin 3 inhibits heat shock cognate protein 70-mediated inflammatory cytokine production through toll-like receptors in human gingival fibroblasts. AB - BACKGROUND: Salivary histatins are bioactive peptides related to the innate immune system associated with antimicrobial activities. However, very little is known about the physiological and biological functions of histatins against host cells or their role in oral cell inflammation. Histatin 3 binds to heat shock cognate protein 70 (HSC70, a constitutively expressed heat shock protein (HSP)). It is unclear whether HSC70 is involved in the inflammatory response in oral cells. Injured oral cells release some intracellular proteins including HSC70. It is possible that released HSC70 induces toll-like receptor (TLR) activation, just as extracellular HSP70 (a stress inducible HSP) does, and that histatin 3 affects this process. Therefore, we tested the hypothesis that HSC70 activates TLR signaling and histatin 3 inhibits this activation and inflammatory cytokine production. METHODS: A nuclear factor (NF)-kappaB-dependent luciferase reporter plasmid was transfected into HEK293 cells stably expressing TLR2 with coreceptor CD14 (293-TLR2/CD14 cells) or stably expressing TLR4 with CD14 and the accessory molecule MD2 (293-TLR4/MD2-CD14 cells). The cells were stimulated with HSC70 in the presence or absence of histatin 3, and examined using luciferase assays. We also stimulated human gingival fibroblasts (HGFs) with HSC70 with or without histatin 3. Then, we analyzed the levels of inflammatory cytokines (interleukin (IL)-6 and IL-8) in the culture media. Cell proteins were analyzed using enzyme linked immunosorbent assay and Western blotting with antibodies of mitogen activated protein kinases and NF-kappaB inhibitor IkappaB-alpha, respectively. Histatin 3-bound form of HSC70 was analyzed using limited V8 protease proteolysis. RESULTS: HSC70 induced NF-kappaB activation in a dose-dependent manner in 293-TLR2/CD14 and 293-TLR4/MD2-CD14 cells, and histatin 3 inhibited this process and when histatin 3 binding to HSC70 was precluded by 15 deoxyspergualin, which augmented NF-kappaB-triggered activation. In HGFs, histatin 3 also inhibited HSC70-induced inflammatory cytokine production, extracellular signal-regulated protein kinase phosphorylation, and degradation of IkappaB-alpha. Moreover, HSC70 in the presence of histatin 3 was relatively resistant to digestion by V8 protease compared with HSC70 in the presence of control peptide. CONCLUSIONS: Histatin 3 may be an inhibitor of HSC70-triggered activation of TLR signaling and inflammatory cytokine production and may be involved in inflammation processes noted in oral cells. PMID- 24495361 TI - DYZ1 arrays show sequence variation between the monozygotic males. AB - BACKGROUND: Monozygotic twins (MZT) are an important resource for genetical studies in the context of normal and diseased genomes. In the present study we used DYZ1, a satellite fraction present in the form of tandem arrays on the long arm of the human Y chromosome, as a tool to uncover sequence variations between the monozygotic males. RESULTS: We detected copy number variation, frequent insertions and deletions within the sequences of DYZ1 arrays amongst all the three sets of twins used in the present study. MZT1b showed loss of 35 bp compared to that in 1a, whereas 2a showed loss of 31 bp compared to that in 2b. Similarly, 3b showed 10 bp insertion compared to that in 3a. MZT1a germline DNA showed loss of 5 bp and 1b blood DNA showed loss of 26 bp compared to that of 1a blood and 1b germline DNA, respectively. Of the 69 restriction sites detected in DYZ1 arrays, MboII, BsrI, TspEI and TaqI enzymes showed frequent loss and or gain amongst all the 3 pairs studied. MZT1 pair showed loss/gain of VspI, BsrDI, AgsI, PleI, TspDTI, TspEI, TfiI and TaqI restriction sites in both blood and germline DNA. All the three sets of MZT showed differences in the number of DYZ1 copies. FISH signals reflected somatic mosaicism of the DYZ1 copies across the cells. CONCLUSIONS: DYZ1 showed both sequence and copy number variation between the MZT males. Sequence variation was also noticed between germline and blood DNA samples of the same individual as we observed at least in one set of sample. The result suggests that DYZ1 faithfully records all the genetical changes occurring after the twining which may be ascribed to the environmental factors. PMID- 24495362 TI - Viremic long-term nonprogressive HIV-1 infection is not associated with abnormalities in known Nef functions. AB - BACKGROUND: A small minority of HIV-1-infected individuals show low levels of immune activation and do not develop immunodeficiency despite high viral loads. Since the accessory viral Nef protein modulates T cell activation and plays a key role in the pathogenesis of AIDS, we investigated whether specific properties of Nef may be associated with this highly unusual clinical outcome of HIV-1 infection. FINDINGS: Comprehensive functional analyses of sequential HIV-1 strains from three viremic long-term non-progressors (VNP) showed that they encode full-length Nef proteins that are capable of modulating CD4, CD28, CD8beta, MHC-I and CD74 cell surface expression. Similar to Nef proteins from HIV 1-infected individuals with progressive infection (P-Nefs) and unlike Nefs from simian immunodeficiency viruses (SIVs) that do not cause chronic immune activation and disease in their natural simian hosts, VNP-Nefs were generally unable to down-modulate TCR-CD3 cell surface expression to block T cell activation and apoptosis. On average, VNP-Nefs suppressed NF-AT activation less effectively than P-Nefs and were slightly less active in enhancing NF-kappaB activity. Finally, we found that VNP-Nefs increased virion infectivity and enhanced HIV-1 replication and cytopathicity in primary human cells and in ex vivo infected lymphoid tissues. CONCLUSIONS: Our results show that nef alleles from VNPs and progressors of HIV-1 infection show only modest differences in established functions. Thus, the lack of chronic immune activation and disease progression in HIV-1-infected VNPs is apparently not associated with unusual functional properties of the accessory viral Nef protein. PMID- 24495363 TI - Patterns and determinants of the use of complementary and alternative medicine: a cross-sectional study of hypertensive patients in Ghana. AB - BACKGROUND: The use of complementary and alternative medicine (CAM) is widespread and high utilization rates are associated with people who have chronic conditions like hypertension which management requires adherence to conventional treatment. Often however, the use of alternative medicines has been linked to negative health outcomes. The purpose of the study therefore was to evaluate the pattern, determinants and the association between CAM use and the adherence behaviour of hypertensive patients in Ghana. METHODS: A cross-sectional study was conducted using 400 hypertensive patients attending Korle-bu and Komfo Anokye Teaching Hospitals in Ghana from May to July, 2012. Information was gathered on the socio demographic characteristics of patients, CAM use, and adherence using the 8-item Morisky Medication Adherence Scale (MMAS). RESULTS: Out of the 400 study participants, 78 (19.5%) reported using CAM with the majority (65.38%) utilizing biological based therapies. About 70% of CAM users had not disclosed their CAM use to their healthcare professionals citing fear and the lack of inquiry by these health professionals as the main reasons for non-disclosure. Males were 2.86 more likely to use CAM than females [odds ratio (OR) = 2.86 (95% CI 1.48 5.52), p = 0.002]. Participants who could not afford their medications had 3.85 times likelihood of CAM use than those who could afford their medicines [OR = 3.85 (1.15-12.5), p = 0.029]. In addition, a significant relationship between CAM use and experiences of anti-hypertensive side effects was observed, X2 = 25.378, p < 0.0001. CAM users were 2.22 times more likely to be non-adherent than participants who did not use CAM [OR = 2.22 (0.70-7.14), p = 0.176]. CONCLUSION: Hypertensive patients in Ghana have shown utilization for CAM. It is important that healthcare providers understand the patterns and determinants of CAM use among their patients. Intervention programmes can then be incorporated to enhance the desired health outcomes of patients. PMID- 24495364 TI - Cognitive status and foot self care practice in overweight diabetics, engaged in different levels of physical activity. AB - BACKGROUND: Type 2 diabetes along with chronic hyperglycemia may result in cognitive impairment. This can negatively affect the patient's adherence to diabetes treatment. The purpose of this study was to compare the cognitive status and foot self care practice in overweight type 2 diabetic patients who exercised regularly and those who did not. METHODS: The comparative study was conducted on 160 consecutive patients from an outpatient diabetes clinic. They were divided into two groups: The active group comprised of 80 patients engaged in regular exercise for at least 15-30 minutes, three times per week during the past 6 months. The control group included 80 patients who had not exercised regularly for the past 12 months, matched for sex, age, education, diabetes duration, hemoglobin A1C and body mass index (BMI: 25-29.9Kg/m2). Data on the patients' demographic information, foot care practice and physical activity habits were gathered using a questionnaire. The Mini Mental Status examination (MMSE) was applied to assess cognitive status. RESULTS: MMSE score was significantly higher in the active group. A significant negative correlation was noted between MMSE scores and BMI in the control group (r = -0.2, P = 0.03). A significant difference was noted in the four domains of foot self care practice between the active (4.77 +/- 0.77) and control (4.45 +/- 0.83) groups (P < 0.01). CONCLUSIONS: Regular physical activity can help promote cognitive status and foot self care practice in overweight patients with type 2 diabetes. PMID- 24495365 TI - Using SMS reminders in psychology clinics: a cautionary tale. AB - BACKGROUND: As healthcare services become progressively more stretched, there is increasing discussion of ways in which technological adjuncts may be used to deliver more cost-efficient services. Before widespread implementation, however, the use of these adjuncts requires proper scrutiny of their effects on psychological practice. AIMS: This research examined the effectiveness of SMS reminders on client appointment attendance and dropout in a psychological treatment setting. It was predicted that the reminders would result in increased initial appointment attendance, increased total appointment attendance, and decreased client dropout. METHOD: A randomized controlled trial investigated the impact of SMS appointment reminders (two levels: present or absent) on client attendance (three levels: attended, rescheduled, or did not attend) and dropout (two levels: completed treatment or terminate early). Participants (N = 140) at an outpatient psychology clinic were randomly allocated to either receive an SMS appointment reminder one day before their scheduled appointment, or to receive no reminder. RESULTS: No significant differences were found between the SMS and no SMS conditions in relation to appointment attendance. There were more client dropouts in the SMS compared to the no SMS condition. CONCLUSIONS: The SMS appointment reminders were not effective at increasing appointment attendance. The current research suggests that there is more to client non-attendance in psychological settings than the simple forgetting of appointments. Technological adjuncts may be useful in increasing the cost-efficiency of current services; however, this research highlights the importance of understanding the effects of technology before widespread implementation. PMID- 24495366 TI - [Neonatal outcomes of prevention of vertical HIV transmission; 15 years of experience in a non-university HIV centre]. AB - OBJECTIVE: To evaluate the neonatal outcomes of the policy for the prevention of vertical HIV transmission in a non-university HIV centre. DESIGN: Retrospective, descriptive study. METHOD: We analysed the HIV status of newborns of HIV-positive mothers during pregnancy in the period between 1 January 1995 and 31 December 2010 in St. Elisabeth Hospital, Tilburg, the Netherlands and compared these results with the Dutch HIV monitoring foundation (SHM) registration data. RESULTS: Eighty-seven children from 84 pregnancies and their 71 HIV-positive mothers were included. Compared with SHM data, more women were African, younger at HIV diagnosis and had less resistance to the usual combination antiretroviral therapy (cART). In line with SHM data, the percentage of elective caesarean sections declined in the study period. There were fewer preterm births than in SHM data. There were no significant differences between preterm birth (p = 0.18), SGA (p = 0.25) or congenital abnormality (p = 0.45) and detectable HIV-RNA or cART use during pregnancy. During 10 (12%) pregnancies the mother presented to the HIV centre too late. At the age of 18 months, all 72 tested children were HIV negative. Of the 15 children lost to follow-up, 8 (9%) left to an unknown destination. CONCLUSION: All newborns of HIV-positive mothers were HIV negative, 12% of the HIV-positive mothers presented too late and 9% of the children disappeared from medical control. These results emphasize the importance of better communication between HIV centres, medical services of asylum centres and first-line obstetric care for female asylum seekers and their children. PMID- 24495367 TI - [A young boy with pulmonary tuberculosis]. AB - BACKGROUND: Infectious pulmonary tuberculosis in young children is rare in the Netherlands. Young children with a tuberculosis infection are at high risk of developing miliary tuberculosis or tuberculous meningitis. CASE DESCRIPTION: A 12 month-old boy of Turkish descent was brought to our hospital because of coughing present for a few weeks and fever for 10 days. Nine weeks previously the patient had visited family in western Turkey, where, as far as is known, he did not come into contact with anyone who had tuberculosis. A chest X-ray showed infiltration of the middle lobe. He did not recover with empirical treatment for community acquired pneumonia. Because of treatment failure, tuberculin skin testing was performed, the result of which was positive. The boy fully recovered during tuberculostatic treatment. Open tuberculosis was subsequently confirmed in a family member in Turkey after the boy's visit. CONCLUSION: In the event of pneumonia with an atypical course, testing for tuberculosis is justified, even if there is no or little likelihood of contact with a tuberculosis patient in the history. PMID- 24495368 TI - [A soccer player with a painful and swollen knee]. AB - A 19-year-old man was evaluated for medial knee pain 1.5 year after repeated distortion of the right knee. The medial side of his knee was swollen and painful upon running and playing soccer. An anteroposterior knee radiograph showed a calcification located at the proximal medial collateral ligament. He was diagnosed with Pellegrini-Stieda syndrome. Treatment of this syndrome includes rest, range of motion exercises, nonsteroidal anti-inflammatory drugs, local infiltration with corticosteroids or excision in refractory cases. DIAGNOSIS: Pellegrini-Stieda syndrome. PMID- 24495369 TI - [AL amyloidosis-associated factor X deficiency]. AB - BACKGROUND: An acquired bleeding tendency is a specific symptom that can indicate an underlying disease. CASE DESCRIPTION: Here we describe a 69-year-old patient with an acquired bleeding tendency resulting from a factor X deficiency due to an underlying amyloid light-chain (AL) amyloidosis. Factor X deficiency in AL amyloidosis arises from a quantitative and qualitative deficiency of factor X because it binds to amyloid fibrils exposed to circulating blood. CONCLUSION: Bleeding tendency is a rare complication of AL amyloidosis, often resulting from a factor X deficiency. PMID- 24495370 TI - [People with dementia have more contact with their general practitioners: contact with GPs peaks around the time of diagnosis]. AB - OBJECTIVE: To investigate how often and why people with dementia and their partners have contact with the general practitioner (GP) before and after the diagnosis of dementia. DESIGN: Retrospective cohort study. METHOD: Patients given the diagnosis of 'dementia' in the period 2006-2011 were selected from patient records of GP practices participating in the NIVEL Primary Care Database; data were also collected from the patients' partners. Patients and their partners were compared with a reference group. The number of GP contacts from 2 years before until 1 year after diagnosis were analysed. RESULTS: There were data on 823 patients with dementia and 184 partners. People with dementia had more frequent GP contacts from 4 months before diagnosis until 8 months thereafter. The mean number of GP contacts was 21.5 for people with dementia versus 17.4 for people without dementia in the total 3-year period. Reasons for more frequent contact were depression, abrasions/scratches/blisters and memory/concentration/orientation disorders before diagnosis. After diagnosis, memory/concentration/orientation disorders and general decline were more common reasons for contact than in the reference group. The frequency of GP contacts for partners was not significantly higher. CONCLUSION: People with dementia have more contact with their GP than people without dementia. From 1.5 years before diagnosis they visit the GP with specific complaints more often. Their partners also have regular contact with their GP, especially in the year after diagnosis. PMID- 24495371 TI - [A woman with shortness of breath and butterfly shaped cell nuclei]. AB - A 53-year-old woman with respiratory discomfort came to the Emergency Department. The blood smear, made because of a new thrombocytopenia, showed leukocytes with butterfly-shaped nuclei and fine cytoplasmic granulation. The diagnosis 'microgranular variant of acute promyelocytic leukemia' was made. PMID- 24495372 TI - [Meta-analysis: principles and pitfalls]. AB - In a meta-analysis results of different studies are summarized quantitatively. This gives a much more precise effect estimate than is possible in individual studies. Prior to the analysis, all relevant studies should be traced, including studies with less favourable results. Exclusion of 'negative' studies may lead to overestimation of the effect. Because the results of a meta-analysis depend on the quality of the included studies, the quality and risk of bias of all studies should be systematically assessed. Quantitative summary of results is only practicable if the studies are homogeneous, i.e. sufficiently similar with respect to the study populations, interventions or exposure, outcomes and point of measurement. In cases of clinical heterogeneity, meta-analysis could be conducted in clinically homogeneous subgroups. Statistical heterogeneity can be discounted by using a random-effects model. Meta-analyses can be applied to research questions regarding aetiology, diagnosis, treatment or prognosis. PMID- 24495373 TI - [A 9-year-old boy with sudden memory loss]. AB - BACKGROUND: Transient global amnesia is a recognised phenomenon in adults. However in children it is rarely described. It is characterised by a sudden loss of memory in an otherwise healthy patient. What is striking is that other cognitive functions and neurological examination are normal. CASE DESCRIPTION: A 9-year-old boy presented at the paediatric ward with acute onset retrograde and anterograde amnesia. He had no history of headache or other (neurological) symptoms. There were no known emotional or physical stressors. A general physical and neurological examination showed no abnormalities. The boy was hospitalised for observation overnight. The next day he was fully recovered. CONCLUSION: Transient global amnesia may occur in childhood. Since patients recover spontaneously, watchful waiting is justified. PMID- 24495374 TI - [Transanal total mesorectal excision: a new treatment option for rectal cancer]. AB - The transanal total mesorectal excision (TME) for colorectal tumours is a new endoscopic approach in which the rectum is mobilized transanally from down-to-up using a flexible transanal single-access port. The advantage of this technique is that it could result in fewer conversions from laparoscopic to open procedures and consequently fewer complications and more radical resections. Standard endoscopic armamentarium is used for the transanal technique so that costs remain low. The length of the learning curve is expected to be comparable to other laparoscopic techniques, and is even shorter for an experienced laparoscopic surgeon. Additional research is needed to compare long-term oncological and clinical results of transanal TME to laparoscopic and open TME. PMID- 24495375 TI - [A woman with needle-shaped crystals in the urine]. AB - A 24-year-old female patient was admitted to the ICU with suspected meningo encephalitis. She was treated with antibiotics and acyclovir 1500 mg/day. Forty eight hours later she developed acute renal failure with needle-shaped crystals in the urine. Acyclovir treatment was suspended and renal function replacement therapy was initiated. After two weeks, her renal function had fully recovered. Based on the typical clinical course and the typical crystalluria, we diagnosed her with acyclovir-induced acute renal failure. PMID- 24495376 TI - [Health care consumers about over-the-counter drugs]. AB - Dutch consumers can now purchase 'over-the-counter drugs' (OTCs) at three distribution channels: (a) the pharmacy; (b) the chemist; (c) other sales outlets such as supermarkets and petrol stations. However, little is known about whether consumers consider themselves and others to have adequate knowledge to purchase OTCs in relative freedom. During a recent study, members of the Healthcare Consumer Panel of the Netherlands Institute for Health Services Research completed a survey on freely available analgesics. These consumers were very confident of their personal skills in handling OTCs responsibly. However, they had less confidence in how others would deal with OTCs. Regarding the wider availability of OTCs, only 1-8% believed it would be preferable to have these drugs available in the supermarket or petrol station, depending on the type and frequency of side effects of the medication. The government would be wise in conducting this type of qualitative study before measures are taken for wider availability of medicines. PMID- 24495378 TI - Electrocardiogram artifact caused by rigors mimicking narrow complex tachycardia: a case report. AB - BACKGROUND: The electrocardiogram (ECG) is useful in the diagnosis of cardiac and non-cardiac conditions. Rigors due to shivering can cause electrocardiogram artifacts mimicking various cardiac rhythm abnormalities. CASE PRESENTATION: We describe an 80-year-old Sri Lankan man with an abnormal electrocardiogram mimicking narrow complex tachycardia during the immediate post-operative period. Electrocardiogram changes caused by muscle tremor during rigors could mimic a narrow complex tachycardia. CONCLUSIONS: Identification of muscle tremor as a cause of electrocardiogram artifact can avoid unnecessary pharmacological and non pharmacological intervention to prevent arrhythmias. PMID- 24495377 TI - Family history of cancer and gastroesophageal disorders and risk of esophageal and gastric adenocarcinomas: a case-control study. AB - BACKGROUND: There is a paucity of data on familial risk of developing esophageal adenocarcinoma, gastric cardia adenocarcinoma and distal gastric adenocarcinoma from population-based studies. METHODS: A population-based case-control study of newly diagnosed gastroesophageal adenocarcinoma was conducted in Los Angeles County. This analysis included data of case-patients whom we were able to interview directly (147 patients with esophageal adenocarcinoma, 182 with gastric cardia adenocarcinoma, and 285 with distal gastric adenocarcinoma) and 1,309 control participants. Multivariate polytomous logistic regression was used to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) for the three cancer types. RESULTS: Risk of esophageal adenocarcinoma was positively associated with a family history of prostate cancer (OR = 2.84; 95% CI = 1.50 5.36) and a family history of hiatal hernia (OR = 2.04; 95% CI = 1.12-3.71). Risk of gastric cardia adenocarcinoma was strongly associated with a family history of esophageal cancer (OR = 5.18; 95% CI = 1.23-21.79) and a family history of hiatal hernia (OR = 2.31; 95% CI = 1.37-3.91). Risk of distal gastric adenocarcinoma was positively associated with a family history of gastric cancer (OR = 2.15; 95% CI = 1.18-3.91), particularly early-onset (before age 50) gastric cancer (OR = 2.82; 95% CI = 1.11-7.15). CONCLUSIONS: This study provides evidence that family history of hiatal hernia is a risk factor for esophageal adenocarcinoma and gastric cardia adenocarcinoma and that cancer in specific sites is associated with risk of esophageal adenocarcinoma, gastric cardia adenocarcinoma, and distal gastric adenocarcinoma. It is important to determine the extent to which shared environmental and genetic factors explain these familial associations. PMID- 24495379 TI - Effect of peer-led outreach activities on injecting risk behavior among male drug users in Haryana, India. AB - BACKGROUND: For the past two decades, there has been an enduring HIV epidemic among injecting drug users (IDUs) in India, and the Indian national AIDS control program (NACP) led by the National AIDS Control Organization (NACO) has kept IDUs at the forefront along with other key populations, in its efforts to prevent HIV. Given this, the objective of this study is to examine the association between IDUs' degree of exposure to peer-led education sessions (under NACP) and their needle sharing practices in Haryana, India. METHODS: The data for this study were drawn from a program monitoring system for the years 2009-2010 and 2010-2011. The relationship between IDUs' background characteristics/injecting practices and degree of exposure to the program was assessed using chi-square and Student's t tests. Generalized estimating equations (GEE) were used to examine changes in needle sharing practices over time by degree of exposure to peer-led education sessions. Further, the analysis was stratified by frequency of injecting drug use. All statistical analyses were conducted using STATA version 11. RESULTS: The proportion of IDUs who shared needles substantially decreased from 2009 to 2011, particularly among those who attended three or more peer-led education sessions (49% vs 11%, p < 0.001) in a month. Further, subgroup analysis by frequency of injecting drugs demonstrates that this decline was significant among IDUs who injected frequently (adjusted odds ratio = 0.6, 95% confidence interval = 0.3 0.9, p = 0.043). CONCLUSION: The study results indicate that repeated peer-led outreach sessions are more effective than exposure to a single education session. Hence, HIV prevention programs must promote repeated peer contacts with IDUs every month (at least two meetings) in order to promote safe injecting practices and behavior change. PMID- 24495381 TI - Antioxidant activities of ethanol extracts and fractions of Crescentia cujete leaves and stem bark and the involvement of phenolic compounds. AB - BACKGROUND: Antioxidant compounds like phenols and flavonoids scavenge free radicals and thus inhibit the oxidative mechanisms that lead to control degenerative and other diseases. The aim of this study was to investigate the antioxidant activity in vitro, total phenolic and flavonoid contents in ethanol extracts and fractions of Crescentia cujete leaves and stem bark. METHODS: Crescentia cujete leaves and bark crude ethanol extract (CEE) and their partitionates petroleum ether (PEF), chloroform (CHF), ethyl acetate (EAF) and aqueous (AQF) were firstly prepared. Different established testing methods, such as 1, 1-diphenyl-2-picryl hydrazyl (DPPH) radical, ferric reducing power (FRP), and total antioxidant capacity (TAC) assays were used to detect the antioxidant activity. Further, the total yield, total phenolic (TPC) and total flavonoid contents (TFC) of CEE and all the fractions were determined. Ethanol extracts of both leaves and stem bark were also subjected to preliminary phytochemical screening to detect the presence of secondary metabolites, using standard phytochemical methods (Thin layer chromatography and spray reagents). RESULTS: Phytochemical screening of crude ethanol extract of both leaves and stem bark revealed the presence of steroids, flavonoids, saponins, tannins, glycosides and terpenoids. All the fractions and CEE of leaves and bark exhibited antioxidant activities, however, EAF of leaves showing the highest antioxidant activity based on the results of DPPH, FRP and TAC assay tests. The above fraction has shown the significant DPPH scavenging activity (IC50 = 8.78 MUg/ml) when compared with standard ascorbic acid (IC50 =7.68 MUg/ml). The TAC and FRP activities increased with increasing crude extract/fractions content. The TPC (371.23 +/- 15.77 mg GAE/g extract) and TFC (144.64 +/- 5.82 mg QE/g extract) of EAF of leaves were found significantly higher as compared to other solvent fractions for both leaves and bark. TPC were highly correlated with the antioxidant activity (R2 = 0.9268 and 0.8515 in DPPH test for leaves and bark, respectively). CONCLUSION: The results of the study show that leaves of C. cujete possesses significant free radical scavenging properties compared with stem bark and a clear correlation exists between the antioxidant activity and phenolic content. PMID- 24495380 TI - Microbial exposure alters HIV-1-induced mucosal CD4+ T cell death pathways Ex vivo. AB - BACKGROUND: Early HIV-1 infection causes massive CD4+ T cell death in the gut and translocation of bacteria into the circulation. However, the programmed cell death (PCD) pathways used by HIV-1 to kill CD4+ T cells in the gut, and the impact of microbial exposure on T cell loss, remain unclear. Understanding mucosal HIV-1 triggered PCD could be advanced by an ex vivo system involving lamina propria mononuclear cells (LPMCs). We therefore modeled the interactions of gut LPMCs, CCR5-tropic HIV-1 and a commensal gut bacterial species, Escherichia coli. In this Lamina Propria Aggregate Culture (LPAC) model, LPMCs were infected with HIV-1BaL by spinoculation and cultured in the presence or absence of heat killed E.coli. CD4+ T cell numbers derived from flow cytometry and viable cell counts were reported relative to mock infection. Viable cells were identified by viability dye exclusion (AqVi), and intracellular HIV-1 Gag p24 protein was used to identify infected cells. Annexin V and AqVi were used to identify apoptotic versus necrotic cells. Caspase-1 and Caspase-3 activities were blocked using specific inhibitors YVAD and DEVD, respectively. RESULTS: CD4+ T cell depletion following HIV-1 infection was reproducibly observed by 6 days post infection (dpi). Depletion at 6 dpi strongly correlated with infection frequency at 4 dpi, was significantly blocked by Efavirenz treatment, and was primarily driven by p24-negative cells that were predominantly necrotic. HIV-1 infection significantly induced CD4+ T-cell intrinsic Caspase-1 activity, whereas Caspase-1 inhibition, but not Caspase-3 inhibition, significantly blocked CD4+ T cell depletion. Exposure to E.coli enhanced HIV-1 infection and CD4+ T depletion, and significantly increased the number of apoptotic p24+ cells. Notably, CD4+ T cell depletion in the presence of E.coli was partially blocked by Caspase-3, but not by Caspase-1 inhibition. CONCLUSIONS: In the LPAC model, HIV-1 induced Caspase-1 mediated pyroptosis in bystander CD4+ T cells, but microbial exposure shifted the PCD mechanism toward apoptosis of productively infected T cells. These results suggest that mucosal CD4+ T cell death pathways may be altered in HIV-infected individuals after gut barrier function is compromised, with potential consequences for mucosal inflammation, viral dissemination and systemic immune activation. PMID- 24495383 TI - Oral health-related quality of life in diabetic patients: comparison of the Persian version of Geriatric Oral Health Assessment Index and Oral Health Impact Profile: A descriptive-analytic study. AB - BACKGROUND: Diabetes mellitus is one of the systemic disease which is show important oral manifestation and influence oral health. This study describes how diabetes mellitus affects oral health and oral health-related quality of life. The aim of this study was to evaluate the oral health and oral health-related quality of life of diabetic patients and compare the discriminative capability of Persian versions of two GOHAI and OHIP-14 questionnaires in these patients. METHODS: A total of 350 patients with Type II diabetes mellitus, referring to the Diabetes Clinic, were selected and data were collected by GOHAI and OHIP-14 questionnaires completed by patients and clinical examinations. Oral health parameters (CAL,BI,GI,PLI,DMFT and xerostomia) were measured, also concurrent validity and conformity of two questionnaires were assessed. In order to test Discriminant analysis capabilities of two questionnaires, ADD and SC scores of questionnaires were divided into two parts and a logistic regression model was designed, which included subjective and objective variables. RESULTS: Mean patients age was 55 years (with 75.4% female patients). The results showed that some oral conditions such as xerostomia, clinical attachment loss, number of missing teeth and plaque index were correlated to diabetes control level (HbA1c) and type of anti-diabetic medication. ADD and SC scores of two questionnaires were at high level. However, the effect of oral problems on decreasing OHRQoL was evident. Both questionnaires had acceptable concurrent validity and conformity. Moreover, there was a strong correlation between GOHAI and OHIP-14. OHIP-14 questionnaire had a higher discriminant analysis capability compared to GOHAI and better diagnosed patients who needed dental treatments: patients with higher GI, xerostomia and those wearing partial dentures. CONCLUSION: Diabetic patients did not show acceptable oral health status and in some extent, oral problems affected oral health-related quality of life. Psychotherapy courses and solving oral problems of the patients can improve OHRQoL. OHIP-14 had higher discriminant analysis capability and was more effective in diagnosing oral problems. PMID- 24495384 TI - Neuralgic amyotrophy (Parsonage Turner syndrome). PMID- 24495382 TI - Characterization of the membrane proteome and N-glycoproteome in BV-2 mouse microglia by liquid chromatography-tandem mass spectrometry. AB - BACKGROUND: Microglial cells are resident macrophages of the central nervous system and important cellular mediators of the immune response and neuroinflammatory processes. In particular, microglial activation and communication between microglia, astrocytes, and neurons are hallmarks of the pathogenesis of several neurodegenerative diseases. Membrane proteins and their N linked glycosylation mediate this microglial activation and regulate many biological process including signal transduction, cell-cell communication, and the immune response. Although membrane proteins and N-glycosylation represent a valuable source of drug target and biomarker discovery, the knowledge of their expressed proteome in microglia is very limited. RESULTS: To generate a large scale repository, we constructed a membrane proteome and N-glycoproteome from BV 2 mouse microglia using a novel integrated approach, comprising of crude membrane fractionation, multienzyme-digestion FASP, N-glyco-FASP, and various mass spectrometry. We identified 6928 proteins including 2850 membrane proteins and 1450 distinct N-glycosylation sites on 760 N-glycoproteins, of which 556 were considered novel N-glycosylation sites. Especially, a total of 114 CD antigens are identified via MS-based analysis in normal conditions of microglia for the first time. Our bioinformatics analysis provides a rich proteomic resource for examining microglial function in, for example, cell-to-cell communication and immune responses. CONCLUSIONS: Herein, we introduce a novel integrated proteomic approach for improved identification of membrane protein and N-glycosylation sites. To our knowledge, this workflow helped us to obtain the first and the largest membrane proteomic and N-glycoproteomic datesets for mouse microglia. Collectively, our proteomics and bioinformatics analysis significantly expands the knowledge of the membrane proteome and N-glycoproteome expressed in microglia within the brain and constitutes a foundation for ongoing proteomic studies and drug development for various neurological diseases. PMID- 24495385 TI - Early postoperative failure of a new intramedullary fixation device for midshaft clavicle fractures. PMID- 24495386 TI - Caring for the incarcerated: an orthopedic perspective. PMID- 24495388 TI - Limb-length discrepancy after total hip arthroplasty. PMID- 24495389 TI - Effect of all-trans-retinoic acid on enterovirus 71 infection in vitro. AB - Our previous studies have shown that vitamin A (VA) status is associated with antiviral immunity and pathogenic conditions in enterovirus 71 (EV71)-infected children. In the present study, we established an in vitro model to investigate the effects and potential mechanism of the antiviral activity of VA. Human monocytic U937 cells were cultured in vitro and infected with EV71. All-trans retinoic acid (ATRA), the active metabolite of VA, and Ro 41-5253, a retinoic acid receptor-alpha (RAR-alpha) antagonist, were used as the experimental treatment agents. The percentage of EV71-infected cells and apoptosis induced by EV71 were determined using flow cytometry. The level of interferon-alpha (IFN alpha) in the supernatants of the cultures was detected using ELISA. The expression of retinoid-induced gene I (RIG-I) and its downstream genes was examined with real-time quantitative PCR. The results indicated that ATRA reduced the percentage of EV71-infected cells and protected cells against EV71-induced apoptosis. Correspondingly, ATRA increased the production of IFN-alpha one of the most important antiviral cytokines, at both mRNA and protein levels in EV71 infected cells. In addition, the expression of RIG-I mRNA and its downstream genes was up-regulated by ATRA in EV71-infected cells. Ro 41-5253 abrogated the inhibitory effects of ATRA on EV71. The present findings suggest that ATRA is an interferon-inducing agent with antiviral activity against EV71 in vitro and that its actions are mediated at least in part by RAR-alpha activity and the RIG-I signalling pathway. PMID- 24495390 TI - Lower cortical serotonin 2A receptors in major depressive disorder, suicide and in rats after administration of imipramine. AB - We have attempted to replicate studies showing higher levels of serotonin 2A receptors (HTR2A) in the cortex of people with mood disorders and to determine the effects of treating rats with antidepressant drugs on levels of that receptor. In situ [3H]ketanserin binding and autoradiography was used to measure levels of HTR2A in Brodmann's area (BA) 46 and 24 from people with major depressive disorders (MDD, n = 16), bipolar disorders (BD, n = 14) and healthy controls (n = 14) as well as the central nervous system (CNS) of rats (20 per treatment arm) treated for 10 or 28 d with fluoxetine (10 mg/kg/d) or imipramine (20 mg/kg/d). Compared with controls, HTR2A were lower in BA 24, but not BA 46, from people with MDD (p = 0.005); HTR2A were not changed in BD. Levels of HTR2A were lower in BA 24 (p = 0.007), but not BA 46, from people who had died by suicide. Finally, levels of HTR2A were lower in the CNS of rats treated with imipramine, but not fluoxetine, for 28 d, but not 10 d. From our current and previous data we conclude cortical HTR2A are lower in schizophrenia, MDD, people with mood disorders who died by suicide, rats treated with some antipsychotic or some antidepressant drugs. As levels of cortical HTR2A can be affected by the aetiologies of different disorders and mechanisms of action of different drugs, a better understanding of how such changes can occur needs to be elucidated. PMID- 24495391 TI - Bithionol inhibits ovarian cancer cell growth in vitro - studies on mechanism(s) of action. AB - BACKGROUND: Drug resistance is a cause of ovarian cancer recurrence and low overall survival rates. There is a need for more effective treatment approaches because the development of new drug is expensive and time consuming. Alternatively, the concept of 'drug repurposing' is promising. We focused on Bithionol (BT), a clinically approved anti-parasitic drug as an anti-ovarian cancer drug. BT has previously been shown to inhibit solid tumor growth in several preclinical cancer models. A better understanding of the anti-tumor effects and mechanism(s) of action of BT in ovarian cancer cells is essential for further exploring its therapeutic potential against ovarian cancer. METHODS: The cytotoxic effects of BT against a panel of ovarian cancer cell lines were determined by Presto Blue cell viability assay. Markers of apoptosis such as caspases 3/7, cPARP induction, nuclear condensation and mitochondrial transmembrane depolarization were assessed using microscopic, FACS and immunoblotting methods. Mechanism(s) of action of BT such as cell cycle arrest, reactive oxygen species (ROS) generation, autotaxin (ATX) inhibition and effects on MAPK and NF-kB signalling were determined by FACS analysis, immunoblotting and colorimetric methods. RESULTS: BT caused dose dependent cytotoxicity against all ovarian cancer cell lines tested with IC50 values ranging from 19 MUM - 60 MUM. Cisplatin-resistant variants of A2780 and IGROV-1 have shown almost similar IC50 values compared to their sensitive counterparts. Apoptotic cell death was shown by expression of caspases 3/7, cPARP, loss of mitochondrial potential, nuclear condensation, and up-regulation of p38 and reduced expression of pAkt, pNF kappaB, pIkappaBalpha, XIAP, bcl-2 and bcl-xl. BT treatment resulted in cell cycle arrest at G1/M phase and increased ROS generation. Treatment with ascorbic acid resulted in partial restoration of cell viability. In addition, dose and time dependent inhibition of ATX was observed. CONCLUSIONS: BT exhibits cytotoxic effects on various ovarian cancer cell lines regardless of their sensitivities to cisplatin. Cell death appears to be via caspases mediated apoptosis. The mechanisms of action appear to be partly via cell cycle arrest, ROS generation and inhibition of ATX. The present study provides preclinical data suggesting a potential therapeutic role for BT against recurrent ovarian cancer. PMID- 24495393 TI - Aging related changes in determinants of muscle force generating capacity: a comparison of muscle aging in men and male rodents. AB - Human aging is associated with a progressive decline in skeletal muscle mass and force generating capacity, however the exact mechanisms underlying these changes are not fully understood. Rodents models have often been used to enhance our understanding of mechanisms of age-related changes in human skeletal muscle. However, to what extent age-related alterations in determinants of muscle force generating capacity observed in rodents resemble those in humans has not been considered thoroughly. This review compares the effect of aging on muscle force generating determinants (muscle mass, fiber size, fiber number, fiber type distribution and muscle specific tension), in men and male rodents at similar relative age. It appears that muscle aging in male F344*BN rat resembles that in men most; 32-35-month-old rats exhibit similar signs of muscle weakness to those of 70-80-yr-old men, and the decline in 36-38-month-old rats is similar to that in men aged over 80 yrs. For male C57BL/6 mice, age-related decline in muscle force generating capacity seems to occur only at higher relative age than in men. We conclude that the effects on determinants of muscle force differ between species as well as within species, but qualitatively show the same pattern as that observed in men. PMID- 24495392 TI - Communication breakdown: the impact of ageing on synapse structure. AB - Impaired synaptic plasticity is implicated in the functional decline of the nervous system associated with ageing. Understanding the structure of ageing synapses is essential to understanding the functions of these synapses and their role in the ageing nervous system. In this review, we summarize studies on ageing synapses in vertebrates and invertebrates, focusing on changes in morphology and ultrastructure. We cover different parts of the nervous system, including the brain, the retina, the cochlea, and the neuromuscular junction. The morphological characteristics of aged synapses could shed light on the underlying molecular changes and their functional consequences. PMID- 24495394 TI - Experimental endometriosis remission in rats treated with Achillea biebersteinii Afan.: histopathological evaluation and determination of cytokine levels. AB - OBJECTIVE: The aim of the present study is to assess the beneficial effects of Achillea biebersteinii Afan. in the treatment of endometriosis in order to find scientific evidence for the folkloric use of this plant. STUDY DESIGN: Experimental endometriosis was induced in six-week-old female, nonpregnant, Sprague Dawley rats by suturing a 15mm piece of endometrium from uterine cornu into abdominal wall. After twenty-eight days, a second laparotomy was performed: the endometrial foci areas were measured and intra-abdominal adhesions were scored, and the abdomen was closed. Different groups then received n-hexane, ethyl acetate (EtOAc) and methanol (MeOH) extracts prepared from the aerial parts of A. biebersteinii, and a control group received inert material, administered per os once a day throughout the experiment. At the end of the treatment procedure all rats were sacrified and endometriotic foci areas and intra abdominal adhesions were again evaluated and compared with the previous findings. The tissues were also histopathologically investigated. Moreover, peritoneal fluid was collected to detect tumor necrosis factor-alpha (TNF-alpha), vascular endothelial growth factor (VEGF) and interleukin-6 (IL-6) levels. Dunnett's test was used to determine the significance of differences between groups. In order to compare two groups Student's t test was used. RESULTS: Post-treatment volumes of endometrial foci were found to be significantly decreased, and no adhesion was detected, in the EtOAc extract treated group. The levels of TNF-alpha, VEGF and IL-6 also fell after the treatment with EtOAc extract. The therapeutic effect of the EtOAc extract of A. biebersteinii could be attributed to the flavonoid aglycones found in the extract. CONCLUSION: The EtOAc extract of A. biebersteinii appears to be a promising alternative for the treatment of endometriosis. PMID- 24495395 TI - Assessing quality of life-shortening Wolbachia-infected Aedes aegypti mosquitoes in the field based on capture rates and morphometric assessments. AB - BACKGROUND: Recent releases have been carried out with Aedes aegypti mosquitoes infected with the wMelPop mosquito cell-line adapted (wMelPop-CLA) strain of Wolbachia. This infection introduced from Drosophila provides strong blockage of dengue and other arboviruses but also has large fitness costs in laboratory tests. The releases were used to evaluate the fitness of released infected mosquitoes, and (following termination of releases) to test for any effects of wMelPop-CLA on wing size and shape when mosquitoes were reared under field conditions. METHODS: We monitored gravid females via double sticky traps to assess the reproductive success of wMelPop-CLA-infected females and also sampled the overall mosquito population post-release using Biogent Sentinel traps. Morphometric analyses were used to evaluate infection effects on wing shape as well as size. RESULTS: Oviposition success as assessed through double sticky traps was unrelated to size of released mosquitoes. However, released mosquitoes with lower wing loading were more successful. Furthermore, wMelPop-CLA-infected mosquitoes had 38.3% of the oviposition success of uninfected mosquitoes based on the predicted infection frequency after release. Environmental conditions affected wing shape and particularly size across time in uninfected mosquitoes, but not in naturally-reared wMelPop-CLA-infected mosquitoes. Although the overall size and shape do not differ between naturally-reared wMelPop-CLA-infected and uninfected mosquitoes, the infected mosquitoes tended to have smaller wings than uninfected mosquitoes during the cooler November in comparison to December. CONCLUSION: These results confirm the lower fitness of wMelPop-CLA infection under field conditions, helping to explain challenges associated with a successful invasion by this strain. In the long run, invasion may depend on releasing strains carrying insecticide resistance or egg desiccation resistance, combined with an active pre-release population suppression program. PMID- 24495396 TI - TRPV1 receptor inhibition decreases CCL2-induced hyperalgesia. AB - Modulation of nociceptive synaptic transmission in the spinal cord is implicated in the development and maintenance of several pathological pain states. The chemokine CCL2 (C-C motif ligand 2) was shown to be an important factor in the development of neuropathic pain after peripheral nerve injury. In our experiments we have studied the effect of CCL2 application and TRPV1 (transient receptor potential vanilloid 1) receptor activation on nociceptive signaling and the modulation of synaptic transmission. Intrathecal drug application in behavioral experiments and patch-clamp recordings of spontaneous, miniature and dorsal root stimulation-evoked excitatory postsynaptic currents (sEPSCs, mEPSCs, eEPSCs) from superficial dorsal horn neurons in acute rat spinal cord slices were used. The intrathecal application of CCL2 induced thermal hyperalgesia and mechanical allodynia, while pretreatment with the TRPV1 receptor antagonist SB366791 diminished the thermal but not the mechanical hypersensitivity. Patch-clamp experiments showed an increase of sEPSC and mEPSC (124.5 +/- 12.8% and 161.2 +/- 17.3%, respectively) frequency in dorsal horn neurons after acute CCL2 application. This CCL2-induced increase was prevented by SB366791 pretreatment (89.4 +/- 6.0%, 107.5 +/- 14.2%). CCL2 application increased the amplitude of eEPSCs (188.1 +/- 32.1%); this increase was significantly lower in experiments with SB366791 pretreatment (120.8 +/- 17.2%). Our results demonstrate that the activation of spinal TRPV1 receptors plays an important role in the modulation of nociceptive signaling induced by CCL2 application. The mechanisms of cooperation between the CCL2 activated receptors and TRPV1 receptors on the central branches of primary afferent fibers may be especially important during different pathological pain states and need to be further investigated. PMID- 24495397 TI - Inhibiting 11beta-hydroxysteroid dehydrogenase type 1 prevents stress effects on hippocampal synaptic plasticity and impairs contextual fear conditioning. AB - 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD1) catalyzes intracellular regeneration of corticosterone and cortisol, thereby enhancing glucocorticoid action. Inhibition of 11beta-HSD1 reverses the deficits in cognition with aging, a state of elevated glucocorticoid levels. However, any impact of 11beta-HSD1 inhibition during high glucocorticoid states in younger animals is unknown. Here we examined whether a single injection of the selective 11beta-HSD1 inhibitor UE2316 modifies the effect of stress on hippocampal long-term potentiation and fear conditioning, a learning paradigm that is strongly modulated by glucocorticoids. We found that novelty stress suppresses hippocampal synaptic potentiation. This effect was completely prevented by administration of UE2316 one hour before stress exposure. A single injection of UE2316 also impaired contextual, but not tone-cue-fear conditioning. These observations suggest that local metabolism of glucocorticoids is relevant for the outcome of stress effects on hippocampal synaptic plasticity and contextual fear conditioning. Selective 11beta-HSD1 inhibitors may be an interesting new approach to the prevention of trauma-associated psychopathology. PMID- 24495398 TI - Epigenetic modifications in the nervous system and their impact upon cognitive impairments. AB - Epigenetic regulation has been long considered to be a critical mechanism in the control of key aspects of cellular functions such as cell division, growth, and cell fate determination. Exciting recent developments have demonstrated that epigenetic mechanisms can also play necessary roles in the nervous system by regulating, for example, neuronal gene expression, DNA damage, and genome stability. Despite the fact that postmitotic neurons are developmentally less active then dividing cells, epigenetic regulation appears to provide means of both long-lasting and very dynamic regulation of neuronal function. Growing evidence indicates that epigenetic mechanisms in the central nervous system (CNS) are important for regulating not only specific aspects of individual neuronal metabolism but also for maintaining function of neuronal circuits and regulating their behavioral outputs. Multiple reports demonstrated that higher-level cognitive behaviors, such as learning and memory, are subject to a sophisticated epigenetic control, which includes interplay between multiple mechanisms of neuronal chromatin modification. Experiments with animal models have demonstrated that various epigenetic manipulations can affect cognition in different ways, from severe dysfunction to substantial improvement. In humans, epigenetic dysregulation has been known to underlie a number of disorders that are accompanied by mental impairment. Here, we review some of the epigenetic mechanisms that regulate cognition and how their disruption may contribute to cognitive dysfunctions. Due to the fact that histone acetylation and DNA methylation are some of the best-studied and critically important epigenomic modifications our research team has particularly strong expertise in, in this review, we are going to concentrate on histone acetylation, as well as DNA methylation/hydroxymethylation, in the mammalian CNS. Additional epigenetic modifications, not surveyed here, are being discussed in depth in the other review articles in this issue of Neuropharmacology. PMID- 24495399 TI - Gabapentin increases extracellular glutamatergic level in the locus coeruleus via astroglial glutamate transporter-dependent mechanisms. AB - Gabapentin has shown to be effective in animals and humans with acute postoperative and chronic pain. Yet the mechanisms by which gabapentin reduces pain have not been fully addressed. The current study performed in vivo microdialysis in the locus coeruleus (LC) in normal and spinal nerve ligated (SNL) rats to examine the effect of gabapentin on extracellular glutamate concentration and its mechanisms of action with focus on presynaptic GABA-B receptors, astroglial glutamate transporter-1 (GLT-1), and interactions with alpha2delta subunits of voltage-gated Ca(2+) channels and endogenous noradrenaline. Basal extracellular concentration and tissue content of glutamate in the LC were greater in SNL rats than normal ones. Intravenously administered and LC-perfused gabapentin increased extracellular glutamate concentration in the LC. The net amount of glutamate increased by gabapentin is larger in SNL rats compared with normal ones, although the percentage increases from the baseline did not differ. The gabapentin-related alpha2delta ligand pregabalin increased extracellular glutamate concentration in the LC, whereas another alpha2delta ligand, 3-exo-aminobicyclo [2.2.1] heptane-2-exo-carboxylic acid (ABHCA), did not. Selective blockade by the dihydrokainic acid or knock-down of GLT-1 by the small interfering RNA abolished the gabapentin-induced glutamate increase in the LC, whereas blockade of GABA-B receptors by the CGP-35348 and depletion of noradrenalin by the dopamine-beta-hydroxylase antibody conjugated to saporin did not. These results suggest that gabapentin induces glutamate release from astrocytes in the LC via GLT-1-dependent mechanisms to stimulate descending inhibition. The present study also demonstrates that this target of gabapentin in astrocytes does not require interaction with alpha2delta subunits in neurons. PMID- 24495400 TI - Periprosthetic wear particle migration and distribution modelling and the implication for osteolysis in cementless total hip replacement. AB - In total hip replacement (THR), wear particles play a significant role in osteolysis and have been observed in locations as remote as the tip of femoral stem. However, there is no clear understanding of the factors and mechanisms causing, or contributing to particle migration to the periprosthetic tissue. Interfacial gaps provide a route for particle laden joint fluid to transport wear particles to the periprosthetic tissue and cause osteolysis. It is likely that capsular pressure, gap dimensions and micromotion of the gap during cyclic loading of an implant, play defining roles to facilitate particle migration. In order to obtain a better understanding of the above mechanisms and factors, transient two-dimensional computational fluid dynamic simulations have been performed for the flow in the lateral side of a cementless stem-femur system including the joint capsule, a gap in communication with the capsule and the surrounding bone. A discrete phase model to describe particle motion has been employed. Key findings from these simulations include: (1) Particles were shown to enter the periprosthetic tissue along the entire length of the gap but with higher concentrations at both proximal and distal ends of the gap and a maximum rate of particle accumulation in the distal regions. (2) High capsular pressure, rather than gap micromotion, has been shown to be the main driving force for particle migration to periprosthetic tissue. (3) Implant micromotion was shown to pump out rather than draw in particles to the interfacial gaps. (4) Particle concentrations are consistent with known distributions of (i) focal osteolysis at the distal end of the gap and (ii) linear osteolysis along the entire gap length. PMID- 24495402 TI - Carer-led health interventions to monitor, promote and improve the health of adults with intellectual disabilities in the community: a systematic review. AB - Using carers to help assess, monitor, or promote health in people with intellectual disabilities (ID) may be one way of improving health outcomes in a population that experiences significant health inequalities. This paper provides a review of carer-led health interventions in various populations and healthcare settings, in order to investigate potential roles for carers in ID health care. We used rapid review methodology, using the Scopus database, citation tracking and input from ID healthcare professionals to identify relevant research. 24 studies were included in the final review. For people with ID, the only existing interventions found were carer-completed health diaries which, while being well received, failed to improve health outcomes. Studies in non-ID populations show that carers can successfully deliver screening procedures, health promotion interventions and interventions to improve coping skills, pain management and cognitive functioning. While such examples provide a useful starting point for the development of future carer-led health interventions for people with ID, the paucity of research in this area means that the most appropriate means of engaging carers in a way that will reliably impact on health outcomes in this population remains, as yet, unknown. PMID- 24495403 TI - Delirium detection based on monitoring of blinks and eye movements. AB - OBJECTIVE: To investigate whether delirious patients differ from nondelirious patients with regard to blinks and eye movements to explore opportunities for delirium detection. METHODS: Using a single-center, observational study in a tertiary hospital in the Netherlands, we studied 28 delirious elderly and 28 age- and gender-matched (group level) nondelirious elderly, postoperative cardiac surgery patients. Patients were evaluated for delirium by a geriatrician, psychiatrist, or neurologist using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition criteria. Blinks were automatically extracted from electro-oculograms and eye movements from electroencephalography recordings using independent component analysis. The number and duration of eye movements and blinks were compared between patients with and without delirium, based on the classification of the delirium experts described above. RESULTS: During eyes-open registrations, delirious patients showed, compared with nondelirious patients, a significant decrease in the number of blinks per minute (median: 12 [interquartile range {IQR}: 5-18] versus 18 [IQR: 8-25], respectively; p = 0.02) and number of vertical eye movements per minute (median: 1 [IQR: 0-13] versus 15 [IQR: 2-54], respectively; p = 0.01) as well as an increase in the average duration of blinks (median: 0.5 [IQR: 0.36-0.95] seconds versus 0.34 [IQR: 0.23 0.53] seconds, respectively; p <0.01). During eyes-closed registrations, the average duration of horizontal eye movements was significantly increased in delirious patients compared with patients without delirium (median: 0.41 [IQR: 0.15-0.75] seconds versus 0.08 [IQR: 0.06-0.22] seconds, respectively; p <0.01). CONCLUSION: Spontaneous eye movements and particularly blinks appear to be affected in delirious patients, which holds promise for delirium detection. PMID- 24495404 TI - Beta-amyloid associated differential effects of APOE epsilon4 on brain metabolism in cognitively normal elderly. AB - OBJECTIVE: Although apolipoprotein (APOE) epsilon4 allele is a well-established risk factor for late-onset Alzheimer disease (AD), the mechanism of its effects on AD pathogenesis is not fully understood. We aimed to investigate the effects of APOE genotype on regional cerebral glucose metabolism in cognitively normal (CN) elderly. We further tried to elucidate whether or not such effects are associated with beta-amyloid protein (Abeta) deposition. METHODS: 31 CN elderly participants underwent clinical examination, a range of neuropsychological tests, APOE genotyping, and Pittsburgh compound-B- and fluorodeoxyglucose-PET scans. RESULTS: 17 APOE epsilon4 carriers and 15 non-carriers were included. Both hypometabolic and hypermetabolic regions were observed in epsilon4 carriers compared with noncarriers when age, education, and sex were controlled. When the degree of global cerebral Abeta deposition was adjusted, the hypometabolic regions in the temporo-parietal area (i.e., BA 22 and 39) largely disappeared, whereas the hypermetabolic regions persisted in medial frontal and anterior temporal areas (i.e., BA 38, 11, and 39). Behaviorally, verbal episodic memory scores of APOE epsilon4 carriers were slightly lower than those of noncarriers, though still within normal range. CONCLUSIONS: Our findings indicate that decreased cerebral glucose metabolism in the temporoparietal junction associated with APOE epsilon4 in CN elderly appears to be mediated by Abeta deposition, and the effect of APOE epsilon4 on hypermetabolism in the frontal and anterior temporal regions is independent of Abeta and may be associated with presence of compensatory mechanism in CN elderly with the epsilon4 allele. PMID- 24495405 TI - Psychiatric and medical comorbidities: results from a bipolar elderly cohort study. AB - OBJECTIVE: Bipolar disorder is associated with concurrent mental and physical disorders. Although well studied among younger adults, less is known about concurrent morbidity among older patients. This is important because comorbidity may increase with age and optimal treatment requires awareness of medical and psychiatric comorbidities. This study analyzed psychiatric and medical comorbidity in a Dutch bipolar elderly cohort. METHODS: This cross-sectional descriptive study included demographic and clinical data on 101 bipolar patients aged 60 and over (mean age: 68.9 +/- 7.8 years); 53.4% were women. Psychiatric diagnoses were confirmed by semistructured diagnostic interviews. Somatic history, including current somatic complaints, was obtained by interview. Medication and indicators of metabolic syndrome were obtained via record review. RESULTS: Most patients received outpatient care. Bipolar I disorder was diagnosed in 56.4% of patients, and 75.6% had an onset of first affective symptoms before age 50. The prevalence rates of psychiatric comorbidities were low, except for lifetime alcohol dependence (24.8%) and abuse (13.9%). On average, there were 1.7 (SD: 1.6) medical comorbid conditions, predominantly hypertension (27.8%), arthrosis (29.1%), and allergies (25.6%). Polypharmacy was found in 31.7% of patients and metabolic syndrome in 28.7%. CONCLUSION: Psychiatric comorbidity (especially anxiety disorders) was relatively uncommon, except for substance use disorder. Geriatric bipolar patients had on average two comorbid medical conditions and relatively high medication use. Findings underline the need to assess for comorbid conditions in bipolar elders, thereby enabling tailored treatment to optimize the general condition of these patients. PMID- 24495406 TI - Trazodone improves sleep parameters in Alzheimer disease patients: a randomized, double-blind, and placebo-controlled study. AB - OBJECTIVES: There are no randomized clinical trials regarding efficacy of trazodone in the treatment of sleep disturbances (SD) in patients with Alzheimer disease (AD). We tested the efficacy and safety of trazodone to treat SD in patients with AD. DESIGN: We conducted a double-blind, randomized and controlled trial during periods of 7-9 days at baseline and 2 weeks of treatment. SETTING: Geriatric medical center of the university's general hospital. PARTICIPANTS: Individuals with probable AD and SD. The complete analysis comprised 30 patients assigned to either the active treatment group (N = 15) or the placebo group (N = 15). INTERVENTION: Patients received 50 mg of trazodone once daily at 10:00 P.M. or placebo in a 1:1 ratio for 2 weeks. MEASUREMENTS: Patients were evaluated using actigraphy and structured scales before and after intervention. RESULTS: Compared with the placebo group, trazodone users slept 42.5 more minutes per night and had their nighttime percent sleep increased 8.5 percentage points according to actigraphic data post-treatment. Neither trazodone nor placebo induced significant daytime sleepiness or naps. The treatments with trazodone or placebo did not show any effects either on cognition (Mini-Mental State Examination, forward/backward digit span task, letter-number sequencing, arithmetic, digit symbol-coding, and symbol search) or functionality (Katz index). There were no differences in frequency or severity rating of adverse events between the groups. CONCLUSIONS: This study shows significant therapeutic effects of trazodone 50 mg in community-dwelling AD patients with SD. PMID- 24495407 TI - Loss of CDKN2A expression is a frequent event in primary invasive melanoma and correlates with sensitivity to the CDK4/6 inhibitor PD0332991 in melanoma cell lines. AB - We have investigated the potential for the p16-cyclin D-CDK4/6-retinoblastoma protein pathway to be exploited as a therapeutic target in melanoma. In a cohort of 143 patients with primary invasive melanoma, we used fluorescence in situ hybridization to detect gene copy number variations (CNVs) in CDK4, CCND1, and CDKN2A and immunohistochemistry to determine protein expression. CNVs were common in melanoma, with gain of CDK4 or CCND1 in 37 and 18% of cases, respectively, and hemizygous or homozygous loss of CDKN2A in 56%. Three-quarters of all patients demonstrated a CNV in at least one of the three genes. The combination of CCND1 gain with either a gain of CDK4 and/or loss of CDKN2A was associated with poorer melanoma-specific survival. In 47 melanoma cell lines homozygous loss, methylation or mutation of CDKN2A gene or loss of protein (p16(INK) (4A) ) predicted sensitivity to the CDK4/6 inhibitor PD0332991, while RB1 loss predicted resistance. PMID- 24495408 TI - Fyn kinase inhibition as a novel therapy for Alzheimer's disease. AB - Alzheimer's disease (AD) is a devastating neurodegenerative disorder, afflicting more than one-third of people over the age of 85. While many therapies for AD are in late-stage clinical testing, rational drug design based on distinct signaling pathways in this disorder is only now emerging. Here we review the putative signaling pathway of amyloid-beta (Abeta), by which the tyrosine kinase Fyn is activated via cell surface binding of Abeta oligomers to cellular prion protein. Several lines of evidence implicate Fyn in the pathogenesis of AD, and its interaction with both Abeta and Tau renders Fyn a unique therapeutic target that addresses both of the major pathologic hallmarks of AD. We are currently enrolling patients in a phase Ib study of saracatinib (AZD0530), a small molecule inhibitor with high potency for Src and Fyn, for the treatment of AD. The results of this trial and a planned phase IIa multisite study will provide important data regarding the potential for this therapeutic strategy in AD. PMID- 24495409 TI - Retroperitoneal Castleman's disease: advocating a multidisciplinary approach for a rare clinical entity. AB - BACKGROUND: Castleman's disease is a rare and poorly understood disease entity that may resemble more common conditions and represents a clinical challenge to the treating surgeon. CASE PRESENTATION: In this report, we describe a case of a 61-year-old Caucasian woman with a symptomatic retroperitoneal mass. The specimen obtained from her resection contained a protuberant encapsulated mass, exhibiting microscopic features consistent with localized, unicentric Castleman's disease. These characteristics included architectural features and immunohistochemical findings consistent with the hyaline vascular variant of Castleman's disease. CONCLUSION: We report a very rare case of a retroperitoneal hyaline vascular type of Castleman's disease. We discuss the diagnostic dilemma Castleman's disease may present to the surgeon, with an emphasis on multidisciplinary management of these patients. We also review current data on pathogenesis, treatment and outcomes. PMID- 24495411 TI - Quantitative exponential modelling of copycat suicides: association with mass media effect in South Korea. AB - BACKGROUND: There is ample evidence media reporting of celebrity suicides increases copycat suicides. This study had three aims: (a) to quantitatively examine copycat suicides with exponential modelling that predicts the copycat suicide effect of South Korean celebrity suicides; (b) to investigate the association between media effect and subsequent suicides following celebrity deaths; and (c) to investigate the extent in which media influences the increase and rate of decline of copycat suicides following a celebrity suicide. METHODS: All suicides during 1991-2010 in South Korea were included in this study utilising a nationwide database. Fifteen celebrities were selected based on the frequency of media reports following 1 week after their suicide. The media effect was obtained through the Korean Integrated Newspaper Database System. Exponential curve fits and correlation analyses investigated the quantitative effect of copycat suicides. RESULTS: After controlling for baseline number of average suicides, there was a marked increase in the number of suicides following each celebrity suicides, which followed an exponential model. There was a significant correlation between the total number of copycat suicides and number of media following the celebrity suicide (r = 0.74, p < 0.01). There were weak-to-moderate correlations between the amplitude of increase in suicides (r = 0.45, p = 0.09) and rate of decline (r = 0.38, p = 0.16) with the total number of media coverage. CONCLUSIONS: Copycat suicides following celebrity suicides follow exponential modelling. Additionally, there is a strong media effect between the number of media reports following the days after celebrity suicides and subsequent copycat suicides. This may also be associated with the amplitude and rate of decline of copycat suicides. This suggests that improving media reporting and implementing preventative interventions for vulnerable populations may be important. PMID- 24495410 TI - Involvement of activating ERK1/2 through G protein coupled receptor 30 and estrogen receptor alpha/beta in low doses of bisphenol A promoting growth of Sertoli TM4 cells. AB - Sertoli cells play a pivotal role in supporting proliferation of germ cells and differentiation during spermatogenesis in mammals. Nanomolar concentrations of Bisphenol A (BPA) can significantly stimulate the proliferation of mouse immature Sertoli (TM4) cells. However, mechanisms by which BPA caused these effects were still unclear. In the present study, an inverse U-shaped curve was observed when treating TM4 cells with increasing doses of BPA: 1 to 10nM BPA significantly stimulated the proliferation of TM4 cells and increased the proportion of cells in S phase; >1 MUM BPA caused lesser proliferation of cells. Exposure of TM4 cells to G15 or ICI 182,780, which are specific antagonists of GPR30 and estrogen receptor alpha/beta (ERalpha/beta), respectively, abolished BPA-induced proliferation of cells, which suggests that both GPR30 and ERalpha/beta were involved in the observed effects of BPA. Furthermore, exposure to BPA caused rapid (5 min) activation of ERK1/2 via both GPR30 and ERalpha/beta. Blocking the GPR30/EGFR signal transduction pathway by antagonists suppressed both phosphorylation of ERK and BPA-induced cell proliferation. BPA up-regulated mRNA and protein expression of GPR30 in a concentration-dependent manner. In summary, the results reported here indicated that activating ERK1/2 through GPR30 and ERalpha/beta is involved in low doses of BPA that promoted growth of Sertoli TM4 cells. The GPR30/EGFR/ERK signal is the downstream transduction pathway in BPA induced proliferation of TM4 Sertoli cells. PMID- 24495412 TI - Identification of potential serum peptide biomarkers of biliary tract cancer using MALDI MS profiling. AB - BACKGROUND: The aim of this discovery study was the identification of peptide serum biomarkers for detecting biliary tract cancer (BTC) using samples from healthy volunteers and benign cases of biliary disease as control groups. This work was based on the hypothesis that cancer-specific exopeptidases exist and that their activities in serum can generate cancer-predictive peptide fragments from circulating proteins during coagulation. METHODS: This case control study used a semi-automated platform incorporating polypeptide extraction linked to matrix-assisted laser desorption/ionisation time-of-flight mass spectrometry (MALDI-TOF MS) to profile 92 patient serum samples. Predictive models were generated to test a validation serum set from BTC cases and healthy volunteers. RESULTS: Several peptide peaks were found that could significantly differentiate BTC patients from healthy controls and benign biliary disease. A predictive model resulted in a sensitivity of 100% and a specificity of 93.8% in detecting BTC in the validation set, whilst another model gave a sensitivity of 79.5% and a specificity of 83.9% in discriminating BTC from benign biliary disease samples in the training set. Discriminatory peaks were identified by tandem MS as fragments of abundant clotting proteins. CONCLUSIONS: Serum MALDI MS peptide signatures can accurately discriminate patients with BTC from healthy volunteers. PMID- 24495413 TI - Probabilistic mapping of the cervical sympathetic trunk ganglia. AB - The goal of this study was to create a heat map indicating the probabilistic location of major ganglia of the cervical sympathetic trunk (CST). Detailed dissections of human cadaveric specimens, followed by spatial registration and analysis of the cervical sympathetic ganglia in the neck and upper thorax regions (C1-T1) were performed in 104 neck specimens (both sides from 52 cadavers). Unbiased parametric mapping, visualized with a heat map, revealed a general pattern of two major ganglia located on both sides of the neck: The superior cervical ganglion (SCG) was located 80-90 mm superior to the point at which the vertebral artery entered the transverse foramen (VA-TF); the stellate ganglion (SG) was located approximately 10 mm inferior to the VA-TF in 80% of our sample, or surrounding the VA-TF in the remaining 20% of our sample. In between these ganglia, a highly variable number of smaller and less prevalent ganglia were present on either side of the neck. The middle ganglia on the right side of the neck were located closer to the SCG, possibly indicative of the middle cervical ganglion. On the left side the middle ganglia were located closer to the SG, perhaps indicative of the vertebral ganglion or the inferior cervical ganglion. Individual specimens could be classified into one of seven different patterns of cervical trunks. The results may help surgeons and anesthesiologists more accurately target and preserve these structures during medical procedures. PMID- 24495414 TI - Outcome disparities in African American women with triple negative breast cancer: a comparison of epidemiological and molecular factors between African American and Caucasian women with triple negative breast cancer. AB - BACKGROUND: Although diagnosed less often, breast cancer in African American women (AAW) displays different characteristics compared to breast cancer in Caucasian women (CW), including earlier onset, less favorable clinical outcome, and an aggressive tumor phenotype. These disparities may be attributed to differences in socioeconomic factors such as access to health care, lifestyle, including increased frequency of obesity in AAW, and tumor biology, especially the higher frequency of triple negative breast cancer (TNBC) in young AAW. Improved understanding of the etiology and molecular characteristics of TNBC in AAW is critical to determining whether and how TNBC contributes to survival disparities in AAW. METHODS: Demographic, pathological and survival data from AAW (n = 62) and CW (n = 98) with TNBC were analyzed using chi-square analysis, Student's t-tests, and log-rank tests. Frozen tumor specimens were available from 57 of the TNBC patients (n = 23 AAW; n = 34 CW); RNA was isolated after laser microdissection of tumor cells and was hybridized to HG U133A 2.0 microarrays. Data were analyzed using ANOVA with FDR <0.05, >2-fold difference defining significance. RESULTS: The frequency of TNBC compared to all BC was significantly higher in AAW (28%) compared to CW (12%), however, significant survival and pathological differences were not detected between populations. Gene expression analysis revealed the tumors were more similar than different at the molecular level, with only CRYBB2P1, a pseudogene, differentially expressed between populations. Among demographic characteristics, AAW consumed significantly lower amounts of caffeine and alcohol, were less likely to breastfeed and more likely to be obese. CONCLUSIONS: These data suggest that TNBC in AAW is not a unique disease compared to TNBC in CW. Rather, higher frequency of TNBC in AAW may, in part, be attributable to the effects of lifestyle choices. Because these risk factors are modifiable, they provide new opportunities for the development of risk reduction strategies that may decrease mortality by preventing the development of TNBC in AAW. PMID- 24495415 TI - Post-tonsillectomy morbidities: randomised, prospective controlled clinical trial of cold dissection versus thermal welding tonsillectomy. AB - BACKGROUND: New surgical techniques and devices have been described that decrease post-tonsillectomy morbidities. This study aimed to compare the two most popular tonsillectomy techniques. METHOD: Forty children underwent tonsillectomies using both the thermal welding and cold dissection techniques. In each patient, one side was removed with thermal welding and the other was removed with cold dissection. RESULTS: There was a significant decrease in intra-operative blood loss, and the mean operation time was significantly lower on the thermal welding side compared with the cold dissection side. On the cold dissection side, tissue healing (i.e. the rate of complete tissue healing) was better and less pain was reported compared with the thermal welding side. However, there were no significant differences between the two techniques in terms of throat pain scores on the 1st, 3rd or 14th day post-operatively, or tissue healing scores on any of the post-operative days assessed. CONCLUSION: Cold dissection resulted in better tissue healing and lower pain scores than thermal welding, but thermal welding was associated with less intra-operative blood loss and lower mean operation time than cold dissection. PMID- 24495416 TI - Comparison of fenestrated and nonfenestrated patients undergoing extracardiac Fontan. AB - BACKGROUND: The purpose of this study is to compare morbidity and mortality between fenestrated (F, 61 patients) and nonfenestrated (NF, 54 patients) extracardiac Fontan patients during two eras from July 1995 to December 2010: era 1(1995 to 2004) and era 2 (2005 to 2010). METHODS: Variables evaluated included morphology, hemodynamics, chest tube volume and duration, intensive care and hospital stay, oxygen saturation, neurologic events, rhythm, and readmissions for chylous effusions. Follow-up in 114 hospital survivors was longer in the nonfenestrated cohort (F, 5.0 +/- 3.3 years; NF, 7.1 +/- 4.6 years; p < 0.005). RESULTS: Cohorts were similar in body size, morphology, and hemodynamics. Fenestration in hypoplastic left heart syndrome was appreciatively higher in era 2. Bypass time (F, 69 +/- 27 minutes; NF, 57 +/- 21 minutes) and conduit size (F, 18.8 mm; NF, 19.1 mm) were similar. There was 1 early nonfenestrated Fontan death (1 of 54; 2%) and 4 late deaths (F, 2 of 61, 5%; NF, 2 of 53, 4%; p = 0.86). Room air saturation was higher in NF patients (F, 89%; NF, 94%; p < 0.05). Total chest tube volume was similar, but fenestration was associated with greater chest tube drainage among hypoplastic left heart patients (HLHS, 5,582 +/- 3,286 mL; non HLHS, 3,405 +/- 2,533 mL; p = 0.06; odds ratio; 2.0). Readmission to treat chylous effusions, loss of sinus rhythm, actuarial freedom from death, all neurologic events, pacemaker insertion, and Fontan takedown were similar in both cohorts. CONCLUSIONS: Fenestration was associated with lower discharge oxygen saturations, but late outcomes in fenestrated and nonfenestrated patients are equivalent. PMID- 24495417 TI - Comparison of three next-generation sequencing platforms for metagenomic sequencing and identification of pathogens in blood. AB - BACKGROUND: The introduction of benchtop sequencers has made adoption of whole genome sequencing possible for a broader community of researchers than ever before. Concurrently, metagenomic sequencing (MGS) is rapidly emerging as a tool for interrogating complex samples that defy conventional analyses. In addition, next-generation sequencers are increasingly being used in clinical or related settings, for instance to track outbreaks. However, information regarding the analytical sensitivity or limit of detection (LoD) of benchtop sequencers is currently lacking. Furthermore, the specificity of sequence information at or near the LoD is unknown. RESULTS: In the present study, we assess the ability of three next-generation sequencing platforms to identify a pathogen (viral or bacterial) present in low titers in a clinically relevant sample (blood). Our results indicate that the Roche-454 Titanium platform is capable of detecting Dengue virus at titers as low as 1X102.5 pfu/mL, corresponding to an estimated 5.4X104 genome copies/ml maximum. The increased throughput of the benchtop sequencers, the Ion Torrent PGM and Illumina MiSeq platforms, enabled detection of viral genomes at concentrations as low as 1X104 genome copies/mL. Platform specific biases were evident in sequence read distributions as well as viral genome coverage. For bacterial samples, only the MiSeq platform was able to provide sequencing reads that could be unambiguously classified as originating from Bacillus anthracis. CONCLUSION: The analytical sensitivity of all three platforms approaches that of standard qPCR assays. Although all platforms were able to detect pathogens at the levels tested, there were several noteworthy differences. The Roche-454 Titanium platform produced consistently longer reads, even when compared with the latest chemistry updates for the PGM platform. The MiSeq platform produced consistently greater depth and breadth of coverage, while the Ion Torrent was unequaled for speed of sequencing. None of the platforms were able to verify a single nucleotide polymorphism responsible for antiviral resistance in an Influenza A strain isolated from the 2009 H1N1 pandemic. Overall, the benchtop platforms perform well for identification of pathogens from a representative clinical sample. However, unlike identification, characterization of pathogens is likely to require higher titers, multiple libraries and/or multiple sequencing runs. PMID- 24495418 TI - Out of the bush: the Asian bush mosquito Aedes japonicus japonicus (Theobald, 1901) (Diptera, Culicidae) becomes invasive. AB - The Asian bush or rock pool mosquito Aedes japonicus japonicus is one of the most expansive culicid species of the world. Being native to East Asia, this species was detected out of its original distribution range for the first time in the early 1990s in New Zealand where it could not establish, though. In 1998, established populations were reported from the eastern US, most likely as a result of introductions several years earlier. After a massive spread the mosquito is now widely distributed in eastern North America including Canada and two US states on the western coast. In the year 2000, it was demonstrated for the first time in Europe, continental France, but could be eliminated. A population that had appeared in Belgium in 2002 was not controlled until 2012 as it did not propagate. In 2008, immature developmental stages were discovered in a large area in northern Switzerland and bordering parts of Germany. Subsequent studies in Germany showed a wide distribution and several populations of the mosquito in various federal states. Also in 2011, the species was found in southeastern Austria (Styria) and neighbouring Slovenia. In 2013, a population was detected in the Central Netherlands, specimens were collected in southern Alsace, France, and the complete northeastern part of Slovenia was found colonized, with specimens also present across borders in adjacent Croatia. Apparently, at the end of 2013 a total of six populations occurred in Europe although it is not clear whether all of them are completely isolated. Similarly, it is not known whether these populations go back to the same number of introductions. While entry ports and long-distance continental migration routes are also obscure, it is likely that the international used tyre trade is the most important mode of intercontinental transportation of the mosquito. Aedes j. japonicus does not only display an aggressive biting behaviour but is suspected to be a vector of various disease agents and to displace indigenous culicid species. Therefore, Aedes j. japonicus might both cause public health problems in the future and have a significant impact on the biodiversity of the invaded territories. PMID- 24495421 TI - Effects of melody and technique on acoustical and musical features of western operatic singing voices. AB - OBJECTIVE: The operatic singing technique is frequently used in classical music. Several acoustical parameters of this specific technique have been studied but how these parameters combine remains unclear. This study aims to further characterize the Western operatic singing technique by observing the effects of melody and technique on acoustical and musical parameters of the singing voice. METHODS: Fifty professional singers performed two contrasting melodies (popular song and romantic melody) with two vocal techniques (with and without operatic singing technique). The common quality parameters (energy distribution, vibrato rate, and extent), perturbation parameters (standard deviation of the fundamental frequency, signal-to-noise ratio, jitter, and shimmer), and musical features (fundamental frequency of the starting note, average tempo, and sound pressure level) of the 200 sung performances were analyzed. RESULTS: The results regarding the effect of melody and technique on the acoustical and musical parameters show that the choice of melody had a limited impact on the parameters observed, whereas a particular vocal profile appeared depending on the vocal technique used. CONCLUSIONS: This study confirms that vocal technique affects most of the parameters examined. In addition, the observation of quality, perturbation, and musical parameters contributes to a better understanding of the Western operatic singing technique. PMID- 24495420 TI - Technical refinements to the minithyrotomy procedure. AB - OBJECTIVES/HYPOTHESIS: Although the minithyrotomy (MT) procedure was introduced in 1999, it has not been widely used for voice restoration. Its limited dissemination is due in part to lack of appropriate implants and in part due to technical challenges. The 2011 introduction of the composite thyroid ala perichondrium flap (CTAP) into a vocal fold through an MT was designed to supply an appropriate implanted tissue. However, technical difficulties persisted. Noted impediments have included limited surgical access, potential CTAP pedicle constriction during healing, lack of specialized surgical instrumentation, and potential retraction or extrusion of CTAPs. This study was performed to address these technical challenges with or without the use of CTAP reconstruction. STUDY DESIGN: Experimental. Cadaveric and in vivo canine model. METHODS: Experimentation on canine cadaveric larynges yielded MT and CTAP alterations, instrument creation, and implant affixation procedures. These refinements were applied in vivo using canine subjects. Two weeks post-CTAP repair, subjects were humanely euthanized, followed by laryngeal harvest and histologic analysis of the vocal folds. RESULTS: Refinements to CTAP modification, MT, instrumentation, and CTAP affixation are successful in vivo, just as in preliminary cadaveric trials. CONCLUSIONS: The proposed refinements were designed to improve the outcomes achieved via a CTAP specifically but have utility for any MT approach. Continued improvements to specialized instrumentation are necessary. Enhanced affixation of a CTAP, with improved accuracy and easier deployment are also essential. Further refinements should allow more reliable implementation of the MT by a growing number of laryngeal surgeons. PMID- 24495419 TI - Pathophysiological and neurochemical mechanisms of postoperative nausea and vomiting. AB - Clinical research shows that postoperative nausea and vomiting (PONV) is caused primarily by the use of inhalational anesthesia and opioid analgesics. PONV is also increased by several risk predictors, including a young age, female sex, lack of smoking, and a history of motion sickness. Genetic studies are beginning to shed light on the variability in patient experiences of PONV by assessing polymorphisms of gene targets known to play roles in emesis (serotonin type 3, 5 HT3; opioid; muscarinic; and dopamine type 2, D2, receptors) and the metabolism of antiemetic drugs (e.g., ondansetron). Significant numbers of clinical trials have produced valuable information on pharmacological targets important for controlling PONV (e.g., 5-HT3 and D2), leading to the current multi-modal approach to inhibit multiple sites in this complex neural system. Despite these significant advances, there is still a lack of fundamental knowledge of the mechanisms that drive the hindbrain central pattern generator (emesis) and forebrain pathways (nausea) that produce PONV, particularly the responses to inhalational anesthesia. This gap in knowledge has limited the development of novel effective therapies of PONV. The current review presents the state of knowledge on the biological mechanisms responsible for PONV, summarizing both preclinical and clinical evidence. Finally, potential ways to advance the research of PONV and more recent developments on the study of postdischarge nausea and vomiting (PDNV) are discussed. PMID- 24495422 TI - Resident editors. PMID- 24495423 TI - Backstage at Broadway: a demographic study. AB - OBJECTIVES/HYPOTHESIS: To provide insight into the demographics and vocal habits of current Broadway musical theater performers. STUDY DESIGN: Prospective, Questionnaire. METHODS: Adult musical theater performers in Broadway Productions as defined by the League of American Theater Producers and the Actors' Equity Association were asked to complete a survey collecting demographic information, vocal health and habits, alcohol, tobacco, and drug use and information regarding their level of vocal comfort and threshold to miss performances based on their voice. Data were subjected to descriptive and statistical analysis based on sex and role type (lead vs. ensemble). RESULTS: One hundred thirty-five performers completed the survey from seven actively running shows. Ensemble members were younger and had not been in the business as long as performers in lead roles. Over 25% of respondents had been diagnosed with a vocal injury, yet the number of days missed per year due to voice problems was relatively low (1.7-4.7). Across all respondents, only approximately 54.8% reported consistently warming up before a performance and 7.4% reported consistently cooling down afterward. Nearly 91% of respondents reported regular alcohol consumption and tobacco use was 10.4%; 23.0% reported illicit drug use. CONCLUSIONS: This study marks the first time that vocal health has been addressed in this elite group of vocal professionals. The performer's low self-reported numbers of missed days is interesting particularly given that they appear to participate in harmful vocal health activities at the same rate as the general public. PMID- 24495424 TI - Establishment of a normative database for the Voice-Related Quality of Life (V RQOL) measure. AB - OBJECTIVES: The Voice-Related Quality of Life (V-RQOL) measure is a well established disease-specific quality of life instrument for voice disorders. This study aims to establish a large, heterogenous V-RQOL normative database. METHODS: The V-RQOL measure was completed by adult volunteers with no voice complaints in the preceding 6 months. Standardized scores were calculated. Mean scores and standard deviations (SDs) were calculated by demographic category and analyzed using a one-way analysis of variance test. RESULTS: Results were available for 253 responders with a mean V-RQOL score of 94.8 (SD 10.1). There was no difference in scores among age groups, gender, or employment status. CONCLUSIONS: This study provides normative values for the V-RQOL measure. Clinicians using this instrument for clinical or research purposes may use this database for a more complete understanding and interpretation of their results. PMID- 24495425 TI - Coping strategies in teachers with vocal complaint. AB - OBJECTIVES: To understand the coping strategies used by teachers with vocal complaints, compare the differences between those who seek and those who do not seek voice therapy, and investigate the relationships among coping and voice perceptual analysis, coping and signs and symptoms of voice, and coping and participation restrictions and limitations in vocal activities. STUDY DESIGN: Cross-sectional nonrandomized prospective study with control group. METHODS: Ninety female teachers participated in the study, of similar ages, divided into three groups: group 1 (G1) comprised 30 teachers with vocal complaints who sought voice therapy, group 2 (G2) comprised 30 teachers with vocal complaints who never sought voice therapy, and group 3 (G3) comprised 30 teachers without vocal complaints. The following analysis were conducted: identification and characterization questionnaire, addressing personal and occupational description, recording speech material for voice perceptual analysis, Voice Signs and Symptoms Questionnaire, Voice Activity and Participation Profile (VAPP), and Voice Disability Coping Questionnaire (VDCQ)-Brazilian Version. RESULTS: In relation to the voice perceptual analysis, there was statistically significant difference between the groups with vocal complaint (G1+G2), which had showed voices with mild-to-moderate deviation, and the group without vocal complaint (G1), which showed voices within the normal variability of voice quality (mean for G1 = 49.9, G2 = 43.7, and G3 = 32.3, P < 0.001). G1 had higher mean of voice signs and symptoms (G1 = 8.6, G2 = 6.6, and G3 = 2.0, P < 0.001) and higher scores in almost all dimensions of VAPP (P < 0.001), except for the aspects effect on job and effect on social communication. Individuals with vocal complaints who looked for voice therapy (G1) tended to use more problem-focused strategies and had higher scores in VDCQ (G1 = 45.4, G2 = 38.5, and G3 = 9.5, P < 0.001). The aspects that were correlated with VDCQ in the three groups were degree of vocal deviation, VAPP total score, VAPP partial scores of self-perceived severity of voice problem, effect on daily communication, effect on emotion, and participation restriction for G1; VAPP total score and partial score of effect on daily communication for G2; and all VAPP scores for G3. No correlation was found between voice signs and symptoms and coping. CONCLUSION: Teachers with vocal complaints who looked for voice therapy use more coping strategies. Moreover, they present a tendency to use more problem-focused coping strategies. Voice symptoms prompt the teachers into seeking treatment; however, they are not correlated with the coping itself. In general, the higher the perception of limitation and restriction of participating in vocal activities, the greater the use of coping strategies. PMID- 24495426 TI - Using the perturbation of the contact quotient of the EGG waveform to analyze age differences in adult speech. AB - This study examines electroglottographic (EGG) recordings for 15 young and 14 old male speakers of New Zealand English. Analysis was performed on the sustained vowels /i:/ and /a:/ at three target levels for both pitch and loudness. Jitter was greater for older speakers, and the contact quotient (Qx) was significantly lower for older speakers. The greater jitter for older speakers indicates a decrease in the stability of the vocal production mechanism of the older speakers. The jitter is an acoustic measure, so to examine the stability at a physiological level, a perturbation measure of the Qx is developed and applied to the EGG recordings. The contact quotient perturbation (CQP) showed a significant increase for older speakers (1.55% and 3.54% for young and old, respectively), and this demonstrated more about the variability than the jitter data alone. When loudness is also considered, the Qx was significantly greater for louder vowels, whereas its perturbation was significantly lower for louder vowels. This relationship combined with the age effect, with the CQP for all three loudness levels being greater for the older speakers. The findings of this study will contribute to the development of vocal fold models that account for aging. PMID- 24495427 TI - Efficacy of super high dose proton pump inhibitor administration in refractory laryngopharyngeal reflux: a pilot study. AB - OBJECTIVES: Proton pump inhibitors (PPIs) are the mainstay of current medical management for laryngopharyngeal reflux (LPR) but may be insufficient in managing some patients' disease. This study was designed to investigate the effectiveness of superdose PPI therapy in the improvement of 24-hour pH impedance studies and stroboscopy findings in patients with LPR refractory to standard dosing (BID PPI). STUDY DESIGN: Retrospective chart review. METHODS: This study examined 35 patients ranging from 20 to 76 years diagnosed with refractory LPR who were treated with super high dose PPIs. Reflux finding scores (RFS) obtained by three blinded raters and 24-hour pH impedance study scores were compared for patients on standard and then super high dose PPI regimens. RESULTS: Statistical analysis of the stroboscopy evaluation revealed a modest but statistically significant decrease in the RFS scores for those patients on super high dose therapy, with good intrarater reliability. The DeMeester score showed no significant change between standard and super high dose regimens. The results of the 24-hour pH impedance monitoring showed no statistically significant decrease in acid reflux episodes despite an average of 7.6 fewer proximal acid reflux episodes. CONCLUSION: Super high dose therapy seems to improve laryngeal signs of irritation as reflected by RFS. This improvement was not reflected in our patient population's severity of reflux while on super high dose therapy when compared with standard LPR therapy as measured by 24-hour pH impedance monitoring, although this finding may reflect selection bias. RFS and 24-hour pH impedance may be insufficiently sensitive to detect improvements in LPR with adequate treatment. PMID- 24495428 TI - The vocal aerodynamic change in female patients with muscular tension dysphonia after voice training. AB - OBJECTIVE: To investigate the changes of vocal aerodynamics indicators after voice training in female patients with muscular tension dysphonia (MTD). METHODS: Twenty-one female MTD patients (before voice training and 12 weeks after voice training) and 20 female volunteers with normal voices (the control group) received vocal aerodynamic analysis. Parameters included subglottal pressure (SGP), aerodynamic power (AP), mean expiratory airflow (MEA), and maximum phonation time (MPT) were recorded and analyzed by phonatory aerodynamic system. RESULTS: Before voice training, the median SGP and mean AP were higher than control group, whereas median MPT was shorter, and these differences were statistically significant. After 12 weeks of voice training, the median SGP and mean AP were decreased and the median MPT was increased compared with the measurements obtained before training, and these differences were statistically significant. The differences of median SGP, mean AP, mean MEA, and median MPT between MTD after 12 weeks of training and control group were not statistically significant. CONCLUSION: Voice training is an effective treatment for MTD patients. Aerodynamic analysis can effectively evaluate the vocal functional status of MTD patients before and after training, which is beneficial for the treatment efficacy evaluation. PMID- 24495429 TI - Vocal fold fibroblast response to growth factor treatment is age dependent: results from an in vitro study. AB - INTRODUCTION: Vocal fold (VF) fibroblasts (VFFs) are the central target in developing new strategies for treatment of VF injury and scarring. Nevertheless, only little is known about the basic biological characteristics of these cells. The aim of this study was to explore the impact of age of VFFs on the response to external growth factor stimulation. STUDY DESIGN: In vitro cell study using a rat model. METHODS: VFFs were extracted from young and aged rat VF 3 months after establishing unilateral injury. Resulting scar fibroblasts (SFs) and normal fibroblasts (NFs) were subsequently cultured separately with or without the addition of hepatocyte growth factor (HGF). After 24 and 72 hours, the production of hyaluronic acid (HA) was examined in the supernatant culture media using enzyme-linked immunosorbent assay. RESULTS: Only cultured SF and NF from young animals could be stimulated significantly in the production of HA by HGF. Within these, average percentage increase was higher in NF compared with SF. CONCLUSION: The response of VFFs in cell culture to growth factors stimulation is highly depending on the age of the animals. This is another step in a nearer characterization of scar VFF and could furthermore be an important point when estimating the success of an intervention. Age-depending effects must be considered as an important factor in developing possible therapeutic agents for VF scarring. PMID- 24495430 TI - The acoustic correlates of valence depend on emotion family. AB - The voice expresses a wide range of emotions through modulations of acoustic parameters such as frequency and amplitude. Although the acoustics of individual emotions are well understood, attempts to describe the acoustic correlates of broad emotional categories such as valence have yielded mixed results. In the present study, we analyzed the acoustics of emotional valence for different families of emotion. We divided emotional vocalizations into "motivational," "moral," and "aesthetic" families as defined by the OCC (Ortony, Clore, and Collins) model of emotion. Subjects viewed emotional scenarios and were cued to vocalize congruent exclamations in response to them, for example, "Yay!" and "Damn!". Positive valence was weakly associated with high-pitched and loud vocalizations. However, valence interacted with emotion family for both pitch and amplitude. A general acoustic code for valence does not hold across families of emotion, whereas family-specific codes provide a more accurate description of vocal emotions. These findings are consolidated into a set of "rules of expression" relating vocal dimensions to emotion dimensions. PMID- 24495431 TI - Characterization of the vocal fold vertical stiffness in a canine model. AB - OBJECTIVES/HYPOTHESIS: Characterizing the vertical stiffness gradient that exists between the superior and inferior aspects of the medial surface of the vocal fold. Characterization of this stiffness gradient could elucidate the mechanism behind the divergent glottal shape observed during closing. STUDY DESIGN: Basic science. METHODS: Indentation testing of the folds was done in a canine model. Stress-strain curves are generated using a customized load-cell and the differential Young's modulus is calculated as a function of strain. RESULTS: Results from 11 larynges show that stress increases as a function of strain more rapidly in the inferior aspect of the fold. The calculations for local Young's modulus show that at high strain values, a stiffness gradient is formed between the superior and inferior aspects of the fold. CONCLUSIONS: For small strain values, which are observed at low subglottal pressures, the stiffness of the tissue is similar in both the superior and inferior aspects of the vocal fold. Consequently, the lateral force that is applied by the glottal flow at both aspects results in almost identical displacements, yielding no divergence angle. Conversely, at higher strain values, which are measured in high subglottal pressure, the inferior aspect of the vocal fold is much stiffer than the superior edge; thus, any lateral force that is applied at both aspects will result in a much greater displacement of the superior edge, yielding a large divergence angle. The increased stiffness observed at the inferior edge could be due to the proximity of the conus elasticus. PMID- 24495432 TI - Design and preliminary evaluation of the FINGER rehabilitation robot: controlling challenge and quantifying finger individuation during musical computer game play. AB - BACKGROUND: This paper describes the design and preliminary testing of FINGER (Finger Individuating Grasp Exercise Robot), a device for assisting in finger rehabilitation after neurologic injury. We developed FINGER to assist stroke patients in moving their fingers individually in a naturalistic curling motion while playing a game similar to Guitar Hero. The goal was to make FINGER capable of assisting with motions where precise timing is important. METHODS: FINGER consists of a pair of stacked single degree-of-freedom 8-bar mechanisms, one for the index and one for the middle finger. Each 8-bar mechanism was designed to control the angle and position of the proximal phalanx and the position of the middle phalanx. Target positions for the mechanism optimization were determined from trajectory data collected from 7 healthy subjects using color-based motion capture. The resulting robotic device was built to accommodate multiple finger sizes and finger-to-finger widths. For initial evaluation, we asked individuals with a stroke (n = 16) and without impairment (n = 4) to play a game similar to Guitar Hero while connected to FINGER. RESULTS: Precision design, low friction bearings, and separate high speed linear actuators allowed FINGER to individually actuate the fingers with a high bandwidth of control (-3 dB at approximately 8 Hz). During the tests, we were able to modulate the subject's success rate at the game by automatically adjusting the controller gains of FINGER. We also used FINGER to measure subjects' effort and finger individuation while playing the game. CONCLUSIONS: Test results demonstrate the ability of FINGER to motivate subjects with an engaging game environment that challenges individuated control of the fingers, automatically control assistance levels, and quantify finger individuation after stroke. PMID- 24495434 TI - Outcomes of childhood asthma to the age of 50 years. AB - BACKGROUND: In 1964, The Melbourne Asthma Study was established to describe the spectrum and natural history of childhood asthma. OBJECTIVE: To describe the clinical and lung function outcome of childhood asthma to the age of 50 years. METHOD: Subjects were invited to complete an interviewer-administered questionnaire, skin prick testing, and measurement of lung function from the age of 7 years to the age of 50 years at 7-year intervals. RESULTS: Of 458 survivors (from the original 484 subjects at recruitment), 346 subjects (76%) participated, of whom, 197 completed lung function measurement. Asthma remission at the age of 50 years was 64% in those with wheezy bronchitis, 47% for those with persistent asthma, and 15% for those with severe asthma in childhood. Multivariable analysis identified severe asthma in childhood (odds ratio [OR] 11.9 [95% CI, 3.4-41.8]), female sex (OR 2.0 [95% CI, 1.1-3.6]), and childhood hay fever (OR 2.0 [95% CI, 1.0-4.0]) as risk factors for "current asthma" at age 50 years. There was no evidence of a difference in the rate of decline in FEV1 (mL/y, 95% CI) between the severe asthma group (15 mL/y [95% CI, 9-22 mL/y]) and all the other recruitment groups: control (16 mL/y [95% CI, 12-20 mL/y]), mild wheezy bronchitis (14 mL/y [95% CI, 8-19 mL/y]), wheezy bronchitis (16 mL/y [95% CI, 11 20 mL/y]), and persistent asthma (19 mL/y [95% CI, 13-24 mL/y]). CONCLUSION: The clinical and lung function outcome in adult life is strongly determined by asthma severity in childhood. The reduced lung function seen in adults is established in childhood and does not appear to decline more rapidly in adult years despite continuing symptoms. PMID- 24495433 TI - Dissecting childhood asthma with nasal transcriptomics distinguishes subphenotypes of disease. AB - BACKGROUND: Bronchial airway expression profiling has identified inflammatory subphenotypes of asthma, but the invasiveness of this technique has limited its application to childhood asthma. OBJECTIVES: We sought to determine whether the nasal transcriptome can proxy expression changes in the lung airway transcriptome in asthmatic patients. We also sought to determine whether the nasal transcriptome can distinguish subphenotypes of asthma. METHODS: Whole transcriptome RNA sequencing was performed on nasal airway brushings from 10 control subjects and 10 asthmatic subjects, which were compared with established bronchial and small-airway transcriptomes. Targeted RNA sequencing nasal expression analysis was used to profile 105 genes in 50 asthmatic subjects and 50 control subjects for differential expression and clustering analyses. RESULTS: We found 90.2% overlap in expressed genes and strong correlation in gene expression (rho = .87) between the nasal and bronchial transcriptomes. Previously observed asthmatic bronchial differential expression was strongly correlated with asthmatic nasal differential expression (rho = 0.77, P = 5.6 * 10(-9)). Clustering analysis identified TH2-high and TH2-low subjects differentiated by expression of 70 genes, including IL13, IL5, periostin (POSTN), calcium-activated chloride channel regulator 1 (CLCA1), and serpin peptidase inhibitor, clade B (SERPINB2). TH2-high subjects were more likely to have atopy (odds ratio, 10.3; P = 3.5 * 10(-6)), atopic asthma (odds ratio, 32.6; P = 6.9 * 10(-7)), high blood eosinophil counts (odds ratio, 9.1; P = 2.6 * 10(-6)), and rhinitis (odds ratio, 8.3; P = 4.1 * 10(-6)) compared with TH2-low subjects. Nasal IL13 expression levels were 3.9-fold higher in asthmatic participants who experienced an asthma exacerbation in the past year (P = .01). Several differentially expressed nasal genes were specific to asthma and independent of atopic status. CONCLUSION: Nasal airway gene expression profiles largely recapitulate expression profiles in the lung airways. Nasal expression profiling can be used to identify subjects with IL13-driven asthma and a TH2-skewed systemic immune response. PMID- 24495435 TI - Calibration for position tracking of swept motor 3-D ultrasound. AB - Tracking the position and orientation of a 3-D ultrasound transducer has many clinical applications. Tracking requires calibration to find the transformation between the tracking sensor and the ultrasound coordinates. Typically the set of image slice data are scan converted to a Cartesian volume using assumed motor geometry and a single transformation to the sensor. We propose, instead, the calibration of individual slices using a 2-D calibration technique. A best fit to a subset of slices is performed to decrease data collection time compared with that for calibration of all slices, and to reduce the influence of random errors in individual calibrations. We compare our technique with four scan conversion based techniques: 2-D N-wire on the center slice, N-wire using a 3-D volume, N wire using a 3-D volume including the edge points and a new closed-form planar method using a 3-D volume. The proposed multi-slice technique produced the smallest point reconstruction error (0.82 mm using a tracked stylus). PMID- 24495436 TI - Carotid wall elastography to assess midterm vascular dysfunction secondary to intrauterine growth restriction: feasibility and comparison with standardized intima-media thickness. AB - Several studies have suggested that intrauterine growth restriction (IUGR) increases the risk of cardiovascular disease and early atherosclerosis. Early detection of arteriopathy is essential to early intervention. Although arterial intima-media thickness (IMT) is considered an index of subclinical atherosclerosis in the adult, its validity in pediatric patients may be limited. We have recently introduced a novel imaging-based biomarker (ImBioMark) to assess intrinsic mechanical features of the arterial wall from B-mode ultrasound data. The aim of the work described here was to evaluate the potential of ImBioMark in investigation of cardiovascular health status at the level of the common carotid artery (CCA) in adolescents born after IUGR. We also compared ImBioMark results with automated IMT measurements, a well-established biomarker used in clinical practice and research. The potential sequelae of IUGR on the CCA were examined in a group of adolescents in comparison with healthy controls. Patients with IUGR (n = 7) were 13.85 +/- 0.46 y old; the healthy controls (n = 7) were 14.58 +/- 0.80 y old (p = 0.058). Cine loops of the CCA B-mode data were digitally recorded, and the arterial elastic modulus was estimated a posteriori with ImBioMark. IMT of the CCA was automatically calculated using QLAB software (Philips, Andover, MA, USA). All patients had been evaluated in utero in our fetal echocardiographic laboratory. ImBioMark detected a significant increase in CCA stiffness in patients with IUGR as compared with healthy controls: elastic modulus = 90.74 +/- 11.86 versus 61.30 +/- 15.94 kPa, respectively (p = 0.002). There was, however, no significant difference between patients with IUGR and controls in IMT (0.483 +/- 0.067 versus 0.476 +/- 0.051 mm, respectively, p = 0.831). The impact of IUGR on CCA wall dynamics was confirmed by ImBioMark. The apparent limitation of IMT measurement in this cohort may be the result of geometric arterial changes, that is, the expected thickening, below the level of detection at this age. As early detection of vascular modulation is essential to early intervention in a population at risk, we now intend to extend ImBioMark to investigate larger pathologic cohorts with various degrees of arteriopathy. PMID- 24495437 TI - Ultrasonographic measurement of the respiratory variation in the inferior vena cava diameter is predictive of fluid responsiveness in critically ill patients: systematic review and meta-analysis. AB - Respiratory variation in the inferior vena cava (DeltaIVC) has been extensively studied with respect to its value in predicting fluid responsiveness, but the results are conflicting. This systematic review was aimed at investigating the diagnostic accuracy of DeltaIVC in predicting fluid responsiveness. Databases including Medline, Embase, Scopus and Web of Knowledge were searched from inception to May 2013. Studies exploring the diagnostic performance of DeltaIVC in predicting fluid responsiveness were included. To allow for more between- and within-study variance, a hierarchical summary receiver operating characteristic model was used to pool the results. Subgroup analyses were performed for patients on mechanical ventilation, spontaneously breathing patients and those challenged with colloids and crystalloids. A total of 8 studies involving 235 patients were eligible for analysis. Cutoff values of DeltaIVC varied across studies, ranging from 12% to 40%. The pooled sensitivity and specificity in the overall population were 0.76 (95% confidence interval [CI]: 0.61-0.86) and 0.86 (95% CI: 0.69-0.95), respectively. The pooled diagnostic odds ratio (DOR) was 20.2 (95% CI: 6.1-67.1). The diagnostic performance of DeltaIVC appeared to be better in patients on mechanical ventilation than in spontaneously breathing patients (DOR: 30.8 vs. 13.2). The pooled area under the receiver operating characteristic curve was 0.84 (95% CI: 0.79-0.89). Our study indicates that DeltaIVC measured with point-of care ultrasonography is of great value in predicting fluid responsiveness, particularly in patients on controlled mechanical ventilation and those resuscitated with colloids. PMID- 24495438 TI - Endovascular shear strain elastography for the detection and characterization of the severity of atherosclerotic plaques: in vitro validation and in vivo evaluation. AB - This work explores the potential of shear strain elastograms to identify vulnerable atherosclerotic plaques. The Lagrangian speckle model estimator (LSME) elasticity imaging method was further developed to estimate shear strain elasticity (SSE). Three polyvinyl alcohol cryogel vessel phantoms were imaged with an intravascular ultrasound (IVUS) scanner. The estimated SSE maps were validated against finite-element results. Atherosclerosis was induced in carotid arteries of eight Sinclair mini-pigs using a combination of surgical techniques, diabetes and a high-fat diet. IVUS images were acquired in vivo in 14 plaques before euthanasia and histology. All plaques were characterized by high magnitudes in SSE maps that correlated with American Heart Association atherosclerosis stage classifications (r = 0.97, p < 0.001): the worse the plaque condition the higher was the absolute value of SSE, i.e. |SSE| (e.g., mean |SSE| was 3.70 +/- 0.40% in Type V plaques, whereas it was reduced to 0.11 +/- 0.01% in normal walls). This study indicates the feasibility of using SSE to highlight atherosclerotic plaque vulnerability characteristics. PMID- 24495440 TI - The efficacy of glucocorticoids for the prevention of atrial fibrillation, or length of intensive care unite or hospital stay after cardiac surgery: a meta analysis. AB - AIMS: cardiopulmonary bypass and cardiac surgery are associated with a significant systemic inflammatory response that has been suggested playing a causative role in the development of perioperative atrial fibrillation (POAF). The goal of this meta-analysis was to determine the efficacy of glucocorticoid prophylaxis in preventing POAF, or length of intensive care unite (ICU) or hospital stay. METHODS: A systematic electronic database literature search of Cochrane controlled trials register (2013, issue 4) and MEDLINE (1966 to April, 2013) was conducted using specific search terms for all relevant articles. Including criteria were: randomized controlled clinical trials, participants were adults (>=18 years of age) undergoing cardiac surgery, evaluated glucocorticoid prophylaxis in cardiac surgery with adequately reported data on incidence of POAF, or length of ICU or hospital stay. RESULTS: Forty-two randomized controlled trials involving 7621 participants were included in the meta-analysis. Overall, glucocorticoids prophylaxis significantly lowered participants' risk of developing POAF (Relative Risk [RR] 0.77; 95% confidence interval [CI] 0.66 0.90), P < 0.01), reduced length of ICU stay by 0.25 day (95% CI -0.40 to -0.10, P < 0.01). Glucocorticoid prophylaxis in cardiac surgery was not associated with increased all-cause of infection (RR 0.68; 95% CI 0.58-0.78, P < 0.01) and mortality (RR 0.75; 95% CI 0.52-1.08, P = 0.12). CONCLUSIONS: Pooled evidence suggests that glucocorticoid prophylaxis may reduce the incidence of POAF. The beneficial effect on POAF is associated with reduced length of ICU and hospital stay, and infection rate. PMID- 24495439 TI - Comparison between botulinum neurotoxin type A2 and type A1 by electrophysiological study in healthy individuals. AB - Botulinum neurotoxin type A1 (BoNTs/A1) and type B (BoNT/B) have been used for treating hyperactive muscle contractions. In the present study, we compared the effect of botulinum neurotoxin subtype A2 (6.5 mouse LD50 units A2 neurotoxin, A2NTX) and onabotulinumtoxinA (10 mouse LD50 units BoNT/A1 product) by measuring the compound muscle action potentials (CMAPs) before and after administration. In total, 8 healthy subjects were examined in the present study. A2NTX was injected into the extensor digitorum brevis (EDB) muscle, followed by onabotulinumtoxinA injection into the contralateral EDB muscle after 16 weeks. The CMAP amplitudes from the EDB, abductor hallucis (AH), and abductor digiti minimi pedis (ADM) muscles were measured after each BoNT injection on days 1, 3, 7, 14, 28, 56, 84, and 112 to assess the effect of the toxin. On day 14, both A2NTX and onabotulinumtoxinA produced an approximately 70% decline in EDB CMAP amplitude compared to the baseline values; significant reduction of the CMAP continued through day 112. The CMAP amplitudes from neighboring muscles (AH and ADM) remained intact throughout the study period, except for a slight but significant drop at day 28 after onabotulinumtoxinA injection compared to A2NTX. The current findings indicate that small doses (6.5 units and 10 units) of A2NTX and onabotulinumtoxinA have at least comparable onset and duration of action, although similar clinical effects were obtained with lower dose using A2NTX. PMID- 24495441 TI - Evaluation of the sparse coding shrinkage noise reduction algorithm in normal hearing and hearing impaired listeners. AB - Although there are numerous single-channel noise reduction strategies to improve speech perception in noise, most of them improve speech quality but do not improve speech intelligibility, in circumstances where the noise and speech have similar frequency spectra. Current exceptions that may improve speech intelligibility are those that require a priori knowledge of the speech or noise statistics, which limits practical application. Hearing impaired (HI) listeners suffer more in speech intelligibility than normal hearing listeners (NH) in the same noisy environment, so developing better single-channel noise reduction algorithms for HI listeners is justified. Our model-based "sparse coding shrinkage" (SCS) algorithm extracts key speech information in noisy speech. We evaluate it by comparison with a state-of-the-art Wiener filtering approach using speech intelligibility tests with NH and HI listeners. The model-based SCS algorithm relies only on statistical signal information without prior information. Results show that the SCS algorithm improves speech intelligibility in stationary noise and is comparable to the Wiener filtering algorithm. Both algorithms improve intelligibility for HI listeners but not for NH listeners. Improvement is less in fluctuating (babble) noise than in stationary noise. Both noise reduction algorithms perform better at higher input signal-to-noise ratios (SNR) where HI listeners can benefit but where NH listeners have already reached ceiling performance. The difference between NH and HI subjects in intelligibility gain depends fundamentally on the input SNR rather than the hearing loss level. We conclude that HI listeners need different signal processing algorithms from NH subjects and that the SCS algorithm offers a promising alternative to Wiener filtering. Performance of all noise reduction algorithms is likely to vary according to extent of hearing loss and algorithms that show little benefit for listeners with moderate hearing loss may be more beneficial for listeners with more severe hearing loss. PMID- 24495442 TI - Mechanisms for reduced pulmonary diffusing capacity in haematopoietic stem-cell transplantation recipients. AB - Lung diffusing capacity for CO (DLCO) is compromised in haematopoietic stem-cell transplantation (HSCT) recipients. We derived alveolar-capillary membrane conductance (DM,CO) and pulmonary capillary volume (VC) from DLCO and diffusing capacity for NO (DLNO). Forty patients were studied before and 6 weeks after HSCT. Before HSCT, DLNO and DLCO were significantly lower than in 30 healthy controls. DM,CO was ~40% lower in patients than in controls (p<0.001), whereas VC did not differ significantly. After HSCT, DLNO and DM,CO further decreased, the latter by ~22% from before HSCT (p<0.01) while VC did not change significantly. Lung density, serum CRP and reactive oxygen metabolites were significantly increased, with the latter being correlated (R2=0.71, p<0.001) with the decrement in DLNO. We conclude that DLNO and, to a lesser extent, DLCO are compromised before HSCT mainly due to a DM,CO reduction. A further reduction of DM,CO without VC loss occurs after HSCT, possibly related to development of oedema, or interstitial fibrosis, or both. PMID- 24495443 TI - Prophylaxis for Pneumocystis pneumonia in patients with rheumatoid arthritis treated with biologics, based on risk factors found in a retrospective study. AB - INTRODUCTION: Pneumocystis pneumonia (PCP) is one of the most prevalent opportunistic infections in patients undergoing immunosuppressive therapy. In this article, we discuss risk factors for PCP development in patients with rheumatoid arthritis (RA) during the course of biologic therapy and describe a prophylactic treatment for PCP with trimethoprim/sulfamethoxazole (TMP/SMX). We also evaluate the effectiveness and safety of the treatment. METHODS: We retrospectively analyzed 702 RA patients who received biologic therapy and compared the characteristics of patients with vs. without PCP to identify the risk factors for PCP. Accordingly, we analyzed 214 patients who received the TMP/SMX biologic agents as prophylaxis against PCP at the start of treatment to evaluate their effectiveness and safety. RESULTS: We identified the following as risk factors for PCP: age at least 65 years (hazard ratio (HR) = 4.37, 95% confidence interval (CI) = 1.04 to 18.2), coexisting pulmonary disease (HR = 8.13, 95% CI = 1.63 to 40.0), and use of glucocorticoids (HR = 11.4, 95% CI = 1.38 to 90.9). We employed a protocol whereby patients with two or three risk factors for PCP would receive prophylactic treatment. In the study with 214 patients, there were no cases of PCP, and the incidence of PCP was reduced to 0.00 per 100 person-years compared with that before the procedure (0.93 per 100 person-years). There were no severe adverse events induced by the TMP/SMX treatment. CONCLUSIONS: RA patients with two or three risk factors for PCP who are receiving biologic therapy can benefit from safe primary prophylaxis. PMID- 24495444 TI - Ephrin (Eph) receptor A1, A4, A5 and A7 expression in human non-small cell lung carcinoma: associations with clinicopathological parameters, tumor proliferative capacity and patients' survival. AB - BACKGROUND: Ephrin (Eph) receptors are frequently overexpressed in a wide variety of human malignant tumors, being associated with tumor growth, invasion, metastasis and angiogenesis. The present study aimed to evaluate the clinical significance of EphA1, A4, A5 and A7 protein expression in non-small cell lung carcinoma (NSCLC). METHODS: EphA1, A4, A5 and A7 protein expression was assessed immunohistochemically in tissue microarrays of 88 surgically resected NSCLC and was analyzed in relation with clinicopathological characteristics and patients' survival. RESULTS: Elevated EphA4 expression was significantly associated with low histopathological stage and presence of inflammation (p = 0.047 and p = 0.026, respectively). Elevated EphA7 expression was significantly associated with older patients' age, presence of fibrosis and smaller tumor size (p = 0.036, p = 0.029 and p = 0.018, respectively). EphA1, A5 and A7 expression were positively associated with tumor proliferative capacity (p = 0.047, p = 0.002 and p = 0.046, respectively). Elevated EphA4, A5 and A7 expression were identified as predictors of favourable patients' survival at both univariate (Log-rank test, 0 = 0.019, p = 0.006 and p = 0.012, respectively) and multivariate levels (Cox-regression analysis, p = 0.029, p = 0.068 and p = 0.044, respectively). CONCLUSIONS: The present study supported evidence that Ephs may be involved in lung cancer progression, reinforcing their utility as clinical biomarkers for patients' management and prognosis, as also as potential targets for future therapeutic interventions. PMID- 24495445 TI - Clinicopathological characteristics and outcomes of surgically excised renal masses in African Americans. AB - OBJECTIVES: In the present study, we report on the clinical and pathological characteristics of African American (AA) patients with surgically excised renal masses and assess the associations between race and oncological outcomes. METHODS AND MATERIALS: We conducted a retrospective review of patients who underwent partial or radical nephrectomy for renal masses at our institution between 2000 and 2010. Patients were divided into 2 groups based on self-reported race: AA and non-AA. Patient demographics and disease characteristics, and overall, cancer specific, recurrence-free, distant, and local recurrence-free survival for localized renal cell carcinoma (RCC) were compared between AA and non-AA patients. Multivariable proportional hazard analyses were used to assess the associations of race with oncological outcomes. RESULTS: A total of 1,467 patients, of whom 359 (24.5%) were AA, were included. Rates of benign disease were comparable between AA patients and non-AA (18.2% vs. 17.6%, P = 0.556). AA patients presented with higher rates of localized disease (83% vs. 71%, P<0.001). Papillary subtype accounted for 40.8% of RCCs in AA patients compared with 11.6% in non-AA patients (P<0.001). The high proportion of papillary RCC in AA patients was maintained across disease stages. On univariable analyses, AA patients had better recurrence-free and cancer-specific survival. On multivariable analyses, AA race was not a significant predictor of oncological outcomes after adjusting for patient and disease characteristics. CONCLUSION: In this study, AA patients presented with more localized disease than non-AA patients, whereas rates of benign disease were comparable between the groups. Furthermore, AA patients had roughly 3 times higher rates of papillary RCC across disease stages. On univariable analyses, AA patients appeared to have more favorable oncological outcomes. However, this association is likely explained by tumor stage, grade, and histology as outcomes were similar across races when the analyses were adjusted for these and other characteristics. PMID- 24495446 TI - Neoadjuvant therapy for localized prostate cancer: Examining mechanism of action and efficacy within the tumor. AB - OBJECTIVES: Efforts to improve the clinical outcome for patients with localized high-risk prostate cancer have led to the development of neoadjuvant systemic therapies. We review the different modalities of neoadjuvant therapies for localized prostate cancer and highlight emerging treatment approaches including immunotherapy and targeted therapy. METHODS: We performed a PubMed search of clinical trials evaluating preoperative systemic therapies for treating high-risk prostate cancer published after 2000, and those studies with the highest clinical relevance to current treatment approaches were selected for review. The database at clinicaltrials.gov was queried for neoadjuvant studies in high-risk prostate cancer, and those evaluating novel targeted therapies and immunotherapies are spotlighted here. RESULTS: Neoadjuvant chemotherapy has become standard of care for treating some malignancies, including breast and bladder cancers. In prostate cancer, preoperative hormonal therapy or chemotherapy has failed to demonstrate improvements in overall survival. Nevertheless, the emergence of novel treatment modalities such as targeted small molecules and immunotherapy has spawned neoadjuvant clinical trials that provide a unique vantage from which to study mechanism of action and biological potency. Tissue-based biomarkers are being developed to elucidate the biological efficacy of these treatments. With targeted therapy, these can include phospho-proteomic signatures of target pathway activation and deactivation. With immunotherapies, including sipuleucel-T and ipilimumab, recruitment of immune cells to the tumor microenvironment can also be used as robust markers of a biological effect. Such studies can provide insight not only into mechanism of action for these therapies but can also provide paths forward to improving clinical efficacy like with rationally designed combinations and dose selection. CONCLUSIONS: The use of neoadjuvant androgen-deprivation therapy and chemotherapy either singly or in combination before radical prostatectomy is generally safe and feasible while reducing prostate volume and tumor burden. However, pathologic complete response rates are low and no long term survival benefit has been observed with the addition of neoadjuvant therapies over surgery alone at present, and therefore preoperative therapy is not the current standard of care in prostate cancer treatment. PMID- 24495447 TI - Compared with radical nephrectomy, nephron-sparing surgery offers a long-term survival advantage in patients between the ages of 20 and 44 years with renal cell carcinomas (<=4 cm): an analysis of the SEER database. AB - PURPOSE: Compared with radical nephrectomy (RN), partial nephrectomy (PN) decreases the risk of developing chronic kidney disease. Although numerous studies have demonstrated the survival advantage of PN in older patients, they have been criticized by selection bias toward the procedure owing to comorbidities. We hypothesized that long-standing effects of renal preservation would manifest in a survival advantage of a younger patient population, where selection bias owing to comorbidities is minimized. MATERIALS AND METHODS: The Surveillance, Epidemiology, and End Results 18-registries database was queried for patients aged 20 to 44 years surgically treated between 1993 and 2003 for renal cell carcinoma (RCC) <= 4 cm with known grade and histology. Patients with prior RCC, multiple tumors, and metastatic or locally advanced disease were excluded. The final cohorts consisted of 222 and 494 subjects treated with PN and RN, respectively. The chi-square and log-rank analyses compared patient and tumor characteristics and patient survival, respectively. RESULTS: There were no differences between the groups in demographics or tumor characteristics. Additionally, there was no difference in cancer-specific survival at 5 or 10 years (P = 0.34 and P = 0.1, respectively). Although there was no difference in 5 year overall survival (P = 0.07), PN offered an advantage in 10-year overall survival (P = 0.025). CONCLUSIONS: Present Surveillance, Epidemiology, and End Results analyses demonstrate that compared with RN, PN improved overall survival in patients with small, localized RCC. As expected, the survival advantage is observed late and supports the importance of long-term renal functional preservation. Although our study is limited by lack of comorbidities, the results suggest that detrimental effects of RN may have implications on overall survival in younger patients with RCC. PMID- 24495448 TI - Effect of tumor size on recurrence-free survival of upper tract urothelial carcinoma following surgical resection. AB - OBJECTIVE: To identify predictors of recurrence-free survival (RFS) based on the clinicopathological features of patients with upper tract urothelial carcinoma (UTUC) who have undergone radical nephroureterectomy (RNU) with bladder cuff resection. MATERIALS AND METHODS: We retrospectively reviewed the records of patients from October 1998 to July 2012 at our tertiary institution and identified 120 patients with sufficient data who underwent RNU for UTUC. We recorded various clinical and histopathological parameters as potential predictors of outcome. Recurrence was defined as any occurrence of urothelial carcinoma after RNU either intravesically, local/regionally, or at distant sites. Univariate, multivariate, and RFS analyses were conducted using the Cox regression and Kaplan-Meier methods. RESULTS: The median age of our cohort was 71 years (interquartile range: 64-78). Median RNU-specimen tumor size was 3.0 cm (interquartile range: 2.0-5.0 cm). Fifty-four patients (45%) had a tumor<3.0 cm and 66 (55%) had a tumor>=3.0 cm. Eighty patients (66.7%) had organ-confined UTUC (<=pT2) and 40 (33.3%) had non-organ-confined UTUC (>=pT3). Sixty-five patients (54.2%) experienced at least 1 recurrence. Forty-three patients (35.8%) had at least 1 episode of intravesical recurrence and 28 (23.3%) had distant recurrence. A multivariate analysis revealed non-organ-confined disease (hazard ratio [HR] = 3.62, P<0.001), tumor diameter>=3 cm (HR = 1.97, P = 0.011), and male gender (HR = 1.81, P = 0.047) to be significant independent predictors of disease recurrence. The 5-year RFS rate was 46.9% and 25.8% for patients with tumor size<3 and >=3 cm, respectively. CONCLUSIONS: Following RNU, the incidence of recurrence remains high among patients with UTUC. In our cohort of patients, tumor diameter>=3.0 cm, non-organ-confined UTUC, and male gender constitute important risk factors for poor RFS outcomes following RNU. These patients require diligent postoperative surveillance and may potentially benefit from perioperative systemic therapy. PMID- 24495449 TI - MTDH/AEG-1 contributes to central features of the neoplastic phenotype in bladder cancer. AB - OBJECTIVES: Carcinoma of the bladder is the fifth most common cancer whose incidence continues to rise. MTDH/AEG-1 is associated with the initiation and progression of many cancers including breast, hepatocellular, ovarian, and colorectal carcinomas. However, the expression and functional importance of MTDH/AEG-1 in bladder cancer remains unknown. The present study was aimed at exploring the functional role of MTDH/AEG-1 in selected bladder cancer cell lines. METHODS AND MATERIALS: The relative expression of MTDH/AEG-1 was assessed by real-time quantitative reverse transcription-polymerase chain reaction in several human bladder cancer cell lines as well as cancerous and benign bladder tissues. Then, expression of MTDH/AEG-1 in RT112 and 647V bladder cancer cell lines was knocked down by an RNA interference strategy. Cell viability and apoptosis were determined after treatment with specific interfering RNA. Potential effects of MTDG/AEG-1 specific interfering RNA on the cell cycle were investigated by flow cytometry. We also performed anchorage-independent growth and wound-healing assays to study MTDH/AEG-1 function. RESULTS: Down-regulation of MTDH/AEG-1 did not significantly affect the cell cycle distribution but rather reduced cell viability via apoptosis, as evidenced by increased annexin V staining and caspase 3/7 activities as well as mitochondrial potential disruption. Of note, serum starvation did not exacerbate the effects of MTDH/AEG 1 knockdown. Furthermore, MTDH/AEG-1 down-regulation significantly decreased anchorage-independent growth and migration of bladder carcinoma cells. CONCLUSION: Overexpression of MTDH/AEG-1 contributes to the neoplastic phenotype of bladder cancer cells by promoting survival, clonogenicity, and migration. PMID- 24495450 TI - Prostate cancer biomarkers: an update. AB - Many aspects of prostate cancer diagnosis and treatment could be greatly advanced with new, effective biomarkers. Prostate-specific antigen (PSA) has multiple weaknesses as a biomarker, such as not distinguishing well between cancer and benign prostatic hyperplasia or between indolent and aggressive cancers, thus leading to overtreatment, especially unnecessary biopsies. PSA also often fails to indicate accurately which patients are responding to a given treatment. Yet PSA is the only prostate cancer biomarker routinely used by urologists. Here, we provide updated information on the most relevant of the other biomarkers currently in use or in development for prostate cancer. Recent research shows improvement over using PSA alone by comparing total PSA (tPSA) or free PSA (fPSA) with new, related markers, such as prostate cancer antigen (PCA) 3, the individual molecular forms of PSA (proPSA, benign PSA, and intact PSA), and kallikreins other than PSA. Promising results have also been seen with the use of the fusion gene TMPRSS2:ERG and with various forms of the urokinase plasminogen activation receptor. Initially, there were high hopes for early PCA, but those data were not reproducible and thus research on early PCA has been abandoned. Much work remains to be done before any of these biomarkers are fully validated and accepted. Currently, the only markers discussed in this paper with Food and Drug Administration-approved tests are PCA 3 and an isoform of proPSA, [ 2]proPSA. Assays are in development for most of the other biomarkers described in this paper. While the biomarker validation process can be long and filled with obstacles, the rewards will be great-in terms of both patient care and costs to the health care system. PMID- 24495451 TI - Effect of ABO blood type on mortality in patients with urothelial carcinoma of the bladder treated with radical cystectomy. AB - OBJECTIVE: ABO blood type is an inherited characteristic that has been associated with the prognosis of several malignancies, but there is little evidence in urothelial carcinoma of the bladder (UCB). The purpose of this study was to evaluate the effect of ABO blood type on mortality in patients with UCB treated with radical cystectomy (RC). METHODS: Multi-institutional data from 7,906 patients with UCB treated with RC between 1979 and 2012 were retrospectively analyzed. The effect of ABO blood type on UCB-related mortality was evaluated with univariable and multivariable competing-risks regression models. RESULTS: ABO blood type was O in 3,728 (47%), A in 2,748 (35%), B in 888 (11%), and AB in 532 (7%) patients. Blood type B was associated with a greater likelihood of lymphovascular invasion (P = 0.010) and positive soft tissue margins (P = 0.008). The median follow-up was 41 months. The 5-year cumulative UCB-related mortality rates for blood type O, A, B, and AB were 29.5%, 30.5%, 33.2%, and 25.8%, respectively. In univariable competing-risks regression, patients with blood type B had worse UCB-related mortality than those with blood type O (P = 0.026) and AB (P = 0.020). In multivariable analysis, however, blood type lost its statistical significance. CONCLUSIONS: Among patients treated with RC, ABO blood type is associated with a statistically significant but clinically insignificant difference in UCB-related mortality. This association was not present in multivariable analysis. Our data therefore suggest no relevant association of ABO blood type with UCB-related prognosis. PMID- 24495452 TI - Renal carcinoma pharmacogenomics and predictors of response: Steps toward treatment individualization. AB - Molecular knowledge has deeply affected the treatment and outcome of kidney cancer in recent years, and several therapeutic options have become available. However, there are no validated biomarkers to select the best drug for each patient. Already published studies and ongoing investigations could change this scenario in the near future. Regarding antiangiogenic drugs, several works on single nucleotide polymorphisms have achieved promising results, with some SNPs predicting resistance to sunitinib and pazopanib being validated. If more evidence is gained, it could prompt prospective studies exploring a molecularly driven selection of treatment. Another relevant line of investigation for antiangiogenic drugs is the cytokines and antiangiogenic factors. Different studies have found that cytokines and antiangiogenic factors are able to predict the outcome of patients treated with sunitinib, pazopanib, or sorafenib. Issues regarding the thresholds of normality and the best time for assessment are pending, but the communicated results are encouraging. Less evidence is available for mammalian target of rapamycin inhibitors but recent data support a key role of the phosphoinositide 3-kinase/Akt pathway in clear cell renal cell carcinoma and points toward poor response to angiogenic drugs when the pathway is activated. Whether modern phosphoinositide 3-kinase inhibitors could be the best option for these patients is a question that should be addressed. Additionally, a new class of immunomodulators, like anti-programmed death 1 drugs, has demonstrated to achieve long-lasting stabilizations even in some patients with no radiological response or early progression. This is a singular situation where the identification of reliable predictors of efficacy will be key in the development of these drugs in renal cell carcinoma. Finally, germline mutations of the c-Met gene have been proposed as the first predictor of response to targeted therapies in papillary renal cell carcinoma. As a conclusion, translational research will be a cornerstone to move a next step forward in kidney cancer. PMID- 24495453 TI - Radical hysterectomy with adjuvant radiotherapy versus radical radiotherapy for FIGO stage IIB cervical cancer. AB - BACKGROUND: The goal of this study was to compare treatment outcomes for Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical carcinoma patients receiving radical surgery followed by adjuvant postoperative radiotherapy versus radical radiotherapy. METHODS: Medical records of FIGO stage IIB cervical cancer patients treated between July 2008 and December 2011 were retrospectively reviewed. A total of 148 patients underwent radical hysterectomy with pelvic lymph node dissection followed by adjuvant radiotherapy (surgery based group). These patients were compared with 290 patients that received radical radiotherapy alone (RT-based group). Recurrence rates, progression-free survival (PFS), overall survival (OS), local control rates, and treatment-related complications were compared for these two groups. RESULTS: Similar rates of recurrence (16.89% vs. 12.41%, p = 0.200), PFS (log-rank, p = 0.211), OS (log rank, p = 0.347), and local control rates (log-rank, p = 0.668) were observed for the surgery-based group and the RT-based group, respectively. Moreover, the incidence of acute grade 3-4 gastrointestinal reactions and late grade 3-4 lower limb lymphedema were significantly higher for the surgery-based group versus the RT-based group. Cox multivariate analyses found no significant difference in survival outcome between the two groups, and tumor diameter and histopathology were identified as significant prognostic factors for OS. CONCLUSIONS: Radical radiotherapy was associated with fewer treatment-related complications and achieved comparable survival outcomes for patients with FIGO stage IIB cervical cancer compared to radical hysterectomy followed by postoperative radiotherapy. PMID- 24495454 TI - Incidence of unlicensed and off-label prescription in children. AB - BACKGROUND: Many common drugs have not been licensed for use in children. METHODS: This study evaluated the incidence of unlicensed and off-label prescriptions at the Department of Pediatrics during a period of six months. A total of 8,559 prescriptions for 4,282 children were processed. RESULTS: Off label and unlicensed prescriptions were found in 9.01% and 1.26% of all prescriptions, respectively. Unlicensed prescriptions were significantly more common in boys (1.5%) than in girls (1.0%) (p = 0.037). There was no significant difference between off-label prescriptions in boys (9.0%) and in girls (9.1%) (p = 0.89). The prescription of unlicensed drugs was significantly more frequent in school age children (p < 0.0001). The most commonly prescribed unlicensed drugs were angiotensin-converting enzyme inhibitors; among off-label drugs, antihistamines and bronchodilators. CONCLUSIONS: This study shows that the incidence of unlicensed and off-label drug prescriptions in our patients is not as high as in other studies. PMID- 24495455 TI - Per-oral flexible laryngoscopy in awake neonates and infants: the 'pacifier' technique. AB - BACKGROUND: It is common for ENT specialists to be called to neonatal intensive care units to assess neonates with suspected laryngomalacia. At Addenbrooke's Hospital, Cambridge, UK, it is standard practice to initially try to assess the larynx whilst the patient is awake. This can cause the patient to cry and become irritable, and can induce worry in the parents. A literature search revealed that numerous procedures have been successfully performed on neonates and infants whilst they were being pacified. OBJECTIVES: This paper describes various procedures where pacification has been used effectively. Furthermore, it reports a pacification technique developed for per-oral flexible laryngoscopy in awake neonates and infants. PMID- 24495456 TI - Do antidepressants prolong the QT interval? AB - According to a recent cross-sectional study, some antidepressants, including amitriptyline, citalopram and escitalopram, are associated with QTc prolongation. However, the magnitude of this association is relatively small, and the clinical implications uncertain. In this article, the main strengths and weaknesses of this cross-sectional study are briefly analysed alongside recent warnings issued by regulatory authorities. Implications for research and practice are discussed. PMID- 24495457 TI - Quartz crystal microbalance for comparison of calcium phosphate precipitation on planar and rough phospholipid bilayers. AB - The planar and rough phospholipid bilayers at the surfaces of quartz crystal and titania-modified quartz crystal were fabricated via the surface modification, respectively, and characterized by scanning electron microscopy (SEM), atomic force microscopy (AFM), cyclic voltammetry (CV) and piezoelectric measurement. The formation of calcium phosphate on planar and rough phospholipid bilayers was investigated in detail using in situ quartz crystal microbalance (QCM) and X-ray diffraction (XRD) techniques. The obtained results showed that the calcium phosphate precipitation was closely related to the roughness and surface potential of phospholipid bilayers. Compared with planar phospholipid bilayers, the rough phospholipid bilayers exhibited a higher deposition rate of calcium phosphate. The presence of anionic phosphatidylserine (PS) in phosphatidylcholine (PC)/PS phospholipid induced PC/PS surface with negative charge, thus showing significantly enhanced calcium phosphate precipitation. PMID- 24495458 TI - Impact of agglomeration on the bioaccumulation of sub-100 nm sized TiO2. AB - To improve our understanding on the impact of extrinsic properties of NPs on their bioaccumulation and toxicity, we have investigated the bioaccumulation of sub 100 nm sized P25 TiO2 nanoparticles (NPs) by Daphnia magna (D. magna) in toxicity testing media. Based on our quantitative ICP-MS measurements as well as spectromicroscopic observations, we found that the bioaccumulation by D. magna were strongly influenced by the extrinsic properties of NPs as well as the biological uptake characteristics of D. magna. New sets of effective dosimetry parameters well correlated with the amount of NPs bioaccumulated within D. magna were also proposed. Based on these findings, we suggested that the extrinsic physicochemical properties of NPs (e.g., interfacial and colloidal properties of NPs) and biological characteristics for NPs (e.g., uptake cutoff sizes of testing organisms) should be considered and included when developing alternative dosimetry of NPs. PMID- 24495459 TI - Intracellular delivery and activation of the genetically encoded photosensitizer Killer Red by quantum dots encapsulated in polymeric micelles. AB - We have prepared polymeric micelle-encapsulating quantum dots (QDots) for delivering the optically activatable protein Killer Red (KR) as a plasmid to cancer cells. QDots absorb light at a lower wavelength and emit light at a higher wavelength in the cell cytoplasm, activating the expressed KR. Once activated, KR triggers the generation of reactive oxygen species (ROS). We prepared cadmium selenide (CdSe)/zinc sulphide (ZnS) QDots and evaluated their optical properties. Subsequently, we performed morphology studies, elemental analysis, thermogravimetric analysis (TGA), and measurements of particle size and surface charge of prepared QDots encapsulated in PHEA-g-PEG-bPEI (PPP-QDot). Cellular uptake of PPP-QDot and PPP-QDot/KR nanoparticles was confirmed using confocal microscopy, and the cellular toxicity and transfection efficiency associated with uptake of PPP-QDot/KR nanoparticles were analyzed. KR expression in normal cells and cancer cells was confirmed using confocal microscopy and Western blotting. Cellular morphologies before and after intracellular activation of KR were observed using phase contrast, fluorescence, and confocal microscopy. Cell fate after exposure to blue light-emitting diode lighting was determined using apoptosis staining and a cell proliferation assay, confirming a suppression in proliferation and a reduction in metabolic activity. We determined that ROS generation contributed to cellular damage after treatment with PPP-QDot/KR nanoparticles and blue light exposure. PMID- 24495460 TI - Effects of striatal DeltaFosB overexpression and ketamine on social defeat stress induced anhedonia in mice. AB - BACKGROUND: Chronic social defeat stress (CSDS) produces persistent behavioral adaptations in mice. In many behavioral assays, it can be difficult to determine if these adaptations reflect core signs of depression. We designed studies to characterize the effects of CSDS on sensitivity to reward because anhedonia (reduced sensitivity to reward) is a defining characteristic of depressive disorders in humans. We also examined the effects of striatal DeltaFosB overexpression and the N-methyl-D-aspartate receptor antagonist ketamine, both of which promote resilience, on CSDS-induced alterations in reward function and social interaction. METHODS: Intracranial self-stimulation (ICSS) was used to quantify CSDS-induced changes in reward function. Mice were implanted with lateral hypothalamic electrodes, and ICSS thresholds were measured after each of 10 daily CSDS sessions and during a 5-day recovery period. We also examined if acute intraperitoneal administration of ketamine (2.5-20 mg/kg) reverses CSDS induced effects on reward or, in separate mice, social interaction. RESULTS: ICSS thresholds were increased by CSDS, indicating decreases in the rewarding impact of lateral hypothalamic stimulation (anhedonia). This effect was attenuated in mice overexpressing ?FosB in striatum, consistent with pro-resilient actions of this transcription factor. High, but not low, doses of ketamine administered after completion of the CSDS regimen attenuated social avoidance in defeated mice, although this effect was transient. Ketamine did not block CSDS-induced anhedonia in the ICSS test. CONCLUSIONS: This study found that CSDS triggers persistent anhedonia and confirms that DeltaFosB overexpression produces stress resilience. The findings of this study also indicate that acute administration of ketamine fails to attenuate CSDS-induced anhedonia despite reducing other depression-related behavioral abnormalities. PMID- 24495462 TI - TEG(r) and RapidTEG(r) are unreliable for detecting warfarin-coagulopathy: a prospective cohort study. AB - BACKGROUND: Thromboelastography(r) (TEG) utilizes kaolin, an intrinsic pathway activator, to assess clotting function. Recent published studies suggest that TEG results are commonly normal in patients receiving warfarin, despite an increased International Normalized Ratio (INR). Because RapidTEGTM includes tissue factor, an extrinsic pathway activator, as well as kaolin, we hypothesized that RapidTEG would be more sensitive in detecting a warfarin-effect. METHODS: Included in this prospective study were 22 consecutive patients undergoing elective cardioversion and receiving warfarin. Prior to cardioversion, blood was collected to assess INR, Prothrombin Time, TEG, and RapidTEG. RESULTS: INR Results: 2.8 +/- 0.5 (1.6 to 4.2). Prothrombin Time Results: 19.1 +/- 2.2 (13.9. to 24.3).TEG Results (Reference Range): R-Time: 8.3 +/- 2.7 (2-8); K-Time: 2.1 +/- 1.4 (1-3); Angle: 62.5 +/- 10.3 (55-78); MA: 63.2 +/- 10.3 (51-69); G: 9.4 +/- 3.5 (4.6-10.9); R Time within normal range: 10 (45.5%) with INR 2.9 +/- 0.3; Correlation coefficients for INR and each of the 5 TEG variables were insignificant (P > 0.05).RapidTEG Results (Reference Range): ACT: 132 +/- 58 (86-118); K-Time: 1.2 +/- 0.5 (1-2); Angle: 75.4 +/- 5.2 (64-80); MA: 63.4 +/- 5.1 (52-71); G: 8.9 +/- 2.0 (5.0-11.6); ACT within normal range: 9 (40.9%) with INR 2.7 +/- 0.5; Correlation coefficients for INR and each of the 5 RapidTEG variables were insignificant (P > 0.05). CONCLUSIONS: TEG, using kaolin activation, and RapidTEG, with kaolin and tissue factor activation, were normal in a substantial percent of warfarin patients, despite an increased INR. The false-negative rate for detecting warfarin coagulopathy with either test is unacceptable. The lack of correlation between INR and all TEG and RapidTEG components further indicates that these methodologies are insensitive to warfarin effects. Findings suggest that intrinsic pathway activation may mitigate detection of an extrinsic pathway coagulopathy. PMID- 24495463 TI - Insights into naturally minimised Streptomyces albus J1074 genome. AB - BACKGROUND: The Streptomyces albus J1074 strain is one of the most widely used chassis for the heterologous production of bioactive natural products. The fast growth and an efficient genetic system make this strain an attractive model for expressing cryptic biosynthetic pathways to aid drug discovery. RESULTS: To improve its capabilities for the heterologous expression of biosynthetic gene clusters, the complete genomic sequence of S. albus J1074 was obtained. With a size of 6,841,649 bp, coding for 5,832 genes, its genome is the smallest within the genus streptomycetes. Genome analysis revealed a strong tendency to reduce the number of genetic duplicates. The whole transcriptomes were sequenced at different time points to identify the early metabolic switch from the exponential to the stationary phase in S. albus J1074. CONCLUSIONS: S. albus J1074 carries the smallest genome among the completely sequenced species of the genus Streptomyces. The detailed genome and transcriptome analysis discloses its capability to serve as a premium host for the heterologous production of natural products. Moreover, the genome revealed 22 additional putative secondary metabolite gene clusters that reinforce the strain's potential for natural product synthesis. PMID- 24495464 TI - Insights into structural mechanisms of gating induced regulation of aquaporins. AB - Aquaporin family comprises of transmembrane channels that are specialized in conducting water and certain small, uncharged molecules across cell membranes. Essential roles of aquaporins in various physiological and pathophysiological conditions have attracted great scientific interest. Pioneering structural studies on aquaporins have almost solved the basic question of mechanism of selective water transport through these channels. Another important structural aspect of aquaporins which seeks attention is that how the flow of water through the channel is regulated by the mechanism of gating. Aquaporins are also regulated at the protein level, i.e. by trafficking which includes changes in their expression levels in the membrane. Availability of high resolution structures along with numerous molecular dynamics simulation studies have helped to gain an understanding of the structural mechanisms by which water flux through aquaporins is controlled. This review will summarize the highlights regarding structural features of aquaporins, mechanisms governing water permeation, proton exclusion and substrate specificity, and describe the structural insights into the mechanisms of aquaporin gating whereby water conduction is regulated by post translational modifications, such as phosphorylation. PMID- 24495461 TI - The Effects of Acutely Administered 3,4-Methylenedioxymethamphetamine on Spontaneous Brain Function in Healthy Volunteers Measured with Arterial Spin Labeling and Blood Oxygen Level-Dependent Resting State Functional Connectivity. AB - BACKGROUND: The compound 3,4-methylenedioxymethamphetamine (MDMA) is a potent monoamine releaser that produces an acute euphoria in most individuals. METHODS: In a double-blind, placebo-controlled, balanced-order study, MDMA was orally administered to 25 physically and mentally healthy individuals. Arterial spin labeling and seed-based resting state functional connectivity (RSFC) were used to produce spatial maps displaying changes in cerebral blood flow (CBF) and RSFC after MDMA administration. Participants underwent two arterial spin labeling and two blood oxygen level-dependent scans in a 90-minute scan session; MDMA and placebo study days were separated by 1 week. RESULTS: Marked increases in positive mood were produced by MDMA. Decreased CBF only was observed after MDMA, and this was localized to the right medial temporal lobe (MTL), thalamus, inferior visual cortex, and the somatosensory cortex. Decreased CBF in the right amygdala and hippocampus correlated with ratings of the intensity of global subjective effects of MDMA. The RSFC results complemented the CBF results, with decreases in RSFC between midline cortical regions, the medial prefrontal cortex, and MTL regions, and increases between the amygdala and hippocampus. There were trend-level correlations between these effects and ratings of intense and positive subjective effects. CONCLUSIONS: The MTLs appear to be specifically implicated in the mechanism of action of MDMA, but further work is required to elucidate how the drug's characteristic subjective effects arise from its modulation of spontaneous brain activity. PMID- 24495465 TI - The future of randomised controlled trials in urology. AB - Randomised controlled trials in urology are challenging yet essential for generating high-quality, practice-changing evidence. Future trials should focus on high-priority questions, be conducted by multidisciplinary investigative teams with patient and public stakeholder involvement, and be grounded in successful feasibility studies. PMID- 24495466 TI - Gonadotropin-releasing hormone agonists and acute kidney injury in patients with prostate cancer. AB - BACKGROUND: Androgen deprivation therapy (ADT) might increase the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). OBJECTIVE: To examine the impact of ADT on AKI in a large contemporary cohort of patients with nonmetastatic PCa representing the US population. DESIGN, SETTING, AND PARTICIPANTS: Overall, 69 292 patients diagnosed with nonmetastatic PCa between 1995 and 2009 were abstracted from the Surveillance Epidemiology and End Results Medicare database. OUTCOMES MEASUREMENTS AND STATISTICAL ANALYSES: Patient in both treatment arms (ADT vs. no ADT) were matched using propensity-score methodology. Ten-year AKI rates were estimated. Competing-risks regression analyses tested the association between ADT and AKI, after adjusting for the risk of death during follow-up. RESULTS AND LIMITATIONS: Overall, the 10-yr AKI rates were 24.9% versus 30.7% for ADT-naive patients versus those treated with ADT, respectively (p<0.001). When patients were stratified according to the type of ADT, the 10-yr AKI rates were 31.1% versus 26.0% for men treated with gonadotropin-releasing hormone (GnRH) agonists and bilateral orchiectomy, respectively (p<0.001). In multivariable analyses, the administration of GnRH agonists (hazard ratio [HR]: 1.24; 95% confidence interval [CI], 1.18-1.31; p<0.001), but not bilateral orchiectomy (HR: 1.11; 95% CI, 0.96-1.29; p=0.1), was associated with the risk of experiencing AKI. Our study is limited by its retrospective design. CONCLUSIONS: ADT is associated with an increased risk of AKI in patients with nonmetastatic PCa. In particular, the administration of GnRH agonists, but not surgical castration, may substantially increase the risk of experiencing AKI. These observations should help provide physicians with better patient selection to reduce the risk of AKI. PATIENT SUMMARY: The administration of gonadotropin-releasing hormone agonists, but not bilateral orchiectomy, increases the risk of acute kidney injury (AKI) in patients with prostate cancer (PCa). These observations should help provide physicians with better patient selection to reduce the risk of AKI in PCa patients. PMID- 24495467 TI - Cocksfoot mottle virus coat protein is dispensable for the systemic infection. AB - BACKGROUND: The Sobemovirus genome consists of polycistronic single-stranded positive-sense RNA. The first ORF encodes P1, a suppressor of RNA silencing required for virus movement. The coat protein (CP) is expressed from the 3' proximal ORF3 via subgenomic RNA. In addition to its structural role, the CP of some sobemoviruses has been reported to be required for systemic movement and to interact with P1. The aim of this study was to analyse the role of Cocksfoot mottle virus (CfMV) CP in the suppression of RNA silencing and virus movement. METHODS: Agrobacterium-mediated transient expression method was used for testing CfMV CP capacity to suppress RNA silencing. CP substitution and deletion mutants were generated to examine the role of this protein in CfMV infection, using three host plants (oat, barley and wheat). The viral movement was characterised with CfMV expressing EGFP fused to the C-terminus of CP. RESULTS: In the current study we show that CfMV CP is an additional RNA silencing suppressor. Interestingly, we observed that all CP mutant viruses were able to infect the three tested host plants systemically, although usually with reduced accumulation. CfMV expressing EGFP was detected in epidermal and mesophyll cells of inoculated leaves. Although EGFP fluorescence was not detected in upper leaves, some plants displayed CfMV symptoms. Analysis of the upper leaves revealed that the viruses had lost the EGFP sequence and sometimes also most of the CP gene. CONCLUSIONS: The present study demonstrates that CfMV CP suppresses RNA silencing but, surprisingly, is dispensable for systemic movement. Thus, CfMV does not move as virion in the tested host plants. The composition of the movement RNP complex remains to be elucidated. PMID- 24495469 TI - Feature extraction and pattern classification of colorectal polyps in colonoscopic imaging. AB - A computer-aided diagnostic system for colonoscopic imaging has been developed to classify colorectal polyps by type. The modules of the proposed system include image enhancement, feature extraction, feature selection and polyp classification. Three hundred sixty-five images (214 with hyperplastic polyps and 151 with adenomatous polyps) were collected from a branch of a medical center in central Taiwan. The raw images were enhanced by the principal component transform (PCT). The features of texture analysis, spatial domain and spectral domain were extracted from the first component of the PCT. Sequential forward selection (SFS) and sequential floating forward selection (SFFS) were used to select the input feature vectors for classification. Support vector machines (SVMs) were employed to classify the colorectal polyps by type. The classification performance was measured by the Az values of the Receiver Operating Characteristic curve. For all 180 features used as input vectors, the test data set yielded Az values of 88.7%. The Az value was increased by 2.6% (from 88.7% to 91.3%) and 4.4% (from 88.7% to 93.1%) for the features selected by the SFS and the SFFS, respectively. The SFS and the SFFS reduced the dimension of the input vector by 57.2% and 73.8%, respectively. The SFFS outperformed the SFS in both the reduction of the dimension of the feature vector and the classification performance. When the colonoscopic images were visually inspected by experienced physicians, the accuracy of detecting polyps by types was around 85%. The accuracy of the SFFS with the SVM classifier reached 96%. The classification performance of the proposed system outperformed the conventional visual inspection approach. Therefore, the proposed computer-aided system could be used to improve the quality of colorectal polyp diagnosis. PMID- 24495468 TI - Melatonin reduces tachycardia in postural tachycardia syndrome: a randomized, crossover trial. AB - BACKGROUND: Postural tachycardia syndrome (POTS) induces disabling chronic orthostatic intolerance with an excessive increase in heart rate (HR) upon standing, and many POTS patients have a hyperadrenergic state. Medications that restrain HR are a promising approach to this problem. OBJECTIVE: We tested the hypothesis that melatonin will attenuate the tachycardia and improve symptom burden in patients with POTS. METHODS: Patients with POTS (n = 78) underwent acute drug trials with melatonin 3 mg orally and placebo, on separate mornings, in a randomized crossover design. Blood pressure, HR, and symptoms were assessed while seated and after standing for up to 10 min prior to, and hourly for 4 h following study drug administration. RESULTS: The reduction in standing HR was significantly greater 2 h after melatonin compared with placebo (P = 0.017). There was no significant difference in the reduction of systolic blood pressure between melatonin and placebo, either with standing or while seated. The symptom burden was not improved with melatonin compared with placebo. CONCLUSION: Oral melatonin produced a modest decrease in standing tachycardia in POTS. Further research is needed to determine the effects of regular night-time use of this medication in POTS. PMID- 24495470 TI - Phytochemical profiles and biological activity evaluation of Zanthoxylum bungeanum Maxim seed against asthma in murine models. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Zanthoxylum bungeanum Maxim seed (ZBMS) has been used in Traditional Chinese Medicine (TCM) as an ingredient of polyherbal formulations for the treatment of inflammation and asthma. The aim of this study was to analyze the major composition and to evaluate the anti-asthma activity of ZBMS. MATERIALS AND METHODS: Some murine models including acetylcholine/histamine induced asthma, ovalbumin-induced airway inflammation, ear edema and toe swelling measurement, citric acid-induced cough, and anti-stress abilities were investigated to fully study the anti-asthma activity of ZBMS.GC chromatography was also performed to analyze the major fatty acid composition of ZBMS. RESULTS: The results demonstrated that the major fatty acid composition of ZBMS includes oleic acid (20.15%), linoleic acid (26.54%), and alpha-linolenic acid (30.57%), which was the leading component of ZBMS, and that the total fatty acid content of ZBMS was 77.27%. The murine models demonstrated that ZBMS displays a protective effect on guinea pig sensitization, a dose-dependent inhibition of the increases in RL and decreases in Cdyn, which resulted in the relief of auricle edema and toe swelling in mice and anti-stress activity. CONCLUSION: Our results validate the traditional use of ZBMS for the treatment of asthma and other inflammatory joint disorders, and suggest that ZBMS has potential as a new therapeutic agent for asthma management. PMID- 24495471 TI - Anti-inflammatory effect of Phellinus linteus grown on germinated brown rice on dextran sodium sulfate-induced acute colitis in mice and LPS-activated macrophages. AB - ETHNOPHARMACOLOGICAL RELEVANCE AND AIM OF THE STUDY: Phellinus linteus is a herb used in traditional Asian medicine to treat stomachache, inflammation, and tumors. Recent studies show that the extract of Phellinus linteus has anti inflammatory and antitumor activities. However, Phellinus linteus extract has limitation of high cost and limited availability because of supply shortage. Here, we grew Phellinus linteus on germinated brown rice to address the issue of supply shortage and investigated anti-inflammatory effect in vivo as well as in vitro. MATERIALS AND METHODS: Phellinus linteus grown on germinated brown rice (PBR) were extracted using filtration steps, which included gamma-aminobutyric acid (GABA). The PBR (200, 500mg/kg/day) was applied into the mouse model of dextran sodium sulfate (DSS)-induced colitis and lipopolysaccharide (LPS) stimulated mouse macrophage RAW264.7 cells. We used sulfasalazine as a reference drug. In addition, mechanism related to anti-inflammatory was investigated by Western blotting. RESULTS: In the mouse model of DSS-induced colitis, PBR ameliorated the pathological characteristics of colitis such as shortening of colon length and improved the disease activity index score. In addition, we showed that PBR reduced the expression of nuclear factor-kappa B (NF-kappaB) in colitis. Western blotting showed that PBR decreased the expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (Cox-2) proteins. Further, PBR treatment reduced the expression of mitogen-activated protein kinases (MAPKs) (e.g., extracellular signal-regulated protein kinase (ERK) and p38) in the mouse model of DSS-induced colitis. CONCLUSIONS: Treatment of RAW 264.7 macrophages with a combination of PBR and LPS showed a significant concentration-dependent inhibition of nitric oxide (NO) and prostaglandin E2 (PGE2) production. In addition, we determined the ability of PBR to reduce the iNOS and tumor necrosis factor (TNF)-alpha expression. PBR inhibited the expression of iNOS, NF-kappaB, and Cox-2 proteins in LPS-stimulated RAW264.7 macrophages. This study presents the potential use of PBR as a drug candidate against colitis. PMID- 24495472 TI - Anti-hyperalgesic and anti-allodynic activities of capillarisin via suppression of inflammatory signaling in animal model. AB - ETHNOPHARMACOLOGICAL RELEVANCE: Artemisia capillaris has widespread traditional and pharmacological applications such as analgesic, anti-inflammatory, anti pyretic, enhance immunity and anti-tumor activity properties. To evaluate the pharmacological activities of this plant, capillarisin, one of the potent constituent of Artemisia capillaris was studied based on anti-hyperalgesic and anti-allodynic effects with detailed mechanism. It can be assumed that measurement of anti-nociceptive effects of capillarisin is one of the parameter for the evaluation of this herb. Capillarisin has extensive pharmacological properties and has been considered to have promising ant-inflammatory and anti nociceptive activities. The aim of the current study is to investigate the effect of capillarisin and underlying molecular mechanisms of action in preventing acute and subchronic inflammatory pain. MATERIALS AND METHODS: The inflammatory pain was induced after 40 min or 1h of administration of vehicle, 70% EtOH extract of Artemisia capillaris (100mg/kg) or capillarisin (20 and 80 mg/kg) by intraplantar (i.p.l.) injections of CFA and carrageenan in ICR mice, respectively. Mechanical hyperalgesia and allodynia were evaluated in both acute and subchronic models. Further analysis was performed in CFA-induced mice exploring various molecular and signaling pathways such as NF-kappaB, AP-1, and ERK-CREB involved in the persistent pain sensations. RESULTS: In acute model, mechanical hyperalgesia and allodynia were evaluated after every 2h until 6h of CFA and after 4h of carrageenan injections. Whereas, in subchronic inflammatory pain model, mechanical hyperalgesia and paw edema were measured after 4h of CFA injection and every day after 4h of daily treatment until 5 days with interval of day four in order to assess the tolerance effect of capillarisin. Further analysis was performed in CFA-induced mice exploring various molecular and signaling pathways such as NF-kappaB, AP-1 and ERK-CREB involved in the persistent of pain sensations. Pre-treatment of capillarisin strongly inhibited NF-kappaB mediated genes (iNOS, COX-2), involved in pain. The plasma leading nitrite production was significantly reduced by capillarisin. Moreover, i.p. administration of capillarisin markedly suppressed the adenosine 5'-triphosphate (ATP) in plasma and substance P in CFA-induced paw tissue. CONCLUSIONS: The present study indicates that capillarisin possessed promising anti-hyperalgesic and anti allodynic effects through the inhibition of various inflammatory pain signaling, suggesting that capillarisin constitutes a significant component for the treatment of inflammatory pain. PMID- 24495473 TI - Contemporary issues concerning informed consent in Japan based on a review of court decisions and characteristics of Japanese culture. AB - BACKGROUND: Since Japan adopted the concept of informed consent from the West, its inappropriate acquisition from patients in the Japanese clinical setting has continued, due in part to cultural aspects. Here, we discuss the current status of and contemporary issues surrounding informed consent in Japan, and how these are influenced by Japanese culture. DISCUSSION: Current legal norms towards informed consent and information disclosure are obscure in Japan. For instance, physicians in Japan do not have a legal duty to inform patients of a cancer diagnosis. To gain a better understanding of these issues, we present five court decisions related to informed consent and information disclosure. We then discuss Japanese culture through reviews of published opinions and commentaries regarding how culture affects decision making and obtaining informed consent. We focus on two contemporary problems involving informed consent and relevant issues in clinical settings: the misuse of informed consent and persistence in obtaining consent. For the former issue, the phrase "informed consent" is often used to express an opportunity to disclose medical conditions and recommended treatment choices. The casual use of the expression "informed consent" likely reflects deep rooted cultural influences. For the latter issue, physicians may try to obtain a signature by doing whatever it takes, lacking a deep understanding of important ethical principles, such as protecting human dignity, serving the patient's best interest, and doing no harm in decision-making for patients.There is clearly a misunderstanding of the concept of informed consent and a lack of complete understanding of ethical principles among Japanese healthcare professionals. Although similar in some respects to informed consent as it originated in the United States, our review makes it clear that informed consent in Japan has clear distinguishing features. SUMMARY: Japanese healthcare professionals should aim to understand the basic nature of informed consent, irrespective of their attitudes about individualism, liberalism, and patient self-determination. If they believe that the concept of informed consent is important and essential in Japanese clinical settings, efforts should be made to obtain informed consent in an appropriate manner. PMID- 24495474 TI - Off-the-job microsurgical training on dry models: Siberian experience. AB - BACKGROUND: Microsurgical training has become an obligatory part of many neurosurgical training programs. OBJECTIVE: To assess the cost and effectiveness of acquiring and maintaining microneurosurgical skills by training on an off-the job basis using dry models. METHODS: A dry off-the-job microneurosurgical training module was set up. Training exercises involved microdissection in a deep operation field, suturing and tying on gauze, untying, pushing of thread end, and microanastomosis. The time to complete the task and success rate were evaluated. The total cost of all necessary equipment and expendables for the training module was US$910. RESULTS: Fifteen residents participated in the continuous off-the-job training. The average time taken to perform the anastomosis decreased after the month of training from 90 to 20 minutes. Authors revealed that at 2 months, the total time and time to complete anastomosis increased significantly for the participants who discontinued practice after the first month, compared with those who just practiced suturing on gauze after the first month (P < 0.01). The average Northwestern Objective Microanastomosis Assessment Tool score was 36 for novice and 65 for experienced participants. CONCLUSION: The dry off-the-job training showed to be readily available and can be helpful for microsurgical training in the low-income regions of the world. Our data suggest that microsurgical training should be continuous and repetitive. Simulation training may benefit from models for repetitive training of relevant technical part skills. PMID- 24495475 TI - Binary Solvents Dispersive Liquid-Liquid Microextraction (BS-DLLME) Method for Determination of Tramadol in Urine Using High-Performance Liquid Chromatography. AB - BACKGROUND: Tramadol is an opioid, synthetic analog of codeine and has been used for the treatment of acute or chronic pain may be abused. In this work, a developed Dispersive liquid liquid microextraction (DLLME) as binary solvents based dispersive liquid-liquid microextraction (BS-DLLME) combined with high performance liquid chromatography (HPLC) with fluorescence detection (FD) was employed for determination of tramadol in the urine samples. This procedure involves the use of an appropriate mixture of binary extraction solvents (70 MUL CHCl3 and 30 MUL ethyl acetate) and disperser solvent (600 MUL acetone) for the formation of cloudy solution in 5 ml urine sample comprising tramadol and NaCl (7.5%, w/v). After centrifuging, the small droplets of extraction solvents were precipitated. In the final step, the HPLC with fluorescence detection was used for determination of tramadol in the precipitated phase. RESULTS: Various factors on the efficiency of the proposed procedure were investigated and optimized. The detection limit (S/N = 3) and quantification limit (S/N = 10) were found 0.2 and 0.9 MUg/L, respectively. The relative standard deviations (RSD) for the extraction of 30 MUg L of tramadol was found 4.1% (n = 6). The relative recoveries of tramadol from urine samples at spiking levels of 10, 30 and 60 MUg/L were in the range of 95.6 - 99.6%. CONCLUSIONS: Compared with other methods, this method provides good figures of merit such as good repeatability, high extraction efficiency, short analysis time, simple procedure and can be used as microextraction technique for routine analysis in clinical laboratories. PMID- 24495476 TI - The role of EVI1 in myeloid malignancies. AB - The EVI1 oncogene at human chr 3q26 is rearranged and/or overexpressed in a subset of acute myeloid leukemias and myelodysplasias. The EVI1 protein is a 135 kDa transcriptional regulator with DNA-binding zinc finger domains. Here we provide a critical review of the current state of research into the molecular mechanisms by which this gene plays a role in myeloid malignancies. The major pertinent cellular effects are blocking myeloid differentiation and preventing cellular apoptosis, and several potential mechanisms for these phenomena have been identified. Evidence supports a role for EVI1 in inducing cellular quiescence, and this may contribute to the resistance to chemotherapy seen in patients with neoplasms that overexpress EVI1. Another isoform, MDS1-EVI1 (or PRDM3), encoded by the same locus as EVI1, harbors an N-terminal histone methyltransferase(HMT) domain; experimental findings indicate that this protein and its HMT activity are critical for the progression of a subset of AMLs, and this provides a potential target for therapeutic intervention. PMID- 24495477 TI - BRAF--a new player in hematological neoplasms. AB - BRAF oncogenic kinase has become a target for specific therapy in oncology. Genetic characterization of a predominant V600E mutation in melanoma, thyroid cancer, and other tumors became a focus for developing specific inhibitors, such as vemurafenib or dabrafenib. Our knowledge regarding the role of mutated BRAF in hematological malignancies has grown quickly as a result of new genetic techniques such as next-generation sequencing. This review summarizes current knowledge regarding the role of BRAF in lymphoid and myeloid neoplasms, with a focus on hairy-cell leukemia, Langerhans cell histiocytosis, and Erdheim-Chester disease. PMID- 24495478 TI - Concerted down-regulation of immune-system related genes predicts metastasis in colorectal carcinoma. AB - BACKGROUND: This study aimed at the identification of prognostic gene expression markers in early primary colorectal carcinomas without metastasis at the time point of surgery by analyzing genome-wide gene expression profiles using oligonucleotide microarrays. METHODS: Cryo-conserved tumor specimens from 45 patients with early colorectal cancers were examined, with the majority of them being UICC stage II or earlier and with a follow-up time of 41-115 months. Gene expression profiling was performed using Whole Human Genome 4x44K Oligonucleotide Microarrays. Validation of microarray data was performed on five of the genes in a smaller cohort. RESULTS: Using a novel algorithm based on the recursive application of support vector machines (SVMs), we selected a signature of 44 probes that discriminated between patients developing later metastasis and patients with a good prognosis. Interestingly, almost half of the genes was related to the patients' immune response and showed reduced expression in the metastatic cases. CONCLUSIONS: Whereas up to now gene signatures containing genes with various biological functions have been described for prediction of metastasis in CRC, in this study metastasis could be well predicted by a set of gene expression markers consisting exclusively of genes related to the MHC class II complex involved in immune response. Thus, our data emphasize that the proper function of a comprehensive network of immune response genes is of vital importance for the survival of colorectal cancer patients. PMID- 24495479 TI - Three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging findings in a patient with relapsing polychondritis. AB - OBJECTIVE: We report three-dimensional fluid-attenuated inversion recovery magnetic resonance imaging findings in a patient with relapsing polychondritis. METHOD: Case report. RESULT: A 76-year-old woman initially presented with bilateral auricular swelling together with dyspnoea. Three months later, she experienced left hearing loss and recurrent vertigo. A biopsy of the auricle was performed and relapsing polychondritis was diagnosed. The patient underwent three dimensional fluid-attenuated inversion recovery magnetic resonance imaging 4 hours after intravenous injection of a standard dose of gadolinium. Gadolinium enhancement was visible throughout the vestibule and the endolymphatic space could not be visualised, suggesting breakdown of the blood-labyrinth barrier. CONCLUSION: This is the first radiological report to demonstrate breakdown of the blood-labyrinth barrier in a case of relapsing polychondritis with inner ear impairment. PMID- 24495480 TI - Endothelial protein C receptor-associated invasiveness of rheumatoid synovial fibroblasts is likely driven by group V secretory phospholipase A2. AB - INTRODUCTION: Rheumatoid synovial fibroblasts (RASFs) mediate joint inflammation and destruction in rheumatoid arthritis (RA). Endothelial protein C receptor (EPCR) is a specific receptor for the natural anticoagulant activated protein C (APC). It mediates the cytoprotective properties of APC and is expressed in rheumatoid synovial tissue. A recent report shows that group V secretory phospholipase A2 (sPLA2V) prevents APC from binding to EPCR in endothelium and inhibits EPCR/APC function. The aim of this study was to investigate the expression and function of EPCR on RASFs. METHODS: Human synovial fibroblasts (SFs) were isolated from RA or osteoarthritis (OA) synovial tissues and treated with control, EPCR, or sPLA2V small interfering RNA (siRNA); recombinant human APC, tumor necrosis factor-alpha (TNF-alpha), or sPLA2V. RASF viability and migration/invasion were measured by 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide (MTT) and collagen gel migration/invasion assays, respectively, and cartilage degradation by 1,9-dimethylmethylene blue (DMMB) assay in the presence of human OA articular cartilage explants. The expression or activation of cytokines, EPCR, cadherin-11, mitogen-activated protein (MAP) kinases, and nuclear factor-kappa-B (NF-kappaB) or both were detected by enzyme linked immunosorbent assay, Western blotting, or immunostaining. RESULTS: EPCR was expressed by both OASFs and RASFs but was markedly increased in RASFs. When EPCR was suppressed by siRNA or blocking antibody cell viability, cell invasion and cartilage degradation were reduced by more than 30%. Inflammatory mediators interleukin-1-beta (IL-1beta), cadherin-11, and NF-kappaB were significantly reduced by EPCR suppression under control or TNF-alpha-stimulated conditions. The expression or activation (or both) of MAP kinases ERK, p38, and JNK were also markedly decreased in cells transfected with EPCR siRNA. Further analysis revealed that sPLA2V co-localized with EPCR on RASFs. Suppression of sPLA2V reduced cell viability and cartilage degradation and increased APC binding to RASFs. Conversely, recombinant sPLA2V increased cartilage degradation, blocked APC binding to RASFs, and could not rescue the effects induced by EPCR suppression. CONCLUSIONS: Our results demonstrate that EPCR is overexpressed by RASFs and mediates the aggressive behavior of RASFs. This function of EPCR is contrary to its cytoprotective role in other settings and is likely driven by sPLA2V. PMID- 24495481 TI - Significance of TP53 mutations as predictive markers of adjuvant cisplatin-based chemotherapy in completely resected non-small-cell lung cancer. AB - Adjuvant cisplatin-based chemotherapy only marginally improves survival in patients with completely resected non-small-cell lung cancer (NSCLC). We have evaluated the predictive value of mutations in TP53, encoding the tumour suppressor p53, in the International Adjuvant Lung Cancer Trial (IALT), a randomized trial of adjuvant cisplatin-based chemotherapy against observation. TP53 (exons 4-8) was sequenced in 524 archived specimens of IALT patients with a median follow-up of 7.5 years. Predictive analyses were based on Cox models adjusted for clinical and pathological variables. P-values <= 0.01 were considered as significant. Mutations were detected in 221 patients (42%) and had no predictive value for the effect of chemotherapy (interaction between TP53 and treatment: p = 0.17 for Overall Survival (OS); p = 0.06 for Disease-Free Interval, (DFS)). However, among patients with mutations, outcome appeared worse in treatment compared to observation arms (HR for OS = 1.36 (95% CI [0.97-1.31), p = 0.08; DFS = 1.40 (95% CI [1.01-1.95]), p = 0.04). When grouping mutations into classes according to predicted effects on protein structure, the tendency towards worse outcomes was restricted to "structure" mutations affecting residues of the hydrophobic core that are not located at the p53 protein-DNA interface (HR for death in this class vs wild-type T53 = 1.66; 95% CI [1.10-2.52], p = 0.02). Overall, TP53 mutations are not significant predictors of outcome in this trial of cisplatin-based chemotherapy, although a specific class of structural mutations may be associated with a tendency towards worse outcomes upon treatment. PMID- 24495482 TI - Highly sensitive glucose biosensor based on Au-Ni coaxial nanorod array having high aspect ratio. AB - An effective glucose biosensor requires a sufficient amount of GOx immobilizing on the electrode surface. An electrode of a 3D nanorod array, having a larger surface-to-volume ratio than a 2D nanostructure, can accommodate more GOx molecules to immobilize onto the surface of the nanorods. In this study, a highly sensitive Au-Ni coaxial nanorod array electrode fabricated through the integration of nano electroforming and immersion gold (IG) method for glucose detection was developed. The average diameter of the as-synthesized Ni nanorods and that of the Au-Ni nanorods were estimated to be 150 and 250 nm, respectively; both had a height of 30 MUm. The aspect ratio was 120. Compared to that of a flat Au electrode, the effective sensing area was enhanced by 79.8 folds. Actual glucose detections demonstrated that the proposed Au-Ni coaxial nanorod array electrode could operate in a linear range of 27.5 MUM-27.5mM with a detection limit of 5.5MUM and a very high sensitivity of 769.6 MUA mM(-1)cm(-2). Good selectivity of the proposed sensing device was verified by sequential injections of uric acid (UA) and ascorbic acid (AA). Long-term stability was examined through successive detections over a period of 30 days. PMID- 24495483 TI - Temporal occurrence of two morpho butterflies (Lepidoptera: Nymphalidae): influence of weather and food resources. AB - The seasonality of fruit-feeding butterflies is very well known. However, few studies have analyzed the influence of climatic variables and resource availability on the temporal distributions of butterflies. Morpho helenor achillides (C. Felder and R. Felder 1867) and Morpho menelaus coeruleus (Perry 1810) (Nymphalidae) were used as models to investigate the influences of climatic factors and food resources on the temporal distribution of these Morphinae butterflies. These butterflies were collected weekly from January 2005 to December 2006 in the Parque Nacional de Brasilia (PNB). In total, 408 individuals were collected, including 274 of M. helenor and 134 of M. menelaus. The relative abundance of the two species was similar in 2005 (n = 220) and 2006 (n = 188). Of the variables considered, only the relative humidity and resource availability measured in terms of phenology of zoochorous fruits of herbaceous plants explained a large proportion of the variation in the abundance of these butterflies. Both of the explanatory variables were positively associated with the total abundance of individuals and with the abundances of M. helenor and M. menelaus considered separately. The phenology of anemochorous fruits was negatively associated with butterfly abundance. The temporal distribution of the butterflies was better predicted by the phenology of the zoochorous fruits of herbaceous plants than by the climatic predictors. PMID- 24495484 TI - Estimates of home and leisure injuries treated in emergency departments in the adult population living in metropolitan France: a model-assisted approach. AB - BACKGROUND: Home and leisure injuries (HLIs) are currently a major public health concern, because of their frequency, associated consequences, and considerable medical costs. As in many other countries in Europe, in France the population coverage of the surveillance system of HLIs is low. In this study, a model assisted approach is developed to estimate the incidence rates of HLIs in adults treated in emergency departments (EDs) in metropolitan France between 2004 and 2008. METHODS: Using a sample of the hospitals participating in the French ED based surveillance system, a generalized linear mixed model was applied, which describes the relationship between the numbers of ED visits for HLIs and the sex and age of the patients on the basis of the number of injury-related stays recorded by the hospitals. Statistics on hospital stays were provided by the French hospital discharge databases in the participating hospitals. The same statistics were available at the national level, which made it possible to extrapolate national incidence estimates. RESULTS: Over the 2004-2008 period, the estimated incidence rate of HLIs age-standardized on the European population aged 15 years and over was 48.7 per 1,000 person-years (95% confidence interval: 39.4 58.0), and displayed little variability over time. This rate corresponded to an average of 2.5 million emergency hospital visits each year due to an HLI in people aged over 15 in France. CONCLUSIONS: The method made it possible to use medico-administrative datasets available nationwide to provide informative estimates despite the small number of participating EDs. The consequences and costs generated by hospital emergency visits can sometimes be onerous, and these estimated rates confirm the scale of the problem and the need to continue investing in preventive actions. PMID- 24495485 TI - A genomic perspective to assessing quality of mass-reared SIT flies used in Mediterranean fruit fly (Ceratitis capitata) eradication in California. AB - BACKGROUND: Temperature sensitive lethal (tsl) mutants of the tephritid C. capitata are used extensively in control programs involving sterile insect technique in California. These flies are artificially reared and treated with ionizing radiation to render males sterile for further release en masse into the field to compete with wild males and disrupt establishment of invasive populations. Recent research suggests establishment of C. capitata in California, despite the fact that over 250 million sterile flies are released weekly as part of the state's preventative program. In this project, genome-level quality assessment was performed, measured as expression differences between the Vienna-7 tsl mutants used in SIT programs and wild flies. RNA-seq was performed to provide a genome-wide map of the messenger RNA populations in C. capitata, and to investigate significant expression changes in Vienna-7 mass reared flies. RESULTS: Flies from the Vienna-7 colony showed a markedly reduced abundance of transcripts related to visual and chemical responses, including light stimuli, neural development and signaling pathways when compared to wild flies. In addition, genes associated with muscle development and locomotion were shown to be reduced. This suggests that the Vienna-7 line may be less competitive in mating and host plant finding where these stimuli are utilized. Irradiated flies showed several transcripts representing stress associated with irradiation. CONCLUSIONS: There are significant changes at the transcriptome level that likely alter the competitiveness of mass reared flies and provide justification for pursuing methods for strain improvement, increasing competitiveness of mass reared flies, or exploring alternative SIT approaches to increase the efficiency of eradication programs. PMID- 24495486 TI - Biodegradable polymeric vesicles containing magnetic nanoparticles, quantum dots and anticancer drugs for drug delivery and imaging. AB - We have developed biodegradable polymeric vesicles as a nanocarrier system for multimodal bio-imaging and anticancer drug delivery. The poly(lactic-co-glycolic acid) (PLGA) vesicles were fabricated by encapsulating inorganic imaging agents of superparamagnetic iron oxide nanoparticles (SPION), manganese-doped zinc sulfide (Mn:ZnS) quantum dots (QDs) and the anticancer drug busulfan into PLGA nanoparticles via an emulsion-evaporation method. T2*-weighted magnetic resonance imaging (MRI) of PLGA-SPION-Mn:ZnS phantoms exhibited enhanced negative contrast with r2* relaxivity of approximately 523 s(-1) mM(-1) Fe. Murine macrophage (J774A) cellular uptake of PLGA vesicles started fluorescence imaging at 2 h and reached maximum intensity at 24 h incubation. The drug delivery ability of PLGA vesicles was demonstrated in vitro by release of busulfan. PLGA vesicle degradation was studied in vitro, showing that approximately 32% was degraded into lactic and glycolic acid over a period of 5 weeks. The biodistribution of PLGA vesicles was investigated in vivo by MRI in a rat model. Change of contrast in the liver could be visualized by MRI after 7 min and maximal signal loss detected after 4 h post-injection of PLGA vesicles. Histological studies showed that the presence of PLGA vesicles in organs was shifted from the lungs to the liver and spleen over time. PMID- 24495487 TI - Cisplatin crosslinked pH-sensitive nanoparticles for efficient delivery of doxorubicin. AB - pH responsive cisplatin prodrug crosslinked polysaccharide-based nanoparticles were developed from succinic acid decorated dextran (Dex-SA) for active loading and triggered intracellular release of doxorubicin (DOX). Nanoparticles with uniform size were formed spontaneously in aqueous medium via electrostatic interaction between anionic Dex-SA and cationic DOX, and subsequently transformed into crosslinked nanoparticles (CL-Nanoparticles) in situ by readily crosslinking the micelles via chelate interactions between the ionic polymeric carrier and the platinum (II) antitumor drug. This strategy eliminated the need of organic solvents and sophisticated processes in the drug loading procedure. The in vitro release studies showed that DOX was released from the CL-Nanoparticles in a controlled and pH-dependent manner. Furthermore, the pharmacokinetics and biodistribution investigations indicated that, as compared to the non-crosslinked nanoparticles (NCL-Nanoparticles) and free DOX, the CL-Nanoparticles significantly prolonged the blood circulation time of drug, decreased accumulation in the normal tissues and enriched drug into the tumors. As a consequence, the DOX-loaded CL-Nanoparticles exhibited enhanced therapeutic efficacy in tumor-bearing mice compared with the NCL-Nanoparticles and free DOX, which were further confirmed by the histological and immunohistochemical analyses. These cisplatin prodrug crosslinked polysaccharide nanoparticles proved to be a promising nanomedicine drug delivery system for tumor-targeted delivery of DOX. PMID- 24495488 TI - Comparison of behavioral and biochemical deficits in rats with hereditary defined or D-galactose-induced accelerated senescence: evaluating the protective effects of diosgenin. AB - One of the important factors in aging is oxidative stress and aging-related disturbances are believed be ameliorated by antioxidants. Diosgenin is a bio active ingredient of dioscorea that is widely used in Chinese medicine, shows anti-oxidant activity and improves some aging-related deficits in senescent and menopausal animals. We compared alterations in behavior, biochemical parameters (plasma levels of the uric acid, creatinine, calcium, phosphate, total cholesterol, low-density lipoprotein cholesterol and triglycerides, and the plasma activity of aminotransferases AST and ALT), and sperm motility in two models of accelerated senescence (d-galactose-induced (150 mg/kg/day, i.p., 57 days) aging in Wistar rats vs. genetically defined in OXYS rats) and examined the protective effects of diosgenin (10 or 50mg/kg/day, p.o., 57 days). Both models had augmented levels of ALT activity indicating hepatopathology. Compared to d galactose-treated animals, OXYS rats demonstrated profound biochemical alterations (hypocalcemia, hypophosphatemia, and hypocholesterolemia) and behavioral deficits (impaired object recognition, decreased sexual motivation and locomotor activity, retarded learning) that confirmed the difference in the mechanisms of accelerated senescence in these models. We first showed diminished sperm motility in males of both models of accelerated senescence studied. Chronic diosgenin treatment failed to improve biochemical and behavioral disturbances and had some undesirable side effects on body weight and working memory in OXYS rats. However, diosgenin restored moderately decreased sperm motility in d-galactose treated Wistar males and might be recommended for treatment of mild age-related reproductive dysfunctions. PMID- 24495489 TI - Studies of inactivation mechanism of non-enveloped icosahedral virus by a visible ultrashort pulsed laser. AB - BACKGROUND: Low-power ultrashort pulsed (USP) lasers operating at wavelengths of 425 nm and near infrared region have been shown to effectively inactivate viruses such as human immunodeficiency virus (HIV), M13 bacteriophage, and murine cytomegalovirus (MCMV). It was shown previously that non-enveloped, helical viruses such as M13 bacteriophage, were inactivated by a USP laser through an impulsive stimulated Raman scattering (ISRS) process. Recently, enveloped virus like MCMV has been shown to be inactivated by a USP laser via protein aggregation induced by an ISRS process. However, the inactivation mechanism for a clinically important class of viruses--non-enveloped, icosahedral viruses remains unknown. RESULTS AND DISCUSSIONS: We have ruled out the following four possible inactivation mechanisms for non-enveloped, icosahedral viruses, namely, (1) inactivation due to ultraviolet C (UVC) photons produced by non-linear optical process of the intense, fundamental laser beam at 425 nm; (2) inactivation caused by thermal heating generated by the direct laser absorption/heating of the virion; (3) inactivation resulting from a one-photon absorption process via chromophores such as porphyrin molecules, or indicator dyes, potentially producing reactive oxygen or other species; (4) inactivation by the USP lasers in which the extremely intense laser pulse produces shock wave-like vibrations upon impact with the viral particle. We present data which support that the inactivation mechanism for non-enveloped, icosahedral viruses is the impulsive stimulated Raman scattering process. Real-time PCR experiments show that, within the amplicon size of 273 bp tested, there is no damage on the genome of MNV-1 caused by the USP laser irradiation. CONCLUSION: We conclude that our model non enveloped virus, MNV-1, is inactivated by the ISRS process. These studies provide fundamental knowledge on photon-virus interactions on femtosecond time scales. From the analysis of the transmission electron microscope (TEM) images of viral particles before and after USP laser irradiation, the locations of weak structural links on the capsid of MNV-1 were revealed. This important information will greatly aid our understanding of the structure of non-enveloped, icosahedral viruses. We envision that this non-invasive, efficient viral eradication method will find applications in the disinfection of pharmaceuticals, biologicals and blood products in the near future. PMID- 24495490 TI - Children's rights and school psychology: an introduction to the multiple journal series honoring the 25th anniversary of the United Nations Convention on the Rights of the Child. PMID- 24495491 TI - Children's rights and school psychology: children's right to participation. AB - The Convention on the Rights of the Child detailed an international imperative to fulfilling, protecting, and respecting the rights of every child. In particular, the Convention set out a clear mandate for guaranteeing opportunities for children to be heard on all matters of concern to them. The attainment of these goals involves respecting and valuing children as active participants in the educational process. If fully implemented, the right of children to express views and have them taken seriously, throughout the school environment, would represent one of the most profound transformations in moving towards a culture of respect for children's rights, for their dignity and citizenship, and for their capacities to contribute significantly towards their own well-being. These values and principles are consistent with those of the school psychology profession, thus, school psychologists are encouraged to be at the Center of the process advocating and actualizing the Convention in schools throughout the world. PMID- 24495492 TI - Generalizability theory: a practical guide to study design, implementation, and interpretation. AB - Generalizability Theory (GT) offers increased utility for assessment research given the ability to concurrently examine multiple sources of variance, inform both relative and absolute decision making, and determine both the consistency and generalizability of results. Despite these strengths, assessment researchers within the fields of education and psychology have been slow to adopt and utilize a GT approach. This underutilization may be due to an incomplete understanding of the conceptual underpinnings of GT, the actual steps involved in designing and implementing generalizability studies, or some combination of both issues. The goal of the current article is therefore two-fold: (a) to provide readers with the conceptual background and terminology related to the use of GT and (b) to facilitate understanding of the range of issues that need to be considered in the design, implementation, and interpretation of generalizability and dependability studies. Given the relevance of this analytic approach to applied assessment contexts, there exists a need to ensure that GT is both accessible to, and understood by, researchers in education and psychology. Important methodological and analytical considerations are presented and implications for applied use are described. PMID- 24495493 TI - School absenteeism and mental health among sexual minority youth and heterosexual youth. AB - Adolescent school absenteeism is associated with negative outcomes such as conduct disorders, substance abuse, and dropping out of school. Mental health factors, such as depression and anxiety, have been found to be associated with increased absenteeism from school. Sexual minority youth (youth who are attracted to the same sex or endorse a gay, lesbian, or bisexual identity) are a group at risk for increased absenteeism due to fear, avoidance, and higher rates of depression and anxiety than their heterosexual peers. The present study used longitudinal data to compare sexual minority youth and heterosexual youth on excused and unexcused absences from school and to evaluate differences in the relations between depression and anxiety symptoms and school absences among sexual minority youth and heterosexual youth. A total of 108 14- to 19-years-old adolescents (71% female and 26% sexual minority) completed self-report measures of excused and unexcused absences and depression and anxiety symptoms. Compared to heterosexual youth, sexual minority youth reported more excused and unexcused absences and more depression and anxiety symptoms. Sexual minority status significantly moderated the effects of depression and anxiety symptoms on unexcused absences such that depression and anxiety symptoms were stronger predictors of unexcused absences for sexual minority youth than for heterosexual youth. The results demonstrate that sexual minority status and mental health are important factors to consider when assessing school absenteeism and when developing interventions to prevent or reduce school absenteeism among adolescents. PMID- 24495494 TI - Assessing spelling in kindergarten: further comparison of scoring metrics and their relation to reading skills. AB - Early reading and spelling development share foundational skills, yet spelling assessment is underutilized in evaluating early reading. This study extended research comparing the degree to which methods for scoring spelling skills at the end of kindergarten were associated with reading skills measured at the same time as well as at the end of first grade. Five strategies for scoring spelling responses were compared: totaling the number of words spelled correctly, totaling the number of correct letter sounds, totaling the number of correct letter sequences, using a rubric for scoring invented spellings, and calculating the Spelling Sensitivity Score (Masterson & Apel, 2010b). Students (N=287) who were identified at kindergarten entry as at risk for reading difficulty and who had received supplemental reading intervention were administered a standardized spelling assessment in the spring of kindergarten, and measures of phonological awareness, decoding, word recognition, and reading fluency were administered concurrently and at the end of first grade. The five spelling scoring metrics were similar in their strong relations with factors summarizing reading subskills (phonological awareness, decoding, and word reading) on a concurrent basis. Furthermore, when predicting first-grade reading skills based on spring-of kindergarten performance, spelling scores from all five metrics explained unique variance over the autoregressive effects of kindergarten word identification. The practical advantages of using a brief spelling assessment for early reading evaluation and the relative tradeoffs of each scoring metric are discussed. PMID- 24495495 TI - Direct behavior rating as a school-based behavior universal screener: replication across sites. AB - The purpose of this study was to evaluate the utility of Direct Behavior Rating Single Item Scale (DBR-SIS) targets of disruptive, engaged, and respectful behavior within school-based universal screening. Participants included 31 first , 25 fourth-, and 23 seventh-grade teachers and their 1108 students, sampled from 13 schools across three geographic locations (northeast, southeast, and midwest). Each teacher rated approximately 15 of their students across three measures, including DBR-SIS, the Behavioral and Emotional Screening System (Kamphaus & Reynolds, 2007), and the Student Risk Screening Scale (Drummond, 1994). Moderate to high bivariate correlations and area under the curve statistics supported concurrent validity and diagnostic accuracy of DBR-SIS. Receiver operating characteristic curve analyses indicated that although respectful behavior cut scores recommended for screening remained constant across grade levels, cut scores varied for disruptive behavior and academic engaged behavior. Specific cut scores for first grade included 2 or less for disruptive behavior, 7 or greater for academically engaged behavior, and 9 or greater for respectful behavior. In fourth and seventh grades, cut scores changed to 1 or less for disruptive behavior and 8 or greater for academically engaged behavior, and remained the same for respectful behavior. Findings indicated that disruptive behavior was particularly appropriate for use in screening at first grade, whereas academically engaged behavior was most appropriate at both fourth and seventh grades. Each set of cut scores was associated with acceptable sensitivity (.79 .87), specificity (.71-.82), and negative predictive power (.94-.96), but low positive predictive power (.43-.44). DBR-SIS multiple gating procedures, through which students were only considered at risk overall if they exceeded cut scores on 2 or more DBR-SIS targets, were also determined acceptable in first and seventh grades, as the use of both disruptive behavior and academically engaged behavior in defining risk yielded acceptable conditional probability indices. Overall, the current findings are consistent with previous research, yielding further support for the DBR-SIS as a universal screener. Limitations, implications for practice, and directions for future research are discussed. PMID- 24495496 TI - Confirmatory factor analysis of the Early Arithmetic, Reading, and Learning Indicators (EARLI). AB - Despite growing interest in early intervention, there are few measures available to monitor the progress of early academic skills in preschoolers. The Early Arithmetic, Reading, and Learning Indicators (EARLI; DiPerna, Morgan, & Lei, 2007) were developed as brief assessments of critical early literacy and numeracy skills. The purpose of the current study was to examine the factor structure of the EARLI probes via confirmatory factor analysis (CFA) in a sample of Head Start preschoolers (N=289). A two-factor model with correlated error terms and a bifactor model provided comparable fit to the data, although there were some structural problems with the latter model. The utility of the bifactor model for explaining the structure of early academic skills as well as the utility of the EARLI probes as measures of literacy and numeracy skills in preschool are discussed. PMID- 24495497 TI - Teaching letter sounds to kindergarten English language learners using incremental rehearsal. AB - Proficiency in letter-sound correspondence is important for decoding connected text. This study examined the effects of an evidence-based intervention, incremental rehearsal (IR), on the letter-sound expression of three kindergarten English language learners (ELLs) performing below the district benchmark for letter-sound fluency. Participants were native speakers of Hmong, Spanish, and Polish. A multiple-baseline design across sets of unknown letter sounds was used to evaluate the effects of IR on letter-sound expression. Visual analysis of the data showed an increase in level and trend when IR was introduced in each phase. Percentage of all non-overlapping data (PAND) ranged from 95% to 100%. All participants exceeded expected growth and reached the spring district benchmark for letter-sound fluency. Results suggest that IR is a promising intervention for increasing letter-sound expression for ELLs who evidence delays in acquiring letter sounds. PMID- 24495498 TI - A long-kept secret in the heart. PMID- 24495499 TI - Procedures of recruiting, obtaining informed consent, and compensating research participants in Qatar: findings from a qualitative investigation. AB - BACKGROUND: Very few researchers have reported on procedures of recruiting, obtaining informed consent, and compensating participants in health research in the Arabian Gulf Region. Empirical research can inform the debate about whether to adjust these procedures for culturally diverse settings. Our objective was to delineate procedures related to recruiting, obtaining informed consent, and compensating health research participants in the extremely high-density multicultural setting of Qatar. METHODS: During a multistage mixed methods project, field observations and qualitative interviews were conducted in a general medicine clinic of a major medical center in Qatar. Participants were chosen based on gender, age, literacy, and preferred language, i.e., Arabic, English, Hindi and Urdu. Qualitative analysis identified themes about recruitment, informed consent, compensation, and other research procedures. RESULTS: A total of 153 individuals were approached and 84 enrolled; the latter showed a diverse age range (18 to 75 years); varied language representation: Arabic (n = 24), English (n = 20), Hindi (n = 20), and Urdu (n = 20); and balanced gender distribution: women (n = 43) and men (n = 41). Primary reasons for 30 declinations included concern about interview length and recording. The study achieved a 74% participation rate. Qualitative analytics revealed key themes about hesitation to participate, decisions about participation with family members as well as discussions with them as "incidental research participants", the informed consent process, privacy and gender rules of the interview environment, reactions to member checking and compensation, and motivation for participating. Vulnerability emerged as a recurring issue throughout the process among a minority of participants. CONCLUSIONS: This study from Qatar is the first to provide empirical data on recruitment, informed consent, compensation and other research procedures in a general adult population in the Middle East and Arabian Gulf. This investigation illustrates how potential research participants perceive research participation. Fundamentally, Western ethical research principles were applicable, but required flexibility and culturally informed adaptations. PMID- 24495500 TI - Predictive ability of B-type natriuretic peptide for cardiovascular events with reference to renal function. PMID- 24495501 TI - Angiographic features of ruptured sinus of Valsalva aneurysm: new classification. AB - BACKGROUND: The formal classification system for ruptured sinus of Valsalva aneurysm (RSVA) is from a surgical aspect and is seldom utilized for percutaneous closure. This study was undertaken to introduce a new classification for RSVA according to the angiographic features of patients. METHODS: We retrospectively studied 30 cases of RSVA undergoing percutaneous closure between July 2005 and September 2013. The data of patients' angiographic features, management, and outcomes were collected and analyzed. RESULTS: The patients included 18 males and 12 females with a median age of 42.5 years (range, 24-74 years). According to the shape of left to right shunt jet, patients were divided into four types: type I, window-like, 56.7% (n=17); type II, aneurysmal, 16.7% (n=5); type III, tubular, 16.7% (n=5); and type IV, other rare conditions, 10.0% (n=3). One patient in type IV had a giant RSVA and the other 2 in type IV presented with angiographic features of long and funnel shape. Total occlusion rate was 93.3% (28 out of 30 patients) at discharge and during a median follow-up of 18.5 months (1-96 months). In patients with types I and II, small-waist double-disk ventricular septal defect (VSD) occluders were selected. In patients with type III, muscular VSD occluders were chosen. We failed in 2 out of 3 patients in type IV for serious hemolysis and occluders were retrieved finally. The proportion of patients in New York Heart Association class III/IV was reduced from 73.3% at baseline to 10% at the time of last follow-up (p<0.001). CONCLUSION: According to the shape of left to right shunt jet, we propose a new and simple classification for RSVA. It could help toward the better understanding of angiographic morphology of RSVA and facilitate the selection of occluders for percutaneous closure. PMID- 24495502 TI - Author's reply: To PMID 24299986. PMID- 24495503 TI - Deterioration of the circadian variation of heart rate variability in Brugada syndrome may contribute to the pathogenesis of ventricular fibrillation. AB - AIMS: Abnormal sympathetic innervation triggers ventricular fibrillation (VF). We examined the circadian variation of autonomic nervous system and its relevance to risk stratification of VF in patients with Brugada syndrome (Brs). METHODS: We enrolled 12 male Brs patients with documented VF (Brs-S; mean age, 42+/-4 years), 17 without documented VF (Brs-N; mean age 48+/-4 years), and 16 age- and gender matched controls. The clinical data, 12-lead electrocardiography (ECG), signal averaged ECG, electrophysiological study (EPS), and heart rate variability from 24h Holter ECG were compared between the groups. RESULTS: The low frequency components (LF) in Brs-S and Brs-N and high frequency components (HF) in Brs-S patients were significantly lower than in the controls (409.8+/-128.6ms(2), 329.5+/-108ms(2) vs. 945.3+/-111.3ms(2); 135.1+/-73.8ms(2) vs. 391.8+/-63.9ms(2), respectively). The circadian variation of the LF and LF/HF decreased in the Brs patients, the standard deviation (SD) of LF/HF (<2.5) and SD of LF (<400ms(2)) had sufficiently high sensitivity (96.6%) and specificity (92.9%) for the diagnosis of Brs. Most of the Brs-S patients (83.3%) were located under the line formed by the SD/mean of HF=SD/mean of LF in the scatter plots. CONCLUSION: Lack of the circadian variation of autonomic function occurs in Brs, and this may contribute to the pathogenesis of VF. PMID- 24495504 TI - Long-term prognosis and clinical characteristics of young adults (<=40 years old) who underwent percutaneous coronary intervention. AB - BACKGROUND: Limited data exist regarding the long-term prognosis of percutaneous coronary intervention (PCI) in young adults. The aim of this study was to retrospectively assess the long-term clinical outcomes in young patients who underwent PCI. METHODS AND RESULTS: Between 1985 and 2011, 7649 consecutive patients underwent PCI, and data from 69 young adults (age <=40 years) and 4255 old adults (age ?65 years) were analyzed. A Cox proportional hazards regression analysis was used to determine the independent predictors of a composite endpoint that included all-cause death and acute coronary syndrome (ACS) during the follow up period. The mean age of the 69 young patients was 36.1+/-4.9 years, and 96% of them were men. Approximately 30% were current smokers, and their body mass index (BMI) was 26.7+/-5.0kg/m(2). The prevalence of diabetes and hypertension was 33% and 48%, respectively. All patients had >=1 conventional cardiovascular risk factor. At a median follow-up of 9.8 years, the overall death rate was 5.8%, and new-onset ACS occurred in 8.7%. Current smoking was an independent predictor of the composite endpoint (hazard ratio 4.46, confidence interval 1.08-19.1, p=0.04) for young adults. CONCLUSION: Current smoking and obesity (high BMI) are the important clinical characteristics in young Japanese coronary heart disease patients who undergo PCI. The long-term prognosis in young patients is acceptable, but current smoking is a significant independent predictor of death and the recurrence of ACS in young Japanese coronary heart disease patients who are obese. PMID- 24495505 TI - Chinese consensus statement on the evaluation and intervention of collateral circulation for ischemic stroke. AB - BACKGROUND: Collateral circulation is becoming more significant in the individual management strategy of ischemic stroke, there are more data updated recently. AIM: To make the further acknowledgment of the evaluation and how to improving collateral flow, for better treatment selection. METHOD: A panel of experts on stroke providing related statement based on review the results from most up-to date clinical research. RESULTS: DSA is the gold standard in evaluating all levels of collaterals. CTA can be used for evaluating leptomeningeal collaterals, MRA for CoW, TCD or TCCS can be used as screening tool for primary evaluation. The treatment modalities include direct interventions, such as Extracranial Intracranial bypass, and indirect interventions, as External counterpulsation and pressor therapy. The consideration of methodology to augment and improve can be considered on an individual basis. DISCUSSION: In this consensus, we interpret the definition, neuroimaging evaluation, intervention and potential strategy on collaterals in the future. CONCLUSION: Assessment of collateral circulation is crucial for selecting therapeutic options, predicting infarction volume and making prognosis after ischemic stroke. Data is still needed to provide therapeutic evidence for many new developed technologies. Until more evidence is available, the clinical significance of applying the new technologies is unclear and perhaps limited. PMID- 24495506 TI - The effect of adipose derived stromal cells on oxidative stress level, lung emphysema and white blood cells of guinea pigs model of chronic obstructive pulmonary disease. AB - BACKGROUND: Chronic obstructive pulmonary disease (COPD) is a worldwide epidemic disease and a major cause of death and disability. The present study aimed to elucidate pharmacological effects of adipose derived stromal cells (ASCs) on pathological and biochemical factors in a guinea pig model of COPD. Guinea pigs were randomized into 5 groups including: Control, COPD, COPD + intratracheal delivery of PBS as a vehicle (COPD-PBS), COPD + intratracheal delivery of ASCs (COPD-ITASC) and COPD + intravenous injection of ASCs (COPD-IVASC). COPD was induced by exposing animals to cigarette smoke for 3 months. Cell therapy was performed immediately after the end of animal exposure to cigarette smoke and 14 days after that, white blood cells, oxidative stress indices and pathological changes of the lung were measured. RESULTS: Compared with control group, emphysema was clearly observed in the COPD and COPD-PBS groups (p < 0.001). Lung histopathologic changes of COPD-ITASC and COPD-IVASC groups showed non significant improvement compared to COPD-PBS group. The COPD-ITASC group showed a significant increase in total WBC compared to COPD-PBS group but there was not a significant increase in this regard in COPD-IVASC group. The differential WBC showed no significant change in number of different types of leukocytes. The serum level of malondialdehyde (MDA) significantly decreased but thiol groups of broncho-alveolar lavage fluid (BALF) increased in both cell treated groups (p < 0.05 for all cases). Weight of animals decreased during smoke exposure and improved after PBS or cell therapy. However, no significant change was observed between the groups receiving PBS and the ones receiving ASCs. CONCLUSION: Cell therapy with ASCs can help in reducing oxidative damage during smoking which may collectively hold promise in attenuation of the severity of COPD although the lung structural changes couldn't be ameliorated with these pharmacological therapeutic methods. PMID- 24495507 TI - Acute and long term mineral metabolism adaptation in living kidney donors: a prospective study. AB - BACKGROUND: Living kidney donors (LKDs) experience an abrupt decline in glomerular filtration rate (GFR). Mineral metabolism adaptations in early CKD are still debated and not well studied in LKDs. We prospectively studied acute and long term mineral metabolism adaptation of LKDs. METHODS: From May 2010 to December 2012, we included 27 adult LKDs. Their mineral parameters and renal function were repeatedly measured at days 0, 1, 2, 3, 180 and 360 after donation. We also measured in uninephrectomized rats' Klotho in the remnant kidney and FGF23 circulating levels. RESULTS: In the first days after nephrectomy, LKDs experience transient dilution hypocalcemia and secondary hyperparathyroidism. Urinary phosphate reabsorption decreases in spite of an abrupt decline in circulating FGF23 and Klotho. In a more chronic stage, at days 180 and 360 after donation, LKDs have lower GFR and 1,25(OH)2D compared to pre-donation levels, with unchanged 25(OH)D. PTH levels increase, resulting in decreased plasma phosphate levels and renal tubular reabsorption of phosphate. In comparison to pre-donation, FGF23 levels are not significantly changed whereas circulating Klotho levels are lower than pre-donation but higher than immediately post donation. In uninephrectomized rats, Klotho kidney expression increases after three weeks, whereas circulating FGF23 levels are unchanged. CONCLUSION: From six months after kidney donation, LKDs develop secondary hyperparathyroidism related to a decrease in 1,25(OH)2D, and decreased plasma phosphate levels. FGF23 levels do not rise in LKDs. Middle term mineral metabolism adaptations to decreased eGFR in donors include decrease in 1,25(OH)2D and increase in PTH and fractional excretion of phosphate resulting in lowered plasma phosphate levels, independently of FGF23. These adaptations differ from those described in CKD patients. PMID- 24495508 TI - Looking at the evidence. PMID- 24495509 TI - Peritumoral ductular reaction: a poor postoperative prognostic factor for hepatocellular carcinoma. AB - BACKGROUND: The role of ductular reaction (DR) in hepatocellular carcinoma (HCC) remains to be elucidated. METHODS: In this study, we tried to uncover possible effect by correlating peritumoral DR in a necroinflammatory microenvironment with postoperative prognosis in HCC. The expression of peritumoral DR/CK19 by immunohistochemistry, necroinflammation and fibrosis were assessed from 106 patients receiving curative resection for HCC. Prognostic values for these and other clinicopathologic factors were evaluated. RESULTS: Peritumoral DR significantly correlated with necroinflammation (r = 0.563, p = 3.4E-10), fibrosis (r = 0.435, p = 3.1E-06), AFP level (p = 0.010), HBsAg (p = 4.9E-4), BCLC stage (p = 0.003), TNM stage (p = 0.002), multiple nodules (p = 0.004), absence of tumor capsule (p = 0.027), severe microscopic vascular invasion (p = 0.031) and early recurrence (p = 0.010). Increased DR was significantly associated with decreased RFS/OS (p = 4.8E-04 and p = 2.6E-05, respectively) in univariate analysis and were identified as an independent prognostic factor (HR = 2.380, 95% CI = 1.250-4.534, p = 0.008 for RFS; HR = 4.294, 95% CI = 2.255-8.177, p = 9.3E-6 for OS) in multivariate analysis. CONCLUSIONS: These results suggested that peritumoral DR in a necroinflammatory microenvironment was a poor prognostic factor for HCC after resection. PMID- 24495510 TI - Survivin but not Fms-like tyrosine kinase 3 ligand is up-regulated before the onset of rheumatoid arthritis: a pilot study. AB - INTRODUCTION: Antibodies against citrullinated peptides (anti-CCP) and increased levels of cytokines precede the development of rheumatoid arthritis (RA) by several years. Recently, the proteins survivin and Fms-like tyrosine kinase 3 ligand (Flt3L) have been identified as biomarkers of RA associated with joint destruction. Our objective was to investigate the potential of survivin and Flt3L as predictors of RA in samples from patients prior to onset of symptoms. METHODS: This study included 47 individuals sampled before onset of RA (median 2.5 years (IQR 4.5) and 155 matched controls, all were donors to the Medical Biobank of Northern Sweden, and 36 RA patients. Levels of anti-CCP, survivin and Flt3L were measured using ELISAs and 29 cytokines/chemokines by multiplex detection. RESULTS: Levels of survivin were increased in pre-symptomatic individuals compared with controls (P = 0.003), whilst the levels of Flt3L were similar. The frequency of survivin positivity in the pre-symptomatic individuals was increased compared with the controls (36.2 vs.14.2%, P = 0.001) and predicted disease development (odds ratio (OR) =3.4 (95% confidence interval (CI) 1.6-7.2)). The frequency of survivin and Flt3L in RA patients was increased compared with the controls (both, P <0.0001, OR = 12.1 (95% CI, 5.3-27.6) and OR = 11.0 (95% CI, 3.9-30.9), respectively). Anti-CCP positive pre-symptomatic individuals and patients had significantly higher levels of survivin compared with anti-CCP2 negative individuals. In pre-symptomatic individuals, survivin correlated with IL 12, IL-1beta and IL-9 whereas Flt3L correlated to a significantly broader spectrum of cytokines in RA patients. CONCLUSION: Proto-oncogene survivin was increased in individuals prior to onset of symptoms of RA and was correlated to cytokines suggesting its role at pre-clinical stages of the disease. PMID- 24495511 TI - Incidence rates and disease course of paediatric inflammatory bowel diseases in Western Hungary between 1977 and 2011. AB - BACKGROUND: Limited data are available on paediatric inflammatory bowel diseases in Eastern Europe. Our aim was to analyse disease characteristics in the population-based Veszprem province database between 1977 and 2011. METHODS: 187 (10.5%, ulcerative colitis/Crohn's disease/undetermined colitis: 88/95/4) out of 1565 incident patients were diagnosed with a paediatric onset in this population based prospective inception cohort. RESULTS: The incidence of Crohn's disease and ulcerative colitis increased from 0 and 0.7 in 1977-1981 to 7.2 and 5.2 in 2007 2011 per 100,000 person years. Ileocolonic location (45%) and inflammatory disease behaviour (61%) were most frequent in Crohn's disease, while azathioprine use was frequent (66%) and surgical resection rates were high (33% at 5 years) in cases with paediatric onset. In ulcerative colitis, 34% of patients were diagnosed with extensive disease, with high rates of disease extension (26% and 41% at 5 and 10 years), fulminant episodes (19.3%) and systemic steroid use (52.3%). The cumulative rate of colectomy was low (6.9%). CONCLUSIONS: The incidence of paediatric inflammatory bowel diseases has rapidly increased in the last three decades in Western Hungary. Ileocolonic disease and a need for azathioprine were characteristic in paediatric Crohn's disease, while paediatric onset ulcerative colitis was characterised by extensive disease and disease extension, while the need for colectomy was low. PMID- 24495512 TI - Bacterial growth: global effects on gene expression, growth feedback and proteome partition. AB - The function of endogenous as well as synthetic genetic circuits is generically coupled to the physiological state of the cell. For exponentially growing bacteria, a key characteristic of the state of the cell is the growth rate and thus gene expression is often growth-rate dependent. Here we review recent results on growth-rate dependent gene expression. We distinguish different types of growth-rate dependencies by the mechanisms of regulation involved and the presence or absence of an effect of the gene product on growth. The latter can lead to growth feedback, feedback mediated by changes of the global state of the cell. Moreover, we discuss how growth rate dependence can be used as a guide to study the molecular implementation of physiological regulation. PMID- 24495513 TI - Histoplasma capsulatum and Pneumocystis spp. co-infection in wild bats from Argentina, French Guyana, and Mexico. AB - BACKGROUND: Histoplasma capsulatum and Pneumocystis organisms cause host infections primarily affecting the lung tissue. H. capsulatum is endemic in the United States of America and Latin American countries. In special environments, H. capsulatum is commonly associated with bat and bird droppings. Pneumocystis host specificity has been primarily studied in laboratory animals, and its ability to be harboured by wild animals remains as an important issue for understanding the spread of this pathogen in nature. Bats infected with H. capsulatum or Pneumocystis spp. have been found, with this mammal serving as a probable reservoir and disperser; however, the co-infection of bats with both of these microorganisms has never been explored. To evaluate the impact of H. capsulatum and Pneumocystis spp. infections in this flying mammal, 21 bat lungs from Argentina (AR), 13 from French Guyana (FG), and 88 from Mexico (MX) were screened using nested-PCR of the fragments, employing the Hcp100 locus for H. capsulatum and the mtLSUrRNA and mtSSUrRNA loci for Pneumocystis organisms. RESULTS: Of the 122 bats studied, 98 revealed H. capsulatum infections in which 55 of these bats exhibited this infection alone. In addition, 51 bats revealed Pneumocystis spp. infection of which eight bats exhibited a Pneumocystis infection alone. A total of 43 bats (eight from AR, one from FG, and 34 from MX) were found co-infected with both fungi, representing a co-infection rate of 35.2% (95% CI = 26.8-43.6%). CONCLUSION: The data highlights the H. capsulatum and Pneumocystis spp.co-infection in bat population's suggesting interplay with this wild host. PMID- 24495514 TI - Pilot trial of Stop Delirium! (PiTStop)--a complex intervention to prevent delirium in care homes for older people: study protocol for a cluster randomised controlled trial. AB - BACKGROUND: Delirium (or acute confusion) is a serious illness common in older people, in which a person's thinking and perceptions may be affected. Reducing delirium is important because of the considerable distress it causes, and the poor outcomes associated with it, such as increased admissions to hospital, falls, mortality and costs to the National Health Service (NHS). Preventing delirium is possible using multicomponent interventions; successful interventions in hospitals have reduced it by one-third. However, there is little research to guide practice in care homes, where it is common because of the clustering of known risk factors (older age, frailty, and dementia). In previous work we developed a multicomponent intervention to prevent delirium in care homes, called Stop Delirium! The intervention was based upon evidence from the research literature relating to the prevention of delirium and on strategies to change professional practice. Before starting a large costly trial of Stop Delirium!, this pilot study will test and help improve the design and feasibility of the trial protocol. METHODS/DESIGN: We plan to conduct a cluster randomised pilot trial in 14 care homes (independent residential and nursing). Following recruitment of residents (over 60 years, consenting or with consultee agreement, able to communicate in English, and not in palliative care) participating homes will be randomised, stratified by size of home and proportion of residents with dementia. Stop Delirium! will be delivered to intervention homes over 16 months, with controls receiving usual care. The primary outcome measure will be the presence of delirium on any day during a one-month post-intervention period.We will collect data to determine 1) recruitment and attrition rates, 2) feasibility of various outcomes measurements, and 3) feasibility of capturing health resource use (resident diaries and by examining health records). We will estimate the between-cluster variation for the primary outcome, delirium occurrence. DISCUSSION: This pilot study will refine methods for the definitive trial. The lessons learnt will also contribute to implementing National Institute for Health and Clinical Excellence (NICE) delirium guidelines, which recommend multicomponent interventions for delirium prevention. TRIAL REGISTRATION: ISRCTN27972532. PMID- 24495515 TI - Evaluating the implementation of HeLP-Diabetes within NHS services: study protocol. AB - BACKGROUND: Self-management by people with type 2 diabetes is central to good health outcomes and the prevention of associated complications. Structured education to teach self-management is recommended by the National Institute for Heath and Clinical Excellence; however, only a small proportion of patients report being offered this education and even fewer attend. This study aims to evaluate the implementation of a new internet-based self-management intervention: HeLP-Diabetes (Healthy Living for People with type 2 Diabetes) within the National Health Service. Specific objectives are to a) determine the uptake and use of HeLP-Diabetes by services and patients; b) identify the factors which inhibit or facilitate use; c) identify the resources needed for effective implementation; d) explore possible effects of HeLP-Diabetes use on self-reported patient outcome measures. METHODS/DESIGN: This study will use an iterative design to implement HeLP-Diabetes into existing health services within the National Health Service. A two stage implementation process will be taken, whereby batches of General Practice surgeries and diabetes clinics will be offered HeLP-Diabetes and will subsequently be asked to participate in evaluating the implementation. We will collect data to describe the number of services and patients who sign up to HeLP-Diabetes, the types of services and patients who sign up and the implementation costs. Semi-structured interviews will be conducted with patients and health professionals and cohorts of patient participants will be asked to complete self-report measures at baseline, 3 months, and 12 months. DISCUSSION: This study will evaluate the implementation of a new online self-management intervention and describe what happens when it is made available to existing National Health Services and patients with type 2 diabetes. We will collect data to describe the uptake and use of the intervention and the resources needed for widespread implementation. We will report on patient benefits from using HeLP Diabetes and the resources needed to achieve these in routine practice. Interviews with key stake holders will identify, define and explain factors that promote or inhibit the normalization of new patterns of patient and professional activity arising from HeLP-Diabetes. PMID- 24495516 TI - MicroRNA-362 induces cell proliferation and apoptosis resistance in gastric cancer by activation of NF-kappaB signaling. AB - BACKGROUND: According to cancer-related microRNA (miRNA) expression microarray research available in public databases, miR-362 expression is elevated in gastric cancer. However, the expression and biological role of miR-362 in gastric progression remain unclear. METHODS: miR-362 expression levels in gastric cancer tissues and cell lines were determined using real-time PCR. The roles of miR-362, in promoting gastric cancer cell proliferation and apoptosis resistance, were assessed by different biological assays, such as colony assay, flow cytometry and TUNEL assay. The effect of miR-362 on NF-kappaB activation was investigated using the luciferase reporter assay, fluorescent immunostaining. RESULTS: MiR-362 overexpression induced cell proliferation, colony formation, and resistance to cisplatin-induced apoptosis in BGC-823 and SGC-7901 gastric cancer cells. MiR-362 increased NF-kappaB activity and relative mRNA expression of NF-kappaB-regulated genes, and induced nuclear translocation of p65. Expression of the tumor suppressor CYLD was inhibited by miR-362 in gastric cancer cells; miR-362 levels were inversely correlated with CYLD expression in gastric cancer tissue. MiR-362 downregulated CYLD expression by binding its 3' untranslated region. NF-kappaB activation was mechanistically associated with siRNA-mediated downregulation of CYLD. MiR-362 inhibitor reversed all the effects of miR-362. CONCLUSION: The results suggest that miR-362 plays an important role in repressing the tumor suppressor CYLD and present a novel mechanism of miRNA-mediated NF-kappaB activation in gastric cancer. PMID- 24495518 TI - S-adenosylmethionine inhibits the activated phenotype of human hepatic stellate cells via Rac1 and matrix metalloproteinases. AB - OBJECTIVE: To investigate the effects of S-adenosylmethionine (SAM) on the proliferation, adhesion, migration, invasion and apoptosis of activated human hepatic stellate cells (HSCs) and to explore the relevant potential mechanisms. METHODS: Human HSCs LX-2 were cultured with SAM. The proliferation and adhesion were detected by CCK-8. Cell apoptosis rate were analyzed by flow cytometry, and cell migration and invasion were tested by the transwell assay. The expression of Rac1 and MMP-2 was identified by real-time PCR or Western blotting, and activated Rac1 was detected by GST pull-down assay. The activity of MMP-2 and MMP-9 was analyzed by substrate zymography. RESULTS: The proliferation of LX-2 cells was inhibited by SAM, exhibiting a dose-dependent manner. Cell apoptosis rate induced by SAM was remarkably increased. SAM decreased the adhesion, migration and invasion of LX-2 cells. The expression and activation of Rac1 in LX-2 cells were significantly suppressed by SAM. In contrast, the activity of MMP-2 and MMP-9 was enhanced by SAM. SAM attenuated the up-regulated expression of Smad3/4 and Rac1 induced by TGF-beta1. CONCLUSION: SAM inhibits the proliferation, adhesion, migration and invasion of LX-2 cells in vitro probably via attenuating the expression and activation of Rac1 and up-regulating MMP-2 and MMP-9 expression, which possibly provide a molecular basis for potential application of SAM in the therapy of liver fibrosis. PMID- 24495517 TI - BioHackathon series in 2011 and 2012: penetration of ontology and linked data in life science domains. AB - The application of semantic technologies to the integration of biological data and the interoperability of bioinformatics analysis and visualization tools has been the common theme of a series of annual BioHackathons hosted in Japan for the past five years. Here we provide a review of the activities and outcomes from the BioHackathons held in 2011 in Kyoto and 2012 in Toyama. In order to efficiently implement semantic technologies in the life sciences, participants formed various sub-groups and worked on the following topics: Resource Description Framework (RDF) models for specific domains, text mining of the literature, ontology development, essential metadata for biological databases, platforms to enable efficient Semantic Web technology development and interoperability, and the development of applications for Semantic Web data. In this review, we briefly introduce the themes covered by these sub-groups. The observations made, conclusions drawn, and software development projects that emerged from these activities are discussed. PMID- 24495520 TI - Pulmonary embolism and Takotsubo syndrome in tandem: an interplay of pathologies needing our vigilance. PMID- 24495519 TI - Effect of a multi-level intervention on nurse-patient communication in the intensive care unit: results of the SPEACS trial. AB - OBJECTIVE: To test the impact of two levels of intervention on communication frequency, quality, success, and ease between nurses and intubated intensive care unit (ICU) patients. DESIGN: Quasi-experimental, 3-phase sequential cohort study: (1) usual care, (2) basic communication skills training (BCST) for nurses, (3) additional training in augmentative and alternative communication devices and speech language pathologist consultation (AAC + SLP). Trained observers rated four 3-min video-recordings for each nurse-patient dyad for communication frequency, quality and success. Patients self-rated communication ease. SETTING: Two ICUs in a university-affiliated medical center. PARTICIPANTS: 89 intubated patients awake, responsive and unable to speak and 30 ICU nurses. MAIN RESULTS: Communication frequency (mean number of communication acts within a communication exchange) and positive nurse communication behaviors increased significantly in one ICU only. Percentage of successful communication exchanges about pain were greater for the two intervention groups than the usual care/control group across both ICUs (p = .03) with more successful sessions about pain and other symptoms in the AAC + SLP group (p = .07). Patients in the AAC + SLP intervention group used significantly more AAC methods (p = .002) and rated communication at high difficulty less often (p < .01). CONCLUSIONS: This study provides support for the feasibility, utility and efficacy of a multi-level communication skills training, materials and SLP consultation intervention in the ICU. PMID- 24495521 TI - Psychometric evaluation of the Perceived Barriers to Health Care-seeking Decision in Chinese patients with acute coronary syndromes. AB - OBJECTIVES: This study aimed to develop the Chinese version of the Perceived Barriers to Health Care-seeking Decision (PBHSD-C) and evaluate its psychometric properties in Chinese patients with acute coronary syndromes (ACS). BACKGROUND: The assessment of the level of perceived barriers in the care-seeking trajectory of ACS patients is important for the understanding of its impact on pre-hospital delay in seeking care. METHODS: The psychometric properties of PBHSD-C were evaluated among 114 ACS patients in the cardiac unit of two major hospitals in Hong Kong. RESULTS: The Content Validity Indexes were ranged from .88 to 1. The Cronbach's alpha of the PBHSD-C was .74. The intraclass correlation coefficients of all items were above .80. The convergent validity of the PBHSD-C was also supported. CONCLUSION: The PBHSD-C is reliable and valid to be used to assess the level of perceived barriers in the care-seeking of Chinese patients with ACS. PMID- 24495522 TI - Improving the physical activity and nutrition environment through self-assessment (NAP SACC) in rural area child care centers in North Carolina. AB - OBJECTIVE: To determine if child care centers in rural, Western North Carolina met recommendations for nutrition and physical activity, if focusing on nutrition and physical activity practices and policies was effective in improving the center environment, and if differences existed between centers affiliated or unaffiliated with schools. METHODS: Of 33 child care centers in three counties, 29 submitted mini-grant requests and participated in a pre-post evaluation using Nutrition and Physical Activity Self-Assessment for Child Care (NAP SACC). NAP SACC assesses compliance for nutrition and physical activity recommendations and standards. Between October 2011 and April 2012, centers participated in workshops and goal setting specific to nutrition and physical activity. RESULTS: At baseline, over 95% of the centers met all recommendations. However, post intervention, Wilcoxon Signed Ranks Test (p<0.05) indicated significant improvement across center types in five out of 37 nutrition and seven out of 17 physical activity standards following the intervention. Centers unaffiliated with schools made significant changes in ten nutrition standards, while those affiliated with schools improved in only two standards and decreased on one standard. CONCLUSION: Overall, rural child care centers in Western North Carolina were meeting standards, they were still able to strengthen policies and practices by following NAP SACC. This was especially true for centers unaffiliated with schools. Continued financial support may assist centers in sustaining increased physical activity in children. PMID- 24495523 TI - Pulmonary manifestation as initial presentation for systemic lupus erythematosus. AB - We report a 29-year-old Malay man who had pulmonary manifestations as an initial presentation for systemic lupus erythematosus. He had prolonged hospitalization and was treated with intensive care therapy with immunosuppressants. PMID- 24495524 TI - Precise and low-cost monitoring of plum curculio (Coleoptera: Curculionidae) pest activity in pyramid traps with cameras. AB - Incorporating camera systems into insect traps potentially benefits insect phenology modeling, nonlethal insect monitoring, and research into the automated identification of traps counts. Cameras originally for monitoring mammals were instead adapted to monitor the entrance to pyramid traps designed to capture the plum curculio, Conotrachelus nenuphar (Herbst) (Coleoptera: Curculionidae). Using released curculios, two new trap designs (v.I and v.II) were field-tested alongside conventional pyramid traps at one site in autumn 2010 and at four sites in autumn 2012. The traps were evaluated on the basis of battery power, ease-of maintenance, adaptability, required-user-skills, cost (including labor), and accuracy-of-results. The v.II design fully surpassed expectations, except that some trapped curculios were not photographed. In 2012, 13 of the 24 traps recorded every curculio entering the traps during the 18-d study period, and in traps where some curculios were not photographed, over 90% of the omissions could be explained by component failure or external interference with the motion sensor. Significantly more curculios entered the camera traps between 1800 and 0000 hours. When compared with conventional pyramid traps, the v.I traps collected a similar number of curculios. Two observed but not significant trends were that the v.I traps collected twice as many plum curculios as the v.II traps, while at the same time the v.II traps collected more than twice as many photos per plum curculio as the v.I traps. The research demonstrates that low-cost, precise monitoring of field insect populations is feasible without requiring extensive technical expertise. PMID- 24495525 TI - Positioning of term infants during delivery room routine handling - analysis of videos. AB - BACKGROUND: Delivery room management (DR) of the newly born infant should be performed according to international guidelines, but no recommendations are available for an infant's position immediately after birth. The present study was performed to answer the following questions: 1. How often is DR-management performed in term infants in side position? 2. Is routine DR-management possible in side position? 3. Is there any benefit of side position with respect to agitation or vital parameters? METHODS: Cross-sectional study of video-recorded DR-management in term newborns delivered by C-section in 2012. Videos were analysed for infant's position, administered interventions, vital parameters and agitation. RESULTS: 187 videos were analysed. The Main Position (defined as position spent more than 70% of the time) was "supine" in 91, "side" in 63 and "not determinable" in 33 infants. "Supine" infants received significantly (p < 0.001) more often stimulation (12.5% of the total time) than "side" infants (3.9% of time). There were no differences between both groups with regard to suctioning; CPAP was exclusively (98%) administered in supine position. Newborns on side were less agitated than those on supine. There was a trend towards a better oxygenation in "side" positioned infants (p = 0.055) and significantly (p = 0.04) higher saturation values in "left-sided" infants than "right-sided" infants at 8th minute. "Side" positioned infants reached oxygen saturation values >90% earlier than "supine" positioned infants (p = 0.16). CONCLUSIONS: DR management is feasible in the side position in term infants. Side position seems to be associated with reduced agitation and improved oxygenation. However, it remains unclear whether this represents a causal relationship or an association. The study supports the need for a randomized controlled trial. PMID- 24495526 TI - Losing touch with opioids: New insights into a chemokine signaling cascade controlling morphine analgesia. PMID- 24495527 TI - 'The way to a man's heart is through his gut microbiota'--dietary pro- and prebiotics for the management of cardiovascular risk. AB - The human gut microbiota has been identified as a possible novel CVD risk factor. This review aims to summarise recent insights connecting human gut microbiome activities with CVD and how such activities may be modulated by diet. Aberrant gut microbiota profiles have been associated with obesity, type 1 and type 2 diabetes and non-alcoholic fatty liver disease. Transfer of microbiota from obese animals induces metabolic disease and obesity in germ-free animals. Conversely, transfer of pathogen-free microbiota from lean healthy human donors to patients with metabolic disease can increase insulin sensitivity. Not only are aberrant microbiota profiles associated with metabolic disease, but the flux of metabolites derived from gut microbial metabolism of choline, phosphatidylcholine and l-carnitine has been shown to contribute directly to CVD pathology, providing one explanation for increased disease risk of eating too much red meat. Diet, especially high intake of fermentable fibres and plant polyphenols, appears to regulate microbial activities within the gut, supporting regulatory guidelines encouraging increased consumption of whole-plant foods (fruit, vegetables and whole-grain cereals), and providing the scientific rationale for the design of efficacious prebiotics. Similarly, recent human studies with carefully selected probiotic strains show that ingestion of viable microorganisms with the ability to hydrolyse bile salts can lower blood cholesterol, a recognised risk factor in CVD. Taken together such observations raise the intriguing possibility that gut microbiome modulation by whole-plant foods, probiotics and prebiotics may be at the base of healthy eating pyramids advised by regulatory agencies across the globe. In conclusion, dietary strategies which modulate the gut microbiota or their metabolic activities are emerging as efficacious tools for reducing CVD risk and indicate that indeed, the way to a healthy heart may be through a healthy gut microbiota. PMID- 24495528 TI - Timing of pubertal stages and breast cancer risk: the Breakthrough Generations Study. AB - INTRODUCTION: Breast development and hormonal changes at puberty might affect breast cancer risk, but epidemiological analyses have focussed largely on age at menarche and not at other pubertal stages. METHODS: We investigated associations between the timing of pubertal stages and breast cancer risk using data from a cohort study of 104,931 women (Breakthrough Generations Study, UK, 2003-2013). Pubertal variables were reported retrospectively at baseline. Breast cancer risk was analysed using Cox regression models with breast cancer diagnosis as the outcome of interest, attained age as the underlying time variable, and adjustment for potentially confounding variables. RESULTS: During follow-up (mean = 4.1 years), 1094 breast cancers (including ductal carcinoma in situ) occurred. An increased breast cancer risk was associated with earlier thelarche (age when breast growth begins; HR [95% CI] = 1.23 [1.02, 1.48], 1 [referent] and 0.80 [0.69, 0.93] for <=10, 11-12 and >=13 years respectively), menarche (initiation of menses; 1.06 [0.93, 1.21], 1 [referent] and 0.78 [0.62, 0.99] for <=12, 13-14 and >=15 years), regular periods (0.99 [0.83, 1.18], 1 [referent] and 0.74 [0.59, 0.92] for <=12, 13-14 and >=15 years) and age reached adult height (1.25 [1.03, 1.52], 1 [referent] and 1.07 [0.87, 1.32] for <=14, 15-16 and >=17 years), and with increased time between thelarche and menarche (0.87 [0.65, 1.15], 1 [referent], 1.14 [0.96, 1.34] and 1.27 [1.04, 1.55] for <0, 0, 1 and >=2 years), and shorter time between menarche and regular periods (1 [referent], 0.87 [0.73, 1.04] and 0.66 [0.50, 0.88] for 0, 1 and >=2 years). These associations were generally similar when considered separately for premenopausal and postmenopausal breast cancer. CONCLUSIONS: Breast duct development may be a time of heightened susceptibility to risk of carcinogenesis, and greater attention needs to be given to the relation of breast cancer risk to the different stages of puberty. PMID- 24495530 TI - Incomplete flexible sigmoidoscopy insertion after cesarean section. PMID- 24495529 TI - Feasibility of using the predisposition, insult/infection, physiological response, and organ dysfunction concept of sepsis to predict the risk of deterioration and unplanned intensive care unit transfer after emergency department admission. AB - BACKGROUND: Recognizing patients at risk for deterioration and in need of critical care after emergency department (ED) admission may prevent unplanned intensive care unit (ICU) transfers and decrease the number of deaths in the hospital. The objective of this research was to study if the predisposition, insult, response, and organ dysfunction (PIRO) concept of sepsis can be used to predict the risk of unplanned ICU transfer after ED admission. METHODS: The ICU transfer group included 313 patients with unplanned transfer to the ICU within 48 hours of ED admission, and the control (non-transfer) group included 736 randomly sampled patients who were not transferred to the ICU. Two-thirds of the total 1049 patients in this study were randomly assigned to a derivation group, which was used to develop the PIRO model, and the remaining patients were assigned to a validation group. RESULTS: Independent predictors of deterioration within 48 hours after ED admission were identified by the PIRO concept. PIRO scores were higher in the ICU transfer group than in the non-transfer group, both in the derivation group [median (mean +/- SD), 5 (5.7 +/- 3.7) vs. 2 (2.5 +/- 2.5); p < 0.001], and in the validation group [median (mean +/- SD), 6 (6.0 +/- 3.4) vs. 2 (2.4 +/- 2.6); p < 0.001]. The proportion of ICU transfer patients with a PIRO score of 0-3, 4-6, 7-9, and >=10 was 14.1%, 46.5%, 57.3%, and 83.8% in the derivation group (p < 0.001) and 12.8%, 37.3%, 68.2%, and 70.0% in the validation group (p < 0.001), respectively. The proportion of inpatient mortality in patients with a PIRO score of 0-3, 4-6, 7-9, and >=10 was 2.6%, 10.1%, 23.2%, and 45.9% in the derivation group (p < 0.001) and 3.3%, 12.0%, 18.2%, and 20.5% in the validation group (p < 0.001), respectively. CONCLUSION: The PIRO concept of sepsis may be used in undifferentiated medical ED patients as a prediction system for unplanned ICU transfer after admission. PMID- 24495531 TI - Acute scrotal pain: an uncommon manifestation of renal vein thrombosis. AB - The clinical manifestation of renal vein thrombosis varies with the speed and degree of venous occlusion. Such patients may be asymptomatic, have minor nonspecific symptoms such as nausea or weakness, or have more specific symptoms such as upper abdominal pain, flank pain, or hematuria. Acute scrotal pain is a very uncommon clinical expression of renal vein thrombosis. Here, we report a case of membranous glomerulonephritis-induced renal vein thrombosis presented with the symptom of acute scrotal pain caused by thrombosis-induced varicocele. This case report suggests that renal vein thrombosis should be considered in the diagnosis of acute scrotal pain; it also emphasizes that an investigation of retroperitoneum should be performed for adult patients with the sudden onset of varicocele. PMID- 24495533 TI - Trends in the types and quality of childhood immunisations research output from Africa 1970-2010: mapping the evidence base. AB - BACKGROUND: Over the past four decades, extraordinary progress has been made in establishing and improving childhood immunization programmes around Africa. In order to ensure effective and sustainable positive growth of these childhood immunisations programmes, the development, adaptation and implementation of all interventions (programme activities, new vaccines, new strategies and policies) should be informed by the best available local evidence. METHODS: An assessment of the peer-reviewed literature on childhood immunization research published in English from 1970 to 2010 was conducted in PubMed and Africa-Wide databases. All study types were eligible for inclusion. A standard form was used to extract information from all studies identified as relevant and entered into a Microsoft Access database for analysis. RESULTS: Our initial search yielded 5436 articles from the two databases, from which 848 full text articles were identified as relevant. Among studies classified as clinical research (417), 40% were clinical trials, 24% were burden of disease/epidemiology and 36% were other clinical studies. Among studies classified as operational research (431), 77% related to programme management, 18% were policy related and 5% were related to vaccine financing. Studies were conducted in 48 African countries with six countries (South Africa, The Gambia, Nigeria, Senegal, Guinea-Bissau and Kenya) accounting for 56% of the total research output. Studies were published in 152 different journals with impact factors ranging from 0.192 to 53.29; with a median impact factor of 3.572. CONCLUSION: A similar proportion of clinical versus operational research output was found. However, an uneven distribution across Africa was observed with only six countries accounting for over half of the research output. The research conducted was of moderate to high quality, with 62% being published in journals with 2010 impact factors greater than two. Urgent attention should be given to the development of research capacity in low performing countries around Africa, with increased focus on the process of turning immunisations programme research evidence into policy and practice, as well as increased focus on issues relating to vaccine financing and sustainability in Africa. PMID- 24495534 TI - Prevalence and characteristics of Salmonella in the beef chain in the Republic of Ireland. AB - The study investigated the prevalence, concentration and characteristics of Salmonella spp. in the Irish beef chain. A total of 900 samples including bovine hides, carcasses and ground beef were examined for the pathogen over a 2-year study (July 2007-June 2009). Salmonella prevalence was low in all sample types; bovine hide (0.75%, 3 of 400); carcasses (0.25%, 1 of 400); and ground beef (3%, 3 of 100). All positive samples contained the pathogen in low concentrations (<10 CFU per cm(2) or per g). Serovars recovered were S. Dublin from hide and carcasses and S. Braenderup in ground beef. All isolates were susceptible to 13 anti-microbials. The study highlights that Salmonella can be found at low levels at all stages of beef chain production, processing and retail and that there is a need for multiple hurdle interventions and practices along the beef chain, which will reduce consumer exposure to this pathogen. PMID- 24495532 TI - Pharmaco-MEG evidence for attention related hyper-connectivity between auditory and prefrontal cortices in ADHD. AB - The ability to attend to particular stimuli while ignoring others is crucial in goal-directed activities and has been linked with prefrontal cortical regions, including the dorsolateral prefrontal cortex (DLPFC). Both hyper- and hypo activation in the DLPFC has been reported in patients with attention deficit/hyperactivity disorder (ADHD) during many different cognitive tasks, but the network-level effects of such aberrant activity remain largely unknown. Using magnetoencephalography (MEG), we examined functional connectivity between regions of the DLPFC and the modality-specific auditory cortices during an auditory attention task in medicated and un-medicated adults with ADHD, and those without ADHD. Participants completed an attention task in two separate sessions (medicated/un-medicated), and each session consisted of two blocks (attend and no attend). All MEG data were coregistered to structural MRI, corrected for head motion, and projected into source space. Subsequently, we computed the phase coherence (i.e., functional connectivity) between DLPFC regions and the auditory cortices. We found that un-medicated adults with ADHD exhibited greater phase coherence in the beta (14-30Hz) and gamma frequency (30-56Hz) range in attend and no-attend conditions compared to controls. Stimulant medication attenuated these differences, but did not fully eliminate them. These results suggest that aberrant bottom-up processing may engulf executive resources in ADHD. PMID- 24495536 TI - Remarkable solvent and extractable lignin effects on enzymatic digestibility of organosolv pretreated hardwood. AB - Low solvent concentration effect on substrate digestibility of ethanol organosolv pretreated sweetgum was examined. Surprisingly, lower ethanol concentration in organosolv pretreatments resulted in faster initial rates and higher 72h hydrolysis yields in pretreated substrates. A strong correlation (r(2)=0.96) between pretreatment combined severity factor and residual xylan/glucan ratio was observed. The residual xylan/glucan ratio was associated with the initial hydrolysis rate closely. Furthermore, it was found that preserving extractable lignin in the pretreated substrates could improve enzymatic hydrolysis yield by 33%. This has an important implication in reducing the pretreatment and enzyme cost, because the typical solvent washing after pretreatment could be eliminated and preserving extractable lignin could reduce enzyme loading. Finally, we observed that xylan removal by xylanase could improve the initial rate by 53% and increase the 72h hydrolysis yield by 21%. The extractable lignin precipitation on pretreated substrates increased the 72h hydrolysis yield by 10%. PMID- 24495535 TI - Impact of methodology on estrogens' effects on cerebral ischemia in rats: an updated meta-analysis. AB - BACKGROUND: Although most animal stroke studies have demonstrated potent neuroprotective effects of estrogens, there are a number of articles reporting the opposite. In 2009, we made the case that this dichotomy was related to administered estrogen dose. Several other suggestions for the discordant results have also been propagated, including the age of the experimental animals and the length of hypoestrogenicity prior to estrogen administration. These two suggestions have gained much popularity, probably because of their kinship with the window of opportunity hypothesis, which is commonly used to explain the analogous dichotomy among human studies. We were therefore encouraged to perform an updated meta-analysis, and to improve it by including all relevant variables in a large multiple regression model, where the impact of confounders could be controlled for. RESULTS: The multiple regression model revealed an indisputable impact of estrogen administration mode on the effects of estrogens in ischemic stroke. Subcutaneous slow-release pellets differed from the injection and silastic capsule treatments in terms of impact of estrogens on ischemic stroke, showing that the first mentioned were more prone to render estrogens damaging. Neither the use of elderly animals nor the adoption of longer wash-out periods influenced estrogens' effects on experimental ischemic stroke in rats. CONCLUSIONS: We conclude that the discordant results regarding estrogens' effects in rat models of ischemic stroke are a consequence of differences in estrogen administration modes. These results are not only of importance for the ongoing debate regarding menopausal hormone therapy, but also have an important bearing on experimental stroke methodology and the apparent translational roadblock for suggested stroke interventions. PMID- 24495537 TI - Scale-up cultivation of Chlorella ellipsoidea from indoor to outdoor in bubble column bioreactors. AB - The cultivation of Chlorella ellipsoidea in bubble column bioreactors was investigated at different scales under indoor and outdoor conditions. The algal cells were able to quickly adapt to the outdoor conditions and achieved a growth rate of 31.55mg L(-1)day(-1). Due to differences in light and temperature, the outdoor culture produced a higher percentage of unsaturated fatty acids compared to the indoor cultures, while the amino acid composition was unaffected. The overall cost of the biomass produced by the 200L outdoor cultivation (58.70US$/kg dry weight) was estimated to be more than 7 times lower than that of the 20L indoor cultivation (431.39US$/kg-dry weight). Together these results provide a basis for the cultivation of C. ellipsoidea for the large-scale production of biofuels, high-value nutrients and/or recombinant proteins. PMID- 24495538 TI - A horizontal plug flow and stackable pilot microbial fuel cell for municipal wastewater treatment. AB - An application-oriented stackable horizontal MFC (SHMFC) was designed and proved to be capable for sewage treatment and simultaneously energy recovery. The system consisted of multiple stackable 250L modules, which is the largest single MFC module by far. Domestic wastewater was fed into SHMFC in horizontal advection. During the stable operation period, a maximum current 0.435+/-0.010A in each module was observed under the external resistance of 1Omega and the maximum power density was 116mW. The effluent COD was 70+/-17mgL(-1) with a removal rate of 79+/-7% and the effluent TN was 13+/-3mgL(-1) with a removal rate of 71+/-8%. From the comparison between SHMFC module (250L) and 4-cm cubic MFC (28mL), the internal resistance distribution changes and the contact resistance becomes assignable and even limiting factor in the enlargement. PMID- 24495539 TI - Stabilization of sewage sludge by different biochars towards reducing freely dissolved polycyclic aromatic hydrocarbons (PAHs) content. AB - The objective of the study was to identify the effect of various biochars on the content of freely dissolved (Cfree) PAHs in sewage sludge. Apart from the evaluation of biochars obtained from various materials, the study also included the determination of the effects of biochar particle sizes and biochar production temperature on their ability to bind PAHs in sewage sludge. Increase in biochar dose caused a gradual reduction of Cfree PAHs content, but only up to the biochar dose of 5%. Depending on the kind of initial material from which the biochar was produced, the reduction of Cfree PAHs content in sewage sludge varied from 17.4% to 58.0%. Both the temperature and the particle size of biochar had an effect on PAH free concentration reduction. Biochars characterised by a low polarity index (O/C or (O+N)/C) reduced the level of Cfree PAHs better than biochars with a higher polarity index value. PMID- 24495540 TI - Nitrogen stress triggered biochemical and morphological changes in the microalgae Scenedesmus sp. CCNM 1077. AB - The aim of present study was to investigate the effects of nitrogen limitation as well as sequential nitrogen starvation on morphological and biochemical changes in Scenedesmus sp. CCNM 1077. The results revealed that the nitrogen limitation and sequential nitrogen starvation conditions significantly decreases the photosynthetic activity as well as crude protein content in the organism, while dry cell weight and biomass productivity are largely unaffected up to nitrate concentration of about 30.87mg/L and 3 days nitrate limitation condition. Nitrate stress was found to have a significant effect on cell morphology of Scenedesmus sp. CCNM 1077. Total removal of nitrate from the growth medium resulted in highest lipid (27.93%) and carbohydrate content (45.74%), making it a potential feed stock for biodiesel and bio-ethanol production. This is a unique approach to understand morphological and biochemical changes in freshwater microalgae under nitrate limitation as well as sequential nitrate removal conditions. PMID- 24495541 TI - Complete degradation of the azo dye Acid Orange-7 and bioelectricity generation in an integrated microbial fuel cell, aerobic two-stage bioreactor system in continuous flow mode at ambient temperature. AB - In this study, the commercially used model azo dye Acid Orange-7 (AO-7) was fully degraded into less toxic intermediates using an integrated microbial fuel cell (MFC) and aerobic bioreactor system. The integrated bioreactor system was operated at ambient temperature and continuous-flow mode. AO-7 loading rate was varied during experiments from 70gm(-3)day(-1) to 210gm(-3)day(-1). Colour and soluble COD removal rates reached>90% under all AO-7 loading rates. The MFC treatment stage prompted AO-7 to undergo reductive degradation into its constituent aromatic amines. HPLC-MS analysis of metabolite extracts from the aerobic stage of the bioreactor system indicated further oxidative degradation of the resulting aromatic amines into simpler compounds. Bioluminescence based Vibrio fischeri ecotoxicity testing demonstrated that aerobic stage effluent exhibited toxicity reductions of approximately fivefold and ten-fold respectively compared to the dye wastewater influent and MFC-stage effluent. PMID- 24495542 TI - Variability in research ethics review of cluster randomized trials: a scenario based survey in three countries. AB - BACKGROUND: Cluster randomized trials (CRTs) present unique ethical challenges. In the absence of a uniform standard for their ethical design and conduct, problems such as variability in procedures and requirements by different research ethics committees will persist. We aimed to assess the need for ethics guidelines for CRTs among research ethics chairs internationally, investigate variability in procedures for research ethics review of CRTs within and among countries, and elicit research ethics chairs' perspectives on specific ethical issues in CRTs, including the identification of research subjects. The proper identification of research subjects is a necessary requirement in the research ethics review process, to help ensure, on the one hand, that subjects are protected from harm and exploitation, and on the other, that reviews of CRTs are completed efficiently. METHODS: A web-based survey with closed- and open-ended questions was administered to research ethics chairs in Canada, the United States, and the United Kingdom. The survey presented three scenarios of CRTs involving cluster level, professional-level, and individual-level interventions. For each scenario, a series of questions was posed with respect to the type of review required (full, expedited, or no review) and the identification of research subjects at cluster and individual levels. RESULTS: A total of 189 (35%) of 542 chairs responded. Overall, 144 (84%, 95% CI 79 to 90%) agreed or strongly agreed that there is a need for ethics guidelines for CRTs and 158 (92%, 95% CI 88 to 96%) agreed or strongly agreed that research ethics committees could be better informed about distinct ethical issues surrounding CRTs. There was considerable variability among research ethics chairs with respect to the type of review required, as well as the identification of research subjects. The cluster-cluster and professional-cluster scenarios produced the most disagreement. CONCLUSIONS: Research ethics committees identified a clear need for ethics guidelines for CRTs and education about distinct ethical issues in CRTs. There is disagreement among committees, even within the same countries, with respect to key questions in the ethics review of CRTs. This disagreement reflects variability of opinion and practices pointing toward possible gaps in knowledge, and supports the need for explicit guidelines for the ethical conduct and review of CRTs. PMID- 24495543 TI - Response to letter to the editor: 'a precise knowledge of ozonated oils will help to define the favourable and peculiar properties of these functional dermatological matrices'. PMID- 24495545 TI - Nitric oxide as a non-innocent ligand in (bio-)inorganic complexes: spin and electron transfer in Fe(II)-NO bond. AB - The nature of electron density transfer upon bond formation between NO ligand and Fe(II) center is analyzed on the basis of DFT calculation for two {Fe-NO}(7) complexes with entirely diverse geometric and electronic structures: Fe(II)P(NH3)NO (with bent Fe-N-O unit) and [Fe(II)(H2O)5(NO)](2+) (with linear Fe N-O structure). Proper identification of an electronic status of the fragments, "prepared" to make a bond, was found necessary to get meaningful resolution of charge and spin transfer processes from a spin-resolved analysis of natural orbitals for chemical valence. The Fe(II)P(NH3)NO adduct (built of NO(0) (S=1/2) and Fe(II)P(NH3) (S=0) fragments) showed a strong pi*-backdonation competing with spin transfer via a sigma-donation, yielding significant red-shift of the NO stretching frequency. [Fe(II)(H2O)5(NO)](2+) (built of NO(0) (S=1/2) antiferromagnetically coupled to Fe(II)(H2O)5 (S=2) fragment) gave no noticeable charge or spin transfer between fragments; a slight blue-shift of the NO stretching frequency could be related to a residual pi-donation due to weak pi bonding. PMID- 24495549 TI - It's all about them: strategies to engage undergraduates in a research course. PMID- 24495546 TI - Generation of a monoclonal antibody against the glycosylphosphatidylinositol linked protein Rae-1 using genetically engineered tumor cells. AB - BACKGROUND: Although genetically engineered cells have been used to generate monoclonal antibodies (mAbs) against numerous proteins, no study has used them to generate mAbs against glycosylphosphatidylinositol (GPI)-anchored proteins. The GPI-linked protein Rae-1, an NKG2D ligand member, is responsible for interacting with immune surveillance cells. However, very few high-quality mAbs against Rae-1 are available for use in multiple analyses, including Western blotting, immunohistochemistry, and flow cytometry. The lack of high-quality mAbs limits the in-depth analysis of Rae-1 fate, such as shedding and internalization, in murine models. Moreover, currently available screening approaches for identifying high-quality mAbs are excessively time-consuming and costly. RESULTS: We used Rae 1-overexpressing CT26 tumor cells to generate 60 hybridomas that secreted mAbs against Rae-1. We also developed a streamlined screening strategy for selecting the best anti-Rae-1 mAb for use in flow cytometry assay, enzyme-linked immunosorbent assay, Western blotting, and immunostaining. CONCLUSIONS: Our cell line-based immunization approach can yield mAbs against GPI-anchored proteins, and our streamlined screening strategy can be used to select the ideal hybridoma for producing such mAbs. PMID- 24495550 TI - Intracellular ascorbate enhances hypoxia-inducible factor (HIF)-hydroxylase activity and preferentially suppresses the HIF-1 transcriptional response. AB - Hypoxia-inducible factor (HIF)-1 drives the transcription of hundreds of genes to support cell survival under conditions of microenvironmental and metabolic stress. HIF-1 is downregulated by iron-containing 2-oxoglutarate-dependent enzymes that require ascorbate as a cofactor. The HIF hydroxylases control both protein stability and the formation of an active transcription complex and, consequently, ascorbate could affect HIF-1alpha stabilization and/or gene expression, but the relative effect of ascorbate on these separate processes has not been well characterized. In this study we examined the effects of known intracellular ascorbate concentrations on both processes in response to various means of hydroxylase inhibition, including CoCl2, NiCl2, desferrioxamine, dimethyloxalylglycine, and hypoxia. Ascorbate inhibited HIF-1 activity most dramatically with all mechanisms of iron competition. In addition, HIF-1 dependent gene expression was effectively prevented by ascorbate and was inhibited even under conditions that allowed HIF-1alpha protein stabilization. This suggests that (1) ascorbate acts primarily to stabilize and reduce the iron atom in the hydroxylase active site and (2) the asparagine hydroxylase controlling HIF-1 transcriptional activity is particularly susceptible to fluctuations in intracellular ascorbate. These findings suggest that ascorbate plays a significant role in supporting HIF-hydroxylase function and that it could thereby modulate the cell survival response. PMID- 24495544 TI - Modulation of nuclear receptor function by cellular redox poise. AB - Nuclear receptors (NRs) are ligand-responsive transcription factors involved in diverse cellular processes ranging from metabolism to circadian rhythms. This review focuses on NRs that contain redox-active thiol groups, a common feature within the superfamily. We will begin by describing NRs, how they regulate various cellular processes and how binding ligands, corepressors and/or coactivators modulate their activity. We will then describe the general area of redox regulation, especially as it pertains to thiol-disulfide interconversion and the cellular systems that respond to and govern this redox equilibrium. Lastly, we will discuss specific examples of NRs whose activities are regulated by redox-active thiols. Glucocorticoid, estrogen, and the heme-responsive receptor, Rev-erb, will be described in the most detail as they exhibit archetypal redox regulatory mechanisms. PMID- 24495551 TI - Early predictive biomarkers for postpartum depression point to a role for estrogen receptor signaling. AB - BACKGROUND: Postpartum depression (PPD) affects approximately 13% of women and has a negative impact on mother and infant, hence reliable biological tests for early detection of PPD are essential. We aimed to identify robust predictive biomarkers for PPD using peripheral blood gene expression profiles in a hypothesis-free genome-wide study in a high-risk, longitudinal cohort. METHOD: We performed a genome-wide association study in a longitudinal discovery cohort comprising 62 women with psychopathology. Gene expression and hormones were measured in the first and third pregnancy trimesters and early postpartum (201 samples). The replication cohort comprised 24 women with third pregnancy trimester gene expression measures. Gene expression was measured on Illumina Human HT12 v4 microarrays. Plasma estradiol and estriol were measured. Statistical analysis was performed in R. RESULTS: We identified 116 transcripts differentially expressed between the PPD and euthymic women during the third trimester that allowed prediction of PPD with an accuracy of 88% in both discovery and replication cohorts. Within these transcripts, significant enrichment of transcripts implicated that estrogen signaling was observed and such enrichment was also evident when analysing published gene expression data predicting PPD from a non-risk cohort. While plasma estrogen levels were not different across groups, women with PPD displayed an increased sensitivity to estrogen signaling, confirming the previously proposed hypothesis of increased sex-steroid sensitivity as a susceptibility factor for PPD. CONCLUSIONS: These results suggest that PPD can be robustly predicted in currently euthymic women as early as the third trimester and these findings have implications for predictive testing of high-risk women and prevention and treatment for PPD. PMID- 24495552 TI - Mechanism of 1-(1-propylsulfonic)-3-methylimidazolium chloride catalyzed transformation of D-glucose to 5-hydroxymethylfurfural in DMSO: an NMR study. AB - The conversion of D-glucose to 5-hydroxymethylfurfural (HMF) in the presence of 5.48 mol% 1-(1-propylsulfonic)-3-methylimidazolium chloride acidic ionic liquid catalyst in DMSO at 150 degrees C was studied using (1)H, (13)C NMR, and visible spectroscopy. The HMF yield rapidly increases in the first 100 min of reaction, however yield drops beyond 100 min and levels off to a maximum yield of about 15.7% around 600 min. The visible spectroscopy study of the reaction mixture suggests that rate of HMF formation slows down after 100 min due to increase in the rate of humin formation after first 100 min. A mechanism has been proposed and key intermediates in the pathway could be identified by studying the (13)C NMR spectra of acidic ionic liquid catalyzed transformations of C-1 and C-2 (13)C labeled d-glucose under identical conditions. The proposed mechanism involves the isomerization of d-glucose to d-fructose via the complexation of the open chain sugar with the imidazolium cation of the acidic ionic liquid catalyst. PMID- 24495553 TI - Accounting for cellular heterogeneity is critical in epigenome-wide association studies. AB - BACKGROUND: Epigenome-wide association studies of human disease and other quantitative traits are becoming increasingly common. A series of papers reporting age-related changes in DNA methylation profiles in peripheral blood have already been published. However, blood is a heterogeneous collection of different cell types, each with a very different DNA methylation profile. RESULTS: Using a statistical method that permits estimating the relative proportion of cell types from DNA methylation profiles, we examine data from five previously published studies, and find strong evidence of cell composition change across age in blood. We also demonstrate that, in these studies, cellular composition explains much of the observed variability in DNA methylation. Furthermore, we find high levels of confounding between age-related variability and cellular composition at the CpG level. CONCLUSIONS: Our findings underscore the importance of considering cell composition variability in epigenetic studies based on whole blood and other heterogeneous tissue sources. We also provide software for estimating and exploring this composition confounding for the Illumina 450k microarray. PMID- 24495554 TI - Error rate for imputation from the Illumina BovineSNP50 chip to the Illumina BovineHD chip. AB - BACKGROUND: Imputation of genotypes from low-density to higher density chips is a cost-effective method to obtain high-density genotypes for many animals, based on genotypes of only a relatively small subset of animals (reference population) on the high-density chip. Several factors influence the accuracy of imputation and our objective was to investigate the effects of the size of the reference population used for imputation and of the imputation method used and its parameters. Imputation of genotypes was carried out from 50,000 (moderate density) to 777,000 (high-density) SNPs (single nucleotide polymorphisms). METHODS: The effect of reference population size was studied in two datasets: one with 548 and one with 1289 Holstein animals, genotyped with the Illumina BovineHD chip (777 k SNPs). A third dataset included the 548 animals genotyped with the 777 k SNP chip and 2200 animals genotyped with the Illumina BovineSNP50 chip. In each dataset, 60 animals were chosen as validation animals, for which all high density genotypes were masked, except for the Illumina BovineSNP50 markers. Imputation was studied in a subset of six chromosomes, using the imputation software programs Beagle and DAGPHASE. RESULTS: Imputation with DAGPHASE and Beagle resulted in 1.91% and 0.87% allelic imputation error rates in the dataset with 548 high-density genotypes, when scale and shift parameters were 2.0 and 0.1, and 1.0 and 0.0, respectively. When Beagle was used alone, the imputation error rate was 0.67%. If the information obtained by Beagle was subsequently used in DAGPHASE, imputation error rates were slightly higher (0.71%). When 2200 moderate-density genotypes were added and Beagle was used alone, imputation error rates were slightly lower (0.64%). The least imputation errors were obtained with Beagle in the reference set with 1289 high-density genotypes (0.41%). CONCLUSIONS: For imputation of genotypes from the 50 k to the 777 k SNP chip, Beagle gave the lowest allelic imputation error rates. Imputation error rates decreased with increasing size of the reference population. For applications for which computing time is limiting, DAGPHASE using information from Beagle can be considered as an alternative, since it reduces computation time and increases imputation error rates only slightly. PMID- 24495555 TI - Viral infections associated with Kawasaki disease. AB - BACKGROUND/PURPOSE: Kawasaki disease (KD) is a disease of unknown cause. To investigate the infectious etiology of Kawasaki disease, we initiated a prospective case-control study to investigate possible links between common viral infections and Kawasaki disease. METHODS: We enrolled 226 children with KD and 226 age- and sex-matched healthy children from February 2004 to March 2010. Throat and nasopharyngeal swabs were taken for both viral isolation and polymerase chain reaction (PCR) for various viruses. RESULTS: The mean age of the 226 KD cases was 2.07 years, and the male to female ratio was 1.43 (133 boys to 93 girls). Their mean fever duration was 7.5 days with a mean peak temperature of 39.7 degrees C. In addition to the typical symptoms of fever, neck lymphadenopathy, lip fissure and/or strawberry tongue, skin rash, nonpurulent bulbar conjunctivitis, palm/sole erythema, and induration followed by periungual desquamation, these KD cases also exhibited cough (69%), rhinorrhea (58%), and diarrhea (45%). Cases of KD had a significantly higher positive rate of viral isolation in comparison with the control group (7.5% vs. 2.2%, p = 0.02). Compared with the control group, cases of KD were more likely to have overall positive rates of viral PCR (50.4% vs. 16.4%, p < 0.001) and for various viruses including enterovirus (16.8% vs. 4.4%, p < 0.001), adenovirus (8.0% vs. 1.8%, p = 0.007), human rhinovirus (26.5% vs. 9.7%, p < 0.001), and coronavirus (7.1% vs. 0.9%, p = 0.003). CONCLUSION: We found that some common respiratory viruses, such as adenoviruses, enteroviruses, rhinoviruses, and coronaviruses, were associated with KD cases. PMID- 24495556 TI - Evodiamine and rutaecarpine alkaloids as highly selective transient receptor potential vanilloid 1 agonists. AB - Despite that among non-camptothecin natural products promising anticancer therapeutics are evodiamine derivatives, involved into mechanism of physiological function of topoisomerase-I. But, more recent findings have been shown that substituted quinazole alkaloids act as transient receptor potential vanilloid 1 agonists. The TRP(V1) is a calcium ion channel, activated by pH, heat and inflammatory activators. I is implicated in pain sensing. TRPV1 agonist is capsaicine (1). Both 1 and evodiamine (2), therefore, produce same physiological response, but are structurally unrelated from chemical viewpoint. Furthermore precise mechanistic aspects of drugs receptor interactions are still not fully understood. This study is the first one, which provides assessment of molecular factors contributing significantly to selectivity of 2 and rutaecarpine (3) as well as their twenty-two new functionalized derivatives towards (TRP)V1. The suggested new functionalization type of molecular skeleton, which is completely different one in respect the known derivatives, which is implicated in treatment of variety of cancer cell lines interacting preferably with topoisomerase-I. It resulted to increasing of the binding affinity and selectivity of the functionalized derivatives specifically to (TRP)V1?1.36-1.72 and ?2.50-3.16 higher than 1-3. PMID- 24495557 TI - Effect of hyaluronan molecular weight on structure and biocompatibility of silk fibroin/hyaluronan scaffolds. AB - The structure of scaffolds is known to play a key role in tissue engineering as it provides structural support and physical environment allowing cells to reside and rebuild the target tissue. In this work we investigated the effects of hyaluronan (HA) molecular weight (MW: 0.6, 1.6 and 2.6*10(6) Da) on the pore structure, secondary structure, and biocompatibility of lyophilized silk fibroin (SF)/HA composite scaffolds. The results showed that HA promoted the pore structure formation and restrained the formation of separate sheet like structures in the SF/HA blend scaffolds, which was dependent on HA MW. The 3D pore structure maintained the scaffold shape during the process of 75% ethanol annealing. Structural studies indicated that HA did not induce but hinder SF conformation transition from random coil to beta-sheet before and after treatment. In addition, SF/HA scaffolds showed an increase in cell proliferation compared to pure SF scaffold. These findings demonstrated the important role of HA MW in preparing SF/HA blend scaffolds suitable for application in tissue engineering. PMID- 24495558 TI - Fetal and Postnatal Magnetic Resonance Imaging of Unilateral Cystic Renal Dysplasia in a Neonate with Tuberous Sclerosis. AB - Tuberous sclerosis (TS) is an autosomal dominant condition associated with mutations in the TSC1 and/or TSC2 genes. Clinical manifestations are multisystemic, and they often include lesions in the brain, skin, heart, kidneys, and bones. TSC2 gene mutations can be seen concomitantly with autosomal dominant polycystic kidney disease gene mutations. We present a case of a fetus with prenatal diagnosis of TS that had unique asymmetrical distribution of renal cystic disease. We describe the extensive work up with both fetal and neonatal magnetic resonance imaging with correlating images of the unilateral polycystic renal disease in addition to typical TS brain findings. PMID- 24495559 TI - Study on genes of the serotonergic system and suicidal behavior: protocol for a case-control study in Mexican population. AB - BACKGROUND: Suicidal behavior is a leading cause of injury and death worldwide. Several studies have provided a possible relationship between genetic factors and suicidal behavior. Also, these studies have shown evidence for altered serotonergic neural transmission in the pathogenesis of suicidal behavior. In addition, genes pertaining to the serotonergic system have been proposed as candidates to establish biological correlates between suicidal behavior and the serotonergic system. The most studied genes are SCL6A4, HTR2A, HTR2C, HTR1A, HTR1B, TPH-1, and TPH-2. To get a comprehensive understanding of the association with suicidal behavior we will conduct genotype assays studies in a Mexican population. METHODS/DESIGN: We will conduct a case-control study. The population sample will comprise adolescent and adult patients admitted for attempted of suicide and diagnosed by a psychiatrist. A peripheral blood sample will be taken from all the subjects (cases and controls). Genomic DNA from the leukocytes blood sample will be extracted. The genotypes of interest are distributed in the following genes: SCL6A4, HTR2A, HTR1A, HTR1B, HTR2C, TPH-2 and TPH-1. All the samples will be analyzed using a polymerase chain reaction (PCR) end-point method. We will evaluate the Hardy-Weinberg Equilibrium. The chi-squared test or Fisher's exact test will be used to compare genotype and allele frequencies between control and case groups. The Quanto 1.2 software will measure the sample size of the association. For all the association analyses the level of significance will be set at p = 0.05 and the confidence interval at 95%. DISCUSSION: Suicidal behavior has been increase in Mexico, principally in young population. Our study will demonstrate the association between serotoninergic genes and suicide behavior in Mexican population. PMID- 24495561 TI - The role of the renin-angiotensin system in the pathogenesis of preeclampsia - new insights into the renin-angiotensin system in preeclampsia. AB - The renin-angiotensin system (RAS) plays an important role in the pathogenesis of hypertension. However, the role of RAS in preeclampsia is largely unknown, because the plasma concentration of renin and angiotensin (AII) is lower in preeclampsia than in normal pregnancy, whereas its cardinal sign is hypertension. A pressor response to AII infusions can predict the onset of preeclampsia, resulting in involvement of RAS in the pathogenesis of preeclampsia. It has been reported that patients with preeclampsia exhibit angiotensin type I receptor agonistic autoantibody (AT1-AA), suggesting the involvement of RAS in the pathogenesis of this condition. The physiological action of AT1-AA can explain the various clinical symptoms of preeclampsia. However, the significance of circulatory RAS, including AT1-AA, in the pathogenesis of preeclampsia remains obscure. Since many reports state that circulating RAS is thought to be suppressed in preeclampsia it is difficult to explain the onset of hypertension in preeclampsia by circulating RAS. Therefore, I propose new insights into the role of RAS in preeclampsia to resolve the contradiction as above-mentioned. The recent discovery of tissue RAS, on which prorenin and its receptor act, suggests a promising new direction in understanding the role of RAS in the pathogenesis of preeclampsia. PMID- 24495560 TI - Inflammatory biomarkers in type 2 diabetic patients: effect of glycemic control and impact of LDL subfraction phenotype. AB - BACKGROUND: Type 2 diabetes mellitus (T2D) is associated with higher cardiovascular risk partly related to an increase in inflammatory parameters. The aim of this study was to determine the association of inflammatory biomarkers with low-density lipoprotein (LDL) subfraction phenotype and glycemic control in subjects with T2D and poor glycemic control. METHODS: A cross-sectional study was performed comparing 122 subjects with T2D (59 +/- 11 years old, body mass index 30.2 +/- 5.6 kg/m2) with 54 control subjects. Patients with T2D were classified according to their LDL subfraction phenotype and inflammatory biomarkers (C reactive protein, Interleukin-6, Interleukin-8, Transforming growth factor beta1, Monocyte chemotactic protein 1, Leptin, Adiponectin) were evaluated according to the degree of glycemic control, LDL phenotype and other clinical characteristics. Forty-two subjects with T2D were studied before and after 3 months of improving glycemic control by different strategies. RESULTS: Patients with T2D had higher C reactive protein (CRP) and monocyte chemotactic protein-1 (MCP1) levels and lower adiponectin concentration, compared to controls. T2D subjects with body mass index >= 30 kg/m2 had higher CRP levels (5.2 +/- 4.8 mg/l vs 3.7 +/- 4.3 mg/l; p < 0.05). The presence of LDL phenotype B was related to higher levels of transforming growth factor-beta1 (TGF-beta1) (53.92 +/- 52.82 ng/l vs 31.35 +/- 33.74 ng/l; p < 0.05) and lower levels of adiponectin (3663 +/- 3044 ng/l vs 2723 +/- 1776 ng/l; p < 0.05). The reduction of HbA1c from 9.5 +/- 1.8% at baseline to 7.4 +/- 0.8% was associated with a significant reduction of TGF-beta1 (41.86 +/- 32.84 ng/l vs 26.64 +/- 26.91 ng/l; p = 0.02). CONCLUSIONS: Subjects with T2D, especially those with LDL phenotype B and obesity, have higher levels of inflammatory biomarkers. Improvement of glycemic control reduces TGF-beta1 levels, which may contribute partly to its renoprotective role. PMID- 24495562 TI - The CYP2D6 gene determines oxycodone's phenotype-specific addictive potential: implications for addiction prevention and treatment. AB - We propose a hypothesis for predicting addictive potential of oral drugs, in general, and oxycodone's addictive potential, in particular. We hypothesize that a patient's CYP2D6 phenotype determines oxycodone's addictive potential, in part, via genotype-specific regulation of its clearance; although, other possible modulators of oxycodone's addiction potential exist. For example, brain CYPs related to phenotype could be involved. To pilot test our hypothesis, we used a mathematical model which postulates that oxycodone's addictive potential is given by: LAP=E/(ka/ke), where LAP represents addictive potential, E represents euphoric potency, ka is the absorption rate constant of drug from the gastrointestinal tract, and ke is the systemic elimination rate constant of drug by all processes responsible for its removal from plasma. Using CYP2D6 phenotype specific oxycodone pharmacokinetic parameter values derived from published data, our hypothesis predicted that the canonical order of oxycodone's addictive potential was UM>EM>IM>PM, with corresponding LAP values of 0.24, 0.21, 0.17, and 0.15 respectively. Our hypothesis about oxycodone's addictive potential may provide a unifying approach useful for both personalized medicine dosing and predicting addictive potential of oral drugs in humans, since it is based on both oxycodone's pharmacogenetics and pharmacokinetics. PMID- 24495563 TI - An intermittent exhaustion of the pool of glycogen in the human organism as a simple universal health promoting mechanism. AB - Glycogen storage in human organism is providing reserve source of glucose which is critical for normal functioning of the nervous system during periods between meals and is also important for many other tissues. Overwhelming excessive consumption of carbohydrates and decreasing physical activity among the world population lead to dramatic increase in incidence and mortality related to cardiovascular diseases, metabolic syndrome and diabetes mellitus type 2. There is an observation that many interventions with proved clinical efficiency like physical activity, intermittent fasting, caloric restriction and some pharmacological treatments have in common the ability to decrease content of glycogen in the liver and skeletal muscles. This effect leads to increased ability of these organs to uptake the next dose of glucose and store it in the form of glycogen. Moreover these interventions lead to significant life span extension, provide better body fitness and prevent development of multiple age related diseases. In contrast excessive glucose load and saturation of tissues with glycogen provide a metabolic shift toward synthesis of fatty acids by liver. In advanced stages decreased glucose tolerance, insulin resistance, hyperinsulinemia, fatty liver disease, impairment of liver function and derangements of cholesterol metabolism are observed. It is suggested that noninvasive measurement of glycogen content in tissues could serve as important diagnostic and follow-up parameter for clinical practice and healthy lifestyle in wide population groups. PMID- 24495564 TI - A simple scoring system based on neutrophil count in sepsis patients. AB - BACKGROUND: The assessment of critically ill patients is often a challenge for clinicians. There are a number of scoring systems such as Acute Physiology and Chronic Health Evaluation II (APACHE II), Sequential Organ Failure Assessment (SOFA) and C-reactive protein test (CRP), which have been shown to correlate with outcome in a variety of Intensive Care Unit (ICU) patients. Therefore, use of repeated measures of these preexisting scores over time is a reasonable attempt to assess the severity of organ dysfunction and predict outcome in critically ill patients. Several reports suggest that the neutrophil is a useful marker of sepsis. However, since both a large number and a small number of neutrophils indicate a severe situation, neutrophil count is difficult to use to directly predict patients'. THE HYPOTHESIS: We proposed a novel scoring system identify predictive factors using a simple blood cell count that may be associated with mortality in ICU patients. Our novel scoring system (n-score) was calculated as follows: ranges of neutrophils of 0-4999 cells/mm(3) and 5000-9999 cells/mm(3) were defined as 3 and 1 points, respectively. When the neutrophil count was over 10,000 cells/mm(3), the score was calculated by dividing the number of cells by 10,000. Then, 1 or 2 points were added when patients were female or male, respectively. We hypothesize that n-score may be a simple and easy scoring system to estimate mortality of the patients with sepsis and severe sepsis/septic shock without requirement of special methods or special measuring equipment, and may be as reliable as the APACHE II score or SOFA score. EVALUATION OF THE HYPOTHESIS: The retrospective evaluation was conducted at the Department of Emergency, Disaster and Critical Care Medicine at the Hyogo College of Medicine. Seventy seven patients who were admitted to the emergency center and diagnosed sepsis or severe sepsis/septic shock between June 2007 and December 2012 and gave informed consent were enrolled. The n-score was significantly higher in non-survivors of sepsis and severe sepsis/septic shock (p<0.01, t-test) than in survivors. The ROC curve showed a sensitivity of 61.5% and a specificity of 80.4% at an n-score of 3.8 points; the area under the curve was 0.736. In addition, n-score correlated with APACHE II score (p<0.01, R=0.378) and SOFA score (p<0.05, R=0.256) on admission. CONCLUSION: Based on these preliminary evaluations, we hypothesize that n-score may be a useful scoring system to detect risk of death in sepsis and severe sepsis/septic shock. PMID- 24495565 TI - Altitude is a risk factor for completed suicide in bipolar disorder. AB - Bipolar disorder (BD) is a severe brain disease that is associated with a significant risk for suicide. Recent studies indicate that altitude of residence significantly affects overall rate of completed suicide, and is associated with a higher incidence of depressive symptoms. Bipolar disorder has shown to be linked to mitochondrial dysfunction that may increase the severity of episodes. The present study used existing data sets to explore the hypothesis that altitude has a greater effect of suicide in BD, compared with other mental illnesses. The study utilized data extracted from the National Violent Death Reporting System (NVDRS), a surveillance system designed by the Centers for Disease Control and Prevention (CDC) National Center for Injury Prevention and Control (NCIPC). Data were available for 16 states for the years 2005-2008, representing a total of 35,725 completed suicides in 922 U.S. counties. Random coefficient and logistic regression models in the SAS PROC MIXED procedure were used to estimate the effect of altitude on decedent's mental health diagnosis. Altitude was a significant, independent predictor of the altitude at which suicides occurred (F=8.28, p=0.004 and Wald chi-square=21.67, p<0.0001). Least squares means of altitude, independent of other variables, indicated that individuals with BD committed suicide at the greatest mean altitude. Moreover, the mean altitude at which suicides occurred in BD was significantly higher than in decedents whose mental health diagnosis was major depressive disorder (MDD), schizophrenia, or anxiety disorder. Identifying diagnosis-specific risk factors such as altitude may aid suicide prevention efforts, and provide important information for improving the clinical management of BD. PMID- 24495566 TI - Expression of Cry1Ab protein in a marker-free transgenic Bt rice line and its efficacy in controlling a target pest, Chilo suppressalis (Lepidoptera: Crambidae). AB - A marker-free Bt transgenic rice line, mfb-MH86, was recently developed in China, which contains a cry1Ab gene driven by a ubiquitin promoter. This Bt gene confers resistance to a range of lepidopteran species, including the striped stem borer, Chilo suppressalis (Walker). The expression of Cry1Ab protein in mfb-MH86 leaves, stems and leaf sheaths (hereinafter referred to as stems), and roots was evaluated throughout the rice-growing season using an enzyme-linked immunosorbent assay. In addition, mfb-MH86 resistance to C. suppressalis, a major pest of rice, was evaluated in a laboratory bioassay with field-collected rice stems. Cry1Ab protein levels of mfb-MH86 were highest in leaves (9.71-34.09 MUg/g dry weight [DW]), intermediate in stems (7.66-18.51 MUg/g DW), and lowest in roots (1.95 13.40 MUg/g DW). In all tissues, Cry1Ab levels in mfb-MH86 were higher in seedling and tillering stages than in subsequent growth stages. In the laboratory bioassay, mortality of C. suppressalis after 6 d of feeding on mfb-MH86 stems was 100% throughout the rice-growing season; mortality of C. suppressalis when feeding on stems of the nontransformed isoline, MH86, ranged from 15.0 to 38.3%. The results indicate that Cry1Ab protein levels in mfb-MH86 stems are sufficient to protect plants against C. suppressalis throughout the rice-growing season. Although our results are promising, further comprehensive evaluations of mfb MH86, including field surveys, will be needed before commercial use. PMID- 24495567 TI - The punctate localization of rat Eag1 K+ channels is conferred by the proximal post-CNBHD region. AB - BACKGROUND: In mammals, Eag K+ channels (KV10) are exclusively expressed in the brain and comprise two isoforms: Eag1 (KV10.1) and Eag2 (KV10.2). Despite their wide presence in various regions of the brain, the functional role of Eag K+ channels remains obscure. Here we address this question by characterizing the subcellular localization of rat Eag1 (rEag1) and rat Eag2 (rEag2) in hippocampal neurons, as well as determining the structural basis underlying their different localization patterns. RESULTS: Immunofluorescence analysis of young and mature hippocampal neurons in culture revealed that endogenous rEag1 and rEag2 K+ channels were present in both the dendrosomatic and the axonal compartments. Only rEag1 channels displayed a punctate immunostaining pattern and showed significant co-localization with PSD-95. Subcellular fractionation analysis further demonstrated a distinct enrichment of rEag1 in the synaptosomal fraction. Over expression of recombinant GFP-tagged Eag constructs in hippocampal neurons also showed a significant punctate localization of rEag1 channels. To identify the protein region dictating the Eag channel subcellular localization pattern, we generated a variety of different chimeric constructs between rEag1 and rEag2. Quantitative studies of neurons over-expressing these GFP-tagged chimeras indicated that punctate localization was conferred by a segment (A723-R807) within the proximal post-cyclic nucleotide-binding homology domain (post-CNBHD) region in the rEag1 carboxyl terminus. CONCLUSIONS: Our findings suggest that Eag1 and Eag2 K+ channels may modulate membrane excitability in both the dendrosomatic and the axonal compartments and that Eag1 may additionally regulate neurotransmitter release and postsynaptic signaling. Furthermore, we present the first evidence showing that the proximal post-CNBHD region seems to govern the Eag K+ channel subcellular localization pattern. PMID- 24495568 TI - Conceptual design and optimization of a plastic scintillator array for 2D tomography using a compact D-D fast neutron generator. AB - A conceptual design optimization of a fast neutron tomography system was performed. The system is based on a compact deuterium-deuterium fast neutron generator and an arc-shaped array of individual neutron detectors. The array functions as a position sensitive one-dimensional detector allowing tomographic reconstruction of a two-dimensional cross section of an object up to 10 cm across. Each individual detector is to be optically isolated and consists of a plastic scintillator and a Silicon Photomultiplier for measuring light produced by recoil protons. A deterministic geometry-based model and a series of Monte Carlo simulations were used to optimize the design geometry parameters affecting the reconstructed image resolution. From this, it is expected that with an array of 100 detectors a reconstructed image resolution of ~1.5mm can be obtained. Other simulations were performed in order to optimize the scintillator depth (length along the neutron path) such that the best ratio of direct to scattered neutron counts is achieved. This resulted in a depth of 6-8 cm and an expected detection efficiency of 33-37%. Based on current operational capabilities of a prototype neutron generator being developed at the Paul Scherrer Institute, planned implementation of this detector array design should allow reconstructed tomograms to be obtained with exposure times on the order of a few hours. PMID- 24495570 TI - A CCD-based reader combined with CdS quantum dot-labeled lateral flow strips for ultrasensitive quantitative detection of CagA. AB - Immunochromatographic assays are widely used to detect many analytes. CagA is proved to be associated closely with initiation of gastric carcinoma. Here, we reported that a charge-coupled device (CCD)-based test strip reader combined with CdS quantum dot-labeled lateral flow strips for quantitative detection of CagA was developed, which used 365-nm ultraviolet LED as the excitation light source, and captured the test strip images through an acquisition module. Then, the captured image was transferred to the computer and was processed by a software system. A revised weighted threshold histogram equalization (WTHE) image processing algorithm was applied to analyze the result. CdS quantum dot-labeled lateral flow strips for detection of CagA were prepared. One hundred sera samples from clinical patients with gastric cancer and healthy people were prepared for detection, which demonstrated that the device could realize rapid, stable, and point-of-care detection, with a sensitivity of 20 pg/mL. PMID- 24495571 TI - Changes in cost of treating schizophrenia: comparison of two studies done a decade apart. AB - Objective of this study was to compare the cost of care of schizophrenia estimated in the same catchment area separated by a decade. Cost of care of schizophrenia was estimated in 50 outpatients in 2001-2002 and 53 outpatients 2010-2011 using the same methodology along with structured assessments of psychopathology. Overall cost of care of schizophrenia has doubled in the last one decade. The total direct cost of the treatment has not changed much in the monetary terms in last one decade, but total indirect cost has increased 2.35 times. In terms of proportion of cost, there was no significant change in the proportion of the provider cost, however, the proportion of indirect cost increased from 63% to 77.57% from the year 2001-2002 to the year 2010-2011. Cost of care of schizophrenia is more for those have lower level of functioning and have to visit the hospital more often. Cost of care of schizophrenia in India has doubled in the last one decade. PMID- 24495569 TI - Liver regeneration. AB - The liver is unique in its ability to regenerate in response to injury. A number of evolutionary safeguards have allowed the liver to continue to perform its complex functions despite significant injury. Increased understanding of the regenerative process has significant benefit in the treatment of liver failure. Furthermore, understanding of liver regeneration may shed light on the development of cancer within the cirrhotic liver. This review provides an overview of the models of study currently used in liver regeneration, the molecular basis of liver regeneration, and the role of liver progenitor cells in regeneration of the liver. Specific focus is placed on clinical applications of current knowledge in liver regeneration, including small-for-size liver transplant. Furthermore, cutting-edge topics in liver regeneration, including in vivo animal models for xenogeneic human hepatocyte expansion and the use of decellularized liver matrices as a 3-dimensional scaffold for liver repopulation, are proposed. Unfortunately, despite 50 years of intense study, many gaps remain in the scientific understanding of liver regeneration. PMID- 24495572 TI - Meaning of psychoses as perceived by patients, their relatives and clinicians. AB - Making sense of psychoses supports insight and personal recovery. Relatives' and clinicians' different perspectives on psychoses might impede such processes e.g., in family interventions. This study compares the meaning of psychosis as perceived by patients, their relatives and clinicians and investigates factors associated with discrepancies between them. Meaning of psychosis was assessed in 70 interrelated patients, relatives and clinicians with the SUSE-questionnaire. Severity of disorder, therapeutic relationship and other clinical variables were analysed in patient groups with deviant SUSE-ratings compared to their relative or clinician respectively. The majority of patient-relative- and patient clinician-dyads made equal ratings of meaning of psychosis. Relatives and clinicians tended to have a less optimistic view on long-term-effects than patients. Discrepancy in ratings between patients and relatives was best explained by the family relationship (i.e. not being a parent) and between patients and clinicians by the severity of positive symptoms. Strong consensus was found among patients, relatives and clinicians about a relatively positive, meaningful picture of psychosis. Sufficient opportunities to discuss experiences and understanding of psychosis help to make sense of it consensually. If clinicians' attitudes towards psychosis are negatively biased by symptomatology, they will struggle to see and support personal recovery. PMID- 24495573 TI - Disinhibited reactive attachment disorder symptoms impair social judgements from faces. AB - Typically developing adults and children can rapidly reach consensus regarding the trustworthiness of unfamiliar faces. Maltreated children can have problems with trusting others, yet those with the disinhibited form of reactive attachment disorder (dRAD) can be indiscriminately friendly. Whether children with dRAD symptoms appraise and conform to typical judgements about trustworthiness of faces is still unknown. We recorded eye movements of 10 maltreated dRAD children and 10 age and gender matched typically developing control children while they made social judgements from faces. Children were presented with a series of pairs of faces previously judged by adults to have high or low attractiveness or trustworthiness ratings. Typically developing children reached a consensus regarding which faces were the most trustworthy and attractive. There was less agreement among the children with dRAD symptoms. Judgments from the typically developing children showed a strong correlation between the attractiveness and trustworthiness tasks. This was not the case for the dRAD group, who showed less agreement and no significant correlation between trustworthiness and attractiveness judgments. Finally, both groups of children sampled the eye region to perform social judgments. Our data offer a unique insight in children with dRAD symptoms, providing novel and important knowledge for their rehabilitation. PMID- 24495574 TI - Environmental factors during adolescence associated with later development of psychotic disorders - a nested case-control study. AB - Etiologies of psychotic disorders (schizophrenia and bipolar disorder) are conceptualized as interplay between genetic and environmental factors. The adolescent period is characterized by changes in social roles and expectations that may interact with biological changes or psychosocial stressors. Few studies focus on the adolescents' own reports of perceived risk factors. To assess differences at age 16 between persons who later develop psychotic disorders ("Confirmed Psychosis", CP) and their class-mates ("Population Controls", PC) we collected information on: (1) Social support factors (size of social network and expectancies of social support from friends), (2) Cognitive functioning (concentrating in the classroom, actual grades and expectancies of own academic achievements) and (3) Problems and stressors in families (illness or loss of work for parents), and in relationship with others (exposure to bullying, violence or sexual violation). Self-reported data from students at 15-16 years of age were linked to the case-registers from the "Thematically Organized Psychosis (TOP) Study". The CP group reported more economic problems in their families, smaller social network and lower academic expectation than the PC group. The results support the notion that long-term socioeconomic stressors in adolescence may serve as risk factors for the development of psychotic disorders. PMID- 24495576 TI - Demographic features and premorbid personality disorder traits in relation to age of onset and sex in paranoid schizophrenia. AB - Personality disorders in the premorbid period of schizophrenia and particularly in relation to age of onset and sex, seem to be a rather under-researched area. In the present study, 88 patients with paranoid schizophrenia were examined, regarding demographic characteristics and premorbid personality disorder traits, in order to investigate for differences in the premorbid period of the disease, in relation to age of onset and sex. Age cutoff points were set at <30 years and >=35 years of age for young and late onset groups, respectively. The Structured Clinical Interview for DSM-IV-Patient Edition for Axis I disorders (SCID-P) was used prospectively for diagnoses. Premorbid personality disorder traits were retrospectively assessed by using the Structured Clinical Interview for DSM-IV Patient Edition for Axis II disorders (SCID-II). Comparisons were performed by applying the two-tailed Wilcoxon rank-sum and the chi(2) statistical tests. Young onset patients were characterized by significantly higher proportion of urban birth, single status, more avoidant premorbid personality disorder traits, and less passive-aggressive premorbid personality disorder traits, than late onset counterparts. Differences were more prominently shown in men. Earlier age of onset seems to be associated to increased social inhibition and worse psychosocial adaptation in the premorbid period of paranoid schizophrenia. PMID- 24495575 TI - Development of the Clinician Assessment of Financial Incapability (CAFI). AB - The Social Security Administration (SSA) provides financial support to adults disabled by psychiatric conditions to provide for their basic needs. For beneficiaries identified as incapable of managing their funds, representative payee assignment is mandated. However, studies indicate that the current SSA method of determining capability leads to idiosyncratic payee assignment, with a tendency to under-identify beneficiaries needing payees. Over two phases with data from 78 mental health clinicians treating 134 patient-beneficiaries, we describe the development of a new assessment, the Clinician Assessment of Financial Incapability (CAFI). Item generation, subscale construction, and preliminary assessments of validity are described. We also describe the simultaneous development of a criterion measure of capability, a comprehensive review of all data. Experts identified four subscales mapping to four criteria of incapability; factor analysis provided support for this item structure. Close to one-half of patients were determined to be incapable by review of all data. CAFI and SSA methods correctly classified 73% of cases, but errors with CAFI were more evenly distributed between false negatives and false positives. The implications of classification error are considered, and advantages of CAFI over the SSA method are enumerated. Plans for future instrument revision are briefly described. PMID- 24495577 TI - Psychotic-like experiences and their relationship to suicidal ideation in adolescents. AB - Studies have suggested that psychotic-like experiences (PLEs) are associated with behavioral problems in adolescents. The aim of this study was to investigate relationships between domains of PLEs, suicidal ideation, and depression in a large community sample of adolescents. The sample consisted of 8096 Korean subjects (3184 boys and 4912 girls) aged 14 to 19 years. The level of PLEs, depression, and suicidal ideation were assessed by the Eppendorf schizophrenia inventory (ESI), Beck's depression inventory, and Beck's scale for suicidal ideation, respectively. Both the level of depression and suicidal ideation were significantly associated with PLEs. Among the four domains of the ESI, the deviant perception, ideas of reference, and auditory uncertainty were associated with the suicidal ideation. Additionally, subjects with more PLEs had significantly more suicidal ideation and depressive symptoms. PLEs in adolescents are associated with potential risk of suicide and depressive symptoms significantly mediated the association between suicidal ideation and PLEs. The presence of perceptual disturbances, ideas of reference, and depression may be regarded as warning signs for suicide-related behaviors. PMID- 24495578 TI - Academic dishonesty in schools of nursing: a literature review. AB - Academic dishonesty in schools of nursing is surprisingly common. The following literature review defines academic dishonesty, describes the scope of the problem, and sheds light on factors that affect student behaviors that lead to academic dishonesty in schools of nursing. Finally, barriers to and best practices for solutions to the problem will be reviewed as they appear within the literature. PMID- 24495579 TI - Resolving intraluminal drug and formulation behavior: Gastrointestinal concentration profiling in humans. AB - Despite the wide use of the oral route to deliver systemic drugs to humans, the intestinal absorption process is still not fully understood. Especially for complex absorption-enabling strategies (e.g. solubilization, supersaturation, etc.), the in vivo performance is difficult to predict. Considering the current share of drug candidates that suffer from a non-favorable absorption potential and therefore rely on these strategies, there is a growing interest in approaches that aim to resolve the multitude of interactions between drugs, formulation factors and the gastrointestinal environment. In this respect, gastrointestinal concentration profiling following drug administration to humans is a recent but promising strategy that complements more established techniques including gastrointestinal imaging. In the present review, a number of case studies will be discussed to demonstrate the added value of gastrointestinal concentration profiling to gain in-depth knowledge of intraluminal drug and formulation behavior and to identify those processes key for drug absorption. Examples include a better understanding of intestinal precipitation of weakly basic drugs, clarifying inter-individual or food-induced variability in absorption, and an improved insight into the solubility-permeability interplay. As manifested in a recently initiated European project on oral biopharmaceutics tools (OrBiTo), intraluminal concentration profiling will contribute to the development of relevant simulation models that are built upon a solid understanding of human drug and formulation behavior, and allow for a more predictive in vitro and in silico evaluation of absorption. PMID- 24495580 TI - KDM5B focuses H3K4 methylation near promoters and enhancers during embryonic stem cell self-renewal and differentiation. AB - BACKGROUND: Pluripotency of embryonic stem (ES) cells is controlled in part by chromatin-modifying factors that regulate histone H3 lysine 4 (H3K4) methylation. However, it remains unclear how H3K4 demethylation contributes to ES cell function. RESULTS: Here, we show that KDM5B, which demethylates lysine 4 of histone H3, co-localizes with H3K4me3 near promoters and enhancers of active genes in ES cells; its depletion leads to spreading of H3K4 methylation into gene bodies and enhancer shores, indicating that KDM5B functions to focus H3K4 methylation at promoters and enhancers. Spreading of H3K4 methylation to gene bodies and enhancer shores is linked to defects in gene expression programs and enhancer activity, respectively, during self-renewal and differentiation of KDM5B depleted ES cells. KDM5B critically regulates H3K4 methylation at bivalent genes during differentiation in the absence of LIF or Oct4. We also show that KDM5B and LSD1, another H3K4 demethylase, co-regulate H3K4 methylation at active promoters but they retain distinct roles in demethylating gene body regions and bivalent genes. CONCLUSIONS: Our results provide global and functional insight into the role of KDM5B in regulating H3K4 methylation marks near promoters, gene bodies, and enhancers in ES cells and during differentiation. PMID- 24495581 TI - Cost-effectiveness of telehealth interventions for chronic heart failure patients: a literature review. AB - OBJECTIVES: Evidence exists that telehealth interventions (e.g., telemonitoring, telediagnostics, telephone care) in disease management for chronic heart failure patients can improve medical outcomes, and we aim to give an overview of the cost effectiveness of these interventions. METHODS: Based on the literature search on "heart failure" in combination with "cost" and "telehealth" we selected 301 titles and abstracts. Titles and abstracts were screened for a set of inclusion criteria: telehealth intervention, heart failure as the main disease, economic analysis present and a primary study performed. In the end, thirty-two studies were included for full reading, data extraction, and critical appraisal of the economic evaluation. RESULTS: Most studies did not present a comprehensive economic evaluation, consisting of the comparison of both costs and effects between telehealth intervention and a comparator. Data on telehealth investment costs were lacking in many studies. The few studies that assessed costs and consequences comprehensively showed that telehealth interventions are cost saving with slight improvement in effectiveness, or comparably effective with similar cost to usual care. However, the methodological quality of the studies was in general considered to be low. CONCLUSIONS: The cost-effectiveness of telehealth in chronic heart failure is hardly ascertained in peer reviewed literature, the quality of evidence is poor and there was a difficulty in capturing all of the consequences/effects of telehealth intervention. We believe that without full economic analyses the cost-effectiveness of telehealth interventions in chronic heart failure remains unknown. PMID- 24495582 TI - Developing core outcomes sets: methods for identifying and including patient reported outcomes (PROs). AB - BACKGROUND: Synthesis of patient-reported outcome (PRO) data is hindered by the range of available PRO measures (PROMs) composed of multiple scales and single items with differing terminology and content. The use of core outcome sets, an agreed minimum set of outcomes to be measured and reported in all trials of a specific condition, may improve this issue but methods to select core PRO domains from the many available PROMs are lacking. This study examines existing PROMs and describes methods to identify health domains to inform the development of a core outcome set, illustrated with an example. METHODS: Systematic literature searches identified validated PROMs from studies evaluating radical treatment for oesophageal cancer. PROM scale/single item names were recorded verbatim and the frequency of similar names/scales documented. PROM contents (scale components/single items) were examined for conceptual meaning by an expert clinician and methodologist and categorised into health domains. A patient advocate independently checked this categorisation. RESULTS: Searches identified 21 generic and disease-specific PROMs containing 116 scales and 32 single items with 94 different verbatim names. Identical names for scales were repeatedly used (for example, 'physical function' in six different measures) and others were similar (overlapping face validity) although component items were not always comparable. Based on methodological, clinical and patient expertise, 606 individual items were categorised into 32 health domains. CONCLUSION: This study outlines a methodology for identifying candidate PRO domains from existing PROMs to inform a core outcome set to use in clinical trials. PMID- 24495583 TI - Acute disturbance of calcium homeostasis in PC12 cells as a novel mechanism of action for (sub)micromolar concentrations of organophosphate insecticides. AB - Organophosphates (OPs) and carbamates are widely used insecticides that exert their neurotoxicity via inhibition of acetylcholine esterase (AChE) and subsequent overexcitation. OPs can induce additional neurotoxic effects at concentrations below those for inhibition of AChE, indicating other mechanisms of action are also involved. Since tight regulation of the intracellular calcium concentration ([Ca(2+)]i) is essential for proper neuronal development and function, effects of one carbamate (carbaryl) and two OPs (chlorpyrifos, parathion-ethyl) as well as their -oxon metabolites on [Ca(2+)]i were investigated. Effects of acute (20min) exposure to (mixtures of) insecticides on basal and depolarization-evoked [Ca(2+)]i were measured in fura-2-loaded PC12 cells using single-cell fluorescence microscopy. Acute exposure to chlorpyrifos and its metabolite chlorpyrifos-oxon (10MUM) induced a modest increase in basal [Ca(2+)]i. More importantly, the tested OPs concentration-dependently inhibited depolarization-evoked [Ca(2+)]i. Chlorpyrifos already induced a ~30% inhibition at 0.1MUM and a 100% inhibition at 10MUM (IC50=0.43MUM), whereas parathion-ethyl inhibited the depolarization-evoked [Ca(2+)]i increase with ~70% at 10MUM. Interestingly, -oxon metabolites were more potent inhibitors of AChE, but were less potent inhibitors of depolarization-evoked [Ca(2+)]i compared to their parent compound (chlorpyrifos-oxon) or were even without effect (paraoxon-ethyl and -methyl). Similarly, acute exposure to carbaryl had no effect on [Ca(2+)]i. Exposure to mixtures of chlorpyrifos with its oxon-analog or with parathion-ethyl did not increase the degree of inhibition, indicating additivity does not apply. These data demonstrate that concentration-dependent inhibition of depolarization evoked [Ca(2+)]i is a novel mechanism of action of (sub)micromolar concentrations of OPs that could partly underlie OP-induced neurotoxicity. PMID- 24495584 TI - Is geriatric assessment being incorporated into general oncology? PMID- 24495585 TI - Development of a comprehensive multidisciplinary geriatric oncology center, the Thomas Jefferson University Experience. AB - BACKGROUND: The proportion of older patients with cancer is expected to grow exponentially in the next two decades. This population has large heterogeneity and it is well known that chronologic age is a poor predictor of outcomes. Research has shown that these patients are best served with a Comprehensive Geriatric Assessment (CGA) to formulate individualized treatment plans for better outcomes. However, the best model for CGA has yet to be determined. MATERIALS AND METHODS: Our objective was to develop a highly functional model for the establishment of a comprehensive multidisciplinary geriatric oncology center in the setting of a university based NCI-designated cancer center. Each patient is evaluated by medical oncology, geriatric medicine, pharmacy, social work and nutrition. Expert navigation is provided to enhance the patient experience. At the conclusion, the inter-professional team meets to review each case and formulate a comprehensive treatment plan. The patient is classified as Fit, Vulnerable, or Frail based on the complete CGA. RESULTS: The average age of patients seen was 80.7 with the most common diagnoses being breast, colorectal and lung cancers. Twenty four percent of patients were determined to be Fit, 47% Vulnerable, and 29% Frail. Twenty one percent of patients determined to be Frail by CGA received an ECOG score of 0-1 by the oncologist. Our pharmacists made specific recommendations in over 75% of patients and social work provided assistance in over 50% of patients. CONCLUSIONS: We were able to observe some interesting trends such as potential discordance with ECOG score and assessment of Fit/Vulnerable/Frail but due to limitations in the data, this paper is not able to illustrate definitive correlations. Several challenges with the development of the clinic include 1) patient related issues, 2) navigation, 3) financial reimbursement, 4) referral patterns, and 5) coordination of care during office hours. We feel that we have been able to establish a model for a comprehensive multidisciplinary geriatric oncology evaluation center in the setting of a university based cancer center. PMID- 24495586 TI - Anaerobic green fluorescent protein as a marker of Bifidobacterium strains. AB - Some strains of Bifidobacterium are considered as probiotics and are being added as adjunct culture in food products due to their potential in maintaining a healthy intestinal microbial balance. However, despite these benefits, bifidobacteria still remain poorly understood at the genetic level compared with other microorganisms of industrial interest. In this work, we have developed a non-invasive green fluorescent based reporter system for real-time tracking of Bifidobacterium species in vivo. The reporter vector pNZ:Tu-GFPana is based on the pNZ8048 plasmid harboring a bifidobacterial promoter (elongation factor Tu from Bifidobacterium longum CECT 4551) and a fluorescent protein containing a flavin-mono-nucleotide-based cofactor (evoglow-Pp1) which is fluorescent under both aerobic and anaerobic conditions. pNZ:Tu-GFPana was constructed and found to stably replicate in B. longum CECT 4551 and in the intestinal strain Bifidobacterium breve INIA P734. The subsequent analysis of these strains allowed us to assess the functionality of this plasmid. Our results demonstrate the potential of pNZ:Tu-GFPana as a real-time reporter system for Bifidobacterium in order to track the behavior of this probiotic species in complex environments like food or intestinal microbiota, and to estimate their competition and colonization potential. PMID- 24495587 TI - Putrescine production via the ornithine decarboxylation pathway improves the acid stress survival of Lactobacillus brevis and is part of a horizontally transferred acid resistance locus. AB - Decarboxylation pathways are widespread among lactic acid bacteria; their physiological role is related to acid resistance through the regulation of the intracellular pH and to the production of metabolic energy via the generation of a proton motive force and its conversion into ATP. These pathways include, among others, biogenic amine (BA) production pathways. BA accumulation in foodstuffs is a health risk; thus, the study of the factors involved in their production is of major concern. The analysis of several lactic acid bacterial strains isolated from different environments, including fermented foods and beverages, revealed that the genes encoding these pathways are clustered on the chromosome, which suggests that these genes are part of a genetic hotspot related to acid stress resistance. Further attention was devoted to the ornithine decarboxylase pathway, which affords putrescine from ornithine. Studies were performed on three lactic acid bacteria belonging to different species. The ODC pathway was always shown to be involved in cytosolic pH alkalinisation and acid shock survival, which were observed to occur with a concomitant increase in putrescine production. PMID- 24495588 TI - Evidence for radiation-induced disseminated intravascular coagulation as a major cause of radiation-induced death in ferrets. AB - PURPOSE: The studies reported here were performed as part of a program in space radiation biology in which proton radiation like that present in solar particle events, as well as conventional gamma radiation, were being evaluated in terms of the ability to affect hemostasis. METHODS AND MATERIALS: Ferrets were exposed to 0 to 2 Gy of whole-body proton or gamma radiation and monitored for 30 days. Blood was analyzed for blood cell counts, platelet clumping, thromboelastometry, and fibrin clot formation. RESULTS: The lethal dose of radiation to 50% of the population (LD50) of the ferrets was established at ~ 1.5 Gy, with 100% mortality at 2 Gy. Hypocoagulability was present as early as day 7 postirradiation, with animals unable to generate a stable clot and exhibiting signs of platelet aggregation, thrombocytopenia, and fibrin clots in blood vessels of organs. Platelet counts were at normal levels during the early time points postirradiation when coagulopathies were present and becoming progressively more severe; platelet counts were greatly reduced at the time of the white blood cell nadir of 13 days. CONCLUSIONS: Data presented here provide evidence that death at the LD50 in ferrets is most likely due to disseminated intravascular coagulation (DIC). These data question the current hypothesis that death at relatively low doses of radiation is due solely to the cell-killing effects of hematopoietic cells. The recognition that radiation-induced DIC is the most likely mechanism of death in ferrets raises the question of whether DIC is a contributing mechanism to radiation-induced death at relatively low doses in large mammals. PMID- 24495589 TI - Local recurrence after complete clinical response and watch and wait in rectal cancer after neoadjuvant chemoradiation: impact of salvage therapy on local disease control. AB - PURPOSE: To review the risk of local recurrence and impact of salvage therapy after Watch and Wait for rectal cancer with complete clinical response (cCR) after chemoradiation therapy (CRT). METHODS AND MATERIALS: Patients with cT2-4N0 2M0 distal rectal cancer treated with CRT (50.4-54 Gy + 5-fluorouracil-based chemotherapy) and cCR at 8 weeks were included. Patients with cCR were enrolled in a strict follow-up program with no immediate surgery (Watch and Wait). Local recurrence-free survival was compared while taking into account Watch and Wait strategy alone and Watch and Wait plus salvage. RESULTS: 90 of 183 patients experienced cCR at initial assessment after CRT (49%). When early tumor regrowths (up to and including the initial 12 months of follow-up) and late recurrences were considered together, 28 patients (31%) experienced local recurrence (median follow-up time, 60 months). Of those, 26 patients underwent salvage therapy, and 2 patients were not amenable to salvage. In 4 patients, local re-recurrence developed after Watch and Wait plus salvage. The overall salvage rate for local recurrence was 93%. Local recurrence-free survival at 5 years was 69% (all local recurrences) and 94% (after salvage procedures). Thirteen patients (14%) experienced systemic recurrence. The 5-year cancer-specific overall survival and disease-free survival for all patients (including all recurrences) were 91% and 68%, respectively. CONCLUSIONS: Local recurrence may develop in 31% of patients with initial cCR when early regrowths (<= 12 months) and late recurrences are grouped together. More than half of these recurrences develop within 12 months of follow-up. Salvage therapy is possible in >= 90% of recurrences, leading to 94% local disease control, with 78% organ preservation. PMID- 24495590 TI - Immunophenotypic and clinical differences between the nasal and extranasal subtypes of upper aerodigestive tract natural killer/T-cell lymphoma. AB - PURPOSE: To investigate, in a large cohort of patients, the immunophenotypic and clinical differences of nasal and extranasal extranodal nasal-type natural killer/T-cell lymphoma of the upper aerodigestive tract (UADT-NKTCL) and examine the relevance of the immunophenotype on the clinical behavior, prognosis, and treatment. METHODS AND MATERIALS: A total of 231 patients with UADT-NKTCL were recruited. One hundred eighty-one patients had primary location in the nasal cavity (nasal UADT-NKTCL), and 50 patients had primary extranasal UADT-NKTCL. RESULTS: Patients with extranasal UADT-NKTCL had more adverse clinical features, including advanced-stage disease, regional lymph node involvement, B symptoms, and poor performance status, than patients with nasal UADT-NKTCL. In addition, CD56 and granzyme B were less frequently expressed in extranasal UADT-NKTCL. The 5-year overall survival rate was 74.1% for the entire group and 76.0% for early stage disease. The 5-year overall survival rate for extranasal UADT-NKTCL was similar or superior to that of nasal UADT-NKTCL for all disease stages (76.9% vs 73.4%, P=.465), stage I disease (75.9% vs 79.2%, P=.786), and stage II disease (83.3% vs 50.3%, P=.018). CD56 expression and a Ki-67 proliferation rate >= 50% predicted poorer survival for extranasal UADT-NKTCL but not for nasal UADT-NKTCL. CONCLUSIONS: Patients with nasal and extranasal UADT-NKTCL have significantly different clinical features, immunophenotypes, and prognosis. Extranasal UADT NKTCL should be considered as a distinct subgroup apart from the most commonly diagnosed prototype of nasal UADT-NKTCL. PMID- 24495591 TI - A population-based comparative effectiveness study of radiation therapy techniques in stage III non-small cell lung cancer. AB - PURPOSE: Concerns have been raised about the potential for worse treatment outcomes because of dosimetric inaccuracies related to tumor motion and increased toxicity caused by the spread of low-dose radiation to normal tissues in patients with locally advanced non-small cell lung cancer (NSCLC) treated with intensity modulated radiation therapy (IMRT). We therefore performed a population-based comparative effectiveness analysis of IMRT, conventional 3-dimensional conformal radiation therapy (3D-CRT), and 2-dimensional radiation therapy (2D-RT) in stage III NSCLC. METHODS AND MATERIALS: We used the Surveillance, Epidemiology, and End Results (SEER)-Medicare database to identify a cohort of patients diagnosed with stage III NSCLC from 2002 to 2009 treated with IMRT, 3D-CRT, or 2D-RT. Using Cox regression and propensity score matching, we compared survival and toxicities of these treatments. RESULTS: The proportion of patients treated with IMRT increased from 2% in 2002 to 25% in 2009, and the use of 2D-RT decreased from 32% to 3%. In univariate analysis, IMRT was associated with improved overall survival (OS) (hazard ratio [HR] 0.90, P=.02) and cancer-specific survival (CSS) (HR 0.89, P=.02). After controlling for confounders, IMRT was associated with similar OS (HR 0.94, P=.23) and CSS (HR 0.94, P=.28) compared with 3D-CRT. Both techniques had superior OS compared with 2D-RT. IMRT was associated with similar toxicity risks on multivariate analysis compared with 3D-CRT. Propensity score matched model results were similar to those from adjusted models. CONCLUSIONS: In this population-based analysis, IMRT for stage III NSCLC was associated with similar OS and CSS and maintained similar toxicity risks compared with 3D-CRT. PMID- 24495592 TI - Phase 2 trial of hypofractionated high-dose intensity modulated radiation therapy with concurrent and adjuvant temozolomide for newly diagnosed glioblastoma. AB - PURPOSE/OBJECTIVES: To assess the effect and toxicity of hypofractionated high dose intensity modulated radiation therapy (IMRT) with concurrent and adjuvant temozolomide (TMZ) in 46 patients with newly diagnosed glioblastoma multiforme (GBM). METHODS AND MATERIALS: All patients underwent postsurgical hypofractionated high-dose IMRT. Three layered planning target volumes (PTVs) were contoured. PTV1 was the surgical cavity and residual tumor on T1-weighted magnetic resonance images with 5-mm margins, PTV2 was the area with 15-mm margins surrounding the PTV1, and PTV3 was the high-intensity area on fluid-attenuated inversion recovery images. Irradiation was performed in 8 fractions at total doses of 68, 40, and 32 Gy for PTV1, PTV2, and PTV3, respectively. Concurrent TMZ was given at 75 mg/m(2)/day for 42 consecutive days. Adjuvant TMZ was given at 150 to 200 mg/m(2)/day for 5 days every 28 days. Overall and progression-free survivals were evaluated. RESULTS: No acute IMRT-related toxicity was observed. The dominant posttreatment failure pattern was dissemination. During a median follow-up time of 16.3 months (range, 4.3-80.8 months) for all patients and 23.7 months (range, 12.4-80.8 months) for living patients, the median overall survival was 20.0 months after treatment. Radiation necrosis was diagnosed in 20 patients and was observed not only in the high-dose field but also in the subventricular zone (SVZ). Necrosis in the SVZ was significantly correlated with prolonged survival (hazard ratio, 4.08; P=.007) but caused deterioration in the performance status of long-term survivors. CONCLUSIONS: Hypofractionated high-dose IMRT with concurrent and adjuvant TMZ altered the dominant failure pattern from localized to disseminated and prolonged the survival of patients with GBM. Necrosis in the SVZ was associated with better patient survival, but the benefit of radiation to this area remains controversial. PMID- 24495593 TI - Locally targeted delivery of a micron-size radiation therapy source using temperature-sensitive hydrogel. AB - PURPOSE: To propose a novel radiation therapy (RT) delivery modality: locally targeted delivery of micron-size RT sources by using temperature-sensitive hydrogel (RT-GEL) as an injectable vehicle. METHODS AND MATERIALS: Hydrogel is a water-like liquid at room temperature but gels at body temperature. Two US Food and Drug Administration-approved polymers were synthesized. Indium-111 (In-111) was used as the radioactive RT-GEL source. The release characteristics of In-111 from polymerized RT-GEL were evaluated. The injectability and efficacy of RT-GEL delivery to human breast tumor were tested using animal models with control datasets of RT-saline injection. As proof-of-concept studies, a total of 6 nude mice were tested by injecting 4 million tumor cells into their upper backs after a week of acclimatization. Three mice were injected with RT-GEL and 3 with RT saline. Single-photon emission computed tomography (SPECT) and CT scans were performed on each mouse at 0, 24, and 48 h after injection. The efficacy of RT GEL was determined by comparison with that of the control datasets by measuring kidney In-111 accumulation (mean nCi/cc), representing the distant diffusion of In-111. RESULTS: RT-GEL was successfully injected into the tumor by using a 30 gauge needle. No difficulties due to polymerization of hydrogel during injection and intratumoral pressure were observed during RT-GEL injection. No back flow occurred for either RT-GEL or RT-saline. The residual tumor activities of In-111 were 49% at 24 h (44% at 48 h, respectively) for RT-GEL and 29% (22%, respectively) for RT-saline. Fused SPECT-CT images of RT-saline showed considerable kidney accumulation of In-111 (2886%, 261%, and 262% of RT-GEL at 0, 24, and 48 h, respectively). CONCLUSIONS: RT-GEL was successfully injected and showed much higher residual tumor activity: 170% (200%, respectively), than that of RT-saline at 24 h (48 h, respectively) after injection with a minimal accumulation of In-111 to the kidneys. Preliminary data of RT-GEL as a delivery modality of a radiation source to a local tumor are promising. PMID- 24495594 TI - Definitive chemoradiation therapy following surgical resection or radiosurgery plus whole-brain radiation therapy in non-small cell lung cancer patients with synchronous solitary brain metastasis: a curative approach. AB - PURPOSE/OBJECTIVES: The aim of this study was to evaluate the impact of definitive thoracic chemoradiation therapy following surgery or stereotactic radiosurgery (SRS) and whole-brain radiation therapy (WBRT) on the outcomes of patients with non-small cell lung cancer (NSCLC) with synchronous solitary brain metastasis (SSBM). METHODS AND MATERIALS: A total of 63 NSCLC patients with SSBM were retrospectively evaluated. Patients were staged using positron emission tomography-computed tomography in addition to conventional staging tools. Thoracic radiation therapy (TRT) with a total dose of 66 Gy in 2 Gy fractions was delivered along with 2 cycles of cisplatin-based chemotherapy following either surgery plus 30 Gy of WBRT (n=33) or SRS plus 30 Gy of WBRT (n=30) for BM. RESULTS: Overall, the treatment was well tolerated. All patients received planned TRT, and 57 patients (90.5%) were also able to receive 2 cycles of chemotherapy. At a median follow-up of 25.3 months (7.1-52.1 months), the median months of overall, locoregional progression-free, neurological progression-free, and progression-free survival were 28.6, 17.7, 26.4, and 14.6, respectively. Both univariate and multivariate analyses revealed that patients with a T1-T2 thoracic disease burden (P=.001), a nodal stage of N0-N1 (P=.003), and no weight loss (P=.008) exhibited superior survival. CONCLUSIONS: In the present series, surgical and radiosurgical treatments directed toward SSBM in NSCLC patients were equally effective. The similarities between the present survival outcomes and those reported in other studies for locally advanced NSCLC patients indicate the potentially curative role of definitive chemoradiation therapy for highly selected patients with SSBM. PMID- 24495595 TI - Localization and neurochemical features of the sympathetic trunk ganglia neurons projecting to the urethral muscle. An experimental study in a porcine animal model. AB - The striated perineal urethral muscle (UM) is involved in the voluntary control of the micturition requiring complex interactions between afferent and efferent (autonomic and somatic) pathways to store and periodically eliminate urine. Our aim was to define the site, cross sectional area and phenotype of sympathetic trunk ganglia (STG) neurons projecting to the porcine UM, combining retrograde neuronal tracer Fast Blue (FB) and double immunohistochemical labelling methods. The research was carried out on 3 male intact pigs, in which we counted a total number of 4992.67 +/- 834.35 (mean +/- S.E.M., n = 3) FB+ neurons distributed in the bilateral T12-S3 STG. These neurons were significantly larger in lumbar STG than in the sacral ones. Moreover we highlighted the presence of Dopamine beta hydroxylase (DbetaH), Vesicular Acetylcholine Transporter (VAChT), neuronal Nitric Oxyde Sinthase (n-NOS), Calcitonine Gene Related Peptide (CGRP), Leu Enkephaline (LENK), Neuropeptide Y (NPY), Substance P (SP), Vasoactive Intestinal Polypeptide (VIP) and Somatostatine (SOM) and their eventual co-existence with Tyrosine Hydroxylase(TH) in both lumbar and sacral FB+ neurons. In particular, lumbar and sacral STG neurons expressed similar percentages of immunoreactivity for TH, SP and CGRP, but showed significantly different levels of immunoreactivity for NPY, VIP, VAChT, LENK, nNOS, DbetaH and SOM. Taken together, these data indicate a different contribution of lumbar and sacral pathways in the sympathetic transmission to the boar UM. PMID- 24495596 TI - Detection of recombination events, haplotype reconstruction and imputation of sires using half-sib SNP genotypes. AB - BACKGROUND: Identifying recombination events and the chromosomal segments that constitute a gamete is useful for a number of applications in genomic analyses. In livestock, genotypic data are commonly available for half-sib families. We propose a straightforward but computationally efficient method to use single nucleotide polymorphism marker genotypes on half-sibs to reconstruct the recombination and segregation events that occurred during meiosis in a sire to form the haplotypes observed in its offspring. These meiosis events determine a block structure in paternal haplotypes of the progeny and this can be used to phase the genotypes of individuals in single half-sib families, to impute haplotypes of the sire if they are not genotyped or to impute the paternal strand of the offspring's sequence based on sequence data of the sire. METHODS: The hsphase algorithm exploits information from opposing homozygotes among half-sibs to identify recombination events, and the chromosomal regions from the paternal and maternal strands of the sire (blocks) that were inherited by its progeny. This information is then used to impute the sire's genotype, which, in turn, is used to phase the half-sib family. Accuracy (defined as R2) and performance of this approach were evaluated by using simulated and real datasets. Phasing results for the half-sibs were benchmarked to other commonly used phasing programs - AlphaPhase, BEAGLE and PedPhase 3. RESULTS: Using a simulated dataset with 20 markers per cM, and for a half-sib family size of 4 and 40, the accuracy of block detection, was 0.58 and 0.96, respectively. The accuracy of inferring sire genotypes was 0.75 and 1.00 and the accuracy of phasing was around 0.97, respectively. hsphase was more robust to genotyping errors than PedPhase 3, AlphaPhase and BEAGLE. Computationally, hsphase was much faster than AlphaPhase and BEAGLE. CONCLUSIONS: In half-sib families of size 8 and above, hsphase can accurately detect block structure of paternal haplotypes, impute genotypes of ungenotyped sires and reconstruct haplotypes in progeny. The method is much faster and more accurate than other widely used population-based phasing programs. A program implementing the method is freely available as an R package (hsphase). PMID- 24495598 TI - Large enhancement of light extraction efficiency in AlGaN-based nanorod ultraviolet light-emitting diode structures. AB - Light extraction efficiency (LEE) of AlGaN-based nanorod deep ultraviolet (UV) light-emitting diodes (LEDs) is numerically investigated using three-dimensional finite-difference time-domain simulations. LEE of deep UV LEDs is limited by strong light absorption in the p-GaN contact layer and total internal reflection. The nanorod structure is found to be quite effective in increasing LEE of deep UV LEDs especially for the transverse magnetic (TM) mode. In the nanorod LED, strong dependence of LEE on structural parameters such as the diameter of a nanorod and the p-GaN thickness is observed, which can be attributed to the formation of resonant modes inside the nanorod structure. Simulation results show that, when the structural parameters of the nanorod LED are optimized, LEE can be higher than 50% and 60% for the transverse electric (TE) and TM modes, respectively. The nanorod structure is expected to be a good candidate for the application to future high-efficiency deep UV LEDs. PACS: 41.20.Jb; 42.72.Bj; 85.60.Jb. PMID- 24495597 TI - Mitochondrial and sex steroid hormone crosstalk during aging. AB - Decline in circulating sex steroid hormones accompanies several age-associated pathologies which may influence human healthspan. Mitochondria play important roles in biosynthesis of sex steroid hormones, and these hormones can also regulate mitochondrial function. Understanding the cross talk between mitochondria and sex steroid hormones may provide insights into the pathologies associated with aging. The aim of this review is to summarize the current knowledge regarding the interplay between mitochondria and sex steroid hormones during the aging process. The review describes the effect of mitochondria on sex steroid hormone production in the gonads, and then enumerates the contribution of sex steroid hormones on mitochondrial function in hormone responsive cells. Decline in sex steroid hormones and accumulation of mitochondrial damage may create a positive feedback loop that contributes to the progressive degeneration in tissue function during aging. The review further speculates whether regulation between mitochondrial function and sex steroid hormone action can potentially influence healthspan. PMID- 24495601 TI - Thanking Cancer Cell International's 2013 reviewers. AB - CONTRIBUTING REVIEWERS: The Editor-in-Chief would like to thank all the reviewers who contributed to the journal in 2013. PMID- 24495599 TI - Results of a pilot randomised controlled trial to measure the clinical and cost effectiveness of peer support in increasing hope and quality of life in mental health patients discharged from hospital in the UK. AB - BACKGROUND: Mental health patients can feel anxious about losing the support of staff and patients when discharged from hospital and often discontinue treatment, experience relapse and readmission to hospital, and sometimes attempt suicide. The benefits of peer support in mental health services have been identified in a number of studies with some suggesting clinical and economic gains in patients being discharged. METHODS: This pilot randomised controlled trial with economic evaluation aimed to explore whether peer support in addition to usual aftercare for patients during the transition from hospital to home would increase hope, reduce loneliness, improve quality of life and show cost effectiveness compared with patients receiving usual aftercare only, with follow-up at one and three months post-discharge. RESULTS: A total of 46 service users were recruited to the study; 23 receiving peer support and 23 in the care-as-usual arm. While this pilot trial found no statistically significant benefits for peer support on the primary or secondary outcome measures, there is an indication that hope may be further increased in those in receipt of peer support. The total cost per case for the peer support arm of the study was L2154 compared to L1922 for the control arm. The mean difference between costs was minimal and not statistically significant. However, further analyses demonstrated that peer support has a reasonably high probability of being more cost effective for a modest positive change in the measure of hopelessness. Challenges faced in recruitment and follow up are explored alongside limitations in the delivery of peer support. CONCLUSIONS: The findings suggest there is merit in conducting further research on peer support in the transition from hospital to home consideration should be applied to the nature of the patient population to whom support is offered; the length and frequency of support provided; and the contact between peer supporters and mental health staff. There is no conclusive evidence to support the cost effectiveness of providing peer support, but neither was it proven a costly intervention to deliver. The findings support an argument for a larger scale trial of peer support as an adjunct to existing services. TRIAL REGISTRATION: Current Controlled Trials ISRCTN74852771. PMID- 24495602 TI - Liver transplantation for pediatric metabolic disease. AB - Liver transplantation (LTx) was initially developed as a therapy for liver diseases known to be associated with a high risk of near-term mortality but is based upon a different set of paradigms for inborn metabolic diseases. As overall outcomes for the procedure have improved, LTx has evolved into an attractive approach for a growing number of metabolic diseases in a variety of clinical situations. No longer simply life-saving, the procedure can lead to a better quality of life even if not all symptoms of the primary disorder are eliminated. Juggling the risk-benefit ratio thus has become more complicated as the list of potential disorders amenable to treatment with LTx has increased. This review summarizes presentations from a recent conference on metabolic liver transplantation held at the Children's Hospital of Pittsburgh of UPMC on the role of liver or hepatocyte transplantation in the treatment of metabolic liver disease. PMID- 24495603 TI - Altered nociceptive, endocrine, and dorsal horn neuron responses in rats following a neonatal immune challenge. AB - The neonatal period is characterized by significant plasticity where the immune, endocrine, and nociceptive systems undergo fine-tuning and maturation. Painful experiences during this period can result in long-term alterations in the neurocircuitry underlying nociception, including increased sensitivity to mechanical or thermal stimuli. Less is known about the impact of neonatal exposure to mild inflammatory stimuli, such as lipopolysaccharide (LPS), on subsequent inflammatory pain responses. Here we examine the impact of neonatal LPS exposure on inflammatory pain sensitivity and HPA axis activity during the first three postnatal weeks. Wistar rats were injected with LPS (0.05mg/kg IP, Salmonella enteritidis) or saline on postnatal days (PNDs) 3 and 5 and later subjected to the formalin test at PNDs 7, 13, and 22. One hour after formalin injection, blood was collected to assess corticosterone responses. Transverse spinal cord slices were also prepared for whole-cell patch clamp recording from lumbar superficial dorsal horn neurons (SDH). Brains were obtained at PND 22 and the hypothalamus was isolated to measure glucocorticoid (GR) and mineralocorticoid receptor (MR) transcript expression using qRT-PCR. Behavioural analyses indicate that at PND 7, no significant differences were observed between saline- or LPS-challenged rats. At PND 13, LPS-challenged rats exhibited enhanced licking (p<.01), and at PND 22, increased flinching in response to formalin injection (p<.05). LPS-challenged rats also displayed increased plasma corticosterone at PND 7 and PND 22 (p<.001) but not at PND 13 following formalin administration. Furthermore, at PND 22 neonatal LPS exposure induced decreased levels of GR mRNA and increased levels of MR mRNA in the hypothalamus. The intrinsic properties of SDH neurons were similar at PND 7 and PND 13. However, at PND 22, ipsilateral SDH neurons in LPS-challenged rats had a lower input resistance compared to their saline-challenged counterparts (p<.05). These data suggest neonatal LPS exposure produces developmentally regulated changes in formalin-induced behavioural responses, corticosterone levels, and dorsal horn neuron properties following noxious stimulation later in life. These findings highlight the importance of immune activation during the neonatal period in shaping pain sensitivity later in life. This programming involves both spinal cord neurons and the HPA axis. PMID- 24495604 TI - Contributions of sex, testosterone, and androgen receptor CAG repeat number to virtual Morris water maze performance. AB - The possibility that androgens contribute to the male advantage typically found on measures of spatial cognition has been investigated using a variety of approaches. To date, evidence to support the notion that androgens affect spatial cognition in healthy young adults is somewhat equivocal. The present study sought to clarify the association between testosterone (T) and spatial performance by extending measurements of androgenicity to include both measures of circulating T as well as an androgen receptor-specific genetic marker. The aims of this study were to assess the contributions of sex, T, and androgen receptor CAG repeat number (CAGr) on virtual Morris water task (vMWT) performance in a group of healthy young men and women. The hypothesis that men would outperform women on vMWT outcomes was supported. Results indicate that CAGr may interact with T to impact navigation performance and suggest that consideration of androgen receptor sensitivity is an important consideration in evaluating hormone-behavior relationships. PMID- 24495600 TI - The C-terminal propeptide of a plant defensin confers cytoprotective and subcellular targeting functions. AB - BACKGROUND: Plant defensins are small (45-54 amino acids), basic, cysteine-rich proteins that have a major role in innate immunity in plants. Many defensins are potent antifungal molecules and are being evaluated for their potential to create crop plants with sustainable disease resistance. Defensins are produced as precursor molecules which are directed into the secretory pathway and are divided into two classes based on the absence (class I) or presence (class II) of an acidic C-terminal propeptide (CTPP) of about 33 amino acids. The function of this CTPP had not been defined. RESULTS: By transgenically expressing the class II plant defensin NaD1 with and without its cognate CTPP we have demonstrated that NaD1 is phytotoxic to cotton plants when expressed without its CTPP. Transgenic cotton plants expressing constructs encoding the NaD1 precursor with the CTPP had the same morphology as non-transgenic plants but expression of NaD1 without the CTPP led to plants that were stunted, had crinkled leaves and were less viable. Immunofluorescence microscopy and transient expression of a green fluorescent protein (GFP)-CTPP chimera were used to confirm that the CTPP is sufficient for vacuolar targeting. Finally circular dichroism and NMR spectroscopy were used to show that the CTPP adopts a helical confirmation. CONCLUSIONS: In this report we have described the role of the CTPP on NaD1, a class II defensin from Nicotiana alata flowers. The CTPP of NaD1 is sufficient for vacuolar targeting and plays an important role in detoxification of the defensin as it moves through the plant secretory pathway. This work may have important implications for the use of defensins for disease protection in transgenic crops. PMID- 24495605 TI - Increased serum interleukin-6 levels in early stages of psychosis: associations with at-risk mental states and the severity of psychotic symptoms. AB - Schizophrenia patients experience activated inflammatory responses, but little is known about the presence of such inflammatory processes at or prior to disease onset. We measured interleukin-6 (IL-6) and C-reactive protein (CRP) serum levels and plasma fibrinogen in 17 at-risk mental state (ARMS) subjects, 77 patients with psychotic disorder (PD) and 25 healthy control subjects (HC). ARMS subjects were followed-up, and transition to psychosis was registered. IL6 rs1800795 SNP was genotyped, as IL-6 levels may be influenced by this genetic variant. We did not observe significant differences in the IL6 rs1800795 SNP genotype frequencies between the groups. ARMS subjects exhibited significantly higher IL-6 levels than did controls (p=0.019). In subjects not taking cannabis, we found that patients diagnosed with ARMS or PD exhibited increased IL-6 levels when compared with HC (p=0.004). In both ARMS and PD subjects, IL-6 levels were positively associated with negative symptoms. However, with respect to positive psychotic symptoms, a different relationship was observed in the ARMS and PD groups (positive relationship in ARMS; negative relationship in PD). These findings could not be attributed to confounding variables, including gender, body mass index (BMI), tobacco consumption or the rs1800795 genotype. Six of 17 ARMS subjects (35%) exhibited a transition to psychosis during the follow-up period of 26 months. ARMS subjects who developed psychosis exhibited increased median IL-6 levels compared with those who did not transition (0.61 vs. 0.35pg/mL). However, this difference was not statistically significant, which could be explained by a lack of statistical power due to the small sample size. Our results suggest that IL-6 may be a biomarker for early psychotic symptoms; however, further studies in larger samples are needed to confirm this result. PMID- 24495607 TI - HPA axis and aging in depression: systematic review and meta-analysis. AB - One of the most consistent findings in the biology of depression is an altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. However, data concerning this issue have never been examined with a focus on the older population. Here we present a systematic review and meta-analysis, based on studies investigating levels of cortisol, adrenocorticotropic hormone (ACTH) and corticotropin-releasing hormone (CRH) in depressed participants older than 60 and compared with healthy controls. We found 20 studies, for a total of 43 comparisons on different indices of HPA axis functioning. Depression had a significant effect (Hedges' g) on basal cortisol levels measured in the morning (0.89), afternoon (0.83) and night (1.39), but a smaller effect on cortisol measured continuously (0.51). The effect of depression was even higher on post dexamethasone cortisol levels (3.22), whereas it was non-significant on morning ACTH and CRH levels. Subgroup analyses indicated that various methodological and clinical factors can influence the study results. Overall, older participants suffering from depression show a high degree of dysregulation of HPA axis activity, with differences compared with younger adults. This might depend on several mechanisms, including physical illnesses, alterations in the CNS and immune-endocrinological alterations. Further studies are needed to clarify the implications of altered HPA axis activity in older patients suffering from depression. Novel pharmacological approaches might be effective in targeting this pathophysiological feature, thus improving the clinical outcomes. PMID- 24495606 TI - Within-adolescent coupled changes in cortisol with DHEA and testosterone in response to three stressors during adolescence. AB - It is hypothesized that hypothalamic-pituitary-adrenal and hypothalamic-pituitary gonadal axes function together to maintain adaptive functioning during stressful situations differently in adolescence than the characteristic inverse relations found in adulthood. We examined within-person correlated changes (coupling) in cortisol, DHEA and testosterone in response to parent-adolescent conflict discussion, social performance, and venipuncture paradigms. Data are derived from two samples of boys and girls from the Northeastern US (213 adolescents aged 11 16, M=13.7, SD=1.5 years; 108 adolescents aged 9-14, M=11.99, SD=1.55) using different biological sampling vehicles (saliva and blood). Results consistently show that across samples, vehicles, and contexts, cortisol and DHEA and cortisol and testosterone are positively coupled in response to environmental stimuli. Findings underscore the importance of considering the effects of multiple hormones together in order to further our understanding of the biological underpinnings of behavior, especially during adolescence, as adolescence is a developmental transition period that may be qualitatively different from adulthood in terms of hormone functioning. PMID- 24495608 TI - Salivary cortisol and depression in public sector employees: cross-sectional and short term follow-up findings. AB - INTRODUCTION: Increased cortisol levels have been suggested to play a role in the development of depression. An association has been shown in some studies but not consistently. The timing of an association is uncertain, and long-term follow-up studies may miss associations in narrower time windows. In the present study, we examined the association of several cortisol measures and depression in a repeated cross-sectional and short-term follow-up design. Depression was assessed by both self-reported symptoms of depression and clinical interviews. METHOD: In 2007, 10,036 public sector employees received a questionnaire along with salivary cortisol test tubes for home administration. Morning (30min after awakening) and evening (2000h) salivary samples were collected. Questionnaires and valid saliva samples were returned from 3536 employees. Approximately 3.6 months later a subsample of the participants collected three morning saliva samples (at awakening, 20min and 40min after awakening) plus an evening sample (2000h); participants with high baseline scores of self-reported depressive symptoms, burnout and perceived stress were invited to a standardized interview (SCAN) to detect clinical depression; and the symptom questionnaire was repeated for subsample participants. The study was repeated in 2009 with questionnaires and salivary test tubes (n=2408). In four cross-sectional and two short-term follow up analyses odds ratios of depressive symptoms and of clinical depression were estimated by logistic regression for morning, evening, mean and the difference between morning and evening cortisol (slope). For the subsample, awakening response (CAR) and area under the curve (AUC) cortisol measures were calculated. We adjusted for sex, age, income, education, family history of depression, physical activity and alcohol consumption. RESULTS: None except one of the measures of salivary cortisol were associated with self-reported depressive symptoms or clinical depression, neither in the four cross-sectional analyses nor in the two short term follow-up analyses. E.g. in 2007, the adjusted odds ratios (OR) of depressive symptoms by a one unit increase in morning and evening cortisol (ln(nmol/litre saliva)) were 1.01 (95% CI: 0.88-1.17) and 1.05 (0.93 1.18), respectively. The one exception was significant at p=0.04 and was considered as due to chance. CONCLUSION: In this large study, salivary cortisol was not associated with self-reported symptoms of depression or with clinical depression. PMID- 24495610 TI - Exposure to stress attenuates fear retrieval in healthy men. AB - The stress hormone cortisol reduces retrieval of emotional memories, which has been suggested to support the treatment of psychiatric disorders characterized by exaggerated fear-related memories. Indeed, studies in patients with anxiety disorders have indicated that the success of exposure therapy can be enhanced with accompanying cortisol administration. Fear renewal refers to the clinically relevant phenomenon that successfully extinguished fear can return after a context change. It remains to be investigated whether the effects of stress hormones on fear retrieval also generalize across different contexts. Healthy men were exposed to a fear renewal design with fear acquisition in context A and extinction in context B. Pictures of rooms served as contexts, coloured lights were introduced as conditioned stimuli (CS), and an electrical stimulation served as the unconditioned stimulus (UCS). On the next day, participants were randomly assigned to a stress (Socially Evaluated Cold Pressor Test) or a control condition (n=20 each). We tested for fear retrieval in contexts A and B during peak cortisol concentrations after stress induction. Overall, a context*stress interaction occurred, revealing that stress attenuated skin conductance responses in the extinction context B. Stress also reduced UCS expectancy in context B. Additionally, stress abolished the renewal effect (differentiation between CS in context A) at the electrodermal level. These results demonstrate a decreased return of fear after acute exposure to stress. Stress interferes with the retrieval of the original fear memory which in turn affects extinction responding. Thus, acute stress reduces rather than promotes the return of fear. PMID- 24495609 TI - Loss of Gabrd in CRH neurons blunts the corticosterone response to stress and diminishes stress-related behaviors. AB - The hypothalamic-pituitary-adrenal (HPA) axis is under tight regulation by strong GABAergic inhibition onto corticotropin-releasing hormone (CRH) neurons in the paraventricular nucleus (PVN) of the hypothalamus. CRH neurons receive two forms of GABAergic inhibition, phasic and tonic, but the specific roles of these two types of signaling have not yet been studied in this cell type. Our lab recently demonstrated a role for the GABAAR delta subunit in the tonic GABAergic regulation of CRH neurons. Using a floxed Gabrd mouse model established in our laboratory, we generated mice in which the GABAAR delta subunit is selectively removed from CRH neurons (Gabrd/Crh mice), resulting in a loss of tonic GABAergic inhibition in these neurons. Interestingly, the loss of this tonic GABAergic constraint did not significantly alter basal levels of corticosterone (CORT). However, the loss of the GABAAR delta subunit in CRH neurons blunted the CORT response to stress, likely due to the loss of the disinhibitory effect of GABA following acute stress. This blunting of HPA axis reactivity was associated with a decrease in depression-like and anxiety-like behaviors. Exogenous CORT was sufficient to increase anxiety-like and depression-like behaviors in Gabrd/Crh mice. Together, these results show the importance of the GABAAR delta subunit in the regulation of CRH neurons, and thus the HPA axis, and demonstrate that dysregulation of CRH neurons alters stress-related behaviors. PMID- 24495611 TI - Cortisol mediates the effects of stress on the contextual dependency of memories. AB - Stress is known to exert considerable impact on learning and memory processes. Typically, human studies have investigated memory for single items (e.g., pictures, words), but it remains unresolved how exactly stress may alter the storage of memories into their original encoding context (i.e., memory contextualization). Since neurocircuitry underlying memory contextualization processes is sensitive to the well-known stress hormone cortisol, we here investigated whether cortisol mediates stress effects on memory contextualization. Forty healthy young men were randomly assigned to a psychosocial stress or control group. Ten minutes after stress manipulation offset, participants were instructed to learn and remember neutral and negative words, each of which was depicted against a unique background picture. Approximately 24h later, memory was tested by means of cued retrieval and recognition tasks. To assess memory contextualization half of the words were tested in intact item-contexts pairs, and half in rearranged item-context combinations. Recognition data showed that cortisol, but no other indices of stress such as heart rate or subjective stress, mediated the effects of stress on contextualization of neutral and negative memories. The mediation analysis further showed that stress resulted in increases in cortisol and that cortisol was positively related to memory contextualization, but unrelated to other measures of memory. Thus, there seems to be a specific role for cortisol in the integration of a central memory into its surrounding context. PMID- 24495612 TI - Self-esteem change and diurnal cortisol secretion in older adulthood. AB - OBJECTIVE: Research suggests that self-esteem can decline in older adulthood. This process could remove a buffer that normally protects individuals against distress-related changes in cortisol secretion. We examined this possibility by testing whether change in self-esteem would predict alterations in cortisol secretion, particularly among older adults who reported high levels of depressive symptoms or perceived stress. METHODS: 147 older adults (aged 60+) completed three days of diurnal cortisol measurements at three different time points, namely every two years over a total period of four years. Measures of self esteem, depressive symptoms, and perceived stress were assessed at T1 and T2. Potential demographic and health-related confounds were measured at baseline (partnership status, SES, mortality risk index, and medication). RESULTS: Linear regression models indicated that a decline in self-esteem from T1 to T2 predicted elevated cortisol output (AUCG) from T2 to T3, F (1, 137)=8.09, beta=-.25, R(2)=.05, p=.005. Interaction analyses revealed that this association was particularly strong among participants who experienced higher T1 or T2 levels of depressive symptoms or perceived stress, +1SD: betas=-.34 to -.51, ps<.001, but not significant among their counterparts who reported relatively lower levels of depressive symptoms or perceived stress, -1SD: betas=.03 to 11, ps>.43. CONCLUSIONS: Declines in self-esteem represent a mechanism that contributes to higher levels of diurnal cortisol secretion if older adults experience psychological distress. Increases in self-esteem, by contrast, can ameliorate older adults' cortisol regulation in stressful circumstances. PMID- 24495613 TI - Impact of acute aerobic exercise and cardiorespiratory fitness on visuospatial attention performance and serum BDNF levels. AB - The purpose of the current study was to explore various behavioral and neuroelectric indices after acute aerobic exercise in young adults with different cardiorespiratory fitness levels when performing a cognitive task, and also to gain a mechanistic understanding of the effects of such exercise using the brain derived neurotrophic factor (BDNF) biochemical index. Sixty young adults were separated into one non-exercise-intervention and two exercise intervention (EI) (i.e., EIH: higher-fit and EIL: lower-fit) groups according to their maximal oxygen consumption. The participants' cognitive performances (i.e., behavioral and neuroelectric indices via an endogenous visuospatial attention task test) and serum BDNF levels were measured at baseline and after either an acute bout of 30min of moderate intensity aerobic exercise or a control period. Analyses of the results revealed that although acute aerobic exercise decreased reaction times (RTs) and increased the central Contingent Negative Variation (CNV) area in both EI groups, only the EIH group showed larger P3 amplitude and increased frontal CNV area after acute exercise. Elevated BDNF levels were shown after acute exercise for both EI groups, but this was not significantly correlated with changes in behavioral and neuroelectric performances for either group. These results suggest that both EI groups could gain response-related (i.e., RT and central CNV) benefits following a bout of moderate acute aerobic exercise. However, only higher-fit individuals could obtain particular cognition-process related efficiency with regard to attentional resource allocation (i.e., P3 amplitude) and cognitive preparation processes (i.e., frontal CNV) after acute exercise, implying that the mechanisms underlying the effects of such exercise on neural functioning may be fitness dependent. However, the facilitating effects found in this work could not be attributed to the transient change in BDNF levels after acute exercise. PMID- 24495615 TI - Early follicular testosterone level predicts preference for masculinity in male faces - but not for women taking hormonal contraception. AB - It has been shown that women's preference for masculinity in male faces changes across the menstrual cycle. Preference for masculinity is stronger when conception probability is high than when it is low. These findings have been linked to cyclic fluctuations of hormone levels. The purpose of the present study is to further investigate the link between gonadal steroids (i.e. testosterone, estradiol, and progesterone) and masculinity preference in women, while holding the cycle phase constant. Sixty-two female participants were tested in their early follicular cycle phase, when conception probability is low. Participants were shown face pairs and where asked to choose the more attractive face. Face pairs consisted of a masculinized and feminized version of the same face. For naturally cycling women we found a positive relationship between saliva testosterone levels and masculinity preference, but there was no link between any hormones and masculinity preference for women taking hormonal contraception. We conclude that in naturally cycling women early follicular testosterone levels are associated with masculinity preference. However, these hormonal links were not found for women with artificially modified hormonal levels, that is, for women taking hormonal contraception. PMID- 24495614 TI - Associations of socioeconomic and psychosocial factors with urinary measures of cortisol and catecholamines in the Multi-Ethnic Study of Atherosclerosis (MESA). AB - BACKGROUND: Stress hormones have been hypothesized to contribute to the social patterning of cardiovascular disease but evidence of differences in hormone levels across social groups is scant. PURPOSE: To examine the associations of socioeconomic and psychosocial factors with urinary levels of cortisol and catecholamines and determine whether these associations are modified by race/ethnicity. METHODS: Measures of cortisol, epinephrine, norepinephrine and dopamine were obtained on 12-h overnight urine specimens from 942 White, African American and Hispanic participants in the Multi-Ethnic Study of Atherosclerosis (MESA). Linear regression was used to examine associations of income-wealth index, education, depression, anger, anxiety and chronic stress with the four hormones after adjustment for covariates. RESULTS: Higher income-wealth index was associated with lower levels of urinary cortisol, epinephrine, norepinephrine and dopamine, after adjustment for age, sex, race/ethnicity, medication use, body mass index, smoking, and alcohol use. Education and psychosocial factors were not associated with urinary stress hormone levels in the full sample. However, there was some evidence of effect modification by race: SES factors were more strongly inversely associated with cortisol in African Americans than in other groups and anger was inversely associated with catecholamines in African Americans but not in the other groups. CONCLUSIONS: Lower SES as measured by income-wealth index in a multi-ethnic sample is associated with higher levels of urinary cortisol and catecholamines. Heterogeneity in these associations by race/ethnicity warrants further exploration. PMID- 24495616 TI - Bcl-2/caspase 3 mucosal imbalance favors T cell resistance to apoptosis in dogs with inflammatory bowel disease. AB - Canine idiopathic inflammatory bowel disease (IBD) is believed to result from complex interplay between genetic, microbial, and immunologic factors. Abnormal cell death by apoptosis may result in the persistence of activated intestinal T cells that contribute to mucosal inflammation and clinical severity. To test this hypothesis, we investigated the mucosal expression of pro- and anti-apoptotic proteins in different intestinal compartments and their association with inflammatory indices in dogs with IBD. Apoptosis of lamina propria (LP) T cells in duodenal, ileal, and colonic tissues in control and IBD dogs was analyzed by caspase 3/Bcl-2 immunohistochemistry and TUNEL assays. Densities and distributions of LP caspase 3 and Bcl-2 cells were correlated to histopathologic lesions and the clinical activity index (CIBDAI). Compared to control tissues, IBD dogs had significantly (P<0.01) fewer caspase 3 cells in colonic mucosa. Double immunostaining identified the majority of apoptotic cells as TUNEL(+)/caspase 3(+). Within intestinal mucosa of IBD dogs, there were significantly greater numbers of Bcl-2 cells at the apical and basilar villus in the duodenum as compared to the colon and to the apical and basilar villus in the ileum (P<0.001 for all comparisons). There were significantly greater numbers of Bcl-2 cells at the apical and basilar villus of the duodenum but significantly fewer numbers of Bcl-2 cells at the apical villus of the ileum in IBD dogs compared with controls (P<0.001, P<0.001, and P<0.02, respectively). There was a significant association between the number of Bcl-2 cells in the duodenum of IBD dogs and the CIBDAI (P<0.001 each for mild, moderate and severe clinical IBD). In conclusion, apoptosis of T lymphocytes varies within intestinal compartments of dogs with IBD. Mucosal imbalance of Bcl-2/caspase 3 expression favors T cell resistance to apoptosis which may contribute to T cell accumulation and chronic intestinal inflammation, similar to human IBD. PMID- 24495617 TI - Detection and effects on serum and urine steroid and LH of repeated GnRH analog (leuprolide) stimulation. AB - Non-steroidal drugs that increase endogenous testosterone (T) may be used to exploit ergogenic effects of androgens in power sports. While superactive GnRH analog use is suspected, neither screening nor detection tests are developed. This study aimed to determine if (a) stimulation for 5 days by leuprolide (a superactive GnRH analog) of serum and urine steroids and urine LH is reproducible at a 2 week interval, (b) nandrolone decanoate (ND) co-administration masks responses to leuprolide administration, (c) performance of urine measurement of leuprolide and M1, its major metabolite, as a detection test. Healthy men were randomized into a 4 week parallel group, open label clinical study in which all men had daily sc injections of leuprolide (1mg) for 4 days in the 1st and 3rd weeks with hormone-free 2nd and 4th weeks. In the 3rd week, men were randomized to either ND injections or no extra treatment. Serum steroids were determined by liquid chromatography, tandem mass spectrometry (LC-MS), urine steroids by gas chromatography, mass spectrometry (GC-MS), urine leuprolide and M1 by high resolution LC-MS and urine LH by immunoassay. Leuprolide stimulated striking, reproducible increases in serum and urine LH and steroids (serum T, dihydroT (DHT), 3alpha diol; urine T, epitestosterone (E) and androsterone (A). ND suppressed basal serum T, E2, 3alpha diol, and urinary E but did not mask or change the magnitude of responses to leuprolide. Urine leuprolide and M1 measurement had 100% sensitivity and specificity in detecting leuprolide administration up to one day after cessation of injections with the detection window between 1 and 3 days after last dose. Screening using urine steroid and LH measurements, optimally by urinary log10(LHxT), correctly classified 82% of urine samples. It is concluded that leuprolide stimulation of endogenous testosterone is reproducible after a 10-day interval, is not masked by ND and is reliably detected by urine leuprolide or M1 measurement for at least 1 day after administration. PMID- 24495618 TI - Broadening the focus. PMID- 24495619 TI - IgG-effector functions: "the good, the bad and the ugly". AB - IgG-antibodies are potent and versatile mediators of host protection. They elicit their biological effects through specific interaction of the Fc-part with complement, specific cellular receptors, or both. Several factors should be taken into consideration when analyzing the nature and intensity of the immunological response elicited via IgG-effector functions, especially for the family of IgG-Fc receptors (FcgammaRs) exclusively expressed on immune cells. These include the various classes of leukocyte FcgammaR, expressed variably on different immune cells, each with distinct affinity for every IgG subclass, as well as genetic FcgammaR-polymorphisms affecting expression and affinity for IgG. Furthermore, various aspects of the IgG itself are also crucial for the outcome of the biological response. These include endogenously encoded IgG-polymorphisms, such as IgG3 polymorphisms, and post-transcriptional IgG-modifications, in particular IgG-Fc-glycosylation, affecting IgG effector functions through modified binding affinity to FcgammaR. These latter aspects concerning the variability in IgG3 on its half-life and placental transport and the clinical consequences of altered IgG-quality through glycosylation, will be the focus of this review. PMID- 24495620 TI - Association between video display terminal use and dry eye disease in school children. AB - PURPOSE: To evaluate the risk factors of dry eye disease in school children associated with video display terminal use. METHODS: Two-hundred eighty-eight children were classified in either a dry eye disease group or control group according to the diagnostic criteria of dry eye disease. The results of ocular examinations, including best-corrected visual acuity, slit-lamp examination, and tear break-up time, were compared between groups. The results of questionnaires concerning video display terminal use and ocular symptoms were also compared. RESULTS: Twenty-eight children were included in the dry eye disease group and 260 children were included in the control group. Gender and best-corrected visual acuity were not significantly different between the two groups. Smartphone use was more common in the dry eye disease group (71%) than the control group (50%) (P = .036). The daily duration of smartphone use and total daily duration of video display terminal use were associated with increased risk of dry eye disease (P = .027 and .001, respectively), but the daily duration of computer and television use did not increase the risk of dry eye disease (P = .677 and .052, respectively). CONCLUSIONS: The results showed that smartphone use is an important dry eye disease risk factor in children. Close observation and caution regarding video display terminal use, especially smartphones, are needed for children. PMID- 24495621 TI - Differences in breast carcinoma immunohistochemical subtypes between immigrant Arab and European women. AB - BACKGROUND: There is a dearth of information on the clinicopathological differences, including the molecular subtypes, of breast carcinomas from immigrant Arab women in Europe. Therefore, the aim of our study was to examine and compare these features in immigrant Arab/Moroccan patients with those of European women. METHODS: Included in this study were 441 cases of breast cancer: 91 Arab/Moroccan women and 350 European women. Age, size, grade, node involvement, and immunohistochemical profile (classification into the following subtypes: luminal A, luminal B, HER2 +/ER -, and triple negative) were analyzed. RESULTS: The average age of breast cancer presentation in Arab women is almost a decade earlier than in European women (49 versus 60 years old; p = 0.00001). Arab patients also had a higher average tumor size (25 mm versus 19 mm; p =0,008) and more grade 3 and less grade 1 tumors (p = 0.02). It should be noted, however, that this variability in the size and grade do not appear statistically significant when compared in Arab and European patients under 50 years old. In contrast, independent of age, the immunohistochemical subtypes were different between the two populations, with a greater number of luminal B subtype and fewer luminal A subtype (p <0.02) in Arab patients. CONCLUSIONS: Arab patients with breast carcinoma have different clinicopathological features from European patients, mainly the age of cancer presentation. Their immunohistochemical profile is also different, with more luminal B and less luminal A subtypes, suggesting that there are not only clinicopathological differences but also disparities in the expression profiling in these women. VIRTUAL SLIDE: The virtual slides for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/2104813621113288. PMID- 24495622 TI - The relationship of the superficial radial nerve and its branch to the thumb to the first extensor compartment. AB - PURPOSE: The superficial radial nerve and its branches are vulnerable during surgery for de Quervain tenovaginitis. We studied the proximity of the nerve branches to the first extensor compartment. METHODS: We dissected 20 forearms of 11 cadavers and measured the branching point of the superficial radial nerve relative to the radial styloid. We defined the midline of the first extensor compartment and measured distances of nerves adjacent to it. RESULTS: The superficial radial nerve gave the lateral dorsal digital branch to the thumb at 50 +/- 13 mm (minimum, 26 mm; maximum, 72 mm) proximal to the radial styloid. Average distances of the lateral dorsal digital branch to the thumb to the midline of first extensor compartment from proximal to distal were 2, 2, and 2 mm, respectively. In 8 forearms, the lateral dorsal digital branch to the thumb passed directly over the first extensor compartment along its entire length. We found that as the superficial radial nerve diverged from the first extensor compartment, its lateral dorsal digital branch to the thumb coursed parallel and in close relation to it. CONCLUSIONS: Anatomic knowledge of the course of the superficial radial nerve and its branches is important during open release for avoiding nerve injury. CLINICAL RELEVANCE: The close relation of the superficial radial nerve and its lateral dorsal digital branch to the thumb with the first extensor compartment may guide surgeons during surgery for de Quervain tenovaginitis. PMID- 24495623 TI - Ciprofloxacin-resistant Aeromonas infection following leech therapy for digit replantation: report of 2 cases. AB - Medicinal leeches are commonly used after finger replantation to treat surgically unsalvageable venous congestion. Infection from Aeromonas hydrophila is a recognized complication of leech therapy that can be underestimated by the medical community. Ciprofloxacin and trimethoprim-sulfamethoxazole are the most commonly recommended prophylactic antibiotics used to prevent A. hydrophila infections during leech therapy. Here, we report 2 cases of ciprofloxacin resistant Aeromonas infections, occurring within 4 months of each other. Both cases developed after leech therapy for unsuccessful digital replantation. These infections were successfully treated with ceftriaxone. Ciprofloxacin-resistant Aeromonas should be recognized when determining prophylactic antibiotic protocols for replant centers when leech therapy is used for finger replantation. PMID- 24495624 TI - A stepwise algorithm for surgical treatment of type II displaced pediatric phalangeal neck fractures. AB - PURPOSE: To evaluate a stepwise reduction algorithm including closed, percutaneous, and open reduction techniques followed by percutaneous pin fixation for displaced pediatric phalangeal neck fractures. METHODS: Sixty-one consecutive children (mean age, 9.4 y; range, 2-18 y) presenting with closed, type II displaced phalangeal neck fractures were treated using the following algorithm. If satisfactory reduction was achieved with closed reduction, percutaneous pinning (CRPP) was performed. If not achieved, then percutaneous reduction and pinning (PRPP) was performed using a temporary intrafocal joystick for reduction and for osteoclasis as needed. If percutaneous reduction failed, open reduction and percutaneous pinning (ORPP) was performed. Using the Al-Qattan system, radiographic and clinical outcomes were retrospectively graded for union, deformity, range of motion, and function. RESULTS: Satisfactory alignment was achieved in all 61 fractures, by CRPP in 49 and PRPP in 12. No fracture required open reduction. Mean number of days from injury to surgery was 8 days for CRPP and 17 days for PRPP. All fractures treated after 13 days required percutaneous pinning. Fifty-three patients were followed for at least 1 year or until full functional recovery was achieved, with 45 excellent, 4 good, 1 fair, and 3 poor results. Four complications accounted for the fair and poor results, including 1 flexion contracture, 1 nonunion following pin track infection, and 1 case of avascular necrosis following a severe crush injury in the CRPP group and 1 flexion contracture following PRPP. CONCLUSIONS: Our stepwise algorithm for surgical treatment of closed, type II displaced pediatric phalangeal neck fractures produced 92% good to excellent results while minimizing the need for open reduction even in late-presenting fractures. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic IV. PMID- 24495625 TI - Thoracic outlet syndrome in the pediatric population: case series. AB - We present 4 patients, 4 months to 10 years of age, with thoracic outlet syndrome. All were referred to the brachial plexus clinic. Three patients were diagnosed with vascular thoracic outlet syndrome after clinical evaluation and diagnostic imaging. Three had a cervical rib and 1 had an anomalous first rib. All patients were treated surgically through a supraclavicular approach and had resolution of the symptoms. No postoperative complications were noted. PMID- 24495626 TI - Distal radius fractures: percutaneous treatment versus open reduction with internal fixation. PMID- 24495627 TI - The influence of thumb metacarpophalangeal joint rotation on the evaluation of ulnar collateral ligament injuries: a biomechanical study in a cadaver model. AB - PURPOSE: To determine whether variation in thumb metacarpophalangeal (MCP) joint pronosupination influences perceived ulnar collateral ligament (UCL) stability during clinical stress testing. METHODS: Twelve fresh-frozen specimens underwent sequential evaluation for the following conditions: ligament intact (LI), proper UCL deficient (-pUCL), and proper and accessory UCL deficient (UCL). Valgus stress testing was completed in both 0 degrees and 30 degrees MCP joint flexion for thumb pronation, neutral, and supination. RESULTS: Compared with neutral MCP joint rotation, supination decreased and pronation increased stability such that established treatment guidelines could be incorrectly applied. During evaluation in supination and 0 degrees flexion, 9/12 -pUCL had greater than 35 degrees laxity and, similarly, the mean laxity of -pUCL was similar to the UCL group in neutral rotation and 0 degrees flexion, incorrectly suggesting a complete ligament tear. In comparison, mean laxity of the *UCL in pronation and 0 degrees flexion was not different than -pUCL in neutral rotation and 0 degrees flexion, emphasizing the stabilizing effect of pronation. CONCLUSIONS: Thumb MCP joint pronosupination significantly influenced the evaluation of joint stability, where pronation improved valgus stability in contrast to supination that tended to increase joint instability, In pronation and 0 degrees flexion, a complete UCL injury could be misdiagnosed as a partial injury. In supination and 30 degrees flexion, an intact UCL could be misdiagnosed as a partial UCL injury. In supination and 0 degrees , a partial UCL injury could be misdiagnosed as a complete UCL injury. CLINICAL RELEVANCE: Accurate evaluation of thumb UCL stability is critical for guiding treatment. Variations in thumb MCP joint rotation during stress testing may influence clinical interpretation and, therefore, we recommend standardization of testing with the thumb MCP joint in neutral rotation. PMID- 24495628 TI - Innate immunity. PMID- 24495629 TI - Association between allelic variation due to short tandem repeats in tRNA gene of Entamoeba histolytica and clinical phenotypes of amoebiasis. AB - Genotypes of Entamoeba histolytica (E. histolytica) may contribute clinical phenotypes of amoebiasis such as amoebic liver abscess (ALA), dysentery and asymptomatic cyst passers state. Hence, we evaluated allelic variation due to short tandem repeats (STRs) in tRNA gene of E. histolytica and clinical phenotypes of amoebiasis. Asymptomatic cyst passers (n=24), patients with dysentery (n=56) and ALA (n=107) were included. Extracted DNA from stool (dysentery, asymptomatic cyst passers) and liver aspirate was amplified using 6 E. histolytica specific tRNA-linked STRs (D-A, A-L, N-K2, R-R, S-Q, and S(TGA)-D) primers. PCR products were subjected to sequencing. Association between allelic variation and clinical phenotypes was analyzed. A total of 9 allelic variations were found in D-A, 8 in A-L, 4 in N-K2, 5 in R-R, 10 in S(TAG)-D and 7 in S-Q loci. A significant association was found between allelic variants and clinical phenotypes of amoebiasis. This study reveals that allelic variation due to short tandem repeats (STRs) in tRNA gene of E. histolytica is associated different clinical outcome of amoebiasis. PMID- 24495630 TI - Urban schistosomiasis and soil transmitted helminthiases in young school children in Dar es Salaam and Tanga, Tanzania, after a decade of anthelminthic intervention. AB - Rapid urbanization in resource poor countries often results in expansion of unplanned settlements with overcrowding and inadequate sanitation. These conditions potentially support transmission of schistosomiasis and soil transmitted helminths (STH), but knowledge on the occurrence, transmission and control of these infections in urban settings is limited. The present study assessed the status of urinary schistosomiasis and STH across two different-sized cities in Tanzania - Dar es Salaam and Tanga - after a decade of anthelminthic intervention. Primary school children were examined for parasite eggs in urine and stool. Questionnaires were administered to the children, and observations were made on the urban environments. The burden of urinary schistosomiasis and STH was found to be low in both cities (overall 1.2% in Dar es Salaam and 0.3% in Tanga for urinary schistosomiasis; overall <1% in Dar es Salaam and 1-2% in Tanga for each STH infection), and the identified cases showed no clear pattern of spatial distribution. The findings indicated that a marked decrease in prevalence of these infections had occurred in the two cities during recent years. The observed promising developments appeared to have been accomplished by implementation of drug based intervention programs, in combination with environmental change (fewer snail habitats) and generally improved levels of hygiene. Continued efforts, including anthelminthic treatment and health education, are important to maintain these positive achievements. PMID- 24495631 TI - A new surveillance and response tool: risk map of infected Oncomelania hupensis detected by Loop-mediated isothermal amplification (LAMP) from pooled samples. AB - Although schistosomiasis remains a serious health problem worldwide, significant achievements in schistosomiasis control has been made in the People's Republic of China. The disease has been eliminated in five out of 12 endemic provinces, and the prevalence in remaining endemic areas is very low and is heading toward elimination. A rapid and sensitive method for monitoring the distribution of infected Oncomelania hupensis is urgently required. We applied a loop-mediated isothermal amplification (LAMP) assay targeting 28S rDNA for the rapid and effective detection of Schistosoma japonicum DNA in infected and prepatent infected O. hupensis snails. The detection limit of the LAMP method was 100 fg of S. japonicum genomic DNA. To promote the application of the approach in the field, the LAMP assay was used to detect infection in pooled samples of field collected snails. In the pooled sample detection, snails were collected from 28 endemic areas, and 50 snails from each area were pooled based on the maximum pool size estimation, crushed together and DNA was extracted from each pooled sample as template for the LAMP assay. Based on the formula for detection from pooled samples, the proportion of positive pooled samples and the positive proportion of O. hupensis detected by LAMP of Xima village reached 66.67% and 1.33%, while those of Heini, Hongjia, Yangjiang and Huangshan villages were 33.33% and 0.67%, and those of Tuanzhou and Suliao villages were 16.67% and 0.33%, respectively. The remaining 21 monitoring field sites gave negative results. A risk map for the transmission of schistosomiasis was constructed using ArcMap, based on the positive proportion of O. hupensis infected with S. japonicum, as detected by the LAMP assay, which will form a guide for surveillance and response strategies in high risk areas. PMID- 24495632 TI - Mosquito-borne diseases are a threat in many parts of the world. Foreword. PMID- 24495633 TI - Nurse-led telecoaching of people with type 2 diabetes in primary care: rationale, design and baseline data of a randomized controlled trial. AB - BACKGROUND: Despite the efforts of the healthcare community to improve the quality of diabetes care, about 50% of people with type 2 diabetes do not reach their treatment targets, increasing the risk of future micro-and macro-vascular complications. Diabetes self-management education has been shown to contribute to better disease control. However, it is not known which strategies involving educational programs are cost-effective. Telehealth applications might support chronic disease management. Transferability of successful distant patient self management support programs to the Belgian setting needs to be confirmed by studies of a high methodological quality. "The COACH Program" was developed in Australia as target driven educational telephone delivered intervention to support people with different chronic conditions. It proved to be effective in patients with coronary heart disease after hospitalization. Clinical and cost effectiveness of The COACH Program in people with type 2 diabetes in Belgium needs to be assessed. METHODS/DESIGN: Randomized controlled trial in patients with type 2 diabetes. Patients were selected based on their medication consumption data and were recruited by their sickness fund. They were randomized to receive either usual care plus "The COACH Program" or usual care alone. The study will assess the difference in outcomes between groups. The primary outcome measure is the level of HbA1c. The secondary outcomes are: Total Cholesterol, LDL Cholesterol, HDL-Cholesterol, Triglycerides, Blood Pressure, body mass index, smoking status; proportion of people at target for HbA1c, LDL-Cholesterol and Blood Pressure; self-perceived health status, diabetes-specific emotional distress and satisfaction with diabetes care. The follow-up period is 18 months. Within-trial and modeled cost-utility analyses, to project effects over life-time horizon beyond the trial duration, will be undertaken from the perspective of the health care system if the intervention is effective. DISCUSSION: The study will enhance our understanding of the potential of telehealth in diabetes management in Belgium. Research on the clinical effectiveness and the cost-effectiveness is essential to support policy makers in future reimbursement and implementation decisions. PMID- 24495635 TI - [Current situation and reflection on rehabilitation after burn injury in China]. AB - After over 50 years' development, the modern burn care system of China has made remarkable progress, however, we still lack ample attention to functional rehabilitation and quality of life of burn patients recovering from burn injury. The burn rehabilitation in China is still in juvenile stage, but it is really encouraging that more and more burn care facilities are paying attention to it. To further promote the development of burn rehabilitation in China, more emphasis must be stressed on the formation of multidisciplinary team in our burn care system, the concept of early and integral rehabilitation should be promoted, and therapeutic regimens and research work on function and aesthetics related body parts like hand and face should be emphasized. Moreover, we should also carry out rehabilitation on pediatric burn patients and promulgate the idea of burn rehabilitation in the society at large with the purpose of seeking supports for burn rehabilitation from all sectors of the society. PMID- 24495634 TI - Allele frequency changes due to hitch-hiking in genomic selection programs. AB - BACKGROUND: Genomic selection makes it possible to reduce pedigree-based inbreeding over best linear unbiased prediction (BLUP) by increasing emphasis on own rather than family information. However, pedigree inbreeding might not accurately reflect loss of genetic variation and the true level of inbreeding due to changes in allele frequencies and hitch-hiking. This study aimed at understanding the impact of using long-term genomic selection on changes in allele frequencies, genetic variation and level of inbreeding. METHODS: Selection was performed in simulated scenarios with a population of 400 animals for 25 consecutive generations. Six genetic models were considered with different heritabilities and numbers of QTL (quantitative trait loci) affecting the trait. Four selection criteria were used, including selection on own phenotype and on estimated breeding values (EBV) derived using phenotype-BLUP, genomic BLUP and Bayesian Lasso. Changes in allele frequencies at QTL, markers and linked neutral loci were investigated for the different selection criteria and different scenarios, along with the loss of favourable alleles and the rate of inbreeding measured by pedigree and runs of homozygosity. RESULTS: For each selection criterion, hitch-hiking in the vicinity of the QTL appeared more extensive when accuracy of selection was higher and the number of QTL was lower. When inbreeding was measured by pedigree information, selection on genomic BLUP EBV resulted in lower levels of inbreeding than selection on phenotype BLUP EBV, but this did not always apply when inbreeding was measured by runs of homozygosity. Compared to genomic BLUP, selection on EBV from Bayesian Lasso led to less genetic drift, reduced loss of favourable alleles and more effectively controlled the rate of both pedigree and genomic inbreeding in all simulated scenarios. In addition, selection on EBV from Bayesian Lasso showed a higher selection differential for mendelian sampling terms than selection on genomic BLUP EBV. CONCLUSIONS: Neutral variation can be shaped to a great extent by the hitch-hiking effects associated with selection, rather than just by genetic drift. When implementing long-term genomic selection, strategies for genomic control of inbreeding are essential, due to a considerable hitch-hiking effect, regardless of the method that is used for prediction of EBV. PMID- 24495637 TI - [Important role of orthoses in the management of postburn scar contracture]. AB - Joints involved in deep burn often result in joint contracture, limb dysfunction, psychological disorder, or even loss of living and working abilities. The management of post-burn joint contracture will directly orientate the functional recovery of the patients. Comprehensive intervention may prevent the contracture process of the affected joints. Orthoses application is an important measure and should be maintained throughout the whole process of burn care, from positioning the joints at the early stage to maintaining the range of joint motion at the late stage. Orthoses should be used on the premise of protecting the joint functions. In order to maintain the tissue tension while enhancing the joint mobility and muscle strength, the static orthoses and the dynamic orthoses are often alternately used. It is showed in clinical practice that orthoses are designed and applied on the basis that biomechanics will lead to a better outcome. PMID- 24495636 TI - [Effects of pressure therapy on the proliferation and apoptosis of cells in hypertrophic scar of burn patients]. AB - OBJECTIVE: To explore the effects of pressure therapy on proliferation and apoptosis of cells in hypertrophic scar (HS) of burn patients. METHODS: Twenty patients who were hospitalized from September 2010 to September 2012 and started to wear pressure garment tailored by rehabilitation therapists over 20 hours a day beginning from two weeks after healing of burn wounds with the depth from deep partial-thickness to full-thickness (early stage of formation of HS) were set as pressure treatment group (PT). Another group of patients who were hospitalized in the same period with HS formed 3, 6, 12, 24 months (with 5 patients at each time point) after deep partial-thickness to full-thickness burns without receiving any treatment were set as control group. HS tissue samples from limbs and face were excised at post treatment month (PTM) 3, 6, 12, 24 in group PT (with 5 patients at each time point), and 2 to 3 days after admission in control group. Five patients out of the above-mentioned 40 patients were selected according to the random number table, and normal skin tissue samples from abdomen and thigh were also obtained to serve as normal control. The expressions of proliferating cell nuclear antigen (PCNA) in HS and normal skin tissue were determined with immunohistochemical staining. The apoptosis status was detected with situ end labeling technique. The mRNA expressions of P57(kip2) and Cyclin E were determined with real-time fluorescence quantification PCR. Data were processed with t test, one-way analysis of variance, or LSD test. RESULTS: (1) In normal skin tissue, PCNA-positive cells were observed in the epidermal basal layer and prickle cell layer. In group PT and control group, PCNA-positive cells were observed in the epidermal basal layer, prickle cell layer, lower part of the granular cell layer, and dermis of HS. The percentages of PCNA-positive cells in HS in group PT were respectively (40.4 +/- 2.9)%, (28.2 +/- 6.2)%, (9.9 +/- 0.7)% at PTM 3, 6, 12, which were significantly lower than those of HS formed 3, 6, 12 months after wound healing in control group [(48.3 +/- 4.7)%, (36.2 +/- 3.2)%, (11.4 +/- 0.9)%, with t values respectively 3.186, 2.559, 2.880, P values all below 0.05]. (2) In normal skin tissue, apoptotic cells were observed in the epidermal basal layer. In group PT and control group, apoptotic cells were observed in each layer of epidermis of HS. The apoptotic indexes of HS in group PT were respectively (20.4 +/- 1.2)%, (26.1 +/- 0.4)%, (26.6 +/- 1.0)% at PTM 6, 12, 24, which were significantly higher than those of HS formed 6, 12, 24 months after wound healing in control group [(16.2 +/- 1.5)%, (23.1 +/- 2.0)%, (24.8 +/- 1.1)%, with t values respectively -4.904, -3.366, -2.606, P < 0.05 or P < 0.01]. (3) The mRNA expressions of P57(kip2) of HS in group PT were respectively 3.87 +/ 0.20, 8.60 +/- 0.78, 10.00 +/- 0.57 at PTM 3, 6, 12, which were significantly higher than those of HS formed 3, 6, 12 months after wound healing in control group (3.34 +/- 0.15, 6.36 +/- 0.29, 9.34 +/- 0.12, with t values respectively 4.880, -6.014, -2.375, P < 0.05 or P < 0.01). The mRNA expression of P57(kip2) in normal skin tissue was close to those of HS in group PT at PTM 12, 24 and those of HS formed 12, 24 months after wound healing in control group (with P values all above 0.05). (4) The mRNA expressions of Cyclin E of HS in group PT were respectively 19.30 +/- 0.18, 12.77 +/- 0.30, 9.21 +/- 0.18 at PTM 3, 6, 12, which were significantly higher than those of HS formed 3, 6, 12 months after wound healing in control group (19.79 +/- 0.34, 15.41 +/- 0.26, 9.47 +/- 0.17, with t values respectively 3.186, 2.559, 2.880, P < 0.05 or P < 0.01). The mRNA expression of Cyclin E in normal skin tissue was close to those of HS in group PT at PTM 12, 24 and those of HS formed 12, 24 months after wound healing in control group (with P values all above 0.05). CONCLUSIONS: Pressure therapy can accelerate the evolution process of HS through accelerating apoptosis and inhibition of cell proliferation, thereby scar proliferation is inhibited. PMID- 24495638 TI - [Comprehensive rehabilitation of burn-induced dysfunctions in China]. AB - Burn patients often suffer from different degrees of dysfunction, such as residual burn wounds, formation of hyperplastic scar, scar itching, cardiopulmonary dysfunction, limitation of motion, and psychological disorders, which exert severe impact on their daily life. This article reviews various rehabilitation treatments for dysfunction after burn injury to promote rehabilitation of burn patients. PMID- 24495639 TI - [Determination and correlation analysis of contents of putrescine, cadaverine, and histamine in necrotic tissue, blood, and urine of patients with diabetic foot]. AB - OBJECTIVE: To determine and perform a correlation analysis of the contents of putrescine, cadaverine, and histamine in necrotic tissue, blood, and urine of patients with diabetic foot (DF). METHODS: Ten patients with severe wet necrotizing DF hospitalized from January 2011 to January 2012 were assigned as group DF, and 10 orthopedic patients with scar but without diabetes or skin ulcer hospitalized in the same period were assigned as control group. Samples of necrotic tissue from feet of patients in group DF and normal tissue from extremities of patients in control group, and samples of blood and 24-hour urine of patients in both groups were collected, and the amount of each sample was 10 mL. Contents of putrescine, cadaverine, and histamine were determined with high performance liquid chromatography-mass spectrometry. The data got from the determination of blood and urine were processed with t test, and those from necrotic or normal tissue with Wilcoxon rank sum test. The correlation of contents of polyamines between necrotic tissue and blood, blood and urine were processed with simple linear regression analysis. RESULTS: (1) Contents of putrescine, cadaverine, and histamine in the necrotic tissue of group DF were (186.1 +/- 26.8), (78.553 +/- 12.441), (33 +/- 10) mg/kg, which were significantly higher than those in normal tissue of control group [(2.2 +/- 1.2), (1.168 +/- 0.014), 0 mg/kg, with Z values respectively -3.780, -3.781, -4.038, P values all below 0.01]. The content of putrescine in necrotic tissue of group DF was significantly higher than those of cadaverine and histamine (with Z values respectively -3.780, -3.630, P values all below 0.01). (2) Contents of putrescine, cadaverine, and histamine in the blood of group DF were (0.075 +/- 0.013), (0.022 +/- 0.003), (0.052 +/- 0.014) mg/L, and they were significantly higher than those in the blood of control group [(0.014 +/- 0.009), (0.013 +/- 0.003), (0.016 +/- 0.008) mg/L, with t values respectively 6.591, 2.207, 3.568, P < 0.05 or P<0.01]. The content of putrescine in the blood of group DF was significantly higher than those of cadaverine and histamine (with t values respectively 13.204, 3.096, P values all below 0.01). (3) Contents of putrescine, cadaverine, and histamine in the urine of group DF were (0.735 +/- 0.088), (0.450 +/- 0.012), (0.1623 +/- 0.0091) mg/L, and only the contents of putrescine and cadaverine were significantly higher than those in the urine of control group [(0.050 +/- 0.014), (0.035 +/- 0.007) mg/L, with t values respectively 3.270, 4.705, P<0.05 or P<0.01]. The content of putrescine in the urine of group DF was significantly higher than that of cadaverine (t = 6.686, P < 0.01). (4) There were significant and positive correlations in contents of putrescine, cadaverine, and histamine between necrotic tissue and blood in patients of group DF (with r values respectively 0.981, 0.994, 0.821, P values all below 0.01). There were no significant correlations in contents of putrescine, cadaverine, and histamine between blood and urine in patients of group DF (with r values respectively 0.150, 0.239, 0.177, P values all above 0.05). CONCLUSIONS: Putrescine, cadaverine, and histamine exist in the necrotic tissue of patients with DF in high concentrations, among which putrescine predominates. These polyamines can be absorbed into the blood through wound and excreted through the urine. PMID- 24495640 TI - [Regulatory effects of lanthanum chloride on the activation of nuclear factor kappa B inhibitor kinase beta induced by tumor necrosis factor alpha]. AB - OBJECTIVE: To investigate the regulatory effects of lanthanum chloride (LaCl3) on the activation of nuclear factor kappa B inhibitor (IkappaB) kinase beta (IKKbeta) induced by tumor necrosis factor alpha (TNF-alpha). METHODS: (1) Hela cells were cultured routinely in vitro. One portion of cells were collected and divided into TNF-alpha group (cultured with serum-free RMPI 1640 medium containing 20 ng/mL TNF-alpha for 30 min), low-dose LaCl3 + TNF-alpha group, moderate-dose LaCl3 + TNF-alpha group, high-dose LaCl3 + TNF-alpha group, LaCl3 group (cultured with serum-free RMPI 1640 medium containing 100 umol/L LaCl3 for 30 min), and control group (cultured with serum-free RMPI 1640 medium for 30 min) according to the random number table. Cells in low-dose LaCl3 + TNF-alpha group, moderate-dose LaCl3 + TNF-alpha group, high-dose LaCl3 + TNF-alpha group were first cultured with serum-free RMPI 1640 medium containing 5, 25, 100 umol/L LaCl3 for 4 h, and then stimulated with serum-free RMPI 1640 medium containing 20 ng/mL TNF-alpha for 30 min. There were 3 samples in each group. Cells were collected for detection of intracellular location of NF-kappaB/p65 protein by immunofluorescence staining. (2) Another portion of cells were collected and divided into TNF-alpha group, low-dose LaCl3 + TNF-alpha group, moderate-dose LaCl3 + TNF-alpha group, high-dose LaCl3 + TNF-alpha group, and control group with the same treatment as above. There were 3 samples in each group. The protein levels of NF-kappaB/p65 in nuclei, and the protein levels of IkappaBalpha, phosphorylated IkappaBalpha (p-IkappaBalpha) as well as IKKbeta and phosphorylated IKKbeta (p-IKKbeta) in cytoplasm were determined by Western blotting. The binding activity between NF-kappaB/p65 in the nuclear and target gene was determined by NF-kappaB/p65 transcription factor kit (denoted as absorption value). Data were processed with analysis of variance or LSD-t test. RESULTS: (1) High expression of NF-kappaB/p65 was observed in cytoplasm of control group. High expression of NF-kappaB/p65 was observed in nuclei of TNF alpha group. The expression of NF-kappaB/p65 in cytoplasm of LaCl3 group was lower than that of control group. In groups treated with LaCl3 and TNF-alpha, NF kappaB/p65 expression levels in nuclei and cytoplasm were decreased along with the increase in the concentration of LaCl3, which were all lower than those in TNF-alpha group. (2) There was certain amount of NF-kappaB/p65 protein expressed in nuclei of control group. The expression of NF-kappaB/p65 protein in nuclei of TNF-alpha group was higher than that of control group. In groups treated with LaCl3 and TNF-alpha, the expressions of NF-kappaB/p65 protein in nuclei were decreased along with an increase in the concentration of LaCl3. The level of IkappaBalpha in TNF-alpha group was significantly decreased but that of p IkappaBalpha increased as compared with those in control group. Along with the increase in the concentration of LaCl3, the levels of IkappaBalpha gradually increased and the levels of p-IkappaBalpha gradually decreased in groups treated with LaCl3 and TNF-alpha. There were no statistical differences in expression levels of IKKbeta among the 5 groups. The expression of p-IKKbeta could be hardly observed in control group, but it was obviously increased in TNF-alpha group. The expression levels of p-IKKbeta in groups treated with LaCl3 and TNF-alpha were gradually decreased along with the increase in the concentration of LaCl3. The absorption value in TNF-alpha group was 0.39 +/- 0.03, which was higher than that in control group (0, t = -7.23, P<0.01). The absorption values in low-dose LaCl3 +TNF-alpha group, moderate-dose LaCl3 + TNF-alpha group, and high-dose LaCl3 +TNF alpha group were respectively 0.17 +/- 0.03, 0.15 +/- 0.03, and 0, which were obviously lower than that in TNF-alpha group (with t values respectively -6.54, 5.92, -7.23, P values all below 0.01). CONCLUSIONS: LaCl3 can block the activation of NF-kappaB signaling pathway by blocking the phosphorylation of IKKbeta of Hela cells. PMID- 24495641 TI - [Analgesic and sedative effects of inhaling a mixture of nitrous oxide and oxygen on burn patient during and after dressing change]. AB - OBJECTIVE: To investigate the analgesic and sedative effects of inhaling a mixture of nitrous oxide and oxygen on burn patient during and after dressing change. METHODS: A total of 240 burn patients hospitalized in the Institute of Burn Research of Changhai Hospital Affiliated to the Second Military Medical University, Department of Burns of the First People's Hospital in Zhengzhou, and Department of Burns and Plastic Surgery of General Hospital of Ningxia Medical University from October 2011 to September 2012 were enrolled in our study, and they were all in accordance with the inclusion criteria. The 240 patients were divided into control group (n = 60, treated with inhalation of oxygen during dressing change) and treatment group (n = 180, treated with inhalation of a mixture of 65% nitrous oxide and oxygen during dressing change) according to the computer-generated list of random number. The other treatments in control group and treatment group were the same. Before, during, and after dressing change, heart rate (HR), systolic blood pressure (SBP), diastolic blood pressure (DBP), oxygen saturation (SO2), and adverse effects were observed. The degree of pain and anxiety felt by the patients were respectively evaluated with the visual analogue scale (VAS) and Chinese version of the burn specific pain anxiety scale (C-BSPAS) at the same time points as above. Data were processed with analysis of covariance, chi-square test, analysis of variance, and rank sum test. RESULTS: There were no significant differences between control group and treatment group in the levels of HR, SBP, DBP, and SO2 before dressing change (with F values respectively 0.76, 0.06, 1.11, 0.70, P values all above 0.05). Compared with those of control group, the levels of HR, SBP, DBP, and SO2 in treatment group were significantly ameliorated during dressing change (with F values respectively 81.78, 146.36, 226.44, 205.62, P values all below 0.01). After dressing change, the levels of DBP in the two groups were close (F = 0.31, P > 0.05), but the levels of HR, SBP, and SO2 showed statistical differences (with F values respectively 7.02, 8.69, 12.23, P < 0.05 or P < 0.01). Before dressing change, the VAS scores were approximate between control group and treatment group (Z = 0.21, P > 0.05). Compared with those in control group (9.4 +/- 0.7, 1.7 +/- 2.5), the VAS scores were significantly lowered in treatment group during and after dressing change (1.6 +/- 1.3, 0.7 +/- 1.1, with Z values respectively 11.84, 3.35, P values all below 0.01). There was no significant difference in C-BSPAS score between control group and treatment group before dressing change (Z = 0.62, P > 0.05). Compared with those in control group (75 +/- 13, 73 +/- 12), the C BSPAS scores in treatment group were decreased during and after dressing change (9 +/- 15, 9 +/- 14, with Z values respectively 11.91, 12.28, P values all below 0.01). There were no obvious adverse effects in two groups before, during, and after dressing change. CONCLUSIONS: A mixture of nitrous oxide and oxygen seems to have obvious analgesic and sedative effects on burn patients during dressing change, and it can be widely used. PMID- 24495642 TI - [Effects of microporous porcine acellular dermal matrix combined with bone marrow mesenchymal cells of rats on the regeneration of cutaneous appendages cells in nude mice]. AB - OBJECTIVE: To observe the effects of microporous porcine acellular dermal matrix (ADM) combined with bone marrow mesenchymal cells (BMMCs) population containing bone mesenchymal stem cells (BMSCs) of rats on the regeneration of cutaneous appendages cells in nude mice. METHODS: Split-thickness dermal grafts, 20 cm*10 cm in size and 0.3 mm in thickness, were prepared from a healthy pig which was sacrificed under sanitary condition. Laser microporous porcine ADM (LPADM) was produced by laser punching, hypertonic saline solution acellular method, and crosslinking treatment, and nonporous porcine ADM (NPADM) was produced by the latter two procedures. Then the appearance observation, histological examination and scanning electron microscope observation were conducted. BMMCs were isolated and cultured from tibia and femur after sacrifice of an SD rat. Osteogenic and adipogenic differentiation experiments were conducted among the adherent cells in the third passage. Then they were inoculated to LPADM and NPADM to construct BMMCs-LPADM and BMMCs-NPADM materials. Twenty-one healthy nude mice were divided into BMMCs-LPADM+NPADM group (A, n = 6), LPADM+split-thickness skin graft group (B, n = 6), BMMCs-LPADM+split-thickness skin graft group (C, n = 6), BMMCs NPADM+split-thickness skin graft group (D, n= 3) according to randomized block. After anesthesia, a 2 cm*2 cm full-thickness skin defect reaching deep fascia was reproduced in the middle of the back of each nude mouse, and a split-thickness skin graft of the same size was obtained, and then prepared skin grafts were transplanted to cover the wounds respectively. On post transplantation day (PTD) 5, 7, and 14, local condition and adverse effects observation was conducted; one nude mouse was sacrificed each time to harvest all the transplant for tissue structure observation with HE staining. On PTD 7 and 14, neonatal skin appendages in corresponding composite materials were observed with transmission electron microscope. RESULTS: (1) LPADM and NPADM appeared to be porcelain white, soft, and flexible. No cellular component was observed in acellular dermal matrix. Scanning electron microscope showed that the collagen fibers were orderly arranged. LPADM had microporous structure. (2) Cells in the third passage were orderly arranged with the shape similar to fibroblasts with high growth speed. (3) Induced differentiation experiments showed that cells could differentiate into osteoblasts and adipocytes. (4) On PTD 5, the NPADM in group A was dry in part; skin grafts in group D were dry and necrotic, and there was no infection and inflammation in groups A and D; skin grafts in groups B and C survived. On PTD 7 and 14, the overlaying material in group A was black, dry, and hard in part; the skin grafts in group D turned to be completely black, dry, and necrotic, and pale yellow clear exudate was found in subcutaneous area; there was no obvious purulent discharge in groups A and D; the appearance of skin grafts in groups B and C was close to the surrounding skin. (5) On PTD 5 and 7, in groups A, B, and C, vascularization was apparent in the pores of dermal matrix, and red blood cells could be found. In group D, skin grafts were dry and necrotic. On PTD 14, in groups A, B, and C, the pore structure of dermal matrix was fully vascularized in which a large number of red blood cells were visible. In group A, the microporous dermal matrix survived, but the overlaying NPADM was not attached closely. In groups B and C, the skin grafts were closely connected to the dermal matrix, and no cutaneous appendages were observed. In group C, special monolayer cells were found at the junction between skin graft and dermal matrix. (6) Skin grafts in group D failed to survive; they were not observed with the electron microscope. On PTD 7, there were no significant differences among groups A, B, and C. On PTD 14, no sebaceous gland-like cell or sweat gland-like cell and no newborn nerve ending were observed in skin grafts in groups A and B, in spite of the immigration of fibroblasts. In group C, a large number of new capillaries were observed at the junction between the skin graft and dermal matrix; rough endoplasmic reticulum of fibroblasts proliferated exuberantly; newborn unmyelinated nerve endings were observed; single free sweat gland-like cells and sebaceous gland-like cells were observed in superficial dermal matrix. CONCLUSIONS: LPADM, which provides a "cell niche-like" micro-environment for the migration and differentiation of the BMMCs population, when combining with the split-thickness skin graft, can induce exogenous differentiation of BMSCs in vivo, thus achieving the reconstruction of skin appendages. PMID- 24495643 TI - [Effects of cuttlefish bone-bone morphogenetic protein composite material on osteogenesis and revascularization of bone defect in rats]. AB - OBJECTIVE: To study the effects of cuttlefish bone-bone morphogenetic protein (BMP) composite material on osteogenesis and revascularization of bone defect in rats. METHODS: The cuttlefish bone was formed into cylinder with the diameter of about 5 mm and height of about 2 mm after the shell was removed, and then it was soaked in the recombinant human BMP 2 to make a cuttlefish bone-BMP (CBB) composite material. Thirty SD rats, with a defect of skull in every rat, were divided into the CBB and pure cuttlefish bone (PCB) groups according to the random number table, with 15 rats in each group. The rats in the group CBB and group PCB were transplanted with the corresponding material to repair the skull defect. At post transplantation week (PTW) 4, 6, and 8, 5 rats from every group were sacrificed by exsanguination, and ink perfusion was performed. One day later, all the transplants and part of the skull surrounding the defect were harvested, and general observation was conducted at the same time. The specimens were paraffin sectioned for HE staining and Masson staining. The area of microvessel and the area of newborn bone were observed and analyzed through histopathological techniques and image collection system. Data were processed with the analysis of variance of factorial design and LSD test. The correlation between the area of microvessel and the area of newborn bone of the group CBB was analyzed with Pearson correlation analysis. RESULTS: (1) The general observation of the transplant region showed that the transplants were encapsulated by a capsule of fibrous connective tissue. The texture of capsule was soft and relatively thick at PTW 4. The texture was tenacious and thin, but rather compact at PTW 6 and 8. The transplants became gelatinous at PTW 4, and similar to the cartilage tissue at PTW 6 and 8. (2) Histological observation showed that the structure of the transplants in two groups was damaged at PTW 4. A moderate quantity of inflammatory cell infiltration could be observed. The amounts of the primary bone trabeculae and microvessels in group CBB were more abundant than those of group PCB, while the number of osteoclasts was less than those of group PCB. At PTW 6, the inflammatory cell infiltration in the transplants in both groups decreased obviously, the cuttlefish bone was found to be further degraded, and the number of newborn microvessels was increased. There were mature bone trabeculae around the transplants in both groups. And there were also mature bone trabeculae in the degraded CBB in group CBB. At PTW 8, the inflammatory reaction in the transplants in both groups disappeared; there were more mature bone trabeculae; the structure of the cuttlefish bone was found to be damaged basically. Bone trabeculae in group PCB were found around the transplant, while the bone trabeculae could be observed not only around the transplant but also in the degraded CBB in group CBB. The amount of the microvessels in group CBB was still larger than that of group PCB. (3) From PTW 4 to 8, the area of microvessel in group CBB [(63 +/- 4), ( 136 +/- 36), ( 347 +/- 31) um(2)] was larger than that in group PCB [(44 +/- 7), (73 +/- 4), (268 +/- 42) um(2), P < 0.05 or P < 0.01]. From PTW 4 to 8, the area of newborn bone in group CBB [(236 +/- 26), (339 +/- 42), (553 +/- 40) um(2)] was larger than that in group PCB [(137 +/- 15), (243 +/- 21), (445 +/- 29) um(2), with P values all below 0.01]. (4) The relation between the area of microvessel and the area of newborn bone was significantly positive (r = 0.948, P = 0.001). CONCLUSIONS: The CBB may exert good effect on osteogenesis and vascularization of rats with bone defect. It is a good three dimensional scaffold in bone tissue engineering. PMID- 24495644 TI - [Advances in the research of fluid resuscitation and its monitoring in burn patients]. AB - Shock is the one of the most serious complications during the early stage of burn injury. Early effective fluid resuscitation, enabling the burn patient to pass through the shock stage smoothly and uneventfully, plays a necessary and essential role in the prevention of the subsequent organ complications, reduction of mortality and morbidity, and improvement in life quality. Rapid restoration of blood volume is the fundamental measure to prevent burn shock. In this review, the history and the current status of several important issues related to burn shock resuscitation, including the fluid replacement formula, quality of fluids, and monitoring of physiological parameters, were over viewed. The authors also proposed that a new therapeutic strategy to prevent microvascular permeability should be emphasized and developed in future, which may hopefully act as the most basic approach to prevent burn shock and its related complications. PMID- 24495645 TI - Left ventricular remodeling with preserved function after coronary microembolization: the effect of methylprednisolone. AB - BACKGROUND: The objective of this study was to evaluate changes in left ventricular ejection fraction (LVEF) and left ventricular remodeling after coronary microembolization (CME) and to investigate the protective effects of methylprednisolone (MTP). METHODS: CME was induced by injection of microspheres (42 MUm Dynospheres) into left anterior descending artery of mini swine. The animals were divided into two groups. Group 1 (n = 9) received 120,000 microspheres and Group 2 (n = 7) received 120,000 microspheres following intravenous administration of 30 mg/kg MTP. Contrast-enhanced magnetic resonance imaging (CeMRI) was performed at baseline, 6 h after intervention, and 1 week later. RESULTS: In Group 1, LVEF was significantly decreased at 6 h but recovered 1 week. This was accompanied by continuing left ventricular remodeling. In Group 2, LVEF remained unchanged at all assessment times. LVEF measured at 6 h and 1 week after CME in Group 1 and Group 2 was 0.39 +/- 0.06 and 0.44 +/- 0.04, and 0.44 +/- 0.04 and 0.48 +/- 0.03, respectively (Both P >0.05). Hyperenhancement at the anterior wall of the left ventricle was shown by MRI at 6 h in Group 1 but not in Group 2. The hyperenhanced area in Group 1 was 7.77 +/- 1.49% of left ventricular mass. CONCLUSIONS: The consequence of CME is left ventricular dilation with preserved LVEF. Pretreatment with MTP appears to have a cardioprotective effect on left ventricular remodeling. PMID- 24495646 TI - Cost-effectiveness of reducing salt intake in the Pacific Islands: protocol for a before and after intervention study. AB - BACKGROUND: There is broad consensus that diets high in salt are bad for health and that reducing salt intake is a cost-effective strategy for preventing chronic diseases. The World Health Organization has been supporting the development of salt reduction strategies in the Pacific Islands where salt intakes are thought to be high. However, there are no accurate measures of salt intake in these countries. The aims of this project are to establish baseline levels of salt intake in two Pacific Island countries, implement multi-pronged, cross-sectoral salt reduction programs in both, and determine the effects and cost-effectiveness of the intervention strategies. METHODS/DESIGN: Intervention effectiveness will be assessed from cross-sectional surveys before and after population-based salt reduction interventions in Fiji and Samoa. Baseline surveys began in July 2012 and follow-up surveys will be completed by July 2015 after a 2-year intervention period.A three-stage stratified cluster random sampling strategy will be used for the population surveys, building on existing government surveys in each country. Data on salt intake, salt levels in foods and sources of dietary salt measured at baseline will be combined with an in-depth qualitative analysis of stakeholder views to develop and implement targeted interventions to reduce salt intake. DISCUSSION: Salt reduction is a global priority and all Member States of the World Health Organization have agreed on a target to reduce salt intake by 30% by 2025, as part of the global action plan to reduce the burden of non-communicable diseases. The study described by this protocol will be the first to provide a robust assessment of salt intake and the impact of salt reduction interventions in the Pacific Islands. As such, it will inform the development of strategies for other Pacific Island countries and comparable low and middle-income settings around the world. PMID- 24495647 TI - Maskless micro/nanofabrication on GaAs surface by friction-induced selective etching. AB - In the present study, a friction-induced selective etching method was developed to produce nanostructures on GaAs surface. Without any resist mask, the nanofabrication can be achieved by scratching and post-etching in sulfuric acid solution. The effects of the applied normal load and etching period on the formation of the nanostructure were studied. Results showed that the height of the nanostructure increased with the normal load or the etching period. XPS and Raman detection demonstrated that residual compressive stress and lattice densification were probably the main reason for selective etching, which eventually led to the protrusive nanostructures from the scratched area on the GaAs surface. Through a homemade multi-probe instrument, the capability of this fabrication method was demonstrated by producing various nanostructures on the GaAs surface, such as linear array, intersecting parallel, surface mesas, and special letters. In summary, the proposed method provided a straightforward and more maneuverable micro/nanofabrication method on the GaAs surface. PMID- 24495649 TI - Leukoaraiosis and ambulatory blood pressure load in a healthy elderly cohort study: the PROOF study. AB - BACKGROUND: Old age and hypertension are consistently reported to be the main risk factors of leukoaraiosis. The association between white matter lesions (WMLs) and other cardiovascular risk factors (CVRF) remains controversial. We evaluated the association between CVRF and WMLs in a cohort study and determined the blood pressure variables that could predict WML severity. METHODS: 830 subjects (65+/-1 years of age, 60% women) from the PROOF study, with a reliable ABPM and brain MRI, were included. The exclusion criteria included prior myocardial infarction, stroke, heart failure, atrial fibrillation, type 1 diabetes mellitus, and pacing. White matter changes on MRI were defined as hyperintensities >5mm on FLAIR images. We used the total degree of WML (range: 0 30) by adding the region-specific scores of both hemispheres. RESULTS: Linear regression analyses demonstrated a significant relationship between total leukoaraiosis score and 24h systolic blood pressure (SBP), 24h diastolic BP, daytime SBP and DBP and nighttime SBP. No significant relationship was found between leukoaraiosis score and clinical SBP, clinical DBP, or nocturnal DIP. There was also no significant relationship between leukoaraiosis and other recognized cardiovascular risk factors. Based on a ROC curve analysis, we identified the optimal threshold separating high-risk WML patients for a mean 24h SBP above 123 mmHg (p<0.05). CONCLUSIONS: Even moderate increases in 24h SBP promote arteriolar fragility of the cerebral white matter in a population aged 65. The prognostic implications of such abnormalities in asymptomatic and moderate cardiovascular risk populations remain to be evaluated. PMID- 24495648 TI - Sensitization of U937 leukemia cells to doxorubicin by the MG132 proteasome inhibitor induces an increase in apoptosis by suppressing NF-kappa B and mitochondrial membrane potential loss. AB - BACKGROUND: The resistance of cancerous cells to chemotherapy remains the main limitation for cancer treatment at present. Doxorubicin (DOX) is a potent antitumor drug that activates the ubiquitin-proteasome system, but unfortunately it also activates the Nuclear factor kappa B (NF-kB) pathway leading to the promotion of tumor cell survival. MG132 is a drug that inhibits I kappa B degradation by the proteasome-avoiding activation of NF-kB. In this work, we studied the sensitizing effect of the MG132 proteasome inhibitor on the antitumor activity of DOX. METHODS: U937 human leukemia cells were treated with MG132, DOX, or both drugs. We evaluated proliferation, viability, apoptosis, caspase-3, -8, and -9 activity and cleavage, cytochrome c release, mitochondrial membrane potential, the Bcl-2 and Bcl-XL antiapoptotic proteins, senescence, p65 phosphorylation, and pro- and antiapoptotic genes. RESULTS: The greatest apoptosis percentage in U937 cells was obtained with a combination of MG132 + DOX. Likewise, employing both drugs, we observed a decrease in tumor cell proliferation and important caspase-3 activation, as well as mitochondrial membrane potential loss. Therefore, MG132 decreases senescence, p65 phosphorylation, and the DOX-induced Bcl-2 antiapoptotic protein. The MG132 + DOX treatment induced upregulation of proapoptotic genes BAX, DIABLO, NOXA, DR4, and FAS. It also induced downregulation of the antiapoptotic genes BCL-XL and SURVIVIN. CONCLUSION: MG132 sensitizes U937 leukemia cells to DOX-induced apoptosis, increasing its anti-leukemic effectiveness. PMID- 24495650 TI - Ancient Persian medical views on the heart and blood in the Sassanid era (224-637 AD). AB - The Sassanid Empire in Persia (224-637 AD) ruled one of the most influential eras in world history. They with the Romans and later the Byzantines were two global powers in ancient times. Medicine was well organized in the official Sassanid system. Hospitals, medical centers, and universities were developed throughout Persia during their reign. This study brings to light for the first time the era's medical views on the heart and blood, based on extant Sassanid Pahlavi manuscripts and documents. Although these documents are non-medical texts (because Sassanid medical texts were destroyed in attacks on Iran by neighboring powers, such as Alexander the Macedonian and leaders of the Arab Empire throughout history), some novel theories on the history of cardiology can be found among them. Physicians of that time made a preliminary description of pulmonary circulation. They knew about the role of blood circulation in feeding bodily organs. They believed that blood is a factor for spreading infection because of its invisible monsters (divan). Their beliefs can be considered as the first theories on infection due to an external living factor, today known as the microbe. Other Sassanid beliefs and findings about the heart and blood in medicine are described in this review. PMID- 24495651 TI - Chronic takotsubo syndrome with acute exacerbations may be the villain in the increase of morbidity and mortality in patients with decompensated chronic heart failure. PMID- 24495652 TI - Low-dose dipyridamole treatment partially prevents diabetes mellitus-induced vascular endothelial and renal abnormalities in rats. PMID- 24495653 TI - No more metallic cages: an attractive hybrid strategy with bioresorbable vascular scaffold and drug-eluting balloon for diffuse or tandem lesions in the same vessel. PMID- 24495654 TI - A lady with atrial myxoma presenting with myocardial infarction and cerebral aneurysm. PMID- 24495655 TI - Simultaneous onset of myocardial infarction and ischemic stroke in a patient with atrial fibrillation: multiple territory injury revealed on angiography and magnetic resonance. PMID- 24495656 TI - Endoscopic recanalization technique for complete ligation of bile duct after cholecystectomy. PMID- 24495657 TI - Superficial esophageal squamous cell carcinoma over esophageal varices treated by endoscopic submucosal dissection. PMID- 24495658 TI - Can a chimp say "no"? Reenvisioning chimpanzee dissent in harmful research. AB - Among the "hard cases" of captive animal research is the continued use of chimpanzees in harmful experimental science. In a recent article I contend that contemporary animal welfare science and chimpanzee behavioral studies permit, if not require, a reappraisal of the moral significance of chimpanzee dissent from participation in certain experiments. In what follows, I outline my earlier argument, provide a brief survey of some central concepts in pediatric research ethics, and use these to enrich an understanding of chimpanzee dissent useful for research ethics. PMID- 24495659 TI - Cannabinoid receptor agonist disrupts behavioral and neuroendocrine responses during lactation. AB - It has been shown that the endocannabinoid system is involved in the neurohypophyseal hormone secretion produced by exposure to several different stimuli; however, the influence of this system on neuroendocrine responses during lactation is unclear. Therefore, the aim of our study was to investigate the influence of an acute peripheral administration of WIN55,212-2 (cannabinoid receptor agonist) on behavioral and neuroendocrine responses during lactation. On day 6 of lactation, female rats were treated with vehicle or WIN55,212-2 30 min before the start of our experiments. To evaluate maternal behavior, the pups were returned to their home cages to the side of the cage opposite the previous nest, and the resulting behavior of the lactating rats was recorded for the next 30 min. Aggressive behavior was evaluated for 10 min following the placement of an intruder male rat in the home cage. The plasma level of oxytocin and the amount of milk consumption by the pups were evaluated 15 min after the onset of suckling. In addition, double-labelled c-Fos/oxytocin neurons in the medial magnocellular subdivision of the paraventricular nucleus and in the supraoptic nucleus were quantified for each lactating rat. The results show that WIN decreased maternal care, decreased aggressive behaviors, suppressed maternal anxiolysis, decreased plasma oxytocin levels and milk consumption by pups and decreased activation of oxytocinergic neurons in hypothalamic nuclei. Our results indicate that the changes in the behavioral responses of lactating rats treated with WIN maybe can be related to disruption in the neuroendocrine control of oxytocin secretion. PMID- 24495660 TI - Reinstatement of encoding context during recollection: behavioural and neuroimaging evidence of a double dissociation. AB - In both a behavioural and neuroimaging study, we examined whether memory performance and the pattern of brain activation during a word recognition task differed depending on the type of visual context presented during encoding. Participants were presented with a list of words, paired with either a picture of famous face, a famous scene, or a scrambled image, to study for a later recognition test. During the recognition test, participants made 'remember', 'know', or 'new' responses to words presented alone. In the neuroimaging experiment, the retrieval phase was scanned using event-related fMRI and brain activation was compared for remember and know responses given to words studied with famous faces and famous scenes. Behaviourally, in both studies, memory was enhanced if initial encoding was accompanied by a meaningful image (famous face or famous scene) relative to a scrambled image which contained no semantic information. At the neural level, whole brain analysis showed a double dissociation during recollection: BOLD signal in the right fusiform gyrus (within the Fusiform Face Area) was higher for remember responses given to words studied with famous faces compared to famous scenes, and was higher in the left parahippocampus (within the Parahippocampal Place Area) for words studied with famous scenes relative to famous faces. No such differential activation was found for know responses. Results suggest that participants spontaneously integrate item and meaningful contexts at encoding, improving subsequent item recollection, and that context-specific brain regions implicated during encoding are recruited during retrieval for the recollective, but not familiarity, memory process. PMID- 24495661 TI - Metabolic cancer biology: structural-based analysis of cancer as a metabolic disease, new sights and opportunities for disease treatment. AB - The cancer cell metabolism or the Warburg effect discovery goes back to 1924 when, for the first time Otto Warburg observed, in contrast to the normal cells, cancer cells have different metabolism. With the initiation of high throughput technologies and computational systems biology, cancer cell metabolism renaissances and many attempts were performed to revise the Warburg effect. The development of experimental and analytical tools which generate high-throughput biological data including lots of information could lead to application of computational models in biological discovery and clinical medicine especially for cancer. Due to the recent availability of tissue-specific reconstructed models, new opportunities in studying metabolic alteration in various kinds of cancers open up. Structural approaches at genome-scale levels seem to be suitable for developing diagnostic and prognostic molecular signatures, as well as in identifying new drug targets. In this review, we have considered these recent advances in structural-based analysis of cancer as a metabolic disease view. Two different structural approaches have been described here: topological and constraint-based methods. The ultimate goal of this type of systems analysis is not only the discovery of novel drug targets but also the development of new systems-based therapy strategies. PMID- 24495662 TI - Treatment of auditory hallucinations with bilateral theta burst stimulation: a randomized controlled pilot trial. PMID- 24495663 TI - Lack of hepatitis B virus reactivation after anti-tumour necrosis factor treatment in potential occult carriers with chronic inflammatory arthropathies. AB - BACKGROUND: Hepatitis B virus (HBV) reactivation in patients positive for antibody to HB core antigen (anti-HBc), negative for HB surface antigen (HBsAg) and HBV-DNA (potential occult HBV carriers), treated with anti-tumor necrosis factor (TNF)alpha, is a debated question. The aim of the study was to evaluate the safety of anti-TNFalpha therapy in anti-HBc positive/HBsAg negative subjects with rheumatoid arthritis (RA) and spondyloarthropathy (SpA). METHODS: All consecutive HBsAg negative RA and SpA outpatients referring to the Immuno Rheumatology Institute at the S. Andrea hospital, Sapienza, University of Rome who had to undergo anti-TNFalpha therapy. RESULTS: Among the 169 enrolled subjects, 20 (12%) were potential occult HBV carriers (anti-HBc positive, HBsAg and HBV-DNA negative patients with or without anti-HBs). During the follow-up (mean +/- SD 45 +/- 22 months), aminotransferases and HBV-DNA, tested every two and six months respectively, did not change. CONCLUSION: This study confirms the substantial safety of anti-TNFalpha therapy in potential occult HBV carriers RA and SpA patients. PMID- 24495664 TI - Experience with the delegation of anaesthesia for disbudding and castration to trained and certified livestock owners. AB - BACKGROUND: Anaesthesia is mandatory for disbudding and castrating calves and lambs of any age, in Switzerland. According to the "anaesthesia delegation model" (ADM), anaesthesia for disbudding calves <3 weeks of age and castrating calves and lambs <2 weeks of age may be administered by certified farmers. Experience with this unique model is not available. The aim was to evaluate the experience of the veterinary practitioners with the ADM. The response rate was 42%. The survey consisted of one questionnaire for each procedure. Procedure I was the delegation of anaesthesia for disbudding calves and procedures II and III were anaesthesia for castrating calves and lambs. RESULTS: Procedure I was performed with local anaesthesia in all farms of 51.8% of the veterinary practices, while this was only 39.3% and 7.6% for procedures II and III (p < 0.001). Anaesthesia for procedure I was administered technically correctly by farmers in at least 66% of the farms of 58.3% of the practitioners, while this was 45.4% and only 23.6% for procedures II and III (p < 0.001). The ADM was assessed as a moderate to very good model to reinforce the legal obligations for procedures I, II, or III by 74.8%, 76.5% and 62.0% of the veterinary practitioners (p < 0.005). CONCLUSIONS: The delegation of anaesthesia to certified farmers may be a promising model to reinforce the obligation to provide local anaesthesia for disbudding and castrating calves, but to a lesser extent for castrating lambs. PMID- 24495665 TI - Multiple distant adenomyosis mimicking carcinomatosis on FDG PET/CT. PMID- 24495666 TI - Neurocognitive functioning following preeclampsia and eclampsia: a long-term follow-up study. AB - OBJECTIVE: Women who suffered preeclampsia and eclampsia may report subjective cognitive difficulties in daily life, the interpretation of which is cumbersome, because these are affected by emotional factors. Previous studies only included preeclamptic women investigated shortly after pregnancy. We aimed to determine whether these subjective reports of cognitive difficulty could be interpreted as reflecting objective cognitive dysfunction. Therefore, cognitive functioning was assessed using standardized neurocognitive tests in both preeclamptic and eclamptic women several years following the index pregnancy. STUDY DESIGN: Forty six formerly eclamptic, 51 formerly preeclamptic, and 48 control women who had normotensive pregnancies, age-matched, participated in this study. Average elapsed time since index pregnancy was 7 years. Neurocognitive tests were divided into 6 domains; visual perception, motor functions, working memory, long-term memory, attention, and executive functioning. Subjective cognitive functioning was measured by the Cognitive Failures Questionnaire and anxiety/depression by the Hospital Anxiety and Depression Scale. RESULTS: Both preeclamptic and eclamptic women performed worse on the motor functions domain (P < .05), without differences on the other domains. They scored worse on the Cognitive Failures Questionnaire (P < .01), the Hospital Anxiety and Depression Scale anxiety (P < .01), and depression (P < .05) subscales. CONCLUSION: Women who suffered eclampsia and/or preeclampsia demonstrate no objective cognitive impairment as compared with controls. Contrary to the well-structured test setting, both groups do report more cognitive failures, which are thought to reflect neurocognitive dysfunction in complex, stressful daily-life situations. Such report of cognitive failures may be compounded by anxiety and depression. Future studies should focus on the relationship of neurocognitive functioning with structural cerebral abnormalities. PMID- 24495667 TI - Risk of placental dysfunction disorders after prior miscarriages: a population based study. AB - OBJECTIVE: The objective of the investigation was to study the association between prior miscarriages and the risks of placental dysfunction disorders, including preeclampsia, stillbirth, birth of a small for gestational age (SGA) infant, placental abruption, and spontaneous preterm birth. STUDY DESIGN: In a population-based cohort study including 619,587 primiparous women, we estimated risks of placental dysfunction disorders for women with 1 (n = 68,185), 2 (n = 11,410) and 3 or more (n = 3823) self-reported prior miscarriages. Risks were calculated as odds ratios by unconditional logistic regression analysis and adjustments were made for maternal age, early pregnancy body mass index, height, smoking habits, country of birth, years of formal education, in vitro fertilization, chronic hypertension, pregestational diabetes, hypothyroidism, systemic lupus erythematosis, fetal sex, and year of childbirth. RESULTS: Compared with women with no prior miscarriage, women with 1 prior miscarriage had almost no increased risks. Women with 2 prior miscarriages had increased risks of spontaneous preterm birth, preterm (<37 weeks) SGA infant, and placental abruption. The rates of all disorders were higher for women with 3 or more prior miscarriages compared with women without prior miscarriages: preeclampsia, 5.83% vs 4.27%; stillbirth, 0.69% vs 0.33%, SGA infant, 5.09% vs 3.22%, placental abruption, 0.81% vs 0.41%; and spontaneous preterm birth, 6.45% vs 4.40%. The adjusted odds ratios for preterm (<37 weeks) disorders in women with 3 prior miscarriages were approximately 2. CONCLUSION: History of 2 or more miscarriages is associated with an increased risk of placental dysfunction disorders and should be regarded as a risk factor in antenatal care. PMID- 24495668 TI - Dilation and evacuation training in maternal-fetal medicine fellowships. AB - OBJECTIVE: Many maternal-fetal medicine (MFM) specialists provide dilation and evacuation (D&E) procedures for their patients with fetal or obstetric complications. Our study describes the D&E training opportunities that are available to MFM trainees during their fellowship. STUDY DESIGN: National surveys of MFM fellows and fellowship program directors assessed the availability of D&E training in fellowship. Univariate and multivariate comparisons of correlates of D&E training and provision were performed. RESULTS: Of the 270 MFM fellows and 79 fellowship directors who were contacted, 92 (34%) and 44 (56%) responded, respectively. More than one-half of fellows (60/92) and almost one-half of fellowship programs (20/44) report organized training opportunities for D&E. Three-quarters of fellows who were surveyed believe that D&E training should be part of MFM fellowship, and one-third of fellows who have not yet been trained would like training opportunities. Being at a fellowship that offers D&E training is associated with 7.5 times higher odds of intending to provide D&E after graduation (P = .005; 95% confidence interval, 1.8-30). CONCLUSION: MFM physicians are in a unique position to provide termination services for their patients with pregnancy complications. Many MFM subspecialists provide D&E services during fellowship and plan to continue after graduation. MFM fellows express a strong interest in D&E training; therefore, D&E training opportunities should be offered as a part of MFM fellowship. PMID- 24495669 TI - ENMD-1068, a protease-activated receptor 2 antagonist, inhibits the development of endometriosis in a mouse model. AB - OBJECTIVE: Protease-activated receptor 2 plays an important role in the pathogenesis of endometriosis. We studied the effect of ENMD-1068, a protease activated receptor 2 antagonist, on the development of endometriosis in a noninvasive fluorescent mouse model. STUDY DESIGN: A red fluorescent protein expressing xenograft model of human endometriosis was created in nude mice. After endometriosis induction, the mice were injected intraperitoneally with either 25 mg/kg or 50 mg/kg ENMD-1068 or with 200 MUL of the vehicle control daily for 5 days. The endometriotic lesions that developed in the mice were then counted, measured, and collected. The lesions were assessed for the production of interleukin 6 and monocyte chemotactic protein-1 by enzyme-linked immunosorbent assays and evaluated for the activation of nuclear factor-kappaB and the expression of vascular endothelial growth factor by immunohistochemical analyses. Cell proliferation and apoptosis were assessed by immunohistochemistry for Ki-67 and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling, respectively. RESULTS: ENMD-1068 dose-dependently inhibited the development of endometriotic lesions (P < .05) without apparent toxicity to various organs of the treated mice. Consistently, ENMD-1068 dose-dependently inhibited the expression of interleukin 6 and nuclear factor-kappaB (P < .05) and cell proliferation (P < .05) in the lesions, as well as increased the percentage of apoptotic cells (P < .05). ENMD-1068 reduced the levels of monocyte chemotactic protein-1 and vascular endothelial growth factor in the lesions (P < .05), but not in a dose-dependent manner. CONCLUSION: Our study suggests that ENMD-1068 is effective in suppressing the growth of endometriosis, which might be attributed to the drug's antiangiogenic and antiinflammatory activities. PMID- 24495670 TI - The potential role of prolactin as a modulator of the secretion of proinflammatory mediators in chorioamniotic membranes in term human gestation. AB - OBJECTIVE: To test the effect of prolactin (PRL) on expression of proinflammatory cytokines and matrix metallopeptidase 9 (MMP-9) in vitro. STUDY DESIGN: Tissue explants were incubated from 4 to 48 hours alone or in the presence of 500 ng/mL PRL, and mRNA expression in tissues and secretion of interleukin (IL)-1beta, tumor necrosis factor alpha (TNF-alpha), MMP-2, and MMP-9 was quantified. RESULTS: Fetal membranes secreted IL-1beta, TNF-alpha, and MMP-9 in culture with consistent low concentration during the first 24 hours and then increased progressively. The presence of PRL during explant incubation significantly decreased the patterns of IL-1beta, TNF-alpha and MMP-9 secretion along culture (P < .001). MMP-2 secretion was unaffected by PRL. The relative basal expression of IL-1beta mRNA (1.2 +/- 0.87) was reduced by 80% in the presence of PRL after 32 hours of incubation of the membranes (P = .001). The expression of the TNF alpha mRNA was not modified by the presence of PRL (0.06 +/- 0.01) compared with the basal expression levels (0.05 +/- 0.01). MMP-9 mRNA basal expression (0.018 +/- 0.008) was significantly reduced (P = .001) in the presence of PRL after 32 hours (0.002 +/- 0.0005). CONCLUSION: PRL may be a potential candidate as a key signal controlling the expression of signals related to the proinflammatory reaction associated with human labor. PMID- 24495671 TI - Racial/ethnic disparities in contraceptive use: variation by age and women's reproductive experiences. AB - OBJECTIVE: Disparities in unintended pregnancy in the United States are related, in part, to black and Hispanic women being overall less likely to use effective contraceptive methods. However, the fact that these same groups are more likely to use female sterilization, a highly effective method, suggests there may be variability in disparities in contraceptive use across a woman's life course. We sought to assess the relationship between race/ethnicity and contraceptive use in a nationally representative sample and to approximate a life course perspective by examining effect modification on these disparities by women's age, parity, and history of unintended pregnancy. STUDY DESIGN: We conducted an analysis of the 2006 through 2010 National Survey of Family Growth to determine the association between race/ethnicity and: (1) use of any method; (2) use of a highly or moderately effective method among women using contraception; and (3) use of a highly effective method among women using contraception. We then performed analyses to assess interactions between race/ethnicity and age, parity, and history of unintended pregnancy. RESULTS: Our sample included 7214 females aged 15-44 years. Compared to whites, blacks were less likely to use any contraceptive method (adjusted odds ratio, 0.65); and blacks and Hispanics were less likely to use a highly or moderately effective method (adjusted odds ratio, 0.49 and 0.57, respectively). Interaction analyses revealed that racial/ethnic disparities in contraceptive use varied by women's age, with younger women having more prominent disparities. CONCLUSION: Interventions designed to address disparities in unintended pregnancy should focus on improving contraceptive use among younger women. PMID- 24495672 TI - Regulation of Myelination in the Central Nervous System by Nuclear Lamin B1 and Non-coding RNAs. AB - Adult-onset autosomal dominant leukodystrophy (ADLD) is a progressive and fatal hereditary demyelination disorder characterized initially by autonomic dysfunction and loss of myelin in the central nervous system (CNS). Majority of ADLD is caused by a genomic duplication of the nuclear lamin B1 gene (LMNB1) encoding lamin B1 protein, resulting in increased gene dosage in brain tissue. In vitro, excessive lamin B1 at the cellular level reduces transcription of myelin genes, leading to premature arrest of oligodendrocyte differentiation. Murine models of ADLD overexpressing LMNB1 exhibited age-dependent motor deficits and myelin defects, which are associated with reduced occupancy of the Yin Yang 1 transcription factor at the promoter region of the proteolipid protein gene. Lamin B1 overexpression mediates oligodendrocyte cell-autonomous neuropathology in ADLD and suggests lamin B1 as an important regulator of myelin formation and maintenance during aging. Identification of microRNA-23 (miR-23) as a negative regulator of lamin B1 can ameliorate the consequences of excessive lamin B1 at the cellular level. miR-23a-overexpressing mice display enhanced oligodendrocyte differentiation and myelin synthesis. miR-23a targets include a protein coding transcript PTEN (phosphatase and tensin homolog on chromosome 10), and a long noncoding RNA (2700046G09Rik), indicating a unique role for miR-23a in the coordination of proteins and noncoding RNAs in generating and maintaining healthy myelin. Here, we provide a concise review of the current literature on clinical presentations of ADLD and how lamin B1 affects myelination and other developmental processes. Moreover, we address the emerging role of non-coding RNAs (ncRNAs) in modulating gene networks, specifically investigating miR-23 as a potential target for the treatment of ADLD and other demyelinating disorders. PMID- 24495673 TI - The utility of low-density genotyping for imputation in the Thoroughbred horse. AB - BACKGROUND: Despite the dramatic reduction in the cost of high-density genotyping that has occurred over the last decade, it remains one of the limiting factors for obtaining the large datasets required for genomic studies of disease in the horse. In this study, we investigated the potential for low-density genotyping and subsequent imputation to address this problem. RESULTS: Using the haplotype phasing and imputation program, BEAGLE, it is possible to impute genotypes from low- to high-density (50K) in the Thoroughbred horse with reasonable to high accuracy. Analysis of the sources of variation in imputation accuracy revealed dependence both on the minor allele frequency of the single nucleotide polymorphisms (SNPs) being imputed and on the underlying linkage disequilibrium structure. Whereas equidistant spacing of the SNPs on the low-density panel worked well, optimising SNP selection to increase their minor allele frequency was advantageous, even when the panel was subsequently used in a population of different geographical origin. Replacing base pair position with linkage disequilibrium map distance reduced the variation in imputation accuracy across SNPs. Whereas a 1K SNP panel was generally sufficient to ensure that more than 80% of genotypes were correctly imputed, other studies suggest that a 2K to 3K panel is more efficient to minimize the subsequent loss of accuracy in genomic prediction analyses. The relationship between accuracy and genotyping costs for the different low-density panels, suggests that a 2K SNP panel would represent good value for money. CONCLUSIONS: Low-density genotyping with a 2K SNP panel followed by imputation provides a compromise between cost and accuracy that could promote more widespread genotyping, and hence the use of genomic information in horses. In addition to offering a low cost alternative to high-density genotyping, imputation provides a means to combine datasets from different genotyping platforms, which is becoming necessary since researchers are starting to use the recently developed equine 70K SNP chip. However, more work is needed to evaluate the impact of between-breed differences on imputation accuracy. PMID- 24495674 TI - A qualitative study of CVD management and dietary changes: problems of 'too much' and 'contradictory' information. AB - BACKGROUND: Nutrition education for cardiovascular disease (CVD) management is not effective for all population groups. There is little understanding of the factors that hinder patients from adhering to dietary recommendations. METHODS: 37 interviews were conducted with people living with CVD in Adelaide, Australia. Recruitment occurred via General Practitioner (GP) clinics and hospital cardiac rehabilitation programs. Participants were either receiving preventive treatment or active treatment for established CVD. RESULTS: The volume and contradictory nature of dietary information were the most prominent barriers to making changes identified in interviews, especially by order participants. CONCLUSION: Patients will seek out, or come into contact with information which contradicts advice from their GPs. The volume of information may lead them to resort to old and familiar habits. GPs play a valuable role in highlighting key take-home messages and reliable external sources of information. The findings have implications for GP practice given that lifestyle changes are a cost- and clinically-effective means of managing CVD. PMID- 24495675 TI - Two-dimensional NQR using ultra-broadband electronics. AB - We have recently developed an ultra-broadband instrument that can effectively excite and detect NMR and NQR signals over a wide frequency range. Our current system operates between 100 kHz and 3.2 MHz using an un-tuned sample coil. The major benefits of this instrument compared to conventional NQR/NMR systems include increased robustness, ease of use (in particular for multi-frequency experiments), and elimination of the need for tuning adjustments in the hardware. Here we describe its use for performing two-dimensional (2D) scans, which allow improved interpretation of complex NQR spectra by detecting the connected resonances. Our method relies on population transfers between the three energy levels of spin-1 nuclei (such as (14)N) by using multi-frequency excitation and a single RF coil. Experimental results on pure samples and mixtures are also presented. PMID- 24495676 TI - Objective assessment of urban built environment related to physical activity- development, reliability and validity of the China Urban Built Environment Scan Tool (CUBEST). AB - BACKGROUND: Some aspects of the neighborhood built environment may influence residents' physical activity, which in turn, affects their health. This study aimed to develop an urban built environment evaluation tool and conduct necessary reliability and validity tests. METHODS: A 41-item urban built environment scan tool was developed to objectively assess the neighborhood built environment features related to physical activity. Six neighborhoods in Hangzhou were selected from three types of administrative planning units. A pair of auditors independently assessed all of the 205 street segments at the same time. Half of the segments (n = 104) were audited twice by the same auditor after a two-week time interval. Inter-rater reliability was assessed by comparing the audits of paired observers, while intra-rater reliability was evaluated by comparing an auditor's repeated assessments of the same segments. The construct validity was tested using factor analysis. RESULTS: The inter-rater reliability for most items was above 0.8. The intra-rater reliability for most items was above 0.4, and was lower than corresponding inter-rater reliability. Six factors were extracted by factor analysis and the factor loading matrix showed good construct validity. CONCLUSIONS: The CUBEST is a reliable and valid instrument that can be used to assess the physical activity-related built environment in Hangzhou, and potentially other cities in China. PMID- 24495677 TI - [Pay attention to screening of endometrial carcinoma]. PMID- 24495679 TI - [Different methods for the diagnosis of endometrial histological comparative study]. AB - OBJECTIVE: To evaluate the feasibility of endometrial sampler Pipelle for endometrial histologic diagnosis. METHODS: Using prospective and self-control methods, 200 patients with endometrial biopsy firstly used Pipelle endometrial sampler for endometrial tissue, then followed by diagnostic curettage, the same pathologist evaluated the specimen quality and made the histologic diagnosis. RESULTS: Totally 200 patients completed the observation, the specimen satisfaction of Pipelle was 93.0% (in this 200 cases, 186 cases were satisfactory), its pathological accuracy was 85.0% (in this 200 cases, 170 cases' pathological results are highly consistent with diagnostic curettage). There was no significant difference between two kinds of endometrial sampling (P > 0.05). There was no pain for patients during the Pipelle using process. CONCLUSION: Pipelle could obtain satisfactory samples used for histological diagnosis in normal endometrium, simple hyperplasia, complex hyperplasia, atypical hyperplasia and endometrial cancer disease, because its pathological accuracy is so close to the diagnostic curettage, which may be used as a routine screening tool of endometrial diseases. PMID- 24495678 TI - [Screening and sampling of endometrial carcinoma accuracy of the endometrial cytology test for the screening of endometrial cancer]. AB - OBJECTIVE: To evaluate the accuracy of endometrial cytology test (ECT) for the diagnosis of endometrial cancer or precancerous lesions and then discuss the value of ECT as a screening tool for endometrial cancer.Secondly, to investigate related characteristics and independent risk factors of epidemiology of endometrial carcinomas and atypical endometrial hyperplasia to advise proper crowd for endometrial carcinomas screening and monitoring. METHODS: Totally 1717 preoperative questionnaires on hysteroscopy + dilation & curettage, histopathology and endometrial cytological tests in Peking University First Hospital, People's Hospital of Beijing Daxing District and Beijing Cancer Hospital, from March 2009 to May 2013 were completed. Histopathologic diagnoses were used as the gold standard for determining the accuracy of ECT.Extrapolation: applied binary logistic regression method to narrow down the risk factors of histopathology and endometrial cytological examination. RESULTS: Satisfaction rate of cytological specimens and pathological specimens were 96.45% (1656/1717) and 91.44% (1570/1717), respectively. ECT provided sufficient material for the diagnosis significantly more often than histopathology (P < 0.05). For the ECT diagnosis of endometrial cancer: accuracy was estimated at 88.2%, sensitivity at 87.3%, specificity at 88.3%, positive predictive value (PPV) at 41.9%, negative predictive value (NPV)at 98.6%.Univariate analysis revealed that risk factors of diagnosis of endometrial carcinomas and atypical hyperplasia of histopathology were included:body mass index (BMI) >= 25 kg/m(2), age >= 40 years old, diabetes mellitus, hypertension, menopause, family history of malignant tumor (all P < 0.10). Multifactor analysis revealed that the independent risk factors were included:BMI >= 25 kg/m(2), age >= 40 years, menopause and family history of malignant tumor (all P < 0.05). CONCLUSIONS: The results of the current study indicated that the accuracy of ECT for the diagnosis of endometrial cancer was high.Furthermore, ECT could be a useful tool for the screening of endometrial cancer.Independent risk factors of endometrial carcinomas and atypical endometrial hyperplasia including:age over 40 years, BMI >= 25 kg/m(2), menopause and family history of malignant tumor. PMID- 24495680 TI - [Application of endometrial sampling device during the follow-up visit for the conservative treatment of endometrial cancer]. AB - OBJECTIVE: To study the feasibility of endometrial sampling device as a sampling tool during the follow-up visit for endometrial cancer patients undergone conservative treatment. METHODS: Before the hysteroscopy examination, endometrial sampling device was used to take the endometrium specimens 43 times in 19 patients who had been diagnosed as endometrial cancer or atypical hyperplasia, and were undergone conservative treatment during May 2012 to Mar. 2013. All cases accepted vaginal ultrasound screening before every sampling by endometrial sampling device. The histological results were compared with those done by hysteroscopy. RESULTS: The average age of those patients was (30 +/- 6) years old. The mean thickness of the endometrium during the treatment was (0.81 +/- 0.65) cm. The qualified rate for the sampling was 95% (41/43). Compared with the specimens undergone by hysteroscopy direct sampling, 32 samples got by the endometrial sampling device with thicker endometrium (0.93 +/- 0.70) cm had the same histological results, while the other 9 patients with thinner endometrium (0.40 +/- 0.14) cm were not (P = 0.031). CONCLUSION: The endometrial sampling device could be used during the follow-up visit for the conservative treatment patients with endometrial cancer or atypical hyperplasia, the vaginal ultrasound screening should be used together to figure out those with thinner endometrium. PMID- 24495681 TI - [Analysis of the effects of gestational diabetes mellitus based on abnormal blood glucose on pregnancy outcomes]. AB - OBJECTIVE: To investigate the relationship of different types of gestational diabetes mellitus (GDM) and pregnancy outcomes. METHODS: A total of 4090 cases, who received prenatal examination and delivered in Peking University First Hospital and performed a 75 g oral glucose tolerance test (75 g OGTT) at 24-28 gestational weeks, from January. 1(st), 2011 to Jul 31(st), 2012 , were divided into 2 groups. Normal blood glucose group:the result of OGTT (fasting plasma glucose, 1 hour glucose and 2 hour glucose ) was normal; Gestational diabetes mellitus group (GDM group): the result of OGTT was abnormal at any time point. GDM group were separated into A, B and C. GDM A means fasting plasma glucose annormal but others were normal, GDM B:fasting plasma glucose, 1 hour and/or 2 hour glucose abnormal, GDM C:fasting plasma glucose normal. To analyse the effect of different number of abnormal result of OGTT on pregnancy outcomes, GDM group were divided into I, II and III.GDMI means one abnormal blood glucose of OGTT result, GDM II: two abnormal blood glucose and GDM III:three abnormal blood glucose. We analyzed the pregnant outcomes of each group. RESULTS: (1) Among the 4090 cases, 858 cases (21.98%) were diagnosed as GDM (GDM group), and 82 cases (9.6%, 82/858) were treated with insulin.other 3232 cases with normal blood glucose (normal blood glucose group). In GDM group, the rate of cesarean section (51.9%, 445/858), premature delivery (8.4%, 72/858) and LGA (5.9%, 51/858) were respectively significantly higher than those of normal blood glucose group [ (43.5%, 1406/3232), (5.8%, 189/3232) and(4.2%, 137/3232)] (P < 0.05). But, there was no statistically significant differences for the rate of macrosomia (P > 0.05) between the GDM group(6.8%, 58/858) and normal blood glucose group (6.2%, 199/3232) . (2) In the GDM group, GDM A was 317 cases (36.9%), GDM B 239 cases (27.8%), GDM C 302 cases (35.2%). The incidence of Macrosomia and LGA in GDM B was significantly higher than that in GDM C and normal blood glucose group (P < 0.05). Comparing with GDM A , there was no statistically significance in GDM B and GDM C (P > 0.05). (3) In GDM group, GDMIwas 521 cases (60.7%), GDM II203 cases (15.6%), GDM III 134 cases (23.7%). Compared with the normal blood glucose group, GDM III had a significantly higher incidence of macrosomia and LGA and cesarean section(P < 0.01);and GDM IIhad only a significantly higher incidence of cesarean section(P < 0.01). (4) Among the 4090 cases, there were 1118 patients (27.3%) whose fasting blood glucose was below 4.4 mmol/L, of which 55 cases were diagnosed as GDM. There were 4 premature infants and 1 macrosomia. CONCLUSIONS: The GDM group with more than FBG >= 5.1 mmol/L had a higher incidence of adverse pregnancy outcomes, it suggested that we should pay more attention and take actively intervented; the pregnant woman is not recommended for 75g OGTT detection when fasting blood glucose was below 4.4 mmol/L because of the low rate of GDM and adverse pregnancy outcomes among them. PMID- 24495682 TI - [Study on positive rate of blocking antibody in women with recurrent spontaneous abortion administered by route and frequency of paternal lymphocyte immunotherapy]. AB - OBJECTIVE: To investigates factors affecting the positive rate of blocking antibody treated by paternal lymphocyte immunotherapy in patients with recurrent spontaneous abortion (RSA). METHODS: From January 2008 to August 2012, 326 RSA cases undergoing treatment in Infertility Center of Qilu Hospital were studied retrospectively. Those patients were divided into 2 groups randomly: 260 cases in intradermal injection group were administered via bilateral forearm intradermal injections for immunotherapy once 21 days, then the blocking antibody was determined after 2 (23 cases) , 3(73 cases), 4 (74 cases) , 5(90 cases) times respectively, while in subcutaneous injection group, the 66 cases were administered via subcutaneous injection once 21 days, the blocking antibody measured after 3 times; In both cases, the blocking antibody was all determined 2 weeks later. The positive rate of blocking antibodies and the rate of successful pregnancy was recorded, and then followed up after the blocking antibody turning positive. RESULTS: (1) Positive rate of blocking antibodies:the positive rate of blocking antibodies were 17% (4/23) , 58% (42/73), 72% (53/74) and 84% (76/90) in the 2, 3, 4, and 5 times of intradermal injection group, respectively (P < 0.05). In subcutaneous injection group, the positive rate of blocking antibodies was 38 % (25/66), which was significantly lower than that in group intradermal injection receiving 3 times immunotherapy (P < 0.05). (2) The rate of pregnancy:the 176 patients out of 200 patients were pregnant when antibody was positive after immunotherapy, with 71.6% (126/176) of patients gained successful pregnancy(the length of pregnancy more than 5 months). CONCLUSIONS: The route and frequency of administration of immunotherapy could influence the positive rate of blocking antibody. The rate of successful pregnancy will be increased after blocking antibody turning positive. PMID- 24495683 TI - [Study on microRNA expression in endometrium of luteal phase and its relationship with infertility of endometriosis]. AB - OBJECTIVE: To study the different expression of microRNA(miRNA) including mir 29c, mir-200a, mir-145 in the mid-secretary endometrium and its relationship with infertility of endometriosis. METHODS: From August 2011 to February 2013, 36 infertile cases with endometriosis confirmed by laparoscopy and pathology and excluded the other infertile factors in Department of Reproductive Medicine in Peking University Shenzhen Hospital were enrolled in this study, which were divided into 17 cases with stage I-II, 19 cases with stage III-IV according to the revised classification American Fertility Society. Forty-four healthy women with male factor infertility were chosen as control group. The relative expression levels of mir-29c, mir-200a, mir-145 in the endometrium of women in two groups were detected by using real-time quantitative polymerase chain reaction. Those women were followed up for pregnancy outcome of endometriosis group after assisted reproductive techniques (pregnancy and non-pregnancy group respectively). RESULTS: (1) The expression of miRNA between endometriosis and control groups:the average expression level of mir-29c, mir-200a, mir-145 in the endometrium of endometriosis group was 2.46 +/- 1.98, 3.20 +/- 2.45, 6.378 +/- 3.275, which were significantly higher than 1.36 +/- 1.05, 2.04 +/- 1.16, 4.548 +/- 1.885 in control group (P = 0.026, 0.027, 0.041, respectively). (2) The expression of miRNA between I-II stage and III-IV: the average expression level of mir-29c, mir-200a, mir-145 in the endometrium was 0.53 +/- 0.51, 0.33 +/- 0.26, 0.048 +/- 0.021 in patients with of stage I-II, while 0.26 +/- 0.18, 0.28 +/- 0.12, 0.045 +/- 0.016 in stage III-IV respectively, there were no statistically significant differences between the two groups (P = 0.191,0.661,0.753, respectively) . (3) The expression of miRNA between pregnancy and non-pregnancy groups:the average expression level of mir-29c, mir-200a, mir 145 in the endometrium were 0.60 +/- 0.30, 1.23 +/- 0.48, 0.886 +/- 0.238 in pregnancy group, while 2.64 +/- 1.73, 4.39 +/- 2.58, 7.199 +/- 3.945 in non pregnancy group, there were statistically significant differences between the two groups (P = 0.030,0.039,0.028, respectively). CONCLUSION: Up-regulation of mir 29c, mir-200a, mir-145 in the endometrial tissue might play a role in endometriosis associated infertility. PMID- 24495684 TI - [Expression of RhoA and Rho kinase in junctional zone of human adenomyosis and its relationship with dysmenorrheal]. AB - OBJECTIVE: To investigate the expression of RhoA and Rho kinase in junctional zone (JZ) of adenomyosis and normal myometrium and explore its relationship with severity of dysmenorrheal. METHODS: From Mar. to Dec. 2012, 32 cases with adenomyosis undergoing hysterectomy were enrolled as adenomyosis group including 18 cases with proliferative endometrium and 14 cases with secretory endometrium matched with 29 cases with hysterectomy due to cervical disease and ovarian tumor as control group including 12 cases with proliferative endometrium and 17 cases with secretory endometrium in Beijing Obstetrics and Gynecology Hospital Affiliated to Capital Medical University. JZ smooth muscle cells were isolated and cultured immediately after the operation. The expression of mRNA and protein of RhoA and ROCK1 in JZ in two groups were measured by real-time fluorescence quantitative RT-PCR and western blot. RESULTS: (1) The mRNA expression of RhoA and ROCK1 in JZ of adenomyosis group did not show cyclic change. In proliferative phase, the expression of RhoA and ROCK1 (1.41 +/- 0.16, 1.05 +/- 0.15) was not significantly higher than that in secretory phase (1.17 +/- 0.25, 0.98 +/- 0.10) (P > 0.05). While JZ in control group, it showed obviously cyclic change. The expression level of them in proliferative phase (0.93 +/- 0.10, 1.00 +/- 0.18) was significantly higher than that in secretory phase (0.48 +/- 0.03, 0.55 +/- 0.05) (P < 0.05); It also showed that expressions of RhoA and ROCK1 in adenomysis group were significant higher than those in the control (P < 0.05). (2) The mRNA and protein expression of RhoA and ROCK1 was positively correlated in each of two groups(r = 0.48, P < 0.01;r = 0.67, P < 0.01). (3)The expression of RhoA and ROCK1 were 1.66 +/- 0.19, 1.32 +/- 0.11 in severe dysmenorrheal, 1.28 +/- 0.12, 1.09 +/- 0.08 in moderate dysmenorrheal and 0.93 +/- 0.09,0.81 +/- 0.06 in mild dysmenorrheal, it all reached statistical difference when compared the other group. (All P < 0.05). CONCLUSIONS: The expressions of RhoA and ROCK1 in JZ in adenomyosis group were higher than those in control group, and positively correlated with the severity of dysmenorrheal in adenomysis group, but it does not change with the menstrual cycle. High expression of RhoA and ROCK1 might be involved in abnormal contraction of uterine myometrium and correlated with the dysmenorrheal in adenomysis. PMID- 24495685 TI - [Epidemiologic study of the risk factors of the adult female urinary incontinence in Uygur of Kashi in Xinjiang]. AB - OBJECTIVE: To evaluate the prevalence and associated risk factors of stress urinary incontinence(SUI) in adult women in Xinjiang. METHODS: In the cross sectional study, 3403 Uygur women aged over 20 years were interviewed through a questionnaire of International Consultation on Incontinence Questionnaire Female Lower Urinary Tract Symptoms Module (ICIQ-FLUTS) and the adult questionnaire were used in our research. All parts of the content were according to the characteristics of women in Xinjiang and the purpose of our research. The risk factors were studied by Logistic regression analysis. RESULTS: The prevalence of urinary incontinence(UI) was 41.96% (1428/3403) and 28.21% (960/3403) of SUI in Uygur women. In multivariate logistic regression analysis, the risk factors of SUI are body mass index (OR = 1.672, 95%CI:1.082-2.584), parity (OR = 5.092, 95%CI:3.889-6.666), neonatal birth weight (OR = 5.623, 95%CI:3.335-9.480), the mode of delivery (OR = 2.247, 95%CI:1.634-3.090), the lateral episiotomy (OR = 4.448, 95%CI:3.112-6.357), menopause(OR = 5.145, 95%CI: 3.613-7.328), chronic pelvic pain (OR = 3.869, 95%CI:1.051-14.250), pelvic organ prolapse (OR = 3.501, 95%CI:2.508-4.887). CONCLUSION: The incidence of SUI is related with multiple factors, especially with obesity and the obstetric factor. PMID- 24495686 TI - [Results of different postoperative adjuvant therapies for stage Ib-IIa cervical carcinoma with risk factors]. AB - OBJECTIVE: To investigate the effects of postoperative adjuvant chemotherapy (CT) and chemoradiotherapy (CRT) or radiotherapy(RT) for Ib-IIa cervical cancer with risk factors. METHODS: From March 1995 to June 2010, there were 137 patients underwent radical hysterectomy and systematic pelvic lymphadenectomy for stage Ib IIa cervical cancer admitted at Peking University First Hospital. These patients had risk factors, intermediate risk factors including bulky tumor ( > 4 cm) , lymph vascular space invasion, deep stromal invasion; high risk factors including positive surgical margin, parametrial invasion, lymph node involvement. Of the all patients, 79 cases of them were treated with CT, 58 of them were treated with RT or CRT. The 5-year survival and prognosis factors were analyzed retrospectively, the prognosis was compared between two adjuvant therapy groups. RESULTS: The univariate analysis shown that types of pathology, different grade of risk factors, stroma invasion and lymph node involvement were prognostic factors of 5-year overall survival. Patients with squamous cell carcinoma, intermediate risk factors, no parametrial invasion, and no lymph node involvement had better prognosis(P < 0.05). Whether patients with high-risk factors or intermediate-risk factors, the 5-year overall survival and 3-year disease-free survival had no difference between CT and RCT or RT groups respectively. Cox regression multivariate analysis of survival indicated that clinical stages, types of histology, different grade of risk factors were independent prognostic indicator. Patients with early stage, squamous cell carcinoma, intermediate risk factors had better prognosis. Univariate and multivariate analysis indicated that different postoperative adjuvant therapies had no effects on the prognosis. The 5 year overall survival was 88.6% in patients treated with CT, and 89.7% in patients treated with RT or CRT (P = 0.455) . CONCLUSION: There are equivalent therapeutic results between CT and RT or CRT for patients with risk factors after radical surgery, CT may be as one choice of postoperative adjuvant therapy for stage Ib-IIa cervical carcinoma with risk factors. PMID- 24495687 TI - [Clinical analysis for 18 cases of vulvar Bowen's disease]. AB - OBJECTIVE: To analyse the clinical and pathological characteristics, diagnosis, treatment and prognosis of vulvar Bowen's disease. METHODS: Clinical data including pathological characteristics, diagnosis, treatment methods and follow up of 18 cases with vulvar Bowen's disease admitted to Cancer Hospital, Chinese Academy of Medical Sciences during January 1991 to June 2011 were retrospectively analyzed. RESULTS: The median age of the 18 patients was 37 years (range:23 to 64 years) . Sixteen patients had symptoms of vulvar itching and two patients had no symptom. Five cases were single neoplasm focus and the other 13 cases were multiple focuses. The diagnosis of vulvar Bowen's disease was according to the pathological diagnosis. Its diagnostic characteristic was giant round or ovoid cells with mono nucleolus in the whole layer of epidermis. All the patients received operation, eleven with simple vulvectomy and other seven cases with lumpectomy. The median follow-up time was 123 months (range: 5 to 197 months). Relapse was found in two cases. One patient relapsed five months postoperation and received vulvectomy. Another patient relapsed fifteen moths post-operation and received lumpectomy again. And they were follow-up for 192 months and 55 months respectively after second operation without relapse. CONCLUSIONS: The diagnostic characteristic of vulvar Bowen's disease is giant round or ovoid cell with mono nucleolus in the whole layer of epidermis, itsdiagnosis is according to the pathological diagnosis. Operation could get very good curative effect for patients with primary vulvar Bowen's disease and even for the recurrent patients. The prognosis of vulvar Bowen's disease is good. PMID- 24495688 TI - [Quantitative detection of APC/RASSF1A promoter methylation in the plasma of patients with cervical diseases]. AB - OBJECTIVE: To quantitatively detect adenomatous polyposis coli(APC) and Ras association domain family 1A( RASSF1A) promoter methylation levels in the plasma of patients with cervical disease and to determine the diagnostic value of the indicators of cervical disease. METHODS: Preoperative blood samples were collected from 25 cases of healthy women and 118 cases of cervical disease, and tissue samples were also collected from 31 cases of them. The APC/RASSF1A promoter methylation levels of plasma and tissue were determined by duplex real time quantitative methylation specific PCR (qMSP). RESULTS: Among 31 paired plasma and tissue samples, true negative rate of APC and RASSF1A genes were all 100%, and true positive rate of APC and RASSF1A genes were 3/5 and 7/9, respectively. In 143 cases of plasma samples, total positive rate of APC and (or) RASSF1A methylation was 3% (2/59) for control/low-grade lesions groups and 48% (40/84) for high-grade lesions/tumor groups (P < 0.01) . RASSF1A methylation rate was related to lymph node metastasis and International Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.05). CONCLUSION: The plasma APC/RASSF1A methylation detection may be with some application prospect in the diagnosis of cervical diseases. PMID- 24495689 TI - [Effects of raloxifene combined with conjugated equine estrogen on prothrombotic state in ovariectomized rats]. AB - OBJECTIVE: To study effects of raloxifene (RLX) with different doses of conjugated equine estrogen(CEE) on prothrombotic profiles in the ovariectomized rats model. METHODS: Total of 32 healthy female SD rats at age of 9 to 10 months were equally divided into every 8 rats at 4 groups randomly. One week after ovariectomized, they were treated by drugs, including control group with placebo(0.9% Nacl intragastric administration), RLX group with RLX 6 mg/(kg.d), RLX and low CEE group with RLX 6 mg/(kg.d) + CEE 0.07 mg/ (kg.d) and RLX and high CEE group with RLX 6 mg/ (kg.d) + CEE 0.5 mg/ (kg.d) for 10 weeks before death. Thrombin turbidimetry method was used to evaluate the plasma fibrinogen(FIB), transmitting substrate method for antithrombin III(ATIII) activity, double antibody sandwich ELISA for plasminogen activator inhibitor 1 (PAI-1), D-dimer (D D) and von Willebrand factor (vWF) and nitrate reductase method for nitric oxide(NO). RESULTS: (1) Coagulation and anticoagulation indicators: it was observed (1.62 +/- 0.22) g/L FIB at control group, (2.02 +/- 0.54) g/L at RLX group, (1.97 +/- 0.16) g/L at RLX and low CEE group, (2.00 +/- 0.18) g/L at RLX and high CEE group. There was a statistically significant difference between control group and any one of treatment groups (P < 0.05) and no statistical significance among those three treatment groups (P > 0.05). No significant change was observed in plasma ATIII activity among groups (P > 0.05). (2) Fibrinolytic and anti-fibrinolytic indicators: it was observed (14.1 +/- 2.8) ug/L PAI-1 at control group, (20.0 +/- 3.3) ug/L at RLX group, (41.5 +/- 5.5) ug/L at RLX and low CEE group, (38.9 +/- 6.0) ug/L at RLX and high CEE group. A remarkable increase was observed between control group and any one of treatment groups (P < 0.05) . But there was no significant difference of D-D among groups (P > 0.05) . (3) Endothelial function: it was (43 +/- 7) % vWF at control group, (49 +/- 5) % at RLX group, (46 +/- 6) % at RLX and low CEE group, (36 +/- 5) % at RLX and high CEE group. The vWF of RLX and high CEE group was the lowest among all groups (P < 0.05) . There was no difference of NO among groups (P > 0.05). CONCLUSIONS: In the different links of thrombosis, RLX gives different function and may increase the risk. CEE plays a synergism role in the matter of fibrinolysis and anti fibrinolysis with RLX, further giving rise to thrombosis effect of RLX. And it also has a protective role in the function of vascular endothelium to some extent. But this only works with high dose. PMID- 24495690 TI - Detection of Shiga toxin (Stx)-producing Escherichia coli (STEC) in bovine dairy herds in Northern Italy. AB - The aim of this study was to monitor the presence of Shiga toxin (Stx)-producing Escherichia coli in dairy farms authorized to sell raw milk and other farms, located in the same area, which sell milk to industry or use it to produce Parmesan or Grana cheese. Our research was focused on the serogroups O157 and O26, which are the most common in human cases in Italy and genetic markers that characterize the strains that can cause hemorrhagic colitis and hemolytic uremic syndrome (EHEC) in humans. Overall, 255 bulk-milk and 225 milk filter samples were screened for the presence of Shiga toxin genes (stx1 and stx2), O157 and O26 serogroups by using PCR. The samples were collected in 193 bovine dairy farms located in Northern Italy, including 32 farms selling raw milk to consumers. According to the preliminary PCR screening test, 32 out of 255 (12.5%; CI95%, 8.7% to 17.3%) bulk milk samples and 68 out of 225 (30.2%; CI95%, 24.3% to 36.7%) milk filters were positive for stx genes. Of the 32 milk samples that were stx positive, 4 (1.6%, CI95%, 0.4% to 4%) were also positive by PCR for the rfbEO157 gene and 6 (2.4%, CI95%, 0.9% to 5.1%) were positive for the wzxO26 gene. The culture detection method, which was based on the immunomagnetic separation, achieved isolation rates of E. coli serogroups O157 and O26 in 25-67% of the milk samples that tested positive by PCR for these serogroups. STEC O26 was detected in one milk filter (1.6%) from a farm that sells raw milk to consumers directly and one sample (1.4%) of bulk milk intended for pasteurization. The presence of STEC O157 was also detected in 2 milk filters (1.7%) from farms that use milk to produce Grana cheese. All the STEC stains O157 and O26 isolated carried the genes eae and espK and genes belonging to the pathogenicity island OI-122 (efa1/2, sen, pagC), which are markers suitable for screening the human virulent EHEC strains. These virulence markers were also detected in the three strains of stx-negative E. coli O157 isolated from two filters and one milk sample. These strains could be therefore EHEC strains that have lost the stx genes (EHEC-derivative strains). Concern arise for the presence of EHEC O26 and E. coli O157 isolates that are suspected to be an EHEC-derivative in the milk filters sampled in farms that are used to sell raw milk to consumers and in other dairy farms. PMID- 24495692 TI - Crystallographic order and decomposition of [MnIII6CrIII]3+ single-molecule magnets deposited in submonolayers and monolayers on HOPG studied by means of molecular resolved atomic force microscopy (AFM) and Kelvin probe force microscopy in UHV. AB - Monolayers and submonolayers of [MnIII6CrIII]3+ single-molecule magnets (SMMs) adsorbed on highly oriented pyrolytic graphite (HOPG) using the droplet technique characterized by non-contact atomic force microscopy (nc-AFM) as well as by Kelvin probe force microscopy (KPFM) show island-like structures with heights resembling the height of the molecule. Furthermore, islands were found which revealed ordered 1D as well as 2D structures with periods close to the width of the SMMs. Along this, islands which show half the heights of intact SMMs were observed which are evidences for a decomposing process of the molecules during the preparation. Finally, models for the structure of the ordered SMM adsorbates are proposed to explain the observations. PMID- 24495691 TI - Communicating the AMFm message: exploring the effect of communication and training interventions on private for-profit provider awareness and knowledge related to a multi-country anti-malarial subsidy intervention. AB - BACKGROUND: The Affordable Medicines Facility - malaria (AMFm), implemented at national scale in eight African countries or territories, subsidized quality assured artemisinin combination therapy (ACT) and included communication campaigns to support implementation and promote appropriate anti-malarial use. This paper reports private for-profit provider awareness of key features of the AMFm programme, and changes in provider knowledge of appropriate malaria treatment. METHODS: This study had a non-experimental design based on nationally representative surveys of outlets stocking anti-malarials before (2009/10) and after (2011) the AMFm roll-out. RESULTS: Based on data from over 19,500 outlets, results show that in four of eight settings, where communication campaigns were implemented for 5-9 months, 76%-94% awareness of the AMFm 'green leaf' logo, 57% 74% awareness of the ACT subsidy programme, and 52%-80% awareness of the correct recommended retail price (RRP) of subsidized ACT were recorded. However, in the remaining four settings where communication campaigns were implemented for three months or less, levels were substantially lower. In six of eight settings, increases of at least 10 percentage points in private for-profit providers' knowledge of the correct first-line treatment for uncomplicated malaria were seen; and in three of these the levels of knowledge achieved at endline were over 80%. CONCLUSIONS: The results support the interpretation that, in addition to the availability of subsidized ACT, the intensity of communication campaigns may have contributed to the reported levels of AMFm-related awareness and knowledge among private for-profit providers. Future subsidy programmes for anti-malarials or other treatments should similarly include communication activities. PMID- 24495693 TI - The asymmetrical contributions of pleasure and pain to animal welfare. AB - Recent results from the neurosciences demonstrate that pleasure and pain are not two symmetrical poles of a single scale of experience but in fact two different types of experiences altogether, with dramatically different contributions to well-being. These differences between pleasure and pain and the general finding that "the bad is stronger than the good" have important implications for our treatment of nonhuman animals. In particular, whereas animal experimentation that causes suffering might be justified if it leads to the prevention of more suffering, it can never by justified merely by leading to increased levels of happiness. PMID- 24495694 TI - Versatile broad-host-range cosmids for construction of high quality metagenomic libraries. AB - We constructed IncP broad-host-range Gateway(r) entry cosmids pJC8 and pJC24, which replicate in diverse Proteobacteria. We demonstrate the functionality of these vectors by extracting, purifying, and size-selecting metagenomic DNA from agricultural corn and wheat soils, followed by cloning into pJC8. Metagenomic DNA libraries of 8*10(4) (corn soil) and 9*10(6) (wheat soil) clones were generated for functional screening. The DNA cloned in these libraries can be transferred from these recombinant cosmids to Gateway(r) destination vectors for specialized screening purposes. Those library clones are available from the Canadian MetaMicroBiome Library project (http://www.cm2bl.org/). PMID- 24495696 TI - Feasibility and promise of a 6-week program to encourage physical activity and reduce joint symptoms among elderly breast cancer survivors on aromatase inhibitor therapy. AB - BACKGROUND: National guidelines suggest that women with hormone receptor positive breast cancer be considered for adjuvant endocrine treatment with an aromatase inhibitor (AI). Joint symptoms (arthralgia) are a common AI side-effect. There is a need for effective approaches to arthralgia management that enable survivors to remain on AI therapy while optimizing as pain-free a life as possible. This feasibility study investigates a 6-week self-directed walking program in a sample of elderly female breast cancer survivors on AIs reporting joint pain. METHODS: INTERVENTION: Walk With Ease (WWE) goal--minimum 30 min of walking 5 days a week (150 min per week). Eligibility: age >65; Stage I-III breast cancer; >=3 months of AI therapy; self-reported joint pain/stiffness. MEASURES: (1) walking--number of days/week and number of minutes/walk, (2) visual analog scales (VAS) for joint pain, fatigue and stiffness, and (3) arthritis self-efficacy (ASE) to manage joint pain and fatigue. STATISTICS: t-tests, correlation coefficients and effect sizes. RESULTS: Sample target of 20 was achieved--mean age 71 (65-87), 85% Caucasian, mean BMI 29. Proportion walking 150 min/week increased from 21% at baseline to 50% at 6 weeks (p < 0.001). Mean joint pain at baseline (39.7 + 26.9) decreased 10% (p = 0.63), fatigue (37.4+33.3) decreased 19% (p = 0.31), joint stiffness (46.1 + 27.2) decreased 32% (p = 0.07). CONCLUSIONS: A self-directed walking program among elderly breast cancer survivors on AI therapy significantly increased total time of walking per week over a 6 week period. Joint pain, stiffness, and fatigue also decreased, although not significantly. Testing within a larger sample is warranted. PMID- 24495695 TI - Evaluating the physiological reserves of older patients with cancer: the value of potential biomarkers of aging? AB - Aging of an individual entails a progressive decline of functional reserves and loss of homeostasis that eventually lead to mortality. This process is highly individualized and is influenced by multiple genetic, epigenetic and environmental factors. This individualization and the diversity of factors influencing aging result in a significant heterogeneity among people with the same chronological age, representing a major challenge in daily oncology practice. Thus, many factors other than mere chronological age will contribute to treatment tolerance and outcome in the older patients with cancer. Clinical/comprehensive geriatric assessment can provide information on the general health status of individuals, but is far from perfect as a prognostic/predictive tool for individual patients. On the other hand, aging can also be assessed in terms of biological changes in certain tissues like the blood compartment which result from adaptive alterations due to past history of exposures, as well as intrinsic aging processes. There are major signs of 'aging' in lymphocytes (e.g. lymphocyte subset distribution, telomere length, p16INK4A expression), and also in (inflammatory) cytokine expression and gene expression patterns. These result from a combination of the above two processes, overlaying genetic predispositions which contribute significantly to the aging phenotype. These potential "aging biomarkers" might provide additional prognostic/predictive information supplementing clinical evaluation. The purpose of the current paper is to describe the most relevant potential "aging biomarkers" (markers that indicate the biological functional age of patients) which focus on the biological background, the (limited) available clinical data, and technical challenges. Despite their great potential interest, there is a need for much more (validated) clinical data before these biomarkers could be used in a routine clinical setting. This manuscript tries to provide a guideline on how these markers can be integrated in future research aimed at providing such data. PMID- 24495697 TI - Effects of a gift certificate incentive and specialized delivery on prostate cancer survivors' response rate to a mailed survey: a randomized-controlled trial. AB - OBJECTIVES: Most men diagnosed with prostate cancer become long-term survivors, but are at risk for medical late-effects that can affect their long-term health. Mailed surveys are well suited to study late-effects in this population, but low response rates can compromise survey validity. This study investigated whether an unconditional $5.00 gift certificate incentive or Priority Mail delivery increased prostate cancer survivors' response to mailed surveys. MATERIALS AND METHODS: 976 participants (mean age = 66.8 years), 2-8 years post-diagnosis, were randomized to one of four groups: Incentive; Priority Mail; Incentive & Priority Mail; or Control. After an introductory letter, initial study packets were mailed based on randomization; 46 days later, a second study packet was mailed to all non-responders by First-Class Mail. RESULTS: The first mailing yielded a significant variation in response rates across groups (chi(2) = 9.34; p = 0.025). Priority Mail (64.7%; p = 0.008) and Incentive & Priority Mail (63.6%; p = 0.016) groups had significantly higher response rates than Controls (52.9%). After the second mailing, the overall response rate increased significantly from 59.6% to 71.4% (p < 0.001); however, response rates no longer differed across groups (range, 69.3% [Incentive group] to 73.9% [Priority Mail group]). CONCLUSIONS: Long-term prostate cancer survivors' response rates to mailed surveys increased with the use of Priority Mail and a repeat survey mailing, but the unconditional gift certificate incentive was not supported in this population. By identifying and applying specialized survey methods, studies targeting survivors of prostate cancer and other geriatric cancers may improve response rates, thus limiting a source of potential bias. PMID- 24495698 TI - Age-related trends in utilization of the internet and electronic communication devices for coordination of cancer care in elderly patients. AB - OBJECTIVES: In this rapidly changing electronic era, we implemented a study to define age dependent variations in access and use of internet and electronic devices in the exchange of healthcare related information (HRI) and coordination of clinical care (CCC) among elderly patients with cancer. MATERIALS AND METHODS: Data was collected through independently completed surveys after obtaining IRB approval in a single institution cancer center over a 4-month period. Questions regarding internet access and use of electronic media to obtain health information and coordinate care were distributed. The sample was divided in two groups based upon the World Health Organization (WHO) definition of geriatric patients: <65 y/o (group A) and >=65 y/o (group B). RESULTS: One hundred and twenty-six surveys were analyzed with 70 patients in group A and 56 patients in group B. Access to the internet and use of email was higher in the group A (77% and 71%) vs. group B (36% and 33%, p < 0.001). The younger group felt more comfortable using the internet when compared to the older group (70% vs. 40%, p = 0.01). Patients in group B demonstrated a strong preference for paper copy based HRI and phone calls to CCC than text messages or emails (73% and 95%, p < 0.001). A transition zone between the ages of 65 and 70 years was defined to identify patients with increased reluctance to use internet and electronic devices to exchange HRI and CCC. CONCLUSION: The data supports that there is an age-defined underutilization of internet and electronic devices to exchange HRI and CCC. Characterization of this age-dependent transition zone will enable clinicians to identify patients who may not interface well with electronic communication strategies, and to improve delivery of HRI and CCC for the elderly. PMID- 24495699 TI - Lymphopenia and clinical outcome of elderly patients treated with sunitinib for metastatic renal cell cancer. AB - OBJECTIVE: Lymphopenia is associated with toxicity and outcomes in several cancer types. We assessed the association between pre-treatment lymphopenia, toxicity, and clinical outcomes in elderly patients with metastatic renal cell cancer (mRCC) treated with first-line sunitinib. Prognostic factors in these patients were also evaluated. PATIENTS AND METHODS: We reviewed the clinical records of 181 patients with mRCC aged >=70 years treated with first-line sunitinib in 17 Italian Oncology Units from February 2006 to September 2011. Baseline lymphopenia was defined as lymphocyte counts <1000/MUL. RESULTS: Twenty-nine (16%) patients had a baseline lymphocyte count <1000/MUL (group A) and 152 (84%) patients had a lymphocyte count >=1000/MUL (group B). Although no differences between the two groups were reported in terms of overall response rate (P = 0.207), dose reductions (P = 0.740), discontinuation due to adverse events (P = 0.175) or overall incidence of grade 3-4 toxicities (P = 0.112), more patients in the lymphopenia group had grade 3-4 neutropenia (P = 0.017), grade 3-4 thrombocytopenia (P = 0.017) and grade 3-4 diarrhea (P = 0.006). In multivariate analysis, performance status and Heng score were predictors of progression-free survival (P = 0.015 and P = 0.0006, respectively), while performance status, Heng score, and lymphopenia were found to be significantly associated with overall survival (P = 0.007, P < 0.0001 and P = 0.023, respectively). CONCLUSIONS: Sunitinib appears to be safe and active in elderly patients with lymphopenia. Lymphocyte count is an independent prognostic factor for overall survival in elderly patients with mRCC treated with first-line sunitinib. PMID- 24495700 TI - Geriatric screening results and the association with severe treatment toxicity after the first cycle of (radio)chemotherapy. AB - BACKGROUND: Screening tools are used in geriatric oncology to determine who should receive a Comprehensive Geriatric Assessment (CGA). However, in this prospective study, we evaluated the association between geriatric screening results, measured with the G8 and Groningen Frailty Indicator (GFI), and severe treatment toxicity. METHODS: Patients over 65 years with various types and stages of cancer were screened with the G8 and the GFI prior to the start of treatment. The association between geriatric screening results and Serious Adverse Events (SAE) after the first cycle of (radio)chemotherapy were studied with bivariate analysis (normal versus abnormal screening test) and logistic regression analysis. RESULTS: From 170 screened patients, 85 patients were eligible for this study. The median age was 76 years (range: 66-88 years). The treatment intent was curative in 46% and palliative in 54%. A SAE occurred in 15 patients (18%) of which three resulted in death. There was no significant association between the G8, as a dichotomous predictor (p = 0.376) or as a continuous predictor (p = 0.298), and risk of a SAE. We also found no significant association for the GFI analysed as a dichotomous predictor (cut-off >=4: p = 0.384; cut-off >=3: p = 0.773), nor as a continuous predictor (p = 0.734). All associations remained insignificant when adjusted for treatment type and comorbidity. CONCLUSION: The G8 and the GFI can be used to select patients for CGA, but they do not seem to be predictive for short-term severe treatment toxicity. PMID- 24495701 TI - Pain is prevalent and persisting in cancer survivors: differential factors across age groups. AB - OBJECTIVE: The Institute of Medicine documents a significant gap in care for long term side effects of cancer treatment, including pain. This paper characterizes age differences in the prevalence and predictive characteristics of pain to guide clinicians in identification and treatment. MATERIALS AND METHODS: A sample of 170 adults with head and neck, esophageal, gastric, or colorectal cancers were recruited from two regional Veterans Administration Medical Centers. Face to face interviews were conducted 6, 12, and 18 months after diagnosis with the PROMIS scale to assess pain and PHQ-9 scale to assess depression. Descriptive statistics characterized incidence and prevalence of pain impact and intensity ratings. Multivariate linear hierarchical regression identified clinical characteristics associated with pain in older versus younger age groups. RESULTS: Clinically significant pain was endorsed in one third (32%) of the sample, with younger adults reporting higher levels of the impact of pain on daily activities and work, and also higher pain intensity ratings than older adults. In younger adults, pain ratings were most associated with lower social support and higher depression, as well as advanced cancer stage. In older adults, pain was multifactorial, associated with baseline comorbidities, adjuvant treatment, and both combat post-traumatic stress disorder (PTSD) and depression. CONCLUSIONS: Pain is a significant persisting problem for one in three cancer survivors, requiring ongoing assessment, even months later. Important differences in pain's determinants and impact are present by age group. Identification and treatment of pain, as well as associated conditions such as depression, may improve the quality of life in cancer survivors. PMID- 24495702 TI - A comparison of the characteristics, treatment and outcome after 5 years, of Australian women aged 70+ with those aged <70 years at the time of diagnosis of breast cancer. AB - BACKGROUND: Management of older women with breast cancer (BC) is challenging, as age-related comorbidities may limit treatment. We present 5-year follow-up data from women aged 70 years or older (70+), at the time of diagnosis of their BC, compared with younger women (<70 years). METHODS: Data is from an Australian cohort study of women with their first episode of invasive BC (Bupa study). Participants completed an enrollment questionnaire (EQ) within 12 months of diagnosis and annual follow-up questionnaires (FQ) for 5 years (FQ1-5). Data collected included details of the BC and its treatment. Psychological wellbeing was measured by the Psychological General Wellbeing Index (PGWB). RESULTS: At diagnosis, 274 (16%) women were aged 70+ and of them, 90% were aged 70-79 years. Compared with women aged <70 years, the women aged 70+ were less likely to have positive nodes, they were less likely to receive radiotherapy and chemotherapy and were more likely to have pre-existing cardiovascular morbidities. By FQ5 women aged 70+ were less likely to be taking oral adjuvant endocrine therapy (OAET) and were more likely to have died from causes other than BC. At FQ5, women 70+ reported less anxiety and better self-control. CONCLUSIONS: Women aged 70+, compared to <70 years, had less advanced disease, received radiation and chemotherapy less often, were more likely to have cardiovascular disease at the time of diagnosis, were less likely to be taking OAET at the 5-year assessment, and were more likely to die of causes other than breast cancer. PMID- 24495704 TI - The influence of age on the outcome of treatment of elderly patients with colorectal cancer. AB - OBJECTIVES: We investigated factors associated with post-operative mortality rates in those aged >=60, and in particular, the relative survival of age bands within this group. METHODS: Secondary analysis of a large comprehensive cohort of the elderly treated for colorectal cancer in the North of England during 1998 2003. We investigated seven risk factors associated with 30-day and 6-month post operative mortality from colorectal surgery. RESULTS: 6083 patients aged >=60 underwent colorectal cancer surgery. Approximately 8% had died within 30 days of surgery and 17% had died within 6 months. Thirty-day mortality was greater in the elderly (80 years+) compared to the young-old (60-69 years) (adjusted OR: 3.2, 95% CI 2.4 to 4.4). There was neither a significant difference between the proportions offered curative resections across the age-groups, nor was there a significant association between intent of surgery and 30-day mortality. Six-month mortality rose with age, but the association was stronger in those having curative surgery (adjusted OR: 3.8, 95% CI 2.8 to 5.2) than palliative surgery (adjusted OR: 1.5, 95% CI 1.1 to 2.1). Mortality from emergency surgery at 6 months was particularly high in elderly females. CONCLUSIONS: This large population study adds more weight to the findings that age itself is a major risk factor in the outcome of colorectal surgery in elderly and that 30-day mortality underestimates the longer-term outcome in this age group. There was no significant association between radical resections and 30-day mortality in elderly patients compared to the younger age groups; however, a disproportionately higher mortality at 6 months was seen in elderly female patients. PMID- 24495703 TI - Tolerability and efficacy of docetaxel in older men with metastatic castrate resistant prostate cancer (mCRPC) in the TAX 327 trial. AB - OBJECTIVE: Prostate cancer is a disease of older men. Weekly docetaxel (DPq1w) is often favored over the standard three-weekly regimen (DPq3w) due to concerns about safety and tolerability in this population. MATERIALS AND METHODS: Two subgroup analyses of TAX 327 were conducted. Among patients receiving DPq3w, tolerability and efficacy were compared between three age groups: <65, 65-74 and >=75 years. For men >=75 years, these outcomes were compared between DPq3w, DPq1w, and mitoxantrone (MP) arms. Tolerability outcomes included dose delivery, grade 3/4 adverse events and quality of life. Efficacy outcomes included overall survival and tumor response. RESULTS: Of 1006 men with metastatic castrate resistant prostate cancer (mCRPC) in the trial, 335 received DPq3w. Among these, 20% were age >=75 years. For DPq3w, there were non-significant associations of worse tolerability and efficacy with advancing age. Twenty-eight percent of men age >=75 years had an objective pain response, compared to 38% and 34% of patients 65-74 and <65 years, respectively. There were no significant differences in prostate-specific antigen (PSA) response (43-48%, p = 0.74) or measurable tumor response (7-17%, p = 0.30) according to age. Among men >=75 years, DPq3w resulted in more dose reductions than DPq1w (22% versus 8%, p = 0.007), but tolerability was otherwise comparable. Both were associated with more favorable efficacy than mitoxantrone. CONCLUSIONS: Tolerability and efficacy of DPq3w appear less favorable with advancing age. Compared to DPq1w, DPq3w is associated with better survival outcomes, but similar tolerability, and remains the standard first-line chemotherapy option in mCRPC. Toxicity is substantial, therefore careful patient selection, close monitoring and early management of toxicities is advised. PMID- 24495705 TI - Multiple component interventions for preventing falls and fall-related injuries among older people: systematic review and meta-analysis. AB - BACKGROUND: Limited attention has been paid in the literature to multiple component fall prevention interventions that comprise two or more fixed combinations of fall prevention interventions that are not individually tailored following a risk assessment. The study objective was to determine the effect of multiple component interventions on fall rates, number of fallers and fall related injuries among older people and to establish effect sizes of particular intervention combinations. METHODS: Medline, EMBASE, CINAHL, PsychInfo, Cochrane, AMED, UK Clinical Research Network Study Portfolio, Current Controlled Trials register and Australian and New Zealand Clinical Trials register were systematically searched to August 2013 for randomised controlled trials targeting those aged 60 years and older with any medical condition or in any setting that compared multiple component interventions with no intervention, placebo or usual clinical care on the outcomes reported falls, number that fall or fall-related injuries. Included studies were appraised using the Cochrane risk of bias tool. Estimates of fall rate ratio and risk ratio were pooled across studies using random effects meta-analysis. Data synthesis took place in 2013. RESULTS: Eighteen papers reporting 17 trials were included (5034 participants). There was a reduction in the number of people that fell (pooled risk ratio = 0.85, 95% confidence interval (95% CI) 0.80 to 0.91) and the fall rate (pooled rate ratio = 0.80, 95% CI 0.72 to 0.89) in favour of multiple component interventions when compared with controls. There was a small amount of statistical heterogeneity (I(2) =20%) across studies for fall rate and no heterogeneity across studies examining number of people that fell. CONCLUSIONS: This systematic review and meta-analysis of randomised controlled trials found evidence that multiple component interventions that are not tailored to individually assessed risk factors are effective at reducing both the number of people that fall and the fall rate. This approach should be considered as a service delivery option. PMID- 24495706 TI - The safety of beta-blocker use in chronic obstructive pulmonary disease patients with respiratory failure in the intensive care unit. AB - BACKGROUND: The safety of beta-blockers as a heart rate-limiting drug (HRLD) in patients with acute respiratory failure (ARF) due to chronic obstructive lung disease (COPD) has not been properly assessed in the intensive care unit (ICU) setting. This study aims to compare the use of beta-blocker drugs relative to non beta-blocker ones in COPD patients with ARF due to heart rate-limiting with respect to length of ICU stay and mortality. METHODS: We performed a retrospective (January 2011-December 2012) case-control study in a level III ICU in a teaching hospital. It was carried out in a closed ICU by the same intensivists. All COPD patients with ARF who were treated with beta-blockers (case group) and non-beta-blocker HRLDs (control group) were included. Their demographics, reason for HRLD, cause of ARF, comorbidities, ICU data including acute physiology and chronic health evaluation (APACHE II) score, type of ventilation, heart rate, and lengths of ICU and hospital stays were collected. The mortality rates in the ICU, the hospital, and over 30 days were also recorded. RESULTS: We enrolled 188 patients (46 female, n = 74 and n = 114 for the case and control groups, respectively). Reasons for HRLD (case and control group, respectively) were atrial fibrillation (AF, 23% and 50%), and supraventricular tachycardia (SVT, 41.9% and 54.4%). Patients' characteristics, APACHE II score, heart rate, duration and type of ventilation, and median length of ICU-hospital stay were similar between the groups. The mortality outcomes in the ICU, hospital, and 30 days after discharge in the case and control groups were 17.6% versus 15.8% (p > 0.75); 18.9% versus 19.3% (p > 0.95) and 20% versus 11% (p > 0.47), respectively. CONCLUSIONS: Our results suggest that beta-blocker use for heart rate control in COPD patients with ARF is associated with similar ICU stay length and mortality compared with COPD patients treated with other HRLDs. PMID- 24495707 TI - REM sleep behavior disorder in Parkinson disease: association with abnormal ocular motor findings. AB - BACKGROUND: The anatomical substrates associated with generalized muscle atonia during REM sleep are located on the pontine tegmentum and medial medulla oblongata. We examined whether patients with REM sleep behavior disorder (RBD) have abnormal ocular movements suggesting brainstem or cerebellar dysfunction in Parkinson's disease (PD). METHODS: Cross-sectional survey for the existence of RBD and abnormal ocular movements. Ocular movements were examined by video oculography (VOG). RESULTS: A total of 202 patients were included in this study. One hundred and sixteen (57.4%) of the 202 patients have clinically probable RBD, and 28 (24.1%) of the 116 with clinically probable RBD patients had abnormal VOG findings suggesting brainstem or cerebellar dysfunction; whereas 86 of the 202 patients did not have clinically probable RBD, and only 7 (8.1%) of the 86 patients had abnormal VOG findings suggesting brainstem or cerebellar dysfunction (P=0.001). CONCLUSION: This study suggests that the presence of RBD is associated with more severe or extensive brainstem pathology or different distribution of pathology in PD. PMID- 24495708 TI - Cognitive profiling of Parkinson disease patients with mild cognitive impairment and dementia. AB - BACKGROUND: Prevalence of mild cognitive impairment (MCI) and dementia in Parkinson disease (PD) is variable because different classification criteria are applied and there is lack of consensus about neuropsychological tests and cut-off used for cognitive profiling. Given the important therapeutic consequences for patient management, we aimed at identifying suitable diagnostic cognitive tests and respective screening cut-off values for MCI and dementia in PD (PDD). METHODS: We evaluated 105 PD patients using an extensive neuropsychological battery categorized as PD without cognitive impairment (PD-CNT) (35%), PD-MCI (47%) and PDD (18%) based on established criteria and calculated Receiver Operating Characteristic (ROC) curves. RESULTS: We found different sensitivity and specificity among neuropsychological tests in detecting PD-MCI and PDD. In particular performance in attention/set shifting, verbal memory and language abilities, discriminated both PD-MCI and PDD from PD-CNT. Abilities involved mainly in semantic retrieval mechanisms discriminated PD-CNT from PD-MCI but also PD-MCI from PDD. Finally deficits in executive and visual-spatial abilities were only affected in PDD. CONCLUSION: Our data point to an independent and different load of each test in defining different PD cognitive statuses. These findings can help selection of appropriate cognitive batteries in longitudinal studies and definition of stage-specific therapeutic targets. PMID- 24495709 TI - Phonemic verbal fluency decline after subthalamic nucleus deep brain stimulation does not depend on number of microelectrode recordings or lead tip placement. AB - BACKGROUND: Evidence suggests that both motor improvement and decline in verbal fluency in Parkinson's disease (PD) patients undergoing deep brain stimulation (DBS) may be attributed to a lead implantation effect. OBJECTIVE: We investigated whether the number of microelectrode recording (MER) passes influenced either motor UPDRS scores just prior to stimulation initiation at 4 weeks or decline in verbal fluency 6-24 months after surgery. METHODS: We retrospectively analyzed 50 PD patients who underwent bilateral STN DBS. Off medication UPDRS III motor scores were obtained before surgery and before stimulation was initiated. Neuropsychological testing was completed pre- and post-operatively in 28 patients at a mean of 377 days. Coordinates of lead tip and active stimulation site were calculated. RESULTS: There was no improvement in off-medication UPDRS III motor scores at a mean 33.9 days following surgery, with mean change of 0.04 +/- 10.48 (p = 0.98). There was no correlation between the number of MER passes and change in individual UPDRS motor score (r = -0.0001, p = 1.0). We observed significant decline in phonemic verbal fluency by 16% (p = 0.003) but it was not correlated with number of left hemisphere (r = -0.15, p = 0.46), or total number of passes (r = -0.02, p = 0.94) or coordinates of the lead tip or active stimulation site. There was a trend toward correlation with age (r = 0.38, p = 0.07). CONCLUSIONS: Significant decline in phonemic verbal fluency did not correlate with surgical passes nor with location of the lead tip or active stimulation site. These data suggest that age may influence verbal fluency decline more than surgical technique. PMID- 24495710 TI - Usefulness of FEES and responsiveness to tetrabenazine in a case of blepharospasm associated with dystonic-tremorous dsyphagia. PMID- 24495711 TI - Is crime associated with over-the-counter pharmacy syringe sales? Findings from Los Angeles, California. AB - BACKGROUND: More than 50,000 new HIV infections occur annually in the United States. Injection drug users represent twelve percent of incident HIV infections each year. Pharmacy sales of over-the-counter (OTC) syringes have helped prevent HIV transmission among injection drug users in many states throughout the United States. However, concerns exist among some law enforcement officials, policymakers, pharmacists, and community members about potential links between OTC syringe sales and crime. METHODS: We used a geographic information system and novel spatial and longitudinal analyses to determine whether implementation of pharmacy-based OTC syringe sales were associated with reported crime between January 2006 and December 2008 in Los Angeles Police Department Reporting Districts. We assessed reported crime pre- and post-OTC syringe sales initiation as well as longitudinal associations between crime and OTC syringe-selling pharmacies. RESULTS: By December 2008, 9.3% (94/1010) of Los Angeles Police Department Reporting Districts had at least one OTC syringe-selling pharmacy. Overall reported crime counts and reported crime rates decreased between 2006 and 2008 in all 1010 Reporting Districts. Using generalized estimating equations and adjusting for potential confounders, reported crime rates were negatively associated with OTC syringe sales (adjusted rate ratio: 0.89; 95% confidence interval: 0.81, 0.99). CONCLUSION: Our findings demonstrate that OTC pharmacy syringe sales were not associated with increases in reported crime in local communities in Los Angeles during 2006-2008. PMID- 24495713 TI - Neuroethics, painience, and neurocentric criteria for the moral treatment of animals. AB - Neuroscience affords knowledge that can be leveraged in the ontological valuation of individuals, groups, and species. Sociocultural sentiments, norms, and mores may impede embracing such knowledge to revise moral attitudes, ethics, and policies. We argue that the practices of neuroethics will be valuable in that they ground ethico-legal discourse in (1) naturalistic philosophy; (2) the current epistemological capital of neuroscience; (3) the issues, problems, and solutions arising in and from neuroscientific research and its applications; and 4) the use of neurocentric criteria-such as painience-to define and resolve ethical decisions regarding attitudes toward and treatment of nonhuman animals. PMID- 24495712 TI - Combined exposure to cigarette smoke and nontypeable Haemophilus influenzae drives development of a COPD phenotype in mice. AB - BACKGROUND: Cigarette smoke (CS) is the major etiologic factor of chronic obstructive pulmonary disease (COPD). CS-exposed mice develop emphysema and mild pulmonary inflammation but no airway obstruction, which is also a prominent feature of COPD. Therefore, CS may interact with other factors, particularly respiratory infections, in the pathogenesis of airway remodeling in COPD. METHODS: C57BL/6 mice were exposed to CS for 2 h a day, 5 days a week for 8 weeks. Mice were also exposed to heat-killed non-typeable H. influenzae (HK-NTHi) on days 7 and 21. One day after the last exposure to CS, mice were sacrificed and lung inflammation and mechanics, emphysematous changes, and goblet cell metaplasia were assessed. Mice exposed to CS or HK-NTHi alone or room air served as controls. To determine the susceptibility to viral infections, we also challenged these mice with rhinovirus (RV). RESULTS: Unlike mice exposed to CS or HK-NTHi alone, animals exposed to CS/HK-NTHi developed emphysema, lung inflammation and goblet cell metaplasia in both large and small airways. CS/HK NTHi-exposed mice also expressed increased levels of mucin genes and cytokines compared to mice in other groups. CS/HK-NTHi-exposed mice infected with RV demonstrated increased viral persistence, sustained neutrophilia, and further increments in mucin gene and chemokine expression compared to other groups. CONCLUSIONS: These findings indicate that in addition to CS, bacteria may also contribute to development of COPD, particularly changes in airways. Mice exposed to CS/HK-NTHi are also more susceptible to subsequent viral infection than mice exposed to either CS or HK-NTHi alone. PMID- 24495714 TI - The contributing role of physical education in youth's daily physical activity and sedentary behavior. AB - BACKGROUND: School physical education (PE) is considered as an effective channel for youth to accumulate moderate-to-vigorous physical activity (MVPA) and reduce sedentary time. The purpose of this study was to determine the contributing role of PE in daily MVPA and sedentary time among youth. METHODS: The study recruited 67 sixth grade children (29 boys; Mean age = 11.75) from two suburban schools at a U.S. Midwest state, 48 of whom contributed >=10 hours of physical activity (PA) data per day were included for analysis. An objective monitoring tool (i.e., Sensewear armband monitor) was used to capture the participants' MVPA and sedentary time for 7-14 days. Pearson product-moment correlation analysis (r), multi-level regression analyses, and analysis of variance were conducted for data analysis. RESULTS: MVPA and sedentary time in PE showed significant positive associations with daily MVPA and sedentary time, respectively (r = 0.35, p < 0.01; r = 0.55, p < 0.01). Regression analyses revealed that one minute increase in MVPA and sedentary behavior in PE was associated with 2.04 minutes and 5.30 minutes increases in daily MVPA and sedentary behavior, respectively, after controlling for sex and BMI. The participants demonstrated a significantly higher level of MVPA (p = .05) but similar sedentary time (p = 0.61) on PE days than on non-PE days. Boys had significantly more daily MVPA (p < .01) and less sedentary time (p < .01) than girls; while higher BMI was associated with more sedentary time (p < .01). CONCLUSIONS: PE displayed a positive contribution to increasing daily MVPA and decreasing daily sedentary time among youth. Active participation in PE classes increases the chance to be more active and less sedentary beyond PE among youth. PMID- 24495715 TI - A qualitative study to assess community barriers to malaria mass drug administration trials in The Gambia. AB - BACKGROUND: Mass drug administration (MDA) is a strategy widely used in the control of human parasitic diseases but has been rarely attempted with malaria, the most common and dangerous parasitic disease in humans. MDA is an intervention strategy that involves simultaneously dispensing treatment to an entire population in a given geographic area. With some areas in sub-Saharan Africa documenting a decline in malaria transmission, the feasibility of MDA to further reduce malaria transmission is being considered. Understanding community perceptions of such an activity is vitally important for the design of the study and gaining the support of participants in order to maximize compliance and adherence. METHODS: A qualitative study to assess factors likely to influence community acceptance of MDA in the seasonal and low malaria transmission setting of The Gambia was conducted. Using in-depth interviews, the perceptions, knowledge and attitudes of medical personnel and community members who have undergone MDA trials in The Gambia were investigated. RESULTS: Several major themes emerged, namely: 1) the importance of timing of rounds of MDA doses for maximum participation; 2) the need to educate the target population with accurate information on the procedures, drug regimen, and possible side effects to enhance adherence; 3) the need for continuous sensitization meetings to maintain and increase uptake of MDA; and, 4) the importance for defining roles in the delivery and assessment of MDA, including existing healthcare structures. DISCUSSION: To increase the likelihood of participation in MDA trials in this setting, activities should be undertaken just before and during the rainy season when community members are less mobile. Importantly, fears regarding blood sampling and side effects of the drug regimen need to be addressed prior to the start of the trial and repeated throughout the study period. Accurate and frequent communication is essential, and village leaders should consistently be included in sensitization meetings to enhance community participation. Additionally, village healthcare workers should be included in training and implementation, with supervision by a fieldworker permanently posted in every few villages during the trial. Future collaboration with Senegal may prove important for enhanced elimination efforts in The Gambia. PMID- 24495716 TI - Purification and characterization of a hyaluronidase from venom of the spider Vitalius dubius (Araneae, Theraphosidae). AB - BACKGROUND: Venom hyaluronidase (Hyase) contributes to the diffusion of venom from the inoculation site. In this work, we purified and characterized Hyase from the venom of Vitalius dubius (Araneae, Theraphosidae), a large theraphosid found in southeastern Brazil. Venom obtained by electrical stimulation of adult male and female V. dubius was initially fractionated by gel filtration on a Superdex(r) 75 column. Active fractions were pooled and applied to a heparin sepharose affinity column. The proteins were eluted with a linear NaCl gradient. RESULTS: Active fractions were pooled and assessed for purity by SDS-PAGE and RP HPLC. The physicochemical tests included optimum pH, heat stability, presence of isoforms, neutralization by flavonoids and assessment of commercial antivenoms. Hyase was purified and presented a specific activity of 148 turbidity-reducing units (TRU)/mg (venom: 36 TRU/mg; purification factor of ~4). Hyase displayed a molecular mass of 43 kDa by SDS-PAGE. Zymography in hyaluronic-acid-containing gels indicated an absence of enzyme isoforms. The optimum pH was 4-5, with highest activity at 37 degrees C. Hyase was stable up to 60 degrees C; but its activity was lost at higher temperatures and maintained after several freeze-thaw cycles. The NaCl concentration (up to 1 M) did not influence activity. Hyase had greater action towards hyaluronic acid compared to chondroitin sulfate, and was completely neutralized by polyvalent antiarachnid sera, but not by caterpillar, scorpion or snakes antivenoms. CONCLUSION: The neutralization by arachnid but not scorpion antivenom indicates that this enzyme shares antigenic epitopes with similar enzymes in other spider venoms. The biochemical properties of this Hyase are comparable to others described. PMID- 24495717 TI - [Evidence based medicine and medicine based evidence & follow up some thinkings]. PMID- 24495718 TI - [The application of a new method of microvascular anastomosis: a review of 109 microvascular anastomosis surgery]. AB - OBJECTIVE: To evaluate the feasibility and clinical significance of the new method for microvascular anastomosis. METHODS: Between February 2013 and May 2013, 108 patients aged 31 to 73 years underwent free flap reconstruction of the defects as a result of resection of oralmaxillofacial tumors. Of 108 patients, 78 were men and 30 were women. The cases were divided into experimental group(46 flaps) and control group (63 flaps) according to different methods of microvascular anastomosis.Isometric double notches end to end microvascular anastomosis was used for artery anastomosis in experimental group, conventional end to end anastomosis was used for artery anastomosis in control group and venous anastomosis was performed in both groups. RESULTS: The entire procedure of artery anastomosis took (7.3 +/- 1.7) min in experimental group, (14.5 +/- 2.6) min in control group, the difference between the two groups was significant (P = 0.00). There was only one venous compromise which was complete failure in experimental group. There were two venous compromise and one artery compromise in control group, and one of the venous compromise was a complete failure. CONCLUSIONS: The isometric double notches end to end microvascular anastomosis proved successful and clinically feasible with advantages of fixed-point accuracy, time-saving and high patency rate. PMID- 24495719 TI - [Evaluation of soft tissue lesions affecting the masticator space with dynamic contrast enhanced MRI]. AB - OBJECTIVE: To determine the characteristics and diagnostic value of dynamic contrast enhanced MRI (DCE-MRI) in differentiating benign soft tissue lesions from malignant tumors affecting the masticator space (MS). METHODS: Prior to managements, conventional MRI and DCE-MRI were performed in 53 patients who suffered from primary or secondary soft tissue lesions affecting the MS. The time to peak (TTP), relative maximum enhancement (RME) and relative washout ratio (RWO) were separately calculated. RESULTS: Mean TTP of benign and malignant lesions were (130.3 +/- 13.2) and (69.6 +/- 6.9) s, respectively. Mean RWO of benign and malignant lesions were (29.7 +/- 5.5)% and (8.7 +/- 2.1)%, respectively. Malignant lesions had a significantly shorter TTP(P = 0.001) and lower RWO (P = 0.003) than benign lesions. When TTP was less than 92.2 s and RWO less than or equal to 16.0%, malignant tumors were considered. DCE-MRI had a sensitivity of 72.3%, specificity of 93.5%, accuracy of 84.9%, positive predictive value of 88.9%, and negative predictive value of 82.9%. CONCLUSIONS: As a non-invasive imaging technique, DCE-MRI is valuable to differentiate benign soft tissue lesions from malignant tumors affecting the MS. PMID- 24495720 TI - [Measurement of sagittal root position and the thickness of the facial and palatal alveolar bone of maxillary anterior teeth]. AB - OBJECTIVE: To classify the relationship of the sagittal root positions of the maxillary anterior teeth to their respective osseous housings, and to measure the thickness of facial and palatal alveolar bone by cone-beam computed tomography (CBCT). METHODS: Twenty-three subjects [9 male, 14 female, mean age: (24.5 +/- 1.6) years] who fulfilled the inclusion criteria were involved in this study. The CBCT images were evaluated and the relationship of the sagittal root position of the maxillary anterior teeth to its associated osseous housing was recorded as Kan's Class 1, 2, 3, 4. The facial and palatal alveolar bone thickness at three locations:2 mm apical to crest level, mid-root level and apical level, was measured respectively. RESULTS: Ninety seven point one percent(134/138)of the anterior maxillary teeth were classified as Class 1. Only 2.9% (4/138) were Class 4.Occurrences of > 2 mm thickness of maxillary facial alveolar bone were found 2.2% (6/276 sites) at 2 mm apical to crest level and mid-root level in the sample of maxillary anterior teeth. CONCLUSIONS: The majority of the anterior maxillary teeth roots were positioned close to the labial cortical plate. Most tooth sites in the anterior maxilla had a thin facial bone wall. PMID- 24495721 TI - [Clinical effect of sequential therapy for maxillary central incisor with horizontal mid-root fracture]. AB - OBJECTIVE: To evaluate the clinical effect of sequential therapy for traumatized maxillary central incisor with horizontal mid-root fracture. METHODS: Twenty maxillary central incisors with horizontal mid-root fracture following dental trauma were included in our study. The distance between root fracture plane and root apical segment was more than 5 mm. The sequential therapy included stabilizing the traumatized incisor with a flexible splint after repositioning the coronal segment of the tooth, temporarily filling with calcium hydroxide after root preparation, sealing the root apex with warm gutta-percha obturation technique and internal fixation with fiber post combined with composite resin adhesion. The patients were followed for 6 to 24 months. RESULTS: Two cases healed without sign of fracture line and eighteen cases healed with sign of fracture line. No case failed. Abnormal mobility and translocation, percussion pain, gingival swelling, sinus tract and periodontal pocket were not observed in all the traumatized teeth.Radiology showed normal root apex and periodontium. CONCLUSIONS: Sequential therapy for maxillary central incisor with horizontal mid root fracture could acquire a satisfactory therapeutic effect. PMID- 24495722 TI - [Confirmatory study on the regression equation for children dental behavior in Beijing]. AB - OBJECTIVE: To test and verify the regression equation got before for children's dental behavior management problems(BMP). METHODS: The study group included 279 children aged 2- < 8 years who received dental treatment by 16 pediatric dentists in the Department of Pediatric Dentistry, Peking University School of and Hospital of Stomatology. Interviews were conducted with accompanying guardians and children's dental behavior was rated by a modified Venham's clinical anxiety scale and a cooperative behavior rating scale. The variables were put into the regression equation and the results were compared with their dental behavior scale. RESULTS: The accuracy rate of regression equation reached 84.2% (235/279) , sensitivity was 0.613 (95%CI:0.514-0.712) and specificity was 0.957 (95%CI:0.928-0.986). CONCLUSIONS: The regression equation is characterized by its accuracy rate at a good level. Younger age, negative guardian expectations of the child's behavior during treatment, anxiety or shyness around strangers, and presence of toothache were four risk factors for children's dental BMP. PMID- 24495723 TI - [Expression of triggering receptors expressed on myeloid-1 in innate response to Porphyromonas gingivalis in macrophages]. AB - OBJECTIVE: To investigate the role of triggering receptors expressed on myeloid 1(TREM-1) in innate response to Porphyromonas gingivalis(Pg) in mice macrophages and its potential role in periodontitis development. METHODS: Peritoneal macrophages from mice were harvested, separated and cultured, then challenged with viable Pg. Transcription and protein expression in macrophages were assessed with real time PCR and flow cytometry respectively.LP-17 peptide (10, 100 and 1000 ug/L) was utilized to block TREM-1, and tumor necrosis factor-alpha (TNF alpha) and interleukin-6 (IL-6) were detected by enzyme linked absorbent analysis. RESULTS: At 2 h after Pg challenge, transcription of TREM-1 was significantly up-regulated after Pg challenge[(7.99 +/- 1.11) fold vs blank]. At 24 h after bacteria infection, increased TREM-1 expression was demonstrated by flow cytometry, with mean fluorescent intensity increasing from (7.05 +/- 1.85) in blank group to (13.17 +/- 2.33) in experimental group. Proinflammatory cytokine (TNF-alpha and IL-6) production was significantly decreased after blocking TREM-1 by LP-17 peptide(100 and 1000 ug/L). CONCLUSIONS: TREM-1 enhanced innate immune response to Pg in macrophages, which may facilitate periodontitis development. PMID- 24495724 TI - [Human beta-defensin-3 regulates the proliferation and the secretion of prostaglandin E2 and matrix metalloproteinase-1 in human gingival fibroblasts]. AB - OBJECTIVE: To observe the effect of human beta-defensin-3 (HBD-3) on proliferation and the secretion of prostaglandin E2 (PGE2) and matrix metalloproteinase-1(MMP-1) in human gingival fibroblasts(HGF). METHODS: The HGF were cultured with tissue-explant method and the fourth-generation HGF were plated in 96-well plate. All groups except the control group were treated with different concentrations of HBD-3 for 7 days. Then the HGF proliferation was evaluated with methyl thiazolyl tetrazolium(MTT) colorimetry and the secretions of PGE2 and MMP-1 at the 12th hours of each group were detected by enzyme-linked immunosorbent assay (ELISA). RESULTS: The result of MTT dynamic monitoring showed that the amount of HGF increased with time in all groups in concentration dependent manner.ELISA showed that the secretions of PGE2 and MMP-1 in 1.0 mg/L HBD-3 group were (350.56 +/- 63.96) ng/L and (13.22 +/- 0.59) ug/L, significantly higher than those in the control group and 10.0 mg/L HBD-3 group (P < 0.05). CONCLUSIONS: HBD-3 promoted the proliferation of HGF. The low concentration of HBD-3 may play a role in immunoregulation through increasing the secretions of PGE2 and MMP-1. PMID- 24495725 TI - [Three-dimensional finite element analysis of different reactive force direction of maxillary protraction on temporomandibular joint]. AB - OBJECTIVE: To analyze the influence of different reactive force direction of protractions on temporomandibular joint (TMJ) by establishing a three-dimensional finite element model (FEM) of craniomaxillofacial complex. METHODS: The CT image of the head of a healthy young male volunteer was obtained.With the help of Mimics software, we established a three-dimensional finite element model of craniomaxillofacial complex which included TMJ. The force pattern of maxillary protraction appliance was imitated. The force (5 N) was applied on the chin and the direction of force was from 22 degrees to 49 degrees relative to the occlusal plane. The displacement and stress distribution of TMJ were analyzed. RESULTS: The contact stress on the maxilla decreased with the angle of the force direction increased from 22 degrees to 40 degrees , and increased with the angle increased from 40 degrees to 49 degrees . The stress on the condyle decreased with the angle of the force direction increased. The stress on the condylar neck decreased initially and then increased with the angle of the force direction increased. Comprehensively, the stress was the smallest when the angle of the force direction was 40 degrees . The clockwise rotation of the mandible was found when the angle of the force direction was smaller than 40 degrees . The displacement value was relatively small when the angle was 40 degrees . CONCLUSIONS: Stress and displacement were relatively small when the angle of the force direction was 40 degrees relative to the occlusal plane. PMID- 24495726 TI - [Effect of orthodontic force on expression of Asporin after tooth auto transplantation: an experimental study in Beagle dogs]. AB - OBJECTIVE: To evaluate the effect of orthodontic light force on the expression of Asporin, bone morphogenetic proteins-2 (BMP-2) and alkaline phosphatase (ALP) after auto-transplantation. METHODS: Thirty-two maxillary and mandibular incisors in four 13 month-old male Beagle dogs were auto-transplanted to the other side of the same jaw. The teeth were all endodontically treated and divided into four groups, control (group 1) and three experimental groups (groups 2, 3 and 4).In control group, the teeth were unloaded. In the other three experimental groups, continuous force was applied in the 1st week (group 2), 2nd week (group 3) and 4th week (group 4) after auto-transplantation, respectively. The dogs were sacrificed in the 8th week. The mRNA expressions of Asporin,BMP-2 and ALP were examined by real time PCR. The expression of periodontal ligament associated protein-1 (PLAP-1) was examined by Western blotting. The data were statistically analyzed using SPSS 17.0 and one-way analysis of variance (ANOVA). RESULTS: In group 3, the expression of Asporin mRNA (2.047 +/- 0.281) was higher than that in the other three groups, while the expression of BMP-2 (1.358 +/- 0.095) was lower than that in group 2 and control group (P < 0.05). The expression of PLAP-1 (1.054 +/- 0.113) in group 3 was higher than other groups, while significant difference was found between any two groups. CONCLUSIONS: Orthodontic force could stimulate the expression of Asporin and PLAP-1. The orthodontic force applied in the 2nd week after the tooth auto-transplantation, the expression of Asporin and PLAP-1 reached the highest level. PMID- 24495727 TI - [Relationship between abnormal swallowing and mouth breathing]. AB - OBJECTIVE: To investigate the relationship between abnormal swallowing and mouth breathing. METHODS: Thirty-eight patients with abnormal swallowing and 38 patients with normal swallowing were selected. All patients presented with no airway constriction. The age range of the patients was 11-14 years old. The number of patients with mouth breathing was calculated. Statistical analysis (chi(2) test) was performed. RESULTS: The number of patients with mouth breathing in the abnormal swallowing group (17, 45%) was significantly higher than that in the normal swallowing group (5, 13%) (chi(2) = 9.212, P = 0.002). CONCLUSIONS: Abnormal swallowing was related to mouth breathing. PMID- 24495729 TI - [The periodontal initial therapy on chronic periodontics with periodontal endodontic lesion: a case report]. PMID- 24495728 TI - [Expression of Prion protein and its clinical significance in oral squamous cells carcinoma and oral leukoplakia]. AB - OBJECTIVE: To examine Prion protein(PrP) expression and its clinical significance in oral mucosa, oral leukoplakia, oral squamous cell carcinoma(OSCC) and its subgroups. METHODS: Expression of PrP in OSCC, oral leukoplakia and mucosa specimen was detected by immunohistochemistry. The association between the expression and gender, TNM clinical stages, pathological grades was evaluated. RESULTS: The positive expression rate of PrP in normal, oral leukoplakia and OSCC tissues was 15% (3/20) , 42% (11/26) and 95% (80/84) , respectively. There was a significant difference between the expression of PrP in leukoplakia and in high, moderately and poorly differentiated OSCC(P < 0.05). The positive expression rate was increased with the declining of pathological differentiation (P < 0.05). There was no significant difference in PrP expression among lymph node metastasis and gender. PrP expression of stages I and II was up-regulated with the decreased differentiation (P < 0.05). There was no significant difference in PrP expression between stage III and IV (P > 0.05). Between stages I+II and III+IV in the overa II expression of PrP, there was a significant difference(P < 0.05). CONCLUSIONS: The high expression of PrP in OSCC and the progressive expression from leukoplakia to OSCC was closely related to the carcinogenesis of OSCC, pathologic stage and clinical TNM stage. PMID- 24495730 TI - [Surgical treatment of atrophic, infected, comminuted and defect fractures in mandible]. PMID- 24495731 TI - [Anatomical reduction and selective fixation of zygomatic complex fractures]. PMID- 24495732 TI - [Influence of oral structure's changes in the elderly on dental implant restoration]. PMID- 24495733 TI - [Zirconia dental implant: a review of literature on clinical application and animal studies]. PMID- 24495734 TI - Comparison of three common DNA concentration measurement methods. AB - Accurate measurement of DNA concentration is important for DNA-based biological applications. DNA concentration is usually determined by the ultraviolet (UV) absorption, fluorescence staining, and diphenylamine reaction methods. However, the best method for quality assurance of measurements is unknown. Here, we comprehensively compared these methods using different types of samples. We found that all three methods accurately determined the concentrations of high-purity DNA solutions. After digestion of DNA samples, concentration measurements revealed that the PicoGreen dye method was very sensitive to the degradation of DNA. The three methods displayed different anti-jamming ability when contaminants such as transfer RNA (tRNA), protein, and organic chemicals were included in DNA solutions. The diphenylamine reaction method gave the highest accuracy, with an average error of approximately 10% between measured and true values. The PicoGreen dye method was influenced by tRNA and protein, and the UV absorption method was susceptible to all kinds of impurities. Overall, the diphenylamine reaction method gave the most accurate results when DNA was mixed with contaminants, the PicoGreen dye method was most suitable for degraded DNA samples or DNA extracted from processed products, and the UV absorbance method was best for evaluating the impurities in DNA solutions. PMID- 24495735 TI - A decision aid regarding long-term tube feeding targeting substitute decision makers for cognitively impaired older persons in Japan: a small-scale before-and after study. AB - BACKGROUND: In Japan, there is no decision-making guide regarding long-term tube feeding that specifically targets individuals making decisions on behalf of cognitively impaired older persons (substitute decision makers). The objective of this study was to describe the development and evaluation of such a decision aid. METHODS: In this before-and-after study, participants comprised substitute decision makers for 13 cognitively impaired inpatients aged 65 years and older who were being considered for placement of a percutaneous endoscopic gastrostomy tube in acute care hospitals and mixed-care hospitals in Japan. Questionnaires were used to compare substitute decision makers' knowledge, decisional conflict, and predisposition regarding feeding tube placement before and after exposure to a decision aid. The acceptability of the decision aid was also assessed. Paired t tests were used to compare participants' knowledge and decisional conflict scores before and after using the decision aid. RESULTS: Substitute decision makers showed significantly increased knowledge (P < .001) and decreased decisional conflict (P < .01) regarding long-term tube feeding after using the decision aid. All substitute decision makers found the decision aid helpful and acceptable. CONCLUSIONS: The decision aid facilitated the decision-making process of substitute decision makers by decreasing decisional conflict and increasing knowledge. PMID- 24495736 TI - Human beta-defensin HBD3 binds to immobilized Bla g2 from the German cockroach (Blattella germanica). AB - Human beta-defensin 3 (HBD3) is a small, well-characterized peptide in mucosal secretions with broad antimicrobial activities and diverse innate immune functions. Among these functions is the ability of HBD3 to bind to antigens. In this study, we hypothesize that HBD3 binds to the allergen Bla g2 from the German cockroach (Blattella germanica). The ability of HBD1 (used as a control beta defensin) and HBD3 to bind to Bla g2 and human serum albumin (HSA, used as a control ligand) was assessed using the SensiQ Pioneer surface plasmon resonance (SPR) spectroscopy biosensor system. HBD1 was observed to bind weakly to Bla g2, while HBD3 demonstrated a stronger affinity for the allergen. HBD3 was assessed under two buffer conditions using 0.15 M and 0.3 M NaCl to control the electrostatic attraction of the peptide to the chip surface. The apparent K(D) of HBD3 binding Bla g2 was 5.9+/-2.1 MUM and for binding HSA was 4.2+/-0.7 MUM, respectively. Thus, HBD3, found in mucosal secretions has the ability to bind to allergens like Bla g2 possibly by electrostatic interaction, and may alter the ability of Bla g2 to induce localized allergic and/or inflammatory mucosal responses. PMID- 24495737 TI - Dynamic DNA-toolbox reaction circuits: a walkthrough. AB - In living organisms, the integration of signals from the environment and the molecular computing leading to a cellular response are orchestrated by Gene Regulatory Networks (GRN). However, the molecular complexity of in vivo genetic regulation makes it next to impossible to describe in a quantitative manner. Reproducing, in vitro, reaction networks that could mimic the architecture and behavior of in vivo networks, yet lend themselves to mathematical modeling, represents a useful strategy to understand, and even predict, the function of GRN. In this paper, we define a set of in vitro, DNA-based molecular transformations that can be linked to each other in such a way that the product of one transformation can activate or inhibit the production of one or several other DNA compounds. Therefore, these reactions can be wired in arbitrary networks. This approach provides an experimental way to reproduce the dynamic features of genetic regulation in a test tube. We introduce the rules to design the necessary DNA species, a guide to implement the chemical reactions and ways to optimize the experimental conditions. We finally show how this framework, or "DNA toolbox", can be used to generate an inversion module, though many other behaviors, including oscillators and bistable switches, can be implemented. PMID- 24495738 TI - Apolipoprotein A-I truncations in Chagas disease are caused by cruzipain, the major cysteine protease of Trypanosoma cruzi. AB - Trypanosoma cruzi is the etiologic agent of Chagas disease. Approximately 10 million people are infected worldwide. We have previously reported that in individuals infected with T. cruzi, apolipoprotein A-I (Apo A-I), the major structural component of host high-density lipoprotein, was truncated into fragments that are specific to Chagas disease and have the potential to be used as diagnostic biomarkers. We investigated the possibility that cruzipain, the major cysteine protease of T. cruzi, is responsible for truncating host Apo A-I. We found that due to Apo A-I truncation, the high-density lipoprotein subspecies profile is altered in individuals with Chagas disease compared with healthy controls. Western blot analysis revealed that both purified Apo A-I protein and Apo A-I in the high-density lipoprotein complex were susceptible to cruzipain cleavage, and the sizes of the truncation product in the latter matched the sizes of Apo A-I biomarkers. We also found that in vitro feeding T. cruzi-infected differentiated human adipocytes with purified human high-density lipoprotein led to the appearance of the biomarker fragments of Apo A-I. Cruzipain is found both on the cytoplasmic membrane and in the internal lysosomal structure of T. cruzi. We demonstrate that cruzipain from both sources contributes to the production of Apo A-I truncation in the biomarker set. PMID- 24495740 TI - Prevalence of methicillin-resistant Staphylococcus aureus carrying mecA or mecC in dairy cattle. AB - In the Netherlands, livestock-associated methicillin-resistant Staphylococcus aureus (LA-MRSA) has been found in pigs, veal calves, horses and poultry. However, little is known about its prevalence in healthy dairy cattle. Recently, a new mec gene, called mecC, has been found in methicillin-resistant S. aureus (MRSA) isolates from humans and animals in several countries. The objective of our pilot study was to investigate the prevalence of MRSA (mecA and mecC) in dairy cows at a large slaughterhouse. Samples from the skin between the udder and hind leg were taken from 411 cows. The samples were incubated in Mueller-Hinton enrichment broth with 6.5% NaCl, followed by selective enrichment and plated onto Columbia agar with 5% sheep blood, Brilliance MRSA 2 agar and Baird-Parker agar. Suspected colonies were tested by PCR for a S. aureus specific DNA fragment, the mecA and mecC genes and the Panton-Valentine leucotoxin (PVL) genes. All MRSA isolates and methicillin-susceptible S. aureus (MSSA) isolates were typed by spa typing and MLVA typing. Sixteen of 411 (3.9%) cows, all originating from different farms, were found to be MRSA positive and this prevalence is lower than in Dutch pigs, veal calves and broilers. All MRSA isolates belonging to livestock associated MLVA complex 398, were PVL-negative and spa type t011 predominated. MSSA isolates (n=39) were of many different MLVA types and spa type t543 was found most often. Four MSSA isolates belonging to MLVA clonal complex 398 and spa types t011 (n=2), t108 and t034 were isolated from different MRSA-negative animals. In conclusion, the prevalence of MRSA in dairy cows was low and isolates carrying the mecC gene were not found, indicating that it is absent or has a low prevalence (<0.73%) in Dutch dairy cows. PMID- 24495739 TI - Morphine inhibits migration of tumor-infiltrating leukocytes and suppresses angiogenesis associated with tumor growth in mice. AB - Tumor cells secrete factors that stimulate the migration of peripheral blood leukocytes and enhance tumor progression by affecting angiogenesis. In these studies, we investigated the effect of morphine, a known immunosuppressant, on leukocyte migration and recruitment to conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells. Our results indicate that morphine treatment reduced the migration and recruitment of tumor-infiltrating leukocytes into Matrigel plugs and polyvinyl alcohol sponges containing conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells when compared with placebo. A reciprocal increase in peripheral blood leukocytes was observed at the time of plug or sponge removal in morphine-treated mice. Decreased angiogenesis was observed in conditioned media derived from long-term cultures of mouse Lewis lung carcinoma cells Matrigel plugs taken from morphine-treated wild type mice when compared with placebo but was abolished in morphine-treated MU opioid receptor knockout mice. In addition, in vitro studies using trans-well and electric cell substrate impedance sensing system studies reveal for the first time morphine's inhibitory effects on leukocyte migration and their ability to transmigrate across an activated endothelial monolayer. Taken together, these studies indicate that morphine treatment can potentially decrease leukocyte transendothelial migration and reduce angiogenesis associated with tumor growth. The use of morphine for cancer pain management may be beneficial through its effects on angiogenesis. PMID- 24495741 TI - Tightly regulated bacteriolysis for production of empty Salmonella Enteritidis envelope. AB - To avoid leaky expression of the bacterial host-toxic PhiX174 lysis gene E from the lambdapR promoter, a convergent promoter construct was made in which gene E was placed between a sense lambdapR promoter and an anti-sense P araBAD promoter. In the presence of l-arabinose, leaky transcription of lysis gene E at 28 degrees C from the sense lambdapR promoter was repressed by an anti-sense RNA simultaneously expressed from the P araBAD promoter. The stringent repression of lysis gene E in the absence of induction temperature resulted into higher concentration of bacteria in culture suspension, and consequently higher and stable production of a Salmonella Enteritidis (S. Enteritidis) ghost. The immunogenicity of the S. Enteritidis ghost was evaluated by immunizing chickens. Chickens from the immunized group demonstrated a significant increase in the levels of S. Enteritidis-specific plasma IgG, intestinal sIgA, and lymphocyte proliferative response. After virulent S. Enteritidis challenge, the immunized group exhibited decreased bacterial recovery from organs compared with the non immunized group. Together, these results demonstrate that the stringent molecular control over leaky transcription of lysis gene E enabled the stable production of S. Enteritidis ghost, and immunization with the S. Enteritidis ghost can protect chickens by inducing robust humoral and cellular immune responses. PMID- 24495742 TI - Epidemiological characteristics of acute disseminated encephalomyelitis in Nanchang, China: a retrospective study. AB - BACKGROUND: Acute disseminated encephalomyelitis (ADEM) is an autoimmune disease that typically follows a monophasic course and may affect any age group. The precise population-based incidence of ADEM is still unknown in most countries. In China, there is no ADEM surveillance system. The exact incidence of ADEM is difficult to estimate, and other epidemiological characteristics of ADEM are unknown. The purpose of this study is to investigate the epidemiological characteristics of ADEM in Nanchang, China. METHODS: A retrospective investigation was conducted with ADEM patients admitted to second-level and third level hospitals in Nanchang from 2008 to 2010, aiming to analyse the epidemiologic characteristics of ADEM in the population in Nanchang. ADEM patients, defined as patients who were diagnosed according to the consensus definition of ADEM provided by the International Pediatric MS Study Group, were enrolled in the study. The data were extracted from the ADEM patients' medical records. RESULTS: Forty-seven ADEM patients were investigated. The average annual incidence was 0.31/100,000; the incidence among males (0.31/100,000) was nearly equal to that among females (0.31/100,000). The median age of onset was 25.97 years old, and the peak incidence was observed in the 5- to 9-year-old age group (0.75/100,000), followed by the over-60 age group (0.55/100,000). ADEM occurs throughout the year, but it occurs most frequently in March (n = 7) and least frequently in April and July (both n = 2). The patient numbers are roughly even in the other months. In the 2 months before the onset of ADEM, 15 patients presented with a preceding infection, but none of the patients received a vaccination. An increased number of vaccination was not accompanied by a corresponding increased number of cases of ADEM. CONCLUSIONS: The average annual incidence of ADEM was 0.31/100,000 in Nanchang. The incidence among males was nearly equal to that among females. The peak age of onset was 5-9 years old. The peak season of onset was not apparent. There was no evidence of an association between increased number of vaccines administered and number of cases of ADEM in Nanchang, China. PMID- 24495743 TI - The effect of bone allografts combined with bone marrow stromal cells on the healing of segmental bone defects in a sheep model. AB - BACKGROUND: The repair of large bone defects is a major orthopedic challenge because autologous bone grafts are not available in large amounts and because harvesting is often associated with donor-site morbidity. Considering that bone marrow stromal cells (BMSC) are responsible for the maintenance of bone turnover throughout life, we investigated bone repair at a site of a critically sized segmental defect in sheep tibia treated with BMSCs loaded onto allografts. The defect was created in the mid-portion of the tibial diaphysis of eight adult sheep, and the sheep were treated with ex-vivo expanded autologous BMSCs isolated from marrow aspirates and loaded onto cortical allografts (n = 4). The treated sheep were compared with control sheep that had been treated with cell-free allografts (n = 4) obtained from donors of the same breed as the receptor sheep. RESULTS: The healing response was monitored by radiographs monthly and by computed tomography and histology at six, ten, fourteen, and eighteen weeks after surgery. For the cell-loaded allografts, union was established more rapidly at the interface between the host bone and the allograft, and the healing process was more conspicuous. Remodeling of the allograft was complete at 18 weeks in the cell-treated animals. Histologically, the marrow cavity was reestablished, with intertrabecular spaces being filled with adipose marrow and with evidence of focal hematopoiesis. CONCLUSIONS: Allografts cellularized with AOCs (allografts of osteoprogenitor cells) can generate great clinical outcomes to noncellularized allografts to consolidate, reshape, structurally and morphologically reconstruct bone and bone marrow in a relatively short period of time. These features make this strategy very attractive for clinical use in orthopedic bioengineering. PMID- 24495744 TI - Effectiveness of pharmacologic therapies on smoking cessation success: three years results of a smoking cessation clinic. AB - BACKGROUND: Pharmacologic therapies have an important role in the success of interventions for smoking cessation. This study aims to determine the efficacy of several pharmacologic treatments in patients who applied to a smoking cessation clinic. METHODS: This retrospective study includes 422 patients who presented to our smoking cessation clinic between January 2010 and June 2013, used the pharmacologic treatment as prescribed and completed the one-year follow-up period. All patients were assessed using the Fagerstrom Test for Nicotine Dependence (FTND) and received both behavioral therapy and pharmacotherapy. Patients' smoking status at one year was assessed by telephone interview. RESULTS: The patients were 24.3% female (103/422) and 75.7% male (319/422) with a mean age of 38 +/- 10 years. Patients were divided into three groups: varenicline (166 patients), bupropion (148 patients) and nicotine replacement therapy (108 patients).The smoking cessation rates of these groups were 32.5%, 23% and 52.8%, respectively, and were statistically significant (p > 0.001). The overall success rate was 35%. Further analysis revealed that pharmacologic therapy (p > 0.001) and gender (p = 0.01) were factors that showed statistically significant effects on smoking cessation rates. Males had higher success rates than females. The overall relapse rate was 21.6% and the bupropion group showed the highest relapse rate among treatment groups. Lack of determination emerged as the most important factor leading to relapse. CONCLUSION: Nicotine replacement therapy was found to be more effective at promoting abstinence from smoking than other pharmacologic therapies. PMID- 24495745 TI - Animal minds and neuroimaging--bridging the gap between science and ethics? AB - As Colin Allen has argued, discussions between science and ethics about the mentality and moral status of nonhuman animals often stall on account of the fact that the properties that ethics presents as evidence of animal mentality and moral status, namely consciousness and sentience, are not observable "scientifically respectable" properties. In order to further discussion between science and ethics, it seems, therefore, that we need to identify properties that would satisfy both domains. In this article I examine the mentality and moral status of nonhuman animals from the perspective of neuroethics. By adopting this perspective, we can see how advances in neuroimaging regarding (1) research into the neurobiology of pain, (2) "brain reading," and (3) the minimally conscious state may enable us to identify properties that help bridge the gap between science and ethics, and hence help further the debate about the mentality and moral status of nonhuman animals. PMID- 24495746 TI - DRUMS: Disk Repository with Update Management and Select option for high throughput sequencing data. AB - BACKGROUND: New technologies for analyzing biological samples, like next generation sequencing, are producing a growing amount of data together with quality scores. Moreover, software tools (e.g., for mapping sequence reads), calculating transcription factor binding probabilities, estimating epigenetic modification enriched regions or determining single nucleotide polymorphism increase this amount of position-specific DNA-related data even further. Hence, requesting data becomes challenging and expensive and is often implemented using specialised hardware. In addition, picking specific data as fast as possible becomes increasingly important in many fields of science. The general problem of handling big data sets was addressed by developing specialized databases like HBase, HyperTable or Cassandra. However, these database solutions require also specialized or distributed hardware leading to expensive investments. To the best of our knowledge, there is no database capable of (i) storing billions of position-specific DNA-related records, (ii) performing fast and resource saving requests, and (iii) running on a single standard computer hardware. RESULTS: Here, we present DRUMS (Disk Repository with Update Management and Select option), satisfying demands (i)-(iii). It tackles the weaknesses of traditional databases while handling position-specific DNA-related data in an efficient manner. DRUMS is capable of storing up to billions of records. Moreover, it focuses on optimizing relating single lookups as range request, which are needed permanently for computations in bioinformatics. To validate the power of DRUMS, we compare it to the widely used MySQL database. The test setting considers two biological data sets. We use standard desktop hardware as test environment. CONCLUSIONS: DRUMS outperforms MySQL in writing and reading records by a factor of two up to a factor of 10000. Furthermore, it can work with significantly larger data sets. Our work focuses on mid-sized data sets up to several billion records without requiring cluster technology. Storing position-specific data is a general problem and the concept we present here is a generalized approach. Hence, it can be easily applied to other fields of bioinformatics. PMID- 24495747 TI - Targeted therapies in gastroesophageal cancer. AB - Gastroesophageal cancers comprising gastric cancer (GC), and cancers of the distal oesophagus and gastroesophageal junction (GEJ) are a global health threat. In Western populations the incidence of GC is declining which has been attributed to effective strategies of eradicating Helicobacter pylori infection. To the contrary, GEJ cancers are on the rise, with obesity and reflux disease being viewed as major risk factors. During the past decade perioperative chemotherapy, pre- or postoperative radio-chemotherapy, and, in Asian populations, adjuvant chemotherapy have been shown to improve the outcome of patients with advanced GC and GEJ cancers suited for surgery. Less progress has been made in the treatment of metastatic disease. The introduction of trastuzumab in combination with platinum/fluoropyrimidine-based chemotherapy for patients with HER2-positive disease has marked a turning point. Recently, several novel agents targeting growth factor receptors, angiogenic pathways, adhesion molecules and mediators of intracellular signal transduction have been clinically explored. Here we summarise the current status and future developments of molecularly targeted therapies in GC and GEJ cancer. PMID- 24495748 TI - Moving forward with effective goals and methods for conservation: a reply to Marvier and Kareiva. PMID- 24495749 TI - The application of glycosphingolipid arrays to autoantibody detection in neuroimmunological disorders. AB - Humans with autoimmune peripheral neuropathies frequently harbour serum antibodies to single glycosphingolipids, especially gangliosides. Recently it has been appreciated that glycolipid and lipid complexes, formed from two or more individual species, can interact to create molecular shapes capable of being recognised by these autoantibodies whilst not binding to the single individuals. As a result of this, novel autoantibody targets have been identified. This newly termed 'combinatorial glycomic' approach has provided the impetus to redesigning the assay methodologies traditionally used in the neuropathy-associated autoantibody field. Combinatorial glycoarrays can be readily constructed in house using lipids of interest. Herein we especially highlight the role of the neutral lipids cholesterol and galactocerebroside in modifying glycosphingolipid orientation that subsequently favours or inhibits autoantibody binding. PMID- 24495751 TI - The cancer-obesity connection: what do we know and what can we do? PMID- 24495750 TI - Dovitinib synergizes with oxaliplatin in suppressing cell proliferation and inducing apoptosis in colorectal cancer cells regardless of RAS-RAF mutation status. AB - BACKGROUND: Cancer is the result of a multistep process of genomic alterations, including mutations in key regulatory proteins that result in loss of balanced gene expression and subsequent malignant transformation. Throughout the various stages of colorectal carcinoma (CRC), complex genetic alterations occur, of which over-expression of growth factors, such as vascular endothelial growth factor, fibroblast growth factor and platelet-derive growth factor and their corresponding receptor tyrosine kinases, have been shown to correlate with invasiveness, tumor angiogenesis, metastasis, recurrence, and poor prognosis of colorectal cancer. To evaluate the therapeutic effect, we combined Dovitinib, an orally bioavailable, potent inhibitor of class III-V receptor tyrosine kinases with chemotherapeutic drug, oxaliplatin in preclinical models of colon cancer. METHODS: Human colon cancer cells with different RAS-RAF mutation status (HCT 116, HT-29, SW-480, CaCO2 and LS174T) were treated with a combination of Dovitinib and Oxaliplatin at low dosage followed by assays to investigate the effect of the combination on cell proliferation, cell migration, cell apoptosis and signaling pathways involved in molecular mechanism of drug(s). The antitumor effects of either of the drugs were compared to the combination using human colon carcinoma cell line HT-29 xenograft model. Treated vs untreated tumor sections were also compared for proliferation and angiogenesis markers by immunohistochemistry. RESULTS: The combination of dovitinib and oxaliplatin showed higher in vitro cytotoxicity in colon cell lines irrespective of their RAS RAF status as compared to either of the drugs alone. Simultaneous inhibition of MAP kinase and AKT pathways and induction of apoptosis via activation of caspases 9/caspases 3 contributed to the synergistic effect of this combination therapy. In the xenograft model, the combination showed a significantly higher antitumor activity. Immunohistochemistry of post treatment tumors showed a significant decrease in proliferation and angiogenesis as compared to either of the treatments alone. CONCLUSIONS: This study demonstrates the synergistic antitumor activity of combination of dovitinib and oxaliplatin against colon cancer with different RAS-RAF status. The combination also showed its antitumor efficacy in a multidrug resistant phenotype xenograft model. This provides a basis for further investigation for its potential in clinical setting for colorectal cancer. PMID- 24495752 TI - In vitro assessment of the influence of aortic annulus ovality on the hydrodynamic performance of self-expanding transcatheter heart valve prostheses. AB - BACKGROUND: Although CT-studies as well as intraoperative analyses have described broad anatomic variations of the aortic annulus, which is predominantly found non circular, commercially available transcatheter aortic heart valve prostheses are circular. In this study, we hypothesize that the in vitro hydrodynamic function of a self-expanding transcatheter heart valve (Medtronic CoreValve) assessed in an oval compartment representing the aortic annulus will differ from the conventionally used circular compartment. METHODS: Medtronic CoreValve prostheses were tested in specifically designed and fabricated silicone compartments with three degrees of defined ovalities. The measurements were performed in a left heart simulator at three different flow rates. In this setting, regurgitation flow, effective orifice area, and systolic pressure gradient across the valve were determined. In addition, high speed video recordings were taken to investigate leaflet kinematics. RESULTS: The pressure difference across the prosthesis increased with rising ovality. The effective orifice areas were only slightly impacted. The analyses of the regurgitation showed minor changes and partially lower regurgitation when switching from round to slightly oval settings, followed by strong increases for further ovalization. The high speed videos show minor central leakage and impaired leaflet apposition for strong ovalities, but no leaflet/stentframe contact in any setting. CONCLUSION: This study quantifies the influence of oval expansion of transcatheter heart valve prostheses on their hydrodynamic performance. While slight ovalities were well tolerated by a self-expanding prosthesis, more significant ovality led to worsening of prosthesis function and regurgitation. PMID- 24495753 TI - In vitro assessment of a combined radiofrequency ablation and cryo-anchoring catheter for treatment of mitral valve prolapse. AB - Percutaneous approaches to mitral valve repair are an attractive alternative to surgical repair or replacement. Radiofrequency ablation has the potential to approximate surgical leaflet resection by using resistive heating to reduce leaflet size, and cryogenic temperatures on a percutaneous catheter can potentially be used to reversibly adhere to moving mitral valve leaflets for reliable application of radiofrequency energy. We tested a combined cryo anchoring and radiofrequency ablation catheter using excised porcine mitral valves placed in a left heart flow loop capable of reproducing physiologic pressure and flow waveforms. Transmitral flow and pressure were monitored during the cryo-anchoring procedure and compared to baseline flow conditions, and the extent of radiofrequency energy delivery to the mitral valve was assessed post treatment. Long term durability of radiofrequency ablation treatment was assessed using statically treated leaflets placed in a stretch bioreactor for four weeks. Transmitral flow and pressure waveforms were largely unaltered during cryo anchoring. Parameter fitting to mechanical data from leaflets treated with radiofrequency ablation and cryo-anchoring revealed significant mechanical differences from untreated leaflets, demonstrating successful ablation of mitral valves in a hemodynamic environment. Picrosirius red staining showed clear differences in morphology and collagen birefringence between treated and untreated leaflets. The durability study indicated that statically treated leaflets did not significantly change size or mechanics over four weeks. A cryo anchoring and radiofrequency ablation catheter can adhere to and ablate mitral valve leaflets in a physiologic hemodynamic environment, providing a possible percutaneous alternative to surgical leaflet resection of mitral valve tissue. PMID- 24495754 TI - Integrin activation and internalization mediated by extracellular matrix elasticity: a biomechanical model. AB - Cells sense and respond to the elasticity of extracellular matrix (ECM) via integrin-mediated adhesion. As a class of well-documented mechanosenors in cells, integrins switch among inactive, bound, and dissociated states, depending upon the variation of forces acting on them. However, it remains unclear how the ECM elasticity directs and affects the states of integrins and, in turn, their cellular functions. On the basis of our recent experiments, a biomechanical model is proposed to reveal the role of ECM elasticity in the state-switching of integrins. It is demonstrated that a soft ECM can increase the activation level of integrins while a stiff ECM has a tendency to prevent the dissociation and internalization of bound integrins. In addition, it is found that more stable focal adhesions can form on stiffer and thinner ECMs. The theoretical results agree well with relevant experiments and shed light on the ECM elasticity-sensing mechanisms of cells. PMID- 24495755 TI - Predicting response to endovascular therapies: dissecting the roles of local lesion complexity, systemic comorbidity, and clinical uncertainty. AB - Through decades of use and refinement, endovascular stents have become part and parcel of the management of obstructive atherosclerotic lesions. Upon stent placement, a variety of biophysical reactions ensue, governed not only by the mechanical and material properties of the device, but also the impact these properties have on the local vascular biology. Anatomic changes and vascular deformations give rise to solid mechanical and fluid forces that are the proximate, functional drivers of the induced reparative response. Powerful computational tools and advanced imaging techniques allow us to define these forces with high precision and increasingly, at a patient-specific level. We have also gained fundamental insights into how these forces influence subcellular and cellular processes, and, through application of a variety of model systems, how they subsequently drive an integrated tissue response. Clinical studies extend understanding to actual patients and pathophysiologic scenarios. These tools and insights take on added weight given the real risks that accompany the many substantial benefits of stenting. Complex lesions remain difficult to manage and continue to be associated with worse outcomes. While many patients respond well to treatment, others suffer treatment failures and recurrent events - sometimes catastrophic. Overcoming such variability requires that we move towards individualized treatment plans. Doing so necessitates that we develop not just a qualitative understanding of involved phenomena, but a quantitative ability to predict integrated outcomes. Given the multi-scale nature of the vascular response to stenting, it is critical that models, be they computational, bench top, animal, or clinical, can be verified, validated, and made interrelated. This review provides an overview of the biophysics governing endovascular stenting, their integration in real-world endovascular settings, and how simulation and statistical approaches are helping to bridge the gap between qualitative model understanding and quantitative clinical prediction. PMID- 24495756 TI - [Multicenter investigation of diagnosis and treatment of Henoch-Schonlein purpura nephritis in childhood]. AB - OBJECTIVE: To retrospectively investigate the current diagnosis and treatment of children with Henoch-Schonlein purpura nephritis in hospital, to survey the application of practical evidence-based guidelines in children with Henoch Schonlein purpura nephritis. METHOD: A nationwide survey in 40 hospitals was conducted and data of hospitalized children diagnosed as Henoch-Schonlein purpura nephritis for the first time during the period of 1st July 2008 to 30th June 2011 were analyzed. The collected information included age, gender, disease duration, clinical manifestations, relevant auxiliary examination results, renal biopsy, and treatment and so on. The data were collected and analyzed by the subspecialty group of nephrology, Chinese Society of Pediatrics. RESULT: There were 4863 hospitalized children with Henoch-Schonlein purpura nephritis from July 1, 2008 to June 30, 2011 in 40 hospitals. The male (n = 2935) to female (n = 1928) ratio was 1.52: 1, the peak incidence between 6 to 13 years old. Renal impairment occurred in 96.7% (n = 4702) with 6 months from the onset of Henoch-Schonlein purpura. The most common clinical findings were proteinuria and hematuria (2831 patients, 58.2%); 1448 patients received renal biopsy, subclass III and II were the most common histological types; 3677 patients (75.6%) were treated with corticosteroids and immunosuppressants. The most common treatment scheme was corticosteroids only (1655 patients, 34.0%). More than half of the patients (362 patients, 56.2%) with pure hematuria received no corticosteroids or immunosuppressants. Patients with hematuria and proteinuria always received corticosteroids only (1017 patients, 35.9%). Corticosteroids with or without tripterygium glycosides were always given to the patients with subclass I and II in renal biopsy. The patients with subclass III and IV were mainly treated with combination of corticosteroids, cyclophosphamide and methylprednisolone. CONCLUSION: The incidence of purpura nephritis has increased; the duration of renal impairment had no correlation with the gender. Compared to the female, the male patients are more likely to have proteinuria. The patients with mild proteinuria also can present with severe renal histological impairment. There was no unified treatment scheme in the immunosuppressants and non-specific drugs. Multi-center randomized controlled trials (RCTs) are needed to explore and manage the treatment of purpura nephritis. PMID- 24495757 TI - [Survey on common pediatric drugs for renal diseases]. AB - OBJECTIVE: Development and use of better medicine for children is a worldwide problem recently, especially in China. The current situation of drugs for children's renal diseases is far from well-understood now. This survey focused on drugs for pediatric renal diseases including immunosuppressants, corticosteroids, diuretics, anticoagulants, hypotensives and antilipemic agents.Information regarding the dosage, form, precaution, usage and administration in inserts was collected in this study. METHOD: Drugs for pediatric renal diseases were selected according to the guidelines established by the Chinese Society of Pediatric Nephrology. The detailed information about the dosage, form of drugs was searched on the website of China-State Food and Drug (SFDA). The information of the precaution, usage and administration was obtained from the China Pharmaceutical Reference, the first edition. RESULT: In this study, there were 5 categories of medicine including immunosuppressants, corticosteroids, diuretics, anticoagulants, hypotensives and antilipemic agents, and 89 kinds of medicine for renal diseases. Among these medicines, 65.2% were found not suitable for children in terms of drug dosage and form, 19.1% did not indicate the precaution, 51.7% did not indicate clearly the safety and effectiveness for children, and 56.2% lacked the detailed information about the usage and administration for children. There were only 4 kinds of these medicines which were studied via clinical trials in children population. CONCLUSION: There is a lack of drugs for children with renal diseases. Most of the time, the medicines used by doctors are not specially manufactured for children. The safety and efficacy of drugs that are currently used to treat pediatric renal diseases are not clear and definite.In addition, few clinical trials have been conducted for evaluation of drugs for pediatric renal diseases.In clinic, the situation of off-label drug treatment is very serious. PMID- 24495758 TI - [Seasonal influence on the diagnosis of food allergy in children less than 3 years of age]. AB - OBJECTIVE: To investigate the seasonal influence on the diagnosis of food allergy in children under 3 years of age. METHOD: The data of epidemiological studies about food allergy of children under 3 years of age attending routine well-baby checks at the Department of Primary Child Care, Children's Hospital of Chongqing Medical University in the winter and summer, 2009, including questionnaires, results of skin prick test (SPT), food elimination and oral food challenge (OFC) were analyzed. All the data were analyzed by SPSS 17.0. RESULT: The age and sex distribution, and both the rates of the drop-out in two studies were similar. Ninety infants were positive for SPT, 40 infants were positive for OFC, and 31 infants dropped out in winter; while 65 infants were positive for SPT, 25 positive for OFC, and 31 dropped out in summer. The percentage of positive SPT in the children performed in winter was higher than that in summer (14.9%, 90/603 vs 10.7%, 65/607) (P = 0.028). Skin prick test accuracy was similar when the studies were performed in winter and in summer [sensitivity 0.85 and 0.84, positive predictive value (PPV) 0.54 and 0.47, negative predictive value (NPV) 0.99 and 0.99]. The prevalence of food allergy in the children studied in winter was higher than that in summer (7.0% vs 4.3%), but the difference was not significant. After correcting the prevalence for dropout children, the prevalence of food allergy (FA) investigated in winter was significantly higher than that in summer (9.3% vs 5.9%). The results of circular distribution analysis showed the date of birth corresponding to estimated value of peak point of SPT in winter were not consistent with it in summer, so was OFC. Either the results of skin prick test or oral food challenge in two studies were not correlated with the seasons of birth. CONCLUSION: Our data showed that the rates of positive SPT and the prevalence of food allergy were correlated with the seasons, but the seasons of birth did not influence the results of skin prick test or oral food challenge in children, while the real age of children were related to them. PMID- 24495759 TI - [Profiles of innate immune receptors and cytokines in peripheral blood mononuclear cells in children with measles]. AB - OBJECTIVE: The aim of this study was to explore the roles and clinical significance of innate immune receptors and cytokine in children with measles. METHOD: The children with measles hospitalized in the department of infectious diseases, Children's Hospital of Fudan University during 2009-2011 were enrolled into measles group, while the healthy children examined in well baby clinic were enrolled into control group. The mRNA expression of TLR2/3/4/7, melanoma differentiation-associated gene-5 (MDA-5), retinoic acid-inducible gene I (RIG I), IFN-alpha/beta and IL-10 in peripheral blood mononuclear cells were detected by real-time PCR. The protein levels of IFN-alpha, IFN-beta and IL-10 in plasma were measured using ELISA. SPSS 13.0 software was applied to analyze the difference between two groups. RESULT: Data from a total of 98 patients in measles group and 59 children in control group were collected. The mRNA expressions of TLR2, MDA-5 and RIG-I had no statistical significance between two groups (P > 0.05, respectively). The relative mRNA expressions of TLR3, TLR4, TLR7 in measles group (2.25 +/- 0.74, 2.05 +/- 0.72, 2.12 +/- 0.29) were significantly lower than those in control group (2.09 +/- 0.78, 1.90 +/- 0.75, 1.87 +/- 0.68) (P < 0.01; respectively). Both IFN-alpha and IFN-beta had significantly decreased mRNA expressions in measles patients (2.41 +/- 1.31, 2.47 +/- 1.26) compared with those in controls (2.22 +/- 0.48, 2.35 +/- 0.64)(P < 0.01 respectively); however, IL-10 mRNA levels significantly increased (2.49 +/- 0.58 vs. 2.62 +/- 0.95) (P < 0.001). The IL-10 levels in plasma in measles group were significantly higher during the whole period of fever [<5 d group: 29.89 (25.82 38.15) ng/L and >= 5 d group:34.55 (28.26-38.70) ng/L] than that in control group [25.15 (24.20-27.38) ng/L] (P < 0.05 respectively). CONCLUSION: TLR3/4/7 mRNA expression was low in peripheral blood mononuclear cells of measles patients. Levels of IL-10 were significantly raised in the early stage after infection and lasted for a long time, and reduced IFN-alpha levels in plasma were associated with the fever durations of measles patients. These results indicated that multiple TLRs and cytokines may participate in the immune response after measles virus infection. PMID- 24495760 TI - [Different species of human rhinovirus infection in children with acute respiratory tract infections in Beijing]. AB - OBJECTIVE: To understand the clinical characteristics of different groups human rhinovirus (HRV)-A, B and C infection in children with acute respiratory tract infections (ARI) in Beijing. METHOD: Respiratory tract specimens (n = 1412) collected from children with ARI during Jan. 2011 to Dec. 2012 were tested for HRV by using semi-nested PCR. Gene fragments of VP4/VP2 capsid protein amplified from HRV positive specimens were sequenced for HRV genotype confirmation. Then epidemiological characteristics of these HRV-positive cases were analyzed. RESULT: Among these 1412 specimens tested, 103 (7.3%) were HRV positive, including 54 (52.4%) positive for HRV-A, 14 (13.6%) for HRV-B, 35 (34.0%) for HRV C determined by sequence analysis. The positive rates of HRV-A, B and C (2.5%, 16/638; 0.3%, 2/638 and 1.3%, 8/638) in children with acute upper respiratory tract infections (URI) were lower than those (5.8%, 36/623; 1.8%, 11/623 and 3.9%, 24/623) in children with acute lower respiratory tract infections (LRI) (P = 0.003, 0.011, 0.003). In children with LRI, the positive rates of HRV-A, C were similar to each other (P = 0.112), and both were higher than that of HRV-B (P = 0.000, P = 0.026). The severity of ARI among children positive for different groups HRV showed no significant difference evaluated by Kruskal-Wallis H test (Hc = 0.044, P > 0.05), as well as that between children co-infected with HRV and other viruses and those infected with HRV only evaluated by Wilcoxon rank sum test (Zc = 0.872, P > 0.05). CONCLUSION: HRV is one of important pathogens for children with ARI, especially LRI in Beijing. The positive rates of HRV-A and HRV C are similar to each other, and both are higher than that of HRV-B. No significant difference was shown among children with different HRV genotypes by evaluation of the severity of ARI, and co-infections of HRV with other viruses do not significantly increase the severity of ARI. PMID- 24495761 TI - [Clinical, biochemical and genetic analysis of the mitochondrial disorders presenting with cardiac damage]. AB - OBJECTIVE: Mitochondrial disease is a group of energy metabolic disorders, characterized by involvement of multisystem with high energy requirements. Encephalomyopathies are common clinical findings of the mitochondrial diseases. However, mitochondrial cardiac damage is not rare. In this study, the clinical, biological, and genetic analyses were performed in three patients with mitochondrial cardiac damage, in order to understand the characteristics of mitochondrial diseases. METHOD: Three girls presented with arrhythmia and cardiac enlargement from the age of 3, 4 and 8 years respectively. They were admitted into the Peking University First Hospital. Infection, autoimmune diseases, aminoacidopathies, organic acidurias, mitochondrial-fatty acid oxidation defects, and lysosomal storage disease were excluded by routine laboratory examinations and metabolic analysis for blood amino acids, acylcarnitines, urinary organic acids, and lysosome activity assay. Peripheral leukocytes mitochondrial respiratory chain enzyme I to V activities were measured by spectrophotometry. The entire sequence of the mitochondrial DNA was analyzed. RESULT: In two patients (case 1 and case 3), hypertrophic cardiomyopathy and grade I to grade II of cardiac function were found. One patient (case 2) was diagnosed with arrhythmia and grade I of cardiac function. Increased creatine phosphokinase and creatine kinase isoenzyme MB were observed. Mitochondrial respiratory chain complex deficiencies were indentified in the three patients. Patient 1 had combined deficiencies of complex III and V. The activity of complex I+III was 18.7 nmol/(min.mg mitochondrial protein) (control 84.4 +/- 28.5). The activity of complex V was 20.4 nmol/(min.mg mitochondrial protein) (control 103.7 +/- 29.2). In her mitochondrial gene, A14693G on tRNA(Glu) and T16519C on D-loop were found. Patient 2 had an isolated complex I deficiency. The activity was 22.0 nmol/(min.mg mitochondrial protein) (control 44.0 +/- 5.4). A16183C, T16189C and G15043A mutations on D-loop were found. Patient 3 had a combined deficiency of complex IV and V. The activity of complex IV was 21.0 nmol/(min.mg mitochondrial protein) (control 54.1 +/- 12.3). The activity of complex V was 23.2 nmol/(min.mg mitochondrial protein) (control 103.7 +/- 29.2). C253T and C16187T mutations on D loop were detected. Haplotype analysis showed that three patients belong to H2a2a. Improvement was observed after the treatment with L-carnitine, coenzyme Q10, vitamin C and E. At present, the patients are 7, 5 and 8 years old. Although excise intolerance still persists, they had a good general condition with normal school life. CONCLUSION: The mitochondrial diseases with cardiac damage show cardiomyopathy, arrhythmia and exercise intolerance. Many kinds of mitochondrial respiratory chain deficiency were observed. A14693G in mitochondrial tRNA(Glu) gene is probably one of the causes in China. PMID- 24495762 TI - [AGL gene analysis of a pedigree with glycogen storage disease type III and identification of a novel mutation]. AB - OBJECTIVE: To reveal the molecular genetic pathogenesis of the glycogen storage disease type III (GSDIII) and to provide a prerequisite for prenatal gene diagnosis in future. METHOD: All the coding regions as well as the border areas between exons and introns of the AGL gene and the parental relevant mutation sites were directly sequenced, so that to affirm the origin of the mutation. Then, detected novel heterozygous mutation was confirmed by cloning sequencing. Finally, definite diagnoses of the novel mutation were performed by a series of identification methods, including screening for the 100 normal controls by DHPLC in order to count the mutational frequency, analyze the conservative of the mutant amino acid sequence from 11 kinds of species and comprise the difference of the tertiary structure between the mutant protein and the normal one. RESULT: The patient had compound heterozygous mutations, the c.100C>T (p.R34X) nonsense mutation and c. 1176_1178 del TCA deletion mutation. The p.R34X has been reported abroad, but the 1176_1178 del TCA/p.His392fs mutation is a novel one. The proband's father is heterozygous with the p.R34X mutation while his mother carries the c.1176_1178 del TCA mutation. The result from searching the dbSNP database, HGMD database and papers published in recent years showed that the c.1176_1178 del TCA is a novel mutation, but not an SNP. Conservative analysis results in 11 species indicate that the amino acid of the mutation site is highly conserved in the stage of evolution. Comparison results between the mutant protein and the normal one demonstrate that the deletion mutation results in the obvious variation of the spatial conformation of AGL protein. CONCLUSION: The "c.1176_1178 del TCA (p.392delHis)" mutation is a novel pathogenic mutation. This mutation and the c.100C>T (p.R34X) is the cause that the proband suffer from the GSDIIIa disease. These two mutations are inherited from mother and father respectively. The methods from this paper can be used for further prenatal gene diagnosis. PMID- 24495763 TI - [Clinical characteristics of Pneumocystis carinii pneumonia in children with systemic lupus erythematosus]. AB - OBJECTIVE: To identify the risk factors which will indicate the Pneumocystis carinii (Pc) infection in children with systemic lupus erythematosus (SLE) and investigate the clinical features and to elevate the level to find out the high risk patients and make early diagnosis and treatment. METHOD: The characteristics, clinical features, laboratory examinations, treatment and prognosis of Pneumocystis carinii pneumonia (PCP) in children with SLE under 18 years of age treated in our hospital between January 2000 and January 2013 were prospectively reviewed. A comparison was made with the 26 cases of SLE children without PCP who were matched for gender, age and course, and a literature review was made. RESULTS: (1) Five cases were enrolled, 3 were male and 2 female. Their age range was 13-17 (14.0 +/- 1.6) years. All the children had kidney involvement. The courses were from 3 months to 4.5 years. All patients were receiving daily glucocorticoid therapy and immunosuppressive drugs before the diagnosis of PCP.Four patients were in the inactive phase of SLE (SLEDAI 2-4 points), and the fifth case was in active phase (SLEDAI 8, low complement 2 points, anti-dsDNA antibody positive 2 points, urine-protein 4 points). (2) Besides the clinical manifestations of SLE, most patients had progressive dyspnea, fever and dry cough at onset of PCP. Two children accepted mechanical ventilation because of respiratory failure. The mean duration of the symptoms to diagnosis was 10-30 (17.6 +/- 7.8) days. Lactose dehydrogenase (LDH) was elevated more or less, median was (700 +/- 263) U/L. Lymphocyte count were (0.3 1.4)*10(9)/L (median 0.5*10(9)/L), and three children had CD4 T lymphocyte count <0.3*10(9)/L. Arterial blood gas analyses showed severe hypoxemia. Chest radiographs showed in all cases diffuse interstitial infiltration. Pc was positive in the sputum. All patients were treated with trimethoprim sulfamethoxazole and corticosteroids. CONCLUSION: When SLE children are treated with corticosteroids and immunosuppressive drugs, low lymphocyte count is the risk factor for Pc infection.It is essential to monitor lymphocyte count.We should pay more attention to fever, dry cough and hypoxemia. Chest radiologic examination may help diagnose the PCP in SLE children.It may be helpful for SLE children whose CD4T lymphocyte was below 0.3*10(9)/L to take trimethoprim sulfamethoxazole for PCP prophylaxis. PMID- 24495764 TI - [Six Kawasaki disease patients with acute coronary artery thrombosis]. AB - OBJECTIVE: To improve the awareness of acute coronary artery thrombosis in Kawasaki disease (KD). METHOD: Six KD patients with acute coronary artery thrombosis (Jan. 2004 to Jan. 2013) were studied retrospectively. The basic information, clinical manifestations, laboratory data, echocardiography and electrocardiography (ECG), method and consequence of thrombolytic therapy were analyzed. RESULT: The mean age of patients with coronary artery thrombosis (5 males and 1 female) was (17.2 +/- 11.3) months.Five cases had thrombosis in left coronary artery (LCA), and four cases had thrombosis in aneurysm of left anterior descending artery (LAD). One case had thrombosis in both left and right coronary artery (RCA).One case died. Maximum thrombus was about 1.60 cm * 0.80 cm, locating in LAD. The diameter of LCA and RCA was (0.44 +/- 0.07) cm and (0.45 +/- 0.07) cm. Two patients showed abnormal ECG. Case 3 showed ST segment depression in lead V5. Case 6 showed myocardial infarction.In acute phase of KD, three patients received treatment with intravenous immunoglobin (IVIG), five patients were treated with aspirin.In sub-acute and convalescent phase of KD, all patients were treated with low-dose aspirin.Warfarin and dipyridamole were applied in 5 patients. All cases were treated with thrombolytic therapy using urokinase and/or heparin. After thrombolytic therapy, echocardiography showed thrombolysis in four cases and no change in one.One patient died of myocardial infarction. CONCLUSION: Most of acute coronary thrombosis in KD occurred in LAD. KD patients with coronary artery thrombosis are at risk of sudden death due to myocardial infarction. PMID- 24495765 TI - [Analysis of clinical manifestations and genetic mutations in a child with Laron syndrome]. AB - OBJECTIVE: To analyze clinical manifestations and gene mutations in a child with severe short stature, explore its molecular mechanism and further clarify the diagnostic procedure for short stature. METHOD: We observed clinical characteristics of a patient with short stature and did diagnostic examinations, assessed the function of GH-IGF-1 axis, and surveyed its family members.Genomic DNA was extracted from peripheral blood, GHR, IGFALS, STAT5b and GH1 gene were amplified by PCR for sequencing, including exons and splicing areas. RESULT: The patient presented symmetrical short stature (height -8.2 SDS) and facial features, and other congenital abnormalities.It displayed non-growth hormone deficiency. The baseline value of GH was 21 ug/L, and the peak was 57.9 ug/L. The value of IGF-1 was less than 25 ug/L, and the IGFBP-3 less than 50 ug/L. And IGF 1 generation test showed no response. There was no similar patients in the family members.Sequencing of GHR in the patient revealed a homozygous point mutation (c.Ivs6+1G>A), and her father and mother had the same heterozygous mutation. The same mutation was not identified for her sister.No other candidate gene was found. CONCLUSION: As the result of combined clinical characteristics and lab examinations, as well as gene detection, the case was diagnosed with Laron syndrome and GHR gene mutation is the molecular mechanism.We should explicit the etiological diagnosis for short stature, and avoid missed diagnosis and misdiagnosis. PMID- 24495766 TI - [One case of 2q37 deletion syndrome: clinical and genetic diagnosis]. AB - OBJECTIVE: To diagnose a new born baby with 2q37 deletion syndrome by comprehensive use of cytogenetic and molecular techniques and to investigate the phenotype characteristics and applicability of array-comparative genomic hybridization (array-CGH) and multiplex ligation-dependent probe amplification (MLPA) for detection of this syndrome. METHOD: Following conventional chromosome preparation, G banded karyotyping was performed.Genomic DNA was extracted using standard procedures, which were then analyzed by array-CGH and MLPA. RESULT: The patient presented with a typical face, special fist posture and congenital heart disease in 2q37 deletion syndrome. A 4.709 Mb deletion at 2q37.3 (chr2:237, 967, 852-242, 677, 269.NCBI36/hg18, including genes from COL6A3 toPDCD1) was detected by array-CGH. The results of MLPA and G banded karyotyping confirmed the existence of this deletion. CONCLUSION: 2q37.3 deletion was determined to be the cryptic cause of this case.2q37 deletion syndrome has some clinically recognizable characteristics. And array-CGH is a powerful technique for the accurate diagnosis and genotype-phenotype correlation study of this syndrome. PMID- 24495767 TI - [Report of a case with secondary acute promyelocytic leukemia after therapy for hemophagocytic lymphohistiocytosis and review of literature]. AB - OBJECTIVE: To explore the characteristics and risk of etoposide-related leukemia in the treatment of hemophagocytic lymphohistiocytosis (HLH). METHOD: Clinical characteristics of a case with secondary acute promyelocytic leukemia (APL) were summarized and 10 cases of secondary leukemia after treatment for HLH from literature were analyzed. RESULT: The child was diagnosed with Epstein-Barr virus associated HLH and received HLH-2004 protocol. The cumulative dose of etoposide (VP16) was 3520 mg/m(2). The patient was diagnosed with APL after 28 months of HLH.He achieved complete remission after induction chemotherapy of all-trans retinoic acid and darubicin. Consolidated chemotherapy was continued. There were 10 reports of etoposide-related leukemia after treatment for HLH in the literature.Review of 11 cases treated with VP16, of which cumulative doses were 900-20 500 mg/m(2). The interval period between HLH and secondary leukemia was 24 months. The types of secondary leukemia included 1 case with acute lymphoblastic leukemia, 1 case with myelodysplastic syndrome and 9 cases of acute myeloid leukemia. The abnormalities of chromosome included 3 patients with 11q23, 3 APL patients with t (15, 17).Seven patients survived and 4 died. CONCLUSION: The latency period of etoposide-related leukemia is short. Acute myeloid leukemia and balanced chromosomal abnormality are common in etoposide-related leukemia. The risk factors for development of secondary leukemia are related to cumulative drug doses of etoposide, treatment schedules and co-administration of other antineoplastic agents.It is appropriate to keep suitable range of the cumulative dose of etoposide in HLH therapy in order to reduce the risk of therapy related leukemia. PMID- 24495768 TI - [A case of left coronary artery originating from the right coronary sinus associated with acute myocardial infarcition]. PMID- 24495769 TI - [Familial hemophagocytic lymphohistiocytosis with the MUNC13-4 mutation after unrelated hematopoietic stem cell transplantation: a case report]. PMID- 24495770 TI - [Review of the relationship between human TLR9 gene polymorphisms and infectious diseases]. PMID- 24495771 TI - [Brief summary of the 12th National Conference on Pediatric Liver Diseases and Infectious Diseases]. PMID- 24495772 TI - [A brief introduction to NICU management in Canada]. PMID- 24495775 TI - What are the most important infectious diseases among those >=65 years: a comprehensive analysis on notifiable diseases, Norway, 1993-2011. AB - BACKGROUND: As the population ages, the burden on the healthcare system might increase and require changed public health priorities. As infections are often more severe at older age, we rank notifiable infectious diseases (ID) and describe trends of ID among the general population aged >=65 years in Norway in order to inform public health priorities for the aging population. METHODS: We included all eligible cases of the 58 IDs notified between 1993 and 2011 (n = 223,758; 12% >=65 years) and determined annual notification rates as the number of notified cases divided by the number of inhabitants of the corresponding year. We ranked diseases using their average annual notification rate for 2007-2011. Trends in notification rates from 1993 onwards were determined with a non parametric test for trend. Using notification rate ratios (NRR), we compared results in those aged >=65 years to those aged 20-64 years. RESULTS: Invasive pneumococcal disease was the most common ID among the population >=65 years (notification rate 58/100,000), followed by pertussis (54/100,000) and campylobacteriosis (30/100,000). Most ID notification rates did not change over time, though the notification rate of symptomatic MRSA infections increased from 1/100,000 in 1995 (first year of notification) to 14/100,000 in 2011.Overall, fewer cases were notified among the population >=65 years compared to 20-64 year olds (NRR = 0.73). The NRR of each of the invasive bacterial diseases and antibiotic-resistant infections were above 1.5 (i.e. more common in >=65), while the NRR of each food- and waterborne disease, blood-borne disease/STI and (non invasive) vaccine preventable disease was below 1. CONCLUSIONS: Based on our results, we emphasise the importance of focusing public health efforts for those >=65 years on preventing invasive bacterial infections. This can be achieved by increasing pneumococcal and influenza vaccine uptake, and risk communication including encouraging those aged >=65 years and their caretakers to seek healthcare at signs of systemic infection. Furthermore, good compliance to infection control measures, screening of the at-risk population, and careful use of antibiotics may prevent further increase in antibiotic-resistant infections. PMID- 24495776 TI - Synthesis, docking and pharmacological evaluation of novel indole based potential atypical antipsychotics. AB - A series of substituted indole derivatives have been synthesized and the target compounds evaluated for atypical antipsychotic activity in apomorphine induced mesh climbing and stereotypy assays in mice. The compounds 11 and 12 have emerged as important lead compounds showing potential atypical antipsychotic profile. In silico (docking studies) have been carried out to postulate a hypothetical binding model for the target compounds with respect to the dopaminergic D2 and 5 HT2A receptors. Theoretical ADME profiling of the compounds based on selected physicochemical parameters has suggested an excellent compliance with Lipinski's rules. The potential of these compounds to penetrate the blood brain barrier (log BB) was computed through an online software program and the values obtained for the compounds suggest good potential for brain permeation. PMID- 24495777 TI - Anxiolytic-like effects of a new 1-N substituted analog of melatonin in pinealectomized rats. AB - In spite of the wide variety of drugs available for treating anxiety, this disorder continues to represent a worldwide health problem that is classified within the first 10 causes of disability. Therefore, the search continues for new antianxiety agents, particularly those not related to benzodiazepines. Even though melatonin has been prescribed as an anxiolytic drug, its use is currently limited due to its short half-life and photo-sensitivity, among other disadvantages. The present study explores the antianxiety properties of a new 1-N substituted melatonin analog, M3C, in pinealectomized rats submitted to two behavioral tests (the cumulative burying behavior paradigm and the elevated plus maze). Results from both tests show that M3C is effective as an anxiolytic-like agent, at doses lower than any other melatonin analog previously reported. The blocking of these actions by luzindole together with the available data suggests that the anxiolytic properties of M3C are mediated by MT1 and MT2 receptors. PMID- 24495778 TI - Serum lipids, recent suicide attempt and recent suicide status in patients with major depressive disorder. AB - OBJECTIVE: Major depressive disorder (MDD) is associated with suicide. Although several studies have reported its association with low serum lipid, few studies have investigated relationships between current suicidality and lipid profiles, comparing with other blood measures in MDD patients. METHODS: The study population consisted of 555 subjects with MDD who were >= 18 years old, evaluated by the Mini International Neuropsychiatric Interview (MINI) with the suicidality module. At the evaluation visit, we measured serum lipid profiles including total cholesterol, triglycerides (TG), low-density lipoprotein (LDL), high-density lipoprotein (HDL), and very low-density lipoprotein (VLDL), and blood measures such as fasting glucose, total protein, albumin, blood urea nitrogen, creatinine, thyroid hormones, red and white blood cells, platelet count, hemoglobin, and hematocrit. RESULTS: Recent attempters who had attempted suicide within the past month showed significantly lower TG and higher HDL levels than lifetime and never attempters, using Tukey's post-hoc analysis. Recent attempters exhibited lower TG and higher HDL than those with recent suicide ideation and wish to self-harm and those without previous attempt. Linear regression analysis revealed that TG was negatively associated with current suicidality scores (beta = -0.187, p = 0.039), whereas VLDL was positively associated with the recent suicide status (beta = 0.198, p = 0.032) after controlling for age and sex. There were no significant differences between the groups in terms of other serum lipid profiles and blood measures. CONCLUSIONS: Low serum TG, high HDL and VLDL levels are associated with recent suicide attempt or recent suicide status in patients with MDD. PMID- 24495779 TI - Release of endogenous cannabinoids from ventral tegmental area dopamine neurons and the modulation of synaptic processes. AB - Endogenous cannabinoids play important roles in a variety of functions in the mammalian brain, including the regulation reward-related information processing. The primary mechanism through which this is achieved is the presynaptic modulation of synaptic transmission. During reward- and reinforcement-related behavior dopamine levels increase in forebrain areas and this has recently been shown to be modulated by the endocannabinoid system. Therefore, understanding how endocannabinoids are mobilized to modulate synaptic inputs impinging on midbrain dopamine neurons is crucial to a complete understanding of the roles that these molecules play in reward behavior, drug abuse and addiction. Here we summarize the literature describing short-term and long-term regulation of afferent connections on dopamine neurons in the ventral tegmental area via endocannabinoid activation of cannabinoid CB1 receptors, and describe the mechanisms through which these molecules are released during reward-based behavior and exposure to abused drugs. PMID- 24495780 TI - A pharmacogenetic study of risperidone on chemokine (C-C motif) ligand 2 (CCL2) in Chinese Han schizophrenia patients. AB - Previous observations of the pathophysiological distribution and pharmacological profile of the chemokine (C-C motif) ligand 2 (CCL2) have indicated its potential role in antipsychotic drug actions. More information on the pharmacogenetics of CCL2 may therefore be useful in developing individualized therapy. However, to our knowledge, rare studies have been reported in this area. This investigation was attempted to clarify whether CCL2 polymorphism could affect risperidone efficacy. We genotyped four SNPs (rs4795893, rs1024611, rs4586 and rs2857657) distributed throughout the CCL2 gene and examined them for association using the Positive and Negative Syndrome Scale (PANSS) score in two independent cohorts of Chinese schizophrenic patients (n = 208) from two different geographic areas, following an 8-week period of risperidone monotherapy. We found that all genotyped SNPs were significantly associated with risperidone treatment (rs4795893: p = 1.66E-04, rs4586: p = 0.001, rs2857657: p = 0.004, at week 4, in ANOVA). Our results indicate that there may be some effect of variations in the CCL2 gene on therapeutic efficacy of risperidone, and the associated polymorphisms may be a potential genetic marker for predicting the therapeutic effect of risperidone. PMID- 24495781 TI - 'Get Healthy, Stay Healthy': protocol for evaluation of a lifestyle intervention delivered by text-message following the Get Healthy Information and Coaching Service(r). AB - BACKGROUND: Behavioural lifestyle interventions can be effective at promoting initial weight loss and supporting physical activity and dietary behaviour change, however maintaining improvements in these outcomes is often more difficult to achieve. Extending intervention contact to reinforce learnt behavioural skills has been shown to improve maintenance of behaviour change and weight loss. This trial aims to evaluate the feasibility, acceptability and efficacy of a text message-delivered extended contact intervention to enhance or maintain change in physical activity, dietary behaviour and weight loss among participants who have completed a six month Government-funded, population-based telephone coaching lifestyle program: the Get Healthy Information and Coaching Service (GHS). METHODS/DESIGN: GHS completers will be randomised to the 6-month extended contact intervention (Get Healthy, Stay Healthy, GHSH) or a no contact control group (standard practice following GHS completion). GHSH participants determine the timing and frequency of the text messages (3-13 per fortnight) and content is tailored to their behavioural and weight goals and support preferences. Two telephone tailoring calls are made (baseline, 12-weeks) to facilitate message tailoring. Primary outcomes, anthropometric (body weight and waist circumference via self-report) and behavioural (moderate-vigorous physical activity via self-report and accelerometer, fruit and vegetable intake via self report), will be assessed at baseline (at GHS completion), 6-months (end of extended contact intervention) and 12-months (6-months post intervention contact). Secondary aims include evaluation of: the feasibility of program delivery; the acceptability for participants; theoretically-guided, potential mediators and moderators of behaviour change; dose-responsiveness; and, costs of program delivery. DISCUSSION: Findings from this trial will inform the delivery of the GHS in relation to the maintenance of behaviour change and weight loss, and will contribute to the broader science of text message lifestyle interventions delivered in population health settings. TRIAL REGISTRATION: ACTRN12613000949785. PMID- 24495782 TI - Protease-activated receptor-2 modulates hepatic stellate cell collagen release and apoptotic status. AB - The pathogenesis of hepatic fibrosis is to be further investigated. Protease activated receptor-2 (PAR2) plays a role in hepatic fibrosis. This study aims to elucidate the role of activation of PAR2 in the regulation of hepatic stellate cell activities. In this study, the expression of PAR2, Fas and caveolin-1 in human hepatic stellate cell line, HHStec cell (HHStecs) was assessed by real time RT-PCR and Western blot. The levels of collagen were determined by enzyme-linked immunosorbent assay. The PAR2 gene was silenced in HHStecs using RNA interference. Apoptosis of HHStecs was assessed by flow cytometry. The results showed that HHStecs expressed PAR2, which was up regulated by activation with phorbol myristate acetate (PMA). Activation of PAR2 increased the release of collagen from HHStecs. Exposure to PMA induced HHStec apoptosis, which was significantly inhibited by activation of PAR2. The PAR2 activation also suppressed the expression of caveolin-1 and Fas in HHStecs. Over expression of caveolin-1 in HHStecs blocked PAR2-reduced apoptosis. We conclude that HHStecs express PAR2. Activation of PAR2 increases HHStecs to release collagen and reduces the activation-induced HHStec apoptosis, which can be inhibited by the over expression of caveolin-1. PMID- 24495783 TI - Antimicrobial function of SHbetaAP, a novel hemoglobin beta chain-related antimicrobial peptide, isolated from the liver of skipjack tuna, Katsuwonus pelamis. AB - A 2.3 kDa of antimicrobial peptide was purified from an acidified liver extract of skipjack tuna, Katsuwonus pelamis, by preparative acid-urea-polyacrylamide gel electrophoresis and C18 reversed-phase HPLC. A comparison of the amino acid sequence of the purified peptide with those of other known polypeptides revealed high homology with the C-terminus of hemoglobin beta-chain; thus, this peptide was designated as the Skipjack Hemoglobin beta chain-related Antimicrobial Peptide (SHbetaAP). SHbetaAP showed potent antimicrobial activity against Gram positive bacteria, such as Bacillus subtilis, Staphylococcus aureus, and Streptococcus iniae (minimal effective concentrations [MECs], 6.5-57.0 MUg/mL), Gram-negative bacteria, such as Escherichia coli D31, Pseudomonas aeruginosa, Salmonella enterica, Shigella sonnei, and two Vibrio parahaemolyticus species (MECs, 2.0-19.0 MUg/mL), and against Candida albicans (MEC; 12.0 MUg/mL) without significant hemolytic activity. Antimicrobial activity of this peptide was heatstable and pH resistant but is sensitive to proteases and salt. SHbetaAP did not show membrane permeabilization and killing ability. The secondary structural prediction and the homology modeling expected that this peptide formed an amphipathic alpha-helical structure. This is the first report the purification of a novel antimicrobial peptide related to the C-terminus of hemoglobin beta-chain from marine fish. PMID- 24495784 TI - Nonmedical prescription drug users in private vs. public substance abuse treatment: a cross sectional comparison of demographic and HIV risk behavior profiles. AB - BACKGROUND: Little is known regarding the demographic and behavioral characteristics of nonmedical prescription drug users (NMPDUs) entering substance abuse treatment settings, and information on the HIV-related risk profiles of NMPDUs is especially lacking. Participation in substance abuse treatment provides a critical opportunity for HIV prevention and intervention, but successful initiatives will require services appropriately tailored for the needs of NMPDUs. METHODS: This paper compares the HIV risk profiles of NMPDUs in public (n = 246) and private (n = 249) treatment facilities. Participants included in the analysis reported five or more recent episodes of nonmedical prescription drug use, a prior HIV negative test result, and current enrollment in a substance abuse treatment facility. A standardized questionnaire was administered by trained interviewers with questions about demographics, HIV risk, and substance use. RESULTS: Private treatment clients were more likely to be non-Hispanic White, younger, and opioid and heroin users. Injection drug use was higher among private treatment clients, whereas public clients reported higher likelihood of trading or selling sex. Public treatment clients reported higher rates of HIV testing and availability at their treatment facilities compared to private clients. CONCLUSIONS: Findings suggest differing demographics, substance use patterns, profiles of HIV risk and access to HIV testing between the two treatment samples. Population tailored HIV interventions, and increased access to HIV testing in both public and private substance treatment centers, appear to be warranted. PMID- 24495785 TI - Phenethyl isothiocyanate and paclitaxel synergistically enhanced apoptosis and alpha-tubulin hyperacetylation in breast cancer cells. AB - Combination of phenethyl isothiocyanate (PEITC) and paclitaxel (taxol) has been shown to work synergistically to increase apoptosis and cell cycle arrest in breast cancer cells. In this report, we further explored the mechanisms for the synergistic activity of PEITC and taxol in MCF7 and MDA-MB-231 (MB) breast cancer cell lines. By Western blotting analysis, treatment of MCF7 cells with both PEITC and taxol led to a 10.4-fold and 5.96-fold increase in specific acetylation of alpha-tubulin over single agent PEITC and taxol, respectively. This synergistic effect on acetylation of alpha-tubulin was also seen in MB cells. The combination of PEITC and taxol also reduced expressions of cell cycle regulator Cdk1, and anti-apoptotic protein bcl-2, enhanced expression of Bax and cleavage of PARP proteins. In conclusion, this study provided biochemical evidence for the mechanism of synergistic effect between the epigenetic agent PEITC and the chemotherapeutic agent taxol. PMID- 24495786 TI - Playing God: the rock opera that endeavors to become a bioethics education tool. AB - This article describes and introduces a new innovative tool for bioethics education: a rock opera on the ethics of genetics written by two academics and a drummer legend. The origin of the idea, the characters and their development, and the themes and approaches as well as initial responses to the music and the show are described, and the various educational usages are explored. PMID- 24495787 TI - Considering the senses in the diagnosis and management of dementia. AB - Associations between dementia and impairments in hearing, vision, olfaction and (to a lesser degree) taste have been identified. Hearing impairment has been shown to precede cognitive decline, but it is not clear if the hearing loss is an early marker of dementia or a modifiable risk factor. Olfactory impairment is seen in many neurodegenerative conditions, but it has been shown that those with dementia have particular difficulties with the recognition and identification of odours rather than the detection, suggesting a link to impairment of higher cognitive function. Olfactory impairment has been shown to be predictive of conversion from mild cognitive impairment to Alzheimer's disease with 85.2% sensitivity. As cognitive function deteriorates, the world is experienced at a sensory level, with reduced ability to integrate the sensory experiences to understand the context. Thus, people with dementia are very sensitive to sensory experiences and their environment needs to be managed carefully to make it understandable, comfortable, and (if possible) therapeutic. Light can be used to stabilise the circadian rhythm, which may be disturbed in dementia. Music therapy, aromatherapy, massage and multisensory stimulation are recommended by NICE for the management of behavioural and psychological symptoms of dementia (BPSD), although the mechanisms behind such interventions are poorly understood and evidence is limited. Sensory considerations are likely to play a greater role in dementia care in the future, with the development of purpose-built dementia care facilities and the focus on non-pharmacological management strategies for BPSD. PMID- 24495788 TI - Prospects for automated diagnosis of verbal autopsies. AB - Verbal autopsy is a method for assessing probable causes of death from lay reporting of signs, symptoms and circumstances by family members or caregivers of a deceased person. Several methods of automated diagnoses of causes of death from standardized verbal autopsy questionnaires have been developed recently (Inter VA, Tariff, Random Forest and King-Lu). Their performances have been assessed in a series of papers in BMC Medicine. Overall, and despite high specificity, the current strategies of automated computer diagnoses lead to relatively low sensitivity and positive predictive values, even for causes which are expected to be easily assessed by interview. Some methods have even abnormally low sensitivity for selected diseases of public health importance and could probably be improved. Ways to improve the current strategies are proposed: more detailed questionnaires; using more information on disease duration; stratifying for large groups of causes of death by age, sex and main category; using clusters of signs and symptoms rather than quantitative scores or ranking; separating indeterminate causes; imputing unknown cause with appropriate methods. Please see related articles: http://www.biomedcentral.com/1741-7015/12/5; http://www.biomedcentral.com/1741-7015/12/19; http://www.biomedcentral.com/1741 7015/12/20; http://www.biomedcentral.com/1741-7015/12/21; http://www.biomedcentral.com/1741-7015/12/22; http://www.biomedcentral.com/1741 7015/12/23. PMID- 24495789 TI - Editorial on "modern chromatographic and mass spectrometric techniques for protein biopharmaceutical characterization" by K. Sandra, I. Vandenheede and P. Sandra. PMID- 24495790 TI - Focused ultrasound solid-liquid extraction for the determination of perfluorinated compounds in fish, vegetables and amended soil. AB - In the present work a method was developed for the determination of different perfluorinated compounds (PFCs), including three perfluorinated sulfonic acids (PFSAs), seven perfluorocarboxylic acids (PFCAs), three perfluorophosphonic acids (PFPAs) and perfluorooctanesulfonamide (PFOSA) in fish, vegetables and amended soil samples based on focused ultrasound solid-liquid extraction (FUSLE) followed by solid-phase extraction (SPE) clean-up and liquid chromatography-tandem mass spectrometry (LC-MS/MS). Different variables affecting the chromatographic separation (column type and pH of the mobile phase), the electrospray ionization (capillary voltage, nebulizer pressure and drying gas flow) and mass spectrometric detection (fragmentor voltage and collision energy) were optimized in order to improve the sensitivity of the separation and detection steps. In the case of FUSLE variables such as the solvent type, the solvent volume, the extraction temperature, the sonication and extraction time and the percentage of applied irradiation power were studied. Under optimized conditions, sonication of 2.5min with pulse times on of 0.8s and pulse times off of 0.2s in 7mL of (9:1) acetonitrile (ACN): water mixture in duplicate guaranteed exhaustive extraction of the matrices analyzed. Due to the non-selective extraction using FUSLE, different SPE cartridges (200-mg Waters Oasis-HLB, 150-mg Waters Oasis-WAX and 150-mg Waters Oasis-MAX) were tested in terms of extraction efficiency and matrix effect both in the extraction and detection steps. Mix mode SPE using Waters Oasis-WAX provided the best extraction efficiencies with the lowest matrix effect. The final method was validated in terms of recovery at two fortification levels (in the 80-120% for most of the analytes and matrices), precision (relative standard deviation in the 2-15% range) and method detection limits (MDLs, 0.3-12.4ng/g for vegetables, 0.2-12.5ng/g for fish and 1-22ng/g for amended soil). Finally the method was applied for the determination of the 14 PFCs in different vegetables and fish samples from a local supermarket and in a soil amended with a compost from a local wastewater treatment plant (WWTP). PMID- 24495791 TI - Enhanced high-performance liquid chromatography method for the determination of retinoic acid in plasma. Development, optimization and validation. AB - When determining endogenous compounds in biological samples, the lack of blank or analyte-free matrix samples involves the use of alternative strategies for calibration and quantitation. This article deals with the development, optimization and validation of a high performance liquid chromatography method for the determination of retinoic acid in plasma, obtaining at the same time information about its isomers, taking into account the basal concentration of these endobiotica. An experimental design was used for the optimization of three variables: mobile phase composition, flow rate and column temperature through a central composite design. Four responses were selected for optimization purposes (area under the peaks, quantity of peaks, analysis time and resolution between the first principal peak and the following one). The optimum conditions resulted in a mobile phase consisting of methanol 83.4% (v/v), acetonitrile 0.6% (v/v) and acid aqueous solution 16.0% (v/v); flow rate of 0.68 mL min(-1) and an column temperature of 37.10 degrees C. Detection was performed at 350 nm by a diode array detector. The method was validated following a holistic approach that included not only the classical parameters related to method performance but also the robustness and the expected proportion of acceptable results lying inside predefined acceptability intervals, i.e., the uncertainty of measurements. The method validation results indicated a high selectivity and good precision characteristics that were studied at four concentration levels, with RSD less than 5.0% for retinoic acid (less than 7.5% for the LOQ concentration level), in intra and inter-assay precision studies. Linearity was proved for a range from 0.00489 to 15.109 ng mL(-1) of retinoic acid and the recovery, which was studied at four different fortification levels in phuman plasma samples, varied from 99.5% to 106.5% for retinoic acid. The applicability of the method was demonstrated by determining retinoic acid and obtaining information about its isomers in human and frog plasma samples from different origins. PMID- 24495792 TI - Treatment with telmisartan/rosuvastatin combination has a beneficial synergistic effect on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. AB - OBJECTIVES: To explore synergistic effect between angiotensin II receptor blockers (ARBs) and statins on Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. METHODS: This study was a 2 * 2 factorial randomized, prospective, double-blind, placebo-controlled trial. One hundred and fifty nine hypertensive patients with carotid atherosclerosis were randomized to the administration of control group, telmisartan group, rosuvastatin group, and combination group (telmisartan plus rosuvastatin) base on hydrochlorothiazide treatment. Carotid ultrasonography, parameters of Th17/Treg functional axis, interleukin (IL)-1beta, IL-2, interferon (IFN)-gamma, hypersensitive C-reactive protein (hsCRP), monocyte chemotactic protein (MCP)-1 were evaluated. RESULTS: Blood pressure level markedly reduced in four groups. There was significantly synergistic effect of combination of telmisartan with rosuvastatin on reducing carotid imtima-media thickness (IMT), Th17 cells frequency, IL-17, IL-6, IL-23, tumor necrosis factor (TNF)-alpha, expression of retinoic acid receptor-related orphan receptor (ROR)gammat mRNA, Th17/Treg ratio, IL-1beta, IL-2, IFN-gamma, hsCRP, and MCP-1, and increasing Treg cells frequency, IL-10, transforming growth factor(TGF)-beta1, and expression of forkhead/winged helix transcription factor (Foxp3) mRNA (all P<0.05). Change rate of IMT statistical positively related to descent rates of Th17 cells frequency, IL-17, IL-6, IL-23, TNF-alpha, expression of RORgammat mRNA, Th17/Treg ratio, IL-1beta, IL-2, IFN-gamma, hsCRP, and MCP-1, and negatively related to increased rates of Treg frequency, IL-10, TGF-beta1, and expression of Foxp3 mRNA, respectively (all P<0.05). CONCLUSION: There is a synergistic effect of combination of telmisartan with rosuvastatin on ameliorating Th17/Treg functional imbalance in hypertensive patients with carotid atherosclerosis. PMID- 24495793 TI - Diastolic blood pressure, aortic atheroma, and prognosis in hypertension: new insights into a complex association. AB - OBJECTIVES: Our study aimed at determining the interaction between the prognostic value of diastolic blood pressure (DBP) and aortic atherosclerosis (ATS). BACKGROUND: With aging, equal systolic blood pressures (SBPs) become associated with low DBPs; i.e., high pulse pressures (PPs) become associated with a high risk of cardiovascular death. This association is usually ascribed to aortic stiffening with age but the precise impact of low DBP per se is yet uncertain. METHODS: 938 hypertensive patients recruited in the seventies had an aortic ATS score at pretreatment aortography. All-cause and cardiovascular deaths were assessed 20 years later. The prognostic values of DBP and SBP were assessed by a multivariate Cox regression model and their interactions with ATS examined. RESULTS: In the presence of ATS, an increase of 10 mmHg in DBP was associated with a protective effect: hazard ratios 0.84 [0.72-0.99] for cardiovascular death and 0.88 [0.78-1.00] for all-cause death. However, in the absence of ATS, DBP had no prognostic value: hazard ratios 1.05 [0.89-1.23] for cardiovascular death and 0.99 [0.88-1.11] for all-cause death (p for interaction: 0.061 and 0.087, respectively). No interaction was found between SBP and ATS (p for interaction > 0.40). CONCLUSIONS: The prognostic values of DBP and aortic atheroma are not superimposable; yet, they are tightly connected: a low DBP is disadvantageous only in the presence of a pathologic aorta. Aortic atherosclerosis may explain, at least partly, in some high risk populations, the J-shape of the already reported DBP-outcome relationship. PMID- 24495794 TI - Circulating cf-DNA: a promising, noninvasive tool for assessment of early cardio metabolic risk. PMID- 24495795 TI - Application of mean-shift clustering to blood oxygen level dependent functional MRI activation detection. AB - BACKGROUND: Functional magnetic resonance imaging (fMRI) analysis is commonly done with cross-correlation analysis (CCA) and the General Linear Model (GLM). Both CCA and GLM techniques, however, typically perform calculations on a per voxel basis and do not consider relationships neighboring voxels may have. Clustered voxel analyses have then been developed to improve fMRI signal detections by taking advantages of relationships of neighboring voxels. Mean shift clustering (MSC) is another technique which takes into account properties of neighboring voxels and can be considered for enhancing fMRI activation detection. METHODS: This study examines the adoption of MSC to fMRI analysis. MSC was applied to a Statistical Parameter Image generated with the CCA technique on both simulated and real fMRI data. The MSC technique was then compared with CCA and CCA plus cluster analysis. A range of kernel sizes were used to examine how the technique behaves. RESULTS: Receiver Operating Characteristic curves shows an improvement over CCA and Cluster analysis. False positive rates are lower with the proposed technique. MSC allows the use of a low intensity threshold and also does not require the use of a cluster size threshold, which improves detection of weak activations and highly focused activations. CONCLUSION: The proposed technique shows improved activation detection for both simulated and real Blood Oxygen Level Dependent fMRI data. More detailed studies are required to further develop the proposed technique. PMID- 24495797 TI - Pre-IVF hysteroscopy to enhance uterine receptivity may be justified. PMID- 24495796 TI - SAP domain-dependent Mkl1 signaling stimulates proliferation and cell migration by induction of a distinct gene set indicative of poor prognosis in breast cancer patients. AB - BACKGROUND: The main cause of death of breast cancer patients is not the primary tumor itself but the metastatic disease. Identifying breast cancer-specific signatures for metastasis and learning more about the nature of the genes involved in the metastatic process would 1) improve our understanding of the mechanisms of cancer progression and 2) reveal new therapeutic targets. Previous studies showed that the transcriptional regulator megakaryoblastic leukemia-1 (Mkl1) induces tenascin-C expression in normal and transformed mammary epithelial cells. Tenascin-C is known to be expressed in metastatic niches, is highly induced in cancer stroma and promotes breast cancer metastasis to the lung. METHODS: Using HC11 mammary epithelial cells overexpressing different Mkl1 constructs, we devised a subtractive transcript profiling screen to identify the mechanism by which Mkl1 induces a gene set co-regulated with tenascin-C. We performed computational analysis of the Mkl1 target genes and used cell biological experiments to confirm the effect of these gene products on cell behavior. To analyze whether this gene set is prognostic of accelerated cancer progression in human patients, we used the bioinformatics tool GOBO that allowed us to investigate a large breast tumor data set linked to patient data. RESULTS: We discovered a breast cancer-specific set of genes including tenascin-C, which is regulated by Mkl1 in a SAP domain-dependent, serum response factor-independent manner and is strongly implicated in cell proliferation, cell motility and cancer. Downregulation of this set of transcripts by overexpression of Mkl1 lacking the SAP domain inhibited cell growth and cell migration. Many of these genes are direct Mkl1 targets since their promoter-reporter constructs were induced by Mkl1 in a SAP domain-dependent manner. Transcripts, most strongly reduced in the absence of the SAP domain were mechanoresponsive. Finally, expression of this gene set is associated with high-proliferative poor-outcome classes in human breast cancer and a strongly reduced survival rate for patients independent of tumor grade. CONCLUSIONS: This study highlights a crucial role for the transcriptional regulator Mkl1 and its SAP domain during breast cancer progression. We identified a novel gene set that correlates with bad prognosis and thus may help in deciding the rigor of therapy. PMID- 24495798 TI - Application of response surface methodology and artificial neural network methods in modelling and optimization of biosorption process. AB - A review on the application of response surface methodology (RSM) and artificial neural networks (ANN) in biosorption modelling and optimization is presented. The theoretical background of the discussed methods with the application procedure is explained. The paper describes most frequently used experimental designs, concerning their limitations and typical applications. The paper also presents ways to determine the accuracy and the significance of model fitting for both methodologies described herein. Furthermore, recent references on biosorption modelling and optimization with the use of RSM and the ANN approach are shown. Special attention was paid to the selection of factors and responses, as well as to statistical analysis of the modelling results. PMID- 24495800 TI - Specific chemical interactions between metal ions and biological solids exemplified by sludge particulates. AB - The adsorption of metals onto biological surfaces was studied exemplified by municipal sludge particulates of the primary, the secondary, and the tertiary sludge types from four regional wastewater treatment plants. Major factors affecting the extent of metal adsorption including pH, DOM, total biomass, and total metal loading were studied. The acidity-basicity characteristics of the DOM, the metal ions (Lewis acids), and the surface of the sludge particulates make pH the most important parameter in metal adsorption. Change in pH can modify the speciation of the metal ions, the DOM, and the surface acidity of the sludge particulates and subsequently determines the degree of metal distribution between the aqueous phase and the sludge solids. Information on the acidity-basicity characteristics of the DOM and the sludge particulates are used to calculate the stability constant of metal ion-sludge complexes. PMID- 24495799 TI - Non-cellulosic heteropolysaccharides from sugarcane bagasse - sequential extraction with pressurized hot water and alkaline peroxide at different temperatures. AB - The xylan-rich hemicellulose components of sugarcane bagasse were sequentially extracted with pressurized hot-water extraction (PHWE) and alkaline peroxide. The hemicelluloses were found to contain mainly arabinoxylans with varying substitutions confirmed by different chemical and spectroscopic methods. The arabinoxylans obtained from PHWE were found to be more branched compared to those obtained after alkaline extraction. Sequential extraction could be useful for the isolation of hemicelluloses with different degree of branching, molar mass, and functional groups from sugarcane bagasse, which can be of high potential use for various industrial applications. PMID- 24495801 TI - The return-to-work process of individuals sick-listed because of whiplash associated disorder: a three-year follow-up study in a Danish cohort of long-term sickness absentees. AB - BACKGROUND: The chronic course of whiplash-associated disorder (WAD) has implications for both the individual and society. It has been shown that up to 50% of patients have not yet returned to work six months after a whiplash injury. We wanted to study the return-to-work (RTW) process in individuals sick-listed for more than eight weeks in six Danish municipalities. RTW in individuals sick listed due to WAD was compared to that in those sick-listed for other musculoskeletal disorders (MSD). METHODS: Information about long-term sick-listed individuals in six Danish municipalities was retrieved from an existing database. Data on public transfer income were collected and the RTW process was followed on a weekly basis. Multivariate logistic regression analysis of RTW was done four times during the first three years after the start of sick-listing. RESULTS: One hundred and four individuals were sick-listed due to WAD and 3,204 individuals were sick-listed due to other MSDs. After 6 months, the RTW was significantly lower in the WAD group. OR for RTW in the WAD group was 0.29 (0.18-0.49) compared to the MSD group. The RTW process for both groups stabilised after two years of follow-up; 44% returned to work in the WAD group as compared to 58% in the MSD group. CONCLUSION: Sick-listed individuals with whiplash-associated disorder are less likely to return to work than individuals who are sick-listed because of other musculoskeletal disorders. In both groups, RTW stabilised after two years of follow-up. PMID- 24495802 TI - Short message service or disService: issues with text messaging in a complex medical environment. AB - BACKGROUND: Hospitals today are experiencing major changes in their clinical communication workflows as conventional numeric paging and face-to-face verbal conversations are being replaced by computer mediated communication systems. In this paper, we highlight the importance of understanding this transition and discuss some of the impacts that may emerge when verbal clinical conversations are replaced by short text messages. METHODS: In-depth interviews (n=108) and non participatory observation sessions (n=260h) were conducted on the General Internal Medicine wards at five academic teaching hospitals in Toronto, Canada. RESULTS: From our analysis of the qualitative data, we identified two major themes. De-contextualization of complex issues led to an increase in misinterpretation and an increase in back and forth messaging for clarification. Depersonalization of communication was due to less verbal conversations and face to-face interactions and led to a negative impact on work relationships. CONCLUSIONS: Text-based communication in hospital settings led to the oversimplification of messages and the depersonalization of communication. It is important to recognize and understand these unintended consequences of new technology to avoid the negative impacts to patient care and work relationships. PMID- 24495804 TI - Ultra structure analysis of cell-cell interactions between pericytes and neutrophils in vitro. AB - Neutrophils' adhesion to the endothelium during inflammatory is a well-known processes. In contrast the interaction of neutrophils with cells of the neurovascular unit after they have been transmigrated into the brain is less clear. Recently, lymphocyte function-associated antigen-1 (LFA-1) dependent subendothelial crawling of neutrophils has been observed in vivo. This is mediated by intracellular adhesion molecule-1 (ICAM-1), which is expressed on the cell surface of pericytes. In our work we demonstrated in vitro a cell-cell interaction between porcine brain capillary pericytes (PBCPs) and neutrophils, with further characterization of the initial contact between these cells. PBCPs increase ICAM-1 protein expression in response to the cytokine tumor necrosis factor-alpha (TNF-alpha). Furthermore, an increase in neutrophil adhesion to PBCPs was determined by immunofluorescence staining. By means of scanning force microscopy (SFM), we could additionally show that pericytes as well as neutrophils form cell extensions towards the neighboring cell. Interestingly, these extensions differ for different cell types. PMID- 24495805 TI - MiR-22 suppresses the proliferation and invasion of gastric cancer cells by inhibiting CD151. AB - Gastric cancer (GC) is the second common cause of cancer-related death worldwide. microRNAs (miRNAs) play important roles in the carcinogenesis of GC. Here, we found that miR-22 was significantly decreased in GC tissue samples and cell lines. Ectopic overexpression of miR-22 remarkably suppressed cell proliferation and colony formation of GC cells. Moreover, overexpression of miR-22 significantly suppressed migration and invasion of GC cells. CD151 was found to be a target of miR-22. Furthermore, overexpression of CD151 significantly attenuated the tumor suppressive effect of miR-22. Taken together, miR-22 might suppress GC cells growth and motility partially by inhibiting CD151. PMID- 24495803 TI - Integrin alpha1beta1 participates in chondrocyte transduction of osmotic stress. AB - BACKGROUND/PURPOSE: The goal of this study was to determine the role of the collagen binding receptor integrin alpha1beta1 in regulating osmotically induced [Ca(2+)]i transients in chondrocytes. METHOD: The [Ca(2+)]i transient response of chondrocytes to osmotic stress was measured using real-time confocal microscopy. Chondrocytes from wildtype and integrin alpha1-null mice were imaged ex vivo (in the cartilage of intact murine femora) and in vitro (isolated from the matrix, attached to glass coverslips). Immunocytochemistry was performed to detect the presence of the osmosensor, transient receptor potential vanilloid-4 (TRPV4), and the agonist GSK1016790A (GSK101) was used to test for its functionality on chondrocytes from wildtype and integrin alpha1-null mice. RESULTS/INTERPRETATION: Deletion of the integrin alpha1 subunit inhibited the ability of chondrocytes to respond to a hypo-osmotic stress with [Ca(2+)]i transients ex vivo and in vitro. The percentage of chondrocytes responding ex vivo was smaller than in vitro and of the cells that responded, more single [Ca(2+)]i transients were observed ex vivo compared to in vitro. Immunocytochemistry confirmed the presence of TRPV4 on wildtype and integrin alpha1-null chondrocytes, however application of GSK101 revealed that TRPV4 could be activated on wildtype but not integrin alpha1-null chondrocytes. Integrin alpha1beta1 is a key participant in chondrocyte transduction of a hypo-osmotic stress. Furthermore, the mechanism by which integrin alpha1beta1 influences osmotransduction is independent of matrix binding, but likely dependent on the chondrocyte osmosensor TRPV4. PMID- 24495806 TI - Production of soluble Neprilysin by endothelial cells. AB - A non-membrane bound form of Neprilysin (NEP) with catalytic activity has the potential to cleave substrates throughout the circulation, thus leading to systemic effects of NEP. We used the endothelial cell line Ea.hy926 to identify the possible role of exosomes and A Disintegrin and Metalloprotease 17 (ADAM-17) in the production of non-membrane bound NEP. Using a bradykinin based quenched fluorescent substrate (40 MUM) assay, we determined the activity of recombinant human NEP (rhNEP; 12 ng), and NEP in the media of endothelial cells (10% v/v; after 24 h incubation with cells) to be 9.35+/-0.70 and 6.54+/-0.41 MUmols of substrate cleaved over 3h, respectively. The presence of NEP in the media was also confirmed by Western blotting. At present there are no commercially available inhibitors specific for ADAM-17. We therefore synthesised two inhibitors TPI2155-14 and TPI2155-17, specific for ADAM-17 with IC50 values of 5.36 and 4.32 MUM, respectively. Treatment of cells with TPI2155-14 (15 MUM) and TPI2155-17 (4.3 MUM) resulted in a significant decrease in NEP activity in media (62.37+/-1.43 and 38.30+/-4.70, respectively as a % of control; P<0.0001), implicating a possible role for ADAM-17 in NEP release. However, centrifuging media (100,000g for 1 h at 4 degrees C) removed all NEP activity from the supernatant indicating the likely role of exosomes in the release of NEP. Our data therefore indicated for the first time that NEP is released from endothelial cells via exosomes, and that this process is dependent on ADAM-17. PMID- 24495807 TI - Do Sector Wide Approaches for health aid delivery lead to 'donor-flight'? A comparison of 46 low-income countries. AB - Sector Wide Approaches (SWAp) emerged during the 1990s as a new policy mechanism for aid delivery. Eschewing many features of traditional project-based aid, SWAps give greater control of aid allocation to recipient countries. Some critics have questioned whether reducing a donor's level of influence over aid allocation might lead to a decrease in donor contributions. While some qualitative evaluations have described the level of fund pooling and donor participation in SWAps, no previous study has empirically examined this potential 'donor-flight' response to health SWAp implementation. This paper utilises a uniquely compiled dataset of 46 low-income countries over 1990-2009 and a variety of panel data regression models to estimate the impact of health SWAp implementation on levels of health aid. Results suggest that amongst 16 especially poor low-income countries, SWAp implementation is associated with significant decreases in health aid levels compared with non-implementers. This suggests donors are not indifferent to how their contributions are allocated by recipients, and that low income countries considering a SWAp may need to weigh the benefits of greater control of aid allocations against the possibility of reduced aid income. PMID- 24495808 TI - Social capital, mental health and biomarkers in Chile: assessing the effects of social capital in a middle-income country. AB - In high-income countries, higher social capital is associated with better health. However, there is little evidence of this association in low- and middle-income countries. We examine the association between social capital (social support and trust) and both self-rated and biologically assessed health outcomes in Chile, a middle-income country that experienced a major political transformation and welfare state expansion in the last two decades. Based on data from the Chilean National Health Survey (2009-10), we modeled self-rated health, depression, measured diabetes and hypertension as a function of social capital indicators, controlling for socio-economic status and health behavior. We used an instrumental variable approach to examine whether social capital was causally associated with health. We find that correlations between social capital and health observed in high-income countries are also observed in Chile. All social capital indicators are significantly associated with depression at all ages, and at least one social capital indicator is associated with self-rated health, hypertension and diabetes at ages 45 and above. Instrumental variable models suggest that associations for depression may reflect a causal effect from social capital indicators on mental well-being. Using aggregate social capital as instrument, we also find evidence that social capital may be causally associated with hypertension and diabetes, early markers of cardiovascular risk. Our findings highlight the potential role of social capital in the prevention of depression and early cardiovascular disease in middle-income countries. PMID- 24495809 TI - Specificity of stimulus-evoked fMRI responses in the mouse: the influence of systemic physiological changes associated with innocuous stimulation under four different anesthetics. AB - Functional magnetic resonance (fMRI) in mice has become an attractive tool for mechanistic studies, for characterizing models of human disease, and for evaluation of novel therapies. Yet, controlling the physiological state of mice is challenging, but nevertheless important as changes in cardiovascular parameters might affect the hemodynamic readout which constitutes the basics of the fMRI signal. In contrast to rats, fMRI studies in mice report less robust brain activation of rather widespread character to innocuous sensory stimulation. Anesthesia is known to influence the characteristics of the fMRI signal. To evaluate modulatory effects imposed by the anesthesia on stimulus-evoked fMRI responses, we compared blood oxygenation level dependent (BOLD) and cerebral blood volume (CBV) signal changes to electrical hindpaw stimulation using the four commonly used anesthetics isoflurane, medetomidine, propofol and urethane. fMRI measurements were complemented by assessing systemic physiological parameters throughout the experiment. Unilateral stimulation of the hindpaw elicited widespread fMRI responses in the mouse brain displaying a bilateral pattern irrespective of the anesthetic used. Analysis of magnitude and temporal profile of BOLD and CBV signals indicated anesthesia-specific modulation of cerebral hemodynamic responses and differences observed for the four anesthetics could be largely explained by their known effects on animal physiology. Strikingly, independent of the anesthetic used our results reveal that fMRI responses are influenced by stimulus-induced cardiovascular changes, which indicate an arousal response, even to innocuous stimulation. This may mask specific fMRI signal associated to the stimulus. Hence, studying the processing of peripheral input in mice using fMRI techniques constitutes a major challenge and adapted paradigms and/or alternative fMRI readouts should also be considered when studying sensory processing in mice. PMID- 24495810 TI - Brain lateralization of holistic versus analytic processing of emotional facial expressions. AB - This study investigated the neurocognitive mechanisms underlying the role of the eye and the mouth regions in the recognition of facial happiness, anger, and surprise. To this end, face stimuli were shown in three formats (whole face, upper half visible, and lower half visible) and behavioral categorization, computational modeling, and ERP (event-related potentials) measures were combined. N170 (150-180 ms post-stimulus; right hemisphere) and EPN (early posterior negativity; 200-300 ms; mainly, right hemisphere) were modulated by expression of whole faces, but not by separate halves. This suggests that expression encoding (N170) and emotional assessment (EPN) require holistic processing, mainly in the right hemisphere. In contrast, the mouth region of happy faces enhanced left temporo-occipital activity (150-180 ms), and also the LPC (late positive complex; centro-parietal) activity (350-450 ms) earlier than the angry eyes (450-600 ms) or other face regions. Relatedly, computational modeling revealed that the mouth region of happy faces was also visually salient by 150 ms following stimulus onset. This suggests that analytical or part-based processing of the salient smile occurs early (150-180 ms) and lateralized (left), and is subsequently used as a shortcut to identify the expression of happiness (350-450 ms). This would account for the happy face advantage in behavioral recognition tasks when the smile is visible. PMID- 24495811 TI - Examining brain structures associated with perceived stress in a large sample of young adults via voxel-based morphometry. AB - Perceived stress reflects the extent to which situations are appraised as stressful at a given point in one's life. Past brain imaging studies have examined activation patterns underlying the stress response, yet focal differences in brain structures related to perceived stress are not well understood, especially when considering gray matter (GM) and white matter (WM) structures simultaneously. In this study, voxel-based morphometry was used to investigate relations between GM/WM volume and perceived stress levels in a large young adult sample. Participants (138 men, 166 women) completed the Perceived Stress Scale (PSS; Cohen et al., 1983) and underwent an anatomical magnetic resonance imaging scan. Higher PSS scores were associated with larger GM volume in a cluster that included regions in the bilateral parahippocampal gyrus, fusiform cortex, and entorhinal cortex and smaller GM volume in a cluster that included regions of the right insular cortex. Higher PSS scores were also related to smaller WM volume in a cluster that included the body of the corpus callosum. This pattern of results remained significant even after controlling for effects of general intelligence, socioeconomic status, and depression. Together, findings suggest a unique structural basis for individual differences in perceived stress, distributed across different GM and WM regions of the brain. PMID- 24495812 TI - Contrast gain control and horizontal interactions in V1: a DCM study. AB - Using high-density electrocorticographic recordings - from awake-behaving monkeys - and dynamic causal modelling, we characterised contrast dependent gain control in visual cortex, in terms of synaptic rate constants and intrinsic connectivity. Specifically, we used neural field models to quantify the balance of excitatory and inhibitory influences; both in terms of the strength and spatial dispersion of horizontal intrinsic connections. Our results allow us to infer that increasing contrast increases the sensitivity or gain of superficial pyramidal cells to inputs from spiny stellate populations. Furthermore, changes in the effective spatial extent of horizontal coupling nuance the spatiotemporal filtering properties of cortical laminae in V1 - effectively preserving higher spatial frequencies. These results are consistent with recent non-invasive human studies of contrast dependent changes in the gain of pyramidal cells elaborating forward connections - studies designed to test specific hypotheses about precision and gain control based on predictive coding. Furthermore, they are consistent with established results showing that the receptive fields of V1 units shrink with increasing visual contrast. PMID- 24495813 TI - Compressed sensing fMRI using gradient-recalled echo and EPI sequences. AB - Compressed sensing (CS) may be useful for accelerating data acquisitions in high resolution fMRI. However, due to the inherent slow temporal dynamics of the hemodynamic signals and concerns of potential statistical power loss, the CS approach for fMRI (CS-fMRI) has not been extensively investigated. To evaluate the utility of CS in fMRI application, we systematically investigated the properties of CS-fMRI using computer simulations and in vivo experiments of rat forepaw sensory and odor stimulations with gradient-recalled echo (GRE) and echo planar imaging (EPI) sequences. Various undersampling patterns along the phase encoding direction were studied and k-t FOCUSS was used as the CS reconstruction algorithm, which exploits the temporal redundancy of images. Functional sensitivity, specificity, and time courses were compared between fully-sampled and CS-fMRI with reduction factors of 2 and 4. CS-fMRI with GRE, but not with EPI, improves the statistical sensitivity for activation detection over the fully sampled data when the ratio of the fMRI signal change to noise is low. CS improves the temporal resolution and reduces temporal noise correlations. While CS reduces the functional response amplitudes, the noise variance is also reduced to make the overall activation detection more sensitive. Consequently, CS is a valuable fMRI acceleration approach, especially for GRE fMRI studies. PMID- 24495814 TI - The clinical significance of a failed initial intubation attempt during emergency department resuscitation of out-of-hospital cardiac arrest patients. AB - OBJECTIVE: Advanced airway management is one of the fundamental skills of advanced cardiac life support (ACLS). A failed initial intubation attempt (FIIA) is common and has shown to be associated with adverse events. We analysed the association between FIIA and the overall effectiveness of ACLS. METHODS: Using emergency department (ED) out-of-hospital cardiac arrest (OHCA) registry data from 2008 to 2012, non-traumatic ED-resuscitated adult OHCA patients on whom endotracheal intubation was initially tried were identified. Prehospital and demographic factors and patient outcomes were retrieved from the registry. The presence of a FIIA was determined by reviewing nurse-documented CPR records. The primary outcome was achieving a return of spontaneous circulation (ROSC). The secondary outcomes were time to ROSC and the ROSC rate during the first 30min of ED resuscitation. RESULTS: The study population (n=512) was divided into two groups based on the presence of a FIIA (N=77). Both groups were comparable without significant differences in demographic or prehospital factors. In the FIIA group, the unadjusted and adjusted odds ratios (ORs) for achieving a ROSC were 0.50 (95% confidence interval [CI], 0.31-0.81) and 0.40 (95% CI, 0.23-0.71), respectively. Multivariable median regression analysis revealed that FIIA was associated with an average delay of 3min in the time to ROSC (3.08; 95% CI, 0.08 5.80). Competing risk regression analysis revealed a significantly slower ROSC rate during the first 15min (adjusted subhazard ratio, 0.52; 95% CI, 0.35-0.79) in the FIIA group. CONCLUSION: FIIA is an independent risk factor for the decreased effectiveness of ACLS. PMID- 24495815 TI - Improvement in toxicity in high risk prostate cancer patients treated with image guided intensity-modulated radiotherapy compared to 3D conformal radiotherapy without daily image guidance. AB - BACKGROUND: Image-guided radiotherapy (IGRT) facilitates the delivery of a very precise radiation dose. In this study we compare the toxicity and biochemical progression-free survival between patients treated with daily image-guided intensity-modulated radiotherapy (IG-IMRT) and 3D conformal radiotherapy (3DCRT) without daily image guidance for high risk prostate cancer (PCa). METHODS: A total of 503 high risk PCa patients treated with radiotherapy (RT) and endocrine treatment between 2000 and 2010 were retrospectively reviewed. 115 patients were treated with 3DCRT, and 388 patients were treated with IG-IMRT. 3DCRT patients were treated to 76 Gy and without daily image guidance and with 1-2 cm PTV margins. IG-IMRT patients were treated to 78 Gy based on daily image guidance of fiducial markers, and the PTV margins were 5-7 mm. Furthermore, the dose-volume constraints to both the rectum and bladder were changed with the introduction of IG-IMRT. RESULTS: The 2-year actuarial likelihood of developing grade > = 2 GI toxicity following RT was 57.3% in 3DCRT patients and 5.8% in IG-IMRT patients (p < 0.001). For GU toxicity the numbers were 41.8% and 29.7%, respectively (p = 0.011). On multivariate analysis, 3DCRT was associated with a significantly increased risk of developing grade > = 2 GI toxicity compared to IG-IMRT (p < 0.001, HR = 11.59 [CI: 6.67-20.14]). 3DCRT was also associated with an increased risk of developing GU toxicity compared to IG-IMRT.The 3-year actuarial biochemical progression-free survival probability was 86.0% for 3DCRT and 90.3% for IG-IMRT (p = 0.386). On multivariate analysis there was no difference in biochemical progression-free survival between 3DCRT and IG-IMRT. CONCLUSION: The difference in toxicity can be attributed to the combination of the IMRT technique with reduced dose to organs-at-risk, daily image guidance and margin reduction. PMID- 24495816 TI - Zip nucleic acid: a new reliable method to increase the melting temperature of real-time PCR probes. AB - TaqMan genotyping with real-time PCR is a reliable method for single nucleotide polymorphism detection, which is done by probes. These oligonucleotides should be short enough to avoid mismatch hybridization, as well as having 5-10 degrees C higher melting temperature than the primers of real-time PCR reaction. One approach for these qualities is to conjugate the probe with minor groove binder (MGB). Having no access to MGB probes, we searched for an alternative. In the current study, we used Zip Nucleic Acids (ZNA) as probes to increase its stability and melting temperature. Our aim was to genotype the -265 T/C changes of Apolipoprotein A-2 gene. We set up the real-time PCR reaction with ZNA probes, and by repeating the reactions, we confirmed the reliability of this new approach. It is now recommended to use ZNA probes, as an alternative to MGB probes, to increase the probe Tm value and its binding to target DNA. PMID- 24495817 TI - Measuring the mortality impact of breast cancer screening. AB - OBJECTIVE: To i) estimate how large the mortality reductions would be if women were offered screening from age 50 until age 69; ii) to do so using the same trials and participation rates considered by the Canadian Task Force; iii) but to be guided in our analyses by the critical differences between cancer screening and therapeutics, by the time-pattern that characterizes the mortality reductions produced by a limited number of screens, and by the year-by-year mortality data in the appropriate segment of follow-up within each trial; and thereby iv) to avoid the serious underestimates that stem from including inappropriate segments of follow-up, i.e., too soon after study entry and too late after discontinuation of screening. METHODS: We focused on yearly mortality rate ratios in the follow up years where, based on the screening regimen employed, mortality deficits would be expected. Because the regimens differed from trial to trial, we did not aggregate the yearly data across trials. To avoid statistical extremes arising from the small numbers of yearly deaths in each trial, we calculated rate ratios for 3-year moving windows. RESULTS: We were able to extract year-specific data from the reports of five of the trials. The data are limited for the most part by the few rounds of screening. Nevertheless, they suggest that screening from age 50 until age 69 would, at each age from 55 to 74, result in breast cancer mortality reductions much larger than the estimate of 21% that the Canadian Task Force report is based on. DISCUSSION: By ignoring key features of cancer screening, several of the contemporary analyses have seriously underestimated the impact to be expected from such a program of breast cancer screening. PMID- 24495818 TI - Rates of cancer incidence across terciles of the foreign-born population in Canada from 2001-2006. AB - OBJECTIVES: To address the issue of comparative risk of cancer in Canada's immigrant population, an area-based methodology was applied to examine whether or not estimated cancer incidence rates among individuals living in given areas vary systematically according to the concentration of foreign-born individuals living in the same area. This method provides an alternative, accessible surveillance method in the absence of linked individual-level information to extend the work of others by providing both national and subnational standardized, hence comparable, results to address this issue. METHODS: Canadian Cancer Registry data (2001 to 2006) and 2006 Census data provided dissemination area information regarding the concentration of the foreign-born population and population estimates for rate denominators. Cancer (all cause and cause-specific) incidence rate ratios (age-standardized and by age/sex) were calculated by foreign-born concentration areas at both national and regional levels. RESULTS: An inverse gradient was identified between cancer incidence rates and area concentration of foreign-born, with the all-sites cancer rate ranging from a low of 388 per 100,000 among individuals living in areas with a high concentration of foreign born to a high of 493 per 100,000 among individuals living in areas with a low concentration of foreign-born. This pattern occurred nationally for lung, colorectal, prostate and female breast cancers. However, for liver, nasopharynx, and thyroid cancers, higher cancer rates were observed in areas with a higher versus lower concentration of foreign-born populations. CONCLUSION: The study findings provide suggestive evidence of decreased cancer risk among foreign-born populations for most cancers except nasopharynx, liver and thyroid for which risks were higher. The results of this study demonstrate the value of ecological based methods for disease surveillance in the absence of individual-level information on immigrant status in the national cancer registry. PMID- 24495819 TI - The rising burden of rheumatoid arthritis surpasses rheumatology supply in Ontario. AB - OBJECTIVES: Accurate data on the burden of rheumatoid arthritis (RA) are scarce, but critical in helping health care providers and decision makers to optimize clinical and public health strategies for disease management. We quantified the burden of RA in Ontario from 1996 to 2010 by age, sex and health planning region. METHODS: We used the Ontario Rheumatoid Arthritis administrative Database (ORAD), a validated population-based cohort of all Ontarians with RA, to estimate the crude prevalence and incidence of RA among men and women, and by age group from 1996 to 2010. Burden by area of patient residence and rheumatology supply also were determined. RESULTS: The number of RA patients increased over time, from 42,734 Ontarians (0.5%) in 1996 to 97,499 (0.9%) in 2010. On average 5,830 new RA patients were diagnosed each year. In 2010, the burden was higher among females (1.3%) than males (0.5%) and increased with age, with almost half of all RA patients aged 65 years and older. The burden was higher in northern communities (1.0%) than in southern urban areas (0.7%). During the study period, the number of rheumatologists practicing in Ontario remained unchanged (approximately 160). CONCLUSION: Over a 15-year period, the number of RA patients more than doubled with no concomitant increase in the number of practicing rheumatologists. We observed considerable regional variation in burden, with the highest rates observed in the north. Our findings highlight the need for regional approaches to the planning and delivery of RA care in order to manage the growing burden. PMID- 24495820 TI - Are Campylobacter cases low risk for public health follow-up? AB - OBJECTIVES: Most Campylobacter cases are treated as low risk enterics (LRE) and receive a mailed letter from Toronto Public Health (TPH) with a questionnaire to gather basic risk information. This study sought to identify reasons why Campylobacter cases who were sent this questionnaire did not respond to the letter and to determine whether any of these cases were working in a high-risk occupation. METHODS: Cases reported to TPH between June 11, 2012 and December 6, 2012 who had not returned the questionnaire within 30 days were telephoned. Participants were asked about awareness of the original letter, reasons for not responding, and whether they worked in a high-risk occupation. RESULTS: Of the 226 cases identified as not responding to the letter, 172 (76.1%) were reached, and 162 (71.7%) answered the survey questions. The most frequent reason chosen for not responding to the original letter was "forgot" (54.4%). The most common suggestion chosen for ways to encourage response to the original letter was "more information on importance of returning questionnaire" (19.1%). Of the 119 cases with a known occupation, 3 (2.4%) were employed in a sensitive occupation - these include a family physician, a food server, and a line cook. None worked while ill. When prompted with a list of reasons for not returning the questionnaire, the majority of respondents indicated that they "forgot" (54.4%); the next most frequent response was "recovered by illness no longer considered it relevant" (21.5%). CONCLUSION: To increase response rates in the future, a cover letter should more clearly explain why the response is being solicited by Public Health, even after recovery from the illness, and the form should be simplified for mail return. A very small number of clients originally not reached through the course of the routine LRE program were working in sensitive occupations. Since none reported working while ill, the likelihood of direct or indirect transmission of Campylobacter from these three individuals was low. Using a LRE system to monitor a widespread mostly low-morbidity gastroenteric illness can be an effective public health strategy. PMID- 24495821 TI - Occupational exposures to antineoplastic drugs and ionizing radiation in Canadian veterinary settings: findings from a national surveillance project. AB - OBJECTIVES: Although veterinary workers may encounter various occupational health hazards, a national characterization of exposures is lacking in Canada. This study used secondary data sources to identify veterinary exposure prevalence for ionizing radiation and antineoplastic agents, as part of a national surveillance project. METHODS: For ionizing radiation, data from the Radiation Protection Bureau of Health Canada were used to identify veterinarians and veterinary technicians monitored in 2006. This was combined with Census statistics to estimate a prevalence range and dose levels. For antineoplastic agents, exposure prevalence was estimated using statistics on employment by practice type and antineoplastic agent usage rates, obtained from veterinary licensing bodies and peer-reviewed literature. RESULTS: In 2006, 7,013 (37% of all) Canadian veterinary workers were monitored for ionizing radiation exposure. An estimated 3.3% to 8.2% of all veterinarians and 2.4% to 7.2% of veterinary technicians were exposed to an annual ionizing radiation dose above 0.1 mSv, representing a total of between 536 and 1,450 workers. All monitored doses were below regulatory limits. For antineoplastic agents, exposure was predicted in up to 5,300 (23%) of all veterinary workers, with an estimated prevalence range of 22% to 24% of veterinarians and 20% to 21% of veterinary technicians. CONCLUSION: This is the first national-level assessment of exposure to ionizing radiation and antineoplastic agents in Canadian veterinary settings. These hazards may pose considerable health risks. Exposures appeared to be low, however our estimates should be validated with comprehensive exposure monitoring and examination of determinants across practice areas, occupations, and tasks. PMID- 24495822 TI - Comparing inequalities in oral and general health: findings of the Canadian Health Measures Survey. AB - OBJECTIVE: The aim of this study was to measure and compare the magnitude of income-related inequalities for oral and general health outcomes in Canada. METHODS: Data for this study were from the 2007/09 Canadian Health Measures Survey (CHMS). The sample size consisted of 3,413 Canadians aged 18-79 (1,601 men and 1,812 women). Oral health indicators were the total number of decayed and missing teeth. General health was measured as obesity and high blood pressure. Socio-economic status was measured as equivalized household income. We used the concentration index (CI) to quantify income-related inequalities in these outcomes. Values for the concentration index range from -1 to +1 with negative (or positive) concentration indices showing that the outcome is more concentrated among the less well off (or among the better off). All statistical analyses were weight-adjusted for the complex survey design and standardized for age. RESULTS: The concentration indices for oral health outcomes (decayed teeth = -0.25, missing teeth = -0.15) were greater than for general health outcomes (obesity = 0.05, high blood pressure = -0.04). The concentration indices for oral health outcomes, in contrast to general health outcomes, were statistically significant. CONCLUSION: There were income-related inequalities for oral health outcomes with the disease concentrated more among the poor. Inequalities in oral health were greater than inequalities in general health. The variation in the funding of oral health care and general health care is likely to explain the differences in the magnitude of income-related inequalities for oral and general health. PMID- 24495823 TI - Socio-economic inequalities in cause-specific mortality: a 16-year follow-up study. AB - OBJECTIVES: To examine socio-economic inequalities in cause-specific mortality by examining the independent effects of education, occupation and income in a population-based study of working-age Canadian adults. METHODS: This is a secondary analysis of data from the 1991-2006 Canadian Census mortality and cancer follow-up study (n=2.7 million persons). For this analysis, the cohort was restricted to 2.3 million persons aged 25 to 64 at cohort inception, of whom 164,332 died during the follow-up period. Hazard ratios were calculated by educational attainment (4 levels), occupational skill (6 categories) and income adequacy (5 quintiles) for all-cause mortality and major causes of death. Models were run separately for men and women, controlled for multiple variables simultaneously, and some were stratified by 10-year age cohorts. RESULTS: The magnitude of socio-economic inequalities in mortality differed by indicator of socio-economic position (education, occupation, or income), age group, sex, and cause of death. Compared to age-adjusted models, hazard ratios were attenuated but remained significant in models that adjusted for both age and all three indicators of socio-economic position simultaneously. Socio-economic inequalities in mortality were evident for most of the major causes of death examined. CONCLUSION: This study demonstrates that education, occupation and income were each independently associated with mortality and were not simply proxies for each other. When evaluating socio-economic inequalities in mortality, it is important to use different indicators of socio-economic position to provide a more complete picture. PMID- 24495824 TI - Why the Canadian sedentary behaviour guidelines should reflect sex and gender. AB - The world's first evidence-based sedentary behaviour guidelines were released in Canada in 2011. Based on evidence that time spent in sedentary pursuits poses important health risks, the guidelines recommend limits on the time that children and youth are sedentary throughout the day. Although the guidelines reflect differences in age, they do not include recommendations for adults, nor engage with other important determinants of health such as sex and gender, despite research suggesting that girls and boys, women and men, engage in different sedentary behaviours. For example, it has been suggested that girls spend considerable time in communication-based sedentary behaviours such as talking on the phone, texting and instant messaging, while boys are more likely to watch television and videos, or play computer games. There is also evidence suggesting that the health outcomes associated with sedentary behaviour differ for females and males, and there are gendered social and economic barriers that may influence sedentary behaviour. It is therefore time to consider sex and gender in research and policy on sedentary behaviour in order to effectively reduce time spent sedentary and to improve the health of women and men in Canada. PMID- 24495825 TI - Does living in a neighbourhood with others of the same ethnic background contribute to health of Canada's immigrant children? AB - OBJECTIVES: To understand how neighbourhood characteristics affect the health of immigrant children in Canadian cities. We question whether the health of children is influenced by immigrants living in enclaves of people with similar ethnic and socio-economic backgrounds. METHODS: Two datasets were used: the New Canadian Children and Youth Study (NCCYS) and Statistics Canada census data. The NCCYS comprises children from Hong Kong, the Philippines and Mainland China living in Canada's largest cities. Logistic regression was used to examine the influence of neighbourhood ethnic concentrations and mean income on health. RESULTS: Girls were more likely to be reported to have excellent health compared to boys, as were children living in neighbourhoods with lower mean parental education. Children from Hong Kong were less likely to have excellent health compared to the reference group. For the Mainland Chinese group only, there was an inverse relationship between reported health status and the concentration of people from the same ethnic background in the neighbourhood. CONCLUSION: The health of children from different ethnic backgrounds is influenced by different social and economic factors. In practice and in research, "immigrants" and even broadly defined cultural groupings, such as "Asian immigrants", should be considered as heterogeneous. PMID- 24495826 TI - Too far to walk or bike? AB - Only 25-35% of Canadian children and youth regularly engage in active transportation (AT; e.g., non-motorized travel modes such as walking and cycling) to/from school. Previous research shows that distance between home and school is the strongest barrier to AT. Based on social ecological theory, we describe several strategies to overcome this barrier. At the individual level, children and youth could engage in AT to/from destinations such as parks, shops, friends' and family members' residence, and sport fields which may be located closer than their school. Parents who drive their kids to/from school could drop them within a "walkable" distance so that they can walk for the remainder of the trip. Partnerships could be developed between schools and other nearby institutions that would allow cars and buses to use their parking lot temporarily so that children could do a portion of the school trip on foot. Developing a well connected network of sidewalks along low traffic streets can also facilitate AT. At the policy level, decisions regarding school location have a direct influence on distance. Finally, social marketing campaigns could raise awareness about strategies to incorporate AT into one's lifestyle, and encourage parents to reconsider what constitutes a "walkable" distance. PMID- 24495827 TI - Changes in dietary and physical activity risk factors for type 2 diabetes in Alberta youth between 2005 and 2008. AB - OBJECTIVE: Unhealthy dietary and physical inactivity patterns inspired many initiatives promoting healthy youth and healthy schools in Alberta between 2005 and 2008. The purpose of this study was to examine differences in the prevalence of lifestyle risk factors for type 2 diabetes (T2D) between two province-wide samples of Alberta adolescents (2005 and 2008). METHODS: The dietary and physical activity (PA) patterns of Alberta youth were assessed in two cross-sectional studies of grade 7-10 students, one in 2005 (n=4936) and one in 2008 (n=5091), using a validated web-survey. For each diabetes risk factor, participants were classified as either at risk or not at risk, depending on their survey results relative to cut-off values. Chi-square tests and logistic regression models were used to determine differences in risk factor prevalence between 2005 and 2008. RESULTS: Compared to 2005, mean BMI, energy intake, fat intake, glycemic index (GI) and glycemic load (GL) were lower in 2008 (p<0.05); and carbohydrate, protein, fibre and vegetable and fruit intakes were higher in 2008 (p<0.05). In 2008, a lower proportion of students were: overweight, obese, consuming high GI, high GL, high fat, low fibre, low veg/fruit intake (p<0.05). No differences existed in magnesium or PA levels between the two time points. CONCLUSIONS: Improvements were observed between 2005 and 2008 in terms of the proportion of adolescents having specific risk factors for T2D. The cause of these changes could not be determined. Continued monitoring of adolescent lifestyle habits and monitoring of exposure to health promotion programming is recommended. PMID- 24495828 TI - Energy drink consumption and associations with demographic characteristics, drug use and injury among adolescents. AB - OBJECTIVE: To examine energy drink consumption and its association with demographic characteristics, drug use, and injury among adolescents. METHODS: Data on 4,342 adolescents were derived from the 2011 Ontario Student Drug Use and Health Survey, a province-wide school-based survey of students in grades 7 through 12. The survey was based on a two-stage cluster design and analyses include appropriate adjustments for the complex sample design. RESULTS: Overall, 49.6% of adolescents had consumed energy drinks in the previous year. A total of 13.8% of seventh grade students had consumed energy drinks in the previous week compared to 19.1% of adolescents overall. Energy drink consumption in the previous year was highly associated with having used tobacco and cannabis in the previous year, the non-medicinal use of prescription drugs in the previous year, and binge drinking in the previous month. Consumption was also highly associated with sensation-seeking and self-reports of medical treatment for an injury (reported by 16% and 42% of adolescents, respectively). The odds of consuming energy drinks did not vary significantly for males and females, and sex was not a significant moderator of the associations examined. CONCLUSION: These findings support the need for greater awareness of the extent of energy drink consumption among individual adolescents and the potential that additional health and behavioural risks may be associated with consumption. PMID- 24495830 TI - On the potential public health consequences of "xenophobic" political strategies and policies. PMID- 24495829 TI - Psychosocial risk at work and hazardous alcohol consumption among Chile's working adults. AB - OBJECTIVE: Karasek's demand-control model and Siegrist's effort-reward imbalance model have accumulated solid evidence regarding the associations between exposure to psychosocial risk at work (PSRW) and mental health of workers. However, there is scarce such evidence with regard to its associations with alcohol consumption. This study proposed to estimate the associations between exposure to PSRW and hazardous alcohol consumption (HAC) in Chile's working adult population. METHOD: The study was cross-sectional and a nationally representative survey was applied to 3,010 workers (65% male and 35% female, ages 20 to 65). The analysis included prevalences and logistic regression controlling for covariables. RESULTS: The adjusted analyses show that male workers exposed to low social support (OR=1.47; 95% CI:1.14-1.89), low reward (OR=1.38; 95% CI:1.07-1.78) and effort-reward imbalance (OR=1.34; 95% CI:1.04-1.73) have a higher chance of presenting with HAC compared to those who are not exposed. Female workers exposed to effort-reward imbalance (OR=2.34; 95% CI:1.10-5.58) have twice the risk of HAC compared with their reference group. CONCLUSION: This study shows evidence of the associations between HAC and exposure to a set of psychosocial risk factors from the Karasek and Siegrist models. For future research, it is recommended that HAC and PSRW factors be examined in a longitudinal study in order to control for possible confounding effects on these associations. PMID- 24495831 TI - Rabies in a Calgary puppy adopted from the Arctic. PMID- 24495832 TI - It takes a village... PMID- 24495833 TI - Screening for breast cancer: what truly is the benefit? PMID- 24495834 TI - Study on Abeta34 biology and detection in transgenic mice brains. AB - The beta-amyloid precursor protein undergoes cleavages by beta- and gamma secretasses yielding amyloid-beta peptides (Abeta) that accumulate in Alzheimer's disease. Subsequently, Abeta peptides are targets of additional truncations or endoproteolytic cleavages explaining the diversity of Abeta-related fragments recovered in cell media or pathologic human fluids. Here, we focused on Abeta1-34 (Abeta34) that has been detected both in vitro and in vivo and that derives from the hydrolysis of Abeta by beta-secretase. We have obtained and fully characterized by immunologic and biochemical approaches, a polyclonal antibody that specifically recognizes the C-terminus of Abetax-34. We present immunohistochemical evidence for the presence of Abetax-34 in the brain of 3xTg mice and Alzheimer's disease-affected human brains. Finally, we demonstrate a neprilysin-mediated degradation process of Abeta34 and the ability of synthetic Abeta34 to protect HEK cells overexpressing either wild type or Swedish-mutated beta-amyloid precursor protein from apoptosis. PMID- 24495835 TI - Neuropsychological characteristics of people living in squalor. AB - BACKGROUND: Squalor is an epiphenomenon associated with a range of medical and psychiatric conditions. People living in squalor are not well described in the literature, and prior work has indicated that up to 50% do not have a psychiatric diagnosis. Squalor appears to be linked with neuropsychological deficits suggestive of the presence of impaired executive function. We present a case series of people living in squalor that examines their neuropsychological assessment and diagnosis. METHODS: Clinicians from local health networks were invited to submit neuropsychological reports of patients living in squalor. These selected reports were screened to ensure the presence of squalor and a comprehensive examination of a set of core neuropsychological domains. Assessments were included if basic attention, visuospatial reasoning, information processing speed, memory function, and executive function were assessed. RESULTS: Sixty-nine neuropsychological reports were included. Sixty-eight per cent of the group underwent neuropsychological assessments during an inpatient admission. For participants where it was available (52/69), the mean Mini-Mental State Examination score was 25.29 (SD = 3.96). Neuropsychological assessment showed a range of cognitive impairment with nearly all the participants (92.75%) found to have frontal executive dysfunction. One person had an unimpaired neuropsychological assessment. Results indicated that dorsolateral prefrontal rather than orbitofrontal functions were more likely to be impaired. Vascular etiology was the most common cause implicated by neuropsychologists. CONCLUSIONS: Frontal executive dysfunction was a prominent finding in the neuropsychological profiles of our sample of squalor patients, regardless of their underlying medical or psychiatric diagnoses. Our study highlights the importance of considering executive dysfunction when assessing patients who live in squalor. PMID- 24495836 TI - Structural and optical properties of Er3+/Yb3+ doped barium titanate phosphor prepared by co-precipitation method. AB - In the present work we have synthesized the Er(3+)/Yb(3+) codoped barium titanate phosphor via co-precipitation method and studied its upconversion emission properties. The prepared BaTiO3 powder was found in cubic phase as a major component and having good crystallinity revealed by the XRD analysis. Optical band gap of the cubic barium titanate was calculated using the diffuse reflectance absorption spectrum. Good green upconversion emission is observed from the samples when excited by 980 nm diode laser. The variation in upconversion emission intensity is studied with the increase in excitation power as well as temperature of the sample. It is found that the emission bands centred at 524 and 548 nm are thermally coupled and can act as a temperature sensor in the 300-480 K temperature range. PMID- 24495837 TI - Ultraviolet spectrophotometry (dual wavelength and chemometric) and high performance liquid chromatography for simultaneous estimation of meropenem and sulbactam sodium in pharmaceutical dosage form. AB - UV spectrophotometric and high performance liquid chromatography (HPLC) methods were developed for simultaneous determination of meropenem (MERM) and sulbactam sodium (SB) in injection. UV spectrophotometric methods were developed using 0.1N sodium hydroxide as solvent. The Beer's plot for dual wavelength method was linear in the range of 4-24 MUg mL(-1) and 2-12 MUg mL(-1) for MERM and SB, respectively. The percent recoveries were found to be 98.52+/-1.23% for MERM and 101.45+/-1.1% for SB. Chemometrics assisted UV spectrophotometry was performed using Partial Least Square (PLS) analysis model and Principal Component Regression (PCR) analysis model. The % recoveries of the MERM were found to be 100.61+/-0.06% and 101.31+/-0.12% using PLS and PCR, respectively. The % recoveries of the SB were found to be 98.29+/-0.09% and 97.61+/-0.13% using PLS and PCR, respectively. Chromatography was performed on Hypersil BDS C18 column using methanol:acetonitrile:water (10:20:70 v/v/v) as mobile phase. The retention times of MERM and SB were found to be 2.9 min and 2.25 min, respectively. Developed HPLC method was found to be linear in the range of 50-250 MUg mL(-1) and 25-125 MUg mL(-1) for MERM and SB, respectively. The % recoveries were found to be 98.85+/-0.25% and 98.63+/-0.34% for MERM and SB, respectively. The developed analytical methods did not show any interference of the excipients when applied to pharmaceutical dosage form. PMID- 24495838 TI - Spectroscopic and magnetic properties of solvatochromic complex of Cu2+ and novel 3H-indolium derivative. AB - A new solvatochromic complex of copper (II) and 3H-indolium (HQIndol) with the formula (HQIndol)3Cu has been synthesised and characterised by elemental analysis, UV-vis, IR spectroscopies, electron paramagnetic resonance (EPR), and static magnetic susceptibility and conductance measurements. The stoichiometry of complex has been determined as 1:3 (M:L) and the binding constant was calculated to be 5.86*10(16) mol(-1) L at 25 degrees C in CH3OH. Magnetization measurements indicate that (HQIndol)3Cu sample is paramagnetic with spin S=1/2 for which phase transition from paramagnetic to antiferromagnetic has been registered at TN=2.5 K. The symmetry of the EPR spectrum points to elongated tetragonal octahedral geometry of the complex. Examined heterochelate exhibits solvatochromic properties. Blue shift of the vis absorption band with increased solvent polarity is observed, Deltanu?max in examined solvents amounts to 1466 cm(-1). PMID- 24495841 TI - Intensive blood pressure lowering does not reduce cognitive decline in people with diabetes, study finds. PMID- 24495840 TI - Statistical learning of novel graphotactic constraints in children and adults. AB - The current study explored statistical learning processes in the acquisition of orthographic knowledge in school-aged children and skilled adults. Learning of novel graphotactic constraints on the position and context of letter distributions was induced by means of a two-phase learning task adapted from Onishi, Chambers, and Fisher (Cognition, 83 (2002) B13-B23). Following incidental exposure to pattern-embedding stimuli in Phase 1, participants' learning generalization was tested in Phase 2 with legality judgments about novel conforming/nonconforming word-like strings. Test phase performance was above chance, suggesting that both types of constraints were reliably learned even after relatively brief exposure. As hypothesized, signal detection theory d' analyses confirmed that learning permissible letter positions (d'=0.97) was easier than permissible neighboring letter contexts (d'=0.19). Adults were more accurate than children in all but a strict analysis of the contextual constraints condition. Consistent with the statistical learning perspective in literacy, our results suggest that statistical learning mechanisms contribute to children's and adults' acquisition of knowledge about graphotactic constraints similar to those existing in their orthography. PMID- 24495839 TI - Reliable direct measurement of causes of death in low- and middle-income countries. AB - BACKGROUND: Most of the 48 million annual deaths in low- and middle-income countries (LMICs) occur without medical attention at the time of death so that the causes of death (COD) are largely unknown. A review of low-cost methods of obtaining nationally representative COD data is timely. DISCUSSION: Despite clear historic evidence of their usefulness, most LMICs lack reliable nationally representative COD data. Indirect methods to estimate COD for most countries are inadequate, mainly because they currently rely on an average ratio of 1 nationally representative COD to every 850 estimated deaths in order to measure the cause of 25 million deaths across 110 LMICs. Direct measurement of COD is far more reliable and relevant for country priorities. Five feasible methods to expand COD data are: sample registration systems (which form the basis for the ongoing Million Death Study in India; MDS); strengthening the INDEPTH network of 42 demographic surveillance sites; adding retrospective COD surveys to the demographic household and health surveys in 90 countries; post-census retrospective mortality surveys; and for smaller countries, systematic assembly of health records. Lessons learned from the MDS, especially on low-cost, high quality methods of verbal autopsy, paired with emerging use of electronic data capture and other innovations, can make COD systems low-cost and relevant for a wide range of childhood and adult conditions. SUMMARY: Low-cost systems to obtain and report CODs are possible. If implemented widely, COD systems could identify disease control priorities, help detect emerging epidemics, enable evaluation of disease control programs, advance indirect methods, and improve the accountability for expenditures of disease control programs. PMID- 24495842 TI - Efficacy of dexamethasone on penicillin-induced epileptiform activity in rats: an electrophysiological study. AB - Corticosteroids are extensively used in treatment of many diseases. In neurosurgery practice, dexamethasone (DEX) is commonly used particularly in cerebral edema secondary to brain tumors, head trauma, and central nervous system infections. There are some uncertainties surrounding the secure use of DEX in patients with epilepsy or seizures induced by diseases of the central nervous system such as head trauma and brain tumors. Despite its extensive use, the effect of DEX on epileptiform activity is unclear. In this study the effect of DEX on epileptiform activity was investigated in rats. The effects of 1, 3, and 10mg/kg DEX on epileptiform activity was compared with effects of antiepileptic drugs commonly employed in treatment of epilepsy, namely phenytoin (PHT) 50mg/kg and levetiracetam (LEV) 50mg/kg that were administered intraperitoneally for 1 week. All groups were administered intracortical penicillin (500IU) to induce epileptiform activity. DEX at the doses of 3mg/kg and 10mg/kg significantly reduced spike frequencies compared to the initial values. In conclusion, we think that DEX can effectively decrease the epileptiform activity. PMID- 24495843 TI - The pattern of glutamate-induced nitric oxide dynamics in vivo and its correlation with nNOS expression in rat hippocampus, cerebral cortex and striatum. AB - Nitric oxide (NO) is a diffusible intercellular messenger, acting via volume signaling in the brain and, therefore, the knowledge of its temporal dynamics is determinant to the understanding of its neurobiological role. However, such an analysis in vivo is challenging and indirect or static approaches are mostly used to infer NO bioactivity. In the present work we measured the glutamate-dependent NO temporal dynamics in vivo in the hippocampus (CA1, CA3 and DG subregions), cerebral cortex and striatum, using NO selective microelectrodes. Concurrently, the immunolocalization of nNOS was evaluated in each region. A transitory increase in NO levels occurred at higher amplitudes in the striatum and hippocampus relatively to the cortex. In the hippocampus, subtle differences in the profiles of NO signals were observed along the trisynaptic loop, with CA1 exhibiting the largest signals. The topography of NO temporal dynamics did not fully overlap with the pattern of the density of nNOS expression, suggesting that, complementary to the distribution of nNOS, the local regulation of NO synthesis as well as the decay pathways critically determine the effective NO concentration sensed by a target within the diffusional spread of this free radical. In sum, the rate and pattern of NO changes here shown, by incorporating regulatory mechanisms and processes that affect NO synthesis and decay, provide refined information critical for the understanding of NO multiple actions in the brain. PMID- 24495845 TI - Blowhole colostomy for the urgent management of distal large bowel obstruction. AB - BACKGROUND: Complete obstruction of the distal colon or rectum often presents as a surgical emergency. This study evaluated the efficacy of blowhole colostomy versus transverse loop colostomy for the emergent management of distal large intestinal obstruction. METHODS: Retrospective chart review of all colostomy procedures (CPT 44320) performed for complete distal large bowel obstruction during the past 6 y in a university hospital practice was undertaken. Blowhole was compared with loop colostomy with a primary endpoint of successful colonic decompression. RESULTS: One hundred forty-one patients underwent colostomy creation during the study period. Of these, 61 were completed for acute obstruction of the distal colon or rectum (19 blowhole versus 42 loop colostomy). No differences between study groups were seen in age, gender, body mass index, malnutrition, American Society of Anesthesiology class, time to liquid or regular diet, 30-d or inhospital mortality, or rates of complications. Patients undergoing blowhole colostomy had significantly higher cecal diameters at diagnosis (9.14 versus 7.31 cm, P = 0.0035). Operative time was shorter in blowhole procedures (43 versus 51 min, P = 0.017). Postoperative length of stay was significantly shorter for blowhole colostomy (6 versus 8 d, P = 0.014). The primary endpoint of successful colonic decompression was met in all colostomy patients. CONCLUSIONS: Diverting blowhole colostomy is a safe, quick, and effective procedure for the urgent management of distal colonic obstruction associated with obstipation and massive distention. PMID- 24495844 TI - Pretreatment with hydrogen-rich saline reduces the damage caused by glycerol induced rhabdomyolysis and acute kidney injury in rats. AB - BACKGROUND: Rhabdomyolysis is a leading cause of acute kidney injury. The pathophysiological process involves oxidative stress and inflammation. Hydrogen rich saline (HRS) is an antioxidant and anti-inflammatory. This study explored the protective effect of pretreatment with HRS on the development of glycerol induced rhabdomyolysis acute kidney injury. MATERIALS AND METHODS: Forty-eight rats were randomly divided into four equal groups. Group 1 served as the control, group 2 was given 50% glycerol (10 mL/kg, intramuscular), group 3 was given glycerol after 7 d pretreatment with high dose HRS (10 mL/kg/d, intraperitoneal), and group 4 was given glycerol after 7 d pretreatment with low dose HRS (5 mL/kg/d, intraperitoneal). Renal health was monitored by serum creatinine (Cr), urea, and histologic analysis; rhabdomyolysis was monitored by creatine kinase (CK) levels; and oxidative stress was monitored by kidney tissue reactive oxygen species (ROS), malondialdehyde, 8-hydroxydeoxyguanosine (8-OH-dG), superoxide dismutase (SOD), and glutathione peroxidase (GSH-PX) levels. Inflammation was monitored by interleukin 6 (IL-6) and tumor necrosis factor alpha (TNF-alpha) evaluation. RESULTS: Glycerol administration resulted in an increase in the mean histologic damage score, serum Cr, urea and CK, kidney tissue ROS, malondialdehyde, 8-OH-dG, GSH-PX, IL-6, and TNF-alpha, and a decrease in kidney tissue superoxide dismutase activity. All these factors were significantly improved by both doses of HRS, but the mean histologic damage score, urea, Cr, CK, ROS, 8-OH-dG, GSH-PX, IL-6, and TNF-alpha for the high dose HRS treatment group were even lower. CONCLUSIONS: Pretreatment by HRS ameliorated renal dysfunction in glycerol-induced rhabdomyolysis by inhibiting oxidative stress and the inflammatory response. PMID- 24495846 TI - Lipoxygenase inhibitors derived from marine macroalgae. AB - The solvent extracts from the algae Sargassum thunbergii (Sargassaceae) and Odonthalia corymbifera (Rhodomelaceae) were subjected to soybean lipoxygenase inhibitory screening. Two hydrophobic inhibitors were obtained from the extracts of S. thunbergii through inhibitory assay-guided fractionation. The inhibitors were identified as known exo-methylenic alkapolyenes (6Z,9Z,12Z,15Z)-1,6,9,12,15 henicosapentaene (1) and (6Z,9Z,12Z,15Z,18Z)-1,6,9,12,15,18-henicosahexaene (2). The alkapolyenes 1 and 2 showed higher inhibitory activity than the known inhibitor nordihydroguaiaretic acid (NDGA). Pheophytin a (3) was obtained from the extract of O. corymbifera. The inhibitor 3 also showed higher inhibitory activity than NDGA. This is the first report on lipoxygenase inhibition of exo methylenic alkapolyenes and a chlorophyll a-related substance. PMID- 24495847 TI - Nonsynonymous variant Pro70Ser (rs117648444) in IFNL4 gene identifies carriers of the rs368234815 DeltaG allele with higher HCV RNA decline during the first 4 weeks of pegylated interferon and ribavirin therapy in HCV-1 patients. PMID- 24495848 TI - Fatal enteritis in a renal transplant patient with post-transplant thrombotic microangiopathy undergoing plasma exchange therapy. PMID- 24495849 TI - The influence of context on the processing of emotional and neutral adjectives- an ERP study. AB - The study investigated brain responses to emotional and neutral adjectives within contexts of varying emotional valence. Participants were randomly assigned to 3 context groups where they viewed random sequences of emotional and neutral adjectives intermixed with: emotional pictures (emotional context), neutral pictures (neutral context) and blank screens (zero context). Within the emotional context group the P3 potential was more pronounced in response to positive than either negative or neutral adjectives, and positive picture context impacted positive and negative adjectives differently. In the neutral context group the P2 and P3 potentials were greater in response to the positive adjectives as compared to the neutral ones. There was also a greater negativity of the N400 potential in response to the neutral adjectives. Within the zero context group only the N400 effect was visible. The seeming preference for positive words can be explained in terms of the specific positivity offset phenomenon. PMID- 24495850 TI - Report of an unusual combination of arterial, venous and neural variations in a cadaveric upper limb. AB - In this study an unusual combination of arterial, venous and neural variations discovered during dissection of cervical, axillary and brachial area of a cadaver is described. Variations are thoroughly described and literature is briefly reviewed. Lateral cord of brachial plexus was not formed; Eight Cervical root divided into anterior and posterior division before uniting with First Thoracic root and Upper Trunk was unusually short. Axillary artery gave origin to a superficial brachial artery and then continued as deep brachial artery. Multiple variations in typical axillary artery branches were present including existence of inferior pectoral artery. Cephalic vein was absent. A variety of interventions, from relative simple as central venous catheter placement to most complicated as brachial plexus injury repair demand thorough knowledge of area's regional anatomy. Familiarity with anatomic variations allows more precise and careful interventions. Research on these variations is valuable for anatomists and embryologists but also for clinicians because it may provide useful information for non - typical cases but also helps in raising a high level of suspicion. PMID- 24495854 TI - Only social feedback reduces age-related prospective memory deficits in "Virtual Week". AB - BACKGROUND: Prospective memory, or remembering to do things in the future, is crucial for independent living in old age. Although there is evidence of substantial age-related deficits in memory for intentions, older adults have demonstrated the ability to compensate for their deficits in everyday life. The present study investigated feedback as a strategy for facilitating prospective memory in the elderly. METHOD: Young and older adults played a computer-based task, Virtual Week, in which they had to remember to carry out life-like intentions. After each virtual day, specific feedback on prospective memory performance was automatically provided on the computer screen that participants either proceeded through by themselves (non-social feedback) or were taken through by an experimenter (social feedback). The control group received no feedback. RESULTS: We found that, compared with no-feedback group, only social feedback substantially reduced the age-related deficit in prospective memory. Older adults significantly benefited from feedback provided by the experimenter on the tasks of intermediate difficulty. Unexpectedly, prospective memory with non-social feedback was not only worse than with social feedback, but it was not any better than without any feedback at all. CONCLUSIONS: The results extended previous findings on the effectiveness of feedback in improving the memory performance of older adults to include memory for intentions. Despite the feedback meeting the critical recommendations of being specific, objective, and well-targeted, it was ineffective when the feedback displayed on the computer was not introduced by the experimenter. This has implications for computerized training tasks where automated feedback is considered crucial. PMID- 24495855 TI - Performance of four computer-coded verbal autopsy methods for cause of death assignment compared with physician coding on 24,000 deaths in low- and middle income countries. AB - BACKGROUND: Physician-coded verbal autopsy (PCVA) is the most widely used method to determine causes of death (CODs) in countries where medical certification of death is uncommon. Computer-coded verbal autopsy (CCVA) methods have been proposed as a faster and cheaper alternative to PCVA, though they have not been widely compared to PCVA or to each other. METHODS: We compared the performance of open-source random forest, open-source tariff method, InterVA-4, and the King-Lu method to PCVA on five datasets comprising over 24,000 verbal autopsies from low- and middle-income countries. Metrics to assess performance were positive predictive value and partial chance-corrected concordance at the individual level, and cause-specific mortality fraction accuracy and cause-specific mortality fraction error at the population level. RESULTS: The positive predictive value for the most probable COD predicted by the four CCVA methods averaged about 43% to 44% across the datasets. The average positive predictive value improved for the top three most probable CODs, with greater improvements for open-source random forest (69%) and open-source tariff method (68%) than for InterVA-4 (62%). The average partial chance-corrected concordance for the most probable COD predicted by the open-source random forest, open-source tariff method and InterVA-4 were 41%, 40% and 41%, respectively, with better results for the top three most probable CODs. Performance generally improved with larger datasets. At the population level, the King-Lu method had the highest average cause-specific mortality fraction accuracy across all five datasets (91%), followed by InterVA-4 (72% across three datasets), open-source random forest (71%) and open-source tariff method (54%). CONCLUSIONS: On an individual level, no single method was able to replicate the physician assignment of COD more than about half the time. At the population level, the King-Lu method was the best method to estimate cause-specific mortality fractions, though it does not assign individual CODs. Future testing should focus on combining different computer coded verbal autopsy tools, paired with PCVA strengths. This includes using open source tools applied to larger and varied datasets (especially those including a random sample of deaths drawn from the population), so as to establish the performance for age- and sex-specific CODs. PMID- 24495856 TI - An evaluation of taxonomic concepts of the widespread plant genus Aglaia and its allies across Wallace's Line (tribe Aglaieae, Meliaceae). AB - Similar to other species-rich taxa in the Indo-Australian Archipelago, taxonomy of the genus Aglaia (mahogany family, Meliaceae) remains problematic. This study aims to evaluate taxonomic concepts within Aglaia based on the largest dataset to date. We analyzed sequences of 237 accessions of Aglaia and representatives of all other genera of the tribe Aglaieae, including nuclear ribosomal ITS, the trnL trnF intron and intergenic spacer, the atpF intron and the petD region comprising the petB-petD spacer, the petD-5' exon and the petD intron (all but the first from the plastid genome). Our analyses were set both in maximum likelihood and Bayesian frameworks, which (1) supported paraphyly of Aglaia and Aphanamixis; (2) demonstrated polyphyly of previously described sections for Aglaia; and (3) suggested delimitation problems with 57% of the morphologically "variable species" and all "complex species". In general, there were more genetic entities than species described, which shows that the taxonomy of this group is more complex than has sometimes been previously assumed. For some species, morphological variation suggests the existence of more variants, subspecies or species within various taxa. Furthermore, our study detected additional phylogenetic entities that were geographically distinct, occurring on either side of Wallace's Line but not on both sides. The delineation of these inter-specific taxa needs further investigation by taking into account the morphological variation within and between populations across the entire distribution. PMID- 24495857 TI - The autoimmune disease-associated transcription factors EOMES and TBX21 are dysregulated in multiple sclerosis and define a molecular subtype of disease. AB - We have identified a marked over-representation of transcription factors controlling differentiation of T, B, myeloid and NK cells among the 110 MS genes now known to be associated with multiple sclerosis (MS). To test if the expression of these genes might define molecular subtypes of MS, we interrogated their expression in blood in three independent cohorts of untreated MS (from Sydney and Adelaide) or clinically isolated syndrome (CIS, from San Francisco) patients. Expression of the transcription factors (TF) controlling T and NK cell differentiation, EOMES, TBX21 and other TFs was significantly lower in MS/CIS compared to healthy controls in all three cohorts. Expression was tightly correlated between these TFs, with other T/NK cell TFs, and to another downregulated gene, CCL5. Expression was stable over time, but did not predict disease phenotype. Optimal response to therapy might be indicated by normalization of expression of these genes in blood. PMID- 24495858 TI - [Retroperitoneal hibernoma. A case report and review of the literature]. PMID- 24495859 TI - Influence of proteolytic-antiproteolytic enzymes and prooxidative-antioxidative factors on proteoglycan alterations in children with juvenile idiopathic arthritis. AB - OBJECTIVES: The influence of proteolytic-antiproteolytic enzymes and prooxidative anti-oxidative factors on proteoglycan alterations in children with juvenile idiopathic arthritis (JIA) was evaluated in this study. DESIGN, METHODS, RESULTS: Plasma and urinary glycosaminoglycans (GAGs), as well as plasma levels of matrix metalloproteinases (MMPs) (MMP-3, MMP-10), tissue inhibitors of metalloproteinases (TIMPs) (TIMP-1, TIMP-2), total oxidative status (TOS) and total antioxidative status (TAS), were quantified in samples obtained from 30 healthy subjects and 30 JIA patients before and after treatment. Significantly decreased plasma and urinary concentration of GAGs in JIA patients before treatment was observed. Therapy resulted in an increase in the concentration of the above listed parameters. However, the plasma GAG level still remained significantly lower compared to that in controls. Increased levels of MMP-3 and TIMP-1 in both JIA patient groups were recorded. The plasma MMP-10 and TIMP-2 concentrations in untreated patients were significantly decreased. Anti inflammatory treatment led to normalization of these parameter concentrations. Significant increase of TOS but decrease of TAS was found in the blood of untreated patients. The treatment resulted only in the normalization of TOS concentration. We have revealed a significant correlation between plasma GAGs and: MMP-3 (r=0.54), TOS (r=0.64) and urinary GAGs (r=0.55), respectively. CONCLUSIONS: Proteoglycan/glycosaminoglycan alterations in JIA patients, which are stimulated by MMP-3 and reactive oxygen species (ROS), indicate rather systemic disturbance of extracellular matrix metabolism, and not merely local changes which occur in articular structures. Given the destructive potential of ROS and MMPs and their hyperexpression in JIA, inhibition of these compounds should bring a substantial clinical benefit. PMID- 24495860 TI - Association of the MS4A2 gene promoter C-109T or the 7th exon E237G polymorphisms with asthma risk: a meta-analysis. AB - BACKGROUND AND OBJECTIVE: A large number of studies have examined the association between the Membrane-spanning 4 domains, superfamily A, number 2 (MS4A2) gene C 109T (rs1441586) or E237G (rs569108) variants and asthma risk. However, the results are inconsistent and inconclusive. To derive a more precise estimation, a meta-analysis was performed. METHODS: Meta-analyses were conducted with the data from case-control association studies (24 studies with 4496 asthmatics and 4571 controls for E237G variant and 9 studies including 2005 cases and 1868 control for C-109T polymorphisms, respectively). Random-effects model was used to calculate summary odds ratios (ORs). RESULTS: For the MS4A2 gene E237G variant, no significant associations with asthma were found in overall population; we observed an elevated risk of atopic asthma among subjects with the 237G allele (OR=1.341, 95% CI: 1.039-1.732 for G versus E and OR=1.374, 95% CI: 1.032-1.828 for EG+GG versus EE) in the stratified meta-analysis. As for the MS4A2 gene C 109T polymorphism, no significant associations with asthma risk were observed in the total population; in subgroup analysis by ethnicity of subjects we found increased asthma risk among Asians carrying T allele (OR=1.140, 95% CI: 1.019 1.276 for T versus C and OR=1.359, 95% CI: 1.029-1.794 for TT versus CC). CONCLUSIONS: Data indicated that the MS4A2 gene E237G variant may be a risk factor for developing atopic asthma and the promoter -109T allele is a potential risk factor of asthma in Asians. PMID- 24495861 TI - Red blood cell distribution width is not related with inflammatory parameters in morbidly obese patients. AB - OBJECTIVE: Red blood cell distribution width (RDW) is a hematological parameter that has been studied in several clinical settings and has been found to be related to both anemia and inflammatory status. As obesity is related to increased inflammatory pattern, we aimed to analyze the RDW in this setting. METHODS: We determined hematological and inflammatory parameters in morbidly obese patients before bariatric surgery (n=142) and normo-weight controls (n=144). RESULTS: RDW was higher in patients than in controls (p<0.001), along with C-reactive protein (p<0.001) and fibrinogen, (p<0.001) while hemoglobin (p=0.026), serum iron (p<0.001), MCH (p=0.002) and MCHC (p<0.001) were lower in morbidly obese patients. The logistic correlation analysis revealed that only low serum iron (<62 MUg/dL) and MCH (<28.14 pg) levels were associated with RDW>14% (OR 7.61, 95% CI: 1.93-30.04, p=0.004; OR 5.67, 95% CI: 1.98-16.24, p=0.001; respectively). CONCLUSIONS: These data indicate that the elevated RDW in morbidly obese patients reflects a mild red blood cell hypochromia that does not relate to inflammatory parameters, but to hyposideremia and, consequently, to lower erythrocyte indices, possibly as a result of being on a very low-calorie diet before bariatric surgery. Therefore, RDW should not be considered as an inflammatory marker in this clinical setting. PMID- 24495862 TI - The polymorphism rs2268574 in Glucokinase gene is associated with gestational Diabetes mellitus. PMID- 24495863 TI - Structure activity relationship studies of 3-arylsulfonyl-pyrido[1,2-a]pyrimidin 4-imines as potent 5-HT6 antagonists. AB - Comprehensive structure activity relationship (SAR) studies were conducted on a focused screening hit, 2-(methylthio)-3-(phenylsulfonyl)-4H-pyrido[1,2 a]pyrimidin-4-imine (1, IC50: 4.0 nM), as 5-HT6 selective antagonists. Activity was improved some 2-4 fold when small, electron-donating groups were added to the central core as observed in 19, 20 and 26. Molecular docking of key compounds in a homology model of the human 5-HT6 receptor was used to rationalize our structure-activity relationship (SAR) findings. In pharmacokinetic experiments, compound 1 displayed good brain uptake in rats following intra-peritoneal administration, but limited oral bioavailability. PMID- 24495864 TI - Jeavons syndrome in China. AB - OBJECTIVES: Jeavons syndrome (JS) is one of the underreported epileptic syndromes and is characterized by eyelid myoclonia (EM), eye closure-induced seizures or electroencephalography (EEG) paroxysms, and photosensitivity. In the Western populations, it has been reported to be characterized by focal posterior, occipital predominant epileptiform discharges (OPEDs) or frontal predominant epileptiform discharges (FPEDs) followed by generalized EDs in both interictal and ictal EEG recordings. However, it is not clear if there are different clinical manifestations between OPEDs and FPEDs. The clinical and electrographic presentations in the Chinese population are largely unknown. Here, we report the clinical and electroencephalographic features of 50 Chinese patients with JS and evaluate for the presence of different clinical features between patients with OPEDs and patients with FPEDs. METHODS: We identified 50 cases who met the Jeavons syndrome criteria from 4230 patients with epilepsy at Xijing Hospital, Xi'an, China from the period of January 2010 to November 2011. These patients underwent long-term 24-hour video-EEG recording. Brain imaging was performed using magnetic resonance imaging (MRI) or computerized tomography (CT). Webster IQ testing was performed to determine intellectual development. We reviewed and described the interictal abnormalities, ictal EEG pattern, and demographic, clinical, and neuroimaging findings of these 50 Chinese patients in Xi'an. We divided the 50 patients into two groups according to the predominance of EDs and analyzed their clinical features. RESULTS: Twenty-five of these 50 patients were male. Twenty-two out of 32 patients in the group with FPEDs were male, and 3/18 patients in the group with OPEDs were male. The median age of EMA-EM onset in FPEDs was 8years and that in OPEDs was 5.8years. Eyelid myoclonia occurred in all the 50 patients. Twenty-one out of 32 patients in the group with FPEDs had EM with absences, and 14/32 of them had EM with eyeball rolling up. Two out of 18 patients in the group with OPEDs had EM with absences, and only 1 of 18 had EM with eyeball rolling up. CONCLUSION: Eyelid myoclonia with or without absences or JS diagnosis is easily missed and underreported in China. As an IGE, either the frontal or the occipital lobe may initiate generalized spike-and-wave discharges (GSWDs) and generalized seizures (GSs). There may be two subtypes of JS with distinctive clinical and electroencephalogrphic features: a predominantly male group with frontal predominant epileptiform discharges, eyelid myoclonia, and eyes rolling up and a predominantly female group with occipital predominant epileptiform discharges with eyelid myoclonia alone. PMID- 24495865 TI - Headache and attention deficit and hyperactivity disorder in children: common condition with complex relation and disabling consequences. AB - The aim of this review was to analyze literature data on the complex association between headache and attention deficit and hyperactivity disorder (ADHD) in children, in order to explore its possible consequences on child neurological development. Headache and ADHD are two common conditions in the pediatric population. They both are disabling diseases that impact the child's quality of life and are associated with severe cognitive, emotional, and behavioral impairments. To assess and analyze literature data about the association of ADHD and headache in children and possible physiopathogenesis relationships, we searched for the following terms: headache, migraine, tension-type headache, ADHD, and children (MESH or text words). We found different studies that assess the clinical, epidemiological, and physiopathogenetic overlap between these two diseases, with contrasting results and unresolved questions. Structural and functional abnormalities in brain networks have been found to be central in both headache and ADHD pathophysiology. It will be crucial to gain a better understanding of how subcortical-cortical and corticocortical network development is altered during the onset of the disorders. PMID- 24495866 TI - Age-dependent defective TGF-beta1 signaling in patients undergoing coronary artery bypass grafting. AB - BACKGROUND: Transforming growth factor beta (TGF-beta1) is a pleiotropic cytokine, which is deregulated in atherosclerosis; however the role of age in this process is unknown. We aimed to assess whether TGF-beta1 signaling is affected by age. METHODS: Vascular smooth muscle cells (VSMC) were obtained from patients undergoing abdominal surgery. Levels of TGF-beta1 were measured by ELISA in sera from 169 patients undergoing coronary artery bypass grafting (CABG). The p27 expression was determined by Western blot from internal mammary arteries (IMA) obtained from CABG patients (n=13). In VSMC from these patients undergoing abdominal surgery, secretion of TGF-beta1 was determined by ELISA of cell conditioned media. RESULTS: In VSMC from aged patients we observed a lower TGF beta1 secretion, measured as TGF-beta1 concentration in cell conditioned medium (p<0.001). This effect was correlated to an age-dependent decrease of p27 expression in IMA from aged CABG patients. In a similar manner, there was an age dependent decrease of serum TGF-beta1 levels in CABG patients (p=0.0195). CONCLUSIONS: VSMC from aged patients showed a higher degree of cellular senescence and it was associated to a lower TGF-beta1 secretion and signaling. PMID- 24495869 TI - International Classification of Functioning, Disability and Health core set for physical health of older adults. AB - BACKGROUND: To facilitate a systematic, comprehensive description of functioning and to enable the use of the International Classification of Functioning, Disability and Health (ICF) in clinical practice and research, core sets have been developed. PURPOSE: The aim of this study was to propose a version of the ICF core set to classify the physical health of older adults. METHODS: The proposition of the ICF core set was based on the Delphi technique. The panel of experts included 8 Brazilian researchers (physical therapists, medical doctors, nurses, and physical educators). The communication was wholly electronic. In total, there were 5 rounds of interactivity between the participants to arrive at the final version of the construct. RESULTS: The ICF core set presented 30 categories (14 on body functions, 4 on body structures, 9 on activities or participation, and 3 on environmental factors) and had a Cronbach alpha of 0.964. CONCLUSIONS: The presented core set is a secure, fast, and accurate instrument for assessing the physical health and engagement of older adults. It defines points related to functioning and health that are relevant when evaluating this population, as well as when reevaluating it and monitoring changes. PMID- 24495868 TI - A novel Cdk9 inhibitor preferentially targets tumor cells and synergizes with fludarabine. AB - Cdk9 is a key elongation factor for RNA transcription and functions by phosphorylating the C-terminal domain of RNA polymerase II. Here we present direct evidence that cdk9 is important for cancer cell survival and describe the characterization of the potent cdk9 inhibitor CDKI-73 in primary human leukemia cells. CDKI-73 induced caspase-dependent apoptosis that was preceded by dephosphorylation of cdk9 and serine 2 of RNA polymerase II. CDKI-73 was more potent than the pan-cdk inhibitor flavopiridol and showed >200-fold selectivity against primary leukemia cells when compared with normal CD34+ cells. Furthermore, CDKI-73 was equipotent in poor prognostic sub-groups of leukemia patients and showed cytotoxic synergy with the nucleoside analog fludarabine. The Mechanism of synergy was associated with CDKI-73-mediated transcriptional inhibition of MCL1 and XIAP that was maintained when used in combination with fludarabine. Our data present a strong rationale for the development of cdk9 inhibitors such as CDKI-73 as anticancer therapeutics. PMID- 24495870 TI - Ergodicity, configurational entropy and free energy in pigment solutions and plant photosystems: influence of excited state lifetime. AB - We examine ergodicity and configurational entropy for a dilute pigment solution and for a suspension of plant photosystem particles in which both ground and excited state pigments are present. It is concluded that the pigment solution, due to the extreme brevity of the excited state lifetime, is non-ergodic and the configurational entropy approaches zero. Conversely, due to the rapid energy transfer among pigments, each photosystem is ergodic and the configurational entropy is positive. This decreases the free energy of the single photosystem pigment array by a small amount. On the other hand, the suspension of photosystems is non-ergodic and the configurational entropy approaches zero. The overall configurational entropy which, in principle, includes contributions from both the single excited photosystems and the suspension which contains excited photosystems, also approaches zero. Thus the configurational entropy upon photon absorption by either a pigment solution or a suspension of photosystem particles is approximately zero. PMID- 24495867 TI - Characterization of the biological anti-staphylococcal functionality of hUK-66 IgG1, a humanized monoclonal antibody as substantial component for an immunotherapeutic approach. AB - Multi-antigen immunotherapy approaches against Staphylococcus aureus are expected to have the best chance of clinical success when used in combinatorial therapy, potentially incorporating opsonic killing of bacteria and toxin neutralization. We recently reported the development of a murine monoclonal antibody specific for the immunodominant staphylococcal antigen A (IsaA), which showed highly efficient staphylococcal killing in experimental infection models of S. aureus. If IsaA specific antibodies are to be used as a component of combination therapy in humans, the binding specificity and biological activity of the humanized variant must be preserved. Here, we describe the functional characterization of a humanized monoclonal IgG1 variant designated, hUK-66. The humanized antibody showed comparable binding kinetics to those of its murine parent, and recognized the target antigen IsaA on the surface of clinically relevant S. aureus lineages. Furthermore, hUK-66 enhances the killing of S. aureus in whole blood (a physiological environment) samples from healthy subjects and patients prone to staphylococcal infections such as diabetes and dialysis patients, and patients with generalized artery occlusive disease indicating no interference with already present natural antibodies. Taken together, these data indicate that hUK-66 mediates bacterial killing even in high risk patients and thus, could play a role for immunotherapy strategies to combat severe S. aureus infections. PMID- 24495871 TI - Single cell analysis exposes intratumor heterogeneity and suggests that FLT3-ITD is a late event in leukemogenesis. AB - FMS-like tyrosine kinase 3 receptor-internal tandem duplication (FLT3-ITD) commonly occurs in acute myeloid leukemia and is considered rare in acute lymphocytic leukemia. Acute leukemia has poor prognosis, mainly due to relapse. Standard FLT3-ITD diagnostic techniques are based on genomic polymerase chain reaction and have recently incorporated GeneScan (Applied Biosystems, Foster City, CA) to identify variations of the FLT3 gene. As this is an average-based assay utilized in a heterogeneous leukemic cell population, we hypothesized that cells of acute leukemia, considered FLT3-ITD-negative by standard methods, could possess a fraction of FLT3-ITD-positive cells. The present study employed single cell mutation analysis to evaluate the FLT3-ITD status in newly diagnosed acute myeloid leukemia (n = 5) and acute lymphocytic leukemia (n = 3) patients. A total of 541 single leukemic cells and 36 mononuclear cells from healthy volunteers were analyzed. Seven patients, considered FLT3-ITD-negative according to bulk DNA analysis, appeared to possess a small fraction of FLT3-ITD-positive cells based on single cell analysis. Moreover, this approach revealed the heterogeneity of the tumor as evident by different FLT3-ITD mutations present in the same patient. The presence of a minor clone carrying FLT3-ITD in almost all patients tested provides evidence that this lesion is a common late event in leukemogenesis. Additionally, 3 relapsed patients demonstrated loss of heterozygosity of the normal allele, affecting 25%-100% of the cells found to be FLT3-ITD-positive. Though further clinical testing is warranted, these findings may have implications on the prognostic significance of FLT3-ITD and the use of targeted therapy. PMID- 24495872 TI - Circulating levels of adipokines in Parkinson's disease. AB - INTRODUCTION: Adipokines are adipocyte-derived secretory factors, which have functions in satiety, energetic homeostasis, insulin sensitivity, vascular disease and also immune response. Parkinson's disease (PD) has been associated with unintended weight loss and reduced prevalence of cardiovascular risk factors. In addition, inflammation has been proposed as one of the factors contributing to PD pathophysiology. Therefore, we sought to investigate if adipokine levels - adiponectin, leptin and resistin - are altered in PD patients. Also, we aimed to evaluate association between adipokine levels and clinical variables in PD. METHODS: Forty PD patients and twenty-five age-, gender- and body mass index-matched controls were enrolled in this study. Peripheral blood was drawn and plasma levels of adiponectin, leptin and resistin were measured by Enzyme-Linked Immunosorbent Assay. RESULTS: There was no significant difference between PD patients and controls regarding plasma levels of the evaluated adipokines. In PD patients, higher leptin levels were associated with increased age and body mass index. No other correlation was found between adipokine levels and clinical or demographic data. CONCLUSIONS: Although adipokines play important roles in inflammation, it seems that they are not implicated in the inflammatory response associated with PD. PMID- 24495873 TI - Randomised controlled trials and population-based observational research: partners in the evolution of medical evidence. PMID- 24495874 TI - Using multiple cytokines to predict hepatocellular carcinoma recurrence in two patient cohorts. AB - BACKGROUND: Cytokines are tightly linked to the carcinogenesis, development and prognosis of hepatocellular carcinoma (HCC). We determined the prognostic value of 39 circulating cytokines in HCC patients after radical resection and then developed a novel cytokine-based prognostic classifier (CBPC) for the prediction of patient prognosis. METHODS: A total of 179 patients were divided into two cohorts based on the date of radical resection. Thirty-nine cytokines were simultaneously analysed in patient serum samples using multiplex bead-based Luminex technology. Support vector machine-based methods and Cox proportional hazard models were used to develop a CBPC from the training cohort, which was then validated in the validation cohort. RESULTS: Among seven cytokines significantly correlating with the disease-free survival (DFS) in the training cohort, six of them were validated to be significant prognostic factors to predict DFS and overall survival (OS) in the validation cohort, namely fibroblast growth factor 2 (FGF-2), growth-regulated oncogene (GRO), interleukin 8 (IL-8), interferon gamma-induced protein 10 (IP-10), vascular endothelial growth factor (VEGF), and interferon alpha-2 (IFN-alpha2). By integrating six cytokines and three clinical characteristics, we developed a CBPC to predict the recurrence and 3-year OS of HCC patients (sensitivity, 0.648; specificity, 0.918). In the validation cohort, the CBPC were confirmed to have significant predictive power for predicting tumour recurrence and OS (sensitivity, 0.585; specificity, 0.857). Interestingly, IFN-alpha2 was the only cytokine being independent prognostic factor in both patient cohorts. CONCLUSION: Our study verifies the presence of specific cytokine-phenotype associations with patient prognosis in HCC. The CBPC developed include multiple circulating cytokines and may serve as a novel screening approach for identifying HCC patients with a high risk of post resection recurrence and shorter OS. These individuals may also be suitable for cytokine-targeted therapies. PMID- 24495875 TI - The role of SIRT6 in the differentiation of vascular smooth muscle cells in response to cyclic strain. AB - Vascular smooth muscle cells (VSMCs) may switch their phenotype between a quiescent contractile phenotype and a synthetic phenotype in response to cyclic strain, and this switch may contribute to hypertension, atherosclerosis, and restenosis. SIRT 6 is a member of the sirtuin family, and plays an important role in different cell processes, including differentiation. We hypothesized that cyclic strain modulates the differentiation of VSMCs via a transforming growth factor-beta1 (TGF-beta1)-Smad-SIRT6 pathway. VSMCs were subjected to cyclic strain using a Flexercell strain unit. It was demonstrated that the strain stimulated the secretion of TGF-beta1 into the supernatant of VSMCs. After exposed to the strain, the expressions of contractile phenotype markers, including smooth muscle protein 22 alpha, alpha-actin, and calponin, and phosphorylated Smad2, phosphorylated Smad5, SIRT6 and c-fos were up-regulated in VSMCs by western blot and immunofluorescence. And the expression of intercellular adhesion molecule-1 (ICAM-1) was also increased detected by flow cytometry. The strained-induced up-regulation of SIRT6 was blocked by a TGF-beta1 neutralizing antibody. Furthermore, the effects of strain on VSMCs were abrogated by SIRT6 specific siRNA transfection via the suppression c-fos and ICAM-1. These results suggest that SIRT6 may play a critical role in the regulation of VSMC differentiation in response to the cyclic strain. PMID- 24495876 TI - Current concepts of immune dysregulation in cystic fibrosis. AB - Cystic fibrosis (CF) lung disease is caused by mutations in the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) gene and is characterized by a perpetuated feedback loop of bacterial infection and inflammation. Both intrinsic (CFTR-dependent) and extrinsic (CFTR-independent) mechanisms contribute to the inflammatory phenotype of CF lung disease. Innate immune cells, initially recruited to combat bacterial pathogens, are acting in a dysregulated and non resolving fashion in CF airways and cause harm to the host by releasing proteases and oxidants. Targeting harmful immune pathways, while preserving protective ones, remains the challenge for the future. This review highlights current concepts of innate immune dysregulation in CF lung disease. PMID- 24495877 TI - Coenzyme Q10 as a therapy for mitochondrial disease. AB - Treatment of mitochondrial respiratory chain (MRC) disorders is extremely difficult, however, coenzyme Q10 (CoQ10) and its synthetic analogues are the only agents which have shown some therapeutic benefit to patients. CoQ10 serves as an electron carrier in the MRC as well as functioning as a potent lipid soluble antioxidant. CoQ10 supplementation is fundamental to the treatment of patients with primary defects in the CoQ10 biosynthetic pathway. The efficacy of CoQ10 and its analogues in the treatment of patients with MRC disorders not associated with a CoQ10 deficiency indicates their ability to restore electron flow in the MRC and/or increase mitochondrial antioxidant capacity may also be important contributory factors to their therapeutic potential. PMID- 24495878 TI - The many isoforms of human adenylate kinases. AB - Adenine nucleotides are involved in a variety of cellular metabolic processes, including nucleic acid synthesis and repair, formation of coenzymes, energy transfer, cell and ciliary motility, hormone secretion, gene expression regulation and ion-channel control. Adenylate kinases are abundant phosphotransferases that catalyze the interconversion of adenine nucleotides and thus regulate the adenine nucleotide ratios in different intracellular compartments. Nine different adenylate kinase isoenzymes have been identified and characterized so far in human tissues, named AK1 to AK9 according to their order of discovery. Adenylate kinases differ in molecular weight, tissue distribution, subcellular localization, substrate and phosphate donor specificity and kinetic properties. The preferred substrate and phosphate donor of all adenylate kinases are AMP and ATP respectively, but some members of the family can phosphorylate other substrates and use other phosphate donors. In addition to their nucleoside monophosphate kinase activity, adenylate kinases were found to possess nucleoside diphosphate kinase activity as they are able to phosphorylate both ribonucleoside and deoxyribonucleoside diphosphates to their corresponding triphosphates. Nucleoside analogues are structural analogues of natural nucleosides, used in the treatment of cancer and viral infections. They are inactive prodrugs that are dependent on intracellular phosphorylation to their pharmacologically active triphosphate form. Novel data presented in this review confirm the role of adenylate kinases in the activation of deoxyadenosine and deoxycytidine nucleoside analogues. PMID- 24495879 TI - Increased risk for early periprosthetic fractures after uncemented total hip replacement. AB - INTRODUCTION: The purpose of this study was to describe a new type of proximal periprosthetic fracture occurring within the first six weeks after total hip arthroplasty and to analyse possible causes of a rising incidence. MATERIAL AND METHODS: Patient files and radiographs from 2,408 uncemented hip replacements were analysed and patients with a periprosthetic split fracture reaching from the calcar to the medial femoral shaft below the lesser trochanter were included. RESULTS: A total of 28 fractures in 2,408 uncemented primary hip replacements were included. Almost all fractures were seen in women. No correlation with diagnosis, age, body mass index, operation time, operative technique or implant position could be demonstrated, but a possible correlation with post-operative mobilisation and pain treatment was observed. Trainees had more fractures than experienced surgeons (non-significant). CONCLUSION: We conclude that the increasing use of uncemented hip replacements implies an increasing risk of perioperative femoral fracture. The cause of the fractures remains unclear, but is probably multifactorial. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24495880 TI - Substantial interobserver variation of thyroid volume and function by visual evaluation of thyroid (99m)Tc scintigraphy. AB - INTRODUCTION: (99m)Tc-pertechnetate scintigraphy is much used in the evaluation of patients with nodular goitre. We investigated the ability of experienced observers to estimate the thyroid 24-h (131)I uptake (RAIU) and the thyroid volume by visual evaluation of the scintigram. MATERIAL AND METHODS: Two endocrinologists and two nuclear medicine specialists visually evaluated thyroid scintigrams from 171 patients with nodular goitre. The variables were assessed in a blinded fashion according to predefined categories and then compared with the true values. The assessments were repeated after four weeks. Kappa (kappa omega) statistics were used. RESULTS: There was a low probability (range 6-22%) for the observers to assess the thyroid RAIU correctly. The probability of assessing the thyroid volume correctly was in the 14-22% range. Endocrinologists tended to underestimate the thyroid RAIU, mostly in patients with a RAIU > 30%. All observers significantly underestimated the thyroid volume if this was > 80 ml. There was a low interobserver agreement for the thyroid RAIU assessment (kappa omega-values: 0.03-0.43) as well as for the thyroid volume assessment (kappa omega-values: 0.19-0.48). The corresponding kappa omega-values for the intraobserver agreement were 0.34-0.68 and 0.37-0.62, respectively. Nuclear medicine specialists achieved a significantly higher agreement than endocrinologists in their evaluation of both thyroid parameters. CONCLUSION: Thyroid (99m)Tc scintigraphy has poor interobserver agreement and is inaccurate for assessment of quantitative thyroid parameters, even when performed by experienced specialists. FUNDING: This study was supported by grants from the Danish Agency for Science, Technology and Innovation. TRIAL REGISTRATION: not relevant. PMID- 24495881 TI - Low awareness of the Charles Bonnet syndrome in patients attending a retinal clinic. AB - INTRODUCTION: Visually impaired patients may experience visual hallucinations due to the Charles Bonnet syndrome (CBS). While benign in nature, these hallucinations may cause distress in those unfamiliar with the phenomenon. The overall purpose of this study was to determine the degree of awareness of CBS in patients referred to our retina clinic. MATERIAL AND METHODS: Consenting patients attending our retina clinic over a period of three months underwent a thorough ophthalmological examination, including slit-lamp fundus biomicroscopy, spectral domain optical coherence tomography, fundus autofluorescence imaging and fluorescein/indocyanine green angiography (if applicable). Visual acuity was measured and the participants were subjected to a structured telephone interview. RESULTS: A total of 200 patients were included in this cross-sectional study. Twelve per cent of the participants were familiar with CBS. Patients who were clients at a low-vision rehabilitation clinic or were highly educated were more likely to be familiar with CBS. There was an association between low visual acuity and awareness of CBS. Logistic regression analysis revealed that only low visual acuity and university education were independently associated with familiarity with CBS. Fifteen per cent of the participants admitted to having visual hallucinations. CONCLUSION: Visually impaired patients are largely unfamiliar with CBS. Since unawareness of CBS may cause unnecessary distress in some patients, efforts to educate low-vision patients about CBS should be made. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24495882 TI - Psychiatric diagnosis and criminal record determine the courts' decisions. AB - INTRODUCTION: Section 69 of the Danish Penal Code implies the possibility of sentencing also non-psychotic offenders to treatment when this is considered expedient. The aim of this study was to analyse which factors influence the courts' decisions to sentence offenders to psychiatric treatment instead of punishment. MATERIAL AND METHODS: The psychiatric statements of the Danish Medico Legal Council from 1 April 2005 to 31 December 2007 were screened retrospectively to sample all cases processing non-psychotic offenders under Section 69. Analyses were performed using logistic regression with a verdict of a measure of psychiatric treatment as the response variable as opposed to punishment; the following reference variables were used as the main explanatory variables: demographic data, diagnosis, prior and present charges, and psychiatric history. The selection of the material thus ensures diagnostic validity. RESULTS: A psychiatric diagnosis is clearly the most decisive factor associated with a psychiatric treatment measure, but also psychiatric history and prior offences have a significant impact. The present charge only has limited influence. CONCLUSION: Section 69 of the Danish Penal Code is still used as intended, i.e, treatment measures are given according to psychiatric needs and take into consideration the offender's criminal behaviour. FUNDING: This study received funding from the Ministry of Health and the Health Foundation (Helsefonden). TRIAL REGISTRATION: The Danish Data Protection Agency has approved the study. Approval from the Danish Data Protection Agency was obtained (file no. 2012-41 1272). PMID- 24495883 TI - Intracoronary and systemic melatonin to patients with acute myocardial infarction: protocol for the IMPACT trial. AB - INTRODUCTION: Ischaemia-reperfusion injury following acute myocardial infarctions (AMI) is an unavoidable consequence of the primary percutaneous coronary intervention (pPCI) procedure. A pivotal mechanism in ischaemia-reperfusion injury is the production of reactive oxygen species following reperfusion. The endogenous hormone, melatonin, works as an antioxidant and could potentially minimise the ischaemia-reperfusion injury. Given intracoronarily, it enables melatonin to work directly at the site of reperfusion. We wish to test if melatonin, as an antioxidant, can minimise the reperfusion injury following pPCI in patients with AMI. MATERIAL AND METHODS: The IMPACT trial is a multicentre, randomised, double-blinded, placebo-controlled study. We wish to include 2 * 20 patients with ST-elevation myocardial infarctions undergoing pPCI within six hours from symptom onset. The primary end-point is the Myocardial Salvage Index assessed by cardiovascular magnetic resonance imaging on day 4 (+/- 1) after pPCI. The secondary end-points are high-sensitivity troponin, creatinekinase myocardial band and clinical events. CONCLUSION: The aim of the IMPACT trial is to evaluate the effect of melatonin on reperfusion injuries following pPCI. Owing to its relatively non-toxic profile, melatonin is an easily implementable drug in the clinical setting, and melatonin has the potential to reduce morbidity in patients with AMI. FUNDING: This study received no financial support from the industry. TRIAL REGISTRATION: www.clinicaltrials.gov, clinical trials identifier: NCT01172171. PMID- 24495884 TI - Effectiveness of propanolol for treatment of infantile haemangioma. AB - INTRODUCTION: Infantile haemangiomas (IH) are the most common benign tumours in children. They are characterised by rapid growth during the first year of life followed by spontaneous regression during childhood. Indications for treatment are functional impairment, bleeding/ulceration, rapid growth and severe aesthetic risk. Recently, systemic treatment with propranolol has become the first-line therapy. The objective of this study was to assess the efficacy of propranolol in the treatment of IH and to investigate whether treatment with a low dose of 1 mg/kg/day was sufficient. MATERIAL AND METHODS: This study was retrospective and based on a review of children treated for IH with propranolol from the 2010-2012 period at Rigshospitalet. RESULTS: Overall, propranolol was effective in all but one child (97%). The majority of the children (84%) were treated with an initial dose of 1 mg/kg/day, which was considered sufficient in most cases (71%). Children who started treatment before five months of age had a significantly better response than children who started treatment at a later age. No relation was found between location of IH and the effect of treatment. There were only few and mild side effects. CONCLUSION: Propranolol is effective in the treatment of IH and it has only few and mild side effects. In most cases, a low dose of 1 mg/kg/day was sufficient. Early initiation of treatment is recommended as the response to treatment was better in younger children and because early initiation helps prevent large residual changes. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24495885 TI - Identification of patients with incident cancers using administrative registry data. AB - INTRODUCTION: On-time identification of incident cancer patients is important in cancer research to ensure quality in cancer treatment and care. Nevertheless, the Danish Cancer Registry (DCR) is updated on an annual basis rather than continuously, and no standardised algorithm exists to enable sampling from administrative data which are updated on a monthly basis. The aim of this study was to develop and validate an algorithm for on-time sampling of incident cancer patients based on administrative data. MATERIAL AND METHODS: The study was based on registry and questionnaire data from incident cancer patients' general practitioners (GPs). An algorithm for on-time sampling of incident cancer patients was developed and validated in 2008 (12,747 patients) and further developed and validated in 2010 (7,996 patients). Questionnaire data from the GPs and data from the DCR were used as gold standards. The completeness over time of the 2010 cohort was evaluated. RESULTS: Further development of the 2008 algorithm into the 2010 algorithm increased its positive predictive value (PPV) to 95.0%. The PPV of a patient from the 2010 cohort being registered in the DCR was 97.4%. The 2010 algorithm displayed a completeness of 60% in the first month and 95% after four months. CONCLUSION: A valid and cost-saving algorithm for on-time sampling of incident cancer patients has been developed with great potential for research and quality assurance. FUNDING: This work was funded by the Danish Cancer Society and the Novo Nordisk Foundation. TRIAL REGISTRATION: not relevant. PMID- 24495886 TI - Treatment and follow-up in the psychiatric emergency room can be improved. AB - INTRODUCTION: The first and perhaps only contact many patients have with the psychiatric hospital system is at the psychiatric emergency room (PER). A growing load on the wards has raised the threshold for admission. Thus, it is important to make plans for patients who are seen in the PER, but are not hospitalised. The objective of this study was to investigate what treatment, plans and follow-up patients receive in the PER when they are not admitted. MATERIAL AND METHODS: This is a review of 100 consecutive PER patient reports from 2012 on patients who were seen by a doctor and not admitted at the Psychiatric Centre Frederiksberg, Denmark. The following issues were investigated: diagnosis, which medical and/or psychotherapeutic treatment was given or recommended, social interventions, objective findings, plans for treatment and referrals, and whether relevant referral was neglected. RESULTS: A total of 29 patients started psychopharmacological treatment, but only four received a plan for further treatment. Eleven received psychotherapy. Nine received social intervention. A total of 97 were discharged with follow-up. In 14 cases, relevant referral may have been neglected. Eleven reports lacked a description of psychiatrically objective findings, 20 lacked evaluation of suicidality. CONCLUSION: Doctors in the PER are vigilant to ensure plans for follow-up. However, these plans may sometimes be deficient. Doctors in the PER often use medical approaches to relieve patients' symptoms, but there is a need for a plan for how these treatments should be followed up. Furthermore, there seems to be a need for a stronger focus on psychotherapy and social intervention. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24495887 TI - Sexually assaulted victims are getting younger. AB - INTRODUCTION: From the clinical forensic examination reports produced by the Department of Forensic Medicine, Department of Forensic Medicine, Faculty of Health Sciences, University of Copenhagen, Denmark, in 2007 concerning rape, attempted rape and sexual assault (RAS), circumstances were extracted and analysed focussing on age, relationship, lesions, violence, location and alcohol intoxication. MATERIAL AND METHODS: A total of 184 girls and women over the age of 12 years were included in this retrospective study. RESULTS: The median age of the victims was 20 years (range 12-89 years). 75.5% were under 30 years of age. 53% knew the perpetrator. More than one perpetrator was reported in 11%. 46% of the assaulted victims had a total number of 1-5 observed lesions and these were observed in all types of perpetrator relationship. Eight victims with more than 20 lesions were assaulted by a stranger or an acquaintance (first contact) (ACQ). 50% of the victims who had lesions were assaulted by a stranger or an ACQ. 55% of assaults occurred in private homes. A total of 107 had their blood alcohol concentration (BAC) measured. In all, 133 victims were assessed by the examining doctor to be unaffected by alcohol, eight of these had a BAC exceeding 1.0 per thousand. There was no correlation between the BAC and number of lesions. Two victims had a positive pregnancy test and were pregnant before the RAS. CONCLUSION: In Denmark, RAS victims' age continues to decrease. RAS by a stranger or an ACQ involves a higher risk of lesions and the possibility of many lesions. More than half of those exposed to manual strangulation or other kinds of violence against the neck were assaulted by a stranger or an ACQ. Half of the women knew the perpetrator and the perpetrator was an ACQ in 26% of the cases. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24495888 TI - Guidelines for screening with urinary dipsticks differ substantially--a systematic review. AB - INTRODUCTION: Urinary dipsticks are frequently used for screening as part of health checks and at hospital admission, but the benefits and harms of this are unknown. MATERIAL AND METHODS: Health authorities and a selection of specialist societies in nine countries were identified through internet searches. Recommendations on dipstick screening at health checks or hospital admission were sought on websites as well as by e-mail contact. Other relevant organisations encountered were also included. Recommendations were summarised narratively. RESULTS: A total of 67 organisations were included. No positive or negative recommendations were found regarding screening with combined dipsticks. Screening for bacteriuria in non-pregnant persons was discouraged, while guidance on screening with dipsticks for haemoglobin, glucose and protein was uncommon and often unclear. CONCLUSION: Useful guidance was rare. Practitioners are largely left to themselves when deciding whether or not to offer screening with urinary dipsticks. This situation needs to be remedied as benefit has not been shown and because screening with dipsticks can cause harm. PMID- 24495889 TI - Increased number of applications for late termination of pregnancy in Denmark. AB - INTRODUCTION: Last year, it was 40 years since the introduction of legal abortion until the 12th week of gestation and the possibility of late termination of pregnancy in Denmark. The aim of this study was to describe the development in applications for late termination of pregnancy in the 1986-2011-period focusing on indications related to the women's conditions. MATERIAL AND METHODS: All applications for late termination of pregnancy in 1986 were reviewed by Nordentoft et al, and access to all applications from 2011 was granted by the abortion committees and the Appeals Board. All applications were reviewed in order to explore the development since 1986. RESULTS: The total number of applications for late termination of pregnancy has increased by 45% from 1986 to 2011 with 594 and 862 applications, respectively. Despite this increase, the number of permissions granted with reference to the women's conditions has decreased. In 1986 and 2011, 488 and 382 women, respectively, applied for late termination of pregnancy with reference to the women's conditions. Of the 519 women who were granted permission in 1986, 31% were <= 20 years of age. In 2011 this age group represented only 12%. CONCLUSION: Significant changes in the women's age and the reasons they provide when applying for late termination of pregnancy have been observed from 1986 to 2011. Further investigation of this subject will contribute to securing the best possible conditions for women going through late termination of pregnancy. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24495890 TI - Screening instruments for anxiety and depression in patients with irritable bowel syndrome are ambiguous. AB - INTRODUCTION: Psychiatric disorders are common among patients with irritable bowel syndrome (IBS) which may make a psychiatric evaluation appropriate. The Hospital Anxiety and Depression Scale (HADS) has been recommended internationally for screening. The Common Mental Disorder Questionnaire (CMDQ) is a novel Danish instrument recommended for use in general practice, but it lacks validation. The objective of this study was to test the reliability and the convergent validity of the anxiety and depression subscales of the CMDQ and the HADS in patients with IBS. MATERIAL AND METHODS: A total of 149 patients with IBS completed the CMDQ and the HADS twice in a year. Data were analysed with respect to internal consistency (Cronbach's alpha), agreement on case identification (kappa) and correlation between scores (Spearman's rank correlation coefficient). RESULTS: All subscales showed satisfactory internal consistency. Cases identified by the CMDQ's anxiety and depressions subscales differed considerably from those identified with the HADS with only fair-moderate agreement, while the correlation between the scores on the CMDQ and the HADS was only moderate for both anxiety and depressions. CONCLUSION: The subscales for anxiety disorder and depression on the CMDQ showed internal consistency, but only fair to moderate agreement and correlation, which yielded an unsatisfying convergent validity compared to the HADS. More studies in different populations and research on the cut-off values for possible cases could make the CMDQ more useful. FUNDING: Danish Council for Independent Research; Region Zealand's Health Sciences Research Foundation; Councils for Quality Assurance in Primary Care in Region Zealand. TRIAL REGISTRATION: NCT00659763. PMID- 24495891 TI - Hospitals need to customise care according to patients' differing information seeking behaviour. AB - INTRODUCTION: The aim of the study was to describe how often patients seek information about their disease in connection with contact to a hospital and to elucidate how information-seeking behaviour is related to the patients' perception of this contact. MATERIAL AND METHODS: The study was based on patient surveys from the Danish county of Aarhus from 1999 to 2006 including eight public hospitals. The patients' information-seeking behaviour was related to patient characteristics, organisational context and patient perceptions. RESULTS: Among the 75,769 patients who responded, 33.4% had actively sought information. The frequency of patients seeking information increased from 24.4% in 1999 to 38.3% in 2006 with a variation between organisational units ranging from 7.7% to 81.8%. The share of critical patients among those who actively sought information was 23.7% in 1999 and 18.1% in 2006 compared with 12.9% and 11.3% critical patients, respectively, among those who did not. CONCLUSION: Having sought information correlated with negative patient perceptions. Despite convergence, differences between the perceptions of active and passive information seekers still remain. The health-care system should be prepared to serve patients who have different levels of knowledge. PRACTICE IMPLICATIONS: The health-care system should continuously improve the service provided to patients with different levels of knowledge and different attitudes towards involvement. It is recommended to routinely ask patients about their information seeking and to include questions about patients' information-seeking behaviour in patient satisfaction surveys. FUNDING: Financial support for the research and preparation of this article was provided by TrygFonden, Momsfonden and the Region of Central Jutland. None of the funding sources had any involvement in the study design, the analysis and interpretation of data, the writing of the report, or the decision to submit the paper for publication. TRIAL REGISTRATION: not relevant. PMID- 24495892 TI - One fourth of acutely admitted patients use over-the-counter-drugs 24 hours prior to hospitalisation. AB - INTRODUCTION: Use of over-the-counter (OTC) drugs is increasing and is poorly registered, which can lead to complications. The most commonly used OTC drugs are analgesics, and their usage is highest among elderly patients. Our study investigates the use of OTC drugs 24 hours prior to hospitalisation and the effects of this intake. MATERIAL AND METHODS: Junior physicians on call interviewed patients admitted to the medical admission unit at South-West Jutland Hospital in Esbjerg using a modified chart template. Adult patients aged 15 and older admitted during a two-week period in August 2012 were included. Patients were asked about consumed OTC drugs, dosage, indication and effect. RESULTS: From a total of 349 admissions, 188 usable chart templates were registered (54%), and information on OTC usage was registered on 165 of these (88%). The patients where elderly (median: 70 years) and 43 reported use of OTC drugs (26%). A total of 22 different OTC drugs had been consumed with analgesics being the most widely used OTC drugs (74%). The majority had taken the drugs on a relevant indication (88%), most commonly pain. Half of the patients had taken the drugs in a relevant dosage (51%). In all, 60% felt an effect of the intake and the majority felt an effect on pain symptoms. CONCLUSION: One in four patients used OTC drugs 24 hours prior to hospitalisation and primarily analgesics were used. Most patients used OTC drugs relevantly and half with a positive effect. The intake is poorly registered, and there is a need for an increased focus on the rising intake of OTC drugs to avoid potential side-effects and medicine interactions. FUNDING: not relevant. TRIAL REGISTRATION: not relevant. PMID- 24495893 TI - Risk stratifying asymptomatic aortic stenosis: role of the resting 12-lead ECG. AB - Despite being routinely performed in the clinical follow-up of asymptomatic AS patients, little or no evidence describes the prognostic value of ECG findings in asymptomatic AS populations. This PhD thesis examined the correlates of resting 12-lead ECG variables with echocardiographic measures of AS severity and cardiovascular outcomes in the till date largest cohort (n=1,563) of asymptomatic patients with mild-to-moderate AS. Most importantly, this PhD thesis demonstrated that QRS-duration adds independent predictive value of sudden cardiac death and that the additional presence of ECG LVH/strain for fixed AS severity represents a lethal risk attribute. Finally, ECG abnormalities displayed low/moderate concordance with echocardiographic parameters. This argues that the ECG should be regarded as a separate tool for obtaining prognostically important information. Treatment was not randomized by ECG findings, future studies should therefore examine if and which ECG variables should elicit closer follow-up and/or earlier intervention to improve prognosis in asymptomatic AS populations. PMID- 24495894 TI - The urethral closure function in continent and stress urinary incontinent women assessed by urethral pressure reflectometry. AB - Stress urinary incontinence (SUI) occurs when the bladder pressure exceeds the urethral pressure in connection with physical effort or exertion or when sneezing or coughing and depends both on the strength of the urethral closure function and the abdominal pressure to which it is subjected. The urethral closure function in continent women and the dysfunction causing SUI are not known in details. The currently accepted view is based on the concept of a sphincteric unit and a support system. Our incomplete knowledge relates to the complexity of the closure apparatus and to inadequate assessment methods which so far have not provided robust urodynamic diagnostic tools, severity measures, or parameters to assess outcome after intervention. Urethral Pressure Reflectometry (UPR) is a novel method that measures the urethral pressure and cross-sectional area (by use of sound waves) simultaneously. The technique involves insertion of only a small, light and flexible polyurethane bag in the urethra and therefore avoids the common artifacts encountered with conventional methods. The UPR parameters can be obtained at a specific site of the urethra, e.g. the high pressure zone, and during various circumstances, i.e. resting and squeezing. During the study period, we advanced the UPR technique to enable faster measurement (within 7 seconds by the continuous technique) which allowed assessment during increased intra-abdominal pressure induced by physical straining. We investigated the urethral closure function in continent and SUI women during resting and straining by the "fast" UPR technique. Thereby new promising urethral parameters were provided that allowed characterization of the closure function based on the permanent closure forces (primarily generated by the sphincteric unit, measured by the Po-rest) and the adjunctive closure forces (primarily generated by the support system, measured by the abdominal to urethral pressure impact ratio (APIR)). The new parameters enabled a more detailed description of the efficiency of the closure function and the extent and nature of a possible dysfunction in the individual woman. The urethral closure equation (UCE) and urethral opening pressure at an abdominal pressure of 50 cm H2O (Po-Abd 50), respectively, which combine the permanent and the adjunctive closure forces, could separate continent and SUI women and thus appear to be excellent diagnostic tests. Moreover, the parameters showed highly significant negative correlation with ICIQ-SF, pad test and the number of incontinence episodes per week and are therefore valid as urodynamic severity measures. UPR in SUI women before and after TVT demonstrated a more efficient urethral closure function after the operation. The Po-rest was unchanged suggesting that the sphincteric unit was virtually unaltered and hence the permanent closure forces unchanged. However, the resting opening elastance increased by 18% indicating that at the resting state the TVT somewhat improves the closure function by providing increased resistance against the dilation of the urethra, which probably explains the decreased maximum urine flow rate found after TVT in this and previous studies. The APIR increased in all patients after TVT suggesting that the support system was re-established and thus the adjunctive closure forces improved, regardless of the type of pre-operative dysfunction. The new UPR parameters may be used as outcome measures after treatment. PMID- 24495895 TI - Treatment and prognosis in peptic ulcer bleeding. AB - Peptic ulcer bleeding is a frequent cause of admission. Despite several advances in treatment the 30-day mortality seems unchanged at a level around 11%. Use of risk scoring systems is shown to be advantageous in the primary assessment of patients presenting with symptoms of peptic ulcer bleeding. Studies performed outside Denmark have demonstrated that use of risk scoring systems facilitates identification of low-risk patients suitable for outpatient management. Nevertheless, these systems have not been implemented for routine use in Denmark. This is mainly explained by concerns about the external validity due to considerable inter-country variation in patients' characteristics. In recent years, transcatheter arterial embolization (TAE) has become increasingly used for achievement of haemostasis in patients with peptic ulcer bleeding not responding to endoscopic therapy. As rebleeding is associated with poor outcome TAE could, in theory, also be beneficial as a supplementary treatment in patients with ulcer bleeding responding to endoscopic therapy. This has not been examined previously. Several studies have concluded that peptic ulcer bleeding is associated with excess long-term mortality. These findings are, however, questioned as the studies were based on life-table analysis, unmatched control groups, or did not perform adequate adjustment for comorbidity. Treatment with blood transfusion is, among patients undergoing cardiac bypass surgery, shown to increase the long-term mortality. Despite frequent use of blood transfusion in treatment of peptic ulcer bleeding a possible adverse effect of on long-term survival has not been examined in these patients. PMID- 24495896 TI - Acute rhinosinusitis (ARS). Diagnosis and treatment of adults in general practice. AB - The idea behind this thesis is to present how ARS and especially acute maxillary sinusitis in adults is diagnosed and treated in general practice. The study extends over many years, beginning with the first survey in 1991. Based on doctors' answers, we then investigated the diagnostic values of the symptoms, signs and examinations which the doctors reported using. All patients over 18 years suspected of acute maxillary sinusitis were included consecutively and only once and, after a clinical examination with the GP, they were offered the opportunity to enter into the prospective study referred to acute CT scan and by changes in the CT, immediately referred to sinus puncture. Both examinations were conducted at Aalborg Hospital. The disease was found most frequently in younger and 2/3 were women. The reason for this gender difference is unknown. We have assessed the diagnostic values of the symptoms, objective findings and investigations using 3 different reference standards: sinus puncture, microbiological diagnosis and CT scan described in three articles. In all examinations, it appeared that the usual signs and symptoms of acute maxillary sinusitis occur almost equally often and with a few exceptions in patients, with and without pus in the sinus cavities. Pain in the sinus cavities occurring in 95% of patients, and only elevated levels of CRP and ESR are significantly and independently associated with pus in the sinus cavities. This finding is surprising, because they are two nonspecific markers. CRP tested by near-patient testing has, within the investigations period, been introduced in general practice, and from 1999 the doctors also get reimbursed for performing the test. We have on this background originally defined a clinical criterion with pain over the sinuses accompanied by elevated values of CRP and/or ESR giving a sensitivity of 0.82, specificity 0.57, ppv 0.68 and npv 0.74. But looking at the ROC curve we suggest that a more clinical relevant diagnose will be based on use of CRP alone, as the test can be made easily and fast while the patient is in the clinic compared to the use of ESR. The disease is over-diagnosed in general practice. In only 53% of patients, who the GP suspected of having acute sinusitis, was there detected pus or mucopus at the sinus puncture, furthermore the patients' statements that they had had sinusitis was significantly negatively associated with current acute maxillary sinusitis. Almost all patients are prescribed topical treatment to the nose in the form of vasoconstrictor, and 50-70% also antibiotics. The most common bacteria that can be isolated are S. pneumoniae and H. influenzae. For many years the first drug of choice has been penicillin V, and treatment with penicillin V has followed Scandinavian recommendations. However, the resistance patterns in respect of H. influenzae have changed over the years and if the dominant flora is H. influenzae, then oral penicillin is not sufficient anymore, and should be replaced by amoxicillin with or without clavulanate. It is reported that the MIC of penicillin V is too high, such that oral dosage cannot provide sufficiently high concentrations. However, in daily clinical practice the doctor does not have the possibility to decide whether the infection is caused by either S. pneumoniae or H. influenzae, unless a sinus puncture is performed and it is not considered as a standard procedure. The recommended treatment is therefore starting with penicillin V, and at treatment failure switching to amoxicillin with or without clavulanate. It is well known that URTI's can exacerbate a chronic pulmonary disease - like asthma - in allergic patients, but this influence is also demonstrated as described in article 6 where ARS in adults without any sign of chronic lung disease or allergy is accompanied by a temporary reduction lung function. Future research should focus on the use of CRP in general practice, analysing cost-effectiveness of the use of CRP patient outcome in relation to antibiotic treatment, clarification of ARS as a female disease, and a detailed exploration of the relationship between URTI's and impaired lung function in lung-healthy patients. PMID- 24495897 TI - A wearable and highly sensitive pressure sensor with ultrathin gold nanowires. AB - Ultrathin gold nanowires are mechanically flexible yet robust, which are novel building blocks with potential applications in future wearable optoelectronic devices. Here we report an efficient, low-cost fabrication strategy to construct a highly sensitive, flexible pressure sensor by sandwiching ultrathin gold nanowire-impregnated tissue paper between two thin polydimethylsiloxane sheets. The entire device fabrication process is scalable, enabling facile large-area integration and patterning for mapping spatial pressure distribution. Our gold nanowires-based pressure sensors can be operated at a battery voltage of 1.5 V with low energy consumption (<30 MUW), and are able to detect pressing forces as low as 13 Pa with fast response time (<17 ms), high sensitivity (>1.14 kPa(-1)) and high stability (>50,000 loading-unloading cycles). In addition, our sensor can resolve pressing, bending, torsional forces and acoustic vibrations. The superior sensing properties in conjunction with mechanical flexibility and robustness enabled real-time monitoring of blood pulses as well as detection of small vibration forces from music. PMID- 24495898 TI - A cross-sectional study to investigate pneumococcal vaccination in the elderly in a low income county: patient knowledge, awareness, and attitudes of vaccination and prevalence rates by socioeconomic status. AB - BACKGROUND: Pneumonia represents the leading cause of infection-related death and the fifth cause of overall mortality, in the elderly. With increasing age, the human immune system undergoes characteristic changes which lead to increased incidence and severity of infectious diseases and to insufficient protection following vaccination as antibody response of elderly vaccines are weaker and decline faster. OBJECTIVE: Knowledge and Attitude toward Pneumonia and its Vaccination in elderly patients. RESULT: Among low SES, 54.9% (549/1000) while from high SES, 91.8% (918) responded that they had heard about pneumonia before (P<0.05). 79.5% (795/1000) patients of high SES had heard about pneumococcal vaccination while only 28.8% (288/1000) patients from low SES had heard about pneumococcal vaccine. Only 2.3% of low SES patients were immunized for pneumococcal vaccine while 16.5% high SES patients were vaccinated. Reported reason for not being immunized were; did not hear, no body advised, vaccine is too expensive, and ignored thinking it is not necessary. METHOD: We conducted a cross-sectional study on 2000 elderly patients who were admitted in medicine and surgery wards of Civil Hospital Karachi and Aga Khan University Hospital Karachi from the period of October to December 2012 to determine their knowledge and attitude toward pneumonia and its vaccination in elderly. Study group was divided into low and high socio-economic status on the basis of patients coming to government Hospital i.e., civil hospital and private hospital i.e., Aga khan hospital. Data was collected through convenient sampling technique. Exclusion criteria were patients below 60 years and those who didn't give consent to be part of study. CONCLUSION: Aside from introducing public awareness program about elderly vaccination at state level, free of cost vaccination of elderly individuals should be done. PMID- 24495899 TI - The politics of buzzwords at the interface of technoscience, market and society: the case of 'public engagement in science'. AB - Emerging technologies such as genomics, nanotechnology, and converging technologies are surrounded by a constellation of fashionable stereotyped phrases such as 'public engagement in science', 'responsible innovation', 'green technology', or 'personalised medicine'. Buzzwords are ubiquitous and used ad libitum by science policy makers, industrial companies in their advertisements, scientists in their research proposals, and journalists. Despite their proliferation in the language of scientific and technological innovation, these buzzwords have attracted little attention among science studies scholars. The purpose of this paper is to try to understand if, and how buzzwords shape the technoscientific landscape. What do they perform? What do they reveal? What do they conceal? Based on a case study of the phrase 'public engagement in science', this paper describes buzzwords as linguistic technologies, capable of three major performances: buzzwords generate matters of concern and play an important role in trying to build consensus; they set attractive goals and agendas; they create unstable collectives through noise. PMID- 24495900 TI - Come rain or shine? Public expectation on local weather change and differential effects on climate change attitude. AB - Tailored messages are instrumental to climate change communication. Information about the global threat can be 'localised' by demonstrating its linkage with local events. This research ascertains the relationship between climate change attitude and perception of local weather, based on a survey involving 800 Hong Kong citizens. Results indicate that concerns about climate change increase with expectations about the likelihood and impacts of local weather change. Climate change believers attend to all three types of adverse weather events, namely, temperature rises, tropical cyclones and prolonged rains. Climate scepticism, however, is not associated with expectation about prolonged rains. Differential spatial orientations are a possible reason. Global climate change is an unprecedented and distant threat, whereas local rain is a more familiar and localised weather event. Global climate change should be articulated in terms that respect local concerns. Localised framing may be particularly effective for engaging individuals holding positive views about climate change science. PMID- 24495901 TI - Direct aortic transcatheter aortic valve implantation for pure aortic valve regurgitation after implantation of a left ventricular assist device. PMID- 24495902 TI - Does grafting of the left anterior descending artery with the in situ right internal thoracic artery have an impact on late outcomes in the context of bilateral internal thoracic artery usage? AB - BACKGROUND: Despite their well-established advantages, bilateral internal thoracic arteries (BITA) are still largely underused. This is partly because of the technical complexities associated with the use of the right internal thoracic artery (RITA) to guarantee the universally accepted gold standard left internal thoracic artery (LITA) to left anterior descending artery (LAD) graft. The use of the in situ RITA for LAD grafting is a less technically demanding strategy. The impact of this strategy on early and late outcomes is investigated in the context of BITA usage. METHODS: Among 1667 patients undergoing first-time isolated coronary artery bypass grafting using BITA, in situ RITA for LAD grafting was used in 546 patients compared with in situ LITA to LAD in 1121 patients. Propensity score matching was carried out to investigate the impact of in situ RITA to LAD on early and late outcomes including mortality and need for repeat revascularization. RESULTS: A total of 546 propensity matched pairs were available for comparison. In the propensity matched cohort, the mean follow-up time was 7.8+/-3.8 years. RITA to LAD did not increase the risk for late death (hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.48-1.26), the need for repeat revascularization (HR, 0.83; 95% CI, 0.70-2.42), and the composite of death or repeat revascularization (HR, 0.81; 95% CI, 0.64-1.14). CONCLUSIONS: Using in situ BITA with retrosternal in situ RITA for LAD grafting is a technically less demanding, safe, and effective strategy that can increase usage of BITA by avoiding a composite graft configuration or technically challenging retrocaval routing of in situ RITA through the transverse sinus. PMID- 24495903 TI - Prospective evaluation of 24-hour urine profiles following bariatric surgery in a modern comprehensive care bariatric clinic. AB - AIMS: To prospectively examine the effect of modern bariatric surgery on 24-hour urine parameters in a comprehensive care bariatric practice (CCBP). MATERIALS AND METHODS: 47 consecutive patients in our CCBP underwent serum and 24-hour urine analysis pre-operatively, and 30 returned at 12 months for repeat testing. Paired comparisons for serum metabolite and 24-hour urine measures were performed using a Wilcoxon signed-rank test for continuous variables and McNemar's test for categorical variables. Statistical tests were two-sided, with threshold of significance set at p = 0.05. RESULTS: All 30 patients with pre-operative and 12 month follow-up analysis were free of stone events. 20 (67%) had Roux-en-Y gastric bypass (RYGB), 6 (20%) had laparoscopic gastric banding (LGB), and 4 (13%)h ad laparoscopic sleeve gastrectomy (LSG). 24-hour urinary parameters were available for 27 patients. Median urine oxalate (mmol) was 0.29 pre-operatively and 0.21 at 12 months (p = 0.048). Median urine calcium (mg) was 143 pre operatively and 180 at 12 months (p = 0.11). Median citrate excretion was 527 pre operatively and 782 at 12 months (p = 0.22). Median serum creatinine was 0.7 pre operatively and 0.8 at 12 months (p < 0.001). These trends were preserved with the exclusion of LGB and LSG patients. CONCLUSIONS: Modern bariatric surgery (RYGB, LGB, and LSG) as part of a CCBP can still demonstrate alterations of select urinary parameters (particularly oxalate and citrate) in select patients associated with an increased risk of urolithiasis at 1 year follow-up. PMID- 24495904 TI - Eculizumab for drug-induced de novo posttransplantation thrombotic microangiopathy: A case report. AB - De novo thrombotic microangiopathy (TMA) following renal transplantation is a severe complication associated with high rates of allograft failure. Several immunosuppressive agents are associated with TMA. Conventional approaches to managing this entity, such as withdrawal of the offending agent and/or plasmapheresis, often offer limited help, with high rates of treatment failure and graft loss. We herein report a case of drug induced de novo TMA successfully treated using the C5a inhibitor eculizumab in a renal transplant patient. This report highlights a potentially important role for eculizumab in settings where drug-induced de novo TMA is refractory to conventional therapies. PMID- 24495905 TI - Autochthonous Dobrava-Belgrade virus infection in Eastern Germany. AB - A 21-year-old male patient from Borna, Saxony, in Eastern Germany, suffered from acute kidney injury (AKI) and symptoms typical for a hantavirus infection. These symptoms included nausea, vomiting, abdominal pain, diarrhea, and acute renal failure. Serological investigations by indirect IgM and IgG in-house ELISAs, commercial immunofluorescence and line assays, as well as chemiluminescence focus reduction neutralization assay confirmed an acute Dobrava-Belgrade virus (DOBV) infection of the patient. Serological and RT-PCR analyses of striped field mouse (Apodemus agrarius) trapped in a neighboring region of the residence of the patient identified an infection by DOBV, genotype Kurkino. This is the first report of an autochthonous DOBV infection in a German patient living far from the known endemic region in the north of the country. This finding has implications for the awareness of physicians in areas which are not recognized as hantavirus endemic regions but where the reservoir host of the virus is present. PMID- 24495906 TI - Reprint of "Update on ultrasound elastography: Miscellanea. Prostate, testicle, musculo-skeletal". AB - Nowadays ultrasound elastosonography is an established technique, although with limited clinical application, used to assess tissue stiffness, which is a parameter that in most cases is associated with malignancy. However, although a consistent number of articles have been published about several applications of elastosonography, its use in certain human body districts is still not well defined. In this paper we write on the use of elastosonography in prostate, testicle and musculo-skeletal apparatus. We report and compare the work of several authors, different type of elastosonography (shear wave, strain elastography, etc.) and instrumental data obtained in the study of both benign and malignant lesions. PMID- 24495908 TI - Short-term light adaptation of a cyanobacterium, Synechocystis sp. PCC 6803, probed by time-resolved fluorescence spectroscopy. AB - In photosynthetic organisms, the interactions among pigment-protein complexes change in response to light conditions. In the present study, we analyzed the transfer of excitation energy from the phycobilisome (PBS) and photosystem (PS) II to PSI in the cyanobacterium Synechocystis sp. PCC 6803. After 20 min of dark adaptation, Synechocystis cells were illuminated for 5 min with strong light with different spectral profiles, blue, green, two kinds of red, and white light. After illumination, the energy-transfer characteristics were evaluated using steady-state fluorescence and picosecond time-resolved fluorescence spectroscopy techniques. The fluorescence rise and decay curves were analyzed by global analysis to obtain fluorescence decay-associated spectra, followed by spectral component analysis. Under illumination with strong light, the contribution of the energy transfer from the PSII to PSI (spillover) became greater, and that of the energy transfer from the PBS to PSI decreased; the former change was larger than the latter. The energy transfer pathway to PSI was sensitive to red light. We discuss the short-term adaptation of energy-transfer processes in Synechocystis under strong-light conditions. PMID- 24495907 TI - EFEMP1 induces gamma-secretase/Notch-mediated temozolomide resistance in glioblastoma. AB - Glioblastoma is the most common malignant primary brain tumor. Temozolomide (TMZ) is the standard chemotherapeutic agent for this disease. However, intrinsic and acquired TMZ-resistance represents a major obstacle for this therapy. In order to identify factors involved in TMZ-resistance, we engineered different TMZ resistant glioblastoma cell lines. Gene expression analysis demonstrated that EFEMP1, an extracellular matrix protein, is associated with TMZ-resistant phenotype. Silencing of EFEMP1 in glioblastoma cells resulted in decreased cell survival following TMZ treatment, whereas overexpression caused TMZ-resistance. EFEMP1 acts via multiple signaling pathways, including gamma-secretase-mediated activation of the Notch pathway. We show that inhibition of gamma-secretase by RO4929097 causes at least partial sensitization of glioblastoma cells to temozolomide in vitro and in vivo. In addition, we show that EFEMP1 expression levels correlate with survival in TMZ-treated glioblastoma patients. Altogether our results suggest EFEMP1 as a potential therapeutic target to overcome TMZ resistance in glioblastoma. PMID- 24495909 TI - Differences in antibody responses between trivalent inactivated influenza vaccine and live attenuated influenza vaccine correlate with the kinetics and magnitude of interferon signaling in children. AB - BACKGROUND: Live attenuated influenza vaccine (LAIV) and trivalent inactivated influenza vaccine (TIV) are effective for prevention of influenza virus infection in children, but the mechanisms associated with protection are not well defined. METHODS: We analyzed the differences in B-cell responses and transcriptional profiles in children aged 6 months to 14 years immunized with these 2 vaccines. RESULTS: LAIV elicited a significant increase in naive, memory, and transitional B cells on day 30 after vaccination, whereas TIV elicited an increased number of plasmablasts on day 7. Antibody titers against the 3 vaccine strains (H1N1, H3N2, and B) were significantly higher in the TIV group and correlated with number of antibody-secreting cells. Both vaccines induced overexpression of interferon (IFN)-signaling genes but with different kinetics. TIV induced expression of IFN genes on day 1 after vaccination in all age groups, and LAIV induced expression of IFN genes on day 7 after vaccination but only in children <5 years old. IFN related genes overexpressed in both vaccinated groups correlated with H3N2 antibody titers. CONCLUSIONS: These results suggest that LAIV and TIV induced significantly different B-cell responses in vaccinated children. Early induction of IFN appears to be important for development of antibody responses. PMID- 24495910 TI - Incidence, clearance, and disease progression of genital human papillomavirus infection in heterosexual men. AB - BACKGROUND: In this analysis, we examine the incidence and clearance of external genital human papillomavirus (HPV) infection among heterosexual males aged 16-24 years. METHODS: A total of 1732 males aged 16-24 years old in the placebo arm of a quadrivalent HPV vaccine trial were included in this analysis. Participants were enrolled from 18 countries in Africa, the Asia-Pacific region, Europe, Latin America, and North America. Subjects underwent anogenital examinations and sampling of the penis, scrotum, and perineal/perianal regions. RESULTS: The incidence rate of any HPV DNA genotype 6, 11, 16, and/or 18 detection was 9.0 cases per 100 person-years. Rates of HPV DNA detection were highest in men from Africa. Median time to clearance of HPV genotypes 6, 11, 16, and 18 DNA was 6.1, 6.1, 7.7, and 6.2 months, respectively. Median time to clearance of persistently detected HPV 6, 11, 16, and 18 DNA was 6.7, 3.2, 9.2, and 4.7 months, respectively. CONCLUSION: The study results suggest that the acquisition of HPV 6, 11, 16, and/or 18 in males is common and that many of these so-called infections are subsequently cleared, similar to findings for women. Nevertheless, given the high rate of HPV detection among young men, HPV vaccination of males may reduce infection in men and reduce the overall burden of HPV-associated disease in the community. PMID- 24495911 TI - Unconventional P-35S sequence identified in genetically modified maize. AB - The Cauliflower Mosaic Virus 35S promoter sequence, CaMV P-35S, is one of several commonly used genetic targets to detect genetically modified maize and is found in most GMOs. In this research we report the finding of an alternative P-35S sequence and its incidence in GM maize marketed in Jordan. The primer pair normally used to amplify a 123 bp DNA fragment of the CaMV P-35S promoter in GMOs also amplified a previously undetected alternative sequence of CaMV P-35S in GM maize samples which we term V3. The amplified V3 sequence comprises 386 base pairs and was not found in the standard wild-type maize, MON810 and MON 863 GM maize. The identified GM maize samples carrying the V3 sequence were found free of CaMV when compared with CaMV infected brown mustard sample. The data of sequence alignment analysis of the V3 genetic element showed 90% similarity with the matching P-35S sequence of the cauliflower mosaic virus isolate CabbB-JI and 99% similarity with matching P-35S sequences found in several binary plant vectors, of which the binary vector locus JQ693018 is one example. The current study showed an increase of 44% in the incidence of the identified 386 bp sequence in GM maize sold in Jordan's markets during the period 2009 and 2012. PMID- 24495912 TI - The evolutionary history of vertebrate cranial placodes--I: cell type evolution. AB - Vertebrate cranial placodes are crucial contributors to the vertebrate cranial sensory apparatus. Their evolutionary origin has attracted much attention from evolutionary and developmental biologists, yielding speculation and hypotheses concerning their putative homologues in other lineages and the developmental and genetic innovations that might have underlain their origin and diversification. In this article we first briefly review our current understanding of placode development and the cell types and structures they form. We next summarise previous hypotheses of placode evolution, discussing their strengths and caveats, before considering the evolutionary history of the various cell types that develop from placodes. In an accompanying review, we also further consider the evolution of ectodermal patterning. Drawing on data from vertebrates, tunicates, amphioxus, other bilaterians and cnidarians, we build these strands into a scenario of placode evolutionary history and of the genes, cells and developmental processes that underlie placode evolution and development. PMID- 24495913 TI - New evidence suggests pyroclastic flows are responsible for the remarkable preservation of the Jehol biota. AB - The lower Cretaceous Yixian and Jiufotang formations contain numerous exceptionally well-preserved invertebrate, vertebrate and plant fossils that comprise the Jehol Biota. Freshwater and terrestrial fossils of the biota usually occur together within some horizons and have been interpreted as deposits of mass mortality events. The nature of the events and the mechanisms behind the exceptional preservation of the fossils, however, are poorly understood. Here, after examining and analysing sediments and residual fossils from several key horizons, we postulate that the causal events were mainly phreatomagmatic eruptions. Pyroclastic density currents were probably responsible for the major causalities and for transporting the bulk of the terrestrial vertebrates from different habitats, such as lizards, birds, non-avian dinosaurs and mammals, into lacustrine environments for burial. Terrestrial vertebrate carcasses transported by and sealed within the pyroclastic flows were clearly preserved as exceptional fossils through this process. PMID- 24495914 TI - Probable relationship between partitions of the set of codons and the origin of the genetic code. AB - Here we study the distribution of randomly generated partitions of the set of amino acid-coding codons. Some results are an application from a previous work, about the Stirling numbers of the second kind and triplet codes, both to the cases of triplet codes having four stop codons, as in mammalian mitochondrial genetic code, and hypothetical doublet codes. Extending previous results, in this work it is found that the most probable number of blocks of synonymous codons, in a genetic code, is similar to the number of amino acids when there are four stop codons, as well as it could be for a primigenious doublet code. Also it is studied the integer partitions associated to patterns of synonymous codons and it is shown, for the canonical code, that the standard deviation inside an integer partition is one of the most probable. We think that, in some early epoch, the genetic code might have had a maximum of the disorder or entropy, independent of the assignment between codons and amino acids, reaching a state similar to "code freeze" proposed by Francis Crick. In later stages, maybe deterministic rules have reassigned codons to amino acids, forming the natural codes, such as the canonical code, but keeping the numerical features describing the set partitions and the integer partitions, like a "fossil numbers"; both kinds of partitions about the set of amino acid-coding codons. PMID- 24495915 TI - Differential methylation in visceral adipose tissue of obese men discordant for metabolic disturbances. AB - Obesity is associated with an increased risk of Type 2 diabetes and cardiovascular diseases (CVD). The severely obese population is heterogeneous regarding CVD risk profile. Our objective was to identify metabolic pathways potentially associated with development of metabolic syndrome (MetS) through an analysis of overrepresented pathways from differentially methylated genes between severely obese men with (MetS+) and without (MetS-) the MetS. Genome-wide quantitative DNA methylation analysis in VAT of severely obese men was carried out using the Infinium HumanMethylation450 BeadChip. Differences in methylation levels between MetS+ (n = 7) and MetS- (n = 7) groups were tested. Overrepresented pathways from the list of differentially methylated genes were identified and visualized with the Ingenuity Pathway Analysis system. Differential methylation analysis between MetS+ and MetS- groups identified 8,578 methylation probes (3,258 annotated genes) with significant differences in methylation levels (false discovery rate-corrected DiffScore >= |13| ~ P <= 0.05). Pathway analysis from differentially methylated genes identified 41 overrepresented (P <= 0.05) pathways. The most overrepresented pathways were related to structural components of the cell membrane, inflammation and immunity and cell cycle regulation. This study provides potential targets associated with adipose tissue dysfunction and development of the MetS. PMID- 24495916 TI - Differential regulation of DNA methylation versus histone acetylation in cardiomyocytes during HHcy in vitro and in vivo: an epigenetic mechanism. AB - The mechanisms of homocysteine-mediated cardiac threats are poorly understood. Homocysteine, being the precursor to S-adenosyl methionine (a methyl donor) through methionine, is indirectly involved in methylation phenomena for DNA, RNA, and protein. We reported previously that cardiac-specific deletion of N-methyl-d aspartate receptor-1 (NMDAR1) ameliorates homocysteine-posed cardiac threats, and in this study, we aim to explore the role of NMDAR1 in epigenetic mechanisms of heart failure, using cardiomyocytes during hyperhomocysteinemia (HHcy). High homocysteine levels activate NMDAR1, which consequently leads to abnormal DNA methylation vs. histone acetylation through modulation of DNA methyltransferase 1 (DNMT1), HDAC1, miRNAs, and MMP9 in cardiomyocytes. HL-1 cardiomyocytes cultured in Claycomb media were treated with 100 MUM homocysteine in a dose-dependent manner. NMDAR1 antagonist (MK801) was added in the absence and presence of homocysteine at 10 MUM in a dose-dependent manner. The expression of DNMT1, histone deacetylase 1 (HDAC1), NMDAR1, microRNA (miR)-133a, and miR-499 was assessed by real-time PCR as well as Western blotting. Methylation and acetylation levels were determined by checking 5'-methylcytosine DNA methylation and chromatin immunoprecipitation. Hyperhomocysteinemic mouse models (CBS+/-) were used to confirm the results in vivo. In HHcy, the expression of NMDAR1, DNMT1, and matrix metalloproteinase 9 increased with increase in H3K9 acetylation, while HDAC1, miR-133a, and miR-499 decreased in cardiomyocytes. Similar results were obtained in heart tissue of CBS+/- mouse. High homocysteine levels instigate cardiovascular remodeling through NMDAR1, miR-133a, miR-499, and DNMT1. A decrease in HDAC1 and an increase in H3K9 acetylation and DNA methylation are suggestive of chromatin remodeling in HHcy. PMID- 24495917 TI - Epidemiology of adults receiving acute inpatient rehabilitation for a primary diagnosis of traumatic brain injury in the United States. AB - OBJECTIVE: To estimate the overall and by age-group characteristics at admission and discharge from rehabilitation between 2001 and 2010 of all late-teens and adults undergoing inpatient rehabilitation for a primary diagnosis of traumatic brain injury (TBI) in the United States. DESIGN: Secondary data analysis. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: Patients aged 16 years and older receiving inpatient rehabilitation for a primary diagnosis of TBI between 2001 and 2010. MAIN OUTCOME MEASURES: Functional independence, level of disability, and living situation. RESULTS: The incidence of TBI by age group found the largest proportion of cases to be aged 80 years and older, with a gradual decline in incidence in the age group of 30 years, at which point there was a slight increase. Injuries resulted predominantly from falls (49.8%) and motor vehicle crashes (40.8%); however, injuries to the youngest individuals were largely from motor vehicle crashes with decreasing rates as age increased, while injuries due to falls rose as age increased, with the oldest age groups most likely to incur a TBI. Preinjury alcohol misuse and substance use were found to occur in 22.9% and 12.2% of the total population, respectively; however, age distributions demonstrated high preinjury use among individuals younger than 50 years (eg, 46.4% and 30.6% for those aged 20 and 29 years, respectively) with decreasing misuse as age increased. Of the total population, 49.2% were retired, 31.1% employed, 14.1% not working, and 5.6% students. Trends by age showed that younger individuals were more likely to be students or employed (eg, 14.5% and 62.0% for those aged 20 and 29 years, respectively), with employment status peaking for those aged 30 to 39 years, and declining to 3.2% for the oldest age group (80 years and older). The trend of person(s) living alone between pre- and postrehabilitation showed the least amount of change for those aged 16 to 19 years with steadily increasing changes as age increased. Similar trends were seen for residence changes pre- and postrehabilitation, with the youngest most likely to return to living at a private residence, and a gradual decrease in return to living at a private residence as age increased. FIM instrument ("FIM") Motor and Cognitive subscale scores demonstrated that younger individuals had lower scores at admission to rehabilitation and higher scores at rehabilitation discharge. CONCLUSION: This study provides population estimates for all patients 16 years of age and older receiving inpatient rehabilitation for a primary diagnosis of TBI in the United States between 2001 and 2010. A recent trend shows the aging of the inpatient TBI rehabilitation population. Many characteristics important to rehabilitation outcomes are influenced by age, with older individuals trending toward being female, having less severe TBIs, incurring TBIs as a result of falls, but showing less improvement during rehabilitation, greater resulting disability, and more changes in their living situation postrehabilitation. These findings are of particular interest, as the oldest age groups considered in these analyses did not include the baby boom population. PMID- 24495918 TI - Context-sensitive goal management training for everyday executive dysfunction in children after severe traumatic brain injury. AB - OBJECTIVES: To assess the effectiveness of a metacognitive training intervention, based on an adapted Goal Management Training and Ylvisaker's principles, on 3 activity domains of executive functions: (1) prospective memory (PM) performance in ecological setting, (2) complex cooking task management, and (3) daily executive functioning (EF) at home and at school. PARTICIPANTS: Five children aged 8 to 14 years, who were 3 to 11 years post-severe traumatic brain injury, experiencing severe EF difficulties in daily life. DESIGN: Single-case experimental design and assessment of EF twice prior to intervention, postintervention, and 3 and 6 months postintervention. Progress was monitored by a weekly ecological PM score. The effect on EF was assessed using the Children's Cooking Task. Transfer to the child's natural context was assessed by parental and teacher questionnaires and Goal Attainment Scaling. RESULTS: All children improved both on the measure of PM and on questionnaires of daily EF. Two children improved on the Children's Cooking Task but returned to their preintervention level in a novel cooking task at follow-up. Participation of school personnel and parents in the program was low. CONCLUSIONS: It is feasible but challenging to use Goal Management Training in children with traumatic brain injury. Further research is needed in relation to how to promote generalization and how to increase the involvement of the child's "everyday people" in the intervention. PMID- 24495919 TI - US population estimates of health and social outcomes 5 years after rehabilitation for traumatic brain injury. AB - OBJECTIVE: To estimate the number of adults in the United States from 2006 to 2012 who manifest selected health and social outcomes 5 years following a traumatic brain injury (TBI) that required acute inpatient rehabilitation. DESIGN: Secondary data analysis. SETTING: Acute inpatient rehabilitation facilities. PARTICIPANTS: Patients 16 years and older receiving acute inpatient rehabilitation for a primary diagnosis of TBI. MAIN OUTCOME MEASURES: Mortality, functional independence, societal participation, subjective well-being, and global outcome. RESULTS: Annually from 2001 to 2007, an average of 13 700 patients aged 16 years or older received acute inpatient rehabilitation in the United States with a primary diagnosis of TBI. Approximately 1 in 5 patients had died by the 5-year postinjury assessment. Among survivors, 12% were institutionalized and 50% had been rehospitalized at least once. Approximately one-third of patients were not independent in everyday activities. Twenty-nine percent were dissatisfied with life, with 8% reporting markedly depressed mood. Fifty-seven percent were moderately or severely disabled overall, with 39% having deteriorated from a global outcome attained 1 or 2 years postinjury. Of those employed preinjury, 55% were unemployed. Poorer medical, functional, and participation outcomes were associated with, but not limited to, older age. Younger age groups had poorer mental and emotional outcomes. Deterioration in global outcome was common and not age-related. CONCLUSIONS: Significant mortality and morbidity were evident at 5 years postinjury. The deterioration in global outcomes observed regardless of age suggests that multiple influences contribute to poorer outcomes. Public health interventions intended to reduce post-acute inpatient rehabilitation mortality and morbidity rates will need to be multifaceted and age-specific. PMID- 24495920 TI - An introduction to analyzing dichotomous outcomes in a longitudinal setting: a NIDRR traumatic brain injury model systems communication. AB - An untapped wealth of temporal information is captured within the Traumatic Brain Injury Model Systems National Database. Utilization of appropriate longitudinal analyses can provide an avenue toward unlocking the value of this information. This article highlights 2 statistical methods used for assessing change over time when examination of noncontinuous outcomes is of interest where this article focuses on investigation of dichotomous responses. Specifically, the intent of this article is to familiarize the rehabilitation community with the application of generalized estimating equations and generalized linear mixed models as used in longitudinal studies. An introduction to each method is provided where similarities and differences between the 2 are discussed. In addition, to reinforce the ideas and concepts embodied in each approach, we highlight each method, using examples based on data from the Rocky Mountain Regional Brain Injury System. PMID- 24495922 TI - Clinical grading system for submucous cleft palate. AB - Submucous cleft palate is a structural abnormality of the palate. The clinical features vary, as does the functional impairment, which ranges from none to severe. Although there is a poor correlation between the presenting clinical signs and the severity of velopharyngeal insufficiency during speech, a clinical grading system could assist surgical management and allow more meaningful comparisons to be made between outcome studies. The grading system described is based on clinical examination alone and reflects the likely degree of structural abnormality of the musculature of the soft palate. PMID- 24495921 TI - Limited geographic distribution of the novel cyclovirus CyCV-VN. AB - A novel cyclovirus, CyCV-VN, was recently identified in cerebrospinal fluid (CSF) from patients with central nervous system (CNS) infections in central and southern Vietnam. To explore the geographic distribution of this novel virus, more than 600 CSF specimens from patients with suspected CNS infections in northern Vietnam, Cambodia, Nepal and The Netherlands were screened for the presence of CyCV-VN but all were negative. Sequence comparison and phylogenetic analysis between CyCV-VN and another novel cyclovirus recently identified in CSF from Malawian patients indicated that these represent distinct cycloviral species, albeit phylogenetically closely related. The data suggest that CyCV-VN has a limited geographic distribution within southern and central Vietnam. Further research is needed to determine the global distribution and diversity of cycloviruses and importantly their possible association with human disease. PMID- 24495923 TI - China should reduce the overuse of intravenous infusion. PMID- 24495924 TI - Biosynthesis of bacteriochlorophyll c derivatives possessing chlorine and bromine atoms at the terminus of esterifying chains in the green sulfur bacterium Chlorobaculum tepidum. AB - The green sulfur photosynthetic bacterium Chlorobaculum tepidum newly produced BChl c derivatives possessing a chlorine or bromine atom at the terminus of the esterifying chain in the 17-propionate residue by cultivation with exogenous omega-halo-1-alkanols. The relative ratios of BChl c derivatives esterified with 8-chloro-1-octanol and 10-chloro-1-decanol were estimated to be 26.5% and 33.3% by cultivation with these omega-chloro-1-alkanols at the final concentrations of 300 and 150 MUM, respectively. In contrast, smaller amounts of unnatural BChls c esterified with omega-bromo-1-alkanols were biosynthesized than those esterified with omega-chloro-1-alkanols: the ratios of BChl c derivatives esterified with 8 bromo-1-octanol and 10-bromo-1-decanol were 11.3% and 12.2% at the concentrations of 300 and 150 MUM, respectively. These indicate that omega-chloro-1-alkanols can be incorporated into bacteriochlorophyllide c more than omega-bromo-1-alkanols in the BChl c biosynthetic pathway. The homolog compositions of the novel BChl c derivatives possessing a halogen atom were analogous to those of coexisting natural BChl c esterified with farnesol. These results demonstrate unique properties of BChl c synthase, BchK, which can utilize unnatural substrates containing halogen in the BChl c biosynthesis of Cba. tepidum. PMID- 24495925 TI - Bonding of synthetic hydrogels with fibrin as the glue to engineer hydrogel-based biodevices. AB - We show the fibrous protein fibrin can serve as biocompatible glue with which to bind synthetic cationic or anionic hydrogels together. Both the bonding to and detachment from the hydrogels by fibrin (gelation and degradation, respectively) proceeded enzymatically under physiological conditions. We built a hydrogel-based actuator to demonstrate the method. PMID- 24495926 TI - An in vitro liver model consisting of endothelial vascular networks surrounded by human hepatoma cell lines allows for improved hepatitis B virus replication. AB - The life cycle of viruses, from infection to budding, is dependent upon the physiological activity of the host cells, such as expression of cell surface proteins, activities of organelles and transcription factors and so on. Human hepatitis viruses exploit multiple hepatocyte pathways during their life cycle; however, primary hepatocytes dramatically lose function and die when cultured as a monolayer in vitro. We previously reported the development of an in vitro liver model, IVL, consisting of endothelial networks and mouse primary hepatocytes. Hepatocytes cultured using the IVL achieved higher hepatic gene expression and drug sensitivity. In this study, human IVLs were constructed by using the human hepatoma cell lines, Hep G2 and HuH-7, and human umbilical vein endothelial cell networks on Engelbreth-Holm-Swarm gels. In order that these human IVLs could serve as in vitro models of human viral hepatitis, these human hepatoma cell lines were stably transfected with the hepatitis B virus (HBV) genome. The levels of HBV markers observed in the supernatant of the IVL cultures were significantly increased as compared to those obtained in transfected monocultures. Furthermore, the hepatocytes in the human IVL cultures became polarized, leading to efficient HBV replication and release in vitro. This finding suggests that the IVL culture system could be an effective model for HBV replication. PMID- 24495929 TI - Cytotoxicity and genotoxicity of orthodontic bands with or without silver soldered joints. AB - Stainless steel bands, with or without silver soldered joints, are routinely used in orthodontics. However, little is known about the toxic biological effects of these appliances. The aims of this study were to evaluate the cytotoxic, cytostatic, genotoxic and DNA damage-inducing effects of non-soldered bands (NSB) and silver soldered bands (SSB) on the HepG2 and HOK cell lines and to quantify the amount of ions released by the bands. The 24-h metallic eluates of NSBs and SSBs were quantified by atomic absorption spectrophotometry. An MTT reduction assay was performed to evaluate the cytotoxicity, alkaline and modified comet assays were employed to measure genotoxicity and oxidative DNA damage effects, and cytokinesis-block micronucleus cytome (CBMN-Cyt) assays were used to verify DNA damage, cytostasis and cytotoxicity. Ag, Cd, Cr, Cu and Zn were detected in SSB medium samples, and Fe and Ni were detected in both the SSB and NSB medium samples. The SSB group induced stronger cytotoxic effects than the NSB group in both evaluated cell lines. NSB and SSB induced genotoxicity as evaluated by comet assays; stronger effects were observed in the SSB group. Both groups induced similar increases in the number of oxidative DNA lesions, as detected by the FPG and Endo III enzymes. Nucleoplasmic bridges, biomarkers of DNA misrepair and/or telomere end fusions, were significantly elevated in the SSB group. The SSB eluates showed higher amounts of Ni and Fe than NSB, and all the quantified ions were detected in SSB eluates, including Cd. The SSB eluates were more cytotoxic and genotoxic than the NSB samples. Based on these results, we propose that other brands, materials and techniques should be further investigated for the future manufacture of orthodontic appliances. PMID- 24495930 TI - Assessment of the abiotic and biotic effects of sodium metabisulphite pulses discharged from desalination plant chemical treatments on seagrass (Cymodocea nodosa) habitats in the Canary Islands. AB - Reverse osmosis membranes at many desalination plants are disinfected by periodic shock treatments with sodium metabisulphite, which have potentially toxic effects to the environment for marine life, although no empirical and experimental evidence for this is yet available. The aim of this study was to characterise for the first time, the physico-chemical modification of the marine environment and its biological effects, caused by hypersaline plumes during these membrane cleaning treatments. The case study was the Maspalomas II desalination plant, located in the south of Gran Canaria (Canary Islands, Spain). Toxicity bioassays were performed on marine species characteristic for the infralittoral soft bottoms influenced by the brine plume (Synodus synodus and Cymodocea nodosa), and revealed a high sensitivity to short-term exposure to low sodium metabisulphite concentrations. The corrective measure of incorporating a diffusion system with Venturi Eductors reduced nearly all the areas of influence, virtually eliminating the impact of the disinfectant. PMID- 24495932 TI - Enhanced bio-hydrogen production from protein wastewater by altering protein structure and amino acids acidification type. AB - Enhanced bio-hydrogen production from protein wastewater by altering protein structure and amino acids acidification type via pH control was investigated. The hydrogen production reached 205.2 mL/g-protein when protein wastewater was pretreated at pH 12 and then fermented at pH 10. The mechanism studies showed that pH 12 pretreatment significantly enhanced protein bio-hydrolysis during the subsequent fermentation stage as it caused the unfolding of protein, damaged the protein hydrogen bonding networks, and destroyed the disulfide bridges, which increased the susceptibility of protein to protease. Moreover, pH 10 fermentation produced more acetic but less propionic acid during the anaerobic fermentation of amino acids, which was consistent with the theory of fermentation type affecting hydrogen production. Further analyses of the critical enzymes, genes, and microorganisms indicated that the activity and abundance of hydrogen producing bacteria in the pH 10 fermentation reactor were greater than those in the control. PMID- 24495934 TI - Introduction. Astrocytes in the injured brain: is gliosis adaptive or maladaptive? PMID- 24495933 TI - Clinical and molecular studies reveal a PSEN1 mutation (L153V) in a Peruvian family with early-onset Alzheimer's disease. AB - Presenilin 1 (PSEN1) gene mutations are found in 30-70% of familial early-onset Alzheimer disease (EOAD) cases (onset <60 years). Prevalence of these mutations is highly variable including ethnic differences worldwide. No Peruvian kindred with familial AD (FAD) have been described. Standardized clinical evaluation and cognitive assessment were completed in a Peruvian family with severe EOAD. Clinical course was characterized by very early onset (before age 35 years), progressive cognitive impairment with early memory loss, spatial disorientation and executive dysfunction. We sequenced all exons of PSEN1 in the proband and identified a c.475C>G DNA change resulting in a p.L153V missense mutation in the transmembrane domain 2 of the gene. This mutation is also present in the three additional affected siblings but not in a non-affected family member consistent with segregation of this mutation with the disease. This is the first report of a Peruvian family affected with EOAD associated with a PSEN1 mutation. This same mutation has been reported previously in English and French families, but a novel variants very close to the mutation and ancestry informative markers analysis suggests the mutation might be of Amerindian or African origin in this Peruvian family. PMID- 24495935 TI - Acetylsalicylic acid enhances tachyphylaxis of repetitive capsaicin responses in TRPV1-GFP expressing HEK293 cells. AB - Since many years acetylsalicylic acid (ASA) is known for its antithrombotic, antiphlogistic and analgesic effects caused by irreversible acetylation of cyclooxygenase. ASA also inhibits capsaicin- and heat-induced responses in cultured dorsal root ganglia (DRG) neurons, suggesting TRPV1 (transient receptor potential channel of the vanilloid receptor family, subtype 1) to be an additional target of ASA. We now studied the effect of ASA on heterologously expressed rat TRPV1 using calcium microfluorimetry. Capsaicin dose-dependently increased intracellular calcium with an EC50 of 0.29 MUM in rTRPV1 expressing HEK293 cells. During repetitive stimulation the second response to capsaicin was reduced (53.4 +/- 8.3% compared to vehicle control; p<0.005; Student's unpaired t test) by 1MUM ASA, a concentration much below the one needed to inhibit cyclooxygenase (IC50 of 35 MUM in thromboxane B2 production assay). In contrast, calcium transients induced by a single stimulus of 0.3 or 1 MUM capsaicin were not significantly reduced by 0.3 or 1 MUM ASA. These data suggest that ASA increases the tachyphylaxis of rTRPV1 channel activation. Mechanisms are unknown and may be direct by e.g. stabilization of the desensitized state or indirect via inhibition of intracellular signaling pathways e.g. of the mitogen-activated protein kinase family (MAPK/ERK). PMID- 24495936 TI - Prepubertal girl with vaginal bleeding. AB - BACKGROUND: Prepubertal children with vaginal bleeding are frequently brought in to the Emergency Department (ED) for evaluation with the primary concern of sexual abuse. Appropriate history and physical examination can help recognize the specific cause and allay anxiety of parents and reduce unnecessary work-up. OBJECTIVE: The purpose of this report is to describe a frequently unrecognized cause of vaginal bleeding that is unrelated to sexual abuse. CASE REPORT: We report the case of a 6-year-old African-American girl referred to our ED as a case of vaginal bleeding with suspicion of sexual abuse. She was clinically diagnosed to have urethral prolapse. CONCLUSION: In prepubertal girls with vaginal bleeding, urethral prolapse should be strongly considered as a diagnostic possibility. Increased physician awareness and early recognition of urethral prolapse avoids unnecessary examinations and patient anxiety and prevents misdiagnosis as sexual abuse. PMID- 24495938 TI - Acute lumbar radiculopathy with weak legs. AB - BACKGROUND: Inferior vena cava thrombosis is a rare but important cause of acute low back pain and lumbar radiculopathy. Failure to diagnose and treat this condition could result in propagation of the thrombosis, resulting in fatal pulmonary embolism. CASE REPORT: We report the first known case of inferior vena cava thrombosis in a postpartum woman presenting with acute lumbar radiculopathy and weak legs. She was successfully treated with i.v. heparin and oral anticoagulation. CONCLUSIONS: Inferior vena cava thrombosis is a rare cause of acute lumbar radiculopathy, but is in the differential diagnosis to consider, especially in those patients at increased risk of thrombosis. PMID- 24495937 TI - Intragastric balloon in the emergency department: an unusual cause of gastric outlet obstruction. AB - BACKGROUND: Obesity has become a worldwide epidemic and is associated with significant morbidity and mortality. Many strategies to promote weight loss, including medications and surgical techniques, have been developed; however, few have proven effective. As the rates of obesity and associated complications continue to climb, there is growing pressure on the medical community to develop less invasive procedures that can provide lasting weight loss results. OBJECTIVES: One surgical treatment for obesity, available in several countries but not yet approved for use in the United States, is the intragastric balloon (IGB). The IGB is a temporary, space-occupying device placed endoscopically into the stomach to decrease gastric volume and provide a sense of early satiety. Our objective is to highlight potential complications of this device that emergency physicians should be familiar with, in particular, gastric outlet obstruction. CASE REPORT: We report the case of a morbidly obese 63-year-old Middle Eastern man who presented to an emergency department in Texas with mechanical gastric outlet obstruction 2 months after IGB placement. After three endoscopic attempts, the balloon was successfully removed and the obstruction relieved. CONCLUSION: With an increasingly mobile and obese global population, emergency physicians should be aware of weight loss procedures such as the IGB and appropriate time sensitive management of high-risk complications. PMID- 24495939 TI - Migrating sternal rod: ultrasound identification of an unusual soft tissue foreign body. AB - BACKGROUND: Sternal hardware migration from its original site of implantation is a rare entity. Bedside ultrasound may identify migrated hardware if the site of migration is the subcutaneous tissue. OBJECTIVES: This case report will discuss the unusual phenomenon of migrating sternal hardware, as well as the ultrasonographic characteristics of soft tissue foreign bodies. CASE REPORT: A 51 year-old man presented to the Emergency Department with a 2-month history of intermittent lower abdominal pain, 11 months status post bilateral lung transplant surgery. His examination was remarkable for a palpable mass over the left lower quadrant of the abdomen. Initial bedside ultrasound identified a soft tissue foreign body in the subcutaneous tissue overlying the left lower quadrant of the abdomen. Further evaluation using plain radiography and computed tomography ultimately diagnosed the foreign body as a metal rod, which had migrated from his sternum. The sternal rod was removed at the bedside, and he was discharged the next day without any complications. CONCLUSION: Sternal hardware migration is uncommon, but in patients who have undergone surgery involving sternal fixation, this diagnosis should be considered as a cause for unusual symptoms. PMID- 24495940 TI - A 32-year-old man with delayed onset post-traumatic proptosis and diplopia. AB - BACKGROUND: Proptosis and motility deficits are common findings in the setting of craniofacial trauma, but can indicate the presence of vision and even life threatening pathology. OBJECTIVE: Our aim was to identify presentations consistent with traumatic carotid cavernous fistula (CCF) and to review the appropriate initial work-up and management. CASE REPORT: A 32-year-old man came to our emergency department with proptosis, ocular motility deficits, and decreased vision 1 month after a restrained motor vehicle accident. An orbital bruit was auscultated and four-vessel angiography revealed a CCF. Covered stents and an embolic agent were used to abolish the arteriovenous communication and the patient rapidly returned to his premorbid baseline. CONCLUSIONS: CCF is a relatively rare but important consequence of craniofacial trauma that must be recognized promptly in order to minimize the likelihood of serious sequelae. It should be suspected in patients with antecedent trauma presenting with exophthalmos, arterialized conjunctival vessels, and orbital bruit. PMID- 24495941 TI - The impact of agricultural emergence on the genetic history of African rainforest hunter-gatherers and agriculturalists. AB - The emergence of agriculture in West-Central Africa approximately 5,000 years ago, profoundly modified the cultural landscape and mode of subsistence of most sub-Saharan populations. How this major innovation has had an impact on the genetic history of rainforest hunter-gatherers-historically referred to as 'pygmies'-and agriculturalists, however, remains poorly understood. Here we report genome-wide SNP data from these populations located west-to-east of the equatorial rainforest. We find that hunter-gathering populations present up to 50% of farmer genomic ancestry, and that substantial admixture began only within the last 1,000 years. Furthermore, we show that the historical population sizes characterizing these communities already differed before the introduction of agriculture. Our results suggest that the first socio-economic interactions between rainforest hunter-gatherers and farmers introduced by the spread of farming were not accompanied by immediate, extensive genetic exchanges and occurred on a backdrop of two groups already differentiated by their specialization in two ecotopes with differing carrying capacities. PMID- 24495943 TI - Nano conductive ceramic wedged graphene composites as highly efficient metal supports for oxygen reduction. AB - A novel conductive ceramic/graphene nanocomposite is prepared to prohibit the re stacking of reduced graphene oxide (RGO) by wedging zirconium diboride (ZrB2) nanoparticles (NPs) into multiple layer nanosheets using a simple solvothermal method. Surprisingly, the RGO/ZrB2 nanocomposite supported Pt NPs shows very excellent catalytic activity. Its electrochemical surface area (ECSA) is up to 148 m(2)g(-1) (very approaches the geometry surface area of 155 m(2)g(-1)), much greater than that of the previous report (usually less than 100 m(2)g(-1)). The mass activity is as high as 16.8 A/g(-1), which is almost 2 times and 5 times that of Pt/RGO (8.6 A/g(-1)) and Pt/C (3.2 A/g(-1)), respectively, as benchmarks. Moreover, after 4000 cycles the catalyst shows only 61% of ECSA loss, meaning a predominantly electrochemical stability. The remarkably improved electrochemical properties with much high Pt utilization of the new catalyst show a promising application in low temperature fuel cells and broader fields. PMID- 24495942 TI - Systematic review of the side effects associated with tyrosine kinase inhibitors used in the treatment of gastrointestinal stromal tumours on behalf of the EORTC Quality of Life Group. AB - Tyrosine kinase inhibitors (TKIs) have revolutionised the treatment of advanced gastrointestinal stromal tumours (GISTs). Imatinib is approved as first line therapy and sunitinib is used in cases of imatinib resistance or intolerance. Compared with conventional treatments, TKIs are delivered over longer periods of time and are more specific in their targets (i.e., molecularly targeted), thus presenting different side effect profiles. We review the safety profiles of imatinib and sunitinib, documenting a total of 95 side effects including patient based as well as medically defined outcomes. Gastrointestinal complaints, particularly diarrhoea and nausea, oedema, fatigue and haematological disorders, notably anaemia, are amongst the most prevalent side effects. While there is overlap between the side effect profiles of imatinib and sunitinib, important differences emerge in the frequencies of oedema, hypertension, thyroid functioning, muscle and joint pains, as well as skin and oral conditions. Awareness of potential side effects is informative to both clinician and patient in terms of treatment decision making and can have important implications for treatment adherence and clinical outcome. PMID- 24495944 TI - Amplatzer PFO occluder device may prevent recurrent stroke in patients with patent foramen ovale and cryptogenic stroke: a meta-analysis of randomised trials. AB - OBJECTIVE: To review efficacy of percutaneous closure of patent foramen ovale compared with medical therapy in prevention of recurrent strokes in patients with cryptogenic stroke. METHODS AND RESULTS: Electronic databases; PUBMED, EMBASE, Cochrane registry and web of knowledge were searched for relevant studies. In three randomised clinical trials involving 2303 participants, risk of the recurrent strokes (pooled HR 0.62, 95% CI=0.36-1.07, P=0.09, I(2) =10%) did not show benefit with device closure when compared with medical therapy group on meta analysis of all three trials. However, on sensitivity analysis in trials using Amplatzer PFO occluder device, the closure of PFO was associated with significantly lower recurrent strokes (pooled HR=0.44, 95% CI=0.21-0.94, P=0.03, I(2)=0%) compared with medical therapy. CONCLUSION: The closure of PFO with Amplatzer PFO occluder device was associated with significant reduction in recurrent strokes in patients with cryptogenic stroke and patent foramen ovale. The better outcome in prevention of secondary stroke in patients with cryptogenic stroke and PFO may be associated with type of closure device used. PMID- 24495945 TI - Wear behavior between zirconia and titanium as an antagonist on fixed dental prostheses. AB - The aim of this in vitro study was to investigate the wear behavior of the abrader when tetragonal zirconia polycrystal (TZP), cp-titanium (CpTi) and Ti-6Al 4V alloy (TiAlV) were used as the antagonist on fixed dental prostheses (FDPs). Both hemisphere abrader and flat substrate specimens were prepared using TZP, CpTi and TiAlV. Two-body wear tests were performed in distilled water, and the wear volume of the abrader specimen was measured to evaluate the wear behavior. In addition, scanning microscopic observation and an electron probe micro analysis were performed to elucidate the underlying mechanism of the wear. The wear volume of CpTi and TiAlV abrader specimens was approximately 20 times larger than that of TZP abrader specimen against all substrate specimens. This is due to the differences in hardness between the ultra-hardness of TZP and the comparatively low hardness of CpTi and TiAlV. The wear volume of CpTi and TiAlV abrader specimens against the TZP substrate was significantly smaller than for the CpTi and TiAlV substrates despite the hardness of TZP being much larger than those of CpTi and TiAlV. This phenomenon may be based on the adhesive wear mechanism. Elements of Ti, Al and V originating in the TiAlV substrate were detected adhering to the abrader CpTi specimen. These results suggest that FDPs of CpTi and TiAlV are susceptible to wear against not only TZP but also CpTi and TiAlV in contrast to TZP FDPs. PMID- 24495946 TI - Chronic domiciliary oxygen therapy-year SEPAR. PMID- 24495947 TI - Idiopathic plastic bronchitis as an uncommon cause of massive pulmonary atelectasis. PMID- 24495948 TI - Unusual sinonasal foreign body: presentation of three cases. AB - Sinonasal foreign bodies are rare clinical entities. Their presence in the sinuses can originate complications, so their removal is always indicated. We present 3 cases of sinonasal foreign body, indicating their symptoms, imaging findings and surgical removal. Each patient was assessed with computerized tomography of the sinuses, rigid endoscopy, and then surgical removal. We confirmed the presence of the foreign bodies in all 3 cases and then performed a successful surgical removal by transnasal endoscopy. Sinonasal foreign bodies are infrequent entities that require surgical removal to prevent complications, with transnasal endoscopic surgery being the most commonly used surgical approach. PMID- 24495949 TI - Neuroprotective effects of the cannabinoid agonist HU210 on retinal degeneration. AB - Cannabinoids have been demonstrated to exert neuroprotective effects on different types of neuronal insults. Here we have addressed the therapeutic potential of the synthetic cannabinoid HU210 on photoreceptor degeneration, synaptic connectivity and functional activity of the retina in the transgenic P23H rat, an animal model for autosomal dominant retinitis pigmentosa (RP). In P23H rats administered with HU210 (100 MUg/kg, i.p.) from P24 to P90, ERG recordings showed an amelioration of vision loss, as compared to vehicle-administered animals. Under scotopic conditions, the maximum a-wave amplitudes recorded at P60 and P90 were higher in HU210-treated animals, as compared to the values obtained in untreated animals. The scotopic b-waves were significantly higher in treated animals than in untreated rats at P30, P60 and P90. This attenuation of visual deterioration correlated with a delay in photoreceptor degeneration and the preservation of retinal cytoarchitecture. HU210-treated animals had 40% more photoreceptors than untreated animals. Presynaptic and postsynaptic elements, as well as the synaptic contacts between photoreceptors and bipolar or horizontal cells, were also preserved in HU210-treated P23H rats. These results indicate that HU210 preserves cone and rod structure and function, together with their contacts with postsynaptic neurons, in P23H rats. These data suggest that cannabinoids are potentially useful to delay retinal degeneration in RP patients. PMID- 24495950 TI - Human recombinant lysozyme downregulates advanced glycation endproduct-induced interleukin-6 production and release in an in-vitro model of human proximal tubular epithelial cells. AB - Diabetic nephropathy is the leading cause of chronic renal disease and one of the major causes of cardiovascular mortality. Evidence suggests that its progression is due to the chronic hyperglycemia consequent to the production and accumulation of advanced glycation endproducts (AGEs). Lysozyme was shown to posses AGE sequestering properties and the capacity to reduce the severity of the early stage manifestations of the diabetic nephropathy. This study was aimed to contribute to the understanding the molecular mechanisms of lysozyme effectiveness in the diabetic nephropathy, using an in-vitro cellular model, represented by the HK-2 cells, human proximal tubular epithelial cells. Lysozyme significantly reduced the AGE-induced IL-6 mRNA and an ELISA assay showed also a decreased release of the functional protein with a dose-dependent trend. In addition, lysozyme prevented macrophage recruitment, suggesting its capacity to elicit an anti-inflammatory action. We may conclude that the protective action of lysozyme on the nephrotoxic effects of AGE may depend, at least in part, on its ability to prevent the production and release of inflammatory mediators, such as IL-6 and to reduce macrophage recruitment in the inflammatory sites. PMID- 24495952 TI - Histone acetylation and expression of mono-aminergic transmitters synthetases involved in CUS-induced depressive rats. AB - Histone acetylation has been linked to depression, the etiology of which involves many factors such as genetics, environments, and epigenetics. The aim of the present study was to investigate whether it was associated with epigenetic histone modification and gene expression of enzymes responsible for the biosynthesis of norepinephrine and serotonin in rat depression model induced by chronic unpredictable stress (CUS). Eight-week-old male Sprague-Dawley rats were exposed to CUS over 28 days. It was shown that the CUS-induced rats displayed remarked anxiety- and depression-like behavior with weakened locomotor activity in open field test and prolonged immobility in forced swimming test. Western blot revealed that CUS led to significant decrease in acetylation of H3 at Lysine 9 (K9) and H4 at Lysine 12 (K12) with obviously increasing histone deacetylases 5 (HDAC5) expression in hippocampus of CUS-induced rats. Meanwhile, there was an obviously decreased expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH) both at protein and mRNA levels. Administration of sodium valproate (VPA), a histone deacetylase 5 (HDAC5) inhibitor, not only significantly relieved the anxiety- and depression-like behaviors of CUS-induced rats but also clearly blunted decrease of H3(K9) and H4(K12) acetylation and expression of TH and TPH, and prevented increase of HDAC5 expression. The results indicate that there exists possible interrelation between TH and TPH gene expression and epigenetic histone acetylation in CUS-induced depressive rats, which at least partly contributes to the etiology of depression. PMID- 24495953 TI - Detection of four important Eimeria species by multiplex PCR in a single assay. AB - The oocysts of some of the recognized species of chicken coccidiosis are difficult to distinguish morphologically. Diagnostic laboratories are increasingly utilizing DNA-based technologies for the specific identification of Eimeria species. This study reports a multiplex polymerase chain reaction (PCR) assay based on internal transcribed spacer-1 (ITS-1) for the simultaneous diagnosis of the Eimeria tenella, Eimeria acervulina, Eimeria maxima, and Eimeria necatrix species, which infect domestic fowl. Primer pairs specific to each species were designed in order to generate a ladder of amplification products ranging from 20 to 25 bp, and a common optimum annealing temperature for these species was determined to be 52.5 degrees C. Sensitivity tests were performed for each species, showing a detection threshold of 1-5 pg. All the species were amplified homogeneously, and a homogenous band ladder was observed, indicating that the assay permitted the simultaneous detection of all the species in a single-tube reaction. In the phylogenic study, there was a clear species clustering, which was irrespective of geographical location, for all the ITS-1 sequences used. This multiplex PCR assay represents a rapid and potential cost effective diagnostic method for the detection of some key Eimeria species that infect domestic fowl. PMID- 24495951 TI - Colon cancer cell apoptosis is induced by combined exposure to the n-3 fatty acid docosahexaenoic acid and butyrate through promoter methylation. AB - DNA methylation and histone acetylation contribute to the transcriptional regulation of genes involved in apoptosis. We have demonstrated that docosahexaenoic acid (DHA, 22:6 n-3) and butyrate enhance colonocyte apoptosis. To determine if DHA and/or butyrate elevate apoptosis through epigenetic mechanisms thereby restoring the transcription of apoptosis-related genes, we examined global methylation; gene-specific promoter methylation of 24 apoptosis related genes; transcription levels of Cideb, Dapk1, and Tnfrsf25; and global histone acetylation in the HCT-116 colon cancer cell line. Cells were treated with combinations of (50 uM) DHA or linoleic acid (18:2 n-6), (5 mM) butyrate or an inhibitor of DNA methyltransferases, and 5-aza-2'-deoxycytidine (5-Aza-dC, 2 uM). Among highly methylated genes, the combination of DHA and butyrate significantly reduced methylation of the proapoptotic Bcl2l11, Cideb, Dapk1, Ltbr, and Tnfrsf25 genes compared to untreated control cells. DHA treatment reduced the methylation of Cideb, Dapk1, and Tnfrsf25. These data suggest that the induction of apoptosis by DHA and butyrate is mediated, in part, through changes in the methylation state of apoptosis-related genes. PMID- 24495956 TI - Iona Heath: not keen on posh boys. PMID- 24495955 TI - Polarity of water transport across epidermal cell membranes in Tradescantia virginiana. AB - Using the automated cell pressure probe, small and highly reproducible hydrostatic pressure clamp (PC) and pressure relaxation (PR) tests (typically, applied step change in pressure = 0.02 MPa and overall change in volume = 30 pL, respectively) were applied to individual Tradescantia virginiana epidermal cells to determine both exosmotic and endosmotic hydraulic conductivity (L(p)(OUT) and L(p)(IN), respectively). Within-cell reproducibility of measured hydraulic parameters depended on the method used, with the PR method giving a lower average coefficient of variation (15.2%, 5.8%, and 19.0% for half-time, cell volume [V(o)], and hydraulic conductivity [L(p)], respectively) than the PC method (25.4%, 22.0%, and 24.2%, respectively). V(o) as determined from PC and PR tests was 1.1 to 2.7 nL and in the range of optically estimated V(o) values of 1.5 to 4.9 nL. For the same cell, V(o) and L(p) estimates were significantly lower (about 15% and 30%, respectively) when determined by PC compared with PR. Both methods, however, showed significantly higher L(p)(OUT) than L(p)(IN) (L(p)(OUT)/L(p)(IN) ? 1.20). Because these results were obtained using small and reversible hydrostatically driven flows in the same cell, the 20% outward biased polarity of water transport is most likely not due to artifacts associated with unstirred layers or to direct effects of externally applied osmotica on the membrane, as has been suggested in previous studies. The rapid reversibility of applied flow direction, particularly for the PR method, and the lack of a clear increase in L(p)(OUT)/L(p)(IN) over a wide range of L(p) values suggest that the observed polarity is an intrinsic biophysical property of the intact membrane/protein complex. PMID- 24495954 TI - Emerging roles of Jab1/CSN5 in DNA damage response, DNA repair, and cancer. AB - Jab1/CSN5 is a multifunctional protein that plays an important role in integrin signaling, cell proliferation, apoptosis, and the regulation of genomic instability and DNA repair. Dysregulation of Jab1/CSN5 activity has been shown to contribute to oncogenesis by functionally inactivating several key negative regulatory proteins and tumor suppressors. In this review, we discuss our current understanding of the relationship between Jab1/CSN5 and DNA damage and summarize recent findings regarding opportunities for and challenges to therapeutic intervention. PMID- 24495957 TI - Terpenoid indole alkaloids from Mappianthus iodoides Hand.-Mazz. AB - Ten terpenoid indole alkaloids, mappiodines A-C and mappiodosides A-G, together with eight known compounds, were isolated from stems of Mappianthus iodoides Hand.-Mazz. Their structures were elucidated by spectroscopic analyses including 1D, 2D NMR, MS and CD methods. The ten compounds were evaluated for their cytotoxic activity, but were inactive. PMID- 24495958 TI - Occupational heat strain in a hot underground metal mine. AB - OBJECTIVE: In a hot underground metal mine, this study evaluated the relationship between job task, physical body type, work shift, and heat strain. METHODS: Thirty-one miners were evaluated during 98 shifts while performing deep shaft sinking tasks. Continuous core body temperature, heart rate, pre- and postshift urine specific gravity (USG), and body mass index were measured. RESULTS: Cutting and welding tasks were associated with significantly (P < 0.05) increased core body temperature, maximum heart rate, and increased postshift urine specific gravity. Miners in the obese level II and III body mass index categories, as well as those working night shift, had lower core body temperatures (P < 0.05). CONCLUSIONS: This study confirms that job task, body type, and shift are risk factors for heat strain. PMID- 24495959 TI - A quality study to improve prophylactic antithrombotic therapy prescribed to patients with atrial fibrillation. AB - INTRODUCTION: Atrial fibrillation is the most common cardiac arrhythmia and has important clinical repercussions, increasing thromboembolic events and mortality. The CHA2DS2-VASc and HAS-BLED scores assist the clinician in assessing the benefits and risks of antithrombotic therapy. OBJECTIVE: The aim of this study was to assess and improve the quality of prophylactic antithrombotic therapy prescribed to patients with atrial fibrillation. METHODS: This was a quality study, based on a cycle of assessment and improvement, applied to the population of a family health unit, consisting of an initial assessment, an educational intervention and a second assessment. Both scores were calculated for all patients. Whenever the CHA2DS2-VASc score recommended initiation of anticoagulation, the risk was calculated by the HAS-BLED score; it was thus possible to determine for each patient if the prescribed therapy was appropriate. RESULTS: The first assessment included 105 patients, of whom 49.5% had appropriate prophylactic therapy according to their scores. In the second assessment, four months after the educational intervention, 60.0% had been prescribed appropriate therapy, which represented a 21.2% improvement. CONCLUSIONS: In both assessments, inappropriate treatment was due to non prescription of prophylactic oral anticoagulation. This quality cycle serves as a tool for continuous assessment in the pursuit of improved care for patients with atrial fibrillation. PMID- 24495960 TI - All questions. PMID- 24495961 TI - Impressed with InSHAPE program. PMID- 24495964 TI - Drugs to treat hypertension. PMID- 24495968 TI - Higher anxiety and larger amygdala volumes in carriers of a TMEM132D risk variant for panic disorder. PMID- 24495967 TI - Common polymorphisms in dopamine-related genes combine to produce a 'schizophrenia-like' prefrontal hypoactivity. AB - Individual changes in dopamine-related genes influence prefrontal activity during cognitive-affective processes; however, the extent to which common genetic variations combine to influence prefrontal activity is unknown. We assessed catechol-O-methyltransferase (COMT) Val108/158Met (rs4680) and dopamine D2 receptor (DRD2) G-T (rs2283265) single nucleotide polymorphisms and functional magnetic resonance imaging during an emotional response inhibition test in 43 healthy adults and 27 people with schizophrenia to determine the extent to which COMT Val108/158Met and DRD2 G-T polymorphisms combine to influence prefrontal response to cognitive-affective challenges. We found an increased number of cognitive-deficit risk alleles in these two dopamine-regulating genes predict reduced prefrontal activation during response inhibition in healthy adults, mimicking schizophrenia-like prefrontal hypoactivity. Our study provides evidence that functionally related genes can combine to produce a disease-like endophenotype. PMID- 24495970 TI - Single incision retro-peritoneoscopic paediatric nephrectomy: early experience. AB - Single incision, single port, or single site surgery for retro-peritoneoscopic nephrectomy and nephro-ureterectomy in paediatric practice using an advanced access platform (GelPOINT Mini) is described in two patients. One patient had bilateral synchronous nephrectomy. The technique, advantages, and challenges are reported. Beyond the initial hurdles and learning curve, this technique is promising and has the potential to be extended to other procedures in paediatric urology. PMID- 24495969 TI - Follow-up of loci from the International Genomics of Alzheimer's Disease Project identifies TRIP4 as a novel susceptibility gene. AB - To follow-up loci discovered by the International Genomics of Alzheimer's Disease Project, we attempted independent replication of 19 single nucleotide polymorphisms (SNPs) in a large Spanish sample (Fundacio ACE data set; 1808 patients and 2564 controls). Our results corroborate association with four SNPs located in the genes INPP5D, MEF2C, ZCWPW1 and FERMT2, respectively. Of these, ZCWPW1 was the only SNP to withstand correction for multiple testing (P=0.000655). Furthermore, we identify TRIP4 (rs74615166) as a novel genome-wide significant locus for Alzheimer's disease risk (odds ratio=1.31; confidence interval 95% (1.19-1.44); P=9.74 * 10(-)(9)). PMID- 24495971 TI - Surgical complications and graft function following live-donor extraperitoneal renal transplantation in children 20 kg or less. AB - OBJECTIVES: To evaluate the effect of patient, surgical, and medical factors on surgical complications and graft function following renal transplantation (Tx) in children weighing <= 20 kg, because the number of this challenging group of children is increasing. PATIENTS AND METHODS: Between June 2009 and October 2013, 26 patients received living donor renal allotransplant using the extraperitoneal approach (EPA). The immunosuppression regimen was composed of prednisolone, mycophenolate mofetil, and ciclosporin or tacrolimus. RESULTS: The mean weight was 16.46 +/- 2.61 kg. Mean cold ischemia time was 53.85 +/- 12.35 min. The graft survival rate (GSR) and patient survival rate (PSR) were 96% at 3 years. Acute rejection episodes (AREs) occurred in eight patients (30%). Postoperative surgical complications were ureteral leakage (3), vesicoureteric reflux (2), and renal vein thrombosis (2) (with one graft nephrectomy). Mean follow-up was 37.5 +/- 7.4 months. CONCLUSION: Excellent PSR and GSR can be achieved in low weight (<20 kg) recipients. Even in very low weight patients, the EPA was used. No cases were reported with primary graft non-function due to use of living donors, increasing pre-Tx body weight to at least 10 kg and maintaining adequate filling pressure before graft reperfusion. The presence of related donors and use of induction therapy and tacrolimus decreased the rate of ARE while the presence of pre-Tx lower urinary tract surgical interventions increased the rate of ureteric complications, but this was statistically insignificant. PMID- 24495972 TI - Tailless and Atrophin control Drosophila aggression by regulating neuropeptide signalling in the pars intercerebralis. AB - Aggressive behaviour is widespread throughout the animal kingdom. However, its mechanisms are poorly understood, and the degree of molecular conservation between distantly related species is unknown. Here we show that knockdown of tailless (tll) increases aggression in Drosophila, similar to the effect of its mouse orthologue Nr2e1. Tll localizes to the adult pars intercerebralis (PI), which shows similarity to the mammalian hypothalamus. Knockdown of tll in the PI is sufficient to increase aggression and is rescued by co-expressing human NR2E1. Knockdown of Atrophin, a Tll co-repressor, also increases aggression, and both proteins physically interact in the PI. tll knockdown-induced aggression is fully suppressed by blocking neuropeptide processing or release from the PI. In addition, genetically activating PI neurons increases aggression, mimicking the aggression-inducing effect of hypothalamic stimulation. Together, our results suggest that a transcriptional control module regulates neuropeptide signalling from the neurosecretory cells of the brain to control aggressive behaviour. PMID- 24495973 TI - Low-frequency stimulation of dorsal norephinephrine bundle reverses behavioral long-term potentiation and learning performance in rats. AB - Dorsal norepinephrine bundle (DNEB) is the major source of noradrenergic input to the hippocampus and norepinephrine could regulate long-term potentiation (LTP) reversal. In the present study, we investigated the effects of low-frequency stimulation (LFS) of DNEB on behavioral LTP and Y-maze learning task, by using electrophysiological recording in freely moving rats combined with behavioral tests. We found that LFS on DNEB, including 1 and 5Hz, could inhibit reversibly basal synaptic transmission within 100-min recordings in hippocampal perforant path projections to dentate gyrus (PP-DG) pathway. 1-Hz stimulating DNEB, delivered 5min after the daily training session, reverses behavioral LTP completely and depresses the behavioral learning as well. However, 5-Hz-treated only reverses behavioral LTP partially and reduces the behavioral learning accordingly. These results indicate that behavioral LTP in PP-DG pathway can be reversed by LFS on DNEB, and display a similar impact on Y-maze learning performance. Our data provide a new characterization of LTP reversibility and will ultimately be helpful in understanding how new information is to detect and determine storage in the hippocampus. PMID- 24495975 TI - Disseminated cryptococcosis involving the head and neck. AB - A middle-aged patient with HIV presented with very distinctive maculopapular cutaneous lesions involving the face and lymphadenopathy confined to the neck. A diagnosis of disseminated cryptococcosis was made based on pathological analysis of lymph node and skin lesions. PMID- 24495974 TI - Intradural extramedullary and intracranial tuberculomas with concurrent communicating syringomyelia. AB - Tuberculosis is the most common chronic central nervous system infection in developing countries like India. Non-osseous spinal cord involvement is a rare manifestation of tuberculosis. The use of MRI, as an imaging modality of choice, has revolutionised the imaging of tuberculomas with reasonable certainty and thereby avoiding unnecessary surgical intervention. We report an unusual presentation of intradural extramedullary and intracranial tuberculomas with communicating syringomyelia complicated with tubercular meningitis. PMID- 24495976 TI - Unidentified intralesional and intracellular coccoid microorganism discovered in the young man with a diffuse erosive gastroduodenitis and multiple superficial ulcerations. AB - A Helicobacter pylori-negative young Japanese man with dyspeptic symptoms suffered from a diffuse erosive gastroduodenitis and multiple superficial ulcerations. Histology and electron microscopic examinations on the biopsy specimens revealed the presence of multiple unidentified intralesional and intracellular coccoid microorganisms in the pathological gastroduodenal mucosa. Microaerophilic and anaerobic Gram-negative coccoid and filamentobacillary bacteria were cultured from the gastric aspirate. The triple therapy containing tetracycline for 14 days followed by 4 months treatment with omeprazole resulted in the resolution of the gastroduodenal pathology. The question, therefore, was raised regarding a possible role for the cultured coccoid bacteria in the pathogenesis. 16S rRNA gene sequence analysis of the isolated Gram-negative coccoid bacteria revealed a close relationship with Haemophilus haemolyticus. The unidentified coccoid microorganisms and cultured X and V factors independent coccoid bacteria, however, shared similar phenotypic, microbiological and pathological characteristics to the novel Gram-negative Streptococcaceae: Okadaella gastrococcus. PMID- 24495977 TI - Loeys-Dietz syndrome: life threatening aortic dissection diagnosed on routine family screening. AB - A 52-year-old man was found to have a severely dilated aortic root and a Stanford type A dissection on familial screening echocardiography, following diagnosis of a dilated aorta in his son. The dissection required urgent surgical repair. Clinical examination suggested features of Loeys-Dietz syndrome type II, and subsequent demonstration of a mutation in the TGFBR1 gene in the patient and his son confirmed the diagnosis. This article highlights the high prevalence of inherited conditions in dilated aortic root presentations and the importance of family screening and surveillance to allow early surgical intervention. PMID- 24495978 TI - A Trojan horse saddle stuck in the lung. PMID- 24495979 TI - Stellated Ag-Pt bimetallic nanoparticles: an effective platform for catalytic activity tuning. AB - The usefulness of Pt-based nanomaterials for catalysis can be greatly enhanced by coupling morphology engineering to the strategic presence of a second or even third metal. Here we demonstrate the design and preparation of stellated Ag-Pt bimetallic nanoparticles where significant activity difference between the methanol oxidation reaction (MOR) and the oxygen reduction reaction (ORR) may be realized by relegating Ag to the core or by hollowing out the core. In particular the stellated Pt surface, with an abundance of steps, edges, corner atoms, and {111} facets, is highly effective for the ORR but is ineffective for MOR. MOR activity is only observed in the presence of a Ag core through electronic coupling to the stellated Pt shell. The bimetallic Ag-Pt stellates therefore demonstrate the feasibility of tuning a Pt surface for two very different structure sensitive catalytic reactions. Stellated bimetallics may therefore be an effective platform for highly tunable catalyst designs. PMID- 24495980 TI - Making a big thing of a small cell--recent advances in single cell analysis. AB - Single cell analysis is an emerging field requiring a high level interdisciplinary collaboration to provide detailed insights into the complex organisation, function and heterogeneity of life. This review is addressed to life science researchers as well as researchers developing novel technologies. It covers all aspects of the characterisation of single cells (with a special focus on mammalian cells) from morphology to genetics and different omics-techniques to physiological, mechanical and electrical methods. In recent years, tremendous advances have been achieved in all fields of single cell analysis: (1) improved spatial and temporal resolution of imaging techniques to enable the tracking of single molecule dynamics within single cells; (2) increased throughput to reveal unexpected heterogeneity between different individual cells raising the question what characterizes a cell type and what is just natural biological variation; and (3) emerging multimodal approaches trying to bring together information from complementary techniques paving the way for a deeper understanding of the complexity of biological processes. This review also covers the first successful translations of single cell analysis methods to diagnostic applications in the field of tumour research (especially circulating tumour cells), regenerative medicine, drug discovery and immunology. PMID- 24495981 TI - Biocompatible high performance hyperbranched epoxy/clay nanocomposite as an implantable material. AB - Polymeric biomaterials are in extensive use in the domain of tissue engineering and regenerative medicine. High performance hyperbranched epoxy is projected here as a potential biomaterial for tissue regeneration. Thermosetting hyperbranched epoxy nanocomposites were prepared with Homalomena aromatica rhizome oil-modified bentonite as well as organically modified montmorillonite clay. Fourier transformed infrared spectroscopy, x-ray diffraction and scanning and transmission electron microscopic techniques confirmed the strong interfacial interaction of clay layers with the epoxy matrix. The poly(amido amine)-cured thermosetting nanocomposites exhibited high mechanical properties like impact resistance (>100 cm), scratch hardness (>10 kg), tensile strength (48-58 MPa) and elongation at break (11.9-16.6%). Cytocompatibility of the thermosets was found to be excellent as evident by MTT and red blood cell hemolytic assays. The nanocomposites exhibited antimicrobial activity against Staphylococcus aureus (ATCC 11632), Escherichia coli (ATCC 10536), Mycobacterium smegmatis (ATCC14468) and Candida albicans (ATCC 10231) strains. In vivo biocompatibility of the best performing nanocomposite was ascertained by histopathological study of the brain, heart, liver and skin after subcutaneous implantation in Wistar rats. The material supported the proliferation of dermatocytes without induction of any sign of toxicity to the above organs. The adherence and proliferation of cells endorse the nanocomposite as a non-toxic biomaterial for tissue regeneration. PMID- 24495982 TI - Risk of stroke in patients with patent foramen ovale: an updated meta-analysis of observational studies. AB - BACKGROUND: Although patent foramen ovale (PFO) is considered to be associated with cryptogenic stroke (CS), there remains an ongoing disputation on this issue because of unstable results from randomized controlled trials. The aim of this study was to reassess the PFO effect on stroke through observational data. METHODS: An electronic search of PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) were finished. Only case-control studies and cohort studies in Chinese or English were included in the analysis. Then random effected meta-analysis models were performed to assess the association between PFO and stroke. RESULTS: Twelve case-control studies and 6 cohort studies were eligible. Case-control studies showed strong association between PFO and CS (odds ratio [OR]: 2.94, 95% confidence interval [CI]: 2.06, 4.20; P < .001), but cohort studies failed to demonstrate a significant association (hazard ratio [HR]: 1.28, 95% CI: .91, 1.80; P = .155). Subgroup analysis revealed that the pooled OR decreased significantly when the region was limited to the United States (OR: 1.52, 95% CI: 1.00, 2.32; P = .083). OR of studies that adjusted major confounders was 1.74 (95% CI: 1.22, 2.47; P = .119) and high-quality studies was 1.68 (95% CI: 1.14, 2.47; P = .072). For cohort studies, a weak statistical association was observed in using transesophageal echocardiography (TEE) studies (HR: 1.45, 95% CI: 1.06, 2.01; P = .138) and follow-up years less than 4 years' studies (HR: 1.45, 95% CI: 1.00, 2.09; P = .064). CONCLUSIONS: Although case control studies still show a positive effect of PFO on stroke, the results of cohort challenged the credibility. Further trial data are needed to confirm the effect of PFO on stroke. PMID- 24495984 TI - Public health and pipe breaks in water distribution systems: analysis with internet search volume as a proxy. AB - Drinking water distribution infrastructure has been identified as a factor in waterborne disease outbreaks and improved understanding of the public health risks associated with distribution system failures has been identified as a priority area for research. Pipe breaks may pose a risk, as their occurrence and repair can result in low or negative pressure, potentially allowing contamination of drinking water from adjacent soils. However, measuring this phenomenon is challenging because the most likely health impact is mild gastrointestinal (GI) illness, which is unlikely to result in a doctor or hospital visit. Here we present a novel method that uses data mining techniques and internet search volume to assess the relationship between pipe breaks and symptoms of GI illness in two U.S. cities. Weekly search volume for the terms diarrhea and vomiting was used as the response variable with the number of pipe breaks in each city as a covariate as well as additional covariates to control for seasonal patterns, search volume persistence, and other sources of GI illness. The fit and predictive accuracy of multiple regression and data mining techniques were compared, with the best performance obtained using random forest and bagged regression tree models. Pipe breaks were found to be an important and positively correlated predictor of internet search volume in multiple models in both cities, supporting previous investigations that indicated an increased risk of GI illness from distribution system disturbances. PMID- 24495983 TI - Incremental learning with selective memory (ILSM): towards fast prostate localization for image guided radiotherapy. AB - Image-guided radiotherapy (IGRT) requires fast and accurate localization of the prostate in 3-D treatment-guided radiotherapy, which is challenging due to low tissue contrast and large anatomical variation across patients. On the other hand, the IGRT workflow involves collecting a series of computed tomography (CT) images from the same patient under treatment. These images contain valuable patient-specific information yet are often neglected by previous works. In this paper, we propose a novel learning framework, namely incremental learning with selective memory (ILSM), to effectively learn the patient-specific appearance characteristics from these patient-specific images. Specifically, starting with a population-based discriminative appearance model, ILSM aims to "personalize" the model to fit patient-specific appearance characteristics. The model is personalized with two steps: backward pruning that discards obsolete population based knowledge and forward learning that incorporates patient-specific characteristics. By effectively combining the patient-specific characteristics with the general population statistics, the incrementally learned appearance model can localize the prostate of a specific patient much more accurately. This work has three contributions: 1) the proposed incremental learning framework can capture patient-specific characteristics more effectively, compared to traditional learning schemes, such as pure patient-specific learning, population based learning, and mixture learning with patient-specific and population data; 2) this learning framework does not have any parametric model assumption, hence, allowing the adoption of any discriminative classifier; and 3) using ILSM, we can localize the prostate in treatment CTs accurately (DSC ~ 0.89 ) and fast ( ~ 4 s), which satisfies the real-world clinical requirements of IGRT. PMID- 24495985 TI - Adhesion of bacterial pathogens to soil colloidal particles: influences of cell type, natural organic matter, and solution chemistry. AB - Bacterial adhesion to granular soil particles is well studied; however, pathogen interactions with naturally occurring colloidal particles (<2 MUm) in soil has not been investigated. This study was developed to identify the interaction mechanisms between model bacterial pathogens and soil colloids as a function of cell type, natural organic matter (NOM), and solution chemistry. Specifically, batch adhesion experiments were conducted using NOM-present, NOM-stripped soil colloids, Streptococcus suis SC05 and Escherichia coli WH09 over a wide range of solution pH (4.0-9.0) and ionic strength (IS, 1-100 mM KCl). Cell characterization techniques, Freundlich isotherm, and Derjaguin-Landau-Verwey Overbeek (DLVO) theory (sphere-sphere model) were utilized to quantitatively determine the interactions between cells and colloids. The adhesion coefficients (Kf) of S. suis SC05 to NOM-present and NOM-stripped soil colloids were significantly higher than E. coli WH09, respectively. Similarly, Kf values of S. suis SC05 and E. coli WH09 adhesion to NOM-stripped soil colloids were greater than those colloids with NOM-present, respectively, suggesting NOM inhibits bacterial adhesion. Cell adhesion to soil colloids declined with increasing pH and enhanced with rising IS (1-50 mM). Interaction energy calculations indicate these adhesion trends can be explained by DLVO-type forces, with S. suis SC05 and E. coli WH09 being weakly adhered in shallow secondary energy minima via polymer bridging and charge heterogeneity. S. suis SC05 adhesion decreased at higher IS 100 mM, which is attributed to the change of hydrophobic effect and steric repulsion resulted from the greater presence of extracellular polymeric substances (EPS) on S. suis SC05 surface as compared to E. coli WH09. Hence, pathogen adhesion to the colloidal material is determined by a combination of DLVO, charge heterogeneity, hydrophobic and polymer interactions as a function of solution chemistry. PMID- 24495986 TI - A two-site chlorine decay model for the combined effects of pH, water distribution temperature and in-home heating profiles using differential evolution. AB - A general framework for modeling the bulk chlorine decay that accommodates effects of pH, temperature in water distribution system and in-home heating profiles is developed. With a single set of readily interpreted parameters, and various fictive concentrations of reactive constituents in the water, chlorine decay for the different water systems could be simultaneously modeled. Differential Evolution is employed to estimate the parameters stochastically. By using Bayesian Information Criterion, it is shown that a model consisting of two reactive species is preferred over models that consist of one or three reactive species. The flexibility and power of the framework is demonstrated with a case study of both types of effects. PMID- 24495987 TI - Complaining and the management of face in online counseling. AB - In this article, we analyze how clients in online counseling by email do complaining. Complaining is a "face-threatening act" and can jeopardize the relationship between interlocutors. In online health interventions, we see high dropout rates. We suggest that because the interaction between client and counselor is at the basis of counseling, it is important to understand how a communicative act (e.g., a complaint) that signals potential dropout is constructed sequentially. Based on a corpus of 20 email exchanges, we illustrate how clients constructed complaints over several sentences and sometimes various emails, and how they designed the complaints to minimize threat to the counselor's face. Counselors, in their responses, used various strategies to manage face threats. We show how complaints were mitigated to protect the counseling relationship and suggest that this is useful knowledge for health professionals. PMID- 24495988 TI - Paramedics' experiences and coping strategies when encountering critical incidents. AB - Paramedics frequently encounter critical incidents (CIs). Their emotional, cognitive, and behavioral responses to these encounters present them with a variety of difficulties on the way to, during, and after events. The aim of our study was to examine how paramedics working in a large emergency service organization in Israel experienced CIs and the coping strategies they used to deal with these experiences. We interviewed 15 paramedics from this organization. Through data analysis, we revealed two main themes: (1) between connection and detachment and (2) between control and lack of control of the situation. Paramedics, who connected with their feelings regarding the patient and/or the family in different CIs, as well as those who sensed a lack of control, experienced difficult and negative emotions. To achieve detachment, they used a variety of coping strategies. Those who experienced cognitive and functional control of the situation reported a positive and empowering experience. PMID- 24495989 TI - Constant negotiating: managing work-related musculoskeletal disorders while remaining at the workplace. AB - We used grounded theory to explore processes and strategies used by workers affected by work-related musculoskeletal disorders (WMSDs) while they remained in the workplace, and we developed a theory to describe the overall process. Participants included 25 workers affected by WMSDs who were currently employed in various workplaces in Newfoundland and Labrador, Canada. The theoretical model has five main phases: (a) becoming concerned, (b) getting medical help, (c) dealing with the workplace, (d) making adjustments to lifestyle, and (e) taking charge, each with separate subphases. Constant negotiating was the core variable that explained the overall process, with workers engaged in negotiations with others in occupational, health, and social contexts. Using a two-dimensional figure, we illustrate the negotiation strategies workers used. We discuss implications for health care, workplaces, education, and research for creating a culture of understanding and respect for injured workers who wish to remain working after developing WMSDs. PMID- 24495990 TI - Negotiating parental accountability in the face of uncertainty for attention deficit hyperactivity disorder. AB - Despite extensive research into attention-deficit hyperactivity disorder (ADHD), parents' constructions of their children's behaviors have received limited attention. This is particularly true outside North American contexts, where ADHD is less established historically. Our research demonstrates how United Kingdom parents made sense of ADHD and their own identities postdiagnosis. Using discourse analysis from interviews with 12 parents, we show that they drew from biological and social environmental repertoires when talking about their child's condition, paralleling repertoires found circulating in the United Kingdom media. However, in the context of parental narratives, both these repertoires were difficult for parents to support and involved problematic subject positions for parental accountability in the child's behavior. In this article we focus on the strategies parents used to negotiate these troublesome identities and construct accounts of moral and legitimate parenting in a context in which uncertainties surrounding ADHD existed and parenting was scrutinized. PMID- 24495991 TI - Explaining sex differences in reactions to relationship infidelities: comparisons of the roles of sex, gender, beliefs, attachment, and sociosexual orientation. AB - To the extent that sex differences are mediated by mechanisms such as sex-roles and beliefs, individual differences in these more proximate traits should account for significant portions of relevant sex differences. Differences between women and men in reactions to sexual and emotional infidelity were assessed in a large sample of participants (n = 477), and these target reactions were evaluated as a function of many potential proximate mediators (infidelity implications beliefs, gender-role beliefs, interpersonal trust, attachment style, sociosexuality, and culture of honor beliefs) and as a function of participant sex. Results found a consistent sex difference that was not mediated by any other variables, although a handful of other variables were related to male, but not female, individual differences. These findings suggest particularly promising directions for future research on integrating evolutionarily based sex differences and proximate individual differences. PMID- 24495992 TI - A novel approach to gradual correction of severe spinal deformity in a pediatric patient using the magnetically-controlled growing rod. AB - BACKGROUND CONTEXT: Acute correction of severe spinal deformities significantly increases the risk of neurologic complications. Previously used methods to safely correct these deformities include halo-traction devices and internal distraction rods. PURPOSE: This report introduces a novel method for gradual correction of severe spinal deformity by using the magnetically controlled growing rod (MCGR). STUDY DESIGN: This is a case report. METHODS: A 12-year-old girl with severe kyphoscoliosis and concurrent syringomyelia and Arnold-Chiari Type I malformation underwent implantation of the MCGR. After implantation of the device, daily distractions of the implant were performed over the course of 2.5 months. RESULTS: The patient underwent MCGR implantation without acute correction of her left-sided thoracic scoliosis (109 degrees from T6 to T11) and upper thoracic kyphosis (72 degrees ). After 2.5 months of daily distractions in the ward, the scoliosis improved to 66 degrees and the kyphosis to 62 degrees . Final fusion was performed without problems, and her overall truncal balance was much improved. CONCLUSIONS: This report is the first to note the safety and efficacy of the MCGR in treating young patients with severe spinal deformities. This technique allows correction of the deformity while the patient is awake so that neurology can be continuously monitored. The patient is also ambulatory throughout the distraction process and can be distracted on an outpatient basis. Repeated surgery can be avoided, and the MCGR has been shown to be safe and effective with this case illustration. PMID- 24495993 TI - The role of dietary fat on the association between dietary amino acids and serum lipid profile in European adolescents participating in the HELENA Study. AB - BACKGROUND/OBJECTIVES: The objective of this study was to examine the relationship between amino acid (AA) intake and serum lipid profile in European adolescents from eight European cities participating in the cross-sectional (2006 2007) HELENA (Healthy Lifestyle in Europe by Nutrition in Adolescence) study, and to assess whether this association was independent of total fat intake. SUBJECTS/METHODS: Diet, skinfold thickness, triglycerides (TG), total cholesterol (TC), high-density lipoprotein cholesterol (HDL-c), TC/HDL-c ratio, low-density lipoprotein cholesterol (LDL-c), apolipoprotein B (Apo B), apolipoprotein A1 (Apo A1) and Apo B/Apo A1 ratio were measured in 454 12.5- to 17.5-year-old adolescents (44% boys). Intake was assessed via two non-consecutive 24-h dietary recalls. Data on maternal education and sedentary behaviors were obtained via questionnaires. Physical activity was objectively measured by accelerometry. RESULTS: Alanine, arginine, asparaginic acid, glycine, histidine, lysine and serine intakes were inversely associated with serum TG concentrations in both boys and girls. Intake of other AA like alanine and/or arginine was also inversely associated with serum TC, LDL-c and Apo B/Apo A1 ratio only in girls. An inverse association was observed between intakes of alanine, isoleucine, leucine, methionine, serine, tryptophan, tyrosine and valine and TC/HDL-c ratio among female adolescents. Similar results were found in males for serine and tryptophan intakes. It is noteworthy, however, that associations were no longer significant in both genders when total fat intake was considered as a confounding factor. CONCLUSIONS: In this sample of adolescents, the association between AA intakes and serum lipid profile did not persist when dietary fat was considered. Therefore, dietary interventions and health promotion activities should focus on fat intake to improve lipid profile and potentially prevent cardiovascular disease. PMID- 24495994 TI - Effect of 1-methylcyclopropene on shelf life, visual quality and nutritional quality of netted melon. AB - The effects of 1-methylcyclopropene (1-MCP) on shelf life, fruit visual quality and nutritional quality were investigated. Netted melons were treated with air (control) and 0.6 ul l(-1) 1-MCP at 25 C for 24 h, and then stored at 25 C or 10 C for 10 days. 1-MCP significantly extended the shelf life, inhibited weight loss and delayed firmness decline of melon fruits. Ethylene production was also inhibited and respiration rate was declined. 1-MCP retarded 1-aminocyclopropane-1 carboxylic acid (ACC) increases and inhibited ACC synthase and ACC oxidase activity. Moreover, 1-MCP treatment reduced the decrease in total soluble solids and titratable acidity, as well as the decrease of the content of sugars (sucrose, fructose and glucose). These results indicated that 1-MCP treatment is a good method to extend melon shelf life and maintain fruit quality, and the combination of 1-MCP and low temperature storage resulted in more acceptable fruit quality. PMID- 24495996 TI - Characterization of PMN-PT piezoelectric single crystal and PMN-PT 1-3 composite at elevated temperatures by electrical impedance resonance analysis. AB - In this paper, lead magnesium niobate-lead titanate (PMN-PT) piezoelectric single crystal and its 1-3 composite counterpart were characterized and analyzed under different stable temperatures using both a Simulated Annealing (SA) optimization algorithm and the commercial software PRAP (Piezoelectric Resonance Analysis Program). Electrical impedance resonance characteristics of the two material samples over the range 25-125 degrees C were measured. The correlation between experimental data and numerical fits derived from both SA and PRAP is considered. Calculation of the determination coefficient (R1(2)) between numerically fitted and measured results is above 95% for both methods. Furthermore, variations in the number of data values used for the fit introduced no more than 3.1% uncertainty on the calculated material parameters. It is found that the complex material parameters of PMN-PT composite are more dependent on temperature than the single crystal. The phase transition of the PMN-PT, which is close to 90 degrees C, has an effect on the high temperature material characteristics of both piezoelectric materials. These calculated complex material parameters can be used for the design of ultrasonic transducers for elevated temperature applications. PMID- 24495997 TI - Modeling of micromachined silicon-polymer 2-2 composite matching layers for 15MHz ultrasound transducers. AB - Silicon-polymer composites fabricated by micromachining technology offer attractive properties for use as matching layers in high frequency ultrasound transducers. Understanding of the acoustic behavior of such composites is essential for using them as one of the layers in a multilayered transducer structure. This paper presents analytical and finite element models of the acoustic properties of silicon-polymer composites in 2-2 connectivity. Analytical calculations based on partial wave solutions are applied to identify the resonance modes and estimate effective acoustic material properties. Finite Element Method (FEM) simulations were used to investigate the interaction between the composite and the surrounding load medium, either a fluid or a solid, with emphasis on the acoustic impedance of the composite. Composites with lateral periods of 20, 40 and 80MUm were fabricated and used as acoustic matching layers for air-backed transducers operating at 15MHz. These composites were characterized acoustically, and the results were compared with analytical calculations. The analytical model shows that at low to medium silicon volume fraction, the first lateral resonance in the silicon-polymer 2-2 composite is defined by the composite period, and this lateral resonant frequency is at least 1.2 times higher than that of a piezo-composite with the same polymer filler. FEM simulations showed that the effective acoustic impedance of the silicon-polymer composite varies with frequency, and that it also depends on the load material, especially whether this is a fluid or a solid. The estimated longitudinal sound velocities of the 20 and 40MUm period composites match the results from analytical calculations within 2.7% and 2.6%, respectively. The effective acoustic impedances of the 20 and 40MUm period composites were found to be 10% and 26% lower than the values from the analytical calculations. This difference is explained by the shear stiffness in the solid, which tends to even out the surface displacements of the composites. PMID- 24495995 TI - In silico derived small molecules bind the filovirus VP35 protein and inhibit its polymerase cofactor activity. AB - The Ebola virus (EBOV) genome only encodes a single viral polypeptide with enzymatic activity, the viral large (L) RNA-dependent RNA polymerase protein. However, currently, there is limited information about the L protein, which has hampered the development of antivirals. Therefore, antifiloviral therapeutic efforts must include additional targets such as protein-protein interfaces. Viral protein 35 (VP35) is multifunctional and plays important roles in viral pathogenesis, including viral mRNA synthesis and replication of the negative sense RNA viral genome. Previous studies revealed that mutation of key basic residues within the VP35 interferon inhibitory domain (IID) results in significant EBOV attenuation, both in vitro and in vivo. In the current study, we use an experimental pipeline that includes structure-based in silico screening and biochemical and structural characterization, along with medicinal chemistry, to identify and characterize small molecules that target a binding pocket within VP35. NMR mapping experiments and high-resolution x-ray crystal structures show that select small molecules bind to a region of VP35 IID that is important for replication complex formation through interactions with the viral nucleoprotein (NP). We also tested select compounds for their ability to inhibit VP35 IID-NP interactions in vitro as well as VP35 function in a minigenome assay and EBOV replication. These results confirm the ability of compounds identified in this study to inhibit VP35-NP interactions in vitro and to impair viral replication in cell-based assays. These studies provide an initial framework to guide development of antifiloviral compounds against filoviral VP35 proteins. PMID- 24495998 TI - Comparative outcomes of elderly stage I lung cancer patients treated with segmentectomy via video-assisted thoracoscopic surgery versus open resection. AB - INTRODUCTION: Video-assisted thorcacic surgery (VATS) is considered an alternative to open lobectomy for the treatment of non-small-cell lung cancer (NSCLC). Limited data are available, however, regarding the equivalence of open versus VATS segmental resections, particularly among elderly patients. METHODS: From the Surveillance, Epidemiology, and End Results-Medicare database we identified 577 stage I NSCLC patients aged more than 65 years treated with VATS or open segmentectomy. We used propensity score methods to control for differences in the baseline characteristics of patients treated with VATS versus open segmentectomy. Outcomes included perioperative complications, need for intensive care unit, extended hospital stay, perioperative mortality, and survival. RESULTS: Overall, 27% of patients underwent VATS. VATS-treated patients had lower rates of postoperative complications (odds ratio [OR]: 0.55, 95% confidence interval [CI]: 0.37-0.83), intensive care unit admissions (OR: 0.18, 95% CI: 0.12-0.28), and decreased length of stay (OR: 0.41, 95% CI: 0.21-0.81) after adjusting for propensity scores. Postoperative outcomes were not significantly different across groups after adjusting for surgeon characteristics. Overall (hazard ratio: 0.80, 95% CI: 0.60-1.06) and lung cancer specific (hazard ratio: 0.71, 95% CI: 0.45-1.12) survival was similar across groups. CONCLUSIONS: VATS segmentectomy can be safely performed among elderly NSCLC patients and is associated with equivalent postoperative and oncologic outcomes. PMID- 24495999 TI - Detection of rearrangements and transcriptional up-regulation of ALK in FFPE lung cancer specimens using a novel, sensitive, quantitative reverse transcription polymerase chain reaction assay. AB - INTRODUCTION: The approved dual-color fluorescence in situ hybridization (FISH) test for the detection of anaplastic lymphoma receptor tyrosine kinase (ALK) gene rearrangements in non-small-cell lung cancer (NSCLC) is complex and represents a low-throughput assay difficult to use in daily diagnostic practice. We devised a sensitive and robust routine diagnostic test for the detection of rearrangements and transcriptional up-regulation of ALK. METHODS: We developed a quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay adapted to RNA isolated from routine formalin-fixed, paraffin-embedded material and applied it to 652 NSCLC specimens. The reliability of this technique to detect ALK dysregulation was shown by comparison with FISH and immunohistochemistry. RESULTS: qRT-PCR analysis detected unbalanced ALK expression indicative of a gene rearrangement in 24 (4.6%) and full-length ALK transcript expression in six (1.1%) of 523 interpretable tumors. Among 182 tumors simultaneously analyzed by FISH and qRT-PCR, the latter accurately typed 97% of 19 rearranged and 158 nonrearranged tumors and identified ALK deregulation in two cases with insufficient FISH. Six tumors expressing full-length ALK transcripts did not show rearrangements of the gene. Immunohistochemistry detected ALK protein overexpression in tumors with gene fusions and transcriptional up-regulation, but did not distinguish between the two. One case with full-length ALK expression carried a heterozygous point mutation (S1220Y) within the kinase domain potentially interfering with kinase activity and/or inhibitor binding. CONCLUSIONS: Our qRT-PCR assay reliably identifies and distinguishes ALK rearrangements and full-length transcript expression in formalin-fixed, paraffin embedded material. It is an easy-to-perform, cost-effective, and high-throughput tool for the diagnosis of ALK activation. The expression of full-length ALK transcripts may be relevant for ALK inhibitor therapy in NSCLC. PMID- 24496000 TI - Postoperative pain and subsequent PTSD-related symptoms in patients undergoing lung resection for suspected cancer. AB - BACKGROUND: Because lung cancer resection is at the crossroad between cancer and high-risk surgery, we hypothesized that the patients undergoing lung resection for cancer are exposed to develop a post-traumatic stress disorder (PTSD) syndrome-related symptoms. METHODS: Forty-seven adult patients were included in the study. Patients were eligible for inclusion if they underwent lung resection for suspected cancer, if they were able to speak and read French, and if they agreed to be reached for a telephone interview. We assessed before, immediately after, and 3 months after surgery the presence of symptoms of anxiety and depression (Hospital Anxiety and Depression Scale) and PTSD-related symptoms (impact of events scale revised [IES-R]). At the 3-month assessment, an IES-R score > 22 was used as criteria for predicting the patients at risk of PTSD related symptoms. RESULTS: We identified an IES-R score higher than 22 in 24 participants (51%). Patients with a preoperatory Hospital Anxiety and Depression Scale(anxiety) score more than 7 (T0) and a maximal visual analogic scale score more than 40 during the first 24 hours after surgery were more likely to develop PTSD-related symptoms at 3-months with odd ratios at 4.61 [1.20-17.73] (p = 0.03) and 1.34 [1.05-1.75] (p = 0.02). CONCLUSION: The prevalence of PTSD-related symptoms after lung cancer resection is high, showing that lung cancer patients undergoing surgical resection are at high risk of postprocedure burden. The presence of preoperative symptoms of anxiety and acute procedural pain during the early postoperative period are strong predictors for developing PTSD-related symptoms after lung cancer surgery. PMID- 24496001 TI - RANKL inhibition blocks osteolytic lesions and reduces skeletal tumor burden in models of non-small-cell lung cancer bone metastases. AB - INTRODUCTION: Bone metastasis is a serious complication in patients with lung cancer, occurring in up to 40% of patients. Tumor cell-mediated osteolysis occurs ultimately through induction of RANK ligand (RANKL) within the bone stroma although this hypothesis has not been tested extensively in the setting of non small-cell lung cancer (NSCLC). By using two novel NSCLC bone metastasis mouse models, we examined the effects of RANKL inhibition on osteolysis and tumor progression. METHODS: We treated mice bearing skeletal NSCLC tumors with osteoprotegerin-Fc (OPG-Fc) to assess whether osteoclast inhibition through RANKL inhibition would affect bone metastases at early or late stages of bone colonization. Progression of skeletal tumor was determined by radiography, longitudinal bioluminescent imaging, and histological analyses. RESULTS: OPG-Fc reduced development and progression of radiographically evident osteolytic lesions and also significantly reduced skeletal tumor progression in both NSCLC bone metastasis models. In the H1299 human NSCLC bone metastasis model, OPG-Fc plus docetaxel in combination resulted in significantly greater inhibition of skeletal tumor growth compared with either single agent alone. The observed ability of RANKL inhibition to reduce NSCLC osteolytic bone destruction or skeletal tumor burden was associated with decreases in tumor-associated osteoclasts. CONCLUSIONS: These results demonstrate that RANKL is required for the development of tumor-induced osteolytic bone destruction caused by NSCLC cells in vivo. RANKL inhibition also reduced skeletal tumor burden, presumably through the indirect mechanism of blocking tumor-induced osteoclastogenesis and resultant production of growth factors and calcium from the bone microenvironment. RANKL inhibition also provided an additive benefit to docetaxel treatment by augmenting the reduction of tumor burden. PMID- 24496002 TI - Impact of extratumoral lymphatic permeation on postoperative survival of non small-cell lung cancer patients. AB - INTRODUCTION: Lymphatic permeation has been reported as a prognostic factor for patients with resected non-small-cell lung cancer (NSCLC). Lymphatic canals are located in both intratumoral and extratumoral areas. Since 2001, we have prospectively evaluated lymphatic permeation based on its location. The purpose of this study was to determine the survival impact of extratumoral lymphatic permeation in patients with resected NSCLC by analyzing the long-term follow-up data. METHODS: We reviewed 1069 consecutive patients with NSCLC who underwent complete resection between 2001 and 2006. Lymphatic permeation was classified as follows: ly0, absence of lymphatic permeation; ly1, intratumoral; and ly2, extratumoral. RESULTS: There were 845 patients (79%) with ly0, 134 (12%) with ly1, and 90 (9%) with ly2. Ly2 was more frequently observed in patients with advanced disease and intrapulmonary metastases than ly0-1. The 5-year overall survival (OS) rates of the ly0, ly1, and ly2 groups were 75%, 63%, and 34%, respectively. The OS rate was significantly worse in the ly2 group compared with OS rate in the ly0 (p < 0.01) and ly1 groups (p < 0.01). In multivariate analyses, ly2 proved to be an independent poor prognostic factor (hazard ratio, 1.73; p < 0.01). OS and recurrence-free survival of patients with T1 and T2 tumors with ly2 were not statistically different from that of the patients with T3 tumor (OS, p = 0.43 and p = 0.77; recurrence-free survival, p = 0.94 and p = 0.94, respectively). CONCLUSIONS: The adverse prognostic impact of lymphatic permeation was remarkably different whether it is detected in intratumoral or extratumoral lymphatic canals. We recommend that lymphatic permeation in resected NSCLC should be evaluated by considering its location. PMID- 24496003 TI - HIP1-ALK, a novel ALK fusion variant that responds to crizotinib. AB - INTRODUCTION: The aim of this study was to identify anaplastic lymphoma kinase (ALK) rearrangements in lung cancer patient-derived xenograft (PDX) models and to explore their responses to crizotinib. METHODS: Screening of 99 lung cancer PDX models by the NanoString ALK fusion assay identified two ALK-rearranged non-small cell lung cancer (NSCLC) tumors, including one harboring a previously known echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion and another containing an unknown ALK fusion variant. Expression array, RNA-Seq, reverse transcription polymerase chain reaction, and direct sequencing were then conducted to confirm the rearrangements and to identify the novel fusion partner in the xenograft and/or the primary patient tumor. Finally, pharmacological studies were performed in PDX models to evaluate their responses to ALK inhibitor crizotinib. RESULTS: Two ALK-rearranged NSCLC PDX models were identified: one carried a well-known EML4-ALK variant 3a/b and the other harbored a novel huntingtin interacting protein 1 (HIP1)-ALK fusion gene. Exon 28 of the HIP1 gene located on chromosome 7 was fused to exon 20 of the ALK gene located on chromosome 2. Both cases were clinically diagnosed as squamous cell carcinoma. Compared with the other lung cancer PDX models, both ALK-rearranged models displayed elevated ALK mRNA expression. Furthermore, in vivo efficacy studies demonstrated that, similar to the EML4-ALK-positive model, the HIP1-ALK containing PDX model was sensitive to treatment with crizotinib. CONCLUSIONS: Discovery of HIP1 as a fusion partner of ALK in NSCLC is a novel finding. In addition, the HIP1-ALK-rearranged tumor is sensitive to treatment with crizotinib in vivo, implicating HIP1-ALKas an oncogenic driver of lung tumorigenesis. Collectively, our results indicate that HIP1-ALK-positive NSCLC may benefit from clinical applications of crizotinib. PMID- 24496004 TI - Phase I safety and pharmacokinetic study of the PI3K/mTOR inhibitor SAR245409 (XL765) in combination with erlotinib in patients with advanced solid tumors. AB - INTRODUCTION: The primary objectives of this phase I study were to evaluate the safety and maximum tolerated dose (MTD) of SAR245409, a pan-class I phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin inhibitor, combined with erlotinib in patients with advanced solid tumors. METHODS: Forty six patients with advanced solid tumors were enrolled. Patients with lung cancer (n = 37) had received an epidermal growth factor receptor (EGFR) inhibitor before study entry. SAR245409 30, 50, 70, or 90 mg once daily (QD) or 20 or 30 mg twice daily (BID) was administered, in combination with erlotinib 100 mg QD, in 28-day cycles. Dose escalation of SAR245409 followed a standard 3 + 3 design. Patients were evaluated for adverse events (AEs). Additional evaluations included pharmacokinetics, pharmacodynamic effects on PI3K and EGFR/mitogen-activated protein kinase signaling pathways in tumor and skin samples, and tumor response. RESULTS: The MTDs of SAR245409, in combination with erlotinib 100 mg QD, were 70 mg QD and 20 mg BID. The most frequently reported treatment-related AEs (any grade) were diarrhea (35%), rash (35%), and nausea (28%). No treatment-related AE occurred at grade 3/4 in more than one patient (2.2%). No major pharmacokinetic interaction between SAR245409 and erlotinib was noted. Suppression of PI3K and EGFR/mitogen-activated protein kinase signaling pathway biomarkers was observed in skin and tumor samples. Stable disease was the best overall response reported, occurring in 12 of 32 (37.5%) evaluable patients. CONCLUSION: MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction. PMID- 24496005 TI - Survival in women with NSCLC: the role of reproductive history and hormone use. AB - INTRODUCTION: Although lung cancer is the leading cause of cancer death in women, few studies have investigated the hormonal influence on survival after a lung cancer diagnosis and results have been inconsistent. We evaluated the role of reproductive and hormonal factors in predicting overall survival in women with non-small-cell lung cancer (NSCLC). METHODS: Population-based lung cancer cases diagnosed between November 1, 2001 and October 31, 2005 were identified through the Metropolitan Detroit Surveillance, Epidemiology, and End Results Registry. Interview and follow-up data were collected for 485 women. Cox proportional hazard regression models were used to determine hazard ratios (HRs) for death after an NSCLC diagnosis associated with reproductive and hormonal variables. RESULTS: Use of hormone therapy (HT) was associated with improved survival (HR, 0.69; 95% confidence interval, 0.54-0.89), adjusting for stage, surgery, radiation, education level, pack-years of smoking, age at diagnosis, race, and a multiplicative interaction between stage and radiation. No other reproductive or hormonal factor was associated with survival after an NSCLC diagnosis. Increased duration of HT use before the lung cancer diagnosis (132 months or longer) was associated with improved survival (HR, 0.54; 95% confidence interval, 0.37-0.78), and this finding remained significant in women taking either estrogen alone or progesterone plus estrogen, never smokers, and smokers. CONCLUSION: These findings suggest that HT use, in particular use of estrogen plus progesterone, and long-term HT use are associated with improved survival of NSCLC. PMID- 24496006 TI - Digital-Direct-RT-PCR: a sensitive and specific method for quantification of CTC in patients with cervical carcinoma. AB - The detection of circulating tumour cells (CTC) in cancer patients may be useful for therapy monitoring and prediction of relapse. A sensitive assay based on HPV oncogene transcripts which are highly specific for cervical cancer cells was established. The Digital-Direct-RT-PCR (DD-RT-PCR) combines Ficoll-separation, ThinPrep-fixation and one-step RT-PCR in a low-throughput digital-PCR format enabling the direct analysis and detection of individual CTC without RNA isolation. Experimental samples demonstrated a sensitivity of one HPV-positive cell in 500,000 HPV-negative cells. Spike-in experiments with down to 5 HPV positive cells per millilitre EDTA-blood resulted in concordant positive results by PCR and immunocytochemistry. Blood samples from 3 of 10 CxCa patients each contained a single HPV-oncogene transcript expressing CTC among 5 to 15*10(5) MNBC. Only 1 of 7 patients with local but 2 of 3 women with systemic disease had CTC. This highly sensitive DD-RT-PCR for the detection of CTC may also be applied to other tumour entities which express tumour-specific transcripts. PMID- 24496007 TI - Abundant and selective RNA-editing events in the medicinal mushroom Ganoderma lucidum. AB - RNA editing is a widespread, post-transcriptional molecular phenomenon that diversifies hereditary information across various organisms. However, little is known about genome-scale RNA editing in fungi. In this study, we screened for fungal RNA editing sites at the genomic level in Ganoderma lucidum, a valuable medicinal fungus. On the basis of our pipeline that predicted the editing sites from genomic and transcriptomic data, a total of 8906 possible RNA-editing sites were identified within the G. lucidum genome, including the exon and intron sequences and the 5'-/3'-untranslated regions of 2991 genes and the intergenic regions. The major editing types included C-to-U, A-to-G, G-to-A, and U-to-C conversions. Four putative RNA-editing enzymes were identified, including three adenosine deaminases acting on transfer RNA and a deoxycytidylate deaminase. The genes containing RNA-editing sites were functionally classified by the Kyoto Encyclopedia of Genes and Genomes enrichment and gene ontology analysis. The key functional groupings enriched for RNA-editing sites included laccase genes involved in lignin degradation, key enzymes involved in triterpenoid biosynthesis, and transcription factors. A total of 97 putative editing sites were randomly selected and validated by using PCR and Sanger sequencing. We presented an accurate and large-scale identification of RNA-editing events in G. lucidum, providing global and quantitative cataloging of RNA editing in the fungal genome. This study will shed light on the role of transcriptional plasticity in the growth and development of G. lucidum, as well as its adaptation to the environment and the regulation of valuable secondary metabolite pathways. PMID- 24496008 TI - Fast and efficient estimation of individual ancestry coefficients. AB - Inference of individual ancestry coefficients, which is important for population genetic and association studies, is commonly performed using computer-intensive likelihood algorithms. With the availability of large population genomic data sets, fast versions of likelihood algorithms have attracted considerable attention. Reducing the computational burden of estimation algorithms remains, however, a major challenge. Here, we present a fast and efficient method for estimating individual ancestry coefficients based on sparse nonnegative matrix factorization algorithms. We implemented our method in the computer program sNMF and applied it to human and plant data sets. The performances of sNMF were then compared to the likelihood algorithm implemented in the computer program ADMIXTURE. Without loss of accuracy, sNMF computed estimates of ancestry coefficients with runtimes ~10-30 times shorter than those of ADMIXTURE. PMID- 24496009 TI - Complex craniofacial changes in blind cave-dwelling fish are mediated by genetically symmetric and asymmetric loci. AB - The genetic regulators of regressive craniofacial morphologies are poorly understood. To shed light on this problem, we examined the freshwater fish Astyanax mexicanus, a species with surface-dwelling and multiple independent eyeless cave-dwelling forms. Changes affecting the skull in cavefish include morphological alterations to the intramembranous circumorbital bones encircling the eye. Many of these modifications, however, have evolved separately from eye loss, such as fragmentation of the third suborbital bone. To understand the genetic architecture of these eye-independent craniofacial alterations, we developed and scored 33 phenotypes in the context of an F2 hybrid mapping pedigree bred from Pachon cavefish and surface fish. We discovered several individuals exhibiting dramatic left-right differences in bone formation, such as extensive fragmentation on the right side only. This observation, along with well known eye size asymmetry in natural cave-dwelling animals, led us to further evaluate left-right genetic differences for the craniofacial complex. We discovered three phenotypes, inclusive of bone fragmentation and fusion, which demonstrated a directional heritable basis only on one side. Interestingly, the overall areas of affected bones were genetically symmetric. Phenotypic effect plots of these novel craniofacial QTL revealed that cave alleles are associated with abnormal conditions such as bony fusion and fragmentation. Moreover, many linked loci overlapped with other cave-associated traits, suggesting regressive craniofacial changes may evolve through linkage or as antagonistic pleiotropic consequences of cave-associated adaptations. These novel findings illuminate significant craniofacial changes accompanying evolution in complete darkness and reveal complex changes to the skull differentially influenced by genetic changes affecting the left and right sides. PMID- 24496011 TI - Exact vs. approximate computation: reconciling different estimates of Mycobacterium tuberculosis epidemiological parameters. AB - Exact computational methods for inference in population genetics are intuitively preferable to approximate analyses. We reconcile two starkly different estimates of the reproductive number of tuberculosis from previous studies that used the same genotyping data and underlying model. This demonstrates the value of approximate analyses in validating exact methods. PMID- 24496010 TI - Template switching during break-induced replication is promoted by the Mph1 helicase in Saccharomyces cerevisiae. AB - Chromosomal double-strand breaks (DSBs) that have only one end with homology to a donor duplex undergo repair by strand invasion followed by replication to the chromosome terminus (break-induced replication, BIR). Using a transformation based assay system, it was previously shown that BIR could occur by several rounds of strand invasion, DNA synthesis, and dissociation. Here we describe a modification of the transformation-based assay to facilitate detection of switching between donor templates during BIR by genetic selection in diploid yeast. In addition to the expected recovery of template switch products, we found a high frequency of recombination between chromosome homologs during BIR, suggesting transfer of the DSB from the transforming linear DNA to the donor chromosome, initiating secondary recombination events. The frequency of BIR increased in the mph1Delta mutant, but the percentage of template switch events was significantly decreased, revealing an important role for Mph1 in promoting BIR-associated template switching. In addition, we show that the Mus81, Rad1, and Yen1 structure-selective nucleases act redundantly to facilitate BIR. PMID- 24496012 TI - The evolution of phenotypic switching in subdivided populations. AB - Stochastic switching is an example of phenotypic bet hedging, where offspring can express a phenotype different from that of their parents. Phenotypic switching is well documented in viruses, yeast, and bacteria and has been extensively studied when the selection pressures vary through time. However, there has been little work on the evolution of phenotypic switching under both spatially and temporally fluctuating selection pressures. Here we use a population genetic model to explore the interaction of temporal and spatial variation in determining the evolutionary dynamics of phenotypic switching. We find that the stable switching rate is mainly determined by the rate of environmental change and the migration rate. This stable rate is also a decreasing function of the recombination rate, although this is a weaker effect than those of either the period of environmental change or the migration rate. This study highlights the interplay of spatial and temporal environmental variability, offering new insights into how migration can influence the evolution of phenotypic switching rates, mutation rates, or other sources of phenotypic variation. PMID- 24496013 TI - Enhancing the power to detect low-frequency variants in genome-wide screens. AB - In genetic association studies a conventional test statistic is proportional to the correlation coefficient between the trait and the variant, with the result that it lacks power to detect association for low-frequency variants. Considering the link between the conventional association test statistics and the linkage disequilibrium measure r(2), we propose a test statistic analogous to the standardized linkage disequilibrium D' to increase the power of detecting association for low-frequency variants. By both simulation and real data analysis we show that the proposed D' test is more powerful than the conventional methods for detecting association for low-frequency variants in a genome-wide setting. The optimal coding strategy for the D' test and its asymptotic properties are also investigated. In summary, we advocate using the D' test in a dominant model as a complementary approach to enhancing the power of detecting association for low-frequency variants with moderate to large effect sizes in case-control genome wide association studies. PMID- 24496014 TI - The extracellular matrix protein artichoke is required for integrity of ciliated mechanosensory and chemosensory organs in Drosophila embryos. AB - Sensory cilia are often encapsulated by an extracellular matrix (ECM). In Caenorhabditis elegans, Drosophila melanogaster, and vertebrates, this ECM is thought to be directly involved in ciliary mechanosensing by coupling external forces to the ciliary membrane. Drosophila mechano- and chemosensory cilia are both associated with an ECM, indicating that the ECM may have additional roles that go beyond mechanosensory cilium function. Here, we identify Artichoke (ATK), an evolutionarily conserved leucine-rich repeat ECM protein that is required for normal morphogenesis and function of ciliated sensilla in Drosophila. atk is transiently expressed in accessory cells in all ciliated sensory organs during their late embryonic development. Antibody stainings show ATK protein in the ECM that surrounds sensory cilia. Loss of ATK protein in atk null mutants leads to cilium deformation and disorientation in chordotonal organs, apparently without uncoupling the cilia from the ECM, and consequently to locomotion defects. Moreover, impaired chemotaxis in atk mutant larvae suggests that, based on ATK protein localization, the ECM is also crucial for the correct assembly of chemosensory receptors. In addition to defining a novel ECM component, our findings show the importance of ECM integrity for the proper morphogenesis of ciliated organs in different sensory modalities. PMID- 24496015 TI - Synthesis of Fmoc-Gly-Ile Phosphinic Pseudodipeptide: Residue Specific Conditions for Construction of Matrix Metalloproteinase Inhibitor Building Blocks. AB - The efficient synthesis of an Fmoc-Gly-Ile phosphinic pseudodipeptide was desired as an eventual building block for construction of matrix metalloproteinase inhibitors. A Michael-type addition reaction of bis(tri-methylsilyl) phosphonite with the appropriate acrylate generated the pseudodipeptide bond. Additional of adamantyl (Ad) protection by our prior route (reaction of in situ generated phosphinic acid chloride with the sodium salt of adamantanol) was surprisingly inefficient. Adamantyl protection was achieved in high yield by refluxing the phosphinic acid, Ag2O, and 1-AdBr in chloroform. Subsequently a concise one-pot three-step reaction comprising a double deprotection of the N- and C-termini under catalytic hydrogenation conditions followed by selective protection of the N-terminus with an Fmoc group yielded Fmoc-NHCH2PO(OAd)CH2CH(2-butyl)CO2H in 41 % overall yield. These results indicate that, as the diversity of phosphinic pseudodipeptides is increased to create selective matrix metalloproteinase inhibitors, different synthetic pathways may be required for efficient building block preparation. PMID- 24496017 TI - Changing behavior through an e-mail newsletter. PMID- 24496018 TI - Assessment of student experience in a problem-based learning course using the course experience questionnaire. PMID- 24496016 TI - Targeting the unfolded protein response, XBP1, and the NLRP3 inflammasome in fibrosis and cancer. AB - Increasing health care costs in the US are due in a large part to the increasing prevalence of chronic diseases in an aging population. Current therapeutic strategies for treating chronic diseases alleviate symptoms allowing patients to live longer with these diseases, but they do little, however, to alter the underlying disease course. Recent advances in molecular biology are revealing new drug targets that may significantly alter the course of these diseases and, as a result, offer economic relief from burgeoning health care costs. Endoplasmic reticulum (ER) stress has been implicated as an underlying pathology in many chronic diseases, and, therefore, the development of therapies designed to ameliorate ER stress may yield novel, effective treatment strategies. Herein, we report that X-box binding protein 1 (XBP1) may be one of the earliest proteins engaged in response to ER stress. We show that a new signaling peptide derived from the ER-embedded transient receptor potential calcium channel protein 1 (TRPC1) engages XBP1 upstream of NLRP3 inflammasome-mediated maturation and secretion of IL-1beta/IL-18. Moreover, we show that a synthetic homolog of this signaling peptide (NaclynamideTM) administered intravenously twice weekly over a 4-week treatment course induced suppuration and evoked partial or complete resolution of lesions associated with a fibrotic granuloma, a lymphosarcoma, and a colo-rectal carcinoma in canine patients. The mode of action for NaclynamideTM as a first-in-class anti-cancer drug candidate is discussed. PMID- 24496019 TI - Surface characteristics determining the cell compatibility of ionically cross linked alginate gels. AB - In this study we investigated differences in the characteristics determining the suitability of five types of ion (Fe(3+), Al(3+), Ca(2+), Ba(2+) and Sr(2+)) cross-linked alginate films as culture substrates for cells. Human dermal fibroblasts were cultured on each alginate film to examine the cell affinity of the alginates. Since cell behavior on the surface of a material is dependent on the proteins adsorbed to it, we investigated the protein adsorption ability and surface features (wettability, morphology and charge) related to the protein adsorption abilities of alginate films. We observed that ferric, aluminum and barium ion-cross-linked alginate films supported better cell growth and adsorbed higher amounts of serum proteins than other types. Surface wettability analysis demonstrated that ferric and aluminum ion-cross-linked alginates had moderate hydrophilic surfaces, while other types showed highly hydrophilic surfaces. The roughness was exhibited only on barium ion-cross-linked alginate surface. Surface charge measurements revealed that alginate films had negatively charged surfaces, and showed little difference among the five types of gel. These results indicate that the critical factors of ionically cross-linked alginate films determining the protein adsorption ability required for their cell compatibility may be surface wettability and morphology. PMID- 24496020 TI - Estrogen-dependent effects on behavior, lipid-profile, and glycemic index of ovariectomized rats subjected to chronic restraint stress. AB - Stress has been shown to negatively affect the immune system, alter the body's metabolism, and play a strong role in the development of mood disorders. These effects are mainly driven through the release of hormones from the hypothalamic pituitary-adrenal axis (HPA). Additionally, women are more likely to be affected by stress due to the estrogen fluctuation associated with their menstrual cycle. This study aims to evaluate the effect of chronic restraint stress, applied for 30 days, and estrogen replacement on behavior, glucose level, and the lipid profile of ovariectomized rats. Our results suggest that stress increases sweet food consumption in OVX females treated with estradiol (E2), but reduces consumption in animals not treated. Furthermore, stress increases locomotor activity and anxiety as assessed by the Open Field test and in the Elevated Plus Maze. Similarly, our results suggest that E2 increases anxiety in female rats under the same behavioral tests. In addition, stress reduces glucose and TC levels. Moreover, stress increase TG levels in the presence of E2 and decrease in its absence, as well as the estradiol increase TG levels in stressed groups and reduced in non-stressed groups. Our data suggest an important interaction between stress and estrogen, showing that hormonal status can induce changes in the animal's response to stress. PMID- 24496021 TI - Assessment of the water quality of Klodnica River catchment using self-organizing maps. AB - Risk assessment of industrial areas heavily polluted due to anthropogenic actions is of increasing concern worldwide. So is the case of Polish Silesia region where mostly heavy industry like smelters, mining, chemical industries as well as heat and electricity production facilities are being located. Such situation raises numerous questions about environmental state of local water bodies with special attention paid to the Klodnica Catchment which is receiving waste waters from numerous industrial plants. The efforts have been undertaken to describe the situation (spatial and temporal distribution of pollution) in the area of interest with the help of self-organizing maps - modern non-parametric data mining method - yet still rarely applied in environmental studies where numerous input parameters have to be considered. As a result of studies clear distinction into 3 pollution groups could be obtained as well as the seasonal variation of pollution could be distinguished. PMID- 24496022 TI - Comparison of abundances, compositions and sources of elements, inorganic ions and organic compounds in atmospheric aerosols from Xi'an and New Delhi, two megacities in China and India. AB - Wintertime TSP samples collected in the two megacities of Xi'an, China and New Delhi, India were analyzed for elements, inorganic ions, carbonaceous species and organic compounds to investigate the differences in chemical compositions and sources of organic aerosols. The current work is the first time comparing the composition of urban organic aerosols from China and India and discussing their sources in a single study. Our results showed that the concentrations of Ca, Fe, Ti, inorganic ions, EC, PAHs and hopanes in Xi'an are 1.3-2.9 times of those in New Delhi, which is ascribed to the higher emissions of dust and coal burning in Xi'an. In contrast, Cl(-), levoglucosan, n-alkanes, fatty alcohols, fatty acids, phthalates and bisphenol A are 0.4-3.0 times higher in New Delhi than in Xi'an, which is attributed to strong emissions from biomass burning and solid waste incineration. PAHs are carcinogenic while phthalates and bisphenol A are endocrine disrupting. Thus, the significant difference in chemical compositions of the above TSP samples may suggest that residents in Xi'an and New Delhi are exposed to environmental hazards that pose different health risks. Lower mass ratios of octadecenoic acid/octadecanoic acid (C18:1/C18:0) and benzo(a)pyrene/benzo(e)pyrene (BaP/BeP) demonstrate that aerosol particles in New Delhi are photochemically more aged. Mass closure reconstructions of the wintertime TSP indicate that crustal material is the most abundant component of ambient particles in Xi'an and New Delhi, accounting for 52% and 48% of the particle masses, respectively, followed by organic matter (24% and 23% in Xi'an and New Delhi, respectively) and secondary inorganic ions (sulfate, nitrate plus ammonium, 16% and 12% in Xi'an and New Delhi, respectively). PMID- 24496023 TI - Functional traits of selected mangrove species in Brazil as biological indicators of different environmental conditions. AB - Ecological studies on phenotypic plasticity illustrate the relevance of this phenomenon in nature. Conditions of biota reflect environmental changes, highlighting the adaptability of resident species that can be used as bioindicators of such changes. We report the morpho-anatomical plasticity of leaves of Avicennia schaueriana Stapf & Leechm. ex Moldenke, Laguncularia racemosa (L.) C.F.Gaertn. and Rhizophora mangle L., evaluated in three estuaries (Vitoria bay, Santa Cruz and Itaunas River; state of Espirito Santo, Brazil), considering five areas of mangrove ecosystems with diverse environmental issues. Two sampling sites are part of the Ecological Station Lameirao Island in Vitoria bay, close to a harbor. A third sampling site in Cariacica (Vitoria bay) is inside the Vitoria harbor and also is influenced by domestic sewage. The fourth studied area (Santa Cruz) is part of Piraque Mangrove Ecological Reservation, while the fifth (Itaunas River) is a small mangrove, with sandy sediment and greater photosynthetically active radiation, also not strongly influenced by anthropic activity. Results pointed out the morpho-anatomical plasticity in studied species, showing that A. schaueriana and L. racemosa might be considered the most appropriate bioindicators to indicate different settings and environmental conditions. Particularly, the dry mass per leaf area (LMA) of A. schaueriana was the main biomarker measured. In our study, LMA of A. schaueriana was positively correlated with salinity (Spearman 0.71), Mn content (0.81) and pH (0.82) but negatively correlated with phosphorus content (-0.63). Thus, the evaluation of modification in LMA of A. schaueriana pointed out changes among five studied sites, suggesting its use to reflect changes in the environment, which could be also useful in the future to evaluate the climate change. PMID- 24496024 TI - A new optional recycled water pre-treatment system prior to use in the household laundry. AB - With a constantly growing population, water scarcity becomes the limiting factor for further social and economic growth. To achieve a partial reduction in current freshwater demands and lessen the environmental loadings, an increasing trend in the water market tends to adopt recycled water for household laundries as a new recycled water application. The installation of a small pre-treatment unit for water purification can not only further improve the recycled water quality, but also be viable to enhance the public confidence and acceptance level on recycled water consumption. Specifically, this paper describes column experiments conducted using a 550 mm length bed of zeolite media as a one-dimensional flow reactor. The results show that the zeolite filter system could be a simple low cost pre-treatment option which is able to significantly reduce the total hardness level of recycled water via effective ion exchange. Additionally, depending on the quality of recycled water required by end users, a new by-pass controller using a three-level operation switching mechanism is introduced. This approach provides householders sufficient flexibility to respond to different levels of desired recycled water quality and increase the reliability of long term system operation. These findings could be beneficial to the smooth implementation of new end uses and expansion of the potential recycled water market. The information could also offer sound suggestions for future research on sustainable water management and governance. PMID- 24496025 TI - Pollution and health risk of potentially toxic metals in urban road dust in Nanjing, a mega-city of China. AB - Spatial variations in concentrations of a suite of potentially toxic metals (Ba, Cr, Cu, Fe, Mn, Ni, Pb and Zn) and Ca in road dusts (n=99) from urban trunk roads (TR) in Nanjing, a mega-city in China, were established. Metal pollution levels, sources and human health risk (non-carcinogenic) were studied. In contrast to previous studies, we labeled the indicative metals relating to non-exhaust traffic emissions by comparing metal pollution between crossroad and park road dusts, and then anthropogenic sources of metals in TR dusts were assessed combining their spatial pollution patterns, principal component analysis and Pb isotopic compositions. Results showed that the metals were enriched in TR dusts compared to background soil concentrations with mean enrichment factors (EFs) of 2.2-23, indicating considerable anthropogenic influence. The degrees of metal pollution ranged from minimal to extremely high and ranked by Ca>Cu>Pb~Zn>Cr~Fe>Ni~Ba>Mn on average. Pollution of Cr, Cu, Fe, Mn, Ni, Pb and Zn in TR dusts resulted primarily from industrial emissions (e.g., coal combustion and smelting) and high pollution levels were found close to suburb industrial complexes, whereas pollution of Ba and Ca was mainly related to construction/demolition sources and was generally distributed homogeneously. The relatively minor contribution of non-exhaust traffic emissions to metal pollution in TR dusts was considered to be due to overwhelming industrial and construction/demolition contributions, as well as to the dilution effect of natural soil particles. Ingestion appears to be the major route of exposure for road dust for both adults and children, followed by dermal contact. The non carcinogenic health risk resulting from exposure to the potentially toxic metals in TR dusts was within the safe level based on the Hazard Index (HI), except in pollution hotspots where exposure to Pb, Cr, and Cu may be hazardous to children. PMID- 24496026 TI - Effects of a fungicide (imazalil) and an insecticide (diazinon) on stream fungi and invertebrates associated with litter breakdown. AB - The intensification of agriculture has promoted the use of pesticides such as fungicides and insecticides. Many pesticides readily leach into natural water bodies and affect both organisms and ecosystem processes such as leaf breakdown, a crucial process in headwater streams. As leaf breakdown in streams involves sequential steps by different groups of organisms (first microbial conditioning, then invertebrate shredding), pesticides targeting different organisms are likely to affect one or the other step, and a mixture of contaminants might have interactive effects. Our objective was to evaluate the effect of a fungicide (imazalil) and an insecticide (diazinon) on stream fungal and invertebrate activities, and their effects on leaf consumption. After an initial assay to define 'effective concentration' of both pesticides in a laboratory experiment, we manipulated pesticide presence/absence during the conditioning and shredding phases. Both pesticides affected fungal community and reduced the performance of the shredding amphipod Echinogammarus berilloni, and leaf consumption. The impact of pesticides on fungal sporulation depended on the length of the exposure period. In addition, pesticides seemed to cause an energetic imbalance in the amphipod, affecting body condition and mortality. The combined effect of both pesticides was similar to those of the fungicide. Overall, our results show that the effects of pesticide mixtures on leaf breakdown are hard to predict from those observed in either fungi or macroinvertebrate performance. PMID- 24496027 TI - Predicting daily ragweed pollen concentrations using Computational Intelligence techniques over two heavily polluted areas in Europe. AB - Forecasting ragweed pollen concentration is a useful tool for sensitive people in order to prepare in time for high pollen episodes. The aim of the study is to use methods of Computational Intelligence (CI) (Multi-Layer Perceptron, M5P, REPTree, DecisionStump and MLPRegressor) for predicting daily values of Ambrosia pollen concentrations and alarm levels for 1-7 days ahead for Szeged (Hungary) and Lyon (France), respectively. Ten-year daily mean ragweed pollen data (within 1997 2006) are considered for both cities. 10 input variables are used in the models including pollen level or alarm level on the given day, furthermore the serial number of the given day of the year within the pollen season and altogether 8 meteorological variables. The study has novelties as (1) daily alarm thresholds are firstly predicted in the aerobiological literature; (2) data-driven modelling methods including neural networks have never been used in forecasting daily Ambrosia pollen concentration; (3) algorithm J48 has never been used in palynological forecasts; (4) we apply a rarely used technique, namely factor analysis with special transformation, to detect the importance of the influencing variables in defining the pollen levels for 1-7 days ahead. When predicting pollen concentrations, for Szeged Multi-Layer Perceptron models deliver similar results with tree-based models 1 and 2 days ahead; while for Lyon only Multi Layer Perceptron provides acceptable result. When predicting alarm levels, the performance of Multi-Layer Perceptron is the best for both cities. It is presented that the selection of the optimal method depends on climate, as a function of geographical location and relief. The results show that the more complex CI methods perform well, and their performance is case-specific for >=2 days forecasting horizon. A determination coefficient of 0.98 (Ambrosia, Szeged, one day and two days ahead) using Multi-Layer Perceptron ranks this model the best one in the literature. PMID- 24496028 TI - The stress of being contaminated? Adrenocortical function and reproduction in relation to persistent organic pollutants in female black legged kittiwakes. AB - High levels of environmental pollutants such as persistent organic pollutants (POPs) including PCB and DDT have been found in the Arctic and many of those pollutants may impair reproduction through endocrine disruption. Nevertheless, their effects on stress hormones remain poorly understood, especially in free ranging birds. Corticosterone, the principal glucocorticoid in birds, can indirectly impair reproduction. The aim of the present study was to examine the relationships between POPs and reproduction through their potential consequences on different reproductive traits (breeding decision, egg-laying date, breeding success) and corticosterone secretion (baseline and stress-induced levels). We addressed those questions in an Arctic population of female black-legged kittiwakes during the pre-breeding stage and measured several legacy POPs (PCBs and pesticides: HCB, p,p'-DDE, CHL) in whole blood. POP levels were not related to breeding decision neither to breeding success, whereas females with high levels of pesticides laid their eggs earlier in the season. We found a negative relationship between POP levels and body condition index in non-breeding females. Black-legged kittiwakes with higher levels of PCB showed stronger adrenocortical response when subjected to a capture-handling stress protocol. We suggest that PCBs may disrupt corticosterone secretion whereas the positive relationship between pesticides and egg-laying date could either originate from a direct effect of pesticides or may be related to other confounding factors such as age or individual's quality. Although no direct negative reproduction output of POPs was found in this study, it is possible that the most contaminated individuals would be more sensitive to environmental stress and would be less able to maintain parental investment than less polluted individuals. PMID- 24496029 TI - Trichoderma sp. PDR1-7 promotes Pinus sylvestris reforestation of lead contaminated mine tailing sites. AB - Vegetation is critical to stabilize and remediate mine tailing sites, but plant growth is often poor due to toxicity from heavy metal(loid)s (HMs). A non symbiotic endophytic fungus, Trichoderma sp. PDR1-7, isolated from Pb contaminated mine tailing soil, exhibited both high tolerance to HMs and desirable plant growth-promoting characteristics. PDR1-7 promoted HM solubilization in mine tailing soil and removed significant amounts of Pb and other HMs from liquid media containing single and multiple metals. Pb removal efficiency increased with initial pH from 4 to 6 and with Pb concentration from 100 to 125 mg L(-1). Inoculating soil with PDR1-7 significantly increased nutrient availability and seedling growth, chlorophyll and protein contents, as well as antioxidative enzyme (superoxide dismutase) activity. A decrease in malondialdehyde indicated less oxidative stress. HM concentrations were much higher in Pinus sylvestris roots when PDR1-7 was present. These observations suggest the utility of Trichoderma sp. PDR1-7 for pine reforestation and phytoremediation of Pb-contaminated mine soil. PMID- 24496031 TI - Multivariate statistical analysis of the hydrogeochemical and isotopic composition of the groundwater resources in northeastern Peloponnesus (Greece). AB - The present study involves an integration of the hydrogeological, hydrochemical and isotopic (both stable and radiogenic) data of the groundwater samples taken from aquifers occurring in the region of northeastern Peloponnesus. Special emphasis has been given to health-related ions and isotopes in relation to the WHO and USEPA guidelines, to highlight the concentrations of compounds (e.g., As and Ba) exceeding the drinking water thresholds. Multivariate statistical analyses, i.e. two principal component analyses (PCA) and one discriminant analysis (DA), combined with conventional hydrochemical methodologies, were applied, with the aim to interpret the spatial variations in the groundwater quality and to identify the main hydrogeochemical factors and human activities responsible for the high ion concentrations and isotopic content in the groundwater analysed. The first PCA resulted in a three component model, which explained approximately 82% of the total variance of the data sets and enabled the identification of the hydrogeological processes responsible for the isotopic content i.e., delta(18)Omicron, tritium and (222)Rn. The second PCA, involving the trace element presence in the water samples, revealed a four component model, which explained approximately 89% of the total variance of the data sets, giving more insight into the geochemical and anthropogenic controls on the groundwater composition (e.g., water-rock interaction, hydrothermal activity and agricultural activities). Using discriminant analysis, a four parameter (delta(18)O, (Ca+Mg)/(HCO3+SO4), EC and Cl) discriminant function concerning the (222)Rn content was derived, which favoured a classification of the samples according to the concentration of (222)Rn as (222)Rn-safe (<11 Bq.L(-1)) and (222)Rn contaminated (>11 Bq.L(-1)). The selection of radon builds on the fact that this radiogenic isotope has been generally related to increased health risk when consumed. PMID- 24496030 TI - Historical records, sources, and spatial trends of PCBs along the Rhone River (France). AB - Despite bans on PCB use since 1975 (open systems) and 1987 (closed systems), concentrations of PCBs in riverine fish in France continue to exceed regulatory levels. We present historical records of PCB concentrations in sediment cores from eight sites on the Rhone River, from Lake Geneva to the Mediterranean Sea. Maximum PCB concentrations (sum of seven indicator PCBs) increase downstream, from 11.50 MUg/kg at the most upstream site to 417.1 MUg/kg at the most downstream site. At some sites peak concentrations occur in sediment deposited as recently as the 2000s. Hierarchical clustering (five clusters) identified differences in PCB congener profiles within and between sites. Exponential models fit to decadal time windows indicate that rapid reductions in concentrations during about 1990-2000 have slowed, and that it might be decades before target concentrations in sediment that correspond to regulatory thresholds in fish will be reached at some sites. PMID- 24496032 TI - The history of widespread decrease in oak dominance exemplified in a grassland forest landscape. AB - Regionally-distinctive open oak forest ecosystems have been replaced either by intensive agriculture and grazing fields or by denser forests throughout eastern North America and Europe. To quantify changes in tree communities and density in the Missouri Plains, a grassland-forest landscape, we used historical surveys from 1815 to 1864 and current surveys from 2004 to 2008. To estimate density for historical communities, we used the Morisita plotless density estimator and applied corrections for surveyor bias. To estimate density for current forests, we used Random Forests, an ensemble regression tree method, to predict densities from known values at plots using terrain and soil predictors. Oak species decreased from 62% of historical composition to 30% of current composition and black and white oaks historically were dominant species across 93% of the landscape and currently were dominant species across 42% of the landscape. Current forest density was approximately two times greater than historical densities, demonstrating loss of savanna and woodlands and transition to dense forest structure. Average tree diameters were smaller than in the past, but mean basal area and stocking remained similar over time because of the increase in density in current forests. Nevertheless, there were spatial differences; basal area and stocking decreased along rivers and increased away from rivers. Oak species are being replaced by other species in the Missouri Plains, similar to replacement throughout the range of Quercus. Long-term commitment to combinations of prescribed burning and silvicultural prescriptions in more xeric sites may be necessary for oak recruitment. Restoration of open oak ecosystems is a time sensitive issue because restoration will become increasingly costly as oaks are lost from the overstory and the surrounding matrix becomes dominated by non-oak species. PMID- 24496033 TI - A nanofiltration-coagulation integrated system for separation and stabilization of arsenic from groundwater. AB - A membrane-integrated hybrid treatment system has been developed for continuous removal of arsenic from contaminated groundwater with simultaneous stabilization of arsenic rejects for safe disposal. Both trivalent and pentavalent arsenic could be removed by cross flow nanofiltration following a chemical pre-oxidation step for conversion of trivalent arsenic into pentavalent form. The very choice of the membrane module and its judicious integration with upstream oxidation and downstream stabilization resulted in continuous removal of more than 98% arsenic from water that contained around 190 mg L(-1) of total suspended solid, 205 mg L( 1) of total dissolved solid, 0.18 mg L(-1) of arsenic and 4.8 mg L(-1) of iron at a pH of 7.2. The used flat sheet cross flow membrane module yielded a high flux of 144-145 L m(-2) h(-1) at a transmembrane pressure of only 16 kgf.cm(-2) without the need for frequent replacement of the membranes. Transmembrane pressure, cross flow rate through the membrane module and oxidant dose were found to have pronounced effects on arsenic rejection and pure water flux. For the first time, an effective scheme for protection of the total environment has been ensured in this context where arsenic separated with high degree of efficiency has been stabilized in a solid matrix of iron and calcium under response surface optimized conditions. The study culminated in a total and sustainable solution to the problem of arsenic contamination of groundwater by offering arsenic-free water at a reasonably low price of only 1.41$.m(-3). PMID- 24496034 TI - Effect of different organic amendments on the dissipation of linuron, diazinon and myclobutanil in an agricultural soil incubated for different time periods. AB - Dissipation kinetics of pesticides belonging to three chemical groups (linuron, diazinon and myclobutanil) was studied in an unamended agricultural soil and in this soil amended with three organic residues: sewage sludge (SS), grape marc (GM) and spent mushroom substrate (SMS). The soils were incubated with the residues outdoors for one and 12 months. Mineralized, extracted and non extractable fractions were also studied for (14)C-linuron and (14)C-diazinon. The dissipation kinetics was fitted to single first-order or first-order multicompartment models. The dissipation rate (k) decreased in the order diazinon>linuron>myclobutanil, and DT50 values decreased for linuron (1.6-4.8 times) or increased for myclobutanil (1.7-2.6 times) and diazinon (1.8-2.3 times) in the amended soils relative to the unamended soil. The lowest DT50 values for the three pesticides were recorded in GM-amended soil, and the highest values in SMS-amended soil. After 12 months of soil incubation, DT50 values decreased in both the unamended and amended soils for linuron, but increased for the unamended and SMS-amended soil for diazinon and myclobutanil. A certain relationship was observed between the sorption of pesticides by the soils and DT50 values, although it was significant only for myclobutanil (p<0.05). Dissipation mechanism recorded the lowest mineralization of (14)C-pesticides in the GM-soil despite the highest dissipation rate in this soil. The extracted (14)C-residues decreased with incubation time, with increased formation of non-extractable residues, higher in amended soils relative to the unamended soil. Soil dehydrogenase activity was, in general, stimulated by the addition of the organic amendments and pesticides to the soil after one month and 12 months of incubation. The results obtained revealed that the simultaneous use of amendments and pesticides in soils requires a previous study in order to check the environmental specific persistence of these compounds and their effectiveness in amended soils. PMID- 24496036 TI - Fluctuations in the electron system of a superconductor exposed to a photon flux. AB - In a superconductor, in which electrons are paired, the density of unpaired electrons should become zero when approaching zero temperature. Therefore, radiation detectors based on breaking of pairs promise supreme sensitivity, which we demonstrate using an aluminium superconducting microwave resonator. Here we show that the resonator also enables the study of the response of the electron system of the superconductor to pair-breaking photons, microwave photons and varying temperatures. A large range in radiation power (at 1.54 THz) can be chosen by carefully filtering the radiation from a blackbody source. We identify two regimes. At high radiation power, fluctuations in the electron system caused by the random arrival rate of the photons are resolved, giving a straightforward measure of the optical efficiency (48 +/- 8%) and showing an unprecedented detector sensitivity. At low radiation power, fluctuations are dominated by excess quasiparticles, the number of which is measured through their recombination lifetime. PMID- 24496035 TI - Polybrominated diphenyl ethers (PBDEs) in fish tissue may be an indicator of plastic contamination in marine habitats. AB - The accumulation of plastic debris in pelagic habitats of the subtropical gyres is a global phenomenon of growing concern, particularly with regard to wildlife. When animals ingest plastic debris that is associated with chemical contaminants, they are at risk of bioaccumulating hazardous pollutants. We examined the relationship between the bioaccumulation of hazardous chemicals in myctophid fish associated with plastic debris and plastic contamination in remote and previously unmonitored pelagic habitats in the South Atlantic Ocean. Using a published model, we defined three sampling zones where accumulated densities of plastic debris were predicted to differ. Contrary to model predictions, we found variable levels of plastic debris density across all stations within the sampling zones. Mesopelagic lanternfishes, sampled from each station and analyzed for bisphenol A (BPA), alkylphenols, alkylphenol ethoxylates, polychlorinated biphenyls (PCBs) and polybrominated diphenyl ethers (PBDEs), exhibited variability in contaminant levels, but this variability was not related to plastic debris density for most of the targeted compounds with the exception of PBDEs. We found that myctophid sampled at stations with greater plastic densities did have significantly larger concentrations of BDE#s 183 -209 in their tissues suggesting that higher brominated congeners of PBDEs, added to plastics as flame-retardants, are indicative of plastic contamination in the marine environment. Our results provide data on a previously unsampled pelagic gyre and highlight the challenges associated with characterizing plastic debris accumulation and associated risks to wildlife. PMID- 24496037 TI - MicroRNAs and SerpinB3 in hepatocellular carcinoma. AB - miRNAs are small non-coding RNAs which target complementary mRNA sequences, usually resulting in gene silencing. They can exhibit oncogenic or tumor suppressor properties, modulating cell homeostasis. Several data have documented that miRNAs are typically deregulated in different types of cancers, including hepatocellular carcinoma (HCC). Some of the miRNAs such as miR-122, miR-221, miR 1 and miR-21 have been found to repress post-transcriptionally the expression of genes involved in cell cycle regulation, cell proliferation, apoptosis, cell migration and invasion. In HCC serum levels of miR-122, miR-221 and miR-16 have been described deregulated, suggesting that they may be used as molecular targets for early detection, prognosis and treatment. The ov-serpin SerpinB3 was found previously increased in liver tumor cancers and associated with apoptosis resistance, increased cell proliferation and invasiveness. Recent data indicate that this serpin may enhance its oncogenic potential through inhibition of several tumor suppressive miRNAs, typically described in HCC. PMID- 24496039 TI - Excitatory effects of bombesin receptors in urinary tract of normal and diabetic rats in vivo. AB - AIMS: Bombesin receptors (BB receptors) and bombesin related peptides are expressed in the lower urinary tract of rodents. Here we investigated whether in vivo activation of BB receptors can contract the urinary bladder and facilitate micturition in sham rats and in a diabetic rat model of voiding dysfunction. MATERIAL AND METHODS: In vivo cystometry experiments were performed in adult female Sprague-Dawley rats under urethane anesthesia. Diabetes was induced by streptozotocin (STZ; 65mg/kg, i.p.) injection. Experiments were performed 9 and 20weeks post STZ-treatment. Drugs included neuromedin B (NMB; BB1 receptor preferring agonist), and gastrin-releasing peptide (GRP; BB2 receptor preferring agonist). KEY FINDINGS: NMB and GRP (0.01-100MUg/kg in sham rats; 0.1-300MUg/kg in STZ-treated rats, i.v.) increased micturition frequency, bladder contraction amplitude and area under the curve dose dependently in both sham and STZ-treated rats. In addition, NMB (3, 10MUg/kg i.v.) triggered voiding in >80% of STZ treated rats when the bladder was filled to a sub-threshold voiding volume. NMB and GRP increased mean arterial pressure and heart rate at the highest doses, 100 and 300MUg/kg. SIGNIFICANCE: Activation of bombesin receptors facilitated neurogenic bladder contractions in vivo. Single applications of agonists enhanced or triggered voiding in sham rats as well as in the STZ-treated rat model of diabetic voiding dysfunction. These results suggest that BB receptors may be targeted for drug development for conditions associated with poor detrusor contraction such as an underactive bladder condition. PMID- 24496040 TI - Micro-finite element (MUFE) modeling of the siamang (Symphalangus syndactylus) third proximal phalanx: the functional role of curvature and the flexor sheath ridge. AB - Phalangeal curvature is a commonly used morphological feature for the interpretation of extant and fossil primate locomotor behaviour. Here, we build on a recent biomechanical study (Richmond, 2007) in two ways: first, we use a 3D micro-FE model, which models the real internal microstructure (i.e., cortical thickness and trabecular bone structure) and, second, we model four siamang third proximal phalanges. We test identical 2D homogenized FE models and two 3D micro FE phalanx models that are mathematically straightened to isolate the biomechanical significance of curvature. We further investigate how varying the loading configuration (e.g., boundary constraints) and modeling (e.g., 2D versus 3D) affects the biomechanical behaviour of the phalanx. Finally, we examine how intraspecific variation in external and internal bony morphology affects the biomechanical behaviour of the phalanx. Simulation results demonstrate that the general pattern of strain and displacement is similar between the 3D micro-FE and 2D homogenized FE models but the absolute values differ substantially. The biomechanical behaviour of the 3D FE models more closely match the relative strain patterns from the validation experiment than the 2D homogenized FE models, indicating the 3D microstructure model is preferable. Varying the loading configuration can have dramatic effects on the biomechanical behaviour of the phalanx depending on individual morphology, but overall a cantilevered beam model is an equally valid, if not better, configuration for modeling the phalanx as other previously-proposed models. Variation in flexor ridge morphology has a substantial effect on phalanx strain; the taller the ridge, the less strain incurred by other regions of the palmar shaft. Finally, phalangeal curvature reduces overall strain experienced by the phalanx, but does not necessarily reduce bending or increase the compression-to-tension ratio. These results confirm the adaptive role of phalangeal curvature during flexed-finger grasping postures and demonstrate that modeling variation in cortical thickness and flexor ridge morphology improves the behaviour of the FE model, which has important implications for the functional interpretation of phalanx form. PMID- 24496038 TI - SR48692 inhibits non-small cell lung cancer proliferation in an EGF receptor dependent manner. AB - AIMS: The mechanism by which SR48692 inhibits non-small cell lung cancer (NSCLC) proliferation was investigated. MAIN METHODS: The ability of SR48692 to inhibit the proliferation of NSCLC cell lines NCI-H1299 and A549 was investigated in vitro in the presence or absence of neurotensin (NTS). The ability of NTS to cause epidermal growth factor receptor (EGFR) transactivation was investigated by Western blot using NSCLC cells and various inhibitors. The growth effects and Western blot results were determined in cell lines treated with siRNA for NTSR1. KEY FINDINGS: Treatment of A549 or NCI-H1299 cells with siRNA for NTSR1 reduced significantly NTSR1 protein and the ability of SR48692 to inhibit the proliferation of A549 or NCI-H1299 NSCLC cells. Treatment of A549 and NCI-H1299 cells with siRNA for NTSR1 reduced the ability of NTS to cause epidermal growth factor receptor (EGFR) transactivation. SR48692 or gefitinib (EGFR tyrosine kinase inhibitor) inhibited the ability of NTS to cause EGFR and ERK tyrosine phosphorylation. NTS transactivation of the EGFR was inhibited by GM6001 (matrix metalloprotease inhibitor), Tiron (superoxide scavenger) or U73122 (phospholipase C inhibitor) but not H89 (PKA inhibitor). NTS stimulates whereas SR48692 or gefitinib inhibits the clonal growth of NSCLC cells. SIGNIFICANCE: These results suggest that SR48692 may inhibit NSCLC proliferation in an EGFR-dependent mechanism. PMID- 24496041 TI - Global cancer prevalence is growing at "alarming pace," says WHO. PMID- 24496043 TI - Efficacy of the Social Cognition Training Program in a sample of schizophrenic outpatients. AB - Objective: Social cognition is recognized to be a deficit in individuals suffering from schizophrenia. Numerous studies have explored the relationship between social cognition and social functioning in outpatients with schizophrenia through the use of different social cognition training programs. This study examines the efficacy of the Social Cognition Training Program (PECS in Spanish) in adults with a diagnosis of schizophrenia. Methods: Data were derived from a sample of 44 non-hospitalized adult patients, who presented with a DSM-IV-R Axis I diagnosis of schizophrenia, and 39 healthy controls. Patients were divided into an experimental group and a control task group, that received cognitive training. Healthy controls did not receive any treatment. Sociodemographic and clinic variables correlates were computed. 2-way ANOVA was conducted to examine differences between groups in pre and post-treatment measures. Intragroup differences were explores using the paired-samples t-test. Results: At the end of the training, patients in the experimental group showed a higher performance compared to patients in the control task group, in the Hinting Task Test and in the emotion recognition of sadness, anger, fear, and disgust. Conclusions: The PECS proved to be effective in the improvement of some areas of theory of mind and emotion recognition, in outpatients with schizophrenia. The PECS is one of the first programs developed in Spanish to train social cognition, and the data obtained support the importance of expand the social cognition programs to non English language samples. PMID- 24496044 TI - Adjunctive Pregnenolone Ameliorates the Cognitive Deficits in Recent-Onset Schizophrenia: An 8-Week, Randomized, Double-Blind, Placebo-Controlled Trial. AB - PURPOSE: This study aimed to examine the effect of add-on treatment with the neurosteroid pregnenolone (PREG) on neurocognitive dysfunctions of patients with recent-onset schizophrenia (SZ) and schizoaffective disorder (SA). METHOD: Sixty out- and inpatients that met DSM-IV criteria for SZ/SA were randomized to an 8 week, double-blind, randomized, placebo-controlled, 2-center trial. Participants received either pregnenolone (50 mg/d) or placebo added on to antipsychotic medications. Computerized Cambridge Automated Neuropsychological Test Battery measures were administered at baseline and after 4 and 8 weeks of treatment. ANOVA and paired t- or z-tests were applied to examine between- and within-group differences over time. RESULTS: Compared to placebo, adjunctive PREG significantly reduced the deficits in visual attention measured with the Matching to Sample Visual Search task (p=0.002), with moderate effect sizes (d=0.42). In addition, a significant improvement was observed from baseline to end-of-study with respect to the visual (p=0.008) and sustained attention (Rapid Visual Information Processing, p=0.038) deficits, and executive functions (Stockings of Cambridge, p=0.049; Spatial Working Memory, p<0.001) among patients receiving PREG but not among those receiving placebo (all p's>0.05). This beneficial effect of PREG was independent of the type of antipsychotic agents, gender, age, education, and illness duration. CONCLUSIONS: Pregnenolone augmentation demonstrated significant amelioration of the visual attention deficit in recent onset SZ/SA. Long-term, large-scale studies are required to obtain greater statistical significance and more confident clinical generalization. PMID- 24496045 TI - Adherence to Diabetes Medication in Individuals with Schizophrenia: A Systematic Review of Rates and Determinants of Adherence. AB - INTRODUCTION: Despite the importance of medication adherence for the effective treatment of type II diabetes mellitus (T2DM), little research has examined adherence with diabetes medication treatment in schizophrenia. The purpose of this systematic review was to: 1) evaluate rates of adherence and determinants of adherence with medication for T2DM in individuals with schizophrenia; and, where possible, 2) examine the relationship between medication adherence and glycemic control. METHODS: Studies were included if they presented information on dosing regimens and adherence or compliance rates for T2DM and included samples where at least 50% of the participants were individuals with schizophrenia. RESULTS: Six studies were included in this review that predominantly examined men over the age of 50 years. Studies confirmed that many individuals with schizophrenia were not adhering to their diabetes medication as adherence rates ranged from 51-85%. Two studies that compared medication adherence in individuals with and without schizophrenia found those with the mental illness had higher rates of adherence. One study reported that blood glucose control levels were not statistically different between those who did and did not adhere to their medication, indicating more research is necessary in this area. Factors that improved adherence included disease and medical service and medication-related factors. CONCLUSIONS: Interventions to increase diabetes medication adherence in schizophrenia need to address disease and medical service and medication-related factors. Further research needs to examine diabetes medication adherence in women, younger individuals, and those recently diagnosed with diabetes as these individuals have been underrepresented in the literature. PMID- 24496042 TI - Characterization and differential expression of CPD and 6-4 DNA photolyases in Xiphophorus species and interspecies hybrids. AB - Among the many Xiphophorus interspecies hybrid tumor models are those that exhibit ultraviolet light (UVB) induced melanoma. In previous studies, assessment of UVB induced DNA damage and nucleotide excision DNA repair has been performed in parental lines and interspecies hybrids. Species and hybrid specific differences in the levels of DNA damage induced and the dark repair rates for cyclobutane pyrimidine dimers (CPDs) and 6-4 pyrimidine pyrimidine photoproducts (6-4PPs) have been reported. However, UVB induced DNA lesions in Xiphophorus fishes are thought to primarily be repaired via light dependent CPD and 6-4PP specific photolyases. Photolyases are of evolutionary interest since they are ancient and presumably function solely to ameliorate the deleterious effects of UVB exposure. Herein, we report results from detailed studies of CPD and 6-4PP photolyase gene expression within several Xiphophorus tissues. We determined photolyase gene expression patterns before and after exposure to fluorescent light in X. maculatus, X. couchianus, and for F1 interspecies hybrids produced from crossing these two parental lines (X. maculatus Jp 163 B*X. couchianus). We present novel results showing these two photolyase genes exhibit species, tissue, and hybrid-specific differences in basal and light induced gene expression. PMID- 24496046 TI - Clozapine Induced Pericarditis. PMID- 24496047 TI - The foregut theory as a possible mechanism of action for the remission of type 2 diabetes in low body mass index patients undergoing subtotal gastrectomy for gastric cancer. AB - BACKGROUND: The question of whether pure metabolic surgery could be used in nonobese patients with type 2 diabetes has been considered. The objective of this study was to assess the comparative effects of the Billroth I (BI) and Billroth II (BII) reconstruction methods on remission of type 2 diabetes in nonobese patients undergoing subtotal gastrectomy for cancer. METHODS: The charts of 404 patients who underwent radical subtotal gastrectomy for cancer between January 2008 and December 2010 were retrospectively reviewed. From these patients, 49 with type 2 diabetes were included in this study. Diabetes remission rates, the percentage change in fasting plasma glucose levels, glycated hemoglobin levels, body mass index, and fasting total cholesterol levels at 2 years were observed. Outcomes were compared using propensity scores and inverse probability-weighting adjustment that reduced treatment-selection bias. Covariate-adjusted logistic regression models were assessed. RESULTS: The 2-year diabetes remission rate for the 23 patients who underwent BI reconstruction was 39.1%, compared with 50.0% for the 26 patients who underwent BII reconstruction. At 2 years, the BII group showed lower glycated hemoglobin levels (BI, 6.4%; BII, 6.1%; P = .003) and had greater percent reductions in their average glycated hemoglobin levels from baseline (BI,-11.6%; BII,-14.5%; P = .043). BII reconstruction was significantly associated with an increased diabetes remission rate (odds ratio, 3.22; 95% confidence interval, 1.05-9.83) in covariate-adjusted logistic regression analysis. CONCLUSIONS: These propensity score-adjusted analyses of patients who had undergone subtotal gastrectomy indicated that BII reconstruction was associated with increased diabetes remission compared with BI reconstruction during the 2-year follow-up period. This study suggests the possibility of employing the surgical duodenal switch for the treatment of nonobese type 2 diabetes patients. PMID- 24496048 TI - Electromyographic activity after latissimus dorsi transfer: testing of coactivation as a simple tool to assess latissimus dorsi motor learning. AB - BACKGROUND: The purpose of this study was to investigate coactivation (CoA) testing as a clinical tool to monitor motor learning after latissimus dorsi tendon transfer. METHODS: We evaluated 20 patients clinically with the American Shoulder and Elbow Surgeons (ASES) and University of California-Los Angeles (UCLA) outcomes scores, visual analog scale, active external rotation (aER), and isometric strength testing in abduction and external rotation. Measurements of aER were performed while the latissimus dorsi was activated in its new function of external rotation with concomitant activation (coactivation) of its native functions (adduction and extension). Bilateral surface electromyographic (EMG) activity was recorded during aER measurements and the strength testing procedure (EMG activity ratio: with/without CoA). Patients were divided into two groups (excellent/good vs fair/poor) according to the results of the ASES and UCLA scores. RESULTS: The mean follow-up was 57.8 +/- 25.2 months. Subdivided by clinical scores, the superior outcome group lost aER with CoA, whereas the inferior outcome group gained aER (UCLA score: -2.2 degrees +/- 7.4 degrees vs +4.3 degrees +/- 4.1 degrees ; P = .031). Patients with inferior outcomes in the ASES score showed higher latissimus dorsi EMG activity ratios (P = .027), suggesting an inadequate motor learning process. Isometric strength testing revealed that the latissimus dorsi transfer had significantly greater activity compared with the contralateral side (external rotation, P = .008; abduction, P = .006) but did not have comparable strength (external rotation, P = .017; abduction, P = .009). CONCLUSIONS: Patients with inferior clinical results were more likely to be dependent on CoA to gain external rotation. Therefore, CoA testing may be used as a tool to evaluate the status of postoperative motor learning after latissimus dorsi transfer. PMID- 24496049 TI - Superior labrum anterior-to-posterior repair incidence: a longitudinal investigation of community and academic databases. AB - BACKGROUND: Superior labrum anterior-to-posterior (SLAP) lesion repair is controversial regarding indications and potential complications. METHODS: Databases were used to determine the SLAP repair incidence compared with all orthopaedic procedures over a period of 10 years. In part A, the New York Statewide Planning and Research Cooperative System ambulatory surgery database was investigated from 2002 to 2009. In part B, the California Office of Statewide Health Planning and Development ambulatory surgery database was investigated from 2005 to 2009. In part C, the American Board of Orthopaedic Surgery (ABOS) database was investigated from 2003 to 2010. RESULTS: In part A, from 2002 to 2009, there was a 238% increase in SLAP repair volume compared with a 125% increase in all orthopaedic procedures. In part B, from 2005 to 2009, there was a 20.17% increase in SLAP repair volume compared with a decrease of 13.64% in all orthopaedic procedures. In part C, among candidates performing at least 1 SLAP repair, there was no statistically significant difference in likelihood of performing a SLAP repair (95% confidence interval, 0.973-1.003) in 2010 as compared with 2003 (P > .10). CONCLUSIONS: There has been a significant increase in the incidence of SLAP repairs in the past 10 years in statewide databases. This pattern was not seen in the ABOS database, in which the annual volume of SLAP repairs remained stable over the same period. This suggests that SLAP lesions have been over-treated with surgical repair but that part II ABOS candidates are becoming more aware of the need to narrow indications. LEVEL OF EVIDENCE: Epidemiology study, database analysis. PMID- 24496050 TI - The severity of the long head biceps tendinopathy in patients with chronic rotator cuff tears: macroscopic versus microscopic results. AB - BACKGROUND: This study investigated the histopathology of the long head of biceps (LHB) tendon and correlated the findings with the macroscopic appearances of the LHB and the size of rotator cuff tears (RCTs) in patients with chronic RCTs. METHODS: We compared biopsy specimens from LHBs in 34 patients with chronic RCTs and grossly normal LHBs in 8 patients undergoing shoulder hemiarthroplasty (controls). Duration of preoperative symptoms, the severity of RCTs, and macroscopic appearance of LHBs were recorded, classified, and compared with the histologic grading and apoptosis index of terminal deoxynucleotide transferase mediated biotin-deoxy uridine triphosphate nick-end labeling (TUNEL) assays of LHBs. RESULTS: In the RCT group, there were 8 partial-thickness tears with 5 macroscopic LHB lesions, 12 full-thickness tears with 8 macroscopic LHB lesions, and 14 massive tears with 13 macroscopic LHB lesions. There were 6 LHB subluxations. However, the macroscopic grading and the symptom duration were not correlated with the severity of the histology. In patients with massive tears, no matter what the macroscopic appearance of the LHB, the proportion of end-stage (grade 4) histologic LHB tendinopathy significantly increased (85.7%, P < .05) compared with patients with other types of RCTs. There was a consistently high incidence of advanced LHB histology (grade 3 or higher) in each classification of RCTs (75.0%-100.0%). The 8 patients in the control group showed milder histopathology (grade 1 or 2). The apoptosis index significantly increased as the tendinopathy progressed (P < .05). CONCLUSIONS: The macroscopic pathology of LHB may not fully reflect the severity of tendinopathy, and the coexisting size of RCTs plays a role in the severity of LHB tendinopathy. PMID- 24496052 TI - Square-wave adsorptive stripping voltammetric determination of nanomolar levels of bezafibrate using a glassy carbon electrode modified with multi-walled carbon nanotubes within a dihexadecyl hydrogen phosphate film. AB - A highly sensitive method for bezafibrate determination using a glassy carbon electrode (GCE) modified with multi-walled carbon nanotubes within a dihexadecyl hydrogen phosphate film based on square-wave adsorptive stripping voltammetry (SWAdSV) is proposed. The electrochemical behaviour of bezafibrate has been studied by cyclic voltammetry, showing an irreversible anodic peak at a potential of 1.09 V in 0.1 mol L(-1) phosphate buffer solution (pH 2.0). A study of the scan rate showed that the oxidation of bezafibrate is an adsorptive-controlled process, involving the transfer of two electrons and two protons per molecule. The analytical curve was linear over a bezafibrate concentration range from 50 to 910 nmol L(-1), with a detection limit of 16 nmol L(-1). This analytical method was successfully applied for benzafibrate determination in pharmaceutical formulations, with results showing good agreement with those obtained using a comparative spectrophotometric method, and has the potential for field application. PMID- 24496051 TI - Controlling the shape of LiCoPO4 nanocrystals by supercritical fluid process for enhanced energy storage properties. AB - Lithium-ion batteries offer promising opportunities for novel energy storage systems and future application in hybrid electric vehicles or electric vehicles. Cathode materials with high energy density are required for practical application. Herein, high-voltage LiCoPO4 cathode materials with different shapes and well-developed facets such as nanorods and nanoplates with exposed {010} facets have been synthesized by a one-pot supercritical fluid (SCF) processing. The effect of different amines and their roles on the morphology-control has been investigated in detail. It was found that amine having long alkyl chain such as hexamethylenediamine played important roles to manipulate the shape of the nanocrystals by selective adsorption on the specific {010} facets. More importantly, the nanorods and nanoplates showed better electrochemical performance than that of nanoparticles which was attributed to their unique crystallographic orientation with short Li ion diffusion path. The present study emphasizes the importance of crystallographic orientation in improving the electrochemical performance of the high voltage LiCoPO4 cathode materials for Li ion batteries. PMID- 24496053 TI - Mass Modulation of Protein Dynamics Associated with Barrier Crossing in Purine Nucleoside Phosphorylase. AB - The role of protein dynamics on different time scales in enzyme catalysis remains an area of active debate. The connection between enzyme dynamics on the femtosecond time scale and transition state formation has been demonstrated in human purine nucleoside phosphorylase (PNP) through the study of a mass-altered enzyme. Isotopic substitution in human PNP (heavy PNP) decreased the rate of on enzyme chemistry but did not alter either the transition state structure or steady-state kinetic parameters. Here we investigate the underlying atomic motions associated with altered barrier crossing probability for heavy PNP. Transition path sampling was employed to illuminate the molecular differences between barrier crossing in light and heavy enzymes. The mass effect is apparent in promoting vibrations that polarize the N-ribosidic bond, and that promote the stability of the purine leaving group. These motions facilitate barrier crossing. PMID- 24496054 TI - Commercializing diarrhea vaccines for travelers. AB - Continued growth in international travel and forecasts for a great increase in the number of people who travel from industrialized to emerging and developing countries make it necessary to develop and improve the capacity to provide health protection to travelers. Measures available to prevent some diseases include a currently limited number of marketed vaccines which represent extremely useful tools to protect travelers. Travelers very often experience diarrheal and gastrointestinal diseases for which some vaccines are available. Use of these vaccines should be evaluated based on traveler and travel destination and characteristics. Vaccines available include those against cholera, typhoid fever, hepatitis A, hepatitis E (only available in China), and rotavirus. The aim of this review is to provide an updated summary about each of the abovementioned vaccines that may be useful for making decisions regarding their use and assessing their indications in recommendations for travelers. PMID- 24496055 TI - Microbial iron uptake as a mechanism for dispersing iron from deep-sea hydrothermal vents. AB - Deep-sea hydrothermal vents are a significant source of oceanic iron. Although hydrothermal iron rapidly precipitates as inorganic minerals on mixing with seawater, it can be stabilized by organic matter and dispersed more widely than previously recognized. The nature and source of this organic matter is unknown. Here we show that microbial genes involved in cellular iron uptake are highly expressed in the Guaymas Basin deep-sea hydrothermal plume. The nature of these microbial iron transporters, taken together with the low concentration of dissolved iron and abundance of particulate iron in the plume, indicates that iron minerals are the target for this microbial scavenging and uptake. Our findings indicate that cellular iron uptake is a major process in plume microbial communities and suggest new mechanisms for generating Fe-C complexes. This 'microbial iron pump' could represent an important mode of converting hydrothermal iron into bioavailable forms that can be dispersed throughout the oceans. PMID- 24496056 TI - Gratitude and longing: Meanings of health in aging for Puerto Rican adults in the mainland. AB - Puerto Rican adults in the United States mainland live with socioeconomic and health disparities. To understand their contextual experience of aging, we interviewed participants in the Boston Puerto Rican Health Study. Through a Thematic Analysis we identify themes and tensions: normalization and acceptance of aging; gratitude; the importance of aging within social networks; longing to return to Puerto Rico at older age. We address the tensions between 'acceptance' and fatalismo as a cultural belief, and a function of structural barriers. The experience of aging is discussed in the context of Puerto Rico's history and continued dependence on the United States. PMID- 24496057 TI - Cognitive predictors of limited health literacy in adults with heterogeneous socioeconomic backgrounds. AB - The purpose of this study was to explore the relationship between health literacy and specific cognitive abilities in hospital users. A neuropsychological battery was administered and the Short Test of Functional Health Literacy in Adults was used to classify individuals as having adequate or limited functional health literacy. Of the 322 participants, 102 (31.7%) presented limited health literacy. Even after adjusting for demographics, years of education, and quality of education, health literacy was strongly associated with measures of cognitive performance, but the strength of association was variable across different cognitive abilities. PMID- 24496058 TI - Appreciative inquiry: a research tool for mental health services. AB - Appreciative inquiry (AI) provides an alternative approach to the inquisitional style of uncovering "what went wrong and who is at fault" to instead "what can be done to make things better," thus creating an environment that enables one to discover (investigate), dream (what could have been done instead), design (what needs to be done to bring about change), and deliver/ destiny (working with a whole of health and community approach to obtain the positive outcomes for mental health consumers). AI is transformational in nature and provides a way of viewing organizations from an enabling perspective. This article discusses the concept of AI, highlights opportunities and challenges that may be encountered, and explores the possibility of applying the AI concept to mental health research/inquiry. PMID- 24496059 TI - Moving beyond caregiver burden: identifying helpful interventions for family caregivers. AB - Family members serving as informal caregivers for loved ones often experience physical, psychological, emotional, social, and financial consequences that can be conceptualized as caregiver burden. As the number of older adults in our society continues to increase, there will be even more demand for family caregivers. It is important to move beyond a focus on the statistics and characteristics of caregiver burden and identify helpful interventions to reduce this burden. Interventions that decrease caregiver burden can enable family caregivers to delay placement of the individual in an institutional setting and improve quality of life for both the caregiver and care recipient. PMID- 24496060 TI - ERIC: a new governance tool for biobanking. PMID- 24496061 TI - Exome sequencing reveals a heterozygous DLX5 mutation in a Chinese family with autosomal-dominant split-hand/foot malformation. AB - Split-hand/foot malformation (SHFM) is a congenital limb deformity due to the absence or dysplasia of central rays of the autopod. Six SHFM loci have already been identified. Here we describe a Chinese family with autosomal-dominant SHFM1 that has previously been mapped to 7q21.2-21.3. The two affected family members, mother and son, showed deep median clefts between toes, ectrodactyly and syndactyly; the mother also showed triphalangeal thumbs. Exome sequencing and variant screening of candidate genes in the six loci known to be responsible for SHFM revealed a novel heterozygous mutation, c.558G>T (p.(Gln186His)), in distal less homeobox 5 (DLX5). As DLX5 encodes a transcription factor capable of transactivating MYC, we also tested whether the mutation could affect DLX5 transcription acitivity. Results from luciferase reporter assay revealed that a mutation in DLX5 compromised its transcriptional activity. This is the first report of a mutation in DLX5 leading to autosomal-dominant SHFM1. PMID- 24496062 TI - Availability of treatment drives decisions of genetic health professionals about disclosure of incidental findings. AB - Contrasting opinions exist regarding the disclosure of incidental findings detected through clinical genomic testing. This study used a discrete choice experiment to investigate genetic health professionals' preferences for the disclosure of incidental findings in an Australian paediatric setting. Four attributes of conditions relating to incidental findings were investigated: availability of prevention and treatment, chance of symptoms ever developing, age of onset and severity. Questionnaires from 59 Australian genetic health professionals were analysed. Results show that when evaluating incidental findings for disclosure, these professionals value the availability of prevention and treatment for the condition above all other characteristics included in the study. The framework of this discrete choice experiment can be used to investigate the preferences of other stakeholders such as paediatricians and parents about disclosure of incidental findings. The results of this study may be considered when assessing which categories of incidental findings are most suitable for disclosure in clinical practice. PMID- 24496063 TI - More drugs originate outside the industry than it claims. PMID- 24496064 TI - A video demonstration of pacemaker-induced pectoral muscle stimulation. PMID- 24496065 TI - Osteochondroma of condyle: case discussion and review of treatment modalities. AB - Temporomandibular joint (TMJ) forms a synovial articulation between the condyle and the cranium. It is a complex joint and shows hinge and gliding movements. Unlike other articulating heads, condyle grows with intramembranous ossification. TMJ is subjected to excessive loads throughout life as it supports essential functions such as mastication, deglutition, speech and respiration. Traumatic, neoplastic or non-neoplastic pathologies sometimes necessitate joint replacement therapy. Osteochondroma is one such benign tumour originating from condyle which requires surgical replacement of condyle with prosthesis. Various replacement methods have been designed in the past. Alloplastic grafts have been successfully used in joint replacement surgeries like hip joint, knee joint, etc. This case discussion supports the use of titanium-made condylar prosthesis for long-term functional stability of TMJ. PMID- 24496066 TI - Weismann-Netter-Stuhl syndrome: report of two cases and treatment. AB - Weismann-Netter-Stuhl syndrome is a rarely reported cause of bowed legs; hence a thorough clinical and radiological examination is needed for its diagnosis. In view of the paucity of reports guiding the treatment of the deformity, we propose a one-level/two-level osteotomy with intramedullary nail fixation as a treatment modality for the tibial bowing. PMID- 24496067 TI - Early vein graft failure leading to acute myocardial infarction, dehiscence and haemopericardium treated by percutaneous coil embolisation and balloon tamponade. AB - Early vein graft failure is a well-described early complication of coronary artery bypass grafting. Revascularisation with emergency percutaneous coronary intervention (PCI) may limit the extent of myocardial damage and is associated with lower procedural complications compared than with emergency redo bypass surgery. We describe a case of an early saphenous vein graft (SVG) thrombosis presenting as an inferior ST-elevation to our non-surgical PCI site, complicated by SVG graft dehiscence leading to cardiac tamponade, which we treated with coil embolisation and balloon tamponade during the patient's transfer to a surgical facility for emergent haemopericardium evacuation. PMID- 24496068 TI - Clustering clinical trials with similar eligibility criteria features. AB - OBJECTIVES: To automatically identify and cluster clinical trials with similar eligibility features. METHODS: Using the public repository ClinicalTrials.gov as the data source, we extracted semantic features from the eligibility criteria text of all clinical trials and constructed a trial-feature matrix. We calculated the pairwise similarities for all clinical trials based on their eligibility features. For all trials, by selecting one trial as the center each time, we identified trials whose similarities to the central trial were greater than or equal to a predefined threshold and constructed center-based clusters. Then we identified unique trial sets with distinctive trial membership compositions from center-based clusters by disregarding their structural information. RESULTS: From the 145,745 clinical trials on ClinicalTrials.gov, we extracted 5,508,491 semantic features. Of these, 459,936 were unique and 160,951 were shared by at least one pair of trials. Crowdsourcing the cluster evaluation using Amazon Mechanical Turk (MTurk), we identified the optimal similarity threshold, 0.9. Using this threshold, we generated 8806 center-based clusters. Evaluation of a sample of the clusters by MTurk resulted in a mean score 4.331+/-0.796 on a scale of 1-5 (5 indicating "strongly agree that the trials in the cluster are similar"). CONCLUSIONS: We contribute an automated approach to clustering clinical trials with similar eligibility features. This approach can be potentially useful for investigating knowledge reuse patterns in clinical trial eligibility criteria designs and for improving clinical trial recruitment. We also contribute an effective crowdsourcing method for evaluating informatics interventions. PMID- 24496069 TI - Hyperhomocysteinemia and bleomycin hydrolase modulate the expression of mouse brain proteins involved in neurodegeneration. AB - Homocysteine (Hcy) is a risk factor for Alzheimer's disease (AD). Bleomycin hydrolase (BLMH) participates in Hcy metabolism and is also linked to AD. The inactivation of the Blmh gene in mice causes accumulation of Hcy-thiolactone in the brain and increases susceptibility to Hcy-thiolactone-induced seizures. To gain insight into brain-related Blmh function, we used two-dimensional IEF/SDS PAGE gel electrophoresis and MALDI-TOF/TOF mass spectrometry to examine brain proteomes of Blmh-/- mice and their Blmh+/+ littermates fed with a hyperhomocysteinemic high-Met or a control diet. We found that: (1) proteins involved in brain-specific function (Ncald, Nrgn, Stmn1, Stmn2), antioxidant defenses (Aop1), cell cycle (RhoGDI1, Ran), and cytoskeleton assembly (Tbcb, CapZa2) were differentially expressed in brains of Blmh-null mice; (2) hyperhomocysteinemia amplified effects of the Blmh-/- genotype on brain protein expression; (3) proteins involved in brain-specific function (Pebp1), antioxidant defenses (Sod1, Prdx2, DJ-1), energy metabolism (Atp5d, Ak1, Pgam-B), and iron metabolism (Fth) showed differential expression in Blmh-null brains only in hyperhomocysteinemic animals; (4) most proteins regulated by the Blmh-/- genotype were also regulated by high-Met diet, albeit in the opposite direction; and (5) the differentially expressed proteins play important roles in neural development, learning, plasticity, and aging and are linked to neurodegenerative diseases, including AD. Taken together, our findings suggest that Blmh interacts with diverse cellular processes from energy metabolism and anti-oxidative defenses to cell cycle, cytoskeleton dynamics, and synaptic plasticity essential for normal brain homeostasis and that modulation of these interactions by hyperhomocysteinemia underlies the involvement of Hcy in AD. PMID- 24496070 TI - Proteomic analysis of serum proteins in triple transgenic Alzheimer's disease mice: implications for identifying biomarkers for use to screen potential candidate therapeutic drugs for early Alzheimer's disease. AB - Alzheimer's disease (AD) is the most common fatal neurodegenerative disease affecting the elderly worldwide. There is an urgent need to identify novel biomarkers of early AD. This study aims to search for potential early protein biomarkers in serum from a triple transgenic (PS1M146V/APPSwe/TauP301L) mouse model. Proteomic analysis via two-dimensional fluorescence difference gel electrophoresis was performed on serum samples from wild-type (WT) and triple transgenic mice that were treated with or without coenzyme Q10 (CoQ10) (800 mg/kg body weight/day), a powerful endogenous antioxidant displaying therapeutic benefits against AD pathology and cognitive impairment in multiple AD mouse models, for a period of three months beginning at two months of age. A total of 15 differentially expressed serum proteins were identified between the WT and AD transgenic mice. The administration of CoQ10 was found to alter the changes in the differentially expressed serum proteins by upregulating 10 proteins and down regulating 10 proteins. Among the proteins modulated by CoQ10, clusterin and alpha-2-macroglobulin were validated via ELISA assay. These findings revealed significant changes in serum proteins in the AD mouse model at an early pathological stage and demonstrated that administration of CoQ10 could modulate these changes in serum proteins. Our study suggested that these differentially expressed serum proteins could serve as potential protein biomarkers of early AD and that screening for potential candidate AD therapeutic drugs and monitoring of therapeutic effects could be performed via measurement of the changes in these differentially expressed serum proteins. PMID- 24496071 TI - Biomarkers for predicting cognitive decline in those with normal cognition. AB - Most studies evaluating Alzheimer's disease (AD) biomarkers longitudinally have studied patients with mild cognitive impairment (MCI) who progress to AD; data on normal subjects are scarce. We studied which biomarkers best predict cognitive decline on the Alzheimer's Disease Assessment Scale-Cognitive Subscale (ADAS-Cog) among those with normal cognition at baseline, and derived cut points to predict decline. We studied 191 subjects in the Alzheimer's Disease Neuroimaging Initiative (ADNI) who had normal cognition at baseline, 2 + visits (mean follow up 3.1 years), and data on neuropsychological tests, cerebrospinal fluid (CSF) biomarkers, and structural MRI. We used repeated measures linear regression of log ADAS-Cog on age, race, gender, education, APOE4 status, baseline biomarker values, and follow-up time; an interaction between biomarker and time assessed predictive power. Neuropsychological tests did not significantly predict ADAS-Cog decline, while both MRI variables and CSF biomarkers did; CSF markers were the strongest predictors. Optimal cut points for baseline CSF markers to distinguish decliners were < 220 pg/ml (Abeta42), >=61 pg/ml (t-tau), >=21 pg/ml (p-tau), >=0.31 (t-tau/Abeta42), and >=0.10 (p-tau/Abeta42). For progression to MCI/AD (n = 28), the best markers were t-tau, t-tau/Abeta42, and p-tau/Abeta42, with optimal cut points of 58, 0.31, and 0.08, respectively. The optimal cut points across all markers and cut points predicted decline in ADAS-Cog, as well as transition to MCI, with a 65% accuracy. Our findings support current models of AD progression and suggest it is feasible to establish biomarker criteria to predict cognitive decline in individuals with normal cognition. Larger studies will be needed to more accurately characterize optimal cut points. PMID- 24496072 TI - Effects of centrally acting angiotensin converting enzyme inhibitors on functional decline in patients with Alzheimer's disease. AB - BACKGROUND: Centrally acting angiotensin converting enzyme inhibitors (CACE-Is) are associated with reduced rates of cognitive decline in patients with dementia. CACE-Is may also improve exercise tolerance in functionally impaired older adults with normal cognition, suggesting that CACE-Is may positively influence activities of daily living (ADL) in dementia. OBJECTIVE: To compare rates of decline in patients with mild to moderate Alzheimer's disease (AD) receiving CACE Is to those not currently treated with CACE-Is (NoCACE-I), included in the Doxycycline and Rifampicin for Alzheimer's Disease study (n = 406). METHODS: Patients were included if baseline and end-point (twelve months apart) scores were available for measures including the Standardized Alzheimer's Disease Assessment Scale - Cognitive Subscale; Quick Mild Cognitive Impairment screen; Clinical Dementia Rating Scale (CDR-SB), and Lawton-Brody ADL Scale. RESULTS: There was a significant, 25% difference (median one-point) in the 12-month rate of decline in ADL scores in patients taking CACE-Is (n = 91), compared to the NoCACE-I group (n = 274), p = 0.024. This remained significant after adjusting for age, gender, education, and blood pressure, p = 0.034. When individual CACE Is were compared to the NoCACE-I group, a significant reduction in the rate of decline in ADLs (median one versus four points), were only observed for perindopril, p = 0.01. The CDR-SB was also reduced (median one-point) for the perindopril compared to the NoCACE-I group, p = 0.04. CONCLUSION: This observational study suggests that CACE-Is, and potentially perindopril in particular, are associated with a reduced rate of functional decline in patients with AD, without an association with mood or behavior. This suggests that CACE-Is may slow disease progression in AD. PMID- 24496074 TI - Altered expression of the CB1 cannabinoid receptor in the triple transgenic mouse model of Alzheimer's disease. AB - The endocannabinoid system has gained much attention as a new potential pharmacotherapeutic target in various neurodegenerative diseases, including Alzheimer's disease (AD). However, the association between CB1 alterations and the development of AD neuropathology is unclear and often contradictory. In this study, brain CB1 mRNA and CB1 protein levels were analyzed in 3 * Tg-AD mice and compared to wild-type littermates at 2, 6 and 12 months of age, using in-situ hybridization and immunohistochemistry, respectively. Semiquantitative analysis of CB1 expression focused on the prefrontal cortex (PFC), prelimbic cortex, dorsal hippocampus (DH), basolateral amygdala complex (BLA), and ventral hippocampus (VH), all areas with high CB1 densities that are strongly affected by neuropathology in 3 * Tg-AD mice. At 2 months of age, there was no change in CB1 mRNA and protein levels in 3 * Tg-AD mice compared to Non-Tg mice in all brain areas analyzed. However, at 6 and 12 months of age, CB1 mRNA levels were significantly higher in PFC, DH, and BLA, and lower in VH in 3 * Tg-AD mice compared to wild-type littermates. CB1 immunohistochemistry revealed that CB1 protein expression was unchanged in 3 * Tg-AD at 2 and 6 months of age, while a significant decrease in CB1 receptor immunoreactivity was detected in the BLA and DH of 12-month-old 3 * Tg-AD mice, with no sign of alteration in other brain areas. The altered CB1 levels appear, rather, to be age-and/or pathology dependent, indicating an involvement of the endocannabinoid system in AD pathology and supporting the ECS as a potential novel therapeutic target for treatment of AD. PMID- 24496075 TI - Personal memory function in mild cognitive impairment and subjective memory complaints: results from the Australian Imaging, Biomarkers, and Lifestyle (AIBL) Study of Ageing. AB - BACKGROUND: Autobiographical memory (ABM) refers to the recollection of individual experiences, while personal semantic memory (PSM) refers to personally relevant, but shared, facts. Mild cognitive impairment (MCI) is routinely diagnosed with the aid of neuropsychological tests, which do not tap the ABM and PSM domains. OBJECTIVE: We aimed to characterize the nature of ABM and PSM retrieval in cognitively healthy (HC) memory complainers, non-memory complainers, and MCI participants, and to investigate the relationship between neuropsychological tests and personal memory. METHODS: Gender- and education matched participants (HC = 80 and MCI = 43) completed the Episodic ABM Interview (EAMI) and a battery of neuropsychological tests. RESULTS: ABM and PSM did not differ between complainers and non-complainers, but were poorer in MCI participants, after accounting for age and depressive symptomatology. There were significant associations between personal memory and objective memory measures were found in MCI participants, but standard cognitive measures were more sensitive to MCI. CONCLUSION: Personal memory was compromised in MCI, reflected by lower scores on the EAMI. Memory complaining, assessed by current approaches, did not have an impact on personal memory. Standard subjective questionnaires might not reflect the sorts of concerns that bring individuals to clinical attention. Understanding personal memory function in the elderly may aid in the development of a more sensitive measure of subjective memory concerns. PMID- 24496073 TI - Oxidative stress, testosterone, and cognition among Caucasian and Mexican American men with and without Alzheimer's disease. AB - BACKGROUND: The use of testosterone among aging men has been increasing, but results from studies addressing the effectiveness of testosterone replacement therapy have been equivocal. OBJECTIVE: Given our prior pre-clinical studies that reported a major influence of oxidative stress on testosterone's neuroprotective effects, we investigated whether the negative effects of testosterone on brain function were predicted by oxidative load. METHODS: In order to test our hypothesis, we determined whether circulating total testosterone and luteinizing hormone correlated with cognition in a subset of the Texas Alzheimer's Research & Care Consortium (TARCC) cohort, consisting of Caucasian (n = 116) and Mexican American (n = 117) men. We also assessed whether oxidative stress (as indexed by homocysteine levels) modified this relationship between sex hormones and cognition, and whether the levels of two antioxidants, superoxide dismutase-1 and glutathione S-transferase (GST), varied as a function of circulating testosterone. RESULTS: In a low oxidative stress environment, testosterone was positively associated with the level of the antioxidant, GST, while no deleterious effects on cognitive function were noted. In contrast, under conditions of high oxidative stress (homocysteine levels >12 MUmol/L), testosterone and luteinizing hormone were associated with cognitive impairment, but only among Caucasians. The ethnic difference was attributed to significantly higher GST levels among Mexican-Americans. CONCLUSION: While testosterone may be beneficial under conditions of low oxidative stress, testosterone appears to have negative consequences under conditions of elevated oxidative stress, but only in Caucasians. Mexican-Americans, however, were protected from any deleterious effects of testosterone, potentially due to higher levels of endogenous antioxidant defenses such as GST. PMID- 24496076 TI - The perseverance time of informal carers of dementia patients: validation of a new measure to initiate transition of care at home to nursing home care. AB - BACKGROUND: Health care systems aim to involve as much informal care as possible and dementia patients prefer to stay home as long as they can. In this context, perseverance time (Pt)-the period that the informal carer indicates to be able to maintain current care if the situation remains stable-is an important concept. OBJECTIVE: The aim of this study was to introduce the concept Pt and validate it in a sample of informal carers of dementia patients living at home. METHODS: Data were collected from 223 informal carers of dementia patients. Convergent validity was assessed by looking at associations of Pt with validated instruments for measuring subjective burden (CSI, CarerQol-7D, and SRB) and happiness (CarerQol VAS). Content validity was evaluated by performing multivariate correlations between Pt and characteristics of dementia patients, informal carers, and care situations. The Medical Ethics Committee of Utrecht MC advised positively about the study protocol. RESULTS: Correlation coefficients between Pt and the measures of burden CSI, SRB, and CarerQol-VAS were -0.46, -0.63, and 0.23 (p < 0.01), respectively. Health of dementia patient, informal carer living apart from the patient, and male gender of caregiver were positively associated with Pt; need for supervision, intensity of informal care provision, and reductions in working hours and hobbies in order to be able to provide care were negatively associated. CONCLUSIONS: Pt is helpful in monitoring need for support and planning the transition of care from home to nursing home. This study provides a first indication of its validity, but replication is necessary. PMID- 24496077 TI - The emerging role of glutathione in Alzheimer's disease. AB - With millions of older individuals presently suffering from Alzheimer's disease (AD) worldwide, AD is an unduly common form of dementia that exacts a heavy toll on affected individuals and their families. One of the emerging causative factors associated with AD pathology is oxidative stress. This AD-related increase in oxidative stress has been attributed to decreased levels of the brain antioxidant, glutathione (GSH). In this article, we review the role of GSH in AD from a pathological as well as a diagnostic point of view. We recapitulate the literature that has assessed the role of GSH in AD onset and progression. We discuss the various methodologies through which alterations in GSH levels might be monitored, and highlight the yet uncharted potential of assaying GSH levels in vivo with magnetic resonance spectroscopy in AD therapeutics and prognostics. Finally, the present manuscript integrates findings from various studies to elucidate the possible molecular mechanisms through which disruptions in GSH homeostasis may contribute to AD pathology. PMID- 24496078 TI - Brain injury in the context of tauopathies. AB - Traumatic brain injury (TBI) is the most common form of head injury and is a leading cause of death worldwide. Due to the vast variability in the types and severity of trauma, the cellular consequences of head injury are not completely understood. The development of reliable models of TBI will aid in understanding the molecular consequences of head trauma, and they will assist in identifying biological surrogate markers of the degree of damage and prognosis. In doing so, effective therapeutic strategies can be applied. Current in vivo experimental models yield important information, but they too have a significant amount of variation. The goal of this review is to re-evaluate the use of these in vivo models of TBI and assess whether they correlate with the consequence of TBI in humans from the perspective of tau, an axonal microtubule-stabilizing protein. We present and discuss the current models of traumatic head injury, and we focus on those that assess changes in tau. We evaluate reports of TBI in humans that measured changes in tau and that were detectable in serum and cerebrospinal fluid, and as a pathological consequence in brain tissue. PMID- 24496079 TI - Electrochemiluminescence of a nanoAg-carbon nanodot composite and its application to detect sulfide ions. AB - This work presents the enhanced electrochemiluminescence (ECL) of a newly prepared nanosilver-carbon nanodot (Ag-C-dot) composite and its application for the sensitive detection of sulfide (S(2-)) ions. The Ag-C-dot composite was easily prepared by adding silver nitrate into C-dot colloids through an alkaline reduction. The obtained Ag-C-dots were characterized by UV-vis spectra, fluorescence spectra and transmission electron microscopy. The electrochemical and ECL behaviors of the Ag-C-dot composite were investigated by cyclic voltammetry. Moreover, a simple label-free method to detect S(2-) ions with a high selectivity and sensitivity has been developed based on the ECL of the Ag-C dot composite in aqueous media. The sensing mechanism could be due to the strong and specific interaction between the S(2-) ions and the Ag atoms/ions on the surface of the Ag-C-dot composite, which dramatically affects the resulting ECL of the Ag-C-dot composite. The linear response to detect S(2-) ions ranges from 0.05 to 100 MUM with a detection limit of 0.027 MUM (~1 ppb). This work indicates that the Ag-C-dot nanocomposite possesses potential applications for environment sensing. PMID- 24496080 TI - All-trans-retinoic acid antagonizes the Hedgehog pathway by inducing patched. AB - Male germ cell tumors (GCTs) are a model for a curable solid tumor. GCTs can differentiate into mature teratomas. Embryonal carcinomas (ECs) represent the stem cell compartment of GCTs and are the malignant counterpart to embryonic stem (ES) cells. GCTs and EC cells are useful to investigate differentiation therapy and chemotherapy response. This study explored mechanistic interactions between all-trans-retinoic acid (RA), which induces differentiation of EC and ES cells, and the Hedgehog (Hh) pathway, a regulator of self-renewal and proliferation. RA was found to induce mRNA and protein expression of Patched 1 (Ptch1), the Hh ligand receptor and negative regulator of this pathway. PTCH1 is also a target gene of Hh signaling through Smoothened (Smo) activation. Yet, this observed RA mediated Ptch1 induction was independent of Smo. It occurred despite co-treatment with RA and Smo inhibitors. Retinoid induction of Ptch1 also occurred in other RA responsive cancer cell lines and in normal ES cells. Notably, this enhanced Ptch1 expression was preceded by induction of the homeobox transcription factor Meis1, a direct RA target. Direct interaction between Meis1 and Ptch1 was confirmed using chromatin immunoprecipitation assays. To establish the translational relevance of this work, Ptch1 expression was shown to be deregulated in human ECs relative to mature teratoma and the normal seminiferous tubule. Taken together, these findings reveal a previously unrecognized mechanism through which RA can inhibit the Hh pathway via Ptch1 induction. Engaging this pathway is a new way to repress the Hh pathway that can be translated into the cancer clinic. PMID- 24496081 TI - Resveratrol enhances the suppressive effects of arsenic trioxide on primitive leukemic progenitors. AB - Efforts to enhance the antileukemic properties of arsenic trioxide are clinically relevant and may lead to the development of new therapeutic approaches for the management of certain hematological malignancies. We provide evidence that concomitant treatment of acute myeloid leukemia (AML) cells or chronic myeloid leukemia (CML) cells with resveratrol potentiates arsenic trioxide-dependent induction of apoptosis. Importantly, clonogenic assays in methylcellulose demonstrate potent suppressive effects of the combination of these agents on primitive leukemic progenitors derived from patients with AML or CML. Taken together, these findings suggest that combinations of arsenic trioxide with resveratrol may provide an approach for targeting of early leukemic precursors and, possibly, leukemia initiating stem cells. PMID- 24496082 TI - Striatal dopamine D1 receptor is essential for contextual fear conditioning. AB - Fear memory is critical for animals to trigger behavioural adaptive responses to potentially threatening stimuli, while too much or inappropriate fear may cause psychiatric problems. Numerous studies have shown that the amygdala, hippocampus and medial prefrontal cortex play important roles in Pavlovian fear conditioning. Recently, we showed that striatal neurons are required for the formation of the auditory fear memory when the unconditioned stimulus is weak. Here, we found that selective ablation of striatal neurons strongly diminished contextual fear conditioning irrespective of the intensity of footshock. Furthermore, contextual fear conditioning was strongly reduced in striatum-specific dopamine D1 receptor knockout mice. On the other hand, striatum-specific dopamine D2 receptor knockout mice showed freezing responses comparable to those of control mice. These results suggest that striatal D1 receptor is essential for contextual fear conditioning. PMID- 24496083 TI - Validity of diabetes self-reports in the Women's Health Initiative. AB - OBJECTIVE: This study aims to determine the positive and negative predictive values of self-reported diabetes during the Women's Health Initiative (WHI) clinical trials. METHODS: All WHI trial participants from four field centers who self-reported diabetes at baseline or during follow-up, as well as a random sample of women who did not self-report diabetes, were identified. Women were surveyed regarding diagnosis and treatment. Medical records were obtained and reviewed for documented treatment with antidiabetes medications or for physician diagnosis of diabetes supported by laboratory measurements of glucose. RESULTS: We identified 1,275 eligible participants; 732 consented and provided survey data. Medical records were obtained for 715 women (prevalent diabetes, 207; incident diabetes, 325; no diabetes, 183). Records confirmed 91.8% (95% CI, 87.0 95.0) of self-reported prevalent diabetes cases and 82.2% (95% CI, 77.5-86.1) of incident diabetes cases. Among those who never self-reported diabetes, there was no medical record or laboratory evidence for diabetes in 94.5% (95% CI, 89.9 97.2). Women with higher body mass index were more likely to accurately self report incident diabetes. In a subgroup of participants enrolled in fee-for service Medicare, a claims algorithm correctly classified nearly all diabetes cases and noncases. CONCLUSIONS: Among WHI clinical trial participants, there are high positive predictive values of self-reported prevalent diabetes (91.8%) and incident diabetes (82.2%) and a high negative predictive value (94.5%) when diabetes is not reported. For participants enrolled in fee-for-service Medicare, a claims algorithm has high positive and negative predictive values. PMID- 24496084 TI - Association between circulating endogenous androgens and insulin sensitivity changes with exercise training in midlife women. AB - OBJECTIVE: Aging induces a shift in circulating hormones in women, accompanied by weight gain during the late reproductive, menopausal transition, and postmenopausal years. Exercise has been shown to counter weight gain; however, it might increase circulating androgens. A 6-month aerobic and resistance training exercise regimen was implemented to examine interrelationships between circulating sex hormones, body composition, aerobic capacity, insulin sensitivity, and insulin resistance. METHODS: Twenty-eight women, aged 42 to 52 years, completed the 6-month intervention study. They were randomly assigned to either a control (CON; n = 10) group-and maintained their sedentary lifestyle-or an exercise intervention (EXE; n = 18) group. The exercise intervention consisted of combined aerobic and resistance workouts scheduled 6 days/week for 60 minutes/day. Body weight, composition, VO2 peak, plasma insulin, glucose, lipid profile, estradiol, testosterone, progesterone, dehydroepiandrosterone, and dehydroepiandrosterone sulfate (DHEAS) were measured at baseline and on month 6. Insulin sensitivity was estimated using the insulin sensitivity index and the quantitative insulin sensitivity check index, whereas insulin resistance was estimated using the homeostatic model for insulin resistance. RESULTS: There was a trend toward increased DHEAS in both groups (P < 0.1), but not as a function of the intervention. Insulin sensitivity index increased in the EXE group compared with the CON group (P < 0.01). Multiple linear regression indicated that, at 6 months, DHEAS was a negative contributor to insulin sensitivity in the EXE group, but not in the CON group. CONCLUSIONS: In midlife women, an increase in circulating DHEAS, such as that previously reported during the menopausal transition, is associated with higher insulin resistance, but exercise can mitigate this risk by improving insulin sensitivity, thereby countering the effects of DHEAS. PMID- 24496085 TI - Investigation of menopausal stage and symptoms on cognition in human immunodeficiency virus-infected women. AB - OBJECTIVE: We evaluated the separate and interactive associations of menopausal stage, menopausal symptoms, and human immunodeficiency virus (HIV) infection with cognition. We hypothesized that HIV-infected perimenopausal women would show the greatest cognitive difficulties and that menopausal symptoms would be inversely associated with cognition. METHODS: This cross-sectional study included 708 HIV infected and 278 HIV-uninfected premenopausal, perimenopausal, or postmenopausal women (64% African American; median age, 44 y) from the Women's Interagency HIV Study. Participants completed tests of verbal learning and memory, attention/processing speed, and executive function. We administered a menopausal symptom questionnaire that assessed anxiety, vasomotor, and sleep symptoms and obtained measures of depressive symptoms. RESULTS: In multivariable regression analyses controlling for relevant covariates, HIV infection, but not menopausal stage, was associated with worse performance on all cognitive measures (P's < 0.05). Depressive symptoms were associated with lower cognitive performance on measures of verbal learning and memory, attention, and executive function (P's < 0.05); anxiety symptoms were associated with lower performance on measures of verbal learning and memory (P's < 0.05). Vasomotor symptoms were associated with worse attention (P < 0.05). HIV and anxiety symptoms interacted to influence verbal learning (P's < 0.05); elevated anxiety was associated with worse verbal learning in HIV-infected women only. CONCLUSIONS: Vasomotor, depressive, and anxiety symptoms, but not menopausal stage, are associated with worse cognitive performance in both HIV-infected and HIV-uninfected women, although elevated anxiety symptoms are more associated with verbal learning deficits in HIV infected women. Because cognitive problems can interfere with everyday functioning, including treatment adherence, it may be important to screen and treat anxiety in HIV-infected women. PMID- 24496086 TI - Effects of stellate ganglion block on vasomotor symptoms: findings from a randomized controlled clinical trial in postmenopausal women. AB - OBJECTIVE: Uncontrolled intervention studies, including studies involving breast cancer survivors, have demonstrated improvements in vasomotor symptoms (VMS) after stellate ganglion blockade (SGB) with a local anesthetic. This study presents the first randomized sham-controlled trial of SGB for the treatment of VMS. METHODS: Participants included 40 postmenopausal women, aged 30 to 70 years, with moderate to severe VMS. The study was a randomized sham-controlled trial comparing the effects of SGB versus sham injection on the frequencies of total and moderate to severe VMS, as measured by daily diaries. Image-guided SGB was performed with 5 mL of 0.5% bupivacaine. Sham injection of saline was performed in subcutaneous tissues in the neck. VMS were recorded at baseline and for 6 months thereafter. Objective VMS were recorded using ambulatory sternal skin conductance monitoring during a 24-hour period at baseline and on 3-month follow up. RESULTS: There were no significant group differences in overall VMS frequency, but the frequency of moderate to very severe VMS was reduced more in the active group compared with the sham treatment group (event rate ratio, 0.50; 95% CI, 0.35-0.71; P < 0.001). The frequency of objective VMS was also reduced to a greater degree in the SGB group than in the sham group (event rate ratio, 0.71; 95% CI, 0.64-0.99; P < 0.05). There were no study-related serious adverse events. CONCLUSIONS: SGB may provide effective treatment of VMS in women who seek nonhormonal treatments because of safety concerns and personal preference. The finding that SGB significantly reduces objectively measured VMS provides further evidence of efficacy. A larger trial is warranted to confirm these findings. PMID- 24496087 TI - Systemic agents for focal symptoms: a promising pasture or a potential snare? PMID- 24496088 TI - Advantages, limitations, and opportunities in the use of national databases. PMID- 24496089 TI - Menopause and benign paroxysmal positional vertigo. AB - OBJECTIVE: This study was designed to examine the age and sex distribution and the effects of menopause in a large cohort of participants diagnosed with benign paroxysmal positional vertigo (BPPV). METHODS: We analyzed 1,377 BPPV patients and surveyed 935 women from this group-all diagnosed at the Boys Town National Research Hospital in the last decade. RESULTS: A detailed age and sex distribution analysis of BPPV onset showed that aging had a profound impact on BPPV occurrence in both sexes, and that perimenopausal women were especially susceptible to BPPV (3.2:1 female-to-male ratio). The latter is a novel finding and was confirmed by a direct survey of female BPPV patients (168 participated). In addition, there was a pronounced female preponderance (6.8:1 female-to-male ratio) in BPPV in the teenage group despite its low prevalence in this age group. CONCLUSIONS: Data suggest that hormonal fluctuations (especially during menopause) may increase the tendency to develop BPPV. PMID- 24496090 TI - Has the pendulum begun to swing back? PMID- 24496091 TI - Genomic imprinting and the units of adaptation. AB - Two guiding principles identify which biological entities are able to evolve adaptations. Williams' principle holds that, in order for an entity to evolve adaptations, there must be selection between such entities. Maynard Smith's principle holds that, in order for an entity to evolve adaptations, selection within such entities must be absent or negligible. However, although the kinship theory of genomic imprinting suggests that parent-of-origin-specific gene expression evolves as a consequence of natural selection acting between--rather than within--individuals, it evades adaptive interpretation at the individual level and is instead viewed as an outcome of an intragenomic conflict of interest between an individual's genes. Here, I formalize the idea that natural selection drives intragenomic conflicts of interest between genes originating from different parents. Specifically, I establish mathematical links between the dynamics of natural selection and the idea of the gene as an intentional, inclusive-fitness-maximizing agent, and I clarify the role that information about parent of origin plays in mediating conflicts of interest between genes residing in the same genome. These results highlight that the suppression of divisive information may be as important as the suppression of lower levels of selection in maintaining the integrity of units of adaptation. PMID- 24496093 TI - Female preferences for spectral call properties in the western genetic lineage of Cope's gray treefrog (Hyla chrysoscelis). AB - Female frogs discriminate among potential mates based on individual variation in male advertisement calls. While considerable data have accumulated allowing comparisons of female preference functions among species, we still lack fundamental knowledge about how and why the shapes of preference functions for particular call properties vary among populations within all but a few species. Here, we report results from a study aimed at describing female preference functions for spectral call properties in Cope's gray treefrog (Hyla chrysoscelis). Widespread throughout the eastern half of North America, Cope's gray treefrog is the diploid member of the cryptic diploid-tetraploid Hyla versicolor species complex, and its populations are divided into two distinct genetic lineages (eastern and western). In this study of a western lineage population, we recorded and analyzed the spectral properties of 1000 advertisement calls from 50 males and conducted two-choice phonotaxis experiments to estimate a population-level preference function. Females preferred calls with average frequencies over calls with frequencies that were 2 or 3 semitones (1.4 or 2.1 standard deviations, respectively) lower than the population mean. We observed no behavioral discrimination between calls with average and higher-than average frequencies. Preferences discriminating against low-frequency calls were weak and were abolished by attenuating the preferred average call by 3 dB. We discuss these results in light of previous studies of eastern lineage populations, geographic variation in female preference functions, and the potential adaptive value of discriminating against calls with low frequencies. PMID- 24496092 TI - Genome-wide association study identifies novel loci associated with resistance to bovine tuberculosis. AB - Tuberculosis (TB) caused by Mycobacterium bovis is a re-emerging disease of livestock that is of major economic importance worldwide, as well as being a zoonotic risk. There is significant heritability for host resistance to bovine TB (bTB) in dairy cattle. To identify resistance loci for bTB, we undertook a genome wide association study in female Holstein-Friesian cattle with 592 cases and 559 age-matched controls from case herds. Cases and controls were categorised into distinct phenotypes: skin test and lesion positive vs skin test negative on multiple occasions, respectively. These animals were genotyped with the Illumina BovineHD 700K BeadChip. Genome-wide rapid association using linear and logistic mixed models and regression (GRAMMAR), regional heritability mapping (RHM) and haplotype-sharing analysis identified two novel resistance loci that attained chromosome-wise significance, protein tyrosine phosphatase receptor T (PTPRT; P=4.8 * 10(-7)) and myosin IIIB (MYO3B; P=5.4 * 10(-6)). We estimated that 21% of the phenotypic variance in TB resistance could be explained by all of the informative single-nucleotide polymorphisms, of which the region encompassing the PTPRT gene accounted for 6.2% of the variance and a further 3.6% was associated with a putative copy number variant in MYO3B. The results from this study add to our understanding of variation in host control of infection and suggest that genetic marker-based selection for resistance to bTB has the potential to make a significant contribution to bTB control. PMID- 24496094 TI - Investigating the congruence of crowdsourced information with official government data: the case of pediatric clinics. AB - BACKGROUND: Health 2.0 is a benefit to society by helping patients acquire knowledge about health care by harnessing collective intelligence. However, any misleading information can directly affect patients' choices of hospitals and drugs, and potentially exacerbate their health condition. OBJECTIVE: This study investigates the congruence between crowdsourced information and official government data in the health care domain and identifies the determinants of low congruence where it exists. In-line with infodemiology, we suggest measures to help the patients in the regions vulnerable to inaccurate health information. METHODS: We text-mined multiple online health communities in South Korea to construct the data for crowdsourced information on public health services (173,748 messages). Kendall tau and Spearman rank order correlation coefficients were used to compute the differences in 2 ranking systems of health care quality: actual government evaluations of 779 hospitals and mining results of geospecific online health communities. Then we estimated the effect of sociodemographic characteristics on the level of congruence by using an ordinary least squares regression. RESULTS: The regression results indicated that the standard deviation of married women's education (P=.046), population density (P=.01), number of doctors per pediatric clinic (P=.048), and birthrate (P=.002) have a significant effect on the congruence of crowdsourced data (adjusted R2=.33). Specifically, (1) the higher the birthrate in a given region, (2) the larger the variance in educational attainment, (3) the higher the population density, and (4) the greater the number of doctors per clinic, the more likely that crowdsourced information from online communities is congruent with official government data. CONCLUSIONS: To investigate the cause of the spread of misleading health information in the online world, we adopted a unique approach by associating mining results on hospitals from geospecific online health communities with the sociodemographic characteristics of corresponding regions. We found that the congruence of crowdsourced information on health care services varied across regions and that these variations could be explained by geospecific demographic factors. This finding can be helpful to governments in reducing the potential risk of misleading online information and the accompanying safety issues. PMID- 24496095 TI - CO(2) selective 1D double chain dipyridyl-porphyrin based porous coordination polymers. AB - Thermal reactions of MnCl(DPyP) (DPyP = 5,15-di(4-pyridyl)-10,20 diphenylporphyrin) as a metalloligand with Co(II) and Zn(II) ions in dimethylformamide led to neutral one-dimensional (1D) double chain dipyridyl porphyrin-based porous coordination polymers (PCPs), Co3(DPyP)3.4DMF (I) and Zn3(DPyP)3.2DMF.4H2O (II). Both PCPs were structurally characterized by X-ray crystallography. Particularly, the central Mn(III) ion in MnCl(DPyP) was transmetallated with Co(II) or Zn(II) ions and the central Co(II) or Zn(II) ions were further coordinated to pyridyl groups of neighboring M(DPyP) (M = Co or Zn) porphyrin complexes. PCPs I and II are isostructural and each 1D double chain interacts with another 1D double chain by multiple hydrogen bonding to stabilize the resulting framework. Therefore, solvent-free 1D double chain PCPs have permanent porosity, and the void volumes of the solvent-free I and II are calculated to be 22.6% and 23.0%, respectively. Gas sorption analysis indicated that I and II exhibited selective adsorption of CO2 at 196 K. Both PCPs exhibited much smaller sorption abilities for N2 (77 K), H2 (77 K), and CH4 (196 K) than CO2 (196 K). Both PCPs exhibited different PXRD patterns when dried at 373 K, which indicated that the framework transformation of the isostructural M3(DPyP)3 type of PCPs strongly depended on the type of central metal ions. PMID- 24496096 TI - Not so WEE: targeting G2/M to kill mesothelioma cells. AB - It has been known for many years that manipulation of cell cycle checkpoint function represents one approach by which the toxicity of chemotherapy and of ionizing radiation can be increased in tumor cells. (1)(-) (3) In particular, abrogation of the G 2/M checkpoint has been shown to enhance the lethality of a wide range of toxic stresses. (1)(-) (3) Inhibition of the G 2/M checkpoint after chemotherapy/irradiation would result in tumor cells entering mitosis with damaged DNA, which would in turn result in loss of clonogenic survival (i.e., a lethal mitosis). PMID- 24496097 TI - Spatiotemporal parameters of gait during treadmill and overground walking in Parkinson's disease. AB - Despite the increasing number of studies that have examined the therapeutic effect of treadmill training programs in Parkinson's disease (PD), there has been little research to evaluate the modifications of gait induced by treadmill walking. We investigated spatiotemporal differences between treadmill and overground walking in patients with PD. PD patients significantly increased their step length and step height; and reduced their cadence, step width and step width variability on the treadmill in comparison with walking overground. PD patients are able to attenuate their short shuffling steps when walking on a treadmill. PMID- 24496098 TI - Genetic screening for the LRRK2 R1441C and G2019S mutations in Parkinsonian patients from Campania. AB - BACKGROUND: PARK8 is the most common known mendelian form of Parkinson's Disease (PD). It is due to mutations in the leucine-rich repeat kinase 2 (LRRK2) gene and G2019S is considered the most frequent mutation in the Caucasian population, in particular in the Southern Europe and Mediterranean countries. OBJECTIVE: We assessed the frequency of the G2019S and R1441C/H/G mutations in 513 (311 M and 202 F) unrelated PD patients from Campania, in Southern Italy. METHODS: Three hundreds and thirty-six patients presented a sporadic disease, and 177 had a familial history of PD or tremor. Three hundreds and eighty cases originated from the province of Naples. We compared our LRRK2 mutation carriers to idiopathic PD patients matched for recruiting center, gender, age and age at onset. RESULTS: Thirteen patients (8 M and 5 F) carried the R1441C mutation and 4 (3 M and 1 F) the G2019S mutation, all in heterozygous state. All carriers originated from the province of Naples. No carriers of the R1441H or R1441G mutations were found. The LRRK2 mutation carriers were clinically similar to idiopathic PD patients. The R1441C and G2019S mutations are not rare causes of PD in Campania, especially in the province of Naples and among the familial cases, where the overall mutation prevalence is 6.8%. CONCLUSIONS: The R1441C prevalence was higher than that of G2019S (2.5% vs 0.8%), underlining the importance of the geographical differencies in LRRK2 mutation frequency for molecular screening and genetic counseling of PD patients. PMID- 24496100 TI - Dopamine replacement therapy and deep brain stimulation of the subthalamic nuclei induce modulation of emotional processes at different spatial frequencies in Parkinson's disease. AB - BACKGROUND: Deep brain stimulation of the subthalamic nuclei (STN-DBS) is an effective treatment for the most severe forms of Parkinson's disease (PD) and is intended to suppress these patients' motor symptoms. However, be it in association with Dopamine Replacement Therapy (DRT) or not, STN-DBS may in some cases induce addictive or emotional disorders. OBJECTIVE: In the current study, we suggest that PD patients suffer from emotional deficits that have not been revealed in previous studies because in those experiments the stimuli were displayed for a time long enough to allow patients to have recourse to perceptual strategies in order to recognize the emotional facial expressions (EFE). METHODS: The aim of the current article is to demonstrate the existence of emotional disorders in PD by using a rapid presentation of the visual stimuli (200-ms display time) which curtails their perceptual analysis, and to determine whether STN-DBS, either associated or not associated with DRT, has an impact on the recognition of emotions. RESULTS: The results show that EFE recognition performance depends on both STN-DBS ('on' vs. 'off') and medication ('on' vs. 'off'), but also that these variables have an interactive influence on EFE recognition performance. Moreover, we also reveal how these EFE impairments depend on different spatial frequencies perceptual channels (related to different cortical vs. subcortical neural structures). CONCLUSIONS: The effect of PD without therapy seems to be particularly acute for LSF emotional faces, possibly due to a subcortical dysfunction. However, our results indicate that the joint action of STN-DBS and DRT could also disrupt recognition of emotional expressions at the level of occipito-temporal cortical areas (processing HSF visual information) inducing broad global impairment of EFE at the level of HSF visual channels. PMID- 24496101 TI - Foxd1 is a mediator and indicator of the cell reprogramming process. AB - It remains unclear how changes in gene expression profiles that establish a pluripotent state are induced during cell reprogramming. Here we identify two forkhead box transcription factors, Foxd1 and Foxo1, as mediators of gene expression programme changes during reprogramming. Knockdown of Foxd1 or Foxo1 reduces the number of iPSCs, and the double knockdown further reduces it. Knockout of Foxd1 inhibits downstream transcriptional events, including the expression of Dax1, a component of the autoregulatory network for maintaining pluripotency. Interestingly, the expression level of Foxd1 is transiently increased in a small population of cells in the middle stage of reprogramming. The transient Foxd1 upregulation in this stage is correlated with a future cell fate as iPSCs. Fate mapping analyses further reveal that >95% of iPSC colonies are derived from the Foxd1-positive cells. Thus, Foxd1 is a mediator and indicator of successful progression of reprogramming. PMID- 24496099 TI - Inhibition, executive function, and freezing of gait. AB - BACKGROUND: Studies suggest that freezing of gait (FoG) in people with Parkinson's disease (PD) is associated with declines in executive function (EF). However, EF is multi-faceted, including three dissociable components: inhibiting prepotent responses, switching between task sets, and updating working memory. OBJECTIVE: This study investigated which aspect of EF is most strongly associated with FoG in PD. METHOD: Three groups were studied: adults with PD (with and without FoG) and age-matched, healthy adults. All participants completed a battery of cognitive tasks previously shown to discriminate among the three EF components. Participants also completed a turning-in-place task that was scored for FoG by neurologists blind to subjects' self-reported FoG. RESULTS: Compared to both other groups, participants with FoG showed significant performance deficits in tasks associated with inhibitory control, even after accounting for differences in disease severity, but no significant deficits in task-switching or updating working memory. Surprisingly, the strongest effect was an intermittent tendency of participants with FoG to hesitate, and thus miss the response window, on go trials in the Go-Nogo task. The FoG group also made slower responses in the conflict condition of the Stroop task. Physician-rated FoG scores were correlated both with failures to respond on go trials and with failures to inhibit responses on nogo trials in the Go-Nogo task. CONCLUSION: These results suggest that FoG is associated with a specific inability to appropriately engage and release inhibition, rather than with a general executive deficit. PMID- 24496102 TI - Platelet-rich plasma in surgical oncology. PMID- 24496103 TI - Use of a bioprosthetic mesh in complex hernia repair: early results from a French multicenter pilot study. AB - BACKGROUND: Implantation of synthetic meshes for reinforcement of abdominal wall hernias can be complicated by mesh infection, which often requires mesh explantation. The risk of mesh infection is increased in a contaminated environment or in patients who have comorbidities such as diabetes or smoking. The use of biological prostheses has been advocated because of their ability to resist infection. Initial results, however, have shown high hernia recurrence rates and wound occurrences. The objective of the present study is to evaluate early and mid-term outcomes in the largest French series that included 43 consecutive complex abdominal hernias repaired with biological prostheses. MATERIALS AND METHODS: Retrospective observational study of a prospective collected data bank. Patient demographics, history of previous repairs, intraoperative findings and degree of contamination, associated procedures, postoperative prosthetic-related complications, and long-term results were retrospectively reviewed. RESULTS: There were 25 (58%) incisional, 14 parastomal, and 4 midline hernia repairs. Hernias were considered "clean" (n = 5), "clean contaminated" (n = 19), "contaminated" (n = 12), or "dirty" (n = 7). Wound related morbidity occurred in 17 patients; 4 patients needed reoperation for cutaneous necrosis or abscess. Smoking was the only risk factor associated with wound complication (P = .022). No postoperative wound events required removal of the prosthesis. There were 4 hernia recurrences (9%). A previous attempt at repair (P = .018) and no complete fascia closure (P = .033) were associated with hernia recurrence. CONCLUSIONS: This study demonstrated that the use of bioprothesis in complex hernia repair allowed successful single-stage reconstruction. Wound-related complications were frequent. Cost-benefit analyses are important to establish the validity of these findings. PMID- 24496104 TI - Laparoscopic versus open splenectomy for portal hypertension: a systematic review of comparative studies. AB - BACKGROUND: Laparoscopic splenectomy has become the gold-standard procedure for normal to moderately enlarged spleens. However, the safety of laparoscopic splenectomy for patients with portal hypertension remains controversial. We carried out this systematic review to identify the feasibility and safety of laparoscopic splenectomy in treating portal hypertension. DATA SOURCES: A systematic search for comparative studies that compared laparoscopic splenectomy with open splenectomy for portal hypertension was carried out. Studies were independently reviewed for quality, inclusion and exclusion criteria, demographic characteristics, and perioperative outcomes. CONCLUSION: Although laparoscopic splenectomy is associated with longer operating time, it offers advantages over the open procedure in terms of less blood loss, lower operative complications, earlier resumption of oral intake, and shorter posthospital stay. Therefore, laparoscopic splenectomy is a safe and feasible intervention for portal hypertension. PMID- 24496105 TI - Diversity, abundance and natural products of marine sponge-associated actinomycetes. AB - Actinomycetes are known for their unprecedented ability to produce novel lead compounds of clinical and pharmaceutical importance. This review focuses on the diversity, abundance and methodological approaches targeting marine sponge associated actinomycetes. Additionally, novel qPCR data on actinomycete abundances in different sponge species and other environmental sources are presented. The natural products literature is covered, and we are here reporting on their chemical structures, their biological activities, as well as the source organisms from which they were isolated. PMID- 24496107 TI - Carbon nanocoating: an effective nanoreactor towards well-defined carbon-coated GaN hollow nanospindles. AB - Carbon-coated GaN hollow nanospindles with uniform morphology and good structural stability are facilely prepared by nitridizing solid carbon-coated GaOOH nanospindles in an ammonia atmosphere at 800 degrees C for 2 h. The carbon nanocoating acts as a nanoreactor which not only preserves the spindle-like morphology, but also prevents the growth of GaN particles during the thermal treatment. The significant advantage is that the hollow nanostructures so obtained exhibit superior resistance to distortion, collapse, and shrinkage. PMID- 24496108 TI - Elucidating the oxide growth mechanism on platinum at the cathode in PEM fuel cells. AB - Simulations of platinum oxidation in literature have yet to fully replicate an experimental cyclic voltammogram. In this manuscript a mechanism for platinum oxidation is proposed based upon the results of in operando X-ray absorption spectroscopy, where it was found that PtO2 is present at longer hold times. A new method to quantify extended X-ray absorption fine structure data is presented, and the extent of oxidation is directly compared to electrochemical data. This comparison indicated that PtO2 was formed at the expense of an initial oxide species. From previous literature studies it can be concluded that the rate of platinum oxidation is not a function of only potential and coverage. To that end, the concept of a heterogeneous oxide layer was introduced into the model, whereby place-exchanged PtO2 structures of varying energy states are formed through a single transition state. This treatment allowed, for the first time, the simulation of the correct current-potential behavior at varying scan rates and upper potential limits. PMID- 24496106 TI - Screening and discovery of nitro-benzoxadiazole compounds activating epidermal growth factor receptor (EGFR) in cancer cells. AB - Peptide ligand-induced dimerization of the extracellular region of the epidermal growth factor receptor (sEGFR) is central to the signal transduction of many cellular processes. A small molecule microarray screen has been developed to search for non-peptide compounds able to bind to sEGFR. We describe the discovery of nitro-benzoxadiazole (NBD) compounds that enhance tyrosine phosphorylation of EGFR and thereby trigger downstream signaling pathways and other receptor tyrosine kinases in cancer cells. The protein phosphorylation profile in cells exposed to NBD compounds is to some extent reminiscent of the profile induced by the cognate ligand. Experimental studies indicate that the small compounds bind to the dimerization domain of sEGFR, and generate stable dimers providing allosteric activation of the receptor. Moreover, receptor phosphorylation is associated with inhibition of PTP-1B phosphatase. Our data offer a promising paradigm for investigating new aspects of signal transduction mediated by EGFR in cancer cells exposed to electrophilic NBD compounds. PMID- 24496109 TI - The 1% rule in four digital health social networks: an observational study. AB - BACKGROUND: In recent years, cyberculture has informally reported a phenomenon named the 1% rule, or 90-9-1 principle, which seeks to explain participatory patterns and network effects within Internet communities. The rule states that 90% of actors observe and do not participate, 9% contribute sparingly, and 1% of actors create the vast majority of new content. This 90%, 9%, and 1% are also known as Lurkers, Contributors, and Superusers, respectively. To date, very little empirical research has been conducted to verify the 1% rule. OBJECTIVE: The 1% rule is widely accepted in digital marketing. Our goal was to determine if the 1% rule applies to moderated Digital Health Social Networks (DHSNs) designed to facilitate behavior change. METHODS: To help gain insight into participatory patterns, descriptive data were extracted from four long-standing DHSNs: the AlcoholHelpCenter, DepressionCenter, PanicCenter, and StopSmokingCenter sites. RESULTS: During the study period, 63,990 actors created 578,349 posts. Less than 25% of actors made one or more posts. The applicability of the 1% rule was confirmed as Lurkers, Contributors, and Superusers accounted for a weighted average of 1.3% (n=4668), 24.0% (n=88,732), and 74.7% (n=276,034) of content. CONCLUSIONS: The 1% rule was consistent across the four DHSNs. As social network sustainability requires fresh content and timely interactions, these results are important for organizations actively promoting and managing Internet communities. Superusers generate the vast majority of traffic and create value, so their recruitment and retention is imperative for long-term success. Although Lurkers may benefit from observing interactions between Superusers and Contributors, they generate limited or no network value. The results of this study indicate that DHSNs may be optimized to produce network effects, positive externalities, and bandwagon effects. Further research in the development and expansion of DHSNs is required. PMID- 24496110 TI - A lipidomics investigation of the induced hypoxia stress on HeLa cells by using MS and NMR techniques. AB - Induced hypoxia stress on cervical cancer derived cells (HeLa cells) leads to significant changes in their membrane lipid profiles. The lipidome of HeLa cells was characterized by a joint approach wherein liquid chromatography-mass spectrometry (LC-MS) analysis was followed by high resolution NMR measurements. Multivariate data analysis showed apparent separation between control and hypoxia treated HeLa cells and thus demonstrated hypoxia effects on lipid metabolism. The most striking finding was that hypoxia stimulation significantly reduced the total amount of cellular phosphoinositols (PI) but caused a prominent increase in the amount of lyso phosphocholines (lyso-PC) and lyso phosphoethanolamines (lyso PE). The observed decrease of PI amount under hypoxic conditions is probably due to the accumulation of cellular myo-inositol, which is known to play a critical role in de novo synthesis of PI. Moreover, our study suggests that polyunsaturated phospholipid species are stronger biomarkers for discriminating the effect of hypoxia treatment. The evaluation of changes in the average unsaturation index (UI) of the membrane lipids acyl chains reveals that UI slightly increases in several lipid classes, thus affecting membrane fluidity and further membrane-dependent functions. The plausible mechanisms by which HeLa cells adapt to hypoxia conditions are also briefly reported. PMID- 24496111 TI - Computational simulation of CV combination preferences in babbling. AB - There is a tendency for spoken consonant-vowel (CV) syllables, in babbling in particular, to show preferred combinations: labial consonants with central vowels, alveolars with front, and velars with back. This pattern was first described by MacNeilage and Davis, who found the evidence compatible with their "frame-then-content" (F/C) model. F/C postulates that CV syllables in babbling are produced with no control of the tongue (and therefore effectively random tongue positions) but systematic oscillation of the jaw. Articulatory Phonology (AP; Browman & Goldstein) predicts that CV preferences will depend on the degree of synergy of tongue movements for the C and V. We present computational modeling of both accounts using articulatory synthesis. Simulations found better correlations between patterns in babbling and the AP account than with the F/C model. These results indicate that the underlying assumptions of the F/C model are not supported and that the AP account provides a better and account with broader coverage by showing that articulatory synergies influence all CV syllables, not just the most common ones. PMID- 24496112 TI - Climate change will reduce excess death rate from cold in UK, report shows. PMID- 24496113 TI - Caregiver psychological health and hospitalization characteristics of older adult care recipients: an integrative review of U.S. studies. AB - This integrative review involved studies conducted in the United States that assessed hospitalizations of older adults receiving family care and the psychological health of their family caregivers. The primary objectives were to (a) summarize findings between caregiver psychological health and older care recipient hospitalizations, and (b) describe how caregiver psychological health has been measured with regard to older care recipient hospitalizations. Online databases were searched for articles assessing caregiver psychological health (e.g., burden, strain, depressive or anxious symptoms) and older care recipient hospitalizations in the United States. According to the findings, few studies in the United States have assessed hospitalization characteristics of older care recipients and the psychological health of their family caregivers. All analyses incorporated a measure of depression; however, the measurement of other psychological health constructs (e.g., anxious symptoms, perceived burden) was limited or absent. Findings note the potential importance of focusing on readmission rates in light of caregiver psychological health. Findings also note the benefit of caregiver emotional and instrumental support toward reducing hospitalizations among older adults receiving family care. PMID- 24496115 TI - Plasma membrane recovery kinetics of a microfluidic intracellular delivery platform. AB - Intracellular delivery of materials is a challenge in research and therapeutic applications. Physical methods of plasma membrane disruption have recently emerged as an approach to facilitate the delivery of a variety of macromolecules to a range of cell types. We use the microfluidic CellSqueeze delivery platform to examine the kinetics of plasma membrane recovery after disruption and its dependence on the calcium content of the surrounding buffer (recovery time ~ 5 min without calcium vs. ~ 30 s with calcium). Moreover, we illustrate that manipulation of the membrane repair kinetics can yield up to 5* improvement in delivery efficiency without significantly impacting cell viability. Membrane repair characteristics initially observed in HeLa cells are shown to translate to primary naive murine T cells. Subsequent manipulation of membrane repair kinetics also enables the delivery of larger materials, such as antibodies, to these difficult to manipulate cells. This work provides insight into the membrane repair process in response to mechanical delivery and could potentially enable the development of improved delivery methods. PMID- 24496116 TI - Selection of a DNA aptamer for cadmium detection based on cationic polymer mediated aggregation of gold nanoparticles. AB - The demand for selection of aptamers against various small chemical molecules has substantially increased in recent years. To incubate and separate target-specific aptamers, the conventional SELEX procedures generally need to immobilize target molecules on a matrix, which may be impotent to screen aptamers toward small molecules without enough sites for immobilization. Herein we chose Cd(II) as a model of a small molecule with less sites, and proposed a novel SELEX strategy of immobilizing ssDNA libraries rather than target molecules on a matrix, for selection of aptamers with high affinity to Cd(II). After eleven rounds of positive and negative selection, twelve T and G-rich of nonrepeating ssDNA sequences were identified, of which the Cd-4 aptamer displayed the highest binding affinity to Cd(II). The secondary structures of these sequences revealed that a stem-loop structure folded by the domain of their 30-random sequence is critical for aptamers to bind targets. Then the interaction between the selected Cd-4 aptamer and Cd(II) was confirmed by CD analysis, and the binding specificity toward other competitive metal ions was also investigated. The dissociation constant (Kd) of Cd-4 aptamer was determined as 34.5 nM for Cd(II). Moreover, the Cd-4 aptamer was considered a recognition element for the colorimetric detection of Cd(II) based on the aggregation of AuNPs by cationic polymer. Through spectroscopic quantitative analysis, Cd(II) in aqueous solution can be detected as low as 4.6 nM. The selected Cd-4 aptamer will offer a new substitute for the detection of Cd(II) or other applications like recovery of cadmium from polluted samples. PMID- 24496114 TI - Nurse and patient interaction behaviors' effects on nursing care quality for mechanically ventilated older adults in the ICU. AB - The study purposes were to (a) describe interaction behaviors and factors that may effect communication and (b) explore associations between interaction behaviors and nursing care quality indicators among 38 mechanically ventilated patients (age >=60 years) and their intensive care unit nurses (n = 24). Behaviors were measured by rating videorecorded observations from the Study of Patient-Nurse Effectiveness with Communication Strategies (SPEACS). Characteristics and quality indicators were obtained from the SPEACS dataset and medical chart abstraction. All positive behaviors occurred at least once. Significant (p < 0.05) associations were observed between (a) positive nurse and positive patient behaviors, (b) patient unaided augmentative and alternative communication (AAC) strategies and positive nurse behaviors, (c) individual patient unaided AAC strategies and individual nurse positive behaviors, (d) positive nurse behaviors and pain management, and (e) positive patient behaviors and sedation level. Findings provide evidence that nurse and patient behaviors effect communication and may be associated with nursing care quality. PMID- 24496117 TI - A Polymerase Theta-dependent repair pathway suppresses extensive genomic instability at endogenous G4 DNA sites. AB - Genomes contain many sequences that are intrinsically difficult to replicate. Tracts of tandem guanines, for instance, have the potential to adopt stable G quadruplex structures, which are prone to cause genome alterations. Here we describe G4 DNA-induced mutagenesis in Caenorhabditis elegans and identify a non canonical DNA break repair mechanism that generates deletions characterized by an extremely narrow size distribution, minimal homology of exactly one nucleotide at the junctions, and by the occasional presence of templated insertions. This typical mutation profile is fully dependent on the A-family polymerase Theta, the absence of which leads to profound loss of sequences surrounding G4 motifs. Theta mediated end-joining prevails over non-homologous end joining and homologous recombination and prevents genomic havoc at replication fork barriers at the expense of small deletions. G4 DNA-induced deletions also manifest in the genomes of wild isolates of C. elegans, indicating a protective role for this pathway during evolution. PMID- 24496120 TI - Lower critical solution temperature (LCST) phase separation of glycol ethers for forward osmotic control. AB - Lower critical solution temperature (LCST) phase transition of glycol ether (GE) water mixtures induces an abrupt change in osmotic pressure driven by a mild temperature change. The temperature-controlled osmotic change was applied for the forward osmosis (FO) desalination. Among three GEs evaluated, di(ethylene glycol) n-hexyl ether (DEH) was selected as a potential FO draw solute. A DEH-water mixture with a high osmotic pressure could draw fresh water from a high-salt feed solution such as seawater through a semipermeable membrane at around 10 degrees C. The water-drawn DEH-water mixture was phase-separated into a water-rich phase and a DEH-rich phase at around 30 degrees C. The water-rich phase with a much reduced osmotic pressure released water into a low-salt solution, and the DEH rich phase was recovered into the initial DEH-water mixture. The phase separation behaviour, the residual GE concentration in the water-rich phase, the osmotic pressure of the DEH-water mixture, and the osmotic flux between the DEH-water mixture and salt solutions were carefully analysed for FO desalination. The liquid-liquid phase separation of the GE-water mixture driven by the mild temperature change between 10 degrees C and 30 degrees C is very attractive for the development of an ideal draw solute for future practical FO desalination. PMID- 24496119 TI - Convergent validity of a brief self-reported physical activity questionnaire. AB - PURPOSE: The objective of this study is to determine whether summary estimates of a self-report physical activity questionnaire that does not specifically assess frequency or duration (the Coronary Artery Risk Development in Young Adults (CARDIA) physical activity history (PAH)) differs from the summary estimates of one that does (CARDIA Supplemental Questionnaire). METHODS: After the year 25 examination (2010-2011), 203 CARDIA black and white men and women (age 50.3 +/- 3.6 yr) at the Oakland, CA, site participated in this comparison study. The between-questionnaire association and agreement were determined for continuous and categorical estimates on the basis of 1) quartiles and 2) meeting 2008 physical activity guidelines. Differences in participant characteristics by concordance/discordance status were also examined. Finally, receiver operating characteristic curves were computed to determine the accuracy of the PAH compared with the supplemental questionnaire. RESULTS: Reported physical activity levels were high and varied significantly by race and sex (all P < 0.01). Between questionnaire estimates were significantly correlated (rho = 0.75 to 0.90, all P < 0.001) and had high agreement (kappa = 0.51 to 0.80) across all race/sex groups. A higher proportion of women than men were classified as concordant by quartile of vigorous intensity (P = 0.001), but no other participant characteristics were associated with concordant/discordant quartile ranking. Participants classified as concordant on the basis of physical activity guidelines had lower body mass index than those classified as discordant (both P < 0.05). The area under the curve was 0.95, suggesting that the PAH has high accuracy for classifying individuals as meeting physical activity guidelines. CONCLUSIONS: Although it is inconvenient that the PAH is not expressed in more standard units, these findings support the practice of not directly assessing frequency and duration, which are frequent sources of reporting error. PMID- 24496118 TI - Cross-validation of waist-worn GENEA accelerometer cut-points. AB - PURPOSE: The purpose of this study was to determine the classification accuracy of the waist gravity estimator of normal everyday activity (GENEA) cut-points developed by Esliger et al. for predicting intensity categories across a range of lifestyle activities. METHODS: Each participant performed one of two routines, consisting of seven lifestyle activities (home/office, ambulatory, and sport). The GENEA was worn on the right waist, and oxygen uptake was continuously measured using the Oxycon mobile. A one-way chi-squared test was used to determine the classification accuracy of the GENEA cut-points. Cross-tabulation tables provided information on under- and overestimations, and sensitivity and specificity analyses of the waist cut-points were also performed. RESULTS: Spearman rank order correlation for the GENEA gravity-subtracted signal vector magnitude and Oxycon mobile MET values was 0.73. For all activities combined, the GENEA accurately predicted intensity classification 55.3% of the time, and it increased to 58.3% when stationary cycling was removed from the analysis. The sensitivity of the cut-points for the four intensity categories ranged from 0.244 to 0.958, and the specificity ranged from 0.576 to 0.943. CONCLUSION: In this cross-validation study, the proposed GENEA cut-points had a low overall accuracy rate for classifying intensity (55.3%) when engaging in 14 different lifestyle activities. PMID- 24496121 TI - Catalytic regioselective synthesis of pyrazole based pyrido[2,3-d]pyrimidine diones and their biological evaluation. AB - A new type of biopolymer-based heterogeneous catalyst, cellulose supported acidic ionic liquid (Cell-IL), which was developed earlier in our lab, has been found to be very effective for the regioselective synthesis of pyrazole based pyrido[2,3 d]pyrimidine-diones. Its regioselectivity was confirmed by (1)H NMR spectroscopy. All the newly synthesized compounds were characterized by LC-MS, (1)H NMR, (13)C NMR, IR spectroscopy and elemental analysis. The newly synthesized compounds were evaluated for their in vitro antimalarial activity against Plasmodium falciparum, in vitro antitubercular activity against Mycobacterium tuberculosis H37Rv strain and also for their antibacterial activity against a panel of pathogenic strains of bacteria and fungi. Some of them exhibited excellent activity when compared with first line drugs. PMID- 24496122 TI - The first intramolecular silene Diels-Alder reactions. AB - The synthesis of silaheterocycles through the first examples of an intramolecular silene Diels-Alder reaction is described. PMID- 24496124 TI - Anesthesia-related cardiac arrest. AB - BACKGROUND: Much is still unknown about the actual incidence of anesthesia related cardiac arrest in the United States. METHODS: The authors identified all of the cases of cardiac arrest from their quality improvement database from 1999 to 2009 and submitted them for review by an independent study commission to give them the best estimate of anesthesia-related cardiac arrest at their institution. One hundred sixty perioperative cardiac arrests within 24 h of surgery were identified from an anesthesia database of 217,365 anesthetics. An independent study commission reviewed all case abstracts to determine which cardiac arrests were anesthesia-attributable or anesthesia-contributory. Anesthesia-attributable cardiac arrests were those cases in which anesthesia was determined to be the primary cause of cardiac arrest. Anesthesia-contributory cardiac arrests were those cases where anesthesia was determined to have contributed to the cardiac arrest. RESULTS: Fourteen cardiac arrests were anesthesia-attributable, resulting in an incidence of 0.6 per 10,000 anesthetics (95% CI, 0.4 to 1.1). Twenty-three cardiac arrests were found to be anesthesia-contributory resulting in an incidence of 1.1 per 10,000 anesthetics (95% CI, 0.7 to 1.6). Sixty-four percent of anesthesia-attributable cardiac arrests were caused by airway complications that occurred primarily with induction, emergence, or in the postanesthesia care unit, and mortality was 29%. Anesthesia-contributory cardiac arrest occurred during all phases of the anesthesia, and mortality was 70%. CONCLUSION: As judged by an independent study commission, anesthesia-related cardiac arrest occurred in 37 of 160 cardiac arrests within the 24-h perioperative period. PMID- 24496123 TI - Resuscitation with lipid emulsion: dose-dependent recovery from cardiac pharmacotoxicity requires a cardiotonic effect. AB - BACKGROUND: Recent publications have questioned the validity of the "lipid sink" theory of lipid resuscitation while others have identified sink-independent effects and posed alternative mechanisms such as hemodilution. To address these issues, the authors tested the dose-dependent response to intravenous lipid emulsion during reversal of bupivacaine-induced cardiovascular toxicity in vivo. Subsequently, the authors modeled the relative contribution of volume resuscitation, drug sequestration, inotropy and combined drug sequestration, and inotropy to this response with the use of an in silico model. METHODS: Rats were surgically prepared to monitor cardiovascular metrics and deliver drugs. After catheterization and instrumentation, animals received a nonlethal dose of bupivacaine to produce transient cardiovascular toxicity, then were randomized to receive one of the four treatments: 30% intravenous lipid emulsion, 20% intravenous lipid emulsion, intravenous saline, or no treatment (n = 7 per condition; 28 total animals). Recovery responses were compared with the predictions of a pharmacokinetic-pharmacodynamic model parameterized using previously published laboratory data. RESULTS: Rats treated with lipid emulsions recovered faster than did rats treated with saline or no treatment. Intravenous lipid emulsion of 30% elicited the fastest hemodynamic recovery followed in order by 20% intravenous lipid emulsion, saline, and no treatment. An increase in arterial blood pressure underlay the recovery in both lipid emulsion-treated groups. Heart rates remained depressed in all four groups throughout the observation period. Model predictions mirrored the experimental recovery, and the model that combined volume, sequestration, and inotropy predicted in vivo results most accurately. CONCLUSION: Intravenous lipid emulsion accelerates cardiovascular recovery from bupivacaine toxicity in a dose-dependent manner, which is driven by a cardiotonic response that complements the previously reported sequestration effect. PMID- 24496126 TI - Introduction to the Anesthesiology cardiac arrest and resuscitation issue. PMID- 24496125 TI - Beneficial effects of nitric oxide on outcomes after cardiac arrest and cardiopulmonary resuscitation in hypothermia-treated mice. AB - BACKGROUND: Therapeutic hypothermia (TH) improves neurological outcomes after cardiac arrest (CA) and cardiopulmonary resuscitation (CPR). Although nitric oxide prevents organ injury induced by ischemia and reperfusion, role of nitric oxide during TH after CPR remains unclear. In this article, the authors examined the impact of endogenous nitric oxide synthesis on the beneficial effects of hypothermia after CA/CPR. The authors also examined whether or not inhaled nitric oxide during hypothermia further improves outcomes after CA/CPR in mice treated with TH. METHODS: Wild-type mice and mice deficient for nitric oxide synthase 3 (NOS3(-/-)) were subjected to CA at 37 degrees C and then resuscitated with chest compression. Body temperature was maintained at 37 degrees C (normothermia) or reduced to 33 degrees C (TH) for 24 h after resuscitation. Mice breathed air or air mixed with nitric oxide at 10, 20, 40, 60, or 80 ppm during hypothermia. To evaluate brain injury and cerebral blood flow, magnetic resonance imaging was performed in wild-type mice after CA/CPR. RESULTS: Hypothermia up-regulated the NOS3-dependent signaling in the brain (n = 6 to 7). Deficiency of NOS3 abolished the beneficial effects of hypothermia after CA/CPR (n = 5 to 6). Breathing nitric oxide at 40 ppm improved survival rate in hypothermia-treated NOS3(-/-) mice (n = 6) after CA/CPR compared with NOS3(-/-) mice that were treated with hypothermia alone (n = 6; P < 0.05). Breathing nitric oxide at 40 (n = 9) or 60 (n = 9) ppm markedly improved survival rates in TH treated wild-type mice (n = 51) (both P < 0.05 vs. TH-treated wild-type mice). Inhaled nitric oxide during TH (n = 7) prevented brain injury compared with TH alone (n = 7) without affecting cerebral blood flow after CA/CPR (n = 6). CONCLUSIONS: NOS3 is required for the beneficial effects of TH. Inhaled nitric oxide during TH remains beneficial and further improves outcomes after CA/CPR. Nitric oxide breathing exerts protective effects after CA/CPR even when TH is ineffective due to impaired endogenous nitric oxide production. PMID- 24496127 TI - Editorial tribute to case managers: children, parents, spouses, grandparents, and friends. PMID- 24496128 TI - Real-world disparities between patient- and clinician-reported outcomes: results from a disease-specific program in depression and anxiety. AB - PURPOSE: The purpose of this study was to identify potential discordance between physician and patient rated measures of depression used by primary care physicians and psychiatrists. PRIMARY PRACTICE SETTING: This study collected data from primary care physicians and psychiatrists in the United States between October and December 2009. METHODOLOGY AND SAMPLE: A real-world, cross-sectional study was conducted using the Neuroses Disease-Specific Programme (Adelphi Real World, Macclesfield, United Kingdom). Treatment practice data were collected by 180 physicians (100 primary care and 80 psychiatrists) who were asked to provide information for the next 15 outpatients presenting prospectively with symptoms of anxiety and/or depression (n = 2,704 patients). The primary outcome measures were the Clinical Global Impressions-and Patient Global Impressions-Improvement scales, completed by both physicians and their matched patients, respectively. Cohen's kappa coefficient (kappa) was calculated to assess the level of agreement between the Clinical Global Impressions-and Patient Global Impressions Improvement scale responses. RESULTS: Physician- and patient-rated overall improvement in illness was 82% and 89%, respectively. Results of the kappa analysis demonstrated fair agreement between patients and physicians regarding overall improvement in illness (44% agreement; kappa= 0.23). Physician ratings of patient improvement progressively decreased with increased severity of illness. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: These real-world data suggest that the degree of reduction in symptoms of anxiety and/or depression may be estimated differently by physicians when compared with their patients. Understanding the potential for disparities between physician- and patient-rated measures in reviewing patient care, particularly in patients with more severe depressive symptoms, can help ensure that treatment plans are aligned with patient needs. PMID- 24496129 TI - Real-world disparities between patient- and clinician-reported outcomes: results from a disease-specific program in depression and anxiety. PMID- 24496130 TI - Deployment of lean six sigma in care coordination: an improved discharge process. AB - PURPOSE/OBJECTIVES: This article presents a quality improvement project to reduce readmissions in the Medicare population related to heart failure, acute myocardial infarction, and pneumonia. The article describes a systematic approach to the discharge process aimed at improving transitions of care from hospital to post-acute care, utilizing Lean Six Sigma methodology. PRIMARY PRACTICE SETTING: Inpatient acute care hospital. FINDINGS/CONCLUSIONS: A coordinated discharge process, which includes postdischarge follow-up, can reduce avoidable readmissions. Implications for CASE MANAGEMENT: The quality improvement project demonstrated the significant role case management plays in preventing costly readmissions and improving outcomes for patients through better transitions of care from the hospital to the community. By utilizing Lean Six Sigma methodology, hospitals can focus on eliminating waste in their current processes and build more sustainable improvements to deliver a safe, quality, discharge process for their patients. Case managers are leading this effort to improve care transitions and assure a smoother transition into the community postdischarge.. PMID- 24496132 TI - Collaborating for care: initial experience of embedded case managers across five medical homes. AB - PURPOSE OF THE STUDY: The purpose of this intervention was to answer the following question: Does an embedded nurse case manager from a health plan performing embedded care coordination and supporting a quality improvement project impact medical home service use, role satisfaction, and per member per month expense? PRIMARY PRACTICE SETTING(S): The setting for this study was primary care medical home practices with a minimum of 1,000 lives, contracted with a health plan delivering Medicaid and Children's Health Insurance coverage. METHODOLOGY AND SAMPLE: Five medical home practice sites were selected for the intervention. The study began with case manager training and project permission in 5 medical homes, followed by implementation of care coordination with health plan clients. The nurse case manager performed care coordination functions for clients and initiated a Lean Six Sigma quality improvement project at the medical home site. The analysis strategy was to compare each medical home with itself before and after the intervention, as well as to obtain satisfaction information from medical home staff and care coordinators. RESULTS: Reductions in expense, as demonstrated by decreased per member per month claim cost, admissions per thousand, and reduced variation in days per thousand, were documented. Quality projects attained significant improvements in 4 out of 5 sites, and practice staff as well as case managers described satisfaction with the embedded nurse case manager role. These findings support medical homes as being an effective delivery model of the Affordable Care Act. IMPLICATIONS FOR CASE MANAGEMENT PRACTICE: Case managers who practice in primary care sites can make a significant difference in patient outcomes and practice efficiencies. Embedded case managers have the ability to impact the population being served through modeling and supporting interprofessional relationships and case management expertise. Use of motivational interviewing, assessment skills, advocacy, and joint care planning engage patients in their own care, whereas quality initiatives bring efficiencies and effectiveness to overall operations. There is need for research to be conducted across a larger number of practice sites and diverse populations to substantiate the effect of embedded case management in medical home. PMID- 24496133 TI - The importance of leadership followership. PMID- 24496134 TI - Editorial commentary. Health insurance portability and accountability act final rule compliance 6 months later. PMID- 24496135 TI - The case management career path. PMID- 24496136 TI - Annual conference report: NCMN raised the bar on case management. PMID- 24496137 TI - Public sector health care-what every case manager should know. PMID- 24496138 TI - Hollow core-shell structured Si/C nanocomposites as high-performance anode materials for lithium-ion batteries. AB - Hollow core-shell structured Si/C nanocomposites were prepared to adapt for the large volume change during a charge-discharge process. The Si nanoparticles were coated with a SiO2 layer and then a carbon layer, followed by etching the interface SiO2 layer with HF to obtain hollow core-shell structured Si/C nanocomposites. The Si nanoparticles are well encapsulated in a carbon matrix with an internal void space between the Si core and the carbon shell. The hollow core-shell structured Si/C nanocomposites demonstrate a high specific capacity and excellent cycling stability, with capacity decay as small as 0.02% per cycle. The enhanced electrochemical performance can be attributed to the fact that the internal void space can accommodate the volume expansion of Si during lithiation, thus preserving the structural integrity of electrode materials, and the carbon shell can increase the electronic conductivity of the electrode. PMID- 24496139 TI - Why do patients and caregivers seek answers from the Internet and online lung specialists? A qualitative study. AB - BACKGROUND: Since its launch in 2003, the Dutch Lung Cancer Information Center's (DLIC) website has become increasingly popular. The most popular page of the website is the section "Ask the Physician", where visitors can ask an online lung specialist questions anonymously and receive an answer quickly. Most questions were not only asked by lung cancer patients but also by their informal caregivers. Most questions concerned specific information about lung cancer. OBJECTIVE: Our goal was to explore the reasons why lung cancer patients and caregivers search the Internet for information and ask online lung specialists questions on the DLIC's interactive page, "Ask the Physician", rather than consulting with their own specialist. METHODS: This research consisted of a qualitative study with semistructured telephone interviews about medical information-seeking behavior (eg, information needs, reasons for querying online specialists). The sample comprised 5 lung cancer patients and 20 caregivers who posed a question on the interactive page of the DLIC website. RESULTS: Respondents used the Internet and the DLIC website to look for lung cancer related information (general/specific to their personal situation) and to cope with cancer. They tried to achieve a better understanding of the information given by their own specialist and wanted to be prepared for the treatment trajectory and disease course. This mode of information supply helped them cope and gave them emotional support. The interactive webpage was also used as a second opinion. The absence of face-to-face contact made respondents feel freer to ask for any kind of information. By being able to pose a question instantly and receiving a relatively quick reply from the online specialist to urgent questions, respondents felt an easing of their anxiety as they did not have to wait until the next consultation with their own specialist. CONCLUSIONS: The DLIC website with its interactive page is a valuable complementary mode of information supply and supportive care for lung cancer patients and caregivers. PMID- 24496140 TI - Long-term dry storage of an enzyme-based reagent system for ELISA in point-of care devices. AB - Lateral flow devices are commonly used for many point-of-care (POC) applications in low-resource settings. However, they lack the sensitivity needed for many analytes relevant in the diagnosis of diseases. One approach to achieve higher sensitivity is signal amplification, which is commonly used in laboratory assays, but uses reagents that require refrigeration and inherently requires multiple assay steps not normally compatible with POC settings. Enzyme-based signal amplification, such as the one used in ELISA, could greatly improve the limit of detection if it were translated to a format compatible with POC requirements. A signal-amplified POC device not only requires the reagents to be stored in a stable form, but also requires automation of the multiple sequential steps of signal amplification protocols. Here, we describe a method for the long-term dry storage of ELISA reagents: horseradish peroxidase (HRP) conjugated antibody label and its colorimetric substrate diaminobenzidine (DAB). The HRP conjugate retained ~80% enzymatic activity after dry storage at 45 degrees C for over 5 months. The DAB substrate was also stable at 45 degrees C and exhibited no detectable loss of activity over 3 months. These reagents were incorporated into a two dimensional paper network (2DPN) device that automated the steps of ELISA for the detection of a malarial biomarker. These results demonstrate the potential of enzyme-based signal amplification for enhanced sensitivity in POC devices for low resource settings. PMID- 24496141 TI - Antimicrobial properties and interaction of two Trp-substituted cationic antimicrobial peptides with a lipid bilayer. AB - Tryptophan (Trp) residues reportedly exhibit a strong membrane-disruptive activity, and this property endows Trp-containing antimicrobial peptides (AMPs) with a unique ability to interact with the surface of bacterial cell membranes, possibly improving antimicrobial properties. In this study, we investigated the influence of Trp residues engineered to have a distinct preference for the interface region of lipid bilayers on antimicrobial activity. We designed two Trp substituted AMPs (I1WL5W and I4WL5W) by replacing Ile or Leu residues with two Trp residues at different positions in the L-K6 peptide, and determined their antimicrobial activity and mechanism of membrane action. Both I1WL5W and I4WL5W exhibited significantly higher antimicrobial activity and lower cytotoxicity against Gram-negative and Gram-positive bacteria compared with L-K6. The Trp substituted peptides had a disordered structure in aqueous solution and adopted an alpha-helical structure in solutions of 50% trifluoroethanol/water and 30 mM SDS. I1WL5W and I4WL5W caused a significant leakage of calcein from liposomes containing membranes that mimicked those of Escherichia coli and Staphylococcus aureus. Scanning electron microscopy analysis suggested that I1WL5W and I4WL5W killed bacteria by disrupting bacterial cell membranes. Furthermore, fluorescence and quenching data from a variety of liposomes, which mimic different cell membranes, indicated that the Trp-substituted peptides could insert into the lipid bilayers and induce blue shifts in the emission spectra of the Trp residues. I1WL5W and I4WL5W were also less susceptible to acrylamide or KI quenchers. The current work may be important for designing novel Trp-containing peptides exhibiting strong antimicrobial abilities by penetrating bacterial membranes. PMID- 24496142 TI - RK-1355A and B, novel quinomycin derivatives isolated from a microbial metabolites fraction library based on NPPlot screening. AB - Two novel quinomycin derivatives, RK-1355A (1) and B (2), and one known quinomycin derivative, UK-63,598 (3), were isolated from a microbial metabolites fraction library of Streptomyces sp. RK88-1355 based on Natural Products Plot screening. The structural elucidation of 1 and 2 was established through two dimensional NMR and mass spectrometric measurements. They belong to a class of quinomycin antibiotics family having 3-hydroxyquinaldic acid and a sulfoxide moiety. They are the first examples for natural products as a quinoline type quinomycin having a sulfoxide on the intramolecular cross-linkage. They showed potent antiproliferative activities against various cancer cell lines and they were also found to exhibit moderate antibacterial activity. PMID- 24496143 TI - Indole-based alkaloids from deep-sea bacterium Shewanella piezotolerans with antitumor activities. AB - Chromatographic separation of a crude extract obtained from a fermentation broth of a chemically unknown bacterium Shewanella piezotolerans WP3 collected in deep sea yielded three new indole alkaloids namely shewanellines A (1a), B (1b) and C (2), together with 12 known indole alkaloids. The structures were unambiguously elucidated on the basis of 1D and 2D NMR ((1)H, (13)C, COSY, HMBC, HSQC and NOESY) in association with MS and CD data. Compounds 1-4, 7, 9 and 11-14 were selected for the evaluation of their cytotoxic activities against human tumor cell lines HL-60 and BEL-7402, whereas compounds 2, 4 and 9 exhibited significant inhibition toward HL-60. PMID- 24496144 TI - Jomthonic acids B and C, two new modified amino acids from Streptomyces sp. PMID- 24496145 TI - Leucomycin A3, a 16-membered macrolide antibiotic, inhibits influenza A virus infection and disease progression. AB - Severe respiratory disease arising from influenza virus infection has a high fatality rate. Neutrophil myeloperoxidase (MPO) has been implicated in the pathogenesis of severe influenza-induced pneumonia because extracellularly released MPO mediates the production of hypochlorous acid, a potent tissue injury factor. To search for candidate anti-influenza compounds, we screened leucomycin A3 (LM-A3), spiramycin (SPM), an erythromycin derivative (EM900, in which anti bacterial activity has been eliminated), and clarithromycin (CAM), by analyzing their ability to inhibit MPO release in neutrophils from mice and humans. When each candidate was injected into mice infected with a lethal dose of A/H1N1 influenza virus (PR-8), LM-A3 produced the highest survival rate (80.9%). We found that LM-A3 induced beneficial effects on lung pathology and viral proliferation involved in the regulatory activity of MPO release, pro inflammatory cytokines and interferon-alpha production in the lung. SPM and EM900 also induced positive survival effects in the infected mice, whereas CAM did not. We further found that these compounds inhibit virus proliferation in human pneumonia epithelial A549 cells in vitro. LM-A3 showed effective action against influenza A virus infection with high anti-viral activity in human host cells, indicating the possibility that LM-A3 is a prospective lead compound for the development of a drug for human influenza. The positive survival effect induced by EM900 suggests that pharmacological architectures between anti-bacterial and anti-influenza virus activities can be dissociated in macrolide derivatives. These observations provide valuable evidence for the potential development of novel macrolide derivatives that have strong anti-viral but no anti-bacterial activity. PMID- 24496146 TI - Sub-MIC levels of purpurin inhibit membrane ATPase-mediated proton efflux activity in the human fungal pathogen Candida albicans. PMID- 24496147 TI - Ta3N5-Pt nonwoven cloth with hierarchical nanopores as efficient and easily recyclable macroscale photocatalysts. AB - Traditional nanosized photocatalysts usually have high photocatalytic activity but can not be efficiently recycled. Film-shaped photocatalysts on the substrates can be easily recycled, but they have low surface area and/or high production cost. To solve these problems, we report on the design and preparation of efficient and easily recyclable macroscale photocatalysts with nanostructure by using Ta3N5 as a model semiconductor. Ta3N5-Pt nonwoven cloth has been prepared by an electrospinning-calcination-nitridation-wet impregnation method, and it is composed of Ta3N5 fibers with diameter of 150-200 nm and hierarchical pores. Furthermore, these fibers are constructed from Ta3N5 nanoparticles with diameter of ~25 nm which are decorated with Pt nanoparticles with diameter of ~2.5 nm. Importantly, Ta3N5-Pt cloth can be used as an efficient and easily recyclable macroscale photocatalyst with wide visible-light response, for the degradation of methylene blue and parachlorophenol, probably resulting in a very promising application as "photocatalyst dam" for the polluted river. PMID- 24496148 TI - Association between phospholipase C epsilon gene (PLCE1) polymorphism and colorectal cancer risk in a Chinese population. AB - OBJECTIVE: To investigate the association between a single nucleotide polymorphism rs2274223 (adenine [A] to guanine [G]) in the phospholipase C epsilon 1 (PLCE1) gene and susceptibility to colorectal cancer (CRC). METHODS: The PLCE1 rs2274223 polymorphism was genotyped in patients with CRC and age- and sex-matched cancer-free control subjects from a Chinese population in a case control study. PLCE1 mRNA levels in pair-matched tumour and adjacent noncancerous tissue were evaluated by real-time quantitative reverse transcription-polymerase chain reaction. RESULTS: A total of 417 patients with CRC and 416 control subjects were enrolled in the study. The AG and GG genotypes of PLCE1 rs2274223 were associated with a significantly increased risk of CRC (for AG + GG versus AA: adjusted odds ratio 1.52, 95% confidence interval 1.15, 2.00). PLCE1 mRNA levels were significantly lower in tumours than in adjacent noncancerous tissue. Lower levels of PLCE1 mRNA were observed in both AG and GG genotype carriers compared with the AA genotype carriers. CONCLUSIONS: These results indicate that the PLCE1 rs2274223 A > G change might reduce gene expression and that the variant G genotype might contribute to the increased risk of CRC. PMID- 24496149 TI - Association between single nucleotide polymorphisms of sterol regulatory element binding protein-2 gene and risk of knee osteoarthritis in a Chinese Han population. AB - OBJECTIVE: To investigate associations between single nucleotide polymorphisms (SNPs) rs2228314 and rs2267443 in the sterol regulatory element binding protein-2 gene (SREBP-2) and knee osteoarthritis (OA) susceptibility in a Chinese Han population. METHODS: SREBP-2 rs2228314 and rs2267443 polymorphisms were genotyped in patients with knee OA and age- and sex-matched OA-free controls from a Chinese Han population. RESULTS: A total of 402 patients with knee OA and 410 controls were enrolled in the study. GC and CC genotypes of rs2228314, and variant C, were associated with a significantly increased risk of knee OA. On stratification analysis, the association between the risk of OA and rs2228314 GC heterozygotes compared with GG homozygotes was stronger in females and those aged >65 years. In contrast, the GA and AA genotypes of rs2267443 were not significantly associated with the risk of knee OA, even after further stratification analysis according to age or sex. CONCLUSIONS: SREBP-2 rs2228314 G to C change and variant C genotype may contribute to knee OA risk in a Chinese Han population. PMID- 24496150 TI - Mycophenolate mofetil improves neurological function and alters blood T lymphocyte subsets in rats with experimental autoimmune encephalomyelitis. AB - OBJECTIVE: This study evaluated the clinical and pathological effects of the immunosuppressive agent mycophenolate mofetil (MMF) in rats with experimental autoimmune encephalomyelitis (EAE; a model of multiple sclerosis [MS]). METHODS: EAE rats were randomly divided into 4 groups: model alone (n = 7); low- or high dose MMF (20 and 30 mg/kg per day, respectively, n = 6 each) orally for 14 days; methylprednisolone (20 mg/kg per day, n = 6) injected once daily for 3 days. Six normal Wistar rats served as controls. Clinical signs and histopathological findings were evaluated 14 days after treatment started. RESULTS: Oral administration of high-dose MMF significantly ameliorated the course of EAE in rats: cumulative clinical scores were lower and weight loss was less than in rats receiving methylprednisolone. The ameliorated disease course was associated with alleviation of histopathological signs of EAE. Treatment increased the blood proportion of CD8(+), CD4(+)CD25(+) and CD4(+)CD45RA(+) T cells, with a concomitant reduced proportion of CD4(+) T cells and ratio of CD4(+) to CD8(+) T cells, compared with EAE model alone rats. CONCLUSIONS: MMF may have pharmacological potential in MS treatment and these findings may help in understanding the pathophysiological mechanism of MS. PMID- 24496151 TI - Efficient reduced graphene oxide grafted porous Fe3O4 composite as a high performance anode material for Li-ion batteries. AB - Here, we report facile fabrication of Fe3O4-reduced graphene oxide (Fe3O4-RGO) composite by a novel approach, i.e., microwave assisted combustion synthesis of porous Fe3O4 particles followed by decoration of Fe3O4 by RGO. The characterization studies of Fe3O4-RGO composite demonstrate formation of face centered cubic hexagonal crystalline Fe3O4, and homogeneous grafting of Fe3O4 particles by RGO. The nitrogen adsorption-desorption isotherm shows presence of a porous structure with a surface area and a pore volume of 81.67 m(2) g(-1), and 0.106 cm(3) g(-1) respectively. Raman spectroscopic studies of Fe3O4-RGO composite confirm the existence of graphitic carbon. Electrochemical studies reveal that the composite exhibits high reversible Li-ion storage capacity with enhanced cycle life and high coulombic efficiency. The Fe3O4-RGO composite showed a reversible capacity ~612, 543, and ~446 mA h g(-1) at current rates of 1 C, 3 C and 5 C, respectively, with a coulombic efficiency of 98% after 50 cycles, which is higher than graphite, and Fe3O4-carbon composite. The cyclic voltammetry experiment reveals the irreversible and reversible Li-ion storage in Fe3O4-RGO composite during the starting and subsequent cycles. The results emphasize the importance of our strategy which exhibited promising electrochemical performance in terms of high capacity retention and good cycling stability. The synergistic properties, (i) improved ionic diffusion by porous Fe3O4 particles with a high surface area and pore volume, and (ii) increased electronic conductivity by RGO grafting attributed to the excellent electrochemical performance of Fe3O4, which make this material attractive to use as anode materials for lithium ion storage. PMID- 24496152 TI - A disulphide-linked heterodimer of TWIK-1 and TREK-1 mediates passive conductance in astrocytes. AB - TWIK-1 is a member of the two-pore domain K(+) (K2P) channel family that plays an essential part in the regulation of resting membrane potential and cellular excitability. The physiological role of TWIK-1 has remained enigmatic because functional expression of TWIK-1 channels is elusive. Here we report that native TWIK-1 forms a functional channel at the plasma membrane of astrocytes. A search for TWIK-1-binding proteins led to the identification of TREK-1, another member of the K2P family. The TWIK-1/TREK-1 heterodimeric channel is formed via a disulphide bridge between residue C69 in TWIK-1 and C93 in TREK-1. Gene silencing demonstrates that surface expression of TWIK-1 and TREK-1 are interdependent. TWIK-1/TREK-1 heterodimers mediate astrocytic passive conductance and cannabinoid induced glutamate release from astrocytes. Our study sheds new light on the diversity of K2P channels. PMID- 24496153 TI - Esophagectomy: anastomotic leak, stent the rent! PMID- 24496154 TI - SASLT practice guidelines for the management of hepatitis B virus. PMID- 24496156 TI - The role of esophageal stent placement in the management of postesophagectomy anastomotic leak. AB - BACKGROUND/AIM: Anastomotic leak after esophagectomy is one of the most challenging complications resulting in a high morbidity and mortality and prolonged hospitalization. The study intended to assess the outcome of endoluminal self-expanding stent in the treatment of this problem. SETTINGS AND DESIGN: Department of Thoracic and Cardiovascular Surgery, Arhus University Hospital, Skejby, Arhus, Denmark. A retrospective study. PATIENTS AND METHODS: From January 2007 to December 2010, 209 patients underwent esophagectomy for malignant disease of the esophagus or the cardia. Twenty patients developed anastomotic leak. Treatment consisted of conservative measures, surgery, and stent placement. Details of treatment, clinical outcome, complications, and mortality were evaluated. STATISTICAL ANALYSIS: None. RESULTS: One hundred and forty-seven patients (70.3%) had carcinoma of the cardia, whereas 62 patients (29.7%) had esophageal carcinoma. Twenty patients (9.5%) developed anastomotic leak; small (<1 cm) in two patients (10%); managed conservatively and bigger than 1 cm in 15 patients (75%); treated with an esophageal stent (Hanaro stent, DIAGMED Healthcare, Thirsk, YO7 3TD, United Kingdom). In three patients (15%), perforation of the staple line of the intrathoracic gastric conduit was found and managed by reoperation. Functional sealing of anastomoses after stent placement could be achieved in 10 patients (67%). Stent-related morbidity developed in five patients (33%): Migration of the stent, n=3 and tracheoesophageal fistula, n=2. Stents were smoothly removed 3 weeks after discharge. The mean hospital stay was 25 days. There was only one stent-related death (6.6%). CONCLUSION: Endoluminal stent implantation is an effective and safe option in the management of postesophagectomy leaks. PMID- 24496155 TI - Advanced endoscopic imaging for surveillance for dysplasia and colorectal cancer in inflammatory bowel disease: could the pathologist be further helped? AB - Patients with inflammatory bowel disease (IBD) have an increased risk of developing intestinal cancer. The magnitude of that increased risk as well as how best to mitigate it remain a topic of ongoing investigation in the field. It is important to quantify the risk of colorectal cancer in association with IBD. The reported risk varies widely between studies. This is partly due to the different methodologies used in the studies. Because of the limitations of surveillance strategies based on the detection of dysplasia, advanced endoscopic imaging and techniques involving the detection of alterations in mucosal antigens and genetic abnormalities are being investigated. Development of new biomarkers, predicting future occurrence of colonic neoplasia may lead to more biomarker-based surveillance. There are promising results that may lead to more efficient surveillance in IBD patients and more general acceptance of its use. A multidisciplinary approach, involving in particular endoscopists and pathologists, together with a centralized patient management, could help to optimize treatments and follow-up measures, both of which could help to reduce the IBD-associated cancer risk. PMID- 24496157 TI - Efficacy of pneumatic dilatation in Saudi achalasia patients. AB - BACKGROUND/AIMS: Pneumatic dilatation (PD) is one of the effective treatments of achalasia. The aim of this study was to evaluate the efficacy of pneumatic dilation and patient satisfaction in Saudi achalasia patients. PATIENTS AND METHODS: We have retrospectively recruited patients with confirmed achalasia, who underwent at least one dilatation session from January 1990 to January 2010 at a single tertiary center. Symptoms, including weight loss, dysphagia, retrosternal pain, and regurgitation, were assessed with the use of the Eckardt score (which ranges from 0 to 12, with higher scores indicating more pronounced symptoms). All patients were called and asked about their Eckardt score in addition to their satisfaction score post the dilatation procedure. The primary outcome was therapeutic success (Eckardt score<=3) and patient satisfaction at the time of their calls. The secondary outcomes included the need for retreatment and the rate of complications. RESULTS: A total of 29 patients were included, with a mean age of 40.30 (95% CI: 36.1-44.6) and 55.2% of them were males. The mean of the pre-dilatation Eckardt score was 8.3 (95% CI: 7.2-9.4), which dropped to 2.59 (95% CI: 1.7-3.5) after PD (P<0.01) with a clinical remission of 76.7% after the first dilatation and a total failure in two patients (7%) after the third dilatation. The mean number of dilatations was 1.3 (95% CI: 1.1-1.5) where 50.7% required one dilatation, 19.2% required two dilatations, and 30.1% required three dilatations. The mean of the symptoms-free period was 53.4 months (SD 52.7, range 1-180) with symptoms recurring in 35% of patients within 2 years. The mean of post-PD patient satisfaction was 7.45 (95% CI: 6.2-8.7). Perforation, which was treated conservatively, occurred in one patient (3.5%), whereas bleeding occurred in two patients (7%). Age or gender was not found to be a predictor of Eckardt score improvement on multivariate linear regression analysis. CONCLUSION: PD is an efficacious procedure in Saudi achalasia patients with a very good overall patient satisfaction with 53.4 months of symptoms-free period after a successful dilatation. PMID- 24496158 TI - Prognostic significance of Glasgow prognostic score in patients undergoing esophagectomy for esophageal squamous cell carcinoma. AB - BACKGROUND/AIMS: Recent studies have revealed that Glasgow prognostic score (GPS), an inflammation-based prognostic score, is inversely related to prognosis in a variety of cancers; high levels of GPS is associated with poor prognosis. However, few studies regarding GPS in esophageal cancer (EC) are available. The aim of this study was to determine whether the GPS is useful for predicting cancer-specific survival (CSS) of patients for esophageal squamous cell carcinoma (ESCC). PATIENTS AND METHODS: The GPS was calculated on the basis of admission data as follows: Patients with elevated C-reactive protein (CRP) level (>10 mg/L) and hypoalbuminemia (<35 g/L) were assigned to GPS2. Patients with one or no abnormal value were assigned to GPS1 or GPS0, respectively. RESULTS: Our study showed that GPS was associated with tumor size, depth of invasion, and nodal metastasis (P<0.001). In addition, there was a negative correlation between the serum CRP and albumin (r=-0.412, P<0.001). The 5-year CSS in patients with GPS0, GPS1, and GPS2 were 60.8%, 34.7% and 10.7%, respectively (P<0.001). Multivariate analysis showed that GPS was a significant predictor of CSS. GPS1-2 had a hazard ratio (HR) of 2.399 [95% confidence interval (CI): 1.805-3.190] for 1-year CSS (P<0.001) and 1.907 (95% CI: 1.608-2.262) for 5-year CSS (P<0.001). CONCLUSION: High levels of GPS is associated with tumor progression. GPS can be considered as an independent prognostic factor in patients who underwent esophagectomy for ESCC. PMID- 24496159 TI - Association of plasminogen activator inhibitor-1 gene polymorphism with inflammatory bowel disease in Iranian Azeri Turkish patients. AB - BACKGROUND/AIM: Previous studies have shown the association of some genetic factors, such as Plasminogen activator inhibitor type-1 (PAI-1) 4G/5G polymorphism, with the development of inflammatory bowel disease (IBD). We aimed to study this polymorphism as a risk factor in IBD patients in this cohort. PATIENTS AND METHODS: One hundred and fifteen IBD patients and 95 healthy controls were selected from Iranian Azeri Turks and -6754G/5G polymorphism of PAI 1 gene was tested by polymerase chain reaction using allele-specific primers confirmed by sequencing. RESULTS: There was no significant difference of PAI-1 polymorphism between IBD patients and the control group (P>0.05). Furthermore, these data showed no significant difference between Crohn's disease and ulcerative colitis patients. However, 4G/4G homozygotes have reduced probability to progression of loss of appetite, whereas 5G/5G genotypes have increased risk for development of chronic diarrhea without blood, nausea, and loss of appetite. CONCLUSIONS: Although our study showed no significant association of PAI-1 polymorphism between patients and control group, the carriers of 4G/4G genotype and 4G allele had reduced risk for the progression of IBD features in this cohort. PMID- 24496160 TI - Overexpression of cyclooxygenase-2 and transforming growth factor-beta 1 is an independent predictor of poor virological response to interferon therapy in chronic HCV genotype 4 patients. AB - BACKGROUND/AIMS: COX-2 and TGF-beta1 are overexpressed in hepatitis C virus (HCV) infection and are related to hepatitis pathogenesis and hepatic fibrosis. The current study investigated the relationship between pretreatment COX-2 and TGF beta1 hepatic expression in HCV genotype 4 and the virological response to interferon therapy. PATIENTS AND METHODS: Liver biopsies of 55 patients with HCV infection genotype 4 were selected together with 10 liver biopsies as control. The patients' clinicopathological data were collected. Immunohistochemistry was done using anti-COX-2 and anti-TGF-beta1 antibodies. Statistical tests were used to determine the association between both COX-2 and TGF-beta1 expression in relation to clinicopathological parameters and response to interferon therapy. RESULTS: COX-2 was upregulated especially in nonresponders and was an independent predictor of poor virological response. However, COX-2 showed no association with other clinicopathological features. TGF-beta1 was upregulated and associated with nonresponders, histological activity, and fibrosis stage. There was no association between TGF-beta1 and other clinicopathological features. There was an association between COX-2 and TGF-beta1 immunoexpression. CONCLUSION: Overexpression of COX-2 and TGF-beta1 is an independent predictor for poor outcome of interferon and ribavirin therapy and these might be useful markers for the response to treatment. Both molecules are associated together; however, their role during hepatitis treatment has to be clarified. PMID- 24496162 TI - Correlation between hepatitis B surface antigen titers and HBV DNA levels: what about the parameters affecting this correlation? PMID- 24496163 TI - What might be the cause for the emerging inflammatory bowel disease in Saudi outpatients? PMID- 24496161 TI - Evaluation of paraoxonase, malondialdehyde, and lipoprotein levels in patients with asymptomatic cholelithiasis. AB - BACKGROUND/AIM: To compare lipoprotein and malondialdehyde levels and paraoxonase 1 activity between subjects with asymptomatic cholelithiasis and controls. PATIENTS AND METHODS: Eighty subjects with asymptomatic cholelithiasis (55 women, 25 men, mean age: 51, SD 14 years) and 40 control subjects without cholelithiasis (25 women, 25 men, mean age: 51, SD 12 years) were enrolled to the study. Serum paraoxonase activity, lipoproteins, and malondialdehyde were measured. RESULTS: In the cholelithiasis group, serum total cholesterol, low-density lipoprotein cholesterol, and malondialdehyde were significantly higher and high-density lipoprotein cholesterol (HDL-C) and paraoxonase-1 were significantly lower than the controls. In cholelithiasis patients with serum glucose level>100 mg/dL, body mass index, serum total cholesterol, triglyceride (TG), and malondialdehyde levels were significantly higher than cholelithiasis patients with serum glucose level<100 mg/dL. Paraoxonase-1 activity was significantly lower in patients with serum glucose level>100 mg/dL. In cholelithiasis patients with TG>150 mg/dL, mean age, body mass index, glucose, total cholesterol, and malondialdehyde were significantly higher than in cholelithiasis patients with TG<150 mg/dL. In cholelithiasis subgroup with TG>150 mg/dL, HDL-C level and paraoxonase-1 activity were lower than in the cholelithiasis subgroup with TG<150 mg/dL. All of the above comparisons were statistically significant (P<0.05). CONCLUSIONS: Patients with asymptomatic cholelithiasis have evidence of increased lipid peroxidation and decreased antioxidant capacity. Patients with asymptomatic cholelithiasis with components of the metabolic syndrome have more lipid peroxidation and less antioxidant capacity than patients with asymptomatic cholelithiasis but without the components of the metabolic syndrome. PMID- 24496164 TI - Middle-aged woman with dysphagia to solid. Diagnosis: Right-sided aortic arch with an aberrant left subclavian artery. PMID- 24496165 TI - Natural history of premacular hemorrhage due to severe acute anemia: clinical and anatomical features in two untreated patients. AB - Premacular retrohyaloid hemorrhage is a rare complication of acute severe anemia. The authors report two cases of premacular hemorrhage in which no treatment other than clinical and spectral-domain optical coherence tomography observation was performed. The natural history of this condition reveals that complete clinical resolution is not accompanied by full anatomical restoration. [Ophthalmic Surg Lasers Imaging Retina. 2014;45:E5-E7.]. PMID- 24496166 TI - Managing wheeze in preschool children. PMID- 24496167 TI - Feminist self-defense and resistance training for college students: a critical review and recommendations for the future. AB - There remains resistance to feminist self-defense and resistance training programming for women, despite (a) documented effectiveness of rape resistance strategies in avoiding rape, (b) consistently high rates of sexual victimization on college campuses, and (c) limited evidence of lasting change in sexual assault perpetration reduction within existing men's prevention programs. The current article seeks to discuss (1) the rationale for feminist self-defense and resistance training for women, (2) key components of feminist self-defense and resistance training, (3) barriers to its implementation, (4) outcomes of self defense and resistance training programming, and (5) recommendations for future work. Such suggestions include increasing funding for large-scale self-defense and rape resistance outcome research to examine program effectiveness. Specifically, outcome research that examines the role of contextual factors (e.g., alcohol use) and women's victimization histories is needed. Finally, self defense training and resistance training should be combined with bystander intervention and men's programs with the goal of providing synergistic effects on rape reduction. PMID- 24496168 TI - Pneumothorax after ultrasound-guided supraclavicular block: presenting features, risk, and related training. AB - OBJECTIVE: Presenting features and estimate of risk of pneumothorax after ultrasound-guided supraclavicular block are discussed, along with related training strategies. CASE REPORT: We describe a case of a patient with pneumothorax after an ultrasound-guided supraclavicular brachial plexus block for hand surgery. The delayed onset of pain initially on the nonoperative side combined with the absence of respiratory symptoms delayed recognition of the pneumothorax. CONCLUSIONS: We estimate the risk of pneumothorax to be 0.4 per 1000 after ultrasound-guided supraclavicular block. We recommend specific training strategies for needle visualization for this technique to reduce the risk of pneumothorax. PMID- 24496169 TI - Minimum effective volume of combined lidocaine-bupivacaine for analgesic subparaneural popliteal sciatic nerve block. AB - BACKGROUND AND OBJECTIVES: The aim of this study was to determine the minimum effective volume (MEV) of combined lidocaine 1.0%-bupivacaine 0.25% with epinephrine 5 MUg/mL in 90% of patients (MEV90) for ultrasound-guided subparaneural popliteal sciatic nerve block. METHODS: All subjects received an ultrasound-guided subparaneural popliteal sciatic nerve block (at the neural bifurcation) with combined lidocaine 1.0%-bupivacaine 0.25% and epinephrine 5 MUg/mL. Using an out-of-plane technique, a 17-gauge, 8-cm Tuohy needle was advanced until its tip was positioned between the tibial and peroneal nerves inside the paraneural sheath. Volume assignment was carried out using a biased coin design, up-and-down sequential method, where the volume of local anesthetic administered to each patient depended on the response of the previous one. In case of failure, the next subject received a higher volume (defined as the previous volume with an increment of 3.0 mL). If the previous patient had a successful block, the next subject was randomized to a lower volume (defined as the previous volume with a decrement of 3.0 mL), with a probability of b = 0.11, or the same volume, with a probability of 1 - b = 0.89. Using a composite scale encompassing sensory and motor block, success was defined, at 30 minutes, as a minimal score of 6 points (out of 8 points). The 6-point score was intended to mirror successful postoperative analgesia. Patients undergoing surgery of the leg, ankle, or foot were prospectively enrolled until 45 successful blocks were obtained. RESULTS: Fifty-two patients were recruited for this study. Using isotonic regression and bootstrap confidence interval, the MEV90 of combined lidocaine 1.0%-bupivacaine 0.25% with epinephrine 5 MUg/mL was estimated to be 13.3 mL (95% confidence interval, 10.2-16.4 mL). CONCLUSIONS: For ultrasound guided subparaneural (analgesic) popliteal sciatic nerve block, the MEV90 of combined lidocaine 1.0%-bupivacaine 0.25% with epinephrine 5 MUg/mL is 13.3 mL (95% confidence interval, 10.2-16.4 mL). PMID- 24496170 TI - Dislocation of a femur fracture after femoral nerve block. AB - OBJECTIVE: Femoral nerve block (FNB) is increasingly used as an analgesic modality in patients with femoral fracture both in the emergency department and preoperatively. We describe an occurrence of unexpected dislocation of the fracture after FNB. CASE REPORT: An FNB was administered to treat pain in a 48 year-old patient with metastatic breast carcinoma and multiple bone metastases. A diagnostic FNB with 20 mL of 0.25% levobupivacaine resulted in analgesia but also in unexpected gross deformity in the proximal right femur. An x-ray revealed a pathologic fracture of the proximal third femur diaphysis, with reduction and angulation of fragments, necessitating urgent surgery. CONCLUSIONS: Femoral nerve block confers effective analgesia for femur fracture. However, relaxation of the quadriceps femoris muscle may destabilize the fracture because of an unopposed tone of the hamstrings and/or thigh adductors. PMID- 24496171 TI - Quantitative tissue pH measurement during cerebral ischemia using amine and amide concentration-independent detection (AACID) with MRI. AB - Tissue pH is an indicator of altered cellular metabolism in diseases including stroke and cancer. Ischemic tissue often becomes acidic due to increased anaerobic respiration leading to irreversible cellular damage. Chemical exchange saturation transfer (CEST) effects can be used to generate pH-weighted magnetic resonance imaging (MRI) contrast, which has been used to delineate the ischemic penumbra after ischemic stroke. In the current study, a novel MRI ratiometric technique is presented to measure absolute pH using the ratio of CEST-mediated contrast from amine and amide protons: amine/amide concentration-independent detection (AACID). Effects of CEST were observed at 2.75 parts per million (p.p.m.) for amine protons and at 3.50 p.p.m. for amide protons downfield (i.e., higher frequency) from bulk water. Using numerical simulations and in vitro MRI experiments, we showed that pH measured using AACID was independent of tissue relaxation time constants, macromolecular magnetization transfer effects, protein concentration, and temperature within the physiologic range. After in vivo pH calibration using phosphorus ((31)P) magnetic resonance spectroscopy ((31)P-MRS), local acidosis is detected in mouse brain after focal permanent middle cerebral artery occlusion. In summary, our results suggest that AACID represents a noninvasive method to directly measure the spatial distribution of absolute pH in vivo using CEST MRI. PMID- 24496172 TI - Parenchymal spin-lock fMRI signals associated with cortical spreading depression. AB - We found novel types of parenchymal functional magnetic resonance imaging (fMRI) signals in the rat brain during large increases in metabolism. Cortical spreading depression (CSD), a self-propagating wave of cellular activation, is associated with several pathologic conditions such as migraine and stroke. It was used as a paradigm to evoke transient neuronal depolarization leading to enhanced energy consumption. Activation of CSD was investigated using spin-lock (SL), diffusion, blood oxygenation level-dependent and cerebral blood volume fMRI techniques. Our results show that the SL-fMRI signal is generated by endogenous parenchymal mechanisms during CSD propagation, and these mechanisms are not associated with hemodynamic changes or cellular swelling. Protein phantoms suggest that pH change alone does not explain the observed SL-fMRI signal changes. However, increased amounts of inorganic phosphates released from high-energy phosphates combined with pH changes may produce SL- power-dependent longitudinal relaxation in the rotating frame (R1rho) changes in protein phantoms that are similar to those observed during CSD, as seen before in acute ischemia under our experimental conditions. This links SL-fMRI changes intimately to energy metabolism and supports the use of the SL technique as a new, promising functional approach for noninvasive imaging of metabolic transitions in the active or pathologic brain. PMID- 24496173 TI - Arterial spin labeling characterization of cerebral perfusion during normal maturation from late childhood into adulthood: normal 'reference range' values and their use in clinical studies. AB - The human brain changes structurally and functionally during adolescence, with associated alterations in cerebral perfusion. We performed dynamic arterial spin labeling (ASL) magnetic resonance imaging in healthy subjects between 8 and 32 years of age, to investigate changes in cerebral hemodynamics during normal development. In addition, an inversion recovery sequence allowed quantification of changes in longitudinal relaxation time (T1) and equilibrium longitudinal magnetization (M0). We present mean and reference ranges for normal values of T1, M0, cerebral blood flow (CBF), bolus arrival time, and bolus duration in cortical gray matter, to provide a tool for identifying age-matched perfusion abnormalities in this age range in clinical studies. Cerebral blood flow and T1 relaxation times were negatively correlated with age, without gender or hemisphere differences. The same was true for M0 anteriorly, but posteriorly, males but not females showed a significant decline in M0 with increasing age. Two examples of the clinical utility of these data in identifying age-matched perfusion abnormalities, in Sturge-Weber syndrome and sickle cell anemia, are illustrated. PMID- 24496175 TI - The predictive power of brain mRNA mappings for in vivo protein density: a positron emission tomography correlation study. AB - Substantial efforts are being spent on postmortem mRNA transcription mapping on the assumption that in vivo protein distribution can be predicted from such data. We tested this assumption by comparing mRNA transcription maps from the Allen Human Brain Atlas with reference protein concentration maps acquired with positron emission tomography (PET) in two representative systems of neurotransmission (opioid and serotoninergic). We found a tight correlation between mRNA expression and specific binding with 5-HT1A receptors measured with PET, but for opioid receptors, the correlation was weak. The discrepancy can be explained by differences in expression regulation between the two systems: transcriptional mechanisms dominate the regulation in the serotoninergic system, whereas in the opioid system proteins are further modulated after transcription. We conclude that mRNA information can be exploited for systems where translational mechanisms predominantly regulate expression. Where posttranscriptional mechanisms are important, mRNA data have to be interpreted with caution. The methodology developed here can be used for probing assumptions about the relationship of mRNA and protein in multiple neurotransmission systems. PMID- 24496174 TI - Cerebral neovascularization in diabetes: implications for stroke recovery and beyond. AB - Neovascularization is an innate physiologic response by which tissues respond to various stimuli through collateral remodeling (arteriogenesis) and new vessel formation from existing vessels (angiogenesis) or from endothelial progenitor cells (vasculogenesis). Diabetes has a major impact on the neovascularization process but the response varies between different organ systems. While excessive angiogenesis complicates diabetic retinopathy, impaired neovascularization contributes to coronary and peripheral complications of diabetes. How diabetes influences cerebral neovascularization remained unresolved until recently. Diabetes is also a major risk factor for stroke and poor recovery after stroke. In this review, we discuss the impact of diabetes, stroke, and diabetic stroke on cerebral neovascularization, explore potential mechanisms involved in diabetes mediated neovascularization as well as the effects of the diabetic milieu on poststroke neovascularization and recovery, and finally discuss the clinical implications of these effects. PMID- 24496176 TI - T2-weighted MRI detects presymptomatic pathology in the SOD1 mouse model of ALS. AB - Neuroinflammation has been identified as a potential therapeutic target in amyotrophic lateral sclerosis (ALS), but relevant biomarkers are needed. The superoxide dismutase (SOD1)(G93A) transgenic mouse model of ALS offers a unique opportunity to study and potentially manipulate presymptomatic pathology. While T2-weighted magnetic resonance imaging (MRI) has been shown to be sensitive to pathologic changes at symptom onset, no earlier biomarkers were previously identified and the underlying histopathologic correlates remain uncertain. To address these issues, we used a multimodal MRI approach targeting structural (T2, T1, apparent diffusion coefficient (ADC), magnetization transfer ratio (MTR)), vascular (gadolinium diethylene triamine pentaacetic acid), and endothelial (vascular cell adhesion molecule-microparticles of iron oxide) changes, together with histopathologic analysis from presymptomatic to symptomatic stages of disease. Presymptomatic changes in brainstem nuclei were evident on T2-weighted images from as early as 60 days (P<0.05). Histologic indices of vacuolation, astro- and microglial activation all correlated with T2-weighted changes. Significant reductions in ADC (P<0.01) and MTR (P<0.05) were found at 120 days in the same brainstem nuclei. No changes in T1 relaxation, vascular permeability, or endothelial activation were found at any stage of disease. These findings suggest that T2-weighted MRI offers the strongest biomarker potential in this model, and that MRI has unique potential for noninvasive and longitudinal assessment of presymptomatically applied therapeutic and neuroprotective agents. PMID- 24496177 TI - OAT3-mediated extrusion of the 99mTc-ECD metabolite in the mouse brain. AB - After administration of the (99m)Tc complex with N,N'-1,2-ethylenediylbis-L cysteine diethyl ester ((99m)Tc-ECD), a brain perfusion imaging agent, the radioactive metabolite is trapped in primate brain, but not in mouse and rat. Here, we investigate the involvement of metabolite extrusion by organic anion transporter 3 (OAT3), which is highly expressed at the blood-brain barrier in mice, in this species difference. The efflux rate of radioactivity in the cerebrum of Oat3(-/-) mice at later phase was 20% of that of control mice. Thus, organic anion transporters in mouse brain would be involved in the low brain retention of radioactivity after (99m)Tc-ECD administration. PMID- 24496179 TI - The relationship between syncope, depression and anti-depressant use in older adults. AB - BACKGROUND: syncope is a common problem which increases in older age groups. In syncope clinics, patients who are depressed have higher rates of unexplained syncope and higher rates of recurrent syncope. OBJECTIVES: : we aim to examine the rates of depression in older patients reporting syncope and the effect of anti-depressants (ADs) on the rates of syncope. DESIGN: : epidemiological, point prevalence study. SETTING AND PARTICIPANTS: : data came from the Irish Longitudinal Study on Ageing, which includes 8,175 adults aged 50 and older, living in the community in Ireland. MEASUREMENTS: : the Centre for Epidemiological Studies Depression scale was used to assess levels of depression. Multinomial regression was used to analyse the data with a P-value of <0.05 determining significance. RESULTS: : 7,993 participants aged 50 and older were included, and of these 349 reported at least one syncopal episode in the last year. Prevalence of syncope was 4.4%. After controlling for participant characteristics and general health, those with severe depression had a greater risk of single and multiple syncopal events (relative risk ratios [RRR]: 2.78 and 2.84, respectively, P < 0.050) and participants treated with tricyclic anti depressants (TCAs) were also at greater risk for single and multiple syncopal episode in the last year (RRR: 2.31, P = 0.062; RRR: 2.95, P < 0.05). CONCLUSIONS: : this study demonstrates an increased risk of syncope in patients with depression, with higher rates of syncope reported with increasing severity of depression. Treatment with TCAs increases both the risk and frequency of syncope in the community. Depression is a potentially modifiable risk factor for syncope but treatment options need to be tailored in the older patient population. PMID- 24496178 TI - The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic ischemic brain injury. AB - The neonatal brain is vulnerable to oxidative stress, and the pentose phosphate pathway (PPP) may be of particular importance to limit the injury. Furthermore, in the neonatal brain, neurons depend on de novo synthesis of neurotransmitters via pyruvate carboxylase (PC) in astrocytes to increase neurotransmitter pools. In the adult brain, PPP activity increases in response to various injuries while pyruvate carboxylation is reduced after ischemia. However, little is known about the response of these pathways after neonatal hypoxia-ischemia (HI). To this end, 7-day-old rats were subjected to unilateral carotid artery ligation followed by hypoxia. Animals were injected with [1,2-(13)C]glucose during the recovery phase and extracts of cerebral hemispheres ipsi- and contralateral to the operation were analyzed using (1)H- and (13)C-NMR (nuclear magnetic resonance) spectroscopy and high-performance liquid chromatography (HPLC). After HI, glucose levels were increased and there was evidence of mitochondrial hypometabolism in both hemispheres. Moreover, metabolism via PPP was reduced bilaterally. Ipsilateral glucose metabolism via PC was reduced, but PC activity was relatively preserved compared with glucose metabolism via pyruvate dehydrogenase. The observed reduction in PPP activity after HI may contribute to the increased susceptibility of the neonatal brain to oxidative stress. PMID- 24496180 TI - Non-invasive mouthguard biosensor for continuous salivary monitoring of metabolites. AB - The present work describes the first example of a wearable salivary metabolite biosensor based on the integration of a printable enzymatic electrode on a mouthguard. The new mouthguard enzymatic biosensor, based on an immobilized lactate oxidase and a low potential detection of the peroxide product, exhibits high sensitivity, selectivity and stability using whole human saliva samples. Such non-invasive mouthguard metabolite biosensors could tender useful real-time information regarding a wearer's health, performance and stress level, and thus hold considerable promise for diverse biomedical and fitness applications. PMID- 24496181 TI - Generation and characterization of regulatory dendritic cells derived from murine induced pluripotent stem cells. AB - Regulatory dendritic cells (DCregs) represent a potential therapeutic tool for assessing a variety of immune overreaction conditions; however, current approaches for generating DCregs for therapeutic purposes are limited. We attempted to generate and characterize DCregs from murine induced pluripotent stem (iPS) cells. The iPS cells co-cultured with OP9 cells displayed mesodermally differentiated flat colonies. GM-CSF drove most of the colonies exhibiting a differentiated morphology. Thereafter, cells became morphologically heterologous under the effects of TGF-beta and IL-10. Most of the floating cells developed an irregular shape with areas of protrusion. The generated iPS-DCregs demonstrated high CD11b/c and low CD40, CD80, CD86 and MHC-II expressions with a high antigen uptake ability and poor T-cell stimulatory function. Importantly, iPS-DCregs showed immune responsiveness regulation effects both in vitro and in vivo and the ability to generate regulatory T-cells in vitro. Our result illustrates a feasible approach for generating functional DCregs from murine iPS cells. PMID- 24496183 TI - The 16th International Conference on Dialysis, Advances in CKD 2014, January 22 24, 2014, in Las Vegas, Nev., USA. PMID- 24496182 TI - A non-canonical function of telomerase RNA in the regulation of developmental myelopoiesis in zebrafish. AB - Dyskeratosis congenita (DC) is an inherited disorder with mutations affecting telomerase or telomeric proteins. DC patients usually die of bone marrow failure. Here we show that genetic depletion of the telomerase RNA component (TR) in the zebrafish results in impaired myelopoiesis, despite normal development of haematopoietic stem cells (HSCs). The neutropenia caused by TR depletion is independent of telomere length and telomerase activity. Genetic analysis shows that TR modulates the myeloid-erythroid fate decision by controlling the levels of the master myeloid and erythroid transcription factors spi1 and gata1, respectively. The alteration in spi1 and gata1 levels occurs through stimulation of gcsf and mcsf. Our model of TR deficiency in the zebrafish illuminates the non canonical roles of TR, and could establish therapeutic targets for DC. PMID- 24496184 TI - Toward population management in an integrated care model. AB - Under the Patient Protection and Affordable Care Act of 2010, accountable care organizations (ACOs) will be the primary mechanism for achieving the dual goals of high-quality patient care at managed per capita costs. To achieve these goals in the newly emerging health care environment, the nephrology community must plan for and direct integrated delivery and coordination of renal care, focusing on population management. Even though the ESRD patient population is a complex group with comorbid conditions that may confound integration of care, the nephrology community has unique experience providing integrated care through ACO-like programs. Specifically, the recent ESRD Management Demonstration Project sponsored by the Centers for Medicare & Medicaid Services and the current ESRD Prospective Payment System with it Quality Incentive Program have demonstrated that integrated delivery of renal care can be accomplished in a manner that provides improved clinical outcomes with some financial margin of savings. Moving forward, integrated renal care will probably be linked to provider performance and quality outcomes measures, and clinical integration initiatives will share several common elements, namely performance-based payment models, coordination of communication via health care information technology, and development of best practices for care coordination and resource utilization. Integration initiatives must be designed to be measured and evaluated, and, consistent with principles of continuous quality improvement, each initiative will provide for iterative improvements of the initiative. PMID- 24496185 TI - Big data in nephrology: friend or foe? AB - The phrase 'big data' has arrived in today's lexicon with great fanfare and some degree of hyperbole. Generally speaking, big data refer to data sets that are too complex to be successfully interrogated using standard statistical software. A wide variety of business sectors has utilized big data to garner competitive advantage within their respective markets. Medicine and nephrology, in particular, have been late to this table. This is beginning to change, however, as data scientists begin to work with these large data sets, developing predictive models that permit us to peer into the future. Coupled with an expanding understanding of genomics, predictive models constructed with the assistance of big data may soon provide us with a powerful tool to use as we provide care to patients with renal disease. PMID- 24496186 TI - Monitoring dialysis outcomes across the world--the MONDO Global Database Consortium. AB - BACKGROUND/AIMS: Dialysis providers frequently collect detailed longitudinal and standardized patient data, providing valuable registries of routine care. However, even large organizations are restricted to certain regions, limiting their ability to separate effects of local practice from the pathophysiology shared by most dialysis patients. To overcome this limitation, the MONDO (MONitoring Dialysis Outcomes) research consortium has created a platform for the joint analysis of data from almost 200,000 dialysis patients worldwide. METHODS: We examined design and operation of MONDO as well as its methodology with respect to patient inclusion, descriptive data and other study parameters. RESULTS: MONDO partners contribute primary databases of anonymized patient data and collaboratively analyze populations across national and regional boundaries. To that end, datasets from different electronic health record systems are converted into a uniform structure. Patients are enrolled without systematic exclusions into open cohorts representing the diversity of patients. A large number of patient level treatment and outcome data is recorded frequently and can be analyzed with little delay. Detailed variable definitions are used to determine if a parameter can be studied in a subset or all databases. CONCLUSION: MONDO has created a large repository of validated dialysis data, expanding the opportunities for outcome studies in dialysis patients. The density of longitudinal information facilitates in particular trend analysis. Limitations include the paucity of uniform definitions and standards regarding descriptive information (e.g. comorbidities), which limits the identification of patient subsets. Through its global outreach, depth, breadth and size, MONDO advances the observational study of dialysis patients and care. PMID- 24496187 TI - Loss of renal function causes premature aging of the immune system. AB - BACKGROUND: Uremia-associated immune deficiency is a well-known complication of loss of renal function and contributes significantly to the overall mortality and morbidity of patients with end-stage renal disease. Chronic inflammation and increased oxidative stress are underlying the uremia-associated immune deficiency. SUMMARY: In this review, the differential impact of uremia on the cellular immune system is summarized. Virtually all immune cells studied show a combination of an activated status and loss of function. However, uremia preferentially decreases the number and function of lymphoid cells while myeloid cells show normal and/or elevated cell numbers with increased production of inflammatory cytokines and reactive oxygen species. These particular changes are compatible with immunological aging, which is characterized by loss of thymic function, attrition of telomeres and an expanded memory T cell population. Similar to aging in healthy individuals, the proinflammatory and potential cardiotoxic subsets of CD28(null) T cells and CD16(+) monocytes are increased. Epigenetically changed hematopoietic stem cells may be involved in immunological aging as specific DNA regions become hypermethylated. Proinflammatory T cells and monocytes persist after kidney transplantation, which constitutes a persistent cardiovascular risk factor. Possible therapeutic options to reverse or halt uremia-associated immunological aging are discussed. KEY MESSAGES: Premature aging of the immune system is a dominant feature in patients with end-stage renal failure, which corresponds to immunological aging in elderly healthy individuals, which is characterized by preferential loss of cells belonging to the lymphoid cell lineage, inflammation and expansion of proinflammatory immune cells. PMID- 24496188 TI - Stroke in dialysis and chronic kidney disease. AB - BACKGROUND: Renal impairment is a potent risk factor for stroke that is a leading cause of morbidity and mortality worldwide. Dialysis patients experience a 10 fold higher incidence, with case fatality rates reaching 90%. It is important to understand the factors predisposing to stroke in patients with chronic kidney disease (CKD) coupled with an appreciation of preventative strategies. SUMMARY: The heightened risk of stroke in CKD represents the interplay of the vascular comorbidities that cluster with renal impairment as well as pathology inherent in uremia, such as accelerated vascular calcification and the malnutrition inflammation-atherosclerosis syndrome. These factors are most marked in hemodialysis where stroke rates peak at 10-35/1,000 patient years and where hemorrhagic stroke accounts for 20-30% of all events. Older age, hypertension, diabetes and established cerebrovascular disease are all risk factors for stroke with dialysis initiation constituting the highest risk period. Patients with CKD stages 3-5D have worse survival as well as diminished functional outcomes following stroke. Thrombolytic therapy for acute stroke appears safe in all stages of CKD although the therapeutic effect may be attenuated. Control of hypertension and the use of antiplatelet agents form the mainstay of stroke prevention. The benefit of antiplatelet therapies and oral anticoagulants must be balanced against the real risks of bleeding that are most evident in dialysis cohorts. KEY MESSAGES: Understanding the risks and benefits of established stroke treatments is vital in patients with CKD, especially in those on dialysis therapies who are at highest risk of adverse outcomes. PMID- 24496189 TI - Lung congestion as a risk factor in end-stage renal disease. AB - BACKGROUND: Lung congestion is emerging as a pervasive, insidious problem in end stage renal disease (ESRD) patients on dialysis. SUMMARY: Chest ultrasound (US), a novel, easy-to-perform, cheap technique, which is currently applied for objective monitoring of pulmonary congestion in patients with heart failure in Europe, allows reliable quantification of lung water in clinical practice. Before hemodialysis (HD), about 60% of ESRD patients displayed moderate-severe lung congestion and this alteration is frequently asymptomatic. Lung congestion is reduced but not abolished by ultrafiltration dialysis, and about one third to one fourth of patients still have excessive lung water after dialysis. Lung congestion is also prevalent in patients on peritoneal dialysis (PD), and in apparently asymptomatic HD and PD patients this alteration is strongly associated with poor physical performance. Lung water in HD patients correlates in an inverse fashion with echocardiographic parameters of systolic and diastolic function, but it is only weakly related with hydration status measured by bioimpedance analysis. Moderate-severe lung congestion is a strong predictor of death and cardiovascular events and provides prognostic information independent of NYHA class, and traditional and nontraditional risk factors in ESRD patients on HD. KEY MESSAGES: Systematic application of chest US in ESRD patients shows that hidden or clinically manifest lung congestion is exceedingly frequent in this population. This alteration largely reflects left ventricular disorders superimposed on volume overload. The clinical usefulness of systematic application of chest US in ESRD remains to be tested in a formal clinical trial. PMID- 24496190 TI - Fluid management in the intensive care unit: bioelectrical impedance vector analysis as a tool to assess hydration status and optimal fluid balance in critically ill patients. AB - BACKGROUND: Fluid balance disorders are a relevant risk factor for morbidity and mortality in critically ill patients. Volume assessment in the intensive care unit (ICU) is thus of great importance, but there are currently few methods to obtain an accurate and timely assessment of hydration status. Our aim was to evaluate the hydration status of ICU patients via bioelectric impedance vector analysis (BIVA) and to investigate the relationship between hydration and mortality. METHODS: We evaluated 280 BIVA measurements of 64 patients performed daily in the 5 days following their ICU admission. The observation period ranged from a minimum of 72 h up to a maximum of 120 h. We observed the evolution of the hydration status during the ICU stay in this population, and analyzed the relationship between mean and maximum hydration reached and mortality--both in the ICU and at 60 days--using logistic regression. RESULTS: A state of overhydration was observed in the majority of patients (70%) on admission, which persisted during the ICU stay. Patients who required continuous renal replacement therapy (CRRT) were more likely to be overhydrated starting from the 2nd day of observation. Logistic regression showed a strong and significant correlation between mean/maximum hydration reached and mortality, both independently and correcting for severity of prognosis. CONCLUSIONS: Fluid overload measured by BIVA is a frequent condition in critically ill patients--whether or not they undergo CRRT--and a significant predictor of mortality. Hence, hydration status should be considered as an additional prognosticator in the clinical management of the critically ill patient. KEY MESSAGES: (i) On the day of ICU admittance, patients showed a marked tendency to overhydration (>70% of total). This tendency was more pronounced in patients on CRRT. (ii) Hyperhydration persisted during the ICU stay. Patients who underwent CRRT showed significantly higher hyperhydration from the 2nd day of hospitalization. (iii) Nonsurvivors showed worse hyperhydration patterns in comparison to survivors in logistic univariate analysis (p < 0.05). This relationship between hydration and mortality is confirmed even when controlling for the effect of a worse prognosis approximated by any of three ICU scoring systems (APACHE II, SAPS II and SOFA). Mean and maximum hydration levels present a stronger correlation with mortality than with mean and maximum cumulative fluid balance reached during the observation period. PMID- 24496191 TI - Cardiorenal syndrome type 4: management. AB - Cardiorenal syndrome (CRS) type 4, or chronic renocardiac syndrome, has been defined as 'chronic abnormalities in renal function leading to cardiac disease' and recognizes the extreme burden of cardiovascular (CV) disease (CVD) risk in patients with chronic kidney disease (CKD). CKD is common and increasingly recognized as a risk factor for CVD. Although during the past 10 years CV morbidity and mortality have decreased markedly in the general population, their rates still remain high among CKD patients. For this reason, CKD patients should be evaluated thoroughly for CV risk factors which require an aggressive management, given the significant implications of CRS type 4 at both individual and societal level. We will review the management of the most important conventional and nonconventional CVD risk factors related to CKD. PMID- 24496192 TI - Whole grains in the renal diet--is it time to reevaluate their role? AB - Organizations such as the National Kidney Foundation, the American Kidney Fund, the National Institute of Diabetes and Digestive and Kidney Diseases, and the US Department of Health and Human Services recommend not including whole grains as part of the renal diet. The rationale for this recommendation is the high phosphorus content in these foods. While the phosphorus content in whole grains may be indeed high, it is covalently bound to organic molecules (primarily phytate) and requires the enzyme phytase to be released and become available for absorption. While some phytase is contained in some whole grains (corn, oats, and millet have little to no phytase activity), the enzyme is decreased in milling, food preparation and over time. Since the human intestine does not express phytase, the enzyme required for the release of phosphorus from phytate is not present in the intestinal lumen when ingesting cooked food. Consequently, the bioavailability of phosphorus from whole grains is low. For the reasons presented here we believe that the 'grain ban' in the diet for kidney patients should be reconsidered. By doing this, the kidney diet would be enriched and it would provide needed fiber along with its health benefits, diversify the diet with low sodium choices, and possibly provide adequate protein without increasing phosphorous levels. PMID- 24496193 TI - A case off the bell curve: customization of the dialysis prescription--a self report. AB - BACKGROUND/AIMS: In a 35+-year dialysis patient, a series of spontaneous fractures and a history of severe somatic pains of unknown origin, superimposed on a history of generally adequate laboratory values, prompted an attempt at diagnosis of the cause of the condition. The patient was on a regimen of nocturnal home hemodialysis, a 4-night, 7-hour treatment. Physicians were divided on whether the cause might be neuropathic, muscular or osteopathic. METHODS: A bone biopsy was conducted to evaluate the integrity of the bones. RESULTS: The biopsy resulted in a diagnosis of osteomalacia - severe mineral depletion of the skeletal system. This was surprising because the hematologic laboratory values did not seem to indicate this. The calcium level in the dialysate was greatly increased, which was supplemented by moderate inclusion of sodium phosphate. CONCLUSION: The bones strengthened over time, resulting in no further fractures, an easing of general pain, and significantly improved mobility. The results demonstrate that customization of the dialysis prescription should be readily available for hemodialysis, whether treated in-center or at home. PMID- 24496194 TI - Cytotoxic effects of p-cresol in renal epithelial tubular cells. AB - BACKGROUND: The uremic syndrome is characterized by a deterioration of kidney function due to the accumulation of uremic toxins. Currently, 100 different uremic toxins have been identified. Uremic toxins are particularly difficult to remove by conventional dialysis treatments and are the major causes of mortality in patients with chronic kidney disease (CKD). p-Cresol is a well-known uremic toxin which accumulates in uremic serum. Our aim was to evaluate the in vitro effect of p-cresol on apoptosis and necrosis in renal tubular cells (RTCs) to better understand the pathophysiological effect of this toxin on the kidney. METHODS: We studied apoptosis and necrosis in RTCs, which were incubated for 24 h with increasing concentrations of p-cresol. A DNA ladder was noted in treated cells as a qualitative marker of the apoptotic process. Furthermore, we performed quantitative analysis of cell viability using a flow cytometer and assessed caspase-3 activity. RESULTS: Incubation with p-cresol for 24 h resulted in a significant reduction in RTC viability. DNA isolated from RTCs incubated with increasing p-cresol concentrations for 24 h showed a 'ladder' pattern of apoptosis at p-cresol concentrations of 10, 5 and 2.5 mg/l. However, we did not observe any significant changes in apoptosis levels detected by annexin V and caspase-3 compared with untreated cells. Cytofluorimetric analysis of necrosis highlighted significantly higher cell death rates in RTCs incubated with the higher p-cresol concentrations (range 40-10 mg/l) compared with other concentrations (5-2.5 mg/l) and untreated cells (p < 0.05). Necrosis induction was stronger at higher p-cresol concentrations. CONCLUSION: It is necessary to develop new therapeutic and dialytic strategies to manage p-cresol concentrations in CKD. PMID- 24496195 TI - Peritoneal dialysis as a mode of treatment for acute kidney injury in sub-Saharan Africa. AB - BACKGROUND: Developing sustainable treatment programs for kidney failure in most countries of sub-Saharan Africa continues to remain an imposing challenge. While long-term renal replacement therapies in end-stage renal disease appear beyond national financial capabilities, there exist opportunities for a short-term and affordable treatment of acute kidney injury (AKI). Peritoneal dialysis (PD) is an effective and simpler modality compared to hemodialysis (HD) and can be performed without the need for machinery or electricity, making it an ideal choice in a low resource setting. METHODS: Since cost of treatment is the major obstacle, the goal is to develop a program that is cost effective. Developing an HD program requires a large capital investment by the hospital, needing water treatment systems and machinery and providing for their ongoing repair and maintenance. Gravity-driven PD is a simple, effective modality and can be performed in low resource locales. RESULTS: In a pediatric program that we started in the Komfo Anokye Teaching Hospital in Kumasi, Ghana, 28 patients have been treated with PD for AKI so far. Half of them were treated successfully and were discharged having fully recovered kidney function. Seven patients (25%) were determined to have end stage renal disease, whereas 7 others (25%) died during hospitalization. In these cases, late presentation for dialysis may have contributed to the inability to recover. CONCLUSION: For individuals and governments alike, who are concerned about the cost of providing or paying for dialysis, using PD to treat AKI is an effective and simpler modality compared to HD and can be performed without the need for machinery or electricity, making it an ideal choice in a low-resource setting. PMID- 24496196 TI - Gender differences in the quality of life of patients with liver cirrhosis related to hepatitis C after liver transplantation. AB - BACKGROUND: Hepatitis C virus (HCV) infection frequently leads to chronic liver disease, which adversely affects the quality of life (QoL) of the patient. The gender of the patient may be an important variable in the way severity of the disease is perceived. The aim of our study is to evaluate the effect of the gender variable on QoL in HCV-positive patients. METHODS: This study included a total of 52 patients (26 men and 26 women) who completed a 1-year follow-up after liver transplantation. QoL was assessed using the SF-36 questionnaire. RESULTS: Male subjects have significantly higher scores on physical role functioning, bodily pain and physical activity compared with females. Females have a better QoL compared to males with regard to the emotional state and mental health. CONCLUSIONS: These results show a significant effect of the gender variable on QoL in HCV patients. PMID- 24496198 TI - Pre-emptive replacement of water treatment components improves responsiveness to erythropoiesis-stimulating agents in maintenance haemodialysis patients: a quality improvement report. AB - Hypo-responsiveness to erythropoiesis-stimulating agents (ESAs) has been associated with increased mortality. We examined the effect of water treatment component replacement on declining ESA responsiveness in the absence of chemical or microbiological standards failure. Pre-emptive renewal of the water treatment system supplying 802 standard-flux haemodialysis patients resulted in a significant rise in haemoglobin from (mean +/- SD) 12.1 +/- 1.2 to 12.3 +/- 1.0 g/dl (p < 0.0001), accompanied by a significant decrease in prescribed dose of darbepoetin alfa from 47.9 +/- 27.3 to 44.7 +/- 27.6 MUg/week (p < 0.0001). ESA responsiveness improved significantly from 0.060 +/- 0.041 to 0.055 +/- 0.040 MUg/kg/g . dl(-1) (p < 0.0001) and the number of patients no longer requiring ESA therapy increased threefold. These benefits were derived in the absence of haemolysis or significant changes in water quality. Renewal of water system components should be conducted even in the absence of proven microbiological and chemical failure. PMID- 24496199 TI - Successful treatment of extreme hyponatremia in an anuric patient using continuous venovenous hemodialysis. AB - Rapid correction of severe hyponatremia can result in osmotic demyelination syndrome. Patients with severe hyponatremia and renal failure requiring dialysis pose a therapeutic challenge since the use of conventional intermittent hemodialysis will result in a rapid correction of the serum sodium level. We report the case of a 52-year-old woman with extreme hyponatremia and severe acute kidney injury, who was successfully treated with continuous venovenous hemodialysis using a modified dialysate solution with a low sodium concentration that was adjusted on a daily basis. PMID- 24496200 TI - Methylation status of immune response genes promoters in cell-free DNA differs in hemodialyzed patients with diabetic nephropathy according to the intensity of anemia therapy. AB - BACKGROUND: Anemia is a major complication of end-stage renal disease. Hemodialysis itself is regarded as a stimulus activating inflammation. Pro inflammatory cytokines are able to suppress erythropoiesis. In this pilot study, we analyzed the changes in methylation status of promoters of immune response genes in cell-free DNA to detect the differences between diabetic subjects (n = 18) with different therapeutic doses of recombinant erythropoietin. METHODS: The extent of promoter methylation of 24 genes in plasma cell-free DNA was examined before and after hemodialysis using EpiTect Methyl qPCR Array Inflammatory Response and Autoimmunity (Qiagen). RESULTS: The patients with higher methylation status of gene sequences IL13RA1, IL15, EDG3 and INHA in interdialytic interval were significantly overrepresented in the group with none or mild anemia therapy. CONCLUSION: The results are in agreement with the fact that IL13 and IL15 are known inhibitors of erythropoiesis and with considered immunomodulatory role of cell-free DNA. PMID- 24496201 TI - Elimination of middle-sized uremic solutes with high-flux and high-cut-off membranes: a randomized in vivo study. AB - The elimination of substances between 10 and 50 kDa by conventional high-flux membranes is not satisfactory. We investigated in vivo the elimination of middle sized uremic solutes by conventional polyflux (PF) and modified high-cut-off (HCO) membranes. All 12 patients underwent four treatments, two with the HCO dialyzer and two with the PF dialyzer, each in either a haemodialysis (HD) or haemodiafiltration (HDF) mode. The reduction ratio of urea, creatinine, beta2 microglobulin (beta2M), leptin, soluble TNF-RI, complement factor D, IL-6, sIL-6 receptor, advanced glycation end-products (AGEs) and albumin was determined. In addition, the amount removed was determined in the dialysate for beta2M, complement factor D, AGEs and albumin. Treatment with HCO removed beta2M, sTNF RI, factor D, and high molecular AGE significantly better than conventional high flux membranes. The albumin loss was higher when using HCO membranes. HCO membranes are a promising approach to improve removal of uremic toxins not affected by conventional high-flux membranes. PMID- 24496204 TI - Insights into the world. Cancer fight gets a positive, effective boost. PMID- 24496202 TI - Effect of different hemodialyzers on serum levels of interleukin-6, interleukin 10 and interleukin-18. AB - BACKGROUND: The blood and membrane contact during dialysis may elicit an immune reaction. The current study looked at the impact of different dialyzers on blood levels of cytokines. METHODS: During the first month, randomly selected patients were treated with one dialyzer (PF-170H) and then crossed over to another dialyzer (FLX-18GW) during the next month. Pre- and postdialysis blood samples were assayed for interleukin (IL)-6, IL-10 and IL-18. RESULTS: A significant drop of postdialysis systolic blood pressure (pre vs. post 156.4 +/- 31.8 vs. 143.1 +/ 24.8 mm Hg, p = 0.014) and diastolic pressure (80.7 +/- 12.7 vs. 73.4 +/- 10.9 mm Hg, p = 0.002) were found when patients were dialyzed with PF-170H. A significant increase of postdialysis IL-18 levels was found in both groups (pre vs. post 605.5 +/- 278.6 vs. 690.6 +/- 315.3 pg/ml, p = 0.016, for PF-170H and 556.4 +/- 231.0 vs. 647.3 +/- 282.6 pg/ml, p = 0.067, for FLX-18GW). There was a positive correlation between IL-6 and IL-10 levels (p < 0.0001). CONCLUSION: We demonstrated a significant increase of postdialysis serum IL-18 level when either dialyzer was used. There is a strong correlation between serum levels of IL-6 and IL-10. PMID- 24496205 TI - A case of oropharyngeal squamous cell carcinoma with nasopharyngeal extension via the levator veli palatini muscle. PMID- 24496206 TI - Five-year relative survival rate of ovarian cancer in the USA, Europe and Japan. PMID- 24496209 TI - Using three-dimensional 3D grazing-incidence small-angle X-ray scattering (GISAXS) analysis to probe pore deformation in mesoporous silica films. AB - In the past decade, remarkable progress has been made in studying nanoscale objects deposited on surfaces by grazing-incidence small-angle X-ray scattering (GISAXS). However, unravelling the structural properties of mesostructured thin films containing highly organized internal three-dimensional (3D) structures remains a challenging issue, because of the lack of efficient algorithms that allow prediction of the GISAXS intensity patterns. Previous attempts to calculate intensities have mostly been limited to cases of two-dimensional (2D) assemblies of nanoparticles at surfaces, or have been adapted to specific 3D cases. Here, we demonstrate that highly organized 3D mesoscale structures (for example, porous networks) can be modeled by the combined use of established crystallography formalism and the Distorted Wave Born Approximation (DWBA). Taking advantage of the near-zero intensity of symmetry-allowed Bragg reflections, the casual extinction or existence of certain reflections related to the anisotropy of the form factor of the pores can be used as a highly sensitive method to extract structural information. We employ this generic method to probe the slightly compressed anisotropic shape and orientation of pores in a mesoporous silica thin film having P63/mmc symmetry. PMID- 24496208 TI - Bacterial meningitis in Malawian adults, adolescents, and children during the era of antiretroviral scale-up and Haemophilus influenzae type b vaccination, 2000 2012. AB - BACKGROUND: We documented bacterial meningitis trends among adults and children presenting to a large teaching hospital in Malawi during introduction of Haemophilus influenzae type b (Hib) vaccination and the rollout of antiretroviral therapy (ART). METHODS: We analyzed data from 51 000 consecutive cerebrospinal fluid (CSF) samples obtained from adults, adolescents, and children with suspected meningitis admitted to the Queen Elizabeth Central Hospital, Blantyre, Malawi, between 2000 and 2012. RESULTS: There was a significant decline in the total number of CSF isolates over 12 years (incident rate ratio [IRR], 0.93; 95% CI, .92-.94; P < .001). This decline was entirely in children aged <5 years (IRR, 0.87; 95% CI, .85-.88; P < .001) and coincided with the introduction of Hib vaccination. The number of adult isolates has remained unchanged (IRR, 0.99; 95% CI, .97-1.0; P = .135) despite rapid scale-up of ART provision. In children aged <5 years, Streptococcus pneumoniae, nontyphoidal salmonellae (NTS), and Hib were the most frequently isolated pathogens, and have declined over this time period. Streptococcus pneumoniae was the most frequently isolated pathogen in older children and adults. Estimated incidence of bacterial meningitis in 2012 was 20 per 100,000 cases in children aged <14 years, 6 per 100,000 adolescents, and 10 per 100,000 adults. CONCLUSIONS: Rates of bacterial meningitis have declined in children, but not adults, coinciding with the introduction of Hib vaccination. The highly successful rollout of ART has not yet resulted in a reduction in the incidence in adults where the burden remains high. Long-term surveillance of bacterial meningitis outside of the epidemic "meningitis belt" in Africa is essential. PMID- 24496210 TI - The use of leverage in community mental health: ethical guidance for practitioners. AB - BACKGROUND: Leverage is a particular type of treatment pressure that is used within community mental health services to increase patients' adherence to treatment. Because leverage involves practitioners making proposals that attempt to influence patients' behaviours and choices, the use of leverage raises ethical issues. AIM: To provide guidance that can assist practitioners in making judgements about whether it is ethically acceptable to use leverage in a particular clinical context. METHOD: Methods of ethical analysis. RESULTS: Four ethical duties relevant to making such judgements are outlined. These four duties are (1) benefitting the individual patient, (2) benefitting other individuals, (3) treating patients fairly and (4) respecting patients' autonomy. The practical requirements that follow from each of these duties are considered in detail. It is argued that practitioners should determine whether the use of leverage will mean that care is provided in ways that are consistent with the requirements of these four duties, regardless of whether the patient accepts or rejects the terms of the proposal made. CONCLUSION: Particular attention must be paid to determine how the requirements of the four duties should be applied in each specific treatment scenario, and in making careful judgements when these duties pull in opposing directions. PMID- 24496211 TI - Does depression screening improve depression outcomes in primary care? PMID- 24496216 TI - A general model to predict individual exposure to solar UV by using ambient irradiance data. AB - Excessive exposure to solar ultraviolet (UV) is the main cause of skin cancer. Specific prevention should be further developed to target overexposed or highly vulnerable populations. A better characterisation of anatomical UV exposure patterns is however needed for specific prevention. To develop a regression model for predicting the UV exposure ratio (ER, ratio between the anatomical dose and the corresponding ground level dose) for each body site without requiring individual measurements. A 3D numeric model (SimUVEx) was used to compute ER for various body sites and postures. A multiple fractional polynomial regression analysis was performed to identify predictors of ER. The regression model used simulation data and its performance was tested on an independent data set. Two input variables were sufficient to explain ER: the cosine of the maximal daily solar zenith angle and the fraction of the sky visible from the body site. The regression model was in good agreement with the simulated data ER (R(2)=0.988). Relative errors up to +20% and -10% were found in daily doses predictions, whereas an average relative error of only 2.4% (-0.03% to 5.4%) was found in yearly dose predictions. The regression model predicts accurately ER and UV doses on the basis of readily available data such as global UV erythemal irradiance measured at ground surface stations or inferred from satellite information. It renders the development of exposure data on a wide temporal and geographical scale possible and opens broad perspectives for epidemiological studies and skin cancer prevention. PMID- 24496217 TI - Proximity of US schools to major roadways: a nationwide assessment. AB - Long-term exposure to traffic pollution has been associated with adverse health outcomes in children and adolescents. A significant number of schools may be located near major roadways, potentially exposing millions of children to high levels of traffic pollution, but this hypothesis has not been evaluated nationally. We obtained data on the location and characteristics of 114,644 US public and private schools, grades prekindergarten through 12, and calculated their distance to the nearest major roadway. In 2005-2006, 3.2 million students (6.2%) attended 8,424 schools (7.3%) located within 100 m of a major roadway, and an additional 3.2 million (6.3%) students attended 8,555 (7.5%) schools located 100-250 m from a major roadway. Schools serving predominantly Black students were 18% (95% CI, 13-23%) more likely to be located within 250 m of a major roadway. Public schools eligible for Title I programs and those with a majority of students eligible for free/reduced price meals were also more likely to be near major roadways. In conclusion, 6.4 million US children attended schools within 250 m of a major roadway and were likely exposed to high levels of traffic pollution. Minority and underprivileged children were disproportionately affected, although some results varied regionally. PMID- 24496218 TI - Personal exposure to asbestos and respiratory health of heavy vehicle brake mechanics. AB - Asbestos brake linings and blocks are currently used in heavy vehicle brake repair shops (BRSs) in Bogota, Colombia. Some brake products are sold detached from their supports and without holes, requiring manipulation before installation. The aim of this study was to assess asbestos exposures and conduct a preliminary evaluation of respiratory health in workers of heavy vehicles in BRSs. To estimate asbestos exposures, personal and area samples were collected in two heavy vehicle BRSs. Each shop was sampled during six consecutive days for the entire work shift. Personal samples were collected on 10 workers including riveters, brake mechanics, and administrative staff. Among workers sampled, riveters had the highest phase contrast microscopy equivalent (PCME) asbestos concentrations, with 8-h time-weighted average (TWA) personal exposures ranging between 0.003 and 0.157 f/cm(3). Respiratory health evaluations were performed on the 10 workers sampled. Three workers (30%) had circumscribed pleural thickening (pleural plaques), with calcifications in two of them. This finding is strongly suggestive of asbestos exposure. The results of this study provide preliminary evidence that workers in heavy vehicle BRSs could be at excessive risk of developing asbestos-related diseases. PMID- 24496219 TI - Influence of exposure assessment and parameterization on exposure response. Aspects of epidemiologic cohort analysis using the Libby Amphibole asbestos worker cohort. AB - Recent meta-analyses of occupational epidemiology studies identified two important exposure data quality factors in predicting summary effect measures for asbestos-associated lung cancer mortality risk: sufficiency of job history data and percent coverage of work history by measured exposures. The objective was to evaluate different exposure parameterizations suggested in the asbestos literature using the Libby, MT asbestos worker cohort and to evaluate influences of exposure measurement error caused by historically estimated exposure data on lung cancer risks. Focusing on workers hired after 1959, when job histories were well-known and occupational exposures were predominantly based on measured exposures (85% coverage), we found that cumulative exposure alone, and with allowance of exponential decay, fit lung cancer mortality data similarly. Residence-time-weighted metrics did not fit well. Compared with previous analyses based on the whole cohort of Libby workers hired after 1935, when job histories were less well-known and exposures less frequently measured (47% coverage), our analyses based on higher quality exposure data yielded an effect size as much as 3.6 times higher. Future occupational cohort studies should continue to refine retrospective exposure assessment methods, consider multiple exposure metrics, and explore new methods of maintaining statistical power while minimizing exposure measurement error. PMID- 24496220 TI - The impact of source contribution uncertainty on the effects of source-specific PM2.5 on hospital admissions: a case study in Boston, MA. AB - Epidemiologic studies of particulate sources and adverse health do not account for the uncertainty in the source contribution estimates. Our goal was to assess the impact of uncertainty on the effect estimates of particulate sources on emergency cardiovascular (CVD) admissions. We examined the effects of PM2.5 sources, identified by positive matrix factorization (PMF) and absolute principle component analysis (APCA), on emergency CVD hospital admissions among Medicare enrollees in Boston, MA, during 2003-2010, given stronger associations for this period. We propagated uncertainty in source contributions using a block bootstrap procedure. We further estimated average across-methods source-specific effect estimates using bootstrap samples. We estimated contributions for regional, mobile, crustal, residual oil combustion, road dust, and sea salt sources. Accounting for uncertainty, same-day exposures to regional pollution were associated with an across-methods average effect of 2.00% (0.18, 3.78%) increase in the rate of CVD admissions. Weekly residual oil exposures resulted in an average 2.12% (0.19, 4.22%) increase. Same-day and 2-day exposures to mobile related PM2.5 were also associated with increased admissions. Confidence intervals when accounting for the uncertainty were wider than otherwise. Agreement in PMF and APCA results was stronger when uncertainty was considered in health models. Accounting for uncertainty in source contributions leads to more stable effect estimates across methods and potentially to fewer spurious significant associations. PMID- 24496221 TI - Resolving the role of femtosecond heated electrons in ultrafast spin dynamics. AB - Magnetization manipulation is essential for basic research and applications. A fundamental question is, how fast can the magnetization be reversed in nanoscale magnetic storage media. When subject to an ultrafast laser pulse, the speed of the magnetization dynamics depends on the nature of the energy transfer pathway. The order of the spin system can be effectively influenced through spin-flip processes mediated by hot electrons. It has been predicted that as electrons drive spins into the regime close to almost total demagnetization, characterized by a loss of ferromagnetic correlations near criticality, a second slower demagnetization process takes place after the initial fast drop of magnetization. By studying FePt, we unravel the fundamental role of the electronic structure. As the ferromagnet Fe becomes more noble in the FePt compound, the electronic structure is changed and the density of states around the Fermi level is reduced, thereby driving the spin correlations into the limit of critical fluctuations. We demonstrate the impact of the electrons and the ferromagnetic interactions, which allows a general insight into the mechanisms of spin dynamics when the ferromagnetic state is highly excited, and identifies possible recording speed limits in heat-assisted magnetization reversal. PMID- 24496222 TI - A microfluidic platform for chemoresistive testing of multicellular pleural cancer spheroids. AB - This study reports on a microfluidic platform on which single multicellular spheroids from malignant pleural mesothelioma (MPM), an aggressive tumor with poor prognosis, can be loaded, trapped and tested for chemotherapeutic drug response. A new method to detect the spheroid viability cultured on the microfluidic chip as a function of the drug concentration is presented. This approach is based on the evaluation of the caspase activity in the supernatant sampled from the chip and tested using a microplate reader. This simple and time saving method does only require a minimum amount of manipulations and was established for very low numbers of cells. This feature is particularly important in view of personalised medicine applications for which the number of cells obtained from the patients is low. MPM spheroids were continuously perfused for 48 hours with cisplatin, one of the standard chemotherapeutic drugs used to treat MPM. The 50% growth inhibitory concentration of cisplatin in perfused MPM spheroids was found to be twice as high as in spheroids cultured under static conditions. This chemoresistance increase might be due to the continuous support of nutrients and oxygen to the perfused spheroids. PMID- 24496223 TI - Deterministic and electrically tunable bright single-photon source. AB - The scalability of a quantum network based on semiconductor quantum dots lies in the possibility of having an electrical control of the quantum dot state as well as controlling its spontaneous emission. The technological challenge is then to define electrical contacts on photonic microstructures optimally coupled to a single quantum emitter. Here we present a novel photonic structure and a technology allowing the deterministic implementation of electrical control for a quantum dot in a microcavity. The device consists of a micropillar connected to a planar cavity through one-dimensional wires; confined optical modes are evidenced with quality factors as high as 33,000. We develop an advanced in-situ lithography technique and demonstrate the deterministic spatial and spectral coupling of a single quantum dot to the connected pillar cavity. Combining this cavity design and technology with a diode structure, we demonstrate a deterministic and electrically tunable single-photon source with an extraction efficiency of around 53 +/- 9%. PMID- 24496224 TI - The intriguing pathology of infectious diseases. PMID- 24496225 TI - Streptococcus iniae in gilthead seabream (Sparus aurata, L.) and red porgy (Pagrus pagrus, L.): ultrastructural analysis. AB - Streptococcosis caused by Streptococcus iniae has become one of the most serious marine and freshwater aquatic diseases in the past decade, causing large losses in farmed and wild fish worldwide. In this study, we performed an ultrastructural study of major lesions in gilthead seabream Sparus aurata and red porgy Pagrus pagrus experimentally infected with the S. iniae IUSA-1 strain, isolated in a natural outbreak in Spain in the mentioned species. The transmission electron micrographs revealed the resistance of this pathogen inside the phagosome, indicating that the macrophage may provide a significant bacterial reservoir for continuing infection, disease dissemination, and tissue injury by crossing the blood-brain barrier. PMID- 24496226 TI - Correlates of service utilization among homeless youth. AB - Though few studies exist on service utilization among homeless youth in the U.S., services are important because without them, many of these young people may resort to delinquent strategies in order to meet their daily survival needs. The current study examines frequency and correlates of service utilization (i.e., shelters, food programs, street outreach, counseling, STI and HIV testing) among a sample of 249 homeless youth ages 14 to 21. Multivariate analysis revealed significant differences in service usage by sex, age, and sexual orientation. Experiencing family physical and/or sexual abuse, being kicked out of the family home, spending more nights per week sleeping on the street, and having ever stayed in a group home facility were significant correlates of homeless youths' service usage. PMID- 24496227 TI - Involvement of fibrinolytic regulators in adhesion of monocytes to vascular endothelial cells induced by glycated LDL and to aorta from diabetic mice. AB - Diabetes mellitus accelerates the development of atherosclerotic cardiovascular diseases. Monocyte adhesion is an early cellular event of atherogenesis. Elevated levels of glyLDL were common in diabetic patients. Our previous studies indicated that HSF1 and p22-phox (a subunit of the NOX complex) were involved in glyLDL induced up-regulation of PAI-1 in vascular EC. The present study demonstrated that glyLDL significantly increased the adhesion of monocytes to the surface of cultured human umbilical vein or PAEC. Transfection of siRNA for PAI-1, p22-phox, or HSF1 in EC prevented glyLDL-induced monocyte adhesion to EC. uPA siRNA increased monocyte adhesion to EC. Exogenous uPA reduced monocyte adhesion induced by glyLDL or uPA siRNA. Exogenous PAI-1 restored monocyte adhesion to EC inhibited by PAI-1 siRNA or uPA. GlyLDL-induced monocyte adhesion to EC was inhibited by treatment of EC with RAP, an antagonist for LRP, and enhanced by uPAR antibody. The adhesion of monocytes to aorta from leptin db/db diabetic mice was significantly greater than to that from control mice, which was associated with elevated contents of PAI-1, uPA, p22-phox, and HSF1 in hearts of db/db mice. The results suggest that oxidative stress and fibrinolytic regulators (PAI-1, uPA, and uPAR) are implicated in the modulation of glyLDL-induced monocyte adhesion to vascular endothelium, which may play a crucial role in vascular inflammation under diabetes-associated metabolic disorder. PMID- 24496228 TI - Unilateral headache and loss of vision. Acute primary angle closure glaucoma (APACG). PMID- 24496229 TI - The challenge of providing palliative care to a rural population with cardiovascular disease. AB - PURPOSE OF REVIEW: There is a growing burden of end-stage cardiovascular disease in the aging Western world and a need to improve access to best evidence-based care, including patients located in rural areas. RECENT FINDINGS: Disparities are evident within rural settings for patients with cardiovascular disease. Useful guidelines exist to guide clinical services integration. Palliative care and cardiac services need to integrate their services defining the primary care lead with heart failure nurses coordinating. Earlier communication around disease implications, symptom burden and objectives of care feed into the integrated model for best and agreed outcomes to be achieved. Telehealth can assist a rural population when it is part of that integrated care model but more research on telemonitoring is required before conclusions can be drawn on the role of this expensive technology. Individual care plans can assist all involved. Subcutaneous furosemide may play a part in keeping a patient at home and with good palliative care the place of death can be the patient's home, if that is desired. SUMMARY: Rural patients with end-stage heart failure can be well supported at home as long as the model of care is united to support them. This includes heart failure nurse coordination based in the cardiac team, palliative care and general practice support. PMID- 24496230 TI - Enhancement of CRF-PEEK osseointegration by plasma-sprayed hydroxyapatite: A rabbit model. AB - Carbon-fibre-reinforced polyether ether ketone (CFR-PEEK) exhibits excellent biomechanical properties as it has an elastic modulus similar to bone. However, CFR-PEEK displays inferior biocompatibility compared with titanium alloy and coating techniques are therefore of interest in order to improve integration. In this paper, the early biological response to CFR-PEEK implants, with and without hydroxyapatite coating, was investigated. Furthermore, a hydroxyapatite-coated titanium alloy reference served as a clinically relevant control. The study was conducted in a rabbit model, both in femur trabecular bone as well as in tibia cortical bone. The results demonstrated that an hydroxyapatite coating significantly enhances the bone response to PEEK implants in vivo. Moreover, in cortical bone, hydroxyapatite-coated PEEK implants induced superior bone response compared with hydroxyapatite-coated Ti ones. These results suggest that hydroxyapatite-coated CFR-PEEK is a suitable material for in vivo implantation. PMID- 24496231 TI - Risk of death in heart disease is associated with elevated urinary globotriaosylceramide. AB - BACKGROUND: Elevated urinary globotriaosylceramide (Gb3) has been considered a hallmark of Fabry disease, an X-linked lysosomal disorder that is a risk factor for most types of heart disease. METHODS AND RESULTS: We screened 1421 consecutive patients with common forms of heart disease for Fabry disease by measuring urinary Gb3 in whole urine using tandem mass spectrometry, alpha galactosidase A activity in dried blood spots, and we looked for GLA mutations by parallel sequencing of the whole gene (exons and introns) in pooled genomic DNA samples followed by Sanger sequencing verification. GLA variants were found in 13 patients. In the 1408 patients without GLA mutations, urinary Gb3 levels were significantly higher in heart disease patients compared to 116 apparently healthy controls (median difference=10.0 ng/mL and P<0.001). Urinary lipid profiling showed that levels of 5 other lipids significantly distinguished between urine of patients with Fabry disease (n=7) and heart disease patients with elevated urinary Gb3 (n=6). Sphingomyelin and Gb3 levels were abnormal in the left ventricular wall of patients with ischemic heart failure. Elevated levels of urinary Gb3 were independently associated with increased risk of death in the average follow-up of 17 months (hazard ratio=1.59 for increase in Gb3 of 200, 95% CI=1.36 and 1.87, and P<0.0001). CONCLUSIONS: In heart disease patients who do not have Fabry disease or GLA gene mutations, a higher level of urinary Gb3 is positively associated with near-term mortality. The elevation of urinary Gb3 and that of other lipids suggests that heart disease is associated with multiorgan lipid abnormalities. CLINICAL TRIAL REGISTRATION URL: clinicaltrials.gov. Unique Identifier: NCT01019629. PMID- 24496232 TI - Age-dependent sex effects on outcomes after pediatric cardiac surgery. AB - BACKGROUND: Sex has been linked to differential outcomes for cardiovascular disease in adults. We examined potential sex differences in outcomes after pediatric cardiac surgery. METHODS AND RESULTS: We retrospectively analyzed data from the Pediatric Cardiac Care Consortium (1982-2007) by using logistic regression to evaluate the effects of sex on 30-day within-hospital mortality after pediatric (<18 years old) cardiac operations and its interaction with age, risk category, z-score for weight, and surgical year for the whole cohort. Of 76 312 operations, 55% were in boys. Unadjusted mortality was similar for boys and girls (5.2% versus 5.0%, P=0.313), but boys were more likely to have cardiac surgery as a neonate and to have more complex operations. After adjustment, the overall test of any association between postsurgical mortality and sex was significant (P=0.002), but the overall test of any interaction was not (P=0.503). However, a potential age-dependent sex effect on postsurgical mortality was observed among infants subjected to high-risk operations, with girls doing worse during the first 6 months of life. CONCLUSIONS: Patient sex has a significant effect on mortality after pediatric cardiac operations, with an increased risk of death in early infancy for girls after high-risk cardiac operations. This age dependent relationship supports a sex-related biological effect on postoperative cardiovascular stress. PMID- 24496233 TI - A systematic review and meta-analysis of Baihui (GV20)-based scalp acupuncture in experimental ischemic stroke. AB - Acupuncture for stroke has been used in China for over 2,000 years and nowadays is increasingly practiced elsewhere in the world. However, previous studies had conflicting findings on the results of acupuncture. Here, we conducted a systematic review and meta-analysis to assess the current evidence for the effect of Baihui (GV20)-based scalp acupuncture in animal models of focal cerebral ischemia. Six databases from the inception of each database up to June 2013 were electronically searched. Primary outcomes were infarct size and neurobehavioral outcome. Ultimately, 54 studies involving 1816 animals were identified describing procedures. Meta-analysis results showed that twelve studies reported significant effects of Baihui (GV20)-based scalp acupuncture for improving infarct volume compared with middle cerebral artery occlusion group (P < 0.01), and thirty-two studies reported significant effects of Baihui (GV20)-based scalp acupuncture for improving the neurological function score when compared with the control group (P < 0.01). In conclusion, Baihui (GV20)-based scalp acupuncture could improve infarct volume and neurological function score and exert potential neuroprotective role in experimental ischemic stroke. PMID- 24496234 TI - Associations between keloid severity and single-nucleotide polymorphisms: importance of rs8032158 as a biomarker of keloid severity. PMID- 24496236 TI - Altered MCM protein levels and autophagic flux in aged and systemic sclerosis dermal fibroblasts. AB - Aging is a common risk factor of many disorders. With age, the level of insoluble extracellular matrix increases leading to increased stiffness of a number of tissues. Matrix accumulation can also be observed in fibrotic disorders, such as systemic sclerosis (SSc). Although the intrinsic aging process in skin is phenotypically distinct from SSc, here we demonstrate similar behavior of aged and SSc skin fibroblasts in culture. We have used quantitative proteomics to characterize the phenotype of dermal fibroblasts from healthy subjects of various ages and from patients with SSc. Our results demonstrate that proteins involved in DNA and RNA processing decrease with age and in SSc, whereas those involved in mitochondrial and other metabolic processes behave the opposite. Specifically, minichromosome maintenance (MCM) helicase proteins are less abundant with age and SSc, and they exhibit an altered subcellular distribution. We observed that lower levels of MCM7 correlate with reduced cell proliferation, lower autophagic capacity, and higher intracellular protein abundance phenotypes of aged and SSc cells. In addition, we show that SSc fibroblasts exhibit higher levels of senescence compared with their healthy counterparts, suggesting further similarities between the fibrotic disorder and the aging process. Hence, at the molecular level, SSc fibroblasts exhibit intrinsic characteristics of fibroblasts from aged skin. PMID- 24496235 TI - Stat3 binds to mtDNA and regulates mitochondrial gene expression in keratinocytes. AB - The nuclear transcription factor signal transducer and activator of transcription 3 (Stat3) has recently been reported to have a localized mitochondrial regulatory function. Current data suggest that mitochondrial Stat3 (mitoStat3) is necessary for maximal mitochondrial activity and for Ras-mediated transformation independent of Stat3 nuclear activity. We have previously shown that Stat3 has a pivotal role in epithelial carcinogenesis. Therefore, the aim of the current study was to determine the role of mitoStat3 in epidermal keratinocytes. Herein, we show that normal and neoplastic keratinocytes contain a pool of mitoStat3. EGF and 12-O-tetradecanoylphorbol-13-acetate induce Stat3 mitochondrial translocation mediated through the phosphorylation of Stat3 at Ser727. In addition, we report that mitoStat3 binds mtDNA and associates with the mitochondrial transcription factor A. Furthermore, Stat3 ablation resulted in an increase of mitochondrial encoded gene transcripts. An increase in key nuclear-encoded metabolic genes, PGC 1alpha and NRF-1, was also observed in Stat3-null keratinocytes; however, no changes in nuclear-encoded electron transport chain gene transcripts or mtDNA copy number were observed. Collectively, our findings suggest a heretofore unreported function for mitoStat3 as a potential mitochondrial transcription factor in keratinocytes. This mitoStat3-mtDNA interaction may represent an alternate signaling pathway that could alter mitochondrial function and biogenesis and have a role in tumorigenesis. PMID- 24496237 TI - The protective effects of melittin on Propionibacterium acnes-induced inflammatory responses in vitro and in vivo. AB - Melittin is the main component in the venom of the honey bee (Apis mellifera). It has multiple effects including antibacterial, antiviral, and anti-inflammatory activities in various cell types. However, the anti-inflammatory mechanisms of melittin have not been elucidated in Propionibactierium acnes (P. acnes)-induced keratinocyte or inflammatory skin disease animal models. In this study, we examined the effects of melittin on the production of inflammatory cytokines in heat-killed P. acnes-induced HaCaT cells. Heat-killed P. acnes-treated keratinocytes increased the expression of pro-inflammatory cytokines and Toll like receptor 2. However, melittin treatment significantly suppressed the expression of these cytokines through regulation of the NF-kappaB and MAPK signaling pathways. Subsequently, the living P. acnes (1 * 10(7) CFU) were intradermally injected into the ear of mice. Living P. acnes-injected ears showed cutaneous erythema, swelling, and granulomatous response at 24 hours after injection. However, melittin-treated ears showed markedly reduced swelling and granulomatous responses compared with ears injected with only living P. acnes. These results demonstrate the feasibility of applying melittin for the prevention of inflammatory skin diseases induced by P. acnes. PMID- 24496238 TI - Suicidal ideation, mental health problems, and social function in adolescents with eczema: a population-based study. AB - There are few studies on psychosocial problems in adolescents with eczema. We performed a cross-sectional, questionnaire-based study to explore the relationship of suicidal ideation, mental health problems, and social functioning with eczema. A total of 4,744 adolescents (18-19 years) were invited for the study, of whom 3,775 (80%) participated. The overall prevalence of current eczema was 9.7%. Among those with current eczema, 15.5% reported suicidal ideation compared with 9.1% among those without eczema, significantly associated in a multivariate model (odds ratio 1.87, 95% confidence interval 1.31-2.68). In a subgroup analyses, the prevalence of suicidal ideation in those with both eczema and itch was 23.8%, and was significantly associated, compared with those without eczema (3.57, 2.46-5.67). Eczema was associated with mental health problems assessed by the Strength and Difficulties Questionnaire (1.72, 1.21-2.45) and the Hopkins Symptom Checklist 10 (1.63, 1.23-2.16). Five questions assessed social function: feeling attached to family and friends; thriving at school; experiencing bullying; and romantic relationships. Boys with current eczema were less likely to have had romantic relationships (1.93, 1.21-3.08). Eczema in late adolescence is associated with suicidal ideation and mental health problems but rarely with social problems. Our findings point to the importance of addressing mental health issues in adolescents with eczema. PMID- 24496240 TI - End-diastolic fractional flow reserve: comparison with conventional full-cardiac cycle fractional flow reserve. AB - BACKGROUND: Diastolic fractional flow reserve (dFFR) has been shown to be highly sensitive for detection of inducible myocardial ischemia. However, its reliance on measurement of left-ventricular pressure for zero-flow pressure correction, as well as manual extraction of the diastolic interval, has been its major limitation. Given previous reports of minimal zero-flow pressure at end-diastole, we compared instantaneous ECG-gated end-diastolic FFR with conventional full cardiac cycle FFR and other diastolic indices in the porcine model. METHODS AND RESULTS: Measurements of FFR in the left anterior descending and left circumflex arteries were performed in an open-chest swine model with an external occluder device on the coronary artery used to produce varying degrees of epicardial stenosis. An ultrasound flow-probe that was placed proximal to the occluder measured absolute blood flow in ml/min, and it was used as a gold standard for FFR measurement. A total of 17 measurements at maximal hyperemia were acquired in 5 animals. Correlation coefficient between conventional mean hyperemic FFR with pressure-wire and directly measured FFR with flow-probe was 0.876 (standard error estimate=0.069; P<0.0001). The hyperemic end-diastolic FFR with pressure-wire correlated better with FFR measured directly with flow-probe (r=0.941, standard error estimate=0.050; P<0.0001). CONCLUSIONS: Instantaneous hyperemic ECG-gated FFR acquired at end-diastole, as compared with conventional full-cardiac cycle FFR, has an improved correlation with FFR measured directly with ultrasound flow probe. PMID- 24496239 TI - Angiographic validation of the American College of Cardiology Foundation-the Society of Thoracic Surgeons Collaboration on the Comparative Effectiveness of Revascularization Strategies study. AB - BACKGROUND: The goal of this study was to compare angiographic interpretation of coronary arteriograms by sites in community practice versus those made by a centralized angiographic core laboratory. METHODS AND RESULTS: The study population consisted of 2013 American College of Cardiology-National Cardiovascular Data Registry (ACC-NCDR) records with 2- and 3- vessel coronary disease from 54 sites in 2004 to 2007. The primary analysis compared Registry (NCDR)-defined 2- and 3-vessel disease versus those from an angiographic core laboratory analysis. Vessel-level kappa coefficients suggested moderate agreement between NCDR and core laboratory analysis, ranging from kappa=0.39 (95% confidence intervals, 0.32-0.45) for the left anterior descending artery to kappa=0.59 (95% confidence intervals, 0.55-0.64) for the right coronary artery. Overall, 6.3% (n=127 out of 2013) of those patients identified with multivessel disease at NCDR sites had had 0- or 1-vessel disease by core laboratory reading. There was no directional bias with regard to overcall, that is, 12.3% of cases read as 3-vessel disease by the sites were read as <3-vessel disease by the core laboratory, and 13.9% of core laboratory 3-vessel cases were read as <3-vessel by the sites. For a subset of patients with left main coronary disease, registry overcall was not linked to increased rates of mortality or myocardial infarction. CONCLUSIONS: There was only modest agreement between angiographic readings in clinical practice and those from an independent core laboratory. Further study will be needed because the implications for patient management are uncertain. PMID- 24496241 TI - Nanomechanical identification of liquid reagents in a microfluidic channel. AB - Integration of promising technologies that can enhance sensitivity, selectivity, and throughput into micro total analysis systems (MUTAS) are important in making them useful in precise screening of reaction byproducts in analytical chemistry, cellular biology and pharmaceutical industries. But unfortunately so far a method to precisely determine molecular signatures of reagents is missing in MUTAS. We have developed a technique whereby molecular signatures of 50 pL of liquid reagents confined within a bimetallic microchannel cantilever can be obtained. This is achieved using wavelength dependent mechanical bending of the cantilever under infrared (IR) radiation. This technique also allows simultaneous physical characterization of the liquid reagent using variations in resonance frequency. It is useful in lab-on-a-chip devices and has a myriad of applications in drug screening, bioreactor monitoring, and petrochemical analysis. PMID- 24496242 TI - Agronomical parameters, sugar profile and antioxidant compounds of "Catherine" peach cultivar influenced by different plum rootstocks. AB - The influence of seven plum rootstocks (Adesoto, Monpol, Montizo, Puebla de Soto 67 AD, PM 105 AD, St. Julien GF 655/2 and Constanti 1) on individual and total sugars, as well as on antioxidant content in fruit flesh of "Catherine" peaches, was evaluated for three years. Agronomical and basic fruit quality parameters were also determined. At twelve years after budding, significant differences were found between rootstocks for the different agronomic and fruit quality traits evaluated. The Pollizo plum rootstocks Adesoto and PM 105 AD seem to induce higher sweetness to peach fruits, based on soluble solids content, individual (sucrose, fructose and sorbitol) and total sugars. A clear tendency was also observed with the rootstock Adesoto, inducing the highest content of phenolics, flavonoids, vitamin C and relative antioxidant capacity (RAC). Thus, the results of this study demonstrate the significant effect of rootstock on the sugar profile and phytochemical characteristics of peach fruits. In addition, this work shows the importance of the sugar profile, because specific sugars play an important role in peach flavour quality, as well as the studied phytochemical compounds when looking for high quality peaches with enhanced health properties. PMID- 24496243 TI - Integrated optical auto-correlator based on third-harmonic generation in a silicon photonic crystal waveguide. AB - The ability to use coherent light for material science and applications is linked to our ability to measure short optical pulses. While free-space optical methods are well established, achieving this on a chip would offer the greatest benefit in footprint, performance and cost, and allow the integration with complementary signal-processing devices. A key goal is to achieve operation at sub-watt peak power levels and on sub-picosecond timescales. Previous integrated demonstrations require either a temporally synchronized reference pulse, an off-chip spectrometer or long tunable delay lines. Here we report a device capable of achieving single-shot time-domain measurements of near-infrared picosecond pulses based on an ultra-compact integrated CMOS-compatible device, which could operate without any external instrumentation. It relies on optical third-harmonic generation in a slow-light silicon waveguide. Our method can also serve as an in situ diagnostic tool to map, at visible wavelengths, the propagation dynamics of near-infrared pulses in photonic crystals. PMID- 24496244 TI - The societal costs and benefits of commuter bicycling: simulating the effects of specific policies using system dynamics modeling. AB - BACKGROUND: Shifting to active modes of transport in the trip to work can achieve substantial co-benefits for health, social equity, and climate change mitigation. Previous integrated modeling of transport scenarios has assumed active transport mode share and has been unable to incorporate acknowledged system feedbacks. OBJECTIVES: We compared the effects of policies to increase bicycle commuting in a car-dominated city and explored the role of participatory modeling to support transport planning in the face of complexity. METHODS: We used system dynamics modeling (SDM) to compare realistic policies, incorporating feedback effects, nonlinear relationships, and time delays between variables. We developed a system dynamics model of commuter bicycling through interviews and workshops with policy, community, and academic stakeholders. We incorporated best available evidence to simulate five policy scenarios over the next 40 years in Auckland, New Zealand. Injury, physical activity, fuel costs, air pollution, and carbon emissions outcomes were simulated. RESULTS: Using the simulation model, we demonstrated the kinds of policies that would likely be needed to change a historical pattern of decline in cycling into a pattern of growth that would meet policy goals. Our model projections suggest that transforming urban roads over the next 40 years, using best practice physical separation on main roads and bicycle-friendly speed reduction on local streets, would yield benefits 10-25 times greater than costs. CONCLUSIONS: To our knowledge, this is the first integrated simulation model of future specific bicycling policies. Our projections provide practical evidence that may be used by health and transport policy makers to optimize the benefits of transport bicycling while minimizing negative consequences in a cost-effective manner. The modeling process enhanced understanding by a range of stakeholders of cycling as a complex system. Participatory SDM can be a helpful method for integrating health and environmental outcomes in transport and urban planning. PMID- 24496245 TI - Synthesis and spectroscopic-electrochemical properties of novel ratiometric Hg (II) chemosensor containing Bodipy and the N-phenylaza-15-crown-5 moiety. AB - The aryl-amine containing azacrown ether ring and alkyl-chloro boradiazaindacene (Bodipy) were synthesized by Schiff base condensation. The absorption and emission of a novel Schiff base derivative (based on azacrown-Bodipy ) were performed in presence of different cations such as Zn2+, Ga3+, Pb2+, Hg2+, NH4+ Ca2+, Cu2+, Na+, Ni2+, Cd2+ and Cr3+. The complexation property of the Schiff base was studied in dimethylformamide (DMF) by interacting azacrown-ether group and transition metal nitrates-ammonium chloride. The electrochemical behavior of the Schiff base has also been investigated by cyclic voltammetry. All experimental results indicated that the new compound act as a selective ratiometric chemosensor for Hg2+. PMID- 24496246 TI - Akt2- and ETS1-dependent IP3 receptor 2 expression in dendritic cell migration. AB - BACKGROUND/AIMS: The protein kinase Akt2/PKBbeta is a known regulator of macrophage and dendritic cell (DC) migration. The mechanisms linking Akt2 activity to migration remained, however, elusive. DC migration is governed by Ca(2+) signaling. We thus explored whether Akt2 regulates DC Ca(2+) signaling. METHODS: DCs were derived from bone marrow of Akt2-deficient mice (akt2(-/-)) and their wild type littermates (akt2(+/+)). DC maturation was induced by lipopolysaccharides (LPS) and evaluated by flow cytometry. Cytosolic Ca(2+) concentration was determined by Fura-2 fluorescence, channel activity by whole cell recording, transcript levels by RT-PCR, migration utilizing transwells. RESULTS: Upon maturation, chemokine CCL21 stimulated migration of akt2(+/+) but not akt2(-/-) DCs. CCL21-induced increase in cytosolic Ca(2+) concentration, thapsigargin-induced release of Ca(2+) from intracellular stores with subsequent store-operated Ca(2+) entry (SOCE), ATP-induced inositol 1,4,5-trisphosphate (IP3)-dependent Ca(2+) release as well as Ca(2+) release-activated Ca(2+) (CRAC) channel activity were all significantly lower in mature akt2(-/-) than in mature akt2(+/+) DCs. Transcript levels of IP3 receptor IP3R2 and of IP3R2 regulating transcription factor ETS1 were significantly higher in akt2(+/+) than in akt2(-/ ) DCs prior to maturation and were upregulated by LPS stimulation (1h) in akt2(+/+) and to a lower extent in akt2(-/-) DCs. Following maturation, protein abundance of IP3R2 and ETS1 were similarly higher in akt2(+/+) than in akt2(-/-) DCs. The IP3R inhibitor Xestospongin C significantly decreased CCL21-induced migration of akt2(+/+)DCs and abrogated the differences between genotypes. Finally, knock-down of ETS1 with siRNA decreased IP3R2 mRNA abundance, thapsigargin- and ATP-induced Ca(2+) release, SOCE and CRAC channel activation, as well as DC migration. CONCLUSION: Akt2 upregulates DC migration at least in part by ETS1-dependent stimulation of IP3R2 transcription. PMID- 24496247 TI - Self-assembly formation of mechanically interlocked [2]- and [3]catenanes using lanthanide ion [Eu(III)] templation and ring closing metathesis reactions. AB - The formation of interlocked lanthanide-based catenanes using Eu(iii)-directed synthesis is described (catenation being achieved via a ring-closing metathesis reaction); the self-assembly formation of the supramolecular structures was analysed by HRMS, NMR and luminescent spectroscopies. PMID- 24496248 TI - A Single-Chain Antibody Using LoxP511 as the Linker Enables Large-Content Phage Library Construction via Cre/LoxP Recombination. AB - To obtain natural or "me-better" antibodies (e.g., affinity-maturated antibodies), phage display libraries are widely used. However, the likelihood of obtaining satisfactory antibodies depends on the library content. Here, we used computer-aided design to model the use of the LoxP511 site as a linker between the heavy and light variable domains of an antibody for construction of a large single-chain fragment (scFv) antibody phage library by using the Cre/LoxP recombinant system. Then, we constructed two novel scFvs based on 2C4, namely, AH_scFv15 (15 amino acid [aa] linker; common [SG4]3 sequence) and AH_scFv21 (21 aa linker; LoxP511 sequence), to verify the use of the LoxP511 site as a linker. Our results indicate that LoxP511 could be used effectively for the construction of a large (e.g., 5 * 10(12)) phage display library of scFv antibodies from which it was possible to isolate an antibody with the same epitope as 2C4 but with higher affinity. PMID- 24496249 TI - Dimensions of critical care nursing. Editorial. PMID- 24496250 TI - Transcatheter aortic valve implantation options for treating severe aortic stenosis in the elderly: the nurse's role in postoperative monitoring and treatment. AB - Severe calcific aortic stenosis (AS) is a progressive cardiac disease that predominantly affects elderly adults. The hallmark symptoms of AS include exertional dyspnea, angina, and syncope. Adults of advanced age do not usually seek treatment for symptoms until their quality of life is greatly diminished. The 2 standard treatments for severe AS are open aortic valve replacement and percutaneous valvuloplasty. As adults age, their comorbid medical conditions often make them too high of a surgical risk for traditional aortic valve replacement, and percutaneous valvuloplasty, although less invasive, often produces only temporary relief of AS symptoms. To provide severe AS patients with alternative less risky treatment options in their later years, transcatheter aortic valve implantation (TAVI) devices were developed. Through this overview of the disease progression of AS and the different TAVI devices and the insertion procedures, a better understanding of the initial postoperative nursing care associated with postoperative TAVI patient management will be achieved. PMID- 24496251 TI - Bleeding risk factors affecting warfarin therapy in the elderly with atrial fibrillation. AB - PURPOSE: Inadequate anticoagulation among elderly individuals with atrial fibrillation (AF) is a common problem. This synthesis of the literature review describes the pathophysiology of AF, explains the mechanism of action of warfarin (Coumadin), identifies factors that contribute to warfarin (Coumadin)-associated bleeding in the elderly population, and explores alternatives to warfarin (Coumadin) therapy. Implications for advanced practice nurse practice, education, and research will be discussed. METHODS: A literature search was conducted using Academic Search Premier, CINAHL Plus with Full Text, and Medline from 1999 to 2012. Search terms included warfarin (Coumadin), warfarin (Coumadin) genetics, diet, interactions, bleeding, atrial fibrillation, genetics, anticoagulation clinic, dabigatran, apixaban, rivaroxaban, and elderly. RESULTS: The literature indicates that the potential bleeding risk associated with warfarin (Coumadin) therapy limits its use in the elderly population. However, some studies have found warfarin (Coumadin) to be more effective than aspirin in preventing stroke. The safety profiles of both medications were comparable; also, effective alternatives to warfarin (Coumadin) that do not require routine testing are now available. CONCLUSIONS: Atrial fibrillation increases the probability of an embolic stroke, especially for the elderly population. Stroke risk and bleeding risk tools, in conjunction with patient preference, determine the best stroke prevention treatment. Anticoagulant clinics manage long-term warfarin (Coumadin) therapy effectively. Newer anticoagulants offer effective alternatives to warfarin (Coumadin) therapy. PMID- 24496253 TI - A name change to create a sea change: nursing introductions using first and last names. PMID- 24496254 TI - Building nurse leaders through the Institute for Healthcare Improvement Open School Student Quality Leadership Academy. AB - The Institute for Healthcare Improvement is an independent not-for-profit organization based in Cambridge, Massachusetts. It is a leading innovator in health and health care improvement with a global following.One important part of the IHI is the development and evolution of the "Open School." Launched in September 2008, the online community currently includes hundreds of thousands of students worldwide. The goals of the Open School are consistent with the IHI initial concepts: to build will for change, seek out innovation, share expertise, and build leaders. Each year, the Open School awards scholarships to select students to attend a Leadership Academy.The Student Quality Leadership Academy allows students to network with other future nurses, physicians, and health care administrators and explores how they feel about leadership. This is important to nursing as we will need to replace many leadership positions in the future, but often new nurses are uncertain about leadership roles. PMID- 24496255 TI - Glucose management in critically ill medical and surgical patients. AB - Currently, many providers treat hyperglycemia in the critically ill based on guidelines suggesting target glucose ranges between 140 and 180 mg/dL. However, recent literature has attempted to challenge this by comparing the effect of intensive insulin therapy (IIT) to conventional insulin therapy. Four studies examining the impact of IIT and conventional insulin therapy on mortality in critically ill patients were examined and analyzed. The outcomes from these studies are mixed with neither therapy showing marked improvement in morbidity and mortality rates; in fact, these studies showed a trend toward increased mortality related to an increased incidence of hypoglycemia with IIT. Factors such as days of mechanical ventilation, infection rates, length of stay in the ICU, and incidence of organ failure were included as secondary end points. The data suggest IIT may improve patient outcomes in some areas, but the data are not statistically significant, and adoption of an IIT protocol is not recommended at this time. PMID- 24496258 TI - Validation of the critical-care pain observation tool in adult critically ill patients. AB - BACKGROUND: Effective management of pain begins with accurate assessment of its presence and severity, which is difficult in critically ill patients. The Critical-Care Pain Observation Tool (CPOT) was developed to evaluate behaviors associated with pain and validated primarily with cardiac surgical patients. OBJECTIVE: The purpose of this study was to examine reliability and validity of the CPOT in a general population of adult, critically ill patients. METHODS: Using a sample of 75 patients from critical care units of a community hospital, pain was evaluated at 3 times (prerepositioning, during repositioning, and postrepositioning) by 2 evaluators, using 3 different pain scales: CPOT; Faces, Legs, Activity, Cry, and Consolability (FLACC) scale; and Pain Intensity Numeric Rating Scale. RESULTS: Results indicated that reliability and validity of the CPOT were acceptable. Interrater reliability was supported by strong intraclass correlations (ranging from 0.74 to 0.91). For criterion-related validity, significant associations were found between CPOT scores and both FLACC (0.87 0.92) and Pain Intensity Numeric Rating Scale (0.50-0.69) scores. Discriminant validity was supported by significantly higher scores during repositioning (mean, 1.85) versus at rest (pre mean, 0.60; post mean, 0.65). DISCUSSION: The CPOT is an acceptable behavioral pain assessment scale for use in the general critical care patient population and is more appropriate for use with adults than the FLACC. PMID- 24496259 TI - Electrocardiographic practices: the current report of monitoring and education in Veterans Affairs facilities. AB - In 2004, practice standards for electrocardiographic (ECG) monitoring were published to address the need for an expanded use of ECG monitoring beyond heart rate and basic rhythm determination. This article reports the data collected from a survey distributed throughout the Veterans Healthcare Administration hospitals to determine the extent to which practice standards have been adopted. Survey data were used to identify the differences between actual practice and evidence based standards. The results were divided into ECG electrode application, lead selection, alarm limits, monitoring capabilities, monitoring during patient transport, and education and competencies. The results confirm the need for improvement, including a thorough evaluation of facility practices and education. The data demonstrate the differences among actual practice and evidence-based recommendations. PMID- 24496263 TI - Making an ethical plan for treating patients in pain. PMID- 24496264 TI - Preventing stroke in patients with atrial fibrillation. AB - Adults with atrial fibrillation are at an increased risk for stroke. New oral antithrombotic agents are now available to help prevent stroke and other thromboembolic events. This article provides an update on factors to consider when determining various treatment options for these high-risk patients in hopes of improving outcomes. PMID- 24496265 TI - In tribute to Newtown: join the discussion to prevent gun violence. PMID- 24496266 TI - Detecting single-abasic residues within a DNA strand immobilized in a biological nanopore using an integrated CMOS sensor. AB - In this paper, we demonstrate the application of a novel current-measuring sensor (CMS) customized for nanopore applications. The low-noise CMS is fabricated in a 0.35MUm CMOS process and is implemented in experiments involving DNA captured in an alpha-hemolysin (alpha-HL) nanopore. Specifically, the CMS is used to build a current amplitude map as a function of varying positions of a single-abasic residue within a homopolymer cytosine single-stranded DNA (ssDNA) that is captured and held in the pore. Each ssDNA is immobilized using a biotin streptavidin linkage. Five different DNA templates are measured and compared: one all-cytosine ssDNA, and four with a single-abasic residue substitution that resides in or near the ~1.5nm aperture of the alpha-HL channel when the strand is immobilized. The CMOS CMS is shown to resolves the ~5A displacements of the abasic residue within the varying templates. The demonstration represents an advance in application-specific circuitry that is optimized for small-footprint nanopore applications, including genomic sequencing. PMID- 24496267 TI - Real-time enzyme-digesting identification of double-strand DNA in a resonance cantilever embedded micro-chamber. AB - A novel direct identification of double-strand DNA is proposed by using real-time enzyme-digestion in a resonant-cantilever embedded microfluidic chip. The new gene-level detection method is expected to replace the conventional DNA hybridization based gene-detection that suffers from not only nonspecific adsorption induced false-positives but also complicated single-strand DNA preparation and hybridization. Since a detected DNA chain features a unique cutting site for a certain restriction-enzyme, the accurately cut-off mass (representing the length of the digested segment) can be online recorded by the frequency-shift signal of the resonant micro-cantilever sensor. This enzyme digestion technique is confirmed by experimental identification of the stx2 gene of E. coli O157:H7. The direct-PCR sample is directly analyzed by using our lab made cantilever-embedded microfluidic-chip. The 3776 bp DNA is immobilized via biotin-streptavidin binding and the added mass is recorded by a frequency decrease of 15.9 kHz within 10 min. Then, with EcoRV-enzyme digestion at the site of 2635 bp, the cut-off mass is real-time detected by a frequency-increase of 10.2 kHz within 6 min. The detected frequency-shift ratio of 15.9/10.2 = 64.2% is consistent with the length ratio between the cut-off fragment and the whole DNA chain (2635/3776 = 69.8%). Hence, the simple and accurate double-strand detection method is verified experimentally. PMID- 24496268 TI - Easy access to a cyclic key intermediate for the synthesis of trisporic acids and related compounds. AB - The synthesis of a cyclohexane skeleton possessing different oxygenated functional groups at C-3, C-8 and C-9, and a D1,6-double bond has been accomplished in 10 steps with an overall 17% yield. This compound is a key intermediate for access to a wide range of compounds of the bioactive trisporoid family. The synthetic sequence consists of the preparation of a properly functionalized epoxygeraniol derivative, and its subsequent stereoselective cyclization mediated by Ti(III). This last step implies a domino process that starts with a homolytic epoxide opening followed by a radical cyclization and regioselective elimination. This concerted process gives access to the cyclohexane moiety with stereochemical control of five of its six carbon atoms. PMID- 24496269 TI - Pauson-Khand reaction of internal dissymmetric trifluoromethyl alkynes. Influence of the alkene on the regioselectivity. AB - The scope of the Pauson-Khand reaction (PKR) of internal trifluoromethyl alkynes, previously described with norbornadiene, is expanded to norbornene and ethylene. A thorough structural analysis of the resulting PK adducts has been carried out to unveil that alpha-trifluoromethylcyclopentenones are preferred in all cases, independently of the electronic properties of the alkyne. The regioselectivity observed with norbornadiene and ethylene is higher than in the case of norbornene. PMID- 24496271 TI - Brain activity. PMID- 24496270 TI - Electrochemical monitoring of an important biomarker and target protein: VEGFR2 in cell lysates. AB - Vascular endothelial growth factor receptor 2 (VEGFR2) is a potential cell-type biomarker in clinical diagnoses. Besides, it's the target protein of many tyrosine kinase inhibitors and its expression significantly associates with clinical performance of these inhibitors. VEGFR2 detection provides an early warning for diseases and a basis for therapy and drug screening. Some methods have been developed for VEGFR2 determination. However, they are usually performed indirectly and complexly. Herein, an electrochemical biosensing platform for VEGFR2 analysis has been first proposed. It can detect the total concentrations of the VEGFR2 protein in cells lysates directly and can be used to monitor the changes of VEGFR2 expression levels induced by treatments of different inhibitors. Moreover, the inhibitor-VEGFR2 interactions are illuminated through theoretical simulation. The simulation results agree well with the experimental data, indicating the veracity of the proposed method. The electrochemical detection methodology for VEGFR2 would be promising in clinical diagnosis and drug screening. PMID- 24496272 TI - Spin-orbit torques in action. PMID- 24496273 TI - Binary challenge. PMID- 24496275 TI - Photovoltaics: an alternative 'Sun' for solar cells. PMID- 24496276 TI - Nanowire transistors: room for manoeuvre. PMID- 24496277 TI - Magnetic nanostructures: vortices on the move. PMID- 24496278 TI - Quantum transport: immune to local heating. PMID- 24496279 TI - Optomechanics: a strained couple. PMID- 24496281 TI - Suitability of common drugs for patients who avoid animal products. PMID- 24496282 TI - The current status of minimal residual disease assessment in myeloma. PMID- 24496283 TI - No chromosome arm unturned: in memory of Roland Berger 1934-2012. PMID- 24496286 TI - Mesoporous silica nanoparticles for enhancing the delivery efficiency of immunostimulatory DNA drugs. AB - We developed a potential immunostimulatory double-stranded DNA (dsDNA) delivery system by the binding of dsDNA to amino-modified mesoporous silica nanoparticles (MSNs) to form MSN-NH2/dsDNA complexes. Serum stability, in vitro cytotoxicity, cell uptake, and type I interferon-alpha (IFN-alpha) induction of MSN-NH2/dsDNA complexes were evaluated. The results showed that MSN-NH2 nanoparticles had no cytotoxicity to Raw 264.7 cells, and MSN-NH2/dsDNA complexes enhanced the serum stability of dsDNA due to the protection by nanoparticles and exhibited a high efficiency of cell uptake due to a small particle size and excellent dispersity. Most importantly, MSN-NH2/dsDNA complexes significantly enhanced the level of IFN alpha induction, triggered by cytosolic DNA sensor proteins. Therefore, binding of immunostimulatory DNA to MSNs would play a promising role for enhancing the delivery efficiency of immunostimulatory DNA drugs. PMID- 24496287 TI - Effect of oxygen tension on the amino acid utilisation of human embryonic stem cells. AB - BACKGROUND/AIMS: Human embryonic stem cells (hESCs) are a potential source of cells for treatment of many degenerative diseases, but in culture have a propensity to spontaneously differentiate, possibly due to suboptimal conditions. Culture at low oxygen tensions improves hESC maintenance and regulates carbohydrate metabolism. Hence, a greater understanding of the nutrient requirements of hESCs will allow production of more appropriate culture media. This study aims to investigate the effect of environmental oxygen tension on the amino acid metabolism of hESCs. METHODS: The production or depletion of amino acids by hESCs cultured at 5% or 20% oxygen in the presence or absence of FGF2 was measured by reversephase HPLC. RESULTS: Atmospheric oxygen, or removal of FGF2 from hESCs cultured at 5% oxygen, perturbed the uptake or release of individual amino acids and the total amino acid turnover compared to hESCs cultured at 5% oxygen. In particular, serine uptake was reduced at 20% oxygen and by removal of FGF2. CONCLUSIONS: Highly pluripotent hESCs, cultured at 5% oxygen, demonstrate a greater amino acid turnover than hESCs cultured at 20% oxygen, or without FGF2. These data suggest that amino acid turnover could be used as a measure of the self-renewal capacity of hESCs. PMID- 24496289 TI - Assessment of children with suspected auditory processing disorder: a factor analysis study. AB - OBJECTIVES: To identify the factors that may underlie the deficits in children with listening difficulties, despite normal pure-tone audiograms. These children may have auditory processing disorder (APD), but there is no universally agreed consensus as to what constitutes APD. The authors therefore refer to these children as children with suspected APD (susAPD) and aim to clarify the role of attention, cognition, memory, sensorimotor processing speed, speech, and nonspeech auditory processing in susAPD. It was expected that a factor analysis would show how nonauditory and supramodal factors relate to auditory behavioral measures in such children with susAPD. This would facilitate greater understanding of the nature of listening difficulties, thus further helping with characterizing APD and designing multimodal test batteries to diagnose APD. DESIGN: Factor analysis of outcomes from 110 children (68 male, 42 female; aged 6 to 11 years) with susAPD on a widely used clinical test battery (SCAN-C) and a research test battery (MRC Institute of Hearing Research Multi-center Auditory Processing "IMAP"), that have age-based normative data. The IMAP included backward masking, simultaneous masking, frequency discrimination, nonverbal intelligence, working memory, reading, alerting attention and motor reaction times to auditory and visual stimuli. SCAN-C included monaural low-redundancy speech (auditory closure and speech in noise) and dichotic listening tests (competing words and competing sentences) that assess divided auditory attention and hence executive attention. RESULTS: Three factors were extracted: "general auditory processing," "working memory and executive attention," and "processing speed and alerting attention." Frequency discrimination, backward masking, simultaneous masking, and monaural low-redundancy speech tests represented the "general auditory processing" factor. Dichotic listening and the IMAP cognitive tests (apart from nonverbal intelligence) were represented in the "working memory and executive attention" factor. Motor response times to cued and noncued auditory and visual stimuli were grouped in the "processing speed and alerting attention" factor. Individuals varied in their outcomes in different tests. Poor performance was noted in different combinations of tests from the three factors. Impairments solely related to the "general auditory processing" factor were not common. CONCLUSIONS: The study identifies a general auditory processing factor in addition to two other cognitive factors, "working memory and executive attention" and "processing speed and alerting attention," to underlie the deficits in children with susAPD. Impaired attention, memory, and processing speed are known to be associated with poor literacy and numeracy skills as well as a number of neurodevelopmental disorders. Individuals with impairments in the "general auditory processing" tests along with tests from the other two cognitive factors may explain the co-occurrence of APD and other disorders. The variation in performance by individuals in the different tests noted was probably due to a number of reasons including heterogeneity in susAPD and less-than ideal test retest reliabilities of the tests used to assess APD. Further research is indicated to explore additional factors, and consensus is needed to improve the reliability of tests or find alternative approaches to diagnose APD, based on the underlying factors. PMID- 24496288 TI - Effects of nonlinear frequency compression on speech identification in children with hearing loss. AB - OBJECTIVES: This study evaluated effects of nonlinear frequency compression (NLFC) processing in children with hearing loss for consonant identification in quiet and for spondee identification in competing noise or speech. It was predicted that participants would benefit from NLFC for consonant identification in quiet when access to high-frequency information was critical, but that NLFC would be less beneficial, or even detrimental, when identification relied on mid frequency cues. Further, it was hypothesized that NLFC could result in greater susceptibility to masking in the spondee task. The rationale for these predictions is that improved access to high-frequency information comes at the cost of decreased spectral resolution. DESIGN: A repeated-measures design compared speech-perception outcomes in 17 pediatric hearing aid users (9 to 17 years of age) wearing Naida V SP "laboratory" hearing aids with NLFC on and off. Data were also collected in an initial baseline session in which children wore their personal hearing aids. Children with a wide range of audiometric configurations were included, but all participants were full-time users of hearing aids with active NLFC. For each hearing aid condition, speech perception was assessed in the sound field by using a closed-set 12-alternative consonant vowel identification measure in quiet, and a closed-set four-alternative spondee identification measure in a speech-shaped noise or in a two-talker speech masker. RESULTS: No significant differences in performance were observed between laboratory hearing aid conditions with NLFC activated or deactivated for either speech-perception measure. An unexpected finding was that the majority of participants had no difficulty identifying the high-frequency consonant /s/ even when NLFC was deactivated. Investigation into individual differences revealed that subjects with a greater difference in audible bandwidth with NLFC on versus NLFC off were less likely to demonstrate improvements in high-frequency consonant identification in quiet, but were more likely to demonstrate improvements in spondee identification in speech-shaped noise. Group results observed in the initial baseline assessment using personal aids fitted with more aggressive NLFC settings than used in laboratory aids indicated better consonant identification accuracy in quiet. However, spondee identification in the two-talker masker was poorer with personal compared with laboratory hearing aids. Comparisons across personal and laboratory hearing aids are tempered, however, by the potential of an order effect. CONCLUSIONS: The observation of comparable performance with NLFC on and NLFC off in the laboratory aids provides evidence that NLFC is neither detrimental nor advantageous when modest in strength. Results with personal hearing aids fitted with stronger compression settings than laboratory aids (NLFC on) highlight the critical need for further research to determine the impact of NLFC processing on speech perception for a wider range of speech-perception measures and compression settings. PMID- 24496290 TI - The effect of differential listening experience on the development of expressive and receptive language in children with bilateral cochlear implants. AB - OBJECTIVES: Growing evidence suggests that children who are deaf and use cochlear implants (CIs) can communicate effectively using spoken language. Research has reported that age of implantation and length of experience with the CI play an important role in a predicting a child's linguistic development. In recent years, the increase in the number of children receiving bilateral CIs (BiCIs) has led to interest in new variables that may also influence the development of hearing, speech, and language abilities, such as length of bilateral listening experience and the length of time between the implantation of the two CIs. One goal of the present study was to determine how a cohort of children with BiCIs performed on standardized measures of language and nonverbal cognition. This study examined the relationship between performance on language and nonverbal intelligence quotient (IQ) tests and the ages at implantation of the first CI and second CI. This study also examined whether early bilateral activation is related to better language scores. DESIGN: Children with BiCIs (n = 39; ages 4 to 9 years) were tested on two standardized measures, the Test of Language Development and the Leiter International Performance Scale-Revised, to evaluate their expressive/receptive language skills and nonverbal IQ/memory. Hierarchical regression analyses were used to evaluate whether BiCI hearing experience predicts language performance. RESULTS: While large intersubject variability existed, on average, almost all the children with BiCIs scored within or above normal limits on measures of nonverbal cognition. Expressive and receptive language scores were highly variable, less likely to be above the normative mean, and did not correlate with Length of first CI Use, defined as length of auditory experience with one cochlear implant, or Length of second CI Use, defined as length of auditory experience with two cochlear implants. CONCLUSIONS: All children in the present study had BiCIs. Most IQ scores were either at or above that found in the general population of typically hearing children. However, there was greater variability in their performance on a standardized test of expressive and receptive language. This cohort of children, who are mainstreamed in schools at age-appropriate grades, whose mothers' education is high, and whose families' socioecononomic status is high, had, as a group, on average, language scores within the same range as the normative sample of hearing children. Further research identifying the predictors that contribute to the high variability in both expressive and receptive language scores in children with BiCIs will provide useful information that can aid in clinical management and decision making. PMID- 24496291 TI - Prevalence of cochlear dead regions in new referrals and existing adult hearing aid users. AB - OBJECTIVES: The primary aim of this study was to identify the prevalence of dead regions (DRs) in new adult hearing aid referrals and existing adult hearing aid users. Secondary aims included determining the effect of hearing threshold levels and slope, age, and sex on the presence of DRs. DESIGN: Three hundred and seventy six adults were recruited from a U.K. National Health Service audiology clinic. Three hundred and forty-three participants (674 ears) with a sensorineural hearing impairment were assessed for the presence of a DR at audiometric frequencies from 0.5 to 4 kHz using the Threshold Equalizing Noise test. RESULTS: The overall prevalence of DRs was 36% (95% confidence interval 31-41). The prevalence in new referrals, and in new and existing hearing aid users was 31% (25-37), 33% (26-40), and 43% (35-51), respectively. The overall prevalence of extensive DRs, defined as spanning >=3 consecutive frequencies, was 3% (1-5). CONCLUSIONS: On the basis of the findings from the Threshold Equalizing Noise test, prevalence of DRs was relatively high in adult hearing aid users with a sensorineural hearing impairment. However, in most cases, the DR was limited to a small frequency region. This suggests that, in most cases, the presence of a DR may not be clinically significant. The difference in DR prevalence between new referrals and existing hearing aid users was not statistically significant. Hearing threshold levels, slope of hearing impairment, age, and sex could not be used to reliably identify DRs. PMID- 24496292 TI - The association between visual, nonverbal cognitive abilities and speech, phonological processing, vocabulary and reading outcomes in children with cochlear implants. AB - OBJECTIVES: The aim of this study was to explore the possibility that specific nonverbal, visual cognitive abilities may be associated with outcomes after pediatric cochlear implantation. The study therefore examined the relationship between visual sequential memory span and visual sequential reasoning ability, and a range of speech, phonological processing, vocabulary knowledge, and reading outcomes in children with cochlear implants. DESIGN: A cross-sectional, correlational design was used. Sixty-six children aged 5 to 12 years completed tests of visual memory span and visual sequential reasoning, along with tests of speech intelligibility, phonological processing, vocabulary knowledge, and word reading ability (the outcome variables). Auditory memory span was also assessed, and its relationship with the other variables examined. RESULTS: Significant, positive correlations were found between the visual memory and reasoning tests, and each of the outcome variables. A series of regression analyses then revealed that for all the outcome variables, after variance attributable to the age at implantation was accounted for, visual memory span and visual sequential reasoning ability together accounted for significantly more variance (up to 25%) in each outcome measure. CONCLUSIONS: These findings have both clinical and theoretical implications. Clinically, the findings may help improve the identification of children at risk of poor progress after implantation earlier than has been possible to date as the nonverbal tests can be administered to children as young as 2 years of age. The results may also contribute to the identification of children with specific learning or language difficulties as well as improve our ability to develop intervention strategies for individual children based on their specific cognitive processing strengths or difficulties. Theoretically, these results contribute to the growing body of knowledge about learning and development in deaf children with cochlear implants. PMID- 24496293 TI - Time-gated pre-resonant femtosecond stimulated Raman spectroscopy of diethylthiatricarbocyanine iodide. AB - We present time-gated femtosecond stimulated Raman spectroscopy (fSRS) under the pre-resonance Raman conditions of diethylthiatricarbocyanine (DTTC) iodide. A 'pseudo emission-free' condition is achieved by delivering the probe beam ahead of the pump beam. Regeneratively amplified pulse trains are employed to create an angle-geometry (non-collimated) mixing between the pump and probe beams, leading to highly sensitive measurement of the stimulated Raman gain. Time-integrated spectroscopy allows for a more quantitative distinction between the contributions of stimulated Raman scattering and stimulated emission. We successfully obtain a highly sensitive (signal-to-noise ratio >100) stimulated Raman spectrum under the optimized conditions, which compares favourably to results obtained using two dimensional correlation spectroscopy (2DCOS). Given the optical pre-resonance of ~0.1 eV, the background signals mostly originate from the stimulated emission of excited electrons and are significantly reduced by partial overlapping of the pump and probe beams; a genuine fSRS spectral profile is obtained for a temporal delay of ~0.2 ps between the two beams. PMID- 24496294 TI - 8DSS-promoted remineralization of initial enamel caries in vitro. AB - Peptides containing 8 repeats of aspartate-serine-serine (8DSS) have been shown to promote the nucleation of calcium phosphate from solution into human enamel. Here we tested the ability of 8DSS to promote the remineralization of demineralized enamel in an in vitro model of artificial early enamel caries. Initial caries lesions were created in bovine enamel blocks, which were then subjected to 12 d of pH cycling in the presence of 25 uM 8DSS, 1 g/L NaF (positive control) or buffer alone (negative control). Absorption of 8DSS was verified by X-ray photoelectron spectroscopy. Mineral loss, lesion depth, and mineral content at the surface layer and at different depths of the lesion body were analyzed before and after pH cycling by polarized light microscopy and transverse microradiography. Mineral loss after pH cycling was significantly lower in the 8DSS samples than in the buffer-only samples, and lesions in the 8DSS samples were significantly less deep. Samples treated with 8DSS showed significantly higher mineral content than buffer-only samples in the region extending from the surface layer (30 um) to the average lesion depth (110 um). No significant differences were found between the samples treated with 8DSS and those treated with NaF. These findings suggest that 8DSS has the potential to promote remineralization of demineralized enamel. PMID- 24496295 TI - A microfluidic photobioreactor array demonstrating high-throughput screening for microalgal oil production. AB - Microalgae are envisioned as a future source of renewable oil. The feasibility of producing high-value biomolecules from microalgae is strongly dependent on developing strains with increased productivity and environmental tolerance, understanding algal gene regulation, and optimizing growth conditions for higher production of target molecules. We present a high-throughput microfluidic microalgal photobioreactor array capable of applying 64 different light conditions to arrays of microscale algal photobioreactors and apply this device to investigate how light conditions influence algal growth and oil production. Using the green colony-forming microalga Botryococcus braunii, the light intensity and light-dark cycle conditions were identified that induced 1.8-fold higher oil accumulation over the typically used culture conditions. Additionally, the studies revealed that the condition under which maximum oil production occurs is significantly different from that of maximum growth. This screening test was accomplished using the developed photobioreactor array at 250 times higher throughput compared to conventional flask-scale photobioreactors. PMID- 24496296 TI - An interdisciplinary approach to personalized medicine: case studies from a cardiogenetics clinic. AB - In the genomic age, the challenges presented by various inherited conditions present a compelling argument for an interdisciplinary model of care. Cardiac arrhythmias with a genetic basis, such as long QT syndrome, require clinicians with expertise in many specialties to address the complex genetic, psychological, ethical and medical issues involved in treatment. The Montefiore-Einstein Center for CardioGenetics has been established to provide personalized, interdisciplinary care for families with a history of sudden cardiac death or an acute cardiac event. Four vignettes of patient care are presented to illustrate the unique capacity of an interdisciplinary model to address genetic, psychological, ethical and medical issues. Because interdisciplinary clinics facilitate collaboration among multiple specialties, they allow for individualized, comprehensive care to be delivered to families who experience complex inherited medical conditions. As the genetic basis of many complex conditions is discovered, the advantages of an interdisciplinary approach for delivering personalized medicine will become more evident. PMID- 24496297 TI - Shared decision making: state of the science. PMID- 24496298 TI - Shared decision making: science and action. PMID- 24496299 TI - A high-fat diet differentially affects the gut metabolism and blood lipids of rats depending on the type of dietary fat and carbohydrate. AB - The aim of this model study was to investigate how selected gut functions and serum lipid profile in rats on high-fat diets differed according to the type of fat (saturated vs. unsaturated) and carbohydrate (simple vs. complex). The experiment was conducted using 32 male Wistar rats distributed into 4 groups of 8 animals each. For 4 weeks, the animals were fed group-specific diets that were either rich in lard or soybean oil (16% of the diet) as the source of saturated or unsaturated fatty acids, respectively; further, each lard- and soybean oil rich diet contained either fructose or corn starch (45.3% of the diet) as the source of simple or complex carbohydrates, respectively. Both dietary factors contributed to changes in the caecal short-chain fatty acid concentrations, especially to the butyrate concentration, which was higher in rats fed lard- and corn starch-rich diets compared to soybean oil- and fructose-rich diets, respectively. The lowest butyrate concentration was observed in rats fed the soybean oil- and fructose-rich diet. On the other hand, the lard- and fructose rich diet vs. the other dietary combinations significantly increased serum total cholesterol concentration, to more than two times serum triglyceride concentration and to more than five times the atherogenic index. In conclusion, a high-fat diet rich in fructose can unfavorably affect gut metabolism when unsaturated fats are predominant in the diet or the blood lipids when a diet is rich in saturated fats. PMID- 24496301 TI - Myeloid progenitors with PTPN11 and nonRAS pathway gene mutations are refractory to treatment with 6-mercaptopurine in juvenile myelomonocytic leukemia. PMID- 24496300 TI - Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. AB - In this report, a panel of European myeloma experts discuss the role of pomalidomide in the treatment of relapsed and refractory multiple myeloma (RRMM). Based on the available evidence, the combination of pomalidomide and low-dose dexamethasone is a well-tolerated and effective treatment option for patients with RRMM who have exhausted treatment with lenalidomide and bortezomib. The optimal starting dose of pomalidomide is 4 mg given on days 1-21 of each 28-day cycle, whereas dexamethasone is administered at a dose of 40 mg weekly (reduced to 20 mg for patients aged >75 years). The treatment should continue until evidence of disease progression or unacceptable toxicity. Dose-modification schemes have been established for patients who develop neutropenia, thrombocytopaenia and other grade 3-4 adverse events during pomalidomide therapy. Guidance on the prevention and management of infections and venous thromboembolism is provided, based on the available clinical evidence and the experience of panel members. The use of pomalidomide in special populations, such as patients with advanced age, renal impairment or unfavourable cytogenetic features, is also discussed. PMID- 24496302 TI - Serial exome analysis of disease progression in premalignant gammopathies. PMID- 24496304 TI - Mesenteric ischemia secondary to toxic epidermal necrolysis: case report and review of the literature. AB - A 28-year-old otherwise healthy man was admitted to the burn center for treatment of toxic epidermal necrolysis (TEN) involving 90% of the TBSA and oropharynx. On hospital day 8, his cutaneous lesions were healing well, but he developed respiratory distress, fever, and abdominal distension. Computerized tomography demonstrated distended bowel, pneumatosis intestinalis, and portal venous gas. He underwent emergent celiotomy. Patchy areas of nonperforated necrosis along the jejunum and ileum were present. No mechanical or embolic source of ischemia could be identified. A 120-cm segment of ischemic small bowel was resected and the abdomen was closed temporarily. On planned "second look" the following day, no further disease was encountered and intestinal continuity was restored. Tube feeds were then initiated and the patient's recovery was uneventful thereafter. Although traditionally considered a skin disorder, TEN may be more accurately described as a disorder affecting the junction of an epithelium and its supporting tissue. It is most prominently manifested at the epidermal-dermal junction, but epithelial-submucosal junctions are also affected. The ocular, respiratory, genitourinary, and gastrointestinal manifestations of TEN are variable and incompletely understood. This disease is rooted in immunological dysfunction and the small bowel is rich in immunologically active tissue; Peyer patches and lymph nodes abound. Clinicians should be vigilant for gastrointestinal tract involvement, which is potentially treatable with resection of the ischemic bowel. The authors suspect that, given the critical condition of many TEN patients, bowel symptoms may be incorrectly attributed to global hypoperfusion and sepsis. PMID- 24496303 TI - CALR and ASXL1 mutations-based molecular prognostication in primary myelofibrosis: an international study of 570 patients. AB - Current prognostication in primary myelofibrosis (PMF) is based on the dynamic international prognostic scoring system (DIPSS)-plus, which employs clinical and cytogenetic variables. We recently reported DIPSS-plus independent prognostic significance for calreticulin (CALR) (favorable) and ASXL1 (unfavorable) mutations. In the current study, 570 PMF patients were recruited for derivation (n=277) and validation (n=293) of a molecular prognostic model based on these two mutations. Survival was the longest in CALR(+)ASXL1(-) (median 10.4 years) and shortest in CALR(-)ASXL1(+) patients (median, 2.3 years; hazard ratio (HR), 5.9; 95% confidence interval (CI), 3.5-10.0). CALR(+)ASXL1(+) and CALR(-)ASXL1(-) patients had similar survival and were grouped together in an intermediate-risk category (median survival, 5.8 years; HR, 2.5; 95% CI, 1.5-4.0). The CALR/ASXL1 mutations-based prognostic model was DIPSS-plus independent (P<0.0001) and effective in identifying low-/intermediate-1-risk patients with shorter (median, 4 years) or longer (median 20 years) survival and high-/intermediate-2-risk patients with shorter (median, 2.3 years) survival. Multivariable analysis distinguished CALR(-)ASXL1(+) mutational status as the most significant risk factor for survival: HR 3.7 vs 2.8 for age >65 years vs 2.7 for unfavorable karyotype. These observations signify immediate clinical relevance and warrant i) CALR and ASXL1 mutation determination in all patients with PMF and ii) molecular revision of DIPSS-plus. PMID- 24496305 TI - Is location of burns related to outcome? A comparison between burns on extremities and burns on head and/or trunk in patients with low to intermediate TBSA in a burn center in The Netherlands. AB - In the literature no study was found about the effect of location of burns on outcome. The objective of this retrospective study was to investigate the effect of location on outcome parameters of 371 patients, admitted to our burn center from January 2009 to December 2011. The patients were included in the study if more than 80% of the burn(s) was localized either on the extremities or on the head and/or trunk. Two groups of TBSA were elaborated, low: 0 to 5% and intermediate: 5 to 15%. Two-hundred ninety-two patients (78.7%) had a low TBSA (<5%) and 79 (21.3%) an intermediate TBSA (5-15%). None of the included patients died. The patients with an intermediate TBSA were on average 8.0 days longer admitted compared with the patients with a low TBSA adjusted for age and depth (95% confidence interval: 6.5-9.4). The patients with burns on the head and/or trunk were more often admitted to the intensive care unit, mostly as a result of suspected inhalation injury (6.2 vs 0.9%; P = .008). More complications were seen in the intermediate TBSA group. In this study no difference in outcome was found between burns on the head and/or trunk or on extremities. The patients with burns on the head and/or trunk group are more frequently admitted to intensive care. PMID- 24496306 TI - Mobile phones and driving. PMID- 24496307 TI - All-graphene planar self-switching MISFEDs, Metal-Insulator-Semiconductor Field Effect Diodes. AB - Graphene normally behaves as a semimetal because it lacks a bandgap, but when it is patterned into nanoribbons a bandgap can be introduced. By varying the width of these nanoribbons this band gap can be tuned from semiconducting to metallic. This property allows metallic and semiconducting regions within a single Graphene monolayer, which can be used in realising two-dimensional (2D) planar Metal Insulator-Semiconductor field effect devices. Based on this concept, we present a new class of nano-scale planar devices named Graphene Self-Switching MISFEDs (Metal-Insulator-Semiconductor Field-Effect Diodes), in which Graphene is used as the metal and the semiconductor concurrently. The presented devices exhibit excellent current-voltage characteristics while occupying an ultra-small area with sub-10 nm dimensions and an ultimate thinness of a single atom. Quantum mechanical simulation results, based on the Extended Huckel method and Nonequilibrium Green's Function Formalism, show that a Graphene Self-Switching MISFED with a channel as short as 5 nm can achieve forward-to-reverse current rectification ratios exceeding 5000. PMID- 24496308 TI - Water-Soluble Derivatives of Octanuclear Iron-Oxo-Pyrazolato Complexes; An Experimental and Computational Study. AB - Two water-soluble iron-pyrazolato complexes, [Fe8], have been prepared by the introduction of twelve hydroxyalkyl groups to the periphery of the approximately spherical octanuclear molecule and they are contrasted with their two organosoluble chloroalkyl analogues. All four new complexes, 1 - 4, have been characterized in solution by 1H-NMR and electrospray ionization mass spectroscopy. The one-electron reduction product of the water-soluble 3, [Fe8]-, has been structurally characterized by single crystal diffraction methods. In aqueous media, the four terminal Fe-Cl bonds of [Fe8] are partially hydrolysed and the resulting chloro/aqua/hydroxo species form supramolecular nanoscale aggregates, as determined by dynamic light scattering and electron microscopy. Preliminary computational studies by density functional theory methods have been employed in order to model the H-bonding interactions controlling the competing solvation and aggregation processes. PMID- 24496309 TI - Impact of embryo number and maternal undernutrition around the time of conception on insulin signaling and gluconeogenic factors and microRNAs in the liver of fetal sheep. AB - This study aimed to determine whether exposure of the oocyte and/or embryo to maternal undernutrition results in the later programming of insulin action in the liver and factors regulating gluconeogenesis. To do this, we collect livers from singleton and twin fetal sheep that were exposed to periconceptional (PCUN; -60 to 7 days) or preimplantation (PIUN; 0-7 days) undernutrition at 136-138 days of gestation (term = 150 days). The mRNA and protein abundance of insulin signaling and gluconeogenic factors were then quantified using qRT-PCR and Western blotting, respectively, and global microRNA expression was quantified using deep sequencing methodology. We found that hepatic PEPCK-C mRNA (P < 0.01) and protein abundance and the protein abundance of IRS-1 (P < 0.01), p110beta (P < 0.05), PTEN (P < 0.05), CREB (P < 0.01), and pCREB (Ser(133); P < 0.05) were decreased in the PCUN and PIUN singletons. In contrast, hepatic protein abundance of IRS-1 (P < 0.01), p85 (P < 0.01), p110beta (P < 0.001), PTEN (P < 0.01), Akt2 (P < 0.01), p-Akt (Ser(473); P < 0.01), and p-FOXO-1 (Thr24) (P < 0.01) was increased in twins. There was a decrease in PEPCK-C mRNA (P < 0.01) but, paradoxically, an increase in PEPCK-C protein (P < 0.001) in twins. Both PCUN and PIUN altered the hepatic expression of 23 specific microRNAs. We propose that the differential impact of maternal undernutrition in the presence of one or two embryos on mRNAs and proteins involved in the insulin signaling and gluconeogenesis is explained by changes in the expression of a suite of specific candidate microRNAs. PMID- 24496311 TI - Eukaryotic translation initiation factor 5A inhibition alters physiopathology and immune responses in a "humanized" transgenic mouse model of type 1 diabetes. AB - Therapeutic options for treatment of type 1 diabetes (T1D) are still missing. New avenues for immune modulation need to be developed. Here we attempted at altering the diabetes outcome of our humanized model of T1D by inhibiting translation initiation factor eIF5A hypusination in vivo. Double-transgenic (DQ8-GAD65) mice were immunized with adenoviral vectors carrying GAD65 for diabetes induction. Animals were subsequently treated with deoxyhypusine synthase (DHS) inhibitor GC7 and monitored for diabetes development over time. On one hand, helper CD4(+) T cells were clearly affected by the downregulation of the eIF5A not just at the pancreas level but overall. On the other hand, the T regulatory cell component of CD4 responded with activation and proliferation significantly higher than in the non-GC7-treated controls. Female mice seemed to be more susceptible to these effects. All together, our results show for the first time that downregulation of eIF5A through inhibition of DHS altered the physiopathology and observed immune outcome of diabetes in an animal model that closely resembles human T1D. Although the development of diabetes could not be abrogated by DHS inhibition, the immunomodulatory capacity of this approach may supplement other interventions directed at increasing regulation of autoreactive T cells in T1D. PMID- 24496310 TI - Hepatic sirtuin 1 is dispensable for fibrate-induced peroxisome proliferator activated receptor-alpha function in vivo. AB - Peroxisome proliferator-activated receptor-alpha (PPARalpha) mediates metabolic remodeling, resulting in enhanced mitochondrial and peroxisomal beta-oxidation of fatty acids. In addition to the physiological stimuli of fasting and high-fat diet, PPARalpha is activated by the fibrate class of drugs for the treatment of dyslipidemia. Sirtuin 1 (SIRT1), an important regulator of energy homeostasis, was downregulated in fibrate-treated wild-type mice, suggesting PPARalpha regulation of Sirt1 gene expression. The impact of SIRT1 loss on PPARalpha functionality in vivo was assessed in hepatocyte-specific knockout mice that lack the deacetylase domain of SIRT1 (Sirt1(DeltaLiv)). Knockout mice were treated with fibrates or fasted for 24 h to activate PPARalpha. Basal expression of the PPARalpha target genes Cyp4a10 and Cyp4a14 was reduced in Sirt1(DeltaLiv) mice compared with wild-type mice. However, no difference was observed between wild type and Sirt1(DeltaLiv) mice in either fasting- or fibrate-mediated induction of PPARalpha target genes. Similar to the initial results, there was no difference in fibrate-activated PPARalpha gene induction. To assess the relationship between SIRT1 and PPARalpha in a pathophysiological setting, Sirt1(DeltaLiv) mice were maintained on a high-fat diet for 14 wk, followed by fibrate treatment. Sirt1(DeltaLiv) mice exhibited increased body mass compared with control mice. In the context of a high-fat diet, Sirt1(DeltaLiv) mice did not respond to the cholesterol-lowering effects of the fibrate treatment. However, there were no significant differences in PPARalpha target gene expression. These results suggest that, in vivo, SIRT1 deacetylase activity does not significantly impact induced PPARalpha activity. PMID- 24496312 TI - De novo synthesis of milk triglycerides in humans. AB - Mammary gland (MG) de novo lipogenesis contributes significantly to milk fat in animals but little is known in humans. OBJECTIVE: To test the hypothesis that the incorporation of (13)C carbons from [U-(13)C]glucose into fatty acids (FA) and glycerol in triglycerides (TG) will be greater: 1) in milk than plasma TG, 2) during a high-carbohydrate (H-CHO) diet than high-fat (H-FAT) diet, and 3) during feeding than fasting. Seven healthy, lactating women were studied on two isocaloric, isonitrogenous diets. On one occasion, subjects received diets containing H-FAT or H-CHO diet for 1 wk. Incorporation of (13)C from infused [U (13)C]glucose into FA and glycerol was measured using GC-MS and gene expression in RNA isolated from milk fat globule using microarrays. Incorporation of (13)C2 into milk FA increased with increased FA chain length from C2:0 to C12:0 but progressively declined in C14:0 and C16:0 and was not detected in FA>C16. During feeding, regardless of diets, enrichment of (13)C2 in milk FA and (13)C3 in milk glycerol were ~ 3- and ~ 7-fold higher compared with plasma FA and glycerol, respectively. Following an overnight fast during H-CHO and H-FAT diets, 25 and 6%, respectively, of medium-chain FA (MCFA, C6-C12) in milk were derived from glucose but increased to 75 and 25% with feeding. Expression of genes involved in FA or glycerol synthesis was unchanged regardless of diet or fast/fed conditions. The human MG is capable of de novo lipogenesis of primarily MCFA and glycerol, which is influenced by the macronutrient composition of the maternal diet. PMID- 24496313 TI - Improvement in sensitivity of an inductive oil palm fruit sensor. AB - Among palm oil millers, the ripeness of oil palm Fresh Fruit Bunch (FFB) is determined through visual inspection. To increase the productivity of the millers, many researchers have proposed with a new detection method to replace the conventional one. The sensitivity of such a sensor plays a crucial role in determining the effectiveness of the method. In our preliminary study a novel oil palm fruit sensor to detect the maturity of oil palm fruit bunches is proposed. The design of the proposed air coil sensor based on an inductive sensor is further investigated to improve its sensitivity. This paper investigates the results pertaining to the effects of the air coil structure of an oil palm fruit sensor, taking consideration of the used copper wire diameter ranging from 0.10 mm to 0.18 mm with 60 turns. The flat-type shape of air coil was used on twenty samples of fruitlets from two categories, namely ripe and unripe. Samples are tested with frequencies ranging from 20 Hz to 120 MHz. The sensitivity of the sensor between air to fruitlet samples increases as the coil diameter increases. As for the sensitivity differences between ripe and unripe samples, the 5 mm air coil length with the 0.12 mm coil diameter provides the highest percentage difference between samples and it is amongst the highest deviation value between samples. The result from this study is important to improve the sensitivity of the inductive oil palm fruit sensor mainly with regards to the design of the air coil structure. The efficiency of the sensor to determine the maturity of the oil palm FFB and the ripening process of the fruitlet could further be enhanced. PMID- 24496314 TI - Electron transfer-based single molecule fluorescence as a probe for nano environment dynamics. AB - Electron transfer (ET) is one of the most important elementary processes that takes place in fundamental aspects of biology, chemistry, and physics. In this review, we discuss recent research on single molecule probes based on ET. We review some applications, including the dynamics of glass-forming systems, surface binding events, interfacial ET on semiconductors, and the external field induced dynamics of polymers. All these examples show that the ET-induced changes of fluorescence trajectory and lifetime of single molecules can be used to sensitively probe the surrounding nano-environments. PMID- 24496315 TI - Blockade of IL-33 release and suppression of type 2 innate lymphoid cell responses by helminth secreted products in airway allergy. AB - Helminth parasites such as the nematode Heligmosomoides polygyrus strongly inhibit T helper type 2 (Th2) allergy, as well as colitis and autoimmunity. Here, we show that the soluble excretory/secretory products of H. polygyrus (HES) potently suppress inflammation induced by allergens from the common fungus Alternaria alternata. Alternaria extract, when administered to mice intranasally with ovalbumin (OVA) protein, induces a rapid (1-48 h) innate response while also priming an OVA-specific Th2 response that can be evoked 14 days later by intranasal administration of OVA alone. In this model, HES coadministration with Alternaria/OVA suppressed early IL-33 release, innate lymphoid cell (ILC) production of IL-4, IL-5, and IL-13, and localized eosinophilia. Upon OVA challenge, type 2 ILC (ILC2)/Th2 cytokine production and eosinophilia were diminished in HES-treated mice. HES administration 6 h before Alternaria blocked the allergic response, and its suppressive activity was abolished by heat treatment. Administration of recombinant IL-33 at sensitization with Alternaria/OVA/HES abrogated HES suppression of OVA-specific responses at challenge, indicating that suppression of early Alternaria-induced IL-33 release could be central to the anti-allergic effects of HES. Thus, this helminth parasite targets IL-33 production as part of its armory of suppressive effects, forestalling the development of the type 2 immune response to infection and allergic sensitization. PMID- 24496317 TI - Herpes simplex virus type-2 stimulates HIV-1 replication in cervical tissues: implications for HIV-1 transmission and efficacy of anti-HIV-1 microbicides. AB - Herpes Simplex virus Type-2 (HSV-2) increases the risk of HIV-1 acquisition, yet the mechanism for this viral pathogen to regulate the susceptibility of the cervicovaginal mucosa to HIV-1 is virtually unknown. Using ex vivo human ectocervical tissue models, we report greater levels of HIV-1 reverse transcription, DNA integration, RNA expression, and virions release in HIV-1/HSV 2 co-infected tissues compared with HIV-1 only infected tissues (P<0.05). Enhanced HIV-1 replication was associated with increased CD4, CCR5, and CD38 transcription (P<0.05) and increased number of CD4(+)/CCR5(+)/CD38(+) T cells in HIV-1/HSV-2 co-infected tissues compared with tissues infected with HIV-1 alone. Tenofovir (TFV) 1% gel, the leading microbicide candidate, demonstrated only partial protection against HIV-1, when applied vaginally before and after sexual intercourse. It is possible that mucosal inflammation, in particular that induced by HSV-2 infection, may have decreased TFV efficacy. HSV-2 upregulated the number of HIV-1-infected cells and elevated the concentration of TFV needed to decrease HIV-1 infection. Similarly, only high concentrations of TFV inhibited HSV-2 replication in HIV-1/HSV-2-infected tissues. Thus, HSV-2 co-infection and mucosal immune cell activation should be taken into consideration when designing preventative strategies for sexual transmission of HIV-1. PMID- 24496318 TI - Patterns of statin initiation, intensification, and maximization among patients hospitalized with an acute myocardial infarction. AB - BACKGROUND: Intensive statins are superior to moderate statins in reducing morbidity and mortality after an acute myocardial infarction. Although studies have documented rates of statin prescription as a quality performance measure, variations in hospitals' rates of initiating, intensifying, and maximizing statin therapy after acute myocardial infarction are unknown. METHODS AND RESULTS: We assessed statin use at admission and discharge among 4340 acute myocardial infarction patients from 24 US hospitals (2005-2008). Hierarchical models estimated site variation in statin initiation in naive patients, intensification in those undergoing submaximal therapy, and discharge on maximal therapy (defined as a statin with expected low-density lipoprotein cholesterol lowering >= 50%) after adjustment for patient factors, including low-density lipoprotein cholesterol level. Site variation was explored with a median rate ratio, which estimates the relative difference in risk ratios of 2 hypothetically identical patients at 2 different hospitals. Among statin-naive patients, 87% without a contraindication were prescribed a statin, with no variability across sites (median rate ratio, 1.02). Among patients who arrived on submaximal statins, 26% had their statin therapy intensified, with modest site variability (median rate ratio, 1.47). Among all patients without a contraindication, 23% were discharged on maximal statin therapy, with substantial hospital variability (median rate ratio, 2.79). CONCLUSIONS: In a large, multicenter acute myocardial infarction cohort, statin therapy was begun in nearly 90% of patients during hospitalization, with no variability across sites; however, rates of statin intensification and maximization were low and varied substantially across hospitals. Given that more intense statin therapy is associated with better outcomes, changing the existing performance measures to include the intensity of statin therapy may improve care. PMID- 24496316 TI - IgG in cervicovaginal mucus traps HSV and prevents vaginal herpes infections. AB - IgG is the predominant immunoglobulin in cervicovaginal mucus (CVM), yet how immunoglobulin G (IgG) in mucus can protect against infections is not fully understood. IgG diffuses rapidly through cervical mucus, slowed only slightly by transient adhesive interactions with mucins. We hypothesize that this almost unhindered diffusion allows IgG to accumulate rapidly on pathogen surfaces, and the resulting IgG array forms multiple weak adhesive crosslinks to mucus gel that effectively trap (immobilize) pathogens, preventing them from initiating infections. Here, we report that herpes simplex virus serotype 1 (HSV-1) readily penetrated fresh, pH-neutralized ex vivo samples of CVM with low or no detectable levels of anti-HSV-1 IgG but was trapped in samples with even modest levels of anti-HSV-1 IgG. In samples with little or no endogenous anti-HSV-1 IgG, addition of exogenous anti-HSV-1 IgG, affinity-purified from intravenous immunoglobulin, trapped virions at concentrations below those needed for neutralization and with similar potency as endogenous IgG. Deglycosylating purified anti-HSV-1 IgG, or removing its Fc component, markedly reduced trapping potency. Finally, a non neutralizing IgG against HSV-gG significantly protected mice against vaginal infection, and removing vaginal mucus by gentle lavage abolished protection. These observations suggest that IgG-Fc has a glycan-dependent "muco-trapping" effector function that may provide exceptionally potent protection at mucosal surfaces. PMID- 24496319 TI - The quality of quality: is it time for new tools? PMID- 24496321 TI - A morphological and immunohistochemical study of the effects of prednisolone or ursodeoxycholic acid on liver histology in feline lymphocytic cholangitis. AB - Feline lymphocytic cholangitis (LC) has been commonly treated with prednisolone, and more recently with ursodeoxycholic acid (UDCA). Previously, we found that prednisolone treatment resulted in a statistically longer survival time than treatment with UDCA. In order to explain this difference, we compared the effects of prednisolone and UDCA treatment on hepatic tissue by evaluating consecutive liver biopsies. Archival serial biopsy materials from cats with LC treated with prednisolone (n = 5) or UDCA (n = 4) were evaluated. We employed haematoxylin and eosin staining to evaluate inflammation, and reticulin staining for fibrosis. Immunohistochemical stainings for Ki-67, K19 (Cytokeratin 19) and alpha-smooth muscle actin were used to evaluate cell type-specific proliferation and activation of hepatic stellate cells. Inflammation decreased more in the group treated with prednisolone, while the number of cholangiocytes, progenitor cells and fibroblasts did not differ between the treatment groups. Additionally, no difference was found for the amount of fibrosis in both treatment groups. PMID- 24496320 TI - Dissociable contributions of anterior cingulate cortex and basolateral amygdala on a rodent cost/benefit decision-making task of cognitive effort. AB - Personal success often requires the choice to expend greater effort for larger rewards, and deficits in such effortful decision making accompany a number of illnesses including depression, schizophrenia, and attention deficit/hyperactivity disorder. Animal models have implicated brain regions such as the basolateral amygdala (BLA) and anterior cingulate cortex (ACC) in physical effort-based choice, but disentangling the unique contributions of these two regions has proven difficult, and effort demands in industrialized society are predominantly cognitive in nature. Here we utilize the rodent cognitive effort task (rCET), a modification of the five-choice serial reaction-time task, wherein animals can choose to expend greater visuospatial attention to obtain larger sucrose rewards. Temporary inactivation (via baclofen-muscimol) of BLA and ACC showed dissociable effects: BLA inactivation caused hard-working rats to 'slack off' and 'slacker' rats to work harder, whereas ACC inactivation caused all animals to reduce willingness to expend mental effort. Furthermore, BLA inactivation increased the time needed to make choices, whereas ACC inactivation increased motor impulsivity. These data illuminate unique contributions of BLA and ACC to effort-based decision making, and imply overlapping yet distinct circuitry for cognitive vs physical effort. Our understanding of effortful decision making may therefore require expanding our models beyond purely physical costs. PMID- 24496322 TI - Evaluation of an in-house dot enzyme-linked immunosorbent assay to detect antibodies against feline panleukopenia virus. AB - Measuring antibody titres to determine a cat's immunity to core diseases instead of just administering annual vaccinations has not been established in Germany so far. An in-house test kit for the detection of antibodies against feline panleukopenia virus (FPV), feline herpesvirus-1 and feline calicivirus-- the ImmunoComb Feline VacciCheck--is now available in several European countries. The aim of this study was to assess the quality of the ImmunoComb Feline VacciCheck to determine antibodies by comparing it to a gold standard. The test is aimed for use in practice to assist decision-making when performing an individual health assessment to see whether a cat is potentially unprotected against FPV and requires FPV vaccination. Sera from 347 cats were included in the study. For antibody detection, haemagglutination inhibition (HI) was performed as gold standard. Sensitivity, specificity and positive and negative predictive values of the ImmunoComb Feline VacciCheck were determined for three different HI titre cut off points (1:20, 1:40, 1:80). In comparison to the HI, the ImmunoComb Feline VacciCheck showed a sensitivity of 79%, 83% and 87%, and a specificity of 89%, 86% and 81%, respectively. Specificity of the ImmunoComb Feline VacciCheck, which was considered the most important parameter, was acceptable in comparison to HI. Especially when considering an antibody titre of 1:20 sufficient for protection (eg, in an adult animal), the ImmunoComb Feline VacciCheck can be recommended for use in veterinary practice. PMID- 24496323 TI - Dermatophilus congolensis in a feral cat. AB - A young adult feral cat presented to the Champaign County Humane Society with a subcutaneous mass near the stifle. The mass was aspirated. Chains of paired cocci organisms were identified, consistent with Dermatophilus congolensis. The identity of these organisms was confirmed by culture and polymerase chain reaction. PMID- 24496324 TI - Experimental observation of ferrielectricity in multiferroic DyMn2O5. AB - One of the major breakthroughs associated with multiferroicity in recent years is the discovery of ferroelectricity generated by specific magnetic structures in some magnetic insulating oxides such as rare-earth manganites RMnO3 and RMn2O5. An unresolved issue is the small electric polarization. Relatively large electric polarization and strong magnetoelectric coupling have been found in those manganites of double magnetic ions: magnetic rare-earth R ion and Mn ion, due to the strong R-Mn (4f-3d) interactions. DyMn2O5 is a representative example. We unveil in this work the ferrielectric nature of DyMn2O5, in which the two ferroelectric sublattices with opposite electric polarizations constitute the ferrielectric state. One sublattice has its polarization generated by the symmetric exchange striction from the Mn-Mn interactions, while the polarization of the other sublattice is attributed to the symmetric exchange striction from the Dy-Mn interactions. We present detailed measurements on the electric polarization as a function of temperature, magnetic field, and measuring paths. The present experiments may be helpful for clarifying the puzzling issues on the multiferroicity in DyMn2O5 and other RMn2O5 multiferroics. PMID- 24496325 TI - A comparison of 2 devices for radial artery hemostasis after transradial coronary intervention. AB - BACKGROUND AND OBJECTIVE: Transradial access is an attractive approach for angiography or percutaneous coronary intervention. Different devices have been used to apply pressure locally at the site of arterial entry for achieving hemostasis. The aim of this study was to evaluate the effect of 2 different hemostatic devices on radial artery outcomes after transradial coronary intervention. SUBJECTS AND METHODS: This study included 600 patients who had undergone transradial coronary intervention who were randomized into 2 groups after the procedure: 300 were treated with a radial compression device (TR Band, Terumo Medical, Tokyo, Japan) (CD group) and the other 300 patients were treated using a chitosan-based pad (Anscare, Daxon, Taoyuan, Taiwan) (CS group). Compression time, major and minor access site bleeding complications, and incidence of radial artery occlusion were recorded. RESULTS: There were no statistical differences in the baseline clinical characteristics of the patients between the 2 groups. Compression time in the CS group was significantly shorter than that in the CD group (P < .001). Although no major access site bleeding complications were observed in either group, 6 patients in each group experienced minor access site bleeding complications. At the same time, 61 patients in the CD group and 21 patients in the CS group experienced errhysis (20% vs 7%, respectively; P < .001). Early radial artery occlusion (24 hours) occurred in 11.7% of the patients in the CD group and 5.4% of the patients in the CS group (P < .05). Chronic radial artery occlusion (30 days) occurred in 10% of the patients in the CD group and 5% of the patients in the CS group (P < .05). CONCLUSION: The application of the chitosan-based pad showed better hemostatic efficacy and a lower incidence of radial artery occlusion after transradial coronary intervention compared with the compression device. PMID- 24496326 TI - Impact of a nurse-led heart failure program on all-cause mortality. AB - BACKGROUND: Nurse-led heart failure programs (HFPs) have been shown to reduce readmissions and improve medication adherence rates. However, their impact on survival is not well demonstrated. OBJECTIVE: The purpose of this study was to evaluate the impact of a nurse-led HFP on all-cause mortality. METHODS: This retrospective review included 413 consecutive patients who were admitted with heart failure exacerbations in 2008 and 2009. All patients were invited to attend a nurse-led HFP; 199 (48%) patients agreed and were compared with the 214 (52%) who chose usual care. Patients were followed for all-cause mortality, which was confirmed by the national death index. Independent predictors of outcomes were identified using multivariable Cox regression. RESULTS: Patients followed in the HFP were younger, more often men with lower ejection fraction, blood urea nitrogen, and systolic blood pressure. After a median follow-up of 15 months (range, 6-30 months), a total of 55 patients died: 14 in the HFP group (7%) compared with 41 patients (19%) in the usual care group. Participation in the HFP was independently associated with reduction in all-cause mortality (hazard ratio, 0.4; 95% confidence interval, 0.2-0.8; P = .008). CONCLUSIONS: Our nurse-led HFP was independently associated with improved survival among patients with decompensated heart failure. Further research is required to confirm this finding. PMID- 24496328 TI - M(o)TOR of pseudo-hypoxic state in aging: rapamycin to the rescue. AB - A groundbreaking publication by Sinclair and coworkers has illuminated the pseudo hypoxic state in aging and its reversibility. Remarkably, these data also fit the mTOR-centered model of aging. Here we discuss that the mTOR pathway can cause cellular pseudo-hypoxic state, manifested by HIF-1 expression and lactate production under normoxia. We found that rapamycin decreased HIF-1 and lactate levels in proliferating and senescent cells in vitro. This reduction was independent from mitochondrial respiration: rapamycin decreased lactate production in normoxia, hypoxia, and in the presence of the OXPHOS inhibitor oligomycin. We suggest that pseudo-hypoxic state is not necessarily caused by mitochondrial dysfunction, but instead mitochondrial dysfunction may be secondary to mTOR-driven hyperfunctions. Clinical applications of rapamycin for reversing pseudo-hypoxic state and lactate acidosis are discussed. PMID- 24496329 TI - Roles of enhancer of zeste homolog 2: from skeletal muscle differentiation to rhabdomyosarcoma carcinogenesis. AB - Polycomb group proteins represent a global silencing system involved in embryonic development and stem-cell maintenance that regulates the transition from proliferation to differentiation during organogenesis. Two main complexes have been discovered: the polycomb repressive complex (PRC) 1 and 2, able to induce gene silencing by a synergistic mechanism or independently by each other. Enhancer of zeste homolog 2 (EZH2), the catalytic subunit of PRC2, represses gene transcription through the tri-methylation of histone H3 lysine 27. EZH2 deregulation is frequently associated with tumorigenesis, metastatic character, and poor prognosis in various cancer types. This review explores the role of EZH2 in normal development and in carcinogenesis. We reviewed the polycomb-mediated silencing mechanisms, the regulation of EZH2 activity and its recruitment to target genes. We also analyzed the role of EZH2 in normal muscle differentiation and in rhabdomyosarcoma, considering EZH2 blockade as a new strategy for developing specific therapies. PMID- 24496330 TI - RB orchestrates fat cell and cell fate. PMID- 24496331 TI - An imPERfect link to cancer? PMID- 24496332 TI - BMP signals: Mediated by stroma or thymocytes? PMID- 24496333 TI - Comparative bioinformatic analysis of the conserved domains, amino acid residues, and binding grooves of tumor necrosis factor. AB - AIM: Comparative structural bioinformatic analysis of the conserved domains and amino acid residues, binding grooves of the tumor necrosis factor (TNF)alpha and beta in order to elucidate structurebased inhibitor development was conducted. METHODS: We carried out the bioinformatics study of TNF proteins at the Department of Bio-informatics (Galgotias University, India) between June and December 2012. TNFalpha and TNF-beta functional protein sequences in FASTA format were obtained from the NCBI database for analysis. The online tool ClustalW from the European Bioinformatic Institute was used for multiple sequence alignment to record similarities. The Jmol server was used for 3D visualization of alpha helix, beta sheet and loops of TNF proteins. The PyMOL molecular visualization system was used to generate surface cavity and to identify binding grooves of TNF proteins. RESULTS: This study showed highly conserved amino acids residues such as LYS11, PRO12, ALA14, HIS15, VAL50, PRO51, GLY54, LEU55, TYR56, LEU57, TYR59, SER60, GLN61, GLY122, VAL123, PHE124, PHE152, and GLY153 are consequent amino acids in TNF-beta while residues such as ALA31, HIS32, SER77, GLN78, PHE166, and GLY167 are consequent amino acids in TNF-beta. Surface cavity and binding grooves showed TNF-beta with larger surface cavities than TNF-alpha with higher chances for drug development since small drug-like molecules can bind easily into the groove. CONCLUSION: The results illustrate the structure of TNF proteins and the novel findings may guide future research on TNF and in the process of assisting the optimization of the pharmacological properties involving the two crucial proteins. PMID- 24496334 TI - Changes of natriuretic peptides concentration in early phase of acute myocardial infarction. AB - AIM: To analyze a change of level of nautriuretic peptide (NT pro- BNP) caused by stress distension of myocardial wall in cases of acute myocardial infarction (AIM), as a possible predictor of early heart failure. METHODS: Patients with myocardial infarction were followed up. Standard clinical and laboratory examination, including NT pro- BNP, and other laboratory analyses, were performed on the day of admission, the next day and on the eighth day of hospitalization. Statistical analyses included variance for repeated measurement (ANOVA), factorial multivariate analysis and test of multiple correlations. RESULTS: The most important predictors of early heart failure in acute myocardial infarction were age, diastolic blood pressure, creatin kinase (CK) on admission, larger field of infarction zone and so on. Multiple correlations showed statistically significant correlation of age, diastolic pressure and larger zone of myocardial infarction with an increase of NT pro-BNP concentration. The activity of CK on the day after admission was higher than on admission (p=0.02) and myocard-binding CK (CK-MB) the next day after admission was higher than on admission (p=0.016). A statistically significant increase was found on the next day for NT pro-BNP in comparison with the value on admission (p=0.0049), but the level of activity of CK was markedly decreased on the eighth hospital day. CONCLUSION: The significant increase of the concentration of NT pro-BNP during myocardial infarction is an important predictor of early heart failure, therefore, in case of a significant increase of NT pro-BNP in the early phase of the infraction a therapy that could prevent clinically relevant heart failure should be administered . PMID- 24496335 TI - Glycogen phosphorylase isoenzyme BB, creatine kinase isoenzyme MB and troponin I for monitoring patients with percutaneous coronary intervention - a pilot study. AB - AIM: The glycogen phosphorylase isoenzyme BB (GPBB), as an ischemic marker, has not yet been investigated after elective percutaneous coronary intervention (PCI). ose aim of the study was to monitor GPBB, creatine kinase myocardial isoform (CK-MB) mass) and troponin I (TnI) value after PCI in correlation with ischemic incidents. METHODS: Forty-two consecutive patients undergoing elective PCI were included in the study. Baseline blood samples and two more after the PCI (3 and 24 hours) were taken. The significance of cardiac markers in twenty-ththe stable patients with baseline values of CK-MB mass and TnI below the upper reference limit (URL) was evaluated based on ischemic incidents after PCI. RESULTS: TnI value was the only biomarker that was statistically significant at 3 and 24 hours after PCI in group of 23 stable patients. An overall comparisonthe biomarkers of 18 patients without and five patients with ischemic incidents displayed significant differences only for the baseline GPBB (p=0.019) and CK-MB mass 24 hours after PCI (p=0.034). Ischemic incidents were independently predictable only based on overall CK-MB mass measurements (OR=1.680, p=0.041) and particularly GPBB at baseline (OR=1.899, p=0.008) and CK-MB mass 24 hours after PCI (OR=2.111, p=0.022). CONCLUSIONS: Only significant increases in TnI were observed after elective PCI with ischemic incidents predicted using GPBB and CK MB mass measurements. PMID- 24496336 TI - Risk factors for the development of arterial hypertension. AB - AIM: To examine risk factors for the development of primary arterial hypertension which is a significant health and public health problem throughout the world. METHODS: This anamnestic study, conducted at the Primary Health Centre "Stari Grad" in Belgrade during 2006, included 63 new cases of arterial hypertension and 63 subjects who formed the control group. Patients and control group were individually matched to each other by sex, age (+/- 3 years) and place of residence. The survey instrument was a questionnaire based on socio-demographic characteristics of respondents (gender, age, residence, education level, occupation, marital status, socio-economic status) and habits (smoking, alcohol consumption, physical activity). Data analysis was performed by applying descriptive statistics (relative numbers) and inferential statistics (chi2 test). RESULTS: There were significant differences in the level of education (p = 0,012) and current smoking status (p=0.017) between the group of patients with arterial hypertension and the control group. The subjects in the control group showed significantly longer consumption of schnapps (p=0.033) and beer (p=0.040) (more than 20 years). There was a significant difference in excessive body weight, and obesity measured by body mass index (p=0.006) and waist circumference (p=0.014) between these groups of patients. CONCLUSION: Risk factors associated with arterial hypertension were low education, long smoking period, excessive body weight and obesity. These results indicate the necessity of introducing programs which should be imperative in future prevention of arterial hypertension. PMID- 24496337 TI - Prevalence of arterial hypertension in obese high school population in Zenica, Bosnia and Herzegovina. AB - AIM: To determine the significance of obesity as a risk factor in high school population with hypertension. METHODS: Testing was conducted during the school year 2006-2007 on a sample of 1121 students, 15-18 years of age (306 boys and 815 girls) from three high schools in Zenica (Grammar School, Teacher Training High School and Secondary School for Nurses). Increased relative risk factor with reliability coefficient that points to the significance of the correlation of risk factors and development of a disease was examined using analytical epidemiological research methods and statistical analysis (the linear correlation coefficient, chi2 test, and the relative risk ) . RESULTS: Obesity, e.g. Body Mass Index (BMI) more than 95 was found in 15 (5%) boys and 57 (7%) girls. Increased relative risk of developing essential arterial hypertension was found in obese boys (RR= 9.00 ) and girls (RR= 2.66) with the coefficient of reliability which pointed to the significance of the relationship between obesity and arterial hypertension morbidity. CONCLUSION: Obesity is a significant risk factor for the occurrence of essential arterial hypertension in boys and girls. Monitoring the nutritional status of youth, regular systematic medical examinations with measuring tension and implementing measures to control nutrition, are important preventive public health tasks. PMID- 24496338 TI - Dyslipidemia as a risk factor for primary intracerebral hemorrhage. AB - AIM: Most of the studies proved association between some lipoprotein fractions and hypocholesterolemia as risk factors for primary intracerebral hemorrhage (ICH). However, there are studies that emphasize hypercholesterolemia (Hyper-Hol) as a risk factor. The present study aims at determining lipid fractions as risk factors for intracerebral hemorrhage in our region. METHODS: A retrospective study included 92 patients with primary ICH treated during one year at the Department of Neurology in the Clinical Centre of Vojvodina, Novi Sad. Following clinical and demographic data, age and gender, risk factors with a focus on certain lipid fractions (total cholesterol, triglycerides, low density- LDL, and high density - HDL cholesterol), types of hyperlipoproteinemia and disease outcome were analyzed. RESULTS: Fifty-one (55%) females and forty-one (45%) males, mean age 67.6 years were enrolled in the study. Hyper-Hol was observed in 63 (69%) patients, hyper-LDL cholesterolemia in 68 (74%) patients and hypo-HDL cholesterolemia in 77 (84%) patients, while triglyceride levels were normal in majority of patients. No statistical significance between males and females was observed considering levels of total cholesterol (p=0.068), LDL cholesterol (p=0.156), triglycerides (p=0.363), while levels of HDL cholesterol were significantly higher in females (p=0.023). Hyperlipoproteinemia IIa was found in 51 (78%). Mortality rate was 25%. CONCLUSION: Hypertrigliceridemia was not proved as a risk factor, while hyper-LDL cholesterolemia, hypo-HDL cholesterolemia, and hyper-Hol can be associated with primary ICH, which could justify further statin treatment in secondary prevention of this disease. PMID- 24496339 TI - Role of D-dimer in predicting mortality in patients with community-acquired pneumonia. AB - AIM: To determine whether D-dimer in patients with communityacquired pneumonia (CAP) can predict mortality risk better than standard biomarkers. METHODS: White blood cell (WBC), C-reactive protein (CRP) and D-dimer in 129 patients with CAP were analyzed. The recommended Pneumonia Severity Index (PSI) score was used to classify CAP patients into five groups according to the severity of disease (Group PSI I-V), and for predicting mortality. Additionally, the patients were divided in surviving and non-surviving group. RESULTS: White blood cell and CRP were not in correlation with the severity of CAP and the risk of mortality. The correlation between plasma D-dimer and severity of CAP was found (r=0.4993; p less than 0.001). The level of D-dimer was significantly higher in nonsurviving (2498.38 +/- 1248.83 ng/mL) than in surviving patients (966.44 +/- 968.73 ng/mL) (p less than 0.001). In predicting mortality risk, D-dimer showed sensitivity of 0.84 (cut of >1538 mg/mL), specificity 0.86 and AUC 0.859 (95%CI; 0.787-0.914). Pneumonia Severity Index in predicting of mortality risk for cut of > PSI III showed sensitivity of 0.92, specificity 0.62 and AUC 0.868 (95%CI; 0.797-0.921). There was no statistical difference between AUC of PSI and D-dimer (delta AUC= 0.00895) (p=0.9005). CONCLUSION: Coagulation abnormalities were presented in older patients with severe infections and comorbidity. Plasma D-dimer correlated better than standard inflammatory markers with severity of disease and risk of mortality in patients with CAP. In predicting mortality risk, D-dimer did not show difference among the PSI score. PMID- 24496340 TI - The role of the tissue culture in granulomatous mediastinal lymphadenitis: tuberculosis or not. AB - AIM: To evaluate the role of the tissue culture via mediastinoscopic biopsy in granulomatous mediastinal lymphadenitis. METHODS: The dossier data of 92 cases with mediastinal lymphadenitis showing granulomatous lymphadenitis features by cervical mediastinoscopy and whose clinical, radiological and bacteriological definitive diagnosis is tuberculosis and sarcoidosis were examined retrospectively. The rate of the positive tissue culture of mediastynoscopic biopsy in the diagnosis of granulomatous lymphadenitis was calculated. RESULTS: There were 65 (71%) females and 27 (29%) males. The mean age of the patients was 42.5 (range 15-75) years. Non necrotizing granulomatous lymphadenitis was detected in 58 (63 %) cases while necrotizing granulomatous lymphadenitis was seen in 34 (37%) cases. There were 29 cases diagnosed with tuberculosis. Acid resistant bacilli culture positive rate was 38% (in 11 cases). There were 21 (62%) cases of necrotizing granulomatous lymphadenitis and eight (14%) cases of non-necrotizing granulomatous lymphadenitis diagnosed with tuberculosis. Culture positivity was identified in two (25%) of eight cases whose differential diagnosis could not be made histopathologically as tuberculosis/sarcoidosis. CONCLUSIONS: In addition to clinical, radiological and histopathological diagnosis, the study aims to highlight the importance of tissue culture in definitive diagnosis, especially undetermined incidents. PMID- 24496341 TI - Asthma control in obesity-associated asthma phenotype in East Croatia. AB - AIM: To determine if obese asthmatics represent a distinct clinical phenotype than non-obese and the level of asthma control in obese asthmatics. METHODS: The study was conducted in the pulmonary clinic of the Department of Pulmonary Diseases, Osijek University Hospital Centre during 201, on 201 outpatients with asthma, who came to a regular examination. Each patient underwent a clinical examination with an extensive anamnesis and lung auscultation. During the examinationIanninternally made questionnaire, spirometry, fractional exhaled nitric oxide (FeNO), Asthma Control Test and Asthma Control Questionnaire were used to estimate the level of asthma control, wheread the Hospital Anxiety and Depression scale was used to estimate the presence of mood disorderd. RESULTS: The severity of asthma was increased in obese patients. There was no significant difference in the number and frequency of hospitalizations in obese compared to non-obese asthmatics. Non-obese asthmatics had more frequent visits to their general practitioner/Emergency medical services (GP/EMS) during the last month compared to obese asthmatics, which is a new finding inconsistent to any study conducted before. Obese asthmatics had more symptoms and had them almost every day. Lung function of obese asthmatic was worse compared to non-obese, especially in women. Values of exhaled nitric oxide showed no significant difference for obese asthmatics. No significant difference in intake of corticosteroids or combination therapy was found. Obese patients with asthma had more frequent and multiple comorbidities. CONCLUSION: Results confirmed that obese asthmatics represent a different phenotype of asthma, more severe and poorly controlled. PMID- 24496342 TI - Pulmonary function parameters as prognostic factors in advanced non-small cell lung cancer. AB - AIM: To investigate the impact of some parameters of lung function (forced expiratory volumen in 1 second - FEV1, forced vital capacity - FVC and ratio FEV1/FVC%) on survival in patients with advanced non-small cell lung cancer (NSCLC). METHODS: It retrospectively analyzed data of 155 patients with NSCLC receiving second-line treatment in the Clinic for Lung Diseases, Clinical Center Nis, Serbia, from October 2009 to December 2012. Fifteen potential prognostic variables were subjected to univariate and multivariate analysis to investigate prognostic impact to survival. RESULTS: Among the total of 155 patients, 124 (80%) were males. The most frequent was squamous carcinoma, 86 (55,5%). Mean FEV1 was 1.89 +/- 0.71 L (61.8%), mean FVC 2.95 +/- 0.8 L (77.2%) and mean FEV1/FVC% was 63.6%. In a multivariate analysis using Cox regression hazard model (hazard ratio, HR), independent prognostic factors for overall survival (OS) were: FEV1 less than 50% of predicted HR= 4.513, 95% confidence interval (CI): 1.433-14.216 (p=0.010), performance status 2 (HR= 0.090, CI= 0.035-0.230 (p=0.000) and weight loss more than 5 % (HR= 0.162, CI= 0.068-0.382 (p=0.000). CONCLUSION: FEV1 in patients with advanced NSCLC receiving chemotherapy is an important independent factor that can predict survival. There was close relationship between impaired lung function and lung cancer patients survival. PMID- 24496343 TI - The incidence of recurrent pleomorphic adenoma of the parotid gland in relation to the choice of surgical procedure. AB - AIM: To investigate an incidence of recurrence of pleomorphic adenoma of the parotid gland in relation to the choice of surgical procedure. METHODS: All patients with a diagnosis of pleomorphic adenoma of parotid gland who underwent surgery at the Department of Maxillofacial Surgery (MFS) of the Clinical Center of the University of Sarajevo (CCU), Bosnia and Herzegovina, in the period 01 January 1992 - 31 December 2010 were included in the study. The incidence of recurrence and complications in relation to the choice of surgical procedure (enucleation, excision of the tumor, superficial parotidectomy and total parotidectomy) as well as the choice of diagnostic procedures were compared. For all variables measured the arithmetic mean (x), standard deviation (SD), the correlation coefficient (r), and chi 2 test were used. RESULTS: A total of 81 operations were performed on 60 patients. The highest recurrence rate was after enucleation (88.9%), then after excision (46.9%), and the least after superficial (4%) and total parotidectomy (0%). The highest number of complications was noted after the surgery of recurrence (8.3%), because it was difficult to preserve facial nerve in the previously treated area. CONCLUSION: Both total or superficial parotidectomy were optimal surgical procedures which, if applied at the first surgery of pleomorphic adenoma, provided almost 100% certainty of healing. All subsequent surgeries carry a higher risk of complications, e.g. severe lesion of facial nerve. PMID- 24496344 TI - Antibiotic susceptibility of isolates from paediatric intensive care units in Zagreb. AB - AIM: Meropenem Yearly Susceptibility Test Information Collection (MYSTIC) Program is a longitudinal global surveillance study to monitor in vitro data on microbial susceptibility in centers that prescribe meropenem. Results of the six years period (2002-2007) for the antimicrobial efficacy of meropenem compared to other broad-spectrum agents against Gram-negative and Gram-positive isolates collected at pediatric intensive care units of the University Hospital Center Zagreb in Croatia were reported. METHODS: A total of 110 Gram-negative and 43 Gram-positive pathogens from pediatric specimens were tested. The minimum-inhibitory concentrations (MICs) were determined by broth microdilution method according to CLSI. RESULTS: There was no resistance to either imipenem or meropenem observed for Escherichia coli, Klebsiella pneumoniae and Proteus mirabilis. High resistance rates of K. pneumoniae to ceftazidime and gentamicin (50%) are a raising concern. Pseudomonas aeruginosa was the most resistant Gram-negative species with two (12%) of the strains resistant to meropenem, three (18%) to imipenem, 10 (47%) to gentamicin and six (35%) to piperacillin/tazobactam and ciprofloxacin. According to our results meropenem remains an appropriate antibiotic for the treatment of severe infections caused by Gram-negative bacteria in pediatric population. CONCLUSIONS: The results indicate that meropenem has excellent potency and spectrum of activity despite being prescribed for a long time for the treatment of seriously ill patients, and still appears to be a reliable option for the initial empirical therapy of serious nosocomial infections in children. However, later studies have shown the emergence of carbapenem-resistant Gram-negative bacteria after 2008. PMID- 24496345 TI - Dominant causes of urinary tract infections at the Clinic for Infectious Diseases Tuzla. AB - AIM: To determine the prevalence and antimicrobial resistance of dominant causes of urinary tract infections (UTI) in patients treated at the Clinic for Infectious Diseases, University Clinical Center Tuzla during the period January 2010 to June 2011. METHODS: This prospective study included 438 patients divided into three groups: hospital-treated patients group (H-T), outpatient- treated group (O-T) and patients with hospital-acquired (H-A) UTI. Identification of UTI causes completed using standard microbiological methods; antimicrobial susceptibility was done by disc-diffusion method according to the CLSI. RESULTS: E. coli was significantly more commonly isolated in females H-T, 111 (68-1%) (p=0.012) and O-T, 148 (82.7%) (p=0.006) groups, as well as in females less than 65 years from the H-T, 87 (84.5%) (p=0.000) and H-A, four (40%) (p=0.044) groups. Klebsiella pneumoniae and Pseudomonas aeruginosa were significantly more commonly isolated in male H-T, 11 (29.7%) (p=0.000) and five (13.5%) (p=0.009), and O-T UTI, two (9.5%) (p=0.009) and three (14.3%) (p=0.000) groups. E. coli showed significantly higher prevalence of resistance to amoxycillin, coamoxiclav, cefuroxime, ceftriaxone, gentamicin and co-trimoxazole in the H-A group comparing to other two groups (p less than 0.05), as well as to ampicillin, amoxycillin and cefixime in the O-T comparing to H-T group (p less than 0.05). CONCLUSION: Empirical antimicrobial therapy should include coamoxiclav, nitrofurantoin, cefepime, and ceftazidime for females less than 65 years old in both H-T and H-A, cefalosporines, co-amoxiclav and nitrofurantoin in O-T UTIs; for females more than 65 years old, cefalosporines, aminoglicosides, and ciprofloxacin, in H-T and O-T UTIs. For H-A UTI in females more than 65 years as well as for all male patients antimicrobial susceptibility testing should be performed. PMID- 24496346 TI - Fluid management in children with diarrhea-related hyponatremic-hypernatremic dehydration: a retrospective study of 83 children. AB - AIM: To investigate serum creatinine and electrolyte status of children with diarrhea-related hyponatremic or hypernatremic dehydration. METHODS: Medical history of 83 patients admitted to the Pediatric Intensive Care Unit of the Konya Education and Research Hospital, Konya, Turkey with diarrhea, dehydration and electrolyte imbalance was retrospectively evaluated according to the degree of dehydration, serum creatinine, electrolytes, blood gas, approaches to the treatment such as content of given fluid, HCO3- and acute periotenal dialysis. Of 65 patients with hyponatremia, 44 (67.7%) were given fluids at appropriate concentration according to their age, and 21 (32.3%) were given fluids at higher concentration. Of 18 hypernatremic patients, 11 (61.1%) were given fluids at appropriate concentration for age, and seven (38.9%) were given fluids at higher concentration. RESULTS: Mean duration of amelioration of serum sodium levels for those admitted with hyponatremia and given fluids at appropriate concentration for age and at higher concentration were 33.9 +/- 28.3 h and 53.7 +/- 31.6 h, respectively. Mean duration of amelioration of serum sodium levels for hypernatremics and given fluids at appropriate concentration for age and at higher concentration were 34.7 +/- 22.1 h and 46.3 +/- 32 h, respectively. Four (4.8%) hyponatremic patients and three (3.6%) with hypernatremia were treated with acute peritoneal dialysis. Mortality rate was 6% (five of all patients). CONCLUSION: The children with severe diarrhea should be closely followed-up as to clinical examination, serum electrolytes, creatinine and blood gases, and because no single intravenous fluid management is optimal for all children, intravenous fluid therapy should be individualized for each patient. PMID- 24496347 TI - The characteristics of patients with chronic hepatitis B in Turkey. AB - AIM: To evaluate the characteristics of patients with hepatitis B virus (HBV) infection and summarize the treatment modalities. METHODS: By September 30, 2011 the data of 7871 HBsAg (+) patients were complied and analysed according to demographic and medical records (age, sex, laboratory tests, treatment with antiviral agents) in thirty centres of Turkey. RESULTS: Of the 7871 patients 3078 (39.1%) were females; mean (standard deviation) age was 35 (14) years, 3180 (40.4%) were HBsAg positive (+) after admission to a hospital, 1488 (18.9%) after blood donation and 967 (11.9%) were found during routine screening. The HBV prevalence among relatives of HBsAg (+) patients was 1764 (22.4%), and most frequently infected family members were siblings and mothers, 4961 (63.0%) and 2149 (27.3%), respectively). Anti-HDV was negative in 7407 94.1% of patients. Three-fourths of the patients 6383 (81.1%) were HBeAg negative (-). Mean (SD) ALT was 85.8 (266.4) U/L. Majority of patients, 5588 (71.0%) were chronic hepatitis-B patients under treatment, while 2283 (29.0%) were asymptomatic carriers without treatment and only 165 (2.1%) of patients were cirrhotic and 6612 (84.0%) of those were compensated. One-third of the patients 2983 (37.9%) were under a combined treatment, while others were under monotherapy. Lamivudine, entecavir and adefovir were the most frequently used oral therapies, used for 2583 (32.8%), 11.6% and 787 (10.0%) of patients, respectively), while 2975 (37.8%) of patients were under interferon treatment. CONCLUSION: Hepatitis B is still a problem in our country. First task of the physicians and our state should be to prevent the development and spread of the disease with education and vaccination programs, safe blood transfusions, and control of barbers. PMID- 24496348 TI - Prognostic markers in patients with decompensated cirrhosis. AB - AIM: To evaluate the easily available laboratory and clinical markers in patients with decompensated cirrhosis and compare their prognostic value. METHODS: The study sample included a group of 80 patients with an established diagnosis of decompensated cirrhosis, hspitalizsed at the Department of Gastroenterohepatology, Clinical Center of the University of Sarajevo, between 2009 and 2011, followed up for 6 months either as outpatients or through repeated hspitalizsation. It was estimated that the accuracy (c-index) of the six variables, laboratory (serum bilirubin, creatinine, International Normalised Ratio (INR) and albumine) and clinical variables (hepatic encephalopathy and ascites) reflect the function of the liver in their ability to predict 6-month mortality. RESULTS: Laboratory values of serum creatinine equvivalent to the area under the receiver operating characteristic curve (AUC) 0.787, 95% CI 0,667 0,898), serum bilirubin (0.701 95% CI 0,582- 0,820), INR (0.647 95% CI 0,526 0,768) and clinical parameter ascites (0.7 95%CI 0,598-0,827), showed a statistically significant prognostic accuracy in predicting six-month mortality, but none of the parameters showed excellent diagnostic accuracy . CONCLUSION: Serum creatinine had the best diagnostic accuracy in predicting 6-month mortality in patients with decompensated cirrhosis and as easily available variable which could be used as predictive parameter in early prognostic assessment ofliver cirrhosis. PMID- 24496349 TI - Does usage of peritonism tests in an emergency department have any benefit? AB - AIM: To evaluate the usage of inspiration, expiration, cough, and heel drop jarring tests that are applied for determination of peritonism in cases with acute abdominal pain. METHODS: A prospective study based on observation of patients between 16-65 years of age and presented to the Emergency Department within a 3-month period starting from June 2007, was conducted. The patients were asked to rate their pain level between "0" and "10". Following the measurement of the vital signs, 4 tests were conducted by an emergency medicine resident. The medical records of all the patients were reviewed after 3 months. Data concerning clinical diagnosis, hospital admission and discharge processes, and surgical results, were all recorded. RESULTS: Seventy-seven patients had peritonism tests performed. Inspiration test was positive in 29 (of 51, 56.9%) patients admitted to the hospital. However, there was no correlation between the cases admitted to the hospital and the other 3 tests (p more than 0.05). Twenty-one (of 34, 61.8%) patients which have been subjected to surgical treatment, showed positive inspiration test results. Surgical treatment was performed on nine (of 11, 81.8%) patients who showed positive results for all 4 tests. CONCLUSION: The applied tests are helpful in determining a serious abdominal disease, particularly alongside findings of rebound, tenderness, and laboratory results. PMID- 24496350 TI - Correlation of atherogenic risk factors with retinal artery occlusion in adults. AB - AIM: To evaluate correlation of atherogenic risk factors between patients with retinal artery occlusion (RAO) and matched population, including those with central RAO and branch RAO. METHODS: Seventy-two participants from 2 groups were evaluated: a group with diagnosed RAO (first group; 45 participants) and a matched control group including those without RAO or any other ophthalmological disease (second group; 27 participants). From those with diagnosed RAO patients with central RAO and patients with branch RAO were evaluated separately. Additional parameters that were observed included body mass index (BMI), blood pressure, fasting glucose levels, triglycerides, LDL and HDL cholesterol fractions levels, presence of metabolic syndrome and hyperlipoproteinemia. RESULTS: There was a significant increase of LDL mean values in the group of patients with RAO. Hypertension (88.9%), hyperlipoproteinemia (68.9%) and metabolic syndrome (53.3%) were significantly more frequent in patients with RAO, while gender and diabetes mellitus were not in direct correlation with the development of RAO. The group of patients with RAO had no significantly higher values of BMI compared to the control. High density lipoprotein fraction was significantly higher in the group of patients with central RAO as compared with those with branch RAO. CONCLUSION: Patients with atherogenic risk factors are more prone to the development of RAO. Furthermore, we demonstrated that HDL had more protective effects on smaller blood vessels (branch retinal artery) than on larger blood vessels (central retinal artery). PMID- 24496351 TI - Evaluation of central corneal thickness in patients with ocular hypertension and primary open-angle glaucoma. AB - AIM: To determine correlation between central corneal thickness (CCT) and applanation intraocular pressure (IOP) in normal patients with primary open angle glaucoma and patients with ocular hypertension. METHODS: Two-year retrospective study designed to determine correlation between CCT and IOP. Records of 121 patients were included in the study. Inclusion criteria were: IOP higher than 22 mm Hg for a group with ocular hypertension but without functional, morphological damage and progression, diagnosis of glaucoma for a group with open-angle glaucoma and normal ophthalmological results for a control group. Patients who were mono-oculus, patients with secondary glaucoma and who had surgical treatment were excluded. The patients were selectively grouped according to types of glaucoma, by gender and age. The IOP values were measured by Goldman's applanation tonometer, CCT values were determined using ultrasonic pachymeter, in the period from January 2011 to December 2012. RESULTS: Of total 121 subjects, 51 had primary open angle glaucoma (POAG), 40 had ocular hypertension (OHT) and 30 had normal ophthalmological findings (control group). The CCT values in OHT group 529.37+/-25.18 MUm were greater than of both POAG, 501.02+/-14.04 MUm and control group, 497.37+/-14.90 MUm. The IOP values in OHT group were 20.25+/- 3.62 mm Hg, and in POAG group were 18.25+/-2.70 mm Hg, while in the control group they were 13.53+/- 3.62 mm Hg. CONCLUSION: Determination of CCT in patients with glaucoma is crucial, considering its impact on IOP values, which represents a parameter in glaucoma diagnosis, as well as monitoring further progress of ocular hypertension and patients diagnosed with glaucoma. PMID- 24496352 TI - The effect of pseudophakia on retinal and cortical functions. AB - AIM: To investigate the effect of pseudophakia on visual electrophysiology. METHODS: Right eyes of 60 pseudophakic (study group) age- and sex-matched 60 phakic (control group) volunteers were included. Subjects without any ocular and systemic disease, who had visual acuity of more than 9/10 underwent full-field electroretinogram (ERG), pattern electroretinogram (PERG), pattern visual evoked potentials (PVEP) and electro-oculogram (EOG) recordings. RESULTS: The P100 latency to 1o-check was significantly shorter in both pseudophakic groups (study group: 102.98 +/- 6.11, control group: 107.06 +/- 10.70, p=0.012). The P100 amplitude to 15'-check was significantly higher in the pseudophakic groups (study group: 13.96 +/- 7.01, control group: 11.60 +/- 4.69, p: 0.033). Regarding ERG, b wave implicit time in rod response and a-wave implicit time in standard combined response (SCR) were significantly shorter in the pseudophakic group (p=0.017, and less than 0.001, respectively). B-wave amplitude in rod response and a-wave amplitude in SCR were significantly higher in the study group (p less than 0.001 for both). The P1 and N1 amplitude and implicit time differences in 30-Hz flicker response were not significant (p more than 0.05). Conversely, P3/P4 implicit times in oscillatory potentials (OPs) were delayed in the pseudophakic group (p=0.001, and 0.002, respectively). The P1 amplitude increase in OPs in the study group was significant (p less than 0.001). The N95 latency in PERG was significantly delayed (p=0.002) and P50 amplitude was increased (p=0.002) in the pseudophakics. Arden ratio in EOG was similar in both groups (p=0.961). CONCLUSION: Pseudophakia seems to influence ocular electrophysiological tests. Possible causes of these influences in the patients with pseudophakia should be clarified by further studies. PMID- 24496353 TI - Pediatric cataract in Tuzla Canton, Bosnia and Herzegovina. AB - AIM: To estimate incidence and to present descriptive epidemiological data on pediatric cataract in Tuzla Canton, Bosnia and Herzegovina. METHODS: Medical records of all patients hospitalized at the Eye Clinic of the University Clinical Center Tuzla over the 8-year period were retrospectively examined. Prevalence, morphology and type of cataract, its possible etiology and existence of other associated ocular and systemic diseases were analyzed. RESULTS: The study included 87 eyes of 58 children. Average age at presentation was 11.12 (SD +/- 9.03) years. A total of 34 (58.62%) patients were males and twenty-four (41.38%) females. Twentynine (50%) cataracts were unilateral. Thirty-seven (63.79%) patients had isolated cataracts and 24 (29.31%) patients had other ocular anomalies associated with pediatric cataract. High refractive anomalies, nystagmus and microphthalmus were most commonly associated ocular findings. Strabismus was present in 14 (24.13%) cases. Posterior cortical cataract was present in 29 (32.58%) and nuclear cataract in 28 (31.46%) cases. Estimated incidence of congenital cataract was 2.62 per 10.000 births and incidence of pediatric cataract was 8.6 per 10.000 births. CONCLUSION: Prevalence of pediatric cataract in Tuzla Canton is within the worldwide range. Late presentation of children with cataract remains the problem that needs to be addressed. Improved patient education and public awareness are needed in order to change the course of avoidable childhood visual impairment. PMID- 24496354 TI - The use of the Karnofsky index in the assessment of clinical state in patients with chronic subdural hematoma: the first observation from Vojvodina. AB - AIM: To evaluate clinical status of patients with chronic subdural hematoma (CSDH) on hospital admission and to predict their outcome after the neurosurgery treatment using Karnofsky index scale (KI). METHODS: Clinical and surgery data of patients with CSDH were collected prospectively. Fifty 50 adults aged over 41 with CSDH diagnosed and hospitalized between November 2010 and April 2012 were investigated. In the analyzed sample there were more CSDHs in males than in females (1.5:1). The diagnosis of CSDH on hospital admission in patients was confirmed by non-contrast computed tomography (CT). Forty-three patients had undergone surgery with Burr-hole drainage and craniotomy, while seven patients were treated conservatively. The KI was used for evaluation of the patient's clinical state before neurosurgery treatment and the quality of survival in all patients, six months after hospital discharge. RESULTS: A statistically significant difference was found between the KI values in patients with CSDHs on hospital admission and KI after the surgical treatment. Six months after, out of 43 patients who underwent surgery in 24 (55.8%) patients KI was between 80-100%, in nine (20.9%) patients KI was between 50-70% and in 10 (23.2%) patients KI was 0-40%. CONCLUSION: Although the elderly with CSDHs are vulnerable because of their age, associated diseases and risk of recurrence of CSDH, their outcome assessed by KI after surgical treatment was good. The Glasgow Coma Scale (GCS) is used for rapid assessment of the state of consciousness in patients on admission and monitoring of the changes in their condition. KI scale could be used as a complementary assessment tool for the general condition of patients with chronic subdural hematoma. This study highlighted that the KI scale had a predictive value for patient's outcome with chronic subdural hematoma. PMID- 24496355 TI - Acute antibody-mediated rejection of the kidney transplant - experience of a single center in Croatia. AB - AIM: To describe the experience of the Department of Nephrology and Dialysis, University Hospital Rijeka, Croatia, in the treatment of patients with acute humoral rejection (AHR) of kidney transplant by using high dose of intravenous immunoglobulin (IVIG) alone and as a first line treatment. METHODS: Eight kidney transplant recipients in whom the AHR appeared at different time after the transplantation were reported. At the time of transplantation cross-match in all patients was negative for both T and B cells. At the time of presentation, all patients had signs of renal allograft dysfunction and the rejection was proven by biopsy of the kidney transplant with positive C4d-staining and histopathological evidence of antibody-mediated injury. Early rejection was considered within 180 days after the transplantation and the late one 180 days after the transplantation. In two cases plasmapheresis (PAF) with albumin as replacement fluid was performed. Plasma exchange was done with a 35 mL/kg/body weight volume exchange with albumin for six times. RESULTS: Acute humoral rejection was classified as early in three patients and in five as late one. In two patients PAF had been performed as the first line treatment. After the completion of PAF, recuperation of severe graft dysfunction was incomplete and in addition IVIG (as a single dose of 2.0 g/kg) was administered to these patients. In six patients IVIG as a single dose of 2.0 g/kg was applied as the first line treatment. CONCLUSION: Usage of high dose IVIG in the treatment of the acute humoral rejection is efficient, safe and relatively well tolerated. PMID- 24496356 TI - Clinical importance of dependent prognostic factors for renal parenchymal carcinoma and a possibility of predicting the treatment outcome. AB - AIM: To determine an influence of dependent predictors (clinical presentation, stage, pH type) on survival of patients suffering from renal carcinoma. METHODS: The research included 158 patients who had been treated for carcinoma of renal parenchyma in the period between 1 January 1998 and 31 December 2011. A disease stage was determined according to the guidelines of the American Joint Committee on Cancer (AJCC). Prognostic factors were tested by the Cox regression analysis, and dependent prognostic factors were determined based on significance. RESULTS: Patient survival was significantly different in relation to the clinical presentation of the disease (p less than 0.0001). Length of patient survival significantly differs with regard to the clinical stage of the disease (p less than 0.0001). The length of patient survival significantly differs depending on a pathohistological type of cancer (p=0.0027) and after five years it was much longer for patients with the conventional cancer type as compared with the chromophobe type, 80.3% vs. 61.5%, respectively. The total survival rate of patients with renal parenchymal cancer is 81.2% after one year, 77.6% after 5 years and 70.4% after 10 years. CONCLUSION: The manner of detection, clinical stage and pathohistological type of the disease did not meet requirements for independent predictors. Success of the therapeutic treatment depends on the manner of the renal cell carcinoma presentation, pathohistological type and tumor stage. PMID- 24496357 TI - Trends in testicular germ cell cancer incidence in Eastern Croatia. AB - AIM: To investigate a possible association between radioactive and toxic elements contamination, mainly depleted uranium (DU) from the Chernobyl accident, Croatian War of Independence and Bosnian War and the increasing incidence of testicular germ cell cancers (TGCC) in the population of Eastern Croatia. METHODS: From 1969 to 2012, 258 testicular cancer (TC) patients were treated at the Department of Urology, University Hospital Centre Osijek. Incomplete data were found in 32 patients who were excluded from the analysis and 10 patients had non-TGCC TC. Seminoma and non-seminoma groups were included out of 216 TGCC patients. The patients were assigned to one of the time periods: 1969-1995 (distant prewar and war period) and 1996- 2012 (postwar period). RESULTS: In the postwar period 3.5 times higher incidence rate for non-seminomas (4.5 patients yearly vs. 1.3), seminomas (4.2 vs. 1.2) and TGCC overall (8.7 vs. 2.5) was found compared to the prewar period, with non-seminoma presenting in more advanced stage III (35.5% vs. 13.9%, p=0.013). CONCLUSION: Usage of depleted uranium in armed conflicts could lead to the development of TGCC after unknown time of latency. Exposure assessment is mandatory to determine a possible causative correlation between the depleted uranium exposure and testicular germ cell cancer. PMID- 24496358 TI - Management of aseptic non-unions of the distal third of the tibial diaphysis using static interlocking intramedullary nailing. AB - AIM: To evaluate the management of aseptic non-unions of the distal third of the tibial diaphysis, using static interlocking intramedullary nailing. METHODS: Between January 2005 and November 2012, a total number of 42 patients who underwent surgery at our hospital for aseptic non-unions of the distal third of the tibial diaphysis, were included in our study. Preoperatively, all the patients were tested for the presence of infection of non-union. The post operative follow up was based on clinical and radiological findings. RESULTS: Union was achieved in 41 (98%) patients, at a mean time of 5.8 months (four-eight months). One (2%) patient developed infection of the wound four weeks after the operation. A small decrease of the tibial length, of about one cm was seen in three (7%) patients. Pain of the patellar tendon, at the entry point of the nail, was observed in six (14%) patients, without impacting the range of motion of the knee. In two (5%) patients, a decrease in dorsiflexion of the ankle joint occurred, of about ten degrees angle. CONCLUSION: Static interlocking intramedullary nailing is the preferable technique in the management of aseptic non-unions of the distal third of the tibial diaphysis, because it provides high union rate and few postoperative complications. A good preoperative evaluation for infections, use of proper surgical technique with respect to soft tissues, use of autogenous bone grafts and early mobilization of patients, are the keys to success of this method. PMID- 24496359 TI - Hydronephrosis during pregnancy: how to make a decision about the time of intervention? AB - AIM: To evaluate the role of doppler ultrasonographorin managing hydronephrosis during pregnancy. METHODS: The study included 27 pregnant patients with unilateral symptomatic persistent hydronephrosis (group 1) and 38 pregnant patients with physiological hydronephrosis of pregnancy (group 2). All pregnant patients underwent Doppler Ultrasonography to determine the Resistive Index (RI) and the difference between the RI of the corresponding and contralateral kidney (Delta Resistive Index = delta RI). RESULTS: There were no statistical differences between the two groups in terms of age, mean gestational period, or number of pregnancies. The mean renal RI of the hydronephrosis side was 0.68 +/- 0.05 in group 1 and 0.60 +/- 0.05 in group 2 (p less than 0.001). The mean delta RI of group 1 was significantly higher than the mean delta RI of group 2 (0.07 +/ 0.03 versus 0.02 +/- 0.01, respectively, p less than 0.001). The RI and delta RI were considered positive with values of more than 0.70 and more than 0.04, respectively, and the RI was sensitive in 44.4% and specific in 92.1% for intervention treatment. The corresponding values for delta RI were 88.9% and 89.5%. The positive predictive value and negative predictive value of delta RI for intervention were 85.7% and 91.9%, respectively. CONCLUSION: It is much better to consider delta RI than RI when deciding on interventional treatment in hydronephrosis during pregnancy. PMID- 24496360 TI - Evaluation of the association of vitamin D deficiency with gonadotropins and sex hormone in obese and non-obese women with polycystic ovary syndrome. AB - AIM: To evaluate the association of vitamin D (VD) deficiency with gonadotropins and sex hormone in obese and non-obese women with polycystic ovary syndrome (PCOS). METHODS: Of the total of 140 women, thirty obese and thirty nonobese, aged 20-40 years, were included in the study. Inclusion criteria were the women with normal level of thyroid-stimulating hormone (TSH), prolactin (PRL), parathyroid hormone (PTH), and calcium, and those who had not received any medication or VD supplementation within the last 6 months. Serum 25- hydroxyvitamin D (25(OH)D), C-reactive protein (CRP), lipid profile, fasting serum glucose, basal insulin, homeostasis model analysis of insulin resistance (HOMA-IR) index, follicle-stimulating hormone (FSH), luteinizing hormone (LH), oestrogen, total testosterone, dehidroepiandrostendion-sulphat (DHEA-S), androstendione, and sex hormone binding globulin (SHBG) were determined at follicular phase. RESULTS: Body mass index (BMI), weight, waist, lipids, and CRP were significantly higher in obese than in non-obese PCOS women (p=0.000). Meanwhile, insulin and HOMA-IR were also higher in the obese PCOS (p less than 0.000), and so was the fasting glucose (p=0.004). Furthermore, obese PCOS showed significantly higher level of LH (p=0.012), but lower level of progesterone (p=0.001) and androstendione (p=0.006) than in non-obese PCOS. In total 68% of PCOS women had VD deficiency but without significant difference among groups according to BMI. There was no association of VD deficiency with gonadotropins and sex hormones except SHBG. CONCLUSION: Insulin resistance was a better independent risk factor for the presence of vitamin D deficiency than SHBG. The insulin resistance and vitamin D deficiency significantly predicted the obesity risk in PCOS women. PMID- 24496361 TI - Basic cognitive functions across the menstrual cycle in a controlled female cohort. AB - AIM: To investigate the role of sex hormones in the modulation of specific cognitive functions across the menstrual cycle of young healthy women, and to apply improved study design by addressing limitations recognized in previous studies. METHODS: A homogenous group of 16 young healthy women, with no history of health problems related to menstrual cycle, major psychiatric and neurological disorders or addictions was included in study. All participants were medical students of similar age (21.56 +/- 0.15 year). They were subjected to various cognitive tasks at three different phases of the menstrual cycle: early follicular phase, proven ovulatory phase and mid-luteal phase. Special concern was taken to validate blood hormone levels and to determine preovulatory luteinizing hormone (LH)-peak. RESULTS: Analysis of blood hormone levels confirmed that the test sessions were performed at appropriate time points. Most women were presented with the above average results on utilized cognitive tasks, with no significant changes in immediate memory, working memory, delayed recall, verbal learning, delayed verbal learning or verbal fluency in any phase of the menstrual cycle. In addition, test results did not correlate to measured hormone levels. CONCLUSIONS: The results suggest that changes in estrogen and progesterone levels during each menstrual cycle did not affect women's everyday functioning to any significant extent. PMID- 24496362 TI - Assessment of effects of ultrasound therapy on reduction of pain in gonarthrosis. AB - AIM: To examine the effects of sonotherapy on the activities of daily living or as well as the reduction of pain in gonarthrosis. METHODS: A retrospective- prospective clinical study included 63 patients, 47 to 86 years old with a verified diagnosis of gonarthrosis. Subjects were divided into two groups. The first group included 26 patients treated with kinesitherapy in combination with electrotherapy; the second group included 37 patients treated with kinesitherapy combined with sonotherapy. The age, sex, activities of daily living by Barthel Index and the intensity of pain by visual pain scale (VAS) was analyzed at admission and discharge of the patients. RESULTS: Both groups were matched for age, sex, and Barthel index values at admission and discharge. There was no statically significant difference between the groups according to demogrfphic characteristics. Visual pain scale at admission was almost identical in both groups; VAS at discharge waa lower in the group treated with kinesiotherapy and sonotherapy. Visual pain scale at discharge was lower in both groups than at admission, but without statisticay difference (p more than 0.05). CONCLUSION: Sonotherapy and electrotherapy improved the activities of patien's' lives. Both types of therapy, in combination with kinesitherapy, led to a decrease of pain in patients with gonarthrosis. PMID- 24496363 TI - By estimating dominant force on femoral neck fracture's crevice reliability of the fracture's classification increases. AB - AIM: To ensure a more reliable classification system for the femur neck fractures by estimating pressure and tensile force on the fracture crevice. METHODS: The study compared the kappa coefficient for the inter and intraobserver agreement of the same five observers on the same radiographic sample of the femur neck fracture with a time gap of one year for the AO group and original proposal of estimated dominant pressure and tensile force on the femur neck fracture's crevice. RESULTS: The kappa coefficient for the AO group was 0.49 and for the system for estimating the dominant force on the fracture's crevice it was 0.78. For the observer our proposal is easier to use than the AO system. CONCLUSION: The estimation system of the dominant force on the fracture's crevice is more reliable and thus more acceptable than the AO group system for femoral neck fractures. PMID- 24496364 TI - Calcaneal bone mineral density and dietary calcium intake in healthy adults from eastern Croatia: what difference do gender and age make? AB - AIM: Adequate nutrition supports optimal bone development and prevents later metabolic bone diseases. The aim of this study was to assess calcium dietary intake and measure calcaneal bone mineral density and based on the obtained values to evaluate gender and age impact on the values itself as well as on their correlation. METHODS: Subjects recruited for this study were 120 healthy adults. Calcaneal bone mineral density was measured by quantitative ultrasound and expressed as estimated bone mineral density (eBMD). Calcium intake was assessed using ten 24-hours recalls. RESULTS: Values were compared between age and gender based sub-groups. The average value of eBMD of the study group was 0.543 g/cm2. There was no difference between females and males in eBMD. The average daily dietary intake of calcium was low (661 mg/day), and males had statistically significantly higher daily dietary intake than females (805 mg/day and 599 mg/day, respectively). The younger group had higher average value for eBMD (0.560 g/cm2), and higher dietary intake of calcium (10.5 mg/kg of body weight) than the older group (eBMD=0.527 g/cm2; calcium intake=9.4 mg/kg of body weight), but the difference was not significant. CONCLUSION: Lack of statistically significant difference in eBMD values between two observed study subgroups based on the years of age, and low eBMD value itself, are obvious evidence of the compromised bone health status within the study population as well as the need for preventive actions. PMID- 24496365 TI - The impact of body weight on aerobic capacity. AB - AIM: To determine the relationship between body mass index (BMI) and predicted values of VO2max estimated by UKK test for the first degree of obesity. METHODS: The participants were included in three groups of ten male subjects each, of different ages and different physical condition, randomly selected from the general population of the city of Kragujevac. BMI was determined first, and then the Urho Kaleva Kekonen (UKK) test on treadmill was performed in order to get a predicted value of cardiovascular capacity (VO2max) of respondents. For continuous variables collected, the mean values and standard deviation were determined, and the correlation coefficient was calculated using the Student test. RESULTS: After a correlation analysis value obtained by UKK VO(2)max test and BMI the negative correlation coefficient (r = - 0.904; p less than 0.001) for the third group (ten males aged 35-40 years with mean BMI of 32.2 +/- 1.31) was found, which also found an inverse dependence of these two values (with an increase of BMI values, the values of VO2max decreased). In the third group, the first fitness category dominated (Fitness index less than 70, which is significantly below the average value). The aim is to improve VO2max values, so the Fitness index value belonging to the Fitness category III dominated meaning that the Fitness index values were in the range 90-100 (mean). CONCLUSION: A significant negative correlation between BMI and VO2max (ml/kg/min) suggesting the possibility of effect or body fat on cardiorespiratory function. PMID- 24496366 TI - Quality of life for tobacco smokers in relation to their socioeconomic status. AB - AIM: To analyze differences in quality of life between smokers and non-smokers in relation to socioeconomic factors. METHODS: This study was conducted on a sample of 600 respondents equally divided in two groups, smokers (300) and non-smokers (300). Former smokers were excluded. The study included both sexes equally further distributed into age groups: 19-34, 35- 49, 50-64 and 65-70 years. A questionnaire SF-36 to test the quality of life (36 questions measuring eight dimensions of quality of life) and questionnaire EuroQoL to examine the socioeconomic status was used. For the assessment of a given factor impact multivariant and univariant analyses of variance were used. RESULTS: A significant difference in the quality of life between smokers and non-smokers according to the gender was found, but only at the subscales of physical functioning and bodily pain (p=0.000). An analysis of individual dimensions of quality of life in relation to marital status of smokers and non-smokers showed significant differences on the subscales of physical functioning (p=0.032), vitality (p=0.0430) and mental health (p=0.016). An analysis of life quality in relation to smoking status of respondents and the average monthly income showed that the average scores on all subscales were higher in non-smokers compared to smokers (p=0.000) and they were increased with the average monthly income. CONCLUSION: The results of this study prove that there are significant differences in quality of life according to the smoking status. Also the socioeconomic factors which include age, gender, the surrounding, marital status, employment, total monthly income and level of education are of great influence on the quality of life with significant differences in relation to smoking status. PMID- 24496367 TI - Outpatient consumption of antibiotics in the City of Zagreb (2006-2010). AB - AIM: To investigate outpatient consumption of antibiotics during the 2006-2010 period in the City of Zagreb and compare it with other European countries. METHODS: Data on outpatient consumption of antibiotics were obtained from all pharmacies in the City of Zagreb. Based on the data obtained, the number of defined daily doses per 1000 inhabitants per day (DDDs/TID) were calculated for each ATC subgroup. Drug Utilization 90% (DU90%) method and ratio indicators were used for the assessment of drug prescribing quality. RESULTS: During the period of five years total antibiotics consumption has declined from 37.38 DDDs/TID in 2006 to 33.28 DDDs/ TID in 2010. The most frequently prescribed subgroup was penicillins (J01C). DU90% segment included 10 out of a total of 32 antibiotics in the year 2006 and 10 out of a total of 23 antibiotics in the year 2010. Leading position in the consumption, in 2006 and 2010, was held by broad-spectrum antibiotics, moreover their consumption increased in 2010. CONCLUSION: Consumption of antibiotics in Zagreb is still very high and is similar to the consumption in European countries with the highest consumption of antibiotics. Reduced consumption of narrow-spectrum antibiotics and unjustified increase in the consumption of broad-spectrum antibiotics suggess that physicians do not follow clinical guidelines. PMID- 24496368 TI - Practical tool to assess reliability of web-based medicines information. AB - AIM: Information disseminated by medicines information systems is not always easy to apply. Nowadays internet provides access to enormous volume and range of health information that was previously inaccessible both for medical specialists and consumers. The aim of this study is to assess internet as a source of drug and health related information and to create test methodology to evaluate the top 10 visited health-related web-sites in Bulgaria. METHODS: Using existing scientific methodologies for evaluation of web sources, a new algorithm of three step approach consisting of score-card validation of the drug-related information in the 10 most visited Bulgarian web-sites was created. RESULTS: In many cases the drug information in the internet sites contained errors and discrepancies. Some of the published materials were not validated; they were out-of-date and could cause confusion for consumers. CONCLUSION: The quality of the online health information is a cause for considerable information noise and threat to patients' safety and rational drug use. There is a need of monitoring the drugs information available online in order to prevent patient misinformation and confusion that could lead to medication errors and abuse. PMID- 24496369 TI - Lorenz Heister's handbook of surgery in the Franciscan monastery in Pazin. AB - The oldest library in Istria (Croatia) is located in the Franciscan Monastery of Pazin, with a rich fund of worthy old books. Our attention was attracted by the book "Chirurgie" written by the German physician, surgeon and anatomist Lorenz Heister in the first half of the 18th century. This worthy book is relatively scanty known in Croatian history of surgery. By studying the contents of the book written in the 18th century, numerous surgical instruments, as well as surgical operations may be found, many of them being used even today with little modifications. Among the instruments different types of pincers, needles, scissors, knives, saws, hammers, chisels and others can be found. The description of different surgical procedures reveals great advancement in the surgical technique. The book was very popular in Europe for a century. PMID- 24496370 TI - Does individual dietary intervention have any impact on adolescents with cardiovascular health risks? AB - The study was aimed at assessing eating habits of adolescent population, diagnosed with one or more cardiovascular risks (CVR) before and two months after the individual dietary intervention. Food frequency questionnaire, anthropometric measurements, blood pressure and biochemical measurements with individual nutrition education were conducted on a group of 17 adolescents aged 14.5 years. Total calorie intake, proteins, total and saturated fats, cholesterol, total and simple carbohydrates and sodium decreased, while fiber intake increased significantly. Significant decrease showed mean body mass index, total cholesterol, LDL, TAG, and blood pressure. The individual dietary education resulted in a positive shift in eating habits as well as CVR values. PMID- 24496371 TI - Challenges in the diagnosis and treatment of recurrent non-resolving pneumonia - the case of foreign body aspiration in adult mimicking lung neoplasm. AB - Foreign-body tracheobronchial aspiration in adults is fairly rare, and it is caused mostly by the failure of airway protective mechanisms. The symptoms of this clinical entity can mimic many other respiratory diseases, such as recurrent or non-resolving pneumonia, asthma, lung neoplasm etc. Flexible bronchoscopy was indicated in this situation, both for diagnostic and therapeutic purposes. We are reporting on a case of a fiftythree- year old women with recurrent, non-resolving pneumonia, recurrent hemoptysis, dyspnea, fiver, chest pain and radiological presentation of middle lobe neoplasm caused by aspirated chicken neck bone. PMID- 24496372 TI - Papillary thyroid carcinoma in a female patient with squamous cell carcinoma of the larynx. AB - The larynx and thyroid gland are the most common sites for head and neck malignancies. The existence of two primary cancers are rare and especially if they are in the same region, and both are very invasive. Subglotic laryngeal cancer is the rarest, with only 1% frequency of all laryngeal cancers. We are reporting on a case of a forty-seven- year-old female urgently admitted to the Ear, Nose and Throat (ENT) Clinic in Tuzla, with severe respiratory insufficiency. The patient underwent total laryngectomy, total thyreoidectomy, radical and functional neck dissection. Histological examination showed laryngeal squamous cell carcinoma and papillary thyroid carcinoma. PMID- 24496373 TI - Bradbury-Eggleston syndrome - an unusual cause of gastroesophageal reflux disease (GERD). AB - The report presents a case of a 46-year-old male patient, previously treated because of dysphagia, pyrosis, vertigo while standing up and impotency. Manometric and pH-metric analysis showed presence of gastroesophageal reflux disease (GERD) caused by transient relaxation of lower esophageal sphincter (TRLES). Heart-rate variability showed decreased sympathetic function. Electromyoneurography showed a neurological lesion in muscles of upper extremities. The patient received midodrine and clonazepam which resolved this condition. These findings suggest that a neurological disorder can be a cause of GERD. PMID- 24496374 TI - Necessity of antihypertensive therapy with alpha-methyldopa for pregnant women with hypertensive disorders after 36 weeks of gestation. PMID- 24496375 TI - Diastereoselective synthesis of a [2]catenane from a pillar[5]arene and a pyridinium derivative. AB - We synthesized a new [2]catenane composed of a pillar[5]arene ring and a pyridinium derivative using ring-closing metathesis. PMID- 24496376 TI - Novel missense mutation C106R in the PROC gene associated with type I protein C deficiency in a young Polish man with high-risk pulmonary embolism. PMID- 24496377 TI - What Is Lacking in Patient-Physician Communication: Perspectives from Asian American Breast Cancer Patients and Oncologists. AB - OBJECTIVES: Interactions between breast cancer patients and their oncologists are important as effective patient-physician communication can facilitate the delivery of quality cancer care. However, little is known about patient-physician communication processes among Asian American breast cancer patients, who may have unique communication needs and challenges. Thus, we interviewed Asian American patients and several oncologists to explore patient-physician communication processes in breast cancer care. METHODS: We conducted in-depth interviews with nine Chinese- or Korean American breast cancer patients and three Asian American oncologists who routinely provided care for Asian American patients in the Washington DC metropolitan area in 2010. We conducted patient interviews in Chinese or Korean and then translated into English. We conducted physicians' interviews in English. We performed qualitative analyses to identify themes. RESULTS: For women with limited English proficiency, language was the greatest barrier to understanding information and making treatment-related decisions. Both patients and oncologists believed that interpretation provided by patients' family members may not be accurate, and patients may neglect to ask questions because of their worry of burdening others. We observed cultural differences regarding expectations of the doctor's role and views of cancer recovery. As expressed by the patients and observed by oncologists, Asian American women are less likely to be assertive and are mostly reliant on physicians to make treatment decisions. However, many patients expressed a desire to be actively involved in the decision-making process. CONCLUSION: Findings provide preliminary insight into patient-physician communication and identify several aspects of patient-physician communication that need to be improved for Asian American breast cancer patients. Proper patient education with linguistically and culturally appropriate information and tools may help improve communication and decision-making processes for Asian American women with breast cancer. PMID- 24496379 TI - Synthesis and microwave absorption enhancement of graphene@Fe3O4@SiO2@NiO nanosheet hierarchical structures. AB - Hierarchical structures of graphene@Fe3O4@SiO2@NiO nanosheets were prepared by combining the versatile sol-gel process with a hydrothermal reaction. Graphene@Fe3O4 composites were first synthesized by the reduction reaction between FeCl3 and diethylene glycol (DEG) in the presence of GO. Then, graphene@Fe3O4 was coated with SiO2 to obtain graphene@Fe3O4@SiO2. Finally, NiO nanosheets were grown perpendicularly on the surface of graphene@Fe3O4@SiO2 and graphene@Fe3O4@SiO2@NiO nanosheet hierarchical structures were formed. Moreover, the microwave absorption properties of both graphene@Fe3O4 and graphene@Fe3O4@SiO2@NiO nanosheets were investigated between 2 and 18 GHz microwave frequency bands. The electromagnetic data demonstrate that graphene@Fe3O4@SiO2@NiO nanosheet hierarchical structures exhibit significantly enhanced microwave absorption properties compared with graphene@Fe3O4, which probably originate from the unique hierarchical structure with a large surface area and high porosity. PMID- 24496378 TI - Regulating the transport of DNA through biofriendly nanochannels in a thin solid membrane. AB - Channels formed by membrane proteins regulate the transport of water, ions or nutrients that are essential to cells' metabolism. Recent advances in nanotechnology allow us to fabricate solid-state nanopores for transporting and analyzing biomolecules. However, uncontrollable surface properties of a fabricated nanopore cause irregular transport of biomolecules, limiting potential biomimetic applications. Here we show that a nanopore functionalized with a self assembled monolayer (SAM) can potentially regulate the transport of a DNA molecule by changing functional groups of the SAM. We found that an enhanced interaction between DNA and a SAM-coated nanopore can slow down the translocation speed of DNA molecules and increase the DNA capture-rate. Our results demonstrate that the transport of DNA molecules inside nanopores could be modulated by coating a SAM on the pore surface. Our method to control the DNA motion inside a nanopore may find its applications in nanopore-based DNA sequencing devices. PMID- 24496380 TI - Single-point mutation detection in RNA extracts using gold nanoparticles modified with hydrophobic molecular beacon-like structures. AB - Gold nanoparticles functionalized with oligonucleotides that bear a cholesterol group are used as gene sensors. The hydrophobic molecule is buried inside the nanostructure but when the complementary RNA sequence is present the structure unfolds exposing the cholesterol group to the water molecules. This rearrangement leads to the aggregation of the nanostructures. PMID- 24496381 TI - BET bromodomain proteins are required for glioblastoma cell proliferation. AB - Epigenetic proteins have recently emerged as novel anticancer targets. Among these, bromodomain and extra terminal domain (BET) proteins recognize lysine acetylated histones, thereby regulating gene expression. Newly described small molecules that inhibit BET proteins BRD2, BRD3, and BRD4 reduce proliferation of NUT (nuclear protein in testis)-midline carcinoma, multiple myeloma, and leukemia cells in vitro and in vivo. These findings prompted us to determine whether BET proteins may be therapeutic targets in the most common primary adult brain tumor, glioblastoma (GBM). We performed NanoString analysis of GBM tumor samples and controls to identify novel therapeutic targets. Several cell proliferation assays of GBM cell lines and stem cells were used to analyze the efficacy of the drug I BET151 relative to temozolomide (TMZ) or cell cycle inhibitors. Lastly, we performed xenograft experiments to determine the efficacy of I-BET151 in vivo. We demonstrate that BRD2 and BRD4 RNA are significantly overexpressed in GBM, suggesting that BET protein inhibition may be an effective means of reducing GBM cell proliferation. Disruption of BRD4 expression in glioblastoma cells reduced cell cycle progression. Similarly, treatment with the BET protein inhibitor I BET151 reduced GBM cell proliferation in vitro and in vivo. I-BET151 treatment enriched cells at the G1/S cell cycle transition. Importantly, I-BET151 is as potent at inhibiting GBM cell proliferation as TMZ, the current chemotherapy treatment administered to GBM patients. Since I-BET151 inhibits GBM cell proliferation by arresting cell cycle progression, we propose that BET protein inhibition may be a viable therapeutic option for GBM patients suffering from TMZ resistant tumors. PMID- 24496382 TI - Collagen hydrolysates increased osteogenic gene expressions via a MAPK signaling pathway in MG-63 human osteoblasts. AB - The present study investigated the effects of CHs on osteogenic activities and MAPK-regulation on bone matrix gene expressions. The effects of CHs on cell proliferation, alkaline phosphatase (ALP) activity, collagen synthesis, and mineralization were measured in human osteoblastic MG-63 cells. Activation of MAPKs and downstream transcription factors such as extracellular-signal-regulated kinase 1/2 (ERK1/2), c-Jun N-terminal kinase 1/2 (JNK1/2), p38, ELK1, and cJUN was examined using Western blot analysis. The expressions of osteogenic genes were measured by quantitative real-time PCR. CHs dose-dependently increased MG-63 cell proliferation, ALP activity, collagen synthesis, and calcium deposition. CHs activated ERK1/2, JNK1/2, p38, and ELK1 phosphorylation except cJUN. The COL1A1 (collagen, type I, alpha 1), ALPL (alkaline phosphatase), BGLAP (osteocalcin), and SPP1 (secreted phosphoprotein 1, osteopontin) gene expressions were increased by CH treatment. The ERK1/2 inhibitor (PD98509) blocked the CH-induced COL1A1 and ALPL gene expression, as well as ELK1 phosphorylation. The JNK1/2 inhibitor (SP600125) abolished CH-induced COL1A1 expression. The p38 inhibitor (SB203580) blocked CH-induced COL1A1 and SPP1 gene expression. In conclusion, CH treatment stimulates the osteogenic activities and increases bone matrix gene expressions via the MAPK/ELK1 signaling pathway. These results could provide a mechanistic explanation for the bone-strengthening effects of CHs. PMID- 24496385 TI - Allowing patients to choose the ethnicity of attending doctors is institutional racism. PMID- 24496383 TI - Synthetic lethal therapy for KRAS mutant non-small-cell lung carcinoma with nanoparticle-mediated CDK4 siRNA delivery. AB - The KRAS mutation is present in ~20% of lung cancers and has not yet been effectively targeted for therapy. This mutation is associated with a poor prognosis in non-small-cell lung carcinomas (NSCLCs) and confers resistance to standard anticancer treatment drugs, including epidermal growth factor receptor tyrosine kinase inhibitors. In this study, we exploited a new therapeutic strategy based on the synthetic lethal interaction between cyclin-dependent kinase 4 (CDK4) downregulation and the KRAS mutation to deliver micellar nanoparticles (MNPs) containing small interfering RNA targeting CDK4 (MNPsiCDK4) for treatment in NSCLCs harboring the oncogenic KRAS mutation. Following MNPsiCDK4 administration, CDK4 expression was decreased, accompanied by inhibited cell proliferation, specifically in KRAS mutant NSCLCs. However, this intervention was harmless to normal KRAS wild-type cells, confirming the proposed mechanism of synthetic lethality. Moreover, systemic delivery of MNPsiCDK4 significantly inhibited tumor growth in an A549 NSCLC xenograft murine model, with depressed expression of CDK4 and mutational KRAS status, suggesting the therapeutic promise of MNPsiCDK4 delivery in KRAS mutant NSCLCs via a synthetic lethal interaction between KRAS and CDK4. PMID- 24496384 TI - Enriched protein screening of human bone marrow mesenchymal stromal cell secretions reveals MFAP5 and PENK as novel IL-10 modulators. AB - The secreted proteins from a cell constitute a natural biologic library that can offer significant insight into human health and disease. Discovering new secreted proteins from cells is bounded by the limitations of traditional separation and detection tools to physically fractionate and analyze samples. Here, we present a new method to systematically identify bioactive cell-secreted proteins that circumvent traditional proteomic methods by first enriching for protein candidates by differential gene expression profiling. The bone marrow stromal cell secretome was analyzed using enriched gene expression datasets in combination with potency assay testing. Four proteins expressed by stromal cells with previously unknown anti-inflammatory properties were identified, two of which provided a significant survival benefit to mice challenged with lethal endotoxic shock. Greater than 85% of secreted factors were recaptured that were otherwise undetected by proteomic methods, and remarkable hit rates of 18% in vitro and 9% in vivo were achieved. PMID- 24496386 TI - Sensitivity and specificity of dosing alerts for dosing errors among hospitalized pediatric patients. AB - OBJECTIVES: To determine the sensitivity and specificity of a dosing alert system for dosing errors and to compare the sensitivity of a proprietary system with and without institutional customization at a pediatric hospital. METHODS: A retrospective analysis of medication orders, orders causing dosing alerts, reported adverse drug events, and dosing errors during July, 2011 was conducted. Dosing errors with and without alerts were identified and the sensitivity of the system with and without customization was compared. RESULTS: There were 47,181 inpatient pediatric orders during the studied period; 257 dosing errors were identified (0.54%). The sensitivity of the system for identifying dosing errors was 54.1% (95% CI 47.8% to 60.3%) if customization had not occurred and increased to 60.3% (CI 54.0% to 66.3%) with customization (p=0.02). The sensitivity of the system for underdoses was 49.6% without customization and 60.3% with customization (p=0.01). Specificity of the customized system for dosing errors was 96.2% (CI 96.0% to 96.3%) with a positive predictive value of 8.0% (CI 6.8% to 9.3). All dosing errors had an alert over-ridden by the prescriber and 40.6% of dosing errors with alerts were administered to the patient. The lack of indication-specific dose ranges was the most common reason why an alert did not occur for a dosing error. DISCUSSION: Advances in dosing alert systems should aim to improve the sensitivity and positive predictive value of the system for dosing errors. CONCLUSIONS: The dosing alert system had a low sensitivity and positive predictive value for dosing errors, but might have prevented dosing errors from reaching patients. Customization increased the sensitivity of the system for dosing errors. PMID- 24496387 TI - Vein diameter after intraoperative dilatation with vessel probes as a predictor of success of hemodialysis arteriovenous fistulas. AB - BACKGROUND: Vascular access is "the life line" for patients on chronic hemodialysis. The autogenous arteriovenous fistula provides the best access to the circulation because of low complication rate, long-term use, and lower cost, compared to arteriovenous graft and central venous catheter. The primary objective of this prospective study was to investigate the predictive value of vein diameter after intraoperative dilatation with vessel probes on hemodialysis fistula maturation. MATERIAL AND METHODS: Ninety-three fistulas were performed by a single surgeon from February 1, 2006 to January 31, 2009. Intraoperative vein dilatation with vessel probes was attempted in all fistulas. Measurements of the feeding artery diameter, vein diameter and the increased vein diameter after intraoperative dilatation were performed and immediate failure, early patency, early failure, primary patency, and fistula survival outcomes were recorded during 48-month follow-up. RESULTS: Early failure occurred in 20% of fistulas and 70% matured sufficiently for cannulation. Variables with significant impact on the failure to mature by univariate analysis were: body-mass index (P=0.041), artery diameter (P<0.001), vein diameter (P=0.004), and vein diameter after dilatation (P=0.002). However, but multivariate analysis showed that only body mass index (P=0.038), artery diameter (P=0.001), and the diameter of the vein after dilatation (P=0.018) significantly affected maturation. In a group of 56 (60%) patients with vein diameter before dilatation <= 2 mm, among vessel characteristics found by multivariate analysis, only vein diameter after dilatation (P=0.004) significantly affected function. CONCLUSIONS: Artery diameter and vein diameter after intraoperative dilatation with vessel probes were the main predictors of fistula function. PMID- 24496388 TI - ER-Golgi transport: authors' response. PMID- 24496389 TI - ER-Golgi transport could occur in the absence of COPII vesicles. PMID- 24496390 TI - Shining light on autophagy. PMID- 24496391 TI - Clinical associations and causes of convexity subarachnoid hemorrhage. AB - BACKGROUND AND PURPOSE: It has been previously found noted that ~15% to 20% of subarachnoid hemorrhage (SAH) is nonaneurysmal. Nontraumatic convexity SAH (cSAH) is increasingly recognized. Data concerning incidence and associations are scant. METHODS: We identified all SAH-coded cases from South Australian public hospitals between January 2005 and July 2011. Electronic discharge summaries were reviewed, and cases of cSAH were ascertained. Clinical and radiological features were recorded, and pathogenesis was assigned. RESULTS: Of 742 cases with SAH, 41 (6%) cases were cSAH, giving a minimum population annual incidence of 5.1 per million (95% confidence interval, 3.7-7.0). Median age was 70 years (interquartile range, 48-79). Commonest causes were cerebral amyloid angiopathy (39%), reversible cerebral vasoconstriction syndrome (17%), cerebral venous sinus thrombosis (10%), large-vessel stenotic atherosclerosis (10%), and posterior reversible encephalopathy syndrome (5%). No cause was identified in 20% (mostly elderly patients with incomplete evaluation). Most (63%) presented with transient neurological symptoms. Many (49%) were misdiagnosed as transient ischemic attacks and treated inappropriately with antithrombotics. CONCLUSIONS: cSAH comprises a significant proportion of SAH. Commonest causes are cerebral amyloid angiopathy in the elderly and reversible cerebral vasoconstriction syndrome in the young, but differential diagnosis is broad. Misdiagnosis is common and leads to potentially harmful treatments. PMID- 24496392 TI - Evaluation of computed tomography angiography plaque thickness measurements in high-grade carotid artery stenosis. AB - BACKGROUND AND PURPOSE: Increasing evidence suggests that carotid artery imaging can identify vulnerable plaque elements that increase stroke risk. We correlated recently proposed markers, soft and hard plaque thickness measurements on axial computed tomography angiography source images, with symptomatic disease status (ipsilateral stroke or transient ischemic attack) in high-grade carotid disease. METHODS: Soft plaque and hard plaque thickness were measured with a recently validated technique using computed tomography angiography source images in subjects with >=70% extracranial carotid artery stenosis. Logistic regression analyses were used to assess the strength of association between soft and hard plaque thickness measurements and previous stroke or transient ischemic attack. Receiver operating characteristic analysis was also performed. RESULTS: Compared with asymptomatic subjects, those with symptomatic carotid disease had significantly larger soft plaque and total plaque thickness measurements and smaller hard plaque thickness measurements. Each 1-mm increase in soft plaque resulted in a 2.7 times greater odds of previous stroke or transient ischemic attack. Soft plaque thickness measurements provided excellent discrimination between symptomatic and asymptomatic disease, with receiver operating characteristic analysis showing an area under the curve of 0.90. A cutoff of 3.5 mm maximum soft plaque thickness provided a sensitivity of 81%, specificity of 83%, positive predictive value of 85%, and a negative predictive value of 78%. CONCLUSIONS: Increasing maximum soft plaque thickness measurements are strongly associated with symptomatic disease status in carotid artery stenosis. Prospective validation of these results may translate into a widely accessible stroke risk stratification tool in high-grade carotid artery atherosclerotic disease. PMID- 24496393 TI - Reliability and validity of the National Institutes of Health Stroke Scale for neuroscience nurses. PMID- 24496394 TI - Essential role of program death 1-ligand 1 in regulatory T-cell-afforded protection against blood-brain barrier damage after stroke. AB - BACKGROUND AND PURPOSE: Our recent research revealed that adoptively transferred regulatory T cells (Tregs) reduced acute ischemic brain injury by inhibiting neutrophil-derived matrix metalloproteinase-9 (MMP-9) and protecting against blood-brain barrier damage. The mechanisms underlying Treg interactions with neutrophils remain elusive. This study evaluates the contribution of program death 1-ligand 1 (PD-L1) to Treg-mediated neutrophil inhibition and neuroprotection after cerebral ischemia. METHODS: In vitro experiments were performed using a transwell system or a coculture system allowing cell-to-cell contact. Focal cerebral ischemia was induced in mice for 60 minutes. Tregs (2*10(6)) isolated from donor animals (wild-type or PD-L1-/-) were intravenously injected into ischemic recipients 2 hours after middle cerebral artery occlusion (MCAO). MMP-9 production, blood-brain barrier permeability, and brain infarct were assessed at 1 or 3 days after MCAO. RESULTS: In vitro experiments reveal that Treg-mediated inhibition of neutrophil MMP-9 required direct cell-to-cell contact. The suppression of MMP-9 was abolished when Tregs were pretreated with PD-L1 neutralizing antibodies or when neutrophils were pretreated with PD-1 antibodies. In vivo studies confirmed that intravenous administration of Tregs pretreated with PD-L1 antibodies or Tregs isolated from PD-L1-deficient mice failed to inhibit MMP-9 production by blood neutrophils 1 day after 60 minutes MCAO. Furthermore, the blood-brain barrier damage after MCAO was greatly ameliorated in PD-L1-competent Treg-treated mice but not in PD-L1-compromised Treg-treated mice. Consequently, PD-L1 dysfunction abolished Treg-mediated brain protection and neurological improvements 3 days after MCAO. CONCLUSIONS: PD-L1 plays an essential role in the neuroprotection afforded by Tregs against cerebral ischemia by mediating the suppressive effect of Tregs on neutrophil-derived MMP 9. PMID- 24496395 TI - Role of preexisting disability in patients treated with intravenous thrombolysis for ischemic stroke. AB - BACKGROUND AND PURPOSE: Little is known about the effect of thrombolysis in patients with preexisting disability. Our aim was to evaluate the impact of different levels of prestroke disability on patients' profile and outcome after intravenous thrombolysis. METHODS: We analyzed the data of all stroke patients admitted between October 2003 and December 2011 that were contributed to the Safe Implementation of Treatments in Stroke-Eastern Europe (SITS-EAST) registry. Patients with no prestroke disability at all (modified Rankin Scale [mRS] score, 0) were used as a reference in multivariable logistic regression. RESULTS: Of 7250 patients, 5995 (82%) had prestroke mRS 0, 791 (11%) had prestroke mRS 1, 293 (4%) had prestroke mRS 2, and 171 (2%) had prestroke mRS>=3. Compared with patients with mRS 0, all other groups were older, had more comorbidities, and more severe neurological deficit on admission. There was no clear association between preexisting disability and the risk of symptomatic intracranial hemorrhage. Prestroke mRS 1, 2, and >=3 were associated with increased risk of death at 3 months (odds ratio, 1.3, 2.0, and 2.6, respectively) and lower chance of achieving favorable outcome (achieving mRS 0-2 or returning to the prestroke mRS; 0.80, 0.41, 0.59, respectively). Patients with mRS>=3 and 2 had similar vascular profile and favorable outcome (34% versus 29%), despite higher mortality (48% versus 39%). CONCLUSIONS: Prestroke disability does not seem to independently increase the risk of symptomatic intracranial hemorrhage after thrombolysis. Despite higher mortality, 1 in 3 previously disabled patients may return to his/her prestroke mRS. Therefore, they should not be routinely excluded from thrombolytic therapy. PMID- 24496396 TI - Structural damage and functional reorganization in ipsilesional m1 in well recovered patients with subcortical stroke. AB - BACKGROUND AND PURPOSE: Both structural atrophy and functional reorganization of the primary motor cortex (M1) have been reported in patients with subcortical infarctions affecting the motor pathway. However, the relationship between structural impairment and functional reorganization in M1 remains unclear. METHODS: Twenty-six patients exhibiting significant recovery after subcortical infarctions were investigated using multimodal MRI techniques. Structural impairment was assessed via cortical thickness, and functional reorganization was analyzed using task-evoked activation, amplitude of low-frequency fluctuation, and resting-state functional connectivity. RESULTS: Compared with healthy controls, patients with stroke exhibited reduced cortical thickness in the ipsilesional M1; however, this region exhibited increased task-evoked activation, amplitude of low-frequency fluctuation, and resting-state functional connectivity in these patients. Patients with stroke demonstrated increased task-evoked activation in another ipsilesional M1 region, in which increased amplitude of low frequency fluctuation and resting-state functional connectivity were observed. The structural and functional changes in M1 were located selectively in the ipsilesional hemisphere. CONCLUSIONS: We provide convincing evidence that indicates extensive functional reorganization in the ipsilesional M1 of patients with chronic subcortical infarctions, including the structurally impaired M1 region. PMID- 24496397 TI - Effects of ionic strength on the antimicrobial photodynamic efficiency of methylene blue. AB - Antimicrobial photodynamic therapy (APDT) may become a useful clinical tool to treat microbial infections, and methylene blue (MB) is a well-known photosensitizer constantly employed in APDT studies, and although MB presents good efficiency in antimicrobial studies, some of the MB photochemical characteristics still have to be evaluated in terms of APDT. This work aimed to evaluate the role of MB solvent's ionic strength regarding dimerization, photochemistry, and photodynamic antimicrobial efficiency. Microbiological survival fraction assays on Escherichia coli were employed to verify the solution's influence on MB antimicrobial activity. MB was evaluated in deionized water and 0.9% saline solution through optical absorption spectroscopy; the solutions were also analysed via dissolved oxygen availability and reactive oxygen species (ROS) production. Our results show that bacterial reduction was increased in deionized water. Also we demonstrated that saline solution presents less oxygen availability than water, the dimer/monomer ratio for MB in saline is smaller than in water and MB presented a higher production of ROS in water than in 0.9% saline. Together, our results indicate the importance of the ionic strength in the photodynamic effectiveness and point out that this variable must be taken into account to design antimicrobial studies and to evaluate similar studies that might present conflicting results. PMID- 24496398 TI - Dietary Patterns and the Risk of Colorectal Cancer. AB - Diet and lifestyle play a significant role in the development of colorectal cancer, but the full complexity of the association is not yet understood. Dietary pattern analysis is an important new technique that may help to elucidate the relationship. This review examines the most common techniques for extrapolating dietary patterns and reviews dietary pattern/colorectal cancer studies published between September 2011 and August 2012. The studies reviewed are consistent with prior research but include a more diverse international population. Results from investigations using a priori dietary patterns (i.e., diet quality scores) and a posteriori methods, which identify existing eating patterns (i.e., principal component analysis), continue to support the benefits of a plant-based diet with some dairy as a means to lower the risk of colorectal cancer, whereas a diet high in meats, refined grains, and added sugar appears to increase risk. The association between colorectal cancer and alcohol remains unclear. PMID- 24496399 TI - The role of n - 6 and n - 3 polyunsaturated fatty acids in the manifestation of the metabolic syndrome in cardiovascular disease and non-alcoholic fatty liver disease. AB - Cardiovascular disease (CVD) and non-alcoholic fatty liver disease (NAFLD) are manifestations of the metabolic syndrome. CVD remains the number one cause of mortality in the West, while NAFLD is the most common liver disease. Growing evidence suggests that polyunsaturated fatty acids (PUFA) influence risk factors including circulating lipids and inflammation on the development of CVD and NAFLD. N - 6 and n - 3 PUFA are comprised of distinct family members, which are increasingly recognized for their individual effects. Therefore, this review examines what is currently known about the specific effects of the major n - 3 and n - 6 PUFA on CVD and NAFLD. Overall, this review supports a beneficial effect of n - 3 PUFA and highlights distinctive effects between alpha-linolenic acid found in plant oils relative to marine derived eicosapentaenoic acid and docosahexaenoic acid. This review also highlights contrasting health effects between the n - 6 PUFA, linoleic and arachidonic acid. PMID- 24496400 TI - Noble-metal-free plasmonic photocatalyst: hydrogen doped semiconductors. AB - The unique capacity of localized surface plasmon resonance (LSPR) offers a new opportunity to overcome the limited efficiency of semiconductor photocatalyst. Here we unravel that LSPR, which usually occurs in noble metal nanoparticles, can be realized by hydrogen doping in noble-metal-free semiconductor using TiO2 as a model photocatalyst. Moreover, its LSPR is located in infrared region, which supplements that of noble metal whose LSPR is generally in the visible region, making it possible to extend the light response of photocatalyst to infrared region. The near field enhancement is shown to be comparable with that of noble metal nanoparticles, indicating that highly enhanced light absorption rate can be expected. The present work can provide a key guideline for the creation of highly efficient noble-metal-free plasmonic photocatalysts and have a much wider impact in infrared bioimaging and spectroscopy where infrared LSPR is essential. PMID- 24496401 TI - The synthesis paradigm in genetics. AB - Experimental genetics with model organisms and mathematically explicit genetic theory are generally considered to be the major paradigms by which progress in genetics is achieved. Here I argue that this view is incomplete and that pivotal advances in genetics--and other fields of biology--are also made by synthesizing disparate threads of extant information rather than generating new information from experiments or formal theory. Because of the explosive expansion of information in numerous "-omics" data banks, and the fragmentation of genetics into numerous subdisciplines, the importance of the synthesis paradigm will likely expand with time. PMID- 24496403 TI - The pyrolysis of 2-methylfuran: a quantum chemical, statistical rate theory and kinetic modelling study. AB - Due to the rapidly growing interest in the use of biomass derived furanic compounds as potential platform chemicals and fossil fuel replacements, there is a simultaneous need to understand the pyrolysis and combustion properties of such molecules. To this end, the potential energy surfaces for the pyrolysis relevant reactions of the biofuel candidate 2-methylfuran have been characterized using quantum chemical methods (CBS-QB3, CBS-APNO and G3). Canonical transition state theory is employed to determine the high-pressure limiting kinetics, k(T), of elementary reactions. Rice-Ramsperger-Kassel-Marcus theory with an energy grained master equation is used to compute pressure-dependent rate constants, k(T,p), and product branching fractions for the multiple-well, multiple-channel reaction pathways which typify the pyrolysis reactions of the title species. The unimolecular decomposition of 2-methylfuran is shown to proceed via hydrogen atom transfer reactions through singlet carbene intermediates which readily undergo ring opening to form collisionally stabilised acyclic C5H6O isomers before further decomposition to C1-C4 species. Rate constants for abstraction by the hydrogen atom and methyl radical are reported, with abstraction from the alkyl side chain calculated to dominate. The fate of the primary abstraction product, 2 furanylmethyl radical, is shown to be thermal decomposition to the n-butadienyl radical and carbon monoxide through a series of ring opening and hydrogen atom transfer reactions. The dominant bimolecular products of hydrogen atom addition reactions are found to be furan and methyl radical, 1-butene-1-yl radical and carbon monoxide and vinyl ketene and methyl radical. A kinetic mechanism is assembled with computer simulations in good agreement with shock tube speciation profiles taken from the literature. The kinetic mechanism developed herein can be used in future chemical kinetic modelling studies on the pyrolysis and oxidation of 2-methylfuran, or the larger molecular structures for which it is a known pyrolysis/combustion intermediate (e.g. cellulose, coals, 2,5-dimethylfuran). PMID- 24496406 TI - First principles prediction of the magnetic properties of Fe-X6 (X = S, C, N, O, F) doped monolayer MoS2. AB - Using first-principles calculations, we have investigated the electronic structure and magnetic properties of Fe-X6 clusters (X = S, C, N, O, and F) incorporated in 4 * 4 monolayer MoS2, where a Mo atom is substituted by Fe and its nearest S atoms are substituted by C, N, O, and F. Single Fe and Fe-F6 substituions make the system display half-metallic properties, Fe-C6 and Fe-N6 substitutions lead to a spin gapless semiconducting behavior, and Fe-O6 doped monolayer MoS2 is semiconducting. Magnetic moments of 1.93, 1.45, 3.18, 2.08, and 2.21 MUB are obtained for X = S, C, N, O, and F, respectively. The different electronic and magnetic characters originate from hybridization between the X and Fe/Mo atoms. Our results suggest that cluster doping can be an efficient strategy for exploring two-dimensional diluted magnetic semiconductors. PMID- 24496404 TI - Facile synthesis of boronic acid-functionalized magnetic carbon nanotubes for highly specific enrichment of glycopeptides. AB - A stepwise strategy was developed to synthesize boronic acid functionalized magnetic carbon nanotubes (MCNTs) for highly specific enrichment of glycopeptides. The MCNTs were synthesized by a solvothermal reaction of Fe(3+) loaded on the acid-treated CNTs and modified with 1-pyrenebutanoic acid N hydroxysuccinimidyl ester (PASE) to bind aminophenylboronic acid (APBA) via an amide reaction. The introduction of PASE could bridge the MCNT and APBA, suppress the nonspecific adsorption and reduce the steric hindrance among the bound molecules. Due to the excellent structure of the MCNTs, the functionalization of PASE and then APBA on MCNTs was quite simple, specific and effective. The glycopeptides enrichment and separation with a magnetic field could be achieved by their reversible covalent binding with the boronic group of APBA-MCNTs. The exceptionally large specific surface area and the high density of boronic acid groups of APBA-MCNTs resulted in rapid and highly efficient enrichment of glycopeptides, even in the presence of large amounts of interfering nonglycopeptides. The functional MCNTs possessed high selectivity for enrichment of 21 glycopeptides from the digest of horseradish peroxidase demonstrated by MALDI-TOF mass spectrometric analysis showing more glycopeptides detected than the usual 9 glycopeptides with commercially available APBA-agarose. The proposed system showed better specificity for glycopeptides even in the presence of non glycopeptides with 50 times higher concentration. The boronic acid functionalized MCNTs provide a promising selective enrichment platform for precise glycoproteomic analysis. PMID- 24496407 TI - An inter-tangled network of redox-active and conducting polymers as a cathode for ultrafast rechargeable batteries. AB - A 1D organic redox-active material is combined with another 1D conductive material for rechargeable batteries. Poly(vinyl carbazole) (or PVK) and poly(3,4 ethylenedioxythiophene) doped with poly(styrenesulfonate) (or PEDOT:PSS) are used as the redox-active and conductive 1D materials, respectively. Due to their extremely anisotropic geometry, the two polymers are expected to be inter-tangled with each other, showing a kinetically ideal model system in which each redox active moiety of PVK is supposed to be directly connected with the conducting pathways of PEDOT:PSS. In addition to its role as a conductive agent providing kinetic benefits, PEDOT:PSS works as an efficient binder that guarantees enhanced electrochemical performances with only a tenth of the amount of a conventional binder (polyvinylidene fluoride or PVdF). The benefit of gravimetric energy density gain obtained using the conductive binder comes mainly from efficient spatial coverage of binding volume due to the low density of PEDOT:PSS. Towards realizing flexible all-polymer batteries, a quasi-all-polymer battery half-cell is designed using the PVK/PEDOT:PSS composite with a polymer gel electrolyte. PMID- 24496408 TI - Learning and memory: unlearning fear. PMID- 24496412 TI - Sleep: a rude awakening. PMID- 24496410 TI - Synaptic tagging during memory allocation. AB - There is now compelling evidence that the allocation of memory to specific neurons (neuronal allocation) and synapses (synaptic allocation) in a neurocircuit is not random and that instead specific mechanisms, such as increases in neuronal excitability and synaptic tagging and capture, determine the exact sites where memories are stored. We propose an integrated view of these processes, such that neuronal allocation, synaptic tagging and capture, spine clustering and metaplasticity reflect related aspects of memory allocation mechanisms. Importantly, the properties of these mechanisms suggest a set of rules that profoundly affect how memories are stored and recalled. PMID- 24496413 TI - Sensory systems: protons: thinking laterally. PMID- 24496417 TI - The impact of bowel cleansing on follow-up recommendations in average-risk patients with a normal colonoscopy. AB - OBJECTIVES: Repeat colonoscopy in 10 years after a normal screening colonoscopy is recommended in an average-risk patient, and it has been proposed by American Gastroenterological Association (AGA), American College of Gastroenterology (ACG), and American Society for Gastrointestinal Endoscopy (ASGE) as a quality measure. However, there are little quantitative data about adherence to this recommendation or factors that may improve adherence. Our study quantifies adherence to this recommendation and the impact of suboptimal bowel preparation on adherence. METHODS: In this retrospective database study, endoscopy reports of average-risk individuals >=50 years old with a normal screening colonoscopy were reviewed. Quality of colon cleansing was recorded using the Aronchick scale as excellent, good, fair, or poor. Main outcome measurements were quality of bowel preparation and recommendation for timing of repeat colonoscopy. Recommendations were considered consistent with guidelines if 10-year follow-up was documented after excellent, good, or fair prep or if <=1-year follow-up was recommended after poor prep. RESULTS: Among 1,387 eligible patients, recommendations for follow-up colonoscopy inconsistent with guidelines were seen in 332 (23.9%) subjects. By bowel preparation quality, 15.3% of excellent/good, 75% of fair, and 31.6% of poor bowel preparations were assigned recommendations inconsistent with guidelines (P<0.001). Patients with fair (odds ratio=18.0; 95% confidence interval 12.0-28.0) were more likely to have recommendations inconsistent with guidelines compared with patients with excellent/good preps. CONCLUSIONS: Recommendations inconsistent with guidelines for 10-year intervals after a normal colonoscopy occurred in >20% of patients. Minimizing "fair" bowel preparations may be a helpful intervention to improve adherence to these recommendations. PMID- 24496418 TI - Interview from anywhere: feasibility and utility of web-based videoconference interviews in the gastroenterology fellowship selection process. AB - OBJECTIVES: Traditional personal interviews are subject to limitations imposed by geographic, financial, and scheduling constraints. Web-based videoconferencing (WVC) has the potential to simplify the interview process. This study was intended to evaluate the feasibility and utility of WVC using standard tablets/computers with videoconferencing capability in gastroenterology (GI) fellowship interviews. METHODS: At a single institution, 16 GI fellowship applicants participated in WVC with one interviewer, who was present at a remote location 750 miles away. In addition, each of the candidates underwent traditional interviews with four faculty members at the program site. All study interviewees used an iPad2 (Apple, iOS 5.1; Apple) with a videoconferencing application (Facetime). The interviewer (SRD) used Facetime on a MacBook Pro (Apple, Mac OS X 10.7.3). Each candidate completed a voluntary paper survey after completion of all assigned faculty interviews. RESULTS: The average age of the candidates was 30 years (range, 27-37 years). Fourteen candidates were native English speakers. Candidates expressed a high level of satisfaction, with 13 candidates (81%) stating that their WVC experience met or exceeded their expectations, and 87% of candidates stating that WVC should be an option in fellowship interviews. In addition, 25% of candidates felt that their WVC experience was equivalent to or better than their traditional interview experience on the same day. CONCLUSIONS: WVC can be an effective and useful tool in the fellowship interview process. It affords candidates increased flexibility, cost saving, convenience, and provides an option for participating in the selection process at more programs. For the programs and faculty, WVC has a potential to be an effective screening tool, can help minimize loss of clinical revenue and can also be an acceptable alternative to in-person interviews. PMID- 24496420 TI - Video of the month. Portal hypertensive enteropathy visualized with capsule endoscopy. PMID- 24496425 TI - Use of hemoclips and other measures to prevent bleeding during colonoscopy by gastroenterologists in Veterans Affairs hospitals. PMID- 24496426 TI - Histiocytic sarcoma: the first reported case of primary esophageal involvement. PMID- 24496427 TI - An adult patient with cyclic vomiting syndrome successfully treated with oral sumatriptan. PMID- 24496428 TI - Successful closure of lateral duodenal perforation by endoscopic band ligation after endoscopic clipping failure. PMID- 24496429 TI - Double plastic stents for distal malignant biliary obstruction: preliminary evidence for a novel cost-effective alternative to metal stenting. PMID- 24496430 TI - A case of Rothia dentocariosa bacteremia in a patient receiving infliximab for ulcerative colitis. PMID- 24496431 TI - Volumetric laser endomicroscopy detects subsquamous Barrett's adenocarcinoma. PMID- 24496432 TI - Hoarseness and hematemesis: a deadly combination. PMID- 24496435 TI - Mechanical Properties and Degradation of Chain and Step Polymerized Photodegradable Hydrogels. AB - The relationship between polymeric hydrogel microstructure and macroscopic properties is of specific interest to the materials science and polymer science communities for the rational design of materials for targeted applications. Specifically, research has focused on elucidating the role of network formation and connectivity on mechanical integrity and degradation behavior. Here, we compared the mechanical properties of chain and step polymerized, photodegradable hydrogels. Increased ductility, tensile toughness, shear strain to yield were observed in step polymerized hydrogels, as compared to the chain polymerized gels, indicating that increased homogeneity and network cooperativity in the gel backbone improves mechanical integrity. Furthermore, the ability to degrade the hydrogels in a controlled fashion with light was exploited to explore how hydrogel microstructure influences photodegradation and erosion. Here, the decreased network connectivity at the junction points in the step polymerized gels resulted in more rapid erosion. Finally, a relationship between the reverse gelation threshold and erosion rate was developed for the general class of photodegradable hydrogels. In all, these studies further elucidate the relationship between hydrogel formation and microarchitecture with macroscale behavior to facilitate the future design of polymer networks, degradable hydrogels, as well as photoresponsive materials as cell culture templates, drug delivery vehicles, responsive coatings, and anisotropic materials. PMID- 24496436 TI - Photoswitchable fluorescent diheteroarylethenes: substituent effects on photochromic and solvatochromic properties. AB - Photoswitchable fluorescent diheteroarylethenes are promising candidates for applications in super-resolution molecular localization fluorescence microscopy thanks to their high quantum yields and fatigue-resistant photoswitching characteristics. We have studied the effect of varying substituents on the photophysical properties of six sulfone derivatives of diheteroarylethenes, which display fluorescence in one (closed form) of two thermally stable photochromic states. Electron-donating substituents displace the absorption and emission spectra towards the red without substantially affecting the fluorescence quantum yields. Furthermore, ethoxybromo, a very electron-donating substituent, stabilizes the excited state of the closed isomer to the extent of almost entirely inhibiting its cycloreversion. Multi-parameter Hammett correlations indicate a relationship between the emission maxima and electron-donating character, providing a useful tool in the design of future photochromic molecules. Most of the synthesized compounds exhibit small bathochromic shifts and shorter fluorescence lifetimes with an increase in solvent polarity. However, the ethoxybromo-substituted fluorescent photochrome is unique in its strong solvatochromic behaviour, constituting a photoactivatable (photochromic), fluorescent and highly solvatochromic small organic compound. The Catalan formalism identified solvent dipolarity as the principal basis of the solvatochromism, reflecting the highly polarized nature of this molecule. PMID- 24496437 TI - Deep Sequencing Insights in Therapeutic shRNA Processing and siRNA Target Cleavage Precision. AB - TT-034 (PF-05095808) is a recombinant adeno-associated virus serotype 8 (AAV8) agent expressing three short hairpin RNA (shRNA) pro-drugs that target the hepatitis C virus (HCV) RNA genome. The cytosolic enzyme Dicer cleaves each shRNA into multiple, potentially active small interfering RNA (siRNA) drugs. Using next generation sequencing (NGS) to identify and characterize active shRNAs maturation products, we observed that each TT-034-encoded shRNA could be processed into as many as 95 separate siRNA strands. Few of these appeared active as determined by Sanger 5' RNA Ligase-Mediated Rapid Amplification of cDNA Ends (5-RACE) and through synthetic shRNA and siRNA analogue studies. Moreover, NGS scrutiny applied on 5-RACE products (RACE-seq) suggested that synthetic siRNAs could direct cleavage in not one, but up to five separate positions on targeted RNA, in a sequence-dependent manner. These data support an on-target mechanism of action for TT-034 without cytotoxicity and question the accepted precision of substrate processing by the key RNA interference (RNAi) enzymes Dicer and siRNA-induced silencing complex (siRISC).Molecular Therapy-Nucleic Acids (2014) 3, e145; doi:10.1038/mtna.2013.73; published online 4 February 2014. PMID- 24496438 TI - In vitro Inactivation of Latent HSV by Targeted Mutagenesis Using an HSV-specific Homing Endonuclease. AB - Following acute infection, herpes simplex virus (HSV) establishes latency in sensory neurons, from which it can reactivate and cause recurrent disease. Available antiviral therapies do not affect latent viral genomes; therefore, they do not prevent reactivation following therapy cessation. One possible curative approach involves the introduction of DNA double strand breaks in latent HSV genomes by rare-cutting endonucleases, leading to mutagenesis of essential viral genes. We tested this approach in an in vitro HSV latency model using the engineered homing endonuclease (HE) HSV1m5, which recognizes a sequence in the HSV-1 gene UL19, encoding the virion protein VP5. Coexpression of the 3' exonuclease Trex2 with HEs increased HE-mediated mutagenesis frequencies up to sixfold. Following HSV1m5/Trex2 delivery with adeno-associated viral (AAV) vectors, the target site was mutated in latent HSV genomes with no detectable cell toxicity. Importantly, HSV production by latently infected cells after reactivation was decreased after HSV1m5/Trex2 exposure. Exposure to histone deacetylase inhibitors prior to HSV1m5/Trex2 treatment increased mutagenesis frequencies of latent HSV genomes another two- to fivefold, suggesting that chromatin modification may be a useful adjunct to gene-targeting approaches. These results support the continuing development of HEs and other nucleases (ZFNs, TALENs, CRISPRs) for cure of chronic viral infections.Molecular Therapy Nucleic Acids (2014) 3, e1; doi:10.1038/mtna.2013.75; published online 4 February 2014. PMID- 24496439 TI - Microlandscaping on a graphene oxide film via localized decoration of Ag nanoparticles. AB - A direct and facile method for micro-landscaping of Ag nanoparticles on reduced graphene oxide (rGO) is presented. This method employs a focused laser beam to achieve local reduction of Ag(+) ions to Ag NPs by laser irradiation on a GO film that is submerged in AgNO3 solution. Using this method, the Ag nanoparticles can be directly anchored on a rGO film, creating a microlandscape of Ag nanoparticles on the rGO film. In addition, varying the intensity of the laser beam can control the shapes, sizes and distributions of Ag nanoparticles. The resulting hybrid materials exhibit surface enhanced Raman scattering of up to 16 times depending on the size and number density of silver nanoparticles. In addition, the hybrid Ag-rGO material shows superior photoresponse when compared to rGO. PMID- 24496443 TI - Implementation of smart pump technology in a paediatric intensive care unit. AB - Patient safety is a matter of major concern that involves every health professional. Nowadays, emerging technologies such as smart pumps can diminish medication errors as well as standardise and improve clinical practice with the subsequent benefits for patients. The aim of this paper was to describe the smart pump implementation process in a paediatric intensive care unit (PICU) and to present the most relevant infusion-related programming errors that were prevented. This was a comparative study between CareFusion Alaris Guardrails((r)) and Hospira MedNet((r)) systems, as well as a prospective and intervention study with analytical components carried out in the PICU of Gregorio Maranon General and Teaching Hospital. All intravenous infusions programmed with a pump in the eleven beds of the unit were analyzed. A drug library was developed and subsequently loaded into CareFusion and Hospira pumps that were used during a three month period each. The most suitable system for implementation was selected according to their differences in features and users' acceptance. Data stored in the pumps were analyzed to assess user compliance with the technology, health care setting and type of errors intercepted. The implementation process was carried out with CareFusion systems. Compliance with the technology was 92% and user acceptance was high. Vacation substitution and drug administration periods were significantly associated with a greater number of infusion-related programming errors. High risk drugs were involved in 48% of intercepted errors. Based on these results we can conclude that implementation of smart pumps proved effective in intercepting infusion-related programming errors from reaching patients. User awareness of the importance of programming infusions with the drug library is the key to succeed in the implementation process. PMID- 24496442 TI - Intake of long-chain omega-3 fatty acids from diet and supplements in relation to mortality. AB - Evidence from experimental studies suggests that the long-chain omega-3 fatty acids eicosapentaenoic acid and docosahexaenoic acid have beneficial effects that may lead to reduced mortality from chronic diseases, but epidemiologic evidence is mixed. Our objective was to evaluate whether intake of long-chain omega-3 fatty acids from diet and supplements is associated with cause-specific and total mortality. Study participants (n = 70,495) were members of a cohort study (the Vitamins and Lifestyle Study) who were residents of Washington State aged 50-76 years at the start of the study (2000-2002). Participants were followed for mortality through 2006 (n = 3,051 deaths). Higher combined intake of eicosapentaenoic acid and docosahexaenoic acid from diet and supplements was associated with a decreased risk of total mortality (hazard ratio (HR) = 0.82, 95% confidence interval (CI): 0.73, 0.93) and mortality from cancer (HR = 0.77, 95% CI: 0.64, 0.92) but only a small reduction in risk of death from cardiovascular disease (HR = 0.87, 95% CI: 0.68, 1.10). These results suggest that intake of long-chain omega-3 fatty acids may reduce risk of total and cancer specific mortality. PMID- 24496444 TI - Fine-tuned bee-flower coevolutionary state hidden within multiple pollination interactions. AB - Relationships between flowers and pollinators are generally considered cases of mutualism since both agents gain benefits. Fine-tuned adaptations are usually found in the form of strict one-to-one coevolution between species. Many insect pollinators are, however, considered generalists, visiting numerous kinds of flowers, and many flower species (angiosperms) are also considered generalists, visited by many insect pollinators. We here describe a fine-tuned coevolutionary state of a flower-visiting bee that collects both nectar and pollen from an early spring flower visited by multiple pollinators. Detailed morphology of the bee proboscis is shown to be finely adjusted to the floral morphology and nectar production of the flower. Behavioral observations also confirm the precision of this mutualism. Our results suggest that a fine-tuned one-to-one coevolutionary state between a flower species and a pollinator species might be common, but frequently overlooked, in multiple flower-pollinator interactions. PMID- 24496445 TI - Purinergic control of AMPK activation by ATP released through connexin 43 hemichannels - pivotal roles in hemichannel-mediated cell injury. AB - Connexin hemichannels regulate many cell functions. However, the molecular mechanisms involved remain elusive. Hemichannel opening causes loss of ATP, we therefore speculated a potential role for AMPK in the biological actions of hemichannels. Activation of hemichannels by removal of extracellular Ca(2+) led to an efflux of ATP and a weak activation of AMPK. Unexpectedly, dysfunction of hemichannels markedly potentiated AMPK activation, which was reproduced by promotion of extracellular ATP degradation or inhibition of P2 purinoceptors but counteracted by exogenous ATP. Further analysis revealed that ATP induced a purinoceptor-dependent activation of Akt and mTOR. Suppression of Akt or mTOR augmented AMPK activation, whereas activation of Akt by transfection of cells with myristoylated Akt, a constitutively active form of Akt, abolished AMPK activation. In a pathological model of hemichannel opening triggered by Cd(2+), disclosure of hemichannels similarly enhanced AMPK activity, which protected cells from Cd(2+)-induced cell injury through suppression of mTOR. In summary, our data point to a channel-mediated mechanism for the regulation of AMPK through a purinergic signaling pathway. Furthermore, we define AMPK as a pivotal molecule that underlies the regulatory effects of hemichannels on cell survival. PMID- 24496446 TI - Palladin promotes assembly of non-contractile dorsal stress fibers through VASP recruitment. AB - Stress fibers are major contractile actin structures in non-muscle cells where they have an important role in adhesion, morphogenesis and mechanotransduction. Palladin is a multidomain protein, which associates with stress fibers in a variety of cell types. However, the exact role of palladin in stress fiber assembly and maintenance has remained obscure, and whether it functions as an actin filament crosslinker or scaffolding protein was unknown. We demonstrate that palladin is specifically required for the assembly of non-contractile dorsal stress fibers, and is, consequently, essential for the generation of stress fiber networks and the regulation of cell morphogenesis in osteosarcoma cells migrating in a three-dimensional collagen matrix. Importantly, we reveal that palladin is necessary for the recruitment of vasodilator stimulated phosphoprotein (VASP) to dorsal stress fibers and that it promotes stress fiber assembly through VASP. Both palladin and VASP display similar rapid dynamics at dorsal stress fibers, suggesting that they associate with stress fibers as a complex. Thus, palladin functions as a dynamic scaffolding protein that promotes the assembly of dorsal stress fibers by recruiting VASP to these structures. PMID- 24496447 TI - Ube2g2-gp78-mediated HERP polyubiquitylation is involved in ER stress recovery. AB - A large number of studies have focused on how individual organisms respond to a stress condition, but little attention has been paid to the stress recovery process, such as the endoplasmic reticulum (ER) stress recovery. Homocysteine induced ER protein (HERP) was originally identified as a chaperone-like protein that is strongly induced upon ER stress. Here we show that, after ER stress induction, HERP is rapidly degraded by Ube2g2-gp78-mediated ubiquitylation and proteasomal degradation. The polyubiquitylation of HERP in vitro depends on a physical interaction between the CUE domain of gp78 and the ubiquitin-like (UBL) domain of HERP, which is essential for HERP degradation in vivo during ER stress recovery. We further show that although HERP promotes cell survival under ER stress, high levels of HERP expression reduce cell viability under oxidative stress conditions, suggesting that HERP plays a dual role in cellular stress adaptation. Together, these results establish the ubiquitin-proteasome-mediated degradation of HERP as a novel mechanism that fine-tunes the stress tolerance capacity of the cell. PMID- 24496448 TI - Cadherin switching during the formation and differentiation of the Drosophila mesoderm - implications for epithelial-to-mesenchymal transitions. AB - Epithelial-to-mesenchymal transition (EMT) is typically accompanied by downregulation of epithelial (E-) cadherin, and is often additionally accompanied by upregulation of a mesenchymal or neuronal (N-) cadherin. Snail represses transcription of the E-cadherin gene both during normal development and during tumour spreading. The formation of the mesodermal germ layer in Drosophila, considered a paradigm of a developmental EMT, is associated with Snail-mediated repression of E-cadherin and the upregulation of N-cadherin. By using genetic manipulation to remove or overexpress the cadherins, we show here that the complementarity of cadherin expression is not necessary for the segregation or the dispersal of the mesodermal germ layer in Drosophila. However, we discover different effects of E- and N-cadherin on the differentiation of subsets of mesodermal derivatives, which depend on Wingless signalling from the ectoderm, indicating differing abilities of E- and N-cadherin to bind to and sequester the common junctional and signalling effector beta-catenin. These results suggest that the downregulation of E-cadherin in the mesoderm might be required to facilitate optimal levels of Wingless signalling. PMID- 24496449 TI - Glypican-3 binds to Frizzled and plays a direct role in the stimulation of canonical Wnt signaling. AB - Glypican-3 (GPC3) is a proteoglycan that is bound to the cell surface. It is expressed by most hepatocellular carcinomas (HCCs) but not by normal hepatocytes. GPC3 stimulates HCC growth by promoting canonical Wnt signaling. Because glypicans interact with Wnts, it has been proposed that these proteoglycans stimulate signaling by increasing the amount of Wnt at the cell membrane, thus facilitating the interaction of this growth factor with its signaling receptor, Frizzled. However, in this study, we demonstrate that GPC3 plays a more direct role in the stimulation of Wnt signaling. Specifically, we show that, in addition to interacting with Wnt, GPC3 and Frizzled interact directly through the glycosaminoglycan chains of GPC3, indicating that this glypican stimulates the formation of signaling complexes between Wnt and Frizzled. Consistent with this, we show that the binding of Wnt at the cell membrane triggers the endocytosis of a complex that includes Wnt, Frizzled and GPC3. Additional support for our model is provided by the finding that glypican-6 (GPC6) inhibits canonical Wnt signaling, despite the fact that it binds to Wnt at the cell membrane. PMID- 24496450 TI - Regulation of the phosphorylation and nuclear import and export of beta-catenin by APC and its cancer-related truncated form. AB - We report the first direct analysis of the endogenous beta-catenin phosphorylation activity in colon cancer SW480 cells. By comparing parental SW480 cells that harbor a typical truncated adenomatous polyposis coli (APC) form, cells expressing full-length APC and APC-depleted cells, we provide the formal demonstration that APC is necessary for beta-catenin phosphorylation, both for priming of the protein at residue serine 45 and for the subsequent phosphorylation of residues 33, 37 and 41. Truncated APC still sustains a surprisingly high phosphorylation activity, which requires the protein to bind to beta-catenin through the APC 20-amino-acid (20AA) repeats, thus providing a biochemical explanation for the precise truncations found in cancer cells. We also show that most of the beta-catenin phosphorylation activity is associated with a dense insoluble fraction. We finally examine the impact of full-length and truncated APC on beta-catenin nuclear transport. We observe that beta-catenin is transported much faster than previously thought. Although this fast translocation is largely insensitive to the presence of wild-type or truncated APC, the two forms appear to limit the pool of beta-catenin that is available for transport, which could have an impact on beta-catenin nuclear activities in normal and cancer cells. PMID- 24496451 TI - SNARE-dependent interaction of Src, EGFR and beta1 integrin regulates invadopodia formation and tumor cell invasion. AB - Acquisition of an invasive phenotype is prerequisite for tumor metastasis. Degradation of the extracellular matrix (ECM), and subsequent invasion by tumor cells, is mediated, in part, through subcellular structures called invadopodia. Src-dependent cytoskeletal rearrangements are required to form invadopodia, and here we identify an association between Src, epidermal growth factor receptor (EGFR), and beta1 integrin that facilitates invadopodia formation. The association of Src, EGFR and beta1 integrin is dependent upon membrane traffic that is mediated by syntaxin13 (officially known as STX12) and SNAP23; a similar dependence on these two SNARE proteins was observed for invadopodium-based matrix degradation and cell invasion. Inhibition of SNARE function impaired the delivery of Src and EGFR to developing invadopodia, as well as the beta1-integrin dependent activation of Src and phosphorylation of EGFR on Tyr residue 845. We also identified an association between SNAP23 and beta1 integrin, and inhibition of beta1 integrin increased this association, whereas the interaction between syntaxin13 and SNAP23 was reduced. The results suggest that SNARE-dependent trafficking is regulated, in part, by beta1 integrin and is required for the delivery of Src and EGFR to sites of invadopodia formation in order to support tumor cell invasion. PMID- 24496453 TI - Dynamic coupling of ALCAM to the actin cortex strengthens cell adhesion to CD6. AB - At the immunological synapse, the activated leukocyte cell adhesion molecule (ALCAM) on a dendritic cell (DC) and CD6 molecules on a T cell contribute to sustained DC-T-cell contacts. However, little is known about how ALCAM-CD6 bonds resist and adapt to mechanical stress. Here, we combine single-cell force spectroscopy (SCFS) with total-internal reflection fluorescence microscopy to examine ALCAM-CD6-mediated cell adhesion. The combination of cells expressing ALCAM constructs with certain cytoplasmic tail mutations and improved SCFS analysis processes reveal that the affinity of ALCAM-CD6 bonds is not influenced by the linking of the intracellular domains of ALCAM to the actin cortex. By contrast, the recruitment of ALCAM to adhesion sites and the propensity of ALCAM to anchor plasma membrane tethers depend on actin cytoskeletal interactions. Furthermore, linking ALCAM to the actin cortex through adaptor proteins stiffens the cortex and strengthens cell adhesion. We propose a framework for how ALCAMs contribute to DC-T-cell adhesion, stabilize DC-T-cell contacts and form a mechanical link between CD6 and the actin cortex to strengthen cell adhesion at the immunological synapse. PMID- 24496452 TI - Sept7b is essential for pronephric function and development of left-right asymmetry in zebrafish embryogenesis. AB - The conserved septin family of filamentous small GTPases plays important roles in mitosis, cell migration and cell morphogenesis by forming scaffolds and diffusion barriers. Recent studies in cultured cells in vitro indicate that a septin complex of septin 2, 7 and 9 is required for ciliogenesis and cilia function, but septin function in ciliogenesis in vertebrate organs in vivo is not understood. We show that sept7b is expressed in ciliated cells in different tissues during early zebrafish development. Knockdown of sept7b by using morpholino antisense oligonucleotides caused misorientation of basal bodies and cilia, reduction of apical actin and the shortening of motile cilia in Kupffer's vesicle and pronephric tubules. This resulted in pericardial and yolk sac edema, body axis curvature and hydrocephaly. Notably, in sept7b morphants we detected strong left right asymmetry defects in the heart and lateral plate mesoderm (situs inversus), reduced fluid flow in the kidney, the formation of kidney cysts and loss of glomerular filtration barrier function. Thus, sept7b is essential during zebrafish development for pronephric function and ciliogenesis, and loss of expression of sept7b results in defects that resemble human ciliopathies. PMID- 24496457 TI - Prokineticins and Merkel cell polyomavirus infection in Merkel cell carcinoma. AB - BACKGROUND: Prokineticin-1 (PROK1) and prokineticin-2 (PROK2) are chemokine-like proteins that may influence cancer growth by regulating host defence and angiogenesis. Their significance in viral infection-associated cancer is incompletely understood. We studied prokineticins in Merkel cell carcinoma (MCC), a skin cancer linked with Merkel cell polyomavirus (MCPyV) infection. METHODS: Carcinoma cell expression of PROK1 and PROK2 and their receptors (PROKR1 and PROKR2) was investigated with immunohistochemistry, and tumour PROK1 and PROK2 mRNA content with quantitative PCR from 98 MCCs. Subsets of tumour infiltrating leukocytes were identified using immunohistochemistry. RESULTS: Merkel cell polyomavirus-positive MCCs had higher than the median PROK2 mRNA content, whereas MCPyV-negative MCCs contained frequently PROK1 mRNA. Cancers with high tumour PROK2 mRNA content had high counts of tumour infiltrating macrophages (CD68+ and CD163+ cells). Patients with higher than the median PROK2 mRNA content had 44.9% 5-year survival compared with 23.5% among those with a smaller content (hazard ratio (HR): 0.53; 95% confidence interval (CI): 0.34-0.84; P=0.005), whereas the presence of PROK1 mRNA in tumour was associated with unfavourable survival (P=0.052). CONCLUSIONS: The results suggest that prokineticins are associated with MCPyV infection and participate in regulation of the immune response in MCC, and may influence outcome of MCC patients. PMID- 24496456 TI - Glyco-engineered anti-EGFR mAb elicits ADCC by NK cells from colorectal cancer patients irrespective of chemotherapy. AB - BACKGROUND: The epidermal growth factor receptor (EGFR) is overexpressed in colorectal cancer (CRC), and is correlated with poor prognosis, making it an attractive target for monoclonal antibody (mAb) therapy. A component of the therapeutic efficacy of IgG1 mAbs is their stimulation of antibody-dependent cellular cytotoxicity (ADCC) by natural killer (NK) cells bearing the CD16 receptor. As NK cells are functionally impaired in cancer patients and may be further compromised upon chemotherapy, it is crucial to assess whether immunotherapeutic strategies aimed at further enhancing ADCC are viable. METHODS: CRC patients before, during and after chemotherapy were immunophenotyped by flow cytometry for major white blood cell populations. ADCC-independent NK cell functionality was assessed in cytotoxicity assays against K562 cells. ADCC dependent killing of EGFR(+) A431 cancer cells by NK cells was measured with a degranulation assay where ADCC was induced by GA201, an anti-EGFR mAb glyco engineered to enhance ADCC. RESULTS: Here, we confirm the observation that NK cells in cancer patients are dysfunctional. However, GA201 was able to induce robust NK cell-dependent cytotoxicity in CRC patient NK cells, effectively overcoming their impairment. CONCLUSIONS: These findings support the evaluation of the therapeutic potential of GA201 in combination with chemotherapy in CRC patients. PMID- 24496458 TI - Risk of bladder cancer in renal transplant recipients: a meta-analysis. AB - BACKGROUND: Renal transplantation has been associated with a significantly increased risk of developing cancers during long-term follow-up, but for bladder cancer, this risk is less clear. We therefore performed a meta-analysis to determine whether bladder cancer risk in renal transplant recipients was increased. METHODS: Eligible studies were identified through searches of PubMed and other public resources. Random-effects meta-analyses were used to pool overall estimates for standardised incidence ratios (SIRs). Heterogeneity test, sensitivity analysis, and assessment of publishing bias were also performed. RESULTS: We identified a 3.18-fold higher SIR (95% confidence intervals (CI): 1.34-7.53, P=0.008) of bladder cancer in patients following renal transplantation compared with the general population, based on data from 79,988 patients with a total follow-up of 308,458 patient-years. When stratified by ethnicity, the SIRs for bladder cancer were 2.00 (95% CI: 1.51-2.65, P=0.001) and 14.74 (95% CI: 3.66 59.35, P<0.001) between European and Asian renal transplant recipients, respectively. CONCLUSIONS: Our study demonstrated that the risk of developing bladder cancer in transplant populations was increased. Such association suggests that physicians should be more vigilant in checking for bladder cancer in transplantation recipient population. PMID- 24496459 TI - Prognostic value of magnetic resonance imaging-detected cranial nerve invasion in nasopharyngeal carcinoma. AB - BACKGROUND: We previously reported that magnetic resonance imaging evidence of cranial nerve invasion was an unfavourable prognostic factor in nasopharyngeal carcinoma. However, the prognostic value of this evidence in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy remains unknown. METHODS: We retrospectively analysed 749 nasopharyngeal carcinoma patients who underwent intensity-modulated radiotherapy. RESULTS: Cranial nerve invasion was observed in 299 (39.9%) patients with T3-4 disease. In T3-4 nasopharyngeal carcinoma, magnetic resonance imaging-detected cranial nerve invasion was associated with inferior 5-year overall survival, distant metastasis-free survival, and locoregional relapse-free survival (P=0.002, 0.003, and 0.012, respectively). Multivariate analyses confirmed that cranial nerve invasion was an independent prognostic factor for distant metastasis-free survival (hazard ratio, 1.927; P=0.019) and locoregional relapse-free survival (hazard ratio, 2.605; P=0.032). Furthermore, the receiver-operating characteristic curves verified that the predictive validity of T classifications was significantly improved when combined with magnetic resonance imaging-detected cranial nerve invasion in terms of death, distant metastasis, and locoregional recurrence (P=0.015, 0.021 and 0.008, respectively). CONCLUSIONS: Magnetic resonance imaging-detected cranial nerve invasion is an independent adverse prognostic factor in nasopharyngeal carcinoma treated with intensity-modulated radiotherapy. PMID- 24496461 TI - Brownian motion in a speckle light field: tunable anomalous diffusion and selective optical manipulation. AB - The motion of particles in random potentials occurs in several natural phenomena ranging from the mobility of organelles within a biological cell to the diffusion of stars within a galaxy. A Brownian particle moving in the random optical potential associated to a speckle pattern, i.e., a complex interference pattern generated by the scattering of coherent light by a random medium, provides an ideal model system to study such phenomena. Here, we derive a theory for the motion of a Brownian particle in a speckle field and, in particular, we identify its universal characteristic timescale. Based on this theoretical insight, we show how speckle light fields can be used to control the anomalous diffusion of a Brownian particle and to perform some basic optical manipulation tasks such as guiding and sorting. Our results might broaden the perspectives of optical manipulation for real-life applications. PMID- 24496455 TI - Effect of oral anticoagulants on the outcome of faecal immunochemical test. AB - BACKGROUND: We aimed to evaluate whether oral anticoagulants (OACs) alter faecal immunochemical test (FIT) performance in average-risk colorectal cancer (CRC) screening. METHODS: Individuals aged 50-69 years were invited to receive one FIT sample (cutoff 75 ng ml(-1)) between November 2008 and June 2011. RESULTS: Faecal immunochemical test was positive in 9.3% (21 out of 224) of users of OAC and 6.2% (365 out of 5821) of non-users (P-trend=0.07). The positive predictive value (PPV) for advanced neoplasia (AN) in non-users was 50.4% vs 47.6% in users (odds ratio, 0.70; 95% CI, 0.3-1.8; P=0.5). The PPV for AN in OAC more antiplatelets (aspirin or clopidogrel) was 75% (odds ratio, 2; 95% CI, 0.4-10.8; P=0.4). CONCLUSIONS: Oral anticoagulant did not significantly modify the PPV for AN in this population-based colorectal screening program. The detection rate of advanced adenoma was higher in the combination OAC more antiplatelets. PMID- 24496462 TI - Structural, mechanical properties and fracture mechanism of RuB(1.1). AB - Polycrystalline RuB(1.1) has been prepared by using an arc-melting method and its structure and mechanical properties including elastic modulus, hardness and fracture behavior have been characterized. Also, the electronic structure and bond characteristics for this compound have been investigated by first-principles calculations. The lattice parameters of RuB(1.1) have been precisely determined by a Rietveld refinement. First-principles calculations show that this compound has a high bulk modulus and a big Poisson's ratio compared to RuB2. The measured hardness of ~10.6 GPa for RuB(1.1) is three times lower than the theoretical value. This low hardness can be attributed to bond characteristics such as the bonding state and orientation, and fracture mechanism, in which the features of the Ru-B bonds plays an important role in the hardness. We found that there is an isosceles triangle bonding state including the B-B and Ru-B bonds, and the two dimensionally inclined Ru-B bonds along the a-b plane weaken the hardness and C33. The scanning electron microscopy images show that this RuB(1.1) compound exhibits a twinning fracture, and this fracture model is also confirmed by first principle calculations. PMID- 24496463 TI - Photophysical properties and electronic structure of retinylidene-chlorin chalcones and analogues. AB - Synthetic chlorins can accommodate diverse substituents about the macrocycle perimeter. Simple auxochromes (e.g., vinyl, acetyl, phenyl) allow systematic tuning of spectral and photophysical features. More extensive spectral tailoring may be achieved by using more potent, highly conjugated substituents that themselves bring new absorption into a target spectral region, if deleterious excited-state quenching processes can be avoided. To explore such an expanded substituent space, herein the spectral and photophysical properties of four chlorin-chalcones are reported. The molecules are free base and zinc chlorins with substituents at the 13-position that include a chalcone and an extended chalcone derived by reaction of the 13-acetylchlorin with benzaldehyde and all trans-retinal, respectively. Measurements of the spectral and photophysical properties (Phif, taus, kf, kic, kisc) are accompanied by density functional calculations that examine the characteristics of the frontier molecular orbitals. The chlorin-chalcones in nonpolar (toluene) and polar (dimethylsulfoxide) media exhibit bathochromically shifted (and intense) Qy absorption bands. The presence of the retinylidene group adds new absorption in the blue-green region where the chlorins are typically transparent; excitation in this region leads to quantitative formation of the chlorin Qy excited state. The spectral properties generally correlate with substituent effects on the frontier MOs. The four chlorin-chalcones in the solvent toluene have high fluorescence yields (0.24 0.30) and multi-nanosecond singlet excited-state lifetimes (3.7-8.4 ns), in addition to the added absorption imparted by the chalcone moiety. Collectively, the studies reported herein provide insight into the fundamental properties of chlorins and illustrate the utility of chalcones as a means of both tuning and augmenting the spectral properties of these chromophores. PMID- 24496460 TI - Galectin-1 has potential prognostic significance and is implicated in clear cell renal cell carcinoma progression through the HIF/mTOR signaling axis. AB - BACKGROUND: Metastatic clear cell renal cell carcinoma (ccRCC) patients have <9% 5-year survival rate, do not respond well to targeted therapy and eventually develop resistance. A better understanding of molecular pathways of RCC metastasis is the basis for the discovery of novel prognostic markers and targeted therapies. METHODS: We investigated the biological impact of galectin-1 (Gal-1) in RCC cell lines by migration and invasion assays. Effect of Gal-1 expression on the mitogen-activated protein kinase pathway was assessed by proteome array. RESULTS: Increased expression of Gal-1 increased cell migration while knocking down Gal-1 expression by siRNA resulted in reduced cellular migration (P<0.001) and invasion (P<0.05). Gal-1 overexpression increased phosphorylation of Akt, mTOR and p70 kinase. Upon hypoxia and increased HIF 1alpha, Gal-1 increased in a dose-dependent manner. We also found miR-22 overexpression resulted in decreased Gal-1 and HIF-1alpha. Immunohistochemistry analysis showed that high Gal-1 protein expression was associated with larger size tumor (P=0.034), grades III/IV tumors (P<0.001) and shorter disease-free survival (P=0.0013). Using the Cancer Genome Atlas data set, we found that high Gal-1 mRNA expression was associated with shorter overall survival (41 vs 78 months; P<0.01). CONCLUSIONS: Our data suggest Gal-1 mediates migration and invasion through the HIF-1alpha-mTOR signaling axis and is a potential prognostic marker and therapeutic target. PMID- 24496464 TI - Identification and quantification of polyfunctionalized hopanoids by high temperature gas chromatography-mass spectrometry. AB - Hopanoids are triterpenoids produced mainly by bacteria, are ubiquitous in the environment, and have many important applications as biological markers. A wide variety of related hopanoid structures exists, many of which are polyfunctionalized. These modifications render the hopanoids too involatile for conventional gas chromatography (GC) separation, so require either laborious oxidative cleavage of the functional groups or specialized high temperature (HT) columns. Here we describe the systematic evaluation and optimization of a HT-GC method for the analysis of polyfunctionalized hopanoids and their methylated homologs. Total lipid extracts are derivatized with acetic anhydride and no further treatment or workup is required. We show that acid or base hydrolysis to remove di- and triacylglycerides leads to degradation of several BHP structures. DB-XLB type columns can elute hopanoids up to bacteriohopane-tetrol at 350 degrees C, with baseline separation of all 2-methyl/desmethyl homologs. DB-5HT type columns can additionally elute bacteriohopaneaminotriol and bacteriohopaneaminotetrol, but do not fully separate 2-methyl/desmethyl homologs. The method gave 2- to 7-fold higher recovery of hopanoids than oxidative cleavage and can provide accurate quantification of all analytes including 2-methyl hopanoids. By comparing data from mass spectra with those from a flame ionization detector, we show that the mass spectromet (MS) response factors for different hopanoids using either total ion counts or m/z 191 vary substantially. Similarly, 2-methyl ratios estimated from selected-ion data are lower than those from FID by 10-30% for most hopanoids, but higher by ca. 10% for bacteriohopanetetrol. Mass spectra for a broad suite of hopanoids, including 2-methyl homologs, from Rhodopseudomonas palustris are presented, together with the tentative assignment of several new hopanoid degradation products. PMID- 24496466 TI - Advances in the environmental transmission electron microscope (ETEM) for nanoscale in situ studies of gas-solid interactions. AB - Although available since the early days of electron microscopy, recent technology developments of the environmental transmission electron microscope (ETEM) have enabled new research in the study of nanomaterials in gaseous environments. Significant improvements in scanning/transmission electron microscope (S/TEM) technologies, while containing a gaseous environment close to the object under investigation, enable now the atomic scale study of phenomena occurring during gas-solid interactions. A focus behind these developments is the research on nanomaterial-based technologies, for instance for efficient energy conversion, use and storage as well as for environmental protection. In situ high spatial resolution characterization provides unique information that is beneficial for understanding the relationship between the structure, properties and function of nanostructures directly on their characteristic length scales. The progress in recent research is reviewed to highlight the potential of the state-of-the-art differentially-pumped microscope platform, based on the latest microscope generation optimized for atomic scale in situ investigations. Using cases from current catalysis research, high resolution imaging reveals structural changes in nanocatalysts when being active and is instrumental in understanding deactivation processes; while spectroscopy gives additional access to reactivity. Also, imaging schemes are discussed that focus on enhancing the achievable imaging resolution, while having the effect of electron beam-solid interaction in the nanomaterial under control. PMID- 24496467 TI - Dispersed crude oil amplifies germ cell apoptosis in Caenorhabditis elegans, followed a CEP-1-dependent pathway. AB - The Deepwater Horizon oil spill is among the most severe environmental disasters in US history. The extent of crude oil released and the subsequent dispersant used for cleanup was unprecedented. The dispersed crude oil represents a unique form of environmental contaminant that warrants investigations of its environmental and human health impacts. Lines of evidence have demonstrated that dispersed oil affects reproduction in various organisms, in a more potent manner than oil- and dispersant-only exposures. However, the action mechanism of dispersed oil remains largely unknown. In this study, we utilized the model organism Caenorhabditis elegans to investigate impacts of dispersed oil exposure on sex cell apoptosis and related gene expressions. Worms were exposed to different diluted levels of crude oil-dispersant (oil-dis) mixtures (20:1, v/v; at 500*, 2,000*, and 5,000* dilutions). The dispersed crude oil significantly increases the number of apoptotic germ cells in treated worms when compared with control at all exposure levels (p < 0.05). Genes involved in the apoptosis pathway were dysregulated, which include ced-13, ced-3, ced-4, ced-9, cep-1, dpl 1, efl-1, efl-2, egl-1, egl-38, lin-35, pax-2, and sir-2.1. Many aberrant expressed genes encoding for core components in apoptosis machinery (cep-1/p53, ced-13/BH3, ced-9/Bcl-2, ced-4/Apaf-1, and ced-3/caspase) displayed consistent expression patterns across all exposure levels. Significantly ced-3/caspase was upregulated at all dispersed oil-treated groups, consistent with the observed apoptosis phenotype. Given cep-1/p53 was activated at all dispersed oil treatments and the germ cell apoptosis was suppressed in the CEP-1 loss of function mutant, the increased apoptosis is likely CEP-1 dependent. In addition, the anti-apoptotic ced-9/Bcl-2 was activated in response to the increase in cell death. This study provides a mechanism understanding of dispersed crude oil induced reproductive toxicity. PMID- 24496468 TI - "Vaccine hesitant" parents affect vaccination rates in some communities. PMID- 24496469 TI - Interface structure and reactivity of water-oxidation Ru-polyoxometalate catalysts on functionalized graphene electrodes. AB - We combine classical empirical potentials and density functional theory (DFT) calculations to characterize the catalyst/electrode interface of a promising device for artificial photosynthesis. This system consists of inorganic Ru polyoxometalate (Ru-POM) molecules that are supported by a graphitic substrate functionalized with organic dendrimers. The experimental atomic-scale characterization of the active interface under working conditions is hampered by the complexity of its structure, composition, as well as by the presence of the electrolyte or solvent. We provide a detailed atomistic model of the electrode/catalyst interface and show that the catalyst anchoring is remarkably dependent on water solvation. A tight host-guest binding geometry between the surface dendrimers and the Ru-POM catalyst is predicted under vacuum conditions. The solvent destabilizes this geometry, leads to unfolding of the dendrimers and to their flattening on the graphitic surface. The Ru-POM catalyst binds to this organic interlayer through a stable electrostatic link between one POM termination and the charged terminations of the dendrimers. The calculated dynamics and mobility of the Ru-POM catalyst at the electrode surface are in fair agreement with the available high-resolution transmission electron microscopy data. In addition, we demonstrate that the high thermodynamic water-oxidation efficiency of the Ru-POM catalyst is not affected by the binding to the electrode, thus rationalizing the similar electrochemical performances measured for homogeneous and heterogeneous Ru-POM catalysts. PMID- 24496471 TI - Low temperature reduction of free-standing graphene oxide papers with metal iodides for ultrahigh bulk conductivity. AB - Here we report a green and facile route for highly efficient reduction of free standing graphene oxide (GO) papers with metal iodide aqueous solutions at low cost. The metal iodides (MgI2, AlI3, ZnI2, FeI2) were synthesized directly from metal and iodine powder with water as a catalyzer. An extremely high bulk conductivity of 55088 S/m for reduced graphene oxide (rGO) papers were obtained with FeI2 solution of which pH = 0 at 95 degrees C for 6 hours. The catalytic effect of strong Lewis acid for the promotion of the nucleophilic substitution reaction is responsible for the greatly improved bulk conductivity. Furthermore, it was found that the layer-to-layer distance (dL) and the crystallinity of the rGO papers are regarded as two main factors affecting the bulk conductivity rather than C/O ratio and defect concentration. PMID- 24496473 TI - Fluorous enzymatic synthesis of phosphatidylinositides. AB - A fluorous tagging strategy coupled with enzymatic synthesis is introduced to efficiently synthesize multiple phosphatidylinositides, which are then directly immobilized on a fluorous polytetrafluoroethylene (PTFE) membrane to probe protein-lipid interactions. PMID- 24496474 TI - Controllable orientation of single silver nanowire using two fiber probes. AB - We report a strategy for realizing precise orientation of single silver nanowire using two fiber probes. By launching a laser of 980 nm wavelength into the two fibers, single silver nanowire with a diameter of 600 nm and a length of 6.5 MUm suspended in water was trapped and rotated by optical torque resulting from its interaction with optical fields outputted from the fiber probes. Angular orientation of the nanowire was controlled by varying the relative distance between the two fiber probes. The angular stiffness, which refers to the stability of orientation, was estimated to be on the order of 10(-19) J/rad(2).mW. The experiments were interpreted by theoretical analysis. PMID- 24496476 TI - Modulation of glyceraldehyde-3-phosphate dehydrogenase activity by surface functionalized quantum dots. AB - Enzymatic regulation is a fast and reliable diagnosis tool via identification and design of inhibitors for modulation of enzyme function. Previous reports on quantum dots (QDs)-enzyme interactions reveal a protein-surface recognition ability leading to promising applications in protein stabilization, protein delivery, bio-sensing and detection. However, the direct use of QDs to control enzyme inhibition has never been revealed to date. Here we show that a series of biocompatible surface-functionalized metal-chalcogenide QDs can be used as potent inhibitors for malignant cells through the modulation of enzyme activity, while normal cells remain unaffected. The in vitro activity of glyceraldehyde-3 phosphate dehydrogenase (GAPDH), an enzyme involved critically in the glycolysis of cancer cells, is inactivated selectively in a controlled way by the QDs at a significantly low concentration (nM). Cumulative kinetic studies delineate that the QDs undergo both reversible and irreversible inhibition mechanisms owing to the site-specific interactions, enabling control over the inhibition kinetics. These complementary loss-of-function probes may offer a novel route for rapid clinical diagnosis of malignant cells and biomedical applications. PMID- 24496477 TI - Rules for recruiting. PMID- 24496475 TI - Differential methylation of the TRPA1 promoter in pain sensitivity. AB - Chronic pain is a global public health problem, but the underlying molecular mechanisms are not fully understood. Here we examine genome-wide DNA methylation, first in 50 identical twins discordant for heat pain sensitivity and then in 50 further unrelated individuals. Whole-blood DNA methylation was characterized at 5.2 million loci by MeDIP sequencing and assessed longitudinally to identify differentially methylated regions associated with high or low pain sensitivity (pain DMRs). Nine meta-analysis pain DMRs show robust evidence for association (false discovery rate 5%) with the strongest signal in the pain gene TRPA1 (P=1.2 * 10(-13)). Several pain DMRs show longitudinal stability consistent with susceptibility effects, have similar methylation levels in the brain and altered expression in the skin. Our approach identifies epigenetic changes in both novel and established candidate genes that provide molecular insights into pain and may generalize to other complex traits. PMID- 24496479 TI - Modeling Controlled Photodegradation in Optically Thick Hydrogels. AB - There is a growing interest in developing dynamically responsive hydrogels whose material properties are modulated by environmental cues, including with light. These photoresponsive hydrogels afford spatiotemporal control of material properties through an array of photoaddition and photodegradation reactions. For photoresponsive hydrogels to be utilized most effectively in a broad range of applications, the photoreaction behavior should be well understood, enabling the design of dynamic materials with uniform or anisostropic material properties. Here, a general statistical-kinetic model has been developed to describe controlled photodegradation in hydrogel polymer networks containing photolabile crosslinks. The heterogeneous reaction rates that necessarily accompany photochemical reactions were described by solving a system of partial differential equations that quantify the photoreaction kinetics in the material. The kinetics were coupled with statistical descriptions of network structure in chain polymerized hydrogels to model material property changes and mass loss that occur during the photodegradation process. Finally, the physical relevance of the model was demonstrated by comparing model predictions with experimental data of mass loss and material property changes in photodegradable, PEG-based hydrogels. PMID- 24496478 TI - Sitagliptin ameliorates lipid profile changes and endothelium dysfunction induced by atherogenic diet in rabbits. AB - The aim of this work was to investigate the effect of sitagliptin on lipid profile and endothelium function in rabbits. Rabbits were fed either normal chow or atherogenic diet for 10 weeks. Sitagliptin (6 mg/kg/twice daily) was given orally for 6 weeks starting from week 4. Blood samples were collected at day 0, week 4, and week 10 to measure serum lipid profile, nitrate/nitrite (NOx), lactate dehydrogenase (LDH), and malondialdehyde (MDA) levels. The aortic arch and thoracic aorta were excised and used for histological study and isolated vascular preparations, respectively. Sitagliptin treatment significantly reduced the levels of low density lipoprotein cholesterol, NOx, total cholesterol, and MDA, but not triglyceridess. Additionally, sitagliptin markedly reversed the decrease in high-density lipoprotein cholesterol level. Moreover, sitagliptin significantly improved the impaired endothelium-dependent relaxation, without affecting phenylepherine-induced contraction and sodium nitroprusside-induced endothelium-independent relaxation in isolated aortic rings. Histopathological examination revealed marked reduction of the atherosclerotic lesions by sitagliptin. Immunohistochemical analysis of nuclear factor-kappa B in aortic tissue showed marked reduction in its expression upon treatment with sitagliptin compared with atherogenic diet-fed rabbits. These results suggest that sitagliptin may be an effective pharmacological approach for preventing atherosclerotic lesion progression in rabbits. PMID- 24496480 TI - Point-of-Care Test Equipment for Flexible Laboratory Automation. AB - Blood tests are some of the core clinical laboratory tests for diagnosing patients. In hospitals, an automated process called total laboratory automation, which relies on a set of sophisticated equipment, is normally adopted for blood tests. Noting that the total laboratory automation system typically requires a large footprint and significant amount of power, slim and easy-to-move blood test equipment is necessary for specific demands such as emergency departments or small-size local clinics. In this article, we present a point-of-care test system that can provide flexibility and portability with low cost. First, the system components, including a reagent tray, dispensing module, microfluidic disk rotor, and photometry scanner, and their functions are explained. Then, a scheduler algorithm to provide a point-of-care test platform with an efficient test schedule to reduce test time is introduced. Finally, the results of diagnostic tests are presented to evaluate the system. PMID- 24496481 TI - Reaction-induced phase separation in a bisphenol A-aniline benzoxazine-N,N' (2,2,4-trimethylhexane-1,6-diyl)bis(maleimide)-imidazole blend: the effect of changing the concentration on morphology. AB - The effect of the concentration changes on morphology was researched by modulating the molar ratio of bisphenol A-aniline benzoxazine (BA-a) and N,N' (2,2,4-trimethylhexane-1,6-diyl)bis(maleimide) (TBMI); the relationships between the concentration changes, the curing rate, rheological properties, and morphologies of blends were examined in this paper. The cured blends showed different morphologies at different concentrations, and the morphologies changed from a sea-island structure to a bi-continuous structure followed by a homogeneous structure when the molar ratio of BA-a was decreased. This effect was caused by the relative rates of the phase separation and the curing reaction. Meanwhile, from the thermodynamic calculations, it was found that the concentration changes altered the Gibbs free energy, while the miscibility of blends improved after decreasing the BA-a content. Moreover, from the analysis and the Flory-Huggins equation, it was found that the phase separation of BA-a TBMI-imidazole occurred due to the molecular weights of the components and the large discrepancy between those weights. PMID- 24496482 TI - Judge gives permission for compulsory caesarean sections twice in a week. PMID- 24496484 TI - Synthesis, structure and reactivity of group 4 corrole complexes. AB - A series of early transition metal corrole complexes has been prepared via salt metathesis with the corresponding lithium corrole. Their characterization by single crystal X-ray diffraction, NMR, and absorption spectroscopy is described. Organometallic derivatives of the titanium complex were obtained via treatment of 2 with NaCp* or ClMgCH2SiMe3. PMID- 24496483 TI - [New developments in the antiarrhythmic therapy of atrial fibrillation]. AB - Atrial fibrillation often affects elderly people with cardiovascular disease and takes a progressive course with increasing resistance to treatment. For the latter, electrical and structural changes (remodelling) seem to be responsible that are directly related to the high excitatory rate in the atria. Therapeutic strategies for atrial fibrillation consist of (i) treating the underlying cardiovascular disease, (ii) re-establishing sinus rhythm and (iii) reducing ventricular rate. Rapid pharmacological or electrical cardioversion is expected to prevent remodelling. Classical antiarrhythmic drugs are notoriously ineffective and burdened with serious cardiac and extracardiac side effects so that there is an urgent need for effective and safe novel compounds. In this review the three recently introduced drugs dronedarone, vernakalant and ranolazine are discussed with respect to the use in atrial fibrillation. Other new antiarrhythmic agents are still in the developmental phase and aim at atria selective mechanisms thereby excluding ventricular proarrhythmic effects. The mechanisms of action will be discussed in the context of the present understanding of the pathophysiology of onset and maintenance of atrial fibrillation. PMID- 24496486 TI - Autocatalytic oxidization of nanosilver and its application to spectral analysis. AB - The stable yellow nanosilver (AgNP) and blue nanosilver (AgNPB) sols were prepared by the NaBH4 procedure. The new nanocatalytic reaction of AgNP-NaCl-H2O2 was investigated by surface plasmon resonance (SPR) absorption, resonance Rayleigh scattering (RRS), surface-enhanced Raman scattering (SERS) and scanning electron microscope (SEM) techniques. The autocatalytic oxidization of Ag on AgNP surface by H2O2 was observed firstly and the AgNP/AgCl nanoparticles were characterized. The [Ag(+)] from AgNP is different to the Ag(+) from AgNO3 that adsorb on the AgNP surface. An autocatalytic oxidization mechanism was proposed to explain experimental phenomena. The relationship between the SPR absorption peaks and the RRS peaks of AgNPB was studied, and three characteristic RRS peaks called as out-of-plane quadrupole, out-of-plane dipole and in-plane dipole RRS peaks were observed firstly. Using AgNP as nanoprobe, a simple, sensitive and selective RRS method was developed for assay of H2O2 in the range of 2.0 * 10(-8) 8.0 * 10(-5) mol/L. PMID- 24496487 TI - Predicting asthma in preschool children at high risk presenting in primary care: development of a clinical asthma prediction score. AB - BACKGROUND: A setting-specific asthma prediction score for preschool children with wheezing and/or dyspnoea presenting in primary healthcare is needed since existing indices are mainly based on general populations. AIMS: To find an optimally informative yet practical set of predictors for the prediction of asthma in preschool children at high risk who present in primary healthcare. METHODS: A total of 771 Dutch preschool children at high risk of asthma were followed prospectively until the age of six years. Data on asthma symptoms and environmental conditions were obtained using validated questionnaires and specific IgE was measured. At the age of six years the presence of asthma was assessed based on asthma symptoms, medication, and bronchial hyper responsiveness. A clinical asthma prediction score (CAPS) was developed using bootstrapped multivariable regression methods. RESULTS: In all, 438 children (56.8%) completed the study; the asthma prevalence at six years was 42.7%. Five parameters optimally predicted asthma: age, family history of asthma or allergy, wheezing-induced sleep disturbances, wheezing in the absence of common colds, and specific IgE. CAPS scores range from 0 to 11 points; scores <3 signified a negative predictive value of 78.4% while scores of >7 signified a positive predictive value of 74.3%. CONCLUSIONS: We have developed an easy-to-use CAPS for preschool children with symptoms suggesting asthma who present in primary healthcare. After suitable validation, the CAPS may assist in guiding shared decision-making to tailor the need for medical or non-medical interventions. External validation of the CAPS is needed. PMID- 24496488 TI - Principles of modern solid-phase oligosaccharide synthesis. AB - The past few decades have seen a renewed interest in the chemical synthesis of oligosaccharides, owing to increased recognition of their biological importance. Of the different approaches to oligosaccharides, solid-phase synthesis has emerged as a particularly attractive option, due in large part to its potential for automation. This perspective describes principles to consider when planning solid-phase oligosaccharide synthesis (SPOS), including recent achievements and areas where future work is necessary. PMID- 24496489 TI - Sleep difficulties are associated with increased symptoms of psychopathology. AB - Sleep problems often co-occur with psychopathological conditions and affective dysregulation. Individuals with mood disorders have significantly higher rates of sleep disturbances than healthy individuals, and among those with mood disorders, sleep problems are associated with lower rates of remission and response to treatment. Sleep disruption may itself be a risk factor for various forms of psychopathology, as experimental sleep deprivation has been found to lead to increased affective, cognitive, and somatic symptoms within healthy volunteers. However, little is known about the relationship between recurring sleep complaints in a naturalistic environment and symptoms of psychopathology among healthy individuals. In the present study, 49 healthy adults (21 males and 28 females) reported sleep quality and completed the Personality Assessment Inventory, a standardized self-report assessment of symptoms of psychopathology. Consistent with prior published findings during total sleep deprivation, individuals endorsing self-reported naturally occurring sleep problems showed higher scores on scales measuring somatic complaints, anxiety, and depression. Furthermore, the reported frequency of sleep disturbance was closely linked with the severity of self-reported symptoms. While causal directionality cannot be inferred, these findings support the notion that sleep and emotional functioning are closely linked. PMID- 24496491 TI - Interrelations between the perception of time and space in large-scale environments. AB - Interactions between perceived temporal and spatial properties of external stimuli (e.g. duration and size) suggest common neural mechanisms underlying the perception of time and space. This conclusion, however, lacks support from studies in large-scale environments, showing that judgements on travelled distances and associated travel times are independent from each other. Here, we used a different approach to test whether the perception of travelled distances is influenced by the perception of time. Unlike previous studies, in which temporal and spatial judgements were related to the same experience of walking, we assessed time and distance perception in analogous, but separate versions of estimation and production tasks. In estimation tasks, participants estimated the duration of a presented sound (time) or the length of a travelled distance (space), and in production tasks, participants terminated a sound after a numerically specified duration (time) or covered a numerically specified distance (space). The results show systematic overestimation of time and underestimation of travelled distance, and the latter reflecting previously reported misperceptions of visual distance. Time and distance judgements were related within individuals for production, but not for estimation tasks. These results suggest that temporal information might constitute a probabilistic cue for path integration. PMID- 24496490 TI - Very early processing of emotional words revealed in temporoparietal junctions of both hemispheres by EEG and TMS. AB - We investigate the contribution of both hemispheres in a lateralised lexical decision paradigm with emotional and neutral words in healthy volunteers. In a first experiment, high-density EEG analysis using source imaging methods revealed early specific participation of the temporoparietal junctions (TPJ) in both hemispheres for the detection of words. Then, in an event-related transcranial magnetic stimulation experiment with the same task, the disruption of left or right TPJ compared with a control stimulation over the vertex showed a slowing that is more pronounced when words are emotional and presented in the left visual field (LVF). This indicates that interference with both left and right TPJ results in impaired processing of words that were presented to the LVF. In addition, these results point to a specific cooperative contribution of the right hemisphere in the processing of words with emotional content compared with neutral words at very early stages. Results from the two experiments can be integrated in a brain-based spatiotemporal model of the early detection of written words. PMID- 24496492 TI - Flanker interference effects in a line bisection task. AB - Previous studies have shown that flanking distractors influence line bisection. In the present study, we examined if reaching the flanker after bisecting the line resulted in a variation of flanker interference on line bisection. Right- and left-handed participants were asked to bisect a horizontal line flanked by a dot (bisection task, B-task) or to bisect the line and then to reach the dot (bisection plus reaching task, BR-task). The dot was placed laterally to, and above or below, the line edge. The results showed that in both tasks the subjective midpoint was shifted away from the position of the dot. However, this effect was greater in the BR-task than in the B-task. We suggest that the requirement to perform an action to the flanker in the BR-task induced participants to pay more attention to the dot, enhancing its salience and distorting effects on line bisection. PMID- 24496493 TI - Effect of ethanolic extract of Capsicum frutescens L. on adult female of Rhipicephalus microplus (Ixodidae). AB - This study evaluated the effects of ethanol extract of Capsicum frutescens L. (Solanaceae), colloquially known as malagueta pepper, on egg production and hatching rate of larvae of Rhipicephalus microplus. Plant samples were collected in Montes Claros, Minas Gerais, Brazil. Selected mature fruits were washed, dehydrated in a forced air oven at 40 +/- 5 degrees C to constant weight. The material was incubated in absolute ethanol during 10 days, and the extract was filtered, dried, and stored in amber vials under refrigeration at 4 degrees C. Engorged adult female ticks were immersed in 10 ml solutions of ethanol extracts at 25, 50, 75, 100, or 150 mg ml(-1) dry matter, solubilized in dimethyl sulfoxide (DMSO) at 1% v/v. These concentrations were compared to distilled water or 1% v/v DMSO in distilled water as negative controls and a commercial product as positive control. The extract resulted in significantly lower oviposition at all tested concentrations when compared to the negative controls. On days 2 and 3 posttreatment, mortality rates of female ticks >=55% were observed for concentrations >=75 mg ml(-1). These concentrations resulted in a significantly lower hatchability mean, and the LC90 on hatching inhibition of R. microplus, estimated by probit analysis, was 91.8 mg ml(-1). High acaricidal in vitro effect was verified, and toxicological tests and analyses in vivo are important to determine appropriate dosages and frequency of the application necessary to promote this extract as safe and effective alternative for control of R. microplus. PMID- 24496494 TI - Protective effects of acetaminophen on ibuprofen-induced gastric mucosal damage in rats with associated suppression of matrix metalloproteinase. AB - Nonsteroidal anti-inflammatory drugs (NSAIDs) are known to cause gastric mucosal damage as a side effect. Acetaminophen, widely used as an analgesic and antipyretic drug, has gastroprotective effects against gastric lesions induced by absolute ethanol and certain NSAIDs. However, the mechanisms that underlie the gastroprotective effects of acetaminophen have not yet been clarified. In the present study, we examined the role and protective mechanism of acetaminophen on ibuprofen-induced gastric damage in rats. Ibuprofen and acetaminophen were administered orally, and the gastric mucosa was macroscopically examined 4 hours later. Acetaminophen decreased ibuprofen-induced gastric damage in a dose dependent manner. To investigate the mechanisms involved, transcriptome analyses of the ibuprofen-damaged gastric mucosa were performed in the presence and absence of acetaminophen. Ingenuity pathway analysis (IPA) software revealed that acetaminophen suppressed the pathways related to cellular assembly and inflammation, whereas they were highly activated by ibuprofen. On the basis of gene classifications from the IPA Knowledge Base, we identified the following five genes that were related to gastric damage and showed significant changes in gene expression: interleukin-1beta (IL-1beta), chemokine (C-C motif) ligand 2 (CCL2), matrix metalloproteinase-10 (MMP-10), MMP-13, and FBJ osteosarcoma oncogene (FOS). Expression of these salient genes was confirmed using real-time polymerase chain reaction. The expression of MMP-13 was the most reactive to the treatments, showing strong induction by ibuprofen and suppression by acetaminophen. Moreover, MMP-13 inhibitors decreased ibuprofen-induced gastric damage. In conclusion, these results suggest that acetaminophen decreases ibuprofen-induced gastric mucosal damage and that the suppression of MMP-13 may play an important role in the gastroprotective effects of acetaminophen. PMID- 24496496 TI - Dissociative electron attachment to gas phase thiothymine: experimental and theoretical approaches. AB - In this contribution we have investigated experimentally and theoretically the interaction of low energy electrons with gas phase thiothymine (a sulphur containing analogue of thymine). We observe that the presence of the sulphur atom within thiothymine strongly controls the fragmentation dynamics. With the exception of the (M - H)(-) anion formation, the most favorable reaction channels are associated with a loss of sulphur containing negative fragments (i.e., the formation of S(-), SCN(-) and (M - S)(-)) suggesting that these resonances are localized at the C=S group. Hence the present results demonstrate that certain reactions can be controlled by substitution of the sulphur atom at specific molecular sites within nucleobases. Our study thus represents a starting point for a physicochemical understanding of the action of sulphur-containing antimetabolites when used in chemoradiotherapy. PMID- 24496495 TI - Evaluating HER2 amplification status and acquired drug resistance in breast cancer cells using Raman spectroscopy. AB - The overexpression of human epidermal growth factor receptor 2 (HER2) is associated with increased breast cancer recurrence and worse prognosis. Effective treatments such as trastuzumab and lapatinib for patients with HER2 overexpression target the blockade of HER2 signaling activities but are often limited by the emergence of acquired drug resistance. This study applied Raman spectroscopy to differentially identify the amplification status of HER2 in cells and to characterize the biochemical composition of lapatinib resistant and sensitive HER2+ breast cancer cells in response to the drug. Raman spectra from BT474 (HER2+ breast cancer cell), MCF-10A (HER2- control), and HER2+ MCF-10A (HER2+ control) were analyzed using lasso and elastic-net regularized generalized linear models (glmnet) for multivariate statistical analysis and were discriminated to groups of different HER2 expression status with an overall 99% sensitivity and specificity. Enhanced lipid content and decreased proteome were observed in HER2+ cells. With lapatinib treatment, lapatinib-resistant breast cancer cells demonstrated sustained lipogenesis compared with the sensitive cells. PMID- 24496498 TI - Catalytic nanoreactors in continuous flow: hydrogenation inside single-walled carbon nanotubes using supercritical CO2. AB - One nanometre wide carbon nanoreactors are utilised as the reaction vessel for catalytic chemical reactions on a preparative scale. Sub-nanometre ruthenium catalytic particles which are encapsulated solely within single-walled carbon nanotubes offering a unique reaction environment are shown to be active when embedded in a supercritical CO2 continuous flow reactor. A range of hydrogenation reactions were tested and the catalyst displayed excellent stability over extended reaction times. PMID- 24496497 TI - Age-specific activation of cerebral areas in motor imagery--a fMRI study. AB - INTRODUCTION: The objectives of this study were to study the age-specific activation patterns of cerebral areas during motor execution (ME) and motor imaging (MI) of the upper extremities and to discuss the age-related neural mechanisms associated with ME or MI. METHODS: The functional magnetic resonance imaging technique was used to monitor the pattern and intensity of brain activation during the ME and MI of the upper extremities in 20 elderly (>50 years) and 19 young healthy subjects (<25 years). RESULTS: No major differences were identified regarding the activated brain areas during ME or MI between the two groups; however, a minor difference was noted. The intensity of the activated brain area during ME was stronger in the older group than in the younger group, while the results with MI were the opposite. The posterior central gyrus and supplementary motor area during MI were more active in the younger group than in the older group. The putamen, lingual, and so on demonstrated stronger activation during dominant hand MI in the older group. CONCLUSION: The results of this study revealed that the brain structure was altered and that neuronal activity was attenuated with age, and the cerebral cortex and subcortical tissues were found to be over-activated to achieve the same level of ME and MI, indicating that the activating effects of the left hemisphere enhanced with age, whereas the inhibitory effects declined during ME, and activation of the right hemisphere became more difficult during MI. PMID- 24496499 TI - Searching for Grendel: origin and global spread of the C9ORF72 repeat expansion. AB - Recent advances are uncovering more and more of the genetic architecture underlying amyotrophic lateral sclerosis (ALS), a fatal neurodegenerative condition that affects ~6,000 Americans annually. Chief among these was the discovery that a large repeat expansion in the C9ORF72 gene is responsible for an unprecedented portion of familial and sporadic ALS cases. Much has been published on how this expansion disrupts neuronal homeostasis and how gene-based therapy might be an effective treatment in the future. Nevertheless, it is instructive to look back at the origins of this important mutation. In this opinion piece, we attempt to answer three key questions concerning C9ORF72. First, how many times did the expansion occur throughout human history? Second, how old is the expansion? And finally and perhaps most importantly, how did the expansion spread throughout Europe? We speculate that the expansion occurred only once in the past, that this event took place in the Finnish population and that the Vikings and their descendants were responsible for disseminating this mutation throughout the rest of the continent. PMID- 24496501 TI - A tuned affinity-based staurosporine probe for in situ profiling of protein kinases. AB - A clickable and cell-permeable affinity-based probe (AfBP) was designed from staurosporine, by incorporating an electrophilic chloroacetamide warhead to facilitate in situ proteome labeling of a range of potential kinase targets. PMID- 24496502 TI - Leaf anatomy and its implications for phylogenetic relationships in Taxaceae s. l. AB - The comparative study on leaf anatomy and stomata structures of six genera of Taxaceae s. l. was conducted. Leaf anatomical structures were very comparable to each other in tissue shape and their arrangements. Taxus, Austrotaxus, and Pseudotaxus have no foliar resin canal, whereas Amentotaxus, Cephalotaxus, and Torreya have a single resin canal located below the vascular bundle. Among them, Torreya was unique with thick-walled, almost round sclerenchymatous epidermal cells. In addition, Amentotaxus and Torreya were comprised of some fiber cells around the vascular bundle. Also, Amentotaxus resembled Cephalotaxus harringtonia and its var. nana because they have discontinuous fibrous hypodermis. However, C. fortunei lacked the same kind of cells. Stomata were arranged in two stomatal bands separated by a mid-vein. The most unique stomatal structure was of Taxus with papillose accessory cells forming stomatal apparatus and of Torreya with deeply seated stomata covered with a special filament structure. Some morphological and molecular studies have already been discussed for the alternative classification of taxad genera into different minor families. The present study is also similar to these hypotheses because each genus has their own individuality in anatomical structure and stomata morphology. In conclusion, these differences in leaf and stomata morphology neither strongly support the two tribes in Taxaceae nor fairly recognize the monogeneric family, Cephalotaxaceae. Rather, it might support an alternative classification of taxad genera in different minor families or a single family Taxaceae including Cephalotaxus. In this study, we would prefer the latter one because there is no clear reason to separate Cephalotaxus from the rest genera of Taxaceae. Therefore, Taxaceae should be redefined with broad circumscriptions including Cephalotaxus. PMID- 24496503 TI - A facile solution route to deposit TiO2 nanowire arrays on arbitrary substrates. AB - A facile solution-based technique was developed to grow vertically aligned TiO2 nanowires with predominantly anatase phase on arbitrary substrates of stainless steel, glass, silicon wafer and carbon cloth at the low temperature of 80 degrees C and in an open atmosphere. PMID- 24496500 TI - Disruption of long-range gene regulation in human genetic disease: a kaleidoscope of general principles, diverse mechanisms and unique phenotypic consequences. AB - The precise control of gene expression programs is crucial for the establishment of the diverse gene activity patterns required for the correct development, patterning and differentiation of the myriad of cell types within an organism. The crucial importance of non-coding regions of the genome in the control of gene regulation is well established and depends on a diverse group of sequence fragments called cis-regulatory elements that reside in these regions. Advances in novel genome-wide techniques have greatly increased the ability to identify potential regulatory elements. In contrast, their functional characterisation and the determination of their diverse modes of action remain a major bottleneck. Greater knowledge of gene expression control is of major importance for human health as disruption of gene regulation has become recognised as a significant cause of human disease. Appreciation of the role of cis-regulatory polymorphism in natural variation and susceptibility to common disease is also growing. While novel techniques such as GWAS and NGS provide the ability to collect large genomic datasets, the challenge for the twenty-first century will be to extract the relevant sequences and how to investigate the functional consequences of disease-associated changes. Here, we review how studies of transcriptional control at selected paradigm disease gene loci have revealed general principles of cis-regulatory logic and regulatory genome organisation, yet also demonstrate how the variety of mechanisms can combine to result in unique phenotypic outcomes. Integration of these principles with the emerging wealth of genome-wide data will provide enhanced insight into the workings of our regulatory genome. PMID- 24496505 TI - One-step repair for cartilage defects in a rabbit model: a technique combining the perforated decalcified cortical-cancellous bone matrix scaffold with microfracture. AB - BACKGROUND: Cartilage repair still presents a challenge to clinicians and researchers alike. A more effective, simpler procedure that can produce hyaline like cartilage is needed for articular cartilage repair. HYPOTHESIS: A technique combining microfracture with a biomaterial scaffold of perforated decalcified cortical-cancellous bone matrix (DCCBM; composed of cortical and cancellous parts) would create a 1-step procedure for hyaline-like cartilage repair. STUDY DESIGN: Controlled laboratory study. METHODS: For the in vitro portion of this study, mesenchymal stem cells (MSCs) were isolated from bone marrow aspirates of New Zealand White rabbits. Scanning electron microscopy (SEM), confocal microscopy, and 1,9-dimethylmethylene blue assay were used to assess the attachment, proliferation, and cartilage matrix production of MSCs grown on a DCCBM scaffold. For the in vivo experiment, full-thickness defects were produced in the articular cartilage of the trochlear groove of 45 New Zealand White rabbits, and the rabbits were then assigned to 1 of 3 treatment groups: perforated DCCBM combined with microfracture (DCCBM+M group), perforated DCCBM alone (DCCBM group), and microfracture alone (M group). Five rabbits in each group were sacrificed at 6, 12, or 24 weeks after the operation, and the repair tissues were analyzed by histological examination, assessment of matrix staining, SEM, and nanoindentation of biomechanical properties. RESULTS: The DCCBM+M group showed hyaline-like articular cartilage repair, and the repair tissues appeared to have better matrix staining and revealed biomechanical properties close to those of the normal cartilage. Compared with the DCCBM+M group, there was unsatisfactory repair tissues with less matrix staining in the DCCBM group and no matrix staining in the M group, as well as poor integration with normal cartilage and poor biomechanical properties. CONCLUSION: The DCCBM scaffold is suitable for MSC growth and hyaline-like cartilage repair induction when combined with microfracture. CLINICAL RELEVANCE: Microfracture combined with a DCCBM scaffold is a promising method that can be performed and adopted into clinical treatment for articular cartilage injuries. PMID- 24496506 TI - Analysis of pitching velocity in major league baseball players before and after ulnar collateral ligament reconstruction. AB - BACKGROUND: Ulnar collateral ligament (UCL) reconstructions are relatively common among professional pitchers in Major League Baseball (MLB). To the authors' knowledge, there has not been a study specifically analyzing pitching velocity after UCL surgery. These measurements were examined in a cohort of MLB pitchers before and after UCL reconstruction. HYPOTHESIS: There is no significant loss in pitch velocity after UCL reconstruction in MLB pitchers. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Between the years 2008 to 2010, a total of 41 MLB pitchers were identified as players who underwent UCL reconstruction. Inclusion criteria for this study consisted of a minimum of 1 year of preinjury and 2 years of postinjury pitch velocity data. After implementing exclusion criteria, performance data were analyzed from 28 of the 41 pitchers over a minimum of 4 MLB seasons for each player. A pair-matched control group of pitchers who did not have a known UCL injury were analyzed for comparison. RESULTS: Of the initial 41 players, 3 were excluded for revision UCL reconstruction. Eight of the 38 players who underwent primary UCL reconstruction did not return to pitching at the major league level, and 2 players who met the exclusion criteria were omitted, leaving data on 28 players available for final velocity analysis. The mean percentage change in the velocity of pitches thrown by players who underwent UCL reconstruction was not significantly different compared with that of players in the control group. The mean innings pitched was statistically different only for the year of injury and the first postinjury year. There were also no statistically significant differences between the 2 groups with regard to commonly used statistical performance measurements, including earned run average, batting average against, walks per 9 innings, strikeouts per 9 innings, and walks plus hits per inning pitched. CONCLUSION: There were no significant differences in pitch velocity and common performance measurements between players who returned to MLB after UCL reconstruction and pair-matched controls. PMID- 24496507 TI - Relationship between concussion history and neurocognitive test performance in National Football League draft picks. AB - BACKGROUND: There are limited empirical data available regarding the relationship between concussion history and neurocognitive functioning in active National Football League (NFL) players in general and NFL draft picks in particular. Potential NFL draft picks undergo 2 neurocognitive tests at the National Invitational Camp (Scouting Combine) every year: the Wonderlic and, since 2011, the Immediate Post-concussion Assessment and Cognitive Testing (ImPACT). After conclusion of the combine and before the draft, NFL teams invite potential draft picks to their headquarters for individual visits where further assessment may occur. PURPOSE: To examine the relationship between concussion history and neurocognitive performance (ImPACT and Wonderlic) in a sample of elite NFL draft picks. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: Over 7 years, 226 potential draft picks were invited to visit a specific NFL team's headquarters after the combine. The athletes were divided into 3 groups based on self-reported concussion history: no prior concussions, 1 prior concussion, and 2 or more prior concussions. Neurocognitive measures of interest included Wonderlic scores (provided by the NFL team) and ImPACT composite scores (administered either at the combine or during a visit to the team headquarters). The relationship between concussion history and neurocognitive scores was assessed, as were the relationships among the 2 neurocognitive tests. RESULTS: Concussion history had no relationship to neurocognitive performance on either the Wonderlic or ImPACT. CONCLUSION: Concussion history did not affect performance on either neurocognitive test, suggesting that for this cohort, a history of concussion may not have adverse effects on neurocognitive functioning as measured by these 2 tests. This study reveals no correlation between concussion history and neurocognitive test scores (ImPACT, Wonderlic) in soon-to-be active NFL athletes. PMID- 24496508 TI - Preoperative factors affecting footprint coverage in rotator cuff repair. AB - BACKGROUND: One of the goals of rotator cuff repair is to restore the torn tendon to its original insertion anatomically. However, it is sometimes difficult to restore the entire footprint. PURPOSE: This study was undertaken to evaluate the variables affecting this repair coverage and to discern the differences in retear rate and clinical results between complete and incomplete footprint coverage in rotator cuff surgery. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: From 2007 to 2009, a total of 85 consecutive repairs for medium-to-large rotator cuff tears were identified as having complete or incomplete coverage of their original footprints. We defined the complete footprint coverage (CC) group as patients who had >50% of their footprint covered during repair and the incomplete (IC) group as <50% of their footprint. Factors affecting the amount of footprint coverage were evaluated, and multivariable analysis was conducted to identify independent factors. To assess the final outcome according to the amount of footprint coverage, retear and clinical outcomes were compared between the CC and IC groups. RESULTS: Fifty-seven repairs were defined in the CC group and 28 repairs in the IC group. Preoperatively, age, tear size in coronal oblique and sagittal oblique planes, Goutallier fatty infiltration, and atrophy of the supraspinatus affected the amount of footprint coverage in univariate analysis. In multivariable analysis, however, tear size in the coronal plane was the only independent factor affecting footprint coverage in rotator cuff repair. On postoperative MRI, 45.6% of the CC group had an intact tendon, 45.6% had a delaminated partial retear, and 8.8% had a full-thickness retear; in the IC group, 17.9% had an intact tendon, 60.7% had a delaminated partial retear, and 21.4% had a full-thickness retear. There was a statistically significant difference in the proportion of tendon integrity between groups (P = .028). Clinical scores and range of motion at final follow-up showed no difference between the 2 groups. CONCLUSION: Tear size in the coronal plane was the only independent factor affecting the amount of footprint coverage. Repair quality based on retear classification was different between the 2 groups. However, both complete and incomplete footprint coverage in rotator cuff repair showed no differences in clinical scores and range of motion at short-term follow-up. PMID- 24496509 TI - The role of immunologic response in fresh osteochondral allografting of the knee. AB - BACKGROUND: Osteochondral allografting, a restorative treatment option for articular cartilage lesions in the knee, involves transplantation of fresh osteochondral tissue with no tissue matching. Although retrieval studies have not consistently shown evidence of immunologic response, development of anti-human leukocyte antigen class I cytotoxic antibodies has been observed in allograft recipients. HYPOTHESIS: Postallograft antibody formation is related to graft size and may affect clinical outcome. STUDY DESIGN: Case-control study; Level of evidence, 3. METHODS: This study retrospectively compared 42 antibody-positive postallograft patients with 42 antibody-negative patients. Groups were matched for age, sex, and body mass index but not intra-articular disease severity. Seventeen patients (20%) were lost to follow-up. Of the remaining 67 patients (33 antibody-positive and 34 antibody-negative), average follow-up time was 50.3 months (range, 24-165 months). Mean age was 38.1 years (range, 15-68 years) with 58% being male. Graft area was categorized as small (<5 cm2), medium (5-10 cm2), or large (>10 cm2). Graft survival and Knee Society function scores were used to measure clinical outcome. RESULTS: Of the 84 patients, 80 had graft area data. Of 27 patients with large graft area, 19 (70%) had positive postoperative antibody screens, compared with 1 of 16 (6%) with small graft area (P < .001). Graft survival rates in the antibody-positive and antibody-negative groups were 64% and 79%, respectively (P = .152). Mean postoperative Knee Society function scores in surviving antibody-positive and antibody-negative groups were 88.3 and 84.6 points, respectively (P = .482). CONCLUSION: Antibody development after fresh, non-tissue-matched osteochondral allograft transplants in the knee appears related to graft size. No difference was observed in clinical outcome between groups. Graft survival is multifactorial, and the effect that the immunologic response has on clinical outcome merits further investigation. PMID- 24496510 TI - Immunocytochemical analysis of misplaced rhodopsin-positive cells in the developing rodent retina. AB - During the first postnatal weeks of the developing rodent retina, rhodopsin can be detected in a number of neuron-like cells in the inner retina. In the present study, we aim to characterize the morphology, number and staining characteristics of this peculiar population. Misplaced rhodopsin-positive cells (MRCs) were analyzed on retinas of four rodent species, labeled with various rhodopsin specific antibodies. To investigate their possible relation with non photoreceptor cells, sections were double-stained against distinct retinal cell types and proteins of the phototransduction cascade. The possibility of synapse formation and apoptosis were also investigated. In all species studied, misplaced cells comprised a few percent of all rhodopsin-positive elements. This ratio declined from the end of the second week and MRCs disappeared nearly completely from the retina by P24. MRCs resembled resident neurons of the inner retina, while outer segment-like processes were seen only rarely. MRCs expressed no other photopigment types and showed no colocalization with any of the bipolar, horizontal, amacrine and ganglion cell markers used. While all MRCs colabeled for arrestin and recoverin, other proteins of the phototransduction cascade were only detectable in a minority of the population. Only a few MRCs were shown to form synaptic-like endings. Our results showed that, during development, some rhodopsin-expressing cells are displaced to the inner retinal layers. Although most MRCs lack morphological features of photoreceptors, they contain some but not all, elements of the phototransduction cascade, indicating that they are most probably misplaced rods that failed to complete differentiation and integrate into the photoreceptor mosaic. PMID- 24496511 TI - Reciprocal disruption of neuronal signaling and Abeta production mediated by extrasynaptic NMDA receptors: a downward spiral. AB - It is becoming increasingly clear that aberrant neuronal activity can be the cause and the result of amyloid beta production. Synaptic activation facilitates non-amyloidogenic processing of amyloid precursor protein (APP) and cell survival, primarily through synaptic NMDA receptors (NMDARs) and perhaps specifically those containing GluN2A-subunits. In contrast, extrasynaptic and GluN2B-containing NMDARs promote beta-secretase cleavage of APP into amyloid-beta (Abeta). The opposing nature of these NMDAR populations is reflected in their control over cell survival and death pathways. Subtle changes in glutamate homeostasis may shift the balance between these pathways and could play a role in Alzheimer's disease (AD). Indeed, Abeta production, regional loss of brain connectivity and neurodegeneration correlate with neuronal activity in AD patients. From another perspective, Abeta oligomers (Abetao) alter neuronal signaling through several mechanisms involving NMDARs and intracellular calcium mishandling. While Abetao affect multiple receptors, GluN2B-NMDARs have emerged as primary mediators of altered synaptic plasticity and neurotoxicity. Memantine and its successor, NitroMemantine, are efficient at blocking or reversing the deleterious actions of Abetao largely due to their selectivity for extrasynaptic NMDARs. Recently, Abetao were shown to trigger astrocytic release of glutamate to the extrasynaptic space where it activates NMDARs to promote further Abeta production and synaptic depression. Combined with the reciprocal regulation between neuronal activity and Abeta production, extrasynaptic glutamate release adds to a maladaptive model and ultimately results in synaptotoxicity and neurodegeneration of AD. Extrasynaptic NMDAR antagonists remain as a promising therapeutic avenue by interfering with this cascade. PMID- 24496512 TI - Roles of chromatin remodeling BAF complex in neural differentiation and reprogramming. AB - ATP-dependent BAF chromatin remodeling complexes play an essential role in the maintenance of the gene expression program by regulating the structure of chromatin. There is increasing evidence that BAF complexes based on the alternative ATPase subunits, Brg1 and Brm, control the differentiation of neural stem cells (NSCs) to generate distinct neural cell types and modulate trans differentiation between cell types. The BAF complexes have dedicated functions at different stages of neural differentiation that appear to arise by combinatorial assembly of their subunits. Furthermore, the differentiation of NSCs is regulated by the tight interactions between the BAF chromatin remodeling complex and the transcriptional machinery. Here, we review recent insights into the functional interaction between BAF complexes and various transcription factors (TFs) in neural differentiation and cellular reprogramming. PMID- 24496513 TI - First trimester pregnancy volumes and subsequent small for gestational age fetuses. AB - OBJECTIVE: To examine whether in the first trimester, placental, gestational sac and fetal volumes are different in pregnancies that result in small for gestational age (SGA) compared to average for gestational age (AGA) neonates. METHODS: Case-control study comparing first trimester 3D volumes of the placenta, the fetus and the gestational sac between SGA and AGA pregnancies. 3D volumes were acquired for quality assurance and documentation. Pregnancy volumes were calculated by the virtual organ computer-aided analysis technique. Linear regression analysis was used to compute a normal range for the placental, gestational sac and fetal volume based on the crown rump length (CRL) in AGA pregnancies. Multiple regression analysis was used to examine significant influencing covariates. A Student's t test was used to compare the difference between the SGA and AGA group. RESULTS: The study population consisted of 19 first trimester pregnancies with subsequent SGA neonates and 105 control pregnancies. In the AGA group, all pregnancy volumes were significantly dependent on the CRL. After controlling the CRL effect, the placental, gestational sac and fetal volumes were not significantly different between the SGA and AGA group. CONCLUSION: First trimester 3D pregnancy volume measurements are not different in SGA or AGA pregnancies. PMID- 24496514 TI - Comprehensive visualization of paresthesia in breast cancer survivors. AB - PURPOSE: As breast cancer survivors are benefiting increasingly from advanced forms of therapy, the side effects of locoregional treatment in the adjuvant setting are becoming more and more important. This article presents a new method of assessing the spatial distribution of paresthesia in breast cancer survivors after different locoregional treatments. METHODS: A structured questionnaire assessing paresthesia, with body pictograms for marking paresthesia areas, was completed by 343 breast cancer survivors. The image information was digitized, generating gray-scale summation images with numbers from 0, indicating black (100 % of the patients had paresthesia), to 255, indicating white (none had paresthesia). The resulting map visualization showed the locations of paresthesia on body pictograms. The group included patients who had undergone breast conserving surgery (BCS) and mastectomy, and also patients who had received percutaneous and interstitial radiation. RESULTS: A total of 56.5 % of the patients stated that they had paresthesia. The paresthesia areas were distributed within the range suggested by clinical experience. Most patients stated that they had paresthesia in the upper outer quadrant and axilla. Patients who had undergone mastectomy or percutaneous radiotherapy appeared to have more paresthesia on some areas of the body surface. Patients who had undergone mastectomy indicated larger areas of paresthesia than those with BCS-4,066 pixels (px) vs. 2,275 px. Radiotherapy did not appear to influence the spatial distribution of paresthesia. CONCLUSIONS: Paresthesia is a common symptom after breast cancer treatment. This paper describes a new method of assessing this side effect to improve and individualize treatment for it in the future. PMID- 24496515 TI - Angiotensin-converting enzyme I/D polymorphism is associated with pneumonia risk: a meta-analysis. AB - BACKGROUND: Previous studies examined the association between angiotensin converting enzyme (ACE) I/D polymorphism and pneumonia, but their results were inconsistent. Thus, a meta-analysis was performed to clarify the effect of ACE I/D polymorphism on pneumonia risk and pneumonia-related mortality. METHODS: The PubMed, Embase, and Chinese National Knowledge Infrastructure (CNKI) databases were searched for relevant studies published up to 27 April 2013. Data were extracted and pooled odds ratios (ORs) with 95% confidence intervals (CIs) were calculated. RESULTS: Pooled analysis of 12 case-control studies (1431 cases and 3600 controls) showed that there was a significant association between ACE I/D polymorphism and pneumonia risk in a recessive genetic model (OR = 1.53, 95% CI 1.30-1.80, p < 0.00001). No significant association between ACE I/D polymorphism and mortality was observed (OR = 2.68, 95% CI 0.80-8.90, p = 0.11). CONCLUSIONS: Our meta-analysis confirmed that ACE I/D polymorphism was associated with pneumonia risk. However, ACE I/D polymorphism was not associated with pneumonia mortality. PMID- 24496516 TI - Effects of renal sympathetic denervation using saline-irrigated radiofrequency ablation catheter on the activity of the renin-angiotensin system and endothelin 1. AB - INTRODUCTION: Excessive activation of the sympathetic nervous system (SNS) and the renin-angiotensin system (RAS) are crucial and interacted closely in the pathogenesis of chronic cardiovascular diseases. This study investigated the effects of renal denervation (RDN) on the RAS. MATERIALS AND METHODS: Eight Chinese Kunming dogs underwent bilateral RDN utilizing saline-irrigated radiofrequency ablation catheter. Blood pressure (BP) measurements, blood sampling assays and renal angiography were performed at baseline, 30 min, one month and three months after ablation. RESULTS: During three months of follow-up, RDN caused a significant and uniform reduction in plasma level of renin, angiotensin II, and endothelin-1(ET-1), with the reduction of -5.7+/-6.8 (p=0.049), -19.4+/-19.3 (p=0.025), and -22.4+/-21 pg/ml (p=0.02) for plasma renin, -10.6+/-7.2 (p=0.004), -15.9+/-8.8 (p=0.001), and -15.2+/-9.6 pg/ml (p=0.003) for plasma angiotensin II, as well as -3.9+/-3 (p=0.007), -10.8+/-5 (p<0.001), and -14.6+/-6.1 pg/ml (p<0.001) for plasma ET-1. RDN utilizing a saline-irrigated catheter also caused a progressive and substantial BP reduction of -19+/-22/-8+/-13, -30+/-13/-13+/-14, and -36+/-20/-16+/-14 mm Hg (p=0.045, p<0.001, and p<0.002 for systolic BP; p=0.14, p=0.036, and p=0.014 for diastolic BP) without ablation-related complications. CONCLUSION: RDN substantially decreased BP and also significantly decreased the plasma levels of RAS and ET-1, which might be implicated in the mechanism of BP reduction by RDN. PMID- 24496520 TI - Top of the ridge: Albert Sheldon Pennoyer. PMID- 24496517 TI - Anti-stress and nootropic activity of drugs affecting the renin-angiotensin system in rats based on indirect biochemical evidence. AB - INTRODUCTION: Various stress hormones are responsible for bringing out stress related changes and are implicated in learning and memory processes. The extensive clinical experience of angiotensin receptor blockers (ARBs) and direct renin inhibitor as antihypertensive agents provides anecdotal evidence of improvements in cognition. The neurochemical basis underlying the anti-stress and nootropic effects are unclear. This study was aimed to determine the effects of aliskiren, valsartan and their combination on the neuromediators of the central nervous system (CNS) and periphery as well as on cognitive function. MATERIALS AND METHODS: Groups of rats were subjected to a forced swim stress for one hour after daily treatment with aliskiren, valsartan and their combination. The 24 h urinary excretion of vanillylmandellic acid (VMA), 5-hydroxyindoleacetic acid (5 HIAA), 6-beta-hydroxycortisol (6-beta-OH) cortisol and homovanillic acid (HVA) was determined in all groups under normal and stressed conditions. Nootropic activity was studied using cook's pole climbing apparatus and acetylcholinesterase (AChE) inhibitory activity by Ellman's method. RESULTS: Administration of aliskiren (10 mg/kg), valsartan (20 mg/kg) and their combination at a dose of 5 and 10 mg/kg respectively reduced the urinary metabolite levels. Further, all drugs showed significant improvement in scopolamine-impaired performance and produced inhibition of the AChE enzyme. CONCLUSIONS: The present study provides scientific support for the anti-stress and nootropic activities of aliskiren, valsartan and their combination. PMID- 24496521 TI - New trials highlight breast cancer therapy and prevention. PMID- 24496522 TI - Emerging data continue to find lack of benefit for vitamin-mineral supplement use. PMID- 24496533 TI - A piece of my mind. Matchbox cars. PMID- 24496532 TI - Patient-centered and practical application of new high cholesterol guidelines to prevent cardiovascular disease. PMID- 24496534 TI - Blood pressure management in early ischemic stroke. PMID- 24496535 TI - Early patterns of blood pressure change and future coronary atherosclerosis. PMID- 24496538 TI - Tablet splitting. PMID- 24496536 TI - Blood pressure trajectories in early adulthood and subclinical atherosclerosis in middle age. AB - IMPORTANCE: Single measures of blood pressure (BP) levels are associated with the development of atherosclerosis; however, long-term patterns in BP and their effect on cardiovascular disease risk are poorly characterized. OBJECTIVES: To identify common BP trajectories throughout early adulthood and to determine their association with presence of coronary artery calcification (CAC) during middle age. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort data from 4681 participants in the CARDIA study, who were black and white men and women aged 18 to 30 years at baseline in 1985-1986 at 4 urban US sites, collected through 25 years of follow-up (2010-2011). We examined systolic BP, diastolic BP, and mid-BP (calculated as [SBP+DBP]/2, an important marker of coronary heart disease risk among younger populations) at baseline and years 2, 5, 7, 10, 15, 20, and 25. Latent mixture modeling was used to identify trajectories in systolic, diastolic, and mid-BP over time. MAIN OUTCOMES AND MEASURES: Coronary artery calcification greater than or equal to Agatston score of 100 Hounsfield units (HU) at year 25. RESULTS: We identified 5 distinct mid-BP trajectories: low-stable (21.8%; 95% CI, 19.9%-23.7%; n=987), moderate-stable (42.3%; 40.3%-44.3%; n=2085), moderate increasing (12.2%; 10.4%-14.0%; n=489), elevated-stable (19.0%; 17.1%-20.0%; n=903), and elevated-increasing (4.8%; 4.0%-5.5%; n=217). Compared with the low stable group, trajectories with elevated BP levels had greater odds of having a CAC score of 100 HU or greater. Adjusted odds ratios were 1.44 (95% CI, 0.83 2.49) for moderate-stable, 1.86 (95% CI, 0.91-3.82) for moderate-increasing, 2.28 (95% CI, 1.24-4.18), for elevated-stable, and 3.70 (95% CI, 1.66-8.20) for elevated-increasing groups. The adjusted prevalence of a CAC score of 100 HU or higher was 5.8% in the low-stable group. These odds ratios represent an absolute increase of 2.7%, 5%, 6.3%, and 12.9% for the prevalence of a CAC score of 100 HU or higher for the moderate-stable, moderate-increasing, elevated-stable and elevated-increasing groups, respectively, compared with the low-stable group. Associations were not altered after adjustment for baseline and year 25 BP. Findings were similar for trajectories of isolated systolic BP trajectories but were attenuated for diastolic BP trajectories. CONCLUSIONS AND RELEVANCE: Blood pressure trajectories throughout young adulthood vary, and higher BP trajectories were associated with an increased risk of CAC in middle age. Long-term trajectories in BP may assist in more accurate identification of individuals with subclinical atherosclerosis. PMID- 24496539 TI - Association between severe retinopathy of prematurity and nonvisual disabilities at age 5 years. PMID- 24496537 TI - Association of atrial tissue fibrosis identified by delayed enhancement MRI and atrial fibrillation catheter ablation: the DECAAF study. AB - IMPORTANCE: Left atrial fibrosis is prominent in patients with atrial fibrillation (AF). Extensive atrial tissue fibrosis identified by delayed enhancement magnetic resonance imaging (MRI) has been associated with poor outcomes of AF catheter ablation. OBJECTIVE: To characterize the feasibility of atrial tissue fibrosis estimation by delayed enhancement MRI and its association with subsequent AF ablation outcome. DESIGN, SETTING, AND PARTICIPANTS: Multicenter, prospective, observational cohort study of patients diagnosed with paroxysmal and persistent AF (undergoing their first catheter ablation) conducted between August 2010 and August 2011 at 15 centers in the United States, Europe, and Australia. Delayed enhancement MRI images were obtained up to 30 days before ablation. MAIN OUTCOMES AND MEASURES: Fibrosis quantification was performed at a core laboratory blinded to the participating center, ablation approach, and procedure outcome. Fibrosis blinded to the treating physicians was categorized as stage 1 (<10% of the atrial wall), 2 (>=10%-<20%), 3 (>=20%-<30%), and 4 (>=30%). Patients were followed up for recurrent arrhythmia per current guidelines using electrocardiography or ambulatory monitor recording and results were analyzed at a core laboratory. Cumulative incidence of recurrence was estimated by stage at days 325 and 475 after a 90-day blanking period (standard time allowed for arrhythmias related to ablation-induced inflammation to subside) and the risk of recurrence was estimated (adjusting for 10 demographic and clinical covariates). RESULTS: Atrial tissue fibrosis estimation by delayed enhancement MRI was successfully quantified in 272 of 329 enrolled patients (57 patients [17%] were excluded due to poor MRI quality). There were 260 patients who were followed up after the blanking period (mean [SD] age of 59.1 [10.7] years, 31.5% female, 64.6% with paroxysmal AF). For recurrent arrhythmia, the unadjusted overall hazard ratio per 1% increase in left atrial fibrosis was 1.06 (95% CI, 1.03-1.08; P < .001). Estimated unadjusted cumulative incidence of recurrent arrhythmia by day 325 for stage 1 fibrosis was 15.3% (95% CI, 7.6%-29.6%); stage 2, 32.6% (95% CI, 24.3%-42.9%); stage 3, 45.9% (95% CI, 35.5%-57.5%); and stage 4, 51.1% (95% CI, 32.8%-72.2%) and by day 475 was 15.3% (95% CI, 7.6%-29.6%), 35.8% (95% CI, 26.2%-47.6%), 45.9% (95% CI, 35.6%-57.5%), and 69.4% (95% CI, 48.6%-87.7%), respectively. Similar results were obtained after covariate adjustment. The addition of fibrosis to a recurrence prediction model that includes traditional clinical covariates resulted in an improved predictive accuracy with the C statistic increasing from 0.65 to 0.69 (risk difference of 0.05; 95% CI, 0.01 0.09). CONCLUSIONS AND RELEVANCE: Among patients with AF undergoing catheter ablation, atrial tissue fibrosis estimated by delayed enhancement MRI was independently associated with likelihood of recurrent arrhythmia. The clinical implications of this association warrant further investigation. PMID- 24496540 TI - Cardiovascular event risk after noncardiac surgery. PMID- 24496541 TI - Cardiovascular event risk after noncardiac surgery--reply. PMID- 24496542 TI - Treatment options for asymptomatic carotid artery stenosis. PMID- 24496543 TI - Diagnosis of neonatal infection with herpes simplex virus. PMID- 24496544 TI - Treatment options for asymptomatic carotid artery stenosis--reply. PMID- 24496546 TI - Diagnosis of neonatal infection with herpes simplex virus--reply. PMID- 24496548 TI - Hypertension as an expression of the lack of the well-balanced life. PMID- 24496549 TI - JAMA patient page. New guideline for treatment of high blood pressure in adults. PMID- 24496551 TI - Evaluation of a newly designed flow diverter for the treatment of intracranial aneurysms in an elastase-induced aneurysm model, in New Zealand white rabbits. AB - INTRODUCTION: In this study, we analyzed angiographic and histologic aneurysm occlusion of a newly designed flow diverting device. Visibility and flexibility, as well as occlusions of side branches and neointimal proliferation were also evaluated. METHODS: Aneurysms were induced in 18 New Zealand white rabbits and treated with a braided, "closed-loop-designed" device of nitinol. Additional devices were implanted in the abdominal aorta to cover the origin of branch arteries.Angiographic follow-ups were performed immediately after placement of the device, after 3 months (n=9) and 6 months(n =9). The status of aneurysm occlusion (using a five-point scale) and the patency of branch arteries were assessed. RESULTS: Aneurysm occlusion rates were noted as grade 0 in 2 (11 %), grade I in 1 (6 %), grade II in 1 (6 %), grade III in 9(50 %), and grade IV in 5 (28 %) of 18 aneurysms, respectively, indicating a complete or near-complete occlusion of 78 % under double antiplatelet therapy. Aneurysm occlusion was significantly higher at 6 months follow-up (P =0.025). Radiopaque markers provided excellent visibility. Limited device flexibility led to incomplete aneurysm neck coverage and grade 0 occlusion rates in two cases. Distal device occlusions were found in three cases, most likely due to an extremely undersized vessel diameter in the subclavian artery.No case of branch artery occlusion was seen. Intimal proliferation and diameter stenosis were moderate. CONCLUSION: The tested flow diverter achieved near-complete and complete aneurysm occlusion under double antiplatelet therapy of elastase-induced aneurysms in 78 %, while preserving branch arteries. PMID- 24496552 TI - Multidimensional texture characterization: on analysis for brain tumor tissues using MRS and MRI. AB - This paper investigates the efficacy of automated pattern recognition methods on magnetic resonance data with the objective of assisting radiologists in the clinical diagnosis of brain tissue tumors. In this paper, the sciences of magnetic resonance imaging (MRI) and magnetic resonance spectroscopy (MRS) are combined to improve the accuracy of the classifier, based on the multidimensional co-occurrence matrices to assess the detection of pathological tissues (tumor and edema), normal tissues (white matter - WM and gray matter - GM), and fluid (cerebrospinal fluid - CSF). The results show the ability of the classifier with iterative training to automatically and simultaneously recover tissue-specific spectral and structural patterns and achieve segmentation of tumor and edema and grading of high and low glioma tumor. Here, extreme learning machine - improved particle swarm optimization (ELM-IPSO) neural network classifier is trained with the feature descriptions in brain magnetic resonance (MR) spectra. This has the characteristics of varying the normal spectral pattern associated with tumor patterns along with imaging features. Validation was performed considering 35 clinical studies. The volumetric features extracted from the vectors of this matrix articulate some important elementary structures, which along with spectroscopic metabolite ratios discriminate the tumor grades and tissue classes. The quantitative 3D analysis reveals significant improvement in terms of global accuracy rate for automatic classification in brain tissues and discriminating pathological tumor tissue from structural healthy brain tissue. PMID- 24496553 TI - Electrical tuning of transport properties of topological insulator ultrathin films. AB - Considering that topological insulator (TI) ultrathin films (UTFs) provide an ideal platform for the transport measurement of topologically protected surface states, we have investigated the transport properties of the three-dimensional (3D) TI UTFs through an array of potential barriers. The 3D TI UTF was considered to be thin enough (5 nm) that the top and bottom surface states of the UTF can hybridize to create an energy gap at the Dirac point, which results in a hyperbola-like energy dispersion. It was found that the Klein tunneling effect disappears due to the interaction between the top and bottom surface states. By tuning the barrier strength or the incident energy, three kinds of transport processes can be realized, and the conditions of the transport processes were determined. The oscillatory characters of the transmission (conductance) spectra without a decaying envelope are due to the novel surface states of TIs, which are quite different from that observed for a conventional two-dimensional electron gas. For the structure consisting of two anti-parallel potential barriers, the conductance spectra exhibit a perfect on/off switching effect by tuning the barrier strength, which is favorable for electrically controllable device applications. In the case of a superlattice (SL) structure, due to the mini-gaps induced by the SL geometry, some additional resonant peaks and valleys can be observed in the transmission spectra, and similar characters are also reflected in the conductance spectra. Owing to the Dirac characters of the charge carriers therein, the transmission (conductance) spectra never decay with increasing barrier strength, which is distinguished from that observed for semiconductor SLs. These findings were not only meaningful for understanding the basic physical processes in the transport of TIs, but also useful for developing nanoscaled TI based devices. PMID- 24496554 TI - Determinants of parental care and offspring survival during the post-fledging period: males care more in a species with partially reversed sex roles. AB - Sexual conflict is magnified during the post-fledging period of birds when the sexes face different trade-offs between continuing parental care or investing in self maintenance or other mating opportunities. Species with reversed sex roles provide a unique opportunity to study the relationship between mating systems and investment in parental care. Here, we provide the first detailed study of the length of care by males versus females (n = 24 pairs) during the post-fledging period, assessing factors that may promote care within and between the sexes. In the northern flicker Colaptes auratus, a species with partly reversed sex roles, males cared longer than females (average 16 versus 12 days, respectively). Overall, 36% of females but no males deserted the brood prior to fledgling independence. Parents that provisioned nestlings at a high rate also spent more days feeding fledglings. Among males, age and nestling feeding rates were positively associated with the length of care. Among females, a low level of feather corticosterone (CORTf) was associated with a longer length of care. About 45% of fledglings died within the first week, but fledglings with intermediate body mass had the highest survival suggesting stabilizing selection on mass. Fledgling survival was also higher in individuals with larger broods and lower levels of CORTf. We demonstrate that because females can be polyandrous they often desert the brood before males, and that the sexes respond to different cues relating to their energy balance when deciding the length of care given to their offspring. PMID- 24496555 TI - Prevalence and correlates of lifetime waterpipe, cigarette, alcohol and drug use among secondary school students in Stoke-on-Trent, UK: a post hoc cross-sectional analysis. AB - INTRODUCTION: Waterpipe smoking is a growing public health concern in the UK. We sought to examine the prevalence and correlates of waterpipe use among young people in Stoke-on-Trent, comparing results with other substances of use. METHODS: We analysed data from the Young People's Lifestyle Survey, conducted among 1252 secondary school students aged 11-16 years in Stoke-on-Trent, UK. Logistic regression models were created to compare correlates of lifetime waterpipe smoking to cigarette, alcohol and drug use. RESULTS: The prevalence of lifetime waterpipe smoking was 12.0%, higher than lifetime drug use (6.5%) but lower than cigarette (22.2%) and alcohol (49.2%) use. All substances of use were significant correlates of each other. Other significant correlates for lifetime waterpipe use included increasing age, male gender and South Asian ethnicity. For lifetime cigarette use, these were increasing age and presence of free school meals. For lifetime alcohol use, these were increasing age, female gender and White ethnicity. Lifetime drug use had no additional significant correlates. CONCLUSIONS: Waterpipe smoking was correlated with different factors compared with other common forms of substance use. Detailed waterpipe questions should be added to routine national health surveys to understand its future epidemiological course in the UK. PMID- 24496556 TI - The relationship between social fragmentation and sleep among adolescents living in Boston, Massachusetts. AB - BACKGROUND: Sufficient sleep is needed for the healthy development of youth. However, only a small minority of adolescents obtain adequate amounts of sleep. Although individual-level correlates of sleep have been identified, studies investigating the influence of the environment on sleep are warranted. METHODS: By using cross-sectional data collected from 1878 urban adolescents living in 38 neighborhoods participating in the 2008 Boston Youth Survey (BYS), we determined the association between neighborhood social fragmentation and sleep. Social fragmentation of each participant's residential neighborhood was composed using 2010 US Census data. Multilevel regression models were used to determine the association between social fragmentation and meeting the recommended hours of sleep (>8.5 h) and sleep duration while controlling for individual-level sex, race, age and nativity. RESULTS: Moderate (OR = 0.51, 95% CI = 0.27, 0.97) and high (OR = 0.33, 95% CI = 0.18, 0.61) social fragmentation within the residential neighborhood was associated with a decreased likelihood of obtaining adequate sleep. Those in moderate (beta = -23.9, 95% CI = -43.1, -4.8) and high (beta = 22.1, 95% CI = -43.3, -0.9) socially fragmented neighborhoods obtained fewer minutes of sleep per night. CONCLUSIONS: Social fragmentation may be an important determinant of sleep among youth living in urban settings. PMID- 24496558 TI - Extended Gabor approach applied to classification of emphysematous patterns in computed tomography. AB - Chronic obstructive pulmonary disease (COPD) is a progressive and irreversible lung condition typically related to emphysema. It hinders air from passing through airpaths and causes that alveolar sacs lose their elastic quality. Findings of COPD may be manifested in a variety of computed tomography (CT) studies. Nevertheless, visual assessment of CT images is time-consuming and depends on trained observers. Hence, a reliable computer-aided diagnosis system would be useful to reduce time and inter-evaluator variability. In this paper, we propose a new emphysema classification framework based on complex Gabor filters and local binary patterns. This approach simultaneously encodes global characteristics and local information to describe emphysema morphology in CT images. Kernel Fisher analysis was used to reduce dimensionality and to find the most discriminant nonlinear boundaries among classes. Finally, classification was performed using the k-nearest neighbor classifier. The results have shown the effectiveness of our approach for quantifying lesions due to emphysema and that the combination of descriptors yields to a better classification performance. PMID- 24496557 TI - CP-HISQC: a better version of HSQC experiment for intrinsically disordered proteins under physiological conditions. AB - (1)H-(15)N HSQC spectroscopy is a workhorse of protein NMR. However, under physiological conditions the quality of HSQC spectra tends to deteriorate due to fast solvent exchange. For globular proteins only a limited number of surface residues are affected, but in the case of intrinsically disordered proteins (IDPs) HSQC spectra are thoroughly degraded, suffering from both peak broadening and loss of intensity. To alleviate this problem, we make use of the following two concepts. (1) Proton-decoupled HSQC. Regular HSQC and its many variants record the evolution of multi-spin modes, 2NxHz or 2NxHx, in indirect dimension. Under the effect of fast solvent exchange these modes undergo rapid decay, which results in severe line-broadening. In contrast, proton-decoupled HSQC relies on Nx coherence which is essentially insensitive to the effects of solvent exchange. Moreover, for measurements involving IDPs at or near physiological temperature, Nx mode offers excellent relaxation properties, leading to very sharp resonances. (2) Cross-polarization (1)H-to-(15)N transfer. If CP element is designed such as to lock both (1)H(N) and water magnetization, the following transfer is effected: [Formula: see text] Thus water magnetization is successfully exploited to boost the amount of signal. In addition, CP element suffers less loss from solvent exchange, conformational exchange, and dipolar relaxation compared to the more popular INEPT element. Combining these two concepts, we have implemented the experiment termed CP-HISQC (cross-polarization assisted heteronuclear in-phase single-quantum correlation). The pulse sequence has been designed such as to preserve water magnetization and therefore can be executed with reasonably short recycling delays. In the presence of fast solvent exchange, kex ~ 100 s(-1), CP HISQC offers much better spectral resolution than conventional HSQC-type experiments. At the same time it offers up to twofold gain in sensitivity compared to plain proton-decoupled HSQC. The new sequence has been tested on the sample of drkN SH3 domain at pH 7.5, 30 degrees C. High-quality spectrum has been recorded in less than 1 h, containing resonances from both folded and unfolded species. High-quality spectra have also been obtained for arginine side chain H(epsilon)N(epsilon) groups in the sample of short peptide Sos. For Arg side chains, we have additionally implemented (HE)NE(CD)HD experiment. Using (13)C-labeled sample of Sos, we have demonstrated that proton-to-nitrogen CP transfer remains highly efficient in the presence of solvent exchange as fast as kex = 620 s(-1). In contrast, INEPT transfer completely fails in this regime. PMID- 24496560 TI - Factors influencing the failure of extracorporeal shock wave lithotripsy with Piezolith 3000 in the management of solitary ureteral stone. AB - Studies of predictive factors of extracorporeal shockwave lithotripsy (ESWL) failure in patients with ureteral stones have not yielded results sufficient to prevent ESWL failure. The present study investigated patients with ureteral stone and analyzed the predictive factors of ESWL failure. Ninety patients with ureteral stone treated from January 2006 to June 2012 using ESWL for ureteral stone were enrolled. Patient's demographic data including age, gender, body mass index (BMI), symptoms and calculous characteristics including location, size, episode and the grade of hydronephrosis were recorded. Statistical results were performed using univariate and multivariate analyses for the predictive factors of ESWL failure. In univariate analysis, calculous location, size, and grade of hydronephrosis between two groups displayed significant differences (p < 0.05). The predictive factors of ESWL failure were BMI >25 kg/m(2) [Odds ratio (OR) = 3.5, 95% confidence interval (CI) 1.1-11.0], calculous size >= 1 cm (OR = 10.5, 95% CI 3.0-36.2), calculous location (mid-ureter; OR = 8.49, 95% CI 1.5-45.7) and severe grade of hydronephrosis (OR = 12.3, 95% CI 1.9-79.5). In conclusions, ESWL failure can be predicted in cases of obesity, calculous size exceeding 1 cm, mid ureteral stone and severe hydronephrosis. When we consider calculous management in patients with these risk factors, initial surgical approach is recommended instead of ESWL. PMID- 24496561 TI - Weight change and its impact on prognosis after adjuvant TAC (docetaxel doxorubicin-cyclophosphamide) chemotherapy in Korean women with node-positive breast cancer. AB - The aim of this study was to characterize weight changes and analyze their effect on prognosis after three-drug combination chemotherapy using docetaxel, doxorubicin and cyclophosphamide (TAC) chemotherapy in Korean women with breast cancer. We analyzed weight changes and the effect of these changes on relapse free survival (RFS) in 108 patients who received adjuvant TAC chemotherapy at the Department of Surgery of St. Vincent's Hospital at the Catholic University of Korea between January 2005 and March 2010. Following chemotherapy, 59 (54.6%) patients experienced weight gain, with their weight significantly increasing compared to their weight at diagnosis (p<0.0001). However, weight gain after chemotherapy was not associated with RFS [hazard ratio (HR) 1.1; 95% confidence interval (CI) 0.4-3.0; p=0.8955]. No significant weight (at 12 months, p=0.522; at 24 months, p=0.632) and body mass index (BMI) (at 12 months, p=0.381; at 24 months, p=0.288) changes were observed compared to the weight and BMI at diagnosis, and weight change at 12 months (HR 1.9; 95% CI 0.6-6.1; p=0.2786) and 24 months (HR 2.7; 95% CI 0.9-8.4; p=0.0776) was not associated with RFS. The present study suggests that weight gain after adjuvant TAC chemotherapy is common in Korean women with breast cancer. In contrast to previous Western studies, weight gain did not appear to be sustained, and there was no relationship between weight gain and poor RFS. PMID- 24496562 TI - Pilot study of gamma-knife surgery-incorporated systemic chemotherapy omitting whole brain radiotherapy for the treatment of elderly primary central nervous system lymphoma patients with poor prognostic scores. AB - Systemic chemotherapy followed by whole brain radiotherapy (WBRT) is a widely used treatment strategy for patients with primary central nervous system lymphoma (PCNSL). However, the outcome of this treatment strategy in elderly patients, particularly with a poor prognostic score, was disappointing compared with younger patients, and the deterioration of cognitive function after WBRT is more problematic in these patients. To avoid this debilitating complication of WBRT and increase treatment efficacy in elderly patients, we designed systemic chemotherapy that incorporated interim gamma-knife surgery (GKS) treatment for elderly PCNSL patients (age>=65 years), omitting WBRT in this pilot trial. A total of four elderly patients with a poor prognostic score based on an International Extranodal Lymphoma Study Group were enrolled in this pilot clinical trial. All study patients acquired complete response and showed stable or improved neuropsychological function during the disease-free state. The median progression-free survival was 9.5 months (range 8.6-22.5 months), and the median overall survival was 15.8 months (range 13.3-25.1 months), which were likely to be similar to those of the chemotherapy followed by WBRT for those patients. This pilot study demonstrated that GKS-incorporated systemic chemotherapy can obtain complete response with high probability and considerably long survival, which suggests that this treatment strategy is efficient and neuropsychologically safe for elderly PCNSL patients with a poor prognostic score. PMID- 24496563 TI - Haplotype analysis of the C677T and A1298C polymorphisms of MTHFR and susceptibility to chronic myeloid leukemia. PMID- 24496564 TI - Phase II study of low-dose fixed-rate infusion of gemcitabine combined with cisplatin and dexamethasone in resistant non-Hodgkin lymphoma and correlation with Bcl-2 and MDR expression. AB - This study aims to assess the efficacy of low-dose fixed-rate infusion of gemcitabine, cisplatin and dexamethasone in resistant non-Hodgkin lymphoma (NHL) patients in addition to evaluating the prognostic value of B cell lymphoma 2 (Bcl 2) and multidrug resistant (MDR) expression in this cohort of patients. Patients with relapsed/refractory NHL following at least two chemotherapy regimens were enrolled. They received gemcitabine 800 mg/m2 in fixed infusion rate of 10 mg/m2/min, cisplatin 35 mg/m2 in days 1, 15 and dexamethasone 20 mg days 1-4, 15 18 every 28 day. Response to treatment, time to disease progression (TTP) and 1 year progression-free survival (PFS) were assessed together with their association with Bcl-2, MDR expression and other prognostic variables. Overall response to treatment was 32% (14% complete response). Median TTP and 1-year PFS were 2 months and 31.3%, respectively. Predictors of response to treatment were early stage [odd ratio (OR)=4.6, 95% CI 1.3-16.4], low/low intermediate International Prognostic Index (IPI) (OR=6.2, 95% CI 1.2-31.7), negative/low Bcl 2 expression (OR=6.2, 95% CI 1.2-31.7) and negative/low MDR expression (OR=18, 95% CI 1.4-28.9). However, IPI status lost its value in multivariate analysis. TTP and 1-year PFS were significantly associated with Bcl-2 expression (p=0.04), tumor status before enrollment (relapse vs. refractory, p<0.0001) and tumor stage (p<0.000). In multivariate analysis, clinical stage was the only predictor of TTP and 1-year PFS. Fixed-rate gemcitabine infusion with cisplatin and dexamethasone had reasonable activity in resistant NHL. Clinical stage, Bcl-2 and MDR expressions were predictors of response to treatment, while only clinical stage was associated with TTP and 1-year PFS. PMID- 24496565 TI - Fractalkine receptor polymorphism and chronic tonsillitis. AB - The objective of this study is to examine whether there is an association of fractalkine gene receptor polymorphisms with chronic tonsillitis. This is a cross sectional study in the setting of a tertiary referral center. The study group included 79 patients with chronic tonsillitis and 76 controls without history of chronic tonsillitis. Genotypes were identified by restriction fragment length polymorphism analyses after polymerase chain reaction. c.745G>A (V249I) single nucleotide polymorphism and the frequencies of the G and A alleles did not differ in the patient and control groups (p = 0.363; p = 0.743, respectively). c.839C>T (T280M) single nucleotide polymorphism was found to be higher in controls than in the patients with chronic tonsillitis (p < 0.001). Consistent with this result, T allele frequency was higher in controls than in the patients with chronic tonsillitis (p < 0.001). In this study, we suggested that fractalkine gene receptor c.839C>T (T280M) single nucleotide polymorphism could be associated with a reduced risk of chronic tonsillitis. PMID- 24496566 TI - Transoral endoscopic thyroidectomy via the tri-vestibular routes: results of a preclinical cadaver feasibility study. AB - The concept of natural orifice transluminal endoscopic surgery (NOTES) is an emerging experimental alternative to conventional surgery that eliminates skin incisions using an endoscope passed through a natural orifice (e.g., mouth, urethra, or anus). This study was designed to evaluate the feasibility and safety of thyroid resection via an entirely transoral tri-vestibular route using endoscopy, and to introduce NOTES to the head and neck area of medicine. We performed ten complete endoscopic thyroid lobectomies with central lymph node dissection via a tri-vestibular approach in fresh-frozen cadavers. A 5-mm endoscope with a deflectable tip was used to visualize the surgical field. Three cannulas were inserted through the midline and bilateral incision sites in the vestibule to position the instruments and endoscope. We refined and described the surgical technique in each step using video clips. We identified and preserved neighboring critical structures during surgery. We also confirmed that there were no obvious remnant thyroid tissues and no injury to the neighboring structures after exploration. The transoral tri-vestibular approach seems to provide a good view and surgical field for endoscopic thyroidectomy. However, the transoral approach for thyroidectomy remains experimental, and the detailed surgical technique should be refined via further clinical studies. PMID- 24496567 TI - Comparison of slit lamp-adapted optical coherence tomography features of fellow eyes of acute primary angle closure and eyes with open angle glaucoma. AB - PURPOSE: The aim of this study was to assess the possibility of discriminating a narrow and occludable chamber angle by means of digital gonioscopy. METHODS: In a prospective controlled clinical study 40 eyes of 40 patients were enrolled. 20 patients that had suffered acute angle closure glaucoma (ACG) on the fellow eye were compared to 20 patients with open angle glaucoma (OAG). Anterior segment imaging with SL-OCT (Heidelberg Engineering, Heidelberg, Germany) enabled the delineation, by means of automatic signal analysis, of several important parameters of the anterior chamber angle region, which were compared to those revealed from direct contact glass gonioscopy and ultrasound biometry. RESULTS: The anterior segment structures were automatically recognized by the SL-OCT software in 70 % of the ACG patients and in all of the OAG cases (100 %) (p = 0.025). Anterior chamber angle (ACA) was 15.55 degrees +/- 6.92 degrees in the ACG group and 34.6 degrees +/- 8.9 degrees in the OAG group, whereas angle opening distance (AOD) was 199.55 +/- 62.29 MUm in ACG and 452.67 +/- 123.91 MUm in OAG. A good correlation was found in the direct gonioscopic findings (r = 0.85, p < 0.001), but there were significant differences between both groups (p < 0.001). Mean real central anterior chamber depth (rACD) was evaluated to be 1.75 and 2.79 mm in ACG and OAG, respectively, showing a significant difference (p < 0.0001) and the highest (although not statistically significant) sensitivity and specificity above all other parameters tested in discriminating between OAG and ACG eyes. Discrimination criteria revealed a relevant narrowing of the anterior chamber angle region for values below 22 degrees (ACA), 276 MUm (AOD) and 2.08 mm (rACD). CONCLUSIONS: Digital gonioscopy by means of SL-OCT allowed a non invasive and objective imaging of the anterior chamber configuration that could be used as a screening method for narrow and occludable angles. The method could contribute to a timely identification of angle closure and alert clinicians to further determine whether a peripheral iridotomy should be performed. PMID- 24496568 TI - Race-based sexual preferences in a sample of online profiles of urban men seeking sex with men. AB - Race-based sexual preferences in the online profiles of men who have sex with men (MSM) may be relevant for understanding the sexual health of this population, including racial/ethnic disparities in HIV infection. In October 2011, a content analysis was conducted of the profiles of Boston-area members of a racially diverse website for MSM. The present analysis formatively examined the use of demographic and partner selection criteria by race/ethnicity appearing in the profiles of men who indicated race-based partner preferences (n = 89). Latino men were the most frequently preferred race (54 %), followed by White (52 %), Black (48 %), and Asian (12 %) men. In separate multivariable models adjusted for age and HIV status disclosure, wanting low-risk foreplay was associated with a preference for White men (aOR) = 4.27; 95 % CI = 1.70-10.75; p = 0.002), while wanting group sex was associated with a preference for Black (OR = 2.28; 95 % CI = 1.08-4.81; p = 0.03) and Latino men (OR = 2.56; 95 % CI = 1.25-5.23; p = 0.01). Future studies are needed to replicate findings in larger online samples. Mixed methods research should explore how racial and behavioral preferences impact the sexual mixing patterns and health of MSM online in urban areas. PMID- 24496569 TI - Effects of resveratrol on the expression and DNA methylation of cytokine genes in diabetic rat aortas. AB - This paper studies the expression of proinflammatory cytokines such as IL-1beta, IL-6, TNF-alpha, and IFN-gamma and anti-inflammatory cytokines such as IL-10 in diabetic rat aortas, the effects of resveratrol on these cytokines, and the potential epigenetic mechanisms involved. The experiment was performed on rats divided into four groups: normal group (NC), normal interventional group (NB), diabetic group (DM), and diabetic interventional group (DB). The NB and DB groups were treated with resveratrol. After more than 3 months, the rats' aortas were removed and analyzed for cytokines by using immunohistochemistry, Western blotting, real-time PCR, and methylation-specific PCR. Histological localization of these cytokines was mainly found in the arterial intima of diabetic rats. The protein and mRNA expression levels of IL-1beta, IL-6, TNF-alpha, and IFN-gamma were significantly higher in the DM group than in the NC group (p < 0.05), whereas in the resveratrol-treated groups (NB and DB), the levels were relatively lower than those in the corresponding groups. The DM group showed reduced levels of DNA methylation at the specific cytosine phosphate guanosine sites of IL 1beta, IL-6, TNF-alpha, and IFN-gamma, relative to those in the NC group (p < 0.01), and these levels were increased by resveratrol. In contrast, IL-10 was dramatically methylated and showed decreased expression in response to high glucose, and resveratrol reversed this effect. These results demonstrate that the inflammatory response is involved in diabetic macroangiopathy. Resveratrol inhibits the expression of proinflammatory cytokines and thus may have a protective effect on the aorta in hyperglycemia. Thus, DNA methylation, an epigenetic gene silencing signal, may be responsible for these two phenomena. PMID- 24496570 TI - Data intelligence is the future of monitoring. PMID- 24496571 TI - Generation and selection of ribozyme variants with potential application in protein engineering and synthetic biology. AB - Over the past two decades, RNA catalysis has become a major topic of research. On the one hand, naturally occurring ribozymes have been extensively investigated concerning their structure and functional mechanisms. On the other hand, the knowledge gained from these studies has been used to engineer ribozyme variants with novel properties. In addition to RNA engineering by means of rational design, powerful techniques for selection of ribozymes from large pools of random sequences were developed and have been widely used for the generation of functional nucleic acids. RNA as catalyst has been accompanied by DNA, and nowadays a large number of ribozymes and deoxyribozymes are available. The field of ribozyme generation and selection has been extensively reviewed. With respect to the field of biotechnology, RNA and DNA catalysts working on peptides or proteins, or which are designed to control protein synthesis, are of utmost importance and interest. Therefore, in this review, we will focus on engineered nucleic acid catalysts for peptide synthesis and modification as well as for intracellular control of gene expression. PMID- 24496573 TI - A model describing the use of a bronchial blocking device and a sheathed bronchoscope for pulmonary aspiration studies in the Gottingen minipig. AB - The administration of test substances into a single lung, or lung lobe, allows the remaining untreated lung to act as an experimental control and effectively halves the number of animals required in a given experiment. It reduces the likelihood of early fatal pulmonary failure when noxious substances are studied which may lessen the need for replacement animals. However, the ease of substance administration and the subsequent analysis of its effects, for example by bronchoalveolar lavage or bronchoscopy, depend critically on the size of the animal model. The advantages of using minipigs; ease of handling, reduced housing requirements, genetic homogeneity, etc. are reduced if their diminutive size makes lung studies difficult. This article describes the use of a bronchial blocking device and a sheathed bronchoscope which enabled sterile endobronchial substance administration in Gottingen minipigs, and allowed pulmonary aspiration studies to be conducted with each animal acting as its own control. PMID- 24496572 TI - Role of Sirt1 during the ageing process: relevance to protection of synapses in the brain. AB - Ageing is a stochastic process associated with a progressive decline in physiological functions which predispose to the pathogenesis of several neurodegenerative diseases. The intrinsic complexity of ageing remains a significant challenge to understand the cause of this natural phenomenon. At the molecular level, ageing is thought to be characterized by the accumulation of chronic oxidative damage to lipids, proteins and nucleic acids caused by free radicals. Increased oxidative stress and misfolded protein formations, combined with impaired compensatory mechanisms, may promote neurodegenerative disorders with age. Nutritional modulation through calorie restriction has been shown to be effective as an anti-ageing factor, promoting longevity and protecting against neurodegenerative pathology in yeast, nematodes and murine models. Calorie restriction increases the intracellular levels of the essential pyridine nucleotide, nicotinamide adenine dinucleotide (NAD(+)), a co-substrate for the sirtuin 1 (Sirt1, silent mating-type information regulator 2 homolog 1) activity and a cofactor for oxidative phosphorylation and ATP synthesis. Promotion of intracellular NAD(+) anabolism is speculated to induce neuroprotective effects against amyloid-beta-peptide (Abeta) toxicity in some models for Alzheimer's disease (AD). The NAD(+)-dependent histone deacetylase, Sirt1, has been implicated in the ageing process. Sirt1 serves as a deacetylase for numerous proteins involved in several cellular pathways, including stress response and apoptosis, and plays a protective role in neurodegenerative disorders, such as AD. PMID- 24496574 TI - Comparison of Ringer's solution with 0.4% glucose or without in intraoperative infusion regimens for the prevention of hypoglycemia in juvenile pigs. AB - Juvenile pigs are prone to hypoglycemia, nevertheless they are commonly used in preclinical studies. The optimal perioperative fluid management with crystalloid solutions in such settings has not yet been studied. The aim of the current study was to correlate the perioperative fluid administration of Ringer's solution, with and without the addition of a minimal amount of glucose (0.4% glucose) to the blood glucose, and the incidence of perioperative hypoglycemia in 20 juvenile pigs (31.7 +/- 5.2 kg) undergoing surgery for approximately one hour. Infusion of Ringer's solution without glucose (group Ri, n = 10) led to a significant decrease of the serum blood glucose level from 105.7 +/- 27.1 mg/dL at baseline compared with 87.8 +/- 31.7 mg/dL post surgery. The pigs (50%) in group Ri were observed to be hypoglycemic (<72 mg/dL). The second group received Ringer's solution containing a final concentration of 0.4% glucose (group Ri-Glu, n = 10) and showed a significant increase in blood glucose level from 104.4 +/- 15.8 mg/dL at baseline compared with 122.3 +/- 14.3 mg/dL post surgery. No animal in group Ri-Glu was observed to be hypoglycemic. In conclusion, we showed that even minor changes in perioperative crystalloid fluid management significantly influence blood glucose levels. In order to avoid hypoglycemia in juvenile pigs we recommend adding a minimal amount of glucose (0.4% final concentration) to the Ringer's solution given perioperatively during surgery of approximately one hour. PMID- 24496575 TI - FELASA recommendations for the health monitoring of mouse, rat, hamster, guinea pig and rabbit colonies in breeding and experimental units. AB - The microbiological quality of experimental animals can critically influence animal welfare and the validity and reproducibility of research data. It is therefore important for breeding and experimental facilities to establish a laboratory animal health monitoring (HM) programme as an integrated part of any quality assurance system. FELASA has published recommendations for the HM of rodent and rabbit colonies in breeding and experimental units (Nicklas et al. Laboratory Animals, 2002), with the intention of harmonizing HM programmes. As stated in the preamble, these recommendations need to be adapted periodically to meet current developments in laboratory animal medicine. Accordingly, previous recommendations have been revised and shall be replaced by the present recommendations. These recommendations are aimed at all breeders and users of laboratory mice, rats, Syrian hamsters, guinea pigs and rabbits as well as diagnostic laboratories. They describe essential aspects of HM, such as the choice of agents, selection of animals and tissues for testing, frequency of sampling, commonly used test methods, interpretation of results and HM reporting. Compared with previous recommendations, more emphasis is put on the role of a person with sufficient understanding of the principles of HM, opportunistic agents, the use of sentinel animals (particularly under conditions of cage-level containment) and the interpretation and reporting of HM results. Relevant agents, testing frequencies and literature references are updated. Supplementary information on specific agents and the number of animals to be monitored and an example of a HM programme description is provided in the appendices. PMID- 24496576 TI - Age-dependent effect of every-other-day feeding and aerobic exercise in ubiquinone levels and related antioxidant activities in mice muscle. AB - Aging affects many biochemical, cellular, and physiological processes in the organisms. Accumulation of damage based on oxidized macromolecules is found in many age-associated diseases. Coenzyme Q (Q) is one of the main molecules involved in metabolic and antioxidant activities in cells. Q-dependent antioxidant activities are importantly involved on the protection of cell membranes against oxidation. Many studies indicate that Q decay in most of the organs during aging. In our study, no changes in Q levels were found in old animals in comparison with young animals. On the other hand, the interventions, caloric restriction based on every-other-day feeding procedure, and physical exercise were able to increase Q levels in muscle, but only in old and not in young animals. Probably, this effect prevented the increase in lipid peroxidation found in aged animals and also protein carbonylation. Further, Q-dependent antioxidant activities such as NADH-cytochrome b5 reductase and NAD(P)H-quinone oxidoreductase 1 are also modulated by both exercise and every other day feeding. Taken together, we demonstrate that exercise and dietary restriction as every other-day procedure can regulate endogenous synthesized Q levels and Q-dependent antioxidant activities in muscle, preventing oxidative damage in aged muscle. PMID- 24496578 TI - Hierarchical nanostructured NiCo2O4 as an efficient bifunctional non-precious metal catalyst for rechargeable zinc-air batteries. AB - A nickel-doped cobalt oxide spinel structure is a promising non-precious metal electrocatalyst for oxygen evolution and oxygen reduction in rechargeable metal air batteries and water electrolyzers operating with alkaline electrolytes. One dimensional NiCo2O4 (NCO) nanostructures were prepared by using a simple electrospinning technique with two different metal precursors (metal nitrate/PAN and metal acetylacetonate/PAN). The effect of precursor concentration on the morphologies was investigated. Single-phase, NCO with an average diameter of 100 nm, porous interconnected fibrous morphology was revealed by FESEM and FETEM analysis. The hierarchical nanostructured 1D-spinel NiCo2O4 materials showed a remarkable electrocatalytic activity towards oxygen reduction and evolution in an aqueous alkaline medium. The extraordinary bi-functional catalytic activity towards both ORR and OER was observed by the low over potential (0.84 V), which is better than that of noble metal catalysts [Pt/C (1.16 V), Ru/C (1.01 V) and Ir/C (0.92 V)], making them promising cathode materials for metal-air batteries. Furthermore, the rechargeable zinc-air battery with NCO-A1 as a bifunctional electrocatalyst displays high activity and stability during battery discharge, charge, and cycling processes. PMID- 24496580 TI - Vascularised composite allotransplantation: implications for the Defence Medical Services. PMID- 24496582 TI - Pathogens, pests, and economics: drivers of honey bee colony declines and losses. AB - The Western honey bee (Apis mellifera) is responsible for ecosystem services (pollination) worth US$215 billion annually worldwide and the number of managed colonies has increased 45% since 1961. However, in Europe and the U.S., two distinct phenomena; long-term declines in colony numbers and increasing annual colony losses, have led to significant interest in their causes and environmental implications. The most important drivers of a long-term decline in colony numbers appear to be socioeconomic and political pressure on honey production. In contrast, annual colony losses seem to be driven mainly by the spread of introduced pathogens and pests, and management problems due to a long-term intensification of production and the transition from large numbers of small apiaries to fewer, larger operations. We conclude that, while other causal hypotheses have received substantial interest, the role of pests, pathogens, and management issues requires increased attention. PMID- 24496581 TI - Decreased spectral entropy modulation in patients with schizophrenia during a P300 task. AB - Spectral entropy (SE), also known as Shannon entropy, is a useful parameter for quantifying the global regularity of the electroencephalographic (EEG) signal. Hence, it is of interest in the assessment of the electrophysiological correlates of cognitive processing in schizophrenia. However, to date, SE has been barely used in studies comparing resting EEG recordings between patients and controls. In this work, we compared SE between resting baseline [-250 0] ms and active task [150 550] ms windows of a P300 task in 31 patients with schizophrenia and 38 controls. Moreover, we also calculated the median frequency (MF) and relative power in each frequency band for these windows to assess the correlates of the possible SE differences. Controls showed a significant (p < 0.0029) SE decrease (i.e., meaning higher signal regularity) from baseline to the active task window at parietal and central electrode sites. This SE decrease from baseline to active conditions was significantly lower in patients. In controls, this SE decrease was accompanied by a statistically significant decrease in MF (i.e., a significant slowing of the EEG activity), not observed in patients. In this latter group, the difference in SE between resting baseline and active task windows was inversely correlated to positive and total symptoms scores, as measured with the positive and negative symptoms scale. Our data support the relevance of SE in the study of cerebral processing in schizophrenia. PMID- 24496583 TI - Personality and illness adaptation in adults with type 1 diabetes: the intervening role of illness coping and perceptions. AB - Inspired by the common sense model, the present cross-sectional study examined illness perceptions and coping as intervening mechanisms in the relationship between Big Five personality traits and illness adaptation in adults with Type 1 diabetes. A total of 368 individuals with Type 1 diabetes (18-35 years old) completed questionnaires on personality, diabetes-related problems, illness perceptions, and illness coping. First, Neuroticism, Agreeableness, and Conscientiousness predicted patients' illness adaptation, above and beyond the effects of sex, age, and illness duration. Second, illness coping was found to be an important mediating mechanism in the relationship between the Big Five and illness adaptation. Finally, perceived consequences and perceived personal control partially mediated the relationship between the Big Five and illness coping. These findings underscore the importance of examining patients' personality to shed light on their daily functioning and, hence, call for tailored intervention programs which take into account the personality of the individual patient. PMID- 24496585 TI - International Skeletal Society outreach 2013: Rwanda. AB - It has been almost 20 years since the horrific events of the Rwandan genocide. Since that time, the country has made a remarkable recovery owing to good government and a great deal of aid. Health-care services are well organized, but remain short of resources and expertise. Musculoskeletal imaging (and treatment) is in its infancy. Given the huge strides that have been made in social order and stability, there is great hope for the future. It is proposed that future International Skeletal Society (ISS) outreach programs plan to make a meaningful commitment to developing expertise in specific hospitals. PMID- 24496584 TI - Hip imaging of avascular necrosis at 7 Tesla compared with 3 Tesla. AB - OBJECTIVES: To compare ultra-high field, high-resolution bilateral magnetic resonance imaging (MRI) of the hips at 7 Tesla (T) with 3 T MRI in patients with avascular necrosis (AVN) of the femoral head by subjective image evaluations, contrast measurements, and evaluation of the appearance of imaging abnormalities. MATERIALS AND METHODS: Thirteen subjects with avascular necrosis treated using advanced core decompression underwent MRI at both 7 T and 3 T. Sequence parameters as well as resolution were kept identical for both field strengths. All MR images (MEDIC, DESS, PD/T2w TSE, T1w TSE, and STIR) were evaluated by two radiologists with regard to subjective image quality, soft tissue contrasts, B1 homogeneity (four-point scale, higher values indicating better image quality) and depiction of imaging abnormalities of the femoral heads (three-point scale, higher values indicating the superiority of 7 T). Contrast ratios of soft tissues were calculated and compared with subjective data. RESULTS: 7-T imaging of the femoral joints, as well as 3-T imaging, achieved "good" to "very good" quality in all sequences. 7 T showed significantly higher soft tissue contrasts for T2w and MEDIC compared with 3 T (cartilage/fluid: 2.9 vs 2.2 and 3.6 vs 2.6), better detailed resolution for cartilage defects (PDw, T2w, T1w, MEDIC, DESS > 2.5) and better visibility of joint effusions (MEDIC 2.6; PDw/T2w 2.4; DESS 2.2). Image homogeneity compared with 3 T (3.9-4.0 for all sequences) was degraded, especially in TSE sequences at 7 T through signal variations (7 T: 2.1-2.9); to a lesser extent also GRE sequences (7 T: 2.9-3.5). Imaging findings related to untreated or treated AVN were better delineated at 3 T (<=1.8), while joint effusions (2.2-2.6) and cartilage defects (2.5-3.0) were better visualized at 7 T. STIR performed much more poorly at 7 T, generating large contrast variations (1.5). CONCLUSIONS: 7-T hip MRI showed comparable results in hip joint imaging compared with 3 T with slight advantages in contrast detail (cartilage defects) and fluid detection at 7 T when accepting image degradation medially. PMID- 24496586 TI - MRI, MDCT features, and clinical outcome of extremity leiomyosarcomas: experience in 47 patients. AB - OBJECTIVE: To describe MRI, MDCT features, and clinical outcome of extremity leiomyosarcomas (LMS). MATERIALS AND METHODS: In this IRB-approved, HIPAA compliant retrospective study, we included 47 patients (23 women, 24 men; mean age: 55.3 years, range: 17-85 years) with pathologically confirmed extremity LMS seen at our adult tertiary cancer center between 2000 and 2012. MRI/MDCT of primary tumors in 23 patients and follow-up in all patients were reviewed by two radiologists in consensus. Clinical data were extracted from electronic medical records. RESULTS: Primary tumors were distributed in bones (6 out of 47), deep soft tissues (24 out of 47), and superficial soft tissues (17 out of 47). On imaging (bone = 4, deep soft tissue = 11, superficial soft tissue = 8), compared with skeletal muscle, they were T1 iso-hypointense and T2 hyperintense. Bone LMS were metaphyseal tumors with cortical destruction (3 out of 4). Deep soft-tissue LMS were large with hemorrhage (7 out of 11) and necrosis (10 out of 11). Superficial soft-tissue LMS were relatively smaller, homogeneously enhancing (6 out of 8) tumors. Distant metastases developed in 32 out of 47 patients (bone LMS [6 out of 6], deep soft-tissue LMS [18 out of 24], superficial soft-tissue LMS [8 out of 17]), commonly to lung (29 out of 47) and bone (14 out of 47). At the time of writing, 22 out of 36 patients (bone LMS [4 out of 6], deep soft-tissue LMS [15 out of 24], superficial soft-tissue LMS [4 out of 17]) have died. There was no statistically significant correlation between metastatic disease and tumor size or grade. CONCLUSION: Extremity LMS arise in bones and in the deep and superficial soft tissues, frequently metastasize to the lungs, and have a poor prognosis. Superficial LMS tend to have a better prognosis than bone or deep soft tissue LMS. PMID- 24496587 TI - Effect of early versus delayed cord clamping on hematological status of preterm infants at 6 wk of age. AB - OBJECTIVE: To compare the effect of early cord clamping (ECC) vs. delayed cord clamping (DCC) on hematocrit and serum ferritin at 6 wk of life in preterm infants. METHODS: This randomized controlled trial was conducted in the delivery room and neonatal intensive care unit of a tertiary hospital. One hundred preterm infants born between 30 (0)/7 and 36 (6)/7 wk were randomized to either early or delayed cord clamping groups. Parental informed consent was obtained prior to the delivery. In the ECC group, the cord was clamped immediately after the delivery of the baby and in the DCC group; the cord was clamped beyond 2 min after the baby was delivered. Hematocrit and serum ferritin at 6 wk of life were the primary outcomes. Incidence of anemia, polycythemia and significant jaundice were the main secondary outcomes. RESULTS: The mean hematocrit (27.3 +/- 3.8 % vs. 31.8 +/- 3.5 %, p value 0.00) and the mean serum ferritin (136.9 +/- 83.8 ng/mL vs. 178.9 +/- 92.8 ng/mL, p value 0.037) at 6 wk of age were significantly higher in the infants randomized to DCC group. The hematocrit on day 1 was also significantly higher in the DCC group (50.8 +/- 5.2 % vs. 58.5 +/- 5.1 %, p value 0.00). The DCC group required significantly longer duration of phototherapy (55.3 +/- 40.0 h vs. 36.7 +/- 32.6 h, p value 0.016) and had a trend towards higher risk of polycythemia. CONCLUSIONS: Delaying the cord clamping by 2 min, significantly improves the hematocrit value at birth and this beneficial effect continues till at least 2nd mo of life. PMID- 24496588 TI - Prognostic relevance of early AKI according to pRIFLE criteria in children undergoing cardiac surgery. AB - BACKGROUND: Acute renal injury increases risk of death after cardiac surgery. The objective of the study was to evaluate the ability of the pediatric Risk, Injury, Failure, Loss, End-Stage Renal Disease (pRIFLE) criteria to characterize the development of postoperative renal damage in children after cardiopulmonary bypass (CPB) and to evaluate the relationship between the severity of kidney injury and mortality, pediatric intensive care unit (PICU) length of stay, and the duration of mechanical ventilation (MV). METHODS: In this retrospective study including children undergoing CPB surgery during a 3-year period in the PICU of a tertiary hospital, demographic, clinical, surgery-related, and postoperative clinical data were collected. Kidney damage was assessed with pRIFLE criteria. RESULTS: Four hundred and nine patients were included. Early acute kidney injury (AKI) was found in 82 patients (achieving categories Risk 44; Injury 16; Failure 22). Early AKI was associated with younger age (P = 0.010), longer CPB, deep hypothermic circulatory arrest (DHCA) use, ICU stay >12 days, MV >4 days, and death (P < 0.001). Controlling the effect of age, CPB, DHCA use, previous cardiac surgeries, and Risk Adjustment in Congenital Heart Surgery Surgical Severity Score (RACHS-1), early AKI development proved to predict ICU stay >12 days [odds ratio (OR) 3.5; 95% confidence interval (CI) 1.9-6.5, P < 0.001)] and need of MV >4 days (OR 5.1; 95% CI 2.6-10.2, P < 0.001). CONCLUSIONS: Early AKI when evaluated with the pRIFLE criteria can predict prolonged ICU stay, need of prolonged MV, and mortality. PMID- 24496589 TI - Intestinal phosphate transport: a therapeutic target in chronic kidney disease and beyond? AB - Hyperphosphatemia is a serious complication of late-stage chronic kidney disease (CKD), contributing to the increased cardiovascular morbidity and mortality seen in this patient group. Results from retrospective studies suggest that small increases in serum phosphate concentration, within the normal or near-normal range, also correlate with increased cardiovascular morbidity and mortality and have led to the suggestion that detection and preventative treatment of positive phosphate balance is important in healthy individuals as well as in those with CKD. Phosphate homeostasis is maintained by the crosstalk between intestinal phosphate absorption and renal phosphate excretion; however, relatively little is known about the mechanisms of intestinal phosphate transport. Our current understanding is that the intestinal type II sodium phosphate cotransporter, NaPi IIb, plays a significant role in absorption. It may also be involved in the sensing of dietary phosphate composition and the release of hormonal factors that modulate renal phosphate reabsorption to achieve phosphate balance. Interestingly, studies using NaPi-IIb knockout mice with adenine-induced CKD show only partial attenuation of hyperphosphatemia, suggesting that an additional sodium-independent pathway is involved in phosphate absorption. The aim of this review is to discuss our current knowledge of the processes and role of the intestine in phosphate homeostasis and to provide evidence that this organ could be targeted for the treatment of hypophosphatemia and hyperphosphatemia. PMID- 24496591 TI - Post-partum hemorrhage and malpractice claims: what can we learn from the findings of placental examination and endometrial curettage? A retrospective analysis of surgical pathology reports. AB - OBJECTIVE: This study reviews the surgical pathology reports of post-partum hemorrhages to support clinicians in malpractice litigation and, potentially, to enhance pregnancy-related diagnoses. STUDY DESIGN: This work is a retrospective study of surgical pathology reports of term pregnancies between January 2000 and January 2012 selected from the Surgical Pathology database of the I.R.C.C.S Azienda Ospedaliera Universitaria San Martino-IST (Istituto Nazionale per la Ricerca sul Cancro, Genoa). RESULTS: Ninety-five revision reports were identified (0.22% "placenta accrete," 0.46% "non-accreta placental tissue retention," and 0.31% "no placental fragments retention"). Secondary post-partum hemorrhages occurred in 0.3%, and primary PPH occurred in 0.05%, regardless of the group examined. Both types of PPH were most often associated with vaginal deliveries (58%). The most frequent endometrial finding was post-partum endometritis (43%). The entire placenta was submitted to the pathologist in 22/95 cases (23%). Hypermaturity and/or villous immaturity were the main histological patterns. CONCLUSIONS: This review supports the hypothesis that the pathological placenta abnormalities observed, rather than underlying myometrium abnormalities, may underlie the contractile failure and the incomplete removal of the placenta. For these reasons, the authors emphasized the importance of investigating the placenta in cases of complicated deliveries not associated with PPH to support clinicians in malpractice claims. PMID- 24496592 TI - Transthoracic ultrasound in the assessment of pleural and pulmonary diseases: use and limitations. AB - Interest in transthoracic ultrasound (US) procedures increased after the availability of portable US equipment suitable for use at the patient's bedside. It is possible to detect space-occupying lesions of the pleura, pleural effusion, focal or diffuse pleural thickening and subpleural lesions of the lung, even in emergency settings. Transthoracic US is useful as a guidance system for thoracentesis and peripheral lesion biopsy, where it minimises the occurrence of pneumothorax and haemorrhage. Transthoracic US imaging is strongly influenced by physical interaction of the ultrasonic beam at the tissue/air interface, which gives rise to reverberations classified as simple (A-line), "comet tail" and "ring down"(B-line) artifacts. Although these artifacts can be suggestive of a disease condition, they are essentially imaging errors present even in normal subjects and in empty-pleura post-pneumonectomy patients. In order to clarify some confusion and to report on the state of the art, we present a review of the literature on transthoracic US in diseases of the pleura and peripheral lung regions and our own clinical experience over 3 decades. The review focuses on quality assurance procedures and their value in diagnostic imaging and patient monitoring and warns against possible inappropriate indications and misleading information. Thoracic US is much more than "fishing for the moon in the well". PMID- 24496593 TI - Decreased CD200R expression on monocyte-derived macrophages correlates with Th17/Treg imbalance and disease activity in rheumatoid arthritis patients. AB - OBJECTIVES: CD200 is expressed on various cell types, including T cells, while the CD200 receptor (CD200R) is expressed on myeloid cells such as monocytes derived macrophages (MDMs). The CD200-CD200R interaction has been shown to play an important role in the prevention of autoimmune disease. Thus, we hypothesized that CD200/CD200R1 is involved in the pathogenesis of rheumatoid arthritis (RA). METHODS: In total, 35 RA patients and 17 healthy controls (HCs) were enrolled in this study. CD200/CD200R1 expression and Th17/Treg were examined by flow cytometry. Serum levels of interleukin (IL)-2, interferon-gamma (IFN-gamma), IL-4 and IL-10 were detected by ELISA. Disease activity was evaluated according to the C-reactive protein (CRP) levels, erythrocyte sedimentation rates (ESR) and 28 joint disease activity score (DAS28) scores. RESULTS: Compared with HCs, RA patients exhibited a significantly decreased level of CD200R1 on MDMs. CD200R1 expression correlated negatively with DAS28, ESR, and CRP levels. This abnormal expression was associated with Th17/Treg imbalance in the active RA patients. However, expression of CD200R1 was not correlated with Th1 (IL-2, IFN-gamma) or Th2 (IL-4, IL-10) cytokine responses. CONCLUSION: In this study, we demonstrate a significant correlation between CD200R1(+) cells and disease severity in RA patients, thus indicating the relevance of the CD200/CD200R1 signaling pathway's potential involvement in the pathogenesis of RA. PMID- 24496596 TI - Nucleic acid-specific photoactivation of oligodeoxyribonucleotides labeled with deuterated dihydro-N,N,N',N'-tetramethylrhodamine using green light. AB - We developed a simple protocol for high-yielding synthesis of conjugates of a deuterated dihydro-N,N,N',N'-tetramethylrhodamine (F*) with oligodeoxyribonucleotides and a 2'-OMe RNA (a representative nuclease-resistant, chemically modified oligonucleotide) using easily accessible starting materials including NaBD4 and conjugates of oligonucleotides with N,N,N',N' tetramethylrhodamine (F). These compounds were found to be stable in air and insensitive to light at 525, 635 and 650 nm, whereas slow activation occurs upon their exposure to 470 nm light. However, at the conditions of the templated reaction, in the presence of a target nucleic acid and a photocatalyst based on the eosin structure, the F* is oxidized forming fluorescent F. This reaction is >30-fold faster than the background reaction in the absence of the template. Moreover, the presence of a single mismatch in the target nucleic acid slows down the templated reaction by eightfold. These activatable dyes can potentially find applications as nucleic acid-specific probes for super-resolution imaging in live cells. PMID- 24496595 TI - Eight years of single-molecule localization microscopy. AB - Super-resolution imaging by single-molecule localization (localization microscopy) provides the ability to unravel the structural organization of cells and the composition of biomolecular assemblies at a spatial resolution that is well below the diffraction limit approaching virtually molecular resolution. Constant improvements in fluorescent probes, efficient and specific labeling techniques as well as refined data analysis and interpretation strategies further improved localization microscopy. Today, it allows us to interrogate how the distribution and stoichiometry of interacting proteins in subcellular compartments and molecular machines accomplishes complex interconnected cellular processes. Thus, it exhibits potential to address fundamental questions of cell and developmental biology. Here, we briefly introduce the history, basic principles, and different localization microscopy methods with special focus on direct stochastic optical reconstruction microscopy (dSTORM) and summarize key developments and examples of two- and three-dimensional localization microscopy of the last 8 years. PMID- 24496598 TI - Probing of metabolites in finely powdered plant material by direct laser desorption ionization mass spectrometry. AB - Natural products continue to serve as an important source of novel drugs since the beginning of human history. High-throughput techniques, such as MALDI-MS, can be techniques of choice for the rapid screening of natural products in plant materials. We present here a fast and reproducible matrix-free approach for the direct detection of UV active metabolites in plant materials without any prior sample preparation. The plant material is mechanically ground to a fine powder and then sieved through different mesh sizes. The collected plant material is dispersed using 1 MUL solvent on a target plate is directly exposed to Nd:YAG 335 nm laser. The strategy was optimized for the analysis of plant metabolites after study of the different factors affecting the reproducibility and effectiveness of the analysis, including particle sizes effects, types of solvents used to disperse the sample, and the part of the plant analyzed. Moreover, several plant species, known for different classes of metabolites, were screened to establish the generality of the approach. The developed approach was validated by the characterization of withaferin A and nicotine in the leaves of Withania somnifera and Nicotiana tabacum, respectively, through comparison of its MS/MS data with the standard compound. Scanning electron microscopy (SEM) and atomic force microscopy (AFM) techniques were used for the tissue imaging purposes. This approach can be used to directly probe small molecules in plant materials as well as in herbal and pharmaceutical formulations for fingerprinting development. PMID- 24496597 TI - Protected amine labels: a versatile molecular scaffold for multiplexed nominal mass and sub-Da isotopologue quantitative proteomic reagents. AB - We assemble a versatile molecular scaffold from simple building blocks to create binary and multiplexed stable isotope reagents for quantitative mass spectrometry. Termed Protected Amine Labels (PAL), these reagents offer multiple analytical figures of merit including, (1) robust targeting of peptide N-termini and lysyl side chains, (2) optimal mass spectrometry ionization efficiency through regeneration of primary amines on labeled peptides, (3) an amino acid based mass tag that incorporates heavy isotopes of carbon, nitrogen, and oxygen to ensure matched physicochemical and MS/MS fragmentation behavior among labeled peptides, and (4) a molecularly efficient architecture, in which the majority of hetero-atom centers can be used to synthesize a variety of nominal mass and sub Da isotopologue stable isotope reagents. We demonstrate the performance of these reagents in well-established strategies whereby up to four channels of peptide isotopomers, each separated by 4 Da, are quantified in MS-level scans with accuracies comparable to current commercial reagents. In addition, we utilize the PAL scaffold to create isotopologue reagents in which labeled peptide analogs differ in mass based on the binding energy in carbon and nitrogen nuclei, thereby allowing quantification based on MS or MS/MS spectra. We demonstrate accurate quantification for reagents that support 6-plex labeling and propose extension of this scheme to 9-channels based on a similar PAL scaffold. Finally, we provide exemplar data that extend the application of isotopologe-based quantification reagents to medium resolution, quadrupole time-of-flight mass spectrometers. PMID- 24496599 TI - Thermodynamics and mechanism of protonated cysteine decomposition: a guided ion beam and computational study. AB - A quantitative molecular description of the decomposition of protonated cysteine, H(+)Cys, is provided by studying the kinetic energy dependence of threshold collision-induced dissociation (CID) with Xe using a guided ion beam tandem mass spectrometer (GIBMS). Primary dissociation channels are deamidation (yielding both NH3 loss and NH4(+) formation) and (H2O + CO) loss reactions, followed by an additional six subsequent decompositions. Analysis of the kinetic energy dependent CID cross sections provides the 0 K barriers for six different reactions after accounting for unimolecular decay rates, internal energy of reactant ions, multiple ion-molecule collisions, and competition among the decay channels. To identify the mechanisms associated with these reactions, quantum chemical calculations performed at the B3LYP/6-311 + G(d,p) level were used to locate the transition states (TSs) and intermediates for these processes. Single point energies of the reactants, products, and key optimized TSs and intermediates are calculated at B3LYP, B3P86, and MP2(full) levels using a 6-311 + G(2d,2p) basis set. The computational characterization of the elementary steps of these reactions, including the structures of the final products, is validated by quantitative agreement with the experimental energetics. In agreement with previous work, deamidation is facilitated by anchimeric assistance of the thio group, which also leads to an interesting rearrangement of the intact amino acid identified computationally. PMID- 24496600 TI - Exploring salt bridge structures of gas-phase protein ions using multiple stages of electron transfer and collision induced dissociation. AB - The gas-phase structures of protein ions have been studied by electron transfer dissociation (ETD) and collision-induced dissociation (CID) after electrospraying these proteins from native-like solutions into a quadrupole ion trap mass spectrometer. Because ETD can break covalent bonds while minimally disrupting noncovalent interactions, we have investigated the ability of this dissociation technique together with CID to probe the sites of electrostatic interactions in gas-phase protein ions. By comparing spectra from ETD with spectra from ETD followed by CID, we find that several proteins, including ubiquitin, CRABP I, azurin, and beta-2-microglobulin, appear to maintain many of the salt bridge contacts known to exist in solution. To support this conclusion, we also performed calculations to consider all possible salt bridge patterns for each protein, and we find that the native salt bridge pattern explains the experimental ETD data better than nearly all other possible salt bridge patterns. Overall, our data suggest that ETD and ETD/CID of native protein ions can provide some insight into approximate location of salt bridges in the gas phase. PMID- 24496601 TI - Implementation of statistical process control for proteomic experiments via LC MS/MS. AB - Statistical process control (SPC) is a robust set of tools that aids in the visualization, detection, and identification of assignable causes of variation in any process that creates products, services, or information. A tool has been developed termed Statistical Process Control in Proteomics (SProCoP) which implements aspects of SPC (e.g., control charts and Pareto analysis) into the Skyline proteomics software. It monitors five quality control metrics in a shotgun or targeted proteomic workflow. None of these metrics require peptide identification. The source code, written in the R statistical language, runs directly from the Skyline interface, which supports the use of raw data files from several of the mass spectrometry vendors. It provides real time evaluation of the chromatographic performance (e.g., retention time reproducibility, peak asymmetry, and resolution), and mass spectrometric performance (targeted peptide ion intensity and mass measurement accuracy for high resolving power instruments) via control charts. Thresholds are experiment- and instrument-specific and are determined empirically from user-defined quality control standards that enable the separation of random noise and systematic error. Finally, Pareto analysis provides a summary of performance metrics and guides the user to metrics with high variance. The utility of these charts to evaluate proteomic experiments is illustrated in two case studies. PMID- 24496602 TI - Recurrence pattern depends on the location of colon cancer in the patients with synchronous colorectal liver metastasis. AB - BACKGROUND: The veins from the lower rectum drain into the systemic venous system, while those from other parts of the colon drain into the portal venous system. The aim of this study was to investigate recurrence pattern and survival according to the anatomical differences in patients with colorectal liver metastases (CRLM). METHODS: From October 1994 to December 2009, synchronous CRLM patients who underwent surgery were identified from our prospectively collected database. The patients were excluded if there had been extrahepatic metastases. The patients were divided into two groups according to the location of the primary colorectal cancer: lower rectal cancer (group 1) and upper rectal or colon cancer (group 2). The recurrence patterns and survival were investigated. RESULTS: A total of 316 patients were included: 53 patients in group 1 and 263 patients in group 2. After a median follow-up of 37 months, the extrahepatic recurrence curve of group 1 was superior to that of group 2 (P < 0.001), although there was no difference between the hepatic recurrence curves (P = 0.93). The disease-free and overall survival curves of group 1 were inferior to those of group 2 (P = 0.004) (P < 0.001). Lower rectal cancer was a significant risk factor for extrahepatic recurrence in Cox proportional hazard model analysis (hazard ratio = 1.7, P = 0.04). CONCLUSIONS: The extrahepatic recurrence rate is high in lower rectal cancer patients after surgical treatment for synchronous CRLM. PMID- 24496603 TI - Comparison of the sendai and fukuoka consensus guidelines for the management of mucinous cystic lesions of the pancreas: are we making progress? PMID- 24496604 TI - New synthesis: the chemistry of partner choice in insect-microbe mutualisms. PMID- 24496605 TI - Transgenic upregulation of the condensed tannin pathway in poplar leads to a dramatic shift in leaf palatability for two tree-feeding Lepidoptera. AB - Transgenic hybrid aspen (Populus tremula x tremuloides) overexpressing the MYB134 tannin regulatory gene show dramatically enhanced condensed tannin (proanthocyanidin) levels, as well as shifts in other phenolic metabolites. A series of insect bioassays with forest tent caterpillars (Malacosoma disstria) and gypsy moth (Lymantria dispar) caterpillars was carried out to determine how this metabolic shift affects food preference and performance of generalist tree feeding lepidopterans. Both species showed a distinct preference for the high tannin MYB134 overexpressor plants, and L. dispar performance was enhanced relative to controls. L. dispar reached greater pupal weight and showed reduced time to pupation when reared on the MYB134 overexpressing poplar. These results were unexpected since enhanced condensed tannin levels were predicted to act as feeding deterrents. However, the data may be explained by the observed decrease in the salicinoids (phenolic glycosides) salicortin and tremulacin that accompanied the upregulation of the condensed tannins in the transgenics. We conclude that for these two lepidopteran species, condensed tannin levels are unlikely to be a major determinant of caterpillar food preference or performance. However, our experiments show that overexpression of a single regulatory gene in transgenic aspen can have a significant impact on herbivorous insects. PMID- 24496606 TI - Retraction Note: EANM Abstracts 2013. PMID- 24496607 TI - Early-life socioeconomic status and mortality in later life: an integration of four life-course mechanisms. AB - OBJECTIVES: Using data from the Wisconsin Longitudinal Study, we examine (a) how socioeconomic status (SES) at age 18 affects all-cause mortality at ages 54-72, and (b) whether the effect of early-life SES is consistent with the critical period, accumulation of risks, social mobility, and pathway models. We also explore gender differences in the effect of early-life SES and life-course mechanisms. METHOD: Participants (N = 6,547) were surveyed in 1957, 1975, and 1993, with vital status established until 2011. We combine discrete-time survival analysis with structural equation modeling. SES and health behaviors are modeled as latent factors. RESULTS: Early-life SES affects mortality indirectly via status attainment and health behaviors in adulthood and midlife. This finding is contrary to the critical period and consistent with the pathway model. Persistent disadvantage at three life stages is a strong risk factor for mortality, thus, supporting the accumulation of risks. Moreover, the mortality risk of individuals who experienced downward socioeconomic mobility is comparable to their peers with persistent disadvantage. DISCUSSION: This study highlights the complexity of interrelated life-course processes underlying the effect of early-life SES on mortality in later life. PMID- 24496608 TI - Backbone and stereospecific (13)C methyl Ile (delta1), Leu and Val side-chain chemical shift assignments of Crc. AB - Carbon catabolite repression (CCR) allows bacteria to selectively assimilate a preferred compound among a mixture of several potential carbon sources, thus boosting growth and economizing the cost of adaptability to variable nutrients in the environment. The RNA-binding catabolite repression control (Crc) protein acts as a global post-transcriptional regulator of CCR in Pseudomonas species. Crc triggers repression by inhibiting the expression of genes involved in transport and catabolism of non-preferred substrates, thus indirectly favoring assimilation of preferred one. We report here a nearly complete backbone and stereospecific (13)C methyl side-chain chemical shift assignments of Ile (delta1), Leu and Val of Crc (~ 31 kDa) from Pseudomonas syringae Lz4W. PMID- 24496609 TI - Peptide-mediated synthesis of gold nanoparticles: effects of peptide sequence and nature of binding on physicochemical properties. AB - Biomimetic nanotechnologies that use peptides to guide the growth and assembly of nanostructures offer new avenues for the creation of functional nanomaterials and manipulation of their physicochemical properties. However, the impacts of peptide sequence and binding motif upon the surface characteristics and physicochemical properties of nanoparticles remain poorly understood. The configurations of the biomolecules are expected to be extremely important for directing the synthesis and achieving desired material functionality, and these binding motifs will vary with the peptide sequence. Here, we have prepared a series of Au nanoparticles capped with a variety of materials-directing peptides with known affinity for metal surfaces. These nanomaterials were characterized by UV-vis and circular dichroism spectroscopies, transmission electron microscopy, and zeta-potential measurement. Then their catalytic activity for 4-nitrophenol reduction was analyzed. The results indicate that substantially different Au-peptide interfaces are generated using different peptide sequences, even when these sequences have similar binding affinity. This is consistent with recent work showing that Au peptide binding affinity can have varying entropic and enthalpic contributions, with enthalpically- and entropically-driven binders exhibiting quite different ensembles of configurations on the Au surface. The catalytic activity, as reflected by the measured activation energy, did not correlate with the particle size or with the binding affinity of the peptides, suggesting that the reactivity of these materials is governed by the more subtle details of the conformation of the bound peptide and on the nanoparticle surface reconstruction as dictated by the peptide structure. Such variations in both nanoparticle surface reconstruction and peptide configuration could potentially be used to program specific functionality into the peptide-capped nanomaterials. PMID- 24496610 TI - Astrocytic dysfunction and addiction: consequences of impaired glutamate homeostasis. AB - Addiction is characterized as a chronic relapsing disorder whereby addicted individuals persistently engage in drug seeking and use despite profound negative consequences. The results of studies using animal models of addiction and relapse indicate that drug seeking is mediated by alterations in cortico-accumbal plasticity induced by chronic drug exposure. Among the maladaptive responses to drug exposure are long-lasting alterations in the expression of proteins localized to accumbal astrocytes, which are responsible for maintaining glutamate homeostasis. These alterations engender an aberrant potentiation of glutamate transmission in the cortico-accumbens circuit that is linked to the reinstatement of drug seeking. Accordingly, pharmacological restoration of glutamate homeostasis functions as an efficient method of reversing drug-induced plasticity and inhibiting drug seeking in both rodents and humans. PMID- 24496612 TI - Pax genes: regulators of lineage specification and progenitor cell maintenance. AB - Pax genes encode a family of transcription factors that orchestrate complex processes of lineage determination in the developing embryo. Their key role is to specify and maintain progenitor cells through use of complex molecular mechanisms such as alternate RNA splice forms and gene activation or inhibition in conjunction with protein co-factors. The significance of Pax genes in development is highlighted by abnormalities that arise from the expression of mutant Pax genes. Here, we review the molecular functions of Pax genes during development and detail the regulatory mechanisms by which they specify and maintain progenitor cells across various tissue lineages. We also discuss mechanistic insights into the roles of Pax genes in regeneration and in adult diseases, including cancer. PMID- 24496611 TI - Cytonemes as specialized signaling filopodia. AB - Development creates a vast array of forms and patterns with elegant economy, using a small vocabulary of pattern-generating proteins such as BMPs, FGFs and Hh in similar ways in many different contexts. Despite much theoretical and experimental work, the signaling mechanisms that disperse these morphogen signaling proteins remain controversial. Here, we review the conceptual background and evidence that establishes a fundamental and essential role for cytonemes as specialized filopodia that transport signaling proteins between signaling cells. This evidence suggests that cytoneme-mediated signaling is a dispersal mechanism that delivers signaling proteins directly at sites of cell cell contact. PMID- 24496614 TI - Foxa2 acts as a co-activator potentiating expression of the Nurr1-induced DA phenotype via epigenetic regulation. AB - Understanding how dopamine (DA) phenotypes are acquired in midbrain DA (mDA) neuron development is important for bioassays and cell replacement therapy for mDA neuron-associated disorders. Here, we demonstrate a feed-forward mechanism of mDA neuron development involving Nurr1 and Foxa2. Nurr1 acts as a transcription factor for DA phenotype gene expression. However, Nurr1-mediated DA gene expression was inactivated by forming a protein complex with CoREST, and then recruiting histone deacetylase 1 (Hdac1), an enzyme catalyzing histone deacetylation, to DA gene promoters. Co-expression of Nurr1 and Foxa2 was established in mDA neuron precursor cells by a positive cross-regulatory loop. In the presence of Foxa2, the Nurr1-CoREST interaction was diminished (by competitive formation of the Nurr1-Foxa2 activator complex), and CoREST-Hdac1 proteins were less enriched in DA gene promoters. Consequently, histone 3 acetylation (H3Ac), which is responsible for open chromatin structures, was strikingly increased at DA phenotype gene promoters. These data establish the interplay of Nurr1 and Foxa2 as the crucial determinant for DA phenotype acquisition during mDA neuron development. PMID- 24496613 TI - How to make an intestine. AB - With the high prevalence of gastrointestinal disorders, there is great interest in establishing in vitro models of human intestinal disease and in developing drug-screening platforms that more accurately represent the complex physiology of the intestine. We will review how recent advances in developmental and stem cell biology have made it possible to generate complex, three-dimensional, human intestinal tissues in vitro through directed differentiation of human pluripotent stem cells. These are currently being used to study human development, genetic forms of disease, intestinal pathogens, metabolic disease and cancer. PMID- 24496615 TI - Growth/differentiation factor 15 promotes EGFR signalling, and regulates proliferation and migration in the hippocampus of neonatal and young adult mice. AB - The activation of epidermal growth factor receptor (EGFR) affects multiple aspects of neural precursor behaviour, including proliferation and migration. Telencephalic precursors acquire EGF responsiveness and upregulate EGFR expression at late stages of development. The events regulating this process and its significance are still unclear. We here show that in the developing and postnatal hippocampus (HP), growth/differentiation factor (GDF) 15 and EGFR are co-expressed in primitive precursors as well as in more differentiated cells. We also provide evidence that GDF15 promotes responsiveness to EGF and EGFR expression in hippocampal precursors through a mechanism that requires active CXC chemokine receptor (CXCR) 4. Besides EGFR expression, GDF15 ablation also leads to decreased proliferation and migration. In particular, lack of GDF15 impairs both processes in the cornu ammonis (CA) 1 and only proliferation in the dentate gyrus (DG). Importantly, migration and proliferation in the mutant HP were altered only perinatally, when EGFR expression was also affected. These data suggest that GDF15 regulates migration and proliferation by promoting EGFR signalling in the perinatal HP and represent a first description of a functional role for GDF15 in the developing telencephalon. PMID- 24496617 TI - Integrin alphavbeta3 and thyroid hormones promote expansion of progenitors in embryonic neocortex. AB - Neocortex expansion during evolution is associated with the enlargement of the embryonic subventricular zone, which reflects an increased self-renewal and proliferation of basal progenitors. In contrast to human, the vast majority of mouse basal progenitors lack self-renewal capacity, possibly due to lack of a basal process contacting the basal lamina and downregulation of cell-autonomous production of extracellular matrix (ECM) constituents. Here we show that targeted activation of the ECM receptor integrin alphavbeta3 on basal progenitors in embryonic mouse neocortex promotes their expansion. Specifically, integrin alphavbeta3 activation causes an increased cell cycle re-entry of Pax6-negative, Tbr2-positive intermediate progenitors, rather than basal radial glia, and a decrease in the proportion of intermediate progenitors committed to neurogenic division. Interestingly, integrin alphavbeta3 is the only known cell surface receptor for thyroid hormones. Remarkably, tetrac, a thyroid hormone analog that inhibits the binding of thyroid hormones to integrin alphavbeta3, completely abolishes the intermediate progenitor expansion observed upon targeted integrin alphavbeta3 activation, indicating that this expansion requires the binding of thyroid hormones to integrin alphavbeta3. Convergence of ECM and thyroid hormones on integrin alphavbeta3 thus appears to be crucial for cortical progenitor proliferation and self-renewal, and hence for normal brain development and the evolutionary expansion of the neocortex. PMID- 24496616 TI - Reconstruction of phrenic neuron identity in embryonic stem cell-derived motor neurons. AB - Air breathing is an essential motor function for vertebrates living on land. The rhythm that drives breathing is generated within the central nervous system and relayed via specialised subsets of spinal motor neurons to muscles that regulate lung volume. In mammals, a key respiratory muscle is the diaphragm, which is innervated by motor neurons in the phrenic nucleus. Remarkably, relatively little is known about how this crucial subtype of motor neuron is generated during embryogenesis. Here, we used direct differentiation of motor neurons from mouse embryonic stem cells as a tool to identify genes that direct phrenic neuron identity. We find that three determinants, Pou3f1, Hoxa5 and Notch, act in combination to promote a phrenic neuron molecular identity. We show that Notch signalling induces Pou3f1 in developing motor neurons in vitro and in vivo. This suggests that the phrenic neuron lineage is established through a local source of Notch ligand at mid-cervical levels. Furthermore, we find that the cadherins Pcdh10, which is regulated by Pou3f1 and Hoxa5, and Cdh10, which is controlled by Pou3f1, are both mediators of like-like clustering of motor neuron cell bodies. This specific Pcdh10/Cdh10 activity might provide the means by which phrenic neurons are assembled into a distinct nucleus. Our study provides a framework for understanding how phrenic neuron identity is conferred and will help to generate this rare and inaccessible yet vital neuronal subtype directly from pluripotent stem cells, thus facilitating subsequent functional investigations. PMID- 24496618 TI - Human embryonic epidermis contains a diverse Langerhans cell precursor pool. AB - Despite intense efforts, the exact phenotype of the epidermal Langerhans cell (LC) precursors during human ontogeny has not been determined yet. These elusive precursors are believed to migrate into the embryonic skin and to express primitive surface markers, including CD36, but not typical LC markers such as CD1a, CD1c and CD207. The aim of this study was to further characterize the phenotype of LC precursors in human embryonic epidermis and to compare it with that of LCs in healthy adult skin. We found that epidermal leukocytes in first trimester human skin are negative for CD34 and heterogeneous with regard to the expression of CD1c, CD14 and CD36, thus contrasting the phenotypic uniformity of epidermal LCs in adult skin. These data indicate that LC precursors colonize the developing epidermis in an undifferentiated state, where they acquire the definitive LC marker profile with time. Using a human three-dimensional full thickness skin model to mimic in vivo LC development, we found that FACS-sorted, CD207(-) cord blood-derived haematopoietic precursor cells resembling foetal LC precursors but not CD14(+)CD16(-) blood monocytes integrate into skin equivalents, and without additional exogenous cytokines give rise to cells that morphologically and phenotypically resemble LCs. Overall, it appears that CD14(-) haematopoietic precursors possess a much higher differentiation potential than CD14(+) precursor cells. PMID- 24496619 TI - Spontaneous hair cell regeneration in the neonatal mouse cochlea in vivo. AB - Loss of cochlear hair cells in mammals is currently believed to be permanent, resulting in hearing impairment that affects more than 10% of the population. Here, we developed two genetic strategies to ablate neonatal mouse cochlear hair cells in vivo. Both Pou4f3(DTR/+) and Atoh1-CreERTM; ROSA26(DTA/+) alleles allowed selective and inducible hair cell ablation. After hair cell loss was induced at birth, we observed spontaneous regeneration of hair cells. Fate mapping experiments demonstrated that neighboring supporting cells acquired a hair cell fate, which increased in a basal to apical gradient, averaging over 120 regenerated hair cells per cochlea. The normally mitotically quiescent supporting cells proliferated after hair cell ablation. Concurrent fate mapping and labeling with mitotic tracers showed that regenerated hair cells were derived by both mitotic regeneration and direct transdifferentiation. Over time, regenerated hair cells followed a similar pattern of maturation to normal hair cell development, including the expression of prestin, a terminal differentiation marker of outer hair cells, although many new hair cells eventually died. Hair cell regeneration did not occur when ablation was induced at one week of age. Our findings demonstrate that the neonatal mouse cochlea is capable of spontaneous hair cell regeneration after damage in vivo. Thus, future studies on the neonatal cochlea might shed light on the competence of supporting cells to regenerate hair cells and on the factors that promote the survival of newly regenerated hair cells. PMID- 24496620 TI - The ERECTA receptor kinase regulates Arabidopsis shoot apical meristem size, phyllotaxy and floral meristem identity. AB - In plants, the shoot apical meristem (SAM) serves as a reservoir of pluripotent stem cells from which all above ground organs originate. To sustain proper growth, the SAM must maintain homeostasis between the self-renewal of pluripotent stem cells and cell recruitment for lateral organ formation. At the core of the network that regulates this homeostasis in Arabidopsis are the WUSCHEL (WUS) transcription factor specifying stem cell fate and the CLAVATA (CLV) ligand receptor system limiting WUS expression. In this study, we identified the ERECTA (ER) pathway as a second receptor kinase signaling pathway that regulates WUS expression, and therefore shoot apical and floral meristem size, independently of the CLV pathway. We demonstrate that reduction in class III HD-ZIP and ER function together leads to a significant increase in WUS expression, resulting in extremely enlarged shoot meristems and a switch from spiral to whorled vegetative phyllotaxy. We further show that strong upregulation of WUS in the inflorescence meristem leads to ectopic expression of the AGAMOUS homeotic gene to a level that switches cell fate from floral meristem founder cell to carpel founder cell, suggesting an indirect role for ER in regulating floral meristem identity. This work illustrates the delicate balance between stem cell specification and differentiation in the meristem and shows that a shift in this balance leads to abnormal phyllotaxy and to altered reproductive cell fate. PMID- 24496621 TI - Oocyte polarity requires a Bucky ball-dependent feedback amplification loop. AB - In vertebrates, the first asymmetries are established along the animal-vegetal axis during oogenesis, but the underlying molecular mechanisms are poorly understood. Bucky ball (Buc) was identified in zebrafish as a novel vertebrate specific regulator of oocyte polarity, acting through unknown molecular interactions. Here we show that endogenous Buc protein localizes to the Balbiani body, a conserved, asymmetric structure in oocytes that requires Buc for its formation. Asymmetric distribution of Buc in oocytes precedes Balbiani body formation, defining Buc as the earliest marker of oocyte polarity in zebrafish. Through a transgenic strategy, we determined that excess Buc disrupts polarity and results in supernumerary Balbiani bodies in a 3'UTR-dependent manner, and we identified roles for the buc introns in regulating Buc activity. Analyses of mosaic ovaries indicate that oocyte pattern determines the number of animal pole specific micropylar cells that are associated with an egg via a close-range signal or direct cell contact. We demonstrate interactions between Buc protein and buc mRNA with two conserved RNA-binding proteins (RNAbps) that are localized to the Balbiani body: RNA binding protein with multiple splice isoforms 2 (Rbpms2) and Deleted in azoospermia-like (Dazl). Buc protein and buc mRNA interact with Rbpms2; buc and dazl mRNAs interact with Dazl protein. Cumulatively, these studies indicate that oocyte polarization depends on tight regulation of buc: Buc establishes oocyte polarity through interactions with RNAbps, initiating a feedback amplification mechanism in which Buc protein recruits RNAbps that in turn recruit buc and other RNAs to the Balbiani body. PMID- 24496623 TI - Ezh2 is required for neural crest-derived cartilage and bone formation. AB - The emergence of craniofacial skeletal elements, and of the jaw in particular, was a crucial step in the evolution of higher vertebrates. Most facial bones and cartilage are generated during embryonic development by cranial neural crest cells, while an osteochondrogenic fate is suppressed in more posterior neural crest cells. Key players in this process are Hox genes, which suppress osteochondrogenesis in posterior neural crest derivatives. How this specific pattern of osteochondrogenic competence is achieved remains to be elucidated. Here we demonstrate that Hox gene expression and osteochondrogenesis are controlled by epigenetic mechanisms. Ezh2, which is a component of polycomb repressive complex 2 (PRC2), catalyzes trimethylation of lysine 27 in histone 3 (H3K27me3), thereby functioning as transcriptional repressor of target genes. Conditional inactivation of Ezh2 does not interfere with localization of neural crest cells to their target structures, neural development, cell cycle progression or cell survival. However, loss of Ezh2 results in massive derepression of Hox genes in neural crest cells that are usually devoid of Hox gene expression. Accordingly, craniofacial bone and cartilage formation is fully prevented in Ezh2 conditional knockout mice. Our data indicate that craniofacial skeleton formation in higher vertebrates is crucially dependent on epigenetic regulation that keeps in check inhibitors of an osteochondrogenic differentiation program. PMID- 24496622 TI - The expression of Y-linked Zfy2 in XY mouse oocytes leads to frequent meiosis 2 defects, a high incidence of subsequent early cleavage stage arrest and infertility. AB - Outbred XY(Sry-) female mice that lack Sry due to the 11 kb deletion Sry(dl1Rlb) have very limited fertility. However, five lines of outbred XY(d) females with Y chromosome deletions Y(Del(Y)1Ct)-Y(Del(Y)5Ct) that deplete the Rbmy gene cluster and repress Sry transcription were found to be of good fertility. Here we tested our expectation that the difference in fertility between XO, XY(d-1) and XY(Sry-) females would be reflected in different degrees of oocyte depletion, but this was not the case. Transgenic addition of Yp genes to XO females implicated Zfy2 as being responsible for the deleterious Y chromosomal effect on fertility. Zfy2 transcript levels were reduced in ovaries of XY(d-1) compared with XY(Sry-) females in keeping with their differing fertility. In seeking the biological basis of the impaired fertility we found that XY(Sry-), XY(d-1) and XO,Zfy2 females produce equivalent numbers of 2-cell embryos. However, in XY(Sry-) and XO,Zfy2 females the majority of embryos arrested with 2-4 cells and almost no blastocysts were produced; by contrast, XY(d-1) females produced substantially more blastocysts but fewer than XO controls. As previously documented for C57BL/6 inbred XY females, outbred XY(Sry-) and XO,Zfy2 females showed frequent failure of the second meiotic division, although this did not prevent the first cleavage. Oocyte transcriptome analysis revealed major transcriptional changes resulting from the Zfy2 transgene addition. We conclude that Zfy2-induced transcriptional changes in oocytes are sufficient to explain the more severe fertility impairment of XY as compared with XO females. PMID- 24496624 TI - Machine learning classification of cell-specific cardiac enhancers uncovers developmental subnetworks regulating progenitor cell division and cell fate specification. AB - The Drosophila heart is composed of two distinct cell types, the contractile cardial cells (CCs) and the surrounding non-muscle pericardial cells (PCs), development of which is regulated by a network of conserved signaling molecules and transcription factors (TFs). Here, we used machine learning with array-based chromatin immunoprecipitation (ChIP) data and TF sequence motifs to computationally classify cell type-specific cardiac enhancers. Extensive testing of predicted enhancers at single-cell resolution revealed the added value of ChIP data for modeling cell type-specific activities. Furthermore, clustering the top scoring classifier sequence features identified novel cardiac and cell type specific regulatory motifs. For example, we found that the Myb motif learned by the classifier is crucial for CC activity, and the Myb TF acts in concert with two forkhead domain TFs and Polo kinase to regulate cardiac progenitor cell divisions. In addition, differential motif enrichment and cis-trans genetic studies revealed that the Notch signaling pathway TF Suppressor of Hairless [Su(H)] discriminates PC from CC enhancer activities. Collectively, these studies elucidate molecular pathways used in the regulatory decisions for proliferation and differentiation of cardiac progenitor cells, implicate Su(H) in regulating cell fate decisions of these progenitors, and document the utility of enhancer modeling in uncovering developmental regulatory subnetworks. PMID- 24496625 TI - Macroglobulin complement-related encodes a protein required for septate junction organization and paracellular barrier function in Drosophila. AB - Polarized epithelia play crucial roles as barriers to the outside environment and enable the formation of specialized compartments for organs to carry out essential functions. Barrier functions are mediated by cellular junctions that line the lateral plasma membrane between cells, principally tight junctions in vertebrates and septate junctions (SJs) in invertebrates. Over the last two decades, more than 20 genes have been identified that function in SJ biogenesis in Drosophila, including those that encode core structural components of the junction such as Neurexin IV, Coracle and several claudins, as well as proteins that facilitate the trafficking of SJ proteins during their assembly. Here we demonstrate that Macroglobulin complement-related (Mcr), a gene previously implicated in innate immunity, plays an essential role during embryonic development in SJ organization and function. We show that Mcr colocalizes with other SJ proteins in mature ectodermally derived epithelial cells, that it shows interdependence with other SJ proteins for SJ localization, and that Mcr mutant epithelia fail to form an effective paracellular barrier. Tissue-specific RNA interference further demonstrates that Mcr is required cell-autonomously for SJ organization. Finally, we show a unique interdependence between Mcr and Nrg for SJ localization that provides new insights into the organization of the SJ. Together, these studies demonstrate that Mcr is a core component of epithelial SJs and also highlight an interesting relationship between innate immunity and epithelial barrier functions. PMID- 24496626 TI - The transmembrane protein Macroglobulin complement-related is essential for septate junction formation and epithelial barrier function in Drosophila. AB - Occluding cell-cell junctions in epithelia form physical barriers that separate different membrane domains, restrict paracellular diffusion and prevent pathogens from spreading across tissues. In invertebrates, these functions are provided by septate junctions (SJs), the functional equivalent of vertebrate tight junctions. How the diverse functions of SJs are integrated and modulated in a multiprotein complex is not clear, and many SJ components are still unknown. Here we report the identification of Macroglobulin complement-related (Mcr), a member of the conserved alpha-2-macroglobulin (alpha2M) complement protein family, as a novel SJ-associated protein in Drosophila. Whereas alpha2M complement proteins are generally known as secreted factors that bind to surfaces of pathogens and target them for phagocytic uptake, Mcr represents an unusual alpha2M protein with a predicted transmembrane domain. We show that Mcr protein localizes to lateral membranes of epithelial cells, where its distribution overlaps with SJs. Several SJ components are required for the correct localization of Mcr. Conversely, Mcr is required in a cell-autonomous fashion for the correct membrane localization of SJ components, indicating that membrane-bound rather than secreted Mcr isoforms are involved in SJ formation. Finally, we show that loss of Mcr function leads to morphological, ultrastructural and epithelial barrier defects resembling mutants lacking SJ components. Our results, along with previous findings on the role of Mcr in phagocytosis, suggest that Mcr plays dual roles in epithelial barrier formation and innate immunity. Thus, Mcr represents a novel paradigm for investigating functional links between occluding junction formation and pathogen defense mechanisms.